Dakin-west reaction of n-thioacylprolines using trifluoroacetic anhydride: Novel access to 5-trifluoromethylthiazoles

Article abstract of DOI:10.3987/COM-13-12904

The reaction between N-thioacylprolines and trifluoroacetic anhydride in the presence of pyridine afforded a good yield of 5-trifluoromethylthiazoles. This reaction proceeded through mesoionic 1,3-thiazolium-5-olates, followed by cleavage of the pyrrolidine ring and the formation of thiazoles, introducing a trifluoromethyl group at position 5 in the thiazole ring.

Full text of DOI:10.3987/COM-13-12904

HETEROCYCLES, Vol. 89, No. 3, 2014
709
HETEROCYCLES, Vol. 89, No. 3, 2014, pp. 709 - 724. © 2014 The Japan Institute of Heterocyclic Chemistry
Received, 2nd December, 2013, Accepted, 29th January, 2014, Published online, 3rd February, 2014
DOI: 10.3987/COM-13-12904
DAKIN-WEST REACTION OF N-THIOACYLPROLINES USING
TRIFLUOROACETIC ANHYDRIDE: NOVEL ACCESS TO
5-TRIFLUOROMETHYLTHIAZOLES
Yuri Hagimoto, Ryosuke Saijo, and Masami Kawase*
Faculty of Pharmaceutical Sciences, Matsuyama University, 4-2 Bunkyo-cho,
Matsuyama, Ehime 790-8578, Japan; E-mail: kawase@cc.matsuyama-u.ac.jp
Abstract – The reaction between N-thioacylprolines and trifluoroacetic anhydride
in the presence of pyridine afforded a good yield of 5-trifluoromethylthiazoles. This
reaction proceeded through mesoionic 1,3-thiazolium-5-olates, followed by
cleavage of the pyrrolidine ring and the formation of thiazoles, introducing a
trifluoromethyl group at position 5 in the thiazole ring.
The Dakin-West (D-W) reaction of -amino acids was originally performed in acetic anhydride in the
presence of pyridine to produce -acetamido methyl ketones.1 Secondary -amino acids are also known
to undergo the D-W reaction, and this mechanism has been studied in detail.1a The D-W reaction
involves the condensation of N-alkyl--amino acids with acetic anhydride in the presence of a base to
produce -acetamido ketones through intermediate mesoionic 1,3-oxazolium-5-olates (münchnone) (A)
(Eq. 1).
R1
R1
R1
R2
+
N
R2
Me
Ac2O
H2O
HN CO2H
R2
N
(1)
-
O
O
Me
- CO2
O
Me
O
A
MeO2C
CO2Me
Ac2O
CO2H
O
N
N
R
N
CO2Me
(2)
O
R
O
R
CO2Me
1
B

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HETEROCYCLES, Vol. 89, No. 3, 2014
However, the D-W reaction of proline or its N-acyl derivatives with acetic anhydride does not yield any
ketonic products.1a On the other hand, a generation of mesoionic oxazolium-5-olates (B), formed
through the dehydration of N-acylprolines (1) with acetic anhydride, has been shown to produce
2,3-dihydro-1H-pyrrolizine derivatives through the 1,3-dipolar cycloaddition reaction with dimethyl
acetylenedicarboxylate (Eq. 2).2
cyclodehydrated by TFAA to intermediary mesoionic compounds (B), which subsequently reacted with
TFAA to produce trifluoromethylated
5-trifluoromethyloxazoles,3a acyloins,3b
We previously demonstrated that N-acylprolines (1) were
3-trifluoroacetyl-4,5-dihydropyrrolidines,3c or enol esters3d depending on the nature of the N-acyl groups
and experimental conditions. We have examined the D-W reaction of N-thioacylprolines (1a-f) with
TFAA. 5-Trifluoromethylthiazoles (2a-f) could be obtained when the reaction proceeded in the same
manner as the D-W reaction of N-acylprolines.3a We here described the results obtained.
The starting N-thioacylprolines (1a-f) were prepared from L-proline in four steps with good overall yields
(Scheme 1); ester formation (3 from L-proline), N-acylation (4 from 3), thionation (5 from 4) by
Lawesson’s reagent (2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide; LR) followed
by hydrolysis (1 from 5). The reaction between the N-pivaloylproline ethyl ester (4f) and LR produced a
low yield of N-thiopivaloylproline esters (5f) (26%). However, the addition of pyridine (0.38 molar
equiv. relative to 4f) to the reaction mixture increased the yield of 5f from 26% to 84%.
Et3N (1.0 equiv.)
RCOCl (0.98 equiv.)
3M NaOH (0.98 equiv.)
SOCl2 (1.2 equiv.)
EtOH (19.5 equiv.)
Cl
LR (0.75 equiv.)
CO2Et
CO2H
CO2Et
CO2Et
N
N
N
in toluene
90 °C
→
in dist.H2O
rt
-10 °C
reflux
H
H
H
R
O
3
4a-f
2M NaOH (1.5 equiv.)
CO2H
N
R
N
in 1,4-dioxane
75 °C
S
R
S
1a-f (>y. 80%)
5a
: R=Ph (y. 73% from
5b: 4-ClC6H4 (y. 65%)
5c: 4-MeOC6H4 (y. 62%)
L-Pro in 3 steps)
5d
: 3,5-(CF3)2C6H3 (y. 60%)
: 3,4,5-(MeO)3C6H2 (y. 80%)
5e
5f
: -Bu (y. 84%)
t
Scheme 1

HETEROCYCLES, Vol. 89, No. 3, 2014
711
Table 1. N-Thiobenzoylproline (1a) reactions under various conditions
1) TFAA, pyridine, DMAP (0.3 equiv.)
in solvent
rt, 1 h → temp, time
N
OH
CO2H
N
Ph
CF3
S
2) 10% HCl in 1,4-dioxane
60 °C, 1 h
Ph
S
2a
1a
Entry
Yield (%)a
TFAA (equiv.) Pyridine (equiv.) Solvent
Temp. (°C) Time (h)
1
2
3
4
5
6
benzene
toluene
xylene
xylene
xylene
DMF
6
6
6
6
4
6
5
5
6
3
3
3
3
2
3
80
57
64
79
24
21
110
138
138
138
153
5
12
12
5
a Isolated yields.
Table 1 shows the results obtained when N-thiobenzoylproline (1a) was reacted with TFAA in the
presence of pyridine and 4-N,N-dimethylaminopyridine (DMAP) following acid hydrolysis. A higher
temperature (entries 1, 2 and 3) and longer reaction time (entries 3 and 4) improved the yield.
The scope of the reaction substrates was investigated using these optimized conditions (Table 1, entry 4).
The results obtained are summarized in Table 2. N-Thioacyl derivatives (1a-f), containing thiobenzoyl
or thiopivaloyl groups, were easily transformed to 5-trifluoromethylthiazoles (2a-f) with good yields.
Table 2. N-Thioacylproline (1) reactions
1) TFAA (3 equiv.), pyridine (6 equiv.)
DMAP (0.3 equiv.) in xylene
rt, 1 h →138 °C, 12 h
2) 10% HCl in 1,4-dioxane
60 °C, 1 h
N
OH
CO2H
N
R
CF3
S
R
S
1a f
2a f
-
-
Yield (%)a
R
Entry
1
Product
1
2
3
4
5
6
a
b
c
d
e
f
Ph
4-ClC6H4
4-MeOC6H4
3,5-(CF3)2C6H3
3,4,5-(MeO)3C6H2
2a
2b
2c
2d
2e
2f
79
70
74
75
61
73
-Bu
t
a Isolated yields.

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HETEROCYCLES, Vol. 89, No. 3, 2014
We previously described the reaction between N-acyl-N-benzyl--amino acids and TFAA, which
produced good yields of 5-trifluoromethyloxazoles.3a Therefore, we attempted to react N-thiobenzoyl-
N-benzylphenylalanine (6) with TFAA; however, the subsequent yield of 5-trifluoromethylthiazole (7)
isolated was poor at 10% (Table 3, entries
1
and 2).
The main product was
4-benzyl-2-phenylthiazol-5(4H)-one (8). The yield of 8 increased to 77% in the case of the
N-(4-methoxybenzyl) derivative 6b because the N-substituent was easily cleaved during the reaction
(entry 3). These results indicated that the intermediates 1,3-thiazolium-5-olates cannot undergo the
trifluoroacetylation easily at position 4 as compared with the case of the intermediate
1,3-oxazolium-5-olates generated from N-acyl-N-benzyl--amino acids.3a
Table 3. D-W reactions of N-alkyl-N-thiobenzoylalanine derivatives
Ph
TFAA (3.0 equiv.)
pyridine (6.0 equiv.)
R
N
Ph
N
Ph
N
CO2H
in solvent
rt, 1 h → temp, time
Ph
O
Ph
CF3
S
S
Ph
S
6
7
8
Yield (%)a
Entry
Temp. (°C) Time (h)
1
R
Solvent
7
8
C6H5CH2
C6H5CH2
1
2
3
a
a
b
xylene
toluene
toluene
12
12
15
10
10
trace
138
110
110
49
21
77
4-MeOC6H4CH2
a Isolated yields.
Compound 7 was alternatively prepared from N-benzoylphenylalanine 9 as shown in equation 3. Thus,
9 was treated with DCC to produce 5(4H)-oxazolone, which reacted with TFAA to yield the
C-trifluoroacetylated 5(4H)-oxazolone 10. The subsequent hydrolysis and decarboxylation of 10 with
oxalic acid produced the hydrated trifluoromethyl ketone 11.4 The treatment of 11 with LR provided
authentic 7 at a yield of 16%.5
Ph
CF3
OH
Ph
O
CF3
Ph
Ph
1) DCC
HN CO2H 2) TFAA
H
N
(CO2H)2
N
LR
N
(3)
Ph
CF3
OH
S
- CO2
- CO
Ph
O
Ph
O
O
Ph
O
9
10
11
7

HETEROCYCLES, Vol. 89, No. 3, 2014
713
As shown in Scheme 2, the 13C NMR spectra of both 7 and 2a showed each peak of their thiazole rings at
the same position. Thus, the carbons at C-2, C-4, and C-5 of the thiazole rings in 7 and 2a appeared at
approximately 169, 158, and 120 ppm, respectively. The structures of 2a-f were also supported by
spectral and analytical data. The presence of the CF3 group in 2a-f was determined on the basis of
13
long-range C-19F coupling. Thus, the carbons of the CF3 group and C-5 appeared at approximately 
1
2
1
123 ppm (quartet, JC-F = 270 Hz) and  120 ppm (quartet, JC-F = 37 Hz), respectively. These H- and
13C-NMR data are consistent with those for the 5-trifluoromethylthiazoles 7, 12,5 and 135 (Scheme 2).
c 158.7(q, 3
JC-F
= 2.4 Hz)
c 157.3 (q, 1
= 2.1 Hz)
JC-F
N
OH
N
Ph
CF3
Ph
c 168.8
CF3
Ph
S
S
c 122.6 (q, 1
JC-F
= 270 Hz)
= 37 Hz)
c 122.7 (q, 1
JC-F
= 270 Hz)
= 37 Hz)
c 120.0 (q, 2
c 168.8
c 120.4 (q, 2
JC-F
JC-F
2a
7
c 146.0 (q, 3
= 2.5 Hz)
JC-F
c 144.4 (q, 3
JC-F
= 3.8 Hz)
8.12 (s, 1H)
O
c 160.7

H
N
N
OMe
CF3
CF3
Ph
c 171.9
Ph
S
S
c 122.1 (q, 1
JC-F
= 269 Hz)
= 38 Hz)
c 121.1 (q, 1
JC-F
c 131.2 (q, 2
= 271 Hz)
= 40 Hz)
c 169.0
c 126.2 (q, 2
JC-F
JC-F
125
135
Scheme 2
A plausible mechanism is described in Scheme 3. The reaction involves a mesoionic 1,3-thiazolium-5-
olate (B) formed through the cyclodehydration of 1 by TFAA. Intermediate B undergoes
trifluoroacetylation followed by decarboxylation to give the enol trifluoroacetate C: a similar mechanism
has been postulated in the Dakin-West reaction of N-acylproline.3a The cyclization of the enol C leads to
the thiazolium salt D. The cleavage of the N-C bond of D readily occurs upon an attack of the
trifluoroacetate anion because of the hindered 5-5 bicyclic system. As described in a previous study, the
formation of 2 could occur through the hydrolysis of E.3a
Trifluoromethyl-substituted thiazoles may be used as a promising skeleton for the development of
medicinal and agrochemical chemistry.6 4-Trifluoromethylthiazole derivatives such as metsulfovax and
thifuzamide are known fungicides in the agricultural field and several synthetic methods have been
reported for the preparation of the 4-trifluoromethylthiazole core.7 However, few practical procedures

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HETEROCYCLES, Vol. 89, No. 3, 2014
are currently available for the syntheses of 5-trifluoromethylthiazoles.8 For example, the reaction of
3-(N-tert-butyl-N-methylhydrazono)-1,1,1-trifluoroalkan-2-ones with silica gel to form
5-trifluoromethyl-3-oxazolines, and the subsequent treatment of 5-trifluoromethyl-3-oxazolines with P2S5
afforded the corresponding 5-trifluoromethylthiazoles, and this has only been applied in a few cases.8a
5,5’-Bistrifluoromethylbisthiazoles were obtained by the reaction of dithioamides with TFAA in
moderate yields, in which the products obtained were restricted to 4,4’-bispyridyl substituents.8b The
unexpected reaction of the 2-dibenzylamino-4,4,4-trifluoro-3-hydroxylbutyric acid ethyl ester with SOCl2
provided 2-phenyl-5-trifluoromethyl-1,3-thiazole-4-carboxylate.8c Moody et al.8d and our group5
recently reported the practical synthesis of a 2-benzoylamino trifluoromethyl ketone hydrate, which
reacted with LR to give 5-trifluoromethylthiazoles.
In summary, we herein described the novel rearrangement of N-thioacylprolines, in which a pyrrolidine
ring was cleaved concomitant with the formation of a thiazole ring. In addition, this reaction is a new
and easy synthetic procedure for thiazole derivatives with a trifluoromethyl group at position 5. This

HETEROCYCLES, Vol. 89, No. 3, 2014
715
method may be useful and convenient in terms of the ready accessibility of the starting materials, cheap
reagents, operational simplicity, and high overall yields.
EXPERIMENTAL
All melting points were determined using a Yanagimoto hot-stage melting point apparatus and are
uncorrected.
tetramethylsilane (Me4Si) as an internal reference and CDCl3 as the solvent. 13C-NMR spectra were
1H-NMR spectra were measured on Bruker AVANCE500 spectrometer with
1
13
obtained on a Bruker AVANCE500 spectrometer (at 125 MHz). Both H- and C-NMR spectral data
are reported in parts per million () relative to Me4Si. The symbols “#1” and “#2” represent two
rotamers.
Infrared (IR) spectra were recorded on a JASCO FT/IR-4100 spectrometer. Low- and
high-resolution MS were obtained with a JEOL JMS-GC mate II spectrometer with a direct inlet system
at 70 eV. Elemental analyses were carried out in the microanalytical laboratory of Ehime University.
Standard work-up means that the organic layers were finally dried over Na2SO4, filtered, and
concentrated in vacuo below 45 °C using a rotary evaporator.
Preparation of N-thioacylproline ethyl esters (5a-f): N-Acylproline ethyl esters (4) were prepared in
good yields by Schotten-Baumann reaction of L-proline ethyl ester (3) and the appropriate acyl chloride
(Scheme 1). A mixture of 4 (4.00 mmol), Lawesson’s reagent (3.00 mmol), and pyridine (1.50 mmol) in
toluene (20 mL) was heated at 90 °C for 1–5 h. After workup with water, the mixture was extracted
with AcOEt (x 3). The combined organic layers were washed with brine, dried over anhyd sodium
sulfate, and evaporated. The residue was purified by column chromatography (silica gel, hexane:AcOEt
= 10:1 to 2:1) to give 5.
(S)-Ethyl 1-(phenylcarbonothioyl)pyrrolidine-2-carboxylate (5a). Light yellowish needles. 73%
yield (3 steps). mp 86 °C (hexane–AcOEt). 1H NMR (500 MHz, CDCl3)  1.15 (t, J = 7.2 Hz, 0.69H,
#2), 1.33 (t, J = 7.1 Hz, 2.31H, #1), 1.97 (m, 0.77H, #1), 2.05−2.18 (m, 0.69H, #2), 2.18−2.05 (m, 1.54H,
#1), 2.31 (m, 0.23H, #2), 2.44 (m, 0.77H, #1), 3.55 (m, 0.77H, #1), 3.66 (m, 0.77H, #1), 3.97−4.09 (m,
0.46H, #2), 4.12 (q, J = 7.2 Hz, 0.46H, #2), 4.27 (q, J = 7.1 Hz, 1.54H, #1), 4.44 (dd, J = 8.5, 2.1 Hz,
0.23H, #2), 5.12 (dd, J = 8.7, 5.0 Hz, 0.77H, # 1), 7.22−7.41 (m, 5H). 13C NMR (125 MHz, CDCl3) 
14.0 (OCH2CH3, #2), 14.2 (OCH2CH3, #1), 22.8 (4-CH2, #2), 25.2 (4-CH2, #1), 29.7 (3-CH2, #1), 31.5
(3-CH2, #2), 53.4 (5-CH2, #2), 54.1 (5-CH2, #1), 61.4 (OCH2CH3, #1), 61.6 (OCH2CH3, #2), 64.7 (2-CH,
#2), 64.9 (2-CH, #1), 125.4 (CH, #2), 125.7 (CH, #1), 128.3 (CH, #1), 128.4 (CH, #2), 128.6 (CH, #2),
128.9 (CH, #1), 143.6 (C, #1), 143.9 (C, #2), 170.4 (CO2Et, #1), 170.6 (CO2Et, #2), 199.5 (C=S, #1),
199.8 (C=S, #2). IR (KBr) cm-1: 2981, 1739, 1463, 1442, 1344, 1284, 1199, 763. MS EI(+) m/z (%):
+
･
263 (M , 75), 121 (100). Anal. Calcd for C14H17NO2S: C, 63.85; H, 6.51; N, 5.32. Found: C, 63.62;

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HETEROCYCLES, Vol. 89, No. 3, 2014
H, 6.26; N, 5.26.
(S)-Ethyl 1-(4-methoxyphenylcarbonothioyl)pyrrolidine-2-carboxylate (5b).
Light yellowish
needles. 62% yield (3 steps). mp 65−66 °C (hexane−AcOEt). 1H NMR (500 MHz, CDCl3)  1.17 (t,
J = 7.1 Hz, 0.66H, #2), 1.32 (t, J = 7.1 Hz, 2.34H, #1), 1.96 (m, 0.78H, #1), 2.17−2.06 (m, 0.66H, #2),
2.06−2.17 (m, 1.56H, #1), 2.31 (m, 0.22H, #2), 2.47 (m, 0.78H, #1), 3.62 (m, 0.78H, #1), 3.72 (m, 0.78H,
#1), 3.80 (s, 0.66H, #2), 3.82 (s, 2.34H, #1), 3.99−4.09 (m, 0.44H, #2), 4.12 (q, J = 7.1 Hz, 0.44H, #2),
4.16 (q, J = 7.1 Hz, 1.56H, #1), 4.50 (dd, J = 8.4, 2.4 Hz, 0.22H, #2), 5.12 (dd, J = 8.5, 5.4 Hz, 0.78H, #1),
6.82 (dt, J = 9.3, 2.4 Hz, 0.44H, #2), 6.87 (dt, J = 9.3, 2.4 Hz, 1.56H, #1), 7.21 (d, J = 9.1 Hz, 0.44H, #2),
7.41 (dt, J = 9.3, 2.4 Hz, 1.56H, #1). 13C NMR (125 MHz, CDCl3)  14.1 (OCH2CH3, #2), 14.2
(OCH2CH3, #1), 22.9 (4-CH2, #2), 25.3 (4-CH2, #1), 29.7 (3-CH2, #1), 31.6 (3-CH2, #2), 53.7 (5-CH2, #2),
54.3 (5-CH2, #1), 55.4 (OCH3, #2), 55.4 (OCH3, #1), 61.4 (OCH2CH3, #1), 61.6 (OCH2CH3, #2), 64.8
(2-CH, #2), 65.1 (2-CH, #1), 113.5 (CH, #1), 113.6 (CH, #2), 127.3 (CH, #2), 127.8 (CH, #1), 136.1 (C,
#1), 136.6 (C, #2), 159.9 (C-OCH3, #1), 160.3 (C-OCH3, #2), 170.5 (CO2Et, #1), 170.8 (CO2Et, #2),
199.4 (C=S, #1), 200.0 (C=S, #2). IR (KBr) cm-1: 2977, 1743, 1514, 1457, 1248, 1192, 1173, 1159,
+
･
1028, 830. MS EI(+) m/z (%): 293 (M , 88), 151 (100). Anal. Calcd for C14H17NO2S: C, 61.41; H,
6.53; N, 4.77. Found: C, 61.49; H, 6.53; N, 4.70.
(S)-Ethyl 1-(4-chlorophenylcarbonothioyl)pyrrolidine-2-carboxylate (5c). Light yellowish needles.
65% yield (3 steps). mp 85−86 °C (hexane−AcOEt). 1H NMR (500 MHz, CDCl3)  1.17 (t, J = 7.1 Hz,
0.69H, #2), 1.32 (t, J = 7.2 Hz, 2.31H, #1), 1.98 (m, 0.77H, #1), 2.06−2.19 (m, 0.69H, #2), 2.06−2.19 (m,
1.54H, #1), 2.32 (m, 0.23H, #2), 2.43 (m, 0.77H, #1), 3.54 (m, 0.77H, #1), 3.66 (m, 0.77H, #1),
4.01−4.15 (m, 0.88H, #2), 4.23−4.29 (m, 1.54H, #1), 4.41 (dd, J = 8.5, 2.4 Hz, 0.23H, #2), 5.10 (dd, J =
8.8, 5.2 Hz, 0.77H, #1), 7.19 (dt, J = 8.7, 2.2 Hz, 0.46H, #2), 7.29 (dt, J = 8.7, 2.0 Hz, 0.46H, #2),
7.32−7.36 (m, 3.08H, #1). 13C NMR (125 MHz, CDCl3)  14.0 (OCH2CH3, #2), 14.2 (OCH2CH3, #1),
22.8 (4-CH2, #2), 25.2 (4-CH2, #1), 29.7 (3-CH2, #1), 31.6 (3-CH2, #2), 53.6 (5-CH2, #2), 54.1 (5-CH2,
#1), 61.5 (OCH2CH3, #1), 61.8 (OCH2CH3, #2), 64.7 (2-CH, #2), 64.9 (2-CH, #1), 127.0 (CH, #2), 127.2
(CH, #1), 128.5 (CH), 134.6 (C, #2), 135.0 (C, #1), 141.9 (C-Cl, #1), 142.2 (C-Cl, #2), 170.2 (CO2Et, #1),
170.5 (CO2Et, #2), 198.1 (C=S, #1), 198.4 (C=S, #2). IR (KBr) cm-1: 2979, 1748, 1464, 1444, 1342,
+
･
+
･
1280, 1192, 1156, 1023, 832, 793, 467. MS EI(+) m/z (%): 299 (M +2, 26), 297 (M , 69), 157 (43),
155 (100). Anal. Calcd for C14H16ClNO2S: C, 56.46; H, 5.42; N, 4.70. Found: C, 56.47; H, 5.60; N,
4.69.
(S)-Ethyl 1-(3,5-bis(trifluoromethyl)phenylcarbonothioyl)pyrrolidine-2-carboxylate (5d).
Light
yellowish needles. 60% yield (3 steps). mp 99−100 °C (hexane-AcOEt). 1H NMR (500 MHz,
CDCl3)  1.15 (t, J = 7.1 Hz, 0.69H, #2), 1.31 (t, J = 7.1 Hz, 2.31H, #1), 2.04 (m, 0.77H, #1), 2.12−2.24

HETEROCYCLES, Vol. 89, No. 3, 2014
717
(m, 0.69H, #2), 2.12−2.24 (m, 1.54H, #1), 2.37 (m, 0.23H, #2), 2.48 (m, 0.77H, #1), 3.51 (m, 0.77H, #1),
3.65 (m, 0.77H, #1), 4.00−4.18 (m, 0.92H, #2), 4.28 (m, 0.23H, #1), 4.23−4.33 (m, 1.54H, #1), 5.10 (dd,
J = 8.6, 4.6 Hz, 0.77H, #1), 7.71 (s, 0.46H, #2), 7.82 (s, 0.23H, #2), 7.85 (s, 1.54H, #1), 7.86 (s, 0.77H,
#1). 13C NMR (125 MHz, CDCl3)  13.8 (OCH2CH3, #2), 14.2 (OCH2CH3, #1), 22.7 (4-CH2, #2), 25.3
(4-CH2, #1), 29.6 (3-CH2, #1), 31.7 (3-CH2, #2), 53.7 (5-CH2, #2), 54.2 (5-CH2, #1), 61.7 (OCH2CH3, #1),
62.2 (OCH2CH3, #2), 64.9 (2-CH, #2), 65.0 (2-CH, #1), 122.3 (m, C-C-CF3, #2), 122.6 (m, C-C-CF3, #1),
122.9 (q, CF3, 1JCF = 273 Hz,), 126.0 (m, C-C-CF3), 131.9 (q, C-CF3, 2JCF = 33 Hz, #2), 132.0 (q, C-CF3,
2JCF = 33 Hz, #1), 144.9 (C, #1), 145.2 (C, #2), 169.8 (CO2Et, #1), 170.2 (CO2Et, #2), 195.1 (C=S, #1),
195.2 (C=S, #2). IR (KBr) cm-1: 2988, 2952, 1740, 1485, 1456, 1383, 1280, 1195, 1125, 898. MS
+
･
EI(+) m/z (%): 399 (M , 45), 58 (100). Anal. Calcd for C16H15F6NO2S: C, 48.12; H, 3.79; N, 3.51.
Found: C, 48.06; H, 4.22; N, 3.51.
(S)-Ethyl 1-(3,4,5-trimethoxyphenylcarbonothioyl)pyrrolidine-2-carboxylate (5e).
Orange
amorphous solid. 80% yield (3 steps). 1H NMR (500 MHz, CDCl3)  1.18 (t, J = 7.1 Hz, 0.72H, #2),
1.34 (t, J = 7.1 Hz, 2.28H, #1), 1.98 (m, 0.76H, #1), 2.07−2.18 (m, 0.72H, #2), 2.07−2.18 (m, 1.52H, #1),
2.30 (m, 0.24H, #2), 2.44 (m, 0.76H, #1), 3.60 (m, 0.76H, #1), 3.69 (m, 0.76H, #1), 3.82 (s, 0.72H, #2),
3.84 (s, 1.44H, #2), 3.84 (s, 2.28H, #1), 3.86 (s, 4.56H, #1), 4.09−4.10 (m, 0.48H, #2), 4.12 (q, J = 7.1 Hz,
0.48H, #2), 4.27 (q, J = 7.1 Hz, 1.52H, #1), 4.45 (dd, J = 7.9, 2.0 Hz, 0.24H, #2), 5.10 (dd, J = 8.7, 5.1 Hz,
0.76H, #1), 6.47 (s, 0.48H, #2), 6.61 (s, 1.52H, #1). 13C NMR (125 MHz, CDCl3)  14.1 (OCH2CH3,
#2), 14.2 (OCH2CH3, #1), 22.8 (4-CH2, #2), 25.2 (4-CH2, #1), 29.7 (3-CH2, #1), 31.5 (3-CH2, #2), 53.4
(5-CH2, #2), 54.2 (5-CH2, #1), 56.2 (OCH3, #2), 56.3 (OCH3, #1), 60.8 (OCH3, #2), 60.9 (OCH3, #1),
61.5 (OCH2CH3, #1), 61.7 (OCH2CH3, #2), 64.8 (2-CH, #2), 64.9 (2-CH, #1), 103.0 (CH, #2), 103.2 (CH,
#1), 138.2 (C, #2), 138.6 (C, #1), 139.0 (C-OCH3, #1), 139.3 (C-OCH3, #2), 153.1 (C-OCH3, #1), 153.1
(C-OCH3, #2), 170.5 (CO2Et, #1), 171.0 (CO2Et, #2), 199.1 (C=S, #1), 199.4 (C=S, #2). IR (NaCl)
-1
+
･
cm : 2941, 1742, 1584, 1442, 1341, 1238, 1125, 832. MS EI(+) m/z (%): 353 (M , 42), 195 (100).
HRMS EI(+) for C17H23NO5S: Calcd, 353.1297. Found, 353.1287.
(S)-Ethyl 1-(2,2-dimethylpropanethioyl)pyrrolidine-2-carboxylate (5f). Colorless oil. 84% yield (3
steps). 1H NMR (500 MHz, CDCl3)  1.27 (t, J = 7.1 Hz, 3H), 1.43 (s, 9H), 1.94−2.06 (m, 2H),
2.18−2.28 (m, 2H), 3.93−4.03 (m, 2H), 4.18 (q, J = 7.1 Hz, 2H), 5.13 (dd, J = 8.8, 4.7 Hz, 1H). 13C
NMR (125 MHz, CDCl3)  14.1 (OCH2CH3), 26.0 (4-CH2), 27.9 (3-CH2), 30.3 (CH3), 43.7 (C(CH3)3),
53.2 (5-CH2), 61.0 (OCH2CH3), 68.6 (2-CH), 170.8 (CO2Et), 211.4 (C=S). IR (NaCl) cm-1: 2976, 1739,
+
･
1409, 1195, 1164, 1023. MS EI(+) m/z (%): 243 (M , 49), 210 (100). HRMS EI(+) for C12H21NO2S:
Calcd, 243.1293. Found, 243.1299.
Hydrolysis of Proline Ethyl Ester Derivatives (5): A solution of 5 (2.50 mmol) and 2N NaOH (1.9 mL,

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HETEROCYCLES, Vol. 89, No. 3, 2014
3.75 mmol) in dioxane (5 mL) was heated at 75 °C for 1 h. The reaction mixture was poured into H2O
(50 mL) and washed with Et2O (50 mL). The aqueous layer was acidified with conc. HCl and extracted
with AcOEt (70 mL x 2) followed by standard workup to give the desired acids (1a-f) in high yields.
(S)-1-(Phenylcarbonothioyl)pyrrolidine-2-carboxylic acid (1a). Yellow amorphous solid. 99%
yield. 1H NMR (500 MHz, CDCl3)  2.01 (m, 1H), 2.14 (m, 1H), 2.31 (m, 1H), 2.47 (m, 1H), 3.56 (m,
0.86H, #1), 3.66 (m, 0.86H, #1), 4.08−4.17 (m, 0.28H, #2), 4.50 (dd, J = 8.5, 2.1 Hz, 0.14H, #2), 5.22 (dd,
J = 8.6, 5.1 Hz, 0.86H, #1), 7.32−7.41 (m, 5H). 13C NMR (125 MHz, CDCl3)  25.2 (4-CH2), 29.5
(3-CH2), 54.1 (5-CH2), 64.6 (2-CH), 125.7 (CH), 128.4 (CH), 129.2 (CH), 143.3 (C), 172.8 (C=S), 200.0
(CO2H). IR (KBr) cm-1: 3430, 2979, 2628, 1715, 1449, 1272, 1238, 1158, 760, 699. MS EI(+) m/z
+
･
(%): 235 (M , 100). HRMS EI(+) for C12H13NO2S: Calcd, 235.0667. Found, 235.0630.
(S)-1-(4-Chlorophenylcarbonothioyl)pyrrolidine-2-carboxylic acid (1b). Yellow amorphous solid.
98% yield. 1H NMR (500 MHz, CDCl3)  2.01 (m, 1H), 2.15 (m, 1H), 2.27 (m, 1H), 2.48 (m, 1H), 3.55
(m, 0.86H, #1), 3.66 (m, 0.86H, #1), 4.09−4.15 (m, 0.28H, #2), 4.48 (m, 0.28H, #2), 5.18 (dd, J = 8.4, 5.3
Hz, 0.86H, #1), 7.20−7.35 (m, 4H). 13C NMR (125 MHz, in CDCl3)  22.7 (4-CH2, #2), 25.2 (4-CH2,
#1), 29.6 (3-CH2, #1), 31.5 (3-CH2, #2), 53.4 (5-CH2, #2), 54.1 (5-CH2, #1), 64.6 (2-CH, #1), 67.0 (2-CH,
#2), 126.9 (CH, #2), 127.2 (CH, #1), 128.6 (CH, #1), 128.8 (CH, #2), 134.8 (C-Cl, #2), 135.2 (C-Cl, #1),
141.5 (C, #2), 142.0 (C, #2), 175.3 (CO2H, #1), 175.6 (CO2H, #2), 198.4 (C=S, #1), 198.8 (C=S, #2).
-1
+
+
･
･
IR (NaCl) cm : 2979, 1715, 1444, 1281, 1091, 826, 754. MS EI(+) m/z (%): 271 (M +2, 38), 269 (M ,
100). HRMS EI(+) for C12H1235ClNO2S (C12H1237ClNO2S): Calcd, 269.0277 (271.0248). Found,
269.0269 (271.0227).
(S)-1-(4-Methoxyphenylcarbonothioyl)pyrrolidine-2-carboxylic acid (1c). Yellowish needles. 98%
yield. mp 152−154 °C (hexane−AcOEt). 1H NMR (500 MHz, CDCl3)  1.99 (m, 1H), 2.12 (m, 1H),
2.29 (m, 1H), 2.45 (m, 1H), 3.61−3.73 (m, 1.72H, #1), 3.79 (s, 0.42H, #2), 3.83 (s, 2.58H, #1), 3.85−4.14
(m, 0.28H, #2), 4.56 (dd, J = 8.2, 1.9 Hz, 0.14H, #2), 5.24 (dd, J = 8.4, 5.4 Hz, 0.86H, #1), 6.84−6.88 (m,
2H), 7.24 (d, J = 8.7 Hz, 0.28H, #2), 7.40 (d, J = 8.7 Hz, 1.72H, #1). 13C NMR (125 MHz, CDCl3) 
22.8 (4-CH2, #2), 25.3 (4-CH2, #1), 29.6 (3-CH2, #1), 31.5 (3-CH2, #2), 53.5 (5-CH2, #2), 54.3 (5-CH2,
#1), 55.4 (OCH3), 64.4 (2-CH, #2), 64.9 (2-CH, #1), 113.5 (CH, #1), 113.8 (CH, #2), 127.2 (CH, #2),
127.9 (CH, #1), 135.7 (C, #1), 136.3 (C, #2), 160.0 (C-OCH3, #2), 160.5 (C-OCH3, #1), 175.6 (CO2H),
199.8 (C=S). IR (NaCl) cm-1: 2974, 1715, 1605, 1511, 1439, 1249, 1174, 832, 756. MS EI(+) m/z (%):
+
･
265 (M , 95), 151 (100). Anal. Calcd for C13H15NO3S: C, 58.85; H, 5.70; N, 5.28. Found: C, 58.83;
H, 5.83; N, 5.31.
(S)-1-(3,5-Bis(trifluoromethyl)phenylcarbonothioyl)pyrrolidine-2-carboxylic acid (1d). Yellow
amorphous solid. 98% yield. 1H NMR (500 MHz, CDCl3)  2.09 (m, 1H), 2.21 (m, 1H), 2.32 (m, 1H),

HETEROCYCLES, Vol. 89, No. 3, 2014
719
2.53 (m, 1H), 3.53 (m, 0.91H, #1), 3.66 (m, 0.91H, #1), 4.06−4.20 (m, 0.18H, #2), 4.76 (dd, J = 8.0, 5.2
Hz, 0.09H, #2), 5.17 (dd, J = 8.2, 4.8 Hz, 0.91H, #1), 7.85 (s, 2H), 7.88 (s, 1H). 13C NMR (125 MHz,
CDCl3)  22.7 (4-CH2, #2), 25.3 (4-CH2, #1), 29.6 (3-CH2, #1), 31.7 (3-CH2, #2), 53.7 (5-CH2, #2), 54.2
(5-CH2, #1), 64.7 (2-CH, #1), 67.1 (2-CH, #2), 122.4 (m, C-C-CF3, #2), 122.8 (m, C-C-CF3, #1), 122.9 (q,
1
CF3, JCF = 273 Hz), 126.0 (m, C-C-CF3, #1), 127.7 (m, C-C-CF3, #2), 144.7 (C, #1), 132.0 (q, C-CF3,
2JCF = 34 Hz), 145.1 (C, #2), 175.0 (CO2H, #1), 175.7 (CO2H, #2), 195.5 (C=S). IR (NaCl) cm-1: 2983,
+
･
1719, 1478, 1451, 1379, 1280, 1179,1135. MS EI(+) m/z (%): 271 (M , 72), 257 (100). HRMS EI(+)
for C14H11F6NO2S: Calcd, 374.0414. Found, 371.0410.
(S)-1-(3,4,5-Trimethoxyphenylcarbonothioyl)pyrrolidine-2-carboxylic acid (1e).
Pale yellow
crystals. 80% yield. mp 174–176 °C (hexane−AcOEt). 1H NMR (500 MHz, CDCl3)  1.96−2.05 (m,
1H), 2.10−2.18 (m, 1H), 2.24−2.31 (m, 1H), 2.44−2.52 (m, 1H), 3.59−3.72 (m, 2H, NCH2), 3.81, 3.82,
3.84, 3.85, and 3.87 (s, 9H, OCH3), 4.49 and 5.16 (dd, J = 8.3, 1.9 and 8.6, 5.4 Hz, 1H, NCH), 6.52 and
6.61 (s, 2H, ArH). 13C NMR (125 MHz, CDCl3)  22.7 and 25.2 (C-4), 29.6 and 31.5 (C-3), 53.4 and
54.2 (C-5), 55.4, 56.2, 56.3, and 60.9 (OCH3), 64.6 and 64.7 (C-2), 103.0 and 103.3 (Ar-2), 132.3 and
132.4 (Ar-1), 138.6 and 138.7 (Ar-4), 153.1 and 153.1 (Ar-3), 174.7 and 175.7 (C=O), 199.5 (C=S). IR
(KBr) cm-1: 3309, 2981, 2946, 1741, 1587, 1447, 1413, 1343, 1241, 1171, 1130, 994 826. MS EI(+) m/z
+
･
(%): 325 (M , 100). Anal. Calcd for C15H19NO5S: C, 55.37; H, 5.89; N, 4.30. Found: C, 55.35; H,
6.27; N, 4.28.
(S)-1-(2,2-Dimethylpropanethioyl)pyrrolidine-2-carboxylic acid (1f). White solid. 94% yield. mp
160–162 °C (hexane−AcOEt). 1H NMR (500 MHz, CDCl3)  1.29 and 1.43 (s, 9H, CCH3), 1.96−2.14
(m, 2H), 2.17−2.30 (m, 2H), 3.90−4.05 (m, 2H, NCH2), 4.61−4.63 and 5.20−5.22 (m, 1H, NCH). 13C
NMR (125 MHz, CDCl3)  20.6 and 26.0 (C-4), 27.3 and 27.8 (C-3), 30.3, 43.8, 48.6 and 53.2 (C-5), 67.1
and 68.3 (C-2), 175.4 (C=O), 212.9 (C=S). IR (KBr) cm-1: 2962, 1706, 1410, 1230, 1152, 937. MS
+
･
EI(+) m/z (%): 215 (M , 47.9), 70 (100). Anal. Calcd for C10H17NO2S: C, 55.78; H, 7.96; N, 6.51.
Found: C, 55.94; H, 8.21; N, 6.52.
General Procedure for the Reaction of N-Thioacylproline with TFAA: To a stirred solution of TFAA
(187 L, 1.35 mmol), pyridine (217 L, 2.69 mmol), and DMAP (16 mg, 0.14 mmol) in xylene (1 mL)
was added the solution of 5 (0.45 mmol) in xylene (1 mL) at 0 °C. The additional amount of xylene (2.5
mL) was added, and the mixture was stirred at rt for 1 h and 138 °C for 12 h. The solvent was
evaporated, and the residue was diluted with dioxane (2.7 mL). To the mixture was added 10% aq. HCl
(0.9 mL), and the mixture was heated at 60 °C for 3 h. 10% aq. HCl (0.45 mL) was added and the whole
was stirred for further 2 h. After workup with water, the mixture was extracted with AcOEt (x 3). The
combined organic layers were washed with brine, dried over anhyd Na2SO4, and evaporated. The

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HETEROCYCLES, Vol. 89, No. 3, 2014
residue was purified by column chromatography (silica gel, hexane:AcOEt = 10:1 to 2:1) to give the
product 2.
3-(2-Phenyl-5-(trifluoromethyl)thiazol-4-yl)propan-1-ol (2a).
Colorless plate crystals.
mp
64−65 °C (hexane−AcOEt). 1H NMR (500 MHz, CDCl3)  2.04 (quin, J = 6.6 Hz, 2H), 2.63 (br, 1H),
3.05 (t, J = 6.8 Hz, 2H), 3.74 (t, J = 6.1 Hz, 2H), 3.87 (s, 3H), 7.44−7.50 (m, 3H), 7.90 (dd, J = 7.7, 1.4
Hz, 2H). 13C NMR (125 MHz, CDCl3)  26.7 (CH2), 31.6 (CH2), 62.0 (CH2OH), 120.0 (q, F3C-C, 2JCF
= 37.2 Hz), 122.6 (q, CF3, 1JCF = 269.6 Hz), 126.7 (CH), 129.2 (CH), 131.2 (CH), 132.3 (CH), 158.7 (q,
3
F3C-C=C, JCF = 2.4 Hz), 168.8 (C=N). IR (KBr) cm-1: 3335, 2949, 2874, 1545, 1462, 1437, 1361,
+
･
1348, 1317, 1168, 1124, 1119, 1062, 1042, 1025, 903.; MS EI(+) m/z (%): 287 (M , 9), 243 (100).;
HRMS ESI(+) for C13H12F3NOS: Calcd, 288.0664. Found, 288.0642. Anal. Calcd for C13H12F3NOS:
C, 54.35; H, 4.21; N, 4.88. Found: C, 54.33; H, 4.26; N, 4.83. UV (EtOH) nm (Abs): 291 (2.65).
3-(2-(4-Methoxyphenyl)-5-(trifluoromethyl)thiazol-4-yl)propan-1-ol (2b). Colorless needles. mp
53−54 °C (hexane). 1H NMR (500 MHz, CDCl3)  1.78 (br, 1H), 2.03 (quin, J = 6.5 Hz, 2H), 3.04 (tq, J
= 7.0 Hz, 3JHF = 1.1 Hz, 2H), 3.74 (t, J = 6.0 Hz, 2H), 3.87 (s, 3H), 6.96 (dd, J = 11.7, 2.9 Hz, 2H), 7.85
(dd, J = 11.7, 2.9 Hz, 2H). 13C NMR (125 MHz, CDCl3)  26.8 (CH2), 31.5 (CH2), 55.5 (OCH3), 62.0
2
1
(CH2OH), 114.5 (CH), 118.9 (q, F3C-C, JCF = 37.1 Hz), 122.7 (q, CF3, JCF = 269.4 Hz), 125.1 (C),
3
128.3 (CH), 158.4 (q, F3C-C=C, JCF = 2.1 Hz), 162.1 (C-OCH3), 168.8 (C=N). IR (KBr) cm-1: 3314,
2968, 2943, 2870, 2844, 1607, 1542, 1520, 1456, 1417, 1348, 1305, 1256, 1158, 1110, 1029, 831. MS
+
･
EI(+) m/z (%): 317 (M , 14), 273 (100). Anal. Calcd for C14H14F3NO2S: C, 52.99; H, 4.45; N, 4.41.
Found: C, 52.84; H, 4.41; N, 4.45.
3-(2-(4-Chlorophenyl)-5-(trifluoromethyl)thiazol-4-yl)propan-1-ol (2c). Colorless amorphous solid.
1H NMR (500 MHz, CDCl3)  2.04 (quin, J = 6.6 Hz, 2H), 2.29 (br, 1H), 3.04 (tq, J = 7.2 Hz, 3JHF = 1.2
Hz, 2H), 3.74 (t, J = 6.1 Hz, 2H), 7.44 (dd, J = 11.1, 2.5 Hz, 2H), 7.85 (dd, J = 11.1, 2.5 Hz, 2H). 13C
2
NMR (125 MHz, CDCl3)  26.7 (CH2), 31.6 (CH2), 62.0 (CH2OH), 120.3 (q, F3C-C, JCF = 37.2 Hz),
1
122.5 (q, CF3, JCF = 269.7 Hz), 127.9 (CH), 129.5 (CH), 130.8 (C-Cl), 137.4 (C), 158.9 (q, F3C-C=C,
3JCF = 2.1 Hz), 167.4 (C=N). IR (KBr) cm-1: 3303, 2948, 2869, 1541, 1447, 1348, 1313, 1164, 1117,
+
･
+
･
1093, 1033, 1014, 833. MS EI(+) m/z (%): 323 (M +2, 4), 321 (M , 11), 277 (100). HRMS EI(+) for
C13H11ClF3NOS: Calcd, 321.0202. Found, 321.0182.
3-(5-(Trifluoromethyl)-2-(3,4,5-trimethoxyphenyl)thiazol-4-yl)propan-1-ol (2d). Colorless needles.
mp 105 °C (hexane−AcOEt). 1H-NMR (500 MHz, CDCl3)  2.05 (quin, J = 6.6 Hz, 2H), 3.04 (t, J = 6.9
Hz, 2H), 3.74 (t, J = 6.1 Hz, 2H), 3.91 (s, 3H), 3.94 (s, 6H), 7.12 (s, 1H). 13C NMR (125 MHz, CDCl3)
 26.8 (CH2), 31.7 (CH2), 56.4 (OCH3), 61.0 (OCH3), 62.1 (CH2OH), 104.7 (CH), 119.7 (q, F3C-C, 2JCF
=
1
37.2 Hz), 122.6 (q, CF3, JCF = 269.4 Hz), 127.7 (C), 140.9 (C-OCH3), 153.7 (C-OCH3), 158.6 (q,

