Lewis acid-mediated reactions of 1-cyclopropyl-2-arylethanone derivatives with allenic ester, ethyl acetoacetate, and methyl acrylate

Article abstract of DOI:10.1021/jo800608h

(Chemical Equation Presented) TMSOTf-mediated reactions of 2-aryl-1-(1-phenylcyclopropyl)ethanones 1 with allenic esters afford a novel method for the synthesis of 6-methyl-3a,7-diaryl-3,3a-dihydro-2H-benzofuran-4- one derivatives 2 in moderate yields. In addition, we also found that TMSOTf-mediated reactions of 1-cyclopropyl-2-arylethanones with ethyl acetoacetate can provide the corresponding 2,3-dihydrobenzofuran-4-ol and dihydrofuro[2,3-h]chromen-2-one in moderate yields via a sequential reaction involving a nucleophilic ring-opening reaction of the cyclopropane by H ₂O, one intermolecular aldol type reaction and two intramolecular aldol type reactions, a cyclic transesterification, dehydration, and aromatization. Moreover, by using methyl acrylate to replace allenic ester, the corresponding 7-aryl-3,5,6,7-tetrahydro-2H-benzofuran-4-one and 5-aryl-3,5,6,7-tetrahydro-2H-benzofuran-4-one can be formed in moderate to high yields in the presence of Bi(OTf)₂Cl. Plausible reaction mechanisms have also been provided on the basis of control experiments.

Full text of DOI:10.1021/jo800608h

Lewis Acid-Mediated Reactions of 1-Cyclopropyl-2-arylethanone
Derivatives with Allenic Ester, Ethyl Acetoacetate, and Methyl
Acrylate
Min Shi,* Xiang-Ying Tang, and Yong-Hua Yang
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China
mshi@mail.sioc.ac.cn
ReceiVed March 18, 2008
TMSOTf-mediated reactions of 2-aryl-1-(1-phenylcyclopropyl)ethanones 1 with allenic esters afford a
novel method for the synthesis of 6-methyl-3a,7-diaryl-3,3a-dihydro-2H-benzofuran-4-one derivatives 2
in moderate yields. In addition, we also found that TMSOTf-mediated reactions of 1-cyclopropyl-2-
arylethanones with ethyl acetoacetate can provide the corresponding 2,3-dihydrobenzofuran-4-ol and
dihydrofuro[2,3-h]chromen-2-one in moderate yields via a sequential reaction involving a nucleophilic
ring-opening reaction of the cyclopropane by H2O, one intermolecular aldol type reaction and two
intramolecular aldol type reactions, a cyclic transesterification, dehydration, and aromatization. Moreover,
by using methyl acrylate to replace allenic ester, the corresponding 7-aryl-3,5,6,7-tetrahydro-2H-
benzofuran-4-one and 5-aryl-3,5,6,7-tetrahydro-2H-benzofuran-4-one can be formed in moderate to high
yields in the presence of Bi(OTf)2Cl. Plausible reaction mechanisms have also been provided on the
basis of control experiments.
Introduction
furo[2,3-h]chromen-2-one and 2,3-dihydrobenzofuran-4-ol
derivatives in moderate to good yields under mild conditions
Cyclopropane-containing compounds, as versatile building
blocks in organic synthesis, have been well understood.1 The
ring-opening reactions of cyclopropyl ketones are syntheti-
cally useful reactions that have been studied extensively.2
Previously, we reported SnCl4 and trimethylsilyl trifluo-
romethanesulfonate (TMSOTf)-mediated reactions of cyclo-
propyl alkyl ketones with R-ketoesters and allenic esters to
affordnovelmethodsforthesynthesisof1,6-dioxaspiro[4.4]non-
3-en-2-ones with high stereoselectivities as well as dihydro-
(1) (a) Reissig, H.-U.; Zimmer, R. Chem. ReV. 2003, 103, 1151. (b) Paquette,
L. A. Chem. ReV. 1986, 86, 733. (c) Wong, H. N. C.; Hon, M.-Y.; Tse, C.-W.;
Yip, Y.-C.; Tanko, J.; Hudlicky, T. Chem. ReV. 1989, 89, 165. (d) de Meijere,
A.; Wessjohann, L. Synlett 1990, 20. (e) Kulinkovich, O. G. Russ. Chem. ReV.
1993, 62, 839. (f) Kulinkovich, O. G. Pol. J. Chem. 1997, 849. (g) Wenkert, E.
Acc. Chem. Res. 1980, 13, 27. (h) Wenkert, E. Heterocycles 1980, 14, 1703. (i)
Seebach, D. Angew. Chem. 1979, 91, 259. . Angew. Chem., Int. Ed. Engl. 1979,
18, 239. (j) Gnad, F.; Reiser, O. Chem. ReV. 2003, 103, 1603. (k) de Meijere,
A.; Kozhushkov, S. I. Eur. J. Org. Chem. 2000, 3809. (l) de Meijere, A.;
Kozhushkov, S. I.; Khlebnikov, A. F. Top. Curr. Chem. 2000, 207, 89. (m) de
Meijere, A.; Kozhushkov, S. I.; Hadjiarapoglou, L. P. Top. Curr. Chem. 2000,
207, 149. (n) Danishefsky, S. Acc. Chem. Res. 1979, 12, 66. (o) Avilov, D. V.;
Malusare, M. G.; Arslancan, E.; Dittmer, D. C. Org. Lett. 2004, 6, 2225.
* Corresponding author. Fax: 86-21-64166128.
10.1021/jo800608h CCC: $40.75
Published on Web 06/21/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 5311–5318 5311

Shi et al.
SCHEME 1. SnCl4 and TMSOTf-Mediated Reactions of 1-Cyclopropyl-2-arylethanones with r-Ketoesters and Allenic Esters
SCHEME 2. Mechanism for the Formation of 6-Methyl-3a,7-diphenyl-3,3a-dihydro-2H-benzofuran-4-one Derivative 2
(Scheme 1).3 In this paper, we wish to report the full details
on the Lewis acid-mediated reactions of 1-cyclopropyl-2-
arylethanone derivatives with allenic ester, ethyl acetoacetate,
and methyl acrylate for the construction of dihydrofuro[2,3-
h]chromen-2-one, 2,3-dihydrobenzofuran-4-ol, 6-methyl-3a,7-
diphenyl-3,3a-dihydro-2H-benzofuran-4-one, and 7-aryl-
3,5,6,7-tetrahydro-2H-benzofuran-4-one skeletons along with
the detailed mechanistic investigations.
2-one and 2,3-dihydrobenzofuran-4-ol derivatives has been
proposed on the basis of a ring-opening reaction of 1-cyclo-
propyl-2-arylethanone, intermolecular and intramolecular
aldol reactions as well as aromatization (also see Scheme
3).3b To get more mechanistic insight into this reaction, we
decided to use 2-phenyl-1-(1-phenylcyclopropyl)ethanone 1a
instead of 1-cyclopropyl-2-arylethanone to react with allenic
ester under the standard conditions because we assumed that
the substituent at the cyclopropane could block out one side
of the aldol-type reaction, subsequently affording one product
regioselectively.
Results and Discussion
As shown in our previous communication, a plausible
Initial examination revealed that the reaction of 2-phenyl-
1-(1-phenylcyclopropyl)ethanone 1a with allenic ester pro-
ceeded smoothly in 1,2-dichloroethane (DCE) at 60 °C to
give the corresponding 6-methyl-3a,7-diphenyl-3,3a-dihydro-
2H-benzofuran-4-one derivative 2a in 41% yield in the
presence of TMSOTf (1.0 equiv) within 15 h (Table 1, entry
1). We further attempted to optimize the reaction conditions
by use of other Lewis acids and find out the best solvent in
this reaction. The results of these experiments are summarized
in Tables 1 and 2, respectively. As can be seen from Tables
1 and 2, changing Lewis acid and solvent did not significantly
improve the yield of 2a. Using Brønsted acid trifluo-
romethanesulfonic acid CF3SO3H (HOTf) as a promoter
afforded 2a in 36% yield in DCE (Table 1, entry 4). The
best conditions are to carry out the reaction in DCE at 60 °C
with TMSOTf as a Lewis acid (Table 1, entry 1). With these
optimal conditions being identified, we next attempted to
examine the scope and limitations of this reaction using a
mechanism for the formation of dihydrofuro[2,3-h]chromen-
(2) (a) Binger, P.; Bu¨ch, H. M. Cyclopropenes and Methylenecyclopropanes
as Multifunctional Reagents. In Transition Metal Catalyzed Reactions. In Topics
in Current Chemistry; de Meijere, A., Ed.; Springer-Verlag: Berlin, Germany,
1987; Vol. 135, pp 109-131. (b) Noyori, R.; Odagi, T.; Takaya, H. J. Am. Chem.
Soc. 1970, 92, 5780. (c) Lewis, R. T.; Motherwell, W. B.; Shipman, M. J. Chem.
Soc., Chem. Commun. 1988, 948. (d) Lautens, M.; Ren, Y. J. Am. Chem. Soc.
1996, 118, 9597, and references cited therein. (e) Liu, L.; Montgomery, J. J. Am.
Chem. Soc. 2006, 128, 5348. (f) Han, Z.; Uehira, S.; Tsuritani, T.; Shinokubo,
H.; Oshima, K. Tetrahedron 2001, 57, 987. (g) Alper, P. B.; Meyers, C.; Lerchner,
A.; Siegel, D. R.; Carreira, E. M. Angew. Chem., Int. Ed. Engl. 1999, 38, 3186.
(h) Smith, A. B., III; Scarborough, R. M. Tetrahedron Lett. 1978, 19, 1649. (i)
Ogoshi, H.; Setsune, J.-I.; Yoshida, Z.-I. J. Organomet. Chem. 1980, 185, 95.
(j) Ogoshi, H.; Kikuchi, Y.; Yamaguchi, T.; Toi, H.; Aoyama, Y. Organometallics
1987, 6, 2175. (k) Hwu, R. J. J. Chem. Soc., Chem. Commun. 1985, 452. (l)
Bertozzi, F.; Gustafsson, M.; Olsson, R. Org. Lett. 2002, 4, 3147. (m) Bertozzi,
F.; Gustafsson, M.; Olsson, R. Org. Lett. 2002, 4, 4333. (n) Lautens, M.; Han,
W. J. Am. Chem. Soc. 2002, 124, 6312. (o) Lautens, M.; Han, W.; Liu, J. H.-C.
J. Am. Chem. Soc. 2003, 125, 4028. (p) Scott, M. E.; Han, W.; Lautens, M.
Org. Lett. 2004, 6, 3309.
(3) (a) Yang, Y.-H.; Shi, M. Org. Lett. 2006, 8, 1709. (b) Shi, M.; Tang,
X.-Y.; Yang, Y.-H. Org. Lett. 2007, 9, 4017.
5312 J. Org. Chem. Vol. 73, No. 14, 2008

Reactions of 1-Cyclopropyl-2-arylethanone DeriVatiVes
TABLE 1. Lewis Acid-Mediated Reactions of
2-Phenyl-1-(1-phenylcyclopropyl)ethanone 1a with Allenic Ester
TABLE 3. Generality on the TMSOTf-Mediated Reactions of
2-Aryl-1-(1-phenylcyclopropyl)ethanone 1 with Allenic Ester under
Optimal Conditions
entry
Lewis acid
yield [%]a of 2a
entry
Ar
yield [%]a of 2
1
2
3
4
5
TMSOTf
Zr(OTf)4
Sc(OTf)3
HOTf
41
12
trace
36
23
1
2
3
4
5
6
7
1b, p-ClC6H4
1c, p-MeC6H4
1d, p-BrC6H4
1e, o-BrC6H4
1f, p-FC6H4
1g, m-FC6H4
1h, o-ClC6H4
2b, 33
2c, 36
2d, 54
2e, 22
2f, 31
2g, 32
2h, 25
Bi(OTf)2Cl
a Isolated yields.
TABLE 2. Solvent Effects on the TMSOTf-Mediated Reactions of
2-Phenyl-1-(1-phenylcyclopropyl)ethanone 1a with Allenic Ester
a Isolated yields.
D, E, and F (Scheme 4 and also see Scheme 5). Therefore,
we examined the Lewis acid-mediated reactions of 1-cyclo-
propyl-2-phenylethanone 1i with ethyl acetoacetate under the
standard conditions. The results of these experiments are
summarized in Table 4. Using SnCl4 as a Lewis acid (1.0
equiv) to react with ethyl acetoacetate (1.5 equiv) indeed
afforded 3a in 20% in DCE at 60 °C (Table 4, entry 1).
BF3 · OEt2 did not catalyze this reaction under similar
conditions (Table 4, entry 2). Using TMSOTf (1.0 equiv) as
a Lewis acid to react with ethyl acetoacetate (1.5 equiv)
produced 3a in 45% yield at 60 °C in DCE, which are the
best reaction conditions for the preparation of 3a as shown
in Table 4 since increasing or decreasing the employed
amounts of ethyl acetoacetate and TMSOTf did not further
improve the yields of 3a under otherwise identical conditions
(Table 4, entries 3-8).
Under these optimal conditions, we next examined many
other 1-cyclopropyl-2-arylethanones 1j-o with ethyl ac-
etoacetate and the results of these experiments are outlined
in Table 5. As can be seen from Table 5, the corresponding
2,3-dihydrobenzofuran-4-ol derivatives 3 were obtained in
moderate yields, although as for 1-cyclopropyl-2-aryletha-
nones 1n and 1o bearing an electron-donating group on the
benzene ring, the corresponding 2,3-dihydrobenzofuran-4-
ol derivatives 3f and 3g were obtained in 22% and 20%
yields, respectively, presumably due to the electron-rich
aromatic moiety not favoring the aldol-type reaction of the
key intermediate A′ with ethyl acetoacetate shown in Scheme
4 (Table 5, entries 6 and 7).
When using a large excess amount of ethyl acetoacetate
(4.5 equiv) in this reaction under identical conditions, the
corresponding dihydrofuro[2,3-h]chromen-2-one derivative
4a was formed in 24% yield along with the formation of 3a
in 36% yield (Scheme 5). The structure of 4a was further
confirmed by an X-ray diffraction. Its CIF data and ORTEP
drawing are presented in the Supporting Information. A
plausible mechanism has been also shown in Scheme 5 via
intermediates D, G, H, and I, which is very similar as the
plausible mechanism shown in Scheme 3 in the TMSOTf-
mediated reactions of 1-cyclopropyl-2-arylethanones 1 with
allenic ester.
entry
solvent
yield [%]a of 2a
1
2
3
4
toluene
CH3CN
THF
30b
complex
N.R.
33
DCM
a Isolated yields. b The reaction temperature was 100 °C.
variety of 2-aryl-1-(1-phenylcyclopropyl)ethanones 1 as the
substrates. The results are summarized in Table 3. The
corresponding products 2 were obtained in 22-54% yields
(Table 3, entries 1-7). The low to moderate yields of this
TMSOTf-mediated transformation are presumably due to
some unidentified byproduct being formed during this tandem
reaction process since some small spots could be recognized
by TLC plates along with the major products 2. Their
structures were determined by spectroscopic data, HRMS,
and microanalyses (see the Supporting Information).
Furthermore, the X-ray crystal structure of 2c was determined
and its CIF data and ORTEP drawing are presented in the
Supporting Information. A plausible reaction mechanism for the
formation of 2 has been outlined in Scheme 2 via intermediates
A, B, and C similarly as we reported in the previous paper (also
see Scheme 3).3b This result suggests that the first aldol-type
reaction with allenic ester indeed takes place from the CR position
in intermediate A preferentially to afford intermediate B and the
next aldol-type reaction from the CR′ position in intermediate B
would be favored by the phenyl substituent under thermodynami-
cally controlled conditions (60 °C in DCE). The phenyl substituent
at the R′-position can suppress the aromatization process. Therefore,
compound 2 could be isolated as the major product.
Interestingly, if we reconsider the reaction mechanism for
the formation of 2,3-dihydrobenzofuran-4-ol derivative 3 and
dihydrofuro[2,3-h]chromen-2-one 4 shown in Scheme 3 in
the TMSOTf-mediated reactions of 1-cyclopropyl-2-aryle-
thanone 1 with allenic ester via intermediates A′-G′ in our
previous paper,3b it is conceivable that using ethyl acetoac-
etate instead of allenic ester could also afford 2,3-dihy-
drobenzofuran-4-olderivative3anddihydrofuro[2,3-h]chromen-
2-one 4 in the TMSOTf-mediated reaction with 1-cyclopropyl-
2-arylethanone 1 under identical conditions since the plausible
reaction mechanism could be very similar via intermediates
To confirm the reaction intermediate A or A′ involved in the
above reactions as shown in Schemes 2–5, we attempted to
directly prepare 5-hydroxy-1-phenylpentan-2-one (intermediate
A′) by another synthetic method and utilize it as the substrate
J. Org. Chem. Vol. 73, No. 14, 2008 5313

Shi et al.
SCHEME 3. Reaction Mechanism on the Formation of Dihydrofuro[2,3-h]chromen-2-one and 2,3-Dihydrobenzofuran-4-ol
Derivatives in the Reaction of 1-Cyclopropyl-2-arylethanones with Allenic Ester
SCHEME 4. TMSOTf-Mediated Reaction of 1-Cyclopropyl-2-arylethanone 1i with Ethyl Acetoacetate and the Plausible
Reaction Mechanism
under these reaction conditions. According to the previous
literature,4 we first prepared 2-benzylidenetetrahydrofuran from
lithiation of 2,3-dihydrofuran with n-butyllithium in THF and
its reaction with benzyl bromide (Scheme 6). The obtained
2-benzylidenetetrahydrofuran (30% yield) was hydrolyzed by
aqueous hydrochloric acid (20% w/w) to afford 5-hydroxy-1-
phenylpentan-2-one in 95% yield (Scheme 6). The control
experiment indicated that when using 5-hydroxy-1-phenylpen-
(4) Helma, M. B.; Alex, B. S.; Jan, C. Tetrahedron 1995, 51, 7495.
