Tandem carbocupration/oxygenation of terminal alkynes.

α-Branched aldehydes represent valuable synthetic intermediates but remain difficult to access. Alkylation of aldehyde enolates generally fails, so recourse has been taken to indirect methods. In a common tactic, reaction of metalated hydrazones or imines with alkyl halides leads to α-branched hydrazones or imines.1 Hydrolysis provides the substituted aldehyde. Alternatively, alkylation of carboxylic acid derivatives and subsequent partial reduction can yield α-branched aldehyde products. In addition to requiring multiple synthetic operations, these indirect methods also suffer from limited reaction scope. Specifically, enolate or metalloenamine alkylation proceeds efficiently only with unhindered and/or electronically activated electrophiles. Hydroformylation of terminal olefins provides an alternative to aldehyde enolate alkylation, but general strategies to control regioselectivity have proved elusive.2 We report here a general and direct approach based on the addition of a carbon-based nucleophile and oxygen-based electrophile to monosubstituted acetylenes – the tandem carbocupration/oxygenation of terminal alkynes (eq 1).3 Carbometalation of terminal alkynes (1) generates stereodefined vinyl metal intermediates (2) which can react with various electrophiles.4 In principle, trapping with an electrophilic oxygen donor (Scheme 1, path a) could provide an α-branched aldehyde (3) or its enol derivative. Among various carbometalation protocols, those based on organocopper reagents display the broadest generality.5 For this reason, we sought a method to effect oxygenation of vinyl copper species (2, M = Cu). However, a significant obstacle to implementing this strategy was related to the known chemistry of organocopper compounds: The oxidative dimerization of phenyl copper has been known since early last century,6 and more than 30 years ago Nomant described a carbocupration/oxidation sequence leading to symmetrical dienes (4, scheme 1, path b).7 Scheme 1 Initial efforts to effect oxygenation of vinyl copper intermediates confirmed the large body of evidence indicating that dimerization constituted the predominant reaction pathway. In particular, oxygen transfer agents such as dimethyl dioxirane and nitrosobenzene provided diene (4) to the exclusion of aldehyde derivatives. Other oxidants, including N-methyl morpholine N-oxide and metal salts of m-CPBA, were unreactive, and terminal olefin (5) was recovered from the reactions. Experiments with LiOOtBu (6) proved more rewarding. Boche and coworkers oxidized phenyl cuprates to phenol with this reagent.8 We have discovered that LiOOtBu in conjunction with carbocupration enables the preparation of α-branched aldehydes and their derivatives from organometallic reagents and terminal alkynes. For example, carbocupration of 1-dodecyne (1a) with ethylcopper was followed by oxidation with LiOOtBu. After addition of acetic anhydride to the reaction mixture, we isolated the trisubstituted enol acetate (7) in moderate yield. Increases in yield and reproducibility accompanied the addition of N,N,N′,N′-tetramethylethylene diamine (TMEDA) to the vinyl copper intermediate prior to oxidation (Table 1, entry 1). Other amine ligands showed no discernible effect while phosphorus-based ligands totally suppressed oxygenation. Table 1 Tandem Carbocupration/Oxygenation of Terminal Alkynes. To expand the scope of the carbo-oxygenation, three carbocupration protocols were developed or appropriated to accommodate primary, secondary and tertiary Gringard and primary alkyl lithium reagents (Table 1). In all cases, the vinyl copper intermediate (2, M = Cu) was oxidized with LiOOtBu at −78 °C; addition of Ac2O to the crude reaction mixture led to trisubstituted enol acetates, 7. Carbometalation with primary Grignard reagents is optimal using CuBr·Me2S and a 1:1.5 Cu:Mg ratio (conditions A), as has been previously reported.9 In contrast, terminal alkynes were inert to organocopper reagents derived from secondary and tertiary alkylmagnesium halides. Diorganocuprates displayed improved reactivity, but these reactions were initially plagued by incomplete consumption of the alkyne and formation of multiple products. The low yields stemmed not from recalcitrance of the alkyne; rather, the cuprate intermediates decomposed under the reaction conditions.10 For instance, reactions involving (c-hexyl)2CuMgBr and 1-dodecyne produced significant quantities of bicyclohexyl and 1,2-di-cyclo-hexyl-1-dodecene. As TMEDA appeared to minimize dimerization during oxidation, we speculated that it might also increase the stability of cyclohexyl cuprates. Indeed, the use of CuBr·TMEDA enabled the carbo-oxygenation to be performed with secondary and tertiary alkyl Grignard reagents (Conditions B). In contrast to a previous report11 we observe efficient carbocupration with organocopper reagents derived from n-butyllithium. Unfortunately, TMEDA did not suppress diene formation during oxidation. However, the amelioratory effects of TMEDA were restored by admixture with MgBr2 (1 equivalent relative to Cu, Conditions C). The carbo-oxygenation reaction tolerates common functionality including esters, silyl ethers, benzyl ethers and tertiary amines. In every case studied to date, the enol acetate has been isolated as a single regio- and stereoisomer.12,13 In many instances, nOe’s were observed between the olefinic proton and the formerly propargylic protons, indicating cis addition to the triple bond. In other cases, stereochemical assignment was made by analogy.15 Oxidation likely generates a metallo-enolate (8), and this intermediate can be trapped with electrophiles other than acetic anhydride. For example, quenching the reaction with benzoic anhydride or chlorotrimethyl silane yields the corresponding enol derivatives 9 and 10 (Scheme 2). Alternatively, α-haloaldehydes (11, 12) can be isolated following addition of Br2 or tBuOCl to the reaction mixture. Scheme 2 Surprisingly, attempts to quench the enolate 8 with proton sources led not to the expected aldehyde 14, but to ketone 13 (Scheme 3). Ultimately, we determined that addition of ethylene diamine prior to the addition of water allowed the isolation of the α-branched aldehyde in good yield. Other Lewis bases (Et3N, Bu3P) were similarly effective, although simple reductive aqueous workup (e.g. Na2S2O3(aq)) led to lower yields of 14. Ketone 13 is likely the product of a Baeyer-Villiger oxidation of aldehydes 11 and/or 15 promoted by excess tert-butyl peroxide. Aldehydes 11 and 15 may arise in situ from α-oxidation of 8 or 14.14 Consistent with this interpretation, aldehydes 11 and 15 both convert to ketone 13 under the reaction conditions.15,16 Scheme 3 Oxidation of the vinyl copper intermediate could occur by direct addition to lithium tert-butyl peroxide. Alternatively, peroxide coordination to copper could precede an alkyl migration from Cu to O. Such a process would resemble the oxidation of alkyl boron and silicon compounds. The stereospecificity of the oxygenation undermines mechanistic proposals involving free radicals. Future efforts will aim to clarify the reaction mechanism with the anticipation that this understanding will aid efforts to expand the utility of the carbocupration/oxygenation method. Irrespective of mechanism, this transformation currently enables the direct synthesis of α-branched aldehydes and stereodefined enol derivatives. The latter hold promise as valuable reagents for asymetric reductions, oxidations and umpolung reactions.17