An Expedient Synthesis of Regioisomeric Pyrazole-Fused Cycloalkanones

Abstract

Described herein is a novel one-pot procedure for the synthesis of pyrazoles through the in situ generation of a monohydrazone of cyclic 1,3-diones and subsequent cyclization with N,N-dimethylformamide dimethyl acetal. This route provides pyrazoles that have limited accessibility by other methods.

Key words

pyrazole - hydrazine - hydrazone - fused-ring system - dione

References and Notes

• 1a Schenone P. Mosti L. Menozzi G. J. Heterocycl. Chem.  1982,  19:  1355 
• 1b Lemke TL. Sawhney KN. J. Heterocycl. Chem.  1982,  19:  1335 
• 1c Dawood KM. Faraq AM. Kandeel ZE. J. Chem. Res., Synop.  1999,  88 
• 2a Molteni V. Hamilton MM. Long M. Crane CM. Termin AP. Wilson DA. Synthesis  2002,  1669 ; also includes a one-pot procedure under microwave irradiation
• 2b Touzot A. Soufyane M. Berber H. Toupet L. Mirand C. J. Fluorine Chem.  2004,  125:  1299 
• For related examples of pyrazoles from enaminones, see:
• 3a Olivera R. SanMartin R. Dominguez E. J. Org. Chem.  2000,  65:  7010 
• 3b Ulrich T. Dersch CM. Rothman RB. Jacobson AE. Rice KC. Bioorg. Med. Chem. Lett.  2001,  11:  2883 
• 3c Olivera R. SanMartin R. Dominguez E. Tetrahedron Lett.  2000,  41:  4353 
• For recent examples of enaminediones in the synthesis of pyrazoles of pharmaceutical relevance, see:
• 4a D’Alessio R. Bargiotti A. Metz S. Brasca G. Cameron A. Ermoli A. Marsiglio A. Polucci P. Roletto F. Tibolla M. Vazquez ML. Vulpetti A. Pevarello P. Bioorg. Med. Chem. Lett.  2005,  15:  1315 
• 4b 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 
• There are few reports of regioisomers obtained from phenylhydrazine. These examples can most likely be attributed to the electrophilicity of the ketone carbonyls (Scheme 1, X = CF₃, Y = CF₃ or aryl), see:
• 5a Soufyane M. Mirand C. Levy J. Tetrahedron Lett.  1993,  34:  7337 
• 5b Okada E. Masuda R. Heterocycles  1992,  34:  791 
• 5c Also see ref. 2b
• 6 Shi Y. Robl JA. Kennedy LJ. Malley MF. Tetrahedron Lett.  2007,  48:  555 
• 8The identical reaction at 21 °C favored 2a (2a/3a = 6:1).
• 9a

  Regioisomer 2 was assigned based on the NOE observed between the R group and the C8 protons (Table [1] ).

• 9b

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

• 10a

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

• 10b

  Ratio of 2/3 from HPLC analysis of crude reaction mixture.

• 10c

  Ethylhydrazine oxalate and benzylhydrazine·2HCl were pretreated with Et₃N (2.2 equiv).

• 10d

  A solution of the hydrazine was added to a refluxing solution of 1a for reactions run at elevated temperature.

• 12 Kenny PW. Robinson MJT. Tetrahedron  1987,  43:  4043 ; and pertinent references cited therein
• 13 The secondary amino group of methylhydrazine was determined experimentally to be the more nucleophilic site, see: Gregory MJ. Bruice TC. J. Am. Chem. Soc.  1967,  89:  4400 ; and pertinent references cited therein
• 14 Martin MJ. Trudell ML. Arauzo HD. Allen MS. LaLoggia AJ. Deng L. Schultz CA. Tan Y.-C. Bi Y. Narayanan K. Dorn LJ. Koehler KF. Skolnick P. Cook JM. J. Med. Chem.  1992,  35:  4105 
• Representative Experimental Procedure for Pyrazoles 3a-h
• 15a

