Mannich adduct

Apparently, 4.54 is extremely reluctant to undergo a retro Mannicli reaction. Riviere demonstrated that this behaviour is not unusual for (3-amino ketones. From the study of a large number of Mannich adducts. Riviere concludes that the retro Mannich reaction requires an aromatic group next to the carbonyl functionality. Qearly, 4.54 lacks this arrangement. 

Conversion of the C-2 amide to a biologically inactive nitrile, which can be further taken via a Ritter reaction (29) to the corresponding alkylated amide, has been accomphshed. When the 6-hydroxyl derivatives are used, dehydration occurs at this step to give the anhydro amide. Substituting an A/-hydroxymethylimide for isobutylene in the Ritter reaction yields the acylaminomethyl derivative (30). Hydrolysis affords an aminomethyl compound. Numerous examples (31—35) have been reported of the conversion of a C-2 amide to active Mannich adducts which are extremely labile and easily undergo hydrolysis to the parent tetracycline. This reverse reaction probably accounts for the antibacterial activity of these tetracyclines. 

Y(03SCF3)3 to afford a monoaminoalkylation product in good yield in aqueous media.40 Zinc tetrafluoroborate is also highly effective for such couplings in aqueous THF.41 Kobayashi also reported a Mannich-type reaction of imines with silyl enolates catalyzed by neutral salts such as sodium triflate in water as a suspension medium. Unusual kinetic behavior indicates that the presence of the Mannich adduct facilitates the rate of its formation.42... 

Benzotriazole-containing resin 167 reacted with aldehydes and amines to give resin-bound Mannich adducts 168, which reacted with Grignard and organozinc reagents to afford tertiary amines 169 <00JCC173>. 

Mannich products. Accordingly, dimethylpiperazine was used in this array to provide uniform reaction conditions, although it is not needed for the formation and isolation of many Mannich adducts in this library. 

Multicomponent reaction systems are highly valued in solid-phase organic synthesis because several elements of diversity can be introduced in a single transformation.1 The Mannich reaction is a classic example of a three-component system in which an active hydrogen component, such as a terminal alkyne, undergoes condensation with the putative imine species formed from the condensation of an amine with an aldehyde.2 The resultant Mannich adducts contain at least three potential sites for diversification specifically, each individual component—the amine, aldehyde, and alkyne—can be varied in structure and thus provide an element of diversity. 

The "Mannich" adduct synthesized from the condensation of formaldehyde, 2-(methylamino)ethanol and poly-4-vinylphenol as shown in Structure I, has been evaluated as a function of molecular weight versus corrosion resistance as measured by salt spray and humidity tests on Bonderite 1000, an iron phosphate conversion coating. The molecular weight of the polymer was varied from approximately = 2,900 to 60,000. The corrosion resistance results were essentially equivalent over the molecular weight range evaluated. 

Following the cinchonine-catalyzed results, Schaus et al. [46] reported the use of cyclic 1,3-dicarbonyl donors to access adjacent quaternary-tertiary stereogenic centers. Under similar reaction conditions cyclic (l-ketoester and 1,3-diketones afforded the corresponding Mannich adducts in excellent yields and stereoselectivities (Scheme 7). The methodology was also applicable to aryl propenyl imines (32) - a class of novel aliphatic imines. 

Scheme 6.79 Conversion of one vinylogous Mannich adduct obtained from the 63-catalyzed Mannich addition of a,a-dicyanoalkenes to N-Boc-protected aldimines to the corresponding chiral 5-lactam.

The construction of a quaternary a-stereocenters was demonstrated in the 117-catalyzed Mannich addition [72] of methylcyclo-pentanone-2-carboxylate to N-Boc-protected aromatic aldimines and furnished the adducts 1-3 in 70-97% yield, with good ee values (85-87%) and diastereoselectivities (Scheme 6.115). The authors exemplified the synthetic utility of the protocol by a simple racemization-free decarboxylation of the Mannich adduct of N-Boc benzaldimine and dimethyl malonate to obtain the respective N-Boc-protected p-amino ester (68% yield/89%... 

