Influence of the structures of α-halo ketones and thioamides on the Hantzsch synthesis of thiazoles and thiazolo[5,4-b]indoles. A new approach to 4-acetyl-2-methyl-4H-thiazolo[5,4-b]indole

Article abstract of DOI:10.1007/s11172-007-0219-5

In reactions with some α-halo ketones (3-bromo-1,1,1-trifluoropropan- 2-one, 1-acetyl-2-bromoindolin-3-one, and α-bromoacetophenone), thioacetamide and a series of thioamides of aromatic and heteroaromatic acids are transformed into 4-hydroxy-Δ²-thiazolines rather than into thiazoles (the expected Hantzsch reaction products). To the contrary, thiazoles are produced in the reactions of the same α-halo ketones with thioamides of phenylacetic, diphenylacetic, 3-indolylacetic, or cyanoacetic acids. The abnormal course of the Hantzsch reaction in the former case results from the fact that 4-hydroxy-Δ²-thiazolines, which are intermediates in the thiazole synthesis, undergo virtually no dehydration under the Hantzsch reaction conditions. The ease of dehydration of hydroxythiazolines under the conditions of the thiazole synthesis and the possibility of the spontaneous thiazole synthesis depend on the nature of the substituent at position 2 and, consequently, on the structure of the starting thioamide. The Me, Ar, and Het substituents impede dehydration, whereas substituents containing the α-methylene (methine) unit at the C(2) atom of the thiazoline moiety substantially facilitate this reaction. The conditions for the dehydration of 4-acetyl-2-methyl-8b-hydroxy-3a,8b-dihydro-4H-thiazolo[5,4-b]indole under basic catalysis were found, and a new procedure was developed for the preparation of thiazoles and 2-R-thiazolo[5,4-b]indoles, whose synthesis presents difficulties or is impossible under standard conditions.

Full text of DOI:10.1007/s11172-007-0219-5

Russian Chemical Bulletin, International Edition, Vol. 56, No. 7, pp. 1441—1446, July, 2007
1441
Influence of the structures of αꢀhalo ketones and thioamides
on the Hantzsch synthesis of thiazoles and thiazolo[5,4ꢀb]indoles.
A new approach to 4ꢀacetylꢀ2ꢀmethylꢀ4Hꢀthiazolo[5,4ꢀb]indole
A. Yu. Lepeshkin,a K. F. Turchin,a A. L. Sedov,a and V. S. Velezhevab
ꢀ
aCenter for Drug Chemistry, AllꢀRussian Chemical and Pharmaceutical Research Institute,
7 Zubovskaya ul., 119815 Moscow, Russian Federation.
Fax: +7 (495) 246 7805
bA. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences,
28 ul. Vavilova, 119991 Moscow, Russian Federation.
Fax: +7 (495) 135 9333. Eꢀmail: vel@ineos.ac.ru
In reactions with some αꢀhalo ketones (3ꢀbromoꢀ1,1,1ꢀtrifluoropropanꢀ2ꢀone, 1ꢀacetylꢀ2ꢀ
bromoindolinꢀ3ꢀone, and αꢀbromoacetophenone), thioacetamide and a series of thioamides of
2
aromatic and heteroaromatic acids are transformed into 4ꢀhydroxyꢀ∆ ꢀthiazolines rather than
into thiazoles (the expected Hantzsch reaction products). To the contrary, thiazoles are proꢀ
duced in the reactions of the same αꢀhalo ketones with thioamides of phenylacetic, diꢀ
phenylacetic, 3ꢀindolylacetic, or cyanoacetic acids. The abnormal course of the Hantzsch
2
reaction in the former case results from the fact that 4ꢀhydroxyꢀ∆ ꢀthiazolines, which are
intermediates in the thiazole synthesis, undergo virtually no dehydration under the Hantzsch
reaction conditions. The ease of dehydration of hydroxythiazolines under the conditions of the
thiazole synthesis and the possibility of the spontaneous thiazole synthesis depend on the
nature of the substituent at position 2 and, consequently, on the structure of the starting
thioamide. The Me, Ar, and Het substituents impede dehydration, whereas substituents conꢀ
taining the αꢀmethylene (methine) unit at the C(2) atom of the thiazoline moiety substantially
facilitate this reaction. The conditions for the dehydration of 4ꢀacetylꢀ2ꢀmethylꢀ8bꢀhydroxyꢀ
3a,8bꢀdihydroꢀ4Hꢀthiazolo[5,4ꢀb]indole under basic catalysis were found, and a new proceꢀ
dure was developed for the preparation of thiazoles and 2ꢀRꢀthiazolo[5,4ꢀb]indoles, whose
synthesis presents difficulties or is impossible under standard conditions.
