Facile Preparation of (Phosphorylalkyl)-Functionalized Cyclopropanols and Cyclopropylamines

Abstract

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...

Advanced Procedure for the Preparation of cis‐1,2‐Dialkylcyclopropanols – Modified Ate Complex Mechanism for Titanium‐Mediated Cyclopropanation of Carboxylic Esters with Grignard Reagents

“…Methyltitanium triisopropoxide had successfully been used earlier for the cyclopropanation of esters and N,N-dialkylcarboxamides with Grignard reagents. [14][15][16] To avoid an additional methyltitanium triisopropoxide preparation procedure, we studied the possibility of employing the sequential addition of organomagnesium reagents to a mixture of titanium(IV) isopropoxide and a carboxylic ester under conventional conditions. Addition of n-propylmagnesium bromide (1 equiv.)…”

Synthesis by Reduction

“…[226] A further improvement in the yield can be achieved by adding the Grignard reagent to the mixture of the amide and the titanium reagent at room temperature instead of at a low temperature. [227] In the second strategy, the initially formed titanacyclopropane (e.g. 137) is subjected to a ligand exchange with an external alkene 138 (Scheme 36): this gives a new titanacyclopropane 139 that reacts with an amide to give the desired cyclopropanamine 140.…”

Titanium-mediated syntheses of cyclopropylamines

“…As reported by the same group, this efficient transformation can also be carried out with substoichiometric amounts of Ti(OiPr) 4 (5-10 mol%) [57,58]. Four years later, development of a very useful and highly versatile preparation of cyclopropylamines was initiated by de Meijere et al [59][60][61][62][63][64][65][66][67][68]. N ,N -Dialkylaminocyclopropanes (11) with up to three additional substituents are readily obtained from carboxylic acid N ,N -dialkylamides (8) and ethyl-as well as substituted ethylmagnesium halides in the presence of titanium tetraisopropoxide or, even better, methyltitanium triisopropoxide.…”

“…Improved yields of cyclopropylamines 11 were obtained by using methyltitanium triisopropoxide (17) instead of titanium tetraisopropoxide [65], as well as by adding the Grignard reagent to the mixture of the amide and the titanium reagent at ambient instead of low temperature (Schemes 4, 5 and Table 2) [61,70]. It is presumed that at room temperature, the rate of formation of the reactive titanacyclopropane intermediate and of its consumption by reaction with the amide are better balanced that at low temperature.…”

“…In view of the versatile new general synthesis of dialkylcyclopropylamines from N ,N -dialkylcarboxamides by way of titanacyclopropane intermediates generated from Grignard reagents and XTi(OiPr) 3 (X ¼ OiPr, Me) [60,65], de Meijere et al also turned their attention to the additional synthetic potential of titanacyclopropane intermediates generated by ligand exchange (Scheme 7) applying cyclohexylmagnesium halides as Grignard reagents [61,62,73]. This approach, which was also simultaneously developed by Cha and co-workers [74][75][76], applying a number of alkenes and favoring the use of cyclopentylmagnesium halides [77], has since been established as an efficient method for the formal dialkylaminocyclopropanation not only of a whole range of mono-, but also of some disubstituted alkenes and cycloalkenes (for selected examples see Table 3).…”