CuCl2/TBHP-mediated direct chlorooxidation of indoles

Article abstract of DOI:10.1016/j.tet.2015.05.065

CuCl₂/TBHP-mediated direct chlorooxidation of indole derivatives under simple aerobic conditions was reported, leading to facile preparations of a range of 3,3-disubstituted 3-chlorooxindoles in good yields and selectivities.

Full text of DOI:10.1016/j.tet.2015.05.065

Accepted Manuscript
CuCl /TBHP-Mediated Direct Chlorooxidation of Indoles
2
Huifei Wang, Dong Liu, Huiyu Chen, Jing Li, David Zhigang Wang
PII:
S0040-4020(15)00736-X
10.1016/j.tet.2015.05.065
TET 26783
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 7 April 2015
Revised Date: 16 May 2015
Accepted Date: 18 May 2015
Please cite this article as: Wang H, Liu D, Chen H, Li J, Wang DZ, CuCl /TBHP-Mediated Direct
2
Chlorooxidation of Indoles, Tetrahedron (2015), doi: 10.1016/j.tet.2015.05.065.
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2
Chlorooxidation of Indoles
*
Huifei Wang, Dong Liu, Huiyu Chen, Jing Li, David Zhigang Wang
Key Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Shenzhen Graduate
School of Peking University, Shenzhen University Town, Shenzhen 518055, China.

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Tetrahedron
journal homepage: www.elsevier.com
CuCl /TBHP-Mediated Direct Chlorooxidation of Indoles
2
∗
Huifei Wang, Dong Liu, Huiyu Chen, Jing Li, David Zhigang Wang
Key Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Shenzhen Graduate School of Peking University,
Shenzhen University Town, Shenzhen 518055, China.
ARTICLE INFO
ABSTRACT
Article history:
Received
Revised
2
CuCl /TBHP-mediated direct chlorooxidation of indole derivatives under simple aerobic
conditions was reported, leading to facile preparations of a range of 3,3-disubstituted 3-
chlorooxindoles in good yields and selectivities.
Accepted
Available online
2015 Elsevier Ltd. All rights reserved.
Keywords:
CuCl /TBHP
2
Chlorooxidation
Indoles
1
. Introduction
ones may proceed with lower efficiency and/or selectivities,
leading to undesirable mixtures of bi- or tri-chloride-substituted
products on5a indole aromatic backbones (see Supporting
Since its early report by Hinman and Bauman in 1964, the 3-
halooxindoles and their related reactions have garnered attentions
as important structural motifs. They were recognized as versatile
electrophiles in a series of substitution reactions to construct
complex molecules, and various heteroatoms (O, N, S) as well
as carbon-based nucleophiles were selectively introduced at the
C-3 position of oxindoles through either intermolecular or
intramolecular fashion during the past decades. A number of
elegant protocols for asymmetric reactions of 3-halooxindoles
have also been developed by the groups of Stoltz and Krische et
t
1
Information). The chlorination reagent BuOCl is less user-
5e
friendly due to its harmful properties. Thus, the development of
1,2
a mild, safe, and regioselective chlorooxidation method that is
directly implementable on 3-substituted indoles would be of
significant synthetic values towards general preparations of 3-
2a,3
chlorooxindoles. Herein, we reported a novel CuCl /TBHP-
2
6
mediated chlorooxidation of indoles, which we believe provides
a likely simplest approach to 3,3-disubstituted-3-chlorooxindoles
under aerobic conditions.
3h-l
al.,
thereby generating all-carbon quaternary stereogenic
centers or vicinal quaternary carbons in highly stereo-controlled
manners. 3-halooxindoles are also used as key intermediates for
syntheses of architecturally fascinating natural products, which
was exemplified by recent disclosures reported from the groups
2
. Results and discussion
Envisioning that readily available metal chlorides may
3d-3g
function as economic chlorination agents, we initially
investigated the reaction of N-methyl tosyltryptamine (1a) with 2
equiv of CuCl using 10 equiv of tert-butyl hydroperoxide (TBHP,
of Funk, Wang and Dalko and their respective co-workers.
Within this context 3,3-disubstituted 3-halooxindoles represent
facile entry to densely functionalized indoles and thus are
arguably more interesting and useful. As to preparation of 3,3-
disubstituted 3-cholooxindoles, most of the approaches chose
7
0% in water) as the oxidant in DME under ambient conditions
(room temperature and in air, entry 1, Table 1). To our delight,
3
h-i,3k,4
the reaction proceeded smoothly to provide 3-chlorooxindole (2a)
as the desired product in the isolated yield of 46%, which was
accompanied by the formation of 3-peroxyoxindole (3)
oxindole skeletons as starting materials.
The known
methods to those motifs usually leverage on nucleophilic
additions of isatin derivatives followed by chlorination using
highly reactive reagents such as SOCl and CF SO Cl. However,
7
byproduct in 15% yield. When RuCl3 was employed in
2
3
2
replacement of CuCl, the reaction also furnished product 2a but
the yield was lower (entry 2, 35% yield). Other oxidants, such as
di-tert-butyl peroxide (DTBP) and 30% H O were also screened
few reports are available that could allow direct chlorooxidations
5
on their corresponding 3-substituted indoles, and the existing
—
——
2
2
∗
Corresponding author. Tel.: +0-86-755-26035307; fax: +0-86-755-26032702; e-mail: dzw@pkusz.edu.cn

and the reactivities were found to be completely inhibited (entries
ACCEPTED MANUSCRIPT
3
-4). The addition of a base (NaOH) into the reaction system was
shown to be detrimental (entry 5). By contrast, addition of an
acid (AcOH) seemed to be well-tolerated (entry 6 vs. entry 1).
Remarkably, the yield of the product was increased to 68% when
a stronger acid (2M HCl) was employed, while the amount of
byproduct was further reduced (less than 5% in entry 7).
Replacing CuCl with CuCl and using diglyme as the solvent
2
enhanced further the product yield to 71% (entry 8). Surprisingly,
when using the hydrated metal salt CuCl ·2H O in the mixed
2
2
solvent of diglyme/H O, the product was obtained in 74% yield
2
8
in the absence of an acid, while the yield was decreased to 56%
under acidic condition (entry 9 vs. entry 10). The reaction
seemed to be insensitive to either oxygen or argon atmosphere
since only minor difference in product yields were observed
(entries 11-12). Finally, control experiments carried out in the
absence of either CuCl ·2H O or TBHP delivered no product,
2
2
confirming that the beneficial interactions of both metal chloride
and oxidant are essential for bringing about the desired
transformation. Collectively these screenings pointed to a set of
optimal reagents and conditions that called for the utilizations of
1
.4 equivalents of CuCl ·2H O and 7 equivalents of TBHP in the
2 2
mixed aqueous solvents of diglyme/H O (20/1) at room
2
temperature and under air.
Table 1. Optimization of the Reaction Conditions.
Cl
NHTs MClx (eq), oxidant (eq),
solvent, air, rt
NHTs
O
N
N
Me
Me
1
a
2a
entrya oxidant (eq)b
additive (eq)
solvent yield (%)
MCl (eq)
x
1
2
3
4
5
6
7
8
9
1
1
1
1
1
TBHP (10)
TBHP (10)
DTBP (10)
H O (10)
CuCl (2.0)
RuCl3 (1.0)
CuCl (2.0)
CuCl (2.0)
CuCl (2.0)
CuCl (2.0)
CuCl (2.0)
CuCl2 (2.0)
/
/
DME
DME
46
35
NR
NR
NR
45
68
71
74
56
62
70
0
a
Scheme 1. Substrate Scope. Unless otherwise noted, the reactions
were performed with 1a-r (0.10 mmol), CuCl •H O (0.14 mmol),
and TBHP (70% in H O, 0.70 mmol) in diglyme/H O (20:1, 0.8 mL)
at rt. Isolated yields were reported. Reaction performed at 45 ºC.
2
2
/
/
DME
DME
2
2
2
2
b
TBHP (10)
TBHP (10)
TBHP (7.0)
TBHP (7.0)
NaOH (0.1)
DME
DME
DME
AcOH (6.0)
HCl (1.5)
c
c
d
HCl (1.5)
diglyme
diglyme/H O
TBHP (7.0) CuCl •2H O (1.4)
2
2
/
2
0c,d TBHP (7.0) CuCl •2H O (1.4)
2
2
HCl (1.5)
diglyme/H O
diglyme/H O
diglyme/H O
2
2
2
2
2
d,e
d,f
d
1
2
3
4
TBHP (7.0) CuCl •2H O (1.4)
TBHP (7.0) CuCl •2H O (1.4)
/
/
/
/
2
2
2
2
/
CuCl •2H O (1.4)
2
2
diglyme/H O
diglyme/H O
d
TBHP (7.0)
/
0
a
Unless otherwise noted, reactions were performed with 1a at 0.10 mmol
scale in solvent (0.8 mL) at rt in air for 12-20 h. Isolated yields were reported.
b
2 2
TBHP 70% in water, H O 30% in water.
c
d
e
f
2
M HCl.
Solvent ratio = 20:1.
Under O atmosphere.
Under Ar atmosphere.
Figure 1. X-ray crystallography for 2c·CHCl
g-2k). The influence of side-chain nitrogen protecting groups
.
3
2
2
were next investigated, and both Boc and methoxycarbonyl
derivatives were capable (2m-2n). Simple aliphatic groups on the
indole nitrogens are readily tolerated, but a benzyl seemed to be
less efficient and resulted in lower yield (2p). Furthermore, the
reaction of indole derivatives bearing a hydroxyalkyl side-chain
under heating conditions can also give the expected products (2q-
The scope of this newly uncovered halooxidation protocol was
next explored on a range of indole derivatives (Scheme 1). These
reactions all uneventfully afforded the expected products in
moderate to good isolated yields (44-74%). The substituents on
the indole ring were first examined, and an alkyl group on the
indole C-4, C-5, C-6 or C-7 position was founded to be tolerated
2
r) in the yield of 70% and 45%, respectively. It is notable,
however, that indoles bearing no coordinative atoms in their side-
chains are not competent substrates, implying the importance of
(
2b-2e). The reactivities evidently also well accommodate either
electron-releasing or -withdrawing aryl ring substituents (2f, 2l,

