A novel base-promoted synthesis of β-indolylketones via a three-component condensation under ultrasonic irradiation

Article abstract of DOI:10.1016/j.tet.2005.08.042

A convenient, efficient, and practical method for the synthesis of β-indolylketones via a condensation of indole, aromatic aldehydes, and deoxybenzoin under ultrasonic irradiation was described. It provided a novel base-promoted approach for the one-pot synthesis of β-indolylketones.

Full text of DOI:10.1016/j.tet.2005.08.042

Tetrahedron 61 (2005) 10552–10558
A novel base-promoted synthesis of b-indolylketones via a
three-component condensation under ultrasonic irradiation
*
Zhi-Liang Shen, Shun-Jun Ji, Shun-Yi Wang and Xiao-Fei Zeng
Key Lab. of Organic Synthesis of Jiangsu Province, College of Chemistry and Chemical Engineering of Suzhou University,
Suzhou, 215006 China
Received 1 April 2005; revised 8 August 2005; accepted 10 August 2005
Available online 15 September 2005
Abstract—A convenient, efficient, and practical method for the synthesis of b-indolylketones via a condensation of indole, aromatic
aldehydes, and deoxybenzoin under ultrasonic irradiation was described. It provided a novel base-promoted approach for the one-pot
synthesis of b-indolylketones.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
for the preparation of b-indolylketones. One thing should be
noted that, since the acidity of Meldrum’s acid is similar to
acetic acid, the above reaction is also an acid-promoted,
one-pot procedure for the synthesis of b-indolylketones, just
the same as the catalytic system of the Michael reaction of
indole with a,b-unsaturated ketones (the paper also
indicated that proline could accelerate the progress of the
reaction). More recently, Yamamoto etc.7 reported acetic
acid-promoted one-pot procedure for the preparation of
b-indolylketones, SF2809-V, as a new class of chymase
inhibitor.
In recent years, a wide variety of organic compounds
bearing indole motif have attracted much attention of
organic chemists due to the fact that many of them are
pharmacologically and biologically active compounds.1 The
b-indolylketones are one of the most significant inter-
mediates for the synthesis of many natural products and
biologically active compounds.2 Therefore, much effort has
been directed towards the synthesis of this class of
compounds. One of the most useful methods for the
synthesis of b-indolylketones is achieved via the protic or
Lewis acid-catalyzed Michael addition of indoles with
a,b-unsaturated ketones at the 3-position.2,3 In our previous
reports, we have described the synthesis of b-indolylketones
by means of the conjugate addition of indole with
a,b-unsaturated ketones catalyzed by Lewis (or protic)
acid CAN,3k I2,3l and PTSA.3m
In continuation of our work aiming at the synthesis of
b-indolylketone, herein, we would like to report a novel
base-induced method for the synthesis of b-indolylketones
via a three-component condensation procedure. Deoxy-
benzoin as the carbonyl compound was introduced into the
reaction (Scheme 1). In addition, all the reactions were
carried out under ultrasonic irradiation since the utilization
of this technique could accelerate the progress of various
organic transformations with mild reaction conditions, short
reaction time and high yields.8,9
Recently, the utilization of multi-component condensations
(MCCs) to generate novel, drug-like scaffolds are replete in
current organic reactions due to the fact that products can be
prepared directly in a single step and the diversity can be
achieved simply by varying the reaction substrates.4 To our
knowledge, one typical MCCs example for the synthesis of
b-indolylketones was reported by Yonemitsu etc.5 via
trimolecular condensation of indole with various aldehydes
and Meldrum’s acid.6 This one-pot synthetic method
provided a very simple, convenient, and efficient approach
Keywords: Indole; b-Indolylketone; One-pot synthesis; Ultrasound.
*
Corresponding author. Tel.: C86 512 65880086; fax: C86 512
65880089; e-mail: shunjun@suda.edu.cn
Scheme 1. One-pot synthesis of b-indolylketones.
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.08.042

Z.-L. Shen et al. / Tetrahedron 61 (2005) 10552–10558
10553
1
2. Results and discussion
structure was confirmed to be 4a by H NMR, IR, HRMS,
and elemental analysis. However, the above MCCs reaction
proceeded sluggishly under similar conditions in the
presence of Lewis (or protic) acids such as InCl3, CAN,
I2, and PTSA, no desired product 4a was formed according
to TLC analysis of the final reaction mixture. It was
interesting to find that such kind of one-pot reaction can
proceed well under basic conditions.
In our initial research, we were surprised to find that when
irradiating the mixture of p-chlorobenzaldehyde 1a
(1 mmol), deoxybenzoin 2 (1 mmol), and indole 3
(1 mmol) in ethanol (5 mL) employing sodium hydroxide
(2 mmol) instead of protic or Lewis acid as the promoter,
after ultrasonic irradiation for 2 h at 70 8C, a large quantity
of white solid was precipitated from the reaction system.
