Use of Cp2TiCl in SynthesisReagent Control of Radical Reactions

Jeff KallemeynMay 21, 2002

Reactions of Cp2TiCl

ChemoselectivityActivated aldehydes (aromatic, a,b-unsaturated) more reactive than aliphatic aldehydes.Esters, nitriles, ketones unaffected.Br, Cl, tosylate stable.Mild radical initiator.

O

HR R

HO

R

OH

1. Pinacol Coupling

2. Epoxide Opening

O

OH

E

R

R

OH

R R

HO

OO

O

Preparation of Cp2TiClIII

TiCl3

Cp

CpTi

Cl

S

IIIIII

IV

Cp

CpTi

Cl

Cl

Cp

CpTi

Cl

ClTi

Cp

Cp

IIIM=Znether

IIITi

ClCp

ClCpM

Cl

ClTi

Cp

Cp

III Solvent (S)2

Zn or MnTHF15 min

Zn, neat TlCp2

Ti(III): [Ar] 3d1

Cp2TiCl generated by in situ reduction with Mn or Zn.Both dimer and trimer work equally well in most cases.In situ regeneration of Ti(III) possible allowing it to function catalytically.

R. Jungst; D. Sekutiwski; J. Davis; M. Luly; G. Stucky, Inorg. Chem. 1977, 16, 1645.

M-Ti-M : 132o

Substrate Controlled Stereoselective Radical Reaction

D. Curran, D. Rakiewicz, Tetrahedron, 1985, 41, 3943.

Substrate directs the stereoselectivity of the reaction.

I

TMS

Bu3SnH

AIBN

TMS

H

H

1. Substrate has stereogenic center

70% yield, 86-97% ee.

2. Chiral Auxiliary

N

O

O

Nt-BuIBu3SnHAIBN

N

O

O

N

t-Bu

N. Porter, D. Scott, I. Rosenstein, B. Giese, A. Viet, H. Zeitz, J. Am. Chem. Soc. 1991, 113, 1791.

72% yield

Reagent Controlled Stereoselective Radical Reaction

M. Sibi, N. Porter, Acc. Chem. Res. 1999, 32, 163.

Control Features:

Chelation locks substrate into rigid conformation.

Chiral ligand allows only 1 face of radical to be accessible.

N

O

O

O

SnBu3t-Bu N

O

O

O

Zn(OTf)2, Ligand5 mol%

t-BuI, Et3B, O2

N

O

N

O

Ph Ph

92% yield, 90% ee

Ligand

1. Complexation

Reagent Controlled Stereoselective Radical Reaction

M. Haque, B. Roberts, Tetrahedron. Lett. 1996, 37, 9123.

2. Chiral Hydrogen Source

O O O OPh3Si

O

OAc

AcOAcO

OAcSH

O OPh3Si

H

+ Ph3SiH5 mol %

72% yield, 50% ee

Ph COMeBr Ph COMe

H

"Sn"Et3B

SnHMe

30% yield, 41% ee

D. Nanni, D. Curran, Tetrahedron Asymm. 1996, 37, 2417.

3. Formation of radical: Cp2TiCl

Pinacol Coupling

Y. Handa, J. Inanaga, Tetrahedron Lett. 1987, 28, 5717.

D. Gibson, Y. Ding, M. Mashuta, J. Richardson, Acta Crys. 1996, 52, 559.

R

OTiCp2ClO

HR

Cp

CpTi

ClS

+

R

OTiCp2Cl

R

ClCp2TiO

R

OTiCp2Cl

R

HO

R

OH

H3O+

General Mechanism

IV

Cp

CpTi

Cl

OCH3

Ti-O 1.839 Cl-Ti-O 93.8 Ti-Cl 2.412 O-Ti_M(1) 109.6 Ti-M 2.088 O-Ti-M(2) 105 Ti-M 2.093 Cl-Ti-M(1) 105 O-C 1.367 Cl-Ti-M(2) 106.3

M(1)-Ti-M(2) 130.8 Ti-O-C 141.4

Bond Lengths and anglesDistorted Tetrahedral

Pinacol Coupling

Y. Handa, J. Inanaga, Tetrahedron Lett. 1987, 28, 5717.

Proposed intermediate leadingto high diastereoselectivity.

Cl Cl

Development of Catalytic Pinacol Coupling

T. Hirao, B. Hatano, M. Asahara, Y. Muguruma, A. Ogawa, Tetrahedron Lett. 1998, 39, 5247.

R

ClCp2TiO

R

OTiCp2Cl

2 TMSCl

R

TMSO

R

OTMS2 TiCp2Cl2+

Product resting statebefore hydrolysis

Development of Catalytic Pinacol Coupling

A. Gansäuer, Synlett. 1998, 801.

TMSCl and Zn can effect the pinacol coupling and proceeds with low diastereoselctivity.

Initial catalytic reactions gave worse diastereoselectivities than stoichiometric (86:14 to 50:50).

Silylation of Ti alkoxide determined to be the slow step in the reaction.

Low diastereoselectivies solved by slow addition of TMSCl, MgBr2 and aldehyde to Ti(III) and Zn.

cis:trans

Modification of Catalytic Pinacol Coupling

Reference

Radicals are stable under protic conditions.

