Titanium(IV) chloride-mediated intramolecular ring enlargement of methylenecyclopropanes with propargylic esters: A concise synthesis of bicyclo[4.2.0]oct-5-ene derivatives

Article abstract of DOI:10.1016/j.tetlet.2011.09.124

Titanium(IV) chloride-mediated intramolecular ring enlargement of methylenecyclopropanes with propargylic esters has been described in this context, affording the corresponding chlorinated bicyclo[4.2.0]oct-5-ene derivatives in moderate to good yields und

Full text of DOI:10.1016/j.tetlet.2011.09.124

Tetrahedron Letters 52 (2011) 6541–6544
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Titanium(IV) chloride-mediated intramolecular ring enlargement
of methylenecyclopropanes with propargylic esters: a concise synthesis
of bicyclo[4.2.0]oct-5-ene derivatives
Zhen Zhang a, Min Shi a,b,
⇑
a Laboratory for Advanced Materials & Institute of Fine Chemicals, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237, China
b State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Titanium(IV) chloride-mediated intramolecular ring enlargement of methylenecyclopropanes with
propargylic esters has been described in this context, affording the corresponding chlorinated
bicyclo[4.2.0]oct-5-ene derivatives in moderate to good yields under mild conditions. The E- and Z-meth-
ylenecyclopropanes could all be converted to the corresponding bicyclo[4.2.0]oct-5-enes with moderate
to high diastereoselectivities.
Received 25 July 2011
Revised 30 August 2011
Accepted 6 September 2011
Available online 5 October 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Carbocyclization
Titanium chloride
Methylenecyclopropanes
Propargylic esters
Ring enlargement
In recent years, propargylic esters have received extensive
attention as a special class of alkynes for their rich reactivities
and easy availabilities. Many transition-metal-catalysts, such as
gold,1 platinum,2 palladium,3 ruthenium,4 and rhodium,5 have
been identified as effective promoters in their transformations to
a variety of valuable substances. To the best of our knowledge,
examples using other metal catalysts in their transformations are
rare. One notable example is the use of metal halide such as FeCl3,
CuCl, or TiCl4 as Lewis acid in nucleophilic displacement reactions
of propargylic esters under mild conditions, affording the corre-
examine other novel intramolecular carbocyclization processes to
access other interesting bicyclic ring skeletons. Herein, we wish
to report an efficient route to accomplish the synthesis of bicy-
clo[4.2.0]oct-5-ene derivatives which have been only synthesized
upon heating allenes at high temperature in dioxane or DMF
through thermal-induced intramolecular [2+2] cycloaddition
reactions.9
Initially, we examined the carbocyclization of E-1a using TiCl4 as
a Lewis acid promoter in various solvents such as toluene, chloro-
form, perchloromethane, 1,2-dichloroethane, and dichloromethane,
and found that the corresponding chlorinated cycloisomerization
product 2a was formed in 56% yield along with 10:1 diastereoselec-
sponding
a
-substituted propargylic compounds in good yields.6
However, using these inexpensive metal halides to produce struc-
turally complex molecules is relatively limited.
Carbocyclization of enynes is a powerful method in organic syn-
thesis to access carbo- or heterobicyclic rings which are important
structural motifs found in many natural and pharmaceutical
materials. Gold, platinum, or palladium-catalyzed intramolecular
cycloisomerization of propargylic esters is an efficient route to syn-
thesize a variety of bicyclo[n.1.0]enol esters in good yields (Scheme
1a).7 More recently, we have found that titanium(IV) chloride and
bismuth(III) chloride can serve as effective promoters to achieve
the synthesis of chlorinated 3-azabicyclo[3.1.0]hexanes from the
corresponding easily available propargylic esters under mild
conditions (Scheme 1b).8 These intriguing results promote us to
AcO
R2
R2
OAc
R1
R1
Au, Pt or Pd cat.
(a)
(b)
n
n
R2
R2
Ar
OAc
R2
Cl
R2
TiCl4 or BiCl3
R1
N
R1
N
Ar
⇑
Corresponding author. Tel.: +86 21 54925137; fax: +86 21 64166128.
E-mail address: Mshi@mail.sioc.ac.cn (M. Shi).
Scheme 1. (a) The Rautenstrauch cyclopropanation catalyzed by Au, Pt, or Pd
catalysts. (b) Carbocyclization of enynes mediated by TiCl4 or BiCl3.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.09.124

6542
Z. Zhang, M. Shi / Tetrahedron Letters 52 (2011) 6541–6544
Table 1
(Table 1, entry 6). Upon changing the employed amount of TiCl4 to
Optimization of the reaction conditions
0.80 or 1.50 equiv, 2a were obtained in 45% and 27% yields, respec-
tively, under otherwise identical conditions (Table 1, entries 7 and
8). Further optimization of the reaction conditions revealed that
decreasing the reaction temperature to 0 and À20 °C did not give
2a in higher yield (Table 1, entries 9 and 10). By slow addition of
the substrate E-1a to the solution of 2.0 equiv TiCl4 in dichlorometh-
ane with a syringe pump, 2a was obtained in 61% yield after 2 h
along with 3:1 diastereoselectivity (cis:trans) (Table 1, entry 11).
Other titanium(IV) Lewis acids were not suitable promoters in this
reaction (Table 1, entries 12 and 13).
Next, with the optimized conditions in hand, we investigated
the substrate scope of this TiCl4-mediated carbocyclization with
various methylenecyclopropanes E-1b–E-1k in the synthesis of
3-azabicyclo[4.2.0]oct-5-enes and the results are summarized in
Table 2. As can be seen from Table 2, as for substrates E-1b, E-1c,
and E-1h–E-1k bearing electron-withdrawing groups (chloride or
bromide) on their benzene rings, the reactions proceeded smoothly
to give the desired products 2b, 2c, and 2h–2k in 44–62% yields at
room temperature along with moderate diastereoselectivities
(25 °C) (Table 2, entries 1, 2, and 7–10). The stereochemistry of
3-azabicyclo[4.2.0]oct-5-ene has been unequivocally confirmed
by X-ray diffraction of the representative product cis-2h. Its ORTEP
drawing is indicated in Figure 1 and the corresponding CIF data
have been presented in the Supplementary data. However, intro-
ducing electron-donating groups (methyl or methoxy group) at
their aryl units, such as substrates E-1d and E-1e, afforded the cor-
responding products in poor yields, presumably due to the elec-
tronic effect (Table 2, entries 3 and 4). For the cycloalkyl group
substituted propargylic esters E-1f and E-1g, the corresponding
products 2f and 2g were obtained in 40% and 39% yields with
Me
Me
Me
Me
OAc
Me
Cl
N
Cl
Ts
N
Ph
Lewis acid
solvent
Ph
Me
+
N
Ts
Ts
Ph
2a
cis-
E-1a
trans-2a
Yieldb (cis:trans)
Entrya
Lewis acid (equiv)
Solvent
T [°C]
1
2
3
4
5
TiCl4 (1.2)
TiCl4 (1.2)
TiCl4 (1.2)
TiCl4 (1.2)
TiCl4 (1.2)
TiCl4 (1.2)
TiCl4 (0.8)
TiCl4 (1.5)
TiCl4 (1.1)
TiCl4 (1.1)
TiCl4 (2.0)
TiCl3 (OiPr) (2.0)
TiCl3 (OTf) (1.2)
Toluene
CHCl3
CCl4
rt
rt
rt
rt
rt
rt
rt
rt
0
-20
rt
rt
rt
Complex
Complex
42% (2:1)
28% (2:1)
56% (10:1)
47% (4:1)
45% (3:1)
27% (5:1)
37% (3:1)
25% (2:1)
61% (3:1)
Complex
21% (2:1)
ClCH2CH2Cl
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
6c
7
8
9d
10e
11f
12
13
a
[E-1a] = 0.10 M, <10 min.
The diastereomeric ratio was determined by 1H NMR spectroscopic data of the
b
isolated product.
c
[E-1a] = 0.05 M.
d
3 h.
6 h.
e
f
E-1a (0.20 M in CH2Cl2) was added to the solution of TiCl4 (0.40 M in CH2Cl2)
using a syringe pump over 2 h.
tivity (cis:trans) in dichloromethane at room temperature within
10 min (Table 1, entries 1–5). Decreasing the concentration of
E-1a from 0.10 to 0.05 M did not improve the reaction outcome
Table 2
TiCl4-mediated synthesis of 2 from E-1
Entrya
Substrate
Product
Yieldb (cis:trans)
1
2
3
4
48% (3:1)
62% (4:1)
30% (5:1)
OAc
Me
Me
Me
Me
E-1b, R = Cl
E-1c, R = Br
2b
48% (3:1)
Cl
R
Ts N
2c 62% (4:1)
15% (>20:1)
E-1d, R = Me
1e
E- , R = OMe
2d
2e
30% (5:1)
N
R
Ts
15% (>20:1)
5
6
40% (>20:1)
39% (5:1)
AcO
n
n
Cl
Br
Br
1f
E- , n = 1
Ts N
2f
40% (>20:1)
E-1g, n = 2
2g 39% (5:1)
Br
Br
N
Ts
OAc
Me
Me
Me
Cl
Bs N
Ts N
Me
1h
E-
2h
52% (3:1)
7
52% (3:1)
N
Bs
8
9
10
44% (3:1)
54% (3:1)
50% (3:1)
OAc
Me
Me
2i
44% (3:1)
54% (3:1)
50% (3:1)
1i
E- , R = 2-Cl
Me
Cl
Me
R
2j
2k
1j
E- , R = 3-Cl
N
E-1k, R = 2,3-Cl2
Ts
R
OAc
Me
Me
Me
Me
Cl
Cl
O
11c
0
E-1l
2l
0
Cl
O
a
b
c
[1] = 0.10 M, 1.2 equiv TiCl4, rt, 10 min.
The diastereomeric ratio was determined by 1H NMR spectroscopic data of the isolated product.
Decomposed.

Z. Zhang, M. Shi / Tetrahedron Letters 52 (2011) 6541–6544
6543
Cl4Ti
R
O
R
O
R
O
O
R
– AcO–
TiCl4
X
N
Ar
X N
X
N
R
R
B
A
Ar
Ar
1
Cl
Cl3
R
Ti
R
R
R
OAc
Cl
N
R
R
Ar
Ar
X
N
Ar
Figure 1. ORTEP drawing of cis-2h.
N
X
X
C
2
D
excellent diastereoselectivities, respectively (Table 2, entries 5 and
6). Moreover, ortho- or meta-substitution on the aromatic ring did
not significantly interfere with the reaction outcomes (Table 2, en-
tries 8–10). Other substrate such as E-1l tethered by an oxygen
atom was also tested under the standard conditions, but none of
the corresponding product 2l was observed (Table 2, entries 11).
To gain more insight into this TiCl4-mediated transformation of
1 to 2, we investigated the stereochemical course of ring enlarge-
ment of methylenecyclopropanes (MCPs) using Z-1a and Z-1d as
the substrates under the standard conditions and found that the
products 2a and 2d having the same diastereoselectivities as those
described in Table 2 were obtained in 52% and 42% yields, respec-
tively (Scheme 2). Substrate 1m having an alkyl group substituted
methylenecyclopropane was also tested in this reaction, but the
corresponding nucleophilic displacement product 3 was afforded
in 52% yield without the formation of 3-azabicyclo[4.2.0]oct-5-
ene under the standard conditions (Scheme 3).
Based on the above investigations, we proposed a plausible
reaction mechanism for this TiCl4-mediated carbocyclization in
Scheme 4. Coordination of the ester group to TiCl4 gives intermedi-
ate A.10 The nucleophilic intramolecular addition of the pendant
methylenecyclopropane to the alkyne moiety along with the
release of acyloxy group affords carbocation B, which contains a
vinylidene moiety.11 Subsequently, carbocationic intermediate B
undergoes intramolecular ring enlargement of cyclopropane12
via 1,2-carbon migration13 gives intermediate C which can give
vinyl cationic intermediate D through isomerization. Then chloride
ion is transferred to vinyl cation from the in situ generated
metal complex, affording the corresponding chlorinated bicy-
Scheme 4. A plausible reaction mechanism.
clo[4.2.0]oct-5-ene 2.14 It should be noted that carbocation B could
be stabilized by the neighboring aryl unit which can serve as a
driving force for this transformation. While alkyl group substituted
methylenecyclopropane could not afford the stabilized intermedi-
ate B, only producing the corresponding chlorinated nucleophilic
displacement compound 3. Moreover, as can be seen from Scheme
4, E- and Z-methylenecyclopropanes give the same benzylic cation
B under identical conditions. This can explain why the same prod-
ucts could be formed using Z-1a and E-1a as the substrates.
In conclusion, we have explored a novel synthetic route to ac-
cess nitrogen-containing heterocycles by means of TiCl4-mediated
carbocyclization of enyne derivatives under mild conditions. The
corresponding chlorinated bicyclo[4.2.0]oct-5-ene derivatives 2
could be afforded by the intramolecular ring enlargement of mono-
arylmethylenecyclopropanes with propargylic esters along with
moderate to high diastereoselectivities. In the cases of enyne deriv-
atives 1 having electron-deficient aromatic ring within MCP moi-
ety, the corresponding chlorinated bicyclo[4.2.0]oct-5-enes were
obtained in moderate to good yields whether they are E- and Z-
monoarylmethylenecyclopropanes. On the basis of the above re-
sults, we believe that TiCl4 could be one of the choices being used
to mediate the cyclization of enyne derivatives for the construction
of various heterocycles as well. Further investigation on the mech-
anistic insights and the extension of this procedure to the synthesis
of other heterocycles are ongoing in our laboratory.
Acknowledgments
OAc
Me
Me
Me
We thank the Shanghai Municipal Committee of Science and
Technology (08dj1400100-2), National Basic Research Program of
China (973)-2009CB825300, the Fundamental Research Funds for
the Central Universities, and the National Natural Science Founda-
tion of China for financial support (21072206, 20472096,
20872162, 20672127, 20821002, and 20732008) and Mr. Jie Sun
for performing X-ray diffraction.
Ts
N
Me
Cl
R
TiCl4 (1.2 equiv)
CH2Cl2, rt, 5 min
N
Ts
1a
Z- , R = H
1d
Z- , R = Me
2a, 52% yield, 3:1 cis:trans
2d, 42% yield, 4:1 cis:trans
R
Supplementary data
Scheme 2. The transformation of Z-1.
Supplementary data associated (general procedures and spec-
tral data) with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2011.09.124.
OAc
Me
Me
Cl
Me
TiCl4 (1.2 equiv)
CH2Cl2,rt, 5 min
Ts
N
Ts N
Me
References and notes
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Scheme 3. The transformation of 1m.

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