New synthesis of 4-(1-adamantyl)-2-aryl-1,3-thiazoles from 4-(1-adamantyl)-1,2,3-thiadiazole

Article abstract of DOI:10.1134/S1070428011120165

Treatment of 4-(1-adamantyl)-1,2,3-thiadiazole with potassium tert-butoxide generated potassium 2-(1-adamantyl)ethynethiolate which reacted with aromatic carboxylic acid chlorides to give unstable S-[2-(1-adamantyl)ethynyl] arenecarbothioates whose acid h

Full text of DOI:10.1134/S1070428011120165

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2011, Vol. 47, No. 12, pp. 1878–1881. © Pleiades Publishing, Ltd., 2011.
Original Russian Text © A.A. Shchipalkin, M.L. Petrov, V.A. Kuznetsov, 2011, published in Zhurnal Organicheskoi Khimii, 2011, Vol. 47, No. 12,
pp. 1842–1845.
New Synthesis of 4-(1-Adamantyl)-2-aryl-1,3-thiazoles
from 4-(1-Adamantyl)-1,2,3-thiadiazole
A. A. Shchipalkin, M. L. Petrov, and V. A. Kuznetsov
St. Petersburg State Institute of Technology, Moskovskii pr. 26, St. Petersburg, 190013 Russia
e-mail: mlpetrov@lti-gti.ru
Received April 13, 2011
Abstract—Treatment of 4-(1-adamantyl)-1,2,3-thiadiazole with potassium tert-butoxide generated potassium
2-(1-adamantyl)ethynethiolate which reacted with aromatic carboxylic acid chlorides to give unstable
S-[2-(1-adamantyl)ethynyl] arenecarbothioates whose acid hydrolysis afforded S-[2-(1-adamantyl)-2-oxo-
ethyl] arenecarbothioates. The latter reacted with ammonium acetate in acetic acid yielding 4-(1-adamantyl)-2-
aryl-1,3-thiadiazoles. Reactions of 4-(1-adamantyl)-2-(4-chloro-3-nitrophenyl)-1,3-thiadiazole with cyclic
secondary amines gave the corresponding products of nucleophilic replacement of the chlorine atom in the
aromatic ring.
DOI: 10.1134/S1070428011120165
and treatment of the latter with thionyl chloride [6].
1,2,3-Thiadiazole I readily undergoes decomposition
by the action of such a strong base as potassium tert-
butoxide in tetrahydrofuran with liberation of nitrogen
molecule and formation of unstable potassium
2-(1-adamantyl)ethynethiolate (II) [7]. Potassium salt
II reacted with aromatic carboxylic acid chlorides
IIIa–IIIc, but we failed to isolate the corresponding
acetylenic thio esters IVa–IVc as individual substances
because of their facile hydrolysis upon chromatog-
raphy on silica gel and decomposition upon vacuum
distillation. Labile S-2-(1-adamantyl)ethynyl arenecar-
bothioates IVa–IVc were subjected to hydrolysis at the
triple bond in the presence of a catalytic amount of
concentrated sulfuric acid to produce S-[2-(1-adaman-
tyl)-2-oxoethyl] arenecarbothioates Va–Vc (Scheme 1).
Several 2-substituted 4-(1-adamantyl)-1,3-thiazoles
have been reported up to now [1–5]. All these com-
pounds were synthesized by reaction of α-halo-1-
acetyladamantanes with the corresponding thioacetic
acid amides. 2-(2-Methylindol-3-ylmethyl)-substituted
4-(1-adamantyl)-1,3-thiazoles were shown to act as
enzyme inhibitors with an activity comparable to
indomethacin [2], while 2-(4-methoxyphenyl)- and
2-(pyridin-3-yl)-4-(1-adamantyl)-1,3-thiazoles exhibit-
ed antituberculous activity [1].
We now propose a novel procedure for the syn-
thesis of 4-(1-adamantyl)-2-aryl-1,3-thiazoles from
readily accessible 4-(1-adamantyl)-1,2,3-thiadiazole
(I) which is prepared from 1-acetyladamantane
through the corresponding ethoxycarbonylhydrazone
Scheme 1.
t-BuOK
RCOCl (IIIa–IIIc)
O
N
N
S– K+
S
R
S
I
II
IVa–IVc
O
H+, H2O
S
R
O
Va–Vc
R = 4-ClC6H4 (a), 1-benzofuran-2-yl (b), 3-O2N-4-ClC6H3 (c).
1878

NEW SYNTHESIS OF 4-(1-ADAMANTYL)-2-ARYL-1,3-THIAZOLES
1879
of these compounds contained the molecular ion peaks
whose isotope composition was consistent with the
calculated value.
The structure of compounds Va–Vc was proved by
their NMR and mass spectra and chemical transforma-
1
tion. In the H NMR spectrum of S-[2-(1-adamantyl)-
2-oxoethyl] 4-chloro-3-nitrobenzenecarbothioate (Vc)
signals from protons in the adamantane fragment were
observed in the region δ 1.78–2.12 ppm. Methylene
protons in the SCH2CO fragment resonated as a singlet
at δ 4.18 ppm, and aromatic protons gave rise to dou-
blets at δ 7.66 (5-H) and 8.09 ppm (6-H) with a cou-
pling constant J of 8.1–8.8 Hz and a singlet at
δ 8.44 ppm (2-H). No molecular ion peak was detected
in the mass spectrum of Vc, but fragment ion peaks
corresponding to decomposition of the molecular ion
at the S–C(O) bond were present.
EXPERIMENTAL
The melting points were measured on a Boetius
1
melting point apparatus. The H and 13C NMR spectra
were recorded on a Bruker AMX-400 spectrometer at
400 and 100 MHz, respectively, using the residual
proton and carbon signals of deuterated solvent as
reference. The mass spectra (electron impact, 70 eV)
were obtained on a Finnigan INCOS MAT 95 mass
spectrometer with direct sample admission into the ion
source (ion source temperature 200°C). The progress
of reactions was monitored by TLC on Silicagel
60 F254 plates; spots were visualized under UV light or
by treatment with iodine vapor. All solvents used in
this work were purified and dehydrated according to
standard procedures.
Carbothioates Va–Vc reacted with anhydrous am-
monium acetate in glacial acetic acid to give 4-(1-ada-
mantyl)-2-aryl-1,3-thiazoles VIa–VIc in high yield
(Scheme 2).
Scheme 2.
S-[2-(1-Adamantyl)-2-oxoethyl] 4-chlorobenzene-
carbothioate (Va). Potassium tert-butoxide, 1.1 g
(9.9 mmol), was added under argon at room tempera-
ture to a solution of 2 g (9 mmol) of thiadiazole I in
25 ml of anhydrous tetrahydrofuran. The mixture was
stirred for 5 min (until nitrogen no longer evolved),
and potassium salt II separated. A solution of 1.9 g
(11 mmol) of 4-chlorobenzoyl chloride (IIIa) in 15 ml
of anhydrous tetrahydrofuran was added, and the mix-
ture turned homogeneous. It was stirred for 10 min,
50 ml of water and three drops of concentrated sulfuric
acid were added, and the mixture was heated for 1.5 h
under reflux, washed with a saturated solution of
potassium carbonate and water, and extracted with
chloroform (3×20 ml). The extracts were combined,
dried over anhydrous sodium sulfate, filtered, treated
with activated charcoal under reflux, and evaporated.
The residue was recrystallized from ethanol. Yield
0.75 g (28%), colorless crystals, mp 119–120°C.
1H NMR spectrum (DMSO-d6), δ, ppm: 1.71 m (6H,
Ad), 1.95 m (6H, Ad), 2.09 m (3H, Ad), 4.19 s (2H,
CH2), 7.58 d (2H, o-H, J = 4 Hz), 7.94 d (2H, m-H,
J = 4.1 Hz). 13C NMR spectrum (DMSO-d6), δC, ppm:
27.39 (CH, Ad), 35.22 (C1, Ad), 35.99 (CH2, Ad),
39.02 (CH2, Ad), 51.27 (COCH2S), 128.89 (Cm),
134.21 (Co), 138.18 (Ci), 141.79 (Cp), 188.67 (COCH2),
206.28 (CH2SCO). Found, %: C 65.58, 65.79; H 6.36,
6.57. C19H21ClO2S. Calculated, %: C 65.41; H 6.07.
NH4OAc, AcOH
Va–Vc
N
R
S
VIa–VIc
R = 4-ClC6H4 (a), 1-benzofuran-2-yl (b), 3-O2N-4-ClC6H3 (c).
The chlorine atom in 4-(1-adamantyl)-2-(4-chloro-
3-nitrophenyl)-1,3-thiazole (VIc) is activated due to
the presence of a nitro group in the ortho position, so
that it is capable of being replaced by the action of
nucleophiles. Reactions of 1,3-thiazole VIc with cyclic
secondary amines afforded the corresponding amino-
phenyl derivatives VIIa–VIId (Scheme 3).
Scheme 3.
NO2
HN
X
VIc
N
X
N
S
VIIa–VIId
X = CH2CH2 (a), CH2CH2CH2 (b), CH2NHCH2 (c),
CH2OCH2 (d).
The structure of compounds VIa–VIc and VIIa–
VIId was confirmed by NMR spectroscopy and mass
spectrometry. Their 1H NMR spectra (DMSO-d6) char-
acteristically displayed a signal from the 5-H proton in
the thiazole ring at δ 6.91–7.25 ppm. The mass spectra
Compounds Vb and Vc were synthesized in a simi-
lar way.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 12 2011

SHCHIPALKIN et al.
1880
S-[2-(1-Adamantyl)-2-oxoethyl] 1-benzofuran-2-
(50), 77 (48), 65 (32), 55 (33), 41 (100). Found, %:
C 69.25, 69.52; H 6.35, 6.44. C19H20ClNS. Calculated,
%: C 69.18; H 6.11. M 329.88.
carbothioate (Vb) was synthesized from 2 g (9 mmol)
of thiadiazole I using 1.1 g (10 mmol) of potassium
tert-butoxide and 2.1 g (10 mmol) of 1-benzofuran-2-
carbonyl chloride (IIIb). Yield 1 g (24%), mp 138–
139°C. 1H NMR spectrum (DMSO-d6), δ, ppm: 1.69 m
(6H, Ad), 1.87 m (6H, Ad), 2.01 m (3H, Ad), 4.30 s
(2H, CH2), 7.38 t (1H, J = 6.9 Hz), 7.56 t (1H, J =
7.8 Hz), 7.74 d (1H, J = 5.9 Hz), 7.81 d (1H, J =
7.8 Hz), 7.56 s (1H). Found, %: C 70.89, 71.21; H 6.03,
6.34. C21H22O3S. Calculated, %: C 71.16; H 6.26.
Compounds VIb and VIc were synthesized in
a similar way. Thin-layer chromatography was per-
formed using the same eluents.
4-(1-Adamantyl)-2-(1-benzofuran-2-yl)-1,3-thia-
zole (VIb) was synthesized from 0.3 g (0.76 mmol) of
carbothioate Vb and 0.37 g (7.6 mmol) of ammonium
1
acetate. Yield 0.29 g (77%), mp 136–137°C. H NMR
spectrum (DMSO-d6), δ, ppm: 1.78 m (6H, Ad),
1.99 m (6H, Ad), 2.08 m (3H, Ad), 7.21 s (4-H), 7.27 t
(1H, 6′-H, J = 7.3 Hz), 7.36 t (1H, 5′-H, J = 7.8 Hz),
7.39 s (1H, 3′-H), 7.58 d (1H, 7′-H, J = 7.8 Hz), 7.67 d
(1H, 4′-H, J = 7.8 Hz). Mass spectrum, m/z (Irel, %):
335 (100) [M]+, 278 (25) [M – C4H9]+, 161 (17), 135
(10) [Ad]+, 91 (22), 77 (21), 41 (43). Found, %:
C 74.78, 74.89; H 6.01, 6.27. C21H21NOS. Calculated,
%: C 75.19; H 6.31. M 335.46.
S-[2-(1-Adamantyl)-2-oxoethyl] 4-chloro-3-nitro-
benzenecarbothioate (Vc) was synthesized from 2 g
(9 mmol) of thiadiazole I using 1.1 g (10 mmol) of
potassium tert-butoxide and 2.25 g (10 mmol)
4-chloro-3-nitrobenzoyl chloride (IIIc). Yield 1 g
(24%), mp 144–145°C. 1H NMR spectrum (CDCl3), δ,
ppm: 1.78 m (6H, Ad), 1.92 m (6H, Ad), 2.12 m (3H,
Ad), 4.18 s (2H, CH2), 7.66 d (1H, 5-H, J = 8.8 Hz),
8.09 d (1H, 6-H, J = 8.1 Hz), 8.44 s (1H, 2-H).
13C NMR spectrum (DMSO-d6), δC, ppm: 27.40 (CH,
Ad), 35.25 (COCH2S), 36.00 (CH2, Ad), 37.75 (CH2,
Ad), 46.03 (C1′, Ad), 128.49 (C2), 128.92 (C5, C6),
130.91 (C1), 134.55 (C4), 138.92 (C3), 188.71 (SCO),
206.31 (AdCO). Mass spectrum, m/z (Irel, %): 184 (6)
[ClNO2C6H3CO]+, 163 (8) [AdCO]+, 135 (100) [Ad]+,
110 (8), 93 (15), 79 (20), 41 (13). Found, %: C 58.13,
58.41; H 5.33, 5.41. C19H20ClNO4S. Calculated, %:
C 57.94; H 5.12. M 393.88.
4-(1-Adamantyl)-2-(4-chloro-3-nitrophenyl)-1,3-
thiazole (VIc) was synthesized from 0.5 g (1.3 mmol)
of carbothioate Vc and 0.66 g (13 mmol) of ammo-
nium acetate. Yield 0.29 g (95%), mp 219–220°C.
1H NMR spectrum (CDCl3), δ, ppm: 1.80 m (6H, Ad),
2.01 m (6H, Ad), 2.10 m (3H, Ad), 6.94 s (1H, 5-H),
7.58 d (1H, 5′-H, J = 8.1 Hz), 8.04 d (1H, 6′-H, J =
8.1 Hz), 8.46 s (1H, 2′-H). 13C (CDCl3), δC, ppm: 28.25
(CH, Ad), 36.45 (CH2, Ad), 41.87 (C1, Ad), 111.68
(C5), 122.71 (C2′), 126.99 (C6′), 130.01 (C5′), 131.90
(C1′), 133.92 (C4′), 148.05 (C3′), 162.39 (C4), 168.69
(C2). Macc spectrum, m/z (Irel, %): 374 (85) [M]+, 331
(5), 317 (12) [M – C4H9]+, 271 (9), 236 (8), 135 (14)
[Ad]+, 115 (12), 91 (39), 77 (42), 65 (25), 53 (34),
41 (100). Found, %: C 60.57, 60.69; H 4.87, 5.16.
C19H19ClN2O2S. Calculated, %: C 60.87; H 5.11.
M 374.88.
4-(1-Adamantyl)-2-(4-chlorophenyl)-1,3-thiazole
(VIa). Compound Va, 0.75 g (2 mmol), was dissolved
in 30 ml of glacial acetic acid, 1.05 g (2 mmol) of
anhydrous ammonium acetate was added, and the mix-
ture was heated for 5 h under reflux. The progress of
the reaction was monitored by TLC following disap-
pearance of initial carbothioate Va. The mixture was
diluted with 150 ml of water, and the precipitate was
filtered off, washed with water on a filter, dried, and
recrystallized from ethanol. Yield 0.5 g (68%), slightly
colored crystals, mp 150–151°C. The product was
chromatographically pure (chloroform–hexane, 1:1;
4-(1-Adamantyl)-2-[3-nitro-4-(pyrrolidin-1-yl)-
phenyl]-1,3-thiazole (VIIa). A mixture of 0.5 g
(1.3 mmol) of thiazole VIb and 10 ml of pyrrolidine
was heated for 5 min under reflux. The mixture was
diluted with 100 ml of water, and the precipitate was
filtered off, washed with water, dried, and recrystal-
lized from ethanol. Yield 0.4 g (74%), mp 249–250°C.
The product was chromatographically pure (chloro-
form–methanol, 9:1; hexane–acetone–diethyl ether,
1
ethyl acetate–hexane, 1:10). H NMR spectrum
(DMSO-d6), δ, ppm: 1.74 m (6H, Ad), 1.95 m (6H,
Ad), 2.04 m (3H, Ad), 7.22 s (1H, 5-H), 7.51 d (2H,
o-H, J = 4.3 Hz), 7.91 d (2H, m-H, J = 4.2 Hz).
13C NMR spectrum (DMSO-d6), δC, ppm: 31.88 (CH,
Ad), 40.21 (CH2, Ad), 42.21 (C1, Ad), 45.71 (CH2,
Ad), 110.09 (C5), 131.59 (Cm), 133.10 (Co), 136.20
(Ci), 138.36 (Cp), 168.52 (C2), 171.22 (C4). Mass spec-
trum, m/z (Irel, %): 329 (43) [M]+, 272 (20) [M –
C4H9]+, 155 (21), 135 (20) [Ad]+, 111 (17), 97 (29), 91
1
5:2:1). H NMR spectrum (CDCl3), δ, ppm: 1.79 m
(6H, Ad), 2.01 m (6H, Ad, and 4H, CH2CH2), 2.08 m
(3H, Ad), 3.27 m (4H, NCH2), 6.75 s (1H, 5-H), 6.91 d
(1H, 5′-H, J = 8.83 Hz), 7.92 d (1H, 6′-H, J =
8.83 Hz ), 8.32 s (1H, 2′-H). Mass spectrum, m/z
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 12 2011

NEW SYNTHESIS OF 4-(1-ADAMANTYL)-2-ARYL-1,3-THIAZOLES
1881
(Irel, %): 409 (60) [M]+, 392 (100), 362 (40), 336 (25),
321 (12), 237 (11), 160 (18), 153 (23), 135 (14) [Ad]+,
115 (19), 102 (30), 91 (53), 79 (50), 67 (28), 55
(32), 41 (98). Found, %: C 67.42, 67.71; H 6.79, 6.83.
C23H27N3O2S. Calculated, %: C 67.45; H 6.64.
M 409.54.
(1 mmol) of thiazole VIb and 10 ml of morpholine.
Yield 0.3 g (66%), mp 167–168°C. 1H NMR spectrum
(DMSO-d6), δ, ppm: 1.73 m (6H, Ad), 1.94 m (6H,
Ad), 2.03 m (3H, Ad), 3.06 m (4H, NCH2), 3.29 m
(4H, OCH2), 7.25 s (1H, 5-H), 7.36 d (1H, 5′-H, J =
8.86 Hz), 7.98 d (1H, 6′-H, J = 8.01 Hz), 8.27 s (1H,
2′-H). 13C NMR spectrum (DMSO-d6), δC, ppm: 27.85
(CH, Ad), 38.20 (C1, Ad), 41.65 (CH2, Ad), 111.82
(C5), 121.41 (C2′), 122.81 (C6′), 126.18 (C5′), 130.93
(C1′), 141.39 (C4′), 145.62 (C3′), 163.49 (C4), 167.13
(C2). Mass spectrum, m/z (Irel, %): 425 (23) [M]+, 408
(11), 336 (9), 135 (17) [Ad]+, 115 (12), 97 (25), 91
(49), 79 (52), 67 (33), 55 (36), 43 (100). Found, %:
C 65.12, 65.28; H 6.51, 6.69. C23H27N3O3S. Calculat-
ed, %: C 64.92; H 6.39. M 425.54.
Compounds VIIb–VIId were synthesized in a simi-
lar way. TLC analysis was performed using the same
eluents.
4-(1-Adamantyl)-2-[3-nitro-4-piperidinophenyl]-
1,3-thiazole (VIIb) was synthesized from 0.5 g
(1.3 mmol) of thiazole VIb and 10 ml of piperidine.
1
Yield 0.56 g (98%), mp 155–156°C. H NMR spec-
trum (CDCl3), δ, ppm: 1.63 m (2H, NCH2CH2CH2),
1.72 m (4H, NCH2CH2), 1.79 m (6H, Ad), 2.01 m (6H,
Ad), 3.08 m (4H, NCH2), 6.80 s (1H, 5-H), 7.09 d (1H,
5′-H, J = 8.83 Hz), 7.95 d (1H, 6′-H, J = 8.83 Hz),
8.35 s (1H, 2′-H). Mass spectrum, m/z (Irel, %): 423
(23) [M]+, 406 (45), 376 (6), 135 (12) [Ad]+, 115 (9),
91 (35), 79 (34), 67 (36), 55 (43), 41 (100). Found, %:
C 68.23, 68.31; H 7.15, 7.29. C24H29N3O2S. Calculat-
ed, %: C 68.06; H 6.90. M 423.57.
This study was performed under financial support
by the Russian Foundation for Basic Research (project
no. 08-03-00383-a).
REFERENCES
1. Khadse, B.G., Lokhande, S.R., Bhamaria, R.P., and
Prabhu, S.R., Indian J .Chem., Sect. B, 1987, vol. 26,
p. 856.
4-(1-Adamantyl)-2-[4-(4-methylpiperazin-1-yl)-
3-nitrophenyl]-1,3-thiazole (VIIc) was synthesized
from 0.5 g (1.3 mmol) of thiazole VIb and 10 ml of
N-methylpiperazine. Yield 0.58 g (86%), mp 170–
2. Woods, K.W., McCroskey, R.W., Michaelides, M.R.,
Wada, K., Hulkower, K.I., and Bell, R.L., Bioorg. Med.
Chem. Lett., 2001, vol. 11, p. 1325.
1
171°C. H NMR spectrum (CDCl3), δ, ppm: 1.78 m
3. Volovenko, Y.M., Tverdokhlebov, A.V., Gorulya, A.P.,
Shishkina, S.V., Zubatyuk, R.I., and Shishkin, O.V., Eur.
J. Org. Chem. 2002, no. 4, p. 663.
(6H, Ad), 2.00 m (6H, Ad), 2.08 m (3H, Ad), 2.35 s
(3H, NCH3), 2.57 m (4H, CH3NCH2), 3.14 m (4H,
NCH2), 6.82 s (1H, 5-H), 7.12 d (1H, 5′-H, J =
8.83 Hz), 7.98 d (1H, 6′-H, J = 8.83 Hz), 8.35 s (1H,
2′-H). Mass spectrum, m/z (Irel, %): 438 (12) [M]+, 408
(23), 391 (17), 348 (23), 336 (43), 237 (9), 134 (13)
[Ad]+, 115 (10), 91 (25), 71 (22), 57 (39), 43 (100).
Found, %: C 65.54, 65.81; H 7.02, 7.13. C24H30N4O2S.
Calculated, %: C 65.73; H 6.89. M 438.59.
4. Ono, Y., Sugihara, Y., Ishii, A., and Nakayama, J., Chem.
Lett., 2002, vol. 31, p. 314.
5. Volovenko, Yu.M., Resnyanskaya, E.V., and Tverdo-
khlebov, A.V., Khim. Geterotsikl. Soedin., 2002, p. 360.
6. Petrov, M.L., Shchipalkin, A.A., and Kuznetsov, V.A.,
Russ. J. Org. Chem., 2007, vol. 43, p. 630.
7. Petrov, M.L., Shchipalkin, A.A., Kuznetsov, V.A., and
Viktorov, B.N., Russ. J. Org. Chem., 2010, vol. 46,
p. 1214.
4-(1-Adamantyl)-2-(4-morpholino-3-nitrophen-
yl)-1,3-thiazole (VIId) was synthesized from 0.4 g
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 12 2011