Chiral Iminophosphorane Organocatalyzed Asymmetric Sulfenyl-ation of 3-Substituted Oxindoles: Substrate-Interrelated Enantio-selectivities

Article abstract of DOI:10.1055/s-0035-1560435

Catalytic asymmetric sulfenylation of 3-substituted oxindoles has been developed through efficient catalysis by tartaric acid derived chiral iminophosphoranes. With N-(phenylthio)phthalimide as the sulfur source, a wide range of optically active 3-phenylt

Full text of DOI:10.1055/s-0035-1560435

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–I
A
special topic
X. Gao et al.
Special Topic
Synthesis
Chiral Iminophosphorane Organocatalyzed Asymmetric Sulfenyl-
ation of 3-Substituted Oxindoles: Substrate-Interrelated Enantio-
selectivities
Xing Gaoa,b
Jianwei Han*b
Limin Wang*a
R1
(Me)/Ar
SPh
(+)-(S)
92–99% yield
up to 90% ee
R2
O
R2
O
N
Boc
N
Boc
catalyst (10 mol%)
a Key Laboratory of Advanced Materials and Institute of Fine
Chemicals, East China University of Science and Technology,
130 Mei Long Road, Shanghai 200237, P. R. of China
wanglimin@ecust.edu.cn
b Shanghai-Hong Kong Joint Laboratory in Chemical Synthesis,
Shanghai Institute of Organic Chemistry, The Chinese Academy
of Sciences, 345 Ling Ling Road, Shanghai, 200032,
P. R. of China
or
+
mesitylene (1 mL)
25 °C
(i-Pr)/Ar
O
SPh
O
(–)-(R)
90–99% yield
up to 90% ee
R2
N
SPh
N
O
Boc
Ar
Ar
Ar
Ar
Ar
Ar
jianweihan@sioc.ac.cn
HN
N
O
O
O
O
Dedicated to Prof. Dr. Dieter Enders on the occasion of his 70th
birthday
P
NH HN
Ar
Ar
catalyst, Ar = p-MeC6H4
Received: 13.01.2016
Accepted after revision: 26.02.2016
Published online: 27.04.2016
Asymmetric sulfenylations employing either stoichio-
metric amounts of chiral agents or chiral auxiliaries have
been reported since 1979,8a and there are a variety of strat-
egies to achieve chiral thio-substituted compounds.8 In re-
cent years, several catalytic methods for the direct asym-
metric sulfenylation of 3-substituted oxindoles have been
developed and the desired products were obtained with
both good yield and excellent enantioselectivities.6 Feng re-
ported catalytic asymmetric sulfenylation of unprotected 3-
substituted oxindoles through cooperative catalysis of a
chiral N,N′-dioxide-Sc(OTf)3 complex in the presence of a
Brønsted base and molecular sieves.6a Simultaneously, the
groups of Enders, Cheng and Jiang reported organocatalytic
sulfenylations of 3-substituted oxindoles independently
with amino-squaramides, cinchona alkaloid or quinidines
derivatives as catalysts.6b,c,d Soon after, Maruoka designed a
family of chiral quaternary phosphonium bromides, which
were applied in this reaction for evaluation of their catalyt-
ic ability as phase-transfer catalysts.9 Very recently, the cat-
alytic asymmetric sulfenylation of 3-pyrrolyl-oxindoles was
achieved by Yuan et al. with cinchonidine as catalyst.6e De-
spite the significant advances that have been achieved in
this field, further exploration of catalytic systems that can
be used to deliver oxindoles bearing a 3-sulfenyl-substitut-
ed quaternary stereocenter with broad substrate scope re-
mains necessary. We recently synthesized a class of chiral
iminophosphoranes that was used as highly effective or-
ganocatalysts in the asymmetric chlorination of 3-substi-
tuted oxindoles.5e In this work, we exploited a similar strat-
egy to catalyze asymmetric sulfenylation of oxindoles by
using N-(phenylthio)phthalimide as the sulfenylating re-
DOI: 10.1055/s-0035-1560435; Art ID: ss-2016-c0026-st
Abstract Catalytic asymmetric sulfenylation of 3-substituted oxin-
doles has been developed through efficient catalysis by tartaric acid de-
rived chiral iminophosphoranes. With N-(phenylthio)phthalimide as the
sulfur source, a wide range of optically active 3-phenylthiooxindoles
were obtained in excellent yields (90–99%) and good enantiomeric ex-
cess (up to 90% ee). Interestingly, 3-aryl and 3-methyl substituted oxin-
doles afforded sulfenylated products in S-configuration, whereas sub-
stituted oxindoles with 3-arylidene or 3-isobutyl substituents gave the
corresponding R-configured sulfenylated products.
Key words organocatalysis, phosphazene, iminophosphorane, sulfe-
nylation, oxindole
Oxindole derivatives have attracted much attention
during the past decades because their core backbone is in-
cluded in many biologically active natural and non-natural
products.1 Enantioselective synthesis of 3,3-disubstituted
oxindoles has been explored intensively in the past, and
various asymmetric synthetic methods have been estab-
lished including organo- and transition-metal catalysis. As
such, many excellent results were achieved with a variety
of 3,3-disubstituted oxindoles. For example, 3-hydroxy-,2 3-
amino-,3 3-fluoro-,4 3-chloro-,5 and 3-thio-substituted6 ox-
indoles were prepared in a catalytic manner. Importantly, it
was reported that many oxindoles with a thio group at the
carbon stereocenter at the 3-position have anticancer, anti-
fungal, or antitubercular activities.7
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

B
X. Gao et al.
Special Topic
Synthesis
agent. Interestingly, we found that stereocontrol based on
changing the substituent in the substrates of 3-substituted
oxindoles afforded the S- or R-configured sulfenylated
products. Herein, we present details of these results.
Initially, we studied the sulfenylation of N-Boc-protect-
ed 3-phenyloxindole 1a with N-(phenylthio)phthalimide
(2) to optimize the reaction conditions and catalysts at
room temperature (Table 1). Firstly, given the ready avail-
ability of iminophosphorane 4a, we used this compound as
catalyst to screen various solvents. Diethyl ether and ethyl
acetate, which were found to be superior in our previous re-
port of asymmetric chlorination,5e gave product 3a in the
sulfenylation in a comparable yield of 95% with the same
enantiomeric excess of 46%. However, the reaction rate was
much faster in ethyl acetate than in diethyl ether based on
analysis by thin-layer chromatography (Table 1, entries 1
and 2). Further screening of the solvents showed that the
use of chloroform and mesitylene led to a slight improve-
ment in the ee to 53 and 57%, respectively (entries 7 and
11). Therefore, mesitylene was selected as solvent to inves-
tigate iminophosphorane catalysts 4b–g in the model reac-
tion, which was carried out at room temperature (entries
12–17). It was found that 4e and 4f were the most suitable
catalysts in this reaction and that catalyst 4e gave the best
enantioselectivity (89% ee). Catalysts 4e and 4f feature alkyl
substituents at the para-position of the aromatic motif
within the iminophosphorane framework (entries 15 and
16). In contrast to 4e and 4f, the use of catalyst 4g, bearing
3,5-dimethyl substituted phenyl rings, gave the desired
product 3a in 71% isolated yield with only 11% ee (entry
17). An attempt to decrease catalyst loading was then per-
formed; the use of 1 mol% catalyst 4e had a clear influence
on both the productivity and the level of enantiodiscrimi-
nation (entry 18; 71% yield, 77% ee). It should be noted that
the reaction was very sluggish when the HCl salt of 4a was
employed as catalyst. Moreover, only a racemic mixture of
3a was obtained in this case (entry 19; 12% yield, 0% ee).
With the optimized reaction conditions described
above, we then explored the generality of the reaction with
respect to substrate scope by varying the structure of N-
Boc-protected oxindoles 1, as summarized in Scheme 1 and
Scheme 2. Scheme 1 shows the results obtained with 3-aryl
and 3-methyl substituted N-Boc-oxindoles 1 with N-(phen-
ylthio)phthalimide (2) under the catalysis of imino-phos-
phorane 4e at 25 °C. Generally, products 3 were obtained in
excellent yields and with good enantiomeric excess after 24
hours (Scheme 1, 3a–n, 92–99% yields, 72–90% ee). In the
case of 7-fluoro substituted oxindoles 3e and 3n, the de-
sired products were obtained in excellent yields but the en-
antiomeric excess was slightly decreased (78 and 76% ee,
respectively). Notably, 3-(2-naphthyl) substituted oxindole
1g gave product 3g in both excellent yield (98%) and with
high enantioselectivity (90% ee). In contrast, the use of 3-
methyl substituted oxindole 1f in this reaction gave prod-
uct 3f in only 72% ee, although with excellent yield (94%).
