Fe-catalyzed highly selective ring expansion of alkynylcyclopropyl alkanols to cyclobutanols

Article abstract of DOI:10.1039/b916623h

A Fe-catalytic highly selective ring expansion reaction of alkynylcyclopropyl alkanols to alkynylcyclobutanols via a 1,2-carbon shift under mild conditions was developed. A new class of homogeneous FeCl ₂/O₂ catalytic system was empl

Full text of DOI:10.1039/b916623h

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Fe-catalyzed highly selective ring expansion of alkynylcyclopropyl
alkanols to cyclobutanolsw
Anjun Chen,ab Riyuan Lin,a Qingjian Liub and Ning Jiao*ac
Received (in Cambridge, UK) 13th August 2009, Accepted 14th September 2009
First published as an Advance Article on the web 30th September 2009
DOI: 10.1039/b916623h
A Fe-catalytic highly selective ring expansion reaction of
alkynylcyclopropyl alkanols to alkynylcyclobutanols via a
1,2-carbon shift under mild conditions was developed. A new
class of homogeneous FeCl2/O2 catalytic system was employed
in these novel transformations.
Table 1 Transition metal-catalyzed ring expansion of 1aa
Yield of 2 (%)
(trans/cis)c
Transition metal-promoted ring expansion reactions of three-
membered carbocycles1 activated by additional functional
groups, such as cyclopropenes,2,3 methylenecyclopropanes
(MCP)4,5 and vinylcyclopropanes (VCP),6,7 have been widely
used in organic synthesis. Unlike the well-known chemistry of
the above three-membered carbocycles, the ring expansion
of relatively inactive alkynylcyclopropanes has not been
well-developed and therefore has attracted much attention.8
Pioneering work has been achieved by the groups of Iwasawa,9a
Toste,9b Ardura9c and Trost9d in the ring expansion of alkynyl-
cyclopropanols catalyzed by Co, Au or Ru catalysts.
Moreover, the groups of Schmalz10a and Zhang10b have
reported the Au-catalyzed ring expansion of alkynylcyclopropyl
ketones. However, examples of the ring expansion of alkynyl-
cyclopropyl alkanols have not been recorded in the relevant
literature so far.
Entry
Catalyst
Solventb
t/h
1
Yb(OTf)3
FeCl3
FeCl3
HCl
FeCl3
FeCl3
FeCl2
FeCl2
FeCl2
FeBr2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
Acetone
1 : 1
1 : 1
1 : 1
1 : 1
1 : 1
48
48
72
48
72
48
48
72
48
48
72
48
48
6 (4 : 1)
33 (9 : 1)
20 (7 : 1)
0
43 (5 : 1)
47 (5 : 1)
78 (9 : 1)e
Trace
63 (8 : 1)
55 (6 : 1)
0
20 (5 : 1)
12 (2 : 1)
2
3d
4
5
6
7
8f
9g
10
11
12
13
Fe(acac)2
Fe(OTf)3
TfOH
1 : 1
1 : 1
1 : 1
a
b
1a (0.25 mmol), catalyst, solvent (2 mL), r.t. under O2. 1 : 1 is the
c
volume ratio of CH3NO2 to acetone. Isolated yield, the ratio was
d
determined by 1H NMR calculation; 3a was not observed. The
e
f
reaction was carried out at 40 1C. 12% of 1a was recovered. The
reaction was carried out under N2. The reaction was carried
out in air.
g
ð1Þ
We initially chose alkynylcyclopropyl methanol 1a as the
substrate (Table 1). However, no product was obviously
observed when catalysts such as AuCl, AgOTf, PtCl4, CuI,
PdCl2, RhCl3 or Sc(OTf)3 were applied to catalyze the
expected ring expansion reaction. It is noteworthy that
alkynylcyclobutanol 2a (trans/cis = 4 : 1) was formed using
Yb(OTf)3 as the catalyst, despite the very low 6% yield
(entry 1, Table 1). The trans- and cis-isomers could be
separated by column chromatography over silica gel.
Gratifyingly, Fe catalysts presented a slightly higher catalytic
efficiency, giving 2a in 33% yield (trans/cis = 9 : 1; entry 2,
Table 1), whereas non-cyclic product 3a was not observed. An
increase in reaction temperature inhibited this transformation.
After a great deal of screening of different parameters (see the
ESIw), we were pleased to find that the ring expansion
catalyzed by FeCl2 using a mixture of CH3NO2 and acetone
(1 : 1) as the solvent at room temperature under O2 (1 atm)
gave the highest efficiency (78% yield; entry 7, Table 1). The
yield decreased slightly when the reaction was carried out in
air (entries 7 and 9, Table 1). In contrast, only a trace of 2a was
transformed under a nitrogen atmosphere (entries 7 and 8,
Table 1). A further investigation indicated that this trans-
formation was not efficiently catalyzed by well-known
On the pathway of sustainable chemistry, Fe catalysts11,12
have been extensively investigated of late because of their
low price and environmentally-benign features. However,
unlike noble metal catalysts such as Au, Pd, Rh, Ru and
Pt,1–10 to the best of our knowledge, Fe catalysts have not been
explored in the ring expansion of carbocycles.13 Herein, we
describe the first highly selective ring expansion reactions of
alkynylcyclopropyl alkanols catalyzed by FeCl2 leading to
alkynylcyclobutanols (2) under mild conditions (path a,
eqn (1)). In contrast to the above ring expansion, C–O bond
cleavage is involved in this mild and highly selective ring
expansion.
a State Key Laboratory of Natural and Biomimetic Drugs, School of
Pharmaceutical Sciences, Peking University, Xue Yuan Rd. 38,
Beijing 100191, China. E-mail: jiaoning@bjmu.edu.cn;
Fax: +86 10-82805297
b Department of Chemistry, Shandong Normal University,
Jinan 250014, China
c State Key Laboratory of Organometallic Chemistry,
Chinese Academy of Sciences, Shanghai 200032, China
w Electronic Supplementary Information (ESI) available: Further
experimental details, characterisation data and spectra. See DOI:
10.1039/b916623h
ꢀc
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6842 | Chem. Commun., 2009, 6842–6844

