Novel double [3 + 2 + 1] heteroannulation for forming unprecedented dipyrazolo-fused 2,6-naphthyridines

Article abstract of DOI:10.1021/ol4008266

A novel four-component strategy for the efficient synthesis of unprecedented dipyrazolo-fused 2,6-naphthyridines through a double [3 + 2+1] heteroannulation has been described. The bond-forming efficiency, accessibility, and generality of this synthesis make it highly valuable to assemble tetra-heterocyclic scaffolds.

Full text of DOI:10.1021/ol4008266

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Novel Double [3 þ 2 þ 1] Heteroannulation
for Forming Unprecedented Dipyrazolo-
Fused 2,6-Naphthyridines
Wei Fan, Qin Ye, Hai-Wei Xu, Bo Jiang,* Shu-Liang Wang, and Shu-Jiang Tu*
School of Chemistry and Chemical Engineering, and Jiangsu Key Laboratory of Green
Synthetic Chemistry for Functional Materials, Jiangsu Normal University, Xuzhou,
221116 Jiangsu, P. R. China
jiangchem@jsnu.edu.cn; laotu@jsnu.edu.cn
Received March 26, 2013
ABSTRACT
A novel four-component strategy for the efficient synthesis of unprecedented dipyrazolo-fused 2,6-naphthyridines through a double [3 þ 2þ1]
heteroannulation has been described. The bond-forming efficiency, accessibility, and generality of this synthesis make it highly valuable to
assemble tetra-heterocyclic scaffolds.
The functionalized fused naphthyridine unit is often
found in many natural products of marine origin1 that
have shown a wide range of biological activities2 such as
HIV-1 integrase inhibition3 and as antitumor agents4 and
selective antagonists of 5-HT4 receptors,.5 In addition, a
variety of synthetic fused 2,6-naphthyridines exhibited
various biological properties, including selective human
PKD1 inhibitor,6 protein kinase CK2 inhibitors,7 and
antimicrobial agents.8 Although many studies on the pre-
paration of fused 2,6-naphthyridine derivatives have been
developed,7aꢀc,8 these methods suffer multistep syntheses.
Thus, the development of general and efficient routes to
(1) (a) Blunt, J. W.; Copp, B. R.; Munro, M. H. G.; Northcote, P. T.;
Prinsep, M. R. Nat. Prod. Rep. 2012, 29, 144. (b) Aoki, S.; Wei, H.;
Matsui, K.; Rachmat, R.; Kobayashi, M. Bioorg. Med. Chem. 2003, 11,
1969. (c) Larghi, E. L.; Obrist, B. V.; Kaufman, T. S. Tetrahedron 2008,
64, 5236.
(2) (a) Rudys, S.; Rios-Luci, C.; Perez-Roth, E.; Cikotiene, I.;
Padron, J. M. Bioorg. Med. Chem. Lett. 2010, 20, 1504. (b) Li, Y.;
Liang, J.; Siu, T.; Hu, E.; Rossi, M. A.; Barnett, S. F.; Jones, D. D.;
Jones, R. E.; Robinson, R. G.; Leander, K.; Huber, H. E.; Mittal, S.;
Cosford, N.; Prasit, P. Bioorg. Med. Chem. Lett. 2009, 19, 834. (c)
Nakamura, H.; Kobayashi, J.; Ohizumi, Y.; Hirata, Y. J. Chem. Soc.,
Perkin Trans. 1 1987, 173.
(3) Johns, B. A.; Weatherhead, J. G.; Allen, S. H.; Thompson, J. B.;
Garvey, E. P.; Foster, S. A.; Jeffrey, J. L.; Miller, W. H. Bioorg. Med.
Chem. Lett. 2009, 19, 1802.
(4) (a) El-Subbagh, H. I.; Abu-Zaid, S. M.; Mahran, M. A.; Badria,
F. A.; Al-Obaid, A. M. J. Med. Chem. 2000, 43, 2915. (b) Kumar, R. R.;
Perumal, S.; Senthilkumar, P.; Yogeeswari, P.; Sriram, D. Bioorg. Med.
