Synthesis of 2,3-Disubstituted 5-Iodo-1H-Pyrrolo[2,3-b]pyridines via Fischer Cyclization

Article abstract of DOI:10.1002/jhet.2865

A simple and convenient procedure for the preparation of some unknown 2,3-disubstituted 5-iodo-1H-pyrrolo[2,3-b]pyridines from readily available starting materials by Fischer indole cyclization in polyphosphoric acid is described. The present methodology provides an alternative synthetic approach to the synthesis of 5-iodo-7-azaindole scaffold. All synthesized compounds were characterized by IR, MS, ¹H and ¹³C NMR, and elemental analysis.

Full text of DOI:10.1002/jhet.2865

Month 2017
Synthesis of 2,3-Disubstituted 5-Iodo-1H-Pyrrolo[2,3-b]pyridines via
Fischer Cyclization
a
b
a
*
Roman S. Alekseyev, Sabina S. Amirova, and Vladimir I. Terenin
aChemistry Department, M. V. Lomonosov Moscow State University, Leninskiye Gory 1/3, Moscow 119991, Russian
Federation
bChemistry Department, M. V. Lomonosov Moscow State University, Baku Branch, Universitetskaya St. 1, Khojasan,
Binagadi, AZ 1144 Baku, Azerbaijan
*
E-mail: alros@hotmail.ru
Additional Supporting Information may be found in the online version of this article.
Received November 13, 2016
DOI 10.1002/jhet.2865
Published online 00 Month 2017 in Wiley Online Library (wileyonlinelibrary.com).
A simple and convenient procedure for the preparation of some unknown 2,3-disubstituted 5-iodo-1H-
pyrrolo[2,3-b]pyridines from readily available starting materials by Fischer indole cyclization in
polyphosphoric acid is described. The present methodology provides an alternative synthetic approach to
the synthesis of 5-iodo-7-azaindole scaffold. All synthesized compounds were characterized by IR, MS,
1H and 13C NMR, and elemental analysis.
J. Heterocyclic Chem., 00, 00 (2017).
INTRODUCTION
The Fischer reaction widely used for indole synthesis
may be applied for the preparative synthesis of
7-azaindole framework in polyphosphoric acid (PPA) at
160–180°C, as we have demonstrated previously for
unsaturated [16] and bromo-substituted derivatives [17].
The main purpose of present work is to extend the field
of application of the Fischer indole synthesis under
thermal conditions for the preparation of 2,3-disubstituted
5-iodo-7-azaindole moiety and to explore the influence of
iodine atom in pyridine ring on the yields of the final
products.
1H-Pyrrolo[2,3-b]pyridines (also known as 7-azaindoles)
and their derivatives possess more favorable bioactive
utilities than the corresponding indole moieties because of
their significant physicochemical properties that are
caused by additional nitrogen atom in six-membered ring
[1]. 7-Azaindoles are widely used as key frameworks in a
variety of drug candidates in medicinal chemistry and drug
discovery [2,3]. The iodine-containing 7-azaindole
scaffold may be useful in the synthesis of biological active
compounds and potential drug candidates, first of all as
substrate in palladium-catalyzed cross-coupling [4] or in
metallation and further metal exchange processes [5].
There are many different methods for the preparation of
7-azaindoles, which have been considered in details in
reviews [6–9]. However, only a few number of synthetic
approaches to the synthesis of 5-iodo-7-azaindole
frameworks have been developed previously. The first
classical approach to 5-iodo-7-azaindole scaffold is based
on electrophilic iodination of pyridine ring in 7-azaindole
moiety in the presence of iodine chloride [10] or N-
iodosuccinimide (NIS) [11]. The second one deals with
metal-catalyzed nucleophilic substitution of halogen to
iodine atom (Finkelstein reaction) [12,13]. And the last
one includes lithiation of 7-azaindole moiety and further
lithium/iodine exchange by electrophilic substitution
[14,15]. Thus, all known strategies for the synthesis of 5-
iodo-7-azaindole moiety propose iodination of starting
1H-pyrrolo[2,3-b]pyridine.
RESULTS AND DISCUSSION
The starting 2-hydrazino-5-iodopyridine (1) was
prepared from commercially available and cheap
2-aminopyridine by the synthetic route, formerly used by
us [16,17], which involves its electrophilic iodination to
2-amino-5-iodopyridine (2), and its further transformation
to 2-bromo-5-iodopyridine (3) (Scheme 1).
The final 2,3-disubstituted 5-iodo-1H-pyrrolo[2,3-b]
pyridines 4a–p were obtained in moderate to good yields
by cyclization of the (5-iodopyridin-2-yl)hydrazones
5a–p in PPA at 160–170°C for 5 min, which were
initially prepared by refluxing the hydrazine 1 with the
appropriate ketone (1 equiv) (Scheme 2, Table 1). All
data of MS, IR, 1H NMR, 13C NMR, and elemental
analysis for synthesized 5-iodo-7-azaindoles 4a–p are
shown in the Experimental section.
© 2017 Wiley Periodicals, Inc.

R. S. Alekseyev, S. S. Amirova, and V. I. Terenin
Vol 000
Scheme 1. Synthesis of 2-hydrazino-5-iodopyridine (1).
