m-Chloroperbenzoic acid-oxchromium (VI)-mediated cleavage of 2,4,5-trisubstituted oxazoles

Article abstract of DOI:10.1016/j.tetlet.2017.02.027

An array of 2-substituted-4,5-diphenyloxazoles were found to be cleaved to triacylamines and diacylamines (imides) using a reagent system composed of m-chloroperbenzoic acid (MCPBA) and 2,2′-bipyridinium chlorochromate (BPCC). The 2-alkyl-4,5-diphenyloxaz

Full text of DOI:10.1016/j.tetlet.2017.02.027

Accepted Manuscript
m-Chloroperbenzoic acid-oxchromium (VI)-mediated cleavage of 2,4,5-trisub-
stituted oxazoles
Pravin C. Patil, Frederick A. Luzzio
PII:
S0040-4039(17)30196-X
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.02.027
TETL 48638
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Accepted Date:
18 January 2017
9 February 2017
Please cite this article as: Patil, P.C., Luzzio, F.A., m-Chloroperbenzoic acid-oxchromium (VI)-mediated cleavage
of 2,4,5-trisubstituted oxazoles, Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.02.027
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Fonts or abstract dimensions should not be changed or altered.
m-Chloroperbenzoic acid-oxochromium (VI)-
Leave this area blank for abstract info.
mediated cleavage of 2,4,5-trisubstituted oxazoles
Pravin C. Patil and Frederick A. Luzzio*
O
O
N
R1
R1
R2
O
R1
O
N
O
BPCC
R3
N
O
+
MCPBA
R3
R2
H
R3
R1, R2=Ph, R3=Ar,
alkyl, cycloalkyl
R1, R2=Ph, R3=Ar
(62-71%)
R1=Ph, R3=alkyl, cycloalkyl
(38-60%)

Tetrahedron Letters
m-Chloroperbenzoic acid-oxchromium (VI)-mediated cleavage of 2,4,5-trisubstituted
oxazoles
Pravin C. Patil and Frederick A. Luzzio
Department of Chemistry, University of Louisville, 2320 South Brook Street, Louisville, Kentucky 40292 USA
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An array of 2-substituted-4,5-diphenyloxazoles were found to be cleaved to triacylamines and
diacylamines (imides) using a reagent system composed of 3-chloroperbenzoic acid (MCPBA)
and 2,2'-bipyridinium chlorochromate (BPCC). The 2-alkyl-4,5-diphenyloxazoles give imides
(38-60%) as the predominant cleavage product while the 2-aryl-4,5-diphenyloxazoles give
triacylamines (44-71%). Two mechanisms involving intermediates such as cyclic endoperoxides
or oxachromacycles were proposed. An application of the oxidative cleavage to the multi-step
synthesis of (±)-phoracantholide I seco acid is detailed.
Available online
Keywords:
cleavage
oxazoles
2016 Elsevier Ltd. All rights reserved.
oxochromium (VI)
peroxides
triacylamines
groups are benzoyl.6 The remaining acyl group is derived from
the 2-oxazole substituent and is incorporated in the target
molecule where it can ultimately be transformed to a carboxylic
acid, amide, ester or lactone. Our recent work with the
preparation and utilization of 4,5-diphenyl-2-extended oxazoles
as fundamental synthetic scaffolds has prompted us to examine
and expand the available options for the conversion of the 2-
substituted-4,5-diphenyloxazole group to the ‘corresponding’
carboxylic acid derivative(s) (Scheme 1).7 We demonstrate
1. Introduction
In principle, an entire natural product synthesis may be
designed around the 2-substituted 4,5-diaryloxazole framework
whereby the oxazole functions as a masked carboxylic acid
component. The oxazole synthons can be elaborated through
nucleophilic or electrophilic reactions and these reactions can be
of sufficient mildness or robustness to allow application at either
the beginning or end of the synthesis.1,2 Once the unmasking or
otherwise deprotection of the carboxylic acid moiety is
warranted, a number of options should be available to
accommodate formation and isolation of a potentially sensitive
product. A prime example of all the above points is the utilization
of the 4,5-diaryloxazole framework in the total synthesis of
oasomycin as reported by the Evans group.3 The oxazole,
functioning as a masked carboxylic acid equivalent, was brought
through several carbon-carbon bond-forming reactions,
protections and deprotections, and then finally unveiled using a
singlet oxygen cleavage.4 A number of earlier natural products
syntheses using a similar overall strategy are described in the
Wasserman review.2 For the oxidative cleavage of 2,4,5-
trisubstituted oxazoles in general, a number of options are
available and may be applied to diverse substrates depending on
the presence of other functional groups.5 A product which is
common to most 2-substituted-4,5-diphenyloxazole oxidative
herein a new method for oxidative cleavage of the title
trisubstituted oxazoles using a readily-available reagent system
composed of a peroxide (m-chloroperbenzoic acid, MCPBA),
and an oxochromium (VI) reagent (2,2-bipyridinium
chlorochromate, BPCC).8 The two-component reagent system is
operationally simple and utilizes components which are readily-
available and inexpensive. While taken individually or together,
the oxochromium (VI) and peroxide reagents represent rather
robust reactants, the reagent system appears to be compatible
cleavage reactions is the triacylamine whereby two of the acyl
———
 Corresponding author. Tel.: +1-502-852-7323; fax: +1-502-852-8149; e-mail: faluzz01@louisville.edu

with a range of oxazole substrates. The reactions are fairly rapid
and provide the pure triacylamines or diacylamines (imides) after
column chromatography on silica gel. We should note that while
singlet oxygen has been the reagent of choice for the
oxazole→triamide transformation, the employment of a ceric
ammonium nitrate/water (CAN/H2O) reagent system was also
disclosed by the Evans group as an alternative method albeit a
viable one in total synthesis.5b By comparison, we feel that the
BPCC/MCPBA is an additional alternative to the singlet oxygen
or CAN-mediated methods.
that in contrast to some previously-reported BPCC/peroxide-
mediated oxidations,10 which utilized only a catalytic amount of
oxochromium reagent, a full two equivalents is required in the
reaction reported herein.
In terms of general mechanism, the generation of
peroxychromium (VI) species from peroxides and oxochromium
(VI) has been reported (Scheme 2, Path A).11 The reactions occur
Path A. Singlet oxygen/endoperoxide pathway:
BipyH+CrO3Cl-
+
RCOOOH
=
CrO5 + BipyHCl + RCOOH
The reaction conditions employed for the oxidative cleavage
were established using the benchmark substrate 2,4,5-
triphenyloxazole 1 (Table 1).9 In a typical procedure, two
equivalents of BPCC and five equivalents of MCPBA in
dichloromethane were used, and as the reaction proceeds, the less
chromatographically-mobile triacylamine 10 could be detected
by thin-layer chromatography (TLC). The reaction mixtures were
yellow-orange heterogeneous suspensions with BPCC being the
only partially insoluble component. Application of the same
conditions to a number of 2-substituted-4,5-diphenyloxazole
substrates 2-9, differing only in substitution at the 2-position of
the oxazole, gave the products 10-18 as listed in Table 1.
Interestingly, the diacylamine (imide) products 15-18 were
formed during the reaction of the 2-alkyl-4,5-diphenyloxazole
substrates 6-9, while the triacylamine products 10-14 were
formed from the 2-(aryl-substituted) substrates 1-5 respectively.
Control reactions which utilized the same solvent and either the
peroxyacid or the chromium reagent alone did not facilitate the
cleavage. Moreover, the substitution of the less expensive and
more shelf-stable pyridinium chlorochromate (PCC) for BPCC,
using the same ratio of reagents, resulted in vigorous
decomposition of the peroxide and did not provide the title
products. The best results were obtained with freshly-prepared,
dried BPCC or reagent which was not more than a few weeks
old, stored under nitrogen and protected from light. We will note
=
CrO5
CrO3
+
1O2
Ph
Ph
Ph
N
N
Ph
R1
R1
+
1O2
O
O
O
O
I
1-9
Ph
O
R1
O
Ph
O
N
N
Ph
R1
Products
O
Ph
O
O
III
Path B. Oxachromacycle pathway:
Ph
N
Ph
R1
O
CrO3Cl-
O
III
1-9
O
O
O
RCOOOH
O
Cr
R
O
Products
II
Scheme 2. Mechanistic pathways of trisubstituted oxazole
cleavage.

under homogeneous conditions in organic solvents, and the
generation of the highly-reactive peroxychromate species is
characterized by an intense transient deep-blue color. In turn,
thermal decomposition of the short-lived peroxychromium
species is known to generate singlet oxygen which is an
established reactant in trisubstituted oxazole cleavage and results
in intermediate endoperoxide I.5a Through multiple pathways,
including rearrangement of I and acyl migration through the
acyliminoester III, the oxidative cleavage then results in the
formation of the tri- and diacylamine products 10-18.5a As the
reaction conditions are heterogeneous and exhibit the yellow-
orange color due to BPCC, it is difficult to detect the
characteristic deep-blue color of peroxychromate and confirm
Path A.12 A second mechanistic consideration (Scheme 2, Path
B) involves delivery of oxygen to the heterocycle via the
intermediate oxachromacycle II.13a Similar intermediates have
been proposed in the oxidative cleavage of 2,5-disubstituted
furans to enediones by oxochromium (VI) as exemplified by
BPCC and PCC.13b, 14 Rearrangement of II, then gives reduced
chromium species, m-chlorobenzoic acid and the common
intermediate III, which in turn, rearranges to products 10-18.
72%). The oxazole-alcohol 23 was submitted to the oxidative
cleavage reaction with the hopes that the expected amide or
imide cleavage products would lactonize directly to 27. However,
the oxidation of the secondary alcohol 23 to the corresponding
methyl ketone 28 predominated over a lengthy (16 h) reaction
period. Treatment of oxazoleacetate 24 with MCPBA/BPCC
(2eq/5eq, 5 ºC→20 ºC, CH2Cl2) gave acetoxyimide 25 (40%).
Finally, hydrolysis of the acetoxyimide 25 (NaOH/MeOH) and
adjustment of the reaction mixture to pH=2 provided the (±)-seco
acid 26 (88%).
In summary, we have detailed a new method for the oxidative
cleavage of 2-substituted-4,5-diphenyl oxazoles to triacylamines
and diacylamines. The method is a complementary or otherwise
alternative one to the well-established method of
photolysis/singlet oxygen and utilizes readily-available reagents.
The substrates having alkyl groups at the 2-position give the
imide products while substrates having aryl groups at the 2-
position give the triacylamines. Using the 4,5-diphenyl-2-
(phenylsulfonylmethyl) oxazole group as a synthon, the oxazole
served as a masked carboxylic acid equivalent in our synthesis
of phoracantholide I seco acid. Ultimately, the oxidative cleavage
was a key step in the seco acid synthesis, but the stability of the
We demonstrate the practical utility of our oxidative cleavage
reaction by the synthesis of (±)-phoracantholide I seco-acid 26,
the acyclic precursor to the macrocyclic lactone, phoracantholide
I (27, Scheme 3) which is a naturally-occuring component of
insect pheromones.15 The synthesis of 26 starts with the key 2-
(phenylsulfonylmethyl)-4,5-diphenyloxazole 19 (Scheme 3). The
diphenylsulfonylmethyloxazole 19 is alkylated with 8-bromo-1-
octene in the presence of potassium tert-butoxide (THF/5 ºC to
rt) which affords the 2-nonenyl-2-(phenylsulfonyl methyl)-4,5-
diphenyl-oxazole 20 in 66% yield. The phenylsulfonyl group of
20 was then removed under reductive conditions
(Mg/HgCl2/MeOH) to give the 2-nonenyloxazole 21 (79%).
Epoxidation of the olefinic oxazole 21 using 30% hydrogen
peroxide in the presence of DCC (KHCO3/MeOH) provided the
epoxynonanyloxazole 22 (85%). Interestingly, during the
conversion of 21→22 the 4,5-diphenyloxazole moiety was not
affected by the peroxide, even after extended reaction periods.
4,5-diphenyloxazole
magnesium/HgCl2, hydrogen peroxide and lithium aluminum
hydride was also demonstrated.
group
to
reagents
such
as
Acknowledgments
The measurement of high and low resolution mass spectra by
the Mass Spectrometry Laboratory, Department of Chemistry and
Biochemistry, University of South Carolina is acknowledged.
Financial Support from the NIH/NIDCR through grant
1RO1DE023206 is gratefully acknowledged.
Supplementary Material
General procedures and supplementary data (FTIR, 1H NMR,
13C NMR) for compounds 5, 10-18, 20-16 and HRMS data for
new compounds 5, 12, 14, 20-25 associated with this article can
be found, in the online version, at http://dx.doi.org/
00.1017/j.tetlet.
References and notes
1.
2.
3.
4.
5.
Boyd, G. V. In Science of Synthesis Vol 11 Schauman, E. Ed.
Thieme, Stuttgart, 2002, 383-479.
Wasserman, H. H.; McCarthy, K. E.; Prowse, K. S. Chem. Rev.
1986, 86 , 845-856.
(a) Evans, D. A.; Nagorny, P.; Reynolds, D. J.; McRae, K. J.
Angew. Chem. Int. Ed. Eng. 2007, 46, 541-544.
Wasserman, H. H.; Gambale, R. J. J. Am. Chem. Soc. 1985, 107,
1423-1424.
For oxidation of 2,4,5-trisubstituted oxazoles see: (a) Pickett, J. E.
Tetrahedron Lett. 2015, 56, 3023-3026. (b) Evans, D. A.;
Nagorny, P.; Wu, R. Org. Lett. 2006, 8, 5669-5671. (c) Gollnick,
K.; Koegler, S. Tetrahedron Lett. 1988, 29, 1007-1010. (d)
Gollnick, K.; Koegler, S. Tetrahedron Lett. 1988, 29, 1003-1006.
(e) Graziano, M. L.; Iesce, M. R.; Scarpati, R. J. Heterocyclic
Chem. 1978, 15, 1205-1207. (f) Graziano, M. L.; Carotenuto, A.
T.; Iesce, M. R.; Scarpati, R. J. Heterocyclic Chem. 1977, 14,
1215-1219. (g) Graziano, M. L.; Iesce, M. R.; Scarpati, R.
Synthesis 1977, 572-573. (h) Graziano, M. L.; Iesce, M. R.;
Exposure of the epoxynonyloxazole 22 to excess lithium
aluminum hydride in THF (0→10 ºC) afforded the oxazolynonyl
secondary alcohol 23 (80%) which was first characterized as the
corresponding acetate 24 (acetic anhydride/triethylamine/DMAP,

Carotenuto, A.; Scarpati, R. J. Heterocyclic Chem. 1977, 14, 261-
265. (i) Terent’ev, P. B.; Lomakina, N. P. Chemistry of
Heterocyclic Compounds 1976, 12, 483-500. (j) Wasserman, H.
H.; Druckey, E. J. Am. Chem. Soc. 1968, 90, 2440-2441.
Luzzio, F. A. In Science of Synthesis Vol 21 Weinreb, S. M. Ed.
Thieme, Stuttgart, 2005, 259-324.
(a) Patil, P. C.; Luzzio, F. A. J. Org. Chem. 2016, 81, 10521-
10526. (b) Patil, P. C.; Luzzio, F. A. Tetrahedron Lett. 2016, 57,
757-759. (c) Patil,, P. C.; Luzzio, F. A.; Demuth, D. R.
Tetrahedron Lett. 2015, 56, 3039-3041.
(a) Luzzio, F. A.; Zacherl, D. P. Tetrahedron Lett. 1999, 40,
2087-2090. (b) Luzzio, F. A.; Bobb, R. A. Tetrahedron Lett. 1997,
38, 1733-1736. (c) For a more recent application of 2,2'-
bipyridinium chlorochromate, See: Dempster, R. K.; Luzzio, F. A.
Tetrahedron Lett. 2011, 52, 4992-4995.
The substrates 1-9 were prepared from an array of benzoin esters
using a previously described method which entails the treatment
of the esters with ammonium acetate in acetic acid. The yields of
the substrate oxazoles 1-19 (Table 1) were 23-98% (See
Supplementary Material).
11. (a) Cotton, F. A.; Wilkinson, G. in Advanced Organic Chemistry,
3rd Ed.; John Wiley and Sons: New York, NY, 1972; pp 842-844.
(b) Zhang, L.; Lay, P. Inorg. Chem. 1998, 37. 1729-1733.
12. Muzart, J. Chem. Rev. 1992, 92, 113-140.
13. (a) Piancatelli, G.; Scettri, A.; D’Auria, M. Tetrahedron 1980, 36,
661-663. (b) Wu, H.-J.; Pan, K. J. Chem. Soc. Chem. Commun.
1987, 898-899.
14. Gunn, B. P; Brooks, D. W. J. Org. Chem. 1985, 50, 2218-4420.
15. (a) Avocetien, K. F.; Li, J. J.; Liu, X.; Wang, Y.; Xing, Y.;
O’Doherty, G. A. Org. Lett. 2016, 18, 4970-4973. (b) Datrika, R.;
Kallam, S. R.; Khobare, S. R.; Gajare, V. S.; Kommi, M.; Mohan,
R. H.; Vidavalur, S.; Pratap, T. V. Tetrahedron: Asymmetry 2016,
27, 603-607. (c) Sharma, A.; Chattopadhyay, S. Molecules 1998,
3, 44-47. (d) Saikia, A. K.; Hazarika, M. J.; Barua, N. C.;
Bezbarua, M. S.; Sharma, R. P.; Ghosh, A. C. Synthesis 1996, 8,
981-985. (e) Ohnuma, T.; Hata, N.; Miyachi, N.; Wakamatsu, T.;
Ban, Y. Tetrahedron Lett. 1986, 27, 219-222. (f) Suginome, H.;
Yamada, S. Tetrahedron Lett. 1985, 26, 3715-3718. (g) Mahajan,
J. R.; de Araujo, H. C. Synthesis 1981, 1, 49-51.
6.
7.
8.
9.
10. Barrett, A. G. M.; Blaney, F.; Campbell, A. D.; Hamprecht, D.;
Meyer, T.; White, A. J. P.; Witty, D.; Williams, D. J. J. Org.
Chem. 2002, 67, 2735-2750.
Click here to remove instruction text...

Highlights
 A new method for the oxidative
cleavage of 2,4,5-trisubstituted
oxazoles to imides and
triacylamines is detailed.
 The oxidation system utilizes a dual
reagent system composed of a
peroxide and oxochromium (VI).
 Mechanisms are proposed for the
oxidative cleavage reaction.
 A synthesis of (±)-phoracantholide
seco-acid is detailed which utilizes
the oxidative cleavage reaction to
ultimately give a carboxyl function
through the product imide.