Synthesis of 4,5,6,7-tetrahydrobenzoxazol-2-ones by a highly regioselective Diels-Alder cycloaddition of exo-oxazolidin-2-one dienes with chalcones

Article abstract of DOI:10.1016/j.tetlet.2019.04.027

The synthesis of novel of 4,5,6,7-tetrahydrobenzoxazol-2-ones is herein reported. They were obtained in moderate to good yields by a highly regio- and stereoselective Diels-Alder cycloaddition of N-substituted exo-oxazolidin-2-one dienes with chalcones or bis-chalcones as dienophiles.

Full text of DOI:10.1016/j.tetlet.2019.04.027

Accepted Manuscript
Synthesis of 4,5,6,7-tetrahydrobenzoxazol-2-ones by a highly regioselective
Diels-Alder cycloaddition of exo-oxazolidin-2-one dienes with chalcones
Salvador Mastachi-Loza, Tania I. Ramírez-Candelero, Asenet Tapia-
Bustamante, Carlos González-Romero, Eduardo Díaz-Torres, Joaquín Tamariz,
Rubén A. Toscano, Aydeé Fuentes-Benítes
PII:
S0040-4039(19)30364-8
https://doi.org/10.1016/j.tetlet.2019.04.027
TETL 50742
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
10 February 2019
10 April 2019
15 April 2019
Please cite this article as: Mastachi-Loza, S., Ramírez-Candelero, T.I., Tapia-Bustamante, A., González-Romero,
C., Díaz-Torres, E., Tamariz, J., Toscano, R.A., Fuentes-Benítes, A., Synthesis of 4,5,6,7-tetrahydrobenzoxazol-2-
ones by a highly regioselective Diels-Alder cycloaddition of exo-oxazolidin-2-one dienes with chalcones,
Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet.2019.04.027
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Graphical Abstract
Synthesis of 4,5,6,7-tetrahydrobenzoxazol-2-
ones by a highly regioselective Diels-Alder
cycloaddition of exo-oxazolidin-2-one dienes
with chalcones.
Leave this area blank for abstract info.
Salvador Mastachi-Loza, Tania I. Ramírez-Candelero, Asenet Tapia-Bustamante, Carlos González-Romero,
Eduardo Díaz-Torres, Joaquín Tamariz, Rubén A. Toscano and Aydeé Fuentes-Benítes.

1
Tetrahedron Letters
Synthesis of 4,5,6,7-tetrahydrobenzoxazol-2-ones by a highly regioselective Diels-
Alder cycloaddition of exo-oxazolidin-2-one dienes with chalcones.
Salvador Mastachi-Loza,[a] Tania I. Ramírez-Candelero,[a] Asenet Tapia-Bustamante,[a] Carlos González-
Romero,[a] Eduardo Díaz-Torres,[a] Joaquín Tamariz,[b] Rubén A. Toscano [c] and Aydeé Fuentes-
Benítes.*[a]
[a] Facultad de Química, Universidad Autónoma del Estado de México, Paseo Tollocan y Colón S/N, 50000, Toluca, México.
*E-mail: mpagfuentesb@uaemex.mx
[b] Departamento de Química Orgánica, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Prol. Carpio y Plan de Ayala S/N, 11340,
CDMX, México.
[c] Instituto de Química, Universidad Nacional Autónoma de México, Circuito exterior, C.U. Coyoacán, 04510, CDMX, México
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The synthesis of novel of 4,5,6,7-tetrahydrobenzoxazol-2-ones is herein reported. They were
obtained in moderate to good yields by a highly regio- and stereoselective Diels-Alder
cycloaddition of N-substituted exo-oxazolidin-2-one dienes with chalcones or bis-chalcones as
dienophiles.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Diels-Alder Reaction
Chalcone
Cyclization
Tetrahydrobenzoxazol-2-one
Benzoxazolone
1. Introduction.
Benzoxazolones (BOAs) are biological important molecules
isolated from many plants. The relevance of this heterocyclic
framework for medicinal chemistry is evidenced by the
descriptions over the last 30 years.1 of its extensive bioactivity in
natural and synthetic derivatives. Considered a privileged
scaffold, BOAs display bioisosterism and have pharmacologial
properties similar to
a
variety of molecules (e.g.,
phenylurethanes, cathecol derivatives and coumarins) with which
they share structural resemblance.2 Some of these properties are
associated with the changes in substituents at the C5 and C6
positions of the skeleton.3,4 Biological studies have demostrated
Scheme 1. Retrosynthesis for N-substituted benzoxazol-2-ones.
On the other hand, chalcones are a group of compounds of
great interest because of their wide scope of biological activity.19
They are characterized by a scaffold formed by two benzene
rings attached to a 2-propen-1-one chain moiety. Trans isomer 5
is the most common configuration found in nature.20,21 This
family of compounds has structural diversity, exemplified by bis-
chalcones 1,5-diarylpenta-1,4-dien-3-ones derivatives 6 that
share several biological properties with chalcones 5 (Figure 1).
6
7
that BOAs exhibit antibacterial,5 antifungal, analgesic, anti-
8
inflammatory,
anticonvulsant,9 dopaminergic,10 and reverse
transcriptase inhibition activity.11
These heterocycles are usually synthesized by a condensation
reaction of o-aminophenols with urea (as the classic procedure),
or less commonly with 1,1'-carbonyldiimidazole,12 ethyl
cloroformate or phosgene.13 Other methods involve Beckmann14
or Lossen rearrangements12 or a reaction between N-alkyl-N-
arylhydroxylamine and trichloroacethyl chloride.15 For instance,
N-substituted benzoxazol-2-ones 1 can be prepared from the
aromatization of 4,5,6,7-tetrahydrobenzoxazolones 2, which are
easily generated through a Diels-Alder addition between dienes 3
and diverse dienophiles 4 (Scheme 1).16–18
Figure 1. Core structure of chalcones 5 and bis-chalcones 6.

2
Tetrahedron
Due to the conjugated double bond to a carbonyl group and
functional groups). However, the endo/exo stereoselectivity was
lower, showing an inverse ratio when changing the polarity of the
solvent. Thus, the endo isomer 9a was the major isomer and
displayed a greater selectivity with a polar mixture of solvents
(method A), while the exo isomer 8a was the main adduct
(though in lower isomeric ratio) with toluene acting as the
solvent.
to a delocalized π-electron system of both benzene rings,
chalcones exhibit low redox potential that allows them to
undergo electron transfer reactions.22 Consequently their diverse
applications include their involvement in Diels- Alder rections
either as dienophiles,23–25 or as dienes26 (the latter for hetero-
Diels-Alder cycloadditions).
We herein present the synthesis of novel 5,6-substituted
4,5,6,7-tetrahydrobenzoxazol-2-ones 8, 9, 11 and 12 obtained by
a Diels-Alder cycloaddition of N-substituted exo-oxazolidin-2-
one dienes 3a-c with chalcones 5a-g and bis-chalcones 6a-f
(Scheme 2).
Table 1. Methods for the Diels-Alder cycloaddition of 3a with 6a.
2. Results and Discussion.
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Ratio
8/9 [b]
Yield
(%)[c]
Method
A
Conditions [a]
Time (h)
MeOH/H2O (9:1)[d]
reflux
72
22:78
65:35
25
B
C
toluene, 180 °C
24
86
79
toluene, 180 °C (MW)
0.5
63:37
Dienes 3a-c were synthesized by following the reported
condensation reaction,18,27 in this case with 2,3-pentanedione (10)
and the corresponding arylisocyanate, in the presence of
triethylamine as the base.
1
[a]With 3a (0.85 mmol) and 6a (0.85 mmol). [b]Determined by H NMR. [c]For
the diastereoisomeric mixture.
results.
[d]
Other mixtures were tested with no better
Following the reaction conditions established in methods A-C,
the series of 4,5,6,7-tetrahydrobenzoxazol-2-ones 8/9 was
prepared by utilizing N-substituted exo-heterocyclic dienes 3a-c
and bis-chalcones 6a-f (Table 2). A change in exo/endo
selectivity was observed with ortho substituents in the aromatic
ring at C5, even when toluene was used as the solvent (adducts
8/9-i, j and k).
Table 2. Synthesized exo/endo tetrahydrobenzoxazol-2-ones 8
and 9.
Scheme 2. Synthesis of tetrahydrobenzoxazol-2-ones.
Reagents and conditions: i) acetone, NaOH aq. 10%, EtOH, rt; ii)
R1-NCO, triethylamine, Li2CO3, toluene; iii) R3-COCH3, NaOH
aq. 10%, EtOH, rt; iv) MW, 180 °C or conventional heating (180
°C).
Ratio
Yield
The preparation of the chalcone derivatives 5a-g and bis-
chalcones 6a-f was carried out with the Claisen-Schmidt
condensation.28–31 By adding equimolar amounts of the
corresponding ketone and aldehyde to a 10% aqueous solution of
NaOH in ethanol as the solvent, the desired products were
provided in good yields. Chalcones 5a-g were afforded by the
condensation reaction between acetone and the series of
benzaldehydes 7, and bis-chalcones 6a-g by the reaction of
acetophenone derivatives with benzaldehydes 7.
Adducts
Method
R1
R2
(%)[b]
8/9[a]
50:50
35:65
4-
8b, 9b
8c, 9c
8d, 9d
C
A
B
phenyl
phenyl
85
28
86
methoxyphenyl
phenyl
4-
4-chlorophenyl 62:38
methoxyphenyl
4-
4-
8e, 9e
8f, 9f
8g, 9g
B
B
C
63:37
91
67
86
methoxyphenyl
methoxyphenyl
Once having dienes and dienophiles on hand, three methods
for evaluating Diels-Alder cycloaddition were tested by using
equimolar amounts of compounds 3a and 6a (Table 1). Method
A consisted of refluxing the reaction mixture in a water/methanol
solution (entry 1), while method B and C involved heating at 180
°C with different energy sources (entries 2-3). The latter methods
furnished higher yields and required shorter reaction times.
4-
phenyl
59:41
50:50
methoxyphenyl
4-
2-thienyl
methoxyphenyl
8h, 9h
8i, 9i
B
B
2-thienyl
2-chorophenyl
2,3-
4-chlorophenyl 55:45
72
95
phenyl
4-
38:62
15:85
It is striking that in all reaction conditions employed, the
cycloadditions proceeded with high regioselectivity, exclusively
yielding the ortho isomers (relative to methyl and enone
8j, 9j
B
91
dimethoxyphenyl methoxyphenyl

3
2,6-
dichlorophenyl
4-
ppm, dd, J = 8.1, 1.0 Hz) and H21 (7.06 ppm, t, J = 8.1 Hz).
8k,9k
B
<1:99
72
methoxyphenyl
This possibility is supported by the fact that the aromatic B ring
protons H14 and H16 are magnetically equivalent (7.35 ppm, d, J =
8.1 Hz), as is H15 (7.20 ppm, t, J = 8.1 Hz), indicating a C11-C12
free bond rotation.
[a] Determined by 1H NMR. [b] For the diastereoisomeric mixture.
Elucidation of the relative configuration of compounds 8/9
was achieved by 2D 1H NMR experiments (COSY and NOESY),
assigning the signals for the H4-H7 protons in the cyclohexene
moiety. In the case of 8h (Figure 2a), for example, the relative
configuration of the C7 methyl group was ascertained through the
measurement of the coupling constants of the H6 proton, the
signal of which (3.12 ppm) is a large-sized doublet of doublet
(dd, J = 11.2, 9.5 Hz). Hence, H6 has axial-axial couplings with
H5 and H7, meaning that the C7 methyl, C5 thiophenyl and C6
thiophenylacryloyl groups adopt an equatorial conformation.
This relative configuration was supported by
a NOESY
experiment, revealing cross peak/diagonal peak signals of H7
with H5 that indicate a spatial syn-axial relationship, leaving the
C5 thiophenyl and the C7 methyl groups in a syn-equatorial
relative configuration (Figure 2b).
For the isomer 9h, the signal of the H6 proton (3.74 ppm) is a
dd (J = 10.7, 5.6 Hz), suggesting an axial-axial relationship with
proton H5 and axial-equatorial relationship with H7. Therefore,
the C7 methyl group adopts an axial conformation. This was
confirmed as the NOESY experiment shows cross peak/diagonal
peak signals for a dipolar interaction of the C7 methyl group with
H5, reflecting a spatial syn-axial relationship between them.
Figure 3. ORTEP plot for 9i.
Figure 4. Compound 9k.
Chalcones 5a-g were also evaluated as dienophiles in the
Diels-Alder reaction with diene 3a under the conditions of
method
B (Table 1, entry 3), to afford a series of
tetrahydrobenzoxazol-2-ones 11/12 (Table 3). Interestingly, there
was a preference of these compounds for the endo versus exo
adduct, except with adducts 11/12c,d. The latter compounds have
a 4-methoxyphenyl group in R1 with endo/exo ratios close to 1:1,
revealing no clear preference for either of the isomers. General
endo preference could be explained by the change of the
cinnamoyl group at C6, present in compounds 8/9, thus changing
the steric repulsive effects and secondary orbital interactions
between diene and dienophile in the transition state during the
formation of compounds 11/12.32
Figure 2. a) Structures for compounds 8h and 9h b) NOESY
correlations for compounds 8h and 9h.
This structural assignment was further supported by an X-ray
diffraction crystallographic analysis of the major diastereoisomer
9i (Figure 3), in which the C7 methyl group showed a syn
relationship to the C6 cinnamoyl and an anti relationship to the C5
aryl groups.
The reaction led to results analogous to those for 8/9. The
products were characterized by 2D 1H NMR analysis (COSY and
NOESY) as a mixture of diastereoisomers 11/12. The reaction
was regioselective, leading only to ortho isomers (with the acyl
group at C6). The relative configuration of the adducts was
established by examining the H6 proton signal, which displayed
coupling constants and multiplicity similar to those found with
the same proton in 8/9. The NOESY experiment gave an
analogous finding regarding the syn spatial interactions. The
structure of the adducts was also confirmed by an X-ray
diffraction crystallography analysis for the minor diastereoisomer
11a (Figure 5).
All compounds in the 8/9 series displayed similar chemical
shifts and NMR patterns of multiplicity, as well as NOESY
spatial relationships. . For compound 9k, however, the chemical
shifts of protons H5 (4.41 ppm) and H6 (4.84 ppm) underwent a
stronger deshielding effect than that observed for other
compounds (ca. 3.50 and 3.70 ppm). This behavior may be
accounted for by a plausible restricted rotation of the C5 aryl ring,
leaving the chlorine atoms close to those protons as suggested by
1H NMR. In such a case, the paramagnetic anisotropic effect of
the chlorine atoms attached at the C19 and C23 atoms would alter
the magnetic environment of the protons at C5 and C6 (Figure 4).
As a consequence of the restricted rotation of the C5 aryl ring, the
aromatic protons H20 and H22 would become magnetically
nonequivalent, as was indeed shown by their signals with a
significant Δδ for H20 (7.16 ppm, dd, J = 8.1, 1.0 Hz), H22 (7.34

4
Tetrahedron
well as Luis Velasco, Javier Pérez, Hector Rios, María I. Chavez,
Beatriz Quiroz and Mario Alfredo Garcia Carrillo for technical
assistance. J.T. is a fellow of the EDI-IPN and COFAA-IPN
programs.
Table 3. Synthesized exo/endo tetrahydrobenzoxazol-2-ones
11/12.
5. References and notes.
Crystallographic data (excluding structure factors) for the structures in this
paper have been deposited with the Cambridge Crystallographic Data Centre
as supplementary publication nos. CCDC. Copies of the data can be obtained,
free of charge, on application to CCDC, 12 Union Road, Cambridge CB2
1EZ, UK, (fax: +44-(0)1223-336033 or e-mail: deposit@ccdc.cam.ac.Uk).
CCDC registry number for 8i/9i: 1033700. CCDC registry number for 11a:
1882393.
Ratio
Yield
Adducts
R1
R3
(%)[b]
11/12[a]
12:88
13:87
54:46
53:47
45:55
23:74
<1:99
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11a, 12a
11b, 12b
11c, 12c
11d, 12d
11e, 12e
11f, 12f
11g, 12g
4-methylthiophenyl
2,4-dichlorophenyl
4-methoxyphenyl
4-methoxyphenyl
phenyl
4-methylphenyl
4-methylphenyl
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phenyl
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62
56
93
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Figure 5 ORTEP plot for 11a.
3. Conclusions.
The synthesis is herein described, for the series of 5,6-
substituted 4,5,6,7-tetrahydrobenzoxazol-2-ones 8/9 and 11/12
via a highly regioselective Diels-Alder cycloaddition. The
endo/exo stereoselectivity of compounds 8/9 was dependent on
the solvent, polarity and substituents. An endo preference existed
when using the solvent with the strongest polarity and an exo
preference with the nonpolar solvent, except for the adducts
bearing C6-2,4-dichlorophenyl, C6-2-chlorophenyl or C6-2,3-
dimethoxyphenyl substituents. On the other hand, compounds
11/12 showed endo preference with the nonpolar solvent. The
adduct structures and relative configuration were established
through NMR spectroscopic and X-ray diffraction analyses.
Synthetic applications of these novel compounds are currently
underway, and the results will be reported in due time.
4. Acknowledgments.
Financial support from UAEMéx (project No.4512/2018/CI)
and CONACyT (postgraduate scholarship grant No. 401195) is
gratefully acknowledged. J.T. is thankful to the SIP/IPN (grant
20180198) and CONACYT (grant 178319) for financial support.
The authors would like to thank Dr. Davir González-Calderón,
M. en C. Nieves Zavala-Segovia, and Lizbeth Triana-Cruz
(CCIQS UAEMéx‒UNAM), Instituto de Química UNAM as
32. Fringuelli F, Taticchi A. The Diels-Alder Reaction: Selected Practical
Methods, John Wiley & Sons, 2002.

5
Highlights
 Synthesis of novel 4,5,6,7-
tetrahydrobenzoxazol-2-ones
 Highly regioselective Diels-Alder
cycloaddition
 The endo/exo stereoselectivity of
synthetized compounds was dependent
on the solvent, polarity and substituents.