Difluoromethanesulfonyl hypervalent iodonium ylides

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Research Cite this article: Arimori S, Matsubara O, Takada M, Shiro M, Shibata N. 2016 Difluoromethanesulfonyl hypervalent iodonium ylides for electrophilic difluoromethylthiolation reactions under copper catalysis. R. Soc. open sci. 3: 160102. http://dx.doi.org/10.1098/rsos.160102 Received: 10 February 2016 Accepted: 19 April 2016 Subject Category: Chemistry Subject Areas: organic chemistry/synthetic chemistry/organometallic chemistry Keywords: difluoromethylthiolation, hypervalent iodonium ylide, carbene, sulfur, fluorine Author for correspondence: Norio Shibata e-mail: [email protected] This article has been edited by the Royal Society of Chemistry, including the commissioning, peer review process and editorial aspects up to the point of acceptance. Electronic supplementary material is available at http://dx.doi.org/10.1098/rsos.160102 or via http://rsos.royalsocietypublishing.org.

Difluoromethanesulfonyl hypervalent iodonium ylides for electrophilic difluoromethylthiolation reactions under copper catalysis Sadayuki Arimori1 , Okiya Matsubara1 , Masahiro Takada1 , Motoo Shiro2 and Norio Shibata1 1 Department of Frontier Materials, Nagoya Institute of Technology, Gokiso, Showa-ku,

Nagoya 466-8555, Japan 2 Rigaku Corporation, 3-9-12 Matsubara-cho, Akishima, Tokyo 196-8666, Japan

Difluoromethanesulfonyl hypervalent iodonium ylides 2 were developed as electrophilic difluoromethylthiolation reagents for a wide range of nucleophiles. Enamines, indoles, β-keto esters, silyl enol ethers and pyrroles were effectively reacted with 2 affording desired difluoromethylthio (SCF2 H)substituted compounds in good to high yields under copper catalysis. The reaction of allyl alcohols with 2 under the same conditions provided difluoromethylsulfinyl (S(O)CF2 H) products in good yields. The difluoromethylthiolation of enamines is particularly effective with wide generality, thus the enamine method was nicely extended to the synthesis of a series of difluoromethythiolated cyclic and acyclic β-keto esters, 1,3-diketones, pyrazole and pyrimidine derivatives by a consecutive, two-step one-pot reaction using 2.

1. Introduction Fluorine (F) and sulfur (S) atoms have been individually recognized over the past couple of decades to be important structural elements with biological activities in drugs [1–10]. These facts, together with the recent successful observation on the market that the trifluoromethyl (CF3 ) group is frequently found in pharmaceuticals and agrochemicals [11–15], have led medicinal chemists to explore the use of the trifluoromethylthio (SCF3 ) group as a strategic functional component to assist in drug discovery [16–38]. In recent years, more than a

2016 The Authors. Published by the Royal Society under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/4.0/, which permits unrestricted use, provided the original author and source are credited.


