Double stereoselective coordination of chiral N,S ligands: Synthesis, coordination chemistry and utilization in Pd-catalyzed allylic alkylation

Article abstract of DOI:10.1002/aoc.4726

A series of chiral pentane-2,4-diyl-based thioether-amine ligands [4 and 5; (R,S)- and (S,S)-R¹SCH(CH₃)CH₂CH(CH₃)NHR², respectively, where 4a R¹ = iPr, R² = Ph; 4b R¹ = tBu, R² = Ph; 4c R¹ = 1-Ad, R² = Ph; 5a R¹ = iPr, R² = Ph; 5b R¹ = tBu, R² = Ph; 5c R¹ = 1-Ad, R² = Ph; 5d R¹ = iPr, R² = 4-MeOC₆H₄; 5e R¹ = iPr, R² = 4-MeC₆H₄; 5f R¹ = iPr, R²?=?3,5-Me₂C₆H₃] with stereogenic S- and N-donor atoms has been prepared starting from cyclic sulfates via optically pure γ-aminoalcohol or 2,4-dimethylazetidine intermediates. The synthesis of the novel diastereomerically related ligand sets 4 and 5 was accomplished starting from the same source of chirality. The modular ligand structure and the novel synthetic strategies developed for their synthesis allowed the easy modification of the ligands’ (i) S- and (ii) N-substituents, as well as (iii) the relative stereochemistry within the ligand backbone. Six-membered [Pd(N,S)Cl₂]-type chelate complexes of the diastereomerically related ligands 4a and 5a were synthesized and characterized by X-ray crystallography in the solid phase, by density functional theory calculations and in solution by NMR spectroscopy. The coordination of 5a resulted in the formation of a single chair conformation by the stereospecific locking of both stereolabile (N and S) donor atoms. In contrast, compound 4a forms rapidly equilibrating palladium species due to the fast inversion of the sulfur donor. Ligands with stereochemically fixed donor atoms provided robust and efficient catalytic systems that can be effectively applied in alkylene carbonates as green reaction media. Remarkably, the phosphine-free catalysts are air-stable, and at room temperature in the presence of moisture gave excellent ee’s (up to 93%) in asymmetric allylation processes thanks to the double stereoselective coordination.

Full text of DOI:10.1002/aoc.4726

Received: 25 September 2018
DOI: 10.1002/aoc.4726
Revised: 27 October 2018
Accepted: 30 October 2018
F U L L P A P E R
Double stereoselective coordination of chiral N,S ligands:
Synthesis, coordination chemistry and utilization in
Pd‐catalyzed allylic alkylation
Máté Miklós Major1 | Gergő Rövid1 | Szabolcs Balogh2 | Attila Bényei3 | György Lendvay4,5
|
Dávid Frigyes6 | József Bakos1
| Gergely Farkas1
1 Department of Organic Chemistry,
University of Pannonia, Egyetem u. 10, H‐
8200 Veszprém, Hungary
2 NMR Laboratory, University of
Pannonia, Egyetem u. 10, H‐8200
Veszprém, Hungary
A series of chiral pentane‐2,4‐diyl‐based thioether‐amine ligands [4 and 5; (R,
S)‐ and (S,S)‐R1SCH(CH3)CH2CH(CH3)NHR2, respectively, where 4a R1 = iPr,
R2 = Ph; 4b R1 = tBu, R2 = Ph; 4c R1 = 1‐Ad, R2 = Ph; 5a R1 = iPr, R2 = Ph;
5b R1 = tBu, R2 = Ph; 5c R1 = 1‐Ad, R2 = Ph; 5d R1 = iPr, R2 = 4‐MeOC6H4;
5e R1 = iPr, R2 = 4‐MeC6H4; 5f R1 = iPr, R2 = 3,5‐Me2C6H3] with stereogenic
S‐ and N‐donor atoms has been prepared starting from cyclic sulfates via
optically pure γ‐aminoalcohol or 2,4‐dimethylazetidine intermediates. The
synthesis of the novel diastereomerically related ligand sets 4 and 5 was
accomplished starting from the same source of chirality. The modular ligand
structure and the novel synthetic strategies developed for their synthesis
allowed the easy modification of the ligands’ (i) S‐ and (ii) N‐substituents,
as well as (iii) the relative stereochemistry within the ligand backbone.
Six‐membered [Pd(N,S)Cl2]‐type chelate complexes of the diastereomerically
related ligands 4a and 5a were synthesized and characterized by X‐ray crystal-
lography in the solid phase, by density functional theory calculations and in
solution by NMR spectroscopy. The coordination of 5a resulted in the forma-
tion of a single chair conformation by the stereospecific locking of both
stereolabile (N and S) donor atoms. In contrast, compound 4a forms rapidly
equilibrating palladium species due to the fast inversion of the sulfur donor.
Ligands with stereochemically fixed donor atoms provided robust and efficient
catalytic systems that can be effectively applied in alkylene carbonates as
green reaction media. Remarkably, the phosphine‐free catalysts are air‐
stable, and at room temperature in the presence of moisture gave excellent
ee’s (up to 93%) in asymmetric allylation processes thanks to the double
stereoselective coordination.
3 Department of Pharmaceutical
Chemistry, University of Debrecen,
Egyetem tér 1, H‐4032 Debrecen, Hungary
4 Institute of Materials and Environmental
Chemistry, Hungarian Academy of
Sciences, Magyar tudósok krt. 2, H‐1117
Budapest, Hungary
5 Department of General and Inorganic
Chemistry, University of Pannonia,
Egyetem u. 10, H‐8200 Veszprém,
Hungary
6 Laboratory of Drug Substance Analytical
Development 1, Egis Pharmaceuticals
PLC, H‐1106 BudapestKeresztúri út 30‐38,
Hungary
Correspondence
József Bakos and Gergely Farkas,
Department of Organic Chemistry,
University of Pannonia, Egyetem u. 10, H‐
8200 Veszprém, Hungary.
Email: bakos@almos.uni‐pannon.hu;
gerifarkas@almos.uni‐pannon.hu
KEYWORDS
asymmetric catalysis, N, S‐ligands, stereoselective coordination
Appl Organometal Chem. 2018;e4726.
wileyonlinelibrary.com/journal/aoc
© 2018 John Wiley & Sons, Ltd.
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https://doi.org/10.1002/aoc.4726

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MAJOR ET AL.
alkyllithium reagents[12] to aldehydes, in the cross‐
coupling reaction of Grignard‐reagents,[13] and in transfer
hydrogenation processes.[7a] Additionally, easily available
and air‐stable pincer‐type N,N,S (ENENES) and S,N,S
ligands with simple alkane diyl backbone have shown
high potential in the hydrogenation of esters[14] or in
the selective hydrogenation of α,β‐unsaturated aldehydes
and ketones.[15]
We envisaged that the development of a new class of
optically pure thioether‐amines would provide an excel-
lent opportunity to evaluate the validity of our concept
that we used successfully in the past. Namely, we intend
to achieve the improvement of the catalytic efficiency by
(i) the combination of the conformational rigidity pro-
vided by the pentane‐2,4‐diyl backbone, with (ii) the
stereoselective coordination of both donor atoms, (iii) by
the electronic differentiation induced by the difference
of donor groups, and (iv) utilizing the modular ligand
structure associated with a convenient synthesis and air
stability. Herein we report on the modular synthesis of
two series of pentane‐2,4‐diyl‐based thioether‐amine
ligands (4a–c and 5a–f) whose structure can easily be
fine‐tuned by the variation of the N‐ and S‐substituents
as well as the relative stereochemistry within the ligand
backbone. The thorough evaluation of the coordination
chemistry and catalytic properties of the two diastereo-
meric ligand sets revealed the high potential of the double
stereoselective coordination in the catalytic processes.
1 | INTRODUCTION
Asymmetric metal catalysis is one of the most powerful
methods for the synthesis of optically pure chiral com-
pounds. The majority of research efforts in this field are
dealing with the synthesis and application of phosphine‐
containing chelate complexes as catalysts.[1] Despite the
spectacular results achieved by such systems, their use
is strongly limited due to the complexity of their synthesis
or their low stability towards oxidation. Furthermore,
important economic factors such as the special conditions
needed for their preparation or the difficulties associated
with their storage, handling or recycling are also respon-
sible for their limited use. A possible solution to over-
come these difficulties is the development of highly
active and selective phosphine‐free catalytic systems.
The substitution of the phosphorus moiety with a
sulfur‐containing coordination site can lead to easily
available and highly stable transition metal catalysts.[2]
Furthermore, the trans‐effect of the sulfur donors, even
if it is lower than that of phosphines, has been found to
be higher in many cases compared with those of N‐ and
O‐donors.[3] Consequently, phosphine‐free heterodonor
systems (e.g. S,O‐ or N,S‐ligands) with C1‐symmetry can
easily preserve their electronic heterogeneity as a remark-
able tool of controlling asymmetric induction.[3e,4]
Besides these promising electronic features, sulfur atom
in a thioether moiety has only two substituents that
can create a less hindered environment than trivalent
phosphorus in phosphines that can lead to a more effi-
cient transfer of chirality.[2] Furthermore, the coordina-
tion of a non‐symmetrically substituted thioether moiety
generates a new stereocenter on the sulfur.[2] The forma-
tion and control of a stereogenic center that is directly
attached to the metal increases the likelihood of effective
stereochemical communication between the heterodonor
ligand and the reactive site.[5] However, the precise con-
trol of the stereoselectivity of sulfur coordination is diffi-
cult due to its low inversion barrier (10–15 kcal mol−1).[6]
Based on these facts, the combination of donor atom
heterogeneity with the possibility of the unique double
stereoselective coordination in simple thioether‐amine
ligands[7] might lead to exceptional catalytic properties.
However, the coordination behavior of chiral chelating
N,S‐ligands with stereogenic nitrogen and sulfur has
scarcely been studied[8] and is rather complicated
because of the configurational isomerism of S‐[9] and N‐
centers,[5i–k,10] and the possible conformational
changes[5i,11] associated with the chelate ring. It is, how-
ever, important to mention that chiral amine‐thioether
ligands have unique stereoelectronic properties and
can provide excellent catalytic properties in allylic
alkylation,[3a,7b,c,f,8a] addition of diethyl zinc[7d] or
2 | RESULTS AND DISCUSSION
2.1 | Synthesis of the ligands
The synthesis of the novel diastereomerically related
ligand sets 4 and 5 was accomplished in moderate yields
starting from the same source of chirality, cyclic sulfate
of (R,R)‐pentane‐2,4‐diol (Scheme 1). In the first step,
the nucleophilic ring opening of the cyclic sulfate with
the corresponding amine resulted in the formation of
zwitterionic compounds 1.[16] The ring closing reaction
of 1a–c produces optically pure azetidines 2a–c in
high yields (60–91%). It should be noted that optically
pure azetidines are valuable starting compounds in syn-
thetic organic chemistry.[17] These four‐membered N‐
heterocycles were then converted to diastereomerically
pure ligands 4a–c in the nucleophilic ring‐opening step
by PhSH in the presence of NaH as a base.[18]
The hydrolysis of 1a–c produced chiral aminoalcohols
3a–c as valuable organic intermediates.[19] In the next step,
the treatment of compounds 3 with a diaryl disulfide in the
presence of (nBu)3P according to the Hata protocol[20]
yielded homochiral ligands 5a–f. It is important to note

MAJOR ET AL.
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SCHEME 1 Synthesis of the novel thioether‐amine ligand library; reaction conditions: (i) R1NH2 in THF, RT, 48 hr; (ii) tBuOK, dioxane,
80°C, 16 hr; (iii) PhSH/NaH, dioxane, 80°C, 16 hr; (iv) 20% H2SO4, 90°C, 8 hr; (v) ArSSAr, (nBu)3P, THF, 30–60°C, 4–8 hr
that ligands 5a and 5d–f can be synthesized in a
diastereomerically pure form, as the substitution of the
hydroxyl function occurs with a complete inversion at the
stereogenic center. This is clearly evidenced by their simple
1H‐NMR spectra that contain only one set of signals.
Ligands with sterically more demanding tert‐butyl (5b) or
1‐adamantyl substituents (5c) were also produced with
high distereoselectivities of 77 and 87%, respectively.
further enhance the number of the possible isomers; how-
ever, these structures are not shown in Scheme 2.
2.2.2 | X‐ray characterization
X‐ray structure determinations were carried out for
complexes 6 and 7 (Figure 1). The single crystals were
grown by slow evaporation of the solvent from their
solution in acetone.
Complex 6 with one independent structure in the unit
cell forms a six‐membered chelate with a square planar
palladium subunit and with interatomic distances of
2.3130(11) (Pd‐Cl trans to S), 2.3025(11) (Pd‐Cl trans to
N), 2.2836(10) (Pd‐S) and 2.060 (3) (Pd‐N) Å (Table 1).
The ring is stabilized in a skew conformation with
pseudo‐equatorial methyl groups and axially disposed
S‐Ph and N‐iPr substituents. Although four diastereoiso-
mers, i.e. (SS,R,S,SN), (RS,R,SN), (SS,RN) and (RS,RN),
might be present in the crystal, only one, (RS,R,S,RN)‐6
is observed by the X‐ray analysis.
The unit cell of complex 7 contains two independent
molecules (see the Supporting Information, Figure S1),
which are so similar that only one of them is discussed
(Table 1) and displayed in Figure 1. The coordination
sphere of the complex has the usual distorted square
2.2 | Coordination chemistry of [Pd(N,S)
Cl2]‐type complexes 6 and 7
2.2.1 | Synthesis
In order to compare the coordination chemistry of the
diastereomerically related ligand sets 4 and 5, we have
synthesized [Pd(N,S)Cl2]‐type chelate complexes 6 and 7
of compounds 4a and 5a, respectively (Scheme 2). They
can be prepared in the reaction of the suitably labile pre-
cursor [Pd (COD)Cl2] and one equivalent of ligand 4a or
5a. Considering the two possible configurations of the
nitrogen and sulfur atoms, four isomers (SS,SN, RS,SN,
SS,RN and RS,RN) can be drawn for both 6 and 7
(Scheme 2). The conformational changes associated with
the six‐membered chelate ring having C1 symmetry can
SCHEME 2 Synthesis and isomers of
complexes 6 and 7 (conformational
isomers are not considered)

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MAJOR ET AL.
the crystal as one well‐defined diastereoisomer with (SS,S,
S,RN) configurations at the stereocenters (Figure 1).
2.2.3 | NMR and density functional theory
studies
1
1
Complexes 6 and 7 were investigated by H, 13C{1H}, H‐
1H‐COSY, 1H‐1H NOESY and 1H‐13C HSQC NMR
methods using CD2Cl2 as solvent. According to the
NMR data, two diastereomeric forms of 6 can be found
1
in solution in a molar ratio of 10:1. The H and 13C reso-
nances can be fully assigned for the major isomer 6A, and
in part for the minor isomer 6B. Interestingly, the minor
isomer gave significantly broader and unresolved signals
1
in the H‐NMR spectrum at room temperature. In order
FIGURE 1 ORTEP view of (RS,R,S,RN)‐6 and (SS,S,S,RN)‐7 at 30%
to gain a deeper insight into the possible dynamic pro-
cesses in the solution of 6, variable‐temperature NMR
experiments were performed between 213 and 293 K.
Upon cooling the sample, the signals of the major com-
plex 6A split, indicating the presence of two equilibrating
diastereomers (6A1 and 6A2) in a molar ratio of 5:1,
respectively. Besides, the signals of the minor isomer 6B
became sharper at 213 K and no splitting could be
observed. The solution structures of 6A1 and 6A2 can be
established on the basis of the corresponding 3J(H,H)
coupling constants. In both cases, one of the backbone
methylene protons (C2Ha) is equally coupled to the two
adjacent methine hydrogens (C1H and C3H) with a
coupling constant of 3J(H,H) = ~10.5 Hz (Figure 2).
Moreover, in 6A1 the coupling constants of the other
diastereotopic methylene hydrogen (C2Hb) to C1H and
C3H are 3J(H,H) = 0.9 and 4.4 Hz, respectively
(Figure 2). Based on the Karplus relation, these coupling
patterns strongly suggest that complexes 6A1 and 6A2 are
stabilized in a skew conformation with pseudo‐equatorial
methyl substituents in the backbone. Therefore, these
structures must differ in the configuration of their donor
atoms that is a consequence of the non‐stereoselective N‐
and/or S‐coordination. Additionally, it can be deduced
that the structure of 6A1 is consistent with the structure
(RS,R,S,RN)‐6 found in the solid phase (Figure 1), as the
S‐phenyl and N‐isopropyl substituents occupy pseudo‐
axial positions, with (RS,RN) donor atom configurations.
This is most obvious from the NOESY spectrum where
cross‐peaks appear between the isopropyl CH and CH3
protons and the corresponding aromatic ortho hydrogens
that is only possible in a 1,3‐diaxial arrangement.
Accordingly, 6A2 can have its donor atom substituents
in axial‐equatorial or equatorial‐equatorial positions.
Unfortunately, the relevant NOESY cross‐peaks could
not be detected for 6A2 because of its relatively low
concentration in solution. In this case, however, simple
probability level
TABLE 1 Selected bond lengths (Å), bond angles (°) and torsion
angles (°) of complexes 6 and 7a
Complex
6
7
Pd‐S
2.2836 (10)
2.060 (3)
2.3130 (11)
2.3025 (11)
92.91 (9)
92.67 (4)
51.0 (5)
2.296 (7)
2.08 (2)
2.329 (7)
2.303 (7)
90.1 (6)
92.1 (3)
−79 (3)
77 (2)
Pd‐N
Pd‐Cl (trans to S)
Pd‐Cl (trans to N)
N‐Pd‐S
Cl‐Pd‐Cl
C1‐C2‐C3‐N
C2‐C3‐N‐Pd
C3‐N‐Pd‐S
N‐Pd‐S‐C1
Pd‐S‐C1‐C2
S‐C1‐C2‐C3
31.9 (4)
−61.1 (3)
27.0 (2)
−59(2)
48(1)
28.7 (3)
−60(2)
71(3)
−82.9 (4)
aComplexes were crystallized via slow evaporation of the solvent from their
solution in acetone.
planar geometry. The Pd‐Cl bond length trans to the sul-
fur [2.329(7) Å] is longer than that trans to the nitrogen
[2.303(7) Å], reflecting the larger trans influence of the
thioether compared with the amine group. Interestingly,
the difference of the Pd‐Cl bond lengths trans to S and
trans to N is larger (0.026 Å) than that in the crystal struc-
ture of 6 (0.0105 Å). The Pd‐S and Pd‐N distances are
2.296(7) and 2.08 (2) Å, respectively. The six‐membered
chelate has a chair conformation with the equatorial
and axial methyl substituents in the backbone moving
from the sulfur towards the nitrogen. The planar S‐Ph
substituent is oriented equatorially while the N‐iPr group
is in an axial position (Figure S2). Complex 7 is present in

MAJOR ET AL.
5 of 14
FIGURE 2 Ring conformation of
stereoisomers 6A1 and 6A2
1H‐NMR spectroscopy provides useful information about
the spatial arrangement of the N‐isopropyl substituent.
In our previous study, we showed that in six‐membered
chelates an axially positioned N‐isopropyl substituent
exhibits a maximal HNCH coupling constant of > 10 Hz
corresponding to a dihedral angle close to 180o.[5i] In
other words, the iPr methine hydrogen points towards
the center of the chelate ring in order to avoid unfavor-
able steric interactions (Figure 2). As the corresponding
HNCH coupling constants for complexes 6A1 and 6A2
are identical and equal to 11.3 Hz, it is reasonable to
assume that 6A2 also has an axially positioned isopropyl
group. As a consequence, the two equilibrating diastereo-
mers 6A1 and 6A2 differ in the configuration of the sulfur
atom (Figure 2). Therefore, 6A2 can be identified as iso-
mer (SS,R,S,RN)‐6. The two diastereomers 6A1 and 6A2
are in dynamic equilibrium via a thermally controlled
inversion of the sulfur configuration.
In order to gain deeper insight into the thermody-
namic stability of the relevant isomers of 6, density
functional theory (DFT) geometry optimizations were
performed using the CAM‐B3LYP functional combina-
tion with the SDD basis set and pseudopotential for Pd
as well as the 6‐31G* basis set for the rest of the atoms.
In the case of isomers 6A1 and 6A2, the theoretical calcu-
lations predict that both structures can form, as their
enthalpy difference is only 1.6 kJ mol−1. These optimized
ground‐state geometries were then utilized to model the
sulfur inversion, without breaking bonds, via a transition
state in which the sulfur atom has a trigonal planar
geometry.[21] The calculation predicts a fast sulfur inver-
sion with activation enthalpies of 58.3 and 56.7 kJ mol−1
for the two directions. More importantly, the theoretical
calculations suggest that the sulfur inversion takes place
independently of ring inversion between palladium che-
lates 6A1 and 6A2. Finally, on the basis of the experimen-
tal and theoretical results, complexes 6A and 6B can be
identified as simple conformational isomers.
coupling constant of ~11 Hz, suggesting the axial orienta-
tion of the N‐substituent. Second, a strong cross‐peak
appears in the NOESY spectrum between the signal of
NH and the adjacent CH3 indicating spatial vicinity for
these protons, while a cross‐peak between the iPr protons
and the C3H is absent (Figure 1). Other prominent cross‐
peaks in the spectrum are the ones between C3CH3 and
C1H, as well as between the isopropyl CH and C2Hb that
suggest a chair conformation with equatorial and axial
Me‐substituents in the backbone moving from the sulfur
towards the nitrogen. Similarly convincing evidences are
provided by the cross‐peaks between the ortho S‐Ph pro-
tons and the C1H and C1CH3 hydrogens. The presence
of these interactions as well as the absence of Ph‐iPr
and Ph‐C2Hb correlations clearly prove the equatorial
arrangement of the S‐phenyl substituent. The structural
data deduced from the NMR spectra confirm in all
respects those found via X‐ray crystallography (Figure 1)
for (SS,S,S,RN)‐7. Furthermore, the DFT calculations
show that the relative enthalpy of the chelate (SS,S,S,
RN)‐7 containing the S‐Ph group in the equatorial
position is 13.1 kJ mol−1 lower compared with that of its
diastereomer (RS,S,S,RN)‐7 with axially positioned S‐Ph
group. Thus, the sulfur inversion of 7 would lead to a
thermodynamically unfavorable isomer. As a result, the
coordination of ligand 5a leads to the formation of
complex (SS,S,S,RN)‐7, exclusively. To the best of our
knowledge this is the first example for the double
stereoselective
coordination
in
a
C1‐symmetry
heterodonor system in solution.
2.3 | Palladium‐catalyzed asymmetric
allylic alkylation in the presence of N,S
ligands
In order to demonstrate the high potential of the double
stereoselective coordination in catalysis, the novel ligands
4 and 5 were tested in the palladium‐catalyzed asymmet-
ric allylic alkylation of benchmark substrate 8 by using
dimethyl‐malonate as nucleophile. The catalytic reactions
were performed at a substrate/catalyst molar ratio of 100
at room temperature using BSA/KOAc as base. Ligands
with sterically demanding 1‐adamantyl or tert‐butyl
substituted amine functionality (4b–c and 5b–c) proved
According to the NMR data of complex (S,S)‐7, only
one diastereomer can be found in solution. Cooling the
1
sample in CD2Cl2 to 193 K, the H‐NMR spectrum still
shows only one set of signals. Furthermore, the NOESY
1
spectrum in combination with the simple H‐NMR data
in solution provides full support for the structure of the
complex. First, the isopropyl substituent exhibits a HNCH

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MAJOR ET AL.
to be inactive in the catalytic transformation of substrate
8.[22] This is possibly due to the lability of sterically
hindered N,S bidentate systems under catalytic condi-
tions.[23] In contrast, ligands with the isopropyl‐
substituted amine moiety (4a and 5a and 5d–f) were
effective in the catalytic reactions (Table 2).
dried solvents and that the ligands were handled without
argon atmosphere.
2.4 | NMR and DFT studies of the cationic
complex [Pd(η3‐PhCHCHCHPh) (5a)]BF4
complex
Initially, to confirm the potential of the unique double
stereoselective coordination of our ligands the catalytic
results achieved by 4a and 5a were compared. The reac-
tion of substrate 8 with dimethyl malonate as nucleophile
resulted in low enantioselectivities when 4a was used as
chiral ligand. The presence of more than one chelate
conformation enhances the number of competitive
catalytic pathways that can lead to a drastic fall in
enantioselectivity (Table 2, entries 2 and 1).[5i] In
contrast, ligands 5a and 5d–f capable of stereoselective
coordination provided excellent enantioselectivities
(Table 2, entries 1–5) using CH2Cl2 as solvent. The best
ee (93%) was obtained by ligand 5e containing S‐p‐tolyl
substituent (entry 4). Ligand 5e provided the same high
enantioselectivities in environmentally friendly solvents,
like ethylene carbonate (EC) and propylene carbonate
(PC) (entries 7 and 8). Furthermore, in these green reac-
tion media the catalysts proved to be much more active
than in dichloromethane as the reaction time was
reduced from 48 hr to 10 hr. It is important to highlight
that the catalytic reactions were performed without using
To substantiate the stereoselective coordination in the
catalytic reaction, we have synthesized the cationic
substrate complex [Pd(η3‐PhCHCHCHPh)(5a)]BF4 (9)
in the reaction of the suitably labile [Pd(η3‐
[5i]
PhCHCHCHPh)(COD)]BF4 and one equivalent of chi-
ral ligand 5a. The 1H‐NMR spectrum of the complex
revealed the presence of two isomers at room tempera-
ture with a molar ratio of 1:5.2 in CD2Cl2.
1
1
The structural analysis of 9 by H, H–1H COSY and
NOESY techniques proved that the chelate ring adopts
the same conformation both in the major and minor iso-
mers as in complex (S,S)‐7, i.e. both donor atoms coordi-
nate stereoselectively. The major and minor species can
be assigned to the exo and endo complexes (Figure 3),
respectively, that can be evidenced by the observed
1
inter‐ligand cross‐peaks in the H–1H NOESY spectrum.
The ratio of these two diastereomers strongly influences
the enantioselectivity of the catalytic reaction. The prefer-
ence of the exo isomer over the endo originates from the
TABLE 2 Palladium‐catalyzed asymmetric allylic alkylation in the presence of N,S ligandsa
Entry
Ligand
Solvent
Reaction time
ee (%)
1
2
3
4
5
6b
4a
5a
5d
5e
5f
CH2Cl2
48 hr
4
90
88
93
92
94
10
7c,d
8d
9
10e
5e
5e
5e
5e
ECe
10 hr
92
92
93
88
PCe
CH3CN
CH2Cl2
Reaction conditions: catalyst prepared in situ from 0.5 mol% of [(η3‐C3H5)PdCl]2 and 1 mol% of chiral ligand; substrate 1.25 mmol; dimethyl malonate 3.75
mmol; solvent 10 mL; BSA 3.75 mmol; KOAc 7 mg; temperature RT. Prevailing configuration of the product: (R).
aConversion and enantiomeric excess were determined by chiral HPLC. Conversions are > 99% in each case.
bSee ref. 5i.
cThe reaction was performed at 50°C.
d5 mL solvent was used. EC, ethylene carbonate; PC, propylene carbonate.
eLiOAc was used instead of KOAc.

MAJOR ET AL.
7 of 14
differences provided by ligands 5a and 10 can easily be
expressed in terms of the corresponding 1H‐ and 13C‐
NMR data of their diphenyallyl Pd‐complexes 9 and 11,
respectively.[25] In the exo‐isomers of 9 and 11 as well as
in endo‐11 the 13C allyl signals trans to the nitrogen
appear at a considerably lower frequency than those trans
to S or P (ΔδC = 10.96, 24.55 and 12.63 ppm, respectively).
These data suggest that the more electrophilic terminal
allylic carbons are those trans to P or S. Interestingly, in
endo‐9 ΔδC is close to 0 ppm. The detailed computational
analysis of the exo and endo isomers of complexes 9 and
11 corresponds well with the spectroscopically observed
differences. In the exo structures and in endo‐11 the ter-
minal Pd‐Callyl bond lengths are longer cis to N than trans
to it. It is only isomer endo‐9 where this trend turns to the
opposite: the terminal Pd‐Callyl bond length is longer
trans to N (2.251 Å) than trans to S (2.187 Å) according
to DFT calculations.
In general, it can be stated that the electronic differ-
ences of the donor atoms are much more pronounced in
the P,N ligated system. It is also reflected by the Pd‐Cl
bond lengths in (S,S)‐7 [trans to S: 2.329(7) Å, trans to
N: 2.303(7) Å] and [Pd(10)Cl2] [trans to P: 2.371 (3) Å,
trans to N: 2.295 (3) Å].
It is also important to compare the steric characteris-
tics of the analogous P,N and N,S systems. The hindered
region defined by the donor atom substituents is clearly
demonstrated by the steric maps shown in Figure 4.[26]
The steric maps report the value along the z‐axis
FIGURE 3 Structures of complexes endo‐ and exo‐[Pd(η3‐
PhCHCHCHPh)(5a)]BF4 (9) (L: large; M: medium; S: small; E:
empty)
face positioned equatorial S‐Ph group that repels the sub-
stituent at the C1 atom of the allyl group.[24] This can eas-
ily be visualized by simple quadrant diagrams (Figure 3).
In addition to the ratio of the exo/endo isomers, the ee
also depends on their relative reaction rates as well as the
site selectivity of the nucleophilic attack at the
diastereotopic 1 and 3 allylic positions. In this respect, it
is interesting to compare the catalytic efficiency of ligand
5a and its phosphorous containing analog, compound 10
(Figure 4).[5i] Both ligand systems gave high
enantioselectivities (90 and 94% ee, respectively) in the
allylic alkylation reaction of substrate 8 with dimethyl
malonate (Table 2, entries 2 and 6). The electronic
FIGURE 4 (a) Steric maps calculated
from the X‐ray strucures of complexes
[Pd(5a)Cl2] ((S,S)‐7) and [Pd(10)Cl2], the
isocontour curves are given in Å.
Palladium is located in the center, and the
coordination plane is perpendicular to the
plane of the paper. The two maps are
computed with a radius of the sphere
equal to 3.5 Å. (b) The exo‐[Pd(η3‐
PhCHCHCHPh)(X,N)]+ complexes of the
N,S ligands 5a (9) and the P,N compound
10 (11)

8 of 14
MAJOR ET AL.
(perpendicular to the plane of the paper) at which the
ligand starts to bury space in the coordination sphere
around the palladium. The most significant steric differ-
ence between the two projections can be found in the
upper right quadrant. The lack of the axially positioned
phenyl substituent in the N,S ligated complex might
strongly influence the steric course of the nucleophilic
attack by providing a sterically less hindered environ-
ment around the metal.
Although the electronic differences between the two
allylic termini are more pronounced in the corresponding
P,N systems, the overall stereoelectronic effects in N,S
complexes, i.e. the double stereoselective coordination of
the heterobidentate ligand, enables these catalysts to
provide high enantioselectivites, commensurate to those
obtained by the analogous P,N systems.
3 | CONCLUSION
Based on our spectroscopic and theoretical studies it
can be stated that in exo‐9 the Pd‐allyl terminus opposite
to the more powerful acceptor sulfur atom will be more
susceptible to cleavage in the nucleophilic attack to
produce the (R) enantiomer of the alkylation product
(Figure 5). Moreover, the nucleophilic attack on the exo‐
isomer trans to S releases the steric strains between the
axially positioned N‐iPr substituent and the adjacent
allylic Ph group (Figure 5). Similarly, the trans‐to‐N
attack of the nucleophile in the endo species would also
lead to the release of steric crowding (Figure 5) producing
the final product with (R) configuration. This site selectiv-
ity might be preferred due to the lack of the axially
positioned S‐Ph group (Figure 4). Furthermore, as the
electronic differences between the terminal allylic car-
bons of endo‐9 are less pronounced, it is reasonable to
assume that the steric factors dominate the nucleophilic
attack. This unique interplay between the steric and elec-
tronic properties of the palladium complexes modified by
the pentane‐diyl‐based N,S ligands is obviously responsi-
ble for the high enantioselectivities achieved in allylic
substitution reactions. As the double stereoselective coor-
dination plays a crucial role in determining the exo/endo
ratio as well as their reactivities towards nucleophiles, it
also directly influences the enantioselectivity of the
catalytic reaction.
In this work we have developed two novel synthetic
methodologies from the same source of chirality, cyclic
sulfate
of
(R,R)‐pentane‐2,4‐diol,
leading
to
diastereomerically related aminoalkyl‐thioethers (N,S).
The new N,S‐ligands 4a–c and 5a–f were synthesized
via optically pure 2,4‐dimethyl azetidines or γ‐amino‐
alcohols. Coordination chemistry of diastereomer
ligands 4a and 5a was thoroughly evaluated by X‐ray
crystallography, various NMR techniques and quantum
chemical calculations. It was clearly evidenced that the
configuration at the stereogenic centers of the backbone
strongly influences not only (i) the ring conformation
and (ii) the configuration of the sulfur atom, but also
(iii) the dynamics of the inversion processes. In the
palladium chelates formed by ligand 5a, both donor
atoms coordinated stereoselectively and the six‐
membered chelate ring was stabilized in a single chair
conformation. The usefulness of the unprecedented dou-
ble stereoselective coordination was demonstrated in
asymmetric allylic alkylation processes. Remarkably,
the new phosphine‐free catalysts are air‐ and moisture‐
stable, and can be used in alkylene carbonates as green
reaction media providing excellent ee’s (as high as 93%)
in asymmetric allylation. We believe that our modular
ligand design could be utilized to other metal‐catalyzed
transformations, and deliver valuable information about
the relationship between ligand architecture and reac-
tion enantioselectivity.
4 | EXPERIMENTAL
All manipulations were carried out under argon using
Schlenk techniques. Solvents were purified, dried and
deoxygenated by standard methods. Compounds [Pd
(COD)Cl2],[27] [Pd(η3‐PhCHCHCHPh)(COD)]BF4,[5i] 3a,
b[16] and 3c[28] were prepared according to literature
methods. All other starting materials were purchased
from Sigma Aldrich and used without further purifica-
1
tion. 13C{1H}‐ and H‐NMR measurements were carried
out on a Bruker Avance 400 spectrometer operating at
161.98, 100.61 and 400.13 MHz, respectively. The 1H‐
NMR and 13C‐NMR signals were assigned from their
FIGURE 5 Selectivity of the nucleophilic attack on the terminal
allylic carbons in endo‐ and exo‐9

MAJOR ET AL.
1
9 of 14
related H‐1H COSY, 13C‐1H HSQC and H‐1H NOESY
spectra, respectively. X‐ray diffraction data were collected
at 298 K using a Bruker‐Nonius MACH3 diffractometer
equipped with a point detector in case of 7 and using a
Bruker‐D8 Venture diffractometer equipped with
INCOATEC IμS 3.0 dual (Cu and Mo) sealed tube
microsources and Photon II Charge‐integrating Pixel
Array detector for 6. Experimental details of the X‐ray
structure determination (Table S1) and crystallographic
data of structures 6 and 7 (Tables S2 and S3) are listed
in the supporting information. EI and HRMS ESI mass
spectra were recorded on a Shimadzu GCMS QP2010 SE
spectrometer and on a Waters Micromass Q‐TOF Premier
mass spectrometer, respectively.
1C), 17.27 (s, 1C). EI mass spectrum of the free base:
m/z 141 [M]+ (calcd 141.15[M]+).
1
4.3 | (2S,4S)‐1‐(Adamantan‐1‐yl)‐2,4‐
dimethylazetidine hydrochloride (2c)
Synthesis of compound 2c was performed as described for
compound 2a using 1c as starting compound. Yield: 69%.
1H‐NMR (400 MHz, DMSO): δ 8.28 (broad s, 1H, NH),
4.71 (m, 1H, diast. CH), 4.51 (m, 1H, diast. CH), 2.72
(dt, J = 11.2, 9.3 Hz, 1H, diast. CHH), 2.14 (m, 3H, CH,
adamantyl), 2.07 (m, 6H, CH2, adamantyl), 1.86 (ddd, J
= 11.3, 8.5, 3.0 Hz, 1H, diast. CHH), 1.73 (d, J = 6.4 Hz,
3H, diast. CH3), 1.67 (d, J = 6.4 Hz, 3H, diast. CH3), 1.66
(m, 6H, CH2, adamantyl). 13C‐NMR (101 MHz, DMSO):
δ 60.33 (s, 1C), 60.07 (s, 1C), 56.76 (s, 1C), 37.04 (s, 3C),
35.09 (s, 3C), 31.66 (s, 1C), 28.46 (s, 3C), 19.44 (s, 1C),
18.18 (s, 1C). EI mass spectrum of the free base: m/z
219 [M]+ (calcd 219.20 [M]+).
4.1 | (2S,4S)‐1‐(Isopropyl)‐2,4‐
dimethylazetidine hydrochloride (2a)
To
a stirred solution of (2S,4R)‐isopropylamino‐4‐
sulfatopentane (1a, 0.77 mmol, 173 mg) in dioxane (10
mL), potassium tert‐butoxide (1.54 mmol, 173 mg) was
added in small portions under argon. The reaction mix-
ture was stirred at 80°C for 16 hr. After stirring, water
(20 mL) was added to the mixture, the pH was adjusted
to 10–11 and the mixture was extracted with ether (3 ×
40 mL). After the addition of several drops of concen-
trated hydrochloric acid to the ethereal solution, the sol-
vent was evaporated in vacuum to give the final product
4.4 | (2R,4S)‐4‐(Isopropylamino)pentan‐2‐
ol (3a)
A solution of sulfuric acid (45 mL, 20 m/m%) was added
to 1a (1 g, 4.43 mmol) and the mixture was stirred for 8
hr at 90°C. The solution was then allowed to cool to room
temperature and its pH was adjusted to 12 by the addition
of Na2CO3. The aqueous solution was then extracted with
ether (3 × 40 mL) and the organic phases were dried with
MgSO4. The solvent was evaporated in vacuo to give the
1
as a white solid. Yield: 70 mg, 55%. H‐NMR (400 MHz,
DMSO): δ 11.88 (broad s, 1H, NH), 4.51 (m, 1H, CH),
4.20 (m, 1H, CH), 3.23 (m, 1H, CH), 2.57 (dt, J = 11.4,
9.3 Hz, 1H, diast. CHH), 1.92 (ddd, J = 11.3, 8.4, 2.8 Hz,
1H, diast. CHH), 1.70 (d, J = 6.4 Hz, 3H, diast. CH3),
1.51 (d, J = 7.0 Hz, 3H, diast. CH3), 1.31 (d, J = 6.3 Hz,
6H, CH3). 13C‐NMR (101 MHz, DMSO): δ 60.39 (s, 1C),
56.72 (s, 1C), 49.96 (s, 1C), 30.64 (s, 1C), 18.93 (s, 1C),
17.90 (s, 1C), 17.57 (s, 1C), 14.40 (s, 1C). EI mass spec-
trum of the free base: m/z 127.2 [M]+ (calcd 127.23 [M]+).
1
title compound as a dense oil. Yield: 456 mg, 71%. H‐
NMR (400 MHz, CDCl3): δ 3.93 (m, 1H, CH), 2.91 (m,
1H, CH, partially overlapped with the next signal), 2.86
(m, 1H, CH, partially overlapped with the previous sig-
nal), 1.47 (ddd, J = 14.2, 2.6, 1.8 Hz, 1H, diast. CHH),
1.16 (m, 1H, diast. CHH), 1.08 (d, J = 6.2 Hz, 3H, CH3),
1.04 (d, J = 6.2 Hz, 3H, CH3), 1.01 (d, J = 6.3 Hz, 3H,
CH3, partially overlapped with the next signal), 1.01 (d,
J = 6.1 Hz, 3H, CH3, partially overlapped with the previ-
ous signal). 13C‐NMR (101 MHz, CDCl3): δ 68.58 (s, 1C),
51.14 (s, 1C), 44.94 (s, 1C), 44.75 (s, 1C), 24.15 (s, 1C),
23.44 (s, 1C), 21.58 (s, 1C), 21.17 (s, 1C). EI mass spec-
trum: m/z 145 [M]+ (calcd 145.15 [M]+).
4.2 | (2S,4S)‐1‐(tert‐Butyl)‐2,4‐
dimethylazetidine hydrochloride (2b)
Synthesis of compound 2b was performed as described for
compound 4a using 1b as starting compound. Yield: 91%.
1H‐NMR (400 MHz, DMSO): δ 10.85 (broad s, 1H, NH),
4.76–4.63 (m, 1H, diast. CH), 4.42–4.28 (m, 1H, diast.
CH), 2.29 (dt, J = 10.7, 9.0 Hz, 1H, diast. CHH), 1.94 (m,
1H, diast. CHH), 1.58 (d, J = 7.1 Hz, 3H, diast. CH3),
1.52 (d, J = 6.4 Hz, 3H, diast. CH3), 1.31 (s, 9H, CH3).
13C‐NMR (101 MHz, DMSO): δ 60.06 (s, 1C), 59.15 (s,
1C), 57.63 (s, 1C), 31.20 (s, 1C), 25.29 (s, 3C), 18.97 (s,
4.5 | (2R,4S)‐4‐(Tertbutylamino)pentan‐2‐
ol (3b)
Synthesis of compound 3b was performed as described for
1
3a using 1b as starting compound. Yield: 60%. H‐NMR
(400 MHz, CDCl3): δ 3.92–3.84 (m, 1H, CH), 2.97 (m,
1H, CH), 1.45 (ddd, J = 14.4, 3.4, 1.6 Hz, 1H, diast.

10 of 14
MAJOR ET AL.
CHH), 1.20 (ddd, J = 14.1, 11.3, 10.4 Hz, 1H, diast. CHH),
1.12 (s, 9H, CH3), 1.11 (d, J = 6.3 Hz, 3H, CH3), 1.08 (d, J
= 6.2 Hz, 3H, CH3). 13C‐NMR (101 MHz, CDCl3): δ 67.73
(s, 1C), 50.93 (s, 1C), 48.31 (s, 1C), 45.71 (s, 1C), 29.60 (s,
3C), 25.21 (s, 1C), 23.44 (s, 1C). EI mass spectrum: m/z
159 [M]+ (calcd 159.16 [M]+).
45.10 (s, 1C), 40.74 (s, 1C), 24.01 (s, 1C), 23.11 (s, 1C),
22.20 (s, 1C), 21.14 (s, 1C). EI mass spectrum: m/z 237
[M]+ (calcd 237.40 [M]+).
4.8 | (2S,4R)‐N‐Tertbutyl‐4‐(phenylthio)
pentan‐2‐amine (4b)
Synthesis of compound 4b was performed as described for
4a using 2b as starting material. Yield: 25%. 1H‐NMR
(400 MHz, CDCl3): δ 7.49–7.17 (m, 5H, aromatic), 3.26
(m, 1H, CH), 3.00 (m, 1H, CH), 1.70 (ddd, J = 14.1, 8.1,
6.2 Hz, 1H, diast. CHH), 1.48 (ddd, 13.8, 7.5, 6.2 Hz, 1H,
diast. CHH), 1.27 (d, J = 6.3 Hz, 3H, CH3), 1.12 (s, 9H,
C (CH3)), 1.10 (d, J = 6.3 Hz, 3H, CH3). 13C‐NMR (101
MHz, CDCl3): δ 135.60 (s), 131.74 (s), 128.93 (s), 126.70
(s), 51.67 (s), 47.44 (s), 45.60 (s), 40.98 (s), 30.07 (s),
23.98 (s), 22.40 (s). EI mass spectrum: m/z 251 [M]+
(calcd 251.17 [M]+).
4.6 | (2R,4S)‐4‐(Adamantan‐1‐ylamino)
pentan‐2‐ol (3c)
Synthesis of compound 3c was performed as described
for 3a using 1c as starting compound. Yield: 97%. H‐
1
NMR (400 MHz, CDCl3): δ 3.92–3.82 (m, 1H, CH), 3.07
(m, 1H, CH), 2.04 (br. s, 3H, adamantyl), 1.69–1.53 (br.
m, 12H, adamantyl), 1.44 (ddd, J = 14.1, 3.3, 1.4 Hz,
1H, diast. CHH), 1.19 (ddd, J = 14.2, 11.3, 10.5 Hz, 1H,
diast. CHH), 1.09 (d, J = 6.3 Hz, 3H, CH3), 1.08 (d, J =
6.2 Hz, 3H, CH3). 13C‐NMR (101 MHz, CDCl3): δ 67.75
(s, 1C), 51.09 (s, 1C), 46.27 (s, 1C), 45.60 (s, 1C), 43.23
(s, 3C), 35.98 (s, 3C), 29.05 (s, 3C), 25.73 (s, 1C), 23.43
(s, 1C). Elemental analysis (%) calcd. For C15H27NO
(237.21): C 75.90, H 11.46, N 5.90; found: C 75.57, H
11.44, N 6.08. EI mass spectrum: m/z 237 [M]+ (calcd
237.21 [M]+).
4.9 | (2S,4R)‐4‐((Phenylthio)pentan‐2‐yl)
adamantan‐1‐amine (4c)
Synthesis of compound 4c was performed as described for
4a using 2c as starting material. Yield: 33%. 1H‐NMR
(400 MHz, CDCl3): δ 7.43–7.40 (m, 2H, aromatic), 7.30–
7.25 (m, 2H, aromatic), 7.21–7.17 (m, 1H, aromatic),
3.30 (m, 1H, CH), 3.05 (m, 1H, CH), 2.05 (m, 3H, CH,
adamantyl), 1.68–1.58 (m, 13H, adamantyl and diast.
CHH), 1.43 (m, 1H, diast. CHH), 1.27 (d, J = 6.6 Hz, 3H,
CH3), 1.06 (d, J = 6.3 Hz, 3H, CH3). 13C‐NMR (101
MHz, CDCl3): δ 135.67 (s, 1C, aromatic), 131.06 (s, 2C,
aromatic), 129.13 (s, 2C, aromatic), 126.54 (s, 1C, aro-
matic), 51.27 (s, 1C), 47.78 (s, 1C), 44.04 (s, 3C), 43.21
(s, 1C), 40.77 (s, 1C), 36.77 (s, 3C), 29.75 (s, 3C), 24.78
(s, 1C), 22.17 (s, 1C). EI mass spectrum: m/z 329 [M]+
(calcd 329.22 [M]+).
4.7 | (2S,4R)‐N‐Isopropyl‐4‐(phenylthio)
pentan‐2‐amine (4a)
To a suspension of NaH (222 mg, 5.55 mmol, 60 m/m%)
in dioxane (20 mL), thiophenol (612 mg, 5.55 mmol,
570 μL) was added and the resulting mixture was stirred
for 30 min at room temperature. The azetidinium salt 2a
was then added portion‐wise and the reaction mixture
was stirred at 80°C for 12 hr. In the next step, 20 mL
water was added and the pH was adjusted to 2 by diluted
HCl solution. The solution was extracted with ether (2 ×
20 mL) and the pH of the aqueous solution was then
adjusted to 12 by the addition of Na2CO3. The resulting
mixture was again extracted with ether (3 × 40 mL).
Finally, the solvent was evaporated in vacuo to yield the
4.10 | (2S,4S)‐N‐Isopropyl‐4‐(phenylthio)
pentan‐2‐amine (5a)
1
product as a dense oil in a pure form. Yield: 31%. H‐
To a solution of 3a (160 mg, 1 mmol) in THF (0.5 mL),
diphenyl disulfide (437 mg, 2 mmol) and tri‐n‐
butylphosphine (405 mg, 2 mmol, 494 μL) were added
and the reaction mixture was stirred for 7 hr at 40°C.
The solvent was then evaporated, 20 mL water was added
and the pH was adjusted to 2 by using a dilute HCl solu-
tion. The mixture was extracted with ether (2 × 20 mL)
and the pH of the aqueous phase was adjusted to 12 with
Na2CO3. The alkaline solution was then extracted with
ether (3 × 40 mL) and the solvent was evaporated in
vacuo. To remove the phosphine oxide byproduct, the
NMR (400 MHz, CDCl3): δ 7.48–7.17 (m, 5H, aromatic),
3.27 (m, 1H, CH), 3.02 (m, 1H, CH), 2.94 (m, 1H, CH),
1.74 (ddd, J = 14.1, 8.3, 6.0 Hz, 1H, diast. CHH), 1.47
(m, 1H, diast. CHH), 1.26 (d, J = 6.6 Hz, 3H, CH3), 1.08
(d, J = 6.1 Hz, 3H, CH3, partially overlapped with the
next signal), 1.08 (d, J = 6.3 Hz, 3H, CH3, partially over-
lapped with the previous signal), 1.05 (d, J = 6.2 Hz, 3H,
CH3). 13C‐NMR (101 MHz, CDCl3): δ 135.28 (s, 1C, aro-
matic), 132.16 (s, 2C, aromatic), 128.90 (s, 2C, aromatic),
126.84 (s, 1C, aromatic), 47.86 (s, 1C), 45.40 (s, 1C),

MAJOR ET AL.
11 of 14
crude mixture was passed through a sort pad of activated
Al2O3 column by using ether as eluent. The evaporation
of the solvent gave the pure product as an oil. Yield:
112 mg, 47%. 1H‐NMR (400 MHz, CDCl3): δ 7.39–7.17
(m, 5H, aromatic), 3.35 (m, 1H, CH), 2.98 (m, 1H, CH,
partially overlapped with the next signal), 2.92 (m, 1H,
CH, partially overlapped with the previous signal), 1.57
(m, 2H, CH2), 1.26 (d, J = 6.7 Hz, 3H, CH3), 1.06 (d, J =
6.3 Hz, 3H, CH3, partially overlapped with the next sig-
nal), 1.05 (d, J = 6.3 Hz, 3H, CH3, partially overlapped
with the previous signal), 1.03 (d, J = 6.2 Hz, 3H, CH3).
13C‐NMR (101 MHz, CDCl3): δ 135.13 (s, 1C, aromatic),
132.32 (s, 2C, aromatic), 128.93 (s, 2C, aromatic), 126.94
(s, 1C, aromatic), 47.95 (s, 1C), 45.80 (s, 1C), 44.72 (s,
1C), 40.67 (s, 1C), 23.72 (s, 1C), 22.82 (s, 1C), 21.91 (s,
1C), 20.92 (s, 1C). EI mass spectrum: m/z 237 [M]+ (calcd
237.40 [M]+).
4.13 | (2S,4S)‐N‐Isopropyl‐4‐((4‐
methoxyphenyl)thio)pentan‐2‐amine (5d)
Synthesis of compound 5d was performed as described
for 5a using 3a and di(p‐methoxyphenyl) disulfide as
starting compounds. Yield: 55%. 1H‐NMR (400 MHz,
CDCl3): δ 7.39–7.35 (m, 2H, aromatic), 6.85–6.81 (m,
2H, aromatic), 3.79 (s, 3H, OCH3), 3.13 (m, 1H, CH),
2.92 (m, 2H, overlapped CH), 1.49 (m, 2H, CH2), 1.21
(d, J = 6.7 Hz, 3H, CH3), 1.04 (d, J = 6.3 Hz, 3H, CH3,
partially overlapped with the next signal), 1.03 (d, J =
6.7 Hz, 3H, CH3, partially overlapped with the previous
signal), 1.01 (d, J = 6.3 Hz, 3H, CH3). 13C‐NMR (101
MHz, CDCl3): δ 159.52 (s, 1C, aromatic), 135.91 (s, 2C,
aromatic), 124.88 (s, 1C, aromatic), 114.44 (s, 2C, aro-
matic), 55.39 (s, 1C), 47.70 (s, 1C), 45.50 (s, 1C), 44.99
(s, 1C), 41.78 (s, 1C), 24.05 (s, 1C), 23.15 (s, 1C), 21.76
(s, 2C), 21.13 (s, 1C). EI mass spectrum: m/z 267 [M]+
(calcd 267.17 [M]+).
4.11 | (2S,4S)‐N‐Tertbutyl‐4‐(phenylthio)
pentan‐2‐amine (5b)
4.14 | (2S,4S)‐N‐Isopropyl‐4‐(p‐tolylthio)
pentan‐2‐amine (5e)
Synthesis of compound 5b was performed as described for
5a using 3b as starting compound. Yield: 34%. H‐NMR
Synthesis of compound 5e was performed as described for
5a using 3a and di(p‐tolyl) disulfide as starting com-
pounds. Yield: 49%. H‐NMR (400 MHz, CDCl3): δ 7.32–
1
(400 MHz, CDCl3): δ 7.40–7.15 (m, 5H, aromatic), 3.30
(m, 1H, CH), 2.95 (m, 1H, CH), 1.52 (m, 2H, CH2), 1.26
(d, J = 6.7 Hz, 3H, CH3), 1.08 (s, 9H, C (CH3)3), 1.05 (d,
J = 6.3 Hz, 3H, CH3). 13C‐NMR (101 MHz, CDCl3): δ
135.18 (s, 1C, aromatic), 131.96 (s, 2C, aromatic), 128.81
(s, 2C, aromatic), 126.68 (s, 1C, aromatic), 51.17 (s, 1C),
47.10 (s, 1C), 45.17 (s, 1C), 40.38 (s, 1C), 30.28 (s, 3C),
24.50 (s, 1C), 21.81 (s, 1C). EI mass spectrum: m/z 251
[M]+ (calcd 251.17 [M]+).
1
7.25 (m, 2H, atomatic), 7.11–7.03 (m, 2H, aromatic),
3.24 (m, 1H, CH), 2.95 (m, 1H, CH), 2.89 (m, 1H, CH),
2.30 (s, 3H, Ar‐CH3), 1.51 (m, 2H, CH2), 1.23 (d, J = 6.7
Hz, 3H, CH3), 1.03 (d, J = 7.1 Hz, 3H, CH3), 1.02 (d, J
= 6.3 Hz, 6H, CH3). 13C‐NMR (101 MHz, CDCl3): δ
136.66 (s, 1C, aromatic), 132.65 (s, 2C, aromatic), 130.66
(s, 1C, aromatic), 129.17 (s, 2C, aromatic), 47.31 (s, 1C),
45.13 (s, 1C), 44.48 (s, 1C), 40.56 (s, 1C), 23.50 (s, 1C),
22.58 (s, 1C), 21.37 (s, 1C), 20.69 (s, 1C), 20.64 (s, 1C).
EI mass spectrum: m/z 251 [M]+ (calcd 251.17 [M]+).
4.12 | (2S,4S)‐4‐((Phenylthio)pentan‐2‐yl)
adamantan‐1‐amine (5c)
4.15 | (2S,4S)‐4‐((3,5‐Dimethylphenyl)
thio)‐N‐isopropylpentan‐2‐amine (5f)
Synthesis of compound 5c was performed as described
1
for 5a using 3c as starting compound. Yield: 28%. H‐
Synthesis of compound 5f was performed as described for
5a using 3a and di(3,5‐dimethylphenyl) disulfide as
starting compounds. Yield: 43%. 1H‐NMR (400 MHz,
CDCl3): δ 7.04–6.97 (m, 2H, aromatic), 6.85–6.80 (m,
1H, aromatic), 3.32 (m, 1H, CH), 2.96 (m, 1H, CH, par-
tially overlapped with the next signal), 2.91 (m, 1H, CH,
partially overlapped with the previous signal), 2.26 (s,
6H, CH3), 1.55 (m, 2H, CH2), 1.26 (d, J = 6.7 Hz, 3H,
CH3), 1.04 (br. d, J = 6.3 Hz, 6H, CH3), 1.02 (d, J = 6.2
Hz, 3H, CH3). 13C‐NMR (101 MHz, CDCl3): δ 137.84 (s,
1C, aromatic), 134.10 (s, 1C, aromatic), 129.15 (s, 2C, aro-
matic), 128.10 (s, 2C, aromatic), 47.27 (s, 1C), 45.08 (s,
NMR (400 MHz, CDCl3): δ 7.43–7.18 (m, 5H, aromatic
signals), 3.33 (m, 1H, CH), 3.11 (m, 1H, CH), 2.04
(broad m, 3H, CH, adamantyl), 1.69–1.57 (m, 13H,
adamantyl and diast. CHH), 1.53 (m, 1H, diast. CHH),
1.26 (d, J = 6.6 Hz, 3H, CH3), 1.04 (d, J = 6.2 Hz, 3H,
CH3). 13C‐NMR (101 MHz, CDCl3): δ 135.16 (s, 1C, aro-
matic), 132.18 (s, 2C, aromatic), 128.84 (s, 2C, aromatic),
51.31 (s, 1C), 47.19 (s, 1C), 44.04 (s, 3C), 43.18 (s, 1C),
40.61 (s, 1C), 36.77 (s, 3C), 29.75 (s, 3C), 25.05 (s, 1C),
22.01 (s, 1C). EI mass spectrum: m/z 329 [M]+ (calcd
329.22 [M]+).

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MAJOR ET AL.
1C), 44.39 (s, 1C), 39.87 (s, 1C), 23.32 (s, 1C), 22.40 (s, 1C),
21.35 (s, 1C), 20.70 (s, 2C), 20.49 (s, 1C). EI mass spec-
trum: m/z 265 [M]+ (calcd 265.19 [M]+).
51.72 (s, 1C), 48.86 (s, 1C), 40.90 (s, 1C), 35.02 (s, 1C),
24.76 (s, 1C), 20.27 (s, 1C), 19.90 (s, 1C), 19.57 (s, 1C).
HRMS (ESI): m/z 421.0518, [M – Cl + CH3CN]+ (exact
mass calcd for C16H26ClN2PdS: 421.0536).
4.16 | [Pd(4a)Cl2] (6)
Ligand 4a (40 mg, 0.17 mmol) dissolved in CH2Cl2 (5 mL)
was added drop‐wise to a solution of [Pd (COD)Cl2] (48
mg, 0.17 mmol) in CH2Cl2 (5 mL). The resulting solution
was stirred for 4 hr, filtered through a sort pad of celite
and concentrated to about 2 mL. The solution was then
treated with ether (10 mL) to precipitate a yellow powder
that was filtered and washed with ether (5 mL) to give 6
as a bright yellow solid. Yield: 62 mg, 87%. Isomer 6A1:
1H‐NMR (400 MHz, CH2Cl2, 239 K): δ 7.90–7.88 (m, 2H,
aromatic), 7.52–7.43 (m, 3H, aromatic), 4.14 (br. s, 1H,
NH), 3.23 (m, 1H, CHS), 2.89 (m, 1H, CHN, partially
overlapped with the next signal), 2.84 (br. m, 1H, CH
(CH3)2, partially overlapped with the previous signal),
2.31 (dt, J = 15.7, 10.4 Hz, 1H, diast. CH2), 2.07 (dd,
2.01, J = 15.7, 4.2 Hz, 1H, diast. CH2), 1.70 (d, J = 6.5
Hz, 3H, diast. CH3(iPr)), 1.44 (br. m, 3H, CH3CHS, par-
tially overlapped with the next signal), 1.42 (d, J = 6.6
Hz, 3H, CH3CHS), 1.25 (d, J = 6.2 Hz, 3H, diast.
CH3(iPr)). 13C‐NMR (101 MHz, CD2Cl2): δ 133.17 (s, 1C,
aromatic), 130.50 (s, 2C, aromatic), 130.19 (s, 2C, aro-
matic), 129.48 (s, 1C, aromatic), 56.80 (s, 1C), 52.90 (s,
1C), 45.62 (s, 1C), 40.30 (s, 1C), 25.74 (s, 1C), 22.60 (s,
4.18 | [Pd(η3‐PhCHCHCHPh) (5a)]BF4 (9)
Ligand 5a (48 mg, 0.202 mmol) dissolved in CH2Cl2 (5
mL) was added drop‐wise to a solution of [Pd(η3‐
PhCHCHCHPh)(COD)]BF4 (100 mg, 0.202 mmol) in
CH2Cl2. The resulting orange solution was stirred for 4
hr, filtered through a short pad of celite and concentrated
to about 2 mL. The solution was then treated with ether
(5 mL) to precipitate an orange powder that was filtered
and washed with ether (3 × 5 mL) to give complex 9.
1
Yield: 104 mg, 83%. exo‐9: H‐NMR (400 MHz, CD2Cl2):
δ = 8.86–7.74 (m, 20H, overlapped with the analogous
endo signals, 20H), 6.49 (dd, J = 12.5, 10.9 Hz, 1H, inter-
nal allylic CH), 5.57 (d, J = 12.5 Hz, 1H, allylic CH trans
to S), 4.43 (d, J = 10.9 Hz, 1H, allylic CH trans to N),
3.91 (dqd, J = 12.6, 6.4 (3), 3.0 Hz, 1H, CHS), 3.42 (m,
1H, CHN), 2.96 (m, 1H, CH (iPr)), 2.04 (ddd, J = 16.2,
12.6, 2.6 Hz, 1H, diast. CHH (ax.)), 1.94 (dt, J = 16.4, 3.3
(2) Hz, 1H, diast. CHH (eq.)), 1.83 (d, J = 6.6 Hz, 3H,
CH3(CHN)), 1.41 (d, J = 10.9 Hz, 1H, NH), 1.10 (d, J =
6.4 Hz, 3H, CH3(CHS)), 1.10 (d, J = 6.6 Hz, 3H, diast.
CH3(iPr)), 0.83 (d, J = 6.2 Hz, 1H, diast. CH3(iPr)). 13C‐
NMR (101 MHz, CD2Cl2): δ 136.26–126.14 (18 C, aro-
matic, partly overlapped with analogous endo signals),
108.57 (s, 1C, internal allylic C), 88.16 (s, 1C, allylic C
trans to S), 77.20 (s, 1C, allylic C trans to N), 49.94 (s,
1C, CH (iPr)), 49.49 (s, 1C, CHN), 42.12 (s, 1C, CHS),
35.01 (s, 1C, CH2), 22.95 (s, 1C, CH3(CHN)), 20.95 (s,
1C, CH3(CHS)), 20.00 (s, 1C, CH3(iPr)), 19.47 (s, 1C,
CH3(iPr)). endo‐9: 1H‐NMR (400 MHz, CD2Cl2): δ =
8.86–7.74 (m, 20H, overlapped with the analogous exo sig-
nals, 20H), 6.70 (d, J = 11.9 Hz, 1H, internal allylic CH),
4.89 (d, J = 11.9 Hz, 2H, terminal allylic CH's), 3.39 (m,
1H, CHS, partly overlapped with the analogous exo sig-
nal), 3.33 (m, 1H, CH (iPr)), 3.24 (m, 1H, CHN), 2.09
(m, 1H, diast. CHH (ax.), partly overlapped with the anal-
ogous exo signal), 1.85 (m, 1H, diast. CHH (eq.), partly
overlapped with the analogous exo signal), 1.75 (d, J =
6.6 Hz, 3H, diast. CH3(iPr)), 1.36 (d, J = 10.5 Hz, 1H,
NH), 1.19 (d, J = 6.7 Hz, 3H, CH3(CHN)), 1.13 (d, J =
6.3 Hz, 1H, diast. CH3(iPr)), 1.01 (d, J = 6.4 Hz, 3H,
CH3(CHS)). 13C‐NMR (101 MHz, CD2Cl2): δ 136.26–
126.14 (18 C, aromatic, partly overlapped with analogous
exo signals), 105.51 (s, 1C, internal allylic C), 83.60 (s, 2C,
terminal allylic C's), 51.06 (s, 1C, CH (iPr)), 50.44 (s, 1C,
CHN), 41.62 (s, 1C, CHS), 35.87 (s, 1C, CH2), 25.73 (s,
1
1C), 21.87 (s, 1C), 21.52 (s, 1C). Isomer 6A2: H‐NMR
(400 MHz, CH2Cl2, 239 K): δ 7.90–7.43 (m, 10H, aromatic,
overlapped with the signals of the major isomer), 4.44 (m,
1H), 3.73 (m, 1H), 3.46 (m, 1H), 3.05 (m, 1H), 1.94 (m,
2H), 1.42 (m, 3H, overlapped with the corresponding
major signals), 1.37 (d, J = 6.6 Hz, 3H, CH3), 1.34 (d, J
= 6.8 Hz, 3H, CH3), 1.17 (br. m, 3H, CH3). HRMS (ESI):
m/z 421.0537, [M – Cl + CH3CN]+ (exact mass calcd for
C16H26ClN2PdS: 421.0536).
4.17 | [Pd(5a)Cl2] (7)
Synthesis of compound 7 was performed as described for
1
complex 6 using 5a as ligand. Yield: 90%. H‐NMR (400
MHz, CH2Cl2): δ 7.71–7.65 (m, 2H, aromatic), 7.52–7.42
(m, 3H, aromatic), 4.15 (d, J = 7.8 Hz, 1H, NH), 3.71 (m,
1H, CHS), 3.20 (m, 1H, CH (CH3)2), 3.04 (m, 1H, CHN),
2.01 (d, J = 6.6 Hz, 3H, diast. CH3(iPr), partially over-
lapped with the next signal), 1.99 (m, 2H, CH2, partially
overlapped with the previous signal), 1.92 (d, J = 6.7 Hz,
3H, CH3CHN), 1.25 (d, J = 6.3 Hz, 3H, diast. CH3(iPr)),
1.09 (d, J = 6.5 Hz, 3H, CH3CHS). 13C‐NMR (101 MHz,
CD2Cl2): δ 133.17 (s, 2C, aromatic), 130.38 (s, 1C, aro-
matic), 128.51 (s, 2C, aromatic), 125.73 (s, 1C, aromatic),

MAJOR ET AL.
13 of 14
2016, 3, 1246. (h) G. Farkas, Z. Császár, K. Stágel, E. Nemes,
S. Balogh, I. Tóth, A. Bényei, G. Lendvay, J. Bakos,
J. Organomet. Chem. 2017, 846, 129. (i) Z. Császár, G. Farkas,
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1C, CH3(iPr)), 21.95 (s, 1C, CH3(iPr)), 21.58 (s, 1C,
CH3(CHS)), 19.62 (s, 1C, CH3(CHN)).
ACKNOWLEDGEMENTS
The authors thank Mr Béla Édes for skilful assistance in
analytical measurements and synthetic experiments. This
research was supported by the ‘National Excellence
Program’ in the framework of the projects TÁMOP‐
4.2.4.A/2‐11/1‐2012‐0001, EFOP‐3.6.1‐16‐2016‐00015 and
by the Hungarian Scientific Research Fund (OTKA
K115539 and K108966). The research was also supported
by the EU and co‐financed by the European Regional
Development Fund under the projects GINOP‐2.3.2‐15‐
2016‐00008, GINOP‐2.3.3‐15‐2016‐00004 and VEKOP‐
2.3.2‐16‐2017‐00013.
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ORCID
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Asymmetry 2004, 15, 1437.
József Bakos https://orcid.org/0000-0003-3502-6473
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SUPPORTING INFORMATION
Additional supporting information may be found online
in the Supporting Information section at the end of the
article.
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How to cite this article: Major MM, Rövid G,
Balogh S, et al. Double stereoselective coordination
of chiral N,S ligands: Synthesis, coordination
chemistry and utilization in Pd‐catalyzed allylic
alkylation. Appl Organometal Chem. 2018;e4726.
https://doi.org/10.1002/aoc.4726
[22] In the case of ligand 1c ~10% conversion and 3% ee could be
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of the product after 48 hr.
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