A Van Leusen deprotection-cyclization strategy as a fast entry into two imidazoquinoxaline families

Article abstract of DOI:10.1016/j.tetlet.2012.08.072

A concise synthesis of two pharmacologically relevant classes of molecules possessing the imidazoquinoxaline core is reported. The protocol involves use of 1,2-phenylenediamines and glyoxylic acid derivatives, namely ethyl glyoxylate or benzylglyoxamide, along with tosylmethylisocyanides in a microwave-assisted Van Leusen three-component condensation. Subsequent unmasking (Boc removal) of an internal amino-nucleophile promotes deprotection and cyclization that take place either spontaneously in a one-pot fashion to give 8 or upon acidic treatment under microwave irradiation after isolation of the imidazole intermediate to give 11. Of note, a tricyclic framework is hence assembled by means of a rapid and straightforward method with a high bond-forming efficiency.

Full text of DOI:10.1016/j.tetlet.2012.08.072

Tetrahedron Letters 53 (2012) 5787–5790
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A Van Leusen deprotection-cyclization strategy as a fast entry into two
imidazoquinoxaline families
Fabio De Moliner a, Christopher Hulme a,b,
⇑
a Department of Pharmacology and Toxicology, College of Pharmacy, BIO5 Oro Valley, The University of Arizona, 1580 E. Hanley Blvd., Oro Valley, Arizona 85737, USA
b Department of Chemistry and Biochemistry, The University of Arizona, Tucson, Arizona 85721, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A concise synthesis of two pharmacologically relevant classes of molecules possessing the imidazoquinox-
aline core is reported. The protocol involves use of 1,2-phenylenediamines and glyoxylic acid derivatives,
namely ethyl glyoxylate or benzylglyoxamide, along with tosylmethylisocyanides in a microwave-
assisted Van Leusen three-component condensation. Subsequent unmasking (Boc removal) of an internal
amino-nucleophile promotes deprotection and cyclization that take place either spontaneously in a one-
pot fashion to give 8 or upon acidic treatment under microwave irradiation after isolation of the imidazole
intermediate to give 11. Of note, a tricyclic framework is hence assembled by means of a rapid and
straightforward method with a high bond-forming efficiency.
Received 19 July 2012
Revised 15 August 2012
Accepted 16 August 2012
Available online 24 August 2012
Keywords:
TOSMICs
Multicomponent reactions
Heterocycles
Ó 2012 Elsevier Ltd. All rights reserved.
Imidazoquinoxalines
Tosylmethylisocyanides (TOSMICs) are a valuable and versatile
class of synthons that are growing increasingly popular in the or-
ganic chemistry community. In addition to the isonitrile functional
group, a well-known multi-purpose synthetic tool, TOSMICs also
display two more reactive features:1 namely, these molecules are
endowed with a tosyl residue that can easily act as a leaving group,2
and with an activated methylene they are prone to attack electro-
philes upon deprotonation. Thanks to their peculiar nature, TOS-
MICs have been fruitfully employed in the preparation of several
families of heterocycles, such as oxazoles,3 pyrroles,4 imidazoles,5
benzofuranes,6 quinoxalines,7 and pyrrolopyrimidines.8 Unsurpris-
ingly, within this diversified panel of synthetic strategies multicom-
ponent-based approaches stand out as a recurrent theme. In fact,
multicomponent reactions (MCRs) represent an extremely powerful
tool for the generation of a high level of molecular diversity and for
the expeditious assembly of complex molecular frameworks in an
efficient, straightforward, and facile manner.9 In this context, the
Van Leusen three-component reaction (V-3CR)2 exemplifies a per-
fect combination between the operational ease and exploratory
power of MCRs and the multiple reactivities of TOSMICs, resulting
in a process that generates a medicinally relevant imidazole nu-
cleus10 upon a cascade mechanism triggered by nucleophilic attack
onto a preformed Schiff base (Scheme 1). As proof of its importance,
numerous reports describing its use to prepare biologically active
compounds are available in the literature,11 and extensive studies
have been dedicated to further elaboration of its products12 by
O
R2
R1 NH2
+
R
Ts 3 N
R2
N
base
C
Ts
N
Ts
N
R2
C
C
R2
N
R3
R3
R1
1
2
R3
R3
H
R3
R2
Ts
R2
Ts
R2
N
N
N
N
N
N
base
- TsH
R1
R1
R1
3
Scheme 1. Mechanism of the Van Leusen three-component reaction (V-3CR).
means of post-condensation modifications, according to a modus
operandi that is quite common in the MCR field.13 Furthermore, a
highly elegant MCR for the synthesis of imidazolines14 has been
developed from the V-3CR by Orru via the replacement of the TOS-
MICs with different a-acidic isocyanides. This merely reflects that
this transformation constitutes a very fertile background for the
development of more enabling novel chemical methodologies.
As a part of our endeavor to design novel general and succinct
multicomponent-based routes that enable fast access to drug-like
chemotypes in an operationally-friendly way,15 we recently turned
⇑
Corresponding author. Tel.: +1 520 626 5322.
E-mail address: hulme@pharmacy.arizona.edu (C. Hulme).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.08.072

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F. De Moliner, C. Hulme / Tetrahedron Letters 53 (2012) 5787–5790
Table 1
Optimization of the one-pot Van Leusen cyclization protocol involving ethyl glyoxylate
Entry
Solvent
Conditions (Step A)
Conditions (Step B)
Yield (%)
1
2
3
4
5
6
7
DMF
DMF
DMF
DMF
DMF
DMF
DMF
MW (5 min, 100 °C)
MW (5 min, 100 °C)
MW (5 min, 100 °C)
MW (10 min, 100 °C)
MW (20 min, 120 °C)
MW (10 min, 100 °C)
MW (10 min, 100 °C)
MW (10 min, 140 °C)
MW (10 min, 160 °C)
MW (10 min, 180 °C)
MW (10 min, 180 °C)
MW (10 min, 180 °C)
MW (20 min, 180 °C)
MW (10 min, 200 °C)
30
35
41
47
38
45
39
sized. The new methodologies represent enticing enhancements to
the V-3CR reactivity domain, delivering tricyclic chemotypes that
will be of high interest in the drug discovery arena.
Initially, ethyl glyoxylate was examined as a partner in the MCR
pathway (Table 1). Based on our previous experience in this field,16
DMF was evaluated as the solvent for both the Schiff base prefor-
mation, which is required for the Van Leusen reaction,9 and the
second, base-promoted step under microwave irradiation condi-
tions. Gratifyingly, short cycle times turned out to be optimal for
both steps, and when intermediate 6 was combined with TOSMIC
7 and potassium carbonate and subjected to elevated tempera-
tures, a one-pot multi-component condensation, Boc-deprotection,
and cyclization rendered 8a. Optimal conditions were found to be
microwave irradiation at 100 °C for 10 min for step A, followed by
further irradiation at 180 °C for 10 min, which pushed the process
Figure 1. Compounds 8a–8g synthesized from ethyl glyoxylate, N-Boc 1,2-pheny-
lenediamines, and TOSMICs.
to completion after the addition of isonitrile and base (entry 4).17
A
good overall yield (47% isolated in 8a) was observed under these
conditions.
our attention to the enticing scenarios unveiled by coupling the Van
Leusen imidazole synthesis with a post-condensation modification
triggered by the unmasking of an internal nucleophile.16 By choos-
ing ethyl glyoxylate and benzyl glyoxamide as the carbonyl inputs
and N-Boc 1,2-phenylenediamines as the amine building blocks,
two diverse imidazoquinoline-based scaffolds were readily synthe-
Encouraged by this result, a small collection of seven imi-
dazo[1,5-a]quinoxalinones (Fig. 1) were thus prepared by means
of the optimized methodology employing a diversity-enhancing
set of four N-Boc 1,2-phenylenediamines and three TOSMICs. All
proceeded smoothly, affording the expected products in yields
ranging from 27% to 47%, representing a good level of efficiency
Table 2
Optimization of the Van Leusen reaction involving benzylglyoxamide
Entry
Solvent
Conditions (Step A)
Conditions (Step B)
Yield (%)
1
2
3
4
5
6
7
8
9
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
MW (10 min, 100 °C)
MW (10 min, 100 °C)
MW (10 min, 100 °C)
MW (10 min, 100 °C)
MW (10 min, 100 °C)
MW (10 min, 100 °C)
MW (10 min, 100 °C)
MW (5 min, 100 °C)
MW (20 min, 120 °C)
MW (10 min, 180 °C)
MW (10 min, 160 °C)
MW (10 min, 140 °C)
MW (10 min, 120 °C)
MW (10 min, 100 °C)
MW (10 min, 80 °C)
rt, overnight
—
—
63
63
62
73
83
75
60
rt, overnight
rt, overnight

F. De Moliner, C. Hulme / Tetrahedron Letters 53 (2012) 5787–5790
5789
With a proficient route21 to 10a in hand, simple dissolution in a
10% TFA solution in DCE at room temperature promoted cyclization,
and unexpectedly debenzylation in one pot afforded 11a. Upon fur-
ther screening (Table 3) this behavior was found to be reproducible
under microwave irradiation, and 11a was constantly recovered in
high yield, with optimal conditions shown in entry 5.22
Table 3
Optimization of the double deprotection-cyclization step
To the best of our knowledge, removal of a benzyl residue in
acidic conditions is unprecedented in the primary literature. From
a biological perspective, this deprotection was highly encouraging,
as imidazoquinoxalines bearing a primary amino group have been
shown to target phosphodiesterases and adenosine receptors.23
The two-step pathway was subsequently used to synthesize se-
ven examples. Four 1,2-phenylenediamines and six TOSMICs were
successfully explored in the Van Leusen reaction along with ben-
zylglyoxamide, giving desired products in good yields ranging from
52% to 83% (Fig. 2). Subsequent acid-induced deprotection–cycliza-
tion proceeded smoothly, and 11a–11g were obtained in excellent
84–99% yields in a very clean manner that required no purification,
with the only loss of material due to the aqueous work-up. Of note,
when heterocyclic diamines having a pyridine or pyrimidine core
were evaluated, the Van Leusen reaction performed poorly (<15%
yield) and no tricyclic products 11 were observed, even under pro-
longed irradiation.
In conclusion, we have herein reported a straightforward MCR-
based methodology exploiting the Van Leusen three-component
reaction (V-3CR) followed by a deprotection–cyclization step to pro-
vide fast entry into two biologically enticing imidazoquinoxaline
families. For the first time ethyl glyoxylate and benzyl glyoxamide
were employed in the V-3CR, resulting in an extension of the scope
of this condensation. With high operational ease and the capability
of furnishing target structures 8 and 11 with two diversity points,
this route appears superior to the existing lengthy multistep path-
ways toward such chemotypes. Thanks to the advantages outlined
above, our strategy is highly amenable for high-throughput applica-
tions and will hopefully represent a valuable new tool available for
the lead generation community.
Entry
Time
Temperature
Yield (%)
1
2
3
4
5
6
Overnight
10 min
10 min
10 min
10 min
10 min
rt
87
80
85
85
88
74
60 °C (MW)
80 °C (MW)
100 °C (MW)
120 °C (MW)
140 °C (MW)
in light of the number of transformations embedded in this path-
way. As regards to the scope, it turned out to be quite general for
the amine input, while TOSMICs with R3 = Aryl were found to be
incompatible where only complex mixtures of side products being
observed.
Having developed a new expeditious route into a medicinally
relevant tricyclic scaffold, which has been reported to be the key
feature in molecules active against a number of pathologies such
as cancer, arthritis, and erectile disfunction,18 we envisaged that
introduction of an exocyclic amino group would be pivotal in gen-
erating one more pharmacologically active chemotype. In fact, imi-
dazo[1,5-a]quinoxalines displaying such a substituent are known
to exert inhibition of important members of the tyrosine kinase
family.19 Additionally, the required use of glyoxamides in this
strategy represents employment of a novel reagent in the V-3CR.
Although scarce commercial availability and synthetic accessibility
impeded evaluation of different amide inputs, benzylglyoxamide
could be readily obtained from the corresponding tartaric acid
amide by means of treatment with periodic acid according to a re-
ported procedure.20 However, in this case, (Table 2) irradiating at
temperatures above 140 °C (entries 1 and 2, step B) afforded no ob-
servable product, while milder conditions proved beneficial (entry
7) even though only imidazole intermediate 10a was recovered
and tricyclic product could not be formed in a one-pot fashion. In
regards to Schiff base formation (step A), heating at 100 °C for
10 min again proved optimal.
Acknowledgements
Financial support from the National Institutes of Health (Grant
P41GM086190) is gratefully acknowledged. We also thank
Dr. Federico Medda and Dr. David Bishop for proofreading and edit-
ing the final version of the manuscript.
Figure 2. Compounds 11a–11g synthesized from ethyl glyoxylate, N-Boc 1,2-phenylenediamines, and TOSMICs (X%, X% = Van Leusen yield, deprotection-cyclization yield).

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F. De Moliner, C. Hulme / Tetrahedron Letters 53 (2012) 5787–5790
reaction mixture was heated at 180 °C for 10 min. After cooling to room
References and notes
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trimethylimidazo[1,5-a]quinoxalin-4(5H)-one 8c as a yellow solid (44 mg, 40%
yield). 1H NMR (400 MHz, DMSO-d6) d: 11.02 s, 1H), 8.75 (s, 1H), 7.87 (s, 1H),
6.98 (s, 1H), 2.52 (s, 3H), 2.23 (s, 3H), 2.20 (s, 3H) ppm. 13C NMR (100 MHz,
DMSO-d6) d: 156.2, 142.2, 135.6, 131.4, 128.2, 127.2, 118.8, 117.3, 116.3, 109.9,
19.7, 19.5, 14.5 ppm.
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21. General procedure exemplified for the preparation of 10e. Benzylglyoxamide
(1 equiv, 0.48 mmol, 78 mg) and tert-butyl (2-aminophenyl)carbamate
(1 equiv, 0.48 mmol, 100 mg) were dissolved in DMF (2 mL) and heated at
100 °C for 10 min by means of microwave irradiation. Potassium carbonate
(2 equiv, 0.96 mmol, 132 mg) and ethyl–TOSMIC (1 equiv, 0.48 mmol, 107 mg)
were then added, and the reaction mixture was stirred overnight at room
temperature. Water (20 mL) was added and extraction with EtOAc (3 Â 20 mL)
was performed. The organic phase was dried over MgSO4 and concentrated
under reduced pressure, and the crude was purified by flash chromatography
(EtOAc/hexane 50–100%) using an ISCO™ purification system to afford tert-
butyl
(2-(5-(benzylcarbamoyl)-4-ethyl-1H-imidazol-1-yl)phenyl)carbamate
10e as an orange oil (138 mg, 69% yield). 1H NMR (400 MHz, CDCl3) d: 7.85–
7.80 (m, 1H), 7.45 (s, 1H), 7.43–7.37 (m, 1H), 7.28–7.21 (m, 3H), 7.15–7.11 (m,
2H), 7.09–7.03 (m, 2H), 6.53 (s, 1H), 6.30 (s, 1H), 4.47–4.35 (m, 2H), 2.88 (q,
J = 7.5 Hz, 2H), 1.41 (s, 9H), 1.33 (t, J = 7.6 Hz, 3H) ppm. 13C NMR (100 MHz,
CDCl3) d: 160.2, 152.9, 148.2, 139.0, 137.6, 134.4, 130.1, 128.6, 128.5, 127.9,
127.5, 127.4, 125.0, 124.9, 123.9, 123.7, 123.2, 81.4, 43.5, 28.1, 21.7, 13.8 ppm.
22. General procedure exemplified for the preparation of 11e. tert-Butyl (2-(5-
(benzylcarbamoyl)-4-ethyl-1H-imidazol-1-yl)phenyl)carbamate 10e (1 equiv,
0.29 mmol, 120 mg) was dissolved in 3 mL of a 10% TFA/DCE solution and
heated at 120 °C for 10 min by means of microwave irradiation. After cooling to
room temperature, the reaction mixture was diluted with NaHCO3 sat. solution
(20 mL) and extraction with EtOAc (3 Â 20 mL) was performed. The organic
phase was dried over MgSO4 and concentrated under reduced pressure to
afford 11e as a pink powder (55 mg, 91% yield) with no need of purification. 1
H
NMR (400 MHz, DMSO-d6) d: 11.13 (br s, 2H), 8.87 (s, 1H), 8.09 (dd, J = 8.2,
1.1 Hz, 1H), 7.33–7.23 (m, 2H), 7.21–7.14 (m, 1H), 2.97 (q, J = 7.5 Hz, 2H), 1.21
(t, J = 7.5 Hz, 3H) ppm. 13C NMR (100 MHz, DMSO-d6) d: 156.0, 148.2, 131.8,
129.4, 129.0, 127.3, 123.1, 120.9, 116.9, 115.9, 21.4, 14.4 ppm.
17. General procedure exemplified for the preparation of 8c: Ethyl glyoxylate
23. (a) Colotta, V.; Cecchi, L.; Catarzi, D.; Filacchioni, G.; Martini, C.; Tacchi, P.;
Lucacchini, A. Eur. J. Med. Chem. 1995, 30, 133; (b) Hoefgen, N.; Stange, S.;
Langen, B.; Egerlan, U.; Schindler, R. WO 09/068320, 2009.; (c) Malamas, M. S.;
Ni, Y.; Erdei, J. J.; Stange, S.; Schindler, R.; Hoefgen, N.; Egerlan, U.; Langen, B.
WO 09/070584, 2009.
(1.5 equiv, 0.72 mmol, 173 lL of a 50% soln. in toluene) and tert-butyl (2-
amino-4,5-dimethylphenyl)carbamate (1 equiv, 0.48 mmol, 113 mg) were
dissolved in DMF (2 mL) and heated at 100 °C for 10 min by means of
microwave irradiation. Potassium carbonate (2 equiv, 0.96 mmol, 132 mg) and
methyl-TOSMIC (1 equiv, 0.48 mmol, 100 mg) were then added, and the