(b) Shibata SO2CF3

Ph I

O +SCF H 2

R1

N

+SCF 3

reagent

R2 R2

I

2a–d reagent

+SCF H 2

O

N H

R1 6

S R

O 12

CF2H

R3 Ph N

O O

R

N 4

R1

SCF2H

SCF2H

R2 SCF2H

10

8 tBu

N N

N H 13

Ar2

Ph

1 reagent

SCF2H SCF2H

R3

SO2CF2H

Ar1

Ph SCF2H

14

Figure 1. Previous studies on (a) + SCF2 H reagent, (b) + SCF3 reagent and (c) hypervalent iodonium ylides as + SCF2 H reagents. dozen attractive synthetic methods for introduction of the SCF3 group into target compounds have been successively reported [16–38]. In this context, the difluoromethylthio group (SCF2 H) has emerged as a next potential subject in this field. While SCF3 is entirely lipophilic, the SCF2 H group has the potential to be a weak hydrogen-bonding donor, which results in a suitable hydrophilic/hydrophobic balance of SCF2 H-substituted molecules [39–42]. Thus, incorporation of SCF2 H into biologically active molecules should permit the efficient design of novel, viable drug candidates. There are several synthetic approaches available for SCF2 H-substituted compounds [43–59], such as nucleophilic reaction of appropriate thiolates to difluoromethyl carbine [43–53] and electrophilic or radical difluoromethylation of thiolates [54–56]. These methods rely upon the construction of a bond between S and CF2 H, and therefore have some limitations, although recently Goossen et al. provided a solution via copper-mediated difluoromethylation of organothiocyanates [57,58]. Impressively, Shen and co-workers [60] reported Sandmeyer-type direct diifluoromethylthiolation using an N-heterocyclic carbene difluoromethylthiolated silver complex to provide aryl SCF2 H compounds. The method is an ideal approach for introducing SCF2 H, but the substrate scope is limited to diazonium salts. The same group reported the first shelf-stable electrophilic difluoromethylthiolation reagent, Ndifluoromethylthiophtalimide or the Shen reagent (figure 1a) [61]. The Shen reagent is efficient, but new reagents and more methods to expand the accessibility to a wide variety of SCF2 H compounds are continuously required. Incidentally, we reported in 2013 that trifluoromethanesulfonyl (SO2 CF3 ) hypervalent iodonium ylide 1 is an efficient reagent for the electrophilic trifluoromethylthiolation reaction (figure 1b) [62]. Despite its carbon-SO2 CF3 structure, a reactive SCF3 species is unexpectedly, but effectively released from 1 via C–S bond cleavage under copper catalysis allowing it to be transferred into a wide variety of nucleophilic substrates including enamines, indoles, β-keto esters, pyrroles [63], allylsilanes, silyl enol ethers [64], allyl alcohols and boronic acids [65]. Inspired by this powerful reactivity and wide substrate generality and linked to the mechanistic uniqueness of iodonium ylide reagent 1, we describe herein an investigation of novel shelf-stable electrophilic difluoromethylthiolation reagents 2 and their reactivity towards a variety of nucleophiles (figure 1c). Difluoromethanesulfonyl (SO2 CF2 H) hypervalent iodonium ylides 2 were found to be useful for electrophilic difluoromethylthiolation of a variety of nucleophiles including enamines 3, indoles 5, pyrroles 7 and β-keto esters 9 to provide corresponding SCF2 H products 4, 6, 8 and 10. The reaction of allyl alcohols 11 with 2 under the same conditions provided difluoromethylsulfinyl (S(O)CF2 H) products 12, instead of SCF2 H products, in good yields. These methods can be applied to the synthesis of a series of difluoromethylthiolated cyclic and acyclic β-keto esters, 1,3-diketones 10, pyrazole 13 and pyrimidine 14 by a consecutive, two-step one-pot reaction using 2 under an enamine strategy. The reactivity and reaction mechanism of 2 are discussed.

................................................

O

N SCF2H

2

(c) this work O

rsos.royalsocietypublishing.org R. Soc. open sci. 3: 160102

previous work (a) Shen O


O

O Br

2a: R = H, 71% 2b: R = NO2, 85%

DMAc, 50°C, 20 h

S NaO CF2H (1.1 equiv.)

O mesityl-I(OAc)2 (1.1 equiv.) KOH (1.5 equiv.)

O SO2CF2H

SO2CF2H I

R MeCN, RT, 1 h or 5 h

R 17a: R = H, 79% 17b: R = NO2, 76%

2c: R = H, 39% 2d: R = NO2, 93%

Scheme 1. Preparation of difluoromethylthiolation reagents 2.

R1

R2

N

R1

reagent 2a (2.0 equiv.) CuBr (20 mol%)

R2

N

SCF2H

R3

R3 1,4-dioxane, RT, 5 h

O

O 4a–p

3a–p nBu NH CO2Me

Me

R

R = H, 4a: 81% R = OMe, 4b: 78% R = Br, 4c: 85%, 85%a

NH CO2Me

Me

Ph

p-Tol

NH CO2Me

Me

NH CO2Me

Ph

Ph

OMe

Ph

NH

O

Me

Ph Me

SCF2H 4m: 90%

4j: 80%

NH

Ph

SCF2H

SCF2H

Br

Ph

NH

Ph SCF2H

4n: 92%

NH CO2Me

4l: 84%

4k: 85%

O

Me

4h: 81%

CO2Me

SCF2H MeO

4i: 76%

SCF2H

NH

CO2Me

SCF2H OMe

CO2Et

Ph

4g: 84%

NH

CO2Me

NH

SCF2H

4f: 90%

NH

CO2Me

Ph

SCF2H

4e: 87%

Ph

NH

Ph

Me

SCF2H

Ph

4d: 84%

SCF2H

SCF2H

4o: 25% (41%)a

NH2

SCF2H

CO2Et

Ph O

SCF2H 4p: 83%

Scheme 2. Difluoromethylthiolation of enamines 3. Superscript ‘a’ denotes reagent 2d was used instead of 2a.

................................................

O

IPh

R

MeCN, RT, 5 h


16a: R = H 16b: R = NO2

R

3

SO2CF2H

PIDA (1.1 equiv.) KOH (1.5 equiv.)


