Alkylation aromatic imine

The alkylation of imines by an alkyl halide to give an iminium salt will be illustrated by selected reactions over a period of years. A more complete survey is available (88). Decker and Becker (89) prepared a number of iminium salts (91, for example) by mixing methyl iodide and aromatic imines in benzene. 2,5-Dimethyl-2-pyrroline (92) has been alkylated and the... 

The groups of Loupy and Jun have presented a chelation-assisted rhodium(I)-cata-lyzed ortho-alkylation of aromatic imines with alkenes (Scheme 6.57) [119]. The use of 2 mol% of Wilkinson s catalyst, RhCl(PPh3)3, and 5 equivalents of the corresponding alkene under solvent-free conditions proved to be optimal, providing the desired ortho-alkylated ketones in high yields after acidic hydrolysis. Somewhat lower yields were obtained when the imine preparation and the ortho-alkylation were realized in a one-pot procedure. 

Nitrogen functionality also assists the alkylation of ortho-Cr-H bonds of aromatics, as shown in Equations (10)—(12). In the case of aromatic imines, Ru3(GO)i2 exhibits a high catalytic activity.8-10 This reaction gives the alkylation product together with the alkenylation product in the reaction with triethoxyvinylsilane. Rhodium catalysts show the same activity to give the alkylation product.11,12,12a For example, the Rh(i)-catalyzed reaction of the imine of aromatic ketones with methyl acrylate... 

Amoxicillin 6-[D-)-a-Amino-p- hydroxyphenylacetamido] penicillanic acidc Aromatic alkylation, amination, imine formation, amidation (sidechain), fermentation, and deamidation (penicillin nucleus)... 

Reports on the synthesis of five-membered heterocycles by intramolecular nitrogen—nitrogen bond formation (N1—N5) came some years ago from our laboratory [79CC891 81 JCS(Pl) 1891 83JCS(P1)2273]. Thus, 4-alkyl(aryl)amino-l-azabutadienes 2, which are readily available in large scale from alkyl(aryl)imines 1 and aliphatic or aromatic nitriles (70S 142 ... 

Acyclic /V-alkylimines, asymmetric hydrogenation, 10, 56 Acyclic ( j3-allyl)cobalt complexes, oxidation reactions, 7, 58 Acyclic allylic esters, alkylation, 11, 76 Acyclic aromatic imines, asymmetric hydrogenation, 10, 56 Acyclic 1-buly l-( )5-pencadienyl) iron cations, preparation and reactivity, 6, 156... 

In general, catalysis by 84a and 85c resulted in good to excellent enantioselec-tivities in the reduction of lcetimines derived from methyl aryl ketones and aromatic amines (80, R1, R3 = aryl, R2 = Me), where the electronic effects of substituents in both aromatic groups did not show any significant influence [79, 80]. On the other hand, imines obtained from aliphatic amines (80, R3 = alkyl) gave virtually racemic products with 85a [80b]. In the reduction of non-aromatic imines, such as 80c, only catalyst 84a maintained high enantioselectivity (Table... 

Reactions of halogen-stabilized carbenoids with imines have been carried out using prefoimed lithium species (e.g. equation 36), or via a carbenoid generated from diiodomethane utilizing zinc-copper couple (Simmons-Smith conditions). A stereospecific ring closure is observed after the addition of lithiodichloromethane to a benzaldimine (equation 37).The addition of lithiochloro(phenylsulfon-yl)methane to aromatic imines affords 2-phenylsulfonyl-substituted aziridines, which can be deproton-ated and alkylated in excellent yield (Scheme 20). 

As described above, N-protected aromatic imines can be successfully employed as substrates for Mannich reactions. However, although N-protected alkyl imines constitute another important class of imine substrates, their instability hampers their use. N-protected alkyl imines are spontaneously tautomerized into the corresponding enamines even at low temperature. In aza-Henry (nitro-Mannich) reactions, this problem was overcome independently by Palomo [33a] and the group of Herrera, Bernardi, and Ricci [33b] by using the stable a-amidosulfones 73 from... 

N-Alkyl benzophenone imines. Amines generally react very slowly with aromatic ketones to form imines. However, if titanium tetrachloride is used as catalyst, the reaction of benzophenones proceeds at room temperature in benzene with yields of 75-98%.3... 

The reactions of aromatic imines with alkyl dichloroacetates in a protic medium afford highly functionalized 1,3-diarylaziridines (equation 31). Excellent yields (65-96%) of 2-aziridine-2-chlorocarb-oxylic acid isopropyl esters (87 R = Ph, R = Pr, X = Cl) are obtained. However, the reaction is limited to aromatic imines in which both R and R are aryl substituents. 

Ruhland et al. [38] reported the combinatorial synthesis of structurally diverse )3-lactams 6, Following removal of the Fmoc protecting group from resin-bound amino acids, a 10- to 15-fold excess of alkyl, aromatic, or a,j3-unsaturated aldehydes in a 1 1 mixture of trimethylorthoformate in dichlo-romethane (DCM) was added to yield resin-bound imines. The [2+2] cycloaddition occurred by addition of acid chlorides to a DCM suspension of... 

Not only the activated C-C unsaturated compounds, but also certain activated C-N unsaturated compounds such as imines and isocyanates undergo the amphiphilic bis-allylation reaction. The reaction of the aromatic imines 8k-m, derived from 4-nitrobenzaldehyde and alkylamines, with allyltributylstan-nane 3a and allyl chloride 12b proceeds very smoothly in the presence of Pd2(dba)3 CHCl3 catalyst in DMF at room temperature, giving N-allyl-N-alkyl-... 

Scheme 19.94 Cobalt-catalyzed ortho alkylation of aromatic imines.

Kobayashi et al. have also applied their chiral coordinative calcium catalysts successfully to asymmetric addition of malonates to imines, and the desired products were obtained in high yields with moderate to good enantioselectivities (Table 25) [97]. Several aromatic IV-Boc-imines bearing electron-withdrawing or donating groups were surveyed, and the enantioselectivities were around 70 % ees (entries 1-13). Unfortunately, an alkyl-substituted imine did not work well (entry 14). 

The first enantioselective Povarov reactions were two-component processes catalyzed by chiral complex of Lewis acids, but gave only modest results in terms of conversion and diastereo- and enantioselectivities [63]. Better results were obtained by Akiyama using a chiral Brpnsted acid derived from (/ )-BINOL (79) to catalyze the reaction of alkyl vinyl ethers with aromatic imines derived from o-hydroxyanilines, which gave derivatives of 8-hydroxytetrahydroquinoline 80 in good yields, with excellent diastereoselectivities and enantiomeric excesses. The authors attribute these results to the formation of a cyclic transition state wherein the chiral catalyst coordinates with both the OH and imine nitrogen, driving the attack of the nucleophile by ih Re face of the imine (Schemes 3.22 and 3.24) [64]. 

Subsequently, the chiral phosphoric acid catalyzed Friedel-Crafts alkylation attracted much attention and became the subject of comprehensive investigations. In particular, the reaction with indole was investigated extensively because it provided pharmacologically important 3-substituted indole derivatives in enantio-merically enriched forms. The groups of You [35], Terada [36], and AntUla [37] almost simultaneously developed a highly enantioselective Friedel-Crafts reaction of indoles 75 with aromatic imines 74 (Scheme 11.20). Interestingly, their reactions... 

Two years later, thiourea 21, functionalized with a cinchona alkaloid, was efficiently used in the synthesis of 3-indolylmethanamines in good yields and selec-tivities (up to 96% ee) [25]. The transformation takes place in the presence of aromatic, aliphatic, and heteroaromatic imine analogs. Chiral phosphoric acids 26a, mf-26d, and ent-26f were also identified as efficient catalysts for the F-C alkylation between indoles and imines [35, 38, 40]. In these cases, in contrast with thiourea 21, the processes were only successful in the presence of aromatic imines. More recently, the fmitful use of a thiourea supported on mesoporous silica (heterogeneous bifunctional catalyst) was reported [61]. The catalyst can be easily separated from the reaction mixture by simple filtration and reused several times without erasing the enantioselectivity. 

Watzke A, Wilson RM, O Malley SJ, Bergman RG, Ellman JA. Asymmetric intramolecular alkylation of chiral aromatic imines via catalytic C—H bond activation. Synlett 2007 2383-2389. 

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