A new approach to methoxyisatins leading to the total synthesis of ophiuroidine and other hydroxytryptanthrins

Article abstract of DOI:10.1055/s-0029-1217004

A new method for the preparation of methoxyisatins from the corresponding methoxyanilines is described. The resulting methoxyisatins were used in the syntheses of several methoxytryptanthrin compounds. The natural product ophiuroidine (4,8,9-trihydroxytry

Full text of DOI:10.1055/s-0029-1217004

3642
PAPER
A New Approach to Methoxyisatins Leading to the Total Synthesis of
Ophiuroidine and Other Hydroxytryptanthrins
Synthesis
e
of Methoxy
f
isatins
a
f
nd
O
phi
r
uroidineey J. Mason, Tomasz Janosik, Jan Bergman*
Unit for Organic Chemistry, Department of Biosciences and Nutrition, Karolinska Institute, 141 57 Huddinge, Sweden
Fax +46(8)6081501; E-mail: Jan.Bergman@ki.se
Received 9 June 2009; revised 30 June 2009
R
Abstract: A new method for the preparation of methoxyisatins
from the corresponding methoxyanilines is described. The resulting
methoxyisatins were used in the syntheses of several methoxytryp-
tanthrin compounds. The natural product ophiuroidine (4,8,9-trihy-
droxytryptanthrin) was obtained from the appropriate trimethoxy
precursor using a microwave-mediated Prey demethylation.
O
N
R
N
O
R
Key words: isatin, tryptanthrin, ophiuroidine, Prey demethylation,
microwave irradiation
1 R = H
2 R = OH
3 R = OMe
Figure 1
Tryptanthrin (1) has a long history, some reports indicate
that it might have been isolated as early as 1822 by Du-
mas,1 and rediscovered again as a decomposition product
of indigo.2 This molecule (1) has lasted the test of time,
first as a dye and pigment,3 and more recently through its
broad biological activity, both in traditional remedies and
in vitro studies.4 Analogues of tryptanthrin, both synthetic
and natural, are still being discovered. A tri-hydroxy ana-
logue of 1, ophiuroidine (2), isolated from the brittle star
Ophiocoma riisei (Phylum - Echinodermata), was report-
ed as the first tryptanthrin-based compound isolated from
a marine invertebrate, and has been shown to display
moderate antiradical activity (DPPH scavenging study).
For characterization purposes, the trimethoxy derivative 3
(Figure 1) was prepared from the natural product due to
the insolubility of 2.5
prepared by initial treatment with ethyloxalyl chloride in
diethyl ether (Scheme 1). The resulting ethyl(methoxy-
phenyl)amino-oxoacetates (5a–e) were converted into the
corresponding morpholino-oxoacetamides (6a–e) by
heating at reflux in neat morpholine. Finally, the meth-
oxyisatins (7a–c) were prepared by heating the morpho-
line-oxoacetamides in neat phosphorus oxychloride
(Scheme 1, Table 1). As one may expect, the (methoxy-
phenyl)morpholino-oxoacetamides containing methoxy
substituents in the meta-position (6a–c) gave the best
yields of the isatins, while substrates containing ortho-
methoxy (6d–e) failed to give the desired products, af-
fording instead complex mixtures, which could not be
separated.
A somewhat related procedure for the preparation of 6-
methoxyisatin, relying on a Friedel–Crafts acylation of a
suitable oxoacetyl chloride derivative, has been de-
scribed, which gave 15% overall yield.8 As a comparison,
our new procedure gave the same compound with a yield
of 67% over the three steps from 4a. It should also be not-
ed that the isomer 4-methoxyisatin9 was not present, as
evidenced by NMR analysis of both the crude isolate and
the purified reaction product.
We decided to synthesize both 2 and 3, and verify the pro-
posed structures, along with several other hydroxytryp-
tanthrins, starting from suitable methoxyisatin and
methoxyisatoic anhydride precursors. The most common
method for isatin (1H-indole-2,3-dione) construction is
the Sandmeyer procedure.6 It is known that the synthesis
of methoxyisatins, especially the dimethoxyisatins, ac-
cording to Sandmeyer, leads to low yields either due to
low reactivity, or the formation of tars, resulting in prob-
lems during purification.7
Table 1 Preparation of Methoxyisatins from 6
Substrate
R1
R2
R3
R4
Time Isatin Yield
We therefore embarked on an exploration of new path-
ways for the preparation of methoxyisatins, and have dis-
covered a useful procedure supplanting the use of the
regulated substance chloral hydrate, a crucial component
of Sandmeyer’s method.
(h)
(%)
73
65
68
–
6a
6b
6c
6d
6e
H
OMe
OMe
OMe
H
H
H
H
4
7a
7b
7c
–
H
OMe
OMe
H
4
Starting from several commercially available methoxy-
anilines (4a–c), the corresponding methoxyisatins were
H
OMe 4
OMe
OMe
H
H
24
24
H
OMe
–
–
SYNTHESIS 2009, No. 21, pp 3642–3648
x
x.
x
x
.
2
0
0
9
Advanced online publication: 08.09.2009
DOI: 10.1055/s-0029-1217004; Art ID: P08309SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of Methoxyisatins and Ophiuroidine
3643
R1
Once the procedure for the preparation of isatins was es-
tablished, the methoxytryptanthrins were prepared, in-
cluding 3, which is the precursor to the natural product 2
(Scheme 3). A previously described method for synthe-
sizing 8,9-dimethoxytryptanthrin (11b) involved heating
the appropriate isatin (7) and isatoic anhydride in toluene
with a small amount of triethylamine, or some other hin-
dered base.11 However, our attempts to repeat this proce-
dure failed, and only starting materials were observed.
Since we have previously prepared the parent compound
tryptanthrin on a regular basis by an alternative method,
utilizing the coupling reagent diisopropylcarbodiimide
(DIC) in the presence of N-methylpiperidine,12 these par-
ticular conditions were instead used, producing the de-
sired tryptanthrins 3 and 11a–c (Table 2). The reagent
DIC was chosen for the coupling over N,N¢-dicyclohexyl-
carbodiimide (DCC), as many tryptanthrin compounds
are known to have poor solubility in most solvents, as
does the urea end-product of DCC reactions;13 the by-
product from DIC coupling is easier to remove by wash-
ing with polar organic solvents or by chromatography.
O
R1
H
N
EtO(CO)2Cl
Et2O
H2N
R2
R3
R2
R3
EtO
morpholine
reflux, 4 h
O
20 °C, 18 h
R4
4a–e
R4
5a–e
R1
O
R1
H
N
H
R2
R3
N
R2
R3
N
POCl3
65 °C
O
O
O
O
R4
7a–c
R4
6a–e
Scheme 1
In an attempt to generate halogenated derivatives of 4-
methoxyisatin, initial bromination of 5a with two equiva-
lents or more of N-bromosuccinimide (NBS) gave 8
(Scheme 2). When only one equivalent of NBS was used,
both 8 and 5a were detected in the reaction mixture. As
expected, heating 8 in neat morpholine gave 9, which was
thereafter treated with phosphorus oxychloride. However,
the annulation failed to take place, and only the starting
material 9 was observed. On the other hand, heating 9 in
Table 2 Syntheses of Methoxytryptanthrins
Isatoic anhydride
Substrate
Product
Yield (%)
R1
R2
R3
H
sulfuric acid gave the uncyclized phenol (10). This series OMe
H
7b
7a
3
89
61
86
65
of reactions would indicate that the position between the
H
H
H
11a
11b
11c
oxamide and the methoxy unit is the least reactive posi-
tion.10 This reactivity pattern can also explain the ob-
H
OMe
H
OMe isatin
7c
served absence of 4-methoxyisatin upon attempted
annulation of the meta-substituted reaction product men-
H
H
tioned above.
Finally the demethylation of the methoxytryptanthrins 3
and 11a–c was performed using the Prey conditions, i.e.
O
Br
NBS (2 equiv
or excess)
MeCN
H
N
morpholine
reflux, 4 h
heating
in
molten
pyridinium
hydrochloride
EtO
5a
(Scheme 4).14 This method sometimes requires long reac-
tion times, and can therefore lead to low yields due to de-
composition of the product under the rather harsh
conditions. A microwave-assisted variant was therefore
developed in order to reduce the reaction times, giving the
desired hydroxytryptanthrin compounds (2 and 12a–c) in
excellent yields (Table 3). The reactions were carried out
in N-methylpyrrolidone (NMP) as the solvent, due to its
high thermal stability and polarity. The introduction of a
solvent was mainly required in order to prevent the instru-
ment’s safety protocols from activating. It was observed
for the demethylation of the methoxytryptanthrin com-
pounds that as the number of substituents increased, so did
O
90 °C, 1 h
Br
OMe
8
O
Br
O
Br
H
H
N
N
H2SO4
N
N
O
O
O
O
100 °C
4 h
Br
Br
OMe
OH
9
10
Scheme 2
O
R
O
R3
R2
N-methylpiperidine
DIC, Py
O
N
R
7a–c
+
N
H
O
N
60 °C, 30 min,
100 °C, 1 h
R1
O
3, 11a–c
Scheme 3
Synthesis 2009, No. 21, 3642–3648 © Thieme Stuttgart · New York

3644
J. J. Mason et al.
PAPER
Preparation of Ethyl 2-(Methoxyphenyl)amino]-2-oxoacetates;
General Procedure
the time required to complete the demethylation; this is in-
dicated in the conditions of Table 3. In this context it
should also be mentioned that a previous example of a mi-
crowave-induced Prey demethylation has been reported,
describing cleavage of methyl aryl ethers under solvent-
free conditions employing domestic microwave equip-
ment (eight heating cycles were required at 215 W for 2
minutes per cycle).15
To a solution of freshly purified methoxyaniline (0.1 mol) in Et2O
(300 mL), ethyloxalyl chloride (14.42 g, 0.105 mol) was added in
portions with continuous stirring. Once the addition was complete,
the resulting slurry was stirred for 24 h, giving a clear solution. The
reaction mixture was transferred to a separating funnel, and washed
with sat. aq NaHCO3 (2 × 50 mL), H2O (50 mL) and brine (50 mL).
The organic portion was dried over anhydrous Na2SO4, and evapo-
rated to dryness, giving the desired product.
R
Note: Some of the products were not very soluble in this quantity of
Et2O, and the solids were collected via filtration before the Et2O
portion was treated as mentioned above. The solids were washed
with H2O, cold EtOH and then Et2O. The filtrate was evaporated to
dryness, redissolved in EtOAc and treated as mentioned above.
O
R
O
Py⋅HCl
NMP, MW
N
N
R
R
N
N
O
O
3, 11a–c
2, 12a–c
Ethyl 2-[(3-Methoxyphenyl)amino]-2-oxoacetate (5a)
Yield: 99%; white needles; mp 96–98 °C (MeOH) (Lit.17 95–
98 °C).
Scheme 4
IR (neat): 3346, 3079, 2982, 2941, 2837, 1720, 1695, 1611, 1556,
1496, 1431, 1370, 1230, 1276, 1200, 1190, 1157, 1053, 1016, 952,
861, 763, 700 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.88 (br s, 1 H), 7.38 (m, 1 H),
7.26 (t, J = 8.2 Hz, 1 H), 7.10 (m, 1 H), 6.73 (m, 1 H), 4.40 (dq,
Jd = 1.2 Hz, Jq = 7.2 Hz, 2 H), 3.80 (d, J = 1.2 Hz, 3 H), 1.41 (dt,
Jd = 1.2 Hz, Jt = 7.2 Hz, 3 H).
13C NMR (75.5 MHz, CDCl3): d = 161.1, 160.4, 154.0, 137.6,
130.0, 112.2, 111.5, 105.7, 63.8, 55.4, 14.1.
MS (ESI): m/z = 224 [M + H]+.
Table 3 Microwave-Assisted Demethylation of Methoxytryptan-
thrins
Substrate
Methoxytryptanthrin Time
Product
R = OH
Yield
(%)
(R)
(min)
3
4,8,9-(OMe)3
9-OMe
7
3
5
7
2
98
98
99
98
11a
11b
11c
12a
12b
12c
2,3-(OMe)2
7,8,9-(OMe)3
Ethyl 2-[(3,4-Dimethoxyphenyl)amino]-2-oxoacetate (5b)
Yield: 98%; white needles; mp 102–103 °C.
The NMR data of 4,8,9-trimethoxytryptanthrin (3) in
CDCl3 were in excellent agreement with those reported in
the literature, however, the structure of ophiuroidine (2)
could not be analyzed by NMR due to its insolubility in
most common solvents.5 The other hydroxytryptanthrins
were found to be equally insoluble. Hence, HRMS and IR
were found to be the best analytical methods in their iden-
tification.
IR (neat): 3344, 2959, 2934, 2839, 1722, 1696, 1602, 1543, 1511,
1461, 1442, 1297, 1274, 1211, 1146, 1021, 860, 799 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.83 (br s, 1 H), 7.43 (d, J = 2.4
Hz, 1 H), 7.05 (dd, J = 8.6, 2.4 Hz, 1 H), 6.83 (d, J = 8.6 Hz, 1 H),
4.39 (q, J = 7.2 Hz, 2 H), 3.87 (s, 3 H), 3.86 (s, 3 H), 1.41 (t, J = 7.2
Hz, 3 H).
13C NMR (75.5 MHz, CDCl3): d = 161.2, 153.8, 149.2, 146.8,
130.0, 112.0, 111.4, 104.4, 63.8, 56.2, 56.0, 14.1.
In conclusion our new method for preparing methoxyisat-
ins has proven to be a useful and effective procedure when
compared to the traditional Sandmeyer method. The struc-
ture of ophiuroidine was confirmed, as the spectroscopic
data obtained of the trimethoxy precursor was identical to
those presented in the original communication.5
MS (ESI): m/z = 254 [M + H]+.
Ethyl 2-[(3,4,5-Trimethoxyphenyl)amino]-2-oxoacetate (5c)
Yield: 93%; white needles; mp 133–134 °C (MeOH) (Lit.17 133–
134 °C).
IR (neat): 3352, 3323, 2978, 2939, 2824, 1708, 1601, 1548, 1505,
1453, 1413, 1286, 1233, 1205, 1183, 1124, 1010, 820 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.80 (br s, 1 H), 6.95 (s, 2 H), 4.40
(q, J = 7.2 Hz, 2 H), 3.85 (s, 6 H), 3.82 (s, 3 H), 1.42 (t, J = 7.2 Hz,
3 H).
13C NMR (75.5 MHz, CDCl3): d = 161.1, 153.9, 153.6, 135.8,
132.5, 97.7, 63.9, 61.1, 56.3, 14.1.
All reagents and solvents were purchased from commercial sources
and used as received, except for the anisidines, which were purified
by vacuum distillation before use. The methoxyisatoic anhydrides
were prepared from the corresponding methoxyanthranilic acids ac-
cording to the procedure by Wagner and Fegley.16 Melting points
were taken using a Büchi Melting Point B-545 capillary apparatus
in open capillary tubes and are uncorrected. IR spectra (neat) were
acquired using a Thermo Nicolet Avatar 330 FT-IR instrument.
MS (ESI): m/z = 284 [M + H]+.
Ethyl 2-[(2-Methoxyphenyl)amino]-2-oxoacetate (5d)
1
NMR data was recorded at 300.1 MHz for H, and 75.5 MHz for
Yield: 99%; white needles; mp 84 °C (MeOH) (Lit.17 81–85 °C).
13C, using the residual solvent signal as reference. The microwave
unit used was a Biotage Advancer. Elemental analyses and mass
spectroscopy services were externally sourced.
IR (neat): 3379, 2989, 1701, 1600, 1532, 1483, 1463, 1439, 1367,
1291, 1248, 1170, 1110, 1045, 1018, 754, 690 cm–1.
1H NMR (300 MHz, CDCl3): d = 9.49 (br s, 1 H), 8.40 (dd, J = 8.0,
1.6 Hz, 1 H), 7.12 (ddd, J = 7.9, 7.8, 1.6 Hz, 1 H), 7.00 (ddd,
J = 7.9, 7.8, 1.2 Hz, 1 H), 6.90 (dd, J = 8.0, 1.2 Hz, 1 H), 4.41 (q,
J = 7.2 Hz, 2 H), 3.91 (s, 3 H), 1.42 (t, J = 7.2 Hz, 3 H).
Synthesis 2009, No. 21, 3642–3648 © Thieme Stuttgart · New York

PAPER
Synthesis of Methoxyisatins and Ophiuroidine
3645
13C NMR (75.5 MHz, CDCl3): d = 161.0, 153.8, 148.6, 126.2,
MS (ESI): m/z = 265 [M + H]+.
HRMS (FAB): m/z [M + H]+ calcd for C13H17N2O4: 265.1188;
125.3, 121.2, 120.0, 110.2, 63.6, 55.9, 14.1.
MS (ESI): m/z = 224 [M + H]+.
found: 265.1188.
Ethyl 2-[(2,4-Dimethoxyphenyl)amino]-2-oxoacetate (5e)
Yield: 95%; white needles; mp 146–147 °C (MeOH) (Lit.18 242–
244 °C).
N-(3,4-Dimethoxyphenyl)-2-(4-morpholinyl)-2-oxoacetamide
(6b)
Yield: 95%; white needles; mp 139–140 °C (MeOH).
IR (neat): 3388, 2980, 2945, 1733, 1695, 1610, 1539, 1499, 1455,
1429, 1416, 1367, 1280, 1207, 1174, 1153, 1130, 1030, 943, 829
cm–1.
1H NMR (300 MHz, CDCl3): d = 9.29 (br s, 1 H), 8.31–8.26 (m,
1 H), 6.50–6.44 (2 H, m), 4.38 (q, J = 7.2 Hz, 2 H), 3.86 (s, 3 H),
3.78 (s, 3 H), 1.40 (t, J = 7.2 Hz, 3 H).
13C NMR (75.5 MHz, CDCl3): d = 161.1, 157.5, 153.4, 149.8,
120.7, 119.8, 103.9, 98.7, 63.5, 55.9, 55.6, 14.1.
MS (ESI): m/z = 254 [M + H]+.
IR (neat): 3295, 2991, 2939, 2837, 1663, 1630, 1601, 1516, 1460,
1442, 1405, 1257, 1237, 1217, 1133, 1107, 1038, 1016, 970 cm–1.
1H NMR (300 MHz, CDCl3): d = 9.27 (br s, 1 H), 7.33 (d, J = 2.4
Hz, 1 H), 7.00 (dd, J = 8.7, 2.4 Hz, 1 H), 6.80 (d, J = 8.7 Hz, 1 H),
4.29–4.21 (m, 2 H), 3.85 (s, 3 H), 3.83 (s, 3 H), 3.76–3.66 (m, 6 H).
13C NMR (75.5 MHz, CDCl3): d = 160.5, 158.1, 149.2, 146.5,
130.4, 112.1, 111.4, 104.5, 67.3, 66.8, 56.1, 56.0, 47.3, 44.0.
MS (ESI): m/z = 295 [M + H]+.
HRMS (FAB): m/z [M]+ calcd for C14H18N2O5: 294.1216; found:
294.1214.
Ethyl 2-[(2,4-Dibromo-5-methoxyphenyl)amino]-2-oxoacetate
(8)
N-(3,4,5-Trimethoxyphenyl)-2-(4-morpholinyl)-2-oxoacet-
amide (6c)
Yield: 98%; white needles; mp 128 °C (MeOH).
To a solution of ethyl (3-methoxyphenylcarbamoyl)formate (5a;
11.62 g, 50.0 mmol) in anhydrous MeCN (150 mL), NBS (17.83 g,
100 mmol) was added portion-wise over 10 min. The reaction mix-
ture was then heated for 1 h at 90 °C then cooled to r.t. The solution
was diluted with EtOAc (300 mL) and washed with aq HCl (2 M,
3 × 100 mL), H2O (2 × 50 mL), and brine (2 × 50 mL). Drying the
organic phase over Na2SO4, evaporation to dryness and recrystalli-
zation from MeOH gave 7.
IR (neat): 3280, 2911, 2839, 1685, 1652, 1597, 1530, 1507, 1446,
1409, 1234, 1198, 1125, 1108, 1004, 828 cm–1.
1H NMR (300 MHz, CDCl3): d = 9.21 (br s, 1 H), 6.89 (s, 2 H),
4.33–4.28 (m, 2 H), 3.85 (s, 6 H), 3.81 (s, 3 H), 3.80–3.69 (m, 6 H).
13C NMR (75.5 MHz, CDCl3): d = 160.2, 158.1, 153.5, 135.5,
132.9, 97.6, 67.3, 66.9, 61.1, 56.3, 47.4, 44.2.
Yield: 19.0 g (98%); white needles; mp 129–131 °C.
MS (ESI): m/z = 325 [M + H]+.
IR (neat): 3337, 3080, 3021, 2983, 2944, 2906, 1709, 1585, 1527,
1458, 1437, 1383, 1368, 1302, 1273, 1213, 1158, 1059, 1043, 1019
cm–1.
1H NMR (300 MHz, CDCl3): d = 9.46 (br s, 1 H), 8.21 (s, 1 H), 7.70
(s, 1 H), 4.43 (q, J = 7.2 Hz, 2 H), 3.90 (s, 3 H), 1.44 (t, J = 7.2 Hz,
3 H).
Anal. Calcd for C15H20N2O6: C, 55.55; H, 6.22; N, 8.64. Found: C,
55.53; H, 6.24; N, 8.59.
N-(2-Methoxyphenyl)-2-(4-morpholinyl)-2-oxoacetamide (6d)
Yield: 90%; white needles; mp 96–97 °C (MeOH).
13C NMR (75.5 MHz, CDCl3): d = 160.3, 156.0, 154.1, 135.4,
IR (neat): 3357, 2975, 2864, 1689, 1634, 1596, 1519, 1479, 1439,
1425, 1244, 1111, 1020, 920 cm–1.
1H NMR (300 MHz, CDCl3): d = 9.66 (br s, 1 H), 8.32 (dd, J = 8.0,
1.6 Hz, 1 H), 7.10 (ddd, J = 7.9, 7.8, 1.6 Hz, 1 H), 6.97 (ddd,
J = 7.8, 7.7, 1.3 Hz, 1 H), 6.90 (dd, J = 8.1, 1.3 Hz, 1 H), 4.30–4.24
(m, 2 H), 3.89 (s, 3 H), 3.79–3.70 (m, 6 H).
134.6, 107.8, 104.7, 103.8, 64.2, 56.6, 14.1.
MS (ESI): m/z = 382 [M + H]+.
HRMS (FAB): m/z [M + H]+ calcd for C11H12Br2NO4: 381.9113;
found: 381.9114.
13C NMR (75.5 MHz, CDCl3): d = 160.0, 157.7, 148.2, 126.0,
124.5, 120.5, 119.2, 109.7, 66.8, 66.3, 55.3, 46.8, 43.4.
Preparation of N-Methoxyphenyl-2-morpholino-2-oxoacet-
amides; General Procedure
A mixture of the appropriate amide 5 (50 mmol) and morpholine
(40 mL) was heated at reflux for 4 h. Evaporation under vacuum
gave a residue, which was triturated with Et2O overnight. The re-
sulting solid was collected and washed with Et2O (2 × 20 mL) giv-
ing compound 6. The filtrates were combined and washed with aq
HCl (2 M, 2 × 20 mL), H2O (20 mL) and brine (20 mL). Drying
over Na2SO4 and evaporation gave a second crop of the product 5.
The two crops were combined and recrystallized from MeOH.
MS (ESI): m/z = 265 [M + H]+.
Anal. Calcd for C13H16N2O4: C, 59.08; H, 6.10; N, 10.60. Found: C,
58.98; H, 6.03; N, 10.57.
N-(2,4-Dimethoxyphenyl)-2-(4-morpholinyl)-2-oxoacetamide
(6e)
Yield: 96%; white needles; mp 123–124 °C (MeOH).
IR (neat): 1356, 2973, 2866, 1678, 1641, 1617, 1535, 1493, 1458,
1445, 1433, 1409, 1251, 1204, 1155, 1126, 1114, 1047, 1030, 835
cm–1.
N-(3-Methoxyphenyl)-2-(4-morpholinyl)-2-oxoacetamide (6a)
Yield: 93%; white needles; mp 89–90 °C (MeOH).
IR (neat): 3297, 3012, 2978, 2954, 2873, 2841, 1699, 1633, 1591,
1531, 1481, 1454, 1431, 1214, 1188, 1113, 1043, 1032, 919, 875,
825, 775 cm–1.
1H NMR (300 MHz, CDCl3): d = 9.29 (br s, 1 H), 7.32 (dd, J = 2.3,
2.3 Hz, 1 H), 7.24 (dd, J = 8.2, 8.2 Hz, 1 H), 7.08 (dd, J = 8.2, 1.2
Hz, 1 H), 6.71 (dd, J = 8.2, 2.3 Hz, 1 H), 4.31–4.25 (m, 2 H), 3.80
(s, 3 H), 3.79–3.68 (m, 6 H).
1H NMR (300 MHz, CDCl3): d = 9.47 (br s, 1 H), 8.20 (d, J = 8.2
Hz, 1 H), 6.50–6.42 (m, 2 H), 4.29–4.24 (m, 2 H), 3.85 (s, 3 H),
3.78 (s, 3 H), 3.77–3.68 (m, 6 H).
13C NMR (75.5 MHz, CDCl3): d = 160.7, 157.8, 157.4, 150.1,
120.5, 120.1, 103.8, 98.8, 67.3, 66.9, 55.8, 55.6, 47.3, 43.9.
MS (ESI): m/z = 295 [M + H]+.
13C NMR (75.5 MHz, CDCl3): d = 160.4, 160.3, 158.3, 138.0,
129.9, 111.3, 111.2, 105.7, 67.3, 66.9, 55.4, 47.4, 44.1.
Anal. Calcd for C14H18N2O5: C, 57.13; H, 6.16; N, 9.52. Found: C,
57.03; H, 6.28; N, 9.51.
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N-(2,4-Dibromo-5-methoxyphenyl)-2-(4-morpholinyl)-2-oxo-
acetamide (9)
IR (neat): 3306, 1755, 1724, 1615, 1486, 1348, 1302, 1235, 1152,
1131, 1000, 792 cm–1.
Yield: 95%; white needles; mp 192–193 °C (MeOH).
1H NMR (300 MHz, CDCl3): d = 8.63 (br s, 1 H), 7.08 (s, 1 H), 6.53
IR (neat): 3267, 3120, 3040, 2994, 2923, 2875, 1693, 1646, 1572,
1509, 1462, 1430, 1381, 1271, 1243, 1203, 1114, 1060, 1033, 925,
877 cm–1.
1H NMR (300 MHz, CDCl3): d = 9.88 (br s, 1 H), 8.12 (s, 1 H), 7.69
(s, 1 H), 4.34–4.28 (m, 2 H), 3.90 (s, 3 H), 3.80–3.70 (m, 6 H).
13C NMR (75.5 MHz, CDCl3): d = 159.36, 158.2, 155.8, 135.4,
135.1, 107.3, 104.5, 104.1, 67.2, 66.9, 56.6, 47.3, 44.3.
(s, 1 H), 4.00 (s, 3 H), 3.85 (s, 3 H).
1H NMR (300 MHz, DMSO-d6): d = 10.71 (br s, 1 H), 7.03 (s, 1 H),
6.47 (s, 1 H), 3.89 (s, 3 H), 3.78 (s, 3 H).
13C NMR (75.5 MHz, DMSO-d6): d = 181.6, 160.7, 158.3, 148.8,
145.0, 108.6, 107.2, 96.4, 56.4, 56.0.
MS (ESI): m/z = 208 [M + H]+.
MS (ESI): m/z = 423 [M + H]+.
HRMS (FAB): m/z [M + H]+ calcd for C13H15Br2N2O4: 422.9378;
4,5,6-Trimethoxyisatin (7c)
Yield: 68%; red-brown powder; mp 218–219 °C [Lit.20 210 °C
(dec.)].
found: 422.9380.
IR (neat): 3301, 3124, 2941, 1746, 1703, 1622, 1594, 1480, 1345,
1300, 1265, 1118, 1057, 988, 972, 916, 829, 808, 728 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.90 (br s, 1 H), 6.26 (s, 2 H), 4.22
(s, 3 H), 3.96 (s, 3 H), 3.77 (s, 3 H).
1H NMR (300 MHz, DMSO-d6): d = 10.92 (br s, 1 H), 6.22 (s, 2 H),
4.02 (s, 3 H), 3.90 (s, 3 H), 3.62 (s, 3 H).
13C NMR (75.5 MHz, DMSO-d6): d = 178.6, 162.4, 160.4, 152.8,
148.9, 135.3, 102.6, 91.7, 61.5, 60.9, 56.7.
N-(2,4-Dibromo-5-hydroxyphenyl)-2-(4-morpholinyl)-2-oxo-
acetamide (10)
A mixture of 9 (1.06 g, 2.5 mmol) and concd H2SO4 (2 mL) was
heated at 80 °C for 4 h. The solution was quenched onto crushed ice
and allowed to stir. The resulting solid was collected via filtration
and purified by chromatography (n-heptane–EtOAc, 3:1), followed
by recrystallization from MeOH to give 10.
Yield: 0.87 g (85%); white needles; mp 181–182 °C.
MS (ESI): m/z = 238 [M + H]+.
IR (neat): 3290 2927, 2868, 1739, 1692, 1643, 1569, 1434, 1409,
1310, 1246, 1179, 1106, 879 cm–1.
Preparation of Methoxytryptanthrins; General Procedure
Under an atmosphere of nitrogen, the appropriate methoxyisatoic
anhydride (2.0 mmol) and methoxyisatin (2.0 mmol) were suspend-
ed in anhydrous pyridine (7.0 mL). To this mixture, N-methylpipe-
ridine (0.05 mL) and DIC (1.0 mL) were added, and the solution
was warmed to 60 °C for 30 min. The temperature was gradually in-
creased to 100 °C over 30 min and heating was continued at 100 °C
for 1 h. The solution was allowed to cool with stirring overnight,
then the resulting precipitate was collected by filtration and washed
with cold MeOH (2 × 20 mL) giving the desired product.
1H NMR (300 MHz, CDCl3): d = 9.81 (br s, 1 H), 8.15 (s, 1 H), 7.65
(s, 1 H), 4.35–4.25 (m, 2 H), 3.84–3.70 (m, 6 H).
13C NMR (75.5 MHz, CDCl3): d = 159.5, 158.2, 135.3, 134.6,
108.6, 105.9, 104.5, 67.3, 66.9, 47.4, 44.4.
ESI-MS: m/z = 409 [M + H]+.
HRMS (FAB): m/z [M + H]+ calcd for C12H13Br2N2O4: 408.9232;
found: 408.9234.
Preparation of Methoxyisatins; General Procedure
4,8,9-Trimethoxyindolo[2,1-b]quinazolin-6,12-dione (3)5
Yield: 89%; orange powder; mp >300 °C.
Compound 6 (20 mmol) was dissolved in POCl3 (5–10 mL) and
warmed at 65 °C for 4 h. The reaction was quenched by pouring
onto crushed ice (150 mL) with stirring, and was thereafter extract-
ed with CHCl3 (3 × 30 mL). The aqueous portion, containing some
unextracted product, was evaporated to dryness and treated with hot
EtOH (50 mL) giving further product, which was collected via fil-
tration and dissolved in CHCl3. The combined organic phases were
purified by chromatography (CHCl3–MeOH) to give 7, which was
recrystallized from MeOH.
IR (neat): 2993, 2942, 2840, 1709, 1679, 1587, 15734, 1492, 1479,
1456, 1434, 1362, 1328, 1273, 1234, 1211, 1149, 1096, 988, 864,
754 cm–1.
The NMR data are in agreement with those given in the literature.5
1H NMR (300 MHz, CDCl3): d = 8.21 (s, 1 H), 7.97 (dd, J = 8.0, 1.2
Hz, 1 H), 7.60 (t, J = 8.0 Hz, 1 H), 7.33 (s, 1 H), 7.29 (dd, J = 8.0,
1.2 Hz, 1 H), 4.10 (s, 3 H), 4.05 (s, 3 H), 3.94 (s, 3 H).
13C NMR (75.5 MHz, CDCl3): d = 180.0, 157.8, 157.3, 157.1,
148.4, 143.1, 144.1, 136.8, 130.8, 124.9, 118.5, 115.6, 114.7, 106.1,
101.2, 57.0, 56.4, 56.3.
6-Methoxyisatin (7a)
Yield: 73%; red crystals; mp 228–230 °C (Lit.19 229–230 °C, H2O).
IR (neat): 3228, 1754, 1730, 1713, 1609, 1592, 1508, 1495, 1449,
1321, 1227, 1201, 1150, 1087, 1010, 946, 857 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.30 (br s, 1 H), 7.58 (d, J = 8.5
Hz, 1 H), 6.57 (dd, J = 8.5, 2.2 Hz, 1 H), 6.43 (d, J = 2.2 Hz, 1 H),
3.91 (s, 3 H).
MS (ESI): m/z = 339 [M + H]+.
HRMS (FAB): m/z [M + H]+ calcd for C18H15N2O5: 339.0981;
found: 339.0978.
1H NMR (300 MHz, DMSO-d6): d = 10.97 (br s, 1 H), 7.49 (d,
J = 8.5 Hz, 1 H), 6.57 (dd, J = 8.5, 2.2 Hz, 1 H), 6.38 (d, J = 2.2 Hz,
1 H), 3.87 (s, 3 H).
13C NMR (75.5 MHz, DMSO-d6): d = 181.6, 167.8, 160.6, 153.6,
127.3, 111.2, 108.8, 97.8, 56.2.
9-Methoxyindolo[2,1-b]quinazolin-6,12-dione (11a)
Yield: 61%; yellow needles; mp 265–266 °C.
IR (neat): 3423, 3129, 3070, 3012, 2842, 1728, 1672, 1585, 1489,
1463, 1443, 1357, 1301, 1262, 1239, 1203, 1122, 1108, 1067, 1040,
1015, 852, 769, 689 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.40 (dd, J = 8.0, 1.6 Hz, 1 H),
8.16 (d, J = 2.2 Hz, 1 H), 8.04–7.98 (m, 1 H), 7.87–7.79 (m, 2 H),
7.67 (ddd, J = 7.8, 7.5, 1.2 Hz, 1 H), 6.87 (dd, J = 8.5, 2.4 Hz, 1 H),
4.01 (s, 3 H).
MS (ESI): m/z = 178 [M + H]+.
5,6-Dimethoxyisatin (7b)
Yield: 65%; red powder; mp 240–241 °C (MeOH) [Lit.6 240–
248 °C (MeOH)].
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Synthesis of Methoxyisatins and Ophiuroidine
3647
1H NMR (300 MHz, DMSO-d6): d = 8.27 (m, 1 H), 7.96 (d, J = 2.2
Hz, 1 H), 7.94–7.89 (m, 2 H), 7.82 (d, J = 8.6 Hz, 1 H), 7.75–7.67
(m, 1 H), 6.98 (dd, J = 8.5, 2.3 Hz, 1 H), 3.98 (s, 3 H).
13C NMR (75.5 MHz, DMSO-d6): d = 179.8, 167.2, 157.6, 148.2,
146.5, 145.5, 135.0, 129.8, 129.7, 126.9, 123.2, 115.5, 112.8, 103.1,
56.5.
MS (ESI): m/z = 279 [M + H]+.
HRMS (FAB): m/z [M + H]+ calcd for C16H11N2O3: 279.0770;
7,8,9-Trihydroxyindolo[2,1-b]quinazolin-6,12-dione (12c)
Yield: 98%; dark amorphous solid; mp >300 °C.
IR (neat): 3168 (br), 1677, 1635, 1597, 1522, 1463, 1421, 1301,
1258, 1169, 1119 cm–1.
MS (ESI): m/z = 297 [M + H]+.
HRMS (FAB): m/z [M + H]+ calcd for C15H9N2O5: 297.0512;
found: 297.0515.
found: 279.0772.
Acknowledgment
2,3-Dimethoxyindolo[2,1-b]quinazolin-6,12-dione (11b)21
We thank Mr. P. Rhönnstad for assistance with the microwave
reactions and LCMS analyses.
Yield: 86%; yellow powder; mp >300 °C [Lit.21 350 °C (dec)].
IR (neat): 1719, 1669, 1590, 1505, 1320, 1283, 1216, 997, 870, 762
cm–1.
These data are in agreement with the literature.21
References
MS (ESI): m/z = 309 [M + H]+.
(1) Seidel, P. Indigo-Studien; BASF: Ludwigshafen, 1938, and
references therein.
(2) (a) Tafel, J. Ber. Dtsch. Chem. Ges. 1892, 25, 1619.
(b) Friedländer, P.; Roschdestwensky, N. Ber. Dtsch. Chem.
Ges. 1915, 48, 1841. (c) Machemer, H. Ber. Dtsch. Chem.
Ges. B. 1930, 63, 1341. (d) Heller, G. Ber. Dtsch. Chem.
Ges. B. 1936, 69, 563. (e) Bird, C. W. Tetrahedron 1963,
19, 901.
7,8,9-Trimethoxyindolo[2,1-b]quinazolin-6,12-dione (11c)
Yield: 65%; yellow needles; mp 266–267 °C.
IR (neat): 3063, 3029, 2941, 1713, 1676, 1592, 1476, 1417, 1370,
1305, 1251, 1230, 1131, 1074, 1010, 984, 934, 845, 770 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.37 (dd, J = 7.9, 1.5 Hz, 1 H),
8.05 (s, 1 H), 8.00 (dd, J = 8.1, 1.1 Hz, 1 H), 7.86–7.79 (m, 1 H)
7.67–7.60 (m, 1 H), 4.24 (s, 3 H), 4.07 (s, 3 H), 3.86 (s, 3 H).
(3) Novotná, P.; Boon, J. J.; van der Horst, J.; Pacáková, V.
Color Technol. 2003, 119, 121.
(4) Witt, A.; Bergman, J. Curr. Org. Chem. 2003, 7, 659.
(5) Utkina, N. K.; Denisenko, V. A. Tetrahedron Lett. 2007, 48,
4445.
(6) Taylor, A. J. Chem. Res., Miniprint 1980, 10, 4154.
(7) (a) Sumpter, W. C. Chem. Rev. 1954, 3, 393. (b) Popp,
F. D. Adv. Heterocycl. Chem. 1975, 18, 2. (c) da Silva,
J. F. M.; Garden, S. J.; Pinto, A. C. J. Braz. Chem. Soc. 2001,
12, 273.
13C NMR (75.5 MHz, CDCl3): d = 177.6, 162.1, 158.4, 153.7,
146.9, 145.3, 144.0, 139.5, 135.2, 130.6, 129.9, 127.4, 123.5, 108.0,
97.3, 62.5, 61.7, 57.2.
MS (ESI): m/z = 339 [M + H]+.
HRMS (FAB): m/z [M + H]+ calcd for C18H15N2O5: 339.0981;
found: 339.0981.
(8) Kaila, N.; Janz, K.; DeBernardo, S.; Bedard, P. W.;
Camphausen, R. T. J.; Tam, S.; Tsao, D. H. H.; Keith, C. K.;
Nickerson-Nutter, C.; Shilling, A.; Young-Sciame, R.;
Wang, Q. J. Med. Chem. 2007, 50, 21.
(9) Hewawasam, P.; Meanwell, N. A. Tetrahedron Lett. 1994,
35, 7303.
Preparation of Hydroxytryptanthrins; General Procedure
The appropriate methoxytryptanthrin (1.0 mmol) and pyridinium
hydrochloride (2.0 g) were suspended in N-methylpyrrolidone (1.0
mL) and heated to 230 °C (for reaction times see Table 3). The so-
lution was treated with H2O (10 mL) and the resulting precipitate
was collected by filtration giving the desired product.
(10) Sadler, P. W. J. Org. Chem. 1956, 21, 169.
(11) Sharma, V. M.; Prasanna, P.; Adi Sheshu, K. V.; Renuka, B.;
Laxman Rao, C. V.; Sunil Kumar, G.; Prasad Narasimuhulu,
C.; Arvind Babu, P.; Puranik, R. C.; Subramanyam, D.;
Venkateswarlu, A.; Rajagopal, S.; Sunil Kumar, K. B.;
Seshagiri Rao, C.; Rao Mamidi, N. V. S.; Deevi, D. S.;
Ajaykumar, R.; Rajagopalan, R. Bioorg. Med. Chem. Lett.
2002, 12, 2303.
4,8,9-Trihydroxyindolo[2,1-b]quinazolin-6,12-dione (2)5
Yield: 98%; dark amorphous solid; mp >300 °C.
IR (neat): 3090, 1753, 1454, 1289, 1154, 1059 cm–1.
MS (ESI): m/z = 297 [M + H]+.
HRMS (FAB): m/z [M + H]+ calcd for C15H9N2O5: 297.0512;
found: 297.0521.
(12) Bergman, J.; Lindström, J.; Tilstam, U. Tetrahedron 1985,
41, 2879.
9-Hydroxyindolo[2,1-b]quinazolin-6,12-dione (12a)
Yield: 98%; dark amorphous solid; mp >300 °C.
(13) Tartar, A.; Gesquiere, J. C. J. Org. Chem. 1979, 44, 5000.
(14) (a) Prey, V. Ber. 1941, 1219. (b) Wahlström, N.; Bergman,
J. Tetrahedron Lett. 2004, 45, 7273. (c) Protective Groups
in Organic Synthesis, 3rd ed.; Greene, T. W.; Wuts, P. G. M.,
Eds.; John Wiley & Sons: New York, 1999.
IR (neat): 1715, 1640, 1589, 1558, 1462, 1347, 1308, 1257, 1202,
1181, 1107, 1043 cm–1.
MS (ESI): m/z = 265 [M + H]+.
(15) Kulkarni, P. P.; Kadam, A. J.; Mane, R. B.; Desai, U. V.;
Wadgaonk, P. P. J. Chem. Res., Synop. 1999, 394.
(16) (a) Wagner, E. C.; Fegley, M. F. Org. Synth. 1917, 27, 15.
(b) Hess, H. J.; Cronin, T. H.; Scriabine, A. J. Med. Chem.
1968, 11, 130.
(17) Sellstedt, J. H.; Guinosso, C. J.; Begany, A. J.; Bell, S. C.;
Rosenthale, M. J. Med. Chem. 1975, 18, 926.
(18) Love, B.; Jones, H.; Brown, R. E.; Huang, F.; Khandwala,
A.; Leibowitz, M. J.; Sonnino-Goldman, P. J. Med. Chem.
1985, 28, 24.
HRMS (FAB): m/z [M + H]+ calcd for C15H9N2O3: 265.0613;
found: 265.0604.
2,3-Dihydroxyindolo[2,1-b]quinazolin-6,12-dione (12b)
Yield: 99%; dark amorphous solid; mp >300 °C.
IR (neat): 3279 (br), 1708, 1657, 1593, 1506, 1460, 1382, 1324,
1293, 1206, 1150, 1047 cm–1.
MS (ESI): m/z = 281 [M + H]+.
HRMS (FAB): m/z [M + H]+ calcd for C15H9N2O4: 281.0562;
found: 281.0566.
Synthesis 2009, No. 21, 3642–3648 © Thieme Stuttgart · New York

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J. J. Mason et al.
PAPER
(20) Giovannini, E.; Portman, P. Helv. Chim. Acta 1948, 31,
(19) Cowell, W. T.; Horner, J. K.; Skinner, W. A. Public Bulletin
Report, AD 435,889; United States Department of
Commerce, Office of Technical Services: Washington, DC,
1964.
1381.
(21) Baker, W. L.; Mitscher, L. A. PCT Int. Appl. WO 9513807,
1995; Chem. Abstr. 1995, 123, 256757.
Synthesis 2009, No. 21, 3642–3648 © Thieme Stuttgart · New York