The Development of a Palladium-Catalyzed Tandem Addition/Cyclization for the Construction of Indole Skeletons

Article abstract of DOI:10.1021/acs.joc.7b00148

A palladium-catalyzed tandem addition/cyclization of 2-(2-aminoaryl)acetonitriles with arylboronic acids has been developed for the first time, achieving a new strategy for direct construction of indole skeletons. This system shows good functional group tolerance and remarkable chemoselectivity. In particular, the halogen (e.g., bromo and iodo) substituents are amenable to further synthetic elaborations thereby broadening the diversity of the products. Preliminary mechanistic experiments indicate that this transformation involves sequential nucleophilic addition followed by an intramolecular cyclization.

Full text of DOI:10.1021/acs.joc.7b00148

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Article
The Development of a Palladium-Catalyzed Tandem Addition/
Cyclization for Direct Construction of Indole Skeletons
Shuling Yu, Linjun Qi, Kun Hu, Julin Gong, Tianxing Cheng, Qingzong Wang, Jiuxi Chen, and Huayue Wu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b00148 • Publication Date (Web): 13 Mar 2017
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The Development of a Palladium-Catalyzed Tandem Addition/Cyclization for
Construction of Indole Skeletons
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Shuling Yu, Linjun Qi, Kun Hu, Julin Gong, Tianxing Cheng, Qingzong Wang, Jiuxi Chen,* and
Huayue Wu*
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College of Chemistry & Materials Engineering, Wenzhou University, Wenzhou 325035, China.
Fax: 86-577-8836-8280. E-mail: jiuxichen@wzu.edu.cn; huayuewu@wzu.edu.cn
ABSTRACT: A palladium-catalyzed tandem addition/cyclization of 2-(2-
aminoaryl)acetonitriles with arylboronic acids has been developed for the first time,
achieving a new strategy for direct construction of indole skeletons. This system shows
good functional group tolerance and remarkable chemoselectivity. Especially, the
halogen (e.g. bromo and iodo) substituents are amenable for further synthetic
elaborations thereby broadening the diversity of the products. Preliminary mechanistic
experiments indicate that this transformation involves sequential nucleophilic addition
followed by an intramolecular cyclization.
____________________________________________________________________
INTRODUCTION
Transition-metal-catalyzed transformations of the activated organonitriles play an
important role in both synthetic and medicinal chemistry due to their well-recognized
chemical versatility.1 It is well known, however, that aliphatic nitriles (e.g. acetonitrile)
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have been used as solvents or ligands in organometallic reactions presumably due to
the inherently inert nature of nitriles.2 The catalytic carbopalladation of nitriles,
pioneered by the Larock group3 and a considerable development within the past few
years, provided a conceptual basis for several other groups4 and our group.5 We recently
reported tandem addition and cyclization for the synthesis of isoquinolines by catalytic
carbopalladation of aromatic nitriles.6
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Compared to aromatic nitriles, nucleophilic addition reactions of aliphatic nitriles are
limited by insufficient electrophilic activation. On the other hand, aliphatic nitriles are
used as carbon pronucleophiles in carbon-carbon bond forming reactions in different
modes of aliphatic nitriles activation, such as α-cyano carbanions or metalated nitriles.7
Despite the remarkable progress made to date, the development of a practical and
general approach to N-heterocycles using aliphatic nitriles as the reaction partners
remains a tremendous challenge.
Indoles are a class of important structural motifs because of their ubiquity in natural
products, bioactive compounds, and other functional molecules.8 Hence, effective
methods for the construction of indoles have been actively pursued during the past
several decades.9 Pschorr-Hoppe indole synthesis,10-13 one of the most common
approaches in which indole and its derivatives were prepared from the reduction of 2-
(2-nitroaryl)acetonitriles has been followed by subsequent intramolecular cyclization.
The direct intramolecular cyclization of 2-(2-aminoaryl)acetonitriles provided an
alternative route to indole by the use of bipyridine-based PNN Ru(II) pincer
complex/H2 (4 bar),14 Pd-C/H2 (balloon).15 Notably, the expansion of the substrate
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scope was not investigated. Recently, Chung16 reported a cobalt−rhodium
heterobimetallic nanoparticle-catalyzed tandem reductive cyclization of 2-(2-
nitroaryl)-acetonitriles to indoles (Scheme 1a). However, these methods are applicable
to the synthesis of 3-substituted indoles only. We envisioned that a Pd-catalyzed
sequential nucleophilic addition followed by an intramolecular cyclization of
functionalized nitriles using arylboronic acids as coupling partner could offer a new and
complementary method for the 2-arylindoles.
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Scheme 1. Synthesis of Indoles from Nitriles
Although transformation of nitriles into various functional groups has been well-
established, aliphatic nitriles as substrate candidates involved in the transition-metal-
catalyzed tandem addition and cyclization processes with organoboron reagents for the
synthesis of indoles have not been achieved to date. As part of the continuing efforts in
our laboratory toward the development of novel transition metal-catalyzed coupling
reactions with organoboron reagents.5-6,17 Herein, we report the first example of
palladium-catalyzed tandem addition/cyclization for the synthesis of structurally
diverse 2-substituted indoles (Scheme 1b).
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RESULTS AND DISCUSSION
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Initially, the readily available N-(2-(cyanomethyl)phenyl)acetamide (1a) and
phenylboronic acid (2a) were chosen as model substrates and extensive investigations
were conducted for the screening of reaction conditions including catalysts, ligands,
additives, and solvents. As shown in Table 1, the desired 2-phenylindole (3a) was
isolated in 49% yield when the combination of Pd(OAc)2, 2,2′-bipyridine (L1), and
trifluoroacetic acid (TFA) was employed in THF-H2O under N2 atmosphere (entry 1).
Among the various additives that we screened (entries 2-6), CF3SO3H (TfOH) was the
most effective and gave the highest yield of 63% (entry 4). An investigation of the effect
of the solvent (entries 4 and 7-11) revealed that the use of THF-H2O as the solvent
achieved the best result (63%, entry 4). Replacement of Pd(OAc)2 with other Pd(II)
catalysts, including PdCl2, Pd(CF3CO2H)2, and Pd(acac)2, resulted in lower yields
(entries 4 and 12-14). But this reaction did not work using Pd(0) such as Pd(PPh3)4 as
a catalyst (entry 15). It is generally believed that fluoride could be of particular value
in boronic acid coupling reactions.18 To our delight, the yield increased to 81% when 2
equiv of KF was added in the reaction (entry 16). The choice of ligand play a key role
in transition metal-catalyzed organic reactions. Among bidentate nitrogen ligands (L1-
L6), 5,5'-dimethyl-2,2'-bipyridine (L3) was found to efficiently promote the reaction
and afforded 3a in 91% yield (entry 18). In contrast, little to no product 3a was detected
using steric ligands, such as 6,6'-dimethyl-2,2'-bipyridine (L4) and 2,2'-biquinoline (L5)
as the ligand (entries 19-20). Alternative fluoride sources other than KF proved to be
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less efficient in this transformation (entry 22). The reaction failed to improve the yield
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under an oxygen or air atmosphere (entries 23-24). The reaction did not work if either
Pd catalyst or the ligand was absent (entries 25-26). It is worth noting that the reaction
of 2-(2-aminophenyl)acetonitrile with 2a under the reaction conditions of entry 18
afforded 3a in 43% yield.
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Table 1. Optimization of Reaction Conditionsa
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Having thus identified optimal conditions for the tandem addition/cyclization, we
next examined the scope of arylboronic acids with 1a to test the feasibility of preparing
a variety of 2-arylindoles. As illustrated in Table 2, the reactivity of para-, meta-, and
ortho-tolylboronic acid were evaluated, and the corresponding desired 3b, 3c and 3d,
were isolated in 86%, 81% and 85% yield, respectively. These results demonstrated
that steric effects of substituents had no obvious effects on the reaction. However, a
relatively large sterically hindered arylboronic acid, such as 2,6-dimethylphenylboronic
acid could also be used as the reaction partner, affording the desired product 3e in 33%
yield. The electronic properties of the substituents on the phenyl ring of the arylboronic
acids affected the yields of the reaction to some extent. 2-(4-(tert-Butyl)phenyl)indole
(3f) and 2-(4-methoxyphenyl)indole (3g) were achieved in 83% and 71% yield,
respectively. Introduction of the moderately electron-withdrawing fluoro, chloro,
bromo and iodo group on the phenyl ring of the arylboronic acids were well tolerated,
and the corresponding desired product 3h-3l were obtained in 51-87% yields. It is
noteworthy that these halogen-substituted products are useful handles for further
synthetic elaborations. However, the use of substrates bearing the relatively strong
electron-withdrawing trifluoromethyl and acetyl group at the para-position decreased
the yield of 3m and 3n to 29% and 42%, respectively. Notably, treatment of 1-
naphthylboronic acid with 1a also proceeded smoothly and gave the desired product 3o
in 83% yield.
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Table 2 Synthesis 2-Arylindole Derivativesa
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Next, arylboronic acids were further reacted with different N-(2-
(cyanomethyl)aryl)acetamides bearing bromo or iodo groups under the optimal
conditions to afford a set of diverse bromo- or iodo- substituted indoles in 47-84% yield
(Table
3).
Initially,
the
tandem
reaction
of
N-(4-bromo-2-
(cyanomethyl)phenyl)acetamide (1b) with different arylboronic acids were performed.
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Functional groups such as methyl, methoxy, halogen and naphthyl were well tolerated.
The mono-substituent positions at the phenyl moiety of arylboronic acids were
examined, and the results demonstrated that steric effects of substituents had some
effects on the reaction. For example, 1b reacted with para-, meta- and ortho-
tolylboronic acid efficiently and afforded 4b, 4c, and 4d in 76%, 71%, and 70% yields,
respectively. However, the reaction of 1b with para-, meta- and ortho-
fluorophenylboronic acid was investigated, 79% of 4e and 62% of 4f were isolated,
while the yield of 4g was decreased to 47%. The electronic properties of the substituents
on the phenyl ring of the arylboronic acids affected the yields of the reaction to some
extent. In general, the arylboronic acids bearing an electron-withdrawing substituent
(e.g., F, Cl, Br, and I) (4e, 4h, 4i, and 4j) produced a slightly higher yield of cyclization
products than those analogues bearing an electron-donating substituent (e.g., OMe)
(4k). It is worth noting that 77% yield of 5-bromo-2-(naphthalen-1-yl)indole (4l) was
isolated when 1-naphthboronic acid was used as the substrate. Additionally, other
halogen substituted N-(2-(cyanomethyl)aryl)acetamides were further investigated.
Treatment of N-(4,5-dibromo-2-(cyanomethyl)phenyl)acetamide with PhB(OH)2, p-
(F)C6H4B(OH)2, and p-(OMe)C6H4B(OH)2 under the optimized conditions afforded the
corresponding desired products 4m, 4n, and 4o in 78%, 82%, and 70% yields,
respectively, indicating that the arylboronic acids bearing an electron-withdrawing
substituent (e.g., F) were more favourable than those analogues bearing an electron-
donating substituent (e.g., OMe). Finally, N-(2-(cyanomethyl)-4-iodophenyl)acetamide
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reacted with PhB(OH)2, p-(F)C6H4B(OH)2, and p-(OMe)C6H4B(OH)2 to give the
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corresponding desired products 4p, 4q, and 4r in 60-69% yields. These results revealed
that this protocol shows remarkable chemoselectivity and substrate scope tolerating
bromo, and iodo substituents (commonly used for cross-coupling reactions).
Table 3 Synthesis of Bromo- or Iodo-substituted Indolesa
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The bromo- or iodo-substituted indoles produced by this chemistry should be
amenable for further synthetic elaborations thereby broadening the diversity of
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substituted indoles. For example, the bromo- or iodo- substituted indoles produced by
this strategy can be further functionalized by applying palladium-catalyzed coupling
reactions. We found that 2,5-diphenylindole (5) was obtained in 71% yield from the
coupling reaction of 5-bromo-2-phenylindole with 2a (Scheme 2).
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Scheme 2 Synthetic Elaboration of 4a
To elucidate the reaction mechanism for the formation of indoles, two control
experiments were performed was listed in Scheme 3. The ketone intermediate N-
(2-(2-oxo-2-phenylethyl)phenyl)acetamide (
yield accompanied by the formation of 3a when the reaction time was shortened
to 1 h (Scheme 3a). Additionally, the ketone intermediate was converted into
the desired product 3a in 81% yield under the standard conditions (Scheme 3b),
suggesting that compound is the key intermediate for the transformation.
6) was successfully isolated in 21%
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Scheme 3 Control Experiments
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On the basis of the above mentioned results and relevant reports in the literature, a
possible mechanism for the formation of indoles is proposed in Scheme 4. The first
step may involve the transmetallation between the Pd(II) catalyst and arylboronic acid
to give the Pd-aryl species, which was followed by the coordination of nitrile affording
intermediate A. Next, intramolecular carbopalladation of nitrile generates the imine
Pd(II) complex B. Protonation of the imine Pd(II) complex B by TfOH, which delivers
the ketone or ketimine intermediate C and regenerates the Pd(II) catalyst. Deacetylation
of the ketone or ketimine intermediate C gives the intermediate D under acidic
conditions. Finally, intramolecular cyclization of the intermediate D yields the
corresponding indoles as the desired products. Preliminary mechanistic experiments
indicate that this transformation involves sequential nucleophilic addition followed by
an intramolecular cyclization. However, a detailed mechanism of this transformation
remains unclear at the current stage.
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Scheme 4 Plausible Reaction Mechanism
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CONCLUSIONS
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In summary, we have developed an efficient strategy for the synthesis of structurally
diverse indoles by palladium-catalyzed tandem addition/cyclization of aliphatic nitriles
with arylboronic acids. Especially, this system shows remarkable chemoselectivity and
substrate scope tolerating chloro, fluoro, bromo, and iodo substituents, leading to a
further synthetic elaborations thereby broadening the diversity of the products. Further
studies to extend this catalytic system to the preparation of other N-heterocycles are
currently underway in our laboratories.
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EXPERIMENTAL SECTION
1
General Information. Melting points are uncorrected. H NMR and 13C NMR
spectra were measured on a 500 MHz spectrometer (1H at 500 MHz, 13C at 125 MHz),
using CDCl3 or DMSO-d6 as the solvent with tetramethylsilane (TMS) as an internal
standard at room temperature. Chemical shifts are given n δ relative to TMS, and the
coupling constants J are given in hertz. High-resolution mass spectra were recorded on
an ESI-Q-TOF mass spectrometer. N-(2-(2-oxo-2-phenylethyl)phenyl)acetamide (6)
was synthesized according to the method described in the literature.19 Other
commercially obtained reagents were used without further purification. All reactions
under nitrogen atmosphere were conducted using standard Schlenk techniques. Column
chromatography was performed using EM silica gel 60 (300−400 mesh).
General Procedure for the Synthesis of Indoles. Under N2 atmosphere, nitriles 1 (0.3
mmol), arylboronic acids 2 (0.6 mmol), Pd(OAc)2 (5 mol %), L3 (10 mol %), TfOH
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(10 equiv), KF (2 equiv), THF (1.5 mL), and H2O (2.0 mL) were successively added
into a Schlenk reaction tube. The reaction mixture was stirred vigorously at 80 °C for
48 h. After the reaction equilibrium, the mixture was poured into ethyl acetate, which
was washed with saturated NaHCO3 (2 × 10 mL) and then brine (1 × 10 mL). After the
aqueous layer was extracted with ethyl acetate, the combined organic layers were dried
over anhydrous Na2SO4 and evaporated under vacuum. The residue was purified by
flash column chromatography (petroleum ether/ethyl acetate = 8:1) to afford the desired
products 3a-3o and 4a-4r.
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Typical Procedure for the Synthesis of 2,5-Diphenylindole (5). Under N2
atmosphere, to a 25 mL sealed tube containing 4a (54.4 mg, 0.2 mmol), Pd(PPh3)4 (4.6
mg, 2.0 mol%), phenylboronic acid (27 mg, 0.22 mmol), and K2CO3 (138 mg, 1.0 mmol)
were added DMF (1 mL) and water (1 mL). The reaction mixture was stirred vigorously
o
and heated to 85 C for 12 h. After the reaction mixture was cooled down to room
temperature, aqueous HCl (1.0 M) was added to quench the reaction. The mixture was
then extracted with ethyl acetate (10 mL × 3). All organic fractions were combined and
washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The
resulting crude product was purified by flash column chromatography on silica gel
(petroleum ether/ethyl acetate = 8:1) to afford product 5.
o
2-Phenyl-1H-indole (3a): White solid (52.6 mg, 91%), mp 189-190 C (lit.20 186-
188.6 oC). 1H NMR (500 MHz, DMSO-d6) δ 11.52 (s, 1H), 7.86 (d, J = 7.5 Hz, 2H),
7.53 (d, J = 8.0 Hz, 1H), 7.46 (t, J = 7.5 Hz, 2H), 7.40 (d, J = 8.0 Hz, 1H), 7.31 (t, J =
7.5 Hz, 1H), 7.10 (t, J = 8.0 Hz, 1H), 7.00 (t, J = 7.5 Hz, 1H), 6.90 (s, 1H); 13C NMR
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(125 MHz, DMSO-d6) δ 137.6, 137.1, 132.2, 128.9, 128.6, 127.4, 125.0, 121.5, 120.0,
6
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119.3, 111.3, 98.6.
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o
2-(p-Tolyl)-1H-indole (3b): White solid (53.4 mg, 86%), mp 219.6-220 C (lit.20
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217.9-219.5 oC). 1H NMR (500 MHz, DMSO-d6) δ 11.45 (s, 1H), 7.75 (d, J = 8.0 Hz,
2H), 7.50 (d, J = 8.0 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.27 (d, J = 7.5 Hz, 2H), 7.09-
7.06 (m, 1H), 7.00-6.96 (m, 1H), 6.83 (s, 1H), 2.34 (s, 3H); 13C NMR (125 MHz,
DMSO-d6) δ 138.1, 137.7, 136.7, 129.7, 129.6, 129.4, 125.1, 122.1, 120.5, 120.2, 110.8,
99.4, 21.2.
2-(m-Tolyl)-1H-indole (3c): White solid (50.6 mg, 81%), mp 138-139 oC (lit.21 140-
142 oC). 1H NMR (500 MHz, DMSO-d6) δ11.48 (s, 1H), 7.70 (s, 1H), 7.65 (d, J = 8.0
Hz, 1H), 7.52 (d, J = 7.5 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.34 (t, J = 8.0 Hz, 1H),
7.13 (d, J = 7.5 Hz, 1H), 7.08 (t, J = 8.0 Hz, 1H), 6.99 (t, J = 7.5 Hz, 1H), 2.38 (s, 3H);
13C NMR (125 MHz, DMSO-d6) δ 138.0, 137.7, 137.0, 132.1, 128.8, 128.6, 128.0,
125.5, 122.2, 121.4, 119.9, 119.3, 111.2, 98.5, 21.1.
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2-(o-Tolyl)-1H-indole (3d): Pale-yellow solid (52.7 mg, 85%), mp 93-94 C (lit.21
92-93 oC). 1H NMR (500 MHz, DMSO-d6) δ 11.27 (s, 1H), 7.57-7.55 (m, 2H), 7.41 (d,
J = 8.0 Hz, 1H), 7.35-7.26 (m, 3H), 7.11 (t, J = 7.0 Hz, 1H), 7.01 (t, J = 7.0 Hz,1H),
6.58 (s, 1H), 2.48 (s, 3H); 13C NMR (125 MHz, DMSO-d6) δ 137.3, 135.4, 130.9, 129.0,
128.3, 127.5, 125.9, 121.2, 119.9, 119.0, 111.2, 101.7, 21.0.
2-(2,6-Dimethylphenyl)-1H-indole (3e): Pale-yellow solid (21.8 mg, 33%), mp 144-
145 oC (lit.22 146-147 oC). 1H NMR (500 MHz, DMSO-d6) δ 11.10 (s, 1H), 7.54 (d, J =
8.0 Hz, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.23 (t, J = 7.5 Hz, 1H), 7.15 (d, J = 7.5 Hz, 2H),
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7.09-7.05 (m, 1H), 7.02-6.99 (m, 1H), 8.30-8.29 (m, 1H), 2.12 (s, 6H); 13C NMR (125
MHz, DMSO-d6) δ 137.4, 136.2, 133.4, 128.2, 128.0, 127.1, 120.5, 119.6, 118.7, 111.0,
100.7, 20.3.
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2-(4-(tert-Butyl)phenyl)-1H-indole (3f): White solid (61.8 mg, 83%), mp 198-199 oC
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(lit.23 not reported). H NMR (500 MHz, DMSO-d6) δ 11.47 (s, 1H), 7.78 (d, J = 8.5
Hz, 2H), 7.51 (d, J =8.0 Hz, 1H), 7.47 (d, J = 8.0 Hz, 2H), 7.39 (d, J = 8.0 Hz, 1H),
7.08 (t, J = 7.5 Hz, 1H), 6.98 (t, J = 7.5 Hz, 1H), 6.83 (s, 1H), 1.32 (s, 9H); 13C NMR
(125 MHz, DMSO-d6) δ 149.9, 137.7, 137.0, 129.4, 128.7, 125.6, 124.7, 121.3, 119.8,
119.2, 111.2, 98.1, 34.3, 31.0.
2-(4-Methoxyphenyl)-1H-indole (3g): Pale-yellow solid (47.5 mg, 71%), mp 228-
229 oC. (lit.20 227.4-230.8 oC). 1H NMR (500 MHz, DMSO-d6) δ 11.40 (s, 1H), 7.79 (d,
J = 9.0 Hz, 2H), 7.49 (d, J = 8.0 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.07-7.02 (m, 3H),
6.98-6.95 (m, 1H), 6.76 (s, 1H), 3.80 (s, 3H); 13C NMR (125 MHz, DMSO-d6) δ 158.8,
137.7, 136.9, 128.8, 126.3, 124.9, 121.0, 119.6, 119.2, 114.3, 111.0, 97.3, 55.2 .
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2-(4-Fluorophenyl)-1H-indole (3h): White solid (55.2 mg, 87%), mp 188-189 C
(lit.24 185 oC). 1H NMR (500 MHz, DMSO-d6) δ 11.52 (s, 1H), 7.91-7.88 (m, 2H), 7.52
(d, J = 7.5 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.30 (t, J = 8.5 Hz, 2H), 7.11-7.08 (m,
1H), 7.01-6.98 (m, 1H), 6.86 (s, 1H); 13C NMR (125 MHz, DMSO-d6) δ 162.5, 160.1,
137.1, 136.7, 128.9, 128.6, 127.0, 126.9, 121.5, 120.0, 119.4, 115.9, 115.7, 111.2, 98.6.
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2-(2-Chlorophenyl)-1H-indole (3i): White solid (34.9 mg, 51%), mp 86.3-87 C
(lit.25 86-87 oC) . 1H NMR (500 MHz, DMSO-d6) δ 11.43 (s, 1H), 7.74 (d, J = 7.5 Hz,
1H), 7.61-7.58 (m, 2H), 7.49-7.43 (m, 2H), 7.41-7.37 (m, 1H), 7.14 (t, J = 7.5 Hz, 1H),
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7.03 (t, J = 7.5 Hz, 1H), 6.88 (s, 1H); 13C NMR (125 MHz, DMSO-d6) δ 136.5, 134.2,
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131.3, 131.0, 130.6, 130.5, 129.0, 127.9, 127.4, 121.9, 120.3, 119.3, 111.4, 103.0.
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2-(4-Chlorophenyl)-1H-indole (3j): White solid (55.1 mg, 81%), mp 202-203 C
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(lit.20 206.3-209 oC). 1H NMR (500 MHz, DMSO-d6 ) δ 11.58 (s, 1H), 7.88 (d, J =8.5
Hz, 2H), 7.53 (t, J =7.5 Hz, 3H), 7.40 (t, J = 8.0 Hz, 1H), 7.11 (t, J = 7.5 Hz, 1H), 7.00
(t, J = 7.5 Hz, 1H), 6.93 (s, 1H); 13CNMR (125MHz, DMSO-d6) δ 137.2, 136.3, 131.7,
131.1, 128.9, 128.5, 126.6, 121.8, 120.1, 119.5, 111.3, 99.3.
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2-(4-Bromophenyl)-1H-indole (3k): White solid (58.5 mg, 72%), mp 211-212 C
(lit.25 212-213 oC). 1H NMR (500 MHz, DMSO-d6) δ 11.57 (s, 1H), 7.82-7.80 (m, 2H),
7.66-7.64 (m, 2H), 7.53 (d, J = 7.0 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.12-7.09 (m, 1H),
7.01-6.99 (m, 1H), 6.94 (s, 1H); 13C NMR (125 MHz, DMSO-d6) δ 137.2, 136.4, 131.8,
131.4, 128.5, 126.9, 121.9, 120.3, 120.1, 119.5, 111.3, 99.3.
2-(4-Iodophenyl)-1H-indole (3l): White solid (61.9 mg, 65%), mp 234-235 oC (lit.26
220-222 oC). 1H NMR (500 MHz, DMSO-d6 ) δ 11.57 (s, 1H), 7.82 (d, J = 8.5 Hz, 2H),
7.66 (d, J = 8.0 Hz, 2H), 7.53 (d, J = 8.0 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.11 (t, J =
8.5 Hz, 1H), 7.00 (t, J = 7.5 Hz, 1H), 6.94 (s, 1H); 13C NMR (125 MHz, DMSO-d6) δ
137.6, 137.2, 136.5, 131.7, 128.5, 126.9, 121.9, 120.1, 119.5, 111.3, 99.3, 93.0.
2-(4-(Trifluoromethyl)phenyl)-1H-indole (3m): White solid (22.7 mg, 29%), mp
231-232 oC (lit.24 235-236 oC). 1H NMR (500 MHz, DMSO-d6 ) δ 11.76 (s, 1H), 8.06
(d, J = 7.5 Hz, 2H), 7.79 (d, J = 7.5 Hz, 2H), 7.57-7.45 (m, 2H), 7.18-7.04 (m, 3H); 13C
NMR (125 MHz, DMSO-d6) δ 137.5, 136.1, 135.8, 128.4, 127.4, 127.2, 125.8, 125.7,
125.4, 125.3, 123.2, 122.4, 120.5, 119.6, 111.5, 100.7.
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1-(4-(1H-indol-2-yl)phenyl)ethan-1-one (3n): Pale-yellow solid (29.4 mg, 42%), mp
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203-204 C (lit.20 200.9-202.3 C). H NMR (500 MHz, DMSO-d6) δ 11.69 (s, 1H),
8.04 (d, J = 8.0 Hz, 2H), 8.00(d, J =8.0 Hz, 2H), 7.57 (d, J = 8.0 Hz, 1H), 7.43 (d, J =
8.5 Hz, 1H), 7.14 (t, J = 8.0 Hz, 1H), 7.09 (s, 1H), 7.02 (t, J = 7.5 Hz, 1H), 2.60 (s, 3H);
13C NMR (125 MHz, DMSO-d6) δ 197.1, 137.6, 136.4, 136.3, 135.3, 128.9, 128.5,
124.8, 122.4, 120.4, 119.6, 111.5, 100.8, 26.6.
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2-(Naphthalen-1-yl)-1H-indole (3o): Pale-yellow solid (60.7 mg, 83%), mp 100-101
oC. (lit.27 97-99 oC). 1H NMR (500 MHz, DMSO-d6) δ 11.54 (s, 1H), 8.33-8.31 (m, 1H),
8.04-8.02 (m, 1H), 7.98 (d, J = 8.0 Hz, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.64-7.58 (m, 4H),
7.45 (d, J = 8.0 Hz, 1H), 7.15 (t, J = 7.5 Hz, 1H), 7.06 (t, J = 7.5 Hz, 1H), 6.73 (s, 1H);
13C NMR (125 MHz, DMSO-d6) δ 136.7, 136.4, 133.6, 130.9, 130.8, 128.4, 128.3,
128.1, 127.2, 126.6, 126.1, 125.4, 121.2, 120.0, 119.2, 111.3, 102.4.
o
5-Bromo-2-phenyl-1H-indole (4a): White solid (68.2 mg, 84%), mp 192-193 C.
(lit.25 195-196 oC). 1H NMR (500 MHz, DMSO-d6) δ 11.76 (s, 1H), 7.86 (d, J = 7.5 Hz ,
2H), 7.72 (s , 1H), 7.48 (d, J = 8.0 Hz, 2H), 7.37-7.33 (m, 2H), 7.22-7.20 (m, 1H), 6.90
13
(s, 1H); C NMR (125 MHz, DMSO-d6) δ 139.1, 135.8, 131.6, 130.5, 128.9, 127.8,
125.2,123.9, 122.1, 113.2, 111.8, 98.2.
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5-Bromo-2-(p-tolyl)-1H-indole (4b): White solid (65.4 mg, 76%), mp 239-240 C.
1H NMR (500 MHz, DMSO-d6) δ 11.70(s, 1H), 7.75 (d, J = 8.0 Hz, 2H), 7.69 (d, J =
1.5 Hz, 1H), 7.34 (d, J = 8.5 Hz, 1H), 7.28 (d, J=7.5 Hz, 2H), 7.18 (dd, J1 = 2.0 Hz , J2
= 8.5 Hz, 1H), 6.83 (d, J = 1.5 Hz, 1H), 2.34 (s, 3H); 13C NMR (125 MHz, DMSO-d6)
δ 139.3, 137.3, 135.6, 130.6, 129.5, 128.8, 125.1, 123.7, 121.9, 113.1, 111.7, 97.6, 20.8.
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IR (KBr): 3444, 1540, 1497, 1444, 1308, 1278, 1049, 907, 875, 824, 798, 776, 734, 663,
650 cm-1. HRMS (ESI) calcd for C15H12BrN [M + H]+: 286.0226, found 286.0232.
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5-Bromo-2-(m-tolyl)-1H-indole (4c): White solid (60.6 mg, 71%), mp 143-144 C.
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1H NMR (500 MHz, DMSO-d6) δ 11.71 (s, 1H), 7.70-7.69 (m, 2H), 7.65 (d, J = 7.5 Hz,
1H), 7.37-7.34 (m, 2H), 7.19 (dd, J1 = 2.0 Hz, J2 = 8.5 Hz, 1H), 7.16 (d, J = 7.5 Hz,
1H), 6.86 (s, 1H), 2.38 (s, 3H); 13C NMR (125 MHz, DMSO-d6) δ 139.3, 138.1, 135.7,
131.6, 130.5, 128.8, 128.5, 125.7, 123.8, 122.4, 122.0, 113.2, 111.8, 98.1, 21.1. IR
(KBr): 3437, 1606, 1590, 1566, 1460, 1311, 1175, 1053, 867, 804, 771, 734, 685, 666
cm-1. HRMS (ESI) calcd for C15H12BrN [M + H]+: 286.0226, found 286.0232.
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5-Bromo-2-(o-tolyl)-1H-indole (4d): White solid (60.2 mg, 70%), mp 104-105 C
(lit.28 not reported). 1H NMR (500 MHz, DMSO-d6) δ 11.52 (s, 1H), 7.74 (s ,1H), 7.55-
7.53 (m, 1H), 7.36 (d, J = 8.5 Hz,1H), 7.34-7.29 (m, 3H), 7.21 (d, J = 8.5 Hz, 1H), 6.57
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(s, 1H), 2.46 (s, 3H); C NMR (125 MHz, DMSO-d6) δ 138.9, 135.6, 135.0, 132.0,
130.9, 130.2, 129.1, 127.9, 126.0, 123.6, 122.0, 113.1, 111.6, 101.3, 20.9.
5-Bromo-2-(4-fluorophenyl)-1H-indole (4e): White solid (68.9 mg, 79%), mp 179-
180 oC (lit.29 178-179 oC). 1H NMR (500 MHz, DMSO-d6) δ 11.75 (s, 1H), 7.91-7.88
(m, 2H), 7.71 (d, J = 2.0 Hz, 1H), 7.36-7.31 (m, 3H), 7.21 (dd, J1 = 2.0 Hz, J2 = 8.5
Hz, 1H), 6.86 (d, J = 2.0 Hz, 1H); 13C NMR (125 MHz, DMSO-d6) δ 162.8, 160.8,138.2,
135.8, 130.5, 128.3, 127.3, 127.2, 124.0, 122.1, 116.0, 115.8, 113.2, 111.9, 98.2.
5-Bromo-2-(3-fluorophenyl)-1H-indole (4f): White solid (47.9 mg, 55%), mp 171-
172 oC. 1H NMR (500 MHz, DMSO-d6) δ 11.83 (s, 1H), 7.72-7.70 (m, 3H), 7.52-7.48
(m, 1H), 7.38 (d, J= 8.5 Hz, 1H), 7.23 (dd , J1 = 2.0 Hz, J2 = 8.5 Hz, 1H), 7.18-7.14 (m,
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1H), 6.97 (d, J = 2.0 Hz, 1H); 13C NMR (125 MHz, DMSO-d6) δ 163.6, 161.7, 137.8,
137.7, 135.8, 134.1, 134.0, 131.0, 130.9, 130.2, 124.5, 122.4, 121.3, 121.2, 114.5, 114.3,
113.3, 112.0, 111.8, 111.6, 99.3. IR (KBr): 3753, 3676, 3655, 3425, 1611, 1459, 1309,
1161, 781, 773 cm-1. HRMS (ESI) calcd for C14H9BrFN [M + H]+: 289.9975, found
289.9973.
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5-Bromo-2-(2-fluorophenyl)-1H-indole (4g): White solid (40.9 mg, 47%), mp 133.5-
134 oC. 1H NMR (500 MHz, DMSO-d6) δ 11.71 (s, 1H), 7.93-7.90 (m, 1H), 7.78 (d, J
= 2.0 Hz, 1H), 7.42-7.33 (m, 4H), 7.25 (dd, J1 = 2.0 Hz, J2 = 8.5 Hz, 1H), 6.91 (d, J =
2.0 Hz, 1H); 13C NMR (125 MHz, DMSO-d6) δ 160.0, 158.0, 135.4, 132.9, 130.1, 129.6,
127.9, 125.0, 124.5, 122.4, 119.6, 116.6, 116.4, 113.4, 111.9, 102.0, 101.9. IR (KBr):
3868, 1577, 1456, 1318, 1207, 1175, 1108, 1050, 907, 880, 797, 757, 539, 501 cm-1.
HRMS (ESI) calcd for C14H9BrFN [M + H]+: 289.9975, found 289.9973.
5-Bromo-2-(4-chlorophenyl)-1H-indole (4h): White solid (65.5 mg, 71%), mp
188.5-189 oC. 1H NMR (500 MHz, DMSO-d6) δ 11.81 (s, 1H), 7.88 (d, J = 8.5 Hz, 2H),
7.72 (d, J = 1.5 Hz, 1H), 7.54 (d, J = 8.5 Hz, 2H), 7.36 (d, J = 8.5 Hz, 1H), 7.21 (dd, J1
= 1.5 Hz, J2 = 8.5 Hz, 1H), 6.92 (s, 1H); 13C NMR (125 MHz, DMSO-d6) δ 137.9, 135.8,
132.3, 130.5, 130.4, 129.0, 126.8, 124.3, 122.2, 113.3, 112.0, 98.8. IR (KBr): 3437,
1533, 1480, 1454, 1444, 1411, 1314, 1278, 1172, 1099, 1049, 1003, 908, 864, 791, 721,
665 cm-1. HRMS (ESI) calcd for C14H9BrClN [M + H]+: 305.9680, found 305.9682.
5-Bromo-2-(4-bromophenyl)-1H-indole (4i): White solid, (73.5 mg, 70%), mp
161.7-162 oC. 1H NMR (500 MHz, DMSO-d6) δ 11.82 (s, 1H), 7.79 (d, J = 8.5 Hz, 2H),
7.70(d, J = 1.5 Hz, 1H), 7.66 (d, J = 8.5 Hz, 2H), 7.36 (d, J = 8.5 Hz, 1H), 7.22 (dd, J1
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= 1.5 Hz, J2 = 8.5 Hz, 1H), 6.90 (d, J = 1.5 Hz, 1H); 13C NMR (125 MHz, DMSO-d6) δ
137.9, 135.9, 131.9, 130.9, 130.4, 127.1, 124.3, 122.2, 120.8, 113.3, 112.0, 98.9. IR
(KBr): 3450, 1530, 1487, 1454, 1417, 1314, 1179, 1076, 1046, 1006, 907, 869, 791,
736, 706, 665 cm-1. HRMS (ESI) calcd for C14H9Br2N [M + H]+: 349.9175, found
349.9182.
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5-Bromo-2-(4-iodophenyl)-1H-indole (4j): White solid (79.7 mg, 67%), mp 222.3-
223 oC. 1H NMR (500 MHz, DMSO-d6) δ 11.79 (s, 1H), 7.83 (d, J = 8.5 Hz, 2H), 7.72
(s, 1H), 7.66 (d, J = 8.5 Hz, 2H), 7.35 (d, J = 8.5 Hz, 1H), 7.21 (dd, J1 = 2.0 Hz, J2 =
8.5 Hz, 1H), 6.92 (s, 1H); 13C NMR (125 MHz, DMSO-d6) δ 138.1, 137.7, 135.9, 131.2,
130.4, 127.1, 124.3, 122.2, 113.3, 112.0, 98.8, 93.7. IR (KBr): 3430, 1533, 1460, 1447,
1420, 1318, 1271, 1172, 1056, 998, 907, 880, 824, 784, 736, 661 cm-1. HRMS (ESI)
calcd for C14H9BrIN [M + H]+: 397.9036, found 397.9048.
5-Bromo-2-(4-methoxyphenyl)-1H-indole (4k): Pale-yellow solid (57.0 mg, 63%),
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mp 224-225 C (lit.30 not reported). H NMR (500 MHz, DMSO-d6) δ 11.64 (s, 1H),
7.79 (d, J = 8.5 Hz, 2H), 7.66 (d, J = 2.0 Hz, 1H), 7.32 (d, J = 8.5 Hz, 1H), 7.16 (dd, J1
= 2.0 Hz, J2 = 8.5 Hz, 1H), 7.04 (d, J = 8.5 Hz, 2H), 6.75 (d, J = 2.0 Hz, 1H), 3.80 (s,
3H); 13C NMR (125 MHz, DMSO-d6) δ 159.1, 139.3, 135.6, 130.7, 126.6, 124.2, 123.4,
121.7, 114.4, 112.9, 111.7, 96.9, 55.2.
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MHz, DMSO-d6) δ 11.83 (s, 1H), 8.29-8.27 (m, 1H), 8.04-7.99 (m, 2H), 7.82-7.81 (m,
1H), 7.72-7.71 (m, 1H), 7.64-7.58 (m, 3H), 7.42 (d, J = 8.5 Hz, 1H), 7.27 (dd, J1 = 2.0
Hz, J2 = 8.5 Hz, 1H), 6.74 (d, J = 2.0 Hz, 1H); 13C NMR (125 MHz, DMSO-d6) δ 138.5,
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135.8, 134.0, 131.1, 130.8, 130.7, 129.0, 128.9, 127.9, 127.3, 126.7, 126.0, 125.7, 124.3,
122.7, 113.8, 112.2, 102.5. IR (KBr): 3411, 1729, 1437, 1391, 1321, 1298, 1116, 1049,
902, 869, 804, 788, 781, 686, 665 cm-1. HRMS (ESI) calcd for C18H12BrN [M + H]+:
322.0226, found 322.0223.
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5,7-Bibromo-2-phenyl-1H-indole (4m): White solid (82.1 mg, 78%), mp 163-164 oC.
1H NMR (500 MHz, DMSO-d6) δ 11.60 (s, 1H), 7.98 (d, J = 7.0 Hz, 2H), 7.76 (s, 1H),
7.49-7.46 (m, 3H), 7.38 (t, J = 7.5 Hz, 1H), 6.99 (s, 1H); 13C NMR (125 MHz, DMSO-
d6) δ 141.0, 134.6, 131.5, 131.0, 128.7, 128.3, 126.3, 125.9, 121.6, 111.7, 104.7, 100.2.
IR (KBr): 3427, 2922, 2364, 1742, 1561, 1457, 1340, 1303, 1180, 1072, 897, 842, 759,
724, 680, 514, 484, 442 cm-1. HRMS (ESI) calcd for C14H9Br2N [M + H]+: 349.9175,
found 349.9175.
5,7-Dibromo-2-(4-fluorophenyl)-1H-indole (4n): Pale-yellow solid (90.8 mg, 82%),
o
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mp 165-166 C. H NMR (500 MHz, DMSO-d6) δ 11.64 (s, 1H), 8.04-8.02 (m, 2H),
7.75 (s, 1H), 7.46 (s, 1H), 7.32 (t, J = 8.5 Hz, 2H), 6.96 (s, 1H); 13C NMR (125 MHz,
DMSO-d6) δ 163.1, 161.1, 140.0, 134.6, 131.5, 128.5, 128.4, 127.7, 127.6, 125.9, 121.6,
115.7, 115.5, 111.7, 104.7, 100.1. IR (KBr): 3447, 2923, 1736, 1602, 1539, 1494, 1461,
1335, 1229, 1186, 1070, 828, 779, 711, 573, 430 cm-1. HRMS (ESI) calcd for
C14H8Br2FN [M + H]+: 367.9081, found 367.9081.
5,7-Dibromo-2-(4-methoxyphenyl)-1H-indole (4o): White solid (80.0 mg, 70%), mp
188.5-189 oC. 1H NMR (500 MHz, DMSO-d6) δ 11.51 (s, 1H), 7.92 (d, J = 8.5 Hz, 2H),
7.71 (d, J = 1.5 Hz, 1H), 7.42 (d, J = 1.5 Hz, 1H), 7.04 (d, J = 8.5 Hz, 2H), 6.87 (d, J =
1.5 Hz, 1H), 3.82 (s, 3H); 13C NMR (125 MHz, DMSO-d6) δ 159.4, 141.2, 134.4, 131.8,
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127.7, 125.3, 123.6, 121.2, 114.1, 111.6, 104.5, 98.8, 55.2. IR (KBr): 3411, 1606, 1543,
1497, 1459, 1279, 1253, 1245, 1179, 1027, 940, 870, 850, 822, 774, 734, 710, 665 cm-
1. HRMS (ESI) calcd for C15H11Br2NO [M + H]+: 379.9280, found 379.9296.
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5-Iodo-2-phenyl-1H-indole (4p): White solid (66.4 mg, 69%), mp 237-238 C. H
NMR (500 MHz, DMSO-d6) δ 11.72 (s, 1H), 7.89 (s,1H), 7.85 (d, J = 8.5 Hz, 2H), 7.47
(t, J = 8.0 Hz, 2H), 7.36-7.32 (m, 2H), 7.26 (d, J = 8.0 Hz, 1H), 6.86 (s, 1H); 13C NMR
(125 MHz, DMSO-d6) δ 138.7, 136.1, 131.6, 131.4, 129.4, 128.9, 128.3, 127.8, 125.2,
113.7, 97.9, 83.0. IR (KBr): 3432, 2922, 2809, 2318, 1451, 1388, 796, 761, 505 cm-1.
HRMS (ESI) calcd for C14H10IN [M + H]+: 319.9931, found 319.9935.
2-(4-Fluorophenyl)-5-iodo-1H-indole (4q): White solid (65.9 mg, 65%), mp 186-187
oC (lit.31 174-175 C). 1H NMR (500 MHz, DMSO-d6) δ 11.72 (s, 1H), 7.90-7.88 (m,
o
3H), 7.36-7.33 (m, 3H), 7.25 (d, J = 8.5 Hz, 1H), 6.84 (m, 1H); 13C NMR (125 MHz,
DMSO-d6) δ 162.7, 160.8, 137.7, 136.1, 131.4, 129.4, 128.3, 127.3, 127.2, 116.0, 115.8,
113.7, 97.9, 83.1.
5-Iodo-2-(4-methoxyphenyl)-1H-indole (4r): White solid (63.4 mg, 60%), mp 195-
196 C (lit.32 not reported). H NMR (500 MHz, DMSO-d6) δ 11.60 (s, 1H), 7.84 (s,
1H), 7.77 (d, J = 8.5 Hz, 2H), 7.31 (d, J = 8.5 Hz, 1H), 7.22 (d, J = 8.5 Hz, 1H), 7.03
(d, J = 8.5 Hz, 2H), 6.71 (s, 1H), 3.80 (s, 3H); 13C NMR (125 MHz, DMSO-d6) δ 159.1,
138.8, 135.9, 131.6, 128.9, 127.9, 126.6, 124.2, 114.4, 113.5, 96.5, 82.9, 55.2.
2,5-Diphenyl-1H-indole (5): White solid (57.8 mg, 71%), mp 191-192 oC (lit.33 192-
193 oC). 1H NMR (500 MHz, DMSO-d6) δ 11.60 (s, 1H), 7.88 (d, J = 7.5 Hz, 2H), 7.80
o
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(s, 1H), 7.68 (d, J = 7.5 Hz, 2H), 7.49-7.40 (m, 6H), 7.35-7.29 (m, 2H), 6.97 (s, 1H);
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13C NMR (125 MHz, DMSO-d6) δ 141.8, 138.4, 136.8, 132.1, 131.9, 129.2, 128.9,
128.7, 127.5, 126.6, 126.2, 125.0, 121.0, 118.0, 111.7, 99.1.
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N-(2-(2-oxo-2-phenylethyl)phenyl)acetamide (6): Pale-red solid, mp 99-100 oC (lit.19
not reported). 1H NMR (500 MHz, DMSO-d6) δ 9.35 (s, 1H), 8.01 (d, J = 7.5 Hz, 2H),
7.65 (t, J = 7.5 Hz, 1H), 7.54 (t, J = 7.5 Hz, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.23 (t, J =
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7.5 Hz, 2H), 7.13 (t, J = 7.5 Hz, 2H),4.40 (s, 2H), 1.92 (s, 3H); C NMR (125MHz,
DMSO-d6) δ 197.4, 168.2, 136.8, 136.7, 133.1, 131.2, 129.8, 128.6, 128.1, 126.9, 125.4,
125.0, 41.3, 23.1.
ASSOCIATED CONTENT
Supporting Information
1H and 13C NMR spectra for all products. This material is available free of charge via
the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: jiuxichen@wzu.edu.cn
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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We thank the National Natural Science Foundation of China (Nos. 21572162 and
21472140), Natural Science Foundation of Zhejiang Province (No. LY16B020012),
Science and Technology Project of Zhejiang Province (No. 2016C31022) and the
Xinmiao Talent Planning Foundation of Zhejiang Province (Nos. 2016R426059 and
2016R426058) for financial support.
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