Novel nucleophilic 5-substitution route to 1,2,3-thiadiazoles

Full text of DOI:10.1021/jo001692c

J . Org. Chem. 2001, 66, 4045-4046
4045
Notes
Sch em e 1
Novel Nu cleop h ilic 5-Su bstitu tion Rou te to
1,2,3-Th ia d ia zoles
Alan R. Katritzky,*,§ Dmytro O. Tymoshenko,§ and
George N. Nikonov§,‡
Department of Chemistry, Center for Heterocyclic
Compounds, University of Florida, Gainesville,
Florida 32611-7200, and A. E. Arbuzov Institute of Organic
and Physical Chemistry, Russian Academy of Sciences,
Arbuzov str. 8, Kazan 420088, Russia
katritzky@chem.ufl.edu
Received December 1, 2000
In tr od u ction
1,2,3-Thiadiazoles are useful pharmacophores: their
cephalosporin derivatives exhibit antimicrobial activity,1
and compounds with a terminal 1,2,3-thiadiazole moiety
are antipsychotic agents,2 platelet-activating factors,3 and
angiotensin II receptor antagonists.4 1,2,3-Thiadiazoles
are valuable as synthetic intermediates for substituted
thioacetylenes,5a,b thioketenes,6a-d and substituted thio-
amides.6b,7
1,2,3-Thiadiazoles are generally prepared by thionyl
chloride induced cyclizations of tosylhydrazones,8 alkyl
1-hydrazonecarboxylates,5b,9 or semicarbazones.10 The
rearrangement of 5-mercapto-1,2,3-triazoles to 5-amino-
1,2,3-thiadiazoles11 is of a narrow scope. 5-Substituted
1,2,3-thiadiazoles are frequently obtained by reactions
of the 5-chloro derivatives with nucleophiles,12 but this
method is limited by the availability of R-chloroketones
and low yields of intermediate 5-chloro-1,2,3-thiadiaz-
oles.9
Readily accessible13a-e R-benzotriazolylalkyl ketones
are useful synthons for the preparation of 3,5-disubsti-
tuted phenols,14 2,4,6-trisubstituted pyridines,15 and
benzannelated- and 1-(2-arylethenyl)-thiazoles, -indoliz-
ines, and -imidazo[1,2-a]pyridines.16 We now describe a
two-step synthetic approach to 1,2,3-thiadiazoles from
R-benzotriazolylalkyl ketone tosylhydrazones 3a -d
(Scheme 1) via key intermediates 4a -d , which allow
facile nucleophilic introduction of 5-substituents.
§ University of Florida.
Resu lts a n d Discu ssion
‡ Russian Academy of Sciences.
(1) J apanese Patent 87099380. MDL Inc., MDDR-3D Database,
Version 99.2.
(2) Lowe, J . A., III. Patent EP 279598; Chem Abstr. 1987-91, 110,
8234q.
(3) Bowles, S. A.; Miller, A.; Whittaker, M. Patent WO 9315047;
Chem. Abstr. 1994, 120, 271175e.
(4) Winn, M.; De, B.; Zydowsky, Th. M.; Kerkman, D. J .; Debernal-
dis, J . F.; Rosenberg, S. H.; Shiosaki, K.; Basha, F. Z.; Spina, K. P.
Patent WO 9317681; Chem Abstr. 1994, 120, 134512y.
(5) (a) Ganjian, I. J . Heterocycl. Chem. 1990, 27, 2037. (b) Raap, R.;
Micetich, R. G. Can. J . Chem. 1968, 46, 1057.
Tosylhydrazones 3 (prepared as shown in Scheme 1,
3a from 1 and 3a -d from 2a -d ) with thionyl chloride
afforded the 1,2,3-thiadiazoles 4a -d in good yields.
Further reactions of 4a -d with S- and O-nucleophiles
gave final products 6a -f and 7a -c (Table 1). Optimiza-
tion of the conditions for displacement was needed;
treatment with thiophenols (NaH in DMF, room tem-
(6) (a) Seybold, G.; Heibl, C. Chem. Ber. 1977, 110, 1225. (b) Seybold,
G.; Heibl, C. Angew. Chem., Int. Ed. Engl. 1975, 14, 248. (c) Murai,
H.; Torres, M.; Strausz, O. P. J . Am. Chem. Soc. 1979, 101, 3976. (d)
Schaumann, E.; Ehlers, J .; Mrotzek, H. Liebigs Ann. Chem. 1979, 1734.
