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Synlett

Volumn , Issue 4, 2008, Pages 600-604

An expedient synthesis of regioisomeric pyrazole-fused cycloalkanones

(1) Kennedy, Lawrence J a

a BRISTOL MYERS SQUIBB (United States)

Author keywords

Dione; Fused ring system; Hydrazine; Hydrazone; Pyrazole

Indexed keywords

ACETAL DERIVATIVE; CYCLOALKANONE; N,N DIMETHYLFORMAMIDE DIMETHYL ACETAL; PYRAZOLE; UNCLASSIFIED DRUG;

ARTICLE; CYCLIZATION; ONE POT SYNTHESIS;

EID: 40949162436 PISSN: 09365214 EISSN: None Source Type: Journal
DOI: 10.1055/s-2008-1032086 Document Type: Article

Times cited : (25)

References (35)

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- (1982) J. Heterocycl. Chem , vol.19 , pp. 1335
- Lemke, T.L.¹ Sawhney, K.N.²

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4
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- (2002) Synthesis , pp. 1669
- Molteni, V.¹ Hamilton, M.M.² Long, M.³ Crane, C.M.⁴ Termin, A.P.⁵ Wilson, D.A.⁶

5
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- also includes a one-pot procedure under microwave irradiation, (b) Touzot, A.; Soufyane, M.; Berber, H.; Toupet, L.; Mirand, C. J. Fluorine Chem. 2004, 125, 1299.
- also includes a one-pot procedure under microwave irradiation, (b) Touzot, A.; Soufyane, M.; Berber, H.; Toupet, L.; Mirand, C. J. Fluorine Chem. 2004, 125, 1299.

6
- 0034693209
- For related examples of pyrazoles from enaminones, see: a
- For related examples of pyrazoles from enaminones, see: (a) Olivera, R.; SanMartin, R.; Dominguez, E. J. Org. Chem. 2000, 65, 7010.
- (2000) J. Org. Chem , vol.65 , pp. 7010
- Olivera, R.¹ SanMartin, R.² Dominguez, E.³

7
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- (b) Ulrich, T.; Dersch, C. M.; Rothman, R. B.; Jacobson, A. E.; Rice, K. C. Bioorg. Med. Chem. Lett. 2001, 11, 2883.
- (2001) Bioorg. Med. Chem. Lett , vol.11 , pp. 2883
- Ulrich, T.¹ Dersch, C.M.² Rothman, R.B.³ Jacobson, A.E.⁴ Rice, K.C.⁵

8
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- (c) Olivera, R.; SanMartin, R.; Dominguez, E. Tetrahedron Lett. 2000, 41, 4353.
- (2000) Tetrahedron Lett , vol.41 , pp. 4353
- Olivera, R.¹ SanMartin, R.² Dominguez, E.³

9
- 13944250941
- For recent examples of enaminediones in the synthesis of pyrazoles of pharmaceutical relevance, see: a
- For recent examples of enaminediones in the synthesis of pyrazoles of pharmaceutical relevance, see: (a) D'Alessio, R.; Bargiotti, A.; Metz, S.; Brasca, G.; Cameron, A.; Ermoli, A.; Marsiglio, A.; Polucci, P.; Roletto, F.; Tibolla, M.; Vazquez, M. L.; Vulpetti, A.; Pevarello, P. Bioorg. Med. Chem. Lett. 2005, 15, 1315.
- (2005) Bioorg. Med. Chem. Lett , vol.15 , pp. 1315
- D'Alessio, R.¹ Bargiotti, A.² Metz, S.³ Brasca, G.⁴ Cameron, A.⁵ Ermoli, A.⁶ Marsiglio, A.⁷ Polucci, P.⁸ Roletto, F.⁹ Tibolla, M.¹⁰ Vazquez, M.L.¹¹ Vulpetti, A.¹² Pevarello, P.¹³

