Medium buffer effects on the condensation of l -cysteine and aryl nitriles to (R)-2-Aryl-4,5-dihydrothiazole-4-carboxylic acids

Article abstract of DOI:10.1055/s-0033-1339492

The condensation of l-cysteine and aryl nitriles to (R)-2-aryl-4,5- dihydrothiazole-4-carboxylic acids in buffered media was reinvestigated. Pure products (yields of 58-95%; up to 99% ee) were obtained in a NaHCO ₃/NaOH-buffered aqueous alcoholic medium. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1339492

PAPER
▌2763
paper
Medium Buffer Effects on the Condensation of L-Cysteine and Aryl Nitriles to
(R)-2-Aryl-4,5-dihydrothiazole-4-carboxylic Acids
Condensation of L-Cysteine and Aryl Nitriles
Oleg V. Maltsev, Valérianne Walter, Matthias J. Brandl, Lukas Hintermann*
Department Chemie, Technische Universität München, Lichtenbergstr. 4, 85748 Garching bei München, Germany
Fax +49(89)28913669; E-mail: lukas.hintermann@tum.de
Received: 02.07.2013; Accepted after revision: 11.07.2013
Abstract: The condensation of L-cysteine and aryl nitriles to (R)-2-
aryl-4,5-dihydrothiazole-4-carboxylic acids in buffered media was
reinvestigated. Pure products (yields of 58–95%; up to 99% ee)
were obtained in a NaHCO3/NaOH-buffered aqueous alcoholic me-
dium.
HOOC
COOH
R
N
S
*
S
Ar
N
1
OH
R2
N
OH
N
OH
Key words: amino acids, heterocycles, nitriles, nucleophilic addi-
tion, thiols
N
S
R1
H
COOH
S
S
H H
micacocidin (3; R1 = n-C5H11, R2 = Me)
yersiniabactin (4; R1 = H, R2 = H)
N
desferrithiocin (2)
The title compounds 2-aryl-4,5-dihydrothiazole-4-car-
boxylic acids 1 or their derivatives are naturally occurring
heterocyclic compounds. Some of them are microbial
siderophores like desferrithiocin (2),1 micacocidin (3),2
yersiniabactin (4)3 or pyochelin (5).4 Other notable cases
are the potent and selective histone deacetylase inhibitor
largazole (6)5 and the well-known firefly luciferin (7), the
biomolecular substrate in the generation of firefly biolu-
minescence (Figure 1).6 The acids 1 possess antibiotic,2
iron chelating,7 histone deacetylase inhibiting,8 antican-
cer,9 metallo-β-lactamase inhibiting,10 and other biologi-
cal activities. The ready oxidation of the dihydrothiazole
ring of 1 produces thiazolecarboxylic acids,11,12a an im-
portant family of pharmacophores themselves.12
S
S
OH
Me
N
N
O
COOH
N
N
O
NH
NH
S
S
HH
pyochelin (5)
O
O
COOH
HO
S
N
N
S
n-C7H15
S
O
largazole (6)
firefly luciferin (7)
Figure 1 Examples of naturally occurring 2-aryl-4,5-dihydrothia-
zole-4-carboxylic acids or their derivatives
Established synthetic approaches to acids 1 are the con-
densation of ethyl benzimidates with cysteine13 or its es-
ters, followed by saponification;14 the reaction of 2-
haloacrylic acids with thiobenzamides,15 and other meth-
ods.2,16 A convenient approach is the condensation of aryl
nitriles with cysteine,7d,f,h,8–10,11b,12,13b–d,17 which is often
carried out in buffered reaction media, apparently with an
intent to avoid racemization of the products 1 when start-
ing from L-cysteine.7d The stereospecifity of this process
has been implied by reported optical activity of the reac-
tion products,7d,8a,13b,c,18 but we are not aware of an analyt-
ical proof of the enantiomeric purity of the product. The
procedures in buffer require prolonged reaction times of
three days or longer,9,12b and heating up to 70 °C.17a These
conditions still generate side-products, necessitating puri-
fication by gel filtration13c or after derivatization.13c,17c Al-
ternatively, refluxing an alcoholic solution of nitrile and
cysteine with base (NaHCO3 or amines) furnishes acids 1
within a few hours,8,11b but with concomitant racemiza-
tion.18
For our ongoing studies of the chemistry of firefly oxylu-
ciferin,19 2-phenyl-4,5-dihydrothiazole-4-carboxylic acid
(1a) was required as a simplified analogue20 of firefly lu-
ciferin. The popular condensation of benzonitrile (8a)
with L-cysteine in buffered (pH 7) solution at 70 °C was
adopted (Scheme 1).17a
H2N
COOH
COOH
CN
N
SH
S
buffer pH 7
MeOH
70 °C, 24 h
8a
1a
Scheme 1 Synthesis of 2-aryl-4,5-dihydrothiazole-4-carboxylic
acids in a buffered, aqueous alcoholic medium
A near quantitative yield of product was obtained, but the
1H NMR spectrum of the crude material21 invariably dis-
played signals of a side-product, in addition to those of
unreacted nitrile. According to LC-MS analysis, the side-
product (m/z = 226) exceeds the mass of the desired 1a
(m/z = 208) by 18 units. The 1H NMR spectrum displays
a doublet of triplets at 5.09 ppm (1 H) and a multiplet at
3.18 ppm (2 H). Based on those data, the side product was
SYNTHESIS 2013, 45, 2763–2767
Advanced online publication: 24.07.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1339492; Art ID: SS-2013-Z0451-OP
© Georg Thieme Verlag Stuttgart · New York

