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CATALYTIC ASYMMETRIC NOZAKI-HIYAMA-KISHI REACTION: ROLE OF ORGANOCHROMIUM COMPOUNDS

AND NOVEL SALEN LIGANDS

ARKAJYOTI CHAKRABARTY

Prof. Uday Maitra’s GroupDepartment of Organic Chemistry

Indian Institute of Science

GRADUATE COLLOQUIUM

3.12.08

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CONTENTS OF THE TALK

INTRODUCTION TO ORGANOCHROMIUM COMPOUNDS

‘NOZAKI-HIYAMA-KISHI’ REACTION

CATALYTIC AND ENANTIOSELECTIVE VERSION OF ‘NHK’ REACTION

NOVEL SALEN LIGANDS ( I & II ) IN ENANTIOSELECTIVE CATALYSIS

CONCLUSION AND REFERENCES

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ORGANOCHROMIUM COMPOUNDS

Chromium(II) reagents are powerful one electron reducing agents

Cr(II) readily inserts into allyl-, alkenyl-, alkynyl-, propargyl- and aryl halides and sulfonates under aprotic conditions, giving rise to the corresponding organochromium(III) reagents Traces of nickel salts exert a catalytic effect on the formation of the C-Cr(III) bond

Cr3++ e- Cr2+ EO = - 0.408 V

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ORGANOCHROMIUM COMPOUNDS AS NUCLEOPHILES

R- YCrX2

(I I )

R

(I I )

R-CrX2Y

(I I I )E+

R- E

CrX3transmetalation

R- M

CrX2

NHK manifold

A. Furstner, Chem. Rev. 1999, 99, 991-1045

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‘NOZAKI-HIYAMA-KISHI’ REACTION

In Nozaki-Hiyama-Kishi reaction, CrCl2 adds to unsaturated halide to form organochromium(III) compounds, which are used as nucleophiles for coupling with aldehyde

For less reactive substrates such as alkenyl and aryl halides or triflates, doping CrCl2 with catalytic amount of Ni(II) or Mn(0) is a standard trick

The driving force of these reactions is the formation of highly stable O-Cr(III) bond

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TYPICAL EXAMPLES OF NHK REACTIONS

R O +X CrCl2

THF/ 25 OC60- 94 %

R

OH

O

BrO

OO

CrCl2

THF25 oC

CO2CH3

O

O

O

CO2CH3

OH

O

I

HH

TBDMSOO

HH

TBDMSO

CrCl2cat. NiCl2

DMSO25 oC65 %

OHO

A. S. K. Hashmi, J. Prakt. Chem. 1996, 338, 491-495

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NHK REACTIONS CATALYTIC IN CHROMIUM

X

CrX2CrX3CrX3

MnMnX2

CrX2

R

OCrX2

RCHO

Me3SiX

R

OSiMe3

A

B

C

A. Furstner et al. , J. Am. Chem. Soc. 1996, 118, 12349-12357

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ENANTIOSELECTIVE VERSION OF NOZAKI-HIYAMA-KISHI

REACTION

First report of enantioselective NHK reaction involves salen as chiral ligand derived from trans-1,2-diaminocyclohexane

N

OH

tBu

tBu

N

HO

tBu

tBu

H HR R

(R,R)-N,N’-bis(3,5-di-tert-butyl-salicylidene)-1,2-cyclohexanediamine ( I )

A. Umani-Ronchi et al., Angew. Chem. Int. Ed. 1999, 38, 3357-3359

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HOW DOES SALEN ( I ) WORK AS THE CHIRAL LIGAND?

CrCl2

Salen

2 [CrI I(Salen)] [CrI I I(Salen)]X

Mn

MnX2

X(Salen)CrI I I

R

OCrI I I(Salen)

RCHO

Me3SiX

R

OSiMe3

N O

tBu

tBu

N O

tBu

tBu

H

H

CrI I

Cr(Salen)

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ENANTIOSELECTIVE NHK REACTIONS CATALYZED BY [Cr

(salen)] COMPLEX

Cl

Entry R-X Yield [ % ] ee [ %]

1.

2.

3.

67

65

70

84 ( R)

65 ( R)

0

Br

I

CrCl3Mn

CH3CNCrCl2

Salen

Et3N[Cr (Salen)]

RCHO[Cr (Salen)]10 mol %1.

X

X = Cl, Br, I2. Me3SiCl

3. H+

R

OH

RR

OH

OH2 3

Table-1: Enantioselective addition of various allyl halides to PhCHO catalyzed by [Cr(salen)] complex

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ENANTIOSELECTIVE NHK REACTIONS CATALYZED BY [Cr

(salen)] COMPLEX

Entry

R’CHO Yield of 2[ % ]

Yield of 3 [ % ]

ee of 2 [%]

1.

2.

3.

