Metal-free (Boc)2O-mediated C4-selective direct indolation of pyridines using TEMPO

Article abstract of DOI:10.1039/c4ob00356j

Direct metal-free C-4-selective indolation of pyridines is achieved for the first time using TEMPO and (Boc)₂O. A variety of substituents on both indoles and pyridines are tolerated to give 3-(pyridin-4-yl)-1H-indole derivatives in moderate to excellent yields. This finding provides a novel approach for developing metal-free C-H functionalization of pyridines. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4ob00356j

Organic &
Biomolecular Chemistry
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Metal-free (Boc)2O-mediated C4-selective direct
indolation of pyridines using TEMPO†
Cite this: Org. Biomol. Chem., 2014,
12, 4252
Wen-Bing Qin, Jia-Yi Zhu, Yu-Bo Kong, Yun-Hong Bao, Zheng-Wang Chen and
Liang-Xian Liu*
Received 16th February 2014,
Accepted 21st April 2014
Direct metal-free C-4-selective indolation of pyridines is achieved for the first time using TEMPO and
(Boc)2O. A variety of substituents on both indoles and pyridines are tolerated to give 3-(pyridin-4-yl)-1H-
indole derivatives in moderate to excellent yields. This finding provides a novel approach for developing
metal-free C–H functionalization of pyridines.
DOI: 10.1039/c4ob00356j
www.rsc.org/obc
Introduction
Substituted pyridines are important intermediates in the syn-
thesis of pharmaceuticals and functional materials.1 In
addition, a pyridine core plays a key role in a number of
natural products, pharmaceuticals, ligands, and functional
materials. However, the presence of electron-withdrawing and
Lewis-basic sp2 nitrogen limits a repertoire of methods to
decorate the heteroaromatic ring.2 The chemistry to directly
functionalize pyridine remains a significant challenge due to the
poor chemoselectivity and the lower energy of the π-system
relative to benzene.3 As a result, most of the synthetic methods
require prefunctionalization, for example by halogenation or
metalation, before subsequent coupling reactions owing to the
low reactivity of pyridine derivatives towards aromatic electro-
philic substitution reactions such as the Friedel–Crafts
reaction.4
These factors have led to the use of pyridines functionalized
at nitrogen to generate cationic pyridinium salts or neutral,
but similarly activated, pyridinium ylides. Generally, the direct
alkylation and arylation of pyridines were carried out using
derivatives (e.g., N-oxides5 and N-iminopyridinium ylides6) ((1) in
Scheme 1 Regioselective direct alkylation and arylation of pyridines.
Scheme 1). However, this approach necessitates two additional significant progress in this field has been achieved.7–12 More
steps: activation of the pyridine starting material, and then recently, Knochel and co-workers reported a novel transition-
unmasking of the arylated product. The use of pyridines directly metal-free BF3·OEt2 mediated regioselective synthesis of 4-sub-
would clearly represent the ideal situation in terms of both cost stituted pyridine derivatives using LiCl activated Grignard or
and simplicity. To tackle such a problem, methodologies for the organozinc reagents. Despite such progress, the direct indola-
direct alkylation and arylation of pyridines have been develo- tion of pyridines still remained elusive ((3) in Scheme 1).13 As
ped. Recently, transition-metal-catalyzed pyridyl C–H function- a solution, we report a novel metal-free regioselective direct
alizations have received extensive attention. Accordingly, indolation of pyridines using TEMPO and (Boc)2O.
We commenced our study with the reaction of 1a with pyri-
dine and TBHP as an oxidant (Table 1). To our delight, the
Key Laboratory of Organo-Pharmaceutical Chemistry of Jiangxi Province, Gannan
reaction in (Boc)2O at rt for 24 h afforded the desired product
Normal University, Ganzhou 341000, PR China. E-mail: liuliangxian1962@163.com
3a in 17% yield (entry 1). To our knowledge, this is the first
†Electronic supplementary information (ESI) available. CCDC 983539. For ESI
example of a metal-free regioselective direct synthesis of tert-
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
butyl 3-(pyridin-4-yl)-1H-indole-1-carboxylate using (Boc)2O
c4ob00356j
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Table 1 Optimization of reaction conditionsa
Table 2 Oxidative coupling reaction of indoles with pyridinesa
Yieldb
(%)
R1
R2
Product
t (h)
(Boc)2O
(equiv.)
Temp
(°C)
Yieldb
(%)
Entry
Entry
Oxidant (equiv.)
1
2
3
4
5
6
7
8
H
5-F
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
24
24
24
24
24
24
36
24
24
24
24
24
24
24
36
30
30
24
48
48
48
48
48
48
80
75
71
82
80
76
56
77
72
79
60
80
84
88
46
75
90
74
57
68
56
70
65
Trace
1
2
3
4
5
6
7
8
TBHP (2.0)
H2O2 (2.0)
DDQ (1.2)
TEMPO (0.3)
—
TEMPO (0.3)
TEMPO (0.3)
TEMPO (0.3)
TEMPO (0.3)
TEMPO (0.2)
TEMPO (0.6)
TEMPO (0.7)
TEMPO (0.8)
TEMPO (0.7)
TEMPO (0.7)
TEMPO (0.7)
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
—
2.0
2.0
2.0
1.0
1.5
2.5
25
25
25
25
25
0
10
35
45
10
10
10
10
10
10
10
17
0
5-Br
5-Me
5-OMe
5-OBn
5-CN
6-F
23
35
Trace
36
45
23
Trace
0
62
80
78
36
70
79
9
6-Cl
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
6-OBn
6-CO2Me
7-Cl
7-Me
7-OBn
7-NO2
2-Me
2-Ph
H
10
11
12
13
14
15
16
H
3-CN
2-(p-Cl-Bn)
2-Bn
2-(p-Cl-Bn)
2-(p-Cl-Bn)
2-Bn
a Reaction conditions: indole (0.5 mmol), pyridine (0.8 mmol).
b Isolated yield.
5-F
3s
3t
3u
3v
3w
3x
5-Me
5-Me
6-F
6-F
H
as an activating agent. Hannah and co-workers reported a
chemoselective four-step Suzuki reaction towards 6-bromo-
3-(pyridin-4-yl)-1H-indole, which was found to be an IMPDA
inhibitor.14
2-CH3
a Reaction conditions: indole (0.5 mmol), pyridine (0.8 mmol), TEMPO
(0.35 mmol), (BoC)2O (1.0 mmol). b Isolated yield.
Encouraged by this finding, we continued our investi-
gations by optimizing the reaction conditions (Table 1). A
screen of oxidants showed that TEMPO was more efficient
than TBHP, H2O2, and DDQ (entries 1–4). In contrast to
TEMPO, when H2O2 was used this transformation did not
occur. Besides, only a trace amount of the desired product was
detected when the reaction was performed in the absence of
TEMPO (entry 5). The influence of the solvent was also
studied. When other solvents, such as benzene, toluene, DCM,
and THF, were applied, a trace or none of the desired product
was observed. To our delight, the yield of 3a was improved to
62% when the reaction was carried out in the absence of a
solvent at 10 °C (entry 11). Control experiments indicated that
(Boc)2O is essential for this transformation (entry 10). After
extensive screening of other parameters (see the ESI,
Table S1†), we found that the indolation of pyridine using
TEMPO (70 mol%) in air as an oxidant and pyridine (160 mol%)
in (Boc)2O (200 mol%) at 10 °C led to the highest efficiency
(80% yield, entry 12).
electron-neutral indoles gave reaction products in good to
excellent yields. Electron-donating substituents showed better
results than electron-withdrawing substituents in this trans-
formation. For example, 7-benzyloxy-1H-indole was trans-
formed into 3n in 88% yield (entry 14). Interestingly, we
observed that indoles with strong electron-withdrawing substi-
tuents at the 5 and 7 positions of indoles, such as CN and
NO2, could provide the corresponding products in lower yields
(entries 7 and 15). Sterically encumbered 2-substituted indoles
also proceeded in good to excellent yields, though extended
reaction times were required (entries 16 and 17). Treatment of
3c with a methanolic solution of hydrochloric acid at room
temperature gave the N-Boc-deprotection product 4, which was
confirmed by X-ray crystallography (see ESI†).
Subsequently, the substrate scope of pyridines was then
investigated (entries 18–23). Pyridines with a substituent at C-2
or C-3 on the pyridyl ring could undergo the expected C-4
coupling reaction to give moderate yields. When using the
pyridine with an electron-withdrawing cyano group at the C-3
position as a coupling partner (entry 18), the yield was
obviously higher than those using C-2 substituted pyridines
(entries 19–23). Unexpectedly, only a trace amount of 3x was
detected when 2-methylpyridine was used as a coupling
partner (entry 24).
With optimized conditions established we explored the
scope of the reaction (Table 2). First, a series of substituted
indoles were subjected to react with pyridine (entries 1–17).
The reaction can tolerate a variety of functional groups at the
2, 5, 6, and 7 positions of indoles, such as F, Cl, Br, CH3,
CH3O, Ph, BnO, CO2CH3, CN, and NO2. The substituent effect
on the indole ring was then investigated. Electron-rich and
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Scheme 2 Addition of indole to 4-phenyl pyridine.
The protocol of the present reaction was very simple: the
substrate, reagent, and catalyst were stirred together in simple
glassware. Thus, this reaction could be applied to a large-scale
synthesis without any difficulties. When the reaction of indole
Scheme 5 A plausible pathway for the formation of 3a.
(1.17 g, 10 mmol) was performed with pyridine (1.26 g, 10 to indole leads to the intermediate 11, which is converted
15.9 mmol), (Boc)2O (4.36 g, 20 mmol), and TEMPO (1.09 g, into the intermediate 12 by C-3 proton elimination from the
7 mmol) under the optimized reaction conditions for 24 h, the indole ring. Finally, 12 undergoes aromatization to afford the
desired product was obtained in 81% yield.
corresponding product 3a.
Some control experiments were also established. While
employing pyridine with a phenyl group at the C-4 position as
a coupling partner, it did not afford the expected 3-pyridyl-
indole 6a, only the dihydropyridine N-Boc 6b was obtained in
good yields (Scheme 2). Similarly, when isoquinoline was sub-
jected to the standard reaction conditions, the additive pro-
ducts 8 were obtained in good yields (Scheme 3). In addition,
when H2O was added, a significant decrease in the yield of 3a
was observed (see ESI†).
We next initiated studies to gain more detailed insights
into the role of (Boc)2O in the cross-coupling. Under optimized
conditions, N-Boc indole 9 was chosen as a substrate instead
of indole. To our surprise, no conversion was observed
(Scheme 4), indicating that the substituents at the N1-position
of the indole had a great influence on the reactivity.
Conclusions
In conclusion, the metal-free direct indolation of pyridines by
TEMPO and (Boc)2O has been realized. This reaction has
revealed an efficient and new strategic way to access
3-(pyridin-4-yl)-1H-indole derivatives from readily available
starting materials in one step. The protocol was very simple,
and tolerated an array of functional groups at the 2, 5, 6, and 7
positions of indoles, including F, Cl, Br, CH3, CH3O, Ph, BnO,
CO2CH3, CN, and NO2 groups. In addition, all the reagents
could be used without purification, and the reaction could be
readily applied to a large-scale synthesis without any difficul-
ties. Importantly, our findings further encouraged us to design
and explore such a dehydrogenation based on cross-coupling
because it has great potential in enabling the rapid construc-
tion of functionalized compounds from simple starting
materials in an atom- and step-economical fashion.
Although the exact mechanism of this cross-coupling reac-
tion is still not clear, based on these preliminary results and
previous reports in the literature,13 a tentative reaction path is
proposed in Scheme 5. In the initial step, treatment of 2a with
(Boc)2O affords the intermediate 10. Subsequent addition of
Experimental section
General
Melting points were determined on a digital melting point
apparatus and temperatures were uncorrected. Infrared spectra
were measured with a Nicolet Avatar 360 FT-IR spectrometer
using film KBr pellet techniques. 1H and 13C NMR spectra
were recorded on a Bruker spectrometer at 400 and 100 MHz,
respectively. Chemical shifts were reported in ppm relative to
TMS for 1H and 13C NMR spectra. CDCl3 or DMSO-d6 was used
as the NMR solvent. Mass spectra were recorded with Bruker
Dalton Esquire 3000 plus LC-MS apparatus. Elemental ana-
lyses were carried out on a Perkin-Elmer 240B instrument.
HRFABMS spectra were recorded on a FTMS apparatus. Silica
gel (300–400 mesh) was used for flash column chromato-
graphy, eluting (unless otherwise stated) with an ethyl acetate–
petroleum ether (PE) (60–90 °C) mixture.
Scheme 3 Addition of indole to isoquinoline.
Scheme 4 Reaction of N-Boc indole 9 with pyridine.
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General procedure for the indolation of pyridines
(d, J = 9.0 Hz, 1H, Ar-H), 7.85 (s, 1H, Ar-H), 7.63–7.54 (br s, 2H,
Ar-H), 7.30 (d, J = 2.5 Hz, 1H, Ar-H), 7.04 (dd, J = 9.0, 2.5 Hz,
1H, Ar-H), 3.90 (s, 3H, OCH3), 1.72 (s, 9H, 3 × CH3). 13C NMR
(100 MHz, CDCl3): δ 156.5, 150.3, 149.4, 141.9, 130.7, 128.8,
125.0, 122.3, 119.2, 116.4, 113.6, 102.5, 84.3, 55.8, 28.2.
HRESIMS calcd for [C19H20N2O3 + H]+ 325.15522 (100%),
found 325.15341 (100%).