Scheme 6.114 Chiral Mannich adducts of the 117-promoted reaction between dimethyl malonate and N-Boc as well as N-Cbz aldimines.

Scheme 6.126 Mannich adducts obtained from the 121- and 124-catalyzed asymmetric addition of dialkyl malonates to N-Boc aldimines. The product configurations were not determined.

In contrast to the results obtained by Jacobsen et al. when utilizing Schiff base catalyst 42, the decrease of reaction temperature to -40 °C reduced the yield as well as enantioselectivity of the resulting Mannich adduct (Scheme 6.175) [201]. Catalyst 198 found to be less effective in the Mannich reaction in terms of yield and enantiomeric induction due to reduced basicity of the N-acylamine and weaker hydrogen-bonding interactions compared to the more basic Strecker substrates (Scheme 6.174). 

Peptide thioesters (Section 15.1.10) are generally prepared by coupling protected amino acids or peptides with thiols and are used for enzymatic hydrolysis. Peptide dithioesters, used to study the structures of endothiopeptides (Section 15.1.11), may be prepared by the reaction of peptide nitriles with thiols followed by thiolysis (Pinner reaction). Peptide vinyl sulfones (Section 15.1.12), inhibitors of various cysteine proteases, are prepared from N-protected C-terminal aldehydes with sulfonylphosphonates. Peptide nitriles (Section 15.1.13) prepared by dehydration of peptide amides, acylation of a-amino nitriles, or the reaction of Mannich adducts with alkali cyanides, are relatively weak inhibitors of serine proteases. 

High anti-diastereoselectivity is observed for several aromatic imines for ortho-substituted aromatic imines the two newly formed stereocenters are created with almost absolute stereocontrol. Aliphatic imines can also be used as substrates and the reaction is readily performed on the gram scale with as little as 0.25 mol% catalyst loading. Furthermore, the Mannich adducts are readily transformed to protected a-hydroxy-/8-amino acids in high yield. The absolute stereochemistry of the Mannich adducts revealed that Et2Zn-linked complex 3 affords Mannich and aldol adducts with the same absolute configuration (2 R). However, the diastereoselectiv-ity of the amino alcohol derivatives is anti, which is opposite to the syn-l,2-diol aldol products. Hence, the electrophiles approach the re face of the zinc enolate in the Mannich reactions and the si face in the aldol reactions. The anti selectivity is... 

The Mannich adducts are readily transformed to optically active a-amino-y-lac-tones via a one-pot diastereoselective reduction and lactonization sequence and the tosyl group exchanged for a Boc group via a two-step procedure. The cop-per(II) ion is crucial for the success of this reaction [21]. It has the properties necessary both to generate the enol species in situ and, in combination with the C2-symmetric ligand, coordinate it as well as the imine in a bidentate fashion. The reaction proceeds via a cyclohexane-like transition state with the R substituent of the enol in the less sterically crowded equatorial position, which is required to obtain the observed diastereoselectivity (Fig. 5). 

Their previous screening of catalysts for of aldol reactions and Robinson annu-lations suggested the possibility that chiral amines might also be able to catalyze the Mannich reaction [30, 31]. Thus, screening of catalysts for Mannich-type reactions between N-OMP-protected aldimines and acetone revealed that chiral diamine salt 10, L-proline 11, and 5,5-dimethylthiazolidine-4-carboxylic acid (DMTC) 12 are catalysts of Mannich-type reactions affording Mannich adducts in moderate yields with 60-88 % ee. To extend the Mannich-type reactions to aliphatic imines, the DMTC 12-catalyzed reactions are performed as one-pot three-component procedures. The o-anisidine component has to be exchanged with p-anisidine for the one-pot reactions to occur. The DMTC 12-catalyzed one-pot three-component direct asymmetric Mannich reactions provide Mannich adducts in moderate yield with 50-86 % ee. 

Addition of nucleophiles to electrophilic glycine templates has served as an excellent means of synthesis of a-amino acid derivatives [2c, 4—6]. In particular, imines derived from a-ethyl glyoxylate are excellent electrophiles for stereoselective construction of optically active molecules [32], This research and retrosyn-thetic analysis led us to believe that amine-catalyzed asymmetric Mannich-type additions of unmodified ketones to glyoxylate derived imines would be an attractive route for synthesis of y-keto-ce-amino acid derivatives [33], Initially, L-proline-catalyzed direct asymmetric Mannich reaction with acetone and N-PMP-protected a-ethyl glyoxylate was examined in different solvents. The Mannich-type reaction was effective in all solvents tested and the corresponding amino acid derivative was isolated in excellent yield and enantioselectivity (ee >95 %). Direct asymmetric Mannich-type additions with other ketones afford Mannich adducts in good yield and excellent regio-, diastereo- and enantioselectivity (Eq. 8). 

The mechanism of proline-catalyzed Mannich reactions is depicted in Scheme 5. The ketone or aldehyde donor reacts with proline to give an enamine. Next, the preformed or in-situ-generated imine reacts with the enamine to give, after hydrolysis, the enantiomerically enriched Mannich adduct the catalytic cycle can then be repeated. 

The Mannich adducts are reduced to the more stabile y-amino alcohols prior to isolation and ee determination due to their lower risk of decomposition, epi-merization and racemization. 

A more general and highly diastereoselective Mannich-type reaction was developed by Ohshima and Shibasaki. The tartrate-derived diammonium salt 43c possessing 4-fluorophenyl substituents was identified as an optimal catalyst for the reaction of 28 with various N-Boc imines under solid (Cs2CC>3)-liquid (fluoroben-zene) phase-transfer conditions, as exemplified in Scheme 4.24 [64]. The usefulness of the Mannich adduct 67b was further demonstrated by the straightforward synthesis of the optically pure tripeptide 68. 

Another example of a prodrug-based molecular design is the Mannich adduct (27) of nitromethylene compound (7) with amine and formaldehyde, which were prepared independently by Kishida et al. [30] and Krtlger et al. (Fig. 9) [31]. Nauen et al. reported that these adducts are hydrolyzed to the original material in acidic milieu [2]. 

Figure 9. Molecular E)esign of Prodrug Mannich Adducts...

Hanak et al (9) presented a paper regarding the use of propoxylated Mannich adducts for the production of continuous laminates and fiberglass-reinforced molded rigid foam characterized by CFC reduction or elimination. Table 46 shows an example of the formulation and process conditions employed (9). 

Soon after, the groups of Ricci [35] and Schaus [36] also employed a-amidosulfones as stable imine precursors in cinchona-catalyzed Mannich reactions. Ricci and coworkers reported [35] that, under PTC conditions (toluene/aqueous K2C03) using 75 as a catalyst (1 mol%), both the aliphatic and aromatic a-amido p-tolylsulfones 76 reacted with the malonates to afford the Mannich adducts 77 with high levels of enantioselectivity (85-99% ee) (Scheme 8.25). The subsequent decarboxylation/ transesterification of 77 gave the corresponding [3-amino acid derivatives without any alternation of the optical purities. The chiral dihydropyrimidones 80 were also successfully synthesized by Schaus and coworkers via the cinchonine catalyzed... 

Another catalytic application of chiral ketene enolates to [4 + 2]-type cydizations was the discovery of their use in the diastereoselective and enantioselective syntheses of disubstituted thiazinone. Nelson and coworkers described the cyclocondensations of acid chlorides and a-amido sulfones as effective surrogates for asymmetric Mannich addition reactions in the presence of catalytic system composed of O-TM S quinine lc or O-TMS quinidine Id (20mol%), LiC104, and DIPEA. These reactions provided chiral Mannich adducts masked as cis-4,5 -disubstituted thiazinone heterocycles S. It was noteworthy that the in situ formation of enolizable N-thioacyl imine electrophiles, which could be trapped by the nucleophilic ketene enolates, was crucial to the success of this reaction. As summarized in Table 10.2, the cinchona-catalyzed ketene-N-thioacyl-imine cycloadditions were generally effective for a variety of alkyl-substituted ketenes and aliphatic imine electrophiles (>95%ee, >95%cis trans) [12]. 

---