Catalytic Asymmetric Bromination of Unfunctionalized Olefins with H2O as a Nucleophile

Article abstract of DOI:10.1002/chem.201502133

The dimeric cinchona alkaloid (DHQD)₂PHAL is used to catalyze an effective asymmetric bromohydroxylation of unfunctionalized olefins with H₂O as nucleophile an N-bromobenzamide as a bromine source. A variety of optically active bromohydrins are formed with up to 88%ee. PHAL's positive: An effective asymmetric bromohydroxylation of unfunctionalized olefins with H₂O as nucleophile catalyzed by the dimeric cinchona alkaloid (DHQD)₂PHAL (see scheme) is described. Optically active bromohydrins are obtained with up to 88%ee.

Full text of DOI:10.1002/chem.201502133

DOI: 10.1002/chem.201502133
Communication
&
Synthetic Methods
Catalytic Asymmetric Bromination of Unfunctionalized Olefins
with H2O as a Nucleophile
Xun Zhang,[a] Jing Li,[a] Hua Tian,[a] and Yian Shi*[a, b, c]
Chem. Eur. J. 2015, 21, 11658 – 11663
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Table 1. Studies on the reaction conditions.[a]
Abstract: The dimeric cinchona alkaloid (DHQD)2PHAL is
used to catalyze an effective asymmetric bromohydroxyla-
tion of unfunctionalized olefins with H2O as nucleophile
an N-bromobenzamide as a bromine source. A variety of
optically active bromohydrins are formed with up to
88% ee.
Entry Cat. Br source
Solvent system (ratio) Yield [%][b] ee [%][c]
1
2
3
4
5
6
7
8
–
PhCONHBr
PhCONHBr
PhCONHBr
PhCONHBr
PhCONHBr
PhCONHBr
PhCONHBr
PhCONHBr
NBS
acetone/H2O (5:1)
acetone/H2O (5:1)
acetone/H2O (5:1)
acetone/H2O (5:1)
acetone/H2O (5:1)
acetone/H2O (5:1)
acetone/H2O (5:1)
acetone/H2O (5:1)
acetone/H2O (5:1)
acetone/H2O (5:1)
acetone/H2O (5:1)
acetone/H2O (5:1)
acetone/H2O (5:1)
MeCN/H2O (5:1)
THF/H2O (5:1)
trace
39
82
73
87
83
65
73
93
93
69
91
72
87
15
59
29
19
99
85
56
76
57
–
0
0
0
78
7
3a
3b
3c
3d
3e
3 f
Electrophilic halogenation of olefins is among the most impor-
tant transformations in organic chemistry and allows simulta-
neous installation of two CÀX bonds by stereoselective ring-
opening of a halonium ion intermediate with a nucleophile. Al-
though asymmetric halogenation had proven to be highly
challenging, significant progress has been made in recent
years.[1–3] For the intermolecular process,[4] great success has
been achieved with olefin substrates containing various func-
tional groups.[5–11] However, for unfunctionalized olefins, asym-
metric halogenation presents new challenges, owing to the
lack of directing groups, and only limited examples have been
reported, primarily with carboxylic acids as nucleophiles.[9,12,13]
The formation of halohydrins via halonium ion intermediates
with H2O is a classic reaction for halogenation of olefins
(Scheme 1) and has great synthetic value. An asymmetric ver-
À9
À46
58
36
0
16
63
65
25
0
76
60
74
78
80
83
84
3g
3d
3d
3d
3d
3d
3d
3d
3d
3d
3d
3d
3d
3d
3d
3d
9
10
11
12
13
14
15
16
17
18
19
20
21
22[d]
23[e]
NBP
TBCO
DBDMH
MeCONHBr
PhCONHBr
PhCONHBr
PhCONHBr
PhCONHBr
PhCONHBr
PhCONHBr
PhCONHBr
PhCONHBr
PhCONHBr
PhCONHBr
DME/H2O (5:1)
DCM/H2O (5:1)
EtOAc/H2O (5:1)
acetone/H2O (2:1)
acetone/H2O (10:1)
acetone/H2O (20:1)
acetone/H2O (5:1)
acetone/H2O (5:1)
[a] Reactions were carried out with substrate 1a (0.30 mmol), catalyst
(0.030 mmol), and Br source (0.36 mmol) in solvent/H2O x:1 solvent mix-
ture (3.0 mL+3:0 mL) at À308C for 48 h, unless otherwise noted. [b] Yield
x
of isolated product. [c] Determined by chiral HPLC analysis. [d] At À408C
for 72 h. [e] At À508C for 144 h.
Scheme 1. Asymmetric intermolecular bromohydroxylation.
sion of this process would thus be highly desirable and has yet
to be reported.[8] Herein, we report our preliminary efforts on
this subject.
Sc(OTf)3 complex 3b (Table 1, entry 3) were used as catalysts,
bromohydrin 2a was obtained as a racemate in 39% and 82%
yield, respectively, indicating that these catalysts were able to
promote the reaction but not enantioselectively. Although
good yields of 2a were obtained in all cases with chiral bases
examined, the enantioselectivities varied dramatically with the
catalyst structures (Table 1, entries 4–8). To our delight, with di-
meric cinchona alkaloid (DHQD)2PHAL (3d) as catalyst 2a was
obtained with 78% ee (Table 1, entry 5). Other reaction condi-
tions, including bromine sources, solvents, and reaction tem-
peratures, were thus investigated with 3d as the catalyst.
Among the different bromine sources examined (Table 1, en-
tries 5, 9–13), N-bromobenzamide gave the highest enantiose-
lectivity for the reaction (Table 1, entry 5). Several solvent sys-
tems were also investigated (Table 1, entries 5, 14–18). A com-
bination of acetone and H2O worked the best. Increasing the
ratio of acetone to H2O led to slightly higher ee values but
lower yields (Table 1, entries 5, 19–21). The ee was slightly in-
creased by lowering the reaction temperature (Table 1, en-
tries 5, 22, and 23). The reaction with (DHQD)2PHAL (3d) as
catalyst and N-bromobenzamide as bromine source in 5:1 ace-
tone/H2O at À408C appeared to be optimal in terms of the
overall results of the yield and enantioselectivity (Table 1,
Several acid and base catalysts were initially investigated for
bromohydroxylation with 2-methylstyrene (1a) as a test sub-
strate and N-bromobenzamide as bromine source in an ace-
tone/H2O solvent mixture at À308C to give bromohydrin 2a
(Figure 1). In the absence of catalyst, a trace amount of bromi-
nation product 2a was formed (Table 1, entry 1). When chiral
phosphoric acid 3a (Table 1, entry 2) or chiral phosphine–
[a] Dr. X. Zhang, Dr. J. Li, H. Tian, Prof. Dr. Y. Shi
Beijing National Laboratory for Molecular Sciences
CAS Key Laboratory of Molecular Recognition and Function
Institute of Chemistry, Chinese Academy of Sciences
Beijing, 10090 (P. R. China)
[b] Prof. Dr. Y. Shi
State Key Laboratory of Coordination Chemistry
Center for Multimolecular Organic Chemistry
School of Chemistry and Chemical Engineering
Nanjing University, Nanjing, 210093 (P. R. China)
[c] Prof. Dr. Y. Shi
Department of Chemistry, Colorado State University
Fort Collins, Colorado, 80523 (USA)
E-mail: Yian.Shi@colostate.edu
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201502133.
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Communication
depended on the nature of the
substituents and their positions
relative to the reacting double
bond. When vinylnaphthalenes
were subjected to the reaction
conditions, the resulting bromo-
hydrins were obtained in 75–
82% yield with 70–72% ee
(Table 2, entries 11 and 12). a-
Substituted styrenes were also
found to be suitable substrates
for the reaction. This class of
compounds displayed higher re-
activity than styrenes, which al-
lowed the reaction to be carried
out at lower temperature. The
corresponding
bromohydrins
were obtained in 66–77% yield
and 55–82% ee at À508C
(Table 2, entries 13–15). The ee
was increased to 88% for 4-
chloro-a-methylstyrene
when
the reaction temperature was
lowered to À608C, although the
yield of product 2o was de-
creased
to
40%
(Table 2,
entry 16). The reaction was also
extended to 1,2-dihydronaphtha-
Figure 1. Structures of catalysts examined.
lenes, giving the bromohydrins
in 73–83% yield and 68–75% ee
(Table 2, entries 17 and 18).
entry 22). Under these reaction conditions, the ee did not vary
over time.
trans-b-Methylstyrene and 1-phenylcyclohexene were found to
be less effective substrates. The corresponding bromohydrins
were formed in 39% ee and 36% ee, respectively (Table 2, en-
tries 19 and 20). No enantioselectivity was obtained for bromo-
hydroxylation of cyclohexene (Table 2, entry 21). However, for
all other substrates (Table 2, entries 1–20), the reaction pro-
ceeded regioselectively and the other regioisomer was not iso-
lated. The absolute configurations of bromohydrins 2b, 2 f, 2k,
2m, and 2p were determined by comparing the optical rota-
tions with reported values.[14] In all cases, the major enantiomer
was found to have the (S)-configuration.
With the optimized reaction conditions in hand, the sub-
strate scope was subsequently investigated for the bromohy-
droxylation. The reaction can be extended to a variety of sub-
stituted styrenes, giving the corresponding bromohydrins in
52–94% yield with 60–83% ee (Table 2, entries 1–10; the X-ray
structure of 2j is shown in Figure 2). In comparison to styrene
(Table 2, entry 2), substituents were found to be generally ben-
eficial to the enantioselectivity. The extent of the increase in ee
Based on the absolute configuration determined, a plausible
transition state model is proposed in Figure 3.[3h,at,bc,6a,9,13] The
substrate is situated in the chiral pocket, owing to via p,p-
Figure 2. X-ray structure of bromohydrin 2j. Thermal ellipsoids are shown at
the 30% level of probability. Hydrogen atoms are not fully shown for clarity.
