A facile and efficient synthesis of 7-azaindoles

Article abstract of DOI:10.1002/jccs.200700081

A practical and efficient synthesis of 2-substituted 7-azaindoles has been developed using a cross-coupling-heteroannulation approach.

Full text of DOI:10.1002/jccs.200700081

Journal of the Chinese Chemical Society, 2007, 54, 569-573
569
Communication
A Facile and Efficient Synthesis of 7-Azaindoles
Li-Ping Sun* (
), Xiang-Hong Huang§ (
Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, P. R. China
) and Jin-Xin Wang (
)
A practical and efficient synthesis of 2-substituted 7-azaindoles has been developed using a cross-
coupling-heteroannulation approach.
Keywords: Synthesis; 7-Azaindoles; Cross-coupling; Heteroannulation.
INTRODUCTION
RESULTS AND DISCUSSIONS
7-Azaindoles are the most widely studied nitrogen
analogue of the indole ring system.1 It has been used as an
indole bioisostere to improve physicochemical and phar-
macokinetic properties of several drug candidates such as
dopamine D4 ligands.2 It is also an emerging pharmaco-
phore in ATP competitive kinase inhibitors as it contains
the typical motif (H-bond donor and acceptor in 1,3-posi-
tion) to dock into the adenine binding pocket.3 To date, the
traditional synthetic approach to 7-azaindoles primarily fo-
cused on the Fischer,4 Madelungroutes, or transition metal
catalyzed cross-coupling/heteroanulation of 2-amino-3-
iodo-pyridines with alkynes or ketones.5-7 Functionaliza-
tion of 7-azaindole also remains of great interest to chem-
ists, and some approaches have been used for modification
of the 7-azaindole scaffold.8 In the course of our previous
research program, we developed an efficient procedure for
the construction of indole rings whereby utilizing 2-amino-
phenol as the starting materials,9a 2-alkynylanilides were
obtained through Pd(0)-Cu(I)-catalyzed cross-coupling of
1-alkynes with 2-carboxamidoaryl triflates which were
subjected to an alkoxide-mediated cyclization to provide
indoles. The method is suited for introducing substitutes
in a pyridine ring incorporated in the azaindole system.
Therefore, as a part of our studies on bioactive heterocy-
cles, we explore here an efficient synthetic approach to 2-
substitited 7-azaindoles starting from commercially avail-
able 2-amino-3-hydroxypyridine and bromo-aminopyri-
dine.
Our previous studies showed that 2-trifoxyanilides
underwent Sonogashira cross-coupling with 1-alkyne cata-
lyzed by Pd(0)-CuI in the presence of additive n-Bu4NI to
afford 2-alkynylanilides.9a This procedure was also suc-
cessfully applied to the synthesis of nitroindoles starting
from nitro 2-aminophenols.9b The weak electron-withdraw-
ing property of the pyridine ring could tolerate the same
conditions in comparison with nitro 2-carboxamidoaryl.
Therefore, 2-amino-3-hydroxypyridine was selected as
starting material, which was then selectively protected by
butyryl chloride followed by esterification to give 2. Initial
attempts examined the reaction of 2 with phenyl alkyne
catalyzed by Pd(PPh3)4-CuI; a cross-coupling reaction
took place at room temperature in MeCN-Et3N (5:1) with
n-Bu4NI as the additive to give 3a (R = Ph) in excellent
yield. We screened the other Pd catalytic systems such as
Pd(PPh3)Cl2-CuI, Pd(PhCN)Cl2-CuI and PdOAc-PPh3-CuI
and found that the Pd(PPh)4-CuI system is the most favor-
able. The reactions tolerate the electron-donating and elec-
tron-withdrawing functional group on alkynes. The results
are summarized in Table 1 (3a-d).
