Unexpected [2 + 2] C-C bond coupling due to photocycloaddition on orthopalladated (Z)-2-aryl-4-arylidene-5(4H)-oxazolones

Article abstract of DOI:10.1039/b907647f

A [2 + 2] photocycloaddition has been observed in regioselectively orthopalladated 2-aryl-4-arylidene-5(4H)-oxazolones, leading to unprecedented cyclobutane-bis(oxazolones). The Royal Society of Chemistry 2009.

Full text of DOI:10.1039/b907647f

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Unexpected [2 + 2] C–C bond coupling due to photocycloaddition
on orthopalladated (Z)-2-aryl-4-arylidene-5(4H)-oxazolonesw
Doru Roiban,a Elena Serrano,b Tatiana Soler,c Ion Grosu,a Carlos Cativielad
and Esteban P. Urriolabeitia*b
Received (in Cambridge, UK) 15th April 2009, Accepted 5th June 2009
First published as an Advance Article on the web 23rd June 2009
DOI: 10.1039/b907647f
A [2 + 2] photocycloaddition has been observed in regioselectively
orthopalladated 2-aryl-4-arylidene-5(4H)-oxazolones, leading to
unprecedented cyclobutane-bis(oxazolones).
(Fig. 1) were studied. Electron-releasing substituents have
been introduced to favour the electrophilic attack to a
given ring.
First attempts of orthopalladation of (1a)–(1e) in standard
conditions [Pd(OAc)2, solvent, reflux] were unsuccessful in a
wide variety of organic solvents. Under these conditions only
1d, containing four strong electron-donating OMe groups, two
of them at the benzylidene ring, affords 2d in acetic acid
(Scheme 1).
Cyclopalladated complexes are recognized as useful tools in
metal-mediated organic synthesis.1 Several preparative methods
are known, but the directed activation of C–H bonds1 is
specially attractive due to its deep implications in function-
alization processes.2,3 The incorporation to a given substrate
of aryl,3a–c acetate,3d halogen,3e,f ethoxycarbonyl,3g arylsulfonyl3h
or alkenyl3i groups has been reported, among others.3j,k Using
this methodology new C–C or C–X (X = O, S, N, hal) bonds
have been formed in a plethora of molecules.
More interestingly, the change of solvent has a noticeable
effect on the general course of the reaction.8 If acetic acid is
replaced by trifluoroacetic acid (TFA), all oxazolones shown
in Fig. 1 can be orthopalladated. The beneficial effect of the
increase in the reaction medium acidity in Pd-mediated C–H
bond activations has already been reported, and it is due to the
increase in the electrophilicity of the Pd(II) center.8 Therefore,
unsubstituted 1a reacts easily with Pd(OAc)2 (4 h, 75 1C) to
afford 3a, which is characterized as a TFA-bridged open-book
dimer, showing the oxazolone metallated at the benzylidene
ring. The presence of strong electron-donating OMe groups at
the 2-aryl ring does not alter the regioselectivity of the
metallation, since in all cases the Pd is incorporated at the
benzylidene ring. This is the case for 3b and 3c, which have one
or two OMe groups at the 2-aryl ring, respectively. As
expected, 3d is also obtained as a single regioisomer, as was
2d. The observed regioselectivity is worthy of note, since the
obtained six-membered palladacycle seems to be more stable
than the hypothetical five-membered ring resulting from C–H
bond activation at the 2-phenyl group. In addition, the
palladation seems to occur in most cases at the more
electron-deficient ring, this fact being hard to justify on the
basis of an electrophilic aromatic substitution (SEAr) mechanism.
However, the consideration of a concerted metalation–
deprotonation (CMD) pathway, which favours the palladation
at the more electron-deficient aryl,9a–f together with factors
such as the planarity of the cycle or the metalloaromaticity9g
could help to understand the observed regioselectivity.
Oxazolones are important organic precursors and useful
building blocks, employed as intermediates in synthesis of
compounds of pharmacological interest, in particular of
amino acids.4 Saturated 5(4H)-oxazolones have been used in
coupling reactions as synthetic equivalents of a-amino acids in
the synthesis of peptides. Asymmetric alkylation reactions
have been reported for the enantioselective synthesis of acyclic
a,a-quaternary amino acids.5 The outstanding reactivity of the
exocyclic double bond of unsaturated 5(4H)-oxazolones made
them attractive intermediates for the asymmetric synthesis of
non-proteinogenic amino acids.6
The orthometallation of 5(4H)-oxazolones is a scarcely
represented process, examples being restricted to saturated
compounds with Pd or Ir.7 The orthometallation of unsaturated
5(4H)-oxazolones has never been studied, so our attention has
been focussed on the use of the orthopalladation strategy to
selectively functionalize these compounds, aiming to design
alternative synthetic routes to high-added value modified
amino acids. Our first goal is the study of the orthopalladation
of oxazolones, the selectivity of the Pd–C bond formation and
its reactivity. 2-Aryl-4-arylidene-5(4H)-oxazolones (1a)–(1e)
a Organic Chemistry Department, Faculty of Chemistry and Chemical
Engineering, Babes-Bolyai University, 400028 Cluj–Napoca,
Romania
b Organometallic Compounds Department, ICMA (CSIC-UZ), Pedro
Cerbuna 12, 50009 Zaragoza, Spain. E-mail: esteban@unizar.es;
Fax: +34976761187; Tel: +34976762302
c
´
Servicios Tecnicos de Investigacion, Facultad de Ciencias Fase II,
03690, San Vicente de Raspeig, Alicante, Spain
´
d Organic Chemistry Department, ICMA (CSIC-UZ),
Pedro Cerbuna 12, 50009 Zaragoza, Spain
w Electronic supplementary information (ESI) available: Complete
experimental section and crystallographic tables of 5cÁ2CH2Cl2.
CCDC 727936. For ESI and crystallographic data in CIF or other
electronic format, see DOI: 10.1039/b907647f
Fig.
1
5(4H)-Oxazolone showing the competitive palladation
Chem. Commun., 2009, 4681–4683 | 4681
positions.
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Scheme 1 Synthesis of six-membered orthopalladated oxazolones.
Surprisingly, 2d and 3a–3d are not stable in solution
(CD2Cl2 or CDCl3) when exposed to sunlight, and evolve
giving 4d or 5a–5d after a [2 + 2] cycloaddition involving the
benzylidenic CQC double bond (Scheme 2). As far as we
know, only one case of cycloaddition is reported in oxazolones,
but it implies the CQN bond.10 The reaction is unprecedented,
not only in oxazolones but in all types of orthopalladated
ligands. NMR spectra evidence strong changes on the
oxazolone skeleton from the high field shift of the benzylidenic
proton H7 (from B7.5 ppm in 2–3 to B4.8 ppm in 4–5),
accompanied with a high field shift of the corresponding
13C signal (C7 from 138 ppm to 60 ppm), reflecting the
hybridization change of this carbon. One of the aromatic
protons appears in turn deshielded, this fact explained from
the X-ray structure of 5c.
Fig. 2 Molecular drawing (50% ellipsoids) of complex 5c. H atoms
and solvent molecules have been omitted for clarity.
cycloaddition, since the open-book structure ensures the close
proximity of the two benzylidenic CQC bonds. In keeping
with this, planar (m-Cl) dinuclear complexes (6b, 6c) or mono-
nuclear acetylacetonate complexes (7b, 7c) (see ESIw) are
stable when exposed to natural sunlight. However, the nature
of the bridge (OAc vs. TFA) seems not to be related to the rate
of the cycloaddition since similar rates are obtained for the
two bridges (2d, 3d).
The X-ray structure of 5c has been determined (Fig. 2 and
ESIw), showing the presence of the cyclobutane ring on a very
distorted bis-oxazolone metallated fragment. In addition, the
structure shows two very noteworthy facts. The Pd1–Pd2 bond
distance [2.7815(7) A] is shorter than those found in related
carboxylate bridged dinuclear complexes;11 this fact is probably
due to the constraint imposed by the cyclobutane ring. On the
other hand, the H atoms bonded to C16, C36, C56 and C76
are in close proximity to the Pd centers (range 2.418–2.692 A)
in such a way that each C–H vector points to the Pd–Pd bond.
This type of hydrogen bond interaction, in which the basic Pd
center behaves as a proton acceptor has already been described
in detail,12 and it is responsible for the low field shift observed
Complex 5e is obtained directly from the reaction of 1e with
Pd(OAc)2 in TFA. The intermediate 3e could not be obtained
in pure form since it was always contaminated with 5e. The
latter is the paradigm of how the classical concepts on the
orthopalladation do not apply here: the most deactivated
4-nitrobenzylidene ring is regioselectively metallated instead
the activated dimethoxyphenyl ring. The necessary role of the
sunlight in the cycloaddition is clear, since solutions of 2d,
3a–3d do not evolve in the dark. Moreover, solutions of 4d and
5d revert partially to the starting 2d or 3d when allowed to
stand in the dark. The cycloaddition rate seems to be directly
related to the nature of the substituents. In the ‘‘symmetric’’ 3d
we observed the slowest photoisomerization (at least 240 h); as
the asymmetry on the charge density increases (one OMe in 3b
or two OMe in 3c) the reaction becomes faster (50 h) and the
fastest reaction is observed when the charge density gradient is
maximum (3e). Therefore, it seems that a higher polarization
of the CQC bond implies a faster reaction. The presence of the
bridge (acetate or TFA) is clearly essential to promote the
1
for one aromatic signal in the H NMR spectra.
In conclusion, a regioselective orthopalladation of 5(4H)-
oxazolones has been achieved. Dimers evolve through [2 + 2]
photocycloaddition, giving unprecedented oxazolones.
Financial support from the Spanish Ministerio de Ciencia e
Innovacion (projects CTQ2008-01784 and CTQ2007-62245) is
gratefully acknowledged. ES thanks Diputacion General de
Aragon for a PhD grant. DR thanks to CNCSIS grant TD87.
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