Pyrrolo pyridines formation

The N-oxide of l-pyrrolo[2,3-b]pyridine 936 is converted by the combination tri-methylsilylisothiocyanate Me3SiNCS 937/MeOCOCl to 21% 6-isothiocyanato-l-methoxycarbonyl-pyrrolo[2,3-b]pyridine 938 and 18% 6-chloro-l-methoxycarbonyl-pyrrolo[2,3-F]pyridine 939 [51] (Scheme 7.14). To avoid formation of the chloro compound 939 a reagent combination of MesSiNCS 937 with triethylamine or DBU, which lacks any competing chloride ion, might give much higher yields of... 

Furthermore, oxazoles of type 9-82 bearing a secondary amino functionality can be converted into pyrrolo[3,4-b]pyridines 9-86 by reaction with appropriate acid chlorides 9-83 in a triple domino process consisting of amide formation/hetero Diels-Alder reaction and retro-Michael cycloreversion via 9-84 and 9-85 (Scheme 9.17). The pyrrolo[3,4-fc]pyridines can be obtained in even higher yields when the whole sequence is carried out as a four-component synthesis in toluene. Here, 1.5 equiv. NH4C1 must be added for the formation of the now intermediate oxazoles [56b]. 

A practical synthesis of pyrrolo[2,3- ]pyridine from succinonitrile and ethyl formate has been reported <20030PD209>. The multistep synthesis proceeds via a substituted cyanopyrtole intermediate to give 3-cyanopyrrolo[2,3- ]pyridine, 67. As shown in Equation (12), 67 can be quantitatively converted into the unsubstituted compound, 1, by heating at reflux in concentrated acid. 

A photocyclization of 3-(2-pyrrolyl)-3-amino-2-alkeneimines under acidic reaction conditions leads to the formation of pyrrolo[3,2-3]pyridine as shown in Equation (22) <1999T14079>. When oxygen or sulfur heteroatoms are substituted for the pyrrole ring nitrogen, the corresponding furo- and thieno[3,2-3]pyridines are formed. All of the photocyclizations require lengthy reaction times and the yields tend to be low, especially for the furopyridine derivatives. 

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. 

We attribute these observations to the rapid self-condensation of the intermediate pyrrolo[3,2-c]pyridine-2,3-dione in analogy with the known sensitivity of 3-oxindole to basic reaction conditions which leads to the rapid formation of indigo. Russell, G. A. Kaupp, G. J. Am. Chem. Soc. 1969,91,3851. 

The most commonly studied pyrrolopyridine is compound (1). This compound is capable of selfassociation, a phenomenon that has led to much investigation, especially by NMR techniques. NMR data in carbon tetrachloride and benzene show that the chemical shift of the H-l proton moves downfield as the concentration of solute is increased. This type of shift is typical for a proton that undergoes hydrogen bond formation. From the NMR data, the dimerization constant for 1H-pyrrolo[2,3-/>]pyridine (1) has been determined to be 18.9 + 10.3 mol l l <8IJPC3l8l>. 

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). 

Much work has been done on the photochemical ring-expansion of pyridine A -imides to 1,2-diazepines, but it has previously not proved possible to extend this reaction to the formation of 2,3-benzodiazepines (58) from isoquinoline A -imides (57). Now, however, it has been shown that this reaction can be effected in 30-50% yield if it is done in the presence of base. Full reports have now been published on the photolysis of thieno-, furo-, and pyrrolo-[ ]- and -[c]-pyridine A -imides. These reactions give both 1,2-and 1,3-diazepines fused to the heteroaromatic rings (see these Reports, Volumes 2 and 3). 

An interesting rearrangement has been observed in the reaction of pyridine JV-imines with triarylketeneimines an initial 1,3-dipolar cycloaddition is followed by a [l,5]-sigmatropic rearrangement with the subsequent loss of hydrogens, leading to the formation of lH-pyrrolo[3,2-h]pyridines 67 (Eq. 29).192... 

B.ii.e Carbonylation and Acylation. The keto function in pyrrolo[3,2-c]pyridin-4-ones and pyrido[3,4- ]pyrrolizidin-l-ones can be enolized and triflated to yield the substrates 72 and 73, respectively (Scheme 34). Replacement of the triflyloxy group by carbonylation is effected with palladium catalysis. Reaction of the pyrido[3,4-fc]-pyrrolizidin-l-ones 73 was complicated by formation of a by-product, namely, the 2-methoxy adduct 74. In the latter case competitive palladium-assisted elimination of the triflyloxy group leads to an imminium intermediate, which adds a methoxy group as a... 

The Larock method for annulation between vicinal iodo-arylamines and 1,2-dienes in the preparation of indoles can be adapted for preparation of azaindoles using corresponding azine substrates. Thus, substituted-3//-pyrrolo[2,3-fc]pyridin-3-ones can be prepared from 2-amino-3-iodopyridine derivatives by a palladium carboannulation process with al-lenic compounds (Scheme 104). The bicychc products, the methylene derivatives 308, and the alkylidenes 309 can be oxidatively cleaved with ketone formation. The reaction may proceed by formation of a pyridinylpaUadium complex followed by the rr-allyl complexa-tion of aUenic derivatives 310. Since the polar substituents on terminal carbons of the 7r-allyl system influence the regiochemistry of the reactions, nucleophilic attack of the nitrogen atom on the most electron-deficient carbon atom of the rr-allyl system affords either of the... 

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. 

Sun X, Wang C, Li Z et al (2004) Zirconocene-mediated intermolecular coupling of one molecule of si- tethered diyne with three molecules of organonitriles one-pot formation of pyrrolo[3,2-c]pyridine derivatives via cleavage of C=N triple bonds of oiganonitriles. J Am Chem Soc 126 7172-7173... 

Formation of Pyrrolo[2,3-c]pyridinone 2-28 from Pyrrole-2,3-diones 2-24 and Hydroxylamine Hydrochloride. In a 20-mL Schlenk tube, hydroxylamine hydrochloride (1.5 mmol, 104 mg) was added to the pyridine solution (10 mL) of compound 2-24a (180 mg, 0.5 mmol). After the reaction mixture was refluxed for 4 h, the solvent was evaporated in vacuo to give a yellow sohd, which was subjected to Si02 column using petroleum ether, ethyl acetate, and triethylamine (100 20 1) as the eluent to give product 2-28. 

Formation of 5-Azaindoles 3-18 (Type III) from One Si-tethered Diyne, One t-BuCN, and Two Identical Oi nonitriles. A Typical Procedure for the Preparation of 4-tert-Butyl-2,6-dicyclohexyl-3,7-diphenyl-lff-pyrrolo[3 -c] pyridine(3-18a) To a toluene (10 ml) solution of CP2Z1CI2 (1.05 mmol, 307 mg) at —78 °C (dry ice/acetone) in a 20-ml Schlenk tube was added dropwise n-BuLi (2.1 mmol, 1.6 M, 1.32 ml) with a syringe. After the addition was complete, the reaction mixture was stirred at -78 °C for 1 h. Then, 1 mmol of bis(phenylethynyl) dimethylsilane was added, and the reaction mixture was warmed up to 50 °C and stirred at this temperature for 1 h. After trimethylacetonitrile (2.0 mmol, 166 mg. 

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