Figure 3. Proposed transition-state model for bromohydroxylation.
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stacking with the quinoline of the catalyst. The tertiary amine
of the catalyst activates N-bromobenzamide[15] and directs the
bromine toward the double bond of the substrate. The phtha-
lazine nitrogen likely increases the nucleophilicity of the H2O
Table 2. (Continued)
Entry Substrate
21
Product[b]
Yield [%][c] ee [%][d]
Table 2. Asymmetric bromohydroxylation of olefins.[a]
58
0
[a] Reactions were carried out with substrate 1 (0.50 mmol), (DHQD)2PHAL
(0.050 mmol), and PhCONHBr (0.60 mmol) in acetone (5.0 mL) and water
(1.0 mL) at À408C for 72 h, unless otherwise noted. [b] For entries 2, 6,
11, 13, and 17, the absolute configurations were determined by compar-
ing the optical rotations of the corresponding bromohydrins with report-
ed values. For entries 1, 3–5, 7–10, 12, 14–16, and 18, the absolute config-
urations were tentatively assigned by analogy. For entries 19–21, the ste-
reochemistry indicated is relative stereochemistry. [c] Yield of isolated
product. [d] Determined by chiral HPLC analysis. [e] At À408C for 120 h.
[f] At À508C for 72 h. [g] At À608C for 120 h.
Entry Substrate
Product[b]
Yield [%][c] ee [%][d]
1
X=o-Me, 1a
2a
2b
2c
2d
2e
2 f
2g
2h
2i
78
64
68
56
52
94
91
71
64
83
60
71
76
73
78
80
82
82
2
3
4
5
6
7
8
9[e]
X=H, 1b
X=o-Et, 1c
X=o-iPr, 1d
X=m-Me, 1e
X=p-Me, 1 f
X=p-Ph, 1g
X=p-F, 1h
and steers it to the reacting site by formation of hydrogen
bonds. Apparently, the substituent on the substrate could in-
fluence the interaction between the substrate and the catalyst,
consequently affecting the enantioselectivity of the reaction. A
precise understanding of the reaction mode and the origin of
the enantioselectivity awaits further study.
X=p-Cl, 1i
10
79
83
In summary, we have developed an effective enantioselec-
tive intermolecular bromohydroxylation of unfunctionalized
olefins using dimeric cinchona alkaloid (DHQD)2PHAL as cata-
lyst, N-bromobenzamide as bromine source, and H2O as nucle-
ophile, giving a variety of optically active bromohydrins in up
to 88% ee. Although the bromohydroxylation of olefins with
H2O via a bromonium ion intermediate to form bromohydrins
is a classic reaction in organic chemistry, to our knowledge, no
asymmetric version has to date been reported. Although the
enantioselectivity needs to be improved, the results obtained
herein represent a significant advance in asymmetric intermo-
lecular halogenation of unfunctionalized olefins, which is still
extremely challenging. Further efforts will be devoted to un-
derstanding the reaction mechanism and expanding the scope
of substrate and nucleophile, as well as developing more effec-
tive catalytic systems.
11
12
82
75
70
72
13[f]
14[f]
15[f]
16[g]
X=H, 1m
X=Br, 1n
X=Cl, 1o
X=Cl, 1o
2m
2n
2o
2o
77
66
74
40
55
82
82
88
Experimental Section
17
18
X=H, 1p
X=Ph, 1q
2p
2q
83
73
68
75
Representative procedure for asymmetric bromohydroxylation
(Table 2, entry 1):
A
mixture of (DHQD)2PHAL (0.0389 g,
0.050 mmol) and N-bromobenzamide (0.120 g, 0.60 mmol) in ace-
tone (5.0 mL) and water (1.0 mL) was stirred at À408C for 15 min.
2-methylstyrene (1a) (0.0591 g, 0.50 mmol) was then added. The
reaction mixture was stirred at À408C for 72 h, quenched with sa-
turated aqueous Na2S2O3 (10 mL) at À408C, extracted with di-
chloromethane (3”10 mL), dried over MgSO4, filtered, concentrat-
ed under reduced pressure, and purified by flash chromatography
on silica gel (eluent=15:1 petroleum ether/ethyl acetate) to afford
bromohydrin 2a as a pale yellow oil (0.0843 g, 78% yield, 83% ee).
19
20
29
79
39
36
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Acknowledgements
We gratefully acknowledge the National Basic Research Pro-
gram of China (973 program, 2011CB808600), the National Nat-
ural Science Foundation of China (21172221), and the Chinese
Academy of Sciences for financial support.
Keywords: bromination
enantioselectivity · olefins · water
·
cinchona
alkaloids
·
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Communication
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Received: June 1, 2015
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Published online on July 2, 2015
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ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim