382

Kulinkovich
Cyclopropanation

A. GENERAL DESCRIPTION OF THE REACTION

This reaction was first reported by Kulinkovich et al. in 1989.1 It is the synthesis
of cis-1,2-dialkylcyclopropan-1-ol by treatment of carboxylic acid esters with at least
2 equivalent of Grignard reagent and a catalytic or equivalent amount of titanium tetraiso-
propoxide. Thus this reaction is referred to as the Kulinkovich reaction,2 Kulinkovich
cyclopropanation,2f,3 Kulinkovich hydroxycyclopropanation,2c,2e,4 Kulinkovich-de Mei-
jere reaction,5 or Kulinkovich cyclopropanol synthesis.6 It is known that this reaction
proceeds through an intermediate of low- valency dialkoxytitanacyclopropane. This reaction
is very easy to manage and can give intrinsically cis-1,2-dialkyl diastereoselectivity when no
chelating substituents are present on the substrates, regardless of the size of the substituent.2e
In addition, the stereochemistry at the carbon bound to titanium is also retained.2c As a
result, this reaction has been extended to amides,7 nitriles,7c lactones,2h THP-protected
hydroxy esters,2h vinylogous esters,8 etc. On the other hand, this reaction has also been
modified to be asymmetric in the presence of the chiral ligand TADDOL.9 Other modifica-
tions include the addition of Grignard reagent to amides in the presence of methyltitanium
triisopropoxide,2d and the catalytic version of this reaction initiated by the ligand-exchange
reaction of Grignard reagent and titanium tetraisopropoxide.2e,10

B. GENERAL REACTION SCHEME

Comprehensive Organic Name Reactions and Reagents, by Zerong Wang

Copyright © 2010 John Wiley & Sons, Inc.

1706
 RELATED REACTIONS 1707

C. PROPOSED MECHANISMS

Because this reaction can proceed either stoichiometrically or catalytically, a catalytic

mechanism is modified according to the proposed one,2e in which the ligand-exchange
reaction between titanium tetraisopropoxide and Grignard reagent affords the dialkoxyl
dialkyl titanium which transforms into dialkoxy titanium cyclopropane, which then under-
goes the α-cycloinsertion and methoxyl group migration to give trialkoxy cyclopropanoxy
titanium, which then forms the final cyclopropanol upon another attack of Grignard reagent
to complete the catalytic cycle, as shown below.

D. MODIFICATION

This reaction has been extensively modified to various conditions, including the reac-
tion with amide to form cyclopropylamine,7 the reaction with lactones2h and vinylogous
esters.8 In addition, this reaction has also been modified to occur either catalytically2e,10 or
asymmetrically.9

E. APPLICATIONS

This reaction has recently been used for the preparation of cyclopropanols and other
noncyclopropyl products.

F. RELATED REACTIONS

N/A
1708 KULINKOVICH CYCLOPROPANATION

G. CITED EXPERIMENTAL EXAMPLES

Reference 2b.

A 50-mL round-bottomed flask containing an oversize cylindrical magnetic stirring bar

was charged with 678 mg neat methyl thiomethyl ether (1.53 mmol). The flask was evacuated
and purged with nitrogen three times to degas the substrate. In a glove bag, a preweighed
portion of Ti(O-i-Pr)3 Cl (997 mg, 3.83 mmol, 2.5 eq.) was added directly to the flask as
a solid. The contents of the flask were then dissolved in 5.5 mL THF, and the resulting
colorless solution was cooled to 0◦ C. Freshly prepared 1.64 M EtMgBr in THF (4.66 mL,
7.64 mmol, 5.0 eq.) was added dropwise to the flask from a syringe over 5 min. The addition
initially caused a dark orange and ultimately a brown-black discoloration of the reaction
mixture. After gas evolution (ethane) had subsided, the ice bath was removed, and the
mixture was warmed to room temperature. The flask was then sealed tightly with a plastic
cap, and the thick, dark brown mixture was stirred vigorously at room temperature for
48 h. After diluting with 10 mL Et2 O, the contents of the flask were then poured into a
separatory funnel containing 125 mL saturated ammonium chloride. The aqueous layer
was then extracted with Et2 O (4 × 100 mL). The combined organic washes were dried over
MgSO4 and filtered to a colorless solution. Concentration and purification over silica gel
(Rf = 0.30 in 4.5:1 hexanes/ EtOAc) afforded 404 mg cyclopropanyl alcohol as a colorless
oil, in a yield of 60%.

O
EtMgBr, Ti(O-i-Pr)4
Si O Si O
O THF OH
80%

Reference 3a.

To a solution of 150 g ethyl 2-{[tert-butyl(diphenyl)silyl]-oxy}acetate (0.46 mol) in

3.0 L THF was added 30 mL Ti(O-i-Pr)4 (0.10 mol) at −10◦ C. A solution of 365 mL
3.0 M EtMgBr in THF (1.09 mol) was added to the mixture dropwise within 4 h
under nitrogen, while temperature was controlled < 5◦ C. The mixture was allowed
to warm to 25◦ C and stirred for an additional h. The reaction mixture was quenched
by adding 400 mL water dropwise for 1 h below 10◦ C. After removal of THF, the
aqueous layer was extracted with n-hexane (3 × 500 mL), and the combined extracts
were washed with 300 mL brine and 300 mL water. The organic layer was concen-
trated in vacuo, and the residue was diluted with 150 mL n-heptane. The solution
was slowly stirred to generate white solids at −5◦ C, and the solids were collected to
afford 84.0 g 1-({[tert-butyl(diphenyl)silyl]oxy}methyl)cyclopropanol. The second crop of
 REFERENCES 1709

1-({[tert-butyl(diphenyl)silyl]oxy}methyl)cyclopropanol (30 g) was obtained from the

mother liquor. A total of 114 g cyclopropanol was obtained, in a yield of 80%.

Other references related to the Kulinkovich cyclopropanation are cited in the literature.11

H. REFERENCES

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(e) Wu, Y.-D. and Yu, Z.-X., J. Am. Chem. Soc., 2001, 123, 5777. (f) Esposito, A.; Piras, P. P.;
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K. E.; Kingree, S. V. and Minbiole, K. P. C., Org. Lett., 2005, 7, 515. (c) de Meijere, A.; Schill,
H.; Kozhushkov, S. I.; Walsh, R.; Müller, E. M. and Grubmüller, H., Russ. Chem. Bull. Int. Ed.,
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and Cha, J. K., Org. Lett., 2002, 4, 3707. (f) Sato, F. and Okamoto, S., Adv. Synth. Catal., 2001,
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