Notably, the absolute S-configuration of the sulfenylated
oxindole product 3a–n was determined by correlation of
the measured specific rotation values with the correspond-
ing reported data.6b,c
Table 1 Optimization of the Reaction Conditionsa
Ph
O
Ph
SPh
O
cat. 4 (10 mol%)
+
O
N SPh
solvent
25 °C, time
N
N
Boc
O
Boc
1a
2
3a
Ar
Ar
Ar
Ar
4a, Ar = Ph; 4b, Ar = 4-FC6H4
HN
N
O
O
O
4c, Ar = 4-ClC6H4; 4d, Ar = 4-PhC6H4
4e, Ar = 4-MeC6H4; 4f, Ar = 4-tBuC6H4
4g, Ar = 3,5-Me2C6H3
P
O
NH HN
Ar
Ar
Ar
Ar
4
Entry
Cat. 4
Solvent
Time (h)
Yield (%)b ee (%)c
1
2
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4b
4c
4d
4e
4f
Et2O
28
6
95
95
98
99
99
99
94
98
89
93
97
53
44
86
98
99
71
71
12
46
46
10
6
EtOAc
3
THF
9
4
MeOH
6
5
MeCN
6
0
6
CH2Cl2
9
30
53
23
41
31
57
11
4
7
CHCl3
6
8
DCE
6
9
hexane
24
6
10
11
12
13
14
15
16
17
18d
19e
toluene
mesitylene
mesitylene
mesitylene
mesitylene
mesitylene
mesitylene
mesitylene
mesitylene
mesitylene
24
24
24
24
24
24
24
24
24
51
89
86
11
77
0
4g
4e
4a·HCl
a Reaction conditions: 1a (0.1 mmol, 1.0 equiv) and catalyst 4 (10 mol%)
were dissolved in solvent (1 mL), then 2 (1.5 equiv) was added into this stir-
ring solution, after completion of the reaction at 25 °C, the solution mix-
ture was purified directly by silica gel column chromatography to afford
product 3a.
b Isolated yield.
Subsequently, a selection of 3-benzyl-substituted N-
c The enantiopurity of the product was determined by HPLC analysis using a
chiral column (CHIRALCEL OD-H) with hexane–isopropanol as solvent.
d Compound 4e (1 mol%) was used.
Boc-oxindoles
1
were
treated
with
N-(phen-
ylthio)phthalimide 2 under the same reaction conditions;
the results are summarized in Scheme 2. We achieved the
e A premade HCl salt of 4a was used.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

C
X. Gao et al.
Special Topic
Synthesis
R1
R1
N
O
SPh
O
cat. 4e (10 mol%)
R2
O
R2
+
N
SPh
mesitylene (1 mL)
25 °C, 24 h
N
O
Boc
Boc
1
2
3
Ph
(2-naphthyl)
SPh
Ph
Ph
Ph
Ph
Me
SPh
SPh
SPh
SPh
SPh
SPh
Me
MeO
F
O
O
N
O
O
O
O
O
N
N
N
N
N
N
Boc
Boc
3g
Boc
Boc
Boc
Boc
Boc
F
3a
3b
3c
3d
3e
3f
95% yield, 89% ee
92% yield, 82% ee
95% yield, 88% ee
98% yield, 82% ee
99% yield, 78% ee
94% yield, 72% ee
98% yield, 90% ee
F
Me
MeO
Me
F
F
F
SPh
SPh
SPh
SPh
SPh
SPh
SPh
F
Me
F
O
N
O
N
O
N
O
O
O
N
O
N
N
N
Boc
F
Boc
3h
93% yield, 83% ee
Boc
3i
96% yield,86% ee
Boc
Boc
Boc
3l
99% yield, 86% ee
Boc
3j
93% yield, 86% ee
3k
96% yield, 87% ee
3m
97% yield, 80% ee
3n
99% yield, 76% ee
Scheme 1 Substrate scope of the reaction with 3-aryl- or 3-methyl-substituted oxindoles
products 5a–l in excellent yields (90–99%) and with good
enantiomeric excess (66–90% ee); the enantiomeric excess
of 5i–l were lower than those of 5g–h when a fluoro-substi-
tuted benzyl group was present in the para-position of the
phenyl ring (5i–l, 74–80% ee). Product 5e was obtained in
only 66% ee, which, together with the results obtained for
3-aryl products 3e and 3n (Scheme 1), suggested that 7-flu-
oro-substituted oxindoles gave unsatisfactory enantioselec-
tivities with this catalytic system. Of note, 3-isobutyloxin-
dole as a substrate afforded 5f in 96% yield together with
80% ee (Scheme 2, 5f). Interestingly, the absolute R-configu-
ration of products 5a–l was determined by both specific ro-
tation values and high-performance liquid chromatography
(HPLC) data in comparison to the previously reported data
(see Scheme 1 and Scheme 2).6b,c Especially, opposite abso-
lute configurations of 3-methyl- and 3-isobutyloxindoles 3f
and 5f, respectively, were observed.
Additionally, with a selection of iminophosphorane cat-
alysts 4f and 4h (a pair of enantiomers) in hand,5e asym-
metric synthesis of both enantiomeric products of sulfe-
R1
R1
O
SPh
cat. 4e (10 mol%)
R2
O
R2
O
+
N
SPh
SPh
mesitylene (1 mL)
25 °C, 24 h
N
N
O
Boc
Boc
1
2
5
Bn
Bn
Bn
Bn
Bn
SPh
SPh
SPh
SPh
SPh
Me
MeO
F
O
O
O
O
O
O
N
N
N
N
N
N
Boc
Boc
Boc
Boc
Boc
F
Boc
5a
5b
5c
5d
95% yield, 80% ee
5e
98% yield, 66% ee
5f
96% yield, 80% ee
97% yield, 90% ee
99% yield, 87% ee
99% yield, 86% ee
Me
OMe
F
F
F
F
SPh
SPh
SPh
SPh
SPh
SPh
F
Me
MeO
O
N
O
N
O
N
O
O
O
N
N
N
Boc
5g
94% yield, 85% ee
Boc
5h
93% yield, 83% ee
Boc
5i
97% yield, 77% ee
Boc
Boc
Boc
5j
97% yield, 74% ee
5k
90% yield, 80% ee
5l
96% yield, 77% ee
Scheme 2 Substrate scope of the reaction with 3-benzyl- or 3-isobutyl-substituted oxindoles
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

D
X. Gao et al.
Special Topic
Synthesis
Ph
Ph
SPh
O
SPh
O
6, (–)-(R)
96% yield
79% ee
3a, (+)-(S)
99% yield
86% ee
Ar
Ar
N
N
Ar
Ar
Ar
Ar
R
2
2
HN
Boc
Boc
N
O
O
O
O
cat. 4h (10 mol%)
cat. 4f (10 mol%)
P
or
or
Bn
O
mesitylene (1 mL)
25 °C
mesitylene (1 mL)
25 °C
N
NH HN
Bn
SPh
O
SPh
O
Boc
Ar
7, (+)-(S)
97% yield
91% ee
5a, (–)-(R)
97% yield
92% ee
Ar
4h, Ar = 4-tBuC6H4
N
N
Boc
Boc
Scheme 3 Representative examples of stereodivergence
nylated oxindoles with 3-phenyl or 3-benzyl group was at-
tempted. As shown in Scheme 3, the reactions catalyzed by
4f gave the products (S)-3-phenyloxindole 3a and (R)-3-
benzyloxindole 5a in excellent yields and with good enan-
tiomeric excess (99% yield, 86% ee and 97% yield, 92% ee, re-
spectively). Similarly, catalyst 4h delivered the products
(R)-3-phenyloxindole 6 in 96% yield, 79% ee and (S)-3-ben-
zyloxindole 7 in 97% yield, 91% ee under the same condi-
tions.
Chiral Iminophosphorane Organocatalyzed Asymmetric Sulfe-
nylation of 3-Substituted Oxindoles; General Procedure
To a reaction tube was added oxindole 1 (0.1 mmol, 1.0 equiv), 4e
(10.7 mg, 0.01 mmol, 10 mol%) and mesitylene (1 mL, 0.1 M) at 25 °C
with magnetic stirring. N-(Phenylthio)phthalimide (2; 38.3 mg, 0.15
mmol, 1.5 equiv) was then added to the mixture of oxindole and cata-
lyst. After stirring for 24 h at 25 °C, the reaction mixture was purified
directly by silica gel column chromatography to give product 3 or 5.
The ee of the product was determined by chiral HPLC analysis.
In summary, we have developed an organocatalytic,
asymmetric sulfenylation of N-Boc-protected oxindoles by
using N-(phenylthio)phthalimide as the sulfenylating agent.
In the presence of chiral iminophosphoranes as the catalyst,
the reaction proceeded smoothly at room temperature, and
afforded a series of sulfenylated products in excellent yields
(90–99%) and with good enantioselectivities (up to 92% ee).
The sulfenylations extend the substrate scope of asymmet-
ric sulfenylation of 3-substituted oxindoles. In particular,
the reactions provided the corresponding sulfenylation
products with reverse absolute configuration according to
the 3-substituted group of oxindoles. Further investigations
into the mechanism of this catalytic system are in progress
in our laboratory.
(S)-tert-Butyl 2-Oxo-3-phenyl-3-(phenylthio)indoline-1-carboxyl-
ate (3a)
Yield: 39.7 mg (95%); white solid; mp 104–105 °C; [α]D27 +133.4
(c = 1.27, CHCl3); 89% ee determined by chiral HPLC analysis (CHIRAL-
CEL OD-H; 254 nm; n-hexane/i-PrOH, 30:1; 1.0 mL/min): tR = 4.54
(major), 5.85 (minor) min.
