1386
V. Stockmann and A. Fiksdahl
Vol 48
(100 MHz, CDCl3): dC 158.2 (C2), 153.9 (C8), 144.8 (C4),
144.2 (C6), 142.9 (py’-C3), 141.7 (C8a), 140.9 (py’-C2),
138.3 (py’-C6), 130.2 (C4a), 124.9 (py’-C4), 123.6 (C3), 121.9
(py’-C5), 116.3 (C5), 18.5 (C4-CH3); NMR assignments are
based on HMBC, HSQC, and NOESY experiments; ESI-
HRMS: calcd for [M þ H]þ C14H13N4: 237.1135; obsd
237.1151; calcd for [M þ Na]þ C14H12N4Na: 259.0954; obsd
259.0962.
0ꢀC. The aqueous solution was extracted with ether (3 ꢂ 20
mL), dried over Na2SO4 and concentrated to give the title
compound 13 as a yellow solid, 83 mg (90%), pure by 1H
NMR; 1H NMR (400 MHz, CDCl3): dH 9.97 (s, 1H, -CHO),
8.24 (s, 1H, py-H2), 8.07 (d, J ¼ 5.2 Hz, 1H, py-H6), 7.33 (d,
J ¼ 5.2 Hz, 1H, py-H5), 6.00 (br s, 2H, NH2).
General procedure for the formation of the 1,7-naph-
thyridines 16–18. 3-Aminoisonicotinaldehyde (13) in dry THF
(1 mL) was added to a solution NaH in dry THF (1 mL) at
0ꢀC. The appropriate ketone 4, 14, or 15 in dry THF (2 mL)
was added dropwise over 10 min. The reaction was stirred
for 15 min at 0ꢀC before it was allowed to heat to room
temperature and stirred for 2 h. Water (15 mL) was added
and the mixture was extracted with EtOAc (3 ꢂ 20 mL). The
combined organic extracts were dried over Na2SO4 and the
solvent was removed under reduced pressure. The products
16–18 were isolated after purification by flash column
chromatography.
4-Methyl-2-(pyridin-4-yl)-1,7-naphthyridine (8). To a so-
lution of NaH (18.0 mg, 0.750 mmol) in dry THF (2 mL) at
0ꢀC was added ketone 4 (100 mg, 0.825 mmol). The reaction
was stirred for 15 min at 0ꢀC and then 15 min at room temper-
ature. Amine 6 (94.0 mg, 0.690 mmol) in THF (1 mL) was
added dropwise over 15 min and the reaction was stirred for 2
h at room temperature. The reaction mixture was diluted with
THF (1 mL) before it was added to water (20 mL). After
extraction with EtOAc (3 ꢂ 20 mL), drying over NaSO4 and
concentration under reduced pressure, the crude product was
purified by flash chromatography (gradient: 5–10% MeOH/
CH2Cl2) to give 126 mg (82%) of the title compound 8 as a
white solid, mp 135–136ꢀC, pure by NMR. Compound 7 was
isolated as a by-product (8 mg, 10%). 8: Rf 0.15 (5% MeOH/
2-(Pyridin-4-yl)-1,7-naphthyridine (16). The title compound
was prepared form aminoaldehyde 13 (34.0 mg, 0.278 mmol),
ketone 4 (37.0 mg, 0.305 mmol) and NaH (15.0 mg, 0.625
mmol). After flash column chromatography (gradient: 5–10%
MeOH/CH2Cl2), product 16 [19] was isolated as a white solid,
41 mg (71%), mp 157–158ꢀC, pure by NMR; Rf 0.45 (10%
MeOH/CH2Cl2); IR (KBr): 3039, 1596, 1489, 1420, 948, 828,
1
CH2Cl2); IR: 1595, 1417, 837, 829, 750, 685 cmꢃ1; H NMR
(400 MHz, CDCl3): dH 9.57 (s, 1H, H8), 8.81 (d, J ¼ 5.6 Hz,
2H, py’-H2, -H6), 8.67 (d, J ¼ 5.6 Hz, 1H, H6), 8.06 (d, J ¼
5.6 Hz, 2H, py’-H3, -H5), 7.92 (s, 1H, H3), 7.79 (d, J ¼ 5.6
Hz, 1H, H5), 2.79 (s, 3H, C4-CH3); 13C NMR (100 MHz,
CDCl3): dC 155.9 (C2), 155.4 (C8), 150.8 (py’-C2, -C6), 146.0
(py’-C4), 145.2 (C4), 144.3 (C6), 143.2 (C8a), 131.2 (C4a),
122.7 (C3), 121.7 (py’-C3, -C5), 116.4 (C5), 18.6 (C4-CH3);
NMR assignments are based on HMBC and HSQC experi-
ments; ESI-HRMS: calcd for [M þ H]þ C14H12N3: 222.1026;
obsd 222.1029.
1
788, 705, 682 cmꢃ1; H NMR (400 MHz, CDCl3): dH 9.61 (s,
1H, H8), 8.82 (dd, J ¼ 4.8, 1.6 Hz, 2H, py’-H2, -H6), 8.66 (d, J
¼ 5.6 Hz, 1H, H6), 8.30 (d, J ¼ 8.4 Hz, 1H, H4), 8.11 (d, J ¼
8.4 Hz, 1H, H3), 8.08 (dd, J ¼ 4.8, 1.6 Hz, 2H, py’-H3, -H5),
7.70 (d, J ¼ 5.6 Hz, 1H, H5); 13C NMR (100 MHz, CDCl3): dC
156.3 (C2), 154.9 (C8), 150.9 (py’-C2, -C6), 145.7 (py’-C4),
144.4 (C6), 143.4 (C8a), 136.2 (C4), 130.7 (C4a), 122.6 (C3),
121.6 (py’-C3, -C5), 119.7 (C5); NMR assignments are based
on HMBC and HSQC experiments; ESI-HRMS: calcd for [M þ
H]þ C13H10N3: 208.0869; obsd 208.0880; calcd for [M þ Na]þ
C13H9N3Na: 230.0689; obsd 230.0691.
3-Amino-N-methoxy-N-methylisonicotinamide (12). To a
solution of MeONHMeꢁHCl (2.00 g, 20.5 mmol) in dry CH2Cl2
(50 mL) at 0ꢀC was added Me2AlCl (1 M in hexanes, 20.5 mL,
20.5 mmol) dropwise over 30 min. The reaction was allowed to
heat to room temperature over 2 h. A solution of amine 11
(1.265 g, 8.21 mmol) in dry CH2Cl2 (50 mL) was added and the
reaction was stirred for 20 h. A solution of borate buffer (pH
8.0, 80 mL) was added and stirring was continued for 10 min.
Extraction with CH2Cl2 (4 ꢂ 60 mL), drying over Na2SO4, con-
centration under reduced pressure and flash chromatography
(gradient: 5–10% MeOH/CH2Cl2) afforded the title compound
12 as a white solid, 1.09 g (73%), mp 94–95ꢀC, pure by NMR;
Rf 0.17 (5% MeOH/CH2Cl2); IR: 3449, 3310, 3141, 1623, 1583,
2-(Naphthalen-1-yl)-1,7-naphthyridine (17). The title com-
pound was prepared form aminoaldehyde 13 (29.0 mg, 0.237
mmol), ketone 14 (42.0 mg, 0.247 mmol), and NaH (15.0 mg,
0.625 mmol). After flash column chromatography [EtOAc/pen-
tane (1:1)], product 17 was isolated as a white solid, 19 mg
(31%), mp 116–117ꢀC, pure by NMR; Rf 0.27 [EtOAc/pentane
(1:1)]; IR: 3045, 1598, 1496, 1409, 1241, 942, 855, 803, 789,
1
773 cmꢃ1; H NMR (400 MHz, CDCl3): dH 9.64 (s, 1H, H8),
8.69 (d, J ¼ 5.6 Hz, 1H, H6), 8.28 (d, J ¼ 8.4 Hz, 1H, H4),
8.12 (m, 1H, Np’-H), 7.97 (m, 2H, Np’-H), 7.92 (d, J ¼ 8.4
Hz, 1H, H3), 7.74 (d, J ¼ 5.6 Hz, 1H, H5), 7.72 (m, 1H,
Np’-H), 7.62 (m, 1H, Np’-H) 7.52 (m, 2H, Np’-H); 13C NMR
(100 MHz, CDCl3): dC 161.4 (C2), 154.7 (C8), 144.1 (C6),
143.4 (C8a), 138.0 (Np’-Cq), 135.1 (C4), 134.2 (Np’-Cq),
131.2 (Np’-Cq), 130.1 (C4a), 129.9 (Np’-C), 128.8 (Np’-C),
128.3 (Np’-C), 127.5 (C3), 127.1 (Np’-C), 126.4 (Np’-C),
125.6 (Np’-C), 125.5 (Np’-C), 119.9 (C5); NMR assignments
are based on HMBC and HSQC experiments; ESI-HRMS:
calcd for [M þ H]þ C18H13N2: 257.1073; obsd 257.1082.
3-Phenyl-2-(pyridin-4-yl)-1,7-naphthyridine (18). The title
compound was prepared form aminoaldehyde 13 (47.0 mg,
0.385 mmol), ketone 15 (82 mg, 0.416 mmol) and NaH (19.0
mg, 0.792 mmol). After flash column chromatography (gradient:
5–10% MeOH/CH2Cl2), product 18 was isolated as an orange
solid, 30 mg (28%), mp 131-132ꢀC, pure by NMR; Rf 0.16 (5%
1
1418, 1384, 983, 968, 832 cmꢃ1; H NMR (400 MHz, CDCl3):
dH 8.18 (s, 1H, py-H2), 7.98 (d, J ¼ 4.8 Hz, 1H, py-H6), 7.25
(d, J ¼ 4.8 Hz, 1H, py-H5), 4.64 (br s, 2H, NH2), 3.57 (s, 3H,
-OCH3), 3.37 (s, 3H, -CH3); 13C NMR (100 MHz, CDCl3): dC
167.5 (C¼¼O), 141.7 (py-C3), 139.8 (py-C2), 138.2 (py-C6),
123.0 (py-C4), 121.8 (py-C5), 61.5 (O-CH3), 33.3 (N-CH3);
NMR assignments are based on HMBC and HSQC experiments;
ESI-HRMS: calcd for [M þ H]þ C8H12N3O2: 182.0924; obsd
182.0931.
3-Aminoisonicotinaldehyde (13). A solution of Weinreb
amide 12 (138 mg, 0.759 mmol) in dry THF (2 mL) was
added dropwise over 15 min to a solution of LiAlH4 (86.4 mg,
2.28 mmol) in dry THF (3 mL) at ꢃ15ꢀC. The reaction was
stirred for 1.5 h at ꢃ15ꢀC and quenched by pouring the mix-
ture into a phosphate buffer solution (1 M, pH 7.5, 30 mL) at
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet