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.
The reactions of esters 1 and dialkylamides 8 of 3-phosphorylpropionic acids with Grignard reagents 6 in the presence of titanium tetraisopropoxide 5 or methyltitanium triisopropoxide 11 give 1-substituted and 1,2-disubstituted phosphorylated cyclopropanols 7 and cyclopropylamines 12 in moderate to very good yields (37-71 and 39-86%, respectively). These useful transformations convincingly demonstrate the wide functional group compatibility and versatility of this new carbonyl group cyclopropanation.A wide variety of cyclopropane derivatives with hydroxy, amino and carboxyl functionalities show interesting and important biological effects. 1 The role of the phosphorus atom in providing vital functions in both animals and plants is also well known. 2-4 Although a variety of phosphoryl-substituted cyclopropane derivatives have been prepared, mostly by addition of carbenes to phosphorylsubstituted alkenes, 5 no convenient synthesis of any oligofunctional cyclopropyl compounds containing both the pharmacophoric phosphoryl and hydroxy or amino moieties has been reported.The reactions of alkanecarboxylates and N,Ndialkylalkanecarboxamides with Grignard reagents mediated by titanium tetraisopropoxide or methyltitanium triisopropoxide are simple and versatile ways to prepare 1-substituted and 1,2-disubstituted cyclopropanols 6 and cyclopropylamines. 7 Although it has long been known that phosphorus acid esters do react with Grignard reagents to yield tertiary phosphine oxides, 8,9 these reactions proceed much more slowly than those of a carbonyl or alkoxycarbonyl group. 10 It appeared, therefore, reasonable to expect that the carbonyl groups in the easily accessible methyl phosphorylalkanecarboxylates 1 and N,Ndimethylphosphorylalkanecarboxamides 8 would preferentially react with organometallic reagents such as the titanium intermediates formed from organomagnesium halides and Ti(OiPr) 4 [or MeTi(OiPr) 3 ] to give C-phosphorylated cyclopropanols 7 and cyclopropylamines 12, respectively.Indeed, when methyl 3-(diphenylphosphinoyl)propionate was treated with two equivalents of ethylmagnesium bromide (6a) in the presence of titanium tetraisopropoxide (5) according to the original protocol 6a,b or its catalytic version, 6c the 1-(2'-diphenylphosphinoylethyl)cyclopropanol 7aa was isolated, albeit in low to moderate yield only (Scheme 1). The modified procedure, 11 in which the Grignard reagent is generated in situ, gave even lower yields. Scheme 1Better results were obtained, however, when the solution of ethylmagnesium bromide 6a (2.2 equiv.) was added to the mixture of the ester 1a (1.0 equiv.) and Ti(OiPr) 4 5 (1.0 equiv.) in THF at 0°C within 10 min, then the reaction mixture was allowed to warm up to room temperature and stirred for an additional 4 h. Using this same procedure, various 1-substituted and 1,2-disubstituted phosphorylalkyl-substituted cyclopropanols 7aa-7cc could be prepared from the correspondingly substituted esters 1a-c and Grignard reagents 6a-c in moderate to good yields (37-71%) ( Table 1). The reactio...
Cyclopropylamines are successfully synthesized by the reaction of different substituted carboxamides with Grignard reagents in the presence of stoichiometric amounts of Me-Ti(O-iPr)3. The present new method is applicable to N,N-dialkyl-and N-alkyl--N-phosphorylalkyl-substituted carboxamides (I) as well as optically active substrates. Using substituted Grignard reagents (VI) or oxygen-functionalized Grignard reagents (VIII), products are obtained as a mixture of cis-and trans-isomers favoring trans-isomers albeit with moderate diastereoselectivity. Under similar conditions dicyclopropylamines (XIV) and cyclopropanol (XVI) are formed. Furthermore, the preparation of sterically demanding cyclopropylamine (XVIII) is achieved using Ti(O-iPr) 4 . For the asymmetric reaction of (I) with (VIa), a chiral titanium/ TADDOL complex is used. The method can also be employed for the synthesis of several bioactive compounds as is shown for spirocyclopropane (XXI) which is a cotinine derivative. -(DE MEIJERE*, A.; CHAPLINSKI, V.; WINSEL, H.; KORDES, M.; STECKER, B.; GAZIZOVA, V.; SAVCHENKO, A. I.; BOESE, R.; SCHILL, F.; Chem. Eur. J. 16 (2010) 46, 13862-13875, http://dx.
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