Heterocycles synthetic approaches

Pharmacologically active N-heterocycles, synthetic approach to 87YZ459. 

Furans, thiophenes and pyrroles have all been obtained by addition of alkynic dienophiles to a variety of other five-membered heterocycles, as illustrated in Scheme 104. As the alkynic moiety provides carbons 3 and 4 of the resulting heterocycle, this synthetic approach provides an attractive way of introducing carbonyl containing substituents at these positions, especially as many of the heterocyclic substrates are readily generated. Such reactions do... 

Thus, reaction of a 1,2-binucleophile with a 1,3-bielectrophile would lead to a five-membered heterocycle, as would the reaction of a 1,4-binucleophile with a 1,1-bielectrophile. Considering the reactions in this manner has several advantages and provides a convenient framework for considering synthetic approaches to target heterocycles. 

Polyfarylene vinylene)s form an important class of conducting polymers. Two representative examples of this class of materials will be discussed in some detail here. There are poly(l,4-phenylene vinylcne) (PPV) 1, poly(l,4-thienylene viny-lenc) (PTV) 2 and their derivatives. The polymers are conceptually similar PTV may be considered as a heterocyclic analog of PPV, but has a considerably lowci band gap and exhibits higher conductivities in both its doped and undoped stales. The semiconducting properties of PPV have been shown to be useful in the manufacture of electroluminescent devices, whereas the potential utility of PTV has yet to be fully exploited. This account will provide a review of synthetic approaches to arylene vinylene derivatives and will give details an how the structure of the materials relate to their performance in real devices. 

The majority of sequential radical reactions deal with cyclizations as the key steps. The constructions of carbocycles, oxygen, and nitrogen heterocycles using (TMSlsSiH as a mediator are many and represents the expansion and importance of these synthetic approaches. For example, Nicolaou and coworkers found that (TMSlsSiH serves as a superior reagent in the radical-based approach toward the synthesis of azadirachtin, an antifeedant agent currently used as an insecticide, and in other related systems. ° ° Here below we collected a number of reactions mostly from the recent work in the area of intramolecular reactions. 

One synthetic approach involves cyclization of a substituted six-membered heterocycle which becomes the central ring of the product (6 6 6). For example, the reaction of 2,6-diaminopyridine with 2,2-dimethyl-l,3-dioxane-4,6-dione and trimethoxymethane gives the bis-adduct 118 which is a precursor to the angular tricyclic product 119 (Scheme 14) <2005AXCol>. 

The diazines pyridazine, pyrimidine, pyrazine, and their benzo derivatives cinnoline, phthalazine, quinazoline, quinoxaline, and phenazine once again played a central role in many investigations. Progress was made on the syntheses and reactions of these heterocycles, and their use as intermediates toward broader goals. Some studies relied on solid-phase, microwave irradiation, or metal-assisted synthetic approaches, while others focused attention more on the X-ray, computational, spectroscopic, and natural product and other biological aspects of these heterocycles. Reports with a common flavor have been grouped together whenever possible. 

In terms of economical synthetic approaches to indoles, the synthesis of this heterocycle from anilines and trialkylammonium chlorides was effected in an aqueous medium (H20-dioxane) at 180°C in the presence of a catalytic amount of ruthenium(III) chloride hydrate and triphenylphosphine together with tin(II)chloride <00TL1811>. Muchowski devised a novel synthetic route to indole-4-carboxaldehydes and 4-acetylindoles 86 via hydrolytic cleavage of W-alkyl-5-aminoisoquinolinium salts 85 to homophthaldehyde derivatives upon heating in a two phase alkyl acetate-water system containing an excess of a 2 1 sodium bisulfite-sodium sulfite mixture <00JHC1293>. 

One of the most important species of six-membered heterocycles is represented by the pyrimidine group. Simple synthetic approaches therefore are of great importance. 

Rhenium(IV) complexes with only one bidentate ligand have been described for chelating phosphines, Schiff bases, and A-heterocycles. The synthetic approaches are different and involve simple ligand exchange procedures as well as reduction of rhenium(V) or oxidation of rhe-nium(III) compounds. 

