Br?nsted Acid-Catalyzed Intramolecular Hydroarylation of β-Benzylstyrenes

Article abstract of DOI:10.1021/acs.orglett.7b00958

Using triphenylmethylium tetrakis(pentafluorophenyl)borate as a convenient Br?nsted acid precatalyst, β-(α,α-dimethylbenzyl)styrenes are shown to cyclize efficiently to afford a variety of new indanes that possess a benzylic quaternary center. The geminal dimethyl-containing quaternary center is proposed to be necessary to arm the substrate for cyclization through steric biasing.

Full text of DOI:10.1021/acs.orglett.7b00958

Letter
pubs.acs.org/OrgLett
Brønsted Acid-Catalyzed Intramolecular Hydroarylation of
β‑Benzylstyrenes
Xiao Cai, Amir Keshavarz, Justin D. Omaque, and Benjamin J. Stokes*
School of Natural Sciences, University of California, Merced, 5200 North Lake Road, Merced, California 95343, United States
S
* Supporting Information
ABSTRACT: Using triphenylmethylium tetrakis(pentafluorophenyl)borate as
a convenient Brønsted acid precatalyst, β-(α,α-dimethylbenzyl)styrenes are
shown to cyclize efficiently to afford a variety of new indanes that possess a
benzylic quaternary center. The geminal dimethyl-containing quaternary center
is proposed to be necessary to arm the substrate for cyclization through steric
biasing.
he hydroarylation of alkenes1 is the most direct means by
Scheme 1. Intramolecular Hydroarylation of β-
Benzylstyrenes: Challenges and Opportunities
2
Twhich to synthesize alkylarenes. Catalytic intramolecular
Friedel−Crafts-type electrophilic alkene hydroarylation reac-
tions are useful for the synthesis of many types of benzocyclo-
alkanes,3 but such methods require the desired ring closure to
outcompete intermolecular side reactions. Thus, there are
relatively few strategies for Friedel−Crafts-type benzocyclo-
pentane (indane4) synthesis, presumably in part due to the
challenging trajectory of electrophilic aromatic attack required
to achieve the formal 5-endo-trig cyclization.5−7 Perhaps the
most common strategy is the Friedel−Crafts-type cyclization of
remote alcohols, which can be difficult to prepare in modular
fashion.4a,7 In contrast, a method for indane synthesis using
strictly aliphatic (unoxidized) substrates has not yet been
developed. Herein, we describe our investigation of electro-
philic cyclizations of β-benzylstyrenes (A, Scheme 1A). The
complication of intermolecular side reactions is made
abundantly clear considering that the simplest β-benzylstyrene,
A (R = H), affords just 7% yield of the cyclized product.
Fortunately, installation of a geminal dimethyl group (R = Me)
enabled cyclization of A to outcompete intermolecular side
reactions, resulting in excellent yield (inset, Scheme 1A). This
disparity suggests that the geminal dialkyl group assists
B have been used in microporous polymers11a and as
cyclization through conformational activation of the substrate
composites in thermoplastics.11b
via both 1,3-allylic strain (A′) and Thorpe−Ingold strain (A″,
Scheme 1B).8 Based on this exciting lead, we devised a rapid
synthesis of β-(α,α-dimethylbenzyl)styrenes to enable mod-
ification of either of the two aromatic rings, as well as the
substituents on the benzylic carbon atom (Scheme 1C). This
route consists of a zinc enolate cross-coupling to produce
benzylic quaternary center-containing benzaldehydes (C),9
followed by Wittig olefination. Thus, in just three steps total,
we can prepare a wide variety of indanes that contain benzylic
geminal dimethyl-containing quaternary centers. Benzylic
geminal dimethyl quaternary centers are medicinally significant
because they are metabolically robust compared to benzylic
methylenes.10 In materials, 1-aryl-3,3-dimethylindanes such as
At the outset of our study, we used β-benzylstyrene 1a as a
model substrate and evaluated a series of Brønsted and Lewis
acids for their propensity to catalyze intramolecular hydro-
arylation (Table 1). Initially, we found that 10 mol % of p-
toluenesulfonic acid monohydrate did not efficiently consume
substrate 1a at 80 °C, but full conversion and fair yield could be
realized at 135 °C (entries 1 and 2). In comparison, under
otherwise identical conditions, 85% aqueous sulfuric acid
converted the substrate much less efficiently (entry 3), while
Received: March 30, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00958
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Optimization of the Intramolecular Hydroarylation
of β-(α,α-Dimethylbenzyl)styrene
Table 2. Influence of Alkyl Substitution at the Benzylic
a
a
Position of β-Benzylstyrenes
conv
b
yield
b
catalyst or
precatalyst
temp
(%) of
(%) of
entry
solvent
C6H6
C6H6
(°C)
1a
2a
1
p-TsOH·H2O
p-TsOH·H2O
H2SO4 (85 wt %) C6H6
80
7
6
2
135
135
135
0→rt
0→rt
0→rt
135
100
40
100
60
71
50
0
3
4
HCl (37 wt %)
HOTf
C6H6
<5
5
CH2Cl2
PhMe
C6H6
100
100
100
<5
60
85
>95
0
6
HOTf
7
HOTf
8
Ph3PAuOTf
Pd(OAc)2
TMSOTf
C6H6
9
TFA/DCM
C6H6
100
100
100
10
58
91
>95
0
a
Reactions were conducted on 0.25 mmol scale unless otherwise
noted and monitored by TLC. In each case, the starting material was
fully consumed within 5 h. Yields refer to isolated product unless
10
11
Ph3CB(C6F5)4
Ph3CB(C6F5)4
Ph3CB(C6F5)4
C6H6
75
c
12
C6H6
75
b
otherwise noted. Reaction was conducted on 1.0 mmol scale.
