Different Reaction Patterns in the Baylis-Hillman Reaction of Aryl Aldehydes with Phenyl Vinyl Ketone, Phenyl Acrylate and Phenyl Thioacrylate

In the Baylis-Hillman reaction of aryl aldehydes with phenyl vinyl ketone we have observed exclusive formation of diadducts 4, and that the yields of diadduct can reach 80% with increasing amounts of phenyl vinyl ketone. On the other hand, for phenyl acrylate and phenyl thioacrylate, only the normal Baylis-Hillman adduct was obtained. The effects of substituents were also examined and a plausible reaction mechanism is proposed for the formation of compounds 4.


Introduction
Great progress has been made in the implementation of the Baylis-Hillman reaction [1], since Baylis and Hillman first reported in 1972 the reaction of acetaldehyde with ethyl acrylate and acrylonitrile in the presence of catalytic amounts of 1,4-diazabicyclo [2,2,2]octane (DABCO) [2], and even a catalytic asymmetric version has been published [3]. During our own investigations of this simple and useful reaction [4], we found that in the reaction of aryl aldehydes with methyl vinyl ketone (MVK) catalyzed by DABCO, the reaction products are not as simple as those reported before. For example, using p-nitrobenzaldehyde (1.0 eq) and MVK (2.0 eq) as substrates in the presence of catalytic amounts of DABCO (0.1 eq) in DMSO or DMF, we found that, besides the normal Baylis-Hillman reaction product 1a, compound 2a was also formed at the same time as a 2:3 mixture of synand anti-isomers [5] (Scheme 1) and the substituent effects of aryl aldehydes were also examined in detail [5]. This interesting result stimulated us to further examine the influence of the R group of the Baylis-Hillman acceptor [C=C-C(O)R] on this reaction. Thus, we synthesized phenyl vinyl ketone (PVK) [6], phenyl acrylate [7], and phenyl thioacrylate [8] as the Baylis-Hillman acceptors and carefully examined the reaction products formed under the traditional Baylis-Hillman reaction conditions.

Results and Discussion
We found that, in the reaction of p-nitrobenzaldehyde (1.0 eq.) with PVK (1.0 eq.) in the presence of DABCO (10 mol-%) in DMF, the corresponding Baylis-Hillman adduct 3a (i.e., the normal Baylis-Hillman adduct) was not formed at all. The major reaction product was a mixture of syn-and antiisomers of the 1:2 adduct 4a, along with some PVK dimer (Scheme 2). Of course, as expected, 4a was obtained in higher yields when 1.0 eq. p-nitrobenzaldehyde and 2.0 eq. of PVK were used in the presence of DABCO (10 mol-%). Results are summarized in Table 1. When the reaction was carried out in DMSO, THF or dichloromethane (CH 2 Cl 2 ), similar results were obtained (Table 1, Entries 1-3). Using 4-(dimethylamino)pyridine (DMAP) as the Lewis base under the same reaction conditions, 4a was obtained in lower yields (Table 1, entries 4-5). Increasing the amounts of PVK did not improve the yields of 4a (Table 1, Entries 6-7). At lower temperatures (-30 o C), 4a was obtained in 70% yield (Table 1, Entry 9) and with PBu 3 as the Lewis base, only traces of 4a were obtained. The optimized reaction conditions were found to be reaction of 1.0 eq. aryl aldehyde with 2.0 eq. PVK in the presence of 10 mol-% DABCO in DMF.  p-chlorobenzaldehyde or benzaldehyde, only trace amounts of the 1:2 adduct 4 were obtained and the PVK dimer was formed almost exclusively (Scheme 3, Table 2) [7]. In all cases, the normal Baylis-Hillman adduct 3 was not formed.  On the other hand, the Baylis-Hillman reactions with phenyl acrylate or phenyl thioacrylate as an acceptor were also examined (Schemes 4 and 5; results are summarized in Table 3). With phenyl acrylate as the acceptor, the normal Baylis-Hillman adducts 5 was exclusively obtained in most cases ( Table 3, entries 1-2 and 4-8). Only in the reaction of o-nitrobenzaldehyde with phenyl acrylate, was diadduct 6c formed in 29% (Table 3, Entry 3). However, with phenyl thioacrylate as a Baylis-Hillman acceptor, only in the reaction of p-chlorobenzaldehyde with phenyl thioacrylate, the corresponding Baylis-Hillman adduct 7 was obtained in good yield (Scheme 5). The reactions of other aryl aldehydes with phenyl thioacrylate were either very sluggish or gave many unidentified products.

Scheme 5
To the best of our knowledge, the exclusive formation of a diadduct in the traditional Baylis-Hillman reaction in which phenyl vinyl ketone (PVK) is used as the acceptor has never been disclosed before. To clarify the mechanism of formation of 4, we carried out reactions of p-nitrobenzaldehyde In Scheme 7, we formulate a plausible reaction mechanism. Two reactions occur for the traditional Baylis-Hillman reaction of aryl aldehydes with PVK. One is the normal Baylis-Hillman reaction, which involves the 1,2-addition of the PVK-derived anion to p-nitrobenzaldehyde. Another is the conjugated addition (Michael addition) of the anion derived from a second molecule of PVK to 3 via intermediate 4' (Scheme 7). Thus, the normal Baylis-Hillman adduct 3 formed can more easily undergo the next conjugate addition (Michael addition) of the anion derived from a second molecule of PVK to afford exclusively the diadduct 4.

Conclusions
We have found that a diadduct 4 was formed exclusively in the Baylis-Hillman reaction of aryl aldehydes with phenyl vinyl ketone (PVK). It was confirmed the 4 was derived from a second reaction of the normal Baylis-Hillman adduct with PVK via a conjugate addition reaction. On the other hand, with phenyl acrylate or phenyl thioacrylate as acceptors, only the normal Baylis-Hillman reaction products were produced. Efforts are currently underway to further elucidate the mechanistic details of this reaction and to disclose its scope and limitations.
IR spectra were recorded on a Nicolet AV-360 spectrometer. 1 H-NMR spectra (300 MHz) were recorded for CDCl 3 solutions on a Bruker AM-300 spectrometer with tetramethylsilane (TMS) as internal standard; J-values are in Hz. Mass spectra were recorded with a HP-5989 instrument and HRMS were measured on a Finnigan MA+ mass spectrometer. Organic solvents were dried by standard methods when necessary. Commercially obtained reagents were used without further purification. All reactions were monitored by TLC using Huanghai GF 254 silica gel coated plates. Flash Column Chromatography was carried out using 200-300 mesh silica gel under pressure. The syn-and anti-isomers of 4 were not separable, thus, the ratios of syn and anti isomers are determined from 1 H-NMR spectroscopic data and their HRMS data were obtained from anti-and syn-mixtures as well.

Preparation of phenyl vinyl ketone.
The phenyl vinyl ketone starting material was prepared according to Scheme 8 [6].

Scheme 8
A solution of the ammonium salt (5 g) in water (200 mL) was distilled at 90 o C. The distillate was extracted with ether (3 x 20 mL) and the organic layer was dried over anhydrous Na 2 SO 4 . The solvent was removed under reduced pressure and residue was purified by flash silica gel chromatography (eluent: ethyl acetate/petroleum ether = 1/10) to give phenyl vinyl ketone (PVK) (1.6 g, 30%) as a colorless oil; 1 H-NMR: