Palladium-catalyzed oxidative cross-coupling of azole-4-carboxylates with indoles: An approach to the synthesis of pimprinine

Article abstract of DOI:10.1039/c4ob01844c

An efficient and straightforward method for the production of 5-(3-indolyl)azoles incorporating the privileged structures indoles and azoles via palladium-catalyzed double C-H bond cleavage under mild conditions was disclosed. As expected, this protocol provided an easy method for the synthesis of indole alkaloids pimprinine and WS-30581 A in moderate yields. This journal is

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Palladium-Catalyzed Oxidative Cross-Coupling
of Azole-4-carboxylates with Indoles: An
Approach to the Synthesis of Pimprinine
Cite this: DOI: 10.1039/x0xx00000x
Haipin Zhou, Kuo Gai, Aijun Lin, Jinyi Xu, Xiaoming Wu* and Hequan Yao*
Received 00th January 2012,
Accepted 00th January 2012
An efficient and straightforward method for the construction of 5-(3-indolyl)-azoles incorporating the
privileged structures indoles and azoles via palladium-catalyzed double C-H bond cleavage under mild
conditions was disclosed. As expected, this protocol provided a concise access to the synthesis of indole
alkaloids pimprinine and WS-30581 A in moderate yields.
DOI: 10.1039/x0xx00000x
www.rsc.org/
the desired 5-(3-indolyl)azoles in moderate to excellent yields
with high regioselectivity.
Introduction
Over the past decades, transition-metal-catalyzed oxidative
cross-coupling reaction between two non-prefunctionalized
heteroarenes has aroused worldwide interest, which represented
an economic and environmentally benign approach to the
synthesis of biheteroaryl skeletons.1,2 As a privileged class of
heterocyclic scaffolds, the 5-(3-indolyl)oxazole moiety is
embedded in many biologically interesting natural products and
therapeutic agents,3 such as Pimprinine,3a-b,4 Labradorin 1 and
Labradorin 2 (Scheme 1).5 Pimprinine, originally isolated from
the Streptomyces pimprina in 1963, exhibits antiepileptic
activity6 and monoamine oxidase inhibitory effect.7 Recently,
increasing efforts have been devoted to the development of
heteroarylation between indoles and azoles. 8 You and co-
Scheme 1 Natural Products containing indolyl-oxazole moieties.
workers
described
a
Pd(OAc)2-CuCl
cocatalyzed
dehydrogenative cross-coupling of indoles and pyrroles with
azoles and xanthines, introducing X-Phos as a ligand to
minimize the oxidative degradation of the sensitive indoles and
pyrroles.2f A number of 2-(3-indolyl)-azoles and 8-(3-indolyl)-
xanthines were synthesized. Comparing the electron density
and reactivity of the C-2 and C-5 positions of azoles, the C-5
position is less efficient and more challenging to couple with
another heteroarene.9 To obtain the 5-substituted azoles, we
suppose to introduce an ester group at the C-4 position of the
azoles, playing as a block group to assist the activation of the
C(5)-H bond. Furthermore, the ester group could be easily
removed and functionalized via simple operations. Recently,
Results and discussion
Our initial investigation focused on the cross-coupling of
methyl 2-methyloxazole-4-carboxylate 1a with N-methyl-
indole 2a as summarized in Table 1. When we applied the
optimum condition of the C5-aryltion of azole-4-carboxylates,
the desired product 3a was obtained in only 15% yield (entry
1).10 Without PivOH, the product was afforded in 21% yield
(entry 2). Oxidant screening indicated that Cu(OAc)2 was the
best choice (entries 3-6). Under an O2 atmosphere with 0.2
equiv of Cu(OAc)2, 3a was obtained in 22% yield (entry 7). In
the subsequent investigation of various phosphine ligands
(entries 8-10), the 3a was completed in low yield (10%-22%).
3-acetylpyridine exhibited good performance in 42% yield.
When 2 equiv of 3-acetylpyridine was employed, the yield
increased to 82% (entry 14). Next screening of pyridine
derivatives (entries 15-20) and other organic bases such as
we have successfully developed the Pd(II)-catalyzed direct C5-
10
arylation of azole-4-carboxylates,
and the diverse C5-
substituted azoles were achieved in high yields. As
a
continuation of our research on azoles and heteroarenes, 11
herein, we will recommend a palladium catalyzed direct C5-
heteroarylation of azole-4-carboxylates with indoles, offering
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DABCO, DBU and Et3N (see supporting information for details) corresponding products 3e and 3f in moderate yields. N-
could not further improve the reaction yield 12 . Without methyl-4-methyl-indole afforded the 3g and 3g’ in 87% total
Pd(OAc)2, the reaction could not occur (entry 21). Replacing yield with a ratio of 1:1.2 due to the steric hinderance.13 The
Pd(OAc)2 with other catalysts such as PdCl2, Pd(TFA)2, methyl group at the C-5 or C-7 position of the indole exhibited
Pd(CH3CN)2Cl2, Pd(OPiv)2 offered 3a in a low reaction less influence on the reaction yield, and offered 3h and 3i in
efficiency (entries 22-25). Prolonging the reaction time failed to high yields. The electron-donating group (-OMe), electron-
improve the outcome of the reaction (entry 26). Accordingly, withdrawing group (-COOMe) and halogen (-Cl) were all
the optimized reaction conditions were determined to be compatible with our reaction in good yield (3j-3l). To our
Pd(OAc)2 (10 mol%), Cu(OAc)2 (2 equiv) and 3-acetylpyridine delight, the N-H free indoles could also furnish the desired 5-
(2 equiv) in DMF (2.0 mL).
