α -Lithioenamines by chlorine-lithium exchange: versatile acyl anion equivalents

The reaction of α -chloroenamines 1 with an excess of lithium and a catalytic amount of 4,4’-di-tert -butylbiphenyl (DTBB) in THF at –90 ºC followed by reaction with an electrophile (D 2 O, Me 3 SiCl, PhCOCH=CHPh/BF 3 , CO 2 , CyNCO) and final hydrolysis gave the expected functionalized enamines 2 . In the case of aldehydes ( t-BuCHO, n -C 5 H 11 CHO, PhCHO) it was necessary to perform the lithiation in the presence of the electrophile (Barbier conditions) at – 40 ºC. Hydrolysis of the obtained enamines either with silica gel or with hydrochloric acid yielded the expected functionalized ketones 3 .


Introduction
Acyl metals are interesting intermediates in synthetic organic chemistry because they are able to transfer the acyl functionality to electrophilic reagents, 1 this reaction being a typical example of reactivity umpolung. 2The corresponding lithium derivatives (I) are very reactive and unstable, and have been prepared at low temperature by (a) carbonylation of some alkyllithium reagents, 3 (b) tellurium-lithium exchange, 4 and (c) in especial cases by direct deprotonation of crowded aldehydes. 5Due to the difficulty to generate acyllithium reagents, other alternatives including mainly the use of lithiated 1,3-dithianes and related systems (II), 6 lithiated imines (III), 7,8 and other lithiated compounds 9 have been developed.Among this last group, are lithiated enol ethers (IV), 10 which can be prepared by direct deprotonation.However, the corresponding enamines cannot be lithiated directly at the α-position (to give intermediates of type V) due to their low acidity.For this reason, we thought that compounds of type V could be prepared from the corresponding α-chloroenamines by a chlorine-lithium exchange using an arene-catalyzed lithiation, [11][12][13] a methodology employed extensively in our group during the last decade for the generation of organolithium compounds under very mild reaction conditions. 14Thus, this technology has allowed us (a) to generate simple organolithiums from non-halogenated materials, 15 (b) to prepare functionalized organolithium compounds 16 by chlorine-lithium exchange 17 or by ring opening of heterocycles, 18 (c) to generate polylithium synthons, 19 and (d) to activate other metals, 20 especially nickel. 21In many cases, for very unstable intermediates, it is necessary to perform the lithiation in the presence of the electrophilic reagent (Barbier type conditions). 22In this paper we report on the application of the mentioned arene-catalyzed lithiation to prepare α-lithioenamines of the type V by chlorine-lithium exchange. 23

Results and Discussion
The reaction of α-chloroenamines 1 (prepared by treatment of the corresponding acyl chlorides with dimethylamine or pyrrolidine followed by reaction of the formed amide with phosphorus oxychloride) 24 with an excess of lithium (1:7 molar ratio) and a catalytic amount of 4,4'-di-tertbutylbiphenyl (DTBB; 1:0.05 molar ratio) in THF at -90 ºC led, after 50 min, to a solution of the corresponding intermediate VI.Treatment of this species with D 2 O or Me 3 SiCl at temperatures ranging between -90 and -40 ºC gave, after hydrolysis with water, the expected compounds 2aa,ba or 2ab, respectively (Scheme 1, Method A, and Table 1, entries 1, 2 and 5).When carbonyl compounds were used as electrophiles, the best results were obtained performing the reaction in the presence of the electrophile (Method B).Thus, for pivalaldehyde, the same lithiation mixture described above was used with starting materials 1 in the presence of the aldehyde at -40 ºC for 1 h and, after hydrolysis, the expected compounds 2ac and 2bc were isolated (Scheme 1 and Table 1, entries 3 and 6).When benzaldehyde was used in the same reaction (Method B), aminoketone 2′ad was obtained, resulting from an isomerization of the expected enaminoalcohol (2ad) under the reaction conditions used (Scheme 1 and Table 1, entry 4).catalysis.
In the second part of this study we performed the hydrolysis of functionalized enamines 2, either after their isolation (from compounds 2ac and 2bc, with silica gel for 20 h) or in an onepot procedure without isolation of the corresponding compound 2 (with 2 M hydrochloric acid for 1 h), to give compounds 3 (Chart 1).For the one-pot procedure, the sequential method (Method A) was used in all cases (with chalcone, carbon dioxide or cyclohexyl isocyanate) except for the case of hexanal, in which the Barbier technology (Method B) was employed.It is worthy to note that in the reaction with chalcone, activation of the electrophile with boron trifluoride was necessary, 25 obtaining only the corresponding 1,2-addition product 3af, which under the reaction conditions isomerized to the diketone 3′af (Chart 1).On the other hand, when crude compound 3ae was submitted to purification by column chromatography (silica gel, hexane/ethyl acetate), an isomerization took place giving a 3:1 mixture of compounds 3ae:3'ae (300 MHz 1 H NMR; Chart 1).The reaction of chloroenamine 1a with carbon dioxide gave a ketoacid, which was isolated and purified after conversion into the corresponding methyl ester 3ag by treatment with methanol under acid catalysis (Chart 1).Finally, the use of cyclohexyl isocyanate as electrophile afforded the expected ketoamides 3ah and 3bh (Chart 1).
As a conclusion, we have reported here the preparation of α-lithioenamines by a chlorinelithium exchange, which represent a versatile class of acyllithium synthons, which by reaction with different electrophiles and final hydrolysis allowed the preparation of functionalized ketones resulting from the transfer of the acyl moiety to the electrophile.

Experimental Section
General Procedures.For general information, see references 17 and 26.

DTBB-Catalyzed lithiation of α-chloroenamines 1 and reaction with chalcone or cyclohexyl isocyanate (Method A). Isolation of compounds 3'af, 3ah and 3bh. General procedure
Once lithiation of starting α-chloroenamines was carried out as it was above described (Method A), the corresponding organolithium intermediate was treated with a 1:1 precooled (-40 ºC) mixture of chalcone and BF 3 •OEt 2 or cyclohexyl isocyanate allowing the temperature to rise to -40 ºC.After hydrolyzing with water, the resulting mixture was acidified with 2 M hydrochloric acid, stirred for 1 h and neutralized with 3 M sodium hydroxide before the final work up as it was above described for compound 2aa.Thus, title compounds 3 were isolated, their yields being included in Chart 1. Spectroscopic and analytical data follow.

Table 1 .
Preparation of functionalized enamines 2 a Method A: two-step reaction; Method B: Barbier-type conditions.b All products 2 (or 2') were >90% pure (GLC and/or 300 MHz 1 H NMR). c Isolated crude yield based on the starting chloro enamine 1. d >90% Deuterium incorporation from mass spectrometry.O Chart 1. Preparation of compounds 3 Isolated yields after column chromatography (silica gel, hexane/ethyl acetate) based on the starting chloro enamine 1 (overall yield) a Method B. b Crude yield before chromatographic purification (see text).c Method A. d BF 3 •OEt 2 was used to activate chalcone (1:1 molar ratio).e Esterification of the corresponding hydroxy acid was performed with methanol under H 2 SO 4