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Keywords: Palladium / Cyclopropanes / Metallacycles / Ligand effects / Solvent effects ortho-Halobenzamides such as compound 1a react in the presence of allene and base with catalytic amounts of palladium(0) complexes to form cyclopropanes such as 3a. This reaction is believed to proceed via an intermediate palladacyclobutane and is the first example of a noncarbon nucleophile attack on the centre carbon of an (η 3 -allyl)palladium[a] Molecular Innovation, Diversity and Automated Synthesis

Our recently reported titanium‐mediated transformation of N,N‐dialkylcarboxamides to cyclopropylamines has been applied to N,N‐dibenzyl‐2‐benzyloxyacetamide using a variety of alkylmagnesium bromides to yield 1‐(benzyloxymethyl)‐1‐(dibenzylamino)cyclopropane (15a, 48%) and 2‐substituted analogs 15b−f (33−48%). These have been transformed in just a few steps into N‐Boc‐protected methyl esters of 1‐aminocyclopropanecarboxylic acid (1, 29% overall), coronamic acid (2, 35%) and norcoronamic acid (21%), 2,3‐methanoglutamic acid (21g, 19%) and 2,3‐methanoornithine (21l, 12%). Similarly, the corresponding derivatives of 3,4‐methano‐γ‐aminobutyric acid (26, 23%) and 4‐spirocyclopropane‐γ‐butyrolactam (32, 44%) have been synthesized.

Thirty-three different N,N-dialkyl- and N-alkyl-N-phosphorylalkyl-substituted carboxamides 9-17 were treated with unsubstituted as well as with 2-alkyl-, 2,2-dialkyl-, and 3-alkenyl-substituted ethylmagnesium bromides 6 in the presence of stoichiometric amounts of titanium tetraisopropoxide or methyltitanium triisopropoxide to furnish substituted cyclopropylamines 20-25 in 20-98% yield, depending on the substituents with no (1:1) to excellent (>25:1) diastereoselectivities. Generally higher yields (up to 98%) of the cyclopropylamines 20-28 without loss of the diastereoselectivity were obtained with methyltitanium triisopropoxide as the titanium mediator. Under these conditions, even dioxolane-protected ketones and halogen-substituted and chiral as well as achiral alkyloxyalkyl-substituted carboxamides could be converted to the correspondingly substituted cyclopropylamines with unsubstituted as well as phenyl- and a variety of alkyl-substituted ethylmagnesium bromides in addition to numerous heteroatom-containing (e.g., halogen-, trityloxy-, tetrahydropyranyloxy-substituted) Grignard reagents (62 examples altogether). The transformation of N,N-diformylalkylamines 54 with ethylmagnesium bromide in the presence of methyltitanium triisopropoxide to N,N-dicyclopropyl-N-alkylamines 55 can be brought about in up to 82% yield (6 examples). An asymmetric variant of the titanium-mediated cyclopropanation of N,N-dialkylcarboxamides has been developed by applying chiral titanium mediators generated from stoichiometric amounts of titanium tetraisopropoxide and chiral diamino or diol ligands, respectively. The most efficient chiral mediators turned out to be titanium bistaddolates that provided the corresponding cyclopropylamines with enantiomeric excesses (ee) of up to 84%. Evaluation of several silyl-based additives revealed that the reaction can also efficiently be carried out with substoichiometric amounts (down to 25 mol%) of the titanium reagent, as long as 2-aryl- or 2-ethenyl-substituted ethylmagnesium halides are used and a concomitant slight decrease in yields is accepted. The newly developed methodology was successfully applied for the preparation of analogues with cyclopropylamine moieties of known drugs and natural products such as the nicotine metabolite (S)-Cotinine as well as the insecticides Dinotefuran and Imidacloprid.