Synthetic approach to alkoxy-β-(trifluoromethyl)styrenes and their application in the synthesis of new trifluoromethylated heterocycles

Article abstract of DOI:10.1055/s-0029-1216697

A new convenient stereoselective pathway to alkoxy-β-(trifluoromethyl) styrenes is described. Reactions of β-chloro- and β-bromo-β- (trifluoromethyl)styrenes with sodium methoxide and potassium tert-butoxide led to methoxy- and tert-butoxy-β-(trifluoromethyl) styrenes in good to excellent yields. Bromination of tert-butoxy-β-(trifluoromethyl)styrenes proceeded with formation of aryl(bromo)methyl trifluoromethyl ketones. The latter compounds were found to be useful starting materials for the synthesis of different heterocyclic compounds bearing a trifluoromethyl group. In this way trifluoromethylated derivatives of imidazopyridine, imidazopyrimidine, imidazobenzimidazole, imidazothiazole, thiazole, and aminothiazole were obtained in moderate to high yield. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1216697

PAPER
2249
Synthetic Approach to Alkoxy-b-(trifluoromethyl)styrenes and Their
Application in the Synthesis of New Trifluoromethylated Heterocycles
Synthesis of
N
ew T
a
r
ifluorome
s
thylated
H
i
eteroc
l
ycle
s
iy M. Muzalevskiy,a Valentine G. Nenajdenko,*a Aleksey V. Shastin,b Elizabeth S. Balenkova,a Günter Haufe*c
a
b
c
Moscow State University, Department of Chemistry, Leninskie Gory, Moscow 119992, Russia
E-mail: nen@acylium.chem.msu.ru
Institute of Problems of Chemical Physics, Chernogolovka, Moscow Region 142432, Russia
E-mail: shastin@icp.ac.ru
Organisch-Chemisches Institut, Westfälische Wilhelms-Universität Münster, 48149 Münster, Germany
Fax +49(251)8339772; E-mail: haufe@uni-muenster.de
Received 29 December 2008; revised 26 March 2009
(trifluoromethyl)styrenes,10 a-bromostyrenes,11 or enam-
Abstract: A new convenient stereoselective pathway to alkoxy-b-
(trifluoromethyl)styrenes is described. Reactions of b-chloro- and
b-bromo-b-(trifluoromethyl)styrenes with sodium methoxide and
potassium tert-butoxide led to methoxy- and tert-butoxy-b-(trifluo-
romethyl)styrenes in good to excellent yields. Bromination of tert-
butoxy-b-(trifluoromethyl)styrenes proceeded with formation of ar-
yl(bromo)methyl trifluoromethyl ketones. The latter compounds
were found to be useful starting materials for the synthesis of differ-
ent heterocyclic compounds bearing a trifluoromethyl group. In this
way trifluoromethylated derivatives of imidazopyridine, imid-
azopyrimidine, imidazobenzimidazole, imidazothiazole, thiazole,
and aminothiazole were obtained in moderate to high yield.
ines,12 bearing trifluoromethyl groups.
In continuation of our investigations on the synthesis and
application of b-halo-b-(trifluoromethyl)styrenes, we
have now found that Z/E-mixtures of b-chloro- 1 and b-
bromo-b-(trifluoromethyl)styrenes 2 (3:1 to 10:1)5b,e eas-
ily reacted with sodium methoxide in N,N-dimethylform-
amide forming methoxy-b-(trifluoromethyl)styrenes 3
and 4 in good to excellent yields (Scheme 1, Table 1).
CF3
X
CF3
OR
RO
Ar
CF3
RO–
Key words: alkenes, alkynes, ethers, fluorine, heterocycles, nu-
cleophilic substitution
+
DMF
Ar
Ar
1 X = Cl
2 X = Br
3 (R = Me)
5 (R = t-Bu)
4 (R = Me)
6 (R = t-Bu)
Recent decades have seen remarkable progress in orga-
nofluorine chemistry and a variety of applications for flu-
orinated compounds.1 Particularly fluorine-containing
drugs and pesticides have enjoyed increased interest in
bioorganic chemistry, as well as for medicinal and agri-
cultural applications due to the remarkable effect of fluo-
rine substitution on biological activity.2 Consequently, a
broad spectrum of synthetic methods towards such com-
pounds has been developed in recent years.3
Scheme 1 Reactions of b-chloro- 1 and b-bromo-b-(trifluoro-
methyl)styrenes 2 with alkoxides
Table 1 Synthesis of the Regioisomeric Methoxy-b-(trifluorometh-
yl)styrenes 3 and 4
Entry Styrenea
Ar
Yield (%) of 3 + 4
Ratiob 3/4
From 1
73
From 2
76
1
2
3
4
5
6
1a or 2a
Ph
80:20
67:33
83:17
100:0
90:10
100:0
Earlier, a new catalytic olefination reaction starting from
aldehydes or ketones was discovered by our research
group.4 Based on this reaction, we elaborated new meth-
ods for the synthesis of various fluorinated alkenes.5 It
was also demonstrated that a halogen atom in b-chloro-
and b-bromo-b-(trifluoromethyl)styrenes or b-bromo-b-
fluorostyrenes, obtained by these methods, can be easily
substituted by different nucleophiles. For example, reac-
tions with copper cyanide, sodium 4-toluenesulfinate, al-
kanethiolates, and arenethiolates led to a-fluoro- and a-
(trifluoromethyl)acrylonitriles,6 a-fluoro-b-arylvinyl sul-
fones,7 or to (trifluoromethyl)vinyl sulfides,8 respectively.
1b or 2b 4-MeC6H4
88
85
c
1c
1d
1e
2f
4-ClC6H4
94
–
c
4-O2NC6H4
3-O2NC6H4
2-MeOC6H4
91
–
c
97
–
c
–
89
a 1 (X = Cl) or 2 (X = Br).
b Determined by 1H NMR spectroscopy.
c The reaction was not carried out.
We supposed that treatment of b-halo-b-(trifluorometh-
yl)styrenes with alkoxides would lead to b-alkoxy-b-(tri-
fluoromethyl)styrenes. Similar compounds have already
been used for the synthesis of epoxy ethers,9 b-alkyl-b-
Remarkable heat evolution and fast consumption of start-
ing material were observed for the compounds containing
a nitro group even at room temperature. In all other cases,
heating at 70–80 °C for 1–2 minutes or stirring of the mix-
ture at room temperature for 24 hours were needed to
complete the reaction. This reaction is quite general and
both methoxy-b-(trifluoromethyl)styrenes bearing elec-
SYNTHESIS 2009, No. 13, pp 2249–2259
x
x.
x
x
.
2
0
0
9
Advanced online publication: 12.05.2009
DOI: 10.1055/s-0029-1216697; Art ID: T22808SS
© Georg Thieme Verlag Stuttgart · New York

2250
V. M. Muzalevskiy et al.
PAPER
tron-withdrawing as well as electron-donating substitu- position. The opposite polarization of the double bond in
ents could be obtained in high yields, independently of the the case of electron-donating substituents led to admix-
nature of the halogen atom. The total yields and ratios of tures of the a-regioisomer. Steric hindrance of the ar-
regioisomers 3 and 4 were almost equal for the reactions yl(hetaryl) ring played a decisive role on the direction of
of b-chloro- 1 and b-bromo-b-(trifluoromethyl)styrenes 2 alkoxide attack, thus, styrenes with ortho-substituents in
bearing the same aryl substituent (Table 1, entries 1 and the aryl ring gave the b-regioisomer exclusively, in spite
2).
of their electronic properties (entries 6 and 9).
As expected, the more bulky tert-butoxy-b-(trifluorome- Interestingly, the reactions proceeded with complete ste-
thyl)styrenes had even better regioselectivity (Scheme 1, reoselectivity and the Z-isomers of the alkenes 3–6 were
Table 2).13
obtained exclusively, although the initial styrenes 1 and 2
were used as mixtures of Z/E isomers (see refs5b,e). Similar
selectivity was previously observed for reactions with
copper cyanide and thioles.6,8
Table 2 Synthesis of the Regioisomeric tert-Butoxy-b-(trifluoro-
methyl)styrenes 5 and 6
Entry Styrenesa Ar
Yield (%) of 5+6 Ratiob5/6 Ref
From 1 From 2
To assign the configuration of the double bond in the
alkoxy-b-(trifluoromethyl)styrenes 3 and 5, the spin-spin
3
coupling constants JC,H of the carbon of the trifluoro-
1
2
3
4
5
6
7
8
9
1a or 2a Ph
41
4
74
49
84
90:10 13
83:17
86:14 13
methyl group and the vinylic proton were determined. The
observed values of 3–4 Hz correspond to Z-isomers.14
1b or 2b 4-MeC6H4
1c or 2c 4-ClC6H4
–
Substitution of vinylic halogen atoms (or other leaving
groups in the general case) was found to proceed as an ad-
dition–elimination process in most cases.15 However, the
elimination–addition sequence is also possible and cannot
be ignored. To clarify this point, we synthesized the acet-
ylenes 7c, 7d, and 7h by elimination of HCl from com-
pounds 1c, 1d, and 1h and reacted them with potassium
tert-butoxide under the same reaction conditions as the
styrenes 1 or 2 (Scheme 2).
83
83
70
c
1d
1e
2f
4-O2NC6H4
3-O2NC6H4
2-MeOC6H4
3-MeOC6H4
4-MeOC6H4
–
100:0
91:9
13
–
c
–
c
–
97
88
91
70
73
98
100:0
92:8
13
13
–
c
2g
2h
–
c
–
67:33
100:0
100:0
67:33
100:0
1i or 2i 2-BrC6H4
65
62
13
–
CF3
t-BuO
Ar
CF3
t-BuOK
DMF
+
Ar
CF3
10 1j or 2j 4-MeO2CC6H4
Ar
Ot-Bu
c
7
11 2k
12 1l
3,4-(MeO)2C6H3
2-pyridyl
–
–
5
6
c
d
h
Ar = 4-ClC6H4
Ar = 4-O2NC6H4
Ar = 4-MeOC6H4
88:12 (86:14)
100:0 (100:0)
87:13 (67:33)
c
72
–
–
a 1 (X = Cl) or 2 (X = Br).
Scheme 2 Reactions of acetylenes 7 with potassium tert-butoxide,
values in parenthesis represent the product ratio for the reactions of
compounds 2
b Determined by 1H NMR spectroscopy.
c The reaction was not carried out.
Indeed, in the case of styrenes with a phenyl substituent
1a and 2a (entry 1) or electron-donating substituents at the
aryl group 1b and 2b (entry 2), the share of the a-regio-
isomer 6 drops significantly comparing to the reactions of
the same styrenes and sodium methoxide, while, in case of
styrenes with electron-withdrawing substituents, a similar
effect was not observed. Again, the nature of halogen in
the starting styrenes did not affect the ratio and the total
yield of products 5 and 6 in case of styrenes with attached
electron-withdrawing substituents 1c and 2c, 1f and 2f,
and 1j and 2j (entries 3, 6, and 10). However, using the
bromostyrenes 2a and 2b bearing no or an electron-donat-
ing substituent, the yields were higher compared to the
chloro compounds 1a and 1b. Moreover, the regioselec-
tivity of the reaction with alkoxides was influenced by
both electronic and steric properties of the aryl(hetaryl)
substituent and the bulkiness of the alkoxide. Caused by
negative mesomeric effect of the electron-deficient aryl
ring, the excessive positive charge on the carbon atom in
b-position of the double bond directed the alkoxide to that
We observed the same distribution of regioisomers in case
of the reactions of the acetylenes 7c and 7d bearing elec-
tron-withdrawing groups, which actually is not conclusive
concerning the reaction mechanism, since the ratio of re-
gioisomers could be equal by chance. However, for the
electron-rich acetylene 7h the share of regioisomer 6h
dropped significantly compared to the reaction of styrene
2h. This noticeable difference suggests that the reaction of
styrenes 2 with potassium tert-butoxide occurs via an ad-
dition–elimination process, at least in case of styrenes
with electron-donating substituents.
For more than a century it has been known that bromina-
tion of enol ethers leads to the corresponding a-bromo ke-
tones.16 However, in the case of bromination of 1-
(trifluoromethyl)enol ethers the nature of the product
strongly depends on the substituent at the oxygen atom. If
the substituent at the oxygen atom can be eliminated as a
stable cation, the aryl(bromo)methyl trifluoromethyl ke-
tone is formed (from silyloxy enol ethers).17 Otherwise
Synthesis 2009, No. 13, 2249–2259 © Thieme Stuttgart · New York

PAPER
Synthesis of New Trifluoromethylated Heterocycles
2251
bromination leads to saturated vicinal dibromides (from The reaction of a-bromo ketones with 2-aminopyridines
alkyl enol ethers).18
is the most general approach to the synthesis of imidazo-
pyridines.23 The imidazopyridine moiety is the pharma-
cophore of several drugs, such as Zolpidem, Alpidem,
Saripidem, and Necopidem, which are used for the short-
term treatment of insomnia, as well as against particular
brain disorders.24,25 Having this interesting biological ac-
tivity in mind, we refluxed the crude bromo ketones 8
with 2-aminopyridine in acetonitrile and obtained the cor-
responding imidazopyridines 9 in moderate yields
(Table 3).
Since the tert-butyl cation belongs to the most stable alkyl
cations, we expected that bromination of tert-butoxy-b-
(trifluoromethyl)styrenes 5c/6c would lead to aryl(bro-
mo)methyl trifluoromethyl ketones. Consequently, we
reacted a mixture of the tert-butoxy-b-(trifluorometh-
yl)styrenes 5c/6c with bromine in dichloromethane at
room temperature. In the 1H NMR spectrum of the prod-
uct mixture we no longer found the signal of a vinylic pro-
ton or the protons of the tert-butyl group. Instead the
signal of one benzylic proton appeared at d = 5.77. The It should be noted, that even when mixtures of styrenes 5
13C NMR spectrum, among others, exhibited the quadru- and 6 were applied, only the regioisomeric imidazopyr-
plet of the trifluoroacetyl carbon at d = 183.0 (J = 35.9 idines 9 were obtained (entries 1, 2, 4, 6, and 7). No start-
Hz). Also the signal of the benzylic carbon was observed ing material and no other products could be isolated. This
at d = 44.6. Thus, the obtained compound is the desired seems to be due to the instability of the a-bromo ketones
bromo ketone 8c, which was isolated as a crude product in and/or intermediates formed from it. In particular, the low
approximately 85% yield. Due to the instability of such yields of the methoxy compounds 9f and 9h support this
ketones9 all following reactions were performed in one hypothesis.
pot without isolation of bromo ketones 8.
To estimate the synthetic scope of aryl(bromo)methyl tri-
a-Halo ketones are very reactive compounds that have fluoromethyl ketones 8 for the preparation of other hetero-
been widely used in the synthesis of heterocycles.19 Al- cycles, we treated the model ketone 8c with several other
though the above-mentioned aryl(bromo)methyl trifluo- binucleophiles. Derivatives of imidazopyridine, imida-
romethyl ketones were previously described,20 only a few zopyrimidine, imidazobenzimidazole, imidazothiazole,
reactions of these compounds have been investigated. For aminothiazole, and methylthiazole, bearing a trifluorome-
example, the reaction with sodium alkoxides leads to sub- thyl group were obtained in moderate to high yields
stitution of bromine giving alkylbenzylic alcohols,20 other (Table 4).
examples are the reactions with thiourea and its N-substi-
The best yields were obtained for trifluoromethylated thi-
tuted derivatives giving aminothiazoles21 and reactions
azole derivatives (entries 5–8). Obviously, the high nu-
with alcohols to give oxiranes.22
cleophilicity of sulfur leads to rapid formation of the
isothiouronic salt preventing side reactions.
In conclusion, the nucleophilic substitution of one halo-
gen atom of b-chloro- and b-bromo-b-(trifluorometh-
yl)styrenes 1 and 2 by methoxide and tert-butoxide
proceeds with complete stereoselectivity and high regio-
Table 3 Synthesis of Imidazopyridines 9 from Aryl(bromo)methyl
Trifluoromethyl Ketones and 2-Aminopyridine
Br
CF3
Br2
CF3
selectivity to give the alkoxy-b-(trifluoromethyl)styrenes
Ar
CH2Cl2
Ar
Ot-Bu
3–6 in good to excellent yields. The isomers with Z-con-
figuration of the double bond were formed exclusively. It
was shown that the tert-butoxystyrenes 5 react with bro-
mine to form unstable aryl(bromo)methyl trifluoromethyl
ketones 8. From these building blocks a series of trifluo-
romethyl-containing heterocycles 9–17, was synthesized
in moderate to high yields.
O
5
8
N
N
NH2
CF3
N
MeCN, reflux
9
Ar
Entry
Styrenes
5a/6a
5c/6c
5d
Ar
Ph
Product
9a
Yield (%)
NMR spectra were recorded on Bruker ARX 300 and Bruker AMX
400 in CDCl3, DMSO-d6, or acetone-d6 with TMS as internal stan-
dard. IR spectra were obtained as films. Mass spectra (ESI-MS)
were measured on a MicroTof Bruker Daltonics. Column and TLC
chromatography were performed using silica gel Merck 60 or
Merck 60F254 plates, respectively. The b-chloro- 1 and b-bromo-b-
(trifluoromethyl)styrenes 2 were synthesized according to our pre-
viously reported procedure.5b,e All solvents were distilled before us-
ing. 1H NMR spectra of compounds 7c, 7d, and 7h are in agreement
with published data.25
1
2
3
4
5
6
7
8
46
52
53
42
31
51
27
51
4-ClC6H4
9c
4-O2NC6H4
3-O2NC6H4
2-MeOC6H4
3-MeOC6H4
4-MeOC6H4
2-BrC6H4
9d
5e/6e
5f
9e
9f
5g/6g
5h/6h
5i
9g
9h
9i
Synthesis 2009, No. 13, 2249–2259 © Thieme Stuttgart · New York

2252
V. M. Muzalevskiy et al.
PAPER
The regioisomers 3 and 4 could not be separated by column chro-
matography.
Table 4 Synthesis of Various Trifluoromethylated Heterocycles
10–17 from 5c/6c
Br
CF3
[(1Z)-3,3,3-Trifluoro-2-methoxyprop-1-enyl]benzene (3a) and
[(1Z)-3,3,3-Trifluoro-1-methoxyprop-1-enyl]benzene (4a)
From styrenes 1a (415 mg, 2 mmol) or 2a (502 mg, 2 mmol) as a
colorless oil; yield (3 + 4): 294 mg (73%, from 1a), 307 mg (76%,
from 2a); ratio 3a/4a 80:20.
Br2
Nu
CF3
10–17
Ar
CH2Cl2
Ar
Ot-Bu
O
5c
Ar = 4-ClC6H4
8c
Entry Nucleophile
Producta
Yield (%)
Anal. Calcd for C10H9F3O: C, 59.41; H, 4.49. Found: C, 59.52; H,
4.63.
N
Br
CF3
Regioisomer 3a
N
1
44
47
Br
1H NMR (400 MHz, CDCl3): d = 3.85 (s, 3 H, OCH3), 6.53 (s, 1 H,
CH=CCF3), 7.37–7.55 (m, 3 H, Ar), 7.72 (d, J = 7.3 Hz, 2 H, Ar).
Ar
N
NH2
10
13C NMR (100 MHz, CDCl3): d = 60.0 (OCH3), 117.2 (q, J = 4.4
Hz, CH=CCF3), 121.4 (q, J = 275.9 Hz, CF3), 128.7 (Ar), 128.9
(Ar), 129.6 (Ar), 132.2 (Ar), 143.5 (q, J = 32.2 Hz, C-CF3).
N
CF3
N
N
2
Ar
N
N
NH2
Regioisomer 4a
11
1H NMR (400 MHz, CDCl3): d = 3.70 (s, 3 H, OCH3), 5.37 (q,
J = 7.6, 1 H, CHCF3).
N
CF3
N
13C NMR (100 MHz, CDCl3): d = 59.0 (OCH3), 100.6 (q, J = 34.4
Hz, C=CHCF3), 123.6 (q, J = 269.3 Hz, CF3), 127.5 (Ar), 128.8
(Ar), 133.1 (Ar); the other signals are identical to those of the regio-
isomer 3a.
N
3
4
52
37
NH2
Ar
N
12
H
N
N
H
N
1-Methyl-4-[(1Z)-3,3,3-trifluoro-2-methoxyprop-1-enyl]ben-
zene (3b) and 1-Methyl-4-[(1Z)-3,3,3-trifluoro-1-methoxyprop-
1-enyl]benzene (4b)
CF3
NH2
N
Ar
From styrenes 1b (440 mg, 2 mmol) or 2b (530 mg, 2 mmol) as a
colorless oil; yield (3 + 4): 380 mg (88%, from 1b), 367 mg (85%,
from 2b); ratio 3b/4b 67:33.
13
S
N
CF3
N
S
N
5
6
7
60
72
80
Anal. Calcd for C11H11F3O: C, 61.11; H, 5.13. Found: C, 61.40; H,
4.94.
NH2
Ar
14
Regioisomer 3b
CF3
1H NMR (400 MHz, CDCl3): d = 2.45 (s, 3 H, CH3), 3.84 (s, 3 H,
OCH3), 6.49 (s, 1 H, CH=CCF3), 7.27 (d, J = 8.0 Hz, 2 H, Ar), 7.61
(d, J = 8.0 Hz, 2 H, Ar).
N
S
⋅HBr
NH2
H2N
S
Ar
H2N
13C NMR (100 MHz, CDCl3): d = 21.3 (CH3), 60.0 (OCH3), 117.3
(q, J = 4.4 Hz, CH=CCF3), 121.6 (q, J = 275.9 Hz, CF3), 127.5 (Ar),
129.4 (Ar), 129.5 (Ar), 139.0 (Ar), 143.8 (q, J = 32.2 Hz, C-CF3).
15·HBr
CF3
N
S
HN
Ph
Ph
S
Ar
H2N
N
H
Regioisomer 4b
1H NMR (400 MHz, CDCl3): d = 2.48 (s, 3 H, CH3), 3.70 (s, 3 H,
OCH3), 5.33 (q, J = 7.8 Hz, 1 H, CHCF3), 7.32 (d, J = 8.0 Hz, 2 H,
Ar), 7.43 (d, J = 8.0 Hz, 2 H, Ar).
16
OH
N
S
CF3
Ar
8
54
13C NMR (100 MHz, CDCl3): d = 58.9 (OCH3), 100.2 (q, J = 33.7
Hz, C=CHCF3), 123.6 (q, J = 268.6 Hz, CF3), 127.5 (Ar), 140.7
(Ar), the other signals are identical to those of the regioisomer 3b.
H2N
S
17
1-Chloro-4-[(1Z)-3,3,3-trifluoro-2-methoxyprop-1-enyl]ben-
zene (3c) and 1-Chloro-4-[(1Z)-3,3,3-trifluoro-1-methoxyprop-
1-enyl]benzene (4c)
From styrene 2c (482 mg, 2 mmol) as a colorless oil; yield (3 + 4):
444 mg (94%); ratio 3c/4c 83:17.
[(1Z)-3,3,3-Trifluoro-2-methoxyprop-1-enyl]benzenes 3 and
[(1Z)-3,3,3-Trifluoro-1-methoxyprop-1-enyl]benzenes 4; Gen-
eral Procedure
A one-neck, 25-mL round-bottomed flask was charged with anhyd
DMF (2 mL), the corresponding styrene 1 or 2 (2 mmol) and a soln
of NaOMe (0.108 g, 2 mmol) in anhyd DMF (2 mL) were added
dropwise with stirring. The mixture was heated at 70–80 °C for 1–
2 min then cooled to r.t. (no heating is necessary for compound 1d)
and poured into H2O (100 mL). The products were extracted with
CH2Cl2 (3 ꢀ 20 mL) and the combined extracts were washed with
H2O (2 ꢀ 50 mL) and brine (50 mL) and dried (Na2SO4). CH2Cl2
was evaporated in vacuo and the residue was filtered through a short
silica gel pad (hexane or appropriate mixtures of hexane–CH2Cl2).
Anal. Calcd for C10H8ClF3O: C, 50.76; H, 3.41. Found: C, 50.52; H,
3.53.
Regioisomer 3c
1H NMR (400 MHz, CDCl3): d = 3.81 (s, 3 H, OCH3), 6.41 (s, 1 H,
CH=CCF3), 7.38 (d, J = 8.4 Hz, 2 H, Ar), 7.60 (d, J = 8.4 Hz, 2 H,
Ar).
Synthesis 2009, No. 13, 2249–2259 © Thieme Stuttgart · New York

PAPER
Synthesis of New Trifluoromethylated Heterocycles
2253
13C NMR (100 MHz, CDCl3): d = 59.9 (OCH3), 115.8 (q, J = 4.4
Hz, CH=CCF3), 121.2 (q, J = 275.9 Hz, CF3), 128.9 (Ar), 130.8
(Ar), 134.5 (Ar), 143.8 (q, J = 32.2 Hz, C-CF3).
J = 275.2 Hz, CF3), 130.0 (Ar), 130.1 (Ar), 143.4 (q, J = 32.2 Hz,
C-CF3), 157.1 (Ar).
Anal. Calcd for C11H11F3O2: C, 56.90; H, 4.77. Found: C, 57.03; H,
4.93.
Regioisomer 4c
1H NMR (400 MHz, CDCl3): d = 3.66 (s, 3 H, OCH3), 5.34 (q,
J = 7.6 Hz, 1 H, CHCF3), 7.19 (d, J = 8.1 Hz, 2 H, Ar), 7.32 (d,
J = 8.1 Hz, 2 H, Ar).
[(1Z)-2-tert-Butoxy-3,3,3-trifluoroprop-1-enyl]benzenes 5 and
[(1Z)-1-tert-Butoxy-3,3,3-trifluoroprop-1-enyl]benzenes 6;
General Procedures
13C NMR (100 MHz, CDCl3): d = 59.1 (OCH3), 101.3 (q, J = 34.4
Hz, C=CHCF3), 123.3 (q, J = 268.6 Hz, CF3), 128.3 (Ar), 129.1
(Ar), 136.5 (Ar).
According to the given protocol using potassium tert-butoxide,13
1
the following tert-butyl enol ethers were prepared. The H NMR
data of compounds 5a, 5c, 5d, 5f, and 5i agree with published data.
1-Nitro-4-[(1Z)-3,3,3-trifluoro-2-methoxyprop-1-enyl]benzene
(3d)
From styrene 1d (502 mg, 2 mmol) as a yellow oil; yield: 450 mg
[(1Z)-2-tert-Butoxy-3,3,3-trifluoroprop-1-enyl]benzene (5a)
and [(1Z)-1-tert-Butoxy-3,3,3-trifluoroprop-1-enyl]benzene
(6a)
(91%).
From styrenes 1a (1035 mg, 5 mmol) or 2a (1255 mg, 5 mmol) as a
colorless oil; yield (5 + 6): 500 mg (41%, from 1a), 903 mg (74%,
from 2a); ratio 5a/6a 90:10.
IR (Nujol): 1660 (C=C) cm–1.
1H NMR (400 MHz, CDCl3): d = 3.85 (s, 3 H, OCH3), 6.44 (s, 1 H,
CH=CCF3), 7.79 (d, J = 8.6 Hz, 2 H, Ar), 8.21 (d, J = 8.6 Hz, 2 H,
Ar).
13C NMR (100 MHz, CDCl3): d = 56.2 (OCH3), 113.8 (q, J = 4.4
Hz, CH=CCF3), 120.0 (q, J = 275.9 Hz, CF3), 123.5 (Ar), 130.1
(Ar), 138.5 (Ar), 145.8 (q, J = 31.5 Hz, C-CF3), 147.2 (Ar).
Anal. Calcd for C13H15F3O: C, 63.93; H, 6.19. Found: C, 64.38; H,
5.83.
Regioisomer 5a
Anal. Calcd for C10H8F3NO3: C, 48.59; H, 3.26. Found: C, 48.79; H,
3.43.
13C NMR (100 MHz, CDCl3): d = 28.8 [OC(CH3)3], 84.3
[OC(CH3)3], 121.4 (q, J = 276.6 Hz, CF3), 122.0 (q, J = 4.4 Hz,
CH=CCF3), 128.3 (Ar), 128.5 (Ar), 129.7 (Ar), 133.4 (Ar), 140.2
(q, J = 32.2 Hz, C-CF3).
1-Nitro-3-[(1Z)-3,3,3-trifluoro-2-methoxyprop-1-enyl]benzene
(3e) and 1-Nitro-3-[(1Z)-3,3,3-trifluoro-1-methoxyprop-1-
enyl]benzene (4e)
From styrene 1e (502 mg, 2 mmol) as a yellow oil; yield (3 + 4): 479
mg (97%); ratio 3e/4e 90:10.
Regioisomer 6a
13C NMR (100 MHz, CDCl3): d = 29.4 [OC(CH3)3], 82.2
[OC(CH3)3], 106.2 (q, J = 33.7 Hz, C=CHCF3), 127.9 (Ar), 128.2
(Ar), 129.0 (Ar), the other signals are identical to those of the regio-
isomer 5a.
Anal. Calcd for C10H8F3NO3: C, 48.59; H, 3.26. Found: C, 48.73; H,
3.41.
Regioisomer 3e
1-[(1Z)-2-tert-Butoxy-3,3,3-trifluoroprop-1-enyl]-4-methylben-
zene (5b) and 1-[(1Z)-1-tert-Butoxy-3,3,3-trifluoroprop-1-enyl]-
4-methylbenzene (6b)
From styrenes 1b (1200 mg, 5 mmol) or 2b (1325 mg, 5 mmol) as
a colorless oil; yield (5 + 6): 52 mg (4%, from 1b), 632 mg (49%,
from 2b); ratio 5b/6b 83:17.
1H NMR (400 MHz, CDCl3): d = 3.84 (s, 3 H, OCH3), 6.43 (s, 1 H,
CH=CCF3), 7.55 (t, J = 8.0 Hz, 1 H, Ar), 7.91 (d, J = 8.0 Hz, 1 H,
Ar), 8.10–8.15 (m, 1 H, Ar), 8.48 (br s, 1 H, Ar).
13C NMR (100 MHz, CDCl3): d = 59.8 (OCH3), 113.9 (q, J = 4.4
Hz, CH=CCF3), 120.6 (q, J = 276.6 Hz, CF3), 123.1 (Ar), 123.9
(Ar), 129.5 (Ar), 133.8 (Ar), 135.1 (Ar), 145.0 (q, J = 32.2 Hz, C-
CF3), 148.3 (Ar).
IR (Nujol): 1660 (C=C) cm–1.
Anal. Calcd for C14H17F3O: C, 65.10; H, 6.63. Found: C, 65.40; H,
6.33.
Regioisomer 4e
1H NMR (400 MHz, CDCl3): d = 3.68 (s, 3 H, OCH3), 5.45 (q,
J = 7.8 Hz, 1 H, CHCF3), 7.65 (t, J = 7.9 Hz, 1 H, Ar), 7.83 (d,
J = 7.9 Hz, 1 H, Ar), 8.27–8.33 (m, 2 H, Ar).
Regioisomer 5b
1H NMR (400 MHz, CDCl3): d = 1.38 [s, 9 H, OC(CH3)3], 2.41 (s,
3 H, CH3), 6.65 (s, 1 H, CH=CCF3), 7.22 (d, J = 8.4 Hz, 2 H, Ar),
7.61 (d, J = 8.4 Hz, 2 H, Ar).
13C NMR (100 MHz, CDCl3): d = 56.1 (OCH3), 102.7 (q, J = 34.4
Hz, C=CHCF3), 123.6 (Ar), 124.9 (Ar), 130.0 (Ar), 132.9 (Ar),
134.1 (Ar), 148.4 (Ar), the other signals are identical to those of the
regioisomer 3d.
13C NMR (100 MHz, CDCl3): d = 21.3 (CH3), 28.8 [OC(CH3)3],
84.0 [OC(CH3)3], 121.6 (q, J = 276.7 Hz, CF3), 122.0 (q, J = 3.7 Hz,
CH=CCF3), 129.0 (Ar), 129.7 (Ar), 130.5 (Ar), 138.5 (Ar), 139.4
(q, J = 32.2 Hz, C-CF3).
1-Methoxy-2-[(1Z)-3,3,3-trifluoro-2-methoxyprop-1-enyl]ben-
zene (3f)
Regioisomer 6b
From styrene 2f (562 mg, 2 mmol) as a colorless oil; yield: 415 mg
(89%).
1H NMR (400 MHz, CDCl3): d = 1.31 [s, 9 H, OC(CH3)3], 2.40 (s,
3 H, CH3), 5.31 (q, J = 7.8 Hz, 1 H, CHCF3), 7.54 (d, J = 8.1 Hz, 2
H, Ar).
1H NMR (400 MHz, CDCl3): d = 3.78 (s, 3 H, OCH3), 3.91 (s, 3 H,
OCH3), 6.93 (s, 1 H, CH=CCF3), 6.97 (d, J = 7.9 Hz, 1 H, Ar), 7.06
(t, J = 7.9 Hz, 1 H, Ar), 7.38 (td, J = 7.9, 1.4 Hz, 1 H, Ar), 7.98 (dd,
J = 7.9, 1.4 Hz, 1 H, Ar).
13C NMR (100 MHz, CDCl3): d = 55.4, 60.1 (both OCH3), 110.9 (q,
J = 3.7 Hz, CH=CCF3), 110.5 (Ar), 120.7 (Ar), 120.9 (Ar), 121.5 (q,
13C NMR (100 MHz, CDCl3): d = 21.2 (CH3), 29.3 [OC(CH3)3],
82.0 [OC(CH3)3], 105.5 (q, J = 32.9 Hz, C=CHCF3), 121.7 (q,
J = 274.5 Hz, CF3), 128.4 (Ar), 129.5 (Ar), 130.9 (Ar), 139.3 (Ar),
the other signals are identical to those of the regioisomer 5b.
Synthesis 2009, No. 13, 2249–2259 © Thieme Stuttgart · New York

2254
V. M. Muzalevskiy et al.
PAPER
1-[(1Z)-2-tert-Butoxy-3,3,3-trifluoroprop-1-enyl]-4-chloroben-
zene (5c) and 1-[(1Z)-1-tert-Butoxy-3,3,3-trifluoroprop-1-enyl]-
4-chlorobenzene (6c)
From styrenes 1c (1205 mg, 5 mmol) or 2c (1425 mg, 5 mmol) as a
colorless oil; yield (5 + 6): 1153 mg (83%, from 1c), 1168 mg (84%,
from 2c); ratio 5c/6c 86:14.
Regioisomer 6e
1H NMR (400 MHz, CDCl3): d = 1.27 [s, 9 H, OC(CH3)3], 5.43 (q,
J = 7.6 Hz, 1 H, CHCF3), 7.66 (t, J = 8.0 Hz, 1 H, Ar), 7.85 (d,
J = 8.0 Hz, 1 H, Ar), 8.27 (dd, J = 8.0 Hz, J = 1.3 Hz, 1 H, Ar), 8.43
(br s, 1 H, Ar).
13C NMR (100 MHz, CDCl3): d = 29.4 [OC(CH3)3], 83.2
[OC(CH3)3], 108.1 (q, J = 33.7 Hz, C=CHCF3), 122.6 (Ar), 124.5
(Ar), 129.5 (Ar), 133.4 (Ar), 138.0 (Ar), 148.1 (Ar), 159.5 (q,
J = 5.1 Hz, C=CHCF3), the other signals are identical to those of the
regioisomer 5e.
IR (Nujol): 1660 (C=C) cm–1.
Anal. Calcd for C13H14ClF3O: C, C 56.02; H, 5.06. Found: C, 55.63;
H, 4.78.
Regioisomer 5c
19F NMR (282 MHz, CDCl3): d = –57.3 (d, J = 7.6 Hz, CF3).
13C NMR (100 MHz, CDCl3): d = 28.7 [OC(CH3)3], 84.6
[OC(CH3)3], 120.7 (q, J = 4.4 Hz, CH=CCF3), 121.4 (q, J = 276.6
Hz, CF3), 128.6 (Ar), 131.0 (Ar), 131.9 (Ar), 134.2 (Ar), 140.7 (q,
J = 32.2 Hz, C-CF3).
1-[(1Z)-2-tert-Butoxy-3,3,3-trifluoroprop-1-enyl]-2-methoxy-
benzene (5f)
From styrene 2f (1405 mg, 5 mmol) as a colorless oil; yield: 1363
mg (97%).
IR (Nujol): 1660 (C=C) cm–1.
19F NMR (282 MHz, CDCl3): d = –67.2 (s, CF3).
Regioisomer 6c
13C NMR (100 MHz, CDCl3): d = 28.7 [OC(CH3)3], 55.4 (OCH3),
83.8 [OC(CH3)3], 110.4 (Ar), 117.0 (q, J = 3.7 Hz, CH=CCF3),
120.1 (Ar), 121.5 (q, J = 275.9 Hz, CF3), 122.2 (Ar), 129.8 (Ar),
130.8 (Ar), 139.7 (q, J = 32.2 Hz, C-CF3), 157.1 (Ar).
19F NMR (282 MHz, CDCl3): d = –67.49 (s, CF3).
HRMS (ESI): m/z [M + Na]+ calcd for C14H17F3NaO2: 297.1078;
13C NMR (100 MHz, CDCl3): d = 29.3 [OC(CH3)3], 82.5
[OC(CH3)3], 106.5 (q, J = 32.9 Hz, C=CHCF3), 123.0 (q, J = 270.1
Hz, CF3), 128.5 (Ar), 129.1 (Ar), 135.8 (Ar), 136.6 (Ar), 161.2 (q,
J = 5.9 Hz, C=CHCF3).
19F NMR (282 MHz, CDCl3): d = –56.9 (d, J = 7.6 Hz, CF3).
found: 297.1073.
1-[(1Z)-2-tert-Butoxy-3,3,3-trifluoroprop-1-enyl]-4-nitroben-
zene (5d)
Anal. Calcd for C14H17F3O2: C, 61.31; H, 6.25. Found: C, 61.33; H
5.93.
From styrene 1d (1250 mg, 5 mmol) as a yellow oil; yield: 1200 mg
(83%).
IR (Nujol): 1360, 1540 (NO2), 1670 (C=C) cm–1.
1-[(1Z)-2-tert-Butoxy-3,3,3-trifluoroprop-1-enyl]-3-methoxy-
benzene (5g) and 1-[(1Z)-1-tert-Butoxy-3,3,3-trifluoroprop-1-
enyl]-3-methoxybenzene (6g)
From styrene 1g (1405 mg, 5 mmol) as a colorless oil; yield (5 + 6):
1205 mg (88%); ratio 5g/6g 92:8.
IR (Nujol): 1660 (C=C) cm–1.
HRMS (ESI): m/z [M + Na]+ calcd for C14H17F3NaO2: 297.1078;
13C NMR (100 MHz, CDCl3): d = 28.8 [OC(CH3)3], 85.9
[OC(CH3)3], 119.7 (q, J = 3.7 Hz, CH=CCF3), 120.8 (q, J = 277.4
Hz, CF3), 123.6 (Ar), 130.3 (Ar), 140.0 (Ar), 143.2 (q, J = 32.9 Hz,
C-CF3), 147.2 (Ar).
19F NMR (282 MHz, CDCl3): d = –67.5 (s, CF3).
HRMS (ESI): m/z [M + Na]+ calcd for C13H14F3NNaO3: 312.0823;
found: 297.1073.
found: 312.0832.
Anal. Calcd for C14H17F3O2: C, 61.31; H, 6.25. Found: C, 61.35; H,
6.03.
Anal. Calcd for C13H14F3NO3: C, 53.98; H, 4.88. Found: C, 53.69;
H, 4.77.
Regioisomer 5g
1-[(1Z)-2-tert-Butoxy-3,3,3-trifluoroprop-1-enyl]-3-nitroben-
zene (5e) and 1-[(1Z)-1-tert-Butoxy-3,3,3-trifluoroprop-1-enyl]-
3-nitrobenzene (6e)
From styrene 1e (1255 mg, 5 mmol) as a yellow oil; yield (5 + 6):
1012 mg (70%); ratio 5e/6e 91:9.
13C NMR (100 MHz, CDCl3): d = 28.8 [OC(CH3)3], 55.2 (OCH3),
84.3 [OC(CH3)3], 114.6 (Ar), 114.7 (Ar), 121.4 (q, J = 276.6 Hz,
CF3), 122.0 (q, J = 4.4 Hz, CH=CCF3), 122.3 (Ar), 129.3 (Ar),
134.6 (Ar), 140.2 (q, J = 32.2 Hz, C-CF3), 159.5 (Ar).
19F NMR (282 MHz, CDCl3): d = –67.2 (s, CF3).
IR (Nujol): 1360, 1540 (NO2), 1660 (C=C) cm–1
.
HRMS (ESI): m/z [M + Na]+ calcd for C13H14F3NNaO3: 312.0823;
found: 312.0818.
Regioisomer 6g
13C NMR (100 MHz, CDCl3): d = 29.3 [OC(CH3)3], 55.2 (OCH3),
82.3 [OC(CH3)3], 105.1 (q, J = 32.9 Hz, C=CHCF3), 113.2 (Ar),
115.5 (Ar), 120.2 (Ar), 159.3 (Ar), the other signals are identical to
those of the regioisomer 5g.
Anal. Calcd for C13H14F3NO3: C, 53.98; H, 4.88. Found: C, 53.87;
H 4.68.
Regioisomer 5e
1-[(1Z)-2-tert-Butoxy-3,3,3-trifluoroprop-1-enyl]-4-methoxy-
benzene (5h) and 1-[(1Z)-1-tert-Butoxy-3,3,3-trifluoroprop-1-
enyl]-4-methoxybenzene (6h)
From styrene 2h (1405 mg, 5 mmol) as a colorless oil; yield (5 + 6):
1247 mg (91%); ratio 5h/6h 67:33.
1H NMR (400 MHz, CDCl3): d = 1.36 [s, 9 H, OC(CH3)3], 6.68 (s,
1 H, CH=CCF3), 7.56 (t, J = 8.1 Hz, 1 H, Ar), 7.88 (d, J = 8.1 Hz, 1
H, Ar), 8.16 (dd, J = 8.1, 1.5 Hz, 1 H, Ar), 8.70 (br s, 1 H, Ar).
13C NMR (100 MHz, CDCl3): d = 28.8 [OC(CH3)3], 85.6
[OC(CH3)3], 119.4 (q, J = 3.7 Hz, CH=CCF3), 121.4 (q, J = 276.6
Hz, CF3), 123.1 (Ar), 124.2 (Ar), 129.4 (Ar), 135.0 (Ar), 135.5 (Ar),
142.6 (q, J = 32.9 Hz, C-CF3), 148.2 (Ar).
IR (Nujol): 1670 (C=C) cm–1.
Anal. Calcd for C14H17F3O2: C, 61.31; H, 6.25. Found: C, 61.85; H,
5.88.
19F NMR (282 MHz, CDCl3): d = –67.3 (s, CF3).
Synthesis 2009, No. 13, 2249–2259 © Thieme Stuttgart · New York

PAPER
Synthesis of New Trifluoromethylated Heterocycles
IR (Nujol): 1660 (C=C) cm–1.
HRMS (ESI): m/z [M + Na]+ calcd for C15H19F3NaO3: 327.1184;
found: 327.1179.
2255
Regioisomer 5h
1H NMR (400 MHz, CDCl3): d = 1.36 [s, 9 H, OC(CH3)3], 3.85 (s,
3 H, OCH3), 6.60 (s, 1 H, CH=CCF3), 6.91 (d, J = 8.8 Hz, 2 H, Ar),
7.65 (d, J = 8.8 Hz, 2 H, Ar).
Anal. Calcd for C15H19F3O3: C, 59.20; H, 6.29. Found: C, 59.19; H,
6.26.
13C NMR (100 MHz, CDCl3): d = 28.8 [OC(CH3)3], 55.2 (OCH3),
83.8 [OC(CH3)3], 113.7 (Ar), 121.6 (q, J = 275.9 Hz, CF3), 121.7
(q, J = 4.4 Hz, CH=CCF3), 125.9 (Ar), 131.2 (Ar), 138.4 (q,
J = 32.2 Hz, C-CF3), 159.7 (Ar).
Regioisomer 5k
1H NMR (400 MHz, CDCl3): d = 1.35 [s, 9 H, OC(CH3)3], 3.90 (s,
6 H, 2 OCH3), 6.57 (s, 1 H, CH=CCF3), 6.85 (d, J = 8.3 Hz, 1 H,
Ar), 7.13 (dd, J = 8.3, 1.8 Hz, 1 H, Ar), 7.35 (d, J = 1.8 Hz, 1 H, Ar).
19F NMR (282 MHz, CDCl3): d = –66.7 (s, CF3).
Regioisomer 6h
13C NMR (100 MHz, CDCl3): d = 28.8 [OC(CH3)3], 55.8 (2 OCH3),
83.9 [OC(CH3)3], 110.7 (Ar), 112.4 (Ar), 121.5 (q, J = 275.9 Hz,
CF3), 122.0 (q, J = 4.4 Hz, CH=CCF3), 123.1 (Ar), 126.1 (Ar),
138.5 (q, J = 32.2 Hz, C-CF3), 148.5 (Ar), 149.3 (Ar).
1H NMR (400 MHz, CDCl3): d = 1.28 [s, 9 H, OC(CH3)3], 3.86 (s,
3 H, OCH3), 5.25 (q, J = 7.8 Hz, 1 H, CHCF3), 6.90 (d, J = 8.9 Hz,
2 H, Ar), 7.43 (d, J = 8.9 Hz, 2 H, Ar).
13C NMR (100 MHz, CDCl3): d = 29.3 [OC(CH3)3], 55.3 (OCH3),
82.0 [OC(CH3)3], 104.9 (q, J = 32.9 Hz, C=CHCF3), 113.5 (Ar),
123.2 (q, J = 269.3 Hz, CF3), 129.3 (Ar), 130.3 (Ar), 160.9 (Ar),
162.3 (q, J = 5.9 Hz, C=CHCF3).
19F NMR (282 MHz, CDCl3): d = –66.7 (s, CF3).
Regioisomer 6k
1H NMR (400 MHz, CDCl3): d = 1.27 [s, 9 H, OC(CH3)3], 3.90 (s,
6 H, 2 OCH3), 5.26 (q, J = 7.8 Hz, 1 H, CHCF3), 6.84 (d, J = 8.2 Hz,
1 H, Ar), 7.01 (d, J = 2.0 Hz, 1 H, Ar), 7.05 (dd, J = 8.2, 2.0 Hz, 1
H, Ar).
19F NMR (282 MHz, CDCl3): d = –56.5 (d, J = 7.8 Hz, CF3).
1-Bromo-[(1Z)-2-tert-butoxy-3,3,3-trifluoroprop-1-enyl]ben-
zene (5i)
13C NMR (100 MHz, CDCl3): d = 29.3 [OC(CH3)3], 55.9 (2 OCH3),
82.1 [OC(CH3)3], 105.1 (q, J = 33.7 Hz, C=CHCF3), 110.6 (Ar),
111.0 (Ar), 120.6 (Ar), 123.1 (q, J = 270.8 Hz, CF3), 130.6 (Ar),
148.4 (Ar), 150.3 (Ar), 162.1 (q, J = 5.9 Hz, C=CHCF3).
From styrene 1i (1425 mg, 5 mmol) or 2i (1650 mg, 5 mmol) as a
colorless oil; yield: 1050 mg (65%, from 1i), 1131 mg (70%, from
2i).
IR (Nujol): 1665 (C=C) cm–1.
13C NMR (100 MHz, CDCl3): d = 28.8 [OC(CH3)3], 84.7
[OC(CH3)3], 121.1 (q, J = 274.5 Hz, CF3), 121.4 (q, J = 4.4 Hz,
CH=CCF3), 124.1 (Ar), 127.0 (Ar), 129.7 (Ar), 131.9 (Ar), 132.5
(Ar), 133.8 (Ar), 141.5 (q, J = 32.9 Hz, C-CF3).
19F NMR (282 MHz, CDCl3): d = –56.5 (d, J = 7.8 Hz, CF3).
2-[(1Z)-2-tert-Butoxy-3,3,3-trifluoroprop-1-enyl]pyridine (5l)
Obtained from styrene 1l (1225 mg, 5 mmol) as a colorless oil;
yield: 884 mg (72%).
19F NMR (282 MHz, CDCl3): d = –68.4 (s, CF3).
IR (Nujol): 1660 (C=C) cm–1.
HRMS (ESI): m/z [M + Na]+ calcd for C13H14BrF3NaO: 345.0078;
found: 345.0072.
1H NMR (400 MHz, CDCl3): d = 1.25 [s, 9 H, OC(CH3)3], 6.75 (s,
1 H, CH=CCF3), 7.11 (dd, J = 7.8, 4.9 Hz, 1 HPy), 7.61 (td, J = 7.8,
1.6 Hz, 1 HPy), 7.89 (d, J = 7.8 Hz, 1 HPy), 8.55 (d, J = 7.8 Hz, 1
HPy).
13C NMR (100 MHz, CDCl3): d = 28.6 [OC(CH3)3], 84.9
[OC(CH3)3], 121.1 (q, J = 276.6 Hz, CF3), 122.7 (q, J = 4.4 Hz,
CH=CCF3), 122.7 (Py), 125.0 (Py), 135.9 (Py), 142.5 (q, J = 32.9
Hz, C-CF3), 149.5 (Py), 153.0 (Py).
Anal. Calcd for C13H14BrF3O: C, 48.32; H, 4.37. Found: C, 48.46;
H 4.31.
Methyl 4-[(1Z)-2-tert-Butoxy-3,3,3-trifluoroprop-1-enyl]ben-
zoate (5j)
From styrenes 1j (1320 mg, 5 mmol) or 2j (1545 mg, 5 mmol) as a
colorless oil; yield: 936 mg (62%, from 1j), 1102 mg (73%, from
2j).
IR (Nujol): 1670 (C=C), 1720 (C=O, CO2Me) cm–1.
1H NMR (400 MHz, CDCl3): d = 1.31 [s, 9 H, OC(CH3)3], 3.78 (s,
3 H, CO2CH3), 6.66 (s, 1 H, CH=CCF3), 7.67 (d, J = 8.6 Hz, 2 H,
Ar), 8.01 (d, J = 8.6 Hz, 2 H, Ar).
19F NMR (282 MHz, CDCl3): d = –67.7 (s, CF3).
HRMS (ESI): m/z [M + Na]+ calcd for C12H14F3NNaO: 268.0925;
found: 268.0920.
Anal. Calcd for C12H14F3NO: C, 58.77; H, 5.75. Found: C, 58.57; H,
5.50.
13C NMR (100 MHz, CDCl3): d = 28.8 [OC(CH3)3], 60.1
(CO2CH3), 85.0 [OC(CH3)3], 121.1 (q, J = 4.4 Hz, CH=CCF3),
121.2 (q, J = 276.6 Hz, CF3), 141.6 (q, J = 32.9 Hz, C-CF3), 129.2
(Ar), 129.7 (Ar), 131.7 (Ar), 137.4 (Ar), 165.3 (CO2CH3).
19F NMR (282 MHz, CDCl3): d = –67.4 (s, CF3).
HRMS (ESI): m/z [M + Na]+ calcd for C15H17F3NaO3: 325.1027;
1-Substituted 4-(3,3,3-Trifluoroprop-1-ynyl)benzenes 7c and
7h; General Procedure
A one-neck, 50-mL round-bottomed flask was charged with anhyd
THF (10 mL) and styrene 1 (5 mmol) and cooled down to 0 °C.
Then a cooled to 0 °C soln of t-BuOK (670 mg, 6 mmol) in anhyd
THF (12 mL) was added dropwise with stirring. The mixture was
stirred at r.t. for 24 h and then poured into H2O (200 mL). The prod-
ucts were extracted with pentane (3 ꢀ 20 mL). The combined ex-
tracts were washed with H2O (2 ꢀ 50 mL) and brine (50 mL) and
dried (Na2SO4). Pentane was evaporated in vacuo, and the residue
was passed through a short filter with silica gel (pentane).
found: 325.1022.
Anal. Calcd for C15H17F3O3: C, 59.60; H, 5.67. Found: C, 59.51; H,
5.71.
4-[(1Z)-2-tert-Butoxy-3,3,3-trifluoroprop-1-enyl]-1,2-dimeth-
oxybenzene (5k) and 4-[(1Z)-1-tert-Butoxy-3,3,3-trifluoroprop-
1-enyl]-1,2-dimethoxybenzene (6k)
From styrene 2k (1555 mg, 5 mmol) as a colorless oil; yield (5 + 6):
1490 mg (98%); ratio 5k/6k 67:33.
1-Chloro-4-(3,3,3-trifluoroprop-1-ynyl)benzene (7c)
From styrene 1c (1205 mg, 5 mmol) as a colorless liquid; yield: 724
mg (71%).
1H NMR (400 MHz, CDCl3): d = 7.37 (d, J = 8.6 Hz, 2 H, Ar), 7.49
(d, J = 8.6 Hz, 2 H, Ar).
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1-Methoxy-4-(3,3,3-trifluoroprop-1-ynyl)benzene (7h)
From styrene 1h (1185 mg, 5 mmol) as a colorless liquid; yield: 640
mg (64%).
1H NMR (400 MHz, CDCl3): d = 6.85 (t, J = 7.7 Hz, 1 H, Im), 7.27–
7.34 (m, 1 H, Im), 7.43–7.48 (m, 2 H, Ar), 7.50–7.55 (m, 3 H, Ar),
7.70 (d, J = 7.7 Hz, 1 H, Im), 7.95 (d, J = 7.7 Hz, 1 H, Im).
1H NMR (400 MHz, CDCl3): d = 3.83 (s, 3 H, OCH3), 6.89 (d,
J = 8.9 Hz, 2 H, Ar), 7.49 (d, J = 8.9 Hz, 2 H, Ar).
13C NMR (100 MHz, CDCl3): d = 114.8 (Imd), 119.1 (Imd), 121.6
(q, J = 2.9 Hz, C=CCF3), 121.7 (q, J = 269.3 Hz, CF3), 123.2 (Imd),
123.6 (Imd), 124.4 (Ar), 131.3 (Ar), 133.4 (Ar), 133.7 (q, J = 38.1
Hz, C-CF3), 145.0 (Imd), 148.4 (Ar).
1-Nitro-4-(3,3,3-trifluoroprop-1-ynyl)benzene (7d)
A one-neck, 50-mL, round-bottomed flask was charged with
CH2Cl2 (10 mL), styrene 1d (1.250 mg, 5 mmol), H2O (5 mL),
NaOH (240 mg, 6 mmol), and benzyltriethylammonium chloride
(23 mg, 1 mmol). The mixture was refluxed for 48 h with vigorous
stirring until styrene 1d disappeared (TLC monitoring). The organic
layer was separated and the aqueous phase was extracted with
CH2Cl2 (20 mL). The combined extracts were washed with H2O
(2 ꢀ 50 mL) and brine (50 mL) and dried (Na2SO4). CH2Cl2 was
evaporated in vacuo and the residue was passed through a short fil-
ter with silica gel (CH2Cl2–pentane, 1:1) to give 7d as colorless
crystals; yield: 925 mg (86%); mp 75–76 °C.
19F NMR (282 MHz, CDCl3): d = –59.4 (s, CF3).
HRMS (ESI): m/z [M + Na]+ calcd for C14H9F3N2Na: 285.0616;
found: 285.0610.
Anal. Calcd for C14H9F3N2: C, 64.12; H, 3.46. Found: C, 63.98; H,
3.54.
3-(4-Chlorophenyl)-2-(trifluoromethyl)imidazo[1,2-a]pyridine
(9c)
From 5c/6c (86:14, 278 mg, 1 mmol) as a viscous brown oil; yield:
155 mg (52%).
1H NMR (400 MHz, CDCl3): d = 7.75 (d, J = 8.9 Hz, 2 H, Ar), 8.27
(d, J = 8.9 Hz, 2 H, Ar).
1H NMR (400 MHz, CDCl3): d = 6.88 (t, J = 7.7 Hz, 1 H, Im), 7.28–
7.35 (m, 1 H, Im), 7.41 (d, J = 8.3 Hz, 2 H, Ar), 7.52 (d, J = 8.3 Hz,
2 H, Ar), 7.69 (d, J = 7.7 Hz, 1 H, Im), 7.93 (d, J = 7.7 Hz, 1 H, Im).
[(1Z)-2-tert-Butoxy-3,3,3-trifluoroprop-1-enyl]benzenes 5c,d,h
and [(1Z)-1-tert-Butoxy-3,3,3-trifluoroprop-1-enyl]benzenes
6c,d,h from Acetylenes 7c,d,h and Potassium tert-Butoxide;
General Procedure
13C NMR (100 MHz, CDCl3): d = 114.1 (Imd), 118.8 (Imd), 122.0
(q, J = 269.3 Hz, CF3), 123.0 (q, J = 2.9 Hz, C=CCF3), 123.8 (Imd),
125.2 (Ar), 126.6 (Imd), 129.6 (Ar), 131.7 (Ar), 132.9 (q, J = 37.3
Hz, C-CF3), 136.0 (Ar), 144.5 (Imd).
A one-neck, 10-mL, round-bottomed flask was charged with anhyd
DMF (2 mL) and the corresponding acetylene 7 (1 mmol) and
cooled down to 0 °C. Then a soln of t-BuOK (135 mg, 1.2 mmol) in
anhyd DMF (2 mL) at 0 °C was added dropwise with stirring. The
mixture was stirred at r.t. for 24 h and then poured into H2O (200
mL). The products were extracted with CH2Cl2 (3 ꢀ 20 mL). The
combined extracts were washed with H2O (2 ꢀ 50 mL) and brine (50
mL) and dried (Na2SO4). CH2Cl2 was evaporated in vacuo, afford-
ing crude material in near quantitative yields. The structures of the
products and the ratio of regioisomers 5 and 6 in the mixtures were
determined using 1H NMR and 19F NMR by comparison with cor-
responding data of styrene reactions.
19F NMR (282 MHz, CDCl3): d = –59.5 (s, CF3).
HRMS (ESI): m/z [M + Na]+ calcd for C14H8ClF3N2Na: 319.0226;
found: 319.0220.
Anal. Calcd for C14H8ClF3N2: C, 56.68; H, 2.72. Found: C, 56.51;
H, 2.67.
3-(4-Nitrophenyl)-2-(trifluoromethyl)imidazo[1,2-a]pyridine
(9d)
From 5d (289 mg, 1 mmol) as a yellow powder; yield: 163 mg
(53%); mp 137–138 °C.
1H NMR (400 MHz, CDCl3): d = 6.98 (t, J = 7.7 Hz, 1 H, Im), 7.38–
7.44 (m, 1 H, Im), 7.73 (d, J = 8.6 Hz, 2 H, Ar), 7.77 (d, J = 7.7 Hz,
1 H, Im), 8.01 (d, J = 7.7 Hz, 1 H, Im), 8.43 (d, J = 8.6 Hz, 2 H, Ar).
Synthesis of 1,1,1-Trifluoroacetone 8c and Heterocycles 9–17
from tert-Butoxystyrenes; General Procedure
A one-neck, 25-mL round-bottomed flask was charged with the cor-
responding tert-butoxystyrene (1 mmol) and CH2Cl2 (3 mL). Then
1 M Br2 in CH2Cl2 (1.1 mL) was added dropwise with vigorous stir-
ring. After the Br2 had been added, CH2Cl2 was evaporated in vac-
uo. The residue was dissolved in MeCN (2 mL) and the soln of the
corresponding nucleophile (1 mmol) in MeCN (2 mL) was added.
Then the mixture was stirred at r.t. for 2 h and refluxed for another
8 h. The mixture was cooled to r.t. and the reaction was quenched
with 25% NH3 soln (0.2 mL). (In case of 15, after cooling down to
r.t., the MeCN was evaporated to one quarter. The formed precipi-
tate of the hydrobromide was filtered off and washed with MeCN
and Et2O). The solvents were removed in vacuo and the residue was
purified by column chromatography (silica gel, CH2Cl2–MeOH).
13C NMR (100 MHz, CDCl3): d = 114.8 (Imd), 119.1 (Imd), 121.6
(q, J = 2.9 Hz, C=CCF3), 121.7 (q, J = 269.3 Hz, CF3), 123.6 (Imd),
124.4 (Ar), 127.2 (Imd), 131.3 (Ar), 133.4 (Ar), 133.7 (q, J = 38.1
Hz, C-CF3), 145.0 (Imd), 148.4 (Ar).
19F NMR (282 MHz, CDCl3): d = –59.4 (s, CF3).
HRMS (ESI): m/z [M + Na]+ calcd for C14H8F3N3NaO2: 330.0466;
found: 330.0461.
Anal. Calcd for C14H8F3N3O2: C, 54.73; H, 2.62. Found: C, 54.42;
H, 2.50.
3-(3-Nitrophenyl)-2-(trifluoromethyl)imidazo[1,2-a]pyridine
(9e)
From 5e/6e (91:9, 289 mg, 1 mmol) as a yellow powder; yield: 129
mg (42%); mp 110–112 °C.
1H NMR (400 MHz, CDCl3): d = 6.97 (t, J = 7.7 Hz, 1 H, Im), 7.37–
7.42 (m, 1 H, Im), 7.75 (d, J = 7.7 Hz, 1 H, Im), 7.79 (t, J = 7.8 Hz,
1 H, Ar), 7.86 (d, J = 7.8 Hz, 1 H, Ar), 7.96 (d, J = 7.7 Hz, 1 H, Im),
8.38 (s, 1 H, Ar), 8.39 (d, J = 7.8 Hz, 1 H, Ar).
3-Bromo-3-(4-chlorophenyl)-1,1,1-trifluoroacetone (8c)
Isolated in crude form from the reaction of 5c/6c (86:14, 278 mg, 1
mmol) with Br2 and evaporation of CH2Cl2; brown oil; yield: 256
mg (~85%).
1H NMR (400 MHz, CDCl3): d = 5.77 (s, 1 H, CHBr), 7.41 (d,
J = 8.6 Hz, 2 H, Ar), 7.45 (d, J = 8.6 Hz, 2 H, Ar).
13C NMR (100 MHz, CDCl3): d = 114.7 (Imd), 119.0 (Imd), 121.4
(q, J = 2.9 Hz, C=CCF3), 121.7 (q, J = 270.1 Hz, CF3), 123.5 (Ar),
124.6 (Imd), 125.2 (Ar), 127.1 (Imd), 128.6 (Ar), 130.5 (Ar), 133.6
(q, J = 37.2 Hz, C-CF3), 136.6 (Ar), 144.8 (Imd), 148.7 (Ar).
13C NMR (100 MHz, CDCl3): d = 44.6 (Ar), 115.2 (q, J = 292.8 Hz,
CF3), 129.6 (Ar), 130.6 (Ar), 134.0 (Ar), 136.4 (Ar), 183.0 (q,
J = 35.9 Hz, CF3-C=O).
19F NMR (282 MHz, CDCl3): d = –59.5 (s, CF3).
3-Phenyl-2-(trifluoromethyl)imidazo[1,2-a]pyridine (9a)
From 5a/6a (91:9, 244 mg, 1 mmol) as a viscous brown oil; yield:
121 mg (46%).
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Synthesis of New Trifluoromethylated Heterocycles
2257
HRMS (ESI): m/z [M + Na]+ calcd for C14H8F3N3NaO2: 330.0466;
found: 330.0461.
13C NMR (100 MHz, CDCl3): d = 113.9 (Imd), 118.6 (Imd), 121.8
(q, J = 269.3 Hz, CF3), 123.1 (q, J = 2.9 Hz, C=CCF3), 124.6 (Imd),
125.4 (Ar), 126.7 (Imd), 128.0 (Ar), 128.1 (Ar), 131.9 (Ar), 133.2
(Ar), 133.2 (q, J = 37.3 Hz, C-CF3), 133.7 (Ar), 144.5 (Imd).
Anal. Calcd for C14H8F3N3O2: C, 54.73; H, 2.62. Found: C, 54.58;
H, 2.61.
19F NMR (282 MHz, CDCl3): d = –60.5 (s, CF3).
3-(2-Methoxyphenyl)-2-(trifluoromethyl)imidazo[1,2-a]pyr-
idine (9f)
From 5f (274 mg, 1 mmol) as a yellow powder; yield: 91 mg (31%);
mp 90–92 °C.
HRMS (ESI): m/z [M + H]+ calcd for C14H9BrF3N2: 340.9901;
found: 340.9896.
Anal. Calcd for C14H8BrF3N2: C, 49.29; H, 2.36. Found: C, 49.42;
H, 2.50.
1H NMR (400 MHz, CDCl3): d = 3.76 (s, 3 H, OCH3), 6.83 (t,
J = 7.7 Hz, 1 H, Im), 7.08 (d, J = 7.8 Hz, 1 H, Ar), 7.12 (t, J = 7.8
Hz, 1 H, Ar), 7.27–7.34 (m, 1 H, Im), 7.39 (d, J = 7.8 Hz, 1 H, Ar),
7.53 (td, J = 7.8 Hz, J = 1.6 Hz, 1 H, Ar), 7.68 (d, J = 7.7 Hz, 1 H,
Im), 7.72 (d, J = 7.7 Hz, 1 H, Im).
13C NMR (100 MHz, CDCl3): d = 55.2 (OCH3), 111.3 (Ar), 113.1
(Imd), 115.4 (Ar), 118.5 (Imd), 121.0 (Ar), 121.5 (q, J = 2.9 Hz,
C=CCF3), 122.1 (q, J = 268.6 Hz, CF3), 125.1 (Imd), 126.1 (Imd),
131.7 (Ar), 132.8 (q, J = 37.3 Hz, C-CF3), 132.9 (Ar), 144.5 (Imd),
157.7 (Ar).
6-Bromo-3-(4-chlorophenyl)-2-(trifluoromethyl)imidazo[1,2-
a]pyridine (10)
From 5c/6c (86:14, 278 mg, 1 mmol) as a white powder; yield: 165
mg (44%); mp 102.5–104.9 °C.
1H NMR (400 MHz, CDCl3): d = 7.39 (dd, J = 9.6, 1.4 Hz, 1 H, Im),
7.42 (d, J = 8.3 Hz, 2 H, Ar), 7.56 (d, J = 8.3 Hz, 2 H, Ar), 7.59 (d,
J = 9.6 Hz, 1 H, Im), 8.03 (d, J = 1.4 Hz, 1 H, Im).
13C NMR (100 MHz, CDCl3): d = 109.2 (Imd), 119.5 (Imd), 121.8
(q, J = 270.1 Hz, CF3), 123.0 (q, J = 1.5 Hz, C=CCF3), 123.9 (Imd),
124.5 (Ar), 129.8 (Ar), 130.3 (Imd), 131.6 (Ar), 133.6 (q, J = 37.3
Hz, C-CF3), 136.5 (Ar), 142.8 (Imd).
Anal. Calcd for C15H11F3N2O: C, 61.64; H, 3.79. Found: C, 61.54;
H, 3.60.
19F NMR (282 MHz, CDCl3): d = –59.7 (s, CF3).
HRMS (ESI): m/z [M + Na]+ calcd for C14H7BrClF3N2Na:
3-(3-Methoxyphenyl)-2-(trifluoromethyl)imidazo[1,2-a]pyr-
idine (9g)
From 5g/6g (92:8, 274 mg, 1 mmol) as a viscous brown oil; yield:
149 mg (51%).
1H NMR (400 MHz, CDCl3): d = 3.81 (s, 3 H, OCH3), 6.82 (t,
J = 7.7 Hz, 1 H, Im), 6.98 (d, J = 1.8 Hz, 1 H, Ar), 7.02 (d, J = 8.1
Hz, 2 H, Ar), 7.24–7.30 (m, 1 H, Im), 7.42 (t, J = 8.1 Hz, 1 H, Ar),
7.66 (d, J = 7.7 Hz, 1 H, Im), 7.97 (d, J = 7.7 Hz, 1 H, Im).
396.9331; found: 396.9325.
Anal. Calcd for C14H7BrClF3N2: C, 44.77; H, 1.88. Found: C, 44.38;
H, 1.77.
3-(4-Chlorophenyl)-5-methyl-2-(trifluoromethyl)imidazo[1,2-
a]pyridine (11)
13C NMR (100 MHz, CDCl3): d = 55.4 (OCH3), 113.9 (Imd), 115.3
(Ar), 115.9 (Ar), 118.6 (Imd), 122.1 (q, J = 269.3 Hz, CF3), 122.5
(Ar), 124.2 (Imd), 126.4 (Imd), 127.9 (Ar), 130.3 (Ar), 132.4 (q,
J = 37.3 Hz, C-CF3), 144.3 (Imd), 160.0 (Ar).
From 5c/6c (86:14, 278 mg, 1 mmol) as a pale yellow powder;
yield: 146 mg (47%); mp 106.7–108.9 °C.
1H NMR (400 MHz, CDCl3): d = 2.41 (s, 3 H, CH3), 6.70 (dd,
J = 7.2, 1.1 Hz, 1 H, Im), 7.39 (d, J = 8.3 Hz, 2 H, Ar), 7.43 (s, 1 H,
Im), 7.51 (d, J = 8.3 Hz, 2 H, Ar), 7.80 (d, J = 7.2 Hz, 1 H, Im).
19F NMR (282 MHz, CDCl3): d = –59.4 (s, CF3).
13C NMR (100 MHz, CDCl3): d = 21.3 (CH3), 116.8 (Imd), 116.9
(Imd), 122.0 (q, J = 269.3 Hz, CF3), 122.4 (q, J = 2.2 Hz, C=CCF3),
122.9 (Imd), 125.4 (Ar), 129.5 (Ar), 131.6 (Ar), 132.6 (q, J = 37.3
Hz, C-CF3), 135.8 (Ar), 137.9 (Imd), 145.0 (Imd).
HRMS (ESI): m/z [M + H]+ calcd for C15H12F3N2O: 293.0902;
found: 293.0896.
Anal. Calcd for C15H11F3N2O: C, 61.64; H, 3.79. Found: C, 61.72;
H, 3.90.
19F NMR (282 MHz, CDCl3): d = –59.5 (s, CF3).
HRMS (ESI): m/z [M + H]+ calcd for C15H11ClF3N2: 311.0563;
found: 311.0557.
3-(4-Methoxyphenyl)-2-(trifluoromethyl)imidazo[1,2-a]pyr-
idine (9h)
From 5h/6h (72:28, 274 mg, 1 mmol) as yellow crystals; yield: 89
mg (27%); mp 87–88 °C.
1H NMR (400 MHz, CDCl3): d = 3.89 (s, 3 H, OCH3), 6.85 (t,
J = 7.7 Hz, 1 H, Im), 7.07 (d, J = 8.7 Hz, 2 H, Ar), 7.27–7.33 (m, 1
H, Im), 7.39 (d, J = 8.7 Hz, 2 H, Ar), 7.70 (d, J = 7.7 Hz, 1 H, Im),
7.95 (d, J = 7.7 Hz, 1 H, Im).
13C NMR (100 MHz, CDCl3): d = 55.4 (OCH3), 113.7 (Imd), 114.7
(Ar), 118.6 (Imd), 122.1 (q, J = 270.1 Hz, CF3), 124.0 (Imd), 124.2
(q, J = 2.2 Hz, C=CCF3), 126.3 (Imd), 131.1 (Ar), 131.7 (Ar), 132.3
(q, J = 36.6 Hz, C-CF3), 144.2 (Imd), 160.7 (Ar).
Anal. Calcd for C15H10ClF3N2: C, 57.99; H, 3.24. Found: C, 57.71;
H, 3.18.
3-(4-Chlorophenyl)-2-(trifluoromethyl)imidazo[1,2-a]pyrim-
idine (12)
From 5c/6c (86:14, 278 mg, 1 mmol) as a yellow powder; yield: 155
mg (52%); mp 117–120 °C.
1H NMR (400 MHz, CDCl3): d = 7.02 (dd, J = 6.8, 4.1 Hz, 1 H, Py-
rimidinyl), 7.43 (d, J = 8.6 Hz, 2 H, Ar), 7.53 (d, J = 8.6 Hz, 2 H,
Ar), 8.34 (dd, J = 6.8, 1.9 Hz, 1 H, Pyrimidinyl), 8.65 (dd, J = 4.0,
1.9 Hz, 1 H, Pyrimidinyl).
13C NMR (100 MHz, CDCl3): d = 110.5 (Imd), 121.6 (q, J = 270.1
Hz, CF3), 121.7 (q, J = 2.2 Hz, C=CCF3), 124.0 (Ar), 129.7 (Ar),
131.6 (Ar), 132.1 (Imd), 133.7 (q, J = 37.3 Hz, C-CF3), 136.5 (Ar),
147.2 (Imd), 152.6 (Imd).
Anal. Calcd for C15H11F3N2O: C, 61.64; H, 3.79. Found: C, 61.42;
H, 3.50.
3-(2-Bromophenyl)-2-(trifluoromethyl)imidazo[1,2-a]pyridine
(9i)
From 5i (323 mg, 1 mmol) as a viscous brown oil; yield: 174 mg
(51%).
1H NMR (400 MHz, CDCl3): d = 6.89 (t, J = 7.7 Hz, 1 H, Im), 7.32–
7.38 (m, 1 H, Im), 7.40–7.45 (m, 2 H, Ar), 7.47 (d, J = 7.7 Hz, 1 H,
Im), 7.61 (d, J = 7.7 Hz, 1 H, Ar), 7.72–7.79 (m, 2 H, Ar, Im).
19F NMR (282 MHz, CDCl3): d = –59.7 (s, CF3).
HRMS (ESI): m/z [M + Na]+ calcd for C13H7ClF3N3Na: 320.0178;
found: 320.0173.
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V. M. Muzalevskiy et al.
PAPER
Anal. Calcd for C13H7ClF3N3: C, 52.45; H, 2.37. Found: C, 51.49;
H, 2.24.
Anal. Calcd for C16H10ClF3N2S: C, 54.17; H, 2.84. Found: C, 54.35;
H, 2.63.
3-(4-Chlorophenyl)-2-(trifluoromethyl)-9H-imidazo[1,2-a]-
benzimidazole (13)
5-(4-Chlorophenyl)-2-methyl-4-(trifluoromethyl)-4,5-dihydro-
thiazol-4-ol (17)
From 5c/6c (86:14, 278 mg, 1 mmol) as yellow crystals; yield: 124
mg (37%); mp 262–265 °C.
From 5c/6c (86:14, 278 mg, 1 mmol) as white crystals; yield: 160
mg (54%); mp 181–183 °C (dec).
1H NMR (400 MHz, DMSO-d6): d = 7.07–7.14 (m, 2 H, C6H4), 7.34
(td, J = 6.8, 1.0 Hz, 1 H, C6H4), 7.48 (d, J = 8.1 Hz, 1 H, C6H4), 7.68
(s, 4 H, 4-ClC6H4), 12.17 (br s, 1 H, NH).
1H NMR (400 MHz, acetone-d6): d = 2.34 (s, 3 H, CH3), 5.46 (s, 1
H, CH, Ar), 6.33 (s, 1 H, OH), 7.37 (d, J = 8.4 Hz, 2 H, Ar), 7.54 (d,
J = 8.4 Hz, 2 H, Ar).
13C NMR (100 MHz, DMSO-d6): d = 111.9 (Het), 112.8 (Het),
120.6 (Het), 120.8 (q, J = 3.7 Hz, C=CCF3), 122.7 (q, J = 267.9 Hz,
CF3), 124.3 (4-ClC6H4), 125.0 (Het), 126.9 (Het), 128.4 (q, J = 35.9
Hz, C-CF3), 129.4 (4-ClC6H4), 132.1 (4-ClC6H4), 134.6 (Het),
136.1 (4-ClC6H4), 148.4 (Het).
19F NMR (282 MHz, CDCl3): d = –58.7 (s, CF3).
HRMS (ESI): m/z [M + H]+ calcd for C16H10ClF3N3: 336.0515;
13C NMR (100 MHz, acetone-d6): d = 19.7 (CH3), 57.1 (CH, Ar),
104.5 (q, J = 28.5 Hz, C-CF3), 124.3 (q, J = 286.2 Hz, CF3), 127.9
(Ar), 131.9 (Ar), 132.8 (Ar), 133.4 (Ar), 174.7 [SC(Me)=N].
19F NMR (282 MHz, CDCl3): d = –82.1 (s, CF3).
HRMS (ESI): m/z [M + Na]+ calcd for C11H9ClF3NNaOS:
317.9943; found: 317.9938.
Anal. Calcd for C11H9ClF3NOS: C, 44.68; H, 3.07. Found: C, 44.63;
H, 2.82.
found: 336.0510.
Anal. Calcd for C16H9ClF3N3: C, 57.24; H, 2.70. Found: C, 57.48;
H, 2.50.
Acknowledgment
5-(4-Chlorophenyl)-6-(trifluoromethyl)imidazo[2,1-b]thiazole
(14)
From 5c/6c (86:14, 278 mg, 1 mmol) as white crystals; yield: 182
mg (60%); mp 135.5–137.2 °C.
1H NMR (400 MHz, CDCl3): d = 7.01 (d, J = 4.7 Hz, 1 H, Thiaz-
olyl), 7.37 (d, J = 4.7 Hz, 1 H, Thiazolyl), 7.43 (d, J = 8.5 Hz, 2 H,
Ar), 7.49 (d, J = 8.5 Hz, 2 H, Ar).
This project was supported by the Deutsche Forschungsgemein-
schaft (DFG) through grant No: 436 RUS 113/858/0-1 and the Rus-
sian Foundation for Basic Research (grants No. 08-03-00736-a,
RFBR-DFG 07-03-91562-NNIO_a).
References
13C NMR (100 MHz, CDCl3): d = 115.7 (Het), 117.2 (Het), 121.4
(q, J = 271.5 Hz, CF3), 125.3 (q, J = 2.9 Hz, C=CCF3), 125.9 (Ar),
129.4 (Ar), 130.4 (Ar), 133.1 (q, J = 37.3 Hz, C-CF3), 135.7 (Ar),
149.4 (Het).
(1) For example: (a) Hiyama, T. Organofluorine Compounds.
Chemistry and Applications; Springer: Berlin, 2000.
(b) Chambers, R. D. Fluorine in Organic Chemistry;
Blackwell: Oxford, 2004. (c) Kirsch, P. Modern
19F NMR (282 MHz, CDCl3): d = –59.4 (s, CF3).
Fluoroorganic Chemistry: Synthesis, Reactivity,
Applications; Wiley-VCH: Weinheim, 2004. (d) Uneyama,
K. Organofluorine Chemistry; Blackwell: Oxford, 2006.
(2) (a) For example see multiauthor Special Issue on Fluorine in
the Life Sciences: ChemBioChem 2004, 5, 559–722. (b)For
example see multiauthor Special Issue on Fluorine in the
Life Science Industry:Chimia 2004, 58, 92–162. For other
examples see: (c) Theodoridis, G. Fluorine-Containing
Agrochemicals: An Overview of Recent Developments, In
Advances in Fluorine Science, Vol. 2; Tressaud, A., Ed.;
Elsevier: Amsterdam, 2006, 121–175. (d) Bégué, J. P.;
Bonnet-Delpon, D. Bioorganic and Medicinal Chemistry of
Fluorine; John Wiley & Sons: Hoboken, 2008. (e) Fluorine
and Health. Molecular Imaging, Biomedical Materials and
Pharmaceuticals; Tressaud, A.; Haufe, G., Eds.; Elsevier:
Amsterdam, 2008, 553–778.
HRMS (ESI): m/z [M + Na]+ calcd for C12H6ClF3N2NaS: 324.9790;
found: 324.9785.
Anal. Calcd for C12H6ClF3N2S: C, 47.61; H, 2.00. Found: C, 47.35;
H, 1.75.
5-(4-Chlorophenyl)-4-(trifluoromethyl)thiazol-2-amine Hydro-
bromide (15·HBr)
From 5c/6c (86:14, 278 mg, 1 mmol) as white crystals; yield: 259
mg (72%); mp 165–167 °C (dec).
+
1H NMR (400 MHz, DMSO-d6): d = 7.09 (br s, 3 H, NH3 ), 7.37 (d,
J = 8.5 Hz, 2 H, Ar), 7.46 (d, J = 8.5 Hz, 2 H, Ar).
13C NMR (100 MHz, DMSO-d6): d = 121.4 (q, J = 271.5 Hz, CF3),
125.7 (Ar), 128.8 (Thiazolyl), 129.1 (Ar), 131.6 (Ar), 133.0 (q,
J = 33.7 Hz, C-CF3), 133.9 (Ar), 168.2 (Thiazolyl).
HRMS (ESI): m/z [M + H]+ calcd for C10H7ClF3N2S: 278.9971;
found: 278.9965.
(3) For example: (a) Enantiocontrolled Synthesis of Fluoro-
Organic Compounds; Soloshonok, V. A., Ed.; Wiley:
Chichester, 1999. (b) Asymmetric Fluoroorganic
Chemistry. Synthesis, Applications, and Future Directions;
Ramachandran, P. V., Ed.; ACS Symposium Series 746:
Washington, 2000. (c) Fluorine-Containing Synthons;
Soloshonok, V. A., Ed.; ACS Symposium Series 911:
Washington, 2005. (d) Science of Synthesis, Vol. 34; Percy,
J. M., Ed.; Georg Thieme Verlag: Stuttgart, 2006.
(e) Current Fluoroorganic Chemistry. New Synthetic
Directions, Technologies, Materials, and Biological
Applications; Soloshonok, V. A.; Mikami, K.; Yamazaki, T.;
Welch, J. T.; Honek, J. F., Eds.; ACS Symposium Series
949: Washington, 2006.
5-(4-Chlorophenyl)-N-phenyl-4-(trifluoromethyl)thiazol-2-
amine (16)
From 5c/6c (86:14, 278 mg, 1 mmol) as white crystals; yield: 284
mg (80%); mp 128–129 °C.
1H NMR (400 MHz, CDCl3): d = 7.20–7.26 (m, 1 H, Ph), 7.38–7.48
(m, 8 H, Ar), 8.91 (br s, 1 H, NH).
13C NMR (100 MHz, CDCl3): d = 120.7 (Ph), 121.0 (q, J = 272.3
Hz, CF3), 125.0 (Ph), 127.0 (4-ClC6H4), 127.8 (Thiazolyl), 128.8
(4-ClC6H4), 129.8 (Ph), 131.1 (4-ClC6H4), 134.4 (q, J = 35.1 Hz, C-
CF3), 135.2 (4-ClC6H4), 139.9 (Ph), 166.1 (Thiazolyl).
(4) Shastin, A. V.; Korotchenko, V. N.; Nenajdenko, V. G.;
Balenkova, E. S. Tetrahedron 2000, 56, 6557.
19F NMR (282 MHz, CDCl3): d = –59.8 (s, CF3).
Synthesis 2009, No. 13, 2249–2259 © Thieme Stuttgart · New York

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