Synthesis of granulatimide positional analogues.

Article abstract of DOI:10.1248/cpb.51.209

The Stille coupling reaction of the stannylindole 13 with the 5-iodoimidazole derivative 14 (or 27) in the presence of PdCl(2)(PPh(3))(2) gave the corresponding indole-imidazole coupling product 15 (or 28), thereby affording a synthetic approach to 10-met

Full text of DOI:10.1248/cpb.51.209

February 2003
Notes
Chem. Pharm. Bull. 51(2) 209—214 (2003)
209
Synthesis of Granulatimide Positional Analogues
Takuji YOSHIDA, Masakazu NISHIYACHI, Nobuyuki NAKASHIMA, Masayuki MURASE,* and Eiichi KOTANI
Showa Pharmaceutical University; Machida, Tokyo 194–8543, Japan.
Received September 26, 2002; accepted December 2, 2002
The Stille coupling reaction of the stannylindole 13 with the 5-iodoimidazole derivative 14 (or 27) in the
presence of PdCl2(PPh3)2 gave the corresponding indole-imidazole coupling product 15 (or 28), thereby affording
a synthetic approach to 10-methylgranulatimide (7), 15-methylgranulatimide (11), and 10,15-dimethylgranula-
timide (12), as well as 10-methylisogranulatimide B (5).
Key words alkaloid; indole; maleimide; imidazole; Stille coupling reaction; synthesis
Granulatimide (1) and isogranulatimide (2), isolated from Results and Discussion
the Brazilian ascidian Didemnum granulatum,1—3) are with-
To obtain the new granulatimide analogues 10, 11, 12 and
out precedent among natural alkaloids having indole/ the 2,5Ј-indole-imidazole coupling product for further struc-
maleimide/imidazole-containing aromatic heterocyclic skele- tural manipulation, we needed to replace the 4-iodoimidazole
tons, and they show strong activity as G2 checkpoint in- moiety with a 5-iodoimidazole derivative. Thus, introduction
hibitors.4) Total syntheses of 1, 2, and their structural ana- of imidazole into compound 14 (or 27) was carried out using
logues, isogranulatimide A (3), isogranulatimide B (4), and 1-methoxy-2-tributylstannylindole (13) (Chart 2).
isogranulatimide C (6) have already been reported by Piers
The 5-iodo-1-methyl-2-phenylthioimidazole (14) and 5-
and colleagues.1,5) In a previous paper, we presented a new iodo-1-methoxymethyl-2-phenylthioimidazole (27) were syn-
synthetic route to granulatimide (1), 10-methylgranulatimide thesized from 1-methylimidazole (or imidazole) according to
(7), 17-methylgranulatimide (8) and 10,17-dimethylgranula- reported methods.7) The stannyl derivative 13 was itself pre-
timide (9).6) The latter analogues are congeners of the struc- pared from 1-methoxyindole8,9) by regioselective lithiation
tural isomers 10, 11 and 12 in the imidazole moiety (Fig. 1).
with n-BuLi10—12) and subsequent reaction with chlorotri-
Previous syntheses of granulatimide and its analogues em- butylstannane.13) The Stille coupling reaction14,15) of 13 with
ployed the Stille coupling reaction of stannylindole with 4- the imidazole 14 in the presence of PdCl2(PPh3)2 in toluene
iodoimidazole in the presence of PdCl2(PPh3)2, affording the afforded the 2,5Ј-indole-imidazole coupling product 15 in
2,4Ј-indole-imidazole coupling product as a key intermedi- 65% yield.
ate. Subsequent reaction of indolyl Grignard reagents with
On the other hand, the reaction of 13 with the imidazole 27
3,4-dibromomaleimide gave the condensation product, which under similar reaction conditions, but in benzene instead of
was converted to granulatimide analogues by photocycliza- toluene, afforded 28 in 64% yield. Subsequent deprotection
tion (route A). Here we wish to report the preparation of new of the 1-methoxy group in 15 and 28 was readily achieved
analogues of 1, 10-methylgranulatimide (10), 15-methylgran- with Mg–MeOH to give, in 92 and 76% yields, 5-(1H-indol-
ulatimide (11), and 10,15-dimethylgranulatimide (12), as 2-yl)-1-methyl-2-phenylthio-1H-imidazole (16) and 5-(1H-
well as 10-methylisogranulatimide B (5), by the use of 5- indol-2-yl)-1-methoxymethyl-2-phenylthio-1H-imidazole
iodoimidazole instead of 4-iodoimidazole in the same syn- (29), key intermediates for synthesizing new analogues. To
thetic strategy (route B) (Chart 1).
confirm the coupling reaction, compounds 15 and 29 were
subjected to a heteronuclear multiple bond connectivity
Fig. 1
* To whom correspondence should be addressed. e-mail: murase@ac.shoyaku.ac.jp
© 2003 Pharmaceutical Society of Japan

210
Vol. 51, No. 2
Chart 1
Chart 2
(THF) gave the MgBr salt 18 (or 19). The condensation of 18
with the maleimide 20a (or 20b) in THF afforded the corre-
sponding synthon condensation product (21 or 23) in a yield
of 47% or 12%, respectively. Similar condensation reaction
of 19 with 20a afforded 22 in 37% yield.
