Lewis acid-catalyzed ring-opening reactions of methylenecyclopropanes with alcoholic or acidic nucleophiles

Article abstract of DOI:10.1021/ol0259544

(matrix presented) Nu-H can be alcohols, thiols, phenols, carboxylic acids yield: 60%-100%. Methylenecyclopropanes can react with various nucleophiles such as alcohols, phenols, carboxylic acids, and thiols to give the corresponding homoallylic esters or

Full text of DOI:10.1021/ol0259544

ORGANIC
LETTERS
2002
Vol. 4, No. 13
2145-2148
Lewis Acid-Catalyzed Ring-Opening
Reactions of Methylenecyclopropanes
with Alcoholic or Acidic Nucleophiles
Min Shi* and Bo Xu
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 April 1, 2002
ABSTRACT
Methylenecyclopropanes can react with various nucleophiles such as alcohols, phenols, carboxylic acids, and thiols to give the corresponding
homoallylic esters or ethers in good yields with good stereoselectivities in the presence of Lewis acids.
Methylenecyclopropanes (MCPs) are highly strained but
readily accessible molecules that have served as useful
building blocks in organic synthesis.1 Strain in an organic
molecule often correlates with increased reactivity. MCPs
can undergo a variety of ring-opening reactions because the
relief of ring strain provides a potent thermodynamic driving
force for this process. Since numerous methodologies have
been developed for the construction of MCPs,1 MCPs have
emerged as versatile tools in organic synthesis. Recently,
much attention has been paid to reactions of MCPs with
various reactants catalyzed by transition metals such as Pd,
Rh, Ru, and Pt. Three kinds of reaction patterns of MCPs
based on the concept of a synthon have been disclosed
(Scheme 1). MCPs can react with polar reactants such as
ROH,2 R2NH,3 malonate derivatives,4 carbon dioxide,5 al-
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, or Rh
metal catalyst to afford type II and/or type III products
depending on the reaction conditions (Scheme 1). But these
reactions usually need severe reaction conditions such as very
high temperatures (120 °C) and/or prolonged reaction time
Scheme 1. Three Reaction Patterns of MCPs
* Fax: 86-21-64166128.
(1) Synthesis of MCPs: Brandi, A.; Goti, A. Chem. ReV. 1998, 98, 598.
(2) (a) Camacho, D. H.; Nakamura, I.; Saito, S.; Yamamoto, Y. Angew.
Chem., Int. Ed. Engl. 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.
(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. Comm. 1979, 982. (b) Binger, P.; Germer, A. Chem. Ber. 1984,
114, 3325.
10.1021/ol0259544 CCC: $22.00 © 2002 American Chemical Society
Published on Web 06/05/2002

