Benzofurans or isochromenes via the ring-opening cyclization of cyclopropene derivatives with organolithiums

Article abstract of DOI:10.1021/ol2032009

A new and efficient approach to benzocycles from cyclopropene derivatives is described. Deprotection by organolithiums and subsequent ring-opening cyclization of the related 2-cyclopropenyl phenyl or benzyl acetates generated benzofurans and isochromenes in one pot.

Full text of DOI:10.1021/ol2032009

ORGANIC
LETTERS
2012
Vol. 14, No. 3
720–723
Benzofurans or Isochromenes via the
Ring-Opening Cyclization of
Cyclopropene Derivatives with
Organolithiums
Yu Liu† and Shengming Ma*,†,‡
Shanghai Key Laboratory of Green Chemistry and Chemical Processes,
Department of Chemistry, East China Normal University, 3663 North Zhongshan Road,
Shanghai 200062, P. R. China, and State Key Laboratory of Organometallic Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Lu,
Shanghai 200032, P. R. China
masm@sioc.ac.cn
Received December 1, 2011
ABSTRACT
A new and efficient approach to benzocycles from cyclopropene derivatives is described. Deprotection by organolithiums and subsequent
ring-opening cyclization of the related 2-cyclopropenyl phenyl or benzyl acetates generated benzofurans and isochromenes in one pot.
Heterocyclic structures are prevalent in many natural
products, and many of them show interesting biological
activities. Particularly, benzofuran and isochromene are
two classes of important bicyclic heterocycles. For exam-
ple, benzofuran derivatives display potent biological prop-
erties such as antifungal1,2 and antibacterial3 activities, etc.
Isochromene derivatives were reported to be a series of
D1 agonists,4 alternethannoxins,5 etc. Cyclopropene deri-
vatives have attracted much attention in organic chemistry
due to their ready availability and the unique reactivities
arising from the highly strained structures.6,7 A ring-open-
ing reaction of cyclopropene derivatives offers an effi-
cient pathway to carbo-8 and heterocycles.9 Previously, we
have developed a novel IÀ- or BrÀ-triggered ring-opening
coupling reaction of cyclopropenes with organic halides
leading to polyfunctionalized 1-alkenyl halides with high
† East China Normal University.
‡ Chinese Academy of Sciences.
(1) Masubuchi, M.; Kawasaki, K.; Ebiike, H.; Ikeda, Y.; Tsujii, S.;
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r
10.1021/ol2032009
Published on Web 01/19/2012
2012 American Chemical Society

stereoselectivity (Scheme 1, eq 1, left).10 Further investigation
showed that Grignard reagents couldalsoleadtoring-opening
reactions of doubly activated cyclopropenes generating a series
of 2-(1-alkenyl)malonate-type derivatives as single stereo-
isomers (Scheme 1, eq 1, right).11 We reasoned that the
intramolecular process of such ring-opening reactions by a
heteroatom anion may lead to some useful functionalized
heterocycles (Scheme 1, eq 2). Here we wish to present such an
intramolecular oxygen-attacked ring-opening cyclization re-
action leading to a series of benzofurans and isochromenes
(Scheme 1, eq 3), which is different from the well-known
general method for those heterocycles via the transition-metal-
catalyzed annulation of ortho-alkynyl (or alkenyl) aryl or
benzyl alcohols or their derivatives (Scheme 1, eq 4).12 It
should be noted that the existing methods leading to benzo-
furans with 3-alkoxycarbonylmethyl groups mainly use benzo-
pyranones13 or benzofuranones14 as precursors; Inter- or in-
tramolecular Heck-type reactions have also been reported.15
protected compound dimethyl 2-(2-acetoxyphenyl)cyclo-
