Clean and atom-economic synthesis of alpha-phenylselenoacrylonitriles and alpha-phenylseleno- alpha,beta-unsaturated esters by knoevenagel reaction under solvent-free conditions

Abstracts

A simple, clean and efficient method has been developed for the synthesis of alpha-phenylselenoacrylonitriles and alpha-phenylseleno-alpha,beta-unsaturated esters by a one-pot reaction of aldehydes with phenylselenoacetonitrile or ethyl(phenylseleno)acetate respectively, in the presence of a solid supported catalyst (KF/Al2O3), without any solvent.

solvent-free reaction; Knoevenagel condensation; phenylselenoacrylonitriles

Um método simples e eficiente foi desenvolvido para a síntese de alfa-fenilselenoacrilonitrilas e ésteres alfa-fenilseleno-alfa,beta-insaturados através, respectivamente, da reação one-pot de aldeídos com fenilselenoacetonitrila ou acetato de (fenilseleno)etila na presença de um catalisador em suporte sólido (KF/Al2O3), sem o uso de solvente.

SHORT REPORT

Clean and atom-economic synthesis of a-phenylselenoacrylonitriles and a-phenylseleno- a,b-unsaturated esters by knoevenagel reaction under solvent-free conditions

Gelson Perin^{I, *}; Raquel G. Jacob^II; Giancarlo V. Botteselle^I; Emerson L. Kublik^I; Eder J. Lenardão^{III, *}; Rodrigo CellaII, ^#; Paulo César Silva dos Santos^II

^IDepartamento de Química Orgânica, Universidade Federal de Pelotas, 96010-900 Pelotas - RS, Brazil

^IIDepartamento de Química, Universidade Federal de Santa Maria, Santa Maria - RS, Brazil

^IIIDepartamento de Química Analítica e Inorgânica, Universidade Federal de Pelotas, 96010-900 Pelotas - RS, Brazil

ABSTRACT

A simple, clean and efficient method has been developed for the synthesis of a-phenylselenoacrylonitriles and a-phenylseleno-a,b-unsaturated esters by a one-pot reaction of aldehydes with phenylselenoacetonitrile or ethyl(phenylseleno)acetate respectively, in the presence of a solid supported catalyst (KF/Al₂O₃), without any solvent.

Keywords: solvent-free reaction, Knoevenagel condensation, phenylselenoacrylonitriles

RESUMO

Um método simples e eficiente foi desenvolvido para a síntese de a-fenilselenoacrilonitrilas e ésteres a-fenilseleno-a,b-insaturados através, respectivamente, da reação one-pot de aldeídos com fenilselenoacetonitrila ou acetato de (fenilseleno)etila na presença de um catalisador em suporte sólido (KF/Al₂O₃), sem o uso de solvente.

Introduction

Organoselenium compounds have been used as key intermediates in several modern organic synthesis.¹ Among the different classes of organoselenium compounds, vinyl selenides constitute a very useful intermediate, because the versatile reactivities of the selanyl group and the carbon-carbon double bond.² Special attention has been devoted to the synthesis of vinyl selenides substituted by electron-withdrawing groups, like nitriles 3 and esters 4. These highly functionalized compounds can be submitted to several transformations, including their use in [2+2] cycloaddition reactions,³ Diels-Alder reactions,^4-6 and like Michael acceptors.^4,7

