Unexpected C-C bond cleavage: Synthesis of 1,2,4-oxadiazol-5-ones from amidoximes with pentafluorophenyl or trifluoromethyl anion acting as leaving group

Article abstract of DOI:10.1021/ol202554m

An unexpected C-C bond cleavage has been observed on pentafluorobenzoylamidoximes under mild basic conditions. This observation has been exploited to develop a new synthesis of 1,2,4-oxadiazol-5-ones from amidoximes using pentafluorobenzoyl chloride or trifluoroacetic anhydride (TFAA) as a double acylating agent. The pentafluorophenyl anion and the trifluoromethyl anion acted as leaving groups in this transformation.

Full text of DOI:10.1021/ol202554m

ORGANIC
LETTERS
2011
Vol. 13, No. 23
6172–6175
Unexpected CÀC Bond Cleavage: Synthesis
of 1,2,4-Oxadiazol-5-ones from Amidoximes
with Pentafluorophenyl or Trifluoromethyl
Anion Acting as Leaving Group
Thibaud Gerfaud,† Hai-Long Wei,† Luc Neuville,*,† and Jieping Zhu*,†,‡
Centre de Recherche de Gif, Institut de Chimie des Substances Naturelles, CNRS, 91198
Gif-sur-Yvette Cedex, France, and Institut of Chemical Sciences and Engineering,
ꢀ ꢀ
Ecole Polytechnique Federale de Lausanne, EPFL-SB-ISIC-LSPN,
CH-1015 Lausanne, Switzerland
jieping.zhu@epfl.ch; luc.neuville@icsn.cnrs-gif.fr
Received September 21, 2011
ABSTRACT
An unexpected CÀC bond cleavage has been observed on pentafluorobenzoylamidoximes under mild basic conditions. This observation has
been exploited to develop a new synthesis of 1,2,4-oxadiazol-5-ones from amidoximes using pentafluorobenzoyl chloride or trifluoroacetic
anhydride (TFAA) as a double acylating agent. The pentafluorophenyl anion and the trifluoromethyl anion acted as leaving groups in this
transformation.
CarbonÀCarbon bond breaking is an important toolkit
for modifying and elaborating molecular structures. How-
ever, such chemical transformations are usually difficult to
achieve because of the inherent CÀC bond strength.1
Nevertheless, a number of powerful reactions involving
CÀC bond cleavage as a key step are known such as the
Grob fragmentations,2 ‘‘retro’’ processes (retroaldol,3
retro-DielsÀAlder,4 retro-allylation5), [3,3]-sigmatropic
rearrangements,6 etc. Recently, powerful metal catalyzed
CÀC bond cleavage/bond-reorganization processes have
been developed that hold tremendous promise in organic
synthesis.7
† Centre de Recherche de Gif, Institut de Chimie des Substances Naturelles,
France.
‡ Institut of Chemical Sciences and Engineering, Ecole Polytechnique
ꢀ ꢀ
Federale de Lausanne, Switzerland.
Ketones are frequently found in CÀC bond cleavage
technologies, ozonolysis, BaeyerÀVilliger,8 haloform,9,10
and HallerÀBauer reactions11 being prominent examples.
Decarboxylation has been abundantly used in synthesis, and
recent metal-catalyzed decarboxylative functionalization
(1) Sattler, A.; Parkin, G. Nature 2010, 463, 523–526.
(2) For a review, see: Prantz, K.; Mulzer, J. Chem. Rev. 2010, 110,
3741–3766.
(3) Quesnel, Y.; Toupet, L.; Duhamel, L.; Duhamel, P.; Poirier, J. M.
Tetrahedron: Asymmetry 1999, 10, 1015–1018.
(4) (a) Kwart, H.; King, K. Chem. Rev. 1968, 68, 415–447. (b) Stajer,
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(10) For selected recent procedures, see: (a) Nicolaou, K. C.; Adsol,
V. A.; Hale, C. R. H. Org. Lett. 2010, 12, 1552–1555 and reference cited
herein. (b) Wang, A.; Jiang, H. J. Org. Chem. 2010, 75, 2321–2326.
