1,3-Diketones. Synthesis and Properties

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2015, Vol. 51, No. 6, pp. 755–830. © Pleiades Publishing, Ltd., 2015. Original Russian Text © E.A. Shokova, J.K. Kim, V.V. Kovalev, 2015, published in Zhurnal Organicheskoi Khimii, 2015, Vol. 51, No. 6, pp. 773–847.

REVIEW

1,3-Diketones. Synthesis and Properties E. A. Shokova, J. K. Kim, and V. V. Kovalev Faculty of Chemistry, Moscow State University, Leninskie gory 1, Moscow, 119991 Russia e-mail: [email protected] Received December 24, 2014

Abstract—The review generalizes and analyzes published data on the synthesis and chemical transformations of 1,3-diketones over the past 10–15 years.

DOI: 10.1134/S1070428015060019 1. Introduction ............................................................................................................................................... 2. Synthesis of β-Diketones ........................................................................................................................... 2.1. Syntheses of β-Diketones Based on the Claisen Condensation .......................................................... 2.1.1. Acylation of Ketones .............................................................................................................. 2.1.2. Acylation of Silyl Enol Ethers ................................................................................................ 2.1.3. Dicarbonyl Compounds in the Synthesis of β-Diketones ....................................................... 2.2. Metal Complex Catalysis in the Synthesis of β-Diketones ................................................................ 2.2.1. Acylation of α,β-Unsaturated Ketones, Aldehydes, and Acylated Enones ............................. 2.2.2. Alkynols in the Synthesis of β-Diketones .............................................................................. 2.2.3. Acetylacetone in the Synthesis of β-Diketones ...................................................................... 2.3. Miscellaneous ..................................................................................................................................... 3. Properties of β-Diketones .......................................................................................................................... 3.1. Chemical Properties of β-Diketones .................................................................................................. 3.1.1. Modification of the α-CH2(CH) Fragment .............................................................................

El’vira Aleksandrovna Shokova was born in Moscow. She graduated from the Faculty of Chemistry, Moscow State University, and finished post-graduate courses at the faculty. Candidate of chemical sciences. Author of more than 170 publications, 16 USSR Inventor’s Certificates, and 2 RF patents. Leading researcher at the Faculty of Chemistry, Moscow State University. Fields of scientific interest: polyfunctional compounds, their synthesis and uses in organic synthesis; chemistry of adamantane and its derivatives; biologically active compounds.

Kim Jun Kyn was born in 1980 in Seoul (Korea). In 2007 he graduated from the Faculty of Chemistry, Moscow State University. Since 2008 till 2012 he worked as researcher at LG Chem and LG Hausys (Korea). In 2012 he entered post-graduate courses at the Faculty of Chemistry, Moscow State University, and in February 2015 has presented a candidate dissertation for defense. Fields of scientific interest: polycarbonyl compounds and their possible applications; chemistry of adamantane and its derivatives.

755

756 756 756 756 762 762 764 765 769 769 771 771 772 772

Vladimir Vasil’evich Kovalev was born in 1952 in Moscow oblast. In 1974 he graduated from the Faculty of Chemistry, Moscow State University, and then finished post-graduate courses at the faculty. Doctor of chemical sciences since 1991. Head of the Macrocyclic Receptor Laboratory at the Faculty of Chemistry, Moscow State University, since 2001. Fields of scientific interest: organic and supramolecular chemistry.

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SHOKOVA et al. 3.1.2. Transformations of β-Diketones 3 Involving the R1CH2 and R2CH2 Fragments .................... 3.1.3. Transformations of β-Diketones 3 via Cleavage of the R1(R2)C–C(O) Bond ........................ 3.1.4. Transformations of β-Diketones Involving the Carbonyl Groups .......................................... 3.1.5. Miscellaneous ......................................................................................................................... 3.2. Biological Activity of β-Diketones .................................................................................................... 3.3. Physicochemical Properties of β-Diketones ....................................................................................... 4. β-Diketones in the Synthesis of Heterocyclic Systems .............................................................................. 4.1. Pyrazoles and Polycyclic Systems with Pyrazole Fragments ............................................................. 4.2. Substituted Pyrimidines and Their Derivatives .................................................................................. 4.3. Substituted Pyrroles and Polycyclic Systems Containing Pyrrole Fragments .................................... 4.4. Complex Nitrogen-Containing Polyheterocyclic Systems ................................................................. 4.5. Oxygen-Containing Mono- and Polyheterocyclic Systems (Furans, Chromenes, Xanthenes, Coumarins, Isocoumarins, Pyranones) ............................................................................................... 4.6. Polyheterocyclic Systems with Two or More Different Heteroatoms ................................................ 4.7. Sulfur-Containing Heterocycles .........................................................................................................

785 786 788 791 793 794 796 796 800 803 806 808 820 825

2. SYNTHESIS of β-DIKETONES

1. INTRODUCTION The importance of 1,3-diketones in synthetic organic chemistry is difficult to overestimate. Their accessibility, stability, and often unique properties make them promising for use in various fields of human activity. High reactivity of 1,3-diketones opens wide prospects for the design of a variety of organic compounds, including those structurally related to natural ones. Continuously growing interest in β-dicarbonyl compounds is observed among researchers working in various fields of medicinal chemistry and chemistry of metal complexes. Sol–gel syntheses with β-diketones afforded organic–inorganic hybrid materials used in gas sensors and molecular thermometers, as well as in the manufacture of optical fiber and lightconverting materials [1–5]. Over the past 10–15 years, not only selectivity parameters and overall yield of reaction products but also such factors as enhanced requirements to starting materials, reaction time, energy consumption, toxicity, etc., have acquired increasing significance in the assessment of the efficiency of chemical syntheses. 1,3-Diketones turned out to be excellent versatile intermediates in multicomponent reactions, in particular regio- and stereoselective, which is especially important in the synthesis of potentially biologically active compounds [6–9]. The present review consists of two parts and comprises data on the synthesis, chemical properties, and biological activity of 1,3-diketones, which have been published over the past 12 years after reviews [1, 2]. Deliberately, complexing properties of diketones are not considered here; relevant publications are so numerous that they should be the subject of a separate review.

Analysis of published data showed that currently, as well as in the past century, the main method for the synthesis of β-diketones is based on the Claisen condensation which has been known since 1887. It implies acylation of monocarbonyl compounds (most frequently, ketones) in the presence of catalysts favoring their enolization [1, 2]. Claisen condensations with dicarbonyl compounds (acetylacetone, benzoylacetone) are very few in number. In recent years, modifications of the Claisen reaction involved mainly selection of reagents (acylating agent, catalyst) and conditions to ensure reaction selectivity, high yield of diketones, easy isolation procedure, and experimental simplicity. Just these goals were set in all publications cited in the present review. Among procedures that are newly developed for the synthesis of β-diketones, those based on metal complex catalysis should be noted. 2.1. Syntheses of β-Diketones Based on the Claisen Condensation 2.1.1. Acylation of ketones. Acetophenone derivatives, including those containing functional groups and heterocyclic substituents in the benzene ring, were converted into β-diketones via acylation with aromatic carboxylic and pyridinemono- and -dicarboxylic acid esters under the classical Claisen conditions (with NaOR or NaNH 2 as catalyst) [10–14]. Bis-1,3-diketones were obtained from phthalic [10, 11] and pyridinedicarboxylic acid derivatives [13, 15]. A soft Lewis acid, magnesium bromide–diethyl ether complex, in the presence of ethyl(diisopropyl)amine catalyzed enolization and regioselective

RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 6 2015

1,3-DIKETONES. SYNTHESIS AND PROPERTIES

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Scheme 1. R'3N, M+, E+

O R

Y

O R

Weak base

O R1

X

R3

R

E

Y

Y R

MgBr2 · Et2O, (i-Pr)2NEt CH2Cl2

O

O

R1

R2

1a, 1b

O

O – M+

Y

O +

M+

R2 R

2

3

3

1, X = 1H-benzotriazol-1-yl (a), C6F5O (b); R1 = Me3CCH2, t-Bu, Ph, PhCH(OSiMe2Bu-t), Bu, CH2=CHCH2CH2, (E)-PhCH=CH; 2, R2 = H, R3 = 2-MeO(HO)C6H4, 4-MeOC6H4, furan-2-yl; R2 = Me, R3 = Ph, (E)-PhCH=CH, Et; R2 = OSiMe2Bu-t, R3 = Ph; R2R3 = CH(Me)(CH2)2CH2, (CH2)4.

C-acylation of ketones [16]. The reaction can be carried out without protection from atmospheric moisture. N-Acylbenzotriazoles and pentafluorophenyl carboxylate were the most efficient acylating agents (Scheme 1). The yields of dicarbonyl compounds 3 ranged from 50 to 99% [17 examples, including 12 β-oxo aldehydes (R2 = H)]. Benzotriazole derivatives ensured the best yield (90–99%), while the yield of compound 3 (R1 = CH2=CHCH2CH2, R2 = H, R3 = Ph) obtained from acetophenone and pentafluorophenyl ester 1b was the lowest (50%). The yield increased to 70% in analogous reaction with the corresponding benzotriazole derivative 1a. Regioselective C-acylation of ketones with acid chlorides in the presence of hexamethyldisilazane lithium salt in toluene was reported in [17]. The reaction was not accompanied by side self-condensation of the initial reactants and O-acylation, so that 1,3-diketones 3 formed in situ could be converted into pyrazole derivatives 4–8 (Scheme 2). The key step in this reaction is selective base-catalyzed formation of

intermediate A from ketone and acid chloride. When sodium or potassium salt was used instead of lithium hexamethyldisilazide, up to 20% of triketone B was formed and converted into symmetrical pyrazoles C [17] (Scheme 3). L-Proline efficiently catalyzed acylation of acetone with substituted and unsubstituted benzoyl, heteroarylcarbonyl, and α,β-unsaturated acyl cyanides [18]. Enamine D derived from acetone and L -proline is capable of reacting at the CO group of acylating agent E (Scheme 4). Several proline derivatives F–I were tested. It was found that replacement of the phenoxy group in F by hydroxy leads to complete loss of catalytic activity. The catalytic efficiency of F and G was similar to that of L-proline, while compounds H and I with bulky substituents showed lower catalytic activity. Elliot and Wordingham [19] were the first to use substituted lactams as acylating agents in the synthesis of β-diketones. The reactions of acetone and acetophenone with N-tert-butoxycarbonylpyrrolidin-2-ones

Scheme 2. OLi

O R2

R1

O

3

(Me3Si)2NLi, PhMe

R4

O

4

R NHNH2, EtOH, THF

R C(O)Cl R1

R1

R3

R2

R1

R2 3

HN

HN

N OMe

4

N

N

R2 5

R

N R3 R2 4–8

R

R Br

R

R4

N

N

3

H N

H N

X

N

N

1

R2 6

Bu

R 7

8 (82%)

4, R = 4-Br(Me2N, CN, NO2)C6H4 (74–89%), pyridin-3-yl (59%), thiophen-2-yl (72%); 5, R = C5H11, Cl(CH2)4, 4-CNC6H4, 4-MeC6H4 (49–74%); 6, R1 = 4-ClC6H4, R3 = 4-MeOC6H4, R4 = H, R2 = Ph (50%), Pr (83%); R1 = 4-MeOC6H4, R2 = H, R3 = 4-O2NC6H4, R4 = Ph (43%); 7, R = 4-MeOC6H4, X = O (71%), t-BuOC(O)N (67%), CH2 (65%). RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 6 2015

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SHOKOVA et al. Scheme 3.

OM

OM

R1 CH2

N

R2

O

R1

R2C6H4C(O)Cl

HN

R1

N2H4, AcOH R2

R2 OM

A

R1

2

R C6H4C(O)Cl

O R2 O B

R2 R2

O B

R2

N2H4, AcOH

O HO

N

R2

R1

–R1C6H4C(O)NHNH2

R1

HN

R2

O O

NH

H 2N

C

Scheme 4. O

O

L-Proline (30 mol %)

+ R

CN

NC

Me

Me

OH O

R

O

OH– Me

O

R

Me 9

9, R = Ph, 4-Me(MeO, F, Cl, Br, NO2)C6H4, 2-Me(F, Cl, Br)C6H4, PhCH=CH, furan-2-yl (yield 87–94% for 11 compounds). O

O N H

H Me

O

N

O

Me Me

O

O –H2O

O– H

N

H

O

O N

Me

OH

O RCOCN

O

H N

CH2

Me

H

D

≠ Me H

CN O

R

E

Me –

–

O N O

HO

Me PhO COOH N H F

Ph

CN

H2O

O O

H

N

R

Me HO

O

Me

HO

O

–L-Proline

CN

HO

Me

R

CN R

O

O

H2O, –HCN Me

R 9

Me O

COOH N H

COOH

O

NH

COOH NH

Me

G

H

in tetrahydrofuran in the presence of lithium diisopropylamide (LDA) afforded functionalized β-diketones 10 (Scheme 5). 1-Acylbenzotriazoles were also efficient acylating agents in the synthesis of β-diketones [20]. According to the improved procedure, indan-1-

I

one, 4-tert-butylcyclohexanone, 3,5-dimethylcyclohex2-en-1-one, and ketenes were reacted with modified resins (polymers) 11a and 11b containing benzotriazole fragments, which were preliminarily converted into N-acyl derivatives 12. Reagent 11a ensured 47–



759

Scheme 5. O + R

Me

O

O

O N

LDA, –78 to 25°C

Boc

NHBoc

Me

2

R1

R1

10

R1 = H, R2 = Me (74%, enol–ketone 5 : 1), Ph (75%, 100% enol); R1 = COOEt, R2 = Me (72%, 100% enol), Ph (74%).

Scheme 6. N N

N

N H 11a

N

R1 = Ph, Me, t-Bu N

O

R2C(O)CH2R3 LiAlH4, THF

N

X

R1C(O)Cl

R2 R3

12

N H

R1

R1

O

N

O

O

8 examples

11b

88% yield of the corresponding diketones [21] (Scheme 6). In the reactions with 11b (0.68 and 0.49 mmol/g), the yield decreased to 18–41%. The reason is that the N-acylbenzotriazolyl fragment in 11a

is linked directly to the polymer support, whereas analogous fragment in 11b is linked through a spacer [21]. N-Acylbenzotriazoles 13a–13e derived from aliphatic and aromatic α,β-unsaturated carboxylic acids C(O)Bt

C(O)Bt

C(O)Bt O 13b O

13c O

Me

C(O)Bt

Me

S

13a O

Me

C(O)Bt

13d

13e

O

O

Me

O Me

Me

t-Bu Me

Me 14a

O

O

14b

R1

14c

14d

O

O

14e

O

O

R2

Me

R3 R1

Bu-t

14f

R

O

O

Me

Ph

R2

Me

Bu-t 15a

O

15b

O

Ph

O

16

O

O

17a (51%)

O

O

Ph

Ph Ph

17b (66%)

O

Bu-t 18a (30%)

Ph

Me 18b (25%)

Ph

18c (30%)

13, Bt = benzotriazol-1-yl; 15a, R1 = H, R2 = Ph (62%), furan-2-yl (51%), thiophen-2-yl (62%), R1 = R2 = Me (38%); 15b, R1 = Me, R2 = H, R3 = Ph, furan-2-yl, thiophen-2-yl; R1 = R2 = Me, R3 = Ph, thiophen-2-yl (42–52%); 16, R = Ph, furan-2-yl (40–53%). RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 6 2015

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SHOKOVA et al.

were used to acylate ketones 14a–14f [22] in THF at –78°C in the presence of LDA. As a result, 16 α,β-unsaturated diketones 15–18 were obtained. Despite numerous modifications of the Claisen condensation, in no case direct synthesis of β-diketones from acids and ketones was accomplished with simultaneous activation of the carbonyl and methylene components. We recently showed [23] that self-acylation of β-(4-R-phenyl)propionic acids (R = H, Br, 1-Ad) catalyzed by trifluoromethanesulfonic acid (TfOH) in trifluoroacetic anhydride (TFAA) provides a simple preparative method for the synthesis of β-diketones. Trifluoroacetic anhydride readily reacts with carboxylic acids to give mixed anhydrides, acyl trifluoroacetates, which are efficient acylating agents. Trifluoromethanesulfonic acid favors their enolization

and catalyzes self-acylation. Phenylacetic acid polymerizes under these conditions, while 3-phenylpropionic acid (19a) in TFAA/CH2Cl2 in the presence of 0.25 equiv of TfOH at room temperature was converted into 2-(3-phenylpropionyl)indan-1-one (21a, yield 51%). The yield of 21a increased to 75% in the presence of 0.5 equiv of TfOH. Obviously, compound 21a is formed via acylation of the initially formed intramolecular cyclization product, indan-1-one 20a, with 3-phenylpropionyl trifluoroacetate. Under analogous conditions (0.5 equiv of TfOH), 3-(4-bromophenyl)- and 3-[4-(adamantan-1-yl)phenylpropionic acids gave rise to 70% of 21b and 35% of 21c, respectively. 4-Phenylbutanoic acid (19d) was quantitatively converted into tetrahydronaphthalen-1-one 20d (Scheme 7). The described procedure for the pre-

Scheme 7. R O

O

R

( )n

n=1

TFAA–TfOH CH2Cl2, 20°C

COOH

R

O

+ 20a–20c

21a–21c

O

R 19a–19d n=2 20d

19–21, n = 2, R = H (a), Br (b), 1-Ad (c); n = 3, R = H (d).

Scheme 8. TfOH–TFA CH2Cl2, 20°C

O RCOOH

+

Ar

23 O

O Ar

Alk 22

R 24–30

O

O

O O

R

R'

O

O R

R' R

24

O

O

25

O

O

Ad

S

O Ad

O

28 (20%)

O Ad

Me Ph

Fe 27 (43%)

26

29 (64%)

O

Me Me Me

O 30 (91%)

24, R = Me, t-BuCH2, 1-AdCH2; R′ = H, F, Br, i-Pr, MeO (37–69%); 25, R = Me, Ph, i-Pr, t-BuCH2, 1-AdCH2; R′ = H, Br (50–86%); 26, R = Me, t-BuCH2, 1-AdCH2 (53–65%). RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 6 2015


761

Scheme 9. O

O

H2NCH2CH2COOH (33) TFA–TfOH, CH2Cl2, 20°C

N O

( )n

( )n

31a, 31b

HCl, EtOH–H2O, Δ

NHAcF

· HCl ( )n 34a, 34b

32a, 32b 33, TFA–TfOH CH2Cl2, 20°C

O Ph

O

O

Ph

Me

OH

NHAcF

31c

32c (15%)

n = 1 (a), 2 (b); 32a (57%), 32b (51%); 34a (95%), 34b (94%).

Scheme 10. O

31a, TFA–TfOH CH2Cl2, 20°C

O

O Ph

P

P(O)Ph2

O Ph

OH

Ph

36 (51%)

(1) TFA–TfOH, Δ (2) H2O–EtOH, Δ

O

O

P

O P

Ph

35

Ph Ph

37 (44%)

Scheme 11.

COOH

HO

O

31a–31c, TFA–TfOH CH2Cl2, 20°C

O OH ( )n

AcFO 38a

O

–

( )n

HO

39a–39c

COOH

HOC(O)

31a, TFA–TfOH CH2Cl2, 20°C

O

40a–40c

O

38b

O

O

O

41 (96%)

n = 1 (a), 2 (b), no bond (c); 39a (88%), 39b (51%), 39c (32%); 40a (72%), 40b (81%), 40c (77%).

paration of β-diketones has underlain one-pot synthesis of polycyclic systems containing pyrazole fragments (see Section 3.1) [23, 24]. The obtained results allowed us to presume that ketones can be directly subjected to acylation in the system TfOH–TFAA–CH2Cl2 [24]. The acylation of alkyl aryl ketones 22 (acetophenone, benzyl methyl ketone, indanone, tetralone, 2-acetylthiophene, 2-acetylbenzofuran) with acids 23 (R = Me, i-Pr, t-BuCH2, 1-AdCH2) gave β-diketones 24-30. In most cases, the reactant ratio 23–22–TfOH–TFA was 1 : 1 : 0.5 : 6. We thus synthesized 20 β-diketones (yield of 15 compounds 47–91%), including adamantane derivatives. Introduction of an adamantane fragment into organic molecules often endows them with new valuable properties (Scheme 8). The scope of this reaction was extended by acylation of ketones with functionally substituted carboxylic

acids. Glycine failed to react with ketones, whereas β-alanine (33) reacted with indan-1-one (31a), 1-tetralone (31b), and acetophenone (31c) in TFAA– TfOH–CH 2 Cl 2 to produce the corresponding N-trifluoroacetyl-β-aminodiketones 32. The best yields were obtained using 1.5 equiv of 33 and 1 equiv of TfOH. The hydrolysis of 32a and 32b was accompanied by intramolecular cyclization with formation of previously unknown heterocycles 34a and 34b (Scheme 9). The acylation of 31a with (diphenylphosphoryl)acetic acid (35) gave 51% of diketone 36. The reaction involved self-acylation of 35 even at room temperature, which significantly complicated the isolation of 36. When acid 35 was heated in CF3SO3H/TFA [24], followed by decarboxylation in aqueous medium, 1,3-bis(diphenylphosphoryl)propan-2-one (37) was obtained in 44% yield (Scheme 10). 3-(Trifluoroacetoxy)adamantan-1-yl-substituted diketones 39a–39c were


762

SHOKOVA et al. (20 min) with complete conversion of the initial trimethylsilyl ethers into the corresponding β-diketones. An efficient procedure for the synthesis of 1,3-dicarbonyl compounds [β-diketones and β-oxo(thioxo)esters] via mild and selective catalytic C-acylation of silyl enol ethers A, ketene silyl acetals and thioacetals B and C with acid chlorides 44–47 in the presence of pentafluoroanilinium trifluoromethanesulfonate was described in [29] [Scheme 13; in most cases, R3 = R4 = Me; in some cases, R 3 = H, R 4 = Alk (Me, Pr, Bu); R3 = Me or Ph, R4 = Et or OSiMe2Bu-t; R5 = Ph or Alk (Pr, i-Pr); R6X = MeO, PhS, C8H17S]. 2.1.3. Dicarbonyl compounds in the synthesis of β-diketones. Aryl and heteroaryl β-diketones were synthesized by reaction of the simplest dicarbonyl compounds (acetylacetone and benzoylacetone) with acylbenzotriazoles in the presence of sodium hydride,

synthesized by acylation of 31 with (3-hydroxyadamantan-1-yl)acetic acid (38a) (Scheme 11). In the synthesis of 39b, tetralone 31b was prepared in situ from 4-phenylbutanoic acid (19d). Trifluoroacetates 39a– 39c were hydrolyzed to hydroxy diketones 40a–40c. The acelation of 31a with adamantane-1,3-diyldi(acetic acid) (38b) gave bis-1,3-diketone 41. 2.1.2. Acylation of silyl enol ethers. Wiles et al. [25] reported regioselective acylation of silyl enol ethers with benzoyl fluoride and benzoyl cyanide in the presence of a catalytic amount of anhydrous tetrabutylammonium fluoroide. According to the authors, intermediate enolate does not react with a soft ammonium counterion but undergoes selective C-acylation. The procedure was subsequently modified for the synthesis of β-diketones by the microreactor technique [26–28] (Scheme 12). The reactions were very fast

Scheme 12. OSiMe3 CH2

O

O (t-Bu)4NF, THF, 20°C

CN

+

O

42

OSiMe3

O

Me

O (t-Bu)4NF, 20°C

F

+

O

Me 43 O

O

OSiMe3

R

+

O

(t-Bu)4NF, 20°C

R = F, CN.

