3
171
Synthesis
R. S. Alekseyev et al.
Paper
The starting 5-bromo-2-hydrazinopyridine (1) was pre-
pared from commercially available and cheap 2-aminopyri-
dine by a known synthetic route, used previously by us for
unsubstituted 2-hydrazinopyridine synthesis. This route
involves its bromination to 2-amino-5-bromopyridine (2),
substitution of the amino group with bromine atom by di-
azotization, and further nucleophilic substitution of the
bromine atom at position 2 of the formed 2,5-dibromopyri-
dine (3) with hydrazine fragment (Scheme 1).
The 2,3-disubstituted 5-bromo-1H-pyrrolo[2,3-b]pyri-
dines 4a–n were obtained from (5-bromopyridin-2-yl)hy-
drazones 5a–n, which were initially prepared by refluxing
the hydrazine 1 with one equivalent of the appropriate car-
bonyl compound (ketone). The cyclization of the hydra-
zones 5a–n was achieved by heating in polyphosphoric acid
In this procedure, most of the hydrazones 5 were ob-
tained as a viscous liquid, and all of them were used with-
out isolation (under reaction conditions they are of suffi-
cient purity to be used for further transformations without
additional purification), but their formation and purity was
8d
1
13
controlled by NMR spectra. The H and C NMR spectral
data of viscous hydrazones are presented in Table 2. The
solid hydrazones 5c,d,f,k,p,q,r,s were isolated from the re-
action mixture as individual compounds by recrystalliza-
tion, and appropriate spectroscopic and physical data for
them are presented in Table 3 and Table 4.
Fischer indolization via [3,3] sigmatropic rearrange-
ment involves an enehydrazine form of the starting hydra-
zone as intermediate, and the cyclization should be facili-
tated by the ease of formation of this enehydrazine (Scheme
2). An earlier study15 of 7-azaindole synthesis by Fischer re-
action suggested that a higher degree of enolization of the
starting ketone correlated with the rate of Fischer cyclization
of the respective hydrazone, and this relationship is applied
both to cyclic as well as aliphatic ketones.
(PPA) for five minutes at 160–180 °C, leading to the required
5
-bromo-7-azaindole derivatives 4a–n in moderate to good
yields (Scheme 1, Table 1). All final 5-bromo-7-azaindole
derivatives 4a–n were characterized by appropriate spec-
1
13
troscopic ( H and C NMR, IR, and MS) and physical data
(melting point and elemental analysis).
Table 2 1H and 13C NMR Data for Viscous Hydrazones 5
Hydrazone 1H NMR (CDCl
): δ
13C NMR (CDCl
): δ
3
3
5
5
a
1.62–1.75 (m, 6 H, 3,4,5-CH
2
), 2.30–2.38 (m, 4 H, 2,6-CH
2
), 7.14 (d, J = 8.9 Hz, 1 H, H-3 Py), 7.61 (dd,
25.7, 25.9, 27.1, 35.5, 42.0, 108.9,
109.0, 140.6, 147.6, 153.2, 156.3
J
1
= 8.9 Hz, J = 2.3 Hz, 1 H, H-4 Py), 7.90 (br s, 1 H, NH), 8.10 (d, J = 2.3 Hz, 1 H, H-6 Py)
2
b
0.97 (d, J = 6.6 Hz, 3 H, CH
3
), 1.10–1.28 (m, 2 H, 3,5-CH
2
), 1.67–1.73 (m, 1 H, 4-CH), 1.87–1.93 (m, 3 H, 21.6, 25.0, 31.9, 33.7, 34.7, 35.1,
), 2.50 (d, J = 14.6 Hz, 1 H, 2,6-CH ), 2.69– 108.9, 109.0, 140.5, 147.8, 152.8,
= 8.9 Hz, J = 2.3 Hz, 1 H, H-4 Py), 7.82 (br 156.3
2,3,5,6-CH
2
), 2.24 (dt, J
1
= 13.7 Hz, J = 4.8 Hz, 1 H, 2,6-CH
2
2
2
2.75 (m, 1 H, 2,6-CH
2
), 7.13 (d, J = 8.9 Hz, H-3 Py), 7.61 (dd, J
1
2
s, 1 H, NH), 8.12 (d, J = 2.3 Hz, 1 H, H-6 Py)
5
5
5
5
5
5
e
g
h
i
2.53 (t, J = 6.6 Hz, 2 H, 4-CH ), 2.97 (t, J = 6.6 Hz, 2 H, 3-CH
