Vinylogous Mannich addition

Triisopropylsilyloxyfurans were effective nucleophiles for the vinylogous Mannich addition to iminium ions that were formed by Rh2(cap)4-catalyzed oxidation of N-alkyl groups by THYDRO <06JA5648>. A stereoselective addition of 2-trimethylsilyloxyfurans to aryl aldehydes-derived aldimines employing a chiral phosphine/Ag complex as catalyst was developed <06AG(I)7230>. The prototypical example is shown below. 

Scheme 6.78 Typical products of the vinylogous Mannich addition of a,a-dicyanoalkenes to N-Boc-protected aldimines catalyzed by 63.

The synthetic utility of vinylogous Mannich additions of 2-silyloxyfurans to cyclic iminum ions <2001T3221> that provided threo- mAucts predominantly was demonstrated by the assembly of the complete carbon framework during the total synthesis of the plant alkaloid, crommine, as shown in Scheme 11 <1996JA3299, 1999JA6990>. 

In the laboratory of S.F. Martin, a biomimetic approach toward the total synthesis of ( )-strychnine was developed by using tandem vinylogous Mannich addition and HDA reaction to construct the pentacyclic heteroyohimboid core of the natural product.The commercially available 4,9-dihydro-3/-/-P-carboline was first converted to the corresponding A/-acylium ion and then reacted with 1-trimethylsilyloxybutadiene in a vinyiogous Mannich reaction. The resulting cycloaddition precursor readily underwent the expected HDA reaction in 85% yield. 

Addition of carbon nucleophiles to furfural tosylhydrazone provides 5-substituted 2E,4E-pentadienyls in good yields <00TL2667>. The ab initio calculations at the RHF/3-21G level have been utilized to study the origins of diastereoselectivity of the vinylogous Mannich reaction of 2-methylfuran with pyrrolinium ion . A simple procedure for isomerization of 2-furylcarbinols to cyclopentenones under neutral condition was reported and a new mechanism was proposed <00H(52)185>. 

The Schneider group independently reported an asymmetric vinylogous Mannich reaction (Scheme 27) [47]. Addition of silyl dienolates 73 to A-PMP-protected imines 74 was promoted by phosphoric acid (R)-3g (5 mol%, R = Mes) with mesityl substituents to afford tra i -a,p-nnsatnrated 8-amino esters 75 in high yields (66-94%) together with good enantioselectivities (80-92% ee). 

Among terpenoid substrates bearing the alkyl ketone moiety, 4-caranone" and 2-pincne-4-one," in addition to camphor, are worth mentioning. The stereoselectivity of aminomethylation" is remarkably affected by the reaction conditions moreover, the tendency of 2-pinene-4-one, like steroid substrates, to give the vinylogous Mannich base (Table 8, Chap. I, C. 1) is important. 

The vinylogous Mannich reaction of 2 silyloxy furans and imines may also be catalyzed through chiral Brpnsted acids, as shown by Akiyama et al. [10]. Previously, Akiyama [11] and Terada [12] had independently discovered that 3,3 substituted BINOL based phosphoric acids were excellent Bronsted acids for a broad range of mainly imine addition reactions via protonation of the imines and in situ formation of chiral iminium contact ion pairs. Using the slightly modified phosphoric acid 28 as catalyst carrying additional iodine substituents in the 6,6 positions, the y amino substituted butenolides 27 were obtained in excellent enantioselectivity and variable diastereoselectivity (Table 5.4). 

The Mannich reaction is a very common process that occurs in many tandem reaction sequences. For example, the Overman Aza-Cope cascade sequence is terminated by a Mannich reaction (cf. Scheme 35). Several groups have used variants of the Mannich reaction to initiate cascades that lead to the formation of heterocyclic molecules. For example, the Lewis acid-catalyzed intermolecular vinylogous Mannich reaction (01T3221) of silyloxy furan 281 with nitrone 282 produced a diastereomeric mixture (49 3 42 6) of azabicycles 284a-d in 97% combined yield (Scheme 52) (96TA1059). These products arose from an intramolecular Michael addition of the initially formed oxonium ion 283. 

In the addition of indole toiV-benzoyl aldimines, 3 also can be put to use. The catalyst IF is for promoting reaction between ketene silyl acetals and A-(o-hydroxyphenyl)aldimines, ° and the 3,3 -dimesityl analogue for vinylogous Mannich reaction. The imines are suitably activated as shown below. 

New Au(III)-pyridine-2-carboxylate complexes were developed to catalyze the intramolecular reaction between furan and acetylene to form phenols <04AE(G)6545>. These pre-catalysts provide higher reaction conversion than AuClj. The Lewis acid catalyzed vinylogous Mukaiyama-Mannich addition of trimethylsilyloxyfuran to aldimines, that generates 6-amino-Y-butenolide intermediates, was applied to the synthesis of piperidines... 

The Mannich reaction and its variants have been reviewed, mainly focussing on asymmetric catalysis thereof. Catalytic, enantioselective, vinylogous Mannich reactions have also been reviewed, covering both direct and silyl dienolate methods. Another review surveys Mannich-type reactions of nitrones, oximes, and hydrazones. A pyrrolidine-thiourea-tertiary amine catalyses asymmetric Mannich reaction of N-Boc-imines (e.g. Ph-Ch=N-Boc) with ethyl-4-chloro-3-oxobutanoate to give highly functionalized product (16). Addition of triethylamine leads to one-pot intramolecular cyclization to give an 0-ethyl tetronic acid derivative (17). ... 

The use of silyl dienolates in additions to iminium ions is known as the vinylogous Mannich reaction and constitutes an important expansion of this classic. Inter- and intramolecular versions of this transformation have been studied in great detail by Martin in the context of numerous total syntheses [110, 117]. As an example, silyl dienolate 128 intercepted iminium ion 127 to yield adduct 129 in 69% yield (Scheme 11.20) [118]. Subsequently, this adduct could be efficiently converted into 131 by addition to methyl vinyl ketone and intramolecular Michael reaction. Further elaborations of this key intermediate afforded the indole alkaloid (-)-ajmalicine (132). 

These two syntheses are prominent examples of advanced synthetic strategies in which polyketides are assembled with only a limited number of C-C bond-forming steps and in which vinylogous aldol reactions play a pivotal role. Besides these syntheses a number of additional examples in which vinylogous aldol reactions were put forward, including Mannich-type reactions, have been published [48-54]. 

Activation of C=N Double Bonds. TBDMS triflate has been used to promote additions to, and for the isomerization of, a number of systems containing carbon-nitrogen double bonds. TBDMS triflate is the optimal silyl triflate to promote the Mukaiyama-type vinylogous imino-aldol (Mannich-type) addition of 2-[(f-butyldimethylsilyl)oxy]furan to the IV-benzyl imine derived from (25)-2,3-0-isopropylideneglyceraldehyde (eq 36). ... 

C-l,4-addition/Mannich-type cyclization through respective intermediates 303 and 304. This finding invoked historical perspectives from Prelog s work in 1949 [139] and the enamine work of Stork et al. in the 1950s [140]. With the latter case, a distinct contrast could be generalized whereby cycloadditions of a,(3-unsaturated carbonyl systems with enamines mostiy led to carbo-[3+3] cycloaddition [138], and those with enaminones, or vinylogous amides, almost exclusively proceeded down the pathway of an aza-[3+3] cycloaddition. 

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