Br?nsted acid TfOH-mediated reactions of methylenecyclopropanes with nitriles

Article abstract of DOI:10.1055/s-2004-832838

In the presence of Br?nsted acid TfOH, methylenecyclopropanes react with nitriles to give [3+2] cycloaddition products in good to high yields along with Ritter reaction products. In many cases, [3+2] cycloaddition products are obtained as the major produc

Full text of DOI:10.1055/s-2004-832838

LETTER
2343
Brønsted Acid TfOH-Mediated Reactions of Methylenecyclopropanes with
Nitriles
T
fOH-M
e
i
diated
R
eactions of
-
Methyle
W
necyclopropanes
w
ith
N
e
itriles n Huang, Min Shi*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin
Lu, Shanghai 200032, P. R. China
Fax +86(21)64166128; E-mail: mshi@pub.sioc.ac.cn
Received 10 August 2004
C6H5
C6H5
O
Abstract: In the presence of Brønsted acid TfOH, methylenecyclo-
propanes react with nitriles to give [3+2] cycloaddition products in
good to high yields along with Ritter reaction products. In many
cases, [3+2] cycloaddition products are obtained as the major prod-
ucts. The reaction conditions have been carefully examined and the
plausible mechanism has been proposed.
C6H5
C6H5
C6H5
C6H5
TfOH
r.t. 4 h
+
MeCN
NH C Me
+
N
2a
4a, 2%
1a
3a, 86%
Scheme 1 The Brønsted acid (TfOH)-mediated reaction of MCP 1a
(1.0 equiv) with acetonitrile (2a) at room temperature (25 °C).
Key words: methylenecyclopropanes, Brønsted acid, acetonitrile,
benzonitrile, [3+2] cycloaddition, Ritter reaction
During our further investigation on this reaction using
other MCPs 1, we found that some MCPs 1 are not soluble
in acetonitrile 2a very well and the co-solvent should be
required. In order to extend the scope and limitations of
this reaction, the solvent effects have been examined by
use of 2a (5.0 equiv) as a reactant in 2.0 mL of dichlo-
romethane, cyclohexane, MeNO2, 1,4-dioxane, THF or
diethyl ether (Et2O) under the same conditions. The re-
sults are summarized in Table 1. The [3+2] cycloaddition
product 3a was obtained in moderate to good yields in
dichloromethane, cyclohexane, MeNO2, THF or 1,4-diox-
ane (Table 1, entries 1–6). In Et2O, this reaction produced
homoallylic ether in 72% as the major product2a along
with 4a in 12% without the formation of 3a (Scheme 2
and Table 1, entry 7). The ring-opened Ritter reaction
product 4a was obtained as a by-product in trace to 12%
yield in all cases (Table 1, entries 1–7).
Recently, we found that the ring-opening reactions of
methylenecyclopropanes (MCPs) 1 with alcohols and
other nucleophiles catalyzed by Lewis acids [Ln(OTf)n]
(Ln = Sn, Yb, Sc) or Brønsted acid such as TfOH
(CF3SO3H) took place via an interesting pathway (ho-
moallylic rearrangement) to give the corresponding ring-
opened products under mild conditions.1–3 This interest-
ing result stimulated us to further investigate the Lewis
acid or Brønsted acid-mediated reactions of MCPs 1 with
other reactants. Herein we wish to report an unprecedent-
ed Brønsted acid TfOH-mediated reaction of MCPs 1 with
nitriles under mild conditions.
Using diphenylmethylenecyclopropane (1a) as the sub-
strate, we found that 1a (1.0 equiv) reacts with acetonitrile
(2a, as a solvent) to give the corresponding [3+2] cycload-
dition product 3a in 86% yield along with a ring-opened
Ritter reaction product 4a4 (with ambient water) in 2%
yield when the reaction was carried out in the presence of
a Brønsted acid TfOH (1.0 equiv) at room temperature
(25 °C) for 4 hours (Scheme 1). This reaction is sluggish
in the presence of a variety of Lewis acids (1.0 equiv) such
as Sn(OTf)2, Sc(OTf)3, Yb(OTf)3, Cu(OTf)2, Zn(OTf)2,
BF3·O Et2 and Ti(Oi-Pr)4. Other Brønsted acids such as
CF3CO2H and TsOH (p-MeC6H4SO3H) did not catalyze
this reaction. Sulfuric acid (99% H2SO4) also gave 3a in
low yield under identical conditions. The strong Brønsted
acid TfOH is the best promoter for this novel transforma-
tion of MCP 1a with acetonitrile to give the corresponding
[3+2] cycloaddition product 3a as the major product, and
ring-opened Ritter reaction product 4a as the minor
product under mild conditions.
Table 1 The Solvent Effects on the Brønsted Acid-Mediated Reac-
tion of MCP 1a with Acetonitrile at Room Temperature
C6H5 C6H5
+
O
C6H5
C6H5
TfOH
C6H5
C6H5
NHCMe
MeCN
+
solvent
N
4a
2a
1a
3a
Yield (%)a
Entry
Solvent
–
Time (h)
0.5
3a
4a
2
1
2
3
4
5
6
7
86
85
84
76
50
40
–
CH2Cl2
0.5
4
Cyclohexane
MeNO2
Dioxane
THF
0.5
–
0.5
–
0.5
–
0.5
–
SYNLETT 2004, No. 13, pp 2343–2346
0
3
.1
1
.2
0
0
4
Et2O
0.5
12
Advanced online publication: 24.09.2004
DOI: 10.1055/s-2004-832838; Art ID: U22604ST
© Georg Thieme Verlag Stuttgart · New York
a Isolated yields.

