Enantioselection nitromethane

The condensation of nitro compounds and imines, the so-called aza-Henry or nitro-Mannich reaction, has recently emerged as a powerful tool for the enantioselective synthesis of 1,2-diamines through the intermediate /3-amino nitro compounds. The method is based on the addition of a nitronate ion (a-nitro carbanion), generated from nitroalkanes, to an imine. The addition of a nitronate ion to an imine is thermodynamically disfavored, so that the presence of a protic species or a Lewis acid is required, to activate the imine and/or to quench the adduct. The acidic medium is compatible with the existence of the nitronate anion, as acetic acid and nitromethane have comparable acidities. Moreover, the products are often unstable, either for the reversibility of the addition or for the possible /3-elimination of the nitro group, and the crude products are generally reduced, avoiding purification to give the desired 1,2-diamines. Hence, the nitronate ion is an equivalent of an a-amino carbanion. 

Recently, enantioselective organo-catalytic procedures for the aza-Henry reaction have been disclosed. The presence of either an acidic or a basic function appears to be a requisite of the catalyst. In fact, the condensation of ni-tromethane with M-phosphinoyl arylimines 72 is catalyzed by the chiral urea 85 derived from (R,R)-l,2-diaminocyclohexane and gives the product (R)-74 with good yield and moderate enantioselectivity (Scheme 15) [50]. The N-phosphinoyl substituent is determinant, as the addition of nitromethane to the N-phenyl benzaldimine failed and the reaction of the N-tosyl ben-zaldimine gave the expected adduct with quantitative yield but almost no... 

Novel chiral thiolated amino alcohols have been recently synthesised and then evaluated by Vilaivan el al. as a potential new class of ligands for Cu-catalysed nitroaldol reactions. Amino alcohol ligands bearing Ai-(2-alkyl-thio)benzyl substituents provided only modest enantioselectivities (22-46% ee) while those carrying Al-2-thienylmethyl substituents provided better enantioselectivities of up to 75% ee for the nitroaldol reaction between p-nitro-benzaldehyde and nitromethane. A range of aromatic aldehydes were acceptable substrates giving moderate to high enantioselectivities of up to 88% ee, as shown in Scheme 10.32. 

The heterobimetallic asymmetric catalyst, Sm-Li-(/ )-BINOL, catalyzes the nitro-aldol reaction of ot,ot-difluoroaldehydes with nitromethane in a good enantioselective manner, as shown in Eq. 3.78. In general, catalytic asymmetric syntheses of fluorine containing compounds have been rather difficult. The S configuration of the nitro-aldol adduct of Eq. 3.78 shows that the nitronate reacts preferentially on the Si face of aldehydes in the presence of (R)-LLB. In general, (R)-LLB causes attack on the Re face. Thus, enantiotopic face selection for a,a-difluoroaldehydes is opposite to that for nonfluorinated aldehydes. The stereoselectivity for a,a-difluoroaldehydes is identical to that of (3-alkoxyaldehydes, as shown in Scheme 3.19, suggesting that the fluorine atoms at the a-position have a great influence on enantioface selection. 

Asymmetric synthesis of tricyclic nitro ergoline synthon (up to 70% ee) is accomplished by intramolecular cyclization of nitro compound Pd(0)-catalyzed complexes with classical C2 symmetry diphosphanes.94 Palladium complexes of 4,5-dihydrooxazoles are better chiral ligands to promote asymmetric allylic alkylation than classical catalysts. For example, allylic substitution with nitromethane gives enantioselectivity exceeding 99% ee (Eq. 5.62).95 Phosphi-noxazolines can induce very high enatioselectivity in other transition metal-catalyzed reactions.96 Diastereo- and enantioselective allylation of substituted nitroalkanes has also been reported.9513... 

Recently, ///)H.YL has been found to catalyze the stereoselective addition of nitroalkanes to aldehydes in an. S -selective fashion, which is in agreement with the known stereopreference of this enzyme. This is the first example for a substitution of HCN by another carbon nucleophile, expanding the synthetic scope of this biocatalytic transformation. The addition of nitromethane to different aldehydes with moderate to good yields and enantioselectivity has been demonstrated (Figure 5.9) [58]. However, large amounts of enzyme are required to... 

Figure 5.9 /ftHNL-catalyzed enantioselective addition of nitromethane to aldehydes... 

A novd example of a catalytic enantioselective domino process1201 is the inter-intramolecular nitro-aldol reaction described by Shibasaki et al which generates substituted indanones. As catalyst a praseodym-heterobimetallic complex with binaph-thol as chiral ligand is employed. Treatment of keto-aldehyde 41 with nitromethane in the presence of the catalyst 46 at -40 °C and successive warming to room temperature affords diredly the produd 42 in an overall yield of 41 % and 96 % ee after several recrystallizations (scheme 9). As intermediates the nitromethane adduct 43 and the hemiacetal 44 can be proposed. In a second aldol reaction 44 leads to 45 which isomerizes to the thermodynamically more stable epimer 42. 

