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DOI: 10.1055/s-2008-1078501
Reaction of 2-Alkynylbenzoyl Cyanides with Carboxylic Acids Producing Functionalized Indenones
Publication History
Publication Date:
19 June 2008 (online)
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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
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References and Notes
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.
6No reaction occurred at room temperature.
7Representative 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.
9When 5ai was exposed to same reaction conditions, a deuterium was incorporated only in 17% at the α-position of the carbonyl group.
10No reaction occurred with secondary amines such as a piperidine and N-benzylmethylamine.
12Representative 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.