Nitro-Mannich-type reaction

Ph (SbFe)2 Ph Ph TIO OTf Ph 84 Scheme 14 Catalytic asymmetric aza-Henry (nitro-Mannich-type) reactions... 

The catalytic asymmetric nitro Mannich-type reaction using the complex Yb, K, and binaphthol gives the best result (see Eq. 4.141).206 The reaction conditions are important to get a good ee, where nitromethane is added very slowly over 27 h. 

K. Yamada, S. J. Harwood, H. Groger, M. Shibasaki, The First Catalytic Asymmetric Nitro-Mannich-Type Reaction Promoted by a New Heterobimetallic Complex, Angew. Chem, 1999, 38, 3504-3506. 

Catalytic asymmetric nitro-Mannich-type reactions have also been introduced very recently by the groups of Shibasaki [37] and Jorgensen [38,39]. 

The catalytic asymmetric nitroaldol reaction was extended to a direct catalytic asymmetric nitro-Mannich-type reaction promoted by hetero-bimetallic catalysts (Scheme 2) [53-55] or by EtjNBOX-Cu complexes [56]. These topics are reviewed in Chap. 28.2. 

For example, an effective procedure for the synthesis of LLB (where LL = lanthanum and lithium) is treatment of LaCls 7H2O with 2.7 mol equiv. BINOL dilithium salt, and NaO-t-Bu (0.3 mol equiv.) in THF at 50 °C for 50 h. Another efficient procedure for the preparation of LLB starts from La(0-/-Pr)3 [54], the exposure of which to 3 mol equiv. BINOL in THF is followed by addition of butyllithium (3 mol equiv.) at 0 C. It is worthy of note that heterobimetallic asymmetric complexes which include LLB are stable in organic solvents such as THF, CH2CI2 and toluene which contain small amounts of water, and are also insensitive to oxygen. These heterobimetallic complexes can, by choice of suitable rare earth and alkali metals, be used to promote a variety of efficient asymmetric reactions, for example nitroaldol, aldol, Michael, nitro-Mannich-type, hydrophosphonylation, hydrophosphination, protonation and Diels-Alder reactions. A catalytic asymmetric nitroaldol reaction, a direct catalytic asymmetric aldol reaction, and a catalytic asymmetric nitro-Mannich-type reaction are discussed in detail below. 

These rare earth-containing heterobimetallic complexes can be utilized for a variety of efficient catalytic asymmetric reactions, as shown in Sch. 13, and quite recently we have succeeded in realizing the first example of a catalytic asymmetric nitro-Mannich-type reaction using the newly developed heterobimetallic complex 71 (Table 17) [72]. 

Employing a similar strategy, Li and co-workers reported a copper-catalyzed nitro-Mannich type reaction between tertiary amines 1 and nitroalkanes 5 (Scheme 4) [20],... 

The first catalytic enantioselective nitro-Mannich-type reaction was developed by Shibasaki by the use of chiral BINOL-derived heterobimetallic complex 90 (Scheme 2.51). The catalyst prepared from Yb(0/-Pr)3, KOt-Bu, and (/ )-BINOL in a ratio of 1 1 3 gave the best result (82-91% ee) in the reaction of aldimines with nitromethane, while the conventional ratio (Yb K BINOL = 1 3 3) was much less effective (52% ee) in the same reaction. Moreover, the complex with a ratio of Yb K BINOL=l l 2 did not promote the reaction. Therefore, the complex YbK((I )-BINOLate)2 itself or its aggregated complex [YbK((I )-BINOLate)2] was not likely to be tbe actual catalyst. The active catalyst might be 90, a complex of YbK((I )-BINOLate)2... 

Scheme 2.51 Enantioselective nitro-Mannich-type reaction with the use of chiral heterohimetallic ytterhium(iii) potassium(i) tris(hinaphtholate).

On the basis of ESl-MS observation as well as positive nmilinear effects of this system, we assumed that p-oxo-p-aiyloxy-trimer complex is the most enantiose-lective active species (Fig. 3). Therefore, Sm50(0-/Pr)i3 with a well-ordered structure would have beneficial effects for the formation of desired trimer species. Postulated catalytic cycle of the reaction based on the initial rate kinetic studies and kinetic isotope effect studies is shown in Fig. 4. In this catalyst system, both Cu and Sm are essential. We assume that the cooperative dual activation of nitroalkanes and imines with Cu and Sm is important to realize the syn-selective catalytic asymmetric nitro-Mannich-type reaction. The Sm-aryloxide moiety in the catalyst would act as a Brpnsted base to generate Sm-nitronate. On the other hand, Cu(ll) would act as a Lewis acid to control the position of iV-Boc-imine. Among possible transition states, the sterically less hindered TS-1 would be more favorable. Thus, the stereoselective C-C bond formation via TS-1 followed by protonation with phenolic proton affords syn product and regenerates the catalyst. 

Fig. 4 Plausible catalytic cycle of Cu/Sm-eatalyzed nitro-Mannich-type reaction...

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... 

Scheme 10 Anti-selective catalytic asymmetric nitro-Mannich-type reaction with a Yb/K hetero-bimetallic catalyst...

Additions of stabilized carbanions to imines and hydrazones, respectively, have been used to initiate domino 1,2-addition/cyclization reactions. Thus, as described by Benetti and coworkers, 2-subshtuted 3-nitropyrrolidines are accessible via a nitro-Mannich (aza-Henry)/SN-type process [165]. Enders research group established a 1,2-addition/lactamization sequence using their well-known SAMP/ RAMP-hydrazones 2-308 and lithiated o-toluamides 2-307 as substrates to afford the lactams 2-309 in excellent diastereoselectivity (Scheme 2.72) [166]. These compounds can be further transformed into valuable, almost enantiopure, dihydro-2H-isoquinolin-l-ones, as well as dihydro- and tetrahydroisoquinolines. 

Enamine nucleophiles react readily with soft conjugated electrophiles, such as a, 3-unsaturated carbonyl, nitro, and sulfonyl compounds [20-22], Both aldehydes and ketones can be used as donors (Schemes 27 and 28). These Michael-type reactions are highly useful for the construction of carbon skeletons and often the yields are very high. The problem, however, is the enantioselectivity of the process. Unlike the aldol and Mannich reactions, where even simple proline catalyst can effectively direct the addition to the C = O or C = N bond by its carboxylic acid moiety, in conjugate additions the charge develops further away from the catalyst (Scheme 26) ... 

An intramolecular Mannich-type cyclization of l,3-dimethyl-6-(2-aminophenylthio)uracil (120) has been utilized for the synthesis of 5, 6-dihydropyrimido[4,5-b][ 1,5]benzothiazepine-2,4( 1H,3//)-diones (121) this synthesis was realized by reaction of 120 with an excess of formaldehyde, benzaldehyde, or p-nitro- or p-methoxybenzaldehyde in chloroform in the presence of a catalytic amount of p-toluenesulfonic acid under reflux for 4-10 hours. The thiazepine cyclization using aliphatic aldehydes other than formaldehyde did not give satisfactory results. In these cases the reaction resulted in the formation of a dimeric product that probably... 

This section deals with the reactions in which the formation of N-heterocycles proceeds through the Mannich-type cyclocondensations of anionic o-adducts of nitroarenes. The reactions of o-adducts with formaldehyde and primary amines result in 1,3-annelation of the piperidine ring to the core structure of nitroarenes. Depending on nitroarene structure, there are two main routes for these reactions to take (a) the o-adduct is formed via the addition of C-nucleophile to a nitroarene bearing the hydroxy group and (b) cyclocondensation of hydride adducts of nitroarenes, where the hydride ion acts as a nucleophile. At least two wcta-positioned nitro groups in aromatic ring are necessary for these reactions to proceed. Scheme 52 demonstrates both of these options. 

Another important type of transformation, which is has inspired the above developments, is the nitro-Mannich (or aza-Henry) reaction catalyzed by Jacobsen thiourea catalysts (Scheme 4.16) [77]. The reaction is highly 5yn-selective, and the corresponding products were isolated in high yields and ees. 

Mannich, Mannich-type and Nitro-Mannich Reactions... 

Disconnection of TM 2.17a requires new knowledge. This stmcture corresponds to the Mannich base since the terf-amino group is present in the fl-posilion to the strong electron-withdrawing nitro group. The retra-Mannich type disconnection of two bonds leads to simple starting materials, piperidine, formaldehyde and 2-nitropropane. In the same scheme are proposed reaction conditions for the synthesis of TM 2.17. More details on the Mannich reaction are presented in Sects. 4. 4.2 and 6.1. Here it suffices to mention that this three-component reaction affords P-amino carbonyl compounds known as Mannich bases. 

It will be demonstrated in later sections that there are several eompli-mentary catalytie systems that can be implemented for the same transformation. For example, nitro-Mannich, Strecker-type, and alkynylation reactions can be performed under a variety of photochemical conditions. Other reactions require more specific conditions to bias pathways involving discrete intermediates, which in some cases may depend upon the use of terminal oxidants or specialized coupling partners. However, controlling the outcome of a photochemical reaction is challenging and may be influenced by certain thermodynamic or electronic properties of the molecule targeted for C-H activation (see the following section). 

The most common preparations of amines on insoluble supports include nucleophilic aliphatic and aromatic substitutions, Michael-type additions, and the reduction of imines, amides, nitro groups, and azides (Figure 10.1). Further methods include the addition of carbon nucleophiles to imines (e.g. the Mannich reaction) and oxidative degradation of carboxylic acids or amides. Linkers for primary, secondary, and tertiary amines are discussed in Sections 3.6, 3.7, and 3.8. 

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