Noncatalytic electrophilic oxyalkylation of some five-membered heterocycles with 2-(trifluoroacetyl)-1,3-azoles

Article abstract of DOI:10.1055/s-0029-1218633

A set of electrophilic 2-(trifluoroacetyl)-1,3-azoles demonstrated- excellent activity in the C-oxyalkylation of pyrrole, furan, thiophene, 1,3-thiazole, and 1,2-oxazole derivatives. The reaction conditions and the yields of the corresponding trifluoromethyl-substituted alcohols depend strongly on both the electronic and steric nature of the 1,3-azole unit. Georg Thieme Verlag Stuttgart ? New York.

Full text of DOI:10.1055/s-0029-1218633

PAPER
979
Noncatalytic Electrophilic Oxyalkylation of Some Five-Membered
Heterocycles with 2-(Trifluoroacetyl)-1,3-azoles
O
xyalkylation
a
of Five-Me
v
mbered Het
e
e
rocycles l V. Khodakovskiy,a,b Pavel K. Mykhailiuk,*a,b Dmitriy M. Volochnyuk,a,c Andrey A. Tolmacheva,b
a
b
c
Enamine Ltd., Oleksandra Matrosova St. 23, 01103 Kyiv, Ukraine
Department of Chemistry, Kyiv National Taras Shevchenko University, Volodymyrska St. 64, 01033 Kyiv, Ukraine
Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Murmanska St. 5, 02660 Kyiv-94, Ukraine
Fax +380(44)2351273; E-mail: Pashamk@gmx.de
Received 18 November 2009; revised 24 November 2009
A1
A2
N
A1
A2
a
N
F3C
Abstract: A set of electrophilic 2-(trifluoroacetyl)-1,3-azoles
demonstrated excellent activity in the C-oxyalkylation of pyrrole,
furan, thiophene, 1,3-thiazole, and 1,2-oxazole derivatives. The re-
action conditions and the yields of the corresponding trifluorometh-
yl-substituted alcohols depend strongly on both the electronic and
steric nature of the 1,3-azole unit.
(14 examples)
d
H
X
X
O
3
b
c
A1
A2
N
F3C
A1
A2
N
F3C
Key words: Friedel–Crafts alkylation, trifluoromethyl alcohols,
heterocycles, pyrroles, furans
X
A1
A2
OH
N
F3C
X
OH
NC
X
N
OH
H
NC
The substitution of fluorine for hydrogen is widely used to
improve the pharmacological characteristics of organic
compounds.1 Moreover, many commercially available
pharmaceuticals are fluorine-containing, although fluo-
rine scarcely occurs in organic matter.2 The trifluorometh-
yl group, in particular, is one of the most attractive
functional groups in organic chemistry, and incorporation
of this group into organic compounds is still a topic of
growing interest.3 The commercially available trifluoro-
methyl ketones hexafluoroacetone (1) and trifluoropyru-
vate (2) are highly valuable building blocks commonly
used to prepare trifluoromethyl-containing compounds.4
However, despite the great potential of both 1 and 2, the
chemistry of other trifluoroacetyl ketones has received
much less attention so far.5
Scheme
1
Reagents and conditions: (a) TFAA, Et3N; (b)
NCCH2CO2H, py, heat; (c) H2C=CHCN, DABCO; (d) indole,
toluene, heat.
Ac
EtO2C
N
N
Cy
7
N
N
H
N
H
Me
4
Tol
8
5
6
Me
N
N
O
O
Me
9
10
CONH2
NH2
CO2Et
NH2
Recently, we started a project aimed at the synthesis and
application of various trifluoromethyl hetaryl ketones 3
(some representative examples are given in Scheme 1).6
We have already shown that indole smoothly reacts with
3 to form the corresponding trifluoromethyl-substituted
alcohols (Scheme 1, reaction d).6d We report here on the
extension of this strategy to other electron-rich heterocy-
cles, namely pyrroles 4–8, furans 9 and 10, thiophenes
11–13, 1,3-thiazoles 14–18, and 1,2-oxazole 19
(Figure 1).
Among the many available representatives of 36a
(Scheme 1), we chose highly reactive 2-(trifluoroacetyl)-
1,3-benzothiazole (3a) as a model compound to test the
potential of 4–19 in C-oxyalkylation reactions
(Scheme 2).
EtO2C
NH2
S
S
S
11
12
13
N
N
N
N
NH2
NH2
NHMe
NHCy
S
S
S
S
14
15
16
17
N
N
NEt2
NH2
S
O
18
19
Figure 1 Derivatives of pyrrole (4–8), furan (9,10), thiophene (11–
13), 1,3-thiazole (14–18), and 1,2-oxazole (19)
SYNTHESIS 2010, No. 6, pp 0979–0984
x
x
.
x
x
.2
0
1
0
Advanced online publication: 04.01.2010
DOI: 10.1055/s-0029-1218633; Art ID: Z24609SS
© Georg Thieme Verlag Stuttgart · New York

980
P. V. Khodakovskiy et al.
PAPER
Table 1 Reaction Conditions for the Synthesis of Trifluoromethyl-
Substituted Alcohols 4a–19a
N
N
toluene
heat
F3C
Het
F3C
+
Het-H
S
S
OH
Azole Conditions
Product
Yield (%)
O
4–19
3a
4a–19a
N
F3C
Scheme 2 Synthesis of trifluoromethyl-substituted alcohols 4a–19a
from 2-(trifluoroacetyl)-1,3-benzothiazole (3a)
3a, toluene,
60 °C, 0.5 h
4
61
S
OH
Me
N
4a
As shown in Table 1, all compounds 4–19 smoothly react
with 3a under heating in toluene to provide the corre-
sponding tertiary alcohols 4a–19a in moderate to excel-
lent yields. The reaction conditions and the yields of the
products depend strongly on both the electronic and steric
nature of the starting heterocycles 4–19.
N
F3C
3a, toluene,
100 °C, 2 h
S
5
64
84
OH
NH
5a
Ac
For example, the reaction of pyrrole derivative 4 with 3a
was already completed after 30 minutes of heating in tol-
uene at 60 °C (Table 1). However, pyrroles 5 and 6 bear-
ing electron-accepting substituents and pyrroles 7 and 8
substituted at the a-positions required harsher conditions
(100–120 °C, 2–4 h) (Table 1). Interestingly, the addition
of 3a to thiazole 15 occurred more easily than the addition
to thiazole 14 (Table 1). The presence of the methyl group
adjacent to the reaction center in 14 hampers the reaction
and deactivates the substrate. The reactions of 15–18 with
3a also illustrate the importance of steric effects. The
yields of the alkylamino-substituted thiazoles 16a and 17a
(99% and 76%, respectively) are significantly higher than
those of amino-substituted product 15a (64%) and dialkyl-
amino-substituted product 18a (52%) (Table 1). Obvious-
ly, incorporation of an electron-donating alkyl group
instead of a hydrogen atom increases the reactivity of thi-
azoles 16 and 17 compared to 15. However, incorporation
of a second bulky alkyl group already reduces the reactiv-
ity of 18 compared to 16 and 17.
N
F3C
3a, toluene,
100 °C, 2 h
S
6
OH
NH
6a
EtO2C
F3C
N
3a, toluene,
120 °C, 4 h
S
7
OH
95
7a
N
Cy
N
F3C
3a, toluene,
120 °C, 4 h
S
8
85
64
OH
8a
N
Tol
N
F3C
3a, toluene,
60 °C, 2 h
Incorporation of the 3a moiety into 4–19 follows the gen-
eral pattern of aromatic electrophilic substitution in the
abovementioned heterocyclic systems. In pyrroles 4–6,
furans 9 and 10, and thiophenes 11 and 12 the substitution
occurs at the 2-position. However, if the 2-position is
blocked (7,8,13), the substitution proceeds at the 3-posi-
tion. The substitution in 15–18 occurs at the 5-position.
S
9
OH
O
9a
N
F3C
S
3a, toluene,
10
OH
34
60 °C, 0.5 h
To demonstrate the applicability of this reaction to a wide
variety of 2-(trifluoroacetyl)-1,3-azoles 3, we performed
several syntheses with diverse ketones 3b–j (Figure 2)
with the electron-rich heterocycles 16 and 19 (Table 2).
The reaction was just as efficient as in the case of 3a
(Table 1), and the corresponding products were obtained
in 53–85% yield.
O
10a
NNMe2
F3C
N
3a, toluene,
11
S
OH
71
80
100 °C, 4 h
S
11a
In summary, we have developed a very simple and effi-
cient one-step procedure to prepare novel trifluoromethyl-
substituted tertiary alcohols from various 2-(trifluoro-
acetyl)-1,3-azoles and derivatives of pyrrole, furan,
thiophene, 1,3-thiazole, and 1,2-oxazole.
H2NOC
NH2
N
F3C
3a, toluene,
12
S
OH
100 °C, 4 h
S
12a
EtO2C
NH2
Synthesis 2010, No. 6, 979–984 © Thieme Stuttgart · New York

PAPER
Oxyalkylation of Five-Membered Heterocycles
981
Table 2 Reaction Conditions for the Synthesis of Trifluoromethyl-
Substituted Alcohols 16b,c and 19d–f,j
Table 1 Reaction Conditions for the Synthesis of Trifluoromethyl-
Substituted Alcohols 4a–19a (continued)
Azole Conditions
Product
Yield (%)
Azole Conditions
Product
Yield (%)
N
N
F3C
F3C
N
3a, toluene,
13
3b, toluene,
16
N
S
83
OH
OH
76
100 °C, 4 h
100 °C, 0.5 h
Me
13a
S
16b
NH2
N
N
S
EtO2C
F3C
NHMe
N
N
F3C
3a, toluene,
14
O
Ph
S
3c, toluene,
16
OH
OH
49
64
99
76
52
85
100 °C, 4 h
100 °C, 0.5 h
S
S
14a
16c
N
NH2
N
NHMe
N
F3C
F3C
3d, toluene,
19
74
81
N
OH
3a, toluene,
15
60 °C, 0.5 h
S
OH
Me
NH2
100 °C, 1 h
19d
S
N
15a
O
N
N
N
NH2
F3C
3e, toluene,
19
N
OH
60 °C, 0.5 h
F3C
NH2
3a, toluene,
16
19e
S
N
OH
O
100 °C, 0.5 h
S
16a
N
N
NHMe
N
S
3f, toluene,
19
N
F3C
53
72
H
N
60 °C, 0.5 h
F3C
OH
3a, toluene,
17
S
OH
NH2
19f
100 °C, 0.5 h
N
O
S
17a
N
N
N
N
F3C
NHCy
Ph
3j, toluene,
19
OH
60 °C, 0.5 h
N
Me
NH2
F3C
19j
N
O
3a, toluene,
18
S
OH
100 °C, 4 h
S
18a
N
2-(Trifluoroacetyl)-1,3-azoles 3 were prepared as described previ-
ously.6a 1H, 13C, and 19F NMR spectra were recorded on a Bruker
Avance 500 spectrometer (at 499.9 MHz, 124.9 and 470.3 MHz, re-
spectively). Chemical shifts are reported in ppm downfield from
TMS (1H, 13C) or CFCl3 (19F) as internal standards. Mass spectra
(CI) were recorded on an Agilent 1100 LCMSD SL instrument.
NEt2
F3C
N
3a, toluene,
19
S
89
OH
60 °C, 0.5 h
19a
NH2
N
O
Alcohols 4a–19a, 16b,c, and 19d–f,j; General Procedure
A mixture of the appropriate trifluoromethyl ketone 3 (1 mmol), the
appropriate heterocycle 4–19 (1 mmol), and toluene (2 mL) was
stirred under the corresponding conditions given in Table 1 or 2.
The reaction mixture was cooled to r.t., and the crystalline solid that
had formed was collected by filtration. The product was washed
with CCl4 on the filter, and recrystallized from i-PrOH.
N
N
N
F3C
N
F3C
F3C
Ph
N
O
N
Me
O
O
O
O
Me
3b
3c
3d
1-(1,3-Benzothiazol-2-yl)-2,2,2-trifluoro-1-(1-methyl-1H-pyr-
rol-2-yl)ethanol (4a)
Yield: 61%; colorless solid; mp 133 °C.
1H NMR (500 MHz, DMSO-d6): d = 3.28 (s, 3 H), 6.02 (s, 1 H),
6.33 (s, 1 H), 6.79 (s, 1 H), 7.42 (dd, J = 8.0, 7.0 Hz, 1 H), 7.52 (dd,
J = 7.5, 7.0 Hz, 1 H), 8.02 (d, J = 8.0 Hz, 1 H), 8.15 (d, J = 7.5 Hz,
1 H), 8.40 (s, 1 H).
N
N
N
N
F3C
F3C
N
N
N
Ph
N
H
F3C
O
Me
3j
S
O
3e
3f
Figure 2 2-(Trifluoroacetyl)-1,3-azoles 3b–j
Synthesis 2010, No. 6, 979–984 © Thieme Stuttgart · New York

982
P. V. Khodakovskiy et al.
PAPER
13C NMR (125 MHz, DMSO-d6): d = 35.74, 76.53 (q,
2JCF = 30.2 Hz), 106.64, 110.65, 122.43, 123.87, 124.55 (q,
1JCF = 288.0 Hz), 126.21, 126.32, 126.44, 126.88, 135.72, 153.18,
170.75.
19F NMR (470 MHz, DMSO-d6): d = –76.15.
MS (CI): m/z = 417 [M + 1].
1-(1,3-Benzothiazol-2-yl)-2,2,2-trifluoro-1-(5-methyl-2-fur-
yl)ethanol (9a)
Yield: 64%; yellowish oil.
1H NMR (500 MHz, DMSO-d6): d = 2.23 (s, 3 H), 6.14 (d, J = 2.4
Hz, 1 H), 6.49 (d, J = 2.4 Hz, 1 H), 7.50 (t, J = 7.6 Hz, 1 H), 7.55 (7,
J = 7.6 Hz, 1 H), 8.06 (d, J = 7.6 Hz, 1 H), 8.17 (d, J = 7.6 Hz, 1 H),
8.61 (s, 1 H).
