DABCO-catalyzed [3+2] cycloaddition reactions of azomethine imines with N-aryl maleimides: Facile access to dinitrogen-fused heterocycles

Article abstract of DOI:10.1016/j.tetlet.2015.11.030

DABCO-catalyzed [3+2] cycloaddition of azomethine imines with maleimides has been developed. This method could efficiently furnish dinitrogen-fused tetracyclic heterocycles in high levels of regioselectivity and with good yields.

Full text of DOI:10.1016/j.tetlet.2015.11.030

Tetrahedron Letters xxx (2015) xxx–xxx
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
DABCO-catalyzed [3+2] cycloaddition reactions of azomethine imines
with N-aryl maleimides: facile access to dinitrogen-fused
heterocycles
y
y
⇑
⇑
Qianfa Jia , Lei Chen , Gongming Yang, Jian Wang , Jia Wei, Zhiyun Du
Allan H. Conney Laboratory for Anticancer Research, Institute of Natural Medicine and Green Chemistry, School of Chemical Engineering and Light Industry, Guangdong University
of Technology, Guang Dong 510006, China
a r t i c l e i n f o
a b s t r a c t
Article history:
DABCO-catalyzed [3+2] cycloaddition of azomethine imines with maleimides has been developed. This
method could efficiently furnish dinitrogen-fused tetracyclic heterocycles in high levels of regioselectiv-
ity and with good yields.
Received 3 October 2015
Revised 4 November 2015
Accepted 9 November 2015
Available online xxxx
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
[3+2] cycloaddition
N,C-Azomethine imine
Maleimide
DABCO catalysis
C,N-Cyclic azomethine imines in which one nitrogen and one
carbon atom are incorporated into a polycyclic system are conve-
nient synthons for building up various heteropolycyclic, fused,
and spirocyclic systems often exhibiting biological activity.1 Of
the systems, dinitrogen-fused heterocycles, especially pyrazolidine
and pyrazolone derivatives, are broadly used in medicinal chem-
istry as important structural elements. As exemplified in Scheme 1,
pyrazolidine derivatives (i and ii) can inhibit dipeptidyl peptidase
IV;2 phenylbutazone (iii) displays anti-inflammatory activity;3
phenidone (iv) can inhibit lipoxygenase.4,5 In sharp contrast, the
construction of dinitrogen-fused tetracyclic heterocyclic com-
pounds has received much less attention compared to their bi- or
tricyclic heterocyclic analogues.6 Therefore, new synthetic
methodologies for the synthesis of more functional dinitrogen-
fused tetracyclic heterocycles are highly desirable.
In the past few decades, novel C,N-cyclic azomethine imines
have been discovered by Tamura et al.7 and further developed by
Maruoka and co-workers,8 thus opening the field to an unexplored
class of dipoles. From then on, numerous 1,3-dipolar cycloaddi-
tions of C,N-cyclic azomethine imines could be employed for the
synthesis of dinitrogen-fused bi- or tricyclic heterocycles.6 Ti-bino-
late or chiral dicarboxylic acid-catalyzed [3+2] cycloaddition reac-
tions of C,N-cyclic azomethine imines with alkenes delivered
tricyclic tetrahydroisoquinoline Phosphine-
derivatives.8c
catalyzed [3+2] cycloaddition reactions of allenoates9 and alke-
nes10 provided tetrahydroisoquinoline derivatives. Furthermore,
catalyst-free [5+1] cycloaddition11 with isocyanides and [4+3]
annulation reaction12 with alkenes were reported. Finally, several
recent reports concern a variety of metal-catalyzed cycloaddition
reactions of azomethine imines.13 All these reactions demonstrate
that the cycloaddition reactions based on C,N-cyclic azomethine
imines are very useful for the synthesis of heterocyclic compounds
with interesting structures.
Recently, our group has developed dienamine-catalyzed enan-
tioselective 1,3-dipolar annulation reactions of aldehydes with C,
N-cyclic azomethine imines, affording important dinitrogen-fused
heterocycles, such as C1-substituted tricyclic tetrahydroisoquino-
lines.14 In addition, we also found that these C,N-cyclic azomethine
imine substrates were used in thermal 1,3-dipolar cycloaddition
with N-arylmaleimides,15a allenoates,15b and thioaldehydes.15c
Notably, the Guo group has developed phosphine-catalyzed
[3+2], [3+3], and [4+3] annulation reactions of N,N0- or C,N-cyclic
azomethine imines with allenoates, and delivered biologically
important dinitrogen-fused heterocycles.16 Inspired by these
works and based on our ongoing program toward the construction
of dinitrogen-fused tetracyclic heterocycles through the amine-
catalyzed cycloaddition strategy,14 we envisaged the possibility
of introducing N-arylmaleimides to react with C,N-cyclic azome-
thine imines to furnish [3+2] cycloaddition reactions under amine
⇑
Corresponding authors.
E-mail addresses: wangjian1999@hotmail.com (J. Wang), zhiyundu@yahoo.com.
cn (Z. Du).
y
Equal contribution.
http://dx.doi.org/10.1016/j.tetlet.2015.11.030
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Jia, Q.; et al. Tetrahedron Lett. (2015), http://dx.doi.org/10.1016/j.tetlet.2015.11.030

2
Q. Jia et al. / Tetrahedron Letters xxx (2015) xxx–xxx
Table 2
O
O
O
nBu
O
Scope of substratea
N
N
N
N
N
iii
iv
NH2
O
Ph
Ph
NH2
O
R1
O
N
N
O
Ph
O
Cat. V (10 mmol)
THF, 60oC, 1h
N
NH
R1
H
H
NH
N
N
H
N
O
N
O
X
O
3
R2
O
N
X
R2
1
2
NO2
ii
N
O
N
Ph
Scope of 1:
i
O
O
N
N
N
N
O
H
H
O
H
N
Scheme 1. Selected examples of biologically active dinitrogen-fused heterocycles.
H
H
H
N
H
H
O
O
O
O
N
N
H
O
N
Table 1
Optimization of the reaction conditionsa
R
R
R = Me, 3ba: 86%; d.r. = 16:1
R = Cl, 3fa: 89%;d.r. = 14:1
R = Br, 3ga; 80%;d.r. = 16:1
R = F, 3ha; 82%; d.r. = 16:1
R =NO2, 3ia;78%; d.r. = 18:1
3aa; 98%; d.r. > 25:1
R = Et, 3ca; 94%;d.r. > 25:1
R = OMe, 3da;94%; d.r. = 15:1
R = OPh, 3ea; 81%; d.r. = 19:1
O
N
O
O
N
Cat. I-VI (10 mmol)
solvent, T oC
H
H
O
N
N
H
O
N
Ph
O
N
O
N
O
N
O
N
1a
2a
3a
Ph
N
H
N
H
N
H
H
O
H
H
O
F
H
H
H
N
N
O
O
O
N
N
O
N
N
N
N
N
H
N
N
H
H
I
VI
II
III
IV
V
F
OH
3ja;89%; d.r. = 19:1
3ka; 76%; d.r. = 19:1
3la; 88%; d.r. = 18:1
Entry
Cat.
Solvent
t (h)
Yieldb (%)
d.r.c
f
1
2
3
4
5
6
7
8
—
I
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
CHCl3
PhCH3
THF
THF
THF
1
1
1
1
1
1
1
1
1
1
1
1
12
N.R.
75
62
N.R.
90
96
N.R.
85
67
78
98
—
O
N
O
N
O
N
12:1
17:1
—
20:1
>25:1
—
>25:1
>25:1
>25:1
>25:1
>25:1
>25:1
II
III
IV
V
VI
V
V
V
V
V
V
N
H
N
H
N
H
H
H
O
H
H
H
H
O
O
O
O
O
N
N
N
iPr
iPr
Me
Cl
Me
Cl
3ma; 89%; d.r. = 19:1
3na; 76%;d.r. = 19:1
3oa; 85%; d.r. = 19:1
9
10
11
12d
13e
O
N
O
N
O
N
32
92
N
H
N
H
N
H
H
H
H
O
H
H
H
a
O
O
O
Unless otherwise noted, reactions were carried out with 1a (0.1 mmol), 2a
O
O
N
N
N
(0.12 mmol), cat. I–VI (10 mmol %) in the solvent (0.6 mL) was stirred at 60 °C for
1 h; DMSO = dimethylsulfoxide, THF = tetrahydrofuran, DMF = N,N-dimethylfor-
mamide, N.R. = no reaction.
N
MeO
OMe
b
MeO
Isolated yield.
Determined by the crude NMR.
Room temperature.
No catalyst.
3qa; 76% ; d.r. = 19:1
3ra; 83%; d.r. = 19:1
Scope of 2:
3pa;
c
93%; d.r. = 14:1
d
e
O
O
N
f
N
N
No catalyst.
N
H
O
N
H
H
H
O
H
H
O
Br
N
H
O
O
N
Me
N
H
O
H
catalysis conditions. To the best of our knowledge, the example of
DABCO-catalyzed organocatalytic [3+2] cycloaddition reaction to
afford dinitrogen-fused tetracyclic heterocycles has not yet been
reported. Herein, we communicate our preliminary results.
Bn
O
N
Ph
3sa;94%; d.r. = 19:1
3ta; 95%;d.r. = 16:1
3ab; 89%; d.r. > 25:1
Initially, we began our investigation by employing N-aryl malei-
mide 1a and C,N-cyclic azomethine imine 2a as the model sub-
strates. Since C,N-cyclic azomethine imine substrates with N-aryl
maleimides in thermal 1,3-dipolar cycloaddition was reported,15a
the potential background reaction from direct cycloaddition of 1a
with 2a was first investigated. The reaction of 1a and 2a was
carried out in DMSO at 60 °C in the absence of catalyst for 1 h.
TLC monitoring revealed that no new spot was generated and the
substrate 1a showed almost no conversion (Table 1, entry 1).
Therefore, the background reaction could be excluded under this
condition. Then, various amine catalysts, including secondary
amines (I–III) and tertiary amine (IV–VI) were screened (entries
2–7). To our delight, tertiary amine V was the best catalyst for
this reaction proceeding with excellent diastereoselectivity
(Table 1, entry 6, d.r. > 25:1). Next we utilized tertiary amine V
as the best catalyst to screen the solvent. The survey showed
O
N
O
N
O
N
Me
N
N
H
N
H
H
H
H
O
H
O
H
O
H
H
O
O
O
Cl
Me
N
N
N
Ph
Ph
Ph
3ad; 89%; d.r. = 18:1
3ae; 91% ; d.r. = 16:1
3ac;
93%; d.r. > 25:1
a
Reaction conditions: a mixture of 1 (0.1 mmol), 2 (0.12 mmol), cat. V (10 mol %),
and THF (0.6 mL) was stirred at 60 °C for 1 h.
that the reaction carried out in THF afforded a higher yield after
1 h at 60 °C (Table 1, entries 11 vs 8–10). When we conducted
the reaction at room temperature for 1 h, the yield was rapidly
decreased to 32% (Table 1, entry 12). However, a 92% yield could
still be achieved at room temperature when the reaction time
was enhanced to 12 h, (Table 1, entry 13). Finally, the best
Please cite this article in press as: Jia, Q.; et al. Tetrahedron Lett. (2015), http://dx.doi.org/10.1016/j.tetlet.2015.11.030

Q. Jia et al. / Tetrahedron Letters xxx (2015) xxx–xxx
3
N
N
Acknowledgments
N
N
O
N
N
O
The authors acknowledge the financial support from National
Natural Science Foundation of China (NSFC 21272043), the Science
and Technology Planning Project of Guangdong Province
(2007A020300007-10, 2011B090400573) and Guangdong Natural
Science Foundation (S2011010004967).
cat. V
2a
H
O
N
N
N
O
N
Ph
O
O
Ph
N
1a
B
A
O
Ph
cat. V
Supplementary data
O
O
N
N
N
Supplementary data (experimental procedures and compound
characterization data) associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.11.
030.
N
H
H
H
O
Michael addition
H+
H
O
O
N
Ph
N
C
Ph
O
3a
Scheme 2. Plausible mechanism.
References and notes
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results were obtained in the presence of 10 mol % of cat. V,
1a:2a = 1.0:1.2 at 60 °C using THF as the solvent (Table 1, entry
11, d.r. > 25:1).
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218.
With the optimized conditions established, the scope of the
substrate 1 was examined (Table 2). Various N-aryl maleimides
bearing different substituents on the benzene rings 1a–l, whether
the substitution patterns are electron-donating or electron-with-
drawing properties, the corresponding products were obtained in
good to high yields (Table 2, 3aa–la, d.r. > 14:1, 76–98%). It is
noteworthy that the pyridine ring and naphthalene ring were also
tolerated in substrates, affording the desired products in high
yields (Table 2, 3qa and 3ra, d.r. = 19:1, 76% and 83%, respectively).
Pleasingly, disubstituted N-aryl maleimides were also found to be
good candidates to generate the desired products in high yields
(Table 2, 3ma–oa, d.r. > 16:1, 85–89%). Moreover, 3pa, which
exhibited an antiproliferative activity,17 could be rapidly synthe-
sized (Table 2, 93%, d.r. = 14:1).
Encouraged by these results, the generality of C,N-cyclic
azomethine imines was then evaluated. As shown in Table 2, the
7-Br- and 7-Me-substituted C,N-cyclic azomethine imines 2b and
2c appeared to be suitable and reacted efficiently with N-aryl
maleimides to provide the corresponding products in high yields
(Table 2, 3ab–ac, 89–93%). Substrates with moderate electron-
donating or electron-withdrawing groups (e.g., Me, Cl) also
provided the desired products in good yields (Table 2, 3ad–ae,
89–91%). Additionally, the reaction scope could further extend to
several other interesting maleimides to give interesting polycyclic
products 3sa and 3ta in high yields (Table 2). The relative configu-
ration of 3aa was determined on the basis of the 2-D NOESY 1H
NMR spectra (see the details in Supporting information).15a
Based on the above experimental results, a plausible catalytic
cycle of the current [3+2] cycloaddition was proposed.18 As shown
in Scheme 2, catalyst V begins to react with N-arylmaleimide 1a to
form zwitterion intermediate A. The subsequent addition of zwit-
terion intermediate A to azomethine imine 2a forms intermediate
B. Then elimination of B produces intermediate C, which can pro-
ceed to the desired product 3aa through an intramolecular Michael
addition.
10. Li, Z.; Yu, H.; Liu, H. L.; Zhang, L.; Jiang, H.; Wang, B.; Guo, H. C. Chem. Eur. J.
2014, 20, 1731.
11. Soeta, T.; Tamura, K.; Ukaji, Y. Org. Lett. 2012, 14, 1226.
12. Hu, X.-Q.; Chen, J.-R.; Gao, S.; Feng, B.; Lu, L.-Q.; Xiao, W.-J. Chem. Commun.
2013, 7905.
13. For recent reviews, see: (a) Imaizumi, T.; Yamashita, Y.; Kobayashi, S. J. Am.
Chem. Soc. 2012, 134, 20049; (b) Zhou, W.; Li, X.-X.; Li, G.-H.; Wu, Y.; Chen, Z.
Chem. Commun. 2013, 3552; (c) Qian, Y.; Zavalij, P. J.; Hu, W.; Doyle, M. P. Org.
Lett. 2013, 15, 1564; (d) Zhou, Y.-Y.; Li, J.; Ling, L.; Liao, S.-H.; Sun, X.-L.; Li, Y.-
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14. Li, W. J.; Wei, J.; Jia, Q. F.; Du, Z. Y.; Zhang, K.; Wang, J. Chem. Eur. J. 2014, 20,
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R. S.; Liu, H. L.; Li, Z.; Wang, B.; Liu, J.; Wang, M. A.; Wang, M.; Zhong, J. C.; Guo,
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Heterocycles 2012, 84, 393.
In summary, we have successfully developed the amine-cat-
alyzed 1,3-dipolar cycloaddition reaction of C,N-cyclic azomethine
imines with N-aryl maleimides. The reaction is catalyzed by
DABCO to give dinitrogen-fused tetracyclic heterocycles in high
yields. Considering dinitrogen-fused bi- or tri-cyclic heterocycles
exhibited considerable biological and pharmaceutical activities,
we believe that these products will have broad use in medicinal
chemistry and drug discovery. Further studies to expand the scope
of the azomethine imines are currently ongoing.
16. For reviews of synthesis of dinitrogen-fused heterocycles via catalytic by
phosphine, see: (a) Liu, J.; Liu, H. L.; Na, R.; Wang, G.; Li, Z.; Yu, H.; Wang, M.;
Zhong, J. C.; Guo, H. C. Chem. Lett. 2012, 41, 218; (b) Na, R.; Liu, H. L.; Li, Z.;
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4
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Wang, B.; Liu, J.; Wang, M.-A.; Wang, M.; Zhong, J. C.; Guo, H. C. Tetrahedron
17. Baytas, S. N.; Inceler, N.; Yılmaz, A.; Olgac, A.; Menevse, S.; Banoglu, E.; Hamel,
E.; Bortolozzi, R.; Viola, G. Bioorg. Med. Chem. 2014, 22, 3096.
18. Li, W. J.; Wang, J. Angew. Chem., Int. Ed. 2014, 53, 1.
2012, 68, 2349; (c) Wu, X.; Na, R.; Liu, H. L.; Liu, J.; Wang, M.; Zhong, J. C.; Guo,
H. C. Tetrahedron Lett. 2012, 53, 342; (d) Zhang, L.; Jing, C. F.; Liu, H. L.; Wang,
B.; Li, Z.; Jiang, H.; Yu, H.; Guo, H. C. Synthesis 2013, 45, 53.
Please cite this article in press as: Jia, Q.; et al. Tetrahedron Lett. (2015), http://dx.doi.org/10.1016/j.tetlet.2015.11.030