2-(Bicyclopropylidenyl)- and 2-(trans-2′-Cyclopropylcyclopropyl)-4,4,5,5-tetramethyl-1,3-dioxa-2-borolane and Their Palladium-Catalyzed Cross-Coupling Reactions

Abstract

The bicyclopropylidenylboronate 2 was prepared in 76% yield from lithiated bicyclopropylidene (1) and 2-isopropyloxy-4,4,5,5-tetramethyl-1,3-dioxa-2-borolane. Birch reduction of 2 furnished 2-(trans-2'-cyclopropylcyclopropyl)-4,4,5,5-tetramethyl-1,3-dioxa-2-borolane (3) in 79% yield. Under palladium catalysis, the latter was successfully coupled with a variety of aryl and alkenyl halides to give the corresponding (2'-cyclopropylcyclopropyl)-substituted arene 6 (52-75% yield) and alkene derivatives 11a,b (48-59%), respectively. Twofold and even threefold couplings of 2 with 1,2-dibromo-and 1,3,5-tribromobenzene were also successful. trans-3-(2'-Cyclopropylcyclopropyl)acrylic acid 12 could easily be obtained from 11a in 74% yield.The palladium-catalyzed cross coupling between various organylboronates and an alkenyl or an aryl halide (Suzuki coupling) has emerged as a powerful general method for C-C-bond formation. 1 Being largely unaffected by the presence of water, and compatible with a broad range of functional groups, the Suzuki reaction has frequently been applied in the synthesis of natural products. 1,2 This cross coupling can favorably be carried out with cyclopropyl derivatives, as demonstrated by the successful coupling of cyclopropylboronates with aryl halides 3 and that of iodocyclopropanes with alkenyl, aryl and cyclopropylboronates, 4 including one case of a bicyclopropylboronate. 4b Some coupling reactions even work with aryl or alkenyl halides and cyclopropylboronic acids, which were obtained by cyclopropanating alkenylboronic acids. 5 The key step in all previously reported syntheses of bicyclopropyl derivatives was a cyclopropanation of a cyclopropylalkenyl derivative. 6 We want to report on a new simple diastereoselective synthesis of a trans-2-cyclopropylcyclopropylboronate and its palladium-catalyzed coupling with various aryl and alkenyl halides.Bicyclopropylidene (1), a readily available C 6 -building block containing two cyclopropane rings, 7 has been shown to be easily transformed to a variety of functionally monosubstituted derivatives by deprotonation with n-butyllithium in THF at 0°C followed by electrophilic substitution with appropriate reagents. 8,9 Thus, reaction of lithiobicyclopropylidene with appropriate trialkylboronates should lead to bicyclopropylidenylboronates, and indeed, treatment of lithiated bicyclopropylidene with 2-isopropyloxy-4,4,5,5-tetramethyl-1,3-dioxa-2-borolane gave the air-stable borolane 2 in 76% yield after chromatographic purification on silica gel. Scheme 1 A: 1) nBuLi, THF, -30°C; 2) 2-isopropyloxy-4,4,5,5-tetramethyl-1,3-dioxa-2-borolane, THF, -78®20°C, 24 h; 3) NH 4 Cl, H 2 O. -B: 1) Li, NH 3 (lq.), -78°C; 2) MeOH (3 equiv.); 3) 2 N HCl (3.5 equiv.). The trans-diastereoselective reduction of the double bond in the bicyclopropylidenylboronate 2 was easily accomplished under Birch conditions with lithium in liquid ammonia at -78°C, as reported for other bicyclopropylidene derivatives by de Meijere et al., 9 to give 2-(trans-2'-cyclopropylcyclopropyl)-4,4,...

Convenient Access to Various 1‐Cyclopropylcyclopropane Derivatives

“…[16] However, 10m is a tertiary and at the same time neopentyl-type alkylboronate, and couplings of such substrates are unknown. Yet, when 10m and phenyl iodide were subjected to typical Suzuki coupling conditions, 1-phenyl-1,1Ј-bicyclopropyl (11n) was obtained in 50 % yield (Scheme 3).…”

Diels–Alder Reactions for the Construction of Cyclopropylarenes

“…1 [21] 4-(Bicycloprop-2-yl)-1,2-dimethylbenzene (21b): After purification by column chromatography (pentane), the product (69 mg, 75 %) was obtained in a diastereomeric ratio of 47:53 as a colorless oil. 1 [21] 4-(Bicycloprop-2-yl)-1,2-dimethylbenzene (21b): After purification by column chromatography (pentane), the product (69 mg, 75 %) was obtained in a diastereomeric ratio of 47:53 as a colorless oil.…”

“…1 [21] 4-(Bicycloprop-2-yl)-1,2-dimethylbenzene (21b): After purification by column chromatography (pentane), the product (69 mg, 75 %) was obtained in a diastereomeric ratio of 47:53 as a colorless oil. [21] 1-(Bicycloprop-2-yl)-4-methoxybenzene (21c): After purification by column chromatography (pentane/methyl tert-butyl ether, 50:1), the product (21c/22c, Ͼ95:5, 58 mg, 60 %) was obtained in a diastereomeric ratio of 37:63 as a colorless oil. [21] 1-(Bicycloprop-2-yl)-4-methoxybenzene (21c): After purification by column chromatography (pentane/methyl tert-butyl ether, 50:1), the product (21c/22c, Ͼ95:5, 58 mg, 60 %) was obtained in a diastereomeric ratio of 37:63 as a colorless oil.…”

Arylcyclopropanes: Properties, Synthesis and Use in Medicinal Chemistry

“…100 The bicyclopropylideneborolane 160, prepared from 158, was found to be unreactive under palladiumcatalyzed coupling conditions (possibly due to the olefin binding to the palladium) and was consequently transformed into its reduced trans-2-cyclopropylcyclopropylborolane 161 counterpart in preparation for the cross-coupling step.…”