2764
O. V. Maltsev et al.
PAPER
identified as N-benzoylcysteine (9), which arises from hy-
drolysis of 1a. Unfortunately, 9 could not be removed
from bulk 1a by either recrystallization or silica gel chro-
matography. We therefore analyzed the effects of various
buffers on the synthesis of 1a, in the hope of finding reac-
tion conditions that prevent the concomitant hydrolysis of
1a to 9 (Table 1).
Table 2 2-Aryl-4,5-dihydrothiazole-4-carboxylic Acids
COOH
H2N
COOH
method A or B
N
+
Ar CN
SH
S
Ar
8
1
Entry
Aryl
Methoda Time (h) Yield (%)
Table 1 Optimization of the Reaction Conditionsa
1
2
Ph (1a)
A
A
A
A
A
A
A
A
A
B
B
24
24
24
24
48
24
24
24
24
48
4
88
78
91
78
95
83
58
81
86
84b
83
COOH
4-ClC6H4 (1b)
4-FC6H4 (1c)
CN
H2N
COOH
+
O
COOH
SH
3
SH
N
Ph
N
4
4-CO2MeC6H4 (1d)
4-MeCOC6H4 (1e)
4-NO2C6H4 (1f)
4-MeC6H4 (1g)
2-Py (1h)
H
phosphate buffer
MeOH
S
Ph
5
1a
9
6
Entry
Temp
(°C)
Time
(h)
pHb
1a
1a/9c
(%)c in crude
7
1
2
70
70
70
70
70
r.t.
50
90
90
r.t.
r.t.
r.t.
24
24
24
24
24
24
24
24
96
24
96
24
6.0
6.5
7.0
7.5
8.0
7.5
7.5
7.5
7.5
8.0
8.0
–
70
83
83
93
96
87
88
51
–
76:24
88:12
92:8
8
9
3-Py (1i)
3
10
11
4-HOC6H4 (1j)
4-MeOC6H4 (1k)
4
95:5
a Reaction conditions: method A: L-cysteine (1.5 equiv), NaHCO3
(1.5 equiv), 1 M aq NaOH (5 mol%), H2O, MeOH, r.t.; method B:
L-cysteine (2 equiv), NaHCO3 (4 equiv), EtOH, 100 °C.
b Isolated as the monohydrate.
5
98:2
6
100:0
96:4
7
8
56:44
0:100
100:0
100:0
100:0
The enantiomeric purity of 1a was analyzed by normal
phase chiral HPLC (chiralcel OD) with addition of
CF3CO2H to the eluent and found to be in excess of 99%
ee;21 a racemic reference sample of 1a for the analysis had
been obtained from rac-cysteine according to the same
synthetic method. Gratifyingly, the slightly basic reaction
conditions had not induced any racemization in the con-
densation with L-cysteine. The use of near neutral buffers,
which had been recommended in earlier protocols is no
requirement for preventing racemization, but promotes
the undesired hydrolysis of 1a to 9 instead.