The a-phenylseleno-a,b-unsaturated esters 4 have been prepared by different routes,² including selenilation of ester enolates,⁸ oxidative elimination of a,a-bis(phenylselanyl)esters,⁸ dehydrochlorination of a-phenylseleno-b-chloro esters⁸ and of a-phenylseleno-a-chloro esters,⁹ and Wittig-type reactions.^6,10 On the other hand, the preparation of a-phenylselenoacrylonitriles 3 was studied in a minor extent.^2,3,4,11,12 Between the described methods for preparation of 3, those involving Wittig-type reactions are the most efficient.^4,12 Recently, Chinese authors have been described the preparation of several a-phenylseleno-a,b-unsaturated nitriles in moderate to good yields via a-phenylselenenyl cyanomethylene triphenylarsorane.¹² However, this method is restrict to aromatic aldehydes and no mention regarding the stereochemistry of the products was made. Besides these drawbacks, these protocols make use of environmentally harmful, volatile organic solvents, inert atmosphere, low temperatures (-78 °C)⁴ or heating,¹² expensive and stoichiometric reagents and strong bases. More recently, an improvement was achieved with the use of MW under solvent-free conditions in the selective preparation of 4, in reasonable yields, by a Wittig-type reaction of selenophosphorane with aldehydes.⁶ In contrast to Wittig type reactions, Knoevenagel condensation is an atom-economic and cleaner tool for constructing the a,b-unsaturated structure unit from a carbonyl and an active methylene components.¹³ Knoevenagel reactions can be promoted by solid supported reagents,¹⁴ fluoride anion,¹⁵ and KF/Al₂O₃¹⁶ and the generation of large amounts of salts at the end of the synthesis as well as the use of stoichiometric strong bases can be avoided.

Looking for cleaner approaches to classical syntheses, we have developed several protocols involving solid supported catalyst under solvent-free conditions and MW irradiation.^17,18 As a continuation of our studies directed toward the development of new methods for the synthesis of vinyl selenides and their great potential in organic synthesis,² we report herein the synthesis of a-phenylselenoacrylonitriles 3 and a-phenylseleno-a,b-unsaturated esters 4 by means of Knoevenagel reactions between phenylselenoacetonitrile 1a or ethyl- phenylselenoacetate 1b and aldehydes 2, using KF/Al₂O₃ without any solvent (Scheme 1, Table 1).

Experimental

General remarks

¹H and ¹³C NMR spectra of CDCl₃ solutions were recorded with a 200 MHz or a 400 MHz spectrometer as noted. Chemical shifts are expressed as parts per million (ppm) downfield from tetramethylsilane as an internal standard. Mass spectra (EI) were obtained at 70 eV with a Hewlett Packard EM/CG HP-5988A spectrometer, infrared spectra were acquired on a Perkin-Elmer 1310 spectrometer and elemental analyses were performed with a Vario EL Elemental Analysis System. The microwave reactions were performed on a domestic apparatus, Brastemp model VIP-38 Sensor Crisp operating at 2.45 GHz. Merck's silica gel (230-400 mesh) was used for flash chromatography.

Preparation of alumina supported potassium fluoride ¹⁹

To a 100 mL beaker was added alumina (6.0g of Al₂O₃ 90, 0.063-0.200 mm, Merck), KF.2H₂O (4.0 g) and water (8 mL). The suspension was stirred for 1 h at 65 °C, dried at 80 °C for 1 h and for additional 4 h at 300 °C in an oven and then cooled in a desiccator. The content of KF is about 30 % (m/m ).

General procedure for the synthesis of a-phenylselenoacrylonitriles (3a-e)

A mixture of aldehyde 2 (1.2 mmol) and phenylselenoacetonitrile 1a²⁰ (0.197g; 1 mmol) was added to KF/Al₂O₃ (0.1g, obtained as described above). The whole mixture was stirred at room temperature until completion of the reaction (4-5 h, Table 1), as monitored by thin layer chromatography (TLC). The catalyst was filtered off, washed with ethyl acetate (10 mL) and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography over silica gel (SiO₂) eluting with hexanes/ethyl acetate (99:1), yielding 3 as mixture of Z and E isomers.

3-(2-Furyl)-2-phenylselanylacrylonitrile (3a)

The aforementioned procedure was used, employing 2-furfuraldehyde 2a. Yield: 0.220g (80%); Z:E ratio = 85:15. Z isomer: ¹H NMR (400 MHz, CDCl₃) d 6.48-6.50 (m, 1H), 6.97 (d, J 3.6 Hz, 1H), 7.29 (s, 1H), 7.32-7.44 (m, 3H), 7.52-7.53 (m, 1H), 7.61-7.64 (m, 2H); E isomer: d 6.54-6.56 (m, 1H), 6.86 (d, J 3.6 Hz, 1H), 7.32-7.44 (m, 4H), 7.68-7.71 (m, 3H); Z + E isomers: ¹³C NMR (100 MHz, CDCl₃) d 93.5, 100.2, 112.4, 112.6, 115.4, 116.3, 117.0, 117.1, 126.7, 127.8, 128.7, 129.4, 129.5, 130.3, 133.5, 133.6, 135.7, 136.4, 144.9, 145.0, 149.5, 150.3; IR (film) n_max/cm^-1: 2203 (CN). MS m/z (rel. int.) 275 (M⁺, 52.7), 157 (59.9), 77 (89.0), 51 (100.0). Anal. Calc. for C₁₃H₉NOSe: C, 56.95; H, 3.31; N, 5.11. Found: C, 56.40; H, 3.48, N, 4.68.

3-Phenyl-2-phenylselanylacrylonitrile (3b) ⁴

The aforementioned procedure was used, employing benzaldehyde 2b. Yield: 0.202g (71%); Z:E ratio = 71:29. Z + E isomers: ¹H NMR (200 MHz, CDCl₃) d 7.35-7.42 (m, 6H), 7.51 (s, 1H), 7.61-7.66 (m, 2H), 7.72-7.77 (m, 2H); ¹³C NMR (50 MHz, CDCl₃) d 97.9, 104.0, 117.2, 117.5, 127.7, 127.8, 128.6, 128.8, 128.9, 129.0, 129.6 (2C), 129.7 (2C), 130.1, 130.9, 133.8, 134.1, 134.4, 135.5, 145.8, 150.1.

3-(2-Chlorophenyl)-2-phenylselanylacrylonitrile (3c)

The aforementioned procedure was used, employing 2-chlorobenzaldehyde 2c. Yield: 0.163g (51%); Z:E ratio = 79:21. Z isomer: ¹H NMR (200 MHz, CDCl₃) d 7.15-7.60 (m, 8H), 7.66 (s, 1H), 7.82-7.92 (m, 1H); E isomer: d 7.15-7.60 (m, 8H), 7.72 (s, 1H), 7.82-7.92 (m, 1H); Z + E isomers: ¹³C NMR (50 MHz, CDCl₃) d 101.9, 107.1, 116.2, 116.8, 126.5, 126.9, 127.1, 128.6, 129.3, 129.5, 129.6, 129.7, 129.8, 129.9, 131.0, 131.4, 132.0, 133.9, 134.7, 135.4, 142.5, 142.6, 144.8; IR (film) n_max/cm^-1: 2206 (CN). MS m/z (rel. int.) 320 (M⁺ + 1, 10.0), 318 (24.0), 286 (19.0), 284 (94.0), 207 (12.0), 162 (5.0), 157 (28.0), 127 (30.0), 77 (100.0), 51 (64.0). Anal. Calc. for C₁₅H₁₀ClNSe: C, 56.54; H, 3.16; N, 4.40. Found: C, 56.59; H, 3.49; N, 3.96.

5,9-dimethyl-2-phenylselanyl-2,8-decadienenitrile (3d)

The aforementioned procedure was used, employing citronellal 2d. Yield 0.140g (42%); Z:E ratio = 60:40. Z isomer: ¹H NMR (200 MHz, CDCl₃) d 0.92 (d, J 6.4 Hz, 3H), 1.05-1.42 (m, 2H), 1.59 (s, 3H), 1.68 (s, 3H), 1.88-2.08 (m, 2H), 2.20-2.53 (m, 1H), 4.98-5.17 (m, 1H), 6.81 (t, J 7.8Hz, 1H), 7.20-7.42 (m, 3H), 7.48-7.63 (m, 2H); E isomer: d 0.94 (d, J 6.2 Hz, 3H), 1.05-1.42 (m, 2H), 1.59 (s, 3H), 1.68 (s, 3H), 1.88-2.08 (m, 2H), 2.20-2.53 (m, 1H), 4.98-5.17 (m, 1H), 6.87 (t, J 7.4Hz, 1H), 7.20-7.42 (m, 3H), 7.48-7.63 (m, 2H); Z + E isomers: ¹³C NMR (50 MHz, CDCl₃) d 17.5, 17.6, 19.3, 19.5, 25.2, 25.3, 25.6, 32.3, 36.4, 36.5, 39.2, 40.6, 100.6, 104.3, 115.9, 117.2, 123.9, 127.2, 127.9, 128.5, 128.7, 129.4, 131.5, 133.4, 134.1, 153.0, 156.4; IR (film) n_max/cm^-1: 2211 (CN). MS m/z (rel. int.) 333 (M⁺, 5.0), 207 (4.0), 176 (74.0), 156 (33.0), 149 (14.0), 77 (53.0), 69 (100.0), 55 (75.0). Anal. Calc. for C₁₈H₂₃NSe: C, 65.05; H, 6.98; N, 4.21. Found: C, 65.07; H, 7.03; N, 3.96.

5,9-dimethyl-2-phenylselanyl-2,4,8-decatrienenitrile (3e)

The aforementioned procedure was used, employing citral 2e. Yield 0.132g (40%); Z:E ratio = 57:43. Z isomer: ¹H NMR (400 MHz, CDCl₃) d 1.62 (s, 3H), 1.70 (s, 3H), 1.93 (s, 3H), 2.12-2.37 (m, 4H), 5.05-5.14 (m, 1H), 6.33 (d, J 10.8Hz, 1H), 7.29-7.38 (m, 3H), 7.43 (d, J 10.8Hz, 1H), 7.50-7.62 (m, 2H); E isomer: d 1.61 (s, 3H), 1.70 (s, 3H), 1.93 (s, 3H), 2.12-2.37 (m, 4H), 5.05-5.14 (m, 1H), 6.44 (d, J 11.2Hz, 1H), 7.29-7.38 (m, 3H), 7.35 (d, J 11.2Hz, 1H), 7.50-7.62 (m, 2H); Z + E isomers: ¹³C NMR (50 MHz, CDCl₃) d 17.7, 17.8, 24.5, 25.6, 26.3, 26.7, 29.6, 33.2, 40.3, 95.7, 96.2, 122.2, 122.3, 127.9, 128.4, 128.5, 128.6, 128.7, 133.9, 135.0, 135.1, 138.1, 138.5, 138.7, 138.8, 139.0, 139.1, 154.0, 154.1, 157.7, 157.8; IR (film) n_max/cm^-1: 2201 (CN). MS m/z (rel. int.) 331 (M⁺, 4.0), 207 (9.0), 183 (54.0), 157 (32.0), 77 (24.0), 69 (100.0), 51 (13.0). Anal. Calc. for C₁₈H₂₁NSe: C, 65.45; H, 6.41; N, 4.24. Found: C, 65.58; H, 6.48; N, 4.25.

General procedure for the synthesis of a-phenylseleno-a,b-unsaturated esters (4a and 4b)

A mixture of aldehyde 2 (1.2 mmol) and ethyl phenylselenoacetate 1b²¹ (0.244g; 1 mmol) was added to KF/Al₂O₃ (0.1g, obtained as described above). The whole mixture was stirred at room temperature for 5 hours. The catalyst was filtered off, washed with ethyl acetate (10 mL) and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography over silica gel (SiO₂) eluting with hexanes/ethyl acetate (99:1), yielding 4 as mixture of Z and E isomers.

Ethyl 3-(2-furyl)-2-phenylselanylpropenoate (4a) ^6,10,22

The aforementioned procedure was used, employing 2-furfuraldehyde 2a. Yield: 0.129g (40%); Z:E ratio = 63:37. Z + E isomers: ¹H NMR (400 MHz, CDCl₃) d 1.04 and 1.18 (2t, J 7.2 Hz, 3H), 4.05 and 4.10 (2q, J 7.2 Hz, 2H), 6.37 (dd, J 3.6 and 2.0 Hz, 1H), 6.48 (dd, J 3.6 and 2.0 Hz, 1H), 6.69 (d, J 3.4 Hz, 1H), 6.77 (s, E isomer), 8.03 (s, Z isomer, E + Z = 1H), 7.14-7.60 (m, 5H).