9
directing group effect in the reactions. We were able to grow
designed and uncovered a simple method to prepare 3,3-
ACCEPTED MANUSCRIPT
single crystals of
a
representative product 2c, thus
disubstituted 3-chlorooxindoles directly from their corresponding
indole precursors under the synergistic actions of
CuCl •2H O/TBHP reagents. The protocol is mild, selective,
10
unambiguously establishing its structural identity (Figure 1). It
merits attention that in all cases examined with this new protocol
no chlorination on the indole aromatic backbone was found.
Thus obtained 3-chlorooxindoles could readily engage on
many synthetically useful transformations, and some of which
were showcased in Scheme 2. Dehalogenation on 2n under Pd/C-
2
2
safe, and easy to operate, these merits should enhance its
synthetic utilities for practitioners who are interested in accessing
to such biologically significant motifs. Our goal is to further
pursue and realize catalytic chlorooxidation and the results would
be disclosed in due course.
11
mediated hydrogenation furnished smoothly 2-indolinone (4).
Base-induced intramolecular nucleophilic displacement in 2q
produced spirocyclic indolin-2-one (5), while an intermolecular
2a
displacement with 2h using Funk’s standard condition delivered
the oxygenated product (6).
Scheme 2. Derivatizations of 3-Chlorooxindole.
A plausible mechanism could be formulated to accommodate
these observed reactivities. As shown in Scheme 3, CuCl may
2
react with TBHP to generate the tert-butylperoxy radical, CuCl
and HCl which was suggested earlier by Kochi and co-workers.
12
Scheme 3. Proposed Mechanism.
CuCl would undergo further reaction with TBHP forming tert-
butoxyl radical and CuCl(OH). Interaction of CuCl(OH) and
t
4
4
. Experimental
TBHP would then produce CuCl(OO Bu) and H O. Thus in-situ
2
formed H O evidently should constitute an oxygen source when
2
.1 General experimental
reactions were performed under anhydrous conditions. On the
other hand, the ammoniumyl radical cation A would be generated
by the reaction of substrate 1a with tert-butoxyl radical via a
single-electron transfer (SET) pathway, which should readily
undergo tautomerization and the side chain coordination with
All reactions were carried out under a nitrogen atmosphere
with dry solvents under anhydrous conditions, unless otherwise
noted. All the chemicals were purchased commercially, and used
without further purification. CuCl ·2H O was purchased from
6h
CuCl to give the radical cation intermediate B. A chlorine
2
2
2
Alfa. Anhydrous tetrahydrofuran (THF) and Et O were distilled
atom transfer of the radical species B could then deliver to the
2
1
3
from sodium-benzophenone, dichloromethane (DCM) were
distilled from calcium hydride. All other solvents were purchased
as ACS reagents and used without further purification. Thin-
Layer chromatography (TLC) was conducted with 0.25 mm
Tsingdao silica gel plates (60F-254) and visualized by exposure
to UV light (254 nm) or stained with potassium permanganate.
Flash column chromatography was performed using Tsingdao
silica gel (60, particle size 0.040–0.063 mm). NMR spectra were
iminium ion C, which subsequently would react with H O to
2
12b,14
give 2a through facile oxidation of intermediate D.
Alternative capture of B by tert-butoxyl radical would lead to
formation of byproduct 3 through a similar sequence. Control
experiments were next conduct by treating 1a with anhydrous
18
CuCl and TBHP (5.5 M in nonane) in diglyme/H2 O (20/1) at
2
room temperature under either air exposure or Ar atmosphere.
18
Both of them gave the product 2a- O, confirming that H O
2
1
13
recorded on Bruker Advance 400 ( H: 400 MHz, C: 100 MHz)
or Bruker Advance 500 ( H: 500 MHz, C: 125 MHz). The
following abbreviations were used to explain the multiplicities: s
could function as a viable oxygen source during the oxidation.
1
13
3
. Conclusion
=
singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br =
broad. For all the HRMS measurements, the ionization method is
ESI and the mass analyzer type is TOF. For full experimental
In summary, guided by a notion that simple metal chloride
salt may function as viable chlorination agent, we have

Krische, C. D. Org. Lett., 2009, 11, 4485. (j) Zuo, J.; Liao, Y.-H.;
details, including procedures for all reactions and
characterizations of all new compounds ( H NMR, C NMR,
mass spectrometry), see the Supplementary Information.
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1
13
Zhang, X.; Yuan, W.-C. J. Org. Chem. 2012, 77, 11325. (k) Dou, X.;
Yao, W.; Zhou, B.; Lu, Y. Chem. Commun., 2013, 49, 9224. (l) Noole,
A.; Oseka, M.; Pehk, T.; Oeren, M.; Javing, I.; Elsegood, M. R. J.;
Malkov, A. V.; Lopp, M.; Kanger, T. Adv. Synth. Catal. 2013, 355, 829.
(
g) Krishnan, S.; Stoltz, B. M. Tetrahedron. Lett. 2007, 48, 7571.
4
.2 General procedure for CuCl /TBHP-mediated direct
2
4
.
(a) Aoyama, H.; Omote, Y.; Hasegawa, T.; Shiraishi, H. J. Chem. Soc.,
Perkin Trans. 1 1976, 1556. (b) Thomson, J. E.; Kyle, A. F.; Ling, K. B.;
Smith, S. R.; Slawin, A. M. Z.; Smith, A. D. Tetrahedron 2010, 66,
3801. (c) Magnus, P.; Turnbull, R. Org. Lett. 2006, 8, 3497. (d) Ghosh,
A. K.; Schiltz, G.; Perali, R. S.; Leshchenko, S.; Kay, S.; Walters, D. E.;
Koh, Y.; Maeda, K.; Mitsuya, H. Bioorg. Med. Chem. Lett. 2006, 16,
chlorooxidation of indoles
To a 10 mL round-bottomed flask placed with a solution of
substrate (0.10 mmol) in diglyme/H O (0.8 mL, 20:1 v/v) at room
temperature, added CuCl ·2H O (0.14 mmol), TBHP (70% in
2
2
2
1
869. (e) Shibata, N.; Kohno, J.; Takai, K.; Ishimaru, T.; Nakamura, S.;
water, 0.70 mmol) via micro-syringe. Then the solution was
stirred at room temperature (or warmed to 45 °C). After stirred
for 10-16 hours, the reaction was quenched with saturated
aqueous Na SO and diluted with EtOAc (5 mL) and water (5
mL), the organic layer was separated. The aqueous layer was
added 10% H SO (0.3 mL) and extracted with EtOAc (2×5 mL).
The combined organic layers were washed with water (4×5 mL)
and brine, dried over anhydrous Na SO4 and concentrated in
vacuo. The residue was purified by flash chromatography on
silica gel (Hex/EtOAc = 3:1) to give the desired products as off-
white solid.
Toru, T.; Kanemasa, S. Angew. Chem.,Int. Ed. 2005, 44, 4204. Selected
recent examples of preparation of asymmetric 3,3-disubstituted 3-
cholooxindoles from oxindole: (f) Cai, Y.; Liu, X.; Zhou, P.; Kuang, Y.;
Lin, L.; Feng, X. Chem. Commun., 2013, 49, 8054. (j) Noole, A.;
Jarving, I.; Werner, F.; M. Lopp, M.; Malkov, A.; Kanger, T. Org. Lett.
2
3
2
012, 14, 4922. (k) Zheng, W.; Zhang, Z.; Kaplan, M. J.; Antilla, J. C. J.
2
4
Am.Chem. Soc. 2012, 133, 3339. (l) Zhao, M.-X.; Zhang, Z.-W.; Chen,
M.-X.; Tang, W.-H.; Shi, M. Eur. J. Org. Chem. 2011, 3001. (m) Wang,
D.; Jiang, J.-J.; Zhang, R.; Shi, M. Tetrahedron: Asymmetry 2011, 22,
2
1
133.
5
6
.
.
(a) Muchowski, J. M. Can. J. Chem. 1970, 48, 422. (b) LopezAlvarado,
P.; Steinhoff, J.; Miranda, S.; Avendano, C.; Carlos Menendez, J.
Tetrahedron 2009, 65, 1660. (c) Breazzano, S. P.; Boger, D. L. J. Am.
Chem. Soc. 2011, 133, 18495. (d) Leong, S. Y.; Smith, P. W.; Zou, B.
Chin. J. Chem. 2014, 32, 1217. (e) Baroni, M.; Lesma, G.; Puleio, L.;
Sacchetti, A.; Silvani, A.; Zanchet, M. Synthesis 2010, 23, 4075.
Acknowledgments
(a) Balogh-Hergovich, E.; Speier, G. J. Chem. Soc., Perkin Trans. 1
1
986, 2305. (b) Barhata, N. B.; Gajare, A. S.; Wakharkar, R. D.;
We thank the National Science Foundation of China (Grants
Bedekar, A. B. Tetrahedron Lett. 1998, 39, 6349. (c) Li, Z.; Li, C.-J. J.
Am. Chem. Soc. 2004, 126, 11810. (d) Ye, Y.; Künzi, S. A.; Sanford, M.
S. Org. Lett. 2012, 14, 4979. (e) Wu, J. C.; Song, R. J.; Wang, Z. Q.;
Huang, X. C.; Xie, Y. X.; Li, J. H. Angew. Chem., Int. Ed. 2012, 51,
2
0972008, 21272014, and 21290180), the national “973 Project”
of the State Ministry of Science and Technology (Grants
013CB911500 and 2012CB722602), and the Shenzhen Bureau
2
3
453. (f) Kumar, G. S.; Pieber, B.; Reddy, K. R.; Kappe, C. O. Chem.
Eur. J. 2012, 18, 6124. (g) Cheng, J-K.; Loh, T-P. J. Am. Chem. Soc.
015, 137, 42. (h) Gogoi, A.; Guin, S.; Rout, S. K.; Patel, B. K. Org.
Lett. 2013, 15, 1802. (i) Yang, X.; Xi, C.; Jiang, Y. Molecules 2006, 11,
78. (j) Rout, S. K.; Guin, S.; Ghara, K. K.; Banerjee, A.; Patel, B. K.
of Science and Technology for financial support.
2
Supplementary material
9
Org. Lett. 2012, 14, 3982. (k) Rout, S. K.; Guin, S.; Gogoi, A.; Ganesh,
M.; Patel, B. K. Org. Lett. 2014, 16, 1614. (l) Li, Z.; Cui, Z.; Liu, Z-Q.
Org. Lett. 2013, 15, 406. (m) Zhao, J.; Fang, H.; Han, J.; Pan, Y. Org.
Lett. 2014, 16, 2530. (n) Tang, S.; Li, J-H.; Xie, Y-X.; Wang, N-X.
Synthesis 2007, 10, 1535.
Experimental
details
and
procedures,
compound
1
13
characterization data, copies of H, C spectra for new
compounds, and X-ray crystallographic data.
7
.
The crystal structure of the byproduct 3-peroxyoxindole 3n was
deposited at the Cambridge Crystallographic Data Centre (tracking
number: 1055715). For more details, see the Supporting Information.
References and notes
1
2
.
.
Hinman, R. L.; Bauman, C. P. J. Org. Chem. 1964, 29, 2431.
8. The yield of byproduct 3 is lower than 5%.
9. When using a 3-substituted indole, such as 1,3-dimethylindole as the
starting material, the yield of chlorooxidation product was lower than
10%.
(a) Fuchs, J. R.; Funk, R. L. Org. Lett. 2005, 7, 677. (b) Ghosh, A. K.;
Schiltz, G.; Perali, R. S.; Leshchenko, S.; Kay, S.; Walters, D. E.; Koh,
Y.; Maeda, K.; Mitsuya, H. Bio. Med. Chem. Lett. 2006, 16. 1869. (c)
Liao, Y-H.; Wu, Z-J.; Han, W-Y.; Zhang, X-M.; Yuan, W-C. Chem.
Eur. J. 2012, 18, 8916. (d) Zhang, H.; Kang, H.; Hong, L.; Dong, W.; Li,
G.; Zheng, X.; Wang, R. Org. Lett. 2014, 16, 2394. (e) Zuo, J.; Wu, J-
Q.; Zhou, M-Q.; Xu, X-Y.; Zhang, X-M.; Yuan, W-C. J. Org. Chem.
3
10. The crystal structure of 2c•CHCl was deposited at the Cambridge
Crystallographic Data Centre (tracking number: 1055643).
11. Volk, B.; Gacsalyi, I.; Pallagi, K.; Poszavacz, L.; Gyonos, I.; Szabo, E.;
Bako, T.; Spedding, M.; Simig, G.; Szenasi, G. J. Med. Chem. 2011, 54,
6657.
2
015, 80, 634.
3
.
(a) Labroo, R. B.; Labroo, V. M.; King, M. M.; Cohen, L. A. J. Org.
Chem. 1991, 56, 3637. (b) Kobayashi, M.; Aoki, S.; Gato, K.;
Matsunami, K.; Kurosu, M.; Kitagawa, I. Chem. Pharm. Bull. 1994, 42,
12. (a) Sheldon, R. A.; Kochi, J. K. Metal-Catalyzed Oxidations of Organic
Compounds, Academic Press, New York, 1981. (b) Rothenberg, G.;
Feldberg, L.; Wiener, H.; Sasson, Y. J. Chem. Soc., Perkin Trans. 2
1998, 2429.
13. (a) Kundu, R.; Ball, Z. T. Org. Lett. 2010, 12, 2460. (b) Van der Jeught,
S.; De Vos, N.; Masschelein, K. G. R.; Ghiviriga, I.; Stevens, C. V. Eur.
J. Org. Chem. 2010, 5444.
2
1
1
2
449. (c) Rajeswaran, W. G.; Labroo, R. B.; Cohen, L. A. J. Org. Chem.
999, 64, 1369. (d) Fuchs, J. R.; Funk, R. L. J. Am. Chem.Soc. 2004,
26, 5068. (e) Menozzi, C.; Dalko, P. I.; Cossy, J. Chem. Commun.
006, 44, 4638. (f) Zhang, H.; Hong, L.; Kang, H.; Wang, R. J. Am.
Chem. Soc. 2013, 135, 14098. (g) Belmar, J.; Funk, R. L. J. Am. Chem.
Soc. 2012, 134, 16941. (h) Ma, S.; Han, X.; Krishnan, S.; Virgil, S. C.;
Stoltz, B. M. Angew. Chem., Int. Ed. 2009, 48, 8037. (i) Grant, C. D.;
14. Ekoue-Kovi, K.; Wolf, C. Org. Lett. 2007, 9, 3429.
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ACCEPTED MANUSCRIPT
Supporting Information
CuCl /TBHP-Mediated Direct Chlorooxidation of Indoles
2
Huifei Wang, Dong Liu, Huiyu Chen, Jing Li, David Zhigang Wang*
Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Shenzhen
Graduate School of Peking University, Shenzhen, China 518055
dzw@pkusz.edu.cn
Table of Contents
Materials and methods
S2
Synthesis of N-tosyl tryptamine derivatives
S3
S5
1
13
H NMR and C NMR spectra data of N-tosyl tryptamine derivatives
Procedure for synthesis of substrate 1m-n, 1q-1r
S10
S13
S14
S15
S21
S23
S24
S24
S25
S69
1
13
H NMR and C NMR spectra data of 1m-n, 1q-1r
General procedure for product synthesis
1
13
H NMR and C NMR spectra data of product
Application and transformation of 3-chlorooxindoles
1
13
H NMR and C NMR spectra data of corresponding products
Mechanistic study
Chlorooxidation of tryptamine derivatives using NCS and DCU
1
13
Copies of H NMR and C NMR spectra
Crystal structures of product 2c·CHCl and byproduct 3n
3
S1

ACCEPTED MANUSCRIPT
Materials and methods： All reactions were carried out under a nitrogen atmosphere with dry
solvents under anhydrous conditions, unless otherwise noted. All the chemicals were purchased
commercially, and used without further purification. CuCl ·2H O was purchased from Alfa.
2
2
Anhydrous tetrahydrofuran (THF) and Et O were distilled from sodium-benzophenone,
2
dichloromethane (DCM) were distilled from calcium hydride. All other solvents were purchased as
ACS reagents and used without further purification. Thin-Layer chromatography (TLC) was
conducted with 0.25 mm Tsingdao silica gel plates (60F-254) and visualized by exposure to UV light
(254 nm) or stained with potassium permanganate. Flash column chromatography was performed
using Tsingdao silica gel (60, particle size 0.040–0.063 mm). NMR spectra were recorded on Bruker
1
13
1
13
Advance 400 ( H: 400 MHz, C: 100 MHz) or Bruker Advance 500 ( H: 500 MHz, C: 125 MHz).
The following abbreviations were used to explain the multiplicities: s = singlet, d = doublet, t =
triplet, q = quartet, m = multiplet, br = broad. For all the HRMS measurements, the ionization
method is ESI and the mass analyzer type is TOF.
S2

ACCEPTED MANUSCRIPT
Synthesis of N-tosyl tryptamine derivatives：
1
,2
N-tosyl tryptamine derivatives prepared according to known literature procedures.
1
General procedure A: (Substrate 1a, 1e-f, 1j-1k, 1o-1p)
To a solution of tryptamine (5.0 mmol) in CH Cl (40 mL) at 0 °C was added Et N (15 mmol), then
2
2
3
added p-toluenesulfonyl chloride (6.0 mmol) in one portion. The mixture was stirred for 0.5 h, the
ice bath removed and allowed to warm up to room temperature. After stirred for an additional 4-8
hours, the reaction was quenched with saturated aqueous NH Cl (15 mL). The mixture diluted with
4
water (30 mL), the organic layer was separated and the aqueous layer was extracted with CH Cl (2
2
2
×20 mL). The combined organic layers were washed with water (2×40 mL) and brine, dried over
anhydrous Na SO and concentrated in vacuo. The residue was purified by flash chromatography on
2
4
silica gel (Hex/EtOAc = 5:1) to give the desired products in the yield of 76-88%.
To a solution of tosyltryptamine (2.0 mmol) in DMF (7 mL) at room temperature was added NaH (60%
dispersion in mineral oil, 7.0 mmol) slowly, with vigorous stirring, and stirring continued at this
temperature for 30 minutes. Then the solution was cooled to 0 °C in an ice bath, and appropriate
alkyl halide (2.0 mmol) was added drop-wise by syringe. Stirring was continued at 0 °C for two
hours, and the reaction allowed to warm up to room temperature and stirred overnight. The reaction
was quenched with saturated aqueous NH Cl (3 mL) and diluted with EtOAc (10 mL) and water (10
4
mL), the organic layer was separated and the aqueous layer was extracted with EtOAc (2×10 mL).
The combined organic layers were washed with water (4×20 mL) and brine, dried over anhydrous
Na SO and concentrated in vacuo. The residue was pre-absorbed onto silica and purified by flash
2
4
chromatography on silica gel (Hex/EtOAc = 4:1) to give the desired products in the yield of 62-75%.
S3

ACCEPTED MANUSCRIPT
1
2
.
.
Kieffer, M. E.; Chuang, K. V.; Reisman, S. E. Chem. Sci. 2012, 3, 3170.
Muratore, M. E.; Holloway, C. A.; Pilling, A. W.; Storer, R. I.; Trevitt, G.; Dixon, D. J. J. Am. Chem. Soc. 2009, 131, 10796.
2
General procedure B: (Substrate 1b-d, 1g-1i)
To a solution of indole (12.0 mmol) in DMF (60 mL) at 0 ºC was added NaH (60% dispersion in
mineral oil, 14.4 mmol) slowly. The mixture was stirred at this temperature for 30minutes, then
methyl iodide (13.2 mmol) was added drop-wise via syringe. Then the reaction was gradually
warmed up to room temperature and stirred for 3 hours. The reaction was quenched with saturated
aqueous NH Cl and diluted with EtOAc (60 mL) and water (60 mL), the organic layer was separated
4
and the aqueous layer was extracted with EtOAc (2×60 mL). The combined organic layers were
washed with water (4×60 mL) and brine, dried over anhydrous Na SO and concentrated in vacuo
2
4
to furnish the desired N-methyl indole as colorless oil that required no further purification.
To a cooled solution of DMF (5 mL, 3 mL per 1 mL of POCl ) at 0 ºC was added phosphorus
3
oxychloride (1.6 mL, 18 mmol) drop-wise, and then the mixture was stirred at the same temperature
for 1 h. Then N-methyl indole (ca. 12 mmol) was added as a DMF solution (10 mL), forming a
heavy suspension that required vigorous stirring. The mixture was then allowed to warm to room
temperature and stirred for 5 hours. Then 2M NaOH (27 mL) was added slowly with vigorous
stirring. The mixture was heated to reflux for 20 minutes. Then the reaction was cooled to room
temperature and diluted with EtOAc (15 mL) and water (15 mL). The organic layer was separated
and the aqueous layer was extracted with EtOAc (2×15 mL). The combined organic layers were
washed with water (4×15 mL) and brine, dried over anhydrous Na SO and concentrated in vacuo
2
4
S4

