Substrate-controlled selective proximal and distal C-C bond cleavage via Lewis acid mediated O-acylation of 2-(arylmethylene)cyclopropylaldehyde: A stereoselective synthesis of bifunctional methylenecyclobutanes and 1,3-conjugated dienes

Article abstract of DOI:10.1021/jo801021f

(Chemical Equation Presented) ZnCl₂-mediated reactions of (E)-2-(arylmethylene)cyclopropylaldehyde 1 with various acyl chlorides provide a novel method for stereoselective synthesis of bifunctional methlylenecyclobutanes via a proximal-bond cleavage process. Nevertheless, when (Z)-1 was employed, the reactions give 1,3-conjugated dienes through distal-bond cleavage.

Full text of DOI:10.1021/jo801021f

SCHEME 1. Reaction of 1a (E:Z ) 2.5:1) with Acetyl
Substrate-Controlled Selective Proximal and
Distal C-C Bond Cleavage via Lewis Acid
Mediated O-Acylation of
Chloridesa
2-(Arylmethylene)cyclopropylaldehyde: A
Stereoselective Synthesis of Bifunctional
Methylenecyclobutanes and 1,3-Conjugated
Dienes
a Reaction conditions: mixture of 1a (0.5 mmol) reacted with acetyl
chloride (0.75 mmol) in the presence of AlCl3 (0.5 mmol). The ratio of the
1
crude products was determined by H NMR.
Xian Huang*,†,‡ and Maozhong Miao†
attractive but often troublesome feature of MCPs is their
multiform reactivities that may lead to formation of a variety
of products. Thus controlling the regio- and stereoselective
reactions of MCPs is a formidable challenge in organic
synthesis.
Department of Chemistry, Zhejiang UniVersity (Xixi
Campus), Hangzhou 310028, People’s Republic of China,
and State Key Laboratory of Organometallic Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy
of Sciences, Shanghai 200032, People’s Republic of China
Recently, MCPs with functional groups attached to a cyclo-
propyl ring have received considerable attention.4 In principle,
the presence of functional groups may facilitate the selective
cleavage of C-C bonds of MCPs, thus delicately tuning the
regio- and stereoselectivity of the reactions. Ma4a previously
reported a highly selective ring-opening cycloisomerization of
methylene- or alkylidenecyclopropyl ketones catalyzed by Pd(II)
catalyst, and Lautens4c has shown a novel ring expansion of
secondary methylenecyclopropyl amides in the presence of
MgI2, leading to useful compounds with synthetic and biological
importance. Herein, we wish to disclose a novel Lewis acid
mediated reaction of formyl-substituted MCPs with acyl chloride
to afford a selective synthesis of bifunctional methylenecy-
clobutanes (MCBs) and 1,3-conjugated dienes.
Initially, we examined the reaction of 1a (E:Z ) 2.5:1) with
acetyl chloride in CH2Cl2 at room temperature in the presence
of 1.0 equiv of AlCl3, affording a mixture of MCB 2a and 1,3-
conjugated diene 3a (2a:3a ) 3:1) in 49% yield (Scheme 1).
With these results, we presumed that the O-acylation-ring-
expansion reaction or O-acylation-ring-opening reaction of 1a
might afford 2a or 3a. In order to confirm the pathway of this
reaction, we then conducted the reaction using (E)-1a and (Z)-
1a, respectively. Gratifyingly, we found that the reaction gave
2a as the only product in 52% yield when (E)-1a was employed
(Table 1, entry 2).
huangx@mail.hz.zj.cn
ReceiVed May 13, 2008
ZnCl2-mediated reactions of (E)-2-(arylmethylene)cyclopro-
pylaldehyde 1 with various acyl chlorides provide a novel
method for stereoselective synthesis of bifunctional meth-
lylenecyclobutanes via a proximal-bond cleavage process.
Nevertheless, when (Z)-1 was employed, the reactions give
1,3-conjugated dienes through distal-bond cleavage.
Methylenecyclopropanes (MCPs) are highly strained but
readily accessible carbocyclic molecules that have served as
useful building blocks in organic synthesis.1 In the past decades,
mounting attention has been paid to the transition metal2 (Pd,
Ni, Pt, and Rh) and Lewis acid3 catalyzed reactions of MCPs,
which have been employed for the construction of highly
complex and interesting organic molecules. However, an
With this encouraging result, a systematic study on optimizing
the reaction conditions was immediately undertaken. We first
investigated the reaction of (E)-1a (0.5 mmol) with acetyl
chloride (0.75 mmol) in CH2Cl2 at room temperature by
employing various Lewis acids (0.5 mmol). As indicated in
Table 1, except for AlCl3, other Lewis acids, e.g., TiCl4,
BF3 ·Et2O, and ZrCl4, could also promote the reaction (Table
1, entries 1-5). The best result was obtained when ZnCl2 was
used as Lewis acid, and 2a could be obtained in 89% yield
(Table 1, entry 6). The following examination of the solvent
† Zhejiang University.
‡ Chinese Academy of Sciences.
(1) Synthesis of MCPs: (a) Brandi, A.; Goti, A. Chem. ReV 1998, 98, 589.
Recent reviews of MCPs: (b) Brandi, A.; Cicchi, S.; Cordero, F. M.; Goti, A.
Chem. ReV. 2003, 103, 1213. (c) Nakamura, I.; Yamamoto, Y. AdV. Synth. Catal.
2002, 2, 111. (d) Nakamura, E.; Yamago, S. Acc. Chem. Res. 2002, 35, 867.
(2) Selected recent articles about transition-metal-catalyzed reactions of
MCPs: (a) Camacho, D. H.; Nakamura, I.; Saito, S.; Yamamoto, Y. J. Org.
Chem. 2001, 66, 270. (b) Camacho, D. H.; Nakamura, I.; Saito, S.; Yamamoto,
Y. Angew. Chem., Int. Ed. 1999, 38, 3365. (c) Nakamura, I.; Itagaki, H.;
Yamamoto, Y. J. Org. Chem. 1998, 63, 6458. (d) Lautens, M.; Meyer, C.; Lorenz,
A. J. Am. Chem. Soc. 1996, 118, 10676. (e) Fu¨rstner, A.; A¨ıssa, C. J. Am. Chem.
Soc. 2006, 128, 6306. (f) Saito, S.; Masuda, M.; Komagawa, S. J. Am. Chem.
Soc. 2004, 126, 10540. (g) Kawasaki, T.; Saito, S.; Yamamoto, Y. J. Org. Chem.
2002, 67, 4911. (h) 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. (i) Chiusoli, G. P.; Costa, M.; Melli, L. J. Organomet.
Chem. 1998, 358, 495.
(3) Selected recent articles about Lewis acid mediated reactions of MCPs: (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.; Liu, L.-P.; Tang, J.
Org. Lett. 2006, 8, 4043.
(4) (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. (c) Lautens, M.; Han, W.;
Liu, J. H.-C. J. Am. Chem. Soc. 2003, 125, 4028. (d) Nakamura, M.; Toganoh,
M.; Ohara, H.; Nakamura, E. Org. Lett. 1999, 1, 7.
6884 J. Org. Chem. 2008, 73, 6884–6887
10.1021/jo801021f CCC: $40.75 2008 American Chemical Society
Published on Web 07/29/2008

TABLE 1. Effects of Reaction Conditions on the Reaction of
TABLE 2. Reactions of (E)-1 with Various Acyl Chlorides in the
a
(E)-1a with Acetyl Chloride in the Presence of Lewis Acida
Presence of ZnCl2
entry
R1
R2
CH3
yield (%)b
Lewis acid
(equiv)
temp
(°C)
time
yield of
1
2
3
4
C6H5 [(E)-1a]
(E)-1a
2a, 91
2b, 83
2c, 90
2d, 86
c
entry
solvent
(min)b
2a (%)c
C6H5
1
2
3
4
5
6
7
8
FeCl3 (1.0)
AlCl3 (1.0)
TiCl4 (1.0)
BF3 ·Et2O (1.0)
ZrCl4 (1.0)
ZnCl2 (1.0)
ZnCl2 (1.0)
ZnCl2 (1.0)
ZnCl2 (1.0)
ZnCl2 (1.0)
ZnCl2 (1.0)
ZnCl2 (1.0)
ZnCl2 (0.1)
ZnCl2 (2.0)
25
25
25
25
25
25
25
25
25
-20
0
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
THF
5
5
3
22
52
72
78
87
89
81
trd
87
78
91
39
46
88
(E)-1a
(E)-1a
(E)-1a
CH(CH3)2
(CH2)2CH3
OMe
5
20
12
15
20
120
20
80
20
20
120
20
6
7
8
9
10
11
12
13
14
15
16
17
18
p-ClC6H4 [(E)-1b]
(E)-1b
(E)-1b
p-BrC6H4 [(E)-1c]
(E)-1c
p-MeOC6H4 [(E)-1d]
(E)-1d
(E)-1d
p-MeC6H4 [(E)-1e]
(E)-1e
m-ClC6H4 [(E)-1f]
o-BrC6H4 [(E)-1g]
2-furan [(E)-1h]
CH3
C6H5
CHdCH2
CH3
C6H5
CH3
C6H5
CHdCH2
CH3
C(CH3)3
CH3
2e, 93
2f, 77
2g, 82
2h, 96
2i, 72
2j, 85
2k, 79
2l, 89
2m, 92
2n, 88
2o, 90
2p, 89
2q, 74
9
DCE
10
11
12
13
14
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
40
0
0
CH3
PhCH2
a Unless otherwise specified, the reaction was carried out using (E)-1a
(0.5 mmol) and acetyl chloride (0.75 mmol) in 5 mL of CH2Cl2 in a N2
atmosphere. b The reaction was monitored by TLC. c Isolated yields.
d 58% of (E)-1a was recovered.
a Unless otherwise specified, the reaction was carried out using E-1
(0.5 mmol) and acyl chloride (0.75 mmol) in 5 mL of CH2Cl2 in a N2
atmosphere. b Isolated yields. c No reaction occurred.
effects indicated that CH2Cl2 was the most suitable solvent.
Slightly lower yields were observed when the reaction was
carried out in solvents such as toluene and DCE (Table 1, entries
6, 7, and 9). Nevertheless, the solvent THF turned out to be
totally disfavored (Table 1, entry 8). Our further experiments
to examine the temperature effects (Table 1, entries 10-12)
showed that the yield could be enhanced to 91% when the
reaction was conducted at 0 °C (Table 1, entry 11). Moreover,
the ratios of catalyst also affected the yields of 2a (Table 1,
entries 13 and 14), and using stoichiometric amount of ZnCl2
is a necessity. Thus, the best conditions are to carry out the
reaction in CH2Cl2 at 0 °C using 1.0 equiv of ZnCl2 (Table 1,
entry 11).
FIGURE 1. Structure of compound 3a.
SCHEME 2. Reaction of (Z)-1a with Various Acyl
Chlorides
With the optimal conditions in hand, we examined the ring-
expansion reaction of a series of (E)-1 with different acyl
chlorides. The results are summarized in Table 2. As for (E)-
1a-g, the reactions proceeded smoothly with acetyl chloride
to give the corresponding products in 85-96% yields (Table
2, entries 1, 6, 9, 11, 14, 16, and 17). The nature and position
of substituents on the aromatic ring of (E)-1 have little effect
on this reaction. Moreover, heteroaromatic group such as a furan
ring in (E)-1 could also been tolerated (Table 2, entry 18). Other
acyl chlorides such as isobutyryl chloride, pivaloyl chloride,
acryloyl chloride, and benzoyl chloride could also been applied
to the current reaction. For example, with acryloyl chloride, the
expected MCBs 2g and 2l were obtained in 82% and 89% yield,
respectively (Table 2, entries 8 and 13). When benzoyl chloride
was employed, moderate yields were observed as well (Table
2, entries 2, 7, 10, and 12). However, when using methyl
chloroformate as O-acylation reagent under the established
conditions, no reaction occurred (Table 2, entry 5).
Interestingly, when (Z)-1a was employed as substrate, the
reaction gave a different product 3a in 81% yield (Scheme 2).
Benzoyl chloride and isobutyryl chloride were also successfully
applied to the reactions, furnishing the corresponding 1,3-
conjugated dienes 3b and 3c in 72% and 86% yield, respectively
(Scheme 2). The structures of these compounds were determined
by spectroscopic analysis, and the stereochemistry of 3a was
further established by the NOESY analysis (Figure 1). Notably,
these 1,3-conjugated dienes are very important intermediates
that have been frequently utilized as dienes in Diels-Alder
reactions to construct various ring systems in organic synthesis.5
(5) (a) Shi, M.; Wang, B.; Huang, J. J. Org. Chem. 2005, 70, 5606. (b) Wang,
K.-T.; Hung, Y.-Y. Tetrahedron Lett. 2003, 44, 8033. (c) Itazaki, M.; Nishihara,
Y.; Osakada, K. J. Org. Chem. 2002, 67, 6889. (d) Nakamura, I.; Siriwardana,
A.; Saito, S.; Yamamoto, Y. J. Org. Chem. 2002, 67, 3445. (e) Taylor, D. K.;
Avery, T. D.; Greatrex, B. W.; Tiekink, E. R. T.; Macreadie, I. G.; Macreadie,
P. I.; Humphries, A. D.; Kalkanidis, M.; Fox, E. N.; Klonis, N.; Tilley, L. J. Med.
Chem. 2004, 47, 1833. (f) Fringuelli, F.; Taticchi, A. Dienes in the Diels-Alder
Reaction; Wiley: NewYork, 1990. (g) Oppolzer, W. In ComprehensiVe Organic
Synthesis; Trost, B. M., Fleming, I. Eds.; Pergamon Press: Oxford, U.K., 1991;
Vol. 5, Chapter 4.1, pp 315-400. (h) Roush, W. R. In ComprehensiVe Organic
Synthesis; Trost, B. M., Fleming, I. Eds.; Pergamon Press: Oxford, U.K., 1991;
Vol. 5, Chapter 4.4, pp 513-550.
In all cases only the trans-1,4-diastereomers were observed.
1
The structures of these compounds were determined by H
NMR, 13C NMR, IR, and HRMS. The structure of 2i was further
confirmed by single-crystal X-ray diffraction analysis (see
Supporting Information).
J. Org. Chem. Vol. 73, No. 17, 2008 6885

TABLE 3. Synthesis of Cyclopentanones Derivatives
SCHEME 3. Proposed Mechanism for the Reaction
entry
2 (R1)
yield (%)a
1
2
3
4
5
6
2a (C6H5)
7a, 65
7b, 61
7c, 53
7d, 42
7e, 67
7f, 72
2e (p-ClC6H4)
2h (p-BrC6H4)
2j (p-MeOC6H4)
2m (p-MeC6H4)
2o (m-ClC6H4)
SCHEME 4. Possible Mode for the Formation of
Cyclopentenones
a Isolated yields.
efficient and practical routes for the construction of these
compounds are still required.
We examined the reaction of MCB 2a (0.2 mmol) with
m-CPBA (0.5 mmol) in CH2Cl2. After stirring overnight and
subsequent treatment with (Tf)2O (0.2 mmol), the reaction gave
the expected cyclopentenone 7a in 65% yield. The results,
summarized in Table 3, show that various cyclopentenones 7
could be obtained smoothly in moderate yields using the current
protocol.
In conclusion, we have disclosed a novel Lewis acid mediated
reaction of formyl-substituted MCPs with acyl chloride. The
reaction features a substrate-controlled cleavage of the C-C
bond, leading to a facile synthesis of bifunctional MCBs 2 and
1,3-conjugated dienes 3 with high stereoselectivities. We also
demonstrated that the obtained MCBs could be applied to the
synthesis of cyclopentanones 7. Further studies on this trans-
formation are being carried out in our laboratory.
Therefore, our reaction to produce these analogues will be
synthetically useful.
A possible mechanism for these reactions is proposed as
depicted in Scheme 3. In the presence of ZnCl2, the acyl chloride
might first convert to an acyl cation.6 Then a selective attack
of acyl cation to carbonyl oxygen of MCPs 1 would produce a
carbonium ion 4. When (Z)-4 was employed, a nucleophilic
attack of chlorine anion at the less sterically hindered C3 in the
cyclopropyl ring might cause a distal cleavage to afford the
thermodynamically stable product 3 (path a). When (E)-4 was
employed, as a result of the steric hindrance of the aromatic
ring that blocks the nucleophilic attack of chlorine anion at C3,
an intramolecular nucleophilic attack might proceed first to
produce a nonclassic carbocation-bicyclobutonium ion 5.7 Then
the attack of chlorine anion from the back side at C2 of
intermediate 5 would finally give the product 2 stereoselectively
via proximal cleavage (path b).
Experimental Section
As a result of the inherent ring strain, MCBs have shown
interesting reactivity in organic synthesis, and many reactions
based on MCBs have been developed in the past for the
synthesis of various acyclic and cyclic systems.8 Considering
the readily available bifuctional MCBs 2 with our protocol, we
envisioned that a possible route to cyclopentenones 7 from 2
could be realized via a process of epoxidation, pinacol-type ring
enlargement9 and further elimination (Scheme 4). Therefore,
we next investigated a new one-pot synthesis of cyclopentenones
using MCBs 2 as starting materials. Here, it should be mentioned
that cyclopentenones are not only important structural motifs
in the synthesis of natural products but also key structural units
in compounds with interesting biological activities.10 Although
a wide range of synthetic methods have been developed,11
General Procedure for Synthesis of MCBs 2 and 1,3-Conju-
gated Dienes 3. Under an atmosphere of dry nitrogen, 1.0 equiv of
ZnCl2 (0.5 mmol) was added to a solution of 2-(arylmethylene)clo-
propylaldehyde 1 (0.5 mmol) in 5 mL of dry CH2Cl2 at 0 °C. Then
1.5 equiv of acyl chloride (0.75 mmol) was injected. After being
stirred for 10-40 min (monitored by TLC), the mixture was
quenched with 5 mL of water and extracted with EtOAc (3 × 10
mL). The combined organic layers were dried over anhydrous
MgSO4. After filtration and removal of the solvent in vacuo, the
residues were purified with flash silica chromatography (petroleum
ether/ethyl acetate 15:1 v/v) to afford 2 or 3.
trans-Acetic Acid-(E)-2-benzylidene-4-chloro-cyclobutyl Ester
(2a). Oil, 1H NMR (400 Hz, CDCl3) δ 7.29-7.36 (m, 2H),
7.17-7.27 (m, 3H), 6.41-6.45 (m, 1H), 5.76-5.81 (m, 1H),
4.28-4.35 (m, 1H), 3.36-3.45 (m, 1H), 2.90-3.00 (m, 1H), 2.17
(s, 3H); 13C NMR (100 Hz, CDCl3) δ 20.7, 37.1, 52.4, 79.9, 124.4,
127.5, 127.8, 128.5, 132.7, 135.7, 169.9; IR (neat) 3057, 3027, 2931,
1740, 1599, 1493, 1224, 1052, 695, 511 cm-1; MS (70 eV, EI)
m/z 236 (M+); HRMS (EI) m/z calcd for C13H13O2Cl (M+)
236.0604, found 236.0607.
(6) (a) Olah, G. A.; Krishnamurti, R.; Prakash, G. K. S. In ComprehensiVe
Organic Synthesis; Trost, B. M., Fleming, I. Eds.; Pergamon Press: Oxford, 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. (c) Huang, X.; Yang, Y.-W. Org. Lett. 2007, 9, 1667.
(7) (a) Mazur, R. H.; White, W. W.; Semenoe, D. A.; Lee, C. C.; Silver,
M. S.; Roberts, J. D. J. Am. Chem. Soc. 1959, 81, 4390. (b) Wiberg, K. B.;
Shobe, D. S. J. Org. Chem. 1999, 64, 7768. (c) Shi, M.; Tian, G.-Q. Tetrahedron
Lett. 2003, 47, 8059.
(8) (a) Jan, C.-N.; Dieter, E.-K. Chem. ReV. 2003, 103, 1485. (b) Kakiuchi,
K.; Nakamura, I.; Matsuo, F.; Nakata, M.; Ogura, M.; Tobe, Y.; Kurosawa, H.
J. Org. Chem. 1995, 60, 3318. (c) Murakami, M.; Miyamoto, Y.; Ito, Y. J. Am.
Chem. Soc. 2001, 123, 6441. (d) Suffert, J.; Salem, B.; Klotz, P. J. Am. Chem.
Soc. 2001, 123, 12107.
General Procedure for Synthesis of Cyclopentanones 7. To a
stirred solution of MCBs 2 (0.2 mmol) in CH2Cl2 (2 mL) was added
m-CPBA (0.5 mmol) at room temperature. The mixture was stirred
overnight, and then (Tf)2O (0.2 mmol) was injected. After the
reaction was complete (1 h), the mixture was quenched with 5 mL
(11) (a) Schore, N. E. Chem. ReV. 1988, 88, 1081. (b) Giese, S.; Kastrup,
L.; Stiens, D.; West, F. G. Angew. Chem., Int. Ed. 2000, 39, 1970. (c) Morimoto,
T.; Fuji, K.; Tsutsumi, K.; Kakiuchi, K. J. Am. Chem. Soc. 2002, 124, 3806. (d)
Evans, P. A.; Robinson, J. E. J. Am. Chem. Soc. 2001, 123, 4609. (e) Sturla,
S. J.; Buchwald, S. L. Organometallics 2002, 21, 739.
(9) (a) Farcasiu, D.; Schleyer, P. v. R.; Ledlie, D. J. Org. Chem. 1973, 38,
3455. (b) Mahuteau-Betzer, F.; Ghosez, L. Tetrahedron Lett. 1999, 40, 5183.
(10) Chung, L. W.; Wiest, O.; Wu, Y.-D. J. Org. Chem. 2008, 73, 2649.
6886 J. Org. Chem. Vol. 73, No. 17, 2008

of water and extracted with EtOAc (3 × 5 mL). The combined
organic layers were dried over anhydrous MgSO4. After filtration
and removal of the solvent in vacuo, the residues were purified
with flash silica chromatography (petroleum ether/ethyl acetate 15:1
v/v) to afford 7.
Acknowledgment. We are grateful to the National Natural
Science Foundation of China (Project No. 20672095 and
20732005) and CAS Academician Foundation of Zhejiang
Province for financial support.
4-Chloro-2-phenylcyclopent-2-enone (7a). Oil, 1H NMR (400 Hz,
CDCl3) δ 7.70-7.76 (m, 2H), 7.64 (d, J ) 2.8 Hz 1H), 7.38-7.44
(m, 3H), 5.12-5.18 (m, 1H), 3.20 (dd, J1 ) 6.0, J2 ) 19.6 Hz,
1H), 2.85 (dd, J1 ) 2.0, J2 ) 19.2 Hz, 1H); 13C NMR (100 Hz,
CDCl3) δ 46.2, 52.6, 127.5, 128.6, 129.5, 129.8, 144.3, 154.5, 202.5;
IR (neat) 1712, 1126, 933, 762, 692 cm-1; MS (70 eV, EI) m/z
192 (M+); HRMS (EI) m/z calcd for C11H9OCl (M+) 192.0342,
found 192.0350.
Supporting Information Available: General experimental
procedures and spectroscopic data for all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
JO801021F
J. Org. Chem. Vol. 73, No. 17, 2008 6887