Reaction of 2-Alkynylbenzoyl Cyanides with Carboxylic Acids Producing Functionalized Indenones

Abstract

2-Alkynylbenzoyl cyanides react with carboxylic acids via a cyclic allene intermediate to produce 2-acylamino-3-acylindenones in good yield. The high reactivity of the 2-acylamino moiety of the product for a substitution reaction can be utilized for the synthesis of fused heterocycles.

Key words

cyclization - carboxylic acids - heterocycles - benzoyl cyanides - indenones

References and Notes

• For attack of carbon nucleophiles to the cyano group, see:
• 1a Veronese AC. Callegari R. Basato M. Valle G. J. Chem. Soc., Perkin Trans. 1  1994,  13:  1779 
• 1b Veronese AC. Gandolfi V. Basato M. Corain B. J. Chem. Res., Synop.  1988,  8:  246 
• 1c Basato M. Corain B. Cofler M. Veronese AC. Zanotti G. J. Chem. Soc., Chem. Commun.  1984,  23:  1593 
• For recent examples of attack of carbon nucleophiles to the carbonyl group, see:
• 2a Ikeda Z. Hirayama T. Matsubara S. Angew. Chem. Int. Ed.  2006,  45:  8200 
• 2b Shen Z. Li B. Wang L. Zhang Y. Tetrahedron Lett.  2005,  46:  8785 
• 2c Zhou S. Yan B. Liu Y. J. Org. Chem.  2005,  70:  4006 
• 2d Duplais C. Bures F. Sapountzis I. Korn TJ. Cahiez G. Knochel P. Angew. Chem. Int. Ed.  2004,  43:  2968 
• 2e Gohain M. Gogoi BJ. Prajapati D. Sandhu JS. New J. Chem.  2003,  27:  1038 
• 2f Wiles C. Watts P. Haswell SJ. Pombo-Villar E. Chem. Commun.  2002,  1034 
• 2g Wiles C. Watts P. Haswell SJ. Pombo-Villar E. Tetrahedron Lett.  2002,  43:  2945 
• 2h Yoo BW. Hwang SK. Kim DY. Choi JW. Ko JJ. Choi KI. Kim JH. Tetrahedron Lett.  2002,  43:  4813 
• 3 Shimizu H. Murakami M. Chem. Commun.  2007,  2855 
• 5 Normant JF. Piechucky C. Bull. Soc. Chem. Fr.  1972,  6:  2402 
• 8 Compound 2f was prepared by the SnCl₄-catalyzed reaction of acid chloride with TMSCN: Olah GA. Arvanaghi M. Prakash GKS. Synthesis  1983,  636 
• For cyclocondensation of β-enamino carbonyl compounds with amidines and hydrazines, see:
• 11a Bredereck H. Sell R. Effenberger F. Chem. Ber.  1964,  97:  3407 
• 11b Kvita V. Synthesis  1986,  786 
• 11c Bredereck H. Herlinger H. Schweizer E. Chem. Ber.  1960,  93:  1208 
• 11d Plath P. Rohr W. Synthesis  1982,  318 
• 14 For selective formation of N-substituted pyrazoles from N-methoxy-N-methyl-β-enaminoketoesters, see: Persson T. Nielsen J. Org. Lett.  2006,  8:  3219 

4

Representative Procedure for the Preparation of 2-Alkynylbenzoyl Cyanide 2 Oxalyl chloride (1.60 mL, 18.7 mmol) was added dropwise to a mixture of 2-(1-hexyn-1-yl) benzoic acid (1a, 3.43 g, 17.0 mmol) and DMF (2 drops) in CH₂Cl₂ (35 mL). The reaction mixture was stirred for 1.5 h at r.t. Then, volatile components were removed in vacuo to give crude acid chloride. A solution of the crude acid chloride in MeCN (20 mL) was added to a stirred suspension of CuCN (3.00 g, 33.5 mmol) in MeCN (20 mL) at r.t. After the mixture was stirred for 1 h at 70 ˚C, the resulting clear solution was cooled to r.t. and concentrated in vacuo. The residue was washed with Et₂O, filtrated and concentrated in vacuo again. The residue was purified rapidly by silica gel column chromatography (hexane and then hexane-Et₂O, 50:1) to afford 2-(1-hexyn-1-yl)benzoyl cyanide (2a) (2.83 g, 79%). ^¹H NMR (300 MHz, CDCl₃): δ = 0.96 (3 H, t, J = 7.2 Hz), 1.42-1.58 (2 H, m), 1.58-1.72 (2 H, m), 2.51 (2 H, t, J = 7.2 Hz), 7.42-7.52 (1 H, m), 7.54-7.67 (2 H, m), 8.05-8.12 (1 H, m). ^¹³C NMR (75 MHz, CDCl₃): δ = 13.8, 19.8, 22.2, 30.4, 77.9, 101.6, 113.5, 125.9, 127.9, 132.6, 133.7, 135.2 (two signals overlapping), 166.9. IR (neat): 2959, 2220, 1682, 1663, 1482, 1231 cm^-¹. HRMS (EI): m/z calcd for C₁₄H₁₃ON [M⁺]: 211.0997; found: 211.0997. Compounds 2b-e were prepared by a similar procedure.

6

No reaction occurred at room temperature.

