PAPER
Conversion of Amines to Protected Guanidines
41
N,N¢-Bis(Cbz)-N¢¢-isobutylguanidine (11)
White solid; mp 95–97 °C.
H), 5.29 (s, 2 H), 7.12–7.60 (m, 8 H), 8.44 (br s, 1 H), 11.83 (br s, 1
H).
1H NMR (200 MHz, CDCl3): d = 0.94–0.97 (d, 6 H, J = 6.6 Hz),
1.77–1.97 (m, 1 H), 3.24–3.30 (dd, 2 H, J = 6.9, 5.3 Hz), 5.13 (s, 2
H), 5.18 (s, 2 H), 7.29–7.39 (m, 10 H), 8.38–8.39 (br s, 1 H), 11.76
(br s, 1 H).
13C NMR (50 MHz, CDCl3): d = 20.10, 27.88, 48.49, 67.15, 68.13,
127.89, 128.14, 128.39, 128.45, 128.70, 128.79, 134.62, 136.84,
153.98, 156.09, 163.50.
13C NMR (125 MHz, CDCl3): d = 20.11, 27.90, 48.51, 66.56, 67.51,
122.53, 123.37, 127.40, 127.65, 128.93, 129.12, 129.92, 130.21,
132.55, 132.95, 133.98, 136.21, 153.76, 156.17, 163.55.
Anal. Calcd for C21H23Br2N3O4: C, 46.60; H, 4.28; N, 7.76; Br,
29.53. Found: C, 46.32; H, 4.12; N, 7.61; Cl, 29.45.
Treatment of 15 with TFA
Compound 15 (3.5 mg, 0.006 mmol) was treated with TFA–CH2Cl2
solution (50%, 0.1 mL) for 24 h at r.t. TLC revealed only the start-
ing compound in the solution. No reaction with Sakaguchi reagent30
was observed.
Anal. Calcd for C20H25N3O4: C, 65.78; H, 6.57; N, 10.96. Found: C,
65.95; H, 6.44; N, 11.05.
N,N¢-Bis(Cbz)-N¢¢-cyclopentylguanidine (12)
White solid; mp 95–96 °C.
Catalytic Hydrogenolysis of 15
1H NMR (200 MHz, CDCl3): d = 1.38–2.02 (m, 8 H), 4.37–4.47 (m,
1 H), 5.13 (s, 2 H), 5.16 (s, 2 H), 7.27–7.42 (m, 10 H), 8.31–8.34 (d,
1 H, J = 6.8 Hz), 11.76 (s, 1 H).
13C NMR (50 MHz, CDCl3): d = 23.56, 32.99, 52.50, 67.12, 68.05,
127.87, 128.12, 128.39, 128.42, 128.53, 128.70, 128.77, 134.69,
136.95, 153.93, 155.41, 163.80.
Compound 15 (20 mg, 0.037 mmol) was dissolved in MeOH
(2 mL) and 10% Pd/C (100 mg) was added. The solution was stirred
for 2 h under H2 atmosphere. The catalyst was filtered off and the
solvent removed under reduced pressure. TLC analysis of the prod-
uct revealed absence of the starting material. In order to verify the
cleavage of both protecting groups the product was subjected to
Sakaguchi reaction. Intense red color implied the presence of a free
guanidine derivative.
Anal. Calcd for C22H25N3O4: C, 66.82; H, 6.37; N, 10.63. Found: C,
66.99; H, 6.33; N, 10.65.
N,N¢-Bis(Cbz)-N¢¢-isopropylguanidine (13)
White solid; mp 116–118 °C.
References
(1) (a) Historical, Biological, Biochemical and Clinical Aspects
of the Naturally Occuring Guanidino Compounds; Mori, A.;
Cohen, B. D.; Lowenthal, A., Eds.; Plenum: New York,
1983. (b) The Organic Chemistry of Drug Synthesis, Vol. I;
Lednicer, D.; Mitscher, L. A., Eds.; Wiley: New York,
1977. (c) The Organic Chemistry of Drug Synthesis, Vol. II;
Lednicer, D.; Mitscher, L. A., Eds.; Wiley: New York,
1980. (d) Berlinck, R. G. S. Fortschr. Chem. Org. Naturst.
1995, 66, 119. (e) Riordan, J. F.; McElvany, K. D.; Borders,
C. L. Jr. Science 1977, 195, 884.
1H NMR (200 MHz, CDCl3): d = 1.19–1.22 (d, 6 H, J = 6.6 Hz),
4.25–4.36 (m, 1 H), 5.13 (s, 2 H), 5.17 (s, 2 H), 7.30–7.38 (m, 10
H), 8.20 (br s, 1 H), 11.76 (br s, 1 H).
13C NMR (50 MHz, CDCl3): d = 25.54, 42.98, 67.10, 68.05, 127.87,
128.11, 128.39, 128.42, 128.61, 128.70, 128.77, 128.85, 134.70,
136.93, 153.89, 155.07, 163.82.
Anal. Calcd for C20H23N3O4: C, 65.03; H, 6.28; N, 11.37. Found: C,
65.21; H, 6.22; N, 11.35.
(2) Xian, M.; Li, X.; Tang, X.; Chen, X.; Zheng, Z.; Galligan, J.
J.; Kreulen, D. L.; Wang, P. G. Bioorg. Med. Chem. Lett.
2001, 11, 2377.
(3) Baker, T. J.; Luedke, N. W.; Tor, Y.; Goodman, M. J. Org.
Chem. 2000, 65, 9054.
(4) Hui, Y.; Ptak, R.; Pallansch, M.; Chang, C.-W. W.
Tetrahedron Lett. 2002, 43, 9255.
(5) Izdebski, J.; Witkowska, E.; Kunce, D.; Orłowska, A.;
Baranowska, B.; Radzikowska, M.; Smoluch, M. J. Peptide
Sci. 2002, 8, 289.
(6) Bajusz, S.; Ronai, A. Z.; Szekely, J. J.; Miglecz, E.; Berzetei,
J. FEBS Lett. 1980, 110, 85.
(7) Poss, M. A.; Iwanowicz, E.; Reid, J. A.; Lin, J.; Gu, Z.
Tetrahedron Lett. 1992, 33, 5933.
(8) Iwanowicz, E.; Poss, M. A.; Lin, J. Synth. Commun. 1993,
23, 1443.
(9) Kim, K. S.; Qian, L. Tetrahedron Lett. 1993, 34, 7677.
(10) Robinson, S.; Roskamp, E. J. Tetrahedron 1997, 53, 6697.
(11) Bergeron, R. J.; McManis, J. S. J. Org. Chem. 1987, 52,
1700.
(12) Guo, Z.-X.; Cammidge, A. N.; Horwell, D. C. Synth.
Commun. 2000, 30, 2933.
(13) Santagada, V.; Fiorino, F.; Severino, B.; Salvadori, S.;
Lazarus, L. H.; Bryant, S. D.; Caliendo, G. Tetrahedron Lett.
2001, 42, 3507.
(14) De Mong, D. E.; Williams, R. M. Tetrahedron Lett. 2001,
42, 3529.
(15) Verdini, A. S.; Lucietto, P.; Fossati, G.; Giordani, C.
Tetrahedron Lett. 1992, 33, 6541.
N,N¢-Bis(Cbz)-N¢¢-tert-butylguanidine (14)
White solid; mp 89–90 °C.
1H NMR (200 MHz, CDCl3): d = 1.44 (s, 9 H), 5.14 (s, 2 H), 5.16
(s, 2 H), 7.25–7.40 (m, 10 H), 8.33 (br s, 1 H), 11.81 (br s, 1 H).
13C NMR (50 MHz, CDCl3): d = 28.78, 52.59, 67.10, 67.90, 127.71,
127.73, 128.37, 128.40, 128.67, 128.71, 134.76, 137.16, 154.03,
154.57, 163.39.
Anal. Calcd for C20H25N3O4: C, 65.78; H, 6.57; N, 10.96. Found: C,
65.88; H, 6.48; N, 10.84.
N,N¢-Bis(o-Cl-Cbz)-N¢¢-isobutylguanidine (15)
Yield: 191 mg (84%); white solid; mp 101–103 °C.
1H NMR (200 MHz, CDCl3): d = 0.96–0.99 (d, 6 H, J = 6.6 Hz),
1.79–1.99 (m, 1 H), 3.27–3.33 (dd, 2 H, J = 7.0, 5.4 Hz), 5.26 (s, 2
H), 5.31 (s, 2 H), 7.21–7.48 (m, 8 H), 8.43 (br s, 1 H), 11.71 (br s, 1
H).
13C NMR (50 MHz, CDCl3): d = 20.11, 27.91, 48.52, 64.33, 65.32,
126.78, 127.03, 128.91, 129.04, 129.31, 129.69, 129.96, 130.05,
132.35, 134.62, 153.81, 156.17, 163.59.
Anal. Calcd for C21H23Cl2N3O4: C, 55.76; H, 5.13; N, 9.29; Cl,
15.68. Found: C, 55.61; H, 5.11; N, 9.28; Cl, 15.61.
N,N¢-Bis(o-Br-Cbz)-N¢¢-isobutylguanidine (16)
Yield: 180 mg (67%); white solid; mp 103–105 °C.
1H NMR (500 MHz, CDCl3): d = 0.97–0.98 (d, 6 H, J = 7.0 Hz),
1,86–1,91 (m, 1 H), 3.29–3.32 (dd, 2 H, J = 7.0, 5.5 Hz), 5.23 (s, 2
Synthesis 2004, No. 1, 37–42 © Thieme Stuttgart · New York