Scheme 2. Synthesis of 5-iodo-7-azaindoles 4a–p and estimated mechanism of their formation.
Table 1
Synthesis of 5-iodo-7-azaindoles 4a–p.
Entry
1
Starting ketone
Product
Yield, %a
4a
4b
69
2
3
71
4c
77
4
5
4d
4e
53
49
(Continued)
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Synthesis of 2,3-Disubstituted 5-Iodo-1H-Pyrrolo[2,3-b]pyridines via Fischer
Cyclization
Table 1
(Continued)
Entry
6
Starting ketone
Product
Yield, %a
57
4f
7
4g
52
8
9
4h
4i
0b
53
10
4j
51
11
12
4k
4l
59
38
13
4m
46
14
15
4n
4o
43
63
(Continued)
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R. S. Alekseyev, S. S. Amirova, and V. I. Terenin
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Table 1
(Continued)
Entry
16
Starting ketone
Product
Yield, %a
42
4p
aIsolated yields based on the starting hydrazine 1.
bStarting hydrazone 5h was isolated in unchanged form.
Scheme 3. Cyclization of methyl ketone hydrazones 5q,r.
It should be noted that hydrazones 5a–p were used
without isolation and additional purification (spectral
data for them are presented in the Supporting
Information). In contrast to 5-bromo- and unsubstituted
7-azaindoles, 5-iodo-derivatives are sensitive to
overheating: the temperature must be carefully controlled
and kept below 170–175°C during the Fischer
indolization; otherwise, decomposition occurs with
elimination of iodine. Increased reaction time also
provides resinification of the reaction mixture under this
conditions and leads to lower yields of the target 5-iodo-
7-azaindoles 4a–p.
Fischer cyclization proceeds via [3] sigmatropic shift,
which involves an enehydrazine form of the starting
hydrazone 5a–p as intermediate (Scheme 2), and the
indolization rate depends on the ease of enhydrazine
formation, which correlates with a degree of enolization
of the starting ketone [16]. The best results (yields 69%–
77%) were observed for cyclic six-membered ketones
(entries 1–3) and several acyclic ketones, including
aliphatic (entries 9–11) and benzyl ones (entry 15).
However, no traces of the corresponding 5-iododerivative
4h were detected, and only starting hydrazone 5h was
isolated unchanged for indan-1-one (entry 8). It may be
explained by the very low ability of this substrate to
transform into the enehydrazine form.
We have previously reported on the synthesis of
5-bromo-7-azaindole derivatives by the Fischer reaction
in PPA under the same conditions [17]. If we compare
the yields of 5-iodo- and 5-bromo-derivatives, the
azaindole yields are similar or slightly lower for 5-iodo-
substituted ones. It can be explained by lower
thermodynamic stability of 5-iodo-substituted hydrazones
(decomposition above 170–175°C in PPA). Comparison
with the yields of unsubstituted 1H-pyrrolo[2,3-b]
pyridines [16] shows the absence of definite correlations
between the yields of 5-iodo- and unsubstituted
7-azaindoles from the presence of the iodine atom on the
pyridine ring, which promotes the resinification with
increasing temperature or reaction time.
CONCLUSIONS
In summary, we have proposed a simple and efficient
synthesis of some previously unknown 2,3-disubstituted
5-iodo-7-azaindole derivatives via aza-Fischer reaction in
polyphosphoric acid under thermal conditions, leading to
the required fused-ring heterocycles in moderate to good
yields. This procedure is common for various alkyl and
aryl ketones, and also useful for the preparation of 5-
iodo-7-azaindoles at multigram scale level, but these
reaction conditions are not appropriate for methyl ketones.
The same results were observed in the case of methyl
ketone hydrazones 5q,r (Scheme 3): instead of the
respective 5-iodo-7-azaindoles 4q,r, the starting
hydrazone 5q (R = Ph) or the hitherto unknown
triazinone 6 (R═COOEt) were isolated. The structure of
compound 6 was offered on the basis of the analysis of
spectral data set for this one.
EXPERIMENTAL
1H and 13С NMR spectra were acquired on a Bruker
Avance-400 spectrometer (400 and 100 MHz,
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1
respectively) in CDCl3 or DMSO-d6, with residual solvent
protons as internal standard (7.27 and 2.51 ppm for H
1547, 1439, 1354, 1085, 994, 828. H NMR (CDCl3) δ,
1
ppm: 7.29 (d, J = 8.3 Hz, 1H, H-3), 7.82 (dd,
J1 = 8.3 Hz, J2 = 2.3 Hz, 1H, H-4), 8.59 (d, J = 2.3 Hz,
1H, H-6). 13C NMR (CDCl3) δ, ppm: 91.7, 130.0, 141.5,
146.6, 156.2. MS (EI, 70 eV) m/z (%): 285 [M(81Br)]+
(93), 283 [M(79Br)]+ (100), 204 (47), 127 [I]+ (51), 77
(16), 76 (16), 50 (30). Anal. Calcd for C5H3BrIN: C,
21.15; H, 1.07; N, 4.93. Found: C, 21.04; H, 1.14; N, 4.89.
