Phosphoric acid derivatives Mannich reactions

Most notably, the Antilla laboratory has employed VANOL and VAPOL phosphoric acid derivatives in several novel asymmetric transformations. In addition, TADDOL and phosphordiamide phosphoric acid derivatives have been applied in several Mannich-type reactions. 

Substrates usefully employed in Mannich reactions are, in general, XH compounds having nucleophilic properties, with X being equal to C, N, or other heteroatoms (Fig. 4). In particular, CH compounds are suitably activated saturated and unsaturated derivatives, and NH substrates may be amines, amides, hetcrocyclcs, etc. Out of OH sub-stratcs, alcohols are mainly able to give stable Mannich products. Sulfur- and phosphorus-containing substrates are XH derivatives having the H atom bonded to the hetcroatom in the lower oxidation state, i.e., thiols, sulfinic acids, and, respectively, phosphine and phosphorous acid derivatives. As and Se compounds have also been successfully used. All these substrates are listed in more detail in Sec. D of this chapter. 

In parallel, Akiyama used the same type of catalysts for highly enantioselective indirect Mannich-type reactions [8]. His group also disclosed that these chiral phosphoric acid derivatives can catalyse the aza-Diels-Alder reaction with high stereoselectivity [75]. In addition, chiral-phosphoric acids can mediate similar transformations as the proline-catalyzed domino Mannich/aza-Michael reactions with high enantioselectivity [76]. 

Examples of the Bronsted-acid catalysts and hydrogen-bond catalysts are shown in Figure 2.1. We have recently reported the Mannich-type reaction of ketene silyl acetals with aldimines derived from aromatic aldehyde catalyzed by chiral phosphoric acid 7 (Figure 2.2, Scheme 2.6) [12]. The corresponding [5-amino esters were obtained with high syn-diastereoselectivities and excellent enantioselectivities. 

In Ught of the recent developments in thiourea, diol, and phosphoric-acid-mediated catalysis, far fewer studies have focused on the use of chiral carboxyhc acids as suitable hydrogen bond donors. To this end, Mamoka synthesized binaphthyl-derived dicarboxylic acid 49 which catalyzes the asymmetric Mannich reaction of N-Boc aryl imines and tert-diazoacetate (Scheme 5.65) [120]. The authors postulate that catalytic achvity is enhanced by the presence of an addihonal car-boxyhc acid moiety given that use of 2-napthoic acid as catalyst provided only trace amounts of product... 

Flame retardants—Whereas halogen-containing Mannich bases arc mainly used as modifiers of macromolccular materials, as mentioned before, phosphorus derivatives arc employed as additives. These products arc obtained from phosphorous acid or phosphites 584 " and from other analogous phosphorus-containing compounds. N-Heterocyclcs, after reaction with melamine and formaldehyde (585), are also used as (lame retardants. -... 

The present F C reaction proceeded through the in situ generation of aliphatic imines that were delivered via the protonation of the enecarbamates by the phos phoric acid catalyst (Figure 3.4). Phosphoric acid functioned as an efficient catalyst for the dual transformation that involved the in situ generation of imine and the enantioselective carbon carbon bond formation with indole. This protocol offers the distinct advantage of generating in situ unstable aliphatic imines from storable and thus easily handled enecarbamates, and hence is applicable to other organic transformations. In fact, Terada et al. applied the present method to an enantiose lective direct Mannich reaction [51]. The method provides an efficient pathway to p alkyl P aminocarbonyl derivatives in optically active forms. 

Many syntheses of (aminoalkyl)phosphonic derivatives have been listed which rely on the participation of phosphorous acid, H3PO3 this, like its diesters, exists in the quinque-valent phosphonic acid structure, (H0)2P(0)H. Such reactions include Mannich-type aminomethylations Similar types of reactions with the involvement of hypophosphorous acid and primary amines lead to (aminomethyl)phosphinic acids (Scheme 54) (R = H), during which the formation of376 (R = H) undoubtedly occurs initially. However, such products cannot be isolated, and views differ as to the relative importance of the subsequent formation of polymers and that of the bis(aminoalkyl)phosphinic acids (377 R = fj 5S4,585 latter type of acid is available through reactions with pre-... 

A three-component Mannich-type reaction of a diazo compound, Ph-C(=N2)-C02Me, a carbamate, Bn02CNH2, and an imine, PhCH=NPh, gives access to both syn- and anP-Q ,jS-diamino acid derivatives (20). Co-catalysed by Rh2(OAc)4 and BINAP-derived phosphoric acids, the reaction involves diastereoselectively switch-able enantioselective trapping of proton carbamate ammonium ylide intermediates. (J) High levels of chemo-, diastereo-, and enantio-selectivities were achieved... 

