A Regioselective Route to 5- and 6-Azaindoles

Abstract

The synthesis of 4,7-dimethoxy 5- and 6-azaindoles, a structural unit that is present in recently developed anti-HIV-1 agents, was achieved in a regioselective manner. The developed strategy is based on the appropriate choice of a protecting group during a lithium-mediated formylation step, followed by thermal cyclization of azidoacrylates.

5- and 6-azaindoles - pyridines - metalations - azides - ­regioselectivity

References

1a Sundberg RJ. In Comprehensive Heterocyclic Chemistry   Vol. 4:  Katritzki AR. Rees CW. Pergamon; Oxford: 1984.  p.313-376  

1b For a recent review of indole-containing natural products, see: Lounasmaa M. Tolvanen A. Nat. Prod. Rep.  2000,  17:  175 

For reviews on indole syntheses, see:

2a

ref. 1a.

2b Sundberg RJ. Indoles   Academic; London: 1996. 

2c Gribble GW. J. Chem. Soc., Perkin Trans. 1  2000,  1045 

3a Zhang Z. Yang Z. Meanwell NA. Kadow JF. Wang T. J. Org. Chem.  2002,  67:  2345 ; and references cited therein

3b Cottineau B. O’Shea DF. Tetrahedron Lett.  2005,  46:  1935 ; and references cited therein

3c Debenham SR. Chan A. Liu K. Price K. Wood HB. Tetrahedron Lett.  2005,  46:  2283 ; and references cited therein

3d For a review on 7-azaindoles, see: Mérour J.-Y. Joseph B. Curr. Org. Chem.  2001,  5:  471 

4a De Clercq E. J. Med. Chem.  2005,  48:  1297 

4b Yeung K.-S, Farkas M, Kadow JF, Meanwell NA, Taylor M, Johnston D, Coulter TS, and Wright JJK. inventors; PCT Int. Appl. WO  2005/004801. 

5a Hemetsberger H. Knittel D. Weidmann H. Monatsh. Chem.  1969,  100:  1599 

5b For a review, see: Moody CJ. In Comprehensive Organic Synthesis   Vol. 7:  Trost BM. Fleming I. Ley SV. Pergamon Press; Oxford: 1991.  p.21-38  

5c For a recent application of the Hemetsberger reaction directed towards the total synthesis of Variolin B, see: Molina P. Fresneda PM. Delgado S. J. Org. Chem.  2003,  68:  489 

6 Compound 4 was prepared in two steps from commercially available 2-methoxypyridine, following a literature procedure: Van de Poël H. Guillaumet G. Viaud-Massuard M.-C. Heterocycles  2002,  57:  55 

7 Trécourt F. Mallet M. Marsais F. Quéguiner G. J. Org. Chem.  1988,  53:  1367 

8

After trying DMF as the electrophilic agent, we found that this reagent gave better results.

For a precedent on the ortho-directing properties of the MOM ether group on a pyridine ring, see:

9a Ronald RC. Winkle MR. Tetrahedron  1983,  39:  2031 

9b

See ref. 6.

10

The ratio 4-formyl pyridine/3-formyl pyridine derivatives was determined by ¹H NMR on the crude product and estimated to be 95:5, respectively.

11

No trace of the 4-formyl derivative was detected by ¹H NMR on the crude product. In this case, a small amount (less than 10%) of the starting material 8 was detected and separated from the desired product 9 by flash chromatography on silica gel.