Compared with the large number of nitrosyl complexes, only a few examples of thionitrosyl complexes have been studied. Although NS does not exist, a number of synthetic approaches to thionitrosyl complexes have been reported the reaction of nitrido complexes with S2CI2 or TMSNCS, treatment of chloro or 0x0 complexes with trithiazyl chloride or S(NTMS)2, or the use of heterocyclic nitrogen-sulfur rings. Pre-formed thionitrosyl cations in [NS][SbF6] or [NS)[AsFg] have been used to prepare the cationic complex [Re(NS)(CO)5] " in liquid S02. ... 

The synthetic approaches described thus far for 191 resemble quite closely those reported for similar heterocycles. The system has been prepared for the first time by Tamura and co-workers (79CPB2521). 2-Aminothiadiazole can be aminated with O-mesitylsulfonylhydroxylamine, giving an N-3-aminated product that on treatment with acylating agents (benzoyl chloride, acetic acid anhydride, 200°C) yields the desired compounds (192, R = Me, Ph). Yields are low (15-26%). 

Scheme 41. Reactions of heterocycles 25, 121 with Fischer carbene complexes as a synthetic approach to bicyclic j0-lactams 122-124 [26,33,59]...

In several subsequent publications, this promising multicomponent synthetic approach was used for the synthesis of certain types of biologically active heterocyclic compounds. For instance. Boros and co-authors [35] reported application of the three-component heterocyclization between bicyclic aminoazole 2, acetoacetic acid derivatives 3, and aldehyde 4 to obtain compound 5 being aza-analog of known [36] agonist of the calcetonine receptor (Scheme 4). 

However, there are numerous examples when both these synthetic approaches give different heterocyclic systems, which lets additional powerful tool for tuning of reactions selectivity. 

Pitavastatin (3) was launched in 2003 and is currently marketed in Japan under the trade name Livalo . Like rosuvastatin and fluvastatin, pitavastatin is a completely synthetic HMG-CoA reductase inhibitor that was developed by Kowa, Nissan Chemical, and Sankyo (Sorbera et al., 1998). Multiple syntheses of pitavastatin have been reported and an exhaustive review of these efforts is beyond the scope of this text (Hiyama et al., 1995a, b Minami and Hiyama, 1992 Miyachi et al., 1993 Takahashi et al., 1993, 1995 Takano et al., 1993). Instead, we will focus our discussion on two related and innovative synthetic approaches that differ strategically from the routes we have previously examined for rosuvastatin and fluvastatin. These routes to pitavastatin employed palladium-mediated coupling reactions to install the 3,5-dihydroxyheptanoic acid side-chain. This key retrosynthetic disconnection is highlighted in Scheme 12.6, in which a suitable functionalized side-chain (52 or 53) is attached to the heterocyclic core of pitavastatin (51) through palladium-mediated coupling. 

A variety of 2,4-oxazolidinedione moieties have been prepared as precursors to A-acyliminium ions. These, in turn, have been used in synthetic approaches to 13-aza-16-oxasteroids, interesting and novel heterocycles, " and natural products such as ( )-p-conhydrine, 294b, ( )-6>-methylpaUidinine, 297, 4-oxa-2-aza-podophyllotoxin, 299, and morphine, 302. Introduction of the 2,4-oxazolidinedione can be achieved by conventional alkylation. However, it is normally introduced through Mitsunobu chemistry using diisopropyl azodicar-boxylate or diethyl azodicarboxylate. " The former reagent is favored by... 

The synthetic approaches to these heterocyclic systems are discussed and exemplified in the following sections and a compilation of the new derivatives reported in the period 1995-2006 is given in Tables 1-15. Derivatives prepared prior to 1995 are tabulated in CHEC-II(1996) <1996CHEC-II(7)49>. 

Deaza analogs of purines continue to be a major topic of interest to heterocyclic chemists, and especially those with a research focus on biological activity. The synthetic approaches divide, nearly equally, between using pyrimidines or pyrroles as precursors. 

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