A synthetic protocol of trans-substituted cyclopentenes via the ring-opening rearrangement of MCP alkenyl derivatives

Article abstract of DOI:10.1021/jo902512q

(Chemical Equation Presented) A efficient method to stereospecifically synthesize trans-substituted cyclopentene derivatives via the ring-opening rearrangement of readily available MCP alkenyl derivatives in moderate to good yields has been described. The control experiment based on the deuterium labeling experiment and the addition of TEMPO revealed that this transformation might proceed through a fast concerted pericyclic process rather than a simple radical pathway or an ionic pathway.

Full text of DOI:10.1021/jo902512q

pubs.acs.org/joc
A Synthetic Protocol of Trans-Substituted Cyclopentenes via the
Ring-Opening Rearrangement of MCP Alkenyl Derivatives
Xiang-Ying Tang and Min Shi*
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 November 26, 2009
A efficient method to stereospecifically synthesize trans-substituted cyclopentene derivatives via the
ring-opening rearrangement of readily available MCP alkenyl derivatives in moderate to good yields
has been described. The control experiment based on the deuterium labeling experiment and the
addition of TEMPO revealed that this transformation might proceed through a fast concerted
pericyclic process rather than a simple radical pathway or an ionic pathway.
Introduction
accessibility as well as diverse reactivity driven by the relief
of ring strain.1 The ring-opening reactions of MCPs are
synthetically useful protocols in the construction of com-
plex product structures that have been studied extensively
thus far.2 For example, during the last 10 years, Lewis acids
and transition metal-catalyzed reactions involving ring-
opening of MCPs to form a variety of different carbocycles
and heterocycles have been extensively investigated. How-
ever, the ring-opening reactions of MCPs by thermally
induced rearrangements are relatively limited due to that
high temperature is usually required because of the huge
activation energy.3 Previously, we reported an efficient
synthetic route to 2,3-disubstituted pyrrolamides by ring-
opening cyclization of benzylidene and alkylidenecyclo-
propylcarbaldehydes with hydrazides upon heating in
toluene in moderate to good yields.4 Such a transformation
involves a ring-opening and thermally induced rearrange-
ment of MCPs to produce the five-membered nitrogen
atom containing heterocyclic ring. Herein, we wish to
report an efficient synthetic method to stereospecifically
produce trans-disubstituted cyclopentene derivatives 2, a
class of novel carbocycles, in moderate to good yields
(40-80%) by ring-opening rearrangement of MCP alkenyl
derivatives 1.
Methylenecyclopropanes (MCPs) are generally used
as building blocks in organic synthesis for their ready
*To whom correspondence should be addressed. Fax: 86-21-64166128.
(1) For selected reviews on MCPs, see: (a) Lautens, M.; Klute, W.; Tam,
W. Chem. Rev. 1996, 96, 49–92. (b) de Meijere, A.; Kozhushkov, S. I.;
Khlebnikov, A. F. Top. Curr. Chem. 2000, 207, 89–147. (c) Binger, P.;
Wedemann, P.; Kozhushkov, S. I.; de Meijere, A. Eur. J. Org. Chem. 1998,
113–119. (d) de Meijere, A.; Kozhushkov, S. I. A. Eur. J. Org. Chem. 2000,
3809–3822. (e) Nakamura, I.; Yamamoto, Y. Adv. Synth. Catal. 2002, 344,
111–129. (f ) Brandi, A.; Cicchi, S.; Cordero, F. M.; Goti, A. Chem. Rev.
2003, 103, 1213–1270. (g) Nakamura, E.; Yamago, S. Acc. Chem. Res. 2002,
35, 867–877. (h) Shao, L.-X.; Shi, M. Curr. Org. Chem. 2007, 11, 1135–1137.
(i) Rubin, M.; Rubina, M.; Gevorgyan, V. Chem. Rev. 2007, 107, 3117–3179.
( j) Yamago, S.; Nakamura, E. Org. React. 2002, 61, 1–217. (k) de Meijere,
A.; Kozhushkov, S. I.; Spath, T.; von Seebach, M.; Lohr, S.; Nuske, H.;
Pohomann, T.; Es-Sayed, M.; Brase, S. Pure. Appl. Chem. 2000, 72, 1745–
1756.
(2) For selected examples on the reactions of MCPs, see: (a) Hu, B.; Xing,
S. Y.; Wang, Z. W. Org. Lett. 2008, 10, 5481–5484. (b) Shi, M.; Liu, L.-P.;
Tang, J. Org. Lett. 2006, 8, 4043–4046. (c) Shi, M.; Xu, B.; Huang, J.-W. Org.
Lett. 2004, 6, 1175–1178. (d) Huang, X.; Yang, Y. Org. Lett. 2007, 9, 1667–
1670. (e) Lautens, M.; Han, W.; Liu, J. H. J. Am. Chem. Soc. 2003, 125, 4028–
4029. (f ) Lautens, M.; Ren, Y. J. Am. Chem. Soc. 1996, 118, 10668–10669. (g)
Yu, L.; Meng, J. D.; Xia, L.; Guo, R. J. Org. Chem. 2009, 74, 5087–5089. (h)
Ma, S.; Zhang, J. Angew. Chem., Int. Ed. 2003, 42, 183–187. (i) Ma, S.; Lu, L.;
Zhang, J. J. Am. Chem. Soc. 2004, 126, 9645–9660. ( j) Lu, L.; Chen, G.; Ma,
S. Org. Lett. 2006, 8, 835–838. (k) Scott, M. E.; Lautens, M. J. Org. Chem.
2008, 73, 8154–8162. (l) Taillier, C.; Lautens, M. Org. Lett. 2007, 9, 591–593.
(m) Smolensky, E.; Kapon, M.; Eisen, M. S. Organometallics 2007, 26, 4510–
4527. (n) Diev, V. V.; Tung, T. Q.; Molchanov, A. P. Eur. J. Org. Chem. 2009,
525–530. (o) Hu, B.; Zhu, J. L.; Xing, S. Y.; Fang, J.; Du, D.; Wang, Z. W.
Chem.;Eur. J. 2009, 15, 324–327. (p) Bagutski, V.; de Meijere, A. Adv.
Synth. Catal. 2007, 349, 1247–1255. (q) Hang, X.-C.; Chen, Q.-Y.; Xiao,
J.-C. Eur.J. Org.Chem. 2008, 1101–1106. (r) Nakamura, I.; Oh, B. H.;Saito,S.;
Yamamoto, Y. Angew. Chem., Int. Ed. 2001, 40, 1298–1300. (s) Kurahashi, T.;
de Meijere, A. Angew. Chem., Int. Ed. 2005, 44, 7881–7884. (t) Huang, X.;
Zhou, H. Org. Lett. 2002, 4, 4419–4422.
(3) In fact, the thermally induced rearrangement of MCPs is rare. How-
ever, vinylcyclopropane is investigated extensively and there are a few
examples; please see: (a) Houk, K. N.; Nendel, M.; Wiest, O.; Storer,
J. W. J. Am. Chem. Soc. 1997, 119, 10545–10546. (b) Baldwin, J. E.; Bonacorsi,
S., Jr. J.Am. Chem. Soc. 1996, 118, 8258–8265. (c) Gajewski, J. J. Hydrocarbons
Thermal Isomerizations; Academic: New York, 1980; pp 81-87.
(4) Tang, X.-Y.; Shi, M. J. Org. Chem. 2009, 74, 5983–5986.
902 J. Org. Chem. 2010, 75, 902–905
Published on Web 01/13/2010
DOI: 10.1021/jo902512q
r
2010 American Chemical Society

Tang and Shi
JOCArticle
TABLE 1. Rearrangement of MCP Alkenyl Derivative (1a) under
Various Reaction Conditions
entrya
solvent
toluene
t (°C)
time (h)
yield (%)b of 2a
1
2
3
4
5
6
7
8
9
90
90
12.0
2.0
1.5
1.0
0.8
0.7
0.5
1.0
1.0
1.0
1.0
1.0
25
48
57
80
69
70
63
60
55
56
78
58
toluene
toluene
toluene
toluene
toluene
xylene
100
100
100
110
120
100
100
100
100
100
DCE
dioxane
isopropanol
CH3NO2
DMSO
10
11
12
aReaction scale: 0.2 mmol of 1a in 2.0 mL of toluene. bIsolated yields.
Results and Discussion
We initially utilized 1a as a model to investigate its
reaction outcomes upon heating in toluene (Table 1, entries
1-4) (for the synthesis of 1a, please see the Supporting
Information). It was found that treatment of 1a at 90 °C in
toluene for 12 h delivered one major product as a yellow
liquid, which was later characterized as 1-(4-methylene-
5-phenylcyclopent-2-enyl)ethanone (2a), in 25% yield on
the basis of its spectral and analytical data after usual
workup and purification by column chromatography on
silica gel, although the relative configuration of the two
substituents on the cyclopentene ring could not be deter-
mined on the basis of its 1H NMR spectroscopic data
(Table 1, entry 1). Fortunately, its structure was further
confirmed by the X-ray single-crystal analysis of its analogue
2p (Figure 1).5 Therefore, the configuration of the two
substitutes on the cyclopentene ring could be identified as
trans.6 Considering that the reaction time might be the
crucial factor in the yield of 2a, we monitored the reaction
proceeding by TLC plates under the same conditions and
found that the starting material 1a was consumed within 2 h,
affording 2a in 48% yield (Table 1, entry 2). Moreover, when
raising the reaction temperature to 100 °C and reducing the
reaction time to 1.5, 1.0, and 0.8 h, the resulting 2a was given
in 57%, 80%, and 69% yield, respectively (Table 1, entries
3-5). However, if running the reaction at 110 or 120 °C in
toluene for 0.7 h or xylene for 0.5 h, 2a was obtained in 70%
and 63% yield, respectively (Table 1, entries 6 and 7). Other
solvents such as 1,2-dichloromethane (DCE), dioxane, iso-
propanol, nitromethane, and dimethyl sulfoxide (DMSO)
were also investigated under the standard conditions, leading
to formation of 2a in 55-78% yields, respectively (Table 1,
entries 8-12). Therefore, the optimized reaction conditions
FIGURE 1. X-ray crystal and two-dimensional structure of 2p.
TABLE 2. Rearrangement of Various MCP Alkenyl Derivatives
entrya
R1
R2
yield (%)b of 2
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
p-BrC6H4, 1b
p-ClC6H4, 1c
o-BrC6H4, 1d
3,5-Br2C6H3, 1e
3,4,5-(MeO)3C6H2, 1f
4-MeC6H4, 1g
3,4-Me2C6H4, 1h
m-CH3C6H4, 1i
C7H15, 1j
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
2b, 60
2c, 63
2d, 64
2e, 51
2f, 75
2g, 76
2h, 71
2i, 71
2j, 40
Z-1a
C6H5, 1k
2a, 70
2k, 72
2l, 66
2m, 68
2n, 54
2o, 76
no reaction
p-BrC6H4, 1l
p-ClC6H4, 1m
p-BrC6H4, 1n
2-furan, 1o
C6H5
C6H5
p-BrC6H4
Me
C6H5, 1a0
OEt
aReaction scale: 0.2 mmol of 1a in 2.0 mL of toluene. bIsolated yields.
were determined to carry out the reaction in toluene
at 100 °C.
With these optimized reaction conditions in hand, we next
attempted to study the scope and limitations of this reaction
by using a variety of other MCP alkenyl compounds. The
results are outlined in Table 2. As for substrates 1b-d having
an electron-withdrawing group substituted aromatic group
(R1), the corresponding cyclopentene derivatives 2b-d were
obtained in 60-64% yields (Table 2, entries 1-3). However,
if two electron-withdrawing Br atoms were introduced on the
benzene ring of R1, the yield of 2e decreased to 51% (Table 1,
entry 4). On the other hand, in the cases of substrates 1f-i in
(5) The crystal data of 2p have been deposited in CCDC with number
752267. Empirical formula: C25H19BrO; formula weight: 415.31; crystal size:
0.397 ꢀ 0.269 ꢀ 0.172; crystal color, habit: colorless, prismatic; crystal sys-
˚
tem: monoclinic; lattice type: primitive; lattice parameters: a=6.3664(10) A,
o
˚
˚
b=8.9574(14)A, c=34.323(5)A, R=90°, β=94.721(3) , γ=90°, V=1950.7(5)
A ; space group: P2(1)/n; Z=4; Dcalc=1.414 g/cm3; F000=848; R1=0.0461,
3
˚
wR2=0.1036. Diffractometer: Rigaku AFC7R.
(6) No cis isomers were detected in this reaction on the basis of the 1H
NMR spectrum of crude 2a. See the Supporting Information.
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SCHEME 1. A One-Pot Manner for the Synthesis of Cyclo-
pentenes
SCHEME 2. Deuterium Labeling Experiment
SCHEME 3. A Control Experiment
which the aryl groups have electron-donating Me or MeO
substitutes, the reaction proceeded more cleanly and
smoothly, affording the corresponding products 2f-i in
higher yields (71-76%) (Table 2, entries 5-8). We also
turned our interest to alkyl group substituted substrate 1i
(R1=C7H15). After heating at 100 °C in toluene for 1.0 h, the
corresponding cyclopentene product 2i was given in 40%
yield (Table 2, entry 9). It also should be noted that, using
(Z)-4-[(E)-2-benzylidenecyclopropyl]but-3-en-2-one (Z-1a)
as the substrate, the same product 2a could be formed in
70% yield under identical conditions (Table 2, entry 10).
Furthermore, the R2 group was also not restricted to a
methyl group. Changing it into an ethyl and aryl group, to
our delight, the corresponding cyclopentene derivatives
2k-n were obtained in 54-72% yields (Table 2, entries
11-14). When a heteroaromatic ring was introduced into
the substrate (R1=2-furanyl), the corresponding product 2o
was formed in 76% yield (Table 2, entry 15), suggesting that
this synthetic method to cyclopentenes has a broad substrate
generality. As for MCP alkenyl derivative 1a0, no reaction
occurred under the standard conditions (Table 2, entry 16).
Considering that it might be feasible to synthesize the
cyclopentene derivatives from more common starting mate-
rials, therefore, two experiments were carried out by using a
one-pot manner by heating MCP aldehyde and phosphorane
ylide in toluene together. Interestingly, as assumed, the
corresponding cyclopentenes 2n and 2p were obtained in
42% and 32% yield, respectively, although the reaction
time should be prolonged to 3 h because such a Wittig
reaction was sluggish under the standard reaction conditions
(Scheme 1). The moderate yields of 2n and 2p were presum-
ably due to that the prolonged heating time did not favor the
formation of cyclopentene derivatives.
To gain more mechanistic insight into the ring-opening/
recyclization reaction, two control experiments were con-
ducted under identical reaction conditions. Upon treating
1b-d (D content: >99%) at 100 °C in toluene for 1.0 h, we
found that no H-D exchange or migration was observed in
product 2b-d (D content: >99%) (Scheme 2, for the details,
see the Supporting Information). Another control experi-
ment was carried out by adding 2.0 equiv of 2,2,6,6-tetra-
methyl-1-piperidinyloxy (TEMPO) as a free radical scaven-
ger into the reaction system to quench the supposed biradical
intermediate. However, it was found that the formation of 2a
was unaffected by the addition of the radical inhibitor such
as TEMPO since 2a was formed in 79% yield, rendering
unlikely the intervention of a radical pathway (Scheme 3).
On the basis of these results, a concerted pericyclic process is
a more reasonable mechanism for the formation of 2a.
SCHEME 4. Plausible Reaction Mechanism
Thereby, we consider that the reaction may proceed through
a Cope rearrangement.7 A plausible mechanism for the
formation of 2a is outlined in Scheme 4, using 1a as a model.
This transformation proceeds via a chairlike transition state
(TS) in which the steric interaction between the substituents
is minimal. It should also be noted that if using Z-1a as
the substrate, the same product 2a could be formed in
70% yield under identical conditions (Table 2, entry 10).
Moreover, compound 2a0 was not observed on the basis of
NMR spectroscopy, suggesting that 2a0 is unstable and it
might be quickly transformed to 2a under the standard
conditions.8
At this stage, we also conducted some simple transforma-
tion of 2a to understand its chemical behavior. Treatment of
2a with 1.2 equiv of methylmagnesium bromide gave a
tertiary alcohol derivative in 88% yield (for the details, see
the Supporting Information). On the other hand, after
reduction of 2a with NaBH4 in dichloromethane (DCM),
the resulting alcohol was condensed without purification
with 3,5-bis(benzyloxy)benzoic acid in the presence of N,N0-
dicyclohexylcarbodiimide (DCC) and 4-N,N-dimethylpyri-
dine (DMAP) in DCM, yielding the corresponding ester in
74% yield (for the details, see the Supporting Information).
In summary, a convenient and efficient method for
the synthesis of novel cyclopentene derivatives 2 has been
(7) (a) Baird, M. S. Chem. Rev. 2003, 103, 1271–1294. (b) Cope, A. C.;
Hardy, E. M. J. Am. Chem. Soc. 1940, 62, 441. (c) Evans, D. A.; Golob, A. M.
J. Am. Chem. Soc. 1975, 97, 4765.
(8) It can be seen from the 1H NMR spectrum of crude 2a (see the
Supporting Information) that none of 2a0 is contained in the reaction
mixture. According to this result, we assume that 2a0 is unstable and it might
be quickly transformed to 2a under the standard conditions.
904 J. Org. Chem. Vol. 75, No. 3, 2010

Tang and Shi
JOCArticle
developed through the thermally induced ring-opening re-
arrangement of MCPs 1. This synthetic protocol is asso-
ciated with readily available starting materials, a wide rang
of substrates, and easy control of the reaction conditions.
Furthermore, the plausible reaction mechanism has been
discussed on the basis of deuterium labeling and control
experiments, rendering that a pericyclic mechanism may be
responsible for this thermally induced rearrangement. The
potential utilization and extension of the scope of the
methodology are currently under investigation.
14.6, 17.0, 26.8, 120.8, 126.0, 126.8, 127.5, 128.5, 129.5, 136.7,
149.7, 197.7; IR (CH2Cl2) ν 3060, 3028, 3003, 2922, 1783, 1713,
1626, 1495, 1452, 1360, 1256 cm-1; MS (EI) m/z (%) 198 [Mþ]
(19.2), 172 (50.7), 157 (29.8), 155 (100.0), 129 (43.9), 128 (36.2),
115 (30.4), 43 (29.2); HRMS (EI) calcd for C14H14O (Mþ)
requires 198.1045, found 198.1044.
Compound 2a: yellow oil; 1H NMR (CDCl3, 400 MHz, TMS)
δ 2.17 (s, 3H, CH3), 3.78-3.80 (m, 1H, CH), 4.18-4.21 (m, 1H,
CH), 4.64 (br s, 1H, CH), 5.07 (d, J=2.4 Hz, 1H, CH), 6.13-6.16
(m, 1H, CH), 6.39 (dd, J=5.6, 2.4 Hz, 1H), 7.18-7.25 (m, 3H,
Ar), 7.28-7.32 (m, 2H, Ar); 13C NMR (CDCl3, 100 MHz, TMS)
δ 28.5, 49.1, 69.1, 107.5, 126.6, 127.8, 128.6, 133.4, 136.0, 144.3,
156.5, 206.5; IR (CH2Cl2) ν 3057, 2938, 2838, 1712, 1633, 1588,
1505, 1460, 1423 cm-1; MS (EI) m/z (%) 198 [Mþ] (37.8), 156
(29.9), 155 (100.0), 154 (23.6), 153 (33.0), 152 (14.3), 115 (15.3),
43 (15.7); HRMS (EI) calcd for C14H14O (Mþ) requires
198.1045, found 198.1044.
Experimental Section
General Procedure for the Preparation of 1a. To 5 mL of DCM
in a 25 mL round-bottomed flask was added (E)-2-benzylide-
necyclopropanecarbaldehyde (158.0 mg, 1.0 mmol) and ylide
(380.0 mg, 1.2 mmol); the mixture was then stirred at room
temperature (rt, 20 °C) until most of the aldehyde was consumed
(ca. 24 h). The solvent was removed under reduced pressure and
the residue was purified by a flash column chromatography to
give 1a (143.0 mg, 0.72 mmol, 72% yield).
General Procedure for the Thermally Induced Rearrangement
of (E)-4-((E)-2-Benzylidenecyclopropyl)but-3-en-2-one, 1a. A
Schlenk tube was charged with (E)-4-((E)-2-benzylidene-
cyclopropyl)but-3-en-2-one (1a) (39.6 mg, 0.2 mmol) and to-
luene (2.0 mL), cooled with liquid nitrogen, then vacuumed by
pump and subsequently vented with Ar. After being warmed to
rt, the reaction was stirred at 100 °C for 1 h. The solvent was
removed under reduced pressure and then the residue was
purified by flash column chromatography.
Acknowledgment. We thank the Shanghai Municipal
Committee of Science and Technology (06XD14005 and
08dj1400100-2), National Basic Research Program of China
(973)-2009CB825300, and the National Natural Science
Foundation of China for financial support (20872162,
20672127, 20732008, 20821002, and 20702013) and Mr. Jie
Sun (State Key Laboratory of Organometallic Chemistry,
Shanghai Institute of Organic Chemistry) for performing
X-ray diffraction.
Supporting Information Available: The spectroscopic data
(1H, 13C spectroscopic data), HRMS of the compounds shown
in Tables 1 and 2, the X-ray crystal structure of compound 2p
along with the detailed description of experimental procedures.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Compound 1a: yellow oil; 1H NMR (CDCl3, 400 MHz, TMS)
δ 1.63-1.67 (m, 1H), 2.08-2.21 (m, 1H), 2.22 (s, 3H, CH3),
2.32-2.38 (m, 1H), 6.25 (d, J=16 Hz, 1H, CH), 6.39 (dd, J=16,
9.2 Hz, 1H), 7.23-7.28 (m, 1H, Ar), 7.32-7.37 (m, 2H, Ar),
7.50-7.53 (m, 2H, Ar); 13C NMR (CDCl3, 100 MHz, TMS) δ
J. Org. Chem. Vol. 75, No. 3, 2010 905