Acylation of alkylidenecyclopropanes for the facile synthesis of αβunsaturated ketone and benzofulvene derivatives with high stereoselectivity

Article abstract of DOI:10.1021/ol070331h

A variety of substituted αβ-unsaturated ketone and benzofulvene derivatives were readily prepared in good to excellent yields via the reaction of alkylidenecyclopropanes with various acyl chlorides in the presence of aluminum chloride. The stereochemistry

Full text of DOI:10.1021/ol070331h

ORGANIC
LETTERS
2007
Vol. 9, No. 9
1667-1670
Acylation of Alkylidenecyclopropanes
for the Facile Synthesis of
r,â-Unsaturated Ketone and
Benzofulvene Derivatives with High
Stereoselectivity
Xian Huang*,†,‡ and Yewei Yang†
Department of Chemistry, Zhejiang UniVersity (Xixi Campus), Hangzhou 310028, PRC,
and State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, Shanghai 200032, PRC
huangx@mail.hz.zj.cn
Received February 8, 2007
ABSTRACT
A variety of substituted
r,â-unsaturated ketone and benzofulvene derivatives were readily prepared in good to excellent yields via the reaction
of alkylidenecyclopropanes with various acyl chlorides in the presence of aluminum chloride. The stereochemistry of the acylation and cyclization
is discussed.
Alkylidenecyclopropanes (ACPs) are highly strained but
readily available molecules that have served as useful
building blocks in organic synthesis.1 So far, increasing
attention has been paid to the transition-metal-catalyzed
reactions of unsubstituted methylenecyclopropanes, which
have been employed for the construction of complex organic
molecules.2,3 Examples of Lewis acid or Brønsted acid
mediated reactions of ACPs have also been disclosed.4 An
attractive but often troublesome feature of methylenecyclo-
propanes is their multiform reactivities that may lead to
formation of a variety of products through various reaction
pathways: addition to a CdC double bond or cleavage of
proximal and distal bonds of the three-membered ring.5
Moreover, for the reactions with unsymmetrical ACPs, the
†
Zhejiang University (Xixi Campus).
(3) (a) Bessmertnykh, A. G.; Blinov, K. A.; Grishin, Y. K.; Donskaya,
N. A.; Tveritinova, E. V.; Yur’eva, N. M.; Beletskaya, I. P. J. Org. Chem.
1997, 62, 6069. (b) Lautens, M.; Meyer, C.; Lorenz, A. J. Am. Chem. Soc.
1996, 118, 10676. (c) Chatani, N.; Takeyasu, T.; Hanafusa, T. Tetrahedron
Lett. 1988, 29, 3979. (d) Ishiyama, T.; Momota, S.; Miyaura, N. Synlett
1999, 1790. (e) Suginome, M.; Matsuda, T.; Ito, Y. J. Am. Chem. Soc.
2000, 122, 11015.
(4) (a) Nakamura, I.; Kamada, M.; Yamamoto, Y. Tetrahedron Lett. 2004,
45, 2903. (b) Patient, L.; Berry, M. B.; Kiburn, J. D. Tetrahedron Lett.
2003, 44, 1015. (c) Shi, M.; Xu, B. Org. Lett. 2002, 4, 2145. (d) Shi, M.;
Xu, B.; Huang, J.-W. Org. Lett. 2004, 6, 1175. (e) Shi, M.; Liu, L.-P.;
Tang, J. Org. Lett. 2006, 8, 4043.
‡ Chinese Academy of Sciences.
(1) (a) Brandi, A.; Goti, A. Chem. ReV. 1998, 98, 589. (b) Nakamura, I.;
Yamamoto, Y. AdV. Synth. Catal. 2002, 344, 111. (c) Brandi, A.; Cicchi,
S.; Cordero, F. M.; Goti, A. Chem. ReV. 2003, 103, 1213.
(2) (a) Nakamura, I.; Itagaki, H.; Yamamoto, Y. J. Org. Chem. 1998,
63, 6458. (b) Siriwardana, A. I.; Kamada, M.; Nakamura, I.; Yamamoto,
Y. J. Org. Chem. 2005, 70, 5932. (c) Camacho, D. H.; Nakamura, I.; Saito,
S.; Yamamoto, Y. Angew. Chem., Int. Ed. 1999, 38, 3365. (d) Camacho,
D. H.; Nakamura, I.; Saito, S.; Yamamoto, Y. J. Org. Chem. 2001, 66,
270. (e) Tsukada, N.; Shibuya, A.; Nakamura, I.; Yamamoto, Y. J. Am.
Chem. Soc. 1997, 119, 8123. (f) Nakamura, I.; Siriwardana, A. I.; Saito,
S.; Yamamoto, Y. J. Org. Chem. 2002, 67, 3445. (g) Nakamura, I.; Oh, B.
H.; Saito, S.; Yamamoto, Y. Angew. Chem., Int. Ed. 2001, 40, 1298. (h)
Oh, B. H.; Nakamura, I.; Saito, S.; Yamamoto, Y. Tetrahedron Lett. 2001,
42, 6203.
(5) (a) Huang, X.; Fu, W.-J. Synthesis 2006, 1016. (b) Zhou, H.; Huang,
X.; Chen, W. J. Org. Chem. 2004, 69, 5471. (c) Huang, X.; Zhou, H.; Chen,
W. J. Org. Chem. 2004, 69, 839. (d) Huang, X.; Zhou, H. Org. Lett. 2002,
4, 4419.
10.1021/ol070331h CCC: $37.00
© 2007 American Chemical Society
Published on Web 03/27/2007

