Asymmetric, regioselective bromohydroxylation of 2-aryl-2-propen-1-ols catalyzed by quinine-derived catalysts

Article abstract of DOI:10.1002/adsc.201200782

The asymmetric bromohydroxylation of 2-aryl-2-propen-1-ols catalyzed by quinine-derived bifunctional catalyst has been developed. The regioselectivity was controlled by employing a boronate ester as tether which was formed in situ and enantioselectivity was introduced by taking advantage of a quinine-derived bifunctional catalyst which activated the boronate ester and N-bromosuccinimide (NBS) at the same time. Chiral bromohydrin, which is a useful feedstock in organic synthesis, was produced in moderate to excellent enantioselectivity in a two-step reaction sequence. Copyright

Full text of DOI:10.1002/adsc.201200782

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DOI: 10.1002/adsc.201200782
Asymmetric, Regioselective Bromohydroxylation of 2-Aryl-2-
propen-1-ols Catalyzed by Quinine-Derived Catalysts
Ye Zhang,a Hui Xing,a Weiqing Xie,b,* Xiaolong Wan,b Yisheng Lai,a,*
and Dawei Mab,*
a
State Key Laboratory of Natural Medicines, Center of Drug Discovery, China Pharmaceutical University, Nanjing 210009,
Peopleꢀs Republic of China
Fax : (+86)-25-8327-1015; phone: (+86)-25-8327-1015; e-mail: lcpu333@yahoo.com.cn
State Key Laboratory of Bioorganic & Natural Products Chemistry, Shanghai Institute of Organic Chemistry Chinese
b
Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, Peoleꢀs Republic of China
Fax : (+86)-21-6416-6128; phone: (+86)-21-5492-5341; e-mail: xiewq@mail.sioc.ac.cn or madw@mail.sioc.ac.cn
Received: August 30, 2012; Revised: October 15, 2012; Published online: January 4, 2013
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200782.
Abstract: The asymmetric bromohydroxylation of
2-aryl-2-propen-1-ols catalyzed by quinine-derived
bifunctional catalyst has been developed. The regio-
selectivity was controlled by employing a boronate
ester as tether which was formed in situ and enan-
tioselectivity was introduced by taking advantage of
a quinine-derived bifunctional catalyst which acti-
vated the boronate ester and N-bromosuccinimide
(NBS) at the same time. Chiral bromohydrin, which
is a useful feedstock in organic synthesis, was pro-
duced in moderate to excellent enantioselectivity in
a two-step reaction sequence.
reactions and have witnessed great progresses over
the past decade.[4] However, the development of an
organocatalyzed halogenation of olefins fell far
behind the other types of organocatalyzed reactions
(e.g., Michael addition reactions, a-fucntionalization
of aldehydes).[5a] Just recently, asymmetric halogen-
promoted nucleophilic addition reactions of olefins
catalyzed by organocatalysts have emerged as a pow-
erful tool for the construction of optically active lac-
tones and other heterocyclic compounds, but those re-
actions were limited to intramolecular processes (for
example, halolactonization[5c–j] and haloetherifica-
tion[5k–m]). The organocatalyzed asymmetric halohy-
droxylation of isolated C=C double bonds has re-
mained a challenge due to the difficulties in control-
ling the regioselectivity and enantioselectivity of the
reaction from the lack of interactions between sub-
strates and catalysts.
