Rapid Access to 3‐Acyl‐5‐alkoxybutyrolactams Using Triplet and Singlet Oxygen

Abstract

A straightforward singlet oxygen‐initiated cascade reaction sequence for the synthesis of a variety of key 3‐acyl‐5‐alkoxybutyrolactams from furans has been developed.

Tandem Oxidative Ritter Reaction/Hydration/Aldol Condensation of α-Arylketones with Propiolonitriles for the Construction of 3-Acyl-3-pyrrolin-2-ones

“…5a Continuing with our interest in the oxidative Ritter reaction, in this work, we find that the CN group of the conjugated alkynyl nitrile is first involved in the oxidative Ritter reaction, followed by hydration of both the resulting nitrilium ion intermediate and the original alkynyl group to yield an amide and an enolized intermediate, respectively; sequential aldol cyclization 8 of the enolized intermediate with the carbonyl group of the substrate α-arylketone releases a dense functional 3-acyl-3pyrrolin-2-one. 9 This represents a novel tandem oxidative Ritter reaction/hydration/aldol condensation in which four bonds, one C−N bond, two C�O bonds, and one C�C bond, were constructed, and a 3-acyl-3-pyrrolin-2-one bearing an aza-quaternary center was simultaneously formed. This reaction not only enriches the types of tandem oxidative Ritter reactions involving conjugated alkynyl nitriles but also provides a direct and efficient approach toward the structurally complex and functionally diverse 3-acyl-3-pyrrolin-2-one skeleton, which is widely found in bioactive molecules 10 unique pharmaceutical activities, such as apoptosis inducement, 10a phosphodiesterase inhibition, 10b and anticancer, 10c antileukemic, and anti-inflammatory activities 10d (Figure 1).…”

“…Following the general procedure, 2-(4methoxyphenyl)cyclohexan-1-one (2g, 40.8 mg, 0.2 mmol) and phenylpropiolonitrile (3a, 127.1 mg, 1.0 mmol) were used at 60 °C for 40 min, recovering the unreacted nitrile 3a (92.0 mg, 72%) and affording the title compound 4ga as a white crystal (42.4 mg, 61%) upon using petroleum ether/EtOAc (9:1−2:1) as the eluent; mp = 173−174. .5, 170.7, 169.5, 159.4, 137.2, 133.8, 130.5, 129.7, 129.5, 128.6, 127.9, 114.7, 65.3, 55.4, 39.0, 28.3, 26.4, 22 23), 318 (7), 306 (9), 242 (100), 105 (42).…”

“…HRMS (ESI) m/z calcd for C 24 H 19 NO 2 Na [M + Na] + , 376.1308; found, 376.1304. MS (EI) m/z (%): 353 (9), 276 (4), 248 (30), 182 (7), 105 (100).…”

“…Following the general procedure, 2-phenylcyclohexanone (2a, 34.8 mg, 0.2 mmol) and 3-(3-bromophenyl)propiolonitrile (3e, 206.0 mg, 1.0 mmol) were used at 60 °C for 50 min, recovering the unreacted nitrile 3e (153.5 mg, 75%) and affording the title compound 4ae as a white crystal (61.0 mg, 77%) upon using petroleum ether/EtOAc (9:1−2:1) as the eluent; mp = 205.2−207.0 °C; 1 H NMR (400 MHz, CDCl 3 ) δ 8.09 (s, 1H), 7.84 (d,J = 7.6 Hz,1H),1H),4H),2H),7.19 (brs,1H),3.10 (d,J = 11.6 Hz,1H),2.86 (d,J = 12.8 Hz,1H),1H),1H),1H),1.70 (td,J = 13.2 Hz,3.6 Hz,1H),2H); 13 C{ 1 H} NMR (100 MHz, CDCl 3 ) δ 190. 1, 171.9, 169.2, 139.0, 137.6, 136.5, 132.4, 130.2, 130.1, 129.5, 128.49, 128.46, 126.5, 122.9, 65.9, 38.9, 28.4, 26.6, 22.0 43), 395 (43), 368 (9), 366 (9), 212 (100), 185 (24), 183 (24), 157 (9), 155 (11), 104 ( 16).…”

“…Following the general procedure, 2phenylcyclohexanone (2a, 34.8 mg, 0.2 mmol) and methyl 4-(cyanoethynyl)benzoate (3j, 185.2 mg, 1.0 mmol) were used at 60 °C for 30 min, and then the mixture was heated to 80 °C and stirred at 80 °C for 3 h, recovering the unreacted nitrile 3j (154.6 mg, 78%) and affording the title compound 4aj as a white crystal (51.5 mg, 69%) upon using petroleum ether/EtOAc (9:1−2:1) as the eluent; mp = 150.0−151.4 °C; 1 H NMR (400 MHz, CDCl 3 ) δ 8.14 (d,J = 8.4 Hz,2H),7.99 (d,J = 8.4 Hz,2H),3H),2H),6.95 (brs,1H),3.96 (s,3H),3.12 (d,J = 11.6 Hz, 1H), 2.90 (d, J = 13.2 Hz, 1H), 2.10−2.02 (m, 1H), 1.97 (brs, 1H), 1.83−1.70 (m, 2H), 1.53−1.45 (m, 2H); 13 C{ 1 H} NMR (100 MHz, CDCl 3 ) δ 190. 9, 172.3, 169.3, 166.4, 140.5, 137.6, 134.3, 130.3, 129.8, 129.6, 129.5, 128.6, 126.6, 65.9, 52.6, 39.0, 28.4, 26.6, 22 44), 346 (9), 334 (12), 212 (100), 163 (51), 104 (39).…”