3978 J . Org. Chem., Vol. 65, No. 13, 2000
Salerno et al.
chromatography (10% MeOH, CH2Cl2, 0.5% DIEA) to give 0.94
g of 2 as a yellow solid, 63% yield. 1H NMR (CDCl3, 400
MHz): δ 3.93 (s, 3 H), 4.0 (s, 3 H), 4.82 (2, 1 H), 4.84 (s, 1 H),
7.17 (s, 1 H), 7.34-7.38 (2 H), 7.66 (s, 1 H), 8.06 (dt, J ) 2 Hz,
J ) 8 Hz, 1 H), 8.70 (s, 1 H), 8.99 (s, 1 H). 13C NMR (CDCl3,
400 MHz): δ 42.2, 56.4, 56.7, 108.0, 114.4, 123.3, 128.0, 134.7,
138.0, 140.5, 147.9, 148.3, 152.2, 153.5, 165.3. HRMS m/z calcd
for C15H15N3O5 (M + 1) 318.1090, found 318.1080.
N-(Eth yl 4-(1-a m in o)eth yl-3-n itr oben zoa te)n icotin a -
m id e (3). Compound 9 (4.0 g, 11.7 mmol) was placed in MeOH
(150 mL) followed by the addition of H2O (38 mL). The solution
was cooled to 4 °C, and K2CO3 (3.23 g, 23.4 mmol) was added
over 10 min. The solution was then stirred for 20 h. The MeOH
was removed under reduced pressure, and enough H2O was
added to bring the remaining solution volume to 60 mL. This
solution was then extracted with CH2Cl2. The aqueous layer
was saved and the solution acidified to pH ) 2.0 with
concentrated HCl. The remaining solvent was removed under
reduced pressure. Concentrated HCl, 10% in 1,4-dioxane (30
mL), was added and the solvent removed under reduced
phthalimide (6.78 g, 36.6 mmol) and the mixture refluxed
under argon for 1 h. The DMF solution was then added directly
to 550 mL CH2Cl2 and extracted with 10% saturated sodium
bicarbonate then H2O. The solvent was removed under reduced
1
pressure to result in 10 g of 6 as a waxy solid, 85% yield. H
NMR (CDCl3, 300 MHz): δ 1.36 (t, J ) 7.2 Hz, 3 H), 1.93 (d,
J ) 7.5 Hz, 3 H), 4.35 (q, J ) 7.2 Hz, 2 H), 5.60 (q, J ) 7.5 Hz,
1 H), 7.55 (d, J ) 8.1 Hz, 2 H), 7.68-7.71 (2 H), 7.80-7.83 (2
H), 8.00 (d, J ) 8.4 Hz, 2 H). 13C NMR (CDCl3, 300 MHz):
14.0, 17.5, 49.2, 60.1, 123.2, 127.2, 129.6, 129.7, 131.7, 133.9,
144.9, 166.1, 167.8. HRMS: m/z calcd for C19H17NO4 (M + 1)
324.1236, found 324.1230.
Eth yl 3-Nitr o-4-(1-ph th alim ido)eth ylben zoate (7). Com-
pound 6 (9.7 g, 30 mmol) was placed in a 250 mL round-bottom
flask and cooled to -10 °C. Fuming nitric acid (100 mL) was
cooled to -10 °C and added to the flask. The reaction was
stirred at -10 °C for 1 h, after which time the solution was
poured onto ∼600 g of crushed ice. The slurry was poured onto
a large fritted funnel (40 Å) and the product slowly ac-
cumulated as a white precipitate until all the ice had melted.
The remaining white solid was then washed with H2O (600
mL). The wet solid was then dissolved and washed through
the funnel with 500 mL of CH2Cl2. The CH2Cl2 was then
extracted with H2O, 10% sodium bicarbonate, and then H2O.
The CH2Cl2 was dried with MgSO4 and filtered. The remaining
solid was purified by silica flash chromatography (30% ethyl
acetate, hexanes, 0.5% DIEA) to give 7.8 g of 7 as a pale yellow
solid, 71% yield. 1H NMR (CDCl3, 400 MHz): δ 1.39 (t, J )
7.2 Hz, 3 H), 1.98 (d, J ) 7.2 Hz, 3 H), 4.40 (q, J ) 7.2 Hz, 2
H), 6.08 (q, J ) 7.2 Hz, 1 H), 7.70-7.27 (2 H), 7.80-7.82 (2
H), 7.99 (d, J ) 8.4 Hz, 1 H), 8.24 (dd, J ) 1.6 Hz, 8.2 Hz, 1
H), 8.44 (s, J ) 2 Hz, 1H). 13C NMR (CDCl3, 400 MHz): δ 14.3,
18.3, 45.8, 61.8, 123.4, 125.3, 129.9, 131.1, 131.4, 131.6, 133.3,
134.2, 139.1, 169.9, 167.6. HRMS: m/z calcd for C19H16N2O6
(M + 1) 360.1087, found 369.1099.
pressure to result in
a white powder. The powder was
thouroughly mixed in H2O (4.0 mL) followed by filtration.
