References
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<A NAME="RD11705ST-1B">1b</A> For a recent review of indole-containing natural products, see:
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<A NAME="RD11705ST-3D">3d</A> For a review on 7-azaindoles, see:
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<A NAME="RD11705ST-5B">5b</A> For a review, see:
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<A NAME="RD11705ST-5C">5c</A> For a recent application of the Hemetsberger reaction directed towards the total
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<A NAME="RD11705ST-6">6</A> 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.
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<A NAME="RD11705ST-7">7</A>
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<A NAME="RD11705ST-8">8</A>
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:
<A NAME="RD11705ST-9A">9a</A>
Ronald RC.
Winkle MR.
Tetrahedron
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2031
<A NAME="RD11705ST-9B">9b</A>
See ref. 6.
<A NAME="RD11705ST-10">10</A>
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.
<A NAME="RD11705ST-11">11</A>
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.
<A NAME="RD11705ST-12">12</A> Methyl azidoacetate was prepared from methyl bromoacetate and sodium azide according
to the following procedure:
Moore AT.
Rydon HN.
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1965,
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47
<A NAME="RD11705ST-13">13</A>
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.
<A NAME="RD11705ST-14">14</A>
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.