(3-indolyl)-oxazoles 3m-3p in 56-74% yields. Replacing the
ester group with -Me or –CH2OCH3 afforded the 5-(2-indolyl)-
oxazoles 3q and 3r in low yield.
Table 1 Optimization of Conditionsa
Table 2 Pd-catalyzed oxidative cross-coupling of 2-methyl-4-substituted
oxazoles with indole derivativesa,b
Catalyst
(10 mol %)
Oxidant
Additive
(2 equiv)
Yield
(%)b
Entry
(2 equiv)
AgOAc
AgOAc
CuCl
1
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
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
/
PivOH
15
21
2
/
/
/
/
/
/
3
trace
12
4
O2
5
Cu(OTf)2
Cu(OAc)2
trace
47
6
c
7
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
22
d
8
PPh3
10
9
Xantphosd
X-phosd
3-acetylpyridined
3-acetylpyridinee
3-acetylpyridinef
3-acetylpyridine
Pyridine
22
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26g
19
42
47
61
82
71
2,6-Lutidine
52
4-methylpyridine
3-fluoropyridine
3-nitropyridine
acridine
67
50
54
44
3-acetylpyridine
3-acetylpyridine
3-acetylpyridine
3-acetylpyridine
3-acetylpyridine
3-acetylpyridine
N.R
71
PdCl2
PdCl2(CH3CN)2
Pd(TFA)2
Pd(OPiv)2
Pd(OAc)2
70
68
50
64
aReaction condition: 1a (0.5 mmol, 1 equiv); 2a (1.0 mmol, 2 equiv); Pd
(0.05 mmol), oxidant (1.0 mmol) and additive (1.0 mmol) in DMF (2 mL) at
135 C for 24 hours under an Ar atmosphere. Isolated yield; Cu(OAc)2 (0.2
mmol) under an O2 atmosphere. d0.2 equiv; e0.4 equiv; f1.0 equiv; g48 hours.
aReaction condition: 1a (0.5 mmol, 1 equiv); 2 (1.0 mmol, 2 equiv);
Pd(OAc)2 (0.05 mmol), Cu(OAc)2 (1.0 mmol) and 3-acetylpyridine (1.0
mmol) in DMF (2 mL) at 135 oC for 24 hours under an Ar atmosphere.
bIsolated yield.
o
b
c
With the optimized conditions in hand, we set out to screening
the scope of indoles. As shown in Table 2, all the indoles
applied in the coupling reaction afforded the corresponding
products in moderate to high yields. Indoles with N-protecting
groups, such as methyl, ethyl, benzyl and MOM groups were
all amenable to the oxidative coupling reaction in 82-96%
The effective conditions were also extended to a variety of
azoles and the results were illustrated in Table 3. Generally, all
azole substrates could afford the desired products in moderate
to good yields. A series of alkyl substitutions at C2-position of
oxazoles were examined, the n-propyl and n-butyl substituted
yields
(3a-3d). The tosyl-protected indoles gave the
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oxazole afforded the 4a and 4b in 75% and 59% yields. The 2-
In order to demonstrate the utility of the present method, the
phenyloxazole substrates, including electron-donating and - reaction was conducted in 5.0 mmol scale under the optimized
withdrawing groups, proceeded smoothly to afford the conditions, and 3a could be smoothly obtained in 72% yield
corresponding products 4c-4e in 70-83% yields. Subsequently,
a series of oxazole-4-carboxylic derivatives were evaluated. 4-
Carboxylates with methyl or ethyl groups gave the cross-
coupling products 3a or 4f in better yield than those with n-
butyl or benzyl groups (4g, 4h). It was noteworthy that the 4-
formamide substrate could also successfully give 4i in 80%
yield. Similarly to the oxazoles, methyl 2-methylthiazole-4-
Scheme 2 Large-scale experiment
carboxylate could couple with various N-protected indoles
(methyl, ethyl, benzyl and MOM group), and for all cases, the
heteroarylated products 4j-4m were obtained in 59-63% yields.
2-Propylthiazole-4-carboxylate gave 4n in a slightly decreased
yield. It should be noted that the 4-ethyl formate substrates
were generally more reactive and afforded higher yields than 4-
methyl formates substrates (4o vs 4j, 4p vs 4n). When 2-alkyl-
oxazoles cross-coupled with N-free indole, the corresponding
products (4r-4t) were obtained in moderate to good yields,
which could be further applied to the total synthesis of the
analogues of pimprinine.
Table 3 Pd-catalyzed oxidative cross-coupling of azole-4-carboxylates with
N-methylindolea,b
Scheme 3 Synthesis of Pimprinine and WS-30581 A
(972 mg) (Scheme 2). Moreover, we applied our C-H/C-H
coupling reaction to the synthesis of the indole alkaloid
pimprinine and WS-30581 A. (Scheme 3). Our route started
from oxazole-4-carboxylates, obtainable through a simple
synthetic process, coupling with the commercially available
indole 2m under the standard condition provided 3l and 4r in
66% and 62% yield. Subsequent hydrolysis of the methyl ester
quantitatively and decarboxylation under acidic condition
delivered the desired natural products in 36% and 31% total
yield respectively.14
aReaction condition: 1 (0.5 mmol, 1 equiv); 2 (1.0 mmol, 2 equiv); Pd(OAc)2
(0.05 mmol), Cu(OAc)2 (1.0 mmol) and 3-acetylpyridine (1.0 mmol) in DMF
(2 mL) at 135 oC for 24 hours under an Ar atmosphere. bIsolated yield.
Scheme 4 Mechanism Studies
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To get some mechanistic insight, kinetic isotope effect (KIE) carboxylates (0.5 mmol), and DMF (2 mL) under argon. After
1
o
studies were carried out (Scheme 4). The kH/kD values (by H stirring at 135 C for 24 hours, the reaction mixture was cooled
NMR) could not be determined between 1-methylindole and 3- to room temperature, diluted with CH2Cl2 (20 mL), filtered
deutero-1-methylindole since the D was rapidly exchanged to through a Celite pad, and washed with CH2Cl2 (10-20 mL). The
the H. A KIE of 2.1 was observed between 2-methyloxazole-4- organic extracts were concentrated, and the resulting residue
carboxylate 1a and its deuterated derivate 1a-[D], indicating was purified by column chromatography on silica gel to afford
that the cleavage of the C-5(H) bond in 1a was involved in the the desired products.
rate-limiting step. Thus, a plausible mechanism for the direct
Methyl
2-methyl-5-(1-methyl-1H-indol-3-yl)oxazole-4-
heteroarylation of azoles-4-carboxylates was set out in Scheme carboxylate (3a) This compound was obtained as a brown
1
4. Firstly, palladation of the indole at C-3 position formed solid (221 mg, 82% yield): mp 133-135 °C; H NMR (300
palladium intermediate A, which was followed by C-H MHz, d6-DMSO) δ 8.56 (s, 1H), 8.07 (d, J = 7.8 Hz, 1H), 7.55
activation of azole to form biaryl Pd(II) species B. Then (d, J = 8.0 Hz, 1H), 7.28 (dt, J = 14.5, 7.0 Hz, 2H), 3.89 (s,
reductive elimination occurred to produce the desired product 3H), 3.85 (s, 3H), 2.52 (s, 3H); 13C NMR (75 MHz, d6-DMSO)
5-(3-indolyl)-azoles along with releasing the Pd(0) species, δ 163.1, 157.8, 154.1, 136.9, 133.6, 125.5, 122.9, 122.5, 121.5,
which reoxidized by Cu(II) to complete the catalytic cycle.
121.3, 111.0, 101.9, 51.8, 33.5, 13.7; IR (KBr) 3144, 3050,
2938, 1705, 1612, 1578, 1522, 1435, 1395, 1334, 1308, 1216,
1102 ,1079, 915, 780, 742 cm−1; HRMS (ESI+): calcd for
C15H14N2NaO3 [M+Na]+ 293.0897, found 293.0898.
Conclusions
In summary, we have developed a palladium-catalyzed C-
H/C-H oxidative cross-coupling reaction between azole-4-
carboxylates and indoles with good functional group tolerance,
offering the 5-(3-indolyl)azoles in moderate to good yields with
excellent regioselectivity. In addition, we applied our method to
accomplish the total synthesis of Pimprinine and WS-30581 A
from commercially available materials. Total synthesis of other
more complex natural products as well as the mechanistic
studies are undertaken in our laboratory.
Methyl
5-(1-ethyl-1H-indol-3-yl)-2-methyloxazole-4-
carboxylate (3b) This compound was obtained as a grey solid
(272 mg, 96% yield): mp 109-109.5 °C ; H NMR (300 MHz,
1
d6-DMSO) δ 8.65 (s, 1H), 8.09 (d, J = 7.6 Hz, 1H), 7.60 (d, J =
7.8 Hz, 1H), 7.37 – 7.17 (m, 2H), 4.31 (quart, J = 6.9 Hz, 2H),
3.86 (s, 3H), 2.53 (s, 3H), 1.43 (t, J = 7.0 Hz, 3H); 13C NMR
(75 MHz, d6-DMSO) δ 163.1, 157.9, 154.1, 135.9, 132.0,
125.7, 122.9, 122.5, 121.5, 111.0, 102.1, 51.8, 41.4, 15.6, 13.7;
IR (KBr) 3156, 3144, 2973, 2937, 1705, 1603, 1578, 1522,
1437, 1405, 1305, 1209, 1097, 1083, 1061, 912, 806, 785, 748
cm−1; HRMS (ESI+): calcd for C16H16N2NaO3 [M+Na]+
307.1053, found 307.1051.
Experimental procedures
General Remarks.
Methyl
5-(1-benzyl-1H-indol-3-yl)-2-methyloxazole-4-
Melting point (m.p.) was measured on a microscopic melting
carboxylate (3c) This compound was obtained as a pale yellow
solid (325 mg, 94% yield): mp 166-167 °C ; 1H NMR (300 MHz,
d6-DMSO) δ 8.73 (s, 1H), 8.16 – 8.04 (d, J = 7.2 Hz, 1H), 7.60
(d, J = 7.2 Hz, 1H), 7.38 – 7.31 (m, 2H), 7.31 – 7.20 (m, 5H),
5.58 (s, 2H), 3.83 (s, 3H), 2.54 (s, 3H); 13C NMR (75 MHz, d6-
DMSO) δ 163.1, 158.2, 153.8, 137.8, 136.3, 133.0, 129.2,
128.1, 127.6, 125.8, 123.3, 122.9, 121.7, 121.5, 111.6, 102.6,
51.9, 50.0, 13.7; IR (KBr) 3126, 3056, 2938, 1699, 1606, 1569,
1434, 1395, 1337, 1304, 1209, 1167, 1099, 1065, 1024, 914,
812, 786, 734, 709, 635 cm−1; HRMS (ESI+): calcd for
C21H18N2NaO3 [M+Na]+ 369.1210, found 369.1211.
1
point apparatus. H and 13C NMR spectra were collected on
BRUKER AV-300 (300MHz) spectrometer using d6-DMSO
and CDCl3 as solvent. Chemical shifts of 1H NMR were
recorded in parts per million (ppm, δ) relative to
tetramethylsilane (δ = 0.00 ppm) with the solvent resonance as
an internal standard (d6-DMSO: δ = 2.5 ppm; CDCl3: δ = 7.26
ppm). Data are reported as follows: chemical shift in ppm (δ),
multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m =
multiplet), coupling constant (Hz), and integration. Chemical
shifts of 13C NMR were reported in ppm with the solvent as the
internal standard (d6-DMSO: δ = 39.52+0.06 ppm; CDCl3: δ =
77.0 ppm). Infrared spectra (IR) were recorded on a Thermo
Scientific iS10 FT/IR spectrometer; absorptions are reported in
reciprocal centimeters. High Resolution Mass measurement
was performed on Agilent Q-TOF 6520 mass spectrometer with
electron spray ionization (ESI) as the ion source. Unless
otherwise indicated, all reagents and solvents were obtained
from commercial suppliers and used as received.
Methyl
5-(1-(methoxymethyl)-1H-indol-3-yl)-2-
methyloxazole-4-carboxylate (3d) This compound was
obtained as a brown solid (252 mg, 84% yield): mp 129.5-
130 °C ; 1H NMR (300 MHz, d6-DMSO) δ 8.68 (s, 1H), 8.07 (d,
J = 7.5 Hz, 1H), 7.66 (d, J = 7.8 Hz, 1H), 7.36 – 7.20 (quint, J =
7.5 Hz, 2H), 5.64 (s, 2H), 3.83 (s, 3H), 3.21 (s, 3H), 2.51 (s,
3H); 13C NMR (75 MHz, d6-DMSO) δ 163.0, 158.4, 153.5,
136.4, 132.9, 126.1, 123.5, 123.4, 122.1, 121.5, 111.6, 103.2,
77.5, 55.9, 51.9, 13.7; IR (KBr) 3138, 2991, 2949, 2920, 1706,
1604, 1580, 1436, 1395, 1340, 1302, 1213, 1186, 1130, 1101,
1071, 913, 750, 668 cm−1; HRMS (ESI+): calcd for
C16H16N2NaO4 [M+Na]+ 323.1002, found 323.1003.
General Procedure for oxidative Cross-Coupling between
Indoles and Azole-4-carboxylates.
A flame-dried Schlenk test tube with a magnetic stirring bar
was charged with Pd(OAc)2 (10 mol%), Cu(OAc)2 (1.0 mmol),
3-acetylpyridine (1.0 mmol), indoles (1.0 mmol), azole-4-
Methyl
5-(1-methyl-1H-indol-3-yl)-2-propyloxazole-4-
carboxylate (4a) This compound was obtained as a light brown
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1
solid (224 mg, 75% yield): mp 84.5-85.5 °C; H NMR (300 to give a pale yellow solid 5a (240 mg, 99% yield), which was
MHz, CDCl3) δ 8.68 (s, 1H), 8.15 (d, J = 7.2 Hz, 1H), 7.39 – used for the next step without further purification.
7.22 (m, 3H), 3.95 (s, 3H), 3.84 (s, 3H), 2.88 (t, J = 7.5 Hz, 2H), 5-(1
H-indol-3-yl)-2-methyloxazole-4-carboxylic acid (5a)
2.00 – 1.83 (sext, J = 7.2 Hz, 2H), 1.06 (t, J = 7.4 Hz, 3H); 13
C
This compound was obtained as a pale yellow solid (240 mg,
1
NMR (75 MHz, CDCl3) δ 163.5, 161.0, 154.7, 136.8, 133.5, 99% yield): mp 210-211 °C; H NMR (300 MHz, d6-DMSO) δ
125.8, 122.8, 122.4, 121.4, 121.3, 109.8, 102.8, 51.8, 33.4, 11.86 (s, 1H), 8.63 (s, 1H), 8.07 (d, J = 8.0 Hz, 1H), 7.53 (d, J =
30.0, 20.7, 13.8; IR (KBr) 3145, 3044, 2965, 2946, 1697, 1576, 7.0 Hz, 1H), 7.29–7.08 (m, 2H), 2.53 (s, 3H); 13C NMR (75
1569, 1442, 1393, 1334, 1224, 1210, 1141, 916, 788, 735, 576 MHz, d6-DMSO) δ 165.2, 157.2, 152.4, 136.5, 130.0, 126.3,
cm−1; HRMS (ESI+): calcd for C17H19N2O3 [M+H]+ 299.1390, 125.4, 122.5, 121.1, 120.8, 112.7, 103.5, 13.9; IR(KBr) 3186,
found 299.1389.
Methyl
2973, 1682, 1606, 1583, 1400, 1268, 1215, 1135, 1082, 948,
-indol-3-yl)-2-butyloxazole-4- 736, 618 cm−1; HRMS (ESI+): calcd for C13H11N2O3 [M + H]+
5-(1-methyl-1
H
carboxylate (4b) This compound was obtained as a light 243.0764, found 243.0766.
brown solid (184 mg, 59% yield): mp 80-80.5 °C; 1H NMR
5-(1 -indol-3-yl)-2-propyloxazole-4-carboxylic acid (5b)
H
(300 MHz, CDCl3) δ 8.68 (s, 1H), 8.15 (d, J = 7.1 Hz, 1H), This compound was obtained as a grey solid (265 mg, 98%
7.39 – 7.21 (m, 3H), 3.95 (s, 3H), 3.84 (s, 3H), 2.90 (t, J = 7.6 yield): mp 228-230 °C; 1H NMR (300 MHz, d6-DMSO) δ 12.06
Hz, 2H), 1.95 – 1.79 (quint, J = 7.5Hz, 2H), 1.55 – 1.37 (sext, J (s, 1H), 8.68 (d, J = 2.3 Hz, 1H), 8.09 (d, J = 7.4 Hz, 1H), 7.57
= 7.2 Hz,2H), 0.98 (t, J = 7.3 Hz, 3H); 13C NMR (75 MHz, (d, J = 7.5 Hz, 1H), 7.33 – 7.14 (m, 2H), 2.87 (t, J = 7.3 Hz,
CDCl3) δ 163.5, 161.2, 154.7, 136.9, 133.5, 125.9, 122.8, 2H), 1.94 – 1.76 (sex, J = 7.3 Hz, 2H), 1.02 (t, J = 7.3 Hz, 3H);
122.4, 121.4, 121.3, 109.8, 102.8, 51.9, 33.4, 29.2, 27.8, 22.3, 13C NMR (75 MHz, d6-DMSO) δ 164.3, 160.7, 153.9, 136.4,
13.7; IR (KBr) 3150, 2961, 2926, 2896, 1691, 1637, 1601, 130.1, 125.3, 123.4, 122.8, 121.2, 120.9, 112.8, 103.0, 29.5,
1475, 1400, 1226, 1097, 1078, 930, 791, 747 cm−1; HRMS 20.4, 13.9
；IR(KBr) 3554, 3455, 3381, 3157, 2964, 2874, 1664,
(ESI+): calcd for C18H21N2O3 [M+H]+ 313.1547, found 1560, 1486, 1459, 1409, 1358, 1329, 1271, 1240, 1116, 1095,
313.1549.
951, 761, 743, 712 cm−1; MS-ES: m/z: 269.1[M-H]-, HRMS
5-(1-methyl-1H-indol-3-yl)-2-phenyloxazole-4- (ESI+): calcd for C15H14N2O3Na [M+Na]+ 293.0902, found
Methyl
carboxylate (4c) This compound was obtained as a light 293.0910.
1
yellow solid (276 mg, 83% yield): mp 208-209 °C; H NMR
(300 MHz, CDCl3) δ 8.74 (s, 1H), 8.34 – 8.22 (m, 1H), 8.22 –
A flame-dried Schlenk test tube with a magnetic stirring bar
8.11 (m, 2H), 7.50 (d, J = 6.8 Hz, 3H), 7.39 – 7.28 (m, 3H), was charged with Ag2CO3 (20 mol %), PivOH (50 mol %), 5a
o
4.00 (s, 3H), 3.84 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 163.5, (0.5 mmol), and DMSO (1 mL). After stirring at 120 C for 12
157.7, 154.9, 136.9, 134.1, 130.5, 128.8, 126.8, 126.5, 125.8, hours, the reaction mixture was cooled to room temperature,
123.0, 121.60, 121.4, 109.9, 102.7, 52.1, 33.4; IR (KBr) 3132, diluted with EtOAc (20 mL), filtered through a Celite pad, and
3050, 2979, 2943,1701, 1577, 1568, 1445, 1392, 1333, 1221, washed with EtOAc (10-20 mL). The organic extracts were
1133, 1109, 1073, 1045, 912, 786, 736, 704, 686 cm−1; HRMS concentrated, and the resulting residue was purified by column
(ESI+): calcd for C20H16N2NaO3 [M+Na]+ 355.1053, found chromatography on silica gel to afford the desired product 6a.
355.1054.
5-(1H-indol-3-yl)-2-methyloxazole (Pimprinine, 6a) This
Methyl
2-(4-methoxyphenyl)-5-(1-methyl-1H-indol-3- compound was obtained as a pale yellow solid (54 mg, 55%
yl)oxazole-4-carboxylae (4d) This compound was obtained as yield): mp 200-201 °C; 1H NMR (300 MHz, d6-DMSO) δ 11.50
1
a light yellow solid (261 mg, 72% yield): mp 159-160 °C; H (s, 1H), 7.81 (d, J = 7.8 Hz, 1H), 7.70 (d, J = 2.6 Hz, 1H), 7.45
NMR (300 MHz, CDCl3) δ 8.70 (s, 1H), 8.23 (dd, J = 5.8, 2.5 (d, J = 7.9 Hz, 1H), 7.21 – 7.15 (m, 2H), 7.15 – 7.07 (m, 1H),
Hz, 1H), 8.10 (d, J = 8.8 Hz, 2H), 7.36 – 7.27 (m, 3H), 7.00 (d, 2.46 (s, 3H).; 13C NMR (75 MHz, d6-DMSO) δ 158.2, 147.3,
J = 8.8 Hz, 2H), 3.99 (s, 3H), 3.85 (s, 3H), 3.81 (s, 3H); 13C 136.3, 123.8, 122.8, 122.0, 119.9, 119.4, 119.2, 112.0, 103.9,
NMR (75 MHz, CDCl3) δ 163.5, 161.0, 157.8, 154.7, 136.8, 13.5; IR(KBr) 3133, 3109, 2930, 2896, 1638, 1585, 1453, 1360,
133.5, 128.2, 125.8, 123.6, 122.9, 122.4, 121.5, 121.3, 114.2, 1248, 1123, 1027, 771, 735 cm−1; HRMS (ESI+): calcd for
109.8, 102.8, 51.8, 33.4, 30.0, 20.7, 13.8; IR (KBr) 3138, 2943, C12H11N2O [M+H]+ 199.0866, found 199.0867.
2837, 1701, 1616, 1578, 1503, 1445, 1421, 1248, 1170, 1103,
5-(1H-indol-3-yl)-2-propyloxazole (WS-30581 A, 6b) This
1087, 1030, 915, 831, 740, 629 cm−1; HRMS (ESI+): calcd for compound was obtained as a pale yellow solid (59mg, 52%
C21H18N2O4 [M+Na]+ 385.1159, found 385.1156.
yield): mp 96-98 °C; H NMR (300 MHz, CDCl3) δ 8.77 (s,
1H), 7.85 (d, J = 7.3 Hz, 1H), 7.52 (d, J = 2.5 Hz, 1H), 7.46 –
7.38 (m, 1H), 7.33 – 7.27 (m, 1H), 7.26 – 7.21 (m, 1H), 7.17 (s,
1
General Procedure for Synthesis of Pimprinine and WS-30581 A
To the solution of methyl 5-(1H-indol-3-yl)-2-methyloxazole- 1H), 2.84 (t, J = 7.5 Hz, 2H), 1.88 (dd, J = 14.9, 7.4 Hz, 2H),
4-carboxylate (256 mg, 1.0 mmol) in EtOH (5 mL) was added a 1.05 (t, J = 7.4 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 162.9,
solution of NaOH (112 mg, 2.0 mmol) in water (1 mL). The 147.7, 136.5, 124.2, 122.9, 122.0, 120.7, 119.9, 119.4, 111.8,
o
resulting mixture was stirred at 80 C overnight. The mixture 105.6, 77.6, 77.2, 76.7, 30.2, 20.7, 13.8; IR(KBr) 3414, 3129,
was concentrated in vacuo and acidified with 1 M HCl to 2932, 2875, 1636, 1571, 1448, 1251, 1119, 1003, 778, 736, 638
precipitate the carboxylic acid. Then vacuum filtration and dry cm−1; HRMS (ESI+): calcd for C14H13N2O [M-H]- 225.1028,
found 225.1034.
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Acknowledgements
Fresneda and P. Almendros, Synthesis, 1993, 01, 54; (c) K. J. Doyle
and C. J. Moody, Synthesis, 1994, 10, 1021; (d) D. Kumar, S.
Sundaree, G. Patel and V. S. Rao, Tetrahedron Lett., 2008, 49, 867;
(e) F. Miyake, M. Hashimoto, S. Tonsiengsom, K. Yakushijin and D.
Generous financial support from the National Natural Science
Foundation of China (NSFC21272276), the Natural Science
Foundation of Jiangsu Province (BK20140655), the Ministry of
Education of China (PSCIRT-1193) and the Foundation of
State Key Laboratory of Natural Medicines (ZZJQ201306) are
gratefully acknowledged.
A. Horne, Tetrahedron, 2010, 66, 4888; (f) D. Kumar, S. Sundaree,
G. Patel and A. J. Kumar, Heterocycl. Chem., 2010, 47, 1425; (g) F.
Zhang and M. F. Greaney, Org. Lett., 2010, 12, 4745.
5
G. R. Pettit, J. C. Knight, L. Delbert, R. Davenport, R. K. Pettit, B. E.
Tucker and J. M. Schmidt, J. Nat. Prod., 2002, 65, 1793.
Notes and references
6
7
M. J.Narasihan and V. G. Ganla, Hindustan Antibiot., 1967, 9, 138.
State Key Laboratory of Natural Medicines and Department of
Medicinal Chemistry, China Pharmaceutical University, Nanjing,
210009, P. R. China. E-mail: xmwu@cpu.edu.cn; hyao@cpu.edu.cn;
Fax: +86 25-83301606; Tel: +86 25-83271042
T. Takeuchi, K. Ogawa, H. Iinuma, H. Suda, K. Ukita, T. Nagatsu, M.
Kato, H. Umezawa and O. Tanabe, J. Antibiot., 1973, 26, 162.
(a) Z. Wang, F. Song, Y. Zhao, Y. Huang, L. Yang, D. Zhao, J. Lan
and J. You, Chem. Eur. J., 2012, 18, 16616; (b) M. Nishino, K.
8
† Electronic supplementary information (ESI) available: Experimental
procedures and characterization of all title compounds. See DOI:
10.1039/c000000x/
Hirano, T. Satoh and M. Miura, Angew. Chem., Int. Ed., 2012, 51
6993; (c) W. Wu and J. Huang, Org. Lett., 2012, 14, 5832.
,
9
(a) J. M. Joo, B. B. Toure and D. Sames, J. Org. Chem., 2010, 75
,
4911; (b) F. Shibahara, E. Yamaguchi and T. Murai, J. Org. Chem.
2011, 76, 2680; (c) S. I. Gorelsky, Organometallics., 2012, 31, 794.
1
For recent reviews and highlights on oxidative C–H/C–H cross-
couplings, see: (a) T. Newhouse and P. S. Baran, Angew. Chem., Int.
Ed., 2011, 50, 3362; (b) C. S. Yeung and V. M. Dong, Chem. Rev.,
2011, 111, 1215; (c) X. Bugaut and F. Glorius, Angew. Chem., Int.
Ed., 2011, 50, 7479; (d) S. H. Cho, J. Y. Kim, J. Kwak and S. Chang,
Chem. Soc. Rev., 2011, 40, 5068; (e) J. A. Ashenhurst, Chem. Soc.