Scheme 13. R

3

R3

OSiMe3

R4 O R

R5 A [C6F5NH3]+ –OSO2Me

O

1 3 R2 R

R4

R5

R4 HN R6 X = O (B), S (C) [C6F5NH3]+ –OSO2Me

O R

1

Cl

O R

44–47 O

Me

Cl

( )n

O Cl

R6

O Cl

Et

Cl

Cl Cl

45

R4

N H

38 examples (60–92%)

O R

O

1 3 R2 R

R2

12 examples (62–92%)

44

OSiMe3

46

Me 47

Me

45, n = 8, R = Me, CH2=CH; n = 4, R = Cl; n = 6, R = MeOC(O); n = 2, R = Ph; n = 1, R = PhCH2O; n = 0, R = Ph. RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 6 2015


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Scheme 14. –

O

O

O

Me

Me

Me –

O Ph

O–

O

Me

Bt

O

O

Bt

Bt

O

Me Bt

Me

–BtC(O)Me

Ph

O

Me O

Ph

Ph

O

BtC(O)Ph

O

OH

H+/H2O Ph

Ph

O Ph

Ph 18%

OH

H+/H2O

O

Ph

O Me

O

Ph

Me

55% (94% enol)

Bt is benzotriazol-1-yl.

Scheme 15. O

O

(1) NaH, THF (2) NH4Cl, aq. NH3

O +

Me

Me

R1

OH

O

O

R2

Bt

R3

O

R2

R3

48

R1 = 4-MeC6H4 (2 equiv), R2 = R3 = 4-MeC6H4 (yield 100%/enol 100%); R1 = thiophen-2-yl (2 equiv), R2 = R3 = thiophen-2-yl (100%/88%); R1 = furan-2-yl (1 equiv) + 4-MeC6H4 (1 equiv), R2 = 4-MeC6H4, R3 = furan-2-yl (52%/94%).

Scheme 16. Na

+

O

O

Ph

Ph

Me

Ph

Me O

Ph

O

O Me

O H2C

O

O

O

+ Me

H2C

Me

(1) Bt– or H2O (2) H+/H3O OH

O

Ph +

Na

O

–

O Ph

Me

O

OH

Me

O

Ph X

X

O

X

X Bt

Scheme 17. O R

MgBr2 · Et2O (i-Pr)2NEt, CH2Cl2

O Bt

+ R'

SPh

O

O

O

O

EtZnI, PdCl2(PPh3)2, PhMe SPh

R

R = t-Bu, R' = Pr

R' 49

49, 12 examples (yield of 9 compounds 80–92%). RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 6 2015

Et

t-Bu Pr 50 (90%)

764

SHOKOVA et al. Scheme 18. F O R1

BF3 · Et2O, PhMe or CH2Cl2, 25°C

O

O

F B

O

R1

OEt

F O

R2Li, THF

F B

O

R1

OEt 51

R2 52

F

F O

O (1) NaH, PhMe (2) O=C(OEt)2

O

O OEt

B

BF3 · Et2O, PhMe

53 (87%)

O OEt

54 (91%) F

F O

B

R2Li, THF, –78°C

O OEt

55 (91%)

52, R1 = Ph, 4-MeOC6H4, furan-3-yl, R2 = Me, n-Bu, t-Bu, Ph, PhC≡C, furan-2-yl, 1,3-thiazol-2-yl (14 examples; 69–98% for 9 compounds, 31–61% for the others); 55, R2 = Me (45%), Bu (72%), Ph (77%), PhC≡C (65%).

followed by hydrolysis [30]. Initially, enolates derived from the diketones undergo C-acylation, and the subsequent in situ deacetylation in aqueous NH4Cl and NH4OH on heating yields a new unsymmetrical diketone. The mechanism of the reaction of acetylacetone with 1-benzoylbenzotriazole is shown in Scheme 14. The formation of symmetrical dibenzoylmethane as by-product indicates the occurrence of further reaction resulting in the replacement of both acetyl groups by benzoyl. Scheme 15 illustrates the reaction of acetylacetone with other 1-acylbenzotriazoles. Unsymmetrical diketones 48 (R 2 = Ph, R 3 = PhSCH2, furan-2-yl, thiophen-2-yl) were the major products (yield 61–62%) in the reactions of benzoylacetone with acylbenzotriazoles. The mechanism of formation of symmetrical diketones 48 (R2 = R3 = Ph, furan-2-yl; yield 15–17%) is shown in Scheme 16). It was presumed that acylbenzotriazoles can be used in the development of one-pot syntheses on the basis of the obtained β-diketones [30]. The acylation of thioesters with acylbenzotriazoles in the presence of magnesium bromide–diethyl ether complex and ethyl(diisopropyl)amine gave a series of β-keto thioesters 49, and one of these (R = t-Bu, R′ = Pr) was converted into unsymmetrical β-diketone 50 according to Fukuyama [31]. The authors believe that

this reaction is the first example of direct alkylation of β-keto thioesters (Scheme 17). Unsymmetrical 1,3-diketones were synthesized from ethyl 3-arylpropanoates activated by treatment with BF3 · Et2O [32]. Boron complexes 51 thus formed reacted with organolithium compounds to give the corresponding 1,3-diketones 52 as complexes with BF2. Complexes 52 can be readily converted into 1,3-diketones. Apart from 3-arylpropanoates, keto ester 53 was used as ester component [32]. Complexes 51 (R1 = Ph) and 54 reacted with trimethylsilylmethyllithium (Me3SiCH2Li) (instead of MeLi) at –78°C to afford methyl ketones 52 and 55 (R2 = Me) in 44 and 39% yield, respectively (Scheme 18). 2.2. Metal Complex Catalysis in the Synthesis of β-Diketones In recent years, syntheses of β-diketones catalyzed by metal complexes have attracted increased attention. As a rule, the final step of the catalytic process is the Claisen condensation or oxidation of the aldol condensation product. An advantageous feature of this procedure is that the carbonyl or methylene component is generated during the process from more accessible reagents; therefore, compounds with functional groups unstable under conventional Claisen conditions can be involved.



765

rhodium catalyst. The synthetic potential of rhodiumcatalyzed α-acylation was demonstrated by one-pot syntheses of diketone 59 from benzoic acid and methyl vinyl ketone and of 3,4-dimethyl-5-phenyl-1H-pyrazole (60) from benzoyl chloride, methyl vinyl ketone, and hydrazine hydrate (Scheme 20). 2-Acetylindan-1-one 61 was synthesized via intraand intermolecular cross-coupling [34, 35]. The reaction of 2-iodobenzaldehyde with methyl vinyl ketone in the presence of 1,4-diazabicyclo[2.2.1]octane (DABCO) (Baylis-Hillman reaction) gave adduct 62 [34] which underwent intramolecular Heck cyclization to 1,3-diketone 61. The cyclization mechanism in-

2.2.1. Acylation of α,β-unsaturated ketones, aldehydes, and acylated enones. Sato et al. [33] synthesized 1,3-diketones by α-acylation of α,β-unsaturated ketones 56 and 57 with acid chlorides 58 in the presence of rhodium catalyst [RhCl(PPh3)3] and diethylzinc (Scheme 19). The reaction of RhCl(PPh3)3 with Et 2 Zn gives rhodium hydride complex A′ through ethylrhodium complex A. The reduction of initial enone 56 with complex A′ initially leads to rhodium enolate B (generation of methylene component), and the subsequent oxidative addition of acid chloride 58 yields complex C. The latter undergoes reductive elimination to produce β-diketone and regenerate

Scheme 19. O + R

1

R

2

R

3

O

Et2Zn, RhCl(PPh3)3 THF, 0°C

O

O R3

R1

Cl R2

56, 57

58

56, R1 = Me, Et, Ph, R2 = H, Me, Ph; 57, R1R2 = (CH2)3; 58, R3 = Ph, 4-Me(MeO, CF3, Cl)C6H4, furan-2-yl, thiophen-2-yl (12 examples, 51–81%) O R3

Cl 58

O

Ln O

I

Rh Ln R1

R1 R2 O R

R2

H

R 56

O

H C

2

LnRh A'

O

R1 LnRhI

I

H 2C

R3

O

B

1

RhIII X

X

R3 R2

H

H

Et2Zn

CH2

LnRhI

CH2CH3

X

A

ZnEt

Scheme 20. SOCl2, DMF CH2Cl2

O Ph

OH

MeC(O)CH=CH2, Et2Zn RhCl(PPh3)3, THF

O Ph

Cl

O

O

Me

Ph Me 59 (56%)

O + Ph

Cl

Me

O

Et2Zn, RhCl(PPh3)3 THF

O CH2

O H2NNH2, AcOH, EtOH

N

H N

Ph

Ph

Me Me


Me

Me 60 (65%)

766

SHOKOVA et al. Scheme 21. OH CHO

Me

+ H 2C

I

O

Pd(OAc)2, P(2-MeC6H4)3 Et3N, MeCN

Me

O

I

O

DABCO (1 equiv) 20°C, 168 h

O

CH2

Me

62 (65%) OH

O

OH

OH

O

Me

CH2

I

O

PdL2

Me

61 (35%)

62

Me

CH2 PdL

PdL

I A

I B

OH

CH2

OH

O

C(O)Me

C

COMe

–L2PdHI

PdL2 I

COMe

61 (enol)

61 (ketone)

Scheme 22. O COOEt

COOEt

Me

+ H 2C

+

COMe

O

Br

61

Scheme 23. O CH2 +

R

1 equiv

O R

O

1

R

2

R' Me

1.3 equiv

O

O

O

O

O

3

Me

Me Pr

63

O

R

H

R'

O R

O

Catalyst (0.1 equiv) PhH, Δ

O

R 64

R Pr 65

R 66

63, R1 = R2 = Me, R3 = H (76%); R1 = R2 = R3 = Me (72%); R1 = R3 = H, R2 = C7H15 (64%); R1 = R3 = H, R2 = i-Pr (64–76%); 64, R = H, F, Me, MeO, Me2N (83–95%); 65, R = Bu, Me(CH2)2CH(Me) (66–69%), MeCH2CH=C(Me) (91%); 66, R = H, F (75%).

volves oxidative addition of acetylpalladium to adduct 62 with formation of palladium complex A; intramolecular coordination in A leads to complex B which cyclizes to intermediate C, and elimination of Pd(OAc)2HI from the latter yields β-diketone 61 [34] (Scheme 21). A small amount of cyclic β-diketone 61 (7%) was detected by GLC while studying electrochemical arylation of methyl vinyl ketone with ethyl 2-bromobenzoate in the presence of a nickel catalyst [35]. Presumably, it was formed as a result of intramolecular acyla-

tion of the cross-coupling product. The major component of the reaction mixture was ethyl benzoate (dehalogenation product of the initial bromo ester; Scheme 22). Fukuyama et al. [36] proposed an efficient procedure for the synthesis of 2-alkyl-1,3-diketones 63–66 by catalytic addition of aldehydes to accessible α,β-unsaturated ketones in the presence of ruthenium hydride complex RuHCl(CO)(PPh3)3 (Scheme 23). The reaction mechanism was studied using deuterated benzaldehyde. It was found that 65% of deuterium in the


1,3-DIKETONES. SYNTHESIS AND PROPERTIES product was linked to the β-carbon atom, and 35%, to the α-carbon atom. Therefore, the formation of two ruthenium enolates A and A′ could be expected in the first step; their aldol condensation with the aldehyde

767

should lead to β-ketoalkoxyruthenium complexes B and B′, and β-elimination from the latter should produce 1,3-diketones C and C′ and regenerate ruthenium hydride which can be recycled [36]. The reaction

Scheme 24. O

O

Me

O

[Ru]

Me

O

Me

PhCDO

[Ru]

O

D

[RuD]

CH2

O

Me –[RuD]

D

D

A

D C (major product)

B

O Me

D

[Ru]

O

O D

Me

CH2

Me

[RuH]

O

[Ru] D

Me

PhCDO

Me

[Ru]

O

D –[RuD]

O +

D

B' Catalyst (20 mol %) CH2

Me

O

O

O

Me

Me Me

1 equiv

Me

C' (minor product) O

CHO

O

Me

Me

A' OCH

O

D

Me

2.3 equiv

67, 77%

Scheme 25. O O

R1

R

2

(1) CH2(ZnI)2, 25°C (2) H+/H3O

O

O

R1

R2

O 68a

R1 = Ph, R2 = Me, i-Pr, t-Bu, Ph, 4-MeOC6H4, 4-CF3C6H4; R1 = Me, R2 = 4-MeC6H4, 4-MeOC6H4, 4-CF3C6H4, naphthalen-2-yl, PhCH2CH2; R1 = PhCH2CH2, R2 = t-Bu, 4-MeOC6H4; R1 = Me, R2 = 4-CF3C6H4 (14 examples; 91–99% for 8 compounds). IZn

IZn

ZnI

O R2

O

R1

1,4-Addition

R

O

IZn Intramolecular acylation

1

R2

O

IZn OZnI

R1

O

O O

O 68a

A ZnI

O

Fragmentation R

CH2 +

1

OZnI

O

H+/H2O

+ R

R2

O

O

C


1

R

2

R2 B OH

H 2C

768

SHOKOVA et al. Scheme 26. O

(1) CH2(ZnI)2, 25°C, 12 h (2) H+/H3O

O O

Ph

O

O

O

Me

O

+

Ph

Ph

Ph

68b

O

Ph

50%

Ph

69, 10%

O O

Ph

O

+ O

Ph

Ph

70, 14%

Scheme 27. O

O

CH2(ZnI)2 (1) 25°C, 1.5–2 h (2) 40°C, 5–10 h

O O X

O

X ( )n

( )n

71

72

X = CH2, n = 1 (78%); X = O, n = 1 (73%), 2 (61%), 3 (61%), 4 (81%). O

O O

Ph

CH2(ZnI)2, 25°C Me

O Ph

O

Me O

73

O 76, 74%

O

O Me

O O

Ph

Me CH2(ZnI)2, 25°C

Ph

O

O

O

74

77, 97%

O O Me

O Me

Me CH2(ZnI)2, 25°C

O O

Me O

75

O 78, 90%

of ethyl vinyl ketone with benzene-1,3-dicarbaldehyde afforded 77% of tetracarbonyl compound 67 [36] (Scheme 24). Sada and Matsubara [37] reported on the formation of 1,3-diketones in the tandem reaction of acylated enones 68a with bis(iodozinc)methane. 1,4-Addition of CH2(ZnI)2 to γ-acyloxy-α,β-unsaturated ketone 68a gives enolate A (generation of methylene component) with a C–Zn bond, and intramolecular acylation in A yields structure B which undergoes Grob type fragmentation through cleavage of the C–Zn bond with formation of enolate C and iodozinc prop-2-enolate

(Scheme 25). Keto ester 68a (R1 = R2 = Ph) gave rise exclusively to symmetrical dibenzoylmethane (97%), whereas a mixture of three compounds was obtained from homologous keto ester 68b (Scheme 26). Compound 69 is the hydrolysis product of enolate A, and 1,5-diketone 70 is formed as a result of intermolecular addition of enolate like A to initial ketone 68b and subsequent Grob fragmentation. Lactones 71 reacted with CH2(ZnI)2 to give cyclic 1,3-diketones 72 via ring contraction in a tandem process. The tandem reaction of diketones 73–75 with CH2(ZnI)2 afforded triketones 76–78 with excellent yields (Scheme 27).


1,3-DIKETONES. SYNTHESIS AND PROPERTIES 2.2.2. Alkynols in the synthesis of β-diketones. Selective synthesis of β-diketones by oxidative rearrangement of alkynols A–D in the presence of IPrAuNTf 2 was reported in [38]. The catalyst was prepared directly from IPrAuCl and AgNTf 2 in CH2Cl2, and 4-methylpyridine N-oxide was used as

769

oxidant (Scheme 28). Two possible reaction paths were considered: (a) coordination of alkyne to L-Au+ with subsequent nucleophilic attack by Py+O– and formation of intermediate E and (b) coordination of Py+O– to L-Au+ with formation of intermediate F. The authors believed path b to be preferred (Scheme 29).

Scheme 28. HO

HO

HO R

HO

Ph

Ph

R

Ph Me R

( )n

A

B

C

D

A, R = 4-Me(MeO, F)C6H4, 3-ClC6H4, 3,5-(MeO)2C6H3, 3,5-(CF3)2C6H3, 2,4,5-Me3C6H2, 6-methoxynaphthalen-2-yl, PhOCH2, Bu, cyclo-C6H11; B, D, R = Me, Ph; C, n = 0, 9, 12. HO R

O

4-Methylpyridine N-oxide IPrAuNTf2, HNTf2, CH2Cl2, 20°C

O R

( )n A, C

HO Ph

R1 2 R

14 compounds (61–94%)

4-Methylpyridine N-oxide (PyO–) IPrAuNTf2, HNTf2, CH2Cl2, 20°C

O

O

R1

O Ph

+

2

R2

Ph 1

R 50% 78% 80% 57%

R1 = Me, R2 = H: R1 = R2 = Me: R1 = H, R2 = Ph: R1 = Me, R2 = Ph:

B, D

O

R 26% – 8% 16%

Scheme 29. +

HO a:

R

LAu+, Py+O–

AuL

AuL

HO

HO

R –

O

R O

Py+

Py+

E OH b:

Py+O– + LAu+

LAu

O

AuL HO

R O

R

Py+ LAu

O

Py+

F

O –LAu+

2.2.3. Acetylacetone in the synthesis of β-diketones. The simplest β-diketone, acetylacetone, was converted into a large number of various β-diketones as a result of three-component carbonylation–α-arylation with aryl bromides [39]. Carbon(II) oxide was generated ex situ [40] from 9-methylfluorene-9-carbonyl chloride in the course of the process. The gen-

O R

eration of CO and arylation of acetylacetone were catalyzed by dichloro(cycloocta-1,5-diene)palladium(II) [PdCl2(cod)], and MgCl2 was added to promote enolization of the initial diketone. The reaction involves intermediate formation of triketones A which can be isolated if necessary. Deacetylation of triketones A on treatment of the reaction mixture with 2 M HCl at


770

SHOKOVA et al.

80°C afforded β-diketones containing an Ar(Het)C=O fragment (Scheme 30). As a result, 25 compounds 79 were obtained in 80–99% (17 examples), 70–80% (4 examples), and 60–70% yield (4 examples). The

reaction can be carried out on a multigram scale. In the absence of MgCl2, aryl bromides were converted into the corresponding acids 80 as shown in Scheme 31 [39]. Further carbonylation–α-arylation of 79 (R =

Scheme 30. O O Ar(Het)Br

O

Me

O

+

Cl

i

+

O

O

Me

2 M HCl, 80°C

Ar(Het)

O

Me

Ar(Het)

Me

Me

O

Me A

79

Ar(Het) = mono-, di-, or trisubstituted phenyl, naphthyl, methoxynaphtyl, pyridyl, quinolyl, thienyl, or benzothienyl. Reaction conditions: i: PdCl2(COD), MgCl2, Et3N, Xantphos, N-methylcyclohexanamine, dioxane, 80°C.

Scheme 31. Br P

Br

Pd

Ar

Pd0

Br

MgCl2

Ar

O

HCl Me

O Me

O

no MgCl2

Pd0

P

P

Mg O

Ar

79

Ar

Ar

P

Mg O

O

PdII

P

Br

P

CO*

P

O

PdII Ar

P

P

Ar

P

Br II

O

O

Me

Me

O

Me

Me

O Me

Ar

O

O

O Me

Ar

Me

OH 80

Scheme 32. O

O

O Me

OMe + CO*

+

R

Br

OMe

R

79a, 79b O

O

O

O

O ( )n

R 82a, 82b

Me

R

R2

83a, 83b O

O

3

( )n

TsO

84a, 84b

O

O

O

85a, 85b O

O

R' R' 86a, 86b

O

R1

R'

R

OMe 81a, 81b

O

Me

O

OMe

Me R

O 87a–87c

( )n

O

Me

88 (63%)

81, R = TsO (a, 72%), Cl (b, 68%); 82, R = H, R′ = t-Bu (a), R = Ph(CH2)3, R′ = Me (b); 83, n = 1 (a), 2 (b); 84, R1 = t-Bu, R2 = CN, R3 = H (a, 81%); R1 = Me, R2 = TsO, R3 = Ph(CH2)3 (b, 73%); 85, n = 1 (a, 64%), 2 (b, 68%); 86, R = 4-CN, R′ = t-Bu (a, 87%); R = 2-F, R′ = Me (b, 86%); 87, R = TsO, n = 1 (a, 79%), 2 (b, 99%); R = CN, n = 2 (c, 87%). RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 6 2015


771

Scheme 33. O

O

O

2 M HCl, 80°C

87a–87c

OH R

Scheme 34. O + R

MeLi

AlCl3 (1 equiv) PhMe, 0°C

O

O

R

Cl

Me

1 equiv

R

RC(O)Cl

CH3 R

R

R

O

O

Me Me C

B

O H

OH +

A

O R

O

+

R

CH2

R

A

B

Me Me

Pr-i t-Bu

R Me

Me

Me

i-Pr

Pr-i

Me

A

–

–

07.9

–

–

–

B

67

34.0

49.9

10.2

–

69.4

C

–

36.1

21.6

84.1

91.1

12.2

Scheme 35. O

OH

O

O

[O], EtOAc, 77°C R1

R3

R1

R2 1

R3 R2

2

1

2

3

R = Me, Et, Pr, Ph, 3-Br-4-MeOC6H3(CH2)2, R = H, Cl, Me, Et, I, R R = (CH2)4, R = Me, Pr, t-Bu, C7H15, 4-O2NC6H4, 4-ClC6H4, 4-PhCH2OC6H4(CH2)2, 2-ClC6H4.