Key words: thiazoles, 2ꢀRꢀthiazolo[5,4ꢀb]indoles, Hantzsch reaction, thioamides, αꢀhalo
ketones, structure, 4ꢀhydroxyꢀ∆2ꢀthiazolines, 2ꢀRꢀ4ꢀacetylꢀ8bꢀhydroxyꢀ3a,8bꢀdihydroꢀ4Hꢀ
thiazolo[5,4ꢀb]indoles, dehydration.
The field of application of thiazoleꢀcontaining comꢀ
pounds is gradually extended.1—7 2ꢀRꢀThiazolo[5,4ꢀb]inꢀ
doles, which we have synthesized earlier, and their deꢀ
rivatives are of interest for pharmacological studies.8,9 One
of the most commonly used procedures for the thiazole
synthesis is based on the Hantzsch reaction (the reaction
of αꢀhalo ketones with thioamides), which proceeds, as a
rule, under heating of the reaction components in ethanol
over a short period of time and gives the target comꢀ
pounds in good yields.10 However, 2ꢀmethylꢀ4ꢀ
phenylthiazole can be prepared only by heating αꢀbromoꢀ
acetophenone with thioacetamide in anhydrous EtOH in
the presence of gaseous hydrogen chloride for many
hours.11 The formation of 4ꢀhydroxyꢀ∆2ꢀthiazolines inꢀ
stead of thiazoles as the final products of the Hantzsch
reaction was documented.11,12 For example, heating of
3ꢀbromoꢀ1,1,1ꢀtrifluoropropanꢀ2ꢀone (1a) (trifluoroꢀ
bromoacetone) in EtOH with thioamides of acetic, benꢀ
zoic, or pyridinecarboxylic acids affords 2ꢀRꢀ4ꢀhydroxyꢀ
4ꢀtrifluoromethylꢀ∆2ꢀthiazolines, which undergo dehydraꢀ
tion to give 2ꢀRꢀ4ꢀtrifluoromethylthiazoles only under
drastic conditions.13 However, the reaction of trifluoroꢀ
bromoacetone 1a with thiourea or phenylthiourea readily
produces 2ꢀaminoꢀ or 2ꢀphenylaminoꢀ4ꢀtrifluoromethylꢀ
thiazole, respectively. Under the same conditions, the
reaction of trifluorobromoacetone 1a with N,N´ꢀdiphenylꢀ
thiourea affords 4ꢀhydroxyꢀ3ꢀphenylꢀ2ꢀphenyliminoꢀ4ꢀ
trifluoromethylthiazolidine hydrobromide. The fact that
4ꢀhydroxythiazolidines, which were prepared by the conꢀ
densation of αꢀhalo ketones with substituted thioureas,
are easily subjected to dehydration giving rise to 2ꢀiminoꢀ
∆4ꢀthiazolines has been documented earlier.14
In addition, we demonstrated that the reaction of
1ꢀacetylꢀ2ꢀbromoꢀ3ꢀindolinone (1b) (bromoindoxyl) with
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 7, pp. 1388—1393, July, 2007.
1066ꢀ5285/07/5607ꢀ1441 © 2007 Springer Science+Business Media, Inc.

1442
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 7, July, 2007
Lepeshkin et al.
Scheme 2
thioamides produces, depending on the nature of the latꢀ
ter compounds, either the corresponding hydroxydiꢀ
hydrothiazoloindoles 2a—d (from thioamides of acetic,
benzoic, or pyridinecarboxylic acids) or thiazoloindoles
3b—d (from thioamides containing the αꢀmethylene
unit)15 (Scheme 1). It should be noted that compounds
2a—d undergo virtually no dehydration in an acidic meꢀ
dium. We succeeded in preparing only 4ꢀacetylꢀ2ꢀmeꢀ
thylꢀ4Hꢀthiazolo[5,4ꢀb]indole hydrobromide (3a) in low
yield from hydrobromide 2a. An unsuccessful attempt16
to synthesize 4ꢀarylꢀ2ꢀ(oꢀhydroxyaryl)thiazoles by the
Hantzsch reaction of αꢀhaloacetophenones with thioꢀ
amides of oꢀhydroxybenzoic acids deserves notice.
