Palladium-Catalyzed Enantioselective Arylation of Aryl Sulfenate Anions: A Combined Experimental and Computational Study

Article abstract of DOI:10.1021/jacs.7b03623

A novel approach to produce chiral diaryl sulfoxides from aryl benzyl sulfoxides and aryl bromides via an enantioselective arylation of aryl sulfenate anions is reported. A (JosiPhos)Pd-based catalyst successfully promotes the asymmetric arylation reaction with good functional group compatibility. A wide range of enantioenriched diaryl, aryl heteroaryl, and even diheteroaryl sulfoxides were generated. Many of the sulfoxides prepared herein would be difficult to prepare via classic enantioselective oxidation of sulfides, including Ph(Ph-d₅)SO (90% ee, 95% yield). A DFT-based computational study suggested that chiral induction originates from two primary factors: (i) both a kinetic and a thermodynamic preference for oxidative addition that places the bromide trans to the JosiPhos-diarylphosphine moiety and (ii) Curtin-Hammett-type control over the interconversion between O- and S-bound isomers of palladium sulfenate species following rapid interconversion between re- and si-bound transmetalation products, re/si-Pd-OSPh (re/si-PdO-trans).

Full text of DOI:10.1021/jacs.7b03623

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Article
Palladium-Catalyzed Enantioselective Arylation of Aryl Sulfenate
Anions: A Combined Experimental and Computational Study
Tiezheng Jia, Mengnan Zhang, Samuel P McCollom, Ana Bellomo, Sonia
Montel, Jianyou Mao, Spencer D. Dreher, Christopher J. Welch, Erik L Regalado,
R. Thomas Williamson, Brian C Manor, Neil C. Tomson, and Patrick J Walsh
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 24 May 2017
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Palladium-Catalyzed Enantioselective Arylation of Aryl Sulfenate
Anions: A Combined Experimental and Computational Study
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Tiezheng Jia,a Mengnan Zhang,a Samuel P. McCollom,a Ana Bellomo,a Sonia Montel,a Jianyou
Mao,b Spencer D. Dreher,c Christopher J. Welch,c Erik L. Regalado,c R. Thomas
Williamson,c Brian C. Manor,c Neil C. Tomson,*,a Patrick J. Walsh *,a,b
aRoy and Diana Vagelos Laboratories, Penn/Merck Laboratory for High-Throughput Experimentation, Department of Chemistry,
b
University of Pennsylvania, 231 South 34th Street, Philadelphia, Pennsylvania 19104-6323, United States, Institute of Advanced
c
Synthesis, Nanjing Tech University, 30 South Puzhu Road, Nanjing, 211816, P. R. China, Department of Process Research & De-
velopment, Merck & Co., Inc., P.O. Box 2000, New Jersey 07065, United States.
ABSTRACT: A novel approach to produce chiral diaryl sulfoxides from aryl benzyl sulfoxides and aryl bromides via an
enantioselective arylation of aryl sulfenate anions is reported. A (JosiPhos)Pd-based catalyst successfully promotes the
asymmetric arylation reaction with good functional group compatibility. A wide range of enantioenriched diaryl, aryl
heteroaryl, and even diheteroaryl sulfoxides were generated. Many of the sulfoxides prepared herein would be difficult to
prepare via classic enantioselective oxidation of sulfides, including Ph(Ph-d5)SO (90% ee, 95% yield). A DFT-based
computational study suggested that chiral induction originates from two primary factors: i) both a kinetic and
thermodynamic preference for oxidative addition that places the bromide trans to the JosiPhos-diarylphosphine moiety,
and ii) Curtin-Hammett-type control over the interconversion between O- and S-bound isomers of palladium sulfenate
species, following rapid interconversion between re- and si-bound transmetallation products, re/si-Pd–OSPh (re/si-PdO-
trans).
Introduction
which must be purified to remove the minor
diastereomer. Overall, the procedure is tedious and
can result in loss of ee in the nucleophilic substitution
(Scheme 1B),10 which is typically done with Grignard
and organolithium reagents. To improve upon the
Andersen method, more elaborate chiral auxiliaries
and reagents have been developed, such as the
Chiral, nonracemic sulfoxides are important components
of natural products,1 synthetic bioactive compounds,2 and
marketed therapeutics, such as Nexium3 and Armodafinil4
(Figure 1). Sulfoxides are widely applied in agricultural
chemistry5 and polymer science.6 Recently, they have
attracted attention as promising ligands, and have been
employed successfully in asymmetric catalysis.7 Moreover,
sulfoxides could serve as starting materials to construct a
variety of scaffolds of great value.8
Senanyake
method11
or
Davis
oxaziridines.12
Nonetheless, moderate yields and enantioselectivities
are obtained in some cases.13 There are a few catalytic
enantioselective
approaches
to
synthesize
sulfoxides.9c,d The most popular is sulfide oxidation
pioneered by Kagan and Modena (Scheme 1C).14 This
approach works well for certain substrates, but gives
poor results when the substituents flanking the
sulfoxide are similar in size. The catalysts can exhibit
low chemoselectivity, resulting in over oxidation to the
sulfone and complicating purification (Scheme 1D).15
Figure 1. Selected sulfoxide-containing marketed
therapeutics.
Enantioenriched sulfoxides are traditionally
prepared by nucleophilic substitution with optically
active sulfinate amides or esters (Scheme 1A). The classic
chiral auxiliary-based Andersen procedure9 requires
diastereoselective synthesis of sulfinyl derivatives,
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Scheme 2. Catalytic asymmetric approaches to
enantioenriched diaryl sulfoxides.
5 mol % Pd(dba)2
7.5 mol % NIXANTPHOS
O
S
O
S
Ar2-Br
+
Ar1
Ar2
NaOtBu, CPME
80 oC, 12 h
Ar1
Ar2Br
O
S
[Pd]
Ar2Br
Ar1SO
Ar1
Ar2
H
N
Scheme 1. Classic approaches to enantioenriched
sulfoxides.
O
PPh2
PPh2
A
novel approach to the synthesis of
NIXANTPHOS
enantioenriched sulfoxides has emerged in the past
decade that involves generation of sulfenate anions16 (R–
SO–) and their transition metal catalyzed arylations.17
Sulfenate anions are formed in situ because of their highly
reactive nature. Despite significant progress, the arylation
strategy has focused primarily on the synthesis of racemic
sulfoxides.17 The only report of enantioselective arylation
of sulfenate anions is the pioneering work of Poli and
Madec in 2007 (Scheme 2a).18 The potential utility of this
approach is overshadowed by the lack of scope and low to
modest enantioselectivities (0-80% ee, average 56% ee).
Scheme 3. Racemic diaryl sulfoxide formation from aryl
benzyl sulfoxides and aryl bromides.
Results and Discussion
Catalyst Identification. We recently reported the
formation of diaryl sulfoxides from aryl benzyl sulfoxides
and aryl bromides via a palladium-catalyzed triple-relay
cascade reaction (Scheme 3).17d In this process, the
palladium catalyzes three different reactions–arylation of
the benzylic sulfoxide, cleavage of the C–S bond and
coupling of the sulfenate anion with the aryl halide. This
procedure was utilized to prepare diaryl sulfoxides
bearing various functional groups in excellent yields.
Thus, it was viewed as a good point of departure for
development of an asymmetric synthesis of diaryl
sulfoxides.
An innovative strategy was used by Dong, Houk
and their coworkers who reported dynamic kinetic
resolution (DKR) of allylic sulfoxides by combining the
Mislow-Braverman-Evans rearrangement17b with Rh-
catalyzed asymmetric hydrogenation (Scheme 2b).19 To
date this method has not been expanded beyond the
synthesis of enantioenriched n-propyl sulfoxides. Herein,
we report a palladium-catalyzed coupling of aryl sulfenate
anions with aryl bromides to afford enantioenriched
diaryl sulfoxides with enantioselectivities up to 98% and
high yields (Scheme 2c). A computational study sheds
light on the reaction pathway, and explores a unique
interconversion between O- and S-bound isomers of
palladium sulfenate species as the enantio-determining
steps.
The cascade reaction between benzyl phenyl
sulfoxide (1a) and 4-tert-butyl bromobenzene (2a) was
used as the test reaction. The enantioselective cross
coupling reaction was initialized with ligand screen under
conditions otherwise identical to the racemic diaryl
sulfoxide formation (1 equiv 1a, 2 equiv 2a, 3 equiv
o
NaOtBu, Pd(dba)2 in CPME at 80 C for 12 h). A large
library of sterically and electronically diverse
enantioenriched mono- and bidentate phosphine ligands
was tested. Of the 192 ligands screened, the four most
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enantioselective catalysts were all JosiPhos derivatives
determined by 1H NMR using 0.1 mmol CH2Br2 as internal
(L1–L4, see Table 1 for structures)20. These four ligands
standard. c 3 equiv 2a, 24 h. d Isolated yield.
1
2
3
were examined on larger scale, leading to excellent assay
yields (94–96%, determined by H NMR) and moderate
1
4
5
6
7
enantioselectivities (70–75%, Table 1, entries 1–4,
determined by chiral phase HPLC, see Supporting
Information for details). Due to the lack of commercial
availability of L3, it was not pursued. When the reaction
o
8
temperature was decreased from 80 to 50 C, the catalyst
9
bearing the parent JosiPhos ligand, L1, was the most
enantioselective (92% ee, 85% yield, entry 5). Ligands L2
and L4 exhibited enantioselectivities approximately 10%
lower (entries 6 and 7) than L1. To further improve the
yield, the equivalents of aryl bromide 2a was increased to
3 and the reaction time was extended to 24 h, resulting in
95% assay yield with no change in ee (91%, entry 8). A
survey of palladium sources, solvents, and bases resulted
in inferior yields and/or enantioselectivities (see
Supporting Information for details). Attempts to decrease
the temperature or catalyst/ligand ratio resulted in lower
yields of 3a (entries 9 and 10). Therefore, the optimized
conditions for the palladium-catalyzed enantioselective
coupling reaction are: 1a as the limiting reagent, 3 equiv
2a, 3 equiv NaOtBu base, 5 mol % Pd(dba)2/7.5 mol % L1
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Reaction Scope. The substrate scope of aryl
bromides with sulfoxide 1a was next determined (Scheme
4). In general, a wide variety of substituted aryl or
heteroaryl bromides were compatible with the optimized
conditions. 2-Bromonaphthlene (2b) proved to be a good
coupling partner, generating 3b in 91% ee and 85% yield.
Aryl bromides bearing electron-donating groups, such as
4-bromothioanisole (2c) or 4-bromoanisole derivatives
(2d), were very good cross-coupling partners, giving 84–
89% yield and 90–92% ee of the desired products (3c, 3d).
Notably, there are two different sulfur-containing
functional groups (sulfoxide and sulfide) in 3c, which
would render this product difficult to prepare by
traditional oxidation strategies. Electron withdrawing
groups, such as 4-F, 4-Cl, 4-CF3 and 3-OMe furnished the
corresponding products (3e–3h) in 86–98% yield and 89–
95% ee.
o
as the catalyst, in CPME at 50 C for 24 h. The absolute
configuration of 3a was determined to be R via X-ray
crystallography, and the crystal structure of 3a is
illustrated in Table 1 (see Supporting Information for
details).
Sulfoxides with heteroaryl moieties exhibit
various bioactivities, but can be difficult to prepare due to
their sensitivity towards oxidizing reagents.2 Our method
is compatible with the synthesis of heteroaryl sulfoxides.
Enantioenriched 3-quinolino phenyl sulfoxide (3i), 6-
quinolino phenyl sulfoxide (3j) and 3-pyridyl phenyl
sulfoxide (3k) required minor adjustments to the general
conditions, such as longer reaction times (see SI). Under
the modified conditions, the sulfoxide products were
generated in 90–97% enantioselectivity and 84–87% yield.
Of note, 3k is the key scaffold of a series of 5-HT2A
antagonists in the treatment of insomnia.2f,g Interestingly,
an aryl bromide possessing a secondary amide group (2l)
was coupled to form the sulfoxide with good
Table 1. Optimization of the enantioselective palladium-
catalyzed coupling reaction between 1a and 2a. a
ent ligan catalyst/ligan T/
Assay
ee
yield/% b /%
oC
80
80
80
80
50
50
50
50
40
50
ry
d
d loading/%
1
L-1
L-2
L-3
L-4
L-1
L-2
L-4
L-1
L-1
L-1
5/7.5
5/7.5
5/7.5
5/7.5
5/7.5
5/7.5
5/7.5
5/7.5
5/7.5
2.5/3.8
95
96
75
71
chemoselectivity,
although
the
yield
and
2
enantioselectivity were diminished (73% yield, 76% ee).
Products from Buchwald-Hartwig arylation21 or amide α-
arylation reactions22 were not observed in this reaction. 4-
Bromobenzophenone (2m) could also be utilized as a
coupling partner under our standard conditions (85%
yield, 90% ee). No products derived from 1,2-addition of
the deprotonated sulfoxide to the carbonyl group were
observed.
3
94
73
70
92
82
80
91
91
91
4
5
94
85
6
87
7
64
96(95d)
8c
9c
10c
23
Scheme 4. Substrate scope of aryl bromides in the
palladium catalyzed enantioselective arylation of
sulfenate anions 1a.
57
a
Unless otherwise stated, reactions were carried out with
1a (1 equiv), 2a (2 equiv), NaOtBu (3 equiv), 5 mol %
Pd(dba)2, 7.5 mol % ligand in CPME for 12 h. b Assay yields
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The scalability of the S-arylation reaction was
explored, as illustrated in Scheme 6. When 5 mmol
phenyl benzyl sulfoxide 1a (1.08 g) was coupled with 4-
bromo benzophenone, the sulfoxide product 3m was
isolated in 88% yield (1.35 g) with 91% ee.
The substrate scope of aryl benzyl sulfoxides in
the arylation with bromobenzene (2n) was next examined
(Scheme 5). Aryl benzyl sulfoxides bearing electronically
neutral (2-naphthyl, 1b) or electron-donating groups,
such as 4-tert butyl (1a), 4-OMe (1n) and 4-NMe2 (1o),
were coupled providing the corresponding products in
85–95% yield with 81–94% ee. As expected, the opposite
enantiomers were obtained in these coupling reactions
compared to those in Scheme 4. With 4-F (1e), 4-Cl (1f),
and 4-CF3 (1g) substituted aryl benzyl sulfoxides, the
desired products were isolated in 87–91% yield and 84–93%
ee. Sterically more hindered 2-tolyl benzyl sulfoxide (1p)
underwent coupling in 86% yield with 91%
enantioselectivity. Heteroaryl sulfoxides (3k, 3j, 3q)
bearing 3-pyridine, 3-quinolino and indole moieties were
prepared via this route (83–88% yield, 81–86% ee).
Scheme 6. Gram scale palladium-catalyzed coupling
between 1a and 2m.
Additionally, the arylation reaction was applied
to 1a and pentadeuterobromobenzene (2o) to prepare
enantioenriched 3r phenyl perdeutero phenyl sulfoxide
(Scheme 7). With assistance of (R)-(-)-1-(9-anthryl)-2,2,2-
trifluoroethanol (Pirkle’s alcohol)23 as the chiral resolving
1
agent, the ee of 3r was determined by H-13C-HSQC and
found to be 90%. Owing to the similarity of the two aryl
groups, this compound could not be prepared by
conventional metal-catalyzed asymmetric oxidations or
chromatographic resolution approaches.
Scheme 5. Substrate scope of aryl benzyl sulfoxides in the
palladium-catalyzed enantioselective coupling reactions
with 2n.
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the oxidative addition step was found to produce
qualitatively identical results to those performed in the
gas phase (see Supporting Information). Further
1
2
3
4
5
computational work was performed on gas phase species.
Scheme 7. Synthesis of 3r by palladium-catalyzed
arylation from 1a and 2o.
6
7
8
9
Diheteroaryl sulfoxides are a class of important
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bioactive scaffolds, yet the synthesis of these molecules
remains a challenge.2 We were pleased to find that the
arylation reaction could be successfully applied to the
synthesis of enantioenriched diheteroaryl sulfoxides.
Simply swapping the heteroaryl groups between
nucleophile and electrophile enabled the synthesis of
both enantiomers of 3-quinolino 6-quinoline sulfoxide (3s)
to be accessed from 1m & 2j and 1n & 2i under the same
conditions in 82–86% yield with 85–92% ee (Scheme 8).
Figure 2. Graphical depiction of the nomenclature used to
describe the computed isomers.
The lowest energy interaction of Ar–Br with Pd(0)
involves a ArBr→Pd dative bond with Pd–Br bond dis-
tances of ca. 2.53 Å. This finding contrasts with related
studies on less sterically demanding L2Pd(0) systems, for
which binding of the arene π-system to the low-valent
metal center is most favorable.25 In the present case, η2-
binding modes, involving the ipso-carbon and one of its
adjacent ortho-carbons (Pd–C bond distances range from
2.22–2.31 Å), lie ca. 4.5 kcal/mol higher in energy than Br-
bound isomers. Multiple Pd(ArBr)-Br and Pd(ArBr)-C
configurations were investigated, resulting in two primary
minima for each interaction type (Figure 3), with one set
constituting the precursors to cis oxidative addition and
the other to trans.
Scheme 8. Synthesis of both enantiomers of 3-quinolino
6-quinolino sulfoxide (3s) by palladium catalyzed
arylation.
Computational Studies. Density Functional
Theory (DFT) computational studies were performed to
investigate the origin of the enantioselectivity provided
by the (L-1)Pd complex. These studies employed the
OLYP functional and a hybrid basis set comprised of the
def2-TZVP bases for Pd (def2-SD ECP), Fe, Br, P, S, and
the ipso carbon of the Pd-bound aryl group as well as the
def2-SVP bases for all other atoms (see Supporting
Information for details). In all cases, the full ligand
framework was employed to capture subtle steric effects
on the enantiodetermining reaction pathway. To simplify
the notation in the following section, reference will be
made to i) the cis/trans position of the PhSO–/Br– ligand
with respect to the diphenylphosphino portion of L1 (Fig.
2, top left), ii) the re/si/R/S (pro)chirality of the Pd-bound
PhSO– ligand (Fig. 2, bottom), and iii) the Fe/Me face of
the complex (Fig. 2, top right), in reference to the
stereochemically active backbone CpFe and Me groups of
the ligand L-1, which lie on opposite faces of the pseudo-
square-planar metal center. When investigating the
oxidative addition of Ar–Br, 4-tBu-bromobenzene was
used as the substrate. In all other cases, the Pd-bound
aryl ligand was simplified to 4-Tol. A conductor-like
screening model (COSMO) using the dielectric constant
of CPME was employed when evaluating the anionic
species involved in transmetallation. In contrast to
related studies,24 the application of a solvation model to
Figure 3. Energy level diagrams for ArBr oxidative addition
to give PdBr-cis (left) and PdBr-trans (right).
The oxidative addition step itself was found to be
facile, leading to the PdBr-cis and -trans products with
energy barriers of 5.0 (trans) and 8.3 (cis) kcal/mol
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relative to the arene-bound, 16 e– Pd(0) complexes
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3
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5
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Pd(ArBr)-C and 9.8 (trans) and 12.6 (cis) versus Pd(ArBr)-
Br. The trans product, as reported by the Hartwig group
via X-ray crystallography,26 lies 2.5 kcal/mol lower in
energy than PdBr-cis, and both structures exhibit a
distortion from planarity that results from the steric
t
pressure exerted by either the Fe-side Bu group in PdBr-
7
8
9
trans or the Me-side Ph group in PdBr-cis (Figure 2). This
distortion manifests as a 30° twist between the planes
defined by P-Pd-P and CAr-Pd-Br. Reductive elimination
of ArBr was also calculated to be accessible (∆G‡ = ~21
kcal/mol), owing to distortion of the PdBr-cis/trans
complexes away from square planar geometries. Related
computational studies have determined ∆G for oxidative
addition from the arene-bound Pd(0) species to lie in the
range of ca. –35 kcal/mol,24 making the oxidative addition
functionally irreversible. In the present case, the inability
of the PdBr species to access square planar coordination
geometries diminishes the activation energy to reductive
elimination from PdBr-cis/trans. Regardless, the clear
kinetic and thermodynamic preference for formation of
PdBr-trans focused our attention on the trans isomer.
The reaction profile resulting from PdBr-cis formation is
described in the Supporting Information.
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Figure 4. Energy level diagrams for R/S-ArS(O)Ph formation,
calculated at the OLYP and TPSS levels of theory, following
transmetallation from PdBr-trans (bottom, center).
A COSMO solvation model was used when
investigating the structures of the anionic complexes that
result during transmetallation of PhSO– for Br–. We were
unable to locate pentacoordinate minima, possibly due to
the presence of high energy intermediates with small
energy barriers against decomposition into the square
The inclusion of a sodium counterion in the
transmetallation step may be important for calculating an
accurate activation energy, but evaluation of this more
elaborate potential energy surface is beyond the scope of
our current study. Doing so would require investigation
into multiple modes of attack, various bridging structures,
and detailed solvation models, leading to a minimum of
128 variations. We have similarly limited the scope of Pd-
based leaving groups to bromide, even though other Pd–X
species (e.g. Pd–OtBu) may form under the reaction
conditions. We believe these to be reasonable limitations
due to the steric profile of the ligand backbone, which
suggests that Pd–O bond formation would be preferred
over Pd–S during transmetallation. As shown below, we
do not believe the stereochemistry of transmetallation to
be enantiodetermining.
planar products.
Transmetallation may also be a
concerted process, which prompted us to search for
transition states that may lead to stereochemical
differentiation of the products. We investigated reaction
coordinates resulting from consideration of i) the two
open faces of the pseudo-square-planar metal center, Fe
and Me, ii) the ability of the PhSO– ligand to bind
through either sulfur or oxygen, and iii) the coordination
of PhSO– to Pd via either the si or re faces of the prochiral
sulfenate anion. Relaxed coordinate scans involving
variations in the Pd–O/S distances allowed us to discount
the four transmetallation mechanisms involving the
addition of PhSO– to the Me face of PdBr-trans. The Fe-
t
side Bu group blocks Br– from undergoing the out-of-
The preference for re-PdO-trans over si-PdO-
trans formation on transmetallation was found ultimately
to be unimportant as the species were determined to
interconvert readily. The re- and si-PdO isomers are
related by changes to the CAr–Pd–O–S and Pd–O–S–CPh
dihedral angles. The CAr–Pd–O–S dihedral angle changed
from 357° (re) to 295° (si) and Pd–O–S–CPh dihedral angles
varied from 266° (re) to 122° (si). Multiple attempts to
locate a transition state near the averages of these
extremes failed, prompting us to scan the potential
energy surface created by these two dihedral angles.
Doing so revealed a low energy pathway involving the
nearly sequential movement of the PhSO– ligand through
first one dihedral angle and then the other (Fig. 5). The
complex traverses ca. 80% of the change in the CAr–Pd–
O–S dihedral angle and ca. 20% of the Pd–O–S–CPh
plane distortion needed for transmetallation to occur via
this pathway. Similar steric constraints were operative in
preventing PhSO transmetallation from the Fe face. Of
the two remaining possible transition state orientations,
the lowest energy pathway involved re-O-binding of the
sulfenate anion to the Fe face of Pd (∆G‡ = +31.5 kcal/mol;
Figure 4, bottom).
This transition state structure
contained a Pd–Br distance of 2.896 Å, a Pd–O distance of
2.564 Å, and a pseudo-trigonal bipyramidal coordination
environment. The PPh–Pd–Br and PPh–Pd–O angles were
found to be nearly identical, at 137.1° and 136.3°,
respectively.
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Reductive elimination initially appeared as a
dihedral angle sweep on reaching the transition state
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(TSO-trans), which was found to lie on a broad saddle
point with an imaginary frequency of –22 cm–1. With an
energy barrier of 8.6 kcal/mol versus si-PdO-trans and 6.7
kcal/mol vs. re-PdO-trans (∆G favors the si-isomer by 1.9
kcal/mol), this low energy transition state allows the re-
and si-PdO isomers to readily equilibrate (Fig. 4), thus
removing transmetallation as the enantiodetermining
step.
likely point in the catalytic cycle at which stereoinduction
would occur. However, reductive elimination to produce
the diarylsulfoxide proceeds with ∆G‡ = 12.4 kcal/mol for
R-PdS-trans and 8.4 kcal/mol for S-PdS-trans, although
the higher absolute energy of S-PdS-trans places its
corresponding transition state (S-TS2-trans) only 0.5
kcal/mol below R-TS2-trans (Figure 4). Regardless, the
significantly lower energy barrier to reductive elimination
compared to PdO-PdS isomerization, coupled with the
more facile transmetallation path to PdO formation over
PdS, indicates that the stereochemical outcome of the
reaction is under Curtin-Hammett control operating in
the PdO-PdS interconversion step.
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To test this conclusion, we sought to
computationally perturb the complex in a manner that
would illustrate the ability of the ligand to effect chiral
induction. The persistent tetrahedral distortion of the
Pd(II) complexes exhibit P–Pd–X angles as low as 145°,
representing a significant deviation from the idealized
value of 180° for a 16 e–, d8 square planar species. These
distortions appear to arise from steric interactions
between the Ar–/Br–/PhSO– ligands and the phosphino
tBu group positioned on the Fe face of the complex. To
investigate if the Fe-side tBu group may be responsible for
stereoinduction, we truncated the tBu-based methyl
group located closest to the binding site of the PhSO–
ligand, creating a phosphine substituted with a Me-side
tBu group and an Fe-side iPr group.
Geometry
optimization of the resulting R/S-PdS’-trans and re/si-
PdO’-trans structures caused the S/O-donors of the
PhSO– ligands to move toward the P2Pd plane, generating
ground state structures with greater square planar
character (Table S7 in Supporting Information).
Following truncation, the PPh2–Pd–S/O angles increased
by an average of 13.4°, the Pd–S/O bond lengths shortened
by up to 0.29 Å, and notably, the PPh2–Pd–CtSO angle
increased by ca. 35° from R-TS1-trans to R-TS1’-trans, as
illustrated in Figure 6. Accordingly, the ∆∆G‡ between R-
and S-TS1’-trans was found to decrease by 65%, to a value
of 0.5 kcal/mol.
Figure 5. Top: Graphical results from a 49-point scan of the
potential energy surface defined by changes to the Pd-O-S-
CPh and CAr-Pd-O-S dihedral angles within PdO-trans. The
lower left corner corresponds to si-PdO-trans and the top
right to re-PdO-trans. Bottom: Depiction of the sequential
torsion angle changes required for passing through TS0-
trans.
We next considered the isomerization between
the PdO and PdS isomers. Transition states were located
that involved η2-binding of the S=O portion of the
molecule. S-TS1-trans, which originated from si-PdO-
trans (Fig. 4), has a larger activation energy (∆G‡ = 20.7
kcal/mol) than R-TS1-trans (∆G‡ = 19.1 kcal/mol). This
difference is mitigated in part by the higher ground state
energy of re-PdO-trans (+1.9 kcal/mol), but ultimately,
the transition state isomers differ in absolute energy by
1.6 kcal/mol. Again, the Fe-side tBu group appears to play
an important role by preventing the PhSO ligand from
coordinating in a mode that positions the S–O centroid
(CtSO) trans to the diarylphosphine. Instead, the η2-
bound sulfenate deviates significantly from square
planarity, with the S–O centroid lying 1.47 Å from the P–
Pd–P plane while subtending a CtSO–Pd–PPh angle of 139°.
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Figure 6. Structural overlay of R-TS1-trans (red) and R- computational study provides the first
A
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TS1’-trans (blue) as optimized at the OLYP level of theory
(see Supporting Information). Hydrogens have been
omitted for clarity.
mechanistic insights into the dynamic processes between
sulfenate anions and transition metals in enantioselective
arylations of these reactive species. DFT calculations
indicate that two primary factors lead to the high degree
of experimental control over the stereochemical outcome
of the reaction. First, the oxidative addition step favors
the formation of PdBr-trans, in which the bromide is
placed trans to the PPh2 portion of the chiral diphosphine
ligand. In so doing, the bromide and the subsequent
sulfenate ligand are forced to lie cis to the sterically
encumbering tBu groups of the PtBu2 portion of the
If the steric interaction of R/S-TS1-trans with the
Fe-side tBu group is in fact responsible for
stereoinduction, then it would stand to reason that the
less sterically encumbered S-TS1-trans isomer – with an
Fe-side PhSO oxygen – would be lower in energy. This
notion comports with the experimentally determined R-
stereochemistry of the diarylsulfoxide product, suggesting
that our computational model at the OLYP level of theory
lacks quantitative accuracy.
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diphosphine.
Once formed, the O-bound sulfenate
complex was found to isomerize to the S-bound sulfenate
species through an eta2-S,O-bound transition state under
Curtin-Hammett-type control.
Additional investigations to explore the
functional dependence of the transition state energies
indicated that the qualitative picture described above, in
which Curtin-Hammett control in TS1 is responsible for
stereoinduction, held true across a number of levels of
theory. Pure, hybrid, and meta-GGA functionals (OLYP,
O3LYP, TPSS, TPSS0, B3LYP) were screened. In all cases,
TS1 was found to be enantiodetermining, and two of them
(TPSS, TPSSh) predicted a lower relative energy for S-TS1-
trans, which would lead to the R-diarylsulfoxide product
(Figure 4; see Supporting Information). As seen for R-
TS1-trans in Figure 6, the steric imposition of the Fe-side
tBu group would be expected to influence the structure of
S-TS1-trans preventing the PhSO unit from binding to the
metal center in a symmetric fashion with respect to the
square planar coordination environment. However, while
the OLYP functional predicted a lower energy for the
isomer that placed the more sterically demanding atom (S)
We envision that our enantioselective palladium-
catalyzed arylation will be of great interest in the
medicinal chemistry and the synthesis of enantioenriched
sulfoxides ligands. We expect that insight gained from
our computational studies will be of use to those
considering the multiple mechanisms by which chiral
ligands can induce stereochemical control in complex
catalytic cycles.
ASSOCIATED CONTENT
Supporting
Information.
Procedures
and
full
characterization of new compounds, crystallographic data
(CIF). This material is available free of charge via the Internet
at http://pubs.acs.org.
t
next to the chiral-inducing Bu group, the experimentally
AUTHOR INFORMATION
consistent TPSS(0) results indicate that the lower energy
TS1 isomer (S-TS1-trans) will place the sterically least
demanding PhSO atom (O) next to the Fe-side Bu group.
Corresponding Author
t
*pwalsh@sas.upenn.edu, *tomson@upenn.edu
Thus, computational work at the OLYP level of theory
provided a qualitatively accurate picture, from which a
near-quantitatively correct view of the reaction profile
could be accessed by evaluating the performance of
various functionals at the enantiodetermining portion of
the reaction manifold.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We thank the National Science Foundation (CHE-1464744)
for financial support.
Conclusions
In summary, a catalytic asymmetric method to
synthesize enantioenriched diaryl sulfoxides from aryl
benzyl sulfoxides and aryl bromides via a palladium-
catalyzed arylation of aryl sulfenate anions is described.
The reaction can be classified as a dynamic kinetic
asymmetric transformation (DyKAT), because the
palladium obliterate the stereocenter of the racemic aryl
benzyl sulfoxide starting material.27 In contrast to S–O
bond formation in the traditional chiral oxidation of
sulfides, the C(sp2)-S bond is formed in this approach.
Thus, it offers a complimentary pathway to produce a vast
array of diaryl sulfoxides, some of which would be a
formidable challenge to prepare via previous catalytic
enantioselective reactions.
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