Efficient synthesis of esermethole and its analogues

Article abstract of DOI:10.1039/c1ob05275f

In this work, a general and flexible synthetic route towards the synthesis of pyrroloindoline alkaloids was developed. This new strategy features with a palladium mediated sequential arylation-allylation of o-bromoanilides and leads to the construction of oxindoles bearing a full carbon quaternary center. The cheap triphenylphosphine was proved to be a highly effective ligand for this one pot transformation. On the basis of this new method, esermethole and its analogues were synthesized.

Full text of DOI:10.1039/c1ob05275f

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PAPER
Efficient synthesis of esermethole and its analogues†
Yongyun Zhou, Yuanhong Zhao, Xiaoyong Dai, Jianping Liu, Liang Li and Hongbin Zhang*
Received 20th February 2011, Accepted 10th March 2011
DOI: 10.1039/c1ob05275f
In this work, a general and flexible synthetic route towards the synthesis of pyrroloindoline alkaloids
was developed. This new strategy features with a palladium mediated sequential arylation–allylation of
o-bromoanilides and leads to the construction of oxindoles bearing a full carbon quaternary center.
The cheap triphenylphosphine was proved to be a highly effective ligand for this one pot
transformation. On the basis of this new method, esermethole and its analogues were synthesized.
Recently, we have established an intermolecular sequential
Introduction
procedure for palladium-BINAP catalyzed arylation and allylic
alkylation of highly functional ketones.7 We envisaged that this
protocol would be a flexible and economic way for the construction
of oxindoles bearing a full carbon quaternary center at its
C-3a position. As indicated in Scheme 1, an intramolecular
arylation of amide 6 followed by an allylation, namely an “one-
pot” palladium mediated reaction (Scheme 1), would furnish the
quaternary carbon center with necessary functionality required for
the synthesis of hexahydropyrrolo[2,3-b]indole alkaloids. Herein
we report our results for the sequential arylation–allylation of o-
bromoanilides and the synthesis of esermethole and its analogues
from simple and inexpensive starting materials.
The hexahydropyrrolo[2,3-b]indole ring system is presented in
a wide selection of natural alkaloids1 and a number of mar-
keted drugs and drug candidates.2 Representative alkaloids of
the hexahydropyrrolo[2,3-b]indole skeleton are shown in Fig. 1.
Those pyrrolidinoindoline containing compounds, exemplified by
physostigmine which was isolated from the African Calabar bean
seeds,3 display a broad range of biological activities.4 Numerous
synthetic efforts have been made towards the synthesis of the
hexahydropyrrolo[2,3-b]indole alkaloids,5 with the anticholinergic
agent physostigmine being a subject of intensive interests.6 As
indicated in Fig. 1, hexahydropyrrolo[2,3-b]indole alkaloids are
characterized by a sterically congested all carbon quaternary
center at its C-3a position. Construction of the full carbon
quaternary center imposes certain synthetic challenges.
Scheme
1
Retrosynthetic analysis towards the synthesis of
hexahydropyrrolo[2,3-b]indole alkaloids.
In the literature, numerous procedures dealing with palladium
catalyzed arylation of amides have been reported.8 Elegant work
on the formation of oxindoles bearing a quaternary carbon center
has also been documented.9 To the best of our knowledge, however,
no flexible and economic “one-pot” arylation–allylation of o-
haloanilides has been conducted. It was therefore our goal to
evaluate the efficacy of some common ligands such as BINAP
and triphenylphosphine in the sequential arylation–allylation of
o-bromoanilides.
Fig. 1 Pyrrolidinoindoline related natural alkaloids.
Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry
of Education, School of Chemical Science and Technology, Yunnan
University, Kunming, Yunnan, 650091, P. R. China. E-mail: zhanghb@
ynu.edu.cnorzhang_hongbin@hotmail.com; Fax: 86-871-5035538
† Electronic supplementary information (ESI) available: 1H-NMR
and 13C-NMR Spectrum for all new compounds. See DOI:
10.1039/c1ob05275f
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Table 1 Evaluation of ligands and reaction conditions for arylation–
allylation of bromoanilidea
Entry
Pd/ligand lactams
Base lactams
Solvents
Yield
1
2
3
4
5
6
7
8
9
Pd2(dba)3, BINAP
Pd2(dba)3, BINAP
Pd2(dba)3, BINAP
Pd2(dba)3, BINAP
Pd2(dba)3, BINAP
Pd2(dba)3, BINAP
Pd2(dba)3, Ph3P
Cs2CO3
toluene
1,4-dioxane
THF
THF
THF
1,4-dioxane
THF
THF
—
—
NaOtBu
KN(SiMe3)2
NaN(SiMe3)2
LiN(SiMe3)2
LiN(SiMe3)2
LiN(SiMe3)2
LiN(SiMe3)2
LiN(SiMe3)2
trace
5%
51%
50%
92%b
87%c
73%d
Pd2(dba)3, Ph3P
Pd2(dba)3, Ph3P
THF
a All reactions were conducted with 1 mmol of o-bromoanilide. Reaction
procedures: see experimental section. Reaction was conducted with
Pd2(dba)3 (0.03 mmol) and BINAP (0.036 mmol) in corresponding solvents
at 75 ◦C oil bath. b Reaction was conducted with Pd2(dba)3 (0.03 mmol)
and Ph3P (0.06 mmol) in THF at 75 ◦C oil bath. c Reaction was conducted
with Pd2(dba)3 (0.03 mmol) and Ph3P (0.09 mmol) in THF at 75 ◦C oil
bath. d Reaction was conducted with Pd2(dba)3 (0.03 mmol) and Ph3P
(0.12 mmol) in THF at 75 ◦C oil bath.
Results and Discussion
2-Bromoanilide 6a was synthesized by treatment of 2-bromo-4-
methylaniline with 2-phenylacetyl chloride in dichloromethane
in the presence of triethylamine (Scheme 2). With amide 6a
in hand, we then initiated the research towards palladium-
mediated arylation–allylation of bromoanilides. After several
fruitless attempts (see Table 1), we finally found that the desired
transformation could be effected with a Pd-ligand complex in the
presence of lithium bistrimethylsilylamide as a base in THF (75 ◦C
oil bath). To our surprise, monodentated triphenylphosphine was
a better ligand than bidentated BINAP for this transformation
(Table 1, entries 5,6 and 7). In general, a better yield was obtained
using less triphenylphosphine (Pd : Ph3P = 1 : 1, Table 1, entry
7).10 It is also noteworthy and of interests that only lithium
bistrimethylsilylamide (the counter ion Li+ with a small ionic
radius) provided good yields in this transformation.