Scheme 1
1: R1 = CF3, R2 = H (а), R1 + R2
R2 = H (c);
=
(b), R1 = Ph,
4: R3 = R4 = H (a); R3 = Ph, R4 = H (b); R3 = CN, R4 = H (c),
3 = R4 = Ph (d), R3 = 3ꢀindolyl, R4 = H (e);
R
5, 6: R1 = Ph, R2 = R3 = R4 = H (a); R1 = R3 = Ph,
R
R
R
2 = R4 = H (b); R1 = Ph, R2 = R4 = H, R3 = CN (c);
1 = Ph, R2 = R4 = H, R3 = 3ꢀindolyl (d); R1 = R3 = R4 = Ph,
2 = H (e); R1 = CF3, R2 = R4 = H, R3 = Ph (f);
2: R = Me (a), Ph (b), 3ꢀpyridyl (c), 4ꢀpyridyl (d), CH2Ph (e)
3: n = 1 (a—c), 0 (d); R´ = H (a), Ph (b), CH2Ph (c), CN (d)
R1 + R2
=
, R3 = Ph, R4 = H (g)
In the present study, we investigated the influence of
the structures of the starting αꢀhalo ketones and thioꢀ
amides on the ease of the Hantzsch reaction and develꢀ
oped efficient procedures for the synthesis of thiazoles
and 2ꢀRꢀthiazolo[5,4ꢀb]indoles, which are difficult, if at
all, to synthesize under standard conditions.
For this purpose, we studied the condensation of
αꢀbromoacetophenone (1c) with thioacetamide (4a) and
thioamides containing the αꢀmethylene (methine) unit
4b—e (thioamides of phenylacetic, cyanoacetic, diphenylꢀ
acetic, and 3ꢀindolylacetic acids) under comparable conꢀ
ditions. The reactions of trifluorobromoacetone 1a and
bromoindoxyl 1b with thioamide 4b were studied under
analogous conditions (Scheme 2).
of hydroxythiazolines 5a,b,d—g; the yields of the latter
are 61—82% (method A, Table 1, see Scheme 2). Under
the same conditions, the reaction of αꢀbromoacetoꢀ
phenone 1c with thioamide 4c also affords hydroxyꢀ
thiazoline 5c (TLC data). However, we failed to isolate
the latter compound in the individual state because it
undergoes dehydration to give thiazole 6c in the course of
recrystallization from PriOH.
Bromoindoxyl 1b reacts with thioamide 4b in Me2CO
at 20 °C and is almost quantitatively transformed into
hydrobromide 2e. The treatment of the latter with ammoꢀ
nium acetate gave free base 5g in 86% yield (method B).
However, the reactions proceed differently if PriOH is
used as the solvent in the absence of bases. For example,
heating of bromo ketones 1a—c with thioamides 4b,d,e
over a short period of time affords thiazoles 6b,d—f conꢀ
It appeared that the cyclocondensation of bromo
ketones 1a—c with thioamides 4a,b,d,e in the presence of
2 equiv. of triethylamine easily proceeds under mild conꢀ
ditions (20 °C, Me2CO) and always stops at the formation

Hantzsch synthesis of thiazoles and thiazolo[5,4ꢀb]indoles Russ.Chem.Bull., Int.Ed., Vol. 56, No. 7, July, 2007
Table 1. Physicochemical characteristics, yields, and elemental analysis data for compounds 5a,b,d—g, 6b,d—f, and 7
1443
Comꢀ
pound
Yield
(%)
M.p./°C
Found
Calculated
Molecular
formula
IR,
M+
(%)
N
ν/cm–1
C
H
S
OH, NH
C=N
1620
5а
5b
5d
5e
79
74
77
80
61
82
83
79
85
56
62
104—105*
116—117*
161—163*
160—162*
104—107
171—173
72—74
62.25
62.18
71.46
71.38
69.94
70.13
76.32
76.52
50.63
50.57
66.56
66.67
76.31
76.49
74.40
74.48
80.67
80.73
54.40
54.32
62.48
62.61
5.79
5.70
5.67
5.58
5.25
5.19
5.60
5.51
3.87
3.83
5.01
4.94
5.25
5.18
4.89
4.83
5.24
5.20
3.33
3.29
7.21
7.25
5.14
5.20
9.03
9.09
4.09
4.06
5.38
5.36
8.66
8.64
5.51
5.57
9.75
9.66
4.32
4.28
5.70
5.76
16.70
16.58
12.02
11.90
10.40
10.39
9.23
C10H11NOS
C16H15NOS
C18H16N2OS
C22H19NOS
C11H10F3NOS
C18H16N2O2S
C16H13NS
3150
3115
3225
3150
3120
3100
—
193
269
308
345
261
324
251
290
327
243
230
1610
1590
1590
1600
1620
1590
1640
1610
1610
1610
9.28
5f
12.36
12.26
9.73
5g**
6b
6d
6e
9.88
12.82
12.75
11.13
11.03
9.81
103—105
99—101
C18H14N2S
C22H17NS
3540, 3400
—
9.79
6f
41—43
13.29
13.17
13.99
13.91
C11H8F3NS
C12H10N2OS
—
7**
128—130
4.42
4.35
12.25
12.17
—
* The compound melts with decomposition.