ACCEPTED MANUSCRIPT
to furnish the desired aldehyde as yellowish solid that required no further purification.
Aldehyde (4 mmol) and ammonium acetate (12 mmol) were refluxed in nitromethane (12 mL) for 1
hour. The solvent was removed in vacuo and the residue washed with water and filtered, furnishing
the desired nitro olefin as yellowish solid that required no further purification.
To an oven-dried 100 mL round-bottomed flask placed with a solution of nitro olefin (3 mmol) in
freshly distilled THF (24 mL) with ice-bath cooling, added lithium aluminium hydride powder (24
mmol) cautiously in three portions. Stirring was continued at 0 °C for 30 minutes, and the reaction
allowed to heat to reflux and stirring overnight. The reaction was cooled to 0 °C and carefully
quenched by the dropwise addition of water (1 mL per 1 g LiAlH ), 10% NaOH (1 mL per 1 g
4
LiAlH ), and water (2 mL per 1 g LiAlH ) under stirring. Filtered and the filtrate was concentrated in
4
4
vacuo to furnish the crude amine. A solution of crude residue in CH Cl (15 mL) at 0 °C was added
2
2
Et N (6 mmol), then added p-toluenesulfonyl chloride (2 mmol) in one portion. The mixture was
3
stirred for 0.5 h, the ice bath removed and allowed to warm up to room temperature. After stirred for
an additional 4-8 hours, the reaction was quenched with saturated aqueous NH Cl (5 mL). The
4
mixture diluted with water (10 mL), the organic layer was separated and the aqueous layer was
extracted with CH Cl (2×10 mL). The combined organic layers were washed with water (2×20
2
2
mL) and brine, dried over anhydrous Na SO and concentrated in vacuo. The residue was purified by
2
4
flash chromatography on silica gel (Hex/EtOAc = 5:1) to give the off-white solid as desired products.
1
13
H NMR and C NMR spectra data of N-tosyl tryptamine derivatives
1
N-tosyl-N’-methyltryptamine (1a): Prepared according to General Procedure A. H NMR (400
MHz, CDCl ) δ 7.65 (d, J = 8.2 Hz, 2H), 7.41 (d, J = 7.9 Hz, 1H), 7.29 (d, J = 8.2 Hz, 1H), 7.25-7.19
3
(m, 3H), 7.06 (dd, J = 8, 8Hz, 1H), 6.82 (s, 1H), 4.58 (t, J = 5.8 Hz, 1H), 3.72 (s, 3H), 3.26 (q, J = 6.5
S5

ACCEPTED MANUSCRIPT
1
3
Hz, 2H), 2.92 (t, J = 6.6 Hz, 2H), 2.41 (s, 3H); C NMR (100 MHz, CDCl ) δ 143.2, 137.1, 136.8,
3
129.6, 127.4, 127.3, 127.0, 121.8, 119.0, 118.6, 110.0, 109.3,43.2, 32.6, 25.4, 21.5; HRMS calc’d for
+
C H N O S [M+H] : 329.1318, found 329.1324.
18
21
2
2
Me
NHTs
N
Me
1e
1
5
-methyl-N-tosyl-N’-methyltryptamine (1e): Prepared according to General Procedure A. H NMR
(
400 MHz, CDCl ) δ 7.64 (dd, J = 8.3 Hz, 2H), 7.22 (d, J = 8.0 Hz, 2H), 7.18 (s, 1H), 7.16 (s, 1H),
3
7
2
1
.05 (d, J = 8.3 Hz, 1H), 6.77 (s, 1H), 4.57 (t, J = 6.0 Hz, 1H), 3.69 (s, 3H), 3.25 (q, J = 6.5 Hz, 2H),
1
3
.89 (t, J = 6.6 Hz, 2H), 2.42 (s, 3H), 2.41 (s, 3H); C NMR (100 MHz, CDCl ) δ 143.2, 136.8,
3
35.6, 129.5, 128.2, 127.5, 127.4, 127.0, 123.4, 118.2, 109.2, 109.1,43.1, 32.6, 25.3, 21.5, 21.4;
+
HRMS calc’d for C H N O S [M+H] : 343.1475, found 343.1474.
1
9
23
2
2
1
5
-methoxy-N-tosyl-N’-methyltryptamine (1f): Prepared according to General Procedure A. H
NMR (400 MHz, CDCl ) δ 7.61 (d, J = 8.3 Hz, 2H), 7.21 (d, J = 8.0 Hz, 2H), 7.17 (d, J = 8.8 Hz,
3
1H), 6.88 (dd, J = 8.8, 2.4 Hz, 1H), 6.82 (d, J = 2.3 Hz, 1H), 6.78 (s, 1H), 4.45 (br s, 1H), 3.80 (s,
13
3
H), 3.70 (s, 3H), 3.23 (q, J = 6.5 Hz, 2H), 2.89 (t, J = 6.6 Hz, 2H), 2.40 (s, 3H); C NMR (100
MHz, CDCl ) δ 153.7, 143.2, 136.6, 132.5, 129.5, 127.9, 127.5, 127.0, 112.0, 110.1, 109.2, 100.3,
3
+
5
5.8, 42.9, 32.8, 25.3, 21.4; HRMS calc’d for C H N O S [M+H] : 359.1424, found 359.1423.
1
9
23
2
3
1
5
-chloro-N-tosyl-N’-methyltryptamine (1j): Prepared according to General Procedure A. H NMR
(
400 MHz, CDCl ) δ 7.61 (d, J = 8.3 Hz, 2H), 7.27 (d, J = 1.7 Hz, 1H), 7.22 (d, J = 8.1 Hz, 2H), 7.18
3
S6

ACCEPTED MANUSCRIPT
–
7.14 (m, 2H), 6.85 (s, 1H), 6.85 (br s, 1H), 4.45 (s, 1H), 3.71 (s, 3H), 3.22 (q, J = 6.5 Hz, 2H), 2.85
1
3
(
t, J = 6.6 Hz, 2H), 2.41 (s, 3H); C NMR (100 MHz, CDCl ) δ 143.4, 136.5, 135.5, 129.6, 128.7,
3
128.2, 126.9, 124.8, 122.0, 118.0, 110.3, 109.5, 42.8, 32.8, 25.1, 21.5; HRMS calc’d for
+
C H ClN O S [M+H] : 363.0929, found 363.0930.
18
20
2
2
1
5
-bromo-N-tosyl-N’-methyltryptamine (1k): Prepared according to General Procedure A. H NMR
(
(
(
400 MHz, CDCl ) δ 7.61 (d, J = 8.3 Hz, 2H), 7.43 (d, J = 1.7 Hz, 1H), 7.29 (d, J = 1.8 Hz, 1H), 7.27
3
s, 1H), 7.24 (d, J = 8.0 Hz, 2H), 7.14 (d, J = 8.7 Hz, 1H), 6.84 (s, 1H), 4.37 (t, J = 5.7 Hz, 1H), 3.71
1
3
s, 3H), 3.22 (q, J = 6.4 Hz, 2H), 2.85 (t, J = 6.6 Hz, 2H), 2.42 (s, 3H); C NMR (100 MHz, CDCl )
3
δ 143.4, 136.5, 135.8, 129.6, 128.9, 128.6, 127.0, 124.5, 121.1, 112.4, 110.8, 109.6, 42.9, 32.8, 25.1,
+
2
1.5; HRMS calc’d for C H BrN O S [M+H] : 407.0423, found 407.0424, 409.0412.
1
8
20
2
2
5-TMS-N-tosyl-N’-methyltryptamine (1l): To an oven-dried 10 mL round bottom flask placed with
a solution of 5-bromo-N-tosyl-N’-methyltryptamine 1k (0.204 g, 0.5 mmol) in freshly distilled THF
5 mL) at -78 ºC, added n-BuLi (2.5 M in hexane, 0.44 mL, 1.1 mmol) dropwise via syringe. The
(
reaction was stirred at -78 ºC for 0.5 h, then TMSCl was added (0.086 mL, 1.0 mmol) dropwise via
syringe. Then the mixture was gradually warmed up to room temperature and stirred overnight. The
reaction was quenched with saturated aqueous NH Cl (1 mL) and diluted with EtOAc (5 mL) and
4
water (5 mL), the organic layer was separated and the aqueous layer was extracted with EtOAc (2×5
mL). The combined organic layers were washed with water (2×5 mL) and brine, dried over
anhydrous Na SO and concentrated in vacuo. The residue was purified by flash chromatography on
2
4
1
silica gel (Hex/EtOAc = 4:1) to afford the desired product (0.078 g, 39% yield). H NMR (400 MHz,
CDCl ) δ 7.66 (d, J = 8.3 Hz, 2H), 7.60 (s, 1H), 7.40 – 7.28 (m, 2H), 7.22 (t, J = 7.3 Hz, 2H), 6.81 (s,
3
S7

ACCEPTED MANUSCRIPT
1
3
1
H), 4.47 (t, J = 6.2 Hz, 1H), 3.73 (s, 3H), 3.27 (q, J = 6.5 Hz, 2H), 2.95 (t, J = 6.6 Hz, 2H), 2.40 (s,
13
H), 0.34 (s, 9H); C NMR (100 MHz, CDCl ) δ 143.2, 137.6, 136.8, 129.6, 129.1, 127.2, 127.1,
3
27.0, 126.5, 123.9, 110.0, 109.0, 43.2, 32.6, 25.4, 21.5, -0.6; HRMS calc’d for C H N O SSi
2
1
29
2
2
+
[
M+H] : 401.1714, found 401.1715.
NHTs
N
Et
1o
1
N-tosyl-N’-ethyltryptamine (1o): Prepared according to General Procedure A. H NMR (400 MHz,
CDCl ) δ 7.66 (d, J = 8.3 Hz, 2H), 7.41 (d, J = 7.9 Hz, 1H), 7.31 (d, J = 8.3 Hz, 1H), 7.22 (d, J = 8.2
3
Hz, 3H), 7.07 – 7.02 (m, 1H), 6.89 (s, 1H), 4.63 (s, 1H), 4.11 (q, J = 7.3 Hz, 2H), 3.27 (q, J = 6.6 Hz,
1
3
2
1
2
H), 2.93 (t, J = 6.7 Hz, 2H), 2.40 (s, 3H), 1.43 (t, J = 7.3 Hz, 3H); C NMR (100 MHz, CDCl ) δ
3
43.2, 136.8, 136.1, 129.6, 127.4, 126.9, 125.4, 121.6, 118.9, 118.7, 110.0, 109.4, 43.2, 40.7, 25.4,
+
1.4, 15.4; HRMS calc’d for C H N O S [M+H] : 343.1475, found 343.1475.
1
9
23
2
2
NHTs
N
Bn
1
p
1
N-tosyl-N’-benzyltryptamine (1p): Prepared according to General Procedure A. H NMR (400
MHz, CDCl ) δ 7.63 (d, J = 8.3 Hz, 2H), 7.42 (d, J = 7.9 Hz, 1H), 7.34 – 7.28 (m, 2H), 7.26 (t, J =
3
4.1 Hz, 2H), 7.22 – 7.14 (m, 3H), 7.12 – 7.08 (m, 2H), 7.08 – 7.02 (m, 1H), 6.86 (s, 1H), 5.25 (s, 2H),
1
3
4
.40 (t, J = 6.0 Hz, 1H), 3.28 (q, J = 6.5 Hz, 2H), 2.92 (t, J = 6.7 Hz, 2H), 2.39 (s, 3H); C NMR
(
100 MHz, CDCl ) δ 143.2, 137.3, 136.7, 129.5, 128.7, 127.6, 127.5, 126.9, 126.7, 126.5, 122.0,
3
+
1
19.2, 118.7, 110.6, 109.8，49.9, 43.0, 25.4, 21.4; HRMS calc’d for C H N NaO S [M+Na] :
24
24
2
2
427.1456, found 427.1443.
S8