N

R2

R1

1,4-dioxane, RT, 5 h

N R3

R3 5a–i

6a–i

SCF2H

SCF2H

SCF2H

SCF2H Me

Me N H 6a: 56%

Ph

N H

N H

6b: 85%

SCF2H

SCF2H

Me 6e: 75%

N H 6f: 74%

6d: 75%

6c: 55%

SCF2H

SCF2H

MeO N H

N H

Cl

N H

6g: 42%a, 31%

N R 6h: R = Me, 83% 6i: R = Bn, 50%

Scheme 3. Difluoromethylthiolation of indoles 5. Superscript ‘a’ denotes reagent 2d was used instead of 2a.

2. Results and discussion Preparation of difluoromethanesulfonyl hypervalent iodonium ylides 2 is shown in scheme 1. 2-Bromoacetophenone (16a) was treated with sodium difluoromethanesulfinate [66] in dimethylacetamide (DMAc) at 50°C for 20 h to give 2-difluoromethanesulfonylacetophenone (17a) in 79% yield. The reaction of 17a with phenyliodonium diacetate (PIDA) in the presence of potassium hydroxide provided 2a in 71% yield. Other reagents 2b, 2c and 2d were prepared using a method similar to that for 2a (scheme 1). All the reagents are crystals and stable enough for practical use, except for 2c. They can be maintained in a refrigerator (0°C). The most stable reagent is 2d and 19 F-NMR-based stability of the reagents can be ranked as 2d > 2b > 2a >>> 2c (electronic supplementary material, table S1). We began our study on difluoromethylthiolation with 2a using β-enamino ester 3a. After screening the reaction conditions (electronic supplementary material, table S2), a catalytic amount of Cu(I)Br (20 mol%) in 1,4-dioxane at room temperature was found to be the best set of conditions, and the difluoromethylthiolation reaction proceeded well providing α-SCF2 H-β-enamino ester 4a in 94% yield (run 4, electronic supplementary material, table S2). Substrate generality for the difluoromethylthiolation of β-enamino esters 3 by 2a was investigated (scheme 2). As shown in scheme 2, a wide range of β-enamino esters 3 were found to be suitable substrates, furnishing the corresponding SCF2 H-enamines 4 in high yields independent of the substitution on the nitrogen atom (benzyl, alkyl and aryl), the size of the ester group (OMe, OEt) or the enamine skeleton (methyl or aryl enamines). The reactions of enamino ketones 3m,n were also efficient under the same conditions to furnish α-SCF2 H-β-enamino ketones 4m,n in 90% and 92% yield, respectively, independent of the existence of enolizable ketone. The use of cyclic enamino ketone 3o was also attempted and the desired product 4o was obtained in 25% yield, which improved slightly to 41% after using reagent 2d. In addition, N-unprotected β-enamino ester 3p was applied under the same conditions to give a high yield of 4p (83%). The structure of 4 was confirmed by 19 F NMR, 1 H NMR, 13 C NMR, IR and mass spectra. The X-ray crystallographic structure of 4c was analysed (CCDC 1446329; electronic supplementary material, figure S1). Reagent 2a was found to have wide applicability as a difluoromethylthiolation reagent not only for enamines, but also for a variety of nucleophiles, such as indoles 5 (scheme 3), pyrroles 7 (scheme 4), β-keto esters 9a–c (scheme 5) and silyl enol ether 9d (scheme 5) under the same or slightly modified conditions to provide corresponding SCF2 H products 6, 8 and 10 in good yields. When yields were not satisfactory, they could be improved by using regent 2d instead of 2a, in particular, for the difluoromethylthiolation of pyrroles 7 (for optimized reaction conditions, see electronic supplementary material, table S3) and β-keto esters 9 (scheme 5). The reaction of allyl alcohol 11a with 2a under the optimized conditions of CuF2 in DMAc (see electronic supplementary material, table S4) gave a difluoromethylsulfinyl, S(O)CF2 H compound 12a

................................................

R1

4


R2

SCF2H

reagent 2a (2.0 equiv.) CuBr (20 mol%)


reagent 2d (2.0 equiv.) CuBr (20 mol%)

R

5

7a–e

8a–e O N H

R

SCF2H

R SCF2H N H R = Me, 8d: 64%, 26%a R = OEt, 8e: 91%

R = H, 8a: 55%, 46%a R = Me, 8b: 46%, 28%a R = Br, 8c: 51%, 38%a

Scheme 4. Difluoromethylthiolation of pyrroles 7. Superscript ‘a’ denotes reagent 2a was used. O CO2Et

reagent 2d (2.0 equiv.) K2CO3 (40 mol%) CuBr (20 mol%)