After routine work-up, a pure product was obtained and its
To test the generality of this reaction, a series of new
Table 1. Base-promoted, one-pot synthesis of b-indolylketonesa
Entry
Aldehyde
Time (h)
Product
Yield (%)b
1
1a
2
4a
70
2
3
4
1b
1c
1d
2
2
3
4b
4c
4d
73
71
77
5
1e
2
4e
69
6
1f
3
4f
88
7
8
1g
1h
2
2
4g
4h
78
73
a The reactions were operated at 70 8C promoted by sodium hydroxide under ultrasound irradiation.
b Isolated yield.

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Z.-L. Shen et al. / Tetrahedron 61 (2005) 10552–10558
b-indolylketones were prepared by varying aromatic
aldehyde using above reaction system, all the results were
summarized in Table 1. The corresponding products 4a–h
were obtained in modest to good yields, respectively, after
reacting for 2–3 h.
Compared with general methods for the synthesis of
b-indolylketones, which utilizing Michael addition of
indoles with a,b-unsaturated ketones in the presence
of Lewis (or protic) acid, especially expensive reagents
such as InCl3, Bi(OTf)3, current base-mediated one-pot
synthetic method provided an original, simple, convenient,
efficient and cheap route to synthesize b-indolylketones and
avoided the complexity of two-step synthetic routes, which
needed to prepare a,b-unsaturated ketones first.
Scheme 2. Two-step experiments for mechanism study.
eventually. According to previous literature report,10 the
possible formation of intermediate 3-indolyl-arylmethanol
via condensation of aldehyde and indole under basic
conditions might be the key step. In fact, we really observed
the partial formation of intermediate 3-indolyl-(4-chloro-
phenyl)methanol in the first step. However, we failed to
isolate it by chromatography since it was decomposed
slowly in organic solvents.
In order to study the influence of different alkalies on the
reaction, other alkalies were also investigated. The results
were listed in Table 2. It was found that when the reaction
was carried out without any additives or in the presence of
weak alkali sodium carbonate, no desired product was
obtained (Table 2, entries 1–2). However, when the reaction
was subjected to the inducement of lithium hydroxide,
sodium hydroxide, potassium hydroxide, and sodium
ethoxide, the desired product was obtained in 68, 74, 85,
and 75% yields, respectively, (entries 3–6). Therefore, these
four bases could promote the reaction effectively, and
sodium hydroxide was commonly used as it was the
cheapest.
To further demonstrate the possibility of above hypothesis,
3-indoly-phenylmethanol was prepared via Grignard
reaction of indole-3-carboxaldehyde with phenylmag-
nesium bromide. As expected, the reaction of 3-indoly-
phenylmethanol with deoxybenzoin was proceeded
efficiently at 70 8C in the presence of sodium hydroxide
(2.0 equiv) under ultrasound irradiation, and afforded the
desired product 4b in 83% yield within 0.5 h (Scheme 3).
Gong11 and Medebielle12 also have reported similar
reactions under basic conditions before.
Table 2. The effect of different alkalies on the reaction
Scheme 3. The reaction of 3-indolyphenylmethanol with deoxybenzoin
under basic conditions.
Entry
Alkali
Time (h)
Yield (%)a
1
2
3
4
5
6
—
2
2
2
2
2
2
0
0
68
74
85
75
According to previous reports,2,3 the reaction might proceed
via the conjugate addition of indole with enone (derived
from the condensation of compound 1 and 2). In our
research it was observed that the reaction of enone (3-(4-
chlorophenyl)-1,2-diphenyl-propenone) with indole did
occur at 70 8C in the presence of sodium hydroxide
(2 equiv) under ultrasonic irradiation, however, the reaction
proceeded slowly to give the product only in 32% yield even
reacted for 6 h (Scheme 4). In contrast with the results
obtained above (entry 1 of Table 1 and Scheme 3), the three-
component condensation reaction was more inclined to
Na2CO3
LiOH
NaOH
KOH
EtONa
a The yield is tested by HPLC.
Further investigation was revealed that ultrasonic irradiation
also played an important role for promoting the progress of
the reaction. Without ultrasonic irradiation, the same
reaction as outlined in Table 2, entry 4 by conventional
heating method only gave the corresponding product 4a in
51% yield, lower than the yield (74%) obtained under
ultrasonic conditions.
Following effort was focused on the investigation of the
reaction mechanism. As shown in Scheme 2, if the
equimolar amount of p-chlorobenzaldehyde 1a and indole
3 were reacted together for 0.5 h beforehand in the presence
of sodium hydroxide under ultrasonic irradiation, then
another equimolar amount of deoxybenzoin 2 was added
and reacted continuously for 1.5 h under the same
conditions, product 4a was afforded in 75% yield
Scheme 4. The reaction of 3-(4-cholorophenyl)-1,2-diphenyl-propenone
with indole. Conditions: NaOH (2.0 equiv), 6 h: 32% yield; CAN or InCl3
(0.1 equiv), 2 h: 0% yield.

Z.-L. Shen et al. / Tetrahedron 61 (2005) 10552–10558
10555
Scheme 5. The probable mechanism for the one-pot reaction of aldehyde, deoxybenzoin, and indole.
Table 3. Base-promoted, one-pot synthesis of new b-indolylketonesa
Entry
1
Aldehyde
Indole
Time (h)
1
Product
Yield (%)b
82
4i
2
3
4
5
6
1
1
1
1
2
4j
81
63
69
71
81
4k
4l
4m
4n
7
2
2
1
2
2
2
4o
4p
4q
4r
4s
4t
65
67
69
67
59
51
8
9
10
11
12
a The reactions were operated at 70 8C promoted by sodium hydroxide under ultrasound irradiation.
b Isolated yield.

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proceed through the formation of intermediate 3-indoly-
arylmethanol instead of enone. Furthermore, it was
unexpectedly found that the above conjugate addition did
not take place in the presence of Lewis acids such as InCl3
and CAN (Scheme 4). It was the first time to know that
conjugate addition of indole and enone could take place
under basic conditions, even though the yield was relatively
low.
4.2. Typical experimental procedure
A mixture of aromatic aldehyde 1 (1 mmol), deoxybenzoin
2 (1 mmol), indole 3 (1 mmol), sodium hydroxide (2 mmol)
and absolute ethanol (5 mL) were irradiated at 70 8C in the
presence of ultrasonic wave for a certain time as shown in
Tables 1 and 3. The progress of the reaction was monitored
by TLC until the disappearance of aromatic aldehyde. After
the completion of the reaction, 10 mL aqueous ethanol
(50%) was added to the reaction system. A few minutes
later, the desired products 4 could be collected by filtration
under reduced pressure. Further purification can be
conducted by recrystallization with 95% ethanol.
Based on the results obtained above, a plausible mechanism
was proposed here (Scheme 5). The reaction might occur via
an initial condensation of aldehyde 1 and indole 3 to afford
3-indolyl-arylmethanol 5. The formed intermediate 5 was
tended to dehydrate to generate intermediate 6, which
further underwent in situ Michael addition with deoxy-
benzoin anion to give intermediate 7. Finally, the anion 7
was protonated by water to form the desired product 4.
4.2.1. 3-(3-Indolyl)-3-(4-chlorophenyl)-1,2-diphenyl-
propan-1-one 4a. White solid; mp 238–240 8C; IR (KBr):
1
n 3407 (NH), 1669 (C]O) cmK1; H NMR (400 MHz,
CDCl3): d 5.29 (d, JZ12 Hz, 1H), 5.56 (d, JZ11.2 Hz, 1H),
6.85 (s, 1H), 6.95–7.51 (m, 16H), 7.83 (s, 1H), 7.90 (d, JZ
To further demonstrate the efficiency and scope of the
reaction, we also applied the three-component reaction to
other methyl substituted indole compounds, all the results
were summarized in Table 3. It was shown that the reaction
involving different methyl substituted indoles could also
proceed smoothly under basic condition to give the desired
products in 51–82% yields. the position of the methyl group
on the indolyl ring also had influence on the reaction time
and final yields (Table 3, entries 2, 5, and 9, entries 3, 7,
and 11).
6.8 Hz, 2H) ppm; HRMS [found: m/z, 437.1377 (MC);
calcd for C29H ClNO: M, 437.1360]. Anal. Calcd for
37
22
C29H22ClNO: C, 79.90; H, 5.09; N, 3.21. Found: C, 79.50;
H, 5.21; N, 2.78.
4.2.2. 3-(3-Indolyl)-1,2,3-triphenylpropan-1-one 4b.
White solid; mp 249–251 8C; IR (KBr): n 3417,
1
1668 cmK1; H NMR (400 MHz, CDCl3): d 5.31 (d, JZ
11.2 Hz, 1H), 5.61 (d, JZ11.6 Hz, 1H), 6.85 (s, 1H), 6.93–
7.48 (m, 17H), 7.80 (s, 1H), 7.88 (d, JZ7.2 Hz, 2H) ppm;
13C NMR (75.4 MHz, CDCl3): d 46.2, 58.1, 110.8, 117.7,
119.2, 119.4, 121.8, 122.37, 126.1, 127.0, 127.1, 128.2,
128.3, 128.4, 128.5, 128.5, 128.9, 132.8, 136.1, 137.5,
137.9, 143.6, 199.6 ppm; HRMS [found: m/z, 401.1750
(MC); calcd for C29H23NO: M, 401.1780].
3. Conclusion
In conclusion, we have demonstrated the first base-
promoted, one-pot protocol for the synthesis of b-indolyl-
ketones via a three-component condensation of aldehydes,
deoxybenzoin, and indoles under ultrasonic irradiation. The
method provides a very efficient, convenient and feasible
method for the preparation of b-indolylketones under basic
conditions in comparision with current available method-
ologies. Attempt to extend the reaction system to other
active methylene compounds are currently in progress.
4.2.3. 3-(3-Indolyl)-3-(4-methylphenyl)-1,2-diphenyl-
propan-1-one 4c. White solid; mp 247–249 8C; IR (KBr):
n 3409, 1668 cmK1; 1H NMR (400 MHz, CDCl3): d 2.18 (s,
3H), 5.27 (d, JZ11.2 Hz, 1H), 5.60 (d, JZ11.6 Hz, 1H),
6.84 (s, 1H), 6.93–7.48 (m, 16H), 7.78 (s, 1H), 7.90 (d, JZ
7.6 Hz, 2H) ppm; HRMS [found: m/z, 415.1939 (MC);
calcd for C30H25NO: M, 415.1936].
4.2.4. 3-(3-Indolyl)-3-(4-methoxyphenyl)-1,2-diphenyl-
propan-1-one 4d. White solid; mp 227–229 8C; IR (KBr):
n 3417, 1670 cmK1; 1H NMR (400 MHz, CDCl3): d 3.67 (s,
3H), 5.27 (d, JZ10.4 Hz, 1H), 5.56 (d, JZ10 Hz, 1H), 6.69
(d, JZ8 Hz, 2H), 6.83 (s, 1H), 6.93–7.46 (m, 14H), 7.78 (s,
1H), 7.88 (d, JZ6 Hz, 2H) ppm; HRMS [found: m/z,
431.1866 (MC); calcd for C30H25NO2: M, 431.1885].
4. Experimental
4.1. General
Melting points were recorded on an Electrothermal digital
melting point apparatus and uncorrected. 1H NMR
(400 MHz) spectra were recorded on a Varian Mercury
400 MHz spectrometer in CDCl3. IR Spectra were obtained
on a Nicolet FT-IR 500 spectrophotometer using KBr
pellets. Elemental analysis was performed by a Carlo-Erba
EA1110 CNNO-S analyzer. High resolution mass spectra
were obtained using GCT-TOF instrument. Ultrasound
irradiation was performed in a KQ-250E ultrasonic cleaner
with a frequency of 40 KHz and a normal power of 250 W.
The reaction flask was located in the water bath of the
ultrasonic cleaner, and the temperature of the water
bath was controlled by inherently heating. 3-Indolyphenyl-
methanol13 and 3-(4-chlorophenyl)-1,2-diphenyl-pro-
penone14 were prepared according to literature methods.
4.2.5. 3-(3-Indolyl)-3-(3,4-methylenedioxyphenyl)-1,2-
diphenylpropan-1-one 4e. White solid; mp 241–243 8C;
IR (KBr): n 3415, 1669 cmK1; 1H NMR (400 MHz, CDCl3):
d 5.25 (d, JZ11.2 Hz, 1H), 5.54 (d, JZ11.6 Hz, 1H), 5.81
(s, 2H), 6.61 (d, JZ7.6 Hz, 1H), 6.85–7.48 (m, 15H), 7.81
(s, 1H), 7.91 (d, JZ7.6 Hz, 2H) ppm; HRMS [found: m/z,
445.1691 (MC); calcd for C30H23NO3 M, 445.1678].
4.2.6. 3-(3-Indolyl)-3-(2-pyridyl)-1,2-diphenylpropan-1-
one 4f. White solid; mp 245–247 8C; IR (KBr): n 3409,
1
1661 cmK1; H NMR (400 MHz, CDCl3): d 5.35 (d, JZ
11.6 Hz, 1H), 6.04 (s, 1H), 6.93–7.51 (m, 16H), 7.86 (s, 1H),

Z.-L. Shen et al. / Tetrahedron 61 (2005) 10552–10558
10557
8.03 (d, JZ7.2 Hz, 2H), 8.37 (s, 1H) ppm; HRMS [found:
m/z, 402.1740 (MC); calcd for C28H22N2O: M, 402.1732].
HRMS [found: m/z, 415.1928 (MC); calcd for C30H25NO:
M, 415.1936].
4.2.7. 3-(3-Indolyl)-3-(4-bromo-2-thienyl)-1,2-diphenyl-
propan-1-one 4g. White solid; mp 226–228 8C; IR (KBr):
n 3419, 1668 cmK1; 1H NMR (400 MHz, CDCl3): d 5.54 (s,
2H), 6.84–7.54 (m, 15H), 7.85 (s, 1H), 7.99 (d, JZ7.2 Hz,
2H) ppm; HRMS [found: m/z, 485.0414 (MC); calcd for
C27H20BrNOS: M, 485.0449].
4.2.14. 3-(3-(6-Methyl)-indolyl)-3-(4-methylphenyl)-1,2-
diphenylpropan-1-one 4n. White solid; mp 217–219 8C;
IR (KBr): n 3454, 1668 cmK1; 1H NMR (400 MHz, CDCl3):
d 2.18 (s, 3H), 2.37 (s, 3H), 5.24 (d, JZ11.6 Hz, 1H), 5.60
(d, JZ12 Hz, 1H), 6.75 (s, 1H), 6.79 (d, JZ8.8 Hz, 1H),
6.90–7.49 (m, 14H), 7.64 (s, 1H), 7.90 (d, JZ7.2 Hz, 2H)
ppm; HRMS [found: m/z, 429.2077 (MC); calcd for
C31H27NO: M, 429.2093].
4.2.8. 3-(3-Indolyl)-3-(2-thienyl)-1,2-diphenylpropan-1-
one 4h. White solid; mp 213–215 8C; IR (KBr): n 3412,
1
1671 cmK1; H NMR (400 MHz, CDCl3): d 5.59 (s, 2H),
4.2.15. 3-(3-(6-Methyl)-indolyl)-3-(3,4-methylenedioxy-
phenyl)-1,2-diphenylpropan-1-one 4o. White solid; mp
6.77 (s, 1H), 6.86 (s, 1H), 6.93 (s, 1H), 7.01–7.53 (m, 12H),
7.80 (s, 1H), 7.98 (d, JZ8.4 Hz, 2H) ppm; 13C NMR
(75.4 MHz, CDCl3): d 41.46, 59.32, 111.01, 117.17, 119.29,
119.54, 121.80, 122.58, 123.46, 124.65, 126.35, 126.67,
127.02, 128.42, 128.56, 128.76, 132.92, 136.13, 137.27,
137.36, 148.12, 199.27 ppm; HRMS [found: m/z, 407.1315
(MC); calcd for C27H21NOS: M, 407.1344]. Anal. Calcd for
C27H21NOS: C, 79.57; H, 5.19; N, 3.44. Found: C, 79.61; H,
5.09; N, 3.55.
243–245 8C; IR (KBr): n 3404, 1668 cmK1 1H NMR
;
(400 MHz, CDCl3): d 2.38 (s, 3H), 5.22 (d, JZ11.6 Hz,
1H), 5.54 (d, JZ11.6 Hz, 1H), 5.80 (s, 2H), 6.60 (d, JZ
7.6 Hz, 1H), 6.76 (s, 1H), 6.81–7.48 (m, 13H), 7.67 (s, 1H),
7.91 (d, JZ8.8 Hz, 2H) ppm; HRMS [found: m/z, 459.1831
(MC); calcd for C31H25NO3: M, 459.1834].
4.2.16. 3-(3-(6-Methyl)-indolyl)-3-(4-methoxyphenyl)-1,
2-diphenylpropan-1-one 4p. White solid; mp 226–
4.2.9. 3-(3-(5-Methyl)-indolyl)-3-(4-chlorophenyl)-1,2-
diphenylpropan-1-one 4i. White solid; mp 232–234 8C;
IR (KBr): n 3403, 1671 cmK1; 1H NMR (400 MHz, CDCl3):
d 2.36 (s, 3H), 5.27 (d, JZ12.4 Hz, 1H), 5.53 (d, JZ
12.8 Hz, 1H), 6.82 (s, 1H), 6.92 (d, JZ7.6 Hz, 1H), 6.97–
7.52 (m, 14H), 7.76 (s, 1H), 7.95 (d, JZ7.6 Hz, 2H) ppm;
HRMS [found: m/z, 449.1589 (MC); calcd for
C30H24ClNO: M, 449.1546].
229 8C; IR (KBr): n 3426, 1666 cmK1 1H NMR
;
(400 MHz, CDCl3): d 2.37 (s, 3H), 3.68 (s, 3H), 5.25 (d,
JZ11.6 Hz, 1H), 5.56 (d, JZ12 Hz, 1H), 6.68–7.49 (m,
16H), 7.65 (s, 1H), 7.89 (d, JZ7.2 Hz, 2H) ppm; HRMS
[found: m/z, 445.2037 (MC); calcd for C31H27NO2: M,
445.2042].
4.2.17. 3-(3-(7-Methyl)-indolyl)-1,2,3-triphenylpropan-
1-one 4q. White solid; mp 218–220 8C; IR (KBr): n 3376,
1
4.2.10. 3-(3-(5-Methyl)-indolyl)-1,2,3-triphenylpropan-
1-one 4j. White solid; mp 236–238 8C; IR (KBr): n 3434,
1668 cmK1; H NMR (400 MHz, CDCl3): d 2.37 (s, 3H),
5.33 (d, JZ11.2 Hz, 1H), 5.64 (d, JZ11.2 Hz, 1H), 6.87–
7.49 (m, 17H), 7.74 (s, 1H), 7.89 (d, JZ6.8 Hz, 2H) ppm;
HRMS [found: m/z, 415.1918 (MC); calcd for C30H25NO:
M, 415.1936].
1
1670 cmK1; H NMR (400 MHz, CDCl3): d 2.34 (s, 3H),
5.28 (d, JZ12.8 Hz, 1H), 5.56 (d, JZ12.8 Hz, 1H), 6.82 (s,
1H), 6.88 (d, JZ8 Hz, 1H), 7.05–7.48 (m, 15H), 7.72 (s,
1H), 7.87 (d, JZ8 Hz, 2H) ppm; HRMS [found: m/z,
415.1932 (MC); calcd for C30H25NO: M, 415.1936].
4.2.18. 3-(3-(7-Methyl)-indolyl)-3-(4-methylphenyl)-1,2-
diphenylpropan-1-one 4r. White solid; mp 225–227 8C; IR
(KBr): n 3435, 1676 cmK1; 1H NMR (400 MHz, CDCl3): d
2.18 (s, 3H), 2.37 (s, 3H), 5.27 (d, JZ11.6 Hz, 1H), 5.62 (d,
JZ11.6 Hz, 1H), 6.86–7.47 (m, 16H), 7.71 (s, 1H), 7.90 (d,
JZ7.2 Hz, 2H) ppm; HRMS [found: m/z, 429.2103 (MC);
calcd for C31H27NO: M, 429.2093].
4.2.11. 3-(3-(5-Methyl)-indolyl)-3-(3,4-methylenedioxy-
phenyl)-1,2-diphenylpropan-1-one 4k. White solid; mp
218–220 8C; IR (KBr): n 3403, 1676 cmK1 1H NMR
;
(400 MHz, CDCl3): d 2.36 (s, 3H), 5.09 (d, JZ10.4 Hz,
1H), 5.28 (d, JZ10.4 Hz, 1H), 5.76 (s, 1H), 5.83 (s, 1H),
6.47 (s, 2H), 6.57 (s, 1H), 6.93 (s, 2H), 7.14–7.53 (m, 10H),
7.75 (s, 1H), 7.99 (d, JZ7.6 Hz, 2H) ppm; HRMS [found:
m/z, 459.1814 (MC); calcd for C31H25NO3: M, 459.1834].
4.2.19. 3-(3-(7-Methyl)-indolyl)-3-(3,4-methylenedioxy-
phenyl)-1,2-diphenylpropan-1-one 4s. White solid; mp
231–233 8C; IR (KBr): n 3392, 1669 cmK1 1H NMR
;
4.2.12. 3-(3-(6-Methyl)-indolyl)-3-(4-chlorophenyl)-1,2-
diphenylpropan-1-one 4l. White solid; mp 213–215 8C;
IR (KBr): n 3458, 1668 cmK1; 1H NMR (400 MHz, CDCl3):
d 2.38 (s, 3H), 5.26 (d, JZ11.6 Hz, 1H), 5.56 (d, JZ
11.6 Hz, 1H), 6.81 (d, JZ7.6 Hz, 1H), 7.01–7.51 (m, 14H),
7.69 (s, 1H), 7.89 (d, JZ7.6 Hz, 2H) ppm; HRMS [found:
m/z, 449.1516 (MC); calcd for C30H24ClNO: M, 449.1546].
(400 MHz, CDCl3): d 2.38 (s, 3H), 5.26 (d, JZ12 Hz, 1H),
5.56 (d, JZ12 Hz, 1H), 5.80 (s, 2H), 6.60 (d, JZ8 Hz, 1H),
6.86–7.48 (m, 14H), 7.74 (s, 1H), 7.91 (d, JZ6.8 Hz, 2H)
ppm; HRMS [found: m/z, 459.1866 (MC); calcd for
C31H25NO3: M, 459.1834].
4.2.20. 3-(3-(7-Methyl)-indolyl)-3-(4-methoxyphenyl)-1,
2-diphenylpropan-1-one 4t. White solid; mp 216–218 8C;
IR (KBr): n 3438, 1683 cmK1; 1H NMR (400 MHz, CDCl3):
d 2.37 (s, 3H), 3.67 (s, 3H), 5.30 (d, 1H), 5.57 (d, 1H), 6.69
(d, JZ8.8 Hz, 2H), 6.86–7.38 (m, 14H), 7.72 (s, 1H), 7.88
(d, JZ7.6 Hz, 2H) ppm; HRMS [found: m/z, 445.2023
(MC); calcd for C31H27NO2: M, 445.2042].
4.2.13. 3-(3-(6-Methyl)-indolyl)-1,2,3-triphenylpropan-
1-one 4m. White solid; mp 206–208 8C; IR (KBr): n
1
3468, 1668 cmK1; H NMR (400 MHz, CDCl3): d 2.37 (s,
3H), 5.28 (d, JZ10 Hz, 1H), 5.61 (d, JZ10.4 Hz,1H), 6.77–
7.49 (m, 17H), 7.67 (s, 1H), 7.89 (d, JZ7.6 Hz, 2H) ppm;

10558
Z.-L. Shen et al. / Tetrahedron 61 (2005) 10552–10558
(l) Domling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 112,
3300–3344.
Acknowledgements
5. Oikawa, Y.; Hirasawa, O.; Yonemitsu, O. Tetrahedron Lett.
1978, 1759–1762.
We thank National Natural Science Foundation of China
(no. 20172039 and 20472062) and Natural Science
Foundation of Jiangsu Province (no. BK2004038) and the
Key Laboratory of Organic Synthesis of Jiangsu Province
(no. JSK008) for financial support.
6. For other one-pot reactions of aldehyde, indole, and
Meldrum’s acid, see: (a) Wang, C.; Zhang, Y. Q.; Li, G. S.;
Li, J. C.; Li, X. L. Chin. J. Org. Chem. 2003, 23, 1416.
(b) Nemes, C.; Jeannin, L.; Sapi, J.; Laronze, M.; Seghir, H.;
Auge, F.; Laronze, J. Y. Tetrahedron 2000, 56, 5479–5492.
(c) Cochard, F.; Laronze, M.; Sigaut, P.; Sapi, J.; Laronze,
J. Y. Tetrahedron Lett. 2004, 45, 1703–1707. (d) Sabitha, G.;
Kumar, M. R.; Reddy, M. S. K.; Yadav, J. S.; Krishna,
K. V. S. R.; Kunwarb, A. C. Tetrahedron Lett. 2005, 46,
1659–1661.
References and notes
1. Sundberg, R. J. The Chemistry of Indoles; Academic: New
York, 1996; p 113.
7. Yamamoto, Y.; Harimaya, K. Chem. Lett. 2004, 33, 238.
8. For review, see: (a) Luche, J. L. Synthetic Organic
Sonochemistry; Plenum: New York, 1998. (b) Mason, T.
J. Chem. Soc. Rev. 1997, 26, 443–451.
2. (a) Harrington, P. E.; Kerr, M. A. Synlett 1996, 11, 1047–1048.
(b) Agnusdei, M.; Bandini, M.; Melloni, A.; Umani-Ronchi, A.
J. Org. Chem. 2003, 68, 7126–7129 and references therein.
3. (a) Bandini, M.; Cozzi, P. G.; Giacomini, M.; Melchiorre, P.;
Selva, S.; Umani-Ronchi, A. J. Org. Chem. 2002, 67,
3700–3704. (b) Harrington, P. E.; Kerr, M. A. Can. J. Chem.
1998, 76, 1256–1265. (c) Yadav, J. S.; Abraham, S.; Subba
Reddy, B. V.; Sabitha, G. Synthesis 2001, 14, 2165–2169.
(d) Manabe, K.; Aoyama, N.; Kobayashi, S. Adv. Synth. Catal.
2001, 174–176. (e) Yadav, J. S.; Subba Reddy, B. V.; Murthy,
V. S. R.; Mahesh Kumar, G.; Madan, C. Synthesis 2001, 5,
783–786. (f) Iqbal, Z.; Jackson, A. H.; Rao, K. R. N.
Tetrahedron Lett. 1988, 29, 2577–2580. (g) Dujardin, G.;
Poirier, J. M. Bull. Soc. Chim. Fr. 1994, 131, 900–909.
(h) Komoto, I.; Kobayashi, S. Org. Lett. 2002, 4, 1115–1118.
(i) Bartoli, G.; Bartolacci, M.; Bosco, M.; Foglia, G.; Giuliani,
A.; Marcantoni, E.; Sambri, L.; Torregiani, E. J. Org. Chem.
2003, 68, 4594–4597. (j) Alam, M. M.; Varala, R.; Adapa, S.
Tetrahedron Lett. 2003, 44, 5115–5119. (k) Ji, S.-J.; Wang,
S.-Y. Synlett 2003, 13, 2074–2076. (l) Wang, S.-Y.; Ji, S.-J.;
Loh, T.-P. Synlett 2003, 15, 2377–2379. (m) Ji, S.-J.; Wang,
S.-Y. Ultrason. Sonochem. 2005, 12, 339–343. (n) Firouzabadi,
H.; Iranpoor, N.; Nowrouzi, F. Chem. Commun. 2005,
789–791. (o) Li, X. L.; Wang, Y. M.; Matsuura, T.; Meng,
J. B. J. Heterocycl. Chem. 1999, 36, 697–701.
9. For examples, see: (a) Palacios, M. L. D.; Comdom, R. F. P.
Synth. Commun. 2003, 33, 1777. (b) Li, J.-T.; Yang, W.-Z.;
Wang, S.-X.; Li, S.-H.; Li, T.-S. Ultrason. Sonochem. 2002, 9,
237. (c) Wang, S.-X.; Li, J.-T.; Yang, W.-Z.; Li, T.-S.
Ultrason. Sonochem. 2002, 9, 159. (d) Li, J.-T.; Li, T.-S.; Li,
L.-J.; Cheng, X. Ultrason. Sonochem. 1999, 6, 199. (e) Qin, Z.;
Chen, F.; Xie, Y. Prog. Chem. 1998, 10, 65. (f) Li, J.-T.; Yang,
W.-Z.; Chen, G.-F.; Li, T.-S. Synth. Commun. 2003, 33, 2619.
(g) Jayasree, J.; Rao, J. M. Synth. Commun. 1996, 26, 3717.
(h) Ji, S.-J.; Shen, Z.-L.; Gu, D.-G.; Huang, X.-Y. Ultrason.
Sonochem. 2005, 12, 161–163. (i) Bettadaiah, B. K.; Gurudutt,
K. N.; Srinivas, P. Synth. Commun. 2003, 33, 2293. (j) Ji, S.-J.;
Shen, Z.-L.; Wang, S.-Y. Chin. Chem. Lett. 2003, 14,
663–666. (k) Yang, J.-H.; Li, J.-T.; Zhao, J.-L.; Li, T.-S.
Synth. Commun. 2004, 34, 993. (l) Winum, J. Y.; Kamal, M.;
Leydet, A.TetrahedronLett. 1996, 37, 1781.(m)Chandrasekhar,
S.; Narsihmulu, Ch.; Jagadeshwar, V. Synlett 2002, 5, 771.
(n) Ando, T.; Cork, D. G.; Kimura, T. Chem. Lett. 1986, 173,
665. (o) Fuentes, A.; Sinisterra, J. V. Tetrahedron Lett. 1986,
27, 2967. (p) Yadav, J. S.; Subba Reddy, B. V.; Srinivas, C.;
Srihari, P. Synlett 2001, 6, 854. (q) Ji, S.-J.; Shen, Z.-L.; Gu,
D.-G.; Wang, S.-Y. J. Organomet. Chem. 2004, 689,
1843–1848. (r) Li, J.-T.; Lin, Z.-P.; Qi, N.; Li, T.-S. Synth.
Commun. 2004, 34, 4339. (s) Comdom, R. F. P.; Palacios,
M. L. D. Synth. Commun. 2003, 33, 921.
4. For reviews, see: (a) Domling, A.; Ugi, I. Angew. Chem., Int.
Ed. 2000, 39, 318. (b) Hulme, C.; Gore, V. Curr. Med. Chem.
2003, 10, 51. (c) Bienayme, H.; Hulme, C.; Oddon, G.;
Schmitt, P. Chem. Eur. J. 2000, 6, 3321. (d) Posner, G. H.
Chem. Rev. 1986, 86, 831–844. (e) Ugi, I. Pure Appl. Chem.
2001, 73, 187–191. (f) Orru, R. V. A.; de Greef, M. Synthesis
2003, 10, 1471. (g) Dax, S. L.; McNally, J. J.; Youngman,
M. A. Curr. Med. Chem. 1999, 6, 255. (h) Domling, A. Comb.
Chem. High Throughput Screening 1998, 1, 1. (i) Armstrong,
R. W.; Combs, A. P.; Tempest, P. A.; Brown, S. D.; Keating,
T. A. Acc. Chem. Res. 1996, 29, 123–131. (j) Ugi, I.; Domling,
A.; Gruber, B.; Almstetter, M. Croat. Chem. Acta 1997, 70,
631. (k) Zhu, J. P. Eur. J. Org. Chem. 2003, 1133–1144.
10. Zhou, P.; Li, Y. F.; Meagher, K. L.; Mewshaw, R. G.;
Harrison, B. L. Tetrahedron Lett. 2001, 42, 7333–7335.
11. Gong, Y. F.; Kato, K.; Kimoto, H. Tetrahedron Lett. 1999, 40,
5743.
12. Medebielle, M.; Fujii, S.; Kato, K. Tetrahedron 2000, 56,
2655.
13. Gordon, W.; Gribble Richard, A.; Silva Mark, S. G. Synth.
Commun. 1999, 29, 729–747.
14. Newkome, G. R.; Robinson, J. M. J. Org. Chem. 1976, 41,
2536–2542.