A novel approach to biologically relevant oxazolo[5,4-d]pyrimidine-5,7-diones via readily available diazobarbituric acid derivatives

Article abstract of DOI:10.1016/j.tetlet.2019.151120

An alternative route from 1,3-disubstituted barbituric acids to biologically relevant oxazolo[5,4-d]pyrimidine-5,7-diones was developed that features sulfonyl-azide-free (SAFE) diazo transfer and Rh₂(esp)₂-catalyzed cycloaddition of

Full text of DOI:10.1016/j.tetlet.2019.151120

Tetrahedron Letters 60 (2019) 151120
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Tetrahedron Letters
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A novel approach to biologically relevant oxazolo[5,4-d]pyrimidine-5,7-
diones via readily available diazobarbituric acid derivatives
⇑
Martha Gecht, Grigory Kantin, Dmitry Dar’in, Mikhail Krasavin
Saint Petersburg State University, Saint Petersburg 199034, Russian Federation
a r t i c l e i n f o
a b s t r a c t
Article history:
An alternative route from 1,3-disubstituted barbituric acids to biologically relevant oxazolo[5,4-d]pyrim-
idine-5,7-diones was developed that features sulfonyl-azide-free (SAFE) diazo transfer and Rh2(esp)2-cat-
alyzed cycloaddition of the resulting 5-diazobarbituric acids with aliphatic and aromatic nitriles. Besides
being shorter compared to the previously described approaches, the method allows introduction of alkyl
substituents at the 1,3-oxazole ring of the fused heterocyclic system.
Received 4 August 2019
Revised 31 August 2019
Accepted 5 September 2019
Available online 6 September 2019
Ó 2019 Elsevier Ltd. All rights reserved.
Keywords:
Diazobarbituric acid
Rh(II) catalysis
1,3-Oxazoles
[2+3]-Cycloaddition
The pyrimidine-2,4-dione core is typically introduced into more
complex heterocyclic frameworks via the use of barbituric acid and
its derivatives as building blocks. The latter have been utilized in
the design and synthesis of diverse types of heterocyclic and carbo-
cyclic compounds [1]. Besides the prominence of barbiturates as
central nervous system drugs [2], fused polycyclic pyrimidine-
2,4-diones can be regarded as privileged motifs [3], considering
the diversity of biological activities displayed by such compounds.
One such chemotype, oxazolo[5,4-d]pyrimidine-5,7-diones, has
recently attracted our attention. It is featured in biologically active
compounds such as FGFR1 inhibitor 1 for cancer treatment [4],
metalloproteinase inhibitor 2 for the treatment of arthritis, inflam-
mation and cancer [5], adenosine receptor antagonist 3 to treat
neurodegenerative disease [6] and Syngenta’s pesticide series rep-
resented by compound 4 (Fig. 1) [7].
The currently described strategies to assemble oxazolo[5,4-d]
pyrimidine-5,7-diones are rather limited and rely on 5-aminopy-
rimidine-2,4,6-trione 5 prepared, in turn, over two steps (nitrosa-
tion followed by nitroso group reduction) from barbituric acid
derivatives 6. In the most exploited approach [4,8–10], amine 5
is first condensed with aromatic aldehydes and the respective
intermediate imines are cyclodehydrated with SOCl2 [4,8,9] or
N-bromosuccinimide [10] to give the target compounds (7).
Alternatively, the latter can be formed by heating amine 5 in aroyl
chlorides as a solvent [11] (Scheme 1). One isolated report [12]
described the synthesis of 7 by direct condensation of 5-nitroso-
1,3-dimethylbarbituric acid with various Wittig phosphonium
ylides; however, subsequent research in the area has not utilized
this methodology and the approach depicted in Scheme 1 currently
remains the principal means to synthesize oxazolo[5,4-d]pyrim-
idine-5,7-diones 7. The following drawbacks of this synthesis are
apparent: it is multistep and the R0 substituent diversity is limited
to (hetero)aryl groups.
Our recent experience preparing heterocycle-fused oxazoles
from heterocyclic a-diazocarbonyl compounds [13] via Rh(II)-cat-
alyzed [2+3]-cycloaddition with nitriles prompted us to consider
an alternative disconnection of scaffold 7. We reasoned that the
oxazole ring could be obtained from a similar coupling of nitriles
(R0CN) with metal carbenes derived from 5-diazobarbituric acids
8. The latter were introduced as early as 1952 [14] and have been
shown to undergo selected transformations which are typical of a-
diazocarbonyl compounds. In particular, Rh(II)-catalyzed OH-
insertion, [15] CAr-H insertion, [16] dichlorination reactions [17]
and [2+3]-cycloadditions with styrenes and arylacetylenes [18]
have been reported, thus making 5-diazobarbituric acids versatile
building blocks (Fig. 2). Thus, we decided to investigate 5-diazo-
barbituric acids 8 in the RhII-catalyzed cycloaddition with nitriles,
which would constitute a simpler and more flexible entry into oxa-
⇑
Corresponding author at: Laboratory of Chemical Pharmacology, Institute of
Chemistry, Saint Petersburg State University, 26 Universitetskii prospect, Peterhof
198504, Russian Federation.
zolo[5,4-d]pyrimidine-5,7-diones
reported approaches. Herein, we present the results of these
studies.
7
compared to previously
E-mail address: m.krasavin@spbu.ru (M. Krasavin).
URL: http://krasavin-group.org (M. Krasavin).
https://doi.org/10.1016/j.tetlet.2019.151120
0040-4039/Ó 2019 Elsevier Ltd. All rights reserved.

2
M. Gecht et al. / Tetrahedron Letters 60 (2019) 151120
Utilizing the previously developed conditions for the RhII-cat-
alyzed [2+3]-cycloaddition of -diazo homophthalimides [13], we
a
screened a number of transition metal catalysts and BF3∙OEt2 as
representative Lewis acid (Table 1). The best result (86% yield)
was obtained in the Rh2(esp)2-catalyzed reaction between 1,3-
dimethyl-5-diazobarbituric acid (8a) and acetonitrile conducted
at 120 °C under microwave irradiation over 2 h (Entry 4). While
shortening the 120 °C reaction time to 1 h under microwave irradi-
ation led to incomplete conversion, slightly increasing the reaction
temperature (130 °C) and time (3 h) resulted in full conversion and
a comparable yield (82%) under conventional heating (Entry 5),
thus making the newly discovered transformation amenable to
both modes of activation.
Fig. 1. Examples of biologically active compounds containing the oxazolo[5,4-d]
pyrimidine-5,7-dione core.
Having identified the optimal conditions for the synthesis of
oxazolo[5,4-d]pyrimidine-5,7-diones, we proceeded to investigate
its scope using a set of 5-diazobarbituric acids 8a–f (Fig. 3) conve-
niently prepared from their 5-unsubstituted counterparts by the
recently developed sulfonyl-azide-free (SAFE) diazo transfer proto-
col [19].
Scheme 1. Typical approaches to oxazolo[5,4-d]pyrimidine-5,7-diones reported in
the literature.
The results of these experiments are presented in Scheme 2. The
formation of target oxazolo[5,4-d]pyrimidine-5,7-diones 7 was
efficient in the case of symmetrically 1,3-disubstituted diazo cores
8a–c and 8f and proceeded well under conventional heating or
microwave irradiation with aliphatic and aromatic nitriles while
tolerating labile haloalkyl groups (albeit with diminished yields,
cf. 7e–f). Non-symmetric 5-diazobarbituric acid 8d reacted primar-
ily at the more ‘enolizable’ carbonyl to give 7j as the major product.
Its identity (as well as that of its regioisomer 7j0) was established
by HMBC correlations (Fig. 4). Monosubstituted 5-diazobarbituric
acid 8e failed to give the desired 1,3-oxazole product 7 l.
Attempts to transfer the [2+3]-cycloadditions described herein
to diazo Meldrum’s acid 9 gave a curious result. While the reaction
gave full conversion and good isolable yield of a product, its struc-
ture was assigned to 2,5-dimethyl-7H-oxazolo[4,5-e] [1,3]oxazin-
7-one (10) rather than the expected adduct 11. Considering that
the reaction was conducted under prolonged microwave irradia-
tion in acetonitrile as a solvent, it is realistic to expect product
10 to arise from a known [20] elimination of an acetone molecule,
formation of acyl ketene 12 and Diels-Alder-like cyclocondensation
[21] of the latter with another molecule of acetonitrile (Scheme 3).
In summary, we have developed a novel approach to biologi-
cally relevant oxazolo[5,4-d]pyrimidine-5,7-diones. It relies on
the convenient synthesis of 5-diazobarbituric acids by SAFE diazo-
transfer and Rh2(esp)2-catalyzed cycloaddition with nitriles conve-
niently conducted under conventional heating or microwave
irradiation. Besides the practical convenience, the synthesis affords
greater diversity of substituents on the 1,3-oxazole ring compared
to the previous cyclodehydration-based methods which work only
for (hetero)aryl-substituted substrates.
Fig. 2. Examples of reactions described for 5-diazobarbituric acids
literature [15–18] and the approach investigated in this work.
8 in the
Table 1
Condition screening for the cycloaddition of 8a and acetonitrile.
Entry
Catalyst
Amount (mol%)
Yield 7a (%)a
1
2
3
4
5
6
7
8
9
Rh2(OAc)4
Rh2(Oct)4
Rh2(C4F7O2)4
Rh2(esp)2
Rh2(esp)2
Rh2(Piv)4
Rh2(CF3CO2)4
BF3ꢀEt2O
1
1
1
1
1
1
1
100
10
65
34
Traceb
86
82c
78
47
Traceb
Traceb
AgOTf
a
b
c
Isolated yield.
according to TLC analysis of the reaction mixture.
reaction was carried out at 130 °C under conventional heating for 3 h.
Fig. 3. 5-Diazobarbituric acids 8 employed in this study.

M. Gecht et al. / Tetrahedron Letters 60 (2019) 151120
3
Scheme 2. Preparation of oxazolo[5,4-d]pyrimidine-5,7-diones 7a–l.
Acknowledgements
This research was supported by the Russian Science Foundation
(project grant 19-75-30008). We thank the Research Centre for
Magnetic Resonance, the Center for Chemical Analysis and Materi-
als Research of Saint Petersburg State University Research Park for
obtaining the analytical data.
Fig. 4. HMBC correlations permitting the distinction between 7j and 7j0
regioisomers.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2019.151120.
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