Facile access to N-thiazolyl α-amino acids from α-bromo ketones and α-amino acids

Article abstract of DOI:10.1016/S0040-4020(00)00190-3

N-Substituted 2-aminothiazoles are synthesized in a one-pot procedure using readily available α-bromo ketones and amines. This method is compatible with a wide range of functional groups and offers a facile and efficient access to the class of N-thiazolyl

Full text of DOI:10.1016/S0040-4020(00)00190-3

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 3161±3165
Facile Access to N-Thiazolyl a-Amino Acids from
a-Bromo Ketones and a-Amino Acids
*
Joachim Rudolph
Bayer AG, Central Research, Chemistry for Life Sciences, D-51368 Leverkusen, Germany
Received 16 February 2000; accepted 29 February 2000
AbstractÐN-Substituted 2-aminothiazoles are synthesized in a one-pot procedure using readily available a-bromo ketones and amines.
This method is compatible with a wide range of functional groups and offers a facile and ef®cient access to the class of N-thiazolyl a-amino
acid derivatives. q 2000 Elsevier Science Ltd. All rights reserved.
Introduction
methods, we tried to synthesize the thiourea derivatives of
selected amino acids as starting materials for the Hantzsch
reaction. In our hands, none of these methods gave the
desired compounds: Whereas no reaction occurred with
The 2-aminothiazole group is a common functionality in
medicinal chemistry. The preferred method for its for-
1
2
mation is the classical Hantzsch synthesis. Following the
4
ammonium thiocyanate, reaction with trimethylsilyl-
isothiocyanate led to decomposition. Using benzyl iso-
5
Hantzsch protocol, N-monosubstituted thioureas are treated
with a-halo ketones to form the N-substituted 2-amino-
thiazole derivative (Scheme 1).
6
thiocyanate, we observed further conversion to the
corresponding thiohydantoine (Scheme 2). We speculate
that such a cyclization reaction may be an intrinsic problem
of thiourea derivatives of a-amino acids in general.
In our laboratory, we were interested in accessing the class
of N-thiazolyl a-amino acids. With the exception of the
corresponding glycine derivatives, not many examples of
However, in a recent paper, an approach to the formation
of the thiourea derivative of an a-amino acids used for a
3
this compound class exist in the literature. Using different
Scheme 1.
0
0
0
Scheme 2. (a) NH
4
SCN; R ˆH, (b) Me
3
SiNCS; R ˆMe
3
Si, (c) BnNCS; R ˆBn
Scheme 3.
Keywords: thiazoles; amines; amino acids and derivatives; thiocyanates.
*
Tel.: 149-214-3057-859; fax: 149-214-3096-57859; e-mail: joachim.rudolph.jr@bayer-ag.de
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00190-3

3
162
J. Rudolph / Tetrahedron 56 (2000) 3161±3165
Scheme 4.
Table 1. Reaction products from two selected aryl bromo ketones and various amino acids and amines
a
Isolated yield (%)
Melting point (8C)
1
43
131±133
2
3
45
34
77±80
144±148
4
39
156±158
5
6
7
8
9
32
58
45
31
150±152
120±123
78±79
155±156
152±154
18
0
1
0
1
±
b
99
1
204±205
Isolated yield (%)
Melting point (8C)
b
12
13
14
96
118±120
41
0
109±110
±
a
Yields have not been optimized.
No column chromatography required.
b

J. Rudolph / Tetrahedron 56 (2000) 3161±3165
3163
subsequent Hantzsch reaction has been described. This
method involves a three step procedure using allyloxy-
carbonyl isothiocyanate. We assume that no cyclization
may ®nd wide application for the laboratory scale and
combinatorial synthesis of N-substituted 2-aminothiazoles.
7
to the thiohydantoine derivative occurs in this case because
the allyloxycarbonyl group suf®ciently decreases the
nucleophilicity of the thiourea nitrogen atom (Scheme 3).
Experimental
General
Results
Melting points were obtained on a Gallenkamp melting
point apparatus and are uncorrected. Optical rotations
were measured on a Perkin±Elmer 241 polarimeter.
