Divergent synthesis of (quinoxalin-2-yl)-1,3-oxazines and pyrimido[1,6-a]quinoxalines via the cycloaddition reaction of acyl(quinoxalinyl)ketenes

Article abstract of DOI:10.1016/j.tetlet.2019.151088

A facile synthetic approach towards two distinct quinoxaline-based heterocyclic scaffolds has been developed from the cycloaddition of acyl(quinoxalinyl)ketenes with carbodiimides. The described reaction represents the first example of a divergent synthesis based on acyl(quinoxalinyl)ketenes providing (quinoxalin-2-yl)-1,3-oxazines or pyrimido[1,6-a]quinoxalines depending on the type of the acyl substituent in the ketenes. The key reactants, acyl(quinoxalinyl)ketenes, are generated in situ via the thermal decarbonylation of readily available pyrroloquinoxaline oxo-derivatives. The proposed diversity-oriented synthesis provides facile access to a library of skeletally diverse pharmaceutically interesting quinoxaline-based heterocycles from inexpensive reagents.

Full text of DOI:10.1016/j.tetlet.2019.151088

Tetrahedron Letters 60 (2019) 151088
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Divergent synthesis of (quinoxalin-2-yl)-1,3-oxazines and pyrimido[1,6-
a]quinoxalines via the cycloaddition reaction of acyl(quinoxalinyl)
ketenes
⇑
⇑
Svetlana Kasatkina, Ekaterina Stepanova , Maksim Dmitriev, Ivan Mokrushin, Andrey Maslivets
Department of Chemistry, Perm State University, ul. Bukireva 15, Perm 614990, Russian Federation
a r t i c l e i n f o
a b s t r a c t
Article history:
A facile synthetic approach towards two distinct quinoxaline-based heterocyclic scaffolds has been devel-
oped from the cycloaddition of acyl(quinoxalinyl)ketenes with carbodiimides. The described reaction
represents the first example of a divergent synthesis based on acyl(quinoxalinyl)ketenes providing
(quinoxalin-2-yl)-1,3-oxazines or pyrimido[1,6-a]quinoxalines depending on the type of the acyl sub-
stituent in the ketenes. The key reactants, acyl(quinoxalinyl)ketenes, are generated in situ via the thermal
decarbonylation of readily available pyrroloquinoxaline oxo-derivatives. The proposed diversity-oriented
synthesis provides facile access to a library of skeletally diverse pharmaceutically interesting quinoxa-
line-based heterocycles from inexpensive reagents.
Received 16 July 2019
Revised 19 August 2019
Accepted 28 August 2019
Available online 29 August 2019
Keywords:
Diversity-oriented synthesis
Heterocumulene
Ó 2019 Elsevier Ltd. All rights reserved.
Quinoxaline
Simultaneous thermal analysis
Diversity-oriented synthesis (DOS) is a powerful strategy in
modern drug discovery [1]. The most tunable and predictable
DOS strategies for small molecule library design are based on the
known properties of certain functional groups introduced in sets
of reactants in different combinations [2]. DOS with an emphasis
on skeletal diversity provides an opportunity to screen wider
chemical space creating diverse compound libraries from a limited
set of reagents, which reduces the cost and facilitates the develop-
ment of new drugs. In this way, the search and investigation of
reactivity for new building blocks bearing several functional
groups is essential for expansion of DOS scope.
Recently, compounds bearing a quinoxalin-2(1H)-one moiety
were found to exhibit a wide range of biological activities [3]. For
example, among them were found 5-HT2C agonists [3a], antihy-
poxants [3b], antiprotozoan [3c] and cytotoxic [3d] agents (Fig. 1).
Acyl(imidoyl)ketenes are highly reactive compounds bearing a
forked diene fragment consisting of a C@C bond conjugated with
geminal C@O and C@N fragments. This structural feature makes
them appealing candidates for the development of DOS with an
emphasis on skeletal diversity. Additionally, the presence of the
C@N bond in acyl(imidoyl)ketenes enables the introduction of a
pharmaceutically important quinoxaline fragment (in particular,
a quinoxalin-2(1H)-one moiety), and the resulting acyl(quinox-
alinyl)ketenes can be easily modified at the O@C@CAC@N or
O@C@CAC@O motifs.
Acyl(quinoxalinyl)ketenes
react
selectively
either
as
O@C@CAC@O [4] or as O@C@CAC@N [5] dienes in reactions with
various dienophiles (Scheme 1). The regioselectivity of the reaction
depends on the type of dienophiles and substituents at the C3 atom
of the quinoxaline moiety of acyl(quinoxalinyl)ketenes. To the best
of our knowledge there are no reported examples of the involve-
ment of acyl(quinoxalinyl)ketenes in a divergent cycloaddition
reaction with a single class of dienophiles.
Herein, we report the first example of a divergent cycloaddition
reaction of acyl(quinoxalinyl)ketenes (bearing a pharmaceutically
valuable quinoxalin-2(1H)-one moiety) resulting in either
(quinoxalin-2-yl)-1,3-oxazines or pyrimido[1,6-a]quinoxalines
(Scheme 1).
Acyl(quinoxalinyl)ketenes 1 are known to react with dieno-
philes exclusively at the O@C@CAC@O system (Scheme 1) [4]. At
the same time, we previously described the reaction of acyl
(quinoxalinyl)ketenes 2 with Schiff bases affording exclusively
the products of cycloaddition at the O@C@CAC@N system
(Scheme 1) [5]. Considering these two facts, we envisioned that
there might be reagents that can react with acyl(quinoxalinyl)kete-
nes 2 both at the oxo-diene and aza-diene fragments under certain
conditions.
The acyl(quinoxalinyl)ketenes 2 of interest are highly reactive
compounds which are most commonly generated in situ via the
⇑
Corresponding authors.
E-mail addresses: caterina.stepanova@psu.ru (E. Stepanova), koh2@psu.ru
(A. Maslivets).
https://doi.org/10.1016/j.tetlet.2019.151088
0040-4039/Ó 2019 Elsevier Ltd. All rights reserved.

2
S. Kasatkina et al. / Tetrahedron Letters 60 (2019) 151088
Scheme 2. Thermal decarbonylation of pyrroloquinoxalinetriones 3.
Fig. 1. Selected examples of skeletally diverse biologically active quinoxalin-2(1H)-
one based compounds.
Scheme 3. Dienophiles 4 scope examination for the reaction with pyrroloquinox-
alinetrione 3a under thermal decarbonylation conditions.
Mixtures of equimolar amounts of pyrroloquinoxalinetrione 3a
with various dienophiles 4a–j (Scheme 3) were heated in Dow-
therm A at 187 °C (onset decarbonylation temperature of 3a [5])
for 1–3 min, and the obtained reaction mixtures were examined
by UPLC-MS.
The reaction of ketene 2a with adamantanone 4a gave adducts
5 or 6 in only trace amounts. Aromatic aldehyde 4b did not give
any detectable adducts. These outcomes could be explained by
the thermal instability of possible adducts which decomposed
rapidly at such a high temperature. Our efforts to increase the
yields of the desired adducts by reducing the reaction temperature
were unsuccessful.
Camphor 4c did not afford the desired adducts 5 or 6, and
instead a complex mixture of adducts of compound 3a with cam-
phor was detected. Possibly, the reaction with camphor 4c pro-
ceeded in
a similar way as described for the reaction of
pyrroloquinoxalinetriones 3 with cyclohexanone [7].
Benzonitrile 4d also did not give any detectable adducts. How-
ever, morpholine-4-carbonitrile 4e was found to react with com-
pound 3a before its thermal decarbonylation, and unspecified
adducts of compound 3a with morpholine-4-carbonitrile were
detected as the major components of this reaction mixture.
Phenyl isothiocyanate 4f, N-thionylaniline 4g and benzoyl
isothiocyanate 4h also did not give any detectable adducts.
Finally, the reactions of compound 3a and carbodiimides (dicy-
clohexylcarbodiimide (DCC) 4i, diisoproylcarbodiimide (DIC) 4j)
gave the desired adducts 5a,b (Table 1) in acceptable yields (4i,
Scheme 1. Directions of cycloaddition reactions of acyl(quinoxalinyl)ketenes with
dienophiles.
thermal decarbonylation of pyrroloquinoxalinetriones 3 (Scheme 2)
[5,6].
To start with, we examined the reaction of pyrroloquinoxa-
linetrione 3a with various dienophiles (Scheme 3), paying special
attention to those described to react with ketenes 1 at the oxo-
diene motif [4].

S. Kasatkina et al. / Tetrahedron Letters 60 (2019) 151088
3
Table 1
Substrate scope examination for the synthesis of (quinoxalin-2-yl)-1,3-oxazines 5.
Entry
R
Ar
R0
5
Yielda (%)
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
Me
Me
Me
Ph
Ph
Ph
Cy
i-Pr
Cy
Cy
Cy
i-Pr
Cy
Cy
5a
82b
61c
73b
79b
81b
69c
73b
77b
80b
61c
64c
68c
71c
78b
79b
5b (CCDC 1935937)
5c
5d
5e
5f
5g
5h
5i
5j (CCDC 1935941)
5k (CCDC 1935940)
5l
5m
5n
5o
C6H4NO2-4
C6H4Cl-4
C6H4OMe-4
C6H4Cl-4
Ph
C6H4Cl-4
C6H4OMe-4
C6H4OMe-4
C6H4NO2-4
Ph
9
Cy
10
11
12
13
14
15
i-Pr
i-Pr
i-Pr
i-Pr
Cy
Ph
Me
Me
Me
Me
C6H4Cl-4
C6H4OEt-4
C6H4Me-4
Cy
a
b
c
Isolated yield.
Conditions A: decarbonylation onset temperature of 3, 1–3 min, solvent-free, 10% excess of carbodiimide 4 (for DCC 4i).
Conditions B: decarbonylation onset temperature of 3, 1–3 min, Dowtherm A, 60% excess of carbodiimide 4 (for DIC 4j).
Table 2
78% yield and 4j, 46% yield). It should be noted that compounds 5a,
b were formed as the sole regioisomers, and no signals of regioiso-
meric cycloadducts 6 (Scheme 3) of ketene 2a with carbodiimides
4i,j were observed by UPLC-MS.
Substrate scope examination for the synthesis of pyrimido[1,6-a]quinoxalines 6.
To improve the discovered reaction conditions, we tested this
reaction under solvent-free conditions, as proposed earlier for the
trapping of ketenes 2 by Schiff bases [5]. For this purpose, equimo-
lar amounts of pyrroloquinoxalinetrione 3a and carbodiimides 4i,j
were thoroughly homogenized and compacted, and then the
obtained mixtures were heated at 187 °C (onset decarbonylation
temperature of 3a [5]) for 1–3 min, and the reaction mixtures were
examined by UPLC-MS. As a result, we observed that the reaction
with DCC 4i proceeded well under solvent-free conditions (5a,
80% yield), and the reaction with DIC 4j showed unsatisfactory
results (5b, 16% yield). Such a trend could be explained by the rel-
atively low boiling point of DIC (145–148 °C) which had evapo-
rated prior to the onset of decarbonylation. Increasing the DIC
amount to a twofold excess did not significantly improve the reac-
tion (5b, 27%). Thus, we established that the solvent-free protocol
can be implemented with DCC 4i and is unsuitable for DIC 4j.
Having optimized the reaction conditions, we screened the
pyrroloquinoxalinetriones 3a–i (bearing an aroyl group) scope to
afford the desired compounds 5a–o (Table 1). As a result, we found
that the reactions of pyrroloquinoxalinetriones 3a–i proceeded
well to form the desired (quinoxalin-2-yl)-1,3-oxazines 5a–o
regardless of the aroyl group substituent.
Entry
R
R0
6
Yielda (%)
1
2
3
4
5
OEt
Cy
i-Pr
Cy
Cy
i-Pr
6a
6b
73b
61c
76b
76b
51c
OMe
OMe
t-Bu
t-Bu
6c (CCDC 1935938)
6d (CCDC 1935939)
6e
a
Isolated yield.
b
Conditions A: decarbonylation onset temperature of 3, 1–3 min, solvent-free,
10% excess of carbodiimide 4 (for DCC 4i).
Conditions B: decarbonylation onset temperature of 3, 1–3 min, Dowtherm A,
60% excess of carbodiimide 4 (for DIC 4j).
c
poor enolization of the pivaloyl carbonyl group due to the strong
electron donor effect of the tert-butyl substituent.
Notably, compounds 6a–e were also formed as sole regioiso-
To implement the alternative direction for the cycloaddition of
carbodiimides 4i,j to ketenes 2, pyrroloquinoxalinetriones 3j,k
bearing alkoxycarbonyl groups (difficult to enolize) were reacted
with DCC 4i and DIC 4j. As expected, the products were pyrimido
[1,6-a]quinoxalines 6a–c (Table 2).
Interestingly, the pivaloyl group bearing pyrroloquinoxalinetri-
one 3 l reacted with carbodiimides 4i,j under thermal decarbonyla-
tion conditions to form pyrimido[1,6-a]quinoxalines 6d,e (Table 2)
instead of the expected (quinoxalin-2-yl)-1,3-oxazines. This can be
explained by steric hindrance induced by the tert-butyl group or
mers, and no signals of regioisomeric cycloadducts
observed by UPLC-MS (Scheme 3).
5 were
We assume that the divergent formation of (quinoxalin-2-yl)-
1,3-oxazines or pyrimido[1,6-a]quinoxalines proceeded
5
6
according to Scheme 4. First, pyrroloquinoxalinetriones 3 under-
went thermal decarbonylation affording in situ generation of acyl
(quinoxalinyl)ketenes 2. Ketenes 2 reacted with carbodiimides 4
to form zwitterionic intermediates A. In the case of aroyl sub-
stituents, zwitterions A underwent charge-controlled intramolecu-
lar cyclization at the readily enolizable carbonyl group of the aroyl

4
S. Kasatkina et al. / Tetrahedron Letters 60 (2019) 151088
Acknowledgment
This work was supported by the Russian Science Foundation,
project # 19-13-00290.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2019.151088. These data include
MOL files and InChiKeys of the most important compounds
described in this article.
References
[1] (a) S.L. Schreiber, Science 287 (2000) 1964–1969, https://doi.org/
10.1126/science.287.5460.1964;
(b) S. Collins, S. Bartlett, F. Nie, H.F. Sore, D.R. Spring, Synthesis 48 (2016) 1457–
1473, https://doi.org/10.1055/s-0035-1561414;
(c) K. Torikai, R. Koga, X. Liu, K. Umehara, T. Kitano, K. Watanabe, T. Oishi, H.
Noguchi, Y. Shimohigashi, Bioorg. Med. Chem. 25 (2017) 5216–5237, https://
doi.org/10.1016/j.bmc.2017.07.067;
(d) S.L. Kidd, Th.J. Osberger, N. Mateu, H.F. Sore, D.R. Spring, Front. Chem. 6
(2018) 460, https://doi.org/10.3389/fchem.2018.00460;
(e) G. Schneider, Nat. Rev. Drug Discov. 17 (2018) 97–113, https://doi.org/
10.1038/nrd.2017.232;
(f) X. Jiang, X. Hao, L. Jing, G. Wu, D. Kang, X. Liu, P. Zhan, Expert Opin. Drug
Discov. 14 (2019) 779–789, https://doi.org/10.1080/17460441.2019.1614910.
[2] (a) S. Dandapani, L.A. Marcaurelle, Curr. Opin. Chem. Biol. 14 (2010) 362–370,
https://doi.org/10.1016/j.cbpa.2010.03.018;
(b) S. Yi, B.V. Varun, Yo Choi, S.B. Park, Front. Chem. 6 (2018) 507, https://doi.
org/10.3389/fchem.2018.00507.
[3] (a) S. Rosenzweig-Lipson, J. Zhang, H. Mazandarani, B.L. Harrison, A. Sabb, J.
Sabalski, G. Stack, G. Welmaker, J.E. Barrett, J. Dunlop, Brain Res. 1073–1074
(2006) 240–251, https://doi.org/10.1016/j.brainres.2005.12.052;
(b) A.N. Maslivets, S.O. Kasatkina, E.E. Stepanova, R.R. Makhmudov. RU Patent 2
676 682, 2019.;
(c) M.A. Martins Alho, Y. Marrero-Ponce, S.J. Barigye, A. Meneses-Marcel, Y.
Machado Tugores, A. Montero-Torres, A. Gómez-Barrio, J.J. Nogal, R.N. García-
Sánchez, M.C. Vega, M. Rolón, A.R. Martínez-Fernández, J.A. Escario, F. Pérez-
Giménez, R. Garcia-Domenech, N. Rivera, R. Mondragón, M. Mondragón, F.
Ibarra-Velarde, A. Lopez-Arencibia, C. Martín-Navarro, J. Lorenzo-Morales, M.G.
Cabrera-Serra, J. Piñero, J. Tytgat, R. Chicharro, V.J. Arán, Bioorg. Med. Chem. 22
(2014) 1568–1585, https://doi.org/10.1016/j.bmc.2014.01.036;
(d) X.F. Wang, F. Guan, E. Ohkoshi, W. Guo, L. Wang, D.Q. Zhu, S.B. Wang, L.T.
