A mild and efficient method for bromination of alcohols using α,α-dibromo-β-dicarbonyl compounds as halogen sources

Article abstract of DOI:10.1016/j.tetlet.2013.10.120

Exploration of α,α-dibromo-β-dicarbonyl compounds as novel bromine agents for the conversion of alcohols to alkyl bromides under neutral conditions has been achieved. This method can be used for acid-sensitive substrates and allows the bromination of various primary and secondary alcohols to proceed at room temperature within a very short period of time.

Full text of DOI:10.1016/j.tetlet.2013.10.120

Tetrahedron Letters 55 (2014) 90–93
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A mild and efficient method for bromination of alcohols using
a,a-dibromo-b-dicarbonyl compounds as halogen sources
Xiao-Meng Cui a, Yong-Hong Guan a, Na Li a, Hao Lv a, Lin-An Fu a, Kun Guo a, Xiaohui Fan a,b,
⇑
a School of Chemical and Biological Engineering, Lanzhou Jiaotong University, Lanzhou 730070, China
b Beijing National Laboratory for Molecular Sciences (BNLMS), Beijing 100190, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Exploration of a,a-dibromo-b-dicarbonyl compounds as novel bromine agents for the conversion of alco-
Received 12 June 2013
Revised 4 September 2013
Accepted 27 October 2013
Available online 1 November 2013
hols to alkyl bromides under neutral conditions has been achieved. This method can be used for acid-sen-
sitive substrates and allows the bromination of various primary and secondary alcohols to proceed at
room temperature within a very short period of time.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Appel reaction
a,a-Dibromo-b-dicarbonyl compound
Alcohol to bromide
Triphenylphosphine
Alkyl halides are one of the most common and important build-
ing blocks with diverse applications in organic chemistry.1 They
are generally prepared from halogenation of the corresponding
alcohols by using thionyl chloride or phosphorous halides under
harsh reaction conditions. An alternatively mild method for this
transformation is the Appel reaction which uses combined systems
of PPh3 with an electrophilic halogen source such as CCl4, CBr4, or
I2.2 Besides these, several other methods have also been developed
for this transformation, including benzoxazolium,3 phenylmethyl-
eniminium,4 Vilsmeier–Haack reagents,5 Viehe salts,6 chlorodi-
methylsilane-benzil,7 cyclopropenium ion,8 BtH–SO2Cl2,9 catalytic
triphenylphosphine oxide with oxalyl chloride,10 and Ru-catalytic
systems in combination with CBr4 and photocatalysis.11 Among
them, the Appel reaction, despite suffering from the generation
of stoichiometric phosphine oxides as byproduct, is found to be
the most utilized method in organic synthesis due to its conve-
nience, mildness, and reliability. However, the electrophilic halo-
gen sources for this reaction are rather limited and toxic such as
CCl4 and CBr4. Therefore, further exploration of new halogen
sources for efficient preparation of alkyl halides under neutral con-
ditions would be valuable. Recent efforts have disclosed several re-
agents for this transformation such as hexabromoacetone,12
trichloroacetonitrile,13 and N-bromosacchsrin.14
prone to release one bromonium ion or two under Lewis acid or
base conditions and could be used as oxidants or brominating
agents for the development of novel reaction methods (Eq. 1).16
As one of our continuous interests in the activation of carbon–oxy-
gen bond for construction of carbon–heteroatom bond,17 recently
we launched a study to test this hypothesis by using
a,a-dibro-
mo-b-dicarbonyl compounds as electrophilic bromine sources in
the Appel reaction. We were gratified to find that the high reactiv-
ity of these compounds allows the Appel reaction to proceed
smoothly under very mild conditions. The results are reported
herein.
R2
O
O
O
O
LA
R1
R2
LA
H
+
Br
(Br)
R1
Br
H(Br)
ð1Þ
(eq 1)
R1
O
O
(Br)H
R2
Base
O
BrB
R1
R2
Br
H(Br)
O
Our work was started by testing the bromination of alcohol 1a
with 1.2 equiv of ethyl -dibromoacetoacetate 2a in DMF in the
a,a
presence of 1.5 equiv of triphenylphosphine. The reaction pro-
ceeded smoothly at room temperature with complete substrate
conversion in 15 min, giving the desired bromide product 3a in
88% isolated yield (Table 1, entry 1). Encouraged by this result,
various solvents were examined (Table 1, entries 2–10). Dichloro-
ethane (DCE) was found to be the most suitable solvent for this
transformation and the isolated yield of product 3a could be
a,a-Dibromo-b-dicarbonyl compounds are a series of less ex-
plored reagents in organic synthesis that possess a similar struc-
ture with NBS.15 We reasoned that these compounds would be
⇑
Corresponding author. Tel./fax: +86 0931 4938 755.
E-mail address: fanxh@mail.lzjtu.cn (X. Fan).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.10.120

X.-M. Cui et al. / Tetrahedron Letters 55 (2014) 90–93
91
Table 1
improved to 91% (Table 1, entry 10). Lowering the amount of elec-
trophilic bromine source 2a from 1.2 equiv to 1 (relative to 1a) is
obviously unfavorable for this reaction (Table 1, entry 11). To our
delight, when the triphenylphosphine loading was increased to
2 equiv, the bromide product 3a was obtained in almost quantita-
tive yield (Table 1, entry 13). It is worth noting that under the opti-
Optimization of reaction conditionsa
O
O
PPh3
OH
Br
+
OEt
solvent, rt, 15 min
Cl
Cl
Cl
Cl
Br
Br
1a
2a
3a
mal reaction conditions ethyl
a,a-dibromoacetoacetate 2a was
Entry
2a (equiv)
PPh3 (equiv)
Solvent
Yieldb (%)
completely converted into ethyl acetoacetate.18 In order to investi-
gate the efficiency of 2a, NBS and CBr4 were subjected to this reac-
tion system (Table 1, entry 13). The desired bromide product 3a
could be separated in 25% (NBS as brominating agent) and 21%
yields (CBr4 as brominating agent) respectively, indicating that
1
2
3
4
5
6
7
8
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.0
1.2
1.2
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.2
2.0
DMF
DCM
88
80
68
81
77
76
86
Trace
53
91
85
88
99
CH3CN
Benzene
Et2O
Dioxane
THF
DMSO
CH3NO2
DCE
ethyl
a,a-dibromoacetoacetate 2a is a more efficient bromine
source in the Appel reaction.19
9c
10
11
12
13
Subsequently, other activated dibromides, such as
a,a-dib-
romoacetylacetone 2b and ethyl
a,a-dibromobenzoylacetate 2c,
DCE
DCE
DCE
were examined for this bromination reaction (Scheme 1). As ex-
pected, under the optimal reaction conditions (Table 1, entry 13),
either 2b or 2c can serve as electrophilic bromine source and gave
the corresponding alkyl bromide 3a in 99% and 82% yields
respectively.
With the optimized reaction conditions in hand (Table 1, entry
13), the generality of this bromination reaction was then investi-
gated on a series of alcohols (Table 2). It was found that the present
reaction conditions showed good substrate compatibility with var-
ious primary and secondary alcohols, providing the corresponding
products in good to excellent yields within a very short period of
reaction time at room temperature (Table 2, entries 1–13). Acid-
sensitive protective groups such as -THP and -TBS can tolerate
the reaction conditions (Table 2, entries 14 and 15), which demon-
strates that the present reaction system is relatively mild.
Unactivated tertiary aliphatic alcohol 1p could not undergo this
transformation even under harsh reaction conditions (Table 2,
a
Reaction conditions: (2,4-Dichlorophenyl)methanol (0.34 mmol), solvent
(3 mL), room temperature, 15 min, in air.
b
Isolated yield.
30 min.
c
Ph3P (2.0 equiv), 2b or 2c (1.2 equiv)
OH
Br
Cl
Cl
DCE, rt, 15 min
Cl
Cl
3a
1a
2b = CH3COCBr2COCH3
2c = PhCOCBr2CO2C2H5
99% yield
82% yield
Scheme 1. Other dibromides for bromination of 1a.
Table 2
Bromination of various alcoholsa
Ph3P (2.0 equiv), 2a (1.2 equiv)
R
Br
R
OH
DCE, r.t
3a-s
1a-s
Entry
1
Alcohol
Product
t (min)
Yieldb (%)
99
OH
Br
3a
1a
1b
15
Cl
Cl
Cl
Cl
Cl
OH
Br
2
3
4
45
30
30
63
99
99
Cl
Br
3b
Cl
Cl
Cl
OH
1c
1d
3c
3d
Cl
OH
Cl
Cl
Br
OH
OH
Br
Br
3e
3f
1e
1f
5
6
15
15
71
78c
OH
Br
3g
1g
7
30
98
99
OH
Br
3h
3i
1h
1i
8
9
15
80
14
14
OH
Br
83
14
14
(continued on next page)