ACCEPTED MANUSCRIPT
1
4
-methyl-N-tosyl-N’-methyltryptamine (1b): Prepared according to General Procedure B. H
NMR (400 MHz, CDCl ) δ 7.68 (d, J = 8.0 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 7.11 (s,1H), 7.11 (d, J
3
=
8.0 Hz, 1H), 6.83 – 6.79 (m, 1H), 6.78 (s, 1H), 4.73 (t, J = 6.1 Hz, 1H), 3.69 (s, 3H), 3.24 (q, J =
1
3
6
1
2
.6 Hz, 1H), 3.07 (t, J = 6.7 Hz, 1H), 2.54 (s, 3H), 2.41 (s, 3H); C NMR (100 MHz, CDCl ) δ 143.3,
3
37.6, 136.8, 130.6, 129.6, 127.5, 127.0, 125.8, 121.8, 120.8, 110.7, 107.2, 44.3, 32.7, 27.0, 21.5,
+
0.2; HRMS calc’d for C H N O S [M+H] : 343.1475, found 343.1473.
1
9
23
2
2
1
6
-methyl-N-tosyl-N’-methyltryptamine (1c): Prepared according to General Procedure B. H NMR
(
400 MHz, CDCl ) δ 7.63 (d, J = 8.0 Hz, 2H), 7.28 (s, 1H), 7.22 (d, J = 8.0 Hz, 2H), 7.08 (s, 1H),
3
6
2
1
2
.89 (dd, J = 8.1, 0.8 Hz, 1H), 6.74 (s, 1H), 4.43 (t, J = 6.1 Hz, 1H), 3.69 (s, 3H), 3.24 (q, J = 6.5 Hz,
1
3
H), 2.89 (t, J = 6.6 Hz, 2H), 2.49 (s, 3H), 2.41 (s, 3H); C NMR (100 MHz, CDCl ) δ 143.2, 137.6,
3
36.8, 131.7, 129.5, 127.0, 126.7, 125.1, 120.7, 118.3, 109.7, 109.3, 77.3, 77.0, 76.7, 43.1, 32.5, 25.4,
+
1.8, 21.4; HRMS calc’d for C H N O S [M+H] : 343.1475, found 343.1474.
1
9
23
2
2
1
7
-methyl-N-tosyl-N’-methyltryptamine (1d): Prepared according to General Procedure B. H
NMR (400 MHz, CDCl ) δ 7.65 (d, J = 8.3 Hz, 2H), 7.24 (s, 1H), 7.24 – 7.21 (m, 2H), 6.92-6.88 (m,
3
2
2
1
H), 6.70 (s, 1H), 4.61(t,J = 6.1 Hz,1H), 3.98 (s, 3H), 3.24 (q, J = 6.5 Hz, 2H), 2.92 – 2.82 (m, 2H),
1
3
.74 (d, J = 6.6 Hz, 3H), 2.42 (d, J = 7.0 Hz, 3H); C NMR (100 MHz, CDCl ) δ 143.2, 136.8, 135.8,
3
29.6, 128.9, 128.4, 127.0, 124.4, 121.4, 119.3, 116.6, 109.6, 43.0, 36.5, 25.3, 21.5, 19.6; HRMS
S9

ACCEPTED MANUSCRIPT
+
calc’d for C H N O S [M+H] : 343.1475, found 343.1473.
1
9
23
2
2
1
5
-fluoro-N-tosyl-N’-methyltryptamine (1g): Prepared according to General Procedure B. H NMR
(
400 MHz, CDCl ) δ 7.62 (d, J = 8.3 Hz, 2H), 7.22 (d, J = 8.0 Hz, 2H), 7.17 (dd, J = 9.7, 4.3 Hz, 1H),
3
6
2
1
1
.95 (d, J = 9.5 Hz, 2H), 6.86 (s, 1H), 4.52 (t, J = 6.0 Hz, 1H), 3.71 (s, 3H), 3.22 (q, J = 6.5 Hz, 2H),
1
3
.85 (t, J = 6.6 Hz, 2H), 2.41 (s, 3H); C NMR (100 MHz, CDCl ) δ 157.5 (d, J = 234.6 Hz), 143.4,
3
36.6, 133.7, 129.6, 129.0, 127.4 (d, J = 9.6 Hz), 126.9, 110.1 (d, J = 20.4 Hz), 109.9 (d, J = 3.8 Hz),
19
09.8 (d, J = 4.8 Hz), 103.4 (d, J = 23.4 Hz), 42.9, 32.9, 25.2, 21.5; F NMR (376 MHz, CDCl3) δ
+
-
125.2.; HRMS calc’d for C H FN O S [M+H] : 347.1224, found 347.1224.
1
8
20
2
2
1
5
-fluoro-N-tosyl-N’-methyltryptamine (1h): Prepared according to General Procedure B. H NMR
(
400 MHz, CDCl ) δ 7.63 (d, J = 8.0 Hz, 2H), 7.29 (s, 3H), 7.20 (s, 1H), 6.96 – 6.89 (m, 1H), 6.84 –
3
6
2
1
3
3
.74 (m, 2H), 4.69 (t, J = 5.7 Hz, 1H), 3.65 (s, 3H), 3.23 (q, J = 6.4 Hz, 2H), 2.87 (t, J = 6.6 Hz, 2H),
1
3
.41 (s, 3H); C NMR (100 MHz, CDCl ) δ 159.9 (d, J = 235.0 Hz), 143.3, 137.2, 136.6, 129.5,
3
27.6, 126.9, 123.8, 119.3 (d, J = 10.3 Hz), 110.3, 107.6 (d, J = 24.7 Hz), 95.7 (d, J = 26.3 Hz), 43.1,
19
+
2.7, 25.3, 21.5; F NMR (376 MHz, CDCl3) δ -120.7; HRMS calc’d for C H FN O S [M+H] :
18
20
2
2
47.1224, found 347.1223.
1
4
-chloro-N-tosyl-N’-methyltryptamine (1i): Prepared according to General Procedure B. H NMR
S10

ACCEPTED MANUSCRIPT
(
400 MHz, CDCl ) δ 7.64 (d, J = 8.2 Hz, 2H), 7.18 (d, J = 8.0 Hz, 2H), 7.16 – 7.12 (m, 1H), 7.07 (t, J
3
=
7.8 Hz, 1H), 6.99 (dd, J = 7.4, 0.7 Hz, 1H), 6.84 (s, 1H), 4.67 (t, J = 5.9 Hz, 1H), 3.68 (s, 3H), 3.30
1
3
(
q, J = 6.4 Hz, 2H), 3.10 (t, J = 6.6 Hz, 2H), 2.38 (s, 3H); C NMR (100 MHz, CDCl ) δ 143, 138.6,
3
136.8, 129.5, 129.2, 126.9, 126.0, 124.0, 122.1, 119.9, 110.4, 108.1, 44.4, 32.9, 26.3, 21.5; HRMS
+
calc’d for C H ClN O S [M+H] : 363.0929, found 363.0931.
1
8
20
2
2
Procedure for synthesis of substrate 1m-n, 1q-1r
To a yellow suspension of tryptamine (2.0 g, 12.5 mmol) in 1,4-dioxane (10 mL) was added Et N
3
(
3.6 mL, 26.0 mmol) at 0 °C. Then a solution of (Boc) O (3.0 g, 13.8 mmol) in 1,4-dioxane (10 mL)
2
was added via cannula. Then the reaction was allowed to warm up to room temperature and stirred
for 2 hours. The reaction solution was concentrated under reduced pressure. The crude residue was
purified by flash chromatography on silica gel (Hex/EtOAc = 4:1) to give the desired
N-Boc-tryptamine as a white solid (3.102 g, 95% )
A mixture of N-Boc-tryptamine (1.041 g, 4 mmol), NaOH (0.640 g, 16 mmol), nBu HSO (0.271 g,
4
4
0
.8 mmol) was stirred in wet CH Cl (20 mL) at 0 °C for 30 minutes, MeI (0.28 mL, 4.4 mmol) was
2 2
added into the solution. The reaction was allowed to warm up to room temperature and stirred for 24
hours. The reaction was quenched with saturated aqueous NH Cl. The mixture diluted with water, the
4
organic layer was separated and the aqueous layer was extracted with CH Cl . The combined organic
2
2
layers were washed with water and brine, dried over anhydrous Na SO and concentrated in vacuo.
2
4
The residue was purified by flash chromatography on silica gel (Hex/EtOAc = 5:1) to give the
desired products (0.602 g, 55%) as a white solid.
S11

ACCEPTED MANUSCRIPT
Tryptamine (10 g, 62.4 mmol) was suspended in a vigorously stirred 1:1 v/v mixture of aqueous
sodium hydroxide solution (2 M in water, 94 mL, 188 mmol) and CH Cl (94 mL). After cooling to
2
2
0
°C, methyl chloroformate (9.6 mL, 125 mmol) was added drop-wise. Once the addition was
complete, the mixture was allowed to warm to room temperature. After 4 hours, the phases were
separated and the aqueous phase extracted with CH Cl . The combined organic extracts were washed
2
2
with brine, dried over anhydrous Na SO and concentrated in vacuo. The crude product was purified
2
4
by crystallisation from a mixture of iso-propanol and hexane to give the desired carbamate (11.246 g,
3%) as a pale beige powder.
8
A mixture of carbamate (1.092 g, 5 mmol), NaOH (0.800 g, 20 mmol), nBu HSO (0.153 g, 0.45
4
4
mmol) was stirred in wet CH Cl (45 mL) at 0 °C for 30 minutes, MeI (0.38 mL, 6 mmol) was added
2
2
into the solution. The reaction was allowed to warm up to room temperature and stirred for 24 hours.
The reaction was quenched with saturated aqueous NH Cl. The mixture diluted with water, the
4
organic layer was separated and the aqueous layer was extracted with CH Cl . The combined organic
2
2
layers were washed with water and brine, dried over anhydrous Na SO and concentrated in vacuo.
2
4
The residue was purified by flash chromatography on silica gel (Hex/EtOAc = 5:1) to give the
desired products (1.059 g, 91%) as off-white solid.
To a solution of indole-3-propionic acid (0.605 g, 3.2 mmol) in acetone (30 mL), was added MeI (1.0
mL, 16 mmol) and KOH (1.068 g, 19.1 mmol) at 0 °C. After 4 hours at rt, the solvent was removed
under reduced pressure. The residue was suspended in H O (65 mL) and KOH (0.900 g, 16 mmol)
2
was added, and the solution stirred at reflux for 2 h. After cooling to 0 °C, the solution was acidified
to pH 1 with aqueous 6M HCl and filtered and the residue was washed by heptane for three times.
The residue was purified by flash chromatography on silica gel (Hex/EtOAc = 2:1) to give the
desired product as a white solid. A solution of acid (0.427 g, 2.1 mmol) in freshly distilled Et O (15
2
mL) with ice-bath cooling, added lithium aluminium hydride powder (0.639 g, 6.3 mmol) cautiously.
S12

