Intermolecular unsaturated aldehydes

In each of the tandem iminium ion/enamine cascade processes described above, the enamine is trapped in an intramolecular fashion. The ability to perform the trapping seQuence in an intermolecular manner would allow for the one—pot introduction of three points of diversity. IVIacNlillan has realised this goal and described a series of secondary amine catalysed conjugate addition—enamine trapping sequences with oc P Unsaturated aldehydes using tryptophan derived imidazolidinone 115 to give the products in near perfect enantiomeric excess (Scheme 47) [178]. 

Intramolecular photoaddition in cis-5,5,6-trimethylhepta-3,6-dien-2-one (284) takes a different course,296 yielding not the oxetane but the two dihydropyrans (285 and 286). This is in contrast to the inter-molecular cycloaddition of a, jS-unsaturated aldehydes to alkenes which affords only oxetanes, and has been accounted for in terms of diradical intermediates (287 and 288) formed from the s-cis conformation (284) of the dienone. The intermolecular equivalent is thought to occur by addition to the s-trans conformation. 

Further efforts demonstrate that the reaction of triethyl phosphite occurs under quite mild conditions in a conjugate manner with a wide range of oc,p-unsaturated aldehydes provided that a proton source is present (Scheme 5.21). The use of protic solvents, such as alcohols or phenols, not only provides a source of proton for the anionic site of the zwitterionic adduct but also furnishes a nucleophile for the required dealkylation step. The simplest hypothesis consistent with all of these facts is that the protonation-valency expansion of the quasiphosphonium ion intennediate using a proton source proceeds at a rate greater than the intermolecular pathway to enol ether. ... 

Hydroacylation is especially interesting in its intramolecular version, converting unsaturated aldehydes to cyclopentanones. Numerous examples of transition metal catalyzed hydroacylations have been described, mostly with 4-alkenals of various substitution patterns. The reaction is used for the construction of starting materials in prostaglandin synthesis and the preparation of other cyclopentanoid systems. Rhodium catalysts, mainly of the Wilkinson type, are used. The steric course of hydroacylation is believed to occur in a m-addition manner. This was deduced from results of intermolecular alkyne hydroacylation56 (vide supra) and the intramolecular hydroacylation of deuterated E- and Z-isomers of 7,5-unsaturated aldehydes39-5 . 

Intermolecular reactions involving non-aromatic precursors have been used to furnish salicylate esters., p-Unsaturated aldehydes have been reacted with the dianion (DA) of ethyl acetoacetate to afford 4-substituted salicylates in good yield (ref. 36). 6-Methylsalicylates result from the addition of the monoanion (MA) at C2 (ref.37). 

A strategy developed by Tietze and coworkers early in his independent career involved the application of intramolecular or intermolecular inverse electron demand hetero-Diels-Alder reactions to iridoid total synthesis. The intermolecular [4+ 2]-cycloaddition of ethyl vinyl ether and unsaturated aldehyde 31 provided acetal 32, which underwent double bond isomerization to afford 33 (Scheme 1) An intramolecular variant of this reaction is discussed in detail later (Scheme 10). More recently, Jacobsen and Chavez extended this work with the enantio- and diastereoselective synthesis of a range of iridoid natural products. Utilizing tridentate Cr(III) catalyst 34, acetal 35 was prepared in 98% ee with good diastereoselectivity (Scheme 1)P... 

Shi and coworkers reported a particularly challenging example in the intermolecular cross-conjugate addition between nitro alkenes and a,p-unsaturated aldehydes catalysed by prolinol lb in methanol as solvent (Scheme 7.14). ... 

Mechanistically related to the Mukaiyama aldol reaction, the carbonyl ene reaction is the reaction between an alkene bearing an allylic hydrogen and a carbonyl compound, to afford homoallylic alcohols. This reaction is potentially 100% atom efficient, and should be a valuable alternative to the addition of organometallic species to carbonyl substrates. However, the carbonyl ene reaction is of limited substrate scope and works generally well in an intermolecular manner only with activated substrates, typically 1,1-disubstituted alkenes and electron-deficient aldehydes (glyoxylate esters, fluoral, a,p-unsaturated aldehydes, etc.), in the presence of Lewis acids. The first use of chiral catalyst for asymmetric carbonyl ene was presented by Mikami et al. in 1989. ° By using a catalytic amount of titanium complexes prepared in situ from a 1 1 ratio of (rPrO)2titaniumX2 (X = Cl or Br) and optically pure BINOL, the homoallylic alcohols 70a,b were obtained in... 

The first organocatalytic intermolecular asymmetric aldol reaction was reported by List and coworkers in 2000 [23]. The aldol reaction between acetone and a variety of aldehydes was accomplished in excellent yields and high levels of e-nantioselectivity. For example, the aldol product of the coupling with o-butyral-dehyde was formed in 97 % yield and 96 % ee ((1), Scheme 4.10). The remarkable levels of selectivity sparked massive interest in the field of proUne-catalysed aldol, Michael and Mannich reactions. Later that year MacMillan reported a phenylalanine-derived catalyst (35) for the Diels-Alder reaction of a-P-unsaturated aldehydes with up to 94 % ee ((2), Scheme 4.10) [24]. Many further applications of... 

Hayashi, et al. developed an enantioselective formal aza [3+3] cycloaddition of a,p-unsaturated aldehydes and enamide (enecarbamate) providing tetrahydropyil-din-2-ol in excellent enantioselectivities and yield. Scheme 3.50 [66]. The reaction comprised four consecutive reactions ene reaction, isomerization of imine to enecarbamate, hydrolysis and hemiacetal formation. Noteworthy, examples of a,P-unsaturated aldehydes acting as enophile in intermolecular catalytic enantioselective ene reaction are rare, and the reaction developed by Hayashi represents one of the successful example in such category. 

