8068 J . Org. Chem., Vol. 66, No. 24, 2001
Hoarau et al.
THF (50 mL) at -78 °C under Ar. The mixture was stirred
for 0.5 h and then allowed to warm to room temperature within
3 h.
1H), 7.97 (dd, J ) 7.8, 1.0 Hz, 1H), 8.65 (d, J ) 4.9 Hz, 1H);13C
NMR (DMSO-d6) δ 27.7, 63.8, 72.4, 97.9, 116.7, 128.2, 129.2,
130.2, 136.4, 139.3, 141.0, 142.2, 144.9, 149.1, 166.2; IR (KBr)
3305, 1676 cm-1. Anal. Calcd for C15H13N2O2I: C, 47.39; H,
3.45, N, 7.37. Found: C, 47.21; H, 3.33, N, 7.45.
For the preparation of the phosphorylated compound 8,
saturated aqueous NH4Cl was added, and the mixture was
extracted with Et2O (2 × 50 mL) and CH2Cl2 (2 × 25 mL).
The organic layer was washed with brine, dried (MgSO4), and
concentrated in vacuo, and the residue was treated with an
additional 25 mL of MeOH and again concentrated in vacuo.
The residue was triturated with Et2O, filtered, and recrystal-
lized from hexane-toluene to yield compound 8 (1.16 g, 83%):
(E)-3-(2-Iodoben zyliden e)-2-m eth yl-2,3-dih ydr o-1H-pyr -
r olo[3,4-c]p yr id in -1-on e (4) fr om 10. The metalation of
(aza)isoindolinone 10 and subsequent trapping with 2-iodo-
benzaldehyde was conducted as described above. To the
solution of oxanion 12 in THF at -78 °C was added freshly
distilled Me3SiCl (218 mg, 2 mmol), and the reaction mixture
was warmed to room temperature over a period of 1 h. The
mixture was recooled to -78 °C, treated with LHMDS (1 M
in hexanes, 2 mL, 2 mmol), warmed again to room tempera-
ture, and finally quenched with aqueous NH4Cl before extrac-
tion with Et2O (3 × 20 mL) and CH2Cl2 (3 × 25 mL). The
organic extracts were combined, washed with water, and dried
(Na2SO4). The solvent was removed under reduced pressure
to afford the arylmethylene(aza)isoindolinone (E)-4 which was
purified by column chromatography on silica gel using hex-
anes-acetone (1:1) as eluent and finally recrystallized from
hexane-toluene to obtain the pure product (E)-4 (550 mg,
1
mp 194-195 °C; H NMR (CDCl3) δ 3.11 (s, 3H), 5.49 (d, J )
10.6 Hz, 1H), 7.39-7.43 (m, 3H), 7.51-7.61 (m, 6H), 7.68-
7.74 (m, 2H), 8.16 (s, 1H), 8.65 (d, J ) 4.5 Hz, 1H);13C NMR
(CDCl3) δ 30.4, 62.8 (d, J CP ) 71 Hz), 117.3, 126.8 (d, J CP ) 98
Hz), 128.1 (d, J CP ) 99 Hz), 129.0 (d, J CP ) 12 Hz), 129.1 (d,
J CP ) 12 Hz), 131.5 (d, J CP ) 9 Hz), 131.7 (d, J CP ) 9 Hz),
133.4 (d, J CP ) 2.5 Hz), 133.6 (d, J CP ) 2 Hz), 139.8, 145.5,
149.6, 166.9; 31P NMR (CDCl3) δ 30.0; IR (KBr) 1682, 1207
cm-1. Anal. Calcd for C20H17N2O2P: C, 68.96; H, 4.92, N, 8.04.
Found: C, 68.85; H, 5.05, N, 7.89.
For the synthesis of the dephosphorylated compound 9,
aqueous KOH (2.5 M, 4 mL) was added, and the mixture was
stirred at room temperature within 15 min. Water was then
added, and the mixture was extracted with Et2O (3 × 20 mL).
The organic layer was washed with water and brine, dried
(MgSO4), and concentrated in vacuo to a residue which was
purified by flash column chromatography with acetone-
hexanes (80:20). Recrystallization from hexane afforded com-
pound 9 (946 mg, 68%): mp 88-89 °C (lit.11 82-84 °C); 1H
NMR (CDCl3) δ 3.15 (s, 3H), 4.42 (s, 2H), 7.63 (dd, J ) 5.0,
0.9 Hz, 1H), 8.66 (d, J ) 5.0 Hz, 1H), 8.73 (d, J ) 0.9 Hz,
1H);13C NMR (CDCl3) δ 29.6, 50.6, 117.3, 135.5, 140.4, 144.5,
149.2, 166.7.
(Z)- a n d (E)-3-(2-Iod oben zylid en e)-2-m eth yl-2,3-d ih y-
d r o-1H-p yr r olo[3,4-c]p yr id in -1-on e (4). A solution of the
appropriate base (1 equiv) was added dropwise to a solution
of 8 (696 mg, 2 mmol) in THF (20 mL) at -78 °C under Ar.
The orange solution was kept at this temperature for 15 min,
and a solution of 2-iodobenzaldehyde (464 mg, 2 mmol) in THF
(5 mL) was then added by syringe. The reaction mixture was
allowed to warm to room temperature over a period of 30 min
followed by addition of aqueous NH4Cl and extraction with
Et2O (100 mL). The organic layer was washed with water and
brine, dried (MgSO4), and concentrated in vacuo to a yellow
oil which was purified by flash column chromatography with
acetone-hexanes (80:20) as eluent to afford 4 as a mixture of
(E)- and (Z)-isomers. The structure and the E/ Z ratio were
established by NOE difference experiments. The N-methyl H3
(δ 3.46) showed a strong NOE to vinylic H (δ 6.46, 15%) for
the (E)-isomer. 4: 1H NMR (CDCl3, mixture of (E)- and (Z)-
isomers) δ 2.96 (s, 3H, Z), 3.46 (s, 3H, E), 6.46 (s, 1H, E), 6.71
(s, 1H, Z), 7.02-7.16 (m, 1H, Z + E), 7.30-7.51 (m, 2H, Z +
E), 7.68-7.73 (m, 1H, Z + E), 7.92 (dd, J ) 8.0, 1.0 Hz, 1H,
Z), 7.99 (dd, J ) 8.0, 1.0 Hz, 1H, E), 8.38 (s, 1H, E), 8.70
(d, J ) 4.9 Hz, 1H, E), 8.82 (d, J ) 4.8 Hz, 1H, Z), 9.18 (s, 1H,
Z).
1
76%): mp 178-179 °C; H NMR (CDCl3) δ 3.46 (s, 3H), 6.46
(s, 1H), 7.12 (dt, J ) 7.3, 1.1 Hz, 1H), 7.43 (dt, J ) 7.4, 1.0 Hz,
1H), 7.51 (dd, J ) 7.6, 1.1 Hz, 1H), 7.73 (dd, J ) 4.9, 1.2 Hz,
1H), 7.99 (dd, J ) 8.0, 1.0 Hz, 1H), 8.37 (d, J ) 1.2 Hz, 1H),
8.69 (d, J ) 4.9 Hz, 1H);13C NMR (CDCl3) δ 26.5, 100.7, 115.5,
116.9, 128.6, 130.1, 130.6, 136.0, 137.2, 138.6, 139.5, 144.7,
150.0, 164.8; IR (KBr) 1694 cm-1. Anal. Calcd for C15H11
-
IN2O: C, 49.75; H, 3.06, N, 7.73. Found: C, 49.52; H, 3.15, N,
7.88.
5-Meth yl-4,5-d ih yd r oben zo[h ]p yr r olo[3,4,5-d ,e]qu in o-
lin -4-on e (3). To a solution of (E)-4 (362 mg, 1 mmol) in dry
degassed benzene (500 mL), refluxing under Ar, was added a
solution of n-Bu3SnH (378 mg, 1.3 mmol) and AIBN (164 mg,
1 mmol) in dry degassed benzene (50 mL) by syringe over a
period of 30 min. Once addition had finished, refluxing was
kept up for a further 3 h. The benzene was evaporated under
reduced pressure, and the residue was dissolved in CH3CN
(100 mL). The solution was washed with hexane (3 × 50 mL)
and concentrated in vacuo to a solid residue which was
recrystallized from EtOH to afford 3 (147 mg, 63%): mp 191-
192 °C (lit.4c 182 °C dec); 1H NMR (CDCl3) δ 3.49 (s, 3H), 7.07
(s, 1H), 7.63-7.67 (m, 2H), 7.84 (dd, J ) 7.0, 2.5 Hz, 1H), 7.90
(d, J ) 4.7 Hz, 1H), 8.98 (dd, J ) 6.8, 2.5 Hz, 1H), 9.21 (d, J
) 4.7 Hz, 1H); 13C NMR (CDCl3) δ 26.7, 105.7, 117.1, 123.9,
126.3, 128.4, 128.8, 129.3, 133.6, 136.0, 137.2, 144.7, 151.7,
167.2; IR (KBr) 1706 cm-1. Anal. Calcd for C15H10N2O: C,
76.91; H, 4.30, N, 11.96. Found: C, 77.03; H, 4.41, N, 11.75.
6-Br om o-5-m et h yl-4,5-d ih yd r ob en zo[h ]p yr r olo[3,4,5-
d ,e]qu in olin -4-on e (2). A solution of Br2 (144 mg, 0.9 mmol)
in CHCl3 (10 mL) was added dropwise to a vigorously stirred
suspension of AcONa (74 mg, 0.9 mmol) in a solution of
(aza)aristolactam 3 (140 mg, 0.6 mmol) in CHCl3 (30 mL). The
mixture was stirred at room temperature for 1 h. Triethyl-
amine (5 mL) was then added, and the organic phase was
successively treated with aqueous NaOH (10%, 3 × 10 mL)
and aqueous sodium thiosulfate (10%, 3 × 10 mL), washed
with water and brine, and finally dried (MgSO4). The solvent
was removed under reduced pressure to afford crude 2 (167
mg, 89%) which was finally purified by recrystallization from
MeOH: mp 244-245 °C; 1H NMR (CDCl3) δ 3.81 (s, 3H), 7.69
(dt, J ) 7.5, 1.1 Hz, 1H), 7.77 (dt, J ) 7.7, 1.4 Hz, 1H), 7.89
(d, J ) 4.6 Hz, 1H), 8.36 (dt, J ) 8.2, 1.1 Hz, 1H), 8.99 (dd, J
) 7.7, 1.4 Hz, 1H), 9.19 (d, J ) 4.6 Hz, 1H); 13C NMR (CDCl3)
δ 29.2, 102.3, 117.1, 121.9, 123.8, 126.7, 127.2, 127.6, 129.3,
3-[1-(2-Iod op h en yl)-1-h yd r oxym eth yl]-2-m eth yl-2,3-d i-
h yd r o-1H-p yr r olo[3,4-c]p yr id in -1-on e (11). A solution of
LHMDS (1 M in hexanes, 2 mL, 2 mmol) was added dropwise
to a solution of 9 (300 mg, 2 mmol) in THF (20 mL) with
stirring under Ar at -78 °C. The mixture was stirred for an
additional 15 min after which time a solution of 2-iodo-
benzaldehyde (466 mg, 2 mmol) in THF (5 mL) was added by
syringe. The reaction mixture was stirred at -78 °C for a
further 30 min, and then quenched with saturated NH4Cl
solution and finally extracted with three 30 mL portions of
Et2O and two 25 mL portions of CH2Cl2. The combined organic
layers were dried (MgSO4) and evaporated on a rotary evapo-
rator to afford 11 (640 mg, 83%) as a single diastereomer which
was finally purified by recrystallization from EtOH: mp 195-
130.0, 132.4, 134.3, 143.9, 151.6, 167.4; IR (KBr) 1711 cm-1
.
Anal. Calcd for C15H9BrN2O: C, 57.53; H, 2.90, N, 8.95.
Found: C, 57.32; H, 2.73, N, 9.05.
P r ep a r a t ion of E u p ola u r a m in e (1) fr om t h e 6-H y-
d r oxy-5-m et h yl-4,5-d ih yd r ob en zo[h ]p yr r olo[3,4,5-d ,e]-
qu in olin -4-on e (14). A solution of the brominated compound
2 (100 mg, 0.32 mmol) in a mixture of THF (40 mL) and HMPA
(5 mL) was cooled to -78 °C and treated with PhLi (1.8 M in
cyclohexane/ether, 0.37 mL, 0.67 mmol). The resulting solution
1
196 °C; H NMR (DMSO-d6) δ 3.15 (s, 3H), 4.99 (d, J ) 3.1
Hz, 1H), 5.26 (t, J ) 4.0 Hz, 1H), 6.03 (d, J ) 5.0 Hz, 1H),
7.20 (td, J ) 7.5, 1.6 Hz, 1H), 7.32 (dd, J ) 7.8, 1.5 Hz, 1H),
7.51 (td, J ) 7.5, 1.6 Hz, 1H), 7.65 (d, J ) 4.9 Hz, 1H), 7.73 (s,