To a solution of indole (0.5 mmol) and TEMPO (0.35 mmol) in
pyridine (0.8 mmol) was added (Boc)2O (1.0 mmol) under an
air atmosphere and the mixture was stirred at 10 °C for
24–48 h. The reaction mixture was concentrated under reduced
pressure. The residue was purified by flash chromatography on
silica gel (eluent: EtOAc–PE = 1 : 4) to yield the corresponding
product.
tert-Butyl
5-(benzyloxy)-3-(pyridin-4-yl)-1H-indole-1-carb-
oxylate (3f). Rf 0.40 (EtOAc–PE = 1/2). White solid, m.p.
136–137 °C. IR (KBr) νmax: 1730, 1605, 1371, 1225, 1156,
816 cm−1. 1H NMR (400 MHz, CDCl3): δ 8.73 (s, 2H, Ar-H), 8.14
(d, J = 8.7 Hz, 1H, Ar-H), 7.85 (s, 1H, Ar-H), 7.56–7.48 (m, 4H,
Ar-H), 7.43 (dt, J = 6.1, 1.6 Hz, 2H, Ar-H), 7.39–7.35 (m, 2H,
Ar-H), 7.12 (dd, J = 9.1, 2.4 Hz, 1H, Ar-H), 5.16 (s, 2H, OCH2),
1.72 (s, 9H, 3 × CH3). 13C NMR (100 MHz, CDCl3): δ 155.5,
150.2, 149.4, 141.9, 137.1, 130.9, 128.7, 128.6, 128.0, 127.5,
125.0, 122.1, 119.2, 116.4, 114.3, 104.2, 84.4, 70.8, 28.2.
HRESIMS calcd for [C25H24N2O3 + H]+ 401.18652 (100%),
found 401.18503 (100%).
tert-Butyl 3-(pyridin-4-yl)-1H-indole-1-carboxylate (3a). Rf 0.25
(EtOAc–PE = 1/4). White solid, m.p. 90.3–91.8 °C. IR (KBr) νmax
:
1727, 1378, 1243, 1160, 756 cm−1. H NMR (400 MHz, CDCl3):
δ 8.70 (d, J = 5.8 Hz, 2H, Ar-H), 8.26 (d, J = 8.0 Hz, 1H, Ar-H),
7.89 (s, 1H, Ar-H), 7.87 (d, J = 8.0 Hz, 1H, Ar-H), 7.59 (d, J =
5.8 Hz, 2H, Ar-H), 7.43 (t, J = 7.5 Hz, 1H, Ar-H), 7.35 (t, J =
7.5 Hz, 1H, Ar-H), 1.73 (s, 9H, 3 × CH3). 13C NMR (100 MHz,
CDCl3): δ 150.3, 149.4, 141.8, 136.0, 127.9, 125.1, 124.4, 123.4,
122.2, 119.6, 119.4, 115.7, 84.5, 28.2. HRESIMS calcd for
[C18H18N2O2 + H]+ 295.14465 (100%), found 295.14389 (100%).
1
tert-Butyl
5-fluoro-3-(pyridin-4-yl)-1H-indole-1-carboxylate
tert-Butyl 5-cyano-3-(pyridin-4-yl)-1H-indole-1-carboxylate
(3b). Rf 0.20 (EtOAc–PE = 1/4). White solid, m.p. 139–140 °C.
IR (KBr) νmax: 1737, 1598, 1464, 1377, 1258, 1152, 1098, 1051,
(3g). Rf 0.20 (EtOAc–PE
144–145 °C. IR (KBr) νmax: 2225, 1743, 1603, 1465, 1372, 1289,
1254, 1157, 815 cm−1 1H NMR (400 MHz, CDCl3): δ 8.77 (s,
= 1/4). Pale yellow solid, m.p.
804 cm−1 1H NMR (400 MHz, CDCl3): δ 8.71 (s, 2H, Ar-H),
.
.
8.22–8.17 (m, 1H, Ar-H), 7.90 (s, 1H, Ar-H), 7.54 (d, J = 5.6 Hz,
2H, Ar-H), 7.50 (dd, J = 9.1, 2.6 Hz, 1H, Ar-H), 7.14 (dt, J = 2.6,
9.1 Hz, 1H, Ar-H), 1.72 (s, 9H, 3 × CH3). 13C NMR (100 MHz,
CDCl3): δ 159.7 (d, J = 240.2 Hz), 150.4, 149.1, 141.3, 132.4,
128.8 (d, J = 9.6 Hz), 125.7, 122.0, 119.1 (d, J = 4.2 Hz), 116.7
(d, J = 9.1 Hz), 112.9 (d, J = 25.0 Hz), 105.3 (d, J = 24.7 Hz),
84.8, 28.1. HRESIMS calcd for [C18H17FN2O2 + H]+ 313.13523
(100%), found 313.13361 (100%).
2H, Ar-H), 8.38 (d, J = 8.7 Hz, 1H, Ar-H), 8.18 (d, J = 1.3 Hz, 1H,
Ar-H), 7.97 (s, 1H, Ar-H), 7.68 (dd, J = 8.7, 1.3 Hz, 1H, Ar-H),
7.56 (s, 1H, Ar-H), 7.55 (s, 1H, Ar-H), 1.74 (s, 9H, 3 × CH3).
13C NMR (100 MHz, CDCl3): δ 150.6, 148.7, 140.4, 137.8, 128.1,
128.0, 126.2, 124.6, 122.3, 119.4, 119.3, 116.6, 107.0, 85.8, 28.1.
MS (ESI): 320 (M + H+, 100). Anal calcd for C19H17N3O2:
C, 71.46; H, 5.37; N, 13.16. Found C, 71.27; H, 5.63; N, 12.85.
tert-Butyl 6-fluoro-3-(pyridin-4-yl)-1H-indole-1-carboxylate
(3h). Rf 0.20 (EtOAc–PE = 1/4). White solid, m.p. 113–114 °C.
IR (KBr) νmax: 1731, 1601, 1483, 1444, 1388, 1252, 1167,
807 cm−1. 1H NMR (400 MHz, CDCl3): δ 8.71 (d, J = 4.8 Hz, 2H,
Ar-H), 7.98 (dd, J = 8.8, 1.4 Hz, 1H, Ar-H), 7.85 (s, 1H, Ar-H),
7.76 (dd, J = 8.8, 5.3 Hz, 1H, Ar-H), 7.56 (dd, J = 4.8, 1.4 Hz, 2H,
Ar-H), 7.10 (dt, J = 2.4, 8.8 Hz, 1H, Ar-H), 1.72 (s, 9H, 3 × CH3).
13C NMR (100 MHz, CDCl3): δ 161.2 (d, J = 240.7 Hz), 150.4,
149.1, 141.4, 136.3 (d, J = 12.8 Hz), 124.4 (d, J = 3.6 Hz), 124.3,
122.1, 120.4 (d, J = 10.0 Hz), 119.3, 117.0 (d, J = 24.3 Hz), 103.0
(d, J = 28.6 Hz), 84.9, 28.1. HRESIMS calcd for [C18H17FN2O2 + H]+
313.13523 (100%), found 313.13358 (100%).
tert-Butyl 6-chloro-3-(pyridin-4-yl)-1H-indole-1-carboxylate
(3i). Rf 0.30 (EtOAc–PE = 1/4). White solid, m.p. 164–165 °C.
IR (KBr) νmax: 1729, 1600, 1463, 1437, 1382, 1252, 1171,
805 cm−1. 1H NMR (400 MHz, CDCl3): δ 8.70 (d, J = 5.9 Hz, 2H,
Ar-H), 8.30 (s, 1H, Ar-H), 7.85 (s, 1H, Ar-H), 7.76 (d, J = 8.5 Hz,
1H, Ar-H), 7.55 (d, J = 5.9 Hz, 2H, Ar-H), 7.32 (dd, J = 8.5,
1.9 Hz, 1H, Ar-H), 1.73 (s, 9H, 3 × CH3). 13C NMR (100 MHz,
CDCl3): δ 150.4, 149.0, 141.2, 136.4, 131.1, 126.4, 124.7, 124.0,
122.2, 120.4, 119.3, 116.0, 85.1, 28.1. HRESIMS calcd for
[C18H17ClN2O2 + H]+ 329.10568 (100%), 331.10273 (33%),
found 329.10403 (100%), 331.10080 (33%).
tert-Butyl 5-bromo-3-(pyridin-4-yl)-1H-indole-1-carboxylate
(3c). Rf 0.20 (EtOAc–PE = 1 : 4). Pale yellow, m.p. 130.7–132.6 °C.
IR (KBr) νmax: 1744, 1379, 1245, 1160, 756 cm−1 1H NMR
.
(400 MHz, CDCl3): δ 8.70 (d, J = 6.0 Hz, 2H, Ar-H), 8.13 (d, J =
8.8 Hz, 1H, Ar-H), 7.96 (d, J = 1.8 Hz, 1H, Ar-H), 7.86 (s, 1H,
Ar-H), 7.54 (d, J = 6.0 Hz, 1H, Ar-H), 7.52 (d, J = 6.0 Hz, 1H,
Ar-H), 7.50 (dd, J = 8.8, 1.8 Hz, 1H, Ar-H), 1.72 (s, 9H, 3 × CH3).
13C NMR (100 MHz, CDCl3): δ 150.4, 149.0, 141.1, 134.7, 129.6,
128.0, 125.3, 122.3, 122.2, 118.7, 117.1, 116.9, 85.0, 28.2.
HRESIMS calcd for [C18H17BrN2O2 + H]+ 373.05517 (100%),
375.05312 (100%), found 373.05420 (100%), 375.05197 (100%).
tert-Butyl 5-methyl-3-(pyridin-4-yl)-1H-indole-1-carboxylate
(3d). Rf 0.20 (EtOAc–PE = 1/4). White solid, m.p. 124–125 °C.
IR (KBr) νmax: 1725, 1601, 1371, 1243, 1150 cm−1 1H NMR
.
(400 MHz, CDCl3): δ 8.70 (d, J = 5.7 Hz, 2H, Ar-H), 8.12 (d, J =
8.3 Hz, 1H, Ar-H), 7.84 (s, 1H, Ar-H), 7.65 (s, 1H, Ar-H), 7.59 (d,
J = 5.7 Hz, 2H, Ar-H), 7.24 (d, J = 8.3 Hz, 1H, Ar-H), 2.51 (s, 3H,
CH3), 1.72 (s, 9H, 3 × CH3). 13C NMR (100 MHz, CDCl3):
δ 150.2, 149.5, 141.9, 134.2, 133.0, 128.1, 126.4, 124.4, 122.3,
119.5, 119.1, 115.3, 84.3, 28.2, 21.5. HRESIMS calcd for
[C19H20N2O2 + H]+ 309.16030 (100%), found 309.15875 (100%).
tert-Butyl 5-methoxy-3-(pyridin-4-yl)-1H-indole-1-carboxylate
(3e). Rf 0.40 (EtOAc–PE = 1/2). White solid, m.p. 106–107 °C.
tert-Butyl 6-(benzyloxy)-3-(pyridin-4-yl)-1H-indole-1-carb-
oxylate (3j). Rf 0.38 (EtOAc–PE = 1/2). White solid, m.p.
IR (KBr) νmax: 1723, 1608, 1385, 1249, 1164, 1115 cm−1
.
1H NMR (400 MHz, CDCl3): δ 8.85–8.60 (br s, 2H, Ar-H), 8.14 135–136 °C. IR (KBr) νmax: 1733, 1601, 1374, 1227, 1152,
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815 cm−1. 1H NMR (400 MHz, CDCl3): δ 8.68 (s, 2H, Ar-H), 7.94 C25H24N2O3: C, 74.98; H, 6.04; N, 7.00. Found C, 74.67;
(s, 1H, Ar-H), 7.78 (s, 1H, Ar-H), 7.74 (d, J = 8.7 Hz, 1H, Ar-H), H, 6.32; N, 6.86.
7.58 (d, J = 4.3 Hz, 2H, Ar-H), 7.51 (dd, J = 8.4, 1.3 Hz, 2H,
Ar-H), 7.44 (dt, J = 1.3, 8.4 Hz, 2H, Ar-H), 7.37 (dt, J = 2.4, (3o). Rf 0.20 (EtOAc–PE = 1/2). Yellow solid, m.p. 116–118 °C.
8.4 Hz, 1H, Ar-H), 7.07 (dd, J = 8.7, 2.4 Hz, 1H, Ar-H), 5.19 (s, IR (KBr) νmax: 1745, 1606, 1531, 1371, 1259, 1149, 818 cm−1
tert-Butyl 7-nitro-3-(pyridin-4-yl)-1H-indole-1-carboxylate
.
1H, OCH2), 1.71 (s, 9H, 3 × CH3). 13C NMR (100 MHz, CDCl3): 1H NMR (400 MHz, CDCl3): δ 8.75 (s, 2H, Ar-H), 8.08 (dd, J =
δ 157.4, 150.2, 149.5, 141.9, 137.1, 136.9, 128.6, 128.0, 127.6, 8.0, 0.8 Hz, 1H, Ar-H), 7.91 (s, 1H, Ar-H), 7.88 (dd, J = 8.0, 0.8
123.1, 122.2, 121.9, 120.2, 119.4, 113.4, 100.9, 84.3, 70.5, 28.2. Hz, 1H, Ar-H), 7.56 (d, J = 8.0 Hz, 2H, Ar-H), 7.45 (t, J = 8.0 Hz,
HRESIMS calcd for [C25H24N2O3 + H]+ 401.18652 (100%), 1H, Ar-H), 1.65 (s, 9H, 3 × CH3). 13C NMR (100 MHz, CDCl3):
found 401.18460 (100%).
