Copper-catalyzed annulation of heteroaromatic β-halo-α,β- unsaturated carboxylic acids with alkynes for the synthesis of indolo[2,3-c]pyrane-1-ones and thieno[2,3-c]pyrane-7-ones

Article abstract of DOI:10.1039/c4ob00996g

The annulation of heteroaromatic β-halo-α,β-unsaturated carboxylic acids with alkynes proceeds efficiently in the presence of Cu(OAc)₂·H₂O as a catalyst to afford the corresponding indolo[2,3-c]pyrane-1-ones and thieno[2,3-c]pyrane-7

Full text of DOI:10.1039/c4ob00996g

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Copper-catalyzed annulation of heteroaromatic
β-halo-α,β-unsaturated carboxylic acids with
alkynes for the synthesis of indolo[2,3-c]pyrane-
1-ones and thieno[2,3-c]pyrane-7-ones†
Cite this: Org. Biomol. Chem., 2014,
12, 6114
Da-Wei Gu and Xun-Xiang Guo*
The annulation of heteroaromatic β-halo-α,β-unsaturated carboxylic acids with alkynes proceeds efficien-
tly in the presence of Cu(OAc)2·H2O as a catalyst to afford the corresponding indolo[2,3-c]pyrane-1-ones
and thieno[2,3-c]pyrane-7-ones in moderate to good yields. This strategy offers a simple and efficient
route for the synthesis of indolo[2,3-c]pyrane-1-ones and thieno[2,3-c]pyrane-7-ones with good toler-
ance to a variety of functional groups from easily available heteroaromatic β-halo-α,β-unsaturated
carboxylic acids.
Received 14th May 2014,
Accepted 18th June 2014
DOI: 10.1039/c4ob00996g
www.rsc.org/obc
Recently, copper salts, with low cost and low toxicity, have
been widely used as catalysts in organic reactions.11 We
Introduction
The synthesis of heterocycles has attracted considerable atten- recently described a novel method for the synthesis of iso-
tion because of their important physiological and biological coumarin derivatives by Cu-catalyzed addition of o-haloben-
activities.1 As one of the important heterocycles, indolo[2,3-c]- zoic acids to internal alkynes.12 As one of our interests in
pyrane-1-ones and thieno[2,3-c]pyrane-7-ones have a wide developing Cu-catalyzed methods to construct heterocycles, we
range of biological and pharmacological properties. For report here an efficient synthesis of indolo[2,3-c]pyrane-1-ones
example, indolo[2,3-c]pyrane-1-one derivatives exhibit anti- and thieno[2,3-c]pyrane-7-ones through Cu-catalyzed annula-
cancer potential towards human cervix adenocarcinoma2 and tions of heteroaromatic β-halo-α,β-unsaturated carboxylic acids
antinociceptive and anti-inflammatory activity,3 and are hepa- with alkynes. Using this reaction protocol, the indolo[2,3-c]-
titis C virus NS5B polymerase inhibitors.4 Thieno[2,3-c]pyrane- pyrane-1-ones and thieno[2,3-c]pyrane-7-ones were obtained in
7-one derivatives are known to be inhibitors of tumor cell moderate to good yields in the presence of an inexpensive
growth.5
copper catalyst from easily available heteroaromatic β-halo-
For the synthesis of indolo[2,3-c]pyrane-1-ones and thieno- α,β-unsaturated carboxylic acids.
[2,3-c]pyrane-7-ones, most reported examples use expensive
transition-metal complexes, such as palladium,6 rhodium,7
ruthenium,8 and gold2 as the catalyst. Recently, the inexpen-
sive transition-metal complexes of copper9 and iron10 have
been employed for the synthesis of indolo[2,3-c]pyrane-1-ones
and thieno[2,3-c]pyrane-7-ones. However, these reactions
suffered from the disadvantages of the need for stoichiometric
amounts of copper or iron complexes and limited substrate
scope. Owing to their important biological and pharmacologi-
cal properties, the development of efficient inexpensive tran-
sition-metal-catalyzed protocols to access indolo[2,3-c]pyrane-
1-ones and thieno[2,3-c]pyrane-7-ones is highly desirable.
