Chiral Selenide-Catalyzed Enantioselective Allylic Reaction and Intermolecular Difunctionalization of Alkenes: Efficient Construction of C-SCF3 Stereogenic Molecules

Article abstract of DOI:10.1021/jacs.8b01513

New approaches for the synthesis of enantiopure trifluoromethylthiolated molecules by chiral selenide-catalyzed allylic trifluoromethylthiolation and intermolecular difunctionalization of unactivated alkenes are disclosed. In these transformations, functi

Full text of DOI:10.1021/jacs.8b01513

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Communication
Chiral Selenide-Catalyzed Enantioselective Allylic Reaction
and Intermolecular Difunctionalization of Alkenes:
Efficient Construction of C–SCF3 Stereogenic Molecules
Xiang Liu, Yaoyu Liang, Jieying Ji, Jie Luo, and Xiaodan Zhao
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 27 Mar 2018
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Xiang Liu, Yaoyu Liang, Jieying Ji, Jie Luo, Xiaodan Zhao*
Institute of Organic Chemistry & MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry, Sun
Yat-Sen University, Guangzhou 510275, P. R. China
Supporting Information Placeholder
lar difunctionalization of alkenes. To achieve this goal, two chal-
ABSTRACT: New approaches for the synthesis of enantiopure
lenging issues needed to be overcome: (i) The difficulty of enan-
tiocontrol of reactions, especially without a binding group assis-
tance.4 (ii) The racemization of thiiranium ion intermediate
through C–S bond cleavage to form a unstable carbocation and
olefin-to-olefin degeneration of thiiranium ion.12 On the basis of
the previous studies,11,12h we envisioned that relatively stable
thiiranium ion might not be easy to racemize. Furthermore, a
proper chiral environment to control the enantioselectivity would
be feasible to provide by tuning catalysts and additives. Thus, it is
possible to gain chiral allylic and difunctionalization products in
high enantioselectivities when allylic proton elimination and nu-
cleophilic attack proceed smoothly after the formation of relative-
ly stable thiiranium ion.
trifluoromethylthiolated molecules by chiral selenide catalyzed
allylic trifluoromethylthiolation and intermolecular difunctionali-
zation of unactivated alkenes are disclosed. In these transfor-
mations, functional groups were well tolerated, and the desired
products were obtained in good yields with excellent chemo-,
enantio- and diastereoselectivities. This work is nicely comple-
mentary to enantioselective trifluoromethylthiolation, allylic func-
tionalization and intermolecular alkene difunctionalization.
Fluorine and fluorine-containing moieties can adjust the chemical,
physical and biological properties of parent molecules.1 Conse-
quently, synthesis of fluorinated molecules is of great interest in
the field of pharmaceuticals and agrochemicals.2,3 Owing to the
prevalence of alkene structural unit on molecules, much attention
has been paid to the synthesis of fluorinated compounds by incor-
poration of a fluorine or fluorine-containing moiety into parent
alkenes. However, construction of chiral fluorinated molecules
from alkenes has been largely limited.2b,d In particular, utilizing
very useful enantioselective allylic C–H functionalization and
intermolecular difunctionalization of alkenes to synthesize fluori-
nated molecules remains a formidable challenge. Only recently, a
few elegant approaches have been developed.4-8 For example,
Toste reported directed allylic fluorination via C–H bond cleavage
by chiral anion phase transfer catalysis (Scheme 1a),4 and Liu
demonstrated Cu-catalyzed enantioselective intermolecular CF3-
functionalization of terminal alkenes via radical process (Scheme
1b).7c,d In comparison with fluoro and trifluoromethyl groups,
trifluoromethylthio (CF3S) group has higher lipophilicity value.3a
Compounds bearing a CF3S group may possess some unique
properties. Herein, we report our discovery that C–SCF3 stereo-
genic molecules could be efficiently produced by chiral selenide-
catalyzed allylic functionalization via C–H bond cleavage and
intermolecular difunctionalization of alkenes (Scheme 1c).
Scheme 1. Catalytic Enantioselective Construction of
Fluorinated Molecules with Alkenes
(a) Directed allylic fluorination
(b) Intermolecular difunctionalization
R

cat.
DG Selectfluor
cat.

CF3
Ar
DG
CF3-reagent
Ar
F
DG = OH, NHR, phenol
Terminal alkene substrates
Chiral anion phase transfer catalysis
Metal-catalyzed radical process
(c) Synthesis of C-SCF3 stereogenic molecules by allylic reaction
and intermolecular alkene difunctionalization: This work
no "Nu-"
via:

Se
R

R1
cat.
chiral selenide
SCF3
R
SCF3
H
R1
R =
NTf2
R
R1
"CF3S+"
Tf2NH
Br, Cl, I, H
OCOR'
Nu

with "Nu-"
R
R1

Nu = F, OH, OR', NCS
SCF3
Keeping the assumption in mind, we first investigated allylic
trifluoromethylthiolation via C–H bond cleavage. Considering
that the formed thiiranium ion from trisubstituted alkenes with an
appropriate electronic property might be relatively stable, easily
prepared (E)-(5-bromopent-2-en-2-yl)benzene (1a) was selected
as the model substrate. Lewis basic selenium catalysis has exhib-
ited great potentials11-13 and different chiral selenide catalysts
were examined for this reaction (Table 1). When 1a was treated
with electrophilic (PhSO2)2NSCF3 (2) using Boc-protected sele-
nide catalyst C1, it was found that allylic reaction occurred to
give the desired product 3a in 42% yield with 10% ee in the pres-
ence of TfOH (entry 1). Although the enantioselectivity was quite
low, this indicated that enantioselective implementation was via-
ble by chiral selenide catalysis. Ts-protected catalyst C2 was fur-
ther tested. Product 3a was generated in trace amounts (entry 2).
In recent years, many efforts have been devoted to the synthesis
of CF3S-molecules.3,9-11 But, the successful examples of enanti-
oselective trifluoromethylthiolation are rare.10,11 To expand this
area, we have developed efficient approaches to construct chiral
CF3S-molecules through bifunctional chalcogenide-catalyzed
intramolecular reactions of alkenes.11b-e In these transformations,
an additional functional group had to be installed on substrates as
a nucleophile group to promote the cyclizations and prevent the
racemization of thiiranium ion. Due to this installation, the scopes
are limited to the relatively specialized substrates, which led to
specific stereogenic CF3S-products. We questionated whether
chiral CF3S-molecules could be accessed not by the former intra-
molecular mode, but by allylic functionalization and intermolecu-
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When selenide catalyst C3 with NHTf group was employed, 3a
a phenylallylic moiety. The high selectivity of allylic unit might
stem from the slight stabilization difference between the formed
ion intermediates from the two double bonds. Based on these
results, this method provides a good pathway for the selective
trifluoromethylthiolation of alkenes with multiple double bonds.
was formed with 78% ee (entry 3). These results revealed that the
NHTf group was crucial and might bind to the TfO- anion to set
up a proper steric hindrance for high enantiocontrol.11e To probe
this spectulation, catalyst C4 with nitrogen protected by two Tf
groups was examined. The enantioselectivity decreased to 43%
(entry 4). Next, effect of electron density and steric hindrance of
aryl group on catalysts was studied (entries 5 and 6). It was found
that methyl and methoxy groups installed at the ortho positions of
the phenyl ring led to improved yield and ee (entry 5). Less steri-
cally hindered C6 resulted in the drop of yield (entry 6). In con-
trast, the sulfide catalyst was not effective for this transformation
(entry 7). We realized that an appropriate anion from the corre-
sponding acid could not only accelerate allylic proton elimination
but also bind to catalyst to provide a proper chiral environment.
So different acids combined with catalyst C5 were screened. The
reactivity and enantioselectivity were largely affected (entries 8-
10). Finally, product 3a was obtained in high yield with 91% ee
using Tf2NH as the acid (entry 10). Less loading of acid affected
the yield slightly (entry 12).
1
2
3
4
5
6
7
8
Scheme 2. Functional Group Tolerancea
Me
C5 (20 mol%)
R
+
R
(PhSO2)2N SCF3
Ph
O
Ph
CH2Cl2/toluene
Tf2NH, -78 oC, 12 h
1b-q
2
3 SCF3
9
3b, 61%, 93% ee
3c, 78%, 94% ee
3d, 66%, 91% ee
3e, 95%, 93% ee
R = Cl
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
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43
44
45
46
47
48
49
50
51
52
53
54
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56
57
58
59
60
O
I
OAc
OBz
O
O
3f, 60%, 91% ee
3g, 74%, 92% ee
O
Me
O
O
O
S
Me
O
O
O
O
3h, 68%, 93% ee 3i, 73%, 93% ee 3j, 61%, 90% ee 3k, 71%, 90% ee
Me
O
Me
O
O
O
Table 1. Condition Optimizationa
O
O
3n, 72%, 90% ee
3l, 68%, 90% ee
3m, 72%, 90% ee
Me
cat.
Me
+
(PhSO2)2N SCF3
Br
Br
O
acid
Ph
O
Ph
O
Ph
Me
CH2Cl2/toluene
-78 oC, 12 h
1a
2
SCF3
3a
O
O
O
3o, 87%, 88% ee
3p, 77%, 91% ee
3q, 65%, 92% ee
SePh
SePh
SePh
SePh
aConditions: 1 (0.1 mmol), 2 (1.5 equiv), Tf2NH (2.0 equiv), C5
(20 mol%), CH2Cl2 (2 mL) + toluene (2 mL), -78 C, 12 h. The
yields refer to isolated yields. The ee value was determined by
HPLC analysis.
o
NHTs
NHBoc
Me
C2
C3 NHTf
C4 NTf2
C1
Me
S
MeO
Se
Se
Scheme 3. Allylic Trifluoromethylthiolation of Different
OMe
OMe
OMe
Alkenesa
C5 NHTf
C6
C7 NHTf
NHTf
R1
ee (%)c
10
--
78
43
90
87
67
82
87
91
83
R1
R
entry
1
2
3
4
5
6
7
8
cat.
acid
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
yield (%)b
42
C5 (20 mol%)
C1
C2
C3
C4
C5
C6
C7
C5
C5
C5
C5
C5
+
(PhSO2)2N SCF3
R
R2
CH2Cl2/toluene
Tf2NH, -78 oC, 12 h
R2
R'
<5
45
14
50
42
12
18
90
1r-al
2
3
SCF3
Br
R'
R'
3r 4-Me
3s 3-Me
3t 4-F
3v 4-Br
79%, 92% ee
86%, 91% ee
88%, 93% ee
85%, 93% ee
70%, 93% ee
85%, 94% ee
89%, 94% ee
3w 4-Ph
3x 3-MeO
3u 4-Cl
SCF3
BF3.OEt2
TMSOTf
Tf2NH
Tf2NH
Tf2NH
Me
9
Br
Br
Br
Ph
10
11d
12e
99(95)
87
92
SCF3
SCF3
SCF3
S
91
3z
3aa (Z/E = 3.3:1), 90%
3y
92%, 93% ee
aConditions: 1a (0.05 mmol), 2 (1.5 equiv), acid (2.0 equiv), cata-
88%, 92% ee
92% ee/91% ee
o
lyst (20 mol%), CH2Cl2/toluene = 1 mL/1 mL, -78 C, 12 h.
R'
R'
OBz
bNMR yield using trifluoromethylbenzene as the internal standard.
Isolated yield is in parentheses on 0.1 mmol scale. cDetermined by
chiral HPLC analysis. dAt -40 oC. eTf2NH (0.5 equiv).
3ab 4-Me
3ac 3-Me
3ad 4-F
3af 4-Br
70%, 92% ee
84%, 94% ee
95%, 94% ee
89%, 95% ee
R'
4-Ph
3-MeO
85%, 92% ee 3ag
90%, 94% ee
75%, 93% ee
3ah
3ae 4-Cl
SCF3
OBz
OBz
OBz
Me OBz
Then, we evaluated the substrate scope of reaction. Different
functional groups on the long chain of alkenes 1 were first studied
under the similar conditions (Scheme 2). When bromo group was
replaced by chloro or iodo group, the corresponding products
were generated in good yields with high enantioselectivities. The
replacement by OAc, OBz or alkyl ester groups slightly affected
the enantioselectivities of the transformation (3d-g, 91-93% ees).
Functional groups containing double bond, triple bond, heterocy-
cle and conjugated diene were well tolerated (3h-q). It is notewor-
thy that when the substrates having two allylic units were used,
the allylic trifluoromethylthiolation always took place at the al-
lylic side where three substituents including aryl group was at-
tached to the double bond. For example, products 3n-q were suc-
cessfully obtained with 88-92% ees. No byproducts derived from
the other allylic unit were observed, even using substrate 1o with
Ph
SCF3
SCF3
SCF3
SCF3
S
3aj
3ak
93%, 70% ee
3al (Z/E = 2.3:1), 95%
92% ee/94% ee
3ai
94%, 91% ee
aConditions: As described in Scheme 2.
82%, 89% ee
We turned our attention to the allylic trifluomethylthiolation of
different aryl-substituted alkenes (Scheme 3). Bromo-substituted
substrates bearing para- or meta-substitutent on the phenyl ring
could efficiently undergo trifluoromethylthiolation to form the
products in good yields with excellent enantioselectivities (e.g.
3r-x, 70-89% yields and 91-94% ees). Electron-rich naphthyl and
thiophen-3-yl alkenes also underwent the same conversion to give
the corresponding products with excellent enantioselectivities (3y,
93% ee; 3z, 92% ee). When 1,1-ethylphenyl-substituted alkene
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was used as the substrate, the isomer products with acceptable
compounds including important cyclic amines and ethers with a
quaternary center can be easily accessed by the developed method.
isomer ratio Z/E = 3.3:1 were obtained. The enantioselectivities of
the isomers were excellent. Similarly, the allylic trifluoromethyl-
thiolation of ester-tethered alkenes proceeded efficiently to give
the corresponding products in good yields (3ab-al, 70-95%
yields). The enantioselectivities were excellent for most cases
except for the formation of 3ak (3ak, 70% ee). The decrease of
enantioselectivity might ascribe the change of steric hindrance
around the double bond on substrate.
1
2
3
4
5
6
7
8
Scheme 4. Intermolecular Difunctionalization of Alkenesa
R1
Nu
R1
R
C5 (10 mol%)
CF3S-reagent 2
+
R
R' Nu
R2
R2
CH2Cl2/toluene
Tf2NH, -78 oC, 12 h
1 or 6
8
9 SCF3
Nu =
F
9a, 68%, 85% ee R'Nu:
Et3N 3HF (4 equiv)
H2O (20 equiv)b
OH 9b, 80%, 93% ee
SCN 9c, 58%, 93% ee
OAc 9d, 76%, 90% ee
OMe 9e, 80%, 91% ee
Me Nu
TMSNCS (4 equiv)
AcOH (50 equiv)
MeOH (4 equiv)
9
C5 (20 mol%)
Me
O
+
+
(PhSO2)2N SCF3
(1)
(2)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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46
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50
51
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58
59
60
Ph
CH2Cl2/toluene
Tf2NH, -78 oC, 12 h
SCF3
Me
Ph
Ar
Ph
HO
SCF3
2
4
(4 equiv)
9f, 72%, 89% ee
5, 89%, 84% ee
Me
OCH3
Me
Me Me
Me OAc
Br
same as above
Me
O
(PhSO2)2N SCF3
Ar
Br
Me
7
2
6
SCF3
SCF3
SCF3
SCF3
9g, 73%, 90% ee
7a: Ar = 4-PhC6H4, 88%, 94% ee; 7b: Ar = 3-MeOC6H4, 85%, 95% ee
Ph
Ph
9h, 72%, 90% ee
9i, 74%, 93% ee
OBz
OBz
+
C5 (0.5 mol%)
Me OAc
Me
Me OAc
Me OAc
(PhSO2)2N SCF3
(3)
OBz
O
O
Ph
CH2Cl2/toluene
Tf2NH, -78 oC, 72 h
Ph
Ph
Ph
SCF3
1e, 1.0 g
2
SCF3
9j, 73%, 93% ee
SCF3
O
SCF3
9l, 62%, 90% ee
O
3e, 1.32 g
90%, 93% ee
9k, 62%, 86% ee
aConditions: 1 or 6 (0.1 mmol), 2 (1.5 equiv), 8 (4 equiv) unless
noted, Tf2NH (2.0 equiv), C5 (10 mol%), AcOH (50 equiv) or
This method was extended to the trifluoromethylthiolation of
pure hydrocarbons. When commerically available alkene 4 was
treated with 2 under the similar conditions, product 5 was ob-
tained in good yield with good ee (eq. 1). When alkene 6a, 3ag’s
analogue, and 6b, 3ah’s analogue, were tested under the condi-
tions, the corresponding products were obtained in high yields
with almost unchanged ees in comparision to 3ag and 3ah, re-
spectively (eq. 2). To evaluate reaction efficiency, the reaction
was scaled up using gram-scale 1e as the substrate in the presence
of 0.5 mol% catalyst C5 (eq. 3). The desired product was still
obtained in excellent yield with the same ee, which indicates that
this method has great potential for practical synthetic application.
It is rationalized that difunctionalization products could be gen-
erated in the presence of a nucleophile in reactions. Satisfactorily,
when nucleophilic reagents such as Et3N·3HF, H2O, TMSNCS,
AcOH, MeOH, propargyl alcohol and methallyl alcohol were
added into reactions, the corresponding difunctionalization prod-
ucts were obtained in moderate to good yields with excellent en-
antio- and stereoselectivities (Scheme 4). Functional groups, i.e.
Br–, double bond and triple bond, were well tolerated under the
conditions. Selectivity for different double bond on substrates was
excellent as what was observed in aforementioned allylic reaction
(i.e. 9k). It is noteworthy that this method provides a intriguing
route for the synthesis of chiral fluorinated compounds with al-
kenes. For instance, 9a was obtained with 85% ee. Its absolute
configuration was determined by X-ray crystallagraphic analysis.
Allylic products are versatile synthetic intermediates and could
be further converted to various compounds (Scheme 5). For ex-
ample, 3a bearing a removable bromo group could be efficiently
transformed to sulfone 10 and nitrile 11 in high yields by substitu-
tion reactions. It also underwent hydroboration-oxidation reaction
to give primary alcohol 12 in good yield with 3:1 dr by an anti-
Markovnikov fashion. The bromo group on 3a was easily re-
placed by TsNH group. The formed product 13 could undergo
bromo-aminocyclization to give a quaternary-containing product
14 with the slight erosion of enantioselectivity. Furthermore, 3e
having a ester group could be easily deprotected to form alcohol
15 under basic conditions, then followed by selenide-catalyzed
cyclization to generate cyclic ether 16 in high yield. The CF3S
group could be oxidized to Tf group, another type of useful fluor-
inated group. These results indicate that a series of CF3S-
o
MeOH (4 equiv), CH2Cl2 (1 mL) + toluene (1 mL), -78 C, 12 h.
The yields refer to isolated yields. The ee value was determined
by HPLC analysis. All the diastereoselectivities are >99:1. TM-
SOTf (1 equiv) instead of Tf2NH.
b
Scheme 5. Further Transformations of Products
(b)
(a)
SO2Ph
Br
CN
Ph
Ph
Ph
SCF3
SCF3
SCF3
10
3a
91% ee
11
(c)
88%, 91% ee
92%, 91% ee
(d)
Br
Ts
N
OH
(e)
NHTs
Br
Ph
F3CS
Ph
Ph
SCF3
SCF3
12, 67%, 3:1 dr
91% ee (major)
90% ee (minor)
13
14, 87%
88% ee, 10:1 dr
78%, 91% ee
Br
Br
OBz
OH
(g)
(f)
(h)
O
O
Ph
Tf
Ph
Ph
Ph
SCF3
SCF3
F3CS
3e
93% ee
17
95%, 93% ee
15
16, 88%
93% ee, 20:1 dr
88%, 93% ee
Conditions: (a) PhSO2Na, DMF, 80 oC, 12 h. (b) TMSCN, K2CO3,
MeCN, 80 oC, 12 h. (c) BH3, THF, rt, 12 h; then NaOH, H2O2, rt,
2 h. (d) TsNH2, K2CO3, acetone, reflux, 12 h. (e) NBS, MsOH,
CH2Cl2, rt, 12 h. (f) KOH, MeOH, rt, 12 h. (g) NBS, PhSePh,
CH2Cl2, rt, 12 h. (h) RuCl3, NaIO4, MeCN/H2O/CCl4, rt, 14 h.
A plausible mechanism is proposed in Scheme 6.11 Ion pair I is
first formed after the reaction of catalyst C5 with 2 in the pres-
ence of Tf2NH. It interacts with alkene 1 to give thiiranium ion II.
Intermediate II is relatively stable and undergoes deprotonation to
generate allylic product 3 with the aid of anion as the base. When
this intermediate is attacked by nucleophilic group, difunctionali-
zation product 9 is formed. In these transformations, trisubstituted
alkenes as the substrates are important to more favor the for-
mation of thiiranium ion intermediate14 than disubstituted al-
kenes.15
Scheme 6. Proposed Mechanism
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(14) When electrophilic N-(4-MeC6H4S)succinimide was used instead
of (PhSO2)2NSCF3 under the similar conditions, no C–S(4-MeC6H4) stere-
ogenic product was observed (see Supporting Information). So the special
property of trifluoromethylthiiranium ion might lead to the occurrence of
reactions.
In summary, we have developed efficient approaches toward
enantioselective allylic C–H trifluoromethylthiolation and inter-
molecular difunctionalization of alkenes by chiral selenide cataly-
sis. Notably, these transformations proceeded without an addi-
tional binding group assistance. As practical applications, the
products were further converted into various valuable compounds
and the reaction was scaled up to gram-scale with low catalyst
loading (0.5 mol%). This work provides a new pathway for the
synthesis of C–SCF3 stereogenic compounds and implicates the
possibility of successful enantiocontrol in other types of alkene
functionalizations without a directing group assistance.
Experimental details, characterization data, NMR spectra of new
compounds, and HPLC traces. This material is available free of
charge via the Internet at http://pubs.acs.org.
*E-mail: zhaoxd3@mail.sysu.edu.cn
The authors declare no competing financial interest.
We thank the “One Thousand Youth Talents” Program of China,
the National Natural Science Foundation of China (Grant No.
21772239), and the Natural Science Foundation of Guangdong
Province (Grant No. 2014A030312018) for financial support.
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(15) Common 1,2-disubstituted alkenes such as 1-phenylpropene and 1-
phenylbutene did not work under the similar conditions (see Supporting
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Journal of the American Chemical Society
Information). Furthermore, tetrasubstituted alkenes such as (E)-2,3-
diphenyl-2-butene did not work under the standard conditions either.
Table of Contents:
1
2
3
Me
R2
catalytic
4
5
6
7
8
9
no additive
R
R
Se
41 examples
60-95% yields
up to 95% ee
R1
R2
OMe
SCF3
R2
Nu
NHTf
R
R1
(PhSO2)2N SCF3
with nucleophiles
12 examples
58-84% yields
R = Br, Cl, I, H, OCOR'
R1
up to 93% ee, >99:1 dr
Nu = F, OH, NCS, OAc, OR''
SCF3
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
ACS Paragon Plus Environment