The enantioselective nitroaldol reaction of phe-nylalaninals 45 with nitromethane was also promoted with the N-anthracenylmethyl ammonium fluorides in the presence of potassium fluoride.1411 Interestingly, as shown in Scheme 16, the major product was the (2R,3S)-isomer 46a when N,N-dibenzyl-(S)-phenylalaninal and 12 (R=benzyl, X=F) were used while the (2S,3S)-isomer 46b was major when N-tert-butoxycarbonyl derivative 45b and 12 (R=allyl, X=Br) together with potassium fluoride were used. The nitroalcohols 46a and 46b were respectively converted to amprenavir 47a, a HIV protease inhibitor, and its diastereomer 47b. The... 

The catalytic activity of a lanthanum (R)-BINOL complex tethered either on silica (62a) or MCM-41 (62b) was evaluated for the enantioselective nitroaldol reaction of cyclohexanecarboxaldehyde (Se), hexanal (Sf), iso-butyraldehyde (Sg) and hydro-cinnamaldehyde (Sh) with nitromethane inTHF (Scheme 12.22) [166]. The silica-anchored lanthanum catalyst 62a gave 55-76% e.e. and yields up to 87%, while the PMS-immobilized catalyst 62b revealed slightly higher e.e.s (57-84%) for the same aldehydes. The homogeneous counterparts showed similar catalytic performance, albeit within a shorter reaction time. The increased enantioselectivity observed for the MCM-41 hybrid catalyst 62b was explained by transformations inside the channels, which is also reflected by lower yields due to hindered diffusion. The recyclability of the immobilized catalysts 62b was checked with hydrocin-namaldehyde (Ph). It was found that the reused catalyst gave nearly the same enantioselectivities after the fourth catalytic run, although the time period for achieving similar conversion increased from initially 30 to 42 h. 

Nitroaldol (Henry) reactions of nitroalkanes and a carbonyl were investigated by Hiemstra [76], Based on their earlier studies with Cinchona alkaloid derived catalysts, they were able to achieve moderate enantioselectivities between aromatic aldehydes and nitromethane. Until then, organocatalyzed nitroaldol reactions displayed poor selectivities. Based on prior reports by Sods [77], an activated thionrea tethered to a Cinchona alkaloid at the quinoline position seemed like a good catalyst candidate. Hiemstra incorporated that same moiety to their catalyst. Snbsequently, catalyst 121 was used in the nitroaldol reaction of aromatic aldehydes to generate P-amino alcohols in high yield and high enantioselectivities (Scheme 27). 

The first report of an enantioselective organocatalytic [3+2] cycloaddition between nitrones and a,P-nnsaturated aldehydes was reported by MacMillan and co-workers who showed that iminium ion activation was effective in this reaction (Scheme 8) [64], After a survey of seven catalysts the imidazolidinonium salt 12 HC10 emerged as the most efficient system. The reactions were conducted in a mixture of nitromethane and water at -20 °C in the presence of 20 mol% catalyst... 

Takemoto et al. discovered N-phosphinoyl-protected aldimines as suitable electrophilic substrates for the enantioselective aza-Henry [224] (nitro-Mannich) reaction [72] with nitromethane, when utilizing thiourea 12 (10mol%) as the catalyst in dichloromethane at room temperature [225]. The (S)-favored 1,2-addition of nitromethane to the electron-deficient C=N double bond allowed access to various P-aryl substituted N-phosphinoyl-protected adducts 1-5 in consistently moderate to good yields (72-87%) and moderate enantioselectivities (63-76%) as depicted in Scheme 6.73. Employing nitroethane under unchanged reaction conditions gave adduct 6 as a mixture of diastereomers (dr 73 27) at an ee value of 67% (83% yield) of the major isomer (Scheme 6.73). 

Ricci and co-workers published a protocol for the enantioselective aza-Henry reaction [224] of N-protected aldimines with nitromethane in the presence of C9-epi-quinine thiourea 121 [8]. The reaction was ophmized for 20mol% loading of... 

For the model Henry reaction between benzaldehyde and nitromethane a solvent dependency of the enantioselectivity was detected (e.g., CH2CI2 6% ee MeOH 49% ee THF 62% ee aU at rt). Under optimized reaction conditions concerning catalyst loading (10 mol% of 131), solvent (TH F), and reaction temperature... 

The catalyst screening experiments were performed in the asymmetric Henry addition of nitromethane (10 equiv.) to 4-nitrobenzaldehyde in the presence of DABCO (20mol %) as the base and (thio)ureas 157, 158, 163, and 170-175 (each 10mol% loading). After 12h in reaction time at room temperature and in THF as the solvent, the corresponding Henry adduct was obtained in excellent yields (99%) but with very low ee values (7-17%) nearly independently of the sterical hindrance of the axiaUy chiral backbone skeleton (e.g., 172 and 174 each 99% yield 11% ee). Thioureas appeared slightly more enantioselective (e.g., 163 83% yield, 33% ee 171 99% yield, 15% ee) than their urea counterparts probably due... 