4-TsO, Cl) afforded 1,3-diarylpropane-1,3-diones 81a and 81b. Furthermore, 13C-labeled diketones 79b and 81b were synthesized using 13CO. Diketones 82 and 83 were converted to 1,3-dicarbonyl compounds 84 and 85, respectively (Scheme 32). Triketones 86a, 86b, 87a–87c, and 88 were isolated when the carbonylation–α-arylation of the corresponding 1,3-diketones was not followed by acid hydrolysis. Acid hydrolysis of 87b and 87c was accompanied by opening of the six-membered ring with formation of 5,7-dioxoheptanoic acid derivatives 89 (Scheme 33). 2.3. Miscellaneous

dep ended on the nat u re o f th e R substitu ent (Scheme 34). Diketone B is likely to result from transformations of the primary product, ketone A [41]. A number of various β-diketones were synthesized by experimentally simple oxidation of hydroxy ketones with o-iodoxybenzoic acid ([O]) in ethyl acetate [42] (Scheme 35). 3. PROPERTIES OF β-DIKETONES This section considers regioselective modifications of 1,3-diketones, which were reported after reviews [1, 2]. The overwhelming majority of these trans-

The formation of 1,3-diketones B in the reaction of bulky acyl chlorides with methyllithium was somewhat surprising [41]. The product composition considerably RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 6 2015

O R1

γ

β

O α

R3

β'

γ'

R2

772

SHOKOVA et al. Xia et al. [44] proposed a procedure for the selective α-alkylation of dibenzoylmethane, benzoylacetone, and acetylacetone with secondary alcohols in nitromethane in the presence of sulfuric acid [44]. The reactions were carried in nitromethane, the ratio H2SO4–alcohol–β-diketone being 0.05 : 1 : 3 (5 min, 101°C), or under the same conditions in combination with MW irradiation. In both cases, the yields of diketones 90 ranged from 80 to 98% and differed only slightly for the two methods (Scheme 37). Pentane2,4-dione and 1-phenylbutane-1,3-dione were converted into the corresponding triketones 91 by alkylation with bromomethyl 4-(methylsulfonyl)phenyl ketone in toluene in the presence of sodium methoxide [45] (Scheme 38). Propargyl alcohols reacted with 1,3-diketones in the presence of TsOH to give two different α-alkylation products, depending on the initial alcohol (Scheme 39). Either propargyl (path a; 92, R2 = H) or allenyl derivatives (path b; 93, R2 = Ph) were selectively formed [46]. The presence of a substituent (R6) on the α-carbon atom in the initial diketone was necessary for the reaction to follow path b. The reactions of di- and triphenylalkynols with acetylacetone and dibenzoylmethane afforded conjugated dienediones 94, presumably through intermediate α,β-unsaturated ketone. These results allowed development of a fairly

formations involved modification of the α-carbon atom of 1,3-diketones and their heterocyclizations with participation of the carbonyl groups (β- and β′-carbons). 3.1. Chemical properties of β-diketones 3.1.1. Modification of the α-CH2(CH) fragment. Alkylation. Selective alkylation of β-diketones with benzyl alcohols was achieved in the presence of trifluoromethanesulfonic acid [43]. As a result, the corresponding monoalkyl derivatives were obtained in high yields. The reaction proceeds either directly with elimination of water or through intermediate ether. Reactions of diketones R 1 C(O)CHR 3 C(O)R 2 [R 1 = R2 = Me, Ph, R3 = H; R1 = R2 = R3 = Me; R1 = Ph, R2 = Me, R3 = H; R1 = Me, R2R3 = (CH2)3] with benzyl alcohols ArCH(OH)R [Ar = Ph, 4-Br(Cl, F, NO2)C6H4, 2(3)-BrC6H4, naphthalen-2-yl; R = Me, Et, Pr, Bu, CH=CH2, Ph, 4-F(Cl)C6H4] were studied. The reaction of benzhydrol with acetylacetone in nitromethane gave an equimolar mixture of diphenylmethane and benzophenone [43]. When trifluoromethanesulfonic acid was replaced by p-toluenesulfonic acid, only the alkylation product was formed. Regardless of the catalyst, alkylation of the diketone was the only process under solvent-free conditions (Scheme 36).

Scheme 36. TsOH (5 mol %) MeNO2, Δ, 30 min

O + Ph

Ph

Ph

Ph

O

O

TsOH (5 mol %), MeNO2 Δ, 30 min (yield 83%) or TsOH or TfOH (5 mol %) 100°C, 30 min (90–93%)

OH +

Me

Me

O

O

Me

Me

Ph

Ph

Ph

Ph

Scheme 37. O O

O

R1

+ R

1

O

OH R

2

Ar

R

3

R2 R3

Ar 90

R1 = R2 = Ph, Me; R1 = Ph, R2 = Me; Ar = substituted phenyl, naphthalen-2-yl; R3 = Me, Ph, PhC≡C, PhCH=CH (13 examples).

Scheme 38. O

O Br

O

O

O O

MeONa, PhMe

+ R1

R1

R2

MeSO2

R2

MeSO2 91 (50–60%) 1

2

1

2

R = R = Ph, Me; R = Ph, R = Me. RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 6 2015


773

Scheme 39. R1 a

R

R3

4

R6

2

R =H O

HO R3 +

R1 2 R

O

TsOH (5 mol %) MeCN, 20°C

O

R4

O 92

R5 R

R5

R1

R3

6

b 2

·

R4

R6

R = Ph O

R2 R5

O 93

a: R2 = H, R1 = Ph, R3 = Ph, Bu, thiophen-3-yl, H; R1 = thiophen-3-yl, R3 = Ph; R1 = 3-MeOC6H4, R3 = Ph; R1 = naphthalen-2-yl, R3 = H; R6 = H, R4 = R5 = Me, Ph; R4 = Ph, R5 = Me; R4 = R5 = R6 = Me; R5 = Me, R4R6 = (CH2)3, (CH2)4 (20 examples; 43–54% for 4 compounds, otherwise 60–90%); b: R1 = R2 = Ph, R3 = H, Ph; R4 = R5 = R6 = Me; R5 = Me, R4R6 = (CH2)3, (CH2)4 (6 examples, 50–72%).

Scheme 40. O

HO R1

Ph Ph

Ph

R1

O Ph

+

R2

R2

TsOH (5 mol %) MeCN, Δ

O

R1

O

R2

Ph Ph

R2

O

94 1

2

1

2

R = R = Ph (83%); R = H, R = Me (51%). O

HO R2 + R1

O

(1) TsOH (5 mol %), MeCN, Δ (2) K2CO3 (1.1 equiv), Δ

O

R3

R3

R

1

R3

R2

R3

O 95 1

2

1

2

1

2

3

R = R = Ph; R = thiophen-3-yl, R = Ph; R = Ph, R = Bu; R = Me, Ph (4 examples, 52–78%).

Scheme 41. O O

O +

R1

CH2OH

Fe

HBF4 (40%), CH2Cl2, 20°C

O

R1

R2

R2 Fc 96

R1 = R2 = Ph, Me; R1 = Me, R2 = Ph.

Scheme 42. O O

Ar N

O

O

OR1

R2

R2

Cu(OTf)2 (10 mol %), CHCl3, 60°C

+

O R3

O

R3

N

Ar

97 1

2

3

2

3

R = Me, Et, i-Pr; Ar = substituted phenyl, thiophen-2-yl, naphthalen-2-yl; R = R = Me, Ph; R = Me, R = Ph (23 examples, 61–87%). RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 6 2015

774


O

Ph

Me

TfOH Cu(OTf)2 Ph

O O

O

O

O

Ph

Me

OEt

O

Cu

N

N

OTf

Me

NO2

A

NO2

N

OTf

EtOH

97 O

NO2

simple one-pot procedure for the synthesis of tetrasubstituted furans 95 from propargyl alcohols and symmetrical diketones [46] (Scheme 40). 2-Ferrocenylmethyl-1,3-diketones 96 were synthesized by reacting acetylacetone, dibenzoylmethane, and 1-phenylbutane-1,3-dione with ferrocenylmethanol (FcCH 2 OH) in CH 2 Cl 2 –40% aq. HBF 4 [47–49] (Scheme 41). Cross-coupling of the same β-diketones with N-substituted pyrrolidin-2-ones, catalyzed by Cu(OTf) 2 , afforded a large series of 2-substituted 1,3-dicarbonyl compounds 97 containing an oxopyrrolidine fragment [50] (Scheme 42). The reaction followed the nucleophilic substitution pattern (Scheme 43). Copper-catalyzed oxidative alkylation of aromatic β-diketones with benzylic hydrocarbons gave the corresponding 2-substituted 1,3-diketones [51] (Scheme 44). The reaction involves intermediate formation of phenylalkyl benzoate which alkylates 1,3-dicarbonyl nucleophile.

Oxidative cross-coupling of β-diketones with 1,3-diarylpropynes was achieved using dichlorodicyanobenzoquinone (DDQ) as oxidant. The resulting dicarbonyl compounds 98 contained an arylethynyl fragment [52]. The reaction mechanism involves abstraction of hydride ion from the benzylic position of diarylpropyne and subsequent nucleophilic attack on the benzyl cation thus formed by the dicarbonyl compound (Scheme 45). Radical alkylation of diketones was reported in only one publication [53]. 1,3-Diketones with unsubstituted α-CH2 group readily reacted with trifluoroiodomethane in DMSO in the presence of Fenton reagent. Presumably, attack by CF 3· radical on the α-carbon atom of the diketone is followed by oxidation of intermediate radical species to produce α-trifluoromethyl-substituted 1,3-diketone 99 (Scheme 46). Introduction of an adamantyl fragment into the α-position of β-diketones has recently been reported

Scheme 44. O Ar

Cu(ClO4)2 (20 mol %) bathophenanthroline (5 mol %) t-BuOOBz (3 equiv), 60°C

O

R1 + R

5 equiv

2

R 1 equiv

O

O

R2

R3

3

Ar

R1

ArCH2R1 = indan, 4-ClC6H4CH2Me, PhCH2X (X = Me, Ph, CH2=CH); R2 = Ph, R3 = Ph, Me; R2 = R3 = 4-BrC6H4, 4-MeOC6H4; R2 = Me, R3 = Me, furan-3-yl (10 examples, 48–75%). RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 6 2015


775

Scheme 45. O

OH

Cl

CN

Cl

CN

MeNO2, 20°C

+

R1 R

2

NC

CN

NC

CN

O

R2

O

O O

R1

O

O

R3

R4

R4

R3

OH Cl

CN

R1

– Cl

CN

R2

OH 2

1

2

98

1

4

3

R = H, R = H, Me, MeO, Cl; R = MeO, R = H; R = Ph, R = 4-Me(MeO, Cl, Br, thiophen-2-yl, furan-2-yl)C6H4, 3-ClC6H4, 3-MeOC6H4, 2-MeC6H4; R4 = Me, R3 = Me, Ph (17 examples, 44–92%).

Scheme 46. O

+ CF3I R

O

FeSO4 (0.3 equiv), H2O2 (2 equiv) DMSO, 20°C, 1 h

O

O

R

R'

R'

CF3 99

3 equiv

R = Me, R′ = Me, Ph, C5H11 (32–42%); R = R′ = t-Bu (25%). H2O2

H O

O

Me

Fe

II

OH–

Me CF3

FeIII

H+

O · OH

H O O

O Me

Me

Me

O · CF3

·O Me

99 O

OH Me

Me

Me

OH S

Me

O

or Me

S

Me

CF3

O

Me

Me

· CF

O

Me·

3

Me MeI

[54–57]. Turmasova et al. [54] described the alkylation of dicarbonyl compounds with adamantan-1-ol in 1,2-dichloroethane, catalyzed by indium, gallium, scandium, and copper trifluoromethanesulfonates. The best yields of adamantyl derivatives were obtained in the presence of In(OTf)3. Depending on the reaction time, selective replacement of one or both hydroxy groups in adamantane-1,3-diol can be achieved [55]

S

OH

CF3I

(Scheme 47). Apart from adamantan-1-ol, 1-chloroand 1-bromoadamantanes were used to alkylate acetylacetone in the presence of iron and manganese acetylacetonates, and the yields of 2-(adamantan-1-yl)pentane-2,4-dione were 75 and 93%, respectively [56]. Dehydroadamantane reacted with fluorinated 1,3-diketones to give 2-(adamantan-1-yl) derivatives in 83–98% yield [57]. The reactions were carried out by


776


O

+ R1

OH

R1

M(OTf)n (5 mol %) ClCH2CH2Cl

O

54–93%

R2

O

R2 1

M(OTf)n = In(OTf)3, Ga(OTf)3, Sc(OTf)3, Cu(OTf)2; R = R = Me, Ph; R = Me, R = OEt; R1 = Ph, R2 = OEt; R1 = R2 = OEt; R1R2 = CH2C(Me)2CH2. R2

O

R1

O

R

2

HO

In(OTf)3 (10 mol %) ClCH2CH2Cl, Δ, 3 h

O R1

OH

Me

In(OTf)3 (10 mol %) ClCH2CH2Cl, Δ, 1 h

O

+

25–83%

R2

1

1

OH O

O

2

O

60%

R2

O

Me

R1 = R2 = Me, Ph; R1 = Me, R2 = naphthalen-2-yl; R1 = CF3, R2 = Ph; R1 = Me, R2 = OEt; R1R2 = CH2C(Me)2CH2.

Scheme 48. O

O

O

O

OH

O

O

OH

H+ + RF

RF

R

RF

R O

H

+

RF

R

O

RF

RF

R

O

R O

83–98% R

RF = CF3, R = CF3, Ph, 4-ClC6H4, 3,4-(MeO)2C6H3, 1,3-benzodioxol-5-yl, furan-2-yl, thiophen-2-yl, 4-(1H-pyrrol-1-yl)phenyl, t-Bu; RF = CHF2, R = Ph.

Scheme 49. O

RFCOOH, 1,1'-carbonyldiimidazole or (RFCO)2O, imidazole O

O

90–92%

O

O

O

O OH

O

RF

O HO

RF

RF

100

RF = CF3, C2F5, C3F7.

Scheme 50. O Et3SiH, TFA, LiClO4 O

OH OH

O

RF

OH

O 3 examples (82–89%)

RF

O O

O RF

(COCl)2

O O

Cl

RNH2

O RNH

RF

RF

101 6 examples (68–90%)

RF = 4-FC6H4, 3,4-F2C6H4, 4-FC6H4CH2, 3-CF3C6H4CH2. RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 6 2015

1,3-DIKETONES. SYNTHESIS AND PROPERTIES heating the reactants in anhydrous diethyl ether in the absence of acid or base catalyst. According to the authors, the acidity of fluorinated 1,3-diketones is sufficient to generate adamantan-1-yl cation from dehydroadamantane (Scheme 48). Acylation. The acylation of cyclopentane-1,3-dione with perfluorinated carboxylic acids in the presence of 1,1′-carbonyldiimidazole or with perfluorinated carboxylic acid anhydrides in the presence of imidazole afforded triketones 100 with completely enolized perfluoroacyl fragment [58] (Scheme 49). The exocyclic carbonyl group in 100 was selectively reduced to hydroxy by ionic hydrogenation. Enamines 101 were synthesized in a one-pot process including treatment of triketone 100 with oxalyl chloride and primary amine [58] (Scheme 50). Shen et al. [59] described selective α-acylation of 1,3-dicarbonyl compounds, including β-diketones, with carboxylic acid chlorides, catalyzed by SmCl3

777

[59]. The products were triketones 102, as well as 103 and 104 (from cyclic diketones, cyclohexane-1,3-dione and 2-acetylcyclopentanone). Intramolecular acylation (cyclization) was observed in analogous reaction with 2-(1,3-dioxo-3-phenylpropyl)benzoyl chloride (105), which afforded polycyclic triketone 106 in excellent yield (Scheme 51). Condensation and addition reactions. Tetraketones 107 and 108 were synthesized from cyclic β-diketones (dimedone and indan-1,3-dione) and aromatic aldehydes by Knoevenagel and Michael reactions catalyzed by sulfonic acid-functionalized silica-coated nano-Fe 3 O 4 particles [60]. The catalyst is readily accessible, and it can be readily removed from the reaction mixture using an external magnet and reused several times without appreciable loss in activity (Scheme 52). Substituted β-diketones 109 were converted into α-oxo(thioketene) dithioacetals 110 by reaction with

Scheme 51. O

O + R1

Cl

O

R2

R2 R

O

SmCl3 (5 mol %) Et3N (1.2 equiv), PhMe, 20°C R2

3

O

O O

R2 O

R3

Ph

O O Me Ph

O

R1 102

O 104 (78%)

103 (90%)

102, R1 = Ph, 4-ClC6H4, 3-O2NC6H4, PhCH2; R2 = Me; R3 = H, Me (5 examples, 72–87%). O

O

O

SmCl3 (5 mol %) Et3N (1.2 equiv), PhMe, 80°C

O

Cl O

O 105

106 (80%)

Scheme 52. O + ArCHO

O

Catalyst, H2O, 20°C 60–170 min

Ar

O

Me

Me

O

Me

Me

Me

O + ArCHO

Catalyst, H2O, 20°C 20–245 min

O

Me

OH HO 107 O

O

Ar

O

O

108

107, Ar = Ph, 4-Br(MeO, NO2, Me, Cl, Me2N, F)C6H4, 3-Br(NO2)C6H4, 2-MeO(Cl, OH)C6H4, 2,4-Cl2C6H3, 3,4-(MeO)2C6H3, PhCH=CH, tiophen-2-yl, naphthalen-2-yl (18 examples, 75–97% for 16 compounds; 108, Ar = Ph, 4-NO2(Cl, Me, Me2N)C6H4, 3-BrC6H4, 2-ClC6H4 (7 examples, 81–97%). RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 6 2015

778


O R1

Me

O– +N(Bu-t)4

O

K2CO3, H2O, (t-Bu)4NBr

(t-Bu)4N+ O–

R1

Me

O R1

Me

109

O CS2, 20°C

O

O R1

Me S

O R1

Me

+

N(Bu-t)4

O R1

Me

+

N(Bu-t)4

S–

HS

S

O

2 R2Br, (t-Bu)4NBr K2CO3, H2O

R2S

SR2

110, 111 1

2

2

2

R = 2-MeC6H4NH, 2-MeOC6H4NH, 4-ClC6H4NH, Me; 110, R = PhCH2, R R = (CH2)3 (12 examples, 92–99%); 111, R2R2 = (CH2)2.

Scheme 54. R1 Electrolysis, 0.1 F/mol (Fe cathode, graphite anode) NaBr, MeOH or EtOH

O

O R

3

+ R1

HO R3

O N

O

R1

R1

O

R

O 2

OH

N R2 112

R1 = H, Me; R2 = H, Me, PhCH2, MeC(O); R3 = H, Me, Cl (9 examples, 71–87%).

Scheme 55. RSH (1 equiv) H2O or NaOH (0.1 equiv) R = Pr, Bu, C6H13 63–92%

O CH2O

+ Me

2 equiv

MeSNa (1 equiv) Na2S, 20°C, 20 min

O Me

99%

O

O

O Me

Me

H

Me

Me

SR

SR SMe

O SMe

Me

+

O

S

SMe

1 equiv

O

Me Me O

1.3 : 1 MeSNa (1 equiv) Na2S, 20°C, 4 h

SMe O

O Me

SMe SMe

+ S Me 18%

carbon disulfide and alkyl bromides [K2CO3, tetrabutylammonium bromide or 4-dodecylbenzenesulfonate] in water [61]. Cyclic thioacetals 111 were obtained using α,ω-dibromoalkanes Br(CH 2 ) n Br (Scheme 53). 2-(3-Hydroxy-2-oxo-2,3-dihydro-1H-indol-3-yl)cyclohexane-1,3-diones 112 were synthesized by aldol condensation of isatins with cyclic 1,3-diketones in a simple electrocatalytic system [62].

Alkoxide ion necessary for the activation of dicarbonyl compounds was generated by cathodic deprotonation of the alcohol taken as solvent (Scheme 54). Multicomponent condensation of acetylacetone with formamide and thiols RSH (or NaSMe) in an alkaline sulfide solution (from Orenburg gas processing plant) was reported in [63] (Scheme 55). Acetylacetone and dibenzoylmethane reacted with acetophenone in


1,3-DIKETONES. SYNTHESIS AND PROPERTIES DMSO in the presence of CuO and I2 to give triketones 113 through phenacyl iodide and phenylglyoxal as intermediates [19] (Scheme 56). Enantioselective conjugate addition of maleimides to acetylacetone and 3-methylpentane-2,4-dione in the presence of chiral N,N′-(cyclohexane-1,2-diyl)bis(1H-benzimidazol-2-amine) (A) as catalyst and TFA as

779

co-catalyst gave adducts 114a with ee 91–97% [64] (Scheme 57). Under analogous conditions, 2-acetylcyclopentanone reacted with N-phenylmaleimide to afford 93% of 114b as a mixture of two diastereoisomers with high enantioselectivity for each one (ee 95/98%). The role of the catalyst consists of deprotonation of the nucleophile (diketone) and activa-

Scheme 56. O O

–H2O, –CuI

Me

Ph

O

CuO, I2

O

DMSO I

Ph

O

O

R CHO

Ph

R O

O

R

Ph

R 113

R = Ph (84%), Me (63%).

Scheme 57. O

O

R1

R3 R

O

O +

R4

N

A (10 mol %), TFA (10 mol %) PhMe, 30°C

O

O R1

2

O

R3

R2

O R4

N

O

N

O

Me

O

O

114a

114b

N

N NH

N H

H

A

H

HN

N H

N

H

N

N

H N

H N

H N

O

O

O

N

A

CF3CO2 H

O 1

3

2

4

1

2

3

4

R = R = Me, R = H; R = H, Me, PhCH2, 4-BrC6H4 (69–100%); R = R = R = Me, R = Ph (6%).

Scheme 58. O O

R' R

O

AcONa, EtOH

+ NO2

O

N

–

O

N

H /H2O

OC(O)CF3

N

O–

R' R

+

–CF3COOH

CF3 O

O– O

R'

O

R

R

Ar

–

Ar

R' –

O–

O CF3

Ar R

CF3

Ar

O

R'

Ar

NO2 115

R = CF3, Ph, R′ = H, Ar = Ph, 4-MeC6H4, 4-MeOC6H4, 4-ClC6H4, thiophen-2-yl; R = CF3, R′ = Me, Ar = Ph, 4-MeC6H4, 4-MeOC6H4, 4-ClC6H4, thiophen-2-yl. RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 6 2015

Ph

780

SHOKOVA et al. Scheme 59. O O

O +

O

R1

[Fe], [O]

PhNMe2

R2

R1

O R2

2 R2 R

O

O

R2

R1 SN2

Ph

N

O

O

O R1

R1

Me 117

116 O

Elimination

O

O

R1

O

R1

R2

R2

Addition

CH2 1

2

1

2

R = R = Ph (70%); R = R = Me (90%). O

O

Ph

OEt N

Ph

O

Fe2(CO)9 (2.5 mol %) t-BuOOH (1 mmol), 20°C

O

+ Ph

Ph Ph

O

O O

O

Ph

+

O O

O

OEt

OEt

Me

Ph Ph

O

Ph

Ph

Scheme 60. O O

Cu(OTf)2 1,2-dichloroethane

O

O +

R

Me

HN

CbzNH

Ph

NH

O

CbzNH

Ph

Me O

R

Cbz = benzyloxycarbonyl; R = Me (43%), Ph (55%). O R2

HN Nu R

Nu

M X Metal salt

H

1

X–

O H N

Active electrophile

M R2

Nu

H

X

Active nucleophile O

R1 HN

R

tion of the electrophile (maleimide) by the protonated benzimidazole fragment via hydrogen bonding with the C=O group. The catalyst can be recovered from the reaction mixture in the form of trifluoroacetate and reused. The reaction of 1-aryl-4,4,4-trifluorobutane-1,3diones with conjugated nitroalkenes involves the

1

R2 Enamine and enecarbamate

Michael addition step, followed by detrifluoroacetylation of the Michael adduct. The products are γ-nitro ketones 115 [65] (Scheme 58). Symmetrical methylene-bridged bis-dicarbonyl compounds 116 were synthesized by reaction of 1,3-diketones with N,N-dimethylaniline, catalyzed by Fe2(CO)9 [66]. tert-Butyl hydroperoxide was used as



781

the presence of In(OTf)3, BuLi, and Et3N [68]. Though the role of BuLi and Et3N was not clearly understood, the obtained data indicated that they are necessary components of the reaction mixture. The amounts of In(OTf)3, BuLi, and Et3N were 2.5 mol % each in the reaction with pentane-2,4-dione and 5.0 mol % in the reactions with other diketones. The addition product to pentane-2,4-dione has enol structure. A probable mechanism of the catalytic addition is shown in Scheme 61.

oxidant. According to the mechanism proposed by the authors, initially formed oxidative addition product 117 reacted with the diketone, yielding compound 116. This mechanism is supported by the formation of polyketone 116 from keto ester 117 and dibenzoylmethane (Scheme 59). A new Cu(OTf)2-catalyzed Mannich-type reaction of 1,3-dicarbonyl compounds, including acetylacetone and benzoylacetone, with enecarbamates, was described in [67]. Supposedly, the copper salt initially reacts with the diketone to produce copper enolate and a strong Brønsted acid. The latter transforms the initial enecarbamate into the active iminium species. Formalistically, the reaction can be regarded as addition of 1,3-dicarbonyl compounds to aliphatic aldehyde imines that are commonly unstable and are difficult to isolate (Scheme 60).

[2 + 2 + 2]-Cyclotrimerization of 1,3-diketones with terminal alkynes, catalyzed by MnBr(CO)5, was proposed as an efficient procedure for the preparation of substituted benzenes [3, 69]. The reaction with arylacetylenes was regioselective, and the corresponding p-terphenyl derivatives were formed with high yields. Analogous reaction with terminal aliphatic alkynes gave mixtures of regioisomers (Scheme 62).

Pentane-2,4-dione and its methyl homolog, 2-acetylcyclopentanone, and 2-acetylcyclohexanone gave addition products with phenyl- and hexylacetylenes in

Photoredox catalytic reaction of 2-bromo-1,3-diketones with arylalkynes led to the formation of polysubstituted naphthols 118 and furans 119 [70]. Naph-

Scheme 61. O Ph

Me

+

Me

OH

In(OTf)3, Et3N BuLi, 100°C

O

97%

Me

O

Me

Me Ph

O

O Ph

Me

Me

+

Me CH2

97%

( )n

O

O

In(OTf)3, Et3N BuLi, 100°C

CH2

( )n

Ph n = 1 (88%), 2 (99%)

Carbometalation R H

OTf OTf In O O

TfO

Me

Deprotonation R

TfO

H

In

O

O

Me

O

Me

Me

O

OTf

Me In(OTf)2

R

Me

OTf

H

H H

R H

O

O

Me

O Me H

R H

Me

Protonation


O Me H

782

SHOKOVA et al. Scheme 62. CH O

MnBr(CO)5 (10 mol %), NMO (10 mol %) MgSO4 (20 mol %), PhMe, 85°C

O +

R1

Ar

CH

Ar

O

MnLn O

R2

Ar

CH

Ar

O

R1 Ar

Ar

R1

TsOH R2

LnMn

Ar

Ar

OH

Ar

LnMn

R2

R1

R2

R2

R1

O

R1 O

O

R2

–H2O

O

Ar

O

NMO is N-methylmorpholine.

Scheme 63. OH O

O

O

Ph

R

+ Ph

i

CH

PF6

R

t-Bu

N

Br Ph

Catalyst =

118 O

O Br

R3

N

t-Bu Ar

R1

O

R2

Ir N

i

R3

+ Ar

R1

N

Ir(ppy)2(dtbbpy)PF6

O

R2 119 1

2

3

118, R = Ph (87%), Me (53%); 119, R = R = R = H, Ar = Ph, 4-MeO(Me, t-Bu, Ph, F, Cl, Br, CF3)C6H4, 2-MeOC6H4, 3-MeOC6H4 (33–96%), 6-methoxynaphthalen-2-yl (81%); R1 = R2 = Me, R3 = H (98%); R1 = R3 = H, R2 = Ph (92%); R1 = R2 = H, R3 = Me (48%); i: catalyst (0.002 mmol), bromodiketone (0.4 mmol), alkyne (0.2 mmol), Na2HPO4 (0.24 mmol), dimethylformamide, white LED (13 W), 20°C. OH

hv

O COPh

COPh

IrIII

Br

Ph

IrIV

O COPh

H

H

CH Ph

O

O

Ph ·

O H

O

IrIV

Ph

Ph

·

Ph

119 Base

O

COPh

Ph O

O COPh

O

·

IrIII

IrIII

O

CH

O

·

Base

COPh ·

Br

O

118

O

hv

O

Ph

IrIII

O

·

Ph O

Ph

thalene derivatives 118 were obtained from 2-bromo1,3-diphenylpropane-1,3-dione and 1-phenylbutane1,3-dione, while 2-bromo-5,5-dimethyl(or 5-phenyl)cyclohexane-1,3-diones gave rise to tetrahydro-1-benzofurans 119. Ethanol as solvent ensured the best

yields. The reaction paths leading to compounds 118 and 119 are shown in Scheme 63. Halogenation, amination, hydroxylation, azo coupling, and other reactions. Aryl-containing β-diketones and dimedone are readily and selectively brominated at


1,3-DIKETONES. SYNTHESIS AND PROPERTIES the α-position with bromodimethylsulfonium bromide in methylene chloride to give the corresponding monobromo derivatives 120 [71]. The reaction is fast, and the resulting bromides can be easily isolated and purified (Scheme 64). Kitamura et al. [72] reported on the fluorination of diketones in the system PhIO– 55% aq. HF–CH2Cl2 at 40°C. The reaction is likely to involve hypervalent iodine intermediate (Scheme 65). α-Halogenation of 1,3-diketones was accomplished using tetraethylammonium halides, and α-azidation, using tetrabutylammonium azide in acetonitrile–H2O (9 : 1) [73]. The reaction was initiated by (diacetoxy-λ3iodanyl)benzene (Scheme 66). Direct α-amination of acetylacetone and dibenzoylmethane with p-toluenesulfonamide in the presence of PhIO as oxidant and Zn(ClO4)2 as catalyst readily afforded compounds 121a [74]. Analogous reaction with dimedone gave iodonium ylide 121b. A plausible mechanism involves initial formation of PhI=NTs from TsNH2 and PhIO, followed by reaction with the di-

783

ketone to give intermediate A. Depending on the diketone nature, intermediate A is converted into either N-tosylimino derivative 121a or cyclic ylide 121b. The latter is fairly stable due to intramolecular bonding of the two carbonyl oxygen atoms with iodine(III) (Scheme 67). 2-Acylindan-1-ones were readily hydroxylated with 3-phenyl-1-tosyloxaziridine in toluene in the presence of chiral guanidine derivative 122 which was prepared from diethyl L-tartrate. 2-Acyl-2-hydroxyindan-1-ones 123 were thus synthesized in 90–99% yield with high enantioselectivity (ee 79–88%) [75] (Scheme 68). Acetylacetone reacted with arenediazonium salts to produce azo derivatives 124 which were fully characterized by spectral (IR, UV, 1H and 13C NMR), potentiometric, X-ray diffraction, and thermogravimetric data [76]. Compounds 124 were found to exist in DMSO solution and in crystal exclusively in the hydrazo form (among four possible tautomers), which is stabilized by intramolecular hydrogen bond

Scheme 64. O R1

Me

Me3S+ Br–, 0 to 20°C 20–30 min

O

Me S

O

R2

O

O

Br– O

R1

R1

R2 Br

R2

120 (86–98%)

R1 = Ph, 4-O2NC6H4; R2 = Ph, Me; R1R2 = CH2C(Me)2CH2.

Scheme 65. PhIO + 2 HF

PhIF 2 + H2O

F– O

O

R

OH R'

O

O

R

O

O

O

PhIF2 –HF

R'

R'

R F

I

–PhI, –F ·

R'

R F

Ph

R = Ph, R′ = Me (47%); R = R′ = Ph (90%); R = R′ = Me (34%).

Scheme 66. O

O Me

O

O

R

O Me

Me

Cl 97%

X

O

R

Me

X = Cl (88%), Br, I (72–73%), N3 (79%)

R'

O

O Me Cl

75%


784


O O

PhI + 1 R

R2

+ PhI=NTs

Zn(ClO4)2

NTs

O R2

R1

121a Zn2+ O

Zn2+

O

O

··

O

R2

R1 O Ph

IPh Me Me 121b (83%)

R1

I

R2

NHTs

A

I

NTs

O Proton shift

R1 = R2 = Me (65%), R1 = R2 = Ph (87%).

Scheme 68. Ph

Me

Ph O O

Ph

N

+

R

O

122 (10 mol %) PhMe, –78°C

Ts

Me

O

NH

Me

O

N

NH

R'

R

O

R'

O

OH 123

Ph Ph

R = H, F, Cl, Br, MeO; R′ = Me, Et, Pr (7 examples).

122

Scheme 69. Me O

O

N

O

H N

Me

O

X Hydrazo

Me

N

H N

Me

O

O

Me

N

Me N

Me

X Keto–azo

O

X E-Enol–azo

O

N

H N

Me

X

Z-Enol–azo

124

X = Br, MeC(O), NO2.

(Scheme 69). β-Diketones 125 containing a triazolylazo group in the 2-position were synthesized by reaction of 1,3-diketones with triazolediazonium salts [77]. Fluorinated 1,3-diketones reacted with hetarenediazonium chlorides, yielding 1,2,3-triketone 2-heteroarylhydrazones 126 [78] (Scheme 70). Moderate yields of 126 were ascribed to side reactions, the main of which is the Japp–Klingemann hydrolytic cleavage. This re-

action becomes the major process when the initial diketone contains a bulky substituent (R = t-Bu). In this case, the product (yield 35%) was a 85 : 15 mixture of hydrazo ketone and azo-enol tautomers 127a and 127b (Scheme 71). β-Diketones 3 (R3 = H), cyclohexane-1,3-dione, and dimedone were subjected to nitrosation with a mixture of NaNO2, moist SiO2 (50 vol. %), and oxal-



785

Scheme 70. O NH2 N N R 3

1

N2 Cl–

NaNO2, HCl 0–5°C

R1 N

N

R3

N

N

3

N

R2 R NaOMe, MeOH

N

N

O

1

N

R3 1

125 1

HetN2 Cl– H2O–EtOH–NaOAc

OH

RF

2

2

O

R2

R = H, R = R = Me (58%), R = R = Ph (62%), R = Me, R = Ph (56%); R = 4-MeCONHC6H4SO2, R1 = R2 = Me (46%), R1 = R2 = Ph (47%), R1 = Me, R2 = Ph (43%).

O

2

O

N

H N

Het

Me

Me

N

HN

N Het =

R

RF

R

3

Ph

N

HN

,

N

N

,

. N

O O 126

O

COOEt

R = Me, Bu, Ph; R′ = HCF2CF2, CF3, C3H7 (9 examples, 30–70%).

Scheme 71. O F2CH

H

Me

Me

Me

N

O

+

Ph

Bu-t

H2O–EtOH–NaOAc

N

N2 Cl

Me N

–

Ph

N H O

Me

Me

N –CHF2COOH

N H

O

Ph

N O

127a

HO

terized by physical and spectral data, and the structure of some of them was optimized by a semiempirical method; the energies, dipole moments, and heats of formation were calculated. Two series of curcumin derivatives, ester (129) and acid (130), were prepared starting from α-carboxymethyl-substituted β-diketones [82] according to two schemes. Scheme a included the following steps: (1) B2O3 (1 mmol), β-diketone 3 (R1 = R2 = H, R3 = tBuOCOCH2, 1 mmol), DMF, 80°C; (2) tributyl borate (4 mmol); (3) ArCHO (1.8 mmol), BuNH2 (0.4 mmol), DMF, 80°C; (4) 0.5 M HCl; (5) 50% CF3COOH in CH2Cl2, 0°C. In this way, all compounds 129 (yield 47–52%) and 130 (except for R1 = OMe, R2 = OH; 30,

Scheme 72. RCHO

O

O

O

+ Me

Bu-t

127b

ic acid dihydrate in methylene chloride [79]. Initially formed nitroso derivatives underwent fast rearrangement into the corresponding oximes. 3.1.2. Transformations of β-diketones 3 involving the R1CH2 and R2CH2 fragments. Benzoylacetone reacted with heterocyclic aldehydes in the presence of boron oxide, tri(sec-butyl) borate, and butan-1-amine to give 5-heteroaryl-1-phenylpent-4-ene-1,3-diones 128 [80] (Scheme 72). Elavarasan et al. [81] synthesized 16 curcumin analogs in high yields (80–95%) by condensation of substituted benzaldehydes with acetylacetone in the presence of calcium oxide under microwave irradiation (Scheme 73). The obtained compounds were characO

O

N

N

Bu-t

O

t-Bu

Me N

N

N

Ph

O

N

N

O

Me

F2CH

Ph

R

Ph 128

R = 1H-imidazol-2-yl (78%), 1H-pyrrol-2-yl (83%), thiophen-2-yl (79%). RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 6 2015

786

SHOKOVA et al. Scheme 73. R5

O

R5

O

4

R4

R

R3

R5 R4

CHO

2

O

R1

R3

R2

CaO, MW (160 W) 60–120 s

O

R1

R2

+ R

3

R R

Me

1

Me

R5

2

OH

R5

O

R4

R4

R3

R1 R

R1

R3

2

R2

Scheme 74. O

R1

O

Me

Me

O

CHO

O

R2 R2

a COOBu-t

R2

COOBu-t R

1

R

1

R

1

129 50% TFA CH2Cl2

O Me

a R1

O Me

O

CHO

O

R2 b

COOH

R2

R2

COOH R

1

130

R1 = MeO, R2 = H, OH, OAc.

43%) were synthesized. Compound 130 (R1 = OMe, R2 = OH; 25%) was synthesized according to scheme b: (1) B2O3 (2.25 mmol), β-diketone 3 (R1 = R2 = H, R3 = HOC(O)CH2, 3 mmol), DMF, 70°C; (2) ArCHO (6 mmol), AcOH, morpholine (0.6 mmol), DMF, 70°C; (3) 20% AcOH (Scheme 74). 3.1.3. Transformations of β-diketones 3 via cleavage of the R 1 (R 2 )C–C(O) bond. Huang et al. [83] used 1,3-diketones as starting compounds for the preparation of 1,2-diketones 131. Selective cleavage of the C–C bond in β-diketones was accomplished in the presence of FeCl3 as catalyst and tert-butyl nitrite as oxidant. The formation of intermediates A–C was promoted by t-BuONO without participation of FeCl3, while the latter coordinates to the C=O group in C, yielding intermediate D which undergoes Wagner– Meerwein rearrangement into E, and the subsequent eliminatio n of C=O y ields 1,2 - diketo ne 1 3 1

(Scheme 75). 1,2-Diketones 132 were readily obtained with high yields by oxidative cleavage of β-diketones with Oxone (2 KHSO 5 · KHSO 4 · K 2 SO 4 )–AlCl 3 in aqueous medium at room temperature; the reaction time ranged from 5 min to 1.5 h [84] (Scheme 76). β-Diketones were also considered to be initial compounds for the synthesis of α-keto esters that constitute important fragments of biologically active molecules [85]. Copper(I)-catalyzed aerobic oxidative esterification involved activation and dissociation of the C–C(O) bond in 1,3-diarylpropane-1,3-diones [Ar = Ph, 4-Me(MeO, t-Bu, F, Cl, Br, CF3)C6H4, thiophen-3yl, naphthalen-1-yl, naphthalen-2-yl; R = PhCH2CH2, 4-Br(MeO)C 6 H 4 CH 2 CH 2 , 4-H(Me, F, Cl, Br, CN) C 6 H 4 CH 2 , 2-(naphthalen-1-yl)ethyl, EtC≡CCH 2, Br(Cl)CH2CH2, Ph2CH, Me, Et, indan-1-yl]. Total of 35 esters 133 were isolated, the yields of 31 of them being 50–92% (Scheme 77). Under analogous condi-



787

Scheme 75. O

O

FeCl3 (20 mol %) t-BuONO (5 equiv), 30°C

O

(Het)Ar

(Het)Ar'

(Het)Ar

(Het)Ar'

O 131

Ar, Ar′ = Ph, 4-Me(MeO, F, Cl, Br, I)C6H4, 2-Me(Br)C6H4, naphthalen-1-yl, naphthalen-2-yl; Ht, Ht′ = furan-2-yl, thiophen-2-yl, pyrrol-2-yl (20 examples, 45–84%). O

O

O

Ph

O

O

t-BuONO

O

O

O

t-BuONO Ph

Ph

Ph N

Ph

Ph –

OH

O

N

A

Ph

N

O

B

O CO + Ph

Ph

–N2O

O

FeCl3

Ph

C

O

O

Ph

Ph

O

O C

131

FeCl3 O

FeCl3

O

Ph

O Ph

Ph

O

O Ph O

D

E

Scheme 76. [Al3+] O

O

R1

O

Oxone, [Al3+] R2

O

R1

O

Oxone, [Al3+] R2

O

O

[Al3+]

R1

R2

OH

R1

R2

O

O

[Al3+] O

[Al3+] R

O

O R

R2

1

1

2

1

1

R2

–CO, –[Al3+] O

O

132 (90–98%)

2

1

R = Ph, R = Me, Ph; R = R = Me, Ph; R = Ph(CH2)2, R2 = Me; R1R2 = (CH2)3.

Scheme 77. O

O +

Ar

ROH

CuBr (10 mol %) pyridine (50 mol %) PhMe, O2 (1 atm), 90°C

O

O OR +

Ar

Ar

Ar

O 133

OR

By-product

O2/pyridine

O

[CuII]

O

Ar

Ar

O

[CuII] · OH

O

O

Ar [Base + H]+

Base

[CuI]

[CuI] + H2O

O

Ar RO O

Ar

Ar Ar [Base + H]

+

Base

O

O2, [Cu]

Ar

OR

OH OR

RO OH

O

Ar RO O OH

C–C bond cleavage

Ar O


O

[O]

H 2O

133

788

SHOKOVA et al. Scheme 78. Me O O

O

Me

+ Ph

Ph

H

Me

H HO

Me O

O

H

H

Ph

H

H

O

H

H

O

33%

Scheme 79. Me

O

S

O S

O

DBSA, H2O, Δ

+ R1

Me

R1

S

R2 S

R2

134

R1 = H, R2 = Bu, Ph, 2-HOC6H4, 4-Me(MeO, HO, Cl, O2N, Me2N)C6H4, thiophen-2-yl, 1,3-benzodioxol-5-yl; R1 = Me, R2 = Bu, Ph, 4-HO(Cl, O2N)C6H4; R1R2 = (CH2)n, n = 5, 6. O CHO

Me

+

S

134, DBSA, H2O, Δ

Ph S

91%

O O

Me

+

S

134, DBSA, H2O, Δ

S 90%

Ph

CHO

O

S

Ph

134, DBSA, H2O, Δ

O

O

S

O 94%

Me

O

S

H O

S

Me

DBSA

S

Deacylation

O S

S

H+

S

Me

HS

Me S

H2 O

R

1

R

2

S

O S

Me

O

O –H+

O

H O Me

R1

S

R2 S

O

tions, the corresponding α-keto ester was synthesized from androsterone and 1,3-diphenylpropane-1,3-dione (Scheme 78). Thioacetalization of aldehydes and ketones in aqueous medium was accomplished using 3-(1,3-dithian-2ylidene)pentane-2,4-dione (134) in the presence of 4 - d o d e c y l b e n z e n e s u l f o n i c a c i d ( D B S A ) [8 6 ] (Scheme 79). Thioacetalization of mixtures of alde-

hydes with ketones under analogous conditions gave only one product. The mechanism proposed in [86] is shown in Scheme 80. Accessibility of the reagent, high yields, easy isolation, and chemoselectivity of the reaction make this procedure promising. 3.1.4. Transformations of β-diketones involving the carbonyl groups. Acetylacetone was converted into 4-amino(methylamino)pent-3-en-2-ones by reac-


1,3-DIKETONES. SYNTHESIS AND PROPERTIES Scheme 80. O Me

OH

O

25% Aq. RNH 2, PhMe Me

NHR

Me

Me

R = H (60%), Me (80%).

tion with ammonia and methylamine [87] (Scheme 80). One-pot reaction of β-diketones with para-substituted anilines, catalyzed by silica ferric hydrogen sulfate, under solvent-free conditions at room temperature gave 80–95% of β-enaminones 135 [88]. As proposed in [88], the α-CH2 group participates in the stabilization of intermediate A and formation of intermediate B which is converted into the final product with regeneration of the catalyst (Scheme 81). According to the B3LYP/6-31G** calculations, enaminoketone tautomer of 135 is more stable than iminoenol both in the gas phase and in solution (CHCl 3 , MeCN, EtOH, cyclohexane, H2O; Scheme 82). Acetylacetone, benzoylacetone, and dibenzoylmethane were reported [89] to readily form enol trifluoromethanesulfonates on

789

treatment with lithium trifluoromethanesulfonate in the presence of bases [NEt3, EtN(i-Pr)2] in CH2Cl2 at 0°C. The reaction is stereoselective: the Z/E isomer ratio is 99 : 1 (yield 41–87%; Scheme 83). 1,3-Bis-silyl ethers 136a and 136b derived from acetylacetone and benzoylacetone, respectively, reacted with benzoyl chloride to give 2-benzoyl derivatives; the reaction of 136a with isophthaloyl dichloride afforded the corresponding bis-triketone [90] (Scheme 84). Unsymmetrical β-diketones can be converted into 1,4-diketones 137 and trans-1,2-disubstituted cyclopropanols 138a and 138b according to one-pot procedure utilizing organozinc compounds [91]. No diastereoisomer 138b was obtained when R2 = Me, R 1 = 4-MeOC 6 H 4 , thiophen-2-yl; R 2 = Pr, R 1 = 4-MeOC 6 H 4 . The reaction mechanism is shown in Scheme 85. 1-Alkyl(aryl)-3-(fluoroalkyl)propane-1,2,3-trione 2-arylhydrazones 139 possess two nonequivalent electrophilic centers, carbonyl groups linked to fluorinated

Scheme 81. R3

O

NH2

O

R1

R2

O

Fe(HSO4)3/SiO2, 20°C

+

HN

R1

R3

R2 135

R1 = R2 = Me; R1 = Ph, R2 = Me; R1R2 = CH2C(Me)2CH2, (CH2)3; R3 = H, Me, MeO, Cl (16 examples, 80–95%). R3

R3 NH2 1

R

R

2

R

R3 N

1

H

R

2

R O

O

OH

N

SiO2

R3

O

1

2

O

R OH

H

[Fe]+

[Fe]

H

–H2O

[Fe]

SiO2

N

H

Me

Ph

O Me

N

H

O

Me

Me

Enamine Enol 135 (R1 = R2 = Me, R3 = H)

Scheme 83. O R1

(1) LiOTf, B–, CH2Cl2 (2) Tf2O

O R2

O R1

R1 = Ph, R2 = Me; R1 = R2 = Me, Ph. RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 6 2015

R1

R2

SiO2

Scheme 82. Ph

O

[Fe]

SiO2 B

A

NH

OTf R2

790

SHOKOVA et al. Scheme 84.

O

H

(1) PhCOCl, CH2Cl2 –78 to 20°C (2) NaHCO3, H2O

O

Ph

R

Me3SiO

OSiMe3

H2C

(1) m-C6H4(COCl)2 CH2Cl2, –78 to 20°C (2) NaHCO3, H2O

R

H

O

H

O

O Me Me

R = Me Me

O Me R = Me (28%), Ph (36%)

O

O

136a, 136b

O

Me

40% (100% enol)

Scheme 85. O CF3COOZnCH2I (2.3 equiv), CH2Cl2 O

R2

R1 O

O

R1

137 R2

Et2Zn (4.0 equiv), TFA (2.0 equiv) CH2I2 (4.0 equiv), CH2Cl2

O

R2

HO

HO +

R

R2

1

O

R1 138a

138b

R1 = Me, Et, Ph, Ph(CH2)2, 4-MeOC6H4, 4-ClC6H4, thiophen-2-yl; R2 = Me, Et, Pr, Ph; 137, 16 examples (44–85%); 138a, 13 examples (60-94% for 8 compounds); 138b, 6 examples (12–47%).

O

O

R1

X Zn

O

XZnCH2I R2

X Zn O

R1

R2

+

ZnX

O

O R1

R2

O R

R1

O

O

2

R

R1

O

2

H+

R2

R1

OZnX

O

Scheme 86. Ar a

N

N

N

RF

H O

O

NH

R O

+

N

OH

RF

Ar

Ar N

RF

–H2O

NHMe

N O

MeNH2

R

b

139

N HO RF

Me

R 140 R

Ar N

H

H

RF > C3

O

–[RFH]

Ar

N H

N

O

O

N

NHMe R

H

Me 141

R = Me, Ph, Bu, t-Bu; RF = CF3, HCF2CF2, C3F7, C4F9, HCF2(CF2)3; 140, 7 examples; 141, 4 examples.

Scheme 87. N

Ar

Ar

Ar

N

N

N

RF

N O

Dissolution

H Me

R Z-B

N O

N RF

140

H

R Z-A

N Me

R

H O

O

N H Me 141 (C)



791

azo–hydrazone rearrangements. Amides 141 prefer hydrazonoketoamide structure C (Scheme 87). A multistep synthesis of analytical reagent 142 containing a β-dicarbonyl fragment was developed by Magano et al. [93]. The required β-diketone with a 4-nitrophenyl substituent was prepared from acetylacetone or tert-butyl acetoacetate (Scheme 88). Following the optimized procedure [94] (Scheme 89), compound 142 was synthesized on a multigram scale with high purity (>99%). It is used for the determination of the number of LysH93 active sites available for conjugation on a catalytic aldolase monoclonal antibody (mAb). The interaction of 142 with mAb yields enamine absorbing at λ 316 nm, and its amount can be measured by UV/Vis spectroscopy (Scheme 90). 3.1.5. Miscellaneous. β-Diketones were brought into catalytic reaction with acetylene derivatives to obtain aromatic compounds [95]. The reaction of acetylacetone with phenylacetylene in the presence of

and nonfluorinated substituents. Compounds 139 with a short fluoroalkyl group (C1 or C2) react with MeNH2 on heating in ethanol to form monocondensation products, 2-aryldiazenyl-1,3-enaminoketones 140 [92]. If the fluoroalkyl group in 139 is C3 or longer, mixtures of compounds 140 (path a) and N-methyl-2-arylhydrazono-3-oxobutanamides 141 (path b) are obtained. Path b is likely to include amine addition to the fluorinated acyl carbonyl and subsequent haloform cleavage (Scheme 86). Compounds 140 and 141 are complex tautomeric systems capable of undergoing azo–hydrazone, keto– enol, imino–enamine, hydrazono–ketoamide, and other tautomeric transformations, as well as of Z/E-isomerism with respect to the C=C and C=N bonds). Compound 140 in CHCl3 exists as one isomer of the hydrazonoiminoketone tautomer (Z-A), and in crystal, as azaenaminoketone tautomer Z-B [92]. Presumably, its dissolution is accompanied by enamino–imine and

Scheme 88. O

(1) LDA (2 equiv), –78°C, THF/HMPA (2) 4-O2NC6H4CH2Br (3) Chromatography

OH

Me

O

O Me

30–40%

Me

O2N

H2, 10% Pd/C, THF, 20°C Me3SiOCH2CH2OSiMe3 Me3SiOTf, CH2Cl2 –5°C, 6 h

O

O

O O

71%

O

O

O2N

Me

HO

O

(1) H2NCH2CH2NMe3 Cl–, HCl HATU, EtN(Pr-i)2, DMF, 20°C, 1 h (2) Lyophilization

28% (2 steps)

O ( )3

O N H

Me

O Cl–

O

Me3N

(1) TFA, H2O, 20°C (2) Reversed-phase chromatography (2) Lyophilization

O

77%

O

O

O

N H

O N H

Me O

Cl

–

Me3N

O N H

N H 142

Me2N HATU =

NMe2

N

PF6 N

N O


O O Me

O

O

O

792


OH

(1) 1 M (Me3Si)2NLi/THF, 2-MeTHF, –20°C (2) 4-O2NC6H4(CH2)2C(O)Me, 0–20°C

O

O Me

OBu-t

Me

O

NO2

O

O

TsOH · H2O, PhMe, 65–80°C

OBu-t

HOCH2CH2OH, TsOH 4-Å molecular sieves MeC(OMe)3, Δ

Me

58%

O

O O

70% NO2

O O O H2 (0.68 atm), 10% Pd/C THF, 20–25°C

O O

O

HO

O

44%

Me

N H

O

Cl–

O

Me3N

O

(1) 4 M HCl (2) 2-MeTHF, extraction (3) NaHCO3 (solid) (4) 2-MeTHF, extraction (5) normal-phase chromatography

O

O

O

O

O

64%

H2NCH2CH2NH3 Cl–, HCl T3P, Et3N, MeCN, 25°C

Me

NO2

O N H

Me

142

O

T3P is glyceraldehyde 3-phosphate.

Scheme 90. O Cl

–

O

Me3N

O

O

O Me +

N H

N H

H 2N

NH O

142

O

Me N H Cl

–

Me3N

O

O

O

N H

NH O

N H

Scheme 91. Me O Me

O

+ Ph

CH

MnBr(CO)5 (5 mol %) PhMe–H2O (1 : 1), 80°C

O

Ph

Me Me

Me

+

+

Ph 20%

MnBr(CO) 5 gave a mixture of three compounds (Scheme 91). When the reaction was carried out in toluene at 50°C with addition of 4-Å molecular sieves (115 wt % of Mn), tetrasubstituted benzene was

OH

Ph

Ph 66%

O Me

Me Ph

O

Traces

formed as the major product (69%), while the yield of the other two products decreased to 5 and 7%, respectively. Polysubstituted benzenes with different combinations of methyl and aryl substituents were also


1,3-DIKETONES. SYNTHESIS AND PROPERTIES obtained by reaction of 3-methylpentane-2,4-dione and 2-methyl-1-phenylbutane-1,3-dione with 4-methoxyphenyl- and diphenylacetylenes in the presence of [ReBr(CO)3(thf)3]. A probable reaction mechanism was discussed [95]. Nontoxic moisture stable iron(III) 1,3-diketonates catalyzed transesterification of esters with alcohols [96]. The catalytic activity of Fe(acac)3, Fe(acac)2, Fe(tmhd)3 (tmdh is 2,2,6,6-tetramethylheptane-3,5dione), Fe(dbm) 3 (dbm is dibenzoylmethane), and Fe(hfacac)3 (hfacac is 1,1,1,5,5,5-hexafluoroacetylacetone). More than twenty alcohols were reacted with more than twenty structurally diverse esters. The optimal conditions were as follows: ester-to-alcohol ratio 1 : 1, Fe(acac) (5 mol %), Na2CO3 (5 mol%), heptane (reflux). In most cases, the yields of the transesterification products exceeded 90%. The reaction mechanism [96] is illustrated by Scheme 92.

O

R

+ R2OH

1

R1 = Me, R2 = Me, i-Pr, CF3, Ph; R1 = Me, R2 = CF3, Ph; R1 = CF3, R2 = Ph, furan-2-yl, thiophen-2-yl. O Me

O

R = Et, Cl. O

R'

OR

OR

2

O RO R'

O H O OMe

O

O

O Fe(L)2

O R

CF3

R

OMe

R'

O

(L)2Fe O MeO

R R

Me

( )n O

R = H, Ph.

n = 1, 2.

O

Me

Me

O

O

O

143

HO

R Fe(L)2

O

O

144a

Me

Me

Fe(L)2 O

R'

R

O H

L = acac, dbm, hfacac, tmdh.

3.2. Biological Activity of β-diketones The cytotoxicity of twenty structurally diverse β-diketones and one ketoaldehyde 143 was studied against normal human oral cells, gingival fibroplast (HGF), and human oral squamous cell carcinoma (HSC-2) [97]. Some substrates were tested on HSC-3, HSG, HL-60, and normal HPC and HPLF cells. The

F3C O 144b

O

MeO

ROH

R (L)2Fe

n = 1, R = H, Et; n = 2, R= H

O

O

O ( )n

R

O

1

R (L)2Fe

O

Me

FeL3

MeOH + O

R

O

CF3

R

H

R2

CHO

Fe(acac)3 (5 mol %) Na2CO3 (5 mol %) C7H16, Δ

OMe(Et)

L

O

R1

Scheme 92. O

793

OMe

Curcumin

OH

cells were treated for 24 h. Curcumin, a dietary pigment from Curcuma longa L., was used as reference. Curcumin exhibits various biological activities such as antioxidant, antiangiogenesis, and anticancer. The cytotoxicity of curcumin [CC50 = 23.6 μg/mL with respect to HSC-2; tumor specific cytotoxicity SI = CC50(HSG)/CC50(HSC-2) = 1.7] is attributed to the presence of a β-dicarbonyl fragment in its molecule. The activity of camphor derivatives 144a and 144b was comparable with that of curcumin (CC 50 = 21.7 μg/mL, SI = 4.3 for 144b and CC50 = 29.7 μg/mL, SI = 3.0 for 144a). Ketoaldehyde 143 considerably exceeded curcumin in cytotoxicity (CC50 = 7.8 μg/mL, SI = 5.4), though only tyrosine kinase inhibition was previously noted for this compound. The antimicrobial activity of curcumin analogs, 5-heteroaryl-1-phenylpent-4-ene-1,3-diones 145 and their copper(II) and nickel(II) complexes was studied with respect to Staphylococus aureus, Bacillus subtilis, Escherichia coli, and Pseudomonas aeruginosa; in addition, their fungicidal effect on Candida albicans


794

SHOKOVA et al. OH

and Aspergillus niger was evaluated [80]. Ciprofloxacin and Fluconazole were used as controls. All the examined compounds revealed significant activity against the above microorganisms, and diketone 145b containing a pyrrole substituent and its copper(II) complex turned out to be highly active. O

O

O OEt

R1

OEt R2

1

147a–147e

R = R = H (a); R = H, R2 = Me (b), Cl (c), Br (d); R1 = Me, R2 = Cl (e).

O

2

OEt

1

R

O

O

145a–145c

R = 1H-imidazol-2-yl (a), 1H-pyrrol-2-yl (b), thiophen-2-yl (c).

Ferrari et al. [82] studied the relations between physicochemical properties of curcumin analogs 129 and 130 (acidity, lipophilicity, kinetic stability, and free radical scavenging activity) and their cytotoxicity against different tumorigenic cell lines (human ovarian carcinoma cells 2008, A2780, C13*, and A2780/CP and human colon carcinoma cells HCT116 and LoVo). Most esters 129 showed lower IC50 values than curcumin and exhibited selectivity for HCT116 and LoVo. The highest activity was observed after 24-h exposure at the micromolar level at a concentration of ~1/3 of the curcumin concentration. The most active were compounds 129 (R1 = OMe, R2 = H, OH, OAc). 1-(2-Hydroxyphenyl)-3-phenylpropane-1,3-diones 146 were tested for antimicrobial activity against gram-negative (E. coli) and gram-positive bacteria (S. aureus, B. subtilis) and fungicidal activity against Aspergillus niger and Fusarium oxysporum [98]. OH

R'

R O

O

OH

HO

OH 148

Ciprofloxacin [99]. Their fungicidal activity against Aspergillus niger and Trichoderma decreased in the series 147a > 147b > 147d > 147e > 147c. Unsymmetrical β-diketone 148 exhibited high antibacterial activity against S. aureus, E. coli, and P. vulgaris; the activity of its copper(II) complex was lower [100]. However, the activity of the latter against B. subtilis was much higher than that of the free ligand. 3.3. Physicochemical Properties of β-Diketones Some physicochemical properties of bis-1,3-diketones 149a and 149b and unsymmetrical 1,3-diarylpropane-1,3-diones 150a and 150b having a methoxycarbonyl group in one aromatic ring were studied in [11]. Their electronic absorption spectra in anhydrous ethanol, acetonitrile, and heptane were examined. Analysis of the 1H NMR spectra in DMSO-d6, acetone-d6, CDCl3, and benzene-d6 showed that keto–enol equilibrium is strongly displaced toward the enol tautomer, while the diketone fraction slightly increased with rise in solvent polarity. All the examined diketones revealed strong absorption in the region λ 320– O

R'

O

O

O

R O

OH

149a, 149b

146

R = H, Cl; R′ = OMe, OEt, Br (6 compounds).

All compounds showed a high activity comparable in many cases with that of Streptomycin. β-Diketones 147a–147e were weakly or moderately active against E. coli and Pseudomonas aeruginosa as compared to

COOMe

O

O 150a, 150b

149, 150, para isomer (a), meta isomer (b).



795

500 nm with a high quantum yield. The absorption and emission maxima of compounds 152 containing a naphthalene fragment (R1 = 6-methoxynaphthalen-2yl, R2 = Ph, 4-t-BuC6H4) are appreciably red-shifted as compared to their benzene analogs (R1 = 4-MeC6H4, R 2 = F, Cl; R 1 = PhOCH 2 C 6 H 4 , R 2 = 4-t-BuC 6 H 4 ). Complexes 152 may be promising for use in fluorescent and electroluminescent materials.

400 nm due to the enol form, regardless of the solvent. Strong bathochromic and hyperchromic effects were observed for aromatic bis-1,3-diketones 149a and 149b compared to dibenzoylmethane. These effects were especially pronounced for tetraketone 149a in which the dicarbonyl fragments are conjugated through the aromatic ring. Compound 149b was considered to be promising for use as sunscreen in cosmetics. Kozlov et al. [101] studied luminescence spectral properties of hydrobenzo[b]phenanthrolin-8-one derivatives 151 in ethanol at 293 and 77 K. The compounds are characterized by a high oscillator strength f for the allowed electron transitions Sn ← S0 (n = 1–3). The authors believed it reasonable to study their luminescent properties in rigid polymeric matrices at room temperature with a view to design of large flexible fine-film panels for photovoltaic elements, optical light filters, and electroluminescent displays. Boron fluoride diaroylmethane complexes 152 [10] showed strong fluorescence in the region λ 400–

F O

F B

O

R1

R2 152

A mixture of 1-tert-butyl-3-(4-dodecylphenyl)octane-1,3-dione with trioctylphosphine oxide showed a synergistic effect in the extraction of zinc from an ammonia solution of ammonium sulfate under conditions close to industrial production; the concentration of zinc in the aqueous phase was 15g/L, and the overall ammonia concentration was 3 M [102].

Scheme 93. F O

F B

F R4

O Me

Me

O

+

CHO

R3 R

OH

2

Me

R1

O

R3 R2

155a–155d

R1

O

O

R3

O 156a–156d F O

R4

F B

R1

O

R

Ar

O

R2

Me

4-Me2NC6H4CHO Ac2O

R4

154a–154d

(1) Na2CO3, EtOH, H2O (2) HCl

O

R1

O

153

O

Ac2O or AcOH H2SO4

F B

R3

O

O

2

(1) Na2CO3, EtOH H2 O (2) HCl

OH

R1

O

R2

Ar

O

R4

R3

O R4

157a, 157b, 157d

R1 = R2 = R4 = H, R3 = Me2N (a), MeO (b); R1 = H, R2 = R3 = R4 = MeO (c); R1 = MeO, R2 = R3 = H, R4 = Br (d); Ar = 4-Me2NC6H4. OH

Me

O

O

OH

R

O 158

Me

O

Me

O

O

OH

Me

O

N

S

Me NMe2

159


Me

O

O 160

796

SHOKOVA et al. and 4-methoxycinnamalde-hydes gave compounds 158, and unsaturated ketones 159 and 160 were obtained from heterocyclic aldehydes.

Manaev et al. [103] described the synthesis of dehydroacetic acid boron difluoride complex 153 and its reactions with various aromatic (154a–154d) and heterocyclic aldehydes (crotonization involving the acetyl group). The reactions were carried out at 60– 90°C in acetic anhydride and/or acetic acid, and concentrated sulfuric acid was added in some cases. Complexes 155 thus obtained were hydrolyzed to aldehydes 156a–156d, while the condensation of 155a, 155b, and 155d with 4-(dimethylamino)benzaldehyde afforded disubstituted hydroxypyran-2-ones 157 (Scheme 93). Complexes 155a–155d are deeply colored and fluorescing. Analogous reactions with 4-dimethylamino-

4. β-DIKETONES IN THE SYNTHESIS OF HETEROCYCLIC SYSTEMS 4.1. Pyrazoles and Polycyclic Systems with Pyrazole Fragments Reactions of structurally diverse 1,3-diketones with hydrazine hydrate and substituted hydrazines lead to the formation of pyrazoles (recent data are collected in Tables 1–3). Other syntheses of pyrazoles from 1,3-di-

Table 1. Reactions of β-diketones with hydrazine and its derivativesa Initial hydrazine derivative, reaction conditions

β-Diketone O

Solid H3N+NHCOO–, no solvent, 70-90°C

R2 R O

NH2NH2

R

R

O

Me

R

N

N

N CF3

N

3 examples, 76–94%

0[53]

Ph

Ph

N

R

+

N

CF3

CF3

35%

35%

O

4-RC6H4

O

O Ph

R'

Fc

R1 = R2 = Ph, Me; R1 = Me, R2 = Ph

Ph

0[53]

N

Ph

CF3

[107]

Et 59–98%

79–89%

3 examples

R

0[47]

R2

Fc R2

N 63%

N

Ar

R′ = CF3, CF2H, Me; Ar = Ph, 4-Br(MeO, O2N)C6H4

R1

N

Ph

N

Et

O

CF3

4-RC6H4 N

CF3

Me

Me

N Me

R'

O

[106]

Me

Ar

R3NHNH2 R = H, Ph, 4-MeOC6H4 A: EtOH, reflux B: PhMe, MW, 80–100°C C: solvent-free, SiO2, MW, 80–100°C


Me

Me

Me

[105]

NH R'

Me

[104]


57–72%

F3C

O

Ph

O

2

Reference

CF3 8 examples,

Me

O

4-RC6H4NHNH2; R = H2NSO2, H, Br

3

R = furan-2-yl, Ph, 4-t-BuC6H4; R' R′ = Ph, naphthalen- R 2-yl, 6-methoxynaphthalen-2-yl, 4-FC6H4

O

CF3

RNHNH2; R = Me, Ph

NH

R = 4-MeO(F, NO2, HN N EtO)C6H4, pyridinCF3 4-yl, naphthalen-2- R 237 yl, 6-methoxynaphthalen-2-yl

R

O

RNHNH2; R = H, Me, Ph

N

R1

3

O

O

NH2NH2

R1 = R2 = Ph, Me, Et; R3 = H, Me

O

R1

Product

1

N

N

5 examples, 88–98% (B)

R3



797

Table 1 (Contd.) Initial hydrazine derivative, reaction conditions

β-Diketone Ph

PhNHNH2 AcOH, EtOH, 90°C

Product Ph

Ph

Ph

O

N

N

O O

Ph Ph

[66]

N

N

O

Reference

Ph Ph

Ph

Ph

74%

1

R NHNH2 R1 = Ph, 4-ClC6H4, acetyl, benzoyl, furan-2-ylcarbonyl, thiophen-2ylcarbonyl. A: H2SO4/polystyrene, H2O, no solvent, 20°C B: no catalyst, MW, 120°C

O

R2

O

Me

R2 = H, Cl, Et

Me R

Me

Me

N

2


N

[108, 109]

R1

One-pot syntheses O

NH2NH2: (1) SmCl3, Et3N, toluene, 20°C (2) NH2NH2

O

O

Me

EtO + RC6H4COCl

Me

OEt

RC6H4

N H

N

R = H, 4-Cl, 4-MeO, 3-O2N 72–81%

[59]

O R

O

COOH

R

R'

R = H, Br; R′ = Ph(CH2)2, 4-BrC6H4(CH2)2 O

O

N

O

AcOH

NH2NH2: (1) TFA, TfOH CH2Cl2, 20°C (2) NH2NH2

NH

R

Me

O Ph(CH2)2COOH

O RCOOH

R'

[23, 24]

R = H, R′ = Ph(CH2)2 (69%) R = Br, R′ = 4-BrC6H4(CH2)2 (72%) R = H, R′ = Me (76%) R = H, R′ = 1-AdCH2 (62%)

O R

R = 1-AdCH2 a

The reactions given in Tables 1 and 2 were carried out in ethanol at 20–80°C unless otherwise stated.

