Straightforward assembly of phenylimidazoquinoxalines via a one-pot two-step MCR process

Article abstract of DOI:10.1021/ol3003282

An efficient multicomponent-based methodology providing a new entry into a medicinally important complex heterocyclic core is presented. The strategy is very general and able to endow target compounds with the highest possible number of diversity points.

Full text of DOI:10.1021/ol3003282

ORGANIC
LETTERS
2012
Vol. 14, No. 5
1354–1357
Straightforward Assembly of
Phenylimidazoquinoxalines via a One-Pot
Two-Step MCR Process
Fabio De Moliner† and Christopher Hulme*,†,‡
College of Pharmacy, BIO5 Oro Valley, 1580 E. Hanley Blvd, The University of Arizona,
Tucson, Arizona 85737, United States, and Department of Chemistry and Biochemistry,
The University of Arizona, Tucson, Arizona 85721, United States
hulme@pharmacy.arizona.edu
Received February 9, 2012
ABSTRACT
An efficient multicomponent-based methodology providing a new entry into a medicinally important complex heterocyclic core is presented. The
strategy is very general and able to endow target compounds with the highest possible number of diversity points. Notably, four new chemical
bonds and two aromatic rings are formed in a one-pot fashion.
Multicomponent reactions (MCRs) are defined as con-
densations of three or more reagents (building blocks)
reacting in a one-pot process, affording in a single step a
final product containing atoms derived from all the react-
ing molecules.1 As they allow for the assembly of very
complex chemotypes from simple starting materials by
means of easy and straightforward experimental opera-
tions, they are particularly suitable for diversity-oriented
synthesis.2
operationallyfriendlyMCR methodologyproducingphar-
macologically relevant molecules for biological evaluation.6
In this context, isocyanide-based multicomponent reac-
tions (IMCRs) have blossomed in an unprecedented way,
thanks to the versatility of isocyanide chemistry. In fact,
because of the divalent nature of the NC moiety, such
species are ableto simultaneously react asnucleophiles and
as electrophiles, giving rise to a manifold of molecular
frameworks suitable for further elaborations.7
Historically, MCRs such as the Biginelli,3 Hantzsch,4
and Strecker5 reactions date back to the 19th century.
However, with an increasing need to explore new regions
of the chemical space in a high-throughput fashion, there
has been an exponential growth in the emergence of
Beyond the well-mined Ugi and Passerini reactions that
furnish a plethora of new scaffolds via postcondensation
modifications,8 other MCRs are underexploited and have
vast untapped potential.9 The Van Leusen imidazole
€
(7) (a) Ugi, I.; Werner, B.; Domling, A. Molecules 2003, 8, 53.
(b) Doemling, A; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168.
(8) (a) Sunderhaus, J. D.; Martin, S. E. Chem.;Eur. J. 2009, 15,
1300. (b) Hulme, C.; Dietrich, J. Mol. Diversity 2009, 13, 195.
(c) Akritopoulou-Zanze, I.; Djuric, S. W. Heterocycles 2007, 73, 125.
(d) Marcaccini, S.; Torroba, T. Nat. Protoc. 2007, 2, 632. (e) Banfi, L.;
Riva, R. Org. React. 2005, 65, 1. (f) Banfi, L.; Riva, R.; Basso, A. Synlett
2010, 23. (g) Basso, A.; Banfi, L.; Riva, R. Eur. J. Org. Chem. 2010, 1831.
(h) Ayaz, M.; De Moliner, F.; Dietrich, J.; Hulme, C. In Evolution
of Isocyanide Chemistry; Nenajdenko, V., Ed.; Wiley-VCH: Weinheim,
Germany, in press.
ꢀ
(1) (a) Multicomponent Reactions; Zhu, J., Bienayme, H., Eds.; Wiley-
€
VCH: Weinheim, Germany, 2005. (b) Domling, A. Chem. Rev. 2006, 106, 17.
(2) (a) Armstrong, W. A.; Brown, S. D.; Keating, T. A.; Tempest,
P. A. In Combinatorial Chemistry; Wilson, S. R., Czarnik, A. W., Eds.;
Wiley-VCH: Weinheim, Germany, 1997. (b) Burke, M. D.; Schreiber, S. L.
Angew. Chem., Int. Ed. 2004, 43, 46. (c) Schreiber, S. L. Science 2000,
287, 1964.
(3) Biginelli, P Gazz. Chim. Ital. 1893, 23, 360.
(4) Hantzsch, A. Justus Liebigs Ann. Chem. 1882, 215, 1.
(5) Strecker, S. Ann. Chem. Pharm. 1850, 75, 27.
(6) (a) Bienayme, H.; Hulme, C.; Oddon, G; Schmitt, P. Chem.;Eur.
J. 2000, 6, 3321. (b) Hulme, C.; Gore, V. Curr. Med. Chem. 2003, 10, 51.
(c) Akritopolou-Zanze, I. Curr. Opin. Chem. Biol. 2008, 12, 324.
(9) For recent reviews discussing less commonly used MCRs, see: (a)
Ruijter, E.; Scheffelaar, R.; Orru, R. V. A. Angew. Chem., Int. Ed. 2011,
50, 6234. (b) De Moliner, F.; Banfi, L.; Riva, R.; Basso, A. Comb. Chem.
High Throughput Screening 2011, 14, 782.
ꢀ
r
10.1021/ol3003282
Published on Web 02/22/2012
2012 American Chemical Society

synthesis, for instance, has been underused to date, with
onlyafewreportsdescribing“diversity-orientedsynthesis”
approaches available in the literature.10 This peculiar
reaction, involving preliminary formation of a Schiff base
1 between an amine and an aldehyde, followed by insertion
of tosylmethylisocyanide 2 triggering cyclization (Scheme 1),11
displays the attractive feature of producing a medicinally
relevant imidazole nucleus 3.12
heating and microwave irradiation, were explored both in
regards to the preliminary imine preparation (step A) and
the TOSMIC addition (step B). Gratifyingly, the pivotal
condensation between ortho-N-Boc-phenylenediamine 4,
phenylglyoxaldehyde 5, and unsubstituted TOSMIC 7 al-
ways exhibited yields above 50% when performed in DMF,
and the ideal conditions were identified as the combination
of a short microwave-promoted heating cycle with over-
night stirring at ambient temperature (Table 1, entry 4).
Scheme 1. Mechanism of the Van Leusen Imidazole Synthesis
Table 1. Optimization of the Van Leusen Imidazole Synthesis
entry solvent
step A
step B
yield (%)
1
2
3
4
5
6
7
8
MeOH overnight, rt
DMF overnight, rt
MeOH MW (50, 100 °C) overnight, rt
DMF
MW (50, 100 °C) overnight, rt
MeOH 1 h, reflux
overnight, rt
overnight, rt
20
60
20
74
23
71
66
57
Thus, we were enticed to investigate possible applications
of this protocol that afford drug-like scaffolds in a concise
manner, specifically to generate imidazole-containing com-
pounds of increased complexity and value. Hence, we de-
cided to place a masked amino nucleophile on an aromatic
amine input and to exploit arylglyoxaldehydes as the car-
bonyl components of the Van Leusen. By doing so, we
purposefully chose widely commercially available building
blocks and thus paved the way to the introduction of a high
diversity level through the use of common starting materi-
als. Design of an efficient and straightforward pathway
started with optimization (Table 1) of the Van Leusen three-
component reaction (V-3CR), which sometimes suffers
from poor yields. Potassium carbonate (2 equiv) was always
used as the base, while both methanol and DMF, reportedly
the best solvents for the V-3CR, were evaluated.13 In this
respect, use of methanol (Table 1, entries 1, 3, and 5) proved
to be detrimental, while DMF never failed to give satisfac-
tory outcomes. Moreover, a panel of different conditions,
ranging from stirring at room temperature to conventional
overnight, reflux
DMF
DMF
DMF
1 h, 80 °C
overnight, 80 °C
MW (50, 100 °C) MW (100, 100 °C)
MW (50, 100 °C) MW (100, 120 °C)
After gaining efficient access to compound 8a, it was
subjected to 10% TFA/DCE at varying temperatures
(Table 2). Interestingly, when mild conditions were em-
ployed (Table 2, entries 1, 2 and 3), not only did the yields
turn out to be improved, but also the title compound 9a
was recovered in extremely pure (100%, NMR and
LCꢀMS) form with no need for purification.
Table 2. Optimization of the DeprotectionꢀCyclization Step
(10) (a) Gracias, V.; Gasiecki, A. F.; Djuric, S. W. Tetrahedron Lett.
2005, 46, 9049. (b) Gracias, V.; Darczak, D.; Gasiecki, A. F.; Djuric, S. W.
Tetrahedron Lett. 2005, 46, 9053. (c) Gracias, V.; Gasiecki, A. F.; Pagano,
T. G.; Djuric, S. W. Tetrahedron Lett. 2006, 47, 8873. (d) Beebe, X.;
Gracias, V.; Djuric, S. W. Tetrahedron Lett. 2006, 47, 3225. (e) Wang, L.;
Woods, K. W.; Li, Q.; Barr, K. J.; McCroskey, R. W.; Hannick, S. M.;
Gherke, L.; Credo, R. B.; Hui, Y.-H.; Marsh, K.; Warner, R.; Lee, J. Y.;
Zielinski-Mozng, N.; Frost, D.; Rosenberg, S. H.; Sham, H. L.
J. Med. Chem. 2002, 45, 1697.
entry
time
temperature
yield (%)
1
2
3
4
5
6
overnight
rt
85
88
87
78
68
68
(11) Van Leusen, A. M.; Wildeman, J.; Oldenziel, O. H. J. Org.
Chem. 1977, 42, 1153.
100
50
100
100
100
60 °C (MW)
80 °C (MW)
80 °C (MW)
100 °C (MW)
120 °C (MW)
(12) For reviews providing an overlook on applications of imidazoles
in medicinal chemistry, see: (a) Bhatnagar, A.; Sharma, P. K.; Kumar,
N. Int. J. PharmTech Res. 2011, 3, 268. (b) De Luca, L. Curr. Med. Chem.
2006, 13, 1. (c) Boiani, M.; Gonzalez, M. Mini-Rev. Med. Chem 2005, 5, 68.
(13) For practical details about the V-3CR standard processes, see
refs 10aꢀ10d.
Org. Lett., Vol. 14, No. 5, 2012
1355

value of this methodology lies in its high simplicity and
powerful capability to form two aromatic rings and four
new chemical bonds in a one-pot fashion, with the possibility
of simultaneous introduction of diversity inputs in almost
every position of the resulting scaffold. Consequently, it is
thus definitely superior to already reported lengthy multistep
routes18 for the preparation of the imidazo[1,5-a]quinoxaline
core, often necessitating exotic and not easily available starting
materials, which make a diversity-oriented approach difficult.
It is interesting to note that the Boc deprotection/cyclization
strategy has therefore been extended to one more MCR, in
addition to the “evergreen” Ugi19 and the more recently
investigated Passerini20 and Petasis21 condensations.
Table 3. Development of the Two-Step One-Pot Processa
entry
solvent
time
temperature (°C)
yield (%)
Having this optimized methodology in hand, we next
explored the scope of the process and evaluated our
modified V-3CR with different ortho-N-Boc-phenylene-
diamines, phenylglyoxaldehydes, and TOSMICs, our goal
being to both determine route generality and to prepare a
small collection of compounds 9. (Table 4)
1
2
3
4
5
6
DMF
DMF
DMF
DMF
DMF
DMF
100
100
100
100
100
200
140
150
160
180
200
180
58
52
64
67
52
55
a Note: Conditions are referred to step B (TOSMIC and base
addition). Imine formation was always conducted with MW (50, 100 °C).
Table 4. Scope of the Van Leusen 3-CR DeprotectionꢀCyclization
One-Pot Route
Noteworthy, this two-step process afforded 9a in a nice
65% overall yield by means of a simple and operationally
friendly strategy requiring only one chromatography step.
Nevertheless, further improvement was possible. Indeed,
when step B of the Van Leusen condensation was conducted
at 120 °C (Table 1, entry 8), 13% of cyclized compound 9a
was isolated. Intrigued by this finding, we were prompted to
attempt harsher conditions in step B to promote the MCR
and direct conversion of imidazole 8a into final product 9a
in one-pot. After careful screening (Table 3), we found
microwave induced heating at 180 °C (Table 3, entry 4)
represented a viable way to directly afford 9a without
isolation of its monocyclic precursor. As a matter of fact,
lower temperatures proved to be sufficient to drive Boc
deprotection and cyclization completely, although slightly
poorer yields were obtained. Conversely, further increments
up to 200 °C (Table 3, entry 5) or longer reaction time
(Table 3, entry 6) led to more side product formation.
To our delight, this resulted in the development of an
efficient one-pot two-step entry into a medicinally relevant
family of imidazo[1,5-a]quinoxalines. Such a moiety is in fact
the key motif of anticancer14 and antiarthritis15 agents, show-
ing remarkable activity in the inhibition of tyrosin-kinases16
and phosphodiesterases.17 From a synthetic point of view, the
compound
R1
R2
R3
yield (%)
9a
9b
9c
9d
9e
9f
H
H
H
H
H
H
67
61
52
53
58
66
74
33
40
39
71
66
59
65
70
55
4-CF3
4-OMe
3-NO2
H
H
H
H
5-OMe
4-Br
H
H
H
9g
9h
9i
H
H
Ph
Et
Et
Et
Ph
Ph
Ph
H
H
5-F
4-OMe
3,4,5-tri-OMe
4-OMe
4-CF3
3,4,5-tri-OMe
4-F
9j
4,5-di-Me
5-OMe
5-OMe
4-Br
9k
9l
9m
9n
9o
9p
9q
9r
4-Br
4-Br-Ph
4-Br-Ph
4-Br-Ph
H
4,5-di-Me
4,5-di-Me
H
3,4,5-tri-OMe
3-NO2
2-OMe
2-F
(14) Moarbess, G.; Deleuze-Masquefa, C.; Bonnard, V.; Gayraud-
Paniagua, S.; Vidal, J-R.; Bressolle, F.; Pinguet, F.; Bonnet, P-A. Bioorg.
Med. Chem. 2008, 16, 6601.
5-OMe
4-Br-Ph
13
(15) Kim, K-H.; Maderna, A.; Schnute, M. E.; Hegen, M.; Mohan, S.;
Miyashiro, J.; Lin, L.; Li, E.; Keegan, S.; Lussier, J.; Wrocklage, C.;
Nickerson-Nutter, C. L.; Wittwer, A. J.; Soutter, H.; Caspers, N.;
Han, S.; Kurumbail, R.; Dunussi-Joannopoulos, K.; Douhan, J., III.;
Wissner, A. Bioorg. Med. Chem. Lett. 2011, 21, 6258.
(16) (a) Chen, P.; Norris, D.; Iwanovicz, E. J.; Spergel, S. H.; Lin, J.;
Gu, H. H.; Shen, Z.; Witjak, J.;Lin, T-A.; Pang, S.;De Fex, H. F.;Pitt, S.;
Shen, D. R.; Doweyko, A. M.; Bassolino, D. A.; Roberge, J. Y.; Poss, M.
A; Chen, B-C.; Schieven, G. L.; Barrish, J. C. Bioorg. Med. Chem. Lett.
2002, 12, 1361. (b) Barrish, J. C.; Spergel, S. H. WO 99/10341, 1999.
(17) Hofgen, N.; Stange, H.; Langen, B.; Egerland, U.; Schindler, R.
U. S. Patent 0143391, 2009.
(18) (a) Chen, B-C.; Zhao, R.; Bednarz, M. S; Wang, B.; Sundeen,
J. E.; Barrish, J. C. J. Org. Chem. 2004, 69, 977. (b) Sundaram, G. S. M.;
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1356
Org. Lett., Vol. 14, No. 5, 2012

The method proved to have a broad applicability and
tolerated a wide range of substituents regardless of their
electron-donating or electron-withdrawing nature. The
only limitation found was with the use of 2-substituted
phenylglyoxaldehydes, which caused either a dramatic
drop in the yield (9r) or even complete failure (9q). This
phenomenon was ascribed to extreme sensitivity of the
pathway toward steric hindrance. The isocyanide inputs
showed quite different reactivity profiles. Indeed, we
observed that phenylsubstituted TOSMICs were gener-
ally beneficial, exemplified by high yields of 9g, 9k, and
9o. This finding was unsurprising, since the presence of
an extra aromatic ring enables further activation of the
R-position of these molecules (Scheme 1). Conversely,
2-ethyl-TOSMIC (9h, 9i, 9j) proved detrimental on
overall yields.
ready functionalization of the target heterocycle with a
broad scope and is able to generate two aromatic rings and
four new chemical bonds by means of two simple synthetic
operations from commercially available building blocks.
Because of its ease and wide applicability, which has
been demonstrated through the preparation of a small
collection of compounds, the protocol is perfectly suitable
for parallel synthesis applications. It is hoped that this
methodology will be embraced by the file enhancement
community at large.
Acknowledgment. Financial support from the National
Institutes of Health (Grant P41GM086190) is gratefully
acknowledged.
Supporting Information Available. Experimental pro-
1
cedures, characterization data, and H and 13C NMR
In summary, we have described herein a facile and
straightforward one-pot two-step multicomponent-based
strategy for the assembly of biologically appealing imidazo-
[1,5-a]quinoxalines. Of note, this approach allows for
spectra for compounds 9aꢀp and 9r. This material is
available free of charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 5, 2012
1357