Friedel-Crafts cyclization of tertiary alcohols using bismuth(III) triflate

Article abstract of DOI:10.1016/j.tetlet.2013.06.026

Bismuth(III) triflate [Bi(OTf)₃] has been developed as an efficient and mild catalyst for intramolecular Friedel-Crafts cyclizations of tertiary alcohols to prepare disubstituted tetrahydronapthalenes, chromans, thiochromans, tetrahydroquinolin

Full text of DOI:10.1016/j.tetlet.2013.06.026

Tetrahedron Letters 54 (2013) 4330–4332
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Tetrahedron Letters
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Friedel–Crafts cyclization of tertiary alcohols using bismuth(III)
triflate
⇑
Baskar Nammalwar, Richard A. Bunce
Department of Chemistry, Oklahoma State University, Stillwater, OK 74078-3071, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Bismuth(III) triflate [Bi(OTf)3] has been developed as an efficient and mild catalyst for intramolecular Fri-
edel–Crafts cyclizations of tertiary alcohols to prepare disubstituted tetrahydronapthalenes, chromans,
thiochromans, tetrahydroquinolines, and tetrahydroiso-quinolines. The method represents a unified
strategy to synthesize a variety of ring systems from tertiary alcohols using a common Lewis acid.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 19 May 2013
Revised 3 June 2013
Accepted 6 June 2013
Available online 13 June 2013
Keywords:
Friedel–Crafts cyclization
Bismuth(III) triflate
Heterocycles
Tertiary alcohols
Several recent publications have described methods for the
preparation of 1,1-disubstituted tetrahydronaphthalenes and 4,4-
disubstituted chromans, thiochromans, tetrahydroquinolines, and
tetrahydroisoquinolines, which are known to have biological activ-
ity.1 To date, several synthetic approaches have been used to access
these systems.2 The most common strategies involve acid-cata-
lyzed ring closure of an alkene on an electron-rich arene,3 radical
cyclization,4 olefin metathesis ring closure,5 and metal-catalyzed
cyclization.6 The use of Lewis or Bronsted acids, such as AlCl3,7
FeCl3ꢀ6H2O,8 Amberlyst-15Ò (A-15),9 H2SO4,10 and polyphosphoric
acid (PPA)11 to promote Friedel–Crafts cyclization of tertiary alco-
hols on aromatic rings has also been attempted, but with varied
success. These reactions gave inconsistent yields largely due to
the harsh nature of these reagents. Therefore, the development of
a general, high-yield, mild, and convenient method to synthesize
carbocyclic and heterocyclic structures using a common catalyst
would be a worthwhile endeavor.
Our investigation began with the goal of developing a more effi-
cient strategy to synthesize the drug SHetA2 (1) and its prodrug 2.
Currently, 1 is being evaluated for clinical studies to treat renal and
ovarian cancer.12 The reported synthesis of this compound7a in-
volved cyclization of tertiary alcohol 3 by a Friedel–Crafts reaction,
using stoichiometric AlCl3 in PhCl, and gave the core heterocycle 4
of the target molecules in 58% yield (entry 1, Table 1). The present
study sought to further evaluate a series of Lewis and Bronsted
acids for this process under different solvent and temperature re-
gimes. Problems were encountered with this transformation, how-
ever, due to substrate insolubility, unwanted side reactions, toxic
and corrosive reagents, elaborate work-up procedures, and irrepro-
ducible yields. Overcoming these challenges in the cyclization was
a critical concern.
OH
H
H
H
H
N
N
N
N
S
S
O2N
S
O2N
S
SHetA2 (1)
SHetA2 Prodrug (2)
During the past decade, Bi(OTf)3 has been employed as a Lewis acid
in a wide range of reactions.13 To determine the suitability of this
catalyst for the current Friedel–Crafts ring closure, a CHCl3 solution
of alcohol 3 was heated in the presence of 20 mol % of Bi(OTf)3, and
was found to give clean conversion to 4 in 90% yield. To the best of
our knowledge, only one prior study has utilized Bi(OTf)3 for the
ring closure of a tertiary alcohol.14 In the current work, this catalyst
gave a significant improvement over previously reported reagents.
Optimization of the Friedel–Crafts ring closure of 3 to 4 was
chosen as the model system to evaluate the efficiency of Bi(OTf)3
compared to previously reported acid catalysts (Table 1). Catalysts,
such as AlCl3, FeCl3ꢀ6H2O, p-TsOH, CH3SO2H, and A-15, all required
prolonged heating at P75 °C, which led to fragmentation of the
substrate, numerous side reactions, and only modest yields of the
desired product. Bi(OTf)3, however, efficiently promoted the reac-
tion under mild heating to afford 4 in good to excellent yields. Fur-
ther investigation of catalyst loadings indicated that 15 mol % of
Bi(OTf)3 provided consistently superior results.
The solvent was also varied to ascertain the most favorable
medium for the reaction. These experiments revealed that the sol-
⇑
Corresponding author. Tel.: +1 405 744 5952; fax: +1 405 744 6007.
E-mail address: rab@okstate.edu (R.A. Bunce).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.06.026