ACCEPTED MANUSCRIPT
Stirring was continued at 0 °C for 30 minutes, and the reaction allowed to warm to room temperature
and stirring overnight. The reaction was cooled to 0 °C and carefully quenched by the dropwise
addition of water (1 mL per 1 g LiAlH ), 10% NaOH (1 mL per 1 g LiAlH ), and water (2 mL per 1
4
4
g LiAlH ) under stirring. Filtered and the filtrate was concentrated in vacuo. The residue was purified
4
by flash chromatography on silica gel (Hex/EtOAc = 5:1) to give the desired product (0.303 g, 50%
for 2 steps) as colorless oil.
A solution of crude acid (2.032 g, 10 mmol) in freshly distilled Et O (100 mL) with ice-bath cooling,
2
added lithium aluminium hydride powder (0.950 g, 2.5 mmol) cautiously. Stirring was continued at
0
°C for 30 minutes, and the reaction allowed to warm to room temperature and stirring for15 hours.
The reaction was cooled to 0 °C and carefully quenched by the dropwise addition of water (1 mL per
g LiAlH ), 10% NaOH (1 mL per 1 g LiAlH ), and water (2 mL per 1 g LiAlH ) under stirring.
1
4
4
4
Filtered and the filtrate was concentrated in vacuo to give the crude alcohol. To a solution of crude
alcohol (ca. 8.4 mmol) in THF (40 mL) at 0 ºC was added NaH (60% dispersion in mineral oil, 0.370
g, 9.24 mmol) slowly. The mixture was stirred at this temperature for 0.5 h, then methyl iodide (0.58
mL, 9.24 mmol) was added dropwise via syringe. Then the reaction was gradually warmed up to
room temperature and stirred for 12 hours. The reaction was quenched with saturated aqueous NH Cl
4
and diluted with EtOAc and water, the organic layer was separated and the aqueous layer was
extracted with EtOAc. The combined organic layers were washed with water and brine, dried over
anhydrous Na SO and concentrated in vacuo. The residue was purified by flash chromatography on
2
4
silica gel (Hex/EtOAc = 5:1) to give the desired product (0.730 g, 36% for 2 steps) as colorless oil.
1
13
H NMR and C NMR spectra data of 1m-n, 1q-1r
S13

ACCEPTED MANUSCRIPT
1
N-Boc-N’-methyltryptamine (1m): H NMR (400 MHz, CDCl ) δ 7.61 (d, J = 7.9 Hz, 1H), 7.31 (d,
3
J = 8.2 Hz, 1H), 7.24 (dd, J = 8.2, 1.1 Hz, 1H), 7.12 (ddd, J = 7.9, 7.0, 1.1 Hz, 1H), 6.89 (s, 1H), 4.64
1
3
(
s, 1H), 3.76 (s, 3H), 3.48 (q, J = 6.1 Hz, 2H), 2.95 (t, J = 6.7 Hz, 2H), 1.45 (s, 9H); C NMR (100
MHz, CDCl ) δ 155.9, 137.1, 127.8, 126.8, 121.7, 118.9, 118.8, 111.6, 109.2, 79.0, 41.0, 32.6, 28.4,
3
+
2
5.7; HRMS calc’d for C H N NaO [M+Na] : 297.1579, found 297.1573.
1
6
22
2
2
1
N-methoxycarbonyl-N’-methyltryptamine (1n): H NMR (400 MHz, CDCl ) δ 7.60 (d, J = 7.9 Hz,
3
1H), 7.31 (d, J = 8.2 Hz, 1H), 7.27 – 7.22 (m, 1H), 7.13 (ddd, J = 7.9, 7.0, 1.1 Hz, 1H), 6.89 (s, 1H),
1
3
4
.78 (s, 1H), 3.76 (s, 3H), 3.67 (s, 3H), 3.51 (dd, J = 12.6, 6.3 Hz, 2H), 2.96 (t, J = 6.7 Hz, 2H); C
NMR (100 MHz, CDCl ) δ 157.0, 137.1, 127.7, 126.8, 121.7, 118.9, 118.8, 111.3, 109.3, 52.0, 41.4,
3
+
3
2.6, 25.7; HRMS calc’d for C H N O [M+H] : 233.1285, found 233.1282.
1
3
17
2
2
1
N-methyl-Indole-3-propanol (1q): H NMR (400 MHz, CDCl ) δ 7.39 (dd, J = 7.5, 0.6 Hz, 1H),
3
7.34 (td, J = 7.8, 1.2 Hz, 1H), 7.12 (td, J = 7.6, 0.9 Hz, 1H), 6.85 (d, J = 7.8 Hz, 1H), 3.58 – 3.50 (m,
1
3
2
H), 3.23 (s, 3H), 2.39 – 2.29 (m, 2H), 1.75 (br s, 1H), 1.50 – 1.36 (m, 2H); C NMR (100 MHz,
CDCl ) δ 173.9, 142.6, 130.2, 129.3, 124.2, 123.5, 108.7, 64.7, 61.9, 35.6, 27.5, 26.6; HRMS calc’d
3
+
for C H NO [M+H] : 190.1226, found 190.1224.
1
2
16
1
N-methyl-Indole-3-butanol (1r): H NMR (500 MHz, CDCl ) δ 7.61 (d, J = 7.9 Hz, 1H), 7.30 (d, J
3
=
8.2 Hz, 1H), 7.25 – 7.21 (m, 1H), 7.11 (ddd, J = 7.0, 5.5, 1.0 Hz, 1H), 6.85 (s, 1H), 3.75 (s, 3H),
S14

ACCEPTED MANUSCRIPT
3
1
3
.68 (t, J = 6.6 Hz, 2H), 2.80 (t, J = 7.5 Hz, 2H), 1.85 – 1.72 (m, 2H), 1.73 – 1.62 (m, 3H), 1.40 (s,
1
3
H); C NMR (125 MHz, CDCl ) δ 137.1, 127.9, 126.1, 121.4, 119.0, 118.5, 115.1, 109.1, 62.9,
3
+
2.7, 32.5, 26.5, 24.8; HRMS calc’d for C H NO [M+H] : 204.1383, found 204.1382.
1
3
18
General procedure C for product synthesis
To a 10 mL round-bottomed flask placed with a solution of substrate (0.10 mmol) in diglyme/H O
2
(
0.8 mL, 20:1 v/v) at room temperature, added CuCl ·2H O (0.14 mmol), TBHP (70% in water, 0.7
2 2
mmol) via micro-syringe. Then the solution was stirred at room temperature (or warmed to 45 °C).
After stirred for 10-16 hours, the reaction was quenched with saturated aqueous Na SO and diluted
2
3
with EtOAc (5 mL) and water (5 mL), the organic layer was separated. The aqueous layer was added
0% H SO (0.3 mL) and extracted with EtOAc (2×5 mL). The combined organic layers were
1
2
4
washed with water (4×5 mL) and brine, dried over anhydrous Na SO and concentrated in vacuo.
2
4
The residue was purified by flash chromatography on silica gel (Hex/EtOAc = 3:1) to give the
desired products as off-white solid.
1
13
H NMR and C NMR spectra data of products
1
chlorooxindole (2a): Prepared according to General Procedure C. H NMR (400 MHz, CD CN) δ
3
7
.64 – 7.57 (m, 2H), 7.44 – 7.37 (m, 2H), 7.35 (dd, J = 5.5, 4.8 Hz, 3H), 7.13 (td, J = 7.6, 0.9 Hz,
H), 6.96 (d, J = 7.9 Hz, 1H), 5.56 (t, J = 6.1 Hz, 1H), 3.15 (s, 3H), 2.85 – 2.77 (m, 2H), 2.45 – 2.29
1
1
3
(
m, 5H); C NMR (100 MHz, CD CN) δ 173.0, 143.6, 142.9 136.9, 130.7, 129.7, 128.4, 126.8,
3
+
1
23.9, 123.2, 109.4, 63.7, 38.8, 37.8, 26.2, 20.5; HRMS calc’d for C H ClN O S [M+H] :
18
20
2
3
S15

ACCEPTED MANUSCRIPT
379.0878, found 379.0828.
1
chlorooxindole (2b): Prepared according to General Procedure C. H NMR (400 MHz, CDCl ) δ
3
7.61 (d, J = 8.3 Hz, 2H), 7.33 – 7.21 (m, 3H), 6.90 (d, J = 7.8 Hz, 1H), 6.70 (d, J = 7.8 Hz, 1H), 4.91
(s, 1H), 3.21 (s, 3H), 2.94 – 2.83 (m, 2H), 2.73 - 2.63 (m, 1H), 2.56 – 2.47 (m, 1H), 2.42 (s, 3H),
1
3
2
1
4
.40 (s, 3H); C NMR (100 MHz, CDCl ) δ 173.9, 143.4, 142.9 136.6, 136.0, 130.4, 129.7, 126.9,
3
+
26.1, 125.0, 106.8, 64.3, 39.3, 36.9, 26.8, 21.5, 17.7; HRMS calc’d for C H ClN NaO S [M+Na] :
1
9
21
2
3
15.0859, found 415.0854.
1
chlorooxindole (2c): Prepared according to General Procedure C. H NMR (400 MHz, CDCl ) δ
3
7
6
2
1
.67 (d, J = 8.3 Hz, 2H), 7.27 (d, J = 8.3 Hz, 2H), 7.18 (d, J = 7.6 Hz, 1H), 6.94 (d, J = 7.6 Hz, 1H),
.68 (s, 1H), 5.28 – 5.12 (m, 1H), 3.20 (s, 3H), 3.17 – 3.02 (m, 2H), 2.54 – 2.43 (m, 1H), 2.41 (s, 3H),
13
.40 (s, 3H), 2.34 – 2.24 (m, 1H); C NMR (100 MHz, CDCl ) δ 174.3, 143.3, 142.4, 141.3, 136.7,
3
29.6, 127.0, 125.9, 124.2, 123.6, 110.0, 63.8, 39.3, 38.3, 26.7, 21.9, 21.5; HRMS calc’d for
+
C H ClN NaO S [M+Na] : 415.0859, found . 415.0851
19
21
2
3
chlorooxindole (2d): Prepared according to General Procedure C.
1
H NMR (400 MHz, CD CN) δ 7.60 (d, J = 8.3 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H), 7.18 (d, J = 7.4 Hz,
3
1H), 7.16 – 7.11 (m, 1H), 7.01 (t, J = 7.6 Hz, 1H), 5.58 (t, J = 6.1 Hz, 1H), 3.42 (s, 3H), 2.81 – 2.73
S16

