Palladium-Catalyzed Oxidation-Hydroxylation and Oxidation-Methoxylation of N -Boc Indoles for the Synthesis of 3-Oxoindolines

Article abstract of DOI:10.1055/s-0036-1589032

The palladium-catalyzed oxidation-hydroxylation and oxidation-methoxylation of N -Boc indoles for the synthesis of tert -butyl 2-hydroxy(methoxy)-3-oxoindoline-1-carboxylates and their derivatives is developed. The process occurs readily using PdCl ₂ as the catalyst and acetonitrile as the solvent to afford 3-oxoindolines in moderate to high yields. A mechanism for this Pd-catalyzed oxidation-hydroxylation and oxidation-methoxylation of N -Boc indoles is proposed.

Full text of DOI:10.1055/s-0036-1589032

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2017, 49, A–H
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A
en
X.-Y. Zhou et al.
Paper
Synthesis
Palladium-Catalyzed Oxidation-Hydroxylation and Oxidation-
Methoxylation of N-Boc Indoles for the Synthesis of 3-Oxoindolines
Xiao-Yu Zhou*a
O
OH
R
Xia Chen*a
Liang-Guang Wangb
Dan Yanga
TsOH·H2O (20 mol%)
MeCN
R'
N
Boc
PdCl2 (5.0 mol%)
H2O2 (12.0 equiv)
Zhi Lia
Up to 92% yield
R
R'
40 °C
N
a Department of Chemistry and Chemical Engineering, Liupanshui
Normal University, Liupanshui, 553004, P. R. of China
zhouxiaoyu20062006@126.com
b College of Chemistry and Chemical Engineering, Anshun
University, Anshun, 561000, P. R. of China
Boc
O
OMe
R = H, alkyl, cycloalkyl or Ph
R' = H, Me, MeO or Cl
MeCN/MeOH (5:1)
R'
R
N
Boc
Up to 96% yield
Received: 22.02.2017
Accepted after revision: 20.04.2014
Published online: 18.05.2017
selectivities. Fortunately, a few methods for the transition-
metal-catalyzed oxidation of indoles have been reported.
The Ru–porphyrin-catalyzed oxidation of N-Ts indoles to
obtain 3-oxoindolines was achieved by Che and co-work-
ers8 using 2,6-Cl2PyNO as the oxidant, which is efficient and
highly selective. Recently, palladium-catalyzed oxidative
dearomatization of indoles was reported by Guchhait’s
group9 for the synthesis of C2-quaternary indolin-3-ones.
Unfortunately, tert-butyl hydroperoxide (TBHP) (2.2 equiv)
and MnO2 (2.0 equiv) were employed in excess as oxidants.
At the same time, palladium-catalyzed Wacker-type oxida-
tion of N-Boc indoles for the preparation of 3-oxoindolines
has been achieved in our group.10 This result encouraged us
to extend the application of the catalysis system to the oxi-
dation of heteroaromatic precursors for the preparation of
oxo-heterocyclic compounds.
In palladium-catalyzed oxidation reactions, the Wacker
oxidation has played an extremely important role in indus-
trial applications.11 Pd-catalyzed Wacker-type oxidations of
alkenes are typical for the synthesis of carbonyl com-
pounds. Palladium-catalyzed oxidation of terminal olefins
for the synthesis of methyl ketones with high conversion
and selectivity has been reported by Mimoun’s group12 and
the mechanism of the reaction was proposed. Subsequent-
ly, Sigman’s13 and Feringa’s14 groups reported the palladi-
um-catalyzed Wacker-type oxidation of styrenes and ke-
tones, respectively, with high selectivity. In addition, the
copper-free Wacker-type oxidation of terminal olefins and
internal olefins has been reported by Kaneda’s group.15
However, palladium-catalyzed oxidation of indoles has
rarely been reported recently. It is expected that palladium-
catalyzed oxidations of indoles would provide an effective
method for the synthesis of oxo-heterocyclic compounds.
The Pd-catalyzed oxidation-hydroxylation and oxidation-
methoxylation of N-Boc indoles using H2O2 as the oxidant is
an interesting alternative. Herein, we report the Pd-cata-
DOI: 10.1055/s-0036-1589032; Art ID: ss-2017-h0109-op
Abstract The palladium-catalyzed oxidation-hydroxylation and oxida-
tion-methoxylation of N-Boc indoles for the synthesis of tert-butyl 2-hy-
droxy(methoxy)-3-oxoindoline-1-carboxylates and their derivatives is
developed. The process occurs readily using PdCl2 as the catalyst and
acetonitrile as the solvent to afford 3-oxoindolines in moderate to high
yields. A mechanism for this Pd-catalyzed oxidation-hydroxylation and
oxidation-methoxylation of N-Boc indoles is proposed.
