Enantioselective Synthesis of 2-Bromomethyl Indolines via BINAP(S)-Catalyzed Bromoaminocyclization of Allyl Aniline

Article abstract of DOI:10.1002/adsc.201700106

An enantioselective bromoamination of allyl aniline with N-bromosuccinimide (NBS) catalyzed by BINAP(S) (BINAP monosulfide) is described. This protocol could provide a range of chiral 2-bromomethyl indolines in good to excellent yields with up to 87% ee.

Full text of DOI:10.1002/adsc.201700106

Title: Enantioselective Synthesis of 2-Bromomethyl Indolines via
BINAP(S)-Catalyzed Bromoaminocyclization of Allyl Aniline
Authors: Jun Deng, Sheng-Nan Yu, and Yin-Long Li
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201700106
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10.1002/adsc.201700106
Advanced Synthesis & Catalysis
UPDATE
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Enantioselective Synthesis of 2-Bromomethyl Indolines via
BINAP(S)-Catalyzed Bromoaminocyclization of Allyl Aniline
Sheng-Nan Yu,a Yin-Long Li,a Jun Deng*a,b
a
School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, 300072, China
School of Pharmaceutical Sciences and Innovative Drug Research Centre, Chongqing University, 55 Daxuecheng South
b
Road, Shapingba, Chongqing 401331, China
E-mail: jdeng@cqu.edu.cn；Fax: (+86)-23-65678460
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. An enantioselective bromoamination of allyl
aniline with N-bromosuccinimide (NBS) catalyzed by
BINAP(S), BINAP monosulfide is described. This protocol
could provide a range of chiral 2-bromomethyl indolines in
good to excellent yields with up to 87% ee. Furthermore,
the resulting chiral 2-bromomethyl indolines could be
easily converted into synthetically useful chiral building
blocks.
Keywords:
enantioselective
synthesis;
indolines;
bromoaminocyclization; allyl aniline; N-bromosuccinimide
(NBS); BINAP(S)
Figure 1. Examples of chiral bioactive indoline derivatives.
Chiral indolines have been found in a wide range of
natural products and synthetic compounds as well as
pharmaceuticals,[1] and the indoline derivatives
possess diverse biological activities and have received
considerable attention from the medicinal chemistry
community.[2] For example, Pentopril, containing the
indoline-2-carboxylate
moiety
could
inhibit
angiotensin converting enzyme.[2a-c] Indapamide,
which
chlorobenzamide moiety and
methylindoline moiety,
antihypertensive/diuretic.[2d]
contains
both
a
polar
a
sulfamoyl
lipid-soluble
an
is
oral
some
Especially,
indoline derivatives have the antitumor and anticancer
activities, such as the compound 3, which could be an
anticancer agent,[2e] SAR-260301 is an antitumor
agent.[2f] In addition, the anti-inflammatory agent 5
also contains the chiral indoline skeleton (Figure
1).[2g]
Due to the unique biological activities and the
wide application in pharmaceuticals, the development
of new and efficient methods to synthesize chiral
indolines has become a booming research topic over
the past decade.[3] Although a diverse array of elegant
work has been established, including asymmetric
Scheme 1. Haloaminocyclization approaches to chiral
indolines.
1
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10.1002/adsc.201700106
Advanced Synthesis & Catalysis
Table 1. Studies of the reaction conditions.[a]
bases,[7b-d] Lewis acids,[ 7e-j] chiral amines,[ 7k] as well
as chiral phosphoric acids.[7l-m] Specifically, the chiral
thiourea-based catalysts and Cu(II)-complex have
achieved great progress in the haloaminocyclization
approaches to chiral indolines. Chemler and co-
workers have accomplished a Cu-catalyzed highly
enantioselective aminohalogenation reaction for the
synthesis of indolines.[3r] More recently, a newly
developed thiourea-based catalyst has been applied in
the synthesis of indolines via iodoamination of
alkenes by Wirth group (Scheme 1).[3s] For its
inherent importance of the chiral indolines, more
types of chiral catalyst for convenient, practical
production of these compounds still remains one of
the top goals to pursuit. Although a few of chiral
phosphines and related compounds have been applied
in asymmetric halogenations of alkene, their diversity
and complexity make them show great potential.[9]
Therefore, we wish to communicate here our success
in achieving the enantioselective synthesis of 2-
bromomethyl indolines via BINAP(S), BINAP
monosulfide catalyzed bromoaminocyclization of
allyl aniline.
Temp
Yield
ee
Entry Cat.
Solvent
[oC]
-40
-40
-40
-40
-40
-40
-50
-78
-78
-78
-78
-78
-78
-78
-78
-78
-78
[%][b] [%][c]
1
2
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
THF
--
--
I
II
70
81
82
81
80
83
76
38
43
82
84
75
90
65
11
93
15
49
64
53
59
69
77
14
20
60
79
51
85
66
70
82
Initially, we chose N-tosyl-2-allylaniline 6a as
the model substrate to evaluate the catalysts and
optimize the reaction conditions (Table 1). The
quinine-based thiourea catalyst I only gave a trace
amount of product 7a (Table 1, entry 1). The desired
product was obtained in 70% yield with low
enantioselectivity by using the catalyst II (Table 1,
entry 2). However, the moderate ee value was
generally obtained with BINAP as the catalyst (Table
1, entry 3). Gratifyingly, when chiral P/P=S double-
site Lewis base catalyst BINAP(S) IV which has been
applied previously in asymmetric catalysis as chiral
ligand was used,[10] the desired product could be
isolated in 84% yield and 64% ee (Table 1, entry 4).
Other chiral BINAP-derivatives such as V and VI
have been proved ineffective to improve the ee value
of 7a. Therefore, BINAP(S) IV was the most
effective catalyst for this reaction in terms of the
conversion and enantioselectivity. The various other
parameters of this reaction by using BINAP(S) as
catalyst have been investigated systematically
afterwards. Eventually, the reaction temperature has
an obvious influence on the enantioselectivity (Table
1, entries 4, 7, 8). The highest ee and yield could be
3
4
5
III
IV
V
6
7
8
9
10
11
12
13
14
15
16
17[d]
VI
IV
IV
IV
IV
IV
IV
IV
EtOAc
CHCl3
toluene/CHCl3
toluene/DCE
IV toluene/CH2Cl2
toluene/CH2Cl2
toluene/CH2Cl2
toluene/CH2Cl2
VII
VIII
IX
[a]
Reaction condition: 6a (0.1 mmol), NBS (0.12 mmol),
catalyst (0.01 mmol), solvent (2.2 mL).
[b] Isolated yields.
[c] Determined by chiral HPLC analysis.
[d] The reaction was run for 24 h.
hydrogenation,[3h-n] asymmetric hydrosilylation,[3o]
asymmetric
hydroamination/cyclization
of
aminoalkenes,[3p] enzymatic or non-enzymatic kinetic
resolutions or aminohalogenation/cyclization.[3q-s]
The catalytic asymmetric alkene halogenation
has witnessed an explosive growth in recent years,[4]
o
obtained at -78 C. Our attention then turned to
halolactonizations,[5]
evaluate the solvent effect on this reaction, various
solvents were examined including THF, CHCl3, ethyl
acetate, and combined solvents (Table 1, entries 9 to
14). Finally, to our delight, the combination of
toluene/CH2Cl2 (10:1) could provide the best result,
90% yield and 85% ee (Table 1, entry 14). In addition,
the lower enantioselectivities were obtained when
catalyzed by BINAP disulfide (VII), BINAP dioxide
(VIII), or BINAP monoxide (IX) under the standard
the
reactions
involved
haloetherifications,[6] haloaminocyclizations[3r,3s, 7] and
so on.[8] It is worth noting that enantioselective
haloaminocyclizations of alkenes could deliver the
chiral vicinal amino halide products which are
versatile synthetic intermediates, have been received
considerable scientific attention. A series of catalysis
systems have been developed, such as chiral Lewis
2
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10.1002/adsc.201700106
Advanced Synthesis & Catalysis
Table 2. Scope of substrate.[a]
Scheme 2. Effect of the halogen sources.
