Asymmetric, Nearly Barrierless C(sp3)-H Activation Promoted by Easily-Accessible N-Protected Aminosulfoxides as New Chiral Ligands

Article abstract of DOI:10.1021/acscatal.8b04946

Although chiral sulfoxides are important motifs in medicinal chemistry and asymmetric synthesis, design and applications of sulfoxide ligands are still limited, in particular in the context of asymmetric C-H activation. We disclose herein the conception a

Full text of DOI:10.1021/acscatal.8b04946

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Article
Asymmetric, Nearly Barrierless C(sp3)-H Activation Promoted by
Easily-Accessible N-protected Aminosulfoxides as New Chiral lig-ands
Soufyan Jerhaoui, Jean-Pierre DJUKIC, Joanna Wencel-Delord, and Françoise Colobert
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b04946 • Publication Date (Web): 04 Feb 2019
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Asymmetric, Nearly Barrierless C(sp3)-H Activation Promoted by
Easily-Accessible N-protected Aminosulfoxides as New Chiral
ligands
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Soufyan Jerhaoui,a Jean-Pierre Djukic,b Joanna Wencel-Delord*a and Françoise Colobert*a
a) Laboratoire d’Innovation Moléculaire et Applications, ECPM, UMR 7042, Université de Strasbourg/Université de Haute –
Alsace, 25 rue Becquerel, 67087, Strasbourg Cedex; b) Institut de Chimie de Strasbourg, UMR 7177, Université de
Strasbourg
ABSTRACT: Although chiral sulfoxides are important motifs in medicinal chemistry and asymmetric synthesis, design and
applications of sulfoxide ligands are still limited, in particular in the context of asymmetric C-H activation. We disclose herein the
conception and synthesis of enantiopure N/S ligands: N-protected aminosulfoxides. The potential of these auxiliaries in asymmetric
C(sp3)-H activation is demonstrated as high enantioselectivity is reached during a Pd-catalyzed direct arylation of cyclopropane
carboxylic acid derivatives. Besides, the capacity of these ligands goes far beyond as yet unknown direct alkynylation could also be
performed with enantiomeric ratio up to 92:8. The preliminary mechanistic studies shed light on their original mode of action; key
non-covalent interactions between the chiral complex and the substrate allows stabilization of agostic M-H-C interaction and 휋-
stacking ligand-substrate bonding. DFT investigations suggest that, thanks to this unusual ligand/substrate activation, commonly
recognized as difficult, the cleavage of the C-H bond is virtually barrier-less.
KEYWORDS: asymmetric C-H, enantioselective C(sp3)-H activation, aminosulfoxide, DFT investigations, cyclopropane
1. INTRODUCTION
ligand was crucial to reach high efficiency and
stereoselectivity. Besides, the same family of chiral auxiliaries
was applied for a rare example of atroposelective direct
arylation (Scheme 1B-c).[10] In clear contrast, chiral sulfoxide
ligands have never been used in direct enantioselective
functionalization of unbiased C(sp3)-H bonds.
Chiral sulfoxides are important structures, present in natural
products and biologically active compounds.[1] Moreover,
stereogenic sulfinyls have established themselves as very
powerful chiral auxiliaries for
a
large panel of
diastereoselective transformations.[2] Chiral character of the
sulfur atom combined with its strong coordinating properties
and high configurational stability render this motif also an
appealing candidate for the design of original chiral ligands
(Scheme 1A). Accordingly, over the last two decades it has
been shown that enantiopure bisulfoxide ligands are efficient
chiral inductors for reactions such as Rh-catalyzed 1,4-
conjugate
additions[3]
whereas
phosphine/sulfoxide,[4]
olefin/sulfoxide[5] and oxazoline/sulfoxide ligands[6] are able to
coordinate Pd, thus enhancing asymmetric allylic alkylation.
However, the design of conceptually new sulfoxide-based
ligands has remained a rather niche topic, in particular
regarding C-H activation.[7]
In 2007 White has demonstrated a unique activity of Pd-bis-
sulfoxide complex for direct C-H activation of allylic
substrates, thus showcasing that sulfoxides might be of great
interest for the development of an extremely challenging field
of asymmetric C-H activation (Scheme 1B-a).[8] Design of a
stereoselective version of such a coupling turned out to be
puzzling and an intramolecular direct allylic C-H activation/C-
O coupling sequence was disclosed recently (Scheme 1B-b).[9]
In this elegant isochromans’ synthesis, oxazoline/sulfoxide
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second chirality element was introduced (L3). These original
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ligands have been prepared using a rapid and robust protocol
employing enantiopure sulfinate precursor.[14] This efficient 4-
steps synthesis involves initial imine formation between an
aldehyde and para-methoxyaniline followed by nucleophilic
addition of in situ deprotonated (R)-1-methyl-4-
(methylsulfinyl)benzene occur smoothly, delivering the
expected stereogenic amine in high diastereoselectivity
(typically 9:1) and efficiency. Purification by recrystallization
delivers a ligand direct precursor as a single diasteromer and
final deprotection and protection sequence furnishes optically
pure N-protected aminosulfoxides. Using this modular
protocol, L3-L13 were synthesized by varying: 1) substituents
on the aliphatic backbone, 2) steric and electronic features of
the sulfoxide moiety and 3) nature of N-protecting group.
