Conversion of oxazolidinediones to isoindoloisoquinolinones via intramolecular friedel-crafts reaction

Article abstract of DOI:10.1021/jo402345q

Treatment of oxazolidinediones with TiCl₄ in CH ₂Cl₂ resulted in conversion to isoindoloisoquinolinones via intramolecular Friedel-Crafts reaction with extrusion of CO₂ in the transformation. The alkaloid nuevamine has been synthesized under these conditions in a regiospecific manner.

Full text of DOI:10.1021/jo402345q

Note
pubs.acs.org/joc
Conversion of Oxazolidinediones to Isoindoloisoquinolinones via
Intramolecular Friedel−Crafts Reaction
Ji-Young Min and Guncheol Kim*
Department of Chemistry, College of Natural Science, Chungnam National University, Daejon 305-764, Korea
S
* Supporting Information
ABSTRACT: Treatment of oxazolidinediones with TiCl4 in CH2Cl2
resulted in conversion to isoindoloisoquinolinones via intramolecular
Friedel−Crafts reaction with extrusion of CO2 in the transformation.
The alkaloid nuevamine has been synthesized under these conditions
in a regiospecific manner.
xazolidine-4,5-diones were first introduced for the
synthesis of 3-aryl-3,4-dihydroisoquinolines through a
Aromatic groups attached on C-10b of the diones should be
O
able to take part in some other type of reaction; however, any
attempt on the derivatives has not been reported so far to our
best knowledge. We envisioned that the aromatic dione
compounds would result in a new transformation under
Lewis acid catalysis, hopefully conversion of oxazolidinediones
to isoindoloisoquinolinones4 via Friedel−Crafts reaction onto
C-3 carbonyl of 5 (Scheme 2).
modified Bischler−Napieralski reaction as the application of
oxalyl chloride to the reaction.1 Treatment of amide 1 with
oxalyl chloride to form 2, subsequent addition of Lewis acid to
facilitate the second cyclization, and the following reaction of 3
with an acid afforded good yields of 3-aryl-3,4-dihydroisoquino-
lines (Scheme 1). Formation of the dione intermediates from
Scheme 1. Oxazolidine-4,5-diones to 3-Aryl-3,4-
dihydroisoquinolines
Scheme 2. Conversion of Oxazolidinediones to
Isoindoloisoquinolinones
First we wanted to obtain precursors having the required
aromatic groups on C-10b. We could not obtain reproducible
yields of compounds 5 by the known procedures.1,2 However,
slight modification of the sequential procedures provided
excellent yields of purified materials: Addition of n-BuLi (2.5
equiv) to a solution of amide and oxalyl chloride (2.5 equiv) in
THF at −78 °C, stirring for 3 h at that temperature, addition of
AlCl3 (3.5 equiv) at 0 °C, and warming the resulting mixture to
room temperature allowed good yields of the desired products.
As the aromatic ring needs to be reactive enough to overcome
the steric factor on the quartenary center in the cyclization,
only the compounds containing electron-donating groups at the
meta and para positions on the aromatic ring (R3 and R4)
afforded the desired products in good yields. AlCl3 was found
to be the best Lewis acid for the Friedel−Crafts cyclization step
(Table 1).
the corresponding (1,2-diphenylethyl)amides (R5 = Ar) was
specifically intended to avoid nitrile elimination causing low
yields through a retro-Ritter reaction before cyclization.2 This
process has been generally carried out without separation of
intermediates, expecting that the formation of the diones would
ensure the desired cyclization. While alkyl or benzylamide
derivatives have been dominantly subjected to the trans-
formation, benzamide precursors have been less explored,
partly because the steric bulkiness of aromatic group on the
quartenary center of 2 was assumed to cause low yields in the
final acylation. Formation of imine 4 was carried out via
extrusion of CO2 and CO from 3, and a few examples of
intramolecular Friedel−Crafts reactions onto C-2 carbonyl of 3
have been reported.3
Received: October 21, 2013
© XXXX American Chemical Society
A
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Note
a
a
Table 1. Synthesis of Oxazolidine-2,3-dione
Table 2. Reaction Optimization for Nuevamine Synthesis
b
entry
acid
TsOH
solvent
T (°C)
yield (%)
1
2
3
4
5
6
7
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
rt
−40
−40
−40
−40
−40
−40
NR
74
98
23
11
70
93
SnCl4
TiCl4
BF3OEt2
AlCl3
ZnCl2
CF3COOH
a
Unless otherwise noted, the reactions were performed with 5a and
acid (2.5 equiv) for 1 h, and less than 1 equiv of acid afforded very
b
poor yields. Yield of the isolated product.
would end up to the desired compound. However, the longer
stirring in the previous step without separation of 5a gave the
desired product less than 5% yield.
The reaction is suggested to be initiated by electrophilic
addition of aromatic group to the activated C-3 carbonyl carbon
to intermediate 8. Proton elimination to 8 was followed by
extrusion of CO2 to 10, and protonation would yield 6a
(Scheme 3). This process suggests a differentiated route for
Scheme 3. Mechanism of the Nuevamine Formation
tetrahydroisoquinoline skeleton from conventional synthetic
protocols such as Pictet−Spengler,6 Bischler−Napieralski,7
Pomeranz−Fritsch−Bobbitt,8 N-acyliminium ion cyclization,9
and Parham-type cyclization.10
The scope of this new transformation has been investigated
under the optimized conditions. Compound 5c did not proceed
to yield 6c. In general, no desired compound has been detected
from the starting materials, which do not have an electron-
donating group on the aromatic nucleophile. Starting materials
have been fully recovered, or complete decomposition has been
detected depending on the reaction temperature. Among
anisole derivatives only meta-substituted compound 5k under-
went the reaction to afford 6k in 99% yield. In the case of 2-
and 3-furans, 6i and 6j, only 3-furan compound 5i reacted to
provide product 6i in 72% yield. However, both 2- and 3-
thiofurans, 5g and 5h, provided the corresponding products 6g
and 6h in 80% and 83% yields, respectively. Neither pyrrole nor
pyridine derivatives went through the transformation at all. In
terms of regioselectivity, products 6b, 6e, 6f, 6h, and 6k have
a
Yields of the isolated product.
Conversion to the desired isoindoloisoquinolinones has been
tested by using intermediate 5a because the desired trans-
formation would result in the synthesis of 6a, an alkaloid
nuevamine. The reaction was investigated by treatment of 5a
with several acids. When the process was carried under p-
toluenesufonic acid catalyst, no reaction occurred even at rt
(Table 2, entry 1). However, CF3COOH and general Lewis
acids provided 6a in a regiospecific manner (entries 2−7).5 The
optimized conditions were found to be the reaction of 5a with
TiCl4 in CH2Cl2 at −40 °C, yielding 98% (entry 3). AlCl3
treatment in CH2Cl2 provided 11% of product (entry 5), which
indicates prolonged reaction time at the dione formation step
B
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Note
added n-BuLi (1.75 mmol) at −78 °C. The reaction mixture was
stirred for 3h at −78 °C and was raised to 0 °C, and AlCl3 (327 mg,
2.45 mmol) in 8 mL CH2Cl2 was added at 0 °C. The resulting mixture
was stirred for 0.5 h at 0 °C and raised to room temperature. CH2Cl2
(5 mL) and H2O (10 mL) were added to the solution and the organic
layer was separated and washed with saturated NaHCO3 solution,
brine, dried over MgSO4, and evaporated. Purification of the residue
by column chromatography (hexane/AcOEt 1/1) provided 5a (228
mg, 96%).
been detected as a single isomer, respectively, from the
corresponding starting materials (Table 3).
a
Table 3. Substrate Scopes for the Transformation
11b-(2,3-Dimethoxyphenyl)-5,6-dihydro-2H-[1,3]dioxolo-
[4,5-g]oxazolo[2,3-a]isoquinoline-2,3(11bH)-dione (5a). 1H
NMR (400 MHz, CDCl3) δ 7.02 (dd, J = 8.3, 1.5 Hz, 1H), 6.94 (s,
1H), 6.91 (t, J = 8.1 Hz, 1H), 6.66 (s, 1H), 6.31 (dd, J = 7.9, 1.5 Hz,
1H), 6.05 (d, J = 1.3 Hz, 1H), 6.01 (d, J = 1.3 Hz, 1H), 4.30 (ddd, J =
13.1, 7.1, 3.0 Hz, 1H), 3.87 (s, 3H), 3.84 (s, 3H), 3.20 (ddd, J = 13.1,
7.1, 2.9 Hz, H), 3.13 (ddd, J = 16.6, 5.9, 2.5 Hz, 2H), 2.75 (ddd, J =
16.6, 5.9, 2.1 Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3) δ 159.6,
153.7, 152.3, 149.2, 148.9, 146.9, 128.2, 127.8, 126.9, 123.2, 122.9,
115.7, 108.3, 107.1, 101.8, 91.7, 60.7, 56.1, 36.3, 27.3 ppm; IR (KBr) γ
1731, 1831 cm−1; HRMS (EI) calcd for C18H17NO4: 311.1158 [M−
(CO + CO2)]+; found: 311.1154.
11b-(3,4-Dimethoxyphenyl)-5,6-dihydro-2H-[1,3]dioxolo-
[4,5-g]oxazolo[2,3-a]isoquinoline-2,3(11bH)-dione(5b). (240
1
mg, 70%) H NMR (400 MHz, CDCl3) δ 6.93 (s, 1H), 6.79 (d, J =
8.4 Hz, 1H), 6.71 − 6.66 (m, 2H), 6.64 (dd, J = 8.5, 1.9 Hz, 1H), 6.03
(d, J = 12.4 Hz, 2H), 4.28 (ddd, J = 13.4, 5.1, 3.7 Hz, 1H), 3.88 (s,
3H), 3.83 (s, 3H), 3.33 (ddd, J = 13.4, 5.1, 3.5 Hz, 1H), 3.11 (ddd, J =
16.6, 4.4, 3.3 Hz, 1H), 2.75 (ddd, J = 16.6, 5.1, 3.9 Hz, 1H) ppm; 13C
NMR (100 MHz, CDCl3) δ 159.0, 151.9, 151.0, 149.6, 149.3, 147.1,
128.9, 127.7, 127.0, 121.4, 110.7, 109.2, 108.3, 106.9, 101.8, 92.0, 56.3,
56.1, 37.0, 27.2 ppm; IR (KBr) γ 1733, 1836 cm−1; HRMS (EI) calcd
for C18H17NO4: 311.1158 [M − (CO + CO2)]+; found: 311.1154.
8,9-Dimethoxy-10b-phenyl-5,6-dihydro-2H-oxazolo[2,3-a]-
1
isoquinoline-2,3(10bH)-dione (5c). (253 mg, 96%) H NMR (400
MHz, CDCl3) δ 7.02 (dd, J = 8.3, 1.5 Hz, 1H), 6.94 (s, 1H), 6.91 (t, J
= 8.1 Hz, 1H), 6.66 (s, 1H), 6.31 (dd, J = 7.9, 1.5 Hz, 1H), 6.05 (d, J =
1.3 Hz, 1H), 6.01 (d, J = 1.3 Hz, 1H), 4.30 (ddd, J = 13.1, 7.1, 3.0 Hz,
1H), 3.87 (s, 3H), 3.84 (s, 3H), 3.41 (m, 1H), 3.21 (ddd, J = 13.1, 7.1,
2.9 Hz, 1H), 2.75 (ddd, J = 16.6, 5.9, 3.0 Hz, 1H) ppm; 13C NMR
(100 MHz, CDCl3) δ 159.6, 153.7, 152.3, 149.2, 148.9, 146.9, 128.2,
127.8, 126.9, 123.2, 122.9, 115.7, 108.3, 107.1, 101.8, 91.7, 60.7, 56.1,
36.3, 27.3 ppm; IR (KBr) γ 1735, 1830 cm−1; HRMS (EI) calcd for
C17H17NO2: 267.1259 [M − (CO + CO2)]+; found: 267.1254.
10b-(2,3-Dimethoxyphenyl)-8,9-dimethoxy-5,6-dihydro-2H-
oxazolo[2,3-a]isoquinoline-2,3(10bH)-dione (5d). (268 mg,
90%) 1H NMR (400 MHz, CDCl3) δ 7.07 (dd, J = 8.3, 1.1 Hz,
1H), 6.96 − 6.91 (m, 2H), 6.74 (s, 1H), 6.28 (dd, J = 7.9, 1.2 Hz, 1H),
4.35 (m, 1H), 3.94 (s, 3H), 3.89 (s, 3H), 3.88 (s, 3H), 3.85 (s, 3H),
3.20 (ddd, J = 13.1, 7.1, 3.0 Hz, 1H), 3.17 (ddd, J = 13.1, 7.1, 3.1 Hz,
1H), 2.82 (m, 1H) ppm; 13C NMR (100 MHz, CDCl3) δ 159.6, 153.4,
152.0, 150.2, 148.6, 147.9, 128.2, 126.2, 125.3, 123.0, 122.9, 115.5,
110.7, 109.3, 91.5, 60.5, 56.0, 55.9, 36.2, 26.7, 14.0 ppm; IR (KBr) γ
1738, 1835 cm−1; HRMS (EI) calcd for C19H21NO4: 327.1471 [M −
(CO + CO2)]+; found: 327.1469.
10b-(3,4-Dimethoxyphenyl)-8,9-dimethoxy-5,6-dihydro-2H-
oxazolo[2,3-a]isoquinoline-2,3(10bH)-dione (5e). (219 mg, 65%)
1H NMR (400 MHz, CDCl3) δ 6.92 (s, 1H), 6.80 (d, J = 8.5 Hz, 1H),
6.71 (d, J = 2.7 Hz, 2H), 6.62 (dd, J = 8.4, 2.2 Hz, 1H), 4.35 (ddd, J =
13.4, 5.1, 3.7 Hz, 1H), 3.93 (s, 3H), 3.88 (s, 3H), 3.86 (s, 3H), 3.82 (s,
3H), 3.31 (ddd, J = 13.4, 5.1, 3.5 Hz, 1H), 3.16 (ddd, J = 16.9, 4.4, 3.3
Hz, 1H), 2.81 (ddd, J = 16.9, 5.1, 2.7 Hz, 1H) ppm; 13C NMR (100
MHz, CDCl3) δ 159.2, 151.7, 150.8, 150.5, 149.5, 148.3, 129.1, 126.3,
125.4, 121.4, 110.7, 110.6, 109.4, 109.2, 92.0, 56.2, 56.1, 56.1, 56.0,
37.0, 26.9 ppm; IR (KBr) γ 1732, 1837 cm−1; HRMS (EI) calcd for
C19H21NO4: 327.1471 [M − (CO + CO2)]+; found: 327.1469.
10b-(Benzo[d][1,3]dioxol-5-yl)-8,9-dimethoxy-5,6-dihydro-
2H-oxazolo[2,3-a]isoquinoline-2,3(10bH)-dione (5f). (240 mg,
91%) 1H NMR (400 MHz, CDCl3) δ 6.89 (s, 1H), 6.76 (d, J = 8.2 Hz,
1H), 6.70 (s, 1H), 6.67 − 6.64 (m, 1H), 6.63 − 6.58 (m, 1H), 6.01 (s,
2H), 4.33 (ddd, J = 13.4, 7.1, 2.9 Hz, 1H), 3.92 (s, 3H), 3.87 (s, 3H),
a
Yield of the isolated product.
In summary, oxazolidinediones containing aromatic groups
on the quaternary center have been converted to isoindoloi-
soquinolones through Friedel−Crafts reaction, and nuevamine
was synthesized in a regiospecific manner.
EXPERIMENTAL SECTION
■
Representative procedure for the formation of dione 5a. To
a solution of N-(3,4-dimethoxyphenethyl)benzamide (200 mg, 0.70
mmol) and oxalyl chloride (0.15 mL, 1.75 mmol) in THF (3 mL) was
C
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Note
3.32 (ddd, J = 13.5, 7.1, 3.1 Hz, 1H), 3.15 (ddd, J = 16.9, 5.9, 3.6 Hz,
1H), 2.81 (ddd, J = 16.9, 5.9, 2.8 Hz, 1H) ppm; 13C NMR (100 MHz,
CDCl3) δ 159.0, 151.6, 150.6, 149.4, 148.5, 148.3, 130.8, 126.2, 122.2,
110.8, 109.2, 108.1, 107.2, 102.0, 91.8, 56.2, 56.1, 36.9, 26.8 ppm; IR
(KBr) γ 1734, 1840 cm−1; HRMS (EI) calcd for C18H17NO4:
311.1158 [M − (CO + CO2)]+; found: 311.1155.
Representative procedure for the formation of isoindoloi-
soquinolinone, nuevamine 6a. To a solution of 5a (100 mg, 0.30
mmol) in CH2Cl2 (3 mL) was added TiCl4 (0.46 mL, 0.63 mmol) at
−40 °C. The reaction mixture was stirred for 1h at −40 °C,
Quenching with H2O (0.5 mL) was followed by washing with
saturated NaHCO3 solution and brine. After dry over MgSO4 and
evaporation, purification of the residue by short column chromatog-
raphy (hexane/AcOEt 1/1) provided 6a (98 mg, 98%).
8,9-Dimethoxy-10b-(thiophen-2-yl)-5,6-dihydro-2H-
oxazolo[2,3-a]isoquinoline-2,3(10bH)-dione (5g). (280 mg,
99%) 1H NMR (400 MHz, CDCl3) δ 7.46 (dd, J = 5.1, 1.2 Hz,
1H), 7.04 (s, 1H), 6.98 (ddd, J = 5.0, 3.7, 1.0 Hz, 1H), 6.89 − 6.86 (m,
1H), 6.68 (s, 1H), 4.42 (ddd, J = 13.4, 7.1, 2.9 Hz, 1H), 3.92 (s, 3H),
3.89 (s, 3H), 3.45 (ddd, J = 13.4, 10.5, 3.2 Hz, 1H), 3.17 (ddd, J =
16.9, 5.9, 4.2 Hz, 1H), 2.83 (ddd, J = 16.9, 5.9, 2.6 Hz, 1H) ppm; 13C
NMR (100 MHz, CDCl3) δ 158.3, 151.3, 150.8, 148.3, 141.9, 130.2,
129.4, 127.4, 125.9, 125.4, 110.8, 109.2, 89.6, 56.3, 56.1, 37.2, 26.9
ppm; IR (KBr) γ 1733, 1837 cm−1; HRMS (EI) calcd for
C15H15NO2S: 273.0824 [M − (CO + CO2)]+; found: 273.0826.
8,9-Dimethoxy-10b-(thiophen-3-yl)-5,6-dihydro-2H-
oxazolo[2,3-a]isoquinoline-2,3(10bH)-dione (5h). (215 mg,
97%) 1H NMR (400 MHz, CDCl3) δ 7.40 (dd, J = 5.0, 3.0 Hz,
1H), 7.05 (s, 1H), 6.96 (s, 2H), 6.68 (s, 1H), 4.41 (ddd, J = 13.6, 7.0,
2.8 Hz, 1H), 3.92 (s, 3H), 3.88 (s, 3H), 3.42 (ddd, J = 13.6, 7.0, 3.2
Hz, 1H), 3.20 (ddd, J = 16.9, 5.9, 4.2 Hz, 1H), 2.83 (ddd, J = 16.9, 5.9,
2.6 Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3) δ 158.9, 151.5, 150.7,
148.4, 139.7, 128.1, 128.1, 125.9, 125.5, 125.3, 110.8, 109.2, 89.3, 56.3,
56.1, 37.2, 27.1 ppm; IR (KBr) γ 1730, 1833 cm−1; HRMS (EI) calcd
for C15H15NO2S: 273.0824 [M − (CO + CO2)]+; found: 273.0824.
10b-(Furan-3-yl)-8,9-dimethoxy-5,6-dihydro-2H-oxazolo-
[2,3-a]isoquinoline-2,3(10bH)-dione (5i). (278 mg, 82%) 1H
NMR (400 MHz, CDCl3) δ 7.48 (t, J = 1.7 Hz, 1H), 7.12 (s, 1H),
6.99 (s, 1H), 6.68 (s, 1H), 6.36 (d, J = 0.9 Hz, 1H), 4.45 (ddd, J =
13.4, 7.5, 2.0 Hz, 1H), 3.91 (s, 3H), 3.89 (s, 3H), 3.36 (ddd, J = 13.4,
7.5, 4.0 Hz, 1H), 3.18 (ddd, J = 16.1, 7.6, 4.9 Hz, 1H), 2.84 (ddd, J =
16.1, 7.6, 1.9 Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3) δ 158.6,
151.5, 150.6, 148.2, 145.1, 144.3, 125.8, 125.4, 124.8, 110.8, 109.0,
107.7, 88.0, 56.1, 56.0, 37.0, 27.0 ppm; IR (KBr) γ 1732, 1836 cm−1;
HRMS (EI) calcd for C17H15NO3: 257.1052 [M − (CO + CO2)]+;
found: 257.1049.
Nuevamine (6a).5e White solid: mp 213-214 °C; H NMR (400
1
MHz, CDCl3) δ 7.58 (d, J = 8.2 Hz, 1H), 7.32 (s, 1H), 7.07 (d, J = 8.2
Hz, 1H), 6.67 (s, 1H), 5.93 − 5.92 (m, 1H), 5.86 (d, J = 1.4 Hz, 1H),
5.63 (s, 1H), 4.00 (s, 3H), 3.99 (m, 1H), 3.98 (s, 3H), 3.56 (dt, J =
12.5, 6.1 Hz, 1H), 3.02 (dt, J = 15.4, 6.1 Hz, 1H), 2.87 (dt, J = 15.4,
6.1 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 167.8, 155.7, 147.0,
146.6, 144.5, 136.3, 129.0, 128.6, 126.8, 119.9, 113.3, 108.6, 107.6,
101.1, 60.6, 58.5, 56.4, 38.8, 28.9. IR (KBr) γ 1675 cm−1. HRMS (EI)
calcd for C19H17NO5: [M ]+ 339.1107; found: 339.1109.
10,11-Dimethoxy-5,6-dihydro-[1,3]dioxolo[4,5-g]isoindolo-
[1,2-a]isoquinolin-8(12bH)-one (6b). (101 mg, 70%) 1H NMR
(400 MHz, CDCl3) δ 7.33 (s, 1H), 7.22 (s, 1H), 7.04 (s, 1H), 6.67 (s,
1H), 5.98 (d, J = 1.2 Hz, 1H), 5.92 (d, J = 1.1 Hz, 1H), 5.48 (s, 1H),
4.32 (dt, J = 12.6, 5.1 Hz, 1H), 4.04 (s, 3H), 3.94 (s, 3H), 3.47 − 3.39
(m, 1H), 3.01 − 2.91 (m, 1H), 2.77 (dt, J = 15.7, 4.6 Hz, 1H) ppm;
13C NMR (100 MHz, CDCl3) δ 168.7, 152.7, 150.1, 146.9, 146.7,
137.9, 128.5, 127.7, 125.3, 109.3, 105.6, 105.4, 105.4, 101.3, 58.9, 56.5,
56.3, 38.6, 29.6 ppm; IR (KBr) γ 1673 cm−1; HRMS (EI) calcd for
C19H17NO5: [M ]+ 339.1107; found: 339.1109.
2,3,11,12-Tetramethoxy-5,6-dihydroisoindolo[1,2-a]-
isoquinolin-8(12bH)-one (6d). (108 mg, 99%) White solid: mp
142−144 °C; 1H NMR (400 MHz, CDCl3) δ 7.65 (s, 1H), 7.58 (dd, J
= 8.2, 1.0 Hz, 1H), 7.06 (d, J = 8.2 Hz, 1H), 6.66 (s, 1H), 5.73 (s, 1H),
4.33 − 4.25 (m, 1H), 4.03 (d, J = 1.1 Hz, 3H), 3.96 (s, 3H), 3.85 (d, J
= 8.3 Hz, 6H), 3.51 − 3.41 (m, 1H), 3.09 − 2.99 (m, 1H), 2.80 (dt, J =
15.7, 4.8 Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3) δ 167.7, 155.8,
148.2, 147.8, 144.5, 136.9, 127.2, 127.1, 126.6, 120.0, 113.2, 111.5,
110.8, 60.9, 58.5, 56.3, 56.0, 55.9, 38.6, 28.5 ppm; IR (KBr) γ 1675
cm−1; HRMS (EI) calcd for C20H21NO5: [M ]+ 355.1420; found:
355.1418.
10b-(Furan-2-yl)-8,9-dimethoxy-5,6-dihydro-2H-oxazolo-
[2,3-a]isoquinoline-2,3(10bH)-dione (5j). (297 mg, 97%) 1H
NMR (400 MHz, CDCl3) δ 7.50 (dd, J = 1.8, 0.8 Hz, 1H), 7.04 (s,
1H), 6.69 (s, 1H), 6.36 (dd, J = 3.3, 1.8 Hz, 1H), 6.20 (dd, J = 3.4, 0.8
Hz, 1H), 4.46 (ddd, J = 13.3, 6.8, 1.8 Hz, 1H), 3.92 (s, 3H), 3.90 (s,
3H), 3.31 (ddd, J = 13.3, 8.1, 4.4 Hz, 1H), 3.19 (ddd, J = 16.5, 6.3, 2.7
Hz, 1H), 2.84 (ddd, J = 16.5, 5.3, 1.7 Hz, 1H) ppm; 13C NMR (100
MHz, CDCl3) δ 158.6, 151.6, 151.0, 148.3, 148.1, 145.3, 126.5, 122.9,
114.7, 111.0, 110.9, 109.4, 87.0, 56.2, 56.1, 37.2, 27.2 ppm; IR (KBr) γ
1737, 1839 cm−1; HRMS (EI) calcd for C15H15NO3: 257.1052 [M −
(CO + CO2)]+; found: 257.1049.
8,9-Dimethoxy-10b-(3-methoxyphenyl)-5,6-dihydro-2H-
oxazolo[2,3-a]isoquinoline-2,3(10bH)-dione (5k). (211 mg, 82%)
1H NMR (400 MHz, CDCl3) δ 7.35 − 7.28 (m, 1H), 6.93 (dd, J =
21.7, 9.6 Hz, 2H), 6.80 − 6.65 (m, 3H), 4.34 (m, 1H), 3.92 (s, 3H),
3.85 (s, 3H), 3.78 (s, 3H), 3.32 (m, 1H), 3.14 (m, 1H), 2.82 (m, 1H)
ppm; 13C NMR (100 MHz, CDCl3) δ 160.0, 159.1, 151.6, 150.6,
148.4, 138.8, 130.1, 126.3, 125.1, 119.4, 115.1, 113.6, 110.8, 109.3,
91.6, 56.2, 56.1, 55.5, 37.0, 26.9 ppm; IR (KBr) γ 1730, 1832 cm−1;
HRMS (EI): calcd for C18H19NO3: 297.1365 [M − (CO + CO2)]+;
found: 297.1361.
2,3,10,11-Tetramethoxy-5,6-dihydroisoindolo[1,2-a]-
isoquinolin-8(12bH)-one (6e). (110 mg, 78%) White solid: mp
1
162−166 °C; H NMR (400 MHz, CDCl3) δ 7.32 (s, 1H), 7.28 (s,
1H), 7.08 (s, 1H), 6.68 (s, 1H), 5.52 (s, 1H), 4.42 (ddd, J = 12.8, 5.6,
3.8 Hz, 1H), 4.02 (s, 3H), 3.93 (s, 6H), 3.86 (s, 3H), 3.44 − 3.35 (m,
1H), 2.98 (ddd, J = 15.9, 10.0, 5.9 Hz, 1H), 2.76 (dt, J = 15.9, 4.1 Hz,
1H) ppm; 13C NMR (100 MHz, CDCl3) δ 168.6, 152.6, 150.1, 148.5,
147.9, 138.3, 127.2, 126.4, 125.3, 112.1, 108.8, 105.6, 105.5, 58.7, 56.3,
56.2, 56.2, 56.0, 38.5, 29.0 ppm; IR (KBr) γ 1672 cm−1; HRMS (EI)
calcd for C20H21NO5: [M ]+ 355.1420; found: 355.1417.
2,3-Dimethoxy-5,6-dihydro-[1,3]dioxolo[4′,5′:5,6]isoindolo-
[1,2-a]isoquinolin-8(13bH)-one (6f). (95 mg, 99%) White solid:
mp 161−165 °C; 1H NMR (400 MHz, CDCl3) δ 7.24 (s, 1H), 7.22 (s,
1H), 7.02 (s, 1H), 6.67 (s, 1H), 6.10 (s, 1H), 6.06 (s, 1H), 5.51 (s,
1H), 4.45 (dd, J = 8.1, 4.2 Hz, 1H), 3.95 (s, 3H), 3.86 (s, 3H), 3.41 −
3.31 (m, 1H), 3.03 − 2.93 (m, 1H), 2.74 (d, J = 15.6 Hz, 1H) ppm;
13C NMR (100 MHz, CDCl3) δ 168.1, 151.6, 148.6, 148.4, 147.9,
140.3, 127.0, 126.9, 126.1, 112.0, 108.5, 103.6, 103.6, 102.2, 58.8, 56.2,
55.9, 38.5, 29.1 ppm; IR (KBr) γ 1672 cm−1; HRMS (EI) calcd for
C19H17NO5: [M ]+ 339.1107; found: 339.1104.
2,3-Dimethoxy-5,6-dihydrothieno[2′,3′:3,4]pyrrolo[2,1-a]-
isoquinolin-8(11bH)-one (6g). (89 mg, 80%) 1H NMR (400 MHz,
CDCl3) δ 7.40 (d, J = 4.9 Hz, 1H), 7.18 (s, 1H), 7.07 (d, J = 4.9 Hz,
1H), 6.59 (s, 1H), 4.17 (dd, J = 13.4, 5.9 Hz, 1H), 3.95 (s, 3H), 3.85
(s, 3H), 3.39 (td, J = 12.7, 4.0 Hz, 1H), 2.91 (ddd, J = 17.9, 12.1, 6.0
Hz, 1H), 2.68 (dd, J = 16.1, 3.4 Hz, 1H) ppm; 13C NMR (100 MHz,
CDCl3) δ 164.1, 157.6, 149.6, 148.3, 138.9, 131.4, 127.2, 126.9, 120.0,
111.3, 110.2, 85.4, 56.2, 56.0, 35.3, 29.1 ppm; IR (KBr) γ 1663 cm−1;
HRMS (EI) calcd for C16H15NO3S: [M ]+ 301.0773; found: 301.0769.
2,3-Dimethoxy-5,6-dihydrothieno[3′,2′:3,4]pyrrolo[2,1-a]-
isoquinolin-8(11bH)-one (6h). (95 mg, 83%) White solid: mp 133−
136 °C; 1H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 4.8 Hz, 1H), 7.32
10b-(2,3-Dimethoxyphenyl)-8-methoxy-5,6-dihydro-2H-
oxazolo[2,3-a]isoquinoline-2,3(10bH)-dione (5l). (278 mg, 67%)
1H NMR (400 MHz, CDCl3) δ 7.42 (d, J = 8.7 Hz, 1H), 7.04 (dd, J =
8.3, 1.4 Hz, 1H), 6.93 − 6.87 (m, 2H), 6.76 (d, J = 2.5 Hz, 1H), 6.24
(dd, J = 8.0, 1.5 Hz, 1H), 4.32 (ddd, J = 12.6, 6.9, 3.0 Hz, 1H), 3.88 (s,
3H), 3.86 (s, 3H), 3.83 (s, 3H), 3.28 − 3.10 (m, 2H), 2.85 (ddd, J =
8.9, 5.5, 2.9 Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3) δ 160.4,
159.5, 153.4, 152.2, 148.6, 135.1, 128.4, 128.3, 125.9, 122.9, 122.7,
115.4, 113.1, 91.6, 60.4, 55.9, 55.3, 36.1, 27.2 ppm; IR (KBr) γ 1738,
1835 cm−1; HRMS (EI) calcd for C18H19NO3: 297.1365 [M − (CO +
CO2)]+; found: 297.1362.
D
dx.doi.org/10.1021/jo402345q | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
(d, J = 4.8 Hz, 1H), 6.96 (s, 1H), 6.66 (s, 1H), 5.57 (s, 1H), 4.44 (ddd,
J = 13.1, 6.0, 2.8 Hz, 1H), 3.92 (s, 3H), 3.84 (d, J = 6.2 Hz, 3H), 3.34
(ddd, J = 13.4, 10.8, 4.4 Hz, 1H), 2.98 (ddd, J = 16.1, 10.4, 6.0 Hz,
1H), 2.77 − 2.69 (m, 1H) ppm; 13C NMR (100 MHz, CDCl3) δ
164.3, 154.7, 148.5, 148.1, 136.1, 135.3, 126.5, 125.4, 121.0, 112.0,
108.8, 58.3, 56.2, 56.0, 38.7, 29.2 ppm; IR (KBr) γ 1667 cm−1; HRMS
(EI) calcd for C16H15NO3S: [M ]+ 301.0773; found: 301.0771.
2,3-Dimethoxy-5,6-dihydrofuro[3′,2′:3,4]pyrrolo[2,1-a]-
isoquinolin-8(11bH)-one (6i). (94 mg, 72%) White solid: mp 103−
107 °C; 1H NMR (400 MHz, CDCl3) δ 7.61 − 7.59 (m, 1H), 7.11 (s,
1H), 6.78 − 6.76 (m, 1H), 6.59 (s, 1H), 4.15 − 4.09 (m, 1H), 3.92 (s,
3H), 3.84 (s, 3H), 3.42 (td, J = 12.9, 4.3 Hz, 1H), 2.89 (ddd, J = 17.7,
11.9, 6.1 Hz, 1H), 2.70 (dd, J = 16.2, 3.4 Hz, 1H) ppm; 13C NMR
(100 MHz, CDCl3) δ 163.9, 158.4, 150.6, 148.2, 144.4, 127.0, 111.5,
111.4, 110.4, 110.3, 107.0, 82.5, 56.2, 56.0, 35.2, 29.2 ppm; IR (KBr) γ
1669 cm−1; HRMS (EI) calcd for C16H15NO4: [M ]+ 285.1001; found:
285.0999.
45, 1253. (c) Bousquet, T.; Fleury, J.; Daich, A.; Netchitailo, P.
Tetrahedron 2006, 62, 706. (d) Pin, F.; Comesse, S.; Garrigues, B.;
Marchalin, S.; Daiech, A. J. Org. Chem. 2007, 72, 1181. (e) Zubkov, F.
I.; Ershova, J. D.; Orlova, A. A.; Zaytsev, V. P.; Nikitina, E. V.;
Peregudov, A. S.; Gurbanov, A. V.; Borisov, R. S.; Khrustalev, V. N.;
Maharramov, A. M. Tetrahedron 2009, 65, 3789. (f) Fleury, J.;
Netchitailo, P.; Daich, A. Synlett 2011, 13, 1821. (g) Zubkov, F. I.;
Airiyan, I. K.; Ershova, J. D.; Galeev, T. R.; Zaytsev, V. P.; Nikitina, E.
V.; Varlamov, A. V. RSC Adv. 2012, 2, 4103. (h) Castro-Castillo, V.;
Suarez-Rozas, C.; Pabon, A.; Perez, E. G.; Cassels, B. K.; Blair, S.
Bioorg. Med. Chem. Lett. 2013, 23, 327.
(5) (a) Valencia, E.; Freyer, A. J.; Shamma, M.; Fajardo, V.
Tetrahedron Lett. 1984, 25, 599. (b) Alonso, R.; Castedo, L.;
Dominguez, D. Tetrahedron Lett. 1985, 26, 2925. (c) Moreau, A.;
Couture, A.; Deniau, E.; Grandclaudon, P.; Lebrun, S. Tetrahedron
2004, 60, 6169. (d) Moreau, A.; Couture, A.; Deniau, E.;
Grandclaudon. Eur. J. Org. Chem. 2005, 16, 3437. (e) Wakchaure, P.
B.; Easwar, S.; Puranik, V. G.; Argade, N. P. Tetrahedron 2008, 64,
1986. (f) Zamudio-Medina, A.; Garcia-Gonzalez, M. C.; Padilla, J.;
Gonzalez-Zamora, E. Tetrahedron Lett. 2010, 51, 4837. (g) Selvakumar,
J.; Ramanathan, C. R. Org. Biomol. Chem. 2011, 9, 7643.
(6) (a) Pictet, A.; Spengler, T. Ber. 1911, 44, 2030. (b) Royer, J.;
Bonin, M.; Micouin, L. Chem. Rev. 2004, 104, 2311. (c) Le Quement,
S. T.; Nielsen, T. E.; Meldal, M. J. Comb. Chem. 2007, 9, 1060.
(7) (a) Bischler, A.; Napieralski, B. Ber. 1893, 26, 1903.
(b) Chrzanowska, M.; Rozwadowska, M. D. Chem. Rev. 2004, 104,
3341. (c) Bailey, K. R.; Ellis, A. J.; Reiss, R.; Snape, T. J.; Turner, N. J.
Chem. Commun. 2007, 3640.
(8) (a) Pomeranz, C. Monatsh. Chem. 1893, 14, 116. (b) Fritsch, P.
Ber. 1893, 26, 419. (c) Bobbitt, J. M.; Kiely, J. M.; Khanna, K. L.;
Ebermann, R. J. Org. Chem. 1965, 30, 2247. (d) Grajewska, A.;
Rozwadowska, M. D. Tetrahedron: Asymmetry 2007, 18, 2910.
(9) (a) Maryanoff, B. E.; Zhang, H. C.; Cohen, J. H.; Turchi, I. J.;
Maryanoff, C. A. Chem. Rev. 2004, 104, 1431. (b) Speckamp, W. N.;
Hiemstra, H. Tetrahedron 1985, 41, 4367. (c) Allin, S. M.; Northfield,
C. J.; Page, M. I.; Slawin, M. Z. Tetrahedron Lett. 1998, 39, 4905.
(10) (a) Parham, W. E.; Bradsher, C. K. Acc. Chem. Res. 1982, 15,
2,3,11-Trimethoxy-5,6-dihydroisoindolo[1,2-a]isoquinolin-
1
8(12bH)-one (6k). (100 mg, 99%) White solid: mp 86−90 °C; H
NMR (400 MHz, CDCl3) δ 7.77 (d, J = 8.4 Hz, 1H), 7.09 (s, 1H),
7.00 (dd, J = 8.4, 2.0 Hz, 1H), 6.66 (s, 1H), 5.54 (s, 1H), 5.29 (d, J =
1.0 Hz, 1H), 4.44 (ddd, J = 12.9, 5.8, 3.3 Hz, 1H), 3.94 (s, 3H), 3.91
(s, 3H), 3.85 (s, 3H), 3.40 − 3.32 (m, 1H), 2.97 (ddd, J = 16.0, 10.0,
5.7 Hz, 1H), 2.73 (dt, J = 15.8, 3.8 Hz, 1H) ppm; 13C NMR (100
MHz, CDCl3) δ 168.3, 162.9, 148.4, 147.9, 147.0, 127.2, 126.1, 125.5,
125.4, 113.9, 112.0, 109.3, 108.6, 58.8, 56.2, 56.0, 55.8, 38.3, 29.1 ppm;
IR (KBr) γ 1670 cm−1; HRMS (EI) calcd for C19H19NO4: [M ]+
325.1314; found: 325.1310.
3,11,12-Trimethoxy-5,6-dihydroisoindolo[1,2-a]isoquinolin-
1
8(12bH)-one (6l). (89 mg, 86%) White solid: mp 96−100 °C; H
NMR (400 MHz, CDCl3) δ 7.67 (d, J = 9.4 Hz, 1H), 7.57 (d, J = 8.2
Hz, 1H), 7.06 (d, J = 8.3 Hz, 1H), 6.77 − 6.72 (m, 2H), 5.68 (s, 1H),
4.12 − 4.03 (m, 1H), 3.98 (d, J = 9.9 Hz, 6H), 3.77 (s, 3H), 3.59 (dt, J
= 12.5, 6.1 Hz, 1H), 3.12 − 2.90 (m, 2H) ppm; 13C NMR (100 MHz,
CDCl3) δ 167.8, 159.0, 155.6, 144.6, 136.9, 136.5, 128.0, 127.6, 126.8,
119.8, 113.7, 113.2, 112.3, 60.5, 58.1, 56.3, 55.3, 38.7, 29.2 ppm; IR
(KBr) γ 1668 cm−1; HRMS (EI) calcd for C19H19NO4: [M ]+
325.1314; found: 325.1311.
́
300. (b) Martínez-Estibalez, U.; Gomez-Sanjuan, A.; García-Calvo, O.;
Aranzamendi, E.; Lete, E.; Sotomayor, N. Eur. J. Org. Chem. 2011,
3610.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra for all new products. This material is
available free for charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: guncheol@cnu.ac.kr.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by the Korea Research
Foundation Grant Funded by the Korean Government (KRF-
2011-0015865).
REFERENCES
■
(1) Larsen, R. D.; Reamer, R. A.; Corley, E. G.; Davis, P.; Grabowski,
E. J. J.; Reider, P. J.; Shinkai, I. J. Org. Chem. 1991, 56, 6034.
(2) (a) Fodor, G.; Nagubandi, S. Tetrahedron 1980, 36, 1279.
(b) Nagubandi, S.; Fodor, G. Heterocycles 1981, 15, 165.
(c) Dominguez, E.; Lete, E. Heterocycles 1983, 20, 1247.
(3) (a) Suau, R.; Lop
1996, 37, 9357. (b) Suau, R.; Lop
Tetrahedron 1997, 53, 14397. (c) Suau, R.; Lop
A.; Rico, R. Tetrahedron 2000, 56, 993.
́
ez-Romero, J. M.; Rico, R. Tetrahedron Lett.
ez-Romero, J. M.; Rico, R.
ez-Romero, J. M.; Ruiz,
́
́
(4) (a) Katritzky, A. R.; Mehta, S.; Hai-Ying, H. J. Org. Chem. 2001,
66, 148. (b) Osante, I.; Lete, E.; Sotomayor, N. Tetrahedron Lett. 2004,
E
dx.doi.org/10.1021/jo402345q | J. Org. Chem. XXXX, XXX, XXX−XXX