Iodine-catalyzed oxidative cross-coupling of indoles and azoles: Regioselective synthesis of N -linked 2-(Azol-1-yl)indole derivatives

Article abstract of DOI:10.1021/jo502933e

A highly efficient iodine-catalyzed regioselective oxidative cross-coupling of an indole C-H bond and azole N-H bond is described. This metal-free reaction can be easily carried out at room temperature under mild and environmentally friendly conditions and provides a series of N-linked 2-(azol-1-yl)indole derivatives in moderate to excellence yields.

Full text of DOI:10.1021/jo502933e

Article
pubs.acs.org/joc
Iodine-Catalyzed Oxidative Cross-Coupling of Indoles and Azoles:
Regioselective Synthesis of N‑Linked 2‑(Azol-1-yl)indole Derivatives
Danupat Beukeaw, Kwanchanok Udomsasporn, and Sirilata Yotphan*
Center for Catalysis and Center of Excellence for Innovation in Chemistry (PERCH−CIC), Department of Chemistry, Faculty of
Science, Mahidol University, Bangkok 10400, Thailand
S
* Supporting Information
ABSTRACT: A highly efficient iodine-catalyzed regioselective oxidative cross-coupling of an indole C−H bond and azole N−H
bond is described. This metal-free reaction can be easily carried out at room temperature under mild and environmentally
friendly conditions and provides a series of N-linked 2-(azol-1-yl)indole derivatives in moderate to excellence yields.
indole−azole linkage from nonactivated indole and azole was
reported by Castle and co-workers.9a This method employed a
stoichiometric amount of N-chlorosuccinimide (NCS) as the
oxidant in the oxidative coupling reaction. The utility of this
methodology was later demonstrated in the total synthesis of
Celogentin C.9b,c
INTRODUCTION
■
Indoles are structural motifs prevalent in a number of
biologically active natural products. They are employed widely
in medicinal chemistry, pharmacological research, and material
applications.1 As a consequence of their importance, the
development of efficient methodologies for the preparation and
functionalization of various indole derivatives has been a subject
of intense research efforts. Among many synthetic strategies
available, direct C−H bond functionalization/C−C bond and
C−N bond formations of indoles have received considerable
attention.2 Over the past decade, a number of studies have
reported the synthesis of indoles via direct C−H bond
functionalization/C−C bond construction approaches.3 How-
ever, there are a few reports on a direct C−H bond
functionalization/C−N bond formation of indole derivatives
due to the lack of control over chemo- and regioselectivity in
the reactions.4
2-(Azol-1-yl)indoles, N-substituted derivatives of indoles at
the C-2 position, exhibit interesting pharmaceutical properties.
This substituted indole moiety is present in some biologically
active compounds, such as melatonin derivatives (with
cardioprotective activity)5 and celogentin and moroidin families
of natural antimitotics (potent inhibitors for tubulin polymer-
ization).6 A general method for the synthesis of novel 2-(azol-1-
yl)indoles is nucleophilic displacement on 2-halogenated indole
derivatives bearing an electron-withdrawing group at the C-3
position (Scheme 1).7 Another way to build up the 2-(azol-1-
yl)indole core was reported by Poirier and Beaulieu using a
thermal or microwave-mediated reaction of azoles and
halogenated indoles.8 A direct C−N bond formation of
Recently, Huang and co-workers also reported an efficient
protocol for the preparation of a series of 2-(azol-1-yl)indole
derivatives from nonprefunctionalized indoles and azoles via
iodine-mediated selective C−N bond formation in aqueous
solution.10 We envisioned that a catalytic version of this
transformation should become feasible and provide an eco-
friendly synthetic option because a number of recent studies
have demonstrated the utility of iodine catalysis in oxidative
coupling reactions.11 The combination of catalytic amounts of
iodine or iodide salts and readily available oxidants such as tert-
butyl hydroperoxide (TBHP) or hydrogen peroxide (H2O2)
has proven to be a versatile and powerful liaison for the
successful carbon−carbon and carbon−heteroatom bond
formation in many catalytic oxidative coupling methods.12
Herein, we report regioselective C−N bond formation at the C-
2 position of indoles with azoles via the I2-catalyzed direct
oxidative C−H and N−H coupling strategy. Our catalytic
approach offers a facile synthesis of 2-(azol-1-yl)indole
derivatives with several advantages, including metal-free
regioselective catalysis, mild and environmentally benign
Received: December 29, 2014
© XXXX American Chemical Society
A
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Scheme 1. Synthetic Strategies for N-linked 2-(Azol-1-yl)indoles
conditions, accommodation of a broad range of substrates, and
avoiding the generation of toxic byproducts.
H2O at room temperature, N-linkage at the C-2 position of
indole (3a) was achieved in a promising 47% yield (Table 1,
entry 1). Screening of solvents revealed that CH3CN is the
optimal solvent, in which the desired product 3a can be
generated in excellent yield (91%, entry 2). Dichloromethane
(CH2Cl2) and 1,2-dichloroethane (DCE) are also viable
solvents for this reaction (88−89%, entries 3 and 4). Other
polar and nonpolar solvents are less effective (entries 5−10).
Employing H2O2 as the oxidant gave lower yield of product
(entry 11). Increasing the amount of TBHP led to a decrease in
yield and caused unwanted side reactions, and incomplete
conversion was observed when using less than 1 equiv of
TBHP.13 Further attempts to drive the reaction to completion
by increasing temperature were unsuccessful; lower yield of
product was found as temperature increased.13 The combina-
tions of TBHP with other forms of iodine/iodide (e.g., KI,
TBAI, and NIS) showed much lower or no catalytic activity
(entries 12−14, respectively). Additionally, no reaction was
observed in the absence of I2 (entry 15), and only 15% yield of
product 3a could be attained when the oxidant was omitted
from the reaction (entry 16). These results indicated that both
the I2 catalyst and the TBHP oxidant play pivotal roles for this
catalytic transformation.
Overall, the optimal conditions for I2-catalyzed direct C−N
bond coupling was established (Table 1, entry 2; 1 equiv of
indole, 2 equiv of azole, 20 mol % of I2, 1 equiv of aq TBHP,
CH3CN, rt, 24 h). This catalytic method employs readily
available nonactivated substrates, avoids the use of excessive
amounts of I2 and TBHP oxidant, generates a minimal amount
of waste, and can be conveniently carried out under mild
conditions. Thus, our protocol offers good economic and
environmental benefits and can be an alternative substitution
for the stoichiometric I2-mediated oxidative cross-coupling
reaction or other previously reported methods.
RESULTS AND DISCUSSION
■
We initiated this study by examining the oxidative C−H and
N−H coupling reaction of 1-methylindole (1a) with pyrazole
(2a) under various catalytic conditions; selected results are
summarized in Table 1.13 When the reaction of 1a and 2a was
carried out in the presence of I2 (20%), aq TBHP (1 equiv) in
a
Table 1. Optimization of Reaction Conditions
b
entry
catalyst
oxidant
solvent
H2O
yield (%)
1
I2
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
H2O2
47
91
88
89
63
13
14
56
42
41
54
0
2
I2
CH3CN
CH2Cl2
DCE
3
I2
4
I2
5
I2
MeOH
DMSO
DMF
6
I2
7
I2
8
I2
THF
9
I2
1,4-dioxane
toluene
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
10
11
12
13
14
15
16
I2
I2
KI
TBAI
NIS
TBHP
TBHP
TBHP
TBHP
0
5
0
I2
15
a
We next explored the generality and functional group
compatibility of this transformation under the established
conditions. Reactions between many indole substrates and
Conditions: 1a (0.5 mmol, 1 equiv), 2a (1 mmol, 2 equiv), catalyst
(0.1 mmol, 0.2 equiv), aq TBHP in water (0.5 mmol, 1 equiv),
b
CH3CN (2 mL), rt, 24 h. GC yield.
B
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a
Table 2. Scope of Indoles
a
Conditions: indole (1 mmol, 1 equiv), 2a (2 mmol, 2 equiv), I2 (0.2 mmol, 0.2 equiv), aq TBHP (1 mmol, 1 equiv), CH3CN (4 mL), rt, 24 h. In
parenthesis: isolated yields after chromatography purification.
pyrazole 2a were tested, and the results were summarized in
Table 2 (3a−3h). The presence of halogen (bromo) at the C-5
position of 1-methylindole does not appear to interrupt the
reaction. This 5-bromo-1-methylindole substrate gave the C−N
coupling product 3b in 44% isolated yield. Gratifyingly, the
electron-rich 4-methoxyl-1-methylindole substrate reacted with
pyrazole to provide product 3c in decent yield. On the other
hand, the presence of the electron poor formyl group at the C-6
position has a negative impact on the transformation; the
corresponding product 3d was obtained in considerably low
yield (16%). Apart from 1-methylindole, we also examined the
reaction scope of other free indole (N−H) substrates. To our
delight, free N−H indole underwent smooth coupling with
pyrazole (2a), affording product 3e in excellent yield (91%). A
self-coupling product between the C−H bond and the N−H
bond of free indole was not observed. A reaction of 3-
methylindole and pyrazole also furnished high yield of indole
product 3f. These outcomes from the successful formation of
products 3e and 3f thus emphasized the usefulness of this
catalytic method for regioselective C−N bond coupling at the
C-2 position of indole.
no reaction was observed in the case of indole substrates
bearing an electron-withdrawing substituent at C-5 position
(nitro and methylcarboxylate groups; 3i). In addition, 1- and 3-
acetylindole do not react under optimal conditions, indicating
that electronic effects from substituents on indole substrates
play essential roles in this transformation.
The reactions between indoles and a variety of azoles were
also examined under optimal conditions. As illustrated in Table
3, both 1-methylindole (1a) and N−H free indoles (indole and
3-methylindole) showed a tolerance toward many azole
coupling partners, and the oxidative cross-coupling reactions
can be achieved without any difficulties, allowing facile
preparation of 2-(azol-1-yl)indoles in moderate to excellent
yields. As anticipated, the reactions of these indole substrates
and halogen-substituted pyrazoles (e.g., 4-bromopyrazole or 4-
iodopyrazole) proceeded smoothly, affording the desired
products 4a1, 4a2, 4b1, and 4b2 in reasonable to excellent
quantities (54−91%). Notably, sterically hindered pyrazole
(3,5-dimethylpyrazole) also gave products 4c1 and 4c2 in
modest amounts. In the case of the imidazole coupling partner,
the N-linked C-2 indole products 4d1 and 4d2 could be
generated in excellent yields. It is noteworthy that reactions of
indoles with 1,2,3-triazole and 1,2,4-triazole resulted in 2-(1-
triazolyl)indole isomer exclusively, and the products 4e1, 4e2,
4e3, 4f1, 4f2, and 4f3 could be collected in good to excellent
yields. Other regioisomers were not observed under our
established coupling conditions. Benzimidazole and benzotria-
zole are also effective substrates for this direct C−H and N−H
oxidative cross-coupling reaction (4g, 4f1, 4f2, and 4f3).
The electronic effects of substitutents on indole substrates
were also evaluated. The indole substrate bearing an electron-
poor cyano group substituted at the C-4 position delivered
product 3g in very good yield. However, electronic variations in
the C-5 position of indole substrates have a dramatic effect on
the efficiency of the reaction. In the case of the electron-
donating group (such as a hydroxyl group), good yield of
product 3h can be achieved (79% isolated yield). Conversely,
C
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a
Table 3. Scope of Azoles
a
Conditions: indole (1 mmol, 1 equiv), azole (2 mmol, 2 equiv), I2 (0.2 mmol, 0.2 equiv), aq TBHP (1 mmol, 1 equiv), CH3CN (4 mL), rt, 24 h. In
parenthesis: isolated yields after chromatography purification.
Interestingly, the azole substrate containing an oxidant-sensitive
hydroxyl group is compatible with the reaction conditions. The
C−N coupling product 4i was formed selectively in one
regioisomer without impacting the hydroxyl group, demonstrat-
ing the mild nature of our protocol. The regiochemistry of the
isolated coupling product (4i) was confirmed by the two-
dimensional NOESY spectrum (see the Supporting Informa-
tion), which exhibits the through-space correlations between
indole-hydrogen at the C-3 position and imidazole-CH2OH at
the C-5 position as well as an indole methyl (CH3) group at the
N-1 position and imidazole-hydrogen at the C-2 position.13
Nonetheless, 2-methylimidazole is unable to couple with
indoles under these conditions; only trace amounts of products
4j1, 4j2, and 4j3 were detected by GCMS. These results
suggested that the steric hindrance from the methyl group at
the C-2 position of imidazole could interfere with product
formation.
in the presence of TEMPO, BHT, and hydroquinone,
respectively. Therefore, these results suggested that the reaction
is not likely to involve a radical pathway. To provide further
evidence regarding the role of iodine and TBHP, the reaction
was carried out without the use of an oxidant. The yield of
product 3a was significantly reduced when subjecting 1 or 2
equiv of I2 to this reaction (Scheme 2b), which implied that I2
is not likely to be the catalytic active species. These results are
different from that reported by Huang and co-workers (2012),
who showed that a stoichiometric amount (1−2 equiv) of I2
can be utilized to mediate the oxidative C−N coupling reaction
in a saturated aqueous ammonium salt solution. Under our
standard conditions, however, the I2 precatalyst could likely be
converted to another active intermediate prior to entering the
catalytic cycle. In the absence of TBHP, excess I2 would
presumably directly react with the starting material and lead to
unwanted side reactions.13
To gain insight into the reaction mechanism, a series of
control experiments were conducted (Scheme 2). When a
radical inhibitor was employed in the reaction of indole 1a and
azole 2a, no inhibition was observed under optimal conditions
(Scheme 2a). The product can be obtained in 60, 96, and 94%
Although the combination of a catalytic amount of iodide
anion (I−) and TBHP oxidant was insufficient to elaborate
successful formation of the N-linked indole product (Table 1,
entries 12 and 13), the reaction of indole 1a and pyrazole 2a in
the presence of catalytic HI (hydroiodic acid) and TBHP
D
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conditions, the initial process could involve in situ iodination,
giving an electrophilic iodine species (“I+”), such as hypoiodous
(HIO) or iodous acid (HIO2).11b,14,15 Then, nucleophilic attack
of this “I+” species by indole will generate either active
iodonium ion A or 3-iodo iminium intermediate B.4f,10 This
intermediate can be trapped by a nucleophilic azole, leading to
the formation of key intermediate C.8,9a Subsequent
elimination of HI would furnish the corresponding 2-(azol-1-
yl)indole product. Further oxidation of HI by TBHP would
reproduce the “I+” species to resume the catalytic cycle as
depicted in Scheme 3.
Scheme 2. Control Experiments
CONCLUSION
■
In summary, we have disclosed an expedient metal-free catalytic
protocol for regio- and chemoselective C−N bond formation of
indoles with azoles. This iodine-catalyzed oxidative coupling
reaction can be carried out at room temperature under mild
conditions with good scope using a ubiquitous and inexpensive
catalytic combination. This catalytic transformation provides a
convenient synthetic route with good economical and environ-
mental advantages to access a series of N-linked 2-(azol-1-
yl)indole derivatives, which have potential applications in
medicinal chemistry. Mechanistic studies and further extension
of this methodology to other substrates are currently under
investigation.
oxidant afforded product 3a in 85% yield (Scheme 2c). This
result implied that a catalytic amount of acid might be required
for conversion of an iodide anion to an active species in this
reaction. We also speculated that H+ and I− (HI) are possibly
involved in the catalytic cycle. To verify whether HI could
facilitate product formation, the reaction of 1a and 2a was
treated with only a stoichiometric amount of HI. In this case,
no product was obtained. This outcome underlined the
necessity of TBHP oxidant to convert not only I2, but also
HI (iodide anion in acidic medium) to the active catalytic
species in this transformation.
EXPERIMENTAL SECTION
■
General Information. Unless otherwise specified, all experiments
were carried out under air atmosphere. All reagents were obtained
from commercial suppliers and used without further purification.
Oven-dried glassware was used in all cases. Column chromatography
was performed over silica gel (SiO2; 60 Å silica gel, 70−230 Mesh).
GC experiments were carried out with a GC-FID on a chromatograph
equipped with an HP-1 polysiloxane column (24.5 m × 0.32 mm ID ×
1
0.17 μm). H and 13C NMR spectra were recorded at 400 and 100
MHz in CDCl3 or DMSO-d6 solution. NMR chemical shifts are
reported in ppm and were measured relative to CHCl3 (7.24 ppm for
1H and 77.00 ppm for 13C) or DMSO (2.51 ppm for H and 39.51
1
On the basis of the results described above and relevant
literature,9−12 a plausible mechanism for this transition-metal-
free oxidative coupling is proposed using 1-methylindole 1a and
pyrazole 2a as the model substrates. Under the optimal reaction
ppm for 13C). IR spectra were recorded on an FT-IR spectrometer,
and only partial data are listed. High resolution mass spectroscopy
(HRMS) data were analyzed by a high-resolution micrOTOF
Scheme 3. Tentative Reaction Mechanism
E
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instrument with electrospray ionization (ESI). The structures of
(d, J = 8.0 Hz, 1H), 7.22−7.13 (m, 2H), 6.51 (t, J = 2.0 Hz, 1H), 2.42
(s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 140.6, 132.9, 131.4,
129.3, 128.6, 122.4, 119.9, 118.7, 110.9, 107.3, 98.1, 8.6. HRMS (ESI+,
m/z): [M + H]+ calcd for C12H12N3, 198.1026; found, 198.1031.
2-(1H-Pyrazol-1-yl)-1H-indole-4-carbonitrile (3g). Following the
general procedure, the product was isolated as a white solid in 177.0
mg (85%) by column chromatography (4:1 hexanes/ethyl acetate).
known compounds were corroborated by comparing their 1H and 13
C
NMR data with values from the literature.9
General Procedure for the Synthesis of Compounds 3a−3h
and 4a−4i. A 20 mL oven-dried scintillation vial equipped with a
magnetic stir bar was charged with a mixture of indole substrate (1.00
mmol, 1.00 equiv), azole (2.00 mmol, 2.00 equiv), iodine (I2, 51 mg,
0.20 mmol, 0.20 equiv), TBHP in water (1.00 mmol, 1.00 equiv), and
acetonitrile (CH3CN) (4.00 mL). The vial was capped, and the
reaction mixture was stirred at room temperature for 24 h. Upon
completion, saturated Na2S2O3 (5 mL) and distilled deionized H2O
(12 mL) was added, and the mixture was extracted with ethyl acetate
(EtOAc) (2 × 25 mL). The combined organic layer was washed with
saturated NaCl, dried over anhydrous Na2SO4, and concentrated in
vacuo. The crude product was purified by SiO2 column chromatog-
raphy to afford the desired N-linked 2-(azol-1-yl)indole product.
1-Methyl-2-(1H-pyrazol-1-yl)-1H-indole (3a).10 Following the
general procedure, the product was isolated as a white solid in 177.5
mg (90%) by column chromatography (4:1 hexanes/ethyl acetate). 1H
NMR (400 MHz, CDCl3): δ 7.81 (d, J = 1.2 Hz, 1H), 7.72 (d, J = 2.4
Hz, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.36−7.34 (m, 1H), 7.31−7.27 (m,
1H), 7.19−7.15 (m, 1H), 6.51 (s, 1H), 6.47 (t, J = 2.0 Hz, 1H), 3.67
(s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 141.8, 135.7, 132.4,
126.0, 122.6, 121.0, 120.4, 109.6, 106.8, 95.9, 29.9. HRMS (ESI+, m/
z): [M + H]+ calcd for C12H12N3, 198.1026; found, 198.1031.
5-Bromo-1-methyl-2-(1H-pyrazol-1-yl)-1H-indole (3b).10 Follow-
ing the general procedure, the product was isolated as a white solid in
121.1 mg (44%) by column chromatography (6:1 hexanes/ethyl
1
Mp 203.6−203.9 °C. H NMR (400 MHz, CDCl3): δ 10.10 (s, 1H),
8.02 (d, J = 2.4 Hz, 1H), 7.75 (d, J = 1.2 Hz, 1H), 7.51 (d, J = 7.6 Hz,
1H), 7.48−7.45 (m, 1H), 7.21−7.16 (m, 1H), 6.61 (d, J = 1.2 Hz,
1H), 6.56−6.55 (m, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ 141.7,
137.6, 132.9, 130.0, 127.8, 125.8, 121.6, 118.6, 115.5, 108.9, 102.6,
85.7. IR (neat, cm−1): 3211, 3123, 2349, 2219, 2013, 1573, 1367, 1195,
1046, 772, 604. HRMS (ESI+, m/z): [M + Na]+ calcd for C12H8N4Na,
231.0641; found, 231.0646.
2-(1H-Pyrazol-1-yl)-1H-indol-5-ol (3h). Following the general
procedure, the product was isolated as a pale-white solid in 158.1
mg (79%) by column chromatography (1:1 hexanes/ethyl acetate).
1
Mp 188.3−189.8 °C. H NMR (400 MHz, DMSO-d6): δ 11.54 (br s,
1H), 8.80 (s, 1H), 8.35 (d, J = 2.4 Hz, 1H), 7.77 (d, J = 1.4 Hz, 1H),
7.17 (d, J = 8.8 Hz, 1H), 6.82 (d, J = 2.0 Hz, 1H), 6.61−6.59 (m, 1H),
6.56−6.55 (m, 1H), 6.41 (d, J = 1.2 Hz, 1H). 13C{1H} NMR (100
MHz, DMSO): δ 151.4, 140.9, 136.2, 128.5, 128.3, 128.2, 112.0, 111.3,
107.8, 104.1, 87.2. IR (neat, cm−1): 3436, 3069, 2920, 1645, 1511,
1476, 1318, 1201, 1052, 792, 740, 641. HRMS (ESI+, m/z): [M +
Na]+ calcd for C11H9N3NaO, 222.0638; found, 222.0640.
2-(4-Bromo-1H-pyrazol-1-yl)-1-methyl-1H-indole (4a1). Following
the general procedure, the product was isolated as a white solid in
163.6 mg (59%) by column chromatography (10:1 hexanes/ethyl
acetate). Mp 131.1−131.9 °C. 1H NMR (400 MHz, CDCl3): δ 7.78 (s,
1H), 7.74 (s, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.37−7.30 (m, 2H), 7.22−
7.18 (m, 1H), 6.52 (s, 1H), 3.67 (s, 3H). 13C{1H} NMR (100 MHz,
CDCl3): δ 142.4, 135.7, 134.7, 132.2, 125.8, 122.9, 121.1, 120.6, 109.7,
96.3, 94.9, 29.9. IR (neat, cm−1): 3137, 2938, 1699, 1480, 1454, 1337,
953, 775,755, 609. HRMS (ESI+, m/z): [M + H]+ calcd for
C12H11BrN3, 276.0131; found, 276.0134.
1
acetate). H NMR (400 MHz, CDCl3): δ 7.80 (d, J = 1.6 Hz, 1H),
7.73−7.72 (m, 2H), 7.37−7.34 (m, 1H), 7.22−7.20 (m, 1H), 6.47 (t, J
= 2.0 Hz, 1H), 6.44 (s, 1H), 3.67 (s, 3H). 13C{1H} NMR (100 MHz,
CDCl3): δ 142.1, 136.6, 134.4, 132.3, 127.7, 125.5, 123.4, 113.6, 111.2,
107.1, 95.2, 30.2. HRMS (ESI+, m/z): [M + H]+ calcd for
C12H11BrN3, 276.0131; found, 276.0130.
4-Methoxy-1-methyl-2-(1H-pyrazol-1-yl)-1H-indole (3c). Follow-
ing the general procedure, the product was isolated as a white solid in
194.6 mg (86%) by column chromatography (4:1 hexanes/ethyl
acetate). Mp 82.3−83.0 °C. 1H NMR (400 MHz, CDCl3): δ 7.79 (d, J
= 1.2 Hz, 1H), 7.71−7.70 (m, 1H), 7.23−7.19 (m, 1H), 6.97 (d, J =
8.0 Hz, 1H), 6.60−6.57 (m, 2H), 6.45−6.44 (m, 1H), 3.95 (s, 3H),
3.65 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 153.5, 141.8,
137.0, 134.3, 132.4, 123.4, 116.6, 106.7, 103.0, 100.2, 93.3, 55.4, 30.2.
IR (neat, cm−1): 3145, 2929, 2838, 1889, 1569, 1501, 1463, 1388,
1355, 1250, 1104, 929, 624. HRMS (ESI+, m/z): [M + Na]+ calcd for
C13H13N3NaO, 250.0951; found, 250.0949.
2-(4-Bromo-1H-pyrazol-1-yl)-3-methyl-1H-indole (4a2). Following
the general procedure, the product was isolated as a white solid in
250.6 mg (91%) by column chromatography (10:1 hexanes/ethyl
1
acetate). Mp 71.0−71.5 °C. H NMR (400 MHz, CDCl3): δ 8.83 (s,
1H), 7.91 (s, 1H), 7.68 (s, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.31 (d, J =
8.0 Hz, 1H), 7.23−7.20 (m, 1H), 7.18−7.14 (m, 1H), 2.40 (s, 3H).
13C{1H} NMR (100 MHz, CDCl3): δ 141.2, 132.8, 130.6, 129.2,
128.4, 122.9, 120.2, 119.0, 110.9, 99.0, 95.4, 8.6. IR (neat, cm−1): 3364,
3244, 3113, 2920, 1718, 1584, 1451, 1381, 950, 736, 576. HRMS (ESI
+, m/z): [M + H]+ calcd for C12H11BrN3, 276.0131; found, 276.0138.
2-(4-Iodo-1H-pyrazol-1-yl)-1-methyl-1H-indole (4b1). Following
the general procedure, the product was isolated as an off-white solid
in 173.6 mg (54%) by column chromatography (10:1 hexanes/ethyl
acetate). Mp 156.3−157.5 °C. 1H NMR (400 MHz, CDCl3): δ 7.80 (s,
1H), 7.76 (s, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.36−7.29 (m, 2H), 7.20−
7.16 (m, 1H), 6.51 (s, 1H), 3.66 (s, 3H). 13C{1H} NMR (100 MHz,
CDCl3): δ 146.8, 136.5, 135.7, 134.5, 125.8, 122.9, 121.1, 120.6, 109.7,
96.3, 58.2, 29.9. IR (neat, cm−1): 3130, 2921, 2337, 1563, 1454, 1334,
1165, 953, 855, 776, 610. HRMS (ESI+, m/z): [M + Na]+ calcd for
C12H10IN3Na, 345.9812; found, 345.9816.
1-Methyl-2-(1H-pyrazol-1-yl)-1H-indole-6-carbaldehyde (3d).
Following the general procedure, the product was isolated as a white
solid in 35.4 mg (16%) by column chromatography (4:1 hexanes/ethyl
1
acetate). Mp 117.9−119.1 °C. H NMR (400 MHz, CDCl3): δ 10.07
(s, 1H), 7.93 (s, 1H), 7.83 (d, J = 1.2 Hz, 1H), 7.78 (d, J = 2.0 Hz,
1H), 7.72−7.67 (m, 2H), 6.55 (d, J = 0.8 Hz, 1H), 6.51 (t, J = 2.0 Hz,
1H), 3.84 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 192.1, 142.4,
139.4, 135.5, 132.0, 131.4, 131.3, 121.9, 121.1, 112.2, 107.5, 95.7, 30.6.
IR (neat, cm−1): 3114, 2922, 1674, 1570, 1468, 1369, 1221, 930, 811,
756, 627. HRMS (ESI+, m/z): [M + H]+ calcd for C13H12N3O,
226.0980; found, 226.0975.
2-(1H-Pyrazol-1-yl)-1H-indole (3e).10 Following the general
procedure, the product was isolated as a brown solid in 166.7 mg
2-(4-Iodo-1H-pyrazol-1-yl)-3-methyl-1H-indole (4b2). Following
the general procedure, the product was isolated as a white solid in
221.5 mg (69%) by column chromatography (10:1 hexanes/ethyl
1
(91%) by column chromatography (4:1 hexanes/ethyl acetate). H
1
NMR (400 MHz, CDCl3): δ 9.41 (br s, 1H), 7.95 (d, J = 2.4 Hz, 1H),
7.71 (d, J = 1.6 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.34 (d, J = 8.0 Hz,
1H), 7.19−7.10 (m, 2H), 6.48 (t, J = 2.0 Hz, 1H), 6.41−6.40 (m, 1H).
13C{1H} NMR (100 MHz, CDCl3): δ 140.8, 135.5, 133.5, 127.8,
127.6, 122.0, 120.6, 120.3, 111.0, 108.0, 87.1. HRMS (ESI+, m/z): [M
+ H]+ calcd for C11H10N3, 184.0869; found, 184.0870.
acetate). Mp 61.7−62.7 °C. H NMR (400 MHz, CDCl3): δ 8.62 (s,
1H), 7.94 (s, 1H), 7.72 (s, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.32 (d, J =
8.0 Hz, 1H), 7.22−7.20 (m, 1H), 7.18−7.14 (m, 1H), 2.41 (s, 3H).
13C{1H} NMR (100 MHz, CDCl3): δ 145.5, 133.4, 132.8, 130.5,
128.4, 122.9, 120.1, 119.0, 110.9, 99.0, 58.6, 8.7. IR (neat, cm−1): 3277,
3139, 2917, 1714, 1595, 1505, 1452, 1019, 939, 737. HRMS (ESI+, m/
z): [M + H]+ calcd for C12H11IN3, 323.9992; found, 323.9999.
2-(3,5-Dimethyl-1H-pyrazol-1-yl)-1-methyl-1H-indole (4c1). Fol-
lowing the general procedure, the product was isolated as a yellow
solid in 116.3 mg (52%) by column chromatography (9:1 hexanes/
ethyl acetate). Mp 45.7−46.3 °C. 1H NMR (400 MHz, CDCl3): δ 7.63
3-Methyl-2-(1H-pyrazol-1-yl)-1H-indole (3f).10 Following the
general procedure, the product was isolated as an off-white solid in
167.2 mg (85%) by column chromatography (4:1 hexanes/ethyl
acetate). 1H NMR (400 MHz, CDCl3): δ 9.33 (br s, 1H), 7.92 (d, J =
2.4 Hz, 1H), 7.75 (d, J = 1.5 Hz, 1H), 7.57 (d, J = 7.6 Hz, 1H), 7.30
F
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The Journal of Organic Chemistry
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(d, J = 8.0 Hz, 1H), 7.34−7.26 (m, 2H), 7.18−7.14 (m, 1H), 6.51 (d, J
= 0.8 Hz, 1H), 6.01 (s, 1H), 3.48 (s, 3H), 2.31 (s, 3H), 2.16 (s, 3H).
13C{1H} NMR (100 MHz, CDCl3): δ 150.1, 142.7, 135.5, 133.6,
126.1, 122.5, 121.1, 120.1, 109.5, 106.0, 98.4, 29.2, 13.6, 11.4. IR (neat,
cm−1): 3053, 2924, 2349, 1563, 1451, 1393, 1345, 1314, 1119, 1030,
783, 730, 656. HRMS (ESI+, m/z): [M + H]+ calcd for C14H16N3,
226.1344; found, 226.1342.
2-(3,5-Dimethyl-1H-pyrazol-1-yl)-3-methyl-1H-indole (4c2). Fol-
lowing the general procedure, the product was isolated as a white solid
in 159.7 mg (71%) by column chromatography (9:1 hexanes/ethyl
acetate). Mp 173.9−174.9 °C. 1H NMR (400 MHz, CDCl3): δ 8.48 (s,
1H), 7.57 (d, J = 7.6 Hz, 1H), 7.30−7.28 (m, 1H), 7.22−7.20 (m,
1H), 7.16−7.12 (m, 1H), 5.97 (s, 1H), 2.26 (s, 3H) 2.18−2.17 (m,
6H). 13C{1H} NMR (100 MHz, CDCl3): δ 150.3, 142.4, 133.7, 129.3,
127.7, 123.0, 119.7, 119.3, 111.0, 106.1, 105.9, 13.6, 11.2, 8.5. IR (neat,
cm−1): 3057, 2917, 2349, 1629, 1452, 1300, 1131, 1037, 778, 735.
HRMS (ESI+, m/z): [M + H]+ calcd for C14H16N3, 226.1344; found,
226.1354.
131.2, 125.6, 123.4, 121.4, 120.8, 109.8, 97.5, 29.9. HRMS (ESI+, m/
z): [M + H]+ calcd for C11H11N4, 199.0978; found, 199.0986.
3-Methyl-2-(1H-1,2,4-triazol-1-yl)-1H-indole (4f2). Following the
general procedure, the product was isolated as a white solid in 169.9
mg (86%) by column chromatography (1:1 hexanes/ethyl acetate).
1
Mp 125.2−125.5 °C. H NMR (400 MHz, CDCl3): δ 8.96 (s, 1H),
8.52 (s, 1H), 8.14 (s, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.34 (d, J = 8.0
Hz, 1H), 7.28−7.25 (m, 1H), 7.23−7.16 (m, 1H), 2.39 (s, 3H).
13C{1H} NMR (100 MHz, CDCl3): δ 152.1, 142.8, 133.3, 128.0,
127.5, 123.5, 120.4, 119.3, 111.1, 101.6, 8.5. IR (neat, cm−1): 3117,
2916, 1721, 1509, 1334, 1144, 983, 962, 729, 666. HRMS (ESI+, m/
z): [M + H]+ calcd for C11H11N4, 199.0978; found, 199.0988.
2-(1H-1,2,4-Triazol-1-yl)-1H-indole (4f3).10 Following the general
procedure, the product was isolated as a white solid in 119.8 mg (65%)
by column chromatography (1:1 hexanes/ethyl acetate). 1H NMR
(400 MHz, CDCl3): δ 9.29 (s, 1H), 8.61 (s, 1H) 8.12 (s, 1H), 7.61 (d,
J = 8.0 Hz, 1H), 7.38 (dd, J = 8.0, 0.8 Hz, 1H), 7.26−7.22 (m, 1H),
7.19−7.15 (m, 1H), 6.58 (d, J = 1.6 Hz, 1H). 13C{1H} NMR (100
MHz, CDCl3): δ 152.2, 141.4, 133.6, 131.3, 127.2, 123.1, 121.1, 120.9,
111.3, 90.0. HRMS (ESI+, m/z): [M + H]+ calcd for C10H9N4,
185.0822; found, 185.0824.
2-(1H-Imidazol-1-yl)-1-methyl-1H-indole (4d1).10 Following the
general procedure, the product was isolated as a yellow solid in 179.2
mg (91%) by column chromatography (1:4 hexanes/ethyl acetate). 1H
NMR (400 MHz, CDCl3): δ 7.69 (s, 1H), 7.63 (d, J = 8.0 Hz, 1H),
7.35−7.29 (m, 2H), 7.25−7.24 (m, 1H), 7.21−7.17 (m, 1H), 7.14 (s,
1H), 6.53 (s, 1H), 3.52 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ
138.7, 135.6, 132.1, 130.0, 125.9, 123.0, 121.3, 121.1, 120.8, 109.7,
97.8, 29.2. HRMS (ESI+, m/z): [M + H]+ calcd for C12H12N3,
198.1026; found, 198.1031.
1-(1-Methyl-1H-indol-2-yl)-1H-benzo[d]imidazole (4g). Following
the general procedure, the product was isolated as a white solid in
193.4 mg (78%) by column chromatography (1:2 hexanes/ethyl
acetate). Mp 144.4−145.1 °C. 1H NMR (400 MHz, CDCl3): δ 7.98 (s,
1H), 7.87−7.85 (m, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.36−7.26 (m,
4H), 7.22−7.16 (m, 2H), 6.60 (s, 1H), 3.43 (s, 3H). 13C{1H} NMR
(100 MHz, CDCl3): δ 143.6, 143.2, 135.9, 135.4, 130.3, 126.2, 124.3,
123.2, 123.1, 121.2, 120.7, 120.6, 110.5, 109.8, 99.1, 29.4. IR (neat,
cm−1); 3113, 2923, 1581, 1454, 1399, 1220, 751, 733, 659. HRMS
(ESI+, m/z): [M + H]+ calcd for C16H14N3, 248.1188; found,
248.1180.
2-(1H-Imidazol-1-yl)-3-methyl-1H-indole (4d2).8 Following the
general procedure, the product was isolated as a white solid in 191.3
mg (97%) by column chromatography (1:4 hexanes/ethyl acetate). 1H
NMR (400 MHz, CDCl3): δ 11.14 (s, 1H), 7.69 (s, 1H), 7.62 (d, J =
8.0 Hz, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.30−7.25 (m, 2H), 7.23−7.19
(m, 1H), 7.15 (s, 1H), 2.29 (s, 3H). 13C{1H} NMR (100 MHz,
CDCl3): δ 137.3, 133.7, 128.5, 127.8, 127.7, 122.8, 120.7, 119.8, 119.0,
111.2, 103.3, 7.9. HRMS (ESI+, m/z): [M + H]+ calcd for C12H12N3,
198.1026; found, 198.1040.
1-(1-Methyl-1H-indol-2-yl)-1H-benzo[d][1,2,3]triazole (4h1). Fol-
lowing the general procedure, the product was isolated as a pale-yellow
solid in 227.7 mg (92%) by column chromatography (4:1 hexanes/
1
ethyl acetate). Mp 158.0−158.7 °C. H NMR (400 MHz, CDCl3): δ
1-Methyl-2-(1H-1,2,3-triazol-1-yl)-1H-indole (4e1).10 Following
the general procedure, the product was isolated as a yellow solid in
184.3 mg (93%) by column chromatography (2:1 hexanes/ethyl
7.99 (d, J = 8.0 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.40−7.36 (m, 2H),
7.30−7.26 (m, 2H), 7.21−7.17 (m, 1H), 7.07−7.03 (m, 1H), 6.58 (s,
1H), 3.46 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 145.4, 136.0,
134.7, 130.2, 128.9, 126.1, 124.7, 123.4, 121.4, 120.8, 120.2, 110.2,
109.9, 98.2, 29.9. IR (neat, cm−1): 3053, 2930, 1561, 1451, 1318, 1286,
1035, 788, 744, 651. HRMS (ESI+, m/z): [M + Na]+ calcd for
C15H12N4Na, 271.0954; found, 271.0963.
1
acetate). H NMR (400 MHz, CDCl3): δ 7.87 (dd, J = 5.2, 0.8 Hz,
2H), 7.65 (d, J = 8.0 Hz, 1H), 7.39−7.32 (m, 2H), 7.22−7.18 (m,
1H), 6.62 (s, 1H), 3.66 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ
135.9, 133.5, 131.4, 126.5, 125.7, 123.4, 121.3, 120.8, 109.9, 97.3, 30.0.
HRMS (ESI+, m/z): [M + H]+ calcd for C11H11N4, 199.0978; found,
199.0984.
1-(3-Methyl-1H-indol-2-yl)-1H-benzo[d][1,2,3]triazole (4h2). Fol-
lowing the general procedure, the product was isolated as a yellow gel,
235.9 mg (95%) by column chromatography (4:1 hexanes/ethyl
acetate). 1H NMR (400 MHz, CDCl3): δ 8.49 (s, 1H), 8.14 (d, J = 8.0
Hz, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.58−7.54 (m, 1H), 7.51−7.48 (m,
1H), 7.47−7.42 (m, 2H), 7.34 (td, J = 8.0, 1.2 Hz, 1H), 7.26−7.22 (m,
1H), 2.27 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 145.4, 134.3,
133.9, 128.7, 127.9, 125.8, 124.6, 123.9, 120.4, 120.3, 119.7, 111.3,
110.3, 106.8, 8.60. IR (neat, cm−1): 3209, 2919, 1920, 1722, 1452,
1278, 1048, 1004, 782, 739. HRMS (ESI+, m/z): [M + H]+ calcd for
C15H13N4, 249.1135; found, 249.1149.
3-Methyl-2-(1H-1,2,3-triazol-1-yl)-1H-indole (4e2).8 Following the
general procedure, the product was isolated as a white solid in 170.6
mg (86%) by column chromatography (2:1 hexanes/ethyl acetate). 1H
NMR (400 MHz, CDCl3): δ 9.03 (s, 1H), 8.04 (d, J = 1.0 Hz, 1H),
7.88 (d, J = 1.0 Hz, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.40 (d, J = 8.0 Hz,
1H), 7.30−7.26 (m, 1H), 7.21−7.17 (m, 1H), 2.40 (s, 3H). 13C{1H}
NMR (100 MHz, CDCl3): δ 134.1, 133.4, 127.9, 127.5, 123.7, 123.5,
120.4, 119.4, 111.3, 101.7, 8.5. IR (neat, cm−1): 3170, 2917, 2349,
1626, 1504, 1417, 1231, 1027, 766, 742. HRMS (ESI+, m/z): [M +
H]+ calcd for C11H11N4, 199.0978; found, 199.0992.
1-(1H-Indol-2-yl)-1H-benzo[d][1,2,3]triazole (4h3). Following the
general procedure, the product was isolated as a white solid in 135.3
mg (58%) by column chromatography (4:1 hexanes/ethyl acetate).
2-(1H-1,2,3-Triazol-1-yl)-1H-indole (4e3).10 Following the general
procedure, the product was isolated as a white solid in 96.9 mg (53%)
by column chromatography (2:1 hexanes/ethyl acetate). 1H NMR
(400 MHz, CDCl3): δ 9.35 (s, 1H), 8.06 (s, 1H), 7.85 (s, 1H), 7.62 (d,
J = 8.0 Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.29−7.25 (m, 1H), 7.19−
7.16 (m, 1H), 6.58−6.57 (m, 1H). 13C{1H} NMR (100 MHz,
CDCl3): δ 134.5, 133.8, 131.4, 127.0, 123.5, 121.7, 121.2, 121.0, 111.4,
90.5. HRMS (ESI+, m/z): [M + Na]+ calcd for C10H8N4Na, 207.0641;
found, 207.0650.
1
Mp 166.1−166.3 °C. H NMR (400 MHz, CDCl3): δ 9.57 (s, 1H),
8.14 (d, J = 8.4 Hz, 1H), 7.89 (d, J = 8.4 Hz, 1H), 7.70−7.68 (m, 1H),
7.64−7.60 (m, 1H), 7.51−7.44 (m, 2H), 7.31−7.26 (m, 1H), 7.22−
7.18 (m, 1H), 6.78 (d, J = 1.6 Hz, 1H). 13C{1H} NMR (100 MHz,
CDCl3): δ 146.2, 133.7, 131.4, 131.2, 129.0, 127.4, 125.0, 123.2, 121.0,
120.9, 120.4, 111.3, 110.8, 91.0. IR (neat, cm−1): 3363, 1561, 1445,
1296, 1061, 766, 748, 738, 648, 548. HRMS (ESI+, m/z): [M + Na]+
calcd for C14H10N4Na, 257.0803; found, 257.0815.
1-Methyl-2-(1H-1,2,4-triazol-1-yl)-1H-indole (4f1).10 Following the
general procedure, the product was isolated as a yellow solid in 124.9
mg (63%) by column chromatography (1:2 hexanes/ethyl acetate). 1H
NMR (400 MHz, CDCl3): δ 8.38 (s, 1H), 8.19 (s, 1H), 7.65 (d, J =
8.0 Hz, 1H), 7.38−7.31 (m, 2H), 7.22−7.18 (m, 1H), 6.61 (s, 1H),
3.66 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 153.2, 145.5, 136.0
(1-(1-Methyl-1H-indol-2-yl)-1H-imidazol-5-yl)methanol (4i). Fol-
lowing the general procedure, the product was isolated as a white solid
in 113.6 mg (50%) by column chromatography (1:9 methanol/ethyl
1
acetate). Mp 156.0−157.2 °C. H NMR (400 MHz, CDCl3): δ 7.63
(d, J = 8.0 Hz, 1H), 7.47 (s, 1H), 7.34−7.28 (m, 2H), 7.18−7.14 (m,
G
DOI: 10.1021/jo502933e
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1H), 7.06 (s, 1H), 6.58 (s, 1H), 4.44 (s, 2H), 3.42 (s, 3H), 3.02 (br s,
1H). 13C{1H} NMR (100 MHz, CDCl3): δ 139.7, 135.7, 133.7, 129.8,
128.5, 125.9, 123.2, 121.2, 120.7, 109.8, 99.8, 53.5, 29.1. IR (neat,
cm−1): 3770, 3591, 3140, 2783, 1670, 1562, 1562, 1467, 1098, 1030,
926, 752, 661. HRMS (ESI+, m/z): [M + H]+ calcd for C13H14N3O,
228.1131; found, 228.1130.
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ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C spectra and spectral data. This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: sirilata.yot@mahidol.ac.th. Tel: +662-201-5154. Fax:
+662-354-7151.
■
Notes
The authors declare no competing financial interest.
(8) Poirier, M.; Goudreau, S.; Poulin, J.; Savoie, J.; Beaulieu, P. L.
Org. Lett. 2010, 12, 2334.
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■
The authors gratefully acknowledge financial support from
Thailand Research Fund (TRF) Grant TRG5780148, Faculty
of Science, Mahidol University, Center of Excellence for
Innovation in Chemistry (PERCH−CIC), Commission on
Higher Education, Ministry of Education, and Center of
Instrumental Facility (CIF) at Faculty of Science, Mahidol
University. The authors also thank Dr. Vichai Reutrakul for
helpful discussions.
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DOI: 10.1021/jo502933e
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