Imines N-Boc

Reactions of nitro compounds with chiral imines have only recently been described. Either chiral 1-phenylethylamine (auxiliary) or the glyceraldehyde acetonide aldehyde was used as the chiral precursors of the imines 66 and 68, which reacted with 3-mesyloxynitropropane to give the 3-nitropyrrolidines dl)-67 and 69, respectively, with good diastereoselectivity. In fact, both products were obtained (almost) exclusively as trans diastereomers with high level of asymmetric induction, but the configurations of the newly formed stereocenters were not determined [44] (Scheme 13). N-Boc imines can be formed... 

The acyl-Pictet-Spengler reaction is also catalyzed by chiral thiourea derivative 6 to provide M-acetyl p-carbolines in high enantioselectivities. Notably, thiourea derivatives can activate not only electronically distinct imine derivatives such as N-alkyl and N-Boc imines but also a weakly Lewis basic N-acyhminium ion with high enantioselectivity using a chiral hydrogen bond donor (Scheme 12.4). 

A more general and highly diastereoselective Mannich-type reaction was developed by Ohshima and Shibasaki. The tartrate-derived diammonium salt 43c possessing 4-fluorophenyl substituents was identified as an optimal catalyst for the reaction of 28 with various N-Boc imines under solid (Cs2CC>3)-liquid (fluoroben-zene) phase-transfer conditions, as exemplified in Scheme 4.24 [64]. The usefulness of the Mannich adduct 67b was further demonstrated by the straightforward synthesis of the optically pure tripeptide 68. 

Discussion Catalyst 62 was synthesized in five steps in 86% overall yield from commercially available starting materials, with a single chromatographic purification [68]. The reaction as described by Jacobsen appears to be relatively insensitive to dilution, reagent stoichiometry, and rate of nucleophile addition. Different low-polarity solvents can be used with little effect on product ee-value. In highly polar aprotic solvents, however, the -values were significantly lower, whereas in protic solvents the imine rapidly decomposed. Aliphatic N-Boc imines were not examined due to a lack of useful methods for their synthesis. The inherent elec-trophilicity of the imine was shown to be important, with less-electrophilic N-allyl... 

A 5-mL flask was charged sequentially with catalyst (15 mg, 25 pmol, 0.05 equiv) and anhydrous toluene (250 pL). 3-Pyridylaldehyde N-Boc imine (0.53 mmol, 1 equiv) was added in one portion with stirring. When the solution was homogeneous, the flask was immersed in a dry ice/acetone bath and cooled to —30 °C. Silyl ketene acetal (216 mg, 1.0 mmol, 2 equiv) was then added slowly along the flask wall over 10 min. The flask was sealed under a nitrogen atmosphere and stirred at -30 °C for 48 h. Excess silyl ketene acetal was quenched at -30 °C via the rapid addition of a 3 M solution of trifluoroacetic acid in toluene (500 pL cooled to -20 °C prior to addition). The reaction was allowed to warm to 5 °C,... 

Herrera, Bernardi, and coworkers demonstrated that the addition of nitromethane to a wide range of aromatic and aliphatic N-Boc imines generated in situ from the... 

More than two decades after Wynberg s pioneering work, in 2006, Pettersen and Fini found that aromatic N-Boc-imines such as 168 also react with diethylphosphonate in the presence of catalytic quantities of quinine (10mol%) to produce the a-aminophosphonates 169 in moderate to good yields and with up to... 

Alternatively, it is also possible to use in situ generated N Boc imines as electro philes [117]. When a carbamoyl sulfones are treated under the rhodium catalyzed addition of arylboronic acids, the imine is formed in situ, and the nucleophilic addition proceeds smoothly to generate the N Boc protected amine (Scheme 1.34). 

Scheme 3.16 Enantioselective 1,2 aza F C reaction of N Boc imines with 2 methoxyfuran.

Aminals, compounds having two amino groups bound to the same carbon atom, are represented in many medicinal agents having versatile therapeutic action, such as proteinase inhibitors and neurotensins. Antilla and coworkers developed an en antioselective synthesis of protected aminals from the amidation reaction of N Boc imines with a series of sulfonamides catalyzed by chiral phosphoric acids (Scheme 3.54a) [111]. In this novel enantioselective transformation, phosphoric acid 9 exhibited excellent catalytic activity and enantioselectivity in addition to N Boc aromatic imines. The enantioenriched aminal products were stable upon storage neither decomposition nor racemization was observed in solution over several days. The same research group reported the enantioselective amidation reaction of N Boc aromatic imines with phthalimide or its derivatives (Scheme 3.54b) [112]. 

Kobayashi et al. developed catalytic asymmetric 1,4-additions using chiral calcium species prepared from calcium isopropoxide and chiral bisoxazoline ligands 39, 166 and 168. They found that calcium pyBOX catalysts could effectively mediate catalytic asymmetric additions of 1,3-dicarbonyl compounds 4 to nitroalkenes 86, N-Boc-imines 138 or unsaturated amides 49 giving products 165,167 and 170, respectively. Neutral coordinative ligands worked well in these reactions, giving a noticeably faster rate of reaction... 

