Triphenylphosphine oxide-catalyzed stereoselective poly- and dibromination of unsaturated compounds

Article abstract of DOI:10.1039/c4cc02847c

A novel PPh₃O catalyzed bromophosphonium salt-mediated dibromination of α,β-unsaturated esters and β,γ- unsaturated α-ketoesters has been developed. The products were obtained with good to excellent yields and excellent diastereoselectivities.

Full text of DOI:10.1039/c4cc02847c

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Triphenylphosphine oxide-catalyzed
stereoselective poly- and dibromination of
unsaturated compounds†
Cite this: Chem. Commun., 2014,
50, 7817
Received 17th April 2014,
Accepted 20th May 2014
Tian-Yang Yu, Yao Wang, Xiu-Qin Hu and Peng-Fei Xu*
DOI: 10.1039/c4cc02847c
www.rsc.org/chemcomm
A novel PPh3O catalyzed bromophosphonium salt-mediated dibromi-
Therefore, due to the importance of such compounds, bromi-
nation of a,b-unsaturated esters and b,c-unsaturated a-ketoesters has nation of unsaturated C–C bond has attracted considerable
been developed. The products were obtained with good to excellent attention from the synthetic community. Elemental bromine is
yields and excellent diastereoselectivities. This dibromination reaction is frequently used in bromination reactions which, however, usually
a good complement to the field of dibromination.
require harsh conditions.2 During the past decades, many novel
dibromination methods have been developed.3–5 Among these
Organobromine compounds can be found in a variety of new alternative methods, the most commonly employed strategies
natural products (some products are shown in Fig. 1). They are either to use suitable bromine carrying reagents3 or to
are widely used as essential intermediates in the manufacture generate bromine in situ involving metal catalysts.4 Despite the
of derivatives of many natural products, pharmaceuticals, significant progress, the use of bromine carrying reagents such
agrochemicals and other fine chemicals.1 Organobromine com- as NBS6 (N-bromosuccinimide) and similar compounds will
pounds are also very useful building blocks for some funda- generate a stoichiometric amount of waste which is difficult to
mental chemical transformations such as Grignard reactions, dispose and the employment of toxic metal reagents will cause
cross-coupling, and nucleophilic substitution, etc.
environmental problems. Therefore, it is highly desired to develop
safer, more practical and environmentally benign methods to
complement the current dibromination research.
It is well known that some reactions, such as Staudinger,7
Wittig,8 Mitsunobu9 and some PPh3-triggered10 reactions, usually
generate PPh3O as a waste product. However, the molecular weight
of PPh3O is high (278) which leads to the decreased efficiency of
these reactions. Therefore, it is necessary to find a practical method
to make use of this waste product and therefore improve the
reaction efficiency. Herein, we report our progress toward solving
these problems through an efficient triphenylphosphine oxide
catalyzed stereoselective dibromination of unsaturated compounds.
To the best of our knowledge, the dibromination reaction
using a combination of oxalyl bromide and triphenylphosphine
oxide has not been reported before. Based on the results of our
previous work (Scheme 1),11 we envisioned that 1,3-dibromination
reaction of unsaturated a-ketoesters might take place if we replace
oxalyl chloride with oxalyl bromide. With this idea in mind, we began
to investigate this bromination reaction. However, to our surprise,
oxalyl chloride and oxalyl bromide showed totally different reactivities
and an unexpected dibromination of double bond occurred while the
1,3-dibromination product did not form (Scheme 1).
Fig. 1 Some bromine-substituted natural products.
State Key Laboratory of Applied Organic Chemistry, College of Chemistry and
Chemical Engineering, Lanzhou University, Lanzhou 730000, P. R. China.
E-mail: xupf@lzu.edu.cn; Fax: +86 931-8915557
† Electronic supplementary information (ESI) available: Experimental proce-
dures, analytical data for all compounds, and copies of 1H and 13C NMR spectra
of all the products. CCDC 992325. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c4cc02847c
To generalize the reaction scope, we investigated the reaction
by employing the most commonly used unsaturated ester 1a as a
model substrate and oxalyl bromide as a bromine source in the
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solvents. Several solvents such as CHCl3, toluene and THF
(Table 1, entries 8–10) were tested, and the results showed that
the optimal one was DCE. Moreover, it was notable that only a
trace amount of the desired product was detected in the absence
of PPh3O (Table 1, entry 11).
Under the optimal conditions, the scope of the triphenyl-
phosphine oxide catalyzed dibromination reaction was investi-
gated by using various functionalized a,b-unsaturated esters to
evaluate the generality of this dibromination reaction.
Generally speaking, as shown in Table 2, the reaction was
effective for a broad range of unsaturated esters and provided
dibrominated products with good to excellent yields (83–98%)
and excellent diastereoselectivities (d.r. 4 19 : 1). In all cases, the
formation of anti-products was preferred. Substrates containing
either electron-withdrawing or -donating functional groups in aro-
matic rings were both tolerated. Meanwhile the substitution position
(ortho-, meta-, and para-) of the substituents on aromatic rings had
little effect on the reaction efficiency and diastereoselectivity. How-
ever, the reaction proceeded faster with substrates containing
electron-neutral and donating groups (24 h) than with those contain-
ing electron-withdrawing substituents (36 h). Other ester groups
were also examined, and it was found that these ester groups could
be tolerated in this dibromination reaction (Table 2, entries 13
and 14). Furthermore, we found that both of the aliphatic
a,b-unsaturated esters and naphthalenyl a,b-unsaturated ester
could work under the reaction conditions and the corresponding
dibrominated products were obtained in excellent yields and
diastereoselectivities (Table 2, entries 10–12).
Scheme 1 Dichlorination and dibromination reactions with PPh3O as
the catalyst.
presence of a catalytic amount of PPh3O (20 mol%) in dry DCE
(1,2-dichloroethane) under reflux (Table 1, entry 1). To our delight,
the reaction proceeded efficiently to afford the anti-selective
dibromination product 2a in excellent yield (92%) with excellent
diastereoselectivity (419:1). Then, the reduced amount of oxalyl
bromide was tested to determine the effect on the reaction
(Table 1, entries 2–4). As expected, the data revealed that a decrease
in the amount of oxalyl bromide resulted in a lower yield (Table 1,
entries 2–4). Considering that the reaction temperature was rela-
tively high (DCE under reflux), we also performed the reaction at
lower temperature (Table 1, entries 5–7). It was observed that nearly
the same excellent yields and stereoselectivities were obtained at
60 1C or even at 40 1C (Table 1, entries 5 and 6). However, when the
reaction was performed at room temperature, only a trace amount
of the product was detected (Table 1, entry 7). Further optimization
of the reaction conditions was carried out by screening the reaction
Having developed the catalytic dibromination of a,b-unsaturated
esters, next, we examined the substrate scope of dibromination
reaction of the b,g-unsaturated a-ketoester (3) (Table 3). Again
it should be noted that the dibromination of b,g-unsaturated
Table 2 Substrate scope of unsaturated estersa
Table 1 Screening of the reaction conditionsa
Entry R1
R2 Product Time (h) Yieldb (%) dr (anti/syn)c
Entry
Solvent
T
Yieldb (%)
dr (anti/syn)c
1
2
3
4
5
6
7
8
9
2-ClC6H4
Me 2b
Me 2c
Me 2d
Me 2e
Me 2f
Me 2g
Me 2h
Me 2i
Me 2j
Me 2k
Me 2l
36
36
36
36
36
24
24
24
24
24
24
36
36
36
91
96
92
92
91
92
83
95
95
91
95
98
88
87
419 : 1
419 : 1
419 : 1
419 : 1
419 : 1
419 : 1
419 : 1
419 : 1
419 : 1
419 : 1
11 : 1
1
DCE
DCE
DCE
DCE
DCE
DCE
DCE
CHCl3
Toluene
THF
Reflux
Reflux
Reflux
Reflux
60 1C
40 1C
RT
40 1C
40 1C
40 1C
40 1C
92
12
53
81
90
90
Trace
80
61
419 : 1
n.d.
419 : 1
419 : 1
419 : 1
419 : 1
n.d.
419 : 1
419 : 1
n.d.
3-ClC6H4
4-ClC6H4
4-BrC6H4
4-FC6H4
2d
3e
4 f
5
2-MeC6H4
3-MeC6H4
4-MeC6H4
4-tBuC6H4
6
7
8
9
10d n-Hexanyl
10
Trace
Trace
11d c-Hexanyl
11g
DCE
n.d.
12
13
14
2-Naphthalenyl Me 2m
Ph
Ph
419 : 1
419 : 1
419 : 1
Et 2n
Bn 2o
a
Unless otherwise noted, the reactions were carried out with 1a
(0.1 mmol, 16.2 mg), oxalyl bromide (29 mL,0.3 mmol), 4 Å MS
a
(40.0 mg), and PPh3O (20 mol%, 0.02 mmol, 5.6 mg) in the indicated
Unless otherwise noted, the reactions were carried out with 1
b
solvent (0.5 mL) for 24 h. Isolated yield after flash chromatography. (0.1 mmol), oxalyl bromide (0.3 mmol), 4 Å MS (40.0 mg), and PPh3O
Determined by 1H NMR spectroscopic analysis of the crude reaction (20 mol%, 0.02 mmol, 5.6 mg) in the dry DCE (0.5 mL). Isolated yield
c
b
mixture. 0.1 mmol oxalyl bromide was used. 0.15 mmol oxalyl after flash chromatography. Determined by 1H NMR spectroscopic
d
e
c
f
g
d
bromide was used. 0.2 mmol oxalyl bromide was used. Without analysis of the crude reaction mixture. Reaction temperature was
PPh3O. n.d. = not determined, MS = molecular sieve.
60 1C. MS = molecular sieve.
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Table 3 Substrate scope of unsaturated ketoestersa
Entry
Ar
Product
Yieldb (%)
dr (anti/syn)c
Scheme 3 Dibromination reaction catalyzed by PPh3.
1
2
3
4
5
6
7
Ph
4a
4b
4c
4d
4e
4f
92
81
94
96
82
92
93
8 : 1
7 : 1
11 : 1
9 : 1
7 : 1
12 : 1
9 : 1
2-ClC6H4
3-ClC6H4
4-ClC6H4
2-MeC6H4
3-MeC6H4
4-MeC6H4
4g
a
Unless otherwise noted, the reactions were carried out with 3
(0.1 mmol), oxalyl bromide (0.3 mmol), 4 Å MS (40.0 mg), and PPh3O
(20 mol%, 0.02 mmol, 5.6 mg) in the dry DCE (0.5 mL) at 40 1C for 5h. b The
yield was determined by 1H NMR using 1,1,2,2-tetrachloroethane(TCE) as an
internal standard. c Determined by 1H NMR spectroscopic analysis of the
crude reaction mixture. MS = molecular sieve.
Fig. 3 The proposed mechanism of dibromination reaction.
Fig. 2 X-ray crystallographic structure of 4a.
Scheme 3, it was found that the dibromination reaction could also
proceed in the presence of a catalytic amount of PPh3 (20 mol%).
However, without a catalyst, only a trace amount of conver-
sion was observed. Based on these results described here, a
possible mechanism is proposed. As shown in Fig. 3, initially,
triphenylphosphine oxide reacts with oxalyl bromide to generate
intermediate M1,13 the in situ generated bromo-triphenylphos-
phonium bromide M1 reacts with unsaturated ester 1 to give a
three-membered cyclic bromonium ion intermediate M2.
The cyclic intermediate then undergoes ring opening reaction
by the bromide ion via the SN2 pathway to produce the anti-
dibrominated product 2 and generate triphenylphosphine (PPh3).
It should be noted that the SN2 ring-opening is the explanation for
high anti-stereoselectivity of the product. Finally, PPh3 reacts with
oxalyl bromide to regenerate M1.
In conclusion, we have developed a novel bromophosphonium
salt-mediated stereoselective dibromination of a,b-unsaturated
esters, b,g-unsaturated a-ketoesters and some other unsaturated
compounds. In this reaction, PPh3O, which is usually considered
as the stoichiometric waste product of some common reac-
tions, is employed as a powerful catalyst. A broad substrate
scope was observed for this reaction, without specially tailored
dibromination reagent, oxalyl bromide can serve as a cheap and
commercially available bromine source. Since the byproduct is
gas, the desired product can be much easily separated. This
methodology also provides a potential route for the synthesis of
enantioselective dibrominated products from achiral substrates.
The study of the asymmetric dibromination reaction is currently
underway in our laboratory.
a-ketoester has not been reported before. In general, the
b,g-unsaturated a-ketoester substrates bearing either electron-
withdrawing or -donating groups reacted smoothly with oxalyl
bromide in the presence of a catalytic amount of PPh3O to
afford the corresponding products in good to excellent yields
with excellent diastereoselectivities. The X-ray crystallographic
structure of 4a is shown in Fig. 2.12 Since products 4a–4g are not
stable, NMR spectroscopic yields were obtained using 1,1,2,2-
tetrachloroethane as an internal standard. As a consequence of
the steric effect, when substrates bearing ortho-substituted groups
on aromatic rings were subjected to the reaction, lower yields were
observed (Table 3, entries 2 and 5).
To further demonstrate the power of this method, we
applied this bromination method to a,b,g,d-unsaturated ester
5 and styrene, as shown in Scheme 2, where tetra-brominated
compound 6 was obtained in moderate yield with excellent
diastereoselectivity, and dibrominated product 7 was obtained
in 49% yield.
In order to explore the mechanism of this dibromination
reaction, some control experiments were performed. As shown in
We are grateful to the NSFC (21032005, 21172097,
21302075), the National Basic Research Program of China
(no. 2010CB833203), the National Natural Science Foundation
Scheme 2 Tetrabromination of compound 5 and dibrominaton of styrene.
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