Ethyl 3-phenyl-2-phenylselanylpropenoate (4b) ^6,10

The aforementioned procedure was used, employing benzaldehyde 2b. Yield: 0.129g (39%); Z:E ratio = 55:45. Z + E isomers: ¹H NMR (400 MHz, CDCl₃) d 1.06 and 1.10 (2t, J 7.2 Hz, 3H), 3.98 and 4.05 (2q, J 7.2 Hz, 2H), 7.04 (s, E isomer), 8.15 (s, Z isomer; E + Z = 1H), 7.16-7.72 (m, 10H).

Results and Discussion

In order to find the best experimental conditions to access 3, a detailed study was performed using furfural 2a as the standard aldehyde. When the reaction was performed using KOH, t-BuOK or KF/Al₂O₃ (stoichiometric amounts) without any solvent or in THF, the desired product was obtained in good yields (78-80%) after 1-4 hours at room temperature. However, when the same protocol was applied to other aldehydes (2b-e), the use of KOH or t-BuOK allowed incomplete consumption of starting material 1a and decomposition of product in all conditions tested.

For example, when phenylselenoacetonitrile 1a was submitted to reaction with benzaldehyde 2b, the a-phenylseleno cinnamonitrile 3b was obtained in unsatisfactory yields (20-25%, after 3-4 hours at rt), together with diphenyl diselenide (40-44%). However, using KF/Al₂O₃ (30%), 3b was obtained in 71% isolated yield, along with a small amount of unreacted 1a (4%). When the same protocol was performed in THF, the product was obtained in poor yield (10%), with incomplete consumption of the starting materials and formation of diphenyl diselenide. The use of higher temperature or a larger amount of solid supported catalysts or aldehyde was not effective to complete consumption of the starting materials and there has been no increase in the yields.

Aiming to reduce the reaction time, we tested the reaction using MW irradiation. The use of "MORE Chemistry" (microwave oven-induced reaction enhancement) under solvent-free conditions is well stablished.²³ In general increases in rates, yields and purities of products have been associated with this technique. In fact, when a mixture of furfural 2a and phenylselenoacetonitrile 1a was irradiated with MW (427W) in the presence of KF/Al₂O₃ (30%), 3a was obtained after 8 min (55% yield). Starting from benzaldehyde 2b, phenylseleno cinnamonitrile 3b was obtained after 20 min under MW in 37% yield. Attempts to increase the yields of 3a,b were unsuccessful. Even increasing the power and time of irradiation no significant change in yields and products distribution was observed.

Thus, the optimum condition for Knoevenagel condensation of 1a and 2 (Scheme 1) consists of stirring for 4-5 h at room temperature a mixture of 1a and 2 in the presence of 0.1g of KF/Al₂O₃ (30%) as base, without any solvent. The products were obtained in moderate to good yields (40-80%, entries 1-5, Table 1). The presence of an electron-withdrawing group in the aromatic ring of the aldehyde (2c, entry 3) caused a reduction in the yield. Similarly, aliphatic aldehydes citronellal and citral (2d and 2e, entries 4 and 5) gave moderated yields of 3d and 3e.

Other bases, such as K₂CO₃, Na₂CO₃, Et₃N or piperidine, and the use of solvents (CH₃CN, EtOH, DMF) proved to be less effective. By using only Al₂O₃, no reaction took place in all conditions tested and 1a was recovered unchanged.

Attempts to directly reuse the solid supported catalysts in a new condensation reaction were unsuccessful, with a complete loss of the catalytic activity. However, the solid supports were regenerated by new treatment with KF. The KF/Al₂O₃ (30%) prepared from used Al₂O₃ showed the same catalytic activity, affording 3 in almost identical yields.

The same protocol was performed using ethyl phenylselenoacetate 1b, affording the products 4a,b in moderate yields after purification (entries 6 and 7, Table 1). The Knoevenagel reaction have been already employed to synthesize this class of compounds.²² However, the procedure early described makes use of strong Lewis acid (TiCl₄), volatile organic solvents (CCl₄ and THF), low temperature and is limited to aromatic aldehydes.

Although the yields of the method described in Scheme 1 are moderate (39 – 80%, Table 1), the simplicity of this clean, solvent-free and atom-economic method makes it suitable for the preparation of products derived from aromatic and aliphatic aldehydes.