Scheme 3 Arylation–allylation of o-bromoanilides.
a full carbon quaternary center at its C3 position. Our reaction
conditions could also be extended to the synthesis of isoquino-
linones as indicated in Scheme 3. To the best of our knowledge,
there are no reported cases of palladium-mediated arylation of o-
bromoanilides that leads to the synthesis of isoquinolinones with
a full quaternary carbon center.11
Having successfully established a new method to oxindoles
bearing a full carbon quaternary center at its C3 position,
we then pursued our next goal, the synthesis of esermethole
and its analogues. Starting from compound 7b, after oxidative
cleavage of the double bond and reductive aminocyclization, the
( )-esermethole was obtained over two steps (60%, Scheme 4).
Following the well established procedure, three other analogues
were also synthesized (see Scheme 4).
Conclusions
In conclusion, we have developed an alternative and efficient
method for the preparation of oxindoles bearing an all carbon
quaternary center at its C3 position. The functionalized oxindole
building blocks are of use for the synthesis of both natural alka-
loids and natural product-like compounds. The results obtained
in this research indicate that the inexpensive triphenylphosphine
is the ligand of choice for sequential arylation–allylation of o-
bromoanilides. Based on this methodology, a practical and flexible
procedure was established for the synthesis of esermethole and its
analogues.
Scheme 2 Synthesis of amide 6a.
To get further examples of the sequential arylation–allylation of
2-bromoanilides, a number of 2-bromoanilides were synthesized
and utilized as substrates in this typical transformation under
optimized conditions. The results are shown in Scheme 3. This
palladium-mediated sequential arylation–allylation procedure is
practical and provides useful oxindole building blocks bearing
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(1.0 M in THF, 0.75 mL, 0.75 mmol, 1.5 eq.) was added followed
by allyl acetate (150 mg, 1.5 mmol, 3.0 eq.). The reaction was then
stirred at room temperature for 6–10 h. Water (0.1 mL) was added.
The solvent was removed under reduced pressure and the residue
was diluted with water (25 mL) and extracted with ethyl acetate
(3 ¥ 15 mL). The organic phases were combined and washed with
brine (10 mL) and dried over anhydrous Na2SO4. After removal
of the solvents, the residue was chromatographed on silica gel to
afford the products.
Compound 7a. Yield 92%, White crystal, mp: 67–68 ◦C, Rf
0.55 (Petroleum ether/EtOAc = 5 : 1). IR (nmax cm-1): 3401 (w),
3060 (w), 3007 (w), 2970 (w), 2926 (w), 2355 (w), 1708 (s), 1608
(m), 1495 (s), 1445 (m), 1350 (s), 1256 (w), 1144 (w), 1082 (m),
999 (w), 917 (m), 807 (m). 1H-NMR (300 MHz, CDCl3), d (ppm):
7.40–7.20 (5H, m), 7.10 (1H, d, J = 7.9 Hz), 7.05 (1H, s), 6.76
(1H, d, J = 7.9 Hz), 5.42–5.26 (1H, m), 5.03 (1H, dd, J = 1.8,
15.2 Hz), 4.90 (1H, dt, J = 0.9, 10.1 Hz), 3.17 (3H, s), 3.01 (2H,
d, J = 7.8 Hz), 2.34 (3H, s). 13C NMR (75 MHz, CDCl3) d (ppm):
178.07 (s), 141.63 (s), 139.92 (s), 132.66 (s), 132.09 (s), 131.98 (d),
128.63 (d), 127.38 (d), 127.17 (d), 125.96 (d), 119.14 (t), 108.00
(d), 56.63 (s), 41.95 (t), 26.47 (q), 21.35 (q). EIMS m/z (%):278
(M++1, 62%), 277 (M+, 89%), 261 (4), 248 (19), 236 (100), 221 (78),
208 (75), 206 (72), 193 (75), 178 (68), 165 (96), 152 (64), 139 (39),
130 (51), 115 (62), 103 (53), 91 (47), 77 (53). HRMS m/z Found:
277.1469, Calcd. for C19H19NO (M)+: 277.1467.
Scheme 4 Synthesis of esermethole and its analogues.
Experimental Section
Compound 7b. Yield 74%, Pale yellow oil, Rf 0.58 (Petroleum
ether/EtOAc = 3 : 1). IR (nmax cm-1): 3447 (w), 2965 (w), 2925 (w),
2357 (w), 1706 (s), 1641 (w), 1605 (w), 1497 (m), 1463 (w), 1366
(w), 1288 (w), 1236 (w), 1213 (w), 1040 (m), 920 (w), 873 (w),
806 (w). 1H-NMR (300 MHz, CDCl3), d (ppm): 6.80 (1H, d, J =
2.3 Hz), 6.77 (1H, dd, J = 2.3, 8.3 Hz), 6.71 (1H, d, J = 8.3 Hz),
5.52–5.32 (1H, m), 4.98 (1H, dd, J = 1.4, 17.0 Hz), 4.91 (1H, d,
J = 10.1 Hz), 3.79 (3H, s), 3.16 (3H, s), 2.56–2.40 (2H, m), 1.35
(3H, s). 13C-NMR (75 MHz, CDCl3), d (ppm): 179.95 (s), 156.06
(s), 136.86 (s), 135.17 (s), 132.65 (d), 118.75 (t), 111.76 (d), 110.86
(d), 108.18 (d), 55.93 (q), 48.78 (s), 42.54 (t), 26.29 (q), 22.88 (q).
EIMS m/z (%):232 (M++1, 60%), 231 (M+, 50%), 216 (32), 204
(30), 191 (73), 189 (82), 175 (71), 161 (73), 145 (75), 132 (88),
117 (91), 104 (100), 91 (95), 78 (72), 63 (56). HRMS m/z Found:
231.1263, Calcd. for C14H17NO2 (M)+: 231.1259.
General
Proton nuclear magnetic resonance (1H-NMR) spectra were
recorded on a Bruker Avance 300 spectrometer at 300 MHz.
Carbon-13 nuclear magnetic resonance (13C-NMR) was recorded
on a Bruker Avance 300 spectrometer at 75 MHz. Chemical shifts
are reported as d values in parts per million (ppm) relative to
tetramethylsilane (TMS) for all recorded NMR spectra. Low-
resolution Mass spectra were recorded on a VG Auto Spec-
3000 magnetic sector MS spectrometer. High Resolution Mass
spectra were taken on an AB QSTAR Pulsar mass spectrometer.
