Imines/enamines, cyclic

Fig. 24 Cyclic imines/enamines from post-Ugi cyclization of amino ketones or amino aldehydes...

Enantioselective exocyclic, endocyclic, and acyclic a-p-tolylsulfinyl ketimines have been reacted with Et2AlCN 45 The cyclic substrates exhibit good yield and diastere-oselectivity, but the acyclic cases are complicated by imine-enamine equilibria. 

Marcus treatment does not exclude a radical pathway in lithium dialkyl-amide reduction of benzophenone. It does, however, seem to be excluded (Newcomb and Burchill 1984a,b) by observations on the reductions of benzophenone by N-lithio-N-butyl-5-methyl-l-hex-4-enamine in THF containing HMPA. Benzophenone is reduced to diphenylmethanol in good yield, and the amine yields a mixture of the acyclic imines no cyclic amines, expected from radical cyclization of a putative aminyl radical, were detected. An alternative scheme (17) shown for the lithium diethylamide reduction, accounts for rapid formation of diphenylmethoxide, and for formation of benzophenone ketyl under these conditions. Its key features are retention of the fast hydride transfer, presumably via the six-centre cyclic array, for the formation of diphenylmethoxide (Kowaski et al., 1978) and the slow deprotonation of lithium benzhydrolate to a dianion which disproportion-ates rapidly with benzophenone yielding the ketyl. The mechanism demands that rates for ketyl formation are twice that for deprotonation of the lithium diphenylmethoxide, and, within experimental uncertainty, this is the case. 

Taylor and Raw recently designed a tethered imine-enamine cascade sequence that converts 1,2,4-triazenes into substituted pyridines. In the presence of molecular sieves, A-methylethylenediamine (147) underwent condensation with excess cyclic ketone 148 (n — 1-4) to give imine-enamine 150 (04CC508). The enamine portion of the molecule then participated in an inverse-demand Diels-Alder cycloaddition reaction with 149 to provide intermediate 151. Cycloreversion of 151 with loss of N2 then gave 152 in which the tertiary amino group underwent addition to the adjacent imine functionality to afford zwiterionic 153. Finally, an intramolecular Cope elimination produced 154 in 74-100% yield. Several other triazines were also shown to participate in this novel cascade (Scheme 27). 

The first stage produces the usual pyridoxal imine/enamine compound and decarboxylation gives a compound that can cyclize and give the cyclic iminiiim salt by loss of pyridoxamine. 

In view of the various types of Pd-catalyzed intermolecular a-substitution of carbonyl compounds discussed above, it might readily be expected that their intramolecular versions can proceed satisfactorily to produce cychc compounds, provided that there is not an excessive ring strain in the cyclic structure to be formed. Indeed, ketones, esters, amides, nitriles, imines, enamines, and phenols containing haloaryl, haloalkenyl, and related electrophilic groups have been converted to the corresponding cyclic compounds under the influence of Pd catalysts, as detailed below. 

The E-isomer is generally more stable than the Z-isomer due to diminished steric hindrance, so it is assumed that the E-isomer is the major product (shown for 83). Water, a reaction by-product, may be removed to give a better yield of product and azeotropic distillation is used as well as molecular sieves (see Section 18.6.3). Enamines are structurally related to an end (HO—C=C) in that the heteroatom is directly attached to the alkene unit. Enamines are often isolable compounds, whereas enols tautomerize spontaneously to the carbonyl form. Note that when imine 76 is formed from iminium salt 80, there is no enamine product. In fact, the C-H in 80 is much less acidic that the N-H unit, so the product is the imine rather than the enamine. It is noted that there is an equilibrium between an imine and an enamine, known as imine-enamine tautomerism, but it will be ignored in this book. Many different secondary amines can be used in this reaction, including cyclic amines (see Chapter 26, Section 26.4.1) such as pyrrolidine (90), piperidine (91), and morpholine (92). It is important to note that it is generally easier to form an enamine from a ketone than from an aldehyde. 

As stated in the previous bullet, imine, enamine, and acetal forming reaction mechanisms are open to debate. Another point in these mechanisms where there is room for argument is in the proton transfers. Usually it is proposed that a solvent or other molecule picks up a proton from one atom and delivers it to another atom (as in Steps 3 and 4 in CTQ 21) but you can also accomplish this via a cyclic transition state. Such intramolecular proton transfer steps do not involve any other molecule, and are most favorable for six-member ring transition states. As noted in the activity, four-member cyclic transition states are not favorable. 

The addition of ketens or keten precursors to cyclic imines to form /3-lactams has been known for some time and has been reviewed in two monographs. Using this method, Bose and co-workers were able to synthesize epi-penicillins in very few steps. The addition is successful with thioimidates " " and dithioimidates such as (146), from which (147) can be obtained. However, when imine-enamine tautomerism is possible [e.g. (148)], the reaction fails and the acylenamine (149) is formed in... 

Tile existence of two annular tautomers in solution has been concluded from NMR spectroscopy for the cyclic A -acylbenzazoles 83 [82JPR(324)569]. Enamine and methylene imine tautomers have been described for condensed azolo-quinoxalines [93JHC782, 93JHC1463 95H2057] this type of tautomerism is discussed in detail for the [6.6]bicyclic compounds (see Section III,E,2). 

When enamines are treated with alkyl halides, an alkylation occurs that is analogous to the first step of 12-14. Hydrolysis of the imine salt gives a ketone. Since the enamine is normally formed from a ketone (16-12), the net result is alkylation of the ketone at the a position. The method, known as the Stork enamine reaction is an alternative to the ketone alkylation considered at 10-105. The Stork method has the advantage that it generally leads almost exclusively to monoalkylation of the ketone, while 10-105, when applied to ketones, is difficult to stop with the introduction of just one alkyl group. Alkylation usually takes place on the less substituted side of the original ketone. The most commonly used amines are the cyclic amines piperidine, morpholine, and pyrrolidine. 

The regioselectivity is an issue in substrates 141. With two alkyl substituents on the distal position, tetrahydropyridines 142 are the product. With only one alkyl substituent, the cyclic imine 143 was isolated for these rearrangement products it is unknown whether they stem from the enamine generated from a 5-endo-trig or 5-exo-digcydization (Scheme 15.44) [98]. 

Aliphatic c a -dibromo ketones, such as 2,4-dibromopentan-3-one (262), react with primary amines RNH2 (R = Me, Et, Pr, /-Pr or t-Bu) to give mixtures of imines 263 and lesser amounts of diimines 264. l,3-Dibromo-l-phenylpropan-2-one yields only the amide 265, the product of a Favorskii rearrangement. The nature of the products from aliphatic amines and cyclic a,a -dibromo ketones depends on ring size the cyclohexanone derivative 266 gave Favorskii amides 267 (R = Pr, /-Pr or t-Bu), while trans-2,5-dibromocyclopentanone afforded the enamines 268 (R = /-Pr or t-Bu) (equation 95)296. 

Most enamines, unfortunately, are sensitive to hydrolysis. The parent enamine, iV,iV-dimethylvinylamine, has in fact been prepared [3], but appears to be unstable. Enamines of cyclic ketones and many aldehydes can readily be isolated, however [4-7]. The instability of enamines might at first appear to diminish the utility of enamines as nucleophiles, but actually this property can be viewed as an added benefit enamines can be readily and rapidly generated catalytically by using a suitable amine and a carbonyl compound. The condensation of aldehydes or ketones with amines initially affords an imine or iminium ion, which then rapidly loses a proton to afford the corresponding enamine (Scheme 1). 

The first asymmetric enamine-catalyzed Mannich reactions were described by List in 2000 [208]. Paralleling the development of the enamine-catalyzed aldol reactions, the first asymmetric Mannich reactions were catalyzed by proline, and a range of cyclic and acyclic aliphatic ketones were used as donors (Schemes 24 and 25). In contrast to the aldol reaction, however, most Mannich reactions are syn selective. This is presumably due to the larger size of the imine acceptor, forcing the imine and the enamine to approach each other in a different manner than is possible with aldehyde acceptors (Scheme 23). 

A simple preparation of electron-poor 2-azadienes and the preliminary study of their ability to participate in [4 + 2] cycloadditions was done almost simultaneously by out group (87CC1195) (Scheme 49). The preparation of 2-azadienes 212 with two appended methoxycarbonyl groups was achieved, in a multigram scale and in nearly quantitative yield, by the insertion reaction of N- trimethylsilyl imines 210 into the carbon—carbon triple bond of dimethyl acetylenedicarboxylate to give 211 followed by protodesilylation with CsF/MeOH. Azadienes 212 underwent at room temperature inverse-electron demand [4 + 2] cycloaddition with cyclic enamines to give exclusively exo-cycloadducts 213 in 82-95% yield. Acid hydrolysis of them resulted in their aromatization to yield 2-pyrindine (n = 1] and isoquinoline (n = 2) derivatives 214. 

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