Cyclopropyl Building Blocks for Organic Synthesis, Part 100. Advanced Syntheses of Cyclopropylideneacetates –Versatile Multifunctional Building Blocks for Organic Synthesis

Abstract

A well reproducible and inexpensive preparation of the cyclopropylideneacetates 2 ± 4 has been developed. The key intermediate 2-(1'-mesyloxycyclopropyl)acetic acid (8), produced either from methyl phenylacetate (1) or 3,3-dimethoxypropionate (5-Me) and 3,3-diethoxypropionate (5-Et) in a sequence of Kulinkovich reductive cyclopropanation, mesylation and oxidative cleavage or cleavage and oxidation, respectively, was either converted to the benzyl ester 11b, or chlorinated (brominated) via the in situ formed acid chloride. The a-chloro-12a and a-bromo ester 12b were dehydromesylated by treatment with triethylamine to furnish methyl 2-chloro-2-cyclopropylideneacetate (3-Me) and the 2-bromo analogue 4-Me with an overall yield of 68% (65%, 68%) and 52% (49%, 51%) respectively, starting from 1 (5-Me, 5-Et). The parent benzyl cyclopropylideneacetate 2-Bn was obtained by dehydromesylation of 11b with potassium t-butoxide in t-butyl methyl ether with an overall yield of 60% (57%, 9%) from 1 (5-Me, 5-Et).

Synthesis of Methylene‐ and Alkylidenecyclopropane Derivatives

“…On the other hand, almost quantitative yields were reported by these authors for the synthesis of methyl 2-chloro-2-cyclopropylidene-A C H T U N G T R E N N U N G acetate 92a and the 2-bromo analogue 92b through the dehydromesylation of the corresponding a-chloro ester 91a and a-bromo ester 91b mediated by TEA, respectively (Scheme 30). [73] A comparable excellent yield of 97% was reported by Kuethe et al for the dehydromesylation of the mesyl acid 93 by treatment with 45% KOH in water (Scheme 30). [74] The formed cyclopropenyl acid 94 was employed as the starting material to prepare highly reactive b,b-cyclopropyla,b-unsaturated N-acyloxazolidinones.…”

Practical Syntheses of Both Enantiomers of Cyclopropylglycine and of Methyl 2‐Cyclopropyl‐2‐N‐Boc‐iminoacetate

“…10 % potassium cyclopropanecarboxylate (due to partial decarboxylative overoxidation); yield: 75 g (ca. 74% based on KMnO 4 and taking in account, that KOH is formed as a byproduct according to the stoichiometry of the reaction); mp 241 8C (decomp. 2-Cyclopropyl-2-hydroxyiminoacetic Acid (7) [7] A mixture of the salt 6·KOH (66 g, ca.…”

“…The filtrate was acidified to pH 2 with 12 N HCl and extracted with CH 2 Cl 2 (5 60 mL). The combined organic extracts were dried over Na 2 SO 4 Reduction of the Oxime 7 with Zinc. Synthesis of Cyclopropylglycine [24] (rac-8) and Methyl 2-(N-tert-Butoxycarbonylamino)-2-cyclopropylacetate [Boc-cPrGly-OMe] (rac-9) [25] Activated zinc powder (see general remarks on reagents and chemicals, 45.4 g, 0.69 mol) was added in portions within 10 min to a solution of the oxime 7 (11.2 g, 86.7 mmol) in glacial AcOH (260 mL), maintaining the reaction temperature at 20 -30 8C.…”

“…The combined organic phases were dried over Na 2 SO 4 Methyl 2-(N-tert-Butoxycarbonyl-N-chloroamino)-cyclopropylacetate (12) [15] From 9 (57.4 g, 250.3 mmol), CaA C H T U N G T R E N N U N G (OCl) 2 (108.5 g, 759 mmol), and moist Al 2 O 3 (398 g) in CHCl 3 (700 mL), compound 12 was obtained according to the literature procedure [15] as a colorless oil; yield: 62.5 g (95%). …”

“…[2] They significantly excel simple acrylates in their reactivity towards nucleophiles and cyclophiles. [3] Alkyl 2-chloro-2-cyclopropylideneacetates, for which an advanced simple synthesis has recently been developed by our group, [4] have emerged as most prolific of this unrivalled family. Their high reactivity combined with their four compactly arranged functionalities make them suitable precursors to various valuable complex molecules such as natural product analogues, unusual heterocyclic compounds and conformationally rigid peptidomimetics.…”