** The absorption of the amide CO group in the IR spectra of compounds 5g and 7 is observed at 1680 and 1675 cm–1, respectively.
taining the αꢀmethylene (methine) unit at the C(2) atom
and 2ꢀbenzylthiazoloindole hydrobromide 3b in 56—85%
yields (method A). Thiazoles 6b,d—f are also produced in
74—85% yields by dehydration of hydroxythiazolines
5b,d—f performed with heating over a short period of time
(1 min for compounds 5b,d,e and 15 min for compound 5f)
in EtOH or PriOH in the presence of an equimolar amount
of HCl (method B). Hydrobromide 2e is subjected to
dehydration giving 2ꢀbenzylthiazoloindole 3b in 95% yield
by heating in PriOH for 5 min.
Therefore, the available data11—13 and the results obꢀ
tained in the present study and our earlier investigaꢀ
tions15,17 show that hydroxythiazolines and their indole
analogs, viz., hydroxydihydrothiazoloindoles, are, as a
rule, easily derived from αꢀhalo ketones and thioamides
in aprotic solvents at room temperature (sometimes, unꢀ
der heating in EtOH).13,15 The reaction time and the
yields of the products are virtually independent of the
structure of the starting thioamide. In an acidic medium,
hydroxythiazolines and hydroxydihydrothiazoloindoles
containing the αꢀmethylene (methine) unit at the C(2)
atom are smoothly transformed into the corresponding
thiazoles and thiazoloindoles. It is noteworthy that 2ꢀ
benzylhydroxythiazolines 5b,f and hydrobromide 2e,
which were prepared from structurally different αꢀhalo
ketones 1a—c and the same thioamide of phenylacetic
acid, are dehydrated under virtually the same conditions.
The dehydration is not hindered by the trifluoromethyl
group at position 4 of hydroxythiazoline 5f. To the conꢀ
trary, according to the published data,11,13,15 intermediꢀ
ate hydroxy compounds prepared from thioacetamide and
halo ketones 1a—c are subjected to dehydration into the
corresponding thiazoles under much more drastic condiꢀ
tions. As mentioned above, our attempt to perform the
acidꢀcatalyzed dehydration of compound 2a failed, and
the thermal dehydration performed by heating in chloꢀ
robenzene afforded 2ꢀmethylthiazoloindole hydrobromide
3a in low yield (12%).15 In the present study, we made an
attempt to perform dehydration of hydroxy compound 2a
under conditions similar to those favorable for this reacꢀ
tion to proceed by the E1cbꢀtype mechanism. We sucꢀ
ceeded in increasing the yield of thiazoloindole 7 to 62%
(method A) by heating compound 2a in a mixture of
acetic anhydride and pyridine for 15 min (Scheme 3).
Thiazoloindole 7 was also synthesized in lower yield (54%)
by storage of compound 2a in a mixture of thionyl chloꢀ
ride and triethylamine in dioxane (method B).
The structures of the resulting compounds were conꢀ
firmed by IR spectroscopy, mass spectrometry, 1H NMR
spectroscopy, and elemental analysis (Tables 1—3). The

1444
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 7, July, 2007
Lepeshkin et al.
Scheme 3
moiety and the protons of the CH2 group of the substituꢀ
ent at the C(2) atom. As a result, the signals for these
protons in the 1H NMR spectra of hydroxythiazolines are
observed as an AB system with the spinꢀspin coupling
constants 2J ~12.5 and 15.5 Hz, respectively (see Table 2).
The 1H NMR spectrum of compound 5g is characterized
by the presence of two sets of analogous signals in a ratio
of ~2 : 1, which correspond to protons of two conformers
with respect to the N—COMe amide bond (see Table 3).
The aboveꢀconsidered data allowed us to make conꢀ
clusions about the influence of the structures of αꢀhalo
ketones and thioamides on the ease of the Hantzsch reacꢀ
tion and about the optimal conditions for the thiazole
synthesis. It was found that thioacetamide and thioamides
of aromatic and heterocyclic acids are transformed
into 4ꢀhydroxyꢀ∆2ꢀthiazolines rather than into thiazoles
(Hantzsch reaction products) in the reactions with such
αꢀhalo ketones as trifluorobromoacetone 1a, bromoꢀ
indoxyl 1b, and bromoacetophenone 1c. To the contrary,
the reactions of the same αꢀhalo ketones with thioamides
of phenylacetic, diphenylacetic, 3ꢀindolylacetic, and
cyanoacetic acids produce thiazoles. In the former case,
the abnormal course of the Hantzsch reaction is attribꢀ
uted to the fact that 4ꢀhydroxyꢀ∆2ꢀthiazolines, which are
intermediates in the thiazole synthesis, undergo virtually
no dehydration under these conditions (except for 4ꢀhydrꢀ
oxyꢀ2ꢀmethylꢀ4ꢀphenylꢀ∆2ꢀthiazoline, which undergoes
dehydration, though under more drastic conditions). The
ease of dehydration of hydroxythiazolines under the conꢀ
ditions of the thiazole synthesis and the possibility of the
spontaneous thiazole synthesis were demonstrated to deꢀ
pend on the nature of the substituent at position 2 and,
IR spectra of compounds 5a,b,e—g, 6b,d—f, and 7 show
characteristic absorption bands of OH, NH, C=N, and
N—COMe groups, whose positions are consistent with
the known data. The EI mass spectra were studied for
compounds 5b and 6b. Compound 5b was also characterꢀ
ized by the fast atom bombardment (FAB) mass specꢀ
trum. The EI mass spectrum of thiazole 6b has the intense
peaks [M]+ (m/z 251) and [M – PhCH2CN]+ (m/z 134).
The EI mass spectrum of hydroxythiazoline 5b has, along
with the molecular ion peak [M]+ (m/z 269), the peak
[M – H2O]+ (m/z 251) with approximately equal intenꢀ
sity, as well as the peaks [M – PhCH2CN]+ (m/z 152),
[M – PhCH2CN –H2O]+ (m/z 134), [PhCH2CNH]+
(m/z 118), [PhCO]+ (m/z 105), [C7H7]+ (m/z 91), and
[Ph]+ (m/z 77). In the mass spectrum of compound 5b
measured with use of the soft ionization method (FAB),
the quasimolecular ion peak [MH]+ (m/z 270) and the
peak [M – H2O]+ (m/z 252) have the maximum intensity
(see Table 1).
The presence of the asymmetric C(4) atom in hydroxyꢀ
thiazolines 5b,d—f results in the nonequivalence of the
geminal protons (2 H) at position 5 of the heterocyclic
Table 2. 1H NMR spectroscopic data for hydroxythiazolines 5b,d—f and thiazoles 6b,d—f
Comꢀ
pound
δ (J/Hz)
2ꢀСH (H2)
4ꢀОH
5ꢀH (H2)
4ꢀR1
R2 (R3)
(s, 1 H)
5b
5d
5e
5f
6.65
6.60
6.72
7.50
—
3.48, 3.35*
3.93, 3.91*
7.25—7.45 (m, 5 H)
7.25—7.45 (m, 5 H)
7.25—7.45 (m, 5 H)
—
7.25—7.45 (m, 5 H)
2
2
(1 H each, J = 12.0) (1 H each, J = 15.3)
3.42, 3.29*
4.04, 3.98*
10.98 (s, NH);
6.95—7.55 (5 H, indole)
7.25—7.45 (m, 10 H)
2
2
(1 H each, J = 12.0) (2 H each, J = 15.8)
3.51, 3.39*
5.44 (s, 1 H)
3.92 (s, 2 H)
4.38 (s, 2 H)
4.47 (s, 2 H)
6.03 (s, 1 H)
4.40 (s, 2 H)
2
(1 H each, J = 12.2)
3.61, 3.30*
7.25—7.35 (m, 5 H)
2
(1 H each, J = 12.8)
6b
6d
6e
6f
7.95 (s, 1 H)
7.87 (s, 1 H)
8.03 (s, 1 H)
8.34 (s, 1 H)
7.94 (d, 2 H, J = 8.0);
7.36 (m, 3 H)
7.95 (d, 2 H, J = 8.0);
7.41, 7.35 (both m,
2 H each); 7.26 (m, 1 H)
11.03 (s, NH);
—
7.42 (t, 2 H); 7.32 (t, 1 H) 6.95—7.50 (m, 5 H, indole)
—
7.91 (d, 2 H, J = 8.0);
7.25—7.45 (m, 3 H)
—
7.25—7.45 (m, 10 H)
—
7.20—7.40 (m, 5 H)
* The AB system.

