Cu(ii) catalyzed oxidation-[3+2] cycloaddition-aromatization cascade: Efficient synthesis of pyrrolo [2, 1-a] isoquinolines

Article abstract of DOI:10.1039/c0cc03186k

A novel and synthetically efficient Cu(ii) catalyzed oxidation-dipolar cycloaddition-aromatization cascade reaction has been developed for a "one-pot" synthesis of biologically important pyrrolo [2, 1-a] isoquinolines.

Full text of DOI:10.1039/c0cc03186k

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Cu(II) catalyzed oxidation-[3+2] cycloaddition-aromatization cascade:
Efficient synthesis of pyrrolo [2, 1-a] isoquinolinesw
Chenguang Yu,ab Yianan Zhang,a Shilei Zhang,a Hao Lic and Wei Wang*ac
Received 11th August 2010, Accepted 18th October 2010
DOI: 10.1039/c0cc03186k
A novel and synthetically efficient Cu(II) catalyzed oxidation-
dipolar cycloaddition-aromatization cascade reaction has been
developed for a ‘‘one-pot’’ synthesis of biologically important
pyrrolo [2, 1-a] isoquinolines.
These studies highlight the challenges and potentials of the
dipolar cycloaddition reactions in construction of the important
molecular architecture. More synthetically efficient strategies
will allow for the target- and diversity-oriented synthesis of the
biologically significant lamellarin alkaloids and the exploration
of their biomedical applications.
Pyrrolo [2, 1-a] isoquinolines constitute the core structure of the
novel marine natural products lamellarin alkaloids with more
than 30 family members.1 They display a broad spectrum of
promising biological properties. For example, lamellarin D is a
potent inhibitor of topoisomerase I,2 while related lamellarin
a-20-sulfonate serves as a selective HIV integrase inhibitor
(Fig. 1).3 Lamellarin I is an MDR inhibitor4 and its analogue
lamellarin K exhibits antitumor activity.5 Their intriguing
biological activities have provoked significant recent interest
in the target-6 and diversity-7 oriented synthesis. Despite the
fact that several strategies involving dipolar8 and azadiene
Diels–Alder cycloadditions,6c oxidative dimerization6b and
double-barreled Heck cyclization9 have been reported in the
preparation of the pyrrolo [2, 1-a] isoquinoline core structures,
the general observation is that they require multiple synthetic
steps and/or highly functionalized substrates. For example,
dipolar [3+2] cycloadditions between azomethines and
activated double bonds are an efficient approach to hexahydro-
pyrrolo [2, 1-a] isoquinolines.8,10,11 Nevertheless, an extra
oxidation step is required to convert the pyrrolidines to the
pyrroles. In addition, the method has a limited scope, restricted
to the substrates bearing electron-donating substituents.
As a result of high reactivity of the essential azomethines in
dipolar cycloaddition reactions,8,12 in general, they are formed
in situ from corresponding labile imines, whose preparations are
nontrivial. The use of readily prepared and stable tetrahydro-
isoquinolines 1 could offer significant synthetic and economic
benefits (Scheme 1). We envisioned that oxidation of tetra-
hydroisoquinolines 1 would lead to formation of azomethines
2, which were trapped by a dipolarophile such as maleimides 3
for a subsequent [3+2] cycloaddition to give adducts 4. Under
the same reaction conditions, the resulting hexahydropyrrolo
[2, 1-a] isoquinolines 4 would be oxidized subsequently to afford
the target pyrrolo [2, 1-a] isoquinolines 5.13 The proposal looks
simple on paper. However, we faced two challenging issues. First,
a direct oxidation of isoquinolines 1 to unstable azomethines 2
has not been reported previously. Moreover, it is unclear if we
could find
a suitable oxidation system for forming the
azomethines 2, while compatible with subsequent dipolar cyclo-
addition and aromatization processes. In this communication, we
wish to disclose the results by the discovery of a new ‘‘one pot’’
approach to the pyrrolo [2, 1-a] isoquinolines from simple
starting materials. A novel Cu(II) catalyzed oxidation-[3+2]
cycloaddition-aromatization cascade process is developed.
Notably, the reaction displays a broad substrate scope that a
variety of dipolarophiles including maleimides, maleic anhydride,
quinones, and alkynes can effectively engage in the process, thus
generating the products with significant structural diversity.
To validate the hypothesis, the reaction of tetrahydroisoquino-
line ester 1a with N-p-bromophenylmaleimide 3a in the presence
of oxidant TBHP (t-butyl hydroperoxide) and a Lewis acid in
toluene at room temperature was performed initially (Table 1).14
It was shown that the catalyst was critical for the process (entries
1–3). Only copper salts delivered the desired product 5a albeit
a low yield (25%). The low yield largely attributed to the
incomplete conversion of the 1, 3-dipolar adduct 4a (38% yield)
to 5a. It was noted that under the oxidative reaction conditions,
the C3–C4 bond was not oxidized and thus 3,4-dihydroquinoline
Fig. 1 Biologically important pyrrolo [2, 1-a] isoquinoline lamellarin
alkaloids.
a Department of Chemistry & Chemical Biology,
University of New Mexico, MSC03 2060, Albuquerque, NM 87131-0001,
USA. E-mail: wwang@unm.edu; Fax: (+1) 505-277-2609
b State Key Laboratory of Chemical Resources Engineering,
Beijing University of Chemical Technology, Beijing 100029, China
c Shanghai Institute of Materia Medica, Chinese Academy of Sciences,
555 Zuchongzhi Road, Shanghai 201203, China
w Electronic supplementary information (ESI) available: Experimental
details and spectroscopic data for the compounds 5 and 7. See DOI:
10.1039/c0cc03186k
Scheme
1 A proposed catalytic oxidation-[3+2] cycloaddition-
aromatization cascade.
c
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1036 Chem. Commun., 2011, 47, 1036–1038

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Table 1 Optimization of reaction conditionsa
Table 2 Reaction scope with maleimides and tetrahydroisoquinolinesa
% Yield
4a/5ab
R1, R2, R3, 5
% Yieldb
Entry Cat.
Oxidant
Solvent
Entry
1
2
3
4
5
6
7
8
CuBr
FeCl3
Pd(OAc)2
CuBr2
CuCl
CuCl2
CuOTfÁ1/2Tol TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
CH2Cl2
DME
MeOH
EtOAc
Toluene/H2O (v/v: 9/1) 30/14
Toluene
Toluene
38/25
o5/o5
0/0
29/30
36/11
40/12
33/4
1
2
3
4
5
6
7
8
H, H, Ph, 5b
57
60
77
50
64
61
76
80
70
66
81
72
H, H, 2-MeC6H4, 5c
H, H, 3-MeC6H4, 5d
H, H, 2,6-Me2C6H3, 5e
H, H, 4-MeOC6H4, 5f
H, H, 2-FC6H4, 5g
H, H, 4-BrC6H4, 5a
H, H, 3,5-(CF3)2C6H3, 5h
H, H, 3-MeO-4-BrC6H3, 5i
H, H, C6H4CH2, 5j
Cu(OTf)2
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr2
CuBr2
CuBr2
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
(t-BuO)2
36/7
9
27/16
16/9
0/0
9
10
11
12
13
14
15
16
17
18
19
20
21
10
11
12c
H, Br, 4-BrC6H4, 5k
MeO, MeO, 4-BrC6H4, 5l
32/21
a
Reaction conditions: unless specified, see footnote a in Table 1 and
b
0/0
c
ESI.w Isolated yields. 1.5 equiv. of 1a and 5 equiv. of TBHP used.
24/26
33/29
15/5
13/42
0/55
0/52
0/76
(PhCO2)2O Toluene
PhCO3t-Bu Toluene
TBHPc
TBHPc
TBHPd
TBHPe
Toluene
Toluene
Toluene
Toluene
substituents in aryl groups and aliphatic moiety (entry 10). It
appeared that the steric hindrance of the substituents had some
degree of influence on the process and relatively lower reaction
yields were obtained (entries 2, 4 and 6). Probing the electronic
impact of substituents on tetrahydroisoquinolines 1 indicated
that such effect was limited (entries 11 and 12). It is noteworthy
that the structure of the product 5l bearing two MeO groups is
related to the lamellrin alkaloids.
a
Reaction conditions: unless specified, to a solution of an ethyl
2-(3,4-dihydroisoquinolin-2(1H)-yl)acetate (0.1 mmol) and 60 mL of TBHP
(3.3 equiv.) in the presence of 10 mol% catalyst CuBr2 in toluene (1.0 mL)
was added a N-substituted maleimide (or other dipolarophiles) (0.1 mmol)
b
and the resulting solution was stirred for 48 h at 50 1C. Isolated yields.
c
d
3.3 equiv. of TBHP used. 6.6 equiv. of TBHP used. e At 50 1C.
To demonstrate the powerful Cu(II) promoted oxidation-
[3+2] cycloaddition-aromatization cascade with the broader
synthetic utility, we also examined other dipolarophiles and gave
good yields (Table 3). Maleic anhydride (entry 1), 1, 4-naphtho-
quinone (entry 2), activated alkynes (entries 3–5) were found to
be effective dipolarophiles engaged in the reaction in good yields.
It is noted that high regioselectivity of the reaction was observed
and only one regioisomer was formed (entries 4 and 5).
Compound 7e is a known compound, which allows us to
establish the structure of the regioisomer.16 The high regio-
selectivity may attribute to the steric and electronic effects.17
A controlled experiment using compound 4a as an example
showed that the end products pyrrolo [2, 1-a] isoquinolines 5
indeed were transformed from [3+2] cyclcoaddition adducts 4
(Scheme 2). This indicates that the formed final products
go through an oxidation-[3+2] cycloaddtion-aromatization
sequence in a cascade manner.
was obtained. Therefore the method is complementary to that
was developed by Porco and co-workers, where the quinolines
were produced.11 Furthermore, the 3,4-dihydroquinolines can be
conveniently converted to the quinolines by DDQ oxidation.15
We decided to employ Cu salts as catalysts for the optimization
of reaction conditions (entries 4–8). It was found that CuBr gave
the best total yield (63%, entry 1), while CuBr2 afforded the
better yield of product 5a (30%, entry 4). Survey of solvent effect
using CuBr as a catalyst concluded that toluene was the preferred
medium for the reaction. TBHP proved to be the most effective
among the oxidants including (tBuO)2, benzoyl peroxide and
PhCO2OtBu probed (entries 1 and 14–17). Increasing the loading
of TBHP (3.3 equiv.) resulted in the improvement of the yield of
5a (42%), but still a pronounced amount of 4a remained
(entry 18). A cleaner reaction with exclusive formation of 5a
was obtained with CuBr2 and the yield was also improved
(55%, entry 19). Further increasing the loading of the oxidant
(6.6 equiv.) was not beneficial (entry 20). Nevertheless, elevating
the reaction temperature to 50 1C enhanced the yield (76%)
dramatically (entry 21).
In conclusion, we have developed a synthetically efficient
strategy, relying on a novel Cu(II) catalyzed oxidation-dipolar
cycloaddition-aromatization cascade for the ‘‘one-pot’’
synthesis of highly valuable pyrrolo [2, 1-a] isoquinolines. A
wide range of substrates can effectively participate in the
reactions under mild reaction conditions to create structurally
diverse products. Notably, the cascade processes involve an
unprecedented dipolar cycloaddition reaction with in situ
formation of azomethine ylides from simple and stable amines.
Further investigations of the powerful strategy in the develop-
ment of new reactions are under way in our laboratory.
With the optimized condition in hand, we then explored the
scope and limitations of the reaction using various maleimides 3
and tetrahydroisoquinolines 1. As shown in Table 2, the reac-
tion proceeded smoothly with N-substituted maleimides, which
have significant structural variations bearing electron-neutral
(entry 1), donating (entries 2–5) and withdrawing (entries 6–9)
c
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Chem. Commun., 2011, 47, 1036–1038 1037

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Entry
Dipolarophile 6
Product 7
% Yieldb
1
72
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´
2
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3
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4c
70
57
´
F. Albericio and M. Alvarez, Org. Lett., 2003, 5, 2959;
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5d
a
+
(b) J. Toth, A. Nedves, A. Dancso, G. Blasko, L. Toke and
´ ´ ´
Unless specified, see footnote a in Table 1 and supporting informa-
b
tion. Isolated yield. 2 equiv. 6d used. Reaction time: 2 h.
c
d
M. Nyerges, Synthesis, 2007, 1003; (c) L. Chen and M.-H. Xu,
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3, 198; (b) J. To
Synlett, 2007, 1259.
´
th, L. Varadi, A. Dancso, L. Toke and M. Nyerges,
´
´
¨
11 S. Su and A. J. Porco, Jr., J. Am. Chem. Soc., 2007, 129, 7744.
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Scheme 2 Oxidation of hexahydropyrrolo [2, 1-a] isoquinoline 4a to
pyrrolo [2, 1-a] isoquinoline 5a.
14 For reviews of Lewis acid catalyzed oxidation of C–N bonds, see:
(a) K. R. Campos, Chem. Soc. Rev., 2007, 36, 1069;
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15 D. Pla, A. Marchal, C. A. Olsen, F. Albericio and M. Alvarez,
J. Org. Chem., 2005, 70, 8231. We have demonstrated the
transformation in high efficiency under a microwave irradiation.
Financial support provided by the National Science Founda-
tion (CHE-0704015, W. Wang) and the Chinese Scholarship
Council (C. Yu) is gratefully acknowledged.
´
Notes and references
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+
17 M. Nyerges, B. Somfai, J. Tth, L. Toke, A. Dandcs and G. Vlask,
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c
1038 Chem. Commun., 2011, 47, 1036–1038
This journal is The Royal Society of Chemistry 2011