Novel condensations of nitroacetic esters with aromatic aldehydes leading to 5-hydroxy-1,2-oxazin-6-ones

Article abstract of DOI:10.1016/j.tetlet.2012.11.132

Contrary to the early literature [Dornow, A.; Wiehler, G. Justus Liebigs Ann. Chem. 1952, 578, 113-121], esters of 2,4-dinitro-3-arylglutaric acids 2 could not be obtained by double condensation of aryl aldehydes with alkyl nitroacetates. Instead, under these conditions, we observed formation of novel 4-aryl-5-hydroxy-1,2-oxazin-6-one-3-carboxylates 1. The roles of the solvent, the reaction conditions, and the nature of the reagents in this new condensation were investigated. The data obtained suggest that the heterocyclic products 1 originate from intramolecular oxidation (similar to the Nef reaction) of dinitro derivative 2, followed by nucleophilic attack of the oxime oxygen at the carboxylate group. The condensation presented provides a novel general synthetic route to these types of heterocycle.

Full text of DOI:10.1016/j.tetlet.2012.11.132

Accepted Manuscript
Novel condensations of nitroacetic esters with aromatic aldehydes leading to 5-
hydroxy-1,2-oxazin-6-ones
Mikhail S. Baranov, Ilia V. Yampolsky
PII:
S0040-4039(12)02095-3
DOI:
http://dx.doi.org/10.1016/j.tetlet.2012.11.132
TETL 42228
Reference:
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Tetrahedron Letters
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Revised Date:
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1 November 2012
21 November 2012
28 November 2012
Please cite this article as: Baranov, M.S., Yampolsky, I.V., Novel condensations of nitroacetic esters with aromatic
aldehydes leading to 5-hydroxy-1,2-oxazin-6-ones, Tetrahedron Letters (2012), doi: http://dx.doi.org/10.1016/
j.tetlet.2012.11.132
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Graphical Abstract
Novel condensations of nitroacetic esters
with aromatic aldehydes leading to 5-
hydroxy-1,2-oxazin-6-ones
Leave this area blank for abstract info.
Mikhail S. Baranov, Ilia V. Yampolsky

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Novel condensations of nitroacetic esters with aromatic aldehydes leading to 5-
hydroxy-1,2-oxazin-6-ones
Mikhail S. Baranov, Ilia V. Yampolsky
Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya 16/10, Moscow, 117997 Russia
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Contrary to the early literature [Dornow, A.; Wiehler, G. Justus Liebigs Ann. Chem. 1952, 578,
113-121], esters of 2,4-dinitro-3-arylglutaric acids 2 could not be obtained by double
condensation of aryl aldehydes with alkyl nitroacetates. Instead, under these conditions, we
observed formation of novel 4-aryl-5-hydroxy-1,2-oxazin-6-one-3-carboxylates 1. The roles of
the solvent, the reaction conditions and the nature of the reagents in this new condensation were
investigated. The data obtained suggest that the heterocyclic products 1 originate from
intramolecular oxidation (similar to the Nef reaction) of dinitro derivative 2, followed by
nucleophilic attack of the oxime oxygen at the carboxylate group. The condensation presented
provides a novel general synthetic route to these types of heterocycle.
Available online
Keywords:
Heterocycles
1,2-Oxazin-6-ones
Nitroacetic esters
2,4-Dinitro-3-arylglutarates
2009 Elsevier Ltd. All rights reserved.
Aliphatic nitro compounds have proven to be valuable
intermediates for the synthesis of different classes of organic
molecules.1 Among these, alkyl nitroacetates are of particular
utility as versatile synthetic tools.2 In the course of our research
in the field of the chemistry of chromophores of fluorescent
proteins3 we were faced with the necessity of obtaining 2,4-
dinitro-3-arylglutarates 2.
A successful double condensation of nitroacetic esters with
aromatic aldehydes leading to the desired dinitroglutaric esters 2
has been reported earlier.4 However, our attempts to reproduce
these results were unsuccessful. Instead, we observed formation
of novel 4-aryl-5-hydroxy-1,2-oxazin-6-one-3-carboxylates
1
(Scheme 1).
Scheme 1. Formation of 4-aryl-5-hydroxy-1,2-oxazin-6-one-
3-carboxylates 1 from aromatic aldehydes and nitroacetic
esters, a proposed mechanism.
We studied various aromatic aldehydes, alkyl nitroacetates
and secondary amines in this reaction. Methanol, ethanol or
isopropanol were used as solvents corresponding to the alkyl
nitroacetate employed, in order to avoid transesterification. In the
majority of cases, precipitation of the ammonium salts of
oxazinones 1 was observed (Table 1).5 In the case of 4-
———
 Corresponding author. Tel.: +7-499-742-8122; fax: +7-499-742-8122; e-mail: ivyamp@ibch.ru

2
Tetrahedron Letters
nitrobenzaldehyde derivatives 1z, formation of a precipitate did
reaction. Only with 2-pyridinecarboxaldehyde derivative 2c did
this transformation not take place. The nature of the alkyl
nitroacetate and amine did not appear to affect the ratio of
products 1:2.
not take place, and the products were isolated in protonated form.
However, some aldehydes gave 2,4-dinitroglutarates 2 (also as
ammonium salts). We observed gradual transformation of
dinitroglutarates 2 into oxazinones 1 during the course of the
Table 1. Oxazinones 1 and dinitroglutarates 2 produced via Scheme 1
Ar
Product, %
Time, (d)
Ar
Product, %
Time,( d)
3
Ph
1a(Me)•Et2NH, 56%
1a(Et)•Et2NH, 31%
or 2a(Et)•Et2NH, 56%a
1a(iPr)•Et2NH, 43%
or 1a(iPr)•Et2NH + 2a(iPr) •Et2NHa,b
1b(Me)•Et2NH, 27%
1b(Et)•Et2NH, 54%
1b(iPr)•Et2NH, 23%
1z(Me),c 22%
2
Ph
1a(Me)•Cy2NH, 33%
2 or 1
3 or 1
Ph
Ph
Ph
Ph
1a(Me)•piperidine, 13%
3
3
1a(Me)•pyrrolidine,
39%
4-MeO-Ph
4-MeO-Ph
4-MeO-Ph
4-NO2-Ph
4-NO2-Ph
4-HO-Ph
3
3
3
3
3
2
2
2
1
1
thiophen-2-yl
3-MeO-C6H4
4-iPr-C6H4
1e(Me)•Et2NH, 36%
1f(Me)•Et2NH, 46%
1g(Me)•Et2NH, 35%
1h(Me)•Et2NH, 43%
1i(Me)•Et2NH, 32%
1j(Me)•Et2NH, 47%
1k(Me)•Et2NH, 37%
1l(Me)•Et2NH, 36%
1m(Me) + 2m(Me)b
1n(Me) + 2n(Me)b
3
2
2
2
3
3
3
3
3
3
4-Br-C6H4
1z(iPr),c 15%
3,4-(MeO)-C6H3
4-N(Et)2-C6H4
2-F-C6H4
1d(Me)•Et2NH, 45%
1d(Et)•Et2NH, 44%
1d(iPr)•Et2NH, 53%
2c(Et)•Et2NH, 58%
2c(iPr)•Et2NH, 33%
4-HO-Ph
4-HO-Ph
4-F-C6H4
pyridin-2-yl
pyridin-2-yl
2-Br-C6H4
2-HO-C6H4
a Compound 1 or 2, or their mixture was isolated depending on the reaction time
b Complete conversion of 2 into 1 could not be achieved even after prolonged reaction times
c Precipitation of the ammonium salts of 1 and 2 was not observed; 1 was isolated from the reaction mixture in protonated form.
The structures of novel heterocyclic products
1
were
mechanisms do not explain the formation of the six-membered
ring of 1. Therefore, we speculate that oxazinones 1 may
originate from intramolecular oxidation (similar to the Nef
reaction) of dinitroglutarates 2 followed by nucleophilic attack of
the oxime oxygen at the carboxylate (Scheme 1). It should be
noted that our mechanism does not contradict the experimental
data reported in the discussed papers.8,9
confirmed by NMR spectroscopy and X-ray crystallography
(Figure 1).6
In conclusion, contrary to the earlier literature,4 esters of 2,4-
dinitro-3-arylglutaric acids 2 cannot be isolated by double
condensation of aryl aldehydes with alkyl nitroacetates.
Generally, compounds 2 are unstable in solution and transform
spontaneously into novel 4-aryl-5-hydroxy-1,2-oxazin-6-one-3-
carboxylates 1. To the best of our knowledge, only one example
of the synthesis of 5-hydroxylated 1,2-oxazines has been reported
in the literature.10 The present report offers a novel general
synthetic route to these heterocycles.
Acknowledgments
The authors gratefully acknowledge support from the MCB
program of the Russian Academy of Sciences, the Russian
Foundation for Basic Research grant 11-04-01293-а, the Program
of the Government of the Russian Federation ―Measures to
attract leading scientists to Russian educational institutions‖
(grant No 11. G34.31.058). I.V.Y. is supported by a grant from
the President of the Russian Federation.
Figure 1. General view of compound 1b(Me)•Et2NH. Thermal ellipsoids
at the 50% probability level.
Other products (isoxazoles and isoxazoline N-oxides) have
been reported to arise from condensation of two molecules of an
alkyl nitroacetate and one molecule of an aromatic aldehyde.7-9
Proposed mechanisms8,9 for these transformations include initial
formation of adduct 2 followed by intramolecular cyclization via
nucleophilic substitution of the nitro group. However, these
References and notes
1. Rosini, G.; Ballini, R. Synthesis 1988, 833-847.
2. Shipchandler, M. T. Synthesis 1979, 666-686.