Table 2. Reactions of β-diketone hydrazones and enamino ketoesters with hydrazine and its derivatives Initial hydrazine derivative, reaction conditions RNHNH2, R = Ph, PhCO, 2,4-(O2N)2C6H3, H2NC(S), H2C=CHCH2NHC(S) R1NHNH2, R1 = Me, Ph, HO(CH2)2, EtOH, reflux, BF3 · Et2O

β-Diketone F 3C

R'

N

O

Het N H RF

N

R

N

[110, 111]

Ph

R

N

N

R′ = Me, Cl

Ph

10 examples, 40–70% R2

2

O

Reference

N

R'

O

N

Product

RF = H(CF2)2, HCF2, CF3

Het

O


N

N N RF

N

R1


[78]

798

SHOKOVA et al.

Table 2. (Contd.) Initial hydrazine derivative, reaction conditions

β-Diketone

Product

Reference

Het(Ar)

Het(Ar) N

HN Y

N

O

N

O H

OEt

R

EtO N H

O

R = Ph, 4-MeO(Cl, F, O2N)C6H4, thiophen-2-yl, 1-benzofuran-2-yl, CCl3, CF3

[112]

O

R

O

Me2N

R cis-azo

O

O

R

H2NNHCOOMe t-BuNHNH2 · HCl

CF3

N

Ar = Ph, R = R′ = Me Ar = 4-MeC6H4, R = Me, Ph, R′ = CF3 Het = 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl, R = R′ = Me Het = 4-ethoxycarbonyl-1H-pyrazol-3-yl, R = Me, R′ = CF3 Het = 1,2,4-triazol-3-yl, R = Me, Ph, R′ = Ph

R'

N

CF3 N

N N R trans-azo

O

O

Ar(Het)NHNH2

N

F3C

R' = CF3

CF3

R'

N

Het(Ar)

N

R'

F3C

O

N

NH

EtO

N

N O

R ≠ CCl3, CF3 7 examples, 73–94%

N

[113]

Bu-t


Table 3. β-Diketones in the synthesis of polycyclic systems containing pyrazole fragments Initial compound, reaction conditions

β-Diketone

Me

O

NH2 N

DMFDMA, DMF, MW, 150°C

Me

R2

O

NH

DMFDMA,a DMF, MW, 150°C N

O

R = Me, H R3

O

R3

R2

R2

Me N

R2

NH2

O

O

N

R1 = Me, H, 4-MeC6H4| R2 = H, CN, Ph, 2-MeOC6H4, 4-ClC6H4, 4-MeOC6H4 TFA, EtOH, 20°C

n = 1, 2 ( )n

R3

R3

O

Me

R2 1

N

NMe2 Me

NH

O

N

NH2

HN

[114] N

R1

DMF, MW, 150°C

R

N

N

O

Me

R3

3

N

N

R1

O NH2

N

R3

N

Me

R1

Reference

R2

NH

a

Ph

Product

Me

R1

N N A

N R1 N

N

( )n

( )n Me

B

[115]

15 examples, 74–90% A/B: 83 : 17 to 100 : 0 (n = 1), 40 : 60 to 58 : 42 (n = 2)



799

Table 3. (Contd.) Initial compound, reaction conditions

β-Diketone

Product R1 = CF3, X = 4-MeC6H4, 4-MeOC6H4; R1 = Me, X = 1,5-dimethyl-3-oxo-

X +

N

–

X–N ≡N Cl X = Ar, 1,5-dimethyl-3-oxo-2phenyl-2,3-dihydro-1H-pyrazol-4yl, 4-ethoxycarbonyl-1H-pyrazol3-yl, 1,2,4-triazol-3-yl H2O, EtOH, NaOAc

R1

F3C H

O

O

Y

F3C O

N

F3C

NH2

N

F 3C NH2

N

N N

N

S

O

F3C

R1 = Me, Ph,

N

NH2 N

R2 4-ClC6H4; R2 = H, Ph

NH

O

MW, no solvent S N

N

CF3

Pyridine, MW (300 W) R

N

O

S

N

NH

Pyridine, MW (5 min)

N

S O

N

R1 (82%) R2

R1 = Me, R2 = Ph (86%)

83%

N S

R1 = Ph, R2 = H

N

CF3

N2 HSO4

Pyridine, MW (5 min)

N

N

N

N N H

91% N

F3C

O

[116]

CF3

N2 Cl– N

R1

N

1

R2

4 examples, 100%

N

S

O

N2 NO3

N H

91%

O

R2 R1

83%

O

CH(OEt)3, MW (300 W)

a

N N

N N H

H

S

CH(OEt)3, MW (300 W) N

Y = CCO2Et, R1 = CF3, Me, Ph; Y = N, R1 = Ph O 5 examples, 59–68%

N N

[112]

R1

N

HN

N H

2-phenyl-2,3-dihydro1H-pyrazol-4-yl, Ph 5 examples, 37–57%

R1 O

O

NH

F3C

Reference

N

N

N

DMFDMA stands for dimethylformamide dimethyl acetal [dimethoxy-N,N-dimethylmethanamine, (MeO)2CNMe2]

ketones are few in number. In particular, enol trifluoromethanesulfonates derived from acetylacetone and benzoylacetone (161) reacted with ethyl diazoacetate in DMF in the presence of palladium catalyst and N-methylmorpholine to produce 3,4,5-substituted pyrazoles 162 [117] (Scheme 94). Analogous reaction

of 3-substituted (Z)-4-oxopent-2-en-2-yl trifluoromethanesulfonates gave trisubstituted pyrazoles 163 instead of expected tetrasubstituted derivatives. This was rationalized by the migration of the C-acyl group to the nitrogen atom and subsequent hydrolysis on treatment of the reaction mixture with K2CO3–H2O at


800

SHOKOVA et al. Scheme 94. OTf Me

O R

+ N 2

O

Pd(PPh3)4 (5 mol %) NMM ( 2 equiv), DMF, 20°C

O

N2

EtO

60°C

O

HN

O EtO

OEt Me

161

N

O

Me

R

R

162

R = Me (81%), Ph (73%).

Scheme 95. O

O

OTf Me

O N

O Me

+ N 2

EtO

OEt

Me

R

N

O N

K2CO3, H2O Me

EtO

R

Me 163

NH R

R = PhCH2 (74%), Ph (87%), cyclohexylmethyl (72%), thiophen-2-yl (83%).

165 was formed even at room temperature. The reaction with unsymmetrical diketone 166a was regioselective, and the fluoroalkyl substituent (R2 = CHF2CF2) occupied the 4-position in the pyrimidine ring. Heating of the product in boiling toluene in the presence of TsOH resulted in dehydration (Scheme 98).

room temperature (Scheme 95). 5-Aryl(heteroaryl)-3trifluoromethyl-1H-pyrazoles 237 were tested for antibacterial and antifungal activity in vitro against E.coli, S.aureus, P. oryzae, and R.solani [105] (Table 1). All these compounds showed some activity, and the best results were observed for 5-(4-fluorophenyl) and 5-(pyridin-4-yl) derivatives.

Knoevenagel condensation of acetylacetone with benzaldehyde and anisaldehyde in the system [Bmim][BF4]–Pip][OAc] afforded the corresponding phenylmethylidene derivatives [120] (Scheme 99). The catalytic system [Bmim] [BF4]–Pip][OAc] enabled one-pot synthesis of dihydropyrimidine derivative 167 from 3-benzylidenepentane-2,4-dione via reaction with O-methylisourea, N-ethoxycarbonylation with ethyl chloroacetate, and O-demethylation (Scheme 100).

4.2. Substituted Pyrimidines and Their Derivatives 2,3-Dihydropyrimidin-2(1H)-ones(thiones) 164 were synthesized by the Biginelli reaction of acetylacetone and dimedone with aldehydes and urea (thiourea), catalyzed by alkylammonium or alkylimidazolium salts under solvent-free conditions [118] (Scheme 96). 5-Aroyl(heteroaroyl)-4-fluoroalkyl-4-hydroxytetrahydropyrimidine-2(1H)-ones(thiones) 165 were isolated in the condensation of fluorinated β-diketones 166a and 166b with aromatic (heteroaromatic) aldehydes and urea (thiourea) in a ionic liquid ([Bmim] [BF4]) in the presence of piperidinium acetate [119] (Scheme 97). Symmetrical diketone 166b was the most reactive, and the corresponding pyrimidine

β-Diketones and β-keto esters were converted into 3,4-dihydropyrimidin-2-(1H)-ones 168 by a modified Biginelli reaction [121] (Scheme 101). One-pot condensation of aromatic aldehyde with urea (thiourea) and 1,3-dicarbonyl compound was carried out in the presence of a new inexpensive catalyst prepared by treatment of bioglycerol with sulfuric acid (the

Scheme 96. O R1

O + R

2

R3CHO

Catalyst (0.6 mol %) 120–125°C

X + H2 N

O R2 R

NH2

R3 NH

1

N H 164

X

R1 = H, R2 = Me; R1R2 = C(Me)2CH2; R3 = Ph, 3-O2NC6H4, 4-O2N(Cl, F)C6H4, thiophen-2-yl; X = O, S (10 examples, 65–89%). Catalyst = Et3N · HBF4, Et3N · HPF6,

Me

N

N

Bu

AlCl4 ,

Me

N

N

Bu

Al2Cl7 .



801

Scheme 97. R3

O O

O +

R1

Catalyst (0.6 mol %) 120–125°C

X

3

R CHO

+

R2

H 2N

R1

NH

HO

NH2

165

166a, 166b 1

2

X

N H

R2

1

2

3

R = Ph, R = HCF2CF2; R = R = CF3, R = Ph, 4-FC6H4, thiophen-2-yl; X = O, S (10 examples; 75–92% for 7 compounds); catalyst = [Bmim][BF4] (1-butyl-3-methylimidazolium tetrafluoroborate) + [Pip][OAc] (piperidinium acetate).

Scheme 98. O

Ph

Ph

O TsOH, PhMe, Δ

NH

HO F2CHCF2

N H

Ph

Ph

O

NH

F2CHCF2

N H

O

Scheme 99. O CHO

O

O

[Bmim][BF4], [Pip][OAc]

+ Me

R

Me

Me

R

O

Me

E/Z 3 : 2, 75–85%

R = H, MeO.

Scheme 100. O Ph

NH2

Me + O

Me

H2N

· [0.5 SO4]–

[Bmim][BF4] (4 equiv) NaHCO3 (4 equiv), 50°C

O

Ph N

Me

OMe

N H

Me

O (1) ClC(O)OEt, pyridine, CH2Cl2, 20°C (2) HCl (0.1 equiv, MeOH, 2°C

O

Ph

Me

N H

NH

+ Me OMe

Me

N

OMe

2:1

O N

Me

Ph

OEt O

167

procedure was not given). The reaction is experimentally simple and fast, compounds 168 are formed with excellent yields, and the catalyst can be recycled at least four times without loss of activity. About 30 pyrimidin-2-one derivatives were synthesized (including polycyclic compounds) in 80–92% yield. In the reaction of benzaldehyde with urea and cyclohexane-1,3dione or dimedone, bicyclic compounds 169 were isolated (yield 80–81%). Fresh pineapple juice (pH 3.7, acidity percentage 53.5%) catalyzed the Biginelli reaction of substituted benzaldehydes with urea and acetylacetone to afford a series of dihydropyrimidines 170 [122]. The reaction was fairly fast at room temperature, and the isolation

procedure was not difficult. The amount of the catalyst was 1 mL per 10 mmol of each reactant (Scheme 102). Acyclic β-diketone 171a was used as starting compound in the synthesis of 5-bromomethyl-, 5-hydroxymethyl-, and 5-formylpyrimidines as precursors to rosuvastatin (172), a hypolipidemic agent reducing the size of atherosclerosis plaques and increasing the blood vessel lumen [123] (Scheme 103). In the reaction with diketone 171b, the cyclization step was catalyzed by cesium carbonate in methyltetrahydrofuran as solvent, which ensured high selectivity of the process. The retro-Claisen reaction product (ethyl 4-fluorophenyl ketone) was formed in a low yield (6%), the conversion of 171b being 99% (Scheme 104).


802

SHOKOVA et al. Scheme 101. HO3S O

X

O

+ R

3

Cl

O

H 2N

R

NH2

1

R

O

Ph

SO3H

MeCN, 75–80°C

+

R3

O

HO3S

R2

NH

NH

2

R1

N H 168

R

X

3

N H

R1

O

169

168, R1 = Me, Ph, Et, CF3, R2 = Me, Ph, Et, OEt, OMe, OCH2Ph; R3 = YC6H4, anthracen-9-yl, naphthalen-2-yl, dibenzo[b,d]furan-?-yl, thiophen-2-yl, 2,2′-bithiophen-5-yl; X = O, S; 169, R1 = R3 = H, Me.

Scheme 102. O O

O

RCHO +

Pineapple juice 20°C, 2–5.5 h

O

+ H2N

NH2

Me

NH

Me

Me

R

N H

Me

O

170

R = H, Ph, 2-Cl(HO, O2N)C6H4, 4-Cl(HO, MeO)C6H4, 3-MeO-4-HOC6H3, furan-2-yl, PhCH=CH (22 examples, 51–93%).

Scheme 103. R O

O

i

Me

R

O

O

R

96%

ii

Me

Me

Me

N

92%

Me

Me

171a

R iv 80%

CH2Br

N

v

Me

Me

100%

Me

N

SO2Me

Me

Me

N

SO2Me

vi

Me

CHO

N

31%

Me

N

SO2Me

Me

N

N

R CH2OH

N

Me

N

91%

Me

N

N H

iii

R

N Me

R Me

Me

Me

N

Me

N

SO2Me

Me

vii 94% 4-FC6H4

OH

O O–

N Me

N

N

SO2Me

Ca2+

Me Me

2

172

R = 4-FC6H4; i: MeI, K2CO3, Me2CO, 20°C, 48 h; ii: N-methylguanidine hydrochloride, Cs2CO3, 2-methyltetrahydrofuran, 70°C, 24 h; iii: MsCl, Et3N, CH2Cl2, –5°C, 11 h; iv: NBS, hν, MeCN, 20°C, 16 h; v: H2O, THF, Δ, 6 h; vi: Ac2O, DMSO, 85°C, 17 h; vii: (1) NaHCO3, NaI, DMSO, 20°C, 68 h; (2) Ac2O, DMSO, 70°C, 7 h.

Scheme 104. O

C6H4F-4

O Me

I

Me 171b

Me

NMe +

· HCl H2N

NH2

70°C, 24 h

N Me

N H

O

Me

Me

+ Me

N 94%

I Me

6%



803

densation of acetylacetone with amines, aldehydes, and nitromethane in ionic liquid ([Hbim] BF 4 ) without a catalyst gave pyrrole derivatives 174 [125] (Scheme 106). A simple procedure for the regioselective synthesis of tetrasubstituted pyrroles 175 and 177 and polysubstituted indoles 176 from 1,3-dicarbonyl compounds (β-keto esters and β-diketones), benzoin derivatives (including furoin), and ammonium acetate

4.3. Substituted Pyrroles and Polycyclic Systems Containing Pyrrole Fragments Polysubstituted pyrroles 173 were synthesized by one-pot four-component reaction of aromatic aldehydes with primary amines, 1,3-diketones (1 : 1.5 : 1), and nitromethane, catalyzed by 10 mol % of FeCl3 [124] (Scheme 105). Analogous four-component con-

Scheme 105. O R1NH2

+

O

R2CHO + R

3

R

+ MeNO2

4

O

H

R

· · N OH NH – O R1

3

R

R

1

NO2

4

R2

O –HNO, –H2O

N OH

N

R3

3

R2 H

R4

R4

O + R2

R

R2

O

R1 · · NH

FeCl3, Δ

R4

N R3 173

OH

R1

R1 = Ph, 4-Me(MeO, F, Cl, Br)C6H4, PhCH2, C6H13, cyclo-C6H11; R2 = Ph, 4-Me(MeO, Cl, O2N)C6H4, 2-Br(O2N)C6H4, 3-BrC6H4, furan-2-yl, thiophen-2-yl; R3 = R4 = Me; R3 = Me, R4 = Ph (19 examples, 46–85%).

Scheme 106. R2

O O R1NH2

+

O

R2CHO +

[HBim] BF4, 20°C, 38–60 min

+ MeNO2 Me

Me

Me

N Me

R1

174 [HBim] BF4 =

H

N

N

Bu

BF4

1

R = cyclopropyl (7 examples), cyclohexyl (4 examples), substituted phenyl (12 examples), MeC≡CCH2 (6 examples); R2 = substituted phenyl, furan-2-yl (70–94%). O

R2 O

Me Me 174

+ R1NH2

N

Me

R1 H

R2 H

Me

R1

O R2

O

Me

[HBim]BF4 –H2O –HNO3

Aromatization

O

+ [HBim]BF4

Me O

MeNO2

OH

O

Me

N Me

NH

R

N

2

O

OH

N

Addition

R1

Cyclization

O

O

R2

H

R2

Me Me

N :

Me

N

OH

NH O

R1


Me

N O R1

OH

804

SHOKOVA et al. Scheme 107. HO

O + R

R3

O

O

3

R

O

R1

R2

+

R2

90°C

NH4OAc

R1

3

N H

R3

175, 176

175, R1 = Me, R2 = Me, Ph (82–90%); 176, R1R2 = (CH2)3, CH2C(Me)2CH2, R3 = H (76–82%). HO

O

O O +

O

O

O

R1

R +

R2

O

2

NH4OAc

O

R1

N H 177 (83–85%)

1

2

R = Me, R = Me, Ph. O

O

O O H

O

+

+ Me

Me

50°C

NH4OAc

OH

Me Me

N H 91%

Ph

Scheme 108. NH HO

O

NH2 O

Ar Ar

O

R1

Ar

R2 –H2O

Ar

Ar

H N

Ar

O

R1 R2

–H2O

R2

Ar Ar

O

O

–H2O O R1

~1,5-H H N

O

O R2

+ HO

Ar

R2 Ar

–H2O Ar O OH

O

R1

O 175

R2

Ar

R1

Ar

+ NH4OAc

Ar

Ar

R1

N

H

NH4OAc –H2O

O

Ar HO

Ar R1

H

HN

R2

was described in [126]. The reactions were carried out under solvent-free conditions in the absence of a catalyst, the reactant ratio being 1.1 : 1 : 1.5. Analogous reaction of acetylacetone with phenylglyoxal gave polysubstituted 3-hydroxypyrrole, whereas dibenzoylmethane failed to react (Scheme 107). The mechanism of formation of pyrroles 175 is shown in Scheme 108.

~1,5-H

R2

Ar

O OH H2N

–H2O

R1

Wang and Shi [127] reported a simple and efficient one-pot procedure for the synthesis of dihydro-1Hindol-4(5H)-one derivatives 178 by three-component condensation of 1,3-dicarbonyl compounds with phenylglyoxal hydrate and enamino ketones 179 in boiling ethanol without a catalyst (Scheme 109). Ten compounds 178 were isolated in 75–80% s yield. Apart



805

Scheme 109. O

O

O Ph + PhC(O)CHO · H2O

Me

–2 H2O

Me

O

Me

Ph Ar HN

HO

Me

Me

Me

O

O

N

O

O

Ar

Ph

HO

Me

Me

Ar N

H

Me

HO

Ph

O

Me

Me

Me

HO

179

O

O

Me

HO O

Me Me

ArNH

–H2O

O

Ar

Ph

N

Me

Me

O

Me Me

Me

Me

O

O

Me

178

Ar = 4-Me(Cl, MeO)C6H4.

Scheme 110. O

NH

O

H+

+ 2 Me

N H

Me

N Me H

N H

Me

N Me H

NH

OH

N Me H

Me N H

··

NH

NH

OH

OH2 Me N H

N Me H

NH N Me H

HN

Me

Me2CO, BF3 · Et2O 30 min

N

–H+

Me

Me

Me

NH

HN

Me N H

Me N

N

N Me Me N H H 180 (17–21%)

Me

NH

HN

Me

Me

Me 181

Scheme 111. O

O NHBoc

R2 R 1

R2

TFA (2 equiv), 25°C NH R1

1

2

1

O

182

2

R = H, R = Me (85%), Ph (74%); R = EtOC(O), R = Me (55%), Ph (44%).

from dimedone, cyclohexane-1,3-dione, 5-phenylcyclohexane-1,3-dione, cyclopentane-1,3-dione, furan2,4-dione, and indan-1,3-dione were used as dicarbonyl component.

Acetylacetone reacted with pyrrole in the presence of trifluoroacetic acid (or aqueous HCl) to give 1,3-dimethyl-1,3-bis(1H-pyrrol-2-yl)-2,3-dihydro-1H-pyrrolizine 180 [128]. The condensation of 180 with


806

SHOKOVA et al.

acetone, catalyzed by BF3 · Et2O, and subsequent intramolecular cyclization afforded calix[4]pyrrole-type macrocycle 181 (Scheme 110). β-Diketones synthesized in [19] readily underwent cyclization in TFA at room temperature, yielding (Z)-acylmethylidenepyrrolidines 182 (Scheme 111). 4.4. Complex Nitrogen-Containing Polyheterocyclic Systems Fast and highly efficient synthesis of 1,8-dioxodecahydroacridines 183 was achieved by multicomponent reactions of dimedone with aldehydes and amines, catalyzed by Amberlite IR-120H ion ex-

changer [129] (Scheme 112). Palladium-catalyzed Sonogashira, Suzuki, and Heck reactions with iodo derivative 183 (R 1 = 3-HOC 6 H 4 , R 2 = 4-IC 6 H 4 ) afforded compounds 184a–184c (Scheme 113). Compounds 183 [129] were tested as potential inhibitors of yeast sirtuin Sir2, a protein involved in such biological processes as aging, apoptosis, and stress resistance. The highest activity (40%) was observed for 183 (R1 = 3-HOC6H4, R2 = 4-IC6H4). Molecular docking study showed the possibility for the formation of a stable complex between this compound and Sir2 active site. Phthalazino[2,3-b]phtalazine-1,7,12-triones 185 were synthesized by one-pot reaction of phthalazine-

Scheme 112. O + R1CHO + R2NH2 Me

O

Amberlite IR120H EtOH, 60°C, 2–4 h Me

O

Me

R1

O

Me

N

Me

Me

R2 183

1

2

R = Ph, 3-HO(O2N, F)C6H4, 2-HOC6H4, naphthalen-2-yl, thiophen-2-yl; R = Ph, 4-Me(Br, I, F, Cl, Ac, CN, CF3)C6H4, 2-IC6H4, 3-ethoxycarbonyl-4,5,6,7-tetrahydro-1-benzothiophen-2-yl (16 examples, 85–95% for 15 compounds)

Scheme 113. OH

O

OH Me(CH2)3C≡CH, 10% Pd/C, PPh3 CuI, Et3N, EtOH, 60°C

O

Me

Me

N

Me

PhB(OH)2, Pd(OAc)2, K2CO3 DMF, 80°C

Me

O

O

Me

H2C=CHCOOEt, Pd(OAc)2 K2CO3, DMF, 80°C

Me

N

Me

I

R

183

184a–184c

Me

R = BuC≡C (a), Ph (b), (Z)-EtOC(O)CH=CH (c).

Scheme 114. R1 O

O NH NH

O

CHO +

+ R

1

Ce(NO3)3, PEG 400 R2 R2

O

O

O N N

R2 R2

O 185 (90–94%)

R1 = H, 4-Br(Me, HO, Me2N, Cl, MeO, O2N)C6H4, 3-O2N(HO)C6H4, 2-HOC6H4; R2 = H, Me. RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 6 2015


807

Scheme 115. O CHO

O +

R1

R

NH2

2

O

LaCl3 · 7 H2O AcOH, 60°C

O R

R2

3

R1

R3

N

R3

+ R1

R2

N

A

B

R1 = H, F, MeO; R2 = CF3, R3 = Me, t-Bu, Ph, naphthalen-2-yl, thiophen-2-yl; R2 = Me, R3 = i-Pr, t-Bu, Ph, furan-2-yl; R2 = i-Pr, R3 = t-Bu.

Scheme 116. O CHO

O

O

LaCl3, AcOH, 60°C

+ Me

NH2

N

Ph

Ph

N

N

Me

186

Scheme 117. O

COOEt OH

N

O

NaOAc, Me2CO, 0°C

+ R

RF

H

R

N

N

Et

O RF

N

N

O

OEt

O

N2 Cl–

N H

H

N

NH

O

RF

N

R

N

O

H B

A

RF = CF3, R = Me, t-Bu, Ph, furan-2-yl, naphthalen-1-yl; RF = HCF2CF2, R = Ph; RF = C3F7, R = Me, Ph (8 examples, 62–74%).

Scheme 118. Me O + R1

O

R2

CHO

Me

Mannich

R1

O

Me

HN N

R1

O

Me

R2

O

O

R1

Me

R2

H2N

O

Me

O

Me

Hofmann–Martius

N

R2

Me

Me Me

O

O

O

R1

N

NH

Me

R1

O

O

O N

R2

R1

R1 N Me

R1

Me

Hofmann–Martius N R2

H N

R2 Me Me

R2

Me Me

Me

R2

Me

O

Me

R2

NH2

O

HO

O

O

O N R2 R1

Me

Me

R1

R1 = HO, MeO, Me2N, Et2N, O2N, R2 = H (5 examples, 53–75%); R2 = MeOC(O) (5 examples, 51–71%). RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 6 2015

808

SHOKOVA et al.

1,4-dione with aromatic aldehydes and cyclic β-diketones (cyclohexane-1,3-dione and dimedone) in the presence of cerium nitrate (5 mol %) using PEG 400 as solvent [130] (Scheme 114). Apart from substituted benzaldehydes, 2-hydroxynaphthalene-1-carbaldehyde, piperonal, and aliphatic aldehydes RCHO (R = Et, Pr, i-Bu, C6H11) were involved. In the reactions with aliphatic aldehydes, the yield decreased to 62–64%.

and methyl 2,2-dimethyl-4,6-dioxocyclohexane-1-carboxylate with quinolin-8-amine and aromatic aldehydes afforded ten hexahydrobenzo[b][1,10]phenanthrolin-8-one derivatives [101] (Scheme 118).

About twenty quinoline derivatives were obtained from unsymmetrical 1,3-diketones and 4-substituted 2-aminobenzaldehydes in the presence of LaCl3 · 7 H2O in acetic acid (Friedländer reaction) [131]. The reaction was highly regioselective, and in all cases, isomer B was formed preferentially or exclusively (ratio B/A 90 : 10 to 100 : 0). Even in the reaction with sterically hindered β-diketone (R2 = i-Pr, R3 = t-Bu), the fraction of isomer B was 80%. The overall yield of isomers A and B ranged from 81 to 85% (Scheme 115). Analogous reaction of 2-aminopyridine-3-carbaldehyde with benzoylacetone gave 90% of 1,8-naphthyridine 186 with 94% selectivity (Scheme 116).

2-Substituted 4-(benzenesulfonylmethyl)furans 187 were prepared by reaction of 1,3-diketones [hexane2,4-dione, benzoylacetone, MeCOCH2COR (R = alkyl, alkenyl, phenylalkyl) with 1-(benzenesulfonyl)-2,3-dibromoprop-1-ene [133] (Scheme 119). 4-(Benzenesulfonyl)-2-methylfuran (188) was formed as byproduct. The lowest overall yield of 187 and 188 was obtained with R = Ph(CH2)3 (36%, 187/188 5 : 1), and the highest yields were for R = Bu (93%, 187/188 16 : 1) and i-Pr (95%, 187/188 38 : 1). Acetylacetone, dibenzoylmethane, and cyclohexane-1,3-dione reacted with phenylacetylene to form a new Csp–Csp3 bond as result of direct functionalization of Csp–H and Csp3–H bonds. Intermediate α-phenylethynyl β-diketone underwent cyclization to substituted furan 189. The reaction was catalyzed by Ag2CO3 and AcOK in DMF [134] (Scheme 120). Tetrasubstituted furans 190 were synthesized from propargylic acid esters and 1,3-diketones in the presence of Sn/Cu catalyst and 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) in toluene [135] (Scheme 121). The reaction of but-3-yne-1,4-diols with 1,3-diketones catalyzed by

Polyfluoroalkyl-substituted dihydroimidazotriazines were synthesized by azo coupling of fluorinated 1,3-diketones with 4-ethoxycarbonyl-1H-imidazole-5diazonium chloride [132] (Scheme 117). The products in crystal were found to have structure B, while in solution ring–chain isomerism is possible via dissociation of the C4–N5 bond, which is especially characteristic for compounds with the RF substituent longer than C1. The three-component condensation of dimedone

4.5. Oxygen-Containing Monoand Polyheterocyclic Systems (Furans, Chromenes, Xanthenes, Coumarins, Isocoumarins, Pyranones)

Scheme 119. O O O

Br

O

Br

+ Me

R

MeONa MeOH

Me

PhSO2

MeONa

O

–MeOAc

R Br

SO2Ph

R

O

Br SO2Ph

O 187 (8 examples)

R

SO2Ph

PhSO2

MeONa –RCOOMe

Me Br

SO2Ph

O 188

Me

Scheme 120. O Ph

Ag2CO3 (2 equiv) KOAc (2 equiv) DMF, 80°C, N2

O

CH + R1

R1

R1 O

R2 Ph

0.25 mmol

O

O

R2

0.75 mmol

Ph

O 189

R2

R1 = R2 = Me (43%), Ph (76%); R1R2 = (CH2)3 (40%). RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 6 2015


809

Scheme 121. O R1

O

O

+ R3

R2

O

SnCl–CuI (10 mol %) DDQ (1.2 equiv) PhMe, 100°C

R

R4

R1

4

O

R3

O

OR2

190

R1 = H, Ph, COOEt; R2 = Me, Et; R3 = R4 = Me, Ph; R3 = Ph, R4 = Me (8 examples, 51–86%). R3

R1

O ICu O

O R3

R1 O

190

O

R3

R4

CuI

SnCl2

DDQH2

COOR2

O

O

R 2O R1

R3

OH R1

R4

O

O

R2O

O

OR2 O

R4

COOR2

R4

R1

O

SnCl2

R 2O

DDQ R3

OH R1

R4

O

R3 R4

O

Scheme 122. OH R2 R1 +

HO

O

O

R4

O

R1 Ph

R2 Ph

R2

R5

R3

O 191a

R4

O 191

O

Ph Ph

Ph Ph

R5

O

R3 R1

O

R1

O Ph

Ph Ph

Ph

O 191b

Ph

O

Ph

R5

Ph Ph

R3

O 191c

Ph

Ph

O 191d

Ph

Ph

O 191e

R4

191a, R 1 = R 2 = 4-F(Cl, Br, Me)C 6 H 4 (78–86%); 191b, R 1 = 4-Br(Me)C 6H 4, PhC≡C [82–85%; E/Z (1–1.3) : 1]; R 1 = t-Bu (42%, E/Z ~1 : 2); 191c, R3 = 4-F(Br, t-Bu)C6H4 (89–91%); R3 = naphthalen-1-yl, thiophen-2-yl, cyclo-C6H11, Me, t-Bu (72–86%); 191d (45%); 191e, R4 = R5 = Me, 4-MeOC6H4; R4 = Me, R5 = Ph (83–94%).

TsOH in nitromethane at room temperature gave tetrasubstituted furans 191a–191e [136] (Scheme 122). Scheme 123 shows the mechanism of their formation. Albrecht et al. [137] were the first to accomplish enantioselective synthesis of 2-(1-hydroxybutyl)- and 2-(1-aminobutyl)-2,3-dihydrofurans 192a and 192b and 2-[1-hydroxy(amino)butyl]furans 193a and 193b according to the one-pot procedure including highly stereoselective catalytic epoxidation (aziridination) of

(E)-hex-2-enal and subsequent Feist–Bénary reaction. Intermediate dihydrofurans 192 were converted without isolation into furans 193 (Scheme 124, path a). Alternatively, dihydrofurans 194a and 194b having three chiral centers can be isolated (path b). Dhiman and Ramasastry [138] described the transformation of 1-benzofuran-2-ylmethanols 195 and 196a–196c into polysubstituted furans in the reaction with β-diketones, catalyzed by TfOH, which involved


810

SHOKOVA et al. Scheme 123. OH R2 R1

HO

HO

R4

R5

·

HO

R

O

H+

R

4

R

O

·

H 2O

O

a

O

2

R R

HO R

O

4

R

O

2

H

+

R1

2

O R5

· –H2O

O

5

R3

R1

R3

R3 H

5

191a–191c 191e

R4

O

O O

O

Ph

R1

·

HO

R3

R1

R3

O

R2 R1

HO

–H2O

R3

O

Ph

Ph

R1 2

R2 R1

H+

R3

b

R2

OH2

3

= R = Ph R =H

Ph

Ph

H+

Ph

Ph

Ph

Ph

OH

–H2O

OH2

Ph

H

Ph

Ph

+

·

Ph

O

Ph

O H

Ph

Ph

191d

–H+

Ph

Ph

O

Scheme 124.

Pr

O

CHO

O

N

Pr

CHO

or Pr

CHO

O O

R1 R2 MTBD, MgSO4 CH2Cl2, 20°C

O

HO Pr

R

or R

O

HO

2

H O

1

R

CSA CH2Cl2, 20°C

2

H

Pr

R

O

HO

R2

R

1

Pr O

R1

TsNH 193a

193b

O

HO Pr

2

or

HO

O

, MgSO4, CH2Cl2 R1 R2 K2CO3 or EtN(Pr-i)2

R

O

192b

O

O

Pr

1

TsNH 192a

O

Ts

H2O2 (1.3 equiv) or TsNHOTs (1 equiv) no base or NaOAc (1.1 equiv) catalyst (2.5 mol %), CH 2Cl2, 20°C

HO

R2 or

H R1

O HO

R2

H

Pr

R1

O TsNH

194a

194b F 3C

Ar Catalyst =

N H

Ar OSiMe3

; Ar = CF3

MTBD is 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene, CSA is (–)-camphor-10-sulfonic acid; 193a, R1 = R2 = Me (75%, ee 92%), R1R2 = (CH2)3 (52%, ee 92%), R1R2 = CH2C(Me)2CH2 (62%, ee 94%); 193b, R1 = R2 = Me (88%, ee 95%), R1R2 = CH2C(Me)2CH2 (66%, ee 91%); 194a, R1 = R2 = Me (87%, dr 1.6:1), R1R2 = CH2C(Me)2CH2 (80%, dr 1:1); 194b, R1 = R2 = Me (91%, dr 1: 2.5), R1R2 = CH2C(Me)2CH2 (80%, dr 2.5:1). RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 6 2015


811

Scheme 124. (Contd.) R2

R3

O

Base R2

O O

O

CHO

R3 R2

O

R3

O Ar

R1 H 2O

R1

Ar

N H

O

X

OSiMe3

O

X

R2

R1

H2O

R3

O Ar

Ar Ar

N

1

R3

X Ar

N

R

O

R1

O

OH

1

R1

OSiMe3

H2O2 or TsNHOTs

OH

X

OSiMe3 Ar

R

Ar

N

OSiMe3

R2

O

XH

194a, 194b R

1

X

LG

Acid

O R R1

2

O

R1

R3

O

R2

X = NTs

X=O

R3

O NHTs 193b

OH 193a

reacted with 195 to give furans 197a. The reactions of acetylacetone with 196a and 196c afforded adducts 197b and 197c (no rearrangement occurred), while tertiary alcohol 196b underwent dehydration to form

unusual opening of the furan ring and subsequent recyclization. The reactions were carried out in nitromethane at 30–35°C using 0.2 equiv of TfOH (Scheme 125). Acetylacetone and benzoylacetone

Scheme 125. H+ R1

O +

O

OH

O

R2

H R1

H+ R3

R2

–H2O

O

HO

O R

R

O

H R

O

O

2

~H

R

H

O

O R

O

1

R R

O

HO

3

+

R3

R1 R2

O

195 1

H

H+

R3

1

O

2

–H+ OH

R2

O R

H

1

3

2

3

2

3

3

R = H, Me, CH2=CHCH2, Me(CH2)2CH(Me), cyclo-C6H11, Ph, 2-BrC6H4; R = R = Me; R = Me, R = Ph. Me Me Me

Me O 196a

OH

O

OH

Ph

196b


O 196c

OH

812

SHOKOVA et al. Me

R2

OH

O

Me

Me

Me

O

R1

Ph

Me

O

O

Me

Me

Me

O

O

O

Me

O

Me

O

197a

197b

197c

198

O R

R Me

Me

Me

O OH 196d

Me

O

O 197d

196d, R = Bu, MeCH(Me)(CH2)2, Ph, PhCH2; 197a (11 examples, 49–81%); 197b (78%); 197c (74%); 197d (4 examples, 34–51%).

alkenylfuran 198 as a mixture of E and Z isomers at a ratio of 3 : 1. Under analogous conditions, 5-methylfuran-2-ylmethanols 196d with acetylacetone gave rise to tetrasubstituted furans 197d. Enantioselective N-heterocyclic carbene-catalyzed Michael addition of acetylacetone and dibenzoylmethane to α,β-unsaturated aldehydes led to the formation of 3,4-dihydro-2H-pyran-2-ones 199a [139]. The catalyst was camphor-derived triazolium salt (NHC, 10 mol %) in combination with NaBF 4 (5 mol %), DBU (15 mol %) was used as a base, and tetra(tertbutyl)quinone (TBQ, 1 equiv) was used as oxidant

(Scheme 126). 2H-Pyran-2-ones 199b were selectively synthesized from symmetrical and unsymmetrical β-diketones and 3-aryl-3-bromoprop-2-enals in the presence of N-heterocyclic carbene (NHC), TBQ, and NaH [140] (Scheme 127). When the reaction was carried out in the absence of oxidant (TBQ) using chiral precursor NHC-1 instead of NHC, 1,4-diazabicyclo[2.2.2]octane (DABCO) as a base, a mixture of toluene with tert-butyl alcohol as a solvent, and LiCl as an additive, dihydropyranones 199c were obtained in high yield with high enantioselectivity [140] (Scheme 128). A probable reaction mechanism is also shown.

Scheme 126. O

CHO +

R1

O R3

R2

Me

Me

N

N

N O

O R3

O R2 199a

O

t-Bu

Me

R1

NHC, NaBF4, DBU TBQ, THF, 25°C

Bu-t

Ph O

O

BF4 t-Bu

NHC

Bu-t TBQ

R1 = Ph, 2-Me(Br, Cl)C6H4, 3-ClC6H4, 4-Br[Cl, MeO, MeOC(O)]C6H4; R2, R3 = Me, Ph.

Scheme 127. Br Ar

O CHO

O

+ R

1

Ar

NHC (10 mol %), TBQ (1.5 equiv) NaH (1.5 equiv), THF, 50°C R

O R1

2

O

O R2 199b

R1 = R2 = Me, Ar = Ph, MeC6H4, 4-MeO(O2N, F)C6H4, naphthalen-1-yl, thiophen-2-yl (8 examples, 45–90%); R1 = R2 = C5H11, Ph; Ar = Ph; R1 = R2 = Ph, Ar = PhCH=CH; R1 = Me, R2 = Ar = Ph, 4-BrC6H4; R1 = Me, R2 = Ph, Ar = furan-2-yl (6 examples, 45– 90%); R1R2 = (CH2)3, Ar = Ph (58%). RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 6 2015


813

Scheme 128.

Br

O CHO

Ar

1

O

NHC-1 (10 mol %) LiCl (10 mol %) DABCO (1.5 equiv) PhMe–BuOH (10 : 1), 25°C

O

+ R1

Ar

O N

R1

R2

Mes

O R2 199c

O

N

N Cl– NHC-1

2

1

2

R = R = Me, Ar = Ph, 4-F(Me)C6H4, 3-O2NC6H4, 2-MeC6H4, thiophen-2-yl, PhCH=CH; R = R = Pr, Ar = Ph (8 examples, 47–94%, ee 66–93%). O R2

O

O

NaH R3

Br

OH

R2

O

N

R2 R 1

N

[O]

Br

N N

R3

O

OH N

R1

N

N

N

R3

O R2

O 1

+ Br– O

N

199c

N

R2

Br

N

R

··

R3

O

O

1

H

O O

R1 R2

Br R1

O

R3

O

N

OH N

R1

N

O –

H

O

Br

O

R

[O]

N

R1

R3

N

N

N Base

O R

O

Br R3

2

O

N

N

R1

–

Br

N

R1

O–

N

N

N

–Br–

Scheme 129. R

O

NO2 + EtO

NO2

Im or DMAP CHO

O

AcCl, pyridine OEt

R

OH

NO2

O OEt

R OAc 201 (MBH acetate)

R = 3,4-(MeO)2C6H3, 2,5-(MeO)2C6H3, 1,3-benzodioxol-5-yl, 3,4,5-(MeO)3C6H2, 4-MeO(Me2N, Me, Cl)C6H4, Ph, furan-2-yl, thiophen-2-yl, 2-MeOC6H4CH=CH. RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 6 2015

814

SHOKOVA et al.

Polyfunctional polycyclic and fused systems containing a furan (197e, 197f) or pyran fragment (200) were obtained by regioselective cascade reactions of β-dicarbonyl compounds with MBH (Morita–Baylis– Hillman) acetates 201 derived from nitroalkenes and ethyl glyoxalate [141] (Scheme 129). The reactions initiated by DABCO involved the Michael–5-exo-trigoxa-Michael sequence for acyclic and six-membered cyclic β-diketones, yielding the corresponding furan derivatives 197e and 197f. In the reaction with fivemembered cyclic diketones, the Michael–5-endo-trigoxa-Michael cascade resulted in fused 4H-pyrans 200 (Scheme 130). 2-Alkoxy-2H-chromenes 202 were synthesized by reaction of 2-hydroxybenzaldehydes with acetylacetone in alcohols used also as solvent in the presence of L-proline as catalyst [142] (Scheme 131). Dehydroacetic acid obtained from 2H-pyran-2-one was brought into condensation with aromatic and heterocyclic aldehydes to obtain compounds 203 and 204 as potential antitumor agents [143] (Scheme 132). The products (26 compounds) were tested as activators of the

Nrf2/ARE signaling pathway responsible for cell protection against oxidative stress. Compound 203 (R = 3,4-F2) was found to be a potent Nrf2/ARE activator in human colorectal cancer cells. o-Hydroxy-substituted 1,3-diarylpropane-1,3-diones 205 were converted in several steps into 6,7-disubstituted 2-aryl-4H-benzopyran-4-ones 206 which were expected to exhibit antibacterial activity [144] (Scheme 133). Compounds 206 (R1 = OH, R3 = pyrrolidin-1-yl, R2 = Cl, Br, OMe) were tested as solutions in DMF on P. aeruginosa, B. subtilis, and E. coli after 24-h incubation using Norfloxacin as reference. Benzopyranones 206b and 206c showed high activity against P. aeruginosa, 206a was highly active against B. subtilis, and 206a and 206b revealed high activity against E. coli. Ferreira et al. [145] studied in detail the bromination and iodination with N-bromo- and N-iodosuccinimides (NBS, NIS) of (E)-5-aryl-1-(2-hydroxyphenyl)pent-4-ene-1,3-diones containing a styryl fragment. Conditions were found for the synthesis of 3-bromo (iodo)-2-[(E)-2-phenylethenyl]-4H-chromen-4-ones

Scheme 130. O O

O

Me

O Me

O

O

Ph

O

Ph

Me

( )n

O

Me

( )n O H O NO2

O

O DABCO

O O

5-exo-trig

NO2

R

( )n

n=2

O DABCO

H

O

–HNO2

R O 2N

COOEt

R

COOEt COOEt 197e

OEt R

OAc 201

O

( )n O

n=1

H R

O

6-endo-trig

O

O

DABCO R

COOEt NO2

O

O2N

–HNO2

R

O

H COOEt

COOEt 200

197e (13 examples; 85–94% for 12 compounds); 200 (6 examples; 72–81% for 5 compounds). O

NO2 COOEt Ar

COOEt

O

O

DABCO, THF, 20°C

+ R

R

O

Ar

R

EtO O

201

R

197f

R = Me (92%), PhCH=CH (54%). RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 6 2015


815

Scheme 131. O R2

CHO

O

R2

O

Me

OH

Me

Me

R1 1

Me

L-Proline, 20°C

+ R3OH

+

R1

2

OR3 202

3

R = H, MeO, R = H, Cl, Br, O2N; R = Me, Et, Bu, C8H17, HC≡CCH2, 4-MeOC6H4CH2 (18 examples; 73-90% for 16 compounds). O N H

O

Me

O

Me

Me O

Me

·· N Me

Me O

Me

HO

OMe

202 OH2

O

Me O ··

O

HO

O

·· MeOH ·· Me

O

O

OH

O +

O Me

Me O

N

Me OH ·· O

Me

O O–

Me OH ·· O

N

O–

N

O–

Scheme 132. OH

Me

O

OH

AcOH, DMAP, DCC PhMe, 100°C, 2 h O

O Me

Me

O

OH

Ar(Het)CHO, piperidine CHCl3, Δ

O

O Ar(Het)

Me

O

O 203, 204

203, Ar = R

; 204, Het =

. X

DMAP is 4-(dimethylamino)pyridine, DCC is N,N′-dicyclohexylcarbodiimide; 203, R = H, 2-F 2-O2N, 2-Cl, 2-MeO, 2-F3C, 3-F, 3-Cl, 4-F, 4-Cl, 4-MeO, 4-EtO, 4-Me2N, 4-CN, 4-Ph, 2,4-F2, 2,4-Cl2, 2,4-(MeO)2, 3,4-F2, 3,4,5-(MeO)3; Ar = naphthalen-2-yl; 204, X = S, O, NH (23 examples)

207 via intramolecular cyclization of the primary halogenation products. Chromenes 208 and 3,6-diiodo derivatives were formed as by-products. The mechanism of formation of 3-bromo derivatives 207a–207d is shown in Scheme 134. A simple and efficient one-pot procedure for the synthesis of 12-aryl-8,9,10,12-tetrahydrobenzo[b]xanthen-11-ones 209 is based on the reaction of aldehydes (almost exclusively aromatic) with naphthalen-2-ol

and dimedone, catalyzed by thiamine hydrochloride (vitamin B 1 ) in aqueous micellar medium [146] (Scheme 135). 1,3-Diarylpropane-1,3-diones with a halogen atom (I, Br) in the ortho position of one benzene ring were subjected to cyclization by heating in toluene at 110°C in the presence of CuI (catalyst, 10 mol %), pyridine2-carboxylic acid (L, ligand, 20 mol %), and K2CO3 (base, 200 mol %). The reaction involved Ullmann


816

SHOKOVA et al. Scheme 133. O O

O

O

O

R1

O

Me AcOH, Δ R1

R1

O

R2

OH

R2

205 O

O

R2 O

O

R1

O

R32N

Br R1

O R2

R2

206

R1 = HO, Me; R2 = Cl, Br, MeO; R32N = Me2N, pyrrolidin-1-yl (12 examples, 61–75%).

Scheme 134. O OH

O

O Br

O NBS

+

a R

R

207a–207d O OH

O

R

208a–208d O

I

OH

I

NIS

I 208a– + 208d

+

b R

R

207e–207h

R

Conditions: diketone, 0.37 mmol; NBS (NIS), 0.56 mmol; a: MW (800 W), N2, 40 min; b: TFA, 5.6 × 10–3 mmol; TFAA, 5.6 × 10 –3 mmol; NaOAc, 1.48 mmol; 20°C. R = H (a, e), MeO (b, f), Cl (c, g), O 2N (d, h); NBS: 207: 78% (a), 88% (b), 51% (c), 31% (d); 208: 16% (a), 7% (b), 5% (c), 42% (d); NIS: 207: 70% (e), 62% (f), 61% (g), 59% (h); 208: 23% (a), 11% (b), 10% (c), 32% (d).

OH

Br

OH

Br Ar

O

O

OH

Br

–HBr

Br

Ar O

H

OH H

O

Ar O

H+

Ar

Ar –H2O

Br

Br O

OH

O 207a–207d



817

Scheme 135. O + R

CHO + Me

Me ( )n

O

Me

Me

O

B1 (5 mol %) CTAB, H2O, 20°C

OH

R

O

209

NH2 · HCl

Cl N

B1 = Me

–

S OH

Me Thiamine hydrochloride

CTAB is cetyl(trimethyl)ammonium bromide; 209, n = 1, R = Ph, 4-MeO(Me, Cl, HO, O2N)C 6H 4, 2-MeO(Cl, O 2 N)C 6H 4, 3-HO(O2N)C6H4, 2,4-Cl2C6H3, 2-HO-3-MeO(EtO)C6H3, 2-HO-5-O2NC6H3, PhCH=CH, i-Pr, t-Bu (18 examples, 78–92%); n = 2, R = 4-ClC6H4, 3,4-Me2C6H3 (2 examples, 90–91%). R

B1 20°C

OH

O

Me 20°C

O

a

R

Me Me

( )n O

O

O

( )n

Me Me

OH O

R

O Me Me

R

Me Me

OH

O O

( )n

HO

b

O

H

O

B1

OH

R

( )n

O

OH

( )n

Me Me

O O R

OH

H ( )n

O

R Me

Hydrophobic interior O H + O

R B1

O

209 n = 0, 1

Me

OH

Me Me

Hydrophobic interior Me O Me ( )n R

( )n Me Me

Hydrophilic exterior

( )n

O

H2O

H O H

Hydrophilic exterior

: Cationic surfactant


+

O B1

O

( )n

Me Me

818

SHOKOVA et al.

type intramolecular C-arylation, followed by rearrangement. As a result, 22 isocoumarin derivatives 210–212 were obtained in 80–98 (12 compounds) and 61–79% yield (10 compounds) [147] (Scheme 136). 3-Substituted 5-nitroisocoumarins 213 and analogs of 5-aminoisoquinolin-1-one [5-AIQ, water-soluble poly(ADP-ribose)polymerase-1 (PARP-1) inhibitor] were synthesized from β-diketones and 2-bromo-3nitrobenzoic acid by one-pot tandem Hurtley–retro-

Claisen–cyclization reactions [148] (Scheme 137). In the reactions with unsymmetrical diketones, the second product was 3-methyl-5-nitroisocoumarin 213a; for R′= Ph, the amount of 213a was twice as large as that of 3-phenyl derivative 213 (R′ = Ph; 8 and 4%, respectively); in the other cases, the yield of 213a ranged from 3 to 6%. 5-Nitroisocoumarins 213 were readily converted into the corresponding 5-nitroisoquinolin1-ones 214 by treatment with ammonia; the subsequent

Scheme 136. O

O

O R2

R1

R

X

O

3

O

O

R1

O

O

R2 R

3

O Ph

Ph

3

210 1

O

211

212

2

210, R = R = H, R = Ph, 4-MeO(Me, F, O2N, PhO)C6H4, 3-ClC6H4, 2-Me(I)C6H4, naphthalen-2-yl, 1,3-benzodioxol-5-yl; R1 = H, R3 = Me, R2 = Ph; R2 = Ph, R3 = H, R1 = 7-F(Cl, MeO), 6-Cl (F), 5-Me, 6,7-(MeO)2. O

O

O CuI/2 L

Ph

O

O Ph

–HI

I

I

·

CuL2

Ph –CuI/2 L O

O

O

O

O Ph

Ph

Scheme 137. O COOH O

Cu (powder) t-BuOK, t-BuOH, Δ

O

+ Br

R1

O O

O R2

R2

NO2

+ Me

NO2

NO2 213

1

2

1

213a

2

R = R = Me, Et, C5H11, i-Bu, Ph, PhCH2, 4-MeOC6H4 (23–78%); R = Me, R = Ph, C5H11 (4%), 4-Me(MeO, Cl, CF3)C6H4, thiophen-2-yl (15–33%).

Scheme 138. O

O O

NH

i R

NO2

NH

ii R

NO2 213

O

R NH2

214

215

i: NH3, MeO(CH2)2OH, Δ; ii: SnCl2, EtOH or H2, Pd/C, EtOH, aq. HCl. R = Me, Et, C5H11, i-Bu, Ph, PhCH2, 4-Me(MeO, Cl, CF3)C6H4, thiophen-2-yl; 214 (27–89%), 215 (24–92%). RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 6 2015


819

Scheme 139. O O

O

O +

R1

R2

R

N H

3

O

R4 R

+

O

3

N H

R2

I 216 1

2

R4

1

2

1

2

By-product

4

3

R = R = Me, Ph, 4-MeC6H4, 4-MeOC6H4; R = Me, R = Ph; R R = (CH2)3; R = Ph, R = H, 5-Me, 5-MeO, 5-O2N, 5-Cl, 4-F, 4-Cl, 3,5-Br2, 4,5-(MeO)2, 6,7-CH2O2, 5,6-(MeO)2; R3 = H, R4 = Me, Ph, PhCH2, 4-O2NC6H4 (20 examples, 56–98%). O N H Me

Me O

I

O Me

O

Ph

O

N

CuI

O –

O

N O Ph

N H

Me

N O

Cu

O

O Ph

Ph

Me

H Me

Base

Me

Cu+

O

Ph

O

I Me

Me

O

O

O

O Me

O

Me

Ph N

Cu

Me

Me 216 O

O N

Ph

Cu

O Me

Cu I

Ph N

O

Me

O

Me

Me Cu

O

–I–

I

Me

O– O

Scheme 140. O

O N H

R N

Cl

Ph

O

CuI, Cs2CO3 DMSO, N2, 100°C

O

+

O

R

Me

Me

H N

N

+ Me

Me O

217

217, 4 examples (60–75%). Ph O

O N H

I

CuI, Cs2CO3 DMSO, N2, 100°C

Ph + O

reduction of the nitro group gave 5-aminoquinolin-1ones 215 (Scheme 138). Water soluble hydrochlorides derived from 215 (11 compounds) were tested in vitro as human PARP-1 and murine PARP-2 inhibitors

O

N

O 218, 45%

versus 5-AIQ taken as reference (IC 50 = 1.6 ± 0.25 μmol/L for PARP-1). All the compounds tested (except for R = thiophen-2-yl, PhCH2) turned out to be more potent than 5-AIQ. The strongest inhibitory


820

SHOKOVA et al.

effect was observed for 215 (R = Me), IC 50 = 0.23 ± 0.05 μmol/L (1.17–0.32 μmol/L for the other compounds). Seven compounds 215 (except for R = C5H11, Me2CHCH2, PhCH2, thiophen-2-yl) were tested against PARP-2, and their activity was higher than that of 5-AIQ (IC50 0.12 ± 0.03 to 0.83 ± 0.10 μmol/L). Acetylacetone, benzoylacetone, and diaroylmethanes reacted with substituted 2-iodo-N-phenylbenzamides (in some cases, chloro and bromo analogs were used) in the presence of Cs2CO3 and CuI in DMSO at 100°C to give isocoumarin derivatives 216 [149]. The reaction mechanism is shown in Scheme 139. Pyranoquinolinone derivatives 217 and 5-phenyl-3,4dihydrophenanthridine-1,6(2H,5H)-dione (218) were synthesized under analogous conditions (Scheme 140). 4.6. Polyheterocyclic Systems with Two or More Different Heteroatoms A convenient procedure for the preparation of benzothiazole and benzimidazole derivatives 219 and 220 by condensation of 2-aminobenzenethiols or benzene1,2-diamines with β-diketones in the presence of p-toluenesulfonic acid was reported in [150] (Scheme 141). Benzoylacetone reacted with 2-aminobenzenethiol to give 75% of 219 (X = S, R1 = H, R2 = Me), and 72%

of 220 (X = NH, R1 = 4-Cl, R2 = Me) in the reaction with 4-chlorobenzene-1,2-diamine. Three-component reaction of 2-aminobenzothiazole with 3-hydroxybenzaldehyde and acetylacetone at 60°C under solvent-free conditions afforded 60% of 10aH-benzo[4,5][1,3]triazolo[3,2-a]pyrimidine derivative 221 [151] (Scheme 142). Fused heterocyclic systems 222 containing polysubstituted pyrrole and isocoumarin fragments were synthesized by one-pot reaction of acetylacetone first with ninhydrin and then with primary amines under solvent-free conditions using silica sulfuric acid (SSA) as catalyst [152]. The proposed mechanism is shown in Scheme 143. The procedure utilizes accessible and nontoxic reagents and inexpensive catalyst which can be recycled, and the products are easy to isolate. Ganguly et al. [153] developed an efficient one-pot procedure for the synthesis of 9-(1H-indol-3-yl)xanthen-4(9H)-ones 223 by three-component reaction of dimedone with substituted 2-hydroxybenzaldehydes and 1(3)-substituted indoles in aqueous phase, catalyzed by L-proline (10 mol %) and an anionic surfactant, sodium dodecyl sulfite (SDS); the latter was taken in an amount exceeding its critical micelle concentration (0.08 mmol of SDS in 2 mL of water). Compounds 223 were obtained in 86–96% yield. Analogous

Scheme 141. NH2 R1

O

TsOH · H2O (5 mol %) solvent-free or MeCN 20–80°C

O

+ R2

XH

R2

N R2

R1 X 219, 220

219, X = S, R1 = H, 4-Cl, R2 = Me, Et, Pr, Ph (10 examples, 51–92%); 220, X = NH, R1 = H, 4-Cl, Me, MeO, NO2, R2 = Me, Et, Pr, Ph (13 examples, 49–95%).

Scheme 142. S

··

HO

N

Me

CHO

O

O

HO

+ Me

O

S

··

NH2

O–

O Me

NH ·· Me

HO

N N

Me

O

Me

HO Me

O

S

S N

NH2 Me

HO

Me Me

N

O

O 221



821

Scheme 143. O O

OH

O +

Me

O

O H2O, 1 min

O

O

RNH2, SSA 65°C, 60 min

Me

Me

OH

Me

O OH

HO

O

N

O

Me

Me

R 222

SSA is silica sulfuric acid. R = Ph, 2-Cl(MeO)C6H4, 3-Cl(OH, O2N)C6H4, 4-Cl(MeO, Br, O2N)C6H4, Pr, PhCH2 (12 examples, 79–91%). O OH

O

O Me

H

O

O

H

HOSO2O

OH

H+

Me R

Me

N H

S

R

–H2O

O

O

H

O

H

O

Me

O

N

–H+

Me OH

Me O

O

HOSO2O

O

SSA

H

HOSO2O

O S

O

O O

O

H O

R

O

NH

O

Me

O H

O

O

Me O

O S

O

O

Me

Me N H

O

SSA

O

R

H

O

HOSO2O

O

SSA

H

O

Me

O

R

O S

O

HOSO2O

O

SSA

O H

O

Me O S

O O

SSA

O

O O

H

O

O

O H Me

N R HO

HOSO2O

NH

O

Me

Me

N R

Me 222

O S

O O

SSA

reactions with N,N-dimethylaniline instead of indole afforded xanthenes 224 (Scheme 144). Multicomponent reaction of 2-amino-4-methylbenzothiazole with isatin and β-dicarbonyl compounds (including diketones) led to the formation of various spiro heterocyclic systems 225–227 [154]. Commercially available cyclic β-dicarbonyl compounds such as 1,3-dimethylbarbituric acid, dimedone, 4-hydroxy-

coumarin, and 4-hydroxy-6-methylpyran-2-one were used as starting materials. The reactions were carried out in aqueous medium in the presence of a sulfonylfunctionalized ionic liquid {[mim(CH2)4SO3H][HSO4], mim is N-methylimidazol-3-yl} as acid catalyst and co-solvent, and the yields attained 89–94%. The reaction of 2-amino-4-methylbenzothiazole with isatin, 1,3-dimethylbarbituric acid, and dimedone was studied


822

SHOKOVA et al. Scheme 144. R3 R

1

O R

2

+ R3

+ OH

Me

Me

R O R1

O

Me

Me

O

Me

SDS (H2O) L-proline

CHO N

Me

O

O

N R2

NMe2

223

224

R1 = H, Me, Ph; R2 = H, Me; R3 = H, 4-Me, 4-MeO, 4-Cl, 3-Me-4-Cl; 224, R = H, MeO (92–96%). O H 2O

NH Me

O

O

Me N H

Me

O COOH

Me Me

COOH

·· N

H

O

Me

O

OH

223 NH

O

HO

O Me N

Me –

OH

–

O

O O

N

Me

··

Me

H+

OH2

OH

O O

O Me Me N H

·· N

Me N

Me

OH

–

–

O

OH

O O

O

as model. The best yield of spiro[indole-3,5′- pyrimidino[4,5-b]quinoline] derivative 225 (93%) was attained at 80°C at a SFIL–H 2 O ratio of 1 : 2. Compounds 226 and 227 were synthesized in a similar way (Scheme 145). Xie et al. [155] reported a synthesis of oxazole derivatives 228 by oxidative cascade reaction of β-diketones with benzylamine, catalyzed by tetrabutylammonium iodide (Bu4NI), using 70% aqueous tert-butyl hydroperoxide as oxidant (ethyl acetate, 40°C). The reaction involved cascade formation of C–N, C–O, and C=N bonds via dual Csp3–H activation (Scheme 146).

H 2O

β-Diketone with a pyridazine fragment, 4-acetyl5,6-diphenylpyridazin-2(1H)-one (229), was converted into a variety of heterocyclic systems [156]. Compound 229 was first subjected to Claisen condensation (Na, AcONa, reflux) with ethyl acetate to obtain 1-(3-oxo-5,6-diphenyl-2,3-dihydropyridazin-4-yl)butane-1,3-dione (230, 83%) whose subsequent transformations are illustrated by Scheme 147. Ethyl 3-(3-hydroxy-5,6-diphenyl-2,3-dihydropyridazin-4-yl)3-oxopropanoate (231) prepared from 229 and diethyl carbonate in the presence of metallic sodium was used in the synthesis of 5H-pyrano[2,3-c]pyridazin-5-one



823

Scheme 145.

IL-SO3H

O

N

Me

O

Me

N

Me

O

O

O

Me

O N

Me

O

O

Me

N NH2

O S

Me

Me

N

Me

O

N

NH

S

Me

O

N

Me

N

–H2O

O

O

O O

IL-SO3H

Me

Me

NH O

O

Me

IL-SO3H

O

N H

O

Me

O

O O

O

H N

Me

O

NH

O O

Me

Me

Me

Me 225

IL-SO3H is a sulfonic acid-functionalized ionic liquid (SFIL). Me O

R1 R2

N

R3

S

N O O Me

O

R2

N

R3

S

N

NH

R4

O

R1

O

NH O O

R4 Me

Me

226

Me

227

R1 = R2 = R4 = H, Me; R3 = H, Me, Br; 226 (3 examples, 91–92%); 227 (3 examples, 90–94%).

Scheme 146. O O

O + PhCH2NH2

R

Bu4NI, t-BuOOH

N

R'

Ph

R'

O

R

228

R = R′ = Me, Ph; R = Me, R′ = Ph (40–61%). Bu4NI

t-BuOOH

[Bu4N]+ [IO]–

–t-BuOH

t-BuOOH

Ph O

O

PhCH2NH2

Ph

NH

O

[Bu4N]+ [IO2]–

–t-BuOH

N

O OEt

OEt

Me

HO Ph

N

O

Me

[O] Ph

N

OEt

HO Ph

O

I

ONBu4

OEt

Me

–[Bu4N]+ [IO]– –H2O

Ph

NH

O

O

H N

H 2O OEt

Me

N

PhCH2NH2 Me

OEt

Me

Ph

[Bu4N]+ [IO2]–

OEt

Ph

N

O [O]

N

O

Me

O 228


OEt

Ph Me

824


R Ph

N

N

Ph Me

Ph

O

N

Me

Ph

N

N

O N H R = H (88%), Ph (72%)

NH

N

Ph Na, NaOAc, Δ

Me N H 229

O

N

N H

H2NC(=X)NH2 EtOH, Δ

O

Ph

N

N

230

Ph

H2N

O Ph

N

N

O

N

N

Ph

Me

89%

NO2

N

Me

N

NO2

Me N

RCHO, EtOH concd. aq. HCl Ph

N

N H

O

N 91%

POCl3/PCl5

Me Ph

Cl 4-BrC6H4N2 Cl–

Ph

N

O

Ph

S

Ph

Cl

–HCl S

Ph

O Me

O

Concd. H2SO4

O

Ph

POCl3

Me

O

Me

NCCH2C(O)NH2 EtOH, Et3N

Ph

NH

O N H X = S (69%), NH (67%)

83%

O

N

N

O

N H

NH2OH EtOH, Et3N

Ph

Ph Ph

Me

87%

Ph

X

Ph

O

N H

RNHNH2 EtOH, Δ

N

NC Ph

62% N HSCH2COOH PhH, Δ

O

Ph

Cl

N 67%

H N

O

N

O

R

Me

Ph

(86%)

N

N

S

N

N

N

N

N

N

O N

H

N

C6H4Br-4 63%

NO2

63%

C6H4Br-4

N

Me Me

Ph

O

Ph

S

O R = Ph (57%),

Ph

Scheme 148. Ph

Ph

O

Ph

Me N

N H 229 Ph

O EtO

O

Ph

OEt N

OEt

Ph Ac2O

O

Ph N

O– Na+

N

O

O

OEt

O

N

Me Ph

O COOEt

N

O

231 (56%)

Ph N

Na

+

O

O

232 (81%)

Me

4-BrC6H4N2 Cl–

O

Ph

Ph COOEt

N

N

O

N

N H

O

O

Ph C6H4Br

N N

N

O

C6H4Br-4

N

233 (55%)



825

Scheme 149. Ph EtONa, Δ

O

Ph

O Me

N

N H 229

O Cl

N Ph

O

Ph

N H

O

O 234 (87%)

Cl

CHO

EtOH piperidine, Δ

+

O

O

Ph

O

Ph

EtOH piperidine

O N

N

Cl

O O 235 (55%)

Ph

O

Cl

Ph

OH N

Ph

N

Ph

O

O

N

O

N N

Ph NHX

X = H (51%), CN (71%)

N N H

H2NC(=NH)NHX NH2OH

Ph

O

H2NC(=O)NHNH2 OH N

N

O

N H

Ph

N O

O

Cl

OH

84% NH2OH

N

O

235

232 and 6,7-dihydro-5H-pyridazino[4′,5′ : 5,6]pyrano[2,1-c]pyridazine-5,6-dione 233 (Scheme 148). Scheme 149 illustrates the synthetic potential of compounds 234 and 235 obtained from β-diketone 229 and 6-chloro-4-oxo-4H-chromene-3-carbaldehyde [156]. 4.7. Sulfur-Containing Heterocycles It was surprising that, while preparing the present review, we have found almost no data on the synthesis of sulfur-containing heterocycles from β-diketones.

N N

67%

CONH2

O

Cl

Ph

OH N

Ph N

O

O

Ph

Ph

O

N 2H 4 · H 2O

234

Cl

NH

N

O

O

N

Ph

N

O

N NH

83% N 2H 4 · H 2O 235

Wang et al. [157] were the only to report one-pot synthesis of tetrasubstituted thiophenes from acetylacetone which was first treated with carbon disulfide in DMF in the presence of K2CO3, and alkyl bromide and α-bromo carbonyl compound were then added in succession. The thiophene ring was formed via intramolecular cyclization followed by modification. The yields were 86–89%, and the substitution pattern in thiophene ring depended on the order of reactant addition (Scheme 150). Fused thieno[2,3-b]thiophenes 236 were synthesized in 90–91% yield by reaction of


826


O

K2CO3, DMF CS2, 20°C

O

O

Me Me

O

O

RBr (1 equiv) Me

Me

Me

Me S

O

O

O

R' CH2Br (1 equiv)

Me

K2CO3 Me

Me RS

S

S–

RS

S

Me

–H2O R'

R'

S

SR

R = Et, PhCH2, R′ = COOEt, COPh.

Scheme 151. O Me

(1) K2CO3/H2O–Bu4NBr (2) CS2 (3) BrCH2COOEt

O R

Me

R

O EtO

OEt S

S

O

236

R = Me, Ph (90–91%).

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