G. Dra¨ger et al. / Tetrahedron Letters 43 (2002) 1401–1403
1403
References
successively with water, methanol, dichloromethane,
methanol, and dried in high vacuum at 30°C over P2O5.
The dried resin (ca. 2.2 g) was suspended in dry
dichloromethane (30 mL), sodium iodide (8.24 g, 55
mmol) was added, and with stirring under nitrogen
trimethylchlorosilane (6.98 mL, 55 mmol) and acetylace-
tone (1.65 mL, 16 mmol) were added separately during 6
h (syringe pump). The mixture was stirred overnight at rt
and then treated with water (50 mL). After 10 min the
resin was filtered and washed with water, methanol,
acetone, dichloromethane, and dried in high vacuum. The
resin obtained (ca. 3 g) and aminoguanidine hydrochlo-
ride (1.16 g, 10.5 mmol) were stirred in abs. ethanol (30
mL) at 75°C for 20 h. The resin was filtered and washed
1. Hannon, C. L.; Auslyn, E. V. In Bioorganic Chemistry
Frontiers; Dugas, H.; Schmidtchen, F. P., Eds.; Springer:
Berlin, 1993; Vol. 3, pp. 192–255.
2. Greenhill, J. L.; Lue, P. In Progress in Medicinal Chem-
istry; Ellis, G. P.; Luscombe, D. K., Eds.; Elsevier Sci-
ence: New York, 1993; Vol. 30, Chapter 5.
3. Robinson, S.; Roskamp, E. J. Tetrahedron 1997, 53,
6697–6705.
4. Kearney, P. C.; Fernandez, M.; Flygare, J. A. Tetra-
hedron Lett. 1998, 39, 2663–2666.
5. (a) Yong, Y. F.; Kowalski, J. A.; Thoen, J. C.; Lipton,
M. A. Tetrahedron Lett. 1999, 40, 53–56; (b) Pa´tek, M.;
Smrcina, M.; Nakanishi, E.; Izawa, H. J. Comb. Chem.
2000, 2, 370–377.
6. (a) Dodd, D. S.; Wallace, O. B. Tetrahedron Lett. 1998,
39, 5701–5704; (b) Gomez, L.; Gellibert, F.; Wagner, A.;
Mioskowski, C. Chem. Eur. J. 2000, 6, 4016–4020.
7. (a) Yang, R.-Y.; Kaplan, A. P. Tetrahedron Lett. 2000,
41, 7005–7009; (b) Yang, R.-Y.; Kaplan, A. P. Tetra-
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with
methanol,
water,
methanol,
acetone,
dichloromethane, methanol, and dried in high vacuum at
40°C over P2O5. The reagent 2 (ca. 3.5 g) was obtained as
a brown resin. The loading with active groups was deter-
mined to be ca. 1.7 mmol/g based on the weight increase.
Combustion analysis: N 10.3 (corresponds to the loading
ca. 1.8 mmol/g); IR: wCꢀN 1675 cm−1 (strong).
14. Typical amidination using reagent 1. Cyclohexylamine-N-
carboxamidine (first example in Table 1): A solution of
reagent 1 (265 mg, 1 mmol), cyclohexylamine (50 mg, 0.5
mmol) and triethylamine (139 mL, 1 mmol) in dry aceto-
nitrile (1.25 mL) was heated at 60°C for 24 h. The solvent
was removed in vacuo and the residue was treated with
water (5 mL), sonicated for 2 min, and separated by
centrifugation. The supernatant was separated by decan-
tation, and the solid precipitate was treated with water
(2×) in a similar way as described above. The combined
supernatants were washed with ethyl acetate (2×5 mL),
and flushed through a column loaded with Amberlite
IRA-400 (hydroxide-form, 10 mL) by eluting with water.
The eluate was cooled to −30°C and lyophilized furnish-
ing cyclohexylamine-N-carboxamidine as a light-green
8. Bernatowicz, M. S.; Wu, Y.; Matsueda, G. R. J. Org.
Chem. 1992, 57, 2497–2502 and references cited therein.
9. Scott, F. L.; O’Donovan, D. G.; Reilly, J. J. Am. Chem.
Soc. 1953, 75, 4053–4054.
10. Sakai, T.; Miyata, K.; Tsuboi, S.; Utaka, M. Bull. Chem.
Soc. Jp. 1989, 62, 4072–4074.
11. Scott, F. L.; Reilly, J. J. Am. Chem. Soc. 1952, 74,
4562–4566.
12. Preparation of reagent 1: To a solution of benzaldehyde
(2.04 mL, 400 mmol) and acetylacetone (4.1 mL, 40
mmol) in dry dichloromethane (100 mL) under nitrogen
were added sodium iodide (30 g, 200 mmol) and dropwise
trimethylchlorosilane (25.6 mL, 200 mmol). After stirring
for 6 h the mixture was hydrolyzed with an aqueous
solution of sodium thiosulfate and extracted with
dichloromethane (3×20 mL). The combined organic
extracts were dried, and the solvent was removed in
vacuo. The remaining diketone was dissolved in a solu-
tion of methanol (100 mL), aminoguanidine hydrochlo-
ride (4.2 g, 38 mmol) and conc. HCl (7.5 mL), and the
mixture was stirred overnight at rt. The solvent was
evaporated in vacuo, the solid residue was treated with
refluxing ethyl acetate (2×20 mL), filtered and dried in
high vacuum, affording the title compound 1 (8.4 g, 31.7
mmol; 80%): mp 186–188°C (MeOH, ethyl acetate). 1H
NMR (400 MHz, DMSO-d6, TMS) l: 2.10 (s, 3H), 3.45
(s, 3H), 3.79 (s, 2H), 7.15–7.35 (m, 5H), 9.37 (br s, 4H).
13C NMR (100 MHz, DMSO-d6) l: 11.1, 12.1, 28.1,
121.7, 126.2, 128.1, 128.5, 139.4, 139.9, 153.2, 153.7. MS:
228 (M+ as free base). Anal. calcd for C13H16N4·HCl: C,
58.98; H, 6.47; N, 21.16. Found: C, 58.60; H, 6.44; N,
21.09.
1
gummy solid (67.8 mg, 0.48 mmol; 96%). H NMR (400
MHz, DMSO-d6, TMS) l: 1.18, 1.28, 1.53, 1.67, 1.79
(5m, 5×2H), 3.35 (m, 1H), 4.5–6.0 (br s, 3H); 13C NMR
(100 MHz, DMSO-d6) l: 23.9, 24.8, 32.2, 49.1, 156.0;
MS: 141 (M+).
15. Typical amidination using reagent 2. Piperidine-N-carbox-
amidine (11th example in Table 1): Reagent 2 (870 mg),
piperidine (29.7 mL, 0.3 mmol), and Et3N (208 mL, 1.5
mmol) in dry THF (4 mL) were stirred at 60°C for 24 h.
After completion of the reaction (TLC monitoring) the
mixture was filtered, the resin on the filter was washed
with THF (2×2 mL) and methanol (3×4 mL), and the
combined filtrates were evaporated in vacuo. The residue
was taken up in water (5 mL) and passed through a
column of Amberlite IRA-400 (hydroxide-form, 10 mL),
eluting with water. The eluate was cooled to −30°C and
lyophilized affording piperidine-N-carboxamidine (31
1
mg, 0.245 mmol; 82%) as a light green adhesive solid. H
13. Preparation of reagent 2: Merrifield resin (2.5 g, 4.3 mmol
chloride/g, 2% DVB, 200–400 mesh) and sodium bicar-
bonate (9.24 g, 110 mmol) were stirred in dry DMSO (25
mL) at 155°C under nitrogen for 20 h. After cooling
water (50 mL) was added, the resin was filtered, washed
NMR (400 MHz, DMSO-d6, TMS) l: 1.37–1.54 (m, 6H),
3.31 (t, J=5.25 Hz, 4H), 4.3–5.2 (br s, 3H); 13C NMR
(100 MHz, DMSO-d6) l: 24.0, 25.1, 45.9, 158.8; MS: 127
(M+).