Catalytic asymmetric bromochlorination of aromatic allylic alcohols promoted by multifunctional Schiff base ligands

Article abstract of DOI:10.1039/c6ob01306f

It was found that the tridentate O,N,O-type Schiff base ligand bearing suitable substituents was a highly effective promoter in the catalytic asymmetric bromochlorination reaction, in which the corresponding aromatic bromochloroalcohols with vicinal halogen-bearing stereocenters were formed with perfect regioselectivity, with moderate to excellent enantioselectivities (up to 93% ee), and with good yields and chemoselectivities.

Full text of DOI:10.1039/c6ob01306f

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DOI: 10.1039/C6OB01306F
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ARTICLE
Catalytic Asymmetric Bromochlorination of Aromatic Allylic
Alcohols Promoted by Multifunctional Schiff Base Ligands
Received 00th January 20xx,
Accepted 00th January 20xx
Wei-Sheng Huang a, Li Chen a, Zhan-Jiang Zheng a, Ke-Fang Yang*a, Zheng Xu a, Yu-Ming Cui a, Li-
Wen Xu*a,b
DOI: 10.1039/x0xx00000x
It was found that the tridentate O,N,O-type Schiff base ligand bearing suitable substituents was a highly
effective promoter in the catalytic asymmetric bromochlorination reaction, in which the corresponding
aromatic bromochloroalcohols with vicinal halogen-bearing stereocenters were formed with perfect
regioselectivity, with moderate to excellent enantioselectivity (up to 93% ee), and with good yields and
chemoselectivity.
www.rsc.org/
analogues as substrates in this reaction was not described in this
work. However, despite the absence of an enantioselective
approach to the catalytic dihalogenation of cinnamyl alcohol and its
Introduction
The difunctionalization of alkenes with simple reagents provides an
especially attractive and straightforward approach to directly
introduce heteroatom functional groups into each side of an
activated C‒C double bond, and plays a fundamental role in
synthetic chemistry.1 In this regard, dihalogenation of alkenes by
adding two halide groups on adjacent carbons is one of the most
important difunctionalization reactions of carbon‒carbon double
bonds and has been attributed to facile formation of synthetically
useful alkyl halides, that are an important class of compounds and
valuable synthetic intermediates in organic chemistry.2 Despite
numerous advances in this field, relatively few enantioselective
dihalogenation reactions of alkenes have been described.3,4
Additionally, before 2015, no general method had been developed
for the highly regio- and enantioselective addition of two different
halogen atoms to alkene.5 Very recently, Burns and co-workers6
reported the first example of a highly chemo- and enantioselective
bromochlorination reaction of allylic alcohols with chlorotitanium
analogues, the products of such reactions are expected to be useful
in natural products or synthetic chemistry. Inspired by previous
pioneering work in the asymmetric halogenation reaction,6-8
especially with Burns enantioselective bromochlorination of alkenes
(Scheme 1), we envisaged that catalytic asymmetric
bromochlorination of cinnamyl alcohols with novel Schiff base
ligands might be interesting, providing synthetically useful and
multifunctional products with chiral alcohols bearing vicinal C‒Br
and C‒Cl stereogenic centers.
NBS
ClTi(Oi-Pr)3
Me
Ph
Cl
H
HO
10 mol% of L-B1
HO
Ph
Me
Br
hexanes, -20 o
C
Ph
Ph
89% yield
18:1 cr
92% ee
t-Bu
L-B1 =
N (R)
(S)
OH
OH
t-Bu
triisopropoxide and NBS, in which the regioselective addition of two Scheme 1. The Burns catalytic enantioselective bromochlorination.
different halogens, bromine and chlorine, to carbon‒carbon double
Previous work
bond was successfully controlled by a chiral Schiff base. More
R1
importantly, in the Burns enantioselective bromochlorination, most
R1
Burns, JACS 2015
Cl
HO
R2
Br
HO
R2
of allylic alcohols that were evaluated reacted with a high level of
enantioselectivity (up to 97% ee), which provided an extremely
valuable tool for the synthesis of stereocomplex halogenated
natural products.7 Interestingly, the use of cinnamyl alcohol and its
R1, R2, R3 is alkyl group
excellent enantioselectivity
R3
R3
This work
good chemo- and
regioselective
Br
Ar
HO
HO
Ar
up to 93% ee
a.Key Laboratory of Organosilicon Chemistry and Material Technology of Ministry
of Education, Hangzhou Normal University, Hangzhou 311121, P. R. China. Fax:
86 2886 5135; Tel: 86 2886 5135; E-mail: liwenxu@hznu.edu.cn.
b.State Key Laboratory for Oxo Synthesis and Selective Oxidation
Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences, Lanzhou, P.
R. China. E-mail: licpxulw@yahoo.com
Cl
Figure 1. Catalytic chemo-, regio- and enantioselective bromination of allylic alcohols.
Electronic Supplementary Information (ESI) available: [details of any Results and discussion
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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Herein, we describe our effort to determine the steric and Interested in exploring new ligands with good chemVoie-w, rAertgiciloe-Onalninde
DOI: 10.1039/C6OB01306F
electronic effect of differentially substituted Schiff bases on the enantioselectivity, we initially directed our efforts to design and
catalytic asymmetric bromochlorination of cinnamyl alcohol, which prepare a family of Schiff base ligands with various functional
provides probing information for the design and syntheses of chiral groups anticipated to enhance the enantioselectivity of this
Schiff base in this reaction. We hypothesized that probing the reaction.9 The cinnamyl alcohol 1a was used as a model substrate in
modulation of multifunctional Schiff base ligands derived from the catalytic asymmetric bromochlorination with NBS. At first, we
different amino alcohols as well as different aromatic aldehydes wondered whether BINOL derivatives bearing a single ortho-
would be beneficial to the determination of suitable ligands for the substituted amino alcohol moiety could serve as ligands for this
titanium-promoted bromochlorination of allylic alcohols with good reaction. To investigate the activity and enantioselective induction
enantioselectivity. In addition, we want to improve the catalytic of BINOL- or Ar-BINMOL derived ligands L1-L6 showed in Table 1,
asymmetric bromochlorination, as well as the development of new we began investigating the bromochlorination of cinnamyl alcohol
titanium-Schiff base complex, to establish a simple and practical 1a with NBS and ClTi(Oi-Pr)3 under the classic reaction conditions
procedure with high efficiency for the dihalogenation of alkenes, (Table 1).
incorporating two different halogens (Scheme 2).
HO
(S)
(R)
N
(E)
Cl
(R)

Ph
Si
Ph

OH
O
Ligand (10 mol%)
NBS
OH
Br

Br
O
Bn
O

N
OH
ClTi(Oi-Pr)
2a
OH
3
OH
+
Cl
Br

cyclohexane or
o
(S)
(R)
L19
1a
n-hexane, 0
C

OH
(E) N
4a
OH
OH
L13
Br
3a
OH
OH
(S)
R2
R1
(R)


N
OH
R6
Scheme 2. Catalytic asymmetric bromochlorination of cinnamyl alcohol 1a: A model for
OH
N
OH
(R)
the development of new ligands.
R5
OH
L18
R4
R3
Table 1. Preliminary results of BINOL- or Ar-BINMOL- derived ligand mediated
bromochlorination of cinnamyl alcohol 1a.
L14
OH
Ligand (10 mol%)
NBS
Cl

N
Br

N
OH

OH

ClTi(Oi-Pr)
OH
OH
3
+
OH
OH
Br
Br
cyclohexane or
o
O
N
2a
(major)
1a
n-hexane, 0
C
OH
3a
(minor)
OH
L16
Ligand
Yield (%)
ee (%)
Ligand
Yield (%)
ee (%)
L17
L15
t-Bu
L1
L2
L3
L4
L5
L6
50
56
65
58
65
50
0
0
0
0
0
0
L7
L8
L9
L10
L11
L12
55
59
52
0
28
60
80
2
0
0
0
Ph
L20: R1 = R4 = R6 = H, R2 = Ph, R3 = R5 = t-Bu
L21: R1 = R2 = Ph, R4 = R6 = H, R3 = Si(i-Pr)3, R5 = Me
L22: R1 = R2 = Ph, R4 = R6 = H, R3 = TBS, R5 = Me
L23: R1 = R2 = Ph, R4 = R6 = R5 = H, R3 = CH2TMS
L24: R1 = R2 = Ph, R3 = R4 = R6 = H, R5 = F
L25: R1 = R2 = Ph, R4 = R6 = R5 = H, R3 = Me
L26: R1 = R2 = Ph, R4 = R6 = H, R5 = F, R3 = Me
L27: R1 = R2 = Ph, R4 = R6 = H, R5 = F, R3 = Br
L28: R1 = R2 = Ph, R3 = R4 = R5 = R6 = H
F
Ph
OH
N (R)
(S)
0
OH
Br
L27
Ph
HN
Br
L30
t-Bu
Ph
OH
(R)
N
OH
(S)
N
HN
OH
OH
OH
OH
OH
t-Bu
OH
Ph
Ph
L29: R1 = R2 = Ph, R3 = R4 = R6 = H, R5 = Cl
L30: R1 = R2 = Ph, R4 = R6 = H, R5 = Br, R3 = t-Bu
L-B1: R1 = R2 = Ph, R4 = R6 = H, R5 = R3 = t-Bu
(R)
(S)
N
L1
L2
OH
L3
OH
L-B1
t-Bu
N
H
Figure 2. Various Schiff base ligands used in the catalytic asymmetric
bromochlorination of cinnamyl alcohol 1a.
H
NH
OH
NH
OH
N
OH
N
OH
OH
OH
O
According to the procedure used in the Burns enantioselective
bromochlorination,
we
investigated
the
titanium-based
L4
L5
L6
o
enantioselective bromochlorination of cinnamyl alcohol 1a at 0 C
in cyclohexane or n-hexane. Surprisingly, the minor side-product
was not the constitutional isomer 4a, but rather the dibromide 3a,
which was verified by independent synthesis of the dibromide (see
Supporting Information). Table 1 summarizes the reaction results in
the titanium-based bromochlorination of cinnamyl alcohol 1a.
Notably, these chiral Schiff base or commercially available amino
alcohols have been reported in the previous reports10, and have
Ph
Cl
Ph
OH
N
OH
NH
OH
NH
OH
L7
OH
L8
L9
Ph
OH
Ph
OH
N
N
NH
2
H
N
L10
L11
L12
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moiety on the multifunctional ligand constructed from 2-amino-1,2-
also exhibited good enantioselectivity in various reactions. When
these ligands L1-L6 were used in this reaction, the corresponding
products were obtained with moderate yields (50-65%) and good
chemoselectivity (>10:1). However, no enantioselectivity was
observed for 2a for these ligands in this reaction. The use of ligands
L8-L12 in this reaction also led to no or low enantioselectivity,
which illustrated that amino alcohols on their own were not
suitable ligands. Notably, these ligand investigations identified
tridentate Schiff bases as being particularly promising, exemplified
by the ligands L6 and L7, which gave 2% ee and 80% ee respectively.
Further, 2-amino-1,2-diphenyl-ethanol was proven to be a crucial
chiral source for the construction of an effective tridentate ligand in
this reaction. Thus we suspected that the re-examination of
multifunctional Schiff bases would lead to the determination of a
suitable ligand with high enantioselectivity for the titanium-
promoted bromochlorination reaction of cinnamyl alcohol.
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diphenyl-ethanol proved to be very important for achieving
DOI: 10.1039/C6OB01306F
enantioselective induction in this reaction (Entries 10-18). As shown
in Table 2, most of Schiff base ligands L22-L29 gave moderate to
good enantioselectivities (55-85% ee). In particular, L27 gave better
enantioselectivity among these Schiff base ligands at 0 oC. In
addition, similar to the Burns enantioselective bromochlorination of
alkyl allylic alcohols, the Schiff base L-B1 also exhibited good
enantioselectivity at 0 oC (Entry 16, 80% ee). Next, the effects of
solvent and temperature on the enantioselectivity of the titanium-
promoted bromochlorination reaction was evaluated in the
presence of ligands L27 and ligand L-B1, respectively. Most of the
solvents, including toluene, methanol, ethyl acetate, CH3CN, and
THF, etc., exhibited negative effects on the catalytic asymmetric
bromochlorination reaction. Interestingly, it was found that almost
o
no product was detected at lower temperature (-10 or -20 C) for
ligand L27 (Entries 19-24). Gratifyingly, when ligand L-B1 was used
in this reaction, higher enantioselectivity (87% ee) as well as good
yield (80%) could be obtained at -20 oC (Entry 22). More
interestingly, the Schiff base L30 gave better enantioselectivity at
low temperature (Entry 24, 92% ee).
Table 2. Catalytic activity of various Schiff base ligands L13-L29 in the
bromochlorination of cinnamyl alcohol 1a.a
Entry
Ligand
Yield
(%)b
70
<5
<5
58
<10
50
69
<10
68
ee
(%)c
20
-
-
60
-
16
56
-
18
66
55
78
Entry
Ligand
Yield
(%)b
71
70
75
72
68
75
60
60
<10
80
74
80
ee
(%)c Having identified the Schiff base ligands L-B1 and L30 with the best
1
2
3
4
5
6
7
8
L13
L14
L15
L16
L17
L18
L19
L20
L21
L22d
L23d
L24d
13
14
15
16
17
18
19
20
21
22
23
24
L25d
L26d
L27d
L-B1
L28
77
77
enantioselectivity for the dihalogenation of cinnamyl alcohol, under
optimal reaction conditions similar to those in the Burns
enantioselective bromochlorination, we evaluated the substrate
scope of the catalytic asymmetric bromochlorination of aromactic
allylic alcohols. First, a variety of substituents on the aromatic ring
of allylic alcohols were examined with Schiff base L-B1, and the
corresponding optically active bromochloroalcohols (2a-o) were
obtained in moderate to good yields and promising
enantioselectivities (Table 3). The absolute configuration of the
85g
80g
57
67
85
80
-
L29
L7e
L30
9
L27e
L-B1e
L-B1f
L30e
10
11
12
55
60
70
87
85
92
Note: a Reaction conditions: 1.1 eq. ClTi(Oi-Pr)3, 1.1 eq. N-
desired products
2 were assigned by comparison to the
bromosuccinimide, ligand (10 mol%), substrate 1a (0.5 mmol), in hexane
(5.0 mL), at 0 oC. b Isolated yields. c The ee value of 2a was determined by
chiral HPLC. d in cyclohexane. e The reaction carried out in n-hexane at -20
oC; f The reaction carried out in cyclohexane at -10 oC. g This reaction has
been repeated (n = 3) and the ee value was 85% ee with L27 each time.
representative product 2a, which was determined by X-ray
diffraction analysis (CCDC 1435702). As shown in Table 3, most of
the aromatic allylic alcohols resulted in good chemoselectivity (cr,
up to 33:1) and >70% isolated yields except 2k. The stereoselectivity
was generally quite good. These experimental results reveal that
the arene substitution on the aromatic allylic alcohols is a very
important factor in the enantioselective bromochlorination reaction.
For example, variation of the substituents to 3,5-dibromide on the
arene resulted in poor enantioselectivity in the bromochlorination
reaction (Entry 14, 10% ee), and similarly, only moderate ee (Entry
16, 54% ee) was obtained when 3-naphthalen-2-yl-prop-2-en-1-ol
(2-naphthyl substituted allylic alcohol, 1o) was used in this reaction.
These low selectivities may be due to the low solubility of
substrates 1n and 1o under the reaction conditions. Interestingly,
With chiral amino alcohols in hand, we started to investigate the
preparation of chiral Schiff bases from various aromatic aldehydes
(Figure 2). This modification of the Schiff bases would combine axial
chirality with sp3-carbon-stereogenic centers, and maintain
a
geometry capable of ligating titanium. As shown in Figure 2,
eighteen Schiff bases were synthesized for the titanium-promoted
bromochlorination of cinnamyl alcohol 1a. Table 2 summarizes the
reaction results of this selective bromochlorination reaction. When
these multifunctional Schiff base ligands L13-L19 were used in the
reaction, the ee value of corresponding product 2a varied largely
from 16 to 56% ee, while some ligands led to very poor conversion
(Entries 1-7). These examples in Table 2 illustrated that both the
salicylaldehyde and the secondary alcohol chiral center on amino
alcohol backbone were crucial building blocks to guarantee
promising enantioselectivity. As indirect evidence, the Schiff base
when we added
1 eq. tert-butyl alcohol (t-BuOH), better
enantioselectivity and chemoselectivity were achieved in each case
(Entries 15 and 17, with 82% ee and 91% ee respectively), with
comparable yields of 2n and 2o compared to the additive-free
reaction conditions. Notably, the use of t-BuOH as a co-solvent in
the bromochlorination of other aromatic allylic alcohols did not give
an obvious enhancement in enantioselectivity. The origin of the
beneficial effect of t-BuOH on the enantioselectivity for two
substrates is unknown, but it is also possible that it plays a role in
modulating the aggregation state of the catalyst. Next, we
evaluated the catalytic activity of Schiff base L30 in this
bromochlorination because of its similar selectivity to L-B1.
ligands L14 and L15 bearing only
a nitrogen-linked carbon-
stereogenic center on the amino alcohol moiety led to almost no
reaction, which reveals the importance of steric repulsion on the
secondary alcohol moiety in this Schiff base ligand. Similarly, L20,
derived from a simple amino alcohol (R1 =H) also resulted in poor
catalytic activity (Entry 8). Notably, the presence of the benzyl
moiety on the multifunctional BINOL-derived Schiff base ligand led
to almost no reaction (L17). And interestingly, the Schiff base
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leads to a strong inherent electronic preference in VtiheweAsrtuicblesOtrnalitnee
DOI: 10.1039/C6OB01306F
which completely favors chloride attack at the benzylic position
Interestingly, L30 gave better stereoselectivity in most cases (up to
93% ee). However, L30 was found to be more sensitive to ortho-
substitution on the arene (Entries 2 and 7). Therefore, in some
cases, the new Schiff base L30 (method B) resulted in greater
enantioselectivity compared to Schiff base L-B1.
(Figure 4). This substrate-controlled regioselectivity is the opposite
of the catalyst-controlled regioselectivity observed by Burns et al.
with alkyl-substituted allyl alcohols, in which the chloride was
consistently delivered to the closest carbon to the alcohol
regardless of olefin substitution6. While the factors governing
catalyst regiocontrol are still unknown, it is clear that for substrates
containing a strong electronic bias, that bias overrides catalyst
regiocontrol.
Table 3. Enantioselective bromochlorination in the presence of ligand 28a
OH
(S,R)-L-B1 (10 mol%)
or (S,R)-L30 (10 mol%)
R
Br
R
NBS, ClTi(Oi-Pr)
HO
(R)
1a-n
3
(S)
o
or
n-hexane, -20
C
Cl
OH
2a-o
1o
X-ray structure of product 2a =
Entry
1
2
3
4
5
6
7
8
R
H
2-CH3
3-CH3
4-CH3
3-F
4-F
2-Cl
4-Cl
2-Br
Yield (%)b
Ee of 2 (%)c,f
87(92)
70(48)
85(79)
86(93)
78(80)
80(88)
80(74)
80(80)
82
cr (2/3)d
33:1(25:1)
13:1(13:1)
19:1(17:1)
24:1(24:1)
8:1(13:1)
24:1(18:1)
13:1(10:1)
10:1(14:1)
9:1
2a: 80(75)
2b: 71(70)
2c: 74(72)
2d: 81(78)
2e: 74(74)
2f: 77(78)
2g: 72(78)
2h: 72(83)
2i: 75
9
10
11
12
13
14
15
16
17
4-Br
2j: 70(75)
2k: 22
2l: 69(74)
2m: 60
2n: 76
2n:74
75(72)
81
86(90)
80
10:1(11:1)
12:1
32:1(50:1)
3.2:1
6:1
6.3:1
3-CH3O
4-t-Bu
2,6-di-Cl
3,5-di-Br
3,5-di-Br
2-naphthyl
2-naphthyl
Figure 3. Nonlinear effects in Schiff base L-B1 -controlled titanium-promoted
bromochlorination of allylic alcohol 1a.
10
82e
2o: 80
2o:74(76)
54
8:1
11:1(10:1)
76(78)e,f
Note: a Reaction conditions: 1.1 eq. ClTi(Oi-Pr)3, 1.1 eq. N-
Cl
OH
(S)
OH
bromosuccinimide (NBS), (S,R)-L-B1 or (S,R)-L-30 (10 mol% ligand),
substrate 1a (0.5 mmol), in hexane (5.0 mL), at -20 oC. b Isolated yields. c The
ee value was determined by chiral HPLC. d The chemoselectivity of
bromochlorination, the ratio of 2/3 in this reaction. e 1 eq. t-BuOH was added
in this reaction. f The figure in parenthesis refers to the results using method
B, in which (S,R)-L-30 is used instead of (S,R)-L-B1.
(R)
O
Cl Ti
O
R
Br
O
I
II
NBS
R
Br
O
t-Bu
R
Cl Ti
O
O
Ti
Cl
R
O
O
To obtain stereochemical information about the chiral catalyst
system, the Kagan nonlinear effect has been an important
diagnostic tool in mechanistic studies of asymmetric reactions.11
The experimental results of the nonlinear effect study of ligand
enantiopurity (L-B1) on enantiomeric excess of product (2a) by
variation of the optical purity of the Schiff base L-B1 is graphically
depicted in Figure 3 (See Supporting Information). These results
clearly demonstrate that a positive NLE is present, which suggests
the possible presence of dimeric or higher oligomeric species.
However, due to the inherent complexity of titanium-catalyzed
enantioselective reactions, in which multiple forms of the catalyst
may be in exchange with one another, these results alone are
insufficient to characterize the active catalyst.
I
R'
O
N
R'
Ph
Ph
Ph
III
N
Ph
OH
HO
t-Bu
t-Bu
O
Cl
NBS
Ti
R
O
R'
O
N
Ph
Ph
II
Figure 4. Proposed mechanism and transition state for the Ti-Schiff base complex
mediated bromochlorination of allylic alcohol.
Experimental
General Procedure for the Catalytic Asymmetric
Inspired by previous reports4,6 on enantioselective olefin
dihalogenation, and on the basis of present experimental results,
the observed regioselectivity is rationalized as being due to the
benzylic nature of the intermediate bromonium species, which
Bromochlorination of Aromatic Allylic Alcohols, :
Method A[6]
To a solution of allylic alcohol substrate (0.5 mmol) in hexanes
(3.0 mL) in reaction tube is added ClTi(Oi-Pr)3 (0.55 mmol , 1.1
equiv) under nitrogen in at room temperature. To this solution
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is added a solution of L-B1 (0.05mmol, 0.1 equiv) in hexanes (2 of cinnamyl alcohol and its analogues with ViethweArticaleidOnlionef
mL) dropwise over 1 min. then the solution is cooled to -20 oC. multifunctional Schiff base ligand, which is complementary to
DOI: 10.1039/C6OB01306F
To this solution is added all at once solid N-bromosuccinimide the Burns enantioselective bromochlorination of alkyl allylic
(0.55 mmol, 1.1 equiv). The reaction is stirred vigorously (700 alcohols. The new chemistry on the catalytic asymmetric
rpm) over night. Reactions are monitored by TLC. The reaction bromochlorination reaction will possibly promote or inspire
mixture is quenched with saturated aqueous Na2SO3 (5 mL), other researchers to explore conceptually novel and more
diluted with 1M HCl (10 mL), and allowed to warm to room effective ligands for this reaction.
temperature with vigorous stirring for 10 min. The layers are
separated and the aqueous layer is extracted with EtOAc (2 x
10 mL). The combined organic layers are washed with
Acknowledgements
saturated aqueous NaCl (20 mL), dried over Na2SO4, filtered,
and concentrated in vacuo to provide crude material, which is
purified by flash column chromatography (EtOAc : hexane 17:1
to 10:1) to provide the desired bromochloride.
The authors gratefully thank the financial support of the
National Natural Science Foundation of China (No. 51303043,
21472031, and 21503060), and Zhejiang Provincial Natural
Science Foundation of China (LR14B030001 and LY16E030009)
is appreciated. The authors also thank Prof. Z. R. Qu, Dr. K. Z.
Jiang, Dr. C. Q. Sheng, and Dr. Y. Deng (all at HZNU) for their
technical and analytical support. The authors also thank
Frederick J. Seidl and Prof. Noah Z. Burns (at Stanford
University) for their helpful revision of this work.
Method B: To a solution of allylic alcohol substrate (0.5 mmol)
and t-BuOH (0.5 mmol) in hexanes (3.0 mL) in reaction tube is
o
cooled to -20 C for 5 min then ClTi(Oi-Pr)3 (0.55 mmol, 1.1
equiv) was added under nitrogen at -20 0C for 5 min. To this
solution is added a solution of L30 (0.05mmol, 0.1 equiv) in
o
hexanes (2 mL) dropwise over 1 min at -20 C for 30 min. To
this solution is added all at once solid N-bromosuccinimide
(0.55 mmol, 1.1 equiv). The reaction is stirred vigorously (700
rpm) over night. Reactions are monitored by TLC. The reaction
mixture is quenched with saturated aqueous Na2SO3 (5 mL),
diluted with 1M HCl (10 mL), and allowed to warm to room
temperature with vigorous stirring for 15 min. The layers are
separated and the aqueous layer is extracted with EtOAc (2 x
10 mL). The combined organic layers are washed with
saturated aqueous NaCl (20 mL), dried over Na2SO4, filtered,
and concentrated in vacuo to provide crude material, which is
purified by flash column chromatography (EtOAc : hexane 17:1
to 10:1) to provide the desired bromochloride.
Notes and references
‡ Footnotes relating to the main text should appear here. These
might include comments relevant to but not central to the
matter under discussion, limited experimental and spectral data,
and crystallographic data.
1
For recent reviews, see: (a) Y. Shimizu, M. Kanai,
Tetrahedron Lett. 2014, 55, 3727-3737; (b) X. Zeng,
Chem. Rev. 2013, 113, 6864-6900. (c) R. I. McDonald, G.
Liu, S. S. Stahl, J. Am. Chem. Soc. 2011, 111, 2981-3019.
(d) S. E. Allen, R. R. Walvoord, R. Padilla-Salinas, M. C.
Kozlowski, Chem. Rev. 2013, 113, 6234-6458. (e) A.
Minatti, K. Muniz, Chem. Soc. Rev. 2007, 36, 1142-1152.
(f) E. M. Beccalli, G. Broggini, M. Martinelli, S.
Sottocomola, Chem. Rev. 2007, 107, 5318-5365. For
early example, see: (g) E. W. Tan, B. Chan, A. G.
Blackman, J. Am. Chem. Soc. 2002, 124, 2078-2079; (h)
J. P. Shaw, E. W. Tan, J. Org. Chem. 1996, 61, 5635-
5637.
The detailed experimental procedure for the synthesis of Schiff
bases reported as well as the characterization of the products
in this work has been provided in the Supporting information.
2
3
M. Hulce, M. J. Chapdelaine, in B. M. Trost, I. Fleming,
Ed. Comprehensive Organic Synthesis, Pergamon Press:
Oxford, 1991, Vol.4 (volume editor, Semmelhack, M. F.),
page 344-356.
Conclusions
In summary, the Schiff base and titanium-promoted
bromochlorination of aromatic allylic alcohols has been
achieved successfully in this work, in which the corresponding
aromatic bromochloroalcohols with vicinal halogen-bearing
stereocenters were obtained in moderate to excellent
enantioselectivities (up to 93% ee) as well as good yields with
complete regioselectivity, and with up to 50:1
chemoselectivity. Notably, on the basis of present high-
throughput screening of multifunctional Schiff base ligands
that combined with aromatic aldehydes and chiral amino
alcohols, we have demonstrated that the Schiff bases L-B1 and
L30 bearing multifunctional groups with suitable electronic
and steric effects function as efficient ligands in the catalytic
asymmetric bromochlorination reaction. In addition, it can be
seen from previous efforts and this work that the development
of catalytic asymmetric bromochlorination reaction is not an
easy task at present. Although the final selectivities achieved in
this reaction are not perfect, to our knowledge, it is a first and
important example of catalytic asymmetric bromochlorination
(a) E. N. Jacobsen, A. Pfaltz, H. Yamamoto,
Comprehensive Asymmetric Catalalysis, Springer: New
York, 1999; (b) E. M. Carreira, L. Kvaerno, Classics in
Stereoselective Synthesis, Wiley-VCH: Weinheim,
Germany, 2009; (c) A. J. Cresswell, S. T. C. Eey, S. E.
Denmark, Angew. Chem. Int. Ed. 2015, 54, 15642.
(a) D. X. Hu, G. M. Shibuya, N. Z. Burns, J. Am. Chem.
Soc. 2013, 135, 12960-12963; (b) A. J. Cresswell, S. T.-C.
4
5
Eey, S. E. Denmark, Nat. Chem. 2015, 7, 146-152; (c) K.
C. Nicolaou, N. L. Simmons, Y. Ying, P. M. Heretsch, J. S.
Chen, J. Am. Chem. Soc. 2011, 133, 8134-8137; (d) S. A.
Snyder, Z. Y. Tang, R. Gupta, J. Am. Chem. Soc. 2009,
131, 5744-5745.
(a) S. E. Denmark, W. E. Kuester, M. T. Burk, Angew.
Chem. Int. Ed. 2012, 51, 10938-10953; (b) J. Chen, L.
Zhou, Synthesis 2014, 46, 586-595; (c) Y. A. Cheng, W. Z.
Yu, Y. Y. Yeung, Org. Biomol. Chem. 2014, 12, 2333-
2343; (d) A. P. Brucks, D. S. Treitler, S. A. Liu, S. A.
Snyder, Synthesis 2013, 45, 1886-1898.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
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Organic & Biomolecular Chemistry
Page 6 of 7
ARTICLE
Journal Name
6
7
8
D. X. Hu, F. J. Seidl, C. Bucher, N. Z. Burns, J. Am. Chem.
View Article Online
DOI: 10.1039/C6OB01306F
Soc. 2015, 137, 3795-3798.
C. Bucher, R. M. Deans, N. Z. Burns, J. Am. Chem. Soc.
2015, 137, 12784-12787.
(a) B. Soltanzadeh, A. Jaganathan, R. J. Staples, B.
Borhan, Angew. Chem. Int. Ed. 2015, 54, 9517-9522; (b)
K. Mori, M. Kobayashi, T. Itakura, T. Akiyama, Adv.
Synth. Catal. 2015, 357, 35-40; (c) L. S. Zheng, Y. L. Wei,
K. Z. Jiang, Y. Deng, Z. J. Zheng, L. W. Xu, Adv. Synth.
Catal. 2014, 356, 3769-3776; (d) R. J. Van Hoveln, S. C.
Schmid, M. Tretbar, C. T. Buttke, J. M. Schomaker,
Chem. Sci. 2014, 5, 4763-4767; (e) R. Yousefi, K. D.
Ashtekar, D. C. Whitehead, J. E. Jackson, B. Borhan, J.
Am. Chem. Soc. 2013, 135, 14524-14527; (f) D. Huang,
X. Liu, L. Li, Y. Cai, W. Liu, Y. Shi, J. Am. Chem. Soc. 2013,
135, 8101-8104; (g) Y. Zhao, X. Jiang, Y. Y. Yeung,
Angew. Chem. Int. Ed. 2013, 52, 8597-8601.
9
For the preparation of Schiff base ligands and non-
classic amino alcohols, see Supporting Information.
And the synthesis of related intermediates used in this
work has been reported in previous reports: (a) Y. Jiang,
X. Zhou, W. Hu, L. Wu, A. Mi, Tetrahedron: Asymmetry
1995, 6, 405-408. (b) Z. Li, M. Fernꢀndez, E. N.
Jacobsen, Org. Lett. 1999,
C. Dong, Z. J. Zheng, Z. Xu, K. F. Yang, L. W. Xu, RSC Adv.
2015, , 55819-55824; (d) Y. L. Wei, K. F. Yang, F. Li, Z. J.
Zheng, Z. Xu, L. W. Xu, RSC Adv. 2014, , 37859-37867;
(e) Y. L. Wei, W. S. Huang, Y. M. Cui, K. F. Yang, Z. Xu, L.
W. Xu, RSC Adv. 2015, , 3098-3103; (f) W. H. Deng, F.
Ye, X. F. Bai, Z. J. Zheng, Y. M. Cui, L. W. Xu,
ChemCatChem 2015, , 75-79; (g) G. Gao, F. L. Gu, J. X.
1, 1611-1613. (c) C. Y. Wang,
5
4
5
7
Jiang, K. Jiang, C. Q. Sheng, G. Q. Lai, L. W. Xu, Chem.
Eur. J. 2011, 17, 2698-2703.
10 W. S. Huang, Z. Xu, K. F. Yang, L. Chen, Z. J. Zheng, L. W.
Xu, RSC Adv. 2015, , 46455-46463.
5
11 For the early example, see: (a) C. Puchot, O. Samuel, E.
Duñach, S. Zhao, C. Agami, H. B. Kagan, J. Am. Chem.
Soc. 1986, 108, 2353-2357. (b) D. Guillaneux, S. H. Zhao,
O. Samuel, D. Rainford, H. B. Kagan, J. Am. Chem. Soc.
1994, 116, 9430-9439. For the representative review,
see: (c) C. Girard, H. B. Kagan, Angew. Chem. Int. Ed.
1998, 37, 2922-2959.
…
6 | J. Name., 2012, 00, 1-3
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Organic & Biomolecular Chemistry
View Article Online
DOI: 10.1039/C6OB01306F
Graphical Abstract
Catalytic Asymmetric Bromochlorination of Aromatic Allylic Alcohols
Promoted by Multifunctional Schiff Base Ligands
Wei-Sheng Huang, Li Chen, Zhan-Jiang Zheng, Ke-Fang Yang*, Zheng Xu, Yu-Ming Cui, and
Li-Wen Xu*
The aromatic bromochloroalcohols with two
bromide/chloride-linked
carbon-stereogenic
centers were obtained in moderate to excellent
regio- and enantioselectivities (up to 50:1 cr and
93% ee) as well as good yields and
chemoselectivities in the catalytic asymmetric
bromochlorination of allylic alcohols.