The First Practical and Efficient One-Pot Synthesis of 6-Substituted 7-Azaindoles via a Reissert-Henze Reaction

Abstract

A variety of 6-substituted 7-azaindoles (30 examples) were obtained via selective O-methylation of 7-azaindole-N-oxide m-chlorobenzoic acid salt and subsequent, base-catalyzed one-pot reaction with a range of N-, O-, S-nucleophiles or cyanide.

Key words

7-azaindole - pyrrolo[2,3-b]pyridine - addition-elimination - oxidation - N-oxide - O-methylation

References

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• 30d

  For a more comprehensive overview, see Refs. 3c,d.

• 31a 5-Bromo-7-azaindole (four steps from 1): Mazéas D. Guillaumet G. Viaud M.-C. Heterocycles  1999,  50:  1065 
• 31b

  For a synthesis of 4,5-disubstituted 7-azaindoles from 4-substituted 7-azaindoles via directed ortho-metalation, see ref. 30b.

• 32 See the recent comparison of synthetic routes for 5-amino-7-azaindole: Pearson SE. Nandan S. Synthesis  2005,  2503 
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• 35c

  See also ref. 30a.

• 35d Recently, a seven-step de novo synthesis of a new cross coupling-reagent, N1-benzyl-6-triflyloxy-7-azaindole, has been reported, see: Kerr M. Zheng X. Org. Lett.  2006,  8:  3777 
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• 44j

  See also reviews cited in ref. 36.

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• 51 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
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• 60 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 FD. J. Heterocycl. Chem.  1981,  18:  909 
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1

New address: Wyeth Research, 401 N. Middletown Road, Pearl River, NY 109, USA.

41

CAS & Beilstein online searches, June 2007.

42

The MCBA salt 3 is the most practical way to isolate the N-oxide 2 as it readily precipitates from a number of nonpolar solvents during the oxidation of 1 with MCPBA (cf. refs. 27b,d,e). On the other hand, upon freebasing, 20%^27d to 50%^27e loss is typically incurred due to the high water solubility of 2.

43

Methyl ester formation of MCBA was also not observed.

45

A solvent screen for the O-methylation of 3 with dimethyl sulfate (data not shown) revealed MeCN(homogeneous) and butyl acetate(biphasic) as the most favorable solvents. In MeCN, the O-methylation is very clean and proceeds at a somewhat lower (55-60 °C) temperature than in butyl acetate (85-90 °C). On the other hand, butyl acetate results in a clear biphasic mixture with a lower, purple N-oxide salt phase (‘ionic liquid layer’), that can be readily separated and employed for reaction with nucleophiles in other solvents, and a clear, upper phase (butyl acetate) containing most of the m-chlorobenzoic acid. Although the cyanide reaction also proceeds under nonaqueous conditions, NH₄Cl-buffered aqueous cyanide provides the cleanest reaction and highest yield. A ‘blank reaction’ with NH₄Cl alone did not yield the 6-chloro product, in accordance with the observations made with tetraalkylammonium halides under forcing conditions (vide infra).⁴⁸

46

Increasing the steric bulk of the alkylating agent (EtI, i-PrI) did not change the regioselectivity. Other cyanating reagents [BzCN, TMSCN,⁶² (EtO)₂P=O(CN)⁶³] did not lead to cyanated azaindole (data not shown).

47

As clearly evidenced by ³ J _4,5 (8 Hz), which is the typical coupling observed between the m-, and p-protons in ortho-substituted pyridines.⁶⁴

48

Contrary to Ohshiro’s report³⁵ (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.

52

In the absence of a stronger base (typically Hünig base or K₂CO₃), 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).

53

Crude 6-amino adducts are typically ∼85A% LC-pure already and require minimal purification.

54

It is more convenient to isolate the hitherto unknown MCBA complex 28 of 4-chloro-7-azaindole-N-oxide than the free base, since the isolation of the latter typically leads to reduced yields.^27b,28 A convenient protocol is given in the experimental part (vide supra).

55

Chiral N-(7-azaindolyl)-α-amino acids have not been reported (CAS/Beilstein searches July 2007).

58

Contrary to the behavior of the corresponding N,O- and N,S-isosters of pyrrolo[2,3-b]pyridine, where both thieno[2,3-b]-⁶⁵ as well as furo[2,3-b]pyridine-N-oxide⁴⁰ have been reported to give the α-cyanated product in good yields in the Reissert-Henze reaction with benzoyl chloride and cyanide.