Enantioselective Construction of Axially Chiral Amino Sulfide Vinyl Arenes by Chiral Sulfide-Catalyzed Electrophilic Carbothiolation of Alkynes

Article abstract of DOI:10.1002/anie.201915470

The enantioselective construction of axially chiral compounds by electrophilic carbothiolation of alkynes is disclosed for the first time. This enantioselective transformation is enabled by the use of a Ts-protected bifunctional sulfide catalyst and Ms-protected ortho-alkynylaryl amines (Ts=tosyl; Ms=mesyl). Both electrophilic arylthiolating and electrophilic trifluoromethylthiolating reagents are suitable for this reaction. The obtained products of axially chiral vinyl–aryl amino sulfides can be easily converted into biaryl amino sulfides, biaryl amino sulfoxides, biaryl amines, vinyl–aryl amines, and other valuable difunctionalized compounds.

Full text of DOI:10.1002/anie.201915470

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
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Accepted Article
Title: Enantioselective Construction of Axially Chiral Amino Sulfide
Vinyl Arenes via Chiral Sulfide-Catalyzed Electrophilic
Carbothiolation of Alkynes
Authors: Xiaodan Zhao, Yaoyu Liang, Jieying Ji, Xiaoyan Zhang,
Quanbin Jiang, and Jie Luo
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201915470
Angew. Chem. 10.1002/ange.201915470
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10.1002/anie.201915470
Angewandte Chemie International Edition
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Enantioselective Construction of Axially Chiral Amino Sulfide
Vinyl Arenes via Chiral Sulfide-Catalyzed Electrophilic
Carbothiolation of Alkynes
Yaoyu Liang, Jieying Ji, Xiaoyan Zhang, Quanbin Jiang, Jie Luo, and Xiaodan Zhao*
catalyzed ring-opening reaction of diaryliodonium salts,[14] and
Abstract: Enantioselective construction of axially chiral compounds
others.[15] To meet the requirements of broader substitution
via electrophilic carbothiolation of alkynes is disclosed for the first
patterns and structural diversity, attention has been paid to the
development of catalytic enantioselective methods for the
synthesis of axially chiral compounds based on dihydronaphthyl-
time. This enantioselective transformation is enabled by the use of
Ts-protected bifunctional sulfide catalyst and Ms-protected ortho-
alkynylaryl amines. Both electrophilic arylthiolating and electrophilic
naphthyl skeleton with different starting materials in recent
years.[17] In this content, Gu developed palladium-catalyzed
trifluoromethylthiolating reagents are suitable for this reaction. The
enantioselective coupling of aryl bromides with hydrazones
(Scheme 1a),[17a] and Smith reported ammonium salt-catalyzed
atropselective O-alkylation of racemic 1-aryl-2-tetralones via
dynamic kinetic resolution (Scheme 1b).[17c] In these
transforamtions, the formed vinyl-aryl axially chiral compounds
not only could act as an olefin-containing axially chiral ligand or
a precursor for the synthesis of point chiral compounds, but also
could be aromatized to axially chiral binaphthyls under mild
conditions. Despite these advances, structural diversity and the
substituents on the aromatic ring of the prepared axially chiral
compounds still remain limited. These limitations hamper the
wider applications of axially chiral compounds. Thus,
development of new methods for their synthesis is highly
desirable.
obtained products of axially chiral vinyl-aryl amino sulfides can be
easily converted into biaryl amino sulfides, biaryl amino sulfoxides,
biaryl amines, vinyl-aryl amines, and other valuable difunctionalized
compounds.
