Pyrrolo pyridines, 2-alkyl

Pyrrolopyridines — see Indolizines Pyrrolo[l,2-a]pyridines — see Indolizines Pyrrolo[2,3]pyridines alkylation, 4, 504 synthesis, 4, 528... 

Phthalimidobutyl)-2,3,4,4u,5,6-hexahydro-l//-pyrazino[l,2-u]quino-line was obtained in the reaction of 2,3,4,4u,5,6-hexahydro-l//-pyrazino[l,2-u]quinoline and A-(4-bromobutyl)phthalimide in boiling MeCN in the presence of K2CO3 (97MIP12). 2,3,4,4u,6,7-He-xahydro-l//-pyrazino[l,2-ujquinolines were N-alkylated with 3-dimethylaminomethyl-l//-pyrrolo[2,3-6]pyridine and a mixture of l//-pyrrolo[2,3-6]pyridine and 37% aqueous H2CO in aqueous AcOH in the presence of NaOAc (96USP5576319). 3-[3-Substituted 2-propen-l-yl]-2,3,4,4u, 5,6-hexahydro-l//-pyrazino[l,2-u]qui-... 

Potentially tautomeric pyrimidines and purines are /V-alkylated under two-phase conditions, using tetra-n-butylammonium bromide or Aliquat as the catalyst [75-77], Alkylation of, for example, uracil, thiamine, and cytosine yield the 1-mono-and 1,3-dialkylated derivatives [77-81]. Theobromine and other xanthines are alkylated at N1 and/or at N3, but adenine is preferentially alkylated at N9 (70-80%), with smaller amounts of the N3-alkylated derivative (20-25%), under the basic two-phase conditions [76]. These observations should be compared with the preferential alkylation at N3 under neutral conditions. The procedure is of importance in the derivatization of nucleic acids and it has been developed for the /V-alkylation of nucleosides and nucleotides using haloalkanes or trialkyl phosphates in the presence of tetra-n-butylammonium fluoride [80], Under analogous conditions, pyrimidine nucleosides are O-acylated [79]. The catalysed alkylation reactions have been extended to the glycosidation of pyrrolo[2,3-r/]pyrimidines, pyrrolo[3,2-c]pyridines, and pyrazolo[3,4-r/]pyrimidines (e.g. Scheme 5.20) [e.g. 82-88] as a route to potentially biologically active azapurine analogues. 

The benzenesulfonyl substituent has also been used in conjunction with the lithiation of an azaindole derivative (86FRP2574406 89FRP26274931), and thus 1-benzenesulfonyl-1//-pyrrolo[3,2-c ]pyridine was able to be successfully lithiated and alkylated with p-methoxybenzaldehyde, although reaction with more hindered ketones could not be achieved (Scheme 19)[91JCS(P1)3I73]. 

Dimethylpyrrolo[3,2- ]pyridine gives the 3-benzyl derivative with benzyl chloride in the presence of ethylmagnesium bromide and pyrrolof2,3-6]pyridine (4) reacts similarly with chloroacetonitrile in DMF at room temperature after pretreatment with sodium hydride (68AHC(9)27). All four pyrrolo[2,3]pyridines react with acrylonitrile in the absence of base to give mixtures of 2- and 3-alkylated derivatives (23 and 24 Scheme 7) (65BEP659467). 

Azalene salts 90 and 92 are obtained by quaternization of the corresponding heterocyclic bases with alkyl halides or tosylates. If the heterocyclic base contains several nitrogen atoms, alkylation can produce different quaternary salts. Quaternization, however, is surprisingly selective if certain conditions are met.205 Pyrrolo- and indolopyridines containing one pyridine-and one pyrrole-type nitrogen atom in their molecular lattice are (in aprotic solvents) almost exclusively alkylated at the nitrogen atom of the pyridine... 

Only a few investigations of electrophilic substitution reactions of pseudo-azulenes containing a pyrrole-type nitrogen have been reported. There are many examples of alkylations (see Table VI). An alkylation always takes place at the nitrogen of the five-membered ring. For 7H-pyrrolo[2,3-b]-pyridine 68 azocoupling and reaction with dithiolium salts have been reported.166... 

Alkylation of compound (1) to give l-(2-hydroxyethyl)pyrrolo[2,3-Z>]pyridine was achieved in 71% yield using fairly drastic conditions heating the reactants with aluminum chloride in carbon disulfide at 50°C for 30 min. To carry out alkylation at the 3-position of the pyrrole ring, a regiospecific alkylation was done via metallation of 3-bromopyrrolo[2,3-Z>]pyridine (35), giving the 1,3-dianion <84JHC42i>. In this manner, 3-(2-hydroxyethyl)pyrrolo[2,3-i]pyridine (36) was obtained in 57% yield. Further reaction to the bromo derivative (37) was carried out as outlined in Scheme 7. 

The reaction medium was found to be crucial in determining whether N- or C-alkylation of l-pyrrolo[2,3-h]pyridine magnesium bromide with aldehydo-sug T derivatives, such as 2,3,5-tri-O-benzyl-D-arabinofuranose 202, will take place. Although predominant A-alkylation occurred in THF, C-alkylation at C3 of the pyrrolo[2,3-h]pyridine system became almost exclusive in dichloromethane to give the 3-(D-mflnno-tetritol-l-yl)pyr-rolo[2,3-6]pyridine 203 as a single enantiomerically pure isomer as ascertained by NMR, NMR, and reversed-phase HPLC. Acid-catalyzed dehydrocyclization of 203 gave a mixture of the two anomers of 204 (91JOC5466) (Scheme 60). 

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