PAPER
Thieno[3,2-c]pyrazole
99
concentrated. The resulting solid was crystallized (EtOAc) to give
tan needles; yield: 14.1 g (90%).
and concentrated to give a brown oil that was purified by chroma-
tography (silica gel, heptane–10% EtOAc to heptane–40% EtOAc).
Product-containing fractions were combined and concentrated to
give a pink solid; yield: 9 g (56%).
1
H NMR (300 MHz, CDCl ): δ = 7.02 (d, 1 H), 7.41 (d, 1 H), 7.79,
3
(s, 1 H), 10.0–10.6 (br s, 1 H).
1
H NMR (75.4 MHz, DMSO-d ): δ = 7.07 (d, 1 H), 7.56 (d, 1 H),
6
7
+
.71 + 8.00 (s + s, 0.6 H + 0.4 H), 12.98 + 13.30 (br s + br s, 0.6 H References
0.4 H). This spectrum showed that 2 exists as a mixture of the N1-
(1) Heterocycles, part 14. For part 13, see: Weintraub, P. M.
J. Heterocycl. Chem. 1993, 30, 1635.
H and N2-H tautomers in a ratio of 3:2.
LC/MS (ESI): m/z = 125.02.
(2) Current address: Retired.
Anal. Calcd for C H N S: C, 48.37; H 3.25; N, 22.56. Found: C,
(3) Current address: Chemical Research, Sanofi US, 153 2nd
Ave, Waltham, MA 02451, USA.
5
4
2
4
8.17; H, 3.20; N, 22.57.
Base Hydrolysis: A solution of 1-acetylthieno[3,2-c]pyrazole (16,
.75 g. 58.66 mmol) in MeOH (100 mL) was treated with KOH
3.29 g, 58.63 mmol) and the mixture was heated at 60 °C for 3 h.
(
4) Current address: 33 Casale Drive South, Warren, NJ 07059,
USA.
9
(
(5) (a) Görtz, R.; Appelboom, T. Int. J. Tissue React. 1985, 7,
263. (b) Vinge, E.; Bjorkman, S. B. Acta Pharmacol.
The cooled mixture was concentrated, and the residue was parti-
Toxicol. 1986, 59, 165.
tioned between EtOAc (150 mL) and H O (150 mL). The separated
2
(
(
6) (a) Pinto, D. J. P.; Orwat, M. J.; Koch, S.; Rossi, K. A.;
Alexander, R. M.; Smallwood, A.; Wong, P. C.; Rendina, A.
R.; Luettgen, J. M.; Knabb, R. M.; He, K.; Xin, B.; Wexler,
R. R.; Lam, P. Y. S. J. Med. Chem. 2007, 50, 5339.
(b) Martin, M. T.; Nutescu, E. A. Curr. Med. Res. Opin.
aqueous layer was extracted with more EtOAc (2 × 100 mL). The
organic layers were combined, washed with brine (20 mL), dried,
filtered through a plug of silica gel (10 g), and concentrated to give
a yellow solid (7.39 g). Crystallization (EtOAc–heptane) gave beige
needles; yield: 6.58 g (90%); mp 156–158 °C.
2
011, 27, 2123.
1
H NMR (300 MHz, DMSO-d ): δ = 7.11 (d, J = 5.4 Hz, 1 H), 7.60
6
7) Cui, J. J.; Tran-Dubé, M.; Shen, H.; Nambu, M.; Kung, P.-
P.; Pairish, M.; Jia, L.; Meng, J.; Funk, L.; Botrous, I.;
McTigue, M.; Grodsky, N.; Ryan, K.; Padrique, E.; Alton,
G.; Timofeevski, S.; Yamazaki, S.; Li, Q.; Zhou, H.;
Christensen, J.; Mroczkowski, B.; Bender, S.; Kania, R. S.;
Edwards, M. P. J. Med. Chem. 2011, 54, 6342.
(d, J = 5.4 Hz, 1 H), 7.77 (br s, 1 H), 12.99 (br s, 1 H).
LC/MS (ESI): m/z = 125.
MS (ESI): m/z = 125 [M + 1].
3-Bromo-2-thiophenecarboxaldehyde (23)
A solution of 3-bromothiophene (30.0 g, 184 mmol) in THF (200
mL) cooled to 0 °C was added slowly to a 2.0 M solution of LDA
in THF (92 mL, 184 mmol; Aldrich Chemicals). The orange solu-
tion was stirred at 0 °C for 30 min, then piperidine-1-carbaldehyde
(
8) Lin, Q.; Meloni, D.; Pan, Y.; Xia, M.; Rodgers, J.; Shepard,
S.; Li, M.; Galya, L.; Metcalf, B.; Yue, T.-Y.; Liu, P.; Zhou,
J. Org. Lett. 2009, 11, 1999.
(
9) Gronowitz, S.; Westerlund, C.; Hörnfeldt, A. B. Chem. Scr.
(
20.4 mL, 184 mmol) was added. The mixture was stirred for a fur-
1
977, 12, 1.
ther 1 h then diluted with Et O (300 mL), washed with brine
2
(10) Gronowitz, S.; Westerlund, C.; Hörnfeldt, A. B. Acta Chem.