Key words palladium, oxidation, hydroxylation, methoxylation, indole
The oxidation process has been widely recognized as a
powerful strategy for the synthesis of oxocyclic or oxo-het-
erocyclic compounds from the corresponding materials.
However, only a small amount of effort has been devoted to
the oxidation of aromatic and heteroaromatic compounds.
In heteroaromatic compounds, indole and its derivatives
are by far one of the most widely exploited.1 The nucleo-
philic addition and Friedel–Crafts reactions of indoles have
attracted significant attention for their extensive applica-
tions in the synthesis of natural products, pharmaceuticals
and other fine chemicals.2 As examples, 2-hydroxy-3-oxo-
indolines and 2-methoxy-3-oxoindolines are key building
blocks in natural products and biologically active mole-
cules.3 The most effective method to obtain 2-hydroxy-3-
oxoindolines and 2-methoxy-3-oxoindolines is via oxida-
tion of their aromatic precursors due to the atom economy.
In recent decades, molybdenum pentoxide,4 meta-chlo-
roperoxybenzoic acid (mCPBA),5 DDQ6 and dimethyldiox-
irane7 have been employed for the oxidation of indoles to
construct oxoindolines, being the primary synthetic meth-
od to achieve this transformation. But there are many lim-
itations to the process, such as toxic metal pollution, incom-
patibility with many functional groups, and low yields and
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

B
X.-Y. Zhou et al.
Paper
Synthesis
lyzed oxidation-hydroxylation and oxidation-methoxyl-
ation of N-Boc indoles (Scheme 1), which affords 2-hy-
droxy-3-oxoindolines in the presence of TsOH·H2O under
mild reaction conditions, and 2-methoxy-3-oxoindolines in
the presence of MeOH under the standard oxidation-
hydroxylation conditions but without TsOH·H2O.
catalysts were evaluated to improve the yield of product 2a.
Pd(OAc)2, Pd(acac)2, Pd(Quinox)Cl2, CuCl2, and FeCl3 were
tested in the presence of H2O2 in MeCN, however, no im-
provements in the results were obtained (entries 9–13). In
order to increase the activity of the oxidation-hydroxyl-
ation of N-Boc indoles, tert-butyl hydroperoxide (TBHP)
was tested as the oxidant in the reaction, but only a trace
amount of the desired product 2a was detected (entry 14).
This result indicated that H2O2 was the most effective oxi-
dant in the PdCl2-catalyzed oxidation-hydroxylation of N-
Boc indoles for the preparation of product 2a.
O
OH
R
PdCl2 (5.0 mol%)
R'
H2O2 (12.0 equiv)
TsOH·H2O (20 mol%)
MeCN, 40 °C
N
Boc
The above results were not satisfactory and a higher
yield was desired. Based on the initial results, the Brønsted
acid, p-toluenesulfonic acid (TsOH·H2O) (10 mol%), was
added in an attempt to improve the yield of product 2a. This
proved successful and an 87% yield of 2a was obtained (Ta-
ble 1, entry 15). Next, the effect of the amount of additive
(TsOH·H2O) on the reaction was investigated. A higher yield
(92%) was observed when the amount of TsOH·H2O was in-
creased to 20 mol% (entry 16), but the yield decreased sig-
nificantly (to 61%) when 30 mol% of TsOH·H2O was added
(entry 17).
Surprisingly, when MeOH was introduced into the reac-
tion system (without TsOH·H2O) to give the mixed solvent
MeCN/MeOH (10:1) for the palladium-catalyzed oxidation-
hydroxylation of N-Boc indole 1a, tert-butyl 2-methoxy-2-
methyl-3-oxoindoline-1-carboxylate (3a) was isolated as
the product in 82% yield (Table 1, entry 18). Next, the ratio
of the MeCN/MeOH mixed solvent (5:1, 2:1 and 1:1) was
tested and yields of 90%, 76% and 69% (entries 19–21) were
observed, respectively. The results indicated that the mixed
solvent MeCN/MeOH (5:1) was the best choice for the palla-
dium-catalyzed oxidation-methoxylation of N-Boc indole
1a. It should be noted that no product was detected in the
absence of a palladium catalyst or an oxidant (entries 22
and 23).
By optimization of the solvent, catalyst and oxidant, the
best reaction conditions for the Pd-catalyzed oxidation-
hydroxylation of an N-Boc indole were obtained: PdCl2 (5.0
mol%) as catalyst, H2O2 (12.0 equiv) as oxidant with
TsOH·H2O (20 mol%) in MeCN at 40 °C. The best reaction
conditions for the Pd-catalyzed oxidation-methoxylation of
an N-Boc indole were: PdCl2 (5.0 mol%) as catalyst, H2O2
(12.0 equiv) as the oxidant in MeCN/MeOH (5:1) at 40 °C.
Based on the optimized conditions, the substrate scope of
the Pd-catalyzed oxidation-hydroxylation and oxidation-
methoxylation of N-Boc indoles was examined and the re-
sults are shown in Table 2.