Heteroannulation of 3 was carried out in NMP with
t-BuOK at 60 °C to give 2-substituted 7-azainsoles in good
yields (Table 1, 4a, 4b, 4d). Cyano substituted alkyne gave
low yield (Table 1, 4c). The above synthetic route is also
practical to approach the synthesis of receptor 6, which
showed human dopamine D 4 receptor affinity.2b
To expand the synthetic method towards 7-azaindoles,
* Corresponding author. E-mail: chsunlp@yahoo.com.cn
§ Xiang-Hong Huang now is working at Wenzhou University, Wenzhou 325027, P. R. China

570 J. Chin. Chem. Soc., Vol. 54, No. 3, 2007
Table 1. Synthesis of compounds 3 and 4
Sun et al.
CuI at 80 °C for 24 h and gave 2-alkynylaminopyridins 8a
and 8b in 81% and 65% yields, respectively. Subsequent
t-BuOK-mediated ring closure within 8a and 8b afforded
2-substituted 5-meyhyl-7-azaindoles 9a and 9b in excel-
lent yields (Scheme III). The aromatic and aliphatic al-
kynes could tolerate the reaction conditions.
Entry
R
3: Yield (%)
4: Yield (%)
1
2
3
4
Ph
3a: 98
3b: 99
3c: 87
3d: 83
4a: 77
4b: 73
4c: 65
4d: 70
n-Pr
(CH2)3CN
(CH2)3Cl
In summary, we have developed an efficient cross-
coupling-heteroannulation approach toward 2-substituted
7-azaindoles starting from commercially available 2-ami-
no-3-hydroxypyridine and 2-amino-3-bromo-5-methyl-
pyridine. Both electron donating and electron withdrawing
substituents of 1-alkynes could tolerate the reaction condi-
tions. The methods provide an efficient and reliable strat-
egy for the synthesis of 7-azaindole libraries.
2-amino-3-bromo-5-methylpyridine 7 was selected as the
substrate for 3,5-disubstituted 7-azaindole. The Pd(PPh3)4-
CuI catalytic system was also efficient for the cross-cou-
pling reaction of the bromopyridine 7 without protection of
an amino group. Compound 7 underwent Sonogashira cross-
coupling reaction with 1-alkynes catalyzed by Pd(PPh3)4-
Scheme I
Reagents and conditions: (i) butyryl chloride (1.1 eq), pyridine (1.5 eq), THF, reflux; (ii) (TfO)2O
(1.1 eq), Et3N (1.5 eq), DCM, 0 °C; (iii) alkyne (1.5 eq), Pd(PPh3)4 (0.1 eq), CuI (0.3 eq),
MeCN-Et3N (5:1); (iv) t-BuOK (1.2 eq), NMP.
Scheme II
Reagents and conditions: (i) a, alkyne, Pd(PPh3)4, CuI, n-Bu4NI, DMF/Et3N (5:1); b, t-BuOK, NMP; (ii) PPTS,
MeOH, 50 °C, 29 h; (iii) MsCl, Et3N, DCM; (iv) 1,2,3,4-tetrahydroquinoline, K2CO3, IPA, reflux.
Scheme III
Reagents and conditions: (i) alkyne (2.0 eq), Pd(PPh3)4 (0.1 eq), CuI (0.3 eq), Et3N-MeCN (1:5),
80 °C, 24 h (ii) t-BuOK (2.0 eq), NMP, rt, 24 h.

A Facile and Efficient Synthesis of 7-Azaindoles
J. Chin. Chem. Soc., Vol. 54, No. 3, 2007 571
EXPERIMENTAL SECTION
8.28 (dd, J = 1.9, 5.0 Hz, 1H), 8.14 (s, 1H), 7.65 (dd, J = 1.9,
7.8 Hz, 1H), 6.95 (dd, J = 5.0, 7.8 Hz, 1H), 2.72 (t, J = 7.4
Hz, 2H), 2.47 (t, J = 6.9 Hz, 2H), 1.78 (t, J = 7.4 Hz, 2H),
1.67 (t, J = 6.9 Hz, 2H), 1.09-1.01 (m, 6H); 13C NMR (75
MHz, CDCl3) d: 155.4, 152.1, 147.8, 119.0, 110.0, 100.1,
75.4, 40.0, 22.7, 22.3, 19.3, 14.6, 14.3; MS (+CI): m/z
231.2 (M + H+, 100); HRMS calcd. For C14H18N2O [M+
H]+ 230.1491, found 230.1501.
