Cyclopropyl cuprates

Metallo 2-vinylcyclopropanes were introduced independently as a tool for the efficient preparation of 1,2-divinylcyclopropane skeletons in 1976 by the three groups mentioned above ". Either 2-vinylcyclopropyl lithium addition to 3-alkoxyenones " followed by acid treatment will lead to the desired rearrangement precursors (equation 166), or the corresponding cyclopropyl cuprates will add to j5-iodoenones and electrophilic acetylenes " forming directly divinylcyclopropanes (equation 167). 

When the substrates are i -halo-a,)8-unsaturated ketones the reactions with cyclopropyl-cuprates lead to the corresponding )9-cyclopropyl enones, In each case, when a comparison was made, the jS-iodo enone gave the produet in better yield under milder conditions than when the yS-bromo enone was used." It is also noteworthy that products resulting from addition of a cyclopropyl moiety to the initially formed -cyclopropyl enone were not detected. In accordance with this, successive treatment of bromocyclopropane with tert-butyllithium, phenylsulfanylcopper, and 3-iodocyclopent-2-enone gave 3-cyclopropylcy-clopent-2-enone (2a) in 97% yield.Under the same conditions a 1 1 mixture of endo-and cxo-6-bromobicyclo[3.1. Ojhexane was coupled to 3-iodocyclohex-2-enone leading to a 1 1 mixture of endo- and e.xo-3-(bicyclo[3.1.0]hex-6-yl)cyclohex-2-enone (3) in 94% total yield further examples have been reported. ... 

CYCLOPENTANE ANNELATION Lithium phenylthio(cyclopropyl)cuprate. 

A slight modification of the cyclopropyl conjunctive reagent transforms a cyclopentannulation into a cycloheptannulation. Thus, the 2-vinylcyclopropyllithium reagent 3, converted to its cuprate 4, generates a 1,2-divinylcyclopropane. Heating to only 180 °C leads to smooth Cope type rearrangement, driven by the release of the cyclopropyl strain, to create a perhydroazulene ring systerh of many sesquiterpenoids (Eq. 19) 20>. 

The cuprate derived from the cis isomer of this reagent undergoes conjugate addition with cyclohexenone with unusually high diastereoselectivity (5 1, Eq. 23)24). In this case, electrophilically initiated ring opening with mercuric acetate chemo-selectively attacks the sterically least hindered cyclopropyl bond to give a branched product 7. Reductive work-up produces 8 in which the stereochemistry of the... 

A richer structural variety is realized when the propargyl carbonates 90 are treated with cyclopropyl(cyano)thienyl cuprates [56] such as 141, allowing the preparation of allenes with up to four different substituents (Scheme 5.19) [57]. 

Ar= Ph, p-MePh, o-MePh R = allyl, Me, Ph, cyclopropyl, n-butyl Scheme 6.28. Diastereoselective cuprate addition to a planar chiral a lchromium enone complex 145. 

One general method for acyl silane synthesis particularly successful for a-cyclopropyl examples (and even an a-cyclobutyl example) involves treatment of acid chlorides with lithium tetrakis(trimethylsilyl) aluminum or lithium methyl tris(trimethylsilyl) aluminium and cuprous cyanide (vide supra, Section III.A.3)77. For example, cyclopropyl acyl silane (23) was obtained in 89% yield by this process. Improved procedures use lithium t-butyldimethylsilyl cuprate78 and a dimethylphenylsilyl zinc cuprate species79,80 as reagents. 

Lithium (cyelopropyl)(phenylthio) cuprate (l).27 This cuprate is prepared by addition of cyclopropyllithium to phenylthiocopper in THF at -78- — 20°. It converts /J-iodo enones (2) into /1-cyclopropyl enones (3) in excellent yield, even when 2 is substituted at the a-position by a methyl group. The products are useful because they rearrange when heated to annelated cyclopentenes (4 and/or 5). The rearrangement is particularly efficient when R = H, and results in 5 as the major product ( 85% yield). 

Mu, Y.Q., Gibbs, R.A., Eubanks, L., and Poulter, C.D. (1996). Cuprate-mediated synthesis and biological evaluation of tert-butyl and cyclopropyl farnesyl diphosphate analogs. J Org Chem 61 8010-8015. 

Acceptor ability of a group can be enhanced by interaction with a suitable electrophile (proton, Lewis acid). This is very likely in the Ni(acac)2-catalysed reaction of cyclopropyl ketones with trimethylaluminium and in the synthetically more significant addition of several cuprates to alkyl cyclopropyl ketones. The BFs-activated organometallic reagent attacks the less substituted cyclopropane carbon regioselectively. Yet steric hindrance can be a problem in this reaction (equation 40) . 

The high stereospecificity of the ring-opening reaction provides evidence against radical anion intermediates and is interpreted in terms of a direct nucleophilic attack of cuprate at the cyclopropyl carbon atom . 