2-Hydrazino-5-iodopyridine (1). A mixture of 2-bromo-
5-iodopyridine (3) (22.6 g, 79.6 mmol), hydrazine hydrate
(30 mL, 0.6 mol), and 2-propanol (30 mL) was refluxed for
8–10 h, and the excess hydrazine hydrate and 2-propanol
were evaporated under vacuum. The residue was
suspended in cold H2O (30 mL), and the precipitate
formed was filtered off, washed with ice cold H2O
(2 × 5 mL), and air-dried to constant mass. The obtained
precipitate was recrystallized from EtOH to give off-
white crystals; yield 16.8 g (90%); m.p. 124–125°C
(EtOH); Rf = 0.5 (CHCl3–EtOAc, 1:1). IR (KBr) ν,
cmÀ1: 3249, 3171, 3047, 1590, 1506, 1476, 1375, 1135,
984, 809. 1H NMR (CDCl3) δ, ppm: 4.16 (br s, 2H,
NH2), 6.62 (d, J = 8.8 Hz, 1H, H-3), 7.64 (br s, 1H, NH),
7.68 (dd, J1 = 8.8 Hz, J2 = 2.3 Hz, 1H, H-4), 8.12 (d,
J = 2.3 Hz, 1H, H-6). 13C NMR (CDCl3) δ, ppm: 76.0,
108.9, 144.1, 152.5, 160.8. MS (EI, 70 eV) m/z (%): 235
[М]+ (100); 205 (15); 168 (12); 127 [I]+ (12); 91 (8); 78
(12). Anal. Calcd for C5H6IN3: C, 25.55; H, 2.57; N,
17.88. Found: C, 25.67; H, 2.44; N, 17.82.
nuclei, 77.1 and 39.5 ppm for 13C nuclei). Mass spectra
were recorded on a Finnigan MAT ITD-700 instrument,
EI ionization (70 eV), m/z range 45–400. IR spectra were
recorded on a Thermo Nicolet IR200 FTIR spectrometer.
Elemental analysis was performed on a EURO EA
CHNS-analyzer. Melting points were determined in open
capillaries and were not corrected. TLC were run on pre-
coated silica gel plates (Merck 60F254), and the spots
were visualized using
a UV lamp. Commercially
available reagents from Acros, Sigma-Aldrich, Merck,
Alfa Aesar, Fischer Scientific and Reakhim were used in
this work.
2-Amino-5-iodopyridine (2). 2-Aminopyridine (25.0 g,
0.27 mol), NaIO4 (12.0 g, 56.1 mmol), and iodine
(27.7 g, 109.1 mmol) were added to a mixture of AcOH
(200 mL), H2O (30 mL), and H2SO4 (5 mL), and the
final reaction mixture was heated at 80°C for 4 h. After
cooling, Na2SO3 (0.5–1.0 g) was added for decoloration,
and the solvent was evaporated under vacuum. The
residue was suspended in H2O (30 mL) and neutralized
with saturated aqueous solution of K2CO3 (~50 mL). The
solid was filtered off, washed with cold water
(3 × 30 mL), and air-dried to constant weight. The solid
was washed with boiling heptane (20 mL) to remove
traces of 2-amino-3,5-diiodopyridine; off-white fine
crystals; yield 53.2 g (91%); m.p. 127–128°C (heptane)
(lit. m.p. 128–129°C [18]); Rf = 0.7 (CHCl3–EtOAc, 1:1).
IR (KBr) ν, cmÀ1: 3395, 3300, 3139, 1634, 1582, 1482,
Preparation of 5-iodo-1H-pyrrolo[2,3-b]pyridines 4;
general procedure.
A solution of the corresponding
1
carbonyl compound (3.0 mmol) in EtOH (5 mL) was
added drop by drop to a solution of 2-hydrazino-5-
iodopyridine (1; 705 mg, 3.0 mmol) in EtOH (5 mL).
The reaction mixture was refluxed for 30 min, evaporated
under vacuum to constant mass to give corresponding
hydrazone 5 as a solid or viscous liquid. Polyphosphoric
acid freshly prepared by solving P2O5 (2.0 g) in H3PO4
(85%, 1 mL) under heating on water bath for 3 h was
added to the residue. The reaction mixture was heated to
160°C (carefully!) and maintained at 160–170°C for
5 min (temperature should be below 170–175°C). After
cooling to 40–50°C, the reaction mixture was suspended
with H2O (25–30 mL), cooled to ~0°C, and alkalified
with aq 25% ammonia. The precipitate that formed was
filtered off, washed with cold water (10 mL, 0°C) and
MeOH (1 mL, 0°C), and air-dried.
1381, 1258, 1142, 822. H NMR (CDCl3): δ = 4.48 (br s,
2H, NH2), 6.36 (d, J = 8.7 Hz, 1H, H-3), 7.63 (dd,
J1 = 8.7 Hz, J2 = 2.1 Hz, 1H, H-4), 8.22 (d, J = 2.1 Hz,
1H, H-6). 13C NMR (CDCl3): δ = 77.8, 110.9, 145.3,
153.8, 157.4. MS (EI, 70 eV) m/z (%): 220 [М]+ (100),
193 (12), 127 [I]+ (10), 93 (5), 66 (11). Anal. Calcd for
C5H5IN2: C, 27.30; H, 2.29; N, 12.73. Found: C, 27.44;
H, 2.13; N, 12.69.
2-Bromo-5-iodopyridine (3).
2-Amino-5-iodopyridine
(2) (22.0 g, 0.1 mol) was added over 10 min to a cold
(10°C) aq 48% HBr (50 mL, 0.6 mol), then the mixture
was heated until all solid was dissolved, and cooled to 0–
10°C. Bromine (15 mL, 0.3 mol) was added drop by
drop, keeping the temperature below 10°C. Then, a
solution of NaNO2 (20.0 g, 0.2 mol) in water (25 mL)
was added dropwise for 1 h, maintaining the temperature
at 0–5°C. The reaction mixture was stirred for additional
30 min, then treated with a solution of NaOH (35.0 g,
0.9 mol) in water (40 mL) at such a rate that temperature
did not exceed 20–25°C. The solid was filtered off,
slurry-washed with cold water (3 × 10 mL), and air-dried
to afford a pale yellowish powder; yield 24.1 g (85%); m.
p. 116–117°C (hexane) (lit. m.p. 117–119°С (EtOH)
[19]); Rf = 0.6 (CHCl3). IR (KBr) ν, cmÀ1: 3090, 3020,
3-Iodo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole (4a). An
off-white powder; yield 0.62 g (69%); m.p. 223–224°С
(MeOH); Rf = 0.5 (CHCl3–MeOH, 20:1). IR (KBr) ν,
cmÀ1: 3139, 3032, 2932, 2832, 1568, 1407, 1281, 1226,
1
996, 905, 874, 768. H NMR (CDCl3) δ, ppm: 1.78–1.81
(m, 4H, 6,7-CH2), 2.57 (t, J = 5.1 Hz, 2H, 5-CH2), 2.70
(t, J = 5.1 Hz, 2H, 8-CH2), 8.07 (s, 1H, H-4), 8.21 (s,
1H, H-2), 11.38 (br s, 1H, NH). 13C NMR (DMSO-d6) δ,
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R. S. Alekseyev, S. S. Amirova, and V. I. Terenin
Vol 000
ppm: 20.1, 22.4, 22.5, 22.6, 81.8, 106.6, 122.5, 132.4,
137.0, 145.5, 146.8. MS (EI, 70 eV) m/z (%): 298 [M]+
(100); 270 (79); 171 (11); 143 (10); 127 (8); 89 (4).
Anal. Calcd for C11H11IN2: C, 44.32; H, 3.72; N, 9.40.
Found: C, 44.27; H, 3.60; N, 9.59.
(KBr) ν, cmÀ1: 3141, 3043, 2929, 2845, 1580, 1443,
1411, 1274, 876, 769. H NMR (DMSO-d6) δ, ppm: 2.42
1
(quin, J = 7.1 Hz, 2H, 6-CH2), 2.73 (t, J = 7.1 Hz, 2H, 5-
CH2), 2.86 (t, J = 7.1 Hz, 2H, 7-CH2), 8.07 (d,
J = 1.8 Hz, 1H, H-4), 8.19 (d, J = 1.8 Hz, 1H, H-2),
11.60 (br s, 1H, NH). 13C NMR (DMSO-d6) δ, ppm:
24.2, 25.7, 27.3, 82.4, 110.8, 119.8, 132.9, 144.9, 146.3,
151.1. MS (EI, 70 eV) m/z (%): 284 [M]+ (100); 257
(13); 220 (22); 157 (19); 155 (15); 127 [I]+ (21); 75 (6).
Anal. Calcd for C10H9IN2: C, 42.28; H, 3.19; N, 9.86.
Found: C, 42.17; H, 3.30; N, 9.91.
3-Iodo-6-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole
(4b). A pale gravel powder; yield 0.66 g (71%); m.p.
209–210°С (MeOH); Rf = 0.55 (CHCl3–MeOH, 20:1). IR
(KBr) ν, cmÀ1: 3131, 3045, 2924, 2867, 1570, 1488,
1
1409, 1281, 975, 875, 769. H NMR (DMSO-d6) δ, ppm:
1.06 (d, J = 6.6 Hz, 3H, Me), 1.42–1.51 (m, 1H, 7-CHB),
1.85–1.93 (m, 2H, 6-CH, 7-CHA), 2.13 (dd,
J1 = 15.6 Hz, J2 = 9.7 Hz, 1H, 5-CHB), 2.71–2.74 (m,
3H, 5-CHA, 8-CH2), 8.05 (d, J = 2.0 Hz, 1H, H-4), 8.21
(d, J = 2.0 Hz, 1H, H-2), 11.39 (br s, 1H, NH). 13C
NMR (DMSO-d6) δ, ppm: 21.5, 22.2, 28.5, 28.9, 30.5,
81.8, 106.5, 122.4, 132.4, 136.7, 145.5, 147.1. MS (EI,
70 eV) m/z (%): 312 [M]+ (93); 308 (13); 270 (100); 186
(11); 144 (16); 127 [I]+ (6); 89 (3). Anal. Calcd for
C12H13IN2: C, 46.17; H, 4.20; N, 8.97. Found: C, 46.25;
H, 4.25; N, 8.89.
8-Iodo-6,11-dihydro-5H-benzo[g]pyrido[2,3-b]indole (4f).
A
dark gray powder; yield 0.59 g (57%); m.p. 294–295°С
(EtOH); Rf = 0.55 (CHCl3–MeOH, 20:1). IR (KBr) ν,
cmÀ1: 3149, 3058, 2926, 2832, 1566, 1473, 1442, 1275,
1
930, 804, 764, 665. H NMR (DMSO-d6) δ, ppm: 2.85–
2.89 (m, 2H, 5-CH2), 2.96–3.01 (m, 2H, 6-CH2), 7.20–
7.31 (m, 2H, H-2,3), 7.59–7.77 (m, 2H, H-1,4), 8.27 (s,
1H, H-7), 8.32 (s, 1H, H-9), 12.22 (br s, 1H, NH). 13C
NMR (DMSO-d6) δ, ppm: 18.7, 28.5, 82.7, 120.5, 121.9,
122.4, 126.8, 127.6, 127.9, 128.4, 133.8, 134.6, 136.3,
147.1, 149.9. MS (EI, 70 eV) m/z (%): 346 [M]+ (100);
345 (75); 344 (78); 218 (59); 190 (24); 163 (10); 127 (9);
109 (9). Anal. Calcd for C15H11IN2 C, 52.04; H, 3.20; N,
8.09. Found: C, 51.96; H, 3.36; N, 8.05.
6-tert-Butyl-3-iodo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole
(4c). A pale gravel powder; yield 0.82 g (77%); m.p.
208–209°С (MeOH); Rf = 0.6 (CHCl3–MeOH, 20:1). IR
(KBr) ν, cmÀ1: 3140, 3046, 2947, 2863, 1568, 1468,
1
1406, 1363, 876. H NMR (DMSO-d6) δ, ppm: 0.95 (s,
10-Iodo-6,7-dihydro-5H-benzo[e]pyrido[2,3-b]indole (4g).
A
9H, t-Bu), 1.36–1.47 (m, 2H, 7-CH2), 2.03–2.06 (m, 1H,
5-CHB), 2.23–2.34 (m, 1H, 6-CH), 2.69–2.80 (m, 3H, 5-
CHA, 8-CH2), 8.10 (d, J = 2.2 Hz, 1H, H-4), 8.21 (d,
J = 2.2 Hz, 1H, H-2), 11.37 (br s, 1H, NH). 13C NMR
(DMSO-d6) δ, ppm: 21.5, 23.5, 24.0, 27.3 (3C), 32.3,
44.6, 81.7, 107.0, 122.7, 132.4, 137.0, 145.4, 147.2. MS
(EI, 70 eV) m/z (%): 354 [M]+ (83); 297 (9); 270 (100);
169 (11); 144 (15); 116 (4); 57 (12); 41 (12). Anal. Calcd
for C15H19IN2: C, 50.86; H, 5.41; N, 7.91. Found: C,
50.75; H, 5.64; N, 7.87.
pale brown powder; yield 0.54 g (52%); m.p. 275–276°C
(MeOH); Rf = 0.6 (CHCl3–MeOH, 20:1). IR (KBr) ν,
cmÀ1: 3096, 3023, 2822, 2716, 1559, 1501, 1410, 1265,
1
963, 758. H NMR (DMSO-d6) δ, ppm: 2.97–3.02 (m,
4H, 6-CH2, 7-CH2), 7.07 (t, J = 7.4 Hz, 1H, H-3), 7.23–
7.27 (m, 2H, H-2, H-4), 7.73 (d, J = 7.2 Hz, 1H, H-1),
8.34 (s, 1H, H-11), 8.63 (s, 1H, H-9), 12.06 (br s, 1H,
NH). 13C NMR (DMSO-d6) δ, ppm: 21.4, 28.2, 83.6,
107.0, 119.3, 122.1, 124.6, 126.9, 127.5, 128.0, 132.1,
133.8, 136.6, 146.2, 147.2. MS (EI, 70 eV) m/z (%): 346
[M]+ (100); 345 (36); 344 (71); 218 (30); 190 (14); 163
(8); 109 (7). Anal. Calcd for C15H11IN2: C, 52.04; H,
3.20; N, 8.09. Found: C, 52.14; H, 3.04 ; N, 8.01.
3-Iodo-5,6,7,8,9,10-hexahydrocyclohepta[4,5]pyrrolo[2,3-b]
pyridine (4d). A gravel powder; yield 0.50 g (53%); m.p.
191–192°С (MeOH); Rf = 0.5 (CHCl3–MeOH, 20:1). IR
(KBr) ν, cmÀ1: 3134, 3042, 2918, 2844, 1566, 1489,
1
5-Iodo-2,3-dimethyl-1H-pyrrolo[2,3-b]pyridine (4i).
An
1403, 1272, 934, 872, 769, 661. H NMR (DMSO-d6) δ,
off-white powder; yield 0.43 g (53%); m.p. 181–182°С
(MeOH); Rf = 0.5 (CHCl3–MeOH, 20:1). IR (KBr) ν,
cmÀ1: 3136, 3043, 2940, 2858, 1567, 1486, 1404, 1281,
ppm: 1.63–1.69 (m, 4H, 7-CH2, 8-CH2), 1.81–1.85 (m,
2H, 6-CH2), 2.69 (t, J = 5.0 Hz, 2H, 5-CH2), 2.83 (t,
J = 5.0 Hz, 2H, 9-CH2), 8.13 (d, J = 1.8 Hz, 1H, H-4),
8.20 (d, J = 1.8 Hz, 1H, H-2), 11.43 (br s, 1H, NH). 13C
NMR (DMSO-d6) δ, ppm: 23.9, 26.8, 28.2, 28.3, 31.3,
81.9, 110.4, 123.7, 124.7, 132.4, 140.5, 145.3. MS (EI,
70 eV) m/z (%): 312 [M]+ (100); 283 (40); 270 (22); 258
(13); 185 (18); 156 (14); 127 [I]+ (16); 103 (6). Anal.
Calcd for C12H13IN2: C, 46.17; H, 4.20; N, 8.97. Found:
C, 46.09; H, 4.34; N, 8.90.
1
909, 874, 770, 673. H NMR (DMSO-d6) δ, ppm: 2.13
(s, 3H, 3-Me), 2.32 (s, 3H, 2-Me), 8.11 (s, 1H, H-4), 8.21
(s, 1H, H-6), 11.40 (br s, 1H, NH). 13C NMR (DMSO-
d6) δ, ppm: 7.9, 11.2, 81.7, 103.7, 124.1, 132.6, 134.0,
145.5, 146.3. MS (EI, 70 eV) m/z (%): 272 [M]+ (100);
257 (17); 145 (12); 127 (11); 103 (4); 76 (5). Anal. Calcd
for C9H9IN2: C, 39.73; H, 3.33; N, 10.30. Found: C,
39.69; H, 3.45; N, 10.24.
3-Iodo-5,6,7,8-tetrahydrocyclopenta[4,5]pyrrolo[2,3-b]pyridine
(4e). A brown powder; yield 0.42 g (49%); m.p. 225–
2-Ethyl-5-iodo-3-methyl-1H-pyrrolo[2,3-b]pyridine (4j).
A
226°С (MeOH); Rf = 0.45 (CHCl3–MeOH, 20:1). IR
beige powder; yield 0.44 g (51%); m.p. 193–194°С
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
Synthesis of 2,3-Disubstituted 5-Iodo-1H-Pyrrolo[2,3-b]pyridines via Fischer
Cyclization
(MeOH); Rf = 0.6 (CHCl3–MeOH, 20:1). IR (KBr) ν,
5-Iodo-3-methyl-2-phenyl-1H-pyrrolo[2,3-b]pyridine (4n).
An off-white powder; yield 0.43 g (43%); m.p.
cmÀ1: 3145, 3048, 2965, 2851, 1569, 1487, 1404, 1276,
1
908, 872, 768, 657. H NMR (DMSO-d6) δ, ppm: 1.21
220–221°C (MeOH); Rf = 0.6 (CHCl3–MeOH, 20:1). IR
(KBr) ν, cmÀ1: 3124, 3046, 2924, 2857, 1475, 1398,
1275, 1072, 909, 879, 767, 698, 673. 1H NMR
(DMSO-d6) δ, ppm: 2.38 (s, 3H, Me), 7.41 (t,
J = 7.4 Hz, 1H, H-4 Ph), 7.52 (t, J = 7.4 Hz, 2H, H-3,5
Ph), 7.71 (d, J = 7.4 Hz, 2H, H-2,6 Ph), 8.33 (s, 1H,
H-4), 8.36 (s, 1H, H-6), 11.95 (br s, 1H, NH). 13C NMR
(DMSO-d6) δ, ppm: 9.5, 82.3, 105.2, 124.5, 127.8,
128.0 (2C), 128.7 (2C), 131.8, 134.1, 135.5, 146.9,
147.4. MS (EI, 70 eV) m/z (%): 334 [M]+ (100);
257 (10); 205 (11); 127 (4); 103 (7); 77 (6). Anal. Calcd
for C14H11IN2: C, 50.32; H, 3.32; N, 8.38. Found: C,
50.43; H, 3.19; N, 8.42.
(t, J = 7.6 Hz, 3H, 2-Me), 2.13 (s, 3H, 3-Me), 2.69 (q,
J = 7.6 Hz, 2H, CH2), 8.11 (d, J = 2.0 Hz, 1H, H-4),
8.22 (d, J = 2.0 Hz, 1H, H-6), 11.42 (br s, 1H, NH). 13C
NMR (DMSO-d6), δ, ppm: 7.9, 13.9, 18.8, 81.8, 102.9,
124.1, 132.9, 139.7, 145.7, 146.4. MS (EI, 70 eV) m/z
(%): 286 [M]+ (100); 271 (74); 257 (7); 159 (19); 144
(22); 127 (26); 103 (6); 76 (7). Anal. Calcd for
C10H11IN2: C, 41.98; H, 3.88; N, 9.79. Found: C, 42.03;
H, 3.75; N, 9.85.