Axially chiral compounds contain an axial chirality that originates
from restricted rotation about a single bond. They are prevalent
in many natural products and bioactive molecules,[1] and are
useful chiral ligands and catalysts in enantioselective catalysis.[2]
For example, TMC-95A is a biologically active natural product;[3]
(SO,SO)-, (P,S)- or (N,P)-difunctionalized compounds A-C can
serve as ligands for a variety of metal-catalyzed enantioselective
reactions;[4-5] trialkylsulfonium salt D is an efficient bifunctional
organocatalyst for the enantioselective conjugate additions of 3-
substituted oxindoles to maleimides;[6a] biaryl amino alcohol E is
a photocatalyst efficiently promoting the enantioselective [2+2]
photocycloaddition of 4-alkenyl-substituted coumarins (Fig. 1).[6b]
(a) Pd-catalyzed two-component coupling
R2
NNHTs
Br
O
P
R
Pd, L
O
P
R
R
R2
+
R1
OH
O
O
R
HO
R1
p-Tol
Ar
N
H
O
S
S
SPh
O
O
HN
(b) Ammonium salt-catalyzed O-alkylation via dynamic kinetic resolution
N
PPh2
O
H
H
N
O
O
R2
R2
R1
HO
Ar
p-Tol
NH2
chiral ammonium salt
O
OR3
OBn
OR3
+
BnI
A, ligand
B, ligand
N
TMC-95A
H
R1
O
F3C
OTf
SBu2
OH
H
N
(c) Our strategy:
PPh2
NMe2
H
H
H
N
Ar1
N
N
N
Ar
Ar
cat.
SR
N
S
RS+ reagent

O
+
F3C
Ar2
Ar1
C, ligand
D, catalyst
E, catalyst
Ar2
Catalytic enantioselective electrophilic carbothiolation of alkynes
Figure 1. Representative examples of axially chiral bioactive natural product,
ligands, and catalysts.
Ar1
Ar1
Ar1
SR
SR
N
Y
possible
derivatives
or
or



Z
N
Due to the importance of axially chiral compounds, a large
number of catalytic enantioselective synthetic methods have
been developed for their synthesis.[7-16] Most of them focused on
the synthesis of axially chiral biaryls including transition metal-
catalyzed aryl-aryl cross-coupling,[7b,8] oxidative couplings,[9]
kinetic resolution,[10] desymmetrization,[11] point-to-axial chirality
transfer,[12] de novo construction of an aromatic ring,[13] Cu-
Ar2
Ar2
Ar2
Z = PR2...
aromatization
Y = H...
Scheme 1. Catalytic enantioselective construction of axially chiral vinyl-aryl
compounds and our strategy.
Catalytic electrophilic thiolation reaction provides a facile and
straightforward route for the transformation of alkenes and
alkynes to sulfur-containing molecules.[18-23] In the past few
years, considerable efforts have been devoted to the
development of catalytic enantioselective versions. Particularly,
by chiral chalcogenophosphoramide[19,21] and chiral bifunctional
chalcogenide catalysis,[22] a range of chiral sulfur-containing
compounds could be prepared efficiently. However, these
[*] Y. Liang, J. Ji, X. Zhang, Dr. Q. Jiang, J. Luo, and Prof. Dr. X. Zhao
Institute of Organic Chemistry & MOE Key Laboratory of Bioinorganic
and Synthetic Chemistry
School of Chemistry
Sun Yat-Sen University, Guangzhou 510275, China
E-mail: zhaoxd3@mail.sysu.edu.cn
Supporting Information for this article is available on the WWW under
http://XXX (added afterwards)
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10.1002/anie.201915470
Angewandte Chemie International Edition
COMMUNICATION
electrophilic reactions only furnished point chiral compounds and
have never been applied to enantioselective construction of
axially chiral molecules. As a continuation of our interest in
TfOH, TESOTf, TBSOTf, and BF3•Et2O were less effective than
TMSOTf (entries 11-15). Using the mixed solvents of
dichloromethane and chloroform, the best enantioselectivity of
the reaction was achieved (entry 16). Electrophilic sulfur
electrophilic
reactions,[22,24]
we
hypothesized
that
enantioselective electrophilic thiolation might be suitable for
enantioselective synthesis of axially chiral compounds. We
reasoned that using sterically hindered alkynylarenes as
substrates, electrohphilic carbothiolation might generate an
enantiopure axially chiral vinyl-aryl compound in the presence of
chiral catalyst. Because of the good transformability and
appropriate metal coordination property of the amino group,
ortho-alkynylaryl amines were preferred to be used and an
axially chiral amino sulfide based on vinyl-aryl skeleton was
expected as products (Scheme 1c). Herein, we report our
discovery that ortho-alkynylaryl amines could efficiently afford
enantiopure axially chiral vinyl-aryl amino sulfides via chiral Ts-
protected bifunctional sulfide catalysis.
reagents
based
on
phthalimide,
pyrrolidinone,
imidazolidinedione, and saccharin scaffolds were less effective
than 2a (see the supplementary information).
Table 1: Condition optimization.[a]
O
NHMs
cat.
S(p-Tol)
N
S(p-Tol)
+
NHMs
acid, CH2Cl2
-78 oC, 18 h
O
1e
2a
3e
To the best of our knowledge, this is the first successful
example of catalytic enantioselective synthesis of 2-amino-2′-
thio axially chiral compounds.[10a] Importantly, this amino sulfide
is a previliged scaffold and can serve as a platform molecule
(Scheme 1c): (i) It is a precursor of potential (S,N)-ligand and -
catalyst. (ii) It might be easily aromatized to axially chiral biaryl
amino sulfide. (iii) It might be transformed to other axially chiral
difunctionalized compounds because of the transformability of
the thio group and the amino group.
Entry
Cat.
Acid
Yield [%][b]
Ee [%][c]
H
Pg
O
N
1
2
C2
C3
TMSOTf
TMSOTf
TMSOTf
TMSOTf
TMSOTf
TMSOTf
TMSOTf
TMSOTf
TMSOTf
TMSOTf
Tf2NH
96
91
96
89
66
46
88
98
99
95
97
61
85
82
13
96
94
82
69
63
68
66
5
cat.
S(p-Tol)
N S(p-Tol)
(1)
+
TMSOTf
NHPg
3
C4
CH2Cl2, -78 oC, 18 h
O
2a
3a-3e
1a-1e
4
C5
cat.:
Pg:
O O
Pg yield ee
MeO
5
C6
O O
S
6
C7
2
3a Ac
3b Bz
24% 8%
n.d
68% 32%
S
Me
Se
7
C8
73
75
87
89
80
87
88
86
88
93
91
92
-
OMe
8
C9
3d
42%, 19% ee
Me
3e
C1 NHTf
3c
78%, 47% ee
Tf
9
C10
C11
C11
C11
C11
C11
C11
C11
C11
C11
10
11
12
13
14
15
16[d]
17[e]
18[f]
Keeping the hypothesis in mind, we first tested catalytic
electrophilic arylthiolation of Ac-protected alkynylaniline 1a in the
presence of electrophilic sulfur reagent 2a and TMSOTf (eq 1).
Easily prepared, chiral Tf-protected bifunctional selenide C1 was
utilized as catalyst. Gratifyingly, the desired product of axially
chiral amino sulfide 3a was formed, albeit in low yield with only
8% ee. Using Bz-protected alkynylaniline 1b as substrate, the
reaction did not occur at all. Considering the effect of hydrogen
bonding from the substrate, the alkynylaniline was protected by
the Tf group leading to evidently higher enantioselectivity of the
reaction. The protecting groups were further adjusted. Ms-
protected alkynylaniline 1e was found to give the desired
product in higher ee.
TfOH
TESOTf
TBSOTf
BF3·Et2O
TMSOTf
TMSOTf
TMSOTf
[a] Reaction conditions: 1e (0.05 mmol), 2a (1.5 equiv), cat. (10 mol%), acid
(3.0 equiv), CH2Cl2 (2.0 mL), -78 oC, 18 h. [b] NMR yield using quinoline as the
internal standard. [c] Determined by HPLC analysis. [d] CH2Cl2 (1.0 mL) +
CHCl3 (1.0 mL) as solvents. [e] CH2Cl2 (1.0 mL) + ClCH2CH2Cl (1.0 mL) as
solvents. [f] CH2Cl2 (1.0 mL) + toluene (1.0 mL) as solvents.
After the proper protecting group on alkynylaniline was
determined, more reaction conditions were screened (Table 1).
Owing to the effect of hydrogen bonding from the catalyst that
might play a critical role in the reaction,[22a] different protecting
groups were attempted to install on the catalyst. To our delight,
when the selenide catalyst was protected by the Ts group, the
reaction gave the desired product in excellent yield with 69% ee
(entry 1). Other protecting groups, i.e. Ns and 4-isopropyl- and
4-methoxy-substituted benzenesulfonyl groups were slightly less
efficient than the Ts group (entries 2-4). When Bz and
phosphonate groups were used, the products were formed in
almost racemic formation (entries 5 and 6). To our surprise,
sulfide catalyst C8 delivered better enantioselectivity than
selenide catalyst C2 (entry 7). Then, other sulfide catalysts with
different groups at the ortho-position of the phenyl group were
examined. Catalyst with one methyl group led to slightly higher
ee (entry 8). Replacing the methoxy group with propoxy group,
the enantioselectivity increased to 87% (entry 9). Catalyst with
bulky isopropoxy group led to slighly higher ee (entry 10).
Furthermore, Lewis acid and Brønsted acids such as Tf2NH,
With the optimal conditions in hand, the scope of alkynes was
evaluated (Scheme 2). First, various tethered aryl groups as
nucleophiles were investigated. Different substituent groups at
the para position of the phenyl ring did not have a dramatic
impact on the chemical yields and enantioselectivities of the
reactions (3e-3j). When the substituent group was placed at the
ortho position of the phenyl ring or the phenyl group was
replaced by the naphthyl group, the reactions still proceeded
very well to give the desired products in excellent yields with
excellent ees (3k and 3l). Next, different substituent groups on
the phenyl ring of the aniline group were examined (3m and 3n).
Methyl-substituted substrate gave product 3m in only 79% ee
under the standard conditions. However, when N-(p-TolS)-
imidazolidinedione was used as electrophilic sulfur reagent
instead of 2a, the enantioselectivity of reaction increased to 91%.
The phenyl-substituted substrate gave the corresponding
product 3n in high ee under the standard conditions.
Furthermore, a series of substituted naphthylamines were
utilized as substrates, all the reactions underwent electrophilic
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10.1002/anie.201915470
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COMMUNICATION
thiolation to produce axially chiral products in high yields with
excellent ees (3o-3u). It is worthy to mention that the methoxy
substituent did not influence the reaction at all although the
electron-rich aryl ring had a possibility to suffer from direct
thiolation (3o and 3s).
The scope of electrophilic sulfur reagents was explored
(Scheme 3). A range of para-substituted aryl sulfur reagents
gave the desired axially chiral products in excellent yields with
excellent enantioselectivities (3v-3z, 95-97% ees). It was noted
that these sulfur reagents included para-methoxy-substituted
one (3w, 97% ee). Similarly, the reaction of meta-methyl-
substituted sulfur reagent proceeded smoothly to afford the
desired product (3aa, 98% ee). Next, we turned our attention to
the reaction with electrophilic trifluoromethylthiolating reagent
(CF3S+) because the CF3S group is an important class of
fluorine-containing group and has unique properties.[25] Until now,
no report has been demonstrated for enantioselective synthesis
of CF3S-containing axially chiral molecules.[22] Pleasedly,
enantioselective electrophilic trifluoromethylthiolation occurred
efficiently to form the desired axially chiral products using
electrophilic N-CF3S-saccharin after the screening of conditions.
Both o-alkynylanilines and -naphthylamines underwent thiolation
to give the products in high yields with excellent
enantioselectivities (3ab-3af, 90-93% ees). These results
indicated the generality of this method.
NHMs
Ar1
C11
S(p-Tol)
+
2a
Ar2
TMSOTf
CH2Cl2 + CHCl3
-78 oC, 18 h
Ar1
NHMs
Ar2
1e-1u
3e-3t
R
H
yield ee
3e
3f
95% 93%
S(p-Tol)
Me 96% 94%
3g Ph 98%
R
S(p-Tol)
96%
Br 91% 90%
NHMs
NHMs
3h
3i
3j
88% 93%
Cl
F
91% 89%
3k, 91%, 91% ee
Me
S(p-Tol)
S(p-Tol)
O
NHMs
S(p-Tol)
NHMs
MeO
NHMs
(a)
(b)
S(p-Tol)
S(p-Tol)
S
(p-Tol)
NHMs
NHMs
NHMs
R
3m,[a] R = Me, 72%, 91% ee
3n, R = Ph, 86%, 94% ee
3l, 96%, 93%ee
3o, 93%, 96% ee
3e, 93% ee
4, 82%, 91% ee
5, 93%, 91% ee
yield ee
89% 94%
R
H
3q
3r
S(p-Tol)
NHMs
Me
93% 94%
S(p-Tol)
(c)
(f)
SO2(p-Tol)
S(p-Tol)
Br
S(p-Tol)
3s OMe
96%
91%
NHMs
NHMs
NHMs
NH2
3t
Ph
Br
93% 95%
84% 98%
3u
3p, 91%, 91% ee
R
3q, 94% ee
6, 89%, 94% ee
(d)
11, 73%, 94% ee
(e)
(g)
Scheme 2. Enantioselective construction of axially chiral compounds with
different alkynes. Reaction conditions: 1e-1u (0.1 mmol), 2a (1.5 equiv),
TMSOTf (3.0 equiv), C11 (10 mol%), CH2Cl2 (2.0 mL) + CHCl3 (2.0 mL), -78
oC, 18 h. The yields refer to isolated yields. The ee value was determined by
HPLC analysis. [a] N-(p-TolS)-imidazolidinedione instead of 2a.
Me
S(p-Tol)
NHMs
NHMs
Br
7, 81%, 94% ee
9, 77%, 94% ee
12, 56%, 92% ee
O
NHMs
(a)
(h)
(a)
C11
SR
+
N
SR
Ar
TMSOTf
CH2Cl2 + CHCl3
-78 oC, 18 h
NHMs
O
2b-2g
Ar
1
Me
S(p-Tol)
3v-3af
NHMs
NHMs
PPh2
ee
97%
R'
H
yield
91%
3v
SCF3
3w
3x 4-Br
3y
3z
4-MeO 92% 97%
10, 92%, 93% ee
13, 84%, 92% ee
8, 96%, 94% ee
S
96%
95%
79% 97%
86%
84%
R'
NHMs
NHMs
4-Cl
4-F
Scheme 4. Further transformations of products. Conditions: (a) DDQ, DCM, rt,
12 h. (b) saccharin-Cl, THF, -78 oC, 12 h. (c) m-CPBA, DCM, rt, overnight. (d)
MeMgBr, Fe(acac)3, THF, rt, overnight. (e) Mg, MeOH, rt, 12 h. (f) (Boc)2O,
DMAP, DCM, rt, 8 h; then n-BuLi, O2, THF, 0 oC to rt, 2 h; then TFA, DCM, rt,
8 h. (g) NaNO2, H2SO4, AcOH, KBr, ZnBr2, rt, 3 h; then, KBr, hexane, 50 oC,
24 h. (h) n-BuLi, Ph2PCl, THF, -78 oC to rt, 4 h.
3ab,[a] 81%, 91% ee
3aa
3-Me
93%
98%
SCF3
SCF3
SCF3
NHMs
NHMs
MeO
NHMs
R
3ad,[a] R = OMe, 91%, 92% ee
3ae,[a] R = Ph, 79%, 93% ee
To elucidate the practical applications of this method, the
further transformations of the obtained products were carried out
(Scheme 4). For instance, 3e was easily transformed to 2-
amino-2′-thiobiaryl compound 4 under mild conditions, and then
further oxidized to the corresponding chiral sulfoxide 5 in high
yield and excellent stereoselectivity (dr > 20:1). Product 3q was
treated with m-CPBA to afford sulfone 6 efficiently. Sulfone 6
could react with Grignard reagent to generate methylated
compound 7 under the catalysis of Fe(acac)3. The sulfone also
could be transformed to compound 9, a potential axially chiral
(N,olefin)-ligand,[26] via the reduction of the sulfone group.
3ac,[a] 90%, 90% ee
3af,[a] 84%, 92% ee
Scheme 3. Enantioselective construction of axially chiral compounds with
different electrophilic sulfur reagents. Reaction conditions: 1 (0.1 mmol), 2b-2g
(1.5 equiv), TMSOTf (3.0 equiv), C11 (10 mol%), CH2Cl2 (2.0 mL) + CHCl3
(2.0 mL), -78 oC, 18 h. The yields refer to isolated yields. The ee value was
determined by HPLC analysis. [a] N-CF3S-saccharin was used.
Compounds
7
and
9
were aromatized to form chiral
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10.1002/anie.201915470
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COMMUNICATION
monofunctional biarylamines under mild conditions. Furthermore, We thank the National Natural Science Foundation of China
the deprotection of the amino group was easy, which led to the
(Grant Nos. 21772239, 91856109, and 21901261) for financial
support.
formation of amine 11 in good yield. The amine 11 could be
transformed to phosphine 13,
a a
known ligand,[5c] via
bromination-cross coupling process. In these transformations,
the enantiosectivities of the reactions changed slightly. These
transformations indicated that the products are a good platform
molecule, which provides a convenient route for the synthesis of
a variety of valuable axially chiral compounds bearing an amino
group, a thio group or both amino and thio groups.
Keywords: axially chiral compounds · alkynes · thiolation ·
sulfide catalysis · synthetic methods
[1]
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N
SR TMSOTf
+
RS
S
OiPr
H
N
N
TMS
Ar1
R'
NHTs
C11
+
Ms
Me
[3]
[4]
J. Kohno, Y. Koguchi, M. Nishio, K. Nakao, M. Kuroda, R. Shimizu, T.
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TfO
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+
OiPr
SR
O
Ar1
p-Tol
N
H
I
Me
S
Ts
N
S
RS
MsHN
O
OTf
H
F
F
[5]
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O
O
iPr
F
S
O
Ar2 + TfOH
NHMs
Ar2
S
R
O
H
Ms
N
Ar1
Ar2
1
3
[6]
[7]
a) N. Vallavoju, S. Selvakumar, S. Jockusch, M. P. Sibi, J. Sivaguru,
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Ar1
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For selected examples, see: a) A. Bermejo, A. Ros, R. Fernández, J. M.
Lassaletta, J. Am. Chem. Soc. 2008, 130, 15798; b) X. Shen, G. O.
Jones, D. A. Watson, B. Bhayana, S. L. Buchwald, J. Am. Chem. Soc.
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Scheme 5. Possible mechanism.
On the basis of the previous studies,[16b-f,22h] a plausible
reaction pathway is depicted (Scheme 5). First, the electrophilic
sulfur reagent is activated by catalyst C11 to form intermediate I
under the assistance of Lewis acid. Intermediate I reacts with
substrate 1 to give thiirenium ion intermediate II with an acid-
derived anion bridge. Then, intermediate II may be further
converted to a chiral aza-vinylidene-quinone methide (aza-VQM)
intermediate III and regenerate the catalyst.[16b-f] The following
intramolecular hydroarylation on the intermediate III results in
axially chiral product 3. Both the amino groups on catalyst and
substrate are crucial in the enantiocontrol. When they are
protected by appropriate groups, proper hydrogen bonding can
lead to the best enantioselectivity of reaction. Not surprisingly,
when the amino group on substrate was replaced by methoxy or
methyl group, the reaction gave racemic products (see the
supplementary information). Furthermore, the reaction gave
messy products when changing the triple bond on substrate 1 to
a double bond. This result may be attributed to the absence of
the aza-VQM intermediate in the reaction.
In summary, we have developed a new strategy to construct
enantiopure axially chiral amino sulfides with various
substituents by chiral sulfide catalyzed enantioselective
electrophilic carbothiolation of alkynes. The yields were high and
the enantioselectivities of reactions were excellent. The obtained
products could be further converted into valuable axially chiral
compounds under mild conditions in simple steps. The further
applications of the formed axially chiral compounds are ongoing
in our laboratory.
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COMMUNICATION
Table of Contents
COMMUNICATION
Me
catalytic
Yaoyu Liang, Jieying Ji, Xiaoyan Zhang,
Quanbin Jiang, Jie Luo, and Xiaodan
Zhao*
S
OiPr Ar1
NHMs
O
NHTs
SR
+
Ar2
N
SR
NHMs
Ar1
TMSOTf
Page No. – Page No.
Ar2
RS = ArS, CF3S
Enantioselective Construction of Axially
Chiral Amino Sulfide Vinyl Arenes via
Chiral Sulfide-Catalyzed Electrophilic
Carbothiolation of Alkynes
up to 98% ee
Enantioselective construction of axially chiral compounds via electrophilic
carbothiolation of alkynes is disclosed for the first time. This enantioselective
transformation is enabled by the use of Ts-protected bifunctional sulfide catalyst
and Ms-protected ortho-alkynylaryl amines. Both electrophilic arylthiolating and
electrophilic trifluoromethylthiolating reagents are suitable for this reaction. The
obtained products of axially chiral vinyl-aryl amino sulfides can be easily converted
into biaryl amino sulfides, biaryl amino sulfoxides, biaryl amines, vinyl-aryl amines,
and other valuable difunctionalized compounds.
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