Allylation of a-thio-35), a-seleno-35) and a-silyl- 35,77) cyclopropyllithiums was not very successful35) but addition at —78 °C of 0.5 equivalent of copper (I) iodide-dimethylsulfide complex 35,106, W7> prior to the allylhalide leads 35,106,107) to a very high yield of homoallyl cyclopropyl sulfides or selenides (Scheme 24). Similar observations have been made on cyclobutyl derivatives3S). It is not clear at present whether a cuprate is involved in the process but we have evidence ( Se-NMR) that a new species is transiently being formed, at least in the seleno series. The synthesis of homoallyl cyclopropylsilanes was also reported 78) and involves the allylation of a postulated cuprate formed by the addition of lithium dibutyl cuprate to a-lithiocyclopropylsilane (Scheme 26). 

Most reactions have been performed using lithium cyclopropyl(phenylsulfanyl)cuprate, but the homocuprate lithiumdicyclopropylcuprate complexed with dimethyl sulfide has also been used. ° Generally the yields are very good, in most cases above 80%. 

Reduction of 68a with L-selectride gave a 6 1 mixture of cyclopropyl carbinols in 92% with the (R)-alcohol predominating. Highly stereoselective hydroxyl-directed epoxidation from the a-face of the cyclopentane ring followed by silylation of the alcohol gave 69 (contaminated with a small amount of the product derived from the S-alcohol) in 84% yield. This intermediate was then coupled with the allenyl iodide 63 via the cuprate of 69 to afford an 86% yield of the diyne 70. Partial reduction of the alkynes followed by desilylation and chromatography afforded 71a and 71b in 79% and 13% yields, respectively. Conversion of the undesired major (R)-isomer 71a into the minor (5)-compound was accomplished via an oxidation-reduction sequence to provide 71b in 75% yield contaminated with 16% of the (R)-71a. Orthoester 71b was then cleaved... 

CONJUGATE ADDITION Alkylmethyl-magncsiocuprates. 2-Carboethoxyl-benzyl phenyl sulfoxide. Cyanodiethyl-aluminum chloride. 1-Cyclopropyl-l-tiimethylsilyloxyethylene. Lithium 1,3-butadiene-l-olate. Lithium dimethyl-cuprate. Magnesium ethyl malonate. Potassium carbonate. Tri-n-butyl-stannyllithium. Trimethylzinclithium. 

Alkylation of cyclopropyl bromides. - Reaction of a bromocyclopropane with this cuprate (4 -5 equiv.) in THF at — 48 to 0° and then with an alkyl bromide (or iodide) at the same temperature results in stereospecific replacement of the bromo group by the alkyl group with retention of configuration. A mixed cuprate such as a is postulated as an intermediate. An example is the conversion of rra y-l-bromo-... 

Cyclopropyl ketones are formed on addition of an equimolar amount of lithium dimethylcuprate to the acid chlorides of cyclopropanedicarboxylates, but with excess cuprate a ring-opening reduction to pentane-l,S-diones takes place. ... 

Trost and co-workers have reported the coupling of 7-methyloct-Z-2-en-l-yl bromide with the dianion of methyl acetoacetate to give (168) (R=Hi) (186). The diazoderivative (168) (R=Na) was thermolyzed in the presence of copper powder to give the cyclopropane (169). Ring cleavage of the cyclopropyl ring using lithiiun dimethyl cuprate resulted in stereospecific formation of the cholesterol side chain where the relative orientation of the ultimate C-17 and C-20 positions in (170) is the same as that of the natural product. 

Modhephene, 34, was the first isolated propellane natural product. As such, the Weiss-Cook reaction was the perfect method for its construction. The process began with the condensation of 2 with diketone 27. Standard conditions for decarboxylation produced the core scaffold 28. Hydrogenation of the mono-enol phosphate afforded the monoketone 29. The cyclopropyl derivative 30 was prepared by copper-catalyzed decomposition of a diazoketone. gem-Dimethylation to generate 31 preceded carboxylation and esterification to afford the advanced intermediate 32. Cuprate-induced cyclopropane ring opening and methylation of the 3-ketoester introduced the final carbon atoms giving rise to 33. Lithium iodide induced decarboxylation preceded reduction of the ketone followed by dehydration with Martin s sulfurane, thus producing 34. 

Preparative Methods cyclopropylllthlum Is prepared by cooling a 0.25 M THF solution of bromocyclopropane under Ar to —78°C dropwlse addition of 1.0 equiv of a solution of sec-butylllthlum Is followed by stirring for 2 h this cyclopropyl-llthlum solution Is transferred by cannula to a stirred, — 78 °C THF slurry of phenylthIocopper(I) under Ar the resultant mixture Is warmed to —20°C a clear, light brown solution of cuprate forms after stirring for 20 min it is cooled to —78°C and Is used directly. ... 

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