6396 J . Org. Chem., Vol. 65, No. 20, 2000
Benin et al.
(4:1 ratio) to yield red needles of 7(N5) (0.06 g, 30% yield based
on 8a ): mp 136-137 °C; H NMR δ 0.49 (t, J ) 7.3 Hz, 3H),
J 1 ) 8.1 Hz, J 2 ) 1.0 Hz, 1H), 6.76 (dd, J 1 ) 7.9 Hz, J 2 ) 0.7
Hz, 1H), 7.69 (bs, 1H), 7.24 (t, J ) 8.0 Hz, 1H), 7.28 (t, J ) 8.1
Hz, 1H), 7.61 (dd, J 1 ) 8.1 Hz, J 2 ) 0.7 Hz, 1H); IR νmax 3378
(N-H), 1728 (CdO) cm-1; HRMS (FAB+) m/z calcd for
C17H19F3N3OS [M + H]+ 370.1201, found 370.1190.
F or m a tion of Ben zo[c]cin n olin e Der iva tives. Meth od
A. In a typical run, 1 equiv of starting biphenyl was mixed
with 1.9 equiv of Zn dust and 0.75 equiv of CaCl2 per nitro
group in 96% EtOH. The mixture was stirred and refluxed for
12 h, poured into water, and extracted with ether. The organic
extract was dried (MgSO4) and filtered through a short silica
gel pad. The solvent was removed under reduced pressure, and
the residue was further separated on a silica gel column.
Results are shown in Table 1.
Meth od B. In a typical run, 1 equiv of starting biphenyl
was mixed with 1.9 equiv of Zn dust and 0.75 equiv of CaCl2
per nitro group in 96% EtOH. The mixture was carefully
degassed through three cycles of the freeze-pump-thaw
procedure. It was then placed under positive nitrogen pressure
and refluxed for 2 h. The heating was discontinued, and air
was passed through the stirred mixture for 12 h at the rate of
about 1 bubble/s. The mixture was poured into water and
extracted with ether. The organic extract was dried (MgSO4)
and filtered through a short silica gel pad. The solvent was
removed under reduced pressure and the residue was further
separated on a silica gel column. Results are shown in Table
1.
1-P r op ylth io-10-tr iflu or oa ceta m id oben zo[c]cin n olin e
N-Oxid es (10a ). From 8a (0.31 g, 0.73 mmol), according to
method A. The crude mixture was separated on a silica gel
column (hexane-EtOAc, 2:1 ratio) to give 0.23 g (84% yield)
of a yellow glass. 1H NMR analysis indicated it to be a mixture
of both N-oxides in a 2:1 ratio, and the individual spectra were
elucidated on the basis of integral intensity differences: 1H
NMR (major component) δ 0.57 (t, J ) 7.3 Hz, 3H), 1.00-1.12
(m, 2H), 2.32 (t, J ) 7.2 Hz, 2H), 6.89-6.91 (m, 2H), 7.10-
1
0.94-1.01 (m, 2H), 2.14 (t, J ) 7.2 Hz, 2H), 4.21 (bs, 2H), 6.29
(dd, J 1 ) 7.9 Hz, J 2 ) 0.9 Hz, 1H), 6.99 (t, J ) 7.7 Hz, 1H),
7.01 (t, J ) 7.8 Hz, 1H), 7.29 (dd, J 1 ) 7.6 Hz, J 2 ) 1.1 Hz,
1H), 7.64 (dd, J 1 ) 8.0 Hz, J 2 ) 1.1 Hz, 1H), 8.31 (dd, J 1 ) 8.3
Hz, J 2 ) 0.8 Hz, 1H); 13C NMR (100 MHz, CD2Cl2) δ 13.3, 22.5,
37.6, 109.7, 115.0, 118.2, 118.6, 123.9, 128.7, 130.6, 132.1,
133.2, 140.2, 143.4, 145.2; IR νmax 3334 and 3217 (N-H) cm-1
.
