Arene CH-O hydrogen bonding: A stereocontrolling tool in palladium-catalyzed arylation and vinylation of ketones

Article abstract of DOI:10.1002/anie.201300621

Weak is powerful: For the arylation of tin enolates, the palladium catalyst engages in weak CH-O hydrogen bonds to control stereoselectivity (see scheme). Similar catalysts capable of NH-O hydrogen bonding also works well. Copyright

Full text of DOI:10.1002/anie.201300621

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DOI: 10.1002/anie.201300621
Cross-Coupling
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Arene CH O Hydrogen Bonding: A Stereocontrolling Tool in
Palladium-Catalyzed Arylation and Vinylation of Ketones**
Zhiyan Huang, Li Hui Lim, Zuliang Chen, Yongxin Li, Feng Zhou, Haibin Su, and
Jianrong (Steve) Zhou*
Transition-metal-catalyzed a-arylation of carbonyl com-
pounds has become a very useful tool to prepare a-
arylcarboxylic acids and derivatives.[1] Many asymmetric
couplings have been developed for arylation of ketones,[2]
aldehydes,[3] oxindoles[4] and a-methylacetoacetates,[5] etc. For
example, in a nickel-catalyzed method reported by Hartwig,
enolates were formed in situ from cyclic ketones and a strong
base. They coupled efficiently with aryl triflates to form
quaternary centers with high ee values [Eq. (1), Scheme 1].[2e]
These asymmetric processes cannot be used to construct
tertiary centers because arylated products contain acidic a-
protons and the latter cannot survive the basic conditions.
Thus, arylation of enolates to form tertiary centers must use
preformed soft enolates with low basicity.[6] Only recently,
MacMillan et al. and Gaunt et al. independently reported
arylations of enamines derived from aldehydes as well as silyl
enolates of imides to selectively form tertiary centers.
[Eq. (2)–(3)].[7] Reactive diaryliodonium reagents must be
used and ketone substrates were not reported. In 2011, we
realized the first palladium-catalyzed, highly stereoselective
arylation of ester enolates for construction of tertiary centers
[Eq. (4)].[8] In an umpolung approach, Fu et al. reported
asymmetric coupling between a-haloketone electrophiles and
arylmetal reagents.[9] Herein, we report the first palladium-
catalyzed coupling of ketones to produce tertiary centers with
excellent ee values [Eq. (5)].
At first, we attempted to couple a silyl enolate of 1-
tetralone using our ester coupling procedure (2 mol% Pd/
ligand L and LiOAc in PhCF3). However, no product was
formed in the presence of LiOAc. With CsF, arylation
occurred, but the product racemized. To our delight, we
finally found that the tin enolate of 1-tetralone can couple
very efficiently with 91% ee when L1 was used. No erosion of
the ee value was observed over time. The tin enolate was
Scheme 1. Examples of asymmetric coupling of enolates. Tf=trifluoro-
methanesulfonyl, TMS=trimethylsilyl.
[*] Dr. Z. Huang, L. H. Lim, Dr. Z. Chen, Dr. Y. Li, Prof. Dr. J. Zhou
Division of Chemistry and Biological Chemistry, School of Physical
and Mathematical Sciences, Nanyang Technological University
21 Nanyang Link, Singapore 637371 (Singapore)
E-mail: jrzhou@ntu.edu.sg
formed easily by stirring alkenyl acetate with nBu3Sn(OMe)
at room temperature, and it was used directly without
purification.[10]
F. Zhou, Prof. Dr. H. Su
Division of Materials Science, School of Materials Science and
Engineering, Nanyang Technological University
50 Nanyang Avenue, Singapore 639798 (Singapore)
During catalyst discovery, the Pd(OAc)2/difluorphos cat-
alyst, which was previously used by Hartwig et al.,[2e] gave
poor results with 38% ee. [Ni(cod)2]/difluorphos (cod = cyclo-
[**] We thank the Singapore National Research Foundation (NRF-
1,5-octadiene) was catalytically inactive.[2d] Pd/MOP showed
RF2008-10) and Nanyang Technological University for financial
low activity and gave moderate ee values (Scheme 2). We then
modified MOP by installing the more donating PCy2 group
and O-2-naphthyl side chain. The resulting L1 turned out to
be both active and selective. Structural analogues carrying
support, and Prof. Dr. Rong Xu and Dr. Wei Zhang for help in ICP-
MS analysis of residual tin.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201300621.
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Scheme 2. Catalyst discovery in the model arylation reaction. MOP=2-
(diphenylphosphino)-2’-methoxy-1,1’-binaphthyl. Yields are those mea-
sured by GC, and the ee values were determined by HPLC analysis with
a chiral stationary phase.
other O-groups, such as phenyl, 1-naphthyl, and arylmethyl,
all gave lower ee values. Notably, partial saturation of the
binaphthyl backbone led to worse results. O-aryl groups in
ligands were introduced by arylation of naphthol using
diaryliodonium salts.[11]
The Pd/L1 catalyst can be applied to couplings of various
aryl and heteroaryl triflates (Scheme 3a). For aryl triflates
Scheme 3. Arylation of 1-tetralone enolate using ligand L1. See
Scheme 2 for standard reaction conditions. Yields are those reported
for isolated products, and the ee values were determined by HPLC
analysis with a chiral stationary phase.
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carrying aryl Cl and aryl F bonds, the coupling was selective
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at the Ar OTf bond. The same method can be applied to aryl
bromides and chlorides (Scheme 3b). The absolute config-
uration of the major stereoisomer was established to be 2S, by
X-ray diffractional analysis of one benzothiazole product.
Coupling of PhI resulted in low conversion, probably because
of fast decomposition of oxidative adducts of palladium.[2e]
The enolate of cyclohexanone coupled well with many
aryl and heteraryl triflates, bromides, and chlorides (Sche-
me 4a). One exception was electron-rich aryl chlorides, which
coupled slowly. The coupling procedure can be conducted on
a gram scale using 1 mol% palladium (Scheme 4b). The
crude reaction mixture was directly passed through a pad of
silica gel and the filtrate, after concentration, was washed with
n-pentane to give the solid product in 91% yield and 94% ee.
ICP analysis indicated the purified sample contained 28 ppm
of the residual tin. Thus, most of organotin was removed by
washing with n-pentane. The sample was then stirred with
basic alumina in CH2Cl2 at room temperature for 3 h to
reduce the tin content to 3 ppm.
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states of C C reductive elimination (see below). This inspired
us to investigate new ligands, L2 and L3, which are capable of
NH–O hydrogen bonds. Indeed, L2 and L3 gave better results
(Scheme 2). When L3 was used in the coupling of either
cyclohexanone or 1-tetralone enolates, the ee values were
generally better than that obtained with L1 (Scheme 5).
Various aryl bromides and triflates worked very well at room
temperature, and some aryl chlorides, except the electron-rich
ones, also coupled smoothly.
We explored the use of various ketones, such as substi-
tuted 1-tetralones and cyclohexanones (Scheme 6). Seven-
and eight-membered cyclic ketones also underwent the
coupling reaction. Notably, the ee value of the cyclopenta-
none product fell over time from 83% ee at the first 0.5 h. In
fact, 2-aryl cyclopentanones are known to undergo facile
racemization, even on silica gel.[12] 4-Oxa-1-tetralone can
couple to give isoflavanones, which inhibit the growth of
microbes and tumors.[13] The acyclic (E)-propiophenone
enolate gave only 33% ee in the presence of Pd/L1.
Recently, we conducted DFT calculations to determine
the origin of stereoselectivity from the Pd/L1 catalyst. We
were surprised to find that L1 formed a CH–O hydrogen
bond between the side-chain naphthyl group and one
palladium-bound enolate in both the ground and transition
The arylation products can be easily converted into other
chiral building blocks. For example, reduction of 2-phenyl-
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Scheme 4. Arylation and vinylation of cyclohexanone using ligand L1.
See Scheme 2 for standard reaction conditions. Yields are those
reported for isolated products, and the ee values were determined by
HPLC analysis with a chiral stationary phase.
Scheme 5. Arylation and vinylation of ketones using ligand L3. See
Scheme 2 for standard reaction conditions. Yields are those reported
for isolated products, and the ee values were determined by HPLC
analysis with a chiral stationary phase. Boc=tert-butoxycarbonyl.
cyclohexanone using K-Selectride gave the cis alcohol (d.r.
80:1) without erosion of the ee value (Scheme 7).[14] Li/
naphthalene reduction of the same ketone can selectively
give trans-2-arylcycohexanol,[15] which is commonly used as
chiral auxiliary in asymmetric transformations.[16] The 2-
arylketones can also be converted into aryllactones by
Baeyer–Villiger oxidation and into aryllactams by Beckmann
rearrangement. Notably, it is important to prepare the E-
oxime selectively, since the Z-isomer can rearrange to give
a different lactam.[17] One more example is deoxygenation of
2-aryltetralones by catalytic hydrogenolysis. Some 2-arylta-
tralins are potential drugs for treatment of arrhythmias
(irregular heartbeat), by acting as inhibitors of the Na+/Ca2+
exchange mechanism.[18] No asymmetric synthesis of these
compounds has been reported previously.
We have prepared an oxidative adduct from an aryl
bromide, [Pd(dba)2], and L1 (Scheme 8). The dimeric palla-
dium complex is bridged by two bromides.[19] L1 binds to each
palladium center in a monodentate fashion and the putative
interaction between palladium and the bottom naphthyl ring
of L1 was lost. When the complex was treated with a tin
enolate, coupling occurred in good yield in 93% ee. If the
stoichiometric coupling was conducted with the tin enolate
(1 equiv per Pd) in the presence of 3 equivalents of p-
CF3C6H4Br per Pd, the newly formed [(L1)Pd0] underwent
fast oxidative addition at room temperature to regenerate the
Scheme 6. Arylation of various ketones using ArOTf and 2 mol% Pd/
L3 unless indicated otherwise. Results in parentheses were obtained
with 2 mol% Pd/L1.
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Scheme 7. Synthetic application of 2-arylketones. mCPBA=meta-
chloroperbenzoic acid, Ts=4-toluenesulfonyl.
Scheme 8. Stoichiometric reaction of a [(L1)Pd(Ar)(Br)] complex and
a tin enolate. The ORTEP of trans-[{(ligand L1)Pd(Ar)(m-Br)}2] is
shown. Thermal ellipsoids shown at 50% probability with hydrogen
atoms omitted for clarity. dba=dibenzylideneacetone.
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Figure 1. Calculated C C reductive elimination from C-enolate com-
plexes supported by ligand L1.
same dimeric complex in greater than 95% yield (based on
31P NMR spectroscopy).
tively. In the pathway leading to the major product, the
ground state (Int1Ca) and transition state (TS1Ca) were
stabilized by 4.2 and 2.0 kcalmolꢀ1, respectively, relative to
those of the minor-product pathway. The source of the
stabilization was the double CH–O hydrogen bonds between
two O-naphthyl CH bonds and the enolate oxygen atom. In
the minor-product pathway, the carbonyl group pointed away
from the naphthyl side chain and no hydrogen bond was
possible.
We conducted DFT calculations (B3LYP) of the reductive
elimination of the model reaction shown in Figure 1 to learn
why the naphthyl side chain of L1 was special in promoting
stereoselectivity. First, we established the bonding mode of
the bottom ring of L1 in the complexes [(L1)Pd(aryl)-
(enolate)]. The bonding of palladium with the ipso carbon
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atom of the bottom ring was found to be more stable than Pd
O bonding with the aryl ether by about 5–6 kcalmolꢀ1
.
Furthermore, isomerization of the ether-bound form to the
arene-bound form was almost barrier free. Thus, we focused
on studying enolate complexes with the palladium–arene
interaction.
The weak hydrogen bonding of the arene CH—O type is
typically worth 0.5–4 kcalmolꢀ1 of stabilization.[21] This weak
interaction has been found in crystals and biomacromolecules
such as proteins. However, it has not been observed in
asymmetric metal catalysis. In our optimized structures of
enolate complexes, the bond angles and lengths of the
hydrogen bonds all fall into the expected ranges.[22]
We also calculated the reductive elimination step of C-
enolate complexes of Pd/L2 (Figure 2). Again both the
ground state (Int2Ca) and transition state (TS2Ca) were
stabilized by 4.5 and 3.2 kcalmolꢀ1, respectively, for the
major-product pathway, and the stabilization was derived
from one NH–O and one CH–O hydrogen bond.
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Next, we explored possible C C bond formation from O-
enolate complexes.[20] No smooth pathway can directly lead to
coupling products. Instead, an abrupt “jumping” of atoms was
observed at one point as the C-C distance was reduced. In
addition, isomerization of the O-enolate complexes to C-
enolates has relatively high barriers (15–18 kcalmolꢀ1). We
ꢀ
discovered that C-enolate complexes can undergo facile C C
reductive elimination (Figure 1). The barriers were 13 and
15 kcalmolꢀ1 leading to major and minor products, respec-
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entities.[23] More significantly, the Pd/L1 catalyst employs
attractive arene CH–O hydrogen bonding to induce chirality.
This is the first example of its kind in asymmetric metal
catalysis.
Received: January 24, 2013
Revised: February 9, 2013
Published online: April 3, 2013
Keywords: arylation · cross-coupling · hydrogen bonds ·
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ketones · palladium
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Figure 2. Calculated C C reductive elimination from C-enolate com-
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Experimentally, we gained some support for the hydrogen
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ethylphosphoramide (HMPA), a hydrogen-bond disruptor, in
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in the ee values (91!77% ee with L1 and 98%!66% ee with
L3). The catalytic activity was not significantly altered by
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enolate complex was formed, and overall, the C C reductive
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In summary, we have developed a palladium-catalyzed
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[19] CCDC 878815 and 878816 contain the supplementary crystallo-
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