2344
J.-W. Huang, M. Shi
LETTER
for MCPs 1 is required for this novel reaction with nitriles
to give a [3+2] cycloaddition product under mild condi-
tions. Their structures were assigned on the basis of their
1H NMR and 13C NMR spectroscopic data and HRMS or
microanalyses and X-ray diffraction (Figure 1).6
C6H5
C6H5
C6H5
C6H5
TfOH
OEt
+
4a
MeCN/Et2O
12%
72%
Scheme 2 The reaction of MCP 1a with diethyl ether in the
presence of TfOH
Using benzonitrile (2b) as a substrate, we found that the
reactions proceeded smoothly to give the corresponding
[3+2] cycloaddition products 5 in higher yields under sim-
ilar conditions.7 The results are summarized in Table 3. In
most cases, products 5 were obtained in 85–96% yields
and the ring-opened Ritter reaction products 6 were
formed in traces (Table 3, entries 1–5). For MCP 1f hav-
ing a substituent at the o-position of benzene ring, the
[3+2] cycloaddition product was obtained in 42% yield as
mixture of Z- and E-isomers along with the Ritter reaction
product 6f in 56% yield (Table 3, entry 6). This is also
presumably due to the steric hindrance in MCP 1f impairs
the intermolecular [3+2] cycloaddition with 2b [2b is ster-
ically more demanding (bulkier) than 2a]. Therefore, the
reaction with ambient water proceeded to give the Ritter
reaction product in higher yield (56%). For aliphatic MCP
1h, we found that this reaction produced the [3+2] cy-
cloaddition product 7 in 10% yield derived from the Ritter
reaction of the [3+2] cycloaddition product 5h (in trace)
with 2b along with many unidentified products
(Scheme 3). Its structure was assigned on the basis of its
1H NMR, 13C NMR, 2D NMR spectroscopic data and
HRMS (see supporting information). For monosubstitut-
ed MCP 1i, this reaction gave complicated products under
the same conditions (Scheme 3).
We next examined the reactions of various MCPs 1 with
2a using an acetonitrile–dichloromethane (2.0:1) mixture5
in the presence of 1.0 equivalent of TfOH at room temper-
ature for four hours. The results are summarized in
Table 2. The substituents on the benzene ring of MCPs 1
did not significantly affect the reaction. For MCPs 1 hav-
ing an electron-withdrawing group such as a chlorine or
fluorine atom on the benzene ring or an electron-donating
group such as a methyl or methoxy group on the benzene
ring, these reactions proceeded smoothly to give the cor-
responding [3+2] cycloaddition products 3b–g in good
yields (Table 2, entries 1–6). For unsymmetric MCPs 1f
having two different aromatic groups and 1g having a me-
thyl group and an aromatic group, the [3+2] cycloaddition
products 3f and 3g were obtained as mixtures of Z- and E-
isomers (see supporting information; Table 2, entries 5
and 6). For MCP 1f having a substituent at the o-position
of benzene ring, the [3+2] cycloaddition product 3f was
obtained in 60% yield along with the Ritter reaction prod-
uct 4f in 21% (Table 2, entry 5). This is presumably due
to the steric hindrance in MCP 1f impairs the intermolec-
ular [3+2] cycloaddition. Therefore, the reaction with am-
bient water proceeded to give the Ritter reaction product
in higher yield. In other cases, the ring-opened products 4
were obtained as minor products (Table 2, entries 1–4 and
6).
A plausible mechanism for this novel [3+2] cycloaddition
reaction of MCPs 1 and Ritter reaction with nitriles is
shown in Scheme 4. The MCP 1 is first positively charged
(protonated by TfOH) to give intermediate A which
reacts with nitrile to give intermediate B (electrophilically
assisted nucleophilic ring opening).8 The subsequent
For aliphatic MCP 1h, we found that this reaction is slug-
gish and gives many unidentified products under the same
conditions (Table 2, entry 7). Thus, one aromatic group
Table 2 The Reaction of MCPs 1 (1.0 equiv) with Acetonitrile 2a (2.0 mL) in Dichloromethane (1.0 mL) in the Presence of TfOH (1.0 equiv)
R2
R1
R1
R2
O
R1
R2
TfOH
NHCMe
+
MeCN
+
N
CH2Cl2
2a
4
1
3
Yield (%)a
Entry
R1/R2
Time (h)
3
4
1
2
3
4
5
6
7
p-ClC6H4/p-ClC6H4 1b
p-FC6H4/p-FC6H4 1c
4
4
4
4
4
4
4
3b, 85
4b, 10
3c, 75
4c, Trace
4d, Trace
4e, Trace
4f, 21 (14:1)b
–
p-MeC6H4/p-MeC6H4 1d
3d, 73
p-MeOC6H4/p-MeOC6H4 1e
o-ClC6H4/C6H4 1f
p-EtOC6H4/Me 1g
Bu/Bu 1h
3e, 88
3f, 60 (14:1)b
3g, 56 (3:1)b
Complex mixture of products
a Isolated yields.
b Mixtures of Z- and E-isomers (ratio = E/Z).
Synlett 2004, No. 13, 2343–2346 © Thieme Stuttgart · New York

LETTER
TfOH-Mediated Reactions of Methylenecyclopropanes with Nitriles
2345
Table 3 The Reaction of MCPs 1 (1.0 equiv) with Benzonitrile (2b) in the Presence of TfOH (1.0 equiv)
R2
R1
R1
R2
O
R1
R2
TfOH
+
PhCN
+
NH C Ph
N
2b
6
Ph
1
5
Yield (%)a
Entry
R1/R2
C6H5 1a
Time (h)
5
6
1
2
3
4
5
6
7
4
4
4
4
4
4
4
5a, 87
6a, 5
p-ClC6H4/p-ClC6H4 1b
p-FC6H4/p-FC6H4 1c
5b, 93
6b, Trace
6c, Trace
6d, Trace
6e, Trace
6f, 56 (2:1)b
–
5c, 96
p-MeC6H4/p-MeC6H4 1d
p-MeOC6H4/p-MeOC6H4 1e
o-ClC6H4/C6H4 1f
5d, 91
5e, 85
5f, 42 (2:1)b
5g, 30 (4:1)b
p-EtOC6H4/Me 1g
a Isolated yields.
b Mixtures of Z- and E-isomers (ratio = E/Z)
R1
R2
O
Ritter reaction product
NH
C R'
H2O
N
C
Me
R1
R2
H+
+
C
H
N
R'
+
R1
R2
B
R1
R2
A
R1
R2
R1
R2
R1
R2
+
- H+
workup
NH+
N
H
N
R'
R'
R'
C
[3+2] cycloaddition product
Figure 1 The ORTEP plot of 3a
Scheme 4 Proposed mechanism of the reaction of MCPs 1 with
nitriles mediated by TfOH
Bu
Bu
Bu
Bu
Bu
Bu
TfOH
Ph
O
methyl carbocation is required here. Therefore, two sub-
stituents with one aromatic group is at least required to
stabilize intermediate A for this type of reaction.
N
+
+
PhCN
N
NH
Ph
7, 10%
Ph
1h
5h, trace
In conclusion, we disclosed an unknown transformation
of MCPs 1 with nitriles in the presence of the Brønsted
acid TfOH in this paper. In this type of transformation of
MCPs 1, the novel [3+2] cycloaddition products 3 and 5
can be obtained in good to excellent yields depending on
the substituents in MCPs 1.9 Efforts are underway to elu-
cidate the mechanistic details and subsequent transforma-
tion thereof.
complex mixture of
products
+
C6H5
H
+
TfOH
complex mixture of products
PhCN
1i
Scheme 3 The reaction of MCP 1h with 2b in the presence of TfOH
Acknowledgment
intramolecular electrophilic attack produces intermediate
C which gives [3+2] cycloaddition product via deprotona-
tion after workup. The intermediate B reacts with ambient
We thank the State Key Project of Basic Research (Project 973)
(No. G2000048007), Chinese Academy of Sciences (KGCX2-210-
water to give the ring-opened Ritter reaction product 01), Shanghai Municipal Committee of Science and Technology,
and the National Natural Science Foundation of China for financial
(Scheme 4). It appears that an stabilized cyclopropyl-
support (203900502, 20025206 and 20272069).
Synlett 2004, No. 13, 2343–2346 © Thieme Stuttgart · New York

2346
J.-W. Huang, M. Shi
LETTER
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(5) This is because some MCPs 1 such as MCPs 1b and 1c are
not very soluble in MeCN and the co-solvent CH2Cl2 is
therefore required.
(6) The crystal data of 3a has been deposited in CCDC with
number 219397. Empirical Formula: C18H17N; formula
weight: 247.33; crystal color, habit: colorless, prismatic;
crystal dimensions: 0.433 × 0.357 × 0.258 mm; crystal
system: monoclinic; lattice type: primitive; lattice
parameters: a = 23.589 (3)Å, b = 7.8691 (11)Å, c = 18.498
(3)Å, a = 90o, b = 127.366 (2)o, g = 90o, V = 2729.0(6)Å3;
space group: C2/c; Z = 8; Dcalc = 1.204 g/cm3; F000 = 1056;
diffractometer: Rigaku AFC7R; residuals: R, Rw: 0.0432,
0.0784.
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many MCPs 1 are dissolved very well in benzonitrile.
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Synlett 2004, No. 13, 2343–2346 © Thieme Stuttgart · New York