Reactions hetero-annulation

Transition metal catalyzed hetero-annulation provides a useful and convenient tool for the construction of N-heterocycles [1]. Quinolines are of special interest in that they display attractive applications in pharmaceuticals and are synthetic building blocks [2, 3]. Catalytic processes employing palladium [4—6], rhodium [7-9], ruthenium [10-14], and iron [15] have been studied and developed to synthesize quinoline skeletons. There are five common methods used to prepare substituted quinolines the Skraup reaction [16], the Doebner-Von Miller reaction [17], the Conrad-Limpach reaction [18], the Friedlaender reaction [19, 20], and the Pfitz-inger reaction [21, 22]. All five of the reactions require environmentally unfriendly acids or bases, high temperatures, or harsh conditions. Quinoline yields are usually low due to numerous side reactions. Even though much work has been done to find catalytic routes to quinolines, the use of non-precious metals remains an active area of research. 

In the traceless, solid-phase synthesis of hetero-annulated l,3-oxazine-6-ones, significant rate enhancement was observed across a range of steps carried out using microwave heating (Scheme 4.15)." ° In a similar traceless, solid-phase approach, a number of 2,4,6-trisubstituted thiazolo[4,5-rf]pyridine-5,7-dione derivatives have been prepared using microwave heating as a key step. An amino ester resin was first swollen in DMSO then an isocyanate was added, and the reaction mixture was heated to 150 °C to yield a thiazolourea, which was converted to the final product in another three steps on the support before a final cleavage protocol (Scheme 4.16). 

The application of transition metal-mediated reactions on solid support is an area of supreme interest for both peptide chemistry and the synthesis of nonpeptidic drug-like molecules. Although many metal-catalyzed reactions have been carried out on resin-bound scaffolds, there are scarce examples of metal-mediated solid-phase reactions promoted by a complexing agent that is covalently bound with the resin in close proximity of the scaffold. Dai and Sun have recently proposed an ingenious route toward the microwave-assisted solid-phase synthesis of a small library of 2-(hetero)aryl indoles. The authors demonstrated the strategic use of a tailor-made linker that features the dual function of a normal linker for scaffold attachment as well as of a promoter for the Cu(II)-mediated hetero-annulation of the intermediates (Scheme 8.17). 

This reaction principle has considerable scope, as shown by the synthesis of various hetero-annulated 1,4-benzodiazepines. For example, [l,2,3]triazolo[l,5-a]... 

Scheme 3.36 Synthesis of tricyclic furans by a novel tandem reaction intramolecular [3+2] hetero annulation of allylsllanes with cyclic 1,3-diketones.

Another recent development in the field of palladium-catalyzed reactions with alkynes is a novel multicomponent approach devised by the Lee group. Starting from a-bromovinyl arenes and propargyl bromides, the assembly ofeight-membered car-bocycles can be realized via a cross-coupling/[4+4] cycloaddition reaction. The authors also presented the combination of a cross-coupling and homo [4+2], hetero [4+2], hetero [4+4] or [4+4+1] annulation leading to various cyclic products [147]. 

In order to study any chemoselectivity influences of microwave irradiation on the domino Knoevenagel/hetero-Diels-Alder process (the so-called Tietze reaction), Raghunathan and coworkers [31a] investigated the transformation of 4-hydroxy coumarins (10-85) with benzaldehydes 10-86 in EtOH to afford pyrano[2,3-c]cou-marin 10-87 and pyrano[2,3-b]chromone derivatives 10-88. Normal heating of 10-85a and 10-86a at reflux for 4h gave a 68 32 mixture of 10-87a and 10-88 in 57% yield, whereas under microwave irradiation a 97 7 mixture in 82% yield was obtained. Similar results were found using the benzo-annulated substrates 10-85b and 10-86b. 

What is described as a domino Knoevenagel-hetero-Diels-Alder reaction , involving the reaction of the glucose-derived aldehyde 93 with a 1,3-dicarbonyl compound in presence of either proline or ethylenediammonium acetate, leads to the doubly annulated 5 6 6-fused compound 94 (Scheme 30) <2004S1150>. If the dicarbonyl compound is Meldmm s acid, however, the sequence is completed by spontaneous elimination of acetone and carbon dioxide from the Diels-Alder adduct, to give compound 95 <2005ASC1353>. 

The above examples represent Jl-heteroaromatic annulation involving the reaction of allyl anions whose double bond is a part of the heterocyclic ring system (Scheme 1). The corresponding a-oxoketene dithioacetals (1,3-electrophilic component) were generally derived from nonheterocyclic carbonyl precursors. Alternatively the Jl-heteroaromatic annulation can also be employed to a-oxoketene dithioacetals derived from heterocyclic ketones (1,3-bielectrophile) and hetero/nonheteroallyl anions (1,3-binucleophile). These reactions are described below. 

Tandem SNH-SNH cyclizations when a hetero-ring annulation is a result of two consecutive SNH reactions. 