(3 days). These severe reaction conditions have certainly
limited their practical utilization in organic synthesis.
For example, Yamamoto et al.2 recently reported the Pd-
catalyzed reactions of MCPs with alcohols, a powerful tool
in the synthesis of allylic ethers (Scheme 2). This Pd-
reaction and gives the corresponding ring-opening reaction
product 2a in 95% yield within 24 h in ethanol at 70-80
°C (Table 1, entry 3). It should be emphasized here that the
protic acid TfOH (CF3SO3H) can also catalyze this reaction
under the same conditions. But the yield is slightly lower
than that obtained with Sn(OTf)2 (Table 1, entry 5).
Then, we carried out the reactions of various MCPs with
alcohols or phenols in the presence of Sn(OTf)2 (10 mol %)
under the optimized conditions. The results are summarized
in Table 2. In most cases, the ring-opening products 2 were
Scheme 2
Table 2. Reactions of MCPs with ROH in the Presence of the
Lewis Acid Sn(OTf)2
catalyzed addition of alcohols to MCPs was claimed to
proceed via the activation of alcoholic pronucleophiles.
However, the reaction was carried out at 100 °C for 3 days.
On the other hand, Lewis acid-catalyzed ring-opening
reactions of epoxides are very important transformations in
organic synthesis.14 However, to the best of our knowledge,
no attention has been paid to the Lewis acid-catalyzed ring-
opening reaction of MCPs. Herein, we report unprecedented
Lewis acid-catalyzed ring-opening reactions of MCPs with
alcoholic nucleophiles under mild conditions. Then, we
extend the scope of this reaction to other nucleophiles such
as phenols, carboxylic acids, water, and thiols.
entrya
MCPs
ROH
EtOH
iPrOH
tBuOH
EtOH
EtOH
EtOH
EtOH
EtOH
time/h
yieldb of 2 (E/Z)
1
2
3
4
5
6
7
8
9
1a
1a
1a
1b
1c
1d
1e
1f
24
16
48
72
2
48
2
48
48
24
2a , 95%
2b, 99%
2c, 93%
2d , 55% (5.6:1)
2e, 96%
2f, 59% (7.8:1)
2g, 96% (3.2:1)
2h , 98%
2i, 25%
2j, 15%
Use of diphenylmethylenecyclopropane (1a) as a substrate
allowed the reaction of 1a with ethanol to be carefully
examined in the presence of Lewis acids (Table 1). Various
Table 1. Effects of Various Acids in the Reaction of MCPs
(1a) with Alcohols
1a
1a
H2O
p-NO2C6H4OH
10c
a All reactions were carried out using 0.5 mmol of MCPs (1a-d) in
alcohol in the presence of Sn(OTf)2 (10 mol %) at 80 °C. b Isolated yields.
c Using 1,2-dichloroethane (DCE) as a solvent.
obtained in excellent yields. To our surprise, the steric
hindrance of alcohols do not affect this reaction rate (Table
2, entries 1-3). Especially, the reaction rate of diphenyl-
methylenecyclopropane (1a) with iPrOH is even faster than
that of 1a with EtOH (Table 2, entries 1 and 2). Water can
entry
Lewis acid
yield/%a (time/h)
1
2
3
4
5
6
7
8
9
Yb(OTf)3
Sc(OTf)3
Sn(OTf)2
BF3‚Et2O
TfOH
Cu(OTf)2
Zn(OTf)2
Ti(OiPr)4
Al(OiPr)3
95% (72 h)
94% (36 h)
95% (24 h)
90% (50 h)
85% (24 h)
trace (72 h)
trace (72 h)
trace (72 h)
trace (72 h)
(6) Nakamura, I.; Oh, B. H.; Saito, S.; Yamamoto, Y. Angew. Chem.,
Int. Ed. Engl. 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.
a Isolated yields.
(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) Reactions of MCPs with unsaturated carbon bonds have been
extensively studied; please see the following review: Laurens, M.; Klute,
W.; Tam, W. Chem. ReV. 1996, 96, 49.
(14) Lewis acid-catalyzed ring-opening reaction of epoxides: Erden, I.
In ComprenhensiVe Heterocyclic Chemistry II; Padwa, A., Ed.; Pergamon:
Oxford, 1996; p 101.
Lewis acids have been tested in this reaction. We found that
the reaction proceeded smoothly in the presence of Sn(OTf)2,
Sc(OTf)3, Yb(OTf)3, or BF3‚Et2O (10 mol %) (Table 1,
entries 1-4), but no reaction occurred in the presence of
Al(OiPr)3, Ti(OiPr)4, Zn(OTf)2, or Cu(OTf)2 (Table 1, entries
6-9). This result suggests that the Lewis acid plays a critical
role in this reaction. Sn(OTf)2 is the best Lewis acid in this
2146
Org. Lett., Vol. 4, No. 13, 2002

react with MCPs to give homoallylic alcohol as well, but
the reaction is sluggish (Table 2, entry 9). The reaction of
diphenylmethylenecyclopropane 1a with phenols gives the
corresponding product in very low yield along with many
unidentified products. This may due to the Friedel-Crafts-
type side reaction of MCPs with phenols in the presence of
a Lewis acid. Only in the reaction of 1a with p-nitrophenol
in 1,2-dichloroethane (DCE) was 2e obtained (15% yield;
Table 2, entry 10). The substituents on the benzene ring of
MCPs can significantly affect the reaction rate. For example,
the reaction of 1b with ethanol is much slower than that of
1a with ethanol. However, the reaction of 1c with ethanol is
much faster than that of 1a with ethanol (entries 1, 4, and
5). On the basis of these results, we can conclude that the
electron-withdrawing groups on the benzene ring of MCPs
such as Cl- slow the reaction, while electron-donating
groups such as MeO- can significantly accelerate the reac-
tion. For unsymmetric MCPs 1b, 1d, and 1e, 2 was formed
as an E/Z mixture in which E-2 was a major isomer with
fairly good stereoselectivity (Table 2, entries 4, 6, and 7).
To clarify the reaction rate in this novel ring-opening
reaction, we recorded the yields of 2a and 2e from the
reactions of 1a and 1c with EtOH under the same conditions
over time (see Supporting Information). It is very clear that
the reaction rate of 1c is much faster than that of 1a.
The reactions of carboxylic acids, very weak nucelophiles,
with MCPs have also been examined. The reactions were
carried out in DCE in the presence of a Lewis acid. We found
that, in general, they can react more smoothly with MCPs
than alcohols in the presence of Sn(OTf)2 (10 mol %). The
results are shown in Table 3. The corresponding ring-opening
products 3 were obtained in very high yields at 50 °C for
24 h. For unsymmetric MCPs 1b, 1d, 1g, and 1h, 3 was
formed as an E/Z mixture in which E-3 was a major isomer
with fairly good stereoselectivity (Table 3, entries 2-5).
On the other hand, it was reported that thiols can add to
the double bond of MCPs via a radical mechanism.15
However, we found that, in the presence of Sn(OTf)2, thiols
also can react with MCPs to give a ring-opened product 4
similar to that obtained with alcohols, although the achieved
yields are not as high as those of carboxylic acids or alcohols.
The results are summarized in Table 4.
Table 4. Reactions of MCPs with RSH in the Presence of
Sn(OTf)2
entry
substrate
RSH
yield/%b (E/Z)
1
2
3
1a
1b
1c
n-C6H13SH
n-C2H5SH
n-C6H13SH
4a , 50%
4b, 35% (10.8:1)
4c, 42%
a All reactions were carried out using 0.5 mmol of MCPs (1a-c) with
1.0 mmol of thiols in DCE at 50 °C for 24 h. b Isolated yields.
We also examined the reactions of MCPs with amines such
as benzylamine in the presence of Lewis acids, but no
reaction occurred at all. We believe this is because amine
can strongly coordinate to the Lewis acid during the reaction
and, therefore, deactivate the Lewis acid.
A plausible mechanism for the ring-opening reactions of
MCPs with alcoholic or acidic nucleophiles was shown in
Scheme 3. The alcohol first protonates the MCPs in the
presence of the Lewis acid to give cation 5, which im-
mediately rearranges to another cation 6. The subsequent
nucleophilic attack affords the final product (Scheme 3). The
Table 3. Reactions of MCPs with RCO2H in the Presence of
Lewis Acids
Scheme 3. Proposed Mechanism of Ring-Opening Reactions of
MCPs Catalyzed by a Lewis Acid
entrya
substrate
RCO2H
yield/%b (E/Z)
1
2
3
4
5
6
1a
1b
1d
1g
1h
1a
CH3CO2H
CH3CO2H
CH3CO2H
CH3CO2H
CH3CO2H
C6H5CO2H
3a , 97%
3b, 100% (5.6:1)
3c, 64% (7.2:1)
3d , 97% (5.0:1)
3e, 67% (9.2:1)
3f, 83%
a All reactions were carried out using 0.5 mmol of MCPs (1a-f) and
1.0 mmol of acid in DCE or using the acid as a solvent at 50 °C for 24 h.
b Isolated yields.
Org. Lett., Vol. 4, No. 13, 2002
2147

Conclusion
Scheme 4. Trapping of a Carbocation by Et3SiH
We disclose an unknown transformation process of
MCPs in the presence of a Lewis acid in this paper. The
ring-opened products 2-4 can be obtained in good to
excellent yields with fairly good stereoselectivities. A wide
range of alcohols, carboxylic acids, and thiols act as
nucleophiles in this reaction. This process will provide a
novel and efficient route to the synthesis of homoallylic esters
or ethers.
fast rearrangement of cation 5 to 6 was the key step in this
reaction.16 We also examined the reaction of 1b with EtOH
in the presence of the protic acid TfOH under the same
conditions as those of Sn(OTf)2. Product 2d was obtained
with the same regioselectivity, but in a low yield (20%). We
confirmed that Sn(OTf)2 does not decompose to give
CF3SO3H upon heating at 80 °C.17 Thus, as a result of using
Sn(OTf)2 as a Lewis acid, this novel ring-opening reaction
does not involve CF3SO3H at all. We carried out a reaction
of 1a with Et3SiH in the presence of Sn(OTf)2 in which
product 7, derived from a trapping reaction of carboncation
6 with Et3SiH,16 was isolated in 10% yield (Scheme 4). This
result suggests that carbocation 6 is indeed involved in this
reaction.
Acknowledgment. We thank the State Key Project of
Basic Research (Project 973) (No. G2000048007) and the
National Natural Science Foundation of China for fi-
nancial support (20025206). We also thank the Inoue
Photochirogenesis Project (ERATO, JST) for chemical
reagents.
Supporting Information Available: Spectroscopic data
of the compounds shown in Tables 2-4 and a detailed
description of experimental procedures. This material
is available free of charge via the Internet at http://
pubs.acs.org.
OL0259544
(15) (a) Kozhushkov, S. I.; Brandl, M.; Meijere, A. Eur. J. Org. Chem.
1998, 1535. (b) Xu, B.; Chen, Y.; Shi, M. Tetrahedron Lett. 2002, 43,
2781.
(17) Kobayashi has already reported that some metal triflates do not
decompose to give CF3SO3H even upon heating in water at 100 °C.
Kobayashi, S. Synlett 1994, 689.
(16) Carey, F. A.; Tremper, H. S. J. Am. Chem. Soc. 1969, 91, 2967.
2148
Org. Lett., Vol. 4, No. 13, 2002