1H and 13C NMR were recorded on either a Bruker
RX-300 or a Varian300 spectrometer. Chemical shifts are
reported in ppm related to the residual solvent peak. Infra-
red (IR) spectra were taken on a Perkin-Elmer FT-IR spec-
trophotometer as thin film or KBr pellets. Mass spectra
(MS) were measured on a Finnigan TSQ 7000 mass spec-
trometer. Melting points were determined in a capillary
tube with a MEL-TEMP II apparatus and are uncorrected.
Standard flash chromatography was employed to purify the
crude reaction mixture using 200-300 mesh silica gel.
N-[3-(5-Cyano-pent-1-ynyl)-pyridin-2-yl]-butyramide
(3c)
Prepared from 2 in 87% yield. mp: 92-93 °C. IR
(KBr): 3249, 1677 cm-1; 1H NMR (CDCl3) d: 8.31 (dd, J =
1.8, 4.9 Hz, 1H), 8.25 (s, 1H), 7.72 (dd, J = 1.8, 7.5 Hz, 1H),
7.02 (dd, J = 1.8, 7.5 Hz, 1H), 2.73-2.70 (m, 4H), 2.58 (t, J
= 6.6 Hz, 2H), 2.01-1.97 (m, 2H), 1.04 (t, J = 7.2 Hz, 3H);
13C NMR (300 MHz, CDCl3) d: 189.5, 152.0, 147.4, 141.7,
122.9, 119.5, 119.4, 110.2, 96.8, 39.87, 25.0, 19.6, 19.3,
17.1, 14.6; MS (+CI) m/z 256.1 (M + H+, 100); HRMS
calcd. For C15H17N3O [M+H]+ 256.1443, found 256.1450.
Representative procedures for the synthesis of N-(3-
phenylethynyl-pyridin-2-yl)-butyramide (3a-d)
Compound 2 was prepared according to the standard
method.9a mp: 77-78 °C; IR (film) 3278, 2971, 1672, 1513
cm-1; 1H NMR (300 MHz, CDCl3) d: 8.42 (s, 1H), 7.93 (s,
1H), 7.69 (dd, J = 8.1, 0.9 Hz, 1H), 7.26 (s, 1H), 2.50 (t, J =
7.4 Hz, 2H), 1.77 (sextet, J = 7.4 Hz, 2H), 1.02 (t, J = 7.3
Hz, 3H); 13C NMR (75 MHz, CDCl3) d: 173.2, 140.1,
138.8, 131.1, 124.1, 38.6, 18.4, 13.7; MS (+CI) m/z 313 (M
+ H+, 100); Anal. Calcd. for C10H11F3N2O4S C, 38.46; H,
6.47; N, 8.97. Found C, 38.56; H, 3.53; N, 8.73.
N-[3-(5-Chloro-pent-1-ynyl)-pyridin-2-yl]-butyramide
(3d)
Prepared from 2 in 83% yield. mp: 77-78 °C. IR
1
To a solution of 2 (124.8, 0.4 mmol), Pd(PPh3)4 (46.0
mg, 0.04 mmol), CuI (23.1 mg, 0.12 mmol), n-Bu4NI (222.0
mg, 0.6 mmol) in MeCN (5.0 mL), was added Et3N (1.0
mL) and 1-phenylacetylene (0.09 mL, 0.6 mmol) under ni-
trogen. The resulting reaction mixture was stirred at room
temperature for 5 h. The saturated NH4Cl and EtOAc were
added. The organic layer was washed with brine and then
dried over anhydrous NaSO4, concentrated under reduced
pressure and purified by flash chromatography (EtOAc:
hexane = 1:2) to give 3a (103.5 mg, 98%) as white solid.
mp 110-111 °C; IR (KBr) 3256, 1668 cm-1; 1H NMR (300
MHz, CDCl3) d: 8.37 (dd, J = 1.8, 4.9 Hz, 1H), 8.26 (s, 1H),
7.76 (dd, J = 1.8, 7.7 Hz, 1H), 7.54-7.48 (m, 2H), 7.38-7.33
(m, 3H), 7.00 (dd, J = 4.9, 7.7 Hz, 1H), 2.70 (t, J = 7.4 Hz,
2H), 1.77 (sextet, J = 7.4 Hz, 2H), 1.00 (t, J = 7.4 Hz, 3H);
13C NMR (75 MHz, CDCl3) d: 173.2, 151.7, 146.9, 141.9,
132.3, 129.9, 129.1, 122.3, 199.4, 99.0, 83.3, 58.7, 40.0,
19.4, 14.6; MS (+CI) m/z 265.1 (100, M + H+); HRMS
calcd. For C17H16N2O [M+H]+ 265.1335, found 265.1343.
(KBr): 3252, 1675 cm-1; H NMR (300 MHz, CDCl3) d:
8.32 (dd, J = 1.8, 4.9 Hz, 1H), 8.21 (s, 1H), 7.70 (dd, J = 1.8,
7.7 Hz, 1H), 6.99 (t, J = 7.7 Hz, 1H), 3.71 (t, J = 6.2 Hz,
2H), 2.71 (m, 4H), 2.09 (m, 2H), 1.78 (m, 2H), 1.03 (t, J =
7.4 Hz, 3H); 13C NMR (75 MHz, CDCl3) d: 173.4, 152.1,
147.1, 141.6, 119.2, 110.4, 110.2, 98.2, 76.2, 44.3, 40.0,
31.7, 19.9, 14.6; MS (EI) m/z: 265.1 (M + H+, 100); HRMS
calcd. For C14H17ClN2O [M+H]+ 265.1101, found 265.1110.
Representative procedures for the synthesis of 7-
azaindoles (4a-d)
The mixture of 3a (26.4 mg, 0.10 mmol), t-BuOK
(14.2 mg, 0.12 mmol) and NMP (2 mL) was stirred at 50 °C
for 10 h under nitrogen atmosphere then cooled to room
temperature. To the reaction solution was added 2 mL wa-
ter and then extracted with EtOAc 3 times. The organic
layer was washed with brine, dried with anhydrous MgSO4
and evaporated under reduced pressure and purified by
flash chromatography (EtOAc:hexane = 1:4) to give 4a
(14.9 mg, 77%). mp: 67-68 °C. IR (KBr): 3407, 3065, 1620
1
N-(3-Pent-1-ynyl-pyridin-2-yl)-butyramide (3b)
cm-1; H NMR (300 MHz, CD3COCD3) d 11.62 (s, 1H),
Prepared from 2 in 99% yield. mp: 96-98 °C. IR
1
8.39 (dd, J = 1.1, 4.6 Hz, 1H), 8.15- 8.09 (m, 3H), 7.69-7.62
(m, 2H), 7.56-7.50 (m, 1H), 7.23 (dd, J = 4.6, 7.8 Hz, 1H),
(KBr): 3256, 1669 cm-1; H NMR (300 MHz, CDCl3) d:

572 J. Chin. Chem. Soc., Vol. 54, No. 3, 2007
Sun et al.
7.07 (s, 1H); 13C NMR (75 MHz, CD3COCD3) d 148.4,
140.8, 140.3, 132.2, 130.7, 129.7, 129.2, 126.5, 116.6,
98.2; MS (EI) m/z: 195.0 (M + H+, 100); HRMS calcd. For
C13H10N2 [M+H]+ 195.0916, found 195.0923.
149.5, 14.2, 137.6, 134.9, 134.4, 128.6, 127.5, 126.5, 126.0,
125.6, 120.9, 115.5, 99.4, 55.9, 55.4, 50.6; MS (+CI) m/z
264.1 (M + H+, 100). HRMS calcd. For C10H11ClN2 [M+H]+
264.1494, found 264.1486.
2-Propyl-1H-pyrrolo[2,3-b]pyridine (4b)
5-Methyl-3-pent-1-ynyl-pyridin-2-ylamine (8a)
Prepared from 3b in 73% yield. mp 123-124 °C; IR
(KBr): 3217, 2934, 2875 cm-1; 1H NMR (300 MHz, CDCl3)
d: 11.88 (s, 1H), 8.21 (d, J = 4.2 Hz, 1H), 7.85 (d, J = 8.1,
1H), 7.05 (t, J = 6.5 Hz, 1H), 6.21 (s, 1H), 2.87 (t, J = 7.5
Prepared from 7 in 65% yield as a brown oil; IR (film)
2962, 2871, 2223, 1614 cm-1; 1H NMR (300 MHz, CDCl3)
d 7.75 (s, 1H), 7.26 (d, J = 1.3 Hz, 1H), 4.85 (s, 2H), 2.38 (t,
J = 7.0 Hz, 2H), 2.09 (s, 3H), 1.62-1.54 (m, 2 H), 0.99 (t, J =
7.4 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 157.0, 146.5,
140.3, 122.0, 103.6, 96.2, 76.0, 22.1, 21.4, 17.0, 13.4; MS
(+CI) m/z 175.0 (M + H+, 100); HRMS calcd. For C11H14N2
[M+H]+ 175.1229, found 175.1220.
Hz, 2H), 1.88-1.84 (m, 2H), 1.07 (t, J = 7.5 Hz, 3H); 13
C
NMR (75 MHz, CDCl3) d: 149.4, 142.2, 140.7, 128.3,
122.5, 116.0, 97.9, 31.4, 23.1, 14.7; MS (+CI) m/z 161.1 (M
+ H+, 100); HRMS calcd. For C10H12N2 [M+H]+ 161.1072,
found 161.1077.
5-Methyl-3-phenylethynyl-pyridin-2-ylamine (8b)
Prepared from 7 in 65% yield as a yellow solid; mp
155-160 °C (DCM-hexane); IR (film) 3077, 2950, 2873,
2230, 1594, 1560, 1438 cm-1; 1H NMR (300 MHz, CDCl3)
d 7.85 (d, J = 2.2 Hz, 1H), 7.51-7.47 (m, 2H), 7.41 (d, J =
2.2 Hz, 1H), 7.35-7.30 (m, 3H), 2.15 (s, 3H); 13C NMR (75
MHz, CDCl3) d 156.9, 147.5, 140.5, 131.3, 129.4, 128.3,
122.6, 122.2, 102.7, 95.2, 84.5, 17.1; MS (ESI) m/z 209 (M
+ H+, 100); Anal Calcd. for C14H12N2 C, 80.74; H, 5.81; N,
13.45. Found C, 80.31; H, 5.95; N, 13.55.
4-(1H-Pyrrolo[2,3-b]pyridin-2-yl)-butyronitrile (4c)
Prepared from 3c in 78% yield. mp 100-101 °C. IR
1
(KBr): 3420, 2245 cm-1; H NMR (300 MHz, CDCl3) d:
11.57 (s, 1H), 8.22 (d, J = 4.5 Hz, 1H), 7.95 (d, J = 7.8 Hz,
1H), 7.13 (t, J = 6.6 Hz, 1H), 6.33 (s, 1H), 3.07 (t, J = 7.2
Hz, 2H), 2.45 (t, J = 7.2 Hz, 2H), 2.18-2.13 (m, 2H); 13
C
NMR (75 MHz, CDCl3) d: 147.7, 140.0, 139.5, 130.2,
123.1, 119.7, 116.5, 99.7, 27.9, 25.5, 17.3; MS (+CI) m/z
186.1 (M + H+, 100). HRMS calcd. For C11H11N3 [M+H]+
186.1025, found 186.1026.
5-Methyl-2-propyl-1H-pyrrolo[2,3-b]pyridine (9a)
Prepared from 8a in 88% yield. 128: white crystal;
mp 127-128 °C; IR (film) 3418, 2960, 1645 cm-1; 1H NMR
(300 MHz. DMSO-d6) d 11.26 (s, 1H), 2.65 (t, J = 7.2 Hz,
2H), 2.31 (s, 3H), 1.75-1.62 (m, J = 7.2 Hz, 2H), 0.91 (t, J =
7.2 Hz, 3H); 13C NMR (75 MHz, DMSO-d6) d 147.2, 141.5,
141.0, 126.4, 123.2, 120.3, 99.0, 29.9, 21.8, 18.1, 13.7; MS
(ESI) m/z 175 (M + H+, 100); Anal. Calcd. For C11H14N2 :
C, 75.82; H, 8.10; N, 16.08. Found C, 75.53; H, 8.51; N,
16.07.
2-(3-Chloro-propyl)-1H-pyrrolo[2,3-b]pyridine (4d)
Prepared from 2 in 70% yield. mp: 130-131 °C; IR
1
(KBr) 3446, 2833 cm-1; H NMR (300 MHz, CDCl3) d:
11.63 (s, 1H), 8.20 (t, J = 4.8 Hz, 1H), 7.80 (d, J = 8.1 Hz,
1H), 7.00 (t, J = 6.3 Hz, 1H), 6.90 (s, 1H), 4.24 (t, J = 7.2
Hz, 2H), 3.06 (t, J = 7.5 Hz, 2H), 2.64-2.59 (m, 2H); 13
C
NMR (75 MHz, CDCl3) d 145.9, 144.9, 141.5, 128.6, 126.5,
115.9, 91.6, 49.7, 28.5, 25.3; MS (+CI) m/z 195.8 (M + H+,
100); HRMS calcd. For C10H11ClN2 [M+H]+ 195.0682,
found 195.0678.
5-Methyl-2-phenyl-1H-pyrrolo[2,3-b]pyridine (9b)
Prepared from 8b in 95% yield as a white solid, mp >
250 °C; Rf = 0.50 (33% EtOAc in hexane); 1H NMR (300
MHz, DMSO-d6) d 12.09 (s, 1H), 8.16 (d, J = 1.6 Hz, 1H),
8.04-8.00 (m, 2H), 7.81 (d, J = 1.5 Hz, 1H), 7.57-7.39 (m,
3H), 6.92 (d, J = 2.1 Hz, 1H); 13C NMR (75 MHz, DMSO-
d6) d 148.3, 143.62, 138.2, 131.7, 128.8, 127.8, 127.6,
125.2, 124.4, 120.7, 96.5, 18.1; MS (ESI) m/z 209 (M + H+,
100); Anal. Calcd. For C14H12N2 C, 80.74; H, 5.81; N,
2-(1H-Pyrrolo[2,3-b]pyridin-2-ylmethyl)-1,2,3,4-tetra-
hydro-isoquinoline (6)
Prepared from 5 in 34% overall yield. mp: 106-107
°C; IR (film): 3401, 3059, 1615, 1576 cm-1; 1H NMR (300
MHz, Acetone-d6) d 11.58 (s, 1H), 8.34 (dd, J = 1.5, 4.5 Hz,
1H), 8.03 (dd, J = 7.8, 1.2 Hz, 1H), 7.28-7.25 (m, 3H),
7.20-7.13 (m, 2H), 6.58 (s, 1H), 4.08 (s, 2H), 3.87 (s, 1H),
3.11-2.95 (m, 4H). 13C NMR (75 MHz, Acetone-d6) d

A Facile and Efficient Synthesis of 7-Azaindoles
13.45. Found C, 80.50; H, 6.09; N, 12.76.
J. Chin. Chem. Soc., Vol. 54, No. 3, 2007 573
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ACKNOWLEDGEMENT
This work was partially supported by China Pharma-
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