10
- 4544354404
- (b) Menozzi, G.; Merello, L.; Fossa, P.; Schenone, S.; Ranise, A.; Mosti, L.; Bondavalli, F.; Loddo, R.; Murgioni, C.; Mascia, V.; La Colla, P.; Tamburini, E. Bioorg. Med. Chem. 2004, 12, 5465.
- (2004) Bioorg. Med. Chem , vol.12 , pp. 5465
- Menozzi, G.¹ Merello, L.² Fossa, P.³ Schenone, S.⁴ Ranise, A.⁵ Mosti, L.⁶ Bondavalli, F.⁷ Loddo, R.⁸ Murgioni, C.⁹ Mascia, V.¹⁰ La Colla, P.¹¹ Tamburini, E.¹²

11
- 40949151642
- 3 or aryl), see: (a) Soufyane, M.; Mirand, C.; Levy, J. Tetrahedron Lett. 1993, 34, 7337.
- 3 or aryl), see: (a) Soufyane, M.; Mirand, C.; Levy, J. Tetrahedron Lett. 1993, 34, 7337.

12
- 0000911329
- (b) Okada, E.; Masuda, R. Heterocycles 1992, 34, 791.
- (1992) Heterocycles , vol.34 , pp. 791
- Okada, E.¹ Masuda, R.²

13
- 40949089075
- Also see ref. 2b
- (c) Also see ref. 2b.

14
- 33845626111
- Shi, Y.; Robl, J. A.; Kennedy, L. J.; Malley, M. F. Tetrahedron Lett. 2007, 48, 555.
- (2007) Tetrahedron Lett , vol.48 , pp. 555
- Shi, Y.¹ Robl, J.A.² Kennedy, L.J.³ Malley, M.F.⁴

15
- 40949147837
- Representative Experimental Procedure for Pyrazoles 2a-d A solution of 1,3-cycloheptanedione (15.1 g, 120 mmol) in DMFDMA (48 mL, 360 mmol) was heated to reflux for 3 h. The reaction mixture was concentrated at reduced pressure, then dried under high vacuum (3 d, <1 mmHg) until 1a formed as an amber solid (20.6 g, 95, 1H NMR (400 MHz, CDCl3, δ, 7.73 (s, 1 H, 3.31 (s, 3 H, 2.81 (s, 3 H, 2.62-2.58 (m, 4 H, 1.88-1.85 (m, 4 H, 13C NMR (100 MHz, CDCl3, δ, 200.57, 159.94, 113.20, 48,39, 43.61, 40.85, 22.58. HRMS: m/z calcd for C10H16NO2 [M, H, 182.1181; found: 182.1178. To a solution of 1a (507 mg, 2.8 mmol) in MeOH (22 mL) cooled to 0°C was added a solution of methylhydrazine (164 μL, 3.08 mmol) in MeOH (6 mL) over 5 min. After 1 h the reaction mixture was concentrated in vacuo (2a/3a, 6:1, Purification by flash chromatography SiO
- +: 227.1184; found: 227.1179.

16
- 40949127498
- The identical reaction at 21°C favored 2a (2a/3a = 6:1).
- The identical reaction at 21°C favored 2a (2a/3a = 6:1).

17
- 40949130566
- Regioisomer 2 was assigned based on the NOE observed between the R group and the C8 protons (Table 1).
- (a) Regioisomer 2 was assigned based on the NOE observed between the R group and the C8 protons (Table 1).

18
- 40949137050
- Pyrazole 2d was found to be identical to that previously described in the literature (see ref. 2a).
- (b) Pyrazole 2d was found to be identical to that previously described in the literature (see ref. 2a).

19
- 40949084826
- All reactions were performed on a 0.5 mmol scale (0.10 M) using 1.1 equiv hydrazine. Reaction conditions are not optimized,
- (a) All reactions were performed on a 0.5 mmol scale (0.10 M) using 1.1 equiv hydrazine. Reaction conditions are not optimized,

20
- 40949087318
- Ratio of 2/3 from HPLC analysis of crude reaction mixture.
- (b) Ratio of 2/3 from HPLC analysis of crude reaction mixture.