Results and discussion
Initially, we chose compound 1a and dimethyl acetylenedi-
carboxylate (2a) as the model starting materials to test the reac-
tion. The reaction of 1a and 2a in the presence of 10 mol%
CuCl2 in toluene with 2 equiv. of K2CO3 as the base at 130 °C
for 24 hours afforded the desired product 3aa in 39% yield
(Table 1, entry 1). Although the catalyst Cu(OTf)2 gave 36%
yield of the product 3aa (Table 1, entry 2), the yield was
increased to 52% when Cu(OAc)2 was used in the reaction
(Table 1, entry 3). To our delight, the employment of
Cu(OAc)2·H2O as a catalyst provided the product 3aa in 62%
yield (the isolated yield is 61%, Table 1, entry 4). We applied
Cu(OAc)2·H2O to examine other reaction conditions. In the
cases of base examination, the bases Cs2CO3 and K3PO4
afforded the product 3aa in poor yields, and K2CO3 was the
Shanghai Center for Systems Biomedicine, Ministry of Education Key Laboratory of
Systems Biomedicine, Shanghai Jiao Tong University, 800 Dongchuan Road,
Shanghai 200240, China. E-mail: xunxiang_guo@sjtu.edu.cn
†Electronic supplementary information (ESI) available: The copies of NMR
spectra. See DOI: 10.1039/c4ob00996g
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optimal base in this reaction. (Table 1, entries 5–6). We also
investigated several other solvents. The use of mesitylene pro-
vided the product 3aa in 39% yield, while the other solvents,
such as DMF, DMSO, and diglyme gave trace amounts of the
product 3aa (Table 1, entries 7–10). Furthermore, we found
that no desired product was obtained in the absence of a
copper catalyst (Table 1, entry 11).
Table 1 Copper-catalyzed annulation of 1-methyl-3-iodo-indole-2-
carboxylic acid (1a) with dimethyl acetylenedicarboxylate (2a): optimi-
zation of the reaction conditionsa
With the optimal reaction conditions in hand (Table 1,
entry 4), we investigated the scope of the reaction of β-halo-
α,β-unsaturated carboxylic acids (1) with 2a, and the results are
summarized in Table 2. It was found that the compounds with
substituents on the nitrogen-position of 3-iodo-indole-2-
carboxylic acids were suitable for the reaction to provide the
corresponding products in moderate to good yields (Table 2,
entries 1–4). For example, the reaction of 1a with 2a in the
presence of 10 mol% of Cu(OAc)2·H2O as the catalyst with
2 equiv. of K2CO3 as the base in toluene at 130 °C for 24 hours
afforded the product 3aa in 61% yield (Table 2, entry 1).
Although compound 1b, which has an ethyl group substituted
on the nitrogen-position of 3-iodo-indole-2-carboxylic acid,
gave 42% yield of the product 3ba (Table 2, entry 2), the com-
pounds bearing a butyl or benzyl group substituted on the
same position provided the corresponding products in good
yields (Table 2, entries 3–4). We also found that the com-
pounds containing an electron-donating group on the benzene
Entry
[Cu]
Base
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
CuCl2
Cu(OTf)2
Cu(OAc)2
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
K3PO4
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
DMF
39
36
52
62 (61)
7
14
Trace
0
6
39
0
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
—
DMSO
9
10
11
Diglyme
Mesitylene
Toluene
a Reaction conditions: the reactions were performed in a sealed tube
with 1a (0.2 mmol), 2a (0.4 mmol), catalyst (0.02 mmol), and base
(0.4 mmol) in solvent (2.0 mL) at 130 °C for 24 h under N2. b NMR
yields with CH3NO2 as an internal standard, and the data in the
parenthesis is isolated yield.
Table 2 Copper-catalyzed annulation of heteroaromatic β-halo-α,β-unsaturated carboxylic acids with 2aa
Entry
1
Substrate 1
Product 3
Yieldb (%)
61
2
3
42
53
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Table 2 (Contd.)
Entry
4
Substrate 1
Product 3
Yieldb (%)
56
5
52
6c
58
40
7c
8
42
61
9c
a Reaction conditions: unless otherwise noted, the reactions were performed in a sealed tube with heteroaromatic β-halo-α,β-unsaturated
carboxylic acids (0.2 mmol), 2a (0.4 mmol), Cu(OAc)2·H2O (0.02 mmol), and K2CO3 (0.4 mmol) in toluene (2.0 mL) at 130 °C for 24 h under N2.
b Isolated yields. c Cu(OAc)2·H2O (0.04 mmol) was used.
ring of indoles gave higher yields than electron-withdrawing changed to the bromo group, the reaction of 1h and 2a
counterparts, although 20 mol% of Cu(OAc)2·H2O was needed worked, and afforded the product 3aa in 42% yield under the
in the cases of compounds 1f and 1g (Table 2, entries 5–7). optimized conditions (Table 2, entry 8). Furthermore, com-
To our pleasure, when the iodo group in compound 1a was pound 1i proceeded smoothly giving thieno[2,3-c]pyrane-7-one
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3ia in 61% yield in the presence of 20 mol% of Cu(OAc)2·H2O corresponding products in moderate to good yields (Table 3,
as the catalyst (Table 2, entry 9). entries 1–7). The reaction of 2b and 1a afforded the product
The scope of alkynes was examined. As shown in Table 3, 3ab in 60% yield (Table 3, entry 2). Under the same reaction
some alkynes can be employed to this reaction giving the conditions, the product 3ac was obtained in 62% yield when
Table 3 Copper-catalyzed annulation of 1-methyl-3-iodo-indole-2-carboxylic acid (1a) with alkynesa
Entry
1
Alkyne 2
Product 3
Yieldb (%)
61
2
3
4
5
6
60
62
52
40
42
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Table 3 (Contd.)
Entry
7
Alkyne 2
Product 3
Yieldb (%)
56
a Reaction conditions: the reactions were performed in a sealed tube with 1a (0.2 mmol), alkynes (0.4 mmol), Cu(OAc)2·H2O (0.02 mmol), and
K2CO3 (0.4 mmol) in toluene (2.0 mL) at 130 °C for 24 h under N2. b Isolated yields.
2c was used in this reaction (Table 3, entry 3). It was found compounds 2c–2f13 were prepared according to the reported
that treatment of 2d with 1a gave the product 3ad in 52% yield procedure. NMR spectra were recorded on a 400 spectrometer
(Table 3, entry 4). The reactions proceeded with alkynes 2e and (400 MHz for 1H, 100 MHz for 13C) with deuterated chloroform
2f, although the yields of products 3ae and 3af were somewhat (CDCl3) or hexadeuteriodimethyl sulfoxide (DMSO-d6) as a
lower (Table 3, entries 5–6). Interestingly, the terminal alkyne solvent at 298 K. Chemical shifts are reported in δ ppm refer-
2g was also suitable for this reaction exclusively providing the enced to an internal SiMe4 standard for 1H NMR, CDCl3
product 3ag in 56% yield (Table 3, entry 7). Although the (δ 77.16), and DMSO-d6 (δ 39.52) for 13C NMR. The following
mechanistic details are not clear at this stage, this result may abbreviations are used; s: singlet, d: doublet, t: triplet,
indicate an initial step of addition of heteroaromatic β-halo- q: quartet, m: multiplet. High-resolution mass spectra were
α,β-unsaturated carboxylic acids to alkynes involved in the obtained with a Q-TOF MS spectrometer.
present reaction. Further investigations are needed to elucidate
the detailed mechanism.
1-Butyl-3-iodo-indole-2-carboxylic acid (1c). White solid. Mp
162–164 °C. H NMR (DMSO-d6) δ 13.55 (brs, 1H), 7.57 (d, J =
1
8.4 Hz, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.37 (dd, J = 8.0, 8.0 Hz,
1H), 7.21 (dd, J = 8.0, 8.0 Hz, 1H), 4.55 (t, J = 8.0, Hz, 2H),
1.60–1.67 (m, 2H), 1.18–1.25 (m, 2H), 0.85 (t, J = 8.0, Hz, 3H).
13C NMR(DMSO-d6) δ 13.61, 19.47, 32.44, 44.88, 66.78, 111.38,
121.27, 122.96, 125.57, 129.30, 129.59, 138.01, 162.27. HRMS
(ESI) calcd for C13H13NO2I, 341.9991 (M − H)−, found 341.9999.
1,5-Dimethyl-3-iodo-indole-2-carboxylic acid (1e). White
solid. mp 178–180 °C. 1H NMR (DMSO-d6) δ 13.52 (brs, 1H),
7.46 (d, J = 8.6 Hz, 1H), 7.23 (s, 1H), 7.22 (d, J = 8.4 Hz, 1H),
4.00 (s, 3H), 2.44 (s, 3H). 13C NMR(DMSO-d6) δ 21.07, 33.02,
65.91, 111.18, 122.09, 127.58, 129.53, 129.69, 130.32, 137.19,
162.40. HRMS (ESI) calcd for C11H9NO2I, 313.9678 (M − H)−,
found 313.9693.
Conclusions
In conclusion, we described an efficient Cu-catalyzed annula-
tion of heteroaromatic β-halo-α,β-unsaturated carboxylic acids
with alkynes. The indolo[2,3-c]pyrane-1-ones and thieno[2,3]-
pyrane-7-ones were obtained in moderate to good yields using
Cu(OAc)2·H2O as a catalyst. The use of a catalytic amount of an
inexpensive copper catalyst combined with good functional
group tolerance of substrates from easily available hetero-
aromatic β-halo-α,β-unsaturated carboxylic acids should make
the present reaction to become a useful method for the synthesis
of indolo[2,3-c]pyrane-1-ones and thieno[2,3]pyrane-7-ones.
3-Iodo-5-methoxy-1-methyl-indole-2-carboxylic acid (1f).
1
White solid. mp 180–181 °C. H NMR (DMSO-d6) δ 13.34 (brs,
1H), 7.40 (d, J = 9.1 Hz, 1H), 6.94 (dd, J = 9.1, 2.4 Hz, 1H), 6.74
(d, J = 2.4 Hz, 1H), 3.90 (s, 3H), 3.73 (s, 3H). 13C NMR(DMSO-
d6) δ 33.05, 55.37, 65.44, 102.71, 112.56, 116.98, 129.68,
129.88, 133.89, 154.97, 162.20. HRMS (ESI) calcd for
C11H9NO3I, 329.9627 (M − H)−, found 329.9644.
5-Fluoro-3-iodo-1-methyl-indole-2-carboxylic acid (1g). White
solid. mp 206–208 °C. 1H NMR (DMSO-d6) δ 13.71 (brs, 1H),
7.66 (dd, J = 8.7, 3.7 Hz, 1H), 7.28 (t, J = 9.1 Hz, 1H), 7.16 (d, J =
Experimental
General information
All the reactions were carried out with standard Schlenk tech-
niques under predried nitrogen. Toluene was distilled over
benzophenone ketyl under N2. All commercial reagents were
used without further purification. Compounds 1a–1h9 and
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9.1 Hz, 1H), 4.04 (s, 3H). 13C NMR(DMSO-d6) δ 33.27, 65.47, (s, 3H), 3.96 (s, 3H), 2.48 (s, 3H); 13C NMR(CDCl3) δ 21.74,
107.03 (d, JF–C = 24 Hz), 113.32 (d, JF–C = 9.6 Hz), 114.46 (d, 31.77, 53.15, 53.51, 110.82, 117.95, 119.16, 120.49, 120.82,
JF–C = 26 Hz), 129.93 (d, JF–C = 10.3 Hz), 131.39, 135.35, 158.08 123.20, 130.52, 132.57, 137.70, 139.97, 154.17, 160.30, 165.82.
(d, JF–C = 234 Hz), 162.13. HRMS (ESI) calcd for C10H6NO2IF, HRMS (ESI) calcd for C17H16NO6 (M + H)+, 330.0978, found
317.9427 (M − H)−, found 317.9438.
330.0981.
3,4-Dimethoxycarbonyl-6-methoxy-9-methyl-indolo-[2,3-c]-
pyrane-1-one (3fa). White solid, 40.1 mg (58% yield), mp
General procedure for the synthesis of the product 3
A mixture of Cu(OAc)2·H2O (4.0 mg, 0.02 mmol), K2CO3 164–166 °C; 1H NMR(CDCl3) δ 7.42 (d, J = 9.2 Hz, 1H), 7.24
(55.3 mg, 0.4 mmol), 1-methyl-3-iodo-indole-2-carboxylic acid (d, J = 9.2 Hz, 1H), 7.04 (s, 1H), 4.23 (s, 3H), 4.11 (s, 3H), 3.97
(1a) (60.2 mg, 0.2 mmol), and dimethyl acetylenedicarboxylate (s, 3H), 3.88 (s, 3H); 13C NMR(CDCl3) δ 31.88, 53.15, 53.41,
(2a) (56.8 mg, 0.4 mmol) in toluene (2.0 mL) was stirred at 55.71, 101.63, 112.11, 117.85, 118.93, 120.07, 120.77, 123.26,
room temperature under a N2 atmosphere. Then the mixture 136.85, 137.56, 154.18, 155.98, 160.31, 165.79. HRMS (ESI)
was stirred at 130 °C for 24 h. After completion, the mixture calcd for C17H16NO7 (M + H)+, 346.0927, found 346.0917.
