Efficient one-pot synthesis of 3-amino-7-azaindoles under microwave irradiation

Article abstract of DOI:10.1080/00397911.2013.858360

An efficient one-pot synthesis of 3-amino-7-azaindoles was developed, starting from ethyl (3-cyanopyridin-2-yl)carbamate and α -bromoketones by microwave-assisted Thorpe-Ziegler cyclization in the presence of a base. This method features excellent yields, short reaction time (10min), and high functional group compatibility.

Full text of DOI:10.1080/00397911.2013.858360

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An Efficient One-Pot Synthesis of 3-amino-7-azaindoles
Under Microwave Irradiation
Hai-Kui Yang a , Wen-Wei You a , Guang-Hua Yan a , Zhi-Hong Jiang a b , Pei-Liang Zhao a
Zhong-Zhen Zhou a
&
a School of Pharmaceutical Sciences , Southern Medical University , Guangzhou , China
b State key laboratory for Quality Research in Chinese medicines , Macau University of
Science and Technology , Macau , China
Accepted author version posted online: 08 Nov 2013.Published online: 08 Nov 2013.
To cite this article: Synthetic Communications (2013): An Efficient One-Pot Synthesis of 3-amino-7-azaindoles Under
Microwave Irradiation, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, DOI: 10.1080/00397911.2013.858360
To link to this article: http://dx.doi.org/10.1080/00397911.2013.858360
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Zhong-Zhen Zhou
One-Pot Synthesis of 3-Amino-7-azaindoles
An Efficient One-Pot Synthesis of 3-Amino-7-azaindoles under Microwave
Irradiation
An International Journal for Rapid Communication of Synthetic Organic Chemistry
Hai-Kui Yang,1 Wen-Wei You,1 Guang-Hua Yan,1 Zhi-Hong Jiang,1, 2 Pei-Liang Zhao1,,
Zhong-Zhen Zhou1,
1School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China 2
State key laboratory for Quality Research in Chinese medicines, Macau University of
Science and Technology, Macau, China
Address correspondence to Zhong-Zhen Zhou School of Pharmaceutical Sciences,
Southern Medical University, Guangzhou, 510515, People’s Republic of China. E-mail:
zhouzz@smu.edu.cn Pei-Liang Zhao, School of Pharmaceutical Sciences, Southern
Medical University, Guangzhou, 510515, People’s Republic of China. E-mail:
zpl2008@smu.edu.cn.
Abstract
An efficient one-pot synthesis of 3-amino-7-azaindoles was developed, starting from
ethyl (3-cyanopyridin-2-yl)carbamate and α-bromoketones by microwave-assisted
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Thorpe–Ziegler cyclization in the presence of a base. This method features excellent
yields, short reaction time (10 min), and high functional group compatibility.
[Supplementary materials are available for this article. Go to the publisher’s online
edition of Synthetic Communications® for the following free supplemental resource(s):
Full experimental and spectral details.]
KEYWORDS: 3-amino-7-azaindoles, Thorpe–Ziegler cyclization, microwave
irradiation, one-pot synthesis
INTRODUCTION
Azaindole derivatives are important heterocyclic compounds in medicinal chemistry
owing to their broad range of biological activities.[1] In particular, 3-amino-7-azaindoles,
a typical class of azaindole derivatives, have shown a wide variety of pharmacological
properties, and some of them have served as potential drugs, such as adenosine receptor
agonists and antagonists[2a] and tumor necrosis factor release inhibitors.[2b] Moreover,
these compounds are of considerable interest because of their use as suitable scaffolds for
many drugs, namely N-(7-azaindole-3-yl) amide derivatives[3] and
pyridopyrrolopyrimidines.[4]
Generally, 3-amino-7-azaindoles can be prepared by several methods, including the
conversion of 2-(4-chloro-5H-1,2,3-dithiazolylidene-amino) benzonitriles[5] and the
reduction of 3-nitro [3,6a] or 3-nitroso [6b] group of 7-azaindoles. However, the application
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of these methods is limited because of the poor availability of starting materials and toxic
reagents. To overcome these inherent problems, recently an efficient Thorpe–Ziegler
cyclization [2, 4, 7, 8] has been developed for the preparation of 3-amino-7-azaindoles. This
method used 2-chloronicotinonitrile analogs as starting materials which can be easily
substituted with 2-aminoacetamide [4a], ethyl 2-aminoacetate [7a, 7b], ethyl 2-(methylamino)
acetate [7d], and N, N-dimethyl-2-(methylamino)acetamide [2a] to provide substituted
intermediates that can undergo subsequent intramolecular cyclization to yield 3-amino-
1H-7-azaindoles in the presence of bases. However, this sequence has limited
applications because of its narrow scope. Furthermore, these methods generally require a
prolonged reaction time, multi synthetic steps and provide only low to moderate overall
yields.