21
- 40949138352
- 3N (2.2 equiv).
- 3N (2.2 equiv).

22
- 40949123289
- A solution of the hydrazine was added to a refluxing solution of 1a for reactions run at elevated temperature.
- (d) A solution of the hydrazine was added to a refluxing solution of 1a for reactions run at elevated temperature.

23
- 40949086509
- 3N (2.2 equiv) also favored 2a (2a/3a = 5:1).
- 3N (2.2 equiv) also favored 2a (2a/3a = 5:1).

24
- 0002042235
- and pertinent references cited therein
- Kenny, P. W.; Robinson, M. J. T. Tetrahedron 1987, 43, 4043; and pertinent references cited therein.
- (1987) Tetrahedron , vol.43 , pp. 4043
- Kenny, P.W.¹ Robinson, M.J.T.²

25
- 0000110003
- The secondary amino group of methylhydrazine was determined experimentally to be the more nucleophilic site, see: Gregory, M. J, Bruice, T. C. J. Am. Chem. Soc. 1967, 89, 4400; and pertinent references cited therein
- The secondary amino group of methylhydrazine was determined experimentally to be the more nucleophilic site, see: Gregory, M. J.; Bruice, T. C. J. Am. Chem. Soc. 1967, 89, 4400; and pertinent references cited therein.

26
- 0026499445
- Martin, M. J.; Trudell, M. L.; Arauzo, H. D.; Allen, M. S.; LaLoggia, A. J.; Deng, L.; Schultz, C. A.; Tan, Y.-C.; Bi, Y.; Narayanan, K.; Dorn, L. J.; Koehler, K. F.; Skolnick, P.; Cook, J. M. J. Med. Chem. 1992, 35, 4105.
- (1992) J. Med. Chem , vol.35 , pp. 4105
- Martin, M.J.¹ Trudell, M.L.² Arauzo, H.D.³ Allen, M.S.⁴ LaLoggia, A.J.⁵ Deng, L.⁶ Schultz, C.A.⁷ Tan, Y.-C.⁸ Bi, Y.⁹ Narayanan, K.¹⁰ Dorn, L.J.¹¹ Koehler, K.F.¹² Skolnick, P.¹³ Cook, J.M.¹⁴

27
- 40949118171
- Representative Experimental Procedure for Pyrazoles 3a-h (a) Pyrazole 3h: To a solution of 1,3-cyclohexanedione (112 mg, 1.0 mmol) in THF (4 mL) under argon was added a solution of phenylhydrazine (99 μL, 1.0 mmol) in THF (1 mL) quickly. After 2 h, DMFDMA (402 μL, 3.00 mmol) was added quickly and the resulting solution heated to reflux. After 16 h the reaction mixture was concentrated in vacuo and purified via flash chromatography (12 g SiO2, 0-60% EtOAc-hexanes) to afford 3h as an off-white solid (106 mg, 50, 1H NMR (400 MHz, CDCl3, δ, 8.35 (s, 1 H, 7.69 (d, J, 7.7 Hz, 2 H, 7.48 (t, J, 8.0 Hz, 2 H, 7.36 (t, J, 7.4 Hz, 1 H, 2.95 (t, J, 6.1 Hz, 2 H, 2.57 (t, J, 6.6 Hz, 2 H, 2.19 (quin, J, 6.3 Hz, 2 H, 13C NMR 100 MHz, CDCl3, δ, 194.66, 158.08, 139.28, 129.59, 127.65, 126.66, 120.64, 119.73, 38.85, 23.49, 22.99. HRMS: m/z calcd
- +: 227.1184; found: 227.1179

28
- 40949097015
- The regioisomers of pyrazoles 3e-h were independently synthesized via ref. 1a or 2a.
- The regioisomers of pyrazoles 3e-h were independently synthesized via ref. 1a or 2a.

29
- 40949141975
- All reactions were performed on a 1.0 mmol scale (0.20 M) using 1.0 equiv hydrazine and 3.0 equiv DMFDMA. Reaction conditions are not optimized.
- (a) All reactions were performed on a 1.0 mmol scale (0.20 M) using 1.0 equiv hydrazine and 3.0 equiv DMFDMA. Reaction conditions are not optimized.

30
- 40949157634
- 3N (2.2 equiv) for 10 min in MeOH instead of THF due to solubility issues. Otherwise, reactions were run as described in the experimental section.
- 3N (2.2 equiv) for 10 min in MeOH instead of THF due to solubility issues. Otherwise, reactions were run as described in the experimental section.

31
- 0032358043
- 1,3-Cycloheptanedione was purchased from Sigma-Aldrich, or when unavailable, synthesized and distilled as described in: Ragan, J. A.; Makowski, T. W.; am Ende, D. J.; Clifford, P. J.; Young, G. R.; Conrad, A. K.; Eisenbeis, S. A. Org. Process Res. Dev. 1998, 2, 379.
- 1,3-Cycloheptanedione was purchased from Sigma-Aldrich, or when unavailable, synthesized and distilled as described in: Ragan, J. A.; Makowski, T. W.; am Ende, D. J.; Clifford, P. J.; Young, G. R.; Conrad, A. K.; Eisenbeis, S. A. Org. Process Res. Dev. 1998, 2, 379.

32
- 84981837662
- A similar preparation of 3-aryl pyrazoles (Scheme 3) from hydrazone 7 and substituted benzaldehydes has been reported: (a) Teuber, H. J.; Worbs, E.; Cornelius, D. Chem. Ber. 1968, 101, 3918.
- A similar preparation of 3-aryl pyrazoles (Scheme 3) from hydrazone 7 and substituted benzaldehydes has been reported: (a) Teuber, H. J.; Worbs, E.; Cornelius, D. Chem. Ber. 1968, 101, 3918.

33
- 32044448724
- (b) Strakova, I.; Strakovs, A.; Petrova, M. Chem. Heterocycl. Compd. (Engl. Transl.) 2005, 41, 1398.
- (2005) Chem. Heterocycl. Compd. (Engl. Transl.) , vol.41 , pp. 1398
- Strakova, I.¹ Strakovs, A.² Petrova, M.³

34
- 40949101874
- Pyrazole 3h has been previously synthesized by a different route: Bajnati, A.; Kokel, B.; Hubert-Habart, M. Bull. Soc. Chim. Fr. 1987, 2, 318.
- Pyrazole 3h has been previously synthesized by a different route: Bajnati, A.; Kokel, B.; Hubert-Habart, M. Bull. Soc. Chim. Fr. 1987, 2, 318.

35
- 40949130087
- Pyrazoles 2a and 3a are erroneously reported in Le Tourneau, M. E.; Peet, N. P. US Patent 4734430, 1998. In example 3 of the patent, pyrazoles 2a and 3a are reported as 5,6,7,8-tetrahydro-1- methyl-4(1H)-cycloheptapyrazolone and 5,6,7,8-tetrahydro-2-methyl- 4(2H)-cycloheptapyr-azolone, respectively. However, they should have been reported as 5,6,7,8-tetrahydro-1,3-dimethyl-4(1H)-cycloheptapyrazolone and 5,6,7,8-tetrahydro-2,3-dimethyl-4(2H)-cycloheptapyrazolone based on the chemistry described therein.
- Pyrazoles 2a and 3a are erroneously reported in Le Tourneau, M. E.; Peet, N. P. US Patent 4734430, 1998. In example 3 of the patent, pyrazoles 2a and 3a are reported as 5,6,7,8-tetrahydro-1- methyl-4(1H)-cycloheptapyrazolone and 5,6,7,8-tetrahydro-2-methyl- 4(2H)-cycloheptapyr-azolone, respectively. However, they should have been reported as 5,6,7,8-tetrahydro-1,3-dimethyl-4(1H)-cycloheptapyrazolone and 5,6,7,8-tetrahydro-2,3-dimethyl-4(2H)-cycloheptapyrazolone based on the chemistry described therein.

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