Lewis acid-catalyzed tandem acylation-Nazarov cyclization for the syntheses of fused cyclopentenones

Article abstract of DOI:10.1016/j.tet.2013.12.025

Treatment of N-tosylpyrroles or N-tosylindoles with α-unsubstituted α,β-unsaturated carboxylic acids or unsaturated carboxylic acids having an α electron-withdrawing substituent in the presence of TFAA and a Lewis acid catalyst resulted in the formation o

Full text of DOI:10.1016/j.tet.2013.12.025

Tetrahedron 70 (2014) 874e879
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Tetrahedron
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Lewis acid-catalyzed tandem acylationeNazarov cyclization for the
syntheses of fused cyclopentenones
Ertong Li a, Changwei Li a, Jing Wang a, Jinqian Wang a, Lihong Dong b, Xiaohe Guo b,
,
a,b,
*
Chuanjun Song a , Junbiao Chang
*
a College of Chemistry and Molecular Engineering, Zhengzhou University, 100 Science Avenue, Zhengzhou 450001, PR China
b High and New Technology Research Center of Henan Academy of Sciences, Hongzhuan Rd 52#, Zhengzhou 450002, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 22 October 2013
Received in revised form 30 November 2013
Accepted 10 December 2013
Available online 18 December 2013
Treatment of N-tosylpyrroles or N-tosylindoles with a-unsubstituted a,b-unsaturated carboxylic acids or
unsaturated carboxylic acids having an
a electron-withdrawing substituent in the presence of TFAA and
a Lewis acid catalyst resulted in the formation of fused cyclopentenones via a tandem acylationeNazarov
cyclization sequence, while either the acylation product obtained or no reaction occurred in the absence
of the Lewis acid catalyst.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Cyclopentenone
Tandem reaction
Lewis acid
Nazarov cyclization
Bruceolline E
1. Introduction
tertiary carbenium ion could be formed only with acylation prod-
ucts having an
carboxylic acids. Further studies indicated that no reaction oc-
curred when -unsaturated carboxylic acids with an electron-
withdrawing group installed at the -position were subjected to
the same reaction conditions. After careful literature search, we
were inspired by the success in Lewis acid-catalyzed Nazarov cy-
clization of polarized substrates,2,5b,7,10 and decided to examine the
possibility of Lewis acid-catalyzed tandem acylationeNazarov cy-
a-substituent present in the initial a,b-unsaturated
The Nazarov cyclization is a powerful method for the con-
struction of cyclopentenones.1 However, multi-steps were required
to access the divinyl or aryl vinyl ketone precursors.2e8 Previously,
Knight and Song had developed a tandem acylationeNazarov cy-
clization reaction for the synthesis of cyclopentenone[b]pyrroles by
a,b
a
treatment of N-tosylpyrroles with
having an
-alkyl substituent in the presence of TFAA (Scheme 1).9
For -unsubstituted -unsaturated carboxylic acids, only the ac-
a,b-unsaturated carboxylic acids
a
a
a,
b
clization reaction with
electron-withdrawing group at the
unsubstituted -unsaturated carboxylic acids. We hope that the
a,
b-unsaturated carboxylic acids having an
ylation products were obtained. The results are not surprising since
for the Nazarov cyclization reaction to occur, a stable intermediate
a
-position, as well as a-
a,b
added Lewis acid catalyst could also activate the mixed anhydride,
which was believed to be the acylating reagent of TFAA-mediated
direct acylation reaction.11
2. Results and discussion
Initial catalyst screening was carried out with N-tosylpyrrole 1
and a
-methoxycarbonylpentenoic acid 2.12 The results were shown
Scheme 1. Results for treatment of N-tosylpyrroles with a,b-unsaturated carboxylic
acids and TFAA.
in Table 1. No reaction was observed after 36 h with Ti(OiPr)4,
LiClO4, or BBr3 as a catalyst (entries 1e3). Use of AlCl3 showed
promising, although the reaction proceeded very slowly. The de-
sired product 3 was obtained in 10% isolated yield after 36 h in
refluxing DCE, together with substantial amount (w60%) of the
starting pyrrole 1 recovered (entry 4). Sc(OTf)3 caused hydration of
* Corresponding authors. E-mail addresses: chjsong@zzu.edu.cn (C. Song),
changjunbiao@zzu.edu.cn (J. Chang).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.12.025

E. Li et al. / Tetrahedron 70 (2014) 874e879
875
Table 1
Catalyst screening
good isolated yield with all
ing an
ylation step occurred in a highly regioselective manner (2-
acylation) with all acid substrates except 9 with a m-nitro-
phenyl substituent (entry 3). Harsher conditions were needed for
acids with a alkyl substituent (entries 7 and 8) compared with
those having a aryl substituent (entries 1e3, 5, 6). Lewis acid
catalyst of 0.5 equiv was applied in all cases except acid 11 with
furanyl substituent where 1.5 equiv of FeCl3 was needed,
a
,
b
-unsaturated carboxylic acids hav-
a
electron-withdrawing substituent (entries 1e8). The ac-
b
b
b
Entry
Lewis acid
Reaction time (h)
Yield (%) of 3
a
b
a
a
a
1
2
3
4
5
6
7
Ti(OiPr)4
LiClO4
BBr3
AlCl3
Sc(OTf)3
FeCl3
36
36
36
36
36
10
10
probably because of complexation of the furanyl oxygen to the
catalyst. Only one diastereomer with a trans relationship between
the alkoxycarbonyl group and the
b-substituent was isolated
10b
30c
75
where stereochemistry was involved (entries 1e6, 8). The stereo-
chemical assignment was made by comparison of the chemical
shifts and coupling constants patterns of the methine protons at
the ring branches with previously obtained compounds.9 This was
further confirmed by NOE correlations of the methine proton at-
tached to the carbon atom adjacent to both carbonyl groups with
all the seven protons of the isopropyl group in compound 3. As
ZnCl2
62d
a
No reaction.
Incomplete conversion of pyrrole 1.
An inseparable 1:1 mixture of 3 and the double-bond hydrated product was
b
c
obtained. Yield was determined based on 1H NMR integration.
d
3-AcylationdNazarov cyclization product of 17% was isolated.
stated by previous study,9 treatment of N-tosylpyrroles with
unsubstituted -unsaturated carboxylic acids (e.g., 18, 20) and
a-
a,b
TFAA in the absence of a Lewis acid catalyst resulted in the for-
mation of the acylation products, i.e., pyrrolyl vinyl ketones (as
shown in Scheme 1). Delightfully, with added FeCl3, the tandem
reaction proceeded successfully and gave cyclopentenone[b]pyr-
roles 19 (entry 9) and 21 (entry 10) in good isolated yield. Com-
paring the previous study of the reaction of N-tosylpyrrole 4 and
3,3-dimethylacrylic acid 22,9 addition of Lewis acid catalyst FeCl3
afforded higher yield of 23 (74% vs 51%) in shorter reaction time
(4 h vs 16 h, entry 11).
Inspired by the foregoing results, we tested the tandem reaction
of N-tosylindole with acids 7 and 22 in the presence of FeCl3 and
TFAA. However, in each case only the acylation product (indolyl
vinyl ketone) was obtained, which did not react further to give the
Nazarov cyclization product. Fortunately, the desired cyclo-
pentenone[b]indoles 24 and 25 were isolated in 62% and 54% yields,
respectively, by replacing FeCl3 with the more reactive ZnCl2
(Scheme 2). Following a similar procedure as developed by Bade-
nock,13 compound 25 could be transformed into the natural prod-
uct bruceolline E 26 by oxidation of the methylene carbon with
SeO2, followed by deprotection (Scheme 3).
the double-bond. After completion (36 h), an inseparable 1:1
mixture of 3 and the double-bond hydrated product (structure not
shown) in a combined 60% yield was obtained (entry 5). De-
lightfully, when FeCl3 was applied, the reaction proceeded
smoothly and gave 3 in 75% isolated yield upon completion (entry
6). ZnCl2 seemed to be too reactive. Other than 3 (62%),17% of the 3-
acylationdNazarov cyclization product (structure not shown) was
also isolated (entry 7). No improvement was observed by lowering
the reaction temperature (40 ꢀC, 25 ꢀC) or changing the solvent to
toluene, DCM, or nitromethane. Therefore, we selected FeCl3 for
further optimization.
The reaction conditions were screened with N-tosylpyrrole 4
and a,b-unsaturated carboxylic acid 5. It was found that the yield of
6 was comparable for reactions run at 0 ꢀC, 25 ꢀC, 40 ꢀC or 80 ꢀC. For
easy operation, the amount of catalyst loading was examined in
DCM at rt, and the results were collected in Table 2. Good results
were obtained with sub-stoichiometric amount of catalyst loading
(entries 1e3). When the catalyst loading was increased from
0.3 equiv to 0.5 equiv, 6 was isolated in the highest 54% yield (entry
3). Other side-reactions began to take place if 1 equiv (entry 4) or
more (entry 5) FeCl3 was applied, and the desired product 6 was
returned in reduced yield.
3. Conclusion
In summary, we have developed a Lewis acid-catalyzed tandem
acylationeNazarov cyclization protocol for the synthesis of fused
cyclopentenones. We believe that both the acylation and the sub-
sequent Nazarov cyclization steps are activated by the Lewis acid
catalyst, as either the acylation product obtained or no reaction
Table 2
Catalyst loading
occurred with the aforementioned a,b-unsaturated carboxylic acids
in the absence of a Lewis acid catalyst. Application of this meth-
odology to the construction of bioactive natural products is current
underway in our laboratory.
Entry
Catalyst (mol %)
Yield (%) of 6
1
2
3
4
5
20
30
50
100
150
43
48
54
37
26
4. Experimental section
4.1. General
Solvents were dried according to standard procedures where
needed. Melting points were measured on an XT4A melting point
apparatus and were not corrected. IR spectra were obtained using
an IFS25 FT-IR spectrometer. 1H and 13C NMR spectra were obtained
on a Bruker AV300 or AV400 instrument. Mass spectra were
recorded on a Micromass Q-TOF mass spectrometer.
With the optimized conditions in hand, we completed our
survey of FeCl3-catalyzed tandem acylationeNazarov cyclization
for the synthesis of cyclopentenone[b]pyrroles (Table 3). As ex-
pected, the tandem reaction product was obtained in moderate to

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E. Li et al. / Tetrahedron 70 (2014) 874e879
Table 3
FeCl3-catalyzed tandem acylationeNazarov cyclization for the synthesis of cyclopentenone[b]pyrroles
Entry
Pyrrole
a
,
b-Unsaturated carboxylic acid
Reaction conditionsa
Product(s)/yield (%)
1
A
A
2
3
A
4
Bb
5
A
6
A
7
B
8
B

E. Li et al. / Tetrahedron 70 (2014) 874e879
877
Table 3 (continued )
Entry
Pyrrole
a
,
b-Unsaturated carboxylic acid
Reaction conditionsa
Product(s)/yield (%)
9
B
10
B
B
11
a
Condition A: 50 mol % FeCl3, TFAA, DCM, rt, 4 h; condition B: 50 mol % FeCl3 TFAA, DCE, reflux, 4 h.
FeCl3 of 150 mol % was used.
b
DCM was stirred at rt for 4 h. The crude product was purified by
column chromatography on silica gel with EtOAc/petroleum ether
(1:4) as eluent to give 6 (54%) as a syrup: nmax/cmꢁ1 1706, 1678,
1596, 1543, 1495, 1422, 1367, 1323, 1257, 1174, 1140, 1085, 1063 and
1024; dH (300 MHz, CDCl3) 8.09 (dt, J¼7.2, 2.1 Hz, 1H), 7.55e7.46 (m,
4H), 7.38 (d, J¼3.3 Hz, 1H), 7.13 (d, J¼8.4 Hz, 2H), 7.05 (d, J¼8.4 Hz,
2H), 6.55 (d, J¼3.3 Hz, 1H), 5.19 (d, J¼2.4 Hz, 1H), 4.24 (q, J¼7.2 Hz,
2H), 3.66 (d, J¼2.4 Hz, 1H), 2.33 (s, 3H) and 1.29 (t, J¼7.2 Hz, 3H); dC
(75 MHz, CDCl3) 180.8, 168.3, 159.6, 146.0, 140.0, 134.8, 134.4, 131.6,
130.0, 128.9, 128.3, 127.5, 127.1, 108.8, 67.8, 61.7, 43.2, 21.6 and 14.1;
found [MþNa]þ 446.1037, C23H21NNaO5S requires 446.1038.
4.2.2. trans-5-Ethoxycarbonyl-4-(40-methylphenyl)-1-tosyl-4,5-
dihydrocyclopenta[b]pyrrol-6-one 8. The reaction mixture in dry
DCM was stirred at rt for 4 h. The crude product was purified by
column chromatography on silica gel with EtOAc/petroleum ether
(1:4) as eluent to give 8 (65%) as a colourless solid: mp 77e78 ꢀC;
nmax/cmꢁ1 1722, 1706, 1662, 1596, 1514, 1469, 1450, 1420, 1377, 1320,
1259, 1225, 1178, 1139, 1115, 1087, 1035 and 1016; dH (300 MHz,
CDCl3) 8.08 (d, J¼8.4 Hz, 2H), 7.70 (d, J¼3.0 Hz, 1H), 7.34 (d,
J¼8.4 Hz, 2H), 7.11 (d, J¼8.1 Hz, 2H), 7.00 (d, J¼8.1 Hz, 2H), 6.18 (d,
J¼3.0 Hz, 1H), 4.67 (d, J¼3.3 Hz, 1H), 4.23 (q, J¼7.2 Hz, 2H), 3.73 (d,
J¼3.3 Hz, 1H), 2.43 (s, 3H), 2.31 (s, 3H) and 1.28 (t, J¼7.2 Hz, 3H); dC
(75 MHz, CDCl3) 181.1, 168.5, 160.0, 146.1, 137.4, 137.1, 134.8, 134.6,
131.7, 130.1, 129.7, 128.4, 127.2, 108.8, 68.0, 61.8, 43.0, 21.8, 21.1 and
14.2; found [MþNa]þ 460.1189, C24H23NNaO5S requires 460.1195.
Scheme 2. ZnCl2-catalyzed tandem acylationeNazarov cyclization for the synthesis of
cyclopentenone[b]indoles.
Scheme 3. Reagents and conditions: (a) SeO2, dioxane, reflux, 18 h, 91%; (b) KOH,
TBAB, THF/H2O, 70 ꢀC, 3 h, 69%.
4.2. General procedure for the synthesis of cyclopentenone[b]
pyrroles 6, 8, 10a, 10b, 12, 14, 15, 17, 3, 19, 21 and 23
4.2.3. trans-5-Ethoxycarbonyl-4-(30-nitrophenyl)-1-tosyl-4,5-
dihydrocyclopenta[b]pyrrol-6-one 10a and trans-5-ethoxycarbonyl-
6-(30-nitrophenyl)-1-tosyl-4,5-dihydrocyclopenta[b]pyrrol-4-one
10b. The reaction mixture in dry DCM was stirred at rt for 4 h. The
crude product was purified by column chromatography on silica gel
with DCM/petroleum ether (1:2) as eluent to give 10a (36%) and
10b (28%), both as colourless solid.
To a solution of N-tosylpyrrole (1.0 mmol, 1.0 equiv) and a,b-
unsaturated carboxylic acid (2.0 mmol, 2.0 equiv) in dry DCM
(20 mL) or DCE (20 mL) were added TFAA (4.0 mmol, 4.0 equiv) and
FeCl3 (0.5 mmol, 0.5 equiv). The resulting mixture was stirred at rt
or heated to reflux for 4 h and cooled. The bulk of solvent was
evaporated in vacuo. The residue was partitioned between EtOAc
(20 mL) and H2O (20 mL). The separated organic phase was washed
with saturated aqueous NaHCO3 (20 mL), then dried (Na2SO4), fil-
tered and evaporated in vacuo. The residue was purified by column
chromatography on silica gel.
4.2.3.1. Compound 10a. Mp 115e121 ꢀC; nmax/cmꢁ1 1729, 1714,
1595, 1527, 1451, 1419, 1378, 1349, 1296, 1249, 1224, 1191, 1177, 1129,
1088, 1044 and 1031; dH (300 MHz, CDCl3) 8.17e8.05 (m, 3H), 7.97
(m, 1H), 7.77 (d, J¼3.0 Hz, 1H), 7.57e7.45 (m, 2H), 7.37 (dd, J¼8.7,
0.6 Hz, 2H), 6.22 (d, J¼3.0 Hz, 1H), 4.86 (d, J¼3.6 Hz, 1H), 4.27 (q,
J¼7.2 Hz, 2H), 3.72 (d, J¼3.6 Hz, 1H), 2.45 (s, 3H) and 1.31 (t,
4 . 2 .1. t ra n s - 5 - E t h ox yc ar b o nyl-4 - p h e nyl- 1- to s yl - 4, 5 -
dihydrocyclopenta[b]pyrrol-6-one 6. The reaction mixture in dry

878
E. Li et al. / Tetrahedron 70 (2014) 874e879
J¼7.2 Hz, 3H); dC (75 MHz, CDCl3) 179.8, 167.8, 157.6, 148.6, 146.3,
142.2, 135.2, 133.6, 131.8, 130.2, 130.1, 128.4, 122.8, 122.2, 108.4, 67.3,
62.2, 42.6, 21.8 and 14.1; found [MþNa]þ 491.0880, C23H20N2NaO7S
requires 491.0889.