Selection of correct base important as to notoxidize the metal reductant or complex withthe Titanium catalyst.

Addition of Amine HCl salt leads to increaseddiastereoselectivity, faster turnover comparedto TMSCl catalyzed system.

ArAr

OH

OH1

ArAr

OH

OH2

A. Gansäuer, D. Bauer, J. Org. Chem. 1998, 63, 2070.

2,4,6-Collidine

Enantioselective Pinacol Coupling

M. Dunlap, K. Nicholas, Syn. Comm. 1999, 29, 1097.

A. Bensari, J. Renaud, O. Riant, Org. Lett. 2001, 3, 3863.

Mechanism of Epoxide Opening

T. RajanBabu, W. Nugent, J. Am. Chem. Soc. 1994, 116, 986.

A. Gansäuer, H. Bluhm, Chem. Rev. 2000, 100, 2771.

Product ratios show higher substituted radical formed.Titanium attached to radical it created--reagent control.

OTiCp2Cl

R

OTiCp2Cl

R

OTiCp2Cl TiCp2Cl

R

D3O+

OTiCp2Cl

R

D

O

O

D7

D8

OD

R

DCp2TiCl

+

Reductive termination pathway depends on reactivity ofintermediate radical.

Epoxide Opening and Trapping

T. RajanBabu, W. Nugent, J. Am. Chem. Soc. 1994, 116, 986.

O

C8H17

CN

OH

CNOH

CN

H17C8 H17C8

88% 12%

1) Cp2TiCl+

2) H3O+

Radical formation at the higher substituted carbon.

Electrophilic workup

Complementary to nucleophilic epoxide opening

Diastereoselectivity in 5-member ring formation

A. Gansäuer, M. Pierobon, H. Bluhm, Synthesis 2001, 2500

O

Y

Y= CH2, NTs, O

YH

HO CH3

10 mol% Cp2TiCl2Mn, Coll*HClTHF

Diastereoselectivity in 5-member ring formation

A. Gansäuer, M. Pierobon, H. Bluhm, Synthesis 2001, 2500.

Deoxygenation of Epoxides

T. RajanBabu, W. Nugent, J. Am. Chem. Soc. 1994, 116, 986

Deoxygenation discouraged in thepresence of trapping agents withinverse addition of Cp2TiCl tominimize the concentration of Ti(III).

Effective for sensitive functionalgroups, especially acid sensitive.

Effects of Solvent and Water

A. Barrero, J. Oltra, J. Cuerva, A. Rosales, J. Org. Chem. 2002, 67, 2566.

(+)-3a-hydroxyreynosin

Conditions

Effects of Solvent and Water

A. Barrero, J. Oltra, J. Cuerva, A. Rosales, J. Org. Chem. 2002, 67, 2566.

Proposed concerted transition stateleads only to 6-endo cyclization withno 5-exo product.

Tertiary radical hindered--it is nottrapped by Ti(III) or reduced by 1,4-cyclohexadiene.

Deuterium incorporation is observedat C4 when D2O is used.

Formation of a-glycosides

J. Parrish, R. Little, Org. Lett. 2002, 4, 1439

Reaction Scheme

Complementary to NucleophileReaction Scope

Formation of a-glycosides

J. Parrish, R. Little, Org. Lett. 2002, 4, 1439

Reduction

Lewis acidic epoxide opening yieldsthe undesired product.

Trapping agent must be of the correctelectronic nature.

Catalytic Epoxide Opening

A. Gansäuer, H. Bluhm, Chem. Rev. 2000, 100, 2771

A. Gansäuer, M. Pierobon, H. Bluhm, Angew. Chem, Int. Ed. 1998, 37, 101

A. Gansäuer, H. Bluhm, Chem. Rev. 2000, 100, 2771.A. Gansäuer, H. Bluhm, M. Pierobon, M. Keller, Organometallics, 2001, 20, 914.

6

7

Catalytic Asymmetric EpoxideOpening

ReferenceA. Gansäuer, H. Bluhm, T. Lauterbach, Adv. Synth. Catal. 2001, 343, 785

7

7

6666

Catalytic Asymmetric Epoxide Opening

7

7

Conclusion

Cp2TiCl is a mild reducing agent for pinacol and epoxide opening reactions.

Opposite chemoselectivity to nucleophilic epoxide opening.

Reagent controlled enantioselective modifications to the Ti(III) reagent now emerging.

A wide range of functional groups are tolerated.

The oxidation/reduction of reagents and substrates can have significant effect on successof reaction.

Li--Li+ + e

Na--Na+ + e

Mg --> Mg2+ + 2e

Al --> Al3+ + 3e

Mn --> Mn2+ + 2e

Zn --> Zn2+ + 2e

Fe --> Fe2++ 2e

Ni --> Ni3+ + 3e

3.05

2.71

2.37

1.66

1.18

0.76

0.44

0.25

Eo reduction potential

Ti(IV) --> Ti(II)

Ti(IV) --> Ti(III)

Ti(III) + MClx--> Ti(IV) + M

D. Sekutowski, Low Valent Organometallic Titanium Compounds, Dissertation, UIUC, 1975

R. Flowers, Tetrahedron Lett. 1997, 1137

T. Skrydstrup, Chemistry, 2001, 435