  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 for C₁₃H₁₃N₂O [M + H]⁺: 213.1028; found: 213.1018.
  Pyrazole 3a (pale-yellow solid): ¹H NMR (400 MHz, CDCl₃): δ = 7.83 (s, 1 H), 3.85 (s, 3 H), 2.97-2.94 (m, 2 H), 2.70-2.67 (m, 2 H), 1.98-1.90 (m, 4 H). ¹³C NMR (100 MHz, CDCl₃): δ = 197.28, 153.75, 134.02, 122.83, 43.19, 39.03, 27.79, 25.34, 22.79. HRMS: m/z calcd for C₉H₁₃N₂O [M + H]⁺: 165.1028; found: 165.1023.
  Pyrazole 3b (pale-yellow viscous oil): ¹H NMR (400 MHz, CDCl₃): δ = 7.86 (s, 1 H), 4.11 (q, J = 7.3 Hz, 2 H), 2.99-2.94 (m, 2 H), 2.72-2.67 (m, 2 H), 2.01-1.88 (m, 4 H), 1.49 (t, J = 7.4 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 197.37, 153.45, 132.25, 122.46, 47.12, 43.18, 27.85, 25.32, 22.79, 15.07. HRMS: m/z calcd for C₁₀H₁₅N₂O [M + H]⁺: 179.1184; found: 179.1179.
  Pyrazole 3c (pale-yellow viscous oil): ¹H NMR (400 MHz, CDCl₃): δ = 7.81 (s, 1 H), 7.39-7.32 (m, 3 H), 7.29-7.23 (m, 2 H), 5.21 (s, 2 H), 3.00-2.94 (m, 2 H), 2.71-2.65 (m, 2 H), 2.00-1.86 (m, 4 H). ¹³C NMR (100 MHz, CDCl₃): δ = 197.37, 153.78, 134.93, 133.26, 128.96, 128.51, 128.18, 122.94, 56.20, 43.18, 27.82, 25.29, 22.73. HRMS: m/z calcd for C₁₅H₁₇N₂O [M + H]⁺: 241.1341; found: 241.1334.
  Pyrazole 3d (pale-yellow viscous oil): ¹H NMR (400 MHz, CDCl₃): δ = 8.39 (s, 1 H), 7.68 (d, J = 7.7 Hz, 2 H), 7.46 (t, J = 8.0 Hz, 2 H), 7.33 (t, J = 7.4 Hz, 1 H), 3.10-3.05 (m, 2 H), 2.78-2.73 (m, 2 H), 2.05-1.93 (m, 4 H). ¹³C NMR (100 MHz, CDCl₃): δ = 197.46, 154.67, 139.12, 130.42, 129.53, 127.35, 122.62, 119.44, 43.19, 27.82, 25.19, 22.71. HRMS: m/z calcd for C₁₄H₁₅N₂O [M + H]⁺: 227.1184; found: 227.1179.
  Pyrazole 3e (pale-yellow oily solid): ¹H NMR (400 MHz, CDCl₃): δ = 7.81 (s, 1 H), 3.91 (s, 3 H), 2.83 (t, J = 6.3 Hz, 2 H), 2.53-2.46 (m, 2 H), 2.12 (quin, J = 6.3 Hz, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 194.44, 157.32, 130.05, 119.25, 39.18, 38.67, 23.62, 22.79. HRMS: m/z calcd for C₈H₁₁N₂O [M + H]⁺: 151.0871; found: 151.0867.
  Pyrazole 3f (pale-yellow solid): ¹H NMR (400 MHz, CDCl₃): δ = 7.85 (s, 1 H), 4.17 (q, J = 7.2 Hz, 2 H), 2.84 (t, J = 6.3 Hz, 2 H), 2.52-2.46 (m, 2 H), 2.13 (quin, J = 6.3 Hz, 2 H), 1.51 (t, J = 7.4 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 194.54, 157.09, 128.43, 118.92, 47.38, 38.67, 23.65, 22.86, 15.17. HRMS: m/z calcd for C₉H₁₃N₂O [M + H]⁺: 165.1028; found: 165.1022.
  Pyrazole 3g (pale-yellow solid): ¹H NMR (400 MHz, CDCl₃): δ = 7.79 (s, 1 H), 7.39-7.32 (m, 3 H), 7.29-7.24 (m, 2 H), 5.26 (s, 2 H), 2.85 (t, J = 6.3 Hz, 2 H), 2.51-2.45 (m, 2 H), 2.12 (quin, J = 6.3 Hz, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 194.59, 157.37, 134.83, 129.44, 129.01, 128.58, 128.18, 119.37, 56.43, 38.72, 23.62, 22.89. HRMS: m/z calcd for C₁₄H₁₅N₂O [M + H]⁺: 227.1184; found: 227.1179

• 17a

  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.

