Cyanomethylation

Jian-Zhou Huang2013-07-06

IntrductionBasic phosphine and NHCCatalyted by metal

Ruthenium Copper Palladium Nickel

Decarboxylative ReactionCross-couplingConclusion

Contents

Intrduction: pKa

alkyl CN

H

Ph CN

H

pKa = 21.9pKa ~ 31.3

CNH

pKa ~ 21.1 in DMSO

OH

Ph

H2O2 aq, Na2CO3acetone, rt

74 % yield

OH

PhCN O NH2

PhCN

NHTs

Ph

1) NiCl2H2O( 1.0 equiv) (Boc)2O( 2.0equiv) NaBH4(7 equiv)

2) diethylenetriamine(1 equiv) MeOH, 0oC to rt, 15h

Ph

NHTs

PhNHBoc

Ph

NHSO2PyCN

conc HCl, dixoxane,reflux,12hPh

NHSO2PyCOOH

Basic phosphine and NHC

TMSCH2CN PR3+ Si CN

PR3

SiPR3

CH2CN RCHOR

OHCN

Cl

CHO

+ TMSCH2CN1, NHC 5 mol%, DMF, RT

2, H+ Cl

OHCN

83 % yield

NN Ar

Ar

NHC

Ph

O

HTMSCH2CN+

TTMPP(20 mol%)

DMPU, 8h, 50 oC Ph

OHCN

92 %

TTMPP[2,4,6-(OMe)3C6H2]3P

Ph

O

HTMSCH2CN+ 1, cat (2 mol%), THF, 0oC

Ph

OHCN2, H+

PNN

N

N

i-Pri-Pr

i-Pr

89% yield

S, Matsukawa, Tetrahedron Letters 2008, 49, 2982

J. G. Verkade, J. Org. Chem. 2009, 74, 5683L. He, Tetrahedron Letters 2012, 53, 2231

RutheniumRCHO

+ CH3CN

CpRu(PPh3)(CH3CN)2PF6 5 mol%DBU 5 mol%, NaPF6 10 mol%

CH3CN/HMPA 3/1, 4Å MS

R

OHCN

NR2

R1 R1

NHR2

CN

yield 72 - 93 %

yield 79 -91 %

RuPh3P NCCH3

NCCH3

PF6DBU DBU•H

PF6

R

ONaCN

R

OHCN

NaPF6

RuPh3P

NCCH3

N CH2

RuPh3PCH3CN

O

R CN

RuPh3PCH3CN

DBUPF6

DBU•HPF6 R

OHCN

Shibasaki, J. Am. Chem. Soc. 2004, 126, 13632-13633

decomp without NaPF6

CH2CN

Ph3P=ORu black P

ONN

N

HMPA

H

OR

HH

CN

H

pKa 15.7-16.9(H2O)

pKa ~28.9(H2O)

+ nitrile selectivedeprotonation

ROH

CN

RuPh3P NCCH3

NCCH3

PF6Ru

Ph3P NCCH3PPh3

PF6

1a 1b

CH3CN CHOR+

[Ru] 10 %mol, DBU 50 % mol

4 Å MS, CH3CN/HMPA 3/150 0C

38 % yield 64 % yield

2a was added slowly over 7 h, yield = 82 %

ROH

CN

Shibasaki, Chem. Commun., 2005, 3600-3602

Copper

R1 R2

O+ TMSCH2CN

CuF3PPh32EtOH(2.5%)(EtO)3SiF(120 mol%)

3HFNEt3R1

OHCN

R2

O

93 %

Ph

O

75%

O

79%

Ph H

O

92 %

CHO

86 %

CuF·3PPh3 ·2EtOH+

(EtO)3SiF

Si OEtF

EtO

EtO

TMSCH2CN TMSF

Cu(PPh3)3

(EtO)3SiCH2CNF

Cu(PPh3)3

N Cu(PPh3)3

+(EtO)3SiF

NR

H

NSiMe3

CutBuO Si OEt

EtOEtO

FCu

hard interation

soft interation

F

Ph H

OCH3CN

CuOtBu(10 mol%)/dppe(15 %)

DMSO,RT+

Ph

OHCN

95 % yield

H

OCH3CN

CuOtBu(10 mol%)/L*(15 %)

DMSO,500C+

OHCN

72 % yield74 % ee

Masakatsu Shibasaki, Org. Lett, 2005, 7, 3757-3760

5 5PP

tBuO

tButBu

OtBu

O

O

O

O

2

2L*

Masakatsu Shibasaki, Org. Lett, 2003, 5, 3147-3150

2 -Naph

NDpp

+CN [Cu(CH3CN)4]ClO4/L*

Li(OC6H4-p-OPh)

CH2Cl2/THF, -20oC,40h2 -Naph

HN Dpp

CN

2 -Naph

HN Dpp

CN

isomerization

2 -NaphCN

91% yield90 % eeZ/E = 93/7

Masakatsu Shibasaki, J. Am. Chem. Soc. 2008 , 130 , 14477-14479

P P

Ph

Ph

Ph

Ph

CNH

pKa ~ 21.1 in DMSO

Lewis acid/hard Brønsted base/hard

Shibasaki. J. Am. Chem. Soc. 2009,131, 3195

O

+CN [Cu(CH3CN)4]ClO4/L*

Li(OC6H4-p-OPh)

THF, -20oC,40h

P P

Ph

Ph

Ph

Ph

Ph

OH

CN81 % yield97 % ee

CN

Cu*

CN*Cu

C-copper C-copper

PhCOCH3

CuO

NH

Ph

PP

*

*Cu(OC6H4-o-OMe)

Lewis acid/hard Brønsted base/hardLewis base

O

+CN

[Cu(CH3CN)4]ClO4/L*Li(OC6H4-p-OPh)

LB

THF, -40oC,40h

P P

Ph

Ph

Ph

Ph

Ph

OH

CN86 % yield99 % ee

P

P

O PhPh

O PhPh

LB

Shibasaki, M. J. Am. Chem. Soc. 2010,132, 5522

2 -Naph

NDpp

+CN

Mesitylcopper(10 mol%)L*(10 mol %)HOC6H4-p-OMe(10 mol%)

CH2Cl2/THF, -20oC,40h2 -Naph

HNDpp

CN

1) Li free

2) Li free + LiClO4

yield: < 5%, 88% ee

2 -Naph

NDpp

+CN

Mesitylcopper(10 mol%)L*(10 mol %)HOC6H4-p-OPh(10 mol%)

CH2Cl2/THF, -20oC,40h2 -Naph

HNDpp

CN

yield: < 78%, 83% ee

LiClO4(10 mol %

3) without [Cu(CH3CN)4]ClO4 yield 8%

2 -Naph

NDpp

+CN

LiOC6H4-p-OPh(10 mol%)

CH2Cl2/THF, -20oC,40h2 -Naph

HNDpp

CNLiClO4(10 mol %

mechanism

[Cu(CH3CN)4]ClO4

+(R,R)-Ph-BPE

LiOAr

+

THFCu

P L

P L* +LiOAr Cu

P L

P OAr* + LiClO4

inactiveNC

CuP L

P N*

HO

Li

O

soft lewis acid hard bronsted base

31P NMR spectra

Bn2N Ph

S CN+

[Cu(CH3CN)4PF6/L*Li(OC6H4-p-OMe) 5 mol%

Toluene ,0oCBn2N

S Ph

CN

O

O

O

O

PAr2PAr2

L*

P

P

O PhPh

O PhPh

Ph2P PPh2

OO

5

without Phosphine oxide

9 % (83 % ee) 76 % (95 % ee) 81 % (95 % ee)