It is known that, microwave irradiation, because of its significant enhancement in
reaction rates and yields, has emerged as a powerful technique for promoting a variety of
chemical reactions. [8] As part of an ongoing program in our laboratory to synthesize a
variety of 3-amino-7-azaindoles under mild conditions, we herein report an efficient
synthesis of 3-amino-7-azaindoles by microwave-assisted Thorpe–Ziegler cyclization of
α-haloketones and ethyl (3-cyanopyridin-2-yl)carbamate (Scheme 1).
RESULTS AND DISCUSSION
Thorpe–Ziegler cyclization generally proceeds smoothly in the presence of bases in
aprotic solvents to give the corresponding intramolecular condensation products in poor
to moderate yields. Therefore, we first investigated the effect of modifying the base,
solvent, temperature, and reaction time under microwave irradiation. The reaction of 1a
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with phenacyl bromide (2a) in DMF was chosen as a model to optimize the reaction
conditions. The results are summarized in Table 1.
As shown in Table 1, compound 3a could be prepared in moderate yield only in the
presence of cesium carbonate (entries 1–5), and DMF was found to be the best reaction
medium (entries 4 and 6–8). Note, however, that potassium carbonate was the best base
under the conventional method (data not shown). Under the conditions using cesium
carbonate and DMF, the yields increased consistently with an increase in temperature
from 80 to 100 °C. Further increase to 110 °C, however, led to a decrease in the yield
(entries 11 and 12). This might be due to the instability of 3-amino-1H-7-azaindoles at
high temperature. On the other hand, the yields increased with time, from 15% (1 min) to
a maximum of 89% (10 min) (entries 10 and 13–14). Extending the reaction time to
longer than 10 min did not change the yield significantly. Taken together, we concluded
that, under microwave irradiation, the optimal conditions were 100 °C, 10 min, and
cesium carbonate in DMF. We subsequently used these conditions for the microwave-
assisted synthesis of a library of 2-aroylthoxy-3-amino-7-azaindoles. The results,
together with those obtained under the conventional method for comparison, are shown in
Table 2.
The results in Table 2 indicate that moderate to good isolated yields (57%–82%) could be
achieved under the conventional method after a long reaction time (3 h), and the results
were highly dependent on the starting materials that were used. Prolonging the reaction
time or adding excess 2-bromo-1-aroylethanones 2a–l did not significantly improve the
yield. In contrast, under microwave irradiation, the reactions were completed in 10 min
and 2-aroylthoxy-3-amino-7-azaindoles were isolated in good to excellent yields (79%–
91%). Thus, microwave irradiation increased the yield by 7%–22%. Note that
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substituents on the aromatic ring, such as F, Cl, Br, CH3, CH3O, CF3, and NO2, have
practically no obvious effect on the yield under both conventional and microwave
conditions. Most interestingly, ethyl (3-cyanopyridin-2-yl)carbamate and 2-bromo-1-
(naphthalen-1-yl)ethanone worked equally well to give the desired azaindole derivatives
in satisfactory yields (compound 3m, Table 2). However, on the replacement of 2-bromo-
1-aroylethanones with ethyl 2-bromoacetate, the yield was relatively low, especially
under the conventional method (compound 3n, Table 2). Moreover, no product was
detected under both microwave irradiation and conventional heating conditions in the
case of 1-bromopropan-2-one (compound 3o, data not shown in Table 2).
In conclusion, we have developed a highly efficient one-step synthesis of 3-amino-7-
azaindoles directly by the Thorpe–Ziegler cyclization of ethyl (3-cyanopyridin-2-yl)
carbamate with α-bromoketones or ethyl 2-bromoacetate in DMF under microwave
irradiation. This reaction features excellent yields, short reaction time (10 min), and easy
manipulation.
EXPERIMENTAL
All materials were obtained from commercial sources and were used as received unless
stated otherwise. The silica gel (200-300 mesh) for flash column chromatography was
from Qingdao Marine Chemical (China), and the distillation range of petroleum was 60-
90 °C. ESI-MS spectra were measured on a water UPLC/Quattro Premier XE mass
spectrometer. 1H and 13C NMR spectra were recorded in CDCl3 or d6-DMSO using
Varian Mercury 400 spectrometers and TMS as an internal reference. Elementary
analyses were performed on a Vario EL III elemental analysis instrument. Melting points
were measured using a Buchi B-545 melting point apparatus. Microwave-irradiated
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reactions were carried out with a USA CEM Discover Focused Microwave Synthesizer
(Serial Number DU8290).
General Procedures For Conventional Preparation Of 3a-N
ethyl 3-amino-2-benzoyl-1H-pyrrolo[2,3-b]pyridine-1-carboxylate 3a as an
example: phenacyl bromide (1.09g, 5.5 mmol) and potassium carbonate (1.52 g, 11
mmol) were added to a solution of 3-cyanopyridin-2-ylcarbamate (955 mg, 5.0 mmol) in
dry N, N-dimethylformamide (5.0 mL). After stirring for 3 h at 100 ℃, the reaction
mixture was poured into water (80 mL) and extracted with dichloromethane. The
combined organic layer was washed extensively with water and brine, and then dried
over anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified
by chromatography on a silica-gel column (petroleum ether - ethyl acetate, 8/1 by
volume) to give compound 3a (1.16g, 76%).
General Procedures For Microwave-Assisted Preparation Of 3a-N
ethyl 3-amino-2-benzoyl-1H-pyrrolo[2,3-b]pyridine-1-carboxylate 3a as an example:
In a microwave tube, phenacyl bromide (219 mg, 1.1 mmol) and cesium carbonate (652
mg, 2.0 mmol) were added to a solution of ethyl 3-cyanopyridin-2-ylcarbamate (191 mg,
1.0 mmol) in dry N, N-dimethylformamide (1.0 mL). Then, the sealed microwave tube
was placed in CEM Corporation instrumentation and irradiated at 100 ℃ for 10 min.
Then, the reaction mixture was poured into water (15 mL) and extracted with
dichloromethane. The combined organic layer was washed extensively with water and
brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated, and the
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residue was purified by chromatography on a silica-gel column (petroleum ether - ethyl
acetate, 8/1 by volume) to give compounds 3a (275mg, 89%). light yellow solid, m.p.
108~109 oC; 1H NMR (400 MHz, CDCl3): δ = 0.86 (t, J = 7.2 Hz, 3H, CH3), 3.72 (dd, J
= 7.2 Hz, J = 14.4 Hz, 2H, CH2), 5.81 (s, br, 2H, NH2), 7.26 (t, J = 3.8 Hz, 1H),
7.40~7.47 (m, 3H, H-13), 7.76 (t, J = 4.2 Hz, 2H), 7.98 (dd, J = 1.6 Hz, J = 8.0 Hz, 1H),
8.68 (dd, J = 1.6 Hz, J = 4.8 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ = 13.4, 63.3,
115.2, 115.3, 118.6, 127.3, 128.5, 129.0, 131.4, 140.3, 149.3 150.1, 150.3, 187.2; ESI MS
m/z: 332.8 [M+Na]+, 310.7 [M+1]+. Anal. calcd. for C17H15N3O3: C, 66.01; H, 4.89; N,
13.58. Found: C, 65.87; H, 4.78; N, 13.35.
All compounds are new compounds, and were fully characterized by MS, NMR (1H and
13C) and elemental analysis. (See Supporting Information).
ACKNOWLEDGMENTS
This work was financially supported by the Specialized Research Fund for the National
Natural Science Foundation of China (Nos. 21002048 and 21102069) and the project of
science and technology new star in Zhujiang Guangzhou city (No. 2012J2200051)
Supporting Information: Full experimental detail, MS, 1H and 13C NMR spectra,
elemental analysis. This material can be found via the “Supplementary Content” section
of this article’s webpage.’
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REFERENCES
[1] (a) Reader, J. C.; Matthews, T. P.; Klair, S.; Cheung, K. M. J.; Scanlon, J.; Proisy, N.;
Addison, G.; Ellard, J.; Piton, N.; Taylor, S.; Cherry, M.; Fisher, M.; Boxall, K.; Burns,
S.; Walton, M. I.; Westwood, I. M.; Hayes, A.; Eve, P.; Valenti, M.; Brandon, A. H.; Box,
G.; Montfort, R. L. M. V. Williams, D. H.; Aherne, G. W.; Raynaud, F. I.; Eccles, S. A.;
Garrett, M. D.; Collins I. J. Med. Chem. 2011, 54 (24), 8328-8342; (b) Echalier, A.;
Bettayeb, K.; Ferandin, Y.; Lozach, O.; Clelment, M.; Valette, A.; Liger, F.; Marquet, B.;
Morris, J. C.; Endicott, J. A.; Joseph, B.; Meijer, L. J. Med. Chem. 2008, 51, 737-751; (c)
Song, J. J.; Reeves, J. T.; Gallou, F.; Tan, Z.; Yee, N. K.; Senanayake, C. H. Chem. Soc.
Rev. 2007, 36, 1120-1132; (d) Popowycz, F.; Routier, S.; Joseph, B.; Merour, J. Y.
Tetrahedron, 2007, 63, 1031-1064. References cited therein.
[2] (a) Vakalopoulos, A.; Nell, P.; Suessmeier, F.; Albrecht-Kuepper, B.; Zimmermann,
K.; Keldenich, J. (Bayer HealthCare A.-G., Germany). Patent WO2009080197, 2009;
Chem. Abstr. 2009, 151, 101187. (b) Daghish, M.; Schulze, A.; Reichelt, C.; Ludwig, A.;
Leistner, S.; Heinicke, J.n; Kroedel, A. (Curacyte Discovery GmbH, Germany), Patent
WO 2006100095, 2006; Chem. Abstr. 2006, 145, 471557.
[3] (a) Le Huerou, Y.; Blake, J. F.; Gunwardana, I. W.; Mohr, P.; Wallace, E. M.; Wang,
B.; Chicarelli, M.; Lyon, M. (Array BioPharma Inc., USA). Patent WO2009140320,
2009; Chem. Abstr. 2009, 151, 550551; (b) Blake, J.; Gunawardana, I. W.; Huerou, Y. L.;
Mohr, P. J.; Wallace, E. M.; Wang, B.; (Array BioPharma Inc., USA), Patent WO
2009089352, 2009; Chem. Abstr. 2009, 151, 148142;
[4] (a) Dyke, H. J.; Gancia, E.; azzard, L. J.; Goodacre, S. C.; Lyssikatos, J. P.; Macleod,
C.; illiams, K.; (Genentech, Inc., USA), Patent WO 2009151589, 2009; Chem. Abstr.
2009, 152, 75007; (b) Matasi, J. J.; Tulshian, D.; Burnett, D. A.; Wu, W. –L.; Korakas, P.;
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ACCEPTED MANUSCRIPT
Silverman, L. S.; Sasikumar, T. K.; Qiang, Li; Domalski, M. S. (Schering Corporation,
USA). Patent WO2006002051, 2006; Chem. Abstr. 2006, 144, 108348; (c) Gaber, H. M.;
Erian, A. W.; Sherif, S. M.; Ouf, S. A. Afinidad, 2005, 62 (516), 143-150; (d) Hayakawa,
M.; Kaizawa, H.; Moritomo, H.; Kawaguchi, K.; Koizumi, T.; Yamano, M.; Matsuda, K.;
Okada, M.; Ohta, M. (Yamanouchi Pharmaceutical Co., Ltd., Japan; Ludwig Institute for
Cancer Research; Imperial Cancer Research Technology Ltd.). Patent WO2001083456,
2001; Chem. Abstr. 2001, 135, 344500.
[5] Koutentis, P. A.; Michaelidou, S. S. Molbank, 2010, M691, doi:10.3390/M691,
http://www.mdpi.com/1422-8599/2010/3/M691/pdf.
[6] For the synthesis of 3-amino-7-azaindoles via reduction of nitro or nitroso, see: (a)
Ludrigan, R.; Jeffrey, J.; Mermerian, A.; (Ironwood Pharmaceuticals Incorporated, USA),
Patent WO 2010005528A2, 2010; Chem. Abstr. 2010, 152, 168933; (b) Bahekar, R. H.;
Jain, M. R.; Goel, A.; Patel, D. N.; Prajapati, V. M.; Gupta, A. A.; Jadav, P. A.; Patel, P.
R. Bioorg. Med. Chem. 2007, 15(9), 3248-3265. References cited therein.
[7] For the synthesis of 3-amino-7-azaindoles via Thorpe-Ziegler Cyclization, see: (a)
Soliman, A. M. J. Heterocycl. Chem. 2011, 48(3), 592; (b) Abdel-Mohsen, S. A.; Geies,
A. A. Monatsh. Chem. 2008, 139(10), 1233-1240; (c) Kanth, S. R.; Maitraie, D.; Reddy,
G. V.; Narsaiah, B.; Rao, P. S. Heterocycles, 2005, 65(6), 1415-1423; (d) Wang, S.; Wan,
N. C.; Harrison, J.; Miller, W.; Chuckowree, I.; Sohal, S.; Hancox, T. C.; Baker, S.;
Folkes, A.; Wilson, F.; Thompson, D.; Cocks, S.; Farmer, H.; Boyce, A.; Freathy, C.;
Broadbridge, J.; Scott, J.; Depledge, P.; Faint, R.; Mistry, P.; Charlton, P. J. Med. Chem.
2004, 47(6), 1339-1350. References cited therein.
[8] Li, L.; Chua, W. K. S. Tetrahedron Lett. 2011, 52 (14), 1574-1577.
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[9]
Selected papers on microwave-mediated reactions: (a) Obermayer, D.; Gutmann, B.;
Kappe, C. O. Angew. Chem. Int. Ed. 2009, 48, 8321–8324; (b) Zambianchi, M.; Maria, F.
D.; Cazzato, A.; Gigli, G.; Piacenza, M.; Sala, F. D.; Barbarella, G. J. Am. Chem. Soc.
2009, 131, 10892–10900; (c) Zhou, Z. Z.; Deng, Y. H.; Jiang, Z. H.; Chen, W. H. Adv.
Synth. Catal. 2010, 352, 1909-1913; (d) Zhou, Z. Z.; Zhao, P. L.; Huang, W.; Yang, G. F.
Adv. Synth. Catal. 2006, 348, 63–67; (f) Zhou, Z. Z.; Ji, F. Q.; Cao, M.; Yang, G. F. Adv.
Synth. Catal. 2006, 348, 1826–1830; g) Huang, W.; Ming, Y. T.; Ding, M. W.; Yang, G.
F. Synthetic. Commun. 2007, 37, 369-376; h) Huang, W.; Liu, Z. M.; Li, Y.; Yang, G. F.
Bioorg. Med. Chem. 2007, 15, 5191-5197; References cited therein.
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TABLE 1 Optimization of microwave-assisted cyclocondensation of ethyl (3-
cyanopyridin-2-yl)carbamate with phenacyl bromide
t/min
IsolatedYield/
Entry
Solvent
Base
T/ °C
%
1
DMF
DMF
DMF
DMF
DMF
THF
Na2CO3
K2CO3
K3PO4
80
10
10
10
10
10
10
10
10
10
10
10
10
1
trace
trace
trace
31
2
80
3
80
4
Cs2CO3
KOH
80
5
80
10
6
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
80
trace
trace
trace
76
7
DME
1,4-dioxan
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
80
8
80
9
90
10
11
12
13
14
15
16
100
110
120
100
100
100
100
89
83
51
15
5
76
15
20
85
77
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TABLE 2 One-Step Synthesis of 3-aminoazaindoles
Microwave irradiationa
Conventional heating b
Isolated Yield/%
Entry
R
t/min
Isolated Yield/% c
t/min
c
3a
3b
3c
Ph
10
10
10
89
82
87
180
180
180
76
75
70
4-BrPh
4-MePh
4-
3d
10
85
180
68
MeOPh
4-FPh
4-ClPh
3e
3f
3g
3h
3i
10
10
90
91
86
83
84
82
86
180
180
180
180
180
180
180
79
82
75
71
73
69
76
3,4-F2Ph 10
4-CF3Ph 10
4-NO2Ph 10
3j
2-MePh
3-BrPh
2-
10
10
3k
3l
10
81
180
65
MeOPh
3m
3n
10
10
89
79
180
180
72
57
EtO
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a The temperature for these reactions is 100 °C.
b The reaction was carried out at 100 °C.
c Isolated yield.
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SCHEME 1 Microwave-assisted Thorpe–Ziegler cyclization
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