Unexpected extension of usage of PPh3/CBr4, a versatile reagent: Isomerization of aromatic allylic alcohols

Article abstract of DOI:10.1246/cl.2012.1597

The PPh₃/CBr₄-catalyzed isomerization of 2-aromatic allylic alcohols into the corresponding saturated aldehydes or ketones has been achieved at room temperature in good to excellent yields under mild and metal-free conditions. This new methodology has been applied successfully to the synthesis of ibuprofen in four steps.

Full text of DOI:10.1246/cl.2012.1597

doi:10.1246/cl.2012.1597
Published on the web November 24, 2012
1597
Unexpected Extension of Usage of PPh3/CBr4, a Versatile Reagent:
Isomerization of Aromatic Allylic Alcohols
Wanchun Gong, Yun Liu, Jijun Xue, Zhixiang Xie,* and Ying Li*
State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering,
Lanzhou University, Lanzhou 730000, P. R. China
(Received August 21, 2012; CL-120870; E-mail: xiezx@lzu.edu.cn)
X
R1
X
R
X
The PPh3/CBr4-catalyzed isomerization of 2-aromatic
allylic alcohols into the corresponding saturated aldehydes or
ketones has been achieved at room temperature in good to
excellent yields under mild and metal-free conditions. This new
methodology has been applied successfully to the synthesis of
ibuprofen in four steps.
R
C N R'
Appel
Reaction
R2
O
R-OH
X
O
R1
R2
R C NH R'
Halogenation
For example
This work
O
allylic alcohols
O
S
P-N Linkage
O
isomerization
R
Ph3P
N
R
PPh3 + CX4
Dehydration
OH
Merged with tetrahalomethane, tertiary phosphanes can
effect manifold important transformations in organic synthesis
such as halogenation, dehydration, and P-N linkage (Figure 1).1
On the basis of the structural features of the substrates, a variety
of halogenation products can be obtained. For example, the
conversion of an alcohol into an alkyl halide using triphenyl-
phosphine and tetrahalomethane is named the Appel reaction.1
In this reaction, the use of carbon tetrabromide as a halide source
yields alkyl bromides.2 The use of carbonyl compounds as the
starting material to react with the PPh3/CX4 reagent provides
1,1-dihaloolefins. On the other hand, imidoyl halide is obtained
when the substrates are monosubstituted carboxamides.1 In this
letter, we wish to report a new transformation process involving
the PPh3/CBr4-catalyzed isomerization of 2-aromatic allylic
alcohols into the corresponding saturated aldehydes or ketones.
To our best knowledge, this is the first example of the use of the
PPh3/CBr4 reagent in a catalytic amount for a synthetic purpose.
Recently, during our investigations in another project, we
needed compound 2a as a key intermediate. The allylic bromide
2a was expected to be obtained by bromination of the allylic
alcohol 1a. To our surprise, when 1a was treated with 1.0
equivalent of PPh3 and 1.0 equivalent of CBr4, aldehyde 3a was
obtained in 22% yield, accompanying 2a in 62% yield. With the
use of 0.6 equivalent of PPh3 and CBr4, 3a was turned into the
major product in 55% yield (Scheme 1). This unusual trans-
formation of allylic alcohols to saturated carbonyl compounds
encouraged us to study the reaction further, because aldehydes
are versatile synthetic intermediates for various pharmaceuticals,
agrochemicals, and other fine chemicals.3 The conversion of
allylic alcohols to the corresponding saturated aldehydes or
ketones is a synthetic process that usually requires a two-step
sequence of reduction and oxidation reactions. A one-pot
catalytic transformation equivalent to an internal redox process
is an attractive strategy and a completely atom-economical
process,4 which offers several useful applications in natural-
product synthesis and bulk chemical processes. More impor-
tantly, in many cases, the isomerization of allylic alcohols
requires rather harsh reaction conditions and the use of
expensive metals (for instance Rh,5a Ru,5b Pd,5c Pt,5d and
Ir5e);5 few synthetic methods requiring mild and metal-free
conditions for such transformations have been reported. To our
knowledge, there are literature precedents6 for the isomerization
Ar
O
H2N S
O
R
R
Ar
HO
R
H
RCOOH
N
R'
+ 2HNR'R''
O
R C NH2
R''
N R''
R'
Et3N ,
O
R'
R
C N
R
C
N
R''
R
Figure 1. Tertiary phosphane/tetrahalomethane, a versatile
reagent for halogenation, dehydration, and P-N linkage.
O
H
OH
Br
MeO
MeO
MeO
2a
3a
1a
62%
25%
22%
55%
1 equiv PPh3/CBr4
0.6 equiv PPh3/CBr4
Scheme 1. Unexpected 2-aromatic allylic alcohols isomer-
ization.
of allylic alcohols to saturated carbonyls. The reaction of allylic
alcohols with 1.0 equivalent of phosphorus(III)bromide at 0 °C
was reported to furnish isomerized products instead of bromo
derivatives. Considering the advantages of PPh3/CBr4 in terms
of its ease of use and handling and its low cost compared with
noble metals, as well as the extension of the usage of PPh3/
CBr4, the development of novel reactions utilizing these
compounds is of increasing interest to our group.
For the optimization of the reaction conditions, 1a was used
as the model compound for the screening of the reaction
parameters. The results are summarized in Table 1. Running the
reaction without PPh3 or CBr4 resulted in no reaction (Entries 1
and 2). The amount of PPh3 and CBr4 had a significant influence
on the yield of 3a. By reducing the number of equivalents of
PPh3/CBr4, the yield of product 2a was increased (Entries 3-8).
Chem. Lett. 2012, 41, 1597-1599
© 2012 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

1598
Table 1. Optimization of allylic alcohols isomerization con-
ditionsa
Table 2. PPh3/CBr4-catalyzed isomerization reactionsa
OH
Br
OH
O
O
0.2 equiv CBr4, 0.2 equiv PPh3
R1
R1
Conditions
R2
CH2Cl2, RT
R2
H
1a-1l
3a-3l
Entry
1
Substrates 1
Products 3
Yieldb/%
87
MeO
MeO
MeO
2a
1a
3a
CBr4
/equiv
PPh3
/equiv
Time
/h
2a
/%
3a
/%
Entry
O
OH
H
O
1
2
3
4
5
6
7
8
9
1
0
1
0
1
1
24
24
0.5
1
1
2
4
8
0.5
0.5
0.5
0
0
62
50
25
15
Trace
0
74.5
87
89
0
0
22
32
55
62.5
87
87
17
11
7
MeO
MeO
1a
3a
OH
2c
3
0.8
0.6
0.4
0.2
0.1
1.2
1.4
1.5
0.8
0.6
0.4
0.2
0.1
1.2
1.4
1.5
92
97
96
H
3b
1b
OH
O
H
3c
1c
10
11
OH
O
4
H
aAll reactions were conducted with 0.2 mmol of 1a in 10 mL of
dry CH2Cl2 at room temperature.
TBSO
TBSO
3d
1d
OBn
OBn
O
O
OH
OH
5
6
7
8
92
93
83
82
However, the reaction time became longer for the obtainment of
a higher yield. The best result was obtained when 0.2 equivalent
of PPh3/CBr4 were used (Entry 7). On the other hand,
increasing the number of equivalents of PPh3/CBr4 was
beneficial for the formation of product 2a (Entries 9-11).
With these results in hand, the generality of this isomer-
ization reaction was examined. A series of aromatic allylic
alcohols were treated with PPh3 (0.2 equiv) and CBr4 (0.2
equiv). As shown in Table 2, the isomerization reaction of the
aromatic allylic alcohols proceeded smoothly in good to
excellent yields. Electron-donating substituents on the phenyl
ring did not affect the yields of the desired products significantly
(Entries 1-12). However, when a substrate containing an
electron-withdrawing group at the phenyl ring was used, no
desired product was observed. It was notable that the corre-
sponding keto compounds 3k and 3l were obtained in good yield
when the secondary allylic alcohols 1k and 1l were used as
starting materials (Entries 11 and 12). Several aliphatic alcohols,
such as methallyl alcohol, 2-methyl-1-buten-3-ol, and geraniol
were also subjected to the standard procedure; however, the
reaction system was not applicable to these allylic alcohols, and
only minor products of alkyl bromide were obtained with the
recovery of the major substances.
H
H
1e
1f
3e
TBSO
TBSO
3f
MeO
OH
MeO
MeO
PMBO
O
H
MeO
3g
1g
PMBO
OH
O
H
3h
1h
O
OH
9d
78
92
H
OTBS
OTBS
1i
3i
O
OH
10c
H
1j
3j
On the basis of these results, a plausible mechanism for the
PPh3/CBr4-catalyzed isomerization of allylic alcohols to satu-
rated carbonyls is proposed in Scheme 2. In this mechanism, the
phosphonium salt II is first produced from PPh3 and CBr4 via
the phosphonium salt I.7 When the allylic alcohol 1 reacts with
the phosphonium salt I, an SN2 process proceeds to give the
corresponding bromo derivative 2, following a typical Appel
reaction mechanism.1c In contrast, the reaction of the allylic
alcohol 1 with the phosphonium salt II proceeds through the
intermediate IV with the elimination of HBr. The addition of H+
to the double bond of IV follows Markovnikov’s rule to furnish
V. Only electron-donating substituents on the phenyl ring can
O
OH
11
12
83
86
MeO
MeO
MeO
1k
1l
3k
3l
OH
O
MeO
aReactions were run with allylic alcohols (0.2 mmol), CBr4
(0.2 equiv), PPh3 (0.2 equiv) in 10 mL of dry CH2Cl2 at room
temperature in 4 h. Isolated yield. Reaction was run in 8 h.
dReaction was run in 2 d.
b
c
Chem. Lett. 2012, 41, 1597-1599
© 2012 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

1599
ology can be used under mild and metal-free conditions, and has
been applied successfully to the synthesis of ibuprofen. Further
applications and extensions of the methodology are currently
under investigation in our laboratory and will be reported in due
course.
PPh3
Br3C Br
Br PPh3
CBr3
OH
Br3C PPh3
Br
I
II
H
Br
OPPh3Br
OPPh3CBr3
H
I
II
H
We are grateful for the financial support provided by Natural
Science Foundation of China (NSFC Nos. 21072084 and
21272099).
- HCBr3
- HBr
R
R
R
III
IV
1
- Ph3P
O
References and Notes
OPPh3CBr3
1
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pp. 1-39.
Br
H
H
R
R
Br
2
V
2
R = electron-donating group
OPPh3CBr3
O
HBr
R
- II
H
R
3
VI
3
Scheme 2. A plausible mechanism for the formation of 2
and 3.
O
OH
a
b
4
5
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1j
4
5
O
O
c
d
H
OH
3j
6
Scheme 3. Synthesis of ibuprofen. Reagents and conditions:
a) CH3P+Ph3I , n-BuLi, THF, 0 °C-rt, 24 h, 88%; b) SeO2(cat.),
¹
TBHP, AcOH, CH2Cl2, rt, 3 days, 86%; c) CBr4, PPh3, CH2Cl2,
rt, 8 h, 92%; d) KMnO4, MgSO4, CH3COCH3, rt, 2.5 h, 66%.
stabilize the cationic center in V. The proton between the
cationic center and OPPh3CBr3 is more acidic, and is easily
removed by the bromide anion in the solution, which abstracts
it to yield VI, which on acidolysis furnishes the saturated
carbonyl 3.
6
As proof of the effectiveness and usefulness of this new
methodology, ibuprofen, a nonsteroidal anti-inflammatory drug
(NSAID),8 was chosen as the synthetic target, which has been
completed by many research groups.9,10 From the commercially
available 4-(2-methylpropyl)acetophenone (4), the allyl alcohol
1j was prepared in a two-step sequence involving a Wittig
reaction followed by selenium-dioxide-catalyzed allylic oxida-
tion with TBHP.11 Through this new methodology, the aldehyde
3j was obtained in 92% yield from the allyl alcohol 1j.
Subsequent oxidation12 of 3j gave ibuprofen 6. Thus, the
synthesis of ibuprofen was achieved from this readily available
starting material in four steps in 46% overall yield13 (Scheme 3).
In conclusion, we have extended the usage of PPh3/CBr4, a
versatile reagent, to the isomerization of aromatic allylic
alcohols to furnish saturated carbonyl compounds. This method-
7
8
9
J. S. Nicholson, S. S. Adams, U.S. Patent 3385886, 1968.
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12 H. Park, T. V. RajanBabu, J. Am. Chem. Soc. 2002, 124, 734.
13 Supporting Information is available electronically on the
CSJ-Journal Web site, http://www.csj.jp/journals/chem-lett/
index.html.
Chem. Lett. 2012, 41, 1597-1599
© 2012 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/