Organocatalytic Cloke-Wilson Rearrangement: DABCO-Catalyzed Ring Expansion of Cyclopropyl Ketones to 2,3-Dihydrofurans

Article abstract of DOI:10.1021/acs.orglett.7b00805

An organocatalytic Cloke-Wilson rearrangement of cyclopropyl ketones to 2,3-dihydrofurans is exploited utilizing the homoconjugate addition process. With 1,4-diazabicyclo[2.2.2]octane as the catalyst, the rearrangement in DMSO at 120 °C proceeded in gener

Full text of DOI:10.1021/acs.orglett.7b00805

Letter
pubs.acs.org/OrgLett
Organocatalytic Cloke−Wilson Rearrangement: DABCO-Catalyzed
Ring Expansion of Cyclopropyl Ketones to 2,3-Dihydrofurans
Jingfang Zhang, Yuhai Tang, Wen Wei, Yong Wu, Yang Li, Junjie Zhang, Yuansuo Zheng,
and Silong Xu*
Department of Chemistry, School of Science, Xi’an Jiaotong University, Xi’an 710049, P. R. China
S
* Supporting Information
ABSTRACT: An organocatalytic Cloke−Wilson rearrangement of
cyclopropyl ketones to 2,3-dihydrofurans is exploited utilizing the
homoconjugate addition process. With 1,4-diazabicyclo[2.2.2]octane as
the catalyst, the rearrangement in DMSO at 120 °C proceeded in
generally high yields, exclusive regioselectivity, and a broad substrate
scope. An examination of the mechanism including stereochemical
analysis and intermediate isolation supports an SN1-type ring opening of
the mechanism.
yclopropanes1 have been used as versatile building blocks
in organic synthesis due to their remarkable reactivity that
Ring-enlargement of cyclopropanes constitutes a powerful
tool for accessing structurally diverse carbo- and heterocycles.1n
Analogous to the vinylcyclopropane−cyclopentene (VCP−CP)
rearrangement,10 the isomerization of cyclopropyl imines,
aldehydes, and ketones, namely the Cloke−Wilson rearrange-
ment,11 delivers heterocycles of 2-pyrrolines and 2,3-
dihydrofurans, respectively. As this transformation is sub-
strate-dependent and often requires a high temperature,12
considerable efforts have been aimed at developing mild and
general conditions.13 Notably, Yadav and co-workers14 in 2001
disclosed TiCl4-mediated silicon-assisted rearrangement of
(tert-butyldiphenylsilyl)methylcyclopropyl ketones at a low
temperature (Scheme 2, eq a). In 2006, the Johnson group15
realized mild Ni-catalyzed rearrangement of vinyl cyclopropyl
C
originates from the intrinsic ring strain. Lewis acid and
transition-metal catalysis have been extensively applied to the
ring opening of cyclopropanes;1l,m however, organocatalytic
strategies for the activation of cyclopropanes are less well
developed. Extant approaches include N-heterocyclic carbene
(NHC) catalysis,2 urea catalysis,3 iminium activations,4 and
enamine activations.5 Whereas these tactics mostly rely on a
specific substituent pattern on the cyclopropane ring, the
activation of general electrophilic cyclopropanes under Lewis
base catalysis by means of direct nucleophilic ring opening
remains an underutilized approach.6
As early as 1975, Danishefsky and co-workers7 reported the
homoconjugate addition of electrophilic cyclopropanes with
Lewis bases (e.g., piperidine, pyridine) to afford zwitterionic
adducts A (Scheme 1); however, this type of species has been
Scheme 2. Cloke−Wilson Rearrangement under Mild
Conditions
Scheme 1. Zwitterions Generated from Lewis Bases and
Electrophilic Cyclopropanes or Alkenes
rarely engaged in reaction discovery.6,8 This stands in striking
contrast with the homologous intermediates B generated from
the conjugate addition of Lewis bases to electrophilic alkenes,
by which a myriad of transformations have been engendered.9
Therefore, it would be rewarding to explore transformations
utilizing the homoconjugate addition process.
Received: March 17, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00805
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
ketones resting upon a Ni−π-allyl intermediate (eq b).
Recently, Plietker and co-workers16 also demonstrated mild
thermal or photochemical Cloke−Wilson rearrangements for
vinyl and aryl cyclopropyl ketones catalyzed by TBA[Fe] (eq
c). Inspired by these reports, and stemming from our interest in
Lewis base catalysis,17 we envisioned that an organocatalytic
strategy for the Cloke−Wilson rearrangement might be
possible by utilizing the homoconjugate addition process
(vide infra). This hypothesis is reminiscent of the Heine
rearrangement,18 which proceeds in a similar pathway. Herein,
we report an organocatalytic DABCO-catalyzed Cloke−Wilson
rearrangement of cyclopropyl ketones in generally high yields,
complete regioselectivity, and a broad substrate scope (eq d).
1,1-Dibenzoylcyclopropane (1a) was chosen as the model
substrate for an initial investigation (Table 1). Inspired by the
13). Among several common solvents examined, DMF and
acetonitrile gave yields of 74% and 34%, respectively, whereas
THF and 1,4-dioxane inhibited the reaction (entries 14−17). It
was found that a lowered reaction temperature (80 °C)
decreased the yield substantially (53%) (entry 18). Extending
the period of time hardly influenced the yield (entry 19);
however, increasing the loading of DABCO to 50 mol %
upgraded the yield to 85%, and 1.0 equiv increased that to 93%
(entries 20 and 21). In view of the practicality, we established
the standard conditions by using 50 mol % of DABCO as the
catalyst in DMSO at 120 °C.
Success at identifying the organocatalytic Cloke−Wilson
rearrangement prompted us to probe its scope using a range of
cyclopropyl ketones (Table 2). Cyclopropanes 1a−c with
germinal diketones readily converted into 2,3-dihydrofurans
a
Table 1. Optimization of Reaction Conditions
Table 2. Substrate Scope of DABCO-Catalyzed Cloke−
a
Wilson Rearrangement of Cyclopropyl Ketones
b
entry
catalyst
solvent
temp (°C) time (h) yield (%)
1
NaI
acetone
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
reflux
120
120
120
120
120
120
120
120
120
120
120
120
120
reflux
reflux
reflux
80
24
24
24
24
24
48
48
24
24
24
15
15
15
15
15
15
15
15
24
15
15
trace
trace
trace
trace
2
NaI
3
ZnI2
4
MgI2
5
none
6
PBu3
18
10
7
PCy3
8
dppb
trace
trace
trace
75
9
dppe
10
11
12
13
14
15
16
17
PPh3
DABCO
DMAP
DBU
28
44
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
74
acetonitrile
THF
34
trace
trace
53
1,4-dioxane
DMSO
DMSO
DMSO
DMSO
c
18
19
120
120
120
75
d
20
85
e
21
93
a
Under N2 atmosphere, the catalyst (20 mol %) was added to a
solution of 1a (0.2 mmol) in the specified solvent (2.0 mL) in a
b
Schlenk tube (25 mL), and the mixture was heated. Isolated yield.
c
d
Substrate 1a was recovered in 36% yield. 50 mol % catalyst loading.
1.0 equiv of DABCO was used.
e
Heine reaction, we first examined the standard Heine
conditions (NaI in refluxing acetone) and modifications
(entries 1−5), which however, were ineffective for the
rearrangement. Phosphines have been shown by Morgan and
co-workers19 to catalyze the Heine reaction. For the current
system, it was found that PBu3 and PCy3 were able to catalyze
the Cloke−Wilson rearrangement in low yields, while dppb,
dppe, and PPh3 were incompetent (entries 6−10). Gratifyingly,
nucleophilic amines turned out to be superior. In the presence
of DABCO (20 mol %), the rearrangement of 1a in DMSO at
120 °C completed in 15 h, resulting in the isolation of desired
2,3-dihydrofuran 2a in 75% yield (entry 11). DMAP and DBU
were also effective albeit with lowered yields (entries 12 and
a
Typical procedure: under N2 and at 120 °C, to a solution of 1 (0.2
mmol) in DMSO (2.0 mL) was added DABCO (0.1 mmol), and the
mixture was stirred for 15−48 h. Isolated yield. Scaled-up yield of 2d
(1.10 g). 1.0 equiv of DABCO was used. Both diastereomers of
substrates gave the same results. Acrylonitrile (1.0 equiv) was used as
the additive with toluene as the solvent.
b
c
d
e
f
B
DOI: 10.1021/acs.orglett.7b00805
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
2a−c in 85−94% yields (entries 1−3). Cyclopropyl ketones
with an extra substituent were then tested, whose rearrange-
ment would pose a regioselectivity issue. Intriguingly, when a
series of aryl-, vinyl-, or alkyl-substituted cyclopropyl ketones
(1d−p) were treated, the corresponding trisubstituted 2,3-
dihydrofurans 2d−p were generated in good to excellent yields,
with a C−O bond forming solely on the sterically hindered
carbon (entries 4−20). Of interest is that the regioselectivity is
opposite to that of the Heine rearrangement that occurs at the
less hindered position.19 The product structure was unequiv-
ocally established by X-ray crystallography (for 2d, see the
Supporting Information). Subsequent investigation was ex-
tended to cyclopropanes bearing different geminal carbonyls.
Substrates 1q−t, which carry geminal acetyl and benzoyl
groups, produced a pair of 2.3-dihydrofurans in 42−86% yields
(ratios 1.2:1−1.6:1) favoring acetyl-rearranged products
(entries 17−20). However, cyclopropyl ketones 1u−y with a
germinal ester or amide group underwent highly selective
rearrangements toward the ketone, furnishing products 2u−y in
46−93% yields (entries 21−25). Collectively, the DABCO-
catalyzed Cloke−Wilson rearrangement is general for a broad
range of substrates which include aryl-, alkyl-, vinyl-, and
nonsubstituted cyclopropyl ketones (both aromatic and
aliphatic) that are geminally activated by a ketone, ester, or
amide substituent. As 2,3-dihydrofurans are ubiquitous
substructures in natural products and biologically active
molecules,20 this reaction accordingly offers a practical access
to this class of heterocycles under mild metal-free conditions.
To demonstrate the practicality, a scaled-up synthesis of 2,3-
dihydrofuran 2d (85% yield, 1.10 g scale) was carried out
(Table 2, entry 4), and the elaboration of the product to a furan
derivative 3 by DDQ oxidation was exemplified in Scheme 3.
The proposed mechanism could be supported by intermediate
isolation from structurally similar substrates. It was found that
cyclopropyl ketones 4 with a spiro backbone readily reacted
with DABCO in toluene at room temperature, producing
zwitterionic intermediates 5 in good yields as yellow
precipitates (Scheme 5). Attempts to engage these inter-
Scheme 5. Zwitterions Formation from Cyclopropanes 4
mediates in further ring closure, however, were unsuccessful
despite prolonged reaction at a higher temperature (DMSO, 2
days, 180 °C).21 Nevertheless, such intermediates support the
step of regioselective ring opening of the proposed mechanism.
Originally, we assumed that the ring opening of the DABCO-
catalyzed Cloke−Wilson rearrangement may proceed in an SN2
manner as shown in the literature;22 however, stereochemical
analysis with an optically active substrate disfavors this
pathway.23 Under the standard conditions, it was found that
enantioenriched (R)-1m (94% ee) converted into 2,3-
dihydrofurane 2m in 78% yield yet with almost complete loss
of the stereochemical integrity (2% ee) (Scheme 6). With this
result, it is apparent that an SN1-type ring opening process is
responsible for the DABCO-catalyzed Cloke−Wilson rear-
rangement.
Scheme 6. DABCO-Catalyzed Cloke−Wilson
Rearrangement of Enantioenriched 1m
Scheme 3. Synthesis of Furan 3
For the mechanism, a stepwised pathway is proposed to
rationalize the DABCO-catalyzed Cloke−Wilson rearrange-
ment (Scheme 4). Initial nucleophilic attack of DABCO on
In conclusion, our efforts to explore the utility of the
homoconjugate addition have led us to the discovery of an
organocatalytic Cloke−Wilson rearrangement of cyclopropyl
ketones to 2,3-dihydrofurans. The established conditions
(DABCO, DMSO, 120 °C) are compatible with a broad
range of substrates giving good yields and complete
regioselectivity, which may constitute a mild and general
protocol for the Cloke−Wilson rearrangement of cyclopropyl
ketones. Based on the results of intermediate isolation and
stereochemical analysis using an optically active substrate, an
SN1-type ring opening mechanism is proposed for the
rearrangement. Future efforts focus on applying the current
reaction in target-oriented synthesis and exploiting new
reactivities based on the homoconjugate addition process.
Scheme 4. Possible Mechanism for DABCO-Catalyzed
Cloke−Wilson Rearrangement of Cyclopropyl Ketones
ASSOCIATED CONTENT
* Supporting Information
■
S
cyclopropanes 1, in the form of the homoconjugate addition,
produces the enolate intermediate A, which undergoes a
favorable 5-exo-tet cyclization to furnish the product and release
the catalyst. The regioselective ring opening may be ascribed to
the highly polarized C−C bond rendered by the electron-donor
substituent R1 of the donor−acceptor (D−A) cyclopropanes.1k
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b00805.
Experimental procedures, analytical data, NMR spectra,
and crystallographic information (PDF)
C
DOI: 10.1021/acs.orglett.7b00805
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
X-ray data for compound 2d (CIF)
Letter
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: silongxu@mail.xjtu.edu.cn.
ORCID
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W. Chem. Commun. 2016, 52, 6817−6820. (b) Gopi, E.; Namboothiri,
I. N. N. J. Org. Chem. 2013, 78, 910−919. (c) Kaschel, J.; Schneider, T.
F.; Schirmer, P.; Maaß, C.; Stalke, D.; Werz, D. B. Eur. J. Org. Chem.
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Yong Wu: 0000-0002-9460-3579
Silong Xu: 0000-0003-3279-9331
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the National Natural Science
Foundation of China (Nos. 21402149, 21602167), the Natural
Science Basic Research Plan in Shaanxi Province of China
(Nos. 2015JQ2050, 2016JQ2019), the China Postdoctoral
Science Foundation (Nos. 2014M550484, 2015T81013,
2015M580830), and the Shaanxi Province Postdoctoral Science
Foundation is gratefully acknowledged. Dedicated to Professor
Yuhai Tang on the occasion of his 60th birthday.
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