Starting materials and reagents used in reactions were obtained
commercially from Acros, Aldrich, Fluka and were used without
purification, unless otherwise indicated. THF and diethyl ether
used in the reactions were dried by distillation over metallic
sodium and benzophenone; dichloromethane were distilled over
P2O5. Silica gel (Qingdao, 300–400 mesh) was used for column
chromatography.
◦
Compound 7c. Yield 90%, Pale yellow plate, m.p.: 90–91 C,
Rf 0.53 (Petroleum ether/EtOAc = 15 : 1). IR (nmax cm-1): 3394 (w),
3073 (w), 3023 (w), 2918 (w), 1959 (w), 1704 (s), 1603 (m), 1483
(m), 1439 (w), 1356 (m), 1302 (w), 1183 (m), 1079 (w), 1025 (w), 995
(w), 921 (m), 884 (w), 811 (w), 751 (m), 699 (m), 651 (w). 1H-NMR
(300 MHz, CDCl3), d (ppm): 7.39 (2H, dd, J = 1.7, 7.0 Hz), 7.31–
7.18 (9H, m), 7.17 (1H, d, J = 7.7 Hz), 7.05 (1H, t, J = 7.5 Hz), 6.74
(1H, d, J = 7.7 Hz), 5.51–5.32 (1H, m), 5.07 (1H, d, J = 17.0 Hz),
4.95 (1H, d, J = 15.7 Hz), 4.93 (1H, d, J = 10.0 Hz), 4.82 (1H,
d, J = 15.7 Hz), 3.20–3.02 (2H, m). 13C-NMR (75 MHz, CDCl3),
d (ppm): 178.16 (s), 143.10 (s), 139.86 (s), 136.00 (s), 132.59 (d),
131.88 (s), 128.76 (d), 128.72 (d), 128.23 (d), 127.64 (d), 127.46
(d), 127.14 (d), 125.25 (d), 122.61 (d), 119.51 (t), 109.43 (d), 56.52
(s), 44.03 (t), 42.06 (t). EIMS m/z (%):340 (M++1, 52%), 339 (M+,
76%), 310 (11), 299 (86), 298 (98), 280 (13), 270 (54), 268 (26), 254
(8), 248 (13), 233 (12), 230 (13), 220 (28), 208 (46), 193 (37), 179
(67), 165 (70), 152 (48), 139 (21), 128 (33), 115 (43), 103 (20), 91
General procedure for palladium catalyzed arylation–allylation of
bromoanilides
A mixture of tris(dibenzylideneacetone)dipalladium [Pd2(dba)3,
FW 915.72, 13.7 mg, 0.015 mmol, 0.03 eq.] and triphenylphos-
phine (FW 262.29, 7.9 mg, 0.03 mmol, 0.06 eq.) in anhydrous
tetrahydrofuran (5 mL) was degassed and purged with nitrogen
(3 times). A solution of lithium bis(trimethylsilyl)amide (1.0 M
in THF, 0.75 mL, 0.75 mmol, 1.5 eq.) was added followed by
addition of a solution of bromoanilides (0.5 mmol) in anhydrous
tetrahydrofuran (5 mL). The resulting mixture was then stirred
at 75 ◦C (oil bath) under nitrogen for 4–6 h. The reaction was
monitored by thin layer chromatography (TLC). After cooling to
room temperature, a solution of lithium bis(trimethylsilyl)amide
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(100), 77 (43), 65 (72). HRMS m/z Found: 339.1626, Calcd. for
872 (w), 806 (w), 731 (w), 690 (w). 1H-NMR (300 MHz, CDCl3),
d (ppm): 7.41–7.20 (5H, m), 6.87 (1H, s), 6.85 (1H, dd, J = 2.4,
7.8 Hz), 6.79 (1H, d, J = 7.8 Hz), 5.47–5.30 (1H, m), 5.04 (1H,
d, J = 17.0 Hz), 4.92 (1H, dd, J = 0.76, 10.1 Hz), 3.78 (3H, s),
3.17 (3H, s), 3.01 (2H, d, J = 7.1 Hz). 13C-NMR (75 MHz, CDCl3)
d (ppm): 177.75 (s), 155.99 (s), 139.59 (s), 137.54 (s), 133.17 (s),
132.51 (d), 128.64 (d), 127.43 (d), 127.12 (d), 119.28 (t), 112.76
(d), 112.47 (d), 108.51 (d), 56.91 (s), 55.90 (q), 41.94 (t), 26.51 (q).
EIMS m/z (%):294 (M++1, 52%), 293 (M+, 100%), 277 (13), 264
(22), 253 (89), 252 (78), 234 (34), 223 (36), 208 (78), 193 (61), 178
(62), 167 (76), 154 (83), 140 (90), 128 (72), 115 (100), 103 (50),
91 (89), 77 (85), 66 (84). HRMS m/z Found: 293.1420, Calcd. for
C19H19NO2 (M)+: 293.1416.
C24H21NO (M)+: 339.1623.
Compound 7d. Yield 79%, Yellow oil, Rf 0.60 (Petroleum
ether/EtOAc = 5 : 1). IR (nmax cm-1): 3425 (w), 3065 (w), 2968
(w), 2927 (w), 1712 (s), 1610 (m), 1480 (m), 1463 (m), 1364 (m),
1313 (w), 1252 (w), 1124 (w), 1090 (w), 1025 (w), 921 (m), 751
(m), 698 (w). 1H-NMR (300 MHz, CDCl3), d (ppm): 7.26 (1H, t,
J = 7.6 Hz), 7.19 (1H, d, J = 7.5 Hz), 7.05 (1H, t, J = 7.5 Hz),
6.83 (1H, d, J = 7.6 Hz), 5.52–5.34 (1H, m), 4.98 (1H, d, J =
17.0 Hz), 4.91 (1H, d, J = 10.1 Hz), 3.20 (3H, s), 2.60–2.42 (2H,
m), 1.37 (3H, s). 13C-NMR (75 MHz, CDCl3), d (ppm): 180.22
(s), 143.24 (s), 133.67 (s), 132.65 (d), 127.82 (d), 122.93 (d), 122.40
(d), 118.66 (t), 107.96 (d), 48.29 (s), 42.52 (t), 26.15 (q), 22.79 (q).
EIMS m/z (%):202 (M++1, 5%), 201 (M+, 8%), 169 (17), 160 (27),
156 (100), 155 (36), 145 (10), 128 (27), 115 (17), 91 (26), 83 (23),
77 (21). HRMS m/z Found: 201.1156, Calcd. for C13H15NO (M)+:
201.1154.
Compound 7h. Yield 30%, Colorless oil, Rf 0.52 (Petroleum
ether/EtOAc = 5 : 1). IR (nmax cm-1): 3444 (w), 2961 (m), 2354 (w),
1706 (s), 1601 (w), 1495 (s), 1465 (s), 1364 (m), 1285 (m), 1233 (w),
1169 (w), 1124 (w), 1035 (m), 992 (w), 919 (w), 869 (w), 806 (w).
1H-NMR (300 MHz, CDCl3), d (ppm): 6.80 (1H, d, J = 2.3 Hz),
6.76 (1H, dd, J = 2.3, 8.3 Hz), 6.68 (1H, d, J = 8.3 Hz), 5.38–5.20
(1H, m), 4.92 (1H, d, J = 17.0 Hz), 4.79 (1H, d, J = 10.1 Hz), 3.78
(3H, s), 3.13 (3H, s), 2.57 (2H, d, J = 7.2 Hz), 2.16 (1H, sep, J =
6.9 Hz), 0.94 (3H, d, J = 6.9 Hz), 0.72 (3H, d, J = 6.9 Hz). 13C-
NMR (75 MHz, CDCl3), d (ppm): 179.05 (s), 155.68 (s), 137.99
(s), 132.96 (d), 132.43 (s), 118.29 (t), 111.86 (d), 111.36 (d), 107.70
(d), 56.73 (s), 55.84 (q), 39.68 (t), 34.83 (d), 25.94 (q), 17.45 (q),
17.25 (q). EIMS m/z (%):260 (M+, 63%), 259 (48), 219 (47), 216
(73), 203 (48), 202 (40), 190 (46), 188 (52), 174 (46), 160 (38), 144
(55), 131 (58), 130 (56), 117 (82), 115 (100), 103 (79), 91 (88), 77
(74). HRMS m/z Found: 259.1576, Calcd. for C16H21NO2 (M)+:
259.1572.
Compound 7e. Yield 54%, Pale yellow syrup, Rf 0.58
(Petroleum ether/EtOAc = 20 : 1). IR (nmax cm-1): 3444 (w), 3065
(w), 2926 (m), 2862 (w), 1712 (s), 1609 (m), 1479 (m), 1355 (m),
1174 (w), 1084 (w), 996 (w), 920 (w), 745 (m), 699 (w). 1H-NMR
(300 MHz, CDCl3), d (ppm): 7.38–7.20 (5H, m), 7.17 (1H, d, J =
7.1 Hz), 7.12 (1H, dd, J = 1.2, 7.6 Hz), 7.02 (1H, t, J = 7.1 Hz), 6.69
(1H, d, J = 7.6 Hz), 5.50–5.31 (1H, m), 5.01 (1H, d, J = 14.9 Hz),
4.90 (1H, d, J = 14.9 Hz), 4.89 (1H, d, J = 11.3 Hz), 4.85 (1H,
d, J = 15.6 Hz), 2.62–2.49 (2H, m), 1.97 (1H, ddd, J = 4.6, 13.0,
13.1 Hz), 1.80 (1H, ddd, J = 4.2, 13.0, 13.1 Hz), 1.30–1.12 (2H, m),
1.12–0.75 (2H, m), 0.77 (3H, t, J = 7.2 Hz). 13C-NMR (75 MHz,
CDCl3), d (ppm): 179.72 (s), 143.19 (s), 136.24 (s), 132.71 (d),
132.12 (s), 128.72 (d), 127.70 (d), 127.58 (d), 127.52 (d), 123.15
(d), 122.40 (d), 118.76 (t), 108.97 (d), 53.02 (s), 43.77 (t), 42.49 (t),
37.34 (t), 26.57 (t), 22.97 (t), 13.92 (q). EIMS m/z (%):320 (M++1,
55%), 319 (M+, 89%), 279 (71), 278 (99), 263 (53), 250 (16), 236
(36), 222 (42), 206 (19), 186 (12), 172 (22), 158 (29), 145 (19), 132
(34), 130 (38), 115 (32), 103 (16), 91 (100), 77 (33). HRMS m/z
Found: 319.1937, Calcd. for C22H25NO (M)+: 319.1936.
Compound 7i. Yield 51%, Pale yellow syrup, Rf 0.51
(Petroleum ether/EtOAc = 5 : 1). IR (nmax cm-1): 3028 (w), 2966
(w), 2921 (w), 2356 (w), 1712 (s), 1609 (m), 1481 (m), 1461 (m),
1367 (m), 1343 (m), 1250 (w), 1111 (w), 1023 (w), 969 (w), 927 (w),
748 (m), 695 (w). 1H-NMR (300 MHz, CDCl3), d (ppm): 7.30–7.11
(7H, m), 7.06 (1H, t, J = 7.5 Hz), 6.81 (1H, d, J = 7.7 Hz), 6.34
(1H, d, J = 15.7 Hz), 5.88 (1H, dt, J = 7.6, 15.7 Hz), 3.17 (3H, s),
2.64 (2H, d, J = 7.6 Hz), 1.41 (3H, s). 13C-NMR (75 MHz, CDCl3),
d (ppm): 180.27 (s), 143.24 (s), 137.36 (s), 133.79 (d), 133.68 (s),
128.50 (d), 127.94 (d), 127.28 (d), 126.25 (d), 124.31 (d), 123.04
(d), 122.48 (d), 108.08 (d), 48.71 (s), 41.75 (t), 26.24 (q), 22.64 (q).
EIMS m/z (%):278 (M++1, 59%), 277 (M+, 92%), 262 (6), 232 (7),
217 (11), 202 (12), 189 (7), 174 (10), 161 (80), 160 (96), 145 (48),
132 (70), 130 (83), 118 (93), 117 (98), 115 (100), 103 (50), 91 (100),
89 (50), 77 (79), 65 (50). HRMS m/z Found: 277.1469, Calcd. for
C19H19NO (M)+: 277.1467.
Compound 7f. Yield 41%, Colorless oil, Rf 0.59 (Petroleum
ether/EtOAc = 4 : 1). IR (nmax cm-1): 3437 (m), 2927 (m), 2858
(w), 2353 (w), 1708 (s), 1606 (m), 1494 (m), 1462 (m), 1364 (w),
1285 (w), 1227 (w), 1116 (w), 1035 (m), 917 (w), 802 (w). 1H-NMR
(300 MHz, CDCl3), d (ppm): 6.80–6.72 (2H, m), 6.70 (1H, d, J =
8.3 Hz), 5.48–5.30 (1H, m), 4.96 (1H, d, J = 17.0 Hz), 4.87 (1H,
dt, J = 1.0, 10.1 Hz), 3.79 (3H, s), 3.16 (3H, s), 2.58–2.40 (2H, m),
1.88 (1H, ddd, J = 4.7, 12.5, 12.6 Hz), 1.71 (1H, ddd, J = 4.5, 12.5,
12.6 Hz), 1.23–1.08 (2H, m), 0.99–0.76 (2H, m), 0.75 (3H, t, J =
7.3 Hz). 13C-NMR (75 MHz, CDCl3), d (ppm): 179.32 (s), 155.98
(s), 137.65 (s), 133.63 (s), 132.55 (d), 118.59 (t), 111.49 (d), 110.97
(d), 107.96 (d), 55.88 (q), 53.45 (s), 42.30 (t), 37.06 (t), 26.39 (t),
26.17 (q), 22.94 (t), 13.91 (q). EIMS m/z (%):274 (M++1, 48%),
273 (M+, 90%), 256 (5), 242 (23), 232 (100), 217 (23), 204 (40),
190 (83), 176 (82), 174 (68), 162 (16), 160 (15), 146 (17), 131 (12),
115 (17), 99 (13), 91 (16), 85 (30), 71 (40). HRMS m/z Found:
273.1732, Calcd. for C17H23NO2 (M)+: 273.1729.
Compound 7j. Yield 75%, Yellow plate, mp: 139–140 ◦C, Rf
0.58 (Petroleum ether/EtOAc = 3 : 1). IR (nmax cm-1): 3401 (w),
3049 (w), 3002 (w), 2926 (w), 2884 (w), 2354 (w), 1708 (s), 1607
(m), 1539 (w), 1476 (m), 1424 (w), 1342 (m), 1252 (m), 1204 (w),
1132 (w), 1084 (m), 1008 (m), 927 (m), 886 (w), 809 (w), 751 (s),
675 (m). 1H-NMR (300 MHz, CDCl3), d (ppm): 7.30 (1H, t, J =
7.5 Hz), 7.22–6.86 (8H, m), 5.55–5.38 (1H, m), 5.04 (1H, d, J =
17.0 Hz), 4.91 (1H, dt, J = 1.2, 10.1 Hz), 3.65 (3H, s), 3.21 (3H, s),
3.20–3.04 (2H, m). 13C-NMR (75 MHz, CDCl3), d (ppm): 178.29
(s), 143.82 (s), 137.61 (s), 132.46 (d), 132.45 (s), 128.16 (d), 127.54
(d), 125.98 (s), 124.56 (d), 122.51 (d), 121.74 (d), 120.56 (d), 119.23
Compound 7g. Yield 93%, Pale yellow syrup, Rf 0.60
(Petroleum ether/EtOAc = 3 : 1). IR (nmax cm-1): 3470 (w), 3068
(w), 2941 (w), 2835 (w), 1708 (s), 1601 (m), 1495 (s), 1462 (m),
1356 (m), 1285 (m), 1231 (w), 1151 (w), 1034 (m), 992 (w), 921 (w),
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(d), 119.01 (t), 113.41 (s), 109.38 (d), 108.00 (d), 52.52 (s), 40.87 (t),
32.78 (q), 26.33 (q). EIMS m/z (%):317 (M++1, 40%), 316 (M+,
73%), 305 (47), 290 (19), 275 (100), 259 (31), 247 (53), 245 (45), 232
(68), 218 (50), 204 (55), 190 (46), 176 (30), 165 (22), 158 (33), 144
(27), 137 (97), 131 (68), 130 (62), 123 (43), 115 (47), 109 (35), 102
(46), 91 (30). HRMS m/z Found: 316.1579, Calcd. for C21H20N2O
(M)+: 316.1576.
(31), 315 (29), 275 (49), 250 (51), 235 (53), 179 (85), 165 (88), 152
(63), 135 (42), 121 (87), 104 (45), 92 (84), 77 (56), 65 (100). HRMS
m/z Found: 383.1890, Calcd. for C26H25NO2 (M)+: 383.1885.
General procedure for oxidative cleavage of double bond12
To a mixture of olefin 7b or 7f–7h (0.52 mmol) in 1,4-dioxane-H2O
(8 mL, 3 : 1) was added osmium tetroxide (5.3 mg, 0.021 mmol,
0.04 eq.), 2,6-lutidine (0.12 mL, 1.04 mmol, 2.0 eq.) and sodium
periodate (NaIO4, 556 mg, 2.60 mmol, 5.0 eq.). The resulting
mixture was stirred at room temperature. The reaction progress
was monitored by thin layer chromatography. Aqueous saturated
sodium sulfite (5 mL) was added. The reaction mixture was diluted
with water (50 mL) and extracted with ethyl acetate (3 ¥ 15 mL).
The organic phases were combined and washed with brine (10 mL)
and dried over anhydrous sodium sulfate. After removal of the
solvent, the residue was chromatographed on silica gel (Petroleum
ether 60–90 ◦C/ethyl acetate = 4 : 1–2 : 1) to afford the products.
Compound 11a. Yield 28%, Pale yellow syrup, Rf 0.48
(Petroleum ether/EtOAc = 5 : 1). IR (nmax cm-1): 3446 (w), 3069
(w), 3027 (w), 2974 (w), 2925 (w), 1712 (w), 1644 (s), 1489 (m),
1442 (m), 1352 (m), 1305 (w), 1214 (w), 1163 (w), 1082 (w), 996
1
(w), 920 (w), 758 (m), 706 (m). H-NMR (300 MHz, CDCl3), d
(ppm): 7.40–7.22 (7H, m), 7.18 (1H, td, J = 1.6, 7.6 Hz), 7.02 (1H,
d, J = 7.6 Hz), 5.53–5.32 (1H, m), 4.95 (1H, d, J = 16.5 Hz), 4.91
(1H, d, J = 10.2 Hz), 4.90 (1H, d, J = 14.6 Hz), 4.63 (1H, d, J =
14.6 Hz), 4.45 (1H, d, J = 16.1 Hz), 4.30 (1H, d, J = 16.1 Hz), 2.81
(1H, dd, J = 7.2, 13.6 Hz), 2.47 (1H, dd, J = 7.2, 13.6 Hz), 1.61
(3H, s). 13C-NMR (75 MHz, CDCl3), d (ppm): 173.01 (s), 139.27
(s), 137.02 (s), 133.82 (d), 130.38 (s), 128.75 (d), 128.25 (d), 127.60
(d), 126.42 (d), 126.12 (d), 125.35 (d), 118.32 (t), 50.76 (t), 49.64 (t),
46.07 (t), 45.08 (s), 25.21 (q). EIMS m/z (%):292 (M++1, 80%),
291 (M+, 96%), 276 (68), 264 (27), 250 (94), 236 (40), 222 (96),
206 (12), 200 (41), 186 (44), 172 (58), 158 (90), 143 (85), 130 (86),
115 (92), 103 (78), 91 (99), 77 (84), 65 (100). HRMS m/z Found:
291.1624, Calcd. for C20H21NO (M)+: 291.1623.