9
10
11
12d
82
92
95
a Reaction of PhCN (1 mmol) and L-cysteine (1.5 mmol) in 0.1 M buf-
fer (1.7 mL) and MeOH (2.6 mL).
b pH of the aqueous phosphate buffer, measured by pH meter.
c Mol% of 1a and ratio 1a/9 in the crude, based on 1H NMR spectros-
copy.
d No buffer; with NaHCO3/NaOH as base, cf. method A (Table 2).
The synthetic method A could be applied to various aryl
nitriles bearing electron-donating (methyl), electron-with-
drawing functional groups (halogen, ester, acyl, nitro), or
heterocyclic nitriles. The thiazolinic acids were obtained
in 58–95% yields and high purity (Table 2, entries 2–9).
In contrast, aryl nitriles bearing π-donating substituents
(hydroxyl, methoxy) do not readily react under these or
even harsher (heating to 60 °C) conditions. Their conver-
sion into thiazolinic acids occurred only upon refluxing
with excess L-cysteine and NaHCO3 in ethanol (entries
10, 11; method B). However, chiral HPLC analysis of 1k
showed that partial racemization of the product had oc-
curred (80% ee) in its synthesis.
Either slightly acidic pH (Table 1, entries 1–5), higher
temperatures (entries 6–8), or prolonged reaction time
(entry 9) generated increased levels of 9, supporting its
nature as secondary hydrolysis product of 1a. At pro-
longed heating, 9 became the main product (entry 9). At
room temperature and with faintly basic phosphate buffer
(pH 8.0), 1a was obtained free of 9 in consistently high
crude yields (entries 10 and 11), but still admixed with un-
reacted benzonitrile. Eventually, almost full conversion
was attained by performing the reaction in the presence of
an equivalent amount of NaHCO3 relative to cysteine, and
with addition of a catalytic amount (5 mol%) of aqueous
NaOH (method A). Remaining benzonitrile in the reaction
mixture could be removed by extraction with hexane, and
subsequent acidification precipitated 1a in high yield (Ta-
ble 1, entry 12, and Table 2, entry 1).
In conclusion, we have studied the preparation of 2-aryl-
4,5-dihydrothiazole-4-carboxylic acids 1 from aryl ni-
triles and L-cysteine. The reaction is best performed under
mildly basic conditions to give the desired products in
high yield (up to 95%) and purity (>99%) in less than a
Synthesis 2013, 45, 2763–2767
© Georg Thieme Verlag Stuttgart · New York

PAPER
Condensation of L-Cysteine and Aryl Nitriles
2765
(R)-2-Phenyl-4,5-dihydrothiazole-4-carboxylic Acid (1a)
day. Previously established and widely used protocols re-
lying on reactions in near neutral phosphate buffer at ex-
tended reaction times offer no advantage, but suffer from
concomitant hydrolysis of the products to N-aroylcys-
teines. Limitations of the protocol were nevertheless seen
with electron-rich nitriles, which required thermally more
forcing reaction conditions suffering from partial racemi-
zation. On the other hand, thiazolinic acid 1a can now be
considered a readily available enantiopure building block
for asymmetric synthesis.
Reaction performed according to method A (9.7 mmol), workup A;
yield: 1.77 g (88%); white solid; >99% ee; mp 114–115 °C; HPLC:
tR = 6.8 (major, R), 8.9 min (minor, S).
1H NMR (250 MHz, CDCl3): δ = 3.67–3.80 (m, 2 H, CH2), 5.37 (t,
3JH,H = 9.4 Hz, 1 H, CH), 7.40–7.56 (m, 3 H, Ph-H), 7.84–7.89 (m,
2 H, Ph-H), 8.94 (br s, 1 H, CO2H).
13C NMR (63 MHz, DMSO-d6): δ = 35.0 (CH2), 78.4 (CH), 128.1
(2 C, Ph-C), 128.9 (2 C, Ph-C), 131.8 (Ph-C), 132.3 (Ph-C), 168.3
(C=N), 171.8 (CO2H).
Anal. Calcd for C10H9NO2S: C, 57.95; H, 4.38; N, 6.76; S, 15.47.
Found: C, 57.73; H, 4.40; N, 6.76; S, 15.24.
Reactions were performed in Schlenk flasks under argon to avoid
oxidation to thiazoles. Solvents and reagents were obtained from
commercial suppliers and used without further purification. NMR
spectra were recorded at r.t. using SiMe4 as an internal standard for
1H NMR. 13C NMR spectra were referenced to solvent signals
(CDCl3, δ = 77.16; DMSO, δ = 39.52). Chiral HPLC analyses were
performed on a Chiralcel OD column with n-hexane–EtOH–
CF3CO2H (90:10 + 0.1%, v/v) as an eluent (flow 1 mL/min), using
UV detection. Melting points were measured on a metal heating
block with a digital thermometer.