For all the substrates, the formation of Z and E isomers mixture was observed. The stereochemistry of the obtained olefins 3 and 4 was assigned by ¹H NMR.^4,6,10,22 However, for 3b this ratio could not be determined directly by ¹H NMR, because the vinylic hydrogen signals overlaped with the aromatic hydrogens. The Z : E ratio of 3b was determined according to described by Silveira and co-workers.⁴

Conclusions

Several a-phenylselenoacrylonitriles 3 and a-phenylseleno-a,b-unsaturated esters 4 could be prepared by Knoevenagel condensation under solid supported catalysis (KF/Al₂O₃) and solvent-free conditions at room temperature. This atom-economic protocol consists in low consumption of solvent, short reaction time, mild reaction conditions, good yields and simplicity, with non-aqueous work-up. Finally, the elimination of the large amount of salts and other solid residues generated in the conventional methods to the title compounds was achieved.

Acknowledgments

The authors thank SCT-RS, FAPERGS and CNPq for financial support and Pólo Oleoquímico de Três Passos-RS for providing citronellal and citral.

References

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9. Lebarillier, L.; Outurquin, F.; Paulmier, C.; Tetrahedron 2000, 56, 7495.

10. Silveira, C. C.; Botega, C. S.; Rhoden, C. R. B.; Nunes, M. R. S.; Braga, A. L.; Lenardão, E. J.; Synth. Commun. 1998, 28, 3371; For a review on the use of Wittig and Wittig-Horner reactions in preparation of vinyl chalcogenides, see: Silveira, C. C.; Perin, G.; Jacob, R. G.; Braga, A. L.; Phosphorus, Sulfur Silicon Relat. Elem. 2001, 172, 55.

11. Janousek, Z.; Piettre, S.; Gorissen-Hervens, F.; Viehe, H. G.; J. Organomet. Chem. 1983, 250, 197; Piettre, S.; Janousek, Z.; Merényi, R.; Viehe, H. G.; Tetrahedron 1985, 41, 2527.

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14. Kaupp, G.; Naimi-Jamal, M. R.; Schmeyers, J.; Tetrahedron 2003, 59, 3753; Sebti, S.; Tahir, R.; Nazih, R.; Saber, A.; Boulaajaj, S.; Appl. Cat. A: General 2002, 228, 155; For a review on the use of clay-supported reagents in organic synthesis, see: Varma, R. S.; Tetrahedron 2002, 58, 1235.

15. Rand, L.; Swisher, J. V.; Cronix, C. J.; J. Org. Chem. 1962, 27, 3505; Rand, L.; Haiduchewych, D.; Dolinski, R. J.; J. Org. Chem. 1966, 31, 1272; For a review on fluoride ion as a base in organic synthesis, see: Clark, J. H.; Chem. Rev. 1980, 80, 429.

16. Texier-boullet, F.; Villemin, D.; Ricard, M.; Moison, H.; Foucaud A.; Tetrahedron 1985, 41, 1259; Nakano, Y.; Shi, W.; Nishii, Y.; Igarashi, M.; J. Heterocyclic Chem. 1999, 36, 33; For a review on KF/Al₂O₃ mediated organic synthesis, see: Blass, B. E.; Tetrahedron 2002, 58, 9301.

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20. a-Phenylselenoacetonitrile 1a was prepared according to: Martin-Esker, A. A.; Ko, S.; Newcomb, M.; J. Org. Chem. 1993, 58, 4691.

21. Ethyl phenylselenoacetate 1b was prepared according to: Reich, H. J.; Renga, J. M.; Reich, I. L.; J. Am. Chem. Soc. 1975, 97, 5434.

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Received: August 04, 2004

Published on the web: June 9, 2005

#

Present Address: Laboratório de Síntese de Moléculas Bioativas, Universidade de São Paulo, São Paulo – SP, Brazil

Publication Dates

• Publication in this collection
  25 Aug 2005
• Date of issue
  Aug 2005

History

• Received
  04 Aug 2004
• Accepted
  09 June 2005