Efficient synthesis of functionalized dihydro-1 H -indol-4(5 H)-ones via one-pot three-component reaction under catalyst-free conditions

Article abstract of DOI:10.1021/co4000198

A facile and efficient one-pot procedure for the preparation of functionalized dihydro-1H-indol-4(5H)-ones by a catalyst-free, three-component reaction of 1,3-dicarbonyl compounds, arylglyoxal monohydrate and enaminones under mild conditions in excellent yield is reported. This synthesis was confirmed to follow the group-assisted-purification (GAP) chemistry process, which can avoid traditional purifications, chromatography, and recrystallization.

Full text of DOI:10.1021/co4000198

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Article
An Efficient Synthesis of Functionalized Dihydro-1H-indol-4(5H)-ones
via One-Pot Three-Component Reaction under Catalyst-Free Conditions
Hui-Yan Wang, and Da-Qing Shi
ACS Comb. Sci., Just Accepted Manuscript • DOI: 10.1021/co4000198 • Publication Date (Web): 18 Apr 2013
Downloaded from http://pubs.acs.org on April 29, 2013
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An Efficient Synthesis of Functionalized Dihydro-1H-indol-4(5H)-ones via
One-Pot Three-Component Reaction under Catalyst-Free Conditions
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Hui-Yan Wang, Daqing Shi
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O
OH
OH
R2
N
Ar
O
OH Ar
OH
enthol
reflux
+
R1
R1
R1
R1
NH
R2
O
O
O
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An Efficient Synthesis of Functionalized Dihydro-1H-indol-4(5H)-ones via
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One-Pot Three-Component Reaction under Catalyst-Free Conditions
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HuiꢀYan Wang1,2, DaꢀQing Shi1,*
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1Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry,
Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, P.
R. China
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2Department of Chemical Engineering, Huaihai Institute of Technology, Lianyungang
222005, P. R. China
ABSTRACT: A facile and efficient oneꢀpot procedure for the preparation of
functionalized dihydroꢀ1Hꢀindolꢀ4(5H)ꢀones by a catalystꢀfree, threeꢀcomponent
reaction of 1,3ꢀdicarbonyl compounds, arylglyoxal monohydrate and enaminones
under mild conditions in excellent yield is reported. This synthesis was confirmed to
follow the groupꢀassistedꢀpurification (GAP) chemistry process, which can avoid
traditional purifications, chromatography and recrystllization.
KEYWORDS: functionalized dihydroꢀ1Hꢀindolꢀ4(5H)ꢀones, multiꢀcomponent
reactions, groupꢀassistedꢀpurification (GAP) chemistry process.
Introduction
Multiꢀcomponent reactions (MCRs) are chemical transformations in which three
or more different starting materials combine together via a oneꢀpot procedure to give
a final complex product. Such reactions have emerged as powerful and bondꢀforming
efficient tools in organic, combinatorial and medicinal chemistry for their facileness
and efficiency as well as their economy and ecology in organic synthesis.1 In the past
decade, there have been tremendous developments in threeꢀ and fourꢀcomponent
reaction and significant efforts continue to be made to develop new MCRs.2
The indole nucleus is probably the most wellꢀknown heterocyclic compound, a
common and important feature of a variety of natural products and medicinal agents.3
Compounds carrying the indole moiety exhibit antibacterial and antifungal activities.4
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It is used as an important skeleton in organic synthesis5 and is also utilized in other
important fields, such as medicinal chemistry.6 As a consequence, a number of
methods have been reported for the construction of indoles.7 Recently, some
functionalized indoles have been synthesized by using different starting materials.8
4ꢀHydroxycoumarins are a very important class of biologically active substances
in nature and in medicine. They exhibit mainly anticoagulant activity and there are
some drugs which are widely used as anticoagulants.9 They exhibit cytotoxic10 and
antioxidant activities11 as well as activity against HIV.12 However, to the best of our
knowledge, there have been few reports about the synthesis of coumarinꢀfused indole
derivatives by multiꢀcomponent reactions. Our interest in the synthesis of indole
derivatives13 guided by the observation that the presences of two or more different
heterocyclic moieties in a single molecule often enhances remarkably the biological
activity, we herein described a facile synthesis of 3ꢀ(4ꢀhydroxycoumarinꢀ3ꢀyl)ꢀ
dihydroꢀ1Hꢀindolꢀ4(5H)ꢀones derivatives by a threeꢀcomponent reaction of
4ꢀhydroxycoumarin, arylglyoxal monohydrates and enaminones in ethanol without
any catalyst.
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Results and discussion
We initially evaluated the threeꢀcomponent reaction of the 4ꢀhydroxycoumarin
1{1}, phenylglyoxal monohydrate 2{1}, and enaminone 3{1}(Scheme 1). The
reaction mixture, which was composed of a 1:1:1 mixture of 1{1}, 2{1} and 3{3},
was tested under a variety of different conditions. The effects of solvent and
temperature were evaluated for this reaction, and the results are summarized in Table
1. It was found that when the reaction was carried out in water without any catalyst
the yield of product was very low (Table 1, Entry 1). Chloroform and ethanol
provided higher yields than those using other organic solvents (Table 1, Entry 5ꢀ6 vs
Entries 2ꢀ4). Considering the volatility and toxicity of the chloroform, ethanol was
chosen as the solvent for all further reactions. To identify the optimum reaction
temperature, the reaction was carried out at r.t., 40ºC, 60ºC and reflux temperature,
providing the product 4{1,1,1} in yields of 34%, 52%, 80% and 94% (Table 1, Entries
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7ꢀ9 and 6), respectively. The use of additives, such as Lꢀproline, resulted in no
significant improvement of the yield (Table 1, Entry 10). Thus, the optimum
conditions tested were refluxing ethanol without any catalyst.
Scheme 1 . Model Reaction
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O
OH
O
O
OH
+
N
OH
O
+
OH
N
O
H
O O
1{1}
2{1}
3{1}
4{1,1,1}
Table 1. Optimizing the Reaction Conditions for the Synthesis of 4{1,1,1}
Yield a (%)
Entry
Solvent
Temperature (°C)
Time (h)
1
2
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H2O
DMF
80
80
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
34
69
78
80
92
94
34
52
80
Acetone
CH3CN
CHCl3
reflux
reflux
reflux
reflux
r. t.
EtOH
EtOH
EtOH
40
EtOH
60
EtOH+Lꢀproline
(10 mol %)
10
reflux
1.0
90
a
Yield was determined by HPLCꢀMS, if the precipitated solids were occurred during the
reaction, acetonitrile should be added to dissolve the solids before determining the yield.
The optimized reaction conditions were then tested for library construction with
eight 1,3ꢀdicarbonyl compounds 1{1ꢀ8}, five phenylglyoxal monohydrates 2{1ꢀ5},
and sixteen enaminones 3{1ꢀ16} (Figure 1). The corresponding functionalized indole
derivatives 4 were obtained in good yields in catalyst free, refluxing ethanol. The
results are summarized in Table 2. This protocol was efficient with 1,3ꢀdicarbonyl
compounds with either 1,3ꢀdiketones or βꢀketo esters. It was also found that nꢀbutyl
and phenyl groups, bearing either electronꢀwithdrawing or electronꢀdonating groups
on the enaminone ring, were tolerated under the reaction conditions, leading to the
final products in satisfactory yields (up to 94%). Moreover, this synthesis followed
the GAP chemistry (groupꢀassistedꢀpurification chemistry)14 process, which can avoid
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traditional chromatography and recrystallization purifications. Pure products can be
obtained by washing the solid, crude products with cold ethanol.
The structures of all products 4 were characterized by IR, 1H NMR, 13C NMR, and
HRMS analysis. The structure of compound 4{1,1,1} was further confirmed by Xꢀray
diffraction analysis. The molecular structure of compound 4{1,1,1} is shown in
Figure 2.
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Figure 1 . Diversity of reagents.
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Table 2 . Synthesis of functionalized dihydro-1H-indol-4(5H)-one derivatives 4
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Entry
1
Products
4{1,1,1}
4{1,1,2}
4{1,1,3}
4{1,1,4}
4{1,1,5}
4{1,1,6}
4{1,1,7}
4{1,1,8}
4{1,1,9}
4{1,1,10}
4{1,1,12}
4{1,1,13}
4{1,1,14}
4{1,1,15}
4{1,1,16}
4{1,2,3}
4{1,2,11}
4{1,3,1}
4{1,3,3}
4{1,4,1}
4{1,4,3}
4{1,5,3}
4{1,5,11}
Time (h)
1.0
1.0
2.0
1.5
4.0
0.7
1.0
1.0
1.0
1.5
1.0
1.0
1.5
1.0
5.0
1.5
1.0
1.5
1.5
1.5
1.5
1.5
1.0
Isolated Yield (%)
M.P. (ºC)
162ꢀ163
308ꢀ310
170ꢀ172
176ꢀ178
185ꢀ186
270ꢀ271
152ꢀ154
294ꢀ295
268ꢀ269
278ꢀ280
114ꢀ116
282ꢀ284
172ꢀ174
278ꢀ279
167ꢀ170
250ꢀ251
172ꢀ174
264ꢀ265
172ꢀ173
> 300
89
91
88
90
77
90
94
87
88
82
81
87
90
94
72
83
90
85
92
89
94
92
93
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4
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7
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23
> 300
> 300
> 300
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4{2,1,1}
4{2,1,3}
4{2,1,6}
4{2,1,12}
4{3,1,1}
4{3,1,6}
4{4,1,1}
4{5,1,1}
4{5,1,3}
4{6,1,1}
4{6,1,3}
4{7,1,1}
4{8,1,1}
4{8,1,3}
1.0
3.0
0.7
1.0
1.0
0.7
1.0
1.0
1.5
1.0
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1.0
1.5
1.0
81
268ꢀ270
282ꢀ283
142ꢀ144
279ꢀ281
196ꢀ198
183ꢀ184
174ꢀ175
137ꢀ138
154ꢀ156
293ꢀ295
290ꢀ292
142ꢀ144
239ꢀ240
224ꢀ226
88
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Figure 2 . Crystal structure of compound 4{1,1,1}
Although the detailed mechanism of this reaction remains to be fully clarified, the
formation of compound 4 could be explained by the reaction sequence in Scheme 2.
First,
a
Knoevenagel condensation of 1,3ꢀdicarbonyl compounds
1
with
phenylglyoxal 2 is proposed to give intermediate A. Michael addition of enaminone 3
to intermediate A then occurs to provide intermediate B, which undergoes
intramolecular cyclization and dehydration to form the desired product 4.
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Scheme 2 . Proposed Mechanism for the synthesis of 4
R2
HN
5
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R1
R1
H
O
O
O
O
O
9
Ar
-H2O
3
OH
OH
O
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+
Ar
O
O
O
1
2
A
R2
O
Ar
O
R2
OH
HN
O
Ar
OH
N
R1
R1
R1
N
H
O
O
O
O
O
R1
B
R2
Ar
R2
Ar
OH
HO
N
OH
R1
R1
-H2O
R1
R1
O
O O
O
O
O
4
Conclusion
The new GAP synthesis of functionalized dihydroꢀ1Hꢀindolꢀ4(5H)ꢀone
derivatives has been achieved by threeꢀcomponent reaction of 1,3ꢀdicarbonyl
compounds, arylglyoxal monohydrates and enaminones under mild conditions
without any catalyst. Good chemical yields have been achieved without the use of the
traditional purifications, chromatography and recrystallization.
Experimental Section
Melting points are uncorrected. IR spectra were recorded on Varian Fꢀ1000
spectrometer in KBr with absorptions in cmꢀ1. H NMR and 13C NMR were
1
determined on Varian Invoaꢀ400 MHz or Invoaꢀ300 MHz spectrometer in DMSOꢀd6
solution. J values are in Hz. Chemical shifts are expressed in ppm downfield from
internal standard TMS. HRMS analyses were carried out using Bruker micrOTOFꢀQ
instrument or TOFꢀMS instrument.
General Procedure for the Synthesis of 4. A dry 25 mL flask was charged with
1,3ꢀdicarbonyl compounds 1 (1 mmol), phenylglyoxal monohydrate 2 (1 mmol),
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enaminones 3 (1 mmol) and ethanol (5 mL). The mixture was stirred at refluxing
temperature for 0.7ꢀ5 h. After completion of the reaction (confirmed by TLC), the
reaction mixture was cooled to room temperature. The crystalline solids were
collected and washed with little cold ethanol to give the pure products 4.
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Compound 4{1,1,1}: White powder; IR (KBr, ν, cmꢀ1): 3430, 3280, 3058, 2956,
2869, 1729, 1694, 1665, 1624, 1515, 1492, 1451, 1408, 1366, 1270, 1194, 1103, 1044,
1020, 961, 897, 837, 757, 699; 1H NMR (DMSOꢀd6, 400 MHz) δ (ppm): 10.81 (s, 1H,
OH), 7.77 (d, J = 8.0 Hz, 1H, ArH), 7.54 (t, J = 7.6 Hz, 1H, ArH), 7.31ꢀ7.24 (m, 2H,
ArH), 7.19 (d, J = 7.6 Hz, 2H, ArH), 7.09ꢀ6.99 (m, 7H, ArH), 2.56 (d, J = 16.4 Hz,
1H, CH2), 2.47ꢀ2.45 (m, 1H, CH2), 2.30ꢀ2.26 (m, 4H, CH2+CH3), 2.16 (d, J = 15.6 Hz,
1H, CH2), 1.04 (s, 3H, CH3), 1.01 (s, 3H, CH3); 13C NMR (DMSOꢀd6, 75 MHz) δ
(ppm): 192.80, 162.17, 161.17, 152.78, 144.37, 138.06, 135.37, 134.90, 132.36,
131.41, 130.19, 130.02, 129.77, 128.26, 127.96, 127.65, 124.25, 123.86, 118.27,
116.45, 109.36, 100.34, 52.62, 36.85, 35.38, 28.91, 28.38, 21.07; HRMS calcd for
C32H27NNaO4 [M+Na]+: 512.1838, found: 512.1842.
Compound 4{2,1,1}: Light red powder; IR (KBr, ν, cmꢀ1): 3427, 3063, 3035, 2938,
2867, 2735, 2691, 1662, 1637, 1576, 1515, 1492, 1447, 1404, 1367, 1279, 1233, 1209,
1
1107, 1125, 1081, 1050, 1000, 934, 923, 828, 804, 766, 726, 699, 650; H NMR
(DMSOꢀd6, 400 MHz) δ (ppm): 10.64 (s, 1H, OH), 7.17ꢀ6.97 (m, 9H, ArH), 5.91 (s,
1H, =CH), 2.50ꢀ2.45 (m, 2H, CH2), 2.25ꢀ2.18 (m, 5H, CH2+CH3), 2.10 (s, 3H, CH3),
1.00 (s, 6H, 2×CH3); 13C NMR (DMSOꢀd6, 75 MHz) δ (ppm): 192.46, 166.34, 164.14,
160.89, 143.64, 137.88, 134.96, 134.27, 131.88, 130.18, 129.67, 128.19, 127.91,
127.33, 118.14, 110.74, 100.51, 97.07, 52.75, 36.89, 35.19, 28.67, 28.59, 21.05, 19.75;
HRMS calcd forC29H27NO4 [M]+: 453.1940, found: 453.1929.
Compound 4{3,1,6}: White powder ; IR (KBr, ν, cmꢀ1): 3588, 3425, 3056, 3030,
2957, 2892, 2644, 1670, 1585, 1562, 1513, 1486, 1451, 1367, 1299, 1257, 1211, 1166,
1148, 1046, 1028, 1013, 921, 845, 807, 775, 718, 702; 1H NMR (DMSOꢀd6, 400 MHz)
δ (ppm): 9.63 (s, 1H, OH), 7.08ꢀ7.03 (m, 5H, ArH), 6.92ꢀ6.89 (m, 4H, ArH), 3.71 (s,
3H, OCH3), 2.46ꢀ1.96 (m, 8H, 4×CH2), 1.09ꢀ0.87 (m, 12H, 4×CH3); 13C NMR
(DMSOꢀd6, 75 MHz) δ (ppm): 196.51, 192.26, 170.40, 158.83, 143.57, 133.94,
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132.17, 130.50, 129.71, 129.32, 127.92, 126.99, 118.32, 114.69, 112.19, 109.66,
56.49, 55.72, 52.88, 36.93, 35.17, 32.06, 28.77, 28.29, 19.02; HRMS calcd
forC31H33NO4 [M]+: 483.2410, found: 483.2398.
Compound 4{4,1,1}: White powder ; IR (KBr, ν, cmꢀ1): 3431, 3059, 3033, 2952,
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2875, 2620, 1664, 1578, 1515, 1491, 1448, 1422, 1381, 1334, 1280, 1209, 1183, 1160,
1
1117, 1071, 1049, 985, 923, 833, 811, 769, 730, 697, 649; H NMR (DMSOꢀd6, 400
MHz) δ (ppm): 9.76 (s, 1H, OH), 7.15ꢀ6.90 (m, 9H, ArH), 2.47ꢀ1.70 (m, 13H,
CH3+5×CH2), 0.98 (s, 6H, 2×CH3); 13C NMR (DMSOꢀd6, 75 MHz) δ (ppm): 192.36,
143.35, 137.63, 135.27, 133.55, 132.12, 130.10, 129.61, 129.53, 128.07, 127.95,
127.89, 126.92, 118.40, 112.67, 110.82, 52.88, 36.98, 36.95, 35.16, 28.67, 21.04,
20.91, 19.01; HRMS calcd forC29H28NO3 [MꢀH]+: 438.2069, found: 438.2073.
Compound 4{5,1,3}: White powder; IR (KBr, ν, cmꢀ1): 3432, 3089, 3028, 2955, 2892,
1049, 1620, 1578, 1448, 1417, 1383, 1363, 1244, 1116, 1091, 1069, 1050, 1014, 923,
888, 843, 760, 724, 649; 1H NMR (DMSOꢀd6, 400 MHz) δ (ppm): 10.04 (s, 1H, OH),
7.04ꢀ6.93 (m, 14H, ArH), 3.35ꢀ3.10 (m, 1H, CH), 2.61ꢀ2.19 (m, 8H, 4×CH2), 0.99 (s,
6H, 2×CH3); 13C NMR (DMSOꢀd6, 75 MHz) δ (ppm): 192.57, 192.44, 144.09, 143.95,
143.47, 143.42, 136.71, 133.81, 133.56, 132.83, 131.86, 131.74, 130.00, 129.70,
129.65, 129.02, 128.96, 128.22, 128.19, 127.33, 127.15, 118.59, 112.84, 112.79,
110.51, 110.42, 52.90, 52.84, 38.87, 38.53, 36.86, 35.22; 31.14, 28.67; HRMS calcd
forC34H30ClNO3 [M]+: 535.1914, found: 535.1907.
