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Org. Synth. 2021, 98, 430-445
DOI: 10.15227/orgsyn.098.0430
Discussion Addendum for: Intra- and Intermolecular Kulinkovich Cyclopropanation Reactions of Carboxylic Esters with Olefins: Bicyclo[3.1.0]hexan-1-ol and trans-2-benzyl-1-methylcyclopropan-1-ol
Jin Kun Cha1*
Original Article: Org. Synth. 2003, 80, 111
Discussion
The low-valent titanium-mediated cyclopropanation (the Kulinkovich reaction; eq 1) of esters provides easy access to 1,2-cis-alkylcyclopropanols, complementing the venerable Simmons-Smith cyclopropanation of silylenol ethers or derivatives.
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The original Organic Syntheses article describes a convenient variant by making use of cyclopentyl or cyclohexyl Grignard reagents as a sacrificial reagent in the presence of a titanium alkoxide (eq 2). Juxtaposition of a strained three-membered ring and a hydroxyl functionality makes cyclopropanols well suited for subsequent elaboration, especially in carbon-carbon bond forming reactions. The Kulinkovich reaction has been the subject of several reviews, including two recent articles.2,3 In light of these reviews, this discussion addendum presents a brief overview of selected developments in the Kulinkovich cyclopropanation with particular emphasis on ring opening of functionalized cyclopropanols in C–C bond forming reactions, including applications in natural product synthesis. Also briefly discussed are related uses of in situ generated Kulinkovich intermediates (titanacyclopropanes). These examples underscore the synthetic utility of cyclopropanols as a family of attractively functionalized, yet readily accessible homologous enol equivalents.
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Useful Developments in the Kulinkovich Cyclopropanation

Enantioselective approaches to the Kulinkovich reaction of esters were documented in the literature by employing TADDOL derivatives, but generally applicable asymmetric methods, especially for the olefin-exchange mediated variant, remain a missing link.4,5 Satisfactory levels of diastereoselective cyclopropanation reactions are possible by employing 1-alkenes having a suitable adjacent stereocenter6 or secondary homoallylic alcohols (Figure 1).7 The directing effect of the hydroxyl group in the latter substrates leads to the formation of 1,2-trans-alkylcyclopropanols via seven-membered cyclic titanates to override the intrinsic cis-alkyl stereochemical preference of the original Kulinkovich cyclopropanation.
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Figure 1. Enantioselective and diastereoselective approaches
Other carboxylic acid derivatives (such as tertiary amides, cyclic carbonates, and nitriles) also undergo the Kulinkovich reactions to afford the corresponding heteroatom-substituted cyclopropanes (Figure 2).2,3 In the case of nitriles, the use of homoallylic alcohols is required for the olefin exchange-mediated variant to countermand stronger affinity of a nitrile toward low-valent titanium species.8a-c,9 On the other hand, imides and N-acylpyrroles having a non-basic nitrogen instead produce the titanacyclopentanes, arising from preferential addition of the less substituted Ti–C bond of the presumed Kulinkovich intermediate to the respective carbonyl group.8d
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Figure 2. The Kulinkovich cyclopropanation of carboxylic acid derivatives and related coupling reactions
Ring Opening of Cyclopropanols

Cyclopropanols function as a homoenol surrogate in C–C bond forming reactions driven by release of ring strain. A notable exception notwithstanding,10 ring opening reactions of cyclopropanols were limited primarily to non-carbon electrophiles (e.g., halogens) until recently. Electrophilic attack at cyclopropanols by tethered oxocarbenium ions provides a unique approach to common structural motifs such as appropriately functionalized carbocycles (Figure 3),11 oxepanes12 and tetrahydropyrans (Figure 4).13
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Figure 3. Seven-membered ring formation
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Figure 4. Cyclopropanol-mediated synthesis of oxepanes and tetrahydropyrans
The temporary tethering strategy with the homoallylic alcohol functionality is not only effective for the aforementioned cyclopropanation (Figures 1 and 3), but also broadly applicable to coupling of two unsaturated fragments (such as alkynes and imines) by the action of the Kulinkovich intermediate, as elegantly developed by the Micalizio group (Figure 5).14
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Figure 5. Coupling of homoallylic alcohols with alkynes and imine
Allylic alcohols are also versatile substrates that readily react with the ethyl Grignard reagent-derived Kulinkovich intermediate to afford syn-SN2'-type ethylation products, accompanied by elimination of a "Ti=O" moiety (Figure 6).15a Importantly, the presumed intermediates can be trapped with suitable electrophiles such as aldehydes, halogens, and molecular oxygen.15b High levels of diastereoselectivity are obtained with cyclic allylic alcohols and (Z)-allylic alcohols. This reaction is reminiscent of the Dzhemilev–Hoveyda reaction, which employs the Negishi reagent in the place of the Kulinkovich reagent.16 An advantage of this method is an efficient trapping with carbon-based electrophiles (e.g., aldehydes). Styrenes and vinylsilanes also undergo coupling with allylic alcohols in the presence of the cyclopentyl Grignard reagent under the typical Kulinkovich reaction conditions (Figure 6).15a
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Figure 6. Stereoselective alkylation of allylic alcohols by ethylation and trapping
The corresponding coupling reaction of allylic alcohols with imines results in diastereoselective allylation of aromatic and aliphatic imines to afford homoallylic amines diastereoselectively (Figure 7).17 Direct use of an attractively functionalized allylic alcohol as an allylating reagent without pre-derivatization obviates the use of preformed organometallic reagents or activated imine derivatives.