conditions (Table 1, entries 15-17). On the basis of
these results, we speculated that BINAP monosulfide
(IV) is the best catalytic specie for this reaction. The
absolute stereochemistry of 7a was determined to be
R by comparing the optical rotation with the reported
value.[3r]
Next, the efficiency of other brominating
reagents such as 1,3-dibromo-5,5-dimethylhydantoin
(DBDMH),
N-bromophthalimide
(NBP),
N-
bromoacetamide (NBA) and 2,4,4,6-tetrabromo-2,5-
cyclo-hexadienone (TBCO) were explored (Scheme
2). Unfortunately, none of them gave as favorable
result as NBS in terms of the ee value and yield
(Scheme 2). Further attempts to increase the
enantioselectivity including changes in the loadings of
brominating reagent and catalyst proved to be
ineffective. Finally, the optimal reaction conditions
for this transformation have been established [6a (1.0
equiv) and NBS (1.2 equiv) in toluene/CH2Cl2 (10:1)
at -78 °C catalyzed by BINAP(S) IV for 50 hours].
Having established the optimum reaction
conditions, a wide range of substrates to synthesize
various chiral 2-bromomethyl indolines were next
investigated (Table 2). Initially, a variety of
substituents on the nitrogen atom have been examined.
It was found that there is a sharp loss of yield and ee
value when the nosyl group was used (Table 2, 7b).
Changing the tosyl to mesyl, brosyl or 4-
chlorobenzensulfonyl group, the enantioselectivities
were also diminished (Table 2, 7c-e). Whereas, when
[a]
Reaction condition: 6 (0.1 mmol), NBS (0.12 mmol),
catalyst (0.01 mmol), solvent (2.2 mL). Yield of isolated
product. The ees were determined by chiral HPLC analysis.
[b] The reaction was run for 60 h in toluene (2.0 mL).
[c] The reaction was run for 60 h.
tosyl
substituent
replaced
by
4-
methoxylbenzenesulfonyl group, the yield and
enantioselectivity were only slightly decreased (Table
2, 7f). The benzenesulfonyl substituted substrate still
did not offer better ee by comparing with tosyl (Table
2, 7g). After the identification of an appropriate N
substituent,
a
series of substituted N-tosyl-2-
allylanilines 6, including different para-, meta- and
even disubstituted on the aryl unit were examined
(Table 2, 7h-v). Substrates with electron-rich
substituent at the para position of aromatic ring
afforded the desired products with better
enantioselectivities than electron-deficient group, for
example, the best result was provided by para-
methoxyl substitued substrate (Table 2, 7h). However,
switching the substituents from para position to meta
Scheme 3. Demonstration of synthetic utility.
3
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10.1002/adsc.201700106
Advanced Synthesis & Catalysis
1
gel 200-300 mesh. H and 13C NMR spectra were obtained
on 400 or 600 MHz (100 or 150 MHz for 13C NMR)
spectrometers using CDCl3 with TMS or residual solvent as
standard unless otherwise noted. The chemical shifts are
reported in ppm relative to solvent residual peak. The peak
patterns are indicated as follows: s, singlet; d, doublet; t,
triplet; q, quadruplet; m, multiplet; dd, doublet of doublets,
and br s, broad singlet. The coupling constants (J) are
reported in Hertz (Hz). Melting points were determined
position, the opposite results were obtained. Thus, the
electron-withdrawing groups were more helpful to
promote the enantioselectivity than electron-donating
groups (Table 2, 7i, 7n, 7p). Additionally, 3,5-
dimethyl-substituted and 4,6-dimethyl-substituted
substrates could provide the corresponding desired
products in 75% and 32% ee, respectively (Table 2,
7u,v). Substituents on alkene also have great impact
on enantioselectivity. When R2 is phenyl group, the
desired product could be obtained in excellent yield
and up to 87% ee (Table 2, 7w). Although this highly
using
a
micromelting point apparatus and were
uncorrected/calibrated. TLC analysis was performed over
glass-backed plates (60 Å, 250 m) and visualized using
UV. High-resolution mass spectra were obtained using a Q-
TOF micro spectrometer. Enantiomeric excess was
determined by high performance liquid chromatography
(HPLC) using Daicel Chiralcel OJ-H, OD-H or Daicel®
®
enantioselective
construction
of
a
chiral
Chiralpak AD-H, AS-H chiral analytical columns (UV
detection at 254 nm).
tetrasustituted carbon center is another feature of this
methodology and would be fascinating to synthetic
organic chemist, unfortunately, there is a dramatic
loss of ee value whether the electron-rich or electron-
deficient substituent on the phenyl ring (Table 2, 7y
and 7z). In addition, changing the aromatic ring to
methyl group also led to lower enantioselectivity
(Table 2, 7x).
To demonstrate the potential synthetic utility of
this reaction, we then investigated the transformation
of this 2-bromomethyl indoline as the chiral
intermediate (Scheme 3). Firstly, the chiral azide 8
has been successfully provided by substitution of the
bromine atom with NaN3 in 93% yield and 80% ee. In
addition, the reduction of the bromide was
accomplished by AIBN/Bu3SnH followed by removal
of the tosyl group to give 2-methyl indoline 9 in 90%
yield with 82% ee, the product could be used in
synthesis of some important bioactive compounds.[2]
Furthermore, the 2-hydroxymethylindoline 10 was
readily obtained in 50% total yield with good
stereochemical integrity through substitution,
hydrolysis and detosylation reactions.
In summary, an enantioselective organocatalytic
bromoaminocyclization of N-tosyl-2-allylanilines
with NBS using BINAP(S) as catalyst has been
described, and a series of chiral 2-bromomethyl
indolines with various functional groups have been
synthesized in good to excellent yields with high
enantioselectives. The utility of this methodology is
also highlighted by the products can be easily
transformed into other useful synthetic intermediates
and bioactive compounds. This method could be used
by the researchers in the areas of organic and
medicinal chemistry. Further investigations on
catalytic asymmetric alkene halogenation are ongoing
in our group.
General Procedure for Synthesis of Chiral
Indolines
To an oven-dried flask with a stir bar was added substrate 6
(0.1 mmol, 1.0 equiv), catalyst VI (6.6 mg, 0.01 mmol, 1.0
equiv) and toluene/CH2Cl2 (10:1, 2.2 mL) and the flask
was placed in a -78 °C for 10 min, then NBS (21 mg, 0.12
mmol, 1.2 equiv) was added to the resulting mixture and
continued to stirred at -78 °C for 50 h. Upon completion,
the reaction was quenched by saturated aqueous Na2S2O3
(2.0 mL) at -78 °C and was gradually warmed to room
temperature. The separated aqueous layer was extracted
with ethyl acetate and the combined organic layers were
washed with brine, dried over Na2SO4, and concentrated
under reduced pressure. The residue was purified by flash
column chromatography (petro ether/ethyl acetate = 10:1)
to give the product 7.