Compound 4{6,1,1}: White powder; IR (KBr, ν, cmꢀ1): 3427, 3031, 2955, 2932, 2869,
2590, 1665, 1576, 1515, 1487, 1410, 1313, 1208, 1116, 1045, 1018, 924, 840, 802,
771, 721, 699, 665, 649; 1H NMR (DMSOꢀd6, 400 MHz) δ (ppm): 11.36 (s, 1H, OH),
7.15ꢀ6.95 (m, 9H, ArH), 2.47ꢀ1.93 (m, 11H, CH3+4×CH2), 0.97 (s, 6H, 2×CH3); 13C
NMR (DMSOꢀd6, 75 MHz) δ (ppm): 192.42, 143.61, 137.88, 135.07, 134.15, 133.95,
132.03, 131.87, 130.21, 129.73, 128.08, 127.92, 127.18, 118.32, 112.52, 110.16,
52.88, 36.95, 36.87, 35.12, 28.66, 28.58, 21.06; HRMS calcd forC28H26NO3 [MꢀH]+:
424.1913, found: 424.1940.
Compound 4{7,1,1}: Grey powder; IR (KBr, ν, cmꢀ1): 3427, 3001, 2958, 2869, 1755,
1663, 1578, 1515, 1490, 1423, 1281, 1117, 1045, 1014, 924, 831, 768, 728, 698, 649;
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1H NMR (DMSOꢀd6, 400 MHz) δ (ppm): 11.82 (s, 1H, OH), 7.14ꢀ7.03 (m, 9H, ArH),
4.57ꢀ4.00 (m, 2H, CH2), 2.49ꢀ2.23 (m, 7H, CH3+2×CH2), 0.98 (s, 6H, 2×CH3); 13C
NMR (DMSOꢀd6, 75 MHz) δ (ppm): 192.58, 174.58, 173.84, 143.84, 138.07, 134.88,
134.81, 131.43, 130.25, 129.89, 128.25, 127.92, 127.52, 118.34, 107.80, 95.79, 67.08,
52.73, 36.86, 35.17, 28.63, 28.41, 21.05; HRMS calcd forC27H24NO4 [MꢀH]+:
426.1705, found: 426.1714.
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Compound 4{8,1,1}: Yellow powder; IR (KBr, ν, cmꢀ1): 3433, 3001, 2955, 2869,
1751, 1651, 1516, 1490, 1465, 1445, 1417, 1367, 1321, 1246, 1206, 1154, 1114, 1040,
1
1014, 924, 886, 843, 778, 764, 746, 701, 649; H NMR (DMSOꢀd6, 400 MHz) δ
(ppm): 7.88 (s, 4H, ArH), 7.20ꢀ7.15 (m, 7H, ArH), 7.07 (d, J = 7.6 Hz, 2H, ArH), 4.45
(s, 1H, CH), 2.47 (s, 2H, CH2), 2.25 (s, 3H, CH3), 2.05 (s, 2H, CH2), 0.90 (s, 6H,
2×CH3); 13C NMR (DMSOꢀd6, 75 MHz) δ (ppm): 198.95, 193.07, 144.01, 142.27,
138.21, 137.54, 135.54, 134.56, 130.50, 130.27, 129.98, 128.83, 128.26, 127.87,
122.98, 116.47, 110.78, 53.86, 51.35, 36.46, 35.53, 28.47, 21.04; HRMS calcd
forC32H26NO3 [MꢀH]+: 472.1913, found: 472.1923.
Acknowledgement. This work was partially supported by the Major Basic Research
Project of the Natural Science Foundation of the Jiangsu Higher Education
Institutions (No. 10KJA150049), A Project Funded by the Priority Academic Project
Development of Jiangsu Higher Education Institutions and the Foundation of Key
Laboratory of Organic Synthesis of Jiangsu Province (No. JSK0812) and the Jiangsu
College Graduate Research and Innovation Project of the Jiangsu Province
Department of Education (CXZZ11_0090).
Supporting Information Available. Experimental details and spectroscopic
characterization for compounds 4, and the Xꢀray crystallographic information for
compound 4{1,1,1}. This information is available free of charge via the Internet at
http://pubs.acs.org/.
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