Under the optimized conditions, a range of N-Boc in-
doles 1a–l was subjected to the palladium-catalyzed oxida-
tion-hydroxylation and oxidation-methoxylation reaction
(Table 2). For the indoles 1a–e (entries 1–5) with different
substituents at the 2- and/or 5-positions of indole, moder-
ate to high isolated yields (66–96%) of 2 and 3 were
R
R'
N
Boc
O
OMe
R
PdCl2 (5.0 mol%)
R'
H2O2 (12.0 equiv)
MeCN/MeOH (5:1)
40 °C
N
Boc
Scheme 1 The oxidation-hydroxylation and oxidation-methoxylation
of N-Boc indoles
Thus, in continuation of our research on the palladium-
catalyzed oxidation of N-Boc indoles, 2-hydroxy-3-oxoindo-
line was found to be the main product. The initial experi-
ment began with tert-butyl 2-methyl-1H-indole-1-carbox-
ylate (1a) as the model starting material, H2O2 as the oxi-
dant and PdCl2 as the catalyst in ethyl acetate (EtOAc). The
product, tert-butyl 2-hydroxy-2-methyl-3-oxoindoline-1-
carboxylate (2a), was isolated in 18% yield (Table 1, entry 1).
This product is different from that in our previous work in
which PdCl2 with stronger Lewis acidity was used as the
catalyst.10 This result encouraged us to adhere to our initial
hypothesis that a Lewis acidic palladium catalyst can be ap-
plied for the catalyzed oxidation-hydroxylation of N-Boc in-
doles in the presence of an oxidant and water. Next, other
solvents, catalysts and oxidants were evaluated to improve
the yield of the product 2a.
Firstly, MeOH (Table 1, entry 2), CH2Cl2 (entry 3), THF
(entry 4), acetone (entry 5), DMF (entry 6), Et2O (entry 7)
and MeCN (entry 8) were tested as solvents to improve the
yield of 2a in the PdCl2-catalyzed oxidation-hydroxylation.
The results indicated that MeCN was the best solvent for
the Pd-catalyzed oxidation-hydroxylation of N-Boc indoles
affording an 81% yield. The reaction was inhibited com-
pletely when MeOH, CH2Cl2, DMF or Et2O was used as the
solvent in the presence of PdCl2. The results indicated that
the oxidant may lose its oxidative activity in MeOH and
DMF and only trace amounts of the target product were de-
tected (entries 2 and 6). Also, the water remains almost
completely undissolved in CH2Cl2 and Et2O, which results in
only a trace amount of the target product being detected
(entries 3 and 7). Due to the relatively good miscibility of
water and THF, a 77% yield of the product was obtained (en-
try 4) when the reaction was carried out in THF. Next, other
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X.-Y. Zhou et al.
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Synthesis
Table 1 Optimization of the Conditions for the Synthesis of 2a and 3aa
O
O
cat. (5.0 mol%)
Me
OH
Me
OMe
Me
or
N
oxidant
solvent, 40 °C
N
N
Boc
Boc
Boc
3a
1a
2a
Entry
Cat.
Oxidant (wt%/equiv)
Solvent
Yield (%)b
2a
3a
N/A
1
PdCl2
aq H2O2 (30 wt%/12.0)
aq H2O2 (30 wt%/12.0)
aq H2O2 (30 wt%/12.0)
aq H2O2 (30 wt%/12.0)
aq H2O2 (30 wt%/12.0)
aq H2O2 (30 wt%/12.0)
aq H2O2 (30 wt%/12.0)
aq H2O2 (30 wt%/12.0)
aq H2O2 (30 wt%/12.0)
aq H2O2 (30 wt%/12.0)
aq H2O2 (30 wt%/12.0)
aq H2O2 (30 wt%/12.0)
aq H2O2 (30 wt%/12.0)
aq TBHP (70 wt%/3.0)
aq H2O2 (30 wt%/12.0)
aq H2O2 (30 wt%/12.0)
aq H2O2 (30 wt%/12.0)
aq H2O2 (30 wt%/12.0)
aq H2O2 (30 wt%/12.0)
aq H2O2 (30 wt%/12.0)
aq H2O2 (30 wt%/12.0)
–
EtOAc
MeOH
CH2Cl2
THF
18
2
PdCl2
trace
trace
77
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
82
3
PdCl2
4
PdCl2
5
PdCl2
acetone
DMF
41
6
PdCl2
trace
trace
81
7
PdCl2
Et2O
8
PdCl2
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
9
Pd(OAc)2
Pd(acac)2
Pd(Quinox)Cl2
CuCl2
FeCl3
78
10
11
12
13
14
15c
16d
17e
18
19
20
21
22
23
trace
N/A
N/A
N/A
trace
87
PdCl2
PdCl2
PdCl2
92
PdCl2
61
PdCl2
MeCN/MeOH (10:1)
MeCN/MeOH (5:1)
MeCN/MeOH (2:1)
MeCN/MeOH (1:1)
MeCN
N/A
N/A
N/A
N/A
N/A
N/A
PdCl2
90
PdCl2
76
PdCl2
69
PdCl2
N/A
N/A
–
aq H2O2 (30 wt%/12.0)
MeCN
a Reaction conditions: 1a (58 mg, 0.25 mmol), PdCl2 (2.2 mg, 0.0125 mmol, 5.0 mol%), aq H2O2 (30 wt%, 3.0 mmol, 12.0 equiv) or aq TBHP (70 wt%, 0.75 mmol,
3.0 equiv), solvent (3.0 mL), 40 °C, 24 h.
b Yield of isolated product.
c TsOH·H2O (4.8 mg, 0.025 mmol, 10 mol%) was added.
d TsOH·H2O (9.5 mg, 0.05 mmol, 20 mol%) was added.
e TsOH·H2O (14.3 mg, 0.075 mmol, 30 mol%) was added.
achieved under conditions A and B, respectively. However,
for the 5-chloro-substituted indole 1f (entry 6) and 2-cyclo-
hexyl-indole (1g) (entry 7), only 47% and 63% isolated
yields of 2f and 2g were obtained when the reactions were
carried out under conditions A, and no target products
were detected under conditions B. 2-Phenyl-substituted
and 2-unsubstituted substrates 1h–k (entries 8–11) under-
went oxidation to afford the corresponding products in
moderate yields (56–73%) under conditions B and unreact-
ed starting materials were also recovered.
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Synthesis
Table 2 Palladium-Catalyzed Wacker-Type Oxidation of N-Boc Indoles
Entry Substrate
Product
Condi- Yield
tionsa
(%)b
Entry Substrate
Product
Condi- Yield
O
tionsa
(%)b
Cl
Cl
nBu
OH
nBu
O
6
A
47
N
N
Boc
OH
Me
Boc
1f
A
92
2f
N
Boc
O
Me
2a
3a
2b
3b
2c
Cy
Ph
OH
Cy
N
Boc
1
7
N
A
B
B
B
B
63
56
65
70
73
O
N
1a
Boc
OMe
Me
Boc
1g
B
A
B
A
B
A
B
A
B
90
83
88
83
66
93
96
74
80
2g
N
Boc
O
OMe
Ph
O
8
N
N
Boc
OH
nHex
Boc
1h
3h
N
Boc
O
nHex
Me
Me
OMe
Ph
N
2
Ph
O
9
N
Boc
N
1b
Boc
OMe
nHex
Boc
1i
3i
N
Boc
O
OMe
O
O
N
10
N
Boc
OH
Boc
Ph
Ph
1j
3j
N
Boc
Me
Me
3
N
OMe
O
11
Ph
Boc
N
N
1c
Boc
OMe
Boc
1k
3k
N
a Reaction conditions A: 1 (0.25 mmol), PdCl2 (2.2 mg, 0.0125 mmol, 5.0
mol%), aq H2O2 (30 wt%, 3.0 mmol, 12.0 equiv), TsOH·H2O (9.5 mg, 0.05
mmol, 20 mol%), MeCN (3.0 mL), 40 °C, 24 h. Reaction conditions B: 1
(0.25 mmol), PdCl2 (2.2 mg, 0.0125 mmol, 5.0 mol%), aq H2O2 (30 wt%,
3.0 mmol, 12.0 equiv), MeCN/MeOH (5:1, 3.0 mL), 40 °C.
b Yield of isolated product.
Boc
3c
O
Me
OH
Me
N
Me
Boc
Me
2d
4
N
The results indicated that the substrates with 2-phenyl-
substituted and 2-unsubstituted groups (Table 2, entries 8–
11) have no reactivity under conditions A, and no target
products were detected when substrates containing large
sterically hindered substituents such as n-butyl and cyclo-
hexyl were reacted under conditions B (entries 6 and 7).
Notably, the above optimum conditions are not appropriate
for the oxidation of N-H, N-Me and N-Ac indoles owing to
low selectivity. In addition, other alcohols, such as ethanol,
isopropanol and benzyl alcohol, were tested in the palladi-
um-catalyzed oxidation-alkoxylation of N-Boc indoles,
however, almost all of the starting materials were recov-
ered. We speculated that the oxidant may lose its oxidative
activity in the presence of a relatively stronger reductive re-
agent (ethanol, isopropanol, benzyl alcohol).
O
Boc
Me
1d
OMe
Me
N
Boc
3d
O
MeO
OH
Me
N
MeO
Boc
Me
2e
5
N
O
Boc
MeO
1e
OMe
Me
N
Boc
3e
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

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X.-Y. Zhou et al.