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Figure 7. Diastereoselective synthesis of homoallylic amines
By combining ring opening of cyclopropanols with transmetalation of a suitable transition metal, the otherwise unfavorable equilibrium can be shifted to generate in situ β-keto homoenolates, which open new avenues to transition metal-catalyzed transformations with sp3, sp2, and sp electrophiles (eq 3). Additionally, the formation of the presumed 5-membered keto chelate intermediate is advantageous in promoting facile reductive elimination (subsequent to transmetalation) in preference to the competing beta-hydride elimination, as well as minimizing epimerization of the alpha-stereocenter.
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Transition metal-catalyzed cross-coupling reactions of cyclopropanols for the C–C bond formation have been an active area of research: they include: SN2' alkylation, alkenylation, alkynylation, and acylation (Figure 8), in addition trifluoromethylation and related reactions.3,18
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Figure 8. Transition metal-catalyzed cross-coupling reactions
As a representative example of this family of transition metal-catalyzed C–C bond forming reactions, alkenylation and acylation reactions of cyclopropanols are described briefly. The Orellana group reported Pd-catalyzed coupling of cyclopropanols with aryl halides, which proceeded cleanly without beta-hydride elimination (Figure 9).19 This methodology is also amenable to intramolecular processes, providing an efficient route to the otherwise challenging medium-sized (seven- and eight-membered) carbocycles.
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Figure 9. Inter- and intramolecular cross-coupling reactions
of aryl or alkenyl halides and derivatives
An efficient construction of seven- and eight-membered carbocycles can be attributed to facile ligand exchange between the Pd species [from oxidative addition of Pd(0)] and the tethered cyclopropanol to set the stage for beta-carbon elimination of the resulting Pd cyclopropoxide, followed by reductive elimination.18d
The Dai group developed an elegant carbonylative ring opening reaction of cyclopropanols having a tethered hydroxyl group to synthesize spirocyclic and fused bicyclic lactones of varying ring size (Figure 10).20 The cyclopropanol substrates are readily available by the Kulinkovich cyclopropanation of the corresponding lactones.
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Figure 10. Pd-Catalyzed acylation of cyclopropanols: catalytic carbonylative spirolactonization of hydroxyl-tethered cyclopropanols
Conversion of cyclopropanols to the corresponding cyclopropylamines was achieved by the Rousseaux group by trapping of the presumed zinc homoenolates with amines (Figure 11).21a Zinc homoenolates can also be generated by treatment of alpha-chloroaldehydes with CH2(ZnI)2 by the method of Matsubara.21b These studies demonstrate facile interconversion between zinc cyclopropoxides and the corresponding homoenolates for in situ trapping of the latter intermediates.
This Discussion Addendum focuses on regioselective ring opening of cyclopropanols at the unsubstituted carbon. The alternative mode of ring opening relies on generation of beta-keto alkyl radical intermediates. Trapping of the latter has led to a spate of useful transformations. The chemistry of beta-keto radicals has a long rich history, but it is beyond the scope of this Addendum.2,3 Also excluded are vinyl cyclopropanols and donor-acceptor cyclopropanols.
