The modified trifluoromethylation protocol applicable to electronically deficient iodopyridinones

Article abstract of DOI:10.1016/j.tet.2015.07.029

Utilization of a mixed solvent system of DMF/HMPA=1/1 (v/v) to the KF/CuI/TMSCF₃ reagent system proved to significantly affect the reaction, realizing convenient introduction of a trifluoromethyl (CF₃) group not only to electron-deficient iodopyridinones with quite a few previous successful examples but also to aliphatic vinylic iodides.

Full text of DOI:10.1016/j.tet.2015.07.029

Tetrahedron xxx (2015) 1e8
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The modified trifluoromethylation protocol applicable to
electronically deficient iodopyridinones
*
Tomoko Kawasaki-Takasuka , Takashi Yamazaki
Division of Applied Chemistry, Institute of Engineering, Tokyo University of Agriculture and Technology, 2-24-16 Nakamachi, Koganei 184-8588, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Utilization of a mixed solvent system of DMF/HMPA¼1/1 (v/v) to the KF/CuI/TMSCF3 reagent system
proved to significantly affect the reaction, realizing convenient introduction of a trifluoromethyl (CF3)
group not only to electron-deficient iodopyridinones with quite a few previous successful examples but
also to aliphatic vinylic iodides.
Received 2 May 2015
Received in revised form 8 July 2015
Accepted 10 July 2015
Available online xxx
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Trifluoromethylation
Iodopyridinone
RuppertePrakash reagent
Trifluoromethyl copper reagents
Hexamethylphospholic triamide
1. Introduction
lyconadin A.2 Significant attention to huperzine A3 from Huperzia
serrata has been recently paid for its pharmaceutical activity to the
The pyridin-2(1H)-one structure is widely found in a variety of
biologically active naturally occurring compounds (Fig. 1).
Alzheimer’s disease. Pirfenidone has been employed against fi-
brotic disorder and its derivatives with a CF3 group were disclosed
as promising antiasthma compounds.4 3-Iodo-4-phenoxypyridin-
2(1H)-ones were also reported as a new family of highly potent
non-nucleoside inhibitors of HIV-1 reverse transcriptase.5 Thus, it
is easily understood that pyridinone compounds are wide-spread
in nature and some of them display attractive activities for a vari-
ety of diseases.
For example, camptothecin,1 isolated from Camptotheca acumi-
nate in 1966, and its derivatives, topotecan and irinotecan, are
known to show prominent anticancer activity like the case of
Until now, although introduction of a CF3 group to bioactive lead
compounds has been performed in diverse manners for modifica-
tion of original activities,6 a scarce number of methods have been
developed for electron-deficient pyridinones. One route to access
3-(trifluoromethyl)pyridin-2(1H)-one derivatives is substitution of
an iodine atom for a CF3 group by means of methyl 2,2-difluoro-2-
(fluorosulfonyl)acetate in the presence of copper(I) iodide.7 An-
other known process is direct installation of CF3 radical to pyridin-
8
2(1H)-ones, which is realized either by CF3CO2H/XeF2 or
CF3CO2Na/CuI9 systems, and the more attractive generation of this
radical was devised by Yamakawa et al. using a combination of CF3I,
a Fe(II) catalyst, and H2O2 in DMSO.10 Recently, the Baran’s group
attained very practical CeH trifluoromethylation of heterocycles by
CF3SO2Na11 or (CF3SO2)2Zn12 with focusing on various hetero-
aromatics as substrates, however this protocol sometimes suffers
from low regioselectivity.
Fig. 1. Bioactive pyridinone derivatives.
Extension of our interest to pyridines allowed to find out a rel-
atively larger number of precedented work in the literature. For
* Corresponding author. Tel./fax: þ81 42 388 7038; e-mail address: takasuka@cc.
tuat.ac.jp (T. Kawasaki-Takasuka).
http://dx.doi.org/10.1016/j.tet.2015.07.029
0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.
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T. Kawasaki-Takasuka, T. Yamazaki / Tetrahedron xxx (2015) 1e8
example, copper-mediated oxidative trifluoromethylation towards
boronic acids was utilized by Buchwald et al.,13 where 3-(tri-
fluoromethyl)quinoline and 3,6-dimethoxy-4-(trifluoromethyl)
pyridazine were readily constructed.
(Table 1). With reference to the Schlosser’s original recipe (entry
1),22 we changed the stoichiometry of KF, CuI, and TMSCF3 from 1.1
to 2.6 equiv but only disappointing result was obtained at room
temperature (Table 1, entry 2). Clear improvement was recognized
by heating the mixture and the product 2 was detected in 43 and
65% yields at 50 and 80 ꢀC, respectively (entries 3 and 4). Increase of
reagent amounts to 3.9 equiv further improved the yield of 2 to 77%,
while this change affected formation of the undesired as well as
chromatographically inseparable pentafluoroethylated byproduct 3
in 28% yield (entry 5). Cu-promoted trifluoromethylation some-
times led to construction of this compound 3 by the CuC2F5 species,
The Grushin’s group succeeded in the synthesis and isolation of
[(Ph3P)3Cu(CF3)] from [(Ph3P)3CuF]$MeOH and the RuppertePra-
kash reagent (TMSCF3), whose ability was exemplified towards
useful iodine-CF3 exchange reactions of electron-deficient aro-
matics with successful formation of 2-(trifluoromethyl)pyridine in
75% yield.14 They also revealed that a mixture of CF3H, CuCl, and t-
BuOK in DMF smoothly generated CuCF3, which afforded tri-
fluoromethylated pyridines in high yields by coupling with the
corresponding boronic acids.15 Moreover, other CF3 sources like the
which was formed as a result of insertion of in situ generated
15,21
difluorocarbene to the Cu-CF3
bond. Addition of an identical
18
Togni’s reagent,16 2,2,2-trifluoroacetophenone,17 or AgCF3 were
volume of N-methylpyrrolidin-2-one (NMP) or N,N-dimethylpro-
pyleneurea (DMPU) to DMF lowered the yields of 2 (entries 6 and
7), while hexamethylphosphoric triamide (HMPA) was the excep-
tion and this mixed solvent system recorded quantitative con-
struction of 224 at 80 ꢀC (entry 8). The effect of this additive was
remarkable even when only 1 equiv of HMPA to CuI was introduced
(entries 9 vs 4). Efficiency of this additive was lowered by shorter
reaction period (entries 10 and 11 vs 8), and other copper halides
were found not to work appropriately with formation of the
byproduct 3 in about 10% yields (entries 12 and 13). t-BuOK or CsF
instead of KF also afforded the desired trifluoromethylated product
2 in moderate yields (entries 14 and 15). Thus, we eventually
alternative choices for this purpose when appropriate copper re-
agents were employed. A significantly important role of 1,10-
phenanthroline was demonstrated by Amii et al.19 in tri-
fluoromethylation, enabling catalytic usage of CuI. The possible
intermediate (phen)CuCF3 in this process was independently syn-
thesized and isolated by the Hartwig’s group, and they proved
usefulness of this species.20
As mentioned above, in spite of relatively a larger number of
procedures for constructing CF3-possessing pyridines, only a very
few routes have been published for incorporation of this intriguing
group to electronically deficient pyridinones. Moreover, some
previous methods exploited for pyridines were found not to be
applicable to this specific system.21 For such reasons, our work has
been devoted to development of an efficient protocol for this pur-
pose, and we would like to report our successful modification of the
KF/CuI/TMSCF3 reagent system originally reported by Schlosser
et al.,22 which offered a new option to readily prepare desired
compounds in good to excellent chemical yields.