1H NMR (300 MHz, CDCl3): δ = 7.71 (d, J = 7.0 Hz, 2 H), 7.61–7.53 (m,
1 H), 7.48–7.30 (m, 4 H), 7.29–7.20 (m, 3 H), 7.19–7.04 (m, 4 H), 1.55
(s, 9 H).
13C NMR (75 MHz, CDCl3): δ = 173.68, 148.85, 139.52, 136.80, 135.89,
130.06, 129.53, 129.32, 129.16, 128.89, 128.76, 128.68, 128.64,
126.51, 124.75, 114.97, 84.38, 63.02, 28.25.
HRMS (ESI): m/z [M + Na]+ calcd for C25H23NO3SNa+: 440.1291; found:
440.1292.
(S)-tert-Butyl 5-Methyl-2-oxo-3-phenyl-3-(phenylthio)indoline-1-
carboxylate (3b)6b
Yield: 39.7 mg (92%); white solid; mp 109–110 °C; [α]D28 +85.5
(c = 1.12, CHCl3); 82% ee determined by chiral HPLC analysis (CHIRAL-
CEL OD-H; 254 nm; n-hexane/i-PrOH, 30:1; 1.0 mL/min): tR = 4.51
(major), 5.76 (minor) min.
1H NMR (300 MHz, CDCl3): δ = 7.71 (dd, J = 8.0, 1.2 Hz, 2 H), 7.47 (d,
J = 8.3 Hz, 1 H), 7.43–7.30 (m, 3 H), 7.29–7.23 (m, 1 H), 7.21 (s, 1 H),
7.19–7.03 (m, 5 H), 2.38 (s, 3 H), 1.55 (s, 9 H).
13C NMR (75 MHz, CDCl3): δ = 173.72, 148.91, 137.17, 136.82, 136.08,
134.39, 130.02, 129.92, 129.65, 128.87, 128.73, 128.69, 128.63,
126.79, 114.80, 84.19, 63.16, 28.27, 21.44.
N-(Phenylthio)phthalimide was used as obtained from commercial
sources (CAS 14204-27-4, TCI, >98.0%). 1,3,5-Trimethylbenzene was
obtained from Shanghai Tianlian Chemical Technology Co., Ltd. (CAS
108-67-8). Flash column chromatography was performed with Sil-
iaFlash® P60 (230–400 mesh, UltraPure SILICA GELS, SiliCycle). 1H,
13C, and 19F NMR spectra were recorded with a Mercury 300 NMR
spectrometer, and TMS was used as a reference. 1H NMR spectroscop-
ic data are represented as follows: chemical shift (ppm), multiplicity
(s = singlet, d = doublet, t = triplet, dd = doublet of doublets,
m = multiplet), coupling constants in hertz (Hz), integration, assign-
ment. 13C and 19F NMR spectroscopic data are reported in ppm. IR
spectra were recorded with a Nicolet iN10 MX spectrometer and are
reported in wavenumbers (cm–1). High-resolution mass spectra were
measured with an Agilent Technologies 6224 TOF LC/MS spectrome-
ter. Enantiomeric excess was measured by HPLC with CHIRALCEL OD-
H on an DIONEX UltiMate 3000, NO.8074238, ThermoScientific. Opti-
cal rotation was measured with an Autopol I, serial number 30575. All
melting points were determined with a digital melting point appara-
tus and are uncorrected. The starting oxindole derivatives were pre-
pared according to reported procedures.10
HRMS (ESI): m/z [M + Na]+ calcd for C26H25NO3SNa+: 454.1447; found:
454.1449.
(S)-tert-Butyl 5-Methoxyl-2-oxo-3-phenyl-3-(phenylthio)indo-
line-1-carboxylate (3c)6c
Yield: 42.5 mg (95%); white solid; mp 132–133 °C; [α]D27 +75.5
(c = 1.48, CHCl3); 88% ee determined by chiral HPLC analysis (CHIRAL-
CEL OD-H; 254 nm; n-hexane/i-PrOH, 50:1; 1.0 mL/min): tR = 7.12
(major), 9.48 (minor) min.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

E
X. Gao et al.
Special Topic
Synthesis
1H NMR (300 MHz, CDCl3): δ = 7.70 (d, J = 7.4 Hz, 2 H), 7.51 (d,
J = 8.9 Hz, 1 H), 7.43–7.30 (m, 3 H), 7.26 (t, J = 7.2 Hz, 1 H), 7.19 (d,
J = 7.8 Hz, 2 H), 7.11 (t, J = 7.7 Hz, 2 H), 6.95 (d, J = 2.5 Hz, 1 H), 6.80
(dd, J = 8.9, 2.7 Hz, 1 H), 3.79 (s, 3 H), 1.53 (s, 9 H).
HRMS (ESI): m/z [M + Na]+ calcd for C20H21NO3SNa+: 378.1134; found:
378.1135.
(S)-tert-Butyl 3-(Naphthalen-2-yl)-2-oxo-3-(phenylthio)indoline-
13C NMR (75 MHz, CDCl3): δ = 173.67, 157.05, 148.90, 136.76, 135.94,
132.98, 130.08, 129.55, 128.91, 128.77, 128.70, 116.07, 115.03,
111.61, 84.18, 63.40, 55.98, 28.26.
HRMS (ESI): m/z [M + Na]+ calcd for C26H25NO4SNa+: 470.1397; found:
470.1397.
1-carboxylate (3g)
Yield: 45.8 mg (98%); white solid; mp 119–120 °C; [α]D28 +111.8
(c = 1.47, CHCl3); 90% ee determined by chiral HPLC analysis (CHIRAL-
CEL OD-H; 254 nm; n-hexane/i-PrOH, 30:1; 1.0 mL/min): tR = 4.82
(major), 7.00 (minor) min.
IR (KBr): 3054, 3003, 2978, 2927, 1792, 1762, 1728, 1603, 1572, 1505,
1475, 1463, 1438, 1393, 1370, 1337, 1306, 1285, 1247, 1144, 1089,
(S)-tert-Butyl 5-Fluoro-2-oxo-3-phenyl-3-(phenylthio)indoline-1-
1019, 996, 839, 816, 769, 757, 704, 691 cm–1
.
carboxylate (3d)6c
Yield: 42.7 mg (98%); white solid; mp 81–82 °C; [α]D27 +129.5
(c = 1.31, CHCl3); 82% ee determined by chiral HPLC analysis (CHIRAL-
CEL OD-H; 254 nm; n-hexane/i-PrOH, 50:1; 1.0 mL/min): tR = 5.43
(major), 7.24 (minor) min.
1H NMR (300 MHz, CDCl3): δ = 7.68 (dd, J = 8.1, 1.5 Hz, 2 H), 7.58 (dd,
J = 9.0, 4.6 Hz, 1 H), 7.44–7.32 (m, 3 H), 7.31–7.23 (m, 1 H), 7.23–7.08
(m, 5 H), 6.96 (td, J = 8.9, 2.8 Hz, 1 H), 1.54 (s, 9 H).
1H NMR (300 MHz, CDCl3): δ = 8.13 (s, 1 H), 7.97–7.79 (m, 4 H), 7.66
(d, J = 7.3 Hz, 1 H), 7.55–7.44 (m, 3 H), 7.35–7.19 (m, 5 H), 7.13 (t,
J = 7.5 Hz, 2 H), 1.58 (s, 9 H).
13C NMR (75 MHz, CDCl3): δ = 173.66, 148.92, 139.57, 136.88, 133.30,
133.26, 130.14, 129.54, 129.46, 129.00, 128.78, 128.74, 128.68,
128.17, 127.81, 126.99, 126.64, 126.57, 126.14, 124.87, 115.09, 84.47,
63.27, 28.29.
13C NMR (75 MHz, CDCl3): δ = 173.32, 160.05 (d, J = 243.9 Hz), 148.78,
136.79, 135.45 (d, J = 2.3 Hz), 135.35, 130.86 (d, J = 8.2 Hz), 130.30,
129.18, 129.04, 128.99, 128.81, 128.51, 116.45 (d, J = 7.8 Hz), 116.08
(d, J = 23.0 Hz), 113.48 (d, J = 24.7 Hz), 84.58, 63.05, 28.23.
HRMS (ESI): m/z [M + Na]+ calcd for C29H25NO3SNa+: 490.1447; found:
490.1447.
(S)-tert-Butyl 3-(4-Methylphenyl)-2-oxo-3-(phenylthio)indoline-
1-carboxylate (3h)6c
19F NMR (282 MHz, CDCl3): δ = –117.44 (td, J = 8.3, 4.6 Hz).
Yield: 40.1 mg (93%); white solid; mp 95–96 °C; [α]D27 +117.9
(c = 1.34, CHCl3); 83% ee determined by chiral HPLC analysis (CHIRAL-
CEL OD-H; 254 nm; n-hexane/i-PrOH, 50:1; 1.0 mL/min): tR = 4.76
(major), 7.14 (minor) min.
HRMS (ESI): m/z [M + Na]+ calcd for C25H22FNO3SNa+: 458.1197;
found: 458.1198.
(S)-tert-Butyl 7-Fluoro-2-oxo-3-phenyl-3-(phenylthio)indoline-1-
carboxylate (3e)
1H NMR (300 MHz, CDCl3): δ = 7.64–7.54 (m, 3 H), 7.48–7.42 (m, 1 H),
7.29–7.05 (m, 9 H), 2.35 (s, 3 H), 1.55 (s, 9 H).
