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The Bimolecular Aliphatic Mannich and Related Reactions EDWARD F 4.1 The Bimolecular Aliphatic Mannich and Related Reactions EDWARD F. KLEINMAN Pfizer Central Research, Groton, CT, USA 4.1.1 BACKGROUND - THE CLASSICAL MANNICH REACTION 893 4.1.1 .1 Introduction 893 4.1.1 .2 Earlier Reviews and Scope ofthis Chapter 894 4.1.1.3 Mechanism 895 4.1.1.4 Scope and Limitations 896 4.1.1.5 New Modifications 897 4.1.2 USE OF PREFORMED IMINIUM SALTS 898 4.1.2.1 Introduction 898 4.1.2.2 Acyclic N,N-Dialkyliminium Salts 898 4.1.2.2.1 General 898 4.1.2.2.2 N,N-Dimethyl(methylene)iminium salts 899 4.1.2.3 Cyclic Iminium Salts 912 4.1.2.4 N-Silyl- and N,N-Disilyl-iminium Salts 913 4.1.3 USE OF IMINES 915 4.1.3.1 Introduction 915 4.1.3.2 Acyclic N-Aryl- and N-Alkyl-imines 916 4.1.3.2.1 Reactions with highly acidic active methylene compounds 916 4.1.3.2.2 Reactions with carboxylic acid derivatives 917 4.1.3.2.3 Reactions with ketones 933 4.1.3.3 N-Heterosubstituted Imines 934 4.1.3.3.1 N-Silylimines 934 4.1.3.3.2 Oxime ethers 939 4.1.3.3.3 Sulfenimines 940 4.1.3.4 In Situ Methods 941 4.1.3.5 Cyclic Imines 942 4.1.4 ADDENDUM 948 4.1.5 REFERENCES 948 4.1.1 BACKGROUND - THE CLASSICAL MANNICH REACTION 4.1.1.1 Introduction The Mannich reaction is the prototype of carbon-carbon bond forming reactions that involve the addi­ tion of resonance-stabilized carbon nucleophiles to iminium salts and imines. In its original and most widely recognized form, the Mannich reaction consists of three components: (i) ammonia, a primary amine, or a secondary amine; (ii) a nonenolizable aldehyde, usually formaldehyde; and (iii) an active 893 894 Additions ofNucleophilic Alkenes to C=NR and C=NR2+ methylene compound. These components condense with concomitant release of water to produce a new base, known as a 'Mannich base', in which the active hydrogen is replaced by an aminomethyl group (equation 1). A typical example is the reaction of acetophenone (1), paraformaldehyde (2) and piperidine (3) to produce phenyl ~-piperidinoethyl ketone (4; equation 2). The formation of both a carbon-carbon and a carbon-nitrogen bond in this aminomethylation process makes the Mannich reaction an extremely useful synthetic transformation. In addition, Mannich bases have important synthetic applications as in­ termediates for other compounds. They also occur in natural products such as the alkaloids lycopodine (5), cocaine (6) and elaeocarpine (7). R2 0 I 4 RIR2NH + R4H RI/NyR + H2O (1) + R3)lH R3 conc. Hel 0 EtOH ° + (CH2O)n + H-NJ Ph~O (2) Ph~ reflux (1) (2) (3) (4) 0 (;CC02Me NMe 0 0 0 H oJ-.- Ph (5) (6) (7) 4.1.1.2 Earlier Reviews and Scope ofthis Chapter The ManDich reaction has been reviewed comprehensively by Blicke (1942),1Reichert (1959),2 Hell­ mann and Opitz (1960),3 and Tramontini (1973).4 These reviews also include synthetic applications of Mannich bases. Mechanistic studies of the Mannich reaction have been reviewed by Thompson (1968).5 Some variants of the Mannich reaction have been covered as subtopics in other reviews; for example, Layer (1963)6 and Harada (1970)7 have reviewed general additions of stabilized carbanions to imines, while Bohme and Haake (1976)8 have reviewed similar additions to methyleneiminium salts. In more specific reviews, Pai and coworkers (1984)9 have summarized stabilized carbanion additions to 3,4-dihy­ droisoquinolines and 3,4-dihydroisoquinolinium salts in connection with the total synthesis of protober­ berines and phthalide isoquinolines, and Evans et ale (1982)10 have analyzed the stereochemical aspects ofester enolate and silyl ketene acetal additions to imines. Since 1973, when the last comprehensive review of the Mannich reaction appeared,4 there has been an explosive growth in the variant of this reaction that employs preformed iminium salts and imines for the synthesis of Mannich bases. The use of preformed iminium salts and imines, some examples of which date back to the tum of the century, has had a renaissance in recent years primarily because of the advent of modem enolate chemistry, e.g. formation of enolates under kinetic control and the use of enol sHanes with Lewis acid catalysis. As a result, there have been two major advances in the synthesis of Mannich bases: (i) the development of extremely mild conditions, enabling the use of highly functionalized sub­ strates; and (ii) increasing control of regiochemistry and stereochemistry, two aspects of the Mannich re­ action that had been virtually ignored prior to the 1970s. Because of the recent impact which preformed iminium salts and imines have had on the Mannich reaction, this review focuses almost entirely on their applications, which comprise the next two sections. Each of the subsections is arranged according to the type of N-substitution because of the important role N-substituents play in the reactivity of the iminium salt or imine and in the elaboration of the Mannich base. Cyclic preformed iminium salts and imines and in situ methods for the formation of imines are also included as subsections. Additional divisions of sub­ sections are used where the literature is more extensive, especially in Sections 4.1.2.2 and 4.1.3.2, and The Bimolecular Aliphatic Mannich andRelated Reactions 895 are arranged accordingto the nature of the active methylene compound. Every attempt has been made to cite review articles covering prior work with the intent of providing the reader with both a direct and an indirect avenue to all of the literature pertaining to the bimolecular Mannich reaction. Due to the number of excellent review articles of the classical tricomponent Mannich reaction and to the lack of significant new methodology (see, however, Section 4.1.1.5), only a brief overview is given. This overview includes a discussion of the scope and limitations of the classical Mannich reaction as a prelude to the more recent methodology. The reader should note that Mannich reactions involving aromatic hydrogen donors are covered in Chapter 4.2. 4.1.1.3 Mechanism A detailed account of the mechanism of the Mannich reaction and factors that affect the selection of conditions has been written by Thompson.5 Only the salient features of the mechanism are given here. For the conditions under which the Mannich reaction is most commonly performed, i.e. protic solvents and acid catalysis (usually by employing the amine component as its hydrochloride salt), the mechanism is thought to involve the intermediacy of a highly reactive, positively charged iminium ion (10), which reacts with the active methylene component in its enol form (11) to produce the Mannich base (12; Scheme 1). This step has an obvious parallel to the aldol condensation. Formation of (10) occurs by de­ composition of a methylenediamine (9) or, to a lesser extent, a hydroxymethylamine (8), both of which are generated reversibly by condensation of the aldehyde and amine components. Acid catalysis not only promotes the decomposition of (8) and (9) to the iminium salt (10), but also the enolization of the active methylene component. Protic solvents, by virtue of their high dielectric constant, also support the forma­ tion of the charged iminium species. Elevated temperatures are often necessary for generation of suffi­ cient concentrations ofiminium ions. (11) (12) Scheme 1 In Mannich reactions performed in basic media, the active aminomethylating species is less well defined. It may be a methylenediamine (9), a hydroxymethylamine (8), or an alkoxymethylamine (ROCH2NR2') (in alcoholic solvents). Aminomethylation in base-catalyzed Mannich reactions, as shown for cyclohexanone, is believed to occur by an SN2 mechanism in which the enolate (13) displaces either NR2-, OH-, or OR- from one of the intermediates above (Scheme 2). o (X =NR , OH, OR) 6 2 (13) Scheme 2 896 Additions ofNucleophilic Alkenes to C=NR and C NR2+ Depending upon the nature of the substrates involved, the Mannich reaction may be reversible. In cases where isomeric products are possible, product ratios may therefore reflect thermodynamic factors. 4.1.1.4 Scope and Limitations Active methylene compounds ranging in acidity from ~-keto esters, malonates and nitroalkanes (pKa = 9-13) to ketones (pKa = 16-20) can be used in the Mannich reaction. The lack of examples using simple unactivated esters (pKa =25) appears to be due to their weaker acidity or to transamination and/or hydro­ lysis side reactions. Enolizable aldehydes have also been used in certain instances; however, side pro­ ducts arising from subsequent aldol condensation of the resulting ~-amino aldehyde often occur. Best results are achieved with a-branched aldehydes, which produce Mannich bases without enolizable protons. Of the amine components that may be used, secondary amines react the most predictably and in the highest yields, giving tertiary Mannich bases. Here steric factors are important since reactions employing dimethylamine and cyclic amines tend to be more successful than those employing bulkier secondary amines. With primary amines, yields are more unpredictable because the initially formed secondary Mannich base (14) can further react to give a tertiary amine (15; equation 3). Bulky primary amines 11 and, interestingly, use of amine oxalate salts12 instead of hydrochloride salts tend to suppress these cross­ condensation reactions. The use of ammonia for the synthesis of primary Mannich bases is more compli­ cated because of the greater likelihood of obtaining products derived from multiple substitution. The synthesis of primary Mannich bases can be achieved indirectly, however, by condensing a bulky primary amine containing a cleavable alkyl group. As shown in Scheme 3, benzhydrylamine (16) condenses cleanly with acetophenone (1) to give a secondary Mannich base (17), which upon deprotection affords primary Mannich base (18; Scheme 3).11 0 0 0 CH20 RI~NHR2 Rl~N~Rl (3) 0 I Rl~ R2 (14) (15) OMe OMe ~ 0 ~ ~ ~ CH20 0 A ~ N ~ if+HCI-H N ~ 2 I 90% H ~ #' ~ (1) (16) (17) j conc~HCt 74% 0 ~ NH2-HCI ~ (18) Scheme 3 The Bimolecular Aliphatic Mannich and Related Reactions 897 In cases involving unsymmetrical ketones, mixtures of regioisomeric Mannich bases are usually obtained.
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