Palladium-catalyzed tandem addition/cyclization in aqueous medium: Synthesis of 2-arylindoles

Article abstract of DOI:10.1039/c7ob00572e

An efficient protocol to construct 2-arylindoles was developed through palladium-catalyzed tandem addition/cyclization of potassium aryltrifluoroborates with aliphatic nitriles in aqueous medium. The use of water as the reaction medium makes the synthesis process environmentally benign. A plausible mechanism for the formation of 2-arylindoles involving sequential nucleophilic addition followed by an intramolecular cyclization is proposed. Moreover, the utility of this catalytic tandem transformation was also demonstrated in an efficient gram-scale synthesis. This method provides an alternative synthetic tool for accessing a more diverse array of 2-arylindoles.

Full text of DOI:10.1039/c7ob00572e

Organic &
Biomolecular Chemistry
View Article Online
View Journal
PAPER
Palladium-catalyzed tandem addition/cyclization
in aqueous medium: synthesis of 2-arylindoles†
Cite this: DOI: 10.1039/c7ob00572e
Shuling Yu, Kun Hu, Julin Gong, Linjun Qi, Jianghe Zhu, Yetong Zhang,
Tianxing Cheng* and Jiuxi Chen
*
An efficient protocol to construct 2-arylindoles was developed through palladium-catalyzed tandem
addition/cyclization of potassium aryltrifluoroborates with aliphatic nitriles in aqueous medium. The use
of water as the reaction medium makes the synthesis process environmentally benign. A plausible mech-
anism for the formation of 2-arylindoles involving sequential nucleophilic addition followed by an intra-
molecular cyclization is proposed. Moreover, the utility of this catalytic tandem transformation was also
demonstrated in an efficient gram-scale synthesis. This method provides an alternative synthetic tool for
accessing a more diverse array of 2-arylindoles.
Received 7th March 2017,
Accepted 20th March 2017
DOI: 10.1039/c7ob00572e
rsc.li/obc
Transition-metal-catalyzed transformations of the readily
available nitriles would provide an attractive route for the for-
Introduction
Nitrogen-containing heterocycles are ubiquitous in a wide mation of novel carbon–carbon and carbon–heteroatom bonds
variety of bioactive natural products and biological molecules in both the organic chemistry research and fine chemical
that may be good drug candidates.1 In particular, 2-arylindoles industry.8 It is well known, however, that nitriles (e.g. aceto-
and their derivatives represent a medicinally and pharmaceuti- nitrile or benzonitrile) have been used as solvents or ligands
cally important class of heterocyclic motifs that are found as in organometallic reactions presumably due to the inherently
the core structural skeletons in a variety of drug molecules inert nature of nitriles.9 Inspired by the pioneering works of
such as zindoxifene,2 NSC-370875,3 and L-838751 4 (Fig. 1). Larock10 concerning the addition of arylpalladium species to
Not only indole motifs are present in a variety of products with the cyano group and remarkable progress in recent years,11 we
functional significance, but they can be used as an important envisioned that 2-arylindoles might be assembled by Pd-cata-
class of molecular building blocks in organic chemistry for the lyzed tandem addition/cyclization of functionalized nitriles
synthesis of other N-heterocycles.5 Therefore, the development with arylation reagents. Recently, we have also developed the
of effective methods for the preparation of 2-arylindoles has palladium-catalyzed synthesis of alkyl aryl ketones,12a,b benzo-
received much attention during the past several decades. In furans,12a–c 2-aminobenzophenones12d and N-heterocyclic
this context, two strategies for the synthesis of 2-arylindoles compounds12e–g by catalytic carbopalladation of nitriles.
have been developed: first, the introduction of substituents by However, the use of nitriles as reaction partners in the syn-
direct selective C-2 arylation of a preexisting indole ring;6 thesis of indoles has rarely been reported,13 even though the
second, the assembly of the functionalized pyrrole nucleus on prevalence of transformation of nitriles into a wide range of
a benzenoid scaffold.7
functional groups has been well-established.
Although arylboronic acids have advantages of low toxicity,
air- and moisture-stability, they often dimerize and trimerize
to the corresponding anhydrides and boroxines with loss of
water, which result in difficulties in purification and determi-
nation of precise stoichiometry.14 Additionally, a large excess
of arylboronic acids is often required because they easily gene-
rate protodeboronation and homocoupling products. Recently,
potassium aryltrifluoroborates have been focused as attractive
and promising alternatives to arylboronic acids because of
their superior features. Perhaps most importantly, the tetra-
coordinate nature of potassium aryltrifluoroborates, anchored
by exceptionally strong boron–fluorine bonds, makes them
inherently inert to many of the most common reagents utilized
Fig. 1 Representative bioactive 2-arylindole derivatives.
College of Chemistry & Materials Engineering, Wenzhou University, Wenzhou
325035, P. R. China. E-mail: jiuxichen@wzu.edu.cn, chengtx_wzu@163.com
†Electronic supplementary information (ESI) available: 1H and 13C NMR spectra
for products. See DOI: 10.1039/c7ob00572e
This journal is © The Royal Society of Chemistry 2017
Org. Biomol. Chem.

View Article Online
Paper
Organic & Biomolecular Chemistry
Table 1 Optimization of reaction conditionsa
Scheme 1 Palladium-catalyzed one-pot synthesis of 2-arylindoles.
in organic synthesis. To our knowledge, the application of
potassium aryltrifluoroborates in transition-metal-catalyzed
addition of nitriles for the synthesis of 2-arylindoles has not
been reported thus far.
Entry [Pd]
Ligand Additive
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
Pd(OAc)2
L1
L1
L1
L1
L1
L1
L2
L3
L4
L5
L6
L2
L2
L2
L2
L2
L2
L2
TsOH·H2O Toluene
TsOH·H2O DMF
TsOH·H2O THF
21
24
35
48c
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
Additionally, water as a reaction medium for green chem-
istry has recently attracted considerable attention in organic
synthesis due to its environmental acceptability, abundance,
safety and low cost, and would thus be highly advantageous
alternatives to organic solvents from both economical and eco-
logical standpoints.15 This work forms part of the continuing
efforts in our laboratory toward the development of novel tran-
sition metal-catalyzed addition or coupling reactions with
organoboron reagents12,16 and the synthesis of N-heterocycles.17
Herein, we report a simple and efficient protocol for the
synthesis of 2-arylindoles by palladium-catalyzed tandem
addition/cyclization of 2-(2-aminoaryl)acetonitriles with potas-
sium aryltrifluoroborates in aqueous medium (Scheme 1).
TsOH·H2O THF/H2O
TsOH·H2O EtOH/H2O 52c
TsOH·H2O H2O
TsOH·H2O H2O
TsOH·H2O H2O
TsOH·H2O H2O
TsOH·H2O H2O
TsOH·H2O H2O
CH3CO2H H2O
CF3CO2H
TfOH
NsOH
CAS
65
71
69
0
Trace
26
Trace
19
38
62
37
Trace
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
H2O
H2O
H2O
H2O
H2O
HCl
TsOH·H2O H2O
TsOH·H2O H2O
TsOH·H2O H2O
TsOH·H2O H2O
TsOH·H2O H2O
TsOH·H2O H2O
TsOH·H2O H2O
TsOH·H2O H2O
51
Pd(CF3CO2)2 L2
72
Pd(acac)2
Pd(PPh3)4
Pd(dba)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
L2
L2
L2
L2
L2
L2
75 (52d, 83e)
0
0
85f
92g
71h
Results and discussion
We started our investigation employing readily available 2-(2-
aminophenyl)acetonitrile (1a) and potassium phenyltrifluoro-
borate (2a) as model substrates to obtain the optimal reaction
conditions (Table 1).
a Conditions: 1a (0.3 mmol), 2a (0.6 mmol), [Pd] (5 mol%), ligand
(10 mol%), additive (10 equiv.), solvent (3 mL), 80 °C, 48 h, N2.
b Isolated yield. c THF or EtOH (2.5 mL)/H2O (0.5 mL). d TsOH·H2O (5
equiv.). e TsOH·H2O (15 equiv.). f H2O (2 mL). g H2O (1 mL). h In air.
Encouragingly, we found that the model reaction proceeded
in the presence of Pd(OAc)2, 2,2′-bipyridine (L1) and p-toluene-
sulfonic acid monohydrate (TsOH·H2O) in toluene to give the
With the optimized reaction conditions in hand, we next
desired product 3a in 21% yield (entry 1). Through further proceeded to examine the substrate scope (Table 2). First, the
optimization of the reaction conditions, we discovered that the reaction of various potassium aryltrifluoroborates with 2-(2-
yield of 3a was improved to 71% when 4,4′-dimethyl-2,2′-bipyri- aminophenyl)acetonitrile (1a) was investigated under standard
dine (L2) was used as the ligand in water (entry 7). Other larger conditions (3a–3n). A wide variety of substituted potassium
steric bidentate nitrogen ligands, such as 6,6′-dimethyl-2,2′- aryltrifluoroborates are reactive. The reactivity of para-, meta-,
bipyridine (L4) and 2,2′-biquinoline (L5) affected the tandem and ortho-tolyltrifluoroborate were evaluated, and the results
reaction adversely (entries
9 and 10). Replacement of demonstrated that steric effects of substituents had some
TsOH·H2O with other additives, including CH3CO2H, effects on the reaction. For example, the reaction of 1a with
CF3CO2H, CF3SO3H (TfOH), p-nitrobenzenesulfonic acid para-tolyltrifluoroborate gave 90% yield of 3b, while the ortho-
(NsOH), D-camphorsulfonic acid (CSA) and HCl, led to lower and meta-tolyltrifluoroborate afforded the desired products 3c
yields (entries 12–17). A variety of Pd(II) salts are reactive, with and 3d with diminished yields of 82% and 71%, respectively.
Pd(acac)2 being the optimal choice (entries 18–20). In contrast, The same phenomenon was observed in the reaction of 1a
this reaction did not work using Pd(0) such as Pd(dba)2 or Pd with para-, ortho-and meta-fluorophenyltrifluoroborate,
(PPh3)4 as a catalyst (entries 21 and 22). Decreasing the affording the desired products 3e, 3f and 3g in 81%, 58% and
amount of TsOH afforded the desired product 3a in lower yield 63% yields, respectively. Electron deficient potassium aryltri-
(entry 20). We were delighted to find that the yield increased to fluoroborates bearing fluoro (3e–3g), chloro (3h), bromo (3i)
85–92% when the reaction was run at higher concentration by and iodo (3j) groups reacted under these conditions to afford
reducing the quantity of the solvent (entries 23 and 24). The the desired products in moderate to good yields. Both strongly
reaction failed to improve the yield of 3a in air (entry 25). It electron-donating (e.g., –OMe) and electron-withdrawing (e.g.,
should also be noted that no reactivity was observed in the –Ac) groups were compatible with this reaction, affording the
absence of either Pd(acac)2 or the ligand.
corresponding products 3k and 3l in 48% and 31% yields,
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2017

View Article Online
Organic & Biomolecular Chemistry
Paper
Table 2 Synthesis of 2-arylindolesa
isolated yield, albeit with a prolonged reaction time (60 h)
(Scheme 2).
The 2-arylindoles produced by this chemistry should be
amenable for further synthetic applications. For example, sub-
strate 3a smoothly underwent the Baeyer–Villiger oxidation,5d
Baeyer–Villiger oxidation/amination5e and sulfenylation18
(Scheme 3), affording the corresponding products 2-phenyl-
benzoxazinone (4a), 2-phenylquinazolinone (5a) and 2-phenyl-
3-(phenylthio)-1H-indole (6a) in moderate to good yields.
To elucidate the reaction mechanism of the formation of
2-arylindoles, several control experiments were performed
under the standard conditions as shown in Scheme 4. We
found that indolin-2-one (7a) was obtained in 13% yield if
potassium aryltrifluoroborate was absent (Scheme 4a). However,
the reaction failed to afford the desired product 3a when the
reaction of 7a with 2a was performed (Scheme 4b). Our efforts
to isolate the ketone intermediate 2-(2-aminophenyl)-1-phenyl-
ethan-1-one (8a) have been unsuccessful. Alternatively, acetyl-
ation substrate N-(2-(2-oxo-2-phenylethyl)phenyl)acetamide (8b)
was prepared according to the literature procedure.19 The
Scheme 2 Gram-scale synthesis of 3a.
a Conditions: 1 (0.3 mmol), 2 (0.6 mmol), Pd(acac)2 (5 mol%), L2
(10 mol%), TsOH·H2O (10 equiv.), H2O (1 mL), 80 °C, 48 h, N2.
Isolated yield.
respectively. Notably, the treatment of naphthyl-substituted
substrates with 1a also proceeded smoothly and delivered the
desired product 3m and 3n in 81% and 72% yields, respect-
ively. Next, we turned our attention to the scope of other 2-(2-
aminoaryl)acetonitriles under the standard conditions (3o–3x).
As shown in Table 2, the reaction worked well with bromo or
iodo-substituted substrates (commonly used for cross-coupling
reactions), and gave the corresponding products 3o–3w in
50–75% yields. It is worth noting that the presence of the
halogen (Br, I) in the products is very useful for further syn-
thetic elaborations. Finally, the reaction between 2-(2-(methyl-
amino)phenyl)acetonitrile and 2a was performed, affording
the desired product 3x in 37% yield.
Scheme 3 Applications in organic synthesis.
Additionally, the efficiency of this catalytic system was
further demonstrated by running the reaction on a laboratory
preparative scale. For example, we conducted the reaction
on a gram scale (10 mmol), and 3a was obtained in 81% Scheme 4 Control experiments.
This journal is © The Royal Society of Chemistry 2017
Org. Biomol. Chem.

View Article Online
Paper
Organic & Biomolecular Chemistry
spectrometer using DMSO-d6 or CDCl3 as the solvent with
tetramethylsilane (TMS) as an internal standard at room temp-
erature. Chemical shifts are given in δ relative to TMS, and the
coupling constants J are given in hertz. High-resolution mass
spectrometry (HRMS) was performed with a TOF MS instru-
ment with an ESI source. N-(2-(2-Oxo-2-phenylethyl)phenyl)
acetamide was prepared according to the literature pro-
cedures.19 Other commercially obtained reagents were used
without further purification. Column chromatography was per-
formed using EM silica gel 60 (300–400 mesh).
General procedure for palladium-catalyzed tandem synthesis
of 2-arylindoles
Under a N2 atmosphere, 2-(2-aminophenyl)acetonitriles 1
(0.3 mmol), potassium aryltrifluoroborates 2 (0.6 mmol), Pd
(acac)2 (5 mol%), L2 (10 mol%), TsOH·H2O (10 equiv.), and
H2O (1 mL) were successively added into a Schlenk reaction
tube. The reaction mixture was stirred vigorously at 80 °C for
48 h. After the reaction reached 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 evapor-
ated under vacuum. The filtrate was concentrated in vacuo and
purified by a silica gel packed flash chromatography column
with petroleum ether/ethyl acetate (8 : 1) as the eluent to afford
the desired products.
2-Phenyl-1H-indole (3a). White solid (53.4 mg, 92%), mp
189–190 °C (lit.20 186–188.6 °C). 1H NMR (500 MHz, CDCl3)
δ 8.34 (s, 1H), 7.68–7.64 (m, 3H), 7.47–7.41 (m, 3H), 7.34 (t, J =
7.5 Hz, 1H), 7.21 (t, J = 7.5 Hz, 1H), 7.14 (t, J = 7.5 Hz, 1H),
6.84 (d, J = 2.0 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 137.9,
136.8, 132.4, 129.3, 129.0, 127.7, 125.2, 122.4, 120.7, 120.3,
110.9, 100.0.
2-(p-Tolyl)-1H-indole (3b). White solid (56.0 mg, 90%), mp
219.6–220 °C (lit.20 217.9–219.5 °C). 1H NMR (500 MHz,
CDCl3) δ 8.29 (s, 1H), 7.61 (d, J = 7.5 Hz, 1H), 7.54 (d, J =
8.0 Hz, 2H), 7.37 (d, J = 8.5 Hz, 1H), 7.25–7.23 (m, 2H), 7.18
(t, J = 8.0 Hz, 1H), 7.11 (t, J = 7.5 Hz, 1H), 6.78 (s, 1H), 2.38
(s, 3H); 13C NMR (125 MHz, CDCl3) 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,
21.3.
2-(o-Tolyl)-1H-indole (3c). White solid (51.0 mg, 82%),
mp 93–94 °C (lit.21 92–93 °C). 1H NMR (500 MHz, CDCl3)
δ 8.12 (s, 1H), 7.67–7.64 (m, 1H), 7.47–7.45 (m, 1H), 7.40 (d, J =
8.0 Hz, 1H), 7.32–7.27 (m, 3H), 7.23–7.19 (m, 1H), 7.15–7.12
(m, 1H), 6.61 (s, 1H), 2.50 (s, 3H); 13C NMR (125 MHz, CDCl3)
δ 137.5, 136.2, 136.1, 132.7, 131.1, 129.0, 128.9, 128.0, 126.1,
122.1, 120.6, 120.1, 110.8, 103.0, 21.1.
Scheme 5 Possible mechanism for the formation of 2-arylindoles.
desired product 3a was obtained in good yield via cyclization/
deacetylation using 8b as a surrogate of 8a (Scheme 4c).
On the basis of the above experimental results and relevant
reports in the literature, a possible reaction mechanism for the
formation of 2-arylindoles is illustrated in Scheme 5 (1a as a
representative example). The following key steps are included
in the catalytic pathway: (i) transmetallation between the palla-
dium catalyst and potassium aryltrifluoroborates 2 to form the
palladium-aryl species A, which was followed by (ii) the coordi-
nation of 1a to generate intermediate B; (iii) carbopalladation
of 1a to give the corresponding ketimine palladium intermedi-
ate C; (iv) protonation of the intermediate C by TsOH to afford
the ketone or ketimine intermediate D and regenerates an
active palladium species. Finally, intramolecular cyclization of
the intermediate D under acidic conditions readily achieves
2-arylindoles 3 as the desired products. A plausible mechan-
ism for the formation of 2-arylindoles involving sequential
nucleophilic addition followed by an intramolecular cycliza-
tion is proposed. However, a detailed mechanism of this trans-
formation remains unclear at the current stage.
Conclusions
In conclusion, we have developed a Pd-catalyzed tandem
addition/cyclization of potassium aryltrifluoroborates with ali-
phatic nitriles in aqueous medium. This protocol provides an
alternative synthetic pathway to access 2-arylindoles. Further
studies to extend this catalytic system to the preparation of
other useful N-heterocyclic compounds are currently underway
in our laboratories.
2-(m-Tolyl)-1H-indole (3d). Pale-yellow solid (44.2 mg, 71%),
mp 138–139 °C (lit.22 140–142 °C). H NMR (500 MHz, CDCl3)
δ 8.34 (s, 1H), 7.64 (d, J = 7.5 Hz, 1H), 7.50–7.47 (m, 2H), 7.41
(d, J = 8.0 Hz, 1H), 7.35 (t, J = 7.5 Hz, 1H), 7.21 (t, J = 7.5 Hz,
1
Experimental section
General methods
All commercial reagents were used without further purification 1H), 7.17–7.12 (m, 2H), 6.83 (d, J = 2.0 Hz, 1H), 2.44 (s, 3H);
unless otherwise noted. Melting points are uncorrected. 1H 13C NMR (125 MHz, CDCl3) δ 138.7, 138.1, 136.8, 132.3, 129.3,
NMR and 13C NMR spectra were recorded on a 500 MHz 128.9, 128.6, 125.9, 122.3, 122.2, 120.6, 120.2, 110.9, 99.9, 21.5.
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2017

View Article Online
Organic & Biomolecular Chemistry
Paper
2-(4-Fluorophenyl)-1H-indole (3e). White solid (51.5 mg, δ 197.1, 137.6, 136.4, 136.3, 135.3, 128.9, 128.5, 124.8, 122.4,
81%), mp 188–189 °C (lit.23 185 °C). 1H NMR (500 MHz, 120.4, 119.6, 111.5, 100.8, 26.6.
CDCl3) δ 8.26 (s, 1H), 7.64–7.60 (m, 3H), 7.40 (d, J = 8.0 Hz,
2-(Naphthalen-1-yl)-1H-indole (3m). Pale-yellow solid
1H), 7.21 (t, J = 7.0 Hz, 1H), 7.17–7.13 (m, 3H), 6.77–6.76 (m, (59.3 mg, 81%), mp 100–101 °C (lit.27 97–99 °C). 1H NMR
1H); 13C NMR (125 MHz, CDCl3) δ 163.4, 161.4, 137.0, 136.8, (500 MHz, DMSO-d6) δ 11.54 (s, 1H), 8.33–8.31 (m, 1H),
129.3, 128.7, 126.8, 126.9, 122.4, 120.7, 120.4, 116.2, 116.0, 8.04–8.02 (m, 1H), 7.98 (d, J = 8.0 Hz, 1H), 7.71 (d, J = 8.0 Hz,
110.9, 110.0.
1H), 7.64–7.58 (m, 4H), 7.45 (d, J = 8.0 Hz, 1H), 7.15 (t, J =
2-(2-Fluorophenyl)-1H-indole (3f). White solid, (36.9 mg, 7.5 Hz, 1H), 7.06 (t, J = 7.5 Hz, 1H), 6.73 (s, 1H); 13C NMR
58%), mp 96–97 °C (lit.24 97–98.5 °C). 1H NMR (500 MHz, (125 MHz, DMSO-d6) δ 136.7, 136.4, 133.6, 130.9, 130.8, 128.4,
DMSO-d6) δ 11.53 (s, 1H), 7.93 (s, 1H), 7.58–7.34 (m, 5H), 128.3, 128.1, 127.2, 126.6, 126.1, 125.4, 121.2, 120.0, 119.2,
7.14–6.93 (m, 3H); 13C NMR (125 MHz, DMSO-d6) δ 159.9, 111.3, 102.4.
157.9, 136.7, 131.3, 129.0, 128.9, 128.3, 127.7, 124.9, 122.0,
120.3, 120.1, 119.4, 116.5, 111.4, 102.5, 102.4.
2-(Naphthalen-2-yl)-1H-indole (3n). White solid (52.7 mg,
1
72%), mp 167–168 °C (lit.28 163–165 °C). H NMR (500 MHz,
2-(3-Fluorophenyl)-1H-indole (3g). White solid, (40.2 mg, DMSO-d6) δ 11.74 (s, 1H), 8.40 (s, 1H), 8.05–8.03 (m, 1H),
63%), mp 142–143 °C (lit.23 144 °C). 1H NMR (500 MHz, 7.98–7.91 (m, 3H), 7.58–7.54 (m, 2H), 7.52–7.46 (m, 2H), 7.14
CDCl3) δ 8.24 (s, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.39–7.34 (t, J = 7.0 Hz, 1H), 7.05–7.02 (m, 2H); 13C NMR (125 MHz,
(m, 3H), 7.31–7.29 (m, 1H), 7.20 (t, J = 7.5 Hz, 1H), 7.12 (t, J = DMSO-d6) δ 137.6, 137.4, 133.3, 132.3, 129.7, 128.7, 128.4,
7.0 Hz, 1H), 7.01–6.97 (m, 1H), 6.81 (d, J = 2.0 Hz, 1H); 127.8, 127.7, 126.7, 126.0, 123.8, 122.8, 121.8, 120.1, 119.4,
13C NMR (125 MHz, CDCl3) δ 164.3, 162.3, 137.0, 136.7, 136.6, 111.3, 99.6.
134.6, 134.5, 130.6, 130.5, 129.1, 122.9, 120.9, 120.8, 120.7,
120.5, 114.6, 114.4, 112.2, 112.0, 111.1, 100.9.
5-Bromo-2-phenyl-1H-indole (3o). White solid (61.3 mg,
1
75%), mp 192–193 °C (lit.25 195–196 °C). H NMR (500 MHz,
2-(4-Chlorophenyl)-1H-indole (3h). White solid (52.1 mg, DMSO-d6) δ 11.76 (s, 1H), 7.86 (d, J = 7.5 Hz, 2H), 7.72 (s, 1H),
76%), mp 202–203 °C (lit.20 206.3–209 °C). 1H NMR (500 MHz, 7.48 (d, J = 8.0 Hz, 2H), 7.37–7.33 (m, 2H), 7.22–7.20 (m, 1H),
CDCl3) δ 8.29 (s, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.58 (d, J = 6.90 (s, 1H); 13C NMR (125 MHz, DMSO-d6) δ 139.1, 135.8,
8.5 Hz, 2H), 7.42–7.39 (m, 3H), 7.23–7.20 (m, 1H), 7.14 (t, J = 131.6, 130.5, 128.9, 127.8, 125.2, 123.9, 122.1, 113.2, 111.8,
8.0 Hz, 1H), 6.82 (d, J = 2.0 Hz, 1H); 13C NMR (125 MHz, 98.2.
CDCl3) δ 136.9, 136.7, 133.6, 130.9, 129.1, 129.2, 126.3, 122.7,
120.8, 120.5, 111.0, 100.5.
5-Bromo-2-(p-tolyl)-1H-indole (3p). White solid (62.9 mg,
73%), mp 239–240 °C. H NMR (500 MHz, DMSO-d6) δ 11.70
1
2-(4-Bromophenyl)-1H-indole (3i). White solid (58.0 mg, (s, 1H), 7.75 (d, J = 8.0 Hz, 2H), 7.69 (d, J = 1.5 Hz, 1H), 7.34 (d,
1
71%), mp 211–212 °C (lit.25 212–213 °C). H NMR (500 MHz, J = 8.5 Hz, 1H), 7.28 (d, J = 7.5 Hz, 2H), 7.18 (dd, J1 = 2.0 Hz,
CDCl3) δ 8.30 (s, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.58–7.52 J2 = 8.5 Hz, 1H), 6.83 (d, J = 1.5 Hz, 1H), 2.34 (s, 3H); 13C NMR
(m, 4H), 7.40 (d, J = 8.0 Hz, 1H), 7.21 (t, J = 8.0 Hz, 1H), 7.13 (125 MHz, DMSO-d6) δ 139.3, 137.3, 135.6, 130.6, 129.5, 128.8,
(t, J = 7.5 Hz, 1H), 6.83 (d, J = 2.0 Hz, 1H); 13C NMR (125 MHz, 125.1, 123.7, 121.9, 113.1, 111.7, 97.6, 20.8. IR (KBr): 3444,
CDCl3) δ 136.9, 136.7, 132.2, 131.4, 129.2, 126.6, 122.7, 121.5, 1540, 1497, 1444, 1308, 1278, 1049, 907, 875, 824, 798, 776,
120.8, 120.5, 110.9, 100.6.
734, 663, 650 cm−1. HRMS (ESI) calcd for C15H12BrN [M + H]+:
2-(4-Iodophenyl)-1H-indole (3j). White solid (61.9 mg, 65%), 286.0226, found 286.0232.
1
mp 234–235 °C (lit.26 220–222 °C). H NMR (500 MHz, CDCl3)
5-Bromo-2-(4-fluorophenyl)-1H-indole (3q). White solid
δ 8.31 (s, 1H), 7.76 (d, J = 8.5 Hz, 2H), 7.63 (d, J = 8.0 Hz, 1H), (55.8 mg, 64%), mp 179–180 °C (lit.29 178–179 °C). 1H NMR
7.40 (d, J = 8.5 Hz, 3H), 7.23–7.20 (m, 1H), 7.13 (t, J = 7.5 Hz, (500 MHz, DMSO-d6) δ 11.75 (s, 1H), 7.91–7.88 (m, 2H), 7.71
1H), 6.84 (d, J = 2.0 Hz, 1H); 13C NMR (125 MHz, CDCl3) (d, J = 2.0 Hz, 1H), 7.36–7.31 (m, 3H), 7.21 (dd, J1 = 2.0 Hz, J2 =
δ 138.1, 136.9, 136.7, 131.9, 129.2, 126.8, 122.8, 120.8, 120.5, 8.5 Hz, 1H), 6.86 (d, J = 2.0 Hz, 1H); 13C NMR (125 MHz,
111.0, 100.6, 92.8.
2-(4-Methoxyphenyl)-1H-indole (3k). Pale-yellow solid 127.2, 124.0, 122.1, 116.0, 115.8, 113.2, 111.9, 98.2.
(32.3 mg, 48%), mp 228–229 °C (lit.20 227.4–230.8 °C).
5-Bromo-2-(4-chlorophenyl)-1H-indole (3r). White solid
1H NMR (500 MHz, DMSO-d6)
11.40 (s, 1H), 7.79 (56.1 mg, 61%), mp 188.5–189 °C. H NMR (500 MHz, DMSO-
DMSO-d6) δ 162.8, 160.8, 138.2, 135.8, 130.5, 128.3, 127.3,
1
δ
(d, J = 9.0 Hz, 2H), 7.49 (d, J = 8.0 Hz, 1H), 7.37 (d, J = 8.0 Hz, d6) δ 11.81 (s, 1H), 7.88 (d, J = 8.5 Hz, 2H), 7.72 (d, J = 1.5 Hz,
1H), 7.07–7.02 (m, 3H), 6.98–6.95 (m, 1H), 6.76 (s, 1H), 1H), 7.54 (d, J = 8.5 Hz, 2H), 7.36 (d, J = 8.5 Hz, 1H), 7.21 (dd,
3.80 (s, 3H); 13C NMR (125 MHz, DMSO-d6) δ 158.8, 137.7, J1 = 1.5 Hz, J2 = 8.5 Hz, 1H), 6.92 (s, 1H); 13C NMR (125 MHz,
136.9, 128.8, 126.3, 124.9, 121.0, 119.6, 119.2, 114.3, 111.0, DMSO-d6) δ 137.9, 135.8, 132.3, 130.5, 130.4, 129.0, 126.8,
97.3, 55.2.
124.3, 122.2, 113.3, 112.0, 98.8. IR (KBr): 3437, 1533, 1480,
1-(4-(1H-Indol-2-yl)phenyl)ethan-1-one (3l). Pale-yellow solid 1454, 1444, 1411, 1314, 1278, 1172, 1099, 1049, 1003, 908,
(22.0 mg, 31%), mp 203–204 °C (lit.20 200.9–202.3 °C). 864, 791, 721, 665 cm−1. HRMS (ESI) calcd for C14H9BrClN
1H NMR (500 MHz, DMSO-d6) δ 11.69 (s, 1H), 8.04 (d, J = 8.0 [M + H]+: 305.9680, found 305.9682.
Hz, 2H), 8.00 (d, J = 8.0 Hz, 2H), 7.57 (d, J = 8.0 Hz, 1H), 7.43
5-Bromo-2-(4-bromophenyl)-1H-indole (3s). White solid,
(d, J = 8.5 Hz, 1H), 7.14 (t, J = 8.0 Hz, 1H), 7.09 (s, 1H), 7.02 (61.2 mg, 58%), mp 161.7–162 °C. 1H NMR (500 MHz,
(t, J = 7.5 Hz, 1H), 2.60 (s, 3H); 13C NMR (125 MHz, DMSO-d6) DMSO-d6) δ 11.82 (s, 1H), 7.79 (d, J = 8.5 Hz, 2H), 7.70
This journal is © The Royal Society of Chemistry 2017
Org. Biomol. Chem.

View Article Online
Paper
Organic & Biomolecular Chemistry
(d, J = 1.5 Hz, 1H), 7.66 (d, J = 8.5 Hz, 2H), 7.36 (d, J = 8.5 Hz,
2-Phenylquinazolin-4(3H)-one (5a). White solid (47.8 mg,
1
1H), 7.22 (dd, J1 = 1.5 Hz, J2 = 8.5 Hz, 1H), 6.90 (d, J = 1.5 Hz, 86%), mp 245–246 °C (lit.5e 245–246 °C). H NMR (500 MHz,
1H); 13C NMR (125 MHz, DMSO-d6) δ 137.9, 135.9, 131.9, CDCl3) δ 11.05 (s, 1H), 8.34–8.33 (m, 1H), 8.21–8.19 (m, 2H),
130.9, 130.4, 127.1, 124.3, 122.2, 120.8, 113.3, 112.0, 98.9. 7.85–7.80 (m, 2H), 7.61–7.58 (m, 3H), 7.53–7.50 (m, 1H).
IR (KBr): 3450, 1530, 1487, 1454, 1417, 1314, 1179, 1076, 1046,
1006, 907, 869, 791, 736, 706, 665 cm−1. HRMS (ESI) calcd for 71%). 1H NMR (500 MHz, CDCl3) δ 7.07–7.10 (m, 1H),
C14H9Br2N [M + H]+: 349.9175, found 349.9182.
7.14–7.16 (m, 2H), 7.18–7.22 (m, 3H), 7.31 (t, J = 7.5 Hz, 1H),
2-Phenyl-3-(phenylthio)-1H-indole (6a).18 Oil (53.5 mg,
5-Bromo-2-(4-methoxyphenyl)-1H-indole (3t). Pale-yellow 7.38–7.46 (m, 4H), 7.68 (d, J = 8.0 Hz, 1H), 7.77–7.78 (m, 1H),
solid (45.4 mg, 50%), mp 224–225 °C (lit.30 not reported). 8.60 (s, 1H).
1H NMR (500 MHz, DMSO-d6) δ 11.64 (s, 1H), 7.79 (d, J =
Indolin-2-one (7a). White solid, (5.3 mg, 13%), mp
8.5 Hz, 2H), 7.66 (d, J = 2.0 Hz, 1H), 7.32 (d, J = 8.5 Hz, 1H), 127–128 °C (lit.32 128 °C). 1H NMR (500 MHz, DMSO-d6)
7.16 (dd, J1 = 2.0 Hz, J2 = 8.5 Hz, 1H), 7.04 (d, J = 8.5 Hz, 2H), δ 10.38 (s, 1H), 7.20–7.14 (m, 2H), 6.92 (t, J = 7.5 Hz, 1H), 6.80
6.75 (d, J = 2.0 Hz, 1H), 3.80 (s, 3H); 13C NMR (125 MHz, (d, J = 7.5 Hz, 1H), 3.46 (s, 2H); 13C NMR (125 MHz, CDCl3)
DMSO-d6) δ 159.1, 139.3, 135.6, 130.7, 126.6, 124.2, 123.4, δ 177.4, 142.4, 127.9, 125.3, 124.7, 122.4, 109.6, 36.2.
121.7, 114.4, 112.9, 111.7, 96.9, 55.2.
N-(2-(2-Oxo-2-phenylethyl)phenyl)acetamide (8b). White
1
5-Bromo-2-(naphthalen-1-yl)-1H-indole (3u). Oil (64.9 mg, solid, mp 99–100 °C (lit.19 not reported). H NMR (500 MHz,
1
67%). H NMR (500 MHz, DMSO-d6) δ 11.83 (s, 1H), 8.29–8.27 DMSO-d6) δ 9.35 (s, 1H), 8.01 (d, J = 7.5 Hz, 2H), 7.65 (t, J =
(m, 1H), 8.04–7.99 (m, 2H), 7.82–7.81 (m, 1H), 7.72–7.71 (m, 7.5 Hz, 1H), 7.54 (t, J = 7.5 Hz, 1H), 7.42 (d, J = 8.0 Hz, 1H),
1H), 7.64–7.58 (m, 3H), 7.42 (d, J = 8.5 Hz, 1H), 7.27 (dd, J1 = 7.23 (t, J = 7.5 Hz, 2H), 7.13 (t, J = 7.5 Hz, 2H), 4.40 (s, 2H),
2.0 Hz, J2 = 8.5 Hz, 1H), 6.74 (d, J = 2.0 Hz, 1H); 13C NMR 1.92 (s, 3H); 13C NMR (125 MHz, DMSO-d6) δ 197.4, 168.2,
(125 MHz, DMSO-d6) δ 138.5, 135.8, 134.0, 131.1, 130.8, 130.7, 136.8, 136.7, 133.1, 131.2, 129.8, 128.6, 128.1, 126.9, 125.4,
129.0, 128.9, 127.9, 127.3, 126.7, 126.0, 125.7, 124.3, 122.7, 125.0, 41.3, 23.1.
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.
Acknowledgements
We are grateful to the Natural Science Foundation of Zhejiang
Province (no. LY16B020012), National Natural Science
Foundation of China (no. 21572162), Science and Technology
Project of Zhejiang Province (no. 2016C31022) and the
Xinmiao Talent Planning Foundation of Zhejiang Province (no.
2016R426059 and 2016R426058) for financial support.
5,7-Bibromo-2-phenyl-1H-indole (3v). White solid (79.9 mg,
72%), mp 163–164 °C. H NMR (500 MHz, DMSO-d6) δ 11.60
1
(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.
References
5-Iodo-2-phenyl-1H-indole (3w). White solid (60.3 mg, 63%),
mp 237–238 °C. H NMR (500 MHz, DMSO-d6) δ 11.72 (s, 1H),
1 (a) Y. Qu, R. Simonescu and V. De Luca, J. Nat. Prod., 2016,
79, 3143; (b) C.-E. Nge, K.-S. Sim, S.-H. Lim, N. F. Thomas,
Y.-Y. Low and T.-S. Kam, J. Nat. Prod., 2016, 79, 2709;
(c) G. Xu, G. He, H. Bai, T. Yang, G. Zhang, L. Wu and G. Li,
J. Nat. Prod., 2015, 78, 1479; (d) J. Stec, O. K. Onajole,
S. Lun, H. Guo, B. Merenbloom, G. Vistoli, W. R. Bishai
and A. P. Kozikowski, J. Med. Chem., 2016, 59, 6232;
(e) Z. Liu, L. Tang, H. Zhu, T. Xu, C. Qiu, S. Zheng, Y. Gu,
J. Feng, Y. Zhang and G. Liang, J. Med. Chem., 2016, 59,
4637; (f) F. Buonerba, S. Lepri, L. Goracci, B. D. Schindler,
S. M. Seo, G. W. Kaatz and G. Cruciani, J. Med. Chem.,
2017, 60, 517 and references cited therein.
1
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.
1-Methyl-2-phenyl-1H-indole (3x). Yellow solid (23.2 mg,
37%), mp 100.5–101 °C (lit.31 100–101 °C). 1H NMR (500 MHz,
DMSO-d6) δ 7.61–7.56 (m, 3H), 7.54–7.49 (m, 3H), 7.45 (t, J =
7.5 Hz, 1H), 7.19 (t, J = 7.5 Hz, 1H), 7.08 (t, J = 7.5 Hz, 1H), 6.59
(s, 1H), 3.75 (s, 3H); 13C NMR (125 MHz, DMSO-d6) δ 141.0,
138.1, 132.2, 129.0, 128.6, 127.9, 127.4, 121.4, 120.0, 119.5,
110.1, 101.1, 31.1.
2 (a) E. Von Angerer, J. Prekajac and J. Strohmeier, J. Med.
Chem., 1984, 27, 1439; (b) E. von Angerer, W. S. Sheldrick,
J. Engel and M. R. Schneider, Drugs Future, 1985, 10,
281.
2-Phenyl-4H-benzo[d][1,3]oxazin-4-one (4a). White solid
3 (a) E. Von Angerer and J. Prekajac, J. Med. Chem., 1983, 26,
113; (b) M. R. Schneider, E. von Angerer and J. Prekajac,
Drugs Future, 1986, 11, 1023.
4 M. Rowley, D. J. Hallett, S. Goodacre, C. Moyes,
J. Crawforth, T. J. Sparey, S. Patel, R. Marwood, S. Patel,
1
(36.3 mg, 65%), mp 112–113 °C (lit.5d not reported). H NMR
(500 MHz, CDCl3) δ 8.32–8.30 (m, 2H), 8.25–8.23 (m, 1H),
7.85–7.81 (m, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.58–7.56 (m, 1H),
7.64–7.50 (m, 3H).
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2017

View Article Online
Organic & Biomolecular Chemistry
Paper
S. Thomas, L. Hitzel, D. O’Connor, N. Szeto, J. L. Castro, 10 (a) R. C. Larock, Q. Tian and A. A. Pletnv, J. Am. Chem. Soc.,
P. H. Hutson and A. M. MacLeod, J. Med. Chem., 2001, 44,
1603.
1999, 121, 3238; (b) C. Zhou and R. C. Larock, J. Am. Chem.
Soc., 2004, 126, 2302.
5 (a) B. Li, B. Zhang, X. Zhang and X. Fan, Chem. Commun., 11 (a) J. Lindh, P. J. R. Sjöberg and M. Larhed, Angew. Chem.,
2017, 53, 1297; (b) S. Guo, L. Tao, W. Zhang, X. Zhang and
X. Fan, J. Org. Chem., 2015, 80, 10955; (c) P. Li, X. Zhang
and X. Fan, J. Org. Chem., 2015, 80, 7508; (d) X. Lian,
H. Lei, X. Quan, Z. Ren, Y. Wang and Z. Guan, Chem.
Commun., 2013, 49, 8196; (e) Y. Feng, Y. Li, G. Cheng,
L. Wang and X. Cui, J. Org. Chem., 2015, 80, 7099;
(f) P. Sang, Y. Xie, J. Zou and Y. Zhang, Adv. Synth. Catal.,
2012, 354, 1873; (g) T. Tsuchimoto, H. Matsubayashi,
M. Kaneko, E. Shirakawa and Y. Kawakami, Angew. Chem.,
Int. Ed., 2005, 44, 1336.
Int. Ed., 2010, 49, 7733; (b) T. Miao and G. Wang, Chem.
Commun., 2011, 47, 9501; (c) B. Skillinghaug, C. Sköld,
J. Rydfjord, F. Svensson, M. Behrends, J. Savmarker,
P. J. R. Sjöberg and M. Larhed, J. Org. Chem., 2014, 79,
12018; (d) M. Yousuf, T. Das and S. Adhikari, New J. Chem.,
2015, 39, 8763; (e) J.-C. Hsieh, Y.-C. Chen, A. Cheng and
H.-C. Tseng, Org. Lett., 2012, 14, 1282; (f) G. Xia, X. Han
and X. Lu, Adv. Synth. Catal., 2012, 354, 2701; (g) J. Liu,
X. Zhou, H. Rao, F. Xiao, C. Li and G. Deng, Chem. – Eur. J.,
2011, 17, 7996; (h) B. Skillinghaug, J. Rydfjord,
J. Sävmarker and M. Larhed, Org. Process Res. Dev., 2016,
20, 2005 and references cited therein.
6 (a) L. Jiao and T. Bach, J. Am. Chem. Soc., 2011, 133, 12990;
(b) N. Lebrasseur and I. Larrosa, J. Am. Chem. Soc., 2008,
130, 2926; (c) B. S. Lane, M. A. Brown and D. Sames, J. Am. 12 (a) X. Wang, M. Liu, L. Xu, Q. Wang, J. Chen, J. Ding and
Chem. Soc., 2005, 127, 8050; (d) S. Yang, C. Sun, Z. Fang,
B. Li, Y. Li and Z. Shi, Angew. Chem., Int. Ed., 2008, 47,
1473; (e) N. R. Deprez, D. Kalyani, A. Krause and
M. S. Sanford, J. Am. Chem. Soc., 2006, 128, 4972;
(f) B. Sezen and D. Sames, J. Am. Chem. Soc., 2003, 125,
5274; (g) L. Zhang, P. Li, C. Liu, J. Yang, M. Wang and
L. Wang, Catal. Sci. Technol., 2014, 4, 1979; (h) V. K. Tiwari,
N. Kamal and M. Kapur, Org. Lett., 2015, 17, 1766;
(i) C. Liu, L. Ding, G. Guo, W. Liu and F. Yang, Org. Biomol.
Chem., 2016, 14, 2824; ( j) H. P. L. Gemoets, I. Kalvet,
A. V. Nyuchev, N. Erdmann, V. Hessel, F. Schoenebeck and
H. Wu, J. Org. Chem., 2013, 78, 5273; (b) X. Wang, X. Wang,
M. Liu, J. Ding, J. Chen and H. Wu, Synthesis, 2013, 2241;
(c) J. Chen, J. Li and W. Su, Org. Biomol. Chem., 2014, 12,
4078; (d) J. Chen, L. Ye and W. Su, Org. Biomol. Chem.,
2014, 12, 8204; (e) S. Yu, L. Qi, K. Hu, J. Gong, T. Cheng,
Q. Wang, J. Chen and H. Wu, J. Org. Chem., 2017, DOI:
10.1021/acs.joc.7b00148; (f) L. Qi, K. Hu, S. Yu, J. Zhu,
T. Cheng, X. Wang, J. Chen and H. Wu, Org. Lett., 2017, 19,
218; (g) K. Hu, L. Qi, S. Yu, T. Cheng, X. Wang, Z. Li, Y. Xia,
J. Chen and H. Wu, Green Chem., 2017, DOI: 10.1039/
C7GC00267J.
T. Noël, Chem. Sci., 2017, 8, 1046; (k) L. Duan, R. Fu, 13 (a) G. W. Gribble, Indole Ring Synthesis: From Natural
B. Zhang, W. Shi, S. Chen and Y. Wan, ACS Catal., 2016, 6,
1062 and references cited therein.
Products to Drug Discovery, John Wiley & Sons, Inc., 2016,
pp. 353–357 and references cited therein; (b) S. J. Lee,
J. S. Fowler, D. Alexoff, M. Schueller, D. Kim, A. Nauth,
A. Weber, S. W. Kim, J. M. Hooker, L. Ma and W. Qu, Org.
Biomol. Chem., 2015, 13, 11235; (c) I. Choi, H. Chung,
J. W. Park and Y. K. Chung, Org. Lett., 2016, 18, 5508 and
references cited therein.
7 (a) E. Marelli, M. Corpet, Y. Minenkov, R. M. Neyyappadath,
A. Bismuto, G. Buccolini, M. Curcio, L. Cavallo and
S. P. Nolan, ACS Catal., 2016, 6, 2930; (b) H. Lee and
C. S. Yi, Organometallics, 2016, 35, 1973; (c) M. Yamaguchi,
T. Akiyama, H. Sasou, H. Katsumata and K. Manabe, J. Org.
Chem., 2016, 81, 5450; (d) M. Shen, B. E. Leslie and 14 For reviews, see: (a) G. A. Molander and N. Ellis, Acc. Chem.
T. G. Driver, Angew. Chem., Int. Ed., 2008, 47, 5056;
(e) S. Liang, L. Hammond, B. Xu and G. B. Hammond, Adv.
Synth. Catal., 2016, 358, 3313; (f) M. K. Manna, A. Hossian
and R. Jana, Org. Lett., 2015, 17, 672; (g) X. Xia, J. Xuan,
Q. Wang, L. Lu, J. Chen and W. Xiao, Adv. Synth. Catal.,
2014, 356, 2807; (h) Y. Vara, E. Aldaba, A. Arrieta,
J. L. Pizarro, M. I. Arriortua and F. P. Cossío, Org. Biomol.
Chem., 2008, 6, 1763; (i) K. Yang, F. Zhou, Z. Kuang,
G. Gao, T. G. Driver and Q. Song, Org. Lett., 2016, 18, 4088
and references cited therein.
Res., 2007, 40, 275; (b) S. Darses and J.-P. Genet, Chem.
Rev., 2008, 108, 288; (c) G. A. Molander and R. Figueroa,
Aldrichimica Acta, 2005, 38, 49; (d) H. A. Stefani, R. Cella
and S. Adriano, Tetrahedron, 2007, 63, 3623; (e) S. Darses
and J.-P. Genet, Eur. J. Org. Chem., 2003, 4313;
(f) G. A. Molander, J. Org. Chem., 2015, 80, 7837;
(g) G. A. Molander and L. Jean-Gérard, Cross-Coupling
Reactions of Organotrifluoroborate Salts, John Wiley & Sons,
Inc., 2013.
15 For reviews of metal-catalyzed reactions in or on water, see:
(a) C.-J. Li, Acc. Chem. Res., 2010, 43, 581; (b) R. N. Butler
and A. G. Coyne, Chem. Rev., 2010, 110, 6302;
(c) C. I. Herrerias, X. Yao, Z. Li and C.-J. Li, Chem. Rev.,
2007, 107, 2546; (d) U. M. Lindstrom, Chem. Rev., 2002,
102, 2751; (e) C.-J. Li, Chem. Rev., 2005, 105, 3095;
(f) C.-J. Li and T.-H. Chan, Comprehensive Organic Reactions
in Aqueous Media, John Wiley & Sons, Inc., Hoboken, 2nd
edn, 2007.
8 For books, see: (a) Z. Rappoport, Chemistry of the Cyano
Group, Wiley, London, 1970; (b) R. C. Larock,
Comprehensive Organic Transformations:
A
Guide to
Functional Group Preparations, VCH, New York, 1989. For
reviews, see: (c) F. F. Fleming and Q. Wang, Chem. Rev.,
2003, 103, 2035; (d) V. Y. Kukushkin and A. J. L. Pombeiro,
Chem. Rev., 2002, 102, 1771.
9 S. F. Rach and F. E. Kühn, Chem. Rev., 2009, 109, 2061.
This journal is © The Royal Society of Chemistry 2017
Org. Biomol. Chem.

View Article Online
Paper
Organic & Biomolecular Chemistry
16 (a) J. Zhang, J. Chen, M. Liu, X. Zheng, J. Ding and H. Wu, 21 C. M. So, C. P. Lau and F. Y. Kwong, Org. Lett., 2007, 9,
Green Chem., 2012, 14, 912; (b) J. Chen, Y. Peng, M. Liu, 2795.
J. Ding, W. Su and H. Wu, Adv. Synth. Catal., 2012, 354, 22 C. S. Choa, J. H. Kimb, T. J. Kimb and S. C. Shim, J. Chem.
2117; (c) X. Zheng, J. Ding, J. Chen, W. Gao, M. Liu and Res., 2004, 630.
H. Wu, Org. Lett., 2011, 13, 1726; (d) W. Lu, J. Chen, M. Liu, 23 M. Shen, B. E. Leslie and T. G. Driver, Angew. Chem., Int.
J. Ding, W. Gao and H. Wu, Org. Lett., 2011, 13, 6114; Ed., 2008, 47, 5056.
(e) Y. Shen, J. Chen, M. Liu, J. Ding, W. Gao, X. Huang and 24 S. S. Klioze, F. J. Ehrgott and E. J. Glamkowski,
H. Wu, Chem. Commun., 2014, 50, 4292. J. Heterocycl. Chem., 1984, 21, 1257.
17 (a) W. Yang, J. Chen, X. Huang, J. Ding, M. Liu and H. Wu, 25 L. Joucla, N. Batail and L. Djakovitch, Adv. Synth. Catal.,
Org. Lett., 2014, 16, 5418; (b) W. Yang, R. Qiao, J. Chen, 2010, 352, 2929.
X. Huang, M. Liu, W. Gao, J. Ding and H. Wu, J. Org. 26 C. Liu, L. Ding, G. Guo, W. Liu and F. Yang, Org. Biomol.
Chem., 2015, 80, 482; (c) Z. Chen, J. Chen, M. Liu, J. Ding, Chem., 2016, 14, 2824.
W. Gao, X. Huang and H. Wu, J. Org. Chem., 2013, 78, 27 G. A. Kraus and H. Guo, Org. Lett., 2008, 10, 3061.
11342; (d) R. Qiao, L. Ye, K. Hu, S. Yu, W. Yang, M. Liu, 28 F. Nador, Y. Moglie, C. Vitale, M. Yus, F. Alonso and
J. Chen, J. Ding and H. Wu, Org. Biomol. Chem., 2017, 15,
2168.
18 D. Huang, J. Chen, W. Dan, J. Ding, M. Liu and H. Wu,
Adv. Synth. Catal., 2012, 354, 2123.
19 Q. Xing, H. Lv, C. Xia and F. Li, Chem. – Eur. J., 2015, 21,
8591.
20 L. Ackermann, S. Barfüßer and H. K. Potukuchi, Adv. Synth.
Catal., 2009, 351, 1064.
G. Radivoy, Tetrahedron, 2010, 66, 4318.
29 H. Goker, M. Alp, Z. Ates-Alagoez and S. Yıldızb,
J. Heterocycl. Chem., 2009, 46, 936.
30 X. Wang, B. S. Lane and D. Sames, J. Am. Chem. Soc., 2005,
127, 4996.
31 K. Hisler, A. G. J. Commeureuc, S. Zhou and J. A. Murphy,
Tetrahedron Lett., 2009, 50, 3290.
32 S. Ozcan and M. Balci, Tetrahedron, 2008, 64, 5531.
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2017