5314 J. Org. Chem. Vol. 73, No. 14, 2008

Reactions of 1-Cyclopropyl-2-arylethanone DeriVatiVes
SCHEME 5. Reaction of 1i with Ethyl Acetoacetate (4.5 equiv) in the Presence of TMSOTf and the Plausible Reaction
Mechanism
TABLE 4. Lewis Acid-Mediated Reactions of
1-Cyclopropyl-2-arylethanone 1i with Ethyl Acetoacetate
respectively, suggesting that 5-hydroxy-1-phenylpentan-2-one
(intermediate A′) could be the reaction intermediate in the above
reactions shown in Schemes 2–5 (Scheme 6).
On the basis of these control experiments, we can conclude
that the tandem reaction pathways shown in Schemes 2–5
for the formation of 6-methyl-3a,7-diphenyl-3,3a-dihydro-
2H-benzofuran-4-one, dihydrofuro[2,3-h]chromen-2-one, and
2,3-dihydrobenzofuran-4-ol derivatives are reasonable and
the Lewis acid-mediated ring-opening reaction of 1-cyclo-
propyl-2-arylethanone, intermolecular and intramolecular
aldol reactions as well as aromatization are responsible for
these transformations.
entry
x
Lewis acid
solvent
yield [%]a of 3
1
2
3
4
5
6
7
8
1.5
1.5
1.5
1.5
1.0
2.0
4.5
0.5
SnCl4 (1.0 equiv)
DCE
DCE
DCE
toluene
DCE
DCE
DCE
DCE
20
0
BF3 ·Et2O (1.0 equiv)
TMSOTf (1.0 equiv)
TMSOTf (1.0 equiv)
TMSOTf (2.0 equiv)
TMSOTf (2.0 equiv)
TMSOTf (4.0 equiv)
TMSOTf (1.0 equiv)
45
22
30
37
37
30
Moreover, we also attempted to explore the Lewis acid-
mediated reactions of 1-cyclopropyl-2-arylethanones 1j-o
with methyl acrylate since we envision that a similar reaction
pathway might be able to take place to provide interesting
cyclized products as well. Using 1-cyclopropyl-2-(p-chlo-
rophenyl)ethanone 1j as the substrate, we initially examined
the reactions with methyl acrylate in the presence of various
Lewis acids to find out the best one in this transformation
and the results of these experiments are summarized in Table
6. As can be seen, 7-(p-chlorophenyl)-3,5,6,7-tetrahydro-2H-
benzofuran-4-one 5a and 5-(p-chlorophenyl)-3,5,6,7-tetrahy-
dro-2H-benzofuran-4-one 6a were obtained in 88% total yield
as mixtures of regioisomers in the presence of Bi(OTf)2Cl
(1.0 equiv) in DCE at 60 °C without addition of extra water
(Table 6, entry 5). Other Lewis acids such as Bi(OTf)3,
Gd(OTf)3, Nd(OTf)3, and TMSOTf and Brønsted acid HOTf
are not as effective as Bi(OTf)2Cl under identical conditions
even in the presence of water (Table 6, entries 1-6).
BF3 · OEt2, La(OTf)3, Cu(OTf)2, and AlCl3 did not catalyze
this reaction under the standard conditions (Table 6, entries
7-10). To further optimize the reaction conditions, we next
examined the solvent effects using Bi(OTf)2Cl as a Lewis
acid, and the results of these experiments are shown in Table
7. As can be seen, when the reaction was carried out in
a Isolated yield.
TABLE 5. TMSOTf-Mediated Reactions of Various
1-Cyclopropyl-2-arylethanones 1 with Ethyl Acetoacetate
entry
Ar
yield [%]a of 3
1
2
3
4
5
6
7
1i, C6H5
3a, 45
3b, 49
3c, 40
3d, 37
3e, 33
3f, 22
3g, 20
1j, p-ClC6H4
1k, p-BrC6H4
1l, m-BrC6H4
1m, m-FC6H4
1n, m-MeC6H4
1o, p-MeC6H4
a Isolated yield.
tan-2-one (intermediate A′) as the substrate to react with allenic
ester under the standard reaction conditions, the corresponding
products 3a and 4a were indeed formed in 6% and 24% yields,
J. Org. Chem. Vol. 73, No. 14, 2008 5315

Shi et al.
TABLE 6. Lewis Acid-Mediated Reactions of 1-Cyclopropyl-2-(p-chlorophenyl)ethanone 1j with Methyl Acrylate
entry
Lewis acid
yield [%]a of (5a:6a)
1
2
Bi(OTf)3 ·9H2O
HOTf
76c (3.1:1)
59 (3.9:1)
3
4
5
6
7
8
9
10
Gd(OTf)3
Nd(OTf)3
Bi(OTf)2Cl
TMSOTf
BF3 ·Et2O
La(OTf)3
Cu(OTf)2
AlCl3
44 (1.8:1)
15b
88c (5.1:1)
55 (1.7:1)
0
0
0
0
a Isolated yields. b Trace of 6a was obtained. c No water was added.
SCHEME 6. A Control Experiment
TABLE 7. Solvent Effects in the Bi(OTf)2Cl-Mediated Reactions of 1-Cyclopropyl-2-phenylethanone 1j with Methyl Acrylate
entry
solvent
toluene
yield [%]a of (5a:6a)
1
2
3
4
5
6
7
73 (2.9:1)
no reaction
42 (5.2:1)
61 (2.6:1)
32b
MeCN
chlorobenzene
hexane
DCM
toluene
THF
45c (5.6:1)
no reaction
a Isolated yields. b Trace of 6a was obtained. c The reaction temperature was raised to 110 °C.
toluene, chlorobenzene, hexane, or DCM, 5a and 6a were
obtained in lower yields (Table 7, entries 1 and 3-5). Using
acetonitrile (MeCN) or tetrahydrofuran (THF) as the solvent,
no reaction occurred (Table 7, entries 2 and 7). Even in
toluene under reflux, 5a and 6a were obtained in 45% total
yield (Table 7, entry 6). Therefore, the best conditions are
to conduct the reaction in DCE using Bi(OTf)2Cl as a Lewis
acid at 60 °C without addition of extra water.
5316 J. Org. Chem. Vol. 73, No. 14, 2008

Reactions of 1-Cyclopropyl-2-arylethanone DeriVatiVes
SCHEME 7. A plausible Mechanism on the Formation of 5 and 6
TABLE 8. Bi(OTf)2Cl-Mediated Reactions of
1-Cyclopropyl-2-arylethanones 1j-q with Methyl Acrylate
tion). Moreover, the structure of 5c was determined unam-
biguously by X-ray diffraction. Its CIF data and ORTEP
drawing are also presented in the Supporting Information.
A plausible mechanism for the formation of 5 and 6 is
outlined in Scheme 7 with 1j as a model. Similarly, the
reaction of 1j with a trace of ambient water generates 1-(4-
chlorophenyl)-5-hydroxypentan-2-one intermediate J in the
presence of Lewis acid.3 Michael addition of intermediate J
from the CR-position with methyl acrylate in the presence of
Lewis acid produces intermediate K. The subsequent in-
tramolecular aldol reaction from the CR′-position affords
intermediate L. Intramolecular cyclization with two different
carbonyl groups and the subsequent dehydration produce
compounds 5a and 6a, respectively. On the other hand, it
should be noted that 7-(4-chlorophenyl)-3,4,5,7-tetrahydro-
2H-benzofuran-6-one 7 could not be detected in this reaction
via intermediates M and N, suggesting that Michael addition
from the CR′-position is unable to take place, presumably
due to a reactive enol from the CR′ position being hard to
form in the presence of Lewis acid under these reaction
conditions (Scheme 7).
entry
Ar
yield [%]a (5:6)
1
2
3
4
5
6
7
8
1i, C6H5
83 (5b:6b ) 1.2:1)
96 (5c:6c ) 2.7:1)
84 (5d:6d ) 2.6:1)
60 (5e:6e ) 0.7:1)
50 (5f:6f ) 3.5:1)
48 (5g:6g ) 2.3:1)
87 (5h:6h ) 3.4:1)
98 (5i:6i ) 3.2:1)
1k, p-BrC6H4
1l, m-BrC6H4
1m, m-FC6H4
1n, m-CH3C6H4
1o, p-CH3C6H4
1p, o-BrC6H4
1q, m-Cl, p-ClC6H3
a Isolated yields.
With these optimal conditions in hand, we next examined
the generality of this reaction with a variety of 1-cyclopropyl-
2-arylethanones 1i and 1k-q and the results of these
experiments are outlined in Table 8. The corresponding
products 5 and 6 were obtained in moderate to high total
yields whether there was an electron-withdrawing or an
electron-donating group on the benzene ring of 1 (Table 8,
entries 1-8). Adding a moderately electron-donating methyl
group on the benzene ring of 1n and 1o afforded the products
in moderate yields (Table 8, entries 5 and 6). The structures
To clarify the reaction mechanism, several control experi-
ments were carried out under the standard conditions (Scheme
8). We found that in the reaction of 1-cyclopropyl-2-phenyl-
propan-1-one 1r and 1-cyclopropyl-2,2-diphenylethanone 1s
having a substituent at the CR-position with methyl acrylate,
the corresponding products 5j and 5k were obtained in 66%
and 17% yields, respectively, indicating that Michael addition
of intermediate A in Scheme 2 or intermediate J in Scheme
7 from the CR-position with methyl acrylate is a preferred
process in this transformation and a sterically bulky sub-
of 5 and 6 were determined by H and 13C NMR spectro-
scopic data and HRMS analytic data (Supporting Informa-
1
J. Org. Chem. Vol. 73, No. 14, 2008 5317

Shi et al.
SCHEME 8. Control Experiment
General Procedure for the Reaction of 1a with Ethyl Aceto-
acetate (Ethyl 3-Oxobutanoate). 1-Cyclopropyl-2-phenylethanone
1i (48 mg, 0.3 mmol), ethyl acetoacetate (ethyl 3-oxobutanoate)
(58.5 mg, 0.45 mmol), TMSOTf (54 µL, 0.3 mmol), and DCE
(3.0 mL) were added into a Schlenk tube. The reaction mixture
was stirred at 60 °C for 15 h. The solvent was removed under
reduced pressure and then the residue was purified by flash
column chromatography (Table 5, entry 1).
6-Methyl-7-phenyl-2,3-dihydrobenzofuran-4-ol (3a). A yellow
1
liquid; H NMR (300 MHz, CDCl3, TMS) δ 2.11 (s, 3H), 3.17
(t, J ) 8.6 Hz, 2H), 4.56 (t, J ) 8.6 Hz, 2H), 4.92 (s, 1H), 6.28
(s, 1H), 7.26-7.33 (m, 3H), 7.38-7.43 (m, 2H); 13C NMR (75
MHz, CDCl3, TMS) δ 20.0, 27.0, 71.7, 109.3, 109.7, 117.4,
126.8, 128.1, 130.2, 136.4, 137.3, 151.0, 159.4; IR (CH2Cl2) ν
3411, 2957, 2856, 1706, 1619, 1453, 1421, 1306, 1126, 1048,
702 cm-1; MS (EI) m/z (%) 226 (100) [M+], 225 (32.2), 211
(26.5), 227 (17.6), 197 (14.9), 165 (10.8), 183 (10.4), 115 (10.2);
HRMS (EI) calcd for C15H14O2 (M+) requires 226.0994, found
306.0996.
General Procedure for the Lewis Acid-Catalyzed Reaction
of 1-Cyclopropyl-2-arylethanone 1 with Methyl Acylate. 1-Cy-
clopropyl-2-phenylethanone 1i (48 mg, 0.3 mmol), methyl
acylate (129 mg, 1.5 mmol), Bi(OTf)2Cl (162.6 mg, 0.3 mmol),
and DCE (3.0 mL) were added into a Schlenk tube. The reaction
mixture was stirred at 60 °C for 12 h. The solvent was removed
under reduced pressure and then the residue was purified by flash
column chromatography (Table 8, entry 1).
7-Phenyl-2,3,6,7-tetrahydrobenzofuran-4(5H)-one, 5b. A yel-
low liquid; 1H NMR (300 MHz, CDCl3, TMS) δ 2.02-2.17 (m,
1H), 2.34-2.51 (m, 3H), 2.86-2.03 (m, 2H), 3.81-3.83 (m,
1H), 4.57 (t, J ) 9.3 Hz, 2H), 7.22 (d, J ) 7.2 Hz, 2H),
7.26-7.38 (m, 3H); 13C NMR (75 MHz, CDCl3, TMS) δ 26.0,
31.4, 35.0, 41.1, 73.2, 114.7, 127.4, 127.7, 128.8, 138.9, 177.9,
195.4; IR (CH2Cl2) ν 2953, 2926, 1732, 1651, 1599, 1494, 1409,
1235, 1078, 964, 820 cm-1; MS (EI) m/z (%) 214 [M+] (39.8),
186 (40.9), 110 (100.0), 105 (68.6), 77 (50.7), 55 (22.1), 51
(26.3), 43 (17.3); HRMS (EI) calcd for C14H14O2 (M+) requires
214.0994, found 214.1010.