An effect of high pressure on the diastereoselectivity is also observed for intramolecular hetero Diels-Alder reactions as found for the cycloaddition of the benzylidene-isoxazolone 8-23 to afford the cis-annulated 8-24 as the major product together with the frans-diastereomer 8-25 (Fig. 8-8) [549], However, the difference in activation volume with AAV =1.6 0.2 cm3 mol"1 is rather small. The activation volume with AV = 19.6 0.5 cm3 mol-1 at 343 K lies significantly below the usual values found for intermolecular cycloadditions of 1-oxa-1,3-butadienes, indicating that this reaction may be on the border line to a two-step reaction but see also below. 

Mechanistically, the sequence commences by coupling of the (hetero)aroyl chloride 7 and the aUcyne 4 to give the alkynone 8 (Scheme 43). Upon addition of the tryptamine derivative 73 the enaminone 75 is obtained. Finally, the addition of the a, p-unsaturated acid chloride 71 triggers the aza-annulation reaction to furnish the acyliminium ion 76 which terminates the sequence by a Pictet-Spengler cyclization. 

Schweitzer has synthesized alkylidene cyclopropanes by Wittig reaction with a cyclopropyl phosphonium salt. If, however, the electrophilic character of the cyclopropane is enhanced by a second acceptor group (e.g. CO2R, SR), suitable nucleophiles are able to attack the three-membered ring. The resulting ylid can form hetero- and carbocycles by an intramolecular Wittig reactionas demonstrated in equations 62 and 63. These annulation reactions have been applied to terpene and alkaloid preparations. 

Reactions of nitroalkenes and enamines take place not only in good chemical yields but also in excellent diastereomeric yields (>W%) . A topological rule has been formulated for carbon-carbon bond-forming processes between prochiral centres in enamines and nitroalkenes as well as other systems The reaction of enamines and imines with acrylamide results in aza-annulation ° . Other electrophilic alkenes which have been us to alkylate enamines and the products used in hetero- or carbocyclic synthesis include ethyl /5-nitroacrylate, where reaction occurs beta to the nitro not the ester group, 2- phenylseleno)prop-2-enenitrile [CH2 = C(SePh)CN] , phenyl a-phenylselenovinyl sulphone [CH2 = C(SePh)-S02Ph] and phenyl a-bromovinyl sulphone. An electrophilic allene, phenylsulpho-nylpropadiene, has also been used to alkylate enamines (Scheme 44). 

The complex spiro hetero-/-fused naphtho[l,2-6]pyrans e.g. 63 show two absorption bands (444 - 474 and 568 - 582 nm) and have half-lives of 2 - 3 minutes <00JP344761, 00JP344762>. The synthesis of 4-acetoxy-l-phenyl-2-naphthylamine from 4-hydroxy-l-phenylnaphthalene-3-carboxylic acid allows annulation of an isoquinoline unit onto 1-naphthol and subsequent reaction with a propynol yields the fused pyranophenanthridine 64, Xmax 550 nm, t /2= 12 s (polymethacrylate) <02USP6379591>,... 

Dihydroxynaphthalene and 9,10-diacetoxyphenanthrene react with 1,2-diols and 1,2-dithiols in a one-pot synthesis of annulated 2,3-dihydro-1,4-dioxins and -1,4-dithiins (Scheme 26) <04TL1343>. The reaction of 2,3-dihydroxynaphthalene with 1,2-dihalogenated aromatic compounds leads to linearly annulated dioxins of particular interest are tri- and tetra-dioxins and various hetero-fused dioxins e.g. 62 (34%). Several examples yield cation radical salts on electrocrystallisation <04T8899>. Linear arrays of fused pyran-dioxin-cyclohexane rings as found in natural products derived from the milkweed family have been described e.g. 63 <04EJO4911>. 

The majority of the intramolecular (2 + 2)-cycloreversions of hetero-bicyclic compounds proceed via ring opening of an annulated cyclobutene or azetine ring. Only in one instance has the same reaction of a cyclobutane ring been proposed as an intermediate step, viz., in the reaction of a thiirene 1,1-dioxide with enamines (Section II,B).33... 

Nucleophilic reactions take place on the hetero ring of isoquinoline, preferably in the 1-position. For instance, the Chichibabin amination with NaNH2 in liquid ammonia yields 1-aminoisoquinoline 5. The Ziegler reaction with w-butyllithium furnishes the 1-substituted product 7 as with quinoline, benzene ring annulation stabilizes the primary addition product 6 (1,2-dihydroisoquinoline), which can be isolated and dehydrogenated to 7 by nitro compoxmds ... 

A formal [4h-2] cycloaddition between arylidenoxin-doles and ethyl allenoate afforded dihydropyran-fused indoles, as shown by Wang and colleagues (Scheme 10, equation 1) [67]. Density functional theory (DFT) implicates a stepwise mechanism. A not-unrelated synthesis of indole-annulated dihydropyrano[3,4-c]chromenes via a hetero-Diels-Alder reaction was discovered by Jha and colleagues (equation 2) [68]. The requisite precursors 26... 

Kiamehr, M. and Moghaddam, F. M. 2009. An efficient ZnO-catalyzed synthesis of novel indole-annulated thiopyrano-chromene derivatives via Domino Knoevenagel-hetero-Diels-Alder reaction. Tetrahedron Lett. 50(48) 6723-6727. 

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