Of pyrrolopyridines

Reaction of pyrrolopyridines 241 with tosylmethyl isocyanide (TosMIC) in the presence of a phase transfer catalyst tetra- -butylammonium iodide (TBAI) provides the tricyclic pyrimidopyrrolopyrimidine derivatives 242 (Equation 30) <20000L3253, 2004JOC4974, 2005JOC4879>. 

Yamanaka and associates developed a method for the synthesis of 2-butylindole from the Sonogashira adduct of ethyl 2-bromophenylcarbamate and 1-hexyne [65, 66]. Extension of that method to pyridines led to the synthesis of pyrrolopyridines [67]. However, the method was not... 

The mass spectrum of pyrrolopyridine 44, prepared from the reaction of A -hydroxylquinolinimide with aryl amines at elevated temperatures (250 °C), shows interesting fragmentation patterns corresponding to the loss of CO (Scheme 1) <1998SC2871>. 

A recent tutorial review was published covering organometallic chemistry and its uses for synthesis and functionalization of pyrrolopyridines <2007CSR1120>. 

Two complementary routes to the synthesis of pyrido[, y-i/ pyridazines have been developed, the first of which begins by constructing the pyridine ring, and the second by constmcting the pyridazine ring. In addition, ring transformations of pyrrolopyridine, pyridooxazine, pyridopyrimidine, and tetrazine derivatives to the pyrido[x,y-t7 pyridazines have also been reported. 

H-NMR assignments for several simple pyrazolopyridines are given in Table III. Variation of the solvents employed does not facilitate any useful comparison with the H-NMR spectra of pyrrolopyridines.7... 

The 3-formyl derivatives of pyrrolopyridines and pyrrolodiazines are readily available (Section 3.09.3.2.2 and Scheme 22). They show typical aldehyde reactions, some of the more important of which are summarized in Schemes 23 and 24 (68AHC(9)27). 

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). 

An ab initio study of some methyl derivatives of pyrrolopyridines was also conducted. In addition to confirming some of the findings of the unsubstituted pyrrolopyridine study, this study also found that basicity increases with methyl substitution <82T3693,88JA2699). 

Quaternization of pyrrolopyridines at the pyridine nitrogen center occurs readily with methyl bromide. Treatment of the methiodide derivative of compound (1) with sodium hydroxide gives a free base which can be further reacted with methyl iodide at the pyrrole nitrogen center <55JA6554>. 

Unlike the violent bromination of pyrrole or indole, which leads to polybrominated products, the bromination of pyrrolopyridines proceeds readily to a monobrominated product. Table 39 lists some of the pyrrolopyridine derivatives that have been brominated. Common solvents for these bromination reactions are chloroform, dioxane, or acetic acid. 

In spite of the fact that indoles do not undergo acylation at the pyrrole ring carbon atom under typical Friedel-Crafts acylation conditions, the pyrrolopyridines can be successfully acylated in this manner. 3-Formylation is the most useful acylation reaction of pyrrolopyridines <68AHC(9)27>. Scheme 6 shows the acylation of compound (2), which afforded 3-acetylpyrrolo[2,3-c]pyridine (34) in 71% yield <79CHE69>. 

Yamanaka and associates developed a method for the synthesis of 2-butylindole from the Sonogashira adduct of ethyl 2-bromophenylcarbamate and 1-hexyne [97, 98]. Extension of that method to pyridines led to the synthesis of pyrrolopyridines [99]. However, the method was not applicable to the synthesis of pyrrolo[2,3-6/]pyrimidines. They then developed an alternative route involving an initial S Ar displacement at the 4-position of 4,5-dihalopyrimidine followed by a Sonogashira coupling at the 5-position [100]. Thus, 5-iodopyrimidine 200 was obtained from an S Ar displacement at the 4-position of a 4-chloro-5-iodo-2-methylthiopyrimidine (199). The subsequent Sonogashira reaction of 200 with trimethylacetylene at 80°C resulted in adduct 201, which spontaneously cyclized to pyrrolo[2,3-6/]pyrimidine 202. 

In the earlier work, using bases such as sodium ethoxide, drastic conditions were needed, and the yields were often poor and erratic (68AHC27) examples of the synthesis of pyrrolopyridines (141, 142) and pyrrolo[2,3-(f]pyrimidines (143) by this method are summarized by Scheme 32 (64CPB1024). However, with the use of bases such as butyllithium, much milder conditions can be employed, and good yields obtained even with hindered acyl groups, as in the syntheses of r-butylpyrrolopyridines (144, 145) shown in Scheme 33 (83JOC3401). 

Four-Component Synthesis of Pyrrolopyridines If a primary amine were used as an input, the three-component reaction shown in Scheme 15.10 would produce an oxazole bearing a secondary amine. In other words, the so-produced adduct 24 would contain both a diene (oxazole) and a nucleophilic site (amine). Therefore, a dienophile bearing an electrophihc center would pair perfectly with the dual reactivity of 24. In practice, if an activated a,P-unsaturated carboxylic acid derivative were introduced after the three-component reaction, a sequence of N-acylation/intramolecular Diels-Alder reaction (IMDA) might occur to produce the four-component adducts. 

With these conditions in hand, the development of a one-pot four-component synthesis of pyrrolopyridine was straightforward (Scheme 15.18). Thus, heating a toluene solution (60 °C) of an aldehyde, an amine, and an a-isocyanoacetamide (23) in the presence of ammonium chloride (1.5 equiv) for 4 h afforded the oxazole. After cooling the above reaction mixture to 0°C, an a,fi-unsaturated acyl chloride and triethylamine were introduced to it. Heating to reflux the resulting solution produced then pyrrolo[3,4-b]pyridin-5-one (52). In this one-pot four-component reaction, two C-N bonds and three C-C bonds were created with the formation of a bicyclic core. 

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