Heterocyclic syntheses acidic conditions

Alkylations. Treatment of 1 with various primary alkyl halides provides the corresponding substituted dithianes (eqs 3-5 ). Removal of the dithiane under the Lewis acid conditions, illustrated in eqs 3-5, unmasks the acyl silane for subsequent transformations such as photolysis, radical reactions, and heterocyclic synthesis. Other conditions for removing the dithiane moiety of 2-substituted-2-f-butyldimethylsilyl-l,3-dithianes include anodic oxidation, ceric ammonium nitrate (CAN)/NaHC03 in CH3CN/H2O, iodomethane/CaC03 in THF/H20, 8 and l2/CaC03 in THF/H2O. The formyl sUane of 2-t-butyl-dimethylsilyl-l,3-dithiane has also been reported." ... 

Cacchi and Palmier (83T3373) investigated a new entry into the quinoline skeleton by palladium-catalyzed Michael-type reactions. They found that phenyl mercurial 134 was a useful intermediate for the synthesis of quinoline derivatives, and that by selecting the reaction conditions the oxidation level of the heterocyclic ring in the quinoline skeleton can be varied. On such example is shown in Scheme 16. PdCla-catalyzed coupling between organomercurial reagent 134 and enone 135 delivered adduct 136 which was subsequently cyclized to quinoline 137 under acidic conditions. 

Moore and Willer reported the synthesis of some nitramine explosives containing a furazan ring fused to a piperazine ring. The tetranitramine (46) is synthesized from the condensation of 3,4-diaminofurazan (DAF) (24) with glyoxal under acidic conditions followed by A-nitration of the resulting heterocycle (45). The calculated performance for the tetranitramine (46) is very high but the compound proves to be unstable at room temperature. Instability is a common feature of heterocyclic nitramines derived from the nitration of aminal nitrogens. 

The well-known application of 2,4,6-tris(ethoxycarbonyl)-l,3,5-triazine as a diene in inverse electron demand Diels-Alder cyclizations was adapted for the synthesis of purines <1999JA5833>. The unstable, electron-rich dienophile 5-amino-l-benzylimidazole was generated in situ by decarboxylation of 5-amino-l-benzyl-4-imidazolecarboxylic acid under mildly acidic conditions (Scheme 54). Collapse of the Diels-Alder adduct by retro-Diels-Alder reaction and elimination of ethyl cyanoformate, followed by aromatization by loss of ammonia, led to the purine products. The reactions proceeded at room temperature if left for sufficient periods (e.g., 25 °C, 7 days, 50% yield) but were generally more efficient at higher temperatures (80-100 °C, 2-24 h). The inverse electron demand Diels-Alder cyclization of unsubstituted 1,3,5-triazine was also successful. This synthesis had the advantage of constructing the simple purine heterocycle directly in the presence of both protected and unprotected furanose substituents (also see Volume 8). 

Bis-substitution of stilbene produces stronger fluorescence and the bis-triazine derivatives of diaminostilbenes have proved to be the most successful brighteners for cellulosics, in particular, and polyamides (60MI11200). The variety of substitution permutations in (90) is almost endless and many primary and secondary homocyclic and heterocyclic amines, thiols and phenols have been used. Synthesis of such compounds is straightforward and utilizes the convenient selectivity to substitution of cyanuric chloride. 4,4 -Diaminostilbene-2,2 -disulfonic acid condenses readily at 0-5 °C with cyanuric chloride, under slightly acidic conditions. In this case cyanuric chloride behaves as a monofunctional acid chloride and, although some by-products are unavoidable, two molecules of cyanuric chloride condense... 

Heterocyclic synthesis, from nitrilium salts under acidic conditions, 6, 95 Hilbert-Johnson reaction of 2.4-dialkoxy-pytimidities, 8, 115... 

The second example is an interesting synthesis of the heterocyclic amino acid tryptophan (R = 3-indolymethyl) which involves the initial base catalysed 1,4-addition (the Michael reaction, Section 5.11.6, p. 681) of diethyl acetamido-malonate to the oc,/ -unsaturated aldehyde, acrylaldehyde, yielding the aldehydic derivative (38). The derived phenylhydrazone (39) is then cyclised under acidic conditions (see Expt 8.26) to form the indolylacetamidomalonate derivative (40) which is then converted into the corresponding a-amino acid (i.e. tryptophan) in the usual way (Expt 5.184). 

Pyrazolines containing aryl substituents with some functional groups can be used in the synthesis of new heterocycles. For example, the reaction of 5-(2-hydrohyphenyl)pyrazolines 111 with noncyclic 112 or cyclic carbonyl compounds under acidic conditions yields dihydropyrazolo[l,5-c]-l,3-benzox-azines 114 and 115, respectively [167, 168, 169] (Scheme 2.30). 

Cazes et al. reported the Pd-catalyzed intermolecular hydroamination of substituted allenes using aliphatic amines in the presence of triethylammonium iodide leading to allylic amines [19]. In a way similar to the Pd-catalyzed hydrocarbona-tion reactions we reported that the hydroamination of allenes [20], enynes [21], methylenecyclopropanes [22], and cyclopropene [10] proceeds most probably via oxidative addition of an N-H bond under neutral or acidic conditions to give allylic amines. The presence of benzoic acid as an additive promotes the Pd-medi-ated inter- and intramolecular hydroamination of internal alkynes [23]. Intramolecular hydroamination has attracted more attention in recent years, because of its importance in the synthesis of a variety of nitrogen-containing heterocycles found in many biologically important compounds. The metal-catalyzed intramolecular hydroamination/cyclization of aminoalkenes, aminodienes, aminoallenes, and aminoalkynes has been abundantly documented [23]. 

Heterocycles (167) and (168) react with sodium hydride yielding the pyrano[2,3-/>]pyridines (130) <92JOC1930> and 1,8-naphthyridine derivatives (111) <92JMC518> respectively a related synthesis of tetrahydropyrano[2,3-6]pyridines has been reported <71JCS(B)279>. Under acidic conditions, the diester (169) affords heterocycle (170) (44% yield) <93H(35)93>. The sulfone (171) reacts with LDA giving an intermediate (172) which cyclizes yielding the sulfone (173) (Scheme 1) <84JOC5l36>. 

In a recent article by Beifuss and co-workers [126], the synthesis of pyrido [2, l 2,3]imidazo[4,5-c]isoquinolin-5(6//)-ones 90 has been described in good yields by means of a microwave-assisted three-component reaction of a 2-amino-pyridine, an isocyanide and a 2-carboxybenzaldehyde under acidic conditions. The reactions are easy to perform, robust, and highly efficient. This process allows the formation of two heterocyclic rings and four new bonds in a single synthetic operation (Scheme 67) ... 

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