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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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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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CF2
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!
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Y
X
Y
X
!
! = 109°
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X
Y!
! = 109°
YX
5-exo-trig"#$ (favored)
# 5-endo-trig �*FÖfc4Q?P¬SB|?1.ø^®�B�Q?�*�B£�10)�.
5
�<¤`�*�B¥�11)7ÂQ4-2¦6G<0��F>¤~4Q?R
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
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HY
SO2Ph
R1
R2
Y
SO2Ph
R2R
1
KH (0.05 eq)
25 °C, 10 min/ THF
Y = O, NPh, C(CO2Et)2(10)
# E0³�7dP4©>øp6 5-endo-trig �*ªF.V89WL- gem-<%`abk`
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6
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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
# E~}0%&'[\k`l�0 5-endo-trig�*L-.øp�1c4ÅÝÆÇâa�B'
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7
F
FMeO
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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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(14)
8A
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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
E0P¬7.½Lq3] gem-<%`abk`l�0Jd7³?"[#$iÏå0æçB
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C6F5CO2
CF2
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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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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
# ¤}7îï-.k`Å_.�kÝÞÄ�<��(ß)7³? 5-endo-trig �*B.N]7�
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Ph
OCOC6F5N
PhF2C
Pd(PPh3)4 (0.1 eq)PPh3 (1.0 eq)
110 °C, 1 h / DMA
18 60%
(18)
17
# ¼Ô.þ"7½Q4 2ÿ7[]¢´0!"Bq3?R
10
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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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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
$ GHIJAKfA7Fgem-%&'()0'MNijWkf9Ç,012' 30 A/
5-endo-trig :,/���gw�cd9efg\hFÇ,012' 30 7ÈÉÊ~9dKË
Ì'Ê/ 0r34%56stWuvw]D�F^/Í-Kλ/ 5-endo-trig:,K�[b
g°}D�Ï;�15)e
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°}DиObcFgem-%&'()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^�¬/^O°¬FÇ,012' 30 / gem-%&'()0
'MNijKFnN%'×O&Ø+'×�ÙÚbcät»7ÑÒ¥g}cd9D£F01
2'34%56(T)�UVb7¥¥Fåæ/:,��[bg°}DO��¬�9e®^AÅ
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wWè¤w]9^O78_Fλ/ 5-endo-trig:,��[f9^OWéêbDe
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,f9^O78_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°bFλ/ 5-endo-trig:,t 40 K�¬�ýFþÿ� 50%!"w�De
^/�#°¬Fgem-%&'()0'MNij/ÑÒwWè¤w]D³$AKF5-endo-trig
:,W`af9/7%XAKgd^O�\°}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
(vf9^OW��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�9OdEÃĪ�~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
$ ®^AF:,��[bg°}DÇ,012' 38 /nN%'j7ôÖ'×W+,:;bF
gem-%0'P''#78_ü6:7aUVW/�f9^OW��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',bcλ/
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^TFλ/ 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
-7λ/ 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
`Obcõ1&Ø+'öî&÷NWvdccD� 23)F¹º�'U8¥�[bcdgd^O
���¬�9e®^AF¹º`W��f9^O78_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�Fλ/:,t 16 KhOij�¬�g°}D�DNõ12��e&7F¹ºf
�~_FkjYO�g9"ð,��/lmnÔAUVW[}D�DNõ12â�eb°bF
^/Í-KMNoIA^Q/p�qp7ç,bF34%56st�rsbcd9^O�t
uw�DeDFxI7v,.p(N¡lNm&'()wxyð1Ö56Wz{w]F3
4%56st/�0+(NWç�c¹ºw�|w/ç,WéêbD�FO�7'#�g°
}D�DNõ12ãFü�eí]/��AKF_M`Obcõ1&Ø+'öî&÷NWvd
DOc8_�:,t 16 /"UW\]w]9^OKAcýF'U/8dÈÉxW}~f^O
KAcg°}De
$ ±dcF34%56st/�vÊW�¡f^O78_F:,t/"U/\]W��bD
�Ïã�e®/�#Fûõ4Pîõ1&Ø+'öî&÷N34%56(0)WËÌ'ÊFõ1&
Ø+'öî&÷NW 1.2JÌ'Êvd9^OAFλ/:,t 16 /"UW 57%7\]w]
9^O�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��f9λAF0 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_FλObcdDUVFfg\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�|f9^O�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�9^Og¥�¬�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]9^O78_F
&'()pNQN 15 ��¬�9^OW}~bDe^�78_FIÝ7z�9012'34
%56(T)46 / 5-endo-trig:,��[f9^OW�¬°7f9^O�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
C6F5COCl (1.5 eq)Et3N (2 eq)
0 °C, 30 min/ CH2Cl2
C6F5COCl (1.5 eq)Et3N (2 eq)
0 °C, 30 min/ CH2Cl2
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&'()$%&ø-'©¥©ÐC 76 �Y¶1
2«V²³mI·1no��"ò;%P��pz{ú$Ц%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$%&'()*+'.�}�X��¡{�2y�opy�u«z
hf
N
Ph
OCOC6F5
H
N
PhH
O
PhH
Pd(PPh3)4 (0.1eq)PPh3 (1.0 eq)
140 °C, 1 h / DMF
78 79 0% 80 33%
(40)
Ph
O
H
MgCl
N
Ph
OH
O
Ph
OH
Ph
N
Ph
OCOC6F5
O
Ph
O
Ph
(1.2 eq)
0 °C to rt, overnight/ THF
PCC-Silica gel(3.0 eq)
rt, 2 h / CH2Cl2
KN(SiMe3)2 (1.0 eq)MeOTf (2.0 eq)
NH2OH·HCl (10 eq)
reflux, 2 d / pyridine
C6F5COCl (1.5 eq)Et3N (2 eq)
0 °C, 30 min/ CH2Cl2
!78 °C to rt,
overnight / Et2O
KN(SiMe3)2 (1.0 eq)MeOTf (2.0 eq)
!78 °C to rt,
overnight / Et2O
81 71% 82 97%
83 ~quant. 84 88%
85 84% 86 34%
Scheme 12
Ph
NOCOC6F5
N
Ph
N
Ph
Pd(PPh3)4 (0.1eq)PPh3 (1.0 eq)
100 °C, 2 h / DMA
86 87 88
not detected
(41)
35
? å�VÔÕU$%&'()*+',-'./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
Pd(PPh3)4 (0.1eq)PPh3 (1.0 eq)
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.
After removal of the solvent under reduced pressure, the residue was purified by
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.
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 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.
1H NMR (400 MHz, CDCl3) ! 3.72 (2H, s), 5.26 (1H, brs), 5.71 (1H, brs), 7.37-7.41 (3H,
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.
1H NMR (400 MHz, CDCl3) ! 3.80 (2H, s), 5.30 (1H, brs), 5.78 (1H, brs), 7.43-7.48 (2H,
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
reduced pressure, the residue was purified by preparative thin layer chromatography
on silica gel (hexane"AcOEt 5:1) to give 65 (110 mg, 51%) as colorless oil.
1H NMR (400 MHz, CDCl3) ! 1.53 (6H, s), 5.60 (1H, brs), 5.93 (1H, brs), 7.35-7.40 (2H,
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.
1H NMR (400 MHz, CDCl3) ! 1.38 (6H, s), 5.44 (1H, brs), 5.83 (1H, brs), 7.09-7.11 (2H,
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.
1H NMR (400 MHz, CDCl3) ! 1.53 (6H, s), 5.56 (1H, brs), 5.93 (1H, brs), 7.05-7.07 (2H,
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
reduced pressure, the residue was purified by preparative thin layer chromatography
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
1H NMR (400 MHz, CDCl3) ! 1.36 (6H, s), 5.22 (1H, brs), 5.84 (1H, brs), 7.18-7.28 (5H,
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
Compound 69 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, 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.
1H NMR (400 MHz, CDCl3) ! 1.57 (6H, s), 5.58 (1H, brs), 5.94 (1H, brs), 7.10-7.13 (2H,
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
Compound 70 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, 151 mg, 0.587 mmol), triethylamine (0.25 mL,
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.
1H NMR (400 MHz, CDCl3) ! 1.34 (6H, s), 5.34 (1H, brs), 5.77 (1H, brs), 7.09-7.11 (2H,
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
Compound 71 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-
51
fluoromethylbut-3-en-1-one oxime (66, 153 mg, 0.594 mmol), triethylamine (0.25 mL,
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
Compound 72 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, 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
Compound 82 was prepared by the method described for 1-phenyl-3-trifluoromethyl-
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.
1H NMR (400 MHz, CDCl3) ! 1.40 (6H, s), 1.75 (3H, s), 5.02 (1H, s), 5.11 (1H, s),
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.
1H NMR (400 MHz, CDCl3) ! 1.26 (6H, s), 1.89 (3H, s), 4.76 (1H, s), 4.90 (1H, s),
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
Compound 86 was prepared by the method described for 1-phenyl-3-trifluoromethyl-
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.
1H NMR (400 MHz, CDCl3) ! 1.37 (6H, s), 1.93 (3H, s), 4.83 (1H, s), 5.01 (1H, s),
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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)*+,-./012345 5-endo-trig@0'(V\cH_debG?fdgh\Cih
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PdOTfCF2
F
PdOTf
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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F3C Ph
NOCOC6F5
17F3C Ph
NPd
OCOC6F5 N
F2C Ph
18 60%
5-endo-trig
Pd(PPh3)4 (0.1eq)PPh3 (1.0 eq)
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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OCOC6F5 N
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Pd(PPh3)4 (0.1 eq)PPh3 (1.0 eq)
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78 (R = H)
86 (R = Me)not detected
(45)
# fÎz{'(gem--7;QR¦§;012Ï�N7;QR¥�;¦§;0123iBC(
V\cH]^_?ÐÑCabÅÆF)*+,-./012345 5-endo-trig@0xÒ�o
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57
!"#$
1) %&'()*+,)-./0)12345678)9:;<=>?@A2AB (1993)C
DEF)12345GH8)67IJKL; (2003).
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28) de,)f-gh)*ijk)Kl67mn)1985)2131; T. Yamazaki and N. Ishikawa,
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60
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(2)
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100 °C, 1 h / CH3CON(CH3)2
Pd(0) FPdOZ6 7
Z 7 / %
60
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<11
0
trace
(4)
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(6)
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