Ph3PO

74% (95 % ee)Ar = 3,5-(tBu)2-4-MeOC6H2

CN

Cu*

CN*CuBn2N Ph

S

CuSP

P

NBn2

NC H H

* Bn2N

S Ph

CN

Plausible transition state

Masakatsu Shibasaki, Angew. Chem. Int . Ed. 2011 , 50 , 7910 -7914

C-copper C-copper

CNO O

PdPh2P PPh2OCOCF3

NTs

Ph+

cat, 20oC, 5hNaHCO3(1.0 eq), THF

PhCN

NHTs

dr = 3:2yield = 90%

O OPdPh2P PPh2

CNH

O OPdPh2P PPh2

HNC

O OPdPh2P PPh2

CN

O OPdPh2P PPh2NC

HE = 0 kcal/mol E = 1.2 kcal/mol E = 1.2 kcal/mol E = 6.7 kcal/mol

O OPdPh2P PPh2

NCH NTs

PhK. J. Szabo, Org. Lett. 2008 , 10 , 2881

Palladium-pincer ligand

PhCH2CN +Ph H

NTs cat(5 mol%)

NaHCO3( 1equiv)TsHN

PhCN

Phdr = 2:1yield = 99%

O OPdPh2P PPh2OCOCF3

PhCH2CN NTs+

dr = 1.3:1yield = 71%ee = 33 %

O OPdP PTFA

OO

O

O

TsHN

CyCN

Ph

K. J. Szabo, Org. Lett. 2008 , 10 , 5175-5178

20oC, THF, 15h

cat(5 mol%)NaHCO3( 1equiv)

20oC, 15h

N

Ph

Ts+

Ph CN

cat (5 mol%)AgOAc(5 mol%)K2CO3(1.0eq)

THF, MS 5Å,-20oC

HN

Ph

Ts

CN

Ph

97 % yielddr = 93:7er = 95: 5

Pd

N

N N

NCOPh

Ph

PhPh

Ph

PhOC

OAc

PhCH2CN

OAC

Pd

N

N N

NCOPh

Ph

PhPh

Ph

PhOC

N

PhHOAC

HOAC

Pd

N

N N

NCOPh

Ph

PhPh

Ph

PhOC

NC

PhH

Pd

N

N N

NCOPh

Ph

PhPh

Ph

PhOC

N Ts

PhPh

CN

N

Ph

Ts

HN

Ph

Ts

CN

Ph

Pd

N

N N

NCOPh

Ph

PhPh

Ph

PhOC

Brcat

Norio Shibata, Adv. Synth. Catal. 2011, 353, 3385

aza-MBH

NTs

Ph CN

cat(5 mol%), DABCO(5 mol%)AgOAc(5 mol%)

iPrCN, 4Å MS,-10oC

NHTs

Ph CN

93 %, (94 % ee)

+

Pd

N

N N

N

Ph

Ph

Ph

Ph

OAc

Ac Ac

Pd

N

N N

N

Ph

Ph

Ph

Ph

N

Ac AcPd

N

N N

N

Ph

Ph

Ph

Ph

NTs

Ac Ac

Pd

N

N N

N

Ph

Ph

Ph

Ph

N

Ac Ac

CDABCO+

DABCO

NTs

Ph

CN

DABCO+

Ph

AcO-

NHTs

Ph CN CN

OAc-

N. Shibata, Angew. Chem. Int . Ed. 2012 , 51, 10337

Nickel

NPiPr22

iPrP NiOTf

O

H

F

CH3CNsolv, cat

DBU(100 mol%), 45 oC, 24 h

OH

F

CN

75 % yield

[Ni]-DBU-DBU

+DBU[Ni] N CH3 [Ni] N CH2

DBUDBU-H+ RCHO

[Ni] N CH2

O H

R[Ni] N CH2

HO H

R

NCR

OH

+

O

H

F

CH3CNsolv, cat

DBU(100 mol%), 45 oC, 24 hNR(PNP)Ni-OTf

LiCH2CN

CH3CN

LiN(TMS)2

(PNP)Ni-CH2CN

Chem. Commun., 2005, 4450

Base-Free Conditions

PhCHO+ CH3CNcat, rt, CH3CN

Ph

OHCN

cat 1 mol % yield = 91 %cat 0.01mol % yield = 72 %, TON = 10 000

138 mL(1.36 mol)

