Lewis acid-catalyzed intramolecular [3+2] cycloaddition of cyclopropane 1,1-diesters with alkynes for the synthesis of cyclopenta[c]chromene skeletons

Article abstract of DOI:10.1002/asia.201200104

An efficient method to construct cyclopenta[c]chromene skeletons by Lewis acid-catalyzed intramolecular [3+2] cycloaddition of cyclopropane 1,1-diesters with alkynes is presented. Two new fused cycles can be formed in one step in moderate to excellent yie

Full text of DOI:10.1002/asia.201200104

DOI: 10.1002/asia.201200104
Lewis Acid-Catalyzed Intramolecular [3+2] Cycloaddition of Cyclopropane
1,1-Diesters with Alkynes for the Synthesis of Cyclopenta[c]chromene
Skeletons
Xiao-Feng Xia,[a] Xian-Rong Song,[a] Xue-Yuan Liu,[a] and Yong-Min Liang*[a, b]
Polycyclic structures are found in the core of most syn-
thetic and natural bioactive products. Highly efficient con-
struction of polycyclic skeletons is one of the most impor-
tant research topics in organic synthesis. Chromans are val-
uable structures in biological chemistry as well as important
structural units found in many natural and artificial products
such as vitamin E and its derivatives and flavonoids.[1] More
specifically, cyclopenta[c]chromene, one of the chroman de-
rivatives, is found in a wide variety of alkaloids and bioac-
tive agents, which exhibit a broad range of biological activi-
ties (Figure 1).[2] Although diverse synthetic approaches
toward chromans have been developed,[3] versatile method-
ologies to construct cyclopenta[c]chromene were rarely re-
ported until now.[4] Consequently, the development of new
synthetic procedures to access cyclopenta[c]chromene deriv-
atives needs to be actively pursued. This prompted us to de-
velop an efficient method for the straightforward synthesis
of cyclopenta[c]chromene structures from simple, easily
available, and cheap starting materials.
Undoubtedly, cycloadditions are one of the most facile
and direct transformations for the rapid formation of highly
complex molecular scaffolds. Donor–acceptor (DA) cyclo-
propanes are particularly useful synthetic building blocks,
which serve as excellent synthetic equivalents of 1,3-dipolar
compounds under Lewis acid-mediated conditions to access
cycloaddition products often not readily available through
traditional routes.[5] Especially, the ease of running the reac-
tion and the regio- and stereoselectivity make intramolecu-
lar [3+2] cycloaddition an efficient methodology to con-
struct complex cyclic skeletons using DA cyclopropanes.[6]
Although the annulation of DA cyclopropanes with alkynes
has been highly successful in the last decades for the synthe-
sis of cyclopentenes, the modest stereoselectivity and the
need for stoichiometric amounts of a strong Lewis acid have
hampered the applicability of this reaction.[7] Yadavꢀs group
have reported a formal intermolecular [3+2] addition of ac-
ceptor-substituted cyclopropylmethylsilanes with aryl acety-
lenes to afford cyclopentene-based skeletons.[7c] However,
silicon substituents attached to cyclopropane are required
and a stoichiometric amount of TiCl4 was used in this reac-
tion, thus limiting the scope and applicability of the cycload-
dition. Therefore, a straightforward methodology having
wider scope is strongly desired. Our research group was also
interested in searching for an efficient method for construc-
tion of synthetically useful compounds using cyclopropane
as the substrate.[8] We envisioned that the cyclopropane ring
of cyclopropane 1,1-diesters can be expanded by using
alkyne moieties in an intramolecular [3+2] reaction, thereby
Figure 1. Some representative cyclopenta[c]chromene natural products.
[a] Dr. X.-F. Xia, X.-R. Song, Dr. X.-Y. Liu, Prof. Dr. Y.-M. Liang
State Key Laboratory of Applied Organic Chemistry
Lanzhou University
resulting
in
cyclopenta[c]chromene-type
structures
(Scheme 1). Herein, we wish to report a successful realiza-
tion of this concept.
Lanzhou 730000 (P. R. China)
[b] Prof. Dr. Y.-M. Liang
State Key Laboratory of Solid Lubrication
Lanzhou Institute of Chemical Physics
Chinese Academy of Science
Lanzhou 730000 (P. R. China)
E-mail: liangym@lzu.edu.cn
To realize the concept of our design, cyclopropane 1,1-
diesters were synthesized from cheap starting material sali-
cylaldehyde in four steps, as shown in Scheme 2 (for further
details, see the Supporting Information). Then we started
our study by using compound 1a as a model substrate to op-
timize the reaction conditions for an intramolecular [3+2]
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201200104.
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COMMUNICATION
the ethyl diester 1a and the methyl diester 1b in the reac-
tion. Better yields were obtained when R1 was an electron-
donating substituent (Table 2, entries 3–7), whereas an elec-
tron-withdrawing group slightly hindered the reaction
(Table 2, entry 8). This might be due to the fact that the R1
electron-donating substituent enhances the reactivity of cy-
clopropane. Sterically demanding ortho-substitued cyclopro-
panes always gave lower yields of the desired product de-
spite the presence of an electron-donating or an electron-
withdrawing substituent (Table 2, entries 9–12). The reaction
tolerated a variety of functional groups at the ortho, meta,
and para positions in the Ar group (Table 2, entries 13–16).
When an alkyne with an electron-donating substituent at
the para position of Ar was employed, 2m was obtained in
94% yield. The relative config-
Scheme 1. Design of a Lewis acid-catalyzed ring expansion of cyclopro-
pane 1,1-diesters.
uration of product 2m was un-
ambiguously assigned by single-
crystal X-ray crystallography
(see the Supporting Informa-
tion).[9] The sterically demand-
ing ortho-substituted substrate
was also tolerated and gave 2o
in
74%
yield
(Table 2,
entry 15). Nevertheless, a rela-
tively lower yield was observed
when an alkyne moiety with an
electron-withdrawing substitu-
ent in Ar was employed
(Table 2, entry 16). The thienyl
Scheme 2. Modular preparation of cyclization precursors from salicylaldehyde. DMF=N,N-dimethylforma-
mide, THF=tetrahydrofuran, DMSO=dimethyl sulfoxide.
cycloaddition. A variety of Lewis acids were first examined
as catalysts. Using SnCl2 and other Lewis acids such as PtCl2
Table 1. Optimization of the reaction conditions.[a]
and PtCl4, the desired cycloaddition product was not detect-
ed. However, when FeCl3 was added to the reaction system,
a trace amount of 2a was formed (Table 1, entry 2). As tri-
fluoromethanesulfonate salts are often reported as good cat-
alysts to catalyze ring-opening reactions of DA cyclopropa-
nes,[6j] we concentrated on using these catalysts (Table 1, en-
tries 5–9). We found that ScACHTNUTRGNENG(U OTf)3 was the best potential
Entry
Catalyst (%)
Solvent
(CH2)2Cl2
(CH2)2Cl2
(CH2)2Cl2
(CH2)2Cl2
(CH2)2Cl2
(CH2)2Cl2
(CH2)2Cl2
(CH2)2Cl2
(CH2)2Cl2
toluene
CH2Cl2
1,4-dioxane
CH3CN
THF
T [8C]
Yield [%][b]
catalyst and afforded the desired product in 56% yield
(Table 1, entry 9). To optimize the yield of the product fur-
ther, we studied the influence of different reaction media
(Table 1, entries 10–14). From the results obtained,
(CH2)2Cl2 was chosen to be the best solvent (Table 1,
entry 9). After this, we screened the amount of catalyst em-
[d]
1
2
3
4
5
6
7
8
SnCl2 (10)
FeCl3 (10)
PtCl2 (10)
PtCl4 (10)
G
75
75
75
75
75
75
75
75
75
75
40
75
75
60
75
75
75
60
75
–
E
<10
–
–
<10
–
40
<10
56
40
–
–
–
–
68
60
57
50
66
ACHTUNGTRENNUNG
N
Cu
Zn
U
R
ACHTUNGTRENNUNG
Yb
A
N
ployed (Table 1, entries 15–17). When 10 mol% of ScACTHNUTRGNEUNG(OTf)3
Bi
Sc
Sc
Sc
Sc
Sc
Sc
Sc
Sc
Sc
Sc
Sc
N
ACHTUNGTRENNUNG
was used as the catalyst and 4 ꢂ MS as an additive, 2a was
obtained in 68% yield (Table 1, entry 15). A decrease in the
reaction temperature from 758C to 608C led to low conver-
sion and yield of 2a (Table 1, entry 18). A similar result was
obtained when the concentration of the reaction system was
reduced (Table 1, entry 19).
With the optimized reaction conditions (Table 1,
entry 15), we then extended the scope of this transformation
to a wide range of cyclopropane 1,1-diesters. The protocol
was found to be tolerant to both electron-withdrawing and
electron-donating substituents in both aromatic rings (R1
and Ar). No difference in reactivity was observed between
9
ACHTUNGTRENNUNG
10
11
12
13
14
15
16
17
18
19
R
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
[a] Standard reaction conditions: 1a (0.1 mmol) in 1 mL of solvent for
6 h. [b] Yields of isolated products. [c] Using 4 ꢂ MS as the additive.
[d] No reaction. [e] 1a (0.1 mmol) in 2 mL of solvent for 6 h.
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Lewis Acid-Catalyzed Intramolecular [3+2] Cycloadditions
Table 2. ScACHTUNGTRENNUNG
(OTf)3-catalyzed [3+2] cycloaddition.[a]
al elements in many natural products, particularly alkaloids.
Under the optimized reaction conditions, tetrahydroquino-
line derivative 2r could be obtained in 83% yield using our
designed method. Some derivatives of 2r are inhibitors of
human Cdc25B dual specificity phosphatase.[10]
To further establish the synthetic potential of this method,
the transformation of the cyclopenta[c]chromene product
2h was examined (Scheme 3). The reaction worked smooth-
ly on a 1 mmol scale without loss of reactivity. The two ester
groups in product 2h reacted with urea, and then a barbituric
acid derivative product 4 was easily obtained in two steps
from easily prepared substrate 1h.[6d] Barbituric acid deriva-
tives can act as central nervous system depressants and are
used as sedatives and hypnotics. In our opinion, this method
may be used as a platform for new drug screening in the
future.
In conclusion, we have reported a successful method for
the construction of cyclopenta[c]chromene structures
through an intramolecular [3+2] cycloaddition of cyclopro-
pane 1,1-diesters with alkynes in good to excellent yields in
a single step. The efficiency and functional-group tolerance
of this procedure have been demonstrated by synthesizing
a variety of substituted cyclopenta[c]chromenes, for which
truly general synthetic methods are scarce. The products are
expected to be useful intermediates for the preparation of
biologically active compounds and drugs. Our developed
protocol can be used to prepare useful barbituric acid deriv-
atives in acceptable yields.
Entry
R1
R2
Ar
Product
Yield [%][b]
1
2
3
4
5
6
7
8
H
H
Et
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
2a
2b
2c
2d
2e
2 f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
2q
68
73
69
72
70
81
62
65
57
48
60
41
94
63
74
57
77
Me
Me
Et
Me
Me
Me
Et
5-Me
5-MeO
5-tBu
3,5-di-Me
3,5-di-tBu
5-Cl
3-tBu
3-MeO
3-Br
6-Me
H
9
Et
10
11
12
13
14
15
16
17
Me
Me
Me
Me
Me
Et
4-MeO-C6H4
3-Me-C6H4
2-MeO-C6H4
4-Cl-C6H4
thienyl
H
H
H
H
Me
Me
18
2r
83
[c]
19
20
–
–
–
Experimental Section
General Procedure for the Preparation of 2a–2r
Cyclopropane 1,1-diester 1a (0.2 mmol, 78.4 mg), ScACTHNUGTRENUNG(OTf)3 (0.02 mmol,
7.8 mg), 4 ꢂ molecular sieves (50 mg), and (CH2)2Cl2 (2 mL) were added
to a test tube, then the mixture was allowed to stir at 758C. When the re-
action was considered complete as determined by TLC analysis, ethyl
acetate (20 mL) and water (20 mL) were then added to the reaction mix-
ture. The organic layer was extracted with ethyl acetate (2ꢃ20 mL). The
combined organic phases were washed with brine and dried over sodium
sulfate. The residue was purified by flash chromatography on silica gel to
afford corresponding product 2a in 68% yield (53 mg).
[c]
–
[a] Standard reaction conditions: 1 (0.2 mmol), catalyst (10 mol%), and
50 mg of activated 4 ꢂ MS in 2 mL of DCE at 758C. [b] Yields of isolat-
ed products. [c] No product.
substituent was also tolerated and the corresponding prod-
uct 2q was isolated in 77% yield. Aliphatic and terminal al-
kynes failed to give any desired [3+2] product (Table 2, en-
tries 19 and 20). Nitrogen-based functional groups are espe-
cially important in synthetic and medicinal chemistry. In this
respect, tetrahydroquinoline derivatives constitute an impor-
tant subclass of cyclic structures, which are the key structur-
Acknowledgements
We thank the National Science Foundation NSF 21072080, and the Fun-
damental Research Funds for the Central Universities (lzujbky-2011-151
and lzujbky-2010-k09) for financial support. We acknowledge National
Scheme 3. Transformation of the cyclopenta[c]chromene.
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Yong-Min Liang et al.
COMMUNICATION
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Keywords: alkynes
·
cycloaddition
·
cyclopenta[c]chromene · donor–acceptor cyclopropanes ·
lewis acids
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Received: February 3, 2012
Revised: February 24, 2012
Published online: && &&, 0000
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COMMUNICATION
Cycloaddition
Xiao-Feng Xia, Xian-Rong Song,
Xue-Yuan Liu,
Yong-Min Liang*
&&&& — &&&&
Lewis Acid-Catalyzed Intramolecular
[3+2] Cycloaddition of Cyclopropane
1,1-Diesters with Alkynes for the
Synthesis of Cyclopenta[c]chromene
Skeletons
An efficient method to construct cyclo-
penta[c]chromene skeletons by Lewis
acid-catalyzed intramolecular [3+2]
cycloaddition of cyclopropane 1,1-die-
sters with alkynes is presented. Two
new fused cycles can be formed in one
step in moderate to excellent yields
(up to 94%), and the products can be
converted into bioactive barbituric
acid derivatives (1) under simple reac-
tion conditions.
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