Palladium-Catalyzed C-N Cross-Coupling of NH-Heteroarenes and Quaternary Ammonium Salts via C-N Bond Cleavage

Article abstract of DOI:10.1021/acs.oprd.9b00194

In this paper, we extend the substrate class of Buchwald-Hartwig amination to quaternary ammonium salts. In the presence of Pd(OAc)₂ and t-BuXPhos, the coupling of aryl- or arylmethyltrimethylammonium triflates with NH-heteroarenes via C-N bond cleavage affords the desired N-aryl or N-arylmethyl heteroarenes in moderate to excellent yields.

Full text of DOI:10.1021/acs.oprd.9b00194

Communication
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Cite This: Org. Process Res. Dev. XXXX, XXX, XXX−XXX
Palladium-Catalyzed C−N Cross-Coupling of NH-Heteroarenes and
Quaternary Ammonium Salts via C−N Bond Cleavage
Hongyi Chen,† Hongqin Yang,† Nutao Li,† Xinghua Xue,‡ Ze He,† and Qingle Zeng*,†
†State Key Laboratory of Geohazard Prevention and Geoenvironment Protection, College of Materials, Chemistry & Chemical
Engineering, Chengdu University of Technology, Chengdu 610059, China
‡College of Materials and Chemical Engineering, Hainan University, Haikou 570228, China
S
* Supporting Information
ammonium salts can behave as a new class of electrophiles in a
ABSTRACT: In this paper, we extend the substrate class
number of transformations proceeding via C−N bond
cleavage.14−25 There is only one reported example of a Ni-
catalyzed C−N cross-coupling reaction of aryltrimethylammo-
nium triflates with aniline or secondary aliphatic amines.21 To
the best of our knowledge, no C−N coupling reaction of NH-
heteroarenes and quaternary ammonium salts has yet been
reported.
of Buchwald−Hartwig amination to quaternary ammo-
nium salts. In the presence of Pd(OAc)2 and t-BuXPhos,
the coupling of aryl- or arylmethyltrimethylammonium
triflates with NH-heteroarenes via C−N bond cleavage
affords the desired N-aryl or N-arylmethyl heteroarenes in
moderate to excellent yields.
As part of our ongoing research on quaternary ammonium
salts26 and C−N coupling,27−33 we were motivated to expand
the use of quaternary ammonium salts as a new class of
electrophiles in the Buchwald−Hartwig amination. As is well-
known, aromatic and aliphatic halides (commonly including
fluorides, chlorides, bromides, and iodides) are commonly
obtained via direct halogenation (mostly for chlorides and
bromides) with toxic halogens or via indirect multistep
syntheses. However, aryl pseudohalides, such as aryl triflates,
have a narrow scope of cross-coupling reactions (restricted to a
few precious-metal-catalyzed examples) and in some catalytic
cases return to phenols and give no coupling product. In
contrast, quaternary ammonium salts are stable, safe, and
readily available from various amines. Therefore, quaternary
ammonium salts are rapidly emerging as a new class of
electrophiles.
Considering that heteroaromatics are crucial structural units
regularly found in natural products, pharmaceuticals, and other
functional synthetic compounds,34 we decided to study the C−
N cross-coupling of quaternary ammonium salts and NH-
heteroarenes 1 (Scheme 1B). Both arylmethyl (2) and aryl (3)
quaternary ammonium salts are unable to directly react with
NH-heteroarenes via nucleophilic substitution, so both of them
were studied.
KEYWORDS: NH-heteroarenes,
quaternary ammonium salts, C−N cross-coupling,
palladium catalysis, C−N bond cleavage
INTRODUCTION
■
The Buchwald−Hartwig amination has extensive applications
in the synthesis of medicines, natural products, agricultural
chemicals, fine chemicals, and functional materials.1−6 The
reaction constructs carbon−nitrogen bonds via the palladium-
catalyzed coupling of primary or secondary amines with aryl
halides or pseudohalides (Scheme 1A). The aryl halides
Scheme 1. Classical Palladium-Catalyzed C−N Cross-
Coupling (Buchwald−Hartwig Amination) and Our
Exploration of New Substrates
RESULTS AND DISCUSSION
■
In keeping with our former research,26 we initially used
benzyltrimethylammonium triflate (2a) as new type of
electrophile to couple with indole (1a). To optimize the
reaction conditions, several important factors were inves-
tigated, including the Pd source, ligand, base, solvent, and
reaction time. The screening results are shown in Table 1.