δ 150.5, 148.3, 140.5, 139.5, 131.6, 127.8, 126.2, 124.6, 123.1,
1-tert-Butyl 6-methyl 3-(pyridin-4-yl)-1H-indole-1,6-dicarb- 122.5, 120.9, 119.5, 86.8, 27.9. MS (ESI): 340 (M + H+, 100), 362
oxylate (3k). Rf 0.30 (EtOAc–PE = 1/2). Pale yellow solid, (M + Na+, 15). Anal calcd for C18H17N3O4: C, 63.71; H, 5.05;
m.p. 135–137 °C. IR (KBr) νmax: 1740, 1717, 1604, 1438, 1377, N, 12.38. Found C, 63.98; H, 4.89; N, 12.02.
1298, 1241, 1189, 1155, 1100 cm−1. 1H NMR (400 MHz, CDCl3):
δ 8.97 (s, 1H, Ar-H), 8.73 (dd, J = 5.9, 1.4 Hz, 2H, Ar-H), 8.05 (3p). Rf 0.20 (EtOAc–PE
tert-Butyl 2-methyl-3-(pyridin-4-yl)-1H-indole-1-carboxylate
1/6). Pale yellow solid, m.p.
=
(dd, J = 8.4, 1.4 Hz, 1H, Ar-H), 8.02 (s, 1H, Ar-H), 7.89 (d, J = 80–81 °C. IR (KBr) νmax: 1736, 1603, 1358, 1319, 1152, 1119,
8.4 Hz, 1H, Ar-H), 7.58 (d, J = 5.9 Hz, 2H, Ar-H), 3.99 (s, 3H, 834 cm−1. 1H NMR (400 MHz, CDCl3): δ 8.73 (s, 2H, Ar-H), 8.19
OCH3), 1.75 (s, 9H, 3 × CH3). 13C NMR (100 MHz, CDCl3): (d, J = 8.4 Hz, 1H, Ar-H), 7.49 (d, J = 7.6 Hz, 1H, Ar-H), 7.40 (d,
δ 167.3, 150.4, 149.0, 141.1, 135.5, 131.5, 127.0, 126.8, 124.5, J = 7.6 Hz, 2H, Ar-H), 7.33 (dt, J = 1.0, 7.6 Hz, 1H, Ar-H), 7.25
112.2, 119.4, 119.3, 117.6, 85.2, 52.2, 28.1. MS (ESI): 353 (dt, J = 8.4, 1.0 Hz, 1H, Ar-H), 2.65 (s, 3H, CH3), 1.74 (s, 9H,
(M + H+, 100). Anal calcd for C20H20N2O4: C, 68.17; H, 5.72; N, 3 × CH3). 13C NMR (100 MHz, CDCl3): δ 150.5, 150.0, 142.4,
7.95. Found C, 67.83; H, 6.01; N, 7.72.
tert-Butyl 7-chloro-3-(pyridin-4-yl)-1H-indole-1-carboxylate 84.3, 28.3, 14.8. MS (ESI): 309 (M + H+, 100). Anal calcd
(3l). Rf 0.30 (EtOAc–PE = 1/2). Amorphous solid. IR (KBr) νmax for C19H20N2O2: C, 74.00; H, 6.54; N, 9.08. Found C, 73.88;
1753, 1605, 1353, 1266, 1152 cm−1. 1H NMR (400 MHz, CDCl3): H, 6.73; N, 8.89.
135.8, 134.8, 128.3, 125.0, 124.1, 123.1, 118.5, 118.2, 115.6,
:
δ 8.71 (s, 2H, Ar-H), 7.80 (s, 1H, Ar-H), 7.75 (dd, J = 7.9, 0.9 Hz,
tert-Butyl 2-phenyl-3-(pyridin-4-yl)-1H-indole-1-carboxylate
1H, Ar-H), 7.54 (d, J = 7.9 Hz, 2H, Ar-H), 7.43 (dd, J = 7.9, (3q). Rf 0.31 (EtOAc–PE
= 1/4). Pale yellow solid, m.p.
0.9 Hz, 1H, Ar-H), 7.27 (t, J = 7.9 Hz, 1H, Ar-H), 1.70 (s, 9H, 136–138 °C. IR (KBr) νmax: 1727, 1604, 1357, 1321, 1154 cm−1
.
3 × CH3). 13C NMR (100 MHz, CDCl3): δ 150.3, 148.5, 141.2, 1H NMR (400 MHz, CDCl3): δ 8.52 (d, J = 3.4 Hz, 2H, Ar-H),
132.9, 131.4, 127.8, 127.2, 124.3, 122.4, 121.0, 119.2, 118.2, 8.35 (d, J = 8.4 Hz, 1H, Ar-H), 7.63 (d, J = 7.8 Hz, 1H, Ar-H),
85.2, 27.9. MS (ESI): 329 (M + H+, 100), 331 (M + H+, 30). Anal 7.44 (dt, J = 1.2, 7.3 Hz, 1H, Ar-H), 7.39–7.31 (m, 4H, Ar-H),
calcd for C18H17ClN2O2: C, 65.75; H, 5.21; N, 8.52. Found C, 7.30–7.26 (m, 2H, Ar-H), 7.15 (d, J = 5.9 Hz, 2H, Ar-H)), 1.28 (s,
65.61; H, 5.36; N, 8.20.
9H, 3 × CH3). 13C NMR (100 MHz, CDCl3): δ 149.9, 149.6,
142.0, 136.9, 136.6, 133.2, 130.2, 130.1, 128.1, 128.0, 125.1,
124.8, 124.7, 123.4, 119.0, 115.5, 83.8, 27.5. MS (ESI): 371
(M + H+, 100). Anal calcd for C24H22N2O2: C, 77.81; H, 5.99;
N, 7.56. Found C, 77.65; H, 6.18; N, 7.39.
tert-Butyl 7-methyl-3-(pyridin-4-yl)-1H-indole-1-carboxylate
(3m). Rf 0.35 (EtOAc–PE = 1/2). Amorphous solid. IR (KBr)
νmax: 1750, 1604, 1355, 1260, 1225, 1152 cm−1 1H NMR
.
(400 MHz, CDCl3): δ 8.70 (s, 2H, Ar-H), 7.77 (s, 1H, Ar-H), 7.68
(d, J = 7.5 Hz, 1H, Ar-H), 7.57 (d, J = 5.6 Hz, 2H, Ar-H), 7.27 (t,
J = 7.5 Hz, 1H, Ar-H), 7.22 (d, J = 5.6 Hz, 1H, Ar-H), 2.68 (s, 3H,
CH3), 1.69 (s, 9H, 3 × CH3). 13C NMR (100 MHz, CDCl3):
δ 150.2, 149.2, 141.9, 135.6, 129.3, 128.4, 126.6, 126.0, 123.8,
122.5, 119.5, 117.1, 84.1, 28.0, 22.1. MS (ESI): 309 (M + H+,
100). Anal calcd for C19H20N2O2: C, 74.00; H, 6.54; N, 9.08.
Found C, 73.63; H, 6.91; N, 8.71.
tert-Butyl 3-(3-cyanopyridin-4-yl)-1H-indole-1-carboxylate
(3r). Rf 0.33 (EtOAc–PE
116–118 °C. IR (KBr) νmax: 2231, 1725, 1608, 1374, 1259, 1160,
1094, 1055, 798 cm−1 1H NMR (400 MHz, CDCl3): δ 9.15 (s,
= 1/4). Pale yellow solid, m.p.
.
2H, Ar-H), 8.30 (d, J = 8.3 Hz, 1H, Ar-H), 8.22 (s, 1H, Ar-H),
7.95–7.80 (br s, 1H, Ar-H), 7.72 (d, J = 7.9 Hz, 1H, Ar-H), 7.47
(dt, J = 0.9, 8.3 Hz, 1H, Ar-H), 7.38 (dt, J = 0.9, 7.9 Hz, 1H,
Ar-H), 1.73 (s, 9H, 3 × CH3). 13C NMR (100 MHz, CDCl3): δ
153.9, 152.0, 149.0, 145.1, 135.7, 127.4, 126.9, 125.6, 123.7,
119.2, 116.9, 115.9, 115.4, 85.1, 28.1. MS (ESI): 320 (M + H+,
100). Anal calcd for C19H17N3O2: C, 71.46; H, 5.37; N, 13.16.
Found C, 71.20; H, 5.61; N, 12.83.
tert-Butyl 3-(2-(4-chlorobenzyl)pyridin-4-yl)-5-fluoro-1H-indole-
1-carboxylate (3s). Rf 0.25 (EtOAc–PE = 1/6). Pale yellow solid,
m.p. 131–133 °C. IR (KBr) νmax: 1725, 1609, 1374, 1260, 1161,
798 cm−1. 1H NMR (400 MHz, CDCl3): δ 8.64 (d, J = 5.2 Hz, 1H,
Ar-H), 8.18 (dd, J = 8.5, 4.1 Hz, 1H, Ar-H), 7.86 (s, 1H, Ar-H),
7.41 (dd, J = 8.9, 2.4 Hz, 1H, Ar-H), 7.38 (dd, J = 4.1, 1.6 Hz, 1H,
Ar-H), 7.35 (s, 1H, Ar-H), 7.31 (d, J = 8.5 Hz, 1H, Ar-H), 7.30
tert-Butyl 7-(benzyloxy)-3-(pyridin-4-yl)-1H-indole-1-carb-
oxylate (3n). Rf 0.38 (EtOAc–PE = 1/2). White solid, m.
p. 112–113 °C. IR (KBr) νmax: 1744, 1604, 1366, 1239, 1152,
1047 cm−1 1H NMR (400 MHz, CDCl3): δ 8.68 (s, 2H, Ar-H),
.
7.77 (s, 1H, Ar-H), 7.58 (d, J = 7.1 Hz, 2H, Ar-H), 7.56 (d, J =
8.5 Hz, 2H, Ar-H), 7.48 (dd, J = 7.1, 1.0 Hz, 1H, Ar-H), 7.40 (dt,
J = 1.0, 8.5 Hz, 2H, Ar-H), 7.36 (dt, J = 1.0, 7.1 Hz, 1H, Ar-H),
7.28 (t, J = 8.0 Hz, 1H, Ar-H), 6.99 (d, J = 8.0 Hz, 1H, Ar-H), 5.27
(s, 2H, OCH2), 1.58 (s, 9H, 3 × CH3). 13C NMR (100 MHz,
CDCl3): δ 150.2, 148.9, 147.9, 141.9, 137.0, 130.9, 128.4,
127.8, 127.5, 127.0, 125.9, 124.5, 122.3, 119.1, 112.5, 109.0,
84.1, 71.1, 27.8. MS (ESI): 401 (M + H+, 100). Anal calcd for
4256 | Org. Biomol. Chem., 2014, 12, 4252–4259
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(s, 1H, Ar-H), 7.29–7.26 (m, 2H, Ar-H), 7.13 (dd, J = 8.9, 2.4 Hz, 9.3 Hz, 1H, Ar-H), 7.79 (s, 1H, Ar-H), 7.65 (dd, J = 8.8, 5.3 Hz,
1H, Ar-H), 4.21 (s, 2H, CH2), 1.71 (s, 9H, 3 × CH3). 13C NMR 1H, Ar-H), 7.41–7.33 (m, 6H, Ar-H), 7.30–7.23 (m, 1H, Ar-H),
(100 MHz, CDCl3): δ 161.1, 159.6 (d, J = 240.1 Hz), 150.1, 149.3 7.07 (dd, J = 8.8, 2.4 Hz, 1H, Ar-H), 4.26 (s, 2H, CH2), 1.73 (s,
(d, J = 30.5 Hz), 142.0, 137.9, 136.7, 132.4, 130.4, 128.8, 128.7, 9H, 3 × CH3). 13C NMR (100 MHz, CDCl3): δ 161.7, 161.1 (d, J =
125.7, 121.4, 119.9, 119.2 (d, J = 4.1 Hz), 116.7 (d, J = 9.2 Hz), 241.6 Hz), 149.9, 149.2, 141.9, 139.4, 129.2, 129.1, 128.8, 128.6,
112.9 (d, J = 25.0 Hz), 105.3 (d, J = 24.7 Hz), 84.8, 44.0, 28.1. 126.5, 124.3 (d, J = 3.9 Hz), 121.6, 120.4 (d, J = 9.8 Hz), 119.9,
MS (ESI): 437 (M + H+, 100), 439 (M + H+, 30). Anal calcd for 119.5, 111.6 (d, J = 24.2 Hz), 103.0 (d, J = 28.6 Hz), 84.9, 44.8,
C25H22ClFN2O2: C, 68.73; H, 5.08; N, 6.41. Found C, 68.39; 28.1. MS (ESI): 403 (M + H+, 100). Anal calcd for C25H23FN2O2:
H, 5.37; N, 6.14.
C, 74.61; H, 5.76; N, 6.96. Found C, 74.27; H, 6.13; N, 6.61.
tert-Butyl 3-(3-benzylpyridin-4-yl)-5-methyl-1H-indole-1-carb-
oxylate (3t). Rf 0.19 (EtOAc–PE = 1/8). Amorphous solid. IR
(KBr) νmax: 1735, 1372, 1248, 1156 cm−1 1H NMR (400 MHz,
.
General procedure for the synthesis of 4
CDCl3): δ 8.64 (d, J = 5.2 Hz, 1H, Ar-H), 8.09 (d, J = 8.3 Hz, 1H,
Ar-H), 7.80 (s, 1H, Ar-H), 7.49 (s, 1H, Ar-H), 7.42 (dd, J = 5.2,
1.6 Hz, 1H, Ar-H), 7.40 (s, 1H, Ar-H), 7.39–7.35 (m, 4H, Ar-H),
7.30–7.26 (m, 1H, Ar-H), 7.23 (dd, J = 8.3, 1.0 Hz, 1H, Ar-H),
4.27 (s, 2H, CH2), 2.48 (s, 3H, CH3), 1.73 (s, 9H, 3 × CH3).
