Methanolic trimethylamine mediated Baylis − Hillman reaction

Application of methanolic trimethylamine, the tertiary amine containing minimum number of carbon atoms with lowest possible molecular weight, for mediating the Baylis − Hillman coupling of various aldehydes with activated olefins viz. methyl acrylate, acrylonitrile and acrolein is described.


Introduction
The Baylis−Hillman reaction is an important three components reaction involving an atom economical construction of carbon−carbon bonds, between the α−position of an activated vinylic systems and carbon electrophiles under the influence of tertiary amines (most commonly DABCO), and producing an interesting class of synthetically useful densely functionalized molecules (Eq.2][3][4] These Baylis−Hillman adducts, containing chemo-specific functional groups in close proximity, have been extensively used in a number of transformation methodologies often involving high levels of stereoselectivity.  Dur the last fifteen years this reaction has seen a tremendous amount of development with respect to the three essential components (Eq.1).Though the DABCO is the most commonly used tertiary amine catalyst in this fascinating reaction, several other tertiary amines such as 4-DMAP, 22 DBU, 23 3-hydroxyquinuclidine, 1-3 3-quinuclidone, 1-3 indolizine, [1][2][3] and pyrrolizidines 24 have been successfully employed as catalysts/ medium to perform this reaction.2][3] It is worth mentioning here the most recent work of Hu, who reported a remarkable rate acceleration in the Baylis−Hillman reaction in water−dioxane medium. 29ith an objective of developing tertiary amine catalysts containing a minimum number of carbon atoms with lowest possible molecular weight, we have recently employed aqueous trimethylamine to perform the Baylis−Hillman reaction of alkyl acrylates with paraformaldehyde and various reactive aromatic aldehydes (Scheme 1). 30We have also observed that aqueous trimethylamine fails to mediate the Baylis−Hillman reaction of methyl acrylate with benzaldehyde. 30 COOR

Results and Discussion
With a view to understand the scope of application of trimethylamine, and also in order to examine the effect of solvent, we have selected methanolic trimethylamine which is also commercially available and inexpensive as a medium for performing the Baylis−Hillman reaction between benzaldehyde and methyl acrylate.In this direction, the best results were obtained when benzaldehyde (5 mmol) was treated with methyl acrylate (10 mmol) in the presence of methanolic trimethylamine (25% w/w) (5 mmol) at room temperature for 5 days, thus providing the desired adduct i.e. methyl 3-hydroxy-2-methylene-3-phenylpropanoate (1) in 86% yield.This is a very encouraging result.Then we have extended this reaction to representative aldehydes (Eq. 2 and Table 1).A quick comparison of these results with that of DABCO catalyzed results is also mentioned in the Table 1.
These results clearly demonstrate that methanolic trimethylamine is a better medium than aqueous trimethylamine for performing the Baylis-Hillman coupling of methyl acrylate with less reactive aldehydes.We next planned to extend the applicability of this reagent to the other activated alkenes such as acrylonitrile.Accordingly, we have first carried out the reaction between acrylonitrile and benzaldehyde in the presence of methanolic trimethylamine.The best results were obtained when a mixture of benzaldehyde (5 mmol), acrylonitrile (10 mmol) and methanolic trimethylamine (25% w/w) (5 mmol) was left at room temperature for 6h, thus producing the corresponding Baylis−Hillman adduct, i.e. 3-hydroxy-2-methylene-3-phenylpropanenitrile, in 70% yield.Encouraged by this result, we have subjected various aldehydes to the Baylis−Hillman coupling with acrylonitrile under the influence of methanolic trimethylamine to provide the corresponding adducts in good yields and in reasonable reaction times (Eq. 3 and Table 2).A quick comparison of these results with DABCO catalyzed results is mentioned in the Table 2.We have also successfully utilized the methanolic trimethylamine as a medium for performing the Baylis−Hillman reaction of acenaphthenequinone, a non-enolizable ketone, with acrylonitrile to produce the corresponding adduct 2-(1,2-dihydro-1-hydroxy-2oxoacenaphthylen-1-yl)prop-2-enenitrile 16 in 76% yield at room temperature for 12h in THF (Eq.4). 36Though acrolein is an interesting activated alkene, its application in the Baylis−Hillman reaction has not been well studied and only a few reports are available in the literature. 3,44,45It occurred to us that methanolic trimethylamine might perform the Baylis−Hillman reaction between acrolein and aldehydes.Thus, the treatment of acrolein (6 mmol) with 4nitrobenzaldehyde (5 mmol) in the presence of methanolic trimethylamine (25% w/w) (1 mmol) in THF (5 mL) at room temperature for 2h provided the corresponding Baylis−Hillman adduct, i.e. 3-hydroxy-2-methylene-3-(4-nitrophenyl)propanal 17, in 21% yield.We have extended the same reaction to representative aromatic aldehydes (Eq. 5 and Table 3).Though the yields are less in this reaction (Eq.5), these results demonstrate the application of methanolic trimethylamine as a catalyst for the Baylis−Hillman coupling of acrolein with aldehydes.c Isolated yields of the products after silica gel column chromatography (5% EtOAc in hexanes).
In conclusion, we have successfully demonstrated the applicability of methanolic trimethylamine, the tertiary amine containing minimum number of carbon atoms with lowest possible molecular weight, as a catalyst/ medium for conducting the Baylis-Hillman coupling of representative aldehydes with activated olefins such as methyl acrylate, acrylonitrile and acrolein.

