One-step method for the synthesis of aryl olefins from

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Tetrahedron Letters 54 (2013) 1528–1530

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One-step method for the synthesis of aryl olefins from aryl aldehydes and aliphatic aldehydes Hanumant B. Borate a,⇑, Supriya H. Gaikwad b, Ananada S. Kudale a, Subhash P. Chavan a, Shrikant G. Pharande a, Vitthal D. Wagh a, Vikram S. Sawant a a b

Division of Organic Chemistry, CSIR–National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411 008, India Center for Material Characterization, CSIR–National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411 008, India

a r t i c l e

i n f o

Article history: Received 21 December 2012 Revised 31 December 2012 Accepted 3 January 2013 Available online 11 January 2013

a b s t r a c t A conceptually new one-step reaction affording unexpected aryl olefinic product from aromatic aldehyde, aliphatic aldehyde and malononitrile in the presence of acetic acid-ammonium acetate under mild reaction conditions without using any metal catalyst is reported. This novel reaction was used to prepare a number of substituted aryl olefins including new molecules. Ó 2013 Elsevier Ltd. All rights reserved.

Keywords: Aryl olefin Aromatic aldehyde Aliphatic aldehyde Malononitrile Dicyanoaniline

We have recently reported1 the synthesis of 4-alkyl-3-aryl-2,6dicyanoanilines by a multicomponent reaction of aromatic aldehyde, aliphatic aldehyde and malononitrile in the presence of morpholine. Careful analysis of the reaction mixture obtained when anisaldehyde was reacted with propionaldehyde and malononitrile in DMF in the presence of morpholine at 80 °C, afforded 3-(4-methoxyphenyl)-4-methyl-2,6-dicyanoaniline (1a) in 77% yield and 3-ethyl-4-methyl-2,6-dicyanoaniline (2a) in 8% yield while an olefinic compound, (E)-1-methoxy-4-(prop-1-enyl)benzene (3a), was obtained in 10% yield (Scheme 1). Literature survey undertaken for writing a review on 2,6-dicyanoanilines2 revealed that though there are a number of methods reported for the synthesis of 2,6-dicyanoanilines, formation of this type of compounds (3a) during the synthesis of 2,6-dicyanoanilines is not reported. Moreover, as per our knowledge, the crosscondensation of aromatic and aliphatic aldehydes with one-carbon elimination to afford olefin is not known in the literature. Hence, the products obtained in reactions of various aliphatic aldehydes with anisaldehyde and malononitrile in DMF in the presence of morpholine were analysed and it was observed that in reactions with anisaldehyde, the corresponding 4-alkyl-3-(4-methoxyphenyl)-2,6-dicyanoanilines 1 were obtained as major products while 3,4-dialkyl-2,6-dicyanoanilines 2 and trans-aryl olefins 3 were obtained as minor products. ⇑ Corresponding author. Tel.: +91 2025902546; fax: +91 2025902629. E-mail address: [email protected] (H.B. Borate). 0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tetlet.2013.01.008

Substituted styrenes are known to exhibit biological activities like hypolipidemic activity3 and antiplatelet activity3c and there are a number of methods reported to synthesize these compounds which mainly include Wittig reaction,4 Grignard reaction followed by dehydration,5 Suzuki cross-coupling,6 isomerization of allyl benzenes,7 modified Julia olefination,8 Suzuki–Miyaura cross coupling,9 coupling of alkenyl alkyl ethers with aryl Grignard reagent10 etc. Though these methods have their own advantages, some of these methods require bases like phenyllithium, catalysts which are either expensive or not easily available, preparation of intermediates like Grignard reagent or Wittig salts, less easily available starting materials like alkenyl- or arylboronic acids or 4-nitrophenyl sulfones etc. and some of the methods require multistep synthesis of starting materials. The present work involves the reaction of easily available aldehydes as such to obtain the substituted olefins 3 in one step without any need of special catalyst so the efforts were made to increase the yield of olefins 3 and the results are reported herein. Initially, morpholine was replaced with piperidine, triethylamine, sodium methoxide, potassium hydroxide, pyrrolidine etc. and DMF was replaced with ethanol, methanol, dioxane, acetonitrile, dimethyl sulfoxide, polyethylene glycol etc. but the yields could not be increased. Further attempts to carry out the reaction in the presence of various acids or combination of acids–bases were continued as there are reports11 that the reactions of Knoevenagel condensation products yield different products under different conditions. To our delight, it was found that the reaction of

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H. B. Borate et al. / Tetrahedron Letters 54 (2013) 1528–1530 MeO

OMe

Me

+

Et

CN Morpholine, DMF, 80 oC

CHO +

OMe

Me

Me

+

+

CN

NC CHO

NC

CN

CN NH 2

NH2 1a 77%

2a

3a

8%

10%

Me

Scheme 1. Reaction of anisaldehyde with propionaldehyde and malononitrile.

OMe MeO

OMe +

CHO

Malononitrile, AcOH, NH 4 OAc, MeO MeCN, 80oC

C4H9

OMe OMe + NC

C4 H9

Ar + CN

CHO 15%

C 4 H9 3b 60%

Ar

NC

CN NH2 1b 10%

Ar=3,4,5-trimethoxyphenyl

Scheme 2. Preparation of olefin 3b from 3,4,5-trimethoxybenzaldehyde and hexanal.

3,4,5-trimethoxybenzaldehyde with hexanal and malononitrile carried out in the presence of acetic acid-ammonium acetate in acetonitrile afforded the desired olefin 3b as the major product in 60% yield (Scheme 2). It is worth-mentioning that the reported procedure for this olefin12 involved preparation of cyclic phosphonium salt (for getting trans selectivity) by a 5-step sequence followed by its Wittig reaction with 3,4,5-trimethoxybenzaldehyde to afford 3b with trans/cis selectivity as 80:20. It was therefore felt worthwhile to explore this reaction further.

The generality of the reaction was checked13 by the reaction of various aromatic and aliphatic aldehydes (Table 1). The unoptimized isolated yields obtained in case of some of the aldehydes were in the range of 40–60% and the corresponding Knoevenagel products and dicyanoanilines were obtained as minor products with simultaneous formation of unidentified polymeric product. The desired products can be separated from other side products very easily by column chromatography as the desired products elute out in the first few fractions. Though the isolated yields are lower in some cases, the products are obtained in one step and reaction conditions are very mild and special catalysts are not required. A wide variety of olefins can be prepared using this conceptually new reaction. It was observed that the polymeric product was not formed in the blank reaction run under identical conditions without addition of aldehydes. It was also found out that the reaction conditions can tolerate different functional groups and various olefins can be prepared from the corresponding aliphatic and aromatic aldehydes (Table 1). The geometry of double bond formed was assigned based on coupling constants in 1H NMR spectra (copies given in the Supplementary data) and comparison with reported data (References given in Table 1). It is also worth-mentioning that the products obtained were trans olefins and the amounts of the cis isomers were negligible to be detected by 1H NMR spectroscopy. The reaction does not take place in the absence of malononitrile. The corresponding Knoevenagel products are the intermediates which are formed within a few minutes after addition of all reactants. The reaction takes place even in the absence of solvent by stirring the mixture of all reactants at 80 °C but the corresponding Knoevenagel product is obtained in substantial amounts and the reaction carried out in solvent is preferred. In the absence of ammonium acetate, only the corresponding

Table 1 Synthesis of olefins 3 Entry

Aromatic aldehyde

Aliphatic aldehyde

Product 3 (Refs.)b

H 3CO

Yielda

H3 CO

A: 60 B: 57 C: 58

n-C 4H 9

1

H 3CO

CHO

CH3(CH2)4CHO

H3 CO

H 3CO

2 3 4 5 6

3,4,5-Trimethoxybenzaldehyde H3 CO

CHO

H3 CO

CHO

1-Naphthaldehyde

7

O 2N

CHO

8

O 2N

CHO

9

NC

10

CHO

13

CHO

O

11 12

CHO

O

CHO

PMBO

CH3(CH2)10CHO CH3CH2CHO CH3(CH2)4CHO CH3CH2CHO CH3(CH2)10CHO

CHO

S

3b (12)

H3 CO

H3 CO

3d (14)

Ar CH3

S

CH3(CH2)10CHO

O2 N

CH3(CH2)4CHO

NC

3e Ar = 1-naphthyl

A: 51

A: 37 B: 48

n-C 4 H9 3i (17) CH3 O

3j

(18)

CH3 3k CH3 PMBO

A: 46

A: 39

3h

O

A: 49

n-C4 H9 (16)

3g

CH3CH2CHO

A: 51

n-C10 H 21 3f (15)

n-C10H 21

CH3CH2CHO

CH3CH2CHO

(7b)

n-C 4H 9

O2 N

3l

A: 52 A: 56 A: 39 A: 38 A: 42

n-C 5 H 11

CH3(CH2)5CHO Cl

CH 3 3a

H3 CO

CH3(CH2)4CHO

CHO

Cl

n-C10 H 21 3c Ar = 3,4,5-trimethoxyphenyl

Ar

Cl 3m

A: 21

Cl

a Acid-base used: A—Acetic acid, ammonium acetate; B—Alanine, ammonium acetate; C—Proline, ammonium acetate. The yields given are unoptimized yields for the isolated desired products. In addition, the corresponding Knoevenagel products and dicyanoanilines were isolated in minor amounts in varying yields. b The numbers in parentheses indicate the literature reference numbers for the corresponding products used for comparison of spectral data.

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H. B. Borate et al. / Tetrahedron Letters 54 (2013) 1528–1530

O

Ar

Ar

H

Acid or base

CN

R NC

CN

R

O R

CN

+ H

CN

+ H

CN

Ar NC NC

R

NC Ar

H

H +

NC

CN I

NC

CN II

CN

CN CN

CN III

Ar

R

NC

NC

H

Acid or base

Base

CN

Ar

R 3

IV

Scheme 3. The proposed mechanism for formation of olefin 3.

Knoevenagel product is formed and the olefinic product is not obtained. Ammonium acetate can be replaced with ammonium formate while acetic acid can be replaced with proline or alanine affording similar yields. Although the exact mechanism has not been ascertained, the proposed plausible mechanism for the present reaction is depicted in Scheme 3. In conclusion, the present manuscript reports preliminary results19 about a conceptually new method for the synthesis of various aryl olefins using easily available starting materials. The products obtained can be studied for various biological activities as aryl olefins are known to exhibit hypolipidemic activity3 and antiplatelet activity3c or they can be used as intermediates for the synthesis of new molecules taking advantage of various functional groups as depicted in Table 1. Due to the easy availability of starting materials and potential to prepare aryl olefins with a variety of substituents, this method would be useful in organic synthesis as well as medicinal chemistry. Acknowledgment We thank DST, New Delhi and FDC Ltd, Mumbai for partial financial support. Supplementary data Supplementary data (experimental procedures and spectral data) associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.01.008. References and notes 1. Sawargave, S. P.; Kudale, A. S.; Deore, J. V.; Bhosale, D. S.; Divse, J. M.; Chavan, S. P.; Borate, H. B. Tetrahedron Lett. 2011, 52, 5491–5493.

