The Kulinkovich Reaction:

Generation of 1,2-dicarbanionic Titanium Species and Their Use in Organic Synthesis

Literature meeting

Olga Lifchits

September 18, 2007

The next blockbusterThe next blockbuster

“Low-valence titanium – Lord of the small rings”

(M. Oestreich, Nachrichten aus der Chemie, 2004, 52, 805.)

TitaniumTitanium

22Ti [Ar] 3d2 4s2

• Oxophilic early transition metal

• Pure metal is non-toxic even in large quantities

• Toxicity associated with Ti complexes comes from ligands (e.g. cyclopentadienyl)

• Salts are typically harmless except the chlorides

Reactivity of Ti-C sigma bondReactivity of Ti-C sigma bond

• Ti-C bond is strong (typically > 60 kcal/mol) but very reactive (thermally unstable)

TiCH3

CH3Cp

CpCp2Ti=CH2

- CH4

AlMe2ClTi AlMe2

ClCp

Cp

Tebbe's reagent

Ti-C-H angle distortionsuggests an agostic interaction

• Low-energy empty d-orbitals favour agostic interactions with neighbouring σ bonds

• Agostic interaction with Cα-H promotes decomposition into alkylidenetitanium species by α-hydrogen abstraction in the absence of β-hydrogens

organyl TiX3

X = Cl, OR, NR2

Kulinkovich, O.G.; De Meijere, A. Chem. Rev., 2000, 100, 2789; Telnoi, V.I. et al. Dokl. Akad. Nauk SSSR 1967, 174, 1374; Brookhart, M, Green, M.L.H. J. Organomet. Chem. 1983, 250, 395.

Reactivity of the Ti-C sigma bondReactivity of the Ti-C sigma bond

• When β-hydride is present, analogous agostic interaction with Cβ-H assists in β-hydride elimination

86o

LnTi-L

R

R

LnTi R

R

H+ L

RLnTi

RLnTi

RA B

_

• Resulting complex exists as two resonance forms favouring titanacyclopropane B (general trend for oxidized early metals)

• Reactivity patterns of both resonance forms are observed

“1,2- dicarbanion”

Brookhart, M, Green, M.L.H. J. Organomet. Chem. 1983, 250, 395; Steigerwald, M; Goddart, W.A. JACS, 1985, 107, 5027

Oleg G. KulinkovichOleg G. Kulinkovich

• Born in Estonia in 1948

• Honors B.Sc., Belorussian State University (BSU), Minsk (1971)

• PhD, BSU with Prof. I.G. Tishschenko (1975)

• D.Sc., BSU (1987)

• Professor and Head of the Department of Organic and Polymer Chemistry at BSU (since 1991)

The Kulinkovich ReactionThe Kulinkovich Reaction

R1 OR2

OMgBr (2 eqv)

Ti(OiPr)4 (5-10 mol%)

Et2O, 18-20oC

1.

2. H3O+ 10-99%

R1

HO

• Original reaction (1989) used a mixture of stoichiometric amount of Ti(OiPr)4 (1 equiv), EtMgBr (3 equiv) and ester at -78oC to -40oC

• Catalytic version (1991) uses slow addition of EtMgBr (2 equiv) to a mixture of ester and Ti(OiPr)4 (5-10 mol%) at 18-20oC

Kulinkovich, O.G. et al. Zh. Org. Khim. 1989, 25, 2245; Kulinkovich, O.G. et al. Synthesis 1991, 234.

Proposed reaction mechanismProposed reaction mechanism

(OR')2TiEt

EtTi(Oi-Pr)4

2 EtMgBr 2 iPrOMgBr

R' = iPr or R2

CH3-CH3

(OR')2TiR1 OR2

O

(R'O)2TiO R1

OR2

1st C-C bond formation

R1

O(R'O)2Ti

OR2

2nd C-C bond formation

Likely initiated by the attack of Grignard on Ti center

(OR')2Ti

O

OR2

R1

2 EtMgBr

R1 OMgBr

+R2OMgBr

H3O+R1 OH

R'OH

R' = iPr or R2

(R'O)2TiO R1

OR2

Et

MgBr

(R'O)2TiO

R1

Et

Kulinkovich, O.G. Russ. Chem. Bull. Int. Ed. 2004, 53, 1065.

““Classical” Kulinkovich reaction scope Classical” Kulinkovich reaction scope

.