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Synthesis
Me
N
Boc
Me
N
B
H
Boc
O
1a
H2O2
H
O
PdIICl2
ClPd-OOH
PdCl
Me
Boc
A
HCl
N
C
H2O
H
O
O
R = H or Me
Cl-Pd-OH
OR
Me
Me
H2O2
R
H
N
N
D
O
Boc
Boc
2a or 3a
E
Scheme 2 Proposed mechanism for the palladium-catalyzed oxidation-hydroxylation and -methoxylation of N-Boc indoles
Based on the reaction results and the known mecha-
nism of the Pd-catalyzed Wacker oxidation of alkenes,12
possible mechanism for the Pd-catalyzed oxidation-hydrox-
ylation and oxidation-methoxylation of N-Boc indoles is
proposed in Scheme 2.
ditions. The principle behind these reactions is expected to
provide a new strategy to develop new types of catalytic ox-
idation of aromatic compounds.
a
The activated palladium catalyst ClPd-OOH (A) may be
produced from the palladium precursor PdCl2 in the pres-
ence of hydrogen peroxide. The activated catalyst A could
react with N-Boc indole 1a to produce the palladium com-
plex B and then further form the complex C under the stan-
dard reaction conditions. Next, a hydrogen-transfer process
may occur to produce Cl-Pd-OH (D) and the epoxy interme-
diate E.7b The epoxy intermediate E is attacked by the nu-
cleophilic reagent water promoted by TsOH to produce the
target product 2a. Compound 3a was formed in the pres-
ence of the relatively stronger nucleophilic reagent MeOH
without TsOH. The activated palladium catalyst A can be re-
generated in the presence of H2O2.
We previously reported the synthesis of 3-oxoindoles
under conditions employing the less Lewis acidic Pd(acac)2
as the catalyst.10 In contrast, PdCl2 was used as a more Lewis
acidic catalyst in this work. Besides, TsOH was used as the
Brønsted acid for the synthesis of 2-hydroxy-3-oxoindoles 2
and MeOH was used as a more nucleophilic reagent for the
synthesis of 2-methoxy-3-oxoindoles 3. The main differ-
ences between both pieces of work are the catalyst and the
additives employed.
All commercially available reagents were used without further purifi-
cation. The starting materials 1a–k were prepared according to re-
ported methods.10 Flash column chromatography was performed on
Huanghai brand silica gel (200–300 mesh). TLC analysis was per-
formed using Huanghai brand glass-backed plates coated with 0.2
mm silica gel. The chemical shifts for 1H NMR were recorded in ppm
downfield from tetramethylsilane (TMS) with the solvent resonance
as the internal standard. The chemical shifts for 13C NMR were record-
ed in ppm downfield using the central peak of d-chloroform (77.23
ppm) as the internal standard. Coupling constants (J) are reported in
Hz and refer to apparent peak multiplicities.
Oxidation-Hydroxylation of N-Boc Indoles; Typical Procedure
A mixture of N-Boc indole 1 (0.25 mmol) and PdCl2 (2.2 mg, 0.0125
mmol, 5.0 mol%) in MeCN (3 mL) was added to a Schlenk flask (25 mL)
and stirred at r.t. Following the addition of aq 30 wt% H2O2 (3.0 mmol,
12.0 equiv) and TsOH·H2O (9.5 mg, 0.05 mmol, 20 mol%), the mixture
was stirred at 40 °C until the reaction was finished. The solvent was
evaporated under reduced pressure and the residue was purified by
column chromatography (PE/EtOAc, 20:1 to 5:1).
tert-Butyl 2-Hydroxy-2-methyl-3-oxoindoline-1-carboxylate (2a)
Yield: 56.8 mg (88%); white solid; mp 95–97 °C.
IR (KBr): 3445, 2979, 2934, 1712, 1607, 1590, 1470, 1370, 1352, 1255,
1159, 1066, 989, 910, 840, 757 cm–1
.
In summary, using H2O2 as the oxidant, the palladium-
catalyzed oxidation-hydroxylation and oxidation-methox-
ylation of N-Boc indoles has been successfully achieved
with up to 93% and 96% yields, respectively. The reactions
afforded 2-hydroxy-3-oxoindolines and 2-methoxy-3-oxo-
indolines with very high regioselectivity under similar con-
1H NMR (400 MHz, CDCl3): δ = 1.64 (s, 9 H), 1.77 (s, 3 H), 7.13–7.17
(m, 1 H), 7.63–7.67 (m, 1 H), 7.77 (d, J = 7.6 Hz, 1 H), 7.92 (br s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 23.1, 28.4, 87.9, 116.4, 123.5, 125.0,
137.9, 150.9, 196.3.
HRMS: m/z [M + Na]+ calcd for C14H17NO4Na: 286.1055; found:
286.1056.
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X.-Y. Zhou et al.
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Synthesis
tert-Butyl 2-Hexyl-2-hydroxy-3-oxoindoline-1-carboxylate (2b)
Yield: 62.6 mg (76%); colorless oil.