was cooled to room temperature and diluted with ethyl
3,4-Dimethoxycarbonyl-6-fluoro-9-methyl-indolo-[2,3-c]-
acetate. The mixture was passed through a short column of pyrane-1-one (3ga). White solid, 26.7 mg (40% yield), mp
celite with ethyl acetate as an eluent. After evaporation of the 196–198 °C; 1H NMR(CDCl3) δ 7.51 (dd, J = 9.0, 3.8 Hz, 1H),
solvent, the residue was purified by preparative thin-layer 7.37 (d, J = 6.5 Hz, 2H), 4.28 (s, 3H), 4.12 (s, 3H), 3.98 (s, 3H);
chromatography on silica gel with CH2Cl2–MeOH (200/1) as an 13C NMR(CDCl3) δ 32.06, 53.28, 53.66, 106.63, 106.88, 112.42,
eluent to give the product 3aa.
112.52, 117.42, 117.78, 118.05, 119.45, 124.35, 138.13, 154.01,
3,4-Dimethoxycarbonyl-9-methyl-indolo[2,3-c]pyrane-1-one 160.16, 165.43. HRMS (ESI) calcd for C16H13NO6F (M + H)+,
(3aa). White solid, 38.6 mg (61% yield), mp 174–176 °C; 1H 334.0727, found 334.0714.
NMR(CDCl3) δ 7.68 (d, J = 7.9 Hz, 1H), 7.55 (t, J = 7.2 Hz, 1H),
4,5-Dimethoxycarbonyl-thieno[2,3-c]pyrane-7-one
(3ia).
7.47 (d, J = 8.3 Hz, 1H), 7.31 (t, J = 7.4 Hz, 1H), 4.20 (s, 3H), White solid, 32.8 mg (61% yield), mp 96–98 °C; 1H NMR
4.11 (s, 3H), 3.96 (s, 3H); 13C NMR(CDCl3) δ 31.73, 53.16, (CDCl3) δ 7.98 (d, J = 5.1 Hz, 1H), 7.47 (d, J = 5.1 Hz, 1H), 3.98
53.49, 111.13, 117.71, 119.70, 120.24, 121.58, 122.77, 123.24, (s, 6H); 13C NMR(CDCl3) δ 53.50, 53.67, 113.92, 125.27, 126.31,
128.48, 138.01, 141.36, 154.06, 160.17, 165.63. HRMS (ESI) 138.08, 142.93, 146.61, 155.18, 160.50, 164.43. HRMS (ESI)
calcd for C16H14NO6 (M + H)+, 316.0821, found 316.0820.
calcd for C11H9O6S (M + H)+, 269.0120, found 269.0113.
3,4-Dimethoxycarbonyl-9-ethyl-indolo[2,3-c]pyrane-1-one (3ba).
3,4-Diethoxycarbonyl-9-methyl-indolo[2,3-c]pyrane-1-one (3ab).
White solid, 27.7 mg (42% yield), mp 163–164 °C; 1H NMR White solid, 41.2 mg (60% yield), mp 195–197 °C; 1H NMR
(CDCl3) δ 7.73 (d, J = 8.2 Hz, 1H), 7.61–7.55 (m, 2H), 7.34 (t, J = (CDCl3) δ 7.67 (d, J = 8.1 Hz, 1H), 7.49 (t, J = 7.6 Hz, 1H), 7.42
7.3 Hz, 1H), 4.79 (q, J = 7.1 Hz, 2H), 4.13 (s, 3H), 3.98 (s, 3H), (d, J = 8.4 Hz, 1H), 7.24 (t, J = 7.5 Hz, 1H), 4.51 (q, J = 7.1 Hz,
1.47 (t, J = 7.1 Hz, 3H); 13C NMR(CDCl3) δ 15.96, 40.26, 53.26, 2H), 4.35 (q, J = 7.1 Hz, 2H), 4.16 (s, 3H), 1.38 (t, J = 8.0 Hz, 3H),
53.61, 111.24, 117.85, 120.05, 120.59, 121.85, 122.69, 122.79, 1.35 (t, J = 8.0 Hz, 3H); 13C NMR(CDCl3) δ 14.07, 14.29, 31.76,
128.60, 137.96, 140.46, 153.81, 160.29, 165.82. HRMS (ESI) 62.52, 62.75, 111.15, 117.87, 119.97, 120.42, 121.78, 122.71,
calcd for C17H16NO6 (M + H)+, 330.0978, found 330.0967.
9-Butyl-3,4-dimethoxycarbonyl-indolo[2,3-c]pyrane-1-one (3ca). (ESI) calcd for C18H18NO6 (M + H)+, 344.1134, found 344.1122.
White solid, 37.9 mg (53% yield), mp 141–142 °C; 1H NMR
3,4-Dipropoxycarbonyl-9-methyl-indolo[2,3-c]pyrane-1-one
123.29, 128.49, 138.34, 141.47, 154.32, 159.71, 165.26. HRMS
(CDCl3) δ 7.73 (d, J = 8.2 Hz, 1H), 7.54–7.61 (m, 2H), 7.35 (t, J = (3ac). White solid, 46.0 mg (62% yield), mp 152–153 °C; 1H
6.8 Hz, 1H), 4.75 (t, J = 7.2 Hz, 2H), 4.13 (s, 3H), 3.98 (s, 3H), NMR(CDCl3) δ 7.77 (d, J = 8.2 Hz, 1H), 7.61 (t, J = 7.6 Hz, 1H),
1.91–1.75 (m, 2H), 1.32–1.41 (m, 2H), 0.93 (t, J = 7.3 Hz, 3H); 7.54 (d, J = 8.5 Hz, 1H), 7.35 (t, J = 7.5 Hz, 1H), 4.48 (t, J = 6.8,
13C NMR(CDCl3) δ 13.85, 20.03, 32.80, 45.07, 53.17, 53.53, Hz, 2H), 4.32 (t, J = 6.8 Hz, 2H), 4.29 (s, 3H), 1.77–1.90 (m, 4H),
111.50, 117.78, 119.93, 120.53, 121.79, 122.71, 123.04, 128.45, 1.02 (td, J = 7.4, 4.2 Hz, 6H); 13C NMR(CDCl3) δ 10.40, 10.50,
138.04, 140.86, 153.83, 160.27, 165.79. HRMS (ESI) calcd for 21.78, 22.01, 31.73, 68.02, 68.39, 111.13, 117.84, 119.96,
C19H20NO6 (M + H)+, 358.1291, found 358.1284.
120.38, 121.74, 122.66, 123.28, 128.45, 138.33, 141.44, 154.31,
9-Benzyl-3,4-dimethoxycarbonyl-indolo[2,3-c]pyrane-1-one 159.79, 165.36. HRMS (ESI) calcd for C20H22NO6 (M + H)+,
(3da). White solid, 43.8 mg (56% yield), mp 209–211 °C; 1H 372.1447, found 372.1443.
NMR(CDCl3) δ 7.74 (d, J = 8.2 Hz, 1H), 7.52 (d, J = 3.6 Hz, 2H),
3,4-Dibutoxycarbonyl-9-methyl-indolo[2,3-c]pyrane-1-one (3ad).
7.28–7.34 (m, 1H), 7.21–7.26 (m, 3H), 7.18 (d, J = 6.8 Hz, 2H), White solid, 41.6 mg (52% yield), mp 136–137 °C; 1H NMR
5.97 (s, 2H), 4.12 (s, 3H), 3.97 (s, 3H); 13C NMR(CDCl3) δ 48.47, (CDCl3) δ 7.75 (d, J = 8.2 Hz, 1H), 7.59 (t, J = 7.6 Hz, 1H), 7.53
53.25, 53.60, 112.06, 117.74, 120.57, 120.77, 121.87, 123.03, (d, J = 8.5 Hz, 1H), 7.34 (t, J = 7.5 Hz, 1H), 4.52 (t, J = 6.8 Hz,
127.08, 128.02, 128.82, 128.95, 136.52, 138.43, 141.10, 154.02, 2H), 4.37 (t, J = 6.8 Hz, 2H), 4.27 (s, 3H), 1.87–1.71 (m, 4H),
160.23, 165.72. HRMS (ESI) calcd for C22H18NO6 (M + H)+, 1.53–1.38 (m, 4H), 0.97 (q, J = 7.3 Hz, 6H); 13C NMR(CDCl3) δ
392.1134, found 392.1131.
13.78, 13.84, 19.18, 19.24, 30.38, 30.66, 31.82, 66.43, 66.74,
3,4-Dimethoxycarbonyl-6,9-dimethyl-indolo[2,3-c]pyrane-1-one 111.19, 117.92, 120.06, 120.45, 121.83, 122.71, 123.34, 128.56,
(3ea). White solid, 34.3 mg (52% yield), mp 199–200 °C; 138.31, 141.50, 154.41, 159.84, 165.46. HRMS (ESI) calcd for
1H NMR(CDCl3) δ 7.42 (s, 1H), 7.37 (s, 2H), 4.19 (s, 3H), 4.12 C22H26NO6 (M + H)+, 400.1760, found 400.1755.
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Org. Biomol. Chem., 2014, 12, 6114–6120 | 6119

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Paper
Organic & Biomolecular Chemistry
3,4-Dibenzoxycarbonyl-9-methyl-indolo[2,3-c]pyrane-1-one
3 C. Praveen, P. Dheenkumar and P. T. Perumal, J. Chem. Sci.,
2013, 125, 71.
(3ae). Yellow solid, 37.4 mg (40% yield), mp 151–152 °C; 1H
NMR(CDCl3) δ 7.55–7.49 (m, 1H), 7.49–7.43 (m, 3H), 7.43–7.32
(m, 9H), 7.13 (t, J = 7.5 Hz, 1H), 5.35 (s, 2H), 5.31 (s, 2H), 4.22
(s, 3H); 13C NMR(CDCl3) δ 31.81, 68.15, 68.58, 111.08, 117.99,
119.84, 120.35, 121.90, 122.71, 123.34, 128.50, 128.78, 128.83,
128.86, 128.97, 129.28, 134.63, 134.84, 138.00, 141.43, 154.25,
159.47, 164.99. HRMS (ESI) calcd for C28H22NO6 (M + H)+,
468.1447, found 468.1428.
4 (a) A. Gopalsamy, K. Lim, G. Ciszewski, K. Park,
J. W. Ellingboe, J. Bloom, S. Insaf, J. Upeslacis,
T. S. Mansour, G. Krishnamurthy, M. Damarla, Y. Pyatski,
D. Ho, A. Y. M. Howe, M. Orlowski, B. Feld and
J. O’Connell, J. Med. Chem., 2004, 47, 6603;
(b) M. G. LaPorte, T. L. Draper, L. E. Miller,
C. W. Blackledge, L. K. Leister, E. Amparo, A. R. Hussey,
D. C. Young, S. K. Chunduru, C. A. Benetatos, G. Rhodes,
A. Gopalsamy, T. Herbertz, C. J. Burns and S. M. Condon,
Bioorg. Med. Chem. Lett., 2010, 20, 2968.
5 M.-J. R. P. Queiroz, R. C. Calhelha, L. A. Vale-Silva, E. Pinto
and M. S.-J. Nascimento, Eur. J. Med. Chem., 2009, 44, 1893.
6 (a) S. Raju, V. R. Batchu, N. K. Swamy, R. V. Dev,
J. M. Babu, P. R. Kumar, K. Mukkanti and M. Pal, Tetra-
hedron Lett., 2006, 47, 83; (b) S. Raju, V. R. Batchu,
N. K. Swamy, R. V. Dev, B. R. Sreekanth, J. M. Babu,
K. Vyas, P. R. Kumar, K. Mukkanti, P. Annamalai and
M. Pal, Tetrahedron, 2006, 62, 9554; (c) R. R. Suresh and
K. C. K. Swamy, J. Org. Chem., 2012, 77, 6959; (d) H. Wang,
X. Han and X. Lu, Tetrahedron, 2013, 69, 8626.
3,4-Diallyloxycarbonyl-9-methyl-indolo[2,3-c]pyrane-1-one
(3af). White solid, 30.9 mg (42% yield), mp 126–128 °C; 1H
NMR(CDCl3) δ 7.76 (d, J = 8.2 Hz, 1H), 7.58 (t, J = 7.6 Hz, 1H),
7.52 (d, J = 8.5 Hz, 1H), 7.33 (t, J = 7.5 Hz, 1H), 6.15–5.95 (m,
2H), 5.46 (ddd, J = 17.2, 7.6, 1.3 Hz, 2H), 5.40–5.30 (m, 2H),
5.01 (d, J = 6.0 Hz, 2H), 4.85 (d, J = 6.0 Hz, 2H), 4.26 (s, 3H);
13C NMR(CDCl3) δ 31.83, 67.03, 67.37, 111.19, 117.83, 119.83,
120.05, 120.37, 121.91, 122.78, 123.32, 128.58, 131.21, 138.16,
141.47, 154.23, 159.37, 164.94. HRMS (ESI) calcd for
C20H18NO6 (M + H)+, 368.1134, found 368.1136.