19F NMR (470 MHz, DMSO-d6): d = –74.58.
MS (CI): m/z = 313 [M + 1].
1-{5-[1-(1,3-Benzothiazol-2-yl)-2,2,2-trifluoro-1-hydroxyethyl]-
2,4-dimethyl-1H-pyrrol-3-yl}ethanone (5a)
Yield: 64%; colorless solid; mp 194–195 °C.
2
1H NMR (500 MHz, DMSO-d6): d = 1.81 (s, 3 H), 2.29 (s, 3 H),
2.49 (s, 3 H), 7.52 (dd, J = 8.0, 7.5 Hz, 1 H), 7.58 (dd, J = 8.0, 7.5
Hz, 1 H), 8.11–8.17 (m, 2 H), 8.50 (s, 1 H), 11.18 (s, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 12.18, 14.83, 31.54, 75.79 (q,
2JCF = 30.2 Hz), 120.08, 121.68, 122.25, 122.81, 124.11, 124.91 (q,
1JCF = 288.0 Hz), 126.60, 126.95, 135.45, 135.63, 152.31, 170.77,
194.58.
13C NMR (125 MHz, DMSO-d6): d = 13.77, 75.55 (q, JCF = 30.2
1
Hz), 107.38, 112.10, 122.81, 123.87, 124.05 (q, JCF = 288.0 Hz),
126.29, 126.93, 135.25, 147.09, 153.44, 153.67, 169.81.
19F NMR (470 MHz, DMSO-d6): d = –76.66.
MS (CI): m/z = 314 [M + 1].
5-[1-(1,3-Benzothiazol-2-yl)-2,2,2-trifluoro-1-hydroxyethyl]fu-
ran-2-carbaldehyde Dimethylhydrazone (10a)
Yield: 34%; colorless solid; mp 87–88 °C.
1H NMR (500 MHz, DMSO-d6): d = 2.86 (s, 6 H), 6.46 (d, J = 3.2
Hz, 1 H), 6.64 (d, J = 3.2 Hz, 1 H), 7.09 (s, 1 H), 7.50 (dd, J = 7.6,
7.2 Hz, 1 H), 7.55 (dd, J = 7.6, 7.6 Hz, 1 H), 8.06 (d, J = 7.6 Hz, 1
H), 8.17 (d, J = 7.2 Hz, 1 H), 8.72 (s, 1 H).
19F NMR (470 MHz, DMSO-d6): d = –75.13.
MS (CI): m/z = 369 [M + 1].
Ethyl 5-[1-(1,3-Benzothiazol-2-yl)-2,2,2-trifluoro-1-hydroxy-
ethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylate (6a)
Yield: 84%; colorless solid; mp 168–169 °C.
1H NMR (500 MHz, DMSO-d6): d = 1.21 (t, J = 7.0 Hz, 3 H), 1.80
(s, 3 H), 2.43 (s, 3 H), 4.11 (q, J = 7.0 Hz, 2 H), 7.52 (dd, J = 7.5 Hz,
1 H), 7.58 (dd, J = 7.5 Hz, 1 H), 8.10–8.17 (m, 2 H), 8.48 (s, 1 H),
11.19 (s, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 42.74, 42.75, 75.77 (q,
2JCF = 30.2 Hz), 106.76, 113.05, 122.03, 122.80, 123.89, 124.01 (q,
1JCF = 288.0 Hz), 126.34, 126.95, 135.34, 147.40, 153.40, 154.18,
169.64.
13C NMR (125 MHz, DMSO-d6): d = 11.50, 13.85, 14.80, 58.97,
19F NMR (470 MHz, DMSO-d6): d = –76.30.
75.55 (q, 2JCF = 30.6 Hz), 111.73, 120.43, 121.55, 122.80, 124.10,
MS (CI): m/z = 370 [M + 1].
1
124.89 (q, JCF = 288.0 Hz), 126.57, 126.93, 135.61, 135.98,
152.35, 165.46, 170.82.
19F NMR (470 MHz, DMSO-d6): d = –75.22.
2-Amino-5-[1-(1,3-benzothiazol-2-yl)-2,2,2-trifluoro-
1-hydroxyethyl]thiophene-3-carboxamide (11a)
Yield: 71%; colorless solid; mp 173–174 °C.
1H NMR (500 MHz, DMSO-d6): d = 6.65–6.85 (br, 1 H), 7.10–7.60
(br, 3 H), 7.30 (s, 1 H), 7.49 (dd, J = 8.0, 7.0 Hz, 1 H), 7.56 (dd,
J = 8.5, 7.0 Hz, 1 H), 8.07 (d, J = 8.5 Hz, 1 H), 8.15 (d, J = 8.0 Hz,
1 H), 8.57 (s, 1 H).
MS (CI): m/z = 399 [M + 1].
1-(1,3-Benzothiazol-2-yl)-1-(1-cyclohexyl-2,5-dimethyl-1H-pyr-
rol-3-yl)-2,2,2-trifluoroethanol (7a)
Yield: 95%; colorless solid; mp 148–149 °C.
2
1H NMR (500 MHz, DMSO-d6): d = 1.16 (m, 1 H), 1.35 (m, 2 H),
1.63 (m, 1 H), 1.71 (m, 2 H), 1.79 (m, 2 H), 1.87 (m, 2 H), 2.06 (s,
3 H), 2.25 (s, 3 H), 3.91 (m, 1 H), 5.87 (s, 1 H), 7.47 (dd, J = 8.0,
7.5 Hz, 1 H), 7.52 (dd, J = 7.5 Hz, 1 H), 7.73 (s, 1 H), 8.02 (d,
J = 7.5 Hz, 1 H), 8.12 (d, J = 8.0 Hz, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 77.03 (q, JCF = 30.2 Hz),
1
107.03, 117.57, 122.82, 123.87, 124.36 (q, JCF = 288.0 Hz),
126.30, 126.38, 126.94, 135.23, 153.38, 163.42, 167.87, 171.44.
19F NMR (470 MHz, DMSO-d6): d = –76.14.
MS (CI): m/z = 374 [M + 1].
13C NMR (125 MHz, DMSO-d6): d = 12.66, 14.76, 25.45, 26.46,
2
32.24, 56.08, 77.00 (q, JCF = 28.9 Hz), 107.57, 114.88, 122.65,
Ethyl 2-Amino-5-[1-(1,3-benzothiazol-2-yl)-2,2,2-trifluoro-1-
hydroxyethyl]thiophene-3-carboxylate (12a)
1
123.65, 125.28 (q, JCF = 288.0 Hz), 125.93, 126.62, 127.53,
135.38, 153.37, 173.51.
19F NMR (470 MHz, DMSO-d6): d = –74.79.
Yield: 80%; colorless solid; mp 161–162 °C.
1H NMR (500 MHz, DMSO-d6): d = 1.23 (t, J = 7.0 Hz, 3 H), 4.16
(q, J = 7.0 Hz, 3 H), 7.09 (s, 1 H), 7.40 (br, 2 H), 7.51 (dd, J = 7.6,
7.2 Hz, 1 H), 7.57 (dd, J = 8.0, 7.2 Hz, 1 H), 8.09 (d, J = 8.0 Hz, 1
H), 8.17 (d, J = 7.6 Hz, 1 H), 8.71 (s, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 14.90, 59.64, 76.90 (q,
2JCF = 30.2 Hz), 103.80, 118.12, 122.91, 123.80, 124.20 (q,
1JCF = 288.0 Hz), 126.36, 126.40, 127.08, 135.03, 153.34, 164.60,
165.43, 171.17.
MS (CI): m/z = 409 [M + 1].
1-(1,3-Benzothiazol-2-yl)-1-[2,5-dimethyl-1-(4-tolyl)-1H-pyr-
rol-3-yl]-2,2,2-trifluoroethanol (8a)
Yield: 85%; colorless solid; mp 148–149 °C.
1H NMR (500 MHz, DMSO-d6): d = 1.77 (s, 3 H), 1.91 (s, 3 H),
2.34 (s, 3 H), 6.06 (s, 1 H), 7.06 (d, J = 7.5 Hz, 2 H), 7.28 (d, J = 7.5
Hz, 2 H), 7.46 (dd, J = 8.0, 7.0 Hz, 1 H), 7.52 (dd, J = 8.0, 7.0 Hz,
1 H), 7.85 (s, 1 H), 8.04 (d, J = 8.0 Hz, 1 H), 8.11 (d, J = 8.0 Hz, 1
H).
19F NMR (470 MHz, DMSO-d6): d = –76.65.
MS (CI): m/z = 403 [M + 1].
13C NMR (125 MHz, DMSO-d6): d = 12.44, 12.99, 21.09, 77.01 (q,
2JCF = 28.9 Hz), 106.58, 115.48, 122.67, 123.71, 125.34 (q,
1JCF = 288.0 Hz), 125.97, 126.67, 127.08, 128.03, 128.34, 130.37,
135.30, 135.37, 138.11, 153.44, 173.32.
Ethyl 5-Amino-4-[1-(1,3-benzothiazol-2-yl)-2,2,2-trifluoro-1-
hydroxyethyl]-3-methylthiophene-2-carboxylate (13a)
Yield: 83%; colorless solid; mp >250 °C.
Synthesis 2010, No. 6, 979–984 © Thieme Stuttgart · New York

PAPER
Oxyalkylation of Five-Membered Heterocycles
983
1H NMR (500 MHz, DMSO-d6): d = 1.17 (m, 3 H), 1.73 (s, 3 H),
4.08 (m, 2 H), 6.96 (br, 2 H), 7.51 (m, 1 H), 7.57 (m, 1 H), 8.13 (m,
2 H), 8.64 (s, 1 H).
1-(1,3-Benzothiazol-2-yl)-1-[2-(diethylamino)-1,3-thiazol-5-yl]-
2,2,2-trifluoroethanol (18a)
Yield: 52%; colorless solid; mp 128–129 °C.
13C NMR (125 MHz, DMSO-d6): d = 14.80, 14.82, 59.96, 78.96 (q,
2JCF = 29.8 Hz), 106.62, 110.33, 122.92, 124.22, 125.75 (q,
1JCF = 288.0 Hz), 126.81, 127.06, 135.73, 146.99, 151.49, 161.27,
162.38, 170.90.
1H NMR (500 MHz, DMSO-d6): d = 1.11 (m, 6 H), 3.40 (m, 4 H),
7.27 (s, 1 H), 7.50 (m, 1 H), 7.56 (m, 1 H), 8.09 (d, J = 7.5 Hz, 1 H),
8.16 (d, J = 7.5 Hz, 1 H), 8.67 (s, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 12.79, 45.40, 76.35 (q,
19F NMR (470 MHz, DMSO-d6): d = –75.43.
2JCF = 31.0 Hz), 119.70, 122.89, 123.87, 124.27 (q, JCF = 288.0
1
Hz), 126.38, 127.04, 135.09, 140.48, 153.36, 170.63, 171.32.
19F NMR (470 MHz, DMSO-d6): d = –76.79.
MS (CI): m/z = 388 [M + 1].
MS (CI): m/z = 417 [M + 1].
1-(2-Amino-4-methyl-1,3-thiazol-5-yl)-1-(1,3-benzothiazol-2-
yl)-2,2,2-trifluoroethanol (14a)
Yield: 49%; colorless solid; mp 189–190 °C.
1-(5-Amino-3-methylisoxazol-4-yl)-1-(1,3-benzothiazol-2-yl)-
2,2,2-trifluoroethanol (19a)
Yield: 89%; colorless solid; mp 227–228 °C.
1H NMR (500 MHz, DMSO-d6): d = 1.68 (s, 3 H), 6.75 (s, 2 H),
7.48–7.66 (m, 2 H), 8.08–8.27 (m, 2 H), 8.50 (s, 1 H).
1H NMR (500 MHz, DMSO-d6): d = 1.95 (s, 3 H), 6.98 (s, 2 H),
7.51 (m, 1 H), 7.57 (m, 1 H), 8.09 (m, 1 H), 8.16 (m, 1 H), 8.50 (s,
1 H).
13C NMR (125 MHz, DMSO-d6): d = 17.23, 76.54 (q,
2JCF = 30.6 Hz), 112.81, 122.86, 123.89, 124.89 (q, JCF = 288.0
1
2
13C NMR (125 MHz, DMSO-d6): d = 11.83, 75.35 (q, JCF = 30.6
Hz), 126.47, 127.00, 135.40, 148.74, 152.85, 167.97, 172.15.
19F NMR (470 MHz, DMSO-d6): d = –75.95.
MS (CI): m/z = 346 [M + 1].
1
Hz), 86.11, 122.94, 124.04, 125.43 (q, JCF = 288.0 Hz), 126.74,
127.13, 135.25, 152.08, 159.11, 168.36, 171.24.
19F NMR (470 MHz, DMSO-d6): d = –76.69.
MS (CI): m/z = 330 [M + 1].
1-(2-Amino-1,3-thiazol-5-yl)-1-(1,3-benzothiazol-2-yl)-2,2,2-tri-
fluoroethanol (15a)
Yield: 64%; colorless solid; mp 168–169 °C.
1H NMR (500 MHz, DMSO-d6): d = 7.10 (s, 1 H), 7.16 (s, 2 H),
7.51 (dd, J = 8.5, 6.5 Hz, 1 H), 7.57 (dd, J = 8.0, 6.5 Hz, 1 H), 8.08
(d, J = 8.5 Hz, 1 H), 8.17 (d, J = 8.0 Hz, 1 H), 8.65 (s, 1 H).
2,2,2-Trifluoro-1-[2-(methylamino)-1,3-thiazol-5-yl]-1-
(1-methyl-1H-1,2,4-triazol-5-yl)ethanol (16b)
Yield: 76%; colorless solid; mp 193–194 °C.
1H NMR (500 MHz, DMSO-d6): d = 2.79 (d, J = 1.0 Hz, 3 H), 3.81
(s, 3 H), 6.80 (s, 1 H), 7.70 (q, J = 1.0 Hz, 1 H), 7.99 (s, 1 H), 8.21
(s, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 76.37 (q, JCF = 31.0 Hz),
2
1
120.11, 122.89, 123.79, 124.27 (q, JCF = 288.0 Hz), 126.35,
13C NMR (125 MHz, DMSO-d6): d = 31.16, 37.93, 73.66 (q,
127.02, 135.09, 139.60, 153.35, 171.13, 171.43.
19F NMR (470 MHz, DMSO-d6): d = –76.75.
MS (CI): m/z = 332 [M + 1].
1
2JCF = 31.0 Hz), 118.96, 124.29 (q, JCF = 288.0 Hz), 139.66,
149.79, 151.11, 171.90.
19F NMR (470 MHz, DMSO-d6): d = –77.29.
MS (CI): m/z = 294 [M + 1].
1-(1,3-Benzothiazol-2-yl)-2,2,2-trifluoro-1-[2-(methylamino)-
1,3-thiazol-5-yl]ethanol (16a)
Yield: 99%; colorless solid; mp 139–140 °C.
1H NMR (500 MHz, DMSO-d6): d = 2.79 (d, J = 4.5 Hz, 3 H), 7.20
(s, 1 H), 7.51 (dd, J = 8.0, 7.0 Hz, 1 H), 7.57 (dd, J = 8.0, 7.0 Hz, 1
H), 7.69 (q, J = 4.5 Hz, 1 H), 8.09 (d, J = 8.0 Hz, 1 H), 8.17 (d,
J = 8.0 Hz, 1 H), 8.69 (s, 1 H).
2,2,2-Trifluoro-1-[2-(methylamino)-1,3-thiazol-5-yl]-1-(5-phe-
nyl-1,3-oxazol-2-yl)ethanol (16c)
Yield: 85%; colorless solid; mp 165–166 °C.
1H NMR (500 MHz, DMSO-d6): d = 2.82 (s, 3 H), 7.10 (s, 1 H),
7.40 (t, J = 7.5 Hz, 1 H), 7.49 (dd, J = 7.5 Hz, 2 H), 7.68–7.78 (m,
3 H), 7.82 (s, 1 H), 8.15 (s, 1 H).
2
13C NMR (125 MHz, DMSO-d6): d = 31.22, 76.38 (q, JCF = 31.4
13C NMR (125 MHz, DMSO-d6): d = 31.21, 73.91 (q,
1
Hz), 119.69, 122.87, 123.82, 124.26 (q, JCF = 288.0 Hz), 126.36,
2JCF = 31.4 Hz), 119.10, 123.24, 124.04 (q, JCF = 288.0 Hz),
1
127.02, 135.09, 139.88, 153.34, 171.35, 171.89.
19F NMR (470 MHz, DMSO-d6): d = –76.73.
MS (CI): m/z = 346 [M + 1].
124.70, 127.34, 129.55, 129.65, 139.75, 152.26, 158.70, 171.71.
19F NMR (470 MHz, DMSO-d6): d = –77.72.
MS (CI): m/z = 356 [M + 1].
1-(1,3-Benzothiazol-2-yl)-1-[2-(cyclohexylamino)-1,3-thiazol-5-
yl]-2,2,2-trifluoroethanol (17a)
1-(5-Amino-3-methylisoxazol-4-yl)-2,2,2-trifluoro-1-(1-methyl-
1H-imidazol-2-yl)ethanol (19d)
Yield: 74%; colorless solid; mp 230–230 °C.
1H NMR (500 MHz, DMSO-d6): d = 1.29 (s, 3 H), 3.45 (s, 3 H),
6.34 (s, 2 H), 6.88 (s, 1 H), 7.23 (s, 1 H), 7.74 (s, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 10.03, 33.97, 72.24 (q,
2JCF = 30.6 Hz), 85.53, 124.35, 125.85 (q, 1JCF = 286.7 Hz), 126.07,
142.90, 158.81, 168.47.
19F NMR (470 MHz, DMSO-d6): d = –77.12.
Yield: 76%; colorless solid; mp 193–194 °C.
1H NMR (500 MHz, DMSO-d6): d = 2.79 (d, J = 1.0 Hz, 3 H), 3.81
(s, 3 H), 6.80 (s, 1 H), 7.70 (q, J = 1.0 Hz, 1 H), 7.99 (s, 1 H), 8.21
(s, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 31.16, 37.93, 73.66 (q,
1
2JCF = 31.0 Hz), 118.96, 124.29 (q, JCF = 288.0 Hz), 139.66,
149.79, 151.11, 171.90.
19F NMR (470 MHz, DMSO-d6): d = –77.29.
MS (CI): m/z = 277 [M + 1].
MS (CI): m/z = 294 [M + 1].
Synthesis 2010, No. 6, 979–984 © Thieme Stuttgart · New York

984
P. V. Khodakovskiy et al.
PAPER
1-(5-Amino-3-methylisoxazol-4-yl)-2,2,2-trifluoro-1-(1-vinyl-
1H-imidazol-2-yl)ethanol (19e)
Yield: 81%; colorless solid; mp 215–225 °C (sublimation).
1H NMR (500 MHz, DMSO-d6): d = 1.25 (s, 3 H), 4.81 (d, J = 9.0
Hz, 1 H), 5.41 (d, J = 16.0 Hz, 1 H), 6.44 (s, 2 H), 7.03 (s, 1 H), 7.08
(dd, J = 16.0, 9.0 Hz, 1 H), 7.80 (s, 1 H), 8.04 (s, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 9.83, 72.25 (q,
2JCF = 30.2 Hz), 85.99, 102.74, 118.62, 125.65 (q, 1JCF = 288.0 Hz),
127.62, 129.36, 142.62, 158.61, 168.26.
References
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(d) Qiu, X.-L.; Meng, W.-D.; Qing, F.-L. Tetrahedron 2004,
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Fluorine-Containing Amino Acids; John Wiley and Sons:
New York, 1995.
19F NMR (470 MHz, DMSO-d6): d = –77.10.
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(b) Murphy, C. D.; Schaffrath, C.; O’Hagan, D.
MS (CI): m/z = 289 [M + 1].
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1-(5-Amino-3-methylisoxazol-4-yl)-1-[4-(1H-benzimidazol-2-
yl)-1,3-thiazol-2-yl]-2,2,2-trifluoroethanol (19f)
Yield: 53%; colorless solid; mp >250 °C.
1H NMR (500 MHz, DMSO-d6): d = 1.84 (s, 3 H), 6.85 (br, 2 H),
7.32 (m, 2 H), 7.69 (m, 2 H), 8.50 (br, 1 H), 8.68 (s, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 12.28, 75.09 (q,
2JCF = 31.4 Hz), 86.03, 115.62, 123.82, 123.96, 125.34 (q,
1JCF = 288.0 Hz), 137.77, 144.24, 146.00, 159.43, 168.17, 171.96.
19F NMR (470 MHz, DMSO-d6): d = –76.80.
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48, 6555.
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Boulet, L.; Côté, B.; Frenette, R.; Girard, M.; Guay, D.;
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J.; Martins, E.; Masson, P.; Muise, E.; Pon, D. J.; Siegl, P. K.
S.; Styhler, A.; Tsou, N. N.; Turner, M. J.; Young, R. N.;
Girard, Y. J. Med. Chem. 2003, 46, 2413. (f) Middleton, L.
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31, 3828. (i) Ohkura, H.; Berbasov, D. O.; Soloshonok, V.
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MS (CI): m/z = 396 [M + 1].
1-(5-Amino-3-methylisoxazol-4-yl)-2,2,2-trifluoro-1-(4-methyl-
5-phenyl-4H-1,2,4-triazol-3-yl)ethanol (19j)
Yield: 72%; colorless solid; mp 201–202 °C.
1H NMR (500 MHz, DMSO-d6): d = 1.43 (s, 3 H), 3.50 (s, 3 H),
6.58 (s, 2 H), 7.58 (m, 3 H), 7.69 (m, 2 H), 8.15 (s, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 10.36, 32.58, 71.57 (q,
2JCF = 31.4 Hz), 83.69, 125.46 (q, 1JCF = 288.0 Hz), 126.98, 129.36,
129.45, 130.71, 151.13, 156.26, 158.21, 168.94.
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(6) (a) Khodakovskiy, P. V.; Volochnyuk, D. M.; Panov, D. M.;
Pervak, I. I.; Zarudnitskii, E. V.; Shishkin, O. V.;
Yurchenko, A. A.; Shivanyuk, A.; Tolmachev, A. A.
Synthesis 2008, 948. (b) Khodakovskiy, P. V.; Volochnyuk,
D. M.; Tolmachev, A. A. Synthesis 2009, 1099.
19F NMR (470 MHz, DMSO-d6): d = –77.16.
MS (CI): m/z = 354 [M + 1].
(c) Khodakovskiy, P. V.; Volochnyuk, V.; Shivanyuk, A.;
Shishkin, O. V.; Tolmachev, A. A. Synthesis 2008, 3245.
(d) Khodakovskiy, P. V.; Mykhailiuk, P. K.; Volochnyuk, D.
M.; Tolmachev, A. A. Synthesis 2010, DOI: 10.1055/s-
0029-1219219.
Synthesis 2010, No. 6, 979–984 © Thieme Stuttgart · New York