Diversification of Heteroaryl-Aryl Ether via Ligand-Free, Copper-Catalyzed O-Arylation Under Microwave Heating

Article abstract of DOI:10.1002/bkcs.12075

Diverse O-arylated pyrrolo[2,3-d]pyrimidine and pyrrolo[2,3-b]pyridine were obtained using relatively low amounts of Cu catalyst with ligand-free conditions under microwave heating. The O-arylation reaction could be applied to less oxidative heteroaryl-chlorides. The microwave-assisted Cu-catalyzed O-aryaltion would be useful for preparing potent bioactive compounds for drug discovery while reducing waste, time, and saving energy.

Full text of DOI:10.1002/bkcs.12075

Article
DOI: 10.1002/bkcs.12075
BULLETIN OF THE
S. M. Choi et al.
KOREAN CHEMICAL SOCIETY
Diversification of Heteroaryl-Aryl Ether via Ligand-Free,
Copper-Catalyzed O-Arylation Under Microwave Heating
*
Sung Min Choi, Jeong Seob Byeon, and Eul Kgun Yum
Department of Chemistry, Chungnam National University, Yusung, Daejon 34134, Korea.
*E-mail: ekyum@cnu.ac.kr
Received March 19, 2020, Accepted June 28, 2020, Published online August 11, 2020
Diverse O-arylated pyrrolo[2,3-d]pyrimidine and pyrrolo[2,3-b]pyridine were obtained using relatively
low amounts of Cu catalyst with ligand-free conditions under microwave heating. The O-arylation reac-
tion could be applied to less oxidative heteroaryl-chlorides. The microwave-assisted Cu-catalyzed O-
aryaltion would be useful for preparing potent bioactive compounds for drug discovery while reducing
waste, time, and saving energy.
Keywords: Hetroary-aryl ether, Ligand free, Copper catalyst, O-arylation, Microwave heating
Introduction
recognized as an important tool for green chemistry,24–26
because it reduces waste and enhances energy efficiency.
MAOS was shown to be an efficient technology for the pro-
duction of important drugs, fine chemicals, and materials.27,28
Our research to date has focused on green chemical pro-
cesses incorporating metal-catalyzed MAOS for the diversifi-
cation of heterocycles.29–34 This report describes C─O bond
formation with biological interesting pyrrolo[2,3-d]pyrimidine
and 7-azaindole derivatives to diversify hetroaryl-aryl ethers
under copper-catalyzed, ligand-free conditions. This synthetic
approach affords a variety of heteroaryl-aryl ethers suitable for
preparing potent bioactive compounds for drug discovery.
The diaryl ether scaffold is common to a variety of medicinal
agents and biologically active compounds.1,2 In particular, dia-
ryl ethers constitute the core moiety of many important natural
products,3,4 insecticides,5 herbicides,6 and therapeutically
active materials (Figure 1).7–10
Diverse diaryl ethers have been synthesized by the
arylation of phenols with aryl halides using the Ullmann reac-
tion and copper reagents.11–14 However, classical Ullmann
reactions are limited by the need for high temperatures, long
reaction times, and excess amounts of copper reagent. On the
other hand, nucleophilic aromatic substitution (SNAr) showed
efficient synthetic method for the formation of heteroaryl
C─O bonds with electro deficient heterocycles and alcohol
under metal-free conditions.15 Several transition metal-medi-
ated C─O coupling reactions were also reported with
heteroaryl chlorides and phenols under AlCl3, Cu, or Pd.16–19
Recently improved Ullmann reactions, using bidentate
ligands containing a heteroatom and transition metals, have
been shown to significantly promote carbon–heteroatom
coupling at moderate temperatures and long reaction times
(12–24 h).14,20 Specially, the most major advances in C─O
bond-formation reactions have resulted from the use of het-
eroatoms containing ligands with Pd-, Cu-, Rh-, or Fe-
based catalysts.21 The reactivity of substituting aryl halides
with nucleophiles depends strongly on the species of ligand
and catalyst as well as the solvent used and the pH and
temperature of the reaction mixture. Although the use of
bidentate ligands with a heteroatom and copper catalyst has
allowed for milder reaction conditions, the widespread use
of these catalytic systems on an industrial scale is limited
by the low reactivity of heteroaryl chlorides.22
Results and Discussions
The pyrrolo[2,3-d]pyrimidine moiety has attracted consider-
able interest in the synthesis, pharmaceutical, and medicinal
fields due to its bioactivities, which include antibacterial,
antiinflammatory, and anticancer properties.35 Especially, the
chlorine substituent attached ortho or para to the nitrogen-
deficient aromatic ring is an extremely versatile feature that
allows for aromatic substitution with a wide variety of nucleo-
philes. Here, various copper species and bases were screened
to identify the most efficient conditions for heteroaryl-aryl
ether formation. The results of these conditions on C─O bond
formation between 4-chloro-7-methyl-pyrrolo[2,3-d]pyrimi-
dine and phenol are described in Table 1.
CuI-catalyzed O-arylation with 4-chloro-7-methylpyrrolo
[2,3-d]pyrimidine and phenol provided an excellent yield of
4-phenoxy-7-methylpyrrolo[2,3-d]pyrimidine
compared
with those obtained using Cu2O, CuO, and CuBr catalysts
with K3PO4 (Table 1, entries 1, 8–10). The efficiency of
the coupling reaction also depended strongly on the base.
Reactions mixtures containing K3PO4 or Cs2CO3 resulted
in higher yields of the desired product than did those con-
taining K2CO3 or Na2CO3 (Table 1, entries 1–4).
The first microwave-assisted organic syntheses (MAOSes)
using domestic microwave ovens were reported by Gedye
et al.23 in 1986. Since then, microwave irradiation has been
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Unprotected 4-chloro pyrrolo[2,3-d]pyrimidine and phenol
did not yield any coupling product under our optimized con-
ditions due to complex formation between the Cu catalyst
and nitrogen atoms. However, N-methyl-protected 4-chloro
pyrrolo [2,3-d]pyrimidine successfully yielded coupled prod-
ucts (2a–2d). The reaction using 3-hydroxypyridine also
proceeded smoothly with good yields of 2e. However, 4-
hydroxypyridine provided only a 15% yield of N-coupled
product (2f) due to the formation of 4-pyridone as carbonyl
tautomer. The reaction using the bulkier N-isopropyl-4-
chloro pyrrolopyrimidine moiety provided excellent yields
of the desired product 2g, but the same reaction using
substituted phenols gave only moderate yields of 2h and 2i.
The reaction of N-methyl-2-chloro pyrrolo [2,3-d]pyrimidine
with phenol proceeded smoothly and gave high yields of 2j.
The reaction of N-methyl-2-chloro pyrrolo[2,3-d]pyrimidine
with methoxy phenols gave moderate yields of 2k, and the
reaction of N-methyl-2-chloro pyrrolo[2,3-d]pyrimidine with
3-hydroxy pyridine provided good yields of the coupled
product 2l.
Figure 1. Biologically active compounds containing diaryl ether
cores.
We then investigated the effects of various solvents on
reaction efficiency (Table 1, entries 4–7). Excellent yields
of the desired product were obtained in DMF, but reactions
in DMA, DMSO, and NMP produced only moderate-to-
high yields (65–83%). We therefore selected DMF, which
exhibits a relatively high dielectric constant and high boil-
ing point, as the best reaction solvent for C─O coupling.
Microwave-mediated C─O coupling using bidentate ligands
such as L-proline, histidine, and picolinic acid resulted in
only moderate yields (39–49%) of the desired product
(Table 1, entries 11–13). Thus, based on these results, the
best conditions for O-arylation of pyrrolo[2,3-d]pyrimidine
were two equivalents K3PO4 with 10 mol % CuI in DMF
at 180ꢀC. We then examined the diversification of diaryl
ethers with pyrrolopyrimidines and various phenol deriva-
tives. The results are represented in Table 2.
Many natural and synthetic 7-azaindole derivatives report-
edly exhibit biological properties such as antibacterial,
antiinflammatory, and anticancer activities.36 Here, O-arylation
was examined using various substituted phenols and 4-bromo-
or chloro-7-azaindoles under optimal reaction conditions to
produce diverse O-arylated 7-azaindole products. The results
are shown in Table 3.
Our Cu-catalyzed O-arylation system was also extended
to functionally substituted phenols and N-methyl-4-bromo-
Table 1. Optimization of Cu-catalyzed O-arylation 4-chloro-7-methyl–pyrrolo[2,3-d]pyrimidine with microwave heating.
Entrya,b
Cu catalyst
Base
Solvent
Isolated yield (%)
1
2
3
4
5
6
7
8
CuI
CuI
CuI
CuI
CuI
CuI
CuI
Cu2O
K2CO3
Na2CO3
Cs2CO3
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
DMF
DMF
DMF
DMF
DMA
DMSO
NMP
DMF
DMF
DMF
DMF
DMF
DMF
87
84
95
98
72
83
65
80
75
54
49
39
47
9
CuBr
CuO
10
11
12
13
CuI (20 mol % L-proline)
CuI (20 mol % histidine)
CuI (20 mol % picolinic acid)
a All reactions were conducted on a 0.5-mmol scale in 3 mL solvent in a 5-mL Biotage vial sealed with a crimp cap.
b Microwave irradiation was supplied by the Biotage Initiator EXP EU (400 W, 2450 MHz).
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Diversification of Heteroaryl-Aryl ether via Microwave heating
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Table 2. Diversification of pyrrolo[2,3-d]pyrimidine derivatives
with O-arylation.
slightly lower yields of the desired C─O coupling products
than do unsubstituted phenols or 3-hydroxy pyridine.
Experimental
Instrumentation and Analysis. All 1H and 13C NMR
spectra were recorded on Bruker Fourier 300 MHz spec-
trometer, and chemical shifts were referenced to tetra-
methylsilane (TMS) as an internal standard. The LC–MS
spectra were obtained using Waters ACQVI (UPLC) SQD
2 with ion trap and ESI. Microwave-assisted reactions were
performed with an initiator instrument (EXP EU, Biotage,
400 W, 2450 MHz). Reaction temperatures were measured
using infrared sensors on the outer surface of the reaction
vial. Products were purified by flash chromatography on
230-400-mesh ASTM 60 silica gel. All base and copper
species were purchased from Sigma-Aldrich Chemical Co
(St.Louis, MO, USA). Chemicals were used directly as
obtained from commercial sources unless otherwise noted.
Preparation of Starting and Product Materials
General Procedure for N-Alkyl of Heteroaryl Halide
4-Chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidine (1a)
4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (2 mmol) was dis-
solved in 20 mL of anhydrous DMF and added 60% NaH
(4 mmol) into 50 mL round bottom flask. Iodomethane
(4 mmol) was added and stirred for 4 h at room tempera-
ture. The reaction product was extracted with ethyl acetate
with aqueous saturated ammonium chloride. The combined
organic extracts were washed with brine, then dried over
magnesium sulfate, filtered, and evaporated. The filtrate
was purified by silica gel column chromatography using
hexane:ethyl acetate = 1:1. 4-chloro-7-methyl-7H-pyrrolo
[2,3-d]pyrimidine (1a) was obtained in 97% yield as a
7-azaindole. The 2-methoxy or 3-aldehyde substituted phe-
nol provided moderate yields of the desired products 4b
and 4d. The reaction using 3,4-dimethoxyphenol as a
nucleophile yielded 48% of the desired product 4c. Using
3-hydroxypyridine as a nucleophile resulted in a 65% yield
of 4e. The reaction with N-isopropyl- 4-chloro-7-azaindole
provided slightly lower yields of 4g and 4h compared with
the yields obtained with N-methyl 4-bromo-7-azaindole.
These results indicate that substituted phenols result in
1
white solid. mp: 127–129ꢀC. H NMR (300 MHz, CDCl3)
δ 8.65 (s, 1H), 7.22 (d, J = 3.5 Hz, 1H), 6.61 (d,
J = 3.5 Hz, 1H), 3.88 (s, 3H). 13C NMR (75 MHz, CDCl3)
δ 151.98, 150.32, 125.69, 117.70, 108.41, 99.48, 46.72,
22.70. MS(m/z): 167.59 (M + 1).
Table 3. Diversification of 7-azaindole derivatives under ligand-
free, Cu-catalyzed C─O arylation.
4-Chloro-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine (1b)
compound 1b was obtained 95% yields from 4-chloro-7H-
pyrrolo[2,3-d]pyrimidine and 2-iodopropane under 5 h
reaction at 60ꢀC. mp: 58–61ꢀC 1H NMR (300 MHz,
CDCl3) δ 8.63 (s, 1H), 7.35 (d, J = 3.7 Hz, 1H), 6.62 (d,
J = 3.7 Hz, 1H), 5.13 (hept, 1H), 1.54 (s, 3H), 1.51 (s,
3H).; 13C NMR (75 MHz, CDCl3) δ 151.98, 150.32,
125.69, 117.70, 108.41, 99.48, 46.72, 22.70. MS(m/z):
195.65 (M + 1).
4-Bromo-1-methyl-1H-pyrrolo[2,3-b]pyridine (3a)
Compound 3a was obtained 96% yields as a brown oil
from 4-bromo-1H-pyrrolo[2,3-b]pyridine and iodomethane
under 1 h reaction at room temperature.
1H NMR (300 MHz, CDCl3) δ 8.13 (d, J = 5.1 Hz, 1H),
7.25 (d, J = 5.2 Hz, 1H), 7.23 (d, J = 3.5 Hz, 1H), 6.49 (d,
J = 3.5 Hz, 1H), 3.89 (s, 3H). 13C NMR (75 MHz, CDCl3)
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δ 147.64, 142.92, 129.56, 125.12, 122.05, 118.76, 99.56,
31.67. MS(m/z): 211.06 (M + 1).
Compounds (1c and 3b) were prepared with N-alkylation
procedure from 2-chloro-7H-pyrrolo[2,3-d]pyrimidine or 4-
chloro-1H-pyrrolo[2,3-b]pyridine.
3.81 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 162.13,
160.77, 153.87, 152.47, 150.22, 130.09, 128.09, 113.92,
111.63, 107.70, 105.63, 98.93, 55.45, 31.80. MS(m/z):
255.28 (M + 1).
General Procedure for O-Arylation to Heteroaryl
Halides Under Microwave Heating. 4-Chloro-7-methyl-
7-Methy-4-(pyridin-3-yloxy)-7H-pyrrolo[2,3-d]
pyrimidine (2e)
7H-pyrrolo[2,3-d]pyrimidine
(0.5 mmol),
phenol
Compound 2e was obtained 73% yields as a brown solid.
1
mp: 70–72ꢀC; H NMR (300 MHz, CDCl3) δ 8.61 (s, 1H),
(0.75 mmol), CuI (10 mol%), and K3PO4 (1 mmol) and
DMF (3 mL) were charged 5 mL vial.32,33 The reaction
mixtures were sealed with vial crimp cap and placed in a
Biotage initiator microwave cavity. The microwave heating
was conducted under 180ꢀC for 1 h. The resulting mixtures
were subsequently cooled, diluted with saturated aqueous
ammonium chloride and extracted with ethyl acetate. The
ethyl acetate layer was dried with MgSO4, filtered, and con-
centrated. N-Methyl-4-phenoxy-7H-pyrrolo[2,3-d]pyrimi-
dine (2a) was purified by silicagel column chromatography
8.51 (t, J = 9.0 Hz, 1H),8.43 (s, 1H), 7.66 (d, J = 8.1 Hz,
1H), 7.41(m, 1H), 7.15 (d, J = 3.3 Hz, 1H), 6.59 (d,
J = 3.3 Hz, 1H), 3.90 (s, 3H),). 13C NMR (75 MHz,
CDCl3) δ 161.54, 153.04, 150.45, 149.59, 146.23, 143.76,
129.60, 128.26, 124.06, 105.64, 98.23, 31.58. MS(m/z):
227.26 (M + 1).
1-(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyridin-4
(1H)-one (2f)
1
using a hexane:ethyl acetate = 1:1. mp: 82–86ꢀC. H NMR
Compound 2f was obtained 15% yields as a purple solid.
(300 MHz, CDCl3) δ 8.50 (s, 1H), 7.50–7.42 (m, 2H),
7.33–7.22 (m, J = 1.2 Hz, 3H), 7.08 (d, J = 3.5 Hz, 1H),
6.39 (d, J = 3.5 Hz, 1H), 3.90 (s, 3H). 13C NMR (75 MHz,
CDCl3) δ 162.37, 152.99, 152.92, 150.84, 129.67, 127.73,
125.55, 121.82, 105.67, 98.54, 31.55. MS(m/z): 225.25
(M + 1).
The Heteroaryl-Aryl Eher Products (2b–2l) Were Pre-
pared With General Procedure for O-Arylation to
Heteroaryl Halide
1
mp: 160–162ꢀC; H NMR (300 MHz, CDCl3) δ 8.78 (s,
1H), 8.47–8.33(m, 2H), 7.37(d, J = 3.6 Hz, 1H), 6.70 (d,
J = 3.6 Hz, 1H), 6.61–6.51(m, 2H 3.97 (s, 3H), 13C NMR
(75 MHz, CDCl3) δ 180.11, 153.55, 150.66, 150.55,
136.65, 131.03, 119.08, 107.35, 31.79. MS(m/z): 227.23
(M + 1).
7-Isopropyl-4-phenoxy-7H-pyrrolo[2,3-d]pyrimidine (2g)
Compound 2g was obtained 94% yields as a yellow oil. H
1
3-((7-Methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)
benzaldehyde (2b)
NMR (300 MHz, CDCl3) δ 8.45 (d, J = 5.6 Hz, 1H), 7.43
(dt, J = 5.6, 3.6 Hz, 2H), 7.28–7.21 (m, 3H), 7.19 (d,
J = 3.5 Hz, 1H), 6.43 (d, J = 3.6 Hz, 1H), 5.12 (m, 1H),
1.54 (s, 3H), 1.51 (s, 3H). 13C NMR (75 MHz, CDCl3) δ
162.37, 153.05, 152.12, 150.55, 129.66, 125.51, 123.12,
121.84, 115.51, 105.87, 98.63, 46.35, 22.83. MS(m/z):
253.31 (M + 1).
Compound 2b was obtained 79% yields as a yellow solid.
1
mp: 137–139ꢀC. H NMR (300 MHz, CDCl3) δ 10.03 (s,
1H), 8.45 (s, 1H), 7.81–7.76 (m, 2H), 7.65–7.59 (m, 1H),
7.53 (ddd, J = 8.1, 2.2, 1.5 Hz, 1H), 7.12 (d, J = 3.5 Hz,
1H), 6.57 (d, J = 3.5 Hz, 1H), 3.89 (s, 3H). 13C NMR
(75 MHz, CDCl3) δ 191.34, 161.75, 153.57, 153.07,
150.63, 137.93, 130.29, 128.15, 128.03, 126.85, 122.45,
105.75, 98.26, 31.55. MS(m/z): 253.26 (M + 1).
7-Isopropyl-4-(2-methoxyphenoxy)-7H-pyrrolo[2,3-d]
pyrimidine (2h)
Compound 2h was obtained 66% yields as white solid. mp:
4-(4-Nitrophenoxy)-7-methyl-7H-pyrrolo[2,3-d]
pyrimidine (2c)
1
87–90ꢀC, H NMR (300 MHz, CDCl3) δ 8.42 (s, 1H), 7.24
(dd, J = 9.0, 3.6 Hz, 2H), 7.18 (d, J = 3.6 Hz, 1H), 7.07–
6.98 (m, 2H), 6.52 (d, J = 3.6 Hz, 1H), 5.11 (m, 1H), 3.74
(s, 3H), 1.54 (s, 3H), 1.51 (s, 3H). 13C NMR (75 MHz,
CDCl3) δ 162.35, 152.10, 151.88, 150.61, 141.80, 126.67,
123.29, 122.82, 121.04, 112.92, 105.40, 98.55, 55.93,
46.26, 22.84. MS(m/z): 283.33 (M + 1).
Compound 2c was obtained 75% yields as a yellow solid.
1
mp: 118–120ꢀC. H NMR (300 MHz, CDCl3) δ 8.36 (s,
1H), 8.15–8.11 (m, 1H), 7.75–7.68 (m, 1H), 7.47–7.40 (m,
2H), 7.14 (d, J = 3.5 Hz, 1H), 6.67 (d, J = 3.5 Hz, 1H),
3.89 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 161.15,
153.12, 150.30, 146.01, 142.58, 134.67, 128.34, 126.17,
125.83, 125.61, 105.48, 98.28, 31.58. MS(m/z): 270.25
(M + 1).
4-((7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)
benzaldehyde (2i)
4-(3-Methoxyphenoxy)-7-methyl-7H-pyrrolo[2,3-d]
pyrimidine (2d)
Compound 2i was obtained 59% yields as green solid. mp:
1
106–109ꢀC. H NMR (300 MHz, CDCl3) δ 10.02 (s, 1H),
Compound 2d was obtained 79% yields as a brown solid.
mp: 97–102ꢀC; 1H NMR (300 MHz, CDCl3) δ 8.52 (s,
1H), 7.34 (t, J = 8.1 Hz, 1H), 7.09 (d, J = 3.5 Hz, 1H),
6.88–6.78 (m, 3H), 6.36 (d, J = 3.5 Hz, 1H), 3.91 (s, 3H),
8.46 (s, 1H), 7.99 (d, J = 1.6 Hz, 2H), 7.42 (d, J = 8.4 Hz,
2H), 7.27 (d, J = 3.6 Hz, 1H), 6.58 (d, J = 3.6 Hz, 1H),
5.14 (m, 1H), 1.57 (d, J = 6.9 Hz, 6H). 13C NMR
(75 MHz, CDCl3) δ 190.97, 161.32, 158.07, 152.37,
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150.23, 133.47, 131.48, 123.84, 122.21, 106.18, 98.34,
46.52, 22.81. MS(m/z): 281.32 (M + 1).
4-(3,4-Dimethoxyphenoxy)-1-methyl-1H-pyrrolo[2,3-b]
pyridine (4c)
Compound 4c was obtained 48% yield as brown solid. mp:
121–123ꢀC. 1H NMR (300 MHz, CDCl3) δ 8.02 (d,
J = 5.5 Hz, 1H), 6.91 (d, J = 3.5 Hz, 1H), 6.73 (d, J = 8.4 Hz,
1H), 6.60 (d, J = 2.5 Hz, 1H), 6.57 (dd, J = 4.2 Hz,
J = 1.2 Hz, 1H), 6.29 (d, J = 5.5 Hz, 1H), 6.19 (d, J = 3.5 Hz,
1H), 3.76 (s, 3H), 3.74 (s, 3H), 3.69 (s, 3H). 13C NMR
(75 MHz, CDCl3) δ 158.80, 150.42, 149.88, 148.65, 146.37,
144.44, 127.39, 112.17, 111.55, 110.92, 105.27, 102.03,
96.99, 56.25, 56.02, 31.56. MS(m/z): 284.32 (M + 1).
7-Methyl-2-phenoxy-7H-pyrrolo[2,3-d]pyrimidine (2j)
Compound 2j was obtained 96% yields as solid mp: 70–
1
72ꢀC. H NMR (300 MHz, CDCl3) δ 8.56 (s, 1H), 7.29–
7.05 (m, 5H), 6.90 (d, J = 3.6 Hz, 1H), 6.35 (d,
J = 3.6 Hz), 3.62 (s, 3H). 13C NMR (75 MHz, CDCl3) δ
161.1, 153.9, 152.9, 150.7, 129.3, 124.7, 121.4, 119.6,
115.58, 99.8, 30.80. MS(m/z): 226.25 (M + 1).
2-(2-Methoxyphenoxy)-7-methyl-7H-pyrrolo[2,3-d]
pyrimidine (2k)
3-((1-Methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy)
benzaldehyde (4d)
Compound 2k was obtained 70% yields as solid. mp: 110–
Compound 4d was obtained 54% yield as yellow solid.
1
112ꢀC. H NMR (300 MHz, CDCl3) δ 8.63(s, 1H),, 7.23
1
mp: 75–77ꢀC; H NMR (300 MHz, CDCl3) δ 9.99 (s, 1H),
(m, 2H), 7.05–7.00 (m, 3H), 6.45 (d, J = 3.6 Hz, 1H), 3.76
(s, 3H), 3.73(s, 3H). 13C NMR (75 MHz, CDCl3) δ 161.34,
153.17, 151.88, 150.68, 128.99, 125.95, 122.99, 120.96,
115.33, 112.80, 99.67, 55.90, 30.83. MS(m/z): 256.27
(M + 1).
8.24 (d, J = 5.4 Hz, 1H), 7.73 (dt, J = 7.5, 1.2 Hz, 1H),
7.64–7.61 (m, 1H), 7.57 (t, J = 7.8 Hz, 1H), 7.42 (ddd,
J = 8.1, 2.5, 1.1 Hz, 1H), 7.08 (d, J = 3.5 Hz, 1H), 6.55 (d,
J = 5.4 Hz, 1H), 6.26 (d, J = 3.5 Hz, 1H), 3.90 (d,
J = 4.8 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 191.36,
156.95, 156.34, 150.52, 144.39, 138.16, 130.60, 128.12,
126.03, 125.96, 120.12, 111.68, 103.65, 96.91, 31.67.
MS(m/z): 252.27 (M + 1).
7-Methyl-2-(pyridine-3-yloxy)-7H-pyrrolo[2,3-d]
pyrimidine (2l)
Compound 2l s obtained 75 yields as red soild. mp: 110–
1
112ꢀC. H NMR (300 MHz, CDCl3) δ 8.70(s, 1H), 8.62(d,
1-Methyl-4(pyridine-3-yloxy)-1H-pyrrolo[2,3-b]
pyridine (4e)
J = 2.1 Hz, 1H), 8.48(d, J = 4.5 Hz, 1H), 7.63 (dd, J = 8.1,
1.2 Hz), 7.37 (m, 1H),707 (d, J = 3.6 Hz, 1H), 6.52 (d,
J = 3.6 Hz, 1H), 3.76 (s, 3H). 13C NMR (75 MHz, CDCl3)
δ 160.34, 152.59, 150.65, 150.32, 145.52, 143.66, 129.50,
123.79, 115.83, 99.86, 30.76. MS(m/z): 226.23 (M + 1).
Compound 4e was obtained 65% yield from 4-bromo-1-
methyl-1H-pyrrolo[2,3-b]pyridine and 3-hydorxypyridine
1
as a yellow oil. H NMR (300 MHz, CDCl3) δ 8.54 (s,
1H), 8.48 (d, J = 5.4 Hz, 1H),8.23 (d, J = 5.4 Hz, 1H),
7.45–7.34 (m, 2H), 7.10 (d, J = 3.5 Hz, 1H), 6.52 (d,
J = 5.4 Hz, 1H), 6.30 (d, J = 3.6 Hz, 1H), 3.90 (s, 3H). 13C
NMR (75 MHz, CDCl3) δ 156.97, 152.11, 150.58, 145.70,
144.43, 142.20, 127.21, 128.12, 124.20, 111.40, 103.16,
96.86, 31.63. MS(m/z): 226.25 (M + 1).
The O-arylated-1H-pyrrolo[2,3-b]pyridines (4a–4h) Were
Prepared by above Described General Procedure for O-
Arylation to Heteroaryl Halide Under Microwave
Heating
1-Methyl-4-phenoxy-1H-pyrrolo[2,3-b]pyridine (4a)
Compound 4a was obtained 87% yield from 4-bromo-1-
methyl-1H-pyrrolo[2,3-b]pyridine and phenol as a yellow
oil. 1H NMR (300 MHz, CDCl3) δ 8.18 (d, J = 5.5 Hz, 1H),
7.44–7.37 (m, 2H), 7.25–7.12 (m, 3H), 7.06 (d, J = 3.5 Hz,
1H), 6.48 (d, J = 5.5 Hz, 1H), 6.31 (d, J = 3.5 Hz, 1H), 3.89
(s, 3H). 13C NMR (75 MHz, CDCl3) δ 158.07, 155.28,
150.48, 144.42, 129.87, 127.54, 124.74, 120.49, 111.38,
102.88, 97.04, 31.59. MS(m/z): 224.26 (M + 1).
1-Isopropyl-4-phenoxy-1H-pyrrolo[2,3-b]pyridine (4f)
Compound 4f was obtained 78% yield from 4-chloro-1-iso-
propyl -1H-pyrrolo[2,3-b]pyridine and phenol as a yellow
1
oil. H NMR (300 MHz, CDCl3) δ 8.17 (d, J = 5.4 Hz,
1H), 7.40–7.13 (m, 5H), 6.48 (d, J = 3.6 Hz, 1H), 6.34 (d,
J = 3.6 Hz, 1H), 5.19 (m, 1H), 0.150 (d.J = 6.9 Hz, 6H).
13C NMR (75 MHz, CDCl3) δ 158.04, 155.27, 149.62,
144.01, 129.86, 124.73, 122.67, 120.56, 115.47, 111.54,
102,85, 97.21, 45.67, 22.93 MS(m/z): 253.32 (M + 1).
4-(2-Methoxyphenoxy)-1-methyl-1H-pyrrolo[2,3-b]
pyridine (4b)
Compound 4b was obtained 55% yield as a yellow oil. H
1
1-Isopropyl-4-(2-methoxyphenoxy-1H-pyrrolo[2,3-b]
pyridine (4g)
NMR (300 MHz, CDCl3) δ 8.14 (d, J = 5.4 Hz, 1H), 7.22
(d, J = 8.0 Hz, 1H), 7.15 (d, J = 7.6 Hz, 1H), 7.05 (d,
J = 2.1 Hz, 1H), 7.02 (d, J = 5.5 Hz, 1H), 6.97 (d,
J = 7.9 Hz, 1H), 6.36 (d, J = 5.5 Hz, 1H), 6.34 (d,
J = 4.0 Hz, 1H), 3.87 (s, 3H), 3.78 (s, 3H). 13C NMR
(75 MHz, CDCl3) δ 158.59, 151.91, 150.37, 144.34,
143.39, 127.25, 126.24, 122.68, 121.18, 113.03, 110.65,
101.50, 96.95, 55.98, 31.57. MS(m/z): 254.29 (M + 1).
Compound 4g was obtained 78% yield from 4-chloro-1-iso-
propyl-1H-pyrrolo[2,3-b]pyridine and 2-methoxyphenol as
a yellow oil. 1H NMR (300 MHz, CDCl3) δ 8.04 (d,
J = 5.4 Hz, 1H), 7.20–7.04 (m, 4H), 6.32(d, 3.6 Hz, 1H),
6.25 (d, J = 3.6 Hz, 1H), 6.34 (d, J = 3.6 Hz, 1H), 5.15 (m,
1H),, 3.72 (s, 3H), 0.144 (d, J= 6.9 Hz, 6H). 13C NMR
(75 MHz, CDCl3) δ 158.58, 151.98, 143.88, 143.35,
Bull. Korean Chem. Soc. 2020, Vol. 41, 837–842
© 2020 Korean Chemical Society, Seoul & Wiley-VCH GmbH
www.bkcs.wiley-vch.de
841

Diversification of Heteroaryl-Aryl ether via Microwave heating
BULLETIN OF THE
Article
KOREAN CHEMICAL SOCIETY
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1-Isopropyl-4- (pyridine-3-yloxy)-1H-pyrrolo[2,3-b]
pyridine (4h)
Compound 4h was obtained 60% yield from 4-chloro-1-iso-
propyl -1H-pyrrolo[2,3-b]pyridine and 3-hydroxypyridine as
yellow oil. 1H NMR (300 MHz, CDCl3) δ 8.47 (d, J = 2.6 Hz,
1H), 8.41(d, 1H, J = 5.4 Hz, 8.13 (d, J = 5.4 Hz, 1H), 7.39–
7.17 (m, 3H), 6.43 (d, 3.6 Hz, 1H), 6.25 (d, J = 3.6 Hz, 1H),
6.34 (d, J = 3.6 Hz, 1H), 5.15 (m, 1H), 0.146 (d, J = 6.9 Hz,
6H). 13C NMR (75 MHz, CDCl3) δ 156.88, 152.15, 145.65,
144.05, 142.61, 127.26, 124.21, 123.31, 111.55, 103.18. 97.00,
45.78, 22.90. MS(m/z): 254.30 (M + 1).
Conclusions
We examined ligand-free, copper-catalyzed O-arylation
with heteroaryl chlorides and bromides under microwave
heating. Diverse O-arylated-7H-pyrrolo[2,3-d]pyrimidines
and 7-azaindole derivatives were obtained using relatively
low amounts of Cu catalyst and a variety of heteroaromatic
halides and phenols under ligand-free conditions. The syn-
thetic methods described herein would be useful for the
rapid preparation of biologically active compounds while
reducing waste, time, and saving energy.
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Acknowledgment. This research has been performed as a
cooperation project of “Enhancement of Korea Chemical Bank”
and supported by the KRICT. The authors appreciate the finan-
cial support from Basic Science Research Capacity Enhance-
ment Project through KBSI (National Research Facilities and
Equipment Center) grant funded by the Ministry of Education.
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Bull. Korean Chem. Soc. 2020, Vol. 41, 837–842
© 2020 Korean Chemical Society, Seoul & Wiley-VCH GmbH
www.bkcs.wiley-vch.de
842