N alkyl substituted imines

Scheme 1.2 Types of nucleophiles that add to N alkyl substituted imines.

The role of acid in influencing the cyclization of 14 with imines towards imidazolines products is at present unclear. One possibility is suggested by the work of Ferraccioli and Croce (16), who have shown that the electronic nature of the imine can have a significant influence upon its reactivity with Munchnone. In particular, while N-alkyl substituted imines react with Munchnones to form (3-lactams, more electron poor imines, such as the N-tosyl substituted substrates, have been found to undergo a 1,3-dipolar cyclization with 14 to form imidazoles. (16) In our case, the role of acid may be in protonation of the imine substrate, thereby creating a more electrophilic C=N which can undergo a dipolar cycloaddition with 14 (path A, Scheme 2). Subsequent heterolysis of the C-0 bond in 18, would yield the observed imidazoline-carboxylate 17. 

Sigman and Jacobsen reported the first example of a metal-catalyzed enantioselective Strecker-type reaction using a chiral Alnl-salen complex (salen = N,N -bis(salicyhdene)-ethylenediamine dianion) [4]. A variety of N-allylimines 4 were evaluated in the reaction catalyzed by complex 5 to give products 6, which were isolated as trifluoroacetamides in good yields and moderate-to-excellent enantioselectivities (Scheme 3). Substituted arylimines 4 were the best substrates, while alkyl-substituted imines afforded products with considerably lower ee values. Jacobsen and co-workers also reported that non-metal Schiff base catalysts 8 and 9 proved to be effective in the Strecker reaction of imines 7 with hydrogen cyanide to afford trifluoroacetamides 10 after reaction with trifluoroacetic anhydride, since the free amines were not stable to chromatography (Scheme 4) [5]. 

Reduction of nitriles has been used to prepare branched primary amines by alkylation of the nitriles followed by reduction of the imine intermediate with lithium-ammonia.6 4-Amino-2-quinolones were produced by the cyclization of N-(a-halogenoacyl)-N-alkyl substituted anthranilonitriles induced by Grignard or organolithium... 

A Ritter-type alkylation has been used to alkylate benzopyrazole to form the corresponding (V-trifluoromethyl imines. The methodology uses electrophilic hypervalent iodines in the presence of catalytic amount of acid to activate acetonitrile, affording the N-2 alkylated trifluoromethyl imine in 57% yield as the kinetic product in the reaction. The N-2 substituted imine, when subjected to similar reaction conditions over longer reaction times, affords... 

N-alkyl- and N-aryl-substituted acyclic or cyclic imines and the subsequent cycliza-tions providing the heterocyclic target compounds [74, 79]. ... 

Typical 1,3-dipolar cycloreversion is found for the decomposition of alkyl-substituted 2-tetrazolines (43) (88CB1213), l,4-dihydro-l,2,3,4-tetrazol-5-ones (44), and -thiones (45) (97JHC113). For these reactions two paths are possible that can be distinguished when the substituents on N-l and N-4 are different. For 2-tetrazolines ring contraction leading to diaziridines is also possible (discussed earlier). Cycloreversion of 43 yields imines and azides (88CB1213). 

A lithium-induced cyclization of the imine-diene 267, followed by N-alkylation (e.g., with EX = EtBr) or iV-acylation (e.g. with EX = PhCOCl), to form the 4,5-dihydroazepines 268 in poor to fair yields has been reported (Equation 36) <1995TL7065>. By using the different imine-dienes 269 but the same conditions as for 267 to form the anionic intermediate for the 1,7-electrocyclization, the N-substituted 2,3-dihydroazepines 270 were obtained (Equation 37) <1996T14801>. NMR spectroscopy was used to monitor the progress of these reactions. 

Intramolecular nucleophilic displacements are sometimes better suited to difficult cyclizations than additions to C-C multiple bonds, because nucleophilic substitutions are usually irreversible. Some metalated 4-halobutyl imines cydize to yield cydobutanes rather than six-membered cydic enamines (Scheme 9.22). If alkoxides are used as bases, however, exclusive N-alkylation is observed. No examples could be found of the cydization of 4-halobutyl ketones to cyclobutyl ketones, but 5-halopen-... 

Before discussing structural effects on barrier heights, it is necessary to distinguish between the two processes planar nitrogen inversion and rotation about the C=N bond, which may both lead to interconversion of the isomers. Rotation about a non-activated C=N double bond is expected to be hindered by an energy barrier similar to the ethylene barrier, i.e. of the order of 50—60 kcal/mole 121.132) Thus, alkyl- and presumably also aryl-substituted imines, which show interconversion barriers below 30 kcal/mole (Table 6), undergo nitrogen inversion ). 

These substituted imines are the so-called Schiff bases. Although substituted imines are more stable than imines, they still undergo reversible hydrolysis or polymerization. Nevertheless, if the substituting alkyl groups on the C and N atoms are replaced by... 

Insertion of isonitriles into Si-Si bonds takes place in the presence of palladium catalysts to give bis(silyl)imines 85, which show characteristic UV absorbance around 400 nm arising from n-Ji transition (Eq.43) [79]. Aryl and alkyl isonitriles except for tertiary alkyl isonitrile give the corresponding N-substituted imines. 

Another catalytic application of chiral ketene enolates to [4 + 2]-type cydizations was the discovery of their use in the diastereoselective and enantioselective syntheses of disubstituted thiazinone. Nelson and coworkers described the cyclocondensations of acid chlorides and a-amido sulfones as effective surrogates for asymmetric Mannich addition reactions in the presence of catalytic system composed of O-TM S quinine lc or O-TMS quinidine Id (20mol%), LiC104, and DIPEA. These reactions provided chiral Mannich adducts masked as cis-4,5 -disubstituted thiazinone heterocycles S. It was noteworthy that the in situ formation of enolizable N-thioacyl imine electrophiles, which could be trapped by the nucleophilic ketene enolates, was crucial to the success of this reaction. As summarized in Table 10.2, the cinchona-catalyzed ketene-N-thioacyl-imine cycloadditions were generally effective for a variety of alkyl-substituted ketenes and aliphatic imine electrophiles (>95%ee, >95%cis trans) [12]. 

Late transition metal compounds of the Group 10 with coordinated imine donor hgands were often found to yield active catalysts. In this chapter we wish to report on research carried out at or in cooperation with BASF polymer research on catalysts that carry imine donor hgands. Our objective is to introduce a number of unusual hgand frames for active catalysts. Unusual refers to being different to the usual condensates of alkyl-substituted anilines with aldehydes and ketones. The hgand frames that are described in the following include neutral (i) [N,N] diimine, (ii) [N,N,N] bis(imino)pyridine, monoanionic (iii) [N,O] sahcyl imine, and... 

Although N sulfinyl imines can be prepared by several other methods (oxidation of sulfenimines [12] and iminolysis of sulfinates [13]), they are most conveniently synthesized by condensing aldehydes with tert butanesulfinamide in the presence of copper(II) sulfate or magnesium sulfate/pyridinium p toluenesulfonate as a Lewis add catalyst and water scavenger (Scheme 1.4) [14]. When ketones, more sterically hindered aldehydes or even electronically deactivated aldehydes are used, titanium tetraethoxide is the preferred Lewis add and water scavenger. These methods are convenient to synthesize both alkyl and aryl substituted imines. 

Table 1.7 Enantioselective addition to alkyl substituted N phosphinoyl imines.

To extend this methodology to N aryl imines derived from alkyl substituted aldehydes, they developed a three component approach involving in situ imine formation from an appropriate aldehyde and o anisidine followed by the alkylation... 

The mechanism of the alkylation of imines with electrophilic alkenes has been discussed by D Angelo and coworkers S who conclude that reaction occurs via an aza-ene reaction-like transition state 206 involving concerted proton transfer from the nitrogen and carbon-carbon bond formation (Scheme 206). ITiey further propose that the remarkable regiocontrol observed in these reactions originates from this crucial internal proton transfer which would not be possible in a conformation such as 207 of the less substituted enamine tautomer, since the N—H bond would be anti to the enamine double bond. However, although this seems probable, it is by no means proven. Inconsistencies in the argument and the evidence presented cast some doubt on the validity of these conclusions. For example ... 

Studies of deprotonation regioselectivity in mono-N-substituted ketone hydrazones have mainly dealt with the regiochemistry of ketone tosylhydrazone deprdtonations. Deprotonation of these tosylhydra-zones, as well as deprotonation of mono-N-alkyl- or mono-N-aryl-hydrazones, proceeds predominantly syn to the starting —NHR group.16 This regioselectivity is plausibly similar to that reported for oxime and imine deprotonations.38 39... 

The strategies presented in Table 8.1 can be generalized in the following manner (1) carbanion addition to aldimine or ketimine derivatives (2) sequential amination-alkylation of aldehydes (carbanion addition to in situ formed aldimine derivatives) (3) transfer hydrogenation or hydrogenation of imines (4) reductive amination of ketones and (5) N-acetylenamide reduction. Because of the difficulty of their synthesis, a-alkyl,-alkyl substituted amines are highlighted whenever possible. 

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