C. Schroif-Gre´goire et al. / Tetrahedron Letters 48 (2007) 2357–2359
Table 2. Trans-alkoxylation reaction 15!16a–e
2359
References and notes
Entry
ROH
Conditions
Product (Yield %)
1. (a) Durant, G. J.; Colin, E. J., Charon, R. U.S. Patent
3,950,333, 1976, CAN 85:33015; (b) Berlinck, R. G. S.
Fortschr. Chem. Org. Naturst 1995, 66, 119–295; (c) Lam,
P. Y. S.; Clarck, C. G.; Li, R.; Pinto, D. J. P.; Orwat, M.
J.; Galemmo, R. A.; Fevig, J. M.; Teleha, C. A.;
Smallwood, A. M.; Rossi, R. A.; Wright, M. R.; Bai, S.
A.; He, K.; Luettgen, J. M.; Wong, P. C.; Knabb, R. M.;
Wexler, R. R. J. Med. Chem. 2003, 46, 4405–4408; (d)
Fresneda, P. M.; Delgado, S.; Francesch, A.; Manzanares,
I.; Cuevas, C.; Molina, P. J. Med. Chem. 2006, 49, 1217–
1221; (e) Cole, D. C.; Manas, E. S.; Stock, J. R.; Condon,
J. S.; Jennings, L. D.; Aulabaugh, A.; Chopra, R.;
Cowling, R.; Ellingboe, J. W.; Fan, K. Y.; Harrison, B.
L.; Hu, Y.; Jacobsen, S.; Jin, G.; Lin, L.; Lovering, F. E.;
Malams, M. S.; Stahl, M. L.; Strand, J.; Sukhedeo, M. N.;
Svenson, K.; Turner, M. J.; Wagner, E.; Wu, J.; Zhou, P.;
Bard, J. J. Med. Chem. 2006, 49, 6158–6161.
1
2
3
4
5
6
EtOH
Reflux, 2 h
Reflux, 2 h
Reflux, 2 h
Reflux, 3 h
100 °C, 48 h
100 °C, 48 h
16a (100)
16b (100)
16c (100)
9g (100)
16d (69)
16e (21)
n-BuOH
i-PrOH
t-BuOH
BnOH
PhOH
cyanate which was immediately trapped with (R)-meth-
ylbenzylamine to give product 14 in 51% overall isolated
yield. Condensation of ammonia at ꢀ72 °C in the mix-
ture of thiourea 14, EDCI and DIEA in dichlorometh-
ane gave the desired compound 15 in 73% yield
(Scheme 4).
To our delight, by the Troc cleavage procedure of N-alk-
yl-N0-Troc-guanidine under the classical conditions (Zn,
EtOH),11 urethane 16a was obtained cleanly and
quantitatively.
2. Berlinck, R. G. S. Nat. Prod. Rep. 2002, 19, 617–
619.
3. For a recent review, see: (a) Katritzky, A. R.; Rogovoy, B.
V. ARKIVOC 2005, iv, 49–87, and references cited therein;
(b) Rossiter, S.; Smith, C. L.; Malaki, M.; Nandi, M.; Gill,
H.; Leiper, J. M.; Vallance, P.; Selwood, D. L. J. Med.
Chem. 2005, 48, 4670–4678; (c) Ong, T.-G.; O’Brien, J. S.;
Korobkov, I.; Richeson, D. S. Organometallics 2006, 25,
4728–4730.
4. (a) Shinada, T.; Umezawa, T.; Ando, T.; Kozuma, H.;
Ohfune, Y. Tetrahedron Lett. 2006, 47, 1945–1947; (b)
Kim, M.; Mulcahy, J. V.; Espino, C. G.; Du Bois, J. Org.
Lett. 2006, 8, 1073–1076.
5. Zhang, Q.; Guan, J.; Sacci, J.; Ager, A.; Ellis, W.;
Milhous, W.; Kyle, D.; Lin, A. J. J. Med. Chem. 2005,
48, 6472–6481.
6. Bernatowicz, M. S.; Wu, Y.; Matsueda, G. R. Tetrahedron
Lett. 1993, 34, 3389–3392.
Wondering whether the zinc is playing any role, the
reaction was carried out solely in refluxing alcohol.
The substitution of the Troc group by any alkoxy group
was found to be rather general, since all the tested alco-
hols formed the substitution product (Table 2).
Importantly, the reaction with the bulky t-BuOH under-
went the formation of the desired compound N-meth-
ylbenzyl-N0-Boc guanidine 9g in quantitative yield
(entry 4). Reaction with the poorly nucleophilic phenol
gave the lowest yield (entry 6).
7. Zhang, Y.; Kennan, A. J. Org. Lett. 2001, 3, 2341–2344.
8. Compound 7: 1H NMR (300 MHz, CDCl3): d 1.50 (s, 9H),
5.23 (s, 2H), 6.31 (dd, J = 1.5 and 2.7 Hz, 1H), 7.23 (m,
5H), 7.52 (br s, 1H), 8.23 (d, J = 2.7 Hz, 1H), 9.01 (br s,
A similar trans-alkoxylation in an intramolecular reac-
tion which led to a cyclic urethane was observed by
Schmidt and co-workers12 A Mitsunobu O-alkylation
of Fmoc-guanidines with alcohols was also reported.13
1
1H). Compound 11: H NMR (300 MHz, CDCl3): d 1.51
(s, 9H), 1.57 (s, 9H), 6.44 (dd, J = 2.7 and 1.7 Hz, 1H),
7.64 (d, J = 1.7 Hz, 1H), 8.32 (d, J = 2.7 Hz, 1H), 8.94 (br
s, 1H). See Ref.: Drake, B.; Patek, M.; Lebl, M. Synthesis
1994, 579–582.
In conclusion, we have found that the monoprotected
Boc-1H-pyrazole-1-carboxamidine can be conveniently
employed for the synthesis of N-alkyl-N0-Boc guanidine
by reaction with unhindered primary amines. Synthesis
of (R)-N-methylbenzyl-N0-Troc guanidine was achieved
through an isothiocyanate pathway. Transformation of
the Troc group into other carbamate groups (e.g., Boc,
Cbz) was simply achieved by refluxing in the appropri-
ate alcohol. Further development of this reaction includ-
ing solid phase and asymmetric synthesis are under
progress.
9. Linton, B. R.; Carr, A. J.; Orner, B. P.; Hamilton, A. D. J.
Org. Chem. 2000, 65, 1566–1568.
10. For a method using HMDS reagent, see Ref. 4a.
11. Baxter, E. W.; Labaree, D.; Ammon, H. L.; Mariano, P. S.
J. Am. Chem. Soc. 1990, 112, 7682–7692.
12. Streincher, H.; Reiner, M.; Schmidt, R. R. J. Carbohydr.
Chem. 1997, 16, 277–298.
13. Robinson, D. E.; Seth, P. P.; Jefferson, E. A. Synth.
Commun. 2004, 34, 2743–2749.