Palladium-Catalyzed Regio- A nd Enantioselective Hydrosulfonylation of 1,3-Dienes with Sulfinic Acids: Scope, Mechanism, and Origin of Selectivity

Article abstract of DOI:10.1021/jacs.0c05976

Chiral sulfones are important structural motifs in organic synthesis because of their widespread use in pharmaceutical chemistry. In particular, chiral allylic sulfones have drawn particular interest because of their synthetic utility. However, enantioselective synthesis of 1,3-disubstituted unsymmetrical chiral allylic sulfones remains a challenge. In this article, we report a protocol for (R)-DTBM-Segphos/Pd-catalyzed regio- A nd enantioselective hydrosulfonylation of 1,3-dienes with sulfinic acids, which provides atom- A nd step-economical access to 1,3-disubstituted chiral allylic sulfones. The reaction occurs under mild conditions and has a broad substrate scope. Combined experimental and computational studies suggest that the reaction is initiated by a ligand-to-ligand hydrogen transfer followed by a C-S bond reductive elimination via a six-membered transition state. Steric repulsion between the olefinic C-H of the substrate and the tert-butyl group of (R)-DTBM-Segphos was found to be a key factor in the enantiocontrol.

Full text of DOI:10.1021/jacs.0c05976

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Article
Palladium-Catalyzed Regio- and Enantioselective Hydrosulfonylation of 1,3-
Dienes with Sulfinic Acids: Scope, Mechanism, and Origin of Selectivity
Qinglong Zhang, Dongfang Dong, and Weiwei Zi
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c05976 • Publication Date (Web): 19 Aug 2020
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Palladium-Catalyzed Regio- and Enantioselective
Hydrosulfonylation of 1,3-Dienes with Sulfinic Acids: Scope,
Mechanism, and Origin of Selectivity
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Qinglong Zhang, Dongfang Dong, and Weiwei Zi*
State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University,
Tianjin 300071, China
ABSTRACT: Chiral sulfones are important structural motifs in organic synthesis owing to their widespread use in
pharmaceutical chemistry. In particular, chiral allylic sulfones have drawn particular interest because of their synthetic
utility. However, enantioselective synthesis of 1,3-disubstituted unsymmetrical chiral allylic sulfones remains a challenge.
In this article, we report a protocol for (R)-DTBM-Segphos/Pd-catalyzed regio- and enantioselective hydrosulfonylation of
1,3-dienes with sulfinic acids, which provides atom- and step-economical access to 1,3-disubstituted chiral allylic sulfones.
The reaction occurs under mild conditions and has a broad substrate scope. Combined experimental and computational
studies suggest that the reaction is initiated by a ligand-to-ligand hydrogen transfer followed by a C–S bond reductive
elimination via a six-membered transition state. Steric repulsion between the olefinic C–H of the substrate and the tert-
butyl group of (R)-DTBM-Segphos was found to be a key factor in the enantiocontrol.
1. INTRODUCTION
to
construct
sulfone
subunits.
Recently,
hydrosulfonylation
Chiral sulfones are present in many drugs and also exist in
some biologically active natural products (Figure 1).1
Because the sulfone group is bioisosteric with the
carbonyl group, chiral sulfones have been used
extensively in modern pharmaceutical chemistry, and the
ability of sulfone groups to form strong hydrogen bonds
with biological targets makes them useful for improving
drug potency and efficacy.2 Optical pure allylic sulfones
are among the most important chiral sulfone building
blocks because the alkene can be elaborated in many
ways. Therefore, the development of methods for the
construction of allylic sulfones, coupled with subsequent
transformation of the alkene, would afford access to
various functionalized chiral sulfones.3
NH
O
S
O
H2N
O
O
O
S
HN
S
O
S
O
N
N
N
S
O
NH2
N
O
CO2H
NH2EtCl
dorzolamide-HCl
(-)-agelasidine A
antifungal, antimicrobial
tazobactam
-lactamase inhibitor
carbonic anhydrase inhibitor
O
R2
O
H
H
R3
N
N
R1
N
H
H
H
O
O
N
N
S
O
O
O
O
O
O
S
R2
R3
R1
bioisosteres
hepatitis C Virus NS3/4A protease inhibitor
One of the most widely used methods for preparing chiral
allylic sulfones is the transition-metal-catalyzed
enantioselective allylic substitution (the Tsuji–Trost
reaction; Scheme 1a).4 However, this method affords
Figure 1. Natural products and drugs containing chiral
sulfone motifs.
allylic sulfones with
a terminal olefin moiety (γ-
of alkenes and allenes via radical addition7 reactions has
been extensively studied. However, enantioselective
versions of these reactions have not been developed,
largely because of the difficulty to control the
stereochemistry in a radical pathway.8 Herein, we report a
substituent = H) or symmetric sulfones (α-substituent =
γ-substituent).5 Chiral allylic sulfones can also be
synthesized by asymmetric hydrothiolation of allenes or
1,3-dienes followed by oxidation of the resulting
thioethers to sulfones (Scheme 1b).6 Although this
reaction shows good regio- and enantioselectivities,
selective access to 1,3-unsymmetrical chiral allylic
sulfones via this route has also not been achieved.
Moreover, its practicality is limited by the need to use
odorous sulfur reagents and strong oxidants.
(R)-DTBM-Segphos/Pd-catalyzed
enantioselective
hydrosulfonylation reaction of 1,3-dienes9–11 with sulfinic
acids to afford 1,3-unsymmetrical chiral allylic sulfones
which are otherwise challenging to synthesize (Scheme
1c). The reaction occurs under mild conditions and has a
wide substrate scope. Combined experimental and
computational studies suggested that the reaction is
initiated by a ligand-to-ligand hydrogen transfer (LLHT),12
Hydrosulfonylation of unsaturated C–C bonds with
sulfinic acids is the most atom- and step-economical way
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which is followed by a C–S bond reductive elimination via
Page 2 of 11
SO2Ph
4
L
* (4.4 mol%)
Pd2(dba)3·CHCl3 (2 mol%)
THF(0.2 M), 30 o
1
2
1
2
3
4
5
6
7
8
a six-membered transition state. The LLHT is the
enantiodetermining step, and the hydrogen is transferred
to the same prochiral face of the (E,E)- and the (E,Z)-1,3-
dienes, allowing stereoconvergent hydrosulfonylation of
1,3-dienes. Notably, this discovery represents the first
example of palladium involved LLHT process.12e
3
+
PhSO2H
H
Me
C
1a
3aa
2a
PtBu2
PCy2
O
PPh2
PPh2
PAr2
N
Fe
tBu
Scheme 1. Strategies for Synthesis of Chiral Allylic
Sulfones
Ar = 4-CF3C6H4
L3
, (S)-BINAP
35%, -60% ee,
12:1 rr
t
L1
, (R,Sp)-Josiphos
15%, 60% ee,
5:1 rr
L2
, (R)- Bu-PHOX
9
45%, 60% ee,
8:1 rr
(a) Chiral allylic sulfones through allylic substitution
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tBu
O
SO2R
Pd, Ir
RSO2


LG
N
O
O



H
or
NH HN
PPh2
LG
Pd
Fe
P
P
tBu
H
PPh
2 Ph2P
tBu
SO2R
LG

t
L6
, (S,Sp)- Bu-Phosferrox
20%, 95% ee,
5:1 rr
L5
L4
, (S,S)-DACH-Ph-Trost ligand
30%, 45% ee,
, (R,R,S,S)-Duanphos
10%, 63% ee,
3:1 rr


RSO2
13:1 rr
(b) Chiral allylic sulfones through hydrothiolation and oxidation
O
50%, 97% ee, >20:1 rr
13%, 73% ee, 6:1 rr
74%, 93% ee, 17:1 rr
75%, 97% ee, >20:1 rr
27%, 90% ee, 15:1 rr
29%, 96% ee, >20:1 rr
85%, 97% ee, >20:1 rr
91%, 97% ee, >20:1 rr
THF:
SR
DCM:
toluene:
dioxane:
MeCN:
DME:
MTBE:
MTBE:
(0.25M)
MeO
MeO
PAr2
PAr2
O
O
SO2R
PAr2
PAr2

SR
O
SO2R
Rh
oxidant
Ar = 3,5-tBu2-4-OMeC6H2
L7
Ar = 3,5-tBu2-4-OMeC6H2
, (S)-DTBM-MeO-Biphep
RSH
L8
, (R)-DTBM-Segphos
34%, -96% ee,
>20:1 rr
RS
RO2S

aReaction conditions: 1a (2.9:1 EZ/EE, 0.1 mmol), 2a (0.15
mmol), 30 °C, 48 h. Isolated yields are reported. The
regioisomeric ratios (rr) was referred to 1,2-
hydrosulfonylation/4,3-hydrosulfonylation, which were
determined by 1H NMR analysis of crude reaction
mixtures. The enantiomeric excess (ee) values were
determined by HPLC on a chiral stationary phase.
(c) Hydrosulfonylation of 1,3-dienes with sulfinic acids (this work)
SO2R

L*Pd
+
RSO2H

H
atom- and step-economical
2.2. Substrate Scope. Having developed an effective
catalyst system for this regio- and enantioselective
hydrosulfonylation reaction, we investigated its substrate
scope by carrying out reactions of 2a with various 1,3-
dienes 1 (Table 2). We began with substrates for which R1
was a substituted phenyl group and R2 was methyl.
Although good yields and enantioselectivities were
observed for substrates with an electron-withdrawing
fluorine atom (3ba, 3ca and 3da), chlorine atom (3ea),
CF3 group (3fa), bromine atom (3ga) or CO2Me group
(3ha), the regioselectivities were slightly lower than those
observed for 1a. In contrast, electron-donating MeO (3ia)
and Me (3ja) groups were well-tolerated. 1,3-Dienes with a
thiophene or furan ring as R1 gave the corresponding
hydrosulfonylation products (3ka and 3la) in 94% and 93%
yields, respectively. Pyridine derived 1,3-diene was
compatible, affording 3ma in 73% yield with 97% ee,
albeit with a moderate regioselectivity. We reasoned that
electron-deficient arenes (3fa, 3ha and 3ma) might
destabilize the Pd-π-allyl species involved in the 1,2-
hydrosulfonylation, but they were with little influence on
the stability of the Pd-π-allyl species involved in the 4,3-
regio- and enantioselective
toxic, odorous sulfur compounds not required
LLHT and six-membered CS reductive elimination
2. RESULTS AND DISCUSSION
2.1. Reaction Development. We began our studies by
carrying out reactions of 1,3-diene 1a with phenyl sulfinic
acid (2a) with catalysis by Pd2(dba)3·CHCl3 in the
presence of various chiral ligands L (Table 1). Josiphos
(L1), t-Bu-PHOX (L2), BINAP (L3), Duanphos (L4), and
DACH-Ph-Trost ligand (L5) were found to give moderate
yields of the desired product (3aa). However, poor
enantioselectivities and regioselectivities were obtained
with these ligands. The reaction with t-Bu-Phosferrox (L6)
as a ligand gave 3aa with 95% ee; but the yield was only
20%, and the 1,2-/4,3-regioselectivity ratio was 5:1. In
contrast, the use of sterically demanding bisphosphine
ligands DTBM-MeO-Biphep (L7) and DTBM-Segphos (L8)
provided excellent enantio- and regiocontrol, although
the yields of 3aa were somewhat low. Using L8 as the
ligand, we tested various solvents and found that methyl
tert-butyl ether was the best reaction medium (85% yield,
97% ee). Increasing the concentration of 1a to 0.25 M
increased the yield of 3aa to 91% without affecting the
enantio- and regioselectivity (97% ee, >20:1 rr).
hydrosulfonylation pathway.
Therefore, for these
substrates, the regioselectivities dropped. When
a
substrate with two different alkyl groups (R1 = cyclohexyl,
R2 =
Table 1. Reaction Developmenta
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SO2R
Et
Table 2. Scope of the Reaction with Respect to the 1,3-
dienea
L8
(R)- (4.4 mol%)
+
RSO2H
Ph
R1
Pd2(dba)3·CHCl3 (2 mol%)
MTBE (0.25 M), 30 oC, 30 h
Me
1a
2
3
L8
(R)- (4.4 mol%)
SO2Ph
R2
R1
+
PhSO2H
Pd2(dba)3·CHCl3 (2 mol%)
MTBE (0.25 M), 30 oC, 30 h
R2
R1
Cl
2a
1
3
O
O
S
SO2Ph
Et
S
O
O
SO2Ph
Et
SO2Ph
Et
Ph
Et
Ph
Et
, 91%
8
9
3ab
3aa
, 90%
>20:1 rr, 96% ee
F
F
>20:1 rr, 97% ee
F
3ba
3ca
3da
, 80%
, 90%
, 89%
15:1 rr, 95% ee
14:1 rr, 98% ee
SO2Ph
Et
17:1 rr, 96% ee
SO2Ph
Et
F
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Me
O
O
O
SO2Ph
S
F
S
O
O
S
O
Et
Ph
Et
Ph
Et
Ph
Et
F3C
Cl
Br
3ac
3ad
3ae
, 83%
>20:1 rr, 95% ee
, 93%
>20:1 rr, 97% ee
, 90%
3ga
, 89%
14:1 rr, 94% ee
3ea
3fa
, 88%
17:1 rr, 95% ee
, 80%
6:1 rr, 91% ee
>20:1 rr, 95% ee
CN
CF3
SO2Ph
Et
SO2Ph
Et
SO2Ph
Et
O
O
O
S
S
S
O
O
O
F
MeO
Me
MeO2C
Ph
Et
Ph
Et
Ph
Et
3ja
3ia
, 90%
>20:1 rr, 96% ee
, 88%
>20:1 rr, 95% ee
3ha
, 78%
3af
3ag
, 86%
, 75%
3ah
, 75% yied
>20:1 rr, 96% ee
11:1 rr, 96% ee
>20:1 rr, 96% ee
>20:1 rr, 97% ee
SO2Ph
Et
SO2Ph
SO2Ph
Et
CF3
F
Et
O
S
3ka
O
N
O
O
S
O
S
CF3
3ma
, 73%
3la
, 94%
, 93%
S
F
O
O
7.5:1 rr, 97% ee
>20:1 rr, 98% ee
>20:1 rr, 94% ee
Ph
Et
Ph
Et
Ph
Et
3ai
3aj
3akb
, 53%
, 85%
, 65%
SO2Ph
SO2Ph
Et
SO2Ph
>20:1 rr, 93% ee
>20:1 rr, 97% ee
>20:1 rr, 96% ee
O
O
Me
O
3pa
17:1 rr, 94% ee
S
, 78%
S
3na
, 52%
3oa
, 73%
> 20:1 rr, 96% ee
O
O
S
O
>20:1 rr, 96% ee
Ph
Et
Ph
Et
Ph
Et
, 61%
>20:1 rr, 98% ee
SO2Ph
3alb
3amb
3anb
SO2Ph
SO2Ph
, 42%
, 45%
>20:1 rr, 97% ee
CO2Me
O
>20:1 rr, 96% ee
aSee SI for details. Isolated yields are reported. The rr
values were determined by H NMR analysis of crude
3sa
, 92%
3qa
, 70%
12:1 rr, 93% ee
3ra
1
, 80%
> 20:1 rr, 94% ee
17:1 rr, 96% ee
reaction mixtures. The ee values were determined by
HPLC on a chiral stationary phase. The concentration of
1a was 0.4 M, and the reaction time was 72 h.
b
SO2Ph
SO2Ph
Me
SO2Ph
methyl) was prepared and subjected to the reaction
conditions, sulfone 3na was obtained with >20:1
regioselectivity and 96% enantioselectivity, although the
yield was only 52%. Thus, the difference between steric
bulk of R1 and R2 is another significant factor to control
the regioselectivity. The R2 group could be a longer alkyl
group—ethyl (3oa), n-Pr (3pa), or i-Pr (3qa)—with little
effect on the yield and selectivity. In addition, a substrate
bearing an alkyl chain with a terminal OMe group
afforded the desired product 3ra in 80% yield with 17:1 rr
and 96% ee. For a 1,3-diene with phenyl and CO2Me as R1
and R2 group respectively, the hydrosulfonylation
specifically occurred at the olefin adjacent to the ester
group, furnishing 3sa in 92% yield with excellent
stereoselectivity. When R2 was a H atom (3ta), the
enantioselectivity dropped dramatically (to 75% ee), but
the regioselectivity was unaffected. For this substrate, a 91%
ee could be obtained by using L6 as the ligand, but the
yield and rr value were low. Cyclic allylic sulfone (3ua)
and quaternary allylic sulfone (3va) could be prepared by
b
3ta
, 90%, >20:1 rr, 75% ee
50%, 5:1 rr, 91% eec
3ua
, 94%
28% ee
3va
, 86%
>20:1 rr, 40% ee
CF3
CF3
PhO2S
+
SO2Ph
MeO
MeO
3wa + 3xa
, 42% (can't be isolated)
2.8:1 rr, 72% ee (major) and 55% ee (minor)
aSee SI for details. Isolated yields are reported. The rr
values were determined by H NMR analysis of crude
reaction mixtures. The ee values were determined by
HPLC on a chiral stationary phase. bThe reaction time was
2h. cL6 was used as the ligand, and the reaction was
carried out at 5 °C for 48 h.
1
Table 3. Scope of the Reaction with Respect to the
Sulfinic acida
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this method in good yield; however, the enantioselectivity scale, from which 770 mg 3aa was obtained in a yield of
1
2
3
4
5
6
7
8
was poor. Diary 1,3-diene in which one phenyl ring
containing a para-MeO group and the other phenyl ring
containing a para-CF3 group was investigated for this
reaction. We observed that both the regio- and
enantioselectivity was moderate for this substrate
90%. Then using 3aa as a substrate, some derivatization
was demonstrated. Exposure of 3aa under H2 atmosphere
with Pd/C catalyst, the hydrogenation product 4aa was
obtained in 87% yield. Cleavage the olefin with ozone
followed by NaBH4 reduction, affording β-hydroxyl chiral
sulfone 5aa in 84% yield. High enantioselectivities were
maintained in the products during these transformations.
In addition, epoxidation of 3aa was achieved by treatment
with m-CPBA in chloromethane under reflux, from which
the resulting expoxide 6aa was afforded in 56% yield with
good diastereoselectivity.
(3wa/3xa = 2.8:1). Notably, the hydrosulfonylation
preferred to occur at the olefin connecting to the
electron-withdrawing phenyl ring, because a more stable
Pd-π-allyl would be generated during the formation of
this regioisomer.
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Next we probed the scope of the reaction with respect to
the sulfinic acid (Table 3). Phenyl sulfinic acids with a F
or Cl atom or a Me, CF3, or CN group on the phenyl ring
were well-tolerated, giving sulfones 3ab–3aj. For all of
these substrates, the yields exceeded 75%, and the
enantioselectivities were >95%. However, the reaction
with 3,5-bis(trifluoromethyl)-benzenesulfinic acid showed
Scheme 3. Control Experiments
a. olefin isomerization
L8
(R)- (4.4 mol%)
Ph
3aa
+
+
PhSO2H
Ph
Ph
Pd2(dba)3·CHCl3 (2 mol%)
MTBE, 30 o
halted at 5.5 h
C
37%
97% ee
75% recovered
EZ:EE > 20:1
2a
-1a
(E,Z)
a
lower yield and
a
slightly lower ee (3ai).
L8
(R)- (4.4 mol%)
Hydrosulfonylation with aliphatic sulfinic acids gave
lower yields than that with aromatic sulfinic acids.
However, if the concentration of the 1,3-diene was
increased to 0.4 M, cyclopropyl, isopropyl, benzyl, and
even methyl sulfinic acids reacted smoothly with 1a,
generating the desired hydrosulfonylation products 3ak–
3an in good yields (42%–65%) with no decrease in regio-
or enantioselectivity. The absolute configuration of the
products was determined to be S by analogy with 3ab, the
structure of which was confirmed by means of X-ray
crystallographic analysis.13
3aa
+
Ph
+
PhSO2H
Pd2(dba)3·CHCl3 (2 mol%)
MTBE, 30 o
halted at 5.5 h
C
31%
97% ee
79% recovered
EE:EZ > 20:1
-1a
2a
(E,E)
b. reversibility of the coupling
SO2Ph
F
O
O
Et
3ba
O
O
Ph
S
S
as above
F
+
+
Et
Ph
Et
F
3aa
3bd
0%
O
S
0%
F
O
3ba
3ad
recovered
98% and
99%
3ad
Et
Ph
no crossover products
Scheme 2. Transformation of the Coupling Producta
c. Isotopically-labeled sulfinic acid
SO2Ph
L8
(R)- (4.4 mol%)
0.0 D
SO2Ph
1
L8
+
(R)- (4.4 mol%)
PhSO2H
Ph
Ph
4
4
Pd2(dba)3·CHCl3 (2 mol%)
MTBE (0.25 M), 30 oC, 30 h
3aa-
d
1
+
PhSO2D
Ph
Ph
Pd2(dba)3·CHCl3 (2 mol%)
MTBE, 30 oC, 48 h
39% yield
3aa
1a
2a
H
H
2a-
d
(E,Z)/(E,E) = 2.9:1
770 mg, 90% yield
> 20:1 rr, 97% ee
0.57 D
4.5 mmol
3 mmol
1a
0.17 D
0.0 D
Ph
SO2Ph
L8
(R)- (4.4 mol%)
4
4
3aa-
d
SO2Ph
1
+
PhSO2D
Ph
1
Pd2(dba)3·CHCl3 (2 mol%)
MTBE, 30 oC, 48 h
42% yield
H
Pd/C,
2
H
H
2a-
d
1a
(E,E) -
MeOH, RT, 20 h
0.0 D
4aa
, 87 %
96% ee
0.56 D
Scheme 4. Determination of Kinetic Isotope Effect
SO2Ph
SO2Ph
1) Ozone, DCM/MeOH
2) NaBH4
HO
5aa
, 84 %
96% ee
3aa
SO2Ph
O
m-CPBA
CH2Cl2, reflux, 48 h
6aa
, 56 %,
dr > 20:1
aSee SI for details of the reaction conditions. m-CPBA = 3-
chloroperoxybenzoic acid. Enantiomeric ratio of 6aa was
not determined.
2.3. Derivatization of the Product. The alkene group in
the coupling product could be further manipulated to
access various useful functionalities (Scheme 2). We first
performed the hydrosulfonylation reaction in a 3 mmol
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Journal of the American Chemical Society
SO2Ph
catalytic hydrosulfonylation reactions of (E,Z)-1a with 2a
L8
(R)- (4.4 mol%)
Ph
1
Ph
and 2a-d in separate vessels revealed a KIE of 6.0; and a
similar KIE value (6.3) was obtained for reactions of (E,E)-
1a. These large KIE values suggest that cleavage of the O–
H bond of the sulfinic acid was likely involved in the
turnover-limiting step.
+
PhSO2H
Pd2(dba)3·CHCl3 (2 mol%)
H
THF, 30 o
C
3aa
2
3
4
5
-1a
-1a
(E,Z)
2a
SO2Ph
as above
Ph
Ph
+
PhSO2D
2a-
D
3aa-
d
(E,Z)
d
6
7
8
9
10
11
12
13
14
15
16
2.5. Computational Studies. In parallel with
experiments, we also conducted density functional theory
calculations to understand the mechanism. Previous
studies of Pd-catalyzed hydrofunctionalization of 1,3-
dienes indicated that a Pd-hydride migratory insertion of
the olefin was involved.10e–o Because Pd-hydride is usually
formed via protonation of Pd(0) by a Brønsted acid,15 we
began by calculating the energy profiles for this
mechanism (Figure 2). In one possible pathway, the sulfur
atom of the sulfinic acid coordinates to Pd(0), and the Pd-
hydride is formed via a four-membered transition state
TS-2a; the energy barrier for this step is 38.6 kcal/mol. A
second possible pathway involves transition state TS-2b
with a relatively low energy (25.0 kcal/mol), which has a
five-membered ring with an oxygen atom coordinating to
the Pd(0). The latter pathway is more energetically
favorable.
Independent rates: kH/kd = 6.0
SO2Ph
L8
(R)- (4.4 mol%)
Ph
Ph
Ph
Ph
+ PhSO2H
Pd2(dba)3·CHCl3 (2 mol%)
H
THF, 30 o
C
1a
3aa
(E,E)-
2a
SO2Ph
as above
+
PhSO2D
D
1a
2a-
d
(E,E)-
3aa-
d
Independent rates: kH/kd = 6.3
2.4. Mechanistic Studies. To gain insight into the
mechanism, control experiments were conducted. In this
hydrosulfonylation reaction, a mixture of (E,Z)- and (E,E)-
1,3-dienes was employed, but the enantioselectivity of the
reaction was unaffected by the isomeric ratio of the
starting material. One possible scenario is that the olefin
undergoes rapid isomerization under the reaction
conditions. To explore this possibility, we carried out
experiments with isomerically pure starting material
(Scheme 3a). Specifically, pure (E,Z)- and (E,E)-1,3-diene
1a were prepared and separately subjected to the standard
reaction conditions for 5.5 h, at which point the (E,Z)-
1a/(E,E)-1a was determined. Interestingly, we did not
observe any olefin isomerization during these reactions.
These results indicated that the enantioconvergency is
not a result of olefin isomerization.
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Next we calculated the energy for the subsequent
-
migratory insertion. Replacement the PhSO2 with one
molecule 1a in Int-3b afford cationic intermediate Int-4a,
which undergoes Pd-hydride migratory insertion via four-
membered ring transition state (TS-5a). This step has an
activation barrier of 52.5 kcal/mol. We rationalized that
the high energy of Int-4a and TS-5a might be attributed
-
to the dissociation PhSO2 from a neutral Pd complex.
Thus we next calculated the migratory insertion pathway
-
with PhSO2 connecting to the Pd. Neutral complex
Because allylic sulfones are prone to undergo oxidative
addition of the C–S bond to the Pd(0) complex,14 we
examined the reversibility of the hydrosulfonylation
reaction by subjecting a mixture of 3ba and 3ad to the
standard conditions. However, no crossover products 3aa
and 3bd were observed (Scheme 3b). These experiments
suggest that this Pd-catalyzed hydrosulfonylation
reaction is not a reversible transformation.
PhSO2-Pd-hydride Int-4b with a monoligated (R)-DTBM-
Segphos was located and this intermediate has an energy
of 38.5 kcal/mol.16 The thereafter migratory insertion (via
TS-5b) step indeed has a lower activation barrier than
that of TS-5a. However, this possibility is also prohibited
by the high activation barrier (40.2 kcal/mol). These
calculations thus indicated that the Pd-hydride migratory
insertion pathway is energetically unfavorable.
To gain more insight into the mechanism, we next
performed a hydrosulfonylation with deuterium-labeled
sulfinic acid 2a-d, which afforded 3aa-d with deuterium
only at C1 (Scheme 3c). The deuterium ratio of Hα/Hβ was
close to the (E,Z)/(E,E) ratio of substrate 1a. We then
examined the deuterium experiment for pure (E,E)-1a and
found only Hα at C1 was deuterium enriched. This result
indicated that this hydrosulfonylation reaction is
stereospecific cis-addition to the alkene and the H atom
transfer step is irreversible. Furthermore, in previous
studies of Pd-catalyzed hydrofunctionalization of 1,3-
dienes, both C1 and C4 were found to be deuterium-
enriched.10e,f,h, The difference between our results and
these previously reported results suggests that our
G (1,4-dioxane, kcal/mol)
‡
*

P
P
*

Pd
P
P
*
‡
H
Pd
*
P
H
P
Ph
Ph
P
H
P
Pd
H
TS-5a
Pd
O
*
O
P
P
S
P
P
Int-4a
O
O
O
S
TS-5a
Ph
*
Pd
Int-4a
51.3
O
Ph
S
O
S
Ph
52.0
H
Int-3b
Pd
Et
TS-2b
Ph
O
Ph
TS-2a
38.6
Int-1b
Int-6b
-
PhSO2
TS-5b
Int-4b
38.5
40.2
1a
TS-2b
25.0
Int 6b
1a
24.5
Int-3b
20.2
P
Int-1b
*
O
S
P
P
*
20.0
O
Pd
Pd
P
Ph
Int-6a
23.9
Ph
Int-3a
18.5
H
Ph
Int-4b
2a
Int-1a
4
13.4
0.0
‡
1a
P

*
*
‡
P
P
O
S
P
P
*
*
Pd
O
Pd
S
*
P
P
Et
O
P
S
Ph
P
P
S
Pd
Ph
Pd
H
H
Pd
O
O
Ph
O
H
Int 6a
Ph
O
Ph
HO
Ph
Int-1a
TS-2a
hydrosulfonylation reaction might proceeded via
distinct mechanism.
a
Int-3a
TS-5b
We also determined kinetic isotope effect (KIE, Scheme 4)
for this reaction. Comparison of the initial rates of the
Figure 2. Energy profiles for pathways involving Pd-hydride
migratory insertion.
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Haven excluded the Pd-hydride involved pathway, we
Page 6 of 11
1
conjectured that the hydrogen atom might be transferred
directly from the sulfinic acid to the 1,3-diene via a LLHT
process.12 To test this hypothesis, we carried out
calculations for square planar complex Int-7a, in which
Pd is coordinated with one of the P atoms of (R)-L8, the S
atom of sulfinic acid, and one double bond of the 1,3-
diene substrate. Starting from Int-7a, which has an
energy of 11.6 kcal/mol, we calculated the energy profile
for the pathway that leads to (S)-3aa, the major
enantiomer generated from (E,Z)-1aa (indicated in blue in
Figure 3). In this pathway, Int-7a is first converted to Int-
9a by LLHT from the sulfinic acid to the 1,3-diene. The
transition state for this step, TS-8a, features a six-
membered palladacycle and has an energy of 20.9
kcal/mol. Int-9a is then transformed to more thermally
stable intermediate Int-11a via two ligand rearrangements
(S to O and π-allyl η3 to η1). Finally, Int-11a undergoes C–S
reductive elimination17 via
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
*
P
P
‡
‡
P
P
P
*
*
P
G (1,4-dioxane, kcal/mol)
C
P
P
O
P
P
P
P
*
O
Pd
*
Ph
*
3aa
3aa
pathway to (S)-
Ph
S
Pd
Pd
Ph
Ph
O
Ph
Ph
S
S
Pd
O
O
O
O
O
Pd
pathway to (R)-
Ph
Pd
O
Et
O
S
S
Ph
Ph
H
Ph
Ph
Et
P
P
Et
Et
Et
S
O
O
O
*
Ph
Int-13b
Ph
S
TS-8b
Int-9b
Int-10b
Int-11b
TS-12b
Pd
HO
Ph
TS-8b
25.0
Int-7b
O
TS-12a
19.6
O
Ar
Ar
P
Ar
Ar
P
P
=
Int-7b
16.6
*
O
Int-9b
14.2
Int-10a
P
TS-8a
20.9
*
13.7
P
O
P
TS-12b
18.1
Ar = 3,5-tBu2-4-OMeC6H2
Pd
Ph
Int-9a
12.4
Int-10b
11.6
Int-7a
11.6
Int-13a
3.4
4
Int-11a
(E,Z)-1a
4
0.0
1.3
2a
3aa + 4
-2.1
Int-11b
Int-13b
-2.5
-1.4
P
‡
P
*
O
‡
*
*
O
P
P
*
P
*
P
P
*
Ph
P
P
O
P
P
O
S
O
Ph
S
P
Pd
S
*
P
Ph
Ph
Pd
Pd
Ph
Pd
S
O
O
O
S
Pd
O
P
HO
Ph
O
S
Ph
O
Pd
Ph
Pd
O
S
O
H
Ph
Et
Ph
Ph
Ph
Int-7a
Et
Ph
Et
Ph
Et
TS-12a
Et
Int-11a
TS-8a
Int-9a
reaction coordinate
Int-10a
Int-13a
Figure 3. Energy profile for hydrosulfonylation of (E,Z)-1,3-diene 1a with sulfonic acid 2a. Calculations were carried out at
the M06/6-311++g(d,p)/SDD//B3LYP-D3/6-31g(d)/Lanl2dz level of theory.
six-membered-ring transition state TS-12a to deliver the
hydrosulfonylation product, a process with an energy
barrier of 19.6 kcal/mol. The LLHT step has a higher
energy barrier than the subsequent C–S reductive
elimination step. Thus, the LLHT step is irreversible,
which is consistent with the experimental observation
that no isomerization of the (E,Z)-olefin to the (E,E)-
olefin occurred during the reaction. We computed the
energy profile of the pathway that leads to the minor
enantiomer (R)-3aa (indicated in red in Figure 3), which
is similar to that for the pathway leading to (S)-3aa.
Notably, the energy of transition state TS-8b is 25.0
kcal/mol, which is 4.1 kcal/mol higher than the energy of
TS-8a. This is in good agreement with the excellent
enantioselectivities observed in the experiments.
Therefore, the irreversible LLHT step is both turnover-
limiting and enantioselectivity-determining. This result is
consistent with the large KIE observed (Scheme 4).
2.5. Origin of the Enantioselectivity. In this
hydrosulfonylation reaction, high enantioselectivity was
observed regardless of the (E,Z)-/(E,E) ratio of the starting
1a. As mentioned above, we ruled out the possibility of
olefin isomerization during the reaction. Therefore, we
speculated that the reaction occur stereoconvergently;
that is, both (E,Z)-1a and (E,E)-1a reacted to afford the
same enantiomer of the product, (S)-3aa. To explore the
origin of the enantioselectivity, we also calculated the
energies of the transition states of LLHT step for reaction
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1a
from (E,Z)-
of (E,E)-1a to afford (S)- and (R)-3aa (Figure 4, see SI for
1
2
3
4
5
6
7
full energy profile). Comparison of the energies of
transition states TS-8c and TS-8d indicated that the
formation of (S)-3aa was favored over the formation of (R)-
3aa by 3.6 kcal/mol. Thus, both (E,Z)- and (E,E)-1a
underwent the enantiodetermining LLHT step from the
same prochiral face of the olefin, giving (S)-3aa as the
predominant product.
2.27
2.44
3.07
1.25
1.40
Hb
1.26
1.38
Ha
Hc
Hc
Ha
2.18
2.21
2.11
Hb
2.92
8
9
3.34
From (E,E)-1a
From (E,Z)-1a
2.16
2.33
TS-8b to (R)-3aa
tBu
TS-8a to (S)-3aa
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
P
P
‡
O
‡
O
*
OMe
*
Ph
Ph
MeO
S
P
tBu
S
OMe
tBu
P
tBu
Pd
3aa
(R)-
G‡ = 4.1
(S)-
tBu
Ph
O
Pd
O
Ph
O
Ph
O
H
Pd b
tBu
H
H
O
O
O
tBu
MeO
tBu
tBu
P
S
O
O
H
Ph
Me
OMe
S
P
Hc
tBu
O
Pd
P
P
tBu
TS-8d
TS-8b
G‡ = 25.0
O
H
O
MeO
Hc
G‡ = 3.6

H
tBua
G‡ = 27.0

Me
Hb
O
O
tBu
d(MeH ) = 2.27
Å
tBu
b
tBu
OMe
d(MeH ) = 2.33
Å
b
d(HatBu) = 2.16Å
d(HctBu) = 2.21Å
d(HcAr) = 2.11Å
tBu
P
*
P
OMe
P
d(HcAr) = 2.44Å
O
‡
O
‡
*
TS-8a
Ph
TS-8b
Ph
S
S
O
P
Pd
3aa
O
Pd
Ph
Ph
1a
from (E,E)-
H
(observed)
H
TS-8a
TS-8c
G‡ = 23.4
G‡ = 20.9
2.84
2.45
1.27
1.25
1.38
Ha
Figure 4. Calculated energies of transition states of LLHT
step for reactions of (E,E)- and (E,Z) 1a.
2.16
Hc
Ha
1.36
Hc
2.22
2.26
2.43
3.28
The calculated structures of TS-8a, TS-8b, TS-8c and TS-
8d are shown in Figure 5. Comparing the structures of TS-
8a and TS-8b, at least three factors contributed to the
difference in energy between them. First, in TS-8b, there
is substantial repulsion between the olefinic C–H of the
substrate and the t-Bu group of the ligand, whereas no
such repulsion is observed in TS-8a (interatom distances
of 2.16, 2.18, and 2.21 Å versus 2.92, 3.07, and 3.34 Å).
Second, steric repulsion between Hc of the substrate and
one H atom in the phenyl ring of this ligand is stronger in
TS-8b than in TS-8a (2.11 Å versus 2.44 Å). Third, 1,3-
allylic strain is largely released in TS-8a because the
distance between the Me group and the olefinic C–Hb is
2.33 Å, whereas this distance is 2.12 Å in substrate (E,Z)-1a.
Less 1,3-allylic strain is released upon formation of TS-8b,
in which the distance between the Me group and the
olefinic C–Hb is 2.27 Å. This result is consistent with the
observed low ee value of 3pa (75%, Table 2), the
formation of which does not involve the relief of such
allylic strain.
2.52
2.96
2.27
2.30
TS-8d to (R)-3aa
TS-8c to (S)-3aa
MeO
OMe
tBu
tBu
OMe
tBu
tBu
tBu
tBu
O
Ph
O
O
O
O
S
P
S
H
O
Pd b
P
tBu
tBu
OMe
O
Ph
Me
tBu
P
Ha
Pd
Hc
H
MeO
O
P
tBu
H
O
O
MeO
Hc
Me
H
tBua
tBu
O
O
tBu
OMe
TS-8c
tBu
d(Me
) = 2.27
Å
) = 2.26
tBu
tBu
OMe
d(MeH ) = 2.45
Å
a
d(H 
a
tBu
Å
tBu
d(HcAr) = 2.43Å
d(HctBu) = 2.22Å
d(HcAr) = 2.16Å
TS-8d
Figure 5. Structures of transition states for LLHT.
Comparison of the structures of TS-8c and TS-8d (Figure
5) reveals that the aforementioned steric repulsion
between the substrate and ligands is also present in TS-8d；
however ， it is much weaker in TS-8c (interatomic
distances of 2.16, 2.22, 2.26, and 2.30 Å versus 2.43, 2.84,
2.96, and 3.28 Å). The 1,3-allylic strain relief that occurs
upon formation of TS-8d is considerable; the distance
between the Me group and the olefinic C–Ha in this
transition state is 2.52 Å, which is slightly longer than the
distance in substrate (E,E)-1a (2.44 Å). The relief of 1,3-
allylic strain associated with the formation of TS-8c is
negligible (2.45 Å). Nevertheless, in TS-8d, we noticed a
strong repulsive interaction between the Me and t-Bu
groups (the shortest distance between these two groups is
2.27 Å), whereas no such repulsion was observed in TS-8c.
This repulsion likely contributes strongly to the higher
energy of TS-8d.
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Page 8 of 11
by the China Postdoctoral Science Foundation (no.
2019M660973). We thank Professor Bi-Jie Li and Professor
Xiaosong Xue for helpful discussions and suggestions.
These analysis suggests that the t-Bu groups of the ligand
played a key role in controlling the enantioselectivity. To
verify this finding from computation, we tested the
catalytic hydrosulfonylation reaction with (R)-DM-
Segphos, in which the t-Bu groups of (R)-DTBM-Segphos
was replaced by Me groups. Indeed, this reaction afforded
3aa with significantly lower enantioselectivity (80% ee
versus 97% ee; Figure 6). Notably, the yield of 3aa
obtained with (R)-DM-Segphos (28%) was markedly
lower than that with (R)-DTBM-Segphos. Finally, when
we used (R)-Segphos, in which both of the t-Bu groups of
(R)-DTBM-Segphos were replaced by H atoms, the yield
of 3aa was <5%. This result was probably due to the fact
that the less sterically hindered ligand coordinated to the
Pd atom in a bidentate fashion, thus prohibiting the
LLHT step.
1
2
3
4
5
6
7
8
REFERENCES
(1) (a) Feng, M.; Tang, B.; Liang, S. H.; Jiang, X. Sulfur
Containing Scaffolds in Drugs: Synthesis and Application in
Medicinal Chemistry. Curr. Top. Med. Chem. 2016, 16, 1200-1216.
(b) Scott, K. A.; Njardarson, J. T. Analysis of US FDA-Approved
Drugs Containing Sulfur Atoms. Top. Curr. Chem. 2018, 376, 5.
(2) For examples, see: (a) Velázquez, F.; Sannigrahi, M.; Bennett,
F.; Lovey, R. G.; Arasappan, A.; Bogen, S.; Nair, L.; Venkatraman,
S.; Blackman, M.; Hendrata, S.; Huang, Y.; Huelgas, R.; Pinto, P.;
Cheng, K.-C.; Tong, X.; McPhail, A. T.; Njoroge, F. G. Cyclic
Sulfones as Novel P3-Caps for Hepatitis C Virus NS3/4A (HCV
NS3/4A) Protease Inhibitors: Synthesis and Evaluation of
Inhibitors with Improved Potency and Pharmacokinetic Profiles.
J. Med. Chem. 2010, 53, 3075-3085. (b) Kim, C. U.; McGee, L. R.;
Krawczyk, S. H.; Harwood, E.; Harada, Y.; Swaminathan, S.;
Bischofberger, N.; Chen, M. S.; Cherrington, J. M.; Xiong, S. F.;
Griffin, L.; Cundy, K. C.; Lee, A.; Yu, B.; Gulnik, S.; Erickson, J. W.
New Series of Potent, Orally Bioavailable, Non-Peptidic Cyclic
Sulfones as HIV-1 Protease Inhibitors. J. Med. Chem. 1996, 39,
3431-3434.
(3) For other catalytic methods for accessing chiral sulfone, see:
(a) Zhou, T.; Peters, B.; Maldonado, M. F.; Govender, T.
Andersson, P. G. Enantioselective Synthesis of Chiral Sulfones by
Ir-Catalyzed Asymmetric Hydrogenation: A Facile Approach to
the Preparation of Chiral Allylic and Homoallylic Compounds. J.
Am. Chem. Soc. 2012, 134, 13592-13595. (b) Long, J.; Shi, L.; Li, X.;
Lv, H.; Zhang, X. Rhodium-Catalyzed Highly Regio- and
Enantioselective Hydrogenation of Tetrasubstituted Allenyl
Sufones: An Efficient Access to Chiral Allylic Sulfones. Angew.
Chem. Int. Ed. 2018, 57, 13248-13251. (c) Gómez, J. E.; Cristòfol, À.;
Kleij. A. W. Copper-Catalyzed Enantioselective Construction of
Tertiary Propargylic Sulfones. Angew. Chem. Int. Ed. 2019, 58,
3903-3907.
(4) For allylic substitution reactions to prepare chiral sulfones,
see: (a) Hiroi, K.; Makino, K. Asymmetric Induction in the
Palladium-Catalyzed Sulfonylation of Allylic sulfinates and
Acetates with Chiral Phosphine Ligands. Chem. Lett. 1986, 15,
617-620. (b) Trost, B. M.; Organ, M. G.; O’Doherty, G. A.
Asymmetric synthesis of allylic sulfones useful as asymmetric
building blocks J. Am. Chem. Soc. 1995, 117, 9662-9670. (c)
Eichelmann, H.; Gais, H.-J. Palladium-catalyzed asymmetric
allylic sulfonylation Tetrahedron: Asymmetry 1995, 6, 643-646. (d)
Trost, B. M.; Krische, M. J.; Radinov, R.; Zanoni, G. On
Asymmetric Induction in Allylic Alkylation via Enantiotopic
Facial Discrimination J. Am. Chem. Soc. 1996, 118, 6297-6298. (e)
Gais, H.-J.; Spalthoff, N.; Jagusch, T.; Frank, M.; Raabe, G.
Palladium-catalyzed kinetic resolution of racemic cyclic and
acyclic allylic carbonates with sulfur nucleophiles Tetrahedron
Lett. 2000, 41, 3809-3812. (f) Gais, H.-J.; Jagusch, T.; Spalthoff, N.;
Gerhards, F.; Frank, M.; Raabe, G. Highly Selective Palladium
Catalyzed Kinetic Resolution and Enantioselective Substitution
of Racemic Allylic Carbonates with Sulfur Nucleophiles:
Asymmetric Synthesis of Allylic Sulfides, Allylic Sulfones, and
Allylic Alcohols Chem.-Eur. J. 2003, 9, 4202-4221. (g) Ueda, M.;
Hartwig, J. F. Iridium-catalyzed, regio- and enantioselective
allylic substitution with aromatic and aliphatic sulfonates. Org.
Lett. 2010, 12, 92-94. (h) Cai, A.; Kleij, A. W. Regio- and
Enantioselective Preparation of Chiral Allylic Sulfones Featuring
Elusive Quaternary Stereocenters. Angew. Chem., Int. Ed. 2019,
58, 14944−14949. (i) Khan, A.; Zhao, H.; Zhang, M.; Khan, S.;
Zhao, D. Regio- and Enantioselective Synthesis of Sulfone-
9
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25
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41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
SO2Ph
L
(R)- (4.4 mol%)
+
PhSO2H
Ph
Ph
Et
Pd2(dba)3·CHCl3 (2 mol%)
MTBE (0.25 M), 30 o
Me
C
1a
2a
3aa
(R)-DTBM-Segphos
Ar = 3,5-tBu2-4-OMeC6H2
O
91%, 97% ee
O
O
PAr2
PAr2
(R)-DM-Segphos
Ar = 3,5-Me2-C6H2
28%, 80% ee
<5%, ee ND
(R)-Segphos
Ar = Ph
O
Figure 6. Relationship between enantioselectivity and ligand
steric bulk.
3. CONCLUSION
In summary, we have developed a protocol for (R)-DTBM-
Segphos/Pd-catalyzed
enantioselective
hydrosulfonylation reaction of 1,3-dienes with sulfinic
acids. This regio- and enantioselective transformation
provides
otherwise-challenging-to-obtain
1,3-
unsymmetrical chiral allylic sulfones in a step- and atom-
economical fashion. Mechanistic studies indicated that
the reaction does not involves
a
Pd-hydride.
Computational studies suggested that the reaction is
instead initiated by a LLHT, which is followed by C–S
bond reductive elimination via a six-membered-ring
transition state. Steric repulsion between the olefinic C–H
of the substrate and the t-Bu group of the (R)-DTBM-
Segphos ligand was found to be a key enantiodetermining
factor. Improvement of the catalyst activity and further
mechanistic studies are ongoing in our laboratory.
ASSOCIATED CONTENT
Supporting Information. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*zi@nankai.edu.cn
ACKNOWLEDGMENTS
This work was supported by the National Natural Science
Foundation of China (no. 21871150) and Fundamental
Research Funds for Central University. Q.Z. was supported
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Journal of the American Chemical Society
Bearing Quaternary Carbon Stereocenters by Pd-Catalyzed
Malcolmson, S. J. Enantioselective Intermolecular Addition of
Aliphatic Amines to Acyclic Dienes with a Pd−PHOX Catalyst. J.
Am. Chem. Soc. 2017, 139, 7180-7183. (f) Park, S.; Malcolmson, S. J.
Development and Mechanistic Investigations of Enantioselective
Pd-Catalyzed Intermolecular Hydroaminations of Internal
Dienes. ACS Catal. 2018, 8, 8468 − 8476. (g) Adamson, N. J.;
Wilbur, K. C. E.; Malcolmson, S. J. Enantioselective
Intermolecular Pd-Catalyzed Hydroalkylation of Acyclic 1,3-
Dienes with Activated Pronucleophiles. J. Am. Chem. Soc. 2018,
140, 2761 − 2764. (h) Nie, S.-Z.; Davison, R. T.; Dong, V. M.
Enantioselective Coupling of Dienes and Phosphine Oxides. J.
Am. Chem. Soc. 2018, 140, 16450−16454. (i) Park, S.; Adamson, N.
J.; Malcolmson, S. J. Brønsted Acid and Pd − PHOX Dual-
Allylic Substitution. Angew. Chem., Int. Ed. 2020, 59, 1340-1345.
(5) Wu, X.-S.; Chen, Y.; Li, M.-B.; Zhou, M.-G.; Tian, S.-K.
Direct Substitution of Primary Allylic Amines with Sulfinate
Salts. J. Am. Chem. Soc. 2012, 134, 14694-14697.
1
2
3
4
5
6
7
8
(6) (a) Xu, K.; Khakyzadeh, V.; Bury, T.; Breit, B. Direct
Transformation of Terminal Alkynes to Branched Allylic
Sulfones J. Am. Chem. Soc. 2014, 136, 16124-16127. (b) Pritzius, A.
B.; Breit, B. Asymmetric Rhodium-Catalyzed Addition of Thiols
to Allenes: Synthesis of Branched Allylic Thioethers and Sulfones
Angew. Chem. Int. Ed. 2015, 54, 3121-3125. (c) Pritzius, A. B.; Breit,
B. Z-Selective Hydrothiolation of Racemic 1,3-Disubstituted
Allenes: An Atom-Economic Rhodium-Catalyzed Dynamic
Kinetic Resolution Angew. Chem. Int. Ed. 2015, 54, 15818-15822.
(d)Yang, X.- H.; Davison, R. T.; Dong, V. M. Catalytic
Hydrothiolation: Regio and Enantioselective Coupling of Thiols
and Dienes. J. Am. Chem. Soc. 2018, 140, 10443−10446. (e) Yang, X.-
H.; Davison, R. T.; Nie, S.-Z.; Cruz, F. A.; McGinnis, T. M.; Dong,
V. M. Catalytic Hydrothiolation: Counterion-Controlled
Regioselectivity. J. Am. Chem. Soc. 2019, 141, 3006−3013.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Catalysed Enantioselective Addition of Activated
C
Pronucleophiles to Internal Dienes. Chem. Sci. 2019, 10, 5176 −
5182. (j) Zhang, Q.; Yu, H.; Shen, L.; Tang, T.; Dong, D.; Chai, W.;
Zi, W. Stereodivergent Coupling of 1,3-Dienes with Aldimine
Esters Enabled by Synergistic Pd and Cu Catalysis. J. Am. Chem.
Soc. 2019, 141, 14554−14559. (k) Shen, C.; Wang, R.-Q.; Wei, L.;
Wang, Z.-F.; Tao, H.-Y.; Wang, C.-J. Catalytic Asymmetric
Umpolung Allylation/2-Aza-Cope Rearrangement for the
(7) (a) Hell, S. M.; Meyer, C. F.; Misale, A.; Sap, J. B. I.;
Christensen, K. E.; Willis, M. C.; Trabanco, A. A.; Gouverneur, V.
Hydrosulfonylation of Alkenes with Sulfonyl Chlorides under
Visible Light Activation. Angew. Chem. Int. Ed. 2020, 59,
Construction
of
α-Tetrasubstituted
α-Trifluoromethyl
Homoallylic Amines. Org. Lett. 2019, 21, 6940-6945. (l) Zhang, Z.;
Xiao, F.; Wu, H.-M.; Dong, X.-Q.; Wang, C.-J. Pd-Catalyzed
Asymmetric Hydroalkylation of 1,3-Dienes: Access to Unnatural
α-Amino Acid Derivatives Containing Vicinal Quaternary and
Tertiary Stereogenic Centers. Org. Lett. 2020, 22, 569-574. (m)
Onyeagusi, C. I.; Shao, X.; Malcolmson, S. J. Enantio- and
Diastereoselective Synthesis of Homoallylic α ‑ Trifluoromethyl
Amines by Catalytic Hydroalkylation of Dienes Org. Lett. 2020,
22, 1681−1685. (n) Adamson, N. J.; Park, S.; Zhou, P.; Nguyen, A.
L.; Malcolmson, S. J. Enantioselective Construction of
Quaternary Stereogenic Centers by the Addition of an Acyl
Anion Equivalent to 1,3-Dienes Org. Lett. 2020, 22, 2032−2037. (o)
Yang, H.; Xing, D. Palladium-catalyzed Diastereo- and
Enantioselective Allylic Alkylation of Oxazolones with 1,3-Dienes
under Base-free Conditions. Chem. Commun. 2020, 56, 3721-3724
(11) For selected examples of other transition-metal-catalyzed
asymmetric hydrofunctionalization reactions of 1,3-dienes, see:
(a) Zhang, A.; RajanBabu, T. V. Hydrovinylation of 1,3-Dienes: A
10.1002/anie.202004070.
(b)
Wang,
J.-J.;
Yu,
W.
Hydrosulfonylation of Unactivated Alkenes by Visible Light
Photoredox Catalysis. Org. Lett. 2019, 21, 9236-9240. (c)
Storozhenko, O. A.; Festa, A. A.; Detistova, G. I.; Rybakov, V. B.;
Varlamov, A. V.; Van der Eycken, E. V.; Voskressensky, L. G.
Photoredox-Catalyzed Hydrosulfonylation of Arylallenes. J. Org.
Chem. 2020, 85, 2250-2259. (d) Hell, S. M.; Meyer, C. F.;
Laudadio, G.; Misale, A.; Willis, M. C.; Noël, T.; Trabanco, A. A.;
Gouverneur, V. Silyl Radical-Mediated Activation of Sulfamoyl
Chlorides Enables Direct Access to Aliphatic Sulfonamides from
Alkenes. J. Am. Chem. Soc. 2020, 142, 720-725.
(8) For other examples of racemic addition of RSO2 radical to
alkenes: (a) Yuan, Z.; Wang, H.-Y.; Mu, X.; Chen, P.; Guo, Y.-L.;
Liu, G. Highly Selective Pd-Catalyzed Intermolecular
Fluorosulfonylation of Styrenes. J. Am. Chem. Soc. 2015, 137,
2468-2471. (b) Lu, Q.; Zhang, J.; Wei, F.; Qi, Y.; Wang, H.; Liu, Z.;
Lei, A. Aerobic Oxysulfonylation of Alkenes Leading to
Secondary and Tertiary β-Hydroxysulfones. Angew. Chem. Int.
Ed. 2013, 52, 7156-7159. (c) Pagire, S. K.; Paria, S.; Reiser, O.
Synthesis of β-Hydroxysulfones from Sulfonyl Chlorides and
Alkenes Utilizing Visible Light Photocatalytic Sequences. Org.
Lett. 2016, 18, 2106-2109.
New Protocol, an Asymmetric Variation, and
a Potential
Solution to the Exocyclic Side Chain Stereochemistry Problem. J.
Am. Chem. Soc. 2006, 128, 54−55. (b) Yang, Y.; Zhu, S.-F.; Duan,
H.-F.; Zhou, C.-Y.; Wang, L.-X.; Zhou, Q.-L. Asymmetric
Reductive Coupling of Dienes and Aldehydes Catalyzed by
Nickel Complexes of Spiro Phosphoramidites: Highly
Enantioselective Synthesis of Chiral Bishomoallylic Alcohols. J.
Am. Chem. Soc. 2007, 129, 2248−2249. (c) Sasaki, Y.; Zhong, C.;
Sawamura, M.; Ito, H. Copper(I)-Catalyzed Asymmetric
Monoborylation of 1,3-Dienes: Synthesis of Enantioenriched
Cyclic Homoallyl- and Allylboronates. J. Am. Chem. Soc. 2010,
132, 1226−1227. (d) Zbieg, J. R.; Moran, J.; Krische, M. J. Diastereo-
(9) For a review of asymmetric hydrofunctionalization of 1,3-
dienes, see: Adamson, N. J.; Malcolmson, S. J. Catalytic Enantio-
and Regioselective Addition of Nucleophiles in the
Intermolecular Hydrofunctionalization of 1,3-Dienes. ACS Catal.
2020, 10, 1060−1076.
(10)
For
examples
of
Pd-catalyzed
asymmetric
hydrofunctionalization reactions of 1,3-dienes, see: (a) Okada, T.;
Morimoto, T.; Achiwa, K. Asymmetric Hydrosilylation of
Cyclopentadiene and Styrene with Chlorosilanes Catalyzed by
and
Enantioselective
Ruthenium-Catalyzed
Hydrohydroxyalkylation of 2-Silyl-butadienes: Carbonyl syn-
Crotylation from the Alcohol Oxidation Level. J. Am. Chem. Soc.
2011, 133, 10582−10586. (e) Zbieg, J. R.; Yamaguchi, E.; McInturff,
E. L.; Krische, M. J. Enantioselective C−H Crotylation of Primary
Alcohols via Hydrohydroxyalkylation of Butadiene. Science 2012,
336, 324−327. (f) Nguyen, K. D.; Herkommer, D.; Krische, M. J.
Enantioselective Formation of All-Carbon Quaternary Centers
via C−H Functionalization of Methanol: Iridium-Catalyzed Diene
Hydrohydroxymethylation. J. Am. Chem. Soc. 2016, 138, 14210 −
14213. (g) Yang, X.-H.; Dong, V. M. Rhodium-Catalyzed
Hydrofunctionalization: Enantioselective Coupling of Indolines
and 1,3-Dienes. J. Am. Chem. Soc. 2017, 139, 1774−1777. (h) Yang, X.-
Palladium
Complexes
of
Chiral
(β-N-
Sulfonylaminoalkyl)phosphines Chem. Lett. 1990, 19, 999-1002.
(b) Löber, O.; Kawatsura, M.; Hartwig, J. F. Palladium-Catalyzed
Hydroamination of 1,3-Dienes:
A Colorimetric Assay and
Enantioselective Additions. J. Am. Chem. Soc. 2001, 123, 4366-
4367. (c) Han, J. W.; Hayashi, T. Palladium-Catalyzed
Asymmetric Hydrosilylation of 1,3-Dienes. Tetrahedron:
Asymmetry 2010, 21, 2193-2197. (d) Park, H. S.; Han, J. W.;
Shintani, R.; Hayashi, T. Asymmetric Hydrosilylation of
Cyclohexa-1,3-diene with Trichlorosilane by Palladium Catalysts
Coordinated with Chiral Phosphoramidite Ligands. Tetrahedron
Asymmetry 2013, 24, 418 − 420. (e) Adamson, N. J.; Hull, E.;
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 10 of 11
H.; Lu, A.; Dong, V. M. Intermolecular Hydroamination of 1,3-
Process Exploiting in situ Generated Sulfinate Anions. Synlett
2011, 2011, 2943-2496.
Dienes to Generate Homoallylic Amines. J. Am. Chem. Soc. 2017,
139, 14049−14052. (i) Marcum, J. S.; Roberts, C. C.; Manan, R. S.;
Cervarich, T. N.; Meek, S. J. Chiral Pincer Carbodicarbene
Ligands for Enantioselective Rhodium-Catalyzed Hydroarylation
of Terminal and Internal 1,3-Dienes with Indoles. J. Am. Chem.
Soc. 2017, 139, 15580−15583. (j) Gui, Y.-Y.; Hu, N.; Chen, X.-W.;
Liao, L.-L.; Ju, T.; Ye, J.-H.; Zhang, Z.; Li, J.; Yu, D.-G. Highly
Regio- and Enantioselective Copper-Catalyzed Reductive
Hydroxymethylation of Styrenes and 1,3-Dienes with CO2. J. Am.
Chem. Soc. 2017, 139, 17011−17014. (k) Cheng, L.; Li, M.-M.; Xiao, L.-
J.; Xie, J.-H.; Zhou, Q.-L. Nickel(0)-Catalyzed Hydroalkylation of
1,3-Dienes with Simple Ketones. J. Am. Chem. Soc. 2018, 140,
11627−11630. (l) Li, C.; Liu, R. Y.; Jesikiewicz, L. T.; Yang, Y.; Liu, P.;
Buchwald, S. L. CuH-Catalyzed Enantioselective Ketone
Allylation with 1,3-Dienes: Scope, Mechanism, and Applications.
J. Am. Chem. Soc. 2019, 141, 5062−5070. (m) Duvvuri, K.; Dewese,
K. R.; Parsutkar, M. M.; Jing, S. M.; Mehta, M. M.; Gallucci, J. C.;
1
2
3
4
5
6
7
8
(15) For other examples of Pd–H-catalyzed coupling reactions,
see: (a) Trost, B. M.; Jäkel, C.; Plietker, B. Palladium-Catalyzed
Asymmetric Addition of Pronucleophiles to Allenes. J. Am. Chem.
Soc. 2003, 125, 4438-4439. (b) Zhou, H.; Wang, Y.; Zhang, L.; Cai,
M.; Luo, S. Enantioselective Terminal Addition to Allenes by
Dual Chiral Primary Amine/Palladium Catalysis. J. Am. Chem.
Soc. 2017, 139, 3631. (c) Zhou, H.; Wei, Z.; Zhang, J. Yang, H.; Xia,
C.; Jiang, G. From Palladium to Brønsted Acid Catalysis: Highly
Enantioselective Regiodivergent Addition of Alkoxyallenes to
Pyrazolones. Angew. Chem. Int. Ed. 2017, 56, 1077-1081. (d) Kim,
H.; Lim, W.; Im, D.; Kim, D.-g.; Rhee, Y. H. Synthetic Strategy for
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Cyclic Amines:
A Stereodefined Cyclic N,O–Acetal as a
Stereocontrol and Diversity Generating Element Angew. Chem.
Int. Ed. 2012, 51, 12055 – 12058. (e) Kim, H.; Rhee, Y. H.
Stereodefined N,O-Acetals: Pd-Catalyzed Synthesis from
Homopropargylic Amines and Utility in the Flexible Synthesis of
2,6-Substituted Piperidines J. Am. Chem. Soc. 2012, 134, 4011 –
4014. (f) Lim, W.; Kim, J.; Rhee, Y. H. Pd-Catalyzed Asymmetric
Intermolecular Hydroalkoxylation of Allene: An Entry to Cyclic
Acetals with Activating Group-Free and Flexible Anomeric
Control J. Am. Chem. Soc. 2014, 136, 13618−13621.
(16) For (R)-DTBM-Segphos monoligated Pd in enantioselective
transformation: Zheng, W.-F.; Zhang, W.; Huang, C.; Wu, P.;
Qian, H.; Wang, L.; Guo, Y.-L.; Ma, S. Tetrasubstituted allenes
via the palladium-catalysed kinetic resolution of propargylic
alcohols using a supporting ligand. Nat. Catal. 2019, 2. 997-1005.
(17) For a report of a C(sp2)–S(VI) reductive elimination process,
see: Emmett, E. J.; Hayter, B. R.; Willis, M. C. Angew. Chem. Int.
Ed. 2013, 52, 12679-12683.
RajanBabu,
T.
V.
Cationic
Co(I)-Intermediates
for
Hydrofunctionalization Reactions: Regio- and Enantioselective
Cobalt-Catalyzed 1,2-Hydroboration of 1,3-Dienes. J. Am. Chem.
Soc. 2019, 141, 7365-7375. (n) Tran, G.; Shao, W.; Mazet, C. Ni-
Catalyzed Enantioselective Intermolecular Hydroamination of
Branched 1,3-Dienes Using Primary Aliphatic Amines. J. Am.
Chem. Soc. 2019, 141, 14814−14822. (o) Chen, X.-W.; Zhu, L.; Gui,
Y.-Y.; Jing, K.; Jiang, Y.-X.; Bo, Z.-Y.; Lan, Y.; Li, J.; Yu, D.-G.
Highly Stereoselective and Catalytic Generation of Acyclic
Quaternary Carbon Stereocenters via Functionalization of 1,3-
Dienes with CO2. J. Am. Chem. Soc. 2019, 141, 18825−18835. (p) Lv,
X.-Y.; Fan, C.; Xiao, L.-J.; Xie, J.-H.; Zhou, Q.-L. Ligand-Enabled
Ni-Catalyzed Enantioselective Hydroarylation of Styrenes and
1,3-Dienes with Arylboronic Acids. CCS Chem. 2019, 1, 328−334.
(q) Murcum, J. S.; Taylor, T. R.; Meek, S. J. Enantioselective
Synthesis of Functionalized Arenes by Nickel-Catalyzed Site
Selective Hydroarylation of 1,3-Dienes with Aryl Boronates.
Angew. Chem. Int. Ed. 2010, DOI: 10.1002/anie.202004982.
(12) For LLHT in nickel catalysis, see: (a) Guihaumé, J.; Halbert,
S.; Eisenstein, O.; Perutz, R. N. Hydrofluoroarylation of Alkynes
with Ni Catalysts. C−H Activation via Ligand-to-Ligand
Hydrogen Transfer, an Alternative to Oxidative Addition.
Organometallics 2012, 31, 1300−1314. (b) Bair, J. S.; Schramm, Y.;
Sergeev, A. G.; Clot, E.; Eisenstein, O.; Hartwig, J. F. Linear-
Selective Hydroarylation of Unactivated Terminal and Internal
Olefins with Trifluoromethyl-Substituted Arenes J. Am. Chem.
Soc. 2014, 136, 13098-13101. (c) Xiao, L.-J.; Fu, X.-N.; Zhou, M.-J.;
Xie, J.-H.; Wang, L.-X.; Xu, X.-F.; Zhou, Q.-L. Nickel-Catalyzed
Hydroacylation of Styrenes with Simple Aldehydes: Reaction
Development and Mechanistic Insights J. Am. Chem. Soc. 2016,
138, 2957-2960. (d) Nett, A. J.; Montgomery, J.; Zimmerman, P. M.
Entrances, Traps, and Rate-Controlling Factors for Nickel-
Catalyzed C–H Functionalization ACS Catal. 2017, 7, 7352-7362.
(e) Tang, S.; Eisenstein, O.; Nakao, Y.; Sakaki, S. Aromatic C−H
σ- Bond Activation by Ni0 , Pd0 , and Pt0 Alkene Complexes:
Concerted Oxidative Addition to Metal vs Ligand-to-Ligand H
Transfer Mechanism. Organometallics 2017, 36, 2761−2771.
(13)
CCDC
2002855
contains
the
supplementary
crystallographic data for 3ab. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc. cam.ac.uk/data_request/cif.
(14) For Pd(0) oxidative addition reactions involving C–S(VI)
bonds, see: (a) Markovic, T.; Murray, P. R. D.; Rocke, B. N.;
Shavnya, A.; Blackmore, D. C.; Willis, M. C. J. Am. Chem. Soc.
2018, 140, 15916–15923. (b) Le Duc, G.; Bernoud, E.; Prestat, G.;
Cacchi, S.; Fabrizi, G.; Iazzetti, A.; Madec, D.; Poli, G. Palladium-
Catalyzed Aromatic Sulfonylation: A New Catalytic Domino
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Table of Contents (TOC)
1
2
3
4
5
6
7
SO2R3
O
R3SO2H
+
L*
L*
(4.4 mol%)
Pd2(dba)3·CHCl3 (2 mol%)
MTBE, 30 o
R2
R1
O
O
PAr2
PAr2
R1
33 examples
up to 98% ee
> 20:1 rr
C
R2
O
regio- and enantioselective
atom- and step-economical
Ar = 3,5-tBu2-4-OMeC6H2
(R)-DTBM-Segphos
toxic, odorous sulfur compounds not required
8
LLHT and six-membered CS reductive elimination
9
10
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