Regioselectivity of Larock heteroannulation: A contribution from electronic properties of diarylacetylenes

Article abstract of DOI:10.1021/jo402304s

A series of 2,3-diarylindoles were synthesized from 2-iodoaniline and unsymmetrical diarylacetylenes using the Larock heteroannulation. Diarylacetylenes bearing electron-withdrawing substituents lead to 2,3-diarylindoles with substituted phenyl moieties at the 2-position as major products, while those with electron-donating groups preferably yield indole products with substituted phenyl moieties at the 3-position. The regioisomeric product ratios exhibit a clear correlation with Hammett σ_p values. DFT calculations reveal the origin of this effect, displaying smaller activation energy barriers for those pathways leading to the major regioisomer.

Full text of DOI:10.1021/jo402304s

Article
pubs.acs.org/joc
Regioselectivity of Larock Heteroannulation: A Contribution from
Electronic Properties of Diarylacetylenes
Nared Phetrak,† Thanya Rukkijakan,† Jakkapan Sirijaraensre,‡ Samran Prabpai,§ Palangpon Kongsaeree,§
Chayada Klinchan,† and Pitak Chuawong*,†
‡
†Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science and Laboratory for
Computational & Applied Chemistry (LCAC), Chemistry Department, Faculty of Science, Kasetsart University, Bangkok 10900,
Thailand
§Department of Chemistry and Center for Excellence in Protein Structure and Function, Faculty of Science, Mahidol University,
Bangkok 10400, Thailand
S
* Supporting Information
ABSTRACT: A series of 2,3-diarylindoles were synthesized
from 2-iodoaniline and unsymmetrical diarylacetylenes using
the Larock heteroannulation. Diarylacetylenes bearing elec-
tron-withdrawing substituents lead to 2,3-diarylindoles with
substituted phenyl moieties at the 2-position as major
products, while those with electron-donating groups preferably
yield indole products with substituted phenyl moieties at the 3-
position. The regioisomeric product ratios exhibit a clear
correlation with Hammett σp values. DFT calculations reveal
the origin of this effect, displaying smaller activation energy
barriers for those pathways leading to the major regioisomer.
unknown factors also appear to operate, leading to confounding
results.3,7,8,10,15 Therefore, we sought to investigate the
influence electronic effects have on the regioselectivity of the
Larock heteroannulation reaction. Although the electronic
properties of 2-iodoaniline have been shown to affect the
regioselectivity and the rate of this reaction,17,18 the impact of
the electronic properties of the alkyne reaction partner have not
been established. In our study, a model system is employed that
differs only in the electronic character of the alkyne. The model
used here is expected to show negligible steric differences
between reacting ligands, being a function of the different
substituents at the 4-position of one aryl moiety of the alkyne.
The proposed catalytic cycle for our model system is
illustrated in Scheme 1. The regioselectivity of the reaction
arises from the carbopalladation step, where migration of the
Pd(II) catalyst to different sp-carbon atoms leads to
regioisomeric products. Through the analyses of regioisomeric
product ratio and density functional theory (DFT) calculations,
we demonstrate herein that the electronic effect is operative
and significantly influences regioisomerism of the Larock
heteroannulation reaction.
INTRODUCTION
■
Since its first report in 1991, the Larock heteroannulation has
been recognized as a convenient and effective method for the
construction of 2,3-disubstituted indoles.1 The first reaction
condition reported by Larock employs palladium acetate with a
triphenylphosphine ligand as a catalyst in the presence of
inorganic base and n-Bu4NCl or LiCl as an additive. This
method allows the coupling of 2-iodoaniline and disubstituted
alkynes yielding 2,3-disubstituted indoles in a facile manner. It
was later discovered that a less reactive 2-bromo- or 2-
chloroaniline could also be used.2,3 Recently, the scope of this
reaction has been expanded to induce macrocyclization.4,5 The
reaction has also been demonstrated to be regioselective when
a more sterically hindered group is present at the 2-position of
the resulting indoles.6 The nature of the ligand attached to the
palladium catalyst7,8 and the possible coordination of additional
heteroatoms on the substituted alkyne to the palladium
atom6,7,9,10 also play important roles in regioselectivity. In
various synthetic applications utilizing the Larock protocol,
regioselectivity can be secured using silylated alkynes where the
silyl substituents preferentially remain on the 2-position of the
indole products. The silyl groups can be conveniently
functionalized in subsequent synthetic steps.11−14
RESULTS AND DISCUSSION
■
We started our investigation by synthesizing a series of
diarylacetylenes bearing electron-withdrawing or -donating
groups via Sonogashira coupling between phenylacetylene
A reverse regioselectivity was observed during the prepara-
tion of α-C-glycosylamino acids by Nishikawa and co-workers
in 2002.15 They investigated various functionalized alkynes as
reactants but were unable to show clear regioselectivity.16
Despite the fact that the steric demands associated with the
alkyne ligands play a crucial role in regioselectivity, additional
Received: October 15, 2013
Published: November 27, 2013
© 2013 American Chemical Society
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Scheme 1. Proposed Catalytic Cycle for Larock Heteroannulation
and 4-substituted iodobenzenes.19,20 The coupling reactions
proceeded smoothly, providing diarylacetylenes in good to
excellent yield (Table 1).
Regioselectivity was assessed on the basis of regioisomeric
product ratios obtained from the analysis of the NMR spectra
of the crude reactions and the isolated yields (Table 2). It was
found that the regioisomeric product ratios determined by
NMR correlate well with the values calculated from the isolated
yields, indicating that the chromatographic step does not
significantly alter the regioisomeric product ratio.
Table 1. Sonogashira Coupling between Phenylacetylene
and 4-Substituted Aryl Iodides
All reactions were conducted in triplicate in order to verify
the statistical significance of observed regioisomeric product
ratios. A plot between the 4-position substituent and the
average regioisomeric product ratio clearly demonstrates that
the observed regioselectivity is statistically significant (Figure
2). It is worth noting that comparable regioselectivity was not
observed in a similar system where 4-acetamido-3-iodopyridine
was reacted with unsymmetrical diarylacetylenes.21,22
The reaction of diarylacetylenes containing electron-donating
groups preferentially led to the indole product with the 4-
substituted phenyl group located at the 3-position (Table 2,
compound 9, entries 1−3). In contrast, electron-withdrawing
substituents preferably yielded indole products with 4-
substituted phenyl groups at the 2-position (Table 2, isomer
8, entries 4−7). The regioisomeric product ratios were
compared to the σp values compiled by Hansch and co-
workers.23 It is apparent that the introduction of electron-
donating groups (σp < 0) results in a significant increase in the
formation of isomer 9. On the other hand, isomer 8 is
predominantly formed when electron-withdrawing groups (σp
> 0) are introduced. In addition, the log of the regioisomeric
product ratio exhibits a quantitative correlation with σp values
(Figure 3).
a
entry
R
diarylacetylene
yield (%)
1
2
3
4
5
6
7
OH
1
2
3
4
5
6
7
98
91
75
70
58
NH2
CN
Br
NO2
NHAc
CO2Me
b
98
c
81
a
b
Yields for chromatographically pure compound. Yield from
acetylation of 2. Yield from hydrolysis and esterification of 3.
c
With diarylacetylenes in hand, we proceeded with the Larock
heteroannulation. The reactions were conducted at 80 °C for
24 h using 10 mol % of Pd(OAc)2, 20 mol % of PPh3, Na2CO3,
and n-Bu4NCl. As expected, both regioisomers were formed
(Table 2, entries 1−7).
The 2,3-disubstituted indole products were characterized
spectroscopically and compared with known compounds, while
regioisomeric pairs of new compounds, those with amino (9a)
and N-acetylamino substituents (9c), were unequivocally
characterized by X-ray diffraction (Figure 1).
To better understand our experimental results, quantum
calculations for the carbopalladation step were performed using
the hybrid density functional B3LYP method. Two extreme
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Table 2. Regioisomeric Product Ratios and σp Values of Larock Heteroannulation between 2-Iodoaniline and Substituted
Diarylacetylenes
a
a
b
entry
compound
R
σp
8:9
log(8:9)
8:9
1
2
3
4
5
6
7
a
b
c
d
e
f
NH2
OH
−0.66
−0.37
0.00
0.55
0.75
0.92
1.39
1.94
1.60
2.33
−0.26
−0.12
−0.04
0.14
0.55
0.74
0.92
1.33
1.89
1.67
2.62
NHAc
Br
0.23
CO2Me
CN
0.45
0.27
0.66
0.20
g
NO2
0.78
0.37
a
b
1
Regioisomeric product ratio determined by H NMR of crude reaction mixture. Regioisomeric product ratio determined from isolated yield.
Figure 2. Correlation between substituent and average regioisomeric
product ratio determined from isolated yield.
Figure 1. ORTEP representation of compounds 9a and 9c.
Figure 3. Relationship between the substituent σp constant and the log
of the regioisomeric product ratio determined by H NMR.
1
cases were chosen for analysis, namely those with the strong
electron-donating (−NH2) and -withdrawing (−NO2) groups.
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a
Table 3. Bond Distances of Calculated Species and the Energy Profile of the Carbopalladation Step
route I
route II
substituent
R = NO2
distance
ADS (Å)
TS1 (Å)
INT1 (Å)
TS2 (Å)
INT2 (Å)
p
q
r
2.500
2.452
1.230
2.310
2.550
1.240
2.441
2.122
1.281
2.411
2.121
1.281
2.833
2.025
1.351
2.379
1.975
1.397
2.170
2.357
1.271
2.088
2.758
1.289
2.011
2.842
1.352
2.013
2.824
1.352
R = NH2
p
q
r
a
ADS = adsorption complex, TS1 = transition state of route I, TS2 = transition state of route II, INT1 = intermediate of route I, INT2 =
intermediate of route II. Bold numbers represent values discussed in text.
The energy profiles associated with the carbopalladation
process as well as the key bond distances of optimized
structures along the pathway are shown in Table 3.
experimentally observed (i.e., product ratios for 8a/9a and 8g/
9g in Table 2).
The carbopalladation step is found to be exothermic from
our computational results. Thus, an early transition state is
expected according to Hammond’s postulate.24 Indeed, the
geometry of the initial adsorption complex between Pd(II)
catalyst and 4-substituted diphenylacetylenes more closely
resembles the geometry of the transition-state structure
(Table 3). The distance between the Pd and the C1 atom in
the adsorption complex with the amino group is significantly
shorter than that between the Pd and the C2 atom. In contrast,
we observe a shorter distance between the Pd and the C2 atom
compared to the Pd and C1 in the complex with the nitro
group (see p and q values in Table 3). These differences are
even more pronounced in the corresponding transition-state
structures. It is also apparent that, in the lower energy barrier
pathway, Pd(II) preferentially locates close to C1 when R is an
amino group and C2 when R is a nitro group. Mulliken
population analysis was therefore performed on compounds 2
and 5 in order to assess the partial charges found on C1 and
C2. In compound 2, the electron-donating amino group can
directly influence the electron density of the C1−C2 triple
bond and results in a more negative Mulliken charge on C1
(Scheme 2).
Two different carbopalladation pathways, routes I and II,
leading to different regioisomeric products were examined. For
the amino substituent, the energy barrier leading to the indole
product with a 4-aminophenyl group at the 3-position (Table 3,
route II, compound 9a) is lower than the barrier leading to the
regioisomer with the 4-aminophenyl group at the 2-position
(Table 3, route I, compound 8a) by 3.93 kcal/mol. On the
other hand, the energy barrier for the formation of the indole
product with the 4-nitrophenyl group at the 2-position (Table
3, route I, compound 8g) is lower than that leading to the
product with the 4-nitrophenyl group at the 3-position (Table
3, route II, compound 9g) by 2.42 kcal/mol.
The calculated results are in full agreement with the observed
regioisomeric product ratios from our experimental studies; the
experimentally preferred regioisomeric products are all formed
via the lower energy barrier pathways. For instance, with the
electron-releasing amino substituent, the lower energy pathway
leads to compound 9a, which is the major regioisomer obtained
from heteroannulation reaction. In addition, the relatively small
differences in energy between the route I and II barriers are
consistent with the fact that both regioisomers are indeed
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chromatography (TLC) was conducted on aluminum-backed 0.2
mm thick silica gel 60 F254 plates. The plates were visualized under a
254 nm UV lamp and subsequently sprayed with basic solution of
potassium permanganate or with vanillin solution followed by heating.
Column chromatography was performed on silica gel 60 (70−230
mesh).
Scheme 2. Partial Charges on Compounds 2 (A) and 5 (B)
General Procedure for the Sonogashira Coupling (Com-
pounds 1−5). To a three-necked round-bottom flask equipped with a
stirring bar were added 0.5 mol % of Pd(OAc)2 (11.22 mg, 0.05
mmol), 2 mol % of PPh3 (52.44 mg, 0.2 mmol), 0.5 mol % of CuI
(9.52 mg, 0.05 mmol), and 4-substituted aryl iodide (10 mmol). After
evacuation and flushing with N2, phenylacetylene (1.3 mL, 12 mmol),
THF (10 mL), and NEt3 (6.9 mL, 50 mmol) were introduced
subsequently. The reaction mixture was stirred at room temperature
for 1 h. When the starting aryl iodide was completely consumed, the
reaction mixture was diluted with ether and washed with saturated
aqueous NH4Cl and H2O. The organic layer was dried over anhydrous
Na2SO4. The reaction mixture was filtered and concentrated, and the
product was purified by flash column chromatography using 20% ethyl
acetate/hexane.
4-(Phenylethynyl)phenol (1).25 White solid (1.91 g, 98%): 1H
NMR (400 MHz, CDCl3) δ 7.50−7.52 (m, 2H), 7.43 (d, J = 2.2 Hz,
2H), 7.32−7.34 (m, 3H), 6.81 (d, J = 2.2 Hz, 2H), 5.02 (s, 1H); 13C
NMR (100 MHz, CDCl3) δ 155.7, 133.2, 131.4, 128.7, 128.3, 127.9,
115.5, 89.3, 88.0; MS m/z 195 [M + H]+.
4-(Phenylethynyl)aniline (2).26 Dark brown solid (1.76 g, 91%): 1H
NMR (400 MHz, CDCl3) δ 7.50−7.45 (m, 2H), 7.32 (d, J = 8.7 Hz,
2H), 7.31−7.25 (m, 3H), 6.62 (d, J = 8.7 Hz, 2H), 3.79 (s, 2H); 13C
NMR (100 MHz, CDCl3) δ 146.6, 132.9, 131.3, 128.2, 127.6, 123.8,
114.68, 122.5, 90.1, 87.3; MS m/z 194 [M + H]+.
4-(Phenylethynyl)benzonitrile (3).27 Brown solid (1.52 g, 75%): 1H
NMR (400 MHz, CDCl3) δ 7.64−7.57 (m, 4H), 7.55−7.50 (m, 2H),
7.38−7.34 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 132.0, 131.7,
129.1, 128.5, 128.2, 122.2, 118.5, 111.4, 93.7, 87.7; MS m/z 204 [M +
H]+.
The electron-withdrawing nitro group of compound 5 leads
to C2 becoming more negatively charged. These analyses
clearly show that the preferred reaction pathway sees the
electrophilic Pd(II) species migrate to the more electronegative
sp-hybridized carbon atom. Indeed, the DFT predicted unequal
electron distribution around the triple bond can be qualitatively
rationalized from the resonance structures of the two
compounds (Scheme 2).
1-Bromo-4-(phenylethynyl)benzene (4).28 White solid (1.78 g,
70%): 1H NMR (400 MHz, CDCl3) δ 7.54−7.46 (m, 4H), 7.41−7.33
(m, 5H); 13C NMR (100 MHz, CDCl3) δ 133.0, 131.6, 128.5, 128.3,
122.9, 122.4, 122.2, 90.5, 88.3; MS m/z 257 [M + H]+.
1-Nitro-4-(phenylethynyl)benzene (5).29 Yellow solid (1.29 g,
1
58%): H NMR (400 MHz, CDCl3) δ 8.22 (d, J = 9.0 Hz, 2H), 7.67
(d, J = 9.0 Hz, 2H), 7.58−7.54 (m, 2H), 7.40−7.38 (m, 3H); 13C
NMR (100 MHz, CDCl3) δ 146.9, 132.2, 131.8, 130.2, 129.2, 128.5,
123.6, 122.1, 94.7, 87.5; MS m/z 224 [M + H]+.
CONCLUSION
■
In summary, we have reported on the electronic influence of
disubstituted alkynes toward the regioselectivity of the Larock
heteroannulation reaction. By keeping the steric effect
essentially constant, we show that the Pd catalyst preferentially
migrates to the sp-hybridized carbon atom possessing the
greater electron density, resulting in the formation of an indole
product with greater electron density carbon at 2-position as a
major regioisomer. Although the electronic effect observed
herein might not be considered extreme, it confirms that an
electronic effect is operative, and can influence the
regioselectivity outcome in the Larock heteroannulation
reaction.
N-(4-(Phenylethynyl)phenyl)acetamide (Compound 6). To a
solution of 4-(phenylethynyl)aniline (0.8 g, 5 mmol) and Na2CO3 (1.0
g, 10 mmol) in dry THF (20 mL) at −78 °C was added CH3COCl
(0.4 mL, 5.5 mmol). The reaction mixture was stirred at room
temperature for 1 h. After the reactant was completely consumed,
water was added, and the mixture was extracted with ethyl acetate. The
organic layer was dried over anhydrous Na2SO4. The reaction mixture
was filtered and concentrated, and the product was purified by column
chromatography using 50% ethyl acetate/hexane to afford 630 as a
slightly yellow solid (1.16 g, 98%): 1H NMR (400 MHz, DMSO-d6) δ
10.2 (s, 1H), 7.60 (d, J = 7.6 Hz, 2H), 7.50 (m, 2H), 7.45 (d, J = 7.6
Hz, 2H), 7.39 (m, 3H), 2.05 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
168.7, 139.8, 132.1, 131.3, 128.8, 122.6, 118.9, 116.4, 89.6, 88.5, 24.1;
MS m/z 236 [M + H]+.
EXPERIMENTAL SECTION
Methyl 4-(Phenylethynyl)benzoate (Compound 7). A solution
of 4-(phenylethynyl)benzonitrile (0.8 mg, 3.95 mmol) and NaOH (0.4
g, 10.0 mmol) in 50% ethanol/H2O (10 mL) was heated under reflux
for 4 h. After complete consumption of the reactant, the solvent was
removed under reduced pressure. The residue was acidified and
esterified by adding 40% concd H2SO4/methanol (10 mL), and then
the solution was refluxed at 80 °C overnight. The solvent was
removed, and the product was purified by column chromatography
using 20% ethyl acetate/hexane to afford 731 as a white solid (0.75 g,
■
General Methods. 1H NMR and 13C NMR spectra were recorded
at 400 and 100 MHz, respectively, using CDCl3 or DMSO-d6 as a
1
solvent. The peak due to residual CHCl3 (7.26 ppm for H and 77.0
ppm for 13C) or (CH3)2SO (2.50 ppm for 1H and 39.43 ppm for 13C)
was used as an internal reference. TMS was added and used as internal
reference when the solvent residual peak was obscured by signals from
samples. Chemical shifts are quoted in parts per million, and coupling
constants (J) are given in hertz (Hz). Mass spectral data were recorded
on an APCI-ion trap spectrometer. High-resolution mass spectra were
acquired using an ESI-TOF spectrometer. Analytical thin-layer
1
81%): H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 8.2 Hz, 2H), 7.51
(d, J = 8.2 Hz, 2H), 7.49−7.46 (m, 2H), 7.30−7.28 (m, 3H), 3.86 (s,
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3H); 13C NMR (100 MHz, CDCl3) δ 166.5, 131.7, 131.5, 129.5,
128.7, 128.4, 128.0, 122.7, 92.3, 88.6, 52.2; MS m/z 237 [M + H]+.
General Procedure for the Larock Heteroannulation
(Compounds 8a−g and 9a−g). Pd(OAc)2 (10 mol %, 11.22 mg,
0.05 mmol), 20 mol % of PPh3 (26.22 mg, 0.1 mmol), n-Bu4NCl (139
mg, 0.5 mmol), Na2CO3 (264 mg, 2.50 mmol), 2-iodoaniline (109 mg,
0.5 mmol), DMF (5 mL), and diarylalkyne (0.7 mmol) were added to
a three-necked round-bottom flask equipped with a stirring bar and
condenser. The reaction was heated under N2 atmosphere at 80 °C for
24 h. Then, the reaction mixture was diluted with ether and washed
with saturated NH4Cl solution and H2O. The organic layer was
separated and dried over anhydrous Na2SO4. The reaction mixture was
filtered and concentrated, and the product was purified by column
chromatography using 10% ethyl acetate/hexane.
132.3, 131.6, 128.8, 128.3, 128.1, 127.9, 122.8, 120.6, 120.1, 119.3,
113.7, 110.9; HRMS (ESI-TOF) m/z [M + H]+ calcd for C20H15NBr
348.0388, found 348.0389.
Methyl 4-(3-Phenyl-1H-indol-2-yl)benzoate (8e).34 Pale yellow
1
solid (85.6 mg, 52%): H NMR (400 MHz, DMSO-d6) δ 11.73 (s,
1H), 7.92 (d, J = 8.7 Hz, 2H), 7.58 (d, J = 8.7 Hz, 2H), 7.51−7.29 (m,
7H), 7.20 (t, J = 8.1 Hz, 1H), 7.06 (t, J = 8.0 Hz, 1H), 3.84 (s, 3H);
13C NMR (100 MHz, DMS-d6) δ 165.8, 137.0, 136.4, 134.7, 132.5,
129.7, 129.2, 128.7, 128.0, 127.8, 126.4, 122.6, 120.0, 118.8, 114.9,
111.6, 52.0 ; HRMS (ESI-TOF) m/z [M + H]+ calcd for C22H18NO2
328.1338, found 328.1336.
Methyl 4-(2-Phenyl-1H-indol-3-yl)benzoate (9e).36 Pale yellow
1
solid (45.3 mg, 28%): H NMR (400 MHz, CDCl3) δ 8.39 (s, 1H),
8.03 (d, J = 8.6 Hz, 2H), 7.69 (d, J = 8.1 Hz, 1H), 7.52−7.26 (m, 9H),
7.17 (t, J = 8.0 Hz, 1H), 3.92 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
167.3, 140.4, 136.0, 135.1, 132.3, 129.84, 129.80, 128.8, 128.4, 128.2,
128.0, 127.6, 122.9, 120.7, 119.3, 113.9, 111.1, 52.0; HRMS (ESI-
TOF) m/z [M + H]+ calcd for C22H18NO2 328.1338, found 328.1332.
4-(3-Phenyl-1H-indol-2-yl)benzonitrile (8f).37 White solid (49.7
4-(3-Phenyl-1H-indol-2-yl)aniline (8a). Pale yellow solid (30.4 mg,
1
21%): H NMR (400 MHz, CDCl3) δ 8.11 (s, 1H), 7.65 (d, J = 7.8
Hz, 1H), 7.43 (m, 2H), 7.32 (m, 3H), 7.23 (t, J = 7.3 Hz, 1H), 7.25−
7.08 (m, 4H), 6.52 (d, J = 8.5 Hz, 2H), 4.04−3.14 (bs, 2H); 13C NMR
(100 MHz, CDCl3) δ 145.9, 135.6, 135.5, 134.7, 130.0, 129.3, 128.8,
128.4, 125.8, 122.8, 122.0, 120.1, 119.2, 115.1, 113.3, 110.7; HRMS
(ESI-TOF) m/z [M + H]+ calcd for C20H17N2 285.1392, found
285.1391.
1
mg, 34%): H NMR (400 MHz, CDCl3) δ 8.39 (s, 1H), 7.67 (d, J =
7.7 Hz, 1H), 7.62 (d, J = 8.5 Hz, 2H), 7.52 (d, J = 8.5 Hz, 2H), 7.46−
7.32 (m, 6H), 7.28 (t, J = 7.6 Hz, 1H), 7.16 (t, J = 7.5 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ 137.2, 136.4, 134.2, 132.3, 131.6, 130.0,
128.8, 128.7, 126.9, 123.7, 120.8, 120.1, 118.8, 117.5, 111.1, 110.5;
HRMS (ESI-TOF) m/z [M + H]+ calcd for C21H15N2 295.1235,
found 295.1238.
4-(2-Phenyl-1H-indol-3-yl)aniline (9a). Pale yellow solid (54.9 mg,
1
39%): H NMR (400 MHz, CDCl3) δ 8.19 (s, 1H), 7.64 (d, J = 8.0
Hz, 1H), 7.45−7.42 (m, 2H), 7.39 (d, J = 8.0 Hz, 1H), 7.34−7.18 (m,
6H), 7.12 (t, J = 7.5 Hz, 1H), 6.72 (d, J = 8.5 Hz, 2H); 13C NMR (100
MHz, CDCl3) δ 144.4, 135.8, 133.4, 133.0, 131.0, 129.0, 128.6, 128.0,
127.4, 125.4, 122.5, 120.2, 119.8, 115.6, 115.1, 110.8; HRMS (ESI-
TOF) m/z [M + H]+ calcd for C20H17N2 285.1392, found 285.1396.
4-(3-Phenyl-1H-indol-2-yl)phenol (8b).32 White solid (32.0 mg,
22%): 1H NMR (400 MHz, DMSO-d6) δ 11.37 (s, 1H), 9.62 (s, 1H),
7.51−7.23 (m, 9H), 7.12 (t, J = 7.5 Hz, 1H), 7.02 (t, J = 7.4 Hz, 1H),
6.76 (d, J = 8.6 Hz, 2H); 13C NMR (100 MHz, DMSO-d6) δ 156.9,
135.7, 135.5, 134.6, 129.5, 129.4, 128.4, 127.9, 125.7, 123.1, 121.3,
119.4, 118.1, 115.3, 111.7, 111.1; HRMS (ESI-TOF) m/z [M + H]+
calcd for C20H16NO 286.1232, found 286.1225.
4-(2-Phenyl-1H-indol-3-yl)benzonitrile (9f).15,38 White solid (29.8
mg, 20%): 1H NMR (400 MHz, DMSO-d6) δ 11.79 (s, 1H), 7.80 (d, J
= 8.1 Hz, 2H), 7.57−7.33 (m, 9H), 7.21 (t, J = 7.3 Hz, 1H), 7.10 (t, J
= 7.4 Hz, 1H); 13C NMR (100 MHz, DMSO-d6) δ 140.6, 136.1, 135.6,
132.3, 131.7, 130.1, 128.6, 128.5, 128.0, 127.0, 122.2, 120.2, 119.0,
118.1, 111.7, 111.4, 107.9; HRMS (ESI-TOF) m/z [M + H]+ calcd for
C21H15N2 295.1235, found 295.1220.
2-(4-Nitrophenyl)-3-phenyl-1H-indole (8g). Orange solid (60.2
1
mg, 38%): H NMR (400 MHz, CDCl3) δ 8.38 (s, 1H), 8.12 (d, J =
8.8 Hz, 2H), 7.63 (d, J = 8.0 Hz, 1H), 7.52 (d, J = 8.9 Hz, 2H), 7.46−
7.33 (m, 6H), 7.29 (t, J = 7.4 Hz, 1H), 7.16 (t, J = 7.5 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ 146.5, 139.1, 136.5, 134.1, 131.2, 130.1,
128.9, 128.7, 128.2, 127.1, 124.0, 124.0, 121.0, 120.2, 118.2, 111.2;
HRMS (ESI-TOF) m/z [M + H]+ calcd for C20H15N2O2 315.1134,
found 315.1131.
4-(2-Phenyl-1H-indol-3-yl)phenol (9b).33 White solid (43.0 mg,
30%): 1H NMR (400 MHz, DMSO-d6) δ 11.42 (s, 1H), 9.40 (s, 1H),
7.52−7.11 (m, 10H), 7.02 (t, J = 7.9 Hz, 1H), 6.82 (d, J = 8.6 Hz,
2H); 13C NMR (100 MHz, DMSO-d6) δ 155.7, 135.9, 133.2, 132.6,
130.7, 128.3, 128.3, 127.8, 127.1, 125.5, 121.7, 119.3, 118.6, 115.5,
113.4, 111.3; HRMS (ESI-TOF) m/z [M + H]+ calcd for C20H16NO
286.1232, found 286.1224.
3-(4-Nitrophenyl)-2-phenyl-1H-indole (9g).39 Orange solid (23.0
mg, 15%): 1H NMR (400 MHz, DMSO-d6) δ 11.87 (s, 1H), 8.22 (d, J
= 8.0 Hz, 2H), 7.66−7.35 (m, 9H), 7.22 (t, J = 7.6 Hz, 1H), 7.12 (t, J
= 7.5 Hz, 1H); 13C NMR (100 MHz, DMSO-d6) δ 144.9, 142.9, 136.2,
131.7, 130.1, 128.7, 128.6, 128.2, 126.9, 123.8, 122.4, 120.4, 118.2,
111.8, 111.0; HRMS (ESI-TOF) m/z [M + H]+ calcd for C20H15N2O2
315.1134, found 315.1135.
N-(4-(3-Phenyl-1H-indol-2-yl)phenyl)acetamide (8c). Pale yellow
1
solid (65.0 mg, 40%): H NMR (400 MHz, DMSO-d6) δ 11.47 (s,
1H), 10.01 (s, 1H), 7.56 (d, J = 8.6 Hz, 2H), 7.50−7.32 (m, 8H), 7.28
(t, J = 8.7 Hz, 1H), 7.14 (t, J = 8.1 Hz, 1H), 7.03 (t, J = 8.0 Hz, 1H),
2.05 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 168.3, 138.6, 135.9,
135.3, 134.0, 129.6, 128.5, 128.5, 127.9, 127.0, 125.9, 121.7, 119.6,
118.8, 118.3, 112.6, 111.3, 23.9; HRMS (ESI-TOF) m/z [M + H]+
calcd for C22H19N2O 327.1497, found 327.1492.
X-ray Diffraction. X-ray diffraction data were measured on a
diffractometer with graphite-monochromated MoKα radiation (λ =
0.71073 Å) at 298(2) K. The structures were solved by direct methods
with SIR9740 and refined with full-matrix least-squares calculations on
F2 using SHELXL-97.41 Crystallographic data have been deposited at
the Cambridge Crystallographic Data Centre under the reference nos.
CCDC962465-962466. Copies of the data can be obtained, free of
charge, on application to the Director, CCDC, 12 Union Road,
Cambridge, CB2 1EZ, UK (e-mail: deposit@ccdc.cam.ac.uk).
Computational Details. All geometrical structures of reaction
were optimized by employing the hybrid density functional B3LYP
method. For the basis set, the LANDL2DZ effective core potential
(ECP)42−44 and LANL2DZspdf+ECP45 basis sets were used for
palladium and iodine atoms, respectively. The remaining atoms were
treated with the 6-31G(d,p) basis set. All minimum and transition state
structures were confirmed by the frequency calculation in which all
minimum structures had no imaginary frequency and each transition
state structure had only one imaginary frequency. To investigate the
effect of DMF solvent on the energetic profile, all geometrical
structures were reoptimized at the same level within the bulk solvent
treating by the polarizable continuum model (PCM).46 The free
energies at 353.15 K and 1 atm of the gas-phase and PCM models
N-(4-(2-Phenyl-1H-indol-3-yl)phenyl)acetamide (9c). Pale yellow
1
solid (70.4 mg, 43%): H NMR (400 MHz, DMSO-d6) δ 11.50 (s,
1H), 9.97 (s, 1H), 7.61 (d, J = 8.5 Hz, 2H), 7.50−7.24 (m, 9H), 7.15
(t, J = 8.0 Hz, 1H), 7.04 (t, J = 7.9 Hz, 1H), 2.07 (s, 3H); 13C NMR
(100 MHz, DMSO-d6) δ 168.2, 137.4, 136.0, 133.7, 132.5, 129.89,
129.79, 128.4, 128.03, 127.97, 127.3, 121.9, 119.5, 119.2, 118.6, 113.0,
111.4, 23.9; HRMS (ESI-TOF) m/z [M + H]+ calcd for C22H19N2O
327.1497, found 327.1493.
2-(4-Bromophenyl)-3-phenyl-1H-indole (8d).34 Yellow solid (31.8
1
mg, 18%): H NMR (400 MHz, CDCl3) δ 8.19 (s, 1H), 7.66 (d, J =
7.98 Hz, 1H), 7.47−7.22 (m, 11H), 7.15 (t, J = 7.5 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 135.9, 134.6, 132.7, 131.8, 131.6, 130.0, 129.5,
128.7, 128.6, 126.4, 123.0, 121.7, 120.6, 119.7, 115.6, 110.9; HRMS
(ESI-TOF) m/z [M + H]+ calcd for C20H15NBr 348.0388, found
348.0380.
3-(4-Bromophenyl)-2-phenyl-1H-indole (9d).35 Yellow solid (23.9
1
mg, 14%): H NMR (400 MHz, CDCl3) δ 8.26 (s, 1H), 7.63 (d, J =
8.0 Hz, 1H), 7.48 (d, J = 8.4 Hz, 2H), 7.45−7.22 (m, 9H), 7.16 (t, J =
7.9 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 135.8, 134.3, 134.0,
12708
dx.doi.org/10.1021/jo402304s | J. Org. Chem. 2013, 78, 12703−12709

The Journal of Organic Chemistry
Article
were done at the same level by single-point calculations from the
corresponding structures. All theoretical calculations were performed
using the Gaussian 09 package.47
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ASSOCIATED CONTENT
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(21) Livecchi, M.; Calvet, G.; Schmidt, F. J. Org. Chem. 2012, 77,
5006.
S
* Supporting Information
NMR spectra (1H and 13C) for all new compounds, CIF files,
and X-ray crystallographic data for compound 9a and 9c, and
atomic coordinates for optimized structures. This material is
available free of charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
*Phone and Fax: +66 2 5625555 ext 5161. E-mail: Pitak.C@ku.
ac.th.
■
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Kasetsart University Research
and Development Institute (KURDI) and the Faculty of
Science, Kasetsart University, under the Science Research Fund
(ScRF-S5/2555). J.S. thanks the Thailand Research Fund,
National Center of Excellence for Petroleum, Petrochemical,
and Advanced materials (NCE-PPAM), and National Research
University of Kasetsart University for financial support. P.K.
and S.P. acknowledge the National Research University
Initiative for Mahidol University. Financial support from the
Center of Excellence for Innovation in Chemistry (PERCH-
CIC), Commission on Higher Education, Ministry of
Education, is also gratefully acknowledged. We thank Professor
Matthew Paul Gleeson (Chemistry Department, Kasetsart
University) and Professor Tamara Hendrickson (Wayne State
University) for critical reading of the manuscript.
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