Scheme 6.161 Product range for the 163-catalyzed enantioselective Henry reaction of arylaldehydes with nitromethane.

Scheme 6.169 Screening reaction to identify (R,R)-configured guanidine-thiourea 186 as matching catalyst for the anti-diastereoselective and enantioselective Henry reaction of (S)-a-amino aldehydes with nitromethane.

Scheme 118 shows enantioselective condensation of alkanals and ni-tromethane promoted by a binaphthol-modified rare earth alkoxide in wet THF. Reaction of the initially formed metal /3-nitro alkoxide and acidic nitromethane, leading to the j8-nitro alcohol product and chiral metal nitronate, makes the C—C bond formation catalytic (284). 

Kiyooka et al. have shown that the asymmetric aldol reaction of ketene silyl acetals is promoted by 20 mol % of oxazaborolidine catalyst derived from (5)-valine with enantioselectivity employing nitromethane as the solvent [47]. 

Other nucleophiles such as nitromethane can also be used for this reaction. Thus, by the catalysis of (fl)-LPB (LaK3tris((/ )-binaphthoxide) (20 mol %), in which La works as a Lewis acid and K-naphthoxide works as a Brpnsted base, nitromethane reacted with chalcone to give the Michael adduct in 85% yield and 93% ee (Scheme 8D.8) [22], Addition of BuOH (120 mol %) gave a beneficial effect on the reactivity as well as the enantioselectivity of this reaction. 

Asymmetric amplification has also been observed in lanthanum-catalyzed nitro-aldol reaction, Shibasaki used a chiral lanthanum complex 15 prepared from LaCl3 and dilithium alkoxide of chiral BINOL for the enantioselective aldol reaction between naphthoxyacetaldehyde 14 and nitromethane (Scheme 9.11) [26]. When chiral catalyst 15 was prepared from BINOL with 56% ee, the corresponding aldol adduct 16 with 68% ee was obtained. This result indicates that the lanthanum 15 complex should exist as oligomer(s). 

Since Corey s group first reported 0(9)-allyl-N-(9-anthracenylmethyl) cinchonidi-nium bromide as a new phase-transfer catalyst [13], its application to various asymmetric reactions has been investigated. In particular, this catalyst represents a powerful tool in various conjugated additions using chalcone derivatives (Scheme 3.2). For example, nitromethane [14], acetophenone [15], and silyl eno-lates [16] produce the corresponding adducts in high enantioselectivity. When p-alkyl substrates are used under PTC conditions, asymmetric dimerization triggered by the abstraction of a y-proton proceeds smoothly, with up to 98% ee [17]. 

In the case of nitromethane, the observed enantioselectivity is not excellent, and the use of a low reaction temperature and mesitylene as solvent in place of toluene are recommended. In particular, the introduction of an electron-withdrawing trifluor-omethyl substituent on the catalyst li further enhanced the enantioselectivity. This new protocol offers a practical entry to optically active y-amino acid derivatives, as shown in Scheme 5.37 [39a],... 

A cheap and efficient enantioselective aza-Henry reaction of nitromethane with a variety of A-protected arylaldimines has been reported.73 Using zinc triflate and (-)-A-methylephedrine at -20 °C, yields and ees of up to 99% have been achieved with wide tolerance of aryl substituent in terms of both electronic nature and position. The auxiliary is also easily recycled. 

The catalytic asymmetric Henry reaction has been reviewed.42 Mild and efficient enantioselective nitroaldol reactions of nitromethane with various aldehydes have been catalysed by chiral copper Schiff-base complexes yielding the corresponding adducts with high yields and good enantiometric excess.43,44... 

In addition to this highly enantioselective metal-catalyzed approach, several orga-nocatalytic versions of the asymmetric nitroaldol reaction have recently been reported. The Najera group used enantiomerically pure guanidines with and without C2 symmetry as chiral catalysts for the addition of nitromethane to aldehydes [126], When the reaction was conducted at room temperature yS-nitro alcohols of type 120 were obtained in yields of up to 85% but enantioselectivity, 26% ee or below, was low. A selected example is given in Scheme 6.52. Higher enantioselectivity, 54% ee, can be obtained at a low reaction temperature of —65 °C, but the yield (33%) is much lower. 

The enantioselective nitroaldol reaction in the presence of alkaloid-based organo-catalysts has been investigated by the Matsumoto group [127]. A further focus of this study was investigation of the effect of high pressure on the course of the reaction. Addition of nitromethane to benzaldehyde at atmospheric pressure resulted in a low (4%) yield and 18% ee when a catalytic amount (3 mol%) quinidine was... 

Michael addition of nitromethane to chalcones can be catalysed by cinchona alkaloid-derived chiral bifunctional thiourea (142) (0.5-10 mol%) to give the corresponding products at 25-100 °C in high chemical yields and high enantioselectivity ... 

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