Water-Soluble Hypervalent Iodine(III) Having an I-N Bond. A Reagent for the Synthesis of Indoles

Article abstract of DOI:10.1021/acs.orglett.8b01615

A readily accessible and bench-stable water-soluble hypervalent iodine(III) reagent (phenyliodonio)sulfamate (PISA) with an I-N bond was synthesized, and its structure was characterized by X-ray crystallography. With PISA, various indoles were synthesized via C-H amination of 2-alkenylanilines involving an aryl migration/intramolecular cyclization cascade with excellent regioselectivity in aqueous CH₃CN. Notably, using this new method as the key step, not only two drug molecules, indometacin and zidometacin, but also another bioactive molecule, pravadoline, were synthesized.

Full text of DOI:10.1021/acs.orglett.8b01615

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Water-Soluble Hypervalent Iodine(III) Having an I−N Bond. A
Reagent for the Synthesis of Indoles
Hai-Dong Xia, Yan-Dong Zhang, Yan-Hui Wang, and Chi Zhang*
State Key Laboratory of Elemento-Organic Chemistry, Collaborative Innovation Center of Chemical Science and Engineering
(Tianjin), College of Chemistry, Nankai University, Tianjin 300071, China
S
* Supporting Information
ABSTRACT: A readily accessible and bench-stable water-soluble hypervalent iodine(III) reagent (phenyliodonio)sulfamate
(PISA) with an I−N bond was synthesized, and its structure was characterized by X-ray crystallography. With PISA, various
indoles were synthesized via C−H amination of 2-alkenylanilines involving an aryl migration/intramolecular cyclization cascade
with excellent regioselectivity in aqueous CH3CN. Notably, using this new method as the key step, not only two drug molecules,
indometacin and zidometacin, but also another bioactive molecule, pravadoline, were synthesized.
hypervalent iodine reagent by rational ligand design. The
ypervalent iodine reagents have recently attracted
Hconsiderable research attention owing to their versatile development of organic reactions mediated by water-soluble
hypervalent iodine reagents in aqueous media is desirable for
several reasons. First, water molecules can coordinate with the
iodine center of these reagents to enhance their thermal
stability and maintain their high oxidizing ability in water, as
has been shown for aquo(hydroxy)-λ3-iodane−[18]crown-6
complexes.3 Second, when water-soluble hypervalent iodine
reagents are employed for reactions in aqueous organic media,
they can exhibit reactivity different from that of their organic-
soluble parent molecules.2c Third, the development of aqueous
organic reactions mediated by water-soluble hypervalent iodine
reagents can be expected to broaden the application scope of
hypervalent iodine reagents in organic synthesis. Herein, we
report a new water-soluble hypervalent iodine(III) reagent
(phenyliodonio)sulfamate (PISA) having an I−N bond
(Figure 1b).
Most of the previously reported water-soluble hypervalent
iodine reagents are iodine(V) reagents which are synthesized
by introducing a hydrophilic group on the phenyl ring through
multistep reactions. In addition, all of the water-soluble
hypervalent iodine reagents reported to date have I−O
bonds; no water-soluble hypervalent iodine reagents with I−
N bonds have yet been reported. In order to explore a novel
reaction mediated by hypervalent iodine reagents in strongly
acidic aqueous media, we envisaged the synthesis of a first
strongly acidic water-soluble hypervalent iodine reagent with
an I−N bond by introducing a hydrophilic group as a ligand in
reactivity, low toxicity, easy handling, ready availability, and
high stability.1 Nevertheless, the design of new hypervalent
iodine reagents with unprecedented reactivity and the ability to
mediate difficult chemical transformations is of interest to
synthetic chemists. In addition, although many hypervalent
iodine reagents are soluble in organic solvents at ambient or
high temperature, only a few water-soluble hypervalent iodine
reagents have been reported. The main strategy for the
synthesis of such reagents is introducing a hydrophilic group
such as potassium sulfonate, carboxyl, or trimethylammonium
on the phenyl ring, as reported by Zhdankin et al.,2a Kirsch et
al.,2b Vinod et al.,2d and our group (Figure 1a). This strategy
requires the use of risky reagents such as concentrated or
fuming H2SO4 and usually requires multistep synthesis, which
restricts the practical application of these reagents. Thus, we
become interested in tuning the water solubility of the new
Figure 1. Representative water-soluble hypervalent iodine reagents:
(a) existing reagents; (b) our newly developed reagent PISA.
Received: May 22, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01615
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a single-step reaction. To synthesize one such reagent, we
chose NH2SO3H as the ligand. The specific reasons are as
follows: (a) because the sulfonic acid group is hydrophilic,
introduction of a NH2SO3H ligand would impart good water
solubility; (b) the strong acidity of NH2SO3H (pKa = 1.45 at
95 °C4) would make the reagent acidic, allowing it to retain its
oxidative ability even in the absence of an added Brønsted or
Lewis acid.
More interestingly, we also accomplished the first synthesis of
2,3-disubstituted indoles by means of an aryl migration/
intramolecular cyclization cascade. In this reaction, PISA acted
both as an oxidant and as a Brønsted acid.
We began by exploring the reaction of N-(2-(prop-1-en-2-
yl)phenyl)benzamide (2a) with PISA (1.5 equiv) in anhydrous
CH3CN at 60 °C under Ar (Table 1, entry 1). Surprisingly, the
We adopted a ligand-exchange approach for the synthesis of
PISA. We were delighted to find that the reaction of
PhI(OAc)2 with NH2SO3H (1.1 equiv) in anhydrous
CH3CN [0.5 M of PhI(OAc)2] proceeded smoothly at room
temperature: PISA (1a) was obtained in 91% yield within 12 h
as a colorless solid after filtration and washing with diethyl
ether (Scheme 1) (For optimization of the synthesis
Table 1. Optimization of Reaction Conditions for 2-
Methylindole Synthesis
a
isolated
yield (%)
Scheme 1. Synthesis of PISA (1a)
oxidant
(1.5 equiv)
H2O
(equiv)
time
(h)
entry
solvent
3a
3a′
10
6
42
80
42
75
0
0
0
0
0
b
1
PISA
PISA
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
5
5
5
5
5
5
5
5
5
2
5
4
4
4
4
4
65
71
0
0
0
15
31
0
84
88
43
0
2
3
4
5
6
7
8
PhI = NTs
PhI(OAc)2
PhIO
PhICl2
PIFA
IBX
PISA
PISA
PIFA
AIBA
mIBX
AIBX
PIBS
IBX-SO3K
conditions, see Table S1.) Notably, PISA could be prepared
on a large scale (8.45 g) without diminishment of the yield.
The solid showed good solubility in water (up to 0.21 M at
room temperature), and a saturated aqueous solution of PISA
had a pH of 2.05. The oxidation potential of PISA was 1.67 V,
and it could be stored at ambient temperature for at least 2
months.
c
9
10
11
1.5
1.5
1.5
1.5
1.5
1.5
1.5
d
12
13
14
15
16
0
0
0
0
0
0
0
0
A single crystal of PISA·H2O was grown from CH3CN/H2O
at room temperature (Scheme 1). X-ray crystallography
showed that PISA·H2O is a zwitterionic species in which the
oxygen atom of water is bound to the iodine(III) center,
forming a linear N(1)−I(1)···O(4) triad (bond angle 178.60°).
PISA·H2O has the T-shaped structure that is typical of other
commonly used hypervalent iodine(III) reagents, including
PhI(OAc)2. The close contact between I(1) and the oxygen
atom of water (O(4), 2.4912 Å) can stabilize PISA in water, as
has been observed for aquo(hydroxy)-λ3-iodane−[18]crown-6
complexes by Ochiai and Miyamoto.3 The unique structure of
PISA shows that it is both a donor and an acceptor of
hydrogen bonding. The hydrogen bonding between PISA and
H2O can considerably improve the solubility of PISA in water.
The strong acidity of PISA is mainly due to the effective
delocalization of negative charge of the resulting nitrogen
anion through interaction with strongly electron-withdrawing
0
a
Reaction conditions, unless otherwise stated: 2a (0.3 mmol), solvent
b
(3 mL), 60 °C, open flask. The reaction was conducted under Ar.
c
The reaction was carried out with as-supplied CH3CN (not
d
anhydrous). 1.5 equiv of NH2SO3H was used.
reaction formed (2-methyl-1H-indol-1-yl)(phenyl)methanone
(3a, 65%) along with 10% of (3-methyl-1H-indol-1-yl)-
(phenyl)methanone (3a′), an isomer of 3a. Inspired by this
result, we optimized the reaction conditions for the synthesis
of 3a. When the reaction was performed under open-flask
conditions, 3a was obtained in 71% yield (entry 2). Another
iodine(III) reagent such as PhI = NTs, PhI(OAc)2, or PhIO
was employed, giving 3a′ as the only product (entries 3−5).
When PhICl2 was used instead of PISA, the reaction gave 3a′
as the major product (75%), along with a 15% yield of 3a
(entry 6). A reaction in the presence of PIFA gave 3a in a yield
of only 31% (entry 7). We also tested hypervalent iodine(V)
reagent IBX and found that the reaction did not proceed
(entry 8). When the reaction was performed in as-supplied
CH3CN (that is, CH3CN that was not anhydrous), 3a was
exclusively obtained in 84% yield, implying that traces of H2O
played a critical role in improving the yield and selectivity of 3a
(entry 9). After screening other reaction conditions including
CH3CN/H2O solvent systems, reaction solvent, the amount of
PISA, and reaction temperature (for details, see Table S2), we
obtained the optimal reaction conditions for 2-methylindole
synthesis as follows: 1.5 equiv of PISA in anhydrous CH3CN
(0.1 M of 2a) containing 1.5 equiv of H2O at 60 °C for 2 h
−
groups I+ and SO3 .
