Three-Component Coupling Catalyzed by Phosphine : Preparation of α-Amino γ-Oxo Acid Derivatives

The three-component coupling reaction of ethyl propiolate (1), phthalimide (2), and aldehyde (3) catalyzed by triphenylphosphine, was developed. A solution of an equivalent amount of 1 and 2 in benzaldehyde (3a) in the presence of 30 mol% of PPh3 was heated at 100 ̊C for 48 h to give N-(1-ethoxycarbonyl-3-oxo-3-phenylpropyl)phthalimide (4a) in 83% yield. This reaction was thought to proceed via vinylphosphonium salt formed from the reaction of ethyl propiolate (1) with triphenylphosphine in situ.

In the course of our study for the reaction of acetylenecarboxylic esters in the presence of PPh 3 , we found the efficient three-component coupling of acetylene carboxylic esters, phthalimide, and aldehyde catalyzed by phosphine.This three-component coupling reaction is an efficient way to construct a useful framework in a onepot, and we wish to describe the detail here.

Reaction Conditions
The reaction of ethyl propiolate (1) with phthalimide (2) and p-nitrobenzaldehyde (3c) was performed in the presence of two equivalents of Ph 3 P in toluene (5 mL) (Equation ( 1)).From the reaction at 100˚C for 48 h, ethyl 4-oxo-4-(4-nitrophenyl)-2-phthalimidoylbutanoate (4c) was obtained in 15% yield accompanied by ethyl 2-phthalimidoyl-2-propenoate (5) in 19% yield (Table 1, entry 2).This product 4c is not the desired compound by the intermolecular Wittig reaction, but the compound consisted of three components.The reaction conditions were then optimized (Table 1).At higher concentration, the yield of the product 4c was improved.The reaction at room temperature or at reflux resulted a lower yield of 4c (Table 1, entries 1 and 4).Employment of other solvents, such as CH 2 Cl 2 , CHCl 3 , CH 3 CN, resulted in a lower yield.Especially, when acetonitrile was used as the solvent, compound 5 was mainly obtained in 36% yield with a trace amount of 4c.Finally, a mixture of 1 (1.0 mmol), 2 (1.0 mmol), and 3c (2.0 mmol) in toluene (1.5 mL) in the presence of 2.0 mmol of PPh 3 was stirred at 100˚C for 48 h to give 4c in 40% yield (Table 1, entry 3).
The effect of the catalyst was also examined (Table 1).Using PBu 3 instead of PPh 3 decreased the yield of the product (entry 9).Amines, such as NEt 3 and pyridine, did not catalyze this reaction at all.Triphenylphosphine was demonstrated not to be needed in a stoichiometric amount.That is, the use of 30 mol% of Ph 3 P was enough for this reaction (38% yield of 4c, Table were efficiently formed in the mixture of toluene and buffer solution of acetic acid/sodium acetate [34].Therefore, the same system was tried for this reaction.That is, the reaction of 1, 2, and 3c in the presence of 2.0 equiv of PPh 3 in a mixture of toluene, acetic acid, and sodium acetate gave the product 4c in 20% yield and 5 in 14% yield. CHO

Using Various Aldehydes
The aldehyde was then changed for determining the scope and limitation of this reaction by using a catalytic amount of PPh 3 (Table 2).Based on above results, the reaction at a high concentration smoothly proceeds.Therefore, if the aldehyde was a liquid, excess aldehyde (1 mL) can be used without solvent.When the aldehyde is a solid, toluene was used as the solvent, and the yields were moderate to low (entries 3 and 7).Without solvent, good product yields were achieved using aromatic aldehydes.When using benzaldehyde (3a) as the aldehyde, 4a was obtained in 83% yield.Introducing substituents on the benzaldehyde did not significantly affect the yield of the product.Heteroaromatic aldehydes, such as 2-furanecarbaldehyde (3h) and 2-pyridinecarbaldehyde (3i) (Table 2, entries 8 and 9), were also used for this reaction, while aliphatic aldehydes 3j, 3k, gave products in poor yields (Table 2, entries 10 and 11).
For the reaction of 1 with benzaldehyde (3a), using a large quantity of 3a decreased the yield of 4a to 35% (Table 2, entry 12).This result shows that the concentration of the alkynoate, PPh 3 , and/or phthalimide is important for this reaction.Tributylphosphine instead of PPh 3 was not effective similar to that mentioned above (Table 2, entry 13).
Next, several alkynoates were examined for this coupling reaction without solvent.When ethyl 2-butynoate was used for this reaction, no three-component coupling product was obtained.Dimethyl butynedioate, which showed good reactivity for the preparation of heterocyclic compounds via the in situ vinylphosphonium intermediate, was allowed to be used for this three component coupling.Although various nucleophiles such as amines, amides, alcohols, and electrophiles, such as aldehydes, ketones, acid chlorides, were employed for this reaction, the desired product was not obtained, but only polymeric materials were formed.
Various nitrogen-containing nucleophiles having protonation ability were tested next.The primary amine, butylamine, directly reacted with propiolate to give mainly the Michael adducts.N-Tosylamide [34] was subjected to this reaction, but only a trace amount of the desired product was formed.Amides, such as caprolactam, N-acetylaniline, did not react with 1. Pyrrole was employed for this reaction, but no reaction occurred as well.

Plausible Reaction Mechanism
The reaction may occur in the following way (Scheme 1): (1) nucleophilic attack of Ph 3 P to ethyl propiolate (1) to  give zwitterionic intermediate ( 6), (2) protonation of the intermediate 6 by phthalimide, (3) Michael addition of phthalimidate anion to give ylide 7, and (4) ylide attacks to aldehyde to give 8.In the last step, the Wittig alkenylation does not proceed, and the γ-keto α-amino acid derivative 4 is produced.Probably, the hydride shift occurred from the intermediate 8.This type of hydride shift was suggested in the reaction of butanal with the butoxymethylenetriphenylphosphonium ylide forming 1butoxy-2-pentanone [35].In our reaction, the same hydride shift could proceed to give the product 4 in good yield.Alternatively, 7 undergoes intramolecular proton transfer, and elimination of the phosphine (by an E1cb mechanism).The phosphine may add to the aldehyde to generate an umpolung type intermediate, which would undergo conjugate addition to the acrylate (derived from 7) to give an intermediate analogous to 8, which can eliminate the phosphine to give 4 [36].This reaction gives the γ-keto α-amino acid derivatives in one-pot in up to 83% yield.The reaction seems to proceed through vinylphosphonium salts derived from acetylenic ester and phosphine, and via hydride transfer reaction.The application of this unique reaction is now underway.

General
Proton nuclear magnetic resonance ( 1 H NMR) spectra were measured using a JEOL JNM A-400 (400 MHz) spectrometer using tetramethylsilane as the internal standard.IR spectra were measured on a Shimadzu IR-408 spectrometer.Mass spectral (GC-MS) data were recorded on a Shimadzu GP2000A instrument.Elemental analyses were performed at the Microanalytical Center of Kyoto University.High resolution mass spectra (FAB) were measured using a JEOL JMS-700 with meta-nitrobenzyl alcohol as the matrix.Melting points were measured on a Yanako Model MP and were not corrected.All substrates were purchased and used without further purification.