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Brønsted acid catalysts such as HCl or TfOH (entries 4 and 13,
Table 1).
substrates could be smoothly transformed into the desired
products, indicating that the steric effect did not significantly
affect the reactivity. It is noteworthy that alkyl-substituted
alkynyl cyclobutanol 1q underwent a smooth reaction, producing
2q in 54% yield (trans/cis = 4 : 1) (entry 17, Table 2).
ð2Þ
To confirm the structure of the product, 2a was employed in
the reported transformation with iodobenzene catalyzed by
Pd.14 The expected cyclopentanone, 4, was formed in 67%
yield (eqn (2)),15 which suggests that the hypothesized
structure of 2a was correct. As cyclobutanols are a common
structural unit of natural products, they are of great
importance in the area of pharmaceuticals and are also
versatile building blocks for further transformations.16 Our
discovered ring expansions may provide an efficient method
for the construction of alkynylcyclobutanols.
ð3Þ
It is interesting to note that when benzylic alcohol 1r was used
as a substrate, this transformation did not efficiently afford
cyclobutanol 2r (5%, trans/cis 499 : 1) but instead gave
non-cyclic product 3r in 86% yield (eqn (3)). We envision that
the phenyl group could stabilize the cationic intermediate that
assists the 2,3-C–C bond cleavage of intermediate A to afford
non-cyclic cationic intermediate C (path b, Scheme 1).
With the optimized reaction conditions in hand, the scope of
the FeCl2-catalyzed ring expansion was subsequently investi-
gated (Table 2). A range of secondary alkanols were tolerated
Based on these preliminary results, a plausible mechanism
for this transformation is hypothesized, as shown in Scheme 1.
t
FeII is initially oxidized to FeIII 17
,
which then reacts with 1 to
afford cyclopropylmethyl cation5a A (path a, Scheme 1).
subsequent 1,2-carbon shift18 forms intermediate
in this ring expansion (entries 1–8, Table 2). When Bu was
used as a substitutent, trans-2f was formed with a high
diastereoselectively (trans-2f/cis-2f 499 : 1), regardless of the
low yield due to steric hindrance of the Bu group (entry 6,
A
B
t
(path a, Scheme 1). Alternatively, 2,3-C–C bond cleavage of
cationic intermediate A occurs to form intermediate C (path b,
Scheme 1). Hydroxylation of B or C then affords product 2 or
3r, respectively. Diastereoselectivity is possible due to the
effect of steric hindrance. After the formation of cationic
intermediate B, the hydroxyl group favors attack on the face
anti to that of the methyl group, resulting in the formation of
trans-2a (Fig. 1).
Table 2). Furthermore, when tertiary alkanol 1i was employed,
spirocyclic 2i was produced (entry 9, Table 2). In contrast,
primary alcohol 1j failed to furnish the desired product
(entry 10, Table 2). Notably, both aryl- and alkyl-substituted
alkynes perfectly fitted this ring expansion (entries 11–17,
Table 2). All para-, meta- and ortho-substituted phenyl alkynyl
Table 2 The FeCl2-catalyzed ring expansion of 1 via a 1,2-carbon
shifta
In conclusion, we have developed a new class of homo-
geneous FeCl2/O2 catalytic system for ring expansion
reactions. A highly selective 1,2-carbon shift of alkynylcyclo-
propyl alkanols was successfully realized to afford alkynyl-
cyclobutanols under mild conditions. This observation not
only expands the application of inexpensive and environ-
mentally benign Fe catalysts, but also provides a new synthetic
Yield of 2 (%)
(trans/cis)b
Entry R1
R2
R20
1
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
Et
n-Pr
i-Pr
Cyclohexyl
t-Bu
PhCH2CH2
Bn
H
H
H
H
H
H
H
H
1a
1b
1c
1d
1e
1f
1g
1h
1i
78 (9 : 1) (2a)c
88 (6 : 1) (2b)d
57 (4 : 1) (2c)
49 (6 : 1) (2d)
38 (4 : 1) (2e)
14 (499 : 1) (2f)
54 (2 : 1) (2g)
50 (4 : 1) (2h)
20 (2i)e
9
–(CH2)5–
10
11
12
13
14
15
16
17
H
H
H
H
H
H
H
H
H
1j
1k
1l
0
ꢁ
2-Me-C6H4ꢁ
3-Me-C6H4ꢁ
4-Me-C6H4
4-OMe-C6H4
Me
Me
Me
Me
Me
n-Pr
Me
62 (3 : 1) (2k)
53 (3 : 1) (2l)
Scheme 1 Proposed mechanism for the Fe-catalyzed ring expansion
of 1 to alkynylcyclobutanols.
1m 60 (3 : 1) (2m)
ꢁ
1n
1o
1p
1q
63 (5 : 1) (2n)
64 (4 : 1) (2o)
75 (4 : 1) (2p)f
54 (4 : 1) (2q)
ꢁ
4-Ph-C6Hꢁ4
Ph(CH2)3
n-Hexly-
a
b
1a (0.25 mmol), catalyst, solvent (2 mL), r.t. under O2. Isolated
c
yield; noncyclic 3 were not observed, except for 3i. 12% of 1a was
d
recovered. 32% of 1b was recovered. 3i was obtained in 31%
e
f
yield. 25% of 1p was recovered.
Fig. 1 The steric hindrance effect.
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tool for constructing synthetically and medicinally important
alkynylcyclobutanols. Further studies on system’s the scope
and synthetic applications are ongoing in our laboratory.
Financial support from Peking University, the National
Science Foundation of China (nos. 20702002, 20872003), the
PhD Programs Foundation of Ministry of Education of China
(no. 20070001808) and the National Basic Research Program
of China (973 Program) (Grant no. 2009CB825300) are greatly
appreciated.
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This journal is The Royal Society of Chemistry 2009
6844 | Chem. Commun., 2009, 6842–6844