5-Phenyl-2,3,6,7-tetrahydrobenzofuran-4(5H)-one, 6b. A yel-
low liquid; 1H NMR (300 MHz, CDCl3, TMS) δ 2.23-2.39 (m,
2H), 2.47-2.52 (m, 2H), 2.88-2.95 (m, 2H), 3.58 (dd, J ) 9.0
Hz, J ) 7.8 Hz, 1H), 4.63 (t, J ) 9.6 Hz, 2H), 7.17-7.25 (m,
2H), 7.30-7.35 (m, 3H); 13C NMR (75 MHz, CDCl3, TMS) δ
22.8, 26.1, 30.0, 51.7, 73.4, 113.9, 126.8, 128.3, 128.5, 139.9,
177.6, 195.0; IR (CH2Cl2) ν 2961, 2853, 1738, 1683, 1597, 1495,
1407, 1262, 1079, 961, 820 cm-1; MS (EI) m/z (%) 214 [M+]
(30.1), 186 (11.8), 110 (100), 77 (10.9), 57 (15.6), 54 (10.9),
52 (11.5), 43 (13.3); HRMS (EI) calcd for C14H14O2 (M+)
requires 214.0994, found 214.1010.
stituent at the CR-position of 1r and 1s can partially retard
the reaction rate to give the corresponding products in low
yields. Moreover, by using cyclopropylphenylmethanone 1t
as the substrate under the standard conditions, no reaction
occurred, suggesting that a methylene or methine moiety
between the aromatic group and the carbonyl group is
required (Scheme 8).
In conclusion, we have found a reaction process involving
the sequential ring-opening reaction of cyclopropyl alkyl ketones
by H2O, followed by one intermolecular aldol-type reaction with
allenic esters and two intramolecular aldol-type reactions, a
cyclic transesterification along with a dehydration and aroma-
tization mediated by Lewis acids, which affords an efficient
synthetic protocol for the preparation of dihydrofuro[2,3-h]-
chromen-2-one derivatives. Further work directed at elucidation
of the detailed mechanisms of this process and the application
of it to the synthesis of dihydrofuro[2,3-h]chromen-2-one
containing natural products is currently in progress.
Experimental Section
General Procedure for the Reaction of 2-Phenyl-1-(1-phe-
nylcyclopropyl)ethanone with Ethyl Buta-2,3-dienoate. 2-Phen-
yl-1-(1-phenylcyclopropyl)ethanone 1a (71 mg, 0.3 mmol), ethyl
buta-2,3-dienoate (50.4 mg, 0.45 mmol), TMSOTf (54 µL, 0.3
mmol), and DCE (3.0 mL) were added into a Schlenk tube. The
reaction mixture was stirred at 60 °C for 12 h. The solvent was
removed under reduced pressure and then the residue was
purified by a flash column chromatography (Table 1, entry 1).
6-Methyl-3a,7-diphenyl-3,3a-dihydrobenzofuran-4(2H)-one
Acknowledgment. We thank the Shanghai Municipal Com-
mittee of Science and Technology (04JC14083, 06XD14005)
and the National Natural Science Foundation of China for
financial support (20472096, 203900502, 20672127, and
20732008).
1
2a. A yellow oil; H NMR (CDCl3, 300 MHz, TMS) δ 1.85 (d,
3H, J ) 0.9 Hz), 2.56-2.61 (m, 2H), 3.96 (dd, 1H, J ) 15.8
Hz, J ) 9.0 Hz), 4.34-4.40 (m, 1H), 5.58 (d, 1H, J ) 0.9 Hz),
7.34-7.47 (m, 8H), 7.62 (dd, 2H, J ) 8.0 Hz, J ) 1.7 Hz); 13C
NMR (CDCl3, 75 MHz, TMS) δ 22.4, 35.4, 63.2, 70.9, 110.5,
117.3, 126.4, 127.4, 128.3, 128.4, 128.9, 130.2, 134.4, 137.0,
159.0, 166.4, 199.5; IR (CH2Cl2) ν 3057, 2924, 2851, 1674,
1537, 1492, 1380, 1265, 991 cm-1; MS (EI) m/z (%) 302 [M+]
(100), 303 (26.9), 274 (23.3), 259 (21.0), 231 (32.0), 129 (28.8),
128 (24.0), 115 (33.5); HRMS (EI) calcd for C21H18O2 (M+)
requires 302.1307, found 302.1306.
Supporting Information Available: Spectroscopic data of
all new compounds, detailed descriptions of experimental
procedures, and the X-ray data for compounds 2c, 4a, and 5c.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO800608H
5318 J. Org. Chem. Vol. 73, No. 14, 2008