Hantzsch synthesis of thiazoles and thiazolo[5,4ꢀb]indoles Russ.Chem.Bull., Int.Ed., Vol. 56, No. 7, July, 2007
1445
Table 3. 1H NMR spectroscopic data for a mixture of the
major (5gmaj) and minor conformers (5gmin) of 4ꢀacetylꢀ2ꢀbenꢀ
zylꢀ8bꢀhydroxyꢀ3a,8bꢀdihydroꢀ2Hꢀthiazolo[5,4ꢀb]indole 5g
eluent; visualization was carried out with UV light and iodine
vapor. The melting points of compounds 3b15 and 6c18 are conꢀ
sistent with those described earlier.
2
2ꢀ(R3R4CH)ꢀ4ꢀR1ꢀ4ꢀHydroxyꢀ∆ ꢀthiazolines (5a,b,d—f),
4ꢀacetylꢀ2ꢀbenzylꢀ8bꢀhydroxyꢀ3a,8bꢀdihydroꢀ4Hꢀthiazoꢀ
lo[5,4ꢀb]indole (5g), and 2ꢀcyanoꢀ4ꢀphenylmethylthiazole (6c)
(general procedure). Method A. Bromo ketone 1a—c (10 mmol)
was added to a solution of the corresponding thioamide 4a—e
(10 mmol) and Et3N (2.02 g, 20 mmol) in acetone (20 mL). The
reaction solution was stirred at 20 °C for 30 min and then diluted
with water (30 mL). The crystals that precipitated were filtered
off, washed with aqueous acetone (1 : 1), and recrystallized
from PriOH, and compounds 5a,b,d—g were obtained (see
Tables 1—3). After dilution of the reaction mixture with water,
thiazole 6c was extracted with dichloromethane (3×15 mL).
The extract was washed with water and dried with Na2SO4. The
solvent was removed in vacuo, and the residue was recrystallized
from a 5 : 1 petroleum ether—benzene mixture in the presence
of activated carbon. Compound 6c was obtained in a yield of
1.12 g (55%), m.p. 42—44 °C (cf. lit. data18: m.p. 42—44 °C).
Found (%): C, 65.91; H, 4.08; N, 13.89; S, 15.94. C11H8N2S.
Calculated (%): C, 66.00; H, 4.00; N, 14.00; S, 16.00. MS (FAB,
70 eV, m/z): 200 [M]+.
Comꢀ
pound
δ (J/Hz)
H(5) H(3a) С(2)H2 NCOMe
H(6)—H(8)
(m)
(s) (s)
5gmaj
5gmin
7.15—7.55
8.06
(d)
6.32 3.84, 3.79 2.17
(q, 2 H,
2J = 16.0)
7.15—7.55 7.15—7.55 5.80 3.77 (br) 2.40
consequently, on the structure of the starting thioamide.
The Me, Ar, and Het substituents impede dehydraꢀ
tion, whereas substituents containing the αꢀmethylene
(methine) unit at the C(2) atom substantially facilitates
this process.
To summarize, we developed a twoꢀstep procedure for
the preparation of thiazoles and 2ꢀRꢀthiazolo[5,4ꢀb]inꢀ
doles, whose synthesis is difficult or impossible under the
standard conditions. The first step resulting in the formaꢀ
tion of hydroxythiazolines can be performed under rather
mild conditions (see above), whereas the second rateꢀ
determining step should be carried out either under drasꢀ
tic conditions of acid catalysis (for example, according to
the procedure described earlier13 by prolonged heating in
toluene in the presence of pꢀtoluenesulfonic acid) or unꢀ
der conditions favorable for dehydration of intermediate
hydroxythiazolines by the E1cbꢀtype mechanism (in the
presence of an appropriate base accompanied by the transꢀ
formation of the hydroxy group into a good leaving group).
In our opinion, the latter approach is preferable. For exꢀ
ample, it is known that 2ꢀmethylꢀ4ꢀphenylthiazole 6a is
produced by the Hantzsch reaction not only under acid
catalysis but also in the presence of alkalis.12 Apparently,
the modification of this method would also be useful when
the Hantzsch reaction is inhibited in an acidic medium.