Table 2
Introduction of a CF3 group to pyridinone derivatives
Entry
R
Substrates
Products
Isolated yield (%)
X
I
2. Results and discussion
1
Me
1
2
3 h; [67]a
6 h; 84
Investigation of reaction conditions was performed in detail by
using 5-iodo-1-methylpyridin-2(1H)-one 123 as a model substrate
2
3
4
5
6
7
PMB
Ph
MOM
Allyl
H
I
I
I
I
I
Br
3
6
8
10
12
14
4
7
9
11
13
2
68
78
68
76
0
Table 1
Me
3
Optimization of reaction conditions
8
3 h; [92]a
6 h; 87 [98]a
Entry
X
(CuX)
Y
Cosolv.a
T
(ꢀC)
t
(h)
Yieldb (%)
(equiv)
2
3
9b
70c (18:19¼2:1)
1
2
3
4
5
6
7
8
I
I
I
I
I
I
I
I
I
I
I
Br
Cl
I
1.1
2.6
2.6
2.6
3.9
2.6
2.6
2.6
2.6
2.6
2.6
2.6
2.6
2.6
2.6
d
rt
rt
6
6
6
6
6
6
6
6
6
3
1
6
6
6
6
0
0
0
0
0
3
d
d
50
80
80
80
80
80
80
80
80
80
80
80
80
43
65
77
25
49
>99
89
67
70
30
29
67
74
d
d
28
0
10
98
NMP
DMPU
HMPA
HMPAc
HMPA
HMPA
HMPA
HMPA
HMPA
HMPA
0
0
0
0
9
10
11
12
13
14d
15e
0
10
9
0
0
11
12
99
87
I
a
Cosolv.: cosolvent. In the case of HMPA, this amount corresponded to 5.5 equiv
to CuI.
b
c
Yields were determined by 19F NMR spectroscopy.
CuI/HMPA¼1/1 (mol/mol).
a
The yield in brackets were determined by 19F NMR spectroscopy.
The reaction was performed at room temperature for 48 h.
Total yield of mono- and bis-trifluoromethylated compounds.
d
e
b
c
t-BuOK was employed instead of KF.
CsF was used instead of KF.
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T. Kawasaki-Takasuka, T. Yamazaki / Tetrahedron xxx (2015) 1e8
3
determined the reaction conditions in entry 8 as the best for our
purpose, which were applied to various pyridinones.
As summarized in entries 1e5 in Table 2, five different pro-
tecting groups on the nitrogen atom of pyridinone recorded similar
chemical yields, which clearly manifested almost equal utility of
the present protocol, while the substrate without amide protection
12 was not suitable for this transformation (entry 6). The corre-
sponding bromide 14 was found to be a much less attractive sub-
strate with 94% recovery under the identical conditions (entry 7) in
spite of partial success in the Schlosser’s case.22 Complete conver-
sion of 3-iodo-1-methylpyridin-2(1H)-one 15 (entry 8) was ob-
served like the case of the corresponding 5-iodo isomer 1 (entry 1).
Independent 19F NMR measurement after 3 h at 80 ꢀC allowed us to
detect the production of 3- and 5-CF3 isomers in 92 and 67% yields
(entries 1 and 8), respectively, which qualitatively suggested the
faster reaction occurred at the C3 site than the other. This difference
was reflected to the result when 3,5-diiodo-1-methylpyridin-
2(1H)-one 17 was employed as a substrate whose 3-position was
preferentially reacted and then the 5-position, affording 70%
combined yield of 5-iodo-3-CF3- and 3,5-(CF3)2-isomers (18 and 19,
respectively) in a ratio of 2:1 without any proof of formation of the
isomeric 3-iodo-5-CF3 counterpart (entry 9). This outcome would
support that trifluoromethylation by CuCF3 was classified as the
Ullmann type reaction.25 Selective synthesis of the latter bis-CF3
derivative 19 was not realized by such modified conditions as
higher temperature, longer reaction period, and a larger amount of
reagents. The present method was proved to be nicely applicable to
substrates with the 5,6-ring-fused pyridin-2(1H)-one structure
(compounds 20, 22, and 24) in excellent isolated yields (entries 10
to 12), such specific structure being found in the representative
biologically active compounds shown in Fig. 1.
Scheme 2. Application to the pharmaceutical compound.
transformed to the corresponding trifluoromethylated compound
37 at 80 ꢀC (Scheme 3).
As the representative example, deprotection of 5,6-dihydro-1-
(p-methoxybenzyl)-3-(trifluoromethyl)benzo[h]quinolin-2(1H)-
one 25 was carried out under the known TFA/CHCl3 condition26 to
quantitatively furnish 3-(trifluoromethyl)-5,6-dihydrobenzo[h]-
quinolin-2(1H)-one 26, while 10% Pd/C under an H2 atmosphere
afforded only 46% of the desired 26, which was accompanied by
16% of the over-reduction product 27 (Scheme 1).
Scheme 3. Other substrates.
For clarification of the role of HMPA, 19F NMR investigation was
carried out to determine the molar ratios of CuCF3-related species
A, B, and C after 3 h stirring at room temperature in a couple of
different solvents (Table 3). These conditions were applied because
the absence of substrates was found to affect total decomposition of
the RuppertePrakash reagent at the actual reaction temperature of
80 ꢀC. The three singlet signals observed at ꢁ29.5 (A), ꢁ32.0 (B),
and ꢁ35.5 (C) ppm were considered as mono-, bis-, and tetrakis-
trifluoromethylated copper species, respectively, on the basis of
the previous reports,27 and we independently succeeded in iden-
tification of C as the tetrakis-form.28
Burton previously pointed out that “C reacted slowly / only
after A was totally consumed” for their [CuCF3] mixtures prepared
by Cd-to-Cu exchange of the species F3CCdX (X: Cl,þBr, or CF3).27
e
€
Roschenthaler et al. reported that [(F3C)2Cu ]K (B) obtained
Scheme 1. Deprotection of a PMB group.
from a mixture of TMSCF3, KF, and CuBr was easily oxidized to
[(F3C)4Cue]Kþ (C), which was nicely contrasted by the slow con-
version of F3CCu$KBr (A) to C, and also suggested that addition of
DMI to the original solvent DMF (DMF/DMI¼5/1 (v/v)) was found to
stabilize A, leading to suppression of difluorocarbene formation
and reduction of a chance to give the undesired CuC2F5 species.27 As
shown in entry 12 in Table 1, because the similar reagent system
afforded the unacceptable result, we were required to extensively
search adequate conditions to eventually find out a suitable reagent
CuI. Our system including KF, CuI, and TMSCF3 in a DMF solvent at
ambient temperature for 3 h afforded a mixture in an approximate
ratio of A:B:C¼5:3:2 in a total yield of 34% (entry 1 in Table 3).
However, variable temperature (VT) NMR measurement of this
solution demonstrated 90% and complete loss of the species A and
As shown in Scheme 2, the CF3-containing pirfenidone was
previously synthesized by way of SuzukieMiyaura coupling of 5-
(trifluoromethyl)pyridin-2(1H)-one 28 with 2-pyridinylboronic
acid, which attained only 22% yield of the coupling product.4 On
the other hand, our strategy permitted installation of a CF3 group
after modification on the nitrogen atom of 5-iodo-pyridinone 29,
and successfully increased the isolated yield of the target 31 to 50%
in two steps (Scheme 2).
It is very important to mention that the present reagent system
was similarly applicable to 2-iodocyclohex-2-en-1-one 32 and 1-
iodocyclohexene 34, both of which realized ready trifluoro-
methylation in good to excellent yields at room temperature. Fur-
thermore, acyclic 4-phenyl-1-iodobut-1-ene 36 was also
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T. Kawasaki-Takasuka, T. Yamazaki / Tetrahedron xxx (2015) 1e8
Table 3
The effect of solvents toward a ratio of [CuCF3] species
Entry
Solv.a
19F NMR yield (%) (AþBþC)
Molar ratios of [CuCF3] species (A:B:C)
1
DMF
DMF
DMF
34
4
51
30
34
45
53
65
29
13
66
d
:
:
:
:
:
:
:
:
:
:
:
:
:
:
29
0
:
:
:
:
:
:
:
:
:
:
:
:
:
:
21
70
20
34
22
14
60
87
34
d
55
49
27
6
2b
3c
4d
5
32
32
24
30
15
10
1
46
21
25
20
11
0
DMF/HMPA
DMF/NMP
DMF/DMPU
DMF/HMPAe
DMF/HMPA
DMF/HMPA
HMPA
DMF
DMF/HMPA
DMF
6
7
8f
9g
10
11h
12h
13i
14i
0
0
d
32
32
24
9
19
18
13
21
13
20
49
59
DMF/HMPA
a
DMF/cosolvent¼1/1 (v/v). In the case of entry 8, 12, and 14, this amount of HMPA corresponds to 5.5 equiv to CuI.
Results obtained by heating a mixture of entry 1 to 80 ꢀC within ca. 10 min.
Stirring for 0.5 h instead of 3 h.
b
c
d
e
f
Stirring was continued for 2 h after addition of HMPA to a solution of entry 3 so as to make DMF/HMPA¼1/1 (v/v).
In this case, DMF/HMPA¼1/0.18 (v/v) and this amount of HMPA corresponded to 1 equiv to CuI.
Warming this solution to 80 ꢀC resulted in 82% survival of the amount of C.
DMF/HMPA¼1/5 (v/v).
g
h
i
CsF was used instead of KF.
t-BuOK was used instead of KF.
B, respectively, after heating to 80 ꢀC within ca. 10 min while 40% of
C was survived (entry 2). This result unambiguously indicated the
relative thermal instability of the species A and B as was already
silicates and/or toward their transformation to the corresponding
[CuCF3] species, but detail was not clear at present.
At the next stage, examination was performed on the de-
pendence of molar ratios of KF, CuI, and TMSCF3 used in the present
transformation (Table 4). Reduction of one or two of them by half
was proved to lead to serious decrease of the yields of 2. When the
amount of KF was less than that of TMSCF3 like the case of entries 2
and 5, the outcome of 50% yields was quite natural because
1.3 equiv of KF theoretically generated only a half amount of CFꢁ3 of
the one of entry 1. Moreover, the different rate of transmetallation
and CFꢁ3 generation would be the reason for this inconvenience:
thus, the possibly smoother process of the latter19 would render
this anion quenched or decomposed before its capture of CuI. This
was unambiguously supported by the 19F NMR detection of CF3H
and CuC2F5 from the reaction mixture of entry 5 in 17% and 16%
yields, respectively. In entries 4 and 7, excess KF to TMSCF3 would
produce the CF3 anion too quickly to appropriately react with CuI.
Moreover, in the case of CuI/TMSCF3¼2/1 like the case of entries 4
and 6, formation of less stable A and/or B would be favored to result
€
pointed out by Roschenthaler et al. Addition of NMP (entry 5) or
DMPU (entry 6) as a cosolvent slightly increased the proportion of A
while the DMF/HMPA solvent system successfully increased the
ratio of C to as high as 87% (entry 8), which was decreased to 60% by
employing a smaller amount of HMPA (entry 7). NMR analysis of
a solution of entry 8 proved 82% survival of the species C by in-
creasing the temperature to 80 ꢀC, which might stem from the
additional stabilizing effect by HMPA by taking the result in a DMF
solvent described above (entry 2) into consideration. When the
quantity of HMPA exceeded the one of DMF, this additive seemed to
work in a detrimental manner and basically none of the species
AeC was observed (DMF/HMPA¼1/5 for entry 9, HMPA only for
entry 10). This hypothesis was clearly supported by observation of
CHF3 in 37% yield by 19F NMR from a solution of entry 9. Entry 4
showed the ratio of A:B:C¼45:21:34 after an equal amount of
HMPA to DMF was added to a mixture of entry 3 (A:B:C¼34:46:20),
and the comparison of these ratios demonstrated apparent re-
duction of the proportion of B.
Different from the previous trifluoromethylation, our present
system featured requirement of heating of reaction mixtures to
80 ꢀC as shown in Table 1, and thus solvents furnishing A and/or B
as major components were apparently inappropriate because of
their thermal instability (entries 6 and 7 in Table 3 vs 8 in Table 1).
On the other hand, preferential formation of the most stable
[(F3C)4Cue]Kþ (C) in a mixture of DMF/HMPA¼1/1 was quite ef-
fective to avoid a chance of undesired thermal decomposition of
[CuCF3] species. In addition to the systematic consideration of
yields in entries 1 and 7e10, these consequences allowed us to
speculate the role of HMPA to transform A and B to C and/or help
selective formation of C when a suitable amount of this cosolvent
was used.
Table 4
Changing ratios of each reagent
Entry
Amounta (equiv)
19F NMR yield of 2 (%)
KF
CuI
TMSCF3
1
2
3
4
5
6
7
8
2.6
1.3
2.6
2.6
1.3
1.3
2.6
1.3
2.6
2.6
1.3
2.6
1.3
2.6
1.3
1.3
2.6
2.6
2.6
1.3
2.6
1.3
1.3
1.3
Quant.
53
52
3
57
1
It is interesting to note that this pronounced effect of HMPA was
not exerted for other activators like CsF (entries 11e12 in Table 3
and entry 15 in Table 1) and t-BuOK (entries 13e14 in Table 3 and
entry 14 in Table 1). This experimental discrepancy would be trig-
gered by affection of HMPA to the intermediary hypervalent
14
37
a
5.5 equiv of HMPA to CuI was added.
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T. Kawasaki-Takasuka, T. Yamazaki / Tetrahedron xxx (2015) 1e8
5
in ineffective utilization of ‘CFꢁ3 ’ during the reaction process. The
above discussion would lead to conclusion that the balance of these
three reagents to substrates should be extremely important for
attainment of successful incorporation of a CF3 group.
ethyl acetate three times, and the combined extract was succes-
sively washed with water and brine. The crude product, obtained
after drying over MgSO4, followed by concentration in vacuo, was
purified by silica gel chromatography to afford 0.56 g (1.6 mmol,
82% yield) of 5-iodo-1-(p-methoxybenzyl)pyridin-2(1H)-one 4 as
The reaction mechanism for the present process was proposed
as follows. Fluoride ion attack to the silicon atom in TMSCF3 led to
construction of the pentacoordinated intermediate, which might
further follow the counter cation exchange from Kþ to Cuþ to fur-
nish CuCF3 as a source of A to C.21,29 As discussed above, addition of
a strongly coordinating solvent HMPA should affect the proportion
between A to C where the thermally more stable C was favored and
conversion of B to C was also accelerated. C would play an impor-
tant role in preservation of CF3ꢁ species especially under heating
conditions where A and B were not easily tolerated, rendering ef-
fective inhibition of formation of byproduct 3. After reconversion of
C to A or B, possibly by way of the SET process, the desired tri-
fluoromethylated compound 2 would be produced.
a yellow viscose oil. Rf 0.69 (ethyl acetate). 1H NMR:
d 3.80 (s, 3H),
5.01 (s, 2H), 6.41 (d, J¼9.5 Hz, 1H), 6.88 (d, J¼8.7 Hz, 2H), 7.26 (d,
J¼8.7 Hz, 2H), 7.38 (dd, J¼2.6, 9.6 Hz, 1H), 7.46 (d, J¼2.1 Hz, 1H). 13
C
NMR:
d 51.1, 54.9, 64.3, 113.9, 122.4, 127.5, 129.4, 141.7, 146.4, 159.1,
160.6. IR (neat, cmꢁ1):
n 3002, 2957, 2836, 1650, 1578, 1513, 1250,
1177, 1152, 1034, 827. Anal. Calcd for C13H12INO2: C, 45.77; H, 3.55;
N, 4.11. Found: C, 45.40; H, 3.47; N, 4.08.
4.2.3. 5-Iodo-1-phenylpyridin-2(1H)-one (6). To a solution of 5-
iodopyridin-2(1H)-one (0.62 g, 2.8 mmol) in dichloromethane
(14 mL) and DMF (2 mL), Cu(OAc)2 (1.02 g, 5.6 mmol), phenyl-
boronic acid (0.41 g, 3.4 mmol), pyridine (0.44 g, 5.6 mmol), and
MS4A (1.2 g) were added. After stirring at 25 ꢀC for 24 h, the re-
action mixture was filtered off, quenched with 25% NH4OH, and
usual workup and purification by silica gel chromatography affor-
ded 0.81 g (2.7 mmol, 97% yield) of 5-iodo-1-phenylpyridin-2(1H)-
one 6 as a yellow solid. Rf 0.42 (hexane/ethyl acetate¼1/1). Mp:
3. Conclusion
In summary, we have successfully demonstrated that sub-
stitution of CuBr for CuI in the previously reported tri-
fluoromethylation reagent system of KF/CuBr/TMSCF3
and
73e74 ꢀC. 1H NMR:
d
6.49 (d, J¼9.6 Hz, 1H), 7.36 (m, 2H), 7.48 (m,
27b
addition of an equal volume of HMPA to the original solvent DMF
realized convenient introduction of a CF3 group to electron-
deficient pyridinone derivatives in good to excellent chemical
yields. Moreover, this procedure was found to be similarly appli-
cable to vinylic iodides in an efficient manner. This accomplishment
was considered to be attributable to preferential production of
thermally stable intermediate [(F3C)4Cue]Kþ (C), which readily
survived even under heating conditions of 80 ꢀC and nicely par-
ticipated in the desired CF3 incorporation reaction. The present
method successfully opens an important as well as convenient al-
ternative route because of a limited number of reports for con-
struction of target trifluoromethylated materials with electron-
deficient aromatic nuclei already shown in Table 2. Further stud-
ies for clarification of mechanism is ongoing in this laboratory.