10 Z. Li, L. Ma, J. Xu, L. Kong, X. Wu and H. Yao, Chem. Commun.,
2012, 48, 3763.
11 (a) Y. Su, H. Zhou, J. Chen, J. Xu, X. Wu, A. Lin and H. Yao, Org.
Lett., 2014, 16, 4884; (b) L. Zhao, Z. Li, L. Chang, J. Xu, H. Yao and
X. Wu, Org. Lett., 2012, 14, 2066.
Rev., 2010, 39, 540; (f) W. Han and A. R. Ofial, Synlett, 2011, 14
,
12 E. M. Ferreira and B. M. Stoltz, J. Am. Chem. Soc., 2003, 125, 9578.
13 (a) M. D. K. Boele, G. P. F. van Strijdonck, A. H. M. de Vries, P. C.
J. Kamer, J. G. de Vries and P. W. N. M. van Leeuwen, J. Am. Chem.
Soc., 2002, 124, 1586; (b) G. Wang, T. Yuan and X. Wu, J. Org.
Chem., 2008, 73, 4717; (c) G. W. Wang and T. Yuan, J. Org. Chem.,
2010, 75, 476.
1951; (g) C. Liu, H. Zhang, W. Shi and A. Lei, Chem. Rev., 2011,
111, 1780.
2
For selected examples of oxidative C–H/C–H cross-coupling between
two heteroarenes, see: (a) D. R. Stuart and K. Fagnou, Science, 2007,
316, 1172; (b) T. A. Dwight, N. R. Rue, D. Charyk, R. Josselyn and
B. DeBoef, Org. Lett., 2007, 9, 3137; (c) X. Wang, D. V. Gribkov
14 (a) N. P. Pavri and M. L. Trudell, J. Org.Chem., 1997, 62, 2649; (b)
and D. Sames, J. Org. Chem., 2007, 72, 1476; (d) P. Xi, F. Yang, S.
Qin, D. Zhao, J. Lan, G. Gao, C. Hu and J. You, J. Am. Chem. Soc.,
2010, 132, 1822; (e) X. Gong, G. Song, H. Zhang and X. Li, Org.
Lett., 2011, 13, 1766; (f) Z. Wang, K. Li, D. Zhao, J. Lan and J. You,
Angew. Chem., Int. Ed., 2011, 50, 5365; (g) W. Han, P. Mayer and A.
R. Ofial, Angew. Chem., Int. Ed., 2011, 50, 2178; (h) A. D.
Yamaguchi, D. Mandal, J. Yamaguchi and K. Itami, Chem. Lett.,
2011, 40, 555; (i) X. Qin, B. Feng, J. Dong, X. Li, Y. Xue, J. Lan and
J. You, J. Org. Chem., 2012, 77, 7677; (j) B. Liu, Y. Huang, J. Lan
P. Lu, C. Sanchez, J. Cornella and I. Larrosa, Org. Lett., 2009, 11
,
5710; (c) L. J. Gooβen, C. Linder, N. Rodrı´guez, P. P. Lange and A.
Fromm, Chem. Commun., 2009, 45, 7173; (d) J. Cornella, C.
Sanchez, D. Banawa and I. Larrosa, Chem. Commun., 2009, 45, 7176;
(e) S. Seo, J. B. Taylor and M. F. Greaney, Chem. Commun., 2012,
48, 8270.
and F. Song, J. You, Chem. Sci., 2013, 4, 2163; (k) Y. Shang, X. Jie,
H. Zhao, P. Hu and W. Su, Org. Lett., 2014, 16, 416.
3
(a) B. S. Joshi, W. I. Taylor, D. S. Bhate and S. S. Karmarkar,
Tetrahedron, 1963, 19, 1437; (b) K. Umehara, K. Yoshida, M.
Okamoto, M. Iwami, H. Tanaka, M. Kohsaka and H. Imanaka, J.
Antibiot., 1984, 37, 1153; (c) S. Takahashi, T. Matsunaga, C.
Hasegawa, H. Saito, D. Fujita, F. Kiuchi and Y. Tsuda, Chem.
Pharm. Bull., 1998, 46, 1527; (d) S. R. Naik, J. Harindran and A. B.
Varde, J. Biotechnol., 2001, 88, 1; (e) R. Raju, O. Gromyko, V.
Fedorenko, A. Luzhetskyy and R. Müller, Tetrahedron Lett., 2012,
53, 3009.
4
For the synthesis of 5-(3-indolyl)oxazoles natural alkaloid and its
derivatives, see: (a) Y. Oikawa, T. Yoshida, K. Mohri and O.
Yonemitsu, Heterocycles, 1979, 12, 1457; (b) P. Molina, P. M.
6 Org.Biomol.Chem., 2013, 00, 1-3
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