92
X.-M. Cui et al. / Tetrahedron Letters 55 (2014) 90–93
Table 2 (continued)
Entry
Alcohol
OH
Product
t (min)
Yieldb (%)
70
Br
3j
10
11
50
1j
OH
Br
3k
60
86
1k
F
F
OH
3l
Br
12
13
15
15
79
84
1l
OH
Br
1m
3m
TBSO
TBSO
3n
1n
14
30
15
53
60
OH
OH
Br
Br
15d
1o
1p
3o
THPO
12
THPO
OH
OH
16
–
17 h
n.r.
3q
1q
17
18
19
a
30
24 h
15
99
82
85
3r
Ph
OH 1r
Ph
OH
3s
1s
Reaction conditions: Ph3P (2.0 equiv), 2a (1.2 equiv), DCE (3 mL), room temperature, in air.
Isolated yield.
Mixture of Z,E-isomers, E/Z = 2.6:1 (see Supplementary data for details).
Et3N (1.2 equiv) was added to improve the product yield.
b
c
d
compound A to form an ion pair intermediate B, which then reacts
with an alcohol to generate an alkoxyphosphonium salt C and a
molecular ethyl acetoacetate (or ethyl a-bromoacetoacetate). Sub-
sequently, disassociation of species C to give a carbocation inter-
mediate D followed by a simultaneous addition (path I) or b-H
elimination (path II) process would give rise to the corresponding
bromide product or alkene.
R2
H
R1
O
CH2R3
Ph3P Br HOCHPh
O
O
(Br)
(Br) H
O
PPh3
Br
R2
- R1COCH2COR2
R1
A
B
path I
PhCHBrCH2R3
CH2R3
CHPh
path I
path II
PhCH CHR3
H
- Ph3P=O
O
Ph3P
In summary, we have demonstrated a series of novel bromine
Br
Br
PhCH=CHR3
agents,
a,a-dibromo-b-dicarbonyl compounds, for the conversion
C
D
path II
of alcohols to alkyl bromides under neutral conditions. This meth-
od can be used for various primary and secondary alcohols, and
shows good compatibility with acid-sensitive substrates. Further
investigation of these compounds in organic synthesis is underway
in our laboratory.
Scheme 2. A tentative reaction pathway.
entry 16), presumably due to its high steric hindrance. For the p-
activated tertiary alcohols such as benzylic alcohol 1q and propar-
gylic alcohol 1r, the elimination products 3q and 3r were obtained
in higher yields without bromide products being observed. Inter-
estingly, a quite opposite result was obtained when secondary ben-
zylic alcohols were subjected to this reaction. The acyclic alcohols
1c and 1g were compatible with the optimal reaction conditions,
and the desired bromide products 3c and 3g were produced in
99% and 98% yields, respectively (Table 2, entries 3 and 7). In con-
trast, the use of cyclic alcohol 1s resulted in the isolation of elim-
ination product 3s as the sole product (Table 2, entry 19). The
reason for such a difference between acyclic and cyclic secondary
benzylic alcohols is unclear. In addition, the allylic secondary alco-
hol 1b led cleanly to the thermodynamically favored isomeric bro-
mide product 3b, suggesting that the reaction most likely proceeds
via a carbocation pathway. This hypothesis was also supported by
the ring opening of the cyclopropane moiety of the substrates 1j,
1k, and 1l to give the homoallylic bromide products 3j, 3k, and
3l in good yields (Table 2, entries 10–12).
Acknowledgments
We thank the Natural Science Foundation of China (21162013)
and Beijing National Laboratory for Molecular Sciences (BNLMS)
for financial support, Prof. Zhi-Xiang Yu for helpful discussions.
Supplementary data
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
10.120.
References and notes
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studies,9b,14
a
tentative reaction pathway was proposed in
Scheme 2. Firstly, PPh3 reacts with the bromodicarbonyl

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a
-bromoacetoacetate being isolated. This indicates that both ethyl
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a
bromine sources in this reaction, and the releasing of brominium ions is
mediated by PPh3.
19. In contrast to NBS and CBr4, one molecular of
compound can release two bromine atoms, and b-dicarbonyl compounds are
more prone to enolization to release bromine atoms in the -position. So, they
a,a-dibromo-b-dicarbonyl
a
are more efficient bromine sources. Additionally, the reported Appel-type
reactions usually need large excessive amounts of NBS and CBr4 to gain
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