Intramolecular chemoselective acylation of a suitably substituted isoindole: Synthesis of (±)-chilenine and (±)-deoxychilenine

Article abstract of DOI:10.1055/s-0030-1260140

Starting from 3,4-dimethoxyhomophthalic anhydride and 6- bromohomopiperonylamine, concise and efficient syntheses of Chilean berberis products chilenine and deoxychilenine have been demonstrated via partially divergent routes by taking advantage of facile air-oxidation of homophthalimide along with intramolecular chemoselective acylation as the key steps. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1260140

2
838
PAPER
Intramolecular Chemoselective Acylation of a Suitably Substituted Isoindole:
Synthesis of (±)-Chilenine and (±)-Deoxychilenine
S
P
ynthesis of
(
±
r
)-Chilen
a
ine and (
±
)
s
-Deoxych
a
ilenine d B. Wakchaure, Narshinha P. Argade*
Division of Organic Chemistry, National Chemical Laboratory (CSIR), Pune 411 008, India
Fax +91(20)25902629; E-mail: np.argade@ncl.res.in
Received 14 May 2011; revised 6 June 2011
trione 7a into 1 utilizing acid-catalyzed (TFA, H SO /
2
4
Abstract: Starting from 3,4-dimethoxyhomophthalic anhydride
and 6-bromohomopiperonylamine, concise and efficient syntheses
of Chilean berberis products chilenine and deoxychilenine have
AcOH, PTSA/xylene), Lewis acid catalyzed (BF ·OEt ,
3
2
AlCl , AuCl , TMSOTf), and thermal cyclization (DMSO
3
3
been demonstrated via partially divergent routes by taking advan- reflux, neat heating 200 °C) conditions were unsuccessful
tage of facile air-oxidation of homophthalimide along with intramo- and always ended up with either the unreacted starting
lecular chemoselective acylation as the key steps.
material or excessive decomposition. The trione 7a on
Key words: homophthalic anhydride, isoindole, chemoselective base-catalyzed regioselective methanolysis provided the
acylation, chilenine, deoxychilenine, total synthesis
ring-contraction product lactamol 8a in 96% yield with
the desired free ester moiety.
Chilenine (1), deoxychilenine (2), and lennoxamine (3)
were isolated, respectively, from Berbelis empetrifolia,
Berbelis actinacantha, and Berbelis darwinii and they
O
O
O
O
O
O
N
N
1
OMe
OMe
OMe
OMe
O HO
O
belong to the isoindolobenzazepine class of alkaloids
2
(
Figure 1). These natural products are biogenetically re-
lated to protoberberines, hence their ring systems are ac-
chilenine (1)
deoxychilenine (2)
3
cessible by oxidation of berberine alkaloids. On the basis
O
O
O
of the important biological properties of the berberine
class of compounds and the intriguing structural features
of these three natural products 1–3, several elegant syn-
thesis of chilenine and lennoxamine have been reported.4
Recently, Honda and Sakamaki have also reported the
first synthesis of deoxychilenine employing a novel palla-
N
OMe
,5
OMe
lennoxamine (3)
4
c
Figure 1 Chilean berberis products
dium-catalyzed intramolecular arylation. In continuance
of our comprehensive studies on cyclic anhydrides and
derivatives to bioactive natural and unnatural products,6 As depicted in Scheme 1, the product 8a was also directly
recently we serendipitously witnessed the facile air oxida- obtained in one step from the corresponding homophthal-
tion of homophthalimides and utilized it for the synthesis imide 6a in 94% yield by utilizing the combination of a
7
of nuevamine and isoindolo-b-carboline. In this context, similar set of reaction conditions. Conversely, the multi-
we herein report the total synthesis of chilenine and deoxy- functional compound 8a under acidic conditions (TFA,
chilenine from 3,4-dimethoxyhomophthalic anhydride via
H SO /AcOH, PTSA/CH Cl ) was very prone to six-
2 4 2 2
partially divergent routes utilizing intramolecular acyl- membered intramolecular dehydrative cyclization and,
8
ation as the decisive step (Scheme 1).
under the basic hydrolytic conditions, it had a propensity
for decarboxylation. Hence all initial attempts to directly
transform the trione 7a and lactamol 8a to chilenine (1)
were not successful.
The reaction of 3,4-dimethoxyhomophthalic anhydride
9,10
(
4)
and homopiperonylamine (5a) in refluxing o-
dichlorobenzene furnished the required homophthalimide
6
a in 78% yield. As expected, the homophthalimide 6a In the second segment of studies, starting from 3,4-
underwent facile air oxidation at an activated benzylic po- dimethoxyhomophthalic anhydride (4) and 6-bromo-
sition and provided the prospective precursor trione 7a in homopiperonylamine (5b), we similarly synthesized the
9
4% yield. In principle the selective Friedel–Crafts-type o-bromotrione 7b and o-bromolactamol 8b in 96% and
intramolecular acylation of trione 7a would provide direct 95% yields, respectively, in order to use lithium–halogen
access to chilenine (1) via a ring-expansion and recycliza- exchange to induce the essential intramolecular cycliza-
tion mechanism. However, all attempts to transform the tions. Again, the trione 7b on treatment with tert-butyl-
lithium in tetrahydrofuran at –78 °C and –100 °C, with or
without hexamethylphosphoramide, underwent instanta-
SYNTHESIS 2011, No. 17, pp 2838–2842
x
x.
x
x
.
2
0
1
1
neous complete decomposition. However, the o-bromo-
lactamol 8b on treatment with tert-butyllithium (2.20
equiv) in tetrahydrofuran at –78 °C underwent intramo-
Advanced online publication: 27.07.2011
DOI: 10.1055/s-0030-1260140; Art ID: Z50711SS
Georg Thieme Verlag Stuttgart · New York
©

PAPER
Synthesis of (±)-Chilenine and (±)-Deoxychilenine
2839
X
X
OMe
O
MeO
O
O
O
N
O
O
O
N
O
O
o-C6H4Cl2
reflux, 3 h
DMSO, O2
r.t., 24 h
+
O
O
NH2
OMe
OMe
X
O
OMe
OMe
O
O
3,4-dimethoxyhomophthalic
5a X = H
5b X = Br
7a X = H 94%
7b X = Br 96%
6
6
a X = H 78%
b X = Br 84%
anhydride (4)
DMSO, MeOH
MeOH, Et3N
r.t., 3 h
Et3N, O2, r.t., 24 h
X
O
N
O
O
O
O
O
N
t-BuLi, THF, HMPA
–78 °C
known
(ref. 4c)
OMe
OMe
OMe
OMe
N
O
HO
O
O
HO
O
30 min (50%)
X = Br)
(
O
MeOOC
OMe
deoxychilenine (2) 96%
chilenine (1) >99% from 10
OMe
8
a X = H 94% from 6a, 96% from 7a
known
Et3SiH, BF3•OEt2
8b X = Br 95% from 6b, 95% from 7b
(
ref. 4c)
TFA, H2O
r.t., 2 h
CH2Cl2, 0 °C
+
H /H2SO4, MeOH
r.t., 8 h
20 min
O
O
O
O
O
Br
O
N
N
t-BuLi, THF
OMe
OMe
OMe
OMe
HMPA, –78 °C
3
0 min
N
O
O
MeO
MeO
MeOOC
98%
O
lennoxamine (3)
O
OMe
1
0 82%
9
OMe
Scheme 1 Synthesis of chilenine and deoxychilenine
lecular chemoselective acylation to form the crucial displacement of the angular OMe group with a hydride
seven-membered benzazepine core and furnished the tar- ion to provide deoxychilenine (2) in 96% yield.
get compound chilenine (1), but in only 15–20% yield to-
gether with a large amount of debrominated staring
material (45% of 8a).
1
In the H NMR spectrum of deoxychilenine (2) the meth-
ine proton appeared as singlet at d = 5.15 ppm and it was
not exchangeable with deuterium, indicating the absence
In the above-mentioned reaction the use of hexameth- of any associated keto–enol tautomerism. The analytical
ylphosphoramide as a co-solvent improved the yield to and spectral data obtained for both chilenine and deoxy-
5–50%. In the conversion of 8b into 1, the instability of chilenine were in agreement with the reported data.1 The
,4f
4
in situ generated oxyanionic species from compound 8b conversions of deoxychilenine (2) into chilenine (1) and
and/or its display of ring-chain tautomerism might plausi- lennoxamine (3) are well known in the literature.4
c
bly have an effect on the efficiency of the intramolecular
In summary, starting with the unsymmetrical cyclic anhy-
acylation reaction. Hence the free tertiary hydroxy group
in compound 8b was transformed into methoxy by treat-
dride we have accomplished five steps total synthesis of
berberis natural products chilenine and deoxychilenine in
ment with excess methanol and concentrated sulfuric acid
decent overall yields via a penultimate-stage common in-
to obtain lactamol methyl ether 9 in quantitative yield.
termediate. In this present approach, the critical tert-bu-
The above-specified hypothesis turned out to be reason-
able and finally treatment of 9 in tetrahydrofuran and hexa-
methylphosphoramide mixture with tert-butyllithium
tyllithium-induced
intramolecular
chemoselective
acylation that delivered the benzazepine core is notewor-
thy.
(
1.10 equiv) induced intramolecular acylation to give the
corresponding desired cyclized product 10 in 82% yield.
Herein the intramolecular chemoselective demethoxyla-
tive acylation to form the seven-membered benzazepine
ring system over the possible nucleophilic substitution of
an angular methoxy group to furnish the corresponding
1
Melting points are uncorrected. H NMR spectra were recorded on
Bruker NMR spectrometers operating at 200 and 400 MHz, respec-
1
3
tively, with TMS as an internal standard. C NMR spectra were re-
corded on the same instruments operating at 50, 100, and 125 MHz.
IR spectra were recorded on a Shimadzu FT-IR spectrophotometer.
six-membered piperidine unit is remarkable. The com- Mass spectra and HRMS were taken on ESIMS mass spectrometer
pound 10 on usual acid-catalyzed hydrolysis furnished and HRMS (ESI), respectively. Column chromatographic separa-
tions used silica gel (60–120 mesh); petroleum ether = PE. Com-
chilenine (1) in quantitative yield, while the same on treat-
ment with triethylsilane underwent Lewis acid catalyzed
mercially available t-BuLi, BF ·OEt , and Et SiH were used.
3
2
3
Synthesis 2011, No. 17, 2838–2842 © Thieme Stuttgart · New York

2
840
P. B. Wakchaure, N. P. Argade
PAPER
2-[2-(6-Bromo-1,3-benzodioxol-5-yl)ethyl]-7,8-dimethoxyiso-
2
1
-[2-(1,3-Benzodioxol-5-yl)ethyl]-7,8-dimethoxyisoquinoline-
,3(2H,4H)-dione (6a); Typical Procedure
quinoline-1,3,4(2H)-trione (7b)
10
A stirred soln of 3,4-dimethoxyhomophthalic anhydride (4, 500
mg, 2.25 mmol) and homopiperonylamine (5a, 371 mg, 2.25 mmol)
was refluxed in o-dichlorobenzene (10 mL) for 3 h. The mixture
was allowed to cool to r.t. and it was then loaded onto a chromatog-
raphy column (silica gel, PE to remove o-dichlorobenzene and then
PE–EtOAc, 6:4) to give pure 6a (648 mg, 78%) as a yellow solid;
mp 155–157 °C.
Following the typical procedure for 7a using 6b (200 mg, 0.446
mmol) gave 7b (198 mg, 96%) as a yellow solid; mp 192–194 °C.
–1
IR (CHCl ): 1727, 1685 cm .
3
1
H NMR (200 MHz, CDCl ): d = 2.97 (t, J = 8 Hz, 2 H), 3.87 (s, 3
3
H), 3.96 (s, 3 H), 4.19 (t, J = 8 Hz, 2 H), 5.87 (s, 2 H), 6.75 (s, 1 H),
6
.88 (s, 1 H), 7.22 (d, J = 8 Hz, 1 H), 8.01 (d, J = 8 Hz, 1 H).
1
3
–
1
C NMR (50 MHz, CDCl ): d = 33.9, 40.7, 56.6, 61.4, 101.6, 110.4,
IR (CHCl ): 1717, 1673 cm .
3
3
1
1
12.6, 114.6, 116.2, 122.5, 123.9, 126.4, 130.8, 147.2, 147.4, 151.1,
57.1, 159.9, 161.0, 173.7.
1
H NMR (200 MHz, CDCl ): d = 2.77–2.89 (m, 2 H), 3.90 (s, 3 H),
3
3
.92 (br s, 2 H), 3.94 (s, 3 H), 4.07–4.18 (m, 2 H), 5.92 (s, 2 H), 6.74
MS (ESI): m/z = 484, 486 [M + Na]+.
(s, 2 H), 6.82 (s, 1 H), 6.97 (d, J = 8 Hz, 1 H), 7.15 (d, J = 8 Hz, 1 H).
1
3
Anal. Calcd for C H BrNO C, 51.97; H, 3.49; N, 3.03. Found: C,
C NMR (50 MHz, CDCl ): d = 33.7, 36.1, 41.6, 56.2, 61.2, 100.7,
20 16
7
3
5
2.05; H, 3.64; N, 3.32.
1
1
08.0, 109.3, 117.4, 119.3, 121.7, 122.6, 126.4, 132.3, 145.9, 147.4,
50.9, 152.9, 162.5, 169.6.
Methyl 2-[2-(1,3-Benzodioxol-5-yl)ethyl]-1-hydroxy-4,5-
dimethoxy-3-oxo-2,3-dihydro-1H-isoindole-1-carboxylate (8a);
Typical Procedures
MS (ESI): m/z = 392 [M + Na]+.
Anal. Calcd for C H NO : C, 65.03; H, 5.18; N, 3.79. Found: C,
20
19
6
6
4.79; H, 4.97; N, 3.67.
Method A: To the soln of 6a (300 mg, 0.813 mmol) in a mixture of
DMSO (20 mL) and MeOH (5 mL) at r.t. was added Et N (0.50 mL)
3
2
-[2-(6-Bromo-1,3-benzodioxol-5-yl)ethyl]-7,8-dimethoxyiso-
and into the mixture was bubbled excess O gas for 6 h and then it
2
quinoline-1,3(2H,4H)-dione (6b)
was further stirred for 18 h. To the formed dark-blue-colored mix-
ture was added EtOAc (30 mL) and the organic layer was washed
with brine (3 × 15 mL) to remove DMSO and with 2 M HCl (10 mL)
and brine (15 mL), and dried (Na SO ). Concentration of the organ-
Following the typical procedure for 6a using 3,4-dimethoxyho-
mophthalic anhydride (4, 1.00 g, 4.50 mmol) and 6-bromohomopip-
eronyl amine (5b, 1.09 g, 4.50 mmol) gave 6b (1.69 g, 84%) as a
yellow solid; mp 172–174 °C.
2
4
ic layer in vacuo followed by column chromatography (silica gel,
–
1
PE–EtOAc, 4:6) gave 8a (317 mg, 94%) as a brown solid.
IR (CHCl ): 1717, 1673 cm .
3
1
Method B: To a stirred soln of 7a (200 mg, 0.522 mmol) in MeOH
H NMR (200 MHz, CDCl ): d = 3.00 (dd, J = 10, 8 Hz, 2 H), 3.90
3
(
5 mL) was added Et N (cat., 1 drop) at r.t. and the mixture was
3
(
5
7
s, 3 H), 3.91 (s, 2 H), 3.92 (s, 3 H), 4.18 (dd, J = 10, 8 Hz, 2 H),
stirred for 3 h. Concentration of the organic layer in vacuo followed
by column chromatography (silica gel, PE–EtAOc, 4:6) furnished
.94 (s, 2 H), 6.82 (s, 1 H), 6.96 (s, 1 H), 6.96 (d, J = 8 Hz, 1 H),
.15 (d, J = 8 Hz, 1 H).
8
a (208 mg, 96%) as a brown solid; mp 138–140 °C.
1
3
C NMR (50 MHz, CDCl ): d = 34.1, 36.3, 39.9, 56.4, 61.3, 101.6,
3
–1
IR (CHCl ): 3501, 1737, 1705 cm .
3
1
1
10.4, 112.6, 114.7, 117.6, 119.4, 122.7, 126.5, 131.4, 147.0, 147.3,
51.1, 153.0, 162.6, 169.7.
1
H NMR (200 MHz, CDCl ): d = 2.74–3.01 (m, 2 H), 3.20–3.38 (m,
3
MS (ESI): m/z = 470, 472 [M + Na]+.
+
1 H), 3.61–3.79 (m, 1 H), 3.72 (s, 3 H), 3.88 (s, 3 H), 4.09 (s, 3 H),
4
.65 (br s, 1 H), 5.92 (s, 2 H), 6.68–6.78 (m, 3 H), 7.04 (d, J = 8 Hz,
HRMS (ESI): m/z [M + H] calcd for C H BrNO : 448.0396;
2
0
19
6
1 H), 7.12 (d, J = 8 Hz, 1 H).
found: 448.0394.
1
3
C NMR (50 MHz, CDCl ): d = 34.3, 41.9, 53.8, 56.3, 62.3, 87.4,
3
1
1
00.7, 108.1, 109.1, 116.0, 117.1, 121.5, 122.8, 132.6, 136.0, 145.9,
46.5, 147.5, 154.0, 165.8, 171.1.
2
1
-[2-(1,3-Benzodioxol-5-yl)ethyl]-7,8-dimethoxyisoquinoline-
,3,4(2H)-trione (7a); Typical Procedure
To a stirred soln of 6a (300 mg, 0.813 mmol) in DMSO (10 mL) at
MS (ESI): m/z = 438 [M + Na]+.
r.t. was bubbled excess O gas for 12 h and then it was further stirred
for 12 h. To the formed yellow-colored mixture was added EtOAc
+
2
HRMS (ESI): m/z [M + H] calcd for C H NO : 416.1345; found:
2
1
22
8
4
16.1343.
(
30 mL) and the organic layer was washed with brine (3 × 15 mL)
to remove DMSO and dried (Na SO ). Concentration of the organic
2
4
Methyl 2-[2-(6-Bromo-1,3-benzodioxol-5-yl)ethyl]-1-hydroxy-
,5-dimethoxy-3-oxo-2,3-dihydro-1H-isoindole-1-carboxylate
8b)
Following the typical procedure for 8a method A using 6b (1.40 g,
3.12 mmol) gave 8b (1.46 g, 95%) as a brown solid and method B
using 7b (150 mg, 0.324 mmol) gave 8b (152 mg, 95%) a brown
solid; mp 178–180 °C.
layer in vacuo followed by column chromatography (silica gel, PE–
EtOAc, 1:1) gave 7a (292 mg, 94%) as a yellow solid; mp 186–188
4
(
°
C.
–
1
IR (CHCl ): 1681 cm .
3
1
H NMR (400 MHz, CDCl ): d = 2.85–2.92 (m, 2 H), 3.97 (s, 3 H),
3
4
.04 (s, 3 H), 4.17–4.24 (m, 2 H), 5.93 (s, 2 H), 6.72 (s, 2 H), 6.83
–
1
(
s, 1 H), 7.29 (d, J = 8 Hz, 1 H), 8.09 (d, J = 8 Hz, 1 H).
IR (CHCl ): 3503, 1737, 1706 cm .
3
1
3
1
C NMR (100 MHz, CDCl ): d = 33.7, 42.5, 56.6, 61.5, 100.9,
H NMR (200 MHz, CDCl ): d = 2.85–3.19 (m, 2 H), 3.23–3.41 (m,
3
3
1
1
08.3, 109.4, 116.3, 121.9, 122.6, 123.9, 126.5, 131.8, 146.2, 147.7,
51.2, 157.1, 160.0, 161.1, 173.8.
1 H), 3.59–3.74 (m, 1 H), 3.76 (s, 3 H), 3.90 (s, 3 H), 4.12 (s, 3 H),
4.61 (br s, 1 H), 5.95 (s, 2 H), 6.84 (s, 1 H), 6.99 (s, 1 H), 7.09 (br s,
2 H).
13C NMR (50 MHz, CDCl
1
1
MS (ESI): m/z = 406 [M + Na]+.
+
3
): d = 34.9, 39.9, 54.2, 56.5, 62.5, 87.3,
01.6, 110.5, 112.7, 114.5, 116.1, 117.0, 123.0, 131.7, 136.0, 146.9,
47.1, 147.4, 154.3, 166.0, 171.8.
HRMS (ESI): m/z [M + H] calcd for C H NO : 384.1083; found:
3
2
0
18
7
84.1083.
MS (ESI): m/z = 516, 518 [M + Na]+.
Synthesis 2011, No. 17, 2838–2842 © Thieme Stuttgart · New York

PAPER
Synthesis of (±)-Chilenine and (±)-Deoxychilenine
2841
Anal. Calcd for C H BrNO : C, 51.03; H, 4.08; N, 2.83. Found: C,
Method B: Compound 10 (100 mg, 0.25 mmol) was stirred in 50%
21
20
8
5
0.64; H, 3.87; N, 2.48.
aq TFA (4 mL) at r.t. for 2 h. The reaction was quenched by the ad-
dition of sat. aq NaHCO and extracted with EtOAc (20 mL) and the
3
Methyl 2-[2-(6-Bromo-1,3-benzodioxol-5-yl)ethyl]-1,4,5-tri-
methoxy-3-oxo-2,3-dihydro-1H-isoindole-1-carboxylate (9)
To a stirred soln of 8b (1.00 g, 2.02 mmol) in MeOH (30 mL) was
added concd H SO (2 mL) in a dropwise fashion at 0 °C. The mix-
organic layer was washed with brine (10 mL) and dried (Na SO ).
Concentration of organic layer in vacuo followed by column chro-
2
4
matography (silica gel, PE–EtOAc, 4:6) furnished 1 (97 mg, 100%)
4
n
as a faint yellow solid; mp 115–116 °C (Lit. 114–116 °C).
2
4
ture was stirred at r.t. for 8 h and then MeOH was distilled off under
the reduced pressure. The obtained residue was dissolved in EtOAc
–1
IR (CHCl ): 3402, 1704 cm .
1
3
H NMR (200 MHz, CDCl ): d = 3.04 (ddd, J = 15, 6, 4 Hz, 1 H),
(
60 mL) and the organic layer was washed with sat. aq NaHCO (20
3
3
3
3
(
1
.38 (ddd, J = 14, 11, 6 Hz, 1 H), 3.59 (ddd, J = 14, 6, 4 Hz, 1 H),
.84 (s, 3 H), 3.95 (s, 3 H), 4.18 (ddd, J = 14, 10, 4 Hz, 1 H), 4.56
mL) and brine (20 mL), and dried (Na SO ). Concentration of or-
2
4
ganic layer in vacuo followed by column chromatography (silica
gel, PE–EtOAc, 1:1) furnished 9 (1.00 g, 98%) as an off-white
solid; mp 124–126 °C.
br s, 1 H), 5.94 (d, J = 2 Hz, 1 H), 5.96 (d, J = 2 Hz, 1 H), 6.66 (s,
H), 6.74 (s, 1 H), 7.01 (d, J = 10 Hz, 1 H), 7.40 (d, J = 8 Hz, 1 H).
1
3
–
1
C NMR (50 MHz, CDCl ): d = 31.0, 37.8, 56.4, 62.3, 90.4, 101.8,
08.6, 109.5, 116.3, 119.2, 122.6, 129.8, 133.7, 135.6, 146.0, 146.8,
51.4, 154.0, 166.1, 202.4.
MS (ESI): m/z = 406 [M + Na]+.
IR (CHCl ): 1753, 1706 cm .
3
3
1
1
1
H NMR (200 MHz, CDCl ): d = 2.95 (s, 3 H), 3.00–3.22 (m, 2 H),
3
3
.30–3.69 (m, 2 H), 3.76 (s, 3 H), 3.91 (s, 3 H), 4.13 (s, 3 H), 5.95
(
s, 2 H), 6.87 (s, 1 H), 6.99 (s, 1 H), 7.09 (d, J = 8 Hz, 1 H), 7.19 (d,
J = 8 Hz, 1 H).
9
,10-Dimethoxy-5H-[1,3]dioxolo[4¢¢,5¢¢:4¢,5¢]benzo[1¢,2¢:4,5]aze-
1
3
C NMR (50 MHz, CDCl ): d = 34.1, 40.6, 50.4, 53.4, 56.5, 62.5,
3
pino[2,1-a]isoindole-8,13(6H,12bH)-dione (Deoxychilenine, 2)
To a stirred soln of 10 (100 mg, 0.25 mmol) and Et SiH (0.12 mL,
0
–10 °C in a dropwise fashion. The mixture was further stirred for 20
min at the same temperature and then quenched by addition of a few
drops of sat. aq NaHCO . EtOAc (20 mL) was added to the mixture
9
1
2.6, 101.6, 110.5, 112.7, 114.5, 116.0, 118.0, 124.0, 131.3, 132.2,
47.1, 147.2, 147.5, 154.5, 166.6, 168.2.
3
.75 mmol) in CH Cl (5 mL) was added BF ·OEt (0.10 mL) at
2 2 3 2
MS (ESI): m/z = 530, 532 [M + Na]+.
+
HRMS (ESI): m/z [M] calcd for C H BrNO : 508.0607; found:
2
2
22
8
3
5
08.0630.
and the organic layer was washed with H O (10 mL) and brine (10
2
mL), and dried (Na SO ). Concentration of organic layer in vacuo
2
4
9
,10,12b-Trimethoxy-5H-[1,3]dioxolo[4¢¢,5¢¢:4¢,5¢]ben-
followed by column chromatography (silica gel, PE–EtOAc, 4:6)
zo[1¢,2¢:4,5]azepino[2,1-a]isoindole-8,13(6H,12bH)-dione (10)
To a stirred soln of 9 (500 mg, 0.984 mmol) in THF and HMPA
4
c
furnished 2 (89 mg, 96%) as a white solid; mp 155 °C (Lit. 156–
57 °C).
1
(
–
4:1, 15 mL) was added 1.30 M t-BuLi (0.90 mL, 1.18 mmol) at
78 °C in a dropwise fashion. The mixture was further stirred for 30
–
1
IR (CHCl ): 1694, 1613 cm .
3
min at the same temperature and then it was allowed to reach r.t.
1
H NMR (200 MHz, CDCl ): d = 3.01 (ddd, J = 15, 4, 2 Hz, 1 H),
3
The reaction was quenched by adding few drops of sat. aq NH Cl.
4
3
3
.25 (dt, J = 14, 4 Hz, 1 H), 3.59 (ddd, J = 14, 6, 2 Hz, 1 H), 3.90 (s,
H), 4.02 (s, 3 H), 4.27 (dt, J = 14, 4 Hz, 1 H), 5.15 (s, 1 H, not ex-
After removal of THF in vacuo, EtOAc (50 mL) was added to the
mixture and the organic layer was washed with H O (20 mL) and
2
changeable with D O), 6.00 (d, J = 2 Hz, 2 H), 6.71 (s, 1 H), 6.90
(
2
brine (20 mL), and dried (Na SO ). Concentration of organic layer
2
4
s, 1 H), 7.18 (d, J = 8 Hz, 1 H), 7.58 (d, J = 8 Hz, 1 H).
in vacuo followed by column chromatography (silica gel, PE–
1
3
C NMR (125 MHz, CDCl ): d = 31.5, 41.3, 56.6, 62.5, 65.9, 101.9,
EtOAc, 6:4) furnished 10 (0.32 g, 82%) as an off-white solid; mp
3
50–152 °C (Lit.4o 146–147 °C).
108.6, 109.3, 116.5, 120.1, 124.1, 131.2, 132.3, 133.8, 146.5, 147.2,
51.6, 153.1, 167.4, 201.0.
1
1
–
1
IR (CHCl ): 1701, 1685 cm .
3
MS (ESI): m/z = 390 [M + Na]+.
1
H NMR (200 MHz, CDCl ): d = 2.80–3.00 (m, 1 H), 3.06 (s, 3 H),
3
3
5
7
.36–3.60 (m, 2 H), 3.91 (s, 3 H), 4.03 (s, 3 H), 4.14–4.40 (m, 1 H),
.97 (s, 2 H), 6.67 (s, 1 H), 6.82 (s, 1 H), 7.13 (d, J = 8 Hz, 1 H),
.51 (d, J = 8 Hz, 1 H).
Acknowledgment
P.B.W. thanks CSIR, New Delhi for the award of research fel-
lowship. N.P.A. thanks Department of Science and Technology,
New Delhi, for financial support. We thank Professor Toshio Honda
from Hoshi University, Tokyo, Japan for NMR spectra of chilenine
and deoxychilenine.
1
3
C NMR (50 MHz, CDCl ): d = 30.5, 38.7, 51.1, 56.4, 62.3, 94.7,
3
1
1
01.8, 109.0, 109.2, 116.2, 120.4, 123.9, 130.5, 131.6, 133.5, 146.6,
46.9, 151.4, 154.3, 166.4, 199.4.
MS (ESI): m/z = 420 [M + Na]+.
1
2b-Hydroxy-9,10-dimethoxy-5H-[1,3]dioxolo[4¢¢,5¢¢:4¢,5¢]ben-
zo[1¢,2¢:4,5]azepino[2,1-a]isoindole-8,13(6H,12bH)-dione
Chilenine, 1)
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