Morita–Baylis–Hillman Cyclizations of Arene–Ruthenium‐Functionalized Acrylamides

Abstract

The conventional Morita-Baylis-Hillman (MBH) reaction entails condensation of an a,b-unsaturated carbonyl compound with an aldehyde to afford an a-hydroxyalkyl enone. [1] The reaction proceeds by initial conjugate addition between an enone and a nucleophilic promoter (usually a tertiary amine or trialkyl phosphine) to generate a zwitterionic enolate. Addition to an aldehyde electrophile and elimination of the nucleophilic promoter completes the reaction (Scheme 1). The products of MBH reactions are useful synthetic intermediates and building blocks; hence, considerable effort has been directed toward determining the mechanistic details of this transformation.[2] Variations of MBH reactions have been reported in which reactive enolates are prepared from enones in the presence of transition-metal or Lewis acid reagents.[1a] The range of electrophilic reaction partners also has been expanded to include activated ketones, other enones, [3] allylic electrophiles (including p-allyl-palladium complexes), [4,5] alkyl halides, [6] epoxides, [7] and aryl bismuth reagents. [8] Despite these noteworthy advances, the MBH reaction remains limited in scope owing to the reluctant participation of nonactivated and/or substituted a,b-unsaturated carbonyl compounds. Acrylamides especially have proven to be particularly difficult substrates, and only a few examples of MBH reactions between simple acrylamides and activated aldehydes have been reported. [9] In contrast to this generally observed reactivity profile, we have found that N-benzyl acrylamides metalated with a {CpRu II } fragment (Cp = cyclopentadienyl) readily undergo intramolecular MBH cyclizations in the presence of added nucleophile and base (Scheme 2). The ruthenium-arene fragment serves as the electrophilic reaction partner in these transformations, resulting in formation of ruthenium-cyclohexadienyl complexes as the initial products. Subsequent demetalation then delivers highly functionalized spirolactams. These transformations represent the first examples of direct metal-arene participation in MBH-type reactions. [10] We first became interested in exploring the feasibility of the reaction sequence shown in Scheme 2 after discovering that both N-benzyl acetoacetamides (1) and N-benzyl-bamidophosphonates (2) can be converted to 2-azaspirocyclic cyclohexadienyl complexes by an initial nucleophilic aromatic addition followed by enolate trapping and olefination, respectively. [11,12] Generation of a reactive enolate by means of an MBH-type reaction of a coordinated acrylamide, however, offers a more direct and potentially more versatile entry into the azaspiro[4.5]decane framework. Initial attempts to effect the conversion of the simple (N-benzyl acrylamide)-ruthenium complex 3 to the corresponding spirocyclic derivative under MBH conditions seemingly confirmed the sluggish reactivity of unsaturated amide substrates. After considerable experimentation, however, we were pleased to find that the reaction conditions shown in Equation (1) delivered the desired produc...

Cerium(iv) ammonium nitrate mediated 5-endo-dig cyclization of α-amino allenylphosphonates to spirodienones

“…For instance, in 2004, Wu and co-workers isolated annosqualine, a spirodienone lactam, from the stems of Annona squamosa L. 17 The classical methods of formation of azaspirodienones involve dearomative spirocyclization using hypervalent iodine reagents and phenol derivatives, [18][19][20][21][22][23][24] radical cyclization, 25,26 and Ru complex-mediated dearomatization. 27,28 In the course of our recent work on the synthesis of a-amino vinylphosphonates 29,30 through the reduction of a-amino allenylphosphonates, 31 such as 1, we were interested to prepare paramethoxybenzyl protected allenylphosphonates to easily deprotect them as free a-amino allenylphosphonates 2 (Scheme 1). Cerium ammonium nitrate (CAN) is a well-known reagent to deprotect N-sulfonyl N-para-methoxybenzyl compounds.…”

“…The structure of the spirodienone lactam 3 was determined by 1 H and 13 C NMR analysis and compared to similar structures presented in the literature. 28,33 To determine the mechanism of this cyclization we investigated the influence of all the substituents present on the starting material for the formation of the spirodienone lactam 3. The reduction of the allene moiety led to alkene 4 29 which was treated with CAN to prepare the spirodienone lactam 5.…”

Intramolecular Baylis-Hillman reaction: synthesis of heterocyclic molecules

“…When Pigge and co-workers used the β,β-disubstituted acrylamide derivative 32 as a substrate the double bond migrated product 33 was obtained as a major compound (one example is given in Equation 6). 43 Similarly in the case of substrate 34, double bond migrated product 35 was obtained exclusively (Scheme 13). Pigge and co-workers subsequently extended this methodology for polycyclic systems.…”

“…43 They have also performed demetallation of these products 27 using CuCl 2 to provide spirocyclohex-2,5-dien-4-one derivatives 28 (Scheme 11). 43 Similar treatment of enantiomerically pure acrylamide-ruthenium-arene complex 29 with tributylphosphine/NaH provided the spiro compound 30 which on oxidative demetallation with CuBr 2 /CO gave the corresponding oxidized product 31 in enantiomerically pure form in 55% yield (Scheme 12). When Pigge and co-workers used the β,β-disubstituted acrylamide derivative 32 as a substrate the double bond migrated product 33 was obtained as a major compound (one example is given in Equation 6).…”

Synthesis of 1-substituted 2-azaspiro[4.5]deca-6,9-dien-8-ones and 2-azaspiro[4.5]deca-1,6,9-trien-8-ones by condensation of 2,6-dimethylphenol with isobutyraldehyde and nitriles

“…2-Azaspiranes can also be obtained by oxidative radical ipsocyclization of N-[p-methoxy(hydroxy)benzyl]acetamides [18] and substituted N-benzyltrichloroacetamides [19]. Pigge et al [20][21][22][23][24] developed a procedure for the synthesis of 2-azaspiranes via aromatic nucleophilic substitution in the presence of (η 6 -arene)RuCp + complexes. Another possible way to 2-azaspiranes is based on the reaction of tricarbonyl (η 5 -1-alkyl-4-methoxycyclohexadienylium)iron with difunctional nucleophiles [25].…”