フルオロアルケンの逐次反応による

フッ素置換含窒素ヘテロ環構築法

氏　　名　高橋正樹

指導教員　市川淳士

1

Synthetic Strategy of Ring-Flurolinated Heterocycles

CF3

R

SN2'-type SNVCF2

R+ R

1Nu

2NuF

1Nu

2Nu

Ring-fluorinated heterocycles

CF2

R1R2

Nu F

R1R2

NuF

R1R2

F SNVNu－

SN2'-typeCF3

R

CF2

RNu

C

RNu

F F F

Nu−

2-Trifluoromethyl-1-alkenes: SN2'-type reaction 

1,1-Difluoro-1-alkenes: SNV reaction

− F−

− F−

1Nu

2Nu

2

Application to Synthesis of 3-Fluoropyrazoles

Biologically Active 3-Fluoropyrazoles

CF3

R2SN2'-type SNVCF2

R2N

R1

H2N

R2NN

FH2N

R1HN +R1

3-Fluoropyrazole

NNN N

NH

FO

N

NMe

NH2

NN

N N

Me

NF

NH2

HN3

3

thromboembolic diseaseinhibitory effect

protein kinase inhibitor

3

Reported Syntheses of 3-Fluoropyrazoles

NN

OMeO

BrAgF (3.0 eq)

CH3CN, reflux, 1 h

11%

N

Cl

NN

OMeO

F

N

Cl

Clark, D. A., et al. Bioorg. Med. Chem. 2008, 16, 3163.

NN

CH3

NN

CH3

33%

CO2Et CO2Et

F

NN

FH2C

CO2Et

F+

Pyridine(HF)n (22 eq)

7%

Makino, K.; Yoshioka, H. J. Fluorine Chem. 1988, 39, 435.

2.5 V

Low yield and low selectivity of fluorination.

Optimization of SN2’-type Reaction

4

CF3

Ph+

CF2

PhN

R

H2N

2

H2NRHN

Base (2.0 eq)

THF, Conditions

CF2

PhHN

NH

2'

R

+

1

FC

PhN

R

H2N

3

NNH2

R

+

(2.0 eq)

−78 oC, 2 h

−78 oC, 1 h → 0 oC, 2 h

55 oC, 24 h

reflux, 4.5 h

0 oC, 1 h

RT, 24 h

−60 oC, 2 h

30a

0

0

11b

80

41b

75

ConditionsYield (%)

BaseREntry

1

2

3

4

5

6

7

a: Regioisomer ratio. b: 19F NMR yield. c: Hydrazine (1.8 eq) and base (1.8 eq).

(Ts)

(Bz)

(Ac)

(Boc)c

n-BuLi

n-BuLi

NaH

NaH

NaHc

NaHc

NaH

SO2p-Tol

COPh

COMe

CO2t-Bu

Me

Phc

Ph

32'2

20

6

36a

5

Reaction Scope of SN2’-type Reaction

CF3

+Base (1.8 eq)

THF, Conditions

CF2N

R1

H2N

R2 R2

H2NR1HN

(1.8 eq)

1

2

3

4

97

95

72

79

Entry Yield (%)a

H

H

H

H

a: 19F NMR yield.

5

6

7

8

H

OMe

Br

CF3

76

80

88

32

CF2

NBoc

H2N

R2

CF2

NH2N

Product

Boc

Boc

Boc

Boc

C6H5

p-MeC6H4

o-MeC6H4

p-CF3C6H4

Conditions

0 oC, 1 h

0 oC, 7 h

0 oC, 30 min

0 oC, 30 min

−60 oC, 2 h

−60 oC, 2 h

−60 oC, 2 h

−100 oC, 2 h

R

R1 R2

6

Cyclization of Difluoroalkenes

SNV Oxidation

Elimination

NaH (2.2 eq), RT, 24 h

CF2

PhN

R

H2N

HNN

F

PhR

NN

F

PhR

PhNR

NTs

NN

F

PhR

15％

Base

FCF2

PhN

R

NHTs SNV

Base

R = Boc

7

Synthesis of 3-Fluoropyrzoles

Base (2.2 eq)

Solvent, ConditionsN

N

F

PhR−TolSO2−

CF2

PhN

R

NHTs

1 3

NN

F

PhR

Ts

2

+ 2

CF2

PhN

Boc

NH2 TsCl (2.7 eq) CF2

PhN

Boc

NHTs

99%

Pyridine, RT, 2.5 h

ConditionsYield (%)

BaseEntry

47a

86

56

68a

32a

11a

98

RT, 20 h

RT, 5 h

RT, 6.5 h

RT, 12 h

RT, 12 h

reflux, 9 h

RT, 6 h

a : 19F NMR Yield.

Solvent

1

2

3

4

5

6

7

LHMDS

NaH

KH

NaH

NaH

NaH

NaH

DMF

DMF

DMF

DMA

HMPA

THF

DMF

3 2

6a

12

8a

13a

4a

10a

R

Boc

Boc

Boc

Boc

Boc

Boc

Ph

8

Reaction Scope of Tosylation and Cyclization

NaH (2.2 eq)

DMF, RTN

N

F

ArR−TolSO2−

CF2

ArN

R

NHTs

1 3

NN

F

ArR

Ts

2

1

2

3

4

Entry

R2 = H:

R2 = p-Me:

R2 = o-Me:

R2 = p-CF3:

Pyrazole

CF2

NH2N

R2

Yield (%)Difluoroalkene

5

6

7

8

R1 = H:

R1 = OMe:

R1 = Br:

R1 = CF3:

CF2

NBoc

H2N

R1

NBoc

N

R1

F

R2

NN

F98

98

96

97

99

96

98

quant

92b

96c

83c

94b

31 (Tosylation)a

20% (2c)

23% (2d)

a: 19F NMR yield. b: TsCl (2.7 eq), DMAP (0.2 eq), Pyridine (1.8 eq), CH2Cl2 (5 M), 0 oC, 2.5 h.c: TsCl (5.0 eq), DMAP (0.2 eq), Pyridine (1.8 eq), CH2Cl2 (5 M), 0 oC, 2.5 h.

86

85

55

56

9

Mechanistic Consideration

− TolSO2−

R2NN

Ts

R1

CF2

R2N

R1

HN

(a)

(b)

(c)

− TolSO2−

− F−− TolSO2Na

− NaF

− NaF

NaH

NaH

NaH

−

F

CF2

R2N

R1

N−

1,3-H shift

SNV

azomethine imine 4

Diazene 3

CF2

R2NR1

NTs

H

(a)

(c)

−

(b)CF2

R2N

R1

NHTs

NaH NN

F

R2R1

1

2

NN

FTs

Boc

H

NN

F

BocNaH (1.2 eq)

DMF, RT, 24 h

2c 0%1c− TolSO2NaBr Br

10

Mechanistic Consideration

CR2N

Boc

H2N PhI=O (1.1 eq)

THF, RT, 2 h

CR2N

Boc

NPhI CR2N

Boc

N

− PhI

CR2N

Boc

N

75−88％

−

Diazene

Thomson, R. J. et al. J. Am. Chem. Soc. 2011, 133, 14252.

− TolSO2−

R2NN

Ts

R1

CF2

R2N

R1

HN

(a)

(b)

(c)

− TolSO2−

− F−− TolSO2Na

− NaF

− NaF

NaH

NaH

NaH

−

F

CF2

R2N

R1

N−

1,3-H shift

SNV

azomethine imine 4

Diazene 3

CF2

R2NR1

NTs

H

(a)

(c)

−

(b)CF2

R2N

R1

NHTs

NaH NN

F

R2R1

1

2

11

Mechanistic Consideration

CF2

PhN

Ph

H2N PhI=O (1.1 eq)

THF, RT, 4 h

CF2N

Ph

N

Ph

72%

CF2

PhN

Ph

N−

Diazene 3

− TolSO2−

R2NN

Ts

R1

CF2

R2N

R1

HN

(a)

(b)

(c)

− TolSO2−

− F−− TolSO2Na

− NaF

− NaF

NaH

NaH

NaH

−

F

CF2

R2N

R1

N−

1,3-H shift

SNV

azomethine imine 4

Diazene 3

CF2

R2NR1

NTs

H

(a)

(c)

−

(b)CF2

R2N

R1

NHTs

NaH NN

F

R2R1

1

2

12

Mechanistic Consideration

− TolSO2−

R2NN

Ts

R1

CF2

R2N

R1

HN

(a)

(b)

(c)

− TolSO2−

− F−− TolSO2Na

− NaF

− NaF

NaH

NaH

NaH

−

F

CF2

R2N

R1

N−

1,3-H shift

SNV

azomethine imine 4

Diazene 3

CF2

R2NR1

NTs

H

(a)

(c)

−

(b)CF2

R2N

R1

NHTs

NaH NN

F

R2R1

1

2

NN

C(CF3)2

CO2CH3

20 oCF3C CF3

Me Me

NN

C(CF3)2

CO2CH3

F3C CF3

Me Me22 : 78

CF2

R2NR1

HN

azomethine imine 4Burger, K. et al. Angew. Chem., Int. Ed. Engl. 1977, 16, 55.

Electrocyclization

Summary

1) n-BuLi or NaH

2) TsCl

NaHSN2'-type

CF3

R1NHN

R2

CF2

R1 R1NN

F

R2

Electrocyclization

NH2R2HN

+−TolSO2Na

Ts

13

13

Synthesis of 2-Trifluoromethyl-1-alkene

5

CF3

Br

Mg (1.2 eq)

THF, −10 oC to rt

Me2PhSiCl (2.0 eq) CF3

Mg

CF3

SiMe2Ph

80%

H2SO4 Cat

EtOH, reflux

BrRTHF, −78 oC

n-BuLiLiR

THF, −78 oC to RT

60-80 %99%

CF3

OHO THF, −78 oC to RT

CF3

OEtO

CF3

O

R

CF3

R

t-BuOK[CH3PPh3]I

17

Reported Syntheses of 3-Fluoropyrazoles

Fabra, F.; Vilarrasa, J. J. Heterocyclic Chem. 1978, 15, 1447

NN

NH2

Me

NN

F

Me

16%

HBF4 (20 eq )NaNO2 (1.0 eq)

NN

N

Me

NBF4

－hv

H2N NHAr (1.0 eq)

reflux, 2 h

F3CCOOCH3H3CO

NN

FAr

COOCH3

20−79％

K2CO3 (0.5 eq)

propan-2-ol, reflux, 1 h

F3CCOOCH3

80−90％

HNArHN

Volle, J.; Schlosser, M. Eur. J. Org. Chem. 2000, 823.

CF2R1

OR2

H2N NHR3 (2.0 eq)aq. EtOH N

N

FR3

R1

R2

76−95%

rt, 30 min

Ichikawa, J et al. J. Org. Chem. 1996, 61, 2763

R1 = Alkyl

R2 = Alkyl, Aryl

R3 = Alkyl, Aryl

19

Mechanistic Consideration

NNH

Ts

NaOHaq NHN

−

RT, 3 minCF2R2

NR1

NHTs

NHN

2

Carpino, L. A. et al. J. Org. Chem. 1968, 34, 2009.

azomethine imine

− TolSO2−

R2NN

Ts

R1

CF2

R2N

R1

HN

(a)

(b)

(c)

− TolSO2−

− F−− TolSO2Na

− NaF

− NaF

NaH

NaH

NaH

−

F

CF2

R2N

R1

N−

1,3-H shift

SNV

azomethine imine 4

Diazene 3

CF2

R2NR1

NTs

H

(a)

(c)

−

(b)CF2

R2N

R1

NHTs

NaH NN

F

R2R1

1

2

Synthetic Strategy by 1,5-Electrocyclization

F2C

PhN

FCF2

PhNBase

−F− −F−Ph

N

F

−+

Electrocyclization

Fluoroindolizine

Strategy Ⅱ

Strategy Ⅰ

NO

N

Indolizines as histamine H3 receptor

BaseN

R

CF2

Ph− N

R

Ph

F

−F−

Electrocyclization

NRM

CF3

Ph

N

R

Ph

CF2DDQ

N

R

CF2

Ph

15

Synthetic Strategy

R1

F

ON

NH

NH2

H2 N

NH2

NH2XR2

R1

F

N

NR1

F

HN

NR2 X

CF3

R1

SN2'-type Cyclization

1

=

Base Base

NH2O

R2

R1

FN

O

R2

CF2

R1+

1Nu

2Nu

1Nu

2Nu

OH

1Nu

2Nu

4

Syntheses of Fluoropyrazoles

R1 = Alkyl

R2 = Alkyl, Aryl

R3 = Alkyl, Aryl

NNH3C

NNH3C

33%

CO2EtCO2Et

F

NNFH2C CO2Et

F+

Pyridine(HF)n (22 eq)

7%Makino, K.; Yoshioka, H. J. Fluorine Chem. 1988, 39, 435

2.5 V

ビルディングブロック法

直接フッ素化法

Fabra, F.; Vilarrasa, J. J. Heterocyclic Chem. 1978, 15, 1447

NN

NH2

Me

NN

F

Me

16%

HBF4 (20 eq )NaNO2 (1.0 eq)

NN

N

Me

N

hv

官能基変換法

CF2

R1O

R2

H2N NHR3 (2.0 eq)

aq. EtOH NN

FR3

R1

R2

76−95% 63−84%

rt, 30 min

Ichikawa, et al. J. Org. Chem. 1996, 61, 2763.

BF4−