2. Borate, H. B.; Kudale, A. S.; Agalave, S. G. Org. Prep. Proced. Int. 2012, 44, 467– 521. 3. (a) Chamorro, G.; Garduño, L.; Sánchez, A.; Labarrios, F.; Salazar, M.; Martínez, E.; Diaz, F.; Tamariz, J. Drug Dev. Res. 1998, 43, 105–108; (b) Labarrios, F.; Garduño, L.; Vidal, M. D. R.; Garcia, R.; Salazar, M.; Martínez, E.; Diaz, F.; Chamorro, G.; Tamariz, J. J. Pharm. Pharmacol. 1999, 51, 1–7; (c) Popławski, J.; Łozowicka, B.; Dubis, A. T.; Lachowska, B.; Witkowski, S.; Siluk, D.; Petrusewicz, J.; Kaliszan, R.; Cybulski, J.; Strzałkowska, M.; Chilmonczyk, Z. J. Med. Chem. 2000, 43, 3671–3676; (d) Magdziarz, T.; Łozowicka, B.; Gieleciak, R.; Ba˛k, A.; Polan´ski, J.; Chilmonczyk, Z. Bioorg. Med. Chem. 2006, 14, 1630–1643. 4. (a) Tuntiwachwuttikul, P.; Pancharoen, O.; Jaipetch, T.; Reutrakul, V. Phytochemistry 1981, 20, 1164–1165; (b) Mangold, B. L. K.; Hanna, P. E. J. Med. Chem. 1982, 25, 630–638. 5. (a) Sharma, A.; Joshi, B. P.; Sinha, A. K. Bull. Chem. Soc. Jpn. 2004, 77, 2231–2235; (b) Kumar, R.; Sharma, A.; Sharma, N.; Kumar, V.; Sinha, A. K. Eur. J. Org. Chem. 2008, 5577–5582. 6. Peyroux, E.; Berthiol, F.; Doucet, H.; Santelli, M. Eur. J. Org. Chem. 2004, 1075– 1082. 7. (a) Shulgin, A. T. Can. J. Chem. 1965, 43, 3437–3440; (b) Mayer, M.; Welther, A.; von Wangelin, A. J. ChemCatChem 2011, 3, 1567–1571. 8. Mirk, D.; Grassot, J.-M.; Zhu, J. Synlett 2006, 1255–1259. 9. Zhang, H.-P.; Dai, Y.-Z.; Zhou, X.; Yu, H. Synlett 2012, 1221–1224. 10. Xie, L.-G.; Wang, Z.-X. Chem. Eur. J. 2011, 17, 4972–4975. 11. (a) Green, B.; Khaidem, I. S.; Crane, R. I.; Newaz, S. S. Tetrahedron 1976, 32, 2997–3001; (b) Khaidem, I. S.; Singh, S. L.; Singh, L. R.; Khan, M. Z. R. Indian J. Chem. 1996, 35B, 911–914; (c) Helmy, N. M.; El-Baih, F. E. M.; Al-Alshaikh, M. A.; Moustafa, M. S. Molecules 2011, 16, 298–306. 12. Lawrence, N. J.; Beynek, H. Synlett 1998, 497–498. 13. Spectral data for all olefins prepared by this method are given in the Supplementary data. Preparation of (E)-5-(hex-1-en-1-yl)-1,2,3-trimethoxybenzene: To a mixture of 3,4,5-trimethoxybenzaldehyde (0.784 g, 0.004 mol), hexanal (0.5 g, 0.005 mol) and malononitrile (0.66 g, 0.01 mol), was added 30 ml of acetonitrile followed by the addition of glacial acetic acid (0.42 ml 0.0075 mol). The reaction mixture was stirred for 10 min and then ammonium acetate (0.385 g, 0.005 mol) was added. The reaction was stirred at 80 °C for 8 h. The mixture was then allowed to come to room temperature, filtered through Whatmann filter paper and the filtrate was concentrated on rotavapor. The residual oil was then partitioned between water and ethyl acetate and the organic extract was dried over sodium sulfate, concentrated and purified over silica gel using ethyl acetatepet ether (3% ethyl acetate in pet ether) as an eluent to give (E)-5-(hex-1-en-1yl)-1,2,3-trimethoxybenzene as a colourless liquid (0.6 g, 60%); IR (chloroform): 810, 925, 1377, 1506, 1582, 1651, 2929, 2989 cm 1. 1H NMR (200 MHz, CDCl3): d 0.93 (t, J = 7 Hz, 3H), 1.30–1.56 (m, 4H), 2.27 (q, J = 7 Hz, 2H), 3.84 (s, 3H), 3.88 (s, 6H), 6.14 (dt, J = 16, 7 Hz, 1H), 6.32 (d, J = 16 Hz, 1H), 6.58 (s, 2H); 13C NMR (50 MHz, CDCl3): d 13.7, 22.0, 31.3, 32.4, 55.7 (2C), 60.6, 102.6 (2C), 129.4, 130.5, 133.5, 136.9, 153.0 (2C); HRMS (ESI) m/z calcd for [C15H22O3 + Na]+: 273.1461, found 273.1462; [C15H22O3 + H]+: 251.1642, found 251.1642. 14. Han, L.-B.; Kambe, N.; Ogawa, A.; Ryu, I.; Sonoda, N. Organometallics 1993, 12, 473–477. 15. Hodgson, D. M.; Fleming, M. J.; Stanway, S. J. J. Org. Chem. 2007, 72, 4763–4773. 16. Hadebe, S. W.; Sithebe, S.; Robinson, R. S. Tetrahedron 2011, 67, 4277–4282. 17. Negishi, E.; Takahashi, T.; Baba, S.; Van Horn, D. E.; Okukado, N. J. Am. Chem. Soc. 1987, 109, 2393–2401. 18. Bauld, N. L.; Yang, J. J. Phys. Org. Chem. 2000, 13, 518–522. 19. Provisional Indian patent filed; Provisional Filing Number: 3486/DEL/2012 dt Nov 9, 2012.