12 Methyl azidoacetate was prepared from methyl bromoacetate and sodium azide according to the following procedure: Moore AT. Rydon HN. Org. Synth.  1965,  45:  47 

13

Typical Experimental Procedure for the Preparation of Acrylates 3.
To dry MeOH (4 mL) at 0 °C was added Na (189 mg, 8.2 mmol) portionwise and the resulting mixture was stirred until complete consumption of the metal. The temperature was then raised to 30 °C and a solution of aldehyde 2a (335 mg, 2.0 mmol) and methyl azidoacetate (875 mg, 7.6 mmol) in dry MeOH (6 mL) was added in one portion. After stirring during 2 h, the mixture was poured on ice (40 g) and placed at 4 °C during 1 h. The solid was then filtered on a sintered-glass funnel to afford acrylate 3a as an off-white fine powder (299 mg, 57%); mp 123-124 °C (dec.). ¹H NMR (300 MHz, DMSO-d ₆): δ = 3.81 (3 H, s), 3.86 (3 H, s), 3.87 (3 H, s), 7.02 (1 H, s), 7.89 (1 H, d, J = 3.0 Hz), 8.12 (1 H, d, J = 3.0 Hz) ppm. ¹³C NMR (75 MHz, DMSO-d ₆): δ = 53.3, 53.8, 56.2, 115.7, 116.0, 125.3, 127.3, 132.7, 150.4, 155.2, 163.0 ppm. HRMS (CI): m/z calcd for C₁₁H₁₃N₄O₄: 265.0937 [MH⁺]; found: 265.0938.
Acrylate 3b (yellow powder, 268 mg, 51%): mp 117-118 °C (dec.). ¹H NMR (300 MHz, acetone-d ₆): δ = 3.84 (3 H, s), 3.91 (3 H, s), 3.92 (3 H, s), 7.12 (1 H, s), 7.50 (1 H, s), 7.90 (1 H, s) ppm. ¹³C NMR (75 MHz, acetone-d ₆): δ = 53.6, 53.6, 57.2, 111.1, 116.1, 130.3, 130.5, 133.3, 149.3, 159.4, 164.0 ppm. HRMS (EI): m/z calcd for C₁₁H₁₂N₄O₄: 264.0859 [M^+•]; found: 264.0856.

14

Typical Experimental Procedure for the Preparation of Azaindoles 1.
To 13 mL of hot xylene (140 °C) was slowly added under vigorous stirring a suspension of acrylate 3a (423 mg, 1.6 mmol) in 27 mL xylene. After addition, the mixture was stirred for 1 h at 140 °C and then slowly cooled down to r.t. overnight without stirring. Once the solid crystallized, the supernatant was removed and the solid dried under high vacuum to give 5-azaindole 1a as pale pink crystals (310 mg, 82%). For the synthesis of 6-azaindole 1b starting from acrylate 3b, the crystallization occurred only at -20 °C. Additional purification of the supernatant by flash chromatography (silica gel, petroleum ether-EtOAc, 50:50) was necessary to recover all of 1b, which is more soluble in xylene than its 5-aza analogue (compound 1a is quantitatively recovered after crystallization at r.t.).
5-Azaindole 1a: mp 192-193 °C. ¹H NMR (300 MHz, DMSO-d ₆): δ = 3.84 (3 H, s), 3.90 (3 H, s), 3.92 (3 H, s), 7.10 (1 H, s), 7.47 (1 H, s), 12.57 (1 H, br s) ppm. ¹³C NMR (75 MHz, DMSO-d ₆): δ = 51.9, 52.8, 56.4, 106.5, 113.0, 120.4, 127.5, 134.2, 140.0, 152.8, 160.9 ppm. HRMS (CI): m/z calcd for C₁₁H₁₃N₂O₄: 237.0875 [MH⁺]; found: 237.0874.
6-Azaindole 1b (pale yellow powder, 123 mg, 52%): mp 169-170 °C. ¹H NMR (300 MHz, DMSO-d ₆): δ = 3.86 (3 H, s), 3.88 (3 H, s), 3.96 (3 H, s), 7.07 (1 H, s), 7.27 (1 H, s), 12.63 (1 H, br s) ppm. ¹³C NMR (75 MHz, DMSO-d ₆): δ = 52.0, 52.8, 55.9, 104.9, 114.7, 123.0, 124.8, 129.0, 145.7, 146.4, 161.0 ppm. HRMS (EI): m/z calcd for C₁₁H₁₂N₂O₄: 236.0797 [M^+• ]; found: 236.0798.