(7) Malek-Yazdi, F.; Yalpani, M. Synthesis 1977, 328.
(8) Meier, H.; Zimmer, O. J . Heterocycl. Chem. 1980, 17, 1639.
(9) Pain, D. L.; Slack, R. J . Chem. Soc. 1965, 5166.
(10) Modarai, B.; Ghandehari, M. H.; Massoumi, H.; Shafiee, A.;
Badali, A. J . Heterocycl. Chem. 1974, 11, 343.
(11) Tarasov, E. V.; Morzherin, Yu. Yu.; Toppet, S.; Dehaen, W.;
Bakulev, V. A. J . Chem. Res., Synop. 1997, 11, 396.
(12) Kindt-Larsen, T.; Pedersen, C. Acta Chem. Scand., Ser. B 1962,
16, 1800.
(13) (a) Katritzky, A. R.; Shcherbakova, I. V. J . Heterocycl. Chem.
1996, 33, 2031. (b) Katritzky, A. R.; Wang, J .; Karodia, N.; Li, J . J .
Org. Chem. 1997, 62, 4142. (c) Katritzky, A. R.; Abdel-Fattah, A. A.;
Belyakov, S. A.; Fahmy, A. F. M. J . Chem. Res. 1998, 334. (d) Katritzky,
A. R.; Lam, J . N. Heteroatom. Chem. 1990, 1, 21. (e) Katritzky, A. R.;
Wu, J . Synthesis 1994, 597.
(14) Katritzky, A. R.; Belyakov, S. A.; Henderson, S. A.; Steel, P. J .
Org. Chem. 1997, 62, 8215.
(15) Katritzky, A. R.; Abdel-Fattah, A. A.; Tymoshenko, D. O.;
Essawy, S. A. Synthesis 1999, 2114.
(16) Katritzky, A. R.; Tymoshenko, D. O.; Monteux, D.; Vvedensky,
V.; Nikonov, G.; Cooper, C.B.; Deshpande, M. J . Org. Chem., 2000,
65, 8059.
10.1021/jo001692c CCC: $20.00 © 2001 American Chemical Society
Published on Web 05/10/2001

4046 J . Org. Chem., Vol. 66, No. 11, 2001
Notes
Ta ble 1. P r ep a r a tion of 5-Su bstitu ted 1,2,3-Th ia d ia zoles
6 a n d 7
Gen er a l P r oced u r e for th e P r ep a r a tion of Com p ou n d s
3a -d . Meth od A. 1-(2,2-Dimethoxyethyl)-1H-1,2,3-benzotria-
zole (1) (0.67 g, 3.3 mmol) or the corresponding 2-(1H-1,2,3-
benzotriazol-1-yl)-1-R1-ethanone 2 (3.3 mmol), 4-p-toluensulfon-
hydrazide (0.614 g, 3.3 mmol), and 1 mL of HCl (concentrated)
in ethanol (50 mL) were refluxed during 12 h. The solution was
diluted with water (50 mL), and the precipitate was recrystal-
lized from methanol.
product
X
R1
R2
yields, %
6a
6b
6c
6d
6e
6f
7a
7b
7c
S
S
S
S
S
H
p-CH3-C6H4
p-CH3-C6H4
2-naphthyl
Bn
p-CH3-C6H4
p-Cl-C6H4
Ph
42
68
30
24
70
57
45
11
76
Ph
Ph
Ph
thiophen-2-yl
Ph
Ph
Ph
Meth od B. A mixture of the corresponding 2-(1H-1,2,3-
benzotriazol-1-yl)-1-R1-ethanone 2 (4.12 mmol) and 4-p-toluen-
sulfonhydrazide (4.12 mmol) in benzene (50 mL) was refluxed
overnight. The reaction mixture was cooled to room temperature,
and the obtained crystalline product was filtered off and
recrystallized from benzene.
S
O
O
O
2-naphthyl
p-CH3O-C6H4
furan-2-yl
perature) gives products 6a -f in good to moderate yields
and satisfactory conversion of the starting benzotriazole
derivative 4. Displacement with the anion generated from
an aliphatic thiol afforded 1,2,3-thiadiazole 6d in lower
yield. The use of O-nucleophiles required harsher condi-
tions (NaH in DMF, 100 °C) and gave variable yields of
5-aryloxy substituted products 7a -c.
The mechanism for the displacement reactions 4 f 6,7
likely involves the known ring-chain tautomerism of
substituted 1,2,3-thiadiazoles involving cleavage of the
1,2-bond to afford 2-diazoethanethione tautomers 5.
Intermediates 5 undergo a direct nucleophilic substitu-
tion of benzotriazole moiety and sequential ring closure
to yield 5-substituted 1,2,3-thiadiazoles 6,7.
N′-[2-(1H -1,2,3-Ben zot r ia zol-1-yl)et h ylid en e]-4-m et h yl-
ben zen esu lfon h yd r a zid e (3a ). White needles, yield 84%, mp
173 °C; 1H NMR δ 2.30 (s, 3H), 5.39 (d, J ) 4.5 Hz, 2H), 7.22 (d,
J ) 8.1 Hz, 2H), 7.30-7.34 (m, 4H), 7.43 (d, J ) 8.1 Hz, 2H),
7.95-7.97 (m, 1H), 11.33 (s, 1H); 13C NMR δ 21.1, 48.7, 110.5,
119.1, 124.0, 127.1, 127.3, 129.6, 132.9, 135.7, 143.4, 144.0, 145.2.
Anal. Calcd for C15H15N5O2S: C, 54.69; H, 4.60; N, 21.27.
Found: C, 54.80; H, 4.61; N, 21.04.
Gen er a l P r oced u r e for th e P r ep a r a tion of Com p ou n d s
4a -d . The corresponding 4-p-toluensulfonhydrazide 3 (1 mmol)
and thionyl chloride (10 mL) were stirred at room temperature
for 12 h. An excess of thionyl chloride was removed, the reaction
mixture was diluted with ether (20 mL) or acetone, and the
obtained crystalline precipitate was filtered off and washed with
ether (3 × 20 mL) or recrystallized from acetone to give
compounds 4.
1-(1,2,3-Th iadiazol-5-yl)-1H-1,2,3-ben zotr iazole (4a). White
microcrystals, yield 72%, mp 169 °C; 1H NMR δ 7.61 (t, J ) 8.1
Hz, 1H), 7.82 (t, J ) 8.1 Hz, 1H), 8.21 (d, J ) 8.3 Hz, 1H), 8.27
(d, J ) 8.3 Hz, 1H), 9.71 (s, 1H); 13C NMR δ 109.4, 118.7, 124.2,
128.7, 128.9, 134.9, 144.3, 149.6. Anal. Calcd for C8H5N5S: C,
47.28; H, 2.48; N, 34.47. Found: C, 47.31; H, 2.44; N, 34.43.
Con clu sion
In conclusion, a new method for the preparation of
5-substituted 1,2,3-thiadiazoles is presented. The easy
availability of starting materials and mild reaction
conditions for both the cyclization and the O- and
S-nucleophilic substitution steps make this route a useful
complement to previous synthetic approaches.
Gen er a l P r oced u r e for th e P r ep a r a tion of Com p ou n d s
6 a n d 7. The corresponding 1-(1,2,3-thiadiazol-5-yl)-1H-1,2,3-
benzotriazole 4 (2 mmol), thiol, or phenol (2 mmol) and sodium
hydride (0.08 g, 2 mmol, 60% suspension in mineral oil) in DMF
(10 mL) were stirred at room temperature for 6 h (for 6) or
heated for 30 min at 110 °C (for 7). The reaction mixture was
diluted with chloroform (25 mL), poured into a separatory funnel,
and washed with water, saturated sodium hydrocarbonate
solution (2 × 20 mL), and water (3 times). After drying over
magnesium sulfate and evaporation of the solvent, the residue
was purified by column chromatography (silica gel, ethyl acetate/
hexanes 2:1 for 6 and ether/hexanes for 7 as the eluents) and
recrystallized from ethyl acetate (6a ,b ,e,f and 7a ,b) or ether
(6c,d and 7c).
Exp er im en ta l Section
Compounds 2a ,b were synthesized according to the published
procedure.13a Synthesis of 3b has been previously described.13e
2-(1H -1,2,3-Ben zot r ia zol-1-yl)-1-(2-t h ien yl)-1-et h a n on e
(2c). A mixture of 1-[(trimethylsilyl)methyl]-1H-1,2,3-benzo-
triazole (0.615 g, 3 mmol) and 2-thiophenecarbonyl chloride (0.32
mL, 3 mmol) was heated at 50 °C for 0.5 h, dissolved in
chloroform (20 mL), and refluxed for an additional 2 h. The
solvent was removed, and the obtained semisolid was recrystal-
lized from chloroform/hexanes: pale-yellow needles, yield 81%,
mp 121-122 °C; 1H NMR δ 5.98 (s, 2H), 7.18 (t, J ) 3.6 Hz,
1H), 7.35-7.39 (m, 1H), 7.46-7.47 (m, 2H), 7.75 (d, J ) 4.8 Hz,
1H), 7.90 (d, J ) 3.6 Hz, 1H), 8.06 (d, J ) 8.1 Hz, 1H); 13C NMR
δ 53.9, 109.6, 120.0, 124.1, 127.9, 128.7, 133.3, 133.6, 135.6,
140.3, 145.9, 183.4. Anal. Calcd for C12H9N5OS: C, 59.24; H,
3.74; N, 17.28. Found: C, 59.20; H, 3.67; N, 17.17.
2-(1H-1,2,3-Ben zotr iazol-1-yl)-1-(2-fu r yl)-1-eth an on e (2d).
1-[(Trimethylsilyl)methyl]-1H-1,2,3-benzotriazole (0.615 g, 3
mmol) was dissolved in 2-furoyl chloride (0.30 mL, 3 mmol) at
room temperature. The reaction mixture was heated at 50 °C
for 0.5 h, dissolved in chloroform (20 mL), and refluxed for an
additional 2 h. The solvent was removed, and the obtained
semisolid was recrystallized from chloroform/hexanes: white
microcrystals, yield 68%, mp 132-133 °C; 1H NMR δ 5.94 (s,
2H), 6.61 (d, J ) 2.4 Hz, 1H), 7.35-7.48 (m, 4H), 7.68 (s, 1H),
8.07 (d, J ) 8.1 Hz, 1H); 13C NMR δ 53.2, 109.5, 112.9, 119.0,
120.0, 124.0, 127.8, 133.7, 145.9, 147.5, 150.4, 179.6. Anal. Calcd
for C11H9N5O2: C, 63.43; H, 4.00; N, 18.50. Found: C, 63.04; H,
3.89; N, 18.48.
5-[(4-Met h ylp h en yl)t h io]-1,2,3-t h ia d ia zole (6a ). White
microcrystals, yield 42%, mp 152-153 °C; 1H NMR δ 2.40 (s,
3H), 7.25 (d, J ) 7.9 Hz, 2H), 7.47 (d, J ) 7.9 Hz, 2H), 8.29 (s,
1H); 13C NMR δ 21.3, 128.1, 130.9, 133.4, 140.8, 145.0, 156.5.
Anal. Calcd for C9H8N2S2: N, 12.38. Found: N, 12.30. Anal.
HRMS (FAB) Calcd for C9H8N2S2: 209.0207. Found: 209.0216.
5-P h en oxy-4-p h en yl-1,2,3-th ia d ia zole (7a ). White micro-
1
crystals (from acetone), yield 45%, mp 101-102 °C; H NMR δ
7.21-7.52 (m, 8H), 8.18 (d, J ) 7.0 Hz, 2H); 13C NMR δ 119.0,
127.3, 127.5, 129.1, 129.3, 130.6, 131.1, 146.8, 159.7, 172.3. Anal.
Calcd for C14H10N2OS: C, 66.12; H, 3.97; N, 11.02. Found: C,
65.98; H, 3.93; N, 10.95.
Su p p or tin g In for m a tion Ava ila ble: The procedures for
the preparation of compounds 2b, 3a -c, 4a -c, 6 and 7, and
their characterization data. This material is available free of
charge via the Internet at http://pubs.acs.org.
J O001692C