4H), 7.58 (d, J¼2.4 Hz, 1H). 13C NMR:
d
64.3, 123.4, 126.2, 128.7,
3039, 1663, 1577,
129.3, 139.8, 142.5, 147.0, 160.6. IR (KBr, cmꢁ1):
n
1520, 1492, 1279, 1241, 1139, 837, 773, 697, 633, 555. Anal. Calcd for
11H8INO: C, 44.47; H, 2.71; N, 4.71. Found: C, 44.40; H, 2.64; N,
C
5.02.
4.2.4. 5-Iodo-1-(methoxymethyl)pyridin-2(1H)-one (8). To a mix-
ture of 5-iodopyridin-2(1H)-one (0.44 g, 2.0 mmol) and sodium
hydride (55% oil dispersion, 0.10 g, 2.4 mmol) in DMF, chloromethyl
methyl ether (0.16 g, 2.0 mmol) was added. After stirring overnight
at 25 ꢀC, the reaction mixture was quenched with 1 M HCl, and
usual workup and purification by silica gel chromatography affor-
ded 0.16 g (0.6 mmol, 30% yield) of 5-iodo-1-(methoxymethyl)
pyridin-2(1H)-one 8 as a yellow viscose oil. Rf 0.61 (ethyl acetate).
1H NMR:
d
3.40 (s, 3H), 5.26 (s, 2H), 6.40 (d, J¼9.3 Hz, 1H), 7.43 (dd,
4. Experimental section
J¼9.9, 2.7 Hz, 1H), 7.60 (d, J¼2.1 Hz, 1H). 13C NMR:
d 57.2, 64.7, 78.0,
122.9, 140.8, 147.3, 161.1. IR (neat, cmꢁ1):
n 3050, 2957, 2993, 2938,
4.1. General considerations
1647, 1578, 1524, 1151, 1129, 1089, 828. HRMS (FABþ): Calcd for
C7H9INO2 ([MþH]þ): 265.9678, Found: 265.9686.
Unless otherwise mentioned, the NMR spectra for 1H, 13C, and
19F were recorded in CDCl3 at 300, 75.5, and 282 MHz, respectively,
with chemical shifts being reported in parts per million downfield
4.2.5. 1-Allyl-5-iodopyridin-2(1H)-one (10). To a mixture of 5-
iodopyridin-2(1H)-one (0.44 g, 2.0 mmol) and sodium hydride
(55% oil dispersion, 0.10 g, 2.4 mmol) in DMF, allyl bromide (0.24 g,
2.0 mmol) was added. After stirring overnight at 25 ꢀC, the reaction
mixture was quenched with 1 M HCl, and the usual workup and
purification by silica gel chromatography afforded 0.25 g (1.0 mmol,
50% yield) of 1-allyl-5-iodopyridin-2(1H)-one 10 as a yellow vis-
from the internal TMS (d (d:
: 0.00) for 1H and 13C NMR, and C6F6
ꢁ163.00) for 19F NMR spectra. Data were tabulated in the following
order: multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; quint,
quintet; m, multiplet; br, broad peak), coupling constants in Hertz,
and a number of protons. IR spectra were reported in wave num-
bers (cmꢁ1). High resolution mass spectra were obtained by
double-focusing mass spectrometer in the FAB mode.
cose oil. Rf 0.67 (ethyl acetate). 1H NMR:
d
4.52 (d, J¼6.0 Hz, 2H),
5.24 (d, J¼17.1 Hz, 1H), 5.31 (d, J¼10.2 Hz, 1H), 5.93 (ddt, J¼16.8,
10.8, 5.7 Hz, 1H), 6.41 (d, J¼9.3 Hz, 1H), 7.42 (dd, J¼9.6, 2.7 Hz, 1H),
4.2. Physical property data of substrates
7.46 (d, J¼2.1 Hz,1H). 13C NMR:
d 50.8, 64.2, 119.0, 122.5, 131.7, 141.8,
n 3069, 3043, 2984, 2933, 1647, 1579,
146.6, 160.5. IR (neat, cmꢁ1):
4.2.1. 5-Iodo-1-methylpyridin-2(1H)-one (1).23,30 This compound
was prepared by following to the reported method. Rf 0.54 (ethyl
1523, 1155, 826, 631. HRMS (FABþ): Calcd for C8H9INO ([MþH]þ):
261.9729, Found: 261.9734.
acetate). 1H NMR:
d
3.52 (s, 3H), 6.40 (d, J¼9.3 Hz,1H), 7.43 (d, J¼9.6,
2.4 Hz,1H), 7.52 (d, J¼2.7 Hz,1H). 13C NMR:
d
37.2, 63.8,122.0,143.0,
4.2.6. 5-Bromo-1-methylpyridin-2(1H)-one (14).31 This compound
was prepared by following to the reported method. Rf 0.44 (ethyl
146.8, 161.3.
acetate). 1H NMR:
d
3.53 (s, 3H), 6.50 (d, J¼9.9 Hz,1H), 7.36 (d, J¼9.6,
4.2.2. 5-Iodo-1-(p-methoxybenzyl)pyridin-2(1H)-one (4). To a mix-
ture of 5-iodopyridin-2(1H)-one (0.44 g, 2.0 mmol) and potassium
carbonate (0.30 g, 2.2 mmol) in DMF, p-methoxybenzyl chloride
(0.31 g, 2.0 mmol) was added. After stirring overnight at 25 ꢀC, the
reaction mixture was quenched with water and extracted with
2.7 Hz, 1H), 7.43 (d, J¼2.1 Hz, 1H). 13C NMR:
d 37.5, 97.5, 121.6, 138.1,
142.4, 161.3.
4.2.7. 3-Iodo-1-methylpyridin-2(1H)-one (15).32 This compound
was prepared by following to the reported method. Rf 0.46 (ethyl
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6
T. Kawasaki-Takasuka, T. Yamazaki / Tetrahedron xxx (2015) 1e8
acetate). 1H NMR:
d
3.62 (s, 3H), 5.95 (t, J¼6.9 Hz, 1H), 7.32 (dd,
and purification by silica gel chromatography afforded 1.1 g
J¼6.6, 1.8 Hz, 1H), 7.98 (dd, J¼7.2, 1.8 Hz, 1H). 13C NMR:
d
39.1, 91.9,
(2.5 mmol, 48% yield) of 5,6-dihydro-3-iodo-1-(p-methoxybenzyl)
benzo[h]quinolin-2(1H)-one 24 as a yellow oil. Rf 0.48 (hexane/
106.9, 138.9, 148.4, 159.8.
ethyl acetate¼4/1). 1H NMR:
d 2.83 (m, 2H), 2.91 (m, 2H), 3.81 (s,
4.2.8. 3,5-Diiodo-1-methylpyridin-2(1H)-one (17).33 This com-
pound was prepared by following to the reported method. Rf 0.70
3H), 5.49 (s, 2H), 6.92 (d, J¼8.7 Hz, 2H), 7.22 (d, J¼7.5 Hz, 1H), 7.33
(m, 2H), 7.49 (d, J¼8.7 Hz, 2H), 7.87 (s, 1H), 8.25 (d, J¼7.2 Hz,1H). 13
C
(ethyl acetate). Mp: 220e221 ꢀC. 1H NMR:
d
3.58 (s, 3H), 7.52 (d,
NMR: d 26.4, 28.0, 55.1, 68.1, 77.7, 113.6, 124.6, 126.2, 126.8, 127.7,
J¼1.5 Hz, 1H), 8.07 (d, J¼1.2 Hz, 1H). 13C NMR (DMSO-d6, solvent as
129.0, 129.1, 129.4, 133.8, 137.8, 147.5, 149.2, 159.0, 159.8. IR (neat,
reference):
d
38.5, 64.6, 93.7, 145.2, 154.2, 158.5.
cmꢁ1):
n
3008, 2940, 2839, 1613, 1515, 1457, 1435, 1328, 1245, 1174.
Anal. Calcd for C21H18INO2: C, 56.90; H, 4.09; N, 3.16. Found: C,
56.54; H, 3.94; N, 3.11.
