A novel route to synthesize libraries of quinoxalines via Petasis methodology in two synthetic operations

Article abstract of DOI:10.1016/j.tetlet.2011.06.115

This Letter reveals an innovative and facile procedure to prepare quinoxalines in two synthetic steps. The microwave assisted Petasis reaction is followed by the acid mediated unmasking of an internal amino nucleophile, cyclodehydration and oxidation to g

Full text of DOI:10.1016/j.tetlet.2011.06.115

Tetrahedron Letters 52 (2011) 4821–4823
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A novel route to synthesize libraries of quinoxalines via Petasis methodology
in two synthetic operations
Muhammad Ayaz a, Justin Dietrich a, Christopher Hulme a,b,
⇑
a College of Pharmacy, BIO5 Oro Valley, The University of Arizona, Tucson, AZ, USA
b Department of Chemistry and Biochemistry, The University of Arizona, Tucson, AZ 85721, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
This Letter reveals an innovative and facile procedure to prepare quinoxalines in two synthetic steps. The
microwave assisted Petasis reaction is followed by the acid mediated unmasking of an internal amino
nucleophile, cyclodehydration and oxidation to give collections of quinoxalines in good to excellent
yields.
Received 20 May 2011
Revised 28 June 2011
Accepted 30 June 2011
Available online 19 July 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Petasis reaction
Multicomponent reaction
Quinoxaline
Intramolecular cyclization
Microwave
Discovered in 1993, the Petasis reaction joined a relatively short
list of Type-II multi-component reactions (MCRs) which involve
only one irreversible step in their reaction mechanism.1 Interest-
ingly, with competition from a plethora of robust protocols that
employ highly reactive organometallic reagents as nucleophilic
equivalents, the Petasis reaction is probably under-utilized when
one considers the complete specificity of boronic acids for the
C@N bond relative to the C@O bond.2,3 Indeed, unlike other orga-
nometallic reactions, the Petasis reaction is extremely operation-
ally friendly, not requiring special handling, producing only
relatively innocuous boric acid as a side product.4 As such, the
seminal discovery by Petasis of what is a boronic acid variant of
the classical Mannich reaction has demonstrated great value for
the production of libraries of small molecules. Such libraries,
employing post-Petasis chemical modifications, span arrays of
peptidomimetic heterocycles that include piperazinones,5 benzo-
piperazinones, benzodiazepines, aza-b-lactams6 and dihydroiso-
quinoline derivatives.7 All the aforementioned strategies utilize
post-Petasis modifications to rigidify the initial Petasis product.
Of major significance is the application of the Petasis reaction by
workers at Merck during the process development of the substance
P antagonist, Apprepitant™, developed as a potential anti-depres-
sant with a new mode of action.8 In somewhat analogous fashion,
we have been extensively involved in a number of post-MCR
modifications9 which in succint fashion lead to a variety of
pharmacologically relevant scaffolds, adopted by many for the
preparation of thousands of compounds in a high-through modal-
ity for file enhancement of corporate and academic screening col-
lections alike.10
Herein we report a two step Petasis-deprotection–cyclodehy-
dration–oxidation sequence that enables the preparation of
quinoxaline congeners in rapid fashion. The route is even more
attractive due to the easy access to numerous commercially avail-
able diverse reagents. From the perspective of biological relevance,
quinoxalines exhibit a large variety of biological activities such as
antibacterial,11 antimalarial,12 antifungal,13 and antithrombotic.14
Moreover quinoxaline based drugs have shown to be photochem-
ical DNA cleaving agents making them highly attractive and
promising scaffolds for anticancer therapeutics15 In addition they
have found widespread use in dyes and organic semiconductors.16
Of particular interest to the group are reported allosteric kinase
inhibitors of AKT1, that contain the diarylquinoxaline moiety made
accessible through this methodology.17
Our initially explored model Petasis MCR comprised of reac-
tions of mono-protected diamine 1, phenylglyoxal 2 and p-tolyl
boronic acid 3, carried out in different media at a variety of
temperatures, Scheme 1. Reaction progress was monitored by
LC–MS, Table 1. Of the eight solvents and solvent combinations
evaluated, dichloromethane and acetonitrile proved optimal,
requiring 18 h at room temperature (>70% yield) or 15 min at
120 °C irradiated with microwaves (>90% yield) for acceptable
product formation. Under the latter conditions dimethylformam-
ide also proved to be an excellent solvent.
⇑
Corresponding author. Tel.: +1 520 626 5322.
E-mail address: hulme@pharmacy.arizona.edu (C. Hulme).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.06.115

