3- pyrrolo pyridine, preparation

Pyrrolo[2,3-. ]pyridine zinc(ll) and A -(2-pyridyl)pyrrolo[2,3- ]pyridine zinc(ll) compounds have been prepared and characterized by X-ray crystallography <2000IC5248>. The pyrrolo[2,3- ]pyridine zinc compound, formed from pyrrolo[2,3-. ]pyridine and zinc acetate, is a stable compound that can produce a blue light in electroluminescent devices. 

Pyrrolo[2,3-3]- and -[3,2- ]-pyridines can be substituted at the 2-position of N-protected rings via a palladium-catalyzed reaction (Pd(OAc)2) using lithium chloride and sodium acetate in DMF <2000TL919>. This reaction, which proceeds in moderate to good yields (60-92%), is especially useful for preparing 2-aryl- or 2-heteroaryl-substituted pyrrolopyridines. 

Pyrrolopyridines substituted at the 2-position of dipyridodiazepinones have been prepared for study as nonnucleoside inhibitors of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase <1997JME2430>. Compound 141, synthesized from pyrrolo[2,3-, ]pyridine as a starting material, has emerged as a novel inhibitor of HIV-1. Compound 141 acts by interfering with the initial viral entry process <2003JME4236>. 

Pyrrolo[3,4-, ]pyridine derivatives, 147, have been prepared for comparison to the activity of alpidem, an anxiolytic imidazopyridine <1996JME4275>. The reduced derivative shows a significant affinity for the central benzodiazepine receptor. In contrast, the a,/3-unsaturated derivative shows significant affinity for the peripheral benzodiazepine receptor. 

Cyclization of 6-acetylenic derivatives constitutes yet another approach to pyrrolo[3,2-.7 pyrimidines. A series of 6-substituted acetylenes 209, prepared by alkynylation of the chloropyrimidine, undergo cyclization to the A -oxides 210 when heated briefly in pyridine (Equation 72) <2003SL1151, 2004CHE1335>. 

The preparation of 5-azatryptamine (192) is summarized in Scheme 61 (64FES741). It is interesting in starting from diazotized 4-aminopyridine N- oxide and important because pyrrolo[3,2-c]pyridine does not readily react at position 3. 

The pyrimidothiazine (204) extrudes sulfur at 130 °C to give the pyrrolopyrimidine (205 Scheme 64) (71TL4185). (-Butoxybis(dimethylamino)methane (BBDM) is a substitute for dimethylformamide dimethyl acetal. It is used to prepare the pyrimido[5,4-c]pyridazine (206). Hydrogenation gives the pyrrolopyrimidine (207 78% Scheme 65) (78JOC2536). By a similar reduction, pyrido[3,2-c]pyridazine is converted into pyrrolo[3,2-6]pyridine (80RCR428). 

All four pyrrolo[2,3]pyridines can be prepared by photochemical ring contraction of naphthyridine derivatives, e.g. (210). Although reliable, multistep syntheses are needed for the photolysis substrates, which can only be irradiated in small quantities (Scheme 67) <58LA(612)153>. 

A further synthesis of thieno[2,3-6]pyridines (79JHC603) resembles quite closely the preparation of pyrrolo[2,3-fc]pyridines (76AP597). 2-Amino-3-cyanothiophenes (e.g. 268 Scheme 62) were reacted with ethyl aminocrotonate to give enamines, which were cyclized with sodium ethoxide yielding 4-aminothieno[2,3-5]pyridines. 

A number of other five-membered ring nitrogen heterocycles have been prepared by cyclative cleavage. The illustrative examples (Fig. 4) depict the synthesis of pyrazolones,12 succinimides and phthalimides,13 pyrrolo[3,4-h] pyridines,14 2-aminoimidazolones,15 imidazo[4,5-fr]pyridin-2-ones,16 and l,2,4-triazoline-3,5-diones.17... 

The Diels-Alder reaction of 5-acetyl-3-methylthio-l,2,4-triazine with cyclic enam-ines produces 3-acetyl-l-methylthiocycloalka[c]pyridines, which are synthons for the preparation of sempervirine and its analogues.126 Cycloadditions of aryl-substituted 1,2,4-triazines (117) with 2-cyclopropylidene-l,3-dimethylimidazolidine (118) yield Diels-Alder adducts (120) that eliminate N2 to form dispiropyridines (121), which rearrange to pyrrolo[3,2-c]pyridines (122). At low temperatures, zwitterions (119) formed by nucleophilic attack of (118) on the triazines could be detected spectroscopically and, in some reactions, isolated (Scheme 34).127... 

An alternative approach (1991JHC81) to the construction of the thieno[3,2-c] pyridine system is based on C(6)-C(7) bond formation (approach S). For example, heating carboxylic acid 279 in PPA resulted in its cyclization giving 9-oxo-4H, 9f/-pyrrolo[l,2-a]thieno[2,3-<7]pyridine (280) in low yield. An attempt to prepare this compound by an independent synthesis, viz., by cyclization of isomeric acid 281 under analogous conditions, failed. 

Preparation of 7-arylmethyl-17/-pyrrolo[3,4-r-]pyridine-l,3-(27/)-diones 128 from 5-bromonicotinamide, arylaceto-nitriles, and lithium diisopropylamide (LDA) occurs via a pyridyne mechanism (Scheme 21). Under similar conditions, 5-chloro-3-pyridinol and arylacetonitriles afford the C-5 substitution products (Equation 49) <1998T3391>. 

The pyrrolopyridines contain one nitrogen heteroatom in the five-membered pyrrole ring and one nitrogen atom in the six-membered pyridine ring. A more common name is azaindoles, with 7-azaindole (l//-pyrrolo[2,3-6]pyridine (1)) being the most widely studied isomer of the series. Twelve isomers of pyrrolopyridines are listed in the Chemical Abstracts Ring Formula Index. Table 1 lists the pyrrolopyridines with their Chemical Abstracts Registry Numbers. The 1//-pyrrolopyridines (l)-(6) are the most frequently prepared, but some work has also been carried out on the isomers (7), (8), and (10). Isomers (8), (9), (11), and (12) are tautomeric structures which are considered later (see Section 7.06.4.4). 

Pyrrolo[3,2-h]pyridine N-oxide (47) was prepared as an intermediate in a route to the 5-carboxamido derivative (48) (Scheme 11) <92JHC1465>. 

Compound (1) and 2-methyl-1//-pyrrolo[2,3-Z>]pyridine (87) have been prepared by a heterogeneous catalyzed Fischer reaction. A cyclization reaction occurred with acetaldehyde and acetone 2-pyridylhydrazones in the presence of y-alumina and fluorinated aluminum oxide (Equation (20)). In addition to the desired pyrrolopyridine products, 2-aminopyridine (88) and a triazine derivative (89) were also formed. Use of the fluorinated aluminum oxide maximized formation of the desired products <72CHE594, 72CHE1037). 

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