1H), 7.32 (d, J¼8.4 Hz, 2H), 6.20 (d, J¼3.0 Hz, 1H), 4.14 (q, J¼7.2 Hz,
2H), 3.68 (s,1H), 2.41 (s, 3H),1.85e1.78 (m, 8H) and 1.20 (t, J¼7.2 Hz,
3H); dC (75 MHz, CDCl3) 182.6, 169.4, 165.6, 145.9, 134.8, 134.5, 131.1,
130.1, 128.5, 107.1, 69.1, 61.2, 49.4, 41.6, 35.0, 24.0, 23.9, 21.8 and
14.2; found [MþNa]þ 424.1186, C21H23NNaO5S requires 424.1195.
4.2.3.2. Compound 10b. Mp 118e120 ꢀC; nmax/cmꢁ1 1737, 1720,
1596,1533,1444,1380,1349,1293,1225,1205,1189,1177,1142,1131,
1090 and 1012; dH (300 MHz, CDCl3) 8.10 (dt, J¼7.2, 2.1 Hz, 1H),
7.63e7.34 (m, 4H), 7.23e6.99 (m, 4H), 6.56 (d, J¼3.3 Hz,1H), 5.21 (d,
J¼2.4 Hz, 1H), 4.26 (q, J¼7.2 Hz, 2H), 3.68 (d, J¼2.4 Hz, 1H), 2.34 (s,
3H) and 1.30 (t, J¼7.2 Hz, 3H); dC (75 MHz, CDCl3) 187.7, 167.3, 158.0,
148.6, 146.3, 142.0, 134.5, 130.1, 130.0, 129.4, 126.8, 122.7, 122.0,
106.4, 68.7, 62.4, 44.8, 21.6 and 14.2; found [MþNa]þ 491.0884,
4.2.8. trans-2-(60-Heptenyl)-4-isopropyl-5-methoxycarbonyl-1-
tosyl-4,5-dihydrocyclopenta[b]pyrrol-6-one 3. The reaction mixture
in dry DCE was heated to reflux for 4 h. The crude product was
purified by column chromatography on silica gel with EtOAc/pe-
troleum ether (1:6) as eluent to give 3 (78%) as an orange oil: nmax
/
cmꢁ1 1743, 1704, 1440, 1380, 1366 and 1229; dH (400 MHz, CDCl3)
8.01 (d, J¼8.4 Hz, 2H), 7.31 (d, J¼8.4 Hz, 2H), 6.08 (s, 1H), 5.82 (ddt,
J¼17.2, 10.4, 6.8 Hz, 1H), 5.03 (dd, J¼17.2, 1.6 Hz, 1H), 4.97 (d,
J¼10.4 Hz, 1H), 3.77 (s, 3H), 3.57 (d, J¼3.2 Hz, 1H), 3.26 (dd, J¼5.8,
3.2 Hz, 1H), 3.06e2.92 (m, 2H), 2.42 (s, 3H), 2.10e2.06 (m, 2H), 1.92
(m, 1H), 1.72e1.69 (m, 2H), 1.46e1.44 (m, 4H), 0.94 (d, J¼6.6 Hz, 3H)
and 0.89 (d, J¼6.6 Hz, 3H); dC (100 MHz, CDCl3) 180.7, 170.3, 159.3,
152.2, 145.5, 138.8, 135.8, 132.5, 130.0, 127.8, 114.5, 109.0, 61.8, 52.6,
44.4, 33.6, 31.2, 28.8, 28.8, 28.7, 28.6, 21.7, 19.8 and 19.7; found
[MþNa]þ 494.1980, C26H33NNaO5S requires 494.1977.
C
23H20N2NaO7S requires 491.0889.
4.2.4. trans-5-Ethoxycarbonyl-4-(furan-20-yl)-1-tosyl-4,5-
dihydrocyclopenta[b]pyrrol-6-one 12. The reaction mixture in dry
DCE was heated to reflux for 4 h. The crude product was purified by
column chromatography on silica gel with EtOAc/petroleum ether
(1:4) as eluent to give 12 (42%) as an orange oil: nmax/cmꢁ1 1739,
1709, 1597, 1548, 1505, 1494, 1456, 1423, 1381, 1328, 1272, 1218,
1193, 1138, 1090, 1031 and 1011; dH (300 MHz, CDCl3) 8.06 (d,
J¼8.4 Hz, 2H), 7.70 (d, J¼3.0 Hz, 1H), 7.35e7.32 (m, 3H), 6.33 (dd,
J¼3.0, 0.5 Hz, 1H), 6.29 (dd, J¼3.3, 1.8 Hz, 1H), 6.10 (dt, J¼3.3, 0.9 Hz,
1H), 4.80 (d, J¼3.6 Hz, 1H), 4.25 (t, J¼7.2 Hz, 2H), 3.94 (d, J¼3.6 Hz,
1H), 2.42 (s, 3H) and 1.31 (t, J¼7.2 Hz, 3H); dC (75 MHz, CDCl3) 180.2,
168.1,157.2,152.3,146.2,142.6,134.7,134.5,131.2,130.2,128.5,110.4,
108.7, 106.4, 64.3, 62.1, 36.9, 21.8 and 14.2; found [MþNa]þ
436.0826, C21H19NNaO6S requires 436.0831.
4.2.9. 4-Phenyl-1-tosyl-4,5-dihydrocyclopenta[b]pyrrol-6-one
19. The reaction mixture in dry DCE was heated to reflux for 4 h.
The crude product was purified by column chromatography on
silica gel with EtOAc/petroleum ether (1:4) as eluent to give 19
(73%) as an orange oil: nmax/cmꢁ1 1701, 1597, 1542, 1494, 1451, 1422,
1375, 1241, 1173, 1098, 1054 and 978; dH (400 MHz, CDCl3) 8.09 (d,
J¼8.0 Hz, 2H), 7.67 (d, J¼3.2 Hz, 1H), 7.35e7.24 (m, 5H), 7.08 (d,
J¼7.8 Hz, 2H), 6.15 (d, J¼3.2 Hz,1H), 4.28 (dd, J¼6.8, 2.4 Hz,1H), 3.33
(dd, J¼18.4, 6.8 Hz, 1H), 2.78 (dd, J¼18.4, 2.4 Hz, 1H) and 2.43 (s,
3H); dC (100 MHz, CDCl3) 187.7, 161.1,146.0,141.9, 135.0,134.0,133.7,
130.1, 129.0, 128.5, 127.2, 127.2, 108.8, 51.8, 39.3 and 21.9; found
[MþNa]þ 374.0822, C20H17NNaO3S requires 374.0827.
4.2.5. trans-5-Ethoxycarbonyl-2,4-diphenyl-1-tosyl-4,5-
dihydrocyclopenta[b]pyrrol-6-one 14. The reaction mixture in dry
DCM was stirred at rt for 4 h. The crude product was purified by
column chromatography on silica gel with EtOAc/petroleum ether
(1:4) as eluent to give 14 (69%) as a syrup: nmax/cmꢁ1 1712, 1597,
1494, 1464, 1447, 1379, 1291, 1270, 1192, 1177, 1129, 1088 and 1018;
dH (300 MHz, CDCl3) 7.81 (d, J¼8.4 Hz, 2H), 7.49e7.21 (m, 10H),
7.13e7.06 (m, 2H), 6.12 (s, 1H), 4.70 (d, J¼3.3 Hz, 1H), 4.41e4.16 (m,
2H), 3.82 (d, J¼3.3 Hz, 1H), 2.43 (s, 3H) and 1.33 (t, J¼7.2 Hz, 3H); dC
(300 MHz, CDCl3) 181.4, 168.9, 159.4, 151.4, 145.7, 140.3, 135.7, 134.4,
131.2, 130.0, 129.9, 129.7, 129.2, 128.3, 127.9, 127.7, 127.4, 112.1, 67.8,
62.0, 43.2, 21.9 and 14.4; found [MþNa]þ 522.1347, C29H25NNaO5S
requires 522.1351.
4.2.10. 4-Methyl-1-tosyl-4,5-dihydrocyclopenta[b]pyrrol-6-one
21. The reaction mixture in dry DCE was heated to reflux for 4 h.
The crude product was purified by column chromatography on
silica gel with EtOAc/petroleum ether (1:6) as eluent to give 21
(53%) as an orange oil: nmax/cmꢁ11698,1597,1545,1494,1449,1424,
1371, 1310, 1294, 1232, 1190, 1177, 1135,1086, 1055, 1019 and 985; dH
(400 MHz, CDCl3) 8.06 (d, J¼8.4 Hz, 2H), 7.62 (d, J¼3.2 Hz, 1H), 7.31
(d, J¼8.4 Hz, 2H), 6.25 (d, J¼3.2 Hz, 1H), 3.13 (m, 1H), 3.05 (dd,
J¼18.0, 6.4 Hz, 1H), 2.42 (dd, J¼18.0, 2.0 Hz, 1H), 2.41 (s, 3H) and
1.25 (d, J¼6.8 Hz, 3H); dC (100 MHz, CDCl3) 188.1, 164.0, 145.7, 134.9,
133.6, 132.7, 129.9, 128.3, 107.8, 50.3, 28.1, 21.7 and 20.4; found
[MþNa]þ 312.0668, C15H15NNaO3S requires 312.0670.
4.2.6. trans-5-Ethoxycarbonyl-4-(40-methylphenyl)-2-phenyl-1-
tosyl-4,5-dihydrocyclopenta[b]pyrrol-6-one 15. The reaction mix-
ture in dry DCM was stirred at rt for 4 h. The crude product was
purified by column chromatography on silica gel with EtOAc/pe-
troleum ether (1:4) as eluent to give 15 (67%) as a colourless solid:
mp 87e89 ꢀC; nmax/cmꢁ1 1732, 1703, 1594, 1512, 1467, 1445, 1411,
1376, 1329, 1318, 1180, 1160, 1107, 1072 and 1017; dH (400 MHz,
CDCl3) 7.80 (d, J¼8.4 Hz, 2H), 7.48e7.29 (m, 7H), 7.11 (d, J¼7.6 Hz,
2H), 6.98 (d, J¼8.0 Hz, 2H), 6.11 (s, 1H), 4.65 (m, 1H), 4.27 (m, 2H),
3.39 (m, 1H), 2.43 (s, 3H), 2.32 (s, 3H) and 1.32 (td, J¼7.1, 1.6 Hz, 3H);
dC (100 MHz, CDCl3) 181.6, 169.0, 159.7, 151.3, 145.7, 137.4, 137.2,
135.6,134.3,131.2,130.0,129.8,129.8,129.7,128.2,127.9,127.3,112.1,
67.9, 61.9, 42.8, 21.8, 21.2 and 14.3; found [MþNa]þ 536.1502,
4.2.11. 4,4-Dimethyl-1-tosyl-4,5-dihydrocyclopenta[b]pyrrol-6-one
23.9 The reaction mixture in dry DCE was heated to reflux for 4 h.
The crude product was purified by column chromatography on
silica gel with EtOAc/petroleum ether (1:5) as eluent to give 23
(74%) as an orange oil: dH (400 MHz, CDCl3) 8.10 (d, J¼8.2 Hz, 2H),
7.60 (d, J¼3.0 Hz, 1H), 7.32 (d, J¼8.2 Hz, 2H), 6.22 (d, J¼3.0 Hz, 1H),
2.71 (s, 2H), 2.42 (s, 3H) and 1.30 (s, 6H); found [MþH]þ 304.1000,
C16H18NO3S requires 304.1002.
C
30H27NNaO5S requires 536.1508.
4.3. General procedure for the synthesis of cyclopentenone[b]
indoles 24 and 25
4.2.7. 5-Ethoxycarbonyl-spiro[4,10-cyclopentane]-1-tosyl-4,5-
dihydrocyclopenta[b]pyrrol-6-one 17. The reaction mixture in dry
DCE was heated to reflux for 4 h. The crude product was purified by
column chromatography on silica gel with EtOAc/petroleum ether
(1:4) as eluent to give 17 (49%) as an orange oil: nmax/cmꢁ1 1731,
1693, 1597, 1494, 1454, 1423, 1379, 1311, 1243, 1138, 1089, 1069 and
1039; dH (300 MHz, CDCl3) 8.06 (d, J¼8.4 Hz, 2H), 7.63 (d, J¼3.0 Hz,
To a solution of N-tosylindole (1.0 mmol, 1.0 equiv) and
a,b-
unsaturated carboxylic acid (2.0 mmol, 2.0 equiv) in dry DCE
(20 mL) were added TFAA (4.0 mmol, 4.0 equiv) and ZnCl2
(0.5 mmol, 0.5 equiv). The resulting mixture was heated to reflux
for 4 h and cooled. The bulk of solvent was evaporated in vacuo. The
residue was partitioned between EtOAc (20 mL) and H2O (20 mL).

E. Li et al. / Tetrahedron 70 (2014) 874e879
879
The separated organic phase was washed with saturated aqueous
NaHCO3 (20 mL), then dried (Na2SO4), filtered and evaporated in
vacuo. The residue was purified by column chromatography on
silica gel.
petroleum ether (1:1) as eluent to give bruceolline E 26 as an or-
ange solid (76 mg, 69%): dH (400 MHz, DMSO-d6) 12.92 (br, 1H), 7.83
(d, J¼7.7 Hz, 1H), 7.60 (d, J¼8.0 Hz, 1H), 7.39 (t, J¼7.7 Hz, 1H), 7.31 (t,
J¼7.5 Hz, 1H) and 1.42 (s, 6H); dC (100 MHz, DMSO-d6) 206.5, 175.2,
170.8, 139.9, 125.3, 123.4, 121.5, 121.0, 121.0, 113.6, 41.6 and 22.9.
4.3.1. trans-2-Ethoxycarbonyl-3-(40-methylphenyl)-4-tosyl-2,3-
dihydrocyclopenta[b]indol-1-one 24. The reaction mixture in dry
DCE was heated to reflux for 4 h. The crude product was purified by
column chromatography on silica gel with EtOAc/petroleum ether
(1:3) as eluent to give 24 (62%) as an orange oil: nmax/cmꢁ1 1736,
1709,1596,1556,1513,1483,1447,1411,1379,1309,1280,1249,1213,
1176, 1117, 1087, 1057 and 1021; dH (400 MHz, CDCl3) 7.94 (t,
J¼8.6 Hz, 2H), 7.42e7.35 (m, 2H), 7.20 (d, J¼8.4 Hz, 2H), 7.09e7.01
(m, 6H), 5.33 (d, J¼1.2 Hz, 1H), 4.26 (q, J¼7.2 Hz, 2H), 3.82 (d,
J¼1.2 Hz, 1H), 2.37 (s, 3H), 2.32 (s, 3H) and 1.31 (t, J¼7.2 Hz, 3H); dC
(100 MHz, CDCl3) 189.0, 168.2, 167.7, 145.7, 141.1, 137.7, 137.0, 134.4,
129.9, 129.8, 128.0, 127.5, 126.3, 125.1, 124.6, 122.0, 121.6, 114.5, 69.0,
62.2, 46.4, 21.8, 21.3 and 14.4; found [MþNa]þ 510.1346,
Acknowledgements
We are grateful to the National Natural Science Foundation of
China (#20902085; #21172202) for financial support.
Supplementary data
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2013.12.025.
These data include MOL files and InChiKeys of the most important
compounds described in this article.
C
28H25NNaO5S requires 510.1351.
References and notes
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25.13 The reaction mixture in dry DCE was heated to reflux for 4 h.
The crude product was purified by column chromatography on
silica gel with EtOAc/petroleum ether (1:3) as eluent to give 25
(54%) as a light brown solid: mp 124e125 ꢀC; nmax/cmꢁ1 1703, 1594,
1542, 1484, 1445, 1404, 1365, 1317, 1253, 1189, 1167, 1145, 1089 and
1040; dH (400 MHz, CDCl3) 7.96e7.88 (m, 2H), 7.75 (d, J¼8.4 Hz, 2H),
7.35e7.26 (m, 4H), 2.94 (s, 2H), 2.38 (s, 3H) and 1.75 (s, 6H); dC
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A mixture of cyclopentenone[b]indole 25 (200 mg, 0.57 mmol)
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