5-endo-trig@0ab · ›

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!"#

Ac acetyl

Bn benzyl

Boc t-butoxycarbonyl

Bu butyl

dba dibenzylideneacetone

DMA N,N-dimethylacetamide

DMF N,N-dimethylformamide

DMI 1,3-dimethylimidazolidin-2-one

Et ethyl

EWG electron-withdrawing group

gem geminal

c-Hex cyclohexyl

Me methyl

NMR nuclear magnetic resonance

Nu nucleophile

PCC pyridinium chlorochromate

Ph phenyl

Pr propyl

TBS t-butyldimethylsilyl

Tf triflate, trifluoromethanesulfonyl

THF tetrahydrofuran

tol tolyl

trig trigonal

Ts p-toluenesulfonyl

1

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F

F

F

F n

1 poly(tetrafluoroethylene)

HO

N

NN

N

NH2

O F

2 F-ara-ddA

NH

F O O

O

3 !"#$%&

H

NF

H

N

O

N

CH3

N

CO2Na

F3C O

CF3 O

O

O CN

O

4 !"#$%&'( 5 )*+,-./01(

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CF3CO2EtOLi SiMe3

O SiMe3

O

F3C

O

OTBS

F3C

OAc

(1)

CHF2CO2Et

O OH

Me

OOMe

OMe

O O

OOMe

OMe

CHF2OH

O O

OMe

OMe

O

S

CHF2

, LiH

(2)

F3C

OF

F

F

NH2

NH2 N

NH

O

CF3 N

NH

O

RCF3

, NaHCO3

(3)

3

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C C

F

F R1

R2

!+ !"Nu

additionC C

R1

R2

F

F

Nuelimination

" F

F

Nu R1

R2

(4)

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F2CF

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addition elimination

! F(5)

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F2C

Y

R

Y

RF

FY

R

F

n n n

(6)! F

!

(n = 0, 1)

Y

CF3

Y

F2CF

Y

CF2

nn

n

(7)! F

!

(n = 0, 1)

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Y

X

Y

X

!

! = 109°

5-endo-trig"#$ (disfavored)

X

Y!

! = 109°

YX

5-exo-trig"#$ (favored)

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5

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n-C6H13

OHO

n-C6H13

SeArArSeBr (2.1 eq)

!78 °C / CH2Cl2(8)

84%(Ar = 2,4,6-i-Pr3C6H2-)

n-C6H13

OHSe Ar

N

Ph

O

Cl Bu3SnH (1.2 eq)AIBN (0.1 eq)

N

Ph

ON

H

H

O

Ph

(9)reflux, 3 h/ toluene

92%

E~7'c.øp6> 5-endo-trig�*F+õ*967��¤~]S-dP4*><.-i

`á`Û�«0øptu�BC§�0/.çSFÃ}~?0¨Lº�] 12)R

HY

SO2Ph

R1

R2

Y

SO2Ph

R2R

1

KH (0.05 eq)

25 °C, 10 min/ THF

Y = O, NPh, C(CO2Et)2(10)

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5-endo-trig

5-endo-trig

F2C

R

Y

CF3

YY

F2CF

Y

R

F

F Y

R

F

Y

F2C

M = Li, Na; Y = NTs, O, CH267 - 84%

!+ !"

" F"

" F"

82 - 89%M = Na, K; Y = NTs, S, C(EWG)2

(11)

(12)

M

M

C C

F

F

F2C CH2 H2C CH2

F2C C H2C C

!+ !"

Electrostatic charge of carbon atoms(calcd. by Density Functional Theory (B3LYP 6-31G*))

+0.58 "0.45 "0.29 "0.29

13C NMR chemical shifts

! ca. 150

! ca. 90

! ca. 110

! ca. 140

Fig. 1

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7

F

FMeO

I

MeO

F

MeO

FF

+

cat. Pd(OAc)2

Et3N (2.5 eq)

115 °C, 40 h/ DMF

8 60%6 (2.5 eq)

(13)

79

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MeO

PdI

F2C

MeO

PdI

FF

MeO

F

!"!+

!"

!+

" PdIF

(14)

8A

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Ph

NOCOC6F5

N

Ph

Me3SiCl HN

Me

Ph

(15)

cat. Pd(PPh3)4

Et3N

80 °C / DMF rt, 0.5 h/ CH2Cl2

86% from E-isomer83% from Z-isomer

1011

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Ph

NOCOC6F5

CF2

N

Ph

FF

Pd

C6F5CO2

CF2

Ph

N

Pd

OCOC6F5

PPh3

NF

Ph

!+!"

!"

!+Pd(PPh3)4 (0.1 eq)PPh3 (1.0 eq)

13 71%

110 °C, 8 h / DMA

" C6F5CO2PdF(16)

12

Pd(0)

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CF2OTf

F

H2O

O

Pd(PPh3)4 (1.0 eq)PPh3 (1.2 eq)

110 °C, 10 h / DMA

16 57%

(17)

1415 64% (

19F NMR yield)

9

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F3C

N

Ph

OCOC6F5N

PhF2C

Pd(PPh3)4 (0.1 eq)PPh3 (1.0 eq)

110 °C, 1 h / DMA

18 60%

(18)

17

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10

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CF2 N

Ph

OCOC6F5

CF2 N

Ph

Pd

OCOC6F5

NF

Ph

Pd(PPh3)4 (0.1 eq)PPh3 (1.0 eq)

110 °C, 8 h / DMA

5-endo-trig

12 13 71%

(19)

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R

PdXCF2

R

R

F

Pd(0) 5-endo-trig

! XPdF(20)

19 20 21

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¿A�[bcd9ÀÁÂ�~9e

NH

R1

R2

PdXNH

Pd R1

R2

X

NH

X R1

R2

NH

R1

R2

NR

2

R1

H

N

Pd R1

R2

Pd(0) 5-endo-trig

! HX

! Pd(0)

! HPdX

path A

path B

(21)

22 23

24 25

N

R1

R2

HPdOAc

N

HR

1

Pd

R2

H

OAc

N

HR

1

PdOAc

R2

N

HR1

R2

N

H

R2

PdOAc

HR1

NH

R1

R2

5-endo-trig

! HPdOAc

! HPdOAc(22)

26 27

29

path A

path B

28

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12

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CF2

Ph

BrCF2

Ph

PdBrF

Ph

Pd(dba)2PPh3

/ DMF

5-endo-trig

30 31 32

entry Pd(dba)2 / eq PPh3 / eq conditions comment

1 0.1 0.4 70 °C, 10 h 30 !"#78%

2 1.0 4.0 70 °C, 12 h 30 !"#53%

32

0%

0%

Table 1

$ ^/:,UV��[bg°}DÐ¸ObcFgem-%&'()0'MNij/ÑÒw78

9UVÂ/ÓÔ��¬�9e&��/�j�ÕÖ'×O&Ø+'×78}cÙÚw�D

gem-%&'()0'MN 33 OÛ5,0+Ü2' 7 AXYÝ/ Heck ÞUVAKFß�à

1Náza. 34 K�¬�gd��â�15)e"´F1,1-%&'()0'MN 6 / HeckÞ

UVK�[f9��ã�13)e^�¬/Ô°¬FÇ,012' 30 / gem-%&'()0

'MNijKFnN%'×O&Ø+'×�ÙÚbcät»7ÑÒ¥g}cd9D£F01

2'34%56(T)�UVb7¥¥Fåæ/:,��[bg°}DO��¬�9e®ÂÅ

ÆKFÇ,012' 30 /&Ø+'×W²�7ç�Fgem-%&'()0'MNij/ÑÒ

wWè¤w]9Ô78_FÎ»/ 5-endo-trig:,��[f9ÔWéêbDe

F2C n-Bu

Ph I

MeOMeO

F

Ph

n-Bu

+

Pd2(dba)3·CHCl3 (0.05 eq)PPh3 (0.2 eq)Et3N (1.0 eq)

reflux, 5 h / DMF(23)

33 7 34 0%

(33 !" !90%)

13

F

FMeO

I

MeO

F+

cat. Pd(OAc)2

Et3N (2.5 eq)

115 °C, 40 h/ DMF

8 60%6 (2.5 eq) 7

(24)

$ :,ëìtKíÔ/8E7-abD�îP26;�eß'ïNð 35 W²�,1Ö560

'R+56A¹ºbc0'ñ2' 36 7bF·)6ðò1%+56·)1§789ð,A0

'Qó§ 37 W-abDe±dcF%Õ)Ì%&'()ômNOõ1î�%ôÖ'0RS�

öî&÷N°¬øùw�91Np1§Wuvw]c%&'()ôÖúN,f9Ô78_F

gem-%&'()0'MNijWkf9Ç,012' 38 W�De

O

OH

Br

OH

Br

CF2

H

Br

O

H

Br

LiAlH4 (1.25 eq)

rt, 45 min / Et2O

PCC (1.4 eq)

rt, 3 h / CH2Cl2

CF2Br2 (2.0 eq)P(NMe2)3 (4.0 eq)

rt, overnight / THF

35 36 96% 37 41%

38 5%Scheme 1

$ ^/Ç,012' 38 7Fûõ4Pîõ1&Ø+'öî&÷N34%56(0)Wuvw]

D��ü�eb°bFÎ»/ 5-endo-trig:,t 40 K�¬�ýFþÿ� 50%!"w�De

^/�#°¬Fgem-%&'()0'MNij/ÑÒwWè¤w]D³$AKF5-endo-trig

:,Wàf9/7%XAKgdÔ�\°}De

CF2

H

BrCF2

H

PdBr

H

F38

Pd(PPh3)4 (0.1 eq)PPh3 (1.0 eq)

80 °C, 5 h;110 °C, 2.5 h / DMA

5-endo-trig

39 40 0%

(25)

(38 !" 50%)

$ :,W�[w]9D£7FÅÆK&7 gem-%0'P''#�Thorpe-Ingold '#�18)W

14

(vf9ÔW��De gem-%0'P''#OKF:,ëìt7�dc)*i7+,/0

'P'×AÙÚw�D��~9OFXYZAUVij�-.b¡f¥g_F:,�/�

w�9OdE'#A~9e^/'#KUV01/2378_45»7¦w�c�_F¨7

ü6:7a7�dc8479�9OdEÃÄª�~9�îP26�Fâ�19)e

OH

OH

O

R R

OH

O

R R

OH

O

O

RR

O

O

R R

R = H R = Me

Relative rate

1 8400

1 400

:

:

Scheme 2

H+

H+

CO2H

NH2HN

O

R

R

CO2H

NH2HN

O

R

R

H+

H+

NHHN

O

OR

R

HN NH

O

ORR

R = H, H R = H, Me R = Me, Me

1 11 63

1 3 18

Relative rates

: :

: :

Scheme 3

$ ®ÂF:,��[bg°}DÇ,012' 38 /nN%'j7ôÖ'×W+,:;bF

gem-%0'P''#78_ü6:7aUVW/�f9ÔW��bD�<��e

BrCF2

H

H H

OTfCF2

H

Me Me

38 14

Fig. 2

15

$ :,ëìtA~9012'õ1&42õ 14 K&/8E7-abD�îP26ã�e=>

?@/´A78_F2-&'()0+Ü2' 41 OpÜÕÖ)+õ1'°¬FnN%'j7ô

Ö'×W+,:;bD+õ1' 42 W-abD 20)e²�,%pÜÕÖ'0'R+5678

_q0S×W¹ºbc0'Qó§ 43 7bDBF%&'()ôÖúN,78_ gem-%&'

()0'MN 44 W�De^�WCÇ,ö5�789D2û'�EA&ØS2' 45 7çÚ

bDBFõ1&'()ômNî'öNðF².Aó§)Pq×Wõ1&1',bcÎ»/

012'õ1&42õ 14 W�De

OMe

FCN

OMeCF2

H

OMe

CN (i-Bu)2AlH (1.1 eq)

OTfCF2

H

OHCF2

H

OMeO

H

41 42 98% 43 83%

44 96% 45 65%

14 69%Scheme 4

KN(SiMe3)2 (1.5 eq)

(4.0 eq)

60 °C, 11 h/ toluene

!78 °C to rt, 2 h

/ CH2Cl2

CF2Br2 (2.0 eq)P(NMe2)3 (4.0 eq)

rt, 10 h / THF

BBr3 (1.0 eq)

!30 °C, 2 h

/ CH2Cl2

Tf2O (2.6 eq)

rt, overnight / pyridine

$ ^Ebc�¬�D012'õ1&42õ 14 / 5-endo-trig:,WGæDefg\hF14

7 N,N-%ôÖ'0Hõ0R§IAõ1&Ø+'öî&÷NO 0.1 JÌ'Ê/ûõ4Pîõ

1&Ø+'öî&÷N34%56(0)Wuvw]De110 KA 10 LÝMNbDBF1Nð

OPQ�pH 7�78_UVWRSbDO^TFÎ»/ 5-endo-trig:,tA~9&'()p

NQN 15 K�¬�g°}D�F�\_7ü6:za.A~9pNµSN 1621)� 15%/"

UAzabD��V�e

16

OTfCF2

H

14

Pd(PPh3)4 (0.1 eq)PPh3 (1.0 eq)

110 °C, 10 h / DMA

pH 7 buffer

F O

15 0% 16 15%

(26)

$ pNµSN 16 KF&'()pNQN 15 �UVxIA"WzabFUVRSL7M�D

1NðOPQ78}cM²XXw�czabDO��¬�9��Y�22)e

OTfCF2

H

PdOTf

CF2

H

F

H2O

O

Pd(0) 5-endo-trig(27)

14 15 1646

;<â$ UVZ[/��

$ �:,UV��V�AKF0.1JÌ'Ê/ûõ4Pîõ1&Ø+'öî&÷N34%5

6(0)7�bF5-endo-trig:,za. 16 /"UK 15%A~9e®^AF:,t/"UW\

]w]9D£7FUVZ[/��W[}De

$ ýFUV^É/��W[}D�Ï��eN,N-%ôÖ'0Hõ0R§7��Fà)ò(S

+õ1'Fõ'DNF1,4-%(P¶NWvdD�DNõ12�<ã�eb°bF^�¬/Í

-7Î»/ 5-endo-trig:,tA~9pNµSN 16 K�¬�g°}De^/�#°¬Fí

B/��AK^É7 N,N-%ôÖ'0Hõ0R§Wvd9^OObDe

17

OTfCF2

H

O14

Pd(PPh3)4 (0.1 eq)PPh3 (1.0 eq)

conditions / solvent

16

entry conditions / solvent

yield / %

16 14 !"

1 110 °C, 10 h / DMA 15 49

2 refl., 9 h / EtCN 0 34

3 refl., 10 h / toluene 0 64

4 refl., 10 h / 1,4-dioxane trace 76

Table 2

$ &7_M`/��W[}De�UVAKF5-endo-trig :,/B�&��{|78_F&

�,34%56(T)47 �zabcd9O��¬�9eUVWÈÉ»7�[w]9D£7KF

z�D&�,34%56(T)47 W 0r7¹ºf9ab�~9�îP26ü�e^�A¹º

Òbcõ1&Ø+'öî&÷NWvdccD� 23)F¹º�'U8¥�[bcdgdÔ

��¬�9e®ÂF¹º`W��f9Ô78_F'U/8dÈÉxWdebD�Ï

â�e

OTfCF2

H

PdOTf

CF2

H

FPdOTf

F

F F

H

PdOTf

14 15

5-endo-trig

Pd(0)

Pd(0)!"#

Scheme 5

46

47

O16

H2O

18

OTfCF2

H

Pd

Pd(PPh3)4

Pd(OAc)2

Pd(PPh3)4

Pd(PPh3)4

Pd(PPh3)4

O

entry

14

Pd (0.1 eq)additive

conditions / DMA

16

additive conditions16 14 !"

1 PPh3 (1.0 eq) 110 °C, 10 h 15 49

2 P(t-Bu)3 (2.4 eq) 110 °C, 2 h trace 73

3 PPh3 (1.2 eq), CO (1 atm) 140 °C, 6 h trace 62

4 PPh3 (1.2 eq), n-Bu4NCl (6.0 eq) 110 °C, 10 h trace 58

5 PPh3 (1.2 eq), C6F5CO2Li (1.0 eq) 110 °C, 7 h 0 81

yield / %

Table 3

$ ýFõ1&Ø+'öî&÷N8_�¹ºf�gdO��¬�9õ1 t-ÕÖ'öî&÷N

WvdD�FÎ»/:,t 16 KhOij�¬�g°}D�DNõ12��e&7F¹ºf

�~_FkjYO�g9"ð,��/lmnÔAUVW[}D�DNõ12â�eb°bF

^/Í-KMNoIA^Q/p�qp7ç,bF34%56st�rsbcd9Ô�t

uw�DeDFxI7v,.p(N¡lNm&'()wxyð1Ö56Wz{w]F3

4%56st/�0+(NWç�c¹ºw�|w/ç,WéêbD�FO�7'#�g°

}D�DNõ12ãFü�eí]/��AKF_MÒbcõ1&Ø+'öî&÷NWvd

DOc8_�:,t 16 /"UW\]w]9ÔKAcýF'U/8dÈÉxW}~fÔ

KAcg°}De

$ ±dcF34%56st/�vÊW�¡fÔ78_F:,t/"U/\]W��bD

�Ïã�e®/�#Fûõ4Pîõ1&Ø+'öî&÷N34%56(0)WËÌ'ÊFõ1&

Ø+'öî&÷NW 1.2JÌ'Êvd9ÔAFÎ»/:,t 16 /"UW 57%7\]w]

9Ô�AcD�DNõ12ã�eg�Fõ1&Ø+'öî&÷NW_Mbg°}DÍ-F

þÿ 14 /�rK0¥g}D�//F:,t/"UKÓÔbD�DNõ12��e �8_F

��/õ1&Ø+'öî&÷NKUV01W�¥f9�//FUVIÝtWw3,bcd

9O��¬�9e

19

OTfCF2

H

Pd(PPh3)4 / eq

O14

110 °C, time / DMA

16

entry PPh3 / eq time / h16 14 !"

1 0.1 1.0 10 15 38

2 1.0 ! 2 38 0

3 1.0 1.0 10 45 <12

4 1.0 1.2 9 57 18

yield / %

Table 4

Pd(PPh3)4

PPh3

;<ã$ &'()pNQN/��/��

$ L7BCDO�_FpNµSN 16 K&'()pNQN 15 �UVxIA"WzabFU

VRSL7M�D1NðOPQ78}cM²XXbczabD/AKgd°O��D��

�Y�e

OTfCF2

H

PdOTf

CF2

H

F

H2O

O

Pd(0) 5-endo-trig(27)

14 15 1646

^/^OWtuf9D£F��VO��Z[AUVW[}D^Q/ 19F NMR W23bF

UVW��bDe®/�#FþÿA~9 14 /õ1&'()ômNî'ö+'×F%&'(

)ôÖúN×7¸�f9ò2·/�7F24.0 ppm�!F�C6F6/ò2·W×��0 ppm��7

"��/ò2·W�2bDe?@/ 1-&'()pNQN�/ 19F NMR,�q&õ��<â�

O��bc 15,24)F^/ò2·K&'()pNQN 15 /ò2·Obc�GA~9O��De

20

F F

Ph

!F 28.0 (t, JFH = 5.8 Hz) !F 30.8 (td, JFH = 6, 2 Hz)

Fig. 3

3240

$ w¬7FxIAzabcd9O��¬�9&'()pNQN 15 WÖ(*+'D2û'

48 Obc��f9Î»AF0 r34%56WËÌ'ÊvdDUVZ[7�dcFUVRS

L71NðOPQ/�\_7Ö(&ØS2'W_MbD��22)e®/�#F�é7U

bcÖ(*+'D2û' 48 K�¬�g°}D�//F&'()pNQN 15 ®/�/�

64%/"UA�¬�De

OTfCF2

H

SPh F14

Pd(PPh3)4 (1.0 eq)PPh3 (1.2 eq)

110 °C, 9 h / DMA

PhSH (4.0 eq)

48 0% 15 64%

(19

F NMR yield)

(28)

$ ^/�#8_FÎ»ObcdDUVFfg\h012'õ1&42õ 14 O 0r34%5

6st°¬z�9012'34%56(T)46/5-endo-trig:,��[bcd9^OWtu

f9^O�AcD��e

OTfCF2

H

PdOTf

CF2

H

F F

H

PdOTf

F

14

Pd(0) 5-endo-trig

(29)! FPdOTf

15

46

47

21

$ g�F&'()pNQN 15 W�|f9Ô�AcD�#K&/8E7X�Ac9e�;

�7¦bD8E7F5-endo-trig :,/BF�-&��{|78}c&�,34%56(T)s

t 47 �zaf9O��¬�9eUV^Q71NðOPQWM�cUVWRSbDÍ-FU

VxI7�}cd934%56(T)st 47 �'pîðObc&'()pNQN 15 /0'

MNij7uvbFWackerÞUV78}cM²XXW/�bcpNµSN 16 �zaf9e

"´FUVxI7Ö(&ØS2'WM�DÍ-KF34%56(T)st�Ö(&ØS2'/

kj78_'pîðÂWrdF&'()pNQN 15 �M²XXw�9Ôg¥�¬�DO

��¬�9�îP26V�e

OTfCF2

H

F

H2O

PdII

OTf

F

F

PhSH

O

OH14

5-endo-trig

Pd(0)

! inert Pd-S complex

15 (isolated)16

Scheme 6

4715

$ í]Fgem-%&'()0'MNijWkf9012'õ1&42õ 14 7õ1&Ø+'

öî&÷N�8�ûõ4Pîõ1&Ø+'öî&÷N34%56Wuvw]9Ô78_F

&'()pNQN 15 ��¬�9ÔW}~bDe^�78_FIÝ7z�9012'34

%56(T)46 / 5-endo-trig:,��[f9ÔW�¬°7f9Ô�AcD��â �e

OTfCF2

H

PdOTf

CF2

H

F14

5-endo-trig(30)

15 64%

(19

F NMR yield)

46

Pd(PPh3)4 (1.0 eq)PPh3 (1.2 eq)

110 °C, 9 h / DMA

22

!"# $%&'()*+',-'./012(3456789 5-endo-trig:;

<=>? @A

? BCDE'FG)%HCIJKLM2NOPQR:STUVWX9YZ[\]^F_`

]9.abcde2fghVijdklmhnoIVpMq9NOPQR:;r]stu

vI&wP/7x12pyInz{VYZ[\9|}F~��\9��d�2f

��VG)%HC:t�I exo-H&'()*+�C./N� 49 F 50 UVexo-H&'(

)*+�C./�h��;r]I�mVDNA�r��vI|}12y�o��e2

��25)f

HO

MeO N

N

F

FO

H

O

OMeN

N

F

FO

H(CH2)n

O

N

N

F

FO

H

MeO

49

50 (n = 3-5)

Fig. 4

? exo-H&'()*+�C./012G)%HC:/S�12IUV:�9�'�-'.I

¡H¢)£H&'()*¤Cy$%¥�H*+'¦§¨�©¥&ªC«q¬LM2%

CB%D/~�L®2 Wittig¯9°±��qM2f²³>I 4-(3´µ)%C678«

q 4-H&'()*+�Cµ)%C/r¶12�/·1� 26)V�9 49V50 kp9µ)¸¥

/¹{r¶LM{�2f

23

N

O

Boc

CO2BnTHF N

Boc

CO2Bn

F

FCF2Br2

P(NMe2)3, Zn(31)

48%

? pMI ¡º»¼½dUV$%&'()*+',-';r]9u¾� SN2’°±/¿o

5-endo-trig:;InÀVG)%HC:Á¶yÂÃI exo-H&'()*+�C./7x12

°±/ÄÅ¡{�2�²³<�8,27)f1�ÆÇV$4'¦§D./012$%&'()*+

',-';r] 51 IVN,N-H*+'©'5¦§DÈÉP;Ê$%Ë5/~�L®2yV

��IH&'()*+�C.�7xLMhG)%HC 52 �ÌqM2f

F3C

N

R

TsH

N

F3C R

Ts

N

F2C R

TsNaH (1.3 eq)

120 °C / DMF ! F! (32)

51 52 63-94%

R = aryl, alkyl, alkenyl

? LqIV²³³I·1noIVgem-H&'()¦'ÍCs9u¾�¦'3%ÎC¦§¨

ÏÐHË5In2 5-endo-trig:;°±kÄÅ¡{ÑÀV&'()G)E' 13 �ÒÓvI

r¶LM{�2 15)f

CF2 N

Ph

OCOC6F5

CF2 N

Ph

Pd

OCOC6F5

NF

Ph

Pd(PPh3)4 (0.1 eq)PPh3 (1.0 eq)

110 °C, 8 h / DMA

5-endo-trig

12 13 71%

(33)

? ÔÕUVpMq<Ö9°±/×ØrÆ®2py/Ù�hf1�ÆÇV$%&'()*+

',-';r] 53 «qÅY12¦'3%ÎC¦§¨ÏÐHË5 54 InÀÂÚ9

5-endo-trig :;�ÛÜ1M�Vexo-H&'()*+�C./012:ÝB§C 55 �r¶

d�2pyI�2�²³��fÞpdp9°±IÖ�{ßà¡hf

24

F3C

N

R

OCOC6F5

N

R

Pd

OCOC6F5

F3C

N

F2CR

5-endo-trigPd(0)(34)

53 55

54

<=<? $%&'()*+',-'./012 O-áC¤&'()âCãB'(3459r

¶Ñnä:;9ßà

? $%&'()*+',-'./012 O-áC¤&'()âCãB'(345/åæ9ç

èdr¶¡h�¥3E5é�fêëìí9çèInÀV$%&'()*+'¦%'4ÐC 56

yâCî¦'ÎïD«q$%&'()*+'./012©£¦%'¦'ðE' 57 /r¶

¡h 28)fñ)5òG%H-Ë5ñ)%DInÀ¦'ðE' 57 /Í$C 58 Iò;¡hóV

(345;/Ü� 59 s67¡hfôóI(345òP/áC¤&'()âCãB';¡{V

õv9:;ö÷8 60 /Ìhf

CF3CO2EtMe3SiCH2MgCl (2.1 eq)

F3C

OH

Ph

F3C

N

Ph

OH

Me3Si SiMe3

HO CF3

F3C

O

Ph

F3C

N

Ph

OCOC6F5

F3C

SiMe3

PhCHO (1.5 eq)n-Bu4NF (0.15 eq)

MS 4A0 °C, overnight

/ THF

PCC-Silica gel(3.0 eq)

rt, 2 h / CH2Cl2

NH2OH·HCl (2 eq)pyridine (3 eq)

rt, overnight / EtOH

C6F5COCl (1.5 eq)Et3N (2 eq)

0 °C, 30 min/ CH2Cl2

57 75% 58 88%

59 89% 60 88%

rt, 4 h / THF

87% 56 64%

Scheme 7

conc. H2SO4

? po¡{r¶¡h(345 60 IVN,N-H*+'¦¸$¦§DÈd$%&ø-'©¥&

ªCyÒÓù9ú$Ð3¥$%&ø-'©¥&ªCÏÐHË5(0)/~�L®hfÞ9�û

25

üUýþ;¡Výÿ9$%&'()*+';r]�!"LMh�Võv9:;8 61 UÌq

M�«zh�²³Q�f

F3C

N

Ph

OCOC6F5 N

F2C Ph

Pd(PPh3)4 (0.1 eq)PPh3 (1.0 eq)

110 °C, 2 h / DMAcomplex mixture

60 61 0%

(35)

!##IÑ�{Ù$¡hnoIV:;ö÷89*+�C%P�I¦'3'./"Ö7x

12yV°±&�'(12pyInÀ:;�)ÛLM2 gem-H¦'3'*û��d�2

�!##V¥3E5<V³�18,19)fÞpda°±IÑ�{kVgem-H¦'3'*û/+�

1M�õv9:;�ÛÜ129dU��«yÙ�hf1�ÆÇV�QI·1noIV60 9

¦%'��(3459,��I"Ö9*+'./7x¡h(345 17 IÖ�{V:;°±

/ßà12pyI¡hfghV60 9¦%'��(3459,��%P�9µ)$CUò\

-�.XV/°±901y�Ào2f¦%'�I*+'./"Ö7x12pyInÀVp

9[\µ)$C/�X¡/°±/2312*ûk��d�2f�ÑV�49h5V*+'

./#Ö7x¡h(345 62 IÖ�{k6®{:;/ßà12pyy¡hf

F3C

N

Ph

OCOC6F5

H H

F3C

N

Ph

OCOC6F5

R R

60 62 (R, R = Me, H)

17 (R, R = Me, Me)Fig. 5

(345 62V17 Uåæ9çèdr¶¡h�¥3E57�fÍ$C 58 I�%Ë5839

*+'H4ÐHDy$%&'()*¤C¥'©Cò*+'/~�L®2pyInÀVÍ$

C9,�I*+'./#Ö7x¡hÍ$C 63 Ñnä"Ö7x¡hÍ$C 65 /r¶¡hf

ÞM:MV60 9r¶yÂÚI¡{(345;VO-áC¤&'()âCãB';/Ü�Võ

v9:;ö÷8 62V17 /r¶¡hf

26

F3C

O

Ph

F3C

O

Ph

F3C

O

Ph

F3C

N

Ph

OH

F3C

N

Ph

OH

F3C

N

Ph

OCOC6F5

F3C

N

Ph

OCOC6F5

KN(SiMe3)2 (1.0 eq)

MeOTf (1.0 eq)

!78 °C to rt,

overnight / Et2O

NH2OH·HCl (2 eq)pyridine (3 eq)

reflux, 17 h / EtOH

NH2OH·HCl (10 eq)

reflux, 1 d / pyridine

KN(SiMe3)2 (1.0 eq)

MeOTf (1.0 eq)

!78 °C to rt,

overnight / Et2O





58

63 81%

65 51% 66 59%

64 91% 62 50%

17 82%

Scheme 8

? po¡{r¶¡h(345 62 Ñnä 17 IVN,N-H*+'¦¸$¦§DÈ 80 ;dV$

%&ø-'©¥&ªCyÒÓù9ú$Ð3¥$%&ø-'©¥&ªCÏÐHË5(0)/~�

L®hfÞ9�ûV*+'./#Ö7x¡h(345 62 9°±dU*+'.9�� 58 y

ÂÚIü�ýþ;¡õv9:;8 67 UÌqM�«zh��²³<�V*+'./"Ö7x

¡h(345 17 «qUVõv9:;8de2 exo-H&'()*+�C./012:ÝB§

C 18 � 17%9=>dÌqMh�²³é�fghVp9y�/Y¶]y¡{B§C 68 �?

@LMhf

F3C

N

Ph

OCOC6F5N

PhF2C

Pd(PPh3)4 (0.1 eq)PPh3 (1.0 eq)

80 °C, 2 h / DMAcomplex mixture

62 67

(36)

27

F3C

N

Ph

OCOC6F5N

PhF2C F3C

NH

Ph

Pd(PPh3)4 (0.1 eq)PPh3 (1.0 eq)

80 °C, 2 h / DMA

18 17% 68 57%17

(37)

? p9�û«qV$%&'()*+',-';r]IÑ�{kV¦'3%ÎC¦§¨ÏÐ

HË5(A)InÀ 5-endo-trig:;�ÛÜ12py�Bq«I�zhfCIV:;Y¶] 18

9=>/��L®2h5IV°±DE/ßà¡hf

<=³? °±DE9ßà

? gFV°±G-/ 100 ;I�HhypIVõv9:;8 18 9=>/ 60%Igd�H2

py�d�h�KQVJC$%E<�fLqIG-/�H2yV100 ;9y�I�m:;8

18 9=>UKæ¡h�JC$%E³V��fghV(345 17 9Ø/ N,N-H*+'¦¸

$¦§DÈdLM¡hypIV120 ;/N�hehÀ«quO¡P5Výÿ9$%&'(

)*+';r]/YQ2py�?@d�hfp9py«qVõv9:;IULM/RSy

12�VG-�.1T2y.^�uO¡{=>9Kæ/UXy�opy�·LMhf

F3C

N

Ph

OCOC6F5N

PhF2C F3C

NH

Ph

Pd(PPh3)4 (0.1 eq)PPh3 (1.0 eq)

conditions / DMA

18 6817

entry conditions18 68

1 80 °C, 2 h 17 57

2 100 °C, 1 h 60 8

3 120 °C, 40 min 50 17

4 140 °C, 1 h 48 43

yield / %

Table 5

? V�{VWÓ9ßà�K<�/ÜzhfN,N-H*+'¦¸$¦§D�DMA�yÂQ¦§

Dü9WÓde2 N,N-H*+'©'5¦§D�DMF�F 1,3-H*+'-2-B§Xã%H¨

28

C�DMI�/��h�V=>9��IUYq�«zh�JC$%E<V³�f1,4-H(39

CF 2-*$34J+'JEú'�diglyme��Z9JEú'ü9WÓ/��h[rUV0\

�}tu]=LMV:;8 18 UÌqM�«zh�JC$%E�VQ�f$'JC/��h

[rkV=>9^_IUYq�«zh�JC$%E<�f

F3C

N

Ph

OCOC6F5

MeN NMe

O

N

PhF2C

F3C

O

Ph

F3C

NH

Ph

Pd(PPh3)4 (0.1 eq)PPh3 (1.0 eq)

conditions / solvent

18 6817

entry conditions / solvent18 68

comment

1 100 °C, 1 h / DMA 60 8

2 120 °C, 1.5 h / DMF 5 60 65 3%

3 100 °C, 0.5 h / DMI 38 22

4 refl., 4 h / 1,4-dioxane 0

6 refl., 14 h / toluene 27 65 10%

yield / %

Table 6

DMI = 1,3-dimethyl-2-imidazolidinone

65

5 100 °C, 1 h / diglyme 0

? pMgd9°±dUVY¶12 2 `ÏÐHË59abcy¡{$%&ø-'©¥&ªC

/��{�h�VdL12abc9efFg./h�VÒÓü9ßà/Üzh�Ké�f$

%&ø-'©¥&ªC/ViòÏÐHË5(A)FHâCH%ÎC¦¸$C(dba)ÏÐHË5

(0)9×ØrÆ®{��hypIVú$Ð3¥$%&ø-'©¥&ªCÏÐHË5(0)/��

hy�nÀk:;8 18 9=>UKæ¡h�JC$%E<V³�f$%&ø-'©¥&ªC

9JÆÀIj9©¥&ªC/��hÀ©¥&ªC/dL¡�«zh[rIUV:;8 18 U

ÌqM�«zh�JC$%E�=7�fghVg.y¡{$%J+'¦§CF%ò�%Ë5

/��h�V:;8 18 9=>9��IUYqFVk9QR:Y¶]klqM�«zh�J

C$%EmV>n�f

29

1 Pd(PPh3)4 (0.1) PPh3 (1.0) 1 60 8

2 Pd(OAc)2 (0.1) PPh3 (1.0) 1 8 22

3 Pd2(dba)3·CHCl3 (0.05) PPh3 (1.0) 1 36 28

4 Pd2(dba)3·CHCl3 (0.05) P(o-tol)3 (1.0) 4 0 17 !"#76%

P(C6F5)3 (1.0)

6 Pd2(dba)3·CHCl3 (0.05) P(t-Bu)3 (1.0) 4.5 0 17 !"#76%

7 Pd2(dba)3·CHCl3 (0.05) P(c-Hex)3 (1.0) 1 0

8 Pd2(dba)3·CHCl3 (0.05) ! 1 0

9 Pd(PPh3)4 (0.1) Et3N (5.0) 11 31 65 37%

10 Pd(PPh3)4 (0.1) K2CO3 (5.0) 5 36

5 Pd2(dba)3·CHCl3 (0.05) 4 0

F3C

N

Ph

OCOC6F5N

PhF2C F3C

NH

Ph

F3C

O

Ph

68

Pd catalystadditive

100 °C, time / DMA

1817

entry Pd catalyst / eq additive / eq time / h18 68

commentyield / %

Table 7

65

17 !"#27%

65 16%

? V�{V=>9��/��¡{�XÖ«9dLc/o¡hfÞ9�û/K7I·1f£

�3pÐE4E¢¥ 4A /dL¡hypIVdL¡�«zhy�yÂq-9=>d:;8

18 �ÌqMh�JC$%E<�fÉ/dL¡hypIV:;®FI¦§¨ÏÐHË5Èr

8�LÉuO¡hyÙ�qM2B§C 68 �WXÌqMh�JC$%E³�füÈIst1

2 ¦-(C/h;L®2h5V&w;%+Ë5F&w;�%Ë5V$%&'()*¤C

¥'©Còu(v)y�zhg/dL¡{Øh�V:;8 18 9=>U��¡�«zh�JC

$%E�=<�f

30

F3C

N

Ph

OCOC6F5

MS 4A

N

PhF2C F3C

NH

Ph

F3C

O

Ph

68

Pd(PPh3)4 (0.1 eq)PPh3 (1.0 eq)

additive

100 °C, time / DMA

1817

entry additive time / h18 68

comment

2 0.5 <54

3 H2O (5.0 eq) 0.5 trace 66

1 ! 1 60 8

4 LiF (5.0 eq) 0.5 29 34

5 LiCl (5.0 eq) 0.5 trace

6 AgOTf (1.0 eq) 3 <4 15

65 6%

65 11%

17 !"#35%

yield / %

Table 8

65

? å�9ßàdUVN,N-H*+'¦¸$¦§DÈdw£'ù9$%&ø-'©¥&ªCy

0.1 x£'ù9ú$Ð3¥$%&ø-'©¥&ªC/ 100 ;d~�L®2DE�V:;8

18 /ôkn�=>�60%�dy�2y�o�ûI�zhf

? ghV(345òP�9z{.IÖ�{kßà/Üzh�Km�fáC¤&'()âCã

B'.IJ�VâCãB'.VH&ø-'©¥&ª-'.V*¤C¥'©-'.VÑnä

¦¸+'./7x¡h(345IVpMgd9ô|DE/|�¡h�JC$%E<=Q�f

¡«¡VZ9[rIÑ�{kWef9$%&'()*+';r]�Y¶¡{ü�ýþ;¡V

:;8 18 9=>U��¡�«zhf

31

F3C

N

Ph

OZ

OCOC6F5 (17)

OCOPh (69)

OP(O)Ph2 (70)

OSO2Me (71)

OCOMe (72)

N

PhF2C

F3C

NH

Ph

F3C

O

Ph

Pd(PPh3)4 (0.1 eq)PPh3 (1.0 eq)

100 °C, 2 h / DMA

18

entry OZ yield / % comment

1 60 68 8%

2 <8 65 7%, 17 !"#12%

3 <11 complex mixture

4 0 complex mixture

5 trace complex mixture

Table 9

68

65

<=�? °±}Sy&wP9*û9Ù$

? pMgdßà/Üz{�hV$%&'()*+',-'./012 O-áC¤&'()â

CãB'(345 17 9 5-endo-trig:;9°±}SUVC9noI~�LM2�¥3E5

m�fgFVO-áC¤&'()âCãB'(345 17 9OP=òP�r� 0`ÏÐHË5

Iò;v�L¡V¦'3%ÎC¦§¨ÏÐHË5(A)73 �YQ2fV�{ 5-endo-trig:;

�ÛÜ¡heyV&w;ÏÐHË5(A)�8 74 �Y¶12yykI exo-H&'()*+�

C./012:ÝB§C 18 �ÌqM2fYQh&w;ÏÐHË5(A)�8 74 UdL¡h

$%&ø-'©¥&ªCInÀ 0`IabLMVÒÓ9Bñ'�¶�12f

32

F3C Ph

NPd

OCOC6F5

F3C Ph

NOCOC6F5

C6F5CO2PdF

N

F2C Ph

17

73

18

Pd(0)

PPh3

(!"#)

Scheme 9

74

? ppdV5-endo-trig :;9�IUVC9"�À9:;Á²9��\�e2f#ÖUV¥

3E5>nI·1noIV¦'3%ÎC¦§¨ÏÐHË5(A)73 9$%&'()*+',

-'.9(�&ªCt��OP=ÏÐHË5�rI�x¡{ÛÜ12 Heck ¯9:;°±

de2fp9Á²dUV:;ó9Èr8 75 «qV�&wP��InÀ&w;ÏÐHË5(A)

�8 74 y:ÝB§C 18 �YQ{°±��¡{�2f

F3C Ph

NOCOC6F5

N

F2C Ph

17

Pd(0) 5-endo-trig

18

! C6F5CO2PdF

74

Scheme 10

F3C Ph

NPd

OCOC6F5

73

N

PhPd

CF2

F

C6F5CO2

75

insertion(Heck-type)

"-F elimination

ko#ÖUV¦'3%ÎC¦§¨ÏÐHË5 (A)73’9OP0¾�(�&ªCt�9��

%PI��L¡{ÛÜ12 SN2’¯9:;°±de2�¥3E5>>�fpMUV²³<9

OP¦-(CIn2$%&'()*+',-';r]9 5-endo-trig:;yÂÚ9¹�de

33

2f¦'3%ÎC¦§¨ÏÐHË5(A)9OP=ÏÐHË5�rUV��90}ÏÐHË5

;r]I�mB(C\9��py�·�LM{�2 14)fp9py«qV73’9no�OP¦

-(CIn2 SN2’°±d:;�ÛÜ¡{�2��\ke2f

F3C Ph

NOCOC6F5 Pd

C6F5CO2

F3C Ph

N

! C6F5CO2PdF

Pd

C6F5CO2

N

F2C Ph

N

PhCF2

F

17

73'

Pd(0) 5-endo-trig

75'

1874

Scheme 11

addition (SN2')

? a°±� Heck ¯°±« SN2’°±«ZÇqIn2k9«V��v�è��dUUz�À

��d��f

? ghV��U�Bde2�V&w;ÏÐHË5(A)�8 74 9$%&ø-'©¥&ªCI

n2abUV²³7I·1no�¦4)34&'()$%&ø-'©¥©ÐC 76 �Y¶1

2«V²³mI·1no��"ò;%P��pz{ú$Ð¦%E'&'()©¥©ÐC 77

�Y¶12V�FM«9}SdÛÜ¡{�2y~"¡{�2 23,29)f

C6F5

O

OPd

II F PPh3

PPh3Ph3P

C6F5Pd

II F

PPh3Ph3P

PPh3

C6F5

O

OPPh3

F

C6F5PPh3

F

[Pd0(PPh3)2]

[Pd0(PPh3)2]

! CO2

+

+

74

76

77

(38)

(39)

? ppdVa°±IÑ�2&wP9*û/?«52h5V&wP/Ng��¦'ÍC/0

34

12.^IÖ�{kÂÚ9 5-endo-trig:;�ÛÜ12«Zo«/¬mhf

? (345 17 9$%&'()*+'.�ÉPIhÆzh(345 78 /°±L®h[rV

õv9:;8 79 �ÌqM�«zh�²�n�fghV$%&'()*+'./*+'.y

¡h(345 86 /¥3E5><9çèdr¶¡V:;/oØh�²�>�f¡«¡V

5-endo-trig :;�ÛÜ¡h;r] 87V88 /Ì2py�d��«zhfpMInÀVa

5-endo-trig :;9)ÛI$%&'()*+'.�}�X��¡{�2y�opy�u«z

hf

N

Ph

OCOC6F5

H

N

PhH

O

PhH

Pd(PPh3)4 (0.1eq)PPh3 (1.0 eq)

140 °C, 1 h / DMF

78 79 0% 80 33%

(40)

Ph

O

H

MgCl

N

Ph

OH

O

Ph

OH

Ph

N

Ph

OCOC6F5

O

Ph

O

Ph

(1.2 eq)

0 °C to rt, overnight/ THF

PCC-Silica gel(3.0 eq)

rt, 2 h / CH2Cl2

KN(SiMe3)2 (1.0 eq)MeOTf (2.0 eq)

NH2OH·HCl (10 eq)

reflux, 2 d / pyridine



!78 °C to rt,

overnight / Et2O

KN(SiMe3)2 (1.0 eq)MeOTf (2.0 eq)