ACCEPTED MANUSCRIPT
1
3
(
m, 2H), 2.54 (s, 3H), 2.45 – 2.35 (m, 4H), 2.34 – 2.25 (m, 1H); C NMR (100 MHz, CD CN) δ
3
173.7, 143.6, 140.6, 136.9, 134.1, 129.6, 128.9, 126.8, 123.2, 121.9, 121.3, 63.3, 38.8, 38.1, 29.4,
+
2
0.5, 18.0; HRMS calc’d for C H ClN NaO S [M+Na] : 415.0859, found 415.0851.
1
9
21
2
3
Me
Cl
NHTs
O
N
Me
2
e
1
chlorooxindole (2e): Prepared according to General Procedure C. H NMR (400 MHz, CDCl ) δ
3
7
7
2
1
.67 (d, J = 8.3 Hz, 2H), 7.28 (d, J = 7.3 Hz, 2H), 7.16 (d, J = 8.0 Hz, 1H), 7.12 (s, 1H), 6.75 (d, J =
.9 Hz, 1H), 5.30 – 5.22 (m, 1H), 3.20 (s, 3H), 3.17 – 3.03 (m, 2H), 2.54 – 2.43 (m, 1H), 2.41 (s, 3H),
13
.35 (s, 3H), 2.34 – 2.23 (m, 1H); C NMR (100 MHz, CDCl ) δ 173.9, 143.3, 139.9, 136.8, 133.5,
3
30.9, 129.7, 128.9, 126.9, 124.6, 108.8, 63.9, 39.2, 38.3, 26.8, 21.5, 21.1; HRMS calc’d for
+
C H ClN O S [M+H] : 393.1034, found 393.1064.
19
22
2
3
1
chlorooxindole (2f): Prepared according to General Procedure C. H NMR (400 MHz, CDCl ) δ
3
7
1
2
1
.67 (d, J = 8.3 Hz, 2H), 7.27 (d, J = 9.4 Hz, 2H), 6.89 (dd, J = 10.9, 2.5 Hz, 2H), 6.77 (d, J = 8.3 Hz,
H), 5.29 (t, J = 6.3 Hz, 1H), 3.81 (s, 3H), 3.20 (s, 3H), 3.14 – 3.06 (m, 2H), 2.53 – 2.43 (m, 1H),
13
.41 (s, 3H), 2.34 – 2.23 (m, 1H); C NMR (100 MHz, CDCl ) δ 173.6, 156.6, 143.3, 136.6, 135.6,
3
29.9, 129.6, 126.9, 115.1, 110.9, 109.6, 63.9, 55.8, 39.1, 38.3, 26.78, 21.4; HRMS calc’d for
+
C H ClN O S [M+H] : 431.0808, found 431.0802.
19
22
2
4
1
chlorooxindole (2g): Prepared according to General Procedure C. H NMR (400 MHz, CDCl ) δ
3
7
.65 (d, J = 8.3 Hz, 2H), 7.31 – 7.23 (m, 2H), 7.13 – 7.01 (m, 2H), 6.81 (dd, J = 8.5, 4.0 Hz, 1H),
S17

ACCEPTED MANUSCRIPT
5.30 – 5.22 (m, 1H), 3.23 (s, 3H), 3.10 – 3.01 (m, 2H), 2.58 – 2.46 (m, 1H), 2.41 (s, 3H), 2.35 – 2.27
1
3
(
m, 1H); C NMR (100 MHz, CDCl ) δ 173.8, 159.5 (d, J= 241 Hz), 143.5, 138.4, 136.5, 129.7,
3
126.9, 117.1 (d, J = 23.7 Hz), 112.0 (d, J = 25.5 Hz), 109.9 (d, J = 8.0 Hz), 63.3, 39.1, 38.2, 26.9,
+
2
1.5; HRMS calc’d for C H ClFN NaO S [M+Na] : 419.0608, found 419.0605.
1
8
18
2
3
1
chlorooxindole (2h): Prepared according to General Procedure C. H NMR (400 MHz, CDCl ) δ
3
7.69 – 7.64 (m, 1H), 7.32 – 7.23 (m, 4H), 6.86 – 6.76 (m, 1H), 6.60 (dd, J = 8.6, 2.3 Hz, 1H), 5.05
(dd, J = 8.0, 4.9 Hz, 1H), 3.22 (s, 3H), 3.12 – 3.03 (m, 2H), 2.58 – 2.47 (m, 1H), 2.41 (s, 3H), 2.39 –
1
3
2
.28 (m, 1H); C NMR (100 MHz, CDCl ) δ 174.2, 164.2 (d, J = 249.3 Hz), 144.3 (d, J = 11.8 Hz),
3
143.4, 136.5, 129.7, 126.9, 125.3 (d, J = 10.1 Hz), 124.1 (d, J = 3.2 Hz), 109.9 (d, J = 22.9 Hz), 98.1
+
(
d, J = 27.8 Hz), 63.1, 39.2, 38.3, 26.9, 21.5; HRMS calc’d for C H ClFN NaO S [M+Na] :
1
8
18
2
3
419.0608, found 419.0602.
1
chlorooxindole (2i): Prepared according to General Procedure C. Reaction performed at 45 ºC. H
NMR (400 MHz, CDCl ) δ 7.59 (d, J = 8.3 Hz, 2H), 7.34 (t, J = 8.1 Hz, 1H), 7.25 (d, J = 9.3 Hz, 2H),
3
7
2
1
.08 (d, J = 8.2 Hz, 1H), 6.82 (d, J = 7.4 Hz, 1H), 4.84 – 4.76 (m, 1H), 3.26 (s, 3H), 2.95 – 2.85 (m,
1
3
H), 2.80 – 2.71 (m, 2H), 2.39 (s, 3H); C NMR (100 MHz, CDCl ) δ 173.7, 144.9, 143.4, 136.5,
3
31.7, 131.7, 129.7, 126.8, 124.5, 124.1, 107.8, 63.5, 39.6, 35.5, 27.1, 21.5; HRMS calc’d for
+
C H Cl N O S [M+H] : 413.0488, found 413.0486.
18
19
2
2
3
S18

ACCEPTED MANUSCRIPT
1
chlorooxindole (2j): Prepared according to General Procedure C. Reaction performed at 45 ºC. H
NMR (400 MHz, CDCl ) δ 7.66 (d, J = 8.3 Hz, 2H), 7.39 – 7.31 (m, 1H), 7.30 – 7.26 (m, 3H), 6.81
3
(d, J = 8.3 Hz, 1H), 5.14 – 5.06 (m, 1H), 3.23 (s, 3H), 3.11 – 3.02 (m, 2H), 2.51 (dt, J = 13.8, 6.9 Hz,
13
1
H), 2.41 (s, 3H), 2.36 – 2.26 (m, 1H); C NMR (100 MHz, CDCl ) δ 173.6, 143.5, 141.1, 136.6,
3
130.6, 130.3, 129.7, 129.0, 126.9, 124.3, 110.2, 63.0, 39.1, 38.2, 26.9, 21.5; HRMS calc’d for
+
C H C N NaO S [M+Na] : 435.0307, found 435.0308.
18
18 l2
2
3
1
chlorooxindole (2k): Prepared according to General Procedure C. Reaction performed at 45 ºC. H
NMR (400 MHz, CDCl ) δ 7.65 (d, J = 8.3 Hz, 2H), 7.50 (dd, J = 8.3, 1.9 Hz, 1H), 7.41 (d, J = 1.9
3
Hz, 1H), 7.28 (d, J = 8.1 Hz, 2H), 6.76 (d, J = 8.3 Hz, 1H), 5.18 (s, 1H), 3.22 (s, 3H), 3.10 – 2.99 (m,
1
3
2
H), 2.51 (dt, J = 14.1, 6.9 Hz, 1H), 2.41 (s, 3H), 2.31 (dt, J = 14.6, 6.0 Hz, 1H); C NMR (100
MHz, CDCl ) δ 173.5, 143.5, 141.6, 136.5, 133.5, 130.6, 129.7, 127.1, 127.0, 126.9, 116.1, 110.7,
3
+
6
3.0, 39.1, 38.2, 26.9, 21.5; HRMS calc’d for C H BrClN NaO S [M+Na] : 478.9808, found
18
18
2
3
478.9803.
1
chlorooxindole (2l): Prepared according to General Procedure C. H NMR (400 MHz, CDCl ) δ
3
7.68 (d, J = 8.3 Hz, 2H), 7.51 (dd, J = 7.7, 1.1 Hz, 1H), 7.41 (s, 1H), 7.28 (d, J = 8.0 Hz, 2H), 6.85 (d,
J = 7.7 Hz, 1H), 5.26 (dd, J = 8.0, 4.6 Hz, 1H), 3.21 (d, J = 4.0 Hz, 3H), 3.19 – 3.09 (m, 2H), 2.56 –
1
3
2
.44 (m, 1H), 2.41 (s, 3H), 2.32 (dt, J = 14.7, 6.5 Hz, 1H), 0.27 (s, 9H); C NMR (100 MHz, CDCl )
3
δ 174.0, 143.3, 142.9, 136.7, 135.8, 135.7, 129.6, 128.6, 128.2, 126.9, 108.6, 63.8, 39.2, 38.4, 26.7,
S19

ACCEPTED MANUSCRIPT
+
2
1.5, -1.0; HRMS calc’d for C H ClN NaO SSi [M+Na] : 473.1098, found 473.1090.
2
1
27
2
3
Cl
NHBoc
O
N
Me
2
m
1
chlorooxindole (2m): Prepared according to General Procedure C. H NMR (400 MHz, CDCl ) δ
3
7.40 (d, J = 7.4 Hz, 1H), 7.35 (t, J = 7.7 Hz, 1H), 7.13 (t, J = 7.6 Hz, 1H), 6.85 (d, J = 7.8 Hz, 1H),
1
3
4
.66 (s, 1H), 3.23 (s, 3H), 3.21 – 3.10 (m, 2H), 2.57 – 2.34 (m, 2H), 1.38 (s, 9H); C NMR (100
MHz, CDCl ) δ 173.7, 155.5, 142.4, 130.4, 129.0, 124.3, 123.6, 108.8, 79.3, 63.5, 38.7, 36.4, 28.3,
3
+
2
6.7; HRMS calc’d for C H ClN NaO [M+Na] : 347.1138, found 347.1134.
1
6
21
2
3
1
chlorooxindole (2n): Prepared according to General Procedure C. H NMR (400 MHz, CDCl ) δ
3
7
.38 (d, J = 7.7 Hz, 1H), 7.34 (d, J = 7.8 Hz, 1H), 7.12 (t, J = 7.3 Hz, 1H), 6.84 (d, J = 7.8 Hz, 1H),
.03 (s, 1H), 3.57 (s, 3H), 3.30 – 3.15 (m, 5H), 2.51 (dt, J = 13.8, 6.8 Hz, 1H), 2.39 (dt, J = 13.9, 6.8
5
13
Hz, 1H); C NMR (100 MHz, CDCl ) δ 173.7, 156.7, 142.4, 130.5, 129.0, 124.2, 123.6, 108.9, 63.6,
3
+
5
2.0, 38.8, 36.8, 26.6; HRMS calc’d for C H ClN NaO [M+Na] : 305.0669, found 305.0664.
1
3
15
2
3
1
chlorooxindole (2o): Prepared according to General Procedure C. H NMR (500 MHz, CDCl ) δ
3
7.68 (d, J = 8.2 Hz, 2H), 7.37 (td, J = 7.8, 1.1 Hz, 1H), 7.32 (d, J = 4.8 Hz, 1H), 7.28 (d, J = 8.0 Hz,
2H), 7.13 (t, J = 7.3 Hz, 1H), 6.89 (d, J = 7.9 Hz, 1H), 5.25 – 5.11 (m, 1H), 3.85 – 3.68 (m, 2H), 3.19
– 3.05 (m, 2H), 2.56 – 2.44 (m, 1H), 2.42 (s, 3H), 2.32 (dt, J = 14.6, 6.5 Hz, 1H), 1.28 (t, J = 7.2
13
Hz, 3H); C NMR (125 MHz, CDCl ) δ 173.6, 143.4, 141.5, 136.9, 130.6, 129.7, 129.3, 127.1,
3
+
1
24.2, 123.6, 109.2, 63.7, 39.3, 38.4, 35.4, 21.5, 12.3; HRMS calc’d for C H ClN NaO S [M+Na] :
19
21
2
3
S20

ACCEPTED MANUSCRIPT
415.0859, found 415.0851.
1
chlorooxindole (2p): Prepared according to General Procedure C. Reaction performed at 45 ºC. H
NMR (400 MHz, CD CN) δ 7.62 – 7.58 (m, 2H), 7.40 (dd, J = 7.5, 0.7 Hz, 1H), 7.37 – 7.32 (m, 3H),
3
7.32 – 7.26 (m, 5H), 7.11 (td, J = 7.6, 0.9 Hz, 1H), 6.85 (d, J = 7.9 Hz, 1H), 5.60 (t, J = 5.9 Hz, 1H),
1
3
4
.88 (dd, J = 52.9, 15.9 Hz, 2H), 2.89 – 2.74 (m, 2H), 2.54 – 2.42 (m, 2H), 2.40 (s, 3H); C NMR
(
100 MHz, CD CN) δ 173.3, 143.6, 141.8, 136.7, 135.8, 130.6, 129.7, 128.8, 128.3, 127.7, 127.1,
3
1
26.8, 124.3, 123.5, 110.0, 63.6, 43.5, 38.7, 37.8, 20.4; HRMS calc’d for C H ClN NaO S
24 23 2 3
+
[
M+Na] : 477.1016, found 477.1012.
1
chlorooxindole (2q): Prepared according to General Procedure C. Reaction performed at 45 ºC. H
NMR (400 MHz, CDCl ) δ 7.39 (dd, J = 7.5, 0.6 Hz, 1H), 7.34 (td, J = 7.8, 1.2 Hz, 1H), 7.12 (td, J =
3
7
2
1
2
.6, 0.9 Hz, 1H), 6.85 (d, J = 7.8 Hz, 1H), 3.56 (td, J = 6.4, 1.6 Hz, 2H), 3.23 (s, 3H), 2.39 – 2.30 (m,
13
H), 1.75 (s, 2H), 1.48 – 1.37 (m, 2H); C NMR (100 MHz, CDCl ) δ 174.0, 142.6, 130.2, 129.3,
3
+
24.2, 123.5, 108.7, 64.7, 61.9, 35.6, 27.5, 26.6; HRMS calc’d for C H ClNNaO [M+Na] :
1
2
14
2
62.0611, found 262.0610.
Cl
OH
O
N
Me
2r
1
chlorooxindole (2r): Prepared according to General Procedure C. Reaction performed at 45 ºC. H
NMR (400 MHz, CDCl ) δ 7.38 (d, J = 7.4 Hz, 1H), 7.35 (td, J = 7.8, 1.2 Hz, 1H), 7.12 (td, J = 7.6,
3
0
.9 Hz, 1H), 6.85 (d, J = 7.8 Hz, 1H), 3.60 – 3.50 (m, 2H), 3.24 (s, 3H), 2.37 – 2.20 (m, 2H), 1.68 (s,
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ACCEPTED MANUSCRIPT
13
1
H), 1.57 1.48 (m, 2H), 1.30 – 1.17 (m, 2H); C NMR (100 MHz, CDCl ) δ 174.0, 142.7, 130.1,
3
1
29.3, 124.1, 123.4, 108.6, 64.8, 62.2, 38.9, 32.2, 26.6, 20.8; HRMS calc’d for C H ClNNaO
2
1
3
16
+
[
M+Na] : 276.0767, found 276.0761.
Application and transformation of 3-chlorooxindoles
To an oven-dried 10 mL round-bottomed flask placed with a solution of 2n (0.036 g, 0.127 mmol) in
MeOH (5 mL) at room temperature, added 10% Pd/C (10 mmol%) after degassed with H for three
2
times. The reaction was stirred under a balloon hydrogen atmosphere at this temperature for 3 hours.
The solvent was removed under reduced pressure, and the residue was purified by flash
chromatography on silica gel (Hex/EtOAc = 2:1) to afford the desired product 4 (0.025 g, 78%).
To an oven-dried 10 mL round-bottomed flask placed with a solution of 2q (0.046 g, 0.192 mmol) in
DME (2 mL) at room temperature, added t-BuOK (0.043 g, 0.384 mmol) and stirred at this
temperature for 3 hours. Then the reaction was quenched with saturated aqueous NH Cl and diluted
4
with EtOAc and water, the organic layer was separated and the aqueous layer was extracted with
EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous
Na SO and concentrated in vacuo. The residue was purified by flash chromatography on silica gel
2
4
(Hex/EtOAc = 5:1) to give the desired products (0.031 g, 82%) as colorless oil.
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ACCEPTED MANUSCRIPT
To an oven-dried 10 mL round-bottomed flask placed with a solution of 2h (0.020 g, 0.050 mmol)
and p-cresol (0.008g, 0.075 mmol) in CH Cl (0.5 mL) at room temperature, added Cs CO (0.033 g,
2
2
2
3
0.100 mmol) and stirred at this temperature for 13 hours. The solvent was removed under reduced
pressure, and the residue was purified by flash chromatography on silica gel (Hex/EtOAc = 3:1) to
afford the desired product 6 (0.014 g, 58%).
1H NMR and 13C NMR spectra data of corresponding products
1
carbamate (4): H NMR (500 MHz, CDCl ) δ 7.35 – 7.19 (m, 2H), 7.04 (t, J = 7.4 Hz, 1H), 6.80 (d,
3
J = 7.8 Hz, 1H), 5.44 (s, 1H), 3.60 (d, J = 10.4 Hz, 3H), 3.48 – 3.41 (m, 1H), 3.41 – 3.27 (m, 2H),
1
3
3
.17 (s, 3H), 2.25 – 2.06 (m, 1H), 2.06 - 2.01 (m, 1H); C NMR (125 MHz, CDCl ) δ 177.8, 157.1,
3
1
44.0, 128.6, 128.1, 123.8, 122.6, 108.1, 52.0, 43.5, 38.5, 30.7, 26.2; HRMS calc’d for C H N O
3
1
3
17
2
+
[
M+H] : 249.1234, found 249.1234.
1
spirocyclic indolin-2-one(5): H NMR (400 MHz, CDCl ) δ 7.33 – 7.20 (m, 2H), 7.05 (t, J = 7.4 Hz,
3
1H), 6.78 (d, J = 7.6 Hz, 1H), 4.36 – 4.16 (m, 2H), 3.15 (s, 3H), 2.54 – 2.39 (m, 1H), 2.39 – 2.30 (m,
1
3
1
H), 2.30 – 2.17 (m, 1H), 2.16 – 2.01 (m, 1H); C NMR (100 MHz, CDCl ) δ 177.9, 143.6, 130.6,
3
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ACCEPTED MANUSCRIPT
+
1
29.6, 123.4, 123.0, 108.2, 82.7, 70.3, 35.9, 26.4, 26.1; HRMS calc’d for C H NO [M+H] :
12 14 2
204.1019, found 204.1021.
1
indolin-2-one (6): H NMR (400 MHz, CDCl ) δ 7.74 (d, J = 8.3 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H),
3
7
5
3
1
2
.17 (dd, J = 8.2, 5.3 Hz, 1H), 6.84 (d, J = 8.2 Hz, 2H), 6.79 – 6.68 (m, 1H), 6.51 – 6.40 (m, 3H),
.37 (t, J = 6.1 Hz, 1H), 3.39 – 3.25 (m, 2H), 3.09 (s, 3H), 2.43 (s, 3H), 2.37 – 2.29 (m, 1H), 2.17 (s,
13
H), 2.15 – 2.06 (m, 1H); C NMR (100 MHz, CDCl ) δ 175.2, 162.9, 152.4, 144.6 (d, J = 11.6 Hz),
3
43.3, 136.9, 133.4, 129.6 (d, J = 5.3 Hz), 127.0, 125.8 (d, J = 10.0 Hz), 122.5, 120.2, 109.4 (d, J =
2.5 Hz), 97.8 (d, J = 27.6 Hz), 82.2, 38.2, 37.5, 26.4, 21.5, 20.6; HRMS calc’d for
+
C H FN NaO S [M+Na] : 491.1417, found 491.1413.
25
25
2
4
Mechanistic study:
Cl
NHTs
NHTs
CuCl (1.4 eq), TBHP (7.0 eq)
2
18O
N
N
diglyme/H 18O = 20:1, rt, air or Ar
2
Me
Me
1
8
1
a
2a- O
To a 10 mL round-bottomed flask placed with a solution of substrate 1a (0.033g, 0.10 mmol) in
1
8
diglyme/H O (0.8 mL, 20:1 v/v) at room temperature, added CuCl (0.019g, 0.14 mmol), TBHP
2
2
(5.5 M in nonane, 0.127 mL, 0.7 mmol) via micro-syringe. Then the solution was stirred at room
temperature under air or Ar. TLC monitored the reaction was completed, The crude product was
1
2
8
+
analyzed by HRMS. HRMS calc’d for C H ClN O OS [M+H] : 381.0920, found 381.0922. The
1
8
20
2
result showed that the oxygen source in the product was from the water.
Chlorooxidation of tryptamine derivatives using NCS and DCU
3
,4
The procedures were according to the known literature.
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