1H NMR (400 MHz, CDCl3): δ = 0.80–1.28 (m, 7 H), 1.64 (s, 9 H), 2.14–
2.32 (m, 2 H), 7.56–7.59 (m, 1 H), 7.69 (d, J = 2.4 Hz, 1 H), 7.92 (br s, 1
H).
13C NMR (100 MHz, CDCl3): δ = 13.7, 22.4, 25.4, 28.4, 36.8, 90.7, 117.7,
124.0, 129.0, 137.5, 195.6.
HRMS: m/z [M + Na]+ calcd for C17H22NO4ClNa: 362.1135; found:
362.1123.
IR (neat): 3449, 2958, 2930, 1713, 1608, 1468, 1370, 1308, 1252,
1158, 1078, 756 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 0.82 (t, J = 6.8 Hz, 3 H), 1.18–1.23 (m, 8
H), 1.65 (s, 9 H), 2.20–2.24 (m, 2 H), 7.14 (dd, J = 7.6, 8.4 Hz, 1 H),
7.64–7.75 (m, 3 H).
13C NMR (100 MHz, CDCl3): δ = 14.1, 22.6, 23.4, 28.6, 29.1, 29.9, 31.5,
37.2, 83.9, 90.4, 116.5, 122.0, 123.6, 124.8, 138.0, 196.9.
HRMS: m/z [M + Na]+ calcd for C19H27NO4Na: 356.1838; found:
356.1835.
tert-Butyl 2-Cyclohexyl-2-hydroxy-3-oxoindoline-1-carboxylate
(2g)
Yield: 50.8 mg (62%); colorless oil.
IR (neat): 3451, 2931, 2853, 1731, 1708, 1611, 1591, 1469, 1369,
1347, 1307, 1189, 1156, 1104, 1004, 935, 907, 876, 841, 756 cm–1
.
tert-Butyl 2-Hydroxy-3-oxo-2-(3-phenylpropyl)indoline-1-car-
boxylate (2c)
1H NMR (400 MHz, CDCl3): δ = 1.14–2.04 (m, 19 H), 2.40–2.46 (m, 1
H), 7.13 (dd, J = 7.6, 8.4 Hz, 1 H), 7.59–7.63 (m, 1 H), 7.71 (d, J = 7.6 Hz,
1 H), 7.86 (br s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 24.9, 25.9, 26.1, 26.4, 27.6, 28.5, 45.1,
83.9, 92.6, 116.2, 122.7, 123.4, 124.2, 137.5, 151.2, 151.5, 196.6.
Yield: 74.4 mg (80%); colorless oil.
IR (neat): 3444, 3062, 3026, 2977, 2931, 1712, 1607, 1467, 1369,
1317, 1253, 1162, 1114, 982, 942, 843, 755, 701 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.25–1.44 (m, 2 H), 1.55 (s, 9 H), 2.20–
2.61 (m, 4 H), 7.05–7.25 (m, 6 H), 7.59–7.74 (m, 2 H), 7.93 (br s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 25.3, 28.3, 35.5, 36.6, 83.7, 90.0, 116.4,
HRMS: m/z [M + Na]+ calcd for C19H25NO4Na: 354.1681; found:
354.1677.
123.5, 124.6, 126.0, 128.39, 128.40, 137.9, 141.3, 196.6.
HRMS: m/z [M + Na]+ calcd for C22H25NO4Na: 390.1681; found:
Oxidation-Methoxylation of N-Boc Indoles; Typical Procedure
A mixture of N-Boc indole 1 (0.25 mmol) and PdCl2 (2.2 mg, 0.0125
mmol, 5.0 mol%) in MeCN/MeOH (5:1 v/v, 3 mL) was added to a
Schlenk flask (25 mL) and stirred at r.t. Following the addition of aq 30
wt% H2O2 (3.0 mmol, 12.0 equiv), the mixture was stirred at 40 °C un-
til the reaction was finished. The solvent was evaporated under re-
duced pressure and the residue was purified by column chromatogra-
phy (PE/EtOAc, 50:1 to 20:1).
390.1696.
tert-Butyl 2-Hydroxy-2,5-dimethyl-3-oxoindoline-1-carboxylate
(2d)
Yield: 59.1 mg (86%); colorless oil.
IR (neat): 3449, 2979, 2933, 1712, 1622, 1586, 1492, 1371, 1354,
1255, 1159, 1068, 994, 973, 926, 827, 789, 766 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.64 (s, 9 H), 1.75 (s, 3 H), 2.36 (s, 3 H),
7.45–7.48 (m, 1 H), 7.55 (s, 1 H), 7.87 (br s, 1 H).
tert-Butyl 2-Methoxy-2-methyl-3-oxoindoline-1-carboxylate (3a)
Yield: 59.6 mg (86%); white solid; mp 109–111 °C.
13C NMR (100 MHz, CDCl3): δ = 20.6, 28.4, 116.2, 124.6, 133.3, 139.0,
196.4.
