Synthesis of novel Murrapanine analogues by microwave irradiation

Article abstract of DOI:10.1080/00397910500451159

Some new Murrapanine analogues have been synthesized via microwave irradiation by intermolecular Diels-Alder cyclization of 1-tosyl-3-(3-methyl-1, 3-vinylallyl) indole with a dienophile such as quinone. The structure of the compounds has been characterize

Full text of DOI:10.1080/00397910500451159

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Synthesis of Novel Murrapanine Analogues by
Microwave Irradiation
Xiaohe Guo a , Weidong Hu b , Senxiang Cheng b , Limin Wang b & Junbiao
Chang a b
a Department of Chemistry , University of Science and Technology of China ,
Hefei, China
b Henan Key Laboratory of Fine Chemicals , Zhengzhou, China
Published online: 16 Aug 2006.
To cite this article: Xiaohe Guo , Weidong Hu , Senxiang Cheng , Limin Wang & Junbiao Chang (2006)
Synthesis of Novel Murrapanine Analogues by Microwave Irradiation, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 36:6, 781-788, DOI:
10.1080/00397910500451159
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Synthetic Communicationsw, 36: 781–788, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500451159
Synthesis of Novel Murrapanine Analogues
by Microwave Irradiation
Xiaohe Guo
Department of Chemistry, University of Science and Technology
of China, Hefei, China
Weidong Hu, Senxiang Cheng, and Limin Wang
Henan Key Laboratory of Fine Chemicals, Zhengzhou, China
Junbiao Chang
Department of Chemistry, University of Science and Technology
of China, Hefei, China and Henan Key Laboratory of Fine Chemicals,
Zhengzhou, China
Abstract: Some new Murrapanine analogues have been synthesized via microwave
irradiation by intermolecular Diels–Alder cyclization of 1-tosyl-3-(3-methyl-1,3-viny-
lallyl) indole with a dienophile such as quinone. The structure of the compounds has
1
been characterized by H NMR and MS.
Keywords: Synthesis, murrapanine analogues, microwave irradiation
The genus Murraya paniculata of the plant family Rutacaea occurs through-
out tropical and subtropical areas. Certain Murraya species in Taiwan were
known to have a new skeletal cytotoxic indole-naphthoquinone alkaloid,
murrapanine, with high anticancer activity.[1] In the human nasopharyngeal
Received in Japan June 27, 2005
Address correspondence to Junbiao Chang, Henan Key Laboratory of Fine
Chemicals, No. 56 Hongzhuan Road, Zhengzhou 450002, China. E-mail: jbchang@
public2.zz.ha.cn
781

782
X. Guo et al.
epidermoid carcinoma cell (KB) tissue culture assay, murrapanine demon-
strated significant cytotoxicity (ED50 ¼ 3.3 mg/mL).[1]
In biogenesis, there were derivative procedures of murrapanine that were
similar to 3-dehydroprenylindole via a Diels–Alder [4n þ 2] reaction to afford
indole derivatives. They have been synthesized by biomimetic synthesis.[1–3]
A few years ago, the research showed that the compounds with indole or
isoindole groups exhibit anticancer activity.[4–7] To test the effect of murra-
panine analogues in bioactivity and to find new compounds with excellent
anticancer and antiinflammatory activities, we synthesized four novel murra-
panine analogues. The synthesis of these is summarized in Scheme 1. The
indole-3-aldehyde 1 was tosylated to yield 2 and then condensed with
acetone to give 3. The key intermediate 4 was obtained by Wittig reaction
of a,b-unsaturated ketone 3 with ethyltriphenylphosphonium bromide.
Cyclization of 4 with dienophile via a Diels–Alder [4n þ 2] reaction by
conventional heating[8–11] or microwave irradiation afforded compounds 5–8.
1. RESULTS AND DISCUSSION
The conventional heating is conduction heating by thermal radiation of
outside heat source from outside to inside, so that the rate of energy utilization
was low and the distribution of energy wasn’t homogeneous. When the
solution was irradiated by microwave, the polar molecules of solution simul-
taneously absorbed and transmitted energy, so the rate of heating was quick
and the energy of solution from outside to inside was homogeneous. This
was the systemic heating that was homogeneous and efficient by microwave
irradiation. The Arrhenius equation (index relation) between most of the
chemical reaction rate and temperature, shared that the rate of reaction rose
highly by microwave irradiation.[12] The Diels-Alder reaction is a certain
cycloaddition of [4n þ 2]; compared with the conventional heating, the
microwave irradiation might obviously shorten reaction time and increase
the rate of production.[13] The results are reported in Table 1.

Murrapanine Analogues
783
Scheme 1. Synthesis line of compounds 5–8: (a) TsCl/Et2O–20% NaOH/5–108C;
(b) CH3COCH3–10% NaOH/r.t.; (c) Ph3PethylBr–n-BuLi–THF; (d) C6H6/micro-
wave or C6H6/808C; (e) DMSO/microwave or PhMe/1208C; (f) PhMe/microwave
or C6H6/808C; (g) DMSO/microwave or C6H6/808C.
When compound 8 was synthesized, the reaction was performed on inter-
mediate 4 with 1,4-benzoquinone in the light of a molar ratio of 1 : 1. 1,4-Ben-
zoquinone was consumed completely at the moment, but 4 remained
unchanged. Until the reaction of intermediate 4 with 1,4-benzoquinone was
near the molar ratio of 1 : 3, the two reactants were consumed completely.
The cause might be that the Diels–Alder reaction product was oxidized

784
X. Guo et al.
Table 1. Comparison of synthesis of 5, 6, 7, and 8 between
conventional heating and microwave irradiation
Conventional heating
Microwave irradiation
Compound
Time, h
Yield, %
Time, min
Yield, %
5
6
7
8
24
16
12
72
18
18
36
33
20
20
20
20
22
20
38
42
to a more stable aromatized product 8 by 1,4-benzoquinone due to the
electron-donating effect of two methyl groups. 1,4-Benzoquinone was
reduced to hydroquinone, and quinhydrones were formed by hydroquinone
with 1,4-benzoquinone. The amount of by-products of microwave irradiation
were less than with conventional heating in the reaction, and therefore the
yield was obviously increased.
Although some new murrapanine analogues could be prepared easily
with these two methods, a substantial amount of intractable mixtures was
also obtained as red gummy materials in these reactions, rendering
decreased yields of the desired compounds. The important feature of the
Diels–Alder reaction was high stereoselectivity, and the original steric
structure of diene and dienophile was not changed.[14] In this article,
because the substituent groups of dienophiles (chloranil, naphthoquinone,
maleic anh1,4-benzoquinone) were cis structure, these substituent groups in
additive products were still cis. In other words, the desired compounds were
cis-configuration.
2. EXPERIMENTAL
1H NMR spectra were recorded on a Bruker AV-300 (300-MHz) spectrometer
with tetramethylsilane as an internal standard, and the chemical shifts were
expressed in d values. Mass spectra were obtained with a Shimadzu QP-
5000 spectrometer. Melting points were determined on a XT-4 micro-
melting-point apparatus and are uncorrected. Microwave reactions were
carried out in Galanz WP700 microwave oven. TLC was used for monitoring
the reaction, and preparative TLC was performed on silica gel GF 254 (Yantai
Yuanbo Silica Gel Co. Ltd. of China). Column chromatography was
performed on silica gel of 200–300 mesh (Yantai Yuanbo Silica Gel Co.
Ltd. of China).
Ethyltriphenylphosphonium bromide was prepared from bromoethane
and triphenylphosphine.[15]

Murrapanine Analogues
785
2.1. 1-Tosyl-indole-3-aldehyde (2)
A mixture of indole-3-aldehyde (1) (1.45 g, 10 mmol), p-toluenesulfonyl
chloride (2.48 g, 13 mmol), and 20% aqueous sodium hydroxide (10 mL) in
ether (100 mL) was stirred at 5–108C for 20 h. The mixture was poured into
water, and the organic layer was separated. The aqueous layer was
extracted with additional ether, and the combined organic layer was washed
with sodium chloride solution, saturated, and dried. Evaporation of the
solvent gave a residue, which was recrystallized by ethyl acetate afforded 2
(2.77 g, 92%) as light-yellow crystals: mp 143–1458C (lit.[4] 148–1508C);
1H NMR d 2.38 (s, 3H, Ph-CH3), 7.26–7.84 (m, 5H, indole-H), 7.86–8.26
(m, 4H, Ph-H), 10.09 (s, 1H, CHO); MS m/z (%) 299 (Mþ, 58), 155 (58),
116 (18), 91 (100).
2.2. 1-Tosyl-3-(1-methyl vinyl ketone-3) Indole (3)
A solution of 1-tosyl-indole-3-aldehyde (2) (2.99 g, 10 mmol), acetone
(50 mL), and 10 % aqueous sodium hydroxide (10 mL) was stirred at room
temperature for 3 h. Then most of the solvent was removed on a rotary evap-
orator until a slurry resulted; the slurry was poured into water and extracted
with methylene dichloride. The solvent was evaporated off, and the residue
was purified by column chromatography using elution with petroleum
ether/methylene dichloride/tetrahydrofuran/ethyl acetate (12 : 5 : 2 : 1),
which gave 3 (2.14 g, 63%) as yellow crystals: mp 110–1128C (lit.[4] 109–
1118C); 1H NMR d 2.35 (s, 3H, PhCH3), 2.38 (s, 3H, COCH3), 6.84
(d, J ¼ 16.3 Hz, 1H, C55CHCO), 7.60 (d, J ¼ 16.3 Hz, 1H, indole-CH55C),
7.24–7.99 (m, 9H, Ar-H); MS m/z (%) 339 (Mþ, 45), 324 (7), 184 (100),
155 (30), 91 (90), 65 (62), 43 (73).
2.3. 1-Tosyl-3-(3-methyl-1,3-vinylallyl) Indole (4)
A three-necked, round-bottomed flask equipped with a pressure-equalizing
dropping funnel was charged with ethyltriphenylphosphonium bromide
(390 mg, 1.05 mmol) and tetrahydrofuran (1 mL) that was distilled from
sodium–benzophenone ketyl and was flushed with nitrogen. The system
was cooled in an ice bath and a positive pressure of nitrogen, and butyllithium
(0.42 mL, 2.5 M) was added dropwise. Then the ice bath was removed, and
after the reaction mixture was stirred at room temperature for 30 min, 3
(339 mg, 1 mmol) in tetrahydrofuran was added dropwise. The reaction
mixture was stirred at room temperature for 18 h, poured into water, and
extracted with ether. The extract was dried over anhydrous sodium sulfate,
evaporated, and subjected to chromatography on silica gel (GF 254,
petroleum ether/acetone 4 : 1) to give 261 mg of 4 (a small amount of 4

786
X. Guo et al.
was transformed to other compounds due to its unstable character). Begin the
following reaction at once!
2.4. 2,3,4a,8a-Tetrachloro-7,8-dimethyl-5-(1-tosylindole-3-yl)-
4a,5,8,8a-tetrahydro-1,4-naphthoquinone (5)
A solution of 4 (261 mg, 0.7 mmol), benzene (20 mL), and chloranil (490 mg,
2 mmol) was taken in an Erlenmeyer flask and placed in a microwave oven.
The solution was irradiated at 280 W for 20 min. Then the solvent was
removed in a rotary evaporator, and the residue was separated by column
chromatography (silica gel, petroleum ether/acetone 4 : 1) to give 5
1
(130 mg, two steps, yield was 22%) as yellow powder: mp 190–1928C; H
NMR (CDCl3) d 1.60 (d, J ¼ 7.5 Hz, 3H, 8-CH3), 2.01 (s, 3H, 7-CH3), 2.38
(s, 3H, Ph-CH3), 3.49 (m, 1H, 8-H), 4.57 (m, 1H, 5-H), 5.51 (m, 1H, 6-H),
7.03–7.91 (m, 9H, Ar-H), MS m/z (%) 597 (8), 595 (Mþ, 5), 560 (7), 525
(11), 368 (10), 351 (10), 196 (37), 181 (18), 155 (15), 116 (12), 91 (100),
65 (42), 44 (66).
2.5. 1-(1-Tosylindole-3-yl)-3,4-dimethyl-1,4,4a,9a-tetrahydro-
antraquinone (6)
A solution of 4 (261 mg, 0.7 mmol), dimethyl sulfoxide (15 mL), and naphtho-
quinone (112 mg, 0.7 mmol) was taken in an Erlenmeyer flask and placed in a
microwave oven. The solution was irradiated at 119 W for 20 min, poured into
water, and extracted with ethyl acetate. The extract was dried and evaporated;
the residue was chromatographed on silica gel to give 6 (101 mg, two steps,
1
yield was 20%) as light yellow powder: mp 167–1698C; H NMR (CDCl3)
d 1.40 (d, J ¼ 7.5 Hz, 3H, 4-CH3), 1.95 (s, 3H, 3-CH3), 2.40 (s, 3H, Ph-
CH3), 2.63 (m, 1H, 4-H), 3.41 (t, 1H, 4a-H), 3.71 (t, 1H, 9a-H), 4.11
(m, 1H, 1-H), 5.58 (brs, 1H, 2-H), 7.09–7.79 (m, 13H, Ar-H); MS m/z (%)
509 (Mþ, 5), 449 (39), 223 (33), 238 (14), 196 (79), 181 (46), 116 (20), 91
(100), 65 (52), 44 (42).
2.6. 5,6-Dimethyl-3-(1-tosylindole-3-yl)cyclohex-4-ene-1,2-
dicarbox-ylic Anhydride (7)
A solution of 4 (261 mg, 0.7 mmol), dried toluene (15 mL), and maleic
anhydride (70 mg, 0.7 mmol) was taken in an Erlenmeyer flask and placed
in a microwave oven. The solution was irradiated at 462 W for 20 min. The
solvent was removed, and the residue was recrystallized by toluene and
sulfuric ether to give 7 (170 mg, two steps, yield was 38%) as light-yellow
1
granular crystal: mp 191–1938C; H NMR (CDCl3) d 1.58 (d, J ¼ 7.2 Hz,

Murrapanine Analogues
787
3H, 6-CH3), 1.88 (s, 3H, 5-CH3), 2.32 (s, 3H, Ph-CH3), 2.74 (m, 1H, 6-H),
3.40–3.62 (m, 2H, 1-H, 2-H), 3.80 (brs, 1H, 3-H), 6.01 (brs, 1H, 4-H),
7.21–7.96 (m, 9H, Ar-H); MS m/z (%) 449 (Mþ, 14), 351 (7), 222 (9), 206
(10), 196 (100), 181 (54), 116 (38), 91 (97), 65 (54), 39 (35).
2.7. 5-(1-Tosylindole-3-yl)-7,8-dimethyl-1,4-naphthoquinone (8)
A solution of 4 (261 mg, 0.7 mmol), dimethyl sulfoxide (15 mL), and 1,4-ben-
zoquinone (228 mg, 2.1 mmol) was taken in an Erlenmeyer flask and placed in
a microwave oven. The solution was irradiated at 119 W for 20 min, poured
into water, and extracted with ethyl acetate. The extract was dried, evaporated,
and separated by column chromatography (silica gel, petroleum ether/acetone
4 : 1) to give 8 (190 mg, two steps, yield was 42%) as orange-yellow powder:
1
mp 208–2108C; H NMR (CDCl3) d 2.36 (s, 3H, Ph-CH3), 2.45 (s, 3H,
7-CH3), 2.71 (s, 3H, 8-CH3), 6.70, 6.84 each (d, J ¼ 10.2 Hz, 1H, 1,4-benzo-
quinone-H), 7.41 (s, 1H, 6-H), 7.04–7.99 (m, 9H, Ar-H); MS m/z (%) 455
(Mþ, 16), 300 (100), 91 (31), 65 (20), 44 (68).
Compounds 5–8 have been synthesized by 1-tosyl-3-(3-methyl-1,3-viny-
lallyl) indole (4) with dienophile (chloranil, naphthoquinone, maleic
anhydride, 1,4-benzoquinone) in benzene or toluene via conventional
heating. Their yields were described in Table 1.
ACKNOWLEDGMENTS
J. B. Chang acknowledges the National Hi-Tech Research and Development
Program of China for financial support.
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