include aryl chlorides, bromides, and iodides. To date, the
range of aryl pseudohalides deployed in this reaction includes
aryl triflates,7 tosylates,8,9 mesylates,10 nonaflates,11 sulfa-
mates,12 and esters.13
The C−N bond is highly energetic (305 kJ/mol), making it
difficult to cleave directly. One effective approach to C−N
bond breaking is activation of amines into quaternary
ammonium salts, which are stable, inexpensive, and readily
available from amines. It was recently found that quaternary
Special Issue: Honoring 25 Years of the Buchwald-Hartwig
Amination
Received: May 1, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.oprd.9b00194
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Organic Process Research & Development
Communication
a
With the optimized conditions in hand, the C−N coupling
of various NH-heteroarenes 1 and arylmethyl quaternary
ammonium salts 2 was investigated (Table 2). Under the
Table 1. Optimization of the Reaction Conditions
Table 2. Palladium-Catalyzed C−N Coupling of Arylmethyl
a
Quaternary Ammonium Salts 2 with NH-heteroarenes 1
temp.
(°C)
isolated yield
(%)
entry
catalyst (mol %)
ligand (mol %)
1
2
3
4
5
NiCl2 (10)
Ni(OAc)2 (10)
FeCl3 (10)
CuI (10)
Cu(CH3CN)4PF6
(10)
−
−
−
−
−
80
80
80
80
80
18
9
0
10
28
6
[(C6H5)3P]3RhCl
(10)
−
80
0
7
8
9
Pd2(dba)3 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
−
−
−
−
−
−
80
80
80
85
90
100
85
85
85
85
85
85
85
30
46
31
50
45
35
70
89
80
52
13
73
0
b
10 Pd(OAc)2 (10)
11 Pd(OAc)2 (10)
12 Pd(OAc)2 (10)
13 Pd(OAc)2 (10)
14 Pd(OAc)2 (5)
t-BuXPhos (10)
t-BuXPhos (10)
dppp (5)
t-BuXPhos (10)
t-BuXPhos (10)
t-BuXPhos (10)
t-BuXPhos (10)
15 Pd(OAc)2 (5)
c
16
17
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
−
d
e
18
19
f
a
Reaction conditions: 1.0 mmol of 1a, 1.5 mmol of 2a, 2.0 mmol of t-
BuOK, 0.05−0.10 mmol of transition metal salt, 0.05−0.10 mmol of
ligand, and 5.0 mL of CH3CN at the indicated temperature for 24 h,
b
unless otherwise stated. 2 mmol of Cs2CO3 was used as the base.
c
d
The reaction time was 12 h. 5 mL of DMSO was used as the
e
f
solvent. 1.2 mmol of 2a and 1.5 mmol of t-BuOK were used. No
Pd(OAc)2 was added.
Nickel salts have been reported to catalyze various trans-
formations of quaternary ammonium salts;16−23 however, both
the nickel salts tested in the present coupling reaction, NiCl2
and Ni(OAc)2, gave very low yields (Table 1, entries 1 and 2).
FeCl3 achieved nearly no reaction (entry 3). The most
commonly used catalyst for the Ullmann reaction, CuI,
afforded only a 10% yield (entry 4). Cu(CH3CN)4PF6 was
previously found to be an excellent catalyst for C−S coupling
of benzylic quaternary ammonium salts26 but proved to be
unfit for the present coupling (entry 5). Wilkinson’s catalyst,
[(C6H5)3P]3RhCl, gave nothing (entry 6). However, Pd
catalysts, especially Pd(OAc)2, afforded promising yields
(entries 7 and 8). The weak base Cs2CO3 gave a lower yield
(entry 9). Investigation of the temperature showed that 85 °C
was optimal (entries 8 and 10−12). The addition of a bulky
monophosphine ligand, t-BuXPhos, greatly promoted this
reaction (entry 13). Considering the coordination stability and
relatively low cost of palladium salts, the combination of 5 mol
% Pd(OAc)2 and 10 mol % t-BuXPhos was adopted, and to
our surprise, the highest yield of 89% was obtained under these
conditions (entry 14). A bidentate phosphine ligand, dppp,
gave a slightly lower yield (entry 15). Shortening the reaction
time, adopting a strongly polar solvent, or decreasing the molar
ratio of benzyltrimethylammonium triflate and indole from
1.5:1 to 1.2:1 all decreased the yield (entries 16−18). No
product was found in the absence of Pd(OAc)2 (entry 19).
a
Reaction conditions: 1.0 mmol of 1, 1.5 mmol of 2, 2.0 mmol of t-
BuOK, 0.05 mmol of Pd(OAc)2, 0.10 mmol of t-BuXPhos, and 5.0
mL of acetonitrile at 85 °C for 24 h. Isolated yields are shown.
optimized conditions, it transpired that the electronic effect
and steric hindrance of the substituent on the indole, especially
steric hindrance, heavily influenced the Pd-catalyzed C−N
coupling (Table 2). 5-Nitroindole, with a strongly electron-
withdrawing nitro group, gave the highest yield (90%, 4b), and
all of the indoles with electron-donating groups, including
methyl and methoxy, gave good yields (4c−g). Both 7- and 2-
methylindole, with larger steric hindrance, afforded lower (but
still good) yields compared with 5- and 3-methylindole,
respectively (4e and 4g vs 4d and 4f). For 2-phenylindole, with
great steric hindrance, a yield as low as 39% was obtained (4h).
Carbazoles, which are likely to have smaller steric hindrance
than 2-phenylindoles, gave considerably higher yields (4i vs
4h). The synthetically useful 3-formylindole with an electron-
withdrawing formyl group, however, afforded a slightly lower
yield than 3-methylindole (4j vs 4f). It is possible that some
side reactions, such as the Cannizzaro reaction, took place
under strongly basic conditions. The precursors of both
benzimidazole 4k and benzotriazole 4l with multiple nitrogen
atoms reacted smoothly with benzyltrimethylammonium
triflate, affording good yields.
B
DOI: 10.1021/acs.oprd.9b00194
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Next, the reactions of the substituted arylmethyl quaternary
ammonium salts (4-methoxybenzyl)trimethylammonium tri-
flate (2b) and (2-methoxybenzyl)trimethylammonium triflate
(2c) with 1a (yielding 4m and 4n, respectively) were
examined. The yield of 4-methoxybenzyl-substituted indole
4m produced from 2b was higher than that of 2-
methoxybenzyl-substituted indole 4n obtained from 2c. The
lower yield of 4n may be related to the steric hindrance of the
o-methoxy group.
After evaluation of the C−N coupling of arylmethyl
quaternary ammonium salts 2, the coupling of various aryl
quaternary ammonium salts 3 with NH-heteroarenes 1 was
investigated (Table 3). In the coupling of phenyltrimethy-
lammonium triflates with pyrrole, the electronic effect of the
substituent was obvious (5a−c). The phenyltrimethylammo-
nium triflate with an electron-donating methoxy group was
produced in slightly lower yield than that without a substituent
(5c vs 5a). In coupling with phenyltrimethylammonium and p-
tolyltrimethylammonium triflates, pyrazole gave similar yields
as pyrrole (5d and 5e vs 5a and 5b). In reacting with
phenyltrimethylammonium and (4-methoxyphenyl)-
trimethylammonium triflates, indole achieved approximately
10% higher yields than pyrrole (5f and 5g vs 5a and 5c).
The effect of steric hindrance on the coupling of NH-
heteroarenes with aryl quaternary ammonium salts was huge
(5h−j). Similar to the corresponding arylmethyl quaternary
ammonium salts, aryl quaternary ammonium salts gave much
lower yields in couplings with more sterically hindered NH-
heteroarenes (5h and 5j).
Scale-Up. To assess the feasibility of the reaction upon
scale-up, the C−N cross-coupling reaction of 1a and 2a was
performed on a 10 mmol scale (Scheme 2). The 84% yield of
the targeted coupling product 4a demonstrates that this
coupling reaction has potential in industrial production.
Table 3. Palladium-Catalyzed C−N Coupling of Aryl
Quaternary Ammonium Salts 3 with NH-heteroarenes 1
a
Scheme 2. Gram-Scale Synthesis
CONCLUSION
■
We have explored arylmethyl and aryl quaternary ammonium
salts as a new substrate class for Buchwald−Hartwig amination
and developed a viable catalyst system to achieve C−N cross-
coupling between arylmethyl or aryl quaternary ammonium
triflates and NH-heteroarenes. A range of substrates, including
indoles, benzimidazole, benzotriazole, carbazole, 1H-pyrrole,
and 1H-pyrazole, in the presence of a catalytic amount of
Pd(OAc)2 (5 mol %), produced moderate to excellent yields.
The scope of potential application is wide. In most cases
promising results were obtained, in particular for the reaction
of indole and its homologues with benzyltrimethylammonium
triflate. This catalytic system is a valuable supplement to the
Buchwald−Hartwig amination.
EXPERIMENTAL SECTION
■
General. All of the C−N coupling reactions were carried
out under an argon atmosphere in dried glassware. The
glassware used was dried in an electric oven at 120 °C.
Chemicals were purchased from Aladdin, Adamas, Aldrich,
Alfa Aesar, and Kelong Chemical Co. and used as received.
Petroleum ether refers to the fraction boiling in the 60−90 °C
range. Unless otherwise stated, there was no further
purification of the commercial suppliers’ chemicals.
1H NMR spectra were determined on a Bruker Avance III
1
400 MHz instrument. H NMR data are reported in δ units
(ppm) and were measured relative to the signals for residual
chloroform (7.26 ppm), dimethyl sulfoxide (DMSO) (2.50
ppm), or acetone (2.05 ppm) in the deuterated solvent, unless
otherwise stated. 13C NMR spectra are reported in parts per
million relative to deuterochloroform (77.2 ppm), DMSO-d6
(39.5 ppm), or acetone-d6 (206.7 ppm for CO), unless
a
Reaction conditions: 1.0 mmol of 1, 1.5 mmol of 2, 2.0 mmol of t-
BuOK, 0.05 mmol of Pd(OAc)2, 0.10 mmol of t-BuXPhos, and 5.0
mL of acetonitrile at 85 °C for 24 h. Isolated yields are shown.
1
otherwise stated, and all were obtained with H decoupling.
C
DOI: 10.1021/acs.oprd.9b00194
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Mass spectral data for the products were collected by GC−MS
analysis with a QP-2010 SE instrument using electron impact
(EI) ionization.
(400 MHz, CDCl3): δ 7.56−7.52 (m, 1H), 7.39−7.29 (m,
3H), 7.24 (s, 1H), 7.20−7.13 (m, 3H), 7.09 (dd, J = 8.4, 1.6
Hz, 1H), 6.56 (dd, J = 3.1, 0.8 Hz, 1H), 5.34 (s, 2H), 2.54 (s,
3H). 13C NMR (101 MHz, CDCl3): δ 137.79, 134.77, 129.06,
128.78, 128.42, 127.58, 126.77, 123.38, 120.71, 109.48, 101.16,
50.15, 21.51. MS (EI): m/z (%) = 221.15 (75) [M]+.
General Procedure for the Synthesis of Quaternary
Ammonium Salts. To a round-bottom flask were added an
appropriate amount of arylmethyl or aromatic amine, 5 equiv
of HCOOH, and 3 equiv of HCHO. The mixture was kept
refluxing at 100 °C for 24 h. After the mixture was cooled to
room temperature, the pH of the reaction mixture was adjusted
to be alkaline with NaOH solution. The upper organic layer
was separated and distilled in vacuo at 100 °C to collect the
tertiary amine.
Next, an appropriate amount of diethyl ether was added into
a certain amount of tertiary amine in a flask. To the flask kept
in an ice-cold bath was slowly added an equivalent amount of
methyl triflate. After the reaction was completed, excess diethyl
ether was removed under reduced pressure to obtain the
corresponding quaternary ammonium salt.
1-Benzyl-7-methyl-1H-indole (4e).38 Following the general
procedure, 4e was obtained as a white solid with petroleum
ether/ethyl acetate (20/1) used as the eluent in 68% yield
1
(150.7 mg). H NMR (400 MHz, CDCl3): δ 7.46−7.37 (m,
1H), 7.37−7.23 (m, 3H), 7.21−7.09 (m, 4H), 6.96 (dd, J =
5.3, 1.4 Hz, 1H), 6.62 (t, J = 3.1 Hz, 1H), 5.34 (d, J = 3.1 Hz,
2H), 2.62 (t, J = 5.6 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ
137.66, 136.04, 130.45, 128.76, 128.45, 127.65, 127.56, 126.78,
121.87, 119.77, 107.36, 100.17, 50.20, 18.80. MS (EI): m/z
(%) = 221.15 (75) [M]+.
1-Benzyl-3-methyl-1H-indole (4f).39 Following the general
procedure, 4f was obtained as a white solid with petroleum
ether used as the eluent in 79% yield (173.7 mg). Melting
point: 72−73 °C. 1H NMR (400 MHz, CDCl3): δ 7.61 (ddd, J
= 7.7, 1.3, 0.8 Hz, 1H), 7.33−7.26 (m, 4H), 7.21−7.16 (m,
1H), 7.15−7.10 (m, 3H), 6.91 (d, J = 1.0 Hz, 1H), 5.27 (s,
2H), 2.36 (d, J = 1.1 Hz, 3H). MS (EI): m/z (%) = 221.15
(50) [M]+.
General Procedure for Pd-Catalyzed C−N Coupling
Reactions of NH-heteroarenes. To a test tube with a
standard ground joint were added 1.0 mmol of NH-
heteroarene, 1.5 mmol of arylmethyl- or aryltrimethylammo-
nium triflate, 5.0 mL of acetonitrile, and 2.0 mmol of
potassium tert-butoxide. The mixture was stirred at room
temperature for about 0.5 h. Then 0.05 mmol of Pd(OAc)2
and 0.10 mmol of t-BuXPhos were added to the test tube. The
test tube was transferred to an oil bath preheated to 85 °C and
kept stirring for 24 h. Then the reaction mixture was cooled to
room temperature, diluted with 15 mL of saturated NaCl
solution, and extracted with ethyl acetate (3 × 20 mL). The
combined organic layer was dried over anhydrous magnesium
sulfate and then concentrated under reduced pressure in a
rotary evaporator. The residue was purified on a silica gel
chromatography column with a mixed solution of petroleum
ether and ethyl acetate as the eluent to afford the target
product.
1-Benzyl-2-methyl-1H-indole (4g).40 Following the general
procedure, 4g was obtained as colorless oil with petroleum
1
ether used as the eluent in 71% yield (157.5 mg). H NMR
(400 MHz, CDCl3): δ 7.57 (ddd, J = 5.9, 3.4, 1.9 Hz, 1H),
7.29−7.19 (m, 5H), 7.13−7.06 (m, 2H), 7.00−6.95 (m, 2H),
5.32 (s, 2H), 2.38 (s, 3H). MS (EI): m/z (%) = 221.15 (75)
[M]+.
1-Benzyl-2-phenyl-1H-indole (4h).41 Following the general
procedure, 4h was obtained as a white solid with petroleum
ether used as the eluent in 39% yield (109.7 mg). Melting
1
point: 89−92 °C. H NMR (400 MHz, CDCl3): δ 7.73−7.66
(m, 1H), 7.49−7.35 (m, 5H), 7.33−7.14 (m, 6H), 7.08−7.03
(m, 2H), 6.68 (d, J = 0.6 Hz, 1H), 5.39 (s, 2H). 13C NMR
(101 MHz, CDCl3): δ 141.83, 138.20, 137.96, 132.68, 129.21,
128.75, 128.56, 128.30, 128.04, 127.16, 125.96, 121.91, 120.55,
120.17, 110.58, 102.32, 47.74. MS (EI): m/z (%) = 283.20
(60) [M]+.
1-Benzyl-1H-indole (4a).35 Following the general proce-
dure, 4a was obtained as a white solid with petroleum ether
used as the eluent in 89% yield (184.2 mg). Melting point:
1
42−43 °C. H NMR (400 MHz, CDCl3): δ 7.91−7.84 (m,
1H), 7.52−7.20 (m, 9H), 6.76 (dd, J = 3.0, 0.7 Hz, 1H), 5.42
(s, 2H). MS (EI): m/z (%) = 207.15 (75) [M]+.
9-Benzyl-9H-carbazole (4i).42 Following the general
procedure, 4i was obtained as a white solid with petroleum
ether used as the eluent in 63% yield (162.4 mg). Melting
1-Benzyl-5-nitro-1H-indole (4b).36 Following the general
procedure, 4b was obtained as a white solid with petroleum
ether/ethyl acetate (20/1) used as the eluent in 90% yield
1
point: 122−124 °C. H NMR (400 MHz, CDCl3): δ 8.24−
1
(227.3 mg). H NMR (400 MHz, CDCl3): δ 8.61 (d, J = 2.1
8.17 (m, 2H), 7.53−7.45 (m, 2H), 7.42 (t, J = 7.6 Hz, 2H),
7.35−7.26 (m, 5H), 7.21−7.16 (m, 2H), 5.54 (s, 2H). 13C
NMR (101 MHz, CDCl3): δ 140.69, 137.22, 128.81, 127.48,
126.44, 125.90, 123.06, 120.45, 119.26, 108.95, 46.56. MS
(EI): m/z (%) = 257.15 (50) [M]+.
Hz, 1H), 8.07 (dd, J = 9.1, 2.2 Hz, 1H), 7.36−7.26 (m, 5H),
7.14−7.07 (m, 2H), 6.73 (dd, J = 3.3, 0.8 Hz, 1H), 5.37 (s,
2H). 13C NMR (101 MHz, CDCl3): δ 141.71, 139.03, 136.17,
131.47, 129.01, 128.14, 127.91, 126.73, 118.27, 117.44, 109.61,
104.41, 50.61. MS (EI): m/z (%) = 252.10 (25) [M]+.
1-Benzyl-5-methoxyindole (4c).35 Following the general
procedure, 4c was obtained as a white solid with petroleum
1-Benzylindole-3-carboxaldehyde (4j).43 Following the
general procedure, 4j was obtained as a white solid with
petroleum ether/ethyl acetate (5/1) used as the eluent in 70%
1
1
ether used as the eluent in 75% yield (178.2 mg). H NMR
yield (164.5 mg). Melting point: 106−109 °C. H NMR (400
(400 MHz, CDCl3): δ 7.33−7.26 (m, 3H), 7.19−7.07 (m,
5H), 6.84 (dt, J = 6.7, 3.4 Hz, 1H), 6.49 (dd, J = 3.1, 0.8 Hz,
1H), 5.30 (s, 2H), 3.86 (s, 3H). 13C NMR (101 MHz,
CDCl3): δ 154.07, 137.62, 131.59, 129.06, 128.85, 128.74,
127.57, 126.65, 112.01, 110.48, 102.52, 101.16, 55.83, 50.28.
MS (EI): m/z (%) = 237.15 (60) [M]+.
MHz, CDCl3): δ 9.98 (s, 1H), 8.37−8.31 (m, 1H), 7.69 (d, J =
3.4 Hz, 1H), 7.39−7.26 (m, 6H), 7.21−7.13 (m, 2H), 5.34 (s,
2H). 13C NMR (101 MHz, CDCl3): δ 184.66, 138.62, 137.45,
135.32, 129.12, 128.39, 127.22, 125.47, 124.16, 123.07, 122.15,
118.46, 110.42, 50.91. MS (EI): m/z (%) = 235.10 (30) [M]+.
1-Benzylbenzimidazole (4k).44 Following the general
procedure, 4k was obtained as a white solid with petroleum
ether/ethyl acetate (10/1) used as the eluent in 71% yield
(147.4 mg). Melting point: 115−117 °C. 1H NMR (400 MHz,
1-Benzyl-5-methyl-1H-indole (4d).37 Following the general
procedure, 4d was obtained as a yellow oil with petroleum
1
ether used as the eluent in 77% yield (169.5 mg). H NMR
D
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CDCl3): δ 7.95 (s, 1H), 7.86−7.80 (m, 1H), 7.36−7.22 (m,
6H), 7.20−7.15 (m, 2H), 5.35 (s, 2H). MS (EI): m/z (%) =
208.10 (30) [M]+.
1-Phenyl-1H-indole (5f).47 Following the general proce-
dure, 5f was obtained as a colorless oil with petroleum ether
used as the eluent in 78.9% yield (152.5 mg). H NMR (400
MHz, CDCl3): δ 7.78−7.69 (m, 1H), 7.64−7.59 (m, 1H),
7.58−7.48 (m, 4H), 7.43−7.35 (m, 2H), 7.24 (dddd, J = 14.7,
8.1, 7.1, 1.2 Hz, 2H), 6.73 (dd, J = 3.3, 0.8 Hz, 1H). MS (EI):
m/z (%) = 193.10 (100) [M]+.
1
1-Benzyl-1H-benzotriazole (4l).45 Following the general
procedure, 4l was obtained as a white solid with petroleum
ether/ethyl acetate (20/1) used as the eluent in 78% yield
(163.6 mg). Melting point: 114−115 °C. 1H NMR (400 MHz,
CDCl3): δ 8.06 (d, J = 8.2 Hz, 1H), 7.42−7.24 (m, 8H), 5.83
(s, 2H). 13C NMR (101 MHz,CDCl3): δ 146.31, 134.73,
132.77, 128.98, 128.44, 127.55, 127.38, 123.90, 120.03, 109.71,
52.24. MS (EI): m/z (%) = 209.10 (50) [M]+.
1-(4-Methoxyphenyl)indole (5g).47 Following the general
procedure, 5g was obtained as a white solid with petroleum
ether used as the eluent in 69.3% yield (154.7 mg). Melting
point: 70−73 °C. 1H NMR (400 MHz, CDCl3): δ 7.69 (dt, J =
13.3, 6.9 Hz, 1H), 7.60−7.53 (m, 1H), 7.50−7.37 (m, 2H),
7.29 (d, J = 3.2 Hz, 1H), 7.19 (dtd, J = 14.7, 7.1, 1.2 Hz, 2H),
7.07−7.01 (m, 2H), 6.72−6.64 (m, 1H), 3.88 (s, 3H). MS
(EI): m/z (%) = 223.96 (100) [M]+.
1-(4-Methoxybenzyl)-1H-indole (4m).46 Following the
general procedure, 4m was obtained as a white oil with
petroleum ether/ethyl acetate (20/1) used as the eluent in
1
80% yield (188.9 mg). H NMR (400 MHz, CDCl3): δ 7.67
1,2-Diphenyl-1H-indole (5h).48 Following the general
procedure, 5h was obtained as a white solid with petroleum
ether/ethyl acetate (5/1) used as the eluent in 30.3% yield
(d, J = 7.8 Hz, 1H), 7.31 (t, J = 7.9 Hz, 1H), 7.23−7.16 (m,
1H), 7.16−7.06 (m, 4H), 6.88−6.80 (m, 2H), 6.54 (t, J = 8.9
Hz, 1H), 5.27 (s, 2H), 3.78 (s, 3H). 13C NMR (101 MHz,
CDCl3): δ 159.06, 136.23, 129.52, 128.74, 128.20, 128.08,
121.60, 120.95, 119.46, 114.12, 109.70, 101.52, 55.28, 49.58.
MS (EI): m/z (%) = 237.15 (75) [M]+.
1
(81.6 mg). Melting point: 79−81 °C. H NMR (400 MHz,
CDCl3): δ 7.75−7.70 (m, 1H), 7.47−7.17 (m, 13H), 6.84 (s,
1H). 13C NMR (101 MHz, CDCl3): δ 140.74, 138.98, 138.50,
132.53, 129.28, 128.92, 128.26, 128.17, 128.05, 127.31, 127.21,
122.35, 120.72, 120.54, 110.64, 103.70. MS (EI): m/z (%) =
269.15 (100) [M]+.
(2-Methoxybenzyl)-1H-indole (4n).46 Following the general
procedure, 4n was obtained as a white oil with petroleum ether
1
used as the eluent in 75% yield (178.7 mg). H NMR (400
MHz, CDCl3): δ 7.80−7.72 (m, 1H), 7.47−7.40 (m, 1H),
7.35−7.19 (m, 3H), 7.15−7.11 (m, 1H), 6.97 (dd, J = 8.2, 0.8
Hz, 1H), 6.92−6.86 (m, 1H), 6.83−6.77 (m, 1H), 6.65 (dd, J
= 3.1, 0.9 Hz, 1H), 5.42 (s, 2H), 3.95 (s, 3H). MS (EI): m/z
(%) = 237.15 (75) [M]+.
7-Methyl-1-phenyl-1H-indole (5i).49 Following the general
procedure, 5i was obtained as a white solid with petroleum
ether/ethyl acetate (20/1) used as the eluent in 64.7% yield
1
(134.1 mg). H NMR (400 MHz, CDCl3): δ 7.59 (ddd, J =
1-Phenylpyrrole (5a).47 Following the general procedure,
5a was obtained as a white solid with petroleum ether used as
15.4, 11.8, 4.6 Hz, 5H), 7.44 (dt, J = 10.7, 4.7 Hz, 2H), 7.33−
7.22 (m, 1H), 7.12 (dt, J = 7.1, 3.6 Hz, 1H), 6.84 (dd, J = 6.0,
1.9 Hz, 1H), 2.75 (d, J = 6.9 Hz, 3H). 13C NMR (101 MHz,
CDCl3): δ 140.10, 135.68, 130.69, 129.69, 129.26, 127.45,
126.48, 124.47, 122.63, 120.68, 108.29, 102.16, 18.93. MS
(EI): m/z (%) = 207.15 (75) [M]+.
1
the eluent in 72.0% yield (103.1 mg). H NMR (400 MHz,
CDCl3): δ 7.48−7.38 (m, 4H), 7.28−7.23 (m, 1H), 7.11 (dd, J
= 5.3, 3.1 Hz, 2H), 6.37 (dd, J = 5.1, 2.9 Hz, 2H). MS (EI): m/
z (%) = 143.10 (100) [M]+.
9-(4-Methylphenyl)-9H-carbazole (5j).42 Following the
general procedure, 5j was obtained as a white solid with
petroleum ether/ethyl acetate (20/1) used as the eluent in
45.6% yield (117.3 mg). 1H NMR (400 MHz, CDCl3): δ 8.17
(d, J = 7.8 Hz, 2H), 7.50−7.38 (m, 8H), 7.31 (ddd, J = 8.0,
5.9, 2.3 Hz, 1H), 7.27−7.24 (m, 1H), 2.51 (s, 3H). 13C NMR
(101 MHz, CDCl3): δ 141.04, 137.36, 134.98, 130.47, 126.99,
125.85, 123.23, 120.27, 119.72, 109.79, 21.27. MS (EI): m/z
(%) = 257.15 (60) [M]+.
1-(4-Methylphenyl)-1H-pyrrole (5b).47 Following the gen-
eral procedure, 5b was obtained as a white solid with
petroleum ether used as the eluent in 68.3% yield (107.4
mg). 1H NMR (400 MHz, CDCl3): δ 7.33−7.27 (m, 2H), 7.23
(d, J = 8.1 Hz, 2H), 7.08 (dd, J = 5.1, 2.9 Hz, 2H), 6.47−6.21
(m, 2H), 2.39 (s, 3H). MS (EI): m/z (%) = 157.15 (100)
[M]+.
1-(p-Methoxyphenyl)pyrrole (5c).47 Following the general
procedure, 5c was obtained as a white solid with petroleum
1
ether used as the eluent in 59.6% yield (103.2 mg). H NMR
(400 MHz, CDCl3): δ 7.34−7.29 (m, 2H), 7.03−6.99 (m,
1H), 6.98−6.93 (m, 2H), 6.35−6.31 (m, 2H), 3.84 (s, 3H).
13C NMR (101 MHz, CDCl3): δ 157.62, 134.47, 122.18,
119.69, 114.59, 109.82, 55.56. MS (EI): m/z (%) = 173.10
(75) [M]+.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.oprd.9b00194.
1-Phenylpyrazole (5d).47 Following the general procedure,
5d was obtained as a yellow oil with petroleum ether/ethyl
acetate (10/1) used as the eluent in 70.2% yield (101.2 mg).
1H NMR (400 MHz, CDCl3): δ 7.96−7.87 (m, 1H), 7.77−
7.64 (m, 3H), 7.50−7.39 (m, 2H), 7.35−7.22 (m, 1H), 6.50−
6.41 (m, 1H). MS (EI): m/z (%) = 144.15 (100) [M]+.
1-(4-Methylphenyl)-1H-pyrazole (5e).47 Following the
general procedure, 5e was obtained as a yellow oil with
petroleum ether/ethyl acetate (10/1) used as the eluent in
66.9% yield (105.8 mg). 1H NMR (400 MHz, CDCl3): δ 7.88
(d, J = 2.4 Hz, 1H), 7.71 (d, J = 1.6 Hz, 1H), 7.60−7.53 (m,
2H), 7.24 (dd, J = 8.8, 0.5 Hz, 2H), 6.44 (t, J = 2.1 Hz, 1H),
2.38 (s, 3H). MS (EI): m/z (%) = 158.25 (100) [M]+.
1H and 13C NMR spectra and GC−MS (EI mode)
spectra for products 4 and 5 (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: qinglezeng@hotmail.com.
ORCID
Qingle Zeng: 0000-0003-0750-540X
Notes
The authors declare no competing financial interest.
E
DOI: 10.1021/acs.oprd.9b00194
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Communication
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ACKNOWLEDGMENTS
■
This work was supported by the National Natural Science
Foundation of China (21372034) and the State Key
Laboratory of Geohazard Prevention and Geoenvironment
Protection (SKLGP2018Z002).
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ABBREVIATIONS
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t-BuXPhos, 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbi-
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