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Figure 11. Conversion of cyclopropanols to cyclopropylamines
Application in Natural Product Synthesis

A short total synthesis of paeonilide, a monoterpenoid isolated from Paeonia delavayi, was reported by Dai and coworkers: the fused bicyclic lactone moiety was assembled in an appealing manner by Pd-catalyzed carbonylative lactonization of a highly functionalized cyclopropanol (Figure 12).20b
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Figure 12. Short total synthesis of (±)-paeonilide
The sequential orchestration of the olefin exchange-mediated cyclopropanation and anti-SN2' alkylation of the resulting cyclopropanol with a propargyl tosylate was central to a concise total synthesis of alkaloid 205B containing a deceptively simple array of stereocenters.22 Starting from two easily accessible coupling partners, this alkaloid was synthesized in four straightforward steps (Figure 13). Also noteworthy was uncommon solvent effect (THF vs Et2O)22a in LAH reduction of the six-membered imine intermediate to afford the trans-2,6-disubstituted piperidine stereoselectively.
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Figure 13. Concise synthesis of alkaloid (–)-205B
In conclusion, the Kulinkovich cyclopropanation reaction provides ready access to attractively functionalized cyclopropanols. The olefin exchange-mediated variant is a versatile method for coupling of two segments – esters and terminal alkenes. Cross-coupling reactions of cyclopropanols and appropriate partners allow a rapid increase in molecular complexity through an expedient bond connection under mild conditions and with operational simplicity.

References and Notes
  1. Department of Chemistry, Wayne State University, 5101 Cass Ave, Detroit, Michigan 48202. ORCID (0000-0003-4038-3213). We thank the National Science Foundation (1665331) for financial support.
  2. (a) Kulinkovich, O. G.; de Meijere, A. Chem. Rev. 2000, 100, 2789-2834. (b) Kulinkovich, O. G. Chem. Rev. 2003, 103, 2597-2632. (c) Kulinkovich, O. G. Russ. Chem. Bull., Int. Ed. 2004, 53, 1065-1086. (d) Wolan, A.; Six, Y. Tetrahedron 2010, 66, 15-61. (e) Sato, F.; Urabe, H.; Okamoto, S. Chem. Rev. 2000, 100, 2835-2886. (f) Sato, F.; Urabe, H. In Titanium and zirconium in organic synthesis; Marek, I. Ed.; Wiley-VCH: New York, 2002, pp 319. (g) For a closely related Discussion Addendum for facile syntheses of aminocyclopropanes: de Meijere, A.; Kozhushkov, S. I. Org. Synth. 2018, 95, 289-309.
  3. (a) Cha, J. K.; Kulinkovich, O. G. Org. React. 2012, 77, 1-159. (b) McDonald, T. R.; Mills, L. R.; West, M. S.; Rousseaux, S. A. Chem. Rev. 2021, 121, 3-79.
  4. Corey, E. J.; Rao, S. A.; Noe, M. C. J. Am. Chem. Soc. 1994, 116, 9345-9346.
  5. (a) Kulinkovich, O. G.; Kananovich, D. G.; Lopp, M.; Snieckus, V. Adv. Synth. Catal. 2014, 356, 3615-3626. (b) Konik, Y. A.; Kananovich, D. G.; Kulinkovich, O. G. Tetrahedron 2013, 69, 6673-6678. (c) Iskryk, M.; Barysevich, M.; Oseka, M.; Adamson, J.; Kananovich, D. Synthesis 2019, 51, 1935-1948.
  6. Barysevich, M. V.; Kazlova, V. V.; Kukel, A. G.; Liubina, A. I.; Hurski, A. L.; Zhabinskii, V. N.; Khripach, V. A. Chem. Commun. 2018, 54, 2800-2803.
  7. Quan, L. G.; Kim, S.-H.; Lee, J. C.; Cha, J. K. Angew. Chem. Int. Ed. 2002, 41, 2160-2162.
  8. (a) Sung, M. J.; Lee, C.-W.; Cha, J. K. Synlett 1999, 561-562. (b) Kim, S.-H.; Kim, S.-I.; Lai, S.; Cha, J. K. J. Org. Chem. 1999, 64, 6771-6775. (c) Santra, S.; Masalov, N.; Epstein, O. L.; Cha, J. K. Org. Lett. 2005, 7, 5901-5904. (d) Bobrov, D. N.; Kim, K.; Cha, J. K. Tetrahedron Lett. 2008, 49, 4089-4091. (e) Astashko, D.; Lee, H. G.; Bobrov, D. N.; Cha, J. K. J. Org. Chem. 2009, 74, 5528-5532.
  9. Addition of a Lewis acid is necessary to induce the cyclopropane formation for application of the Kulinkovich cyclopropanation conditions to nitriles and imides: (a) Bertus, P.; Szymoniak, J. Chem. Commun. 2001, 1792-1793. (b) Bertus, P.; Szymoniak, J. Synlett 2007, 1346. (c) Bertus, P.; Szymoniak, J. Org. Lett. 2007, 9, 659-662.
  10. Carey, J. T.; Knors, C.; Helquist, P. J. Am. Chem. Soc. 1986, 108, 8313-8314.
  11. Epstein, O. L.; Lee, S.; Cha, J. K. Angew. Chem. Int. Ed. 2006, 45, 4988-4991.
  12. O'Neil, K. E.; Kingree, S. V.; Minbole, K. P. C. Org. Lett. 2005, 7, 515-517.
  13. (a) Lee, H. G.; Lysenko, I.; Cha, J. K. Angew. Chem. Int. Ed. 2007, 46, 3326-3328. (b) Parida, B. B.; Lysenko, I.; Cha, J. K. Org. Lett. 2012, 14, 6258-6261.
  14. Richard, H. A.; Micalizio, G. C. Chem. Sci. 2011, 2, 573-589 and references therein.
  15. (a) Lysenko, I. L.; Kim, K.; Lee, H. G.; Cha, J. K. J. Am. Chem. Soc. 2008, 130, 15997-16002. (b) Das, P. P.; Lysenko, I. L.; Cha, J. K. Angew. Chem. Int. Ed. 2011, 50, 9459-9461.
  16. Hoveyda, A. H. In Titanium and zirconium in organic synthesis; Marek, I. Ed.; Wiley-VCH: New York, 2002, pp 181 and references therein.
  17. Lysenko, I. L.; Lee, H. G.; Cha, J. K. Org. Lett. 2009, 11, 3132-3134.
  18. (a) Das, P. P.; Belmore, K.; Cha, J. K. Angew. Chem. Int. Ed. 2012, 51, 9517-9520. (b) Parida, B. B.; Das, P. P.; Niocel, M.; Cha, J. K. Org. Lett. 2013, 15, 1780-1783. (c) Murali, R. V. N. S.; Nagavaram, N. R.; Cha, J. K. Org. Lett. 2015, 17, 3854-3856. (d) Ydhyam, S.; Cha, J. K. Org. Lett. 2015, 17, 5820-5823.
  19. (a) Rosa, D.; Orellana, A. Org. Lett. 2011, 13, 110-113. (b) Rosa, D.; Orellana, A. Chem. Commun. 2013, 49, 5420-5422. (c) Rosa, D.; Orellana, A. Chem. Commun. 2012, 48, 1922-1924. (d) Cheng, K.; Walsh, P. J. Org. Lett. 2013, 15, 2298-2301.
  20. (a) Davis, D. C.; Walker, K. L.; Hu, C.; Zare, R. N.; Waymouth, R. M.; Dai, M. J. Am. Chem. Soc. 2016, 138, 10693-10699. (b) Cai, X.; Liang, W.; Liu, M.; Li, X.; Dai, M. J. Am. Chem. Soc. 2020, 142, 13677-13682. (c) Ma, K.; Yin, X.; Dai, M. Angew. Chem. Int. Ed. 2018, 57, 15209-15212. (d) Cai, X.; Liang, W.; Dai, M. Tetrahedron 2019, 75, 193-208.
  21. (a) Mills, L. R.; Barrera Arbelaez, L. M.; Rousseaux, S. A. L. J. Am. Chem. Soc. 2017, 139, 11357-11360. (b) West, M. S.; Mills, L. R.; McDonald, T. R.; Lee, J. B.; Ensan, D.; Rousseaux, S. A. L. Org. Lett. 2019, 21, 8409-8413.
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Jin K. Cha was born and raised in Korea. After graduating from Seoul National University in Korea, he obtained his D. Phil. degree from the University of Oxford under the supervision of the late Professor Sir Jack E. Baldwin. The first two years of his doctoral work were performed at MIT. After postdoctoral research (1981-1983) with Professor Y. Kishi at Harvard University, he started his independent academic career and is now professor of chemistry at Wayne State University. His research group initiated the low-valent titanium-mediated cyclopropanation and related reactions at The University of Alabama, Tuscaloosa, AL.