Wang, E. Hamel, D. Yang, L. Li, K. Qian, S.L. Morris-Natschke, S. Yuan, K.H. Lee, L.
Xie, J. Med. Chem. 57 (2014) 1390–1402, https://doi.org/10.1021/jm4016526.
[4] (a) N.Yu. Lisovenko, A.N. Maslivets, Z.G. Aliev, Chem. Heterocycl. Compd. 39
(2003) 132–134, https://doi.org/10.1023/A:1023097414711;
(b) N.Yu. Lisovenko, A.N. Maslivets, Chem. Heterocycl. Compd. 40 (2004) 247–
248, https://doi.org/10.1023/B:COHC.0000027901.78882.86;
(c) N.Yu. Lisovenko, A.N. Maslivets, Z.G. Aliev, Russ. J. Org. Chem. 40 (2004)
1053–1057, https://doi.org/10.1023/B:RUJO.0000045203.69639.83;
(d) N.Yu. Lisovenko, A.N. Maslivets, Z.G. Aliev, Russ. J. Org. Chem. 43 (2007)
117–120, https://doi.org/10.1134/S1070428007010150;
Scheme 4. Plausible pathway for the reaction of acyl(quinoxalinyl)ketenes 2 with
carbodiimides 4.
substituent. Conversely, alkoxycarbonyl/pivaloyl bearing zwitteri-
ons A underwent intramolecular cyclization at the enamino motif
because its enolized resonance structure B is unfavorable.
In conclusion, we have developed
a divergent synthetic
methodology towards two distinct quinoxaline-based heterocycles
based on the substituent controlled cycloaddition reaction of acyl
(quinoxalinyl)ketenes with carbodiimides. Acyl(quinoxalinyl)kete-
nes were generated in situ as a result of the thermal decarbonyla-
tion reaction of pyrroloquinoxalinetriones. In the case of aroyl
substituted acyl(quinoxalinyl)ketenes, the O@C@CAC@O system
underwent the cycloaddition reaction, and (quinoxalin-2-yl)-1,3-
oxazines were obtained as the sole products. Involvement of
alkoxycarbonyl or pivaloyl substituted acyl(quinoxalinyl)ketenes
led to the exclusive formation of pyrimido[1,6-a]quinoxalines,
the products of cycloaddition at the O@C@CAC@N system. Our
study is the first example of a divergent cycloaddition reaction of
acyl(quinoxalinyl)ketenes resulting in either (quinoxalin-2-yl)-
1,3-oxazines or pyrimido[1,6-a]quinoxalines formation. The pro-
posed strategy provides facile access to a library of skeletally
diverse pharmaceutically interesting quinoxaline-based heterocy-
cles from inexpensive reagents.
(e) D.D. Nekrasov, A.S. Obukhova, N.Yu. Lisovenko, A.E. Roubtsov, Chem.
Heterocycl. Compd. 46 (2010) 413–418, https://doi.org/10.1007/s10593-010-
0525-y;
(f) N.Yu. Lisovenko, D.D. Nekrasov, V.I. Karmanov, Chem. Heterocycl. Compd. 48
(2012) 1357–1360, https://doi.org/10.1007/s10593-012-1144-6.
[5] S.O. Kasatkina, E.E. Stepanova, M.V. Dmitriev, I.G. Mokrushin, A.N. Maslivets,
Beilstein J. Org. Chem. 14 (2018) 1734–1742, https://doi.org/10.3762/
bjoc.14.147.
[6] (a) A.N. Maslivets, K.S. Bozdyreva, I.V. Smirnova, I.A. Tolmacheva, I.V.
Mashevskaya, Chem. Heterocycl. Compd. 38 (2002) 498–499, https://doi.org/
10.1023/A:1016056011167;
(b) A.N. Maslivets, Z.G. Aliev, O.P. Krasnykh, O.V. Golovnina, L.O. Atovmyan,
Chem. Heterocycl. Compd. 40 (2004) 1295–1299, https://doi.org/10.1007/
s10593-005-0060-4;
(c) K.S. Bozdyreva, I.V. Smirnova, A.N. Maslivets, Russ. J. Org. Chem. 41 (2005)
1081–1088, https://doi.org/10.1007/s11178-005-0296-6.
[7] E.E. Stepanova, S.O. Kasatkina, M.V. Dmitriev, A.N. Maslivets, Synthesis 50
(2018) 4897–4904, https://doi.org/10.1055/s-0037-1610647.