Acyclic azomethines

Although the first attempts at asymmetric azomethine ylide cycloadditions were reported by Padwa s group (92), the acyclic azomethine ylides chosen, bearing an a-chiral alkyl substituent on the nitrogen, showed poor diastereoselectivities (93,94). When the chiral center is fixed in a cyclic structure (95) or when chirality is introduced in an intramolecular cycloaddition system (96-98), high selectivities have been accomplished. There are only a few examples known of asymmetric cycloadditions of achiral azomethine ylides to chiral dipolarophiles where cyclic azomethine ylides (99,100) or cyclic chiral dipolarophiles (94) were used. 

Another approach employing chiral acyclic azomethine ylides was published in two recent papers by Alcaide et al. (85,86). The azomethine ylide-silver complex (51) was formed in situ by reaction of the formyl-substituted chiral azetidinone (50) with glycine (or alanine) in the presence of AgOTf and a base (Scheme 12.18). Azomethine ylides formed in this manner were subjected to reaction with various electron-deficient alkenes. One example of this is the reaction with nitrostyrene, as illustrated in Scheme 12.18 (86). The reaction is proposed to proceed via a two step tandem Michael-Henry process in which the products 52a and 52b are isolated in a... 

Cycloaddition of thiazolium azomethine ylides with dialkyl acetylenedicarboxylates 61 provides another approach to pyrrolo[2,1 -bjthiazoles 64 <070L4099>. Quatemization of 2-methylthiothiazole with trimethylsilylmethyl trifluoromethanesulfonate (TMSChkOTf) and subsequent fluoride-induced desilylation of the resulting (trimethylsilyl)methylammonium salt generate the acyclic azomethine ylide 62. This ylide readily participates in 1,3-dipolar cycloadditions with acetylene derivatives 61 to give adducts 63, which undergo spontaneous elimination of methylmercaptan to give the A-fuse cl thiazoles 64. ... 

As early as 1965, the first example of the the carbon-carbon bond cleavage of an aziridine generating an azomethine ylide 1,3-dipole was reported by Heine and Peavy (65TL3123). This also offers the first generation of acyclic azomethine ylides by the aziridine route. Thus, 1,2,3-triphenylaziridine, with its stereochemistry unspecified, was heated under reflux in toluene in the presence of diethyl acetylenedicarboxylate. The azomethine ylide (1) generated was captured by the acetylene to give a quantitative yield of diethyl l,2,5-triphenyl-3-pyrroline-3,4-dicarboxylate. 

The chemistry of azomethine ylide 1,3-dipoles, especially that of acyclic azomethine ylides, has completely changed since 1978. Methods of generating azomethine ylides, which were seriously limited before then to the aziridine route (Section II,A) and the deprotonation route (Section II,D), have been much extended. New methods, such as the desilylation route (Section II,B), the tautomerization route (Section II,C), the decarboxylation route (Section II,E), the N-oxide route (Section II,F), and the N-metallation route (Section II,G), are now known and the types of azomethine ylides available have been widely expanded. 

In the same year, chiral dicarboxylic acids 63 were applied to the asymmetric addition of weak nucleophiles to acyclic azomethine imines in this case the protonated acyclic azomethine imine I was generated in situ from aldehyde and N-benzylbenzoylhydrazide thanks to the presence of the chiral Bronsted acid 63f the following addition of a mild nucleophile such as allq l diazoacetate gave 77 with good yields and ee values that ranged from 93% to 99% (Scheme 24.24). 

Scheme 24.25 Catatytic as54iunetric Ugi-type reaction with acyclic azomethine imines.

Finally, a direct Mannich-type approach has been developed for the enantioselective synthesis of hydrazines and amines (Scheme 16.40). Thus, by trapping with alkyl diazoacetates some in s/iw-generated acyclic azomethine imines, in the presence of axially chiral dicarboxylic acids, a series of a-diazo-(3-hydrazino esters were obtained with excellent enantioselectivities [86]. 

In 2012, Maruoka and coworkers developed a new catalytic asymmetric Ugi-3CR through the use of an axially chiral dicarboxylic acid 27 [28], In the approach, a variety of aldehydes, 2-benzoyloxyphenyl isocyanide (26), and an acyclic azomethine imine 25 were initially reacted, yielding heterocyclic compounds 28 in excellent yields and good enantiomeric excesses (Scheme 7.11). Upon acid hydrolysis of the heterocyclic compound 28a, the corresponding a-hydrazino amide 29 was obtained without loss of enantioselectivity (bottom-left. Scheme 7.11). 

T. Hashimoto, H. Kimura, Y. Kawamata, K. Marnoka, Angew. Chem. Int. Ed. 2012, 51, 7279-7281. A catalytic asymmetric Ugi-type reaction with acyclic azomethine imines. 

Maruoka and co-workers reported the first catalytic asymmetric three-component 1,3-dipolar cycloaddition of terminal alkynes with acyclic azomethine imines generated in situ from the corresponding aldehydes and hydrazides, which was realized using CuOAc/Ph-pybox and axially chiral dicarboxylic acid cocatalysts (Scheme 27) [48]. This transformation has abroad tolerance with regard to the substrates, affording diverse chiral 3,4-disubstituted pyrazolines with high enantioselectivities. The role of the axially chiral dicarboxylic acid is to generate the protonated acyclic azomethine imine, which then reacts with chiral Cu-acetylide. 

An additional salient feature of 27 as a chiral Br0nsted acid catalyst was its abihty both to generate in situ a protonated acyclic azomethine imine from an aldehyde and N -benzylbenzoylhydrazide and to control the absolute stereochemistry in the subsequent reaction with a mild nucleophile such as diazoacetates (Scheme 7.51) [78]. A key for inducing a high level of enantiocontrol in this previously elusive yet synthetically valuable catalytic system was the employment of 3,3 -diphenylmethylsilyl-substituted 27e as a catalyst. 

Scheme 7.51 Generation and utilization of acyclic azomethine imines.

Further appUcations of this catalyst class as Br0nsted acids were shown by Maruoka and coworkers in various enantioselective reactions, such as addition of aza-enamines and vinylogous aza-enamines to imines (178,179), addition of diazo compounds to in situ generated acyclic azomethine imines (Scheme 10.72) [180], and 1,3-dipolar cydoaddition reactions of cyclic azomethine imines with enol ethers and vinylogous aza-enamines (Scheme 10.73) (181). 

Scheme 10.72 Addition of diazo compounds to in situ generated acyclic azomethine imines.

A three-component Ugi-type reaction using A/ -alkylbenzohydrazide (instead of amine) has been catalysed by an axially chiral binaphthyl dicarboxylic acid and found to proceed with up to 93% ee with an acyclic azomethine imine. Stereoselectivity of a Ugi reaction starting from an oxanorbornenone / -amino acid, R CHO, and RNC has been improved through solvent selection. ... 

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