Scand., Ser. B 1975, 29, 224.
11) Colburn, V. M.; Iddon, B.; Suschitzky, H.; Gallagher, P. T.
J. Chem. Soc., Chem. Commun. 1978, 453.
(100 mL), dried, and concentrated. The resulting orange oil was pu-
rified by chromatography (silica gel, heptane–EtOAc). Product-
containing fractions were combined and concentrated to give an or-
(
2
1
ange liquid; yield: 29.3 g (85%).
(
12) (a) Dell’Erba, C.; Novi, M.; Petrillo, G.; Tavani, C.
Tetrahedron 1992, 48, 325. (b) Dell’Erba, C.; Novi, M.;
Petrillo, G.; Tavani, C. Tetrahedron 1994, 50, 3529.
(c) Fusco, R.; Marchesini, A.; Sannicolo, F. J. Heterocycl.
Chem. 1987, 24, 773.
(13) (a) Bartsch, R. A.; Yang, I.-W. J. Heterocycl. Chem. 1984,
21, 1063. (b) Hoegerle, K.; L’Écuyer, P. Can. J. Chem.
1959, 37, 2068. (c) Benchidmi, M.; Bouchet, P.; Lazaro, R.
J. Heterocycl. Chem. 1979, 16, 1599. (d) Wrzeciono, U.;
Dudinska-Usarewicz, J.; Majewska, K.; Stasieczko-
Rydelkiewicz, I.; Stefanowicz, J.; Nieweglowska, W.
Pharmazie 1985, 40, 105. (e) Barbet, O.; Minjat, M.; Petavy,
A.-F.; Paris, J. Eur. J. Med. Chem. 1986, 21, 359.
(
1Z)-1-[(3-Bromo-2-thienyl)methylene]-2-(diphenylmeth-
ylene)hydrazine (24)
A mixture of 3-bromo-2-thiophenecarboxaldehyde (23; 29.3 g, 153
mmol) and benzophenone hydrazone (26; 33.1 g, 168 mmol) in
EtOH (200 mL) was stirred at 70 °C for 20 h. The mixture was
cooled to r.t. and the solids were collected by filtration to give a yel-
low solid (42.7 g). The filtrate was concentrated and the resulting
slurry was triturated with EtOH to give additional 24 (4 g); total
yield: 46.7 g (82%).
LC/MS (ESI): m/z = 369.00 [M + 1].
(
2Z)-1-(Diphenylmethylene)-2-({3-[2-(diphenylmethylene)hy-
drazino]-2-thienyl}methylene)hydrazine (25)
(f) Kazimierczuk, Z.; Lönnberg, H.; Vilpo, J.; Pfleiderer, W.
Nucleosides Nucleotides 1989, 8, 599. (g) Sun, J.-H.;
Teleha, C. A.; Yan, J.-S.; Rodgers, J. D.; Nugiel, D. A.
J. Org. Chem. 1997, 62, 5627. (h) Arnautu, A.; Collot, V.;
Ros, J. C.; Alayrac, C.; Witulski, B.; Rault, S. Tetrahedron
Lett. 2002, 43, 2695. (i) Forbes, I. T.; Douglas, S.; Gribble,
A. D.; Ife, R. J.; Lightfoot, A. P.; Garner, A. E.; Riley, G. J.;
Jeffrey, P.; Stevens, A. J.; Stean, T. O.; Thomas, D. R.
Bioorg. Med. Chem. Lett. 2002, 12, 3341.
A mixture of azine 24 (46.6 g, 126 mmol), benzophenone hydra-
zone (26; 29.7 g, 151 mmol), Pd(OAc) (2.12 g, 9.5 mmol), Cs CO
2
2
3
(69.8 g, 214 mmol), dppf (10.5 g, 18.9 mmol) and toluene was
stirred at 100 °C for 24 h, then cooled to r.t. The solids were re-
moved by filtration and the solvent was evaporated to give the crude
product that was used in the next reaction.
LC/MS (ESI): m/z = 485 [M + 1].
1
H-Thieno[3,2-c]pyrazole (2) from Hydrazine 25
(14) (a) Jacobson, P.; Huber, L. Ber. Dtsch. Chem. Ges. 1908, 41,
The crude hydrazine 25 was dissolved in EtOH (500 mL) and the
660. (b) Huisgen, R.; Nakaten, H. Justus Liebigs Ann. Chem.
solution was treated with concd. aq HCl (250 mL). The mixture was
1
954, 586, 84. (c) Ruchardt, C.; Hassmann, V. Liebigs Ann.
heated at 80 °C for 3 h then cooled. H O (1.5 L) and EtOAc (500
2
Chem. 1980, 908.
mL) were added, followed by Na CO until the pH was neutral. The
2
3
(
15) (a) Ockenen, D. W.; Schofield, K. J. Chem. Soc. 1953, 1915.
aqueous layer was separated and extracted with EtOAc
3 × 250 mL). The organic layers were combined, dried, filtered,
(b) Huisgen, R.; Bast, K. Org. Synth. Coll. Vol. V; Wiley:
(
London, 1973, 650. (c) Ruchardt, C.; Hassmann, V.
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Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 96–100