HETEROCYCLES, Vol. 89, No. 3, 2014
721
3
F3C-C=C, JCF = 2.1 Hz), 168.7 (C=N). IR (KBr) cm-1: 3307, 3208, 2934, 2883, 2837, 1586, 1542,
1515, 1460, 1436, 1411, 1352, 1320, 1236, 1148, 1134, 1115, 1063, 1038, 1026, 996. MS EI(+) m/z (%):
+
･
277 (M , 9), 61 (100). Anal. Calcd for C16H18F3NO4S: C, 50.92; H, 4.81; N, 3.71. Found: C, 50.79; H,
4.69; N, 3.81.
3-(2-(3,5-Bis(trifluoromethyl)phenyl)-5-(trifluoromethyl)thiazol-4-yl)propan-1-ol (2e). Colorless
needles. mp 87−88 °C (hexane). 1H NMR (500 MHz, CDCl3)  1.71 (br, 1H), 2.08 (quin, J = 6.8 Hz,
2H), 3.07 (t, J = 7.2 Hz, 2H), 3.76 (t, J = 6.2 Hz, 2H), 7.98 (s, 1H), 8.35 (s, 1H). 13C NMR (125 MHz,
2
3
CDCl3) : 26.6 (CH2), 31.9 (CH2), 62.0 (CH2OH), 121.9 (q, F3C-C, JCF = 37.9 Hz), 124.3 (CH, JCF
=
3.6 Hz), 122.2 (q, CF3, 1JCF = 270.0 Hz), 122.9 (q, CF3, 1JCF = 273.1 Hz), 126.6 (CH), 126.6 (CH), 132.9
(q, F3C-C, 2JCF = 33.9 Hz), 134.4 (C), 159.8 (q, F3C-C=C, 3JCF = 2.8 Hz), 164.9 (C=N). IR (KBr) cm-1:
+
･
3291, 2940, 2880, 1539, 1368, 1321, 1284, 1232, 1173, 1136, 1025, 900. MS EI(+) m/z (%): 423 (M ,
17), 379 (100). Anal. Calcd for C15H10F9NOS: C, 42.56; H, 2.38; N, 3.31. Found: C, 42.73; H, 2.52; N,
3.42.
3-(2-tert-Butyl-5-(trifluoromethyl)thiazol-4-yl)propan-1-ol (2f). Light yellow oil. 1H NMR (500
MHz, CDCl3) 1.43 (s, 9H), 1.96 (quin, J = 6.4 Hz, 2H), 2.99 (tq, J = 6.8 Hz, 3JHF = 1.1 Hz, 2H,), 3.23
(br, 1H), 3.68 (t, J = 5.9 Hz, 2H,). 13C NMR (125 MHz, CDCl3) 26.8 (CH2), 30.6 (C(CH3)3), 31.3
(CH2), 38.0 (C(CH3)3), 62.0 (CH2OH), 119.1 (q, F3C-C, 2JCF = 37.2 Hz), 122.7 (q, CF3, 1JCF = 269.1 Hz),
157.2 (q, F3C-C=C, 3JCF = 2.4 Hz), 183.5 (C=N). IR (NaCl) cm-1: 3357, 2965, 2871, 1544, 1485, 1346,
+
･
1313, 1158, 1124, 1081, 1020. MS EI(+) m/z (%): 267 (M , 12), 223 (100). HRMS EI(+) for
C11H16F3NOS: Calcd, 267.0905. Found, 267.0882. UV (EtOH) nm (Abs): 242 (2.85), 219 (2.24).
Ethyl N-benzyl-N-thiobenzoylphenylalaninate. N-Benzoyl-N-benzylphenylalanine ethyl ester was
prepared in good yield by Schotten-Baumann reaction of N-benzylphenylalanine ethyl ester and benzoyl
chloride. A mixture of N-benzoyl-N-benzylphenylalanine ethyl ester (4.00 mmol), Lawesson’s reagent
(3.00 mmol), and pyridine (1.50 mmol) in toluene (20 mL) was heated at 90 °C for 5.5 h. After workup
with water, the mixture was extracted with AcOEt (x 3). The combined organic layers were washed with
brine, dried over anhyd sodium sulfate, and evaporated. The residue was purified by column
chromatography (silica gel, hexane:AcOEt = 10:1 to 5:1) to give the product. Pale yellow solid. 89%
yield. mp 97–99 °C (hexane). 1H NMR (500 MHz, CDCl3)  1.09 and 1.25 (t, J = 7.2 Hz, 3H,
CH2CH3), 3.07, 3.17, and 3.49 (dd, J = 14.4, 8.3 and 14.3, 6.5 and 14.1, 5.8 Hz, 2H, ArCH2C), 3.59, 3.88,
and 4.03–4.15 (dq, dq, and m, J = 10.7, 7.2 and 10.7, 7.1 Hz, 2H, CH2CH3), 4.68, 5.22, and 5.84 (d, J =
15.4, 15.3, and 15.3 Hz, ArCH2N), 4.99 and 6.63 (t, J = 7.9 Hz, NCH), 6.82–6.84 (m, 1H, ArH),
7.03–7.05 (m, 2H, ArH), 7.17–7.45 (m, 12H, ArH). 13C NMR (125 MHz, CDCl3)  13.8, 14.1, 33.8,
35.7, 51.5, 61.4, 61.8, 65.0, 66.8, 125.4, 127.1, 127.1, 127.4, 127.8, 128.1, 128.3, 128.4, 128.5, 128.6,