(R)-2-(bromomethyl)-1-tosylindoline (7a).11 Yield: 32.8
mg, 90%, white solid, mp: 91-93 °C. [α]D24= -63.6 (c =0.11,
CHCl3), 85% ee, determined by HPLC analysis [Daicel
Chiralcel OD-H, 5% i-PrOH /hexane, 1.0 mL/min, λ= 254
nm, t(minor) = 6.6 min, t(major) = 7.4 min]. 1H NMR (600 MHz,
CDCl3) δ 7.65 (d, J = 8.1 Hz, 1H), 7.56 (d, J = 8.3 Hz, 2H),
7.24-7.20 (m, 1H), 7.18 (d, J = 8.1 Hz, 2H), 7.07-7.03 (m,
2H), 4.46-4.39 (m, 1H), 3.81 (dd, J = 9.9, 3.7 Hz, 1H), 3.41
(t, J = 9.9 Hz, 1H), 2.95-2.87 (m, 2H), 2.36 (s, 3H); 13C
NMR (150 MHz, CDCl3) δ 144.3, 141.1, 134.5, 130.6,
129.8, 128.0, 127.1, 125.3, 125.0, 116.9, 62.2, 36.0, 33.2,
21.6. HRMS-ESI (m/z): calcd for C16H16BrNNaO2S
[M+Na]+ 387.9977, found 387.9968.
(R)-2-(bromomethyl)-1-((4-nitrophenyl)sulfonyl)indo-
line (7b). Yield: 23.3 mg, 59%, yellow solid, mp: 98-
101 °C. [α]D15= -20 (c = 0.10, CHCl3), 34% ee, determined
by HPLC analysis [Daicel Chiralpak AD-H, 5% i-PrOH
/hexane, 1.0 mL/min, λ= 254 nm, t(minor) = 19.4 min, t(major)
= 24.6 min]. 1H NMR (600 MHz, CDCl3) δ 8.25 (d, J = 8.7
Hz, 2H), 7.89 (d, J = 8.7 Hz, 2H), 7.67 (d, J = 8.1 Hz, 1H),
7.32-7.23 (m, 1H), 7.15-7.05 (m, 2H), 4.47-4.44 (m, 1H),
3.80 (dd, J = 10.0, 3.7 Hz, 1H), 3.44 (t, J = 9.8 Hz, 1H),
3.01-2.91 (m, 2H); 13C NMR (150 MHz, CDCl3) δ 150.5,
143.0, 140.1, 130.5, 128.4, 128.3, 125.8, 125.7, 124.4,
116.6, 62.5, 35.4, 33.2. HRMS-ESI (m/z): calcd for
C15H13BrN2NaO4S [M+Na]+ 418.9672, found 418.9648.
(R)-2-(bromomethyl)-1-(methylsulfonyl)indoline
Yield: 22.8 mg, 79%, white solid, mp: 151-153 °C. [α]D
(7c).
24
=
+25 (c =0.08, CHCl3), 68% ee, determined by HPLC
analysis [Daicel Chiralcel OD-H, 5% i-PrOH /hexane, 1.0
mL/min, λ= 254 nm, t(minor) = 17.6 min, t(major) = 25.7 min].
1H NMR (600 MHz, CDCl3) δ 7.43 (d, J = 8.3 Hz, 1H),
7.23 (d, J = 5.1 Hz, 2H), 7.10 (t, J = 7.4 Hz, 1H), 4.58-4.54
(m, 1H), 3.78 (dd, J = 10.0, 3.3 Hz, 1H), 3.50-3.46 (m, 2H),
3.16 (dd, J = 16.8, 3.3 Hz, 1H), 2.88 (s, 3H); 13C NMR
(150 MHz, CDCl3) δ 141.1, 129.7, 128.3, 125.6, 124.8,
115.2, 62.3, 36.3, 36.2, 33.8. HRMS-ESI (m/z): calcd for
C10H12BrNNaO2S [M+Na]+ 311.9664, found 311.9666.
Experimental Section
General Information
All purchased chemicals were used as received without
further purification. Solvents were distilled prior to use.
Chromatographic separations were performed using silica
4
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10.1002/adsc.201700106
Advanced Synthesis & Catalysis
mL/min, λ= 254 nm, t(major) =14.5 min, t(minor) =15.9 min).
1H NMR (600 MHz, CDCl3) δ 7.58 (d, J = 8.2 Hz, 2H),
7.25 (d, J = 2.2 Hz, 1H), 7.20 (d, J = 8.1 Hz, 2H), 6.94 (d, J
= 8.2 Hz, 1H), 6.60 (dd, J = 8.3, 2.3 Hz, 1H), 4.45-4.40 (m,
1H), 3.83 (s, 3H),3.81 (dd, J = 10.2, 3.6 Hz, 1H), 3.41 (t, J
= 9.9 Hz, 1H), 2.85-2.83 (m, 2H), 2.37 (s, 3H); 13C NMR
(150 MHz, CDCl3) δ 159.9, 144.3, 142.3, 134.5, 129.8,
127.1, 125.5, 122.3, 111.2, 102.7, 63.0, 55.7, 36.0, 32.5,
21.6. HRMS-ESI (m/z): calcd for C17H18BrNNaO3S
[M+Na]+ 418.0083, found 418.0085.
(R)-2-(bromomethyl)-1-((4-bromophenyl)sulfonyl)in-
doline (7d). Yield: 35.6 mg, 83%, white solid, mp: 90-
93 °C; [α]D15= -41.7 (c = 0.12, CHCl3), 71% ee, determined
by HPLC analysis [Daicel Chiralcel OD-H, 5% i-PrOH
/hexane, 1.0 mL/min, λ= 254 nm, t(minor) = 7.5 min, t(major)
=
8.5 min]. 1H NMR (600 MHz, CDCl3) δ 7.63 (d, J = 8.4 Hz,
1H), 7.54 (s, 4H), 7.24 (t, J = 7.5 Hz, 1H), 7.10-7.06 (m,
2H), 4.46-4.36 (m, 1H), 3.80 (dd, J = 10.2, 3.7 Hz, 1H),
3.42 (t, J = 9.9 Hz, 1H), 2.96-2.95 (m, 2H); 13C NMR (150
MHz, CDCl3) δ 140.7, 136.4, 132.5, 130.6, 128.6, 128.5,
128.2, 125.5, 125.3, 116.8, 62.3, 35.7, 33.2. HRMS-ESI
(m/z): calcd for C15H13Br2NNaO2S [M+Na]+ 451.8926,
(R)-2-(bromomethyl)-5-methyl-1-tosylindoline
Yield: 33.7 mg, 89%, white solid, mp: 121-123 °C. [α]D
(7j).11
24
=
-137.5 (c = 0.09, CHCl3), 81% ee, determined by HPLC
analysis [Daicel Chiralcel OD-H, 2% i-PrOH /hexane, 1.0
mL/min, λ= 254 nm, t(minor) = 8.7 min, t(major) = 9.3 min]. 1H
NMR (600 MHz, CDCl3) δ 7.54 (dd, J = 15.7, 8.2 Hz, 3H),
7.18 (d, J = 8.1 Hz, 2H), 7.02 (d, J = 8.2 Hz, 1H), 6.87 (s,
1H), 4.42-4.38 (m, 1H), 3.80 (dd, J = 9.9, 3.8 Hz, 1H), 3.39
(t, J = 9.9 Hz, 1H), 2.89-2.82 (m, 2H), 2.36 (s, 3H), 2.28 (s,
3H); 13C NMR (150 MHz, CDCl3) δ 144.2, 138.7, 134.8,
134.4, 130.8, 129.7, 128.6, 127.1, 125.9, 116.7, 62.3, 36.0,
33.1, 21.6, 21.0. HRMS-ESI (m/z): calcd for
C17H18BrNaNO2S [M+Na]+ 402.0134, found 402.0131.
found 451.8905.
(R)-2-(bromomethyl)-1-((4-chlorophenyl)sulfonyl)in-
doline (7e). Yield: 32.3 mg, 84%, white solid, mp: 95-
97 °C. [α]D24= -67 (c =0.06, CHCl3), 73% ee, determined
by HPLC analysis [Daicel Chiralcel OD-H, 5% i-PrOH
/hexane, 1.0 mL/min, λ= 254 nm, t(minor) = 7.4 min, t(major)
=
8.1 min]; 1H NMR (600 MHz, CDCl3) δ 7.65-7.61 (m, 3H),
7.40-7.36 (m, 2H), 7.26-7.22 (m, 1H), 7.10-7.06 (m, 2H),
4.44-4.39 (m, 1H), 3.80 (dd, J = 10.0, 3.8 Hz, 1H), 3.42 (t,
J = 9.9 Hz, 1H), 3.00-2.89 (m, 2H); 13C NMR (150 MHz,
CDCl3) δ 140.7, 140.1, 135.9, 130.6, 129.5, 128.4, 128.1,
125.5, 125.3, 116.8, 62.3, 35.7, 33.2. HRMS-ESI (m/z):
calcd for C15H13BrClNNaO2S [M+Na]+ 407.9431, found
407.9423.
(R)-2-(bromomethyl)-5-(tert-butyl)-1-tosylindoline (7k).
24
Yield: 38.3 mg, 91%, white solid, mp: 136-138 °C. [α]D
=
-100 (c = 0.14, CHCl3), 80% ee, determined by HPLC
analysis [Daicel Chiralcel OD-H, 5% i-PrOH /hexane, 1.0
mL/min, λ= 254 nm, t(minor) = 5.3 min; t(major) = 5.7 min]. 1H
NMR (600 MHz, CDCl3) δ 7.57 (d, J = 8.2 Hz, 2H), 7.54
(d, J = 8.5 Hz, 1H), 7.23 (d, J = 8.5 Hz, 1H), 7.19 (d, J =
8.1 Hz, 2H), 7.08 (s, 1H), 4.42-4.38 (m, 1H), 3.83 (dd, J =
9.8, 3.8 Hz, 1H), 3.39 (t, J = 10.0 Hz, 1H), 2.94-2.87 (m,
2H), 2.37 (s, 3H), 1.27 (s, 9H); 13C NMR (150 MHz,
CDCl3) δ 147.2, 143.1, 137.5, 133.5, 129.1, 128. 7, 126.1,
123.9, 121.2, 115.1, 61.3, 34.8, 33.4, 32.3, 30.4, 20.5.
HRMS-ESI (m/z): calcd for C20H24BrNNaO2S [M+Na]+
444.0603, found 444.0600.
(R)-2-(bromomethyl)-1-((4-methoxyphenyl)sulfonyl)in-
doline (7f). Yield: 32.8 mg, 86%, white solid, mp: 105-
107 °C. [α]D24= -83 (c =0.12, CHCl3), 80% ee, determined
by HPLC analysis [Daicel Chiralcel OD-H, 5% i-PrOH
/hexane, 1.0 mL/min, λ= 254 nm, t(minor) = 10.4 min, t(major)
= 12.2 min]. 1H NMR (600 MHz, CDCl3) δ 7.65 (d, J = 8.1
Hz, 1H), 7.61 (d, J = 8.8 Hz, 2H), 7.23 (t, J = 7.4 Hz, 1H),
7.08-7.04 (m, 2H), 6.85 (d, J = 8.8 Hz, 2H), 4.44-4.39 (m,
1H), 3.83 (d, J = 3.7 Hz, 1H), 3.81 (s, 3H), 3.41 (t, J = 9.9
Hz, 1H), 2.96-2.88 (m, 2H); 13C NMR (150 MHz, CDCl3) δ
163.4, 141.2, 130.7, 129.2, 129.0, 128.0, 125.3, 125.0,
117.0, 114.3, 62.2, 55.6, 36.0, 33.2. HRMS-ESI (m/z):
calcd for C16H16BrNNaO3S [M+Na]+ 403.9926, found
403.9923.
(R)-2-(bromomethyl)-5-phenyl-1-tosylindoline
(7l).
Yiled: 37.5 mg, 85%, colorless oil. [α]D24= -130 (c = 0.1,
CHCl3), 69% ee, determined by HPLC analysis [Daicel
Chiralcel OD-H, 5% i-PrOH /hexane, 1.0 mL/min, λ= 254
1
nm, t(minor) = 11.8 min, t(major) = 16.8 min]. H NMR (600
MHz, CDCl3) δ 7.70 (d, J = 8.4 Hz, 1H), 7.61 (d, J = 8.1
Hz, 2H), 7.52 (d, J = 7.8 Hz, 2H), 7.46 (d, J = 8.3 Hz, 1H),
7.41 (t, J = 7.6 Hz, 2H), 7.32 (dd, J = 15.3, 8.0 Hz, 2H),
7.21 (d, J = 8.1 Hz, 2H), 4.49-4.44 (m, 1H), 3.85 (dd, J =
9.9, 3.6 Hz, 1H), 3.46 (t, J = 9.9 Hz, 1H), 3.04-2.92 (m,
2H), 2.36 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 144.4,
140.5, 140.3, 138.2, 134.5, 131.2, 129.8, 128.8, 127.3,
127.1, 127.0, 126.8, 123.9, 116.9, 62.4, 36.0, 33.3, 21.6.
HRMS-ESI (m/z): calcd for C22H20BrNNaO2S [M+Na]+
464.0290, found 464.0291.
(R)-2-(bromomethyl)-1-(phenylsulfonyl)indoline
(7g).
24
Yield; 28.1 mg, 80%, white solid, mp: 117-119 °C. [α]D
=
-78 (c =0.09, CHCl3), 81% ee, determined by HPLC
analysis [Daicel Chiralcel OJ-H, 5% i-PrOH /hexane, 1.0
mL/min, λ= 254 nm, t(minor) = 13.5 min, t(major) = 16.0 min].
1H NMR (600 MHz, CDCl3) δ 7.68 (dd, J = 12.7, 8.0 Hz,
3H), 7.55 (t, J = 7.4 Hz, 1H), 7.41 (t, J = 7.8 Hz, 2H), 7.24
(t, J = 7.4 Hz, 1H), 7.18-7.04 (m, 2H), 4.47-4.42 (m, 1H),
3.82 (dd, J = 9.9, 3.7 Hz, 1H), 3.42 (t, J = 9.9 Hz, 1H),
2.96-2.87 (m, 2H); 13C NMR (150 MHz, CDCl3) δ 139.9,
136.3, 132.2, 129.5, 128.0, 126.9, 125.9, 124.2, 124.0,
115.7, 61.1, 34.7, 32.0. HRMS-ESI (m/z): calcd for
C15H14BrNNaO2S [M+Na]+, 373.9821, found 373.9814.
(R)-2-(bromomethyl)-5-fluoro-1-tosylindoline
(7m).11
Yield: 30.6 mg, 80%, light yellow solid, mp: 108-109 °C.
[α]D24= -87.5 (c = 0.12, CHCl3), 74% ee, determined by
HPLC analysis [Daical Chiralpak AD-H, 5% i-PrOH
(R)-2-(bromomethyl)-5-methoxy-1-tosylindoline (7h).11
Yield: 32.4 mg, 82%, white solid, mp: 130-132 °C. [α]D
24
/hexane, 1.0 mL/min, λ= 254 nm, t(major) =12.6 min, t(minor)
=
=
13.3 min]. 1H NMR (600 MHz, CDCl3) δ 7.60 (dd, J = 8.8,
4.6 Hz, 1H), 7.54 (d, J = 8.3 Hz, 2H), 7.20 (d, J = 8.1 Hz,
2H), 6.94-6.91 (m, 1H), 6.77 (dd, J = 8.0, 2.4 Hz, 1H),
4.46-4.41 (m, 1H), 3.78 (dd, J = 10.0, 3.8 Hz, 1H), 3.41 (t,
J = 9.9 Hz, 1H), 2.91-2.82 (m, 2H), 2.38 (s, 3H); 13C NMR
(150 MHz, CDCl3) δ 159.7 (d, J = 241.8 Hz), 144.5, 137.2,
134.1, 132.9, 129.8, 127.1, 118.1 (d, J = 8.7 Hz), 114.6 (d,
J = 8.7 Hz), 112.4 (d, J = 24 Hz), 62.6, 35.7, 33.2, 21.6.
HRMS-ESI (m/z): calcd for C16H15BrFNNaO2S [M+Na]+
405.9883, found 405.9864.
-137.5 (c = 0.08, CHCl3), 86% ee, determined by HPLC
analysis [Daicel Chiralcel OD-H, 5% i-PrOH /hexane, 1.0
mL/min, λ= 254 nm, t(minor) = 17.2 min, t(major) = 18.5 min].
1H NMR (600 MHz, CDCl3) δ 7.56 (d, J = 8.8 Hz, 1H),
7.52 (d, J = 8.3 Hz, 2H), 7.18 (d, J = 8.1 Hz, 2H), 6.76 (dd,
J = 8.8, 2.5 Hz, 1H), 6.60 (d, J = 2.3 Hz, 1H), 4.41-4.37 (m,
1H), 3.81-3.74 (m, 4H), 3.37 (t, J = 10.0 Hz, 1H), 2.87-
2.75 (m, 2H), 2.36 (s, 3H); 13C NMR (150 MHz, CDCl3) δ
157.6, 144.2, 134.4, 134.2, 132.6, 129.7, 127.2, 118.2,
113.1, 110.9, 62.5, 55.6, 35.8, 33.3, 21.6. HRMS-ESI (m/z):
calcd for C17H18BrNNaO3S [M+Na]+ 418.0083, found
418.0079.
(R)-2-(bromomethyl)-6-fluoro-1-tosylindoline
(7n).
Yiled: 29.8 mg, 78%, light yellow solid, mp: 120-121 °C.
[α]D15= -15.4 (c = 0.13, CHCl3), 82% ee, determined by
HPLC analysis [Daicel Chiralpak AD-H, 5% i-PrOH
(R)-2-(bromomethyl)-6-methoxy-1-tosylindoline
(7i).
15
Yield: 33.1 mg, 84%, white solid, mp: 125-127 °C. [α]D
=
/hexane, 1.0 mL/min, λ= 254 nm, t(major) = 9.7 min, t(minor)
=
-50 (c = 0.10, CHCl3), 34% ee, determined by HPLC
analysis [Daicel Chiralpak AD-H, 5% i-PrOH /hexane, 1.0
10.3 min)]. 1H NMR (600 MHz, CDCl3) δ 7.60 (d, J = 8.4
5
This article is protected by copyright. All rights reserved.

10.1002/adsc.201700106
Advanced Synthesis & Catalysis
Hz, 2H), 7.40-7.38 (m, 1H), 7.22 (d, J = 7.8 Hz, 2H), 6.98 125.0, 123.2, 122.5, 116.0, 62.4, 35.9, 33.1, 21.6. HRMS-
(dd, J = 7.5, 6.1 Hz, 1H), 6.74-6.71 (m, 1H), 4.47-4.44 (m, ESI (m/z): calcd for C17H15BrF3NNaO2S [M+Na]+
1H), 3.80 (dd, J = 9.9, 3.5 Hz, 1H), 3.44 (t, J = 9.8 Hz, 1H), 455.9851, found 455.9850.
2.90 (d, J = 6.6 Hz, 2H), 2.38 (s, 3H); 13C NMR (150 MHz,
CDCl3) δ 162.5(d, J = 197.4Hz), 143.6, 141.5 (d, J = 12
(R)-2-(bromomethyl)-5-nitro-1-tosylindoline (7t). Yield:
23.5 mg, 57%, yellow solid, mp: 158-161°C. [α]D24= -16.7
(c = 0.06, CHCl3), 51% ee, determined by HPLC analysis
[Daicel Chiralpak AD-H, 5% i-PrOH /hexane, 1.0 mL/min,
Hz), 133.3, 128.9, 126.0, 124.8, 124.7, 110.6 (d, J = 22.6
Hz), 103.7(d, J = 27.8 Hz), 61.9, 34.9, 31.6, 20.6. HRMS-
ESI (m/z): calcd for C16H15BrFNNaO2S [M+Na]+ 405.9883,
found 405.9868.
1
λ= 254 nm, t(major) = 35.7 min, t(minor) = 43.7 min]. H NMR
(600 MHz, CDCl3) δ 8.15 (dd, J = 8.9, 2.2 Hz, 1H), 7.96 (s,
(R)-2-(bromomethyl)-5-chloro-1-tosylindoline
Yield: 27.4 mg, 69%, white solid, mp: 109-111 °C. [α]D
(7o).11 1H), 7.73 (d, J = 8.9 Hz, 1H), 7.64 (d, J = 8.3 Hz, 2H), 7.27
24
=
(d, J = 9.1Hz 2H), 4.58 (m, 1H), 3.84 (dd, J = 10.2, 3.3 Hz,
-42.9 (c = 0.07, CHCl3), 70% ee, determined by HPLC 1H), 3.56 (dd, J = 10.1, 8.9 Hz, 1H), 3.15-3.06 (m, 2H),
analysis [Daicel Chiralpak AD-H, 1% i-PrOH /hexane, 1.0 2.39 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 147.0, 145.3,
mL/min, λ= 254 nm, t(major) = 38.1 min, t(minor) = 42.7 min]. 144.7, 134.2, 131.5, 130.2, 127.0, 124.8, 121.1, 115.2, 62.8,
1H NMR (600 MHz, CDCl3) δ 7.57 (dd, J = 12.3, 8.4 Hz, 36.0, 33.0, 21.6. HRMS-ESI (m/z): calcd for
3H), 7.22-7.18 (m, 3H), 7.04 (s, 1H), 4.45-4.41 (m, 1H), C16H15BrN2NaO4S [M+Na]+ 432.9828, found 432.9800.
3.79 (dd, J = 10.0, 3.7 Hz, 1H), 3.42 (t, J = 9.8 Hz, 1H),
2.93-2.86 (m, 2H), 2.38 (s, 3H); 13C NMR (150 MHz,
(R)-2-(bromomethyl)-4,6-dimethyl-1-tosylindoline (7u).
Yield: 33.4 mg, 85%, colorless oil. [α]D24= -84.6 (c = 0.13,
CHCl3), 75% ee, determined by HPLC analysis [Daicel
Chiralcel OJ-H, 2% i-PrOH /hexane, 1.0 mL/min, λ= 254
CDCl3) δ 143.6, 138.9, 133.2, 131.5, 129.2, 128.9, 127.1,
126.0, 124.4, 116.7, 61.3, 34.8, 32.0, 20.6. HRMS-ESI
(m/z): calcd for C16H15BrClNNaO2S [M+Na]+ 421.9588,
found 421.9589.
1
nm, t(major) = 11.3 min, t(minor) = 14.1 min]. H NMR (600
MHz, CDCl3) δ 7.58 (d, J = 8.2 Hz, 2H), 7.32 (s, 1H), 7.20
(R)-2-(bromomethyl)-6-chloro-1-tosylindoline
(7p). (d, J = 8.1 Hz, 2H), 6.68 (s, 1H), 4.44-4.40 (m, 1H), 3.83
Yield: 30.3 mg, 76%, white solid, mp: 94-97°C. [α]D15= - (dd, J = 9.8, 3.6 Hz, 1H), 3.40 (t, J = 9.9 Hz, 1H), 2.81-
26.7 (c = 0.15, CHCl3), 69% ee, determined by HPLC 2.76 (m, 2H), 2.37 (s, 3H), 2.33 (s, 3H), 2.09 (s, 3H); 13
C
analysis [Daicel Chiralcel OD-H, 2% i-PrOH /hexane, 1.0 NMR (150 MHz, CDCl3) δ 144.2, 140.9, 138.1, 134.6,
mL/min, λ= 254 nm, t(minor) = 9.2 min, t(major) = 9.7 min]. 1H 134.4, 129.8, 127.1, 126.8, 126.3, 114.6, 62.4, 36.4, 32.0,
NMR (600 MHz, CDCl3) δ 7.59 (d, J = 8.2 Hz, 2H), 7.55 21.6, 21.5, 18.7. HRMS-ESI (m/z): calcd for
(d, J = 8.1 Hz, 1H), 7.22 (d, J = 8.1 Hz, 2H), 7.18 (t, J = C18H20BrNNaO2S [M+Na]+ 416.0290, found 416.0277.
8.1 Hz, 1H), 7.02 (d, J = 8.0 Hz, 1H), 4.49-4.40 (m, 1H),
3.83 (dd, J = 10.0, 3.6 Hz, 1H), 3.47 (t, J = 9.8 Hz, 1H),
(R)-2-(bromomethyl)-5,7-dimethyl-1-tosylindoline (7v).
3.02-2.89 (m, 2H), 2.38 (s, 3H); 13C NMR (150 MHz,
24
Yield: 32.6 mg, 83%, white solid, mp: 152-154 °C. [α]D
=
CDCl3) δ 144.7, 142.5, 134.2, 130.9, 130.0, 129.5, 129.1,
127.1, 124.8, 114.6, 61.9, 36.0, 33.0, 21.6. HRMS-ESI
(m/z): calcd for C16H15BrClNNaO2S [M+Na]+ 421.9588,
found 421.9584.
-30 (c =0.10, CHCl3), 32% ee, determined by HPLC
analysis [Daicel Chiralcel OD-H, 2% i-PrOH /hexane, 1.0
mL/min, λ= 254 nm, t(minor) = 11.8 min , t(major) = 13.4 min].
1H NMR (600 MHz, CDCl3) δ 7.38 (d, J = 8.1 Hz, 2H),
7.17 (d, J = 8.0 Hz, 2H), 6.92 (s, 1H), 6.68 (s, 1H), 4.46-
(R)-2-(bromomethyl)-5-bromo-1-tosylindoline
Yield: 36.3 mg, 79%, white solid, mp: 123-125 °C. [α]D
(7q).11 4.42 (m, 1H), 3.55 (dd, J = 10.0, 4.9 Hz, 1H), 3.11 (t, J =
24
=
10.1 Hz, 1H), 2.51 (s, 3H), 2.46 (d, J = 16.3 Hz, 1H), 2.39
-62.5 (c = 0.08, CHCl3), 52% ee, determined by HPLC (s, 3H), 2.28 (s, 3H), 2.11 (dd, J = 16.3, 7.8 Hz, 1H);13C
analysis [Daicel Chiralpak AD-H, 2% i-PrOH /hexane, 1.0 NMR (150 MHz, CDCl3) δ 144.2, 137.7, 136.7, 135.3,
mL/min, λ= 254 nm, t(major) = 22.9 min, t(minor) = 25.4 min]. 134.1, 132.4, 131.3, 129.5, 127.7, 123.2, 64.2, 34.0, 32.3,
1H NMR (600 MHz, CDCl3) δ 7.56 (d, J = 8.1 Hz, 2H), 21.6, 21.0, 19.8. HRMS-ESI (m/z): calcd for
7.53 (d, J = 8.6 Hz, 1H), 7.34 (d, J = 8.6 Hz, 1H), 7.22 (d, J C18H20BrNNaO2S [M+Na]+ 416.0290, found 416.0287.
= 8.1 Hz, 2H), 7.19 (s, 1H), 4.46-4.36 (m, 1H), 3.79 (dd, J
= 10.0, 3.6 Hz, 1H), 3.42 (t, J = 9.8 Hz, 1H), 2.96-2.85 (m,
(R)-2-(bromomethyl)-2-phenyl-1-tosylindoline
Yield: 30.9 mg, 71%, white solid, mp: 167-169 °C. [α]D
(7w).
2H), 2.38 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 144.6,
140.5, 134.2, 132.9, 131.0, 129.9, 128.4, 127.0, 118.1,
117.7, 62.3, 35.8, 33.0, 21.6. HRMS-ESI (m/z): calcd for
C16H15Br2NNaO2S [M+Na]+ 465.9082, found 465.9086.
24
=
+55.6 (c = 0.11, CHCl3), 87% ee, determined by HPLC
analysis [Daicel Chiralpak AD-H, 5% i-PrOH/hexane, 1.0
mL/min, λ= 254 nm, t(minor) = 17.2 min, t(major) = 18.1 min].
1H NMR (600 MHz, CDCl3) δ 7.62 (d, J = 8.2 Hz, 1H),
(R)-2-(bromomethyl)-5-cyano-1-tosylindoline (7r). Yield: 7.24 (d, J = 7.8 Hz, 4H), 7.18 (d, J = 7.4 Hz, 1H), 7.14 (t, J
23.3 mg, 60%, white solid, mp: 132-135 °C. [α]D24= -64 (c = 7.7 Hz, 2H), 7.03 (dd, J = 13.1, 7.8 Hz, 3H), 6.94 (d, J =
= 0.11, CHCl3), 49% ee, determined by HPLC analysis 8.2 Hz, 2H), 4.66 (d, J = 10.5 Hz, 1H), 4.49 (d, J = 10.5 Hz,
([Daicel Chiralcel OD-H, 5% i-PrOH /hexane, 1.0 mL/min, 1H), 3.89 (d, J = 17.1 Hz, 1H), 3.57 (d, J = 17.1 Hz, 1H),
λ= 254 nm, t(minor) = 29.5 min, t(major) = 33.2 min]. 1H NMR 2.29 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 143.2, 142.2,
(600 MHz, CDCl3) δ 7.71 (d, J = 8.4 Hz, 1H), 7.61 (d, J = 140.0, 137.1, 129.0, 128.1, 128.0, 127.6, 127.3, 126.9,
8.3 Hz, 2H), 7.53 (d, J = 8.4 Hz, 1H), 7.35 (s, 1H), 7.26 (d, 124.6, 123.1, 113.4, 73.4, 46.8, 39.9, 21.4. HRMS-ESI
J = 9.2 Hz, 2H), 4.53-4.49 (m, 1H), 3.82 (dd, J = 10.1, 3.3 (m/z): calcd for C22H20BrNNaO2S [M+Na]+ 464.0290,
Hz, 1H), 3.52-3.48 (m, 1H), 3.10-3.01 (m, 2H), 2.39 (s, found 464.0285.
3H); 13C NMR (150 MHz, CDCl3) δ 144.3, 144.1, 133.3,
131.9, 130.4, 129.1, 127.9, 125.9, 117.7, 115.2, 106.9, 61.2,
(R)-2-(bromomethyl)-2-methyl-1-tosylindoline
(7x).
18
34.9, 32.0, 20.6. HRMS-ESI (m/z): calcd for
Yield: 15.5 mg, 41%, white solid, mp: 74-76 °C. [α]D
=
C17H15BrN2NaO2S [M+Na]+ 412.9930, found 412.9918.
+20 (c = 0.10, CHCl3), 20% ee, determined by HPLC
analysis [Daicel Chiralpak AD-H, 5% i-PrOH/hexane, 1.0
mL/min, λ= 254 nm, t(minor) = 12.5 min, t(major) = 15.9 min].
(R)-2-(bromomethyl)-1-tosyl-5-(trifluoromethyl)in-
doline (7s). Yield: 33.7 mg, 78%, white solid, mp: 78- 1H NMR (600 MHz, CDCl3) δ 7.85 (d, J = 8.3 Hz, 2H),
80 °C. [α]D24= -16.7 (c = 0.11, CHCl3), 64% ee, determined 7.43 (d, J = 8.2 Hz, 1H), 7.26 (d, J = 7.8 Hz, 2H), 7.16-
by HPLC analysis [Daicel Chiralpak AD-H, 5% i-PrOH 7.11 (m, 2H), 6.97 (t, J = 7.4 Hz, 1H), 3.98 (d, J = 10.2 Hz,
/hexane, 1.0 mL/min, λ= 254 nm, t(minor) = 10.2 min, t(major) 1H), 3.92 (d, J = 10.2 Hz, 1H), 3.50 (d, J = 16.3 Hz, 1H),
= 11.4 min]. 1H NMR (600 MHz, CDCl3) δ 7.72 (d, J = 8.5 2.92 (d, J = 16.3 Hz, 1H), 2.39 (s, 3H), 1.82-1.75 (m, 3H);
Hz, 1H), 7.61 (d, J = 8.2 Hz, 2H), 7.49 (d, J = 8.4 Hz, 1H), 13C NMR (150 MHz, CDCl3) δ 144.0, 141.8, 138.4, 129.8,
7.32 (s, 1H), 7.24 (d, J = 8.2 Hz, 2H), 4.52-4.48 (m, 1H), 127.8, 127.5, 126.9, 125.1, 123.2, 113.9, 71.5, 42.6, 40.9,
3.83 (dd, J = 10.1, 3.5 Hz, 1H), 3.48 (t, J = 9.7 Hz, 1H), 24.4, 21.6. HRMS-ESI (m/z): calcd for C17H18BrNNaO2S
3.03 (d, J = 5.4 Hz, 2H), 2.38 (s, 3H); 13C NMR (150 MHz, [M+Na]+ 402.0134, found 402.0135.
CDCl3) δ 144.9, 144.3, 134.3, 131.0, 130.0, 127.0, 125.7,
6
This article is protected by copyright. All rights reserved.

10.1002/adsc.201700106
Advanced Synthesis & Catalysis
(R)-2-(bromomethyl)-2-(4-methoxyphenyl)-1-
atmosphere, then the mixture was stirred at room
tosylindoline (7y). Yield: 38.9 mg, 83%, white solid, mp: temperature for 3 h, quenched with saturated NH4Cl (2.0
121-124 °C. 1H NMR (600 MHz, CDCl3) δ 7.64 (d, J = 8.2 mL), and the aqueous layer was extracted with CH2Cl2, The
Hz, 1H), 7.27-7.20 (m, 1H), 7.16 (dd, J = 16.6, 8.1 Hz, 3H), combined organic layers were dried over Na2SO4. The
7.08 (d, J = 8.2 Hz, 2H), 7.02 (t, J = 7.4 Hz, 1H), 6.94 (d, J filtrate was concentrated under reduced pressure and
= 8.1 Hz, 2H), 6.62 (d, J = 8.8 Hz, 2H), 4.65 (d, J = 10.5 purified by flash column chromatography (silica gel, eluent:
Hz, 1H), 4.41 (d, J = 10.5 Hz, 1H), 3.85 (d, J = 17.1 Hz, n-hexane/ethyl acetate = 4/1 to 1/1) to give (S)-2-
1H), 3.78 (s, 3H), 3.54 (d, J = 17.1 Hz, 1H), 2.29 (s, 3H). methylindoline 9.3p 11.0 mg, 90% yield, colorless oil.
13C NMR (150 MHz, CDCl3) δ 159.3, 143.1, 142.2, 137.4, [α]D18= -12.5 (c = 0.08, PhH), 82% ee, determined by
131.8, 128.9, 128.7, 128.1, 127.6, 126.8, 124.6, 123.1, HPLC analysis [Daicel Chiralcel OD-H, 5% i-PrOH
113.5, 113.2, 73.2, 55.3, 46.6, 40.0, 21.4. HRMS-ESI (m/z): /hexane, 1.0 mL/min, λ= 254 nm, t(minor) = 7.6 min, t(major)
=
calcd for C23H22BrNNaO3S [M+Na]+ 494.0401, found 8.6 min]; 1H NMR (600 MHz, CDCl3) δ 7.08 (d, J = 7.2 Hz,
494.0408.
1H), 7.02 (t, J = 7.6 Hz, 1H), 6.71 (dd, J = 10.8, 4.0 Hz,
1H), 6.63 (d, J = 7.7 Hz, 1H), 4.04-3.97 (m, 1H), 3.15 (dd,
J = 15.4, 8.5 Hz, 1H), 2.64 (dd, J = 15.4, 7.8 Hz, 1H), 1.30
(d, J = 6.2 Hz, 3H).; 13C NMR (150 MHz, CDCl3) δ 149.6,
128.0, 126.2, 123.7, 117.7, 108.4, 54.2, 36.7, 21.2. HRMS-
ESI (m/z): calcd for C9H12N [M+H]+ 134.0970, found
134.0976.
(R)-2-(bromomethyl)-1-tosyl-2-(4-(trifluoromethyl)-
phenyl)indoline (7z). Yield: 19.9 mg, 39%, white solid,
mp: 127-130 °C. [α]D18= +11.8 (c = 0.17, CHCl3) 42% ee,
determined by HPLC analysis [Daicel Chiralpak OD-H,
5% i-PrOH/hexane, 1.0 mL/min, λ= 254 nm, t(major) = 7.8
min, t(minor) = 10.2 min]. 1H NMR (600 MHz, CDCl3) δ 7.74
(d, J = 8.2 Hz, 1H), 7.33-7.27 (m, 5H), 7.20 (d, J = 7.4 Hz, Synthesis of (R)-indolin-2-ylmethanol 10.7e, 9c
1H), 7.07 (t, J = 7.4 Hz, 3H), 6.92 (d, J = 8.0 Hz, 2H), 4.72 A flame-dried 10 mL flask was charged with 7a (62.2 mg,
(d, J = 10.7 Hz, 1H), 4.37 (d, J = 10.7 Hz, 1H), 3.91 (d, J = 0.17 mmol, 1.0 equiv, 82% ee), anhydrous KOAc (68.7 mg,
17.2 Hz, 1H), 3.52 (d, J = 17.2 Hz, 1H), 2.29 (s, 3H). 13
C
0.70 mmol, 4.1 equiv), 18-crown-6 (92.4 mg, 0.35 mmol,
NMR (150 MHz, CDCl3) δ 143.64, 143.29, 142.32, 137.27, 2.1 equiv), then dry DMF (4.0 mL) was added to the
129.14, 128.46, 127.75, 127.17, 126.21, 124.89, 124.87， mixture and the resulting solution was stirred at 100 ºC for
124.84, 124.81, 123.52, 113.73, 72.60, 46.82, 39.01, 21.31. 6 h under N2. After the mixture was cooled down to room
HRMS-ESI (m/z): calcd for C23H19BrF3NNaO2S [M+Na]+ temperature, the reaction was diluted with water and the
532.0170, found 532.0163.
aqueous layer was extracted with EtOAc. The combined
organic layers were washed with brine and dried over
Na2SO4. The filtrate was concentrated under reduced
pressure, then K2CO3 (27.6 mg, 0.20 mmol. 1.2 equiv) and
MeOH (5.0 mL) were added to the resulting residue. The
resulting mixture at reflux for 1 h, then 1 N HCl aq. was
slowly added to the solution at 0 ºC and the aqueous layer
was extracted with CH2Cl2. The combined organic layers
were washed with brine and dried over Na2SO4. The filtrate
was concentrated under reduced pressure and the residue
was purified by flash column chromatography (silica gel,
eluent: n-hexanes/ethyl acetate = 4/1 to 1/1) to give (R)-(1-
tosylindolin-2-yl)methanol.13 28.3 mg, 55% yield, white
solid, mp: 92-93°C, [α]D15= -150 (c = 0.12, CHCl3), 81% ee,
determined by HPLC analysis [Daicel Chiralcel OD-H, 2%
i-PrOH /hexane, 1.0 mL/min, λ= 254 nm, t(major) = 27.4 min,
t(minor) = 33.2 min]. 1H NMR (600 MHz, CDCl3) δ 7.70 (d, J
= 8.1 Hz, 1H), 7.53 (d, J = 8.3 Hz, 2H), 7.24-7.20 (m, 1H),
7.18 (d, J = 8.1 Hz, 2H), 7.05 (d, J = 4.7 Hz, 2H), 4.32-
4.28 (m, 1H), 3.72 (d, J = 5.7 Hz, 2H), 2.80 (dd, J = 16.2,
9.8 Hz, 1H), 2.64 (dd, J = 16.3, 3.1 Hz, 1H), 2.36 (s, 3H);
13C NMR (150 MHz, CDCl3) δ 144.3, 141.3, 134.4, 132.0,
129.7, 127.8, 127.2, 125.1, 125.0, 117.7, 65.6, 63.6, 31.3,
21.6. HRMS-ESI (m/z): calcd for C16H16NNaO3S [M+Na]+
326.0827, found 326.0827.
