Reactions of novel trifluoromethyl propargylic carbocation with carbon nucleophiles

Article abstract of DOI:10.1016/j.tetlet.2006.10.088

Trifluoromethyl propargylic carbocation [I] generated from the reaction of 1-amino substituted 3-trifluoromethyl-2-propynyl trimethylsilyl ether 1 with TMSOTf in CH₂Cl₂ at -15 °C, followed by warming to room temperature reacted with

Full text of DOI:10.1016/j.tetlet.2006.10.088

Tetrahedron Letters 47 (2006) 9107–9111
Reactions of novel trifluoromethyl propargylic carbocation
with carbon nucleophiles
Sung Lan Jeon,a Joa Kyum Kim,a Jang Bae Son,a Bum Tae Kimb and In Howa Jeonga,*
aDepartment of Chemistry, Yonsei University, Wonju, Republic of Korea
bKorea Research Institute of Chemical Technology, Daejeon, Republic of Korea
Received 4 September 2006; revised 21 September 2006; accepted 13 October 2006
Abstract—Trifluoromethyl propargylic carbocation [I] generated from the reaction of 1-amino substituted 3-trifluoromethyl-2-prop-
ynyl trimethylsilyl ether 1 with TMSOTf in CH2Cl2 at ꢀ15 °C, followed by warming to room temperature reacted with 1.2 equiv of
substituted benzenes, RMgBr and allylsilane to give the enones 3a–l and 5, respectively. The reaction of [I] with anisole, followed by
treatment with Grignard reagents afforded the corresponding allyl amine derivatives 7, which underwent cyclization reaction to give
indene derivatives 8 by using 2 equiv of TMSOTf.
Ó 2006 Elsevier Ltd. All rights reserved.
The use of trifluoromethylated building block is essen-
tial for the synthesis of trifluoromethyl substituted
molecules, which are very useful in the areas of pharma-
ceuticals, agrochemicals and material science.1–3 Among
such building blocks, trifluoromethyl propargylic moie-
ties have been receiving increasing attention because of
the transformations of triple bond functionality. For
examples, trifluoromethyl propargylic alcohols4–6 were
utilized to give the corresponding allylic alcohols with
high stereoselectivity via Red-Al or Lindlar catalyst
reduction, in which allylic alcohols were transformed
to provide chiral 2,6-dideoxy-6,6,6-trifluorosugars.7,8
Trifluoromethyl propargylic alcohols were also reacted
with ethyl orthoacetate under acidic condition to afford
trifluoromethylated allene derivatives via Claisen rear-
rangement.9 Trifluoromethylated allene derivatives were
also obtained from the palladium-catalyzed coupling
reaction of trifluoromethylated propargyl mesylates
with organozinc reagents in the presence of a catalytic
amount of Pd(PPh3)4.10 In contrast to these synthetic
utilities of trifluoromethylated propargylic building
blocks, there has been a quite limited study of the reac-
tion of trifluoromethyl propargylic carbocation with
nucleophiles. The main reason for the limited study
seems likely due to the unstability of trifluoromethyl
propargylic carbocation species. However, Konno
et al. reported recently that trifluoromethylated propar-
gyl acetate was readily reacted with dicobaltocta-
carbonyl to form the corresponding cobalt complex, in
which dicobaltoctacarbonyl group effectively stabilizes
trifluoromethyl propargylic carbocation.11 In recent
years, we have prepared 1,1,1-trifluoro-4-(N-methoxy-
N-methyl)amino-1-trimethylsiloxy-1-phenyl-2-butyne (1)
as a source of (trifluoromethyl)ethynylation reagent,12
in which the (N-methoxy-N-methyl)amino group could
compensate the destabilizing effect of trifluoromethyl
group and thus enhance the stability of the trifluoro-
methyl propargylic carbocation. We report in this letter
the formation and reactions of the relatively stable tri-
fluoromethyl propargylic carbocation generated from
the reaction of 1 with trimethylsilyl trifluoromethane-
sulfonate (TMSOTf).
Our initial studies began with the reaction of 1 with
TMSOTf to figure out whether trifluoromethyl propar-
gylic carbocation will be formed or not. Treatment of
1 with TMSOTf (1 equiv) in THF at ꢀ78 °C, followed
by warming to room temperature and then quenching
with H2O resulted in the formation of trifluoromethyl-
ated enaminone 2 as a mixture of E- and Z-isomers
(E/Z = 87/13) in 82% yield. A similar result was
obtained even at higher temperature (ꢀ15 °C to rt).
The use of CH2Cl2 as a solvent in this reaction was
Keywords: 3-Trifluoromethyl-2-propynyl trimethylsilyl ether; Trifluoro-
methyl propargylic carbocation; Carbon nucleophiles; Trifluoromethyl-
ated enones; Trifluoromethylated indenes.
*
Corresponding author. Tel.: +82 33 760 2240; fax: +82 33 763
4323; e-mail: jeongih@yonsei.ac.kr
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.10.088