Not much later, Cdrdova and List almost simultaneously reported extensive studies on the use of N-Boc imines as Mannich acceptors. The Cordova group reported that... 

During the same year, Takemoto and coworkers reported the asymmetric aza-Henry reaction of nitroalkanes with N-Boc imines utilising thiourea 15. 5yn-p-Nitroamines were isolated in good diastereoselectivities and high enantioselectivities, while the thiourea group was revealed to play a dual role, both activating the substrates and inducing chirality. Various types... 

Ketenes are attractive due to their remarkable reactivity and wide application in the synthesis of cyclic compounds. Ye et al. and Smith et al. have independently demonstrated that NHCs are efficient catalysts for the reactions of ketenes. In 2008, Ye and co-workers reported the synthesis of chiral NHCs 84 derived from l-pyrolutamic acid, which could catalyze the reaction of aryl(alkyl)ketenes with N-Boc imine to give the corresponding p-lactams in good yield with good diastereo- and high enantioselectivities (Scheme 7.69). More importantly, the NHC-catalyzed... 

The Mannich reaction and its variants have been reviewed, mainly focussing on asymmetric catalysis thereof. Catalytic, enantioselective, vinylogous Mannich reactions have also been reviewed, covering both direct and silyl dienolate methods. Another review surveys Mannich-type reactions of nitrones, oximes, and hydrazones. A pyrrolidine-thiourea-tertiary amine catalyses asymmetric Mannich reaction of N-Boc-imines (e.g. Ph-Ch=N-Boc) with ethyl-4-chloro-3-oxobutanoate to give highly functionalized product (16). Addition of triethylamine leads to one-pot intramolecular cyclization to give an 0-ethyl tetronic acid derivative (17). ... 

N-Boc imines are sufficiently activated to react with both a-diazo esters and a-diazo-A(-acyl oxazolidinones to give trisubstituted aziridines with high yield, de, and... 

Scheme 8.10 Mannich-type reaction of a p-ketophosphonate with N-Boc-imines in the presence of a preformed dinuclear nickel catalyst derived from a Schiff base ligand.

Scheme 6.13 The in situ generation of N-Boc imines from a-carbamoyl sulfone derivatives followed by their enantioseiective arylation with arylboronic acids, as described by Ellman s group [18b].

The one-pot cross double Mannich reactions with two different imines led to the formation of a complex mixture containing Mannich adducts, homocoupling products, as well as the desired cross-Mannich product. In order to circumvent this synthetic problem, the desired cross-Mannich targets were prepared by isolating the initial mono-addition products, which were then engaged in a second L-Pro-catalyzed Mannich reaction with a different N-Boc imine. Under these conditions, the cross-Mannich compounds were obtained in reasonably good yields and high selectivities. 

The heterobimetallic catalytic system using the amide-based ligand as a platform was extended to the diastereo- and enantioselective nitro-Mannich-type reaction. In an initial attempt using the heterogeneous heterobimetallic Nd/Na for the reaction of benzaldehyde-derived N-Boc imine and nitroethane exhibited poor stereoselectivity, likely because the coordination mode of N-Boc imine is different... 

The aza Henry reaction of N-phosphinyl aldimines with nitroalkanes was promoted by (9) to give P-nitroamines with good enantioselectivity (Scheme 2.37) [88]. The thiourea activated the nitro group, thereby facilitating the formation of the nucleophilic nitronate anion. They subsequently found that the use of N-Boc imine improved the enantioselectivity with reversal of the facial selectivity (Scheme 2.38) [89]. 

On the basis of observations from an X-ray crystallographic analysis of the 1 1 complex of 27b and 4-pyrroUdinopyridine, a transition-state model of the Mannich-type reaction was postulated (Scheme 7.47) [73b]. N-Boc imine would be activated by one of the two carboxyl adds in 27b and the steric hindrance of 3,3 -substituents and the binaphthyl moiety would restrict rotation of the O H-N hydrogen bond, thus regulating the conformational orientation of the imine. Then,... 

The reaction of N-Boc imines with diazoacetamides under catalysis of this class of chiral Bronsted acid did not give a Marmich-type adduct but afforded an aziri-dine with complete trans selectivity, and 27c, having 2,4,6-trimethylphenyl (mesityl) substituents, was identified as an optimal catalyst for realizing rigorous enantio-control (Scheme 7.48) [74]. 

Connon introduced binaphthyl-derived bis-thiourea 31 and demonstrated that it could catalyze the addihon of N-methyhndole to various nitroalkenes, including those incorporating P-aliphahc substituents, although the enantioselectivity was generally moderate (Scheme 7.56) [84]. The utility of 31 was also proven by Wulff through use with a sub-catalytic amount of triethylamine for stereoselectively facilitating the aza-Henry reaction of nitroalkanes with N-Boc imines [85]. 

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