150 mL(2.87 mol)

cat(5 ppm)(3.0 mg)

TON = 82 00041% conversion

M N C CH2

B: BHM N C CH3

RCHOM O CN

R

CH3CN+BH+

HOR'+B:

O

Ni

O

PiPr2

PPiPr2

CH2CN

O

Ni

O

PiPr2

PPiPr2

O CH2CN

R

H

RCHO RCHO

CH3CN

R

OHCN cat

with base

base free

H. Guan, Angew. Chem . Int. Ed. 2013 , 52 ,ASAP

VS

Decarboxylative MannichReaction

Ph

NSO2Py

+ HO

OCN

cat(5% mol), AgOTf(5 mol%)

THF, 4Å MS, RT Ph

NSO2PyCN

82 % yield, 88 % ee

Pd

N

N N

NCOMe

Ph

PhPh

Ph

MeOC

Brcat

S. Nakamura, Chem. Eur. J. 2013, 19, 4128

H2CC

N [Pd]

VS O

OC

NPd

decarboxylation deprotonation

NP(O)Ph2

HPh+ CNHOOC

Ph2.5 eq

CuOAc-L*(5 mol%)

THF, 0oC, 12 h

NP(O)Ph2

PhPh

CN

dr = 7.1:1yield = 94 %ee = 87 %

O

O

O

O

P

P

OMe

tBu

tBu

tBu

OMetBu

2

2DTBM-SEGPHOSM, Shibasaki, J. Am. Chem. Soc. 2009 , 131 , 9610

Pd

N

N N

NAc

Ph

PhPh

Ph

Ac

OTf

Pd

N

N N

NAc

Ph

PhPh

Ph

Ac

Pd

N

N N

NAc

Ph

PhPh

Ph

Ac

O

Pd

N

N N

NAc

Ph

PhPh

Ph

Ac

N SO2Py

PhCOO-

CN

N

Ph

NSO2Py

HN

Ph

NSO2Py

CNHO

OCN

HOTf

O

ON

base

base• H+

OCN

H

HOTf

APCI mass (positive, 792.2)exact mass: 792.2 [M+H+]

NH

O

O

HOCN

O

+NH

O

HOEt3N(20mol%), DMF, 70oC

72h95 %

CN

J. Wang, ACS Catal. 2012, 2, 2622 - 2625

N

N CF3

O

CN

COOH

pyridine(solv),70oC

12h N

N CF3

OH CN

70 % yield

D. M. Volochnyuk, Synthesis 2009, 7, 1099

CN

PhO2S NHBoc

SO2TolPh+

1) cat 20 mol%) CsOHH2O(130 mol%) toluene/CH2Cl2 = 9:1

2) Mg, TMSCl MeOH, RT, 3h

NHBoc

Ph CN

90 % yield, 76 % ee

N

O2N

OH

N

O

Cl

CN

PhO2S NBoc

Ph+

1)(DHQ)2PYR (20 mol %) DCM, -40oC, 20h

2) Mg, TMSCl, MeOH,RT,3h

NHBoc

Ph CN

92 % yield 73 % ee

CN

PhO2SCN

C. Palomo, J. Org. Chem. 2010, 75, 3920

Cross coupling

Br+ NC TMS

2 mol% Pd2dba3/Xantphos0.5 eq ZnF2, DMF, 90oC

John F. Hartwig, J. Am. Chem. Soc., 2005, 127, 15824

CN

Cl +NC COONa

tBu 87 % yield

2 mol%[Pd2(allyl)2Cl2]6 mol% S-Phos140oC, 5h, mesitylene

CN

tBu

86% yiled

Lei Liu, Angew. Chem. Int . Ed. 2011 , 50 , 4470

+ CO2

Conclusion

(1) 反应类型比较少，大部分仍需要加入强碱；(2）不对称的反应较少(3) 反应体系复杂，添加剂多(4) 需要活化基团活化，原子经济性差。

Thank You!