Showcasing research from Professor Katsuhiko Moriyama’sgroup, Graduate School of Science, Chiba University, JapanAs featured in:

1,3-Iodo-amination of 2-methyl indoles via Csp2–Csp3 dual
functionalization with iodine reagent
A 1,3-iodo-amination with iodine reagent that involved the Csp2–Csp3
dual functionalization of 2-methyl indoles was developed as aremote dual functionalization by a multicomponent system toprovide 2-aminomethyl-3-iodo-indole derivatives in high yields.

See Katsuhiko Moriyama et al.,Chem. Commun., 2018, 54, 4258.

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Cite this: Chem. Commun., 2018,
54, 4258

1,3-Iodo-amination of 2-methyl indoles via
Csp2–Csp3 dual functionalization with iodine
reagent†

Received 15th January 2018,
Accepted 9th February 2018

Katsuhiko Moriyama,*ab Tsukasa Hamada,a Kazuma Ishidaa and Hideo Togoa

DOI: 10.1039/c8cc00352a
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A 1,3-iodo-amination with iodine reagent that involved theCsp2–Csp3 dual functionalization of 2-methyl indoles was developed
to provide 2-aminomethyl-3-iodo-indole derivatives. The iodoamination proceeded via a 1,4-transfer of an imide group throughthe formation of an indolyl(phenyl)iodonium imide using PhI(OAc)2,
followed by an iodination using DIH or a double iodination of indole
using excess DIH.

The direct functionalization of organic compounds has
attracted considerable attention recently as an exciting alternative for the installation of various heteroatoms into thesecompounds.1 Among the known synthetic methods, the dual
functionalization of organic compounds for the synthesisof functional organic compounds presents a challenging
task.2 We recently developed a regioselective vicinal Csp2–Csp2
dual functionalization that installs two different functionalgroups simultaneously into N-electron-withdrawing-group (EWG)protected indoles through bromo-amination via a 1,3-transfer ofan imide group after the formation of indolyl(phenyl)iodoniumimides.3 To the best of our knowledge, regioselective remote C–H
dual functionalization involving installation of two different functional groups by a multicomponent system has never beenrealized.
The emergence of a direct Csp3–H amination of 2-substituted
indoles has motivated us to establish a novel C–N bondformation of an inert hydrocarbon group to provide 2-aminomethyl indole derivatives that are related to the construction of
the key framework in indole alkaloids, biologically active compounds, and pharmaceuticals.4 In general, the installation ofamino groups into sp3 carbon at the 2-position of 2-substituted
aDepartment of Chemistry, Graduate School of Science, Chiba University, 1-33
Yayoi-cho, Inage-ku, Chiba 263-8522, Japan. E-mail: moriyama@faculty.chiba-u.jp
bMolecular Chirality Research Center, Chiba University, 1-33 Yayoi-cho, Inage-ku,Chiba 263-8522, Japan† Electronic supplementary information (ESI) available: Experimental procedures
and spectral data for all compounds. CCDC 1532903, 1532904 and 1589706. For
ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c8cc00352a

4258 | Chem. Commun., 2018, 54, 4258--4261

Fig. 1

Direct Csp3–H amination of 2-substituted indole derivatives.

indoles is achieved by radical bromination (Wohl–Ziegler reaction), followed by nucleophilic substitution with amines.5 Regarding previous work on the direct Csp3–H amination of indoles, theCsp3–H azidation of 2,3-disubstituted indoles with iodine azide(IN3) (Fig. 1a, eqn (1))6 and the Csp3–H azidation of N-Boc-2-methyl
indole with azidoiodinane using a Cu(II) photoredox catalyst
under visible light conditions (Fig. 1a, eqn (2)) are available.7
However, these practical methods are characterized by a simple
amination as well as limited substrate scope and utility of theaminated products. In this context, we report herein a 1,3-iodoamination of 2-methyl indoles via a regioselective Csp2–Csp3 dual
functionalization by a three-component reaction with iodine
reagent and bis(sulfonyl)imide (Fig. 1b).
First, we investigated the preparation of indolyl(phenyl)iodonium
imide (2a) from N-pivaloyl-2-methyl indole (1a) based on previously
reported reaction conditions3,8 and obtained 2a in 97% yield(88% isolated yield) by treatment of 1a with PhI(OAc)2 andThis journal is © The Royal Society of Chemistry 2018

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Scheme 1 Preparation of indolyl(phenyl)iodonium imide (2a). a Number inparentheses indicates the yield of 2a determined by 1H-NMR analysis
based on an internal standard.

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DIH (substantially 1.2 equiv. as the iodination reagent)decreased the product yield.9
To explore the substrate scope for the direct iodo-amination
using two methods (Methods A and B), the utility of various
imides in the reaction with 1a was examined under theoptimum conditions (Table 1). When aliphatic, aromatic, andasymmetric bis(sulfonyl)imides were used in the reaction underboth conditions, the corresponding products (3b–3g) wereobtained in high yields (78–97%), respectively. A direct
1,3-iodo-amination of various indoles bearing useful substituentson the indole ring (1) with Ms2NH was also examined by using

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Table 2

Scheme 2

1,3-Iodo-amination of indoles (1) with Ms2NH

Direct 1,3-iodo-amination of 1a.

Ts2NH in CH2Cl2 (Scheme 1, eqn (3)). Additionally, halogen
reagents and solvents were screened for the 1,3-iodo-aminationof 2a (Table S1, ESI†) and the optimum conditions were foundto include 2a and 1,3-diiodo-5,5-dimethylhydantoin (DIH)(0.6 equiv.) in CH2Cl2 at room temperature under dark conditions, which aﬀorded 3a in 85% yield (Scheme 1, eqn (4)).
Next, we attempted to conduct a direct iodo-amination of 1awith Ts2NH via the formation of indolyl(phenyl)iodonium
imide (2a) (Scheme 2). By using PhI(OAc)2 as the oxidant in
the formation of 2a and NaHCO3 as the base in the iodoamination, this reaction proceeded to furnish 3a in 90%yield (eqn (5)). Interestingly, use of an excess amount of DIH(substantially 3.2 equiv. as the iodination reagent) also provided 3a in high yield (95%, eqn (6)) whereas use of 0.6 equiv.

Table 1a

1,3-Iodo-amination of 1a with bis(sulfonyl)imides

The reaction was carried out for 24 h. b NaHCO3 (1.2 equiv.) was added.

This journal is © The Royal Society of Chemistry 2018aNIS (2.0 equiv.) was used. b Ms2NH (1.2 equiv.) was used. c DIH(1.0 equiv.) was used. d DIH (1.6 equiv.) was used. e Ms2NH (2.4 equiv.)
was used. f The reaction was carried out without NaHCO3. g Na2SO4(2.0 equiv.) was added. h NIS (2.4 equiv.) was used. i DIH (0.5 equiv.)
was used. j NIS (3.0 equiv.) was used. k NIS (1.2 equiv.) was used.
lMs2NH (1.7 equiv.) was used. m DIH (2.1 equiv.) was used. n Ms2NH(1.5 equiv.) was used. o Number in parentheses indicates the yield of 3z-H.

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both methods (Table 2). Various indoles, including 6-, 5-, and4-substituted indole derivatives (1h–1n), furnished the corresponding products (3h–3n) in high yields (64–96%) by both iodoamination methods. Among them, simultaneous to the iodinationof the aromatic ring, substrates bearing 6-OMe (1k), 5-OMe (1s),5,7-diMe (1y), and naphthyl (1z) groups gave concurrently iodinated products (3k, 3s, 3y, and 3z-I (in Method B)) in good yields(56–95%), respectively. Disubstituted indole derivatives (1x–1z)
and indole derivatives protected with other groups instead of apivaloyl group (1aa and 1ab) were also converted into the desiredproducts (3x–3ab) in 56–95% yields. For the reaction of 1z, adivergent synthesis of a mono-iodinating product (3z-H) and a diiodinating product (3z-I) from 1z was enabled by these iodoaminations with the two methods. Unfortunately, the reactionof 2-ethylindole and 2-benzylindole derivatives did not afford thedesired products.
We performed mechanistic studies on the direct iodoamination of 1 to elucidate the reaction mechanism. In Method A,
the reaction of 1a with PhI(OAc)2, Ts2NH, and DIH produced
iodobenzene as the co-product together with 3a.10 In addition,a crossover iodo-amination of 2a with Ms2NH provided two
iodo-amination products 3a (39%) and 3b (55%) (Scheme 3A).
Time course experiments on the iodo-amination of 3-iodo
indole derivatives 2a and 4a with 0.6 equiv. DIH interestingly
revealed major diﬀerences in the reactivity of the substrates(Scheme 3B). The reaction of 4a was disturbed halfway whereas
the reaction of 2a eﬃciently proceeded to give the desired
product in high yield. Furthermore, the iodo-amination of 4awith I2 was inactive compared to that of 2a with I2 (Scheme 3C).
Based on these mechanistic experiments, we proposed areaction mechanism, as depicted in Scheme 4. In Method A,
2-methyl indole (1) is converted into indolyl(phenyl)iodonium

Scheme 3 Comparison of the iodo-amination between the indolyl(phenyl)iodonium imide (2) and the 3-iodo indole derivative (4). a Numbers inparentheses indicate recovery of substrates.

4260 | Chem. Commun., 2018, 54, 4258--4261

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imide (2) by reacting with PhI(OAc)(N(SO2R)2) generated in situ
from PhI(OAc)2 and (RSO2)2NH. Upon subsequent activation by
the iodine atom in 2 as a Lewis acid, the iodo reagent promotes
electrophilic addition to the enamine moiety in indole byincreasing the electrophilicity of a cationic iodine atom on
the iodo reagent.3 This electrophilic addition converts 2 into an
unstable iodonium cation intermediate (A), which subsequently
forms exo-enamine (B) by ring-opening elimination. The intermolecular SN2 0 nucleophilic substitution of bis(sulfonyl)imide
into B is promoted due to the high leaving ability of thel3-iodanyl group to provide a 2-aminomethyl-3-iodo-indole derivative (3). By contrast, in Method B, after 1 is transformed into a 3-iodo
indole derivative (4) by electrophilic iodination with the iodinating
reagent,11 a second electrophilic iodination (double iodination)induces the formation of an exo-enamine form of indole (C). Finally,
3 is obtained through an SN20 nucleophilic substitution, similar toMethod A. It is important to note that the iodide ion (I) released by
the SN20 nucleophilic substitution binds other cationic iodine atoms
on the iodinating reagent to form molecular iodine (I2), which is aninert iodine source for electrophilic iodination. Therefore, iodoamination through double iodination must use an excess amountof iodine reagent to eﬃciently give the desired product.
To demonstrate the utility of iodo-amination products,
we synthesized a tetracyclic indole derivative (8) and an

Scheme 4

Plausible reaction mechanisms for 1,3-iodo-amination of 1.

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Conflicts of interest
There are no conflicts to declare.

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Notes and references

Scheme 5(3b).

Derivatization of the 2-aminomethyl-3-iodo-indole derivative

indolobenzazepin derivative (12) (Scheme 5). Replacementof the protecting group in 3b by reductive deprotection,
which aﬀords demesylated/depivaloylated indole (5), followedby protection with Boc2O of 5 provided N-Boc protectedindole derivatives (6). Vinylation of 6 by the Stille coupling
reaction12 gave a conjugated diene (7) in 90% yield, and aDiels–Alder reaction with 1,2,4-triazolin-3,5-dione13 afforded apoly-nitrogen tetracyclic indole derivative containing a quaternary carbon center (8) in high yield. Besides, the Suzuki–Miyaura
coupling reaction14 of 6 with 2-methoxycarbonylphenylboronic
acid was also effective in providing a coupling product (9).
The following reactions of 9, namely, cleavage of the two
Boc groups under basic conditions, reduction of the ester
group, bromination of the alcohol group using the Appelreaction, and 7-membered ring cyclization by the nucleophilic
substitution of 11, gave the indolobenzazepin derivative (12) inhigh yield.
In conclusion, we developed a 1,3-iodo-amination of 2-methylindoles (1) using plural iodine compounds, including hypervalentiodine(III) compounds and iodinating reagents, as a novel method
for Csp2–Csp3 dual functionalization. This process is characterized
by the formation of indolyl(phenyl)iodonium imide (2) using
PhI(OAc)2 and the double iodination of excess DIH as an iodine
reagent to afford the 2-aminomethyl-3-iodo-indole derivative (3).
The economical and efficient installation of plural functionalgroups into an organic molecule by a dual functionalization
process is underway in our laboratory.

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