Yield: 43.1 mg (99%); white solid; mp 107–108 °C; [α]D28 +81.0
(c = 1.19, CHCl3); 78% ee determined by chiral HPLC analysis (CHIRAL-
CEL OD-H; 254 nm; n-hexane/i-PrOH, 30:1; 1.0 mL/min): tR = 6.06
(major), 8.69 (minor) min.
13C NMR (75 MHz, CDCl3): δ = 173.33, 148.41, 139.04, 138.21, 136.31,
132.40, 129.54, 129.14, 128.79, 128.58, 128.16, 128.08, 126.03,
124.25, 114.47, 83.82, 62.39, 27.79, 20.92.
IR (KBr): 3067, 3015, 2996, 2981, 2930, 1783, 1722, 1620, 1595, 1581,
1486, 1461, 1454, 1442, 1394, 1369, 1338, 1283, 1263, 1242, 1204,
1143, 1067, 1026, 1005, 990, 924, 864, 842, 801, 785, 769, 747, 732,
HRMS (ESI): m/z [M + Na]+ calcd for C26H25NO3SNa+: 454.1447; found:
454.1448.
701, 694, 668, 617, 582 cm–1
.
(S)-tert-Butyl 3-(4-Methoxyphenyl)-2-oxo-3-(phenylthio)indo-
line-1-carboxylate(3i)6b,c
1H NMR (300 MHz, CDCl3): δ = 7.68 (dd, J = 8.0, 1.5 Hz, 2 H), 7.43–7.09
Yield: 43.0 mg (96%); white solid; mp 91–92 °C; [α]D27 +125.4
(c = 1.44, CHCl3); 86% ee determined by chiral HPLC analysis (CHIRAL-
CEL OD-H; 254 nm; n-hexane/i-PrOH, 50:1; 1.0 mL/min): tR = 8.56
(major), 12.65 (minor) min.
1H NMR (300 MHz, CDCl3): δ = 7.64 (d, J = 8.9 Hz, 2 H), 7.60–7.53 (m,
1 H), 7.48–7.41 (m, 1 H), 7.29–7.19 (m, 3 H), 7.18–7.04 (m, 4 H), 6.91
(d, J = 8.9 Hz, 2 H), 3.79 (s, 3 H), 1.54 (s, 9 H).
13C NMR (75 MHz, CDCl3): δ = 173.42, 159.47, 148.42, 139.02, 136.28,
129.54, 129.25, 128.82, 128.52, 128.18, 127.21, 126.05, 124.26,
114.51, 113.76, 83.85, 62.04, 55.11, 27.79.
(m, 10 H), 7.05–6.95 (m, 1 H), 1.49 (s, 9 H).
13C NMR (75 MHz, CDCl3): δ = 173.23, 148.51 (d, J = 251.8 Hz), 146.97,
136.68, 135.42, 132.38 (d, J = 1.6 Hz), 130.37, 129.17, 129.02, 128.97,
128.40, 126.61 (d, J = 9.9 Hz), 125.63 (d, J = 7.0 Hz), 122.38 (d,
J = 3.6 Hz), 117.25 (d, J = 20.5 Hz), 84.94, 63.43, 27.80.
19F NMR (282 MHz, CDCl3): δ = –120.26 (dd, J = 11.1, 4.2 Hz).
HRMS (ESI): m/z [M + Na]+ calcd for C25H22FNO3SNa+: 458.1197;
found: 458.1198.
(S)-tert-Butyl 3-Methyl-2-oxo-3-(phenylthio)indoline-1-carboxyl-
ate (3f)
HRMS (ESI): m/z [M + Na]+ calcd for C26H25NO4SNa+: 470.1397; found:
470.1397.
Yield: 33.4 mg (94%); colorless syrup; [α]D27 +73.7 (c = 0.89, CHCl3);
72% ee determined by chiral HPLC analysis (CHIRALCEL OD-H; 254
nm; n-hexane/i-PrOH, 30:1; 1.0 mL/min): tR = 4.55 (major), 8.98
(minor) min.
(S)-tert-Butyl 5-Fluoro-3-(4-methylphenyl)-2-oxo-3-(phen-
ylthio)indoline-1-carboxylate (3j)
Yield: 41.8 mg (93%); white solid; mp 141–142 °C; [α]D28 +118.2
(c = 1.31, CHCl3); 86% ee determined by chiral HPLC analysis (CHIRAL-
CEL OD-H; 254 nm; n-hexane/i-PrOH, 30:1; 1.0 mL/min): tR = 4.24
(major), 6.00 (minor) min.
1H NMR (300 MHz, CDCl3): δ = 7.54–7.46 (m, 1 H), 7.43–7.34 (m, 1 H),
7.29–7.04 (m, 7 H), 1.72 (s, 3 H), 1.55 (s, 9 H).
13C NMR (75 MHz, CDCl3): δ = 175.54, 148.85, 138.82, 136.75, 130.28,
129.98, 129.48, 129.20, 128.63, 124.81, 124.00, 114.85, 84.26, 54.85,
28.27, 21.42.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

F
X. Gao et al.
Special Topic
Synthesis
IR (KBr): 3057, 2976, 2918, 1764, 1734, 1608, 1573, 1511, 1482, 1437,
1393, 1368, 1342, 1295, 1264, 1158, 1145, 1094, 1045, 1025, 978,
IR (KBr): 3063, 2984, 2932, 1764, 1732, 1598, 1506, 1478, 1437, 1405,
1392, 1369, 1344, 1298, 1264, 1222, 1145, 1094, 1045, 1026, 1009,
980, 920, 877, 864, 850, 818, 811, 796, 773, 757, 739, 705, 691, 669,
857, 819, 800, 789, 755, 735, 704, 692 cm–1
.
600, 591, 541, 522, 506 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.62–7.51 (m, 3 H), 7.31–7.08 (m, 8 H),
6.95 (td, J = 8.9, 2.6 Hz, 1 H), 2.36 (s, 3 H), 1.54 (s, 9 H).
13C NMR (75 MHz, CDCl3): δ = 173.46, 160.05 (d, J = 243.8 Hz), 148.83,
138.96, 136.76, 135.43 (d, J = 2.3 Hz), 132.33, 131.03 (d, J = 8.3 Hz),
130.24, 129.74, 129.31, 128.79, 128.36, 116.39 (d, J = 7.9 Hz), 116.00
(d, J = 23.0 Hz), 113.45 (d, J = 24.7 Hz), 84.52, 62.88, 28.23, 21.37.
1H NMR (300 MHz, CDCl3): δ = 7.72–7.63 (m, 2 H), 7.57 (dd, J = 9.0,
4.6 Hz, 1 H), 7.32–7.24 (m, 1 H), 7.20–7.03 (m, 7 H), 6.97 (td, J = 8.9,
2.7 Hz, 1 H), 1.54 (s, 9 H).
13C NMR (75 MHz, CDCl3): δ = 173.17, 163.07 (d, J = 249.2 Hz), 160.06
(d, J = 244.4 Hz), 148.70, 136.75, 135.44, 131.09 (d, J = 2.9 Hz), 130.53
(d, J = 8.4 Hz), 130.45 (d, J = 4.0 Hz), 129.03, 128.86, 116.58 (d,
J = 7.7 Hz), 116.25 (d, J = 25.1 Hz), 115.94 (d, J = 21.8 Hz), 113.40 (d,
J = 24.7 Hz), 84.70, 62.34, 28.21.
19F NMR (282 MHz, CDCl3): δ = –113.07 to –113.26 (m), –117.25 (td,
J = 8.3, 4.8 Hz).
HRMS (ESI): m/z [M + Na]+ calcd for C25H21F2NO3SNa+: 476.1102;
19F NMR (282 MHz, CDCl3): δ = –117.56 (td, J = 8.4, 4.7 Hz).
HRMS (ESI): m/z [M + Na]+ calcd for C26H24FNO3SNa+: 472.1353;
found: 472.1356.
(S)-tert-Butyl 3-(4-Fluorophenyl)-5-methyl-2-oxo-3-(phenyl-
thio)indoline-1-carboxylate (3k)
Yield: 43.2 mg (96%); white solid; mp 150–152 °C; [α]D27 +107.7
(c = 1.24, CHCl3); 87% ee determined by chiral HPLC analysis (CHIRAL-
CEL OD-H; 254 nm; n-hexane/i-PrOH, 30:1; 1.0 mL/min): tR = 4.16
(major), 4.93 (minor) min.
found: 476.1102.
(S)-tert-Butyl 7-Fluoro-3-(4-fluorophenyl)-2-oxo-3-(phenyl-
thio)indoline-1-carboxylate (3n)
Yield: 44.9 mg (99%); white solid; mp 96–97 °C; [α]D27 +102.3
(c = 1.17, CHCl3); 76% ee determined by chiral HPLC analysis (CHIRAL-
CEL OD-H; 254 nm; n-hexane/i-PrOH, 30:1; 1.0 mL/min): tR = 5.83
(major), 6.65 (minor) min.
IR (KBr): 3077, 3060, 2986, 2974, 2924, 1760, 1730, 1598, 1572, 1504,
1490, 1472, 1437, 1392, 1368, 1336, 1299, 1281, 1250, 1224, 1152,
1111, 1097, 1045, 1025, 1008, 967, 865, 837, 818, 760, 748, 735, 704,
690, 534, 525, 501 cm–1
.
IR (KBr): 3060, 2982, 2933, 1793, 1755, 1731, 1623, 1601, 1506, 1488,
1463, 1439, 1408, 1395, 1370, 1344, 1290, 1247, 1210, 1145, 1069,
1H NMR (300 MHz, CDCl3): δ = 7.70 (s, 2 H), 7.46 (d, J = 7.6 Hz, 1 H),
7.32–6.92 (m, 9 H), 2.38 (s, 3 H), 1.53 (s, 9 H).
13C NMR (75 MHz, CDCl3): δ = 173.62, 162.93 (d, J = 248.5 Hz), 148.81,
137.14, 136.79, 134.49, 131.77 (d, J = 2.5 Hz), 130.73 (d, J = 8.2 Hz),
130.14, 130.08, 129.47, 128.68, 128.48, 126.70, 115.72 (d, J = 21.6 Hz),
114.91, 84.33, 62.43, 28.23, 21.42.
1013, 873, 843, 812, 779, 767, 750, 734, 692, 581, 519 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.72–7.61 (m, 2 H), 7.34–6.96 (m,
10 H), 1.48 (s, 9 H).
13C NMR (75 MHz, CDCl3): δ = 173.12, 163.04 (d, J = 249.0 Hz), 148.53
(d, J = 251.6 Hz), 146.86, 136.65, 132.01 (d, J = 1.7 Hz), 131.11 (d,
J = 3.2 Hz), 130.49, 130.38, 129.02, 128.98, 126.60 (d, J = 9.9 Hz),
125.72 (d, J = 7.0 Hz), 122.31 (d, J = 3.6 Hz), 117.43 (d, J = 20.6 Hz),
115.92 (d, J = 21.6 Hz), 85.09, 62.69, 27.77.
19F NMR (282 MHz, CDCl3): δ = –113.78 (s).
HRMS (ESI): m/z [M + Na]+ calcd for C26H24FNO3SNa+: 472.1353;
found: 472.1356.
19F NMR (282 MHz, CDCl3): δ = –113.08 to –113.28 (m), –120.06 (dd,
J = 11.1, 4.1 Hz).
HRMS (ESI): m/z [M + Na]+ calcd for C25H21F2NO3SNa+: 476.1102;
(S)-tert-Butyl 3-(4-Fluorophenyl)-2-oxo-3-(phenylthio)indoline-
1-carboxylate (3l)6b,c
Yield: 43.1 mg (99%); white solid; mp 66–67 °C; [α]D27 +145.1
(c = 1.23, CHCl3); 86% ee determined by chiral HPLC analysis (CHIRAL-
CEL OD-H; 254 nm; n-hexane/i-PrOH, 50:1; 1.0 mL/min): tR = 4.69
(major), 5.69 (minor) min.
1H NMR (300 MHz, CDCl3): δ = 7.75–7.66 (m, 2 H), 7.61–7.54 (m, 1 H),
7.45–7.39 (m, 1 H), 7.30–7.20 (m, 3 H), 7.17–7.01 (m, 6 H), 1.54 (s,
9 H).
13C NMR (75 MHz, CDCl3): δ = 173.13, 162.53 (d, J = 249.7 Hz), 148.30,
139.05, 136.33, 131.17, 130.24 (d, J = 8.1 Hz), 129.74, 129.06, 128.91,
128.26, 128.10, 125.98, 124.39, 115.32 (d, J = 21.5 Hz), 114.65, 84.06,
61.86, 27.78.
found: 476.1103.
(R)-tert-Butyl 3-Benzyl-2-oxo-3-(phenylthio)indoline-1-carboxyl-
ate (5a)6b,c
Yield: 41.9 mg (97%); colorless syrup; [α]D27 –42.5 (c = 1.07, CHCl3);
90% ee determined by chiral HPLC analysis (CHIRALCEL OD-H; 254
nm; n-hexane/i-PrOH, 30:1; 1.0 mL/min): tR = 6.58 (major), 5.16 (mi-
nor) min.
1H NMR (300 MHz, CDCl3): δ = 7.47–7.41 (m, 1 H), 7.38–7.31 (m, 1 H),
7.28–7.18 (m, 3 H), 7.17–7.03 (m, 7 H), 7.02–6.94 (m, 2 H), 3.56 (d,
J = 13.4 Hz, 1 H), 3.41 (d, J = 13.4 Hz, 1 H), 1.51 (s, 9 H).
13C NMR (75 MHz, CDCl3): δ = 174.46, 148.62, 139.55, 136.93, 134.88,
130.55, 129.96, 129.15, 128.71, 128.29, 127.74, 127.19, 125.09,
124.38, 114.84, 84.18, 60.40, 41.29, 28.24.
19F NMR (282 MHz, CDCl3): δ = –113.55 to –113.69 (m).
HRMS (ESI): m/z [M + Na]+ calcd for C25H22FNO3SNa+: 458.1197;
found: 458.1198.
HRMS (ESI): m/z [M + Na]+ calcd for C26H25NO3SNa+: 454.1447; found:
454.1450.
(S)-tert-Butyl 5-Fluoro-3-(4-fluorophenyl)-2-oxo-3-(phen-
ylthio)indoline-1-carboxylate (3m)
Yield: 44.0 mg (97%); white solid; mp 119–120 °C; [α]D28 +137.2
(c = 1.28, CHCl3); 80% ee determined by chiral HPLC analysis (CHIRAL-
CEL OD-H; 254 nm; n-hexane/i-PrOH, 30:1; 1.0 mL/min): tR = 4.15
(major), 4.96 (minor) min.
(R)-tert-Butyl 3-Benzyl-5-methyl-2-oxo-3-(phenylthio)indoline-1-
carboxylate (5b)
Yield: 44.1 mg (99%); white solid; mp 135–136 °C; [α]D28 –22.6
(c = 0.90, CHCl3); 87% ee determined by chiral HPLC analysis (CHIRAL-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

G
X. Gao et al.
Special Topic
Synthesis
CEL OD-H; 254 nm; n-hexane/i-PrOH, 50:1; 1.0 mL/min): tR = 7.47
nm; n-hexane/i-PrOH, 200:1; 0.5 mL/min): tR = 43.91 (major), 42.14
(major), 5.39 (minor) min.
(minor) min.
IR (KBr): 3061, 3026, 2969, 2918, 1782, 1713, 1592, 1485, 1454, 1438,
1393, 1370, 1308, 1277, 1254, 1221, 1150, 1117, 1088, 1074, 941,
IR (KBr): 3061, 3032, 2981, 2931, 1789, 1753, 1727, 1624, 1600, 1489,
1465, 1455, 1439, 1394, 1369, 1347, 1292, 1264, 1246, 1188, 1144,
1067, 1024, 1001, 937, 919, 869, 843, 820, 799, 764, 749, 728, 700,
921, 841, 816, 771, 748, 717, 692 cm–1
.
584 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.32–7.20 (m, 5 H), 7.19–7.05 (m, 5 H),
7.02–6.91 (m, 3 H), 3.54 (d, J = 13.4 Hz, 1 H), 3.40 (d, J = 13.4 Hz, 1 H),
2.38 (s, 3 H), 1.51 (s, 9 H).
13C NMR (75 MHz, CDCl3): δ = 174.53, 148.67, 137.21, 136.96, 134.96,
133.97, 130.55, 129.94, 129.75, 129.22, 128.71, 128.27, 127.57,
127.14, 125.46, 114.66, 84.04, 60.32, 41.24, 28.24, 21.46.
1H NMR (300 MHz, CDCl3): δ = 7.33–7.19 (m, 4 H), 7.19–7.01 (m, 6 H),
6.97–6.80 (m, 3 H), 3.54 (d, J = 13.3 Hz, 1 H), 3.35 (d, J = 13.2 Hz, 1 H),
1.39 (s, 9 H).
13C NMR (75 MHz, CDCl3): δ = 174.15, 148.43 (d, J = 251.8 Hz), 146.67,
136.71, 134.30, 131.42 (d, J = 1.8 Hz), 130.31, 130.17, 129.00, 128.76,
128.39, 127.41, 126.65 (d, J = 9.6 Hz), 125.40 (d, J = 7.0 Hz), 120.91 (d,
J = 3.5 Hz), 117.19 (d, J = 20.8 Hz), 84.48, 61.21, 42.02, 27.69.
HRMS (ESI): m/z [M + Na]+ calcd for C27H27NO3SNa+: 468.1604; found:
468.1606.
19F NMR (282 MHz, CDCl3): δ = –119.96 (dd, J = 11.1, 4.1 Hz).
HRMS (ESI): m/z [M + Na]+ calcd for C26H24FNO3SNa+: 472.1353;
(R)-tert-Butyl 3-Benzyl-5-methoxyl-2-oxo-3-(phenylthio)indo-
line-1-carboxylate (5c)
found: 472.1358.
Yield: 45.7 mg (99%); pale-yellow solid; mp 110–111 °C; [α]D29 –18.6
(c = 1.37, CHCl3); 86% ee determined by chiral HPLC analysis (CHIRAL-
CEL OD-H; 254 nm; n-hexane/i-PrOH, 50:1; 1.0 mL/min): tR = 10.73
(major), 7.99 (minor) min.
(R)-tert-Butyl 3-Isobutyl-2-oxo-3-(phenylthio)indoline-1-carbox-
ylate (5f)
Yield: 38.2 mg (96%); colorless oil; [α]D28 –57.5 (c = 1.07, CHCl3); 80%
ee determined by chiral HPLC analysis (CHIRALCEL OD-H; 254 nm; n-
hexane/i-PrOH, 50:1; 0.2 mL/min): tR = 19.21 (major), 20.03
(minor) min.
IR (KBr): 3060, 2979, 2930, 2836, 1765, 1728, 1616, 1488, 1471, 1447,
1434, 1393, 1369, 1334, 1310, 1270, 1249, 1228, 1147, 1106, 1068,
1034, 1008, 922, 844, 823, 769, 750, 701, 691 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.26 (t, J = 8.0 Hz, 4 H), 7.18–7.06 (m,
5 H), 7.05–6.98 (m, 2 H), 6.96 (d, J = 2.5 Hz, 1 H), 6.67 (dd, J = 8.9,
2.5 Hz, 1 H), 3.81 (s, 3 H), 3.54 (d, J = 13.4 Hz, 1 H), 3.40 (d, J = 13.4 Hz,
1 H), 1.51 (s, 9 H).
13C NMR (75 MHz, CDCl3): δ = 174.56, 156.71, 148.63, 136.87, 134.84,
132.97, 130.57, 129.99, 129.09, 128.97, 128.76, 128.33, 127.24,
115.88, 114.58, 110.51, 84.02, 60.63, 55.95, 41.33, 28.24.
IR (KBr): 3054, 2959, 2931, 2871, 1793, 1766, 1731, 1606, 1477, 1466,
1438, 1393, 1369, 1348, 1292, 1252, 1150, 1105, 1073, 1025, 1005,
912, 844, 750, 704, 691, 661, 589 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.50–7.43 (m, 1 H), 7.38–7.31 (m, 1 H),
7.27–7.13 (m, 3 H), 7.11–7.01 (m, 4 H), 2.24 (dd, J = 13.9, 8.0 Hz, 1 H),
2.11 (dd, J = 13.8, 5.7 Hz, 1 H), 1.59–1.45 (m, 1 H), 1.53 (s, 9 H), 0.67
(dd, J = 12.7, 6.6 Hz, 6 H).
HRMS (ESI): m/z [M + Na]+ calcd for C27H27NO4SNa+: 484.1553; found:
484.1555.
13C NMR (75 MHz, CDCl3): δ = 175.01, 148.82, 139.37, 136.90, 129.95,
128.96, 128.54, 128.51, 124.69, 124.54, 114.86, 84.11, 58.92, 42.81,
28.26, 26.35, 23.98, 22.93.
HRMS (ESI): m/z [M + Na]+ calcd for C23H27NO3SNa+: 420.1604; found:
(R)-tert-Butyl 3-Benzyl-5-fluoro-2-oxo-3-(phenylthio)indoline-1-
carboxylate (5d)
420.1604.
Yield: 42.7 mg (95%); white solid; mp 71–72 °C; [α]D28 –39.5 (c = 1.08,
CHCl3); 80% ee determined by chiral HPLC analysis (CHIRALCEL OD-
H; 254 nm; n-hexane/i-PrOH, 50:1; 1.0 mL/min): tR = 7.80 (major),
5.93 (minor) min.
(R)-tert-Butyl 3-(4-Methylbenzyl)-2-oxo-3-(phenylthio)indoline-
1-carboxylate (5g)6b
Yield: 41.9 mg (94%); colorless syrup; [α]D28 –36.0 (c = 1.21, CHCl3);
85% ee determined by chiral HPLC analysis (CHIRALCEL OD-H; 254
nm; n-hexane/i-PrOH, 50:1; 1.0 mL/min): tR = 6.33 (major), 5.90
(minor) min.
IR (KBr): 3033, 2981, 2929, 1767, 1730, 1608, 1483, 1455, 1439, 1394,
1369, 1343, 1298, 1269, 1250, 1225, 1145, 1111, 1068, 1001, 923,
865, 843, 820, 750, 700, 689 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.35–7.19 (m, 4 H), 7.18–7.05 (m, 6 H),
7.03–6.95 (m, 2 H), 6.81 (td, J = 8.9, 2.4 Hz, 1 H), 3.56 (d, J = 13.4 Hz,
1 H), 3.35 (d, J = 13.4 Hz, 1 H), 1.50 (s, 9 H).
13C NMR (75 MHz, CDCl3): δ = 174.18, 159.81 (d, J = 243.5 Hz), 148.49,
136.86, 135.46 (d, J = 2.3 Hz), 134.50, 130.47, 130.17, 129.82 (d,
J = 8.2 Hz), 128.86, 128.74, 128.45, 127.38, 116.25 (d, J = 7.9 Hz),
115.80 (d, J = 22.9 Hz), 112.20 (d, J = 24.6 Hz), 84.43, 60.54, 41.25,
28.22.
1H NMR (300 MHz, CDCl3): δ = 7.46 (d, J = 6.4 Hz, 1 H), 7.36 (d,
J = 7.3 Hz, 1 H), 7.29–7.19 (m, 3 H), 7.19–7.08 (m, 4 H), 6.88 (s, 4 H),
3.53 (d, J = 13.4 Hz, 1 H), 3.39 (d, J = 13.4 Hz, 1 H), 2.18 (s, 3 H), 1.52 (s,
9 H).
13C NMR (75 MHz, CDCl3): δ = 174.55, 148.66, 139.55, 136.92, 136.68,
131.75, 130.44, 129.95, 129.15, 129.10, 129.03, 128.70, 127.86,
125.11, 124.39, 114.83, 84.17, 60.46, 40.78, 28.25, 21.29.
HRMS (ESI): m/z [M + Na]+ calcd for C27H27NO3SNa+: 468.1604; found:
468.1605.
19F NMR (282 MHz, CDCl3): δ = –117.91 (td, J = 8.3, 4.5 Hz).
HRMS (ESI): m/z [M + Na]+ calcd for C26H24FNO3SNa+: 472.1353;
found: 472.1357.
(R)-tert-Butyl 3-(4-Methoxybenzyl)-2-oxo-3-(phenylthio)indo-
line-1-carboxylate (5h)
Yield: 42.9 mg (93%); pale-yellow syrup; [α]D29 –37.7 (c = 1.22, CHCl3);
83% ee determined by chiral HPLC analysis (CHIRALCEL OD-H; 254
nm; n-hexane/i-PrOH, 50:1; 1.0 mL/min): tR = 9.74 (major), 8.69
(minor) min.
(R)-tert-Butyl 3-Benzyl-7-fluoro-2-oxo-3-(phenylthio)indoline-1-
carboxylate (5e)
Yield: 44.1 mg (98%); colorless syrup; [α]D29 –7.9 (c = 1.31, CHCl3);
66% ee determined by chiral HPLC analysis (CHIRALCEL OD-H; 254
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

H
X. Gao et al.
Special Topic
Synthesis
IR (KBr): 3053, 2979, 2930, 2835, 1792, 1763, 1731, 1610, 1583, 1512,
1477, 1465, 1438, 1393, 1369, 1347, 1290, 1249, 1147, 1106, 1077,
(R)-tert-Butyl 3-(4-Fluorobenzyl)-5-methyl-2-oxo-3-(phenyl-
thio)indoline-1-carboxylate (5k)
Yield: 41.7 mg (90%); white solid; mp 88–89 °C; [α]D29 –24.8 (c = 0.73,
CHCl3); 80% ee determined by chiral HPLC analysis (CHIRALCEL OD-
H; 254 nm; n-hexane/i-PrOH, 50:1; 0.5 mL/min): tR = 11.01 (major),
11.59 (minor) min.
1035, 1003, 937, 892, 827, 754, 703, 692, 582, 550, 527 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.45 (d, J = 7.0 Hz, 1 H), 7.35 (d,
J = 7.8 Hz, 1 H), 7.29–7.06 (m, 7 H), 6.90 (d, J = 8.5 Hz, 2 H), 6.60 (d,
J = 8.5 Hz, 2 H), 3.66 (s, 3 H), 3.50 (d, J = 13.5 Hz, 1 H), 3.36 (d,
J = 13.5 Hz, 1 H), 1.52 (s, 9 H).
13C NMR (75 MHz, CDCl3): δ = 174.59, 158.60, 148.61, 139.56, 136.89,
131.62, 129.92, 129.14, 129.11, 128.69, 127.85, 126.84, 125.05,
124.39, 114.85, 113.63, 84.18, 60.50, 55.26, 40.38, 28.23.
IR (KBr): 3004, 2977, 2930, 1785, 1714, 1603, 1508, 1484, 1438, 1393,
1370, 1331, 1306, 1275, 1250, 1222, 1149, 1121, 1080, 944, 923, 876,
830, 815, 769, 750, 725, 705, 693 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.30–7.18 (m, 5 H), 7.13 (t, J = 7.5 Hz,
2 H), 6.97–6.86 (m, 3 H), 6.74 (t, J = 8.6 Hz, 2 H), 3.48 (d, J = 13.5 Hz,
1 H), 3.34 (d, J = 13.5 Hz, 1 H), 2.37 (s, 3 H), 1.49 (s, 9 H).
HRMS (ESI): m/z [M + Na]+ calcd for C27H27NO4SNa+: 484.1553; found:
484.1550.