Method B. A suspension of hydrobromide 2e (1.50 g,
3.70 mmol) and NaOAc (0.61 g, 7.40 mmol) in dioxane (12 mL)
and water (5 mL) was stirred without heating for 15 min.
The resulting emulsion was diluted with water (30 mL)
and stirred for 5 min. The precipitate was filtered off and
washed with water. Compound 5g was obtained in a yield of
1.03 g (86%).
4ꢀR1ꢀ2ꢀ(R3R4CH)ꢀ5ꢀR2ꢀThiazoles 6b,d—f (general proceꢀ
dure). Method A. Thioamide 4b,d,e (10 mmol) was dissolved on
heating in PriOH (30 mL). Then compound 1a (1.91 g, 10 mmol)
or compound 1c (1.99 g, 10 mmol) was added to the solution.
The reaction mixture was refluxed for 3 min (in the case of 1a,
for 15 min) and cooled. Aqueous NH3 was added to the reaction
mixture to pH = 8, and then water (30 mL) was added. The
crystals that precipitated were filtered off and recrystallized from
PriOH. The yields of compounds 6b, 6d, and 6e were 2.13 g
(85%), 2.35 g (81%), and 2.55 g (78%), respectively. In the case
of thiazole 6f, the solvent was removed in vacuo and the residue
was recrystallized from aqueous PriOH. Compounds 6b,d—f were
prepared (see Tables 1 and 2).
Method B. The corresponding 4ꢀR1ꢀ2ꢀ(R3R4CH)ꢀhydroxyꢀ
Experimental
2
∆ ꢀthiazoline 5b,d—f (5 mmol) and concentrated (d
=
1.18 g mL–1) HCl (0.45 mL, 5 mmol) in PriOH (3.5 mL) were
added to PriOH (12 mL). The reaction solution was refluxed for
1 min (in the case of compound 5f, for 15 min). Aqueous NH3
was added to the reaction mixture to pH = 8, and then water
(20 mL) was added. The crystals that precipitated were filtered
off and washed with water. The yields of compounds 6b, 6d, 6e,
and 6f were 1.00 g (80%), 1.23 g (85%), 1.36 g (83%), and 0.90 g
(74%), respectively.
4ꢀAcetylꢀ2ꢀbenzylꢀ8bꢀhydroxyꢀ3a,8bꢀdihydroꢀ4Hꢀthiazoꢀ
lo[5,4ꢀb]indole hydrobromide (2e). Bromo ketone 1b (2.54 g,
10 mmol) was added to a solution of thioamide 4b (1.51 g,
10 mmol) in acetone (30 mL) at 20 °C. The reaction mixture
was stirred for 20 min. The crystals were filtered off and
washed with acetone. Compound 2e was obtained in a yield of
3.85 g (95%), m.p. 162—165 °C (decomp.). Found (%): C, 53.29;
H, 4.20; N, 7.02; S, 7.98. C18H16N2O2S•HBr. Calculated (%):
The elemental analysis for C, H, N, S was carried out on an
EAꢀ1108 analyzer (CHNS/O, TDK detector). The 1H NMR
spectra were measured on a Varian Unity+400 spectrometer
(400 MHz) in DMSOꢀd6. The EI mass spectra were obtained on
a Finnigan SSQꢀ710 instrument by the direct injection of samples
into the ion source (the ionizing electron energy was 70 eV, the
temperature of the ionization chamber was 150 °C, samples
were heated to 350 °C, the heating rate was 163 deg min–1) and
by the FAB method in the oꢀnitrobenzyl alcohol matrix (xenon
as the ionization gas). The IR spectra were recorded on a
Perkin—Elmer 457 instrument (Nujol mulls). The course of the
reactions and the purity of the compounds were monitored by
TLC on Silufol UVꢀ254 plates (before chromatography of comꢀ
pounds 5a,b,d,e, the plates were kept in Et3N vapor for 3 min)
using a 20 : 1 : 3 chloroform—acetone—hexane mixture as the

1446
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 7, July, 2007
Lepeshkin et al.
C, 53.33; H, 4.20; N, 6.91; S, 7.90. MS: (FAB, 70 eV, m/z): 324
[M – HBr]+.
2. V. Beneteau and T. Besson, Tetrahedron Lett., 2001, 42, 2673.
3. J. L. Buchanan, U. N. Mani, H. R. Plake, and D. A. Holt,
Tetrahedron Lett., 1999, 40, 3985.
4. A. Tarraga, P. Molina, D. Curiel, and M. D. Velasco, Tetraꢀ
hedron Lett., 2002, 43, 8453.
5. S. K. Sharma, M. Tandom, and J. W. Lown, Tetrahedron,
2001, 58, 3417.
6. D. S. Millan, R. H. Prager, C. Brand, and P. H. Hart,
Tetrahedron, 2000, 56, 811.
4ꢀAcetylꢀ2ꢀbenzylꢀ4Hꢀthiazolo[5,4ꢀb]indole hydrobromide
(3b). A solution of hydrobromide 2e (1.00 g, 2.50 mmol) in
PriOH (15 mL) was refluxed for 5 min. The reaction mixture
was concentrated to 5 mL, diluted with acetone (15 mL), and
cooled to 10 °C. The crystals that precipitated were filtered off
and washed with acetone. Compound 3b was obtained in a
yield of 0.92 g (95%), m.p. 195—197 °C (cf. lit. data15: m.p.
195—197 °C). Found (%): C, 56.01; H, 3.93; N, 7.17; S, 8.32.
C18H14N2OS•HBr. Calculated (%): C, 55.81; H, 3.88; N, 7.24;
S, 8.27. MS (FAB, 70 eV, m/z): 306 [M – HBr]+.
7. J. Rudolph, Tetrahedron, 2000, 56, 3161.
8. Pat. RF 2024525; Byul. izobret. [Invention Bull.], 1994, 23
(in Russian).
4ꢀAcetylꢀ2ꢀmethylꢀ4Hꢀthiazolo[5,4ꢀb]indole (7). Method A.
Pyridine (5 mL) and 4ꢀacetylꢀ2ꢀmethylꢀ8bꢀhydroxyꢀ3a,8bꢀ
dihydroꢀ4Hꢀthiazolo[5,4ꢀb]indole hydrobromide 2a (5.50 g,
17.5 mmol) were successively added with stirring to Ac2O
(25 mL).15 The reaction mixture was refluxed for 15 min and
concentrated in vacuo. Water (30 mL) was added to the residue,
and the reaction mixture was stirred at 25 °C for 45 min. The
reaction product was extracted with dichloromethane
(3×15 mL), and the extract was washed with water (20 mL).
Dichloromethane was removed in vacuo. The residue was sucꢀ
cessively recrystallized from EtOH and a 1 : 1 heptane—benzene
mixture. Compound 7 was obtained in a yield of 2.34 g (see
Table 1).
Method B. Compound 2a (3.15 g, 10 mmol) and Et3N
(3.03 g, 30 mmol) were added to dioxane (15 mL) at 25 °C.
A solution of SOCl2 (1.19 g, 10 mmol) in dioxane (5 mL) was
added to the reaction solution for 3 min. The reaction mixture
was stirred at ∼20 °C for 30 min and then concentrated in vacuo.
The residue was treated as described in the method A. Comꢀ
pound 7 was obtained in a yield of 1.17 g (54%).
9. Pat. RF 2009141; Byul. izobret. [Invention Bull.], 1994, 5 (in
Russian).
10. J. V. Metzger, in Comprehensive Heterocyclic Chemistry,
Eds A. R. Katritzky and C. W. Rees, Pergamon, Oxford,
UK, 1984, Vol. 6, p. 236.
11. H. Singh, S. Singh, and A. S. Cheema, J. Ind. Chem. Soc.,
1975, 53, 682.
12. K. Arakawa, T. Miyasaka, and H. Ohtsuka, Chem. Pharm.
Bull., 1972, 20, 1041.
13. K. Tanaka, K. Nomura, H. Oda, S. Yoshida, and
K. Mitsuhashi, J. Heterocycl. Chem., 1991, 28, 907.
14. K. M. Murav´eva and M. N. Shchukina, Zh. Obshch. Khim.,
1960, 30, 2334 [J. Gen. Chem. USSR, 1960, 30 (Engl.
Transl.)].
15. V. S. Velezheva, A. Yu. Lepeshkin, O. A. Fedotova, V. I.
Shvedov, K. F. Turchin, A. L. Sedov, and O. S. Anisimova,
Khim.ꢀfarm. Zh., 1996, 30, No. 10, 37 [Pharm. Chem. J.,
1996, 30, 643 (Engl. Transl.)].
16. T. Bach and S. Heuser, Tetrahedron Lett., 2000, 41, 1707.
17. V. Velezheva, A. Lepeshkin, and K. Turchin, Programme
and Abstrs, 11th Europ. Symp. on Organic Chemistry (Goteborg,
July 23—28, 1999), Goteborg, 1999, P181.
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Received July 12, 2006;
in revised form March 20, 2007