IR (KBr): 3124, 3048, 2980, 2932, 1708, 1604, 1586, 1466, 1307, 1258,
1170, 1054, 978, 967, 879, 841, 754, 706, 684 cm–1
.
HRMS: m/z [M
300.1215.
+
Na]+ calcd for C15H19NO4: 300.1212; found:
1H NMR (400 MHz, CDCl3): δ = 1.62 (s, 9 H), 1.69 (s, 3 H), 3.11 (s, 3 H),
7.14 (dd, J = 7.6, 8.4 Hz, 1 H), 7.65–7.69 (m, 1 H), 7.73 (d, J = 7.6 Hz, 1
H), 8.21 (d, J = 8.4 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 21.6, 28.3, 51.7, 82.5, 92.7, 116.7,
tert-Butyl 2-Hydroxy-5-methoxy-2-methyl-3-oxoindoline-1-car-
boxylate (2e)
121.3, 123.1, 124.0, 138.1, 150.8, 152.8, 198.7.
HRMS: m/z [M + Na]+ calcd for C15H19NO4Na: 300.1212; found:
Yield: 52.4 mg (71%); white solid; mp 74–76 °C.
300.1203.
IR (KBr): 3443, 2978, 2934, 1709, 1492, 1370, 1330, 1273, 1158, 1112,
1067, 1031, 924, 836, 803, 786 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.64 (s, 9 H), 1.75 (s, 3 H), 3.82 (s, 3 H),
7.19–7.28 (m, 2 H), 7.84 (br s, 1 H).
tert-Butyl 2-Hexyl-2-methoxy-3-oxoindoline-1-carboxylate (3b)
Yield: 68.2 mg (78%); colorless oil.
13C NMR (100 MHz, CDCl3): δ = 23.2, 28.6, 55.9, 83.7, 105.7, 117.8,
121.4, 127.1, 156.2, 196.5.
IR (neat): 2957, 2931, 2859, 1713, 1607, 1466, 1368, 1306, 1252,
1161, 1116, 1099, 1079, 927, 845, 758, 709 cm–1
.
HRMS: m/z [M + Na]+ calcd for C15H19NO5Na: 316.1161; found:
316.1167.
1H NMR (400 MHz, CDCl3): δ = 0.80–1.23 (m, 11 H), 1.61 (s, 9 H),
2.05–2.06 (m, 1 H), 2.41–2.42 (m, 1 H), 3.10 (s, 3 H), 7.13 (dd, J = 7.6,
8.4 Hz, 1 H), 7.64–7.71 (m, 2 H), 8.23 (d, J = 8.4 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 14.1, 22.6, 22.7, 28.5, 29.2, 31.5, 35.4,
tert-Butyl 2-Butyl-5-chloro-2-hydroxy-3-oxoindoline-1-carboxyl-
ate (2f)
51.6, 82.6, 95.5, 116.7, 122.5, 123.2, 123.7, 138.2, 151.1, 153.9, 199.4.
HRMS: m/z [M + Na]+ calcd for C20H29NO4Na: 370.1994; found:
Yield: 36.0 mg (42%); colorless oil.
370.2003.
IR (neat): 3450, 2961, 2932, 1716, 1608, 1582, 1470, 1370, 1351,
1251, 1159, 1072, 993, 952, 832, 766 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

G
X.-Y. Zhou et al.
Paper
Synthesis
tert-Butyl 2-Methoxy-3-oxo-2-(3-phenylpropyl)indoline-1-car-
boxylate (3c)
1H NMR (400 MHz, CDCl3): δ = 1.23 (s, 9 H), 2.38 (s, 3 H), 3.32 (s, 3 H),
7.27–7.55 (m, 7 H), 8.24 (d, J = 8.4 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 20.8, 28.0, 51.7, 82.2, 94.9, 116.3,
Yield: 58.7 mg (62%); colorless oil.
121.5, 124.4, 125.1, 128.5, 133.5, 137.2, 139.4, 151.1, 152.3, 196.8.
HRMS: m/z [M + Na]+ calcd for C21H23NO4Na: 376.1525; found:
IR (neat): 3026, 2977, 2932, 1731, 1712, 1606, 1465, 1375, 1306,
1253, 1163, 1114, 1079, 927, 845, 756, 700 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 0.85–1.37 (m, 3 H), 1.49 (s, 9 H), 2.10–
2.59 (m, 3 H), 3.08 (s, 3 H), 7.05–7.24 (m, 6 H), 7.61–7.70 (m, 2 H),
8.21 (d, J = 8.0 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 24.9, 28.3, 35.2, 35.9, 51.6, 82.6, 95.2,
116.8, 122.4, 123.3, 123.8, 126.1, 128.5, 128.7, 138.3, 141.6, 151.0,
153.9, 199.3.
