Kulinkovich reaction

The generally accepted reaction mechanism initially utilizes two successive stages of transmetallation of the committed Grignard reagent, leading to an intermediate dialkyldiisopropoxytitanium complex. This complex undergoes a dismutation to give an alkane molecule and a titanacyclopropane 1. The insertion of the carbonyl group of the ester in the weakest carbon-titanium bond, leads to an oxatitanacyclopentane 2 being rearranged to ketone 3. Lastly, the insertion of the carbonyl group of 3 in the residual carbon-titanium connection forms a cyclopropane ring. In the transition state of this elementary stage, which is the limiting stage of the reaction, an agostic interaction stabilizing between the beta hydrogen and the R2 group and the titanium atom was called upon to explain the diastereoselectivity observed. Complex 4 obtained is a tetraalkyloxytitanium compound able to play a part similar to that of the starting tetraisopropyloxytitanate, which closes the catalytic cycle. At the end of the reaction, the product is mainly in the shape of the magnesium alcoholate 5, giving the cyclopropanol after hydrolysis by the reaction medium.

The step leading to the titanacyclopropane has been scrutinized computationally. Although the dialkyldiisopropoxytitanium complex has been proposed to undergo β hydrogen elimination followed by C–H reductive elimination to give the alkane and 1, it was found that β hydrogen abstraction by the alkyl group, leading directly to products without the intermediate titanium hydride, is a more favorable process.{{Cite journal |last=Bertus |first=Philippe |date=2019-11-11 |title=From Dialkyltitanium Species to Titanacyclopropanes: An Ab Initio Study |url=https://pubs.acs.org/doi/10.1021/acs.organomet.9b00509 |journal=Organometallics |language=en |volume=38 |issue=21 |pages=4171–4182 |doi=10.1021/acs.organomet.9b00509 |issn=0276-7333|url-access=subscription }}

In broad strokes, and in a formal retrosynthetic sense, titanacyclopropane 1 behaves like a 1,2-dianion which adds into the ester twice: after the first addition into the ester, the resultant tetrahedral intermediate 2 collapses to give β-titanio ketone 3, which undergoes a second intramolecular addition to give the titanium salt of the cyclopropanol (4). (This species then undergoes transmetalation with Grignard reagent to regenerate 1 and close the catalytic cycle and give the product in the form of the magnesium salt (5).)

Image:RéactionKulinkovich2.png

The reaction mechanism has been the subject of theoretical analysis.{{cite journal|author=Wu, Y.–D. and Yu, Z.-X. |journal= J. Am. Chem. Soc.|year=2001|volume= 123|pages= 5777–86|doi=10.1021/ja010114q|pmid=11403612|title=A theoretical study on the mechanism and diastereoselectivity of the Kulinkovich hydroxycyclopropanation reaction|issue=24}} Certain points remain nevertheless obscure. Intermediate titanium complexes of the ate type have been proposed by Kulinkovich.{{cite journal|author1=Kulinkovich, O. G. |author2=Kananovich, D. G. |journal=Eur. J. Org. Chem.|year=2007|pages= 2121–32|doi=10.1002/ejoc.200601035|title=Advanced Procedure for the Preparation ofcis-1,2-Dialkylcyclopropanols – Modified Ate Complex Mechanism for Titanium-Mediated Cyclopropanation of Carboxylic Esters with Grignard Reagents|volume=2007|issue=13}}

In 1993, the team of Kulinkovich highlighted the aptitude of the titanacyclopropanes to undergo ligand exchange with olefins.{{cite journal|author1=Kulinkovich, O. G. |author2=Savchenko, A. I. |author3=Sviridov, S. V. |author4=Vasilevski, D. A. |journal=Mendeleev Commun.|year=1993|pages= 230–31|doi=10.1070/MC1993v003n06ABEH000304|title=Titanium(IV) Isopropoxide-catalysed Reaction of Ethylmagnesium Bromide with Ethyl Acetate in the Presence of Styrene|volume=3|issue=6}} This discovery was important, because it gave access to cyclopropanols more functionalized by making economic use of the Grignard of which normally at least two equivalents should have been engaged to obtain good yields. Cha and its team introduced the use of cyclic Grignard reagents, particularly adapted for these reactions.{{cite journal|author1=Lee, J. |author2=Kim, H. |author3=Cha, J. K. |journal=J. Am. Chem. Soc.|year=1996|volume= 118|pages= 4198–99|doi=10.1021/ja954147f|title=A New Variant of the Kulinkovich Hydroxycyclopropanation. Reductive Coupling of Carboxylic Esters with Terminal Olefins|issue=17}}

:Image:RéactionKulinkovich3.png

The methodology has been extended to intramolecular reactions{{cite journal|author1=Kasatkin, A. |author2=Sato, F. |journal=Tetrahedron Lett.|year=1995|volume= 36|pages= 6079–82|doi=10.1016/0040-4039(95)01208-Y|title=Diastereoselective synthesis of trans-1,2-disubstituted cyclopropanols from homoallyl or bis-homoallyl esters via tandem intramolecular nucleophilic acyl substitution and intramolecular carbonyl addition reactions mediated by Ti(OPr-i)4 / 2 i-PrMgBr reagent|issue=34}}

{{Reactionbox

| Name = Kulinkovich–De Meijere reaction

| Type = Ring forming reaction

| NamedAfter = Oleg Kulinkovich
Armin de Meijere

| Section3 = {{Reactionbox Identifiers

| OrganicChemistryNamed = kulinkovich-demeijere-reaction

| RSC_ontology_id = 0000683

}}

}}

With amides instead of esters the reaction product is an aminocyclopropane in the De Meijere variation{{cite journal|author1=Chaplinski, V. |author2=De Meijere, A. |journal=Angew. Chem. Int. Ed. |year=1996|volume= 35|pages= 413–14|doi=10.1002/anie.199604131|title=A Versatile New Preparation of Cyclopropylamines from Acid Dialkylamides|issue=4}}De Meijere, A.; Winsel, H. and Stecker, B. [http://www.orgsyn.org/orgsyn/orgsyn/prepContent.asp?prep=v81p0014 Organic Syntheses, Vol. 81, p. 14] {{Webarchive|url=https://web.archive.org/web/20120918005358/http://www.orgsyn.org/orgsyn/orgsyn/prepContent.asp?prep=v81p0014 |date=18 September 2012 }}

:Image:RéactionKdM1.png

The intramolecular reaction is also known:{{Cite journal | last1 = Lee | first1 = J. | last2 = Cha | first2 = J. K. | doi = 10.1021/jo962368d | title = Facile Preparation of Cyclopropylamines from Carboxamides | journal = The Journal of Organic Chemistry | volume = 62 | issue = 6 | pages = 1584 | year = 1997 }}{{Cite journal | last1 = Chaplinski | first1 = V. | last2 = Winsel | first2 = H. | last3 = Kordes | first3 = M. | last4 = De Meijere | first4 = A. | title = A New Versatile Reagent for the Synthesis of Cyclopropylamines Including 4-Azaspiro[2.n]alkanes and Bicyclo[n.1.0]alkylamines| doi = 10.1055/s-1997-17828 | journal = Synlett | volume = 1997 | pages = 111–114 | year = 1997 }}{{Cite journal | last1 = Cao | first1 = B. | last2 = Xiao | first2 = D. | last3 = Joullié | first3 = M. M. | doi = 10.1021/ol9910520 | title = Synthesis of Bicyclic Cyclopropylamines by Intramolecular Cyclopropanation of N-Allylamino Acid Dimethylamides| journal = Organic Letters | volume = 1 | issue = 11 | pages = 1799 | year = 1999 | pmid = 10814442 }}{{Cite journal | last1 = Lee | first1 = H. B. | last2 = Sung | first2 = M. J. | last3 = Blackstock | first3 = S. C. | last4 = Cha | first4 = J. K. | title = Radical cation-mediated annulation. Stereoselective construction of bicyclo[5.3.0]decan-3-ones by aerobic oxidation of cyclopropylamines| doi = 10.1021/ja017043f | journal = Journal of the American Chemical Society | volume = 123 | issue = 45 | pages = 11322–11324 | year = 2001 | pmid = 11697988}}{{Cite journal | last1 = Gensini | first1 = M. | last2 = Kozhushkov | first2 = S. I. | last3 = Yufit | first3 = D. S. | last4 = Howard | first4 = J. A. K. | last5 = Es-Sayed | first5 = M. | last6 = Meijere | first6 = A. D. | doi = 10.1002/1099-0690(200208)2002:15<2499::AID-EJOC2499>3.0.CO;2-V | title = 3-Azabicyclo[3.1.0]hex-1-ylamines by Ti-Mediated Intramolecular Reductive Cyclopropanation of α-(N-Allylamino)-Substituted N,N-Dialkylcarboxamides and Carbonitriles| journal = European Journal of Organic Chemistry | volume = 2002 | issue = 15 | pages = 2499 | year = 2002 }}{{Cite journal | last1 = Tebben | first1 = G. D. | last2 = Rauch | first2 = K. | last3 = Stratmann | first3 = C. | last4 = Williams | first4 = C. M. | last5 = De Meijere | first5 = A. | title = Intramolecular Titanium-Mediated Aminocyclopropanation of Terminal Alkenes: Easy Access to Various Substituted Azabicyclo[n.1.0]alkanes¹| doi = 10.1021/ol027352q | journal = Organic Letters | volume = 5 | issue = 4 | pages = 483–485 | year = 2003 | pmid = 12583749}}{{Cite journal | last1 = Ouhamou | first1 = N. | last2 = Six | first2 = Y. | doi = 10.1039/b306719j | title = Studies on the intramolecular Kulinkovich?De Meijere reaction of disubstituted alkenes bearing carboxylic amide groups | journal = Organic & Biomolecular Chemistry | volume = 1 | issue = 17 | pages = 3007–9 | year = 2003 | pmid = 14518121}}{{Cite journal | last1 = Gensini | first1 = M. | last2 = De Meijere | first2 = A. | doi = 10.1002/chem.200305068 | title = Cyclopropane-Annelated Azaoligoheterocycles by Ti-Mediated Intramolecular Reductive Cyclopropanation of Cyclic Amino Acid Amides | journal = Chemistry: A European Journal | volume = 10 | issue = 3 | pages = 785–790 | year = 2004 | pmid = 14767944}}{{Cite journal | last1 = Larquetoux | first1 = L. | last2 = Kowalska | first2 = J. A. | last3 = Six | first3 = Y. | doi = 10.1002/ejoc.200400291 | title = The Formal [3+2+1] Cyclisation of Cyclopropylamines with Carboxylic Anhydrides: A Quick Access to Polysubstituted 2,3,3a,4-Tetrahydro6(5H)-indolone Ring Systems| journal = European Journal of Organic Chemistry | volume = 2004 | issue = 16 | pages = 3517 | year = 2004 }}{{Cite journal | last1 = Larquetoux | first1 = L. | last2 = Ouhamou | first2 = N. | last3 = Chiaroni | first3 = A. L. | last4 = Six | first4 = Y. | title = The Intramolecular Aromatic Electrophilic Substitution of Aminocyclopropanes Prepared by the Kulinkovich–De Meijere Reaction | doi = 10.1002/ejoc.200500428 | journal = European Journal of Organic Chemistry | volume = 2005 | issue = 21 | pages = 4654 | year = 2005 }}

:Image:RéactionKdM4.png

{{Reactionbox

| Name = Kulinkovich–Bertus-Szymoniak reaction

| Type = Ring forming reaction

| NamedAfter = Oleg Kulinkovich
Philippe Bertus
Jan Szymoniak

| Section3 = {{Reactionbox Identifiers

| OrganicChemistryNamed = kulinkovich-szymoniak-reaction

| RSC_ontology_id = 0000684

}}

}}

In the Bertus-Szymoniak variation the substrate is a nitrile and the reaction product a cyclopropane with a primary amine group.{{Cite journal | last1 = Bertus | first1 = P. | last2 = Szymoniak | first2 = J. | doi = 10.1039/b105293b | title = New and easy route to primary cyclopropylamines from nitriles | journal = Chemical Communications | issue = 18 | pages = 1792–1793 | year = 2001 | pmid = 12240317}}{{Cite journal | last1 = Chaplinski | first1 = V. | last2 = De Meijere | first2 = A. | doi = 10.1002/anie.199604131 | title = A Versatile New Preparation of Cyclopropylamines from Acid Dialkylamides | journal = Angewandte Chemie International Edition in English | volume = 35 | issue = 4 | pages = 413 | year = 1996 }}

:Image:RéactionKSz1.png

The reaction mechanism is akin the Kulinkovich reaction:

:Image:RéactionKSz2.png

• {{Cite journal | last1 = Kulinkovich | first1 = O. G. | last2 = Sviridov | first2 = S. V. | last3 = Vasilevski | first3 = D. A. | doi = 10.1055/s-1991-26431 | title = Titanium(IV) Isopropoxide-Catalyzed Formation of 1-Substituted Cyclopropanols in the Reaction of Ethylmagnesium Bromide with Methyl Alkanecarboxylates | journal = Synthesis | volume = 1991 | issue = 3 | pages = 234 | year = 1991 }}
• {{cite journal|author1=Kulinkovich, O. G. |author2=De Meijere, A. |journal=Chem. Rev.|year=2000|volume= 100|pages= 2789–834|doi=10.1021/cr980046z|pmid=11749306|title=1,n-Dicarbanionic Titanium Intermediates from Monocarbanionic Organometallics and Their Application in Organic Synthesis|issue=8}}
• {{cite journal|author1=Sato, F. |author2=Urabe, H. |author3=Okamoto, S. |journal=Chem. Rev. |year=2000|volume= 100|pages= 2835–86|doi=10.1021/cr990277l|pmid=11749307|title=Synthesis of organotitanium complexes from alkenes and alkynes and their synthetic applications|issue=8}}
• {{cite journal|author1=Wu, Y.-D. |author2=Yu, Z.-X. |journal=J. Am. Chem. Soc.|year=2001|volume= 123|pages= 5777–86|doi=10.1021/ja010114q |pmid=11403612|title=A theoretical study on the mechanism and diastereoselectivity of the Kulinkovich hydroxycyclopropanation reaction|issue=24}}
• {{cite journal|author=Kulinkovich, O. G. |journal=Russ. Chem. Bull.|volume= 53 |year=2004|pages=1065–1086|title=Alkylation of carboxylic acid derivatives with dialkoxytitanacyclopropane reagents|issue=5|doi=10.1023/B:RUCB.0000041303.52400.ca|s2cid=98642553}}
• {{cite journal|author1=Wolan, A. |author2=Six, Y. |journal=Tetrahedron|year=2010|volume=66|pages= 15–61|doi=10.1016/j.tet.2009.10.050|title=Synthetic transformations mediated by the combination of titanium(IV) alkoxides and grignard reagents: Selectivity issues and recent applications. Part 1: Reactions of carbonyl derivatives and nitriles}}
• {{cite journal|author1=Wolan, A. |author2=Six, Y. |journal=Tetrahedron|year=2010|volume=66|pages= 3097–3133|doi=10.1016/j.tet.2010.01.079|title=Synthetic transformations mediated by the combination of titanium(IV) alkoxides and Grignard reagents: Selectivity issues and recent applications. Part 2: Reactions of alkenes, allenes and alkynes|issue=17}}
• {{Cite journal | last1 = Corey | first1 = E. J. | last2 = Rao | first2 = S. A. | last3 = Noe | first3 = M. C. | doi = 10.1021/ja00099a068 | title = Catalytic Diastereoselective Synthesis of Cis-1,2-Disubstituted Cyclopropanols from Esters Using a Vicinal Dicarbanion Equivalent | journal = Journal of the American Chemical Society | volume = 116 | issue = 20 | pages = 9345 | year = 1994 }}

{{Reflist|35em}}

Category:Carbon-carbon bond forming reactions

Category:Coupling reactions

Category:Titanium

Category:Name reactions