After drying over MgSO4, the organic solvent was removed to
afford a crude product. Further purification by silica gel chro-
matography yielded the pure 2a as a white solid (247 mg, 69%).
1H NMR (CDCl3): δ 8.22 (br, 1H); 8.10 (s, 1H); 7.49(s, 1H); 6.87
(s, 1H); 3.54 (m, 4H); 1.55 (m, 6H). 13C NMR (CDCl3): δ 24.3;
26.5; 45.6; 117.2; 128.7; 136.5; 160.3. Anal. Calcd for C9H14N4:
C, 60.65; H, 7.92; N, 31.43. Found: C, 60.52; H, 7.96; N, 31.58.
nation of 1 with BrCN (Scheme 4). Indeed, like 1, 7
reacted readily with piperidine (an alkylamine) and
N-methylaniline (an arylamine), to yield 8a and 8b,
respectively. In turn, 8a was converted to 9a ,b smoothly
upon treatment with piperidine (an alkylamine) and
aniline (an arylamine), respectively, in refluxing THF.
Not surprisingly, no product was observed from the
reaction of 8a with p-nitroaniline, presumably due to the
extremely poor nucleophilicity of the amine. In the case
of 9d , the reaction proceeded at elevated temperatures
with moderate yield (Table 1).
In summary, we have found and successfully demon-
strated the versatility of di(imidazole-1-yl)methanimine
and its derivative di(imidazole-1-yl)cyanomethanimine as
useful reagents for the synthesis of a wide variety of
guanidines and cyanoguanidines, respectively. Their
additional applications in the solid-phase synthesis, as
well as in the formation of heterocyclic compounds,9 are
underway in this laboratory.
Typ ica l P r oced u r e for th e P r ep a r a tion of Gu a n id in es
3 (3b a s a n Exa m p le). To a solution of 2a (89 mg, 0.5 mmol)
in 1.0 mL of DMF was added N-methylaniline (80 mg, 0.75
mmol). After the mixture was allowed to stir at 90 °C overnight,
5 mL of water was added, followed by extraction with CH2Cl2.
The organic layer was washed successively with saturated NH4-
Cl, water, and brine. After drying over MgSO4, the organic
solvent was removed to afford a crude product. Further purifica-
tion by silica gel chromatography yielded the pure 3b as a white
1
solid (83 mg, 76%). H NMR (CDCl3): δ 7.23 (m, 4H); 7.06 (br,
1H); 7.02 (m, 1H); 3.33 (s, 3H); 3.26 (m, 4H); 1.53 (m, 2H); 1.44-
(m, 4H). 13C NMR (CDCl3): δ 24.8; 25.8; 37.8; 45.3; 125.1; 126.8;
128.6; 146.2; 159.1. MS (m/e): 217 (M+). Anal. Calcd for
C13H19N3: C, 71.85; H, 8.81; N, 19.34. Found: C, 71.36; H, 8.86;
N, 19.26.
Di(im id a zole-1-yl)cya n om eth a n im in e (7). To a mixture of
1 (0.3 g, 1.86 mmol) in THF (5 mL) was added CNBr (0.23 g,
2.23 mmol) followed by triethylamine (0.30 mL, 2.23 mmol).
After the mixture was stirred at room temperature overnight,
the solvent was evaporated and the yellow residue chromato-
graphed using 2:1 hexanes-ethyl acetate to provide (0.22 g, 63%)
7 as a pale yellow solid. 1H NMR (DMSO-d6): δ 7.21(s, 1H); 7.61-
(s, 1H); 8.09 (s, 1H). 13C NMR (DMSO-d6): δ 118.3, 130.1, 137.6,
138.2, 144.2. Anal. Calcd for C8H6N6: C, 51.61; H, 3.25; N, 45.14.
Found: C, 51.43; H, 3.21; N, 45.24.
Exp er im en ta l Section
Gen er a l Meth od s. All commercially available starting ma-
terials and solvents were reagent grade. Anhydrous tetrahydro-
furan (THF) and dimethylformamide (DMF) were used. Ana-
lytical thin-layer chromatography was carried out using precoated
silica gel plates. Flash chromatography was performed using
kieselgel 60 (230-400 mesh) silica gel. 1H and 13C NMR spectra
were recorded on a 400 MHz instrument. Chemical shifts are
reported in parts per million (ppm). Mass spectral analyses were
performed. Elemental analyses were determined and are within
(0.4% of the calculated values unless otherwise noted.
Di(im id a zole-1-yl)m eth a n im in e (1). To a solution of imi-
dazole (6.8 g, 100 mmol) in 500 mL of dichloromethane was
added cyanogen bromide (3.7 g, 33 mmol) and the mixture
heated at reflux temperature for 30 min. The mixture was cooled
to rt, the white precipitate removed by filtration, and the filtrate
concentrated to 50 mL and cooled to 0 °C for 2 days. The
crystallized solid was filtered and washed with cold dichlo-
romethane and dried to give 4.4 g (81%) of 1 as a white solid.
1H NMR (DMSO-d6): δ 7.13 (s, 1H); 7.58 (s, 1H); 8.10 (s, 1H);
10.24 (s, 1H). 13C NMR (DMSO-d6): δ 119.3; 130.1; 137.8; 141.3.
Typ ica l P r oced u r e for th e P r ep a r a tion of Im id a zole-1-
ca r boxim id a m id es 2 (2a a s a n Exa m p le). To a solution of 1
(322 mg, 2 mmol) in 5 mL of THF was added piperidine (204
mg, 2.4 mmol). After the mixture was allowed to stir at room
temperature for several hours, TLC indicated that the reaction
was completed. Then, 10 mL of water was added to the mixture,
followed by extraction with CH2Cl2. The organic layer was
washed successively with saturated NH4Cl, water, and brine.
Typ ica l P r oced u r e for th e P r ep a r a tion of Im id a zole-1-
cya n oca r boxim id a m id es (8a a s a n Exa m p le). A solution of
7 (205 mg, 1.1 mmol) and piperidine (187 mg, 2.2 mmol) in THF
was stirred at room temperature. After the reaction was
complete as indicated by TLC, the solvent was evaporated and
the residue subjected to column chromatography to afford 8a
as a solid (148 mg, 66% yield). 1H NMR (CDCl3): δ 1.57 (m, 6H);
3.57 (m, 4H); 6.87 (s, 1H); 7.49(s, 1H); 8.10 (s, 1H). 13C NMR
(CDCl3): δ 25.1; 26.2; 45.2; 117.7; 119.2; 128.3; 136.1; 161.2.
Anal. Calcd for C10H13N5: C, 59.10; H, 6.45; N, 34.46. Found:
C, 58.92; H, 6.43; N 34.5.
Typ ica l P r oced u r e for th e P r ep a r a tion of Cya n ogu a n -
id in es 9 (9b a s a n Exa m p le). A solution of 8a (224 mg, 1.1
mmol) and aniline (205 mg, 2.2 mmol) in THF was refluxed for
12 h. After the reaction was completed as indicated by TLC, the
solvent was evaporated and the residue subjected to column
1
chromatography to afford 9b as a solid (175 mg, 70% yield). H
NMR (CDCl3): δ 1.42 (m, 4H); 1.55 (m, 2H); 3.54 (m, 4H); 6.99
(m, 2H); 7.32(m, 3H). 13C NMR (CDCl3): δ 25.1; 26.2; 44.2; 118.3,
119.2; 129.1; 129.4, 136.1; 162.3. Anal. Calcd for C13H16N4: C,
68.39; H, 7.06; N 24.54. Found: C, 68.30; H, 6.99; N, 24.21.
(9) Wu, Y. Q.; Limburg, D.; Wilkinson, D. E.; Hamilton, G. S. J .
Heterocycl. Chem., submitted.
J O0202381
7556 J . Org. Chem., Vol. 67, No. 21, 2002