Metal-free regioselective C-3 acetoxylation of N-substituted indoles: Crucial impact of nitrogen-substituent

Article abstract of DOI:10.1039/c5ra10428a

A metal-free method for the regioselective C-3 acetoxylation of the N-substituted indoles with PhI(OAc)₂ is described under mild reaction conditions. This method tolerates a broad range of functional groups with moderate to good yields. The π-e

Full text of DOI:10.1039/c5ra10428a

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Metal-free regioselective C-3 acetoxylation of N-substituted
indoles: Crucial impact of nitrogen-substituent†
Vineeta Soni, Ulhas N. Patel and Benudhar Punji*
Organometallic Synthesis and Catalysis Group, Chemical Engineering Division, CSIR–National Chemical
Laboratory (CSIR–NCL), Dr. Homi Bhabha Road, Pune – 411 008, Maharashtra, INDIA. Phone: + 91ꢀ20ꢀ
2590 2733, Fax: + 91ꢀ20ꢀ2590 2621
Eꢀmail: b.punji@ncl.res.in
Abstract: A metalꢀfree method for the regioselective Cꢀ3 acetoxylation of the Nꢀ
substituted indoles with PhI(OAc)2 is described under mild reaction conditions. This
method tolerates a broad range of functional groups with moderate to good yields. The πꢀ
electronꢀdeficient arylꢀsubstituents on the Nꢀatom of indoles and the acidic reaction
medium remarkably favor the Cꢀ3 acetoxylation
.
† Electronic supplementary information (ESI) available.
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Introduction
Direct functionalization of C‒H bond to form C‒O bond is among the most demanding
chemical reaction in synthetic organic chemistry.1 The C‒O bond formation in arenes to
obtain hydroxylatedꢀ,2 alkoxylatedꢀ3 or acetoxylatedꢀarenes4 are considerably explored,
and the regioselectivity has been successfully achieved by the installation of a Lewisꢀbase
directing group. In contrast to many reports on the acetoxylation of arenes, the synthesis
of the regioselectively acetoxylated heteroarenes is relatively scarce.5 Among the
heteroarenes, the indole derivatives are very important building blocks, found in many
pharmaceuticals as well as in the biologically active compounds. In particular, 3ꢀ
acetoxyindoles are potential materials, applied for the detection of acetylcholinesterase in
tissue slices6 and they could also be used as a starting precursors for the synthesis of
potential 5ꢀhydroxytryptamine6 (5ꢀHT6) receptor ligand scafolds.7 Hence, the efficient
synthesis of 3ꢀacetoxyindoles through the regioselective Cꢀ3 acetoxylation of indole
derivatives is highly desirable. The groups of Lei,8 Kwong7 and Suna9 have independently
reported the Cꢀ3 acetoxylation of Nꢀsubstituted indoles using Pd(OAc)2 catalyst, and
PhI(OAc)2 as an external oxidant (Scheme 1a). This palladiumꢀcatalyzed regioselective
acetoxylation process is applicable to the various indole substrates containing methyl,
benzyl, aryl or arenesulfonyl group as the nitrogenꢀsubstituents. However, the
employment of the precious metal catalysts for the functionalization of probable
pharmacological indole derivatives, limit the advancement of these metalꢀcatalyzed
acetoxylation processes.
2

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Scheme 1 Regioselective Cꢀ3 acetoxylation of substitutedꢀIndoles: (a) palladiumꢀ
catalyzed acetoxylation of Nꢀmethyl, Nꢀbenzylꢀ or Nꢀaryl Indoles, (b) this work
demonstrates: metalꢀfree acetoxylation of Nꢀ(hetero)aryl indoles.
In recent years, numerous reports have been described for the C‒H bond
functionalization under the transitionꢀmetalꢀfree conditions.10 A transitionꢀmetalꢀfree Cꢀ3
acetoxylation of the free NHꢀindole has been described under the strong basic condition
by Huang and coꢀworkers.11 However, this method is not applicable to the Nꢀsubstituted
indole substrates and has limited scope. The Cꢀ3 acetoxylation of NꢀBocꢀprotected indole
has been observed by Lei et.al. during their studies directed toward the synthesis of
diacetoxylated indolines.12 To our knowledge, a comprehensive approach for the metalꢀ
free Cꢀ3 acetoxylation of the Nꢀsubstituted indoles with high regioselectivity is not known.
Herein, we present the regioselective Cꢀ3 acetoxylation of the Nꢀsubstituted indoles with
PhI(OAc)2 as an oxidant under the metalꢀfree and mild reaction conditions. Moreover, we
have demonstrated the effect of the Nꢀsubstituents on reactivity and selectivity of the
indole acetoxylations.
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Results and discussion
During the investigation of a less expensive firstꢀrow transition metal catalyst for the
acetoxylation of the Nꢀsubstituted indoles employing PhI(OAc)2 in acetic acid solvent, we
observed that the Cꢀ3 acetoxylation of indole occurred in the absence of metal catalysts,
when a suitable substituent on the nitrogen atom of indole was installed. For example, the
o
reaction of 1ꢀpyrimidinyl indole (1a) with PhI(OAc)2 in AcOH/Ac2O solvent at 60 C,
exclusively produced 1ꢀ(pyrimidinꢀ2ꢀyl)ꢀ1Hꢀindolꢀ3ꢀyl acetate (2a) in 93% isolated yield
(Table 1, entry 1). The 1ꢀarylindoles, like 1ꢀphenylindole (3a) reacted with PhI(OAc)2
under the metalꢀfree condition to afford the corresponding Cꢀ3 acetoxylated indole 4a in
50% yield; whereas the reaction of 1ꢀ(4ꢀmethoxypheny)indole (3b) with PhI(OAc)2 under
the same condition produced only 37% of the acetoxylated compound 4b. Surprisingly,
the free NHꢀindole or indoles having electronꢀrich substituents at the nitrogenꢀcenter, such
as 1ꢀmethylindole, were decomposed to the unknown compounds at room temperature.
However, the indoles bearing strong electronꢀwithdrawing substituents at the nitrogenꢀ
atom, such as 1ꢀ(acetyl)indole and 1ꢀ(tosyl)indole produced the diacetoxylated indolines in
91% and 28% yields, respectively (Table 1, entries 6, 7).12 These studies on the effect of
Nꢀsubstituents towards the acetoxylation of indoles suggested that a πꢀelectronꢀdeficient
(hetero)areneꢀsubstituent on the nitrogen atom of indole greatly enhances the selective Cꢀ
3 acetoxylation reaction.
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Table 1 Effect of nitrogenꢀsubstituents on Cꢀ3 acetoxylation of indolesa
Entry
R
% Yield
(2 or 4)
93 (2a)
5
ꢀ
Recovered
(1 or 3)
ꢀ
1
2
3
4
5
6
2ꢀPym
Ph
50 (4a)
ꢀ
35 (3a)
4ꢀMeOꢀC6H4
H
37 (4b)
ꢀ
ꢀb
ꢀc
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
CH3
ꢀ
ꢀc
C(O)CH3
Tosyl
91
28
5
7
70
a
Reaction conditions: Compound 1 or 3 (0.30 mmol), PhI(OAc)2 (0.106 g, 0.33 mmol),
b
AcOH/Ac2O (1.0 mL), yields of isolated compounds.
Starting compound was not
recovered. c Decomposed into intractable products at room temperature.
After optimizing the effect of Nꢀsubstituent’s on the metalꢀfree acetoxylation of
indoles, we have tested the impact of various solvents and oxidants on the acetoxylation
reaction (Table 2). The use of glacial acetic acid as solvent instead of AcOH/Ac2O,
produced the desired acetoxylated product 2a in 76% isolated yield (entry 2). However,
the complete decomposition of 1a was observed in TFA/TFAA under the reaction
conditions (entry 3). The employment of nonꢀacid solvent 2,2,2ꢀtrifluoroethanol (TFE) gave
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only 20% of product 2a, whereas the reactions in CH3CN or 1,2ꢀdichloroethane (DCE) did
not produce any acetoxylated products (entry 4, 5). The presence of strong oxidant
PhI(TFA)2 resulted in the decomposition of 1a; however, other organic oxidants, such as
mꢀCPBA, tertꢀBuOOH or inorganic oxidants like K2S2O8 and oxone were ineffective, and
most of the starting material was recovered (entry 6ꢀ8).
Table 2 Optimization of reaction parameters for Cꢀ3 acetoxylation of 1aa
Entry Variation from
“standard condition”
Yield
(%)b
1
2
3
4
5
6
7
8
ꢀ
93
76
ꢀc
AcOH instead of AcOH/Ac2O
TFA/TFAA instead of AcOH/Ac2O
TFE instead of AcOH/Ac2O
20
NR
ꢀc
CH3CN, DCE instead of AcOH/Ac2O
PhI(TFA)2 instead of PhI(OAc)2
mꢀCPBA instead of PhI(OAc)2
trace
K2S2O8, Oxone or tꢀBuOOH instead of NR
PhI(OAc)2
9
25 oC instead of 60 oC
15
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a
Reaction conditions: 1a (0.059 g, 0.30 mmol), PhI(OAc)2 (0.106 g, 0.33 mmol),
AcOH/Ac2O (1.0 mL). TFE (2,2,2ꢀTrifluoroethanol), TFA (Trifluoroacetic acid), TFAA
b
c
(Trifluoroacetic anhydride), NR = No reaction.
Decomposed into intractable compounds.
Yields of isolated compounds.
Having the optimized reaction conditions in hand, we probed the scope of the
metalꢀfree Cꢀ3 acetoxylation of the Nꢀheteroarylꢀsubstituted indoles 1 employing
PhI(OAc)2 as the oxidant in AcOH/Ac2O solvent (Scheme 2). Notably, the Nꢀpyrimidinyl
indoles containing electronically different functional groups reacted smoothly to produce
the desired acetoxylated products (2aꢀ2e) in good yields. The tolerability of the functional
groups such as ‒F, ‒Br is significant, as they can be further functionalized into important
compounds. It is noteworthy that the direct acetoxylation of indoles 1 occurred with
excellent regioselectivity to predominantly produce Cꢀ3 acetoxylated indoles. Particularly,
by employing 2ꢀpyrimidinyl as the Nꢀsubstituent on indoles, neither the starting
compounds nor the acetoxylated products were decomposed. More hindered 2ꢀ
substituted indole 1f reacted with low efficacy to produced 2f in 26% yield. In addition to
the Nꢀpyrimidinyl indoles, the indoles containing 2ꢀpyridinyl and 2ꢀpyrazinyl as nitrogenꢀ
substituents reacted efficiently to give the desired acetoxylated products in good yields.
The pyridinylꢀsubstituted indoles, 1h and 1i reacted moderately to yield the corresponding
acetoxylated compounds 2h and 2i, respectively. Evidently, the πꢀelectronꢀrich 2ꢀ
thiophenyl substituted indole 1m produced the acetoxylated compound 2m in low yield.
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H
AcOH/Ac2O
OAc
(7:3)
+
PhI(OAc)2
R
R
60 oC, 5 h
N
N
heteroaryl
heteroaryl
2
1
OAc
N
OAc
OAc
R
Me
N
N
N
N
N
N
N
R = H (2a)
R = Me (2b) 76%
R = OMe (2c) 75%
93%
2g; 81%
2f; 26%
R = F (2d)
R = Br (2e)
86%
73%
OAc
OAc
R
OAc
OAc
N
N
N
N
N
S
N
N
2m; 35%
R = H (2j)
R = F (2k)
R = Br (2l)
93%
61%
70%
N
2h; 56%
2i; 56%
Scheme 2 Scope of Cꢀ3 acetoxylation of Nꢀheteroaryl substituted indoles.
We further extended the metalꢀfree acetoxylation method for the selective
acetoxylation of the Nꢀaryl substituted indoles. Hence, the different substituted Nꢀaryl
indoles 3 undergo acetoxylations at Cꢀ3 position to give the desired products in moderate
yields (Scheme 3). Interestingly, a number of important functional groups like ‒F, ‒CF3,
‒C(O)Me, ‒C(O)OMe, ‒CN and ‒NO2 are well tolerated under the reaction conditions. To
our surprise, the 2,4ꢀdinitrophenyl substituted indoles 3i and 3j produced the acetoxylated
products in good yields. The indoles containing Nꢀaryl substituents with electronꢀ
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withdrawing groups on the aryl backbone were found to produce improved yields of the Cꢀ
3 acetoxylation, than the Nꢀaryl substituents bearing electronꢀdonating groups. Unlike
freeꢀNHꢀindole or indoles bearing electronꢀrich Nꢀprotecting groups, the Nꢀaryl
substituted indoles does not impart decomposition; however they produced 1ꢀarylꢀ
indolinꢀ3ꢀone and 2ꢀoxoꢀ1ꢀarylꢀindolinꢀ3ꢀyl acetate as the side products in different
scale, which accounts for the low yields of the Cꢀ3 acetoxylated products.13 Most
likely, these side products are formed from the hydrolysis of Cꢀ3 acetoxylated and
diacetoxylated indoles.
H
OAc
AcOH/Ac2O
(7:3)
R
+
PhI(OAc)2
R
60 oC, 5 h
N
N
R
R
4
3
OAc
OAc
OAc
R
N
N
N
NO2
CF3
R
F3C
NO2
R = H (4a)
R = OMe (4b)
R = F (4c)
50%
37%
40%
45%
4k; 54%
R = H (4i) 76%
R = F (4j) 61%
R = CF3 (4d)
R = COMe (4e) 35%
R = COOMe (4f) 41%
R = CN (4g)
R = NO2 (4h)
56%
53%
Scheme 3 Scope of Cꢀ3 acetoxylation of Nꢀaryl substituted indoles.
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OAc
OAc
PhI(OAc)2
(0.3 mmol)
+
+
(a)
N
N
AcOH/Ac2O
60 oC, 5 h
N
N
N
N
N
N
1a
(0.6 mmol)
3a
2a; (7%)
(0.6 mmol)
4a; (38%)
OAc
OAc
N
PhI(OAc)2
(0.3 mmol)
(b)
+
+
AcOH/Ac2O
60 oC, 5 h
N
N
S
N
S
N
N
N
N
1a
1m
(0.6 mmol)
2a; (7%)
(0.6 mmol)
2m; (23%)
OAc
OAc
PhI(OAc)2
(0.3 mmol)
MeO
+
MeO
(c)
AcOH/Ac2O
60 oC, 5 h
N
N
N
N
N
+
N
N
N
N
N
N
N
1a
1c
2a; (24%)
2c; (40%)
(0.6 mmol)
(0.6 mmol)
Scheme 4 Intermolecular competition experiments.
In order to obtain the mechanistic insight, the intermolecular competition
experiments between the indoles 1a and 3a as well as between 1a and 1m, were
conducted (Scheme 4a, 4b); which highlighted that the indoles bearing πꢀelectronꢀrich
arene substituents were acetoxylated predominantly, though the yields were
unsatisfactory. Further, an additional experiment between the different substituted Nꢀ
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pyrimidinylꢀindoles 1a and 1c (Scheme 4c) clearly demonstrated that the electronꢀrich
indole was preferentially acetoxylated, which revealed the nucleophilicity parameter14 of
indoles for the acetoxylation process.
Further, to isolate the probable intermediate species, an experiment of 1a with
PhI(OAc)2 was carried out at room temperature, which produced the diacetoxylated
indoline 5a in 53% yield after 1 h (Scheme 5a). The formation of 5a might follow the
pathway proposed for the similar compounds.12 Compound 5a led to the complete
conversion into the acetoxylated product 2a upon heating in AcOH/Ac2O solvent for 3 h
(Scheme 5b). This clearly demonstrated that the formation of 2a from 1a occurred via the
intermediacy of 5a. The dehydroacetoxylation of 5a to 2a also occurred under nonꢀacidic
condition, however with low efficacy. Similar to the indoline 5a, the intermediate species
for the indole 1m could not be observed; instead the direct formation of 2m was
accomplished, including the intractable decomposed products.
Scheme 5 Synthesis and reactivity of intermediate species.
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To understand the dehydroacetoxylation process of the different Nꢀ
substituted diacetoxyindolines, the compound 5a and 1ꢀacetylindolineꢀ2,3ꢀdiyl
o
diacetate were heated in a single pot at 60 C (Scheme 6). The compound 5a was
completely converted into the Cꢀ3 acetoxylated product 2a in 2 h, whereas a trace
amount of the Cꢀ3 acetoxylated product was formed from the 1ꢀacetylindolineꢀ2,3ꢀ
diyl diacetate; suggesting that the dehydroacetoxylation of diacetoxylated indoline
is significant in the presence of 2ꢀpyrimidinyl as the Nꢀsubstituent. Further, looking
into the excellent reactivities of the indoles containing 2ꢀPy, 2ꢀPym, 2ꢀpyrazinyl or 2ꢀ
nitroarene as the Nꢀsubstituents (1aꢀ1g, 1iꢀ1l, 3i and 3j); we assume that the Nꢀatom or
Nꢀgroup at the orthoꢀposition of the substituents might have some additional influence on
the dehydroacetoxylation reaction, in addition to the electronics of the substituents.
Scheme 6 Dehydroacetoxylation of diacetoxylated compounds.
Conclusions
In summary, we have reported an efficient and regioselective method for the Cꢀ3
acetoxylation of the Nꢀsubstituted indoles in the absence of metalꢀcatalysts, wherein a
broad range of functional groups are tolerated. The indoles containing πꢀelectronꢀdeficient
arene substituents on the Nꢀatom are acetoxylated efficiently than the one bearing strong
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sigma electronꢀdonating or sigma electronꢀwithdrawing substituents. The diacetoxylated
indoline is proposed to be the active intermediate for the acetoxylation of the Nꢀsubstituted
indoles, where the dehydroacetoxylation is facilitated in the presence of a πꢀdeficient
arene substituents on the Nꢀatom of indoles.
Experimental section
General information. All manipulations were conducted in an argon atmosphere using
standard Schlenk techniques in preꢀdried glassware. Liquid reagents were flushed with
argon prior to use. The starting compounds, Nꢀacylꢀ1Hꢀindole,12 Nꢀtosylꢀ1Hꢀindole,12 Nꢀ
benzylꢀ1Hꢀindole,7
Nꢀarylꢀ1Hꢀindoles,15
Nꢀpyridinylꢀ1Hꢀindole,16
Nꢀpyrimidinylꢀ1Hꢀ
indole15a,17 and 1ꢀacetylindolineꢀ2,3ꢀdiyl diacetate12 were synthesized according to the
previously described procedures. All other chemicals were obtained from commercial
sources and were used without further purification. Representative starting compounds 1
and 3 as well as PhI(OAc)2 were analyzed by ICPꢀAES, which showed only trace amount
of transition metals (< 0.1 ppm Fe, Co, Ni, Cu, Pd, Rh and Ru). The yields refer to isolated
compounds, estimated to be > 95% pure as determined by 1H NMR. The 1H and 13C NMR
spectra are referenced to the residual solvent signals (CDCl3:
ppm).
δ H = 7.26 ppm, δ C = 77.2
Representative procedures for the preparation of N-substituted indoles
Representative procedure A: To a stirred solution of 1Hꢀindole (0.120 g, 1.00
o
mmol) in DMF (15 mL) at 0 C was added NaH (0.027 g, 1.10 mmol). After stirring the
o
reaction mixture at 0 C for 30 min, (hetero)aryl halide (1.20 mmol) was added and the
o
reaction mixture was heated at 130 C for 24 h. Then the reaction mixture was cooled to
ambient temperature, poured into H2O (20 mL) and extracted with EtOAc (15 mL x 3). The
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combined organic phase was washed with H2O (15 mL x 3) and dried over Na2SO4. After
filtration and evaporation of the solvents in vacuo, the crude product was purified by
column chromatography on silica gel.
Representative procedure B: A mixture of 1Hꢀindole (0.328 g, 2.80 mmol),
(hetero)aryl halide (2.00 mmol), CuI (0.076 g, 0.40 mmol) and Cs2CO3 (1.30 g, 4.00 mmol)
were taken in a flask and DMF (15 mL) was added into it. The reaction mixture was
o
vigorously stirred at 120 C under argon atmosphere for 40 h. Then the reaction mixture
was cooled to ambient temperature, poured into H2O (20 mL) and extracted with EtOAc
(15 mL x 3). The combined organic phase was washed with H2O (15 mL x 3) and dried
over Na2SO4. After filtration and evaporation of the solvents in vacuo, the crude product
was purified by column chromatography on silica gel.
2-Methyl-1-(pyrimidin-2-yl)-1H-indole (1f).18 The representative procedure A was
followed using, 2ꢀmethylꢀ1Hꢀindole (0.40 g, 3.05 mmol), 2ꢀchloropyrimidine (0.489 g, 4.27
mmol), and NaH (0.095 g, 3.96 mmol). Purification by column chromatography on silica
gel (hexane/EtOAc/Et3N: 20/1/0.5) yielded 1f (0.153 g, 24%) as a brown solid. M. p. = 48ꢀ
o
1
50 C. HꢀNMR (500 MHz, CDCl3):
δ = 8.79 (d, J = 4.9 Hz, 2H), 8.37 (d, J = 8.2 Hz, 1H),
7.59 (d, J = 7.3 Hz, 1H), 7.31ꢀ7.24 (m, 2H), 7.11 (t, J = 4.9 Hz, 1H), 6.50 (s, 1H), 2.78 (s,
3H). 13C{1H}ꢀNMR (125 MHz, CDCl3):
δ
= 158.5, 158.1, 137.9, 137.0, 129.6, 122.5, 121.9,
max/cm‒1 3032, 2962, 2853, 1562, 1417, 1305,
119.6, 117.0, 114.1, 106.8, 16.7. IR (neat):
ν
1205, 785, 733. HRMS (ESI) m/z Calcd for C13H11N3+H+ [M+H]+ 210.1026; Found
210.1024.
1-(Pyrazin-2-yl)-1H-indole (1j).19 The representative procedure A was followed,
using 1Hꢀindole (0.120 g, 1.00 mmol), NaH (0.027 g, 1.10 mmol) and 2ꢀiodopyrazine
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(0.246 g, 1.20 mmol). Purification by column chromatography on silica gel (hexane/EtOAc:
o
1
2/1) yielded 1j (0.186 g, 95%) as a brown solid. M. p. = 77ꢀ79 C. HꢀNMR (500 MHz,
CDCl3): = 8.85 (s, 1H), 8.44 (d, J = 2.1 Hz, 1H), 8.36 (d, J = 2.1 Hz, 1H), 8.26 (d, J = 8.2
δ
Hz, 1H), 7.68 (d, J = 3.4 Hz, 1H), 7.64 (d, J = 7.6 Hz, 1H), 7.31 (dd, J = 7.9, 7.3 Hz, 1H),
7.23 (dd, J = 7.9, 7.0 Hz, 1H), 6.74 (d, J = 3.4 Hz, 1H). 13C{1H}ꢀNMR (125 MHz, CDCl3):
δ
= 149.2, 142.8, 140.0, 136.4, 135.2, 130.7, 125.0, 123.9, 122.2, 121.4, 113.5, 107.3. IR
max/cm‒1 3108, 3053, 1450, 1360, 839, 739. HRMS (ESI) m/z Calcd for
(neat):
ν
C12H9N3+H+ [M+H]+ 196.0869; Found 196.0869.
5-Fluoro-1-(pyrazin-2-yl)-1H-indole (1k): The representative procedure A was
followed, using 5ꢀfluoroꢀ1Hꢀindole (0.23 g, 1.70 mmol), NaH (0.045 g, 1.87 mmol) and 2ꢀ
iodopyrazine (0.420 g, 2.04 mmol). Purification by column chromatography on silica gel
o
1
(hexane/EtOAc: 2/1) yielded 1k (0.33 g, 91%) as a brown solid. M. p. = 112ꢀ114 C. Hꢀ
NMR (400 MHz, CDCl3): = 8.84 (d, J = 1.2 Hz, 1H), 8.47ꢀ8.46 (m, 1H), 8.41 (d, J = 2.7
δ
Hz, 1H), 8.30 (dd, J = 9.1, 4.6 Hz, 1H), 7.72 (d, J = 3.7 Hz, 1H), 7.29 (dd, J = 9.1, 2.7 Hz,
1H), 7.06 (td, J = 9.1, 2.5 Hz, 1H), 6.71 (d, J = 3.4 Hz, 1H). 13C{1H}ꢀNMR (100 MHz,
CDCl3):
δ = 159.0 (d, JC‒F = 239.0 Hz), 149.1, 142.6, 140.2, 136.0, 131.8, 131.4 (d, JC‒F =
10.0 Hz), 126.3, 114.9 (d, JC‒F = 9.3 Hz), 111.9 (d, JC‒F = 25.4 Hz), 107.2 (d, JC‒F = 3.8
Hz), 106.5 (d, JC‒F = 23.9 Hz). 19FꢀNMR (377 MHz, CDCl3):
max/cm‒1 2921, 1469, 1443, 1353, 809, 753, 714, 616. HRMS (ESI) m/z Calcd for
C12H8FN3+H+ [M+H]+ 214.0775; Found 214.0775.
δ
= −121.6 (s). IR (neat):
ν
5-Bromo-1-(pyrazin-2-yl)-1H-indole (1l). The representative procedure A was
followed, using 5ꢀbromoꢀ1Hꢀindole (0.330 g, 1.70 mmol), NaH (0.045 g, 1.87 mmol) and 2ꢀ
iodopyrazine (0.420 g, 2.04 mmol). Purification by column chromatography on silica gel
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o
1
(hexane/EtOAc: 2/1) yielded 1l (0.44 g, 95%) as offꢀwhite solid. M. p. = 98ꢀ100 C. Hꢀ
NMR (400 MHz, CDCl3): = 8.84 (d, J = 1.2 Hz, 1H), 8.49ꢀ8.48 (m, 1H), 8.43 (d, J = 2.7
δ
Hz, 1H), 8.20 (d, J = 8.8 Hz, 1H), 7.77 (d, J = 2.0 Hz, 1H), 7.69 (d, J = 3.4 Hz, 1H), 7.40
13
(dd, J = 8.8, 2.0 Hz, 1H), 6.69 (d, J = 3.2 Hz, 1H). C{1H}ꢀNMR (100 MHz, CDCl3):
δ =
149.0, 142.8, 140.5, 136.2, 134.0, 132.3, 126.7, 126.0, 123.9, 115.4, 115.3, 106.7. IR
max/cm‒1 2921, 1519, 1482, 1416, 1198, 1136, 1054, 1004, 957, 752, 709. HRMS
(neat):
ν
(ESI) m/z Calcd for C12H8BrN3+H+ [M+H]+ 273.9974, 275.9954; Found 273.9974,
275.9953.
1-(Thiophen-2-yl)-1H-indole (1m).15c The representative procedure B was
followed, using 1Hꢀindole (0.328 g, 2.80 mmol), 2ꢀbromothiophene (0.326 g, 2.00 mmol),
CuI ( 0.076 g, 0.40 mmol) and Cs2CO3 (1.30 g, 4.00 mmol). Purification by column
chromatography on silica gel (hexane/EtOAc: 100/1) yielded 1m (0.286 g, 72%) as a
green liquid. 1HꢀNMR (400 MHz, CDCl3):
δ = 7.64 (d, J = 7.8 Hz, 1H), 7.57 (d, J = 8.3 Hz,
1H), 7.27ꢀ7.22 (m, 2H), 7.17 (dd, J = 7.1, 6.9 Hz, 1H), 7.12 (dd, J = 5.6, 1.5 Hz, 1H), 7.03
13
(dd, J = 3.7, 1.5 Hz, 1H), 7.01ꢀ6.99 (m, 1H), 6.63 (d, J = 3.2 Hz, 1H). C{1H}ꢀNMR (100
MHz, CDCl3):
δ
= 141.8, 137.2, 129.5, 129.2, 126.2, 123.0, 121.8, 121.2, 121.0, 120.6,
max/cm‒1 3108, 3009, 1611, 1550, 1459, 1312, 1226, 1201, 1013,
110.8, 104.3. IR (neat):
ν
903, 842. HRMS (ESI) m/z Calcd for C12H9NS+H+ [M+H]+ 200.0528; Found 200.0526.
1-(4-(Trifluoromethyl)phenyl)-1H-indole (3d).20 The representative procedure B
was followed, using 1Hꢀindole (0.302 g, 2.58 mmol), 1ꢀiodoꢀ4ꢀ(trifluoromethyl)benzene
(0.50 g, 1.84 mmol), CuI (0.070 g, 0.368 mmol) and Cs2CO3 (1.20 g, 3.68 mmol).
Purification by column chromatography on silica gel (hexane/EtOAc: 20/1) yielded 3d
o
1
(0.408 g, 85%) as a brown solid. M. p. = 50ꢀ52 C. HꢀNMR (400 MHz, CDCl3):
δ
= 7.75
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(d, J = 8.3 Hz, 2H), 7.68 (d, J = 7.6 Hz, 1H), 7.60ꢀ7.56 (m, 3H), 7.31 (d, J = 3.4 Hz, 1H),
13
7.24ꢀ7.17 (m, 2H), 6.70 (d, J = 3.2 Hz, 1H). C{1H}ꢀNMR (100 MHz, CDCl3):
δ = 143.0,
135.7, 129.9, 128.3 (q, JC‒F = 32.4 Hz), 127.6, 127.1 (q, JC‒F = 3.8 Hz), 124.2 (q, JC‒F
171.8 Hz), 124.1, 123.1, 121.6, 121.2, 110.5, 105.1. 19FꢀNMR (377 MHz, CDCl3):
=
=
δ
−62.2 (s). IR (neat): ν
max/cm‒1 3058, 2962, 1607, 1521, 1455, 1318, 1158, 1061, 1013,
840. HRMS (ESI) m/z Calcd for C15H10F3N+H+ [M+H]+ 262.0838; Found 262.0837.
Methyl 4-(1H-indol-1-yl)benzoate (3f).15c The representative procedure B was
followed, using 1Hꢀindole (0.328 g, 2.80 mmol), methyl 4ꢀiodobenzoate (0.524 g, 2.00
mmol ), CuI (0.076 g, 0.40 mmol) and K2CO3 (0.553 g, 4.00 mmol). Purification by column
chromatography on silica gel (hexane/EtOAc: 10/1) yielded 3f (0.231 g, 46%) as a grey
solid. M. p. = 55ꢀ57 oC. 1HꢀNMR (500 MHz, CDCl3):
δ = 8.18 (d, J = 8.5 Hz, 2H), 7.68 (d, J
= 7.9 Hz, 1H), 7.62 (d, J = 8.2 Hz, 1H), 7.58 (d, J = 8.5 Hz, 2H), 7.36 (d, J = 3.4 Hz, 1H),
7.25 (t, J = 7.3 Hz, 1H), 7.19 (t, J = 7.3 Hz, 1H), 6.71 (d, J = 3.4 Hz, 1H), 3.95 (s, 3H).
13C{1H}ꢀNMR (125 MHz, CDCl3):
δ
= 166.6, 143.9, 135.6, 131.4, 130.0, 127.8, 127.6,
max/cm‒1 3106, 3049, 2947,
123.4, 123.0, 121.5, 121.1, 110.7, 105.1, 52.4. IR (neat):
ν
1707, 1602, 1509, 1455, 1433, 1281, 1117, 1097, 720. HRMS (ESI) m/z Calcd for
C16H13NO2+H+ [M+H]+ 252.1019; Found 252.1012.
1-(4-Nitrophenyl)-1H-indole (3h).19,20 The representative procedure B was
followed, using 1Hꢀindole (0.328 g, 2.80 mmol), 1ꢀiodoꢀ4ꢀnitrobenzene (0.50 g, 2.00
mmol), CuI (0.076 g, 0.40 mmol) and K2CO3 (0.553 g, 4.00 mmol). Purification by column
chromatography on silica gel (hexane/EtOAc: 20/1) yielded 3h (0.224 g, 47%) as a yellow
o
1
solid. M. p. = 132ꢀ134 C. HꢀNMR (500 MHz, CDCl3):
δ = 8.33 (d, J = 8.9 Hz, 2H), 7.68
(d, J = 7.6 Hz, 1H), 7.62ꢀ7.60 (m, 3H), 7.33 (d, J = 3.1 Hz, 1H), 7.27 (dd, J = 7.6, 7.3 Hz,
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1H), 7.21 (dd, J = 7.6, 7.3 Hz, 1H), 6.75 (d, J = 3.0 Hz, 1H). 13C{1H}ꢀNMR (125 MHz,
CDCl3):
δ
= 145.3, 145.1, 135.4, 130.2, 127.2, 125.6, 123.5, 123.4, 121.8, 121.7, 110.6,
max/cm‒1 3109, 1592, 1503, 1455, 1317, 1100, 882, 852, 690. HRMS
106.3. IR (neat):
ν
(ESI) m/z Calcd for C14H10N2O2+H+ [M+H]+ 239.0815; Found 239.0811.
1-(2,4-Ninitrophenyl)-1H-indole (3i).21 The representative procedure B was
followed, using 1Hꢀindole (0.351 g, 3.00 mmol), 1ꢀchloroꢀ2,4ꢀdinitrobenzene (0.73 g, 3.60
mmol), CuI (0.114 g, 0.60 mmol), K2CO3 (0.830 g, 6.00 mmol). Purification by column
chromatography on silica gel (hexane/EtOAc: 5/1) yielded 3i (0.424 g, 50%) as an orange
solid. M. p. = 96ꢀ98 oC. 1HꢀNMR (400 MHz, CDCl3):
δ = 8.89 (d, J = 2.5 Hz, 1H), 8.54 (dd,
J = 8.8, 2.5 Hz, 1H), 7.82 (d, J = 8.8 Hz, 1H), 7.71 (d, J = 6.6 Hz, 1H), 7.30ꢀ7.21 (m, 3H),
13
7.15 (d, J = 3.4 Hz, 1H), 6.83 (d, J = 3.2 Hz, 1H). C{1H}ꢀNMR (100 MHz, CDCl3):
δ =
145.4, 144.6, 138.0, 135.8, 129.7, 129.6, 128.1, 127.2, 123.9, 122.2, 121.9, 121.8, 109.4,
max/cm‒1 3103, 1601, 1539, 1493, 1453, 1339, 1231, 1200, 844, 769,
107.5. IR (neat):
ν
752. HRMS (ESI) m/z Calcd for C14H9N3O4+H+ [M+H]+ 284.0666; Found 284.0668.
1-(2,4-Ninitrophenyl)-5-fluoro-1H-indole (3j).22 The representative procedure B
was followed, using 5ꢀfluoroꢀ1Hꢀindole (0.203 g, 1.50 mmol), 1ꢀchloroꢀ2,4ꢀdinitrobenzene
(0.365 g, 1.80 mmol), CuI (0.057 g, 0.30 mmol), K2CO3 (0.415 g, 3.00 mmol). Purification
by column chromatography on silica gel (hexane/EtOAc: 2/1) yielded 3j (0.138g, 31%) as
o
1
a yellow solid. M. p. = 151ꢀ153 C. HꢀNMR (400 MHz, CDCl3):
δ = 8.90 (d, J = 2.2 Hz,
1H), 8.60 (dd, J = 8.8, 2.2 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.34 (dd, J = 9.1, 2.2 Hz, 1H),
7.17 (d, J = 3.4 Hz, 1H), 7.13ꢀ7.10 (m, 1H), 7.00 (td, J = 8.8, 2.2 Hz, 1H), 6.77 (d, J = 2.9
13
Hz, 1H). C{1H}ꢀNMR (100 MHz, CDCl3):
δ = 159.1 (d, JC‒F = 238.1 Hz), 145.8, 145.0,
138.0, 132.6, 130.5 (d, JC‒F = 10.0 Hz), 129.9, 128.9, 128.4, 122.0, 112.3 (d, JC‒F = 27.0
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Hz), 110.3 (d, JC‒F = 9.2 Hz), 107.5 (d, JC‒F = 4.6 Hz), 107.3 (d, JC‒F = 23.9 Hz). 19FꢀNMR
max/cm‒1 3147, 3117, 3100, 1601, 1524,
1339, 1135, 908, 729. MS (EI) m/z: 301 [M]+, 281, 256, 226, 208, 181, 135.
(3k).22
(377 MHz, CDCl3):
δ = −121.5 (s). IR (neat): ν
1-(3,5-Bis(trifluoromethyl)phenyl)-1H-indole
The
representative
procedure B was followed, using 1Hꢀindole (0.328 g, 2.80 mmol), 1ꢀbromoꢀ3,5ꢀ
bis(trifluoromethyl)benzene (0.586 g, 2.00 mmol), CuI (0.076 g, 0.40 mmol) and Cs2CO3
(1.30 g, 4.00 mmol). Purification by column chromatography on silica gel (hexane/EtOAc:
1
10/1) yielded 3k (0.222 g, 34%) as a light yellow liquid. HꢀNMR (400 MHz, CDCl3):
δ =
7.97 (s, 2H), 7.84 (s, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.52 (d, J = 8.3 Hz, 1H), 7.33 (d, J =
3.4 Hz, 1H), 7.29 (dd, J = 8.0, 7.3 Hz, 1H), 7.22 (dd, J = 7.6, 7.3 Hz, 1H), 6.75 (d, J = 3.2
Hz, 1H). 13C{1H}ꢀNMR (100 MHz, CDCl3):
δ = 141.5, 135.6, 133.6 (q, JC‒F = 34.0 Hz),
130.0, 127.3, 124.0 (q, JC‒F = 3.0 Hz), 123.7, 123.1 (q, JC‒F = 272.6 Hz), 121.9, 121.7,
119.8 (q, JC‒F = 3.8 Hz), 109.9, 106.1. 19FꢀNMR (377 MHz, CDCl3):
max/cm‒1 3284, 3062, 2963, 1477, 1402, 1275, 1115, 1103, 890, 847, 702. MS (EI)
m/z: 329 [M]+, 310, 233, 213, 116.
δ
= −63.0 (s). IR
(neat):
ν
Representative procedure for C-3 acetoxylation of N-substituted indoles
Synthesis of 1-(pyrimidin-2-yl)-1H-indol-3-yl acetate (2a). To a flameꢀdried
Schlenk tube equipped with magnetic stir bar was introduced PhI(OAc)2 (0.106 g, 0.33
mmol) and 1ꢀ(pyrimidinꢀ2ꢀyl)ꢀ1Hꢀindole (1a) (0.059 g, 0.30 mmol) under argon. The
Schlenk tube with the mixture was evacuated and refilled with argon. To the above
mixture was added acetic acid and acetic anhydride (7:3) solvent mixture (1.0 mL). The
o
resultant reaction mixture was then degassed, refilled with argon and stirred at 60 C in a
preꢀheated oil bath for 5 h. At ambient temperature, H2O (5 mL) and saturated NaHCO3
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solution (15 mL) were added and the reaction mixture was extracted with ethyl acetate (15
mL x 3). The combined organic layers were dried over Na2SO4 and the solvent was
evaporated in vacuo. The resultant residue was purified by column chromatography on
silica gel (hexane/EtOAc: 5/1) to yielded acetoxylated compound 2a (0.071 g, 93%) as offꢀ
o
white solid. M. p. = 117ꢀ119 C. 1HꢀNMR (500 MHz, CDCl3):
δ = 8.81 (d, J = 8.6 Hz, 1H),
8.66 (d, J = 4.7 Hz, 2H), 8.43 (s, 1H), 7.55 (d, J = 7.8 Hz, 1H), 7.37 (t, J = 7.6 Hz, 1H),
13
7.25 (dd, J = 7.6, 7.3 Hz, 1H), 7.01 (t, J = 4.7 Hz, 1H), 2.40 (s, 3H). C{1H}ꢀNMR (125
MHz, CDCl3):
δ
= 168.3, 158.3, 157.9, 133.7, 133.0, 124.8, 124.2, 122.3, 117.6, 116.6,
max/cm‒1 3195, 2926, 1744, 1455, 1430, 1368, 1208, 809,
116.2, 114.7, 21.2. IR (neat):
ν
787. HRMS (ESI) m/z Calcd for C14H11N3O2+Na+ [M+Na]+ 276.0743; Found 276.0738.
5-Methyl-1-(pyrimidin-2-yl)-1H-indol-3-yl acetate (2b). The representative
procedure was followed, using 5ꢀmethylꢀ1ꢀ(pyrimidinꢀ2ꢀyl)ꢀ1Hꢀindole (1b) (0.063 g, 0.30
mmol) and PhI(OAc)2 (0.106 g, 0.33 mmol). Purification by column chromatography on
silica gel (hexane/EtOAc: 5/1) yielded 2b (0.061 g, 76%) as a brown solid. M. p. = 161ꢀ
163 oC. 1HꢀNMR (500 MHz, CDCl3):
δ = 8.66 (d, J = 8.6 Hz, 1H), 8.62 (d, J = 4.9 Hz, 2H),
8.37 (s, 1H), 7.34 (s, 1H), 7.19 (d, J = 8.6, 1H), 6.95 (t, J = 4.7 Hz, 1H), 2.48 (s, 3H), 2.40
(s, 3H). 13C{1H}ꢀNMR (125 MHz, CDCl3):
δ
= 168.3, 158.1, 157.8, 133.4, 131.8, 131.3,
max/cm‒1 3202, 2917,
126.2, 124.3, 117.3, 116.3, 115.9, 114.7, 21.5, 21.1. IR (neat):
ν
2851, 1747, 1579, 1451, 1430, 1206, 908, 785, 711. HRMS (ESI) m/z Calcd for
C15H13N3O2+Na+ [M+Na]+ 290.0900; Found 290.0894.
5-Methoxy-1-(pyrimidin-2-yl)-1H-indol-3-yl acetate (2c). The representative
procedure was followed, using 5ꢀmethoxyꢀ1ꢀ(pyrimidinꢀ2ꢀyl)ꢀ1Hꢀindole (1c) (0.068 g, 0.30
mmol) and PhI(OAc)2 (0.106 g, 0.33 mmol). Purification by column chromatography on
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silica gel (hexane/EtOAc: 2/1) yielded 2c (0.064 g, 75%) as a light brown crystalline solid.
M. p. = 166ꢀ168 oC. 1HꢀNMR (500 MHz, CDCl3):
4.7 Hz, 2H), 8.39 (s, 1H), 6.99ꢀ6.95 (m, 3H), 3.89 (s, 3H), 2.40 (s, 3H). 13C{1H}ꢀNMR (125
δ
= 8.69 (d, J = 9.5 Hz, 1H), 8.61 (d, J =
MHz, CDCl3):
δ
= 168.2, 158.2, 157.7, 155.7, 133.5, 127.9, 124.8, 117.7, 116.0, 115.2,
max/cm‒1 3209, 2923, 1745, 1435, 1222, 1204, 911,
114.1, 99.5, 55.8, 21.2. IR (neat):
ν
821, 776. HRMS (ESI) m/z Calcd for C15H13N3O3+Na+ [M+Na]+ 306.0849; Found
306.0844.
5-Fluoro-1-(pyrimidin-2-yl)-1H-indol-3-yl acetate (2d). The representative procedure
was followed, using 5ꢀfluoroꢀ1ꢀ(pyrimidinꢀ2ꢀyl)ꢀ1Hꢀindole (1d) (0.064 g, 0.30 mmol) and
PhI(OAc)2 (0.106 g, 0.33 mmol). Purification by column chromatography on silica gel
o
(hexane/EtOAc: 3/1) yielded 2d (0.070 g, 86%) as an offꢀwhite solid. M. p. = 173ꢀ175 C.
1HꢀNMR (500 MHz, CDCl3):
δ = 8.77 (dd, J = 9.2, 4.6 Hz, 1H), 8.66 (d, J = 4.9 Hz, 2H),
8.46 (s, 1H), 7.20 (dd, J = 6.7, 1.8 Hz, 1H), 7.09 (td, J = 9.2, 1.8 Hz, 1H), 7.03 (t, J = 4.9
13
Hz, 1H), 2.39 (s, 3H). C{1H}ꢀNMR (125 MHz, CDCl3):
δ = 168.2, 159.1 (d, JC‒F = 239.4
Hz), 158.3, 157.7, 133.4, 129.4, 124.9 (d, JC‒F = 9.5 Hz), 117.9 (d, JC‒F = 9.5 Hz), 116.4,
116.3, 112.7 (d, JC‒F = 24.8 Hz), 103.2 (d, JC‒F = 24.8 Hz), 21.1. 19FꢀNMR (377 MHz,
CDCl3):
δ = −121.0 (s). IR (neat): ν
max/cm‒1 3208, 2921, 2852, 1745, 1449, 1197, 792,
786, 588. HRMS (ESI) m/z Calcd for C14H10FN3O2+Na+ [M+Na]+ 294.0649; Found
294.0647.
5-Bromo-1-(pyrimidin-2-yl)-1H-indol-3-yl acetate (2e). The representative procedure
was followed, using 5ꢀbromoꢀ1ꢀ(pyrimidinꢀ2ꢀyl)ꢀ1Hꢀindole (1e) (0.082 g, 0.30 mmol) and
PhI(OAc)2 (0.106 g, 0.33 mmol). Purification by column chromatography on silica gel
(hexane/EtOAc: 3/1) yielded 2e (0.073 g, 73%) as a light brown solid. M. p. = 178ꢀ179 oC.
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1HꢀNMR (500 MHz, CDCl3):
δ
= 8.68ꢀ8.65 (m, 3H), 8.42 (s, 1H), 7.67 (d, J = 2.0 Hz, 1H),
13
7.43 (dd, J = 9.2, 2.0 Hz, 1H), 7.04 (t, J = 4.9 Hz, 1H), 2.39 (s, 3H). C{1H}ꢀNMR (125
MHz, CDCl3):
δ
= 168.1, 158.3, 157.6, 132.6, 131.6, 127.6, 125.8, 120.3, 118.2, 116.5,
max/cm‒1 3205, 2923, 1758, 1456, 1433, 1204, 956, 867,
115.9, 115.7, 21.1. IR (neat):
ν
784. HRMS (ESI) m/z Calcd for C14H10BrN3O2+Na+ [M+Na]+ 353.9849, 355.9828; Found
353.9848, 355.9824.
2-Methyl-1-(pyrimidin-2-yl)-1H-indol-3-yl acetate (2f). The representative
procedure was followed, using 2ꢀmethylꢀ1ꢀ(pyrimidinꢀ2ꢀyl)ꢀ1Hꢀindole (1f) (0.075 g, 0.358
mmol) and PhI(OAc)2 (0.127 g, 0.394 mmol). Purification by column chromatography on
silica gel (hexane/EtOAc: 2/1) yielded 2f (0.025 g, 26%) as a yellow solid. M. p. = 54ꢀ56
oC. 1HꢀNMR (500 MHz, CDCl3):
δ = 8.75 (d, J = 4.9 Hz, 2H), 8.42 (d, J = 8.2 Hz, 1H), 7.34
(d, J = 7.6, 1H), 7.27ꢀ7.19 (m, 2H), 7.11 (t, J = 4.9 Hz, 1H), 2.59 (s, 3H), 2.42 (s, 3H).
13C{1H}ꢀNMR (125 MHz, CDCl3):
δ
= 169.2, 158.5, 158.2, 134.1, 131.4, 127.0, 123.5,
max/cm‒1 2923, 2852, 1756, 1575,
123.1, 122.2, 117.1, 116.6, 114.8, 20.8, 12.8. IR (neat):
ν
1559, 1421, 1366, 1205, 733. HRMS (ESI) m/z Calcd for C15H13N3O2+Na+ [M+Na+]
290.0900; Found 290.0896.
1-(Pyridin-2-yl)-1H-indol-3-yl acetate (2g). The representative procedure was
followed, using 1ꢀ(pyridinꢀ2ꢀyl)ꢀ1Hꢀindole (1g) (0.058 g, 0.30 mmol) and PhI(OAc)2 (0.106
g, 0.33 mmol). Purification by preparative TLC (hexane/EtOAc: 5/1) and extraction in
1
CH2Cl2 (15 mL x 3) yielded 2g (0.061 g, 81%) as a yellow liquid. HꢀNMR (500 MHz,
CDCl3):
δ = 8.54 (dd, J = 4.9, 1.2 Hz, 1H), 8.30 (d, J = 8.3 Hz, 1H), 7.95 (s, 1H), 7.79 (dd,
J = 8.3, 7.3 Hz, 1H), 7.60 (d, J = 7.8 Hz, 1H), 7.44 (dd, J = 8.3, 0.5 Hz, 1H), 7.33 (ddd, J =
8.3, 7.1, 1.2 Hz, 1H), 7.24 (ddd, J = 8.1, 7.1, 1.0 Hz, 1H), 7.14 (dd, J = 7.3, 4.9 Hz, 1H),
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2.40 (s, 3H). 13C{1H}ꢀNMR (125 MHz, CDCl3):
δ
= 168.4, 152.6, 149.0, 138.6 133.0, 132.5,
max/cm‒1 3178,
124.3, 122.8, 121.5, 120.1, 117.8, 114.8, 114.4, 113.7, 21.2. IR (neat):
ν
2962, 1752, 1449, 1435, 1357, 1207, 1009, 990, 799, 782. HRꢀMS (ESI) m/z Calcd for
C15H12N2O2+H+ [M+H]+ 253.0972; Found 253.0969.
1-(Pyridin-3-yl)-1H-indol-3-yl acetate (2h). The representative procedure was
followed, using 1ꢀ(pyridinꢀ3ꢀyl)ꢀ1Hꢀindole (1h) (0.058 g, 0.30 mmol) and PhI(OAc)2 (0.106
g, 0.33 mmol). Purification by preparative TLC (hexane/EtOAc: 5/1) and extraction in
1
CH2Cl2 (15 mL x 3) yielded 2h (0.042 g, 56%) as a yellow liquid. HꢀNMR (500 MHz,
CDCl3):
δ = 8.84 (d, J = 1.8 Hz, 1H), 8.60 (d, J = 4.6 Hz, 1H), 7.83 (d, J = 7.9 Hz, 1H),
7.64 (d, J = 7.9 Hz, 1H), 7.59 (s, 1H), 7.50 (d, J = 8.2 Hz, 1H), 7.47 (dd, J = 7.9, 4.6 Hz,
13
1H), 7.28 (dd, J = 7.9, 7.3 Hz, 1H), 7.22 (dd, J = 7.6, 7.3 Hz, 1H), 2.40 (s, 3H). C{1H}ꢀ
NMR (125 MHz, CDCl3):
δ
= 168.5, 147.5, 145.7, 136.3, 133.0, 132.5, 131.7, 124.4, 124.0,
max/cm‒1 3019, 3011, 1745, 1214, 746,
121.8, 121.2, 118.3, 116.6, 110.2, 21.2. IR (neat):
ν
667. HRMS (ESI) m/z Calcd for C15H12N2O2+H+ [M+H]+ 253.0972; Found 253.0969.
1-(Pyridin-4-yl)-1H-indol-3-yl acetate (2i). The representative procedure was
followed, using 1ꢀ(pyridinꢀ4ꢀyl)ꢀ1Hꢀindole (1i) (0.058 g, 0.30 mmol) and PhI(OAc)2 (0.106
g, 0.33 mmol). Purification by preparative TLC (hexane/EtOAc: 5/1) and extraction in
1
CH2Cl2 (15 mL x 3) yielded 2i (0.042 g, 56%) as a yellow liquid. HꢀNMR (400 MHz,
CDCl3):
δ = 8.73 (d, J = 4.7 Hz, 2H), 7.75ꢀ7.66 (m, 3H), 7.49 (d, J = 4.9 Hz, 2H), 7.35 (dd,
J = 7.8, 7.3 Hz, 1H), 7.29 (d, J = 7.3 Hz, 1H), 2.43 (s, 3H). 13C{1H}ꢀNMR (100 MHz,
CDCl3):
δ
= 168.3, 151.4, 146.7, 133.4, 132.2, 124.5, 122.7, 121.7, 118.5, 117.4, 115.6,
max/cm‒1 2928, 2855, 1730, 1586, 1512, 1456, 1367, 1161, 993,
111.0, 21.2. IR (neat):
ν
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943, 807, 659. HRMS (ESI) m/z Calcd for C15H12N2O2+H+ [M+H]+ 253.0972; Found
253.0971.
1-(Pyrazin-2-yl)-1H-indol-3-yl acetate (2j). The representative procedure was
followed, using 1ꢀ(pyrazinꢀ2ꢀyl)ꢀ1Hꢀindole (1j) (0.059 g, 0.30 mmol) and PhI(OAc)2 (0.106
g, 0.33 mmol). Purification by preparative TLC (hexane/EtOAc: 5/1) and extraction in
o
1
CH2Cl2 (15 mL x 3) yielded 2j (0.071 g, 93%) as a brown solid. M. p. = 145ꢀ147 C. Hꢀ
NMR (500 MHz, CDCl3): = 8.86 (d, J = 1.0 Hz, 1H), 8.48 (dd, J = 2.5, 1.7 Hz, 1H), 8.40
δ
(d, J = 2.5 Hz, 1H), 8.34 (d, J = 8.6 Hz, 1H), 8.01 (s, 1H), 7.62 (d, J = 7.8 Hz, 1H), 7.37
13
(dt, J = 8.1, 1.0 Hz, 1H), 7.28 (dd, J = 8.3, 7.8 Hz, 1H), 2.41 (s, 3H). C{1H}ꢀNMR (125
MHz, CDCl3):
δ
= 168.3, 149.3, 142.7, 140.0, 136.3, 134.1, 132.6, 125.0, 123.2, 122.3,
max/cm‒1 3021, 2961, 1737, 1449, 1425, 1365, 1210,
118.1, 114.0, 113.7, 21.2. IR (neat):
ν
1123, 1013, 839, 729. HRMS (ESI) m/z Calcd for C14H11N3O2+Na+ [M+Na]+ 276.0743;
Found 276.0741.
5-Fluoro-1-(pyrazin-2-yl)-1H-indol-3-yl acetate (2k). The representative
procedure was followed, using 5ꢀfluoroꢀ1ꢀ(pyrazinꢀ2ꢀyl)ꢀ1Hꢀindole (1k) (0.064 g, 0.30
mmol) and PhI(OAc)2 (0.106 g, 0.33 mmol). Purification by column chromatography on
silica gel (CH2Cl2/EtOAc: 15/1) yielded 2k (0.050 g, 61%) as an offꢀwhite solid. M. p. =
o
166ꢀ168 C. 1HꢀNMR (500 MHz, CDCl3):
δ = 8.81 (s, 1H), 8.47 (s, 1H), 8.41 (s, 1H), 8.37
(dd, J = 9.2, 4.3 Hz, 1H), 8.03 (s, 1H), 7.27ꢀ7.25 (m, 1H), 7.10 (td, J = 9.2, 2.4 Hz, 1H),
2.40 (s, 3H). 13C{1H}ꢀNMR (125 MHz, CDCl3):
δ
= 168.1, 159.0 (d, JC‒F = 240.3 Hz), 149.1,
142.6, 140.1, 135.8, 133.9, 129.1, 123.9 (d, JC‒F = 9.5 Hz), 115.7 (d, JC‒F = 9.5 Hz), 115.0,
113.2 (d, JC‒F = 24.8 Hz), 103.5 (d, JC‒F = 24.8 Hz), 21.2. 19FꢀNMR (377 MHz, CDCl3):
δ
=
24

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−121.6 (s). IR (neat):
ν
max/cm‒1 2924, 1748, 1480, 1446, 1201, 1007, 911, 839, 764.
HRMS (ESI) m/z Calcd for C14H10FN3O2+H+ [M+H]+ 272.0830; Found 272.0828.
5-Bromo-1-(pyrazin-2-yl)-1H-indol-3-yl acetate (2l). The representative
procedure was followed, using 5ꢀbromoꢀ1ꢀ(pyrazinꢀ2ꢀyl)ꢀ1Hꢀindole (1l) (0.082 g, 0.30
mmol) and PhI(OAc)2 (0.106 g, 0.33 mmol). Purification by column chromatography on
silica gel (CH2Cl2/EtOAc: 20/1) yielded 2l (0.069 g, 70%) as a light brown solid. M. p. =
162ꢀ164 oC. 1HꢀNMR (400 MHz, CDCl3):
δ = 8.81 (s, 1H), 8.48 (s, 1H), 8.42 (d, J = 2.5 Hz,
1H), 8.27 (d, J = 9.1 Hz, 1H), 8.00 (s, 1H), 7.75 (d, J = 1.7 Hz, 1H), 7.44 (dd, J = 8.8, 1.7
Hz, 1H), 2.40 (s, 3H). 13C{1H}ꢀNMR (100 MHz, CDCl3):
δ
= 168.1, 149.0, 142.6, 140.4,
max/cm‒1
136.0, 133.2, 131.2, 127.9, 124.8, 120.8, 115.9, 115.6, 114.6, 21.2. IR (neat):
ν
3170, 2923, 1759, 1446, 1422, 1243, 1061, 1006, 835, 735. HRMS (ESI) m/z Calcd for
C14H10BrN3O2+H+ [M+H]+ 332.0029, 334.0009; Found 332.0030, 334.0008.
1-(Thiophen-2-yl)-1H-indol-3-yl acetate (2m). The representative procedure was
followed, using 1ꢀ(thiophenꢀ2ꢀyl)ꢀ1Hꢀindole (1m) (0.043 g, 0.22 mmol) and PhI(OAc)2
(0.077 g, 0.24 mmol). Purification by preparative TLC (hexane/EtOAc: 5/1) and extraction
in CH2Cl2 (15 mL x 3) yielded 2m (0.020 g, 35%) as a liquid. 1HꢀNMR (400 MHz, CDCl3):
δ
= 7.60ꢀ7.54 (m, 3H), 7.29ꢀ7.25 (m, 1H), 7.22ꢀ7.16 (m, 2H), 7.08ꢀ7.02 (m, 2H), 2.38 (s, 3H).
13C{1H}ꢀNMR (100 MHz, CDCl3):
δ
= 168.4, 141.4, 134.4, 131.9, 126.2, 124.0, 122.0,
max/cm‒1 3010, 2962, 2854,
121.4, 121.1, 120.9, 118.5, 118.0, 110.9, 21.2. IR (neat):
ν
1747, 1613, 1547, 1460, 1366, 1225, 1010, 692. HRMS (ESI) m/z Calcd for
C14H11NO2S+Na+ [M+Na]+ 280.0403; Found 280.0398.
1-Phenyl-1H-indol-3-yl acetate (4a).7 The representative procedure was followed,
using 1ꢀphenylꢀ1Hꢀindole (3a) (0.058 g, 0.30 mmol) and PhI(OAc)2 (0.106 g, 0.33 mmol).
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Purification by column chromatography on silica gel (hexane/EtOAc: 5/1) yielded 4a
1
(0.038 g, 50%) as a liquid. HꢀNMR (500 MHz, CDCl3):
δ = 7.61 (d, J = 7.6 Hz, 1H), 7.57
(s, 1H), 7.53 (d, J = 8.2 Hz, 1H), 7.51ꢀ7.48 (m, 4H), 7.35ꢀ7.31 (m, 1H), 7.23 (dd, J = 7.6,
7.3 Hz, 1H), 7.18 (dd, J = 7.6, 7.3 Hz, 1H), 2.38 (s, 3H). 13C{1H}ꢀNMR (125 MHz, CDCl3):
δ
= 168.6, 139.6, 133.0, 131.7, 129.8, 126.6, 124.6, 123.4, 121.4, 120.6, 118.0, 117.2,
max/cm‒1 3007, 2978, 2873, 1745, 1712, 1501, 1457, 1367, 1223,
110.8, 21.2. IR (neat):
ν
1110, 696. HRMS (ESI) m/z Calcd for C16H13NO2+Na+ [M+Na]+ 274.0838; Found
274.0833.
1-(4-Methoxyphenyl)-1H-indol-3-yl acetate (4b).7 The representative procedure
was followed, using 1ꢀ(4ꢀmethoxyphenyl)ꢀ1Hꢀindole (3b) (0.067 g, 0.30 mmol) and
PhI(OAc)2 (0.106 g, 0.33 mmol). Purification by column chromatography on silica gel
1
(hexane/EtOAc: 4/1) yielded 4b (0.031 g, 37%) as a liquid. HꢀNMR (400 MHz, CDCl3):
δ
= 7.60 (d, J = 7.6 Hz, 1H), 7.49 (s, 1H), 7.43ꢀ7.37 (m, 3H), 7.24ꢀ7.14 (m, 2H), 7.01 (d, J =
13
8.6 Hz, 2H), 3.86 (s, 3H), 2.38 (s, 3H). C{1H}ꢀNMR (100 MHz, CDCl3):
δ = 168.7, 158.5,
133.5, 132.5, 131.2, 126.2, 123.2, 120.9, 120.3, 117.9, 117.6, 114.9, 110.6, 55.8, 21.2. IR
max/cm‒1 3176, 2966, 2840, 1747, 1548, 1510, 1370, 1207, 1029, 739, 588. HRMS
(neat):
ν
(ESI) m/z Calcd for C17H15NO3+Na+ [M+Na]+ 304.0944; Found 304.0935.
1-(4-Fluorophenyl)-1H-indol-3-yl acetate (4c). The representative procedure was
followed, using 1ꢀ(4ꢀfluorophenyl)ꢀ1Hꢀindole (3c) (0.076 g, 0.36 mmol) and PhI(OAc)2
(0.127 g, 0.39 mmol). Purification by column chromatography on silica gel (hexane/EtOAc:
15/1) yielded 4c (0.039 g, 40%) as a yellow liquid. 1HꢀNMR (400 MHz, CDCl3):
δ
= 7.67 (d,
13
J = 7.6 Hz, 1H), 7.56 (s, 1H), 7.49ꢀ7.46 (m, 3H), 7.30ꢀ7.21 (m, 4H), 2.43 (s, 3H). C{1H}ꢀ
NMR (125 MHz, CDCl3):
δ
= 168.6, 161.2 (d, JC‒F = 246.6 Hz), 135.6 (d, JC‒F = 2.3 Hz),
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133.3, 131.7, 126.4 (d, JC‒F = 8.5 Hz), 123.5, 121.3, 120.6, 118.0, 117.2, 116.6 (d, JC‒F
=
23.1 Hz), 110.4, 21.2. 19FꢀNMR (377 MHz, CDCl3): max/cm‒1
δ
= −115.1 (s). IR (neat): ν
3160, 2927, 2854, 1745, 1509, 1366, 1202, 1128, 819, 738, 558. HRMS (ESI) m/z Calcd
for C16H12FNO2+Na+ [M+Na]+ 292.0744; Found 292.0739.
1-(4-(Trifluoromethyl)phenyl)-1H-indol-3-yl acetate (4d). The representative
procedure was followed, using 1ꢀ(4ꢀ(trifluoromethyl)phenyl)ꢀ1Hꢀindole (3d) (0.078 g, 0.30
mmol) and PhI(OAc)2 (0.106 g, 0.33 mmol). Purification by column chromatography on
silica gel (hexane/EtOAc: 10/1) yielded 4d (0.043 g, 45%) as a brown solid. M. p. = 99ꢀ
101 oC. 1HꢀNMR (400 MHz, CDCl3):
δ
= 7.79ꢀ7.76 (m, 2H), 7.66ꢀ7.61 (m, 4H), 7.58 (dd, J
13
= 8.3, 4.9 Hz, 1H), 7.30ꢀ7.20 (m, 2H), 2.40 (s, 3H). C{1H}ꢀNMR (100 MHz, CDCl3):
δ =
168.5, 142.7, 132.8, 132.6, 128.4 (q, JC‒F = 33.1 Hz), 127.1 (q, JC‒F = 3.1 Hz), 124.2 (q,
JC‒F = 272.0 Hz), 124.1, 124.0, 122.0, 121.2, 118.3, 116.6, 110.6, 21.2. 19FꢀNMR (377
MHz, CDCl3):
δ = −62.3 (s). IR (neat): ν
max/cm‒1 3163, 2926, 1746, 1369, 1333, 1106,
1065, 841, 763, 736. HRMS (ESI) m/z Calcd for C17H12F3NO2+Na+ [M+Na]+ 342.0712;
Found 342.0706.
1-(4-Acetylphenyl)-1H-indol-3-yl acetate (4e). The representative procedure was
followed, using 1ꢀ(4ꢀ(1Hꢀindolꢀ1ꢀyl)phenyl)ethanꢀ1ꢀone (3e) (0.071 g, 0.30 mmol) and
PhI(OAc)2 (0.106 g, 0.33 mmol). Purification by column chromatography on silica gel
(hexane/EtOAc: 3/1) yielded 4e (0.031 g, 35%) as a light yellow liquid. 1HꢀNMR (500 MHz,
CDCl3):
δ
= 8.10 (d, J = 8.5 Hz, 2H), 7.64ꢀ7.58 (m, 5H), 7.28 (dd, J = 8.2, 7.0 Hz, 1H), 7.22
13
(dd, J = 7.6, 7.3 Hz, 1H), 2.64 (s, 3H), 2.40 (s, 3H). C{1H}ꢀNMR (125 MHz, CDCl3):
δ =
197.0, 168.5, 143.6, 134.7, 132.7, 132.6, 130.2, 124.0, 123.5, 122.1, 121.3, 118.3, 116.5,
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110.8, 26.8, 21.2. IR (neat): ν
max/cm‒1 2962, 2931, 2861, 1717, 1265, 1128, 1074, 736.
HRMS (ESI) m/z Calcd for C18H15NO3+Na+ [M+Na]+ 316.0944; Found 316.0938.
Methyl 4-(3-acetoxy-1H-indol-1-yl)benzoate (4f). The representative procedure
was followed, using methyl 4ꢀ(1Hꢀindolꢀ1ꢀyl)benzoate (3f) (0.075 g, 0.30 mmol) and
PhI(OAc)2 (0.106 g, 0.33 mmol). Purification by column chromatography on silica gel
(hexane/EtOAc: 5/1) yielded 4f (0.038 g, 41%) as a liquid. 1HꢀNMR (500 MHz, CDCl3):
δ =
8.18 (d, J = 8.5 Hz, 2H), 7.64ꢀ7.60 (m, 3H), 7.57 (d, J = 8.5 Hz, 2H), 7.28 (dd, J = 8.2, 7.3
Hz, 1H), 7.22 (dd, J = 7.6, 7.3 Hz, 1H), 3.96 (s, 3H), 2.40 (s, 3H). 13C{1H}ꢀNMR (125 MHz,
CDCl3):
δ
= 168.5, 166.5, 143.5, 132.7, 132.6, 131.4, 127.7, 124.0, 123.4, 122.0, 121.2,
max/cm‒1 3028, 3012, 2954, 1717, 1605, 1515,
118.2, 116.5, 110.8, 52.4, 21.2. IR (neat):
ν
1457, 1437, 1365, 1280, 1206, 738, 664. HRMS (ESI) m/z Calcd for C18H15NO4+Na+
[M+Na]+ 332.0893; Found 332.0887.
1-(4-Cynophenyl)-1H-indol-3-yl acetate (4g). The representative procedure was
followed, using 4ꢀ(1Hꢀindolꢀ1ꢀyl)benzonitrile (3g) (0.066 g, 0.30 mmol) and PhI(OAc)2
(0.106 g, 0.33 mmol). Purification by column chromatography on silica gel (hexane/EtOAc:
o
1
5/1) yielded 4g (0.046 g, 56%) as a light brown solid. M. p. = 110ꢀ112 C. HꢀNMR (500
MHz, CDCl3): = 7.81 (d, J = 8.2 Hz, 2H), 7.68 (d, J = 7.6 Hz, 1H), 7.66 (s, 1H), 7.63ꢀ7.60
δ
(m, 3H), 7.33 (dd, J = 8.2, 7.3 Hz, 1H), 7.27 (dd, J = 8.2, 7.0 Hz, 1H), 2.43 (s, 3H).
13C{1H}ꢀNMR (125 MHz, CDCl3):
δ
= 168.4, 143.4, 133.9, 133.1, 132.4, 124.3, 124.0,
max/cm‒1 2921, 2851,
122.3, 121.6, 118.5, 118.4, 116.1, 110.6, 109.4, 21.2. IR (neat):
ν
2225, 1776, 1562, 1509, 1366, 1211, 1126, 1012, 845, 743. HRMS (ESI) m/z Calcd for
C17H12N2O2+Na+ [M+Na]+ 299.0791; Found 299.0787.
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1-(4-Nitrophenyl)-1H-indol-3-yl acetate (4h). The representative procedure was
followed, using 1ꢀ(4ꢀnitrophenyl)ꢀ1Hꢀindole (3h) (0.071 g, 0.30 mmol) and PhI(OAc)2
(0.106 g, 0.33 mmol). Purification by column chromatography on silica gel (hexane/EtOAc:
o
5/1) yielded 4h (0.047 g, 53%) as a yellow solid. M. p. = 142ꢀ144 C. 1HꢀNMR (500 MHz,
CDCl3):
δ
= 8.38 (d, J = 8.9 Hz, 2H), 7.68ꢀ7.62 (m, 5H), 7.33 (dd, J = 8.2, 7.3 Hz, 1H), 7.24
13
(dd, J = 7.6, 7.3 Hz, 1H), 2.41 (s, 3H). C{1H}ꢀNMR (125 MHz, CDCl3):
δ = 168.4, 145.2,
145.1, 133.5, 132.5, 125.7, 124.6, 123.5, 122.5, 121.8, 118.6, 116.2, 110.7, 21.2. IR
max/cm‒1 2923, 2852, 1746, 1592, 1524, 1222, 1129, 865, 748, 695, 528. HRMS
(neat):
ν
(ESI) m/z Calcd for C16H12N2O4+Na+ [M+Na]+ 319.0689; Found 319.0688.
1-(2,4-Dinitrophenyl)-1H-indol-3-yl acetate (4i). The representative procedure
was followed, using 1ꢀ(2,4ꢀdinitrophenyl)ꢀ1Hꢀindole (3i) (0.085 g, 0.30 mmol) and
PhI(OAc)2 (0.106 g, 0.33 mmol). Purification by column chromatography on silica gel
(hexane/EtOAc: 4:1) yielded 4i (0.078 g, 76%) as an orange solid. M. p. = 147ꢀ148 oC. 1Hꢀ
NMR (500 MHz, CDCl3):
δ = 8.92 (d, J = 2.4 Hz, 1H), 8.57 (dd, J = 8.9, 2.4 Hz, 1H), 7.84
(d, J = 8.9 Hz, 1H), 7.68 (d, J = 7.9 Hz, 1H), 7.53 (s, 1H), 7.33ꢀ7.27 (m, 2H), 7.16 (d, J =
8.2 Hz, 1H), 2.42 (s, 3H). 13C{1H}ꢀNMR (125 MHz, CDCl3):
δ
= 168.0, 145.5, 144.7, 138.0,
134.3, 133.1, 130.0, 128.3, 125.0, 122.3, 122.2, 122.1, 118.8, 116.2, 109.5, 21.2. IR
max/cm‒1 3158, 3084, 2852, 1751, 1601, 1527, 1366, 1224, 1128, 748, 702, 569.
(neat):
ν
HRMS (ESI) m/z Calcd for C16H11N3O6+Na+ [M+Na]+ 364.0540; Found 364.0533.
1-(2,4-Dinitrophenyl)-5-fluoro-1H-indol-3-yl acetate (4j). The representative
procedure was followed, using 1ꢀ(2,4ꢀdinitrophenyl)ꢀ5ꢀfluoroꢀ1Hꢀindole (3j) (0.09 g, 0.30
mmol) and PhI(OAc)2 (0.106 g, 0.33 mmol). Purification by column chromatography on
silica gel (hexane/EtOAc: 4:1) yielded 4j (0.066 g, 61%) as an orange solid. M. p. = 120ꢀ
29