Complex VIa leads to the observed major cis diastereomer and is more favorable than the diastereomeric VIb due to unfavorable steric interactions between R and Ti OY 3 in the latter Eq. When R1 is bulky, the trans isomer is favored. Despite the possibility of olefin exchange with the titanacyclopropane intermediate see Eq. This drawback seems to limit the scope of the reaction significantly; however, it is possible for the intermediate titanacycle II to exchange with a more substituted olefin to afford more highly substituted cyclopropanols in high yield Eq.
Formation of the more stable monosubstituted titanancyclopropane from the disubstituted intermediate derived from cyclohexylmagnesium chloride drives the formation of the less substituted product Eq. Although 2 is prepared from methylmagnesium bromide, only one equivalent of Grignard reagent is needed for the Kulinkovich reaction because methane evolves as the reaction proceeds Eq.
Significant 1,3-stereocontrol is also observed when chiral homoallylic alcohols are employed Eq. For instance, amides may be cyclopropanated to afford cyclopropylamines in high yield and diastereoselectivity Eq. The trans-1,2-dialkylcyclopropanol is favored under these conditions. This result is a consequence of inversion of configuration at the carbon bound to titanium in the second migratory insertion step when amides are employed contrast with Eq.
This mode of reactivity has made cyclopropanols synthetically useful; for instance, they may serve as homoenolate equivalents in the presence of an electrophile. When the electrophile is part of the cyclopropanol, ring expansion may result Eq. The results of reactions of this type are often sensitive to the nature of the electrophile and other reagents employed.
They may serve as iminium ion equivalents in the presence of a nucleophile. For example, the final step in Eq. The presence of an alcohol in the target means that ketones may be used as electrophiles for intramolecular ring closing to form cyclopropanols. For example, samarium-mediated reductive ring closure provides cyclopropanols in high yield Eq.
Thereafter, the ethylene by-product formed in Equation 1 perpetuates the reaction. Several experimental observations support the importance of ethylene for initiation: 1 higher yields of cyclopropanols are obtained? The extra equivalence of Grignard reagent with a TiIV catalyst can readily generate ethylene; 2 when a ratio of ethyl Grignard reagent to Ti OiPr 4 is employed, yields of the cyclopropanol are lower 30? Ester Interchange as Side Reaction in Kulinkovich Processes Under experimental conditions where certain dialkyltitanium??
Since MgBr OiPr 28 is the by-product formed in producing Et2Ti OiPr 2 according to Scheme 1, we first examined the action of 28 on 1a as the possible path of ester interchange [Equation 5 ].
Gitua 8 or by transfer with iPr2Ti OiPr 2 10 to form 29, which by a reversible redox process could lead to 31, via 30 and thus to ester interchange Scheme 7. The importance and utility of intermediates like 29 and 30 will become evident in our future report on reductive dimerizations of esters by transition metal reagents. Scheme 1. Since subsequent addition of methyl benzoate 1a did not lead to the formation of the cyclopropanol 27, we can conclude that 8 is unable to epititanate directly the ethylene present formed either from 7 or from the excess EtMgCl present to form the titanacyclopropane 9.
Since either a third equivalent of EtMgX the typical Kulinkovich procedure, part a or addition of ethylene gas part c at? The ethylene set free by such epititanation of 7 perpetuates the reaction. We conclude that the rate limiting step is the transfer-epititanation of propylene by Steric hindrance in a transition state similar to 26 involving propyl- 5 However, no ester exchange was found to occur between 1a and 28 in an ethereal solution at room temperature.
But when 1a was treated with Ti OiPr 2 8 in diethyl ether at ambient temperatures ca. Accordingly, as an attractive alternative, we propose a reversible epimetallation of 1a either directly with Ti OiPr 2 Scheme 7 ? After 90 min methyl benzoate 10 mmol, 1 equiv. Thereafter, ethylene gas at 40 psi was bubbled through the cold solution for a period between 30 min and 2 h, before the reaction mixture was warmed to room temperature ca. After 10 min at?
The resulting reaction mixture was warmed to room temperature over 3 h and then subjected to the usual hydrolytic workup and NMR spectral analysis. When the mixture was warmed to room temperature 3 h , it turned black, indicating the decomposition of Et2Ti OiPr 2 7 into Ti OiPr 2 8. Methyl benzoate 10 mmol was then added and the mixture was allowed to stirred for 7 h at ambient temperature ca.
The usual workup gave only recovered methyl benzoate no isopropyl benzoate cf. Modified Kulinkovich Procedure. Reactions with Diisopropyltitanium IV Diisopropoxide. The brown mixture was stirred for 90 min before being quenched at? A similar reaction was conducted by slowly addiing a solution of isopropylmagnesium bromide 20 mmol in diethyl ether 30 mL to a solutionof titanium??
From these results it is clear that propylene does not promote the formation of the titanacyclopropane 11 by transfer epititanation. A solution of isopro? KGaA, Weinheim ene instead of ethylene is the likely barrier retarding the reaction. A further indication of this crucial steric factor emerges from the comparative transfer-epitatanations of ethylene with 10 and of propylene with 7. We conclude that the transfer-epititanation transition state 26 is at a much lower level in energy than the similar, sterically hindered transition state involving propylene coordination.
Experimental Section Instrumentation, Analysis and Starting Reagents: All reactions were carried out under a positive pressure of anhydrous, oxygen-free argon. All solvents employed with organometallic compounds were dried and distilled from a sodium metal-benzophenone ketyl mixture prior to use.
Elmer instrument model and samples were measured either as mineral oil mulls or as KBr films. Packard mass-selectivedetector instrument. The gas chromatographic analyses were performed with a Hewlett?
Packard instrument model provided with a 2-m OV packed column or with a Hewlett? Packard instrument model having a 30 m SE capillary column. Melting points were determined with a Thomas? Hoover Unimelt capillary melting point apparatus and are uncorrected. The Typical Kulinkovich Procedure. The red-brown mixture was stirred at? The reaction mixture was warmed to room temperature ca. Hydrolytic workup with 1?
The only other significant product, present in the crude reaction mixture with this Kulinkovich procedure and all other modifications leading to 27 was 1-phenylpropanol to the extent of 5? No 1H or 13C NMR spectral signals characteristic of cis-2methylphenylcyclopropanol 19 were present. A reaction similar to that described above the same scale was conducted , except that 5 mmol of methyl benzoate was employed.
After 90 min of stirring at? The reaction mixture was allowed to attain room temperature ca. The usual hydrolytic workup led only to the recovery of benzonitrile. A similar reaction involving the admixture and reaction of isopropylmagnesium bromide 20 mmol and titanium?? Ester Interchange. The mixture was stirred for 10 h at ambient temperature ca. The NMR spectral analyses of the crude organic product showed only the presence of methyl benzoate without trace of isopropyl benzoate.
Methyl benzoate The usual workup and analyses showed that the crude material contained only methyl benzoate and isopropyl benzoate 25 as approximately a ? Gitua                   J.
Eisch, J. Gitua, Organometallics , 22 24? For an insightful overview of the Kulinkovich reaction for organic synthesis: B. Breit, J. For more extensive reviews, also covering the applications of other titanium reagents in organic synthesis: [3a] O. Kulinkovich, A. Sato, H. Urabe, S. Okamoto, Chem. Kulinkovich, S. Sviridov, D. Vasilevski, T. Prityckaja, Zh. Vasilevski, Synthesis , Corey, S. Rao, M. Noe, J.
Kasatkin, T. Nakagawa, S. Okamoto, F. Sato, J. Lee, H. Kim, J. Cha, J.
Organic Letters , 21 14 , Several experimental observations support the importance of ethylene for initiation: 1 higher yields of cyclopropanols are obtained? The gas chromatographic analyses were performed with a Hewlett?
Vasilevski, Synthesis , Davis, Dominic G. A reaction similar to that described above the same scale was conducted , except that 5 mmol of methyl benzoate was employed.
Example Procedure  18 To a mL, round-bottomed flask, equipped with a magnetic stirring bar and rubber septum, is added at room temperature a mixture of 2. However, this sequence can be useful for the generation of low valent titanium compounds that can be utilized for example in Pinacol Coupling Reactions. The resulting mixture is stirred for an additional 3 h at room temperature. Therefore, the unavoidable conclusion is that 10 does not decompose to generate intermediate 11 under these experimental conditions.
Organometallics , 37 15 , Sato, H.
The trans-1,2-dialkylcyclopropanol is favored under these conditions. Melting points were determined with a Thomas? Since either a third equivalent of EtMgX the typical Kulinkovich procedure, part a or addition of ethylene gas part c at?
Similarly, decomposition of diisopropyltitanium?? Packard mass-selectivedetector instrument. KGaA, Weinheim www. Cooper, H.
Packard instrument model having a 30 m SE capillary column. Kourdioukov, S. This intermediate may be depicted using either the titanacyclopropane resonance structure IIa or the titanium II -olefin structure IIb. Nakagawa, S.
A reaction similar to that described above the same scale was conducted , except that 5 mmol of methyl benzoate was employed. The dialkyltitanium?? We conclude that the rate limiting step is the transfer-epititanation of propylene by
Thereafter, ethylene gas at 40 psi was bubbled through the cold solution for a period between 30 min and 2 h, before the reaction mixture was warmed to room temperature ca. Organic Letters , 20 23 , Since MgBr OiPr 28 is the by-product formed in producing Et2Ti OiPr 2 according to Scheme 1, we first examined the action of 28 on 1a as the possible path of ester interchange [Equation 5 ].
Journal of the American Chemical Society , 6 , Here, the disproportionation produces methane as a gaseous side product and allows the Grignard reagent to be fully utilized: For more on the topic of 1,n-dicarbanionic titanium intermediates from monocarbanionic organometallics and their application in organic synthesis, see a recent review by Kulinkovich and de Meijere Chem. Organometallics , 33 14 , Cha, J.
Since subsequent addition of methyl benzoate 1a did not lead to the formation of the cyclopropanol 27, we can conclude that 8 is unable to epititanate directly the ethylene present formed either from 7 or from the excess EtMgCl present to form the titanacyclopropane 9.
Organic Letters , 17 9 , Sviridov, D. Gitua, Organometallics , 22, 24? Organic Letters , 17 24 ,