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HETEROCYCLES, Vol. 89, No. 3, 2014
128.6, 128.7, 129.5, 129.6, 134.5, 135.8, 137.8, 143.3, 143.8, 168.4, 158.6, 203.0. IR (KBr) cm-1: 3066,
3027, 2980, 1732, 1495, 1476, 1437, 1275, 1258, 1240, 1220, 1055, 765, 746, 701. MS EI(+) m/z (%):
+
･
403 (M , 34.4), 121 (100). HRMS (EI) for C25H25NO2S: Calcd, 403.1606. Found, 403.1616.
Preparation of N-benzyl-N-thiobenzoylphenylalanine (6a). mixture of ethyl
A
N-benzyl-N-thiobenzoylphenylalaninate (1.41 g, 3.50 mmol) and 2N aq NaOH (2.6 mL, 5.25 mmol) in
dioxane (6.5 mL) was heated at 65 °C for 1 h. The reaction mixture was poured into water and washed
with Et2O. The aqueous layer was acidified with conc. HCl and extracted with AcOEt (x 3). The
combined organic layers were washed with brine, dried over anhyd sodium sulfate, and evaporated to
give 6a as yellow amorphous, which was directly used for the next step without further purification.
Yellow amorphous solid. 98% yield. mp 56–58 °C. 1H NMR (500 MHz, CDCl3)  3.02, 3.17, and
3.48 (dd, J = 14.5, 8.5 and 14.5, 6.0 and 14.5, 5.5 Hz, 2H, ArCH2C), 4.63, 5.39, and 5.59 (d, J = 15.4,
15.5, and 15.4 Hz, 2H, ArCH2N), 5.06−5.11 and 6.64 (m, 1H, NCH), 6.75 (d, J = 7.0 Hz, 1H, ArH),
7.01−7.03 (m, 2H, ArH), 7.15−7.43 (m, 7H, ArH). 13C NMR (125 MHz, CDCl3)  33.8, 35.7, 52.5, 64.6,
67.3, 125.7, 127.1, 127.2, 127.4, 127.8, 128.3, 128.4, 128.4, 128.5, 128.6, 128.6, 128.7, 128.8, 129.4,
129.4, 134.1, 135.6, 135.7, 137.2, 143.2, 143.3, 172.9, 173.8, 206.2. IR (KBr) cm-1: 3061, 3029, 1712,
+
･
1443, 1225, 754, 698, 418. MS EI(+) m/z (%): 375 (M , 52.4), 91 (100). HRMS (EI) for
C23H21NO2S: Calcd, 375.1293. Found, 375.1291.
Ethyl
phenylalanine ethyl ester was prepared in good yield by Schotten-Baumann reaction of
N-(4-methoxybenzyl)phenylalanine ethyl ester and benzoyl chloride. mixture of
N-(4-methoxybenzyl)-N-thiobenzoylphenylalaninate.
N-Benzoyl-N-(4-methoxybenzyl)-
A
N-benzoyl-N-(4-methoxybenzyl)phenylalanine ethyl ester (2.00 mmol), Lawesson’s reagent (1.50 mmol),
and pyridine (0.76 mmol) in toluene (10 mL) was heated at 90 °C for 9 h. After workup with water, the
mixture was extracted with AcOEt (x 3). The combined organic layers were washed with brine, dried
over anhyd sodium sulfate, and evaporated. The residue was purified by column chromatography (silica
gel, hexane:AcOEt = 10:1 to 5:1) to give the product. Pale yellow solid. 83% yield. mp 82–85 °C
(hexane). 1H NMR (500 MHz, CDCl3)  1.11 and 1.26 (t, J = 7.2 and 7.2 Hz, 3H, CH2CH3), 3.06, 3.17,
and 3.48 (dd, J = 14.5, 8.3 and 14.3, 6.4 and 14.2, 5.6 Hz, 2H, ArCH2C), 3.63, 3.91, and 4.05–4.16 (dq,
dq, and m, J = 10.8, 7.2 and 10.7, 7.1 Hz, 2H, CH2CH3), 3.77 and 3.80 (s, 3H, OCH3), 4.61, 5.16, and
5.79 (d, J = 15.2, 15.1, and 15.0 Hz, 2H, ArCH2N), 4.95–4.98 and 6.59 (m, 1H, NCH), 6.76 (d, J = 8.7 Hz,
2H, ArH), 6.82–6.88 (m, 2H, ArH), 6.94 (d, J = 8.6 Hz, 2H, ArH), 7.18–7.41 (m, 8H, ArH). 13C NMR
(125 MHz, CDCl3)  13.8, 14.1, 33.6, 35.6, 51.0, 55.3, 55.3, 61.4, 61.8, 64.7, 66.7, 113.7, 113.8, 125.4,
126.2, 127.0, 127.1, 127.7, 128.3, 128.4, 128.6, 128.7, 129.3, 129.5, 129.6, 130.1, 135.9, 137.9, 143.3,
143.8, 159.0, 159.5, 168.4, 168.6, 202.3, 205.7. IR (KBr) cm-1: 2983, 2933, 2897, 2868, 2837, 1732,

HETEROCYCLES, Vol. 89, No. 3, 2014
723
+
･
1514, 1471, 1252, 1228, 1178, 1033, 763, 700. MS EI(+) m/z (%): 433 (M , 16.1), 121 (100). HRMS
(EI) for C26H27NO3S: Calcd, 433.1712. Found: 433.1701
Preparation of N-thiobenzoyl-N-(4-methoxybenzyl)phenylalanine (6b).
A mixture of ethyl
N-(4-methoxybenzyl)-N-thiobenzoylphenylalaninate (663 mg, 1.53 mmol) and 2N aq NaOH (1.15 mL,
2.29 mmol) in dioxane (3.1 mL) was heated at 65 °C for 1 h. The reaction mixture was poured into
water and washed with Et2O. The aqueous layer was acidified with conc. HCl and extracted with AcOEt
(x 3). The combined organic layers were washed with brine, dried over anhyd sodium sulfate, and
evaporated to give 6b as yellow amorphous, which was directly used for the next step without further
purification. Yellow amorphous solid. 96% yield. mp 61–64 °C. 1H NMR (500 MHz, CDCl3)  3.03,
3.17, and 3.47 (dd, J = 14.3, 8.4 and 14.5, 5.7 and 14.4, 5.2 Hz, 2H, ArCH2C), 3.76 (s, 3H, OCH3), 4.56,
5.39, and 5.52 (d, J = 15.2, 15.1, and 15.0 Hz, 2H, ArCH2N), 5.05 and 6.59 (s, 1H, NCH), 6.76 (d, J = 8.3
Hz, 2H, ArH), 6.92 (d, J = 8.3 Hz, 2H, ArH), 7.16–7.40 (m, 10H, ArH). 13C NMR (125 MHz, CDCl3) 
33.7, 35.6, 52.0, 55.3, 64.2, 67.1, 113.8, 114.0, 125.7, 125.8, 127.1, 127.2, 128.0, 128.3, 128.4, 128.6,
128.7, 128.8, 129.4, 129.4, 130.0, 135.8, 137.3, 143.3, 159.0, 159.6, 172.9, 173.9, 206.1. IR (KBr) cm-1:
+
･
3027, 1712, 1514, 1251, 1176, 1032, 761, 699. MS EI(+) m/z (%): 405 (M , 1.9), 121 (100). HRMS
(EI) for C24H23NO3S (M+): Calcd, 405.1399. Found, 405.1403.
4-Benzyl-2-phenyl-5-(trifluoromethyl)thiazole (7) and 4-benzyl-2-phenylthiazol-5(4H)-one (8). 7:
Light yellow oil. 1H NMR (500 MHz, CDCl3)  4.26 (s, 2H), 7.20−7.23 (m, 2H), 7.28−7.31 (m, 2H),
7.35−7.36 (m, 2H), 7.42−7.45 (m, 3H), 7.92 (dd, J = 7.9, 1.7 Hz, 2H). 13C NMR (125 MHz, CDCl3) 
2
1
36.0 (CH2), 120.4 (q, F3C-C, JCF = 37.0 Hz), 122.7 (q, CF3, JCF = 269.7 Hz), 126.6 (CH), 126.8 (CH),
3
128.5 (CH), 128.9 (CH), 129.1 (CH), 131.1 (CH), 132.6 (C), 138.0 (C), 157.3 (q, F3C-C=C, JCF = 2.1
Hz), 168.8 (C=N). IR (NaCl) cm-1: 3064, 3031, 2927, 2852, 1537, 1496, 1459, 1435, 1341, 1303, 1157,
+
･
1123, 1036, 1027. MS EI(+) m/z (%): 319 (M , 100). HRMS EI(+) for C17H12F3NS: Calcd, 319.0643.
Found, 391.0650. 8: mp 132−133 °C (lit.,9 mp 138–140 °C). 1H NMR (500 MHz, CDCl3)  3.21 (dd,
J = 13.8, 7.0 Hz, 1H), 3.47 (dd, J = 13.8, 4.7 Hz, 1H), 5.06 (dd, J = 7.0, 4.7 Hz, 1H), 7.12−7.53 (m, 8H),
7.76−7.77 (m, 2H).
Preparation of 4-Benzyl-2-phenyl-5-(trifluoromethyl)thiazole (7). A mixture of 114 (244 mg, 0.76
mmol) and Lawesson’s reagent (184 mg, 0.46 mmol) in 1,2-dimethoxyethane (DME, 4 mL) was heated at
reflux under atmosphere of argon for 24 h. After removal of solvent, the residue was purified by column
chromatography (silica gel, hexane:AcOEt = 9:1) to give 7 as a light yellow oil, 39 mg, 16% yield.
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