First asymmetric intermolecular bromoesterification catalyzed by chiral Bronsted acid

Article abstract of DOI:10.1016/j.tetasy.2012.02.016

The first successful enantioselective intermolecular bromoesterification was realized by using a chiral phosphoric acid as a catalyst. The reaction was optimized after screening 2-aminopyridine based basic catalysts, cinchona alkaloid based basic catalyst

Full text of DOI:10.1016/j.tetasy.2012.02.016

Tetrahedron: Asymmetry 23 (2012) 245–251
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
First asymmetric intermolecular bromoesterification catalyzed by chiral
Brønsted acid
Guang-xun Li a,b, Qing-quan Fu a, Xiao-mei Zhang b, , Jun Jiang c, Zhuo Tang a,
⇑
⇑
a Natural Products Research Center, Chengdu Institution of Biology, Chinese Academy of Science, Chengdu 610041, PR China
b Key Laboratory for Asymmetric Synthesis and Chiraltechnology of Sichuan Province, Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu 610041, PR China
c College of Chemistry and Material Engineering, Wenzhou University, Zhejiang Province, Wenzou 325027, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 17 January 2012
Accepted 10 February 2012
The first successful enantioselective intermolecular bromoesterification was realized by using a chiral
phosphoric acid as a catalyst. The reaction was optimized after screening 2-aminopyridine based basic
catalysts, cinchona alkaloid based basic catalysts, and binol backbone based Brønsted acid catalysts.
Up to 70% ee and a moderate yield were achieved under the optimized condition. An ion-pair mechanism
has been suggested in order to explain the reaction results.
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
used were designed based on chiral amines, such as alkaloid deriv-
atives or imidazolines, which catalyzed the halolactonization
The electrophilic halogenations of alkenes via a halogenium ion,
such as haloetherification, halolactonization, and haloamidation
are fundamental transformations in organic chemistry.1 Haloeste-
rification is one of the most important reactions to functionalize
a double bond. The versatile product of this reaction can be
either by activating halonium-cations or by interacting with a car-
boxyl group.
Despite recent efforts in halolactonization, the catalytic asym-
metric intermolecular haloesterification remains a considerable
challenge. To the best of our knowledge, there has been only one
publication which recorded an attempt to catalyze the asymmetric
intermolecular haloesterification up to now. However, no induced
enantioselectivity was observed in this work when using chiral
amine catalysts.11 The development of such methods presents a
particular challenge, due in part to the propensity of the interme-
diate bromonium ions to racemize by transfer between alkenes at
rates that are competitive with nucleophilic capture.12 Herein we
report the first enantioselective intermolecular bromoesterifica-
tion catalyzed by chiral Brønsted acids.
employed in
a
wide range of diverse transformations.2 The
asymmetric halolactonization was initially accomplished either
by substrate-controlled synthesis with a chiral auxiliary3 or by a
reagent-controlled reaction with
a
chiral halonium cation.4
Although much effort has been undertaken, enantioselective cata-
lytic halolactonizations have not been well developed over the past
two decades.5 In 2010, Borhan et al. made a breakthrough in the
highly enantioselective chlorolactonization of 4-aryl-substituted
4-pentenoic acids catalyzed by (DHQD)2PHAL by introducing
DCDPH as a chloronium source.6 Following this work, Tang et al.
reported an highly enantioselective bromolactonization of conju-
gated Z-enynes with a bifunctional cinchona-alkaloid catalyst
bearing a urea moiety.7 The enantioselective iodolactonization cat-
alyzed by a tertiary aminourea derivative was reported by Jacobsen
et al.8 Yeung et al. have also developed an amino-thiocarbamate-
catalyzed asymmetric bromolactonization of unsaturated
carboxylic acids.9 Based on molecular recognition, Fujioka et al.
reported the enantioselective bromolactonization of 5-substituted
5-hexenoic acids catalyzed by a C3-symmetric chiral trisimidazo-
line in the same year.10 The successful haloesterifications have
two common features: (1) all the researches focused on intramo-
lecular haloesterifications without exception. (2) The catalysts
2. Results and discussion
We initiated our research by re-screening the alkaloid deriva-
tives and designing new chiral amine catalysts based on amino-
pyridine which could recognize the carboxyl group through double
hydrogen bonds.13 Less than 10% ee was obtained after screening
large numbers of chiral amines (Scheme 1); this forced us to re-
evaluate our strategy of catalyst design. The first enantioselective
haloesterification was achieved with a chiral titanium complex.14
Lewis acids, such as salen-Co and salen-Cr, had been successfully
employed in the asymmetric cyclic haloetherification with up to
90% ee being obtained.15 Recently, Feng et al. reported a highly effi-
cient haloamination reaction catalyzed by a chiral N, N0-dioxide–
Sc(III) complex.16 The first chiral Lewis acid catalyzed asymmetric
iodolactonization was reported about 20 years ago; since then,
⇑
Corresponding authors. Fax: +86 28 85243250 (Z.T.).
E-mail addresses: xmzhang@cioc.ac.cn (X.-m. Zhang), tangzhuo@cib.ac.cn
(Z. Tang).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2012.02.016

246
G. Li et al. / Tetrahedron: Asymmetry 23 (2012) 245–251
O
O
O
Cat.(10mol %), NBS
OH
Br
+
°
CH2Cl2, -20 C, 24h
3a
2
1
N
HN
O
F
F
O
O
O
O
F
H
O
Cbz
N
O
N
N
H
NH
N
F
NH
O
N
O
O
N
4a (yield: 76% ee: 0)
4b (yield: 70% ee: 2.5)
4c (yield: 50% ee: 1.7)
O
N
N
N
O
H
O
NH
H
NH
BocHN
N
N
H
N
H
O
HN
O
O
N
N
O
O
F3C
CF3
4d (yield: 78% ee: 0)
4e (yield: 78% ee: 0)
4f (yield: 80% ee:0)
N
N
N
OH
H
N
H
N
H
O
O
CF3
H
O
H
O
S
N
CF3
N
N
5a (yield: 80% ee: 10%)
5b (yield: 80% ee: 0)
5c (yield: 45% ee; 0)
H
N
N
O
S
H
H
N
N
N
N
O
H
O
N
N
O
O
H
O
H
O
S
O
O
O
O
N
N
N
N
5d (yield: 80% ee: 7%)
5f (yield: 75% ee: 7.5)
5e (yield: 80% ee: 0)
Scheme 1. Screening of catalysts derived from 2-aminopyridine and a cinchona alkaloid.
there has been only one more work using a chiral Lewis acid in a
haloesterification.5f
benzoic acid and cyclohexene, 21% of trans-2-bromocyclohexyl
benzoate was produced while less than 3% product was obtained
in the background reaction (Table 1, entries 1 and 2), which indi-
cated that phosphoric acid 1a was able to catalyze the bromoeste-
rification between benzoic acid and cyclohexene, even though no
enantioselectivity was detected. This result is noteworthy since
the catalyst 1a itself could react with cyclohexene to give the
bromoesterification product in 78% yield under the same reaction
conditions. Thus, a series of chiral phosphoric acids 1b–1j with dif-
ferent 3,30-substituted BINOL backbones were used in the reaction
(Scheme 2), and their catalytic results are illustrated in Table 1
(entries 2–11).
Chiral phosphoric acids are one of the most widely applied
Brønsted acid catalysts for a variety of organic transformations.17
Compared to chiral metal Lewis acid catalysts, organic phosphoric
acids are not only insensitive to moisture and oxygen, but also low-
cost and environmentally friendly. Recently, several groups have
reported the use of chiral phosphoric acids for enantioselective
intramolecular bromoetherifications5h,i and bromoaminocycliza-
tions.5j However, when they were employed to catalyze an inter-
molecular haloesterification, the self-haloesterification of the
chiral phosphoric acids with alkene substrate could be the greatest
challenge.
The best result obtained was with the 9-phenanthryl substi-
tuted chiral Brønsted acid 1i, which gave the bromoesterification
product with 31% enantioselectivity and 23% yield (Table 1, entry
When 10% of the simplest chiral phosphoric acid 1a (Scheme 2)
was employed in the intermolecular bromoesterification between

G. Li et al. / Tetrahedron: Asymmetry 23 (2012) 245–251
247
O
O
O
Cat. (10 mol%), NBS
+
OH
Br
°
CH2Cl2, -20 C, 24h
R
R
R
O
O
O
O
P
O
P
P
Ph
Ph
O
O
O
O
O
NHTf
P
N
H
OH
R
R
R
R=
C6H5
1k
1l
1o
4-(CH3O)-C6H4
4-biphenyl
R = 9-phenanthryl
R=
1m
1n
1a
1b
1c
1d
1e
1f
H
9-phenanthryl
C6H5
4-(CH3O)-C6H4
4-Cl-C6H4
R
2,4,6-(i-Pr)3C6H2
4-biphenyl
O
O
O
O
P
1g
1h
1i
2-naphthyl
Ph
S
O
N
9-anthryl
NH
H
9-phenanthryl
1-pyren-1-yl
S
O
1j
O
R
1p
1q
R= phenyl
Scheme 2. Chiral Brønsted acids employed in intermolecular bromoesterification.
Table 1
Catalytic result of bromoesterification with catalysts 1a–1q
Table 2
Optimization of the reaction condition
Entry
Cat
Yield (%)
ee %
Entry
Cat
Yield (%)
ee %
Entry
Halogen
Cat (%)
Yield (%)
ee (%)
1
2
3
4
5
6
7
8
9
NO
1a
1b
1c
1d
1e
1f
3
21
20
18
21
21
19
21
20
0
0
10
11
12
13
14
15
16
17
18
1i
1j
1k
1l
1m
1n
1o
1p
1q
23
19
19
15
18
26
16
13
0
31
13
0
0
0
0
0
0
0
1
2
3
4
5
NBS
NCS
NIS
DBDMH
NBP
10
10
10
10
10
15
—
35
80
8
55
—
0
0
38
11
10
11
13
15
11
0
1g
1h
55% ee. However, lowering the temperature further did not in-
crease the enantioselectivity but slightly decreased the yield. Dif-
ferent types of halogen sources including N-chlorosuccinimide
(NCS), N-iodosuccinimide (NIS), N-bromophthalimide (NBP), and
1,3-dibromo-5,5-dimethylhydantoin (DBDMH) were tested, but
none of them were found to be better than NBS in terms of ee (Ta-
ble 2, entries 2–5).
Under the optimized condition, we explored the scope of the
asymmetric intermolecular bromoesterification catalyzed by chiral
phosphoric acid 1i. Benzoic acid derivatives with different substi-
tutions were thus investigated (Scheme 3).
10). Chiral phosphoramides have displayed better catalytic ability
in many asymmetric reactions when compared with phosphoric
acid catalysts because of their enhanced acidity.18 The introduction
of an NHTf group into the phosphoryl moiety may decrease the cat-
alyst’s self-bromoesterification due to the large steric hindrance,
and so the yield of the desired intermolecular bromoesterification
product increases. However, when chiral phosphoramides 1k–1n
(Scheme 2) were employed in our reaction, no enantioselectivity
was observed, and at the same time, the yields of all these reaction
were much less than those of the reactions catalyzed by the corre-
sponding chiral phosphoric acids (Table 1, entries 12–15). Similar
results were obtained by using bulky phosphoramides and chiral
disulfonimide (1o–1q, Scheme 2). These data indicated that
increasing the acidity and steric hindrance of the catalyst did not
improve neither the yield nor the enantioselectivity of the inter-
molecular bromoesterification. After screening different chiral
Brønsted acids, we found the best catalyst to be the chiral phos-
phoric acid 1i.
All of the reactions were performed smoothly with moderate ee
values. Benzoic acid derivatives 3a–3e with electron donating or
electron withdrawing groups, gave lower ee values compared to
benzoic acids (Scheme 3). The more acidic
a-keto acids 3l–3m
were evaluated next (Scheme 3), and gave similar results to those
obtained with benzoic acids. When 2-arylacetic acids 3f–3j were
used in the intermolecular bromoesterification, much better
enantioselectivities were obtained (Scheme 3). Meanwhile, a clear
correlation became obvious between the electronic properties of
the aryl ring and the stereoselectivity: the 2-arylacetic acids
3g–3i with electron donating groups (Scheme 3) afforded higher
enantioselectivities than those with electron withdrawing groups
(3j and 3k, Scheme 3). The highest enantioselectivity of 70% ee
was obtained when 2-(2-methoxyphenyl)acetic acid 3g was re-
acted with cyclohexene (Scheme 3). When one more methylene
Various solvents including CH2Cl2, CHCl3, toluene, ethyl ether,
and mixed solvents were evaluated; the CH2Cl2/cyclohexane
(1:3) mixture was identified as the best solvent system. Next, we
optimized the reaction temperature and found that decreasing
the temperature to ꢀ40 °C increased the enantioselectivity to

248
G. Li et al. / Tetrahedron: Asymmetry 23 (2012) 245–251
NBS 1i (10%), -40 °C,24h
O
O
n
+
R
OH
R
O
cyclohexane/CH2Cl2 (3:1)
n
3
Br
1
2
O
O
O
O
O
O
O
O
Br
Br
Br
Br
Br
Br
O2N
H3CO
NC
3a
3c
3b
3d
15%, 55% ee
10%, 41% ee
11%, 35% ee
13%, 40% ee
O
O
OH
O
O
S
O
O
O
O
O
O
O
Br
Br
O
3m
3l
3n
3e
17%, 44% ee
36%, 30% ee
15%, 39% ee
15%, 34% ee
OCH3
OCH3
O
H3CO
O
O
O
O
O
O
O
3h
3g
Br
Br
Br
Br
3i
Br
3f
20%, 69% ee
18%, 70% ee
18%, 67% ee
O
22%, 57% ee
O
O
F
O
O
O
O
O
Br
NO2
Br
Br
3k
3j
10%, 63% ee
3p
3o
23%, 53% ee
18%, 28% ee
17%, 53% ee
O
O
O
O
O
O
O
O
O
Br
Br
Br
Br
3r
3q
3s
3t
77%, 7.5% ee
9%, 20% ee
13%, 10% ee
20%, 33% ee
Scheme 3. Substrate scope in the catalytic intermolecular bromoesterification reaction.
group was inserted into the 2-phenylacetic acid, the enantioselec-
tivity decreased dramatically (3q, Scheme 3). Sterically hindered
acids were also investigated, but the steric effect appeared to have
a negative influence on the ee values (3o–3p, Scheme 3). Changing
the ring size of the cyclic-olefin resulted in a decrease of the ee val-
ues (3r–3s, Scheme 3). When an oxygenated cyclohexene was ap-
the oxygen of the phosphate group could also attack the cyclic bro-
monium ion to give the self-bromoesterification by-product, which
could result in a decline of the catalytic loading and thus decrease
the reaction yield. The interaction between the chiral phosphoric
acid catalyst and the acid substrate in the transition state (TS,
Fig. 1) explains the disappearance of the enantioselectivity when
phosphoramides were employed in the same reaction. We specu-
late that the bulky NHTf group blocked the connection between
the catalyst and the acid substrate.
plied to the reaction, only a-bromo-b-benzoate tetrahydropyran 3t
was obtained with a high yield (Scheme 3).
The absolute configuration of 3a was assigned according to the
literature.19 On the basis of the experimental data and litera-
tures,20,5h a reaction mechanism was proposed (Fig. 1). The reac-
tion could be initiated by transferring the bromonium ion from
NBS to cyclohexene; the basic N-succinimide anion then forms
an ion pair complex with the positively charged bromonium ion.
The nucleophilic oxygen atom on the phosphate group interacts
with the acid substrate through a hydrogen bond, which thus in-
duces nucleophilic attack on the cyclic bromonium ion by the car-
boxyl group in a chiral environment (TS, Fig. 1). The proton of the
acid substrate is left to the phosphate group to regenerate the chi-
ral phosphoric catalyst. In the ion pair intermediate (ip-M, Fig. 1),
3. Conclusion
In conclusion, we have presented the first successful example of
enantioselective intermolecular bromoesterification by using chi-
ral Brønsted acids as catalysts. Up to 70% ee was achieved by a
9-phenanthryl substituted chiral phosphoric acid catalyst, but
self-bromoesterification of the catalyst meant that the product
was obtained in low yield. The proposed ion pair mechanism pro-
vides new ideas with regards to catalyzing and controlling the ste-
reoselectivity of the haloesterification reactions. Further

G. Li et al. / Tetrahedron: Asymmetry 23 (2012) 245–251
249
O
O
O
O
P
OH
O
O
Br
Br
N
+
O
step3
Step 1
O
O
H
N
O
H
O
O
Br
O
O
P
O
O
P
O
O
O
O
Br
OH
TS
ip-M
step 2
Figure 1. The proposed mechanism.
investigation of the reaction mechanism and the development of
new Brønsted acid catalysts for haloesterification are currently
underway in our laboratory.
4.1.1. 2-Bromocyclohexyl 4-methoxybenzoate) 3b
Yellowish oil, ½a D20
ꢁ
¼ þ2:5 (c 0.07, CH2Cl2); 1H NMR (300 MHz,
CDCl3) d: 8.02 (d, 2H, J = 8.64 Hz), 6.92 (d, 2H, J = 8.82 Hz), 5.10
(m, 1H), 4.15 (m, 1H), 3.86 (s, 3H), 2.41 (m, 1H), 2.27 (m, 1H),
1.97 (m, 1H), 1.82 (m, 2H), 1.42 (m, 1H), 1.24 (m, 1H).13C NMR
(150 MHz, CDCl3) d: 165.33, 163.47, 131.76, 122.67, 113.63,
76.00, 55.44, 52.78, 35.49, 31.08, 25.38, 23.27. HRMS (ESI) m/z
calcd for C14H17BrO3[M+Na]+: 335.0253, found: 335.0257. Enantio-
meric excess was determined by HPLC (Daicel Chirapak AD-H, hex-
ane/iso-propanol = 90:10, flow rate 0.8 mL/min, UV = 280 nm):
tR1 = 11.9 min, tR2 = 13.9 min.
4. Experimental
All reactions that required anhydrous conditions were carried
out by standard procedures under a nitrogen atmosphere. Com-
mercially available reagents from Alfa Aesar and Aldrich were used
as received. The solvents were dried by distillation over the appro-
priate drying reagents. Enantiomeric excesses (ee) were deter-
mined by HPLC analysis using the corresponding commercial
chiral column as stated in the experimental procedures at 23 °C
with a UV detector at 254 and 280 nm. 1H NMR spectra were re-
corded on commercial instruments (300 or 150 MHz). Chemical
shifts were reported in ppm from tetramethylsilane with the sol-
vent resonance as the internal standard (CDCl3, d = 7.26). Spectra
were reported as follows: chemical shift (d ppm), multiplicity
(s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet), cou-
pling constants (Hz), integration, and assignment. 13C NMR spectra
were collected on commercial instruments (300 or 600 MHz) with
complete proton decoupling. Chemical shifts are reported in ppm
from the tetramethylsilane with the solvent resonance as internal
standard (CDCl3, d = 77.0).
4.1.2. 2-Bromocyclohexyl 4-nitrobenzoate 3c
Brown oil, ½a 2D0
ꢁ
¼ þ1:6 (c 0.07, CH2Cl2); 1H NMR (300 MHz,
CDCl3) d: 8.30 (d, 2H, J = 9.9 Hz), 8.24 (d, 2H, J = 9.8 Hz), 5.15 (m,
1H), 4.15 (m, 1H), 2.45 (m, 1H), 2.30 (m, 1H), 2.04 (m, 1H), 1.98
(m, 2H), 1.54 (m, 1H), 1.25 (m, 1H); 13C NMR (150 MHz, CDCl3)
d: 163.77, 150.63, 135.52, 130.85, 123.55, 52.38, 35.81, 31.39,
25.65, 23.35; HRMS (ESI) m/z calcd for C13H14BrNO4 [M+Na]+:
349.9996, found: 349.9998. Enantiomeric excess was determined
by HPLC (Daicel Chirapak AD-H, hexane/iso-propanol = 90:10, flow
rate 0.8 mL/min, UV = 280 nm): tR1 = 13.5 min, tR2 = 14.1 min.
4.1.3. 2-Bromocyclohexyl 4-cyanobenzoate 3d
White powder, mp 65–68 °C, ½a D20
ꢁ
¼ þ4:8 (c 0.07, CH2Cl2); 1H
4.1. General procedure for the intermolecular bromoesterifi-
cation
NMR (300 MHz, CDCl3) d: 8.17 (d, 2H, J = 17.7 Hz), 7.76 (d, 2H,
J = 17.6 Hz), 5.16 (m, 1H), 4.12 (m, 1H), 2.40 (m, 1H), 2.27 (m,
1H), 1.92 (m, 3H), 1.36 (m, 1H). 13C NMR (150 MHz, CDCl3) d:
162.01, 134.08, 132.22, 130.24, 117.96, 116.49, 76.81, 52.40,
35.77, 31.35, 25.62, 23.41; HRMS (ESI) m/z calcd for
To a solution of acid 1 (0.2 mmol) in CH2Cl2, cyclohexane
(0.5 mL: 1.5 mL), catalyst 1i (14 mg, 0.02 mmol), and NBS
(44.5 mg, 0.25 mmol) were added sequentially, the reaction solu-
tion was stirred at ꢀ40 °C for 30 min followed by gradually adding
olefin 2 (0.2 mmol) in 10 min. The reaction mixture was stirred at
ꢀ40 °C for 48 h and directly purified by flash column chromatogra-
phy eluting with ethyl acetate and hexane.
C
14H14BrO2[M+Na]+ = 330.0100, found = 330.0103. Enantiomeric
excess was determined by HPLC (Daicel Chirapak AD-H, hexane/
iso-propanol = 85:15, flow rate 0.8 mL/min, UV = 280 nm):
tR1 = 12.7 min, tR2 = 13.2 min.

250
G. Li et al. / Tetrahedron: Asymmetry 23 (2012) 245–251
4.1.4. 2-Bromocyclohexyl 2-hydroxybenzoate 3e
76.35, 52.58, 40.61, 35.61, 31.11, 25.48, 23.25. HRMS (ESI) m/z
calcd for
14H16BrFO2 [M+Na]+ = 337.0210, found = 349.0216.
Enantiomeric excess was determined by HPLC (Daicel Chirapak
AD-H, hexane/iso-propanol = 90:10, flow rate 0.8 mL/min,
UV = 280 nm): tR1 = 7.4 min, tR2 = 8.0 min.
White powder, mp 59–64 °C, ½a D20
ꢁ
¼ þ3:5 (c 0.1, CH2Cl2); 1H
C
NMR (300 MHz, CDCl3) d: 10.72 (s, 1H), 7.89–7.86 (m, 1H), 7.47–
7.45 (m, 1H), 6.97–6.87 (m, 2H), 5.15–5.14 (m, 1H), 4.15–4.14
(m, 1H), 2.28–1.93 (m, 1H), 1.84–1.81 (m, 1H), 1.77–1.56 (m,
2H), 1.53–1.26 (m, 3H); 13C NMR (150 MHz, CDCl3) d: 165.74,
148.83, 138.82, 132.66, 113.54, 52.58, 35.51, 31.34, 25.65, 23.75;
4.1.10. 2-Bromocyclohexyl 2-(2-nitrophenyl) acetate 3k
HRMS (ESI) m/z calcd for
C
13H15BrO3[M+Na]+ = 321.0310,
Yellowish oil, ½a D20
ꢁ
¼ þ2:2 (c 0.07, CH2Cl2); 1H NMR (300 MHz,
found = 321.0293. Enantiomeric excess was determined by HPLC
(Daicel Chirapak AD-H, hexane/iso-propanol = 85:15, flow rate
0.8 mL/min, UV = 280 nm): tR1 = 15.7 min, tR2 = 18.2 min.
CDCl3) d: 8.11 (d, 1H, J = 6.0 Hz), 7.60 (m, 1H), 7.48 (m, 1H), 7.39
(d, 1H, J = 6.0 Hz), 4.90 (m, 1H), 4.08 (m, 2H), 3.94 (m, 1H), 2.32
(m, 1H), 2.16 (m, 1H), 1.84 (m, 1H), 1.71 (m, 2H), 1.36 (m, 3H).
13C NMR (150 MHz, CDCl3) d: 168.91, 148.81, 133.55, 133.41,
129.73, 128.60, 125.26, 75.35, 52.37, 39.85, 35.40, 30.85, 25.29,
23.13. HRMS (ESI) m/z calcd for C14H16BrO4 [M+Na]+: 364.0155,
found: 364.0155. Enantiomeric excess was determined by HPLC
(Daicel Chirapak AD-H, hexane/iso-propanol = 90:10, flow rate
0.8 mL/min, UV = 280 nm): tR1 = 7.9 min, tR2 = 8.5 min.
4.1.5. 2-Bromocyclohexyl 2-phenylacetate 3f
Colorless oil, ½a D20
ꢁ
¼ þ11:0 (c 0.15, CH2Cl2); 1H NMR (300 MHz,
CDCl3) d: 7.26–7.38 (m, 5H), 4.90 (m, 1H), 3.95 (m, 1H), 3.67 (t,
2H), 2.26 (m, 1H), 2.12 (m, 1H), 1.83 (m, 1H), 1.71 (m, 2H), 1.42–
1.25 (m, 3H). 13C NMR (150 MHz, CDCl3) d: 170.53, 133.96,
129.32, 128.51, 127.05, 76.15, 52.54, 41.49, 35.47, 30.95, 25.36,
23.18. HRMS (ESI) m/z calcd for C14H17BrO2 [M+Na]+: 319.0304,
found: 319.0306. Enantiomeric excess was determined by HPLC
(Daicel Chirapak AD-H, hexane/iso-propanol = 98:2, flow rate
0.8 mL/min, UV = 280 nm): tR1 = 13.4 min, tR2 = 14.3 min.
4.1.11. 2-Bromocyclohexyl 2-oxo-2-phenylacetate 3l
Colorless oil, ½a D20
ꢁ
¼ þ7:1 (c 0.10, CH2Cl2); 1H NMR (300 MHz,
CDCl3) d: 8.07 (d, 2H, J = 7.6 Hz), 7.88 (m, 1H), 7.52 (d, 2H,
J = 7.5 Hz), 5.23 (m, 1H), 4.06 (m, 1H), 2.43 (m, 1H), 2.23 (m, 1H),
1.93 (m, 1H), 1.88 (m, 1H), 1.77 (m, 1H), 1.60 (m, 1H), 1.50 (m,
1H), 1.35 (m, 1H). 13C NMR (150 MHz, CDCl3) d: 186.32, 163.07,
134.94, 132.37, 130.20, 128.90, 76.80, 51.89, 35.81, 31.29, 25.52,
23.35. HRMS (ESI) m/z calcd for C14H15BrO3 [M+Na]+: 333.0097,
found = 333.0096. Enantiomeric excess was determined by HPLC
(Daicel Chirapak OJ-H, hexane/iso-propanol = 95:5, flow rate
0.8 mL/min, UV = 280 nm): tR1 = 11.6 min, tR2 = 13.1 min.
4.1.6. 2-Bromocyclohexyl 2-(2-methoxyphenyl)acetate 3g
Colorless oil, ½a D20
ꢁ
¼ þ6:2 (c 0.10, CH2Cl2); 1H NMR (300 MHz,
CDCl3) d: 7.25 (m, 1H), 7.20 (d, 1H, J = 6.0 Hz), 6.91 (t, 1H,
J = 12.0 Hz), 6.86 (d, 1H, J = 6.0 Hz), 4.92 (m, 1H), 3.97 (m, 1H),
3.81 (s, 3H), 3.65 (s, 2H), 2.29 (m, 1H), 2.12 (m, 1H), 1.85 (m,
1H), 1.70 (m, 2H), 1.37 (m, 3H). 13C NMR (150 MHz, CDCl3) d:
170.82, 157.55, 130.90, 128.49, 123.11, 120.45, 110.36, 75.71,
55.37, 52.52, 36.19, 35.23, 30.68, 25.15, 23.05. HRMS (ESI) m/z
calcd for C15H19BrO3 [M+Na]+: 349.0410, found: 349.0412. Enan-
tiomeric excess was determined by HPLC (Daicel Chirapak AD-H,
hexane/iso-propanol = 90:10, flow rate 0.8 mL/min, UV = 280 nm):
tR1 = 6.4 min, tR2 = 7.9 min.
4.1.12. 2-Bromocyclohexyl 2-(furan-2-yl)-2-oxoacetate 3m
Off white solid, mp 65–68 °C, ½a D20
ꢁ
¼ þ2:2 (c 0.10, CH2Cl2); 1H
NMR (300 MHz, CDCl3) d: 7.77 (m, 2H), 6.68 (d, 1H, J = 6.0 Hz),
5.15 (m, 1H), 4.10 (m, 1H), 2.48 (m, 1H), 2.22 (m, 1H), 1.92 (m,
1H), 1.83 (m, 1H), 1.77 (m, 1H), 1.57 (m, 1H), 1.48 (m, 1H), 1.35
(m, 1H); 13C NMR (150 MHz, CDCl3) d: 171.09, 160.29, 149.75,
149.53, 124.80, 113.01, 78.50, 51.79, 35.73, 31.06, 25.47, 23.33;
4.1.7. 2-Bromocyclohexyl 2-(3-methoxyphenyl)acetate 3h
Colorless oil, ½a D20
ꢁ
¼ þ10:2 (c 0.10, CH2Cl2); 1H NMR (300 MHz,
HRMS (ESI) m/z calcd for
C
12H13BrO4[M+Na]+ = 323.0145,
CDCl3) d: 7.24 (m, 1H), 6.87 (m, 1H), 6.81 (m, 1H), 4.91 (m, 1H),
3.96 (m, 1H), 3.80 (s, 3H), 3.64 (m, 2H), 2.32 (m, 1H), 2.10 (m,
1H), 1.86 (m, 1H), 1.72 (m, 1H), 1.36(m, 1H). 13C NMR (150 MHz,
CDCl3) d: 170.40, 159.71, 135.36, 129.46, 121.69, 114.86, 112.78,
76.19, 55.23, 52.56, 41.52, 35.50, 30.96, 25.38, 23.19. HRMS (ESI)
m/z calcd for C15H19BrO3[M+Na]+: 349.0410, found: 349.0412.
Enantiomeric excess was determined by HPLC (Daicel Chirapak
AD-H, hexane/iso-propanol = 90:10, flow rate 0.8 mL/min,
UV = 280 nm): tR1 = 8.0 min, tR2 = 8.9 min.
found = 323.0139. Enantiomeric excess was determined by HPLC
(Daicel Chirapak AD-H, hexane/iso-propanol = 95:5, flow rate
0.8 mL/min, UV = 280 nm): tR1 = 15.3 min, tR2 = 16.8 min.
