Efficient one-pot synthesis of 1H-pyrazolo[1,5-b]indazoles by a domino Staudinger-aza-Wittig cyclization

Article abstract of DOI:10.1055/s-0032-1317474

1H-Pyrazolo[1,5-b]indazoles were prepared via a domino Staudinger-aza- Wittig cyclization in one-pot fashion, starting from easily accessible azides and triphenylphosphine. Copyright

Full text of DOI:10.1055/s-0032-1317474

2850▌
LETTER
letter
Efficient One-pot Synthesis of 1H-Pyrazolo[1,5-b]indazoles by a Domino
Staudinger–Aza-Wittig Cyclization
Synthesis of 1H-Pyrazolo[1,5-b]indazoles
Fen-Fen Zhao,a Yan-Mei Yan,a Rui Zhang,b Ming-Wu Ding*a
a
Key Laboratory of Pesticide & Chemical Biology of Ministry of Education, Central China Normal University, Wuhan 430079, P. R. of China
b
College of Chemistry and Molecular Sciences, Wuhan University, Wuhan, 430072, P. R. of China
Fax +86(27)67862041; E-mail: mwding@mail.ccnu.edu.cn
Received: 25.08.2012; Accepted after revision: 20.09.2012
was carried out smoothly, and the azides 5 were obtained
Abstract: 1H-Pyrazolo[1,5-b]indazoles were prepared via a domi-
after recrystallization in good yields (Scheme 2).12
no Staudinger–aza-Wittig cyclization in one-pot fashion, starting
from easily accessible azides and triphenylphosphine.
COOEt
COOEt
Key words: 1H-pyrazolo[1,5-b]indazole, domino reaction, aza-
Wittig reaction, azide, iminophosphorane
Ph3P
COOEt
COOEt
N
N N PPh3
N3
1
2
Domino reactions have drawn great interest in modern or-
ganic synthesis and medicinal chemistry because of their
ability to create structurally diverse complex molecules
from simple precursors in efficient one-pot processes.1
Compared to stepwise reactions, domino reactions have
high bond-forming efficiency owning to that they can
form several bonds in one sequence without isolating the
reaction intermediates.
EtOOC
COOEt
N
N=PPh3
N
3
Scheme 1 Literature preparation of indazolyl iminophosphorane 3
from abnormal Staudinger reaction
The indazole unit represents an important structural motif
found in some biologically relevant compounds. Mole-
cules containing this motif are the subject of considerable
interest as potent anti-HIV,2 antiplatelet,3 anticancer,4
antimicrobial,5,6 and antifungal agents.7,8 Much effort has
been invested in the synthesis of indazoles or fused inda-
zoles to deduce structure–activity relationships and dis-
cover new analogues with improved properties.
O
O
COR2
COR1
CHO
N3
R1
R2
piperidine
AcOH
N3
5
4
Scheme 2 Synthesis of the azides 5
The aza-Wittig reaction has become a powerful synthetic
tool for the preparation of acyclic and heterocyclic com-
pounds.9 Molina et al. have reported an effective route for
the synthesis of indazoles by tandem aza-Wittig reaction
(Scheme 1).10 The intermediate indazolyl iminophospho-
rane 3 was directly obtained from the abnormal Stauding-
er reaction of the azides 1 through the phosphazide
intermediate 2 in 53% yield. We envisioned that a domino
Staudinger–aza-Wittig reaction would take place to give
fused indazoles without isolating the iminophosphorane
intermediate, if a suitable azide 1 containing a carbonyl
group was used. Continuing our interest in the synthesis of
N-heterocycles via the aza-Wittig reaction,11 we wish to
report herein an efficient synthesis of 1H-pyrazolo[1,5-
b]indazoles by a domino Staudinger–aza-Wittig reaction
in one-pot fashion.
When azides 5 were treated with triphenylphosphine in
toluene at 0 °C for two hours, and then at refluxing tem-
perature for two to eight hours, the previously seldom re-
ported 1H-pyrazolo[1,5-b]indazoles 9 were isolated
directly in good yields (78–90%, Scheme 3, Table 1).13
The domino formation of 1H-pyrazolo[1,5-b]indazoles 9
can be viewed as an initial abnormal Staudinger reaction
between the azide 5 and triphenylphosphine to create the
phosphazide intermediate 6, which cyclizes to give imino-
phosphorane 7, probably via nucleophilic attack of the
central nitrogen atom of the phosphazide moiety on the β-
carbon atom of the α,β-unsaturated ketones and subse-
quent transformation. Further intramolecular aza-Wittig
reaction of 7 produces cyclized compound 8, in which a
1,3-H shift takes place to give the 1H-pyrazolo[1,5-b]in-
dazoles 9. It is noteworthy that the reaction proceeds un-
der mild conditions to give various substituted 1H-
pyrazolo[1,5-b]indazoles 9, and the overall transforma-
tion is run in a simple one-pot procedure from azides 5 in
good overall yields.
A mixture of 2-azidobenzaldehyde (4) and ketones was
stirred in ethanol at 0 °C for one to two hours in the pres-
ence of piperidinium acetate.10 The condensation reaction
SYNLETT 2012, 23, 2850–2852
Advanced online publication: 18.10.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1317474; Art ID: ST-2012-W0713-L
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of 1H-Pyrazolo[1,5-b]indazoles
2851
COR2
COR1
COR2
It is noteworthy that Smalley et al. have reported the syn-
thesis of quinolines 11 from the normal tandem Stauding-
er–aza-Wittig reaction of some azides 5 with triethyl
phosphite (Scheme 4).14 However, in our laboratory,
when some azides 5 were reacted with triethyl phosphite
at room temperature for two hours and then at refluxing
temperature for three to four hours, only 1H-pyrazolo[1,5-
b]indazoles 9 were obtained with no quinolines 11 forma-
tion.
Ph3P
COR1
N
N3
N
N
PPh3
5
6
O
O
R1
R1
O
R2
R2
–
H
O
+
In conclusion, we have developed an efficient one-pot
synthesis of 1H-pyrazolo[1,5-b]indazoles by a domino
Staudinger–aza-Wittig reaction. The mild reaction condi-
tions and the easy availability of the starting materials
make this method a valuable tool for generating 1H-pyr-
azolo[1,5-b]indazoles, which are of considerable interest
as potential biological active compounds or pharmaceuti-
cals.
N
N=PPh3
N
N=PPh3
N
N
7
O
O
R2
R2
R1
NH
R1
N
N
N
N
N
9
8
Acknowledgment
Scheme 3 Synthesis of the 1H-pyrazolo[1,5-b]indazoles 9 by
domino Staudinger–aza-Wittig reaction
We gratefully acknowledge financial support of this work by the
National Natural Science Foundation of China (No. 21032001,
21172085) and the self-determined research funds of CCNU from
the colleges’ basic research and operation of MOE (No.
CCNU11C01002).
Table 1 Preparation of Compounds 9a–l from Azides 5a–l
Entry
Product 9 R1
R2
Yield (%)a
Supporting Information for this article is available online at
1
2
9a
9b
9c
9d
9e
9f
Me
OEt
90
85
82
85
82
87
81
84
87
81
83
78
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
r
t
iornat
Me
Me
References and Notes
3
Me
PhNH
(1) (a) Tietze, L. F. Chem. Rev. 1996, 96, 115. (b) Tietze, L. F.;
Brasche, G.; Gericke, K. M. Domino Reactions in Organic
Synthesis; Wiley-VCH: Weinheim, 2006.
(2) Rodgers, J. D.; Johnson, B. L.; Wang, H.; Greenberg, R. A.;
Erickson Viitanen, S.; Klabe, R. M.; Cordova, B. C.; Rayner,
M. M.; Lam, G. N.; Chang, C.-H. Bioorg. Med. Chem. Lett.
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C.; Teng, C.-M.; Wu, C.-C.; Cheng, F. C.; Kuo, S.-C.
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(4) Yakaiah, T.; Lingaiah, B. P. V.; Narsaiah, B.; Shireesha, B.;
Kumar, B. A.; Gururaj, S.; Parthasarathy, T.; Sridhar, B.
Bioorg. Med. Chem. Lett. 2007, 17, 3445.
(5) Yakaiah, T.; Lingaiah, B. P. V.; Narsaiah, B.; Kumar, K. P.;
Murthy, U. S. N. Eur. J. Med. Chem. 2008, 341.
(6) Minu, M.; Thangadurai, A.; Wakode, S. R.; Agrawal, S. S.;
Narasimhan, B. Bioorg. Med. Chem. Lett. 2009, 19, 2960.
(7) Park, J. S.; Yu, K. A.; Yoon, Y. S.; Han, M. R.; Kang, T. H.;
Kim, S.; Kim, N. J.; Yun, H.; Suh, Y. G. Drugs Future 2007,
32, 121.
4
Ph
OEt
5
Me
4-MeC6H4NH
4-ClC6H4NH
3-ClC6H4NH
2-MeC6H4NH
n-PrNH
N(CH2)5
Ph
6
Me
7
9g
9h
9i
Me
8
Me
9
Me
10
11
12
9j
Me
9k
9l
Ph
4-O2NC6H4
OEt
a Yields based on azides 5.
COR2
COR2
(8) Park, J. S.; Yu, K. A.; Kang, T. H.; Kim, S.; Suh, Y. G.
Bioorg. Med. Chem. Lett. 2007, 17, 3486.
P(OEt)3
COR1
COR1
N=P(OEt)3
(9) (a) Naganaboina, V. K.; Chandra, K. L.; Desper, J.; Rayat, S.
Org. Lett. 2011, 13, 3718. (b) Kshirsagar, U. A.; Puranik, V.
G.; Argade, N. P. J. Org. Chem. 2010, 75, 2702. (c) Palacios,
F.; Alonso, C.; Aparicio, D.; Rubiales, G.; Santos, J. M.
Tetrahedron 2007, 63, 523. (d) Alajarin, M.; Bonillo, B.;
Ortin, M.-M.; Sanchez-Andrada, P.; Vidal, A.; Orenes, R.-
A. Org. Biomol. Chem. 2010, 8, 4690. (e) Devarie-Baez, N.
O.; Xian, M. Org. Lett. 2010, 12, 752.
N3
10
5
COR2
N
R1
11
(10) Molina, P.; Conesa, C.; Alías, A.; Arques, A.; Velasco, M.
D. Tetrahedron 1993, 49, 7599.
Scheme 4 Literature preparation of quinolines 11 from azides 5
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2850–2852

2852
F.-F. Zhao et al.
LETTER
(11) (a) Xie, H.; Yuan, D.; Ding, M. W. J. Org. Chem. 2012, 77,
2954. (b) Zhong, Y.; Wang, L.; Ding, M. W. Tetrahedron
2011, 67, 3714. (c) He, P.; Nie, Y. B.; Wu, J.; Ding, M. W.
Org. Biomol. Chem. 2011, 9, 1429. (d) He, P.; Wu, J.; Nie,
Y. B.; Ding, M. W. Eur. J. Org. Chem. 2010, 1088. (e) Li,
W. J.; Liu, S.; He, P.; Ding, M. W. Tetrahedron 2010, 66,
8151. (f) Li, W. J.; Zhao, F. F.; Ding, M. W. Synlett 2011,
265. (g) Xie, H.; Yu, J. B.; Ding, M. W. Eur. J. Org. Chem.
2011, 6933. (h) Wu, J.; Liu, J. C.; Wang, L.; Ding, M. W.
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(12) General Procedure for the Preparation of Azides 5
To a mixture of piperidine (0.85 g, 10 mmol) and AcOH (0.6
g, 10 mmol) in EtOH (10 mL) at 0 °C was added 2-
azidobenzaldehyde (1.32 g, 10 mmol) and ketone (10
mmol). After stirring for 1–2 h, the solvent was evaporated
under vacuum, and the residue was recrystallized to give the
azide 5.
124.6, 118.3, 61.5, 26.4, 13.7 ppm. MS (EI, 70 eV): m/z (%)
= 259 (4) [M+], 231 (12), 217 (19), 203 (27), 143 (100), 115
(58). Anal. Calcd for C13H13N3O3: C, 60.22; H, 5.05; N,
16.21. Found: C, 60.01; H, 4.92; N, 16.02.
(13) General Procedure for the Preparation of 9
To a solution of azide 5 (2 mmol) in dry toluene (10 mL) was
added dropwise a solution of Ph3P (0.52 g, 2 mmol) in
toluene (10 mL) at 0 °C. The reaction mixture was stirred for
2 h and then was refluxed for 2–8 h. The mixture was
condensed, and the precipitate was collected or the residue
was chromatographed (PE–Et2O, 4:1) on a silica gel column
to give 1H-pyrazolo[1,5-b]indazole derivatives 9.
Compound 9a: white solid (yield 90%); mp 193–194 °C. 1H
NMR (600 MHz, CDCl3): δ = 12.0 (s, 1 H, NH), 8.27 (d, J =
7.8 Hz, 2 H, ArH), 7.54–7.32 (m, 4 H, ArH), 4.45 (q, J = 7.2
Hz, 2 H, OCH2), 2.67 (s, 3 H, CH3), 1.50 (t, J = 7.2 Hz, 3 H,
CH3) ppm. 13C NMR (150 MHz, CDCl3): δ = 164.0, 152.7,
143.4, 135.5, 128.4, 123.0, 122.4, 116.2, 110.8, 100.2, 59.9,
14.8, 14.3 ppm. MS (EI, 70 eV): m/z (%) = 243 (39) [M+],
198 (10), 144 (100). Anal. Calcd for C13H13N3O2: C, 64.19;
H, 5.39; N, 17.27. Found: C, 63.89; H, 5.22; N, 17.32.
(14) Luheshi, A. B. N.; Salem, S. M.; Smalley, R. K. Tetrahedron
Lett. 1990, 31, 6561.
Compound 5a: light yellow solid (yield 89%), mp 75–76 °C.
1H NMR (600 MHz, CDCl3): δ = 7.80 (s, 1 H, =CH), 7.46–
7.11 (m, 4 H, ArH), 4.30–4.25 (m, 2 H, OCH2), 2.45 (s, 3 H,
CH3), 1.24–1.20 (m, 3 H, CH3) ppm. 13C NMR (150 MHz,
CDCl3): d = 194.7, 167.1, 139.3, 136.2, 135.5, 131.6, 128.9,
Synlett 2012, 23, 2850–2852
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