With thus synthesized library of new chiral ligands, we
embarked on their evaluation in asymmetric C(sp3)-H
activation.[15],[16]
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Scheme 1. Design of new sulfoxide ligands for asymmetric
C(sp3)-H activation.
Recently, our group has shown that a chiral sulfoxide moiety
can be embedded in a bicoordinating N,S directing group, thus
promoting stereoselective C(sp3)-H activation of non-activated
substrates.[11] Encouraged by these results and by the seldom
applications of the sulfoxide ligands in the C-H activation
reactions and following our program on asymmetric C-H
activation using sulfoxide moiety,[12] we embarked on
Scheme 2. Synthesis of N/Sulfoxide ligands.
Regarding prevalence of small cyclopropanes in natural
products and biologically active scaffolds,[17] direct arylation
of 1a was selected as a test reaction (Scheme 3). It should be
highlighted that although direct enantioselective arylation of
cyclopropanes has already been disclosed, specially designed
designing
a conceptually new family of N/sulfoxides
auxiliaries that might be able to induce an enantioselective
metallation of non-activated C(sp3)-H bonds (Scheme 1C).
Our initial hypothesis surmised that the sulfoxide ligand might
showcase a particular mode of action by establishing non-
binding interactions with the substrate. Such a « substrate
activation » via 휋-stacking should facilitate and direct the C-H
activation step by guaranteeing spatial proximity. Besides, the
presence of the N-coordinating moiety should promote the C-
H abstraction step by acting as an internal base. Finally, a
chirality relay between the C-stereogenic center and the N-
coordinating motif could be expected thus giving a promise of
an efficient stereoinduction.
substrates
such
as
cyclopropylmethylamines[18]
or
cyclopropanecarboxamides bearing a quaternary carbon[19]
were required whereas functionalization of simple
cyclopropanecarboxylates has been achieved only recently.[20]
Encouragingly, L1, in combination with Pd(TFA)2 is able to
promote this challenging direct coupling, albeit the desired
product was isolated in low, 25% yield and enantioselectivity
of 70:30 (Scheme 3). Comparable results were obtained when
using the more flexible L2, but a remarkable improvement
was witnessed when conducting the reaction with L3, bearing
an additional stereocenter. In this case the arylated
cyclopropane was delivered in 90% yield and 85:15 er.
Interestingly, the expensive directing group (CONH(4-CF3-
2,3,5,6-C6F4), substrate 1a) could be replaced by a more
economic pentafluoroamide (substrate 1b) without altering the
efficiency of the catalytic system whereas simple benzylamide
directing group (1c) failed. Interestingly, when dia-L3 was
used, the reaction occurred with the same stereoselectivity and
efficiency, furnishing the opposite enantiomer of 3; thus
indicating the key role of the C-stereogenic center of the
ligand. Further ligand screening showed that more flexible L4,
generating upon coordination with Pd a 6-member chelate,
2. RESULTS AND ANALYSIS
Our experimental efforts began by synthesizing a small library
of original S/N ligands (Scheme 2). Initially, an aromatic
ligand L1, showing a rigid architecture and featuring both, C-
central chirality and enantiopure S-atom was synthesized
using enantiopure benzylamine as a starting material.[13]
Besides, surmising that a certain flexibility of the ligand might
be required to accommodate both N and S liganding sites
during coordination of Pd, a selection of more flexible, linear
auxiliaries have been prepared. Firstly, a simple ethane linkage
was installed between N and S atoms (L2) and progressively a
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performed poorly. Increased steric hindrance on the sulfoxide fluorinated motifs such as CF3 (13) and OCF3 (14) are well
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moiety (L5) and a rigidified aliphatic backbone (L6) were
detrimental to both, reactivity and stereoselectivity.