HPLC analyses were performed on a Waters Alliance
2690 system (¯ow: 1 mL/min) with a CC12/4 Nucleosil
100±5C18-HD column (detection: lˆ210 nm) and the
Due to our unfavorable experiences, we preferred to circum-
vent the synthesis of the thiourea derivatives of a-amino
acids required for the Hantzsch reaction by ®nding a more
direct approach for the synthesis of the N-thiazolyl a-amino
acids. From the literature, it is known that 2-aminothiazoles
can be formed from amines and a-thiocyanato ketones.
However, under the reaction conditions applied, yields
were low in most cases, rendering this method unsatis-
following gradient program: 2 min 100% H
O; 10 min
CN (each
H added). H NMR spectra were
recorded on Bruker DPX400 spectrometers in CDCl or
DMSO-d using the solvent signals as internal references.
2
100% H
solvent with 0.01% HCO
O to 100% CH CN; 3 min 100% CH
3 3
2
1
2
3
8
factory for general application.
6
The chemical shifts are reported in d (ppm) relative to TMS
and the coupling constants (J) are given in Hertz (Hz).
Electrospray-high resolution mass spectrometry (ESI-
HRMS) was performed on a Finnigan-MAT 900 double
focusing mass spectrometer. The ESI source was operated
in the positive ion mode, spray needle voltage 3.5 kV,
nitrogen sheath gas pressure 500 kPa, and the heated
metal capillary held at 2508C.
In this report, we present a revised simple one-pot procedure
that allows the rapid synthesis of N-thiazolyl a-amino acid
derivatives and N-substituted 2-aminothiazoles in general.
The a-bromo ketone is being transformed into the corre-
sponding a-thiocyanato ketone by treating it with sodium
thiocyanate in ethanol at 508C. Subsequent addition of the
amino acid ester in the same pot at the same temperature and
reaction for 4±12 h yields the corresponding 2-amino-
thiazole in a clean reaction (Scheme 4).
All reactions were monitored by analytical TLC on alu-
minum backed TLC plates coated with silica gel (Merck
Si 60 F254) and visualization of spots was accomplished
by UV detection. Column chromatography was carried out
using Amicon silica gel (30±70 mm) using a mixture of
cyclohexane and ethyl acetate as an eluent.
During the course of our work, an Austrian group inde-
pendently discovered this method using a slightly different
protocol. However, the scope of their work was only
9
focused on aliphatic and aromatic amines and diamines
with no additional functional groups. In our work we kept
the bromo ketone part constant and focused on varying the
amine part. We found that this method is highly compatible
with a range of functional groups, e.g. esters, thioethers
General procedure for the synthesis of the
aminothiazoles 1±14
(
Table 1, entry 7), S±S bonds (entry 3), alcohols (entry 5),
phenols (entry 6), tertiary and secondary amino groups
entries 2 and 4).
20.5 mmol of the a-bromo ketone and 1.78 g dry sodium
thiocyanate (22.0 mmol) are stirred in 50 mL ethanol for 3 h
at 508C. A solution of 20.5 mmol of the amine (in the case of
(
3
10.5 mmol of the amine) in 20 mL ethanol is added at
In most cases complete conversion of the starting material
was observed, however, a small percentage (15% or less) of
byproducts was found. Puri®cation of most aminothiazoles
was accomplished by ¯ash chromatography. Due to poor
solubility, the reaction product had to be absorbed onto
the silica gel, and considerable product loss was observed
during chromatography.
once and the reaction mixture is stirred for 4±12 h (moni-
toring by TLC). The ethanol is distilled off, and ethyl acetate
and water are added. The aqueous phase is extracted twice
with ethyl acetate, the combined organic phases are dried
with Na SO , and the solvent is removed in vacuo. In the
2
4
cases of 10 and 14 no product was obtained. In the cases of
11 and 12 no further puri®cation was needed according to
H NMR and HPLC analysis. Otherwise, the product was
1
Selectivity of the reaction appears to decrease with
increasing substitution at the a-C atom of the amine part
absorbed onto silica gel and puri®ed via column chroma-
tography.
(
see entries 12±14): With a-mono-substituted amines, no
side reactions are observed; with a,a-disubstituted amines,
reactions are still highly selective; and with a,a,a-trisubsti-
tuted amines no reaction occurs. The only tested aniline was
converted quantitatively to the product (entry 11). Among
the solvents investigated, only ethanol proved to be suitable,
in DMF or acetonitrile, the reaction did not proceed.
(S)-(1)-N-[4-(4-Nitro-phenyl)-thiazol-2-yl]-S-(triphenyl-
methyl)-cysteine methyl ester (1). Puri®ed by ¯ash
chromatography on silica gel (cyclohexane/ethylacetate,
6:1 to 4:1) to give 5.13 g, 43% product as a dark yellow
2
5
solid; mp 131±1338C; [a] ˆ18.5 (c 1.0, CH CN/H O
D
3
2
95:5); HPLC: t ˆ13.53 min; TLC (cyclohexane/ethyl-
R
1
acetate, 2:1): R ˆ0.58; H NMR (400 MHz, DMSO-d ):
f
6
In summary, we have found a simple procedure for synthe-
sizing the interesting class of N-thiazolyl a-amino acids
from readily available starting materials. This reaction
dˆ2.60 (m, 1H, CH ), 2.71 (m, 1H, CH ), 3.60 (s, 3H,
2
2
OCH ), 4.32 (m, 1H, CH), 7.20±7.33 (m, 15H, Trityl-H),
3
7.52 (s, 1H, thiazole-H), 7.99 (d, Jˆ8.9 Hz, 2H, ArH), 8.26

3
164
J. Rudolph / Tetrahedron 56 (2000) 3161±3165
1
3
(
d, Jˆ8.9 Hz, 2H, ArH), 8.36 (d, Jˆ7.8 Hz, 1H, NH);
C
(400 MHz, DMSO-d ): dˆ3.69 (s, 3H, OCH ), 3.82 (m,
6
3
NMR (100.4 MHz, CDCl ): dˆ33.5, 52.8, 56.3, 67.0,
2H, CH ), 4.59 (m, 1H, CH), 5.19 (t, Jˆ5.6 Hz, 1H, OH),
3
2
1
1
05.8, 124.0, 126.4, 126.9, 128.0, 129.5, 140.6, 144.3,
46.8, 148.9, 166.6, 171.3; HRMS (ESI) calcd for
7.50 (s, 1H, thiazole-H), 8.04 (d, Jˆ8.9 Hz, 2H, ArH), 8.23
1
3
(d, Jˆ8.0 Hz, 1H, NH), 8.25 (d, Jˆ8.9 Hz, 2H, ArH);
C
1
[
M1H] C H N O S 582.15213, found 582.15253.
28
NMR (100.4 MHz, CDCl , DMSO-d ): dˆ52.0, 59.5, 61.9,
106.0, 123.7, 126.2, 140.8, 146.2, 147.9, 167.7, 171.5;
HRMS (ESI) calcd for [M1H] C H N O S 324.06542,
13 14 3 5
3
2
3
4
2
3
6
1
(
S)-(2)-N-[4-(4-Nitro-phenyl)-thiazol-2-yl]-tryptophan
methyl ester (2). Puri®ed by ¯ash chromatography on silica
found 324.06509.
gel (cyclohexane/ethylacetate, 2:1) to give 3.89 g, 45%
2
D
5
product as a yellow solid; mp 77±808C; [a] ˆ25.47 (c
(S)-(1)-N-[4-(4-Nitro-phenyl)-thiazol-2-yl]-tyrosine methyl
ester (6). Puri®ed by ¯ash chromatography on silica gel
(cyclohexane/ethylacetate 2:1) to give 4.75 g, 58% product
0
.95, CH CN/H O 95:5); HPLC: t ˆ11.61 min; TLC
3
2
R
1
(
(
cyclohexane/ethylacetate, 2:1): R ˆ0.30;
H
NMR
f
2
5
400 MHz, DMSO-d ): dˆ3.19 (dd, Jˆ14.5 Hz, 8.6 Hz,
as an orange-yellow solid; mp 120±1238C; [a] ˆ118.5 (c
6
D
1
3
H, CH ), 3.28 (dd, Jˆ14.5 Hz, 5.8 Hz, 1H, CH ), 3.61 (s,
1.02, CH CN/H O 95:5); HPLC: t ˆ10.66 min; TLC
2
2
3
2
R
1
H, OCH ), 4.70 (m, 1H, CH), 7.49 (s, 1H, thiazole-H), 7.01
3
(CH Cl /CH OH/17% aq. NH , 15:1:0.1): R ˆ0.60;
H
2
2
3
3
f
(
m, 1H, indole-H), 7.08 (m, 1H, indole-H), 7.21 (d,
NMR (400 MHz, DMSO-d ): dˆ2.90±3.07 (m, 2H, CH ),
6
2
Jˆ2.3 Hz, 1H, indole-H), 7.34 (d, Jˆ7.9 Hz, 1H, indole-
3.63 (s, 3H, OCH ), 4.57 (m, 1H, CH), 6.70 (d, Jˆ8.4 Hz,
3
H), 7.56 (d, Jˆ7.9 Hz, 1H, indole-H), 8.01 (d, Jˆ9.0 Hz,
2H, ArH), 7.08 (d, Jˆ8.4 Hz, 2H, ArH), 7.48 (s, 1H,
thiazole-H), 8.03 (d, Jˆ8.9 Hz, 2H, ArH), 8.24 (d,
Jˆ8.9 Hz, 2H, ArH), 8.29 (d, Jˆ7.6 Hz, 1H, NH), 9.25 (s,
1
3
2
H, ArH), 8.26 (d, Jˆ9.0 Hz, 2H, ArH); C NMR
(
100.4 MHz, CDCl ): dˆ27.9, 52.6, 58.4, 105.2, 109.6,
3
1
3
1
1
11.4, 118.5, 119.7, 122.3, 123.3, 124.1, 126.5, 127.4,
36.2, 139.7, 146.9, 147.8, 167.8, 172.3; HRMS (ESI)
1H, OH); C NMR (100.4 MHz, DMSO-d ): dˆ36.8, 51.8,
6
58.9, 105.8, 115.3, 123.7, 126.2, 126.9, 130.1, 140.9, 146.2,
148.1, 156.1, 167.4, 172.8; HRMS (ESI) calcd for [M1H]
1
1
calcd for [M1H]
23.11210.
C H N O S 423.11270, found
4
2
1
19
4
4
C H N O S 400.09672, found 400.09673.
3
1
9
18
5
(S,S)-(1)-N,N-Bis[4-(4-nitro-phenyl)-thiazol-2-yl]-cystine
dimethyl ester (3). Puri®ed by ¯ash chromatography on
silica gel (cyclohexane/ethylacetate, 2:1) to give 2.37 g,
34% product as a yellow solid; mp 144±1488C (phase
(S)-(2)-N-[4-(4-Nitro-phenyl)-thiazol-2-yl]-methionine
methyl ester (7). Puri®ed by ¯ash chromatography on silica
gel (cyclohexane/ethylacetate 5:1) to give 3.38 g, 45%
2
5
product as an orange solid; mp 78±798C; [a] ˆ251.23
D
2
D
5
change at 70±808C); [a] ˆ19.1 (c 0.90, CH CN/H O
(c 1.14, CH CN/H O 95:5); HPLC: t ˆ11.42 min; TLC
3
2
3
2
R
1
9
5:5); HPLC: t ˆ12.25 min; TLC (cyclohexane/ethyl-
(cyclohexane/ethylacetate 2:1): R ˆ0.58;
H
NMR
R
f
1
acetate, 2:1): R ˆ0.26; H NMR (400 MHz, DMSO-d ):
(400 MHz, DMSO-d ): dˆ2.04 (m, 2H, CH ), 2.07 (s, 3H,
f
6
6
2
dˆ3.19 (m, 2H, 2£CH ), 3.32 (m, 2H, 2£CH ), 3.69 (s,
SCH ), 2.61 (m, 2H, CH ), 3.68 (s, 3H, OCH ), 4.58 (m, 1H,
3 2 3
2
2
6
H, 2£OCH ), 4.82 (m, 2H, 2£CH), 7.41 (s, 2H, 2£
CH), 7.53 (s, 1H, thiazole-H), 8.04 (d, Jˆ8.9 Hz, 2H, ArH),
13
3
thiazole-H), 8.02 (d, Jˆ8.9 Hz, 4H, ArH), 8.19 (d, Jˆ
8.25 (d, Jˆ8.9 Hz, 2H, ArH), 8.29 (d, Jˆ7.6 Hz, 1H, NH);
1
3
8
.9 Hz, 4H, ArH), 8.36 (d, Jˆ7.9 Hz, 2H, 2£NH);
C
C NMR (100.4 MHz, CDCl ): dˆ15.5, 30.1, 31.6, 52.7,
3
NMR (100.4 MHz, DMSO-d ): dˆ52.1, 56.0, 107.0,
56.6, 105.8, 124.0, 126.5, 140.5, 146.8, 149.0, 167.5, 172.9;
HRMS (ESI) calcd for [M1H] C H N O S 368.07388,
found 368.07380.
6
1
1
23.7, 126.2, 140.6, 146.0, 147.5, 167.0, 171.2; HRMS
1
5
18
3
4 2
1
ESI) calcd for [M1H] C H N O S 677.06168, found
(
2
6
25
6
8 4
677.06218.
(4-Chloro-benzyl)-[4-(4-nitro-phenyl)-thiazol-2-yl]-amine
(8). Puri®ed by ¯ash chromatography on silica gel (cyclo-
(S)-(2)-N-[4-(4-Nitro-phenyl)-thiazol-2-yl]-histidine methyl
ester (4). Puri®ed by ¯ash chromatography on silica gel
hexane/ethylacetate 4:1) to give 2.21 g, 31% product as an
orange solid; mp 155±1568C; HPLC: t ˆ12.36 min; TLC
(
CH Cl /CH OH/17% aq. NH , 15:1:0.1) to give 3.00 g,
3
2
2
3
R
1
3
9% product as a dark yellow solid; mp 156±1588C;
(cyclohexane/ethylacetate 2:1): R ˆ0.47;
H
NMR
f
2
5
[
7
a] ˆ227.2 (c 1.03, CH CN/H O 95:5); HPLC: t ˆ
(400 MHz, DMSO-d ): dˆ4.53 (d, Jˆ5.9 Hz, 2H, CH ),
D
3
2
R
6
2
.24 min; TLC (CH Cl /CH OH/17% aq. NH , 15:1:0.1):
3
7.42 (m, 4H, ArH), 7.49 (s, 1H, thiazole-H), 8.07 (d,
Jˆ8.9 Hz, 2H, ArH), 8.24 (d, Jˆ8.9 Hz, 2H, ArH), 8.38
2
2
3
1
R ˆ0.29; H NMR (400 MHz, DMSO-d ): dˆ3.01 (m,
f
6
1
3
2H, CH ), 3.63 (s, 3H, OCH ), 4.68 (m, 1H, CH), 6.87 (s,
2
(t, Jˆ5.9 Hz, 1H, NH); C NMR (100.4 MHz, DMSO-
3
1H, imidazole-H), 7.50 (s, 1H, thiazole-H), 7.58 (s, 1H,
d ): dˆ47.4, 105.6, 123.7, 126.2, 128.2, 129.2, 132.1,
6
imidazole-H), 8.04 (d, Jˆ8.9 Hz, 2H, ArH), 8.25 (d,
137.8, 140.9, 146.1, 148.1, 168.5; HRMS (ESI) calcd for
[M1H] C H ClN O S 346.04170, found 346.04242.
1
3
1
Jˆ8.9 Hz, 2H, ArH); C NMR (100.4 MHz, CDCl ,
3
16 13
3
2
DMSO-d ): dˆ29.5, 51.8, 57.4, 106.1, 123.7, 126.2,
6
1
34.7, 140.8, 146.1, 147.8, 167.4, 172.6; HRMS (ESI)
C H N O S 374.09230, found
16 16 5 4
(^)-a-Phenylethyl-[4-(4-nitro-phenyl)-thiazol-2-yl]-amine
(9). Puri®ed by ¯ash chromatography on silica gel (cyclo-
hexane/ethylacetate 4:1) to give 1.20 g, 18% product as an
ochre to orange solid; mp 152±1548C; HPLC:
t ˆ12.09 min; TLC (cyclohexane/ethylacetate 2:1): R ˆ
1
calcd for [M1H]
74.09230.
3
(
S)-(2)-N-[4-(4-Nitro-phenyl)-thiazol-2-yl]-serine methyl
ester (5). Puri®ed by ¯ash chromatography on silica gel
cyclohexane/ethylacetate 1:1) to give 2.14 g, 32% product
R
f
1
0.59; H NMR (400 MHz, DMSO-d ): dˆ1.49 (d, Jˆ
6
(
6.8 Hz, 3H, CH ), 4.86 (m, 1H, CH), 7.22 (m, 1H, ArH),
3
2
5
as a yellow solid; mp 150±1528C; [a] ˆ269.1 (c 1.02,
7.34 (m, 2H, ArH), 7.43 (m, 3H, ArH1thiazole-H), 8.03 (d,
Jˆ8.9 Hz, 2H, ArH), 8.24 (d, Jˆ8.9 Hz, 2H, ArH), 8.40 (d,
D
CH CN/H O 95:5); HPLC: t ˆ9.49 min; TLC (CH Cl /
3
2
R
2
2
1
13
Jˆ7.5 Hz, 1H, NH); C NMR (100.4 MHz, DMSO-d ):
CH OH/17% aq. NH , 15:1:0.1): R ˆ0.49; H NMR
3
3
f
6

J. Rudolph / Tetrahedron 56 (2000) 3161±3165
3165
dˆ23.5, 55.1, 105.2, 124.0, 126.48, 126.50, 127.3, 128.6,
41.3, 144.2, 146.5, 148.7, 168.5; HRMS (ESI) calcd for
133.3, 146.4, 165.9, 173.9; HRMS (ESI) calcd for
[M1H] C H Cl N O S 331.00748, found 331.00746.
1
1
1
3
13
2
2
2
1
[
M1H] C H N O S 326.09627, found 326.09632.
17 16 3 2
[
(
4-(4-Nitro-phenyl)-thiazol-2-yl]-(4-chloro-phenyl)-amine
11). 6.72 g, 99% product as an orange solid; mp 204±
References
2
058C; HPLC: t ˆ12.66 min; TLC (cyclohexane/ethyl-
1. See, for example: (a) Aubert, D.; Bourrie, B.; Casellas, P.;
Cluzel, M. Sano®-Synthelabo. World Patent WO-9951226, 1999.
(b) Badorc, A.; Bordes, M. F.; de Cintet, P.; Savi, P.; Bernat, A.;
Lale, A.; Petitou, M.; Maffrand, J. P.; Herbert, J. M. J. Med. Chem.
1997, 40, 3393±3401. (c) Tanaka, A.; Sakai, H.; Motoyama, Y.;
Ishikawa, T.; Takasugi, H. J. Med. Chem. 1994, 37, 1189±1199.
(d) Rendenbach-M uÈ ller, B.; Unger, L.; Teschendorf, H. BASF AG.
European Patent EP-409048, 1991.
R
1
acetate 2:1): R ˆ0.42; H NMR (400 MHz, DMSO-d ):
f
6
dˆ7.41 (d, Jˆ9.0 Hz, 2H, ArH), 7.54 (s, 1H, thiazole-H),
7
8
.78 (d, Jˆ9.0 Hz, 2H, ArH), 8.18 (d, Jˆ8.9 Hz, 2H, ArH),
1
3
.29 (d, Jˆ8.9 Hz, 2H, ArH), 10.58 (s, 1H, NH); C NMR
(
1
100.4 MHz, DMSO-d ): dˆ107.0, 118.4, 123.8, 125.3,
6
26.4, 128.6, 139.8, 140.5, 146.3, 148.4, 163.3; HRMS
1
(ESI) calcd for [M1H] C H ClN O S 332.02605,
15 11 3 2
found 332.02629.
2. (a) Hantzsch, A.; Weber, J. H. Ber. Dtsch. Chem. Ges. 1887, 20,
3
118±3132. (b) Liebscher, F. In: Houben Weyl, Methoden der
Organischen Chemie, Bd. E8b III/Teil 2; Schaumann, E., Ed.;
Thieme: Stuttgart, New York, 1984; pp 1±398.
N-[4-(2,4-Dichloro-phenyl)-thiazol-2-yl]-glycine methyl
ester (12). 6.22 g, 96% product as an ochre solid; mp
1
18±1208C; HPLC: t ˆ11.74 min; TLC (cyclohexane/
3. See, for example: Abarghaz, M.; Kerbal, A.; Bourguignon, J.-J.
Tetrahedron Lett. 1995, 36, 6463±6466.
R
1
ethylacetate 2:1): R ˆ0.44; H NMR (400 MHz, DMSO-
f
d ): dˆ3.66 (s, 3H, OCH ), 4.13 (d, Jˆ6.1 Hz, 2H, CH ),
4. Maeda, S.; Suzuki, M.; Iwasaki, T.; Matsumoto, K.; Iwasawa,
Y. Chem. Pharm. Bull. 1984, 32, 2536±2543.
6
3
2
7
7
8
.23 (s, 1H, thiazole-H), 7.47 (dd, Jˆ8.5, 2.1 Hz, 1H, ArH),
.64 (d, Jˆ2.1 Hz, 1H. ArH), 7.87 (d, Jˆ8.5 Hz, 1H, ArH),
5. Neville, R. G.; McGee, J. J. Org. Synth. 1965, 45, 69±73.
6. (a) Elmore, D. T.; Toseland, P. A. J. Chem. Soc. 1956, 188±191.
(b) Behringer, H.; Kuchinka, K. Liebigs Ann. 1961, 650, 179±186.
7. (a) Stadlwieser, J.; Ellmerer-M uÈ ller, E. P.; Tak o , A.; Maslouh,
N.; Bannwart, W. Angew. Chem. 1998, 110, 1487±1489; Angew.
Chem., Int. Ed. Engl. 1998, 37, 1402±1404. (b) In a similar case
Fmoc-isothiocyanate is used for the generation of the thiourea; the
only amino acid example is a glycine amide: Kearney, P. C.;
Fernandez, M.; Flygare, J. A. J. Org. Chem. 1998, 63, 196±200.
8. (a) Mathes, R. A.; Gregory, J. T. J. Am. Chem. Soc. 1952, 74,
3867±3868. (b) Beyer, H.; Ruhlig, G. Chem. Ber. 1956, 89, 107±
114. (c) Teller, J.; Dehne, H.; Zimmermann, T.; Fischer, G. W.;
Olk, B. J. Prakt. Chem. 1990, 332, 453±460. (d) Zimmermann, T.;
Fischer, G. W.; Teller, J.; Dehne, H.; Olk, B. J. Prakt. Chem. 1990,
332, 723±730. (e) Abdelrazek, F. M.; Salah, A. M.; Elbazza, Z. E.
Arch. Pharm. 1992, 325, 301±305.
1
3
.13 (t, Jˆ6.0 Hz, 1H, NH); C NMR (100.4 MHz, CDCl ):
3
dˆ46.7, 52.9, 108.0, 127.5, 130.5, 132.1, 132.6, 133.8,
1
146.8, 166.9, 170.9; HRMS (ESI) calcd for [M1H]
C H Cl N O S 316.99183, found 316.99193.
1
2
11
2
2
2
(S)-(2)-N-[4-(2,4-Dichloro-phenyl)-thiazol-2-yl]-alanine
methyl ester (13). Puri®ed by ¯ash chromatography on
silica gel (cyclohexane/ethylacetate 5:1) to give 2.78 g,
4
2
2
5
1% product as an ochre solid; mp 109±110; [a] ˆ
D
70.1 (c 1.03, CH CN/H O 95:5); HPLC: t ˆ12.24 min;
3
2
R
1
TLC (cyclohexane/ethylacetate 2:1): R ˆ0.58; H NMR
f
(
3
400 MHz, DMSO-d ): dˆ1.40 (d, Jˆ7.1 Hz, 3H, CH ),
6
3
.65 (s, 3H, OCH ), 4.39 (m, 1H, CH), 7.23 (s, 1H,
3
thiazole-H), 7.48 (dd, Jˆ8.5, 2.1 Hz, 1H, ArH), 7.64 (d,
Jˆ2.1 Hz, 1H, ArH), 7.86 (d, Jˆ8.5 Hz, 1H, ArH), 8.15
1
3
(
d, Jˆ7.1 Hz, 1H, NH); C NMR (100.4 MHz, CDCl ):
9. Schantl, J. G.; Lagoja, I. M. Synth. Commun. 1998, 28, 1451±
1462.
3
dˆ18.5, 52.6, 53.3, 107.5, 127.1, 130.1, 131.8, 132.2,