Ester scope:

Grignard scope (cis geometry in the absence of chelating groups):

R1 OR

O

R

MgX

OHn OH OH

O

OH

X

X = Cl, Br

OH

OH

TMS

OH

OR

R = alkyl, aryl

OH

N

OR

HO

OH

HOOH

(PrOi)2P

O

OH OH OH OH OH

Br

Et TIPSO

OMe

MeO

4

Kulinkovich, O.G.; De Meijere, A. Chem. Rev., 2000, 100, 2789, and references therein.

Initial Limitation and ImprovementsInitial Limitation and Improvements

Problem: the reaction requires one “sacrificial” equivalent of the Grignard reagent, which might be expensive and/or difficult to make

Solution: methyltitanium triisopropoxide provides a “sacrificial” methyl group (no β-hydrogens on methyl)

MeTi(OiPr)3R

MgBr(PrOi)2Ti

Me

R- CH4

(PrOi)2Ti

R

De Meijere, A. et al. Synlett, 1997, 111.

Generating titanacycles through ligand exchangeGenerating titanacycles through ligand exchange

Problem: some olefins failed to exchange (eg. 1-heptene, ethyl vinyl ether) likely due to unfavourable equilibrium

Solution: a strained precursor from cyclopentyl or cyclohexyl Grignard

Ti(OiPr)4MgBr

(PrOi)2Ti (PrOi)2Ti

H R1

(PrOi)2Ti

R1R2 OR3

O

R1HO

R2

Monosubstituted olefins only,with a signle exception of norbornene

Ti(OiPr)3XMgBr

(PrOi)2Ti

H R1

(PrOi)2Ti

R1

X = OiPr, Cl 0-1 0-1

Kulinkovich, O.G. et al. Mendeleev Commun., 1993, 230; Cha, K.J. et al. JACS, 1996, 118, 4198.

Extended scope through ligand exchangeExtended scope through ligand exchange

(RO)2B

OHR1

(RO)2B

OH OH OH

OH

HO

Me3Si

(from

(PrOi)3TiO )

OH

HO

(from

HO)

OTBDMS

Bu3Sn

OH

(H2C)7

n-C18H37

87%, 98:2 dr 56% 37% 71%

64% 82%, 7:93 dr

O

51%

Kulinkovich, O.G.; De Meijere, A. Chem. Rev., 2000, 100, 2789, and references therein.

Intramolecular Nucleophilic Acyl Substitution (INAS)Intramolecular Nucleophilic Acyl Substitution (INAS)

O

OMe

Ti(OiPr)4 + i-PrMgCl

Ti(OiPr)2

O

OMe

Ti(OiPr)2 O

(OiPr)2Ti

OEtOH

Can generate a wide variety of bicyclic cyclopropanols:

X OH

R1

R2

X = C, N

R3

n

n = 0, 1, 2

OH

HTIPSO N

HO

OH

75% 94% 98% 88%

OH

Cha, J.K. JACS, 1996, 118, 291; Sato, F. et al. 1997, 119, 6984; Sato, F. Tet. Lett. 1996, 37, 1849.

Intramolecular Nucleophilic Acyl Substitution (INAS)Intramolecular Nucleophilic Acyl Substitution (INAS)

Proximity of the vinyl group to the ester matters:

.. but unsaturated oxacarboxylic acid esters work well for large rings:

HO

H

HO

H

HOH

HO

H

55% 62% 11% does not form

O O

HOH

HO

H

49%62%

O

OMen

Cha, J.K. JACS, 1996, 118, 291; Ollivier, J. Org. Biomol. Chem. 2003, 1, 3600.

Intramolecular Nucleophilic Acyl Substitution (INAS)Intramolecular Nucleophilic Acyl Substitution (INAS)

INAS is otherwise not so easy to achieve!

• Reactive nucleophile must be generated in presence of carbonyl

• The nucleophile must react only intra- and not intermolecularly

• Zn, B are not reactive enough; Mg, Li are too reactive

X X

OR

Nu

Marek, I.,ed. Titanium and Zirconium in Organic Synthesis; Wiley: Weinheim, 2002.

Further possibilities with ligand exchangeFurther possibilities with ligand exchange

Exchange withalkynes:

Exchange with a diene:

OCO2Et

iPrMgClTi(OiPr)4 Ti

(OiPr)2O

O OEt

O

O

Ti(OiPr)2

EtO

O

O(PrOi)2Ti

EtO

Allyltitanium

RCHO

O

O

R

HO

R1 O

OR2

Ti(OiPr)4 + i-PrMgCl

Ti(OiPr)2

R1 O

OR2

(OiPr)2Ti O

R1

(PrOi)2TiOR2

E+O

R1

E

E+ = H+, I2, PhCHO

Sato, F. et al. JACS, 1996, 118, 2208; Sato, F. et al. J. Chem. Soc. Chem. Comm. 1996, 197.

Asymmetric strategies – Titanium bisTADDOLateAsymmetric strategies – Titanium bisTADDOLate

OEt

O

Ph

MgBr(2 eqv)

Et2O, 20oC

O

OO

O

Et

Et

H

H

Ar Ar

Ar Ar

Ar =

CF3

CF3

Ti

2

(0.3-1 eqv)

65-72%, 70-78% ee

PhMeHO

(1S, 2R)-ent

Ti(TADDOL)2

Ti(TADDOL)2 =

Corey, E.J., et al. JACS 1994, 116, 9345.

Proposed origin of stereoselectivityProposed origin of stereoselectivity

OTi

O

ArAr

ArAr

H H

O

O

Et

Et

H

R1

stablest titanacycle, controlledby axial Ar groups sets absolute stereochemistry of R1 at this step

R2 OMe

O

OTi

O

ArAr

ArAr

H H

O

O

Et

Et

H

R1

O OEt

R2

Insertion is bond-specific; R1 and R2grops prefer to sit trans to each other

OTi

O

ArAr

ArAr

H H

O

O

Et

Et

H

R1

OR2O

Et

R1

H

"face-specific pi-donor coordination of C=O to Ti(IV)"

OTi

O

ArAr

Ar

Ar

H H

O

O

Et

EtO

OMe

R2

H R1HO

R2

H R1

Corey, E.J., et al. JACS 1994, 116, 9345.

But why the cis geometry?But why the cis geometry?

Quantum-chemical calculations of a model reaction suggest..

MeOMe

O(MeO)2Ti

OTi(OMe)2

MeO

Insertion into least hindered Ti-C bond (kinetically favoured)

OMe

Me

H

Ti(OMe)3Agostic interaction with the Hatom of alpha carbon bringstwo methyls cis to each other

Me

Me

(MeO)3TiO

When applied to the Ti-TADDOLate reaction, this mechanism gives the same absolute configuration

Wu, Y-D., Yu, Z.-X. JACS, 2001, 123, 5777.

Question for the audienceQuestion for the audience

Draw the mechanism of this intramolecular Kulinkovich reaction and

explain the observed high diastereoselectivity for the trans product:

O

O

Ph

Ti(OiPr)4 + i-PrMgCl

Ti(OiPr)2OH

Ph

85%, dr >97:3

HO

Note: diastereoselectivity is

under thermodynamic control

OH

Ph

HO

EtTemperature Trans:cis

-45oC to 0oC 41:59

-45oC to 20oC 95:5

Trans-selective cyclopropanation: answerTrans-selective cyclopropanation: answer

Sato, F., Kastakin, A. Tet. Lett. 1995, 34, 6079.

O

O

Ph

Ti(OiPr)4 + i-PrMgCl

Ti(OiPr)2

O

O

Ph(PrOi)2Ti

Ti(OiPr)2

OPh

O

O Ti(OiPr)2

Ph

O

O Ti(OiPr)2O

Ph

H+OH

OH

Ph

85%, dr >97:3

Ti(OiPr)2

O

O

Ph

Asymmetric strategies: Oppolzer’s auxiliary Asymmetric strategies: Oppolzer’s auxiliary

SO2

N

O

Ti(OiPr)4 + i-PrMgCl

Ti(OiPr)2HO

90%, 32% ee

SO2

N

O

R1

Ti(OiPr)4 + i-PrMgCl

Ti(OiPr)2HO

R1

SO2

N

O

dr >99:156-87%92:8 - 99:1 dr(>98% ee)

Base

R1X

1 2

3

Sato, F. et al. Angew. Chem. Int Ed. 1998, 37, 2666.

