N-Pyridinium imidates as new sources of 2-aminoimidazole and imidazoline derivatives

Article abstract of DOI:10.1016/j.tetlet.2009.09.101

New 2-aminoimidazole (2-AI) and imidazoline derivatives were obtained in three steps through the reduction of N-pyridinium imidates into 1,2-dihydropyridine imidates and oxidative addition of guanidine derivatives. Among the possible transformations, imid

Full text of DOI:10.1016/j.tetlet.2009.09.101

Tetrahedron Letters 50 (2009) 6826–6829
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Tetrahedron Letters
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N-Pyridinium imidates as new sources of 2-aminoimidazole
and imidazoline derivatives
,
*
*
Sylvain Picon, Anne Zaparucha , Ali Al-Mourabit
Institut de Chimie des Substances Naturelles du CNRS, BP 1, 91198 Gif-sur-Yvette, France
a r t i c l e i n f o
a b s t r a c t
Article history:
New 2-aminoimidazole (2-AI) and imidazoline derivatives were obtained in three steps through the
reduction of N-pyridinium imidates into 1,2-dihydropyridine imidates and oxidative addition of guani-
dine derivatives. Among the possible transformations, imidate substitution allows selectivity in the last
deprotection step, leading to an original 2-aminoimidazolo-imidazoline skeleton.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 21 August 2009
Revised 17 September 2009
Accepted 21 September 2009
Available online 24 September 2009
Keywords:
Imidazole derivatives
Dihydropyridine
Imidate
2-Aminopyrimidine
The 2-aminoimidazole (2-AI) subunit is found in various active
marine metabolites isolated from sponges, for example, 3-amino-
1-(2-aminoimidazol-4-yl)-prop-1-ene (1),1 girolline (2),2 and oroi-
din (3)3 (Fig. 1). Due to various biologically interesting activities of
imidazole and 2-aminoimidazole heterocycles, many lead mole-
cules have been selected as synthetic targets.4
are unstable compounds. To be of practicable use, they have to be sta-
bilized by an N-alkoxycarbonylsubstituent or by the N-acylpyrrole, as
we have demonstrated in the synthesis of oroidin and derivatives.8,9
Inspired by the interesting work of Charrette et al. regarding the use
of 2-substituted-1,2-dihydropyridines in the synthesis of piperidine
alkaloids,11 we thought of using N-pyridinium imidate salts of type
11 as precursor of the desired 1,2-dihydropyridines. This would allow
a large substitution panel on the imidate function as presented by R1
and R2 (Scheme 2).
In the synthesis of the oroidin-type alkaloids, the construction
of the 2-AI core is commonly envisaged by an addition reaction be-
tween acetylguanidine and an a
-halocarbonyl,5 by cyanamide con-
densation on a 2-aminoaldehyde6, or by oxidative addition of
protected guanidines 7 to 1,2-dihydropyridines 6 followed by
dihydropyridine ring opening to give the 2-AI derivatives 9.7 This
latest approach allows selective access to a large library of Z/E ana-
logs of the marine natural compound oroidin (3). An interesting
diversity of the 2-AI core could be simply reached by using various
N-substituted-N0-protected guanidines8,9 (Scheme 1).
For other structural modifications, we have used a second genera-
tion of the early dihydropyridine building block prepared from the
correspondingpyridiniumsalt. Followingasimilarreactionsequence,
a modification of the starting material is needed for the replacement
of the oroidin pyrrole moiety by other groups, for example, phenyl or
alkyl. As reported by Fowler, N-acyl-1,2-dihydropyridines are not
accessible by simple reduction of the corresponding N-acylpyridini-
um salt.10 In general, 1,2-dihydropyridines with a free position at C2
The 1,2-dihydropyridines 12 were synthesized in one pot
from pyridine and the appropriate benzamide derivatives 10
(Scheme 3).12 N-Pyridinium imidate salts of type 11 were obtained
following the optimized reaction conditions. Subsequent borohy-
dride reduction afforded the (E)-1,2-dihydropyridines 12 in 4/1 reg-
ioisomeric ratio of 1,2/1,4, respectively. The latter regioselectivity is
in accordance with the regioselectivities obtained when reducing
the N-acylpyrrole pyridinium by the borohydride (Table 1).8
2-Aminopyrimidine (2-AP) was selected as a highly protected
guanidine. Standard conditions were used for the oxidative addi-
tion of the 2-AP to dihydropyridines 12.8 This led to the formation
of the bicyclic adducts 13 in acceptable yields (Scheme 4).
Deprotection of the guanidine13 and formation of the 2-AI moi-
ety by dihydropyridine ring opening were performed in one step
by treatment with hydroxylamine hydrochloride (3 equiv) and tri-
ethylamine (3 equiv) in absolute ethanol. Under these conditions,
all the starting material was consumed but the resulting reaction
mixture was rather messy. When the amidine function was substi-
tuted by a methyl or a benzyl group the major compound was prod-
uct 17, which exhibited an original 2-aminoimidazolo-imidazoline
* Corresponding authors. Tel.: +33 (0)1 69 82 45 85; fax: +33 (0)1 69 07 72 47.
E-mail address: ali.almourabit@icsn.cnrs-gif.fr (A. Al-Mourabit).
Present address: IG Genoscope-CEA, CNRS-UMR 8030, 2 rue Gaston Cremieux,
91057 Evry Cedex, France.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.09.101

S. Picon et al. / Tetrahedron Letters 50 (2009) 6826–6829
6827
OH
O
H
N
N
N
N
NH2
NH2
N
H
Br
H2N
H2N
H2N
Cl
N
H
N
H
N
H
1
2
Br
3
Figure 1.
NaBH4
N
N
R = OCH3, 1,4/1,2 = 4/96, ref. 10
R = pyrrole, 1,4/1,2 = 27/73, ref. 8
N
+
O
R
O
R
O
R
4
5
6
R
N
O
H
R
HN
R
N
Br2
H
NH
P
N
N
H
N
+
N
NH
P
N
NH2
HN
N
O
O
R = alkyl, aryl
R = alkyl, aryl
HN
HN
P = protecting group
P = protecting group
6
7
8
9
Scheme 1.
R3
N
R3
N
NHR3
NHR4
NHR4
O
NaBH4
R2
11
N
N
HN
NHR4
N
N
N
N
NH
R2
14
R1
N
R2
H
N
R1
N
R1
R2
12
N
R1
R2
N
R1
10
13
Scheme 2.
TfO
N
N
O
N
Pyridine
R
NaBH4, MeOH
-78 °C, 3 h
N
R
N
R
+
N
H
N
R
Tf2O, DCM
12
10
11
15
Scheme 3.
skeleton. When the amidine was substituted by a phenyl group,
the major product was the 2-aminoimidazole derivative 18b
(Scheme 5 and Table 2).
Table 1
Entry
Benzamide
R
12/15a
Yieldb (%)
Product
1
2
3
10a
10b
10c
CH3
Phe
Bn
84/12
73/27
80/20
67
65
34
12a
12b
12c
Deprotection of the guanidine function followed by opening of
the dihydropyridine ring afforded transitorily the expected com-
pound 1614 which immediately rearranges into compound 17. For-
mation of the imidazoline ring was the consequence of the
intramolecular addition of the amidine function on the expected
tautomer generated by the dual reactivity of the 2-AI nucleus.7a
A similar rearrangement has already been observed in the last step
of pyrrolo-2-aminoimidazole alkaloid synthesis while heating un-
der acidic conditions.8 Electrophilic reactivity of the amidine car-
bon of compound 17b was enhanced by substitution of the N100
by a phenyl group, leading to the hydroxylamine nucleophilic addi-
tion, followed by ring opening to afford 18b (Scheme 6).15
The reaction sequence was extended to the dihydropyridine 20
prepared in one pot from the pyrrolidone (19). The dihydropyri-
dine 20 was obtained as described above, in one pot from 19 in
56% yield. Oxidative addition of 2-AP underwent the formation of
the bicyclic adduct 22 in 38% yield. Interestingly, deprotection of
the guanidine and concomitant ring opening afforded three
a
Determined by 1H NMR.
12+15.
b
N
N
Br2 (1 eq.)
N
N
H2N
N
+
N
DMF/AcN 4/1
RT, 15 min.
N
N
R
N
R
12a,b,c
13a R = CH3 38%
13b R = Phe 60%
13c R = Bn 28%
Scheme 4.

6828
S. Picon et al. / Tetrahedron Letters 50 (2009) 6826–6829
N
N
R
HN
H
N
N
R
N
H
N
NH2OH.HCl, Et3N
EtOH, reflux
N
NH2
NH2
Ph
+
N
HN
N
R
N
N
Ph
N
OH
13
17
Scheme 5.
18
(Scheme 7). The known product 247a resulted from the cleavage
of the amidinic bond by the hydroxylamine, departure of the pyrr-
olidin-2-one oxime (25), followed by spontaneous intramolecular
cyclization of the unstable allylic amine on the 2-aminoimidazole
moiety.
Table 2
Entry
Substrate
R
t (h)
17a (%)
18a (%)
1
2
3
13a
13b
13c
CH3
Phe
Bn
3
1
1
17a (41)
17b (6)
17c (33)
—
18b (48)
Finally, in order to limit the rearrangement process, further
examination of the experimental conditions was conducted on
compound 13a. Under optimized conditions, treatment of the bicy-
clic adduct 13a by hydroxylamine hydrochloride (2 equiv) and tri-
ethylamine (2 equiv) in acetonitrile at 50 °C gave the expected
a
Isolated yield.
different compounds. Next to the expected product 23 isolated in
24% yield, the major compound 24 was obtained in 68% yield
N
N
H
H
N
R
N
R
N
N
N
NH2OH
13
N
N
NH2
NH2
N
R
N
Ph
N
H
Ph
N
H
16
H
H
N
H
R
N
R
N
R
N
H
N
1"
N
NH2
NH2
NH2
Ph
Ph
Ph
N
N
N
N
N
N
1
H
17
Ph
HN
OH
H2N
H
N
Ph
N
Ph
N
HO
HN
Ph
H
N
H
1"
NH2
N
NH2
NH2
Ph
N
HN
Ph
N
N
N
N
1
H
17b
18b
N
OH
Scheme 6.
N
N
N
N
O
N
1. Tf2O, pyridine
DCM
N
H2N
N
4 eq.
HN
N
N
Br2 1 eq.
2. NaBH4, CH3OH
-78 °C, 3h
DMF/AcN 4/1
RT, 15 min.
19
20 (56%)
22 (38%)
+ 1,4 21 (7%)
H
NH2
NH
N
HN
NH2
NH2OH.HCl, Et3N
EtOH, reflux
N
NH
+
N
H
N
23 (24%)
24 (68%)
H
N
H
N
NH2
NH2
H
N
HO
N
N
N
ref. 7a
NH
NH
NH2
24
+
NHOH
N
HN
NH2
HN
N
H2N OH
23
25
Scheme 7.

S. Picon et al. / Tetrahedron Letters 50 (2009) 6826–6829
6829
H
N
H
N
N
N
N
NH2
NH2
N
N
NH2OH.HCl, Et3N
CH3CN, 50 °C
N
HN
N
+
N
N
NH
27
1H NOESY
13a
26
26/27, 15/10 (44%)
Scheme 8.
4. (a) Richards, J. J.; Ballard, T. E.; Wolfe, A.; Melander, C. Chem. Eur. J. 2008, 14,
1045–1061; (b) Richards, J. J.; Ballard, T. E.; Huigens, R. X.; Melander, C. Chem.
Biol. Chem. 2008, 9, 1267–1279; (c) Richards, J. J.; Ballard, T. E.; Melander, C.
Org. Chem. Biol. 2008, 6, 1356–1363; (d) Benoît-Vical, F.; Salery, M.; Soh, P. N.;
Ahond, A.; Poupat, C. Planta Med. 2008, 74, 434–438.
5. For pioneering work, see: (a) Little, T. L.; Webber, S. E. J. Org. Chem. 1994, 59, 7299–
7305; For application in synthesis, see: (b) Yamaguchi, J.; Seiple, I. B.; Young, I. S.;
O’Malley, D. P.; Maue, M.; Baran, P. S. Angew. Chem., Int. Ed. 2008, 47, 1–4.
6. (a) Lancini, G. C.; Lazzari, E. J. Heterocycl. Chem. 1966, 3, 152; (b) Fpley, L. H.;
Büchi, G. J. Am. Chem. Soc. 1982, 104, 1776–1777.
product in a reasonable yield of 44%, as two inseparable tautomers
26 and 27 as the sole identifiable products (Scheme 8).
In conclusion, new 2-aminoimidazole and imidazoline deriva-
tives were obtained in three steps from N-pyridinium imidates.
Imidate substitution by a methyl or a benzyl group allowed selec-
tive formation of original 2-aminoimidazolo-imidazoline com-
pounds, while substitution by a phenyl group or a cyclic imidate
function underwent the formation of open interesting rearranged
derivatives. Applications of these selective trends are in progress
and will be reported in due course.
7. (a) Abou-Jneid, R.; Ghoulami, S.; Martin, M.-T.; Tran Huu Dau, E.; Travert, N.;
Al-Mourabit, A. Org. Lett. 2004, 6, 3933–3936; (b) Del Rayo Sanchez Salvatori,
M.; Abou-Jneid, R.; Ghoulami, S.; Martin, M.-T.; Zaparucha, A.; Al-Mourabit, A. J.
Org. Chem. 2005, 70, 8208–8211.
8. Schroif-Grégoire, C.; Travert, N.; Zaparucha, A.; Al-Mourabit, A. Org. Lett. 2006,
8, 2961–2964.
Acknowledgment
9. Schroif-Grégoire, C.; Appenzeller, J.; Martin, M.-T.; Petek, S.; Debitus, C.;
Zaparucha, A.; Al-Mourabit, A. J. Med. Chem, submitted for publication.
10. Fowler, F. W. J. Org. Chem. 1972, 37, 1321–1323.
We wish to thank the Institut de Recherches Servier for funding.
11. (a) Charrette, A. B.; Grenon, M.; Lemire, A.; Pourashraf, M.; Martel, J. J. Am.
Chem. Soc. 2001, 123, 11829–11830; (b) Lemire, A.; Charrette, A. B. Org. Lett.
2005, 7, 2747–2750; (c) Charrette, A. B.; Mathieu, S.; Martel, J. Org. Lett. 2005, 7,
5401–5404.
Supplementary data
12. Charrette, A. B.; Grenon, M. Can. J. Chem. 2001, 79, 1694–1703.
13. Fajgelj, S.; Stanovnik, B.; Tisler, M. Heterocycles 1986, 24, 379–386.
14. Double nucleophilic attack of the hydroxylamine on the pyrimidine ring
afforded deprotected 2-aminoimidazole compound, together with the not
isolated 3-(hydroxyamino)acrylaldehyde oxime as the by-product. The
opening of the dihydropyridine ring was the consequence of heating the
reaction mixture.
15. (a) Fernandez, B. M.; Reverdito, A. M.; Paolucci, G. A.; Perillo, I. A. J. Heterocycl.
Chem. 1987, 24, 1717–1723; (b) Salerno, A.; Ceriani, V.; Perillo, I. A. J. Heterocycl.
Chem. 1997, 34, 709–718; (c) Xia, C.; Tang, Y.; Zhou, P. J. Heterocycl. Chem. 2000,
37, 1329–1332.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.09.101.
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