Nitromethane enantioselective Henry reaction

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.

The use of bifunctional thiourea-substituted cinchona alkaloid derivatives has continued to gamer interest, with the Deng laboratory reporting the use of a 6 -thiourea-substituted cinchona derivative for both the Mannich reactions of malo-nates with imines [136] and the Friedel-Crafts reactions of imines with indoles [137]. In both reports, a catalyst loading of 10-20 mol% provided the desired products in almost uniformly high yields and high enantioselectivities. Thiourea-substituted cinchona derivatives have also been used for the enantioselective aza-Henry reactions of aldimines [138] and the enantioselective Henry reactions of nitromethane with aromatic aldehydes [139]. 

Later, a dramatic jump in the ee values was achieved by the same research group by introducing the thiourea moiety at the 6 -position of 44 [22]. Using 10 mol% of the quinidine-derived catalyst 46, the highly enantioselective Henry reaction between nitromethane and the aromatic aldehydes (electron-rich, electron-deficient, and... 

In 2006, Deng and coworkers reported that the quinidine and quinine derivatives, 49 and 50, respectively, bearing a free OH group at the 6 -position catalyzed the enantioselective Henry reaction of a-ketoesters with nitromethane [23]. In the... 

Quite recently, Bandini, Umani-Ronchi and coworkers also reported the highly enantioselective Henry reaction of the various trifluoromethyl ketones 54 with nitromethane catalyzed by the C6 -hydroxy quinine derivatives S3 (5 mol%) [24]. Various aliphatic and aromatic ketones were smoothly converted to the desired tertiary carbinols SS in high yields and ee values (up to 99%) without any significant electronic or steric demands (Scheme 8.17). The difluoroketones 56 proved just as useful as substrates (Scheme 8.18). Of note, the parent alkaloid, quinine, as a catalyst did not give rise to any asymmetric induction. 

Keywords Aldehydes, nitromethane, chiral diamine ligand (l)-Cu(OAc)2 complex as catalyst, n-propanol, room temperature, enantioselective Henry reaction, nitroalcohols... 

Scheme 29.8 Enantioselective Henry reaction between isatins and nitromethane and targeted products (R)-(+)-dioxibrassinin (20) and (S)-(-)-spirobrassinin (21).

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... 

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). 

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... 

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 chiral PTCs, cinchona-based thioureas have also been proved to serve as catalysts for nitro-Mannich reactions. In 2006, Ricci and coworkers first reported that the quinine-based thiourea 40 (20mol%) can catalyze the aza-Henry reaction between nitromethane and the N-protected imines 93 derived from aromatic aldehydes [40]. N-Boc-, N-Cbz-, and N-Fmoc protected imines gave the best results in terms of the chemical yields and enantioselectivities (up to 94% ee at —40°C) (Scheme 8.30). 

However, structural modification of the BINOL ligand system also plays an important role with regard to stereoselection in the asymmetric Henry reaction. Improved enantioselectivites were obtained using a number of (P)-BINOL derivatives 8 (3 mol equiv) in which the 6,6 -positions were substituted [21 ]. Their utility as asymmetric catalysts was assessed using the nitroaldol reaction of ni-tromethane with hydrocinnamaldehyde 1. Enantioselectivities up to 88% ee accompanied by chemical yields up to 85% were obtained using 3.3 mol % of various catalysts 9 and 10 equiv of nitromethane (-40 °C, 91 h) (Scheme 4). 

Enantioselective nitroaldol reaction (Henry reaction) of simple trifluoromethyl ketone was reported by Tur and Saa [27] (Table 8.7). Reaction of trifluoromethyl ketones with nitromethane in the presence of lanthanum (III) triflate salt complex and Proton Sponge (1) (0.25 equiv. each) gave tertiary nitroaldols in 50-93% yields with... 

In addition, Wulff et al. have reported the first aza-Henry reaction catalysed by a bis-thiourea catalyst, which was based on the 2,2 -diaminobinaphthalene (BINAM) chiral scaffold.The aza-Henry adducts derived from A -Boc imines and nitromethane were isolated in moderate to good yields and good to high enantioselectivities of up to 91% ee (Scheme 3.25). 

Catalytic asymmetric nitroaldol (Henry) reactions of ketones lead to synthetically versatile chiral tertiary nitroaldols. Enantioselective nitroaldol reactions of a-keto esters have been achieved using chiral Cu and Mg complexes, and cinchona alkaloids [140]. However, there are no reports on the asymmetric synthesis of tertiary nitroaldols derived from simple ketones. Even for a racemic version, only a few methodologies with limited substrate scope are available. The difficulty arises from the attenuated reactivity of ketones and their strong tendency toward a retro-nitroaldol reaction under basic conditions. (S)-LLB catalyst was found suitable to promote retro-nitroaldol reaction and a kinetic resolution of racemic tert-nitroaldols was realized. (S)-LLB preferentially converted the matched (R)-enantiomer into ketone and nitromethane, whereas the mismatched (S)-enantiomer remained unchanged and was recovered in an enantiomerically... 

