Angewandte
Chemie
aminoimidazole 10a from 9a but also produced the previ-
ously unobserved product 11 (Table 2, entries 2–4), which
arises from decyanation of the propargyl cyanamide. La-
(OTf)3 was found to catalyze the addition–hydroamination–
isomerization sequence to provide 10a and 10b in good yields
(76 and 91%, respectively). Interestingly, the yield of isolated
10b decreased as the size of the lanthanide/Group-III-metal
ion decreased (Table 2, entries 6–8). These lanthanum(III)-
initiated reactions proceeded smoothly at 958C.
The optimized conditions were applied to a number of
substrate/nucleophile combinations under solvent-free con-
ditions (Table 3). Both cyclic and acyclic secondary amines
reacted well to give the 2-aminoimidazoles 10c–10h in good
yields (Table 3, entries 1–6). In terms of enthalpy, the hydro-
amination of alkynes is greatly favored over that of the
corresponding alkenes, as observed in the selective formation
of 10c (Table 3, entry 1), although an alkene and an alkyne
are present in equivalent positions with respect to the
guanidine moiety in the acylic intermediate.
For more-complex amines that cannot be used under
solvent-free conditions, typically those with a higher molec-
ular weight, 2-propanol can serve as an acceptable solvent.
Thus, treatment of the cyanamide 9 f with the amine (3–
5 equiv) and La(OTf)3 (30 mol%) gave the 2-aminoimida-
zoles 10i–m in good yields (Table 3, entries 7–11). The
catalyst loading can also be decreased to 10 mol% (Table 3,
entry 11); however, the relatively low cost of La(OTf)3
permits a higher catalyst loading for convenience.
procedure was also applied to the synthesis of naamine A (7)
from 10k; in a subsequent step, the phenol was liberated by
hydrogenolysis. This experimental approach proved useful, as
the purification of these compounds is simplified to filtration.
In summary, the described three-step sequence offers a
highly concise and convergent route to selectively substituted
2-aminoimidazoles.[24] The lanthanum(III)-initiated hydroa-
mination–isomerization sequence permits a unique discon-
nection for rapid access to more-complex natural product
skeletons. We are currently studying the role of lanthanum-
(III) in the hydroamination process, so that catalysts can be
developed for the further expansion of this transformation.
Received: January 10, 2009
Published online: March 25, 2009
Keywords: 2-aminoimidazoles · cyanamides · heterocycles ·
.
hydroamination · natural products
[2] R. M. Keenan, W. H. Miller, C. Kwon, F. A. Ali, J. F. Callahan,
R. R. Calvo, S.-M. Hwang, K. D. Kopple, C. E. Peishoff, J. M.
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[4] S. A. Munk, D. A. Harcourt, P. N. Arasasingham, J. A. Burke,
A. B. Kharlamb, C. A. Manlapaz, E. U. Padillo, D. Roberts, E.
We next examined the potential to remove substituents
and provide access to alternate hydrogen-bond-donor/
acceptor topologies (Scheme 3). Unfortunately, standard
[5] U. Bickmeyer, A. Grube, K. W. Klings, M. Koeck, Biochem.
[6] S. Ahmad, K. Ngu, D. W. Combs, S. C. Wu, D. S. Weinstein, W.
Liu, B.-C. Chen, G. Chandrasena, C. R. Dorso, M. Kirby, K. S.
[7] For a recent review of the chemistry and biology of the
Demospongiae alkaloids, see: a) S. M. Weinreb, Nat. Prod.
Zerial, C. Fizames, B. Rabault, A. Curaudeau, Invest. New Drugs
1991, 9, 233 – 244; for oroidin, see: c) S. R. Kelly, E. Garo, P. R.
e) A. Yamada, H. Kitamura, K. Yamaguchi, S. Fukuzawa, C.
Kamijima, K. Yazawa, M. Kuramoto, G. Y. S. Wang, Y. Fujitani,
f) R. W. Huigens III, J. J. Richards, G. Parise, T. E. Ballard, W.
6966 – 6967; for ageladine A, see: g) M. Fujita, Y. Nakao, S.
Matsunaga, M. Seiki, Y. Itoh, J. Yamashita, R. W. M. van Soest,
[8] For dorimidazole, see: a) K. A. Alvi, P. Crews, D. G. Loughhead,
Tetrahedron 1989, 45, 2193 – 2200; d) R. D. James, D. A. Jones,
W. Aalbersberg, C. M. Ireland, Mol. Cancer Ther. 2003, 2, 747 –
751.
Scheme 3. Deprotection of amine groups: a) Pd(OH)2/C, H2 (60 psi),
MeOH, AcOH, 87%; b) HCl, MeCN, then JandaJel-NH2, NH4Cl, EtOH,
70% for 13; c) 10% Pd/C, H2 (1 atm), 63% from 10k.
deallylation conditions failed to remove both allyl groups
from the imidazole core. Building blocks with a benzyl group
at N1, such as 10d, can be hydrogenated to give the
corresponding mono-unsubstituted 2-aminoimidazoles, such
as 12. Treatment of the ketal 10j with HCl/MeCN followed by
aminomethylated JandaJel in a procedure modified slightly
from the protocol described by Carreira and co-workers[19]
delivered 13, with a free 2-amino group, in good yield. This
[9] For cyanamide condensations, see: a) A. Lawson, J. Chem. Soc.
Angew. Chem. Int. Ed. 2009, 48, 3116 –3120
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