4.2.9. 3-Iodo-1-methyl-5,6,7,8-tetrahydroquinolin-2(1H)-one
(20). A solution of 3-cyano-5,6,7,8-tetrahydroquinolin-2(1H)-
one34 (4.4 g, 25 mmol) in 6 M HCl (48 mL) was refluxed for 48 h.
After neutralization, the precipitate was collected by filtration and
dried. To a mixture of this crude material (1.9 g, 13 mmol) in THF-
H2O (16 mL each), potassium carbonate (2.1 g, 15 mmol), iodine
(6.5 g, 25 mmol), and 4-(N,N-dimethylamino)pyridine (0.3 g,
2.5 mmol) were added successively and the whole solution was
stirred overnight at 25 ꢀC. After adding a satd Na2S2O5 solution, THF
was removed under reduced pressure. The precipitate was col-
lected by filtration to afford 1.2 g (4.2 mmol, 34% yield) of 3-iodo-
5,6,7,8-tetrahydroquinolin-2(1H)-one. To a solution of this crude
product (0.32 g, 1.2 mmol) and potassium carbonate (0.20 g,
1.4 mmol) in DMF (5 mL), iodomethane (0.50 g, 3.5 mmol) was
added and the mixture was stirred at 50 ꢀC for 10 h. The usual
workup and purification by silica gel chromatography afforded
4.2.12. 5-Iodo-1-(pyridin-2-yl)pyridin-2(1H)-one (30). Under an
argon atmosphere, to the mixture of copper iodide (I) (0.020 g,
0.1 mmol), 1,10-phenanthroline (0.036 g, 0.2 mmol), cesium car-
bonate (0.652 g, 2.0 mmol) in dry DMF, 5-iodo-pyridin-2(1H)-one
(0.232 g, 1.05 mmol) and 2-bromopyridine (0.158 g, 1.0 mmol) were
added. The mixture was heated to 100 ꢀC for 24 h and allowed to
cool to room temperature. After passing a silica gel cake, the con-
centrated residue was purified by silica gel chromatography to yield
5-iodo-1-(pyridin-2-yl)-pyridin-2(1H)-one 30 0.202 g as a white
crystals. Rf 0.69 (ethyl acetate). Mp: 127e128 ꢀC (dec). 1H NMR:
d
6.48 (d, J¼9.6 Hz, 1H), 7.35 (m, 1H), 7.50 (dd, J¼9.6, 2.4 Hz, 1H),
7.85 (m, 1H), 7.92 (m, 1H), 8.14 (d, J¼2.4 Hz, 1H), 8.57 (m, 1H). 13
C
NMR:
d 65.4, 121.0, 123.4, 123.6, 137.9, 140.7, 147.4, 148.9, 150.7,
160.5. IR (CHCl3, cmꢁ1):
n 3009, 1664, 1596, 1524, 1436, 1216, 771,
0.19
tetrahydroquinolin-2(1H)-one 20 as a pale-yellow crystal. Rf 0.56
(ethyl acetate). Mp: 117e118 ꢀC. 1H NMR:
1.69 (m, 2H), 1.84 (m,
2H), 2.50 (m, 2H), 2.59 (m, 2H), 3.56 (s, 3H), 7.74 (s, 1H). 13C NMR:
21.4, 22.0, 27.1, 27.4, 32.0, 88.1, 116.1, 144.4, 149.7, 160.0. IR (KBr,
cmꢁ1):
3210, 3019, 2940, 2866, 2843, 1641, 1588, 1530, 772, 753.
g
(0.66 mmol, 75% yield) of 3-iodo-1-methyl-5,6,7,8-
761, 748, 454. HRMS (FABþ): Calcd for C10H8IN2O ([MþH]þ):
298.9681, Found: 298.9672.
d
4.2.13. 2-Iodocyclohex-2-en-1-one (32).36 This compound was
prepared by following to the reported method. Rf 0.33 (hexane/
d
n
ethyl acetate¼4/1). 1H NMR:
d
2.09 (quint, J¼6.9 Hz, 2H), 2.45 (dt,
Anal. Calcd for C10H12INO: C, 41.54; H, 4.18; N, 4.84. Found: C, 41.56;
H, 4.42; N, 4.84.
J¼5.7, 4.8 Hz, 2H), 2.67 (dd, J¼6.3, 6.9 Hz, 2H), 7.77 (t, J¼4.5 Hz, 1H).
13C NMR:
d 22.7, 29.8, 37.1, 103.6, 159.4, 192.0.
4.2.10. 3-Iodo-1-methyl-1,5,6,7-tetrahydrocyclopenta[b]pyridin-
2(1H)-one (22). This compound was prepared in 14% total yield
from 2-(hydroxymethylene)cyclopentanone sodium salt 13.4 g
(100 mmol) and 2-cycanoacetamide (9.5 g, 113 mmol) using the
same condition as in the Section 4.2.9. Rf 0.50 (ethyl acetate). Mp:
4.2.14. Iodocyclohexene (34).37 This compound was prepared by
following to the reported method. Rf 0.65 (hexane). 1H NMR:
d
1.61
(m, 4H), 2.02 (m, 2H), 2.44 (m, 2H), 6.27 (m, 1H). 13C NMR:
25.3, 29.0, 39.3, 96.8, 137.4.
d
20.8,
151e152 ꢀC (dec). 1H NMR:
d
2.16 (quint, J¼7.5 Hz, 2H), 2.78 (t,
4.3. General procedure for the trifluoromethylation of iodo
compounds and physical property data of products (Table 2)
J¼7.5 Hz, 2H), 2.88 (t, J¼7.5 Hz, 2H), 3.55 (s, 3H), 7.88 (s, 1H). 13C
NMR:
d 22.6, 29.9, 32.1, 34.2, 88.1, 120.0, 145.6, 151.2, 160.2. IR (KBr,
cmꢁ1):
n
3020, 2917, 2862, 1640, 1577, 1530, 793, 753. HRMS
A mixture of potassium fluoride (0.15 g, 2.6 mmol) and copper
iodide (I) (0.50 g, 2.6 mmol) was heated under reduced pressure
until a greenish color appeared, and after cooling to rt, an iodo
compound (1.0 mmol) in DMF/HMPA (2.5 mL each) and trime-
thyl(trifluoromethyl)silane (0.38 mL, 2.6 mmol) were added to this
flask successively. The mixture was stirred for the specified time
and at the indicated temperature (see Table 2). After quenching
with satd aqueous ammonium chloride, usual workup and purifi-
cation by silica gel chromatography yielded the trifluoromethylated
product.
(FABþ): Calcd for C9H10INO ([Mþ]): 274.9807, Found: 274.9812.
4.2.11. 5,6-Dihydro-3-iodo-1-(p-methoxybenzyl)benzo[h]quinolin-
2(1H)-one (24). To a mixture of 5,6-dihydrobenzo[h]quinolin-
2(1H)-one35 (0.20 g, 1.0 mmol) in 1,4-dioxane (1.6 mL) and H2O
(4.0 mL), potassium carbonate (1.11 g, 8.0 mmol) and iodine (0.28 g,
1.1 mmol) were added. After 2 h, the reaction mixture was diluted
with ethyl acetate (5.0 mL) and water (5.0 mL), and the precipitate
was collected and washed with water and ethyl acetate, then dried
to give 0.31 g (0.96 mmol, 96% yield) of 5,6-dihydro-3-iodobenzo-
[h]quinolin-2(1H)-one as a pale yellow solid. Rf 0.46 (hexane/ethyl
acetate¼1/1). Mp: 240e241 ꢀC (dec). 1H NMR (DMSO-d6, solvent as
4.3.1. 1-Methyl-5-(trifluoromethyl)pyridin-2(1H)-one
84%. Rf 0.60 (ethyl acetate). Mp: 72e73 ꢀC. 1H NMR:
(2).24 Yield
3.60 (s, 3H),
d
reference):
8.10 (m, 1H). 13C NMR (DMSO-d6, solvent as reference):
66.7, 117.3, 123.8, 127.2, 128.6, 128.8, 129.9, 138.2, 150.4, 160.6. IR
(KBr, cmꢁ1):
3020, 2942, 1628, 1593, 1566, 1339, 1190, 914, 773,
d
2.63 (m, 2H), 2.80 (m, 2H), 7.27 (m, 3H), 7.83 (s, 1H),
6.64 (d, J¼9.6 Hz, 1H), 7.47 (dd, J¼9.6, 2.7 Hz, 1H), 7.73 (m, 1H). 13
C
d
24.8, 28.0,
NMR:
d
38.0, 109.4 (q, J¼35.4 Hz), 121.0, 123.2 (q, J¼269.2 Hz), 135.1
(q, J¼2.5 Hz), 137.8 (q, J¼5.6 Hz), 164.2. 19F NMR:
d
ꢁ63.00 (s). IR
n
(KBr, cmꢁ1):
n 3087, 3053, 3013, 1650, 1569, 1316, 1126, 1079, 880,
748, 446, 436. Anal. Calcd for C13H10INO: C, 48.32; H, 3.12; N, 4.33.
Found: C, 48.03; H, 3.27; N, 4.03.
771, 733. Anal. Calcd for C7H6F3NO: C, 47.47; H, 3.41; N, 7.91. Found:
C, 47.69; H, 3.58; N, 7.84.
To a mixture of this intermediate (1.79 g, 5.6 mmol) and po-
tassium carbonate (1.53 g, 11.1 mmol) in DMF (30 mL), p-methox-
ybenzyl chloride (0.87 g, 5.6 mmol) was added and the mixture was
stirred for 3 h at 50 ꢀC. After quenching with water, usual workup,
4.3.2. 1-(p-Methoxybenzyl)-5-(trifluoromethyl)pyridin-2(1H)-one
(5). Yield 68%. Rf 0.56 (hexane/ethyl acetate¼1/1). Mp: 48e49 ꢀC.
1H NMR:
d
3.81 (s, 3H), 5.01 (s, 2H), 6.65 (d, J¼9.6 Hz, 1H), 6.90 (m,
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T. Kawasaki-Takasuka, T. Yamazaki / Tetrahedron xxx (2015) 1e8
7
2H), 7.27 (m, 2H), 7.42 (dd, J¼9.6, 2.7 Hz, 1H), 7.63 (m, 1H). 13C NMR:
1H NMR:
d
1.75 (m, 2H), 1.89 (m, 2H), 2.56 (t, J¼6.0 Hz, 2H), 2.68 (t,
d
52.0, 55.1, 109.6 (q, J¼34.8 Hz), 114.3, 121.4, 123.2 (q, J¼266.6 Hz),
J¼5.7 Hz, 2H), 3.53 (s, 3H), 7.48 (s, 1H). 13C NMR:
d 21.2, 21.8, 27.0,
127.1, 129.8, 134.8 (q, J¼1.8 Hz), 136.5 (q, J¼5.0 Hz), 159.7, 161.8. 19
F
27.6, 30.0, 113.0, 116.1 (q, J¼30.4 Hz), 123.0 (q, J¼270.4 Hz), 139.6 (q,
NMR:
d
ꢁ63.68 (s). IR (neat, cmꢁ1):
n
3008, 2959, 2840, 1677, 1623,
J¼5.0 Hz), 148.6, 158.7. 19F NMR:
d
ꢁ66.92 (s). IR (KBr, cmꢁ1):
n 3037,
1514, 1331, 1251, 1167, 1150, 1127. Anal. Calcd for C14H12F3NO2: C,
59.37; H, 4.27; N, 4.95. Found: C, 58.93; H, 4.36; N, 4.90.
2948, 2874, 1666, 1606, 1557, 1427, 1323, 1174, 1133, 1100, 1071, 983,
944. Anal. Calcd for C11H12F3NO: C, 57.14; H, 5.23; N, 6.06. Found: C,
57.20; H, 4.99; N, 6.07.
4.3.3. 1-Phenyl-5-(trifluoromethyl)pyridin-2(1H)-one (7).38 Rf 0.53
(hexane/ethyl acetate¼1/1). Mp: 62e63 ꢀC. 1H NMR:
d
6.73 (m, 1H),
109.7 (q,
4.3.10. 1-Methyl-3-(trifluoromethyl)-1,5,6,7-tetrahydrocyclopenta[b]
pyridin-2(1H)-one (23). Yield 99%. Rf 0.49 (ethyl acetate). Mp:
7.38 (m, 2H), 7.52 (m, 4H), 7.75 (m, 1H). 13C NMR:
d
J¼34.8 Hz), 122.4, 123.3 (q, J¼269.8 Hz), 126.3, 129.2, 129.6, 135.3 (q,
143e144 ꢀC. 1H NMR:
d
2.20 (quint., J¼7.5 Hz, 2H), 2.83 (t, J¼7.5 Hz,
J¼2.5 Hz), 137.7 (q, J¼5.0 Hz), 139.9, 161.5. 19F NMR:
d
ꢁ63.79 (s). IR
2H), 2.97 (m, 2H), 3.54 (s, 3H), 7.65 (s, 1H). 13C NMR:
d
22.2, 29.8,
(CHCl3, cmꢁ1):
n
3056, 1682, 1546, 1331, 1093, 826, 697, 637. Anal.
32.5 (2C), 115.8 (q, J¼29.2 Hz), 116.9, 123.2 (q, J¼271.0 Hz), 135.4 (q,
Calcd for C12H8F3NO: C, 60.26; H, 3.37; N, 5.86. Found: C, 60.12; H,
3.29; N, 8.09.
J¼5.0 Hz), 155.4, 159.2. 19F NMR:
d
ꢁ66.97 (s). IR (KBr, cmꢁ1):
n 3021,
2918, 2864, 1642, 1577, 1530, 1433, 1231, 791, 753. Anal. Calcd for
C10H10F3NO: C, 55.30; H, 4.64; N, 6.45. Found: C, 55.00; H, 4.43; N,
4.3.4. 1-Methoxymethyl-5-(trifluoromethyl)pyridin-2(1H)-one
5.96.
(9). Yield 70%. Rf 0.72 (ethyl acetate). 1H NMR:
d 3.43 (s, 3H), 5.33 (s,
2H), 6.65 (d, J¼9.9 Hz, 1H), 7.46 (dd, J¼9.3, 1H), 7.79 (s, 1H). 13C
4.3.11. 5,6-Dihydro-1-(p-methoxybenzyl)-3-(trifluoromtheyl)benzo
[h]quinolin-2(1H)-one (25). Yield 87%. Rf 0.40 (hexane/ethyl
NMR:
d
57.5, 78.6, 110.1 (q, J¼33.5 Hz), 121.8, 123.1 (q, J¼269.8 Hz),
135.5 (m), 162.0. 19F NMR:
d
ꢁ64.03 (s). IR (KBr, cmꢁ1):
n
2253, 1678,
acetate¼4/1). 1H NMR:
d 2.92 (m, 4H), 3.80 (s, 3H), 5.57 (s, 2H), 6.90
1330, 1130, 908, 726, 649, 467, 432. HRMS (FABþ): Calcd for
(d, J¼8.7 Hz, 2H), 7.25 (m, 1H), 7.36 (m, 2H), 7.45 (d, J¼8.7 Hz, 2H),
C8H9F3NO2 ([MþH]þ): 208.0585, Found: 208.0556.
7.68 (s, 1H), 8.27 (m, 1H). 13C NMR:
d 26.5, 27.9, 55.1, 67.4, 111.1 (q,
J¼32.2 Hz), 113.7, 123.3 (q, J¼271.0 Hz), 123.5, 125.4, 127.0, 127.9,
4.3.5. 1-Allyl-5-(trifluoromethyl)pyridin-2(1H)-one (11). Yield 81%.
129.1, 129.2, 129.3, 133.4, 136.3 (q, J¼4.4 Hz), 138.5, 152.8, 158.8 (q,
Rf 0.77 (ethyl acetate). 1H NMR:
d
4.60 (dt, J¼17.1, 2.7, 1.5 Hz, 2H),
J¼1.2 Hz), 159.2. 19F NMR:
d
ꢁ64.21 (s). IR (KBr, cmꢁ1):
n 3008, 2940,
5.27 (ddt, J¼17.1, 2.7, 1.5 Hz, 1H), 5.35 (ddt, J¼10.5, 2.4, 1.2 Hz, 1H),
2839, 1614, 1515, 1439, 1304, 1274, 1248, 1135, 1078. Anal. Calcd for
5.95 (ddt, J¼17.1, 10.2, 6.0 Hz, 1H), 6.65 (d, J¼9.6 Hz, 1H), 7.46 (dd,
C22H18F3NO2: C, 68.57; H, 4.71; N, 3.63. Found: C, 68.39; H, 4.78; N,
J¼9.7, 2.7 Hz,1H), 7.65 (m, 1H). 13C NMR:
d
51.4, 109.7 (q, J¼34.8 Hz),
3.54.
117.9, 119.7, 123.2 (q, J¼269.8 Hz), 131.4, 135.0 (q, J¼2.5 Hz), 136.6 (q,
J¼5.6 Hz), 161.6. 19F NMR:
d
ꢁ63.69 (s). IR (neat, cmꢁ1):
n
2942,
4.3.12. 3-Trifluoromethyl-5,6-dihydro-benzo[h]quinolin-2(1H)-one
(26). Yield 90%. Rf 0.38 (hexane/ethyl acetate¼4/1). Mp:
2833, 2252, 1684, 1630, 1330, 1171, 1131, 909. HRMS (FABþ): Calcd
for C9H9F3NO ([MþH]þ): 204.0636, Found: 204.0660.
217e218 ꢀC (dec). 1H NMR:
d
2.74 (t, J¼6.3 Hz, 2H), 2.93 (t, J¼6.9 Hz,
2H), 7.32 (m, 1H), 7.41 (m, 1H), 7.75 (s, 1H), 8.22 (m, 1H), 12.9 (br s,
1H). 13C NMR:
25.4, 28.3, 113.6, 117.5 (q, J¼31.0 Hz), 123.1 (q,
4.3.6. 1-Methyl-3-(trifluoromethyl)pyridin-2(1H)-one
87%. Rf 0.46 (ethyl acetate). Mp: 93e94 ꢀC. 1H NMR:
(16). Yield
3.62 (s, 3H),
d
d
J¼270.0 Hz), 124.6, 127.1, 127.7, 128.4, 131.0, 138.5, 141.2 (q,
6.25 (t, J¼7.2 Hz, 1H), 7.55 (d, J¼6.9 Hz, 1H), 7.76 (d, J¼6.9 Hz, 1H).
J¼4.4 Hz), 144.2, 161.0. 19F NMR:
d
ꢁ66.31 (s). IR (KBr, cmꢁ1):
n 2957,
13C NMR:
d
37.6, 103.8, 119.9 (q, J¼31.0 Hz), 122.7 (q, J¼271.0 Hz),
1659, 1614, 1594, 1559, 1307, 1183, 1129, 783, 451. Anal. Calcd for
138.8 (q, J¼5.0 Hz), 142.4, 158.7. 19F NMR:
d
ꢁ67.35 (s). IR (KBr,
C14H10F3NO: C, 63.40; H, 3.80; N, 5.28. Found: C, 63.60; H, 3.80; N,
5.20.
cmꢁ1):
n
3087, 3053, 3013, 1650, 1569, 1467, 1316, 1126, 1079, 880,
771. Anal. Calcd for C7H6F3NO: C, 47.47; H, 3.41; N, 7.91. Found: C,
47.52; H, 3.18; N, 7.88.
4.3.13. 3-(Trifluoromethyl)-3,4,4a,5,6,10b-hexahydrobenzo[h]quino-
lin-2(1H)-one (27). Yield 16%. Rf 0.19 (hexane/ethyl acetate¼4/1).
4.3.7. 5-Iodo-1-methyl-3-(trifluoromethyl)pyridin-2(1H)-one
Mp: 113e114 ꢀC (dec). 1H NMR:
d 1.74 (m, 2H), 1.99 (m, 1H), 2.25 (dt,
(18). Yield
70%
as
a
mixture
with
1-methyl-3,5-
J¼13.5, 5.7 Hz, 1H), 2.45 (m, 1H), 2.80 (m, 2H), 3.20 (ddt, J¼12.3, 8.7,
bis(trifluoromethyl)pyridin-2(1H)-one in a ratio of 2:1. Rf 0.43
1.5 Hz, 1H), 4.55 (dd, J¼4.8, 3.6 Hz, 1H), 6.66 (br s, 1H), 7.14 (m, 1H),
(hexane/ethyl acetate¼1/1). Mp: 135e136 ꢀC. 1H NMR:
d
3.59 (s,
7.26 (m, 3H). 13C NMR:
d
24.9, 26.4, 26.7, 31.3, 44.8 (q, J¼26.7 Hz),
3H), 7.77 (s, 1H), 7.84 (s, 1H). 13C NMR:
d
37.7, 60.7, 121.6 (q,
52.5, 124.8 (q, J¼278.5 Hz), 126.9, 127.6, 127.8, 128.9, 134.6, 136.0,
J¼272.3 Hz), 121.7 (q, J¼31.0 Hz), 146.1 (q, J¼5.0 Hz), 147.2, 157.3. 19
F
166.0. 19F NMR:
d
ꢁ69.23 (d, J¼6.8 Hz). R (CHCl3, cmꢁ1):
n 3406,
NMR:
d
ꢁ67.41 (s). IR (KBr, cmꢁ1):
n
3046, 1660, 1593, 1556, 1422,
3217, 3019, 2939, 1676, 1216, 756, 749, 485, 467. HRMS (FABþ):
1303, 1175, 1129, 919, 679. Anal. Calcd for C7H5F3INO: C, 27.75; H,
1.66; N, 4.62. Found: C, 27.66; H, 1.74; N, 4.48.
Calcd for C14H15F3NO ([MþH]þ): 270.1106, Found: 270.1069.
4.3.14. 1-(Pyridin-2-yl)-5-(trifluoromethyl)pyridin-2(1H)-one (31),
[1051375-37-1].4 Yield 73%. Rf 0.75 (ethyl acetate). Mp: 125e126 ꢀC
4.3.8. 1-Methyl-3,5-bis(trifluoromethyl)pyridin-2(1H)-one
(19). Yield 70% as a mixture with 5-iodo-1-methyl-3-(trifluoro-
methyl)pyridin-2(1H)-one in a ratio of 1:2. Rf 0.45 (hexane/ethyl
(dec). 1H NMR:
d
6.73 (d, J¼9.6 Hz, 1H), 7.39 (m, 1H), 7.52 (dd, J¼9.6,
2.7 Hz, 1H), 7.89 (m, 1H), 7.96 (m, 1H), 8.35 (m, 1H), 8.60 (m, 1H). 13
NMR:
110.3 (q, J¼35.3 Hz), 121.1, 122.6, 123.3 (q, J¼269.8 Hz),
C
acetate¼1/1). Mp: 76e77 ꢀC. 1H NMR:
d
3.66 (s, 3H), 7.89 (s, 1H),
d
7.92 (s, 1H). 13C NMR:
d
38.4, 107.9 (q, J¼32.0 Hz), 120.7 (q,
123.8, 135.5 (q, J¼2.5 Hz), 136.0 (q, J¼5.6 Hz), 138.0, 149.1, 150.7,
J¼31.0 Hz), 121.9 (q, J¼271.0 Hz), 122.6 (q, J¼269.8 Hz), 134.9 (m),
161.3. 19F NMR:
d
ꢁ64.14 (s). IR (CHCl3, cmꢁ1):
n 3014, 1670, 1599,
141.6 (q, J¼5.0 Hz), 158.0. 19F NMR:
d
ꢁ62.84 (s), ꢁ67.27 (s). IR (KBr,
1585, 1436, 1216, 771, 761, 750, 667. HRMS (FABþ): Calcd for
cmꢁ1):
n
3054, 1636, 1580, 1505, 1417, 1303, 1207, 1117, 892, 752,
C
11H8F3N2O ([MþH]þ): 241.0589, Found: 241.0575.
686. Anal. Calcd for C8H5F6NO: C, 39.20; H, 2.06; N, 5.71. Found: C,
38.72; H, 1.99; N, 5.64.
4.3.15. 2-(Trifluoromethyl)cyclohex-2-en-1-one (33). Yield 69% (by
19F NMR), 26% (isolated). Rf 0.33 (hexane/ethyl acetate¼4/1). 1H
4.3.9. 1-Methyl-3-(trifluoromethyl)-5,6,7,8-tetrahydroquinolin-
2(1H)-one (21). Yield 98%. Rf 0.69 (ethyl acetate). Mp: 111e112 ꢀC.
NMR: d d 21.7,
2.08 (m, 2H), 2.55 (m, 4H), 7.52 (m, 1H). 13C NMR:
25.3, 38.1, 121.6 (q, J¼273.6 Hz), 130.1 (q, J¼28.5 Hz), 152.0 (q,
Please cite this article in press as: Kawasaki-Takasuka, T.; Yamazaki, T., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.07.029

8
T. Kawasaki-Takasuka, T. Yamazaki / Tetrahedron xxx (2015) 1e8
J¼5.0 Hz), 193.2. 19F NMR:
d
ꢁ66.96 (s). IR (neat, cmꢁ1):
n 3437,
15. (a) Zanardi, A.; Novikov, M. A.; Martin, E.; Benet-Buchholz, J.; Grushin, V. V. J.
ꢀ
Am. Chem. Soc. 2011, 133, 20901e20913; (b) Novak, P.; Lishchynskyi, A.;
Grushin, V. V. Angew. Chem., Int. Ed. 2012, 51, 7767e7770; (c) Lishchynskyi, A.;
2960, 2932, 1700, 1383, 1298, 1148, 1012, 769. Anal. Calcd for
C7H7F3O: C,51.23; H, 4.30. Found: C, 51.37; H, 4.40.
ꢀ
ꢀ
Novikov, M. A.; Martin, E.; Escudero-Adan, E. C.; Novak, P.; Grushin, V. V. J. Org.
Chem. 2013, 135, 11126e11146.
4.3.16. (Trifluoromethyl)cyclohexene (35), [454-55-7].39 Yield 93%
16. (a) Liu, T.-F.; Shao, X.-X.; Wu, Y.-M.; Shen, Q.-L. Angew. Chem., Int. Ed. 2012, 51,
540e543; (b) Cai, S.-J.; Chen, C.; Sun, Z.-L.; Xi, C.-J. Chem. Commun. 2013,
4552e4554.
(by 19F NMR). Rf 0.64 (hexane). 1H NMR:
d 1.59 (m, 4H), 2.06 (m,
4H), 6.26 (m, 1H). 13C NMR:
d 21.2, 21.4, 21.8, 24.2, 124.0 (q,
17. Serizawa, H.; Aikawa, K.; Mikami, K. Chem.dEur. J. 2013, 19, 17692e17697.
J¼270.5 Hz), 128.1 (q, J¼29.7 Hz), 130.3 (q, J¼5.6 Hz). 19F NMR:
€
18. Kremlev, M. M.; Mushta, A. I.; Tyrra, W.; Yagupolskii, Y. L.; Naumann, D.; Moller,
A. J. Fluorine Chem. 2012, 133, 67e71.
d
ꢁ70.96 (s).
19. (a) Oishi, M.; Kondo, H.; Amii, H. Chem. Commun. 2009, 1909e1911 See also the
€
followings: (b) Knauber, T.; Arikan, F.; Roschenthaler, G.-V.; Gooßen, L. J. Chem.
4.3.17. (E,Z)-5-Phenyl-1,1,1-trifluoropent-2-ene (37).40 Yield 73%,
dEur. J. 2011, 17, 2689e2697; (c) Weng, Z.-Q.; Lee, R.; Jia, W.-G.; Yuan, Y.-F.;
Wang, W.-F.; Feng, X.; Huang, K.-W. Organometallics 2011, 30, 3229e3232.
20. (a) Morimoto, H.; Tsubogo, T.; Litvinas, N. D.; Hartwig, J. F. Angew. Chem., Int. Ed.
2011, 50, 3793e3798; (b) Litvinas, N. D.; Fier, P. S.; Hartwig, J. F. Angew. Chem.,
Int. Ed. 2012, 51, 536e539 Recently, they also extended this method for in-
troduction of a C2F5 group. See: (c) Mormino, M. G.; Fier, P. S.; Hartwig, J. F. Org.
Lett. 2014, 16, 1744e1747.
21. Recent reviews on trifluoromethylation with metal reagents: (a) Tomashenko,
O. A.; Grushin, V. V. Chem. Rev. 2011, 111, 4475e4521; (b) Wu, X.-F.; Neumann,
H.; Beller, M. Chem.dAsian J. 2012, 7, 1744e1754; (c) Ye, Y.-D.; Sanford, M. S.
Synlett 2012, 2005e2013; (d) Wang, H.; Vicic, D. A. Synlett 2013, 1887e1898.
22. Cottet, F.; Schlosser, M. Eur. J. Org. Chem. 2002, 327e330.
(by 19F NMR, E:Z¼1:2). Rf 0.60 (hexane). 1H NMR:
d 2.47 (m, 2H, E-
isomer), 2.65 (m, 2H, Z-isomer), 2.76 (m, 2H and 2H, E and Z-isomer,
respectively), 5.62 (m, 1H and 1H, E and Z-isomer, respectively),
6.01 (dt, J¼11.4, 7.8 Hz, 1H, Z-isomer), 6.41 (m, 1H, E-isomer), 7.24
(m, 10H and 10H, E and Z-isomer, respectively). 13C NMR:
d 33.2 (E-
isomer), 34.0 (E-isomer), 35.0 (Z-isomer), 36.3 (Z-isomer), 118.9 (q,
J¼33.5 Hz, Z-isomer), 119.0 (q, J¼33.4 Hz, E-isomer), 123.0 (q,
J¼268.6 Hz, E-isomer), 123.2 (q, J¼271.7 Hz, Z-isomer), 126.1 (E-
isomer), 126.2 (Z-isomer), 128.3 (E-isomer), 128.4 (E and Z-isomer),
128.5 (Z-isomer), 140.0 (q, J¼6.2 Hz, E-isomer), 141.0 (E-isomer),
23. Iodination was performed on the basis of the following report with slight
modification Hama, Y.; Nobuhara, Y.; Aso, Y.; Otsubo, T.; Ogura, F. Bull. Chem.
Soc. Jpn. 1988, 61, 1683e1686.
141.7 (q, J¼5.6 Hz, Z-isomer), 145.5 (Z-isomer). 19F NMR:
(d, J¼9.0 Hz, E-isomer), ꢁ65.3 (d, J¼6.8 Hz, Z-isomer).
d
ꢁ59.53
24. The product 2 was identified by the following reference data Topczewski, J. J.;
Quinn, D. M. Org. Lett. 2013, 15, 1084e1087.
25. (a) Beletsukaya, I. P.; Cheprakov, A. V. Coord. Chem. Rev. 2004, 248, 2337e2364;
€
ꢀ
(b) Kurti, L.; Czako, B. Strategic Applicaations of Named Reactions in Organic
Synthesis; Elsevier Academic: Burlington, MA, 2005; p 466.
26. Chida, N.; Ohtsuka, M.; Ogawa, S. J. Org. Chem. 1993, 58, 4441e4447.
Acknowledgements
€
27. (a) Wiemers, D. M.; Burton, D. J. J. Am. Chem. Soc. 1986, 108, 832e834; (b) Kutt,
The authors greatly appreciate a generous gift of TMSCF3 by
Tosoh F-Tech Co., Ltd.
A.; Movchun, V.; Rodima, T.; Dansauer, T.; Rusanov, E. B.; Leito, I.; Kaljurand, I.;
Koppel, J.; Pihl, V.; Koppel, I.; Ovsjannikov, G.; Toom, L.; Mishima, M.; Mede-
€
bielle, M.; Lork, E.; Roschenthaler, G.-V.; Koppel, I. A.; Kolomeitsev, A. A. J. Org.
Chem. 2008, 73, 2607e2620.
28. Our species C was converted to [(CF3)4Cu]ꢁ[n-Bu4N]þ following to the Nau-
mann’s protocol to construct the compound which actually gave a singlet
signal at ꢁ35.3 ppm by 19F NMR spectroscopy and m/z 338.9188 by HRMS
(FABꢁ for [(CF3)4Cu]e, Calcd. 338.9210), allowing confirmation of species C as
[(CF3)4Cu]ꢁ. See: (a) Naumann, D.; Roy, T.; Tebbe, K.-F.; Crump, W. Angew. Chem.
, Int. Ed. Engl. 1993, 32, 1482e1483 More recently, Grushin et al. achieved an
easy access to C with a variety of counter cations and they revealed C was
involved in ligand exchange reaction to liberate one of CF3 groups at 90 ꢀC. See
also: (b) Romine, A. M.; Nebra, N.; Konovalov, A. I.; Martin, E.; Benet-Buchholz,
J.; Grushin, V. V. Angew. Chem., Int. Ed. 2015, 54, 2745e2749.
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Please cite this article in press as: Kawasaki-Takasuka, T.; Yamazaki, T., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.07.029