5-Iodo-2-methyl-3-propyl-1H-pyrrolo[2,3-b]pyridine (4k).
A
beige powder; yield 0.53 g (59%); m.p. 164–165°С
(MeOH); Rf = 0.65 (CHCl3–MeOH, 20:1). IR (KBr) ν,
cmÀ1: 3133, 3037, 2954, 2925, 2852, 1568, 1488, 1404,
2-Ethyl-5-iodo-3-phenyl-1H-pyrrolo[2,3-b]pyridine (4o).
A
1
1282, 1217, 940, 891, 876, 770, 676. H NMR (CDCl3)
light brown powder; yield 0.66 g (63%); m.p. 209–210°C
(MeOH); Rf = 0.65 (CHCl3–MeOH, 20:1). IR (KBr) ν,
cmÀ1: 3134, 3026, 2970, 2932, 2872, 1599, 1500, 1448,
δ, ppm: 0.87 (t, J = 7.3 Hz, 3H, 3-Me), 1.53 (sext,
J = 7.3 Hz, 2H, CH2Me), 2.32 (s, 3H, 2-Me), 2.57 (t,
J = 7.3 Hz, 2H, CH2Et), 8.12 (d, J = 1.6 Hz, 1H, H-4),
8.20 (d, J = 1.6 Hz, 1H, H-6), 11.42 (br s, 1H, NH). 13C
NMR (DMSO-d6) δ, ppm: 11.2, 13.7, 23.5, 25.0, 81.8,
108.8, 123.5, 132.6, 134.1, 145.4, 146.3. MS (EI, 70 eV)
m/z (%): 300 [M]+ (68); 271 (100); 144 (15); 127 (3).
Anal. Calcd for C11H13IN2: C, 44.02; H, 4.37; N, 9.33.
Found: C, 44.15; H, 4.23; N, 9.27.
1
1401, 1267, 930, 759, 704. H NMR (DMSO-d6) δ, ppm:
1.29 (t, J = 7.4 Hz, 3H, Me), 2.83 (q, J = 7.4 Hz, 2H,
CH2), 7.31–7.48 (m, 5H, Ph), 8.11 (s, 1H, H-4), 8.34 (s,
1H, H-6), 11.95 (br s, 1H, NH). 13C NMR (DMSO-d6) δ,
ppm: 14.1, 19.3, 82.9, 110.1, 122.1, 126.2, 128.8 (2C),
128.9 (2C), 133.1, 133.8, 140.3, 146.5, 146.6. MS (EI,
70 eV) m/z (%): = 348 [M]+ (100); 333 (24); 221 (7);
206 (20); 127 [I]+ (4); 103 (4). Anal. Calcd for
C15H13IN2: C, 51.74; H, 3.76; N, 8.05. Found: C, 51.71;
H, 3.65; N, 8.11.
5-Iodo-3-isopropyl-2-methyl-1H-pyrrolo[2,3-b]pyridine (4l).
Off-white needle crystals; yield 0.34 g (38%); m.p. 182–
183°С (hexane); Rf = 0.55 (CHCl3–MeOH, 20:1). IR
(KBr) ν, cmÀ1: 3132, 3029, 2956, 2864, 1560, 1463,
3-Benzyl-5-iodo-2-methyl-1H-pyrrolo[2,3-b]pyridine (4p).
A
1
1401, 1275, 931, 869, 674. H NMR (CDCl3) δ, ppm:
pale brown powder; yield 0.44 g (42%); m.p. 205–206°C
(toluene); Rf = 0.6 (CHCl3–MeOH, 20:1). IR (KBr) ν,
cmÀ1: 3129, 3025, 2927, 2843, 2745, 1569, 1491, 1403,
1.37 (d, J = 7.1 Hz, 6H, Me2CH), 2.46 (s, 3H, 2-Me), 3.13
(sept, J = 7.1 Hz, 1H, CHMe2), 8.22 (s, 1H, H-4), 8.31 (s,
1H, H-6), 10.68 (br s, 1H, NH). 13C NMR (CDCl3) δ,
ppm: 12.2, 23.2 (2C), 25.8, 81.1, 115.9, 123.1, 132.1,
135.0, 145.2, 146.8. MS (EI, 70 eV) m/z (%): 300 [M]+
(56); 285 (100); 158 (20); 127 (10); 89 (3). Anal. Calcd
for C11H13IN2: C, 44.02; H, 4.37; N, 9.33. Found: C,
44.08; H, 4.42; N, 9.25.