(R)-2-(4-Chlorophenyl)-4,5-dihydrothiazole-4-carboxylic Acid
(1b)
Reaction performed according to method A (7.3 mmol), workup B;
yield: 1.37 g (78%); white solid; mp 165–166 °C (dec.).
1H NMR (250 MHz, CDCl3): δ = 3.75 (d, 3JH,H = 9.5 Hz, 2 H, CH2),
3
5.35 (t, JH,H = 9.5 Hz, 1 H, CH), 7.41 (d, 3JH,H = 8.5 Hz, 2 H, Ar-
H), 7.80 (d, 3JH,H = 8.5 Hz, 2 H, Ar-H).
13C NMR (63 MHz, DMSO-d6): δ = 35.3 (CH2), 78.3 (CH), 129.0
(2 C, Ar-C), 129.8 (2 C, Ar-C), 131.1 (Ar-C), 136.5 (Ar-C), 167.2
(C=N), 171.6 (CO2H).
Condensation of L-Cysteine and Aryl Nitriles; General Proce-
dure
Anal. Calcd for C10H8ClNO2S: C, 49.69; H, 3.34; N, 5.80; S, 13.27.
Found: C, 49.31; H, 3.29; N, 5.86; S, 13.19.
Method A: Aryl nitrile (1.0 equiv), L-cysteine (1.5 equiv), and
NaHCO3 (1.5 equiv) were subsequently added to a degassed mix-
ture of MeOH (2.6 mL/mmol), H2O (1.7 mL/mmol), and a catalytic
amount of 1 M NaOH (5 mol%). The reaction mixture, which re-
mained suspended throughout, was stirred at r.t. until TLC analysis
[n-hexane–EtOAc (1:1) + ca 2% of AcOH] indicated disappearance
of the nitrile. MeOH was then removed from the mixture by evapo-
ration under reduced pressure (40–50 °C/300 to 50 mbar).
(R)-2-(4-Fluorophenyl)-4,5-dihydrothiazole-4-carboxylic Acid
(1c)
Reaction performed according to method A (3.0 mmol), workup B;
yield: 0.62 g (91%); white solid; mp 121–123 °C.
1H NMR (250 MHz, CDCl3): δ = 3.75 (d, 3JH,H = 9.6 Hz, 2 H, CH2),
5.35 (t, 3JH,H = 9.6 Hz, 1 H, CH), 7.09–7.16 (m, 2 H, Ph-H), 7.84–
7.90 (m, 2 H, Ph-H), 8.85 (br s, 1 H, CO2H).
Method B: A mixture of aryl nitrile (1.0 equiv), L-cysteine (2.0
equiv), and NaHCO3 (4.00 equiv) in EtOH (1.5 mL/mmol) was
stirred at 100 °C under argon, until TLC analysis indicated disap-
pearance of the nitrile. The solvent was evaporated under reduced
pressure and H2O (5 mL/mmol) was added to the residual white sol-
id.
13C NMR (63 MHz, CDCl3): δ = 35.5 (CH2), 77.8 (CH), 116.0 (d,
J
C,F = 22.1 Hz, 2 C, Ar-C), 128.4 (d, JC,F = 3.2 Hz, Ar-C), 131.1 (d,
JC,F = 9.0 Hz, 2 C, Ar-C), 165.2 (d, JC,F = 253.6 Hz, Ar-CF), 172.1
(C=N), 173.9 (CO2H).
Anal. Calcd for C10H8FNO2S: C, 53.32; H, 3.58; N, 6.22; S: 14.24.
Found: C, 53.26; H, 3.73; N, 6.88; S, 14.51.
Depending on the solubility of the crude sodium salt of the product
in water, the following workup procedures were used:
(R)-2-[4-(Methoxycarbonyl)phenyl]-4,5-dihydrothiazole-4-car-
boxylic Acid (1d)
Reaction performed according to method A (6.2 mmol), workup C;
yield: 1.29 g (78%); white solid; mp 161–163 °C (dec.).
1H NMR (250 MHz, DMSO-d6): δ = 3.66 (dd, 2J = 11.3 Hz, 3J = 8.3
Hz, 1 H, CH2), 3.77 (dd, 2J = 11.3 Hz, 3J = 9.5 Hz, 1 H, CH2), 5.35
(dd, 3J = 8.3 and 9.5 Hz, 1 H, CH), 7.93 (d, 3J = 8.4 Hz, 2 H, Ar-H),
8.07 (d, 3J = 8.4 Hz, 2 H, Ar-H), 13.10 (br s, 1 H, CO2H).
13C NMR (63 MHz, DMSO-d6): δ = 35.2 (CH2), 52.4 (CH3), 78.5
(CH), 128.4 (2 C, Ar-C), 129.6 (2 C, Ar-C), 132.1 (Ar-C), 136.2
(Ar-C), 165.5 (CO2Me), 167.6 (C=N), 171.6 (CO2H).
Workup A, for water-soluble sodium salts: The cold (0 °C) solution
was acidified with aq 2 M HCl to pH 2 (indicator paper). The pre-
cipitated solid was collected by filtration and washed with a small
amount of H2O.
Workup B, for alkali-soluble sodium salts: aq 2 M NaOH was added
until the product was completely dissolved. The cooled (0 °C) solu-
tion was acidified with aq 2 M HCl to pH 2, precipitating a solid,
which was collected by filtration and washed with H2O.
Workup C, for non-water-soluble sodium salts: The mixture was
acidified with aq 2 M HCl to pH 2 and the suspension vigorously
stirred at r.t. The solid was collected by filtration and washed with
H2O.
Anal. Calcd for C12H11NO4S: C, 54.33; H, 4.18; N, 5.28; S, 12.09.
Found: C, 54.46; H, 4.20; N, 5.36; S, 12.27.
Workup D, for hot water-soluble sodium salts: The hot (50–60 °C)
solution was acidified with aq 2 M HCl to pH 2. The precipitated
solid was collected by filtration and washed with H2O.
(R)-2-(4-Acetylphenyl)-4,5-dihydrothiazole-4-carboxylic Acid
(1e)
Reaction performed according to method A (6.9 mmol), workup A;
yield: 1.63 g (95%); white solid; mp 151–152 °C (dec.).
In case the final product still contained sodium salt or inorganic
salts, it was dissolved in hot EtOAc and filtered to remove insoluble
solid. After evaporation of the solvent, pure product remained.
1H NMR (250 MHz, DMSO-d6): δ = 2.63 (s, 3 H, CH3), 3.67 (dd,
2J = 11.2 Hz, 3J = 8.3 Hz, 1 H, CH2), 3.78 (dd, 2J = 11.2 Hz, 3J = 9.5
3
Additional product (10–15%) could be isolated from the mother li-
quors by extraction with EtOAc (TLC monitoring). The purity of
this material was at times lower than that of the bulk material, and
thus it was not included in the final yield (Table 2).
Hz, 1 H, CH2), 5.37 (dd, J = 8.3 and 9.5 Hz, 1 H, CH), 7.93 (d,
3J = 8.4 Hz, 2 H, Ar-H), 8.06 (d, 3J = 8.4 Hz, 2 H, Ar-H), 13.05 (br
s, 1 H, CO2H).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2763–2767

2766
O. V. Maltsev et al.
PAPER
13C NMR (63 MHz, DMSO-d6): δ = 26.9 (CH3), 35.2 (CH2), 78.5
(CH), 128.4 (2 C, Ar-C), 128.7 (2 C, Ar-C), 136.0 (Ar-C), 138.9
(Ar-C), 167.7 (C=N), 171.6 (CO2H), 197.5 (C=O).
HRMS-ESI: m/z [M + H]+ calcd for C12H11NO3S: 249.0454; found:
249.0452.
Anal. Calcd for C9H8N2O2S: C, 51.91; H, 3.87; N, 13.45; S, 15.40.
Found: C, 51.83; H, 3.89; N, 13.43; S, 15.59.
(R)-2-(4-Hydroxyphenyl)-4,5-dihydrothiazole-4-carboxylic
Acid Monohydrate (1j)
Reaction performed according to method B (8.4 mmol), workup A;
yield: 1.71 g (84%); white solid; mp 151–153 °C (dec.).
1H NMR (250 MHz, DMSO-d6): δ = 3.54 (dd, 2J = 11.2 Hz, 3J = 8.1
Hz, 1 H, CH2), 3.65 (dd, 2J = 11.2 Hz, 3J = 9.3 Hz, 1 H, CH2), 5.21
(dd, 3J = 8.1 and 9.3 Hz, 1 H, CH), 6.84 (d, 3J = 8.7 Hz, 2 H, Ar-H),
7.63 (d, 3J = 8.7 Hz, 2 H, Ar-H), 10.28 (br s, 1 H, OH).
13C NMR (63 MHz, DMSO-d6): δ = 34.9 (CH2), 78.3 (CH), 115.5
(2 C, Ar-C), 123.6 (Ar-C), 130.1 (2 C, Ar-C), 160.6 (Ar-C), 167.6
(C=N), 172.1 (CO2H).
(R)-2-(4-Nitrophenyl)-4,5-dihydrothiazole-4-carboxylic Acid
(1f)
Reaction performed according to method A (6.8 mmol), workup A;
yield: 1.42 g (83%); yellow solid; mp 136–137 °C (dec.).
1H NMR (250 MHz, DMSO-d6): δ = 3.71 (dd, 2J = 11.3 Hz, 3J = 8.3
Hz, 1 H, CH2), 3.81 (dd, 2J = 11.2 Hz, 3J = 9.6 Hz, 1 H, CH2), 5.40
(dd, 3J = 8.3 and 9.6 Hz, 1 H, CH), 8.05 (d, 3J = 8.9 Hz, 2 H, Ar-H),
8.34 (d, 3J = 8.9 Hz, 2 H, Ar-H), 13.13 (br s, 1 H, CO2H).
13C NMR (63 MHz, DMSO-d6): δ = 35.6 (CH2), 78.5 (CH), 124.1
(2 C, Ar-C), 129.4 (2 C, Ar-C), 137.6 (Ar-C), 149.2 (Ar-C), 166.9
(C=N), 171.4 (CO2H).
HRMS-ESI: m/z [M + H]+ calcd for C10H8N2O4S: 252.0199; found:
252.0184.
Anal. Calcd for C10H9NO3S·H2O: C, 49.78; H, 4.60; N, 5.81; S,
13.29. Found: C, 49.50; H, 4.66; N, 5.81; S, 13.40.
(R)-2-(4-Methoxyphenyl)-4,5-dihydrothiazole-4-carboxylic
Acid (1k)
Reaction performed according to method B (1 mmol), workup B;
yield: 0.20 g (83%); white solid; 80% ee; mp 165–168 °C (dec.);
HPLC: tR = 10.0 (major, R), 20.9 min (minor, S).
1H NMR (250 MHz, CDCl3): δ = 3.70–3.74 (m, 2 H, CH2), 3.86 (s,
3 H, CH3), 5.33 (t, 3JH,H = 9.2 Hz, 1 H, CH), 6.92 (d, 3J = 8.9 Hz, 2
H, Ar-H), 7.81 (d, 3J = 8.9 Hz, 2 H, Ar-H), 10.31 (br s, 1 H, CO2H).
13C NMR (63 MHz, CDCl3): δ = 35.0 (CH2), 55.6 (CH3), 76.7 (CH),
114.2 (2 C, Ar-C), 124.7 (Ar-C), 130.7 (2 C, Ar-C), 163.1 (C=N),
172.9 (2 C, Ar-C, CO2H).
(R)-2-(4-Methylphenyl)-4,5-dihydrothiazole-4-carboxylic Acid
(1g)
Reaction performed according to method A (8.6 mmol), workup A;
yield: 1.10 g (58%), white solid; mp 150–153 °C.
1H NMR (250 MHz, DMSO-d6): δ = 2.36 (s, 3 H, CH3), 3.59 (dd,
2J = 11.2 Hz, 3J = 8.2 Hz, 1 H, CH2), 3.69 (dd, 2J = 11.2 Hz, 3J = 9.4
3
Hz, 1 H, CH2), 5.27 (dd, J = 8.2 and 9.4 Hz, 1 H, CH), 7.30 (d,
3J = 8.1 Hz, 2 H, Ar-H), 7.69 (d, 3J = 8.1 Hz, 2 H, Ar-H), 12.99 (s,
1 H, CO2H).
Anal. Calcd for C11H11NO3S: C, 55.68; H, 4.67; N, 5.90; S, 13.51.
Found: C, 55.75; H, 4.70; N, 5.92; S, 13.62.
13C NMR (63 MHz, DMSO-d6): δ = 21.0 (CH3), 34.9 (CH2), 78.3
(CH), 128.1 (2 C, Ar-C), 129.4 (2 C, Ar-C), 129.7 (Ar-C), 141.8
(Ar-C), 168.1 (C=N), 171.8 (CO2H).
Acknowledgment
Anal. Calcd for C11H11NO2S: C, 59.71; H, 5.01; N, 6.33; S, 14.49.
Found: C, 59.80; H, 5.02; N, 6.39; S, 14.63.
The authors thank Ms. Ulrike Ammari, Institute of Inorganic
Chemistry, TU München, for elemental analyses. This work was
supported by the Human Frontier Science Program
(RGY0081/2011, Excited-State Structure of the Emitter and Color-
Tuning Mechanism of the Firefly Bioluminescence).
(R)-2-(Pyridin-2-yl)-4,5-dihydrothiazole-4-carboxylic Acid (1h)
Reaction performed according to method A (9.6 mmol), workup A;
yield: 1.62 g (81%); white solid; mp 133–134 °C (dec.).
1H NMR (250 MHz, DMSO-d6): δ = 3.51 (dd, 2J = 11.4 Hz, 3J = 8.3
Hz, 1 H, CH2), 3.62 (dd, 2J = 11.4 Hz, 3J = 9.8 Hz, 1 H, CH2), 5.39
(dd, 3J = 8.3 and 9.8 Hz, 1 H, CH), 7.58 (ddd, JH,H = 7.4 Hz,
3
Supporting Information for this article is available online at
3JH,H = 4.8 Hz,4JH,H = 1.3 Hz, 1 H, 5-Ar-H), 7.95 (td, 3JH,H = 7.7 Hz,
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
m
tgioSrantnugIifoop
r
itmnatr
4JH,H = 1.7 Hz, 1 H, 4-Ar-H), 8.06 (dt, 3JH,H = 7.7 Hz, 4JH,H = 1.3, 1
3
4
3
H, 3-Ar-H), 8.67 (ddd, JH,H = 4.8 Hz, JH,H = 1.7 Hz, JH,H = 1.3
References
Hz, 1 H, 6-Ar-H), 13.03 (br s, 1 H, CO2H).
13C NMR (63 MHz, DMSO-d6): δ = 33.6 (CH2), 78.8 (CH), 121.3
(Ar-C), 126.3 (Ar-C), 137.2 (Ar-C), 149.4 (Ar-C), 149.9 (Ar-C),
171.5 (C=N), 171.6 (CO2H).
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Found: C, 51.91; H, 3.84; N, 13.38; S, 15.60.
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(R)-2-(Pyridin-3-yl)-4,5-dihydrothiazole-4-carboxylic Acid (1i)
Reaction performed according to method A (9.6 mmol), workup A;
yield: 1.72 g (86%); white solid; mp 179–181 °C (dec.).
1H NMR (250 MHz, DMSO-d6): δ = 3.67 (dd, 2J = 11.3 Hz, 3J = 8.2
Hz, 1 H, CH2), 3.77 (dd, 2J = 11.3 Hz, 3J = 9.5 Hz, 1 H, CH2), 5.34
3
(dd, 3J = 8.2 and 9.5 Hz, 1 H, CH), 7.55 (ddd, JH,H = 8.0 Hz,
3JH,H = 4.8 Hz, 5JH,H = 0.9 Hz, 1 H, 5-Ar-H), 8.15 (ddd, 3JH,H = 8.0
4
4
Hz, JH,H = 2.3 Hz, JH,H = 1.7 Hz, 1 H, 4-Ar-H), 8.74 (dd,
3JH,H = 4.8 Hz, JH,H = 1.7 Hz, 1 H, 6-Ar-H), 8.94 (dd, JH,H = 2.3
4
4
Hz, 5JH,H = 0.9 Hz, 1 H, 2-Ar-H), 13.12 (br s, 1 H, CO2H).
13C NMR (91 MHz, DMSO-d6): δ = 35.2 (CH2), 78.3 (CH), 124.0
(Ar-C), 128.2 (Ar-C), 135.6 (Ar-C), 148.5 (Ar-C), 152.4 (Ar-C),
166.1 (C=N), 171.5 (CO2H).
Synthesis 2013, 45, 2763–2767
© Georg Thieme Verlag Stuttgart · New York

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© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2763–2767