376.1533.
tert-Butyl 2-Methoxy-3-oxoindoline-1-carboxylate (3j)
Yield: 42.5 mg (65%); colorless oil.
IR (neat): 2978, 2932, 1716, 1608, 1469, 1376, 1287, 1164, 1093,
1059, 758 cm–1
.
HRMS: m/z [M + Na]+ calcd for C23H27NO4Na: 404.1838; found:
404.1850.
1H NMR (400 MHz, CDCl3): δ = 1.61 (s, 9 H), 3.59 (s, 3 H), 4.21 (s, 1 H),
7.11–7.14 (m, 1 H), 7.60–7.72 (m, 2 H), 8.00 (br s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 28.5, 55.7, 56.5, 83.1, 87.1, 116.7,
122.3, 123.0, 123.5, 124.5, 137.2, 138.0, 151.3, 195.9.
HRMS: m/z [M + Na]+ calcd for C14H17NO4Na: 286.1055; found:
286.1056.
tert-Butyl 2-Methoxy-2,5-dimethyl-3-oxoindoline-1-carboxylate
(3d)
Yield: 61.4 mg (84%); white solid; mp 139–141 °C.
IR (KBr): 2956, 2929, 1723, 1708, 1620, 1583, 1489, 1371, 1360, 1286,
1270, 1154, 1076, 1052, 839 cm–1
1H NMR (400 MHz, CDCl3): δ = 1.56 (s, 9 H), 1.63 (s, 3 H), 2.32 (s, 3 H),
3.04 (s, 3 H), 7.43–7.46 (m, 2 H), 8.52 (br s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 20.7, 21.7, 28.5, 51.7, 82.5, 93.0, 116.7,
121.5, 123.7, 133.1, 139.3, 150.9, 151.0, 198.8.
HRMS: m/z [M + Na]+ calcd for C16H21NO4Na: 314.1368; found:
314.1365.
.
tert-Butyl 2-Methoxy-5-methyl-3-oxoindoline-1-carboxylate (3k)
Yield: 46.9 mg (68%); colorless oil.
IR (neat): 3062, 3028, 2978, 2932, 1716, 1621, 1587, 1493, 1371,
1283, 1256, 1152, 1097, 1062, 826, 789, 763 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.60 (s, 9 H), 2.35–2.36 (m, 3 H), 3.58
(s, 3 H), 4.20 (s, 1 H), 7.43–7.49 (m, 2 H), 7.87 (br s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 20.8, 28.5, 55.9, 56.3, 82.9, 87.3, 116.5,
122.4, 124.2, 132.8, 133.3, 138.3, 139.0, 151.3, 196.0.
HRMS: m/z [M + Na]+ calcd for C15H19NO4Na: 300.1212; found:
300.1201.
tert-Butyl 2,5-Dimethoxy-2-methyl-3-oxoindoline-1-carboxylate
(3e)
Yield: 57.7 mg (75%); white solid; mp 118–120 °C.
IR (KBr): 2980, 2936, 1721, 1705, 1622, 1587, 1490, 1455, 1370, 1332,
1273, 1164, 1076, 1055, 846 cm–1
1H NMR (400 MHz, CDCl3): δ = 1.57 (s, 9 H), 1.64 (s, 3 H), 3.06 (s, 3 H),
.
Funding Information
This work was supported by the Union Foundation of Science and
Technology Department of Guizhou Province (Grant No. qiankehe LH
zi [2015] number 7614) and the High-Level Talents Start-up Founda-
3.79 (s, 3 H), 7.10–7.25 (m, 2 H), 8.10 (br s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 21.8, 28.5, 51.8, 55.9, 62.3, 82.4, 93.2,
104.7, 118.2, 122.0, 126.5, 127.3, 147.8, 155.9, 198.9.
HRMS: m/z [M + Na]+ calcd for C16H21NO5Na: 330.1317; found:
tion of Liupanshui Normal University (Grant No. LPSSYKYJJ201501).
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Supporting Information
tert-Butyl 2-Methoxy-3-oxo-2-phenylindoline-1-carboxylate (3h)
Yield: 44.5 mg (53%); colorless oil.
Supporting information for this article is available online at
https://doi.org /10.1055/s-0036-1589032.
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IR (neat): 2978, 2933, 1736, 1713, 1606, 1465, 1359, 1253, 1199,
1158, 1066, 1031, 993, 969, 901, 887, 843, 757, 743, 700 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.24 (s, 9 H), 3.33 (s, 3 H), 7.16–7.39
(m, 6 H), 7.72 (d, J = 8.4 Hz, 2 H), 8.36 (d, J = 8.4 Hz, 1 H).
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tert-Butyl 2-Methoxy-5-methyl-3-oxo-2-phenylindoline-1-car-
boxylate (3i)
Yield: 52.3 mg (59%); white solid; mp 85–87 °C.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

H
X.-Y. Zhou et al.
Paper
Synthesis
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H