The second most important synthetic application of silyl nitronates in C-C bond-forming reactions is their fluoride-mediated addition to aldehydes. Silyl nitronates from secondary nitroalkanes lead to free nitro aldols such as (4), while those from primary nitro alkanes give silylated products. In contrast to the classical Henry reaction, the silyl variant is highly diastereose-lective with aldehydes, furnishing e yfAro-0-silylated nitro aldols (e.g. 5). It is important that the reaction temperature does not rise above 0 °C, otherwise threo/erythro equilibration takes place. The same erythro-nitio aldol derivatives are available by diastere-oselective protonation of silyloxy nitronates (eq 3) (usually the dr is >20 1), while the nonsilylated fAreo-epimers (R = H, dr = 7 3-20 1) are formed by kinetic protonation of lithioxy lithio nitronates in THF/DMPU (eq 4). Other recent modifications of the nitroaldol addition using titanium nitronates or ClSiRs in situ are less selective. It should also be mentioned that there are recent reports about the enantioselective addition of nitromethane to aldehydes in the presence of rare earth binaphthol complexes. 

Henry Reactions. An enantioselective nitroaldol reaction was catalyzed by a Cu(OAc)2-oxazoline complex. Various aldehydes were treated with nitromethane in the presence of the copper catalyst giving the desired /3-nitroalcohols in good to excellent yields and enantiomeric excesses (eq 32). 

A series of mono- and dialkylated, chiral 1,2-amino-phosphinamide ligands (752) have been successfully applied in the chiral phosphinamide-Zn(ii) catalysed asymmetric Henry reaction between benzaldehyde and nitromethane (Scheme 210). The effects of the N-substituent sizes of chiral ligands (752) on the enantioselectivities in this reaction have been correlated using a predictive quantitative structure-activity relationship (QSAR) mathematical model. A quantitative correlation model has been also established based on subtractive Sterimol parameters. Ligand optimisation based on the QSAR model led to chiral 1,2-amino-phosphinamide ligand (752a), which produced (R)-p-nitroalcohol (753) in excellent yield (99%) and enantioselectivity (92% ee). ... 

The synthetic route to the structurally related bis-thioureas of type 32 from (R)-5,5, 6,6, 7,7, 8,8 -octahydro-l,T-binaphthyl-2,2 -diamine was reported by Shi. The effectiveness of the acid-base synergistic catalysis of parent 32a and N,N-diisopropylethylamine was verified by application to the asymmetric Henry reaction of nitromethane with aromatic aldehydes (Scheme 7.57) [86]. Moreover, the Morita-Bayhs-Hillman reaction between 2-cyclohexen-l-one or 2-cyclopenten-1-one and aromatic aldehydes was found to proceed with moderate to good levels of enantioselectivity under the catalysis of 32b, which has additional 3,5-bis(trifluoromethyl)phenyl groups at the 3,3 -positions of the octahydrobinaph-thyl backbone, and l,4-diazabicyclo[2.2.2]octane (DABCO) (Scheme 7.57) [87]. 

The asymmetric reaction of nitromethane with aldehydes as well as activated ketones (e.g., trifluoroacetophenone and a-ketoesters) is possible with various chiral metallic complexes or organocatalysts under atmospheric pressure with good yield and enantioselectivity. However, the Henry reaction of aryl alkyl ketones still remains problematic and challenging. Matsumoto s group also tested the very difficult reaction of acetophenone and nitromethane with quinidine. No product was observed under Ibar and only traces at 7 kbar, but application of 10 kbar resulted in a significant improvement in yield (31%) -unfortunately, no enantioselectivity was detected (Scheme 21.3). 

Organocatalytic Henry reactions with synthetically useful levels of yields and enantioselectivities came a decade later with the independent work of Nagasawa and Hiemstra. Nagasawa used guanidinium salt/thiourea brfimctional catalyst 2 for the reaction of nitromethane or nitroethane with aliphatic aldehydes (no reaction was observed when aromatic aldehydes were used) [7]. The reaction works under PTC with the assistance of KOH, and to overcome the retro-nitroaldol reaction K1 as an additive was required (Scheme 29.2). Two years later, the same group extended this reaction to nitroalkanes other than nitromethane, a process that yields the corresponding xyn-nitroalcohols preferentially. 

At almost the same time, and based on their earUer studies with cinchona alkaloid organocatalysts bearing both a Br0nsted-base and thiourea residues, Hiemstra and coworkers were able to achieve good enantioselectivities and yields in the Henry reaction between aromatic aldehydes and nitromethane [8]. With unactivated aromatic aldehydes (i.e., R = 4-MeO-Ph) longer reaction times were required (Scheme 29.3). 

Based on catalytic double activation (guanidinium salt/thiourea moiety skeleton), Nagasawa et al. were able to achieve the reaction of nitromethane, nitro-ethane, and nitropropane with aliphatic a-ketoesters in moderate yields and selectivities (Scheme 29.10) [24]. The reaction works with the assistance of 10 mol% KOH and to overcome the retro-nitroaldol reaction, the presence of 50mol% K1 was required. The resulting Henry reaction adducts are obtained with good syn/anti ratios, and enantioselectivities of up to 98%. When aromatic a-ketoesters were subjected to the reaction unsatisfactory results were obtained (e.g., R = Ph, 5% yield and 5% ee). 

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