The first practical and efficient one-pot synthesis of 6-substituted 7-azaindoles via a Reissert-Henze reaction

Synthesis

Volumn , Issue 2, 2008, Pages 201-214

  Storz, Thomas ^a,b   Bartberger, Michael D ^a   Sukits, Steven ^a   Wilde, Chris ^a   Soukup, Troy ^a  

^a AMGEN INC   (United States)

^b WYETH RESEARCH   (United States)

Author keywords

7 azaindole; Addition elimination; N oxide; O methylation; Oxidation; Pyrrolo 2,3 b pyridine

Indexed keywords

AZAINDOLES; CHLOROBENZOIC ACID SALT; REISSERT-HENZE REACTION;

CATALYSIS; CYANIDES; METHYLATION; NUCLEOPHILES; SUBSTITUTION REACTIONS;

HYDROCARBONS;

(INDAZOL 1 YL) 7 AZAINDOLE; 4 CHLORO 6 CYANO 7 AZAINDOLE; 4 CHLORO 6 PROPARGYLAMINO 7 AZAINDOLE; 4 CHLORO 7 AZAINDOLE 7 OXIDE META CHLORO BENZOIC ACID; 6 (1,2,4 TRIAZOL 2 YL) 7 AZAINDOLE; 6 (2 HYDROXYMETHYLPYRROLIDIN 1 YL) 7 AZAINDOLE; 6 (2 NAPHTHYLTHIO) 7 AZAINDOLE; 6 (BENZIMIDAZOL 1 YL) 7 AZAINDOLE; 6 (MORPHOLIN 4 YL)7 AZAINDOLE; 6 (PROPAN 1 OL 2 YL)AMINO 7 AZAINDOLE; 6 (PROPAN 2 OL 3 YL)AMINO 7 AZAINDOLE; 6 (PYRIDIN 4 YLMETHYL)AMINO 7 AZAINDOLE; 6 (TETRAHYDROFURAN 2 YLMETHYL)AMINO 7 AZAINDOLE; 6 ALLYLAMINO 7 AZAINDOLE; 6 ALLYLOXY 7 AZAINDOLE; 6 AMINO 4 CHLORO 7 AZAINDOLE; 6 AMINO 7 AZAINDOLE; 6 BENZYLOXY 7 AZAINDOLE; 6 CYANO 7 AZAINDOLE; 6 CYCLOPROPYLAMINO 7 AZAINDOLE; 6 DIETHYLAMINO 7 AZAINDOLE; 6 DODECYLSULFONYL 7 AZAINDOLE; 6 DODECYLTHIO 7 AZAINDOLE; 6 METHOXY 7 AZAINDOLE; 6 METHYLAMINO 7 AZAINDOLE TRIFLUOROACETIC ACID; 6 PROPARGYLAMINO 7 AZAINDOLE; AZAINDOLE DERIVATIVE; INDOLE DERIVATIVE; N (7 AZAINDOL 6 YL)GLYCINE TERT BUTYL ESTER; N ALPHA (7 AZAINDOL 6 YL)TRYPTOPHAN BENZYL ESTER; UNCLASSIFIED DRUG;

ARTICLE; CHEMICAL STRUCTURE; HIGH PERFORMANCE LIQUID CHROMATOGRAPHY; METHYLATION; NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY; ONE POT SYNTHESIS; SYNTHESIS;

EID: 38849209107     PISSN: 00397881     EISSN: None     Source Type: Journal    
DOI: 10.1055/s-2007-1000853     Document Type: Article

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134. 48
135. 63] did not lead to cyanated azaindole (data not shown).
136. 64
137. 35 (vide supra, Scheme 1), 6-chloroazaindole was not observed as a side-product under our conditions. In test reactions of 4 with TBACl, TBABr and TBAI under forcing conditions (data not shown), no reaction occurred with the chloride, whereas the bromide and iodide reacted via the demethylation pathway (formation of MeBr and MeI, respectively). Thus, it appears the nature of the leaving group at N7 strongly determines the site of nucleophilic attack at the ambident electrophile 4.
138. (a) Vorbrüggen, H.; Krolikiewicz, K. Synthesis 1983, 316.
139. (b) Fife, W. K. J. Org. Chem. 1983, 48, 1375.
140. In pyridine chemistry, 2-(alkyl/aryl)sulfonyl groups are often used to introduce heteroatom substituents ortho to the ring nitrogen; as a rule, they are more reactive than the corresponding 2-halo compounds, see: Furukawa, N.; Ogawa, S.; Kawai, T.; Oae, S. J. Chem. Soc., Perkin Trans. 1 1984, 1839.
141. The reactivity of the O-methyl-7-azaindole-N-oxide salt 4 towards alcoholates, thiolates and azoles was somewhat surprising considering the earlier unsuccessful attempts to obtain the same types of addition products from Reissert-Henze reactions of N-methoxypyridinium salts, see: Kiselyov A. S., Strekowski L.; J. Heterocycl. Chem.; 1993, 30: 1361.
142. 3), N-methylation of the azoles dominates (data not shown). 6-N-(Heteroaromatic)-substituted 7-azaindoles have not been reported (CAS/Beilstein, July 2007). Trace amounts of the 4-isomer are readily removed during purification; all yields are isolated yields for chromatographed products (typically ≥95A% HPLC).
143. Crude 6-amino adducts are typically ∼85A% LC-pure already and require minimal purification.
144. 27b,28 A convenient protocol is given in the experimental part (vide supra).
145. Chiral N-(7-azaindolyl)-α-amino acids have not been reported (CAS/Beilstein searches July 2007).
146. Katritzky, A. R.; Lunt, E. Tetrahedron 1969, 25, 4291.
147. Abramovitch, R. A.; Smith, E. M. Chem. Heterocycl. Comp. 1974, 14 (Suppl. 2), 1.
148. 40 have been reported to give the α-cyanated product in good yields in the Reissert-Henze reaction with benzoyl chloride and cyanide.
149. 67 for a review, see: Poddubnyi, I. S. Chem. Heterocycl. Comp. 1995, 31, 682.
150. To the best of our knowledge, no other reports on Reissert-Henze type reactions of 7-azaindole-N-oxide have appeared in the literature (CAS/Beilstein searches June 2007). On the other hand, Popp et al. had reported on a failed attempt to obtain cyanated azaindole via the classical Reissert reaction conditions: Veeraraghavan, S.; Popp, F. D. J. Heterocycl. Chem. 1981, 18, 909.
151. Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923.
152. Kosower, E. M. J. Am. Chem. Soc. 1956, 78, 3497.
153. Harusawa, S.; Hamada, Y.; Shioiri, T. Heterocycles 1981, 15, 981.
154. Pretsch, E.; Seibl, J.; Clerc, T.; Simon, W. Spectral Data for Structure Determination of Organic Compounds; Springer-Verlag: Heidelberg, 1989, 2nd ed., H275.
155. Klemm, L. H.; Muchiri, D. R. J. Heterocycl. Chem. 1983, 20, 213.
156. Lyle, R. E.; Gauthier, G. J. Tetrahedron Lett. 1965, 6, 4615.
157. Damji, S. W. H.; Fyfe, C. A.; Smith, D.; Sharom, F. J. J. Org. Chem. 1979, 44, 1761.