[PPT] - Direct Conversion of Nitriles into Alkene Isonitriles Y. Li and F. PowerPoint Presentation

SLIDE 1

Direct Conversion of Nitriles into Alkene Isonitriles

Y. Li and F. F. Fleming, Angew. Chem. Int. Ed.

2016, 55, 14770-14773. 11/19/16 Mike Frasso

R1 CN R2Li, CuCN THF then i-PrOCHO R1 N H O POCl3 Et3N R1 NC R2 R2

Mike Frasso @ Wipf Group Page 1 of 22 11/25/2016

SLIDE 2

Most Prominent Physical Characteristic…Stench

‘highly specific, almost overpowering’, ‘horrible’, and

‘extremely distressing’

To quote odor theorist Luca Turin, “isonitriles” are just the

Godzilla of smells, you can’t believe how awful they smell, they make you vomit your guts out instantly.”

Have been used in nonlethal weaponry
“The containment vessel may be comprised of a "paint ball",

grenade, non-lethal land mine, spray bottle, rubber bullet, a modified shotgun shell, or other like vessel.”

Burr, C. The Emperor of Scent: A Story of Perfume, Obsession, and the Last Mystery of the Senses; Random House: New York, 2002. US Pat. 6 352 032, March 5, 2002

J. Org. Chem. 2009, 74, 4110–4117

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SLIDE 3

Two General Reaction Pathways

R N Nu- R N Nu E+ N R Nu E E+ R N E Nu- N R Nu E

Angew. Chem. Int. Ed. 2007, 46, 3563-3566.

NC ~ OTMS NC ~ TMS NC NC ~ O > > Isonitrile Nucleophilicity

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SLIDE 4

Some Characteristic Reactions of Isonitriles

Heterocycle synthesis: furans, pyrroles, oxazoles, etc.
Ugi
Passerini

R1 NC R2 NH2 R3 O R4COOH N H R1 O N R3 R2 R4 O R1 NC R4COOH R3 O apolar solvent N H R1 O O R3 R4 O Ph O Ts NC K2CO3 MeOH, reflux O N Ph van Luesen Reaction

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SLIDE 5

Preparation of Isonitriles

Most Common Methods:
Substitution: X = halide, activated ester, O-PR3; various CN

sources possible

Dehydration

R2 R3 X R1 R2 R3 R1 NC AgCN R2 R3 HN R1 POCl3, Et3N R2 R3 CN R1 O

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SLIDE 6

Preparation of Alkene Isonitriles

NC Tf2O, DIPEA CH2Cl2 N H O

1. AgOCN, I2, Et2O
2. Cl3SiH, Et3N, CH2Cl2, 0oC

3.KOtBu, THF Cu2O NC

1. KHMDS, -78 oC, THF

2. O Ph3P NC Cl- (EtO)2P NC O SeCN NCSe [3,3] P(OR)3 NC Synlett 1990, 603-604.

Angew. Chem. Int. Ed.

1995, 34, 1627-1629 .

J. Org. Chem. 2009,

74, 4110-4117.

Tetrahedron 1971, 27,

3795-3801. .

Tetrahedron Lett. 1989,

30, 3335-3338. .

Mike Frasso @ Wipf Group Page 6 of 22 11/25/2016

SLIDE 7

Preparation of Alkene Isonitriles

NC Tf2O, DIPEA CH2Cl2 N H O

1. AgOCN, I2, Et2O
2. Cl3SiH, Et3N, CH2Cl2, 0oC

3.KOtBu, THF Cu2O NC

1. KHMDS, -78 oC, THF

2. O Ph3P NC Cl- (EtO)2P NC O SeCN NCSe [3,3] P(OR)3 NC Synlett 1990, 603-604.

Angew. Chem. Int. Ed.

1995, 34, 1627-1629 .

J. Org. Chem. 2009,

74, 4110-4117.

Tetrahedron 1971, 27,

3795-3801. .

Tetrahedron Lett. 1989,

30, 3335-3338. .

Mike Frasso @ Wipf Group Page 7 of 22 11/25/2016

SLIDE 8

Preparation of Alkene Isonitriles

NC Tf2O, DIPEA CH2Cl2 N H O

1. AgOCN, I2, Et2O
2. Cl3SiH, Et3N, CH2Cl2, 0oC

3.KOtBu, THF Cu2O NC

1. KHMDS, -78 oC, THF

2. O Ph3P NC Cl- (EtO)2P NC O SeCN NCSe [3,3] P(OR)3 NC Synlett 1990, 603-604.

Angew. Chem. Int. Ed.

1995, 34, 1627-1629 .

J. Org. Chem. 2009,

74, 4110-4117.

Tetrahedron 1971, 27,

3795-3801. .

Tetrahedron Lett. 1989,

30, 3335-3338. .

Mike Frasso @ Wipf Group Page 8 of 22 11/25/2016

SLIDE 9

Preparation of Alkene Isonitriles

NC Tf2O, DIPEA CH2Cl2 N H O

1. AgOCN, I2, Et2O
2. Cl3SiH, Et3N, CH2Cl2, 0oC

3.KOtBu, THF Cu2O NC

1. KHMDS, -78 oC, THF

2. O Ph3P NC Cl- (EtO)2P NC O SeCN NCSe [3,3] P(OR)3 NC Synlett 1990, 603-604.

Angew. Chem. Int. Ed.

1995, 34, 1627-1629 .

Org. Lett. 2016, 18,

1622-1625.

Tetrahedron 1971, 27,

3795-3801. .

Tetrahedron Lett. 1989,

30, 3335-3338. .

Mike Frasso @ Wipf Group Page 9 of 22 11/25/2016

SLIDE 10

Preparation of Alkene Isonitriles

NC Tf2O, DIPEA CH2Cl2 N H O

1. AgOCN, I2, Et2O
2. Cl3SiH, Et3N, CH2Cl2, 0oC

3.KOtBu, THF Cu2O NC

1. KHMDS, -78 oC, THF

2. O Ph3P NC Cl- (EtO)2P NC O SeCN NCSe [3,3] P(OR)3 NC Synlett 1990, 603-604.

Angew. Chem. Int. Ed.

1995, 34, 1627-1629 .

Tetrahedron 1971, 27,

3795-3801. .

Tetrahedron Lett. 1989,

30, 3335-3338. .

Org. Lett. 2016, 18,

1622-1625.

Mike Frasso @ Wipf Group Page 10 of 22 11/25/2016

SLIDE 11

Isonitriles from Benzoxazoles

O N

1. BuLi, THF
2. RCOCl

O NC O R O NC O O NC O O NC O O NC O O CN 85% "malt" 92% "natural rubber" 83% "taffy" 90% "old wood"

J. Org. Chem. 2009, 74, 4110–4117 .

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SLIDE 12

“Convertible” Isonitriles

J. Org. Chem. 2009, 74, 4110–4117 .

N H O N R1 R2 R3 O O O R4 HCl MeOH O O N R1 R2 R3 O O N R4 + N H O N Ph PMB O HCl PhMe, 100 oC 59% MeO2C CO2Me N PMB MeO2C CO2Me Ph O N PMB Ph O O p-Tol O

Definition: Resulting amide from Ugi reaction can be readily activated

for further transformations

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SLIDE 13

“Convertible” Isonitriles

J. Org. Chem. 2009, 74, 4110–4117 .

N H O N R1 R2 R3 O O O R4 HCl MeOH O O N R1 R2 R3 O O N R4 + N H O N Ph PMB O HCl PhMe, 100 oC 59% MeO2C CO2Me N PMB MeO2C CO2Me Ph O N PMB Ph O O p-Tol O