13C NMR (75 MHz, CDCl3): δ = 174.43, 162.00 (d, J = 245.4 Hz), 148.58,
137.23, 136.97, 134.08, 132.07 (d, J = 8.0 Hz), 130.68 (d, J = 3.2 Hz),
129.99, 129.89, 129.08, 128.73, 127.34, 125.29, 115.14 (d, J = 21.2 Hz),
114.74, 84.16, 60.20, 40.38, 28.22, 21.44.
19F NMR (282 MHz, CDCl3): δ = –115.92 to –116.08 (m).
HRMS (ESI): m/z [M + Na]+ calcd for C27H26FNO3SNa+: 486.1510;
(R)-tert-Butyl 3-(4-Fluorobenzyl)-2-oxo-3-(phenylthio)indoline-
1-carboxylate (5i)
Yield: 43.6 mg (97%); white solid; mp 99–100 °C; [α]D28 –38.2
(c = 1.04, CHCl3); 77% ee determined by chiral HPLC analysis (CHIRAL-
CEL OD-H; 254 nm; n-hexane/i-PrOH, 50:1; 1.0 mL/min): tR = 5.86
(major), 6.32 (minor) min.
found: 486.1511.
IR (KBr): 3062, 3012, 2981, 2931, 1758, 1736, 1604, 1508, 1480, 1465,
1440, 1393, 1369, 1348, 1306, 1289, 1250, 1215, 1163, 1149, 1076,
(R)-tert-Butyl 3-(4-Fluorobenzyl)-5-methoxyl-2-oxo-3-(phenyl-
thio)indoline-1-carboxylate (5l)
1003, 841, 824, 773, 762, 744, 691 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.48–7.42 (m, 1 H), 7.35 (d, J = 8.2 Hz,
1 H), 7.29–7.07 (m, 7 H), 6.94 (dd, J = 8.3, 5.6 Hz, 2 H), 6.75 (t,
J = 8.7 Hz, 2 H), 3.53 (d, J = 13.5 Hz, 1 H), 3.37 (d, J = 13.5 Hz, 1 H), 1.52
(s, 9 H).
Yield: 46.0 mg (96%); pale-yellow solid; mp 114–115 °C; [α]D29 –20.2
(c = 1.37, CHCl3); 77% ee determined by chiral HPLC analysis (CHIRAL-
CEL OD-H; 254 nm; n-hexane/i-PrOH, 50:1; 1.0 mL/min): tR = 7.57
(major), 8.45 (minor) min.
13C NMR (75 MHz, CDCl3): δ = 174.42, 162.02 (d, J = 245.5 Hz), 148.51,
139.53, 136.94, 132.09 (d, J = 8.0 Hz), 130.58 (d, J = 3.3 Hz), 130.03,
129.30, 128.94, 128.74, 127.48, 124.94, 124.48, 115.18 (d, J = 21.2 Hz),
114.93, 84.35, 60.31, 40.35, 28.21.
19F NMR (282 MHz, CDCl3): δ = –115.82 to –115.96 (m).
HRMS (ESI): m/z [M + Na]+ calcd for C26H24FNO3SNa+: 472.1353;
IR (KBr): 3056, 3003, 2973, 2935, 1785, 1712, 1615, 1601, 1572, 1509,
1487, 1440, 1393, 1369, 1320, 1286, 1269, 1248, 1233, 1221, 1176,
1150, 1078, 1041, 944, 888, 831, 814, 767, 752, 725, 704, 695, 658,
623, 564 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.31–7.21 (m, 4 H), 7.14 (t, J = 7.6 Hz,
2 H), 6.99–6.91 (m, 3 H), 6.77 (t, J = 8.6 Hz, 2 H), 6.68 (dd, J = 8.9,
2.4 Hz, 1 H), 3.82 (s, 3 H), 3.50 (d, J = 13.5 Hz, 1 H), 3.34 (d, J = 13.5 Hz,
1 H), 1.50 (s, 9 H).
found: 472.1359.
(R)-tert-Butyl 5-Fluoro-3-(4-fluorobenzyl)-2-oxo-3-(phenyl-
thio)indoline-1-carboxylate (5j)
Yield: 45.4 mg (97%); colorless syrup; [α]D29 –36.8 (c = 1.36, CHCl3);
74% ee determined by chiral HPLC analysis (CHIRALCEL OD-H; 254
nm; n-hexane/i-PrOH, 50:1; 1.0 mL/min): tR = 5.84 (major), 6.56
(minor) min.
13C NMR (75 MHz, CDCl3): δ = 174.44, 162.04 (d, J = 245.5 Hz), 156.78,
148.54, 136.87, 132.97, 132.08 (d, J = 8.0 Hz), 130.56 (d, J = 3.2 Hz),
130.03, 128.95, 128.78, 115.96, 115.19 (d, J = 21.2 Hz), 114.50, 110.49,
84.14, 60.54, 55.94, 40.46, 28.21.
19F NMR (282 MHz, CDCl3): δ = –115.76 to –115.90 (m).
HRMS (ESI): m/z [M + Na]+ calcd for C27H26FNO4SNa+: 502.1459;
IR (KBr): 3057, 2981, 2930, 1792, 1766, 1732, 1606, 1509, 1482, 1456,
1439, 1418, 1394, 1370, 1344, 1297, 1269, 1223, 1146, 1111, 1070,
1016, 1003, 942, 910, 892, 866, 830, 796, 748, 735, 703, 692, 611, 590,
found: 502.1460.
561 cm–1
.
Acknowledgment
1H NMR (300 MHz, CDCl3): δ = 7.36–7.18 (m, 4 H), 7.18–7.08 (m, 3 H),
6.98–6.88 (m, 2 H), 6.86–6.71 (m, 3 H), 3.52 (d, J = 13.5 Hz, 1 H), 3.30
(d, J = 13.5 Hz, 1 H), 1.49 (s, 9 H).
13C NMR (75 MHz, CDCl3): δ = 174.09, 162.10 (d, J = 246.0 Hz), 159.83
(d, J = 243.8 Hz), 148.39, 136.86, 135.46 (d, J = 2.2 Hz), 132.02 (d,
J = 8.0 Hz), 130.24 (d, J = 2.2 Hz), 130.22, 129.60 (d, J = 8.1 Hz), 128.88,
128.58, 116.36 (d, J = 7.9 Hz), 115.95 (d, J = 22.9 Hz), 115.34 (d,
J = 21.3 Hz), 112.05 (d, J = 24.6 Hz), 84.56, 60.47, 40.36, 28.19.
This work was supported by grants from the National Nature Science
Foundation of China (NSFC Nos. 21472213, 21202186), as well as by
the Croucher Foundation (Hong Kong) in the form of a CAS-Croucher
Foundation Joint Laboratory Grant. This research program was per-
formed under the auspices of Professor Henry N. C. Wong, whom we
thank for helpful discussions and generous support.
19F NMR (282 MHz, CDCl3): δ = –115.41 to –115.60 (m), –117.70 (td,
J = 8.3, 4.6 Hz).
Supporting Information
Supporting information for this article is available online at
HRMS (ESI): m/z [M + Na]+ calcd for C26H23F2NO3SNa+: 490.1259;
found: 490.1260.
http://dx.doi.org/10.1055/s-0035-1560435.
S
u
p
p
o
nrtIo
g
f
rmoaitn
S
u
p
p
ortiInfogrmoaitn
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

I
X. Gao et al.
Special Topic
Synthesis
References
Nakamura, S.; Toru, T.; Shiro, M. Angew. Chem. Int. Ed. 2008, 47,
4157. (h) Zhang, Y.; Yang, X. J.; Xie, T.; Chen, G. L.; Zhu, W. H.;
Zhang, X. Q.; Yang, X. Y.; Wu, X. Y.; He, X. P.; He, H. M. Tetrahe-
dron 2013, 69, 4933. (i) Wang, F. J.; Li, J. L.; Hu, Q. Y.; Yang, X. J.;
Wu, X. Y.; He, H. M. Eur. J. Org. Chem. 2014, 3607. (j) Zhang, R.;
Wang, D.; Xu, Q.; Jiang, J. J.; Shi, M. Chin. J. Chem. 2012, 30, 1295.
(5) (a) Zheng, W.; Zhang, Z.; Kaplan, M. J.; Antilla, J. C. J. Am. Chem.
Soc. 2011, 133, 3339. (b) Zhao, M. X.; Zhang, Z. W.; Chen, M. X.;
Tang, W. H.; Shi, M. Eur. J. Org. Chem. 2011, 3001. (c) Wang, D.;
Jiang, J. J.; Zhang, R.; Shi, M. Tetrahedron: Asymmetry 2011, 22,
1133. (d) Shibata, N.; Kohno, J.; Takai, K.; Ishimaru, T.;
Nakamura, S.; Toru, T.; Kanemasa, S. Angew. Chem. Int. Ed. 2005,
44, 4204. (e) Gao, X.; Han, J. W.; Wang, L. M. Org. Lett. 2015, 17,
4596.
(6) (a) Cai, Y.; Li, J.; Chen, W.; Xie, M.; Liu, X.; Lin, L.; Feng, X. Org.
Lett. 2012, 14, 2726. (b) Wang, C.; Yang, X.; Loh, C. C. J.; Raabe,
G.; Enders, D. Chem. Eur. J. 2012, 18, 11531. (c) Li, X.; Liu, C.;
Xue, X.-S.; Cheng, J.-P. Org. Lett. 2012, 14, 4374. (d) Han, Z.;
Chen, W.; Dong, S.; Yang, C.; Liu, H.; Pan, Y.; Yan, L.; Jiang, Z. Org.
Lett. 2012, 14, 4670. (e) You, Y.; Wu, Z. J.; Wang, Z. H.; Xu, X. Y.;
Zhang, X. M.; Yuan, W. C. J. Org. Chem. 2015, 80, 8470. (f) Huang,
L. S.; Li, J. T.; Zhao, Y.; Ye, X. Y.; Liu, Y.; Yan, L.; Tan, C. H.; Liu, H.
J.; Jiang, Z. Y. J. Org. Chem. 2015, 80, 8933. (g) For a recent
review, see: Chauhan, P.; Mahajan, S.; Enders, D. Chem. Rev.
2014, 114, 8807.
(1) For reviews, see: (a) Dounay, A. B.; Overman, L. E. Chem. Rev.
2003, 103, 2945. (b) Lin, H.; Danishefsky, S. J. Angew. Chem. Int.
Ed. 2003, 42, 36. (c) Galliford, C. V.; Scheidt, K. A. Angew. Chem.
Int. Ed. 2007, 46, 8748. For examples, see: (d) Malinakova, H. C.;
Liebeskind, L. S. Org. Lett. 2000, 2, 4083. (e) Wearing, X. Z.; Cook,
J. M. Org. Lett. 2002, 4, 4237. (f) Albrecht, B. K.; Williams, R. M.
Org. Lett. 2003, 5, 197. (g) Reisman, S. E.; Ready, J. M.; Weiss, M.
M.; Hasuoka, A.; Hirata, M.; Tamaki, K.; Ovaska, T. V.; Smith, C.
J.; Wood, J. L. J. Am. Chem. Soc. 2008, 130, 2087. (h) Trost, B. M.;
Brennan, M. K. Synthesis 2009, 3003. (i) Zhou, F.; Liu, Y. L.; Zhou,
J. Adv. Synth. Catal. 2010, 352, 1381. (j) Badillo, J. J.; Hanhan, N.
V.; Franz, A. K. Curr. Opin. Drug Discovery Dev. 2010, 13, 758.
(k) Shen, K.; Liu, X.; Lin, L.; Feng, X. Chem. Sci. 2012, 3, 327.
(2) (a) Bui, T.; Candeias, N. R.; Barbas, C. F. III J. Am. Chem. Soc. 2010,
132, 5574. (b) Liu, Y. L.; Wang, B. L.; Cao, J. J.; Chen, L.; Zhang, Y.
X.; Wang, C.; Zhou, J. J. Am. Chem. Soc. 2010, 132, 15176.
(c) Zhang, Z.; Zheng, W.; Antilla, J. C. Angew. Chem. Int. Ed. 2011,
50, 1135. (d) Yang, Y.; Moinodeen, F.; Chin, W.; Ma, T.; Jiang, Z.
Y.; Tan, C. H. Org. Lett. 2012, 14, 4762. (e) Ishimaru, T.; Shibata,
N.; Nagai, J.; Nakamura, S.; Toru, T.; Kanemasa, S. J. Am. Chem.
Soc. 2006, 128, 16488. (f) Sano, D.; Nagata, K.; Itoh, T. Org. Lett.
2008, 10, 1593. (g) Liao, Y. H.; Wu, Z. J.; Han, W. Y.; Zhang, X. M.;
Yuan, W. C. Chem. Eur. J. 2012, 18, 8916.
(3) (a) Yang, Z.; Wang, Z.; Bai, S.; Shen, K.; Chen, D.; Liu, X.; Lin, L.;
Feng, X. Chem. Eur. J. 2010, 16, 6632. (b) Bui, T.; Hernández-
Torres, G.; Milite, C.; Barbas, C. F. III Org. Lett. 2010, 12, 5696.
(c) Mouri, S.; Chen, Z.; Mitsunuma, H.; Furutachi, M.;
Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2010, 132, 1255.
(d) Shen, K.; Liu, X.; Wang, G.; Lin, L.; Feng, X. Angew. Chem. Int.
Ed. 2011, 50, 4684. (e) Bui, T.; Borregan, M.; Barbas, C. F. III
J. Org. Chem. 2009, 74, 8935. (f) Zhang, T.; Cheng, L.; Liu, L.;
Wang, D.; Chen, Y. J. Tetrahedron: Asymmetry 2010, 21, 2800.
(g) Companyo, X.; Valero, G.; Pineda, O.; Calvet, T.; Font-Bard,
M.; Moyano, A.; Rios, R. Org. Biomol. Chem. 2012, 10, 431.
(h) Cheng, L.; Liu, L.; Wang, D.; Chen, Y. J. Org. Lett. 2009, 11,
3874. (i) Zhou, F.; Ding, M.; Liu, Y. L.; Wang, C. H.; Ji, C. B.; Zhang,
Y. Y.; Zhou, J. Adv. Synth. Catal. 2011, 353, 2945. (j) Jia, L. N.;
Huang, J.; Peng, L.; Wang, L. L.; Bai, J. F.; Tian, F.; He, G. Y.; Xu, X.
Y.; Wang, L. X. Org. Biomol. Chem. 2012, 10, 236. (k) Qian, Z. Q.;
Zhou, F.; Du, T. P.; Wang, B. L.; Ding, M.; Zhao, X. L.; Zhou, J.
Chem. Commun. 2009, 6753.
(7) (a) Mehta, R. G.; Liu, J.; Constantinou, A.; Hawthorne, M.;
Pezzuto, J. M.; Moon, R. C.; Moriarty, R. M. Anticancer Res. 1994,
14, 1209. (b) Pedras, M. S. C.; Hossain, M. Org. Biomol. Chem.
2006, 4, 2581. (c) Dandia, A.; Sati, M.; Arya, K.; Sharma, R.;
Loupy, A. Chem. Pharm. Bull. 2003, 51, 1137.
(8) (a) Hiroi, K.; Nishida, M.; Nakayama, A.; Nakazawa, K.; Fujii, E.;
Sato, S. Chem. Lett. 1979, 8, 969. (b) Yura, T.; Iwasawa, N.; Clark,
R.; Mukaiyama, T. Chem. Lett. 1986, 15, 1809. (c) Youn, J. H.;
Herrmann, R.; Ugi, I. Synthesis 1987, 159. (d) Poli, G. J. Org.
Chem. 1993, 58, 3165. (e) Enders, D.; Schäfer, T.; Piva, O.;
Zamponi, A. Tetrahedron 1994, 50, 3349. (f) Enders, D.;
Zamponi, A.; Schäfer, T.; Nübling, C.; Eichenauer, H.; Demir, A.
S.; Raabe, G. Chem. Ber. 1994, 127, 1707. (g) Chibale, K.; Warren,
S. Tetrahedron Lett. 1994, 35, 3991. (h) Enders, D.; Schäer, T.;
Mies, W. Tetrahedron 1998, 54, 10239. (i) Evans, D. A.; Cempos,
K. R.; Tedrow, J. S.; Michael, F. E.; Gagn, M. R. J. Am. Chem. Soc.
2000, 122, 7905. (j) Ohata, K.; Terashima, S. Tetrahedron Lett.
2006, 47, 2787.
(4) (a) Deng, Q. H.; Wadepohl, H.; Gade, L. H. Chem. Eur. J. 2011, 17,
14922. (b) Wu, L.; Falivene, L.; Drinkel, E.; Grant, S.; Linden, A.;
Cavallo, L.; Dorta, R. Angew. Chem. Int. Ed. 2012, 51, 2870. (c) Gu,
X.; Zhang, Y.; Xu, Z.-J.; Che, C.-M. Chem. Commun. 2014, 50,
7870. (d) Li, J.; Cai, Y.; Chen, W.; Liu, X.; Lin, L.; Feng, X. J. Org.
Chem. 2012, 77, 9148. (e) Shibata, N.; Suzuki, E.; Asahi, T.; Shiro,
M. J. Am. Chem. Soc. 2001, 123, 7001. (f) Shibata, N.; Ishimaru,
T.; Nakamura, S.; Toru, T. J. Fluorine Chem. 2007, 128, 469.
(g) Ishimaru, T.; Shibata, N.; Horikawa, T.; Yasuda, N.;
(9) Shirakawa, S.; Kasai, A.; Tokuda, T.; Maruoka, K. Chem. Sci. 2013,
4, 2248.
(10) (a) Hamashima, Y.; Suzuki, T.; Takano, H.; Shimura, Y.; Sodeoka,
M. J. Am. Chem. Soc. 2005, 127, 10164. (b) Rajeswaran, W. G.;
Cohen, L. A. Tetrahedron 1998, 54, 11375. (c) Ishimaru, T.;
Shibata, N.; Nagai, J.; Nakamura, S.; Toru, T.; Kanemasa, S. J. Am.
Chem. Soc. 2006, 128, 16488.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I