B. Nammalwar, R. A. Bunce / Tetrahedron Letters 54 (2013) 4330–4332
4331
Table 1
Table 3
Synthesis of an SHetA2 precursor
Chroman and thiochroman cyclizations using Bi(OTf)3
HO
HO
H
H
Bi(OTf)3
N
N
catalyst
R
R
CHCl3, reflux
O
O
solvent, Δ
X
X
S
S
R
R
7
8
3
4
X
R
Cat (mol %)
t (min)
Yield (%)
Entry
Catalyst
mol %
Solvent
T (°C)
t (min)
Yield (%)
a
b
O
S
H
Me
15
10
20
15
95
88
1
2
3
4
5
6
7
8
AlCl3
AlCl3
100
100
20
10
100
30
100
50
20
15
15
PhCl
PhH
PhH
CHCl3
PhH
PhH
PhH
PhH
CHCl3
CHCl3
PhH
70–75
80
80
61
80
80
80
80
61
30
90
90
60
240
90
180
20
20
35
45
58
70
58
32
0
30
40
75
90
92
78
80
FeCl3ꢀ6H2O
FeCl3ꢀ6H2O
p-TsOH
CH3SO3H
Dry A-15
Bi(OTf)3
Bi(OTf)3
Bi(OTf)3
Bi(OTf)3
Bi(OTf)3
Table 4
Tetrahydroquinoline cyclizations using Bi(OTf)3
HO
9
4
Bi(OTf)3
X
X
10
11
12
61
80
66
3
CHCl3, reflux
N
Ts
N
Ts
1
2
15
THF
45
9
10
X
Cat (mol %)
t (min)
Yield (%)
a
b
c
d
e
H
15
15
15
15
15
30
30
30
30
30
78
82
72
72
75
vent had a significant effect on the product yields. In CHCl3, sub-
strate 3 gave the desired product in 92% yield, while other solvents,
such as PhCl, PhH, and THF, generally afforded lower returns.
Variation of the temperature was also examined. At room tem-
perature, no product was formed, even after an extended reaction
period (24 h). At 90 °C, the solution darkened, and the yields de-
creased as more impurities were produced. Under moderate heat-
ing at 60–65 °C, however, excellent yields were achieved with a
minimum of side reactions. These results further validated CHCl3
(bp 61 °C) as the best solvent for the reaction. An additional advan-
tage to using this solvent was that the catalyst could be easily recy-
cled and reused. Due to the relatively low solubility of Bi(OTf)3 in
CHCl3 at 20 °C, the catalyst could be readily reclaimed and reused
at the end of the reaction. However, since the recovered catalyst
trapped small quantities of product, the recycled Bi(OTf)3 was al-
ways employed for same transformation.
With the optimized protocol established, the methodology was
extended to other substrates. Cyclizations of 1,1-disubstituted-
1,2,3,4-tetrahydronaphthalenes were initially evaluated (Table 2)
using substrates prepared by literature methods.9 Employing our
standard conditions, reactants 5a–f were cleanly converted to tar-
gets 6a–f. Remarkably, even the deactivated substrate 5c under-
went ring closure in excellent yield. Treatment of this substrate
with A-15 in refluxing benzene had previously given only dehydra-
tion products.9 Additionally, hindered substrates incorporating
gem-diphenyl substitution (e.g. 5d and 5e) were also successfully
cyclized using Bi(OTf)3, although the yields were slightly lower
than those observed for the dimethyl cases.
4-OMe
4-Cl
2-Me
2,3-(CH2)4ꢁ
Table 5
Tetrahydroisoquinoline cyclizations using Bi(OTf)3
HO
4
3
Bi(OTf)3
X
X
NTs
CHCl3, reflux
NTs
1
2
11
12
X
Cat (mol %)
t (min)
Yield (%)
a
b
c
d
e
H
4-Cl
4-F
3-OMe
2,3-Benzo
15
15
15
15
15
30
30
30
30
30
92
94
89
78
94
possible (Tables 4 and 5, respectively). In these cases, Bi(OTf)3 gen-
erally provided higher conversions than Al- and Fe-based cata-
lysts.7b,8c Additionally, fragmentation, which typically occurred in
10–35% during the closure of nitrogen heterocycles, never ex-
ceeded 5% for reactions promoted by Bi(OTf)3. Finally, in our earlier
work, several substrates produced alkene by-products, which were
not cyclized by conventional catalysts. In the current study, al-
kenes, intercepted from several of the reactions after short reaction
times, were observed to undergo cyclization upon prolonged heat-
ing. Indeed, Bi(OTf)3 has previously demonstrated utility as a cata-
lyst for Friedel–Crafts reactions of alkenes.16
Finally, it was observed that substrates incorporating a free
amine, such as the N-benzyl alcohol 13 and the N-methyl alkene
14, failed to cyclize with catalytic Bi(OTf)3. Presumably, the basic
nitrogen in these substrates coordinated with the catalyst and
deactivated it for the cyclization. Due to the expense of Bi(OTf)3,
however, no attempt was made to perform the reaction on 13 or
14 using stoichiometric or excess catalyst.
Our method also permitted cyclizations of chroman 8a and
thiochroman 8b in yields comparable to or better than those pre-
viously recorded (Table 3).15 Ring closures to prepare tetrahydro-
quinolines 10a–e and tetrahydroisoquinolines 12a–e were also
Table 2
Tetrahydronaphthalene Cyclizations using Bi(OTf)3
R
R'
R'
HO
X
X
Bi(OTf)3
R
CHCl3, reflux
HO
H
5
6
N
X
R
R0
Cat (mol %)
t (min)
Yield (%)
O
N
N
a
b
c
d
e
f
H
Me
Me
Me
Ph
Ph
Me
Me
Me
Me
Ph
15
15
20
20
20
25
30
30
60
90
90
90
96
92
81
76
74
90
Me
Ph
13
14
OMe
CF3
H
Cl
H
A possible mechanism for the ring closure is given in Figure 1. In
the intial step, the alcohol hydroxyl group would displace triflate
from the catalyst to give 15. This could then be followed by direct
Ph
CH2CO2Me

4332
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flate would regenerate the catalyst.
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using a common Lewis acid catalyst. The catalyst is very mild
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to previously reported methods. Side reactions, such as fragmenta-
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The authors are pleased to acknowledge funding for the State-
wide NMR facility by the NSF (BIR-9512269), the Oklahoma State
Regents for Higher Education, the W.M. Keck Foundation, and
Conoco, Inc. The authors also wish to thank the OSU College of Arts
and Sciences for funds to upgrade our departmental FT-IR instru-
ments. Finally, the authors are indebted to Professor K.D. Berlin
for valuable suggestions to improve the manuscript.
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Supplementary data
Supplementary data (experimental details, 1H and 13C NMR
spectra, and analytical data for all of the cyclized products) associ-
ated with this article can be found, in the online version, at http://
dx.doi.org/10.1016/j.tetlet.2013.06.026.
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