Article

Cite This: J. Org. Chem. 2018, 83, 228−235 pubs.acs.org/joc

Substituent-Directed Regioselective Azidation: Copper-Catalyzed

C−H Azidation and Iodine-Catalyzed Dearomatizative Azidation of
Indole
Jayaraman Dhineshkumar, Karthik Gadde, and Kandikere Ramaiah Prabhu*
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, Karnataka, India
*
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ABSTRACT: Azidation of indoles using iodine and copper bromide as catalysts under ambient reaction conditions is presented.
The regioselectivity is directed by the substituent at the C3-position of indole. A radical stabilizing group such as an ester or
ketone moiety at the C3-position of indole leads to azidation at the C2-position, whereas a less radical stabilizing group such as
an alkyl or amide group at the C3-position of indole furnishes the 3-azidooxindole product. This protocol is mild and efficient to
obtain several 2-azidoindole derivatives and 3-azidooxindole derivatives in moderate to good yields. The reaction conditions hold
well for gram-scale synthesis.

■ INTRODUCTION
The carbon−nitrogen bond is ubiquitous, and the aryl amine
Since the discovery of the “click” reaction of azides and its
applications in peptide chemistry, polymer chemistry, and drug
moiety is widespread in synthetic as well as naturally occurring discovery, the introduction of the azide group into organic
molecules has received considerable attention.14 In this regard,
bioactive molecules.1 Other than Ullman and Goldberg,2 the
azidation of indole has been reported using an excess amount of
pioneering work on sp2 C−N bond formation was accom-
heavy metal reagents such as ceric ammonium nitrate (CAN)
plished by Buchwald and Hartwig in 1994 using Pd catalyst.3
for synthesizing 2-azidoindoline derivatives.15 Recently, Sudalai
Since then, a plethora of C−N bond-forming reactions have
et al.16 reported a regioselective azidation of indoles at the C3-
been reported in the literature. 4,5 Direct C−H bond
position using a stoichiometric amount of iodine. In
functionalization has become one of the important areas of
continuation of our work,17 we envisioned a reaction of 3-
research and has played a pivotal role in direct C−H amination
substituted indole derivatives with (TMS)N3, and the results
reactions.6 Owing to the presence of indole moieties in a variety
are described in the following section (Scheme 1).

of biologically and medicinally active compounds, synthesis and
functionalization have received great attention.7,8 Selective
functionalization of indole is a challenging task due to its
inherent electronic nature.9a To address this issue, directing
group strategies have been employed efficiently, which have led
to the selective functionalization of indole derivatives at the
C2-, C4-, and C7-positions.9 Direct conversion of sp2 C−H
bonds to C−N bonds in indole moieties is an important
approach, as several 2-aminoindole-derived compounds are
found in biologically active natural products such as gliocladins
B, mollenine A, and NITD609 (Figure 1).10 Amination of
prefunctionalized precursors such as 2-haloindole derivatives
has been well explored using harsh or modified Buchwald−
Hartwig reaction conditions.11
Among the direct C−H aminations,12,13 the iodine-mediated
amination reaction has been reported by Liang et al.12a and
others12 for synthesizing aminated indole derivatives. Liang et
al. developed a Pd-catalyzed reaction by employing N-chloro-
N-methyltosyl derivatives as amine sources at room temper-
ature.13
■
RESULTS AND DISCUSSION
In continuation of our work,17 screening studies were started by
employing methyl 1-methyl-1H-indole-3-carboxylate (1a),
(TMS)N3 as an azide source, CuBr (5 mol %) as a catalyst,
and aq TBHP (1 equiv) as an oxidant in CH3CN solvent.
However, instead of the expected dearomatizative azidated
product, a C−H functionalization of indoles occurred,
furnishing the corresponding 2-azido derivative, methyl 2-
azido-1-methyl-1H-indole-3-carboxylate (2a), in 68% yield
(entry 1, Table 1). Increasing the amount of CuBr to 10 mol
% furnished the expected azidated indole 2a in 95% NMR yield
(entry 2). Solvents such as 1,4-dioxane and DCE furnished the
expected product 2a in poor yields (entries 3 and 4), whereas
other solvents such as H2O, DMF, and MeOH failed to furnish
the expected product (entries 5−7). Cu(I) salts such as CuCl
Received: October 11, 2017
Published: December 5, 2017

© 2017 American Chemical Society 228 DOI: 10.1021/acs.joc.7b02591

J. Org. Chem. 2018, 83, 228−235
The Journal of Organic Chemistry
Figure 1. Biologically important compounds.
Scheme 1. Reaction Development: Azidation of Indoles via C−H Functionalization
and CuI did not afford the expected azidated product (entries 8
and 9), whereas the reaction of 1a with CuBr2 (10 mol %)
proceeded smoothly, furnishing 2a in 88% NMR yield (entry
10). The reaction of 1a with other copper salts such as
Cu(OAc)2 or Cu(OTf)2 did not furnish the expected product
(entries 11 and 12). Thus, the screening study clearly indicated
that both copper(I) and copper(II) bromide salts are suitable
for this oxidative functionalization and the bromide counter-
anion plays a crucial role. The azidation reaction using
molecular iodine as a catalyst was not fruitful (entry 13).
Furthermore, it was found that NaN3 is not a useful azide
source for this reaction (entry 14). Using molecular oxygen
instead of aq TBHP failed to furnish the azidated product
(entry 15). The reaction in the absence of CuBr or aq TBHP
failed to furnish the product 2a, indicating that both the catalyst
and the oxidant are indispensable for the reaction (entries 16
and 17). Therefore, the optimal reaction conditions were found
to be 2 equiv of (TMS)N3, CuBr (10 mol %), and aq TBHP (1
equiv), using CH3CN as the solvent at room temperature.
Having found the optimal reaction conditions, the scope and
limitations of the reaction were explored using a variety of
indole derivatives. Thereby, methyl 1-methyl-1H-indole-3-
carboxylate (1a) under the optimal reaction conditions afforded
the expected 2-azidated product 2a in 95% yield (Scheme 2). 5-
Bromo and 6-bromo derivatives of methyl 1-methyl-1H-indole-
3-carboxylate (1b and 1c, respectively) underwent a smooth
reaction, furnishing the expected azidated products 2b and 2c
in excellent yields (99% and 92% yields, respectively). 3-
Substituted carboxylic esters such as ethyl, allyl, propargyl, and
benzyl ester derivatives of indole furnished the azidated
products in excellent yields, (2g, 2h, 2i, and 2j in 95%, 96%,
90%, and 88% yields, respectively). After a successful azidation
of indole-3-carboxylate esters, similar azidation reactions were
attempted using C3-acylated indole derivatives. Thus, under the
same reaction conditions, several 1-(1-alkyl-1H-indol-3-yl)-
ethan-1-ones furnished the azidated products 2k, 2l, 2m, 2n,
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and 2o, respectively, in moderate yields (68%, 63%, 64%, 46%,
and 38% yields, respectively, Scheme 2).
Enthused by the reaction of azidation of indole-3-carboxylate
esters and C3-acylated indole derivatives, a 3-alkylindole
derivative such as 1,3-dimethyl-1H-indole was subjected to
the optimal reaction conditions, which failed to furnish the
expected product (Scheme 3). Nevertheless, the reaction
furnished the dearomatized 3-azido-1,3-dimethylindolin-2-one
(4a) in 32% yield. Most of the other derivatives of 3-methyl-N-
alkylindoles furnished the dearomatized products 4b, 4c, and
4d in poor yields (29%, 23%, and 18% yields, respectively,
Scheme 4).
Attempts to improve the yields by employing different
copper salts were futile. However, when molecular iodine was
employed as a catalyst in place of CuBr, the 3-azidooxindole
products, via dearomatization, were obtained in good yields.
Thereby, several N-alkyl-3-methylindole derivatives furnished
their corresponding 3-azidooxindole derivatives (4a, 4b, 4c, 4d,
4e, and 4f) in good yields (76%, 62%, 91%, 48%, 83%, and 79%
yields, respectively). 3-Cyclohexyl-1-methyl-1H-indole fur-
nished the expected product 4g in 32% yield (using CuBr as
a catalyst) and 74% yield (using I2 as a catalyst). The reaction
of N,1-dimethyl-1H-indole-3-carboxamide using CuBr as a
catalyst furnished the expected product 4h in 39% yield, and a
similar reaction using I2 furnished the product 4h in 42% yield.
The reactions of N-methylindole and 3-methylindole under the
standard reaction conditions (either CuBr or I2 catalysis
conditions) failed to furnish the expected products 4i and 4j.
A gram-scale experiment has been performed for showcasing
the utility of the reaction (Scheme 5). Hence, the reaction of
methyl 1-methyl-1H-indole-3-carboxylate (1a) and 1,3-dimeth-
yl-1H-indole (3a) under the optimal reaction conditions (Cu
conditions and I2 conditions) furnished the expected product
2a and 4a in 88% and 75% yields, respectively.
To understand the reaction pathway, radical inhibition
studies were carried out using BHT and TEMPO under the
optimal reaction conditions (Scheme 6). In these reactions, the
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Table 1. Optimization Studiesa
a
Reaction conditions: 1a (0.25 mmol), (TMS)N3 (0.5 mmol), aq TBHP (70% in water, 1 equiv), CuBr (10 mol %), CH3CN (1 mL), at rt, 12 h.
b
NMR yields, calculated using terephthalaldehyde as an internal standard. Nd = not detected. cA 5 mol % concentration of CuBr was employed.
d
NaN3 was used instead of (TMS)N3.
azidated products were obtained in only 15% and 10% yields,
respectively (NMR yields), for copper-catalyzed C−H azidation
reactions, and no radical intercepted products were obtained.
This suggests that the reaction may go through a radical
pathway. The radical inhibition studies for an I2-catalyzed
reaction furnished 12% 3-azido oxindole derivative using BHT
(1 equiv) and 68% 3-azidooxindole derivative using TEMPO (1
equiv). These experiments suggest an ionic pathway for the
iodine-catalyzed reaction.
On the basis of literature precedence18 and the control
experiments, a tentative mechanism has been proposed wherein
CuBr and trimethylsilyl azide react to generate CuN3 species.
The CuN3 species generates an azide radical, which adds onto
the substrate I to form the intermediate II, which is stabilized
by an ester or ketone moiety. This may be the reason for the
formation of different products in the reactions of C3-alkylated
or C3-amidated indole derivatives (3-azidooxindole-derived) as
the radical intermediate generated in these cases would be less
stable. Furthermore, the intermediate II undergoes a radical
hydrogen cleavage to form the stable 2-azido product III
(Scheme 7).
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Similarly, a tentative mechanism has been proposed on the
basis of the literature prcedence16 and the control experiments.
In this reaction, I2 and trimethylsilyl azide react to generate IN3
species. The IN3 species reacts with the substrate I to form the
intermediates A and A′, which are in equilibrium. Nucleophilic
azide displaces the iodonium ion to form the intermediates B
and B′, which are in equilibrium. Furthermore, the intermediate
B′ reacts with aq TBHP and undergoes rapid oxidation to
furnish the 3-azidooxindole product D (Scheme 8).
Similarly, a tentative mechanism has been proposed for the
copper-catalyzed C3-azidation of indole derivatives. We believe
that, through the single electron transfer (SET) mechanism, the
reaction leads to the intermediate A, which further transforms
to iminium ion intermediate B. The intermediate B reacts with
aq TBHP and undergoes rapid oxidation to furnish the 3-
azidooxindole product D (Scheme 9).
In summary, a direct C−H functionalization and dearoma-
tization of indole derivatives have been achieved using CuBr
and I2 as catalysts and aq TBHP as an oxidant. When the
substitution on the third position of indole is a radical-
stabilizing group such as an ester or ketone moiety, the reaction
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Scheme 2. Substrate Scope: Regioselective Azidation of Indoles Using CuBr as a Catalysta
a
Reaction conditions: 1 (0.25 mmol), (TMS)N3 (0.5 mmol, 2 equiv), CuBr (10 mol %), aq TBHP (70% in water, 1 equiv), and CH3CN (1 mL).
Scheme 3. Reaction Development: Azidation of Indoles via Dearomatization
prefers to form 2-azido products. However, when the
substitution on the C3-position of indole is less radical
stabilizing, such as an alkyl or amide group, then the reaction
prefers to furnish the 3-azidooxindole product. In conclusion,
we discovered that substitution on the C3-position of indole
causes the difference in reactivity under the same reaction
conditions to afford two completely different products. By
employing this protocol, several 2-azidoindole derivatives and
3-azidooxindole derivatives are obtained in good to moderate
yields. The developed protocol was also efficient in a gram-scale
experiment. Further studies to improve the substrate scope and
generality are currently under way in our laboratory.
■ EXPERIMENTAL SECTION
Typical Experimental Procedure for the Synthesis of 2-
Azidoindole Derivatives (Procedure a). (TMS)N3 (2 equiv, 0.50
mmol) was added to a well-stirred solution of indole derivative (0.25
mmol) and CuBr (0.1 equiv, 0.025 mmol) in CH3CN (1 mL). Then
aq TBHP (70% in water, 1 equiv, 0.25 mmol) was added dropwise
into the reaction mixture, and the resulting mixture was stirred at room
temperature for 12 h (monitored by TLC). After completion of the
reaction (monitored by TLC), the reaction mixture was passed
through a short pad of Celite and extracted with 50% EtOAc and
petroleum ether (3 × 20 mL). The combined organic layer was dried
over anhyd Na2SO4 and concentrated under reduced pressure. The
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crude product was purified on a silica gel flash column chromatograph
using hexane/EtOAc to obtain the pure product.
Typical Experimental Procedure for the Synthesis of 3-
Azidooxindole Derivatives (Procedure b). (TMS)N3 (2 equiv,
0.50 mmol) was added to a well-stirred solution of indole derivative
(0.25 mmol) and I2 (0.1 equiv, 0.025 mmol) in CH3CN (1 mL). Then
aq TBHP (70% in water, 2 equiv, 0.5 mmol) was added dropwise into
the reaction mixture, and the resulting mixture was stirred at room
temperature for 48 h (monitored by TLC). After completion of the
reaction (monitored by TLC), the reaction mixture was quenched
using aqueous Na2S2O3 and washed with EtOAc (3 × 20 mL). The
combined organic layer was dried over anhyd Na 2SO4 and
concentrated under reduced pressure. The crude product was purified
on a silica gel flash column chromatograph using hexane/EtOAc to
obtain the pure product.
Characterization Data for C2-Azidation of Indole Deriva-
tives. Methyl 2-Azido-1-methyl-1H-indole-3-carboxylate (2a).
Brown solid. Yield: 95% (52 mg). Mp: 69−71 °C. Rf (10% EtOAc/
hexane): 0.5. Prepared as shown in general experimental procedure a.
IR (KBr, cm−1): 2130, 1694, 1454. 1H NMR (400 MHz, CDCl3): δ
3.64 (s, 3 H), 3.97 (s, 3 H), 7.24−7.26 (m, 3 H), 8.05−8.07 (m, 1 H).
13
C NMR (100 MHz, CDCl3): δ 29, 51, 96.4, 109.2, 121, 122.3, 122.7,
125.5, 133.7, 140.6, 165. HRMS (ESI-TOF) ( m/z): [M + Na]+ calcd
for C11H10N4O2Na 253.0701, found 253.0701.
Methyl 2-Azido-5-bromo-1-methyl-1H-indole-3-carboxylate (2b).
Brown solid. Yield: 99% (76 mg). Mp: 148−150 °C. Rf (10% EtOAc/
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Scheme 4. Substrate Scope: Regioselective Azidation of Indoles Using Iodine as a Catalysta
a
Reaction conditions: 3 (0.25 mmol), (TMS)N3 (0.5 mmol, 2 equiv), I2 (10 mol %) or CuBr (10 mol %), aq TBHP (70% in water, 2 equiv), and
CH3CN (1 mL), at rt for 48 h.
Scheme 5. Gram-Scale Experiments
Scheme 6. Radical Inhibition Studies
hexane): 0.4. Prepared as shown in general experimental procedure a.
IR (KBr, cm−1): 2922, 2140, 1689, 1454. 1H NMR (400 MHz,
CDCl3): δ 3.59 (s, 3 H), 3.96 (s, 3 H), 7.06 (d, J = 8.85 Hz, 1 H), 7.31
(dd, J = 8.54, 1.83 Hz, 1 H), 8.16 (s, J = 1.83 Hz, 1 H). 13C NMR (100
MHz, CDCl3): δ 29.1, 51.1, 96, 110.6, 115.8, 123.5, 125.5, 127, 132.4,
141.3, 164.5. HRMS (ESI-TOF) ( m/z): [M]+ calcd for C11H9BrN4O2
307.9909, found 307.9909.
Methyl 2-Azido-6-bromo-1-methyl-1H-indole-3-carboxylate (2c).
Brown solid. Yield: 92% (71 mg). Mp: 119−121 °C. Rf (10% EtOAc/
hexane): 0.4. Prepared as shown in general experimental procedure a.
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IR (KBr, cm−1): 2139, 1695, 1458. 1H NMR (400 MHz, CDCl3): δ
3.56 (s, 3 H), 3.95 (s, 3 H), 7.30−7.34 (m, 2 H), 7.87−7.89 (m, 1 H).
13
C NMR (100 MHz, CDCl3): δ 29.1, 51, 96.5, 112.2, 115.9, 122.3,
124.3, 125.4, 134.4, 140.9, 164.5. HRMS (ESI-TOF) ( m/z): [M]+
calcd for C11H9BrN4O2 307.9909, found 307.9909.
Methyl 2-Azido-1-ethyl-1H-indole-3-carboxylate (2d). Brown oil.
Yield: 80% (49 mg). Rf (10% EtOAc/hexane): 0.6. Prepared as shown
in general experimental procedure a. IR (neat, cm−1): 2948, 2138,
1693. 1H NMR (400 MHz, CDCl3): δ 1.35 (t, J = 7.33 Hz, 3 H), 3.96
(s, 3 H), 4.11−4.17 (m, 2 H), 7.22−7.24 (m, 3 H), 8.06−8.08 (m, 1
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Scheme 7. Proposed Tentative Reaction Mechanism for CuBr-Catalyzed C−H Azidation
Scheme 8. Proposed Tentative Reaction Mechanism for I2-
Catalyzed Dearomatizative Azidation
H). 13C NMR (100 MHz, CDCl3): δ 14.6, 37.7, 50.9, 96.4, 109.2,
121.1, 122.1, 122.6, 125.7, 132.6, 139.9, 165. HRMS (ESI-TOF) ( m/
z): [M + Na]+ calcd for C12H12N4O2Na 267.0858, found 267.0854.
Methyl 1-Allyl-2-azido-1H-indole-3-carboxylate (2e). Brown oil.
Yield: 74% (47 mg). Rf (10% EtOAc/hexane): 0.4. Prepared as shown
in general experimental procedure a. IR (neat, cm−1): 2137, 1694,
1453. 1H NMR (400 MHz, CDCl3): δ 3.97 (s, 3 H), 4.70 (dt, J = 4.96,
1.79 Hz, 2 H), 4.95−5.00 (m, 1 H), 5.16−5.19 (m, 1H), 5.79−5.98
(m, 1 H), 7.11−7.30 (m, 3 H) 7.99−8.13 (m, 1 H). 13C NMR (100
MHz, CDCl3): δ 44.9, 51, 96.6, 109.6, 117.3, 121.1, 122.3, 122.8,
125.6, 131.7, 133.1, 140.1, 164.9. HRMS (ESI-TOF) (m/z): [M +
Na]+ calcd for C13H12N4O2Na 279.0858, found 279.0858.
Methyl 2-Azido-1-benzyl-1H-indole-3-carboxylate (2f). Oily
liquid. Yield: 93% (71 mg). Rf (10% EtOAc/hexane): 0.6. Prepared
as shown in general experimental procedure a. IR (neat, cm−1): 2140,
1682, 1431. 1H NMR (400 MHz, CDCl3): δ 3.98 (s, 3 H), 5.30 (s, 2
H) 7.11 (d, J = 6.71 Hz, 2 H), 7.18−7.21 (m, 2 H), 7.21−7.36 (m, 4
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Scheme 9. Proposed Tentative Reaction Mechanism for Cu-
Catalyzed Dearomatizative Azidation
H), 8.09 (d, J = 7.93 Hz, 1 H). 13C NMR (100 MHz, CDCl3): δ 46.2,
51, 96.8, 109.8, 121.1, 122.4, 122.9, 125.7, 126.5, 127.8, 128.9, 133.3,
136, 140.3, 164.9. HRMS (ESI-TOF) (m/z): [M + K]+ calcd for
C17H14N4O2K 345.0754, found 345.0752.
Ethyl 2-Azido-1-methyl-1H-indole-3-carboxylate (2g). Brown
solid. Yield: 95% (58 mg). Mp: 65−67 °C. Rf (10% EtOAc/hexane):
0.5. Prepared as shown in general experimental procedure a. IR (KBr,
cm−1): 2137, 1686, 1450. 1H NMR (400 MHz, CDCl3): δ 1.46 (t, J =
7.02 Hz, 3 H), 3.59 (s, 3 H), 4.44 (q, J = 7.2, 2 H), 7.15−7.30 (m, 3
H), 8.02−8.12 (m, 1 H). 13C NMR (100 MHz, CDCl3): δ 14.6, 28.9,
59.8, 96.6, 109.1, 121, 122.2, 122.6, 125.5, 133.7, 140.4, 164.5. HRMS
(ESI-TOF) ( m/z): [M + Na]+ calcd for C12H13N4O2 245.1039, found
245.1038.
Allyl 2-Azido-1-methyl-1H-indole-3-carboxylate (2h). Brown
solid. Yield: 96% (62 mg). Mp: 121−123 °C. Rf (10% EtOAc/
hexane): 0.6. Prepared as shown in general experimental procedure a.
IR (KBr, cm−1): 2129, 1680, 1519. 1H NMR (400 MHz, CDCl3): δ
3.63 (s, 3 H), 4.90 (d, J = 5.49 Hz, 2 H), 5.29 (d, J = 10.38 Hz, 1 H),
5.44 (d, J = 17.40 Hz, 1 H), 6.07−6.16 (m, 1 H), 7.23−7.26 (m, 3 H),
8.07−8.09 (m, 1 H). 13C NMR (100 MHz, CDCl3): δ 29, 64.6, 96.3,
109.2, 118.1, 121.1, 122.3, 122.7, 125.5, 132.8, 133.7, 140.8, 164.2.
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HRMS (ESI-TOF) (m/z): [M + Na]+ calcd for C13H12N2O2Na
251.0796, found 251.0796.
Prop-2-yn-1-yl 2-Azido-1-methyl-1H-indole-3-carboxylate (2i).
Brown solid. Yield: 90% (57 mg). Mp: 60−63 °C. Rf (10% EtOAc/
hexane): 0.5. Prepared as shown in general experimental procedure a.
IR (KBr, cm−1): 2123, 1680, 1091. 1H NMR (400 MHz, CDCl3): δ
2.52 (t, J = 2.44 Hz, 1 H), 3.64 (s, 3 H), 4.99 (d, J = 2.44 Hz, 2 H),
7.22−7.30 (m, 3 H), 8.10 (dd, J = 6.56, 2.59 Hz, 1 H). 13C NMR (100
MHz, CDCl3): δ 29.1, 51.3, 74.7, 78.2, 95.70, 109.2, 121.2, 122.5,
122.9, 125.4, 133.8, 141.3, 163.5. HRMS (ESI-TOF) (m/z): [M +
Na]+ calcd for C13H10N4O2Na 277.0701, found 277.0703.
Benzyl 2-Azido-1-methyl-1H-indole-3-carboxylate (2j). Brown
solid. Yield: 88% (67 mg). Mp: 114−116 °C. Rf (10% EtOAc/
hexane): 0.6. Prepared as shown in general experimental procedure a.
IR (KBr, cm−1): 2124, 1674, 1452. 1H NMR (400 MHz, CDCl3): δ
3.62 (s, 3 H), 5.44 (s, 2 H), 7.20−7.24 (m, 3 H), 7.30−7.40 (m, 3 H),
7.49 (d, J = 7.02 Hz, 2 H), 8.03−8.05 (m, 1 H). 13C NMR (100 MHz,
CDCl3): δ 29, 65.6, 96.3, 109.2, 121.1, 122.4, 122.7, 125.5, 128.0,
128.2, 128.5, 133.7, 136.6, 141, 164.3. HRMS (ESI-TOF) (m/z): [M +
Na]+ calcd for C17H14N4O2Na 329.1014, found 329.1018.
1-(2-Azido-1-methyl-1H-indol-3-yl)ethan-1-one (2k). Brown oil.
Yield: 68% (36 mg). Rf (30% EtOAc/hexane): 0.8. Prepared as shown
in general experimental procedure a. IR (neat, cm−1): 2133, 1754,
1464. 1H NMR (400 MHz, CDCl3):δ 2.70 (s, 3 H), 3.64 (s, 3 H),
7.25−7.30 (m, 3 H), 7.82−7.84 (m, 1 H). 13C NMR (100 MHz,
CDCl3): δ 28.8, 31.1, 106.4, 109.7, 119.9, 122.4, 122.5, 125, 133.9,
141.2, 192.9. HRMS (ESI-TOF) ( m/z): [M + Na]+ calcd for
C11H10N4ONa 237.0752, found 237.0754.
1-(2-Azido-1-ethyl-1H-indol-3-yl)ethan-1-one (2l). Brown oil.
Yield: 63% (36 mg). Rf (30% EtOAc/hexane): 0.7. Prepared as
shown in general experimental procedure a. IR (neat, cm−1): 2145,
1734, 1642, 1485, 1429. 1H NMR (400 MHz, CDCl3): δ 1.36 (t, J =
7.2 Hz, 3 H), 2.71 (s, 3 H), 4.17 (q, J = 7.2 Hz, 2 H), 7.25−7.32 (m, 3
H), 7.84−7.86 (m, 1 H). 13C NMR (100 MHz, CDCl3): δ 14.5, 31.2,
37.5, 106.5, 109.7, 120.1, 122.3, 122.5, 125.2, 132.8, 140.6, 193.1.
HRMS (ESI-TOF) ( m/z): [M + Na]+ calcd for C12H12N4ONa
251.0909, found 521.0912.
1-(2-Azido-1-benzyl-1H-indol-3-yl)ethan-1-one (2m). Brown oil.
Yield: 64% (46 mg). Rf (30% EtOAc/hexane): 0.7. Prepared as shown
in general experimental procedure a. IR (neat, cm−1): 2145, 1642,
1489, 1456. 1H NMR (400 MHz, CDCl3): δ 2.74 (s, 3 H), 5.32 (s, 2
H), 7.14 (d, J = 7.2 Hz, 3 H), 7.22−7.33 (m, 7 H), 7.87 (d, J = 8.0 Hz,
1 H). 13C NMR (100 MHz, CDCl3): δ 31.2, 46.0, 106.6, 110.4, 120.,
122.5, 122.7, 125.1, 126.6, 127.8, 128.9, 133.4, 135.7, 140.9, 193.2.
HRMS (ESI-TOF) ( m/z): [M + Na]+ calcd for C17H14N4ONa
313.1065, found 313.1062.
1-(2-Azido-1-pentyl-1H-indol-3-yl)ethan-1-one (2n). Brown oil.
Yield: 46% (31 mg). Rf (10% EtOAc/hexane): 0.5. Prepared as shown
in general experimental procedure a. IR (neat, cm−1): 2140, 1731,
1642, 1426. 1H NMR (400 MHz, CDCl3): δ 0.90 (t, J = 6.8 Hz, 3 H),
1.21−1.42 (m, 4 H), 1.72−1.77 (m, 2 H), 2.71 (s, 3 H), 4.09 (t, J = 7.2
Hz, 2 H), 7.25−7.30 (m, 3 H), 7.82−7.85 (m, 1 H) . 13C NMR (100
MHz, CDCl3): δ 13.9, 22.3, 28.9, 28.9, 31.1, 42.7, 106.3, 109.9, 120,
122.3, 122.4, 125.1, 133.2, 140.9, 193. HRMS (ESI-TOF) (m/z): [M +
Na]+ calcd for C15H18N4ONa 293.1378, found 293.1380.
1-(2-Azido-6-bromo-1-methyl-1H-indol-3-yl)ethan-1-one (2o).
Brown oil. Yield: 38% (28 mg). Rf (20% EtOAc/hexane): 0.7.
Prepared as shown in general experimental procedure a. IR (neat,
cm−1): 2148, 1763, 1450. 1H NMR (400 MHz, CDCl3) δ 2.65 (s, 3
H), 3.60 (s, 3 H), 7.27−7.45 (m, 2 H), 7.65 (dd, J = 8.39, 2.90 Hz, 1
H). 13C NMR (100 MHz, CDCl3) δ 29, 31, 106.4, 112.7, 115.8, 121.1,
123.8, 125.5, 134.7, 141.6, 192.6. HRMS (ESI-TOF) ( m/z): [M +
H]+ calcd for C11H10BrN2O 264.9976, found 264.9974.
3-Azido-1,3-dimethylindolin-2-one (4a). Brown oil. Yield: 76%
(38 mg). Rf (30% EtOAc/hexane): 0.3. Prepared as shown in general
experimental procedure b. IR (neat, cm−1): 2102, 1726, 1614, 1244.
1
H NMR (400 MHz, CDCl3): δ 1.56 (s, 3 H), 3.22 (s, 3 H), 6.76 (d,J
= 7.6 Hz,1 H), 6.98 (t, J = 8.4, Hz, 1 H), 7.30−7.33 (m, 2 H). 13C
NMR (100 MHz, CDCl3): δ 24.4, 27.0, 65.9, 107.5, 121.2, 123.2,
234
Article
128.3, 130.2, 145.0, 170.5. HRMS (ESI-TOF) ( m/z): [M + Na]+
calcd for C10H10N4ONa 225.0752, found 225.0748.
3-Azido-1-ethyl-3-methylindolin-2-one (4b). Yellow oil. Yield:
62% (34 mg). Rf (20% EtOAc/hexane): 0.2. Prepared as shown in
general experimental procedure b. IR (neat, cm−1): 2098, 1719, 1656,
1606. 1H NMR (400 MHz, CDCl3) δ 1.26 (t, J = 7.2 Hz, 3 H) 1.56 (s,
3 H) 3.74−3.85 (m, 2 H) 6.9 (d, J = 8 Hz, 1 H) 6.99 (t, J = 7.2 Hz, 1
H) 7.30−7.33 (m, 2 H). 13C NMR (100 MHz, CDCl3) δ 11.8, 24.4,
35.4, 66.0, 107.6, 121.1, 123.4, 128.6, 130.2, 144.1, 169.6. HRMS (ESI-
TOF) ( m/z): [M]+ calcd for C11H12N4O 216.1011, found 216.1012.
1-Allyl-3-azido-3-methylindolin-2-one (4c). Brown oil. Yield: 91%
(52 mg). Rf (30% EtOAc/hexane): 0.3. Prepared as shown in general
experimental procedure b. IR (neat, cm−1): 2096, 1658, 1606, 1483.
1
H NMR (400 MHz, CDCl3): δ 1.59 (s, 3 H), 4.32−4.42 (m, 2 H),
5.15−5.22 (m, 2 H), 5.81−5.90 (m, 1 H), 6.75 (d, J = 7.6 Hz, 1 H),
7.02 (t, J = 7.2 Hz, 1 H), 7.27−7.31 (m, 2 H). 13C NMR (100 MHz,
CDCl3): δ 24.6, 42.9, 66.1, 108.3, 116.9, 121.4, 123.3, 128.3, 130.2,
130.8, 144.3, 169.8. HRMS (ESI-TOF) ( m/z): [M]+ calcd for
C12H12N4O 228.1011, found 228.1010.
3-Azido-1-benzyl-3-methylindolin-2-one (4d). Brown oil. Yield:
48% (33 mg). Rf (30% EtOAc/hexane): 0.6. Prepared as shown in
general experimental procedure b. IR (neat, cm−1): 2095, 1657, 1606,
1490. 1H NMR (400 MHz, CDCl3): δ 1.63 (s, 3 H), 4.93−5.02 (m, 2
H), 6.68 (d, J = 7.6 Hz, 1 H), 7.01 (t, J = 7.2 Hz, 1 H), 7.27−7.35 (m,
7 H). 13C NMR (100 MHz, CDCl3): δ 24.7, 44.3, 66.2, 108.4, 121.5,
123.4, 126.8, 127.4, 128.3, 128.7, 130.3, 135.9, 144.3, 170.3. HRMS
(ESI-TOF) (m/z): [M]+ calcd for C16H14N4O 278.1168, found
278.1169.
3-Azido-3-methyl-1-pentylindolin-2-one (4e). Brown oil. Yield:
83% (54 mg). Rf (10% EtOAc/hexane): 0.2. Prepared as shown in
general experimental procedure b. IR (neat, cm−1): 2097, 1723, 1655,
1607, 1467. 1H NMR (400 MHz, CDCl3): δ 0.87−0.91 (m, 3 H),
1.26−1.40 (m, 4 H), 1.56 (s, 3 H), 1.66−1.71 (m, 2 H), 3.65−3.78
(m, 2 H), 6.76 (d, J = 8.4 Hz, 1 H), 6.97 (t, J = 6.8 Hz, 1 H), 7.27−
7.32 (m, 2 H). 13C NMR (100 MHz, CDCl3): δ 13.9, 22.4, 24.4, 26.4,
29.1, 40.7, 66.0, 107.7, 121.0, 123.3, 128.5, 130.1, 144.5, 169.9. HRMS
(ESI-TOF) (m/z): [M]+ calcd for C14H18N4O 258.1481, found
258.1485.
3-Azido-1-(4-(benzyloxy)butyl)-3-methylindolin-2-one (4f).
Brown oil. Yield: 79% (69 mg). Rf (30% EtOAc/hexane): 0.3.
Prepared as shown in general experimental procedure b. IR (neat,
cm−1): 2098, 1653, 1608, 1466. 1H NMR (400 MHz, CDCl3): δ 1.57
(s, 3 H), 1.59−1.74 (m, 2 H), 1.78−1.84 (m, 2 H), 3.52 (t, J = 6.4 Hz,
2 H), 3.76−3.80 (m, 2 H), 4.50 (s, 2 H) 6.79 (d, J = 8.2 Hz, 1 H), 7.03
(t, J = 6.8 Hz, 1 H), 7.28−7.37 (m, 7 H). 13C NMR (100 MHz,
CDCl3): δ 23.8, 24.4, 26.9, 40.8, 66.2, 69.9, 72.9, 108.1, 121.5, 123.3,
127.5, 127.6, 128.3, 128.5, 130.3, 138.3, 144.2, 170.0. HRMS (ESI-
TOF) ( m/z): [M]+ calcd for C20H22N4O2 350.1743, found 350.1741.
3-Azido-3-cyclohexyl-1-methylindolin-2-one (4g). Yellow oil.
Yield: 74% (50 mg). Rf (50% EtOAc/hexane): 0.4. Prepared as
shown in general experimental procedure b. IR (neat, cm−1): 2101,
1656, 1605. 1H NMR (400 MHz, CDCl3): δ 0.63 (qd, J = 3.2 Hz, 1
H), 1.15−1.27 (m, 4 H), 1.53−1.91 (m, 6 H), 3.23 (s, 3 H), 6.76 (d, J
= 7.6 Hz, 1 H), 6.98 (t, J = 7.2 Hz, 1 H), 7.27−7.34 (m, 2 H). 13C
NMR (100 MHz, CDCl3): δ 25.9, 26.0, 26.1, 26.4, 26.5, 27.00, 47.0,
73.5, 107.3, 120.8, 124.6, 125.6, 130.1, 146.1, 170.2. HRMS (ESI-
TOF) (m/z): [M]+ calcd for C15H18N4O 270.1481, found 270.1482.
3-Azido-N,1-dimethyl-2-oxoindoline-3-carboxamide (4h). Brown
solid. Yield: 42% (26 mg). Mp: 125−127 °C. Rf (50% EtOAc/hexane):
0.3. Prepared as shown in general experimental procedure b. IR (KBr,
cm−1): 2102, 1711, 1699, 1465, 1249. 1H NMR (400 MHz, CDCl3): δ
2.87 (d, J = 4.8 Hz, 3 H), 3.25 (s, 3 H), 6.91 (d, J = 8.0 Hz, 2 H), 7.16
(t, J = 8.1 Hz,1 H), 7.42 (t, J = 8.02, 1 H), 7.49 (d, J = 7.2 Hz, 1 H).
13
C NMR (100 MHz, CDCl3): δ 26.7, 26.7, 68.7, 109.2, 123.8, 124.4,
125.3, 131.0, 144.0, 164.9, 171.1. HRMS (ESI-TOF) ( m/z): [M +
Na]+ calcd for C11H11N5O2Na 268.0810, found 268.0812.
DOI: 10.1021/acs.joc.7b02591
J. Org. Chem. 2018, 83, 228−235
The Journal of Organic Chemistry Article

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*
ASSOCIATED CONTENT
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ACKNOWLEDGMENTS
This work was supported by SERB (Grant No. SB/S1/OC-56/
2013), New Delhi, CSIR (Grant No. 02(0226)15/EMR-II),
New Delhi, the Indian Institute of Science, RL Fine Chem,
Bangalore, Synovation Chemicals, and Sourcing Pvt Ltd.,
Bangalore. We thank Dr. A. R. Ramesha (RL Fine Chem) for
useful discussions. We thank Mr. N. Muniraj for performing a
few experiments at the revision stage of the manuscript. J.D.
thanks CSIR, New Delhi, for his senior research fellowship.
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235 DOI: 10.1021/acs.joc.7b02591

J. Org. Chem. 2018, 83, 228−235