With the newly developed hypervalent iodine reagent in
hand, we turned to explore its utility for the synthesis of
indoles, important and valuable heterocycles, in aqueous
media. Intramolecular oxidative C−H amination of 2-
alkenylanilines has been considered as one of the most
straightforward and powerful routes toward the indole skeleton
since the pioneering work of the Hegedus group.5 Zheng et al.
and Youn et al., respectively, reported substituted indole
synthesis via C−H amination of 2-alkenylanilines involving a
migratory process (β- to α-carbon relative to phenyl) by using
[Ru(bpz)3](PF6)2/visible light, DDQ, or Ag2CO3.6 Excitingly,
herein, an inverse migratory process (α- to β-carbon) was first
discovered in the synthesis of 2-substituted indole via C−H
amination of 2-alkenylanilines with PISA in aqueous CH3CN.
B
DOI: 10.1021/acs.orglett.8b01615
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Organic Letters
Letter
(entry 10). A reaction using 1.5 equiv of PIFA and NH2SO3H
only gave 43% of 3a, indicating that PISA was indispensable
for the efficient synthesis of 3a (entry 11). When other water-
soluble hypervalent iodine reagents, such as AIBA (3-oxo-5-
(trimethylammonio)-1λ3-benzo[d][1,2]iodaoxol-1(3H)-olate),
mIBX (1-hydroxy-1,3-dioxo-1,3-dihydro-1λ5-benzo[d][1,2]-
iodaoxole-4-carboxylic acid), AIBX (5-trimethylammonio-1,3-
dioxo-1,3-dihydro-1λ5-benzo-[d][1,2]iodoxol-1-ol anion),
PIBS (potassium 4-iodylbenzenesulfonate), and IBX-SO3K
(potassium 1-hydroxy-1,3-dioxo-1,3-dihydro-1λ5-benzo[d]-
[1,2]iodaoxole-5-sulfonate), were subjected to the standard
reaction conditions (entries 12−16), 3a was not detected.
These results confirm the unique reactivity of PISA.
Inspired by this significant finding, we evaluated some
additional trisubstituted alkenes (Scheme 3). When (E)-
Scheme 3. Substrate Scope of PISA-Mediated Synthesis of
2,3-Disubstituted Indoles on a 0.3 mmol Scale*
With the optimal reaction conditions established, we
explored the generality of the method by testing various
substrates 2 (Scheme 2). When X was alkyl, phenyl, or
Scheme 2. Substrate Scope of PISA-Mediated Synthesis of
2-Substituted Indoles on a 0.3 mmol Scale*
*
a
Isolated yields are reported. 2.5 equiv of PISA was used. The
conversion of 2ae was 91%, and the yield of 3ae was based on this
b
conversion. The conversion of 2ag was 75%, and the yield of 3ag was
based on this conversion.
trisubstituted alkenes 2x−z were subjected to the standard
reaction conditions, the desired 2,3-disubstituted indoles (3x−
z) were obtained in good to high yields with excellent
regioselectivity. We confirmed the E configuration of 2ah by
means of X-ray crystallography (data available in SI) and also
obtained NOESY spectra of (E)- and (Z)-2ac (spectra
available in SI). To confirm the structures of 3w−z, we
deprotected them with N2H4·H2O to give the corresponding
known compounds (see the SI). In addition, substrates bearing
either electron-donating or electron-withdrawing substituents
on the phenyl ring were converted smoothly to the
corresponding 2,3-disubstituted indoles (3aa−ag) in satisfac-
tory yields. The reaction of 2ah, which has a methyl group at
C-6 of the phenyl ring, furnished 3ah in 68% yield, although a
prolonged reaction time (11.5 h) was required, owing to steric
hindrance. A gram-scale reaction of 2ah (1.4 g) afforded 3ah in
61% yield. The structures of 3ab and 3ac were confirmed by X-
ray crystallography.
To demonstrate the synthetic utility of this novel method,
we used it as the key step in the preparation of two
nonsteroidal anti-inflammatory drug molecules: Indometacin
(8) and zidometacin (9) (Scheme 4). A reaction of 1.4 g of 2ai
was also conducted, giving 3ai in 71% yield. The overall yields
of Indometacin and zidometacin were 39% and 16%,
respectively.
In addition, deprotection of 3a provided 2-methylindole
(10, 95% yield), which is a key intermediate in a previously
reported synthesis of the analgesic agent pravadoline (11)
(Scheme S1).8
*
a
Isolated yields are reported. One hour after the start of the reaction,
a solution of concd HCl (3 equiv) in CF3CH2OH was added to the
reaction mixture, which was then stirred at 60 °C for an additional 1.5
h. The conversion of 2f was 90%, and the yield of 3f was based on this
b
conversion. The oxidant was 4-NO2C6H4I+NHSO3− (1b, 1.5 equiv).
The conversion of 2g was 91%, and the yield of 3g was based on this
conversion. The reaction was carried out at 60 °C for the first 2 h
and then at reflux temperature for another 10 h. The conversion of
2m was 93%, and the yield of 3m was based on this conversion. The
oxidant was 1b (1.5 equiv).
c
d
hydrogen, the reaction gave 2-substituted indoles 3a−g as the
sole products; that the formation of 3-substituted indoles was
not observed demonstrates the excellent regioselectivity of this
method. Furthermore, we could also obtain good to high yields
of 2-methylindoles with different substituents on the phenyl
ring (3h−n), and the Cl and Br atoms can serve as handles for
the construction of more complex molecules. Heteroaromatic
motifs such as furyl and thienyl were compatible with the
reaction conditions as well, giving desired products 3o and 3p
in high yields. Considering that the bioactivities of N-protected
indoles vary with the protecting group,7 we next investigated
the effects of various N-protecting groups on the formation of
2-substituted indoles (3q−v). An acryloyl group, which is
susceptible to oxidation, was also compatible (3v).
Surprisingly, when the trisubstituted alkene (E)-N-(2-(pent-
2-en-2-yl)phenyl)benzamide (2w) was used as the substrate,
2,3-disubstituted indole 3w was obtained in 69% yield via
cyclization; this transformation constitutes a formal inter-
change of the methyl and ethyl groups (eq 1).
To study the mechanism of the formation of various indoles,
we conducted a series of control experiments (Scheme 5). At
room temperature (instead of 60 °C), the reaction of substrate
2a gave N-(2-(2-oxopropyl)phenyl)benzamide (12) in 96%
C
DOI: 10.1021/acs.orglett.8b01615
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Letter
In summary, we report the synthesis of PISA, a novel acidic
water-soluble hypervalent iodine(III) reagent with one I−N
bond and a high oxidation potential. We found that a series of
indoles could be synthesized with excellent regioselectivity in
aqueous CH3CN with PISA. In this reaction, PISA acted both
as an oxidant and as a Brønsted acid, and water could act as a
catalyst to enhance the efficiency and selectivity of the reaction.
The method described herein was utilized for rapid synthesis
of the bioactive molecules indometacin, zidometacin, and
pravadoline. The unique reactivities of PISA, which differ from
those of previously reported water-soluble hypervalent iodine
reagents (such as AIBA and mIBX), are currently being
explored further in our laboratory.
Scheme 4. Synthesis of Indometacin (8) and Zidometacin
(9)*
*
Reaction conditions: (a) Cu(acac)2, N2C(COOMe)2, toluene; (b)
LiCl, DMF/H2O for 6, DMSO/H2O for 7, reflux; (c) LiI, pyridine,
a
reflux. The yield in parentheses was obtained from 1.4 g of 2ai.
Scheme 5. Control Experiments
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b01615.
Experimental procedures and characterization of prod-
ucts (PDF)
Accession Codes
yield. Subjecting 12 to the standard reaction conditions
afforded 2-substituted indole 3a in 90% yield, suggesting the
intermediacy of 12. A radical-capture experiment involving the
reaction of 2a in the presence of 2,6-di-tert-butyl-4-
methylphenol (BHT) smoothly produced 3a in 85% yield,
and a radical clock experiment performed with 2d under the
optimal reaction conditions generated 3d in 72% yield as the
sole product; the product of cyclopropyl ring opening was not
detected. These results suggest that a radical intermediate was
not involved in the reaction.
On the basis of the above-described control experiments and
literature precedents,9 we propose the mechanism involving an
aryl migration/intramolecular cyclization cascade shown in
Scheme 6. First, nucleophilic attack on PISA by the substrate
CCDC 1547807, 1811512−1811513, and 1817528 contain the
supplementary crystallographic data for this paper. These data
can be obtained free of charge via www.ccdc.cam.ac.uk/
data_request/cif, or by emailing data_request@ccdc.cam.ac.
uk, or by contacting The Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44
1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: zhangchi@nankai.edu.cn.
ORCID
Chi Zhang: 0000-0001-9050-076X
Notes
Scheme 6. Proposed Reaction Mechanism
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by the National Key R&D
Program of China (2017YFD020030202), The National
Natural Science Foundation of China (21472094, 21172110,
21421062), and The Tianjin Natural Science Foundation
(17JCYBJC20300). We sincerely thank Prof. Q.-L. Zhou
(Nankai University) and Prof. P.-P. Tang (Nankai University)
for their valuable advice on the present work.
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