(c) Miyamoto, K.; Sei, Y.; Yamaguchi, K.; Ochiai, M. J. Am. Chem. Soc.
2009, 131, 1382–1383 and references cited therein.
(11) (a) For a review, see: Mehta, G.; Venkateswaran, R. V. Tetra-
hedron 2000, 56, 1399–1422. (b) For a recent example of an LDA
catalyzed HallerÀBauer reaction, see: Ishihara, K.; Yano, T. Org. Lett.
2004, 6, 1983–1986.
(7) For selected reviews, see: (a) Seiser, T.; Saget, T.; Tran, D. N.;
Cramer, N. Angew. Chem., Int. Ed. 2011, 50, 7740–7752. (b) Murakami,
M.; Matsuda, T. Chem. Commun. 2011, 47, 1100–1105. (c) Bonesi, S. M.;
Fagnoni, M. Chem.;Eur. J. 2010, 16, 13572–13589. (d) Necas, D.;
Kotora, M. Curr. Org. Chem. 2007, 11, 1566–1591. (e) Jun, C.-H.; Park,
J.-W. Top. Organomet. Chem. 2007, 24, 117–143. (f) Satoh, T.; Miura,
M. Top. Organomet. Chem. 2005, 14, 1–20. (g) Takahashi, T.; Kuzuba,
Y.; Kong, F.; Nakajima, K.; Xi, Z. J. Am. Chem. Soc. 2005, 127, 17188–
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870–883.
r
10.1021/ol202554m
Published on Web 11/03/2011
2011 American Chemical Society

processes have largely extended their utility.12 On the
contrary, CÀC bond breaking of esters are scarce.13
Indeed with such functional groups, cleavage of the CÀO
bonds usually prevails over alternative CÀC bonds since
oxygen is a better nucleofuge.
Table 1. Optimization of the Reaction Conditions
Scheme 1. Initial Observation
entry
base (equiv)
solvent
concn
time
1ab
4ab
1
2
3
4
5
6
Et3N (5)
DCM
0.05 M
0.05 M
0.05 M
0.05 M
0.2 M
18 h
18 h
18 h
18 h
18 h
18 h
34
22
83
0
62
69
10
83
69
66
Et3N (5)
MeCN
DCM
K2CO3 (5)
K2CO3 (5)
K2CO3 (5)
K2CO3 (5)
MeCN
MeCN
DMF
0
0.05 M
0
a Reactions were performed at room temperature under an argon
atmosphere. b Isolated yield.
Acyl oximes are prone to hydrolysis under basic condi-
tions leading to the corresponding oximes.16 However,
instead of hydrolysis or migration of the acyl residue to
the adjacent nitrogen via CÀO bond cleavage, the scission
of a CÀC bond occurred with concurrent release of a
pentafluorophenyl anion.17 Garner has recently shown
that when pentafluorobenzylic alcohol was treated under
strong basic conditions (NaOMe, DMSO), ketone was
produced via the elimination of pentafluorobenzene. In
their examples, the pentafluorophenyl anion was the best
leaving group possible relative to other alkyl residues.18
However, in ourcase, transacylation could in principle be a
competitive process if the reaction went through the inter-
mediate A (Scheme 1). Indeed intramolecular O- to N-acyl
transfer is a highly efficient synthetic transformation.
Intrigued by this unusual fragmentation and the fact that
1,2,4-oxadiazol-5(4H)-ones are known to be valuable het-
erocycles as masked amidines19 or as bioisoster of
amides,20,21 we decided to investigate in detail this unex-
pected transformation. In addition, we thought that it
might be possible to access oxadiazolones directly from
amidoximesina one-potfashion usingpentafluorobenzoyl
chloride as a double acylating agent. A rapid screening of
bases and solvents allowed us to select potassium carbo-
nate in acetonitrile at room temperature as the conditions
of choice for this process (entry 4, Table 1).
In the course of our study dedicated to palladium-
catalyzed annulation processes involving acyloximes,14
we attempted to synthesize benzimidazoles 3 by reacting
amidoximes 1a with benzyne precursor 2 in the presence of
Pd and fluoride sources. However, under a variety of
conditions, only 4-propyl-3-(p-tolyl)-1,2,4-oxadiazol-5(4H)-
one (4a) was formed at the expense of the annulation
product 3 (Scheme 1). Control experiments allowed us to
conclude that neither palladium nor 2-trimethylsilyl phe-
nyltriflate (2) was implicated in the reaction and that the
reaction was promoted by a base alone. Mechanistically,
we hypothesized that the reaction may go through the
tetrahedral intermediate A resulting from the intramolec-
ular nucleophilic addition of nitrogen to the ester function.
Fragmentation via CÀC bond cleavage would then give 4a
with release of pentafluorobenzene.15 Contrary to other
CÀC bond cleaving methodologies requiring oxidative
conditions, a strong base, metal catalysis, or/and ele-
vated temperatures, the present reaction occurred at
room temperature in the presence of a weak base such
as K2CO3.
(12) Rodriguez, N.; Goossen, L. J. Chem. Soc. Rev. 2011, 40, 5030–
5048.
(13) For recent examples, see: (a) Nakai, K.; Kurahashi, T.; Matsubara,
S. J. Am. Chem. Soc. 2011, 133, 11066–11068. (b) Chiba, S.; Zhang, L.; Ang,
G. Y.; Hui, B. W.-Q. Org. Lett. 2010, 12, 2052–2055.
(17) Conversion of compound 1a to 4a was monitored by 1H NMR
establishing the clean and exclusive formation of pentafluorobenzene
over time. See Supporting Information.
(18) (a) Garner, C. M.; Fisher, H. C. Tetrahedron Lett. 2006, 47,
7405–7407. (b) Fisher, H. C., PhD Thesis, Baylor University, 2006.
(19) Bolton, R. E.; Coote, S. J.; Finch, H.; Lowdon, A.; Pegg, N.;
Vinader, M. V. Tetrahedron Lett. 1995, 36, 4471–4474.
(20) Wustrow, D. J.; Belliotti, T. R.; Capiris, T.; Kneen, C. O.;
Bryans, J. S.; Field, M. J.; Williams, D.; El-Kattan, A.; Buchholz, L.;
Kinsora, J. J.; Lotarski, S. M.; Vartanian, M. G.; Taylor, C. P.;
Donevan, S. D.; Thorpe, A. J.; Schwarz, J. B. Bioorg. Med. Chem. Lett.
2009, 19, 247–250.
(14) (a) Gerfaud, T.; Neuville, L.; Zhu, J. Angew. Chem., Int. Ed.
2009, 48, 572–577. O-Pentafluorobenzoylamidoximes have been used in
palladium-catalyzed processes: (b) Zaman, S.; Mitsuru, K.; Abell, A. D.
Org. Lett. 2005, 7, 609–611. For reviews of metal-catalyzed CÀN bond-
forming processes involving acyloximes, see: (c) Kitamura, M.; Narasaka,
K. Chem. Record 2002, 2, 268–277. (d) Narasaka, K.; Kitamura, M. Eur. J.
Org. Chem. 2005, 4505–4519.
(15) (a) Substituted cyclopentadienyl anion as a leaving group;
see: Fisher, E. L; Lambert, T. H. Org. Lett. 2009, 11, 4108–4110.
(b) Acetylide as a leaving group; see: Sugiishi, T.; Kimura, A.; Nakamura,
H. J. Am. Chem. Soc. 2010, 132, 5332–5333. (c) 1,3-Dicarbonyl group as a
leaving group; see: Li, H.; Li, W.; Liu, W.; He, Z.; Li, Z. Angew. Chem., Int.
Ed. 2011, 50, 2975–2978.
(21) Selected examples of synthesis: (a) Dianna, G. D.; Volkots,
D. L.; Nitz, T. J.; Bailey, T. R.; Long, M. A.; Vescio, N.; Aldous, S.;
Pevear, D. C.; Dutko, F. J. J. Med. Chem. 1994, 37, 2421–2436. (b) von
€
Wantoch Rekowski, M.; Pyriochou, A.; Papapetropoulos, N.; Stossel,
(16) For a recent example with K2CO3 in MeOH, see: Neufeldt, S. R.;
Sanford, M. S. Org. Lett. 2010, 12, 532–535.
A.; Papapetropoulos, A.; Giannis, A. Bioorg. Med. Chem. 2010, 18,
1288–1296.
Org. Lett., Vol. 13, No. 23, 2011
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although a higher temperature (200 °C) was generally
required.22
Table 2. Scope of the Synthesis of 1,2,4-Oxadiazol-5-ones from
Amidoximesa
To gain information on the reaction pathway, acyl
oxime 7 lacking the internal nucleophile was synthesized.
Reaction of 7 with pyrrolidine under our optimized reac-
tion conditions afforded 8 in 90% yield resulting from the
intermolecular SNAr reaction (eq 1, Scheme 2). This con-
trol experiment indicated that the reaction between 5 and
pentafluorobenzoyl chloride might indeed go through the
tetrahedral intermediate A resulting from the intramole-
cular addition of amine nitrogen to the ester function. A
usual pathway from A would involve cleavage of a CÀO
bondleading tothetransamidation product. However, this
was not observed in our case and alternative CÀC bond
cleavage occurred to provide oxadiazolone 4. We surmised
that cleavage of the CÀO bond (route a) from A leading to
B could take place. However, high nucleophilicity of the
oxime oxygen and high electrophilicity of the amide car-
bon due to the electron-withdrawing effect of the penta-
fluorophenyl may render this process reversible. On the
other hand, cleavage of the CÀC bond (route b) is irrever-
sible, driving therefore the reaction toward the formation
of 4 with concurrent release of pentafluorobenzene (eq 2,
Scheme 2).
Scheme 2. Control Experiment and Mechanistic Considerations
a General conditions: ClCOC6F5 (1 equiv), K2CO3 (5 equiv), MeCN,
25 °C, 18 h. b Isolated yield. c Reaction perfomed at 50 °C.
With these conditions in hand, the scope of the cycliza-
tion was examined (Table 2). Secondary para substituted
aromatic amidoximes bearing electron-donating (OMe, 5c)
or electron-withdrawing groups (Cl and NO2, 5b and 5d)
smoothly underwent the cyclization, affording the corre-
sponding 1,2,4-oxadiazol-5-ones in good yields (entries
1À4). Substitution was also well tolerated at the meta or
ortho position as illustrated with the synthesis of com-
pounds 4e and 4f in 72% and 75% yield, respectively. The
reaction was not limited to aromatic amidoximes since
alkyl amidoxime 5i was found to be a good substrate,
affording 4i in 85% yield. Substituents attached to the
nitrogen atom of the amidoxime had no significant impact
on the reaction outcome since N-alkyl, N-benzyl, and
N-aryl groups were equally effective (entries 1, 7, and 8).
Interestingly, primary amidoxime 5j behaved differ-
ently. In this case 1,2,4-oxadiazole 6 was obtained,
revealing that dehydratation was preferred over CÀC
bond breaking. Formation of a conjugated aro-
matic oxadiazole might explain such a preference. This
type of transformation has been reported previously
To further examine the scope of the present CÀC bond
cleavage process, we prepared a 1,3-diphenylpropan-2-one
O-perfluorobenzoyl oxime (9, Scheme 3) reasoning that
benzylic carbon would potentially act as a nucleophile to
trigger the domino process. Eventually, heating a MeCN
solution of 9 at 50 °C in the presence of Et3N for 24 h
afforded product 10 and 4-oxazolin-2-one 11 in 15% and
43% yield respectively. It is worth noting that compound
11 has previously been synthesized by the reaction of
ketone oximes with a large excess (>20 equivalent) of dialkyl
carbonate. However, harsh conditions (T > 190 °C) were
needed to reach similar efficiency.23
(22) (a) Brown, H. C.; Wetzel, C. R. J. Org. Chem. 1965, 30, 3734–
3738. For microwave heating, see: (b) Wang, Y.; Miller, R. L.; Sauer,
D. R.; Djuric, S. W. Org. Lett. 2005, 7, 925–928. For the synthesis of 6,
see: (c) Buscemi, S.; Pace, A.; Piccionello, A. P.; Pibiri, I.; Vivona, N.
Heterocycles 2004, 63, 1619–1628.
(23) Marques, C. A.; Selva, M.; Tundo, P.; Montanari, F. J. Org.
Chem. 1993, 58, 5765–5770.
6174
Org. Lett., Vol. 13, No. 23, 2011

sealed tube) afforded the corresponding oxadiazolone 4i in
86% yield (Scheme 4). By analogy to the pentafluoroben-
zoyl amidoxime, a fragmentation involving release of fluo-
roform took place under these conditions. ThiÀs represents
a rare example of reactions involving a CF3 extrusion
step.28
Scheme 3. Reactivity of O-Pentafluorobenzoyl Oxime 9
Scheme 4. Oxadiazolone Synthesis from Amidoxime with
TFAA
In summary, we have described a new synthesis of 1,2,4-
oxadiazol-5-ones by reaction of amidoximes with penta-
fluorobenzoylchloride. The reaction involves an unusual
CÀC bond cleavage with the release of pentafluoroben-
zene under very mild conditions. TFAA can also be used in
this one-pot process with the concurrent formation of
oxadiazolone and fluoroform. Since TFAA is available
in bulk, its use as a double acylating agent is of particular
interest from a preparative point of view. Efforts aiming at
intercepting the perfluorinated unit are currently being
pursued.
A possible reaction scenario that accounts for the for-
mation of 10 and 11 is shown in Scheme 3. The ene-
hydroxylamine C, a tautomeric form of acyloxime 9, could
undergo a [3,3]-sigmatropic rearrangement24 to give D.
The imine moiety would next act as a nucleophile to attack
the carbonyl group leading to tetrahedral intermediate E.
The reaction could diverge into two directions at this stage.
Fragmentation of the CÀO bond would lead to acyl-imine
F, which upon isomerization would provide 10. On the
other hand, CÀC bond cleavage would result in the
formation of pentafluorobenzene and G. The latter could
then tautomerize to compound 11.25 The higher yield of 11
over 10 indicated that, in this case again, the CÀC bond
cleavage dominates over the alternative CÀO bond scission.
Reactions involving CÀC bond cleavage of trifluoro-
methylketone derivatives are known in the literature.26
In most cases, the fragmentation occurs with release of
trifluoroacetate.27 Based on our mechanistic rationale
(cf. Scheme 2), we thought that O-trifluoroacetoxy ami-
doximes could undergo the same cyclizative fragmenta-
tion with extrusion of fluoroform. After some experimen-
tation, wefoundthatreaction ofamidoxime 5iwith trifluo-
roacetic anhydride (TFAA) (K2CO3, MeCN, 80 °C, 48 h,
Acknowledgment. Financial support from CNRS and
ICSN is gratefully acknowledged. T.G. thanks ICSN for a
doctoral fellowship; H.L.W. thanks the Government of
China for a National Graduate Student Program of
Building World-Class Universities.
Supporting Information Available. Experimental pro-
cedures, characterization data, and copies of 1H and 13
C
NMR spectra are provided. This material is available free
of charge via the Internet at http://pubs.acs.org.
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M. M.; Kirshner, J.; Colby, D. A. J. Org. Chem. 2011, 76, 3676–3683. (c)
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been observed: (a) Lemmens, J. M.; Blommerde, W. J. M.; Thijs, L.;
Zwaneburg, B. J. Org. Chem. 1984, 49, 2231–2235. (b) Mandal, A. B.;
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