Chem. Lett. 2007, 17, 6459. (c) Sviridenkova, N. V.; Vatsadze, S. Z.;
Manaenkova, M. A.; Zyk, N. V. Russ. Chem. Bull. 2005, 54, 2590. (d)
Gangjee, A.; Zeng, Y.; McGuire, J. J.; Kisliuk, R. L. J. Med. Chem. 2002,
45, 5173.
(6) Zhao, Y.-S.; Wang, K.; Zeng, H.; Zhang, H.-X.; Zhang, J.-H.
Mol. Simul. 2012, 38, 309.
(7) (a) Pierre, F.; Chua, P. C.; O’Brien, S. E.; Siddiqui-Jain, A.;
Bourbon, P.; Haddach, M.; Michaux, J.; Nagasawa, J.; Schwaebe,
M. K.; Stefan, E.; Vialettes, A.; Whitten, J. P.; Chen, T. K.; Darjania,
L.; Stansfield, R.; Bliesath, J.; Drygin, D.; Ho, C.; Omori, M.; Proffitt,
C.; Streiner, N.; Rice, W. G.; Ryckman, D. M.; Anderes, K. Mol. Cell.
Biochem. 2011, 356, 37. (b) Pierre, F.; Chua, P. C.; O’Brien, S. E.;
Siddiqui-Jain, A.; Bourbon, P.; Haddach, M.; Michaux, J.; Nagasawa,
J.; Schwaebe, M. K.; Stefan, E.; Vialettes, A.; Whitten, J. P.; Chen, T. K.;
Darjania, L.; Stansfield, R.; Anderes, K.; Bliesath, J.; Drygin, D.; Ho,
C.; Omori, M.; Proffitt, C.; Streiner, N.; Trent, K.; Rice, W. G.;
Ryckman, D. M. J. Med. Chem. 2011, 54, 635. (c) Meredith, E. L.; Ardayfio,
O.;Beattie,K.;Dobler,M. R.;Enyedy, I.;Gaul,C.;Hosagrahara, V.;Jewell,
C.; Koch, K.; Lee, W.; Lehmann, H.; McKinsey, T. A.; Miranda, K.;
Pagratis, N.; Pancost, M.; Patnaik, A.; Phan, D.; Plato, C.; Qian, M.;
Rajaraman, V.; Rao, C.; Rozhitskaya, O.; Ruppen, T.; Shi, J.; Siska,
S. J.; Springer, C.; van Eis, M.; Vega, R. B.; vonMatt, A.; Yang, L.;
Yoon, T.; Zhang, J.-H.; Zhu, N.; Monovich, L. G. J. Med. Chem. 2010,
53, 5400. (d) Zhou, Y.; Zhang, N.; Zhong, R. Med. Chem. Res. 2013
DOI: 10.1007/s00044-012-0442-y.
(5) Ghotekar, B. K.; Ghagare, M. G.; Toche, R. B.; Jachak, M. N.
Monatsh. Chem. 2010, 141, 169.
(8) Bishnoi, A.; Tiwari, A. K.; Singh, S.; Sethi, A.; Tripathi, C. M.;
Banerjee, B. Med. Chem. Res. 2012 DOI: 10.1007/s00044-012-0333-2.
r
10.1021/ol4008266
XXXX American Chemical Society

regioselective synthesis of fused 2,6-naphthyridine is still
challenging.
with concomitant formation of two new pyridine rings was
readily achieved in domino fashion that involved double
[3 þ 2 þ 1] heteroannulation; up to five σ bonds were
formed in a one-pot operation from common and in-
expensive starting materials (Scheme 1). In addition, the
direct CꢀC formation between two electrophilic centers
of arylglyoxal monohydrates can be easily achieved in this
domino system without the use of any metal or carbene
catalysts. This observation is veryrare and may be useful in
organic chemistry.
The pursuit of highly efficient synthetic strategies con-
tinues to demand enormous efforts aimed at atom-
economic and environmental aspects and remarkable chemo-
and regioselective control of constructing natural products
or natural-like structures.9 Multicomponent domino reac-
tions (MDRs), being one of the most effective methods to
improve synthetic efficiency, can implement reaction cas-
cades and generate high levels of diversity giving rise to
complex structures by simultaneous formation of three or
more bonds from simple substrates.10 It is obvious that
such transformations can avoid tedious steps of protection
and deprotection of functional groups and isolation of
intermediate, thereby minimizing the generation of waste
and rendering the transformations green.11 In recent years,
considerable efforts have been devoted to the development
of various MDRs toward the formation of various hetero-
cycles.12 However, the utilization of MDRs for the construc-
tion of tetracyclic dipyrazolo-fused [2,6]naphthyridine
skeleton through sequential carbonꢀoxygen bonds cleav-
age, to the best of our knowledge, has not been reported
so far.
Scheme 1. Multicomponent Synthesis of Dipyrazolo-Fused 2,6-
Naphthyridines
Recently, our group and others have developed a series
of unique domino reactions for the construction of useful
functionalized complex molecules of chemical and phar-
maceutical interest.13,14 To continue our study on this
topic, herein, we discovered a novel A2B2 type domino
reaction of arylglyoxal monohydrate 1 and electron-rich
pyrazol-5-amines 2. The unique characteristics of this chem-
istry are as indicated below: the domino construction of
unprecedented dipyrazolo-fused 2,6-naphthyridine skeleton
Table 1. Optimization for the Synthesis of 3a under MW
entry
solvent
temp (°C)
time (min)
yielda(%)
1
2
3
4
5
6
7
8
9
10
CH3CN
100
100
100
100
100
100
100
100
120
130
20
20
20
20
20
20
20
20
20
20
no
Toluene
trace
trace
trace
36
CF3COOH
HCOOH
HOAc
EtCOOH
i-PrCOOH
n-PrCOOH
n-PrCOOH
n-PrCOOH
44
48
54
(9) (a) Tietze, L. F.; Brasche, G.; Gerike, K. Domino Reactions in
Organic Chemistry; Wiley-VCH: Weinheim, 2006. (b) Padwa, A. Chem.
Soc. Rev. 2009, 38, 3072. (c) Toure, B. B.; Hall, D. G. Chem. Rev. 2009,
109, 4439. (d) Tietze, L. F.; Kinzel, T.; Brazel, C. C. Acc. Chem. Res.
2009, 42, 367.
68
67
a Isolated yield.
(10) (a) Groenendaal, B.; Ruijter, E.; Orru, R. V. A. Chem. Commun.
2008, 5474. (b) Ismabery, N.; Lavila, R. Chem.;Eur. J. 2008, 14, 8444.
(c) Sunderhaus, J. D.; Martin, S. F. Chem.;Eur. J. 2009, 15, 1300. (d)
Ganem, B. Acc. Chem. Res. 2009, 42, 463. (e) Zhu, J. P.; Bienayme, H.
Multicomponent Reactions; Wiley-VCH: Weinheim, 2004. (f) Tietze, L. F.
Chem. Rev. 1996, 96, 115.
Our investigation was initiated by evaluating the dom-
ino reaction of 2,2-dihydroxy-1-phenylethanone 1a with
electron-rich pyrazol-5-amines 2a. The reaction was tested
under a variety of different conditions. The representative
data were summarized in Table 1. It was found that
the reaction could not proceed at 100 °C for 20 min under
microwave (MW) heating using toluene, CH3CN, HCOOH,
or CF3COOH as a solvent (Table 1, entries 1ꢀ4). An
incomplete reaction was observed when HOAc was used as
a solvent at 100 °C (entry 5). The identical reaction in
propanoic acid (EtCOOH) at 100 °C generated slightly
higher yield of 3a (44%). It was found that acidic solvent
can serve as a suitable media for the present domino
cyclizations. Subsequently, other two acidic solvents,
such as n-butyric acid (n-PrCOOH) and isobutyric acid
(i-PrCOOH), were thus employed as microwave irradia-
tion media. Isobutyric acid at 100 °C resulted in product 3a
in 48% isolated yield (enty 7). The best yield of 54% was
achieved when the reaction was carried out in n-butyric
acid. Gratifyingly, this reaction worked more efficiently
(11) (a) Santra, S.; Andreana, P. R. Angew. Chem., Int. Ed. 2011, 50,
€
9418. (b) Domling, A.; Wang, W.; Wang, K. Chem. Rev. 2012, 112, 3083.
ꢀ
ꢀ
ꢀ
(c) Fustero, S.; Sanchez-Rosello, M.; Barrio, P.; Simon-Fuentes, A.
Chem. Rev. 2011, 111, 6984. (d) Li, G.; Wei, H. X.; Kim, S. H.; Carducci,
M. D. Angew. Chem., Int. Ed. 2001, 40, 4277. (e) Jiang, B.; Rajale, T.;
Wever, W.; Tu, S.-J.; Li, G. Chem.;Asian J. 2010, 5, 2318.
(12) (a) Stearman, C. J.; Wilson, M.; Padwa, A. J. Org. Chem. 2009,
74, 349. (b) France, S.; Boonsombat, J.; Leverett, C. A.; Padwa, A.
J. Org. Chem. 2008, 73, 8120. (c) Topczewski, J. J.; Callahan, M. P.;
Neighbors, J. D.; Wiemer, D. F. J. Am. Chem. Soc. 2009, 131, 14630.
(13) (a) Jiang, B.; Li, C.; Shi, F.; Tu, S.-J.; Kaur, P.; Wever, W.; Li, G.
J. Org. Chem. 2010, 75, 296. (b) Jiang, B.; Tu, S.-J.; Kaur, P.; Wever, W.;
Li, G. J. Am. Chem. Soc. 2009, 131, 11660. (c) Jiang, B.; Yi, M.-S.; Tu,
M.-S.; Wang, S.-L.; Tu, S.-J. Adv. Synth. Catal. 2012, 354, 2504. (d) Ma,
N.; Jiang, B.; Zhang, G.; Tu, S.-J.; Wever, W.; Li, G. Green Chem. 2010,
12, 1357. (e) Jiang, B.; Yi, M.-S.; Shi, F.; Tu, S.-J.; Pindi, S.; McDowell,
P.; Li, G. Chem. Commun. 2012, 808. (f) Jiang, B.; Feng, B.-M.; Wang,
S.-L.; Tu, S.-J.; Li, G. Chem.;Eur. J. 2012, 18, 9823.
(14) (a) Huang, Y.; Walji, A. M.; Larsen, C. H.; MacMillan, D. W. C.
J. Am. Chem. Soc. 2005, 127, 15051. (b) Lu, M.; Zhu, D.; Lu, Y.; Hou,
Y.; Tan, B.; Zhong, G. Angew. Chem., Int. Ed. 2008, 47, 10187. (c)
Snyder, S. A.; Breazzano, S. P.; Ross, A. G.; Lin, Y.; Zografos, A. L.
J. Am. Chem. Soc. 2009, 131, 1753. (d) Yang, J. W.; Fonseca, M. T. H.;
List, B. J. Am. Chem. Soc. 2005, 127, 15036.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 2. Domino Synthesis of 2,6-Naphthyridines 3a
a Reaction conditions: 1 (1.1 mmol), 2 (1.0 mmol), n-butyric acid (1.5 mL), 120 °C, MW. b Time (min). c Isolated yield.
in n-butyric acid at an enhanced temperature of 120 °C,
which afforded the corresponding product 3a in 68% yield
(entry 9). Further increaseofreaction temperature failedto
improvetheyieldofdesired product3a(entry10). Itturned
out that n-butyric acid can be used as an adequate
Brønsted acid promoter for this double [3 þ 2 þ 1]
heteroannulation.
With the optimal conditions in hand, we then explored
the substrate scope of this domino reaction of arylglyoxal
monohydrate 1 and electron-rich pyrazol-5-amines 2.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 2. Mechanism Hypothesis for Forming 3
Figure 1. ORTEP drawing of 3a.
On the basis of experimental results, a tentative reaction
mechanism for this domino reaction is postulated in
Scheme 2. First, arylglyoxal monohydrate protonated by
n-butyric acid underwent an SN2 type reaction of electron-
rich pyrazol-5-amines 2 to convert into intermediate A,
followed intermolecular dipolymerization of itself to yield
macrocyclic dipolymer B. Then, second dehydration and
subsequent intramolecular 6π-azaelectrocyclization of C
occurred, affording final dipyrazolo-fused 2,6-naphthyri-
dines 3 via third dehydration.
In conclusion, we have discovered a novel double
[3 þ 2þ1] heteroannulation of arylglyoxal monohydrate, that
led to new construction of the tetracyclic dipyrazolo-fused 2,6-
naphthyridines skeleton with high regioselectivity. This cas-
cade process involves an SN2-type reaction/dipolymerization/
6π-azaelectrocyclization sequence. Undoubtedly, this multi-
component strategy provides a straightforward and green
pathway to construct the target molecules in an atom-
economic manner, avoiding the use of transition metal cata-
lysts. Other features of this tactic include the mild conditions,
convenient one-pot operations, and high bond-forming effi-
ciency. We believe this methodology may be of value to others
seeking new and original synthetic fragments with unique
properties for medicinal and pharmaceutical chemistry.
The results were presented in Table 2. It was pleasing to
find that the substituents on the aromatic ring of arylglyoxal
monohydrate 1 did not hamper the reaction process.
Reactions of methyl- or chloro-substituted phenylglyoxal
monohydrate 1 with 2 all worked well to provide the
desired products in moderate to good yields. The variation
of nitrogen-tethered substituents on the pyrazole ring 2
including methyl or aryl groups all furnished the unprece-
dented dipyrazolo-fused 2,6-naphthyridines 3 in good
yields within short times. Moreover, methyl-, phenyl-,
and cyclopropyl-substituted of 3-position of pyrazol-5-
amines 2 were all successfully engaged in this reaction
and were readily transformed into the corresponding
dipyrazolo-fused 2,6-naphthyridines 3. The tolerance of
functionalities, such as chloro and bromo, in this protocol
provides the opportunity of their various further chemical
manipulations in products. It is worth mentioning that the
protocol provides an unusual pathway for the generation
of complex tetracyclic dipyrazolo-fused 2,6-naphthyri-
dines, which are normally difficult to prepare by other
methods. Moreover, it also gives a new example for bis-
heterocyclization in an economical and atom-efficient
fashion, providing a valuable strategy to discover new
bioactive compounds.
In general, the reaction occurred at a very fast speed; in
fact, all cases can be finished within short reaction times.
Water is nearly a sole byproduct, which makes the workup
convenient. In most cases, the products can precipitate out
after the reaction mixture was poured into cold water and
was neutralized by diluted basic solution. The structural
elucidation of the products was determined from its IR,
1HNMR, 13C NMR, and HRMS spectra. The structure of
compound 3a was unequivocally confirmed by X-ray
analysis (Figure 1). During these processes, up to two
new rings and five sigma-bonds were formed accompanied
by cleavage of four CꢀO bonds and two CdO of bonds
arylglyoxal monohydrates. This observation is very inter-
esting and useful in organic chemistry.
Acknowledgment. We are grateful for financial support
from the NSFC (Nos. 21072163, 21232004, 21272095, and
21102124), the NSF of Jiangsu Education Committee
(11KJB150016), Jiangsu Sci. and Tech. Support Program
(No. BE2011045), the Qing Lan Project (12QLG006), and
Science Research Foundation of Jiangsu Normal Univ
(Nos. 10XLR20, 11XLA05).
Supporting Information Available. Experimental pro-
cedures and spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX