Synthesis of Oxazolidinone and Tosyl Enamines by Tertiary Amine Catalysis

Abstract

A procedure for the synthesis of oxazolidinone and tosyl enamines is reported. Alkynoyl oxazolidinones and tosyl imides undergo reaction to form enamines in the presence of catalytic amounts of tertiary amines. The data suggest that an amide anion is formed during the reaction, which undergoes conjugate addition to form the final product.

Enamines have become widely used intermediates in organic synthesis since the development of facile methods for their use in the alkylation and acylation of carbonyl compounds by Stork.¹ These substrates are able to form carbon–carbon bonds easily, and the use of chiral amines provides an entry into asymmetric syntheses.² Over the past decade, there has been an expansion of the reactions that may undergo enamine organocatalysis, such as α-oxidations³ and alkylations,⁴ aldol condensation,⁵ Michael additions,⁶ and enantioselective reductions.⁷ These developments have been showcased in the recent syntheses of (−)-anisomycin⁸ and (+)-conicol.⁹ The present report describes a method for preparing enamine products from N-propynoyl oxazolidinones and tosyl imides through tertiary amine catalysis.

In the process of synthesizing N-propynoyl-(4S)-4-benzyl-1,3-oxazolidin-2-one (1) by Evans' conditions¹⁰ to prepare analogues of locostatin, an N-crotonyl oxazolidinone that inhibits cell migration and disrupts specific protein–protein interactions involved in the regulation of cell signaling,¹¹ we unexpectedly discovered that the reaction underwent a secondary transformation to yield the bis-oxazolidinone enamine 2 (Scheme 1). The structure was confirmed by one- and two-dimensional NMR and ESI-MS (Table S1 in Supporting Information).¹² In addition, compound 2 was hydrolyzed under acidic conditions and found to react sluggishly, suggesting that the presence of the electron-withdrawing group adversely affects the ability of the enamine to undergo hydrolysis.

Scheme 1.

Synthesis of N-propynoyl-(4S)-4-benzyl-1,3-oxazolidin-2-one (1), its enamine derivative 2 and its ene-yne dimer derivative 3. Reagents and conditions: (a) 1. n-BuLi, THF, −78 °C;. 2. propiolic acid, pivaloyl chloride, K₂CO₃, THF, r.t.; (b) 1. n-BuLi, THF, −78 °C; 2. propiolic acid, pivaloyl chloride, Et₃N, −78 °C to 0 °C.

To explain how 2 arose from the reaction, we first explored generation of 1. Replacing Et₃N with K₂CO₃ as the base allowed for generation of the propynoyl mixed anhydride, thus facilitating synthesis of 1 in 42% yield without formation of 2 (Scheme 1). Exposure of 1 to not only stoichiometric but also substoichiometric amounts of Et₃N gave 2, along with the ene-yne dimer 3 (Table 1, entries 1–7, and Table S2 in Supporting Information), implying a catalytic reaction. Alternative amines were used at 15 mol% catalyst loading in different solvents, and we found that DABCO also catalyzed the reaction at room temperature (Table 1, entries 8–14). No reaction was observed with DIPEA or imidazole (Table 1, entries 16 and 17). With (−)-sparteine (Table 1, entry 15), mild heating was required for the reaction to reach completion. Other solvents with 15 mol% Et₃N and DABCO were screened (Table 1, entries 1–14). The catalyst–solvent system of Et₃N in toluene gave the best results with an 86% yield of 2 (Table 1, entry 7). From these data, we concluded that the reaction requires a nucleophilic tertiary amine with diminished steric encumbrance, since imidazole and DIPEA failed to react and (–)-sparteine required mild heating.

Table 1. Solvents and Amines Tested for Formation of 2 and 3^a.

Entry	Amine	Solvent	Yield of 2 (%) and E:Z ratiob	Yield of 3 (%)b
1	Et3N	MeCN	36 (12:1)	tracec
2	Et3N	benzene	19 (99:1)	2
3	Et3N	CHCl3	20 (1:1)	25
4	Et3N	Et2O	49 (3:2)	tracec
5	Et3N	EtOAc	65 (12:1)	tracec
6	Et3N	THF	20 (99:1)	8
7	Et3N	toluene	86 (14:1)	tracec
8	DABCO	MeCN	37 (99:1)	31
9	DABCO	benzene	65 (99:1)	14
10	DABCO	CHCl3	56 (99:1)	5
11	DABCO	Et2O	43 (4:1)	5
12	DABCO	EtOAc	54 (8:1)	28
13	DABCO	THF	16 (99:1)	51
14	DABCO	toluene	60 (20:1)	25
15	(−)-sparteined	THF	24 (99:1)	7
16	DIPEA	THF	–e	–e
17	imidazole	THF	–f	–f

^aReactions were performed at 0.22 M and 15 mol% amine at 24 °C.

^bIsolated yield and E:Z ratio in parentheses.

^cTrace signifies less than 1% product.

^dReaction was performed at 0.22 M, 15 mol% amine at 50 °C.

^eNo reaction, with 62% recovered starting material.

^fNo reaction, with 33% recovered starting material.

Other systems (N-propynoyl oxazolidinones and tosyl imides) also underwent a similar reaction with catalytic Et₃N (Table 2) in toluene. While the original oxazolidinone substrate 1 (Table 2, entry 1) furnished the enamine 2 with a yield of 86%, the other oxazolidinone substrates reacted to form enamine products with reduced yields of 26–38% (Table 2, entries 2–4). The tosyl imides, however, gave enamine products with 55–72% yields (Table 2, entries 7–10). Interestingly, the reaction appeared to necessitate the presence of an electron-withdrawing group, since tertiary and secondary alkyl ynamides failed to react under the same conditions (Table 2, entries 5 and 6). This result suggests that the oxazolidinone or tosyl moieties presumably act to facilitate the displacement of the nitrogen anion from the alkynoyl imide, as well as to decrease the hardness of the nitrogen anion to allow for conjugate addition onto a second molecule of the alkynoyl imide.

Table 2. Enamine and Ene-Yne Dimer Products from Et₃N-Catalyzed Reaction of N-Propynoyl Oxazolidinones and Tosyl Imides^a.

Entry	R	Yield of A (%)b	Yield of B (%)b
1		86	tracec
2		26	8
3		38	6
4		38	9
5		–c	–c
6		–c	–c
7		58	traced
8		68	traced
9		72	traced
10		55	traced

^aReactions were performed at 0.22 M and 15 mol% Et₃N.

^bIsolated yield.

^cNo observable reaction.

^dTrace denotes <1% product.

The mechanism of the reaction presumably begins with conjugate addition of the tertiary amine onto the ynamide to form an allenoate intermediate.¹³ The allenoate undergoes elimination of the amide anion to generate the nucleophile for subsequent addition onto a separate ynamide moiety, forming the enamine. Alternatively, the allenoate mediates deprotonation of the acetylenic hydrogen of another equivalent of substrate to ultimately form the eneyne dimer (Scheme 2).¹⁴ Treatment of 1 with NaH and 20% aqueous DCl in D₂O gave deuterated 1, which was subjected to the catalytic conditions with DABCO and Et₃N. We found that in both cases, the β position of the enamine product retained high levels of the deuterium label (70% for DABCO and 58% for Et₃N), while the α-position contained lower levels (26% for DABCO and 39% for Et₃N). The data suggest that it is more likely that deprotonation occurs through residual water than by direct deprotonation of the acetylenic hydrogen. Quenching the reaction mixture with TMSCl or 20% aqueous DCl in D₂O resulted in no incorporation of the trapping species in the final enamine product. Thus, the vinyl anion may not be neutralized during the aqueous workup, and the proton must be incorporated during the reaction.

Scheme 2.

Proposed mechanism of enamine formation; EWG = electron-withdrawing group

We have found that N-propynoyl oxazolidinones and tosyl imides will form enamine products when exposed to catalytic amounts of Et₃N and DABCO.¹⁵ The reaction involves conjugate addition of the tertiary amine onto the alkynoyl imide β carbon to furnish a putative allenoate intermediate. The allenoate then undergoes elimination of an amide (or carbamate) anion, generating the final nucleophile for product formation. This reaction could be used to furnish alternative enamines to yield asymmetric aldol products.