O CO2Et SCF2H

1,4-dioxane, RT 24 h

9a

O Me

H CO2Me

reagent 2d (2.0 equiv.) K2CO3 (40 mol%) CuBr (20 mol%)

10a: 36% O Me

SCF2H

1,4-dioxane, RT 24 h

9b

CO2Me 10b: 41%

reagent 2d (2.0 equiv.) CuF2 (20 mol%) K2CO3 (20 mol%) 9b

10b: 58% (19F NMR yield) DMAc, RT, 18 h

O

reagent 2d (2.0 equiv.) CuF2 (20 mol%) K2CO3 (20 mol%)

H

O SCF2H

CO2Allyl DMAc, RT, 16 h

9c O

SiMe3

CO2Allyl 10c: 75% O

reagent 2d (2.0 equiv.) CuBr (20 mol%)

SCF2H

1,4-dioxane, RT, 18 h 9d

10d: 35%

Scheme 5. Difluoromethylthiolation of β-keto esters 9a–c and silyl enol ether 9d. in moderate yield (46%) via a [2,3]-sigmatropic rearrangement, instead of an SCF2 H compound. Both the electron-donating (OMe) and electron-deficient (Cl) groups were applicable in the reaction (scheme 6). The difluoromethylthiolation reaction by 2 is particularly useful for the reaction of enamines. It should be noted that the difluoromethylthiolation of enamines, i.e. the enamine method, can be expanded to the

................................................

SCF2H

N H



N H

R


OH

reagent 2d (2.0 equiv.) CuF2 (20 mol%)

CF2H

Scheme 6. Reaction of allyl alcohols 11 with 2a.

NH2

(1) reagent 2d (2.0 equiv.) CuBr (20 mol%) (2) 1N HCl aq

O R2

R1

O O

1,4-dioxane, RT, 5 h–12 h

3p–y O CO2R¢ R1 SCF2H

R = H, R¢ = Et, 10p (10a): 73% R = Me, R¢ = Et, 10q: 63% R = Cl, R¢ = Et, 10r: 66% R = Br, R¢ = Me, 10s: 68%

SCF2H

10a, b, p–y

O

R

R2

R1

O

O

R

SCF2H

R2 SCF2H

R1 = Me, R2 = Ph, 10t: 71% R1 = Me, R2 = p-Br-Ph, 10u: 50% R1 = R2= Ph, 10v: 70%

CO2Me 10w (10b): R = Me, 64% 10x: R = OMe, 68% O SCF2H CO2Me 10y: 56%

Scheme 7. Enamine method: two-step, one-pot synthesis of difluoromethylthiolated β-keto esters and 1,3-diketones 10 from NH2 enamines 3p–y.

synthesis of α-SCF2 H-β-keto esters and α-SCF2 H-1,3-diketones by a one-pot combination of reactions that involves difluoromethylation of unprotected, NH2 -enamine esters and enamine ketones 3p–y with 2a and subsequent hydrolysis (scheme 7). A series of acyclic and cyclic α-SCF2 H-β-ketoesters and α-SCF2 H-1,3-diketones with a variety of substituents were obtained in high yields (10a, b, p–y: 63–73%). This enamine method has the advantage of higher yields relative to the direct reaction with β-keto esters. More importantly, acyclic α-SCF2 H, β-keto esters and ketones are not prepared using the Shen reagent [61], presumably due to the lower reactivity of acyclic substrates than cyclic ones (9a–c; scheme 5). The enamine method was further extended to allow the synthesis of biologically attractive SCF2 Hsubstituent heterocycles of pyrazole and pyrimidine by a similar two-step, one-pot, consecutive reaction procedure (scheme 8). First, enamine ketone 3z was treated with 2a in the presence of CuBr in dioxane at room temperature for 5 h. The addition of hydrazine monohydrate (5.0 equiv.) followed by heating and cyclohydration produced 4-difluoromethylthiolated pyrazole 13 in 68% yield. Similarly, the difluoromethylation of 3z with 2a followed by treatment with tert-butylcarbamidine hydrochloride (5.0 equiv.) and sodium methoxide (6.2 equiv.) under heated conditions gave 5-difluoromethylthiolated pyrimidine 14 in 65% yield. A proposed reaction mechanism of difluoromethylthiolation by reagent 2 is postulated in scheme 9. This mechanism is principally the same as a previous consecutive reaction mechanism [62,63] by SCF3 -reagent 1 involving successive (i) copper-catalyzed carbene-generation A, (ii) oxathiirene-2-oxide formation B, (iii) rearrangement to sulfoxide C, and (iv) collapse to thioperoxoate D. Hence, the SCF2 H thioperoxoate D is likely to be an actual species for electrophilic difluoromethylthiolation of nucleophiles via decarboxylation of E. Detection of the residues, Ar2 -I 15 (Ar2 = mesityl) and Ar1 CHO 16 (Ar1 = p-NO2 Ph) after the reaction with reagent 2d, together with the previous mechanistic investigation using SCF3 -reagent 1 [62,63], strongly support the reaction mechanism shown in scheme 9 (also see electronic supplementary material, scheme S3).

