Regioselective C-H activation and sequential C-C and C-O bond formation reactions of aryl ketones promoted by an yttrium carbene

Article abstract of DOI:10.1021/ja107958u

Rare earth carbenes exclusively exhibit Wittig-type reactivity with carbonyl compounds to afford alkenes. Here, we report that yttrium carbenes can effect regioselective ortho-C-H activation and sequential C-C and C-O bond formation reactions of aryl ketones to give iso-benzofurans and hydroxymethylbenzophenones. With MeCOPh, cyclotetramerization occurs giving a substituted cyclohexene. This demonstrates new rare earth carbene reactivity which complements existing Wittig-type reactivity.

Full text of DOI:10.1021/ja107958u

Published on Web 09/27/2010
Regioselective C-H Activation and Sequential C-C and C-O Bond
Formation Reactions of Aryl Ketones Promoted by an Yttrium Carbene
David P. Mills, Lyndsay Soutar, William Lewis, Alexander J. Blake, and Stephen T. Liddle*
School of Chemistry, UniVersity of Nottingham, UniVersity Park, Nottingham, NG7 2RD, U.K.
Received August 3, 2010; E-mail: stephen.liddle@nottingham.ac.uk (S.T.L.)
Scheme 1. Synthesis of 3 and 4
Abstract: Rare earth carbenes exclusively exhibit Wittig-type
reactivity with carbonyl compounds to afford alkenes. Here, we
report that yttrium carbenes can effect regioselective ortho-C-H
activation and sequential C-C and C-O bond formation reactions
of aryl ketones to give iso-benzofurans and hydroxymethylben-
zophenones. With MeCOPh, cyclotetramerization occurs giving
a substituted cyclohexene. This demonstrates new rare earth
carbene reactivity which complements existing Wittig-type reactivity.
Transition metal carbenes are important due to their synthetic
applications which are legion.1 In contrast, rare earth carbenes that
do not derive from stable free carbenes are comparatively sparse.2
This is rationalized on the basis that while novel reactivities are
promised due to highly polar bonding, this polarity renders their
stabilization a challenge.3 Consequently, little is known of the
intrinsic scope of reactivity of rare earth carbenes.4
Following the postulation of rare earth carbenes by Schumann,5
Cavell structurally evidenced the samarium carbene compound
[Sm(LPhTMS)(NCy2)(THF)] [LPhTMS ) C(PPh2NSiMe3)2; Cy )
Substituted iso-benzofurans exist in tautomeric equilibria with
their hydroxymethylbenzophenone forms.16 Reasoning that an
oxymethylbenzophenone could be a precursor to 4, we attempted
to trap this species using 2, as in 2 the yttrium center is rendered
more electrophilic than in 3 as a consequence of the presence of
an iodide rather than an alkoxide coligand, respectively.10 Thus it
cyclohexyl],6 but reactivity studies were not reported. Recently,
rare earth carbenes have been characterized in frozen matrices,7
probed theoretically,8 isolated using {C(PPh2S)2}2-,9 and developed
by us, e.g. [Y(LPhTMS)(R)(THF)n] [R ) CH2SiMe3, n ) 1 (1); R )
I, n ) 2 (2)].10 Without stabilizing phosphorus substituents,
polymetallic methylidene clusters result where the carbene is
stabilized by coordination to more than one metal.11 Where rare
earth carbene reactivity toward carbonyl compounds has been
reported, Wittig-type reactivity to give alkenes has been the
exclusive mode of reactivity.9-13 Herein, we report that yttrium
carbenes can effect regioselective C-H activation and sequential
C-C and C-O bond formation reactions of aryl ketones to afford
substituted iso-benzofurans and/or hydroxymethylbenzophenones.
When MeCOPh is used, cyclotetramerization occurs to give a
substituted cyclohexene. This provides new types of reactivity for
rare earth carbenes that are complementary to existing Wittig-type
and Cketyl-Cketyl/-H coupling reactivities.14
To examine the carbene-based reactivity of 1 toward benzophe-
none we first converted it to the alkoxide-carbene [Y(LPhTMS)-
{OC(CH2SiMe3)Ph2}(THF)] (3), Scheme 1, as DFT calculations
suggested that insertion reactivity of the Y-Calkyl bond of 1 would
occur before carbene reactivity.10c Complex 3 was isolated in 31%
crystalline yield and has been fully characterized (Figure 1a).15
Addition of toluene to a mixture of colorless 3 and 2 equiv of
colorless benzophenone resulted in a dark red solution. After a 7
day stir and workup, colorless [Y(LPhTMSH){OC(CH2SiMe3)Ph2}O-
{(CPh2)(OCPh)C6H4}] (4) was isolated in 51% yield, Scheme 1.
Figure 1b shows the molecular structure of 4, as determined by
X-ray diffraction, which is consistent with the characterization
data15 and confirms the structure.
Figure 1. Molecular structures of (a) 3; (b) 4; (c) 5; (d) 6. Displacement
ellipsoids set at 30% probability; peripheral LPhTMS non-ipso carbon and
nonmethanide hydrogen atoms omitted for clarity.
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C O M M U N I C A T I O N S
Scheme 2. Synthesis of 5, 4 from 5, and 6
methanide hydrogen in 5 originates from benzophenone. A primary
deuterium kinetic isotope effect of kH/kD ) 8.7 was observed which
is consistent with the C-H/C-D bond being directly involved in
the activation step.19 Addition of 1 equiv of [K{O(CH2SiMe3)Ph2}]
to 5 gave 4 quantitatively which suggests that 5 is the precursor to
4, Scheme 2.
Scheme 3. Proposed Mechanism for the Yttrium Carbene
Promoted Formation of the Oxymethylbenzophenone and
Substituted iso-Benzofuran Complexes 5 and 4
was anticipated that using 2 would give an yttrium center that would
resist the Y-O bond rupture step required for valence tautomer-
ization of the oxymethylbenzophenone.
Gratifyingly, treatment of 2 with 2 equiv of benzophenone in
toluene resulted in a dark red solution which after workup gave
[Y(LPhTMSH){OCPh(C6H4)-2-C(O)Ph2}] (5) in 88% yield as a
colorless powder, Scheme 2. Figure 1c shows the molecular
structure of 5 as determined by X-ray crystallography, which
confirmed entrapment of the oxymethylbenzophenone and proton-
ation of the carbene to give a methanide.15
To extend this reactivity to diastereomeric products, 2 was treated
with 2 equiv of PhCOBut to afford [Y(LPhTMSH)(I){O(CPhBut)-
(OCBut)C6H4}] (6) in 31% yield as an almost colorless powder,
Scheme 2.15 The crystal structure of 6 was determined, Figure 1d,
revealing formation of a diastereomeric iso-benzofuran. Whereas
the oxymethylbenzophenone tautomer could be trapped with
benzophenone, PhCOBut gives the iso-benzofuran, which we
attribute to the Thorpe-Ingold effect.17
The intense red color obtained on mixing benzophenone with 2
or 3 in toluene suggests the formation of charge transfer (CT)
benzophenone adducts.15,18 The individual electronic absorption
spectra (400-800 nm) of 2 and benzophenone in toluene are
featureless. Mixing these solutions gives an absorption λmax ) 460
nm (ꢀ ) 153 mol-1 dm3 cm-1). This extinction coefficient is low
for CT, but only a small proportion of the CT species will be
present, as, to coordinate, benzophenone must displace the stronger
ligand THF. Germane to this point, solutions of 2 and benzophenone
in THF remain colorless and no reaction occurs.
These observations suggest the mechanism illustrated in Scheme
3. Coordination of benzophenone to 3 is followed by ortho-C-H
aryl activation and protonation of the carbene. This generates an
aryl carbanion which attacks a ketyl carbon of another benzophe-
none molecule to afford the C-C coupled oxymethylbenzophenone
in 5. The thermodynamic data suggest the C-H abstraction and
C-C coupling steps are concerted in nature, but we cannot rule
out a resting state involving coordination of the carbanion center
to yttrium, or indeed the abstracted proton. However, we believe
the former is unlikely because through resonance the carbonyl
oxygen can acquire substantial alkoxide character, which would
render it a better ligand center for the electropositive yttrium than
a carbanion. Attempts to isolate the intermediate by treating 3 or 2
with 1 equiv of benzophenone were unsuccessful and, instead, gave
50% conversion to 4 and 5, respectively. This suggests that the
C-H activation step is rate limiting, in line with the observed
kinetics, and that the subsequent C-C coupling is rapid, which is
consistent with the suggested concerted nature. Finally, rearrange-
ment of the oxymethylbenzophenone to its iso-benzofuran form in
4 by C-O bond formation occurs. Whether this latter step occurs
depends on the electrophilicity of yttrium, which is modulated by
the coligand (iodide or alkoxide), and the steric demands of the
ketone substituents. Previous bond activation reactions of ben-
The conversion of 2 to 5, monitored by 31P NMR spectroscopy,
was fitted to second-order kinetics overall (first-order with respect
to 2 and Ph2CO) with k ) (2.16 × 10-2) ( (0.1 × 10-2) mol-1
dm3 s-1 (298 K). Eyring and Arrhenius analyses yielded ∆H‡ )
+74.6 ( 3.0 kJ mol-1 and ∆S‡ ) -44.9 ( 9.0 J mol-1 K-1
,
affording ∆G‡ ) +87.9 ( 3.0 kJ mol-1 (298 K) and Ea ) +77.2
( 3.0 kJ mol-1, which is consonant with the reaction time, which
can be decreased to 2 h by conducting the reaction at 50 °C. The
relatively low value of ∆H‡ implies a concerted process where
bonds are cleaved and formed in a cyclic transition state,19 which
is in line with observations that the concentration of 2 decreases
proportionately to the increase in the concentration of 5. The low,
negative ∆S‡ is consistent with closure of the chelate ring in 5 and
possibly the loss of THF. Treatment of 2 with 2 equiv of [D10]-
Ph2CO gave [D20]-5 with deuteration at the carbene confirming the
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C O M M U N I C A T I O N S
zophenone, subsequently considered to lack acidic hydrogens,20
were limited to oxidative addition to a silylene21 or metal-mediated
redox couplings,22 but redox chemistry at d0 yttrium is unlikely.23
G. Pattenden FRS (Nottingham) for stimulating discussions, and
the Reviewers for constructive comments.
Supporting Information Available: Experimental, X-ray, and
mechanistic data for 3-6. This material is available free of charge via
the Internet at http://pubs.acs.org.
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Scheme 4. Synthesis of 7
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whereas previous preparations of dypnopinacol are multistep.28
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Acknowledgment. We thank the Royal Society, EPSRC, and
the University of Nottingham for funding; Dr. R. Denton and Prof.
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