4.1.13. 2-Bromocyclohexyl 2-oxo-2-(thiophen-2-yl)acetate 3n
Green solid, mp 58–62 °C, ½a D20
ꢁ
¼ þ7:7 (c 0.10, CH2Cl2); 1H NMR
(300 MHz, CDCl3) d: 8.17 (m, 1H), 7.83 (m, 1H), 7.21 (m, 1H), 5.18
(m, 1H), 4.09 (m, 1H), 2.43 (m, 1H), 2.24 (m, 1H), 1.98 (m, 1H), 1.85
(m, 1H), 1.59 (m, 2H), 1.49 (m, 1H), 1.36 (m, 1H); 13C NMR
(150 MHz, CDCl3) d: 176.50, 160.91, 139.22, 137.42, 137.37,
128.71, 78.51, 51.81, 35.72, 31.09, 25.47, 23.34; HRMS (ESI) m/z
4.1.8. 2-Bromocyclohexyl 2-(4-methoxyphenyl)acetate 3i
Colorless oil, ½a D20
ꢁ
¼ þ14:2 (c 0.10, CH2Cl2); 1H NMR (300 MHz,
calcd for
C
12H13BrO3S[M+Na]+ = 338.9661, found = 338.9665.
CDCl3) d: 7.21 (d, 2H, J = 6.0 Hz), 6.86 (d, 2H, J = 6.0 Hz), 4.90 (m,
1H), 3.96 (m, 1H), 3.79 (s, 3H), 3.59 (m, 2H), 2.31 (m, 1H), 2.10
(m, 1H), 1.85 (m, 1H), 1.71 (m, 2H), 1.36 (m, 3H). 13C NMR
(150 MHz, CDCl3) d: 170.85, 158.70, 130.34, 126.06, 113.96,
76.07, 55.26, 52.59, 40.58, 35.48, 30.96, 25.37, 23.18. HRMS (ESI)
m/z calcd for C15H19BrO3 [M+Na]+: 349.0410, found: 349.0412.
Enantiomeric excess was determined by HPLC (Daicel Chirapak
AD-H, hexane/iso-propanol = 95:5, flow rate 0.8 mL/min,
UV = 280 nm): tR1 = 11.7 min, tR2 = 12.5 min.
Enantiomeric excess was determined by HPLC (Daicel Chirapak
AD-H, hexane/iso-propanol = 95:5, flow rate 0.8 mL/min,
UV = 280 nm): tR1 = 12.5 min, tR2 = 13.5 min.
4.1.14. 2-Bromocyclohexyl 2-(naphthalen-1-yl)acetate 3o
Colorless oil, ½a D20
ꢁ
¼ þ5:0 (c 0.10, CH2Cl2); 1H NMR (300 MHz,
CDCl3) d: 8.08 (d, 1H, J = 6.0 Hz), 7.84 (m, 1H), 7.79 (m, 1H), 7.55
(m, 1H), 7.49 (m, 1H), 4.92 (m, 1H), 4.11 (m, 2H), 3.98 (m, 1H),
2.23 (m, 1H), 2.07 (m, 1H), 1.81 (m, 1H), 1.67 (m, 2H), 1.31 (m,
3H). 13C NMR (150 MHz, CDCl3) d: 170.54, 133.34, 132.15,
130.53, 128.68, 128.05, 128.02, 126.28, 125.75, 125.44, 12.97,
76.20, 52.46, 39.27, 35.33, 30.81, 25.23, 23.08. HRMS (ESI) m/z
calcd for C18H19BrO2[M+Na]+: 369.0461, found = 369.0452. Enan-
tiomeric excess was determined by HPLC (Daicel Chirapak AD-H,
hexane/iso-propanol = 95:5, flow rate 0.8 mL/min, UV = 280 nm):
tR1 = 9.4 min, tR2 = 11.3 min.
4.1.9. 2-Bromocyclohexyl 2-(4-fluorophenyl) acetate 3j
Yellowish oil, ½a D20
ꢁ
¼ þ10:2 (c 0.20, CH2Cl2); 1H NMR (300 MHz,
CDCl3) d: 7.26 (d, 2H, J = 6.0 Hz), 7.00 (d, 2H, J = 6.0 Hz), 4.90 (m,
1H), 3.96 (m, 1H), 3.62 (m, 2H), 2.32 (m, 1H), 2.10 (m, 1H), 1.86
(m, 1H), 1.72 (m, 2H), 1.35 (m, 3H). 13C NMR NMR (150 MHz,
CDCl3) d: 170.37, 161.22, 130.91, 130.86, 129.64, 115.42, 115.28,

G. Li et al. / Tetrahedron: Asymmetry 23 (2012) 245–251
251
4.1.15. 2-Bromocyclohexyl 1-naphthoate 3p
13C NMR (150 MHz, CDCl3) d: 164.56, 133.53, 129.92, 129.44,
128.51, 94.82, 64.25, 47.08, 29.96, 22.91; HRMS (ESI) m/z calcd
White solid, mp 85–88 °C, ½a D20
ꢁ
¼ þ4:8 (c 0.10, CH2Cl2); 1H NMR
(300 MHz, CDCl3) d: 8.93 (d, 1H, J = 7.0 Hz), 8.22 (d, 1H, J = 6.0 Hz),
8.03 (d, 1H, J = 6.0 Hz), 7.90 (d, 1H, J = 6.0 Hz), 7.64–7.25 (m, 3H),
5.28 (m, 1H), 4.21 (m, 1H), 2.48–2.36 (m, 2H), 2.01 (m, 1H), 1.97
(m, 2H), 1.83 (m, 2H), 1.53 (m, 1H); 13C NMR (150 MHz, CDCl3)
d: 166.53, 133.84, 133.31, 131.37, 130.16, 128.51, 127.73, 127.36,
126.23, 125.83, 124.54, 76.58, 52.86, 35.81, 31.41, 25.61, 23.46;
for C
12H13BrO3[M+Na]+ = 306.9940, found = 306.9935. Enantio-
meric excess was determined by HPLC (Daicel Chirapak AD-H, hex-
ane/iso-propanol = 98:2, flow rate 0.5 mL/min, UV = 280 nm):
tR1 = 20.1 min, tR2 = 22.7 min.
Acknowledgments
HRMS (ESI) m/z calcd for
C
17H17BrO2[M+Na]+ = 349.0304,
found = 335.0311. Enantiomeric excess was determined by HPLC
(Daicel Chirapak AD-H, hexane/iso-propanol = 99:1, flow rate
0.8 mL/min, UV = 280 nm): tR1 = 24.5 min, tR2 = 24.7 min.
This work was supported by Chinese Academy of Science (Hun-
dreds of Talents Program), National Sciences Foundation of China
(225013) and Opening Foundation of Zhejiang Provincial Top Key
Discipline.
4.1.16. 2-Bromocyclohexyl 3-phenylpropanoate 3q
White solid, mp 95–98 °C, ½a D20
ꢁ
¼ þ8:5 (c 0.10, CH2Cl2); 1H NMR
References
(300 MHz, CDCl3) d: 7.22–7.19 (m, 2H), 7.15–7.11 (m, 3H), 4.85–
4.82 (m, 1H), 4.00–3.96 (m, 1H), 2.96–2.88 (m, 2H), 2.64–2.54
(m, 2H), 2.34–2.31 (m, 1H), 2.01–1.90 (m, 2H), 1.73–1.70 (m,
1H), 1.54–1.48 (m, 1H), 1.42–1.34 (m, 1H), 1.28–1.18 (m, 2H);
13C NMR (150 MHz, CDCl3) d: 171.90, 140.44, 128.46, 128.29,
126.24, 75.83, 52.82, 35.96, 35.60, 31.16, 30.98, 25.49, 23.28;
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HRMS (ESI) m/z calcd for
C
15H19BrO2[M+Na]+ = 333.0562,
found = 333.0524. Enantiomeric excess was determined by HPLC
(Daicel Chirapak AD-H, hexane/iso-propanol = 99:1, flow rate
0.8 mL/min, UV = 280 nm): tR1 = 19.5 min, tR2 = 24.7 min.
4.1.17. 2-Bromocyclopentyl benzoate 3r
White solid, mp 67–68 °C, ½a D20
ꢁ
¼ þ3:7 (c 0.10, CH2Cl2); 1H NMR
(300 MHz, CDCl3) d: 8.01 (m, 2H), 7.56 (m, 1H), 7.41 (m, 2H), 5.52
(m, 1H), 4.37 (m, 1H), 2.44–2.39 (m, 2H), 2.15–1.87 (m, 4H); 13C
NMR (150 MHz, CDCl3) d: 165.60, 133.14, 129.99, 129.62, 128.41,
82.67, 52.94, 34.66, 29.54, 21.81; HRMS (ESI) m/z calcd for
C
12H13BrO2[M+Na]+ = 291.0131, found = 291.0129. Enantiomeric
excess was determined by HPLC (Daicel Chirapak AD-H, hexane/
iso-propanol = 98:2, flow rate 0.8 mL/min, UV = 280 nm):
tR1 = 7.5 min, tR2 = 8.1 min.
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4.1.18. 2-Bromocyclooctyl benzoate 3s
White solid, mp 79–82 °C, ½a D20
ꢁ
¼ þ5:8 (c 0.10, CH2Cl2); 1H NMR
(300 MHz, CDCl3) d: 8.07 (d, 2H, J = 6.0 Hz), 7.55 (t, 1H, J = 7.0 Hz),
7.45 (t, 1H, J = 6.0 Hz), 5.43 (m, 1H), 4.49 (m, 1H), 2.33 (m, 1H), 2.15
(m, 1H), 1.92 (m, 3H), 1.61 (m, 1H), 1.49 (m, 2H); 13C NMR
(150 MHz, CDCl3) d: 165.73, 132.94, 130.4, 129.7, 128.36, 76.81,
57.35, 32.22, 31.70, 25.88, 25.46, 25.41, 24.68; HRMS (ESI) m/z
calcd for
C
15H19Br2O4[M+Na]+ = 333.0461, found = 333.0466.
Enantiomeric excess was determined by HPLC (Daicel Chirapak
AD-H, hexane/iso-propanol = 98:2, flow rate 0.8 mL/min,
UV = 280 nm): tR1 = 8.2 min, tR2 = 8.4 min.
17. (a) Akiyama, T. Chem. Rev. 2007, 107, 5744; (b) Terada, M. Synthesis 2010, 1929;
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4.1.19. 3-Bromotetrahydro-2H-pyran-2-ylbenzoate 3t
White solid, mp 68–70 °C, ½a D20
ꢁ
¼ þ2:8 (c 0.10, CH2Cl2); 1H NMR
(300 MHz, CDCl3) d: 8.09 (m, 2H), 7.57 (m, 1H), 7.44 (m, 2H), 6.14
(d, J = 8.6 Hz, 1H), 4.21 (m, 1H), 4.19–4.03 (m, 2H), 3.84–3.82 (m,
1H), 2.51–2.48 (m, 1H), 2.13–2.04 (m, 2H), 1.68–1.57 (m, 1H);