13C NMR (100 MHz, CDCl3): δ 161.6, 149.8, 149.5, 142.4, 139.6,
132.9, 129.2, 128.7, 126.5, 126.3, 124.3, 121.7, 119.9, 119.5,
119.3, 115.2, 84.3, 44.7, 28.2, 21.5. MS (ESI): 399 (M + H+, 100).
Anal calcd for C26H26N2O2: C, 78.36; H, 6.58; N, 7.03. Found C,
78.04; H, 6.91; N, 6.70.
To a solution of 3c (75 mg, 0.2 mmol) in THF (1 mL) was
added a methanolic solution of hydrochloric acid (0.2 mL) at
0 °C under an air atmosphere. It was stirred for 2 h at room
temperature and quenched with saturated aq. NaHCO3 (1 mL)
and water (5 mL). It was extracted with ethyl acetate (8 mL × 3).
The combined organic layer was washed with brine and dried
over Na2SO4. After filtration and concentration, the residue
was purified by flash chromatography on silica gel (eluent:
EtOAc/PE = 1 : 2) to give the corresponding product 4 (49 mg,
90%).
tert-Butyl 3-(2-(4-chlorobenzyl)pyridin-4-yl)-5-methyl-1H-
indole-1-carboxylate (3u). Rf 0.32 (EtOAc–PE = 1/6). Amor-
5-Bromo-3-(pyridin-4-yl)-1H-indole (4). Rf 0.15 (EtOAc–PE =
1 : 1). Waxy solid. IR (KBr) νmax: 3410, 1685, 1602, 1208,
phous solid. IR (KBr) νmax: 1736, 1604, 1371, 1248, 1155 cm−1
.
1
802 cm−1. H NMR (400 MHz, DMSO-d6): δ 12.11 (s, 1H, NH),
1H NMR (400 MHz, CDCl3): δ 8.63 (d, J = 5.2 Hz, 1H, Ar-H),
8.09 (d, J = 8.4 Hz, 1H, Ar-H), 7.79 (s, 1H, Ar-H), 7.49 (s, 1H,
Ar-H), 7.43 (dd, J = 5.2, 1.6 Hz, 1H, Ar-H), 7.37 (s, 1H, Ar-H),
7.31 (t, J = 1.6 Hz, 2H, Ar-H), 7.30 (s, 1H, Ar-H), 7.27 (dd, J =
5.2, 1.2 Hz, 1H, Ar-H), 7.22 (dd, J = 8.4, 1.2 Hz, 1H, Ar-H), 4.22
(s, 2H, CH2), 2.48 (s, 3H, CH3), 1.72 (s, 9H, 3 × CH3). 13C NMR
(100 MHz, CDCl3): δ 161.0, 149.9, 149.5, 142.6, 138.0, 132.9,
132.3, 130.5, 130.4, 128.7, 128.2, 126.4, 124.3, 121.6, 120.1,
119.4, 119.2, 115.3, 84.3, 44.0, 28.2, 21.4. MS (ESI): 433
(M + H+, 100), 435 (M + H+, 30). Anal calcd for C26H25ClN2O2:
C, 72.13; H, 5.82; N, 6.47. Found C, 72.51; H, 5.59; N, 6.13.
8.55 (d, J = 6.0 Hz, 2H, Ar-H), 8.12 (d, J = 1.2 Hz, 2H, Ar-H),
7.74 (d, J = 6.0 Hz, 2H, Ar-H), 7.49 (d, J = 8.6 Hz, 1H, Ar-H),
7.32 (dd, J = 8.6, 1.2 Hz, 1H, Ar-H). 13C NMR (100 MHz, DMSO-
d6): δ 149.9, 143.5, 136.4, 128.2, 126.8, 125.0, 121.8, 121.0,
114.8, 113.7, 112.8. HRESIMS calcd for [C13H9BrN2 + H]+
273.00274 (100%), 275.00069 (100%), found 273.00177 (100%),
274.99942 (100%).
General procedure for the synthesis of 6b
tert-Butyl 3-(2-(4-chlorobenzyl)pyridin-4-yl)-6-fluoro-1H-indole- To a solution of indole (85 mg, 0.5 mmol) and TEMPO (55 mg,
1-carboxylate (3v). Rf 0.29 (EtOAc–PE = 1/6). Pale yellow solid, 0.35 mmol) in 4-phenylpyridine (124 mg, 0.8 mmol) was
m.p. 141–143 °C. IR (KBr) νmax: 1734, 1605, 1484, 1380, 1274, added (Boc)2O (202 mg, 1.0 mmol) under an air atmosphere
1
1155 cm−1. H NMR (400 MHz, CDCl3): δ 8.63 (d, J = 6.1 Hz, and the mixture was stirred at 10 °C for 24 h. The reaction
1H, Ar-H), 7.95 (d, J = 8.8 Hz, 1H, Ar-H), 7.81 (s, 1H, Ar-H), 7.66 mixture was concentrated under reduced pressure. The residue
(dd, J = 8.8, 5.3 Hz, 1H, Ar-H), 7.40 (dd, J = 5.3, 1.6 Hz, 1H, was purified by flash chromatography on silica gel (eluent:
Ar-H), 7.36 (s, 1H, Ar-H), 7.32 (d, J = 6.1 Hz, 1H, Ar-H), 7.30 (t, EtOAc–PE = 1 : 4) to yield the corresponding product 6b
J = 1.6 Hz, 2H, Ar-H), 7.27 (dd, J = 6.1, 2.3 Hz, 1H, Ar-H), 7.08 (159 mg, 86%).
(dd, J = 8.8, 2.3 Hz, 1H, Ar-H), 4.21 (s, 2H, CH2), 1.72 (s, 9H,
3 × CH3). 13C NMR (100 MHz, CDCl3): δ 161.1 (d, J = 241.6 Hz), oxylate (6b). Rf 0.3 (EtOAc–PE = 1/8). Amorphous solid. IR
161.0, 150.0, 149.1, 142.1, 137.9, 132.4, 130.4, 128.9, 128.7, (KBr) νmax: 1680, 1615, 1371, 1232, 1151 cm−1 1H NMR
tert-Butyl 2-(1H-indol-3-yl)-4-phenylpyridine-1(2H)-carb-
.
124.4 (d, J = 3.6 Hz), 124.3, 121.5, 120.3 (d, J = 9.8 Hz), 120.0, (400 MHz, CDCl3): δ 8.15 (s, 1H, NH), 8.03 (s, 1H, Ar-H),
119.3, 111.6 (d, J = 24.2 Hz), 103.1 (d, J = 28.6 Hz), 84.9, 44.0, 7.55–7.45 (m, 2H, Ar-H), 7.43–7.30 (m, 4H, Ar-H), 7.25–7.19 (m,
28.1. MS (ESI): 437 (M + H+, 100), 439 (M + H+, 30). Anal calcd 2H, Ar-H), 8.64 (dt, J = 0.8, 7.9 Hz, 1H, Ar-H), 6.84 (s, 1H), 6.42
for C25H22ClFN2O2: C, 68.73; H, 5.08; N, 6.41. Found C, 68.50; (s, 1H), 6.00 (s, 1H), 5.80 (s, 1H), 1.53 (s, 9H, 3 × CH3).
H, 5.47; N, 6.62.
13C NMR (100 MHz, CDCl3): δ 152.3, 139.1, 136.6, 133.1, 128.5,
tert-Butyl 3-(3-benzylpyridin-4-yl)-6-fluoro-1H-indole-1-carb- 127.5, 126.4, 125.9, 125.7, 124.5, 122.1, 120.8, 119.8, 117.8,
oxylate (3w). Rf 0.19 (EtOAc–PE = 1/6). Amorphous solid. IR 116.0, 111.1, 105.9, 81.4, 48.3, 28.3. MS (ESI): 373 (M + H+,
(KBr) νmax: 1739, 1602, 1374, 1222, 1153 cm−1 1H NMR 100). Anal calcd for C24H24N2O2: C, 77.39; H, 6.49; N, 7.52.
.
(400 MHz, CDCl3): δ 8.64 (d, J = 5.1 Hz, 1H, Ar-H), 7.95 (d, J = Found C, 77.05; H, 6.80; N, 7.31.
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General procedure for the indolation of isoquinoline
References
To a solution of indole (0.5 mmol), TEMPO (0.35 mmol) and
isoquinoline (0.6 mmol) in THF (1 mL) was added (Boc)2O
(0.6 mmol) under an air atmosphere and the mixture was
stirred at room temperature for 3 h. The reaction mixture was
concentrated under reduced pressure. The residue was purified
by flash chromatography on silica gel (eluent: EtOAc–PE = 1 : 8)
to yield the corresponding product.
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3 A. R. Katritzky and R. Taylor, Adv. Heterocycl. Chem., 1990,
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tert-Butyl 1-(1H-indol-3-yl)isoquinoline-2(1H)-carboxylate
(8a). Rf 0.20 (EtOAc–PE = 1/10). White amorphous solid. IR
(KBr) νmax: 1686, 1634, 1362, 1240, 1164, 772 cm−1 1H NMR
.
4 Recent reviews: (a) J. A. Bull, J. J. Mousseau, J. Pelletier and
A. B. Charette, Chem. Rev., 2012, 112, 2642–2713;
(b) H. Andersson, R. Olsson and F. Almqvist, Org. Biomol.
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(400 MHz, CDCl3): δ 8.00 (s, 2H, Ar-H), 7.32 (d, J = 7.9 Hz, 1H,
Ar-H), 7.29–7.24 (br s, 1H, Ar-H), 7.21–7.11 (m, 5H, Ar-H), 6.89
(s, 1H, Ar-H), 6.77 (s, 1H, Ar-H), 6.62 (s, 1H, Ar-H), 6.00 (s, 1H,
Ar-H), 1.57 (s, 9H, 3 × CH3). 13C NMR (100 MHz, CDCl3):
δ 152.1, 136.3, 132.5, 130.8, 127.5, 126.9, 126.8, 125.7, 125.6,
124.5, 124.4, 122.1, 120.5, 119.8, 117.8, 111.0, 108.6, 81.5, 50.8,
28.3. MS (ESI): 347 (M + H+, 100). Anal calcd for C22H22N2O2:
C, 76.28; H, 6.40; N, 8.09. Found C, 75.91; H, 6.73; N, 7.86.
tert-Butyl 1-(2-methyl-1H-indol-3-yl)isoquinoline-2(1H)-carb-
oxylate (8b). Rf 0.23 (EtOAc–PE = 1/8). White amorphous solid.
IR (KBr) νmax: 1682, 1635, 1456, 1341, 1290, 1236, 1164,
769 cm−1. 1H NMR (400 MHz, CDCl3): δ 7.87 (s, 1H, Ar-H), 7.68
(d, J = 6.8 Hz, 1H, Ar-H), 7.22 (d, J = 8.0 Hz, 1H, Ar-H),
7.14–7.04 (m, 4H, Ar-H), 7.02 (dd, J = 8.0, 1.7 Hz, 2H, Ar-H),
7.00 (d, J = 6.8 Hz, 1H, Ar-H), 6.75 (s, 1H, Ar-H), 5.98 (d, J =
8.0 Hz, 1H, Ar-H), 2.58 (s, 3H, CH3), 1.43 (s, 9H, 3 × CH3). 13C
NMR (100 MHz, CDCl3): δ 152.4, 135.1, 132.9, 131.8, 129.9,
127.1, 127.0, 126.8, 126.7, 126.5, 124.4, 120.9, 120.2, 119.6,
119.4, 116.7, 110.0, 106.4, 81.3, 51.7, 28.3, 12.6. MS (ESI): 361
(M + H+, 100). Anal calcd for C23H24N2O2: C, 76.64; H, 6.71; N,
7.77. Found C, 76.93; H, 6.57; N, 7.61.
tert-Butyl 1-(7-chloro-1H-indol-3-yl)isoquinoline-2(1H)-car-
boxylate (8c). Rf 0.22 (EtOAc–PE = 1/16). White amorphous
solid. IR (KBr) νmax: 1694, 1634, 1446, 1342, 1241, 1122,
771 cm−1. 1H NMR (400 MHz, CDCl3): δ 8.21 (s, 1H, Ar-H), 7.85
(s, 1H, Ar-H), 7.32–7.12 (m, 5H, Ar-H), 7.06 (d, J = 7.9 Hz, 1H,
Ar-H), 6.86 (s, 1H, Ar-H), 6.76 (s, 1H, Ar-H), 6.70 (s, 1H, Ar-H),
5.99 (s, 1H, Ar-H), 1.54 (s, 9H, 3 × CH3). 13C NMR (100 MHz,
CDCl3): δ 152.1, 133.5, 132.1, 130.8, 127.7, 127.0, 126.9, 126.8,
125.5, 125.0, 124.6, 121.4, 120.6, 119.2, 118.9, 116.5, 108.5,
81.6, 50.7, 28.3. MS (ESI): 381 (M + H+, 100), 383 (M + H+, 30).
Anal calcd for C22H21ClN2O2: C, 69.38; H, 5.56; N, 7.36. Found
C, 69.25; H, 5.87; N, 7.13.
5 For catalytic alkylation and arylation of pyridine N-oxide,
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Acknowledgements
The authors are grateful to the NSF of China (no. 21162001
and 21202023), the National Key Technology R&D Program of 10 For Ru-catalyzed C–H functionalization of pyridine, see:
China (no. 2009BAI78B01), the Jiangxi Province Key Support
Program (no. 2009BNB06200), the Natural Science Foundation
of Jiangxi Province (no. 20132BAB203007) and the Jiangxi Pro-
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vince Office of Education Support Program (no. GJJ13666) for 11 For Ir-catalyzed C–H functionalization of pyridine, see:
financial support.
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