Highly regio- and diastereoselective oxazol-5-one addition to nitrostyrenes

Article abstract of DOI:10.1002/ejoc.200801005

A convenient and novel oxazol-5-one addition to nitrostyrenes is reported. The reaction is catalyzed by tertiary amines and yields the corresponding adducts with total regio- and diastereoselectivity. The addition exclusively takes place at the C-2 positi

Full text of DOI:10.1002/ejoc.200801005

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200801005
Highly Regio- and Diastereoselective Oxazol-5-one Addition to Nitrostyrenes
Andrea-Nekane Balaguer,[a] Xavier Companyó,[a] Teresa Calvet,[b] Mercé Font-Bardía,[b]
Albert Moyano,*[a] and Ramon Rios*[a][‡]
Keywords: Diastereoselective catalysis / Organocatalysis / Heterocycles / Michael addition / Nitrostyrenes / N,O-Aminals
A convenient and novel oxazol-5-one addition to nitrosty-
renes is reported. The reaction is catalyzed by tertiary amines
and yields the corresponding adducts with total regio- and
diastereoselectivity. The addition exclusively takes place at
the C-2 position of oxazol-5-ones, furnishing diastereopure
N,O-aminals.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
ence at the position that undergoes the addition; only when
strong electron-withdrawing groups are present in position
2 of the oxazol-5-one ring, such as a trifluoromethyl group,
the addition predominantly occurs in position 2.[4]
During the preparation of this work, Jørgensen reported
a very elegant synthesis of α,α-disubstituted amino acid de-
rivatives that relies on the racemic oxazol-5-ones Michael
addition to α,β-unsaturated aldehydes, catalyzed by chiral
secondary amines.[5] In this case, the reaction is C-4-spe-
cific.
On the other hand, when extremely electron-poor
Michael acceptors such as acrylonitrile, fumaric and maleic
esters and the corresponding dinitriles are used, exclusively
C-2 of 2,4-disubstituted oxazol-5-ones reacts. Surprisingly,
to the best of our knowledge, there are no examples of ox-
azol-5-one additions to nitrostyrenes in the literature. With
this chemo-information in mind, we decided to study the
addition of oxazol-5-ones 2 to nitrostyrenes 1[6] in order to
evaluate the regioselectivity and diastereoselectivity of the
process (Scheme 2).
Introduction
The discovery of new reactions that allow us to build
complex molecular scaffolds in an efficient way from readily
available starting materials remains a challenging goal in
chemical synthesis. The stereocontrolled construction of
quaternary stereocenters is one of the most difficult chal-
lenges for synthetic chemists nowadays. Consequently,
asymmetric processes that are able to build quaternary car-
bons have been the subject of intense research in recent
years.[1]
The use of oxazol-5-ones as nucleophilic reactants in
Michael additions has hitherto hardly been studied. Since
oxazol-5-one anions are ambifunctional (Scheme 1), they
can react with activated electrophilic compounds either at
C-2, at C-4 or at the exocyclic oxygen.
Scheme 1. Deprotonated oxazol-5-one.
The most common way to react is at C-4 of the oxazol-
5-one.[2] However, as is already known, the site of the reac-
tion is determined primarily by the kind of activated double
bond.[3] In fact, the nature of oxazol-5-one has little influ-
[a] Departament de Química Orgánica, Universitat de Barcelona,
Martí i Franqués 1–11, 08028 Barcelona, Spain
Fax: +34-933397878
E-mail: rios.ramon@icrea.cat
amoyano@ub.edu
[b] Departament de Cristal·lografia, Mineralogia i Dipòsits
Minerals, Universitat de Barcelona,
Scheme 2. Oxazol-5-one addition to nitrostyrenes.
Martí i Franquès s/n, 08028 Barcelona, Spain
[‡] Dr. Ramon Rios ICREA researcher at University of Barcelona.
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
When the attack takes place at C-2 the obtained com-
pound 4 is a N,O-aminal. These compounds are structural
motifs found in a number of interesting natural products
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A. Moyano, R. Rios et al.
SHORT COMMUNICATION
and pharmaceuticals. For example, chiral N,O-subunits are compound from the reaction was the product obtained by
found in important natural products like zampanolide,[7] the addition at C-2 of the oxazol-5-one ring, according to
echinocandin B, spergualin, tallysomycin, mycalamalide his spectral properties. Remarkably, no addition at C-4 was
A,[8] and other compounds in the peredin[9] family along detected by NMR of the crude reaction, showing the total
with important targets like psymberin[10] The stereochemi- regioselectivity of the process. The reaction does not work
cal relevance of this motif to biological activity is significant without base or with inorganic bases such as NaHCO3,
and well-known as evidenced through cytotoxicity studies
against various human tumor cell lines by De Brabander
with psymberin and by others in the pederin/mycalamide
series.[11]
Table 2. Solvent screening.[a]
Another important aspect of the chiral N,O-aminal sub-
unit is that it represents a particularly difficult synthetic
challenge that had to be addressed in the previous prepara-
tive studies.[9]
Although some elegant methods were developed to con-
struct N,O-aminals, the preparation of chiral N,O-aminals
via asymmetric catalysis is practically unknown. Only very
recently Antilla and co-workers reported an elegant alcohol
addition to imines, catalyzed by chiral phosphoric acids.[12]
Herein, we will report a new organocatalytic approach
to the diastereoselective addition of oxazol-5-ones to nitro-
styrenes, showing that racemic 4-alkyl-2-phenyloxazol-5-
ones only react at position C-2, giving the corresponding
pseudooxazol-5-ones 4 in high yields.
In initial experiments, we screened different bases for the
reaction between β-phenylnitrostyrene 1a and oxazol-5-one
2a.[13] To our delight, when we carried out the reaction with
Et3N in CH2Cl2, we achieved high yield, regioselectivity
and diastereoselectivity (entry 1, Table 1). The only isolated
[a] Experimental conditions: A mixture of 2a (0.30 mmol), Et3N
(0.025 mmol) and 1a (0.25 mmol) in the desired solvent (5 mL) was
stirred at room temperature overnight. Crude product 4a was puri-
fied by column chromatography. [b] Determined by NMR analysis
of crude reaction. [c] Determined by NMR analysis of crude reac-
tion.
Table 1. Base screening.[a]
Table 3. Oxazol-5-one scope.[a]
[a] Experimental conditions: A mixture of 2a (0.30 mmol), base
[a] Experimental conditions: A mixture of 2a–d (0.30 mmol), Et3N
(0.025 mol), 1a (0.25 mmol) in CH2Cl2 (5 mL) was stirred at room (0.025 mmol) and 1a (0.25 mmol) in toluene (5 mL) was stirred at
temperature overnight. Crude product 4a was purified by column
chromatography. [b] Determined by NMR analysis of crude reac-
tion. [c] Determined by NMR analysis of crude reaction.
room temperature overnight. Crude product 4a–d was purified by
column chromatography. [b] Isolated yield. [c] Determined by
NMR analysis of crude reaction. [d] Reaction run in AcOEt.
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Highly Selective Oxazol-5-one Additions to Nitrostyrenes
K2CO3 or KOAc (entries 2, 3, 4 and 5, Table 1). With bulk- Table 4. Nitrostyrene scope.[a]
ier organic bases such as cinchonidine[14] or DABCO, the
diastereoselectivity decreases but the regioselectivity is ab-
solute (entries 6 and 7; Table 1).
Next, we decided to screen different solvents in order to
increase the diastereoselectivity of the process; as the base
catalyst we choose Et3N, which gave the best results. Inter-
estingly enough, when the reaction was performed in tolu-
ene, THF and AcOEt (entries 2, 3 and 4; Table 2) we could
only detect one diastereomer by NMR spectroscopy. As ex-
pected, when the reaction was carried out in MeOH the
addition did not take place because of extensive decomposi-
tion of the oxazol-5-one 2a.
Then, we decided to study the scope of the reaction using
different oxazol-5-ones 2a–d. We decided to run the reac-
tion in toluene and using triethylamine as a base catalyst.
Fortunately, we achieved high levels of diastereoselectivity
and excellent yields in all the entries. When oxazol-5-ones
with R = iPr, iBu or tBu were used (entries 1, 3 and 5;
Table 3), the reaction afforded only one diastereomer by
NMR spectroscopy. Only when the methyl-substituted ox-
azol-5-one 2b was used, the diastereomeric ratio decreased
to 13:1.
Next, we studied the scope of the reaction using different
nitrostyrenes. To our delight, when oxazol-5-one 2a was
treated with nitrostyrenes 1a–e in toluene using 10 mol-%
of Et3N, in the whole set of examples, we only obtained
one diastereomer, with total regioselectivity and in excellent
yields. Remarkably, the use of different substituents in the
phenyl ring does not affect the outcome of the reaction.
Moreover, the presence of electron-withdrawing groups
such as fluoro (entries 3 and 5; Table 4) or of electron-
[a] Experimental conditions: A mixture of 2a (0.30 mmol), Et3N
(0.025 mmol) and nitrostyrene 1a–e (0.25 mmol) in toluene (5 mL)
was stirred at room temperature overnight. Crude product 4a, e–
h was purified by column chromatography. [b] Isolated yield. [c]
Determined by NMR analysis of crude reaction.
Figure 1. X-ray structure of the major diastereomer of 4b.
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A. Moyano, R. Rios et al.
SHORT COMMUNICATION
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donating groups like methoxy or methyl (entries 2 and 4)
does not have any influence on the diastereoselectivity or
yield of the reaction.
[2]
Examples of oxazol-5-one reactions: a) J. Liang, J. C. Ruble,
G. C. Fu, J. Org. Chem. 1998, 63, 3154–3155; b) A. Berkessel,
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In order to confirm the regioselectivity and to ascertain
the stereochemistry of the nitro compounds obtained, an
X-ray diffraction of the major isomer of 4b was per-
formed.[15] As shown in Figure 1, the crystal structure of
this compound confirms the previously assigned regiochem-
istry and shows that the relative configuration is S*,S*.
Finally, acidic hydrolysis of compound 4a furnishes the
ketone 5a[16] (Scheme 3) in excellent yield. This reaction can
be used as a 2C-homologation of nitro compounds. The
preparation of 1-nitro-3-keto compounds represents for-
mally an umpolung reaction between benzoyl chloride and
nitroalkenes that is fairly difficult to achieve.
[3]
[4]
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[5]
[6]
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Scheme 3. Hydrolysis of compound 4a.
A working mechanistic hypothesis that can account for
the observed regio- and diastereoselectivity of the process
is depicted on Figure 2, and involves the formation of a
hydrogen bond between the oxazol-5-one carbonyl oxygen
and the nitro group.
[8]
[9]
[10]
[11]
[12]
[13]
X. Jiang, N. Williams, J. K. DeBrabander, Org. Lett. 2007, 9,
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130, 12216–12217.
For the synthesis of oxazol-5-ones see: a) A. Llinás, N. Ahmed,
M. Cordaro, A. P. Laws, J. M. Frère, M. Delmarcelle, N. R.
Silvaggi, J. A. Kelly, M. I. Page, Biochemistry 2005, 44, 7738–
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Figure 2. Proposed transition state for oxazol-5-one addition.
In summary, we have developed a highly chemo-, regio-
and diastereoselective addition of oxazol-5-ones to nitrosty-
renes. The reaction is efficiently catalyzed by commercially
available tertiary amines and gives the corresponding pseu-
dooxazol-5-ones 4 in high yields and with up to Ͼ25:1 dia-
stereomer ratio. Mechanistic studies, synthetic applications,
a suitable chiral version of this new methodology and the
discovery of new reactions based on this concept are ongo-
ing in our laboratory.
[14]
[15]
In an initial experiment (–)-cinchonidine catalyzed the organo-
catalytic addition of oxazol-5-one 2a to nitrostyrene 1a in 94%
yield; diastereoselective ratio 10:1, ee = 30 %.
X-ray difraction of 4b: A prismatic crystal (0.1ϫ0.1ϫ0.2 mm)
was selected and mounted on a MAR345 diffractometer with
an image plate detector. Unit-cell parameters were determined
from 209 reflections (3 Ͻ θ Ͻ 31°) and refined by least-squares
method. Intensities were collected with graphite-monochro-
matized Mo-Kα radiation. 12257 reflections were measured in
the range 2.59°ՅθՅ30.29°. 4033 of which were non-equiva-
lent by symmetry [Rint(on I) = 0.046]. 3412 reflections were
assumed as observed applying the condition IϾ2σ(I). Lorentz
polarization but no absorption corrections were made. The
structure was solved by Direct methods, using SHELXS com-
puter program (G. M. Sheldrick, A program for automatic solu-
tion of crystal structure, University of Göttingen, Germany,
1990) and refined by full-matrix least-squares method with
SHELX97 computer program (G. M. Sheldrick, A program for
crystal structure refinement, University of Göttingen, Germany,
1997), using 12257 reflections, (very negative intensities were
not assumed). The function minimized was Σw||Fo|2 – |Fc|2|2,
where w = [σ2(I) + (0.0857P)2 + 0.0102P]–1, and P = (|Fo|2 +
2 |Fc|2)/3, f, fЈ and fЈЈ were taken from International Tables of
X-ray Crystallography (International Tables of X-ray Crystal-
Supporting Information (see also the footnote on the first page of
this article): Experimental procedure and crystallographic data of
4b.
Acknowledgments
We thank the Spanish Ministry of Science and Education for finan-
cial support (Project AYA2006-15648-C02-01), and Albert Puig-
pinós for the synthesis of starting materials.
[1] For reviews in this topic see: a) K. Fuji, Chem. Rev. 1993, 93,
2037–2066; b) E. J. Corey, A. Guzmán-Pérez, Angew. Chem.
202
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Highly Selective Oxazol-5-one Additions to Nitrostyrenes
lography, Kynoch Press, 1974, vol. IV, pp. 99–100 and 149). All
H atoms were computed and refined, using a riding model,
with an isotropic temperature factor equal to 1.2 time the
equivalent temperature factor of the atom which are linked.
The final R(on F) factor was 0.056, wR(on |F|2) was 0.063 and
goodness of fit was 1.139 for all observed reflections. The
number of refined parameters was 219; max. shift/esd = 0.00,
mean shift/esd = 0.00; max. and min. peaks in final difference
synthesis was 0.373 and –0.264eÅ–3, respectively. CCDC-
705916 contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.
ac.uk/data_request/cif.
For an alternative synthesis, starting with cyanohydrins: S. A.
Ferrino, L. A. Maldonado, Synth. Commun. 1980, 10, 717–723.
Received: October 15, 2008
[16]
Published Online: December 2, 2008
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