1
1275, 875, 698. H NMR (CDCl3) δ, ppm: 2.39 (s, 3H,
Me), 3.97 (s, 2H, CH2), 7.14 (t, J = 7.3 Hz, 1H, H-4 Ph),
7.19–7.27 (m, 4H, H-2,3,5,6 Ph), 8.1 (s, 1H, H-4), 8.21
(s, 1H, H-6), 11.55 (br s, 1H, NH). 13C NMR (CDCl3) δ,
ppm: 11.4, 29.0, 82.1, 107.9, 123.4, 125.7, 128.1 (2C),
128.3 (2C), 132.8, 134.7, 141.4, 145.7, 146.4. MS (EI,
70 eV) m/z (%): 348 [M]+ (100); 333 (23); 271 (67); 258
(11); 221 (12); 205 (11); 178 (10); 144 (23); 127 (13);
103 (11); 77 (15); 51 (15); 42 (15). Anal. Calcd for
C15H13IN2: C, 51.74; H, 3.76; N, 8.05. Found: C, 51.63;
H, 3.90; N, 7.98.
3-Ethyl-5-iodo-2-propyl-1H-pyrrolo[2,3-b]pyridine (4m).
A
gravel powder; yield 0.43 g (46%); m.p. 104–105°C
(hexane); Rf = 0.65 (CHCl3–MeOH, 20:1). IR (KBr) ν,
cmÀ1: 3141, 3045, 2952, 2864, 1567, 1453, 1403,
1
1255, 930, 874. H NMR (DMSO-d6) δ, ppm: 0.89 (t,
J = 7.2 Hz, 3H, 2-Me), 1.13 (t, J = 7.3 Hz, 3H, 3-
Me), 1.65 (sext, J = 7.2 Hz, 2H, 2-CH2Me), 2.59–2.67
(m, 4H, 3-CH2Me and 2-CH2Et), 8.15 (s, 1H, H-4),
8.22 (s, 1H, H-6), 11.40 (br s, 1H, NH). 13C NMR
(DMSO-d6) δ, ppm: = 13.6, 15.8, 16.4, 22.5, 27.3,
81.7, 110.6, 123.0, 132.8, 137.6, 145.6, 146.5. MS (EI,
70 eV) m/z (%): 314 [M]+ (100); 299 (71); 285 (39);
270 (12); 172 (9); 157 (8); 29 (24). Anal. Calcd for
C12H15IN2: C, 45.88; H, 4.81; N, 8.92. Found: C,
45.80; H, 4.88; N, 8.90.
7-Iodo-3-methyl-4H-pyrido[2,1-c][1,2,4]triazin-4-one (6). If
ethyl pyruvate was used as a carbonyl compound, the only
triazine-4-one 6 was isolated as a pale gray powder from
reaction mixture after alkalization and washing with cold
water; yield 0.38 g (47%); m.p. 228–229°C (decomp);
Rf = 0.42 (EtOAc). IR (KBr) ν, cmÀ1: 3352, 3097, 3081,
3024, 1679, 1541, 1499, 1462, 1436, 1377, 1289, 1153,
1
1095, 1066, 829, 748. H NMR (CDCl3) δ, ppm: 2.57 (s,
3H, Me), 7.44 (d, J = 9.3 Hz, 1H, H-9), 7.76 (d,
J = 9.3 Hz, 1H, H-8), 8.89 (s, 1H, H-6). 13C NMR
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

R. S. Alekseyev, S. S. Amirova, and V. I. Terenin
Vol 000
[6] Mérour, J.-Y.; Joseph, B. Curr Org Chem 2001, 5, 471.
[7] Popowycz, F.; Routier, S.; Joseph, B.; Mérour,
J.-Y. Tetrahedron 2007, 63, 1031.
[8] Song, J. J.; Reeves, J. T.; Gallou, F.; Tan, Z.; Yee, N. K.;
Senanayake, C. H. Chem Soc Rev 2007, 1120.
[9] Mérour, J.-Y.; Routier, S.; Suzenet, F.; Joseph, B. Tetrahedron
2013, 69, 4767.
(CDCl3) δ, ppm: 17.7, 82.7, 125.2, 129.0, 142.6,
145.6, 146.9, 149.2. MS (EI, 70 eV) m/z (%): 287 [M]+
(76); 259 (100); 218 (46); 204 (9); 191 (9); 127 [I]+ (19);
91 (34); 77 (15); 64 (24). Anal. Calcd for C8H6IN3O:
C, 33.47; H, 2.11; N, 14.64. Found: C, 33.56; H, 1.99;
N, 2.09.
[10] Dyke, H. J.; Gazzard, L. J.; Williams, K. Patent WO
2011/73263, 2011.
[11] Arendt, C.; Babin, D.; Bedel, O.; Gouyon, T.; Levit, M.; Li, R.;
Mignani, S.; Mooreroft, N.; Papin, D. US Patent 2011/178053, 2011.
[12] Dorsch, D.; Hoelzemann, G.; Eggenweiler, H.-M.;
Czodrowski, P. US Patent 2014/323481, 2014.
[13] Chen, M.; Ichikawa, S.; Buchwald, S. L. Angew Chem Int Ed
2015, 54, 263.
Acknowledgments. This work was financially supported by
Russian Foundation for Basic Research (grant 14-03-31289).
We also wish to acknowledge Dr. Tarasevich B. N. for
assistance in registration of the IR spectra.
[14] Schneider, C.; David, E.; Toutov, A. A.; Snieckus, V. Angew
Chem Int Ed 2012, 51, 2722.
REFERENCES AND NOTES
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet