Scope and limitations of the TiCl ₄ ‐mediated additions of isocyanides to aldehydes and ketones with formation of α‐hydroxycarboxylic acid amides

Abstract

The adducts obtained from Tic& and achiral (8-12) or chiral, nonraoemic (13-22) isocyanides are combined with aldehydes (aromatic or aliphatic) and ketones (acetone, cyclohexanone, acetophenone) to give, after aqueous workup, a-hydroxyamides (27 -55) [Passerini-type reaction]. The transformation is compatible with a variety of functional groups (aromatic and heterocyclic rings, amino, ether, ester, and amido groups, halides, and phosphonate substituents). The yields range from 14 to over 95% (with the lower values in the case of more highly functionalised isocyanides). No diastereoselectivity is observed with chiral isocyanides. If the R groups of the isocyanide (R -NC) form a rather stable cation (t-alkyl or benzylic), cyanohydrins may result from the reaction, rather than the N-substituted a-hydroxyamides (see Scheme 2).. In 1975 Crociani and his colleagues reported that titanium tetrachloride forms adducts with isocyanides which were unambiguously assigned the C-(trich1orotitanio)formimidoyl structure (A in Scheme 1)6.71. Since this is one of the rare cases in which a titanium-carbon bond is formed without intervention of a polar organometallic compound (transmetalation)'-'"'. we decided to investigate the use of such adducts as nucleophilic reagents. In a first paper, we described the additions of methyl isocyanide to aldehydes and ketones to give the N-methyl-hydroxyamides shown in Equation (1)'". TiC14-mediated reactions ''' of electrophiles other than ketones and aldehydes, such as acetals'" and u,punsaturated carbonyl compounds 14', with isocyanides have been known before or were published during our ongoing investigation. We have been mainly interested in extending the scope of the Passerini-type'"I6' reaction [Equation (l)] with respect to the isocyanide compound "--2'1. The following questions appeared to be important to us: (i) Which functional groups may be part of the isocyanide structure for the reaction still to take place? (ii) Can isocyanides from u-amino acids be employed, producing fragments of depsipeptides [Equation (2)]22'? (iii) Are reagents of type A diastereoface-selective'" in additions to chiral aldehydes? (iv) Do chiral isocyanides show enantioface differentiation in additions to aldehydes and ketones?The isocyanides for our investigation were purchased or prepared from the corresponding amines. Of the numerous

Asymmetric Isocyanide‐Based MCRs

“…However, after the pioneering unsuccessful attempts by Seebach et al [6], this strategy has only recently been reinvestigated by Denmark and Fan [20]. They not only succeeded in obtaining excellent ees, but also solved the problem of efficient catalyst turnover, by taking advantage of the concept of ''Lewis base activation of Lewis acids''.…”

Catalytic Enantioselective Passerini Three‐Component Reaction

“…[3] Although a number of diastereoselective P-3CRs [4] and U-4CRs [5] are known, only limited success has been attained in the development of enantioselective P-3CRs [6][7][8][9][10][11] and U-4CRs. [12] Denmark and Fan developed an asymmetric a-addition of isocyanides to aldehydes catalyzed by a chiral Lewis base with good to excellent enantioselectivity.…”

On the preparation of enantiomerically pure isonitriles from amino acid esters and peptides

“…Others have since reported the preparation of various α-isocyano carboxylic esters; however, in these cases, either limited or no information on the enantiomeric excess of the α-chiral center was provided. 13 In some instances, syntheses of racemates were reported. 14 Herein, we describe the development of an effective protocol for the preparation of a variety of enantiomerically pure isonitriles from amino acid esters and N-terminal peptides.…”