9108
S. L. Jeon et al. / Tetrahedron Letters 47 (2006) 9107–9111
advantageous. From a mechanistic point of view, we
propose that trifluoromethyl propargylic carbocation or
its equivalent [I] was formed and then reacted with
H2O to give allenol [II], which tautomerized to 2.
Addition of H2O towards [I] regiospecifically occurred
at carbon bearing trifluoromethyl group. A plausible
mechanism is shown in Scheme 1.
The reaction mechanism could involve the formation of
immonium ion intermediate [III] via Friedel–Crafts
reaction of [I] with anisole, followed by reaction with tri-
fluoromethanesulfonic acid formed in the reaction pro-
cess, in which same regiospecificity was also controlled
as shown in Scheme 1. Intermediate [III] was further
reacted with H2O to give 3a. Addition of H2O towards
intermediate [III] led exclusively to allylic hemiaminal
intermediate [IV] with perfect regioselectivity, which
underwent deamination to afford enone 3a. A plausible
mechanism for the formation of 3a is shown in Scheme
2.
To trap the intermediate [I], we examined reactions of [I]
with carbon nucleophiles under the optimized reaction
condition. When 1 was reacted with TMSOTf in
13
CH2Cl2 at ꢀ15 °C, followed by warming to room
temperature and then treated with benzene derivatives
having activating groups such as anisole, thioanisole
and N,N-diethylaniline at room temperature for several
hours, b-trifluoromethylated b-aryl substituted enones
3a–c were obtained as a mixture of E- and Z-isomers
in 61–96% yields. The ortho substituted enone 4a was
obtained in 25% yield in the case of the treatment with
N,N-diethylaniline. Phenol was also reacted with [I] at
0 °C for 1 h to give the corresponding enone 3d in
93% yield. In contrast, the reaction of [I] with thio-
phenol or aniline under the same reaction condition
afforded b-trifluoromethyl-b-phenylthio or b-trifluoro-
methyl-b-phenylamino substituted enones 4b, 4c in
93% and 14% yields, respectively. However, the reac-
tions of [I] with toluene, benzene, chlorobenzene and
trifluoromethylbenzene did not provide the desired
products 3g–j under the same reaction condition,
whereas enaminone 2 was obtained as a sole product
for every case. This result indicates that intermediate
[I] is a quite stable species which does not react with benz-
ene derivatives having deactivating group in the reac-
tion solution. The preparation of 3 was summarized in
Table 1.
A similar reaction was extended to allyl trimethylsilane
as a silicon-containing p-nucleophile, in which the nucleo-
phile reacted with [I] in an SE20 fashion to give the
corresponding enone 5 in 97% yield. The use of strong
nucleophiles, for examples, Grignard reagents such as
PhMgBr, MeMgBr and CH3C„CMgBr under the
milder reaction condition facilitated the formation of
enones 3. Therefore, treatment of [I] with PhMgBr
derivatives at ꢀ78 °C for 1 h provided the correspond-
ing enones 3g–j in 79–85% yields along with regioiso-
mers 6g–j (less than 6% yield). This reaction could
provide a potential method for the preparation of
enones, which cannot be prepared via Friedel–Crafts
reaction of [I] with benzene derivatives. However, the
treatment of [I] with MeMgBr under the same reaction
condition resulted in the formation of 3k and 6k in
13% and 76% yields, respectively, in which a steric factor
seems to play an important role to lead to the formation
6k instead of the formation of 3k. Treatment of [I]
with CH3C„CMgBr under the same reaction condition
resulted in the formation of 3l and 6l in 58% and 15%
yields, respectively. These trifluoromethylated enones
3, which methods are limited in the previous litera-
tures,14–17 are valuable intermediates in synthetic organic
chemistry and thus were utilized in recent years to
prepare trifluoromethylated indenes16 and allylic
alcohols.18
O
O
CF3
CF3
NEt2
X
Ph
Ph
H
H
4a
4b (X = S), 4c (X = NH)
OCH3
+
_
OTf
CF3-C C-C
Ph
N
CH3
+
TMS
TMS
O
OTMS
OCH3
CH3
_
_
OCH3
OCH3
_
+
TMSOTf (1 equiv)
OTf
OTf
CF3-C C-C
N
OTf
CF3-C C-C
Ph
N
CF3-C C-C
Ph
N
_
THF, -78 oC
rt
(TMS)2O
CH3
CH3
Ph
1
OCH3
+
CF3-C=C=C
N
CH3
Ph
[ I ]
OCH3
OCH3
N-CH3
H2O
CF3-C C-C
N
HO
CH3
O
OCH3
+
CH3
_
H2O
OTf
N
C=C=C
[ II ]
_
TfOH
F3C
Ph
F3C
Ph
H
Ph
2
Scheme 1.

S. L. Jeon et al. / Tetrahedron Letters 47 (2006) 9107–9111
Table 1. Preparation of b-trifluoromethylated b-aryl substituted enones 3
9109
X
OTMS
OCH3
O
(1.2 equiv)
T (oC), t (h)
X
H2O
TMSOTf (1 equiv)
CH2Cl2, -15 oC rt
CF3-C C-C
N
Ph
CH3
F3C
Ph
H
1
3
Compound no.
T (°C)
t (h)
X
Yielda (%)
E/Zb
3a
3b
3c
3d
3e
3f
rt
rt
rt
0
0
0
rt
rt
rt
rt
3
5
15
1
1
1
15
15
15
15
CH3O
CH3S
Et2N
HO
96
95
61c
93
67/33
40/60
75/25
65/35
—
—
—
—
—
d
HS
—
d
H2N
CH3
H
Cl
CF3
—
e
3g
3h
3i
—
e
—
e
—
e
3j
—
—
a Isolated yield.
b E/Z Ratio was determined by 19F NMR spectroscopy.
c o-Et2N–Ph substituted enone 4a was obtained in 25% yield.
d b-Phenylthio and b-phenylamino substituted enones 4b,c were obtained in 93% and 14% yields, respectively.
e Enone 2 was obtained in 75–78% yield.
H3CO
H3CO
OCH3
OCH3
+
CH3
OCH3
N-CH3
_
H3CO
OCH3
N-CH3
TfOH
[ I ]
CF3-C C-C
Ph
N
OTf
_
TfOH
C=C=C
C=C=C
F3C
TfO-H
Ph
F3C
Ph
OCH3
H3CO
H3CO
OCH3
N-CH3
OCH3
N-CH3
OH
_
H2O
+
O
OTf
_
_
TfOH
HN-CH3
OCH3
C=C-C
C=C-C
H
Ph
F3C
F3C
H
Ph
F3C
Ph
H
[III]
[IV]
3a
Scheme 2.
CH2=CH-CH2
F3C
O
OTMS
OCH3
H2C=CHCH2Si(CH3)3
rt, 3 h
H2O
TMSOTf (1 equiv)
CF3-C C-C
Ph
N
CH2Cl2, -15 o
C
rt
Ph
CH3
H
5(97%)
1
OTMS
R
R
O
OCH3
CH3
OCH3
H2O
TMSOTf (1 equiv)
CH2Cl2, -15 oC rt
RMgBr
-78 oC, 1 h
+
CF3-C C C N
CF3-C C-C
Ph
N
F3C
Ph
CH3
H
Ph
6g(4%)
6h(5%)
6i(6%)
6j(5%)
R =
p-CH3-Ph 3g(85%)
1
3h(84%)
3i(81%)
R = Ph
R =
R =
p
p
-Cl-Ph
-CF3-Ph 3j(79%)
3k(13%)
3l(58%)
C
6k(76%)
6l(15%)
R = Me
R = CH3C
Finally, the reaction of intermediate [III] with Grignard
reagents was also performed to prepare allylic amine
derivatives, which might be extremely valuable synthetic
intermediates to give trifluoromethylated indene deriva-
tives via intramolecular cyclization under acidic condi-
tion. When [III] was treated with MeMgBr, EtMgBr,
n-PrMgBr, i-PrMgBr, PhMgBr, MeC„CMgBr and
PhC„CMgBr at 0 °C, followed by stirring at room tem-
perature for 1 h, the corresponding E- and Z-isomeric
mixtures of allylic amine derivatives 7a–g were obtained

9110
S. L. Jeon et al. / Tetrahedron Letters 47 (2006) 9107–9111
OCH3
Ph
OTMS
OCH3
anisole(1.2 equiv)
rt, 3 h
RMgBr
oC rt, 1 h
TMSOTf (1 equiv)
CH2Cl2, -15 o
rt
R
CF3-C C-C
N
C
0
CH3
F3C
N OCH3
CH3
Ph
H
1
7a(R = Me, 94%)
7b(R = Et, 81%)
7c(R = n-Pr, 86%)
7d(R = i-Pr, 52%)
7e(R = Ph, 83%)
7f(R = MeC C, 86%)
7g(R = PhC C, 88%)
OCH3
Ph
CF3
R
TMSOTf (2 equiv)/CH2Cl2
rt, 7-24h
R
H3CO
F3C
N OCH3
CH3
Ph
H
8a(79%)
8e(90%)
8g(88%)
7a(R = Me)
7e(R = Ph)
7g(R = PhC C)
in 52–94% yields. The reaction mechanism could be
quite similar to the formation of intermediate [IV] as
shown in Scheme 2. Cyclization reaction of 7a by using
the use of 2 equiv TMSOTf in CH2Cl2 at room temper-
ature for 7 h provided the highest yield of indene com-
pound 8a.19 Similarly, indene compounds 8e and 8g
were obtained in 90% and 88% yields, respectively. Gen-
erally, the method for the preparation of trifluoromethyl-
ated indenes was quite limited previously and also had a
lack of generalization.20 However, our method provides
a generalized and high yield preparation of trifluoro-
methylated indenes.
E-isomer), 3.36 (s, 3H, Z-isomer), 2.35 (s, 3H, E-iso-
mer), 2.34 (s, 3H, Z-isomer), 1.79 (s, 3H, Z-isomer),
1.17 (s, 3H, E-isomer); 19F NMR (CDCl3, internal stan-
dard CFCl3) d ꢀ57.63 (s, 3F, Z-isomer), ꢀ67.23 (s, 3F,
E-isomer); MS, m/z (relative intensity) 365 (M+, 1), 305
(100), 227 (84), 197 (69), 177 (24), 118 (12), 91 (12), 77
(13); IR (neat) 3059, 2990, 1609, 1464, 1285, 1172,
1037 cmꢀ1. Anal. Calcd for C20H22F3NO2: C, 65.74;
H, 6.07. Found: C, 65.59; H, 6.00.
Acknowledgement
Formation of trifluoromethyl propargylic carbocation
having methyl group instead of phenyl group at 1-position
in compound 1 was not successful and a messy reaction
mixture was formed under several reaction conditions.
This work was supported by Korea Research Founda-
tion Grant (KRF-2003-041-C00199).
A typical reaction procedure for the preparation of 7a is
as follows. A 25 mL two-neck round bottom flask
equipped with a magnetic stirrer bar, a septum and
nitrogen tee connected to an argon source was charged
References and notes
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1
(0.166 g, 0.5 mmol) and methylene chloride (2 mL) and
then cooled to ꢀ15 °C. TMSOTf (0.111 g, 0.5 mmol)
was added at ꢀ15 °C, followed by warming to room
temperature and then anisole (0.065 g, 0.6 mmol) was
added. After stirring at room temperature for 3 h and
then cooling to 0 °C, CH3MgBr (3 M solution in ether,
0.65 mmol) was added. The reaction mixture was stirred
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(9:1) provided 0.172 g of 7a (E/Z = 3/1) in 94% yield.
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(m, 7H, Z-isomer), 7.29–7.21 (m, 5H, E-isomer), 7.08
(s, 1H, E-isomer), 6.94–6.88 (m, 2H, Z-isomer), 6.73 (s,
1H, Z-isomer), 6.71–6.66 (m, 4H, E-isomer), 3.82
(s, 3H, Z-isomer), 3.76 (s, 3H, E-isomer), 3.43 (s, 3H,
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