13
C6H6
rt
<5
0
c
1
Determined by H NMR analysis using 1,3,5-trimethoxybenzene as
a
d
1
Reactions were conducted on 0.1 mmol scale in a sealed vial.
Determined by H NMR analysis using 1,3,5-trimethoxybenzene as
an internal standard. 10 mol % of triethylamine was used in this case.
an internal standard. Ratio of diastereomers as determined by H
NMR of the crude reaction mixture; the major diastereomer is
depicted.
b
1
c
37% aqueous hydrochloric acid failed to convert the substrate
appreciably (entry 4). The evaluation of a stronger Brønsted
acid, namely trifluoromethanesulfonic acid, was more fruitful,
with the solvents dichloromethane, toluene, and benzene
affording increasing yields of indane 2a; the former provides
nearly quantitative yield of product (entries 5−7). The
transition metal complex Ph3PAuOTf failed to engage the
starting material at all (entry 8), while a modest 58% yield was
realized using Pd(OAc)2 in the presence of trifluoroacetic acid
(entry 9). Main group Lewis acids were more suitable, with
trimethylsilyltriflate (TMSOTf) delivering 2a in 91% yield at
just 40 °C (entry 10). An excellent yield was also achieved
using a triphenylmethylium (tritylium) Lewis acid salt,
specifically commercially available tritylium tetrakis(penta-
fluorophenyl)borate (TPFPB), which delivered indane 2a
virtually quantitatively at temperatures as low as 75 °C (entry
11). Notably, other tritylium salts, including Ph3CBF4,
Ph3CSnCl5, and Ph3CPF6, resulted in little or no conversion
of 1a at 75 °C, presumably due to their visible insolubility. No
product was detected in the presence of triethylamine (entry
12), which suggests that this variant is catalyzed by the in situ
generated Brønsted acid H−TPFPB.12 Finally, no conversion
was observed when the tritylium salt was used at ambient
temperature (entry 13). Although lower reaction temperatures
are possible using either trifluoromethanesulfonic acid (entry 7)
or trimethylsilyltriflate (entry 10), they are noxious, difficult to
measure reliably, prone to decomposition, and volatile, whereas
the tritylium TPFPB salt is an easily handled solid.
just 23% yield, while, as mentioned previously, desmethylated
2c was barely observed. Of note, cis-2b was formed with a slight
preference over trans-2b. We then evaluated the scope of
benzylic dialkyl substituents on β-benzylstyrenes 1. To that
end, 1,1-ethylmethyl-3-phenylindane 2d was formed in good
yield as a 55:45 mixture of diastereomers. Diethyl indane 2e
was also formed in good yield, while cycloalkyl-containing β-
benzylstyrenes 1f−1h afforded diminished yields of the
corresponding hydroarylation products 2f−2h. The attenuated
yields of 2f−2h also support our hypothesis of an enabling
steric bias, such as a Thorpe−Ingold effect, whereby angle
compression is diminished for cyclic alkanes compared to
acyclic ones.8
Our next aim was to investigate the functional group
tolerance of the reaction conditions on hydroarylations of
substituted β-(α,α-dimethylbenzyl)styrenes (Table 3). In
general, the tritylium TPFPB catalyst fully converted substrates
containing a wide variety of functional groups, with the
exception of Lewis basic alkoxyl or hydroxyl groups. However,
in such cases, triflic acid may be used; for example, 3a was
converted to indane 4a, albeit in low yield (entry 1). Also in the
R1 position, nonbasic substituents, such as methyl (entry 2) and
halogens, including bromine, chlorine, and fluorine (entries 3−
5), were effectively hydroarylated in the presence of the trityl
TPFPB salt. In contrast, a substrate bearing a trifluoromethyl
substituent (3f) was fully consumed, but a complex mixture of
undesired products resulted (entry 6). A phenyl-substituted
substrate (3g) afforded a 31% hydroarylation yield when using
triflic acid as the catalyst (entry 7); surprisingly, no cyclization
occurred in the presence of the trityl TPFPB precatalyst.
Excellent yields were obtained for meta-dimethoxy- and meta-
dimethyl-substituted substrates (entries 8 and 9), the former
also requiring triflic acid as the catalyst. Methoxy, methyl,
chloro, and trifluoromethyl-containing substrates afforded only
modest yields in the styrene para-position (entries 10−13),
whereas a m-chloro substituent delivered indane 4n in fair yield
Utilizing the tritylium TPFPB precatalyst, we next system-
atically probed the impact of geminal dialkyl substitution on
empowering the cyclization of β-benzylstyrenes (Table 2).
Affirmatively, whereas 2a is readily formed in excellent yield on
1.0 mmol scale using 5 mol % of the precatalyst at [1a] = 0.5
M, diminishing yields resulted as methyl groups were removed
from the benzylic position. Specifically, despite complete
substrate conversion, monomethyl indane 2b was obtained in
B
DOI: 10.1021/acs.orglett.7b00958
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 3. Scope of the Intramolecular Hydroarylation of β-
(α,α-Dimethylbenzyl)styrenes
Table 4. Assessing the Regioselectivity of Intramolecular
Hydrorylations of β-(α,α-Dimethylbenzyl)styrenes
a
a
b
entry
1
substrate ID
R
yield (%) of 6 + 7
rr (6:7)
substrate
ID
entry
R1
R2
Ar
yield (%) of 4
5a
5b
5c
5d
5e
5f
t-Bu
OMe
F
88
91
85
70
83
78
91
98
96
70
>95:5
81:19
78:22
67:33
60:40
50:50
40:60
35:65
35:65
33:67
bc
c
,
1
3a
3b
3c
3d
3e
3f
OMe
Me
Br
Cl
F
H
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
29
76
62
65
52
0
2
2
H
3
c
3
H
4
OH
i-Pr
Et
4
H
5
5
H
6
6
CF3
Ph
H
H
7
5g
5h
5i
Cl
c
c
7
3g
3h
3i
H
31
93
91
15
28
46
41
73
69
8
Ph
8
OMe
Me
H
9
Br
9
H
10
5j
Me
c
a
10
11
12
13
14
15
3j
H
(p-OMe)C6H4
(p-Me)C6H4
(p-Cl)C6H4
(p-CF3)C6H4
(m-Cl)C6H4
2-naphthyl
Starting material was fully consumed within 5 h. Yields refer to the
b
3k
3I
H
H
sum of regioisomers. rr = regioisomeric ratio, which was determined
by H NMR spectroscopy of the crude mixture. Reaction employed
c
1
H
H
bd
,
10 mol % of trifluoromethanesulfonic acid as catalyst for 1 h.
3m
3n
3o
H
H
e
H
H
H
H
a
Starting material was fully consumed within 5 h. Yields refer to
b
isolated product unless otherwise noted. 1H NMR yield determined
using 1,3,5-trimethoxybenzene as an internal standard. Reaction
c
employed 10 mol % of trifluoromethanesulfonic acid as catalyst at 0 °C
d
for 1 h. Reaction employed 0.6 equiv of trifluoromethanesulfonic acid
e
for 1 h. Reaction employed 15 mol % of Ph3CB(C6F5)4.
in the presence of 15 mol % of tritylium TPFPB (entry 14).
Lastly, we found that substrate 3o, which contains a 2-naphthyl
substituent, afforded a 69% yield of hydroarylation product 4o
(entry 15).
We next evaluated the outcomes of intramolecular hydro-
arylations in which two regioisomeric indane products are
possible (Table 4). The cyclization of t-Bu-substituted substrate
5a formed the least-hindered cyclization product, 6-tert-
butylindane 6a, exclusively (entry 1). Cyclization also favored
the 6-substituted regioisomer in >2:1 ratio for methoxy (entry
2),13 fluoro (entry 3), and hydroxyl (entry 4) substituted β-
benzylstyrenes, which is consistent with cyclization at the more
nucleophilic position.14 In contrast to the t-Bu-bearing
substrate (entry 1), the analogous i-Pr-substituted substrate
5e cyclized with only a modest preference for indane 6e. As
alkyl substituents became even less bulky (entries 6 and 10),
the 4-alkylindanes 7f and 7j were formed preferentially.15 Other
halogenated substrates (5g and 5i) and a phenyl-substituted
substrate (5h) all favored the formation of the corresponding 4-
substituted indane regioisomers 7g−7i (entries 7−9). Finally,
bicyclic arene-containing substrates 5k and 5l (Table 4,
bottom) delivered the corresponding sterically congested
isomers 7k and 7l in near exclusivity.
reaction, including the relative contributions of steric and
electronic effects upon the regioselectivity of the reaction.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b00958.
Experimental procedures and characterization data
(PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: bstokes2@ucmerced.edu.
ORCID
Benjamin J. Stokes: 0000-0002-5982-654X
Notes
We have demonstrated the feasibility and utility of catalytic
intramolecular hydroarylations of β-(α,α-dimethylbenzyl)-
styrenes. These reactions are readily accomplished with an
easily handled trityl TPFPB precatalyst, or catalytic triflic acid.
We are currently pursuing the development of new methods
based on the utility of α,α-dimethylbenzyl-substituted alkenes,
while also working to better understand the mechanism of the
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was funded by the University of California,
Merced.
C
DOI: 10.1021/acs.orglett.7b00958
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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D
DOI: 10.1021/acs.orglett.7b00958
Org. Lett. XXXX, XXX, XXX−XXX