One pot synthesis of novel α,β-dichloro-β-trifluoromethylated enones and their application to the synthesis of trifluoromethylated heterocycles

Article abstract of DOI:10.1016/j.jfluchem.2006.11.003

Trifluoropropynyllithium was reacted with 1 equiv of Weinreb benzamides in THF at -78 to 0 °C, followed by treatment with 4 equiv of trifluoromethanesulfonyl chloride to give α,β-dichloro-β-trifluoromethylated enones 1 in 61-68% yield. The reactions of 1a

Full text of DOI:10.1016/j.jfluchem.2006.11.003

Journal of Fluorine Chemistry 128 (2007) 153–157
www.elsevier.com/locate/fluor
Short communication
One pot synthesis of novel a,b-dichloro-b-trifluoromethylated enones
and their application to the synthesis of trifluoromethylated heterocycles
Sung Lan Jeon a, Joa Kyum Kim a, Jang Bae Son a, Bum Tae Kim b, In Howa Jeong a,
*
a Department of Chemistry, Yonsei University, Wonju 220-710, South Korea
b Korea Research Institute of Chemical Technology, Daejeon 305-606, South Korea
Received 28 September 2006; accepted 7 November 2006
Available online 9 November 2006
Abstract
Trifluoropropynyllithium was reacted with 1 equiv of Weinreb benzamides in THF at À78 to 0 8C, followed by treatment with 4 equiv of
trifluoromethanesulfonyl chloride to give a,b-dichloro-b-trifluoromethylated enones 1 in 61–68% yield. The reactions of 1a with substituted
amidines or hydrazines in refluxing 1,4-dioxane-CH3CN afforded trifluoromethylated chloropyrimidines 3 and chloropyrazoles 6 in 58–98%
yields. The microwave-assisted coupling reactions of 3 with substituted phenylstannane and allylstannane in refluxing CH3CN in the presence of
Pd(PPh3)4 provided the corresponding phenyl and allyl substituted pyrimidines 4 in 89–98% yields.
# 2006 Published by Elsevier B.V.
Keywords: Trifluoropropynyllithium; Trifluoromethanesulfonyl chloride; a,b-Dichloro-b-trifluoromethylated enones; Trifluoromethyl substituted heterocycles;
Microwave-assisted coupling reaction
1. Introduction
report the first preparation of novel a,b-dichloro-b-trifluor-
omethylated enones from trifluoropropyne and their application
to the synthesis of pyrimidines and pyrazoles.
The trifluoromethylated compounds which can be easily
transformed to other functionality have been receiving much
attention as building blocks because of their potential to give a
variety of trifluoromethylated analogs of bioactive and material
molecules [1–3]. Among such building blocks, we are
interested in the preparation of b-chlorinated b-trifluoromethyl
enones which are very useful building blocks to provide
trifluoromethyl substituted heterocycles, such as pyrazoles,
isoxazoles and pyrimidines [4–7]. Although several methods
for the preparation of b-chloro-b-trifluoromethylated enones
and their application to the synthesis of heterocycles have been
well documented in the previous literatures [6,8,9], however,
there has been no report on the preparation of a,b-dichloro-b-
trifluoromethylated enones. Advantage of this a,b-dichloro
enones as compared to b-chloro enones in the synthetic point of
view is to be able to utilize the chloro functionality on the ring
after synthesis of heterocyclic compounds and thus extend the
functionality of heterocyclic ring system. Herein, we wish to
2. Results and discussion
Recently, we reported that trifluoropropynyllithium was
reacted with N-methoxy-N-methylbenzamide (Weinreb benza-
mide) [10] at À78 8C, followed by warming to 0 8C and then
quenching with water to give a mixture of E and Z isomers of
b-trifluoromethyl enaminone in good yield [11]. The reaction
mechanism in this reaction seems likely the formation of
lithium complex intermediate [I] which provided b-trifluor-
omethyl enaminone via the reaction of b-trifluoromethyl ynone
with N-methoxy-N-methylamine formed in the reaction
process. If the same intermediate [I] would be treated with
trifluoromethanesulfonyl chloride (TfCl), trifluoromethanesul-
fonate ester derivative will be formed in the reaction mixture,
which will be further reacted with chloride ion formed in the
reaction process to give chloroallenyl amine derivative which
might be utilized to give the a,b-dichloro-b-trifluoromethy-
lated enones. Therefore, we began with the reaction of
intermediate [I] with TfCl under the several reaction
* Corresponding author. Tel.: +82 33 760 2240; fax: +82 33 763 4323.