Experimental Section
General Procedures.All melting points were recorded on a Superfit (India) capillary melting point apparatus and are uncorrected.IR spectra were recorded on a Jasco-FT-IR model 5300 spectrometer using liquid samples as neat liquids and solid samples as KBr plates. 1 H NMR (200 MHz) and 13 C NMR (50 MHz) spectra were recorded in deuterochloroform (CDCl 3 ) on a Bruker-AC-200 spectrometer using tetramethylsilane (TMS, δ = 0) as internal standard.Coupling constants (J) are given in Hz.Elemental analyses were recorded on a Perkin−Elmer 240C-CHN analyzer.Mass spectra were recorded on a Autospec mass spectrometer (EI) and Shimadzu GCMS-QP5050A gas chromatograph mass spectrometer.

General procedure for the molecules 17-20
These molecules were prepared by the reaction between aldehyde (5 mmol) and acrolein (6 mmol, 0.4 mL) in THF (5 mL) for two hours in the presence of methanolic trimethylamine (25% w/w) (1 mmol, 0.31 mL) at room temperature.Low boiling liquids were evaporated and the residue thus obtained, was purified by silica gel column chromatography (Table 3) to provide the corresponding Baylis−Hillman adducts.

Table 1 .
Methanolic Me 3 N mediated Baylis-Hillman reaction of methyl acrylate with aldehydes a,b,c a All reactions were carried out on a 5 mmol scale of the aldehyde with methyl acrylate (10 mmol) in the presence of methanolic trimethylamine (25% w/w) (5 mmol) at room temperature.bAllcompounds were characterized by IR, 1 H NMR and13C NMR spectral data.c Isolated yields of the pure products after silica gel column chromatography (10% EtOAc in hexanes).d All these molecules are known in the literature.

Table 2 .
Methanolic Me 3 N mediated Baylis−Hillman reaction of acrylonitrile with aldehydes a,b,c All the compounds (5-15) were characterized by IR, 1 H NMR,13C NMR spectral data and the unknown molecules(10, 12 & 13)were further characterized by mass spectral and elemental analyses.
a All reactions were carried out on a 5 mmol scale of the aldehyde with acrylonitrile (10 mmol) in the presence of methanolic trimethylamine (25% w/w) (5 mmol) at room temperature.b The molecules 5-9, 11, 14, 15 are known in the literature.c d Isolated yields of the pure products after silica gel column chromatography (10% EtOAc in hexanes).e The reaction was carried out at 42 o C. f Methanolic trimethylamine (25% w/w) (1 mmol) was employed.ISSN 1424-6376 Page 140 © ARKAT USA, Inc

Table 3 .
Methanolic Me 3 N mediated Baylis−Hillman reaction of acrolein with aldehydes a,b,c b All compounds 17-20 were characterized by IR, 1 H NMR, 13 C NMR spectral data and elemental analyses and the molecules 17, 19 & 20 were further characterized by mass spectral data.