67

41

42

16

40

0

78 ( R )

77 ( R )

89 ( R )

Me

CHO

CHO

F

CHO

Table-2: Enantioselective addition of allyl chloride to aldehyde catalyzed by

Cr (salen) complex

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SYN DIASTEREOSELECTIVE ADDITION PROMOTED BY CHIRAL Cr(salen)

COMPLEX

ArCH2OCrCl2 10%

Salen 20 %Mn, Me3SiCl

H+

Ar

OH

Me

syn:anti = 65 : 35 / 85 : 15

ee = 82- 90 %

Br

Hypothetical open transition state for the addition of crotyl bromide to ArCHO

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A BRIEF EXPLANATION This syn diasteroselective addition is unique as normally aldehydes react with stereogenic allylchromium reagents to afford homoallylic alcohols with excellent degree of anti

selectivity

A cyclic Zimmerman-Traxler transition state is thought to be involved in this reaction

Two molecules of Cr-salen complexes are involved in the transition state

A. Umani Ronchi et al. , Polyhedron 2000, 19, 537-539

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LIMITATIONS OF SALEN LIGAND ( I ) IN ENANTIOSELECTIVE NHK

REACTION

The substrate spectrum is fairly narrow

Ally bromide and iodide were found to add with only moderate ( 52 % ee ) or no selectivity to benzaldehyde

Using this asymmetric NHK process, enantiomerically enriched allylic alcohols can not be generated starting

from vinylic halides

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HOW TO SURPASS THE CURRENT LIMITATIONS?

Modification of the chiral diamine backbone of the salen ligand can lead to better catalytic properties in NHK reactions

A chiral diamine having a larger nitrogen-atom separation may prove to be useful building block for a highly enantioselective catalyst in the asymmetric NHK reaction

Ar

N

Ar

N

H HR R

Salen ( I )

A Highly Enatioselective Catalyst

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A NOVEL SALEN LIGAND ( II ) BASED ON DIANANE

S S

N N

OH

tBu

tBu HO

tBu

tBu

(S,S)- 2

C2 AXI S

This chiral salen ligand has the advantages of possessing C2 symmetry and having a rigid hydrocarbon backbone and the separation between nitrogen atom is larger which

plays an important role in improving the catalytic properties

Ian Paterson et al. , Angew. Chem Int. Ed. 2003, 42, 1032-1035

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ENANTIODIVERGENT SYNTHESIS OF (S,S)-2 AND (R,R)-2

HCO2H

reflux84 %

OCHO

OHCO

J ones reagent

44 %

O

O rac

(1) NH2OH.HCl EtOH, reflux, 1h(2) NiCl2, NaBH4 MeOH,- 35 OC to - 20 oC, 1h 70- 75 %

(3)TsCl, NEt3, CH2Cl2 - 78 oC to rt

NHTs

NHTs

rac

1. Preparative HPLC

2. Li, NH3, - 33 OC 80 min, 85 %

S S

R R

NH2 NH2

NH2 NH2(S,S)

(R,R)

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ENANTIODIVERGENT SYNTHESIS OF (S,S)-2 AND (R,R)-2

( CONTD...)

S S

NH2NH2

(S,S)

S S

N N

OH

tBu

tBu HO

tBu

tBu

(S,S)- 2

CHO

OH

tButBu

MeOHRT, 30 min76- 81 %

R R

NH2NH2

(R,R)

CHO

OH

tButBu

MeOHRT, 30 min76- 81 %

N

OH

tBu

tBu HO

tBu

tBu

(R,R)- 2

R R

N

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CATALYTIC PERFOMANCE OF (S,S)-2

Entry Aldehyde Halide Product ee ( % ) Yield ( % )

1 90 72

2 31 Not Determined

3 79 76

4 54 78

5 64 Not Determined

Ph

O

H

Ph

O

H

Ph

O

H

Ph

O

H

Ph

O

H

Br

I

Cl

Cl

Cl

Ph

OH

Ph

OH

Ph

OH

Ph

OH

Ph

OH

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CATALYTIC PERFOMANCE OF (S,S)-2 ( CONTD…..)

Entry Aldehyde Halide Product ee ( % ) Yield ( % )

6. 92 69

7. 75 59

8. 61 54

Br

I

OTf

PMBO H

O

PMBO H

O

PMBO H

O

PMBO

OH

PMBO

OH

R*

PMBO

OH

R*

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SALIENT FEATURES OF THE CATALYTIC PERFOMANCE OF (S,S)-2

The addition of allyl bromide to benzaldehyde proceeded with high enantioselectivity ( 90 %) and good yield ( 72 % )

THF proved to be the best solvent for these catalytic asymmetric reactions and catalyst concentration of 0.025 M gave the best results

In contrast to salen ligand 1, ligand 2 was able to effect an enantioselective addition of allyl iodide

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SALIENT FEATURES OF THE CATALYTIC PERFOMANCE OF (S,S)-2 ( CONTD…)

Using this ligand, it was possible to synthesise alylic alcohols

in enantioselective fashion from vinyl iodides and triflates

Presence of 2 mol % of NiII was required for these coupling

reactions to occur efficiently

Vinyl halide gave 59 % yield with 75 % ee

Vinyl triflate gave 61 % ee

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CONCLUSION

Organochromium reagents take part as nucleophiles in versatile C-C bond forming reaction involving wide range of functionality

The novel salen ligands ( I & II ) play important role in catalytic and enantioselective Nozaki-Hiyama-Kishi reactions

The DIANANE-based salen ligands, (S,S)-II and (R,R)-II promote the asymmetric additions of allyl iodide and vinyl halides and triflates with useful levels of enatioselectivity

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REFERENCES

1. A. Frustner, Chem. Eur. J. 1998, 4, 567-570

2. C. Chen, K. Tagami, Y. Kishi, J. Org. Chem. 1995, 60, 5386-5387

3. M. Bandini, P.G. Cozzi, A. Umani-Ronchi, Chem. Commun. 2002, 919-927

4. R. T. Hawkins, R. S. Hsu, S. G. Wood, J. Org. Chem. 1978, 43, 4648-4650

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