regiochemistry generally makes the reaction complicated.
Thus, the regio- and stereoselectivity of the insertion and
ring-opening methods have been the highlight of methyl-
enecyclopropane chemistry.6
changing the catalyst to TiCl4, FeCl3, SnCl4, or ZnCl2 only
afforded a trace of 2a (Table 1, entries 1-4). In addition,
using a catalytic amount of AlCl3, only a trace of 2a was
formed (Table 1, entry 6).
The Lewis acid promoted Friedel-Crafts reaction is a
powerful carbon-carbon bond-forming process in organic
chemistry.7 Since the 1960s, the chemistry of the acylation
of cyclopropanes has been explored with regard to the
similarity between the cyclopropane ring and the olefinic
double bond.8 However, the addition of an acyl chloride-
aluminum chloride complex to ACPs has not been reported
so far. Because of the fact that ACPs are generally more
strained than cyclopropanes, they are also expected to react
with the acyl cation. Herein, we wish to report the reaction
of ACPs with various acyl chlorides in the presence of
aluminum chloride. Special emphasis will be placed on the
regio- and stereochemical aspects.
Next, we carried out the AlCl3-mediated acylation of
various ACPs 1 with aliphatic and aromatic acyl chlorides.
The results are summarized in Table 2. The symmetrical ACP
Table 2. Reactions of Various Acyl Chlorides with ACPs in
a
the Presence of 1.0 Equiv of AlCl3
entry
ACP 1 (R1/R2)
C6H5/C6H5 (1a)
1a
1a
R3
yield (%)b
2a, 84
2b, 67
2c, 80
We started our investigations by the reaction of diphen-
ylmethylenecyclopropane 1a and acetyl chloride in the
presence of metal halides, in CH2Cl2 under an N2 atmosphere
(Table 1). The reaction proceeded smoothly in the presence
1
2
3
Me
i-Pr
Ph
4
1a
p-MeOC6H4 2d, 92
5
6
1a
Bn
Me
2e, 89 (3c, 5)
2f, 92
p-MeC6H4/p-MeC6H4 (1b)
Table 1. Effects of Reaction Conditions on the Reaction of
ACP 1a with Acetyl Chloride in the Presence of Metal
Chloridesa
7
8
9
p-MeOC6H4/p-MeOC6H4 (1c) Me
2g, 30
2h, 55
2i, 73
2j, 76
1c
1c
1c
Bn
i-Pr
Ph
Phc
Me
Me
Et
10
11
12
13
14
15
16
17
18
p-ClC6H4/p-ClC6H4 (1d)
p-FC6H4/p-FC6H4 (1e)
C6H5/H (1f)
1f
2k, 79
2l, 66 (3i, 9)
(E)-2m, 68
(E)-2n, 71
(E)-2o, 64
(E)-2p, 50
(E)-2q, 63
(E)-2r, 59
1f
Ph
Me
Et
entry metal chloride (equiv) temp (°C) time (h) yield (%)b
p-BrC6H4/H (1g)
1g
1
2
3
4
5
6
7
8
9
TiCl4 (1)
FeCl3 (1)
SnCl4 (1)
ZnCl2 (1)
ZrCl4 (1)
AlCl3 (0.1)
AlCl3 (1)
AlCl3 (1)
AlCl3 (1)
AlCl3 (1)
-20
-20
-20
rt
-20
-20
rt
-20
-20
-20
0.5
0.5
1
3
0.5
3
0.5
1
2
trace
trace
trace
trace
46
trace
24
84
2,6-Cl2-C6H3/C6H5 (1h)
Me
a
Unless otherwise specified, the reaction was carried out using 1 (1.0
mmol) and acyl chloride (1.0 mmol) in CH2Cl2 at -20 °C for 1 h. b Isolated
c
yields. (p-ClC6H4)2CdCHCH2Cl was obtained with 8% isolated yield.
1a smoothly reacted with various acyl chlorides, affording
the corresponding R,â-unsaturated ketones 2a-e in good
yields (Table 2, entries 1-5). For ACP 1b having an
electron-donating methyl group on the benzene ring, the
corresponding product 2f was obtained in higher yield (Table
2, entry 6). However, using ACP 1c as the substrate, the
products 2g-j were formed in moderate yields, along with
an unidentified polymeric byproduct (Table 2, entries 7-10).
On the other hand, for 1d and 1e having electron-withdraw-
ing substituents on the benzene ring, the corresponding
adducts 2k and 2l were obtained in 79% and 66% yield,
respectively (Table 2, entries 11 and 12). All reactions were
completed within 1 h.
81
56c
10
1
a
Unless otherwise specified, the reaction was carried out using 1a (1.0
mmol) and acetylchloride (1.0 mmol) in CH2Cl2 in the presence of Lewis
b
acids and then quenched by the addition of 10% HCl solution. Isolated
yields and the reaction time are determined by TLC on the basis of
c
consuming the starting materials 1a. Quenched by the addition of Et3N
(0.22 mL, 1.5 mmol) in 4 mL of pentane at -20 °C.
of ZrCl4 to give the R,â-unsaturated ketone derivative 2a,
albeit in moderate yield (Table 1, entry 5). However, when
a stoichiometric amount of AlCl3 was used, the yield was
improved to 84% (Table 1, entry 8). On the other hand,
For the unsymmetric ACPs, only the E isomers of the
products 2 were obtained (Table 2, entries 13-18). The E/Z
(6) (a) Ma, S.; Zhang, J. Angew. Chem., Int. Ed. 2003, 42, 184. (b) Ma,
S.; Lu, L.; Zhang, J. J. Am. Chem. Soc. 2004, 126, 9645.
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1991; Vol. 3, Chapter 1.8, pp 293-339. (b) Meima, G. R.; Lee, G. S.;
Garces, J. M. In Friedel-Crafts Alkylation; Sheldon, R. A., Bekkum, H.,
Eds.; Wiley-VCH: New York, 2001; pp 155-160.
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Hart, H.; Sandri, J. M. J. Am. Chem. Soc. 1959, 81, 320. (c) Hart, H.; Levitt,
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Chem. Soc. 1966, 88, 5030. (e) Hart, H.; Schlosberg, R. H. J. Am. Chem.
Soc. 1968, 90, 5189.
1668
Org. Lett., Vol. 9, No. 9, 2007

1
selectivity was determined by the H NMR spectra of the
If R1 ) CH3, the intermediate carbonium ion 5 gives 4 via
â-proton elimination.10
crude reaction mixture. The structure of the product (E)-2m
was established by spectroscopic analysis and single-crystal
X-ray diffraction analysis (Figure 1).
Controlled experiments with varying stoichiometries of
aluminum chloride revealed an interesting reactivity pattern,
leading to entirely different products. In the presence of 2.0
equiv of AlCl3, 1a was consumed within 12 h at room
temperature to afford 3a as a major product in 74% yield
(Scheme 3).11
Scheme 3. Reaction of ACP 1a with Acetyl Chloride in the
Presence of 2.0 Equiv of AlCl3
Figure 1. Single-crystal X-ray structure of compound (E)-2m.
This reaction also appears to be general, and the results
are summarized in Table 3. ACPs 1 having an electron-
However, for unsymmetric aliphatic ACP 1j, we observed
that the acyl cation easily added to the CdC bond without
cleavage of the cyclopropane ring giving the vinylcyclopro-
pane derivative 4a as a single product under the same
conditions (Scheme 1).
Table 3. Reactions of ACPs with Various Acyl Chlorides in
a
the Presence of 2.0 Equiv of AlCl3
Scheme 1. Reaction of ACP 1j with Acetyl Chloride
entry ACP 1
R3
R4
yield of 3 (%)b
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1b
1c
1d
1d
1e
1e
Me
i-Pr
Bn
H
-
Ph
3a, 74
3b, 19
3c, 63
3d, 70
3e, 81
3f, 54
3g, 57
3h, 88
3i, 49
3j, 86
p-MeOC6H4CH2 p-MeOC6H4
A possible pathway for the observed selectivity is based
on Yamamoto’s model for the HX addition of ACPs (Scheme
2).9 Attack of an acyl cation on the C-1 position of the Cd
Me
Me
Me
Bn
Me
Bn
H
H
H
Ph
H
10
Ph
Scheme 2. Proposed Mechanistic Pathway for the Reaction in
Table 1 and Scheme 1
a
Unless otherwise specified, the reaction was carried out using 1 (1.0
mmol) and acyl chloride (1.0 mmol) in the presence of AlCl3 (2.0 mmol)
in 3 mL of CH2Cl2 at -20 °C for 30 min and stirred for 12 h at room
b
temperature. Isolated yields.
withdrawing group or an electron-donating group which is
para substituted on the aromatic ring did not significantly
affect the reaction, and the reaction proceeded readily in
satisfactory yields. However, the bulky acyl chloride gives
the desired products in low yield (Table 3, entry 2), indicating
that the reaction is sensitive to steric hindrance. We also
found that arylacetyl chloride reacted with various ACPs very
well to give the corresponding adducts in moderate to good
C bond affords cation intermediate 5. Subsequent nucleo-
philic attack of the chloride ion (or AlCl4 ) produces the
stereospecific ring-opened E-isomer 2 (R1 ) H, R2 ) Ar).
-
(9) Siriwardana, A. I.; Nakamura, I.; Yamamoto, Y. Tetrahedron Lett.
2003, 44, 985.
(10) Liu, L.-P.; Shi, M. J. Org. Chem. 2004, 69, 2805.
(11) See the Supporting Information for experimental details.
Org. Lett., Vol. 9, No. 9, 2007
1669

yields (Table 3, entries 3, 4, 8, and 10). The reaction
exhibited a surprising degree of stereochemical control, and
only Z-isomer 3 was isolated. The E/Z selectivity was
Scheme 5. Proposed Mechanism for the Reaction
1
determined by the H NMR spectra of the crude reaction
mixture.
The product 3c was characterized on the basis of spec-
troscopic data and the single-crystal X-ray diffraction analysis
(Figure 2).
The fulvene system represents a very attractive unit which
is known as a model for theoretical studies.13 Therefore, our
methodology for the easy preparation of functionalized
benzofulvene derivatives is unique and important from the
viewpoint of both mechanistic and organic synthesis.
In conclusion, we have developed two novel reactions of
ACPs with acyl chlorides leading to two different ring-
opened products under AlCl3-mediated conditions. In one
case, the acylation products 2 can be obtained in good to
excellent yields. This bifunctional moiety is one of the most
interesting structural units for organic chemists.14 In the other
case, the ACPs are converted to benzofulvene derivatives
efficiently with a high Z-stereoselectivity. Further studies to
expand the scope and synthetic utility of the method are
underway.
Figure 2. Single-crystal X-ray structure of compound 3c.
In addition, we investigated the reaction of 2a with a
stoichiometric amount of aluminum chloride in dry MeCN
under an N2 atmosphere at 50 °C for 12 h. The desired
product was obtained in 92% yield (Scheme 4).
Acknowledgment. We are grateful to the National
Natural Science Foundation of China (Project No. 20472072,
20332060) and CAS Academician Foundation of Zhejiang
Province for financial support.
Supporting Information Available: General experimen-
tal procedures and spectroscopic data for all compounds and
crystallographic data for (E)-2m and 3c (CIF). This material
is available free of charge via the Internet at http://pubs.acs.org.
Scheme 4. Reaction of 2a in the Presence of 1.0 Equiv of
AlCl3
OL070331H
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A possible pathway for the formation of 3 is shown in
Scheme 5. The carbonyl group of 2 coordinates to aluminum
chloride to give the cationic intermediate 6. The intramo-
lecular Friedel-Crafts reaction of 6 produces the bicyclic
intermediate 7. Proton migration in carbocation 7 or 8 gives
intermediate 9. Tandem elimination of water from the
intermediate 9 finally affords product 3 with high stereose-
lectivity through the E1 process.12
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Org. Lett., Vol. 9, No. 9, 2007