A one-step Lewis acid-catalysed intermolecular 4- -3-cycloaddition of aromatic a,)3-unsaturated aldehyde and ketones (105) with epoxides (106) formed seven-membered oxacycles (107) under mild conditions (Scheme 34).The effect of oxygen-, sulfur-, and halogen-substituents on the reactivity of nitrogen-stabilized oxyallyl cations in 4- -3-cycloaddition reactions has been extensively investigated. Aza-oxyallyl cationic intermediates react with cyclopentadiene and furan via an aza-4 -I- 3-cycloaddition reaction to form bicyclic cycloadducts in moderate yields. The intramolecular formal 4- -4-cycloaddition of conjugated enynes with an e-deflcient cyclobutene (108) yielded a strained six-membered cyclic allene (109) that isomerized to a 1,3-cyclohexadiene (110). This intermediate underwent a thermal or acid-promoted six-electron electrocyclic ring opening to yield a 2,4,6-cyclooctatrienone (111) (Scheme 35). ... 

More recently, Enders et al. disclosed a facile access to tetracyclic double annulated indole derivatives 175, which basically relies on the chemistry of the acidic 2-substituted indole and its nitrogen nucleophilicity. Indeed, the employed quadruple cascade is initiated by the asymmetric aza-Michael-type A-alkylation of indole-2-methylene malono-nitrile derivative 174 to o,p-unsaturated aldehydes 95 under iminium activation (Scheme 2.57). The next weU-known enamine-iminium-enamine sequence, which practically is realized with an intramolecular Michael addition followed by a further intermolecular Michael and aldol reactions, gives access to the titled tetracyclic indole scaffold 175 with A-fused 5-membered rings annulated to cyclohexanes in both diastereo- and enantioselectivity [83]. 

Intermolecular Lewis Acid Catalyzed Reactions of a,p-Unsaturated Aldehydes and Ketones with Alkenes. 

Enantioselective organocatalytic 1,4-addition reaction to an a,p-unsaturated aldehyde and an intermolecular Diels-Alder reaction. 

Generation of 1-Azadienes. 0-Silyloximes have also been used to generate 1-azadienes for [4 + 2] cycloadditions. Thus an 0-silyloxime of an a, -unsaturated aldehyde can be treated with an acid chloride or chloroformate in the presence of chlorotri-methylsilane and aluminum chloride to give an a-cyanohydrox-amic acid derivative, which upon mild thermolysis forms an aza-diene (eq 2). These azadienes undergo efficient intermolecular [4 + 2] cycloadditions or, with a tethered alkene, intramolecular cycloadditions. 

Tab. 6.1. Syntheses of alkenes and polyenes by intermolecular McMur reactions of saturated and unsaturated aldehydes and ketones.

A new Rh(III)-catalyzed intermolecular annulation of Af-methoxybenzamides with a, -unsaturated aldehydes or ketones to afford azepinones 118 was reported by Glorias eta/. (Eq. (5.109)) [56a]. The reaction involves a tandem C-H activation, cyclization, and condensation sequence. The substrates with other A/-substituents, such as H, phenyl, and OPiv, did not afford the corresponding products. Vinylcarbenoids were also used as the three-carbon component in the Rh(III)-catalyzed C-H activation and [4-1-3] cycloaddition with benzamides to access azepinones (Eq. (5.110)) [56b]. 

An efficient synthesis of 1,2-oxazepines from Af-phenoxyacetamides and a, P-unsaturated aldehydes under room temperature through Rh(III)-catalyzed intermolecular [4+3] aimulation was reported by Zhao and coworkers (Scheme 6.32) [47]. It is worth noting that 1,2-oxazepine is readily transformed to chroman... 

The generation of an iminium ion of a, 3-unsaturated carbonyl compounds lowers the LUMO energy. As a result, the cx-CH acidity increases as well as the ability to participate in conjugate additions. The first organocatalyzed 1,4-addition to a,j3-unsaturated aldehydes was reported by the MacMillan group [78]. For theoretical explorations of the configurative outcome of Michael additions of pyrroles and indoles to crotonaldehyde see Reference [79]. This transformation has been widely used in Friedel-Crafts alkylations of a,(5-unsaturated carbonyl compounds (see Reference [lb] and reports cited therein). Comparable examples of this transformation with ( )-crotonaldehyde in the intermolecular series were found in aryl alkylation with trifluoroborate (58 and 60) [80], indole alkylation (62) [81], Friedel-Crafts alkylation of electron-rich benzenes (64) [82], and Friedel-Crafts alkylation with phosphonates (65) [83] (Scheme 4.21). 

The use of phosphoric acid ml-lGd for the catalysis of a tandem double F-C reaction gave rise to fluorene derivatives (up to 96% ee) by the reaction between indoles and 2-formylbiphenyl derivatives [74]. Vinyl indole derivatives combined with a,P-unsaturated aldehydes gave rise to functionalized tetrahydrocarbazoles with two or more stereocenters via an intermolecular triple cascade process by means of secondary amine 7a catalysis [75]. Catalyst 7a also promoted a quadruple F-C/Michael/Michael/aldol condensation reaction between indoles, acrolein, and aromatic nitroolefins (Scheme 35.19) [76]. This work provides a straightforward... 

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