Palladium-Catalyzed Enantioselective C?H Olefination of Diaryl Sulfoxides through Parallel Kinetic Resolution and Desymmetrization

Article abstract of DOI:10.1002/anie.201801146

The first example of Pd^II-catalyzed enantioselective C?H olefination with non-chiral or racemic sulfoxides as directing groups was developed. A variety of chiral diaryl sulfoxides were synthesized with high enantioselectivity (up to 99 %) throu

Full text of DOI:10.1002/anie.201801146

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Accepted Article
Title: Palladium-Catalyzed Enantioselective C-H Olefination of Diaryl
Sulfoxides via Parallel Kinetic Resolution and Desymmetrization
Authors: Yu-Chao Zhu, Yan Li, Bo-Chao Zhang, Feng-Xu Zhang, Yi-
Nuo Yang, and Xi-Sheng Wang
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10.1002/anie.201801146
Angewandte Chemie International Edition
COMMUNICATION
Palladium-catalyzed Enantioselective C-H Olefination of Diaryl
Sulfoxides via Parallel Kinetic Resolution and Desymmetrization
Yu-Chao Zhu†, Yan Li†, Bo-Chao Zhang, Feng-Xu Zhang, Yi-Nuo Yang and Xi-Sheng Wang*
Abstract: The first example of Pd(II)-catalyzed enantioselective C-H
olefination with non-chiral or racemic sulfoxides as directing group has
been developed. A variety of chiral diaryl sulfoxides with high enanti-
oselectivity (up to >99%) have been synthesized through both desym-
metrization and parallel kinetic resolution (PKR). This is the first report
of transition-metal-catalyzed enantioselective C(sp2)-H functionaliza-
tion via PKR, and it represents a novel strategy to construct sulfur-
chiral center.
method represents also a novel strategy to construct sulfur-chiral
centers via transition-metal-catalyzed asymmetric C-H activation
(Scheme 2b).
Transition-metal-catalyzed C-H functionalization is emerging as a
powerful strategy to offer novel retrosynthetic disconnection tac-
tics for total synthesis of complex molecules.[1] In particular, the
catalytic enantioselective activation of inert C-H bonds offers a
highly atom- and step-economic approach towards the facile syn-
thesis of optically active molecules and intermediates.[2] Starting
from Yu’s pioneer work with mono-protected amino acids (MPAA)
used as efficient ligands to accelerate the C-H activation, Pd(II)-
catalyzed enantioselective C-H functionalization has been devel-
oped as a reliable method to construct carbon and phosphine ste-
reo centers,[3] in which desymmetrization[4] and kinetic resolution[5]
are included as two main ways (Scheme 2a). However, transition-
metal-catalyzed asymmetric C(sp2)-H functionalization via paral-
lel kinetic resolution (PKR, Scheme 1), in which both enantiomers
of starting material could be transformed to different enantiomeri-
cally enriched products in one-pot, has never been reported and
remains as a big challenge. Herein, we report the first example of
Pd(II)-catalyzed enantioselective C-H olefination using non-chiral
or racemic sulfoxide as directing group,[6] in which a variety of chi-
ral diaryl sulfoxides were obtained with high enantioselectivities
via desymmetrization or parallel kinetic resolution (PKR).[7] This
Scheme 2. Pd(II)-Catalyzed Enantioselective C(sp2)-H Activation
The enantiopure sulfoxides are widely used as active ingredi-
ents of numerous biologically active molecules and market
drugs,[8-14] and such chiral sulfoxides have also been utilized as
an important class of ligands to realize numerous asymmetric
transformations in organic synthesis due to their high optical sta-
bility.[15] The classical strategies towards facile synthesis of enan-
tioriched sulfoxides, including kinetic resolution[16] and nucleo-
philic substitution of chiral sulfinate amides or esters,[17] have
been widely utilized in both academic and industrial research.
However, the use of stoichiometric amount of chiral pools ren-
dered their synthetic applications. So far, the most popular routes
were metal[18] or non-metal catalyzed[19] and biological[20] asym-
metric sulfide oxidation processes, but the requirement of a prom-
inent discrimination between the substituents of sulfides definitely
limited their utilities. The only known method to synthesize chiral
diaryl sulfoxides via catalysis is palladium-catalyzed enantiose-
lective arylation of aryl sulfenate anions.[21] This reaction is not
applicable for sterically hindered substrates, such as ortho-sub-
stituted aryl halides. Hence, more general and efficient methods
based on novel strategies are still in demand for the rapid synthe-
sis of optically active sulfoxides.
Scheme 1. Standard Kinetic Resolution and Parallel Kinetic Resolution
[*]
Y.-C. Zhu+, Dr. Y. Li+, B.-C. Zhang, F.-X. Zhang, Y.-N. Yang, Prof.
Dr. X.-S. Wang
Hefei National Laboratory for Physical Sciences at the Microscale
and Department of Chemistry
Center for Excellence in Molecular Synthesis of CAS
University of Science and Technology of China
Hefei, Anhui 230026, China
We commenced our study by using diphenyl sulfoxide 1a as
the model substrate and ethyl acrylate 3a as the olefinating rea-
gent. The reaction was carried out in the presence of a catalytic
amount of Pd(OAc)2 (10 mol %) in HFIP at 75 °C. Unfortunately,
E-mail: xswang77@ustc.edu.cn
These authors contributed equally to this work.
[†]
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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10.1002/anie.201801146
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COMMUNICATION
Table 1. Pd-catalyzed Enantioselective C-H Olefination of Diaryl Sulfoxides 1a:
Optimization of Conditions[a]
Table 2. Scope of Symmetric Diaryl Sulfoxides and Alkenes[a]
Rec.
(%)[b]
Yield
(%)[c]
ee
(%)[d]
Entry
1 (R1)
3 (R2)
Entry
Ligand
Yield (%)[b]
trace
26
ee (%)[c]
1
1a (H)
3b (CO2Me)
39
30
30
34
52
8
51
68
61
61
47
72
61
43
52
47
31
54
51
46
47
59
51
59
43
70
68
34
48
38
36
42
91
71 (S)
78
98
97
96
97
99
99
98
98
99
93
99
88
99
77
70
92
86
86
85
89
85
86
83
1
-
-
2
1b (4-Me)
1c (3-Me)
1d (2-Me)
1e (2,4-Me2)
1f (2,3-Me2)
1g (2-OMe)
3b
3b
3b
3b
3b
3b
2
Ac-Val-OH
Boc-Val-OH
Fmoc-Val-OH
Cbz-Val-OH
Ac-Leu-OH
Ac-Tle-OH
Ac-Nle-OH
Ac-Gly-OH
ClCH2CO-Leu-OH
iPr-Leu-OH
Ac-Leu-OH
Ac-Leu-OH
Ac-Leu-OH
Ac-Leu-OH
Ac-Val-OH
Ac-Tle-OH
Ac-Leu-OH
77
-
3
3
N.R.
N.R.
N.R.
30
4
4
-
5
5
-
6
6
75
77
80
70
73
11
87
86
92
91
86
86
-
7
28
51
42
50
60
29
32
35
44
37
43
37
50
26
30
61
48
7
23
8
1h (5-F-2-Me) 3b
8
28
9
1i (3-F)
3b
3b
9
20
10
11
12[e]
13[e]
14
15
16
17
18
19
20
21
22
23
24
25
26[f]
1j (2-Cl)
10
20
1k (4-F-2-Me) 3b
11
14
1l (2-Et)
1m (2-F)
1n (2-iPr)
1o (4-Cl)
1p (4-F)
1q (3,4-Me2)
1r (3-OMe)
1a (H)
1a
3b
12[d]
13[d,e]
14[d,e,f]
15[e,f,g]
16[e,f,g]
17[e,f,g]
18[d,f,g,h]
30
3b
47
3b
43
3b
51
3b
46
3b
40
3b
N.R.
3a (CO2Et)
3c (CO2nBu)
[a] Unless otherwise noted, the reaction conditions were as follows: 1a (0.2
mmol), 3a (0.1 mmol), Pd(OAc)2 (10 mol %), Ag2CO3 (2.0 equiv), ligands (30
mol %), HFIP (2.0 mL), 75 °C, 24 hours. [b] Isolated yield. [c] The ee value
was determined by HPLC. [d] 1a (0.1 mmol), 3a (5.0 equiv). [e] 72 hours. [f]
After prestirring of Pd(OAc)2 and Ac-Leu-OH in HFIP (1.0 mL) at 50 °C for 2
hours, the other chemicals were added. [g] 3b (5.0 equiv) instead of 3a. [h]
None of Pd(OAc)2.
i
1a
3d (CO2 Bu)
1a
3e (CO2Cy)
3f (CO2Bn)
1a
trace product 2a was observed when 2.0 equivalents of Ag2CO3
was used as the oxidant (Table 1, entry 1). Inspired by the ligand-
acceleration effect of mono-protected amino acids introduced by
Yu,[5] we surveyed a range of MPAA as ligands to promote this
transformation. To our delight, the olefinated product 2a was ob-
tained with moderate ee (77%) when Ac-Val-OH (30 mol %) was
used as the ligand, albeit in a relatively low yield (26%, entry 2).
Further examination of the N-protecting group on MPAA ligands
showed that t-butyloxycarbonyl (Boc), 9-fluorenylmethoxycar-
bonyl (Fmoc) or benzyloxycarbonyl (Cbz) protected-amino acids
failed to give 2a (entries 3-5). With acetyl as the N-protecting
group, we next screened different kinds of amino acids. It was
revealed that coordination ability of sulfoxide could influence the
complexation of MPAA and Pd(OAc)2, the mixture of the ligand
and Pd(OAc)2 was prestirred in HFIP at 50 °C for 2 hours prior to
the addition of substrates and Ag2CO3.
1a
3g (COPh(3-CF3)) 56
1a
3h (PO(OEt)2)
3i (C6F5)
28
47
1a
[a] Unless otherwise noted, the reaction conditions were as follows:
(0.1 mmol), (0.5 mmol), Pd(OAc)2 (10 mol %), Ag2CO3 (2.0 equiv),
Ac-Leu-OH (30 mol %), HFIP (2.0 mL), 75 °C , 72 hours. [b] Recovery
of isolated substrate [c] Isolated yield. [d] The ee value was deter-
1
3
1.
mined by HPLC. [e] 96 hours. [f] Pd(OAc)2 (15 mol%).
Gratefully, the ee was further improved to 92% as expected (entry
14). Notably, replacing ethyl acrylate 3a with methyl acrylate 3b
slightly boosted the yield to 51% (entry 15). As a control experi-
ment, no reaction happened at all in the absence of palladium
catalyst (entry 18).
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COMMUNICATION
Table 3. Scope of Non-symmetric Diaryl Sulfoxides[a]
With the optimized conditions in hand, we next investigated the
substrate scope of this novel protocol. The enantioselective C-H
olefination of symmetric diaryl sulfoxides 1 was first carried out.
As shown in Table 2, a wide range of diaryl sulfoxides bearing
electron-donating groups, such as methyl, ethyl, isopropyl and
methoxy, or weak electron-withdrawing groups, such as fluoro
and chloro, afforded the corresponding products with excellent ee
(71-99%, entries 2-16). Notably, para-, meta-, as well as ortho-
substituents were well tolerated with good yields and excellent ee.
All the diaryl sulfoxides with substituents at the meta-positions of
the phenyl groups were regioselectively olefinated at the sterically
less hindered ortho-C-H bond (entries 3, 6, 9, 17-18). The fluorine
and chlorine atom in chiral products (entries 8-11, 13, 15-16)
could offer the potential for subsequent synthetic elaboration via
metal-catalyzed cross-coupling. 2,4- and 2,3-Disubstituted diaryl
sulfoxides were also compatible with this palladium-catalyzed
desymmetrization reaction. It is vital that ortho-substituents, in-
cluding fluoro, chloro, methyl, ethyl, isopropyl and methoxy, on
the benzene rings of substrates, improved the enantioselectivity
of this asymmetric transformation to excellent level (97-99% ee;
entries 4-8, 10-14), presumably due to the higher steric hindrance
of ortho-substituted groups. To our satisfaction, mono-olefinated
products were obtained as the mere species in all cases. Of note
is that not only acrylates with different ester groups (3a and 3c-f,
entries 19-23), but also various electron-deficient alkenes (3g-i,
entries 24-26) provided the desired olefinated products in similar
yields and ee. The absolute configuration of product 2b was con-
firmed to be methyl (S,E)-3-(5-methyl-2-(p-tolylsulfinyl)phe-
nyl)acrylate by comparison with the known compound via re-
ported method (for details, see the supporting information).[6b]
Yield (%)[c]
ee (%)[d]
Rec.
(%)[b]
Entry
rac-4 (R3;R4)
5
6
5
6
1
2
3
rac-4a (2-iPr; 2'-Me)
rac-4b (2-Me; 2'-OMe)
rac-4c (2-Me; 2'-Et)
72
21
36
20
33
90
98
95
95
98
96
65
79
41(5c/6c
mixture)
4
rac-4d (2-F; 2'-Cl)
rac-4e (2-Me; 2'-F)
rac-4f (2-OMe; 2'-Cl)
rac-4g (2-Me; H)
69
62
66
42
59
59
59
60
69
62
32
27
25
33
49
25
23
38
24
31
23
98
98
99
97
93
96
96
71
99
90
99
97
70
95
96
70
82
85
5
40
32
40
31
33
35
27
18
36
6
7
8
rac-4h (2-Et; 2'-Cl)
rac-4i (2-iPr; 2'-Cl)
rac-4j (2-Me; 3'-Me)
rac-4k (H; 4'-OMe)
rac-4l (2-Cl; 3'-Me)
rac-4m (4-Me; 2'-OMe)
9
10
11
12
13
77
95
(S)
(S)
To further broaden the substrate scope, non-symmetric diaryl
sulfoxides 4 were then examined in our catalytic system. To our
delight, when the reaction was carried out at 100 °C with a slightly
changed ratio of 4/3b (2:1), olefination occurred at both of the aryl
groups and therefore furnished products 5 and 6. Not surprisingly,
sulfoxides 4 with ortho- substituents on the benzene rings were
olefinated in excellent ee and good yields (Table 3, entries 1-6, 8-
9). In contrast, substrates without ortho-substituents on either
benzene rings gave relatively lower but still acceptable ee (entry
11). For sulfoxides 4 with one ortho-substituted benzene ring,
while a high ee was still obtained for one of the products, the ee
was slightly lower for the other product (entries 7, 12-15). Both
electron-donating groups, including methyl, ethyl, isopropyl, as
well as methoxy, and weak electron-withdrawing groups, such as
fluoro and chloro, were well-tolerated in this reaction. This reac-
tion represents an efficient conversion of racemic compounds to
two different and separable chiral sulfoxides of high enantioselec-
tivity, and the regiodivergent C-H functionalization of racemic non-
symmetric sulfoxides proceeded with catalyst control.
14
15
rac-4n (3-Me; 2'-OMe)
rac-4o (2-Et; 3'-Me)
64
61
36
38
24
30
83
99
97
73
[a] Unless otherwise noted, the reaction conditions were as follows:
(0.2 mmol, 2.0 equiv), 3b (0.1 mmol), Pd(OAc)2 (10 mol %), Ac-Leu-
OH (30 mol %), Ag2CO3 (2.0 equiv), HFIP (2.0 mL), 100 °C , 72 hours.
4
[b] Recovery of isolated substrate
was determined by HPLC.
4. [c] Isolated yield. [d] The ee value
It should be noted that only moderate conversions of the prochi-
ral sulfoxides 1 and racemic sulfoxides 4 have been observed,
which suggests that the strong coordination of the sulfoxides to
palladium may lead a possible catalyst deactivation. Depending
on recovery rates of sulfoxides 1 or 4 in Table 2-3, sulfoxide sub-
strates could be recovered without significant loss, and only trace
amount of the corresponding sulfones could be detected. The re-
covery of substrates and the yields are consistent with mass bal-
ance basically.
Scheme 3. Olefination of (S)-4m and (R)-4m under Standard Conditions
For in-depth research of the stereodivergent olefination, (S)-
4m and (R)-4m were synthesized[6b] and subjected to the reaction
conditions (Scheme 3). As expected, C-H olefination of (S)-4m
occurred exclusively at the benzene ring bearing a para-methyl
group, while olefination of (R)-4m happened mainly at the other
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10.1002/anie.201801146
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COMMUNICATION
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involved in this transformation.
It is noted that
a small amount of methyl (E)-3-(2-
[2]
[3]
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reactions could result from the selective oxidation of one of the
olefinated sulfoxides via kinetic resolution. To rule out this possi-
bility, we investigated the time dependence of the ee values and
the relative yields of sulfoxides 2a. As shown in Scheme 4, the ee
of product 2a remained around 91% while the yield increased
from 13% to 51% as the reaction time prolonged, which clearly
indicated that no kinetic resolution process was involved in the
reaction procedure and the enantioselectivity of this transfor-
mation was induced in the step of Pd(II)/MPAA-catalyzed asym-
metric C-H activation.
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100
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0
20
40
60
80
100
time (h)
yield(%) ee(%)
Scheme 4. Time Course of ee (%) and Yield (%) of Sulfoxides 2a
In summary, we have developed a Pd(II)-catalyzed enantiose-
lective C-H olefination for facile construction of sulfur-chiral cen-
ters. This methodology provides a novel approach for asymmetric
synthesis of biologically active sulfoxides with excellent ee (up to
99%), and both symmetric and non-symmetric sulfoxides could be
well functionalized via desymmetrization and parallel kinetic res-
olution (PKR). Further applications of these enantiopure diaryl
sulfoxides and the development of more effective catalytic sys-
tems are still underway in our laboratory.
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Acknowledgements
We gratefully acknowledge the Strategic Priority Research
Program of the Chinese Academy of Sciences (Grant No.
XDB20000000), the National Basic Research Program of China
(973 Program 2015CB856600), and the National Science
Foundation of China (21602213, 21522208, 21372209) for
financial support.
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Keywords: enantioselective C-H activation • palladium • parallel
kinetic resolution • desymmetrization • S-chiral centers
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Entry for the Table of Contents (Please choose one layout)
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Yu-Chao Zhu†, Yan Li†, Bo-Chao Zhang,
Feng-Xu Zhang, Yi-Nuo Yang and Xi-
Sheng Wang*
Page No. – Page No.
The first example of Pd(II)-catalyzed enantioselective C-H olefination with non-chiral
or racemic sulfoxides as directing group has been developed. A variety of chiral diaryl
sulfoxides with high enantioselectivity (up to >99%) have been synthesized through
both desymmetrization and parallel kinetic resolution (PKR). This is the first report of
transition-metal catalyzed enantioselective C(sp2)-H functionalization via PKR, and it
represents a novel strategy to construct sulfur-chiral center.
Palladium-catalyzed Enantioselective
C-H Olefination of Diaryl Sulfoxides
via Parallel Kinetic Resolution and
Desymmetrization
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