5
1
Compound 7−E. H NMR (CDCl3, 400 MHz): δ 8.43 (d, J =
136.5, 132.8, 132.7, 127.4, 127.4, 123.3, 122.2, 122.1, 120.3,
ACCEPTED MANUSCRIPT
5.00 Hz, 1 H), 7.99 (s, 1 H), 7.86 (s, 1 H), 7.82 (s, 1 H),
7.66−7.62 (t, J = 7.74 Hz, 1 H), 7.14−7.11 (t, J = 7.68 Hz, 1 H),
7.07-7.02 (m, 2 H), 6.86−6.81 (m, 1 H). 13C NMR (CDCl3, 100
MHz): δ 154.1, 151.1, 149.2, 148.7, 147.5, 139.8, 132.7, 125.0,
125.0, 124.2, 120.6, 120.2, 120.1, 115.2, 115.0, 114.8, 114.8,
21.3. ESI-HRMS: m/z calcd for C13H12FN3 [M+H]+ 230.1049
found 230.1076.
116.3, 116.2, 115.3, 115.1, 52.4. ESI-HRMS: m/z calcd for
C13H12FN3O [M+H]+ 246.0998 found 246.1085.
1
Compound 15−E. H NMR (CDCl3, 400 MHz): δ 8.57 (d, J =
4.12 Hz, 1 H), 8.00 (d, 2 H), 7.86 (s, 1 H), 7.72−7.68 (t, J = 7.12
Hz, 1 H), 7.21−7.18 (m, 1 H), 7.01−6.98 (dd, J1 = 6.98 Hz, J2 =
3.02 Hz, 1 H), 6.95−6.90 (q, J1 = 11.80 Hz, J2 = 9.08 Hz, 1 H),
6.21−6.17 (m, 1 H), 2.96 (s, 6 H). 13C NMR (CDCl3, 100 MHz):
δ 154.5, 149.3, 148.5, 144.4, 142.2, 139.0, 136.4, 132.5, 132.4,
122.9, 119.9, 115.3, 115.1, 104.6, 104.6, 99.2, 41.5. ESI-HRMS:
m/z calcd for C14H15FN4 [M+H]+ 259.1314 found 259.1376.
1
Compound 8−E. H NMR (CDCl3, 400 MHz): δ 8.39 (d, J =
5.72 Hz, 1 H), 8.00 (s, 1 H), 7.85 (s, 1 H), 7.63-7.59 (t, J = 7.78
Hz, 1 H), 7.51 (d, J = 2.36 Hz, 1 H), 7.14−7.10 (t, J = 7.74 Hz, 1
H), 7.08−7.03 (q, J1 = 10.70 Hz, J2 = 8.30 Hz, 1 H), 6.86−6.81
(m, 1 H), 6.77−6.75 (dd, J1 = 5.72 Hz, J2 = 2.48 Hz, 1 H), 3.93 (s,
3 H). 13C NMR (CDCl3, 100 MHz): δ 166.1, 156.0, 151.1, 150.5,
148.7, 139.6, 132.6, 125.0, 125.0, 120.3, 120.2, 115.2, 115.0,
114.8, 114.8, 110.4, 104.6, 55.4. ESI-HRMS: m/z calcd for
C13H12FN3O [M+H]+ 246.0998 found 246.1112.
The corresponding aldehydes for synthesis of hydrazones
1−15 can be obtained by reduction of the commercial esters
except for 4-(dimethylamino)picolinaldehyde 18. The
corresponding hydrazines can be synthesized easily from the
commercial amines except for compound methyl 4-fluoro-3-
hydrazinylbenzoate
22
and
4-fluoro-3-hydrazinyl-N,N-
dimethylaniline 27. The synthetic procedures of 18, 22 and 27 are
1
Compound 9−E. H NMR (CDCl3, 400 MHz): δ 8.22 (d, J =
6.00 Hz, 1 H), 7.95 (s, 1 H), 7.83 (s, 1 H), 7.63−7.59 (t, J = 8.06
Hz, 1 H), 7.20 (d, J = 1.60 Hz, 1 H), 7.13−7.09 (t, J = 7.66 Hz, 1
H), 7.07−7.02 (q, J = 6.61 Hz, 1 H), 6.84−6.79 (q, J = 6.66 Hz, 1
H), 6.48−6.47(m, 1 H), 3.08 (s, 6 H). 13C NMR (CDCl3, 100
MHz): δ 154.7, 153.9, 151.1, 149.3, 148.7, 140.7, 132.9, 124.9,
119.9, 115.1, 115.0, 114.7, 106.8, 102.0, 39.4. ESI-HRMS: m/z
calcd for C13H12FN3O [M+H]+ 259.1314 found 246.1963.
in the following.
Compound 16.49 A solution of 4-chloropicolinic acid (0.78 g,
5 mmol) in aqueous dimethylamine (40 %, 10 ml) was stirred at
100 °C for 5 h in a sealed tube. The resulting solution was
concentrated in vacuo, then dissolved in EtOAc (50 ml) and
washed with saturated aqueous NaHCO3 (50 ml) twice. The
organic phase was dried over MgSO4 and evaporated in vacuo to
1
Compound 10−E. H NMR (CDCl3, 400 MHz): δ 8.60 (d, J =
4.40 Hz, 1 H), 8.05−8.02 (m, 2 H), 7.93−7.90 (m, 2 H), 7.78−7.74
(t, J = 7.62 Hz, 1 H), 716−7.11 (m, 2 H). 13C NMR (CDCl3, 100
MHz): δ 153.6, 149.6, 141.9, 136.7, 124.4, 123.7, 120.3, 118.7,
118.4, 116.3, 116.2, 109.4. ESI-HRMS: m/z calcd for
C14H12FN3O2 [M+H]+ 241.0845 found 241.0864.
Compound 11−E. 1H NMR (CDCl3, 400 MHz): δ 8.59 (d, J =
4.56 Hz, 1 H), 8.28 (d, J = 7.56 Hz, 1 H), 8.10 (d, J = 7.92 Hz, 1
H), 8.03 (s, 1 H), 7.76−7.72 (t, J = 7.44 Hz, 1 H), 7.58−7.55 (m, 1
H), 7.25−7.22 (m, 1 H), 7.13−7.08 (q, J1 = 10.86 Hz, J2 = 8.62
Hz, 1 H), 3.94 (s, 3 H). 13C NMR (CDCl3, 100 MHz): δ 166.7,
154.0, 151.3, 149.4, 140.7, 136.5, 132.8, 132.7, 127.4, 127.4,
123.3, 122.2, 120.3, 116.2, 116.2, 115.3, 115.1, 52.4. ESI-
HRMS: m/z calcd for C14H12FN3O2 [M+H]+ 274.0947 found
274.0995.
1
afford compound 16 (0.79 g, 95 %). H NMR (DMSO-d6, 400
MHz): δ 8.20 (d, J = 7.48 Hz, 1 H), 7.43 (d, J = 2.98 Hz, 1 H),
7.10 (dd, J1 = 3.01 Hz, J2 = 7.53 Hz, 1 H), 3.27 (s, 6 H). ESI-
HRMS: m/z calcd for C8H10N2O2 [M+H]+ 189.0634 found
189.0638.
Compound 17. Thionyl chloride (5 ml) was slowly added to a
solution of compound 16 (0.83 g, 5 mmol) in MeOH (30 ml).
The solution was then heated to reflux for 12 h and concentrated
in vacuo. The residue was dissolved in dichloromethane (DCM)
and washed with saturated aqueous NaCl, dried over MgSO4 and
1
1
Compound 12−E. H NMR (CDCl3, 400 MHz): δ 8.59 (d, J =
evaporated in vacuo to afford compound 17 (0.80 g, 89 %). H
4.44 Hz, 1 H), 8.04 (d, J = 8.00 Hz, 1 H), 7.98 (s, 1 H), 7.89 (s, 1
H), 7.75−7.71 (t, J = 7.10 Hz, 1 H), 7.61−7.58 (dd, J1 = 7.10 Hz,
J2 = 2.42 Hz, 1 H), 7.25−7.22 (m, 1 H), 7.00−6.95 (q, J1 = 11.06
Hz, J2 = 8.70 Hz, 1 H), 6.80−6.76 (m, 1 H). 13C NMR (CDCl3,
100 MHz): δ 153.9, 149.5, 140.8, 136.5, 133.6, 133.5, 130.4,
123.4, 120.2, 119.7, 119.6, 116.2, 116.0, 114.7. ESI-HRMS: m/z
calcd for C12H9ClFN3 [M+H]+ 251.0440 found 251.0610.
NMR (CDCl3, 400 MHz): δ 8.32 (d, J = 5.76, 1 H), 7.40 (s, 1 H),
6.60 (d, J = 3.24 Hz, 1 H), 3.98 (s, 3 H), 3.06 (s, 6 H). ESI-
HRMS: m/z calcd for C9H12N2O2 [M+H]+ 181.0932 found
181.0987.
Compound 18.50 Compound 17 (0.90 g, 5 mmol) was
dissolved in anhydrous DCM (25 ml) and the solution was cooled
to −60 °C. Diisobutyl aluminum hydride (DIBAL−H) (1.5 M in
toluene, 6.67 ml) was dropwised. After 5 minutes at the end of
addition, the reaction mixture was treated with the addition of
MeOH (5 ml) and then with aqueous solution of NaOH (10 %, 20
ml). The organic layers were dried over MgSO4, filtered and
1
Compound 13−E. H NMR (CDCl3, 400 MHz): δ 8.58 (d, J =
4.52 Hz, 1 H), 8.02 (d, J = 8.00 Hz, 1 H), 7.98 (s, 1 H), 7.86 (s, 1
H), 7.73−7.69 (m, 1 H), 7.43 (d, J = 6.84 Hz, 1 H), 7.26−7.19 (q,
J1 = 6.38 Hz, J2 = 5.14 Hz, 1 H), 6.95−6.90 (q, J1 = 11.48 Hz, J2
= 8.32 Hz, 1 H), 6.64−6.61 (m, 1 H), 2.35 (s, 3 H). 13C NMR
(CDCl3, 100 MHz): δ 154.4, 149.4, 147.1, 139.3, 136.4, 134.7,
134.7, 132.1, 132.0, 122.9, 120.7, 120.7, 115.1, 115.1, 114.8,
114.6, 21.3. ESI-HRMS: m/z calcd for C13H12FN3 [M+H]+
230.1049 found 230.1104.
1
concentrated to give the product 18 (0.57 g, 76 %). H NMR
(CDCl3, 400 MHz): δ 9.99 (s, 1 H), 8.38 (d, J = 5.80, 1 H), 7.18
(d, J = 2.20, 1 H, 6.66−6.64 (q, J = 2.66 Hz, 1 H), 3.07(s, 6 H).
ESI-HRMS: m/z calcd for C8H10N2O [M+H]+ 151.0827 found
151.0886.
Compound 19.51 To a solution of 4-fluorobenzoic acid (2.80 g,
20 mmol) in concentrated H2SO4 (25 ml) in an ice bath was
added potassium nitrate (2.20 g, 22 mmol) in portions within 30
minutes. The ice bath was removed and the mixture was stirred at
ambient temperature overnight. To the mixture was added
1
Compound 14−E. H NMR (CDCl3, 400 MHz): δ 8.57 (d, J =
4.40 Hz, 1 H), 8.02−8.00 (d, 2 H), 7.87 (s, 1 H), 7.72−7.69 (t, J =
7.20 Hz, 1 H), 7.22−7.16 (m, 2 H), 6.98-6.93 (q, J1 = 10.96 Hz, J2
= 9.00 Hz, 1 H), 6.36−6.32 (m, 1 H), 3.83 (s, 3 H). 13C NMR
(CDCl3, 100 MHz): δ 166.7, 154.0, 153.8, 151.3, 149.4, 140.7,