!78 °C to rt,

overnight / Et2O

81 71% 82 97%

83 ~quant. 84 88%

85 84% 86 34%

Scheme 12

Ph

NOCOC6F5

N

Ph

N

Ph


100 °C, 2 h / DMA

86 87 88

not detected

(41)

35

? å�VÔÕU$%&'()*+',-'./012 O-áC¤&'()âCãB'(34

5 17 I$%&ø-'©¥&ªCyÒÓù9ú$Ð3¥$%&ø-'©¥&ªC(0)/~�

L®2pyInÀV:ÝB§C 18 �ÌqM2py/l�¡hfppdUV$%&'()*

+'./,-'�I7x12pyInÀVÈrIYQ2¦'3%ÎC¦§¨ÏÐHË5

(A)73 9 5-endo-trig:;/ ¶12py�d�h�²�<�f

F3C Ph

NOCOC6F5

17F3C Ph

NPd

OCOC6F5

73

N

F2C Ph

18 60%

5-endo-trig


100 °C, 1 h / DMA(42)

36

!"#$

%&'()*+,-./012&345016

1H 789:;<=>?@A1H NMRB

Bruker Avance500 (500 MHz), Bruker DRX500 (500 MHz), JEOL-AL400 (400 MHz)

13C 789:;<=>?@A13C NMRB

Bruker Avance500 (126 MHz), Bruker DRX500 (126 MHz), JEOL-AL400 (100 MHz)

19F 789:;<=>?@A19F NMRB

Bruker Avance500 (471 MHz), JEOL-AL400 (376 MHz)

CDEF<=>?@AIRB

HORIBA FT-300S

G'HIJK<=>?@AHR-FABMSB

JEOL MS-700M

L NMR<=>?@#MN+OPQR1H NMRS+>TTU@VA! = 7.24 ppmB3R13C

NMRS+W>TTU@VA! = 77.0 ppmB3R19F NMRS+XYZ[@\T]^_ A! =

0.0 ppmB3`$abc0Q45016

L deAmpB+fghi3/O6

L 'jkl>Tm?no[pqAPTLCB.+rstuvwxqy@ B-5FAz{|y@B

3R|oV>Tm?no[pq.+}~z{z��'j5z{|y@ PSQ100BA�

��B3��45016

L �>TT��^+R��{^R��S��|@z�V��0R��Y�oq

zq�< 4AAMS 4AB3��Q ¡01¢#35�16�£¤@£q¥@¦§¨¥?o©

ªT[o^ATHFB+R«¬A®¯��B.MS 4A3��Q ¡01¢#35�16°

{�^+R«¬3��|{�V��0R��|{�V3��Q ¡01¢#3

5�16N,N-��¤@�±?�²ªADMAB+R��³{�V��0RMS 4A 3�

�Q ¡01¢#35�16

L ?{[´µ@U<[p^+£�¶q@��·¸¹01¢#35�16¥?oY<?{[

´µ@U<[p^ºo��V(0)+R»¼#?{[´µ@U<[p^3��Q�@½^¾¿

37

9-SÀ]^_^��·¸¹01¢#35�16

L !"+RÁ.Â�Ã�ÄÅÆÇ-�ÀÈÉ01ÊË34�R�@½^¾¿9-SÌÍ16

ÎÏÐ

2-(2-Bromophenyl)ethanol (36)

Br

OH

To a suspension of lithium aluminum hydride (0.73 g, 19.2 mmol) in ether (30 mL) was

added a solution of 2-bromophenylacetic acid (35, 3.26 g, 15.2 mmol) in ether (25 mL) at

room temperature. After the mixture was stirred for 45 min, hexane, methanol, water

and 10% sulfuric acid was added successively to quench the reaction. The layers were

separated and aqueous layer was extracted with ether three times. The combined

organic extracts were washed with brine and dried over MgSO4. After removal of the

solvent under reduced pressure, the residue was purified by column chromatography on

silica gel (hexane"AcOEt 1:1) to give 36 (2.94 g, 96%) as a colorless liquid.

1H NMR (400 MHz, CDCl3) ! 1.44 (1H, br), 3.04 (2H, t, J = 6.8 Hz), 3.89 (2H, t, J = 6.8

Hz), 7.07-7.13 (1H, m), 7.26-7.30 (2H, m), 7.54-7.57 (1H, m).

2-Bromophenylacetaldehyde (37)

Br

H

O

To a suspension of pyridinium chlorochromate (4.43 g, 20.6 mmol) in dichloromethane

(20 mL) was added 2-(2-bromophenyl)ethanol (36, 2.94 g, 14.6 mmol) at room

temperature. The mixture was stirred for 3 h and then diluted with ether. The solid

was removed by filtration through a short column of silica gel. After removal of the

solvent under reduced pressure, the residue was purified by column chromatography

on silica gel (hexane"AcOEt 8:1 then 1:1) to give 37 (1.18 g, 41%) as yellow oil.

1H NMR (400 MHz, CDCl3) ! 3.87 (2H, d, J = 1.6 Hz), 7.12-7.35 (3H, m), 7.61-7.64 (1H,

38

m), 9.77 (1H, t, J = 1.6 Hz).

1-Bromo-2-(3,3-dif luoroallyl)benzene (38)

Br

H

CF2

To a mixture of dibromodifluoromethane (0.46 mL, 5.0 mmol) and MS 4A powder (0.5 g)

in THF (20 mL) was added tris(dimethylamino)phosphine (1.83 mL, 10.1 mmol) at

"78 Ñ. The whole was stirred for 30 min at that temperature, and then was warmed to

room temperature. 2-bromophenylacetaldehyde (37, 0.50 g, 2.5 mmol) was added and

the mixture was stirred overnight. The reaction was quenched with phosphate buffer

(pH 7). The mixture was extracted with AcOEt three times. The combined organic

extracts were washed with brine and dried over MgSO4. After removal of the solvent

under reduced pressure, the residue was purified by column chromatography on silica

gel (hexane"AcOEt 20:1) to give 38 (31 mg, 5%) as colorless oil.

1H NMR (500 MHz, CDCl3) ! 3.44 (2H, ddd, J = 8.0, 1.6, 1.6 Hz), 4.44 (1H, dtd, J = 24.8,

8.0, 2.2 Hz), 7.09-7.13 (1H, m), 7.24-7.29 (2H, m), 7.55-7.57 (1H, m). 19F NMR (471 MHz,

CDCl3) ! 71.5 (1F, dd, J = 43, 25 Hz), 73.8 (1F, d, J = 43 Hz).

2-(2-Methoxyphenyl)-2-methylpropionaldehyde (43)

OMe

CHO

To a solution of 2-(2-methoxyphenyl)-2-methylpropionitrile (42, 6.81 g, 38.9 mmol) in

dichloromethane (80 mL) was added dropwise a 1.0 M solution of diisobutylaluminum

hydride in toluene (42.8 mL, 42.8 mmol) at "78 Ñ. The reaction mixture was stirred for

2 h at room temperature, and then were added successively hexane, methanol,

saturated aqueous NH4Cl and 10% sulfuric acid to quench the reaction. The layers were

separated and the aqueous layer was extracted with dichloromethane three times. The

combined organic layers were washed with brine and dried over Na2SO4. After removal

39

of the solvent under reduced pressure, the residue was purified by column

chromatography on silica gel (hexane"AcOEt 4:1) to give 43 (5.78 g, 83%) as a colorless

liquid.

1H NMR (400 MHz, CDCl3) ! 1.38 (6H, s), 3.76 (3H, s), 6.89 (1H, dm, J = 8.0 Hz), 7.00

(1H, ddd, J = 8.0, 8.0, 1.2 Hz), 7.25-7.32 (2H, m). 13C NMR (100 MHz, CDCl3) ! 22.1, 48.2,

55.1, 110.9, 120.9, 126.7, 128.5, 131.8, 156.4, 203.5. IR (neat) 2970, 2704, 1724, 1489,

1458, 1437, 1240, 1092, 1026, 752 cm-1. HRMS: Calcd for C11H15O2 ([M + H]+) 179.1072,

found 179.1045.

1-(3,3-Difluoro-1,1-dimethylallyl) -2-methoxybenzene (44)

OMe

CF2

To a mixture of dibromodifluoromethane (5.92 mL, 64.8 mmol) and MS 4A powder (6.6

g) in THF (50 mL) was added tris(dimethylamino)phosphine (23.5 mL, 130 mmol) at

"78 Ñ. The whole was stirred for 30 min at that temperature, and then was warmed to

room temperature. 2-(2-Methoxyphenyl)-2-methylpropionaldehyde (43, 5.78 g, 32.4

mmol) was added and the mixture was stirred for 10 h. The reaction was quenched with

phosphate buffer (pH 7). The mixture was extracted with ether three times. The

combined organic extracts were washed with brine and dried over MgSO4. After

removal of the solvent under reduced pressure, the residue was purified by colum

chromatography on silica gel (hexane"AcOEt 4:1) to give 44 (6.18 g, 96%) as a colorless

liquid.

1H NMR (400 MHz, CDCl3) ! 1.53 (6H, s), 3.82 (3H, s), 4.54 (1H, dd, JHF = 28.4, 5.8 Hz),

6.85-6.93 (2H, m), 7.19-7.24 (1H, m), 7.27-7.30 (1H, m). 13C NMR (100 MHz, CDCl3)

! 28.3 (dd, JCF = 4, 2 Hz), 35.1 (dd, JCF = 5,3 Hz), 55.1, 88.3 (dd, JCF = 22, 14 Hz), 111.5,

120.2, 125.9, 127.6, 135.9, 154.7 (dd, JCF = 290, 280 Hz), 157.7. 19F NMR (376 MHz,

CDCl3) ! 72.1 (1F, dd, JFF = 54 Hz, JFH = 6 Hz), 74.2 (1F, dd, JFF = 54 Hz, JFH = 28 Hz).

IR (neat) 2968, 1734, 1458, 1437, 1329, 1290, 1242, 1215, 1030, 999, 746 cm-1. HRMS:

40

Calcd for C12H15F2O ([M + H]+) 213.1091, found 213.1135.

2-(3,3-Difluoro-1,1-dimethylallyl)phenol (45)

OH

CF2

To a solution of 1-(3,3-difluoro-1,1-dimethylallyl)-2-methoxybenzene (44, 1.11 g, 5.21

mmol) in dichloromethane (25 mL) was added a solution of 1.0 M tribromoborane in

dichloromethane (5.2 mL, 5.2 mmol) dropwise at "30 Ñ. After the reaction mixture was

stirred for 2 h at "30 Ñ, phosphate buffer (pH 7) was added to quench the reaction. The

layers were separated and the aqueous layer was extracted with dichloromethane three

times. The combined organic extracts were washed with brine and dried over Na2SO4

After removal of the solvent under reduced pressure, the residue was purified by

column chromatography on silica gel (hexane"AcOEt 19:1) to give 45 (0.668 g, 65%) as

yellow oil.

