Mechanism of a No-Metal-Added Heterocycloisomerization of Alkynylcyclopropylhydrazones: Synthesis of Cycloheptane-Fused Aminopyrroles Facilitated by Copper Salts at Trace Loadings

Abstract

A mechanistic study of a new heterocycloisomerization reaction that forms annulated aminopyrroles is presented. Density functional theory calculations and kinetic studies suggest the reaction is catalyzed by trace copper salts and that a Z- to E-hydrazone isomerization occurs through an enehydrazine intermediate before the rate-determining cyclization of the hydrazone onto the alkyne group. The aminopyrrole products are obtained in 36-93% isolated yield depending on the nature of the alkynyl substituent. A new automated sampling technique was developed to obtain robust mechanistic data.

Diastereoselective Synthesis of 1,3-Diyne-Tethered Trifluoromethylcyclopropanes through a Sulfur Ylide Mediated Cyclopropanation/DBU-Mediated Epimerization Sequence

“…■ EXPERIMENTAL SECTION General Information. 1 H NMR, 19 F NMR, and 13 C NMR spectra were recorded on an Bruker spectrometer operating at 500 (or 400) MHz, 470 (or 375) MHz, and 125 (or 100) MHz in CDCl 3 , respectively, and chemical shifts (δ) were reported in ppm relative to the center of the singlet at 7.26 ppm for CDCl 3 or downfield from internal tetramethylsilane. The following abbreviations were used to indicate the peak patterns: s = singlet, d = doublet, t = triplet, q = quartet.…”

“…According to the typical procedure, 1f (45 mg, 0.2 mmol) was transformed using 2a (61 mg, 0.3 mmol), MeCN (2 mL), and DBU (15 mg, 0.1 mmol). After purification over silica gel (petroleum ether/ethyl acetate 9:1− 5:1), the desired cyclopropane 3f was obtained (60 mg, 83%) as a pale yellow oil: 1 H NMR (500 MHz, CDCl 3 ) δ 7.96−7.92 (m, 2H), 7.38−7.37 (m, 2H), 3.26 (dd, J = 8.5, 7.3 Hz, 1H), 3.04−2.96 (m, 1H), 2.18−2.12 (m, 1H), 2.08 (s, 1H), 1.72 (dd, J = 8.5, 5.3 Hz, 1H), 1.46 (s, 6H), 1.29 (d, J = 6.9 Hz, 6H); 13 C{ 1 H}NMR (125 MHz, CDCl 3 ) δ 191.2, 155. 5,134.6,128.7,127.0,123.7 (q,J = 273.8 Hz),82.6,70.7,68.0,66.5,65.4,34.3,30.9,28.7,26.0 (q, J = 37.…”

“…According to the typical procedure, 1k (54 mg, 0.2 mmol) was transformed using 2a (61 mg, 0.3 mmol), MeCN (2 mL), and DBU (15 mg, 0.1 mmol). After purification over silica gel (petroleum ether/ethyl acetate 3:1− 2:1), the desired cyclopropane 3k was obtained (57 mg, 70%) as an off-white solid: mp 112−113 °C; 1 H NMR (400 MHz, CDCl 3 ) δ 7.24 (s, 2H), 3.93 (d, J = 1.7 Hz, 3H), 3.91 (s, 6H), 3.16 (dd, J = 8.3, 7.5 Hz, 1H), 2.13−2.09 (m, 1H), 2.00 (s, 1H), 1.72 (dd, J = 8.6, 5.5 Hz, 1H), 1.45 (s, 6H); 13 C{ 1 H}NMR (100 MHz, CDCl 3 ) δ 190.6, 153.3, 143.3, 131.9, 123.9 (q, J = 269.0 Hz), 106.0, 82.8, 70.6, 68.1, 66.5, 65.5, 61.1, 56.3, 30.9, 29.2, 25.7 (q, J = 38.0 Hz), 16.9; 19 (2,2-Dimethyl-2H-chromen-6-yl)(2-(5-hydroxy-5-methylhexa-1,3-diyn-1-yl)-2-(trifluoromethyl)cyclopropyl)methanone (3l). According to the typical procedure, 1l (52 mg, 0.2 mmol) was transformed using 2a (61 mg, 0.3 mmol), MeCN (2 mL), and DBU (15 mg, 0.1 mmol).…”

Skeletally Tunable Seven-Membered-Ring Fused Pyrroles

“…Pyrrole and its derivatives dominate synthetic and medicinal chemistry because of their bioactive and therapeutic properties. , The traditional Paal–Knorr and Hantzsch reactions and the more recent synthetic approaches tolerate various functionalized and substituted pyrroles through different starting materials. − However, the chemistry and applications of several pyrrole derivatives are underdeveloped because reliable synthetic protocols are not in place. Specifically, seven-membered-ring fused pyrroles (7-mrFPs) are a subclass of pyrroles that have received less attention, and only sporadic examples are known. , This limited number of 7-mrFPs can be synthesized via metal-catalyzed − or microwave- or thermal-assisted processes. , The former method encompasses the multistep formation of a structurally complex molecule, which, in turn, transforms to the fused derivative (Scheme A). From a biological and synthetic perspective, Pietruszka et al reported an enzymatic catalytic process that converts 7-mrFPs to the corresponding natural product, prodiginines, thus setting the stage for opening new research directions in 7-mrFP chemistry.…”

A General Copper-Catalyzed Synthesis of Ynamides from 1,2-Dichloroenamides

“…In certain cases, the amide-ynamide products were prone to hydration upon concentration, or during chromatography on neutralized silica gel, giving δ-ketoamides ( 18a / f ). This remarkable β-hydration of the ynamide may be explained by a 5- endo - dig cyclization to oxazolium ion 19 and subsequent hydrolysis, and was particularly apparent for N -phenylamide derivatives . In contrast, N -benzyl benzoyl ynamide 17e was comparatively stable (68%), as were amide-ynamides featuring bulky substituents ( 17b – d ) where adoption of the conformation required for cyclization to the oxazolium ion may be disfavored.…”