The Kulinkovich Reaction

The extension of the Kulinkovich reaction to succinimide 75 gave a new entry into substituted indolizidines. Initially, it was demonstrated that reacting 75 under the Kulinkovich conditions, with terminal alkenes and... 

Schemes. The productive three-step synthesis of bicyclopropylidene (1) utilizing the Kulinkovich reaction of methyl cyclopropanecarboxylate [14]...

Other interesting spirocyclopropanated bicyclopropylidenes, the ring-anne-lated compounds 80a, b have also been prepared applying the Kulinkovich reaction [69, 70] (Scheme 14). The starting materials 79 were obtained by alkoxy-carbonylcarbene addition onto cyclooctene and bicyclo[6.1.0]non-l-ene, respectively. 

Scheme 13. Convergent synthesis of spirocyclopropanated bicyclopropylidenes 55-57 and 61 via repetitive application of the Kulinkovich reaction [14]...

An attempted approach to bis(bicyclopropylidenyls) of type 87 utilizing the Kulinkovich reaction turned out to be unfruitful although the twofold cyclo-propanation of the diester 84 prepared from butadiene, worked perfectly well, and the conversion of the biscyclopropanol 85 to the dibromide 86 also gave a good yield (60%), the twofold dehydrobromination of 86 afforded only 1.7% of a mixture of meso- and d,l-S7 (Scheme 15) [56 a]. However, the direct oxidative coupling of two molecules of lithiobicyclopropylidene was accomplished under... 

The Kulinkovich reaction has been widely developed, offering important synthetic potential. Thus, the intramolecular and enantioselective variants have been reported. More recently, similar Ti-mediated reactions were reported which allow the synthesis of tertiary and primary cyclopropylamines from N,N-dialkylamides [5,6] and nitriles [7], respectively. 

In this context, zirconium chemistry could open up new prospects for developing deoxygenative approaches to cyclopropanes. The Zr-assisted variant of the Kulinkovich reaction has been reported (Scheme 4, Eq. 1) [10]. Cyclopropanols were also formed, as by-products in addition to homoallylic alcohols, from aliphatic acid chlorides (Eq. 2) [ 10]. The conversion of acid chlorides (and also esters in several cases) into the corresponding homoallylic alcohols... 

The key component of the antitumor antibiotic cleomycin, (S)-cleonin, was prepared from (R)-serine using the Kulinkovich reaction as the key step in the laboratory of M. Taddei. The methyl ester of A/-Cbz serine acetonide was exposed to freshly prepared ethylmagnesium bromide in the presence of substoichiometric amounts of titanium tetraisopropoxide to afford the desired cyclopropylamine in good yield. Subsequent functional group manipulations gave (S)-cleonin. 

Cyclopropylamines and their substituted derivatives are important building blocks in a large number of biologically active compounds. The synthesis of potentially biologically active A/,A/-dimethyl bicyclic cyclopropylamines from N-allylamino acid dimethylamides by the intramolecular variant of the Kulinkovich reaction was accomplished by M.M. Joullie and co-workers. 

The recently reported rearrangement of /rani-silyl enol ethers 33 is of special interest because the preparation also involves construction of a hydroxy-substituted three-membered ring via the Kulinkovich reaction. ... 

Functionalized cyclopropanes. The reductive coupling of esters with 1-alkenes by a Grignard reagent and titanium alkoxide gives rise to cyclopropanols (the Kulinkovich reaction). With the use of ethylene carbonate, the condensation gives rise to 2-substituted cyclopropanone hemiacetals. An intramolecular version delivers bicyclic products. ... 

The Kulinkovich reaction is the titanium-catalysed synthesis of cyclo-propanols from carbo ylic esters and Grignard reagents. The reaction is very diastereoselective, and an asymmetric variant was described by Corey et al. in 1994, by using the spirotitanate 79 (Scheme 7.48). Since this work, only a few titanium-catalysed asymmetric syntheses of cyclopropanols were reported, with enantiomeric excesses never higher than 80%. ... 

Kulinkovich himself proposed that the dialkoxytitanacyclopropanes as the key intermediate in the Kulinkovich cyclopropanation. Extensive theoretical study on mechanism was published in 2001. Eisch also provided detailed exploration of the mechanism for the Kulinkovich reaction in 2003. In 2007, Kulinkovich proposed a modified ate complex mechanism for titanium-mediated cyclopropanation of carboxylic esters with Grignard reagents. 

In general, esters, acid chlorides, and anhydrides are most reactive toward the Kulinkovich reagent. Carbonates and thioesters are of moderate reactivity, whereas carbonamides are least reactive. Case in point was made by chemoselective Kulinkovich reaction of succinic ester-amide 12. Cha observed that only the ester portion underwent the Kulinkovich reaction to afford cyclopropanol 13. Szymoniak demonstarted that nitriles are more reactive than ester and amides. 

An important contribution from Sato and Cha was their successful extension of the Kulinkovich reaction to the intramolecular version. For instance, reductive coupling of carboxylic ester 17 with a terminal olefin... 

Cha also explored substrate directed asymmetric synthesis using the Kulinkovich reaction. Sequential treatment of homoallylic alcohol 21 with Ti(0/-Pr)4 and c-C5H9MgCl furnished the putative intermediate 22, which upon exposure to ethyl acetate produced /ra s-l,2dialkylcyclopropanol 23 in... 

Ollivier and co-workers used the Kulinkovich reaction in their total synthesis of heliannuols K and Thus, conversion of ester 38 with pendent olefin... 

Corey employed the Kulinkovich reaction in the total synthesis of P-arianeosene (48). Ester 46 was converted to cyclopropanol 47, which served as the substrate to make cyclobutanone by treating 47 with Al(Me)3. 

The ester Kulinkovich reaction was used to prepare a key allylic bromide 5333 in a synthesis of neolauh-malide and isolaulimalide (Scheme 5.88). The cyclopropanol 5.332 produced by the Kulinkovich reaction of ester 5.331, as its mesylate, was subjected to ring opening with magnesium bromide. This is likely to involve electrocyclic ring opening of the cyclopropyl carbocation, followed by bromide trapping. 

The Kulinkovich reaction is a unique reaction, in which cyclopropane derivatives are formed by a reaction between titanacyclopropanes and ester derivatives. The reaction was established by Kulinkovich in 1989 [273], and a recent review has been published [274, 275], Titanacyclopropanes were generated from a Grignard reagent and Ti(0-/-Pr)4, and the reaction with esters gave cyclopropanol in good yields. When amides are used instead, cyclopropane amine is formed. The mechanistic study on the Kulinkovich reaction was performed [276]. 

Although amides served as a good substrate for the Kulinkovich reaction to give aminocyclopropanes, tertiary amides were also useful for the reaction, and tertiary... 

The Kulinkovich reaction was applied to prepare amino-cyclopropanes attached to sugars 442 and 443 or the poly-hydroxylated stmcture 444. Cyclopropanation occurred in a stereoselective manner (Scheme 1.209) [293]. 

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