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SLIDE 14

A Few Possibilities…

Angew. Chem. Int. Ed. 2016, 55, 14770-14773.
Ph

CN MeLi Ph NLi O X R2 Ph N R2 O +/- H+ Ph NHLi O X R2 Ph N H R2 O H2O Ph O +/- H+ H2O O X R2 Ph N R2 O O R2 O X R2 Ph NH2 O R2

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SLIDE 15

A Few Possibilities…

Angew. Chem. Int. Ed. 2016, 55, 14770-14773.
Ph

CN MeLi Ph NLi O X R2 Ph N R2 O +/- H+ Ph NHLi O X R2 Ph N H R2 O H2O Ph O +/- H+ H2O O X R2 Ph N R2 O O R2 O X R2 Ph NH2 O R2

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SLIDE 16

Foundation of this Work

Org. Lett. 2006, 8, 3903-3906.
R CN

MeLi,LiBr Et2O then Ac2O R N H O N H O N H O N H O N H O F F S O Cl 85% 60% 90% 62%

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SLIDE 17

Screen of Conditions

Angew. Chem. Int. Ed. 2016, 55, 14770-14773.
Using methyl formate favored

formyl imine

Grignard reagents gave

complex mixtures

Ph CN MeLi, MX THF then i-PrOCHO Ph N H O POCl3 Et3N Ph NC Entry Metal Salt (mol%) Yield (%) 1 2 3 4 5 6 7 8

LiBr (120)

CuCN (10) CuI (10) CuBr.SMe2 (10) 4-MePhSCu (10) CuCN (5) CuCN (2) 39 30 43 40 38 34 58 73

H O Cu N O Li N iPr Ph

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SLIDE 18

Substrate Scope

Angew. Chem. Int. Ed. 2016, 55, 14770-14773.
R1

CN R2Li, CuCN THF then i-PrOCHO R1 N H O POCl3 Et3N R1 NC Ph NC R2 R2 Ph NC Ph NC NC Pr NC Ph NC NC BnO NC MeO NC TBSO NC Cl NC CN NC N NC Ph NC 73% 58% 61% 70% 68% 60% 69% 66% 45% 40% 54% 55% 41% 53%

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SLIDE 19

Less Successful Substrate Scope

Angew. Chem. Int. Ed. 2016, 55, 14770-14773.
R1

CN R2Li, CuCN THF then i-PrOCHO R1 N H O POCl3 Et3N R1 NC Ph NC R2 R2 Ph NC Ph NC NC Pr NC Ph NC NC BnO NC MeO NC TBSO NC Cl NC CN NC N NC Ph NC 73% 58% 61% 70% 68% 60% 69% 66% 45% 40% 54% 55% 41% 53% Ph NC NC S NC N Ph NC Hexyl 36% 27% 31% 31% N NC 0 %

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SLIDE 20

[4+2] Cycloaddition

Angew. Chem. Int. Ed. 2016, 55, 14770-14773.
NC

CuMeSal PhMe, 110 oC R R R Ph Ph OMe MeO 54% 71% 41% 69% NC NC H Ph NC 1,3 shift NC Ph NC H Cu Cu

2HCN

2

O OEt O Ph NC CN Unreactive with the folloing in catalyst free reaction Mike Frasso @ Wipf Group Page 20 of 22 11/25/2016

SLIDE 21

[4+2] Cycloaddition

Angew. Chem. Int. Ed. 2016, 55, 14770-14773.
NC

CuMeSal PhMe, 110 oC R R R Ph Ph OMe MeO 54% 71% 41% 69% NC NC H Ph NC 1,3 shift NC Ph NC H Cu Cu

2HCN

2

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SLIDE 22

Conclusion

A new preparation of vinyl isonitriles was developed
Advantages: one-pot process, fairly simple to perform, no E/Z

mixtures

Disadvantages: only primary alkyl lithium reagent are effective,

typical functional group/moisture sensitivity

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