Ring-opening reactions of methylenecyclopropanes promoted by metal halides

Article abstract of DOI:10.1021/ol034142k

(Matrix presented) The methylenecyclopropanes (MCPs) react with various metal chlorides or bromides to give the corresponding homoallylic chlorides or bromides in good yields.

Full text of DOI:10.1021/ol034142k

ORGANIC
LETTERS
2003
Vol. 5, No. 9
1415-1418
Ring-Opening Reactions of
Methylenecyclopropanes Promoted by
Metal Halides
Bo Xu and Min Shi*
State Key Laboratory of Organometallic Chemistry,Shanghai Institute of Organic
Chemistry, Chinese Academy of Science, 354 Fenglin Lu, Shanghai 200032, China
mshi@pub.sioc.ac.cn
Received January 25, 2003 (Revised Manuscript Received March 26, 2003)
ABSTRACT
The methylenecyclopropanes (MCPs) react with various metal chlorides or bromides to give the corresponding homoallylic chlorides or bromides
in good yields.
Methylenecyclopropanes (MCPs) are highly strained but
readily accessible molecules that have served as useful
building blocks in organic synthesis.1 MCPs undergo a
variety of ring-opening reactions because the relief of ring
strain provides a potent thermodynamic driving force. Three
kinds of reaction patterns of MCPs have been disclosed
(Scheme 1) for reactions with transition metals such as Pd,
dehydes,6 and imines7 in the presence of a Pd catalyst to
give type I products. MCPs also can react with nonpolar
reactants such as R3SiH,8 R3SnH,9 R2B-BR2,10 R3Si-BR2,11
R3Si-CN,12 and olefins13 in the presence of a Pd, Ru, Rh,
(1) For a recent review, see: Nakamura, I.; Yamamoto, Y. AdV. Synth.
Catal.s 2002, 2, 111. For the synthesis of MCPs 1, see: Brandi, A.; Goti,
A. Chem. ReV. 1998, 98, 598.
(2) (a) Camacho, D. H.; Nakamura, I.; Saito, S.; Yamamoto, Y. Angew.
Chem., Int. Ed. 1999, 38, 3365. (b) Camacho, D. H.; Nakamura, I.; Saito,
S.; Yamamoto, Y. J. Org. Chem. 2001, 66, 270.
(3) Nakamura, I.; Itagaki, H.; Yamamoto, Y. J. Org. Chem. 1998, 63,
6458.
Scheme 1. Three Reaction Patterns of MCPs
(4) Tsukada, N.; Shibuya, A.; Nakamura, I.; Yamamoto, Y. J. Am. Chem.
Soc. 1997, 119, 8123.
(5) (a) Inoue, Y.; Hibi, T.; Sataka, H.; Hashimoto, H. J. Chem. Soc.,
Chem. Commun. 1979, 982. (b) Binger, P.; Germer, A. Chem. Ber. 1984,
114, 3325.
(6) Nakamura, I.; Oh, B. H.; Saito, S.; Yamamoto, Y. Angew. Chem.,
Int. Ed. 2001, 40, 1298.
(7) Oh, B. H.; Nakamura, I.; Saito, S.; Yamamoto, Y. Tetrahedron Lett.
2001, 42, 6203.
(8) 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.
(9) Lautens, M.; Meyer, C.; Lorenz, A. J. Am. Chem. Soc. 1996, 118,
10676.
(10) Ishiyama, T.; Momota, S.; Miyaura, N. Synlett. 1999, 1790.
(11) Suginome, M.; Matsuda, T.; Ito, Y. J. Am. Chem. Soc. 2000, 122,
11015.
(12) Chatani, N.; Takaya, H.; Hanafusa, T. Tetrahedron Lett. 1988, 29,
3979.
(13) The reactions of MCPs with unsaturated carbon bonds had been
extensively studied; see the review: Laurens, M.; Klute, W.; Tam, W. Chem.
ReV. 1996, 96, 49.
Rh, Ru, and Pt. MCPs can react with polar reactants such as
ROH,2 R2NH,3 malonate derivatives,4 carbon dioxide,5 al-
* To whom correspondence should be addressed. Fax: 86-21-64166128.
10.1021/ol034142k CCC: $25.00 © 2003 American Chemical Society
Published on Web 04/05/2003

or Pt metal catalyst to afford the type II and/or type III
products depending on the reaction conditions (Scheme 1).
Recently, we found that the ring-opening reactions of
MCPs 1 with alcohols and other nucleophiles catalyzed by
Lewis acids [Ln(OTf)3] took place via another novel manner
to give the corresponding ring-opened products under mild
conditions.14 This interesting result stimulated us to further
investigate the Lewis acid-catalyzed reactions of MCPs 1
with other reactants. Herein we wish to report the ring-
opening reactions of MCPs 1 promoted by metal halides
(Lewis acids) under mild conditions in which homoallylic
halides can be obtained in high yields in dichloromethane
(DCM) (Scheme 2).
but using ZnCl2 or CoCl2 (weak Lewis acid) as the catalyst,
no reaction occurred (Table 1, entries 6 and 7). In addition,
only a trace of 2a was formed in the presence of CuCl2
(Table 1, entry 5).
Next, we utilized TiCl4 and BiCl3 as the Lewis acid
promoters to examine the ring-opening reactions of various
MCPs 1. The results were shown in Table 2. For MCPs
Table 2. Reactions of MCPs 1 with TiCl4 or BiCl3
Scheme 2. Reaction of MCPs 1 with Metal Halides
entry
MCPs
MCln
time (h)
yieldb (%) (E/Z)
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1e
1f
TiCl4
TiCl4
TiCl4
TiCl4
TiCl4
BiCl3
TiCl4
BiCl3
TiCl4
TiCl4
BiCl3
BiCl3
2
2
2
2a , 82
2b, 77 (1:1)
2c, 84
During our own investigations, we found that MCPs 1
could react with many metal halides (Lewis acids) to give
the corresponding ring-opened homoallylic halides in good
yields, and the Lewis acidities of metal halides played a
critical role in this reaction. Using diphenylmethylenecyclo-
propane 1a (0.5 mmol) as the substrate, various metal
chlorides (0.75 mmol) have been tested for this ring-opening
reaction in dichloromethane (DCM) at room temperature (20
°C). The results were summarized in Table 1. The reactions
proceeded smoothly in the presence of TiCl4, BiCl3, FeCl3,
or AlCl3 (strong Lewis acids) to give the corresponding
homoallylic chloride 2a in good yields (Table 1, entries 1-4),
2
2d , 93
24
24
24
24
2
2
2
2
2e, 35 (3:4:1)
2e, 78 (3:4:1)
2f,30 (1:8:1)
2f, 75 (1:7:1)
trace
trace
trace
trace
1f
1g
1h
1h
1i
10
11
12
a All reactions were carried out with MCPs (1a-h) (0.5 mmol) and metal
chloride (0.75 mmol) using DCM solvent at room temperature and then
quenched with water. b All yields were isolated yields.
1a-d (both R1 and R2 are aromatic groups), the reactions
proceeded very well to give 2a-g in high yields within 2 h
in the presence of TiCl4 (Table 2, entries 1-4). For MCPs
1e,f (both R1 and R2 are aliphatic groups), the corresponding
homoallylic chlorides 2e and 2f were obtained in higher
yields using BiCl3 as the Lewis acid catalyst (reagent) for
24 h (Table 2, entries 5-8). However, it should be noted
that for 1g,h (R1 is aromatic group and R2 is hydrogen atom)
and 1i (R1 is aromatic group and R2 is methyl group) the
reactions only gave a trace of products in the presence of
TiCl4 or BiCl3 (Table 2, entries 9-12). It seems to us that
this kind of MCP 1g-i polymerizes easily in the presence
of metal halides (Lewis acids).
Table 1. Effects of Metal Chlorides (Lewis Acids) on the
Ring-Opening Reactions of MCP 1a
entrya
metal chloride
yieldb (%)
82
80
58
68
trace
no reaction
no reaction
1
2
3
4
5
6
7
TiCl4
BiCl3
FeCl3
AlCl3
CuCl2
ZnCl2
CoCl2
(14) (a) Shi, M.; Xu, B. Org. Lett. 2002, 4, 2145. (b) Shi, M.; Chen, Y.;
Xu, B.; Tang, J. Tetrahedron Lett. 2002, 43, 8019. On the other hand,
Kilburn reported Lewis acid mediated cascade reactions of silyl-substituted
methylenecyclopropane with ketones and aldehydes. (c) Peron, G. L. N.;
Kitteringham, J.; Kilburn, J. D. Tetrahedron Lett. 2000, 41, 1615. (d) Peron,
G. L. N.; Norton, D.; Kitteringham, J.; Kilburn, J. D. Tetrahedron Lett.
2001, 42, 347. (e) Patient, L.; Berry, M. B.; Kilburn, J. D. Tetrahedron
Lett. 2003, 44, 1015.
a All reactions were carried out with MCP (1a) (0.5 mmol) and metal
chloride (0.75 mmol) using DCM as solvent at room temperature and then
quenched with water. b Isolated yields.
1416
Org. Lett., Vol. 5, No. 9, 2003

The MCPs 1 react with TiBr4 to give the corresponding
homoallylic bromides 3 in good yields. The results are
elucidated in Table 3. For MCPs 1a-c (both R1 and R2 are
Table 4. Reactions of MCPs withTiCl4/n-Bu4N+I-
Table 3. Reactions of MCPs 1 with TiBr4 in CH2Cl2
entrya
MCPs
time (h)
yieldb (%)
1
2
3
1a
1c
1d
2
2
1
5a , 80 (2a , 19)
5c, 75 (2c, 18)
5d , 75 (2d , 17)
a All reactions were carried out with MCPs (1a, 1c, and 1d) (0.5 mmol),
TiCl4 (0.5 mmol), and Bu4N+I- (0.6 mmol) using DCM as solvent at room
temperature and then quenched with water. b All yields were isolated yields.
entrya
MCPs
time (h)
yieldb (%) (E/Z)
1
2
3
4
1a
1b
1c
1f
2
2
2
3a , 80
3b, 89 (1:1)
3c, 84
by Oshima was employed.15 The iodides 5 were indeed
obtained in good yields, but along with small amounts of
the corresponding homoallylic chlorides 3 (Table 4, entries
1-3). Moreover, the two halogenated products could not be
separated by silica gel flash column chromatograph.
24
3f, 45 (1:7:1)
a All reactions were carried out with MCPs 1 (0.5 mmol) and titanium
bromide (0.75 mol) using the DCM as solvents at room temperature and
then quenched with water. b All yields were isolated yields.
To avoid the contamination of the corresponding homo-
allylic chlorides, we examined a BF3‚Et2O/n-Bu4N•+I- (molar
ratio: 1/1.5) system. We found that by means of this reaction
system, the homoallylic iodides 5 could be isolated in
excellent yields. The results were elucidated in Table 5. Only
aromatic groups), the reaction proceeds very well to give
3a-c in high yields within 2 h (Table 3, entries 1-3). For
aliphatic MCP 1f, the corresponding homoallylic bromide
3f was obtained in the presence of TiBr4 in good yield for
24 h as well (Table 3, entry 4).
To complete this version of halogenation of MCPs 1, we
attempted to prepare the corresponding homoallylic iodides.
We first conducted the reaction of MCP 1a with TiI4 under
the same conditions as those described before. But, we found
that this reaction only gave diiodide product 4 in high yield
(95%) (Scheme 3). In fact, diiodide 4 can be obtained in the
Table 5. Reactions of MCPs 1 with BF3‚Et2O/n-Bu4N+I-
Scheme 3. Reaction of MCP 1a with TiI4 in CH2Cl2
entrya
MCPs
time (h)
yieldb (%) (E/Z)
1
2
3
4
1a
1b
1c
1d
2
2
2
2
5a , 95
5b, 100 (1:1)
5c, 98
5d , 53 (36)c
a All reactions were carried out with MCPs (0.5 mmol) and BF3•Et2O
(0.5 mmol) and Bu4N+I- (0.75 mmol) using DCM as solvent at room
temperature and then quenched water. b All yields were isolated yields.
c Yield of monodemethylation product.
presence of iodine (I2) quantitatively in DCM (Scheme 3).
Because we can find the deep color of I2 in the reaction
mixture of MCPs with TiI4, it can be concluded that part of
TiI4 was decomposed to I2 during the reaction and MCP 1a
further react with I2 to give diiodide product 4.
for MCP 1d, the homoallyilc iodide 5d was obtained in low
yield (Table 5, entry 4). This is because the BF3‚Et2O/n-
Bu4N•+I- system can cleave the MeO- group from aromatic
To synthesize the corresponding homoallylic iodides 5,
the TiCl4/n-Bu4N•+I- (molar ratio 1/1.2) system developed
(15) Han, Z.; Uehira, S.; Shinokubo, H.; Oshima, K. J. Org. Chem. 2001,
66, 7854.
Org. Lett., Vol. 5, No. 9, 2003
1417

ring even at room temperature (the mono-demethyl product
was isolated in 36% yield; see the Supporting Information).
In general, for unsymmetric MCPs 1 such as 1b, 1e, and
1f, the corresponding homoallylic halides are obtained as
the E/Z mixture with low stereoselectivities.
Scheme 5. Proposed Mechanism of the Ring-Opening Reaction
of MCPs 1 Promoted by TiCl4
With the success of the BF3‚Et2O/n-Bu4N•+I- system, we
then turned to the BF3‚Et2O/n-Bu4N•+F- system in order to
synthesize the corresponding homoallylic fluorides. But only
a trace of homoallylic fluoride product was obtained under
the same conditions. The major product was the homoallic
alcohol derived from the reaction of MCPs with water in
the presence of Lewis acid BF3‚Et2O.14a This may be due to
the weak nucleophilicity of fluoride ion and the large amount
of water present in commercially available n-Bu4N•+F-.
To probe the mechanism of this reaction and clarify the
proton source of this reaction, we quenched the reaction by
D2O instead of H2O. As a result, the deuterated product 6
was isolated in 75% yield with 70% D (Scheme 4).16 This
result suggest that the hydrogen atoms of homoallylic halides
were derived from the quenching proton source.
HBr proceeds very smoothly at 120 °C to produce the
corresponding homoallylic halides stereoselectively in good
to excellent yields.18
Scheme 4. Quenching Experiment Using D2O in the Reaction
of MCP 1a with TiCl4
In conclusion, we disclosed a transformation process of
MCPs 1 from the reaction with metal halides (Lewis acids)
to give the corresponding homoallylic halides in high yields
under mild reaction conditions. Efforts are in progress to
elucidate the mechanistic details of this reaction and to
determine its scope and limitations.
Acknowledgment. We thank the State Key Project of
Basic Research (Project 973) (No. G2000048007), Shanghai
Municipal Committee of Science and Technology, and the
National Natural Science Foundation of China for financial
support (20025206 and 20272069).
A plausible mechanism for the ring-opening reaction of
MCPs 1 promoted by TiCl4 was shown in Scheme 5. The
rearrangement of carbon cation 7 to 8 induced by Lewis acid
TiCl4 was the key step of this reaction.17 The intramolecular
chlorination of 9 gave intermediate 10, which produced the
final homoallylic chloride 2 by quenching with water.
After this work was submitted, Yamamoto reported that
the reaction of alkylidenecyclopropanes with HCl or with
Supporting Information Available: Spectroscopic data
of the compounds shown in Tables 1-5 and Scheme 3 and
detailed descriptions of experimental procedures. This ma-
terial is available free of charge via the Internet at
http://pubs.acs.org.
(16) The percentage of D was determined by the integration of 1H NMR
spectroscopic data of 6. We believe that part of reaction product was
quenched by ambient moisture (H2O) during reaction.
OL034142K
(18) Siriwardana, A. I.; Nakamura, I.; Yamamoto, Y. Tetrahedron Lett.
2003, 44, 985.
(17) Carey, F. A.; Tremper, H. S. J. Am. Chem. Soc. 1969, 91, 2967.
1418
Org. Lett., Vol. 5, No. 9, 2003