E-mail address: jeongih@yonsei.ac.kr (I.H. Jeong).
0022-1139/$ – see front matter # 2006 Published by Elsevier B.V.
doi:10.1016/j.jfluchem.2006.11.003

154
S.L. Jeon et al. / Journal of Fluorine Chemistry 128 (2007) 153–157
Table 1
the yield of 2a. Thus, the highest yield (65%) of 1a was
obtained from the reaction of [I] with 4 equiv of TfCl, whereas
2a was obtained in only 16% yield. Weinreb benzamides
having substituent, such as chloro, methyl and trifluoromethyl
group on meta or para position of benzene ring also provided
the corresponding enones 1b–f in 61–68% yields under the
same reaction condition. However, treatment of [I] having
R CH3 with TfCl resulted in the formation of a messy reaction
mixture and thus the desired product was not obtained. The
results of these reactions are summarized in Table 1.
Preparation of a,b-dichloro-b-trifluoromethylated enones 1
Compound no.
X
n (equiv)
Yield (%)a,b
1
2
c
c
1a, 2a
1a, 2a
1a, 2a
1a, 2a
1b, 2b
1c, 2c
1d, 2d
1e, 2e
1f, 2f
H
1
2
3
4
4
4
4
4
4
–
–
H
40
52
65
63
67
68
61
65
38
26
16
15
14
16
17
14
The reaction mechanism could involve the first formation of
propargylic triflate [II], from the reaction of intermediate [I]
with 1 equiv of TfCl, which is reacted with chloride ion formed
in reaction process to give allene intermediate [III]. Inter-
mediate [III] was further reacted with another 1 equiv of TfCl to
give immonium ion [IV] which was hydrolyzed to give enone
1a. It seems likely that enone 1a is a reactive species toward
nucleophiles and thus was reacted with (N-methoxy-N-
methyl)amine formed in reaction process to give enaminone
2a. Since the formation of 2a depends on the amount of (N-
methoxy-N-methyl)amine formed in reaction process, TfCl will
suppress the formation of 2a by trapping (N-methoxy-N-
methyl)amine. A plausible mechanism for the formation of 1a
was shown in Scheme 1.
H
H
p-Cl
p-CH3
p-CF3
m-Cl
m-CH3
a
Isolated yield.
b
AII products are E and Z isomeric mixture.
c
Reaction provided a messy reaction mixture which could not afford isolable
products.
conditions. When intermediate [I] was reacted with 1 equiv of
TfCl, a messy reaction mixture was obtained unexpectively.
However, the treatment of [I] with 2 equiv of TfCl under the
same reaction condition resulted in the formation of a,b-
dichloro-b-trifluoromethylated enone 1a (E/Z = 37/63) and a-
chloro-b-trifluoromethylated enaminone 2a (E/Z = 80/20) in
40 and 38% yields, respectively. The assignment of E and Z
isomers of 1a and 2a was made by the comparison of chemical
shift in 19F NMR spectroscopy. It has been well established that
19F NMR signal in the Z-isomer of 1a and 2a is less shielded
than that in the E-isomer by a strong anisotropic effect for the
carbonyl bond to CF3 group [8]. The use of higher equiv of TfCl
in this reaction caused to increase the yield of 1a and decrease
The cyclization reactions between 1a and 2 equiv of
amidine derivatives substituted by methyl, phenyl, amino,
phenylamino and methyamino group in refluxing 1,4-
dioxane-CH3CN cosolvent were successful and 5-chloro-6-
trifluoromethylated pyrimidine derivatives 3b–f were
obtained in 62–98% isolated yields. The use of 1,4-dioxane
and CH3CN as cosolvent was important in these reactions.
Most reactions could be completed in 12–24 h depending on
the substituent of amidine. However, amidine was not reacted
with 1a under several reaction conditions, such as refluxing in
1,4-dioxane, refluxing in 1,4-dioxane-H2O or refluxing in 1,4-
Scheme 1. A plausible mechanism for the formation of a,b-dichloro-b-trifluoromethylated enone 1a.

S.L. Jeon et al. / Journal of Fluorine Chemistry 128 (2007) 153–157
155
Table 2
Preparation of 5-chloro-6-trifluoromethylated pyrimidines 3
Table 3
The coupling reaction of 3 with phenylstannane and allylstannane
Compound no.
R
t (h)
Yield (%)a
Compound no. R
R1
Conversion of 3 (%) Yield (%)a
3a
3b
3c
3d
3e
3f
H
24
18
12
12
18
18
NRb
98
4a
4b
4c
4d
4e
4f
4g
4h
4i
Ph
Ph
97
90
70
53
93
89
98
89
95
98
98
98
97
97
92
95
98
90
97
CH3
Ph
P-FC6H4
p-CF3C6H4
p-MeOC6H4
C6H5
NH2
NHPh
NHMe
95
Ph
81
Ph
58
Ph
CH2 CH–CH2 72
62
Me
Me
Me
Me
Me
Ph
48
39
35
38
p-FC6H4
p-CF3C6H4
p-MeOC6H4
a
Isolated yield.
b
No reaction.
4j
CH2 CH–CH2 38
4k
41
4m
4n
4o
NHC(O)Ph Ph
100
100
100
100
dioxane-CH3CN. The results of these reactions are summar-
ized in Table 2.
NHC(O)Ph p-FC6H4
NHC(O)Ph p-CF3C6H4
NHC(O)Ph p-MeOC6H4
We also tested the coupling reaction of 3c with phenyl-
stannane in the presence of Pd(PPh3)4 catalyst. After several
reaction conditions were examined, it was found that
microwave-assisted coupling reaction in CH3CN at 180 8C
for 1 h afforded the coupling product 4a in 93% isolated yield
based on the 97% conversion of 3c. The only small amount of
reduced pyrimidine 5a was observed. When the microwave-
assisted coupling reaction of 3c with phenylstannane was
performed in the presence of 1 equiv of Pd(PPh3)4 and 1 equiv
of CuI in DMF at 250 8C for 1 h, 4a and 5a were obtained in 38
and 58% isolated yields, respectively, based on the 60%
conversion of 3c. The coupling reaction of 3c with
phenylstannane under no microwave-assisted reaction condi-
tion did not progress at all and 3c was recovered. Substituted
phenylstannane and allylstannane were also undergo the
coupling reaction with 3c to give 4b–e in 89–98% yields
based on the 53–90% conversion of 3c under the same reaction
condition. The reaction between 3b and phenylstannane and
allylstannane also afforded the corresponding coupling
products 4f–j in 97–98% yields, but the conversion(35–48%)
of 3b was worse than 3c. Amido substituted pyrimidine 3g
prepared from the reaction of 3d with benzoly chloride in
refluxing CH2Cl2 in the presence of pyridine was reacted with
substituted phenylstannane and allylstannane under the
same reaction condition provided the coupling products
4k–o in 90–98% isolated yields based on the 100% conversion
of starting material. A small amount of reduced pyrimidine was
obtained in less than 5% yield for each case. The results of the
coupling reaction were summarized in Table 3.
NHC(O)Ph CH2 CH–CH2 100
a
Isolated yield.
trifluoromethylated chloropyrazole derivatives 6a–c in high
yields (Scheme 2), but these products did not undergo the
coupling reaction with phenylstannane reagent under micro-
wave-assisted conditions.
3. Conclusion
In conclusion, we have developed an efficient one-pot
synthesis of novel a,b-dichloro-b-trifluoromethylated enones
and their reactions with substituted amidines and hydrazines
afforded the corresponding trifluoromethylated chloropyrimi-
dines and chloropyrazoles. The microwave-assisted coupling
reactions of trifluoromethylated chloropyrimidines with phe-
nylstannane or allylstannane in the presence of Pd catalyst
provided the corresponding trifluoromethylated phenylpyrimi-
dines or allylpyrimidines. Further study on transformations of
chloro substituent in pyrimidine 3 and pyrazole 6 is in progress.
4. Experimental
1H NMR spectra were recorded on a 200 MHz Gemini-200
NMR spectrometer and 19F NMR spectra were recorded on a
100 MHz Bruker AC-100F NMR spectrometer with tetra-
methylsilane (TMS) and CFCl3 as an internal standard,
respectively, and the upfield as negative. All chemical shifts
(d) are expressed in parts per million and coupling constant (J)
The cyclization reactions of 1a with hydrazine derivatives
were also successful and afforded the corresponding
Scheme 2. Preparation of trifluoromethylated chloropyrazole derivatives 6a–c.

156
S.L. Jeon et al. / Journal of Fluorine Chemistry 128 (2007) 153–157
are given in Hertz. Infrared spectra were determined on a
Mattson Genesis series FT High Resolution Spectrophot-
ometer. Mass spectra were obtained by using GC/MS-Qp1000-
Shimadzu (EI, 70 eV). Melting points were determined in open
capillary tubes and are unconnected.
Anal. Calcd. for C17H10ClF3N2: C, 61.00; H, 3.01. Found: C,
60.87; H, 2.98.
5.3. 4-Trifluoromethyl-2,5,6-triphenylpyrimidine (4a)
Commercially available reagents were purchased from
Aldrich, Lancaster, Tokyo Kasei and Fluorochem. All solvents
were dried by general purification method. Flash chromato-
graphy was performed on 40–60 mm silica gel (230–400 mesh).
A 2 mL microwave reactor was charged with 3c (0.033 g,
0.1 mmol), Pd(PPh3)4 (5 mol%) and 1.5 mL of dry CH3CN.
After bubbling with air gas, phenylstannane (0.048 g,
0.13 mmol) was added into the reactor. The reactor was heated
at 180 8C for 1 h. After quenching with 10% KF solution at
room temperature, the reaction mixture was extracted with
CH2Cl2 twice. The CH2Cl2 solution was dried over anhydrous
MgSO4 and chromatographed on SiO2 column. Elution with a
mixture of hexane and ethyl acetate (9:1) provided 0.035 g of
4a in 93% yield. 4a: mp 127–128 8C: 1H NMR (CDCl3) d 8.68–
8.59 (m, 2H), 7.57–7.49 (m, 3H), 7.42–7.17 (m, 10H); 19F
NMR (CDCl3, internal standard CFCl3) d À63.30 (s, 3F); MS,
m/z (relative intensity) 376 (M+, 51), 375 (100), 355 (8), 168
(13), 151 (12), 77 (20); IR (KBr) 3062, 2929, 1554, 1402, 1196,
1144 cmÀ1. Anal. Calcd. for C23H15F3N2: C, 73.40; H, 4.02.
Found: C, 73.25; H, 4.08.
5. Representative experimental procedures
5.1. 2,3-Dichloro-4,4,4-trifluoro-1-phenyl-2-buten-1-one
(1a)
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 with 3,3,3-trifluoropropyne
(1.128 g, 12.0 mmol) and THF at À78 8C and then n-BuLi
(12.0 mmol) was added. After the reaction mixture was stirring
at À78 8C for 30 min, N-methoxy-N-methylbenzamide
(1.815 g, 11.0 mmol) was added into the mixture at À78 8C
and then slowly warmed to 0 8C, followed by quenching with
trifluoromethanesulfonyl chloride (7.37 g, 44.0 mmol). The
reaction mixture was extracted with diethyl ether twice. The
diethyl ether solution was dried over anhydrous MgSO4 and
chromatographed on SiO2 column. Elution with a mixture of
hexane and ethyl acetate (19:1) provided 1.909 g of 1a (E/
Z = 37/63) in 65% yield. 1a: oil: 1H NMR (CDCl3) d 7.97–7.87
(m, 2H), 7.75–7.65 (m, 1H), 7.60–7.50 (m, 2H): 19F NMR
(CDCl3, internal standard CFCl3) d À63.43 (s, 3F, E-isomer),
À62.86 (s, 3F, Z-isomer); MS, m/z (relative intensity) 270
(M+ + 2, 1), 268 (M+, 2), 217 (10), 105 (100), 77 (71), 69 (35);
5.4. 4-Chloro-3-trifluoromethyl-N-methyl-5-
phenylpyrazole (6b)
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 with 1a (0.135 g, 0.5 mmol) and
1,4-dioxane. Methylhydrazine (0.051 g, 1.1 mmol) was added
into the mixture and then the reaction was stirred at room
temperature for 5 h. After quenching with water, the reaction
mixture was extracted with diethyl ether twice. The diethyl
ether solution was dried over anhydrous MgSO4 and
chromatographed on SiO2 column. Elution with a mixture
of hexane and ethyl acetate (1:2) provided 0.137 g of 6b in
IR (neat) 3069, 1691, 1598, 1312, 1255, 1195, 1079 cmÀ1
.
Anal. Calcd. for C10H5Cl2F3O: C, 44.64; H, 1.87. Found: C,
44.55; H, 1.85.
1
95% yield. 6b: oil: H NMR (CDCl3) d 7.86–7.81 (m, 2H),
7.48–7.36 (m, 3H), 4.04 (s, 3H); 19F NMR (CDCl3, internal
standard CFCl3) d À59.46 (s, 3F); MS, m/z (relative intensity)
262 (M+ + 2, 14), 260 (M+, 41), 191 (13), 167 (21), 149 (56),
125 (15), 111 (11), 97 (19), 83 (34), 69 (72), 57 (70), 43 (100);
IR (neat) 3066, 2058, 1444, 1271, 1132, 1089 cmÀ1. Anal.
Calcd. for C11H8ClF3N2: C, 50.07; H, 3.01. Found: C, 49.91;
H, 3.04.
5.2. 5-Chloro-4-trifluoromethyl-2,6-diphenylpyrimidine
(3c)
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 with 1a (0.135 g, 0.5 mmol) and 1,4-
dioxane-CH3CN. Bezamidine generated from the neutraliza-
tion of benzamidineÁHClÁH2O (0.172 g, 1.1 mmol) with
K2CO3 was added into the mixture and then the reaction
was heated to reflux for 12 h. After quenching with water, the
reaction mixture was extracted with diethyl ether twice. The
diethyl ether solution was dried over anhydrous MgSO4 and
chromatographed on SiO2 column. Elution with a mixture of
hexane and ethyl acetate (9:1) provided 0.159 g of 3c (E/
Z = 37/63) in 95% yield. 3c: mp 114–115 8C: 1H NMR
(CDCl3) d 8.55–8.49 (m, 2H), 7.95–7.86 (m, 2H), 7.61–7.44
(m, 6H); 19F NMR (CDCl3, internal standard CFCl3) d À67.91
(s, 3F); MS, m/z (relative intensity) 336 (M+ + 2, 30), 334 (M+,
89), 299 (49), 231 (14), 162 (53), 127 (38), 103 (100), 77 (29);
Acknowledgment
This work was supported by Korea Research Foundation
Grant (KRF-2003-041-C00199) and the Maeji Institute of
Academic Research (2004–2005), Yonsei University.
References
[1] J.F. Liebman, A. Greenberg, W.R. Dolbier Jr., Fluorine-Containing
Molecules, VCH, New York, 1988.
[2] R.E. Banks, B.E. Smart, J.C. Tatlow, Organofluorine Chemistry – Prin-
ciple and Commercial Applications, Plenum, New York, 1994.
[3] I. Ojima, J.R. McCarthy, J.T. Welch, Biomedical Frontiers of Fluorine
Chemistry, ACS, Washington, DC, 1996.
IR (KBr) 3065, 2926, 1544, 1373, 1226, 1175, 1046 cmÀ1
.

S.L. Jeon et al. / Journal of Fluorine Chemistry 128 (2007) 153–157
157
[4] G. Alvernhe, B. Langlois, A. Laurent, I. Le Drean, A. Selmi, Tetrahedron
Lett. 32 (1991) 643–646.
[8] I. Okano, T. Uekawa, S. Eguchi, Bull. Chem. Soc. Jpn. 62 (1989) 2575–
2579.
[5] G. Alvernhe, D. Greif, B. Langlois, A. Laurent, I. Le Drean, M. Pulst, A.
Selmi, M. Weissenfels, Bull. Soc. Chim. Fr. 131 (1994) 167–171.
[6] R. Arnaud, A. Bensadat, A. Ghobsi, A. Laurent, I. Le Drean, S. Lesniak,
A. Selmi, Bull. Soc. Chim. Fr. 131 (1994) 844–853.
[9] A. Selmi, M.M. El Gaied, G. Alvernhe, J. Fluorine Chem. 72 (1995)
1–7.
[10] S. Nahm, S.M. Weinreb, Tetrahedron Lett. 22 (1981) 3815–3818.
[11] I.H. Jeong, S.L. Jeon, Y.K. Min, B.T. Kim, Tetrahedron Lett. 43 (2002)
7171–7174.
[7] J. Diab, A. Laurent, I. Le Drean, J. Fluorine Chem. 84 (1997) 145–147.