2
2
2
), 3.65 (s, 2 H, 1-CH
2
), 7.18 (d, J = 8.9 Hz, 1
25.2, 27.7, 38.3, 108.8, 109.7, 126.7,
H, H-3 Py), 7.19–7.22 (m, 4 H, C ), 7.65 (dd, J = 8.9 Hz, J
6
H
4
1
= 2.3 Hz, 1 H, H-4 Py), 7.66 (br s, 1 H, NH), 126.9, 127.1, 127.4, 135.6, 137.7,
140.4, 148.2, 150.0, 156.0
8.14 (d, J = 2.3 Hz, 1 H, H-6 Py)
1.14 (t, J = 7.3 Hz, 3 H, CH CH ), 1.86 (s, 3 H, CH
3
2
3
C=N), 2.32 (q, J = 7.3 Hz, 2 H, MeCH
2
), 7.15 (d, J = 8.8
10.9, 14.7, 32.1, 109.0, 109.2, 140.4,
Hz, 1 H, H-3 Py), 7.62 (dd, J
1
= 8.8 Hz, J = 2.2 Hz, 1 H, H-4 Py), 7.76 (br s, 1 H, NH), 8.12 (d, J = 2.2 Hz, 1 148.0, 1503, 156.3
2
H, H-6 Py)
1.12 (t, J = 7.3 Hz, 3 H, CH
H, CH ), 7.16 (d, J = 8.9 Hz, 1 H, H-3 Py), 7.61 (dd, J
NH), 8.11 (d, J = 2.4 Hz, 1 H, H-6 Py)
3
), 1.14 (t, J = 7.3 Hz, 3 H, CH
3
), 2.26 (q, J = 7.3 Hz, 2 H, CH
= 8.9 Hz, J = 2.4 Hz, 1 H, H-4 Py), 7.87 (br s, 1 H,
2
), 2.32 (q, J = 7.3 Hz, 9.7, 10.8, 21.9, 29.7, 108.9, 109.1,
140.4, 148.1, 154.6, 156.4
2
2
1
2
0.92 (t, J = 7.3 Hz, 3 H, CH CH ), 1.35 (sext, J = 7.3 Hz, 2 H, 5-CH
3
2
2
), 1.50–1.58 (m, 2 H, 4-CH
2
), 1.85 (s, 3 14.0, 14.8, 22.4, 28.6, 38.6, 108.8,
= 2.3 109.0, 140.5, 147.7, 149.8, 156.2
H, CH C=O), 2.29 (t, J = 7.5 Hz, 2 H, 3-CH ), 7.14 (d, J = 9.0 Hz, 1 H, H-3 Py), 7.61 (dd, J
Hz, 1 H, H-4 Py), 7.93 (br s, 1 H, NH), 8.09 (d, J = 2.3 Hz, 1 H, H-6 Py)
3
2
1
= 9.0 Hz, J
2
j
0.94 [d, J = 6.6 Hz, 6 H, (CH CH], 1.85 (s, 3 H, CH C=N), 1.97–2.03 (m, 1 H, CH), 2.18 (d, J = 7.2 Hz, 2 H, 15.0, 22.5, 26.1, 48.0, 108.8, 109.0,
3
)
2
3
CH ), 7.15 (d, J = 8.9 Hz, 1 H, H-3 Py), 7.62 (dd, J = 8.9 Hz, J = 2.4 Hz, 1 H, H-4 Py), 7.72 (br s, 1 H, NH), 140.5, 147.9, 149.0, 156.2
.12 (d, J = 2.4 Hz, 1 H, H-6 Py)
2
1
2
8
la
1.02 (t, J = 7.7 Hz, 1.5 H) and 1.18 (t, J = 7.4 Hz, 1.5 H, CH
Hz, 1 H, CH Me), 3.63 (s, 1 H) and 3.66 (s, 1 H, CH Ph), 7.17–7.34 (m, 6 H, H-3 Py, C
H, H-4 Py), 7.93 (br s, 0.5 H) and 7.96 (s, 0.5 H, NH), 8.10 (d, J = 2.4 Hz, 0.5 H) and 8.14 (d, J = 2.4 Hz,
.5 H, H-6 Py)
), 2.22 (q, J = 7.7 Hz, 1 H) and 2.38 (q, J = 7.4
9.6, 10.8, 21.3, 31.0, 35.3, 43.4, 109.0,
3
2
2
6 5
H ), 7.62–7.66 (m, 109.5, 126.7, 127.0, 128.3, 128.6,
1
0
129.1, 134.9, 137.6, 140.3, 140.4,
148.2, 151.0, 152.3, 156.2, 156.3
5
5
mb
n
1.23 (t, J = 7.3 Hz, 3 H, CH
3
), 2.74 (q, J = 7.3 Hz, 1.2 H) and 3.01 (q, J = 7.3 Hz, 0.8 H, CH
), 7.54 (dd, J = 8.8 Hz, J = 2.4 Hz, 1 H, H-4 Py), 7.79 (dd, J
= 8.0 Hz, J = 1.5 Hz, 0.8 H, H-2,6 C ), 8.15 (d, J = 2.4 Hz, 1 H, H-6 Py), 8.33 (s,
2
), 7.33–7.48 (m, 10.3, 11.1, 19.2, 31.5, 108.8, 109.3,
= 8.0 Hz, J = 1.5 Hz, 110.0, 125.8, 127.3, 128.5, 128.6,
1 2
4
1
0
H, H-3 Py, H-3,4,5 C
6
H
5
1
2
.2 H) and 7.97 (dd, J
1
2
6
H
5
129.2, 129.6, 137.5, 140.4, 140.6,
148.1, 148.2, 148.6, 155.8, 155.9
.5 H, NH)
1.91 (s, 3 H, CH
H, H-3 Py), 7.23–7.27 (m, 3 H, H-3,4,5 C
= 2.3 Hz, 1 H, H-4 Py), 7.82 (br s, 1 H, NH), 8.16 (d, J = 2.3 Hz, 1 H, H-6 Py).
3
), 2.66 (t, J = 7.9 Hz, 2 H, CH
2
C=N), 2.96 (t, J = 7.9 Hz, 2 H, CH
2
Ph), 7.17 (d, J = 8.8 Hz, 1
), 7.66 (dd, J = 8.8 Hz,
15.3, 32.7, 40.6, 109.0, 109.4, 126.0,
128.4, 128.5, 140.5, 141.6, 148.0,
148.3, 156.2
6
H
5
), 7.33 (t, J = 7.3 Hz, 2 H, H-2,6 C
6
H
5
1
J
2
a
1
A 1:1 mixture of two diastereomers (by H NMR analysis).
b
1
A 3:2 mixture of two diastereomers (by H NMR analysis).
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3169–3178