Subsequently, the impact of the N-protecting group was
evaluated (L7-L9). TFA-protected ligand L7 turned out to be
slightly less efficient, but the desired product was isolated with
a comparable optical purity. In contrast, in a presence of L8
and L9, bearing respectively Boc and PMP protecting groups,
only low conversions were measured. Finally, the steric and
electronic properties of the phenyl group on L3 were
surveyed. Introduction of a sterically hindering substituent
such as Me or CF3 at para-position or 2-naphthyl-derived
ligand allowed further increase of the stereoselectivity up to
90:10 (L10-12). Finally, optimal results were obtained using
L13 bearing sterically demanding tBu moiety; the expected
product was thus isolated with 94:6 e.r. and 75% conversion.
tolerated. The high reactivity of this catalytic system is further
highlighted by a possible coupling with challenging ortho-
substituted Ar-I, as witnessed by formation of 18 and 19 in
excellent yields and high stereopurity.
O
F
F
Pd(TFA)2 (10 mol%)
L13 (15 mol%)
O
F
F
HN
F
HN
F
Ar-I
+
Ag2CO3 (2 equiv.)
NaTFA (50 mol%)
0.1 M Hex/CHCl3 2:1
80 °C, 24 h
F
F
F
F
R
1b
3-20
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F3C
Ac
MeO2C
NC
3
6
7
8
4
5
78% yield
96:4 e.r.
66% yield
87% yield
93:7 e.r.
77% yield
85:15 e.r.
81% yield
96:4 e.r.
77% yield
94.5:5.5 e.r.
97.5:2.5 e.r.
O2N
Cl
With the optimal ligand in hand, reaction conditions were
optimized.[21] Use of a mixture of hexane and chloroform was
beneficial for the chirality control but a change of silver salt
from Ag2CO3 to AgOAc or AgTFA almost totally shut down
the reactivity. Addition of NaTFA further promoted the
reactivity while decreasing the excess of Ar-I coupling
partner. Finally, arylation of 1b delivered 3 in 78% isolated
yield and e.r. of 96:4 when using 10 mol% of Pd(TFA)2 in
combination with 15 mol% of ligand, 2 equivalents of Ag2CO3
and 50 mol% of NaTFA, in hexane/chloroform mixture at 80
°C over 24h.
Br
NO2
NO2
11
Ac
OCF3
CF3
Cl
15
71% yield
94:6 e.r.
12
92% yield
92:8 e.r.
9
13
14
10
84% yield
94.5:5.5 e.r. 93.5:6.5 e.r.
58% yield
95:5 e.r.
75% yield 67% yield
51% yield
91:9 e.r.
92:8 e.r.
CO2Me
CHO
F
F
OMe
62% yield
96.5:3.5 e.r.
16
17
19
20
28% yield
86.5:13.5 e.r.
18
63% yield
95.5:4.5 e.r.
88% yield
93:7 e.r.
87% yield
93.5:6.5 e.r.
(1R,2S)-8
Scheme 4. Scope of arylation.
One of the important features of new ligands is their potential
to promote few distinct transformations. Accordingly, the
amino-sulfoxide L13 was evaluated in asymmetric
alkynylation that has not yet been reported for the
cyclopropane substrate. Initially 1b was reacted with
(bromoethynyl)triisopropylsilane 21-Br. Unexpectedly, under
the reaction conditions previously optimized, an original
cyclized compound 23 was isolated as a major product
(Scheme 5a). Notably, when switching to the iodinated
partner, ie. (iodoethynyl)triisopropylsilane 21-I, the outcome
of the reaction was altered and further fine tuning of the
reaction protocol allowed synthesis of non-cyclized
alkynylated cyclopropane 22 in more than 10:1 selectivity,
73% isolated yield and 92:8 e.r. (Scheme 5b). Tert-
butyl(iodoethynyl)dimethylsilane 24-I delivered product 25 in
a comparable enantiopurity and high yield.
Scheme 3 Ligand optimization
This enantioselective direct C(sp3)-H arylation turned out to be
highly tolerant to a large panel of aryl iodides (Scheme 4).
Arylation with simple iodobenzene (4) was as efficient as the
coupling with both, electron-rich p-iodotoluene (3), and
aromatics bearing electron withdrawing moieties such as CF3,
CO2Me or Ac, delivering the functionalized products with up
to 95% ee (5-7). In contrast, decreased stereoselectivity was
observed for the CN-substituted Ar-I (8 isolated with 85:15
e.r.). Meta-substituted Ar-I also performed remarkably well;
Br-substituted 9 was isolated in 58% yield and e.r. of 95:5 and
a comparable stereoinduction was reached for aryliodides
bearing NO2-moieties (10 and 11). Biologically relevant
Scheme 5. Asymmetric direct alkynylation of
cyclopropanes.
Subsequently, the removal of the amide auxiliary was studied
(Scheme 6).[11] Under the previously developed conditions 10
was converted into the chiral cyclopropane ester 26 in 90%
yield with no modification of the optical purity. Further
recrystallization allowed almost total enantiomeric enrichment
(Scheme 6a) thus this cis-substituted cycloproprane was build-
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up with ee > 99.5%. Structural X-ray diffraction analysis[22] of
26 confirmed the absence of epimerization of the stereocenters
in the cyclopropane ring. Besides, a large-scale arylation of 1b
proceeded smoothly and the coupling product 16 underwent
hydrolysis and following esterification under Yu’s
conditions[23] provided 552 mg (63% yield) of the ester 27
(Scheme 6b).
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Scheme 8 Putative mechanism of the exogenous-base-less C-H
bond activation promoted by the ancillary acetyl group at Pd-
bound L13
Scheme 6. Cleavage of the auxiliary and large-scale
synthesis.
3. DISCUSSIONS
3.1. Preliminary mechanistic insights on the formation of
the active catalyst species.
The efficient stereoinduction observed during the
functionalization of cyclopropane rings suggests the initial
formation of an active catalyst cat-Pd-L13 from Pd(TFA)2
[24]
and L13
In accordance with this hypothesis, formation of
binuclear cat-Pd-L13 was observed when mixing the
palladium source and the ligand but addition of silver
carbonate was crucial to achieve full conversion into the
desired chelate (Scheme 7) as indicated by NMR, IR and HR-
MS analysis. This structure quite clearly shows the expected
bidentate S,N coordination and formation of a pseudo-planar
five-membered ring. Absolute configuration of L13 imposes
both, Ar-substituent on C-stereocenter and pTol-motif at S-
stereocenter, to point in the same direction. Besides, the
monomeric Pd/L13 units are bridged with 휇–trifluoroaceto
group.
Figure 1. Gibbs energy (in kcal/mol) profiles for the
conversion of pre-dia1 and pre-dia2 into the heteroleptic
bischelated Pd complexes Pd-dia1 and Pd-dia2 a) in the gas
phase at T= 298.15 K and b) in COSMO[30] (hexane) at
383.15 K.
Ac
4-tBuPh
N
H
O
O
H
H
Pd
S
pTol
i. Pd(TFA)2 (1 equiv.), 1 h
O
F3C
F3C
pTol
L13
O
ii. Ag2CO3 (1 equiv.), 1 h
CD2Cl2, rt
H
S
O
H
3.2. DFT investigation of the C-H bond activation step.
H
Pd
O
N
Considering the unprecedented architecture of this ligand,
DFT-based mechanistic studies were subsequently undertaken
to elucidate the mechanism of this coupling. For the purpose
of this study the recourse to DFT-D3[25]was considered
mandatory as the stability of the key agostic reactive
complexes, which are generally considered to take a central
part into the C-H bond activation, strongly depends on the
attractive contribution of London force (also known as
dispersion).[26] All calculations were carried out at the
4-tBuPh
Ac
Scheme 7. Synthesis of dimeric Pd/L13 complex.
ZORA[27]-PBE[28] -D3(BJ)[25]/all electron TZP level
(cf.
details in the SI), which has already shown good performance
in modeling transition metal organometallic systems.[29] For
comparison purposes thermodynamic parameters, that is
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The key C-H bond activation reaction was computed for the
mainly Gibbs energy variations G were computed for models
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2
3
arylation of the amidate arising from 1b in the presence of
L13. It was surmised that enantioselectivity is controlled
during the C-H activation step, when heteroleptic bischelated
Pd intermediates Pd-dia1 and Pd-dia2 are formed.
in the gas phase at 298.15 K (1 atm) and for models optimized
by accounting solvation by the COSMO[30] model
parametrized for n-hexane at 383.15 K (1 atm) (Figure 1).
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Figure 2 Gas phase models of pre-dia1-2 were optimized by DFT-D at the ZORA-PBE-D3(BJ)/all electron TZP level (see SI
for NCI plots for COSMO-DFT models) and analyzed by QTAIM and NCI methods: a) joint QTAIM and NCI plots[31] of
noncovalent interactions for pre-dia1, b) joint QTAIM and NCI[31] plots for pre-dia2. NCIs are materialized by reduced
density gradient isosurfaces (cut-off value s= 0.02 a.u., = 0.05 a.u.) colored according to the sign of the signed density 
(red colored fonts, in Å) : NCI isosurfaces are colored in red and blue for attractive and repulsive (or non bonded) NCI
respectively. Significant interatomic distances (in Å) and atom color codes are detailed on the right hand side models.
QTAIM analysis resulted on a series of bond paths (materialized by rainbowed lines), ring critical points (materialized by
green dots) and bond critical points (3,-1) (materialized by red dots).
In principle this assumption requires, prior to the carbonyl-
assisted C-H bond activation,[32] the formation of reactive
complexes pre-dia1 and pre-dia2 wherein Pd-C-H
“agostic”[33] interactions[34] result from palladium’s interaction
with C-H bonds of cyclopropyl’s 2 and 3 positions (Scheme 8
and Figure 1) positioned cis with respect to the carbonyl
group. Agostic interactions are indeed suspected to establish
prior to effective C-H bond activation.[35] Assuming the model
reaction of amidate an-1b with cationic Pd chelate cat-Pd-
L13 (Scheme 8), computation shows that the formation of
pre-dia2 is slightly more exoergonic than that of pre-dia1 by
only 3 kcal/mol whether computed in the gas phase at 298.15
K or when solvation was accounted for with the COSMO
framework at 383.15K, that is the actual temperature of the
catalysis taking place in a sealed vessel; the overall Gibbs
enthalpy G (298.15 K, 1 atm.) for this model step being ~ -
100 kcal/mol (Figure 1).
(BP) and critical points BCP (3,-1) exist between the
cyclopropylic carbon atom Ccy and the Pd centre and between
the Ccy-bound H atom and the proximal acetyl’s oxygen atom.
In contrast, no interactions have been demonstrated between
the carbon-bound Hcy atom and the Pd centre. Table 1 lists the
most significant informations extracted from the QTAIM
study, i.e densities  and the negative laplacian of the density
¼∇2 at bond critical points (3,-1), and from the analysis of
related atomic Bader charges q and Mayer bond orders m. The
electron density  at those critical points is slightly lower than
for other coordination bonds that involve the Pd centre with
amido and sulfoxide-type ligands. However the situation
encountered here suggests that the acetyl moiety has a central
role as an intramolecular proton scavenger actively involved in
the C-H bond activation already in the early stage of the
reactive complex.
An intuitive way of depicting this peculiar “agostic situation”
would be that of an intramolecularly base-assisted palladation
of the polarized Ccy()-Hcy() bond matching the general so-
called CMD mechanism, i.e the concerted carbon metallation-
deprotonation. Scrutiny of so-called Bader atomic charges for
the main atoms involved in the Ccy-Hcy bond activation,
namely Pd, Ccy, Hcy and O (Table 1) support the hypothesis
that the non-covalent component of the agostic interaction
QTAIM and NCI investigation of the reactive complexes.
The joint analysis of the bonding structure within gas-phase
models of pre-dia1-2 intermediates by the quantum theory of
atoms in molecule (QTAIM[36]) and the intuitive non-covalent
interaction (NCI[31]) plot method reveals the two-sided nature
of the C-H-to-Pd interaction, i.e its covalent and non-covalent
nature. Indeed, QTAIM analysis indicates that bond paths
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bears an ionic character. In fact for all cases of reactive the already electronically favored trans N-Pd-N
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8
complexes displayed in Table 1 the Pd-Ccy bond bears the
properties of a typical ionic bond with 1/4∇2  and a low
value of  in the 10-2 order.[37] Quite interestingly the NCI
isosurfaces in both pre-dia1 and pre-dia2 display clearly an
attractive component in the Pd-Ccy interspace (Figure 2),
notwithstanding the type of models considered (either gas-
phase or COSMO “solvated”, cf. SI). This red-colored
reduced density gradient isosurface perpendicular to the Pd-
Ccy segment contains a hole typical of those situations[38]
where a weak charge transfer interaction is supported by
attractive NCIs. In this case the Ccy-Pd bond path passes
through this “hole” and the associated BCP is positioned in its
center. Furthermore, in pre-dia2 an attractive NCI isosurface
is present in the Hcy-O segment, exactly positioned at a BCP,
whereas in pre-dia1 the same NCI isosurface is non-bonding,
illustrating the active role of the acetamido group.
Comparison of  values at BCPs and Mayer bond orders m[39]
of pre-dia1 and pre-dia2 suggests that the Ccy-Hcy bond is
significantly weaker in pre-dia2 than in pre-dia1. This is
consistent with the interatomic distance that is more elongated
in pre-dia2 (Ccy-Hcy= 1.133 Å, Pd-Hcy= 2.038 Å, Pd-Ccy=
2.394 Å, Hcy-O= 1.926 Å) than in pre-dia1 (1.119 Å).
Consistently the Hcy-O interaction is slightly stronger in pre-
dia2 (m in pre-dia2 is two-fold that in pre-dia1). These slight
differences outline the predisposition of pre-dia2 to undergo
palladation due to the fact that the vicinal acetyl group
contributes to the polarization of this C-H bond and facilitates
the transfer of Hcy onto the O centre. Extended transition
state-natural orbital for chemical valence analysis[40] (abbr.
stereochemistry, which by the way is also the only one
relevant in the CMD mechanism for it brings the cyclopropyl
and acetyl group in close vicinity. It has been reported by
Tsuzuki et al.[41] that the hexafluorobenzene-benzene slipped
parallel complex is expected to have a calculated interaction
energy twice as large as that of the dibenzene dimer due to
dominant dispersion and electrostatic-based attractive
interactions.[12] This feature of fluoroarene-arene[42]
interactions might well be of importance in both reactive
complexes studied here and might contribute to the cohesion
of pre-dia1 and pre-dia2. However, it must be stressed that
the inter-arene stacking in pre-dia1 is significantly less
optimal than in pre-dia2 as the C6F5 moiety only partly
overlaps with the tolyl group: the Cipso-Cipso distance separating
the tolyl ring from the pentafluorophenyl in pre-dia1 (3.745
Å) is significantly longer than that in pre-dia2 (3.363 Å),
wherein the slightly staggered inter-arene parallel overlap is
more optimal. For the purpose of comparison the analogue of
pre-dia2 wherein all F atoms were replaced by H atoms, i.e.
pre-dia2H, was computed and submitted to QTAIM and NCI
analyses (Table 1). As shown in Table 1 the replacement of F
atoms by H results in slight changes in the electron density
topology in the Pd-Ccy-Hcy motif. Although in pre-dia2H the
Pd-Ccy interaction remains roughly identical from the view
point of  and m parameters to that in pre-dia2, the most
significant change occurs in the Hcy-O interaction that bears a
Mayer bond order m about half of that encountered in pre-
dia2 and a density at BCP by one third lower than in the
fluorinated analog (Table 1).
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It is speculated that this difference is the result of combined
conformational strains and slightly lower polarization of the
Ccy-Hcy bond in pre-dia2H. It is not clear yet whether the
presence of the remote C6F5 group is solely responsible for the
peculiar property of the agostic Ccy-Hcy to Pd interaction
though. The exoergonic conversion of pre-dia1 and pre-dia2
into Pd-dia1 and Pd-dia2 respectively involves transition
states TS-dia1 (gas phase model TS= 403 icm-1, COSMO
model TS= 450 icm-1) and TS-dia2 (gas phase model TS=
415 icm-1, COSMO model TS= 479 icm-1), in a quasi barrier-
less fashion for pre-dia2 ( ~0 kcal/mol in the gas phase at
298.15 K and 2 kcal/mol in the COSMO model at 383.15 K)
and with a slightly higher Gibbs activation energy for pre-
dia1 though (1 kcal/mol in the gas phase at 298.15 K and 4
kcal/mol in the COSMO model at 383.15 K). In stark contrast
with the accepted base-assisted Pd(II) C-H bond activation
mechanism[32c] but in rather good accord with the mechanism
proposed by Yu et al.[32b] for a different Pd(II) initiated alkyl
C-H bond activation displaying a higher activation barrier of
ca. 10 kcal/mol, it is now conspicuous that the migration of the
“activated” H atom of the cyclopropyl to the vicinal
acetylamido O atom occurs with the assistance of an attractive
noncovalent HCy-Pd interaction in both TS-dia1 and TS-dia2
according to NCI isosurface plots (Figure 4a,b). The red
isosurface located within the Pd-Ccy-O triangle is not related to
any bond path or bond critical point. The QTAIM analysis of
both TS-dia1 and TS-dia2 locates indeed quite expectedly
BPs and BCPs for the Pd-Ccy, Pd-Hcy and O-Hcy interactions
(cf SI for details).
ETS-NOCV, cf Supporting Information for details),
a
fragment-based orbital interaction analytical method, provides
further confirmation of the charge transfer operating from the
Ccy-Hcy bond to the Pd center (cf SI for details) and
complements the results of QTAIM.
Figure 3  interactions between the pentafluorophenyl
and the tolyl groups in pre-dia1, pre-dia2, pre-dia2H, TS-
dia1, TS-dia2, TS-dia2H: values of Cipso-Cipso distances are
given below each representation. The red arrow designates
the considered Cipso positions.
Note that in all models some -stacking of the C6F5 and p-tolyl
groups (Figure 3) allegedly contributes to the stabilization of
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Table 1. Selected parameters (negative of the laplacian of the density 1/4∇ 2, density at bond critical point @BCP(3,-
1), Mayer bond order m, Bader atomic charges q) for the QTAIM analysis of reactive complexes and associated transition
states pre(TS)-dia1-2
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1/4∇ 2
@BCP(3,-
1) (au)
@BCP(
3,-1) (au)
1/4∇ 2
@BCP(3,-
1) (au)
 @BCP(3,-
1) (au)
structure
bond
path
m
q(Ccy),
q(Hcy),
q(Pd),
q(O)
-0.15,
0.11,
structure
bond
path
m
q(Ccy),
q(Hcy),
q(Pd),
q(O)
-0.30,
0.33,
pre-dia1
TS-dia1
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0.60,
0.57,
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-1.07
-1.03
Pd-Ccy
Ccy-Hcy
Hcy-O
-0.042
0.195
-0.014
0.054
0.251
0.018
0.17
0.94
0.06
Pd-Ccy
Ccy-Hcy
Hcy-O
-0.045
0.091
-0.020
0.082
0.174
0.090
0.26
0.65
0.37
pre-dia2
-0.16,
0.14,
0.60,
-1.06
TS-dia2
-0.30,
0.33,
0.57,
-1.03
Pd-Ccy
Ccy-Hcy
Hcy-O
-0.042
0.183
-0.023
0.054
0.243
0.032
0.20
0.88
0.12
Pd-Ccy
Ccy-Hcy
Hcy-O
-0.045
0.090
-0.022
0.081
0.175
0.089
0.27
0.65
0.36
pre-dia2H
-0.12,
0.10,
0.60,
-1.06
TS-dia2H
-0.33,
0.34,
0.57,
-1.03
Pd-Ccy
Ccy-Hcy
Hcy-O
-0.042
0.191
-0.016
0.052
0.249
0.020
0.17
0.94
0.06
Pd-Ccy
Ccy-Hcy
Hcy-O
-0.046
0.076
-0.017
0.084
0.162
0.097
0.28
0.63
0.39
data, in both reactive complexes the Ccy-Hcy bond is mostly a
“covalent” bond, of “shared” character according to QTAIM;
it is clearly weaker in pre-dia2 than in pre-dia1. Its
activation operates by an ionic interaction with the vicinal O
center leading to a situation in the associated “early transition
state” where still a significant “shared”(covalent) character
remains. According to figure 4 that depicts NCI plots for both
TS-dia1 and TS-dia2, the migration of H atom from the
aromatic carbon atom to the acetate’s oxygen is attractively
assisted by noncovalent interaction with the Pd center, which
to the best of our knowledge is unprecedented. At this turning
point, the driving exergonic formation of Pd-dia1-2 is crucial
to ensure thermodynamic irreversibility.
3.3. Stereochemical model.
Elucidation of key factors governing the stereodiscrimination
during an enantioselective transformation is generally highly
challenging, when comparing rather small energy barriers that
may lead to a favored formation of one enantiomer compared
to the other. However, the experimental results combined with
DFT calculations provide indications allowing to propose of a
plausible stereochemical model for this asymmetric C(sp3)-H
activation. Firstly, electronic in nature factors governing the
stereoselectivity have been uncovered via DFT calculations
(Figures 1, 3) and summarized on Scheme 9a. The energy
difference of pre-dia1 and pre-dia2 of ca. 3 kcal/mol was
found, in agreement with experimentally observed
enantioselectivity. Combination of several effects explains the
preference given to Pd-dia2 in the catalysis.
Based on the DFT calculations, the first effect is the optimal
compactness and cohesion of reactive complex pre-dia2,
which bears the tightest  arrangement and the optimal
trans-N-Pd-N coordination stereochemistry that brings the
cyclopropyl moiety close to the acetamido moiety that acts as
the internal base. It can be seen in Figure 3 that the 
stacking arrangement and Cipso-Cipso distances in the reactive
complexes and transition states vary the most for pre-dia1,
whereas -stacking in pre-dia2 remains mostly unchanged.
Even though TS-dia1 benefits from a better  overlap than
in its precursor reactive complex pre-dia1, the activation
barrier remains slightly higher than for pre-dia2/TS-dia2.
The second effect is an optimal “agostic” C-H-Pd interaction
benefiting from a polarization of the Ccy-Hcy bond by an
effective interaction with the acetylamido side group that is
stronger in pre-dia2 than in pre-dia1. According to QTAIM
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is crucial in ensuring catalytic turnover by allowing the ready
decoordination of the functionalized substrate upon
completion of the full catalytic cycle.
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Figure 4. NCI isosurfaces[31a] in gas-phase models of TS-
dia1 (a) and TS-dia2 (b) with significant interatomic
distances and imaginary frequencies associated to the Ccy-
Hcy bond activation assisted by the vicinal Pd and O
Scheme 9. Speculative stereomodel.
centers.
NCIs are materialized by reduced density
In addition to these mechanistic considerations, the
experimental data provide complementary information about
steric factors governing the stereoinduction. During the
screening of different ligands it was observed that while L13
induces excellent enantioselectivity of 94:6, its thioether
analogue furnished the expected product as 75:25
enantiomeric mixture (cf Supporting Information for details).
This result shows clearly that the chiral induction is mainly
controlled by the C-stereogenic center of the ligand.
Accordingly, a chirality relay from the ligand to the substrate
might be expected (Scheme 9b).[43, 24c] For conformational
reasons, the steric repulsion between the Ar substituent of the
ligand, pointing upwards, and the N-Ac moiety, pushes acetyl
below the Pd-coordination plane. As the acetyl moiety plays
the role of an internal base and a proton shuttle actively
involved in the metallation step, the proton downward would
be abstracted to give the corresponding metallacycle
gradient isosurfaces (cut-off value s= 0.02 a.u., = 0.05
a.u.) colored according to the sign of the signed density 
(Significant interatomic distances are detailed in red
colored fonts, in Å). Atom color code: Pd, orange, O, red, F
green, S, yellow N blue, C grey. The red isosurface in the
Pd-Hcy segment materializes the attractive non-covalent
assistance of the Pd centre to the Hcy migration in the C-H
bond activation process.
Finally, a supplementary important factor that may also be
relevant is the topology or shape of Pd-dia1 and Pd-dia2.
Although being almost isoenergetic, Pd-dia2 displays a
marked helical distortion that tilts the 4-tert-butylphenyl group
about 40-45° out of the mean coordination plane of the Pd
center, whereas in Pd-dia1, the same aryl group remains
roughly in the mean coordination plane. It is not yet clear how
this marked distortion of the amidosulfoxide [N,S] ligand
could create sufficient discrimination between these two
palladacycles to consolidate the enantio-differentiation in the
overall catalysis, which seemingly already favors pre-dia2.
This difference of topology of Pd-dia1 and Pd-dia2 might
result in slight differences of kinetic reactivity in the
intermediate.
Worthy to note is that the optimal
enantioselectivity achieved in the presence of L13 could arise
from the optimal steric repulsion between 4-tBuC6H4 motif
and the N-Ac group, enhanced in presence of encumbering
tBu substituent. Moreover, such chirality relay is favored for
pre-dia2 due to the tightest -stacking (Scheme 9a).
subsequent
arylation
step
entailing
stereochemical
4. CONCLUSIONS
discrimination in the halogenoaryl oxidative addition to the
Pd(II) center and in the last step, i.e. the reductive elimination
step. This point will be addressed elsewhere. Nonetheless, it
must be also stressed that a comparison of gas phase models
of pre-dia2 and pre-dia2H considering the interaction of the
cation cat-Pd-L13 and anions an-1b and an-1bH in their so-
called prepared geometry indicates that in reactive complex
pre-dia2H the F-devoid an-1bH ligand is more tightly bound to
the Pd center than an-1b by 8 kcal/mol, a significant
difference that points the role of the pentafluorophenyl group
in an-1b : it induces a weaker amido-N bonding to Pd, which
In conclusion, we report herein a new family of ligands for
asymmetric C(sp3)-H activation. Remarkably, these new
auxiliaries are highly efficient and stereoselective allowing not
only direct arylation, but also yet unprecedented alkynylation.
DFT calculations further highlight a unique activity of this
auxiliary, prompt to enhance a nearly barrier-less metallation
event. Based on the in-depth mechanistic studies and the
experimental results, the stereomodel for this transformation
could be proposed to rationalize the excellent reactivity of this
new family of ligands in extremely challenging
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Corresponding Author
stereodifferentiation of prochiral H-atoms. The basic
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* E-mail: wenceldelord@unistra.fr; francoise.colobert@unistra.fr
comprehension of this catalytic system and factors governing
stereoinduction, should allow us to achieve a more rational
conception of challenging and alternative asymmetric C(sp3)-
H activation reactions.
Author Contributions
The manuscript was written through contributions of all authors. /
All authors have given approval to the final version of the
manuscript.
Funding Sources
Project ANR “Sulf-As-CH”
ASSOCIATED CONTENT
SUPPORTING INFORMATION
The Supporting Information is available free of charge on the
ACS Publications website.
Experimental data concerning synthesis of ligands, substrates and
products. Analytical data concerning characterization of ligands,
substrates and products (NMR, HRMS, chiral HPLC). Detailed
optimization study. Supplementary Matarial concering DFT
calculations.
ACKNOWLEDGMENT
9
We thank the CNRS (Centre National de la Recherche
Scientifique), the “Ministère de l’Enseignement Supérieur et de la
Recherche“, and ANR (Agence Nationale de la Recherche)
France for financial support. Dr S. J. is very grateful to the ANR
(Agence Nationale de la Recherche), France for a doctoral grant.
We are also very grateful to Dr Lydia Karmazin and Corinne
Bailly for single crystal X-ray diffraction analysis. We
acknowledge Dr Quentin Dherbassy for fruitful discussions.
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AUTHOR INFORMATION
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Pd
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