Efficient pallado-catalyzed C6 -(het)arylation of Imidazo[1,2- b ][1,2,4,5]Tetrazines under microwave irradiations

Article abstract of DOI:10.1021/cc1000456

A versatile protocol for the preparation of a library of 5,6-(het)bisarylated imidazo[1,2-b][1,2,4,5]tetrazines is described. Target compounds were obtained in fairly good yields, starting from ethoxy-7-(4-methoxyphenyl)imidazo[1,2-b][1,2,4,5]tetrazine and a large panel of bromoaryl derivatives, using palladium catalysis under microwave irradiation. Compatibility with various chemical groups and heterocycles was proven. Steric and electronic effects do not have any effect on the efficiency of the reaction. Purifications were performed without any difficulties, and the structure of a final compound was proven by crystal X-ray diffraction studies.

Full text of DOI:10.1021/cc1000456

604
J. Comb. Chem. 2010, 12, 604–608
Efficient Pallado-Catalyzed C6-(het)arylation of
Imidazo[1,2-b][1,2,4,5]Tetrazines under Microwave Irradiations
Laurent Pellegatti,† Emeline Vedrenne,† Jean-Michel Leger,‡ Christian Jarry,‡ and
Sylvain Routier*,†
Institut de Chimie Organique et Analytique, UniVersite´ d’Orle´ans, UMR CNRS 6005, rue de Chartres,
BP 6759, 45067 Orle´ans Cedex 2, France, and EA 4138, Pharmacochimie, UniVersite´ Victor Segalen
Bordeaux II, 146 rue Le´o Saignat, 33076 Bordeaux Cedex, France
ReceiVed March 18, 2010
A versatile protocol for the preparation of a library of 5,6-(het)bisarylated imidazo[1,2-b][1,2,4,5]tetrazines
is described. Target compounds were obtained in fairly good yields, starting from ethoxy-7-(4-methox-
yphenyl)imidazo[1,2-b][1,2,4,5]tetrazine and a large panel of bromoaryl derivatives, using palladium catalysis
under microwave irradiation. Compatibility with various chemical groups and heterocycles was proven.
Steric and electronic effects do not have any effect on the efficiency of the reaction. Purifications were
performed without any difficulties, and the structure of a final compound was proven by crystal X-ray
diffraction studies.
Nitrogen-bridgehead heterocycles containing an imidazole
reactions were run under microwave irradiations (entry 4-6).
Unfortunately, even if the reaction time was considerably
reduced, yields decreased drastically, mainly because of
degradation. Classic thermal conditions were best suited for
the synthesis of those precursors 2 and 3 from 1. Noteworthy,
the 3,5-dimethylpyrazole was easily displaced starting from
2 with sodium ethoxide to afford 3 in 89% yield by a SNAr
reaction.
The Pd(0)-mediated arylation of this C-6 unsubstituted
imidazo[1,2-b][1,2,4,5]tetrazine was then evaluated (Scheme
2). Unfortunately, when a solution of 2 in dioxane was
stirred, under microwave irradiations, with 1-bromo-4-
methoxybenzene in the presence of a Cs2CO3 and Pd(OAc)2/
PPh3, as catalytic system,9 only degradation occurred. The
sensitivity of the 3,5-dimethylpyrazole group in basic media
could explain this disappointing result.
ring are scaffolds which are widely used to design bioactive
molecules. Indeed motifs such as imidazo[1,2-a]pyridines,
imidazo[1,2-a]pyrimidines are interesting cores found in
compounds showing a wide range of biological activities.
Antiviral,1 anti-ulcer,2 antibacterial,3 antifungal,4 herbicidal,5
and cyclin-dependent kinases (CDK) inhibitors6 properties
were, for example, often reported. Among these heterocycles,
imidazo[1,2-b][1,2,4,5]tetrazines attracted, surprisingly, little
attention: only a few reports on this core were published in
the literature.7 On the basis of the interests of our group in
the synthesis of biologically active compounds, we thought
that functionalized imidazo[1,2-b][1,2,4,5]tetrazines could be
considered as aza-bioisosters of imidazo pyridines or pyri-
midines. We thus envisioned the development of a new
methodology giving access to a library containing such
functionalized imidazo[1,2-b][1,2,4,5]tetrazines through a
regioselective palladium-catalyzed (het)arylation as a key
step.
We started our investigations with the synthesis of the
model compounds 2 and 3. Imidazo[1,2-b][1,2,4,5]tetrazine
2 was prepared by the reaction of amino-(1,2,3,4)-tetrazine
18 with the corresponding 2-bromoacetophenone in 72%
yield when the cyclization was run in the presence of a base
(i.e., NaHCO3) in boiling dioxane (Scheme 1). Compound
3 could also be directly prepared from aminotetrazine 1, if
the cyclization step is run in the presence of NaHCO3, but
using EtOH as solvent (Table 1, entry 1). In EtOH but
without any base, the displacement of the 3,5-dimethylpyra-
zole moiety did not occur, and only 2 was isolated in 62%
yield (entry 2). The same behavior was observed when
The Pd(0)-mediated arylation of 3, using 1-bromo-4-
fluorobenzene as coupling partner, was then tried under
classic thermal conditions (Table 2, entry 1). The reaction
afforded the desired C6-arylated imidazotetrazine 4. Unex-
pectedly, the reaction was incomplete and gave an insepa-
rable mixture of 3, 4, and 5. Fortunately, complete conversion
could be obtained in only 20 min using microwave irradia-
tions (entry 2). In that case, the reaction still led to a separable
mixture of 4 and 5. Undoubtedly, this byproduct resulted
from the insertion of Pd(0) into a C-P bond of triph-
enylphosphine. This reactivity is quite rare but has neverthe-
less already been published.10 We thus thought that this side
reaction could be avoided by the use of tricyclohexylphos-
phine. To our delight, this new ligand allowed us to isolate
4 as a single product in a very good yield of 87% (entry
3).11
* To whom correspondence should be addressed. Phone: + 33 238 417
354. Fax: +33 238 417 281. E-mail: sylvain.routier@univ-orleans.fr.
† Universite´ d’Orle´ans.
To propose an eco-compatible alternative for the synthesis
of 4, we also envisioned its preparation through a copper(I)-
phenanthroline catalytic system.12 However the reaction
‡ Universite´ Victor Segalen Bordeaux II.
10.1021/cc1000456  2010 American Chemical Society
Published on Web 05/26/2010

Library of 5,6-(het)Bisarylated imidazo[1,2-b][1,2,4,5]tetrazines
Scheme 1. Preparation of Compounds 2 and 3
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 4 605
failed in our hands. The arylation of this imidazo[1,2-
b][1,2,4,5]tetrazine skeleton thus proved to be efficient only
when the reaction was Pd-catalyzed. All the spectral data
were in concordance with the structure of compound 4. In
addition, isolation of a single crystal of 4 gave access to its
X-ray structure analysis (Figure 1). It showed that the
deviation of each atom in the different rings from the
corresponding mean plane is within 0.008 Å. The dihedral
angles between the 4-methoxyphenyl group and the imida-
zotetrazine core on the one hand, and between this core and
the fluoro phenyl group on the other hand, are 0.58(2)° and
88.6(5)°, respectively. Except this fluoro phenyl group, all
the other atoms are quasi planar (the root mean square (rms)
deviation of fitted atoms is 0.02 Å) and parallel to the (1 0
1) plane. The Oak Ridge thermal ellipsoid plot (ORTEP)
view presents the ethoxy chain in the major statistical
occupancy (65%) for better clarity. At room temperature,
the fluoro phenyl group shows a disordered little twist around
the C(14)-C(17) axis which is not quantified.
Bromobenzene derivatives bearing electron-withdrawing
groups (F, NO2, CN, Cl) gave the desired compounds in very
good yields (Table 3, entries 1-5). The reaction of 3 with
1-bromo-4-chlorobenzene or 1-bromo-3,5-dichlorobenzene
noteworthy afforded imidazotetrazines 6 and 7, as single
compounds, in 80% yield. No trace of the product resulting
from the coupling reaction on the Cl moiety was detected,
showing the complete chemoselectivity of this arylation.
The electronic nature of the bromobenzene derivative did
not really have any influence on the yields, as bromobenzene
and electron-enriched bromobenzenes still led to the desired
compounds in very good yields (entries 6-11). Bromo-
aniline could also be employed (entry 12) but the reaction
failed with bromo-phenols (entries 13-14). The phenate
To explore the scope and limitations of our methodology,
we next envisioned to modify the nature of the bromobenzene
derivative using our optimized conditions (Table 3).
Table 1. Preparation of Compounds 2 and 3
entry
solvent
conditions
base
compound
yield
1
3
4
5
6
EtOH
EtOH
EtOH
dioxane
EtOH
reflux, 12 h
NaHCO3
3
2
3
2
2
71%
62%
45%
52%
38%
reflux, 12 h
MW,a 10 min
MW,a 10 min
MW,a 10 min
NaHCO3
a MW: microwave irradiation.
Figure 1. X-ray crystal structure of compound 4.
Scheme 2. Arylation of Compound 2
Table 2. Preparation of Compound 4
entry
phosphine
heating system
conversion
ratio 4/5
yield of 4b
1
2
3
PPh3
PPh3
PCy3
b
reflux, 12 h
MW,a 20 min
MW,a 20 min
1
82%
100%
100%
60/40
60/40
100/0
41%
45%
87%
a MW: microwave irradiation. Yields were determined by H NMR.

606 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 4
Table 3. Synthesis of Compounds 4-24
Pellegatti et al.
a ND: Not Detected. b 4-iodopyridine was used as starting material.
formation during the reaction thus seems detrimental to its
efficiency. Fortunately, the reactivity could be fully restored
using MOM-protected bromo-phenols (entries 15-16). The
displacement of the substituent to the C-2 position did not
affect the yields (entries 9, 16), demonstrating that sterically
hindered bromobenzenes could be employed without any loss
of reactivity.
skeleton. Bromo-pyridines generally gave good results
(entries 17,18), except 2-bromopyridine (entry 19). In that
case, starting material was fully recovered. Complexation
of palladium with the pyridinic nitrogen atom could inactivate
the catalytic cycle. For the synthesis of 20, the use of
4-iodopyridine, instead of 4-bromopyridine, was needed to
obtain full conversion. Electron-enriched or deactivated
pyridines could also be employed, affording interesting
compounds such as 23 and 24 (entries 20-21).
To prove the efficiency of the CH arylation in heteroaro-
matic series, we then focused our study on the pyridine

Library of 5,6-(het)Bisarylated imidazo[1,2-b][1,2,4,5]tetrazines
Scheme 3. Preparation of Compound 27
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 4 607
Scheme 4. Arylation of Compound 27
To complete our investigations, the arylation of the C-6
and C-7 unsubstituted imidazotetrazine 27 was tested. This
compound was synthesized through the reaction of 1 with
chloroacetaldehyde using acidic conditions (Scheme 3).13
Unfortunately, the intermediate 25 was isolated in only 13%
yield. The major compound of this reaction appeared to be
tetrazine 26 (80%), which results from the hemiacetal
formation by the amino group instead of the commonly
accepted nucleophilic substitution of the chlorine atom (N-2
or N-4 of the tetrazine). All attempts to avoid this side-
reaction failed in our hands (basic or acidic media).
Nevertheless, in the presence of EtONa, the displacement
of the 3,5-dimethylpyrazole of 25 spontaneously occurred,
and 27 was isolated in 52% yield.
When 27 was irradiated with 1-bromo-4-methoxybenzene
using the described conditions, only the product of C-6
arylation 28 was isolated in 88% yield. No trace of 3, which
would result from the C-7 arylation, was observed, showing
the complete regioselectivity of this very interesting C-6
arylation (Scheme 4).
References and Notes
(1) (a) Elhakmaoui, A.; Gueiffier, A.; Milhavet, J. C.; Blache,
Y.; Chapat, J. P.; Chavignon, O.; Teulade, J. C.; Snoeck, R.;
Andrei, G.; De Clercq, E. Bioorg. Med. Chem. Lett. 1994, 4,
1937–1940. (b) Gueiffier, A.; Lhassani, M.; Elhakmoui, A.;
Snoeck, R.; Andrei, G.; Chavignion, O.; Teulade, J. C.; Kerbal,
A.; Essassi, M.; Debouzy, J. C.; Witurowo, J. P.; Blache, Y.;
Balzarini, J.; De Clercq, E.; Chapat, J. P. J. Med. Chem. 1996,
39, 2856–2859. (c) Gudmundsson, K. S.; Drach, J. C.;
Townsend, L. B. J. Org. Chem. 1997, 62, 3453–3459. (d) Pan,
S.; Wang, G.; Shinazi, R. F.; Zhao, K. Tetrahedron Lett. 1998,
39, 8191–8194. (e) Lhassani, M.; Chavignon, O.; Chezal,
J. M.; Teulade, J. C.; Chapat, J. P.; Snoeck, R.; Andrei, G.;
Balzarini, J.; De Clercq, E.; Gueiffier, A. Eur. J. Med. Chem.
1999, 34, 271–274. (f) Hamdouchi, C.; de Blas, J.; del Prado,
M.; Gruber, J.; Heinz, B. A.; Vance, L. J. Med. Chem. 1999,
42, 50–59. (g) Gudmundsson, K. S.; Williams, J. D.; Drach,
J. C.; Townsend, L. B. J. Med. Chem. 2003, 46, 1449–1455.
(2) (a) Kaminsky, J. J.; Puchalski, C.; Solomon, D. M.; Rizvi,
R. K.; Conn, D. J.; Elliot, A. J.; Lovey, R. G.; Guzik, H.;
Chui, P. J. S.; Long, J. F.; McPhail, A. T. J. Med. Chem.
1989, 32, 1686–1700. (b) Kaminsky, J. J.; Doweyko, A. M.
J. Med. Chem. 1997, 40, 427–436.
(3) (a) Rewankar, G. R.; Matthews, J. R.; Robins, R. K. J. Med.
Chem. 1975, 18, 1253–1255. (b) Rival, Y.; Grassy, G.;
Michael, G. Chem. Pharm. Bull. 1992, 40, 1170–1176.
(4) (a) Beswick, P. J.; Campbell, I. B.; Naylor, A. Int. Patent WO
9,631,509, 1996;Beswick, P. J.; Campbell, I. B.; Naylor, A.
Chem. Abstr. 1997, 126, 8117j. (b) Abiegnente, E. Actual.
Chim. Ther. 1991, 18, 1253–1257.
(5) Franke, H.; Geisler, J.; Hartfiel, U.; Franke, W.; Dorfmeister,
G.; Ganzer, M.; Johahann, G.; Rees, R. Patent DE 4,120,108,
1991; Franke, H.; Geisler, J.; Hartfiel, U.; Franke, W.;
Dorfmeister, G.; Ganzer, M.; Johahann, G.; Rees, R. Chem.
Abstr. 1992, 18, 213075v.
In conclusion, we have shown in this article that C-6
functionalized imidazo[1,2-b][1,2,4,5]tetrazines could be
efficiently synthesized using our regioselective palladium-
catalyzed arylation. Good to excellent yields were obtained
with a wide range of bromobenzene derivatives, with no
noticeable effect of the electronic nature of their substituents.
This new methodology should be suitable for the design of
more complex heterocyclic structures, such as bioactive
derivatives containing an imidazo[1,2-b][1,2,4,5]tetrazine
core.
(6) Byth, K. F.; Culshaw, J. D.; Green, S.; Oakes, S.; Thomas,
Acknowledgment. The authors thank the Ligue Contre
le Cancer Re´gion Grand Ouest, le Cance´ropoˆle Grand Ouest
and the MESR for financial support.
A. P. Bioorg. Med. Chem. Lett. 2004, 14, 2245–2248.
(7) (a) Neilson, D. G.; Watson, K. M.; Weakley, T. J. R.
J. Chem. Soc., Perkin Trans. 1 1979, 333–336. (b) Hunter,
D.; Neilson, D. G.; Weakley, T. J, R. J. Chem. Soc., Perkin
Trans. 1 1982, 1165–1170. (c) Hunter, D.; Neilson, D. G.
J. Chem. Soc., Perkin Trans. 1 1985, 1081–1086. (d) Hunter,
D.; Neilson, D. G. J. Chem. Soc., Perkin Trans. 1 1988, 1439–
1445.
Supporting Information Available. Experimental pro-
cedures, spectral data of compounds 1-28. This material
is available free of charge via the Internet at http://pubs.
acs.org.

608 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 4
Pellegatti et al.
(8) Coburn, M. D.; Buntain, G. A.; Harris, B. W.; Hiskey, M. A.;
Lee, K.-Y.; Ott, O. G. J. Heterocycl. Chem. 1991, 28, 2049–
2050.
1946. (g) El Akkaoui, A.; Berteina-Raboin, S.; Mouaddib, A.;
Guillaumet, G. Eur. J. Org. Chem. 2010, 862–871.
(10) Kong, K.-C.; Cheng, C.-H. J. Am. Chem. Soc. 1991, 113,
6313–6315.
(9) (a) Ermolat’ev, D. S.; Gime´nez, V. N.; Babaev, E. V.; Van
der Eycken, E. J. Comb. Chem. 2006, 8, 659–663. (b)
Koubachi, J.; El Kazzouli, S.; Berteina-Raboin, S.; Mouaddib,
A.; Guillaumet, G. Synlett 2006, 3237–3242. (c) Koubachi,
J.; El Kazzouli, S.; Berteina-Raboin, S.; Mouaddib, A.;
Guillaumet, G. J. Org. Chem. 2007, 72, 7650–7655. (d)
Koubachi, J.; El Kazzouli, S.; Berteina-Raboin, S.; Mouaddib,
A.; Guillaumet, G. Synthesis 2008, 2537–2542. (e) Koubachi,
J.; Berteina-Raboin, S.; Mouaddib, A.; Guillaumet, G. Syn-
thesis 2009, 271–276. (f) Koubachi, J.; Berteina-Raboin, S.;
Mouaddib, A.; Guillaumet, G. Tetrahedron 2010, 66, 1937–
(11) Compound 4 proved to be stable, even when irradiated for a
longer period of time. No release of N2 was observed.
(12) (a) Do, H.-Q.; Daugulis, O. J. Am. Chem. Soc. 2007, 129,
12404–12405. (b) Do, H.-Q.; Daugulis, O. J. Am. Chem. Soc.
2008, 130, 1128–1129. (c) Do, H.-Q.; Kashif Khan, R. M.;
Daugulis, O. J. Am. Chem. Soc. 2008, 130, 15185–15192.
(13) Dudfield, P. J.; Le, V.-D.; Lindell, S. D.; Rees, C. W. J. Chem.
Soc., Perkin Trans. 1 1999, 2929–2936.
CC1000456