• 17b

  Ethylhydrazine oxalate and benzylhydrazine dihydrochloride were pretreated with Et₃N (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.

• 18 1,3-Cycloheptanedione was purchased from Sigma-Aldrich, or when unavailable, synthesized and distilled as described in: Ragan JA. Makowski TW. am Ende DJ. Clifford PJ. Young GR. Conrad AK. Eisenbeis SA. Org. Process Res. Dev.  1998,  2:  379 
• A similar preparation of 3-aryl pyrazoles (Scheme 3) from hydrazone 7 and substituted benzaldehydes has been reported:
• 19a Teuber HJ. Worbs E. Cornelius D. Chem. Ber.  1968,  101:  3918 
• 19b Strakova I. Strakovs A. Petrova M. Chem. Heterocycl. Compd. (Engl. Transl.)  2005,  41:  1398 
• 20 Pyrazole 3h has been previously synthesized by a different route: Bajnati A. Kokel B. Hubert-Habart M. Bull. Soc. Chim. Fr.  1987,  2:  318 
• 21 Le Tourneau M. E, and Peet N. P. inventors; US Patent  4734430. Pyrazoles 2a and 3a are erroneously reported in . 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

7

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 (SiO₂, eluting with 10-20% acetone-CH₂Cl₂) afforded 2a as a pale-yellow solid (0.355 g, 77%) which was dissolved in warm EtOAc (3 mL), then hexanes (9 mL) was added, and the resulting solution was placed in a -20 °C freezer. The resulting solid was filtered, then dried in vacuo to afford 2a as small pale-yellow needles (0.278 g); 2a/3a >99:1 by HPLC analysis. ¹H NMR (400 MHz, CDCl₃): δ = 7.91 (s, 1 H), 3.79 (s, 3 H), 2.91 (t, J = 6.3 Hz, 2 H), 2.71 (t, J = 6.1 Hz, 2 H), 2.07-2.02 (m, 2 H), 1.95-1.90 (m, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 196.58, 145.01, 141.05, 122.69, 44.55, 37.08, 27.41, 25.72, 22.95. HRMS: m/z calcd for C₉H₁₃N₂O [M + H]⁺: 165.1028; found: 165.1029.
Pyrazole 2b: ¹H NMR (400 MHz, CDCl₃): δ = 7.93 (s, 1 H), 4.10 (q, J = 7.2 Hz, 2 H), 2.93 (t, J = 6.4 Hz, 2 H), 2.71 (t, J = 6.1 Hz, 2 H), 2.07-2.02 (m, 2 H), 1.95-1.90 (m, 2 H), 1.42 (t, J = 7.2 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 196.13, 143.79, 140.68, 122.78, 44.31, 43.83, 26.43, 25.26, 22.48, 14.89. HRMS: m/z calcd for C₁₀H₁₅N₂O [M + H]⁺: 179.1184; found: 179.1180.
Pyrazole 2c: ¹H NMR (400 MHz, CDCl₃): δ = 8.00 (s, 1 H), 7.39-7.25 (m, 3 H), 7.14-7.09 (m, 2 H), 5.30 (s, 2 H), 2.82 (t, J = 6.4 Hz, 2 H), 2.82 (t, J = 6.1 Hz, 2 H), 1.98-1.92 (m, 2 H), 1.90-1.84 (m, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 196,18, 144.75, 141.00, 135.77, 128.91, 122.97, 126.71, 122.82, 53.55, 43.99, 26.78, 25.24, 22.46. HRMS: m/z calcd for C₁₅H₁₇N₂O [M + H]⁺: 241.1341; found: 241.1344.
Pyrazole 2d: ¹H NMR (400 MHz, CDCl₃): δ = 8.10 (s, 1 H), 7.53-7.40 (m, 5 H), 2.96-2.93 (m, 2 H), 2.77-2.75 (m, 2 H), 1.98-1.95 (m, 4 H). ¹³C NMR (100 MHz, CDCl₃): δ = 196.26, 145.76, 141.61, 138.85, 129.24, 128.76, 125.67, 123.36, 43.35, 27.26, 25.39, 22.56. HRMS: m/z calcd for C₁₄H₁₅N₂O [M + H]⁺: 227.1184; found: 227.1179.

11

The identical reaction at 0 °C with methylhydrazine sulfate and Et₃N (2.2 equiv) also favored 2a (2a/3a = 5:1).

16

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