................................................

R = H, 12a: 46% R = Cl, 12b: 50% R = OMe, 12c: 41%

11a–e

6


O

R

DMAc, RT, 24 h

R

S


SCF2H

Ph

reagent 2a (1) (2.0 equiv.) CuBr (20 mol%)

O Ph

NMe2

N H

1,4-dioxane, 90°C, 5 h

13: 68%


3z

(2) tBuC(=NH)NH2HCl (5.0 equiv.)

tBu

N

Ph

N

MeONa (6.2 equiv.) 1,4-dioxane/EtOH 80°C, 20 h

SCF2H 14: 65%

Scheme 8. Enamine method: two-step, one-pot synthesis of difluoromethylthiolated pyrazole 13 and pyrimidine 14 from enamine 3z.

Ar2-I

O

15

SO2CF2H

Ar1

O

O

O CF2H

.. A

I-Ar2

S

Ar1

CF2H

CuBr

2

C

2d: Ar1 = p-NO2C6H5 Ar2 = mesityl

O

O

O

S

Ar1

O

O

O S

Ar1

CF2H

O

B O

O Ar1 16

O

Ar1

H CO2

O

Ar1 O

H O

SCF2H D

Nu-H

E Nu-SCF2H

Scheme 9. The proposed reaction mechanism.

The roles of copper catalysts, CuF2 and CuBr, depending on the substrates are not known. The Lewis acid centre of CuF2 is harder than the Lewis acid centre of CuBr; since Cu(II) is harder than Cu(I), F− is harder than Br− . The reaction mechanism in scheme 9 includes sulfur atoms with different oxidation states with different softness and hardness (from soft to hard: S, S(O) and SO2 ) [67], thus the catalyst of CuF2 or CuBr might also activate the different stage of each transition state. The more clear explanation should be required based on the detailed study such as molecular calculations.

3. Conclusion In conclusion, the preparation and application of novel electrophilic difluoromethylthiolation reagents 2a–d have been developed. Reagents 2 were found to be useful for the difluoromethylthiolation of a wide range of enamines, indoles, pyrroles and β-keto esters. Allylic alcohols were also reacted with 2 to provide allylic S(O)CF2 H compounds via sigmatropic rearrangement. The difluoromethylthiolation of enamines (enamine method) can be widely extended to the synthesis of a variety of SCF2 H-β-keto esters, 1,3-diketones, pyrazole and pyrimidine under a two-step one-pot procedure. High yields are obtained with a wide substrate scope and the reactions proceed at room temperature. This should be compared with Shen’s recent papers on SCF2 H transfer, which need elevated temperatures and prolonged reaction times [61] or stoichiometric amounts of a silver complex. Besides, the access to the SCF2 H-β-keto esters

................................................

N

7


(2) H2NNH2-H2O (5.0 equiv.)


material.

Authors’ contributions. S.A., O.M. and M.T. conducted and analysed the experiments and compounds. M.S. conducted X-ray crystallographic analysis and gave useful discussion. N.S. designed, directed the project and wrote the manuscript with contributions from S.A., O.M., M.T. and M.S. All authors contributed to discussions and gave final approval for publication. Competing interests. We declare we have no competing interests. Funding. This research is partially supported by the Platform Project for Supporting in Drug Discovery and Life Science Research from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), the Japan Agency for Medical Research and Development (AMED), the Advanced Catalytic Transformation (ACT-C) from the Japan Science and Technology (JST) Agency, the Kobayashi International Foundation and the Hoansha Foundation. Acknowledgement. We thank Daikin Industries Ltd for gifting a chemical for the preparation of sodium difluoromethanesulfinate.

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Data accessibility. The datasets supporting this article have been uploaded as part of the electronic supplementary

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and 1,3-diketones is more general by our reagents than the Shen reagent [61]. Because the fluorine often induces some expectation and something interesting [9,10,68–72], our new SCF2 H reagents would be efficient tools for the development of novel drugs and functional materials. Further investigation of reagent 2 for the difluoromethylthiolation of other substrates, such as heteroatom nucleophiles (N-, Sor P-nucleophiles), is underway.


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