Aza-Mannich reaction

Aube and co-workers have found that enolizable ketones react with benzyl azide in triflic acid to yield /V-(phenylamino)-methylated products [Eq. (5.354)]. The transformation is an aza-Mannich reaction interpreted with the involvement of the Mannich reagent A -phenyl iminium ion 295 formed in situ in a Schmidt rearrangement. Cyclic tertiary alcohols react with alkyl azides in triflic acid to yield N-alkylamines (296, 297)983 [Eq. (5.355)]. The Schmidt rearrangement was used to transform Merrifield resin into amino-polystyrene resin by reacting the azido derivative in excess triflic acid (CH2CI2, 0°C).984... 

The aza-Cope/Mannich reaction takes advantage of the facility with which a y,<5-unsaturated itninium ion, such as 6, participates in a [3,3] sigmatropic rearrangement to give an isomeric species which is suitably functionalized for an intramolecular and irreversible Mannich cyclization (see intermediate 7). The aza-Cope rearrangement substrate 6 is simply an unsaturated iminium ion which can be fashioned in a number of ways from a homoallylic... 

The prerequisite for an evaluation of the utility of the aza-Cope/ Mannich strategy for a synthesis of strychnine has now been satisfied. Using unsaturated azabicyclo[3.2. ljoctanols closely related to 14, the Overman group had previously demonstrated the impressive facility with which the aza-Cope/Mannich reaction can construct the complex molecular frameworks of ( )-dehydrotubifoline and... 

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. 

Scheme 2.198. Domino condensation/aza-Cope/Mannich reaction sequence leading to 2-889.

A domino Claisen/ene strategy was employed for the synthesis of (+)-9(l l)-dehy-droestrone [82] methyl ether, while an example of a domino aza-Cope rearrange-ment/Mannich reaction is the above-mentioned synthesis of (-)-preussin (4-14) [5]. 

As a true testament to the potential long-term impact of H-bonding activation, a number of ureas, thioureas, and acid catalysts are now finding broad application in a large number of classical and modem carbon-carbon bond-forming processes. On one hand, Johnston s chiral amidinium ion 28 was elegantly applied to the asymmetric aza-Henry reactions (Scheme 11.12d). On the other hand, chiral phosphoric acids (e.g., 29 and 30), initially developed by Akiyama and Terada, have been successfully employed in Mannich reactions, hydrophosphonylation reac-tions, aza-Friedel-Crafts alkylations (Scheme 11.12e), and in the first example... 

Scheme 27 Vinylogous Mannich reaction of silyl dienolates 2.3.5 Aza-Ene-Type Reaction...

Mechanistically, the present transformation probably comprises two steps. Mannich reaction of in situ-generated cyclohexadienol 103 with iminium ion 104 is followed by an intramolecular aza-Michael reaction to furnish isoquinuclidine 102 (Scheme 41). Three stereogenic centers are created in this process. 

The groups of Rueping [25] and Gong [26] have developed the aza-hetero-Diels-Alder reaction of aryl imines and cyclohexenone to give isoquinuclidines in good endojexo selectivities and high yields and ee s by 1 and la, respectively (Scheme 5.13). In the presence of acid, cyclohexenone enolizes to afford the dienol which subsequently undergoes a Mannich reaction with the protonated aldimine followed by intramolecular aza-Michael addition to produce the formal Diels-Alder adducts. 

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). 

Scheme 6.73 Typical products of the enantioselective aza-Henry (nitro-Mannich) reaction between nitroalkanes and N-phosphinoylimines proceeding in the presence of catalyst 12.

The N-sulfinyl (thio)ureas are modular and easily accessible in one step by condensing tert-butanesulfinamide with the appropriate isocyanate or isothiocyanate. Figure 6.64 shows a representative selection of the prepared N-sulfinyl (thio)ureas evaluated for their catalytic activity in the aza-Henry (nitro-Mannich) reaction of N-Boc-protected benzaldimine and nitroethane producing adduct 1. 

Transannular Mannich reaction of an iminium enol intermediate derived from an aza-Cope rearrangement allows access to an angular arylindolone derivative which is a synthetic precursor of crinine [153],... 

In an elegant approach to gelsemine [238] based on a similar strategy the cationic aza-Cope rearrangement was superseded by a simple Mannich reaction because the twistane skeleton is more highly strained. However, the desired transformation is achievable using the anionic version. 

In 1997, the first truly catalytic enantioselective Mannich reactions of imines with silicon enolates using a novel zirconium catalyst was reported [9, 10]. To solve the above problems, various metal salts were first screened in achiral reactions of imines with silylated nucleophiles, and then, a chiral Lewis acid based on Zr(IV) was designed. On the other hand, as for the problem of the conformation of the imine-Lewis acid complex, utilization of a bidentate chelation was planned imines prepared from 2-aminophenol were used [(Eq. (1)]. This moiety was readily removed after reactions under oxidative conditions. Imines derived from heterocyclic aldehydes worked well in this reaction, and good to high yields and enantiomeric excesses were attained. As for aliphatic aldehydes, similarly high levels of enantiomeric excesses were also obtained by using the imines prepared from the aldehydes and 2-amino-3-methylphenol. The present Mannich reactions were applied to the synthesis of chiral (3-amino alcohols from a-alkoxy enolates and imines [11], and anti-cc-methyl-p-amino acid derivatives from propionate enolates and imines [12] via diastereo- and enantioselective processes [(Eq. (2)]. Moreover, this catalyst system can be utilized in Mannich reactions using hydrazone derivatives [13] [(Eq. (3)] as well as the aza-Diels-Alder reaction [14-16], Strecker reaction [17-19], allylation of imines [20], etc. 

It was also reported that diastereo- and enantioselective Mannich reactions of activated carbonyl compounds with a-imino esters were catalyzed by a chiral Lewis acid derived from Cu(OTf)2 and a bisoxazoline (BOX) ligand [31] [(Eq. (6)]. Catalytic enantioselective addition of nitro compounds to imines [32], and aza-Henry reactions of nitronates with imines [33] also proceeded under similar reaction conditions. 

The aza-Michael reaction yields, complementary to the Mannich reaction, P-amino carbonyl compounds. If acrylates are applied as Michael acceptors, P-alanine derivatives such as 64 and 65 are obtained. The aza-Michael reaction can be catalyzed by Bronsted acids or different metal ions. Good results are also obtained with FeCl3, as shown in Scheme 8.29. The addition of HNEt2 to ethyl acrylate (41f), for example, requires 10mol% of the catalyst and a reaction time of almost 2 days [94], The addition of piperidine to a-amino acrylate 41g is much faster and yields a,P-diaminocarboxylic acid derivative 65 [95]. 

---