Keywords: asymmetric organocatalysis; bifunctional
catalysts; boron tethers; bromohydroxylation; re-
gioselectivity
Chiral bromohydrin 4 is a common synthetic inter-
mediate of triazole antifungal reagents such as
Halohydroxylation of the C=C double bond is an im- ZD0870 and Sch45450.[6] Although Sharpless asym-
portant transformation in organic chemistry for pro- metric dihydroxylation of allyl halide,[7a] or enzymatic
viding a direct method to bifunctionalized C=C resolution of diols[7b] provided a direct way to synthe-
double bonds.[1] The halohydroxylation products are size bromohydrin 4, moderate enantioselectivity or
versatile feedstocks in organic synthesis since both low yields of the desired enantiomer retards their
halogen atom and hydroxy group offer a good handle practical application. Other stepwise protocols initiat-
for further derivatization (e.g., nucleophilic substitu- ed with the Sharpless asymmetric epoxidation of allyl
tion of halogen atoms).[2] Although a few direct asym- alcohol,[7c] or asymmetric cyanosilylation[7d] suffer
metric halohydroxylation reactions of C=C double from long synthetic steps and a need for transition
bonds have been reported to date, the reactions suf- metals. Herein we would like to report the first asym-
fered from low enantioselectivity, limited substrate metric bromohydroxylation of 2-aryl-2-propen-1-ols
scope, high catalyst loadings and the need for metal 1 catalyzed by a quinine-derived bifunctional catalyst
catalysts.[3] Organocatalyzed reactions have attracted to provide bromohydrin 4 with moderate to excellent
much attention from the chemical community for enantioselectivity.
their environmentally benign, and operationally
Inspired from recent advances in enantioselective
friendly advantages over transition metal-catalyzed halolcyclization catalyzed by bifunctional catalysts,[5]
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Adv. Synth. Catal. 2013, 355, 68 – 72

Asymmetric, Regioselective Bromohydroxylation of 2-Aryl-2-propen-1-ols
Table 1. Optimization of the reaction conditions.[a]
Entry Catalyst Solvent Temp. Yield[b] [%] ee[c,d] [%]
1
2
3
4
5
6
7
8
quinine DCM
158C
158C
158C
158C
158C
158C
158C
158C
158C
158C
158C
158C
43
30
35
32
54
40
32
54
43
43
52
58
48
45
NR
NR
8
10
L1
L2
L3
L4
L5
L6
L7
L8
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
À3
À6
7
3
À60
À63
À69
À69
À73
À66
À88
À45
ND
ND
À94
À94
À95
9
10
11
12
13
14
15
16
17
18
19
L9
L10
L11
L10
L10
L10
L10
L10
L10
L8
Scheme 1. Boron-tethered asymmetric bromohydroxylation
of allyl alcohol 1.
CHCl3 158C
DCE
tolune
THF
CHCl3 À408C 69
CHCl3 À408C 86[e]
CHCl3 À608C 86[e]
158C
158C
158C
we envisioned that the enantioselective bromohydrox-
ylation of allyl alcohol 1 could be realized by employ-
ing a boron-tethered intramolecular bromolactoniza-
tion strategy. As shown in Scheme 1, initially boronic
acid formed boronic acid hemiester 2 with alcohol
1 in the presence of dehydration agents such as mo-
lecular sieves, which has been utilized in many kinds
of transformations.[8] We speculated that in the pres-
ence of a quinine-derived bifunctional catalyst, the
nucleophilicity of the remaining hydroxy group on
boronic acid hemiester 2 would be greatly improved
by complexing with a Lewis base. In the meantime,
N-bromosuccinimide (NBS) could also be activated
by forming a hydrogen bond with a quinine-derived
bifunctional catalyst as demonstrated by Yeungꢀs and
Tangꢀs pioneering reports.[5d,g] In consequence, a tight
transition state would be formed and a 5-exo cycliza-
tion would lead to boronate ester 3 regioselectively
and enantioselectively. Subsequent oxidative cleavage
[a]
Raction conditions: (1) 1a (0.2 mmol), PhB(OH)2
(0.24 mmol), catalyst (0.01 mmol), NBS (0.24 mmol), 1 h
at the indicated temperature; (2) 30% H2O2 (0.15 mL),
MeOH (2.0 mL).
Isolated yields.
Determined by HPLC on Phenomenex Lux 5u Cellulose-
2 column.
Negative ee indicates the formation of the opposite enan-
tiomer.
Isolated yields obtained by using 30% H2O2 (0.4 mmol)
in ethyl acetate (1 mL) and acetone (1 mL) in the second
step.
[b]
[c]
[d]
[e]
boronate ester 3 would afford asymmetric bromohy- tries 8 to 11). A small library of sulfonamide catalysts
drin 4. (Figure 1) was then synthesized and evaluated. 4-Me-
At the outset, we focused on finding out suitable thoxyphenylsulfonamide L10 was found to be the best
quinine-derived bifunctional catalyst enabling the catalyst to produce bromohydrin 4a in 73% ee with
enantioselective bromohydroxylation of 2-phenyl-2- 52% yield (entry 11), and 4-nitrophenylsulsulfona-
propen-1-ol 1. First quinine and O-protected quinines mide L8 and 4-phenysulfonamide L9 afforded slightly
were found to be ineffective, which only led to negli- lower ee values (entries 9 and 10).
gible enantioselectivity in moderate yield (Table 1,
Next, we turned our attention to improve the enan-
entries 1 to 4). After a series of trials, the enantiose- tioselectivity by adjusting the other reaction condi-
lectivity was greatly improved using 1-naphthoyla- tions. Screening of solvents showed that CHCl3 was
mide L6 as catalyst (entry 7, 60% ee). However, fur- the best choice (entry14, 80% ee) while no product
ther structural modification of the catalysts by varying was isolated when using toluene and THF as solvents
the acyl group proved to be unfruitful (entries 4 and (entries 15 and 16). Further lowing of the reaction
5, see the Supporting Information), which drove us to temperature down to À408C provided the product in
survey new catalyst scaffolds. Consequently, we found 94% ee (entry 17), and higher temperature or lower
that sulfonamide catalysts performed better than L6 temperature only led to deleterious results (see the
probably due to the decreasing pKa of the NH bond, Supporting Information). Although, excellent enan-
which could form a stronger H-bond with NBS (en- tioselectivity was obtained, the problem of low overall
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Ye Zhang et al.
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Table 2. Substrate variations of bromohydroxylation of allyl
alcohol 1.
Entry 1, R
Catalyst Yield[b] [%] ee[c] [%]
1
2
3
4
5
6
1b, 4-FC6H4
L8
L8
L8
L8
L8
L8
L10
L8
L10
L8
90
70
77
67
71
61
47
82
90
55
51
71
73
47
33
40
54
80
37
93
87
86
93
96
79
96
89
91
78
79
87
90
64
56
57
53
30
61
1c, 4-ClC6H4
1d, 4-BrC6H4
1e, 4-PhC6H4
1f, 3-MeC6H4
1g, 4-MeC6H4
Figure 1. Selected quinine-derived catalysts.
7
8
9
1h, 3-MeOC6H4
1i, 2-MeC6H4
1j, 2-naphthyl
yields of the reaction remained to be solved. It was
reasoned that bromohydrin 4a was not stable under
the oxidative conditions since the yield of the first
L10
L8
L10
1
step was 90% as determined by H NMR of the crude
product. By employing less amounts of H2O2 and
non-protic solvents, a satisfactory yield was obtained
while the enantioselectivity was maintained
(entry 18). At last, re-examination of the catalyst
under the optimal reaction condition revealed that L8
afforded a slightly higher ee with comparable yield
(entry 19). The absolute configuration of bromohydrin
4a was established to be S by comparison of its optical
rotation with reported data.[7b]
With the optimal reaction conditions in hand, the
substrate scope of the reaction was then examined. 2-
Aryl-2-propen-1-ols with differently substituted aro-
matic rings were prepared and subjected to the stan-
dard reaction conditions (Table 2). Disappointingly,
the enantioselectivity of the reaction was found to be
sensitive to the electronic property of the phenyl
group. Moderate electron-withdrawing and electron-
10
11
12
13
14
15
1k, 4-MeO2CC6H4 L8
1l, 4-CF3C6H4
1m, 3-F C6H4
1n, 2-FC6H4
1o, 4-MeOC6H4
1p, benyzl
L8
L8
L8
L8
L10
[a]
Reaction conditions: (1)
1
(0.2 mmol), PhB(OH)2
(0.24 mmol), catalyst (0.01 mmol), NBS (0.24 mmol),
CHCl3 (4 mL), 1 h at À608C (when L8 was used as cata-
lyst) or À408C (when L10 was used as catalyst). (2) 30%
H2O2 (0.4 mmol) in ethyl acetate (1 mL) and acetone
(1 mL).
[b]
[c]
Isolated yields.
Determined by HPLC on a chiral stationary phase.
donating groups on the benzene ring seemed to be tions. Unfortunately, the product was obtained in only
tolerated, affording products with good to excellent 61% ee with 37% yield, which was consistent with the
ee. (entries 1 to 9, 78% ee to 96% ee). Although cata- result of 1k (entry 10), i.e., that an unstable bromoni-
lyst L8 performed excellently on substrates with elec- um intermediate led to decreased ee.
tron-deficient substitutents (entries 1 to 4), catalyst
The multifunctionalities of bromohydrin 4 provided
L10 gave better results on substrates with electron- versatile transformations to access other useful chiral
rich substitutents and sterically encumbered sub- building blocks. For example, protection of bromohy-
strates (entries 6 to 9). Strong electron-withdrawing drin 4a with the acetonide (Scheme 2), followed by
groups on phenyl deteriorated the enantioselectivity debromination using AIBN/Bu3SnH provided protect-
accompanied with low yields (entries 10–13, 53%– ed diol 6 in 92% yield. Moreover, substitution of bro-
64% ee), presumably due to the destability of bromo- mide of bromohydrin 5 with sodium azide in DMF
nium intermediate by electron deficiency of the smoothly gave amino alcohol derivative 7 in 95%
phenyl group. The 4-methoxypenyl group was also yield. In all these reactions, the enantiomeric purity
not compatible with the reaction conditions, only of the products was almost unchanged as judged by
giving 43% ee under the effect of L8. This could be chiral HPLC analysis.
ascribed to the formation of a localized cationic inter-
In summary, a highly regioselective and asymmetric
mediate on the benzyl position which led to a stepwise bromohydroxylation of 2-aryl-2-propen-1-ols is de-
reaction pathway and low enantioselectivity was ob- scribed. By employing a boronate ester as a tether
tained because of a lack of catalyst control over the and quinine-derived bifunctional catalysts, regioselec-
cationic intermediate. 2-Benzyl-2-propen-1-ol 1p was tive and enantioselective bromohydroxylation was re-
also synthesized and submitted to the reaction condi- alized. The reaction was found to be strongly depen-
70
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Adv. Synth. Catal. 2013, 355, 68 – 72

Asymmetric, Regioselective Bromohydroxylation of 2-Aryl-2-propen-1-ols
Acknowledgements
The authors are grateful to the Chinese Academy of Sciences
and the National Natural Science Foundation of China
(grants 21202187 and 20921091) for financial support.
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choice of catalyst when 2-aryl-2-propen-1-ols with
moderate electron-withdrawing and electron-donating
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Experimental Section
General Procedure for Bromohydroxylation of Allyl
Alcohol 1
To a suspension of allyl alcohol 1 (0.2 mmol, 1 equiv.), phe-
nylboronic acid (29.4 mg, 0.24 mmol, 1.2 equiv.), catalyst (L8
or L10, 5.1 mg or 4.9 mg, 0.01 mmol, 0.05 equiv.), 4ꢂ molec-
ular sieves (300 mg) in CHCl3 (2 mL), was added a solution
of NBS (42.7 mg, 0.24 mmol, 1.2 equiv.) in CHCl3 (2 mL)
dropwise at the temperature of À608C (when L8 was used
as catalyst) or À408C (when L10 was used as catalyst) under
argon. After stirring at the same temperature under Ar for
1 h, the reaction mixture was diluted with DCM and filtered
through a pad of celite. Then the filtrate was concentrated,
and the resulting residue was dissolved in AcOEt (1 mL)
and acetone (1 mL), then treated with H2O2 (41 mL,
0.4 mmol, 2 equiv.). After the reaction was completed
(monitored by TLC), the solvent was removed and the resi-
due was purified by column chromatography on silica gel
(eluting with AcOEt/PE) to give bromohydrin 4. The enan-
tiomeric excess (ee) of the products was determined by
HPLC on a chiral stationary phase.
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