Compound 12. Yield 85%, White plate, mp: 96–97 ◦C, Rf 0.45
(Petroleum ether/EtOAc = 2 : 1). IR (nmax cm-1): 3416 (w), 2963
(m), 2933 (m), 2872 (m), 2757 (w), 1707 (s), 1604 (m), 1498 (s),
1383 (m), 1335 (w), 1291 (s), 1226 (s), 1184 (w), 1125 (m), 1033 (m),
1
909 (w), 867 (w), 804 (s), 747 (w), 703 (w). H-NMR (300 MHz,
CDCl3), d (ppm): 9.50 (1H, d, J = 1.1 Hz), 6.81–6.75 (3H, m),
3.77 (3H, s), 3.22 (3H, s), 2.98 (1H, d, J = 17.3 Hz), 2.90 (1H, d,
J = 17.3 Hz), 1.39 (3H, s). 13C-NMR (75 MHz, CDCl3), d (ppm):
198.82 (d), 179.26 (s), 156.26 (s), 136.82 (s), 134.27 (s), 112.29 (d),
110.49 (d), 108.75 (d), 55.91 (q), 50.67 (t), 45.51 (s), 26.60 (q),
24.09 (q). EIMS m/z (%):234 (M++1, 32%), 233 (M+, 95%), 218
(11), 205 (55), 204 (100), 190 (94), 175 (40), 174 (29), 162 (23),
147 (34), 146 (18), 132 (16), 118 (27), 103 (9), 91 (16). HRMS m/z
Found: 233.1056, Calcd. for C13H15NO3 (M)+: 233.1052.
Compound 11b. Yield 60%, Colorless oil, Rf 0.52 (Petroleum
ether/EtOAc = 6 : 1). IR (nmax cm-1): 3444 (w), 3066 (w), 3019 (w),
2921 (w), 2847 (w), 2354 (w), 1649 (s), 1486 (m), 1439 (m), 1349
(w), 1272 (m), 1202 (w), 1077 (w), 995 (w), 917 (w), 754 (m), 704
(m). 1H-NMR (300 MHz, CDCl3), d (ppm): 7.35–7.11 (11H, m),
7.10–7.02 (3H, m), 5.73–5.56 (1H, m), 5.13 (1H, d, J = 17.2 Hz),
4.99 (1H, d, J = 10.2 Hz), 4.77 (1H, d, J = 15.9 Hz), 4.72 (1H, d,
J = 15.9 Hz), 4.14 (2H, s), 3.64 (1H, dd, J = 6.1, 14.4 Hz), 2.98
(1H, dd, J = 6.5, 14.4 Hz). 13C-NMR (75 MHz, CDCl3), d (ppm):
171.30 (s), 143.14 (s), 137.78 (s), 136.85 (s), 135.22 (d), 132.78 (s),
128.65 (d), 128.55 (d), 128.40 (d), 128.09 (d), 127.51 (d), 127.24
(d), 126.98 (d), 126.78 (d), 125.36 (d), 117.93 (t), 55.13 (s), 50.85
(t), 49.49 (t), 42.61 (t). EIMS m/z (%):354 (M++1, 34%), 353 (M+,
51%), 337 (7), 326 (12), 312 (30), 297 (10), 284 (52), 262 (36),
249 (21), 234 (30), 217 (26), 205 (36), 192 (39), 179 (42), 165 (35),
152(56), 142 (40), 127 (46), 117 (48), 105 (93), 104 (84), 92 (74), 77
(100), 65 (97). HRMS m/z Found: 353.1783, Calcd. for C25H23NO
(M)+: 353.1780.
Compound 13a (R = n-Butyl). Yield 75%, Pale yellow oil, Rf
0.41 (Petroleum ether/EtOAc = 4 : 1). IR (nmax cm-1): 2944 (w),
2864 (w), 2733 (w), 2356 (w), 1708 (s), 1601 (w), 1494 (m), 1462
(m), 1366 (w), 1287 (m), 1232 (w), 1168 (w), 1121 (w), 1035 (m),
918 (w), 882 (w), 808 (m), 755 (w), 698 (w). 1H-NMR (300 MHz,
CDCl3), d (ppm): 9.43 (1H, d, J = 1.3 Hz), 6.82–6.70 (3H, m), 3.75
(3H, s), 3.21 (3H, s), 2.95 (1H, d, J = 17.3 Hz), 2.87 (1H, d, J =
17.3 Hz), 1.94–1.68 (2H, m), 1.20–1.08 (2H, m), 1.08–0.70 (2H,
m), 0.74 (3H, t, J = 7.2 Hz). 13C-NMR (75 MHz, CDCl3), d (ppm):
198.90 (d), 178.67 (s), 156.13 (s), 137.54 (s), 132.59 (s), 112.01 (d),
110.64 (d), 108.48 (d), 55.80 (q), 50.42 (t), 49.65 (s), 37.70 (t), 26.43
(q), 25.55 (t), 22.71 (t), 13.82 (q). EIMS m/z (%):276 (M++1, 8%),
275 (M+, 33%), 246 (67), 233 (20), 218 (9), 204 (44), 190 (100), 174
(27), 147 (8), 118 (6), 91 (7). HRMS m/z Found: 275.1518, Calcd.
for C16H21NO3 (M)+: 275.1521.
Compound 11c. Yield 45%, Pale yellow syrup, Rf 0.59
(Petroleum ether/EtOAc = 8 : 1). IR (nmax cm-1): 3471 (w), 3068
(w), 3019 (w), 2926 (w), 2843 (w), 1648 (s), 1504 (m), 1442 (m),
1352 (w), 1250 (m), 1183 (m), 1118 (w), 1033 (m), 917 (w), 827
Compound 13b (R = i-Propyl). Yield 78%, Colorless oil, Rf 0.38
(Petroleum ether/EtOAc = 4 : 1). IR (nmax cm-1): 3440 (s), 2956 (m),
2913 (m), 2839 (w), 2729 (w), 1705 (s), 1607 (m), 1495 (m), 1459
(m), 1373 (m), 1287 (m), 1124 (w), 1036 (m), 919 (w), 803 (w),
739 (w). 1H-NMR (300 MHz, CDCl3), d (ppm): 9.39 (1H, d, J =
1.4 Hz), 6.86–6.68 (3H, m), 3.76 (3H, s), 3.20 (3H, m), 2.99 (2H,
s), 2.20–2.02 (1H, m), 0.94 (3H, d, J = 6.9 Hz), 0.69 (3H, d, J =
6.7 Hz). 13C-NMR (75 MHz, CDCl3), d (ppm): 199.12 (d), 178.65
(s), 155.84 (s), 137.99 (s), 131.20 (s), 111.95 (d), 111.65 (d), 108.26
(d), 55.81 (q), 52.75 (s), 48.61 (t), 35.28 (d), 26.29 (q), 16.98 (q),
16.81 (q). EIMS m/z (%):262 (M++1, 99%), 261 (M+, 78%), 246
1
(w), 751 (m), 705 (m). H-NMR (300 MHz, CDCl3), d (ppm):
7.38–7.13 (8H, m), 7.06 (1H, d, J = 7.2 Hz), 6.98 (2H, d, J =
7.8 Hz), 6.74 (2H, d, J = 7.8 Hz), 5.73–5.52 (1H, m), 5.12 (1H, d,
J = 17.2 Hz), 4.97 (1H, d, J = 10.2 Hz), 4.74 (2H, s), 4.15 (2H, s),
3.74 (3H, s), 3.61 (1H, dd, J = 6.1, 14.4 Hz), 2.94 (1H, dd, J = 7.1,
14.4 Hz). 13C-NMR (75 MHz, CDCl3), d (ppm): 171.50 (s), 158.48
(s), 137.98 (s), 136.90 (s), 135.30 (d), 132.72 (s), 128.66 (d), 128.65
(s), 128.47 (d), 128.37 (d), 128.09 (d), 127.49 (d), 126.72 (d), 125.33
(d), 117.86 (t), 113.72 (d), 55.30 (q), 54.42 (s), 50.84 (t), 49.48 (t),
42.73 (t). EIMS m/z (%):384 (M++1, 19%), 383 (M+, 23%), 342
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(16), 233 (62), 232 (95), 218 (93), 204 (36), 191 (100), 190 (62),
174 (95), 160 (40), 159 (38), 147 (41), 146 (37), 131 (26), 130 (26),
118 (39), 117 (43), 103 (26), 102 (19), 91 (43). HRMS m/z Found:
261.1373, Calcd. for C15H19NO3 (M)+: 261.1365.
153.31 (s), 147.28 (s), 136.53 (s), 112.36 (d), 110.36 (d), 107.73 (d),
95.07 (d), 57.49 (s), 56.15 (q), 52.58 (t), 39.87 (t), 39.74 (t), 38.06
(q), 37.31 (q), 28.12 (t), 23.23 (t), 14.08 (q). EIMS m/z (%):275
(M++1, 66%), 274 (M+, 85%), 259 (51), 245 (43), 230 (78), 217
(67), 203 (58), 188 (70), 174 (100), 159 (69), 145 (43), 144 (52), 131
(68), 130 (46), 115 (55), 101 (43), 96 (34), 85 (77). HRMS m/z
Found: 274.2050, Calcd. for C17H26N2O (M)+: 274.2045.
Compound 13c (R = Phenyl). Yield 83%, Colorless oil, Rf 0.32
(Petroleum ether/EtOAc = 3 : 1). IR (nmax cm-1): 3429 (w), 2926
(w), 2835 (w), 2729 (w), 1712 (s), 1601 (w), 1496 (m), 1458 (w),
1358 (w), 1285 (w), 1231 (w), 1165 (w), 1111 (w), 1035 (m), 927
Compound 15. Yield 41%, pale yellow plate, mp: 55–56 ◦C, Rf
0.35 (CH2Cl2/CH3OH = 15 : 1). IR (nmax cm-1): 3439 (s), 2923 (m),
2855 (w), 2351 (w), 1634 (m), 1491 (m), 1450 (m), 1379 (m), 1286
(w), 1216 (w), 1090 (m), 1037 (m), 915 (w). 1H-NMR (300 MHz,
CDCl3), d (ppm): 6.75 (1H, dd, J = 2.5, 8.5 Hz), 6.67 (1H, d,
J = 2.5 Hz), 6.49 (1H, d, J = 8.5 Hz), 4.79 (1H, brs), 3.76 (3H,
s), 3.38–3.30 (1H, m), 3.01 (3H, s), 2.67 (3H, s), 2.61–2.38 (2H,
m), 2.23–2.03 (2H, m), 0.97 (3H, d, J = 6.9 Hz), 0.72 (3H, d, J =
6.7 Hz). 13C-NMR (75 MHz, CDCl3), d (ppm): 152.02 (s), 143.64
(s), 130.04 (s), 111.21 (d), 108.98 (d), 106.56 (d), 91.76 (d), 59.93
(s), 53.81 (q), 50.91 (t), 35.32 (q), 33.92 (t), 33.41 (d), 32.40 (q),
16.36 (q), 15.93 (q). EIMS m/z (%):261 (M++1, 24%), 260 (M+,
100%), 245 (13), 231 (5), 217 (60), 216 (23), 202 (38), 188 (32), 187
(15), 174 (68), 160 (15), 144 (9), 131 (15), 115 (6), 102 (4). HRMS
m/z Found: 260.1890, Calcd. for C16H24N2O (M)+: 260.1889.
1
(w), 808 (w), 730 (w), 700 (w). H-NMR (300 MHz, CDCl3), d
(ppm): 9.52 (1H, s), 7.40–7.20 (5H, m), 6.91–6.75 (3H, m), 3.77
(3H, s), 3.43 (1H, d, J = 17.3 Hz), 3.34 (1H, d, J = 17.3 Hz), 3.23
(3H, s). 13C-NMR (75 MHz, CDCl3), d (ppm): 198.57 (d), 177.40
(s), 156.22 (s), 138.76 (s), 137.52 (s), 132.49 (s), 128.93 (d), 127.82
(d), 126.62 (d), 112.87 (d), 112.32 (d), 109.07 (d), 55.86 (q), 53.13
(s), 50.55 (t), 26.85 (q). EIMS m/z (%):296 (M++1, 15%), 295 (M+,
73%), 267 (24), 266 (100), 252 (51), 237 (8), 209 (14), 190 (13), 180
(8), 165 (3), 153 (2), 126 (1), 115 (1), 91 (2). HRMS m/z Found:
295.1203, Calcd. for C18H17NO3 (M)+: 295.1208.
General procedure for reductive aminocyclization
To a solution of aldehyde 12 or 13 (0.43 mmol), triethylamine
(435 mg, 4.3 mmol, 10 eq.) and MeNH2–HCl (291 mg, 4.3 mmol,
10 eq.) in anhydrous THF (10 ml) was added a powder of MgSO4
(361 mg, 3.0 mmol). The resulting mixture was stirred at room
temperature for 12–15 h. A powder of lithium aluminum hydride
(163 mg, 4.3 mmol, 10 eq.) was added and the resulting mixture
was stirred at reflux for 2–3 h. After cooling to room temperature,
ethyl acetate (20 mL) was added followed by saturated aqueous
sodium bicarbonate (20 mL). The mixture was then extracted with
ethyl acetate (3 ¥ 10 mL). The organic phases were combined and
dried over anhydrous sodium sulfate. After filtration and removal
of the solvent, the residue was chromatographed on silica gel
(dichloromethane/methanol = 40 : 1–10 : 1) to afford the products.
Compound 16. Yield 40%, Brown syrups, Rf 0.48
(CH2Cl2/CH3OH = 40 : 1). IR (nmax cm-1): 3427 (w), 2928
(m), 2859 (w), 2355 (w), 1663 (m), 1499 (s), 1454 (m), 1280 (m),
1219 (m), 1149 (w), 1106 (w), 1034 (m), 923 (w), 860 (w), 806
1
(w), 765 (w), 704 (m). H-NMR (300 MHz, CDCl3), d (ppm):
7.35–7.12 (5H, m), 6.69 (1H, dd, J = 2.5, 8.5 Hz), 6.54 (1H, d,
J = 2.5 Hz), 6.43 (1H, d, J = 8.5 Hz), 4.46 (1H, s), 3.70 (3H,
s), 2.95 (3H, s), 2.98–2.70 (3H, m), 2.53 (3H, s), 2.35–2.25 (1H,
m). 13C-NMR (75 MHz, CDCl3), d (ppm): 153.17 (s), 147.05 (s),
146.63 (s), 136.64 (s), 128.52 (d), 126.70 (d), 126.34 (d), 113.07
(d), 111.78 (d), 107.80 (d), 99.19 (d), 61.71 (s), 56.14 (q), 53.49 (t),
39.86 (t), 38.29 (q), 37.42 (q). EIMS m/z (%):295 (M++1, 52%),
294 (M+, 100%), 279 (33), 264 (20), 250 (92), 237 (50), 236 (54),
222 (65), 207 (37), 194 (31), 191 (21), 174 (42), 165 (18), 147 (19),
139 (19), 131 (12), 115 (13), 105 (12), 91 (17), 77 (16). HRMS m/z
Found: 294.1725, Calcd. for C19H22N2O (M)+: 294.1732.
◦
Esermethole. Yield 70%, Pale yellow plate, mp: 51–52 C, Rf
0.51 (CH2Cl2/CH3OH = 20 : 1). IR (nmax cm-1): 3444 (m), 2945 (m),
2862 (w), 2786 (w), 2354 (w), 2320 (w), 1677 (m), 1494 (s), 1454
(m), 1382 (w), 1286 (m), 1213 (s), 1173 (w), 1119 (m), 1031 (s), 959
(w), 866 (w), 804 (w). 1H-NMR (300 MHz, CDCl3), d (ppm): 6.63
(1H, dd, J = 2.4, 8.0 Hz), 6.64 (1H, d, J = 2.4 Hz), 6.34 (1H, d, J =
8.0 Hz), 4.06 (1H, s), 3.72 (3H, s), 2.87 (3H, s), 2.80–2.54 (2H, m),
2.52 (3H, s), 1.98–1.90 (2H, m), 1.42 (3H, s). 13C-NMR (75 MHz,
CDCl3), d (ppm): 153.97 (s), 146.43 (s), 138.12 (s), 112.16 (d),
109.70 (d), 107.50 (d), 98.20 (d), 55.90 (q), 53.12 (t), 52.73 (s),
40.72 (t), 38.00 (q), 38.00 (d), 27.37 (q). EIMS m/z (%):232 (M+,
78%), 218 (81), 203 (43), 190 (55), 188 (85), 174 (100), 160 (76),
146 (33), 131 (30), 117 (21), 96 (21), 77 (15). HRMS m/z Found:
232.1575, Calcd. for C14H20N2O (M)+: 232.1576.
Acknowledgements
This work was supported by grants (20832005, 20925205) from
the Natural Science Foundation of China, the National Basic
Research Program of China (973 Program 2009CB522300) and
the Natural Science Foundation of Yunnan Provincial Science &
Technology Department (2010GA014).
Compound 14. Yield 50%, Yellow syrups, Rf 0.45
(CH2Cl/CH3OH = 40 : 1). IR (nmax cm-1): 3471 (w), 2928
(m), 2861 (w), 1715 (w), 1677 (w), 1601 (w), 1496 (s), 1459 (m),
1380 (w), 1343 (w), 1279 (m), 1218 (m), 1168 (w), 1119 (m), 1074
Notes and references
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Heterocycles, 2001, 55, 1029; (c) N. H. Greig, X.-F. Pei, T. T. Soncrant,
D. K. Ingram and A. Brossi, Med. Res. Rev., 1995, 15, 3; (d) L. A.
Sorbera and J. Castaner, Drugs Future, 2003, 28, 18.
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Clin. Neuropharmacol., 1993, 16, 61; (b) A. Al-Jafari, M. A. Kamal,
1
(w), 1032 (m), 951 (w), 884 (w), 804 (w). H-NMR (300 MHz,
CDCl3), d (ppm): 6.65 (1H, dd, J = 2.5, 8.4 Hz), 6.59 (1H, d,
J = 2.5 Hz), 6.36 (1H, d, J = 8.4 Hz), 4.22 (1H, s), 3.74 (3H, s),
2.89 (3H, s), 2.80–2.70 (1H, m), 2.61–2.45 (1H, m), 2.52 (3H,
s), 2.12–1.86 (2H, m), 1.84–1.60 (2H, m), 1.35–0.98 (4H, m),
0.83 (3H, t, J = 7.1 Hz). 13C-NMR (75 MHz, CDCl3), d (ppm):
4096 | Org. Biomol. Chem., 2011, 9, 4091–4097
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