A mixture of (R)-(1-tosylindolin-2-yl)methanol (28.3 mg,
0.09 mmol，1.0 equiv) and Mg powder (11.7 mg, 0.48
mmol, 5.0 equiv) in dry MeOH (1.0 mL) was sonicated
under N2 atmosphere, then the mixture was stirred at room
temperature for 3 h, quenched with saturated NH4Cl (2.0
mL), and the aqueous layer was extracted with CH2Cl2, The
combined organic layers were dried over Na2SO4. The
filtrate was concentrated under reduced pressure and
purified by flash column chromatography (silica gel, eluent:
n-hexanes/ethyl acetate = 4/1 to 1/1) to give the (R)-
indolin-2-ylmethanol (10).14 12.1 mg, 90% yield, pale
yellow oil, [α]D15= -200 (c = 0.13, EtOH), 81% ee,
determined by HPLC analysis [Daicael Chiralpak AD-H,
5% i-PrOH /hexane, 1.0 mL/min, λ= 254 nm, t(minor) = 21.0
min, t(major) = 24.7 min]. 1H NMR (600 MHz, CDCl3) δ 7.10
(d, J = 7.2 Hz, 1H), 7.04 (t, J = 7.6 Hz, 1H), 6.75 (t, J = 7.4
Hz, 1H), 6.69 (d, J = 7.8 Hz, 1H), 4.08 (s, 1H), 3.75 (dd, J
= 10.9, 3.7 Hz, 1H), 3.60 (dd, J = 10.9, 6.3 Hz, 1H), 3.13
(dd, J = 15.7, 9.3 Hz, 1H), 2.86 (dd, J = 15.7, 7.8 Hz, 1H);
13C NMR (150 MHz, CDCl3) δ 150.2, 128.9, 127.4, 124.9,
119.4, 110.2, 65.1, 60.4, 32.0. HRMS-ESI (m/z): calcd for
C9H12NO [M+H]+ 150.0919, found 150.0920.
Preparation of (R)-2-(azidomethyl)-1-tosylindoline (8).3r
To an oven dried flask with a stir bar was added (R)-2-
(bromomethyl)-1-tosylindoline (7a) (36.6 mg, 0.10 mmol,
1.0 equiv, 82% ee) under argon, sodium azide (20 mg, 0.30
mmol, 3.0 equiv) and DMF (2.0 mL). The mixture was
then allowed to stir at room temperature for 24 h, then
quenched by water (25.0 mL) and extracted with EtOAc (5
mL×3). The combined organic layers were washed with
brine, dried by Na2SO4 then dried by Na2SO4, and
concentrated under reduced pressure. The crude residue
was purified by flash column chromatography (silica gel,
gradient eluent: 10% to 20% EtOAc in hexanes) to provide
the azide 8.12 30.5 mg, 93% yield, white crystals, mp: 108-
110 °C. [α]D15= -125 (c = 0.20, CHCl3), 80% ee,
determined by HPLC analysis [Daicel Chiralcel OD-H, 2%
i-PrOH /hexane, 1.0 mL/min, λ= 254 nm, t(minor) = 14.3 min,
t(major) = 15.3 min]. 1H NMR (600 MHz, CDCl3) δ 7.68 (d, J
= 8.1 Hz, 1H), 7.54 (d, J = 8.3 Hz, 2H), 7.25-7.21 (m, 1H),
7.18 (d, J = 8.1 Hz, 2H), 7.08-7.03 (m, 2H), 4.36-4.28 (m,
1H), 3.62 (dd, J = 12.3, 4.4 Hz, 1H), 3.52 (dd, J = 12.3, 7.3
Hz, 1H), 2.85-2.78 (m, 1H), 2.72 (dd, J = 16.4, 2.9 Hz, 1H),
2.36 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 144.2, 141.2,
134.6, 131.1, 129.7, 128.0, 127.1, 125.1, 125.0, 117.3, 61.0,
55.3, 32.1, 21.5. HRMS-ESI (m/z): calcd for
C16H16N4NaO2S [M+Na]+ 351.0892, found 351.0893.
Procedure for synthesis of (S)-2-methylindoline(9).7e, 9c
To a solution of 7a (36.6 mg, 0.1 mmol, 1.0 equiv, 82% ee)
in toluene (10 mL) was added n-Bu3SnH (72.5 mg, 0.25
mmol, 2.5 equiv), then the solution was heated at 80 °C for
15 h. Solvent was removed under reduced pressure and the
residue was purified by flash column chromatography
(silica gel, petro ether/EtOAc=4:1) to give (S)-2-methyl-1-
tosylindoline.3p 27.2 mg, 95% yield, pale pink oil. [α]D15= -
151.9 (c = 0.20, CHCl3), 82% ee, determined by HPLC
analysis [Daicel Chiralpak AD-H, 5% i-PrOH /hexane, 1
mL/min, λ = 254 nm, t(major) = 9.7 min, t(minor) = 13.3 min].
1H NMR (600 MHz, CDCl3) δ 7.65 (d, J = 7.8 Hz, 1H),
7.55 (d, J = 8.4 Hz, 2H), 7.20 (t, J = 7.5 Hz, 1H), 7.16 (d, J
= 7.8 Hz, 2H), 7.05-7.00 (m, 2H), 4.37-4.32 (m, 1H), 2.88
(dd, J = 15.9, 9.4 Hz, 1H), 2.43 (dd, J = 15.9, 2.6 Hz, 1H),
2.34 (s, 3H), 1.42 (d, J = 6.6 Hz, 3H); 13C NMR (150 MHz,
CDCl3) δ 143.7, 141.1, 135.3, 131.6, 129.5, 127.7, 127.0,
125.2, 124.5, 117.2, 58.5, 36.2, 23.4, 21.5. HRMS-ESI
(m/z): calcd for C16H17NNaO2S [M+Na]+ 310.0872, found
310.0878.
A mixture of (S)-2-methyl-1-tosylindoline (27.2 mg,
0.09mmol, 1.0 equiv) and Mg powder (10.7 mg, 0.45 mmol,
5.0 equiv) in dry MeOH (1.0 mL) was sonicated under N2
Acknowledgements
7
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10.1002/adsc.201700106
Advanced Synthesis & Catalysis
This work is founded by the Scientific Research Foundation for
the Returned Overseas Chinese Scholars, State Education
Ministry, and the National Natural Science Foundation of China
(grant no. 21572154).
Wang, Q.-A. Chen, W. Li, C.-B. Yu, Y.-G. Zhou, X.
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Advanced Synthesis & Catalysis
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Advanced Synthesis & Catalysis
UPDATE
Enantioselective Synthesis of 2-Bromomethyl
Indolines
via
BINAP(S)-Catalyzed
Bromoaminocyclization of Allyl Aniline
Adv. Synth. Catal. Year, Volume, Page – Page
Sheng-Nan Yu,a Yin-Long Li,a Jun Deng*a,b
10
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