3
3. (a) Ivashkin, P. E.; Yampolsky, I. V.; Lukyanov, K. A. Russ. J.
Bioorg. Chem. 2009, 35, 652-669; (b) Baranov, M. S.; Lukyanov,
K. A.; Yampolsky, I. V. Russ. J. Bioorg. Chem., in press.
4. (a) Dornow, A.; Wiehler, G. Justus Liebigs Ann. Chem. 1952, 578,
113-121; (b) Dornow, A.; Frease, A. Justus Liebigs Ann. Chem.
1953, 581, 211-218.
6. Crystals of 1b(Me)•Et2NH•MeOH (C18H26N2O7, M = 382.41)
are monoclinic, space group P21/c, at 100(2) K: , a = 9.1912(15) ,
b = 12.701(2) , c = 16.895(3) Å, β = 96.130(3)°, V = 1961.0(6) Å3,
Z = 4 (Z’=1), dcalc = 1.295 g·sm–3, =1.00 сm-1, F(000) = 816.
Intensities of 16556 reflections were measured with a ―Bruker
SMART APEX2‖ CCD diffractometer and 4703 independent
reflections [Rint = 0.0402] were used in further refinement. The
refinement converged to wR2 = 0.0951 and GOF = 1.006 for all
independent reflections (R1 = 0.0374 was calculated against F for
3668 observed reflections with I > 2(I)). All calculations were
performed using SHELXTL PLUS 5.0 [Sheldrick, G. M.; Acta
Cryst., 2008, A64, 112-122]. Atomic coordinates, bond lengths,
angles and thermal parameters have been deposited at the
Cambridge Crystallographic Data Cent, CCDC 905699.
7. Zen, S.; Umezawa, S. Bull. Chem. Soc. Jpn. 1963, 36, 1146-1149.
8. Chen, K.-P.; Chen, Y.-J.; Chuang, C.-P. Eur. J. Org. Chem. 2010,
5292–5300.
5. Representative example for the synthesis of 1b(Me)•Et2NH: 4-
methoxybenzaldehyde (140 mg, 1.0 mmol) and methyl 2-
nitroacetate (260 mg, 2.2 mmol) were dissolved in dry MeOH (1
mL) at 0 oC. After complete dissolution, diethylamine (160 mg,
2.2 mmol) was added and the mixture was stirred at r.t. for 72 h.
The resulting precipitate was filtered, washed with MeOH (1 mL,
0 oC) and Et2O (2x2 mL) and dried in vacuo. Yield 95 mg (27%).
White solid, mp 171-174 oC. 1H NMR (700 MHz, CDCl3) δ 9.19
(s, 2H), 7.19 (d, J = 8.6 Hz, 2H), 6.90 (d, J = 8.7 Hz, 2H), 3.81 (s,
3H), 3.62 (s, 3H), 2.31 (q, J = 7.1 Hz, 4H), 1.00 (t, J = 7.2 Hz,
6H). 13C NMR (176 MHz, CDCl3) δ 170.08 (C), 163.60 (C),
159.07 (C), 156.81 (C), 154.05 (C), 130.81 (CH), 126.38 (C),
113.97 (CH), 110.68 (C), 55.37 (CH), 52.68 (CH), 43.07 (CH),
11.76 (CH). HRMS m/z: 276.0521 found (calculated for
C13H11NO6, [M-H]- requires 276.0508).
9. Chatterjee, A.; Jha, S. C.; Joshi, N. N. Tetrahedron Lett. 2002, 43,
5287-5289.
10. Dang, T. T.; Albrecht, U.; Langer, P. Synthesis 2006, 2515-2522.