Intermolecular reactions unsaturated aldehydes

This has been applied to the cyclization of dihalides [45, 46], nonconjugated, unsaturated ketones [47] and esters [48], oxoalkylpyridinium salts [49], aldehydes and unsaturated nitriles [50], halides, and unsaturated esters [51], The umpoled acceptors, mostly radical anions or carban-ions (see Scheme 1), can also be used in intermolecular reactions such as acylation, alkylation, or carboxylation (Eq. 5). 

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 . 

Several contributions have appeared in which intermolecular reductive couplings between ketones or aldehydes and electron-deficient alkenes have been described [30h, 53]. Reactions of aldehydes and ketones with unsaturated esters result in the formation of lactones. Diastereoselectivities are normally modest in these cases, but can be quite high for certain substitution patterns (Eq. 45). 

Some diversity among the carbonyl components of the reaction has also been examined in the intermolecular reactions. For example, two groups have reported that the reaction of Cr(CO)3-complexed aryl aldehydes and ketones with oi,f -unsaturated esters leads to diastereomerically pure lactones, with radical coupling directed anti to the metal tricarbonyl center (Eq. 52) [60]. 

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... 

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). ... 

It is also worthwhile comparing the intramolecular photochemical cycloaddition reactions of ethylenic aldehydes and ketones with free radical intramolecular additions. For instance, irradiation of 5-hexen-2-one (470) (Scheme 161) in the gas phase gives the oxetane 471 as only cyclized product, as expected from the known photochemical intermolecular reaction between olefins and ketones. If the irradiation is conducted in solution 470 gives 471 (26%) and 472 (18%). With other y,< -unsaturated ketones, the bicyclic compound analogous to 472 may become the major product. With 2-allylcyclanones such as 473 (Scheme 161) bicyclic compounds are obtained (80% yield) as a mixture of 474 and 475, with 475 being the major product, but such compounds are difficult to isolate. " In the same manner, selective irradiation of the carbonyl group of 2-acyl-2,3-dihydro-4/f-pyrans (476) leads exclusively (23% yield) to exo-brevicomin (477) (a sex attractant), neither oxetane formation nor Norrish type II reaction being observed. The formation of the compounds 472, 475, and 477 which was considered as unexpected... 

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. 

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

Initial work in the early 1970s by Stetter and co-workers established the scope of the intermolecular reaction. Aromatic and heteroaromatic aldehydes are smoothly coupled to a,(3-unsaturated ketones, esters and nitriles under sodium cyanide or thiazolylidine catalysis (entries 1-5, 3a-d). In contrast, the coupling of aliphatic aldehydes and activated olefins (entry 6, 3e) is successful only under thiazolylidine catalysis. ... 

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]. 

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... 

---