Hetero-annulation

In the 1998, Groebke [125], Blackburn [126], and Bienayme [127] independently reported an efficient method for the synthesis of imidazo[l,2-a]annulated hetero-bicyclic compounds. 

Except for several chapters in the comprehensive monograph on heterocyclic chemistry (84MI1) no special articles covering the recent past are available. This review is an attempt to discuss the literature up to Volume 117 (1992) covered by Chemical Abstracts together with some accessible papers published in 1993. Only isolable or spectroscopically identifiable thio-, seleno-, and teluropyrans without exocyclic double bonds (hetero-pyrones and heteropyranylidene derivatives) are considered. All benzo derivatives and their annulated heteroanalogs (spiroheteropyrans) are excluded. 

Thiazoles are important heterocycles and continue to be interesting synthetic targets because several classes of annulated thiazoles and thiazolyl (hetero)arenes display a diverse array of biological activities. 

In a synthesis of 2,3-di(hetero)arylpyrido[3,2 [l,4]thiazepines developed by Couture, 2-chloro-3-formylpyridine is reacted with arylmethylamines to form the imines. Deprotonation with LDA at -78 °C followed by treatment with non enolisable aryl thioesters gives the title compounds which may be further annulated by irradiation in benzene in the presence of iodine and propylene oxide <96S986> (Scheme 14). 

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. 

HETERO AROMATIC ANNULATION THROUGH HETEROALLYL ANIONS... 

Similarly, the [3-1-4] annulation of the E- and Z-isomers of /3-hetero-substituted acryloylsilanes 52 with lithium enolates of a,-unsaturated methyl ketones 54 gave stereospecifically the c -6,7-cyclopentyl-5-trimethylsilyl-3-cycloheptenone 55 (equation 20). The stereospecificity in the annulation was explained by an anionic oxy-Cope isomerization of the 1,2-divinylcyclopropanediol intermediate 56, which was generated through the Brook isomerization of the initial 1,2-adduct (equation 20). 

The synthesis of hetero annulated azocines is treated by L.G. Voskressensky, L.N Kulikova, T.N. Borisova, A.V. Varlamov (all of Russian Peoples Friendship University, Moscow). While azocino-[4,3- 7]indoles have been studied because many alkaloids contain this ring system the present survey covers all six isomeric azocinoindoles. 

Friedlander Hetero-Annulation for the Synthesis of Quinoline Derivatives... 251... 

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. 

Phthalodinitriles annulated with a hetero ring 04MI9. 

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). 

---