Free-Radical-Promoted Copper-Catalyzed Intermolecular Cyanosulfonylation and Cyanotrifluoromethylation of Unactivated Alkenes in Water-Containing Solvents

Article abstract of DOI:10.1021/acs.joc.8b02073

A novel and practical copper-catalyzed strategy for intermolecular cyanosulfonylation and cyanotrifluoromethylation of unactivated alkenes in water-containing solvents is described. The methodology developed provides an efficient and convenient access to a variety of β-sulfonyl nitriles and β-trifluoromethyl nitriles, which would have wide applications in chemical and pharmaceutical industries.

Full text of DOI:10.1021/acs.joc.8b02073

Subscriber access provided by University of Sunderland
Article
Free-Radical-Promoted Copper-Catalyzed Intermolecular
Cyanosulfonylation and Cyanotrifluoromethylation
of Unactivated Alkenes in Water-Containing Solvents
Yan Zhu, Jinlong Tian, Xianfeng Gu, and Yonghui Wang
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 10 Oct 2018
Downloaded from http://pubs.acs.org on October 10, 2018
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 23
The Journal of Organic Chemistry
1
2
3
4
5
6
7
Free-Radical-Promoted Copper-Catalyzed Intermolecular Cyanosulfonylation
and Cyanotrifluoromethylation of Unactivated Alkenes in Water-Containing
Solvents
8
9
Yan Zhu, ‡ Jinlong Tian, ‡ Xianfeng Gu and Yonghui Wang*
School of Pharmacy, Fudan University, 826 Zhangheng Road, Pudong, Shanghai 201203, China
yonghuiwang@fudan.edu.cn
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
R2SO2Na
CF3SO2Na
TMSCN
Copper catalyst n = 1, 2, 3...
R1
CN
CN
O
S
TMSCN
O
R2
R1
CF3
n
R1
Copper catalyst
DMSO : H2O
= 5:1, MW, 90 oC
n
n
DMSO : H2O
= 5:1, MW, 90 oC
Unactivated
Alkene
R1, R2 = Alkyl or aryl
ABSTRACT: A novel and practical copper-catalyzed strategy for intermolecular cyanosulfonylation and
cyanotrifluoromethylation of unactivated alkenes in water-containing solvents is described. The methodology
developed provides an efficient and convenient access to a variety of β-sulfonyl nitriles and β-trifluoromethyl nitriles,
which would have wide applications in chemical and pharmaceutical industries.
Introduction
Difunctionalization of alkenes is an excellent step-economic strategy that incorporates two functional groups onto
one carbon–carbon double bond, providing tremendous convenience for chemists to construct multifunctional and
complicated skeletons in organic synthesis.1,2 Among the methods developed, the atom transfer radical addition
(ATRA) is a fascinating methodology for the difunctionalization of alkenes to form vicinal carbon–carbon or carbon–
heteroatom bonds in a single step and has been broadened in recent decades.3 Although significant progress on the
three-component ATRA-type difunctionalization of alkenes has been made through the unremitting endeavours of
chemists, there still existed a lot of challenges due to low conversion, selectivity and yield, as well as undesired by-
products such as formation of oligomers.4
Figure 1. Biologically active compounds containing β-sulfonyl nitrile and β-trifluoromethyl nitrile core structure
ACS Paragon Plus Environment
1

The Journal of Organic Chemistry
Page 2 of 23
1
2
3
4
5
6
7
8
CN
O
S
F
O
N
O
N
O
CN
F3C
9
N
N
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
F3C
N
A
B
β-Sulfonyl nitriles and β-trifluoromethyl nitriles comprise a substantial proportion in pharmaceuticals and
agrochemicals due to their unique properties in modulating physicochemical, pharmacokinetic and pharmacodynamic
profiles of drug molecules.5 For example, compound A (Figure 1) containing β-sulfonyl nitrile moiety is extremely
useful in the control of plant diseases caused by fungal plant pathogens,6 while compound B containing β-
trifluoromethyl nitrile moiety plays an important role in preventing microbial infection, particularly fungal infection.7
Tremendous progress has been made toward the incorporation of cyano, sulfonyl or trifluoromethyl groups into
aromatic compounds.8 However, direct cyanosulfonylation and cyanotrifluoromethylation of alkenes, especially for
synthesizing β-sulfonyl nitriles and β-trifluoromethyl nitriles using inexpensive and easily available sodium sulfinates
such as sodium benzenesulfinate and sodium trifluoromethanesulfinate as radical precursors were seldom reported.
Recently, Chu group reported a catalytic, metal-free two-component sulfonylcyanation of alkenes by using tosyl
cyanide (TsCN) under visible light organophotoredox catalysis.9 Primitive work of the radical addition of alkenes with
TsCN in the presence of UV-light irradiation or radical initiators were described by Fang and Barton group
independently.10 (Scheme 1. (a)) However, these reactions were restricted only to tosylcyanation, whereas other
interesting and practical β-sulfonyl nitriles, especially alkyl substituted sulfonyl nitriles which were frequently
appeared in pharmaceuticles11, cannot be obtained through this method. Also, the reagent TsCN is a bit expensive. In
2016, Liu group reported
a
pioneering work on enantioselective copper-catalyzed intermolecular
cyanotrifluoromethylation of alkenes with TMSCN and Togni’s reagent generating a variety of CF3-containing
alkylnitriles with excellent enantiomeric excess.12 (Scheme 1. (b)) Similar works producing racemic CF3-containing
alkylnitriles were reported by Liang, Wang and Szabo et al.13 (Scheme 1. (c)) Togni’s reagent exhibited high reactivity
in the cyanotrifluoromethylation of alkenes, but is relative expensive and requires multistep synthesis. Based on the
reported cyanosulfonylation and cyanotrifluoromethylation reactions of alkenes, we tried to develop a new
methodology that uses inexpensive and easily available reagents, employs green reaction system and widens substrate
scope. Herein, we report a free-radical-promoted copper-catalyzed three-component ATRA-type difunctionalization of
ACS Paragon Plus Environment
2

Page 3 of 23
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
alkenes, providing a broad substrate scope of β-sulfonyl and β-trifluoromethyl nitriles under mild, convenient and eco-
friendly conditions. To the best of our knowledge, this is the first example of cyanosulfonylation and
cyanotrifluoromethylation of alkenes performed in water-containing solvents.
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
Scheme 1. Research background and summary of this work
Two-component ATRA Type Cyanotosylation of Alkene with TsCN.
Organophoto Catalyst8
CN
Blue LED
or hv9a, or AIBN9b,c
(a)
(b)
R
TsCN
Ts
R
Three-component ATRA Type Cyanotrifluoromethylation of Alkene with
Togni's Reagent or CF3I.
CN
Cu(I)/L*11
Togni's
Reagent

R
CF3
TMSCN
R
Togni's12a,c
Reagent
or CF3I12b
CN
TMSCN
or
CuCN12d
Copper Catalyst
R
(c)
O
CF3
R
Our Work:
CN
R2SO2Na
TMSCN
CF3SO2Na
TMSCN
CN
R1
O
R2
R1
S
R1
CF3
n
Copper catalyst
DMSO : H2O
Copper catalyst
DMSO : H2O
= 5:1, MW, 90 o
n = 1, 2, 3...
n
n
Unactivated
Alkene
C
= 5:1, MW, 90 o
C
R1, R2 = Alkyl or aryl
Results and Discussion
Initially, 4-phenyl-1-butene (1a), TMSCN (2) and sodium p-tolylsulphinate (3a) were taken as representative
reactants to optimize the intermolecular cyanosulfonylation reaction condition under copper-catalyzed system. As
depicted in entry 1 of Table 1, only 9% of the desired cyanosulfonylation product 4a was detected by using
CuSO4 ·5H2O as catalyst, Na2S2O8 as oxidant and DMSO as solvent. Further attempts in screening of a series of
oxidants showed that no other oxidant was superior to Na2S2O8 (Table S1, entry 1-7, ESI†). Obviously, the reaction
could not occur in the absence of oxidant (Table 1, entry 2). We speculated that the low solubility of sodium sulfinate
3a and inorganic oxidant in DMSO could possibly cause low yield of the reaction. Gratifyingly, a markedly increase of
yield was observed by using water as an additive to the solution which possibly promotes the dissolution of sodium
sulfinate 3a and oxidant Na2S2O8 (Table 1, entry 3 and 4). Further screening focusing on different amounts of water
indicated that one-sixth of water in DMSO performed best by delivering the desired product 4a in 74% yield (Table 1,
entry 5-7). A slightly increase of yield to 84% was obtained by raising the temperature to 90 °C (Table 1, entry 8).
Further varying species of copper catalysts showed that cupric nitrate trihydrate was the best catalyst among the tested,
ACS Paragon Plus Environment
3

The Journal of Organic Chemistry
Page 4 of 23
1
2
3
4
5
6
7
with the isolated yield of 85% (Table 1, entry 9). The controlled experiment showed that the copper catalyst was
essential in this intermolecular cyanosulfonylation reaction (Table 1, entry 10).
8
9
Table 1. Screening of the reaction conditionsa
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
CN
O
S
SO2Na
O
Copper Catalyst
Oxidant
TMSCN
2
Ph
Ph
Solvent
1a
3a
4a
Additive
(equiv)
-
Yield
Entry
1
Oxidant
Na2S2O8
Solvent
DMSO
Catalyst
(%)b
9
CuSO4·5H2O
CuSO4·5H2O
CuSO4·5H2O
2
-
-
DMSO
NR
3
4
5
Na2S2O8
H2O (5)
DMSO
DMSO
15
35
70
CuSO4·5H2O Na2S2O8 H2O (50)
CuSO4·5H2O
CuSO4·5H2O
CuSO4·5H2O
CuSO4·5H2O
Na2S2O8
Na2S2O8
Na2S2O8
-
-
-
DMSO:H2O
(10:1)
6
7
DMSO:H2O
(5:1)
74
35
84
DMSO:H2O
(1:1)
8c
Na2S2O8
-
-
DMSO:H2O
(5:1)
DMSO:H2O 89(85d)
(5:1)
9c
Cu(NO3)2
·3H2O
Na2S2O8
10c
-
Na2S2O8
-
DMSO:H2O
(5:1)
NR
[a] Reaction conditions: 1a (0.4 mmol), 2 (1.5 euqiv, 0.6 mmol), 3a (3.0 equiv, 1.2 mmol), catalyst (20% mmol, 0.08
mmol), oxidant (3.0 equiv, 1.2 mmol), additive, solvent, microwave, 80 °C, 1 h, air; [b] HPLC yield; [c] 90 °C; [d]
Isolated yield based on 1a.
Under the optimized reaction conditions, a wide range of inactivated alkenes bearing multiple functional groups
were subjected to the intermolecular cyanosulfonylation reactions, as summarized in Table 2. Simple alkenes (Table 2,
1a and 1b) processed smoothly to transform into the desired products in good yields. Phenyl allyl ethers were found to
be suitable candidates to provide the corresponding products 4c-4f in good to excellent yields. Besides, some linear
ACS Paragon Plus Environment
4

Page 5 of 23
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
olefins were well tolerated in this protocol (Table 2, 4g-4i). Terminal olefins bearing a benzoate group exhibited a
higher reactivity in this transformation (Table 2, 4k-4m). In addition, vinylcyclohexane could give the desired product
4n in 65% yield. It is noteworthy that terminal alkenes with a hydroxyl or carbonyl group could undergo
cyanosulfonylation in satisfactory yields (Table 2, 4o and 4p). Furthermore, for the less reactive internal alkenes such
as norbornene and cyclohexene, excellent regio-selectivity was observed to generate the desired product 4q and 4r.
Unfortunately, when trans-2-hexene was used as a substrate, trace of the desired difunctionalization product 4s was
detected.
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
Table 2. Substrate scope for cyanosulfonylation reaction of various unactivated alkenesab
Cu(NO3)2.3H2O 20% mmol
Na2S2O8 3.0 equiv
CN
O
SO2Na
O
R
R
S
TMSCN
n = 1, 2, 3...
n
n
DMSO : H2O = 5 : 1,
90 oC, MW, 1 h
1
2
3a
4
CN
O
CN
O
O
CN
O
S
O
O
S
O
S
n
n = 1, 4c, 69%
n = 2, 4d, 90%
n = 3, 4e, 87%
n = 4, 4f, 82%
4a, 85%
4b, 73 %
CN
CN
O
S
O
O
O
Me
Ph
O
S
n
CN
O
S
n
O
O
n = 2, 4g, 71%
n = 3, 4h, 84%
n = 5, 4i, 78%
n = 7, 4j, 63%
n = 2, 4k, 80%
n = 3, 4l, 82%
n = 4, 4m, 94%
4n, 65%
CN
O
S
CN
O
S
O
CN
O
HO
O
Ts
4q, 76%
4o, 85%
CN
4p, 72%
Ts
Ts
4r, 63%
CN
4s, trace
[a] Reaction conditions: 1 (0.4 mmol), 2 (0.6 mmol), 3a (1.2 mmol), Cu(NO3)2 ·3H2O (0.08 mmol), Na2S2O8 (1.2
mmol), DMSO : H2O = 5:1, microwave, 90 °C, 1 h, air; [b] Isolated yield based on 1.
Significantly, the scope of this protocol could be extended to various aromatic sodium sulfinates and
pharmaceutically relevant aliphatic sodium sulfinates (Table 3). For example, benzenesulfinate and tertiary butyl
substituted benzenesulfinate could smoothly generate the corresponding products 5a and 5b in 79% and 75% yields.
ACS Paragon Plus Environment
5

The Journal of Organic Chemistry
Page 6 of 23
1
2
3
4
5
6
7
8
9
With respect to electron-withdrawing substituents such as fluoro- (5c), chloro- (5d) and bromo- (5e) on the para
position of the aromatic ring, the reactions gave the desired products in moderate to good yields. Strikingly, the
developed cyanosulfonylation reaction could also be applied to alkyl substituted sodium sulfinates such as sodium
methanesulfinate, sodium ethanesulfinate and sodium cyclopropanesulfinate by delivering the corresponding β-
sulfonyl nitriles 5f-5h in 70-82% yields, which are important in pharmaceuticals.
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
Table 3. Substrate scope for cyanosulfonylation reaction of aromatic and aliphatic sodium sulfinatesab
Cu(NO3)2.3H2O 20% mmol
CN
O
O
R
Na2S2O8 3.0 equiv
Ph
Ph
O
Ph
O
S
TMSCN
2
RSO2Na
3
4
4
DMSO : H2O = 5 : 1,
90 oC, MW, 1 h
O
O
1m
5
CN
O
S
CN
O
S
CN
O
S
O
O
O
O
Ph
O
Ph
O
4
4
4
O
O
O
t-Bu
F
5a, 79%
5b, 75%
CN
5c, 72%
CN
CN
O
S
O
O
O
O
O
Ph
O
Ph
O
S
Ph
O
S
Me
4
4
4
O
O
O
Cl
Br
5d, 59%
CN
5e, 81%
CN
5f, 82%
O
S
O
S
O
O
Ph
O
Ph
O
4
4
O
O
5g, 76%
5h, 70%
[a] Reaction conditions: 1m (0.4 mmol), 2 (0.6 mmol), 3 (1.2 mmol), Cu(NO3)2·3H2O (0.08 mmol), Na2S2O8 (1.2
mmol), DMSO : H2O = 5:1, microwave, 90 °C, 1 h, air; [b] Isolated yield based on 1m.
Encouraged by the promising results, we continued our efforts toward exploring the reactivity of
cyanotrifluoromethylation by using sodium trifluoromethanesulfinate as radical precursor. As shown in Table 4,
terminal olefins bearing a benzoate group were proved to be highly efficient in this transformation (Table 4, 7a-7c).
Furthermore, the nitrogen-containing phthaloyl group was well tolerated delivering the corresponding products in good
yields (Table 4, 7d-7f). Phenyl allyl ethers were also compatible with this three-component cyanotrifluoromethylation
system (Table 4, 7g and 7h). Gratifyingly, moderate yield of β-difluoromethyl nitriles were achieved under the same
reaction conditions (Table 4, 7i and 7j), expending the use of this intermolecular cyanotrifluoromethylation protocol.
Table 4. Substrate scope for cyanotrifluoromethylation reaction of sodium trifluoromethanesulfinateab
ACS Paragon Plus Environment
6

Page 7 of 23
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Cu(NO3)2.3H2O 20% mmol
CN
R
Na2S2O8 3.0 equiv
RSO2Na
(R = CF3 or CHF2)
R
R
TMSCN
2
n
DMSO : H2O = 5 : 1,
90 oC, MW, 1 h
n
7
n = 1, 2, 3...
1
6
CN
CN
CN
Ph
O
CF3
Ph
O
CF3
Ph
O
CF3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
3
2
4
O
O
O
O
7a, 73%
O
7b, 77%
O
7c, 86%
O
CN
CN
CN
N
CF3
N
CF3
N
CF3
2
4
3
O
O
7d, 79%
7e, 83%
CN
7f, 85%
CN
CN
O
CF3
Ph
O
CHF2
O
2
CF3
Ph
Ph
Ph
3
4
O
7g, 68%
7h, 72%
7i, 61%
CN
O
CHF2
4
7j, 57%
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
[a] Reaction conditions: 1 (0.4 mmol), 2 (0.6 mmol), 6 (1.2 mmol), Cu(NO3)2 ·3H2O (0.08 mmol), Na2S2O8 (1.2
mmol), DMSO : H2O = 5:1, microwave, 90 °C, 1 h, air; [b] Isolated yield based on 1.
To gain some insight into the mechanism, several experiments were designed and performed (Scheme 2). First，
reaction with the radical clock precursor 1t provided the cyclized product 4t in 71% yield (cis:trans = 3.73:1), which
was a direct evidence for a radical mechanism. Then 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) was attempted
under the optimized conditions, the desired transformation was found to be completely quenched. Furthermore, when
2,6-di-tert-butyl-4-methylphenol (BHT) was added as a radical scavenger, the yield of desired product 4a was sharply
decreased to 12%, and meanwhile, the radical trapping product 8 was isolated in 75% yield. The above experimental
results indicated that the reaction proceeded through a free-radical mechanism. According to the literature precedent
and experimental evidence, a plausible mechanism was proposed as shown in Scheme 3. Initially, the radical of Ts or
CF3 was produced under the role of oxidant.14 Addition of ●R to alkene gave radical INT-I. The CuII species was
generated by rapid ligand exchange, which was subsequently combined with INT-I delivering a CuIII species (INT-
II).12, 13b A reductive elimination of INT-II then occurred, generating the desired product and simultaneously releasing
a CuI species. The detailed mechanism is still not clear and needs further investigation.
Scheme 2. Experimental probes on the reaction mechanism
ACS Paragon Plus Environment
7

The Journal of Organic Chemistry
Page 8 of 23
1
2
3
4
5
6
7
Cu(NO3)2.3H2O 20% mmol
SO2Na
Ts
NC
Na2S2O8 3.0 equiv
TMSCN
2
DMSO : H2O = 5 : 1,
90 oC, MW, 1 h
O
O
8
4t, 61%
1t
3a
(cis:trans = 3.73:1)
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
Cu(NO3)2.3H2O 20% mmol
Na2S2O8 3.0 equiv
CN
SO2Na
TEMPO 6.0 equiv
DMSO : H2O = 5 : 1,
90 oC, MW, 1 h
Ph
Ts
TMSCN
2
Ph
1a
3a
4a, 0
OTs
Cu(NO3)2.3H2O 20% mmol
Na2S2O8 3.0 equiv
BHT 6.0 equiv
CN
t-Bu
t-Bu
Ts
1a
2
3a
Ph
DMSO : H2O = 5 : 1,
90 oC, MW, 1 h
Me
8, 75%
4a, 12%
Scheme 3. Proposed mechanism
SO2Na
[O]
R
(R = Ts or CF3)
or
CF3SO2Na
CuIII(CN)2
R
Alkyl
R
Alkyl
CN
INT-II
R
Alkyl
R
Alkyl
INT-I
Extraneous
CuICN
cyanide
CuII(CN)2
CuII
[O]
Conclusions
In summary, we have developed a new intermolecular cyanosulfonylation and cyanotrifluoromethylation of
unactivated alkenes in water-containing solvents based on the difunctionalization strategy. Good functional group
compatibility and expanded substrate scope were exhibited in this context. In particular, less costly and easily available
feedstock sodium benzenesulfinate and sodium trifluoromethanesulfinate were used as radical precursors in the
protocol providing an efficient and convenient access to a variety of β-sulfonyl nitriles and β-trifluoromethyl nitriles,
which had wide applications in chemical and pharmaceutical industries. Further investigation on detailed mechanistic
study and synthetic applications are currently underway.
Experimental Section
ACS Paragon Plus Environment
8

Page 9 of 23
The Journal of Organic Chemistry
1
2
3
4
5
6
7
General Information: All commercially available reagents were used without further purification unless
otherwise stated. All of the microwave-assisted reactions were performed in an initiator microwave system at the
specified temperature which was monitored by external surface sensor using the standard mode of operation. The
reactions were monitored by thin-layer chromatography (TLC analysis. Silica gel (200-300 mesh) was used for column
chromatography. High-resolution MS (HRMS) was analyzed by a TOF analyzer. The ion source is electrospray
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
1
ionization (ESI). H, 19F NMR spectra were recorded at 400 MHz and 13C NMR spectra was recorded on 600 MHz.
Chemical shifts in 1H NMR spectra are reported in parts per million (ppm) on the δ scale from an internal standard of
CDCl3 (7.26 ppm). Data are reported as follows: chemical shift (δ ppm), multiplicity (s = singlet, d = doublet, t =
triplet, q = quartet, m = multiplet, br = broad), coupling constant in hertz (Hz), and integration. Chemical shifts of 13C
NMR spectra are reported in ppm from the central peak of CDCl3 (77.0 ppm) on the δ scale.
The procedure for the synthesis of sodium 4-(tert-butyl)benzenesulfinate (3b) 15
To a round-bottom flask added sodium sulfite (1.25 g, 10 mmol), sodium bicarbonate (0.84 g, 10 mmol) and 4-
tert-butylbenzenesulfonyl chloride (2.33g, 10 mmol) and H2O (5.0 mL). After stirred at 80 °C for 4 h. Water was
removed by rotary evaporator. Then the remaining solid was extracted and recrystallized by ethanol to get a white solid
- the required compound 3b. Other sodium sulfites are commercial available.
General procedures of the cyanosulfonylation and cyanofluoroalkylation of alkenes.
To a sealed microwave reaction vial were added olefins 1 (0.4 mmol), TMSCN (0.6 mmol, 59.5 mg), sodium p-
tolylsulfinate (1.2 mmol, 213.7 mg), Cu(NO3)2·3H2O (0.08 mmol, 19.3 mg), Na2S2O8 (1.2 mmol, 285.7 mg), DMSO
(2.0 mL) and H2O (0.4 mL). Then the reaction mixture was stirred at 90 °C for 1 h in microwave reactor. After
completion of the reaction, the resulting mixture was diluted with ethyl acetate (EA) and washed with water. The
separated aqueous phase was washed with EA. The combined organic layers were dried over MgSO4, filtered, and
concentrated under vacuo. The crude mixture was purified by column chromatography on silica gel (petroleum: ethyl
acetate = 10:1~3:1) to afford the desired product 4a-4t.
To a sealed microwave reaction vial were added hex-5-en-1-yl benzoate (0.4 mmol, 81.6 mg), TMSCN (0.6 mmol,
59.5 mg), sodium sulfinate 3 (1.2 mmol), Cu(NO3)2·3H2O (0.08 mmol, 19.3 mg), Na2S2O8 (1.2 mmol, 285.7 mg),
DMSO (2.0 mL) and H2O (0.4 mL). Then the reaction mixture was stirred at 90 °C for 1 h in microwave reactor. After
completion of the reaction, the resulting mixture was diluted with ethyl acetate (EA) and washed with water. The
separated aqueous phase was washed with EA. The combined organic layers were dried over MgSO4, filtered, and
ACS Paragon Plus Environment
9

The Journal of Organic Chemistry
Page 10 of 23
1
2
3
4
5
6
7
concentrated under vacuo. The crude mixture was purified by column chromatography on silica gel (petroleum: ethyl
acetate = 8:1~2:1) to afford the desired product 5a-5h.
8
9
To a sealed microwave reaction vial were added olefins 1 (0.4 mmol), TMSCN (0.6 mmol, 59.5 mg), CF3SO2Na
(1.2 mmol, 187.3 mg) or CHF2SO2Na (1.2 mmol, 165.7 mg), Cu(NO3)2·3H2O (0.08 mmol, 19.3 mg), Na2S2O8 (1.2
mmol, 285.7 mg), DMSO (2.0 mL) and H2O (0.4 mL). Then the reaction mixture was stirred at 90 °C for 1 h in
microwave reactor. After completion of the reaction, the resulting mixture was diluted with ethyl acetate (EA) and
washed with water. The separated aqueous phase was washed with EA. The combined organic layers were dried over
MgSO4, filtered, and concentrated under vacuo. The crude mixture was purified by column chromatography on silica
gel (petroleum: ethyl acetate = 10:1~4:1) to afford the desired product 7a-7j.
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
4-phenyl-2-(tosylmethyl)butanenitrile (4a) 106.5 mg, 85% yield; Pale yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.72
(d, J = 7.8 Hz, 2H), 7.36 (d, J = 7.8 Hz, 2H), 7.31 (t, J = 7.3 Hz, 2H), 7.25 (t, J = 6.4 Hz, 1H), 7.17 (d, J = 7.8 Hz, 2H),
3.42 (dd, J = 14.4, 7.3 Hz, 1H), 3.21 (dd, J = 14.3, 5.7 Hz, 1H), 3.07 – 3.01 (m, 1H), 2.93 – 2.87 (m, 1H), 2.78 – 2.70
(m, 1H), 2.46 (s, 3H), 2.18 – 1.99 (m, 2H); 13C {1H} NMR (150 MHz, CDCl3) δ 145.7, 139.0, 135.0, 130.2, 128.8,
128.4, 128.2, 126.7, 118.8, 57.0, 33.6, 32.7, 25.9, 21.7; HRMS (ESI): m/z [M + H]+ calcd for C18H20NO2S: 314.1209,
found: 314.1215.
1
2-benzyl-3-tosylpropanenitrile (4b)9 87.3 mg, 73% yield; Pale yellow solid, mp: 101.1 – 102.8 °C; H NMR (400
MHz, CDCl3) δ 7.80 (d, J = 7.7 Hz, 2H), 7.39 (d, J = 7.7 Hz, 2H), 7.32 (t, J = 8.0 Hz, 3H), 7.24 (d, J = 6.7 Hz, 2H),
3.40 – 3.32 (m, 2H), 3.26 – 3.23 (m, 1H), 3.12 – 3.02 (m, 2H), 2.47 (s, 3H); 13C {1H} NMR (150 MHz, CDCl3) δ
145.8, 135.3, 134.8, 130.3, 129.2, 129.0, 128.2, 127.9, 118.7, 56.1, 37.6, 28.2, 21.7; MS (ESI) m/z 300.2 [M + H]+.
1
3-phenoxy-2-(tosylmethyl)propanenitrile (4c) 87.0 mg, 69% yield; Colorless oil; H NMR (400 MHz, CDCl3) δ 7.83
(d, J = 7.8 Hz, 2H), 7.39 (d, J = 7.8 Hz, 2H), 7.28 (dd, J = 13.9, 6.2 Hz, 2H), 7.02 (d, J = 7.3 Hz, 1H), 6.86 (d, J = 8.1
Hz, 2H), 4.23 (d, J = 4.0 Hz, 2H), 3.63 – 3.51 (m, 3H), 2.45 (s, 3H); 13C {1H} NMR (150 MHz, CDCl3) δ 157.3, 145.9,
135.2, 130.3, 129.7, 128.2, 122.2, 117.2, 114.7, 66.0, 54.1, 27.3, 21.7; HRMS (ESI): m/z [M + H]+ calcd for
C17H18NO3S: 316.1002, found: 316.0995.
1
4-phenoxy-2-(tosylmethyl)butanenitrile (4d) 118.5 mg, 90% yield; White solid, mp: 89.5 – 91.0 °C; H NMR (400
MHz, CDCl3) δ 7.83 (d, J = 8.1 Hz, 2H), 7.39 (d, J = 8.1 Hz, 2H), 7.29 (t, J = 7.8, 2H), 6.98 (t, J = 7.1 Hz, 1H), 6.86
(d, J = 8.4 Hz, 2H), 4.12 (t, J = 5.4 Hz, 2H), 3.56 – 3.41 (m, 2H), 3.37 (dd, J = 13.0, 4.2 Hz, 1H), 2.46 (s, 3H), 2.33 (td,
ACS Paragon Plus Environment
10

Page 11 of 23
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
J = 12.3, 5.5 Hz, 1H), 2.20 – 2.12 (m, 1H); 13C {1H} NMR (150 MHz, CDCl3) δ 158.0, 145.8, 135.1, 130.2, 129.5,
128.3, 121.4, 118.6, 114.4, 63.9, 56.9, 31.6, 24.0, 21.7; HRMS (ESI): m/z [M + H]+ calcd for C18H20NO3S: 330.1158,
found: 330.1149.
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
5-phenoxy-2-(tosylmethyl)pentanenitrile (4e) 119.4 mg, 87% yield; Colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.80
(d, J = 8.0 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H), 7.27 (t, J = 7.7 Hz, 2H), 6.95 (t, J = 7.2 Hz, 1H), 6.85 (d, J = 8.1 Hz, 2H),
13
3.96 (t, J = 4.0 Hz, 2H), 3.50 – 3.44 (m, 1H), 3.26 – 3.23 (m, 2H), 2.43 (s, 3H), 2.02 – 1.85 (m, 4H); C {1H} NMR
(150 MHz, CDCl3) δ 158.0, 145.7, 135.1, 130.2, 129.4, 128.1, 120.9, 118.9, 114.3, 66.3, 57.1, 29.2, 26.3, 26.2, 21.6;
HRMS (ESI): m/z [M + H]+ calcd for C19H22NO3S: 344.1315, found: 344.1308.
1
6-phenoxy-2-(tosylmethyl)hexanenitrile (4f) 117.1 mg, 82% yield; Pale yellow solid, mp: 66.0 – 67.9 °C; H NMR
(400 MHz, CDCl3) δ 7.81 (d, J = 8.1 Hz, 2H), 7.38 (d, J = 8.1 Hz, 2H), 7.27 (t, J = 7.7, 2H), 6.94 (t, J = 7.3 Hz, 1H),
6.87 (d, J = 8.2 Hz, 2H), 3.94 (t, J = 5.8 Hz, 2H), 3.45 (dd, J = 13.6, 7.9 Hz, 1H), 3.18 (dt, J = 13.1, 5.2 Hz, 2H), 2.45
(s, 3H), 1.89 – 1.64 (m, 6H); 13C {1H} NMR (150 MHz, CDCl3) δ 158.7, 145.7, 135.3, 130.2, 129.4, 128.1, 120.6,
118.9, 114.3, 66.9, 57.1, 31.7, 28.3, 26.4, 23.4, 21.6; HRMS (ESI): m/z [M + H]+ calcd for C20H24NO3S: 358.1471,
found: 358.1474.
1
2-(tosylmethyl)hexanenitrile (4g) 71.3 mg, 71% yield; Colorless oil; H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 8.0
Hz, 2H), 7.39 (d, J = 8.0 Hz, 2H), 3.43 (dd, J = 14.1, 7.8 Hz, 1H), 3.21 (dd, J = 14.2, 5.2 Hz, 1H), 3.14 – 3.09 (m, 1H),
2.46 (s, 3H), 1.79 – 1.64 (m, 2H), 1.62 – 1.41 (m, 2H), 0.94 (t, J = 7.3 Hz, 3H); 13C {1H} NMR (150 MHz, CDCl3) δ
145.7, 135.3, 130.2, 128.2, 119.1, 57.2, 34.0, 26.2, 21.7, 19.9, 13.2; HRMS (ESI): m/z [M + Na]+ calcd for
C13H17NO2SNa: 274.0872, found: 274.0870.
1
2-(tosylmethyl)hexanenitrile (4h) 89.1 mg, 84% yield; Colorless oil; H NMR (400 MHz, CDCl3) δ 7.83 (d, J = 8.1
Hz, 2H), 7.41 (d, J = 8.1 Hz, 2H), 3.44 (dd, J = 14.2, 7.9 Hz, 1H), 3.21 (dd, J = 14.2, 5.2 Hz, 1H), 3.17 – 3.10 (m, 1H),
2.47 (s, 3H), 1.83 – 1.66 (m, 2H), 1.52 – 1.25 (m, 4H), 0.91 (t, J = 7.1 Hz, 3H); 13C {1H} NMR (150 MHz, CDCl3) δ
145.7, 135.3, 130.2, 128.2, 119.1, 57.3, 31.8, 28.6, 26.4, 21.9, 21.7, 13.6; HRMS (ESI): m/z [M + H]+ calcd for
C14H20NO2S: 266.1209, found: 266.1211.
2-(tosylmethyl)octanenitrile (4i) 91.4 mg, 78% yield; Colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.83 (d, J = 7.9 Hz,
2H), 7.41 (d, J = 7.9 Hz, 2H), 3.44 (dd, J = 14.2, 7.8 Hz, 1H), 3.20 (dd, J = 14.3, 4.8 Hz, 1H), 3.15 – 3.10 (m, 1H),
2.47 (s, 3H), 1.81 – 1.66 (m, 2H), 1.52 – 1.28 (m, 8H), 0.88 (t, J = 5.0 Hz, 3H); 13C {1H} NMR (150 MHz, CDCl3) δ
ACS Paragon Plus Environment
11

The Journal of Organic Chemistry
Page 12 of 23
1
2
3
4
5
6
7
145.7, 135.4, 130.2, 128.2, 119.1, 57.3, 32.1, 31.3, 28.4, 26.5, 26.4, 22.4 21.7, 13.9; HRMS (ESI): m/z [M + H]+ calcd
for C16H24NO2S: 294.1522, found: 294.1524.
8
9
2-(tosylmethyl)decanenitrile (4j) 80.9 mg, 63% yield; Colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.83 (d, J = 7.5 Hz,
2H), 7.41 (d, J = 7.5 Hz, 2H), 3.44 (dd, J = 13.9, 7.9 Hz, 1H), 3.21 – 3.13 (m, 2H), 2.48 (s, 3H), 1.77 – 1.69 (m, 2H),
1.50 – 1.26 (m, 12H), 0.87 (t, J = 6.0 Hz, 3H); 13C {1H} NMR (150 MHz, CDCl3) δ 145.8, 135.4, 130.3, 128.2, 119.1,
57.3, 32.2, 31.7, 29.1, 29.0, 28.7, 26.6, 26.5, 22.6, 21.7, 14.0; HRMS (ESI): m/z [M + H]+ calcd for C18H28NO2S:
322.1835, found: 322.1838.
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
1
3-cyano-4-tosylbutyl benzoate (4k) 114.3 mg, 80% yield; White solid, mp: 127.5 – 128.0 °C; H NMR (400 MHz,
CDCl3) δ 8.01 (d, J = 7.6 Hz, 2H), 7.79 (d, J = 7.6 Hz, 2H), 7.59 (t, J = 7.3 Hz, 1H), 7.45 (t, J = 7.5 Hz, 2H), 7.34 (d, J
= 7.8 Hz, 2H), 4.55 – 4.42 (m, 2H), 3.51 (dd, J = 12.4, 5.4 Hz, 1H), 3.40 – 3.32 (m, 2H), 2.42 (s, 3H), 2.38 – 2.33 (m,
1H), 2.26 – 2.17 (m, 1H); 13C {1H} NMR (150 MHz, CDCl3) δ 166.1, 145.8, 135.0, 133.3, 130.2, 129.6, 129.4, 128.4,
128.1, 118.5, 61.1, 56.6, 31.0, 24.0, 21.6; HRMS (ESI): m/z [M + H]+ calcd for C19H20NO4S: 358.1108, found:
358.1104.
1
4-cyano-5-tosylpentyl benzoate (4l) 121.7 mg, 82% yield; White solid, mp: 75.8 – 77.6 °C; H NMR (400 MHz,
CDCl3) δ 8.02 (d, J = 7.7 Hz, 2H), 7.80 (d, J = 7.7 Hz, 2H), 7.57 (t, J = 6.4 Hz, 1H), 7.45 (t, J = 7.3 Hz, 2H), 7.37 (d, J
= 7.6 Hz, 2H), 4.33 (t, J = 8.0 Hz, 2H), 3.47 (dd, J = 15.6, 9.3 Hz, 1H), 3.24 (d, J = 10.0 Hz, 2H), 2.44 (s, 3H), 2.03 –
1.87 (m, 4H); 13C {1H} NMR (150 MHz, CDCl3) δ 166.4, 145.8, 135.2, 133.1, 130.3, 129.8, 129.5, 128.4, 128.2,
118.7, 63.5, 57.1, 29.1, 26.4, 26.0, 21.7; HRMS (ESI): m/z [M + H]+ calcd for C20H22NO4S: 372.1264, found:
372.1265.
1
5-cyano-6-tosylhexyl benzoate (4m) 144.8 mg, 94% yield; Colorless oil; H NMR (400 MHz, CDCl3) δ 8.02 (d, J =
8.0 Hz, 2H), 7.81 (d, J = 8.0 Hz, 2H), 7.56 (t, J = 7.0 Hz, 1H), 7.44 (t, J = 7.4 Hz, 2H), 7.38 (d, J = 7.2 Hz, 2H), 4.31
(t, J = 5.0 Hz, 2H), 3.47 – 3.42 (m, 1H), 3.24 – 3.16 (m, 2H), 2.45 (s, 3H), 1.90 – 1.61 (m, 6H); 13C {1H} NMR (150
MHz, CDCl3) δ 166.5, 145.8, 135.3, 133.0, 130.2, 130.1, 129.5, 128.3, 128.2, 118.8, 64.0, 57.1, 31.7, 27.9, 26.4, 23.3,
21.6; HRMS (ESI): m/z [M + H]+ calcd for C21H24NO4S: 386.1421, found: 386.1436.
2-cyclohexyl-3-tosylpropanenitrile (4n)9 75.7 mg, 65% yield; White solid, mp: 107.2 – 109.0 °C; 1H NMR (400 MHz,
CDCl3) δ 7.83 (d, J = 7.9 Hz, 2H), 7.41 (d, J = 7.9 Hz, 2H), 3.41 (dd, J = 14.4, 9.0 Hz, 1H), 3.22 (dd, J = 14.4, 4.1 Hz,
1H), 3.07 – 3.05 (m, 1H), 2.48 (s, 3H), 1.78 – 1.63 (m, 6H), 1.26 – 1.19 (m, 5H); 13C {1H} NMR (150 MHz, CDCl3) δ
145.7, 135.4, 130.2, 128.3, 118.2, 55.7, 39.6, 32.6, 31.1, 28.4, 25.7, 25.6, 25.5, 21.7; MS (ESI) m/z 292.2 [M + H]+.
ACS Paragon Plus Environment
12

Page 13 of 23
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
1
5-oxo-2-(tosylmethyl)hexanenitrile (4o)9 94.9 mg, 85% yield; White solid, mp: 94.4 – 95.7 °C; H NMR (400 MHz,
CDCl3) δ 7.81 (d, J = 8.1 Hz, 2H), 7.39 (d, J = 8.1 Hz, 2H), 3.43 (dd, J = 15.7, 9.4 Hz, 1H), 3.21 (dd, J = 9.4, 6.2 Hz,
2H), 2.75 – 2.60 (m, 2H), 2.45 (s, 3H), 2.15 (s, 3H), 2.13 – 2.06 (m, 1H), 1.90 – 1.81 (m, 1H); 13C {1H} NMR (150
MHz, CDCl3) δ 206.0, 145.7, 135.1, 130.2, 128.2, 118.7, 57.1, 39.7, 29.9, 25.8, 25.6, 21.6; MS (ESI) m/z 280.2 [M +
H]+.
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
1
6-hydroxy-2-(tosylmethyl)hexanenitrile (4p) 81.0 mg, 72% yield; White solid, mp: 43.7 – 45.0 °C; H NMR (400
MHz, CDCl3) δ 7.80 (d, J = 7.9 Hz, 2H), 7.38 (d, J = 7.9 Hz, 2H), 3.61 (t, J = 4.0 Hz, 2H), 3.43 (dd, J = 14.0, 8.1 Hz,
1H), 3.21 (dd, J = 14.2, 5.1 Hz, 1H), 3.17 – 3.11 (m, 1H), 2.45 (s, 3H), 1.99 (s, 1H), 1.84 – 1.71 (m, 2H), 1.62 – 1.51
(m, 4H); 13C {1H} NMR (150 MHz, CDCl3) δ 145.8, 135.2, 130.2, 128.1, 119.1, 61.9, 57.0, 31.7, 31.4, 26.3, 22.9,
21.6; HRMS (ESI): m/z [M + H]+ calcd for C14H20NO3S: 282.1158, found: 282.1147.
1
3-tosylbicyclo[2.2.1]heptane-2-carbonitrile (4q) 83.6 mg, 76% yield; White solid, mp: 129.2 – 130.8 °C; H NMR
(600 MHz, CDCl3) δ 7.78 (d, J = 8.2 Hz, 2H), 7.40 (d, J = 8.2 Hz, 2H), 3.14 (ddd, J = 6.0, 3.9, 2.0 Hz, 1H), 3.09 (d, J
= 6.0 Hz, 1H), 2.88 (d, J = 2.9 Hz, 1H), 2.69 (s. 1H), 2.47 (s, 3H), 1.98 (d, J = 10.7 Hz, 1H), 1.75 – 1.70 (m, 2H), 1.67
– 1.60 (m, 2H), 1.42 – 1.40 (m, 1H); 13C {1H} NMR (150 MHz, CDCl3) δ 145.5, 134.5, 130.3, 128.4, 119.2, 70.3, 40.4,
38.8, 36.6, 33.9, 29.2, 23.9, 21.7; HRMS (ESI): m/z [M + H]+ calcd for C15H18NO2S: 276.1053, found: 276.1042.
1
2-tosylcyclohexanecarbonitrile (4r)9 66.3 mg, 63% yield; White solid, mp: 133.2 – 134.6 °C; H NMR (400 MHz,
CDCl3) δ 7.81 (d, J = 7.7 Hz, 2H), 7.39 (d, J = 7.7 Hz, 2H), 3.19 (td, J = 9.4, 4.2 Hz, 1H), 2.90 (td, J = 9.3, 4.0 Hz,
1H), 2.46 (s, 3H), 2.31 – 2.26 (m, 1H), 2.13 – 2.09 (m, 1H), 1.94 – 1.87 (m, 1H), 1.78 – 1.64 (m, 2H), 1.62 – 1.53 (m,
1H), 1.42 – 1.32 (m, 2H); 13C {1H} NMR (150 MHz, CDCl3) δ 145.5, 134.0, 130.0, 129.1, 119.5, 62.6, 29.6, 27.8,
24.4, 23.3, 22.9, 21.7; MS (ESI) m/z 264.1 [M + H]+.
1
4-(tosylmethyl)tetrahydrofuran-3-yl)acetonitrile (4s) 68.1 mg, 61% yield; Colorless oil; H NMR (600 MHz, CDCl3)
δ 7.75 (d, J = 8.2 Hz, 2H), 7.35 (d, J = 8.2 Hz, 2H), 4.04 (dd, J = 9.5, 6.9 Hz, 0.22H), 3.98 (t, J = 8.6 Hz, 0.81H), 3.94
(dd, J = 9.4, 6.6 Hz, 0.22H), 3.90 (dd, J = 9.4, 5.6 Hz, 0.81H), 3.77 (dd, J = 9.4, 2.9 Hz, 0.80H), 3.58 – 3.53 (m, 1H),
3.51 (dd, J = 9.5, 6.0 Hz, 0.20H), 3.28 (dd, J = 14.0, 5.1 Hz, 0.22H), 3.20 (dd, J = 14.1, 6.6 Hz, 0.82H), 3.12 (dd, J =
14.2, 7.2 Hz, 0.17H), 3.08 (dd, J = 14.1, 8.0 Hz, 0.85H), 2.85 – 2.79 (m, 0.81H), 2.69 – 2.66 (m, 0.81H), 2.51 (dd, J =
7.7, 6.5 Hz, 0.38H), 2.48 (dd, J = 16.7, 5.3 Hz, 0.86H), 2.42 (s, 3H), 2.34 (dd, J = 16.7, 9.4 Hz, 0.81H); 13C {1H} NMR
(150 MHz, CDCl3) δ 145.3, 145.2, 135.7, 135.5, 130.0, 129.9, 127.7, 127.6, 118.3, 117.8, 72.6, 71.9, 71.6, 70.3, 58.7,
ACS Paragon Plus Environment
13

The Journal of Organic Chemistry
Page 14 of 23
1
2
3
4
5
6
7
54.1, 40.9, 38.9, 38.1, 35.9, 21.4, 20.0, 16.5; HRMS (ESI): m/z [M + H]+ calcd for C14H18NO3S: 280.1002, found:
280.1011.
8
9
1
5-cyano-6-(phenylsulfonyl)hexyl benzoate (5a) 117.3 mg, 79% yield; Pale yellow oil; H NMR (400 MHz, CDCl3) δ
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
8.02 (d, J = 7.3 Hz, 2H), 7.94 (d, J = 7.5 Hz, 2H), 7.70 (t, J = 6.9 Hz, 1H), 7.65 (t, J = 7.8 Hz, 2H), 7.54 (d, J = 7.0 Hz,
1H), 7.43 (t, J = 7.2 Hz, 2H), 4.31 (t, J = 5.6 Hz, 2H), 3.47 (dd, J = 13.7, 7.2 Hz, 1H), 3.23 (dd, J = 20.5, 6.6 Hz, 2H),
1.92 – 1.61 (m, 6H); 13C {1H} NMR (150 MHz, CDCl3) δ 166.4, 138.2, 134.6, 132.9, 130.0, 129.6, 129.5, 128.3,
128.1, 118.8, 64.0, 57.0, 31.7, 27.9, 26.3, 23.3; HRMS (ESI): m/z [M + H]+ calcd for C20H22NO4S: 372.1264, found:
372.1257.
1
6-((4-(tert-butyl)phenyl)sulfonyl)-5-cyanohexyl benzoate (5b) 128.1 mg, 75% yield; Pale yellow oil; H NMR (400
MHz, CDCl3) δ 8.03 (d, J = 7.5 Hz, 2H), 7.85 (d, J = 7.5 Hz, 2H), 7.60 (d, J = 8.1 Hz, 2H), 7.56 (t, J = 7.8 Hz, 1H),
7.44 (t, J = 7.3 Hz, 2H), 4.32 (t, J = 5.7 Hz, 2H), 3.45 (dd, J = 15.1, 8.2 Hz, 1H), 3.25 – 3.17 (m, 2H), 1.95 – 1.59 (m,
13
6H), 1.35 (s, 9H); C {1H} NMR (150 MHz, CDCl3) δ 166.5, 158.7, 135.3, 133.0, 130.1, 129.5, 128.4, 128.0, 126.7,
118.9, 64.1, 57.1, 35.3, 31.7, 31.0, 28.0, 26.4, 23.4; HRMS (ESI): m/z [M + H]+ calcd for C24H30NO4S: 428.1890,
found: 428.1875.
1
5-cyano-6-((4-fluorophenyl)sulfonyl)hexyl benzoate (5c) 112.1 mg, 72% yield; Pale yellow oil; H NMR (400 MHz,
CDCl3) δ 8.03 (d, J = 7.6 Hz, 2H), 7.97 (dd, J = 8.2, 5.2 Hz, 2H), 7.57 (t, J = 7.4 Hz, 1H), 7.44 (t, J = 7.6 Hz, 2H), 7.28
(d, J = 8.3 Hz, 2H), 4.33 (t, J = 6.0 Hz, 2H), 3.49 (dd, J = 14.0, 8.1 Hz, 1H), 3.23 – 3.16 (m, 2H), 1.92 – 1.59 (m, 6H);
13C {1H} NMR (150 MHz, CDCl3) δ 166.4, 166.2 (d, J = 256.5 Hz), 134.3, 133.0, 131.2 (d, J = 9.7 Hz), 130.0, 129.4,
128.3, 118.7, 117.0 (d, J = 22.8 Hz), 64.0, 57.2, 31.7, 27.9, 26.4, 23.2; 19F {1H} NMR (376 MHz, CDCl3) δ -101.45;
HRMS (ESI): m/z [M + H]+ calcd for C20H21FNO4S: 390.1170, found: 390.1163.
1
6-((4-chlorophenyl)sulfonyl)-5-cyanohexyl benzoate (5d) 95.6 mg, 59% yield; Pale yellow oil; H NMR (400 MHz,
CDCl3) δ 8.03 (d, J = 7.3 Hz, 2H), 7.88 (d, J = 8.4 Hz, 2H), 7.57 (t, J = 8.4 Hz, 3H), 7.44 (t, J = 7.6 Hz, 2H), 4.33 (t, J
= 6.0 Hz, 2H), 3.46 (dd, J = 14.0, 7.9 Hz, 1H), 3.26 – 3.17 (m, 2H), 1.93 – 1.77 (m, 4H), 1.75 – 1.59 (m, 2H); 13C {1H}
NMR (150 MHz, CDCl3) δ 166.5, 141.6, 136.8, 133.0, 130.1, 130.0, 129.7, 129.5, 128.4, 118.6, 64.0, 57.2, 31.7, 28.0,
26.4, 23.3; HRMS (ESI): m/z [M + H]+ calcd for C20H21ClNO4S: 406.0874, found: 406.0864.
1
6-((4-bromophenyl)sulfonyl)-5-cyanohexyl benzoate (5e) 145.5 mg, 81% yield; Pale yellow oil; H NMR (400 MHz,
CDCl3) δ 8.01 (d, J = 7.5 Hz, 2H), 7.79 (d, J = 8.2 Hz, 2H), 7.73 (t, J = 8.2 Hz, 2H), 7.56 (t, J = 7.2 Hz, 1H), 7.43 (t, J
= 7.4 Hz, 2H), 4.32 (t, J = 5.9 Hz, 2H), 3.47 (dd, J = 13.9, 7.9 Hz, 1H), 3.26 – 3.18 (m, 2H), 1.92 – 1.56 (m, 6H), 1.75
ACS Paragon Plus Environment
14

Page 15 of 23
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
– 1.59 (m, 2H); 13C {1H} NMR (150 MHz, CDCl3) δ 166.4, 137.2, 132.9, 132.6, 130.1, 130.0, 129.7, 129.5, 128.3,
118.7, 64.0, 57.0, 31.6, 27.9, 26.3, 23.2; HRMS (ESI): m/z [M + H]+ calcd for C20H21BrNO4S: 450.0369, found:
450.0361.
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
5-cyano-6-(methylsulfonyl)hexyl benzoate (5f) 101.4 mg, 82% yield; White solid, mp: 97.7 – 99.0 °C; 1H NMR (400
MHz, CDCl3) δ 8.01 (d, J = 7.3 Hz, 2H), 7.55 (t, J = 7.4 Hz, 1H), 7.43 (t, J = 7.6 Hz, 2H), 4.32 (t, J = 6.0 Hz, 2H), 3.44
(dd, J = 14.1, 9.1 Hz, 1H), 3.29 – 3.22 (m, 1H), 3.14 (dd, J = 14.4, 3.4 Hz, 1H), 3.05 (s, 3H), 1.86 – 1.60 (m, 6H); 13C
{1H} NMR (150 MHz, CDCl3) δ 166.4, 132.9, 130.0, 129.4, 128.3, 119.4, 64.0, 55.6, 42.0, 31.5, 27.8, 26.3, 23.3;
HRMS (ESI): m/z [M + H]+ calcd for C15H20NO4S: 310.1108, found: 310.1111.
1
5-cyano-6-(ethylsulfonyl)hexyl benzoate (5g) 98.2 mg, 76% yield; Colorless oil; H NMR (400 MHz, CDCl3) δ 8.02
(d, J = 7.1 Hz, 2H), 7.55 (t, J = 6.7 Hz, 1H), 7.43 (t, J = 7.2 Hz, 2H), 4.33 (t, J = 6.0 Hz, 2H), 3.39 (dd, J = 13.6, 8.8
Hz, 1H), 3.32 – 3.23 (m, 1H), 3.14 (q, J = 7.9 Hz, 2H), 3.06 (d, J = 13.9 Hz, 1H), 1.85 – 1.65 (m, 6H), 1.42 (t, J = 7.2
Hz, 3H); 13C {1H} NMR (150 MHz, CDCl3) δ 166.5, 132.9, 130.0, 129.4, 128.3, 119.4, 64.0, 52.9, 48.5, 31.6, 27.9,
26.1, 23.4, 6.4; HRMS (ESI): m/z [M + H]+ calcd for C16H22NO4S: 324.1264, found: 324.1262.
5-cyano-6-(cyclopropylsulfonyl)hexyl benzoate (5h) 93.8 mg, 70% yield; Colorless oil; 1H NMR (400 MHz, CDCl3) δ
8.02 (d, J = 7.2 Hz, 2H), 7.56 (t, J = 7.5 Hz, 1H), 7.43 (t, J = 7.5 Hz, 2H), 4.33 (t, J = 6.0 Hz, 2H), 3.46 (dd, J = 13.9,
8.8 Hz, 1H), 3.31 – 3.24 (m, 1H), 3.14 (dd, J = 14.1, 4.6 Hz, 1H), 2.55 (qd, J = 7.5, 5.0 Hz, 1H), 1.89 – 1.58 (m, 6H),
1.38 – 1.35 (m, 1H), 1.24 – 1.08 (m, 3H); 13C {1H} NMR (150 MHz, CDCl3) δ 166.5, 132.9, 130.0, 129.4, 128.3,
119.5, 64.0, 55.0, 31.7, 30.3, 27.9, 26.3, 23.4, 5.6, 5.3; HRMS (ESI): m/z [M + H]+ calcd for C17H22NO4S: 336.1264,
found: 336.1272.
3-cyano-5,5,5-trifluoropentyl benzoate (7a) 79.2 mg, 73% yield; Colorless oil; 1H NMR (400 MHz, CDCl3) δ 8.04 (d,
J = 7.5 Hz, 2H), 7.59 (t, J = 7.0 Hz, 1H), 7.46 (t, J = 7.4 Hz, 2H), 4.58 (dt, J = 10.6, 5.3 Hz, 1H), 4.52 – 4.46 (m, 1H),
3.18 – 3.11 (m, 1H), 2.67 – 2.56 (m, 1H), 2.48 – 2.40 (m, 1H), 2.26 – 2.14 (m, 2H); 13C {1H} NMR (150 MHz, CDCl3)
δ 166.1, 133.4, 129.6, 129.4, 128.5, 124.9 (q, J = 277.3 Hz), 118.9, 61.1, 36.2 (q, J = 30.1 Hz), 31.2, 22.9 (d, J = 2.4
Hz); 19F {1H} NMR (376 MHz, CDCl3) δ -64.83 (t, J = 10.6 Hz, 3F); HRMS (ESI): m/z [M + Na]+ calcd for
C13H12F3NO2Na: 294.0712, found: 294.0722.
1
4-cyano-6,6,6-trifluorohexyl benzoate (7b)13a 87.8 mg, 77% yield; Colorless oil; H NMR (400 MHz, CDCl3) δ 8.03
(d, J = 7.6 Hz, 2H), 7.58 (t, J = 7.2 Hz, 1H), 7.45 (t, J = 7.4 Hz, 2H), 4.44 – 4.34 (m, 2H), 3.02 – 2.95 (m, 1H), 2.59 –
2.51 (m, 1H), 2.43 – 2.31 (m, 1H), 2.13 – 2.05 (m, 1H), 2.01 – 1.92 (m, 1H), 1.89 (t, J = 7.4 Hz, 2H); 13C {1H} NMR
ACS Paragon Plus Environment
15

The Journal of Organic Chemistry
Page 16 of 23
1
2
3
4
5
6
7
8
9
(150 MHz, CDCl3) δ 166.4, 133.2, 129.8, 129.5, 128.4, 125.0 (q, J = 277.2 Hz), 119.2, 63.4, 36.4 (q, J = 30.0 Hz),
28.9, 26.1, 25.4 (d, J = 2.0 Hz); 19F {1H} NMR (376 MHz, CDCl3) δ -64.71 (t, J = 10.7 Hz, 3F); MS (ESI) m/z 286.1
[M + H]+.
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
1
5-cyano-7,7,7-trifluoroheptyl benzoate (7c) 102.9 mg, 86% yield; Colorless oil; H NMR (400 MHz, CDCl3) δ 8.03
(d, J = 7.5 Hz, 2H), 7.56 (t, J = 7.0 Hz, 1H), 7.44 (t, J = 7.4 Hz, 2H), 4.58 (t, J = 5.8 Hz, 2H), 2.94 – 2.87 (m, 1H), 2.62
13
– 2.48 (m, 1H), 2.37 – 2.28 (m, 1H), 1.84 – 1.78 (m, 5H), 1.71 – 1.59 (m, 1H); C {1H} NMR (150 MHz, CDCl3) δ
166.5, 133.0, 130.1, 129.5, 128.4, 125.0 (q, J = 277.3 Hz), 119.4, 64.1, 36.4 (q, J = 29.9 Hz), 31.6, 28.0, 25.6 (d, J =
2.0 Hz), 23.4; 19F {1H} NMR (376 MHz, CDCl3) δ -65.01 (t, J = 10.8 Hz, 3F); HRMS (ESI): m/z [M + Na]+ calcd for
C15H16F3NO2Na: 322.1025, found: 322.1024.
1
2-(2-(1,3-dioxoisoindolin-2-yl)ethyl)-4,4,4-trifluorobutanenitrile (7d) 93.6 mg, 79% yield; Pale yellow oil; H NMR
(400 MHz, CDCl3) δ 7.87 – 7.84 (m, 2H), 7.73 (dt, J = 5.3, 2.4 Hz, 2H), 3.89 (t, J = 6.7 Hz, 2H), 3.00 – 2.95 (m, 1H),
2.62 – 2.53 (m, 1H), 2.47 – 2.37 (m, 1H), 2.22 – 2.07 (m, 2H); 13C {1H} NMR (150 MHz, CDCl3) δ 168.1, 134.3,
131.7, 125.8 (q, J = 277.4 Hz), 123.5, 118.9, 35.9 (q, J = 30.1 Hz), 34.8, 30.6, 23.4 (d, J = 2.2 Hz); 19F {1H} NMR
(376 MHz, CDCl3) δ -64.73 (t, J = 10.7 Hz, 3F); HRMS (ESI): m/z [M + H]+ calcd for C14H12F3N2O2: 297.0845,
found: 297.0841.
5-(1,3-dioxoisoindolin-2-yl)-2-(2,2,2-trifluoroethyl)pentanenitrile (7e)13c 103.0 mg, 83% yield; White solid, mp: 99.5
– 101.0 °C; 1H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 3.2 Hz, 2H), 7.74 (d, J = 2.5 Hz, 2H), 3.76 (t, J = 6.4 Hz, 2H),
3.04 – 2.97 (m, 1H), 2.59 – 2.46 (m, 1H), 2.35 – 2.26 (m, 1H), 2.05 – 1.85 (m, 2H), 1.81 – 1.64 (m, 2H); 13C {1H}
NMR (150 MHz, CDCl3) δ 168.3, 134.2, 131.9, 125.9 (q, J = 277.3 Hz), 123.4, 119.2, 36.6, 36.4 (q, J = 29.9 Hz), 29.3,
26.0, 25.1; 19F {1H} NMR (376 MHz, CDCl3) δ -65.23 (t, J = 10.8 Hz, 3F); MS (ESI) m/z 311.1 [M + H]+.
6-(1,3-dioxoisoindolin-2-yl)-2-(2,2,2-trifluoroethyl)hexanenitrile (7f) 110.2 mg, 85% yield; White solid, mp: 86.7 –
87.5 °C; 1H NMR (400 MHz, CDCl3) δ 7.82 (d, J = 2.8 Hz, 2H), 7.74 (d, J = 1.0 Hz, 2H), 3.70 (t, J = 6.8 Hz, 2H), 2.90
– 2.83 (m, 1H), 2.54 – 2.46 (m, 1H), 2.37 – 2.27 (m, 1H), 1.78 – 1.73 (m, 4H), 1.68 – 1.47 (m, 2H); 13C {1H} NMR
(150 MHz, CDCl3) δ 168.3, 134.0, 131.9, 125.9 (q, J = 277.3 Hz), 123.2, 119.4, 37.1, 36.2 (q, J = 29.8 Hz), 31.4, 27.7,
25.4 (d, J = 1.6 Hz), 23.8; 19F {1H} NMR (376 MHz, CDCl3) δ -64.84 (t, J = 11.0 Hz, 3F); HRMS (ESI): m/z [M + H]+
calcd for C16H16F3N2O2: 325.1158, found: 325.1170.
1
4,4,4-trifluoro-2-(2-phenoxyethyl)butanenitrile (7g) 66.1 mg, 68% yield; Pale yellow oil; H NMR (400 MHz,
CDCl3) δ 7.32 (t, J = 7.6 Hz, 2H), 7.01 (t, J = 7.3 Hz, 1H), 6.92 (d, J = 8.2 Hz, 2H), 4.18 (t, J = 5.5 Hz, 2H), 3.36 –
ACS Paragon Plus Environment
16

Page 17 of 23
The Journal of Organic Chemistry
1
2
3
4
3.26 (m, 1H), 2.69 – 2.56 (m, 1H), 2.54 – 2.41 (m, 1H), 2.25 – 2.12 (m, 2H); 13C {1H} NMR (150 MHz, CDCl3) δ
5
6
7
19
158.0, 129.6, 125.1 (q, J = 277.3 Hz), 121.5, 119.1, 114.5, 63.9, 36.3 (q, J = 30.0 Hz), 31.8, 22.8 (d, J = 1.6 Hz); F
8
9
{1H} NMR (376 MHz, CDCl3) δ -64.85 (t, J = 10.9 Hz, 3F); HRMS (ESI): m/z [M + Na]+ calcd for C12H12F3NONa:
266.0763, found: 266.0754.
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
5-phenoxy-2-(2,2,2-trifluoroethyl)pentanenitrile (7h) 74.0 mg, 72% yield; Yellow oil; 1H NMR (400 MHz, CDCl3) δ
7.29 (t, J = 6.9 Hz, 2H), 6.96 (t, J = 6.9 Hz, 1H), 6.89 (d, J = 8.5 Hz, 2H), 3.97 (t, J = 5.4 Hz, 2H), 2.99 – 2.97 (m, 1H),
2.54 (dq, J = 19.1, 9.7 Hz, 1H), 2.42 – 2.30 (m, 1H), 2.09 – 1.88 (m, 4H); 13C {1H} NMR (150 MHz, CDCl3) δ 158.5,
129.5, 125.1 (q, J = 277.3 Hz), 121.0, 119.5, 114.3, 66.4, 36.4 (q, J = 29.9 Hz), 29.2, 26.5, 25.4 (d, J = 2.0 Hz); 19F
{1H} NMR (376 MHz, CDCl3) δ -65.01 (t, J = 10.7 Hz, 3F); HRMS (ESI): m/z [M + Na]+ calcd for C13H14F3NONa:
280.0920, found: 280.0930.
5-cyano-7,7-difluoroheptyl benzoate (7i) 68.6 mg, 61% yield; Colorless oil; 1H NMR (400 MHz, CDCl3) δ 8.03 (d, J =
7.8 Hz, 2H), 7.56 (t, J = 7.3 Hz, 1H), 7.44 (d, J = 7.6 Hz, 2H), 6.01 (t, J = 55.6 Hz, 1H), 4.34 (t, J = 6.2 Hz, 2H), 2.80
(dd, J = 13.5, 8.6 Hz, 1H), 2.30 – 2.02 (m, 2H), 1.84 – 1.58 (m, 6H); 13C {1H} NMR (150 MHz, CDCl3) δ 166.5,
133.0, 130.1, 129.5 128.4, 120.1, 114.7 (t, J = 240.4 Hz), 64.1, 36.4 (t, J = 22.6 Hz), 31.8, 28.1, 25.6 (t, J = 6.0 Hz),
23.6; 19F {1H} NMR (376 MHz, CDCl3) δ -116.50 (dt, J = 55.9, 14.6 Hz, 1F), -117.15 (ddd, J = 56.6, 22.1, 15.6 Hz,
1F); HRMS (ESI): m/z [M + H]+ calcd for C15H18F2NO2: 282.1300, found: 282.1304.
1
2-(2,2-difluoroethyl)-6-phenoxyhexanenitrile (7j) 57.7 mg, 57% yield; Colorless oil; H NMR (400 MHz, CDCl3) δ
7.28 (t, J = 7.6 Hz, 2H), 6.95 (t, J = 7.2 Hz, 1H), 6.89 (d, J = 8.0 Hz, 2H), 6.01 (t, J = 55.4 Hz, 1H), 3.98 (t, J = 5.6 Hz,
2H), 2.85 – 2.77 (m, 1H), 2.21 – 2.03 (m, 2H), 1.84 – 1.66 (m, 6H); 13C {1H} NMR (150 MHz, CDCl3) δ 158.8, 129.5,
120.8, 120.3, 114.8 (t, J = 238.5 Hz), 114.4, 67.1, 36.5 (t, J = 22.6 Hz), 31.9, 28.5, 25.6 (t, J = 4.5 Hz), 23.8; 19F {1H}
NMR (376 MHz, CDCl3) δ -116.50 (dt, J = 56.1, 14.6 Hz, 1F), -117.15 (ddd, J = 56.7, 22.3, 15.5 Hz, 1F); HRMS
(ESI): m/z [M + H]+ calcd for C14H18F2NO: 254.1351, found: 254.1352.
2,6-di-tert-butyl-4-methylphenyl 4-methylbenzenesulfonate (8)16 336.7 mg, 75% yield; White solid, mp: 106.4 –
107.9 °C; 1H NMR (400 MHz, CDCl3) δ 7.49 (d, J = 7.8 Hz, 2H), 7.17 (d, J = 7.8 Hz, 2H), 6.62 (s, 2H), 2.34 (s, 3H),
1.79 (s, 3H), 1.08 (s, 18H); 13C {1H} NMR (150 MHz, CDCl3) δ 183.6, 151.1, 145.2, 135.6, 130.6, 130.2, 128.7, 65.7,
35.1, 28.9, 21.5, 18.5; MS (ESI) m/z 375.1 [M + H]+.
Associated Content
ACS Paragon Plus Environment
17

The Journal of Organic Chemistry
Page 18 of 23
1
2
3
4
5
Supporting Information
6
7
8
9
The Supporting Information is available free of charge on the ACS Publications website at DOI: XXX
Segmental experiment data, 1H, 13C and 19F NMR data for all compounds. (PDF)
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
Author Information
Corresponding Author
*E-mail for Y. Wang: yonghuiwang@fudan.edu.cn
Author Contributions
‡Zhu. Y. and Tian. J.-L. contributed equally.
Notes
The authors declare no competing financial interest.
Acknowledgments
This work was supported by Grant 81573276 from the National Science Foundation of China and Grant 17431902100
from Shanghai Bio-pharmaceutical Science and Technology Supporting Plan.
References
1. For selected examples, see: (a) Lan, X.-W.; Wang, N.-X.; Xing, Y.-L. Recent Advances in Radical
Difunctionalization of Simple Alkenes. Eur. J. Org. Chem. 2017, 5821-5851. (b) Yin, G.-Y.; Mu, X.; Liu, G.-S.
Palladium(II)-Catalyzed Oxidative Difunctionalization of Alkenes:Bond Forming at a High-Valent Palladium
Center. Acc. Chem. Res. 2016, 49, 2413-2423. (c) Studer, A.; Curran, D. P. Catalysis of Radical Reactions: a
Radical Chemistry Perspective. Angew. Chem. Int. Ed. 2016, 55, 58-102. (d) Koike, T.; Akita, M. A Radical New
Look for Alkene Carboboration. Chem 2018, 4, 1205-1207, and references cited therein.
2. For selected examples, see: (a) Li, X.-T.; Gu, Q.-S.; Dong, X.-Y.; Meng, X.; Liu, X.-Y. A Copper Catalyst with a
Cinchona-Alkaloid-Based Sulfonamide Ligand for Asymmetric Radical Oxytrifluoromethylation of Alkenyl
Oximes. Angew. Chem. Int. Ed. 2018, 57, 7668-7672. (b) Cheng, Y.-F.; Dong, X.-Y.; Gu, Q.-S.; Yu, Z.-L.; Liu, X.-
Y. Achiral Pyridine Ligand-Enabled Enantioselective Radical Oxytrifluoromethylation of Alkenes with Alcohols.
ACS Paragon Plus Environment
18

Page 19 of 23
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
Angew. Chem. Int. Ed. 2017, 56, 8883-8886. (c) Zhu, R.; Buchwald, S. L. Enantioselective Functionalization of
Radical Intermediates in Redox Catalysis: Copper-Catalyzed Asymmetric Oxytrifluoromethylation of Alkenes.
Angew. Chem. Int. Ed. 2013, 52, 12655-12658. (d) Wang, F.-L.; Dong, X.-Y.; Lin, J.-S.; Zeng, Y.; Jiao, G.-Y.; Gu,
Q.-S.; Guo, X.-Q.; Ma, C.-L.; Liu, X.-Y. Catalytic Asymmetric Radical Diamination of Alkenes. Chem 2017, 3,
979-990. (e) Lin, J.-S.; Dong, X.-Y.; Li, T.-T.; Jiang, N.-C.; Tan, B.; Liu, X.-Y. A Dual-Catalytic Strategy to
Direct Asymmetric Radical Aminotrifluoromethylation of Alkenes. J. Am. Chem. Soc. 2016, 138, 9357-9360. (f)
Zhu, R.; Buchwald, S. L. Versatile Enantioselective Synthesis of Functionalized Lactones via Copper-Catalyzed
Radical Oxyfunctionalization of Alkenes. J. Am. Chem. Soc. 2015, 137, 8069-8077.
3. For selected examples, see: (a) Kharasch, M. S.; Engelamann, H.; Mayo, F. R. The Peroxide Effect in the
Addition of Reagents to Unsaturated Compounds. XV. the Addition of Hydrogen. J. Org. Chem. 1937, 2,
288-302. (b) Minisci, F. Free-Radical Additions to Olefins in the Presence of Redox Systems. Acc. Chem.
Res. 1975, 8, 165-171. (c) Pintauer, T. Catalyst Regeneration in Transition-Metal-Mediated Atom-Transfer
Radical Addition (ATRA) and Cyclization (ATRC) Reactions. Eur. J. Inorg. Chem. 2010, 2449-2460. (d)
Molina, J. M.; Belderrain, T.R.; Pérez, P. J. Atom Transfer Radical Reactions as a Tool for Olefin
Functionalization-on the Way to Practical Applications. Eur. J. Inorg. Chem. 2011, 3155-3164. (e) Jensen, K.
H.; Sigman, M. S. Mechanistic Approaches to Palladium-Catalyzed Alkene Difunctionalization Reactions.
Org. Biomol. Chem. 2008, 6, 4083-4088. (f) Prier, C. K.; Rankic, D. A.; MacMillan, D. W. C. Visible Light
Photoredox Catalysis with Transition Metal Complexes: Applications in Organic Synthesis. Chem. Rev.
2013, 113, 5322-5363. (g) Narayaman, J. M. R.; Stephenson, C. R. J. Visible Light Photoredox Catalysis:
Applications in Organic Synthesis. Chem. Soc. Rev. 2011, 40, 102-113. (h) Zhang, N.; Samanta, S. R.;
Rosen, B. M.; Percec, V. Single Electron Transfer in Radical Ion and Radical-Mediated Organic, Materials
and Polymer Synthesis. Chem. Rev. 2014, 114, 5848-5958.
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
4. (a) Haszeldine, R. N.; Steele, B. R. The Addition of Free Radicals to Unsaturated Systems. II. Radical
Addition of Olefins of the Type RCH: CH2. J. Chem. Soc. 1953, 1199-1206. (b) Elsheimer, S.; Dolbier, W.
R.; Murla, J. M. Difluorodiiodomethane: Its Preparation, Properties and Free-Radical Reactions. J. Org.
Chem. 1984, 49, 205-207. (c) Tang, X.-J.; Dolbier, W. R. Heterogeneous Platinum-Catalyzed C-H
Perfluoroalkylation of Arenes and Heteroarenes. Angew. Chem. Int. Ed. 2015, 54, 4320-4324. (d) Bagal, D.
B.;
Kachkovskyi,
G.;
Knorn,
M.;
Rawner,
T.;
Bhanage,
B.
M.;
Rieser,
O.
ACS Paragon Plus Environment
19

The Journal of Organic Chemistry
Page 20 of 23
1
2
3
4
5
6
7
8
9
Trifluoromethylchlorosulfonylation of Alkenes: Evidence for an Inner-Sphere Mechanism by a Copper
Phenanthroline Photoredox Catalyst. Angew. Chem., Int. Ed. 2015, 54, 6999-7002. (e) Daniel, M.; Dagousset,
G.; Klein, P. A.; Tuccio, B.; Goncalves, A. M.; Masson, G.; Magnier, E. Fluorinated Sulfilimino Iminiums:
Efficient and Versatile Sources of Perfluoroalkyl Radicals under Photoredox Catalysis. Angew. Chem. Int.
Ed. 2017, 56, 3997-4001. (f) Gu, J.; Min, Q.-Q.; Yu, L.; Zhang, X. Tandem Difluoroalkylation-Arylation of
Enamides Catalyzed by Nickel. Angew. Chem. Int. Ed. 2016, 55, 12270-12274.
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
5. For selected examples, see: (a) Murphy, S.; Case, T. H. L.; Ellsworth, E.; Hagen, S.; Huband, M.; Joannides,
T.; Limberakis, C.; Marotti, K. R.; Ottolini, A. M.; Rauckhorst, M.; Starr, J.; Stier, M.; Taylor, C.; Zhu, T.;
Blaser, A.; Denny, W. A.; Lu, G.-L.; Smaill, J. B.; Rivault, F. The Synthesis and Biological Evaluation of
Novel Series of Nitrile-Containing Fluoroquinolones as Antibacterial Agents. Bioorg. Med. Chem. Lett.
2007, 17, 2150-2155. (b) Fleming, F. F.; Yao, L.; Ravikumar, P. C.; Funk, L.; Shook, B. C. Nitrile-
Containing Pharmaceuticals: Efficacious Roles of the Nitrile Pharmacophore. J. Med. Chem. 2010, 53, 7902-
7917. (c) Mowry, D. T. The Preparation of Nitriles. Chem. Rev. 1948, 42, 189-283. (d) Alba, A. N. R.;
Companyo, X.; Rios, R. Sulfones: New Reagents in Organocatalysis. Chem. Soc. Rev. 2010, 39, 2018-2033.
(e) Meadows, D. C.; Hague, J. G. Vinyl Sulfones: Synthetic Preparations and Medicinal Chemistry
Applications. Med. Res. Rev. 2006, 26, 793-814. (f) Zhu, Y.; Gong, J.-W.; Wang, Y.-H. Free-Radical-
Promoted Copper-Catalyzed Decarboxylative Alkylation of α, β-Unsaturated Carboxylic Acids with
ICH2CF3 and Its Analogues. J. Org. Chem. 2017, 82, 7428-7436. (g) Yamazaki, T. Taguchi, T. Ojima, I. In
Fluorine in Medicinal Chemistry and Chemical Biology, I. Ojima, Ed. Wiley-Blackwell: Chichester, 2009, p
3. (h) Yale, H. L. The Trifluoromethyl Group in Medical Chemistry. J. Med. Pharm. Chem. 1959, 1, 121-
133.
6. Pasteris, R. J.; Bereznak, J. F.; Chittaboina, S. Fungicidal Oxadiazoles. WO Patent 2018080859, 2018.
7. Corsi, C.; Titulaer, R.; Kessabi, J.; Bartovic, A.; Bobbio, C.; Wendeborn, S. V.; Jeanmart, S. A. M. 4,5-
Dihydro-Isoxazole Derivatives as Fungicides. WO Patent 2012143395, 2012.
8. For selected examples, see: (a) Liu, X.; Xu, C.; Wang, M.; Liu, Q. Trifluoromethyltrimethylsilane:
Nucleophilic Trifluoromethylation and Beyond. Chem. Rev. 2015, 115, 683-730. (b) Charpentier, J.; Fruh,
N.; Tongi, A. Electrophilic Trifluoromethylation by Use of Hypervalent Iodine Reagents. Chem. Rev. 2015,
115, 650-682. (c) Xu, X.-H.; Matsuzaki, K.; Shibata, N. Synthetic Methods for Compounds Having CF3-S
ACS Paragon Plus Environment
20

Page 21 of 23
The Journal of Organic Chemistry
1
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
Units on Carbon by Trifluoromethylation, Trifluoromethylthiolation, Triflylation, and Related Reactions.
Chem. Rev. 2015, 115, 731-764. (d) Yue, H.-F.; Zhu, C.; Magnus, R. Cross-Coupling of Sodium Sulfinates
with Aryl, Heteroaryl, and Vinyl Halides by Nickel/Photoredox Dual Catalysis. Angew. Chem. Int. Ed. 2018,
57, 1371-1375. (e) Cabrera-Afonso, M. J.; Lu, Z.-P.; Kelly, C. B.; Lang, S. B.; Dykstra, R.; Gutierrez O.;
Molander, G. A. Engaging Sulfinate Salts via Ni/Photoredox Dual Catalysis Enables Facile Csp2-SO2R
Coupling. Chem. Sci. 2018, 9, 3186-3191. (f) Johnson, T. C.; Elbert, B. L.; Farley, A. J. M.; Gorman, T. W.;
Castro, J. L.; MacCoss, M.; Dixon, D. J.; Paton, R. S.; Schofield, C. J.; Smith, M. D.; Willis, M. C. Direct
Sulfonylation of Anilines Mediated by Visible Light. Chem. Sci. 2018, 9, 629-633. (g) Wang, L.-J.; Chen, M.-
M.; Qi, L.; Xu, Z.-D.; Li, W. Copper-Mediated Oxysulfonylation of Alkenyl Oximes with Sodium Sulfinates:
A Facile Synthesis of Isoxazolines Featuring a Sulfone Substituent. Chem. Commun. 2017, 53, 2056-2059.
9. Sun, J.-F.; Li, P.; Guo, L.; Yu, F.; He, Y.-P.; Chu, L.-L. Catalytic, Metal-Free Sulfonylcyanation of Alkenes
via Visible Light Organophotoredox Catalysis. Chem. Commun. 2018, 54, 3162-3165.
10. (a) Fang, J.-M.; Chen, M.-Y.; Cheng, M.-C.; Lee, G.-H.; Wang, Y.; Shie-Ming, P. Toluene-p-Sulfonyl
Cyanide in Photochemical and Azobisisobutyronitrile-Initiated Radical Reactions. J. Chem. Res. 1989, 272-
273. (b) Barton, D. H. R.; Jaszberenyi, J. C.; Theodorakis, E. A. The Invention of Radical Reactions. Part
XXIII New Reactions: Nitrile and Thiocyanate Transfer to Carbon Radicals from Sulfonyl Cyanides and
Sulfonyl Isothiocyanates. Tetrahedron 1992, 48, 2613-2626. (c) Fang, J.-M.; Chen, M.-Y. Free Radical Type
Addition of Toluenesulfonyl Cyanide to Unsaturated Hydrocarbons. Tetrahedron Lett. 1987, 28, 2853-2856.
11. (a) Chen, J.-Y.; Jiang, C.; Wang, S.-M. LDK378: a Promising Anaplastic Lymphoma Kinase (ALK)
Inhibitor. J. Med. Chem. 2013, 56, 5673-5674. (b) Perez, V. L.; Pflugfelder, S. C.; Zhang, S.; Shojaei. A.;
Haque, R. Lifitegrast, a Novel Integrin Antagonist for Treatment of Dry Eye Disease. Ocul Surf. 2016, 14,
207-215. (c) Perez-Aso, M.; Montesinos, M. C.; Mediero, A.; Wilder, T.; Schafer, P. H.; Cronstein, B.
Apremilast, a Novel Phosphodiesterase 4 (PDE4) Inhibitor, Regulates Inflammation through Multiple cAMP
Downstream Effectors. Arthritis Res Ther. 2015, 17, 249-261. (d) Chen, X.-H.; Bai, J.-Y.; Shen, F.; Bai, A.-
P.; Guo, Z.-R.; Cheng, G.-F. Imrecoxib: a Novel and Selective Cyclooxygenase 2 Inhibitor with Anti-
Inflammatory Effect. Acta Pharmacol Sin. 2004, 25, 927-931.
ACS Paragon Plus Environment
21

The Journal of Organic Chemistry
Page 22 of 23
1
2
3
4
5
6
7
8
9
12. Wang, F.; Wang, D.-H.; Wan, X.-L.; Wu, L.-Q.; Chen, P.-H.; Liu, G.-S. Enantioselective Copper-Catalyzed
Intermolecular Cyanotrifluoromethylation of Alkenes via Radical Process. J. Am. Chem. Soc. 2016, 138,
15547-15550.
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
13. (a) He, Y.-T.; Li, L.-H.; Yang, Y.-F.; Zhou, Z.-Z.; Hua, H.-L.; Liu, X.-Y.; Liang, Y.-M. Copper-Catalyzed
Intermolecular Cyanotrifluoromethylation of Alkenes. Org. Lett. 2014, 16, 270-273. (b) Guo, Q.-P.; Wang,
M.-R.; Wang, Y.-F.; Xu, Z.-Q.; Wang, R. Photoinduced, Copper-Catalyzed Three Components
Cyanofluoroalkylation of Alkenes with Fluoroalkyl Iodides as Fluoroalkylation Reagents. Chem. Commun.
2017, 53, 12317-12320. (c) Liang, Z.-L.; Wang, F.; Chen, P.-H.; Liu, G.-S. Copper-Catalyzed Intermolecular
Cyanotrifluoromethylation of Alkenes: Convenient Synthesis of CF3-Containing Alkyl Nitriles. J. Fluorine
Chem. 2014, 167, 55-60. (d) Ilchenko, N. O.; Janson, P. G.; Szabo, K. J. Copper-Mediated
Cyanotrifluoromethylation of Styrenes Using the Togni Reagent. J. Org. Chem. 2013, 78, 11087-11091.
14. (a) Wu, W.-Q.; Yi, S.-J.; Huang, W.; Luo, D.; Jiang, H.-F. Ag-Catalyzed Oxidative Cyclization Reaction of
1,6-Enynes and Sodium Sulfinate: Access to Sulfonylated Benzofurans. Org. Lett. 2017, 19, 2825-2828. (b)
Prasad, C. D.; Sattar, M.; Kumar, S. Transition-Metal-Free Selective Oxidative C(sp3)–S/Se Coupling of
Oxindoles, Tetralone, and Arylacetamides: Synthesis of Unsymmetrical Organochalcogenides. Org. Lett.
2017, 19, 774-777. (c) Xiang, Y.-C.; Li, Y.-W.; Kuang, Y.-Y.; Wu, J. Stereoselective Vicinal
Difunctionalization of Alkynes through a Three-Component Reaction of Alkynes, Sodium Sulfinates, and
Togni Reagent. Adv. Synth. Catal. 2017, 359, 2605-2609. (d) Deb, A.; Manna, S.; Modak, A.; Patra, T.;
Maity, S.; Maiti, D. Oxidative Trifluoromethylation of Unactivated Olefins: An Efficient and Practical
Synthesis of α-Trifluoromethyl-Substituted Ketones. Angew. Chem. Int. Ed. 2013, 52, 9747-9750. (e) Lu,
Q.-Q.; Liu, C.; Huang, Z.-Y.; Ma, Y.-Y.; Zhang, J.; Lei, A.-W. Relay Cooperation of K2S2O8 and O2 in
Oxytrifluoromethylation of Alkenes Using CF3SO2Na. Chem. Commun. 2014, 50, 14101-14104. (f) Yang,
B.; Xu, X.-H.; Qing, F.-L. Copper-Mediated Radical 1,2-Bis(trifluoromethylation) of Alkenes with Sodium
Trifluoromethanesulfinate. Org. Lett. 2015, 17, 1906-1909.
15. Du, B.-N.; Qian, P.; Wang, Y.; Mei, H.-B.; Han, J.-L.; Pan, Y. Cu-Catalyzed Deoxygenative C2-Sulfonylation
Reaction of Quinoline N-Oxides with Sodium Sulfinate. Org. Lett. 2016, 18, 4144-4147.
16. Yang, X.-D.; Zhao, L.-B.; Yuan, B.-X.; Qi, Z.-J.; Yan, R.-L. TBAI/K2S2O8 Initiated Radical Cyclization to
Synthesize β-Arylsulfonyl Naphthalenes from Homopropargylic Alcohols and Sulfonyl Hydrazides. Adv. Synth.
ACS Paragon Plus Environment
22

Page 23 of 23
The Journal of Organic Chemistry
1
2
3
4
5
Catal. 2017, 359, 3248-3253.
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
ACS Paragon Plus Environment
23