Anal. Calcd for C15H15N3OS x 0.5 C6H6: C, 66.64; H, 5.59; N,
12.95. Found: C, 66.35; H, 5.53; N, 13.09.
The less mobile dark red fraction yielded a solid material,
which upon recrystallization gave reddish-brown crystals (0.09
g, 46% yield based on 8a ). NMR analysis indicated it to be a
mixture of 7(N5) and 7(N6) and the 1H NMR spectrum of
7(N6) was elucidated from the difference of the spectra for
the mixture and that for the pure 7(N5): 1H NMR δ 0.49 (t,
J ) 7.3 Hz, 3H), 0.90-1.01 (m, 2H), 2.13 (t, J ) 7.1 Hz, 2H),
4.02 (bs, 2H), 6.27 (dd, J 1 ) 7.9 Hz, J 2 ) 1.2 Hz, 1H), 6.87 (dd,
J 1 ) 8.3 Hz, J 2 ) 7.7 Hz, 1H), 7.10 (t, J ) 7.9 Hz, 1H), 7.33
(dd, J 1 ) 7.6 Hz, J 2 ) 1.3 Hz, 1H), 7.37 (dd, J 1 ) 8.0 Hz, J 2
)
1.2 Hz, 1H), 8.64 (dd, J 1 ) 8.4 Hz, J 2 ) 1.3 Hz, 1H). Anal.
Calcd for C15H15N3OS: C, 63.14; H, 5.30; N, 14.72. Found: C,
63.23; H, 5.31; N, 14.78.
2,2′-Din itr o-6-p r op ylth io-6′-tr iflu or oa ceta m id obip h en -
yl (8a ). Amine 5 (1.13 g, 3.40 mmol) was treated with
trifluoroacetic anhydride (1.13 g, 5.10 mmol, 0.76 mL) in dry
methylene chloride (10 mL) and pyridine (0.38 g, 5.10 mmol,
0.38 mL) at 0 °C. The reaction mixture was gradually warmed
to ambient temperature, and stirring was continued for 3 h.
The mixture was washed with water (×3). The organic layer
was dried (MgSO4), passed through a silica gel plug and the
solvent removed to give 1.40 g (96% yield) of the amide as a
pale yellow glass: 1H NMR δ 0.51 (t, J ) 7.1 Hz, 3H), 1.00-
1.06 (m, 2H), 1.99-2.06 (m, 2H), 6.64 (t, J ) 8.1 Hz, 1H), 6.68
(t, J ) 8.7 Hz, 1H), 6.72 (dd, J 1 ) 8.1 Hz, J 2 ) 1.1 Hz, 1H),
7.26 (dd, J 1 ) 1.1 Hz, J 2 ) 8.1 Hz, 1H), 7.39 (dd, J 1 ) 1.1 Hz,
J 2 ) 8.3 Hz, 1H), 7.51 (bs, 1H), 8.05 (dd, J 1 ) 1.0 Hz, J 2 ) 8.3
Hz, 1H); 13C NMR δ 13.0, 21.5, 34.0, 114.1 and 117.9 (CF3),
120.5, 122.5, 123.3, 124.7, 128.5, 129.9, 130.3, 130.4, 134.8,
141.6, 148.6, 150.2, 154.5 and 155.0 (CO); IR νmax 3401 and
3322 (N-H), 1741 (CdO), 1530 and 1350 (NO2) cm-1; MS m/e
429 (M+, 7), 295 (100). Anal. Calcd for C19H14F3N2O5S: C,
47.55; H, 3.29; N, 9.78. Found: C, 48.05; H, 3.62; N, 9.48.
2-Acet a m id o-2′,6-d in it r o-6′-p r op ylt h iob ip h en yl (8b ).
Amine 5 (0.22 g, 0.66 mmol), dissolved in dry methylene
chloride (5 mL), was treated with acetyl chloride (0.06 g, 0.79
mmol, 0.06 mL) and pyridine (0.06 g, 0.79 mmol, 0.06 mL) at
0 °C. The mixture was stirred for 3 h at ambient temperature
and poured into water, and the organic layer was separated
and dried (MgSO4). The solvent was removed under reduced
pressure, and the crude product (0.22 g) was dissolved upon
heating in a mixture of hexane-EtOAc (5:1 ratio). The solution
was rapidly cooled to -20 °C, and the separated solid was
filtered off. Subsequent recrystallization from 50% ethanol
gave 0.19 g (76% yield) of yellow crystals: mp 134-135 °C;
1H NMR (400 MHz, CDCl3) δ 0.95 (t, J ) 7.4 Hz, 3H), 1.55-
1.64 (m, 2H), 1.94 (s, 3H), 2.84 (t, J ) 7.2 Hz, 2H), 6.68 (bs,
1H), 7.58-7.60 (m, 2H), 7.63 (t, J ) 8.2 Hz, 1H), 7.91 (dd,
J 1 ) 6.5 Hz, J 2 ) 2.8 Hz, 1H), 7.96 (d, J ) 8.1 Hz, 1H), 8.56
(bs, 1H); IR νmax 3367 and 3297 (N-H), 1692 (CdO), 1527 and
1348 (NO2) cm-1; MS m/e 375 (M+, 8), 245 (100). Anal. Calcd
for C17H17N3O5S: C, 54.39; H, 4.56; N, 11.19. Found: C, 54.27;
H, 4.55; N, 11.10.
7.21 (signals for 2H, not resolved), 8.12 (dd, J 1 ) 8.0 Hz, J 2
)
1.1 Hz, 1H), 8.20 (dd, J 1 ) 8.5 Hz, J 2 ) 1.2 Hz, 1H), 9.64 (bs,
1
1H); H NMR (minor component) δ 0.55 (t, J ) 7.3 Hz, 3H),
1.00-1.12 (m, 2H), 2.25 (t, J ) 7.3 Hz, 2H), 6.85 (t, J ) 8.4
Hz, 1H), 7.10-7.21 (signals for 2H, not resolved), 7.29 (dd,
J 1 ) 7.7 Hz, J 2 ) 1.0 Hz, 1H), 7.74 (dd, J 1 ) 8.4 Hz, J 2 ) 1.1
Hz, 1H), 8.04 (dd, J 1 ) 7.5 Hz, J 2 ) 1.7 Hz, 1H), 9.76 (bs, 1H);
MS (major peak with retention time 16.50 min or minor peak
at 16.70 min) m/e 381 (M+, 33), 365 (11), 306 (100).
1-P r op ylth io-10-tr iflu or oa ceta m id oben zo[c]cin n olin e
(11a ). A mixture of benzo[c]cinnoline N-oxides 10 (0.22 g, 0.52
mmol) was dissolved in 95% ethanol (15 mL), and Zn dust (0.15
g, 2.40 mmol) and CaCl2 (0.10 g, 0.75 mmol) were added to
the solution. The mixture was stirred at reflux for 1 h, cooled
to ambient temperature, and then stirred for 12 h. Zn dust
(0.10 g, 1.60 mmol) was added, and the mixture was refluxed
for 1.5 h. The solvent was removed under reduced pressure.
Water and methylene chloride were added to the residue, and
the organic layer was separated, dried (MgSO4), and passed
through a silica gel pad. The solvent was removed and the
residue separated on a silica gel column (benzene-EtOAc, 8:1
ratio) to yield 0.15 g (79% yield) of intensely yellow material.
It was sufficiently pure to be used for further preparations:
1H NMR δ 0.42 (t, J ) 7.3 Hz, 3H), 0.80-0.91 (m, 2H), 2.06 (t,
J ) 7.1 Hz, 2H), 7.07 (t, J ) 7.8 Hz, 1H), 7.27 (t, J ) 8.0 Hz,
1H), 7.37 (dd, J 1 ) 7.6 Hz, J 2 ) 0.9 Hz, 1H), 8.09 (d, J ) 7.9
Hz, 1H), 8.24 (dd, J 1 ) 7.8 Hz, J 2 ) 1.0 Hz, 1H), 8.38 (dd,
J 1 ) 7.9 Hz, J 2 ) 1.0 Hz, 1H), 9.11 (bs, 1H); MS m/e 365
(M+, 47), 290 (100).
1-Acet a m id o-10-p r op ylt h iob en zo[c]cin n olin e (11b ).
Compound 1 (0.03 g, 0.09 mmol) and triethylamine (0.01 g,
0.09 mmol, 0.01 mL) were dissolved in dry methylene chloride
(2 mL). Acetyl chloride (0.01 g, 0.09 mmol, 0.01 mL) in dry
methylene chloride (1 mL) was added dropwise at 0-5 °C and
stirring was continued for 2 h at ambient temperature. The
mixture was washed with water, the organic layer was dried
(MgSO4) and the solvent removed. The residue was separated
on a silica gel column (hexane-EtOAc, 1:1 ratio) to give 0.025
g (79% yield) of yellow solid. Additional purification via
2,2′-Diam in o-6-pr opylth io-6′-tr iflu or oacetam idobiph en -
yl (9a ). A mixture of amide 8a (0.116 g, 0.27 mmol) and PtO2
(0.012 g, 0.05 mmol) in 10 mL of EtOH-EtOAc mixture (4:1
ratio) was hydrogenated at 50 psi for 4 h at ambient temper-
ature. The resulting colorless solution was filtered through a
Celite pad and the solvent removed. The residue was separated
on a silica gel column (hexane-EtOAc, 2:1 ratio) to give 0.08
g (82% yield) of the diamine as a pale yellow oil which solidified
1
upon standing: mp 84-85 °C; H NMR (400 MHz, CD2Cl2) δ
0.97 (t, J ) 7.3 Hz, 3H), 1.58-1.65 (m, 2H), 2.74-2.85 (m, 2H),
3.68 (bs, 4H), 6.65 (dd, J 1 ) 8.0 Hz, J 2 ) 0.9 Hz, 1H), 6.72 (dd,