Domino ring-opening/recyclization reactions of doubly activated cyclopropanes as a strategy for the synthesis of furoquinoline derivatives

Article abstract of DOI:10.1002/anie.200604276

(Chemical Equation Presented) In one easy step, doubly activated cyclopropanes 1 can be transformed into furoquinoline derivatives 2 through a tandem ring-opening/recyclization reaction mediated by SnCl₄·5 H₂O. A variety of substrates 1 derived from cheap starting materials were converted into the corresponding furoquinolines in good to excellent yields with high chemo- and regioselectivity. R = H, Me, OMe, Cl, or aromatic group is naphthyl.

Full text of DOI:10.1002/anie.200604276

Communications
DOI: 10.1002/anie.200604276
Synthetic Methods
Domino Ring-Opening/Recyclization Reactions of Doubly Activated
Cyclopropanes as a Strategy for the Synthesis of Furoquinoline
Derivatives**
Zhiguo Zhang, Qian Zhang,* Shaoguang Sun, Tao Xiong, and Qun Liu*
Furoquinoline alkaloids,[1] widely distributed among plants of
the Rutaceae family,[2] have attracted considerable attention
because of their diverse pharmacological and biological
properties.[1–3] The development of efficient syntheses of
furoquinolines has been the focus of much research for many
decades and continues to be an active and rewarding research
area.[4] However, most of the existing methods suffer from the
limited availability of substrates or require multistep proce-
dures to construct the pyridine and furan rings individually.
Recently, in conjunction with drug development, new syn-
thetic routes to furoquinoline derivatives have been devel-
oped.[5] For example, furoquinolines were synthesized in a
single step by a multicomponent domino reaction of an ortho-
alkynyl aniline, an isocyanoacetamide, and an aldehyde[5a] and
by the tandem radical annulation of unsaturated N-aryl
thiocarbamates,[5b] although there are limitations in terms of
the starting materials, expensive reagents are involved, and
the regioselectivity is not controllable in some cases. Herein,
we report a new strategy for the synthesis of furo[2,3-b]-
quinoline derivatives 2 in a single step from doubly activated
cyclopropane precursors in the form of readily available 1-
acyl N-aryl cyclopropanecarboxamides 1 (Scheme 1). The
mechanistic details of this highly chemo- and regioselective
domino ring-opening/recyclization process are also discussed.
Cyclopropanes are extremely versatile building blocks in
organic synthesis owing to their ready accessibility and good
reactivity.[6,7] Since the first report by Cloke in 1929 that
cyclopropyl ketones can be transformed into dihydrofuran
derivatives,[8] such reactions have been well studied
(Scheme 2).[9] Although there have been fewer studies on
the synthetic utility of cyclopropyl amides, some interesting
results have been obtained,[10] including the formation of ring-
expanded products, such as N-substituted pyrrolidin-2-ones
(Scheme 2).[10a]
Scheme 2. Ring opening/recyclization of cyclopropyl ketones and
amides.
So far, to the best of our knowledge, there have been no
reports on the synthetic applications of cyclopropane deriv-
atives with both acyl and carbamoyl activating groups,
although doubly activated cyclopropanes have proven very
useful,[11] especially in the synthesis of tetrahydro-1,2-ox-
azines[11c,d] and 4-nitro-/4-cyanodihydropyrroles.[11e] During
our research on the synthesis of carbocyclic and heterocyclic
compounds via a-alkenoyl a-carbamoyl ketene dithioacetals
derived from the corresponding 3-oxobutanamides,[12] we
prepared a series of 1-acyl N-aryl cyclopropanecarboxamides
1 in good to excellent yields from cheap starting materials
(acetoacetanilides and 1,2-dibromoethane or 1,2-dibromo-
propane)[13] and investigated their synthetic potential.
We first focused on the reactivity of the doubly activated
cyclopropane precursor 1-acetyl-N-(2-methoxyphenyl)cyclo-
propanecarboxamide (1a),[13] which was obtained in 99%
yield from the reaction of N-(2-methoxyphenyl)-3-oxobutan-
amide and 1,2-dibromoethane (K2CO3, N,N-dimethylform-
amide, room temperature, 11 h) in the presence of a Lewis
acid. After many attempts, it was found that the furoquinoline
derivative 8-methoxy-4-methyl-2,3-dihydrofuro[2,3-b]quino-
line (2a) could be isolated in 88% yield when 1a was treated
with SnCl4·5H2O (1.2 equiv) in xylene at 1208C for 4.5 h
(Scheme 3; Table 1, entry 1). Other Lewis acids, including
FeCl3·6H2O and BF3·OEt2, gave 2a in lower yields (Table 1,
entries 2 and 3). When TiCl4 was used as the catalyst, and the
reaction was carried out in nitromethane at room temper-
ature, instead of 2a, the ring-opened product 2-(2-chloro-
ethyl)-N-(2-methoxyphenyl)-3-oxobutanamide (3a) was
obtained in 75% yield (Scheme 3).[13] Surprisingly, the
reactions mediated by anhydrous FeCl3 and SnCl4 provided
2a in lower yields than those with the hydrated Lewis acids
Scheme 1. Synthesis of furo[2,3-b]quinolines 2 from doubly activated
cyclopropanes 1.
[*] Dr. Z. Zhang, Prof. Q. Zhang, Dr. S. Sun, T. Xiong, Prof. Q. Liu
Department of Chemistry
Northeast NormalUniversity
Changchun, 130024 (P.R. China)
Fax: (+86)431-8509-8213
E-mail: zhangq651@nenu.edu.cn
liuqun@nenu.edu.cn
[**] Financialsupport of this research by the Key Grant Project of the
Chinese Ministry of Education (10412), the NNSFC (20672019), and
the Science Foundation for Young Teachers of Northeast Normal
University (20060301) is gratefully acknowledged.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Chemie
aryl ring were reactive under the optimized conditions given
in Table 1, entry 1, and the corresponding products 2 were
obtained in excellent yields (Table 2, entries 1, 2, 5, and 7).[14]
In the case of precursors 1e and 1g with an electron-
withdrawing chloro group on the aryl ring, the desired
products 2e and 2g were also obtained in good yields
(Table 2, entries 4 and 6). However, substrate 1i with a
strongly electron-withdrawing acetyl group on the aryl ring
did not react to give the desired product 2i (Table 2, entry 8),
but the product of the hydrolysis of 1i, 4-acetylaniline, was
produced in 80% yield. The naphthalene derivatives 1j and
1k underwent the desired reaction smoothly to provide 2j and
2k, respectively, in high yields (Table 2, entries 9 and 10).
The reactions described exhibit very high regioselectivity.
For example, precursors 1g, 1h, and 1k reacted to give 2g, 2h,
and 2k as single regioisomers (Table 2, entries 6, 7, and 10); 1l
and 1m (with a methyl group on the cyclopropane ring) also
gave the single regioisomers 2l and 2m (with a methyl group
at the 2-position) in excellent yields (Table 2, entries 11 and
12). In a study on acid-catalyzed cyclization by Ashrof and
Raman, 2l was also obtained in 92.7% yield from
a-allylacetoacetanilide. However, a mixture of the corre-
sponding furo- and pyrano[2,3-b]quinolines was produced in
19% combined yield from a-(but-2-enyl)acetoacetanilide,
and no furo[2,3-b]quinolines were obtained from other a-
allylacetoacetanilides.[4i] In our studies, besides the 1-acetyl N-
aryl cyclopropanecarboxamides 1a–1h and 1j–1m, 1-(4-
methoxybenzoyl)-N-phenylcyclopropanecarboxamide (1n;
with a substituted benzoyl group as one of the activating
groups) was used successfully as a substrate to prepare the
furoquinoline 2n in moderate yield under identical conditions
Scheme 3. Reaction products obtained from 1a depending on the
reagents used.
Table 1: The reaction of 1a in the presence of a Lewis acid under different
conditions.
Entry Lewis acid (equiv)
Solvent
T [8C] t [h] Yield
of 2a [%][a]
1
2
3
4
5
6
7
8
9
SnCl4·5H2O (1.2)
FeCl3·6H2O (1.2)
BF3·OEt2 (1.2)
anhydrous FeCl3 (1.2) xylene
anhydrous SnCl4 (1.2) xylene
SnCl4·5H2O (0.5)
SnCl4·5H2O (1.2)
SnCl4·5H2O (1.2)
SnCl4·5H2O (1.2)
xylene
xylene
xylene
120
120
120
120
120
120
110
80
4.5 88
6.0 52
5.0 28
7.0 27
4.5 45
0.5 11[b]
8.0 58
40.0 63
10.0 45
xylene
toluene
benzene
nitromethane 101
[a] Yield of the isolated product. [b] The yield was not increased with a
longer reaction time (6 h).
(Table 1, entries 4 and 5). Further-
more, the reaction was not efficient
Table 2: Synthesis of furo[2,3-b]quinolines 2 from 1.[a]
when only a small amount of
SnCl4·5H2O (for example, 0.5
equivalents) was used (Table 1,
entry 6). The reaction could also
be carried out in toluene, benzene,
and nitromethane, but the yields of
2a were lower than when xylene
was used (Table 1, entries 7–9).
In contrast to usual ring-open-
ing/recyclization reactions of cyclo-
propyl ketones[9] and amides[10]
(Scheme 2), in the transformation
from 1a to 2a the oxygen atom on
the dihydrofuran ring of the prod-
uct originates from the carbamoyl
group of 1a. As this transformation
constitutes one of the simplest
routes to a furo[2,3-b]quinoline
derivative,[1–5] and the correspond-
ing doubly activated cyclopropanes
can be produced readily from very
cheap raw materials,[13] we next
investigated the scope of the reac-
tion.
Entry
Substrate 1
t [h] Product
Yield [%][b]
1
R1
R2
R3
R4
R5
1
2
3
4
5
6
7
8
1b
1c
1d
1e
1 f
1g
1h
1i
Me
Me
Me
Me
Me
Me
Me
Me
H
H
H
H
H
H
H
H
Me
Me
H
H
H
H
H
H
H
H
H
H
H
Me
H
Cl0.5
Me
4.0
5.5
1.0
2b
2c
2d
2e
2 f
2g
2h
2i
90
87
75
57
86
56
91
0
H
1.5
1.3
ClH
Me
H
0.5
H
CH3CO 0.5
9
1j
0.5
68
75
10
1k
1l
0.5
11
12
13
Me
Me
H
H
H
H
H
H
H
1.5
5.0
0.5
2l
2m
2n
93
85
45
1m Me
1n p-MeOC6H4
Me OMe
H
H
Precursors 1 with one or two
electron-donating groups on the
[a] Reactions were carried out with SnCl4·5H2O (1.2 mmol) and 1 (1.0 mmol) in xylene (3 mL) at 1208C
for 0.5–5.5 h. [b] Yield of the isolated product.
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Communications
(Table 2, entry 13). Our results show the wide scope of the
The overall transformation may involve the SnCl4·5H2O-
initiated opening of the cyclopropane ring in 1 (1!4),
followed by a novel annulation to form the dihydrofuran
intermediate 5. Furoquinolines 2 were then produced through
a Combes-type annulation.[17] Further evidence for this
mechanism was provided by the annulation reaction of 3a.
Both 5a and 2a were obtained in 45% yield when 3a was
heated for 0.5 h under the conditions described in entry 1 of
Table 1. Thus, the conversion of 1 into 2 involves a novel
tandem ring-opening and annulation process (doubly acti-
vated cyclopropane!furan!furoquinoline).
novel domino ring-opening/recyclization reaction with
respect to a range of substituents R1, R2, R3, R4, and R5
(Tables 1 and 2). Thus, this new synthetic strategy provides an
efficient route to furo[2,3-b]quinolines.
In general, b-ketoanilides are the precursors of 2-quino-
lones in the Knorr synthesis.[4i,15] To gain an understanding of
the mechanism of the ring-opening/recyclization reaction,
some further experiments were conducted. The reaction of 1a
with SnCl4·5H2O (1.2 equiv) in xylene at 1208C for 10 min
gave the dihydrofuran 5a, compound 7a, and the furoquino-
line 2a in yields of 42, 20, and 33%, respectively, and the
reaction of 5a under the same conditions with a reaction time
of 2 h produced 7a (31%) and 2a (47%; Scheme 4). Under
In conclusion, we have developed a new strategy for the
synthesis of furoquinoline derivatives 2 through an SnCl4-
mediated tandem ring-opening/recyclization reaction of the
doubly activated cyclopropanes 1. The advantages of this
method, which include high chemo- and regioselectivity, high
efficiency, operational simplicity, and the ready availability of
a wide range of substrates from cheap starting materials,
make this new strategy very powerful. Further studies
towards the expansion of the scope of the reaction to various
heterocyclic substrates are in progress.
Received: October 18, 2006
Published online: January 19, 2007
Keywords: cyclization · cyclopropanes · domino reactions ·
.
furoquinolines · synthetic methods
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Scheme 4. Proposed mechanism for the synthesis of furo[2,3-b]-
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otherwise identical conditions but with 0.2 equivalents of
SnCl4·5H2O, the reaction of 7a for 2 h gave 2a in quantitative
yield, and the reaction of 5a for 4.5 h produced 2a in only 5%
yield. These results suggest that 5 and 7 are involved as
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