7

Representative Procedure for the Cyclization Reaction of 2 with 4 A mixture of 2-(1-hexyn-1-yl)benzoyl cyanide (2a, 42.3 mg, 0.20 mmol) and benzoic acid (4a, 48.8 mg, 0.40 mmol) in p-xylene (1.0 mL) was stirred at 140 ˚C for 24 h under an argon atmosphere, and then the solvent was evaporated in vacuo. The residue was purified by preparative thin-layer chromatography (toluene-EtOAc, 10:1) to afford 2-benzoylamino-3-pentanoylindenone 5aa (55.9 mg, 84%). ^¹H NMR (300 MHz, CDCl₃): δ = 0.91 (3 H, t, J = 7.2 Hz), 1.38 (2 H, pseudo sext, J = 7.5 Hz), 1.74 (2 H, pseudo quin, J = 7.5 Hz), 2.75 (2 H, t, J = 7.5 Hz), 7.14 (2 H, t, J = 7.5 Hz), 7.35 (1 H, dt, J = 1.2, 7.5 Hz), 7.44-7.56 (3 H, m), 7.56-7.64 (1 H, m), 7.87-7.94 (2 H, m), 8.40 (1 H, br s). ^¹³C NMR (75 MHz, CDCl₃): δ = 14.1, 22.6, 25.8, 44.1, 121.9, 124.4, 126.8, 127.3, 127.6, 127.9, 129.1, 132.5, 132.7, 133.0, 135.6, 145.5, 164.9, 193.0, 201.1. IR (KBr): 3312, 2959, 1726, 1678, 1662, 1512, 1277 cm^-¹. HRMS (EI): m/z calcd for C₂₁H₁₉O₃N [M⁺]: 333.1365; found: 333.1361.

9

When 5ai was exposed to same reaction conditions, a deuterium was incorporated only in 17% at the α-position of the carbonyl group.

10

No reaction occurred with secondary amines such as a piperidine and N-benzylmethylamine.

12

Representative Procedure for the Synthesis of Indenopyrimidine A mixture of 5ai (27.2 mg, 0.10 mmol) and benzamidine hydrochloride (8a, 38.5 mg, 0.20 mmol) in pyridine (1.0 mL) was stirred at 100 ˚C for 24 h under an argon atmosphere, and then the reaction mixture was cooled and diluted with EtOAc (5 mL) and H₂O (5 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (3 × 3 mL). The combined extracts were washed with H₂O and brine, and dried over MgSO₄. The solvent was evaporated in vacuo. The residue was purified by preparative thin-layer chromatography (toluene-EtOAc, 20:1) to afford 4-butyl-2-phenyl-9H-indeno[2,1-d]pyrimidin-9-one (9aia, 28.1 mg, 89%). ^¹H NMR (300 MHz, CDCl₃): δ = 1.04 (3 H, t, J = 7.5 Hz), 1.45-1.65 (2 H, m), 1.92 (2 H, quin, J = 7.7 Hz), 3.13 (2 H, t, J = 7.5 Hz), 7.33-7.47 (1 H, m), 7.47-7.57 (3 H, m), 7.57-7.69 (2 H, m), 7.82 (1 H, d, J = 7.5 Hz), 8.47-8.62 (2 H, m). ^¹³C NMR (75 MHz, CDCl₃): δ = 14.2, 22.8, 29.4, 35.9, 123.7, 125.6, 128.6, 128.7, 129.7, 131.17, 131.23, 131.9, 136.3, 137.1, 141.8, 160.3, 165.3, 165.5, 193.4. IR (KBr): 2959, 1730, 1572, 1458, 1390, 1186 cm^-¹. HRMS (EI): m/z calcd for C₂₁H₁₈ON₂ [M⁺]: 314.1419; found: 314.1422.

13

Representative Procedure for the Synthesis of Indenopyrazole
To a stirred solution of 5ai (27.2 mg, 0.10 mmol) in 1,4-dioxane (0.5 mL) under an argon atmosphere was added a solution of methylhydrazine (5.5 mg, 0.12 mmol) in 1,4-dioxane (0.5 mL) at 60 ˚C over 5 min. After being stirred for 3 h, the reaction mixture was cooled and diluted with EtOAc (5 mL) and H₂O (5 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (4 × 3 mL). The combined extracts were washed with H₂O and brine, and dried over MgSO₄. The solvent was evaporated in vacuo. The residue was purified by preparative thin-layer chromatography (CHCl₃-EtOAc, 10:1) to afford 3-butyl-2-methyl-8H-indeno[2,1-c]pyrazol-8-one (12ai, 12.4 mg, 52%). ^¹H NMR (300 MHz, CDCl₃): δ = 0.97 (3 H, t, J = 7.3 Hz), 1.39-1.49 (2 H, m), 1.63-1.73 (2 H, m), 2.74 (2 H, t, J = 7.5 Hz), 3.83 (3 H, s), 7.09-7.14 (2 H, m), 7.35 (1 H, dt, J = 1.1, 7.5 Hz), 7.52 (1 H, dd, J = 1.3, 7.7 Hz). ^¹³C NMR (75 MHz, CDCl₃): δ = 13.8, 22.3, 25.0, 30.7, 37.1, 120.2, 124.7, 126.8, 129.6, 134.4, 137.5, 138.0, 138.4, 152.3, 186.2. IR (KBr): 2939, 1714, 1603, 1491, 1317, 1169 cm^-¹. HRMS (EI): m/z calcd for C₁₅H₁₆ON₂ [M⁺]: 240.1263; found: 240.1260. The position of the methyl group was identified by NOE measurement.