1H NMR (400 MHz, CDCl3) ! 1.54 (6H, s), 4.59 (1H, dd, JHF = 26.7, 4.9 Hz), 5.13 (1H, br),

6.72 (1H, d, J = 7.7 Hz), 6.89 (1H, dd, J = 7.7, 7.7 Hz), 7.11 (1H, ddd, J = 7.7, 7.7, 1.6 Hz),

7.26 (1H, dd, J = 7.7, 1.6 Hz). 13C NMR (100 MHz, CDCl3) ! 28.3 (dd, JCF = 3, 2 Hz), 34.8

(dd, JCF = 5, 3 Hz), 116.7, 120.6, 126.1, 127.8, 133.5, 153.6, 155.1 (dd, JCF = 294, 285 Hz).

19F NMR (376 MHz, CDCl3) ! 75.5 (1F, dd, JFF = 45 Hz, JFH = 5 Hz), 77.2 (1F, dd, JFF =

45 Hz, JFH = 27 Hz).

Trifluoromethanesulfonic acid 2-(3,3-difluoro-1,1-dimethylallyl)pheny l

ester (14)

OTf

CF2

To a solution of 2-(3,3-Difluoro-1,1-dimethylallyl)phenol (45, 0.668 g, 3.37 mmol) in

pyridine (17 mL) was added trifluoromethanesulfonic anhydride (1.47 mL, 8.74 mmol).

41

After the reaction mixture was stirred overnight at room temperature, 1 M HCl was

added to quench the reaction. The mixture was extracted with ether three times. The

combined organic extracts were washed with 1 M HCl and brine, and dried over Na2SO4.


column chromatography on silica gel (hexane"AcOEt 19:1) to give 14 (765 mg, 69%) as

yellow oil.

1H NMR (400 MHz, CDCl3) ! 1.55 (6H, s), 4.61 (1H, dd, JHF = 27.2, 4.0 Hz), 7.29-7.35

(3H, m), 7.46-7.51 (1H, m). 13C NMR (100 MHz, CDCl3) ! 29.1 (dd, JCF = 3, 2 Hz), 34.8

(dd, JCF = 6, 2 Hz), 88.1 (dd, JCF = 22, 14 Hz), 118.3 (q, JCF = 319 Hz), 121.2 (dd, JCF = 4, 3

Hz), 127.7, 127.8, 128.4, 139.7, 148.6, 155.2 (dd, JCF = 292, 286 Hz). 19F NMR (376 MHz,

CDCl3) ! 75.0 (1F, dd, JFF = 44 Hz, JFH = 4 Hz), 77.4 (1F, dd, JFF = 44 Hz, JFH = 27 Hz),

87.5 (3F, s). IR (neat) 2979, 1736, 1419, 1325, 1211, 1140, 1066, 895, 879, 766, 598 cm-1.

Anal. Calcd for C12H11F5O3S: C, 43.64; H, 3.36%. Found: C, 43.49; H, 3.54%.

3,3-Dimethylindan-1-one (16)21)

O

To a solution of triphenylphosphine (50.8 mg, 0.194 mmol) and

tetrakis(triphenylphosphine)palladium (180.3 mg, 0.156 mmol) in

N,N-dimethylacetamide (10 mL) was added trifluoromethanesulfonic acid

2-(3,3-difluoro-1,1-dimethylallyl)phenyl ester (14, 51.5 mg, 0.156 mmol). After the

reaction mixture was stirred at 110 Ñ for 9 h, phosphate buffer (pH 7) was added to

quench the reaction. The mixture was extracted with ether three times. The combined

organic extracts were washed with water three times and brine, and dried over MgSO4.


preparative thin layer chromatography on silica gel (hexane"AcOEt 4:1) to give 16 (14.2

g, 57%) as a colorless liquid.

1H NMR (400 MHz, CDCl3) ! 1.43 (6H, s), 2.60 (2H, s), 7.36--7.71 (4H, m). IR (neat)

42

2958, 1709, 1604, 1471, 1323, 1290, 1246, 766 cm-1.

3-Fluoro-1,1-dimethyl-1H-indene (15)

F

To a solution of triphenylphosphine (124.1 mg, 0.473 mmol) and

tetrakis(triphenylphosphine)palladium (454.9 mg, 0.394 mmol) in

N,N-dimethylacetamide (20 mL) was added rifluoromethane-sulfonic acid

2-(3,3-difluoro-1,1-dimethylallyl)phenyl ester (14, 130.0 mg, 0.394 mmol). After the

reaction mixture was stirred at 110 Ñ for 9 h, thiophenol (0.16 mL, 1.58 mmol) was

added. Phosphate buffer (pH 7) was added and the mixture was extracted with ether

three times. The combined organic extracts were washed with water three times and

brine, and dried over MgSO4. After removal of the solvent under reduced pressure, the

residue was purified by preparative thin layer chromatography (pentane) to give 15

(64%, 19F NMR yield).

1H NMR (400 MHz, CDCl3) ! 1.35 (6H, s), 5.62 (1H, s), 7.24-7.34 (4H, m). 19F NMR (376

MHz, CDCl3) ! 24.0 (1F, s). IR (neat) 2956, 2924, 2854, 2360, 2332, 1458, 1375, 1219,

771 cm-1. HRMS: Calcd for C11H12F ([M + H]+) 163.0923, found 163.0924.

Î�Ð

1-Phenyl-3-trifluoromethylbut-3-en-1-one (58)

F3C

O

Ph

To a suspension of pyridinium chlorochromate (38.4 g, 178 mmol) and silica gel (38.4 g)

in dichloromethane (350 mL) was added 1-phenyl-3-trifluoromethylbut-3-en-1-ol (57,

13.9 g, 64.4 mmol). The reaction mixture was stirred for 2 h at room temperature and

43

then diluted with ether. The solid was removed by filtration through a short column of

florisil. After removal of the solvent under reduced pressure, the residure was purified

by column chromatography on silica gel (hexane"AcOEt 4:1) to give 58 (12.16 g, 88%) as

colorless crystals.

1H NMR (400 MHz, CDCl3) ! 3.85 (2H, s), 5.51 (1H, brs), 5.95 (1H, brs), 7.46-7.51 (2H,

m), 7.57-7.62 (1H, m), 7.94-7.98 (1H, m). 13C NMR (100 MHz, CDCl3) ! 38.7, 122.6 (q,

JCF = 6 Hz), 123.1 (q, JCF = 272 Hz), 128.3, 128.7, 131.8 (q, JCF = 31 Hz), 133.5, 135.9,

194.8. 19F NMR (376 MHz, CDCl3) ! 92.9 (3F, s). IR (neat) 3062, 1689, 1414, 1358, 1323,

1169, 1115, 1005, 949, 754, 688 cm-1. Anal. Calcd for C11H9F3O: C, 61.68; H, 4.24%.

Found: C, 61.75; H, 4.39%.

1-Phenyl-3-trifluoromethylbut-3-en-1-one oxime (59)

F3C

N

Ph

OH

To a solution of 1-phenyl-3-trifluoromethylbut-3-en-1-one (58, 120 mg, 0.56 mmol) in

ethanol (3 mL) was added hydroxylamine hydrochloride (81 mg, 1.17 mmol) and

pyridine (0.15 mL, 1.85 mmol). After the reaction mixture was stirred overnight at room

temperature, phosphate buffer (pH 7) was added to quench the reaction. The mixture

was extracted with AcOEt three times. The combined organic extracts were washed

with 1 M HCl and brine, and dried over Na2SO4. After removal of the solvent under

reduced pressure, the residue was purified by preparative thin layer chromatography

on silica gel (hexane"AcOEt 4:1) to give 59 (114 mg, 89%) as a colorless solid.


m), 7.57-7.62 (2H, m). 13C NMR (100 MHz, CDCl3) ! 26.3, 118.9 (q, JCF = 5 Hz), 123.3 (q,

JCF = 273 Hz), 125.9, 128.7, 129.8, 132.4 (q, JCF = 31 Hz), 134.4, 154.6. 19F NMR (376

MHz, CDCl3) ! 92.4 (3F, s). IR (neat) 3249, 3070, 2925, 1319, 1288, 1219, 1163, 1111,

968, 941, 773 cm-1. Anal. Calcd for C11H10F3NO: C, 57.64; H, 4.40; N, 6.11%. Found: C,

57.48; H, 4.54; N, 5.91%.

44

1-Phenyl-3-trifluoromethylbut-3-en-1-one oxime O-pentafluorobenzoate

(60)

F3C

N

Ph

OCOC6F5

To a solution of 1-phenyl-3-trifluoromethylbut-3-en-1-one oxime (59, 70.2 mg, 0.306

mmol) in dichloromethane (2 mL) was added triethylamine (0.085 mL, 0.61 mmol) and

pentafluorobenzoyl chloride (0.065 mL, 0.45 mmol) at 0 Ñ. The reaction mixture was

stirred for 20 min at 0 Ñ, and phosphate buffer (pH 7) was added to quench the

reaction. The layers were separated and the aqueous layer was extracted with

dichloromethane three times. The combined organic extracts were washed with brine

and dried over Na2SO4. After removal of the solvent under reduced pressure, the

residue was purified by preparative thin layer chromatography on silica gel

(hexane"AcOEt 4:1) to give 60 (113 mg, 88%) as a colorless solid.


m), 7.49-7.54 (1H, m), 7.77-7.80 (2H, m). 13C NMR (100 MHz, CDCl3) ! 28.7, 119.6 (q,

JCF = 5 Hz), 122.9 (q, JCF = 272 Hz), 127.2, 128.9, 131.6, 131.9 (q, JCF = 31 Hz), 132.4,

136.3-136.7 (m), 138.8-139.2 (m), 142.3-145.4 (m), 144.2-147.0 (m), 163.1. 19F NMR (376

MHz, CDCl3) ! 2.1-2.3 (2F, m), 14.9-15.0 (1F, m), 24.8-24.9 (2F, m), 92.2 (3F, s). IR

(neat) 1761, 1651, 1525, 1491, 1327, 1288, 1171, 1117, 1003, 895, 764 cm-1. HRMS:

Calcd for C18H10F8NO2 ([M + H]+) 424.0584, found 424.0584.

2-Methyl-1-phenyl-3-tr if luoromethylbut-3-en-1-one (63)

F3C

O

Ph

To a solution of 1-phenyl-3-trifluoromethylbut-3-en-1-one (58, 500 mg, 2.33 mmol) in

ether (20 mL) was added a solution of potassium hexamethyldisilazide in toluene (0.56

M, 4.1 mL, 2.3 mmol) dropwise and the reaction mixture was stirred for 40 min at

"78 Ñ. Methyl triflate (0.26 mL, 2.3 mmol) was added at that temperature, and then

the mixture was warmed to room temperature and stirred for 6 h. Phosphate buffer (pH

45

7) was added to quench the reaction. The layers were separated and the aqueous layer

was extracted with AcOEt three times. The combined organic extracts were washed

with brine and dried over Na2SO4. After removal of the solvent under reduced pressure,

the residue was purified by preparative thin layer chromatography on silica gel

(hexane"AcOEt 4:1) to give 63 (429 mg, 81%) as colorless oil.

1H NMR (400 MHz, CDCl3) ! 1.42 (3H, d, J = 6.8 Hz), 4.36 (1H, q, J = 6.8 Hz), 5.52 (1H,

brs), 5.87 (1H, brs), 7.45-7.49 (2H, m), 7.55-7.60 (1H, m), 7.94-7.98 (2H, m). 13C NMR

(100 MHz, CDCl3) ! 17.8, 40.2, 120.7 (q, JCF = 6 Hz), 123.5 (q, JCF = 272 Hz), 128.4, 128.7,

133.3, 135.5, 137.9 (q, JCF = 30 Hz), 198.5. 19F NMR (376 MHz, CDCl3) ! 94.0 (3F, s). IR

(neat) 2987, 2943, 1687, 1273, 1219, 1169, 1115, 962, 704, 687 cm-1. Anal. Calcd for

C12H11F3O: C, 63.16; H, 4.86%. Found: C, 63.13; H, 5.05%.

2-Methyl-1-phenyl-3-tr if luoromethylbut-3-en-1-one oxime (64)

F3C

N

Ph

OH

To a solution of 2-methyl-1-phenyl-3-trifluoromethylbut-3-en-1-one (63, 100.4 mg, 0.44

mmol) in ethanol was added hydroxylamine hydrochloride (62.5 mg, 0.90 mmol) and

pyridine (0.11 mL, 1.36 mmol). The reaction mixture was heated to reflux for 17 h, and

then phosphate buffer (pH 7) was added to quench the reaction. The mixture was

extracted with AcOEt three times. The combined organic extracts were washed with 1

M HCl and brine, and dried over Na2SO4. After removal of the solvent under reduced

pressure, the residue was purified by preparative thin layer chromatography on silica

gel (hexane"AcOEt 4:1) to give 64 (97 mg, 91%, mixture of two isomers (major : minor =

53 : 47)) as colorless oil.

. 1H NMR (400 MHz, CDCl3) major ! 1.41 (3H, d, J = 7.0 Hz), 3.67 (1H, q, J = 7.0 Hz),

5.47 (1H, brs), 5.82 (1H, brs), 7.28-7.41 (5H, m), 9.30 (1H, brs). minor ! 1.46 (3H, d, J =

7.2 Hz), 4.48 (1H, q, J = 7.2 Hz), 5.48 (1H, brs), 5.86 (1H, brs), 7.28-7.41 (5H, m), 9.68

(1H, brs). 13C NMR (100 MHz, CDCl3) major ! 18.3, 39.7, 120.4 (q, JCF = 6 Hz), 123.5 (q,

46

JCF = 273 Hz), 127.8, 128.1, 128.9, 132.4, 138.1 (q, JCF = 28 Hz), 158.5. minor 15.7, 32.8,

119.8 (q, JCF = 6 Hz), 123.5 (q, JCF = 273 Hz), 127.6, 128.1, 128.9, 134.6, 139.2 (q, JCF =

29 Hz), 159.0. 19F NMR (376 MHz, CDCl3) major ! 94.2 (3F, s). minor ! 94.9 (3F, s). IR

(neat) 3296, 2889, 1417, 1302, 1169, 1119, 949, 768, 694 cm-1. HRMS: Calcd for

C12H13NF3O ([M + H]+) 244.0949, found 244.0962.

2-Methyl-1-phenyl-3-tr if luoromethylbut-3-en-1-one oxime

O-pentafluorobenzoate (62)

F3C

N

Ph

OCOC6F5

Compound 62 was prepared by the method described for 1-phenyl-3-trifluoromethylbut-

3-en-1-one oxime O-pentafluorobenzoate (60) using 2-methyl-1-phenyl-3-trifluoro-meth-

ylbut-3-en-1-one oxime (64, 90 mg, 0.37 mmol), triethylamine (0.11 mL, 0.79 mmol) and

pentafluorobenzoyl chloride (0.08 mL, 0.45 mmol) in dichloromethane (4 mL) at 0 Ñ

for 45 min. Purification by preparative thin layer chromatography on silica gel

(hexane"AcOEt 4:1) gave 62 (81.3 mg, 50%) as a colorless solid.

1H NMR (400 MHz, CDCl3) ! 1.54 (3H, d, J = 7.0 Hz), 3.84 (1H, q, J = 7.0 Hz), 5.59 (1H,

brs), 5.92 (1H, brs), 7.19-7.21 (2H, m), 7.38-7.42 (3H, m). 19F NMR (376 MHz, CDCl3)

! 1.7-1.8 (2F, m), 13.9-14.0 (1F, m), 24.5-24.6 (2F, m), 94.1 (3F, s).

2,2-Dimethyl-1-phenyl-3-trifluoromethylbut-3-en-1-one (65)

F3C

O

Ph

To a solution of 2-methyl-1-phenyl-3-trifluoromethylbut-3-en-1-one (63, 205 mg, 0.90

mmol) in ether(10 mL) was added a solution of potassium hexamethyldisilazide in

toluene (0.56 M, 1.6 ml, 0.90 mmol) dropwise and the reaction mixture was stirred for 1

h at "78 Ñ. Methyl triflate (0.11 mL, 0.90 mmol) was added at that temperature, and

then the mixture was warmed to room temperature and stirred overnight. Phosphate

47

buffer (pH 7) was added to quench the reaction. The layers were separated and the

aqueous layer was extracted with AcOEt three times. The combined organic extracts

were washed with brine and dried over Na2SO4. After removal of the solvent under


on silica gel (hexane"AcOEt 5:1) to give 65 (110 mg, 51%) as colorless oil.


m), 7.46-7.50 (1H, m), 7.84-7.87 (2H, m). 13C NMR (100 MHz, CDCl3) ! 26.4, 49.8, 120.4

(q, JCF = 6 Hz), 123.6 (q, JCF = 276 Hz), 128.1, 129.2, 132.1, 135.6, 143.5 (q, JCF = 27 Hz),

200.8. 19F NMR (376 MHz, CDCl3) ! 100.3 (3F, s). IR (neat) 2987, 1684, 1323, 1246, 1178,

1119, 1092, 972, 719, 690 cm-1. Anal. Calcd for C13H13F3O: C, 64.46; H, 5.41%. Found: C,

64.25; H, 5.58%.

2,2-Dimethyl-1-phenyl-3-trifluoromethylbut-3-en-1-one oxime (66)

F3C

N

Ph

OH

To a solution of hydroxylamine hydrochloride (325 mg, 4.68 mmol) in pyridine (5 mL)

was added 2,2-dimethyl-1-phenyl-3-trifluoromethylbut-3-en-1-one (65, 110 mg, 0.454

mmol) and the reaction mixture was heated to reflux for 1 d. Phosphate buffer (pH 7)

was added to quench the reaction. The mixture was extracted with AcOEt three times.

The combined organic extracts were washed with 1 M HCl and brine, and dried over

Na2SO4. After removal of the solvent under reduced pressure, the residue was purified

by preparative thin layer chromatography on silica gel (hexane"AcOEt 4:1) to give 66

(68.5 mg, 59%) as a white solid.


m), 7.33-7.44 (3H, m), 8.39 (1H, s). 13C NMR (100 MHz, CDCl3) ! 26.2, 43.4, 120.9 (q, JCF

= 6 Hz), 123.9 (q, JCF = 276 Hz), 127.8, 127.9, 128.3, 132.3, 142.6 (q, JCF = 27 Hz), 162.6.

19F NMR (376 MHz, CDCl3) ! 101.3 (3F, s). IR (neat) 3257, 2983, 1323, 1176, 1149, 1117,

1097, 955, 766, 702 cm-1.

48

2,2-Dimethyl-1-phenyl-3-trifluoromethylbut-3-en-1-one oxime

O-pentafluorobenzoate (17)

F3C

N

Ph

OCOC6F5

Compound 17 was prepared by the method described for 1-phenyl-3-trifluoromethyl-

but-3-en-1-one oxime O-pentafluorobenzoate (60) using 2,2-dimethyl-1-phenyl-3-tri-

fluoromethylbut-3-en-1-one oxime (66, 82.7 mg, 0.32 mmol), triethylamine (0.09 mL,

0.65 mmol) and pentafluorobenzoyl chloride (0.07 mL, 0.48 mmol) in dichloromethane (5

mL) at 0 Ñ for 30 min. Purification by preparative thin layer chromatography on silica

gel (hexane"AcOEt 4:1) gave 17 (119.2 mg, 82%) as a colorless solid.


m), 7.37-7.38 (3H, m). 13C NMR (100 MHz, CDCl3) ! 26.0, 44.6, 122.1 (q, JCF = 6 Hz),

123.7 (q, JCF = 276 Hz), 126.7, 127.9, 129.0, 131.3, 136.0-136.4 (m), 138.5-138.9 (m),

141.4 (q, JCF = 27 Hz), 141.7-144.7 (m), 143.6-146.5 (m), 156.5, 173.4. 19F NMR (376

MHz, CDCl3) ! 1.4-1.6 (2F, m), 13.5-13.6 (1F, m), 24.4-24.5 (2F, m), 101.2 (3F, s). IR

(neat) 2991, 1763, 1653, 1522, 1498, 1325, 1184, 1124, 1090, 995, 926, 879, 700 cm-1.

Anal. Calcd for C20H13F8NO2: C, 53.23; H, 2.90; N, 3.10%. Found: C, 53.05; H, 3.00; N,

2.86%.

General procedure for 5-endo-trig cyclization of oxime derivatives using

palladium catalyst: To a solution of triphenylphosphine (145 mg, 0.553 mmol) and

tetrakis(tri-

phenylphosphine)palladium (63.6 mg, 0.055 mmol) in N,N-dimethylacetamide (20 mL)

was added 2,2-dimethyl-1-phenyl-3-trifluoromethylbut-3-en-1-one oxime O-pentafluoro-

benzoate (17, 247 mg, 0.547 mmol). After the reaction mixture was stirred at 100 Ñ for

9 h, phosphate buffer (pH 7) was added to quench the reaction. The mixture was

extracted with ether three times. The combined organic extracts were washed with

49

water three times and brine, and dried over MgSO4. After removal of the solvent under


on silica gel (hexane"AcOEt 4:1).

3-Difluoromethylene-4,4-dimethyl-5-phenyl-3,4-dihydro-2H-pyrrole (18)

N

F2CPh

1H NMR (400 MHz, CDCl3) ! 1.52 (6H, s), 4.61 (2H, dd, JHF = 3.6R3.6 Hz), 7.37-7.42 (3H,

m), 7.69-7.73 (2H, m). 13C NMR (100 MHz, CDCl3) ! 24.6 (dd, JCF = 3, 2 Hz), 51.6 (dd, JCF

= 4, 3 Hz), 57.8 (dd, JCF = 3, 2 Hz), 97.5 (dd, JCF = 21, 15 Hz), 127.9, 128.2, 129.7, 133.7

(dd, JCF = 2, 2 Hz), 149.3 (dd, JCF = 287, 282 Hz), 178.5. 19F NMR (376 MHz, CDCl3)

! 68.5 (1F, dt, JFF = 64 Hz, JFH = 3.6 Hz), 76.3 (1F, dt, JFF = 64 Hz, JFH = 3.6 Hz). IR

(neat) 2978, 1765, 1466, 1267, 1223, 1132, 1047, 1014, 775, 694, 598 cm-1. HRMS: Calcd

for C13H14NF2 ([M + H]+) 222.1094, found 222.1091.

2,2-Dimethyl-1-phenyl-3-trifluoromethylbut-3-enylideneamine (68)

F3C

NH

Ph


m), 9.56 (1H, br). 19F NMR (376 MHz, CDCl3) ! 101.1 (3F, s). IR (neat) 2983, 1616, 1323,

1178, 1124, 1093, 957, 895, 758, 702 cm-1. HRMS: Calcd for C13H15NF3 ([M + H]+)

242.1156, found 242.1141.

2,2-Dimethyl-1-phenyl-3-trifluoromethyl-but-3-en-1-one oxime O-benzoate

(69)

F3C

N

Ph

OCOPh



fluoromethylbut-3-en-1-one oxime (66, 148 mg, 0.575 mmol), triethylamine (0.24 mL,

50

1.7 mmol) and benzoyl chloride (0.134 mL, 1.15 mmol) in dichloromethane (5 mL) at

0 Ñ for 10 h. Purification by preparative thin layer chromatography on silica gel

(hexane"AcOEt 3:1) gave 69 as a colorless solid.


m), 7.25-7.29 (1H, m), 7.38-7.59 (6H, m), 8.11-8.18 (2H, m). 19F NMR (376 MHz, CDCl3)

! 101.1 (3F, s).

2,2-Dimethyl-1-phenyl-3-trifluoromethyl-but-3-en-1-one oxime

O-diphenylphosphinate (70)

F3C

N

Ph

OPPh2

O




1.8 mmol) and diphenylphosphinic chloride (0.23 mL, 1.2 mmol) in dichloromethane (5

mL) at 0 Ñ for 10 h. Purification by column chromatography on silica gel

(hexane"AcOEt 1:1) gave 70 (266 mg, 99%) as a colorless solid.


m), 7.31-7.41 (7H, m), 7.45-7.48 (2H, m), 7.58-7.62 (4H, m). 19F NMR (376 MHz, CDCl3)

! 100.9 (3F, s).

2,2-Dimethyl-1-phenyl-3-trifluoromethyl-but-3-en-1-one oxime

O-methanesulfonate (71)

F3C

N

Ph

OSO2Me



51


1.8 mmol) and methanesulfonic chloride (0.092 mL, 1.2 mmol) in dichloromethane (5

mL) at 0 Ñ for 10 h. Purification by preparative thin layer chromatography on silica

gel (hexane"AcOEt 4:1) gave 71 (202 mg, 99%) as colorless oil.

1H NMR (400 MHz, CDCl3) ! 1.47 (6H, s), 3.11 (3H, s), 5.30 (1H, brs), 5.94 (1H, brs),

7.04-7.07 (2H, m), 7.37-7.43 (3H, m). 19F NMR (376 MHz, CDCl3) ! 101.5 (3F, s).

2,2-Dimethyl-1-phenyl-3-trifluoromethyl-but-3-en-1-one oxime O-acetate

(72)

F3C

N

Ph

OCOMe



fluoromethylbut-3-en-1-one oxime (66, 154 mg, 0.597 mmol), triethylamine (1 mL, 7.2

mmol), and acetic anhydride (0.11 mL, 1.2 mmol) in dichloromethane (4 mL) at 0 Ñ for

15 h. Purification by preparative thin layer chromatography on silica gel

(hexane"AcOEt 4:1) gave 72 (161 mg, 90%) as a colorless solid.

1H NMR (400 MHz, CDCl3) ! 1.52 (6H, s), 1.96 (3H, s), 5.22 (1H, brs), 5.90 (1H, brs),

6.99-7.04 (2H, m), 7.34-7.40 (3H, m). 19F NMR (376 MHz, CDCl3) ! 101.2 (3F, s).

3-Methyl-1-phenylbut-3-en-1-ol (81)

OH

Ph

To a suspension of magnesium turnings (4.86 g, 0.2 mol) in THF (40 mL) was added a

small amount of iodine. To this was added dropwise 3-chloro-2 methylpropene (4 mL,

0.04 mol) over 30 min and the mixture was stirred at room temperature for 1 h. This

solution of Grignard reagent was added dropwise to a solution of benzaldehyde (3.1 mL,

0.03 mol) in THF (30 mL) at 0 Ñ . The reaction mixture was stirred at room

52

temperature overnight and then poured into saturated aqueous ammonium chloride.

The mixture was extracted with AcOEt three times. The combined organic extracts

were washed with brine and dried over Na2SO4. After removal of the solvent under

reduced pressure, the residue was purified by column chromatography on silica gel

(hexane"AcOEt 10:1) to give 81 (4.64 g, 71%) as a colorless liquid.

1H NMR (400 MHz, CDCl3) ! 1.80 (3H, s), 2.13 (1H, br), 2.43 (2H, d, J = 7.0 Hz), 4.82 (1H,

td, J = 7.0, 2.4 Hz), 4.86 (1H, brs), 4.93 (1H, brs), 7.25-7.29 (2H, m), 7.33-7.39 (3H, m).

3-Methyl-1-phenylbut-3-en-1-one (82)

O

Ph


but-3-en-1-one (58) using 3-methyl-1-phenylbut-3-en-1-ol (81, 4.37 g, 26.9 mmol) and

pyridinium chlorochromate (17.4 g, 80.7 mmol) in dichloromethane (180 mL) at room

temperature for 2 h. Purification by column chromatography on silica gel gave 82 (4.16

g, 97%) as a light yellow liquid.

1H NMR (400 MHz, CDCl3) ! 1.82 (3H, s), 3.69 (2H, s), 4.85 (1H, s), 4.98 (1H, s),

7.44-7.48 (2H, m), 7.54-7.58 (1H, m), 7.97-7.99 (2H, m).

2,3-Dimethyl-1-phenylbut-3-en-1-one (83)

O

Ph

Compound 83 was prepared by the method described for 2-methyl-1-phenyl-3-tri-

fluoromethylbut3-en-1-one (63) using 3-methyl-1-phenylbut-3-en-1-one (82, 1.04 g, 6.47

mmol), potassium hexamethyldisilazide (0.5 M solution in toluene, 13 mL, 6.5 mmol)

and methyl triflate (1.46 mL, 12.9 mmol) in ether (15 mL) at "78 Ñ to room

temperature overnight. Purification by column chromatography on silica gel gave 83

(1.13 g, #quant.) as a yellow liquid.

1H NMR (400 MHz, CDCl3) ! 1.34 (3H, d, J = 7.2 Hz), 1.74 (3H, s), 4.12 (1H, q, J = 7.2

53

Hz), 4.88 (1H, s), 4.90 (1H, s), 7.41-7.46 (2H, m), 7.51-7.55 (1H, m), 7.96-7.99 (2H, m).

2,2,3-Trimethyl-1-phenylbut-3-en-1-one (84)

O

Ph

Compound 84 was prepared by the method described for 2,2-dimethyl-1-phenyl-3-tri-

fluoromethylbut-3-en-1-one (65) using 2,3-dimethyl-1-phenylbut-3-en-1-one (83, 1.13 g,

6.5 mmol), potassium hexamethyldisilazide (0.5 M solution in toluene, 13 mL, 6.5 mmol)

and methyl triflate (1.46 mL, 12.9 mmol) in ether (15 mL) at "78 Ñ to room

temperature overnight. Purification by column chromatography on silica gel gave 84

(1.07 g, 88%) as yellow oil.


7.34-7.38 (2H, m), 7.43-7.49 (1H, m), 7.94-7.99 (2H, m).

2,2,3-Trimethyl-1-phenylbut-3-en-1-one oxime (85)

N

Ph

OH

Compound 85 was prepared by the method described for 2,2-dimethyl-1-phenyl-3-tri-

fluoromethylbut-3-en-1-one oxime (66, 0.99 g, 5.26 mmol) and hydroxylamine

hydrochloride (3.66 g, 52.6 mmol) in pyridine (25 mL) refluxed for 2 d. Purification by

column chromatography on silica gel (hexane"AcOEt 8:1) gave 85 (0.90 g, 84%) as a

colorless solid.


7.08-7.11 (2H, m), 7.25-7.34 (3H, m), 8.41 (1H, br).

2,2,3-Trimethyl-1-phenylbut-3-en-1-one oxime O-pentafluorobenzoate (86)

54

N

Ph

OCOC6F5


but-3-en-1-one oxime O-pentafluorobenzoate (60) using 2,2,3-Trimethyl-1-phenylbut-3-

en-1-one oxime (85, 0.78 g, 3.84 mmol), triethylamine (1.1 mL, 7.9 mmol) and

pentafluorobenzoyl chloride (0.83 mL, 5.76 mmol) in dichloromethane at 0 Ñ for 30

min. Purification by column chromatography on silica gel (hexane"AcOEt 20:1) gave 86

(523 mg, 34%) as colorless oil.


7.02-7.05 (2H, m), 7.29-7.35 (3H, m). 19F NMR (376 MHz, CDCl3) ! 1.3-1.5 (2F, m),

13.2-13.4 (1F, m), 24.1-24.3 (2F, m).

55

!"

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F

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F F

H2O

O

Pd(PPh3)4 (1.0 eq)PPh3 (1.2 eq)

110 °C, 10 h / DMA

14 15 64% (NMR yield) 16 57% (from 14)

Pd(0)! FPdOTf

5-endo-trig

(43)

# K¤MH'(:;tNu=:vw+,-./(P)345�N7;QR¥�;¦§;012

? 5-endo-trig@03ABCDEFJ

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56

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17F3C Ph

NPd

OCOC6F5 N

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18 60%

5-endo-trig


100 °C, 1 h / DMA(44)

# ÃÄ? 5-endo-trig@0'789xnFbB:;<=��x)o5Qt·/ 78(86 H'

®¯ybÅÆFVZ4T(�N7;QR¥�;²`$@03iBCÇÈbÉÊxËFyC

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78 (R = H)

86 (R = Me)not detected

(45)

# fÎz{'(gem--7;QR¦§;012Ï�N7;QR¥�;¦§;0123iBC(

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57

!"#$

1) %&'()*+,)-./0)12345678)9:;<=>?@A2AB (1993)C

DEF)12345GH8)67IJKL; (2003).

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1992, 54.

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Trainor, and J. D. Rodgers, Bioorg. Med. Chem. Lett., 10, 1729 (2000).

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Chem. Lett., 33, 1206 (2004); Y. Wada, T. Mori, and J. Ichikawa, Chem. Lett., 32,

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Planchenault, Synlett, 1995, 1191; B. H. Lipshutz and T. Gross, J. Org. Chem., 60,

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Ikeda, J. Chem. Soc., Perkin Trans. 1, 1995, 1115; A. V. R. Rao, A. K. Singh, K. M.

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Clayden, D. W. Watson, M. Helliwell, and M. Chambers, Chem. Commun., 2003,

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59

21) D. W. Boykin, R. L. Hertzler, J. K. Delphon, and E. J. Eisenbraun, J. Org. Chem., 54,

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27) bNc)\RS#)TUV7W2004X.

28) de,)f-gh)*ijk)Kl67mn)1985)2131; T. Yamazaki and N. Ishikawa,

Chem. Lett., 1984, 521.

60

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(2)

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(3)

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60

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0

trace

(4)

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(5)

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(6)

5-endo-trig@0ab · ›

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