4822
M. Ayaz et al. / Tetrahedron Letters 52 (2011) 4821–4823
O
NH2
H
N
O
NHBoc
conditions
0.3 mL solvent
N
O
1
2
N
O
NHBoc
HN
B(OH)2
NHBoc
5
4
4
3
Scheme 1. Model Petasis reaction.
Scheme 2. Boc removal and cyclodehydration–oxidation.
Table 1
Optimization of the Petasis reactiona
Table 2
Optimization of reaction conditionsa
Entry Solvent
Yieldb (%)
0.5 h, rt
Yieldb (%)
18 h, rt
Yieldb (%) 15 min,
120 °C
Entry
System
Time (h)
Temp (°C)
Yieldb (%)
1
2
3
4
5
6
7
DMF
DCM
MeCN
Toluene
THF
Ethanol
Dioxane/water
(3:1)
MeCN/DMF
(1:1)
<5
26
36
<5
<5
16
0
17
84
72
16
<5
<5
<5
97
98
91
31
27
<5
<5
1
2
3
4
5
6
7
8
AcOH/i-PrOH
PTSA/DCM
PTSA/MgSO4/DCM
PTSA/TFA/DCE
TFA/DCC/DCE
TFA/DCE
18
18
18
18
18
18
18
0.25
rt
rt
rt
rt
rt
rt
rt
80 °C
<5
18
6
25
14
100
99
72
HCl/EtOAc
TFA/DCE
8
5
24
87
a
All the reactions were carried out at 0.1 mmol scale.
LC–MS area% purity as judged by Evaporative Light Scattering (ELS) yield.
b
a
All the reactions were carried out at 0.1 mmol scale.
b
LC–MS area% purity as judged by Evaporative Light Scattering (ELS).
R1
R1
NH2
R3
O
H
R1
R2
N
R3
R2
R1
R1
N
µW, 120 ºC
15 min
20% TFA/DCE
rt,18 h
R2
R2
NHBoc
O
O
1a or 1b
R3
2
N
NHBoc
4a - 4l
B(OH)2
5a - 5l
3
1a, R1 = R2 = H
1b, R1 = R2 = CH3
Scheme 3. Two step sequence to quinoxalines.
Summarizing, it is clear that protic solvents whether used alone
having different substituents (both electron withdrawing and
donating groups) were screened (mainly using mono-N-Boc-pro-
tected o-phenylene-diamine as the amine equivalent). The Petasis
reaction showed good to excellent yields in most examples, regard-
less of the electronic or steric properties of the boronic acid or
glyoxaldehydes used (Table 3, entries 1–3, 5, 7, 9, and 10). Notice-
ably, however, using a highly hindered glyoxaldehyde (2,4,6-tri-
methyl glyoxaldehyde) proved to be detrimental showing no
Petasis product at all (Table 3, entries 4 and 8). On the contrary,
a highly sterically hindered boronic acid had much lower, if any
impact on the Petasis reaction (Table 3, entry 9). Furthermore, un-
der the conditions employed boronic acids of a non-aryl origin
were seen to poorly perform in the Petasis reaction (Table 3, entry
6). Replacing N-Boc-protected o-phenylene-diamine with 3,4-di-
methyl N-Boc-protected o-phenylene-diamine resulted in
relatively lower yields than normal for the Petasis reaction (Table
3, entries 11 and 12), as can be seen by comparing yields of entry
9 and 12. Attempts to expand the scope of accessible chemotypes
to potential pyrazines via the use of N-Boc-ethylene-diamine were
unsatisfactory due to very low Petasis reaction yields.18
or in combination were unsuited for optimal progression of the
Petasis reaction (Table 1, entries 6 and 7). Likewise toluene and tet-
rahydrofuran afforded only modest yields of the desired product
(Table 1, entries 4 and 5), whilst DMF, dichloromethane and aceto-
nitrile proved to be almost equally effective as solvents (Table 1,
entries 1, 2, and 3). For operational ease, dichloromethane was se-
lected as the solvent of choice for further studies.
Following optimization of the Petasis conversion, a variety of
reagents were quickly screened to unmask the internal nucleophile
present on the Petasis product and trigger simultaneous cycliza-
tion onto the carbonyl group derived from phenylglyoxal and oxi-
dation to the quinoxalinone, Scheme 2. Differing combinations of
dehydrating and/or drying agents and solvents were evaluated at
room temperature, Table 2. Somewhat predictably both TFA/DCE
and HCl/EtOAc systems resulted in excellent yields of the quinox-
aline product (Table 2, entries 6 and 7). However, due to its milder
nature, the TFA/DCE combination seemed to be superior since pro-
longed exposure of reaction mixtures to HCl/EtOAc solution
resulted in disintegration of the final quinoxaline. An attempt to
speed up the reaction (20% TFA/DCE, 80 °C, 15 min., microwave
irradiation CEM Explorer™) proved to be counterproductive as
the quinoxaline interestingly started to fragment.
In contrast to the Petasis reaction the subsequent deprotection–
cyclodehydration–oxidation sequence worked smoothly, furnish-
ing products in excellent yields for nearly all examples.19
Subsequently, the reaction scope in terms of substrate tolerance
was explored, Scheme 3. Various glyoxaldehydes and boronic acids
In conclusion, we have reported a short, convenient and robust
two step procedure to prepare diversified quinoxalines. Use of

M. Ayaz et al. / Tetrahedron Letters 52 (2011) 4821–4823
4823
Table 3
Reactivity domain for Petasis/deprotection/cyclodehydration/oxidation protocola
Entry
R1
R2
R3
Yield (%) (4a–l)
Yield (%) (5a–l)
1
2
3
4
5
6
7
8
9
H
H
H
H
H
H
H
H
H
H
CH3
CH3
4-F-Ph
4-CF3-Ph
Ph
2,4,6-tri-Me-Ph
4-CF3-Ph
Ph
4-Me-Ph
4-Me-Ph
3-F-Ph
57 (4a)
49 (4b)
48 (4c)
0 (4d)
71 (4e)
39 (4f)
63 (4g)
0 (4h)
83 (4i)
87 (4j)
45 (4k)
24 (4l)
98 (5a)
92 (5b)
77 (5c)
nd (5d)
91 (5e)
nd (5f)
85 (5g)
nd (5h)
98 (5i)
81 (5j)
93 (5k)
35 (5l)
2-MeO-Ph
2-Naphthyl
trans-b-Styryl
2-MeO-Ph
4-Me-Ph
2,4,6-tri-F-Ph
3-CF3-Ph
2-Naphthyl
2,4,6-tri-F-Ph
Ph
2,4,6-tri-Me-Ph
Ph
4-CF3-Ph
4-CF3-Ph
Ph
10
11
12
a
All the reactions were carried out at a 1 mmol scale and isolated yields are reported. [Note: nd = not determined].
Pharm. Res. 2003, 26, 107–113; (d) Nasr, M. N. A. Arch. Pharm. Med. Chem. 2002,
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808–815; (f) El-Gendy, A. A.; El-Meligie, S.; El-Ansary, A.; Ahmedy, A. M. Arch.
Pharm. Res. 1995, 18, 44–47.
microwave makes this process more attractive since the reaction
time has been considerably diminished for a usual Petasis reaction.
Current efforts are focusing on optimizing the routes to additional
chemotypes of pharmacological importance.
12. (a) Rangisetty, J. B.; Gupta, C. N. V. H. B.; Prasad, A. L.; Srinivas, P.; Sridhar, N.;
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Acknowledgment
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Wewould like to thank the Office of theDirector, NIH, and theNa-
tional Institute of Mental Health for funding (1RC2MH090878-01).
References and notes
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18. Using 4-methylphenyl boronic acid, phenyl glyoxaldehyde and N-Boc-
ethylenediamine gave a complex mixture from the Petasis reaction with a
negligible amount of the desired product. Similarly in Table 3, entry 3,
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19. General procedure for preparation of 5c: One millimolar of each diamine,
glyoxaldehyde and boronic acid were taken into a microwave vial already
equipped with a magnetic bar. 1 mL of dichloromethane was added to the
system followed by heating it at 120 °C for 15 min. The crude Petasis product
was then directly loaded to an ISCO™ purification system and using
ethylacetate/hexane as eluent (0–100% gradient over 25 min) the products
were purified. A weighed out amount of Petasis product (0.10–0. 30 mmol) was
then subjected to 1–2 mL of 20% TFA in dichloromethane. The reaction was
stirred for ꢀ18 h at room temperature, evaporated in vacuo and crude material
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