We carried out the photocyclization of 21, 22 or 23 ac-
cording to the reported procedure.1,5) Thus, when 21, 22, or
23 was irradiated with an external light source (60 W, low-
pressure mercury lamp) in MeCN, we obtained the granula-
timide derivative 24, 12 or 26 in 85%, 70% or 71% yield, re-
spectively. The structures of 24 and 26 were confirmed by
1H- and 13C-NMR, and high resolution (HR)-MS. The 13C-
NMR of 24 indicated that the imidazole C-4Ј tertiary carbon
signal (131.5 ppm) of 21 had disappeared, and a new quater-
nary carbon signal had appeared at 135.5 ppm, while the
molecular ion peak at m/z 412 (Mϩ) was observed in the
mass spectrum. Deprotection of the phenylthio group in 24
or 26 was performed with Raney Ni in MeOH (Chart 3).
10,15-Dimethylgranulatimide (12) and 15-methylgranula-
timide (11) were obtained in 33% and 41% yields, respec-
tively. Compound 12 was converted to 11 without isolation
of the intermediate, according to Steglich’s procedure.16) The
maleimide group was transformed into the anhydride (25) by
alkaline hydrolysis followed by treatment with acid. Heating
ۍ
Fig. 2. Long-Range Correlations (1H 13C) in the HMBC Spectrum
(HMBC) study. As shown in Fig. 2, 15 was demonstrated to
be the 2,5Ј-coupling product, since we observed a correlation
between the methyl protons and C(2Ј), as well as C(5Ј). The
HMBC spectrum of 29 was similar to that of 15, except for
the long-range correlations of methylene protons of the
methoxymethyl (MOM) group to C(2Ј) and C(5Ј).
Removal of the phenylthio group in product 16 was per-
formed by treatment with Raney Ni (W-2) in MeOH to give
17 in 71% yield.
The next stage in the syntheses of 15-methylgranulatimide
(11) and its analogues was carried out by the reaction of the
maleimide 20a (or 20b) with the Grignard reagent 18 (or 19)
generated from the coupling product 16 (or 17) in the man-
ner described previously.16) The reaction of 16 (or 17) with
ethylmagnesium bromide in anhydrous tetrahydrofuran

February 2003
211
Chart 3
Chart 4
of the crude anhydride with ammonium acetate gave 11 in teraction destabilizing the HN-15 tautomer may be responsi-
17% overall yield. Thus, a straightforward and efficient syn- ble for suppressing the imidazole NH tautomerization in
thesis of new granulatimide analogues, 11 and 12, has been granulatimide (1). Direct comparison of 7 with a previously
developed.
synthesized sample6) confirmed the identity of the two in all
We then turned to the syntheses of 10-methylgranula- respects [mp, TLC, MS, IR, 1H- and 13C-NMR spectra], sup-
timide (7) (a tautomer of 10) and 10-methylisogranulatimide porting the HN-17 tautomer structure of 7.
B (5). A similar sequence of reactions to that described
When the order of the above reactions was changed, the re-
above for the preparation of 21 provided ready access to the moval of the MOM function from 31 by refluxing with 10%
condensation product of 29 with 20a, via Grignard reaction HCl led to 32, and subsequent photocyclization reaction af-
in THF, affording 31 in 50% yield. Subsequent photocycliza- forded 34 in 95% yield.
tion reaction afforded a mixture of products. Flash chro-
On the other hand, when a solution of 32 in nitrobenzene
matography of this material on silica gel provided 33 and 34 was heated at 200 °C, thermal cyclization proceeded to give
in 50 and 47% yields, respectively. It was considered that the 35 in 62% yield. In the 1H-NMR spectrum of 35, in compari-
leaving HBr reacted with the cyclization product 33 to re- son with that of 32, the imidazole NH proton signal (d
move the N-MOM protecting group, affording 34.
13.07) had disappeared, and the C-4 proton signal (d 7.73)
1
As expected, the H-NMR spectrum of 33 is very similar remained (d 8.94), while HR-MS showed Mϩ at m/z 398 and
to that of 24, except that the resonance due to the imidazole gave a molecular formula of C22H14N4O2S. Consequently,
N-MOM function in 33 (d 3.27) replaces the corresponding this product was confirmed to be 10-methyl-17-phenylthio-
N–Me signal (d 4.17) of 24. Furthermore, the H–1H and isogranulatimide B (35).
1
1H–13C COSY data substantiated the structure of 33.
Subsequent desulfurization with Raney Ni in MeOH gave
1
The conversion of 33 into 34 by refluxing in 10% HCl was isogranulatimide B (5) in 45% yield. As expected, the H-
clean and efficient. The phenylthio group of 34 was easily re- NMR spectrum of 5 is very similar to that of 4, except that
moved in moderate yield by the use of excess Raney Ni in re- the maleimide N-Me proton signal (d 3.07) in 5 replaces the
fluxing MeOH to give 7.
corresponding N–H signal of 4, as reported previously.5)
As anticipated for this analogues series, 35 and 5 were ex-
Based on the structural determination of 1 by Berlinck and
co-workers,1) the combination of an intramolecular hydrogen tremely insoluble in most common organic solvents.
bond stabilizing the HN-17 tautomer and a severe steric in-
Thus, a new synthetic route to positional analogues of

212
Vol. 51, No. 2
yl]-1-methyl-pyrrole-2,5-dione (21) Compound 16 (305 mg, 1 mmol) in
THF (7 ml) was added to the solution of EtMgBr, prepared from Mg (48 mg,
2 mmol) and EtBr (436 mg, 4 mmol) in THF (4 ml), and the resulting mix-
ture was stirred at ambient temperature under nitrogen atmosphere for
30 min. Then, 20a (322 mg, 1.2 mmol) in THF (4 ml) was added dropwise,
and the mixture was stirred for 1 h. The reaction mixture was worked up
with aq. NH4Cl, extracted with AcOEt, washed with brine, dried and con-
centrated. The residue was subjected with silica gel chromatograph
granulatimide, 11, 12, 7, and to isogranulatimide B (5), has
been established by the construction of the indole-imidazole
(2,5Ј-) nucleus (route B) based on the same strategy as in the
previous synthesis. Studies on the biological activity of these
analogues are in progress.
Experimental
All melting points (mp) were determined on a Yanagimoto micromelting (acetone : n-hexaneϭ1 : 4) to give 231 mg (47%) of 21 as an orange needles
point apparatus and are uncorrected. Infrared (IR) spectra were recorded (from acetone–n-hexane). mp 245—247 °C. IR (KBr) cmϪ1: 1768, 1711,
with a JASCO IR-700 spectrometer. 1H- and 13C-NMR spectra were ob- 1626, 1591, 1431, 1379, 738. H-NMR (DMSO-d6, 500 MHz) d: 2.96 (3H,
1
tained on JMN-AL 300 and JMN-a 500 spectrometers. The chemical shifts s, CO–N–Me), 3.65 (3H, s, N–Me), 7.15—7.20 (3H, m, indole Ar–H and
were given in ppm (d) values with tetramethylsilane as an internal standard SPh–H), 7.25—7.30 (3H, m, indole Ar–H, SPh–H and imidazole H-4), 7.37
(DMSO-d6 and CDCl3). Mass spectra were recorded on JEOL JMS-D 300, (2H, t, Jϭ7.6 Hz, SPh–H), 7.52 (1H, d, Jϭ8.2 Hz, indole Ar–H), 7.59 (1H,
JMS-HX 110 and Shimadzu QP-5000 spectrometers. Wako silica gel C-200 d, Jϭ7.9 Hz, indole Ar–H), 12.30 (1H, s, indole NH). 13C-NMR (DMSO-d6,
(200 mesh) was used for column chromatography. Merck Kieselgel 60F254
was used for thin-layer chromatography (TLC), and spots were detected by 126.7, 127.3 (ϫ2), 128.0, 129.4 (ϫ2), 129.6, 130.0, 131.5, 134.2, 136.6,
125.65 MHz) d: 24.6, 32.5, 103.9, 112.0, 120.5, 121.1, 121.6, 123.1, 125.5,
ultraviolet (UV) illumination and by spraying 1% Ce(SO4)4 in 10% H2SO4
138.0, 165.9, 168.2. LR-MS m/z: 492 [Mϩ], 494 [Mϩϩ2]. HR-MS m/z:
followed by heating. The organic extract was dried over Na2SO4. Tetrahydro- 492.0237 [Mϩ] (Calcd for C23H1779BrN4O2S, 492.0254), 494.0232 [Mϩϩ2]
furan (THF) was distilled from sodium-benzophenone under nitrogen atmos- (Calcd for C23H1781BrN4O2S, 494.0233).
phere before use. Low pressure mercury lamp (EL-120) was used for irradi-
ation.
3-Bromo-4-[2-(1-methyl-1H-imidazol-5-yl)-1H-indol-3-yl]-1-methyl-
pyrrole-2,5-dione (22) EtBr (218 mg, 2 mmol) was added dropwise to the
5-(1-Methoxy-1H-indol-2-yl)-1-methyl-2-phenylthio-1H-imidazole mixture of 17 (98 mg, 0.5 mmol) and Mg (24 mg, 1 mmol) in THF at ambi-
(15) n-BuLi in n-hexane (1.5 mol/l, 8 ml, 12 mmol) was added to the ent temperature under nitrogen atmosphere, and the mixture was stirred until
stirred solution of 1-methoxyindole (1.47 g, 10 mmol) in THF (70 ml) at Mg was dissolved. Further, this mixture was stirred for 1 h. Then, 20a
Ϫ78 °C under nitrogen atmosphere, and the mixture was stirred for 30 min. (134 mg, 0.5 mmol) in THF (5 ml) was added dropwise, and the mixture was
Then, Bu3SnCl (4.88 g, 15 mmol) in THF (30 ml) was added dropwise, and stirred overnight. The reaction mixture was worked up with aq. NH4Cl, ex-
the mixture was stirred for 30 min. The reaction mixture was allowed to tracted with CH2Cl2, washed with brine, dried and concentrated. The residue
warm to ambient temperature, and stirred additional 30 min. The reaction was purified by silica gel chromatograph (MeOH : benzeneϭ3 : 20) to give
mixture was extracted with Et2O, washed with brine, dried and concentrated. 71 mg (37%) of 22 as a yellow powder. mp 254—256 °C. IR (KBr) cmϪ1
:
The residue was treated with 14 (3.16 g, 10 mmol) and PdCl2(PPh3)2 3210, 1710, 1694, 1665. 1H-NMR (DMSO-d6, 300 MHz) d: 2.95 (3H, s,
(702 mg, 1 mmol) in toluene (50 ml). The reaction mixture was refluxed CO–N–Me), 3.68 (3H, s, N–Me), 6.99 (1H, s, imidazole H-4), 7.13 (1H, t,
overnight. Then, solvent was removed in vacuo, and the residue was ex-
tracted with AcOEt, washed with brine, dried and concentrated. The residue Jϭ8.1 Hz, indole Ar–H), 7.54 (1H, d, Jϭ8.0 Hz, indole Ar–H), 7.79 (1H, s,
was subjected with silica gel chromatograph (AcOEt : n-hexaneϭ1 : 4) to
imidazole H-2), 12.11 (1H, s, indole NH). 13C-NMR (DMSO-d6,
Jϭ7.5 Hz, indole Ar–H), 7.24 (1H, t, Jϭ7.5 Hz, indole Ar–H), 7.48 (1H, d,
give 2.19 g (65%) of 15 as a white powder (from Et2O–n-hexane). mp 73— 75.45 MHz) d: 24.6, 32.0, 103.3, 111.8, 120.3, 120.8, 121.6, 122.8, 123.9,
74 °C. IR (KBr) cmϪ1: 1577, 1476, 1440, 1365, 1324, 1303, 963, 845, 770, 125.8, 128.9, 130.8, 136.6, 138.5, 140.1, 166.0, 168.2. LR-MS m/z: 384
1
736, 686. H-NMR (CDCl3, 500 MHz) d: 3.70 (3H, s, N–Me), 3.81 (3H, s,
[Mϩ], 386 [Mϩϩ2]. HR-MS m/z: 384.0259 [Mϩ] (Calcd for C17H1379BrN4O2,
O–Me), 6.49 (1H, s, indole H-3), 7.16 (1H, t, Jϭ7.9 Hz, indole Ar–H), 384.0220), 386.0220 [Mϩϩ2] (Calcd for C17H1381BrN4O2, 386.0199).
7.20—7.31 (6H, m, indole Ar–H and SPh–H), 7.46 (1H, d, Jϭ8.2 Hz, indole
3-Bromo-4-[2-(1-methyl-2-phenylthio-1H-imidazol-5-yl)-1H-indol-3-
Ar–H), 7.55 (1H, s, imidazole H-4), 7.60 (1H, d, Jϭ7.9 Hz, indole Ar–H). yl]-pyrrole-2,5-dione (23) Compound 16 (76 mg, 0.25 mmol) was treated
13C-NMR (CDCl3, 125.65 MHz) d: 33.0, 64.7, 99.9, 108.6, 120.9, 121.1,
123.3, 123.8, 125.0, 126.1, 126.9, 128.5 (ϫ2), 129.4 (ϫ2), 131.3, 132.9,
with EtMgBr, followed by 20b (63 mg, 0.25 mmol) as described for 21 to
give 14 mg (12%) of 23 as an orange powder (from AcOEt–n-hexane). mp
134.4, 140.4. LR-MS m/z: 335 [Mϩ]. HR-MS m/z: 335.1083 [Mϩ] (Calcd 162—164 °C. IR (KBr) cmϪ1: 3372, 3064, 1772, 1722, 1628, 1440, 1331,
1
for C19H17N3OS, 335.1091).
1021, 734. H-NMR (DMSO-d6, 300 MHz) d: 3.60 (3H, s, N–Me), 7.13—
5-(1H-Indol-2-yl)-1-methyl-2-phenythio-1H-imidazole (16) The mix- 7.38 (8H, m, indole Ar–H, SPh–H and imidazole H-4), 7.49 (1H, d,
ture of 15 (167 mg, 0.5 mmol) and Mg (240 mg, 10 mmol) in MeOH (10 ml) Jϭ8.1 Hz, indole Ar–H), 7.56 (1H, d, Jϭ8.1 Hz, indole Ar–H), 11.33 (1H, s,
was refluxed for 1 h. Then, the reaction mixture was worked up with aq. CO–NH–CO), 12.24 (1H, s, indole NH). 13C-NMR (DMSO-d6, 75.45 MHz)
NH4Cl, extracted with AcOEt, washed with brine, dried and concentrated. d: 32.4, 103.8, 112.0, 120.4, 121.0, 122.6, 123.1, 125.5, 126.6, 127.2 (ϫ2),
The residue was purified by silica gel chromatograph (acetone : n- 128.0, 128.1, 129.4 (ϫ2), 131.7, 134.3, 136.6, 138.4, 138.6, 166.7, 169.2.
hexaneϭ1 : 2) to give 140 mg (92%) of 16 as a colorless needls (from LR-MS m/z
: :
478 [Mϩ], 480 [Mϩϩ2]. HR-MS m/z 478.0093 [Mϩ] (Calcd
AcOEt–n-hexane). mp 158—159 °C. IR (KBr) cmϪ1: 3100, 1576, 1476, for C22H1579BrN4O2S, 478.0096), 480.0064 [Mϩϩ2] (Calcd for
1456, 1439, 1371, 1343, 1325, 731. 1H-NMR (CDCl3, 300 MHz) d: 3.79 C22H1581BrN4O2S, 480.0075).
(3H, s, N–Me), 6.62 (1H, s, indole H-3), 7.10—7.27 (7H, m, indole Ar–H
10,15-Dimethyl-16-phenylthiogranulatimide (24) The solution of 21
and SPh–H), 7.37 (1H, s, imidazole H-4), 7.40 (1H, d, Jϭ7.9 Hz, indole (49 mg, 0.1 mmol) in MeCN (8 ml) was irradiated with low-pressure mer-
Ar–H), 7.62 (1H, d, Jϭ7.9 Hz, indole Ar–H), 9.19 (1H, br, indole NH). 13C- cury lamp (60 W) for 12 h. Then, the resulting solid material was corrected
NMR (CDCl3, 75.45 MHz) d: 33.0, 101.8, 111.1, 120.3, 120.6, 122.9, 126.7, to give 35 mg (85%) of 24 as a yellow solid (from MeOH). mp Ͼ300 °C. IR
126.9, 128.4 (ϫ2), 128.5, 128.6, 129.4 (ϫ2), 129.5, 134.3, 136.4, 140.0.
(KBr) cmϪ1: 3374, 1750, 1692, 1581, 1452, 1378, 1329, 747. 1H-NMR
LR-MS m/z: 305 [Mϩ]. HR-MS m/z: 305.1006 [Mϩ] (Calcd for C18H15N3S, (DMSO-d6, 500 MHz) d: 3.01 (3H, s, CO–N–Me), 4.17 (3H, s, N–Me), 7.30
305.0986).
(1H, t, Jϭ7.9 Hz, indole Ar–H), 7.37 (1H, t, Jϭ7.0 Hz, SPh–H), 7.42 (2H, t,
Jϭ7.0 Hz, SPh–H), 7.47 (2H, d, Jϭ7.3 Hz, SPh–H), 7.51 (1H, t, Jϭ8.2 Hz,
indole Ar–H), 7.66 (1H, d, Jϭ8.2 Hz, indole Ar–H), 8.89 (1H, d, Jϭ7.9 Hz,
indole Ar–H), 12.10 (1H, s, indole NH). 13C-NMR (DMSO-d6, 125.65 MHz)
5-(1H-Indol-2-yl)-1-methyl-1H-imidazole (17) The mixture of 16
(61 mg, 0.2 mmol) and Raney Ni (dissolved in EtOH) in MeOH (10 ml) was
refluxed for 2 h. The reaction mixture was filtered through celite, and the fil-
trate was concentrated in vacuo. The residue was purified by silica gel chro- d: 23.3, 33.4, 111.7, 112.9, 114.1, 120.3, 120.4, 121.9, 123.8, 126.4, 126.5,
matograph (AcOEt) to give 28 mg (71%) of 17 as a white powder (from 127.9, 128.5, 129.6 (ϫ2), 130.0 (ϫ2), 131.4, 135.5, 140.6, 149.7, 167.2,
MeOH). mp 178—180 °C. IR (KBr) cmϪ1: 3462, 3102, 1623, 1574, 1515. 169.2. LR-MS m/z: 412 [Mϩ]. HR-MS m/z: 412.0983 [Mϩ] (Calcd for
1H-NMR (DMSO-d6, 300 MHz) d: 3.84 (3H, s, N–Me), 6.67 (1H, s, indole C23H16N4O2S, 412.0993).
H-3), 7.01 (1H, t, Jϭ7.5 Hz, indole Ar–H), 7.11 (1H, t, Jϭ7.5 Hz, indole
15-Methyl-16-phenylthiogranulatimide (26) Compound 23 (59 mg,
Ar–H), 7.36 (1H, s, imidazole H-4), 7.38 (1H, d, Jϭ8.1 Hz, indole Ar–H), 0.12 mmol) was irradiated as described for 24 to give 34 mg (71%) of 26 as
7.54 (1H, d, Jϭ7.9 Hz, indole Ar–H), 7.80 (1H, s, imidazole H-2), 11.34
a yellow solid (from MeOH). mp Ͼ300 °C. IR (KBr) cmϪ1: 3430, 3202,
(1H, s, indole NH). 13C-NMR (DMSO-d6, 75.45 MHz) d: 32.9, 99.0, 110.9, 1712, 1646, 1471, 1450, 1328, 993, 950, 746. 1H-NMR (DMSO-d6,
119.2, 119.8, 121.5, 125.8, 127.4, 128.4, 136.3, 139.8. LR-MS m/z: 197 300 MHz) d: 4.24 (3H, s, N–Me), 7.31 (1H, t, Jϭ7.9 Hz, indole Ar–H),
[Mϩ]. HR-MS m/z: 197.0964 [Mϩ] (Calcd for C12H11N3, 197.2369).
7.32—7.53 (6H, m, SPh–H and indole Ar–H), 7.69 (1H, d, Jϭ8.3 Hz, indole
3-Bromo-4-[2-(1-methyl-2-phenylthio-1H-imidazol-5-yl)-1H-indol-3- Ar–H), 8.97 (1H, d, Jϭ7.9 Hz, indole Ar–H), 10.88 (1H, s, CO–NH–CO),

February 2003
213
12.18 (1H, s, indole NH). 13C-NMR (DMSO-d6, 75.45 MHz) d: 33.5, 111.8,
114.1, 114.2, 120.4, 120.7, 123.1, 124.0, 126.5, 126.8, 128.0, 128.9, 129.7
(ϫ2), 130.1 (ϫ2), 131.4, 135.6, 140.7, 149.8, 168.7, 170.8. LR-MS m/z: 398
[Mϩ]. HR-MS m/z: 398.0821 [Mϩ] (Calcd for C22H14N4O2S, 398.1950).
10,15-Dimethylgranulatimide (12) From 24: Compound 24 (41 mg,
0.1 mmol) was treated with Raney Ni as described for 17 to give 10 mg
(33%) of 12 as a yellow powder (from MeOH).
From 22: Compound 22 (39 mg, 0.1 mmol) was irradiated as described for
24 to give 21 mg (70%) of 12 as yellow powder (from MeOH). mp Ͼ300 °C.
IR (KBr) cmϪ1: 3394, 1743, 1691, 1467, 1385, 1339, 1227, 807, 748, 736.
1H-NMR (DMSO-d6, 300 MHz) d: 3.07 (3H, s, CO–N–Me), 4.29 (3H, s,
N–Me), 7.33 (1H, t, Jϭ7.7 Hz, indole Ar–H), 7.52 (1H, t, Jϭ7.7 Hz, indole
Ar–H), 7.72 (1H, d, Jϭ8.1 Hz, indole Ar–H), 8.44 (1H, s, imidazole H-2),
8.98 (1H, d, Jϭ7.0 Hz, indole Ar–H), 12.20 (1H, br, indole NH). 13C-NMR
(DMSO-d6, 75.45 MHz) d: 23.4, 33.3, 111.8, 113.8, 113.9, 120.2, 120.7,
121.6, 123.8, 124.8, 126.4, 129.4, 137.1, 140.7, 147.3, 167.7, 169.6. LR-MS
m/z: 304 [Mϩ]. HR-MS m/z: 304.0981 [Mϩ] (Calcd for C17H12N4O2,
304.0959).
15-Methylgranulatimide (11) From 12: Compound 12 (30 mg,
0.1 mmol) in 10% aq. KOH (10 ml) was refluxed for 1 h. After cooling, the
reaction mixture was acidified with 10% aq. HCl. The resulting yellow pre-
cipitate 25 was collected and dried. Then, 25 was heated with AcONH4
(500 mg) at 140 °C for 30 min. After cooling, H2O was added to the reaction
mixture, and the resulting yellow material was collected, dried and purified
by silica gel chromatograph (benzene : MeOHϭ20 : 3) to give 5 mg (17%) of
11 as a yellow powder (from MeOH).
C19H17N3OS, 335.1088).
3-Bromo-4-[2-(1-methoxymethyl-2-phenylthio-1H-imidazol-5-yl)-1H-
indol-3-yl]-1-methyl-pyrrole-2,5-dione (31) Compound 29 was treated
with EtMgBr, followed by 20a (807 mg, 3 mmol) as described for 21 to give
788 mg (50%) of 31 as an orange solid (from AcOEt–n-hexane). mp 145—
147 °C. IR (KBr) cmϪ1: 3420, 1768, 1709, 1628, 1435, 1378, 1102, 981,
732. 1H-NMR (CDCl3, 300 MHz) d: 3.10 (3H, s, N–Me), 3.49 (3H, s,
O–Me), 5.51 (2H, s, –CH2–), 7.19 (1H, s, imidazole H-4), 7.22—7.35 (7H,
m, indole Ar–H and SPh–H), 7.47 (1H, d, Jϭ7.9 Hz, indole Ar–H), 7.61
(1H, d, Jϭ8.1 Hz, indole Ar–H), 9.84 (1H, s, indole NH). 13C-NMR (CDCl3,
75.45 MHz) d: 24.9, 56.8, 75.5, 104.3, 111.9, 121.2, 121.5, 122.9, 124.0,
125.8, 127.2, 127.7, 128.1 (ϫ3), 129.4 (ϫ2), 133.1, 133.9, 136.4, 138.7,
140.9, 165.9, 168.2. LR-MS m/z: 522 [Mϩ], 524 [Mϩϩ2]. HR-MS m/z:
522.0361 [Mϩ] (Calcd for C24H1979BrN4O3S, 522.0357), 524.0296 [Mϩϩ2]
(Calcd for C24H1981BrN4O3S, 524.0336).
3-Bromo-4-[2-(2-phenylthio-1H-imidazol-5-yl)-1H-indol-3-yl]-1-
methyl-pyrrole-2,5-dione (32) The mixture of 31 (261 mg, 0.5 mmol) and
10% aq. HCl (10 ml) in MeOH (6 ml) was refluxed for 3 h. After cooling, the
reaction mixture was basified with aq. NaHCO3, and extracted with CH2Cl2,
washed with brine, dried and concentrated. The residue was purified by sil-
ica gel chromatograph (acetone : n-hexaneϭ1 : 2) to give 228 mg (95%) of
32 as a red powder (from CHCl3–n-hexane). mp 138—140 °C. IR (KBr)
cmϪ1: 3346, 1768, 1707, 1628, 1434, 1379, 988, 841, 807, 730. 1H-NMR
(DMSO-d6, 300 MHz) d: 2.95 (3H, s, N–Me), 7.05 (1H, t, Jϭ7.5 Hz, indole
Ar–H), 7.15 (1H, t, Jϭ7.5 Hz, indole Ar–H), 7.20—7.25 (3H, m, SPh–H),
7.30—7.36 (2H, m, SPh–H), 7.39 (1H, d, Jϭ7.7 Hz, indole Ar–H), 7.45
(1H, d, Jϭ7.9 Hz, indole Ar–H), 7.73 (1H, s, imidazole H-4), 11.99 (1H, s,
indole NH), 13.07 (1H, br, imidazole NH). 13C-NMR (DMSO-d6,
75.45 MHz) d: 24.5, 98.2, 111.7, 119.9, 121.9, 126.5, 127.5 (ϫ2), 129.3
(ϫ2), 133.5, 135.0, 135.6, 135.9, 139.9, 166.2, 168.3. FAB-MS m/z: 479
[MϩϩH], 481 [MϩϩHϩ2]. HR-FAB-MS m/z: 479.0178 [MϩϩH] (Calcd
for C22H1679BrN4O2S, 479.0174), 481.0152 [MϩϩHϩ2] (Calcd for
C22H1681BrN4O2S, 481.0153).
15-Methoxymethyl-10-methyl-16-phenylthiogranulatimide (33) The
solution of 31 (52 mg, 0.1 mmol) in MeCN (6 ml) was irradiated with low-
pressure mercury lamp (60 W) for 17 h. The reaction mixture was concen-
trated, and the residue was purified by silica gel chromatograph (CHCl3) to
give 22 mg (50%) of 33 as a yellow powder (from MeOH) and 19 mg (47%)
of 34 as a yellow powder (from acetone–n-hexane). mp 212—214 °C. IR
(KBr) cmϪ1: 3344, 1748, 1695, 1459, 1434, 1379, 1086, 1060, 805, 736. 1H-
NMR (DMSO-d6, 300 MHz) d: 3.05 (3H, s, N–Me), 3.27 (3H, s, O–Me),
6.19 (2H, s, –CH2–), 7.26 (1H, t, Jϭ7.5 Hz, indole Ar–H), 7.42—7.51 (4H,
m, SPh–H and indole Ar–H), 7.54 (1H, d, Jϭ8.1 Hz, indole Ar–H), 7.67
(2H, dd, Jϭ2.0, 7.8 Hz, SPh–H), 8.85 (1H, d, Jϭ7.9 Hz, indole Ar–H), 12.53
(1H, s, indole NH). 13C-NMR (DMSO-d6, 75.45 MHz) d: 23.6, 55.2, 76.6,
107.4, 111.7, 114.1, 120.2, 120.9, 122.7, 124.1, 126.7, 128.8, 129.6 (ϫ2),
129.8, 130.1, 132.31 (ϫ2), 132.33, 134.3, 140.9, 152.3, 167.6, 168.8. LR-
MS m/z: 442 [Mϩ]. HR-MS m/z: 442.1118 [Mϩ] (Calcd for C24H18N4O3S,
442.1095).
From 26: Compound 26 (20 mg, 0.05 mmol) was treated with Raney Ni as
described for 17 to give 6 mg (41%) of 11 as a yellow powder (from
1
MeOH). mp Ͼ300 °C. IR (KBr) cmϪ1: 3428, 1720, 1692, 1105, 1071. H-
NMR (DMSO-d6, 300 MHz) d: 4.33 (3H, s, N–Me), 7.34 (1H, t, Jϭ7.5 Hz,
indole Ar–H), 7.53 (1H, t, Jϭ7.0 Hz, indole Ar–H), 7.73 (1H, d, Jϭ8.1 Hz,
indole Ar–H), 8.47 (1H, s, imidazole H-2), 9.02 (1H, d, Jϭ7.7 Hz, indole
Ar–H), 10.85 (1H, s, CO–NH–CO), 12.16 (1H, s, indole NH). 13C-NMR
(DMSO-d6, 75.45 MHz) d: 37.6, 111.8, 114.7, 115.0, 120.5, 120.9, 121.8,
124.1, 124.5, 126.7, 129.0, 134.5, 140.1, 141.5, 167.3, 167.7. LR-MS m/z:
290 [Mϩ]. HR-MS m/z: 290.0781 [Mϩ] (Calcd for C16H10N4O2, 290.0802).
5-(1-Methoxy-1H-indol-2-yl)-1-(methoxymethyl)-2-phenylthio-1H-im-
idazole (28) n-BuLi in n-hexane (2.6 mol/l, 4 ml, 11 mmol) was added to
the stirred solution of 1-methoxyindole (1.47 g, 10 mmol) in THF (10 ml) at
Ϫ78 °C under nitrogen atmosphere, and the mixture was strried for 20 min.
Then, the solution of Bu3SnCl (3.9 g, 12 mmol) in THF (6 ml) was slowly
added to the mixture, and the reaction mixture was warmed to ambient tem-
perature, and stirred for 30 min. The reaction mixture was worked up with
H2O, extracted with Et2O, washed with brine, dried and concentrated. The
residue was treated with 27 (3.46 g, 10 mmol) and PdCl2(PPh3)3 (70 mg,
0.1 mmol) in benzene (30 ml), and the mixture was refluxed under nitrogen
atmosphere overnight. The solvent was removed in vacuo, and the residue
was dissolved in AcOEt. The organic layer was washed with brine, dried and
concentrated. The residue was purified by silica gel chromatograph
(AcOEt : n-hexaneϭ1 : 10) to give 2.34 g (64%) of 28 as an oil. IR (KBr)
cmϪ1: 2938, 1581, 1443, 1219, 1107, 962, 746. 1H-NMR (CDCl3, 300 MHz)
d: 3.27 (3H, s, N–OMe), 3.86 (3H, s, –OMe), 5.52 (2H, s, –CH2–), 6.74
(1H, s, indole H-3), 7.15 (1H, t, Jϭ7.5 Hz, indole Ar–H), 7.24—7.37 (6H,
m, indole Ar–H and SPh–H), 7.46 (1H, d, Jϭ8.2 Hz, indole Ar–H), 7.61
(1H, d, Jϭ7.9 Hz, indole Ar–H), 7.66 (1H, s, imidazole H-4). 13C-NMR
(CDCl3, 75.45 MHz) d: 56.2, 64.7, 75.4, 100.0, 108.5, 120.8, 121.2, 123.3,
123.8, 124.5, 125.8, 127.3, 129.1 (ϫ2), 129.3 (ϫ2), 131.4, 133.0, 133.9,
141.4. LR-MS m/z: 365 [Mϩ]. HR-MS m/z: 365.1197 [Mϩ] (Calcd for
C20H19N3O2S, 365.1198).
10-Methyl-16-phenylthiogranulatimide (34) From 33: The suspension
of 33 (44 mg, 0.1 mmol) in 10% aq. HCl (6 ml) was heated at 100 °C for 4 h.
After cooling, the reaction mixture was basified with aq. NaHCO3, and then
the resulting solid material was corrected to give 38 mg (95%) of 34 as a
yellow powder (from acetone–n-hexane).
From 32: Compound 32 (47 mg, 0.1 mmol) was irradiated as described for
24 to give 38 mg (95%) of 34 as a yellow powder (from acetone–n-hexane).
mp 275—277 °C. IR (KBr) cmϪ1: 3390, 3290, 1740, 1679, 1598, 1467,
1
1367, 1325, 1236, 1066, 984, 737, 638. H-NMR (DMSO-d6, 300 MHz) d:
3.09 (3H, s, N–Me), 7.26 (1H, dt, Jϭ7.5, 1.1 Hz, indole Ar–H), 7.39—7.49
(4H, m, SPh–H and indole Ar–H), 7.55 (1H, d, Jϭ8.1 Hz, indole Ar–H),
7.60—7.64 (2H, m, SPh–H), 8.85 (1H, d, Jϭ7.9 Hz, indole Ar–H), 12.43
(1H, s, indole NH), 13.98 (1H, br, imidazole NH). 13C-NMR (DMSO-d6,
75.45 MHz) d: 23.5, 111.6, 113.6, 120.1, 121.1, 121.4, 123.7, 126.3, 128.5,
129.5 (ϫ2), 130.6, 132.1 (ϫ2), 140.6, 151.0, 167.8, 169.4. LR-MS m/z: 398
[Mϩ]. HR-MS m/z: 398.0816 [Mϩ] (Calcd for C22H14N4O2S, 398.0834).
10-Methylgranulatimide (7)6) Compound 34 (20 mg, 0.05 mmol) was
treated with Raney Ni as described for 17 to give 8 mg (55%) of 7 as a yel-
low powder (from MeOH).
5-(1H-Indol-2-yl)-1-(methoxymethyl)-2-phenylthio-1H-imidazole (29)
The mixture of 28 (164 mg, 0.45 mmol) and Mg (216 mg, 9 mmol) in MeOH
(10 ml) was refluxed under nitrogen atmosphere for 1 h. The reaction mix-
ture was worked up with aq. NH4Cl, extracted with CH2Cl2, washed with
brine, dried and concentrated. The residue was purified by silica gel chro-
matograph (AcOEt : n-hexaneϭ1 : 2) to give 114 mg (76%) of 29 as a color-
less needles (from AcOEt–n-hexane). mp 122—123 °C. IR (KBr) cmϪ1
:
1
3166, 1577, 1455, 1376, 1296, 1108, 914, 801, 736, 682. H-NMR (CDCl3,
500 MHz) d: 3.42 (3H, s, O–Me), 5.54 (2H, s, –CH2–), 6.80 (1H, s, indole
H-3), 7.13 (1H, t, Jϭ7.9 Hz, indole Ar–H), 7.20—7.29 (6H, m, indole Ar–H
and SPh–H), 7.40 (1H, d, Jϭ8.2 Hz, indole Ar–H), 7.53 (1H, s, imidazole
H-4), 7.63 (1H, d, Jϭ7.9 Hz, indole Ar–H), 9.41 (1H, s, indole NH). 13C-
NMR (CDCl3, 125.65 MHz) d: 56.5, 75.4, 102.6, 111.2, 120.4, 120.7, 122.7,
126.5, 127.2, 128.4, 128.5 (ϫ2), 129.4 (ϫ2), 129.7, 130.2, 134.2, 136.7,
140.0. LR-MS m/z: 335 [Mϩ]. HR-MS m/z: 335.1088 [Mϩ] (Calcd for
10-Methyl-17-phenylthioisogranulatimide B (35) The solution of 32
(96 mg, 0.2 mmol) in nitrobenzene (2 ml) was heated at 200 °C for 3 h. After
cooling, the reaction mixture was purified by silica gel chromatograph
(AcOEt : n-hexaneϭ1 : 4) to give 49 mg (62%) of 35 as a red powder (from
MeOH). mp 280—282 °C. IR (KBr) cmϪ1: 3438, 1762, 1701, 1522, 1438,
1389, 1257, 1079, 977, 802, 728. 1H-NMR (DMSO-d6, 300 MHz) d: 3.12

214
Vol. 51, No. 2
(3H, s, N–Me), 7.15—7.27 (5H, m, SPh–H), 7.32 (1H, t, Jϭ7.5 Hz, indole
Ar–H), 7.44 (1H, t, Jϭ7.5 Hz, indole Ar–H), 7.82 (1H, d, Jϭ8.1 Hz, indole
Ar–H), 8.55 (1H, d, Jϭ7.7 Hz, indole Ar–H), 8.94 (1H, s, imidazole H-4),
12.11 (1H, s, indole NH). 13C-NMR (DMSO-d6, 75.45 MHz) d: 23.2, 106.5,
112.9, 118.9, 120.4, 121.3, 121.9, 122.0, 125.1, 125.4, 125.7, 127.1 (ϫ2),
128.6 (ϫ2), 129.3, 129.4, 130.4, 136.8, 139.2, 163.7, 166.9. LR-MS m/z:
398 [Mϩ]. HR-MS m/z: 398.0874 [Mϩ] (Calcd for C22H14N4O2S, 398.0834).
10-Methylisogranulatimide B (5) Compound 35 (15 mg, 0.038 mmol)
was treated with Raney Ni as described for 17 to give 5 mg (45%) of 5 as a
red powder (from MeOH). mp Ͼ300 °C. IR (KBr) cmϪ1: 3442, 3392, 3332,
2922, 2858, 1758, 1706, 1652, 1526, 1435, 1372, 1253, 1104, 1070, 934,
747. 1H-NMR (DMSO-d6, 300 MHz) d: 3.07 (3H, s, N–Me), 7.30 (1H, t,
Jϭ7.5 Hz, indole Ar–H), 7.41 (1H, t, Jϭ7.5 Hz, indole Ar–H), 7.62 (1H, d,
Jϭ8.3 Hz, indole Ar–H), 7.89 (1H, s, imidazole H-2), 8.47 (1H, d,
Jϭ8.1 Hz, indole Ar–H), 8.82 (1H, s, imidazole H-4), 12.88 (1H, br, indole
NH). LR-MS m/z: 290 [Mϩ]. HR-MS m/z: 290.0815 [Mϩ] (Calcd for
C16H10N4O2, 290.0804).
4) Roberge M., Berlinck R. G. S., Xu L., Anderson H. J., Lim L. Y., Cur-
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5701—5706 (1998).
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