Another cinchona alkaloid-catalysed Mannich reaction was reported by Barbas et al, occurring between a thioester and an a-amido sulfone, leading in the presence of KOH to the unti-Mannich product in 79% yield, with both moderate diastereo- and enantioselectivity of 64% de and 45% ee, respectively. Finally, Akiyama et al. have developed a new method for the enantioselec-tive synthesis of y-butenolide derivatives, which involved the vinylogous Mannich-type reaction catalysed by a novel chiral phosphoric acid bearing iodine groups at the 6,6 -positions. Aliphatic as well as aromatic aldimines... 

Later, these authors reported the utilisation of a combination of Rh2(OAc)4 with a chiral BINOL-derived phosphoric acid to induce an enantioselective three-component Mannich-type reaction of diazo compounds, carbamates and imines, providing a rapid and efficient access to... 

Akiyama and coworkers, who had pioneered BINOL-derived phosphoric acids, noticed that aldimines 365 available from 2-aminophenol and aromatic, heteroaromatic, and cinnamyl aldehydes can be activated by the chiral acid catalyst 367, so that they are electrophilic enough to react with silyl ketene acetals 366 in diastereoselective and enantioselective Mannich reactions. Thus, P-amino esters 368 are formed with a high preference for the syn-diastereomers that are obtained in high enantiomeric excess (Scheme 5.96) [182]. 

Similar BINOL-derived phosphoric acids were also found to effectively catalyze the asymmetric vinylogous Mannich reaction. Sickert and Schneider reported that various /V-PMP-protected imines react with acyclic silyl dieno-lates in the presence of the Brpnsted acid catalyst 137 to afford the desired 5-amino a,p-unsaturated carboxylic esters (139) in good yields (83-94%) with complete regi-oselectivity and high enantioselectivities (80-92% ee) (Scheme 11.29) [96], Remarkably, the one-pot three-component process (i.e., imine is formed in situ) is comparable... 

Our group has synthesized chiral cyclic phosphoric acid diesters (41), derived from (P)-BINOL, and studied their catalytic activity in the Mannich-type reaction of ketenesilylacetal with aldimines (Scheme 2.83). Although (41a) was not effective as... 

Synthetically important chiral 1-monosubstituted 1,3-diamines (145) are synthesized in Mannich-t)fpe reactions of enecarbamates (140) with aromatic and aliphatic hemiaminal ethers (141) in the presence of phosphoric acid 95a. This process involves the highly reactive Mannich-t)fpe product (144), which is entrapped by a methanol molecule generated during the formation of the imine (143) derived from the hemiaminal ether (141) (Scheme 28.15) [72]. Similarly, diastereo- and enantio-enriched anti-l,2-disubstituted 1,3-diamines are prepared by the Mannich-type reaction of aldehydes, anilines, and enecarbamates in the presence of chiral phosphoric acid [73]. 

The aza-Petasis-Ferrier rearrangement is not a true concerted sigmatropic reaction, since it is thought to proceed via C-O bond cleavage of a hemiaminal vinyl ether by the action of an acid catalyst to afford a reactive iminium cation and the enol form of an aldehyde these two intermediates combine subsequently in a Mannich-type process, leading to 3-amino aldehydes (Scheme 40.45) [54]. Recently, Terada and Toda used a BINOL-derived phosphoric acid diester as a catalyst for this interesting reaction [55]. 

Biphenyl derivatives. A biphenol-based chiral phosphoric acid (218) catalysed the asymmetric Mannich-type reaction of iV-Boc protected imine (214) with difluoroenol silyl ethers (215) in the presence of 3 A moleculear sieves in THF to afford p-amino-i ,l -difluoroketones (216) in good yields and with excellent enantioselectivities (up to 94% ee). Optically pure 3,3-difluoroazetidin-2-one (217) was readily synthesised from the Mannich-adduct (216) (Scheme 57), ... 

In 2004, Akiyama s and Terada s groups independently pioneered the development of chiral BINOL-derived phosphoric acids 197, which have subsequently found wide resonance as catalysts in various asymmetric transformations [33, 41, 42]. Akiyama reported that silyl ketene acetals such as 237 participate in additions to aromatic aldimines with high diastereo- and enantioselectivity in the presence of catalyst 238 (Equation 21) [146]. In parallel studies, Terada demonstrated that the chiral phosphoric acid 242 readily catalyzes direct asymmetric Mannich reactions between acetylacetone (241) and N-Boc-protected aromatic aldimines such as 240 (Equation 22) [145]. 

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