A.Zafar et al./ Tetrahedron 58 02002) 683±690
689
was ®ltered and washed with water and methanol and dried
under vacuum to afford the desired product :0.06 g, 68%):
6.1.12. 6-.4,5-Dihydro-1H-imidazol-2-ylamino)-pyridine-
3-carboxylic acid ethyl ester. To a solution of the crude
activated thiourea from the previous step in DMSO
:10 mL), was added ethylenediamine :33 mL, 0.44 mmol)
and the reaction mixture was heated at 1108C for 15 h.
The mixture was then cooled to room temperature and
water :20 mL) was added followed by the addition of a
15% solution of ammonium hydroxide :10 mL). The
precipitated product was extracted with diethyl ether
:2£25 mL). The combined ether extract was dried over
anhydrous sodium sulfate and the solvent was removed
under reduced pressure. The residue was then dried under
vacuum for 30 min to afford a brown solid as the desired
product :0.07 g, 69% based on the previous step): mp 1548C
1
mp 2808C :decomp.); H NMR :300 MHz, TFA-d) d 7.92
:2H, m, Ph-H at C-2 and C-20), 7.07 :2H, m, Ph-H at C-3 and
C-30), 3.62 :4H, s, guanidinyl CH2); MS m/e calcd for
C10H11N3O2: 205.0851, found 205.0859.
6.1.9.
6-.3-Benzoylthioureido)-pyridine-3-carboxylic
acid ethyl ester. To a solution of benzoyl isothiocyanate
:0.27 g, 1.65 mmol) in benzene :50 mL) was added ethyl
6-aminonicotinate :0.25 g, 1.50 mmol) and the reaction
mixture was re¯uxed for 12 h. The solvent was then
removed under reduced pressure and the crude material
was puri®ed by silica gel chromatography using a mixture
of hexane and diethyl ether :3:1, Rf0.1) as the eluent
followed by drying under vacuum to afford a yellow solid
1
:decomp.); H NMR :300 MHz, CDCl3) d 8.81 :1H, d,
J2.7 Hz, Pyr. C±H at C-2), 8.03 :1H, dd, Ja2.4 Hz and
Jb8.7 Hz, Pyr. C±H at C-4), 6.77 :1H, d, J8.4 Hz, Pyr.
C±H at C-5), 4.34 :2H, q, J7.2 Hz, OCH2), 3.69 :4H, s,
guanidine CH2), 1.63 :1H, br, guanidine N±H), 1.37 :3H, t,
J7.2 Hz, ester CH3); 13C NMR :75 MHz, CDCl3) d 166.2,
165.6, 162.9, 149.5, 137.9, 117.3, 60.7, 42.2, 14.5; MS m/e
calcd for C11H14N4O2: 234.1116, found 234.1113; Anal.
calcd for C11H14N4O2: C, 56.40; H, 6.02; N, 23.92; found:
C, 56.41; H, 6.04; N, 23.82.
1
as the desired product :0.23 g, 47%): mp 150±1528C; H
NMR :300 MHz, CDCl3) d 11.25 :br, urea N±H), 9.08±
8.99 :3H, m, urea N±H, Pyr. C±H at C-2 and C-4), 8.37
:1H, dd, Ja2.2 Hz and Jb8.7 Hz, Pyr. C±H at C-5), 7.92
:2H, d, J7.4 Hz, Ph-H at C-2 and C-20), 7.66 :1H, t, J
7.4 Hz, Ph-H at C-4), 7.55 :2H, t, J7.8Hz, Ph-H at C-3
and C-30), 4.41 :2H, q, J7.1 Hz, OCH2), 1.41 :3H, t, J
7.1 Hz, ester CH3); 13C NMR :75 MHz, CDCl3) d 177.4,
166.6, 164.9, 154.4, 150.4, 139.4, 134.1, 131.6, 129.4,
128.5, 127.8, 123.9, 114.6, 61.5, 14.5; MS m/e calcd for
C16H15N3O3S: 329.0834, found 329.0825; Anal. calcd for
C16H15N3O3S: C, 58.35; H, 4.59; N, 12.76; S, 9.73; found:
C, 58.45; H, 4.62; N, 12.74; S, 9.62.
6.1.13. 6-.4,5-Dihydro-1H-imidazol-2-ylamino)-pyridine-
3-carboxylate .10). To a solution of the above ethyl ester
:0.50 g, 2.15 mmol) in a mixture of 4:1 ethanol and water
:40 mL) was added lithium hydroxide monohydrate :0.1 g,
2.37 mmol). The reaction mixture was then re¯uxed for 2 h.
The solvent was then evaporated under reduced pressure
and the residue was dissolved in water. The aqueous solu-
tion was ®ltered and the pH of the ®ltrate was adjusted to 6.5
by using HCl :6 M) and saturated NaHCO3 solution. The
light yellow precipitate was ®ltered and washed with excess
water and dried under vacuum to afford a light yellow solid
:0.4 g, 90%): mp 3038C :decomp.); MS m/e calcd for
C9H10N4O2: 206.0803, found 206.0801; Anal. calcd for
C9H10N4O2´H2O: C, 48.21; H, 5.39; N, 24.99; found: C,
47.60; H, 5.30; N, 24.76. We were not able to characterize
this compound by NMR because of extremely low solubility
in most solvents. However, the structure was con®rmed by
X-ray crystallography :see text).
6.1.10. 6-Thioureidopyridine-3-carboxylic acid ethyl
ester. To a solution of the above benzoylthiourea :0.5 g,
1.518mmol) in absolute ethanol :50 mL) was added
anhydrous potassium carbonate :0.21 g, 1.52 mmol) and
the reaction mixture was re¯uxed for 2 h. After cooling,
the reaction mixture was ®ltered and the residue was washed
with excess ethanol and then with excess water and dried
under vacuum to afford the deprotected thiourea 16 :0.23 g,
1
66%): mp 2458C :decomp.); H NMR :300 MHz, DMSO-
d6) d 10.88 :1H, s, N±H at pyridine), 10.5 :1H, s, hydrogen
bound urea N±H), 9.15 :1H, s, urea N±H), 8.75 :1H, d,
J2.1 Hz, C±H at C-2 on pyridine), 8.18 :1H, dd, Ja
2.4 Hz and Jb8.7 Hz, C±H at C-4 on pyridine), 7.21
:1H, d, J8.7 Hz, C±H at C-5 on pyridine), 4.28 :2H, q,
J6.9 Hz, OCH2), 1.28:3H, t, J6.9 Hz, ester CH3); 13C
NMR :75 MHz, DMSO-d6) d 180.7, 164.2, 156.0, 148.2,
139.1, 119.6, 112.3, 60.8, 14.1; MS m/e calcd for
C9H11N3O2S: 225.0571, found 225.0581; Anal. calcd for
C9H11N3O2S: C, 47.99; H, 4.92; N, 18.65; S, 14.23; found:
C, 48.08; H, 4.97; N, 18.61; S, 14.16.
Acknowledgements
We thank the National Science Foundation for their ®nan-
cial support of this work.
6.1.11. 6-.2-Methylisothioureido)-pyridine-3-carboxylic
acid ethyl ester. To a solution of the above thiourea
:0.1 g, 0.44 mmol) in methanol :20 mL) was added methyl
iodide :41.5 mL, 0.66 mmol) and the reaction mixture was
heated at 708C for 15 h. The solvent was then removed on a
rotary evaporator and the crude material was dried under
vacuum and used for the next step without further puri®ca-
tion: 1H NMR :300 MHz, CDCl3) d 8.85 :1H, s, Pyr. C±H at
C-2), 8.31 :1H, br s, urea N±H), 8.18 :1H, d, J8.6 Hz, Pyr.
C±H at C-3), 6.83 :1H, d, J8.7 Hz, Pyr. C±H at C-4), 4.38
:2H, q, J7.1 Hz, ester CH2), 2.17 :3H, s, S±CH3), 1.39
:3H, t, J7.1 Hz, ester CH3).
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