CYANIDE ADDITION TO CARBONYL COMPOUNDS

Presented By: Aleena

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CYANIDE ADDITION TO CARBONYL COMPOUNDS

Presentation Outline
INTRODUCTION CYANIDE ADDITION TO CARBONYL COMPOUNDS

ASYMMETRIC SYNTHESIS OF CYANOHYDRIN BIOCATALYSTS METAL BASED CATALYSTS

REFERENCES

INTRODUCTION
Chemical compound having Cyano group -CN is called cyanide -CN is isoelectronic to Carbon mono oxide and Nitrogen molecule Nitrile Organic compounds having cyanide as functional group

CYANIDE

Cyanohydrin Compounds having OH- and CN- groups at same carbon atom Release CN- ion readily Organic nitrides do not release CN- readily

Release CN- ion readily

Trimethyl silyl cyanide

ADDITION OF CYANIDE TO CARBONYL COMPOUNDS

Geometry of Carbonyl Compounds
Planar SP2

Cyanide ion as Nucleophile

Carbonyl compound as electrophile

ADDITION OF CYANIDE TO CARBONYL COMPOUNDS

Aldehyde cyanohydrins are stable & formed more easily as compared to Ketone cyanohydrins

Reaction in Buffered solution (PH 6-8) Acidic solutions HCN gas creates problem

CN- added to Fe of Hemoglobin

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IMPORTANCE OF CYANOHYDRIN
OH R1 R2

NH2 CH2

- amino alcohol

LiAlH4
OH OH

aq HCL
R1 C N R2

OH C O

R1 R2

-hydroxy acid
H2, Ni
OH

All theses products can be converted into different compounds

OH

R1 R2

H C NH

H 2O

R1 R2

H C O

Imine

-hydroxy aldehyde

CYANOHYDRIN SYNTHESIS IN THE PRESENCE IODINE CATALYST

Najmedin and Saidi (2003)
O CN

OSiMe3
CH3

C
R2 R1

H3C

Si
CH3

I2 (0.2 mol %) CH2Cl2 , rt, 3 min

C
R2 R1 CN

Carbonyl compounds

TMSCN

86-97%

CH2Cl2 is best solvent Acetonitrile gave poor yield Advantages Simple Improved yield High reaction rate Work up is simple Applicable to both aromatic &Aliphatic aldehydes

CYANOHYDRIN SYNTHESIS IN THE PRESENCE IODINE CATALYST

Me3SiI Me3SiCN CN ArCHO

I2
Ar Ar OSiMe3 CN CN O-

Me3SiI

Catalytic cycle of Iodine catalyzed Cyanohydrins synthesis

ASYMMETRIC SYNTHESIS OF CYANOHYDRINS

Two types of catalysts systems Biocatalysts Enzymes like Oxinitrilase Dipeptides Metal based catalysts Coreys catalyst Shibasaki catalyst Salen catalysts Lewis acid base catalysts

ASYMMETRIC SYNTHESIS OF CYANOHYDRINS

OH

Biocatalysts L. Rosenthaler 1908

e las itri xin H -O EtOent R r/ ate Solv W g. Or
H

H C CN

R- mandelonitrile 86 % ee

Organic solvents are used in amide, ester formation and water only promotes cyanide addition to carbonyl compounds

O C

HCN

xin W itri las Or ater/ e g. EtO So l ve H nt

SO

OH H C CN

Buffered solution PH 6-8

S- mandelonitrile

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ASYMMETRIC SYNTHESIS OF CYANOHYDRINS

R- Oxinitrilase
Substrates: Benzaldehyde, aromatic, aliphatic and hetero cyclic aldehydes

S- Oxinitrilase
Substrates: Benzaldehyde, aromatic, and heteroaromatic aldehydes but not aliphatic

FAD prosthetic group

Without FAD prosthetic group

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ASYMMETRIC SYNTHESIS OF CYANOHYDRINS

Dipeptides Cyclic dipeptides having histidine residue can catalyze hydrocyanation reactions
H N Ph O HN N O N H

Cyclo [(S)-Phe-(S)-Histidine]

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ASYMMETRIC SYNTHESIS OF CYANOHYDRINS

Imidazole group is protonated to generate CN-

H-CN
O Ph

C
H

-CN

R=Ph (97% ee) & 97% conversion R= 2-Naphth (96% ee) & 61% conversion R= t Bu (58% ee) & 60% conversion
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ASYMMETRIC SYNTHESIS OF CYANOHYDRINS

Metal based catalysts

Ti, Al, V, Gd, Mg

Shibasaki Catalyst Al &Ti Lewis acid base catalysts

Salen complexes Ti, Gd, V

Corey's catalyst Bis-oxazoline Mg complex

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Titanium Metal Complexes

Titanium

Different ligands for complexation to Titanium metal

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Titanium Metal Complexes

O OH

TMSCN, CH2Cl2
Ph H

*
Ph CN

Ti(O Pr)4 / ligand H3O+

Cyanohydrin

These Titanium ligand complexes gave ee in the range of 85-94% The most efficient catalyst is based on ligand (A) used only 0.1 mol %

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Titanium metal complexes with Schiff bases

Rosa M Moreno et al 2006
O OSiMe3

+
R H

Me3SiCN

0.2 eq. Ti(OiPr)4 CH2Cl2,-80 0C 0.2 eq. (A)

R CN

R:S= 98:2

H
tBu

Me

OH

Me

OH

(S)

Schiff base (A)

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Titanium metal complexes with Schiff bases

Si
CNR

Transition state for cyanohydrins synthesis

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Titanium metal complexes with Schiff bases

R2

Lucia-Z-Flore et al 2007

R3

R1 R4 N OH

* *
R5 OH

O Me3SiO H H

TMSCN, (B) Ti(OiPr)4

Schiff base (B)

CN

Moderate % ee and moderate yield

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Ti METAL COMPLEXES LEWIS ACID LEWIS BASE CATALYSTS

M. Shibasaki et al (2000) Cyanosilylation of carbonyl compounds D-glucose derivative ligand for Ti metal complexation

Ligand (1 mol%) Me3SiCN (2 eq) THF, -10 0C, 92 h

NC O Me3SiO

R:S 98 : 2

R product is obtained

Ligand

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Ti METAL COMPLEXES LEWIS ACID LEWIS BASE CATALYSTS

M. Shibasaki et al (2000) Mechanism:

Lewis base

Ti(iPrO)4 -2 iPrOH

Lewis acid

Ligand

Ti metal complex

Ti metal complexation with D-glucose derivative ligand

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Ti METAL COMPLEXES LEWIS ACID LEWIS BASE CATALYSTS

+ Me3SiCN -iPrO-SiMe3
C N
+M eS 3 i CN +K eto ne

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Ti METAL SALEN COMPLEXES

Yuri N. Belokon (2001) Bimetallic Ti(IV) Salen complex Addition of Trimethyl silyl Cyanide to ketones
O

Me3SiCN
R H

OSiMe3

Catalyst*

H R

CN

Salen complex (A)

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Ti METAL SALEN COMPLEXES

H Ph

CN

Me3SiCN

PhCHO

CN

CN

PhCHO
CN

OSiMe3

NC

Ph

Rate determining step

CN-

Me3SiCN
N

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Ti Salen complexes

CN

Proposed geometry of Cyanohydrins synthesis by using catalyst (A)

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VANADIUM SALEN COMPLEXES

Yuri N. Belokon (2001) Bimetallic V(IV) Salen complex Addition of Trimethyl silyl Cyanide to Aldehydes

Cl

Cl

CN

(S,S) Catalyst (A) 10 mol% Me3SiCN CH2Cl2, r.t.

OSiMe3 H

R- Cyanohydrin product

(S,S) V-Salen complex (A)

First step in synthesis of clopidogrel (Antithrombitic)

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VANADIUM SALEN COMPLEXES

Synthesis of Catalyst:

VOSO4 EtOH-pyridine Reflux 2 min 90%

(S,S)-Salen ligand

(S,S) V-Salen complex

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VANADIUM SALEN COMPLEXES

Mechanism:
2 Me3SiCN Ar-CHO -(Me3Si)2O

(S,S)V-Salen

Ar-CHO

OSiMe3

H Ar

CN

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Gd Metal Complexes

NC OSiMe3

Me3SiCN

4 Me3SiCN -2 iPrOSiMe3 -2 HCN

O

Dimeric complex Gd: ligand 2:3

D-glucose derivative as Ligand

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Al -BINOL-based complexes
Shibasaki and co-workers (2001) Bifunctional asymmetric cyanation catalyst

Catalyst (A) 9 mol% 36 mol% Bu3P(O)

H

HO

CN

TMSCN, CH2Cl2 -40 0C

Al-BINOL complex

ee in the range of 83-98%

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Al -BINOL-based complexes
Nucleophile is activated by chelation with phosphorus Aldehyde is coordinated with aluminium Orientation allowed attack from Re face

C H O R

Model for Asymmetric induction

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Lewis Base catalyzed Trimethylsilyl cyanation of carbonyl compounds

Scott E. Denmark (2006) Different chiral amine Lewis bases for the trimethylsilyl cyanation of benzaldehyde

(S)--methyl benzyl amine

(1S,2R)-N-methyl ephedrine

(-) Strychnine

(DHQ)2PHAL

(DHQD)2PHAL
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Lewis Base catalyzed Trimethylsilyl cyanation of carbonyl compounds

Unfortunately all these amines gave racemic instead of asymmetric products Reasons: High reactivity of TMSCN in CH3CN and low steric interaction between aldehyde and chiral catalyst Lewis catalyst ionized TMSCN and resulting cyanide ion react with aldehyde in asymmetric fashion

General Reaction:
O OTMS

+
R H

Catalyst TMSCN
R CN

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Lewis Base catalyzed Trimethylsilyl cyanation of carbonyl compounds

TMSCN

LB

LB Cycle A Cycle B

Catalytic cycle
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Asymmetric cyanohydrin synthesis from ketone

Different metal based & organic ligands Mild reaction conditions High ee
O 10 mol % Catalyst (A) Ph Me HO CN

TMSCN, 25 0C 49 % Yield

Ph

Me

(R) 65%

Oxaborolidine salt (A)

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Asymmetric cyanohydrin synthesis from ketone

OH

CN

0C ol % 10 m CN,-30 S TM Yield 85 %

(B )/

i T i(O

Pr) 4

Ph

Me

(R) 92%

Ph

Me

10 m TM ol % 92 SC ( % N, B)/ -40 Gd Yi eld 0C (O iP r) 4

OH

CN

Ph

Me

(S) 92%

Ligand (B)
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Asymmetric cyanohydrin synthesis By metal free organocatalyst

O OH CN

Ph

Me

10 mol % Catalyst (C) TMSCN,-450C 96 % Yield

Ph

Me

(S) 94%

Amino acid salt Catalyst (C)

OH

CN

Ph

Me

10 mol % Catalyst (D) TMSCN,-780C 96 % Yield

Ph

Me

(S) 97%

Aromatic and - unsaturated ketones

Catalyst (D)
37 Thiourea bifuctional catalyst

Cyanohydrin synthesis catalyzed by Coreys catalyst

E. J Corey & Z. Wang (1993) Two catalyst system Bisoxazoline Mg complex (activates carbonyl group) Bisoxazoline as co-catalyst (provides asymmetric environment to HCN)

OTMS CHO

TMSCN Catalyst

CN

Catalyst (A)

Catalysts, enantioselectivity (%) A, 82.5 B, 53 A+B, 97

Co-catalyst (B)
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Cyanohydrin synthesis catalyzed by Coreys catalyst

Re

Cyclohexyl= Cy

Only Re face is available for attack

Proposed mechanism for Cyanohydrin synthesis by using two Bis-oxazolines

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REFERENCES
1. A. Najmedin., S. R. Muhammad, Phosphorus, Sulfur and Silicon, 2003. 178, 21112115 2. L. Rosenthaler, Biochem. Z, 1908. 14, 238-253 3. F. Effenberger, Angew. Chem. Int. Ed. 1994, 33, 1555 4. L. Xie, W. Hua, A. S. C. Chan, Y-C. Leung, Tetrahedron: Asymmetry, 1999, 10, 4715 5. E. J. Corey, Z. Wang, Tetrahedron letters, 1993, 34, 4001 6. D. E. Scott, C. Wong-Jin, JOC Notes, 2006 7. B. N. Yuri, G. Brendan, I.S. Nicolai, Tetrahedron, 2001, 57, 771-779 8. M. Shibasaki, J. Am. Chem. Soc. 2000, 122, 7412 9. F. Z. Lucia, I. L. Ana, G. Angeles, J. Mex. Cem. Soc, 2007, 51(4), 175-180 10. M. M. Rosa, R. Malgorzata, M. Albert, Tetrahedron Asymmetry, 2006, 7(17), 10891103 11. C. Vittrio, W. M. J. Jonathan, Wiley, 2009, 2nd Edition
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Thanks For Your Patience

Questions???
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