Superacid-catalyzed Friedel-Crafts cyclization of unactivated alkenes

Article abstract of DOI:10.1016/j.tetlet.2012.06.082

Trifluoromethanesulfonimide is an effective catalyst for Friedel-Crafts cyclizations of simple, nonpolarized alkenes with a variety of pendant arenes. A catalyst loading of 0.5 - 1.0 mol % effects clean cyclization to form 5- to 7-membered carbocycles wit

Full text of DOI:10.1016/j.tetlet.2012.06.082

Tetrahedron Letters 53 (2012) 4600–4603
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Tetrahedron Letters
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Superacid-catalyzed Friedel–Crafts cyclization of unactivated alkenes
Sara A. Bonderoff a, F. G. West a, , Martin Tremblay b
⇑
a Department of Chemistry, University of Alberta, Edmonton, AB, Canada T6G 2G2
b Boehringer Ingelheim (Canada) Ltd, 2100 rue Cunard, Laval, QC, Canada H7S 2G5
a r t i c l e i n f o
a b s t r a c t
Article history:
Trifluoromethanesulfonimide is an effective catalyst for Friedel–Crafts cyclizations of simple, nonpolar-
ized alkenes with a variety of pendant arenes. A catalyst loading of 0.5 – 1.0 mol % effects clean cycliza-
tion to form 5- to 7-membered carbocycles with generally short reaction times and good to excellent
yields under reflux or microwave heating.
Received 25 May 2012
Revised 14 June 2012
Accepted 15 June 2012
Available online 22 June 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Friedel–Crafts alkylation
Trifluoromethanesulfonimide
Tetralin synthesis
Unactivated alkene
Superacid
The Friedel–Crafts reaction occupies a prominent position in the
chemist’s toolbox for the addition of carbon functionality to arene
moieties, and intramolecular versions are well established. Alkenes
can function as the electrophilic partners in intramolecular Fri-
edel–Crafts reactions, though typically this is limited to Michael
acceptor alkenes activated by Brønsted or Lewis acids.1,2 This can
necessitate additional steps to remove the activating group when
it is not desired in the target molecule.3 Historically, Brønsted acid
mediated Friedel–Crafts reactions of simple alkenes have used one
or more equivalents of acid to promote cyclization.4 More recently,
it was found that simple alkenes participate in these cyclizations in
the presence of catalytic promoters such as In(OTf)3,5 RuCl3,6
Pt(II),7 and Bi(OTf)3.8 Cyclization of less substituted alkenes is
preferred when metals are used, so the use of Brønsted acids is
Scheme 1. Unexpected Friedel–Crafts reaction of 1a.
⇑
Corresponding author. Tel.: +1 780 492 8187; fax: +1 780 492 8231.
E-mail address: frederick.west@ualberta.ca (F.G. West).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.06.082

S. A. Bonderoff et al. / Tetrahedron Letters 53 (2012) 4600–4603
4601
Table 1
Moreover, the resulting cyclopentenyl cation can be intercepted
by electrophilic aromatic substitution onto a pendent arene.12
We initially set out to extend the generality of this latter process
through the preparation of benzylic ether 1a and examination of
its behavior in the presence of 1 equiv of AgNTf2 (Scheme 1). In
the event, we found to our surprise that the sole product was intra-
molecular Friedel–Crafts alkylation product 2a, a 1,3,4,5-tetrahy-
dro-2-benzoxepin formed in moderate yield as a 1.2:1 mixture of
diastereomers. No evidence was observed for the anticipated Naz-
arov process to produce either 3a or 3b. On further investigation, it
was found that optimal Friedel–Crafts reactivity of 1a could be
realized using 10 mol % of AgNTf2 in DCM at reflux, and these con-
ditions were applied to several other substrates (Table 1) to afford
benzo-fused 7- and 8-membered cyclic ethers 2a–d (along with
minor amounts of regioisomer 4 in the case of dimethyl-substi-
tuted 1b, entry 2).
Given the prior observation that metal triflates and triflimides
are known to form the corresponding Brønsted acids TfOH and
Tf2NH in the presence of water or other protic impurities,13 we
speculated that the observed Friedel–Crafts cyclization reactivity
might arise from traces of HNTf2. To probe the nature of the actual
catalyst, we prepared the simplified substrate 5a, and subjected it
to cyclization conditions in the presence of AgNTf2 with or without
added water, HNTf2, and other Brønsted acids (Table 2). When the
reaction components were filtered through dry potassium carbon-
ate under inert atmosphere to remove the residual water from the
dichloromethane as well as any trace HNTf2 that may be in the
AgNTf2, no reaction occurred upon extended stirring, supporting
the need for trace acid to catalyze this reaction (entry 1). HNTf2 it-
self proved to be a very effective catalyst for the process, and the
reaction proceeded to completion within 1 h with only 0.5% load-
ing of the acid (entry 2). Increasing the catalyst loading to 1% HNTf2
has little effect on the yield of 6a; however, the time required for
the consumption of 5a was significantly reduced (entry 3). Con-
versely, decreasing the catalyst to 0.1% led to an unacceptable reac-
tion time and inconsistent yields.
Friedel–Crafts cyclization of dichlorocyclopropane substratesa
Entry
Substrate
R1
R2
n
Yieldb (%)/product ratio
1
2
3
4
1a
1b
1c
1d
Ph
Me
4-MeOC6H4
4-MeOC6H4
Me
Me
H
1
1
1
2
79/1.9:1c
43/2.4:1d
64/1:1c
H
52/1:1c
a
Conditions: substrates
1 were dissolved in DCM (0.05 M) with AgNTf2
(10 mol %) and stirred at reflux until 1 was consumed (ca. 20 h).
b
Yields given are for pure product after chromatographic purification.
Ratio of diastereoisomers of 2.
Ratio of regioisomers 2b and 4.
c
d
complementary with a preference for bond formation of more
highly substituted alkenes. With the advent of modern ‘superac-
ids’,9 it stands to reason that the cyclization of simple alkenes
should be amenable to catalysis, and this has been shown in an
example of a triflic acid-catalyzed cyclization of arene–alkene units
in a polymeric system.10 However, to our knowledge there has
been no definitive work on the optimization and scope of this reac-
tion, despite the recent interest in the corresponding metal-cata-
lyzed versions. Here we describe
a Brønsted acid-catalyzed
intramolecular Friedel–Crafts alkylation between various aromatic
partners and simple alkenes. The reaction is high-yielding, conve-
nient, and atom-economical.
We have previously shown that 2-alkenyl-1,1-dichloro-2-silyl-
oxycyclopropanes undergo a domino process involving Ag(I)-pro-
moted electrocyclic opening of the cyclopropane, followed by
Nazarov cyclization of the resulting pentadienyl cation.11
A controlled amount of water was added to 5 and AgNTf2 to dem-
onstrate that hydrolysis of the silver salt by amounts of water avail-
able in ‘dry’ dichloromethane14 can lead to generation of sufficient
Brønsted acid active catalyst to effect conversion of 5a to 6a. In all
of these cases, reactivity was at least partially restored, with
0.5 mol % water being optimal, and higher concentrations led to
Table 2
Effect of added water or Brønsted acida
Entry
AgNTf2 (mol %)
Brønsted acid (mol %)
H2O (mol %)
Time (h)
Yield of 6ab (%)
1
2
3
4
5
6
7
8
9
10
–
–
10
10
10
10
–
–
–
–
–
0.5
1
10
–
–
–
–
24
1
0
HNTf2 (0.5)
HNTf2 (1.0)
–
–
–
HNTf2 (0.5)
TsOHÁH2O (0.5)
MsOH (0.5)
CSA (0.5)
TfOH (0.5)
94
89
96
70c
36c
96
NR
NR
NR
38c
0.25
24
24
24
1
1
1
1
1
–
–
–
10
11
–
a
Reaction conditions: 0.05 M substrate in DCM at reflux. See Supplementary data for detailed procedure. Reactions were allowed to continue until consumption of 5a
(except for entries 1, 5, 6, 8–11).
b
Yields given are for pure product after chromatographic purification.
c
Product yield was calculated using the 1H NMR ratio of an inseparable mixture of 6a and unconsumed 5a.

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S. A. Bonderoff et al. / Tetrahedron Letters 53 (2012) 4600–4603
Table 3
Scope of Friedel–Crafts cyclization of simple arene-tethered olefins
Entry Substrate
Reaction conditions
Product
Yielda (%)
1
0.5 mol % HNTf2, DCM, reflux, 2 h
92
2
1.0 mol % HNTf2, DCE, 180 °C (microwave), 20 min
80
3
4
1.0 mol % HNTf2, DCE, 180 °C (microwave), 15 min
1.0 mol % HNTf2, DCE, 180 °C (microwave), 2 h
90 (2.8:1 dr)
87
5
6
1.0 mol % HNTf2, DCE, 180 °C (microwave), 15 min
74
60
1.0 mol % HNTf2, DCM, reflux, 20 h
7
8
1.0 mol % HNTf2, CD2Cl2, reflux, 21 h; then 100 °C (microwave), 30 min
NR
56
1.0 mol % HNTf2, DCE, 180 °C (microwave), 5 min
a
Yields given are for pure product after chromatographic purification.
apparent inhibition of the reaction (entries 4–6). In entry 7, AgNTf2
was used in combination with HNTf2 to check for an additive effect;
however, the results did not differ significantly from the use of
HNTf2 alone. Finally, other strong Brønsted acids failed to catalyze
the cyclization, with the exception of triflic acid in moderate yield.
When these optimized reaction conditions were applied to
other substrates, it was found that in the majority of cases it was
necessary to increase the catalyst loading to 1% and employ micro-
wave heating in dichloroethane to encourage expedient and com-
plete reaction of the substrate (Table 3). Methyl-substituted 5b
cyclized cleanly to provide 6b in excellent yield (entry 1), whereas
5c required more forcing conditions to form the congested 1,2,3-
trisubstituted benzene moiety 6c in 80% yield (entry 2). Branched
substrate 5d was cyclized to 6d in 90% yield with an unremarkable
2.8:1 ratio of diastereomers15 (entry 3). Electron-deficient 3-chloro
substrate 5e was cleanly converted into tetralin 6e in excellent
yield under the microwave conditions (entry 4). The noteworthy
tolerance of halogen substitution16 suggests the possibility of
sequential C–C bond formation by Friedel–Crafts alkylation
followed by various transition metal-catalyzed cross-coupling
processes.17
1,1-Disubstitution on the alkene effects a reversal in cyclization
regiochemistry (entry 5), affording indane 6f in good yields. Exten-
sion of the tether provides benzocycloheptene 6g in moderate
yield (entry 6). The analogous enone 5h was unreactive under
the conditions employed, which may arise from a preference for
the s-cis conformation by the enone moiety.18,19 Furan 5i
underwent cyclization with microwave heating to afford tetra-
hydrobenzofuran 6i (entry 8). No competing cyclization at C-4 to
afford the tetrahydroisobenzofuran isomer was observed.
Friedel–Crafts cyclization of unactivated alkenes proceeds read-
ily under superacid catalysis. This is an improvement over the clas-
sical reagents with respect to milder conditions and decreased acid
waste, and should be more amenable to highly functionalized sub-
strates. Electron-rich and electron-poor arenes as well as furans are
compatible, and 5-, 6-, and 7-membered rings are formed with
excellent regioselectivity in good to excellent yields with the
creation of a quaternary center.

S. A. Bonderoff et al. / Tetrahedron Letters 53 (2012) 4600–4603
4603
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The authors thank NSERC for generous funding of the project,
Boehringer Ingelheim (Canada) Ltd for an Industrial Cooperative
Research Award in Synthetic Organic Chemistry, and Alberta Inge-
nuity for a Ph.D. Graduate Student Scholarship (S.A.B.).
Supplementary data
Supplementary data (Experimental procedures, physical data,
and NMR spectra for 1a–d, 2a–d, 4, 5a–i, 6a–g, 6i and synthetic
intermediates, and X-ray crystallographic data for 2d) associated
with this article can be found, in the online version, at http://
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with periodic NMR analysis. Longer reactions times furnished 6g in acceptable
yield, and the reaction was scaled up using DCM. However, 5h remained
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