F. Howard et al. / Tetrahedron Letters 51 (2010) 4208–4210
4209
1
was not observed in the H NMR spectrum. This isomer has been re-
ported by other groups during the dimerization of 4 and would have
been detected by its characteristic chemical shift at d 6.14, if pres-
BiBr3
Ph
OH
CH Cl
Ph
Ph
2
2
1
0 ºC
2
3
,4
ent. The temperature was increased to 15 °C, during which the
build-up of 4 and 2 continued. After 30 min, the ratio of 1:4:2
was 7:3:90. At this temperature, no other signals were visible in
DCE
0 ºC
BiBr3
5
DCE
0 ºC
1
BiBr3
the H NMR spectrum. Notably, 4 was not a rapidly consumed inter-
5
mediate in the reaction. When the temperature was increased to
2
0 °C, characteristic signals of the diastereotopic methylene pro-
1
tons at d 2.29 and d 2.52 of 3 were observed in the H NMR spectrum
after 20 min. It has been proposed that the formation of 2 is revers-
ible starting from 4. As the low temperature NMR spectroscopy
3
Ph
3
experiments presented above proved that 4 was stable below
2
0 °C, this equilibrium could easily be studied. A pure sample of 2
was mixed with an equimolar amount of BiBr in CDCl overnight
at 10 °C. However, only starting material 2 was visible in the
Scheme 3. Temperature dependence of the formation of 2 and 3.
3
3
1
H
and an inert atmosphere. However, the reaction outcome was
dependent on the temperature. When the reaction was run at
NMR spectrum and no trace of compound 4 was evident. According
to the rule of microscopic reversibility, 4 would have been visible if
the reaction was reversible. Based on these results the following
1
5
0
°C, product 2 was formed in 88% isolated yield after column chro-
10
matography (Scheme 3). When the reaction was run at 50 °C, in-
dane 3 was generated in above 95% conversion and in 82% yield.
The fact that 2 was generated at lower temperatures implies that
it is the kinetic product and 3 is the thermodynamic product. This
mechanism is proposed: alcohol 1 eliminates water in the presence
of BiBr to yield 4 which undergoes an irreversible dimerization to
3
yield 2 (Scheme 5). At temperatures above 20 °C cyclization to 3
occurs.
was supported by transforming 2 into 3 in the presence of BiBr
5
3
at
0 °C in a separate experiment. The dimerization of 1 could be
performed using catalytic amounts of BiBr , albeit with a lower
reaction rate. When the reaction was run using 5 mol % of BiBr
0% of 1 was converted into the product within 2 h.12
When alcohol 1 was used as the starting material a possible
reaction mechanism includes elimination of water to generate 4
Scheme 4). This was proposed by Stavber’s group.7a The Lewis acid
11
BiBr3
BiBr3
0 ºC
2
3
Ph
OH
-H O
Ph
2
3
,
1
0 ºC
CDCl3
4
6
CDCl
3
(
BiBr3
0 ºC
coordinates to the double bond in 4, which is reversibly attacked
with Markovnikov selectivity by another molecule of 4 to generate
Ph
Ph
2
2
Ph
CDCl3
3
2. The Lewis acid then coordinates to the double bond of 2, and at
temperatures above 20 °C is attacked by an electron pair from the
phenyl group to generate 3 via a Friedel–Crafts-type reaction with
Markovnikov selectivity. Earlier attempts to observe 4 during the
reaction failed, which implies an overall reaction where the rate
of dimerization is faster than the rate of the elimination.7a An alter-
native mechanism has been proposed, which includes the forma-
Scheme 5. Proposed reaction mechanism.
In conclusion, we have reinterpreted the reported etherification
9
of 1 with either methanol or butanol. Instead of giving unsymmet-
3
rical ethers, reaction of 1 with BiBr generates dimeric compounds
tion of an
g
6-coordinated intermediate between BiBr
3
and the
2 or 3 or both. By controlling the temperature, high chemoselectiv-
ity can be achieved. At temperatures below 15 °C, 2 is generated as
the sole product, whilst at temperatures above 20 °C indane 3 is
produced. Both compounds can be synthesized selectively in good
yields. The kinetic product 2 can rearrange into the thermody-
13
aryl groups of two molecules of the alcohol. As this mechanism
does not involve the elimination product, it was worthwhile to
study the first step of this reaction.
An NMR tube was charged with BiBr
3
and cooled to À78 °C. Alco-
hol 1, dissolved in CDCl , was then added slowly. The NMR tube was
3
3
namic product 3 in the presence of BiBr . The mechanism involves
inserted into a probe pre-cooled to À50 °C. At this temperature, sig-
elimination of water to generate 4 which undergoes an irreversible
dimerization following Markovnikov selectivity to yield 2. At tem-
peratures above 20 °C alkene 2 is irreversibly cyclized into 3.
1
nals at d 2.28 and d 1.60 originating from 1 were visible in the H
NMR spectrum. The temperature was increased by 10 °C every
3
0 min. At 0 °C, broad methylene signals at d 5.20 and d 5.52 corre-
1
14
sponding to 4 appeared in the H NMR spectrum. After 30 min at
Acknowledgement
0
°C, methylene protons at d 4.90 and d 5.26 due to 2 were observed
1
in the H NMR spectrum in addition to the signals of 4. It is note-
worthy that 4-methyl-2,4-diphenyl-2-pentene, an isomer of 2,
Financial support from the Department of Biochemistry and
Organic Chemistry, University of Uppsala, is gratefully acknow-
ledged.
BiBr3
2
BiBr3
Supplementary data
Ph
OH
Ph
-H
2
O
Ph
Ph
1
4
4
Br Bi
3
References and notes
Ph
1. Metal-Catalyzed Cross-Coupling Reactions; de Meijere, A., Diederich, F., Eds.;
2
3
Wiley-VCH: Weinheim, 2004.
2.
Green Chemistry and Catalysis; Sheldon, R. A., Arends, I., Hanefeld, U., Eds.;
Scheme 4. Originally proposed mechanism for the dimerization of 1.
Wiley-VCH: Weinheim, 2007.
Howard, Fredrick
