10066 J . Org. Chem., Vol. 63, No. 26, 1998
Notes
in CDCl3 unless otherwise noted. Proton chemical shifts are
reported in parts per million (ppm) relative to internal refer-
ence: the residual CHCl3 resonance at δ 7.24. All exchangeable
protons were confirmed as such by the addition of D2O. For 13C
NMR, the center line of the CDCl3 triplet was used as the
internal reference: δ 77.0. Unless otherwise noted, each carbon
resonance represents a single carbon (relative intensity); inverse
gated decoupled spectra were used for carbon resonance integra-
tion to establish relative intensities >1 C. Melting points were
determined in capillaries and are uncorrected. Dichloromethane
was distilled immediately prior to use from calcium hydride. All
reactions were carried out in oven-dried (105 °C) glassware
under a dry argon atmosphere. All chromatography refers to
flash chromatography performed using silica gel-60 (43-60 µm).
Trimethylaluminum (2.0 M in hexanes) was purchased from
Fluka and used as received. Triethylaluminum (1.9 M in toluene)
and ethyl ethynyl ether (50% in hexanes) were purchased from
Aldrich and used as received. It is important to note that the
number of equivalents of trialkylaluminum reagent required for
the ketonizations depended upon the “freshness” of the reagent.
Thus, in each procedure, the reagent is noted as “aged” or “new”.
Meth yl 1-Acetyl-5H-p yr id a zin o[4,5-b]in d ole-4-ca r boxy-
la te (4a ). To a solution of 31a (0.123 g, 0.432 mmol) in anhydrous
CH2Cl2 (5 mL) was added dropwise with stirring Al(CH3)3 (aged,
2.0 M in hexanes, 0.86 mL, 1.728 mmol) at 0 °C. The reaction
mixture was allowed to slowly warm to room temperature over
30 min, stirred for 24 h at room temperature, then quenched by
the addition of 1 N HCl (5 mL), and stirred for 30 min. The layers
were separated, and the aqueous layer extracted with CH2Cl2/
EtOAc (1:1, 3 × 20 mL). The combined organic extracts were
dried over Na2SO4, and then the solvent was removed in vacuo
to afford crude 4a . Chromatography (CH2Cl2) gave pure 4a (83.6
mg, 72% yield) as a yellow crystalline solid: mp 218-220 °C;
IR (KBr) νmax 3372, 1700, 1684 cm-1; 1H NMR (400 MHz, CDCl3)
δ 10.29 (br s, ex, NH), 9.07 (bd, J ) 8.2 Hz, 1 H), 7.74 (ddd, J )
8.2, 6.7, 1.2 Hz, 1 H), 7.67 (dd, 1 H, J ) 8.2, 1.2 Hz, 1 H), 7.48
(dd, J ) 6.7, 8.2 Hz, 1 H), 4.20 (s, 3 H), 3.09 (s, 3 H);13C NMR
(67.5 MHz, CDCl3) δ 201.0, 166.1, 151.1, 141.1, 137.9, 136.6,
131.3, 127.9, 122.9, 120.0, 118.8, 111.9, 53.4, 28.3; EIHRMS (70
eV) m/z 269.0811 ([M]+, 100%), calcd for C14H11N3O3 269.0800.
1,4-Dia cetyl-5H-p yr id a zin o[4,5-b]in d ole (4b). Meth od A.
To a solution of 4a (0.040 g, 0.149 mmol) in anhydrous CH2Cl2
(10 mL) was added dropwise with stirring Al(CH3)3 (aged, 2.0
M in hexanes, 0.30 mL, 0.595 mmol) at -78 °C. The reaction
mixture was allowed to warm to -20 °C over 30 min and then
stirred at this temperature for 24 h. The reaction was quenched
by the addition of 1 N HCl (2 mL) and stirred for 30 min. The
layers were separated, and the aqueous layer was extracted with
CH2Cl2/EtOAc (1:1, 3 × 20 mL). The combined organic extracts
were dried over Na2SO4, and then the solvent was removed in
vacuo to afford crude 4b. Chromatography (CH2Cl2) gave pure
4b (14.0 mg, 41%) as a yellow crystalline solid. Meth od B. To
a solution of tetrazine 15b (32.0 mg, 0.193 mmol) in anhydrous
CH2Cl2 (10 mL) was added a solution of indole (22.6 mg, 0.193
mmol) also in anhydrous CH2Cl2 (3 mL) at room temperature.
The reaction mixture was stirred at room temperature for 6 h
and then solvent removed in vacuo. Chromatography as above
gave pure 4b (25.0 mg, 52%): mp 216-217 °C; IR (KBr) νmax
5:1) gave pure 6a (8.1 mg, 48% yield). Meth od B. To a mixture
of tetrazine 15a (37.0 mg, 0.203 mmol) and anthranilic acid (84
mg, 0.406 mmol) in anhydrous CH2Cl2 (30 mL) at 0 °C was added
isoamylnitrite (93 µL, 0.480 mmol). The reaction mixture was
stirred at this temperature for 1 h and then concentrated in
vacuo, and the residue was purified by chromatography (CH2-
Cl2/EtOAc, 5:1) to give 6a (62.3 mg, 84% yield) as a light yellow
crystalline solid: mp 124-126 °C; IR (KBr) νmax 1724, 1694 cm-1
;
1H NMR (400 MHz, CDCl3) δ 8.96 (dd, J ) 7.0, 1.8 Hz, 1 H),
8.63 (dd, J ) 7.5, 1.8 Hz, 1 H), 8.04-7.96 (m, 2 H), 4.14 (s, 3 H),
2.97 (s, 3 H); 13C NMR (67.5 MHz, CDCl3) δ 200.9, 164.8, 153.4,
151.5, 134.3, 133.5, 126.1, 125.4 (2C), 124.4, 53.5, 28.9; EIHRMS
(70 eV) m/z 230.0694 ([M]+, 13.9%), calcd for C12H10N2O3
230.0691.
1,4-Dia cetylp h th a la zin e (6b). Meth od A. To a solution of
dimethyl phthalazine-1,4-dicarboxylate7 (5, 70.0 mg, 0.285 mmol)
in anhydrous CH2Cl2 (10 mL) was added dropwise with stirring
Al(CH3)3 (new, 2.0 M in hexanes, 0.43 mL, 0.854 mmol) at -30
°C. The reaction mixture was stirred at -30 °C for 24 h and
then quenched by the addition of 1 N HCl (10 mL) and stirred
for 10 min, warmed to 0 °C and stirred for an additional 30 min
and then allowed to warm to room temperature. The layers were
separated and the aqueous layer extracted with CH2Cl2 (3 × 30
mL). The combined organic extracts were dried over Na2SO4,
and the solvent was removed in vacuo to afford crude 6b.
Chromatography (CH2Cl2) gave pure 6b (40.1 mg, 67% yield).
Meth od B. To a mixture of tetrazine 15b (14.0 mg, 0.084 mmol)
and anthranilic acid (23.1 mg, 0.169 mmol) in anhydrous CH2-
Cl2 (10 mL) at 0 °C was added isoamylnitrite (34 µL, 0.253
mmol). The reaction mixture was stirred at this temperature
for 1.5 h and then concentrated in vacuo, and the residue was
purified by chromatography (CH2Cl2) to give 6a (7.0 mg, 39%
yield) as a light yellow crystalline solid: mp 121-122 °C; IR
1
(KBr) νmax 1702 cm-1; H NMR (400 MHz, CDCl3) δ 8.94-8.90
(m, 1 H), 8.02-7.98 (m, 1 H), 2.99 (s, 3 H); 13C NMR (100 MHz,
CDCl3) δ 200.8, 154.0, 134.1, 126.1, 125.0, 29.1; EIHRMS (70
eV) m/z 214.0741 ([M]+, 1.4%), calcd for C12H10N2O2 214.0742.
3-Acetyl-5,6-d ip h en yl-1,2,4-tr ia zin e (8a ).17 To a solution
of ethyl 5,6-diphenyl-1,2,4-triazine-3-carboxylate (7)18 (63.0 mg,
0.216 mmol) in anhydrous CH2Cl2 (30 mL) was added dropwise
with stirring Al(CH3)3 (aged, 2.0 M in hexanes, 0.32 mL, 0.649
mmol) at -78 °C. The reaction mixture was allowed to slowly
warm to -20 °C over 30 min, stirred for 24 h at this temperature,
then quenched by the addition of 1 N HCl (10 mL) at -20 °C
followed by stirring for 10 min, warming to 0 °C, and stirring
for an additional 30 min, and allowed to warm to room temper-
ature. The layers were separated, and the aqueous layer was
extracted with CH2Cl2 (3 × 40 mL). The combined organic
extracts were dried over Na2SO4, and the solvent was removed
in vacuo to afford crude 8a . Chromatography (CH2Cl2/EtOAc,
10:1) gave pure 8a (25.0 mg, 42% yield) as a light yellow
crystalline solid: mp 166-167 °C (lit. 159.5-161.5 °C,17a 162-
163 °C17b); IR (KBr) νmax 1715 cm-1; 1H NMR (400 MHz, CDCl3)
δ 7.64-7.60 (m, 4 H), 7.46-7.32 (m, 6 H), 2.95 (s, 3 H); 13C NMR
(100 MHz, CDCl3) δ 196.1, 158.0, 156.84, 156.80, 134.8, 134.7,
131.3, 130.5, 129.9 (2C), 129.6 (2C), 128.79 (2C), 128.71 (2C),
27.3; CIHRMS (NH3, 140 eV) m/z 276.1160 ([M + H]+, 6.4%),
calcd for C17H13N3O 276.1137.
1
3340, 1701, 1683 cm-1; H NMR (400 MHz, CDCl3) δ 10.62 (br
3-P r op ion yl-5,6-d ip h en yl-1,2,4-tr ia zin e (8b). To a solution
of 7 (184.0 mg, 0.632 mmol) in anhydrous CH2Cl2 (15 mL) was
added dropwise with stirring Al(CH2CH3)3 (aged, 1.9 M in
toluene, 1.0 mL, 1.896 mmol) at -78 °C. The reaction mixture
was allowed to slowly warm to -20 °C over 1 h, stirred for 24 h
at this temperature, then quenched by the addition of 1 N HCl
(5 mL), and stirred for 30 min. The layers were separated and
the aqueous layer extracted with CH2Cl2 (3 × 20 mL) The
combined organic extracts were dried over Na2SO4, and the
solvent was removed in vacuo to afford crude 8b. Chromatog-
raphy (CH2Cl2) gave pure 8b (62.0 mg, 36% yield) as a yellow
s, ex, NH), 9.05 (d, J ) 8.2 Hz, 1 H), 7.72 (ddd, J ) 7.9, 7.0, 1.0,
1 H), 7.66 (dd, J ) 7.9, 1.0, 1 H), 7.48 (ddd, J ) 8.2, 7.0, 1.0, 1
H), 3.11 (s, 3 H), 3.08 (s, 3 H); 13C NMR (75.5 MHz, CDCl3) δ
202.4, 200.8, 151.0, 141.6, 141.3, 136.3, 131.2, 127.8, 122.9, 120.5,
118.6, 112.0, 28.4, 26.5; EIHRMS (70 eV) m/z 253.0866 ([M]+,
48.3%), calcd for C14H11N3O2 253.0851.
Meth yl 4-Acetylp h th a la zin e-1-ca r boxyla te (6a ). Meth od
A. To a solution of dimethyl phthalazine-1,4-dicarboxylate7 (5,
18.0 mg, 0.073 mmol) in anhydrous CH2Cl2 (20 mL) was added
dropwise with stirring Al(CH3)3 (new, 2.0 M in hexanes, 0.14
mL, 0.073 mmol) at -45 °C. The reaction mixture was stirred
at -45 °C for 12 h and then quenched by the addition of 1 N
HCl (10 mL) and stirred for 10 min, warmed to 0 °C, and stirred
for an additional 30 min and then allowed to warm to room
temperature. The layers were separated and the aqueous layer
extracted with CH2Cl2 (3 × 30 mL). The combined organic
extracts were dried over Na2SO4, and the solvent was removed
in vacuo to afford crude 6a . Chromatography (CH2Cl2/EtOAc,
1
solid: mp 107-108 °C; IR (KBr) νmax 1718 cm-1; H NMR (400
(17) Previous synthesis: (a) Konno, S.; Fujimura, S.; Yamanaka,
H. Heterocycles 1984, 22, 2245-2248. (b) Ohba, S.; Konno, S.;
Fujimura, S.; Yamanaka Chem. Pharm. Bull. 1991, 39, 486-488.
(18) (a) Schmidt, D.; Druey, J . Helv. Chim. Acta 1955, 38, 1560-
1564. (b) Elix, J . A.; Wilson, W. S.; Warrener, R. N.; Calder, I. Aust. J .
Chem. 1972, 55, 865-874.