Convenient Access to Various 1‐Cyclopropylcyclopropane Derivatives

Abstract

Abstract1‐Bromo‐1‐cyclopropylcyclopropane (1), which is easily accessible in two steps from methyl cyclopropanecarboxylate, does not form a stable Grignard reagent upon reaction with elemental magnesium, yet it readily undergoes bromine/lithium exchange without rearrangement upon treatment with tert‐butyllithium in diethyl ether/pentane at –78 °C, and the resulting 1‐lithio‐1‐cyclopropylcyclopropane can be trapped with various electrophiles to give the correspondingly 1‐substituted bicyclopropyl derivatives 10 in yields ranging from 38 to over 90 % (13 examples). The (1‐cyclopropylcyclopropyl)boronate 10m, which is also obtained from the 1‐lithio derivative, has been subjected to Suzuki cross couplings with a number of aryl halides to furnish 1‐aryl‐1,1′‐bicyclopropyl compounds 11 (4 examples, 14–50 % yield), predominantly without rearrangement. Further transformations of 1‐cyclopropylcyclopropanecarbaldehyde (10e) have provided 2‐(1‐cyclopropylcyclopropyl)glycine (16), ethyl 3‐(1‐cyclopropylcyclopropyl)acrylate (17), and its cycloadducts with the nitrone 18 and cyclopentadiene 19, albeit the latter only in poor yield.

Diels–Alder Reactions for the Construction of Cyclopropylarenes

“…Cyclopropylacetylene (1) [6] is now commercially available in bulk quantities, [7] and (1-cyclopropylcyclopropyl)acetylene (2) as well as (2-cyclopropylcyclopropyl)acetylene (3) were easily prepared from the corresponding aldehydes 11 [8] and 14, respectively. Aldehydes 11 and 14 were obtained from bromides 10 [8] and 13, [9] respectively, by using a bromine-lithium exchange with tert-butyllithium and then trapping the corresponding cyclopropyllithium species with dimethylformamide (Scheme 1).…”

“…1-Cyclopropylcyclopropanecarbaldehyde [8] (8.07 g, 73 mmol) was added, and the reaction mixture was stirred for an additional 72 h. The reaction mixture was then poured into pentane (400 mL), and the insoluble materials were removed by filtration. The mixture was then stirred for 30 h at room temperature.…”

Convenient Synthesis of Ethenylcyclopropane and Some 2-Cyclopropylcyclopropane Derivatives¹

“…5,12 For example, dibromocarbene addition to 5 furnishes 2,2-dibromobicyclopropyl (6) 13 in 82% yield, 4b and the latter can be reduced to a mixture of the diastereomeric monobromides cis-7 and trans-7 (ratio 45:55) with ethylmagnesium bromide in the presence of titanium tetraisopropoxide (45% yield) 14 or tri-n-butyltin hydride (75% yield) (Scheme 2). 15 Bromine-lithium exchange on cis/trans-7 under conditions as previously published for 1-bromobicyclopropyl, 16 The most straightforward approach to a dibenzyl-protected 2-cyclopropylcyclopropanamine would be by direct (dibenzylamino)cyclopropanation of ethenylcyclopropane (5) with dibenzylformamide in the presence of methyltitanium triisopropoxide and cyclohexylmagnesium bromide, as previously developed for a wide range of alkenes. 17 However, several attempts to perform this conversion were not met with success.…”

Scalable synthesis of (1-cyclopropyl)cyclopropylamine hydrochloride

“…Preparation of the acid 2 from the known 1-bromo-1-cyclopropylcyclopropane ( 1 ) [ 21 – 22 ] according to the published procedure [ 17 ] was accomplished on a 100 g scale ( Scheme 1 ). However, the yield of the carboxylation on a scale of 12.4 mmol, 900 mmol and 1400 mmol, was 89, 64 and 62%, respectively.…”

“…Thus, this procedure was not easily scalable to 10–50 g quantities. To meet such demands, we have developed an alternative route to 4 from the easily available corresponding carboxylic acid 2 [ 17 – 18 ] by Curtius degradation [ 19 – 20 ].…”