Cyclopropyl building blocks for organic synthesis. Part 22. Facile synthesis of stable analogs of 2-oxocyclobutanecarboxylates: 2-[(diphenylmethylene)amino]cyclobutenecarboxylates, derivatives and reactions

Versatile Access to 2‐Aminocyclobutene‐1‐carboxylic Acid Derivatives and Their Incorporation into Small Peptides

“…of lithium iodide and ethyldiisopropylamine (Hünig's base) at 0–20 °C for 3 d, methyl 2‐(benzylamino)cyclobut‐1‐ene‐1‐carboxylate ( 3a ) was isolated in 85 % yield. Apparently, the initially formed Michael adduct of 2a onto 1 , just like those of benzophenoneimine and secondary amines under certain conditions,9,10 immediately underwent rearrangement with ring enlargement and ensuing elimination of hydrogen chloride. As the multifunctional structural unit of 3a appeared to be interesting for incorporation into small peptides to be subjected to biological screening, p ‐chloro‐ ( 2b ), m ‐methoxy‐ ( 2c ) and o ‐methoxybenzylamine ( 2d ) were employed under the same conditions to furnish the correspondingly substituted products 3b – d in very good yields (Scheme and Table 1).…”

“…Whether this carries any advantage over previously developed routes16 is debatable. One advantage might be, that the new route is extendable to 3‐ and 4‐substituted analogues of 4a , which would be accessible from the correspondingly substituted 2‐chloro‐2‐cyclopropylideneacetates according to previously published procedures 9…”

“…Michael adducts of benzophenoneimine and secondary amines with 1 have been found to undergo facile transformations to protected 2‐aminocyclobutene‐1‐carboxylates under appropriate conditions 9,10. So far, the only two examples of sensitive adducts of primary amines to 1 have been prepared in moderate yields and employed in the synthesis of the first 2‐azaspiropentanecarboxylic acid derivatives 10.…”

Product Class 7: Imines

“…[44] A wide variety of nitriles has been used. [45,46] Scheme 5 Preparation of N-Unsubstituted Ketimines by Addition of an Organometallic Reagent to a Nitrile [41,43,45 [41] Et 2-pyridyl MgBr R 2 M (1 equiv), Et 2 O, reflux, 4 h 41 [41] 1-methylcyclopropyl Ph MgBr R 2 M (1 equiv), Et 2 O, rt, 2 h 76 [45] Ph t-Bu MgCl 2 M R 2 M/THF (1.10 equiv), CuBr (0.018 equiv), reflux, 14 h 95 [43] cyclopropyl Ph Li R 2 M (1.2 equiv), Et 2 O, rt, 5 min 70 [49] Organolithium reagents have also been employed. Examples are the addition of cyclopropyllithium compounds to cyclopropanecarbonitriles, [47] the addition of organolithium reagents to aziridine-2-carbonitriles, [48] the reaction of phenyllithium with cyclopropanecarbonitrile (see Scheme 5), [49] and the addition of 1-naphthyllithium to pivalonitrile.…”

A new cascade ring enlargement of isoxazolidines formed from 2-chloro-2-cyclopropylideneacetates

“…2 This process has been applied to the synthesis of natural and non-natural heterocyclic compounds and it has proved particularly useful for the synthesis of heterocycles with nitrogen at the bridgehead. 3 We now report a new selective thermal cascade ring enlargement process of 4-chloro substituted spiro[cyclopropane-1,5A-isoxazolidine]s, obtained by nitrone cycloaddition to methyl 2-chloro-2-cyclopropylideneacetate 1 4,5 and to methyl (Z)-2-chloro-2-spiropentanylideneacetate 2 6 which further expands the synthetic utility of this class of compounds.…”