Synthesis of 3-fluoro-3-aryl oxindoles: Direct enantioselective α arylation of amides

Article abstract of DOI:10.1002/anie.201200206

Modus operandi: Catalytic access to the title compounds through a new asymmetric α-arylation protocol is reported (see scheme). These products are formed in good yields and excellent enantioselectivities by using a new and easily synthesized chiral N-heterocyclic carbene (NHC) ligand. Advanced DFT calculations reveal the properties of the NHC ligand and the mode of operation of the catalyst. Copyright

Full text of DOI:10.1002/anie.201200206

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Angewandte
Communications
DOI: 10.1002/anie.201200206
Heterocycles
Synthesis of 3-Fluoro-3-aryl Oxindoles: Direct Enantioselective
a Arylation of Amides**
Linglin Wu, Laura Falivene, Emma Drinkel, Sharday Grant, Anthony Linden, Luigi Cavallo,
and Reto Dorta*
Monodentate N-heterocyclic carbene (NHC) ligands have
become ubiquitous in organometallic chemistry and cataly-
sis.[1] Conversely, development of chiral monodentate NHC
ligands that induce high selectivity in asymmetric metal
catalysis is still at an early stage with relatively few reports
detailing enantioselectivities of 90% ee and higher.[2–6] The
main difficulties in designing efficient ligands of this type
reside in placing stereocontrol elements at positions near the
metal center without affecting the overall reactivity of the
catalysts. Scheme 1 shows some of the most promising ligand
and more recently developed further by Murakami et al.[3]
Decreasing the rotation of the N substituents is also key in the
successful C2-symmetric ligands reported by Kꢀndig et al.,[4]
who have been able to show that such ligands can be used very
effectively in palladium chemistry.[5] Probably the most
versatile ligand system developed so far was first reported
by Grubbs et al.,[6,7] and they rely on transferring chirality
from a chiral N-heterocyclic backbone onto unsymmetrically
substituted aryl side chains and ultimately onto the metal
coordination sphere. While the design permits easy access to
the precursor imidazolinium salts, such side chains will in
principle create three diastereomers which would have to be
separated for optimal use in catalysis. Our own efforts,[8] have
indeed highlighted the pivotal role the respective orientation
of naphthyl wingtips can have on enantioselectivity and,
contrary to what other groups have proposed or found, the
best ligands with 2-alkyl-substituted naphthyl side chains
position their alkyl substituents directly below the corre-
sponding phenyl group of the backbone [(Ra,Ra)-isomer].
Encouraged by our first results, we became interested in
ways of exclusively accessing this particular diastereomer, as
it would undoubtedly allow a more straightforward synthesis
and use of these ligands. After testing several substitution
patterns, we were pleased to find that placing a relatively rigid
cyclooctyl group at the 2-position of the naphthyl moieties
and ring-closing the corresponding chiral diamine A at 1208C
for 2 hours (Scheme 2) generated the virtually pure NHC salt
(Ra,Ra)-B. The salt showed one set of signals and a diagnostic
single peak for the C2 proton of the imidazolinium ring in the
1H NMR spectrum.
Scheme 1. Examples of chiral, monodentate NHC ligands.
designs to date and highlights the fact that the inherent
flexibility of the N substituents has to be restricted to afford
ligands that efficiently transfer their chiral information. This
restriction can be done by fusing these wingtips onto the
N heterocycle, a design motif pioneered by Glorius et al.,[2]
This salt was then used to synthesize the palladium
cinnamyl complex (Ra,Ra)-C in high yield, the structure of
which was unambiguously confirmed by single-crystal X-ray
crystallography.[9,10] Qualitative assessment of the structure
shows both the relative bulk and the C2 symmetry of the
ligand. The overall steric demand of the ligand was then
quantified by its buried volume (%VBur), a parameter
describing the amount of volume in the first coordination
sphere of a metal occupied by a given ligand and its
topographic steric map (see the Supporting Information).[11,12]
To understand how the C2 symmetry of the ligand affects the
environment around the metal, we evaluated the %VBur in the
four single quadrants of (Ra,Ra)-C and plotted the steric
contour map highlighting zones of different steric pressures as
shown in Figure 1.[12,13] This analysis was performed on the
geometry of the (Ra,Ra)-C obtained from its crystal structure
without additional modifications.[9] This analysis shows that
the two quadrants where the 2-cyclooctyl groups are located
are heavily hindered (bottom left and top right quadrants,
[*] L. Wu, Dr. E. Drinkel, S. Grant, Priv.-Doz. Dr. A. Linden,
Prof. Dr. R. Dorta[+]
Organisch-chemisches Institut, Universitꢀt Zꢁrich
Winterthurerstrasse 190, 8057 Zꢁrich (Switzerland)
E-mail: dorta@oci.uzh.ch
L. Falivene, Prof. Dr. L. Cavallo[$]
Dipartimento di Chimica, Universitꢂ di Salerno
Via Ponte don Melillo, 84084 Fisciano (Italy)
[+] New address: School of Chemistry and Biochemistry, University of
Western Australia, 35 Stirling Highway, Crawley 6009 (Australia)
E-mail: reto.dorta@uwa.edu.au
[$] New address: King Abdullah University of Science and Technology
(KAUST), Chemical and Life Sciences and Engineering, KAUST
Catalysis Center,
Thuwal 23955-6900 (Saudi Arabia)
[**] Support from the Swiss National Science Foundation (LW) is
gratefully acknowledged.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201200206.
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enantioenriched oxindoles with qua-
ternary carbon centers.[8] In this con-
text, an attractive transformation
involving such an a-arylation reac-
tion would see the introduction of
a fluorine atom onto the oxindole
moiety, effectively resulting in the
direct formation of enantioenriched
3-fluoro-3-aryl oxindoles. Owing to
the often attractive properties of
such fluorinated compounds for
pharmaceutical
applications,[14]
incorporation of fluorine into
organic molecules through enantio-
selective catalytic processes has been
extensively investigated in the past
decade and fluorinated oxindole
products can be obtained through
Scheme 2. Synthesis of the chiral NHC complex.
the catalytic enantioselective fluori-
nation reaction,[15] employing an
electrophilic source of fluorine
(Scheme 3).[15d,g,h,l] However, up to now no attempts at
developing direct a-arylation reactions to gain access to
these or other enantioenriched fluorinated compounds have
been documented (Scheme 3).[16,17]
Our catalytic investigation began by screening reaction
parameters using model substrate 1a and 5 mol% of (Ra,Ra)-
C as a precatalyst (see the Supporting Information for
details). Crucial to obtaining good yields of the product was
Table 1: Substrate scope for the NHC/Pd-catalyzed a arylation.[a]
Figure 1. Steric contour maps of the NHC ligand in (Ra,Ra)-C. The
complex is oriented as shown in the sketch. The number close to each
quadrant is the %Vur of this quadrant.
Entry Substrate R[b]
R’
T
[8C]
Product Yield ee
[%]
[%]
1
2
3
4
1a
1b
1c
1d
1e
1e
1 f
1g
1h
1i
1j
1k
1l
1m
1m
1n
1o
1p
H
5-Me
5-Me
H
2-F
4-Me
RT 2a
RT 2b
RT 2c
2d
RT 2e
RT 2e
83
62
70
58
82
89
82
85
70
76
81
86
59
65
94
50
80
61
97
>99
99
94
99
91
99
98
96
>99
94
82
96
>99
95
95
96 (S)
94
%VBur ꢀ 46%), while the other two quadrants are clearly
more open (bottom right and top left quadrants, %VBur
ꢀ 35%). The map therefore demonstrates that the NHC
ligand wraps around the metal center with almost perfect
C2 symmetry, a result that boded well for its application as an
effective ancillary ligand in asymmetric transformations.
In earlier work, we had shown that relatives of (Ra,Ra)-C
can be used as precatalysts in the a arylation of amides to give
5-MeO 1-Nap 50
5-MeO
5-MeO
5-MeO 2-F
5-MeO 2-CF3
5-F
5-F
6-CF3
6-Me
H
5
H
H
6[c]
7
50
50
2 f
2g
8
9
H
2-F
H
2-Cl
2-Me
2-F
2-F
3-MeO RT 2n
3-F
4-Ph
RT 2h
RT 2i
RT 2j
10
11
12
13
14
15[c]
16
17
18
60
2k
RT 2l
RT 2m
RT 2m
H
H
H
H
RT 2o
RT 2p
H
[a] Reaction conditions: 1 (0.20 mmol, 1.0 equiv), (Ra,Ra)-C (5.0 mol%),
NaOtBu (1.1 equiv), toluene (2.0 mL), 16 h. We assume that all
substrates follow the same reaction pathway to give the same relative
configuration; [b] Numbering based on the oxindole product. [c] DME as
solvent.
Scheme 3. Catalytic enantioselective synthesis of 3-fluoro-3-aryl oxin-
doles.
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not to use excess of the base (NaOtBu), as the substrate would
otherwise decompose. Under optimized reaction conditions
using toluene as a solvent and running the reaction at ambient
temperature, product 2a was obtained in 83% yield upon
isolation and with an excellent enantioselectivity of 97% ee.
As evidenced from data collected in Table 1, a variety of
substrates are tolerated in this reaction. For instance, the
introduction of electron-donating and electron-withdrawing
groups (methoxy, methyl, phenyl, chloro, fluoro and trifluor-
omethyl) on the ortho-, meta-, or para-positions of the 3-
phenyl groups lead to excellent enantioselectivities and good
yields within 16 hours at room temperature or 508C. Selected
examples with substituents at the 5- and 6-position of the
oxindole core lead to equally satisfying results. When DME is
used as a solvent (entries 6, 15), reactivity increases while the
selectivity is slightly lower. In several cases, virtually enantio-
pure products were obtained (2b, 2 f, 2i, and 2m), a rather
unique result when employing chiral, monodentate NHC
ligands.[18]
toluene, a value correctly reflecting the high enantioselectiv-
ity observed.
In conclusion, we have developed a new catalytic method
for the enantioselective construction of carbon–fluorine
bonds that relies on an asymmetric a-arylation protocol and
have demonstrated its efficacy for the direct synthesis of 3-
fluoro-3-aryl oxindoles. These target molecules were obtained
in good yields and with excellent enantioselectivities when
employing a new NHC ligand with a chiral N-heterocycle and
naphthyl side chains that is easily accessed as a single
diastereomer. Detailed mechanistic studies are in progress
to shed light on the whole reaction pathway connecting
reactants and products. Ongoing research aims to broaden the
scope of this promising new catalytic way of accessing
enantioenriched fluorinated compounds and to test ligand
(Ra,Ra)-B in other transformations.
Received: January 10, 2012
Published online: February 6, 2012
The absolute stereochemistry of the products was
deduced from an X-ray crystallographic analysis of compound
2o, the stereogenic carbon center of which had the S configu-
ration.[9]
Keywords: asymmetric catalysis · N-heterocyclic carbenes ·
oxindoles · palladium · synthetic methods
.
To further support the assigned stereochemistry of the
products and to gain first insights into the reaction mechanism
we performed a DFT study of the key intermediates, in the
case of the prototype substrate 1a, corresponding to the
expected compounds before final reductive elimination and
release of product 2a.[19] The optimized geometries are
reported in Figure 2. Structural analysis indicates that in the
most stable intermediate (Figure 2a) leading to the exper-
imentally favored S enantiomer, the aromatic ring that will
form the skeleton of the oxindole product and the Ph
substituent on the final chiral C atom of the product are
placed below the naphthyl ring, which is in the less buried
quadrants highlighted in the steric map of Figure 1. By
contrast, in the key intermediate (Figure 2b) leading to the
experimentally less favored R enantiomer, the Ph substituent
on the final chiral C atom of the product is placed below the
cyclooctyl ring, which is in a buried quadrant highlighted in
the steric contour map of Figure 1. According to calculations,
the intermediate of in Figure 2a is favored by 4.4 kcalmolÀ1 in
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[19] Geometry optimizations were performed with the Gaussian09
implementation of the BP86 functional using the SVP basis set
on main group atoms and the SDD-ECP basis set on Pd. The
reported free energies have been obtained via single point
energy calculations with the M06 functional, using the TZVP
basis set on main group atoms. Solvent effects from toluene were
included with the PCM approach. Thermal corrections were
added from the BP86 vibrational analysis. Other details are
provided in the SI.
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