4-Methoxycarbonyl-9-methyl-indolo[2,3-c]pyrane-1-one (3ag).
White solid, 28.9 mg (56% yield), mp 218–220 °C; 1H NMR
(CDCl3) δ 7.87–7.96 (m, 2H), 7.59 (t, J = 7.6 Hz, 1H), 7.50 (d, J =
8.4 Hz, 1H), 7.36 (t, J = 7.3 Hz, 1H), 4.24 (s, 3H), 3.97 (s, 3H);
13C NMR(CDCl3) δ 31.70, 52.85, 108.45, 111.08, 121.58, 121.66,
122.31, 122.88, 123.88, 128.44, 141.47, 141.49, 155.34, 160.88.
HRMS (ESI) calcd for C14H12NO6 (M + H)+, 258.0766, found
258.0761.
7 M. Shimizu, K. Hirano, T. Satoh and M. Miura, J. Org.
Chem., 2009, 74, 3478.
8 R. K. Chinnagolla and M. Jeganmohan, Chem. Commun.,
2012, 48, 2030.
9 S. I. Ngi, V. Guilloteau, M. Abarbri and J. Thibonnet, J. Org.
Chem., 2011, 76, 8347.
10 Z. Li, J. Hong, L. Weng and X. Zhou, Tetrahedron, 2012, 68,
1552.
Acknowledgements
11 For selected reviews on Cu-catalyzed reactions, see:
(a) S. E. Allen, R. R. Walvoord, R. Padilla-Salinas and
M. C. Kozlowski, Chem. Rev., 2013, 113, 6234; (b) C. Zhang,
C. Tang and N. Jiao, Chem. Soc. Rev., 2012, 41, 3464;
(c) Z. Shi, C. Zhang, C. Tang and N. Jiao, Chem. Soc. Rev.,
2012, 41, 3381; (d) A. E. Wendlandt, A. M. Suess and
S. S. Stahl, Angew. Chem., Int. Ed., 2011, 50, 11062;
(e) D. S. Surry and S. L. Buchwald, Chem. Sci., 2010, 1, 13;
(f) F. Monnier and M. Taillefer, Angew. Chem., Int. Ed.,
2009, 48, 6954; (g) D. Ma and Q. Cai, Acc. Chem. Res., 2008,
41, 1450; (h) G. Evano, N. Blanchard and M. Toumi, Chem.
Rev., 2008, 108, 3054; (i) Z. Li, D. S. Bohle and C.-J. Li, Proc.
Natl. Acad. Sci. U. S. A., 2006, 103, 8928; ( j) I. P. Beletskaya
and A. V. Cheprakov, Coord. Chem. Rev., 2004, 248, 2337;
(k) S. V. Ley and A. W. Thomas, Angew. Chem., Int. Ed.,
2003, 42, 5400.
This work was supported by the Natural Science Foundation of
China (no. 21172142).
Notes and references
1 For selected reviews on synthesis of heterocycles, see:
(a) C. C. Nawrat and C. J. Moody, Angew. Chem., Int. Ed.,
2014, 53, 2056; (b) D. Garella, E. Borretto, A. D. Stilo,
K. Martina, G. Cravotto and P. Cintas, Med. Chem.
Commun., 2013, 4, 1323; (c) C. J. Ball and M. C. Willis,
Eur. J. Org. Chem., 2013, 425; (d) T. Liu and H. Fu, Synthesis,
2012, 2805; (e) B. Godoi, R. F. Schumacher and G. Zeni,
Chem. Rev., 2011, 111, 2937; (f) A. S. K. Hashmi, Pure Appl.
Chem., 2010, 82, 657; (g) S. Minakata, Acc. Chem. Res., 2009,
42, 1172.
12 X.-X. Guo, J. Org. Chem., 2013, 78, 1660.
13 W. Zhang, J. K. Sprafke, M. Ma, E. Y. Tsui, S. A. Sydlik,
G. C. Rutledge and T. M. Swager, J. Am. Chem. Soc., 2009,
131, 8446.
2 C. Praveen, A. Ayyanar and P. T. Perumal, Bioorg. Med.
Chem. Lett., 2011, 21, 4170.
6120 | Org. Biomol. Chem., 2014, 12, 6114–6120
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