Proposed origin of stereoselectivity Proposed origin of stereoselectivity

• Cooperative effect of the auxiliary and the chiral α-alkyl group

• “Mismatched” sultam 3 gave a lower dr (92:8)

• Absence of auxiliary (ester 4) gave a lower dr (66:34)

• Evans auxiliary (N-acyloxazolidinone 5) gave a lower dr (74:26)

N

O

Bn3

SO2

EtO

O

Bn4

N

O

Bn

O

O

MePh5

SO2

N

O

Bn

Ti(OiPr)4 + i-PrMgCl

Ti(OiPr)2HO

Bn

dr >99:1

86%> 99:1 dr> 98% ee

1 2

Sato, F. et al. Angew. Chem. Int Ed. 1998, 37, 2666.

Bicyclic cyclopropanol scopeBicyclic cyclopropanol scope

HO

58%, >95:5 dr>98% ee

HO

80%, >95:5 dr>98% ee

HO

87%, >95:5 dr>98% ee

HO

74%, >95:5 dr>98% ee

HOTBDMSO

84%, >95:5 dr>98% ee

HOtBuO2C

56%, 92:8 dr>98% ee

Sato, F. et al. Angew. Chem. Int Ed. 1998, 37, 2666.

Kulinkovich-de Meijere ReactionKulinkovich-de Meijere Reaction

R1 NR2

OR3 R4

MgBr

Ti(OiPr)4

R1

NR2

R3

R4

R1 NR2

OR3 R4

MgBr

Ti(OiPr)4

(PrOi)2Ti O R1

NHR2

R4

R3

(PrOi)2TiO

R1

NR2

R4

R3Ti(OiPr)2

O

n

R1

NR2

R3

R4

H2O

TiO2

De Mejere, A, Chaplinski, V. Angew. Chem. Int. Ed. Engl. 1996, 35, 413.

Kulinkovich-de Meijere ReactionKulinkovich-de Meijere Reaction

• Requires stoichiometric Ti(OiPr)4 for useful yields

• Diastereoselectivity is generally lower than with esters

• Can use ligand exchange to generate active titanacycles

• Disubstituted alkenes and cycloalkenes react!

• Can easily access primary amines by catalytic debenzylation:

R1 NBn2

OR3 R4

MgBr

Ti(OiPr)4

R1

NBn2

R3

R4

H2, Pd/C R1

NH2

R3

R4

De Mejere, A, Chaplinski, V. Angew. Chem. Int. Ed. Engl. 1996, 35, 413.

Kulinkovich-de Meijere Reaction scopeKulinkovich-de Meijere Reaction scope

NBn2

EtOMe

61%

NBn2

OO

92%

NBn2

89%

NBn2

63%

H

NBn2

28%

NBn2

43%

Bu3Sn O

NEt2

68%

Me Et

NBn2

26%

Kulinkovich, O.G.; De Meijere, A. Chem. Rev., 2000, 100, 2789, and references therein.

Surprising behaviour with dienesSurprising behaviour with dienes

NBn2

Bn2N

Given a choice, a more substituted double bond is cyclopropanated..

… but in the absence of a less substituted bond, there’s no conversion:

no conversion

no conversion

De Meijere, A. et al. Chem. Eur. J. 2002, 8, 3789.

Surprising behaviour with dienes - rationalizationSurprising behaviour with dienes - rationalization

R

Ti(OiPr)2

Ti(OiPr)2R Ti(OiPr)2R

RNBn2

H NBn2

O

Ti(OiPr)2

O

R

Bn2N

Ti(OiPr)2

O

R

Bn2N

Intramolecular allyl addition

De Meijere, A. et al. Chem. Eur. J. 2002, 8, 3789.

Application in natural product synthesisApplication in natural product synthesis

NH

NH2

87% over 2 steps> 2:98 dr

N N

F

O

HO

O

F

F

HH

N

NH2

H

H

Antibiotic Trovafloxacin (Trovan)

NBn

H NBn2

O MeTi(OiPr)3 (1.2 eqv)

MgCl

(2.5 eqv) NBn

NBn2

H2, Pd/C

MeOH/AcOH

De Meijere, A. et al. Chem. Eur. J. 2002, 8, 3789.

Intramolecular Kulinkovich – de Meijere reactionIntramolecular Kulinkovich – de Meijere reaction

O

NEt2

N

Ph

O

MgCl

ClTi(OiPr)3

64%

H

NEt2

NPh

H

Me

MgCl

ClTi(OiPr)3

93%

Lee, J., Cha, J.K. J. Org. Chem. 1997, 62, 1584.

Beyond cyclopropanes – J.K. ChaBeyond cyclopropanes – J.K. Cha

HTBSO

ROHOOxy-Cope O

OMe

Kulinkovich

Making the Oxy-Cope precursor HOO

OMeTiX(OiPr)3

X = OiPr or Cl

MgBr

R1

R

R1

RMgBr

RO

R = TIPS, 77%R = THP, 46%

TiCl(OiPr)3

HO

OR

1. TBAF (75%) PPTS (60%)

2. Swern3. TBSOTf, Et3N

TBSO

TBSO

exclusively (Z)

single diastereomer

Lee, J., Kim, H., Cha, J.K. JACS, 1995, 117, 9919.

Beyond cyclopropanes – J.K. ChaBeyond cyclopropanes – J.K. Cha

H H

TBSO

OTBS H H

TBSO

OTBSH H

TBSO

TBSO

PhH, reflux

76-81% over 3 steps

TBSO

HTBSO

Lee, J., Cha, J.K. J. Org. Chem. 1997, 62, 1584.

Beyond cyclopropanes – J.K. ChaBeyond cyclopropanes – J.K. Cha

TBSO

HTBSO

Et2ZnCH2I2

PhH, reflux75%

TBSO

HTBSO

1. H2, PdC95%

2. HF, MeCNH2O, 73%

O

HHO

H3C

Cl3CCO2EtNaOMe99%

OTBS

HTBSO

Cl Cl1. H2, Pd/C100%

2. AgNO3acetone-H2O70%

H

Cl OTBS

O

Lee, J., Cha, J.K. J. Org. Chem. 1997, 62, 1584.

Beyond cyclopropanes – G. MicalizioBeyond cyclopropanes – G. Micalizio

Typical convergent approaches must form a central ketone first

Take that, aldol!

• No protecting group manipulations (free -OH)

• Stereodefined trisubstituted double bond with no intermediate ketone

• Double bond can be further functionalized

Me

OH

Me Me

OH

Me

R2

Me

OH

Me Me

Ti(OiPr)2H

O

R2

Me

R1

Me

OH

Me

Me

Me

OC

Me

H Me

SiMe3

OR OR

OR

Bahadoor, A.B., Flyer, A., Micalizio, G.G. JACS, 2005, 127, 3694.

Beyond cyclopropanes – G. MicalizioBeyond cyclopropanes – G. Micalizio

• Various diastereomers of the homopropargylic alcohol and aldehyde were coupled – Felkin selectivity in all cases (generally ≥ 2:1)

• Regioselectivity was found to be a function of the stereochemistry of both coupling partners!

• The role of a neighbouring alkoxide implicated in regioselectivity

Me

OLi

Me Me

Ti(OiPr)2

H

O

Me

OR

Me

OH

Me

MeOR

1. n-BuLi, PhMe, -78oC2. ClTi(OiPr)3, cPentMgCl-78oC to -40oC

3. BF3-OEt2, -78oCthen

Pr

OTBSMe

OH

Me Me

OH

Me

OR

Pr

OTBS

66%19:1 regioselectivity

1.5:1 dr

Felkin product

Bahadoor, A.B., Flyer, A., Micalizio, G.C. JACS, 2005, 127, 3694; Bahadoor, A.B., Micalizio, G.C. J. Org. Lett. 2006, 8, 1181.

SummarySummary

TiOiPr

OiPr

R1

R2

R3 OR

O

OH

R3

R1

X

O

OMenR3

R4

R5

X OH

R5

R4

X = C, N,O

R3

n

n = 0-3

R3 O

OR2nO

R3

E

n

R3 NR4 2

O

R1

NR4 2

R3

R4

HO

R4

SO2

N

O

R4

Micalizio’s polypropionate synthesisMicalizio’s polypropionate synthesis

Substrate-controlled diastereoselective cyclopropanationSubstrate-controlled diastereoselective cyclopropanation

Cha, J,K. et al. Angew. Chem. Int. Ed. 2002, 41, 2160.

R

OH Ti(OiPr)4

toluene, RT R

OTi(OiPr)3 c-HexMgCl

THF, RT

Ti O

R

OiPr

R1 OR2

O

OHR1

RHO

trans onlydr = 3.5:1 to 12.2: 1

R

O

O

c-HexMgCl

TiCl(OiPr)3

OHR1

RHO

trans onlyno 1,3 diastereoselectivity

Substrate-controlled diastereoselective cyclopropanationSubstrate-controlled diastereoselective cyclopropanation

Cha, J,K. et al. Angew. Chem. Int. Ed. 2002, 41, 2160.