α-Aminoester-derived imidazoles by 1,5-electrocyclization of azavinyl azomethine ylides

Article abstract of DOI:10.1021/ol901051z

An efficient and practical method for the preparation of α-lmldazol-1-yl esters from 1,2-dlaza-1,3-dlenes (DDs), α-amlno esters, and aldehydes Is described. The overall sequence features a Michael-type conjugate addition between the a-amlno ester and the

Full text of DOI:10.1021/ol901051z

ORGANIC
LETTERS
2009
Vol. 11, No. 13
2840-2843
r-Aminoester-Derived Imidazoles by
1,5-Electrocyclization of Azavinyl
Azomethine Ylides
Orazio A. Attanasi,† Emilia Caselli,‡ Paolo Davoli,‡ Gianfranco Favi,*,†
Fabio Mantellini,† Claudia Ori,‡ and Fabio Prati*,‡
Istituto di Chimica Organica, UniVersita` degli Studi di Urbino “Carlo Bo”,
Via I Maggetti 24, 61029 Urbino, Italy, and Dipartimento di Chimica, UniVersita` degli
Studi di Modena e Reggio Emilia, Via Campi 183, 41100 Modena, Italy
gianfranco.faVi@uniurb.it; fabio.prati@unimore.it
Received May 13, 2009
ABSTRACT
An efficient and practical method for the preparation of r-imidazol-1-yl esters from 1,2-diaza-1,3-dienes (DDs), r-amino esters, and aldehydes
is described. The overall sequence features a Michael-type conjugate addition between the r-amino ester and the DD, followed by iminium ion
formation via condensation with the aldehyde and 1,5-electrocyclization of the resulting thermally generated azavinyl azomethine ylide to
afford eventually r-imidazol-1-yl esters. Such a protocol allows access to enantiomerically pure imidazoles from optically pure r-amino esters.
The reaction of azomethine ylides with π bonds is a powerful
tool for the construction of a variety of N-containing
heterocycles.1 In fact, azomethine ylides behave as 1,3-
dipoles and typically react with dipolarophiles via [3 +
2]-cycloaddition to afford five-membered heterocycles such
as pyrrolidines or pyrrolines, where the ylide nitrogen atom
is incorporated in the final ring product. Intramolecular
cycloadditions of azomethine ylides are also possible, thus
allowing the synthesis of complex heterocyclic architec-
tures.1f When the azomethine ylide is conjugated with a
double bond, a 1,5-electrocyclization pathway may occur.2
In the course of our painstaking research on the chemistry
of 1,2-diaza-1,3-dienes3 (DDs), we have disclosed a new
access to highly decorated imidazoles via 1,5-electrocycliza-
tion of R-aziridinohydrazone-derived conjugated azavinyl
azomethine ylides.4 The reaction sequence hinged on the ease
of DDs to undergo 1,4-conjugate addition with a most diverse
range of nucleophiles,3,5 including N-unsubstituted aziridines,
which in turn are prone to thermal or photochemical electro-
cyclic ring opening at the C-C bond to generate azomethine
ylides.6 Unprecedentedly, incorporation of two nitrogen
atoms of the conjugated azavinyl azomethine ylide into the
1,5-electrocyclization product was observed, and imidazoles
† Universita` degli Studi di Urbino “Carlo Bo”.
‡ Universita` degli Studi di Modena e Reggio Emilia.
(1) For reviews on azomethine ylides, see: (a) Huisgen, R. 1,3-Dipolar
Cycloaddition Chemistry; Padwa, A., Ed.; Wiley: New York, 1984; Vol.
1, pp 1-177. (b) Tufariello, J. J. 1,3-Dipolar Cycloaddition Chemistry;
Padwa, A., Ed.; Wiley: Chichester, UK, 1984; Vol. 2, pp 83-168. (c)
Gothelf, K. V.; Jørgensen, K. A. Chem. ReV. 1998, 98, 863–909. (d)
Harwood, L. M.; Vickers, R. J. The Chemistry of Heterocyclic Compounds:
Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry toward
Heterocycles and Natural Products; Padwa, A., Pearson, W. H., Eds.; Wiley
and Sons: New York, 2002; Vol. 59, pp 169-252. (e) Na´jera, C.; Sansano,
J. M. Curr. Org. Chem. 2003, 7, 1105–1150. (f) Coldham, I.; Hufton, R.
Chem. ReV. 2005, 105, 2765–2809. (g) Bonin, M.; Chauveau, A.; Micouin,
L. Synlett 2006, 2349–2363. (h) Pandey, G.; Banerjee, P.; Gadre, S. R.
Chem. ReV. 2006, 106, 4484–4517.
(2) Eberbach, W. Science of Synthesis: Houben-Weyl Methods of
Molecular Transformations; Padwa, A., Bellus, D., Eds.; Thieme Verlag:
Stuttgart, 2004; Vol. 27, pp 441-498. For a specific review on conjugated
azomethine ylides, see: Pinho e Melo, T. M. V. D. Eur. J. Org. Chem.
2006, 2873–2888.
10.1021/ol901051z CCC: $40.75
Published on Web 06/10/2009
 2009 American Chemical Society

Table 1. Synthesis of R-Imidazol-1-yl Esters 5a-p
a Isolated yield (after silica gel chromatography) based on DDs 1a-d. b Under the reaction conditions, loss of the hydroxy ethyl side chain of threonine
through a retro-aldol process occurred, and only the imidazole 5a was isolated.
were ultimately obtained through an overall [3 + 2]
annelation strategy whereby three atoms of the azo-ene
system7 and two atoms of the aziridine participated. Such
an approach, however, required preliminary synthesis of the
aziridine nucleophile, which clearly limited the range of
available partners. Since azomethine ylides can also be
formed by deprotonation of iminium ions,1 we envisaged a
much easier access to stabilized azavinyl azomethine ylides
using DD-derived secondary R-aminoester hydrazones. In
fact, these would be accessible by Michael-type addition of
R-amino acid derivatives to DDs and are expected to undergo
condensation with aldehydes to give an iminium ion which
in turn is susceptible to deprotonation to generate conjugated
azavinyl azomethine ylides.
Therefore, we wish to report a novel synthetic procedure
which allows the straightforward conversion of R-ami-
Org. Lett., Vol. 11, No. 13, 2009
2841

noesters into imidazoles through 1,5-electrocyclization of
DD-derived azavinyl azomethine ylides.
Table 2. Synthesis of R-Imidazol-1-yl Esters 5q-s
R-Aminoester hydrazones 3a-p were prepared by 1,4-
conjugate addition of R-amino acid methyl esters 2a-h to
DDs 1a-d.8 The adducts 3a-p did not require purification
and were used as such for the following chemistry. Con-
densation of hydrazones 3a-p with paraformaldehyde (4a)
and subsequent heating in toluene under reflux afforded
2-unsubstituted imidazoles 5a-p in moderate to excellent
overall yields (Table 1).9 Reaction of the adduct between
threonine methyl ester and DD 1a (Table 1, entry 3) was
accompanied by loss of the hydroxy ethyl side chain through
a retro-aldol process and resulted in imidazole 5a in 69%
yield. When adducts prepared from optically pure R-ami-
noesters (L-Phe, L-Leu, L-Glu) were used (Table 1, entries
5-7, 10, 14, and 16), enantiomerically pure imidazoles
5e-g,j,n,p were recovered (ee > 95%).10 Only in the case
of D-phenylglycine (Table 1, entries 7 and 11), partial
racemization was observed for the resulting imidazoles (5h
and 5k).
The adduct 3a between glycine methyl ester and DD 1a
was also reacted with aromatic and aliphatic aldehydes,
namely, p-anisaldehyde (4b), butanal (4c), and octanal (4d),
under the same reaction conditions. R-Imidazol-1-yl esters
5q-s were obtained in good to excellent yield (Table 2).
On the basis of these findings, the formation of R-imidazol-
1-yl ester 5 can be rationalized as shown in Scheme 1.
R-Aminoester hydrazone 3 arises from 1,4-conjugated ad-
a Isolated yield (after silica gel chromatography) based on DD 1a.
dition of an R-aminoester to DD 1.5 Condensation of adduct
3 with aldehyde 4 leads to iminium ion A which upon heating
may generate the conjugated azavinyl azomethine ylides B
and C. Although the negative charge of both ylide species
is stabilized by an adjacent electron-withdrawing carboxy
group, ylide C benefits from additional stabilization by the
DD-derived hydrazone moiety. Hence, 1,5-electrocyclization
(3) For reviews on the chemistry of DDs, see: (a) Attanasi, O. A.; De
Crescentini, L.; Filippone, P.; Mantellini, F.; Santeusanio, S. ArkiVoc 2002,
xi, 274–292. (b) Attanasi, O. A.; De Crescentini, L.; Favi, G.; Filippone,
P.; Mantellini, F.; Perrulli, F. R.; Santeusanio, S. Eur. J. Org. Chem. 2009,
DOI: 10.1002/ejoc200900243. For selected articles, see: (c) Boeckman,
R. K., Jr.; Ge, P.; Reed, J. E. Org. Lett. 2001, 3, 3651–3653. (d) Rossi, E.;
Arcadi, A.; Abbiati, G.; Attanasi, O. A.; De Crescentini, L. Angew. Chem.,
Int. Ed. Engl. 2002, 41, 1400–1402. (e) Yang, H.-T.; Wang, G.-W.; Xu,
Y.; Huang, J.-C. Tetrahedron Lett. 2006, 47, 4129–4231. (f) Attanasi, O. A.;
Favi, G.; Filippone, P.; Perrulli, F. R.; Santeusanio, S. Org. Lett. 2009, 11,
309–312. (g) Attanasi, O. A.; Berretta, S.; De Crescentini, L.; Favi, G.;
Giorgi, G.; Mantellini, F. AdV. Synth. Catal. 2009, 351, 715–719. (h)
Attanasi, O. A.; De Crescentini, L.; Favi, G.; Filippone, P.; Giorgi, G.;
Mantellini, F.; Moscatelli, G.; Behalo, M. S. Org. Lett. 2009, 11, 2265–
2268. (i) Attanasi, O. A.; Favi, G.; Giorgi, G.; Mantellini, F.; Karapetyan,
V.; Langer, P. Tetrahedron 2009, DOI: 10.1016/j.tet. 2009.04.018.
(4) Attanasi, O. A.; Davoli, P.; Favi, G.; Filippone, P.; Forni, A.;
Moscatelli, G.; Prati, F. Org. Lett. 2007, 9, 3461–3464.
Scheme 1. Postulated Mechanism for the Formation of
R-Imidazol-1-yl Esters 5 via 1,5-Electrocyclization of Azavinyl
Azomethine Ylide C
(5) (a) Bozzini, S.; Felluga, F.; Nardin, G.; Pizzioli, A.; Pitacco, G.;
Valentin, E. J. Chem. Soc., Perkin Trans. 1 1996, 1961–1969. (b) Palacios,
F.; Aparicio, D.; Lo´pez, Y.; de los Santos, J. M. Tetrahedron 2005, 61,
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G.; Mantellini, F.; Mazzanti, A. Synlett 2006, 2403–2406.
(6) Aziridines and Epoxides in Organic Synthesis; Yudin, A. K., Ed.;
Wiley-VCH: Weinheim, Germany, 2006.
(7) For recent [3 + 2] pyrrole syntheses that involve the C-CdN
fragment of DDs, see: (a) Attanasi, O. A.; Favi, G.; Filippone, P.; Lillini,
S.; Mantellini, F.; Spinelli, D.; Stenta, M. AdV. Synth. Catal. 2007, 349,
907–915. (b) Attanasi, O. A.; Favi, G.; Filippone, P.; Giorgi, G.; Mantellini,
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350, 1331–1336.
(8) 1,2-DDs 1a-d were synthesized from the corresponding chlorohy-
drazones by treatment with base (see Supporting Information).
(9) The structure of imidazoles 5a-s was confirmed by mono- (1H, 13C)
and bidimensional (COSY, HSQC, and HMBC) NMR analysis and by mass
spectroscopy (see Supporting Information).
(10) Enantiomeric excesses (ee) were determined either from 1H NMR
spectra recorded in the presence of the chiral solvating agent (R)-(-)-2,2,2-
trifluoro-l-(9-anthryl)ethanol or by chiral HPLC analysis (see Supporting
Information).
2842
Org. Lett., Vol. 11, No. 13, 2009

of conjugated ylide C to 2,3-dihydroimidazole D, followed
by aromatization with concomitant loss of a carbamate
residue through cleavage of the N-N bond,11 results
eventually in the formation of the imidazole 5 (Scheme 1).
Such a reaction mechanism is corroborated by the isolation
of enantiomerically pure imidazoles when adducts prepared
from optically pure R-aminoesters were used, as formation
of ylide C proceeds without affecting the stereogenic carbon
atom. In the case of the D-Phg-derived adduct 3h, however,
additional stabilization of ylide B by the phenyl ring would
account for the partial racemization that has been observed
in imidazoles 5h and 5k. In this case, in fact, phenyl-
stabilized ylide B is also generated, and the resulting
imidazoles are ultimately formed through tautomeric equili-
bration of B to C and subsequent 1,5-electrocyclization.
Further support to this view is lent by the fact that upon
prolonged heating at 110 °C in toluene the ee value of D-Phg-
based imidazole 5h remained unchanged, thus ruling out that
racemization occurred after the electrocyclization event.
In summary, we have reported a novel, efficient, and
straightforward method for the synthesis of R-imidazol-1-yl
ester from readily available starting material such as R-ami-
noesters and aldehydes.12 The present approach is flexible
and useful for the synthesis of a wide range of different
substituted imidazoles. Furthermore, modulation of substit-
uents at the C-2 and C-5 atoms of the final imidazole product
is made possible by appropriate choice of the aldehyde and
DD partners, respectively. Noteworthily, the amino group
of the R-aminoester is incorporated into the resulting
imidazole,13 which may therefore be viewed as a rigid amino
acid analogue bearing an aromatic heterocyclic scaffold that
mimics an amide bond. Since a variety of aromatic hetero-
cyclic rings such as pyrroles, tetrazoles, triazoles, pyrazoles,
and imidazoles have been embodied in enzyme inhibitors
as surrogates for replacement of the otherwise scissile peptide
bond,14,15 our synthetic approach may represent a versatile
and attractive access to amino acid derived, heterocycle-based
peptidomimetics. Further extension of this 1,5-electrocy-
clization pathway is currently being pursued in our labora-
tories and will be reported in due course.
Acknowledgment. This work was financially supported
by the Ministero dell’Universita`, dell’Istruzione e della
Ricerca (MIUR) - Rome, Universita` degli Studi di Urbino
“Carlo Bo”, and Universita` degli Studi di Modena e Reggio
Emilia.
Supporting Information Available: Experimental pro-
cedures and full characterization for all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL901051Z
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Kelly, J. W. Org. Lett. 2004, 6, 1681–1683. (c) Zaman, S.; Mitsuru, K.;
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hydrazines, see: Tang, Q.; Zhang, C.; Luo, M. J. Am. Chem. Soc. 2008,
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(12) For reviews on the chemistry of imidazoles, see: (a) Grimmett,
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