prop-2-ene-1,1-dicarboxylate 1a with 1.2 equiv of n-BuLi
at À20 °C, benzofuran 2a was formed directly together with a
byproduct which could not be separated by flash chroma-
tography (Table 1, entry 1). When the loading of n-BuLi
was increased to 2.5 equiv, both the yield and purity were
improved (Table 1, entry 2). Lowering the temperature
gave higher purity but with lower yields (Table 1, entries
2À5). So we tried to further increase the equivalent of
n-BuLi (Table 1, entries 6, 7, 10, 13, and 14); the result went
better until the loading was up to 6.0 equiv, giving 2a as a
single product in good yield (Table 1, entry 13). Examina-
tionofsolvent effectorother organolithium reagentsfailed
to show better results (Table 1, entries 8À12). Thus, it
requires 6.0 equiv of n-BuLi in THF at À60 °C to afford
2a in good yield as the only product, indicating that a large
excess of n-BuLi would guarantee good yield and selectiv-
ity. So wetried toadd 1aton-BuLislowly to ensurethatthe
organolithium reagent was in excess during the whole
addition process. This did work, as 4.0 equiv of n-BuLi
were enough to give a competitive result, generating 2a as
the only product in 72% yield (Table 1, entry 15). The
structure of the product 2a was further confirmed by X-ray
diffraction studies (Figure 1, left).17
Scheme 1. Ring-Opening Reactions of Cyclopropene Deriva-
tives and the Syntheses of Benzofurans
(12) For some reviews on such reactions, see: (a) Zeni, G.; Larock,
R. C. Chem. Rev. 2004, 104, 2285. (b) Patil, N. T.; Yamamoto, Y. Chem.
Rev. 2008, 108, 3395. (c) Luca, L. D.; Nieddu, G.; Porcheddu, A.;
Giacomelli, G. Curr. Med. Chem. 2009, 16, 1. (d) Majumdar, K. C.;
Chattopadhyay, B.; Maji, P. K.; Chattopadhyay, S. K.; Samanta, S.
Heterocycles 2010, 81, 517. (e) Heravi, M. M.; Fazeli, A. Heterocycles
2010, 81, 1979. (f) Sadig, J. E. R.; Willis, M. C. Synthesis 2011, 1. (g)
Cacchi, S.; Fabrizi, G.; Goggiamani, A. Org. Biomol. Chem. 2011, 9, 641.
When Y = alkoxyalkayl, see:Nakamura, I.; Mizushima, Y.; Yamamoto,
Y. J. Am. Chem. Soc. 2005, 127, 15022.
(13) (a) Dulenko, V. I.; Golyak, V. M.; Gubar, V. I.; Alekseev, N. N.
Chem. Heterocycl. Compd. 1979, 15, 815. (b) Crombie, L.; Jones,
R. C. F.; Palmer, C. J. J. Chem. Soc., Perkin Trans. 1 1987, 33. (c)
Piloto, A. M.; Costa, S. P. G; Goncalves, S. T. Tetrahedron Lett. 2005,
46, 4757. (d) Piloto, A. M.; Fonseca, A. S. C.; Costa, S. P. G; Goncalves,
S. T. Tetrahedron 2006, 62, 9258. (e) Filzen, G. F.; Bratton, L.; Cheng,
X.-M.; Erasga, N.; Geyer, A.; Lee, C.; Lu, G.; Pulaski, J.; Sorenson,
R. J.; Unangst, P. C.; Trivedi, B. K.; Xu, X. Bioorg. Med. Chem. Lett.
2007, 17, 3630.
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Olson, J. P.; Davies, H. M. L. Org. Lett. 2006, 10, 573. (c) Kozikowski,
A. P.; Gaisina, I. N.; Yuan, H.; Petukhov, P. A.; Blond, S. Y.; Fedolak,
A.; Caldarone, B.; McGonigle, P. J. Am. Chem. Soc. 2007, 129, 8238. (d)
Venkatesan, A. M.; Santos, O. D.; Ellingboe, J.; Evrard, D. A.;
Harrison, B. L.; Smith, D. L.; Scerni, R.; Hornby, G. A.; Schechter,
L. E.; Andree, T. H. Bioorg. Med. Chem. Lett. 2010, 20, 824.
(15) (a) Negishi, E.; Nguyen, T.; O’Connor, B. Heterocycles 1989, 28,
55. (b) Samizu, K.; Ogasawara, K. Heterocycles 1994, 38, 1745. (c)
Siqueira, F. A.; Taylor, J. G.; Correia, R. D. Tetrahedron Lett. 2010, 51,
2102. (d) Mavunkel, B. J.; Perumattam, J. J.; Tan, X.; Luedtke, G. R.;
Lu, Q.; Lim, D.; Kizer, D.; Dugar, S.; Chakravarty, S.; Xu, Y.; Jung, J.;
Liclican, A.; Levy, D. E.; Tabora, J. Bioorg. Med. Chem. Lett. 2010, 20,
1059.
At first, we synthesized tetrahydro-2H-pyran- and
acetoxy-protected phenol-substituted cyclopropenes, which
we thought, after deprotection, would be transformed
to benzofurans. However, we failed after trying several
deprotection reagents such as K2CO3, NaHCO3, LiOH,
PPTS, etc.16 Interestingly, when we tried to treat the
(16) For some reports on the corresponding deproteciton methods
for tetrahydro-2H-pyran- and acetoxy-protected compounds, see: (a)
Shashidhar, M. S.; Bhatt, M. V. J. Chem. Soc., Chem. Commun. 1987, 9,
654. (b) Montforts, F.-P.; Zibulak, I. G.; Grammenos, W.; Schneider,
M.; Laumen, K. Helv. Chim. Acta 1989, 72, 1852. (c) Crisp, G. T.;
Bubner, T. P. Tetrahedron 1997, 53, 11899.
(9) For some recent examples on ring-openning reactions of cyclo-
propene derivatives affording heterocycles, see: (a) Ma, S.; Zhang, J.
J. Am. Chem. Soc. 2003, 125, 12386. (b) Muler, P.; Allenbach, Y. F.;
Bernardinelli, G. Helv. Chim. Acta 2003, 86, 3164. (c) Chuprakov, S.;
Gevorgyan, V. Org. Lett. 2007, 9, 4463. (d) Diev, V. V.; Stetsenko, O. N.;
Tung, T. Q.; Kopf, J.; Kostikov, R. R.; Molchanov, A. P. J. Org. Chem.
2008, 73, 2396. (e) Chen, S.; Ren, J.; Wang, Z. Tetrahedron 2009, 65,
9146. (f) Miege, F.; Meyer, C.; Cossy, J. Org. Lett. 2010, 12, 248. (g) Zhu,
Z.-B.; Shi, M. Org. Lett. 2010, 12, 4462. (h) Lyaskovskyy, V.; Elders, N.;
Ehlers, A. W.; Lutz, M.; Slootweg, J. C.; Lammertsma, K. J. Am. Chem.
Soc. 2011, 133, 9704.
(17) Crystal data for 2a: C13H12O5, MW = 248.23, Monoclinic,
space group P2(1), Final R indices [I > 2σ(I)], R1 = 0.0299, wR2 =
˚
0.0825, R indices (all data) R1 = 0.0304, wR2 = 0.0834, a = 6.8563(2) A,
˚
˚
b = 8.0054(2) A, c = 11.0535(3) A, R = 90°, β = 102.3850°, γ = 90°,
V = 592.58(3) A , T = 123(2) K, Z = 2, reflections collected/unique:
3
˚
14594/2217 (Rint = 0.0288), number of observations [>2σ(I)] 1107,
parameters: 163. CCDC 832369. For crystallographic data in CIF or other
electronic format see Supporting Information.
(10) Ma, S.; Zhang, J.; Cai, Y.; Lu, L. J. Am. Chem. Soc. 2003, 125, 13954.
(11) Liu, Y.; Ma, S. Chem. Sci. 2011, 2, 811.
Org. Lett., Vol. 14, No. 3, 2012
721

(entries 3 and 7). It should be noted that, in all the cases
presented in Table 2, the reaction afforded 2 exclusively.
Table 1. Optimization of Conditionsa
Table 2. Scope of n-BuLi Participated Ring-Opening Cycliza-
tion Reaction of 2-Acetoxyphenyl Cyclopropenesa
isolated
yield of
2a (%)
purity
of 2ab
(%)
organolithium
(equiv)
conditions
solv/temp
entry
1
n-BuLi (1.2)
n-BuLi (2.5)
n-BuLi (2.5)
n-BuLi (2.5)
n-BuLi (2.5)
n-BuLi (3.5)
n-BuLi (5.0)
n-BuLi (5.0)
n-BuLi (5.0)
n-BuLi (5.5)
MeLi (5.5)
THF/À20 °C
THF/À20 °C
THF/0 °C
21
38
28
22
20
52
60
19
11c
67
61
39
73
73
72
81
isolated
yield
2
87
3
84
entry
R1
R2
R3
of 2 (%)
4
THF/À60 °C
THF/À80 °C
THF/À60 °C
THF/À60 °C
CH2Cl2/À60 °C
Et2O/À60 °C
THF/À60 °C
THF/À60 °C
THF/À60 °C
THF/À60 °C
THF/À60 °C
THF/À60 °C
94
5
100
100
100
66
1
H
CO2Me (1a)
Ph (1b)
CO2Me
CO2Me
CO2Et
CO2Me
CO2Me
CO2Me
CO2Et
CO2Me
CO2Me
CO2Me
72 (2a)
48 (2b)
44 (2c)
53 (2d)
67 (2e)
67 (2f)
59 (2g)
60 (2h)
64 (2i)
69 (2j)
6
2
H
7
3
H
SO2Ph (1c)
CO2Me (1d)
CO2Me (1e)
CO2Me (1f)
SO2Ph (1g)
CO2Me (1h)
Ph (1i)
8
4
5-Me
4-Me
5-Cl
5-Cl
4-Cl
4-Cl
4-F
9
84
5
10
11
12
13
14
15d
100
100
100
100
100
100
6
7
t-BuLi (5.5)
n-BuLi (6.0)
n-BuLi (9.0)
n-BuLi (4.0)
8
9b
10
CO2Me (1j)
a A solution of 1 (0.25 mol) in 3 mL of THF was added dropwise to a
solution of n-BuLi (1.0 mol, 2.5 M in hexane, 0.4 mL) in 1 mL of THF
at À60 °C around 10 min and quenched with saturated NH4Cl after
another 45 min. b An unidentified byproduct was isolated.
a Procedures unless noted: the organolithium was added to a solution of
1a in THF at the indicated temperature and quenched with saturated NH4Cl
after 45 min. b An unkown product was formed. The purity was determined
based on 1H NMR analysis on the integration of the methoxy groups. c NMR
yield. d A solution of 1a in THF was added dropwise to a solution of n-BuLi in
10 min and was quenched with saturated NH4Cl after another 55 min.
Furthermore, the reaction with 2-acetoxymethylphenyl
cyclopropenes 3k and 3l also worked very well under the
optimized conditions to give isochromenes 4k and 4l in
moderate yield (Scheme 2). The structure of 4k was also
confirmed by X-ray diffraction studies (Figure 1, right).18
Scheme 2. Syntheses of Isochromenes
Figure 1. X-ray diffraction studies of 2a (left) and 4k (right).
With the optimized conditions, the generality of the
reaction was examined (Table 2): Substituents such as
methyl (entries 4 and 5), a chlorine atom (entries 6À9),
or fluorine atom (entry 10) may be introduced to the
phenyl group. For the cyclopropene moiety, in addition
to the alkoxycarbonyl group (R3), R2 may be CO2Me
(entries 1, 4À6, 8, 10), Ph (entries 2 and 9), and SO2Ph
A deuterium experiment was conducted to probe
the mechanism (Scheme 3): quenching the reaction of
1a and 4.0 equiv of n-BuLi at À60 °C with AcOD
afforded the double-deuterated product 2a-dd. The
sp3 carbon was 98% deuterated as judged by 1H
NMR analysis of the crude product. This deuteration
disappeared during chromatographic purification,
which was caused by the smooth exchange of this acidic
D-atom with the H-atom from the environment. The
(18) Crystal data for 4k: C14H14O5, MW = 262.25, Orthorhombic,
space group P2(1)2(1)2(1), Final R indices [I > 2σ(I)], R1 = 0.0310,
wR2 = 0.0751, R indices (all data) R1 = 0.0342, wR2 = 0.0775,
˚
˚
˚
a = 8.0662(3) A, b = 8.5553(3) A, c = 18.2403(6) A, R = 90°, β = 90°,
3
˚
γ = 90°, V = 1258.74(8) A , T = 173(2) K, Z = 4, reflections collected/
unique: 6870/1126 (Rint = 0.0155), number of observations [>2σ(I)]
2072, parameters: 172. CCDC 832370. For crystallographic data in CIF
or other electronic format see Supporting Information.
722
Org. Lett., Vol. 14, No. 3, 2012

deutaration at the 2-position of the furan moiety was
70%. This result indicated that a dianion interme-
diate D was formed together with the intermediate C
(Scheme 4).
naphthyl (entries 2 and 6), and p-methoxyphenyl group
(entries 2 and 5) could all be introduced into the pro-
ducts, generating aryl substituted benzofurans 5 in good to
excellent yields.
Table 3. Suzuki Coupling Reactions of the Benzofurans Con-
taining CÀCl Bonds
Scheme 3. Deuterium Experiment
Accordingly, we propose the following mechanism
(Scheme 4): the reaction of 1a with n-BuLi forms the
intermediate A. The oxygen anion in A may attack the
cyclopropene moiety generating the benzofuranyl anion C.
Alternatively, anexcessofn-BuLimay furtherdeprotonate
the olefinic proton11 to generate dianion B, which may also
undergo ring-opening cyclization forming the benzofu-
ranyl dianion D. The reaction of intermediates C and D
with AcOD would form 2a-dd.
K3PO4
(equiv)/temp (°C)/
time (h)
isolated
yield of
5 (%)
entry
2
Ar
1
2
3
4
5
6
2f
2f
2f
2i
2i
2i
2.0/80/6
2.0/80/10
2.0/80/6
3.5/110/8
3.5/110/5
3.5/110/5
Ph
84 (5fa)
91 (5fb)
75 (5 fc)
86 (5ia)
87 (5ib)
84 (5ic)
p-MeOC6H4
2-naphthyl
Ph
p-MeOC6H4
2-naphthyl
Inconclusion, wehavedevelopedanefficient method for
the synthesis of benzofuran and isochromene derivatives
with moderate to good yields and an excellent selectivity
from the treatment of 2-acetyl or 2-acetoxymethyl cyclo-
propenes with n-BuLi. The benzofurans containing CÀCl
bonds could be further transformed to aryl substituted
compounds by Suzuki coupling reactions. The reaction
will be useful in organic synthesis and medicinal chemistry.
Further study in this area such as preparing other types of
useful heterocycles is being pursued in this laboratory.
Scheme 4. A Plausible Mechanism
Acknowledgment. Financial support from the National
Natural Science Foundation of China (21172192) and the
National Basic Research Program of China (2011CB808700)
is greatly appreciated. We thank Mr. R. Zeng in this group for
reproducing the results of the preparation of 2e, 5l, and 6ia.
Further studies showed that the benzofurans 2 contain-
ing CÀCl bonds in the aryl group could be applied to
our previously reported Suzuki coupling reaction19 with
LB-phos as the ligand (Table 3). A phenyl (entries 1 and 4),
Supporting Information Available. Analytical data for
all products not listed in the text. This material is available
free of charge via the Internet at http://pubs.acs.org.
€
€
(19) (a) Lu, B.; Fu, C.; Ma, S. Chem.;Eur. J. 2010, 16, 6434. (b) Lu,
€
B.; Fu, C.; Ma, S. Tetrahedron Lett. 2010, 51, 1284. (c) Lu, B.; Li, P.; Fu,
C.; Xue, L.; Lin, Z.; Ma, S. Adv. Synth. Catal. 2011, 353, 100.
Org. Lett., Vol. 14, No. 3, 2012
723