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

Diisopropyl (2 S ,3 S )‐2,3‐ O ‐isopropylidenetartrate product: diisopropyl (2S,3S)‐2,3‐O‐isopropylidenetartrate byproduct: Ti(OCHMe2)4

The known title compound 6 formed by addition of titanium tetrachloride to methyl isocyanide in methylene chloride adds to the carbonyl group of aldehydes and ketones. The adducts 7 are hydrolized to N-methyl-a -hydroxycarboxamides 8 which are (from ketones) or are not branched (from aldehydes) in the a-position. The yields in this new modification of the Passerini reaction are near 90%, also with readily enolized ketones such as acetone and acetophenone. In contrast to the previously used organotitanium reagents of the type RTiX3, the preparation of the reagent 6 does not require any Li-, Mg-or Zn-derivative as a precursor.Organotitan-und Organozirkoniumverbindungen erwiesen sich als ausserordentlich nutzliche, hochselektive nucleophile Reagentien fur C, C-Verknupfungen in der organischen Synthese. Zwei Obersichten uber die vielseitigen Anwendungen haben wir vor kurzem publiziert [ 11 [2]. Sie belegen, dass diese Reagentien vom Typ 1-5 stets durch Ummetallierung entsprechender Lithium-, Magnesium-oder Zinkderivate erzeugt werden. Im Rahmen unserer Untersuchungen uber die, vor allem RTiX3 1 C=C-OTiX3 3 [RTiX4]-M+ 5 R2TiX2 2 C=C-NTiX, 4 auch fur Anwendung im grossen MaBstab attraktivere direkte Erzeugung, stiessen wir auf eine Arbeit von Crociani et al. aus dem Jahre 1975 [3]. Darin wird gezeigt, dass sich aus TiC1, und Isocyaniden C-metallierte Imidoylchloride bilden, die IRund NMR-spektroskopisch identifiziert wurden. Wir haben jetzt das aus Methylisocyanid [4] hergestellte Addukt 6 als Reagenz fur nucleophile Additionen getestet. Bei Zugabe des Isocyanids zu aquimolaren Mengen TiC1, bildet sich 6 in CH2C.12 I )Teil der geplanten Dissertation von M. Sch., ETH Zurich.

Trichlorotitanium dialkylamino-alkoxides (2; titanates of N,O-hemiacetals) are generated either from the corresponding lithium alkoxides and titanium tetrachloride (Scheme I) or by addition of trichloro-dialkylamino-titanium to aldehydes. The electrophilic (dialky1amino)alkylating reagents 2 are used to convert lithium enolates to /3-dialkylamino-ketones and -esters 5 (Mannich bases), see Scheme 2 and Table. One diastereoisomer of the products 5g-5p thus obtained with cyclohexenolate is formed preferentially (66-84 YO). The configuration of the products of this first diastereoselective version of the Munnich reaction could not yet be determined. A typical procedure for carrying out the reaction is given.Wie wir zeigen konnten [7], wird die (Metall-0)-Gruppe von Lithium-N,O-halbacetal-alkoholaten5) des in Schema 1 gezeigten Typs 1 durch Transmetallierung mit TiCl, in die entsprechenden Titanderivate 29 zu einer Abgangsgruppe : Mit lithium-und