Drying for 48 h in vacuo resulted in 3.6 g of nicotinamide 3 in
87% yield, HCl salt. 1H NMR (DMSO-d6, 300 MHz): δ 1.30 (t,
J ) 6.9 Hz, 3 H), 1.59 (d, J ) 6.9 Hz, 3 H), 4.33 (q, J ) 7.2 Hz,
2 H), 5.45 (m, 1 H), 7.49 (m, 1 H), 7.91 (d, J ) 8.1 Hz, 1 H),
8.15-8.25 (2 H), 8.34 (d, J ) 1.5 Hz, 1 H), 8.69 (s, 1 H), 9.00
(s, 1 H), 9.36 (d, J ) 6.3 Hz, 1 H). 13C NMR (DMSO-d6, 400
MHz): δ 45.8, 55.6, 116.6, 118.5, 121.1, 122.2, 122.8, 124.5,
125.3, 134.2, 135.5, 136.4, 140.1, 154.6, 161.7. HRMS: m/z
calcd for C15H13N3O5 (M + 1) 316.0933, found 316.0942.
N-(Eth yl 2-n itr op h en ylglycin e)n icotin a m id e (4). Com-
pound 13 (1.7 g, 6.54 mmol) was saponified over 10 h using
the method described for (3). Following purification, the
remaining solid was dried in vacuo for 48 h to give 1.78 g of 4
1
as a white powder in 83% yield. H NMR (DOCD3, 400 MHz):
Eth yl 4-(1-Am in o)eth yl-3-n itr oben zoa te (8). Compound
7 (7.5 g, 20.3 mmol) was added to anhydrous EtOH (80 mL).
Hydrazine-H2O, 85% w/v (1.34 mL, 21.3 mmol), was added
and the solution heated to 50 °C for 1.5 h. The solution was
then cooled to 25 °C, and hydrazine-H2O, 85% w/v (1.34 mL,
21.3 mmol), was added. The solution was again heated to 50
°C for an additional 45 min. The resulting precipitate was then
filtered to separate the phthalyl hydrazide salt. The filtrate
was saved and the EtOH removed under reduced pressure.
CH2Cl2 (250 mL) was added to the remaining oil followed by
extraction with H2O. The CH2Cl2 was then dried with MgSO4
followed by filtration. The solvent was removed under vacuum
followed by silica chromatography (5% MeOH, CH2Cl2, 0.5%
DIEA). The solvent was then removed under reduced pressure
followed by addition of 10% concentrated HCl-1,4 dioxane (30
mL). The dioxane was then removed under reduced pressure
to result in 4.44 g of amine 8 as the HCl salt, 80% yield. NMR
characterization carried out on the free amine. 1H NMR
(CDCl3, 400 MHz): δ 1.39 (t, J ) 7.2 Hz, 3 H), 1.44 (d, J ) 6.3
Hz, 3 H), 4.62 (q, J ) 6.6 Hz, 1 H), 7.89 (d, J ) 8.1 Hz, 1 H),
8.22 (dd, J ) 1.5 Hz, 8.1 Hz, 1 H), 8.38 (d, J ) 1.8 Hz, 1 H).
13C NMR (CDCl3, 400 MHz): δ 14.1, 24.6, 46.0, 61.5, 124.7,
127.6, 129.6, 133.1, 146.2, 148.3, 163.9. HRMS: m/z calcd for
δ 6.41 (s, 1H), 7.56 (m, 1 H), 7.65-7.69 (2 H), 7.94 (m, 1 H),
8.03 (d, J ) 8.8 Hz, 1 H), 8.72 (dt, J ) 1.2 Hz, 6.8 Hz, 1 H),
8.85 (s, 1 H), 9.14 (s, 1 H).13C NMR (DOCD3, 400 MHz) 55.3,
126.0, 128.0, 130.6, 131.6, 132.3, 134.0, 134.7, 143.6, 144.9,
145.9, 149.6, 164.1, 172.2. HRMS: m/z calcd for C14H12N3O5
(M - H + Na) 324.0596, found 324.0583.
N-1-(2-Nitr op h en yl)eth yln icotin a m id e (5). Compound
16 (1.04 g, 6.23 mmol) was coupled with nicotinoyl chloride
and purified using the method described for compound 2.
Following purification, 5 was afforded in 1.6 g as a pale yellow
1
solid, 90% yield. H NMR (CDCl3, 300 MHz): δ 1.59 (d, J )
6.9 Hz, 3 H), 5.62 (m, 1 H), 7.27-7.34 (2 H), 7.50 (t, J ) 8.1,
1 H), 7.56-7.58 (1 H), 7.73 (d, J ) 6.9 Hz, 1 H), 7.79 (d, J )
7.8 Hz, 1 H), 8.06 (d, J ) 8.1 Hz), 9.04 (s, 1 H). 13C NMR
(CDCl3, 300 MHz): δ 21.3, 46.9, 123.6, 124.6, 128.0, 128.3,
133.4, 129.8, 135.8, 138.3, 147.4, 148.4, 151.2, 164.4. HRMS:
m/z calcd for C14H13N3O3 (M + 1) ) 272.1035, found 272.1027.
Eth yl 4-(1-P h th a lim id o)eth ylben zoa te (6). (a) 4-(1-Bro-
moethyl)benzoic acid (Lancaster) (10 g, 43.8 mmol) was added
to anhydrous EtOH (100 mL). The solution was placed under
argon and cooled to -10 °C. AcCl (12.4 mL, 175 mmol) was
then slowly added via syringe. The solution was brought to 0
°C and then stirred for 0.5 h followed by 25 °C, 24 h. Crushed
ice, 600 g, was then added. After 5 min, saturated sodium
bicarbonate (250 mL) was slowly added. To the aqueous slurry
was added CH2Cl2 (600 mL) and the solution extracted. The
organic phase was saved and further extracted with 20%
sodium bicarbonate and H2O. The solution was then dried with
MgSO4 followed by filtration. The CH2Cl2 was removed under
reduced pressure to yield 10.3 g of ethyl 4-(1-bromoethyl)-
C
11H15N2O4 (M + 1) 239.1032, found 239.1037.
N-(Eth yl 4-(1-a m in o)eth yl-3-n itr oben zoa te)n icotin a -
m id e (9). Compound 8 (4.0 g, 14.5 mmol) was coupled with
nicotinoyl chloride and purified using the method described
for compound 2. Purification provided 9 (4.5 g) as a light yellow
1
oil, 91% yield. H NMR (DMSO-d6, 300 MHz): δ 1.30 (t, J )
6.9 Hz, 3 H), 1.59 (d, J ) 6.9 Hz, 3 H), 4.33 (q, J ) 7.2, 2 H),
5.45 (m, 1 H), 7.49 (m, 1 H), 7.91 (d, J ) 8.1 Hz, 1 H), 8.15-
8.24 (2 H), 8.34 (d, J ) 1.5 Hz, 1 H), 8.69 (s, 1 H), 9.00 (s, 1
H), 9.36 (d, J ) 6.3 Hz, 1 H). 13C NMR (DMSO-d6, 300 MHz):
δ 14.1, 20.9, 45.1, 61.4, 123.2, 124.2, 128.4, 129.0, 129.4, 133.4,
134.9, 144.3, 148.0, 148.2, 151.8, 163.5, 164.4. HRMS: m/z
calcd for C17H17N3O5 (M + 1) 344.1246, found 344.1256.
Meth yl r-Br om o-2-n itr op h en yla ceta te (10). (a) O-Ni-
trophenylacetic acid (20 g, 109 mmol) (Aldrich) was dissolved
in dry DMF (350 mL) along with sodium bicarbonate (18.5 g,
175 mmol). The solution was allowed to stir for 15 min, after
1
benzoic acid as a yellow liquid in 92% yield. H NMR (CDCl3,
400 MHz): δ 1.37 (t, J ) 7.2 Hz, 3 H), 2.02 (d, J ) 6.8, 3 H),
4.36 (q, J ) 7.2 Hz, 2 H), 5.18 (q, J ) 6.8 Hz, 1 H), 7.48 (d, J
) 8.4 Hz, 2 H), 8.00 (d, J ) 8.4 Hz, 2 H). 13C NMR (CDCl3,
400 MHz): δ 14.4, 26.6, 48.0, 61.0, 126.6, 129.6, 129.7, 147.6,
165.7. HRMS: m/z calcd for C11H13O2Br (M + 1) 259, found
259.
(b) Ethyl-4-(1-bromoethyl)benzoic acid (9.4 g, 36.4 mmol)
was added to dry DMF (30 mL) followed by potassium