Nickel-Catalyzed Intramolecular Desulfitative C - N Coupling: A Synthesis of Aromatic Amines

Article abstract of DOI:10.1021/acs.joc.0c00009

A nickel-catalyzed intramolecular C - N coupling reaction via SO₂ extrusion is presented. The use of a catalytic amount of BPh₃ allows the transformation to take place under much milder conditions (60 °C) than previously reported C - N coupling reactions by CO or CO₂ extrusion (160-180 °C). In addition, this method displays good functional group tolerance and versatility, as it can be applied to the synthesis of dialkyl aryl amines, alkyl diaryl amines, and triaryl amines. The robustness of the desulfitative C - N coupling is demonstrated by three high-yielding gram-scale reactions.

Full text of DOI:10.1021/acs.joc.0c00009

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Note
Nickel-Catalyzed Intramolecular Desulfitative C
-N Coupling: Synthesis of Aromatic Amines
Jiangjun Liu, Xiuwen Jia, Xuemeng Chen, Haotian Sun, Yue Li, Søren Kramer, and Zhong Lian
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00009 • Publication Date (Web): 30 Mar 2020
Downloaded from pubs.acs.org on March 30, 2020
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Page 1 of 10
The Journal of Organic Chemistry
Nickel-Catalyzed Intramolecular Desulfitative C−N Coupling:
Synthesis of Aromatic Amines
Jiangjun Liu,†,⊥ Xiuwen Jia,†,⊥ Xuemeng Chen,† Haotian Sun,† Yue Li,† Søren Kramer,§ Zhong Lian*†‡
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†Department of Dermatology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China
School of Pharmacy, Sichuan University, Chengdu 610041 (P.R. China).
‡Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory
for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of
Pharmacy, Sichuan University, Chengdu, 610041 (P.R. China).
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§
Department of Chemistry, Technical University of Denmark, 2800 Kgs. Lyngby, Denmark.
ABSTRACT: A nickel-catalyzed intramolecular C−N coupling reaction via SO2 extrusion is presented. The use of a catalytic amount
of BPh3 allows the transformation to take place under much milder conditions (60 °C) compared to previously reported C−N coupling
reactions by CO or CO2 extrusion (160−180 °C). In addition, this method displays good functional group tolerance and versatility as
it can be applied to the synthesis of dialkyl aryl amines, alkyl diaryl amines, and triaryl amines. The robustness of the desulfitative
C−N coupling is demonstrated with three high-yielding gram-scale reactions.
Aromatic amines are important building blocks in organic
synthesis and they are present in numerous natural products,1
bioactive compounds,2 pharmaceuticals,3 and polymers4.
Therefore, the preparation of aromatic amines is an important task
which has attracted significant attention in the past decades.
Common synthetic routes include direct nucleophilic substitution
and cross-coupling reactions between amines and aryl halides such
as palladium- and nickel-catalyzed Buchwald-Hartwig aminations5
and copper-catalyzed Ullmann reactions6 (Scheme 1a).
Recently, coupling reactions via SO2 extrusion has started to
gain attention. Since 2017, few groups have reported
a
intermolecular desulfitative coupling reactions for C−C bond
formation.10 Subsequently, Yorimitsu and Wei independently
reported nickel-catalyzed intramolecular C−C coupling reactions
of sulfones via SO2 extrusion.11 Recently, we reported both a
nickel- and a palladium-catalyzed intramolecular desulfitative
C−O coupling of sulfonates.12 Despite these efforts there are still
no examples of transition-metal-catalyzed intramolecular C−N
bond forming reactions by SO2 extrusion.13 Herein, we report the
first example of such a transformation. We demonstrate that C−N
bond formation by SO2 extrusion from sulfonamides can be
performed under much milder conditions than the previously
reported C−N coupling reactions via CO or CO2 extrusion.
a) Classical methods for C-N coupling
R1
R2
X
R1
R2
Pd, Ni, Cu etc.
Ar
N
+
Ar
H
N
-HX
X = halides or pseudo halides
Inspired by many of the inter- and intramolecular desulfitative
coupling reactions, we initiated our study with a substrate
containing a pyridyl group as a potential directing group.10-12
Importantly, pyridines are pivotal in medicinal chemistry. Our
initial investigation employed 4-(pyridin-2-ylsulfonyl)morpholine
(1a) as substrate, 10 mol % Ni(COD)2 as catalyst, 1.5 equiv KOtBu
as base, and xylene as solvent at 140 °C (Table 1). However, the
desulfitative product 4-(pyridin-2-yl)morpholine (2a) was not
detected after 16 h (entry 1). The addition of monodentate
phosphine ligands (PPh3, PCy3, or XPhos) or bidentate phosphine
ligand (DPPP, BINAP, DPEPhos, or XantPhos) did not improve
the reaction outcome (entries 2-3). When bidentate nitrogen ligands
were used, compound 2a was produced in up to 6% yield (entries
4-5). The use of NHC ligands (IPr·HCl, SIPr·HCl, and IMes·HCl)
significantly improved the yield of this desulfinative C−N
coupling, and among of them IPr·HCl showed the best performance
(entries 6-8). Nonetheless, the yield of 2a was still moderate. We
envisaged that the addition of a Lewis acid could aid activating the
substrate either by binding to the pyridine nitrogen or to the
sulfonyl group. To our delight, a catalytic amount of the Lewis
acid, BPh3, improved the yield to 47% (entry 9). The use of
B(C6F5)3 as additive led to inhibition of product formation, while
other boron- or metal-based Lewis acids only led to minor changes
in yield compared to the additive-free conditions (entries 10-18). A
subsequent screening of other tert-butoxide bases than KOtBu
revealed as small improvement with NaOtBu (entries 19-20). To
our surprise, lowering the reaction temperature would suppress the
decomposition of 1a and lead to a significant increase in yield
leading to 78% yield of 2a (entry 21). NaOtBu still showed the best
performance among tert-butoxide bases at 60 °C (entries 21-23).
Finally, control experiments revealed that the catalyst and ligand
b) Intramolecular decarbonylative/decarboxylative C-N coupling
O
R1
C
R1
Ni cat.
N
N
Ar
Ar
Ar
-CO
180 °C
R2
R1
R1
R1
Ni cat.
O
N
C
R2
N
Ar
-CO2
160 °C
R2
O
c) Intramolecular desulfitative C-N coupling (This work)
O O
R1
R2
S
R1
Ni cat.
N
N
Ar
N
Ar
N
R2
-SO2
Mild conditions (60 °C)
Broad scope (39 examples, up to 99% yield)
Catalytic BPh3
Scheme 1. Strategies for C-N coupling reactions.
Bond formation via gas extrusion followed by intramolecular
recombination is considered atom-economic, since the only
byproduct is a small gaseous molecule.7 During the last decade
significant progress has been achieved for these intramolecular
coupling reactions via CO and CO2 extrusion. For CO extrusion,
the formation of a range of different bonds have been reported
(C−X; X = C, O, N, P, S, Cl)7b-7d, 8 while only C−N coupling via
CO2 extrusion9 has been developed. Albeit intramolecular C−N
coupling reactions via both CO and CO2 extrusion has been
achieved, both transformations require harsh conditions with
elevated temperatures (Scheme 1b).
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are necessary for this desulfitative C−N coupling reaction (entries
play a role. In addition to pyridine substrates, an isoquinoline
1
2
3
4
5
6
7
8
24-27).
sulfonamide also produced a good yield of the SO2 extrusion
product (2m). Lastly, some unsuccessful heteroaromatic
sulfonamides were concluded in Table 2. (2n-2q)
Table 1. Optimization of Reaction Conditions for the
Desulfitative C−N Coupling.a
Table 2. Substrate Scope of Dialkyl Sulfonamides.a
Ni(COD)2 (10 mol %)
Ligand (20 mol %)
Additive (20 mol %)
Ni(COD)2 (10 mol %)
IPr•HCl (20 mol %)
BPh3 (20 mol %)
R1
O
O O
S
O
S
O
R1
N
N
R2
N
R2
N
SO2
Ar1
+
Ar1
SO2
+
N
NaOtBu (1.5 equiv)
xylene, 60 °C, 16 h
N
1
2
N
O
Base (1.5 equiv)
xylene, 140 °C, 16 h
N
1a
2a
Ph
Ph
Me
N
Bn
9
entry
1
ligand
-
additive
base
yield of 2ab (%)
N
N
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
N
N
N
-
-
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
0
0
2b
2c
2d
2e
, 85%
, 79%
, 78%
, 37%
2
monodentate phosphinesb
bidentate phosphinesc
2,2'-bipyridine
1,10-phenanthroline
IPr·HCl
Me
Me
nBu
N
nPr
N
3
-
0
N
O
N
O
nPr
N
nBu
N
N
N
4
-
6
2f
2g
2h
2i
, 73%
, 56%
N
, 78%
, 82%
O
N
5
-
trace
30
25
27
47
0
F3C
N
O
Me
O
N
O
O
N
6
-
N
N
N
Me
2j
2k,
2l
2m
N
, 70%
N
76%
, 43%
O
, 59%
N
7
SIPr·HCl
IMes·HCl
IPr·HCl
-
O
O
N
N
N
8
-
N
N
N
N
9
BPh3
B(C6F5)3
PhB(OH)2
B(OH)3
B(OPh)3
FeCl3
MgCl2
CuCl2
CuBr2
AlCl3
BPh3
BPh3
BPh3
BPh3
BPh3
2n
, trace
2p
, trace
2o
,
trace
2q
,
trace
10
11
12
13
14
15
16
17
18
19
20
21e
22 e
23e
24 e
25e,g
26e,h
27e,i
IPr·HCl
a The reactions were set up on 0.2 mmol scale.
IPr·HCl
40
34
26
32
33
24
26
24
59
35
81 (78)f
49
61
67
0
Next, we examined if the method could be applied to alkyl aryl
substituted sulfonamides (Table 3). Indeed, under the standard
conditions (Table 1, entry 21), phenylmethylpyridine (4a) was
obtained in 75% yield. By changing the ligand to 3,4-
bis(dicyclohexylphosphino)thiophene (Dcypt), the yield of 4a
increased to 99%.14 Continuing with Dcypt as ligand, a range of
different alkyl aryl substituted sulfonamides were examined. An N-
butyl substituted sulfonamide afforded the aryl amine in good yield
(4b). Also, substrates with various electron-neutral aromatic rings
led to high yields of the desulfinated product (4c-4e). Sulfonamides
containing different methyl-substituted phenylamines were also
examined (4f-4h). While meta- and para-methyl substituents are
well-tolerated, an ortho-methyl substituent leads to a lower yield.
This contrasts with the limited steric effect observed for the methyl-
substituents on the pyridine moiety when morpholine sulfonamides
were used. Substrates bearing functional groups such as ether,
amine, fluoride, trifluoromethyl, and nitrile also afforded the
desulfinated product (4i-4m). The trend in terms of yield seems to
suggest that strongly electron-donating and electron-withdrawing
substituents decrease the yield, while functional groups with
moderate electronic features lead to high yields. On the pyridine
moiety, both 5-CF3 (4n) and 3-Me (4o) substituents were tolerated.
In addition, an isoquinoline substituted sulfonamides led to the
formation of 4p in 75% yield. Due to the competition between the
C−halide (halide = Cl and Br) and S−N bond cleavage, these
sulfonamides produced the corresponding products (4r and 4s) in
trace yields. Ester and ketone substituted sulfonamides were not
subjected to the standard conditions (4s and 4t), leading to the
decomposition of the starting materials.
IPr·HCl
IPr·HCl
IPr·HCl
IPr·HCl
IPr·HCl
IPr·HCl
IPr·HCl
IPr·HCl
NaOtBu
LiOtBu
NaOtBu
KOtBu
IPr·HCl
IPr·HCl
IPr·HCl
IPr·HCl
LiOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
IPr·HCl
IPr·HCl
BPh3
BPh3
BPh3
-
0
-
0
a Reactions in this table were performed under an Ar atmosphere at 0.2 mmol
scale. Yields were determined by GC using dodecane as an internal standard.
b GC yield using dodecane as an internal standard. c Monodentate phosphine
d
ligands: PPh3, PCy3, and XPhos. Bidentate phosphine ligands: DPPP,
BINAP, DPEPhos, and XantPhos. e At 60 °C. Product yield in parenthesis. g
f
In the absence of Ni(COD)2. h In the absence of IPr·HCl. I In the absence of
Ni(COD)2 and IPr·HCl.
With satisfactory reaction conditions established, we set out to
examine the scope of the reaction. First, a variety of dialkyl-
substituted sulfonamides were evaluated (Table 2). Both
sulfonamides bearing cyclic and acyclic amines can be successfully
employed (2b-2g), leading to high yields in most cases. In order to
evaluate the influence of steric and electronic effects on the
pyridine moiety, 3-, 4-, 5-, and 6-methylpyridyl substrates were
examined (2h-2k) as well as a substrate bearing a 3-trifluoromethyl
substituent (2l). The consistently good yields for the different
methyl-substituted pyridines, even in the 3-position, indicate
minimal influence of the steric effect from the methyl group on the
reaction outcome. In contrast, the strongly electron-withdrawing
CF3-group decreases the yield suggesting that electronic effects do
Table 3. Substrate Scope of Alkyl Aryl Sulfonamides.a
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The Journal of Organic Chemistry
Ni(COD)2 (10 mol %)
Dcypt (12 mol %)
BPh3 (20 mol %)
tripelennamine (Scheme 2d). Cross-over experiment between 3f
R
N
O
S
O
Ar2
1
2
3
4
5
6
7
8
and 3o was set up and four amines were detected, which indicated
that this reaction might proceed via both intra- and intermolecular
pathway. (Scheme 3)
Ar2
Ar1
SO2
+
N
Ar1
N
NaOtBu (1.5 equiv)
xylene, 60 °C, 16 h
N
R
3
4
Me
N
Bu
Me
N
Me
N
N
Scheme 2. Three Examples of Gram Scale Desulfitative C−N
Coupling Reactions (a-c) and an Example of Application for
Medicinal Chemistry (d).
N
N
N
N
N
N
4d
, 96%
4a
4c
, 90%
, 99%
4b
, 83%
Me
Me
Me
N
Me Me
N
N
Me
N
Ni(COD)2 (10 mol %)
O
S
O
N
N
N
IPr•HCl (20 mol %)
BPh3 (20 mol %)
Me
Ph
4hb
4e
4f
4g
, 94%
, 94%
, 88%
, 52%
N
9
(a)
(b)
N
O
Me
N
Me
N
Me
N
Me
N
NaOtBu (1.5 equiv)
xylene, 60 °C, 16 h
-SO2
N
O
N
10
11
12
13
14
15
1a
2a
, 0.53 g, 72%
N
N
N
OMe
R1
NMe2
CN
4i
, 52%
4m
, 82%
4j
1
, 45%
4k
, 94%, R =F;
1
Ni(COD)2 (10 mol %)
Dcypt (12 mol %)
BPh3 (20 mol %)
4l
, 59%, R =CF3;
Me
N
Me
O
S
O
N
Me
N
Me Me
N
N
N
N
R1
N
NaOtBu (1.5 equiv)
xylene, 60 °C, 16 h
-SO2
N
Me
1
N
N
N
4q
, trace, R =Cl;
F3C
Ph
1
Me
4r
, trace, R =Br;
3a
4a
, 0.73 g, 88%
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
4n
4o
4p
, 75%
, 50%
, 56%
4s
, 0%, R =CO2Me;
1
4t
, trace, R =COMe;
Ni(COD)2 (10 mol %)
Dcypt (12 mol %)
BPh3 (20 mol %)
a The reactions were set up on 0.2 mmol scale. b 80 °C.
O
S
O
N
Finally, we investigated the desulfitative C−N coupling reaction
for diaryl substituted sulfonamides (Table 4). When diphenyl
substituted sulfonamide 5a was subjected to the reaction conditions
with Dcypt as ligand, the desulfitative product 6a was isolated in
90% yield. Other diaryl substituted sulfonamides were also
investigated. Similar to the trend observed for alkyl aryl
sulfonamides, substrates containing substituents that are only
moderately electron-donating/withdrawing produce the highest
yields (6b-6f). Methyl substituents on the pyridine moiety was also
tolerated (6g-6j). However, due to the steric bulk of the diarylamine
moiety, the best yields are obtained when the methyl group is
located away from the amine.
(c)
NaOtBu (1.5 equiv)
xylene, 60 °C, 16 h
-SO2
N
N
N
5a
6a
, 0.78 g, 90%
Ni(COD)2 (10 mol %)
IPr•HCl (20 mol %)
BPh3 (20 mol %)
N
O
S
O
N
(d)
N
Me
N
N
NaOtBu (1.5 equiv)
xylene, 60 °C, 16 h
-SO2
Tripelennamine
N
Me
7
8
, 49%
Scheme 3. Cross-over experiment between 3f and 3o.a
Table 4. Substrate Scope of Diaryl Sulfonamides.a
Me
N
Me Me
N
Me
O
S
O
Ni(COD)2 (10 mol %)
Dcypt (12 mol %)
BPh3 (20 mol %)
Ni(COD)2 (10 mol %)
Dcypt (12 mol %)
BPh3 (20 mol %)
N
O
S
O
Ar2
N
N
Ar3
N
Me
Ph
3f
N
Me
4f
4o
, 20%
, 21%
N
Ar1
SO2
+
+
NaOtBu (1.5 equiv)
xylenes, 60 °C, 16 h
N
NaOtBu (1.5 equiv)
xylenes, 60 °C, 16h
Ph
Me
N
Me Me
N
+
Me
O
S
O
Ar3
Ar2
Ar1
5
6
N
N
N
N
Ph
Me
N
Me 3o
4e
4o'
, 4%
, 35%
Based on the results above and previous studies, we propose a
mechanistic hypothesis (Scheme 4).7b, 8e, 9-11 Initially, low-valent
nickel undergo oxidative addition into either the S−N or S−C bond
of the sulfonamide forming intermediate I or I’. We hypothesize
that the pyridine moiety serves as directing group for nickel since
no product is formed when 4-(pyridin-3-ylsulfonyl)morpholine or
4-(pyridin-4-ylsulfonyl)morpholine are used as substrates. From
intermediate I/I’, SO2 can be released, and a subsequent reductive
elimination from II affords the aryl amine product and regenerates
the low-valent nickel catalyst. The beneficial role of BPh3 is
unclear at this point. Potentially, it could aid the oxidative addition
by coordination to the sulfonyl moiety, aid the desulfination, and/or
aid the reductive elimination by coordination to pyridine.
N
N
N
N
N
N
N
N
Me
F
Ph
6c
, 99%
6b
6d
, 91%
, 99%
Me
6a
, 90%
Me
N
Me
N
N
N
N
N
6h, 38%
N
CF3
N
6fc
CF3
6eb
, 39%
6g
, 39%
, 48%
N
N
N
N
Me
6i
, 68%
6j
, 93%
Me
Scheme 4. Proposed Mechanism.
a The reactions were set up on 0.2 mmol scale. b 100 °C. c 80 °C.
Having established the generality of the developed desulfitative
C−N coupling, we set out to investigate the scalability of the
method. Encouragingly, on a 4.5 mmol scale, sulfonamide 1a
produced the desired amine 2a in 72% yield (Scheme 2a). Similarly,
the use of two other sulfonamides also led to high yields on gram-
scale (Scheme 2b and 2c). In all three cases, the yields are very
close to those obtained on 0.2 mmol scale, thus indicating the
robustness of the method toward scaling up. Finally, we
demonstrated the relevance of the desulfitative C−N coupling for
medicinal chemistry with the synthesis of the antihistamine,
3
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BPh3
at room temperature and the crude product was used without further
purification in the next step.
R1
N
O
O
1
2
3
4
S
R1
R2
N
[Ni]
oxidative addition
R2
Synthesis of pyridine-2-sulfonamides: [Method A]16 General
procedure for compounds 1a-1c, 1f, 1g. To a solution of
pyridylsulfonyl chloride (5 mmol) in CH2Cl2 (15 mL) was added
amine (3.0 equiv, 15 mmol) in ice bath. The resulting mixture was
allowed to reach room temperature and stirred at room temperature
overnight. The reaction mixture was quenched with water,
extracted with CH2Cl2 (3 × 30 mL) and dried over Na2SO4. After
filtration, the solvent was removed by evaporation at reduced
pressure. The residue was purified via flash column
chromatography to give the desired product.
N
N
reductive
elimination
O
O
5
[Ni]
S
O
O
NR1R2
[Ni] NR1R2
or
S
R1
6
N
R2
N
N
N
[Ni]
I'
I
II
7
8
9
desulfination
SO2
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
In summary, we have developed the first nickel-catalyzed
intramolecular desulfitative C−N coupling reaction. The
transformation proceeds at much lower temperature than the
analogous reactions via CO or CO2 extrusion. The scope is broad
as the method can be used for synthesis of dialkyl aryl amines, alkyl
diaryl amines, and triaryl amines. The results provide new
perspectives for sulfonamides as functional handles for aryl amine
synthesis.
[Method B]17 General procedure for compounds 1d, 1e, 7. 4 M
solution of aq.K2CO3 (8 mL) was added to a solution of 4 mmol
amine and 4.8 mmol pyridine-2-sulfonyl chloride in ether (8 mL),
the resulting mixture was stirred vigorously for 1-6 h at 0oC. After
completion, Separating the aqueous phase and the organic phase,
and the aqueous phase was then extracted with CH2Cl2 (3 × 20 mL),
dried over Na2SO4. After filtration, the solution was evaporated to
dryness under reduced pressure. The residue was purified via flash
column chromatography to give the desired product.
[Method C]15 General procedure for compounds 1h-1m, 3a-
3p. To a solution of amine (5.0 mmol) and pyridine (1.5 equiv, 7.5
mmol) in THF (50 mL) at 0oC, 2-pyridylsulfonyl chloride (1.5
equiv, 7.5 mmol) was added slowly. The resulting mixture was
allowed to reach room temperature and stirred at room temperature
overnight. The mixture was quenched with saturated aq. NH4Cl
solution (10 mL) and extracted with EtOAc (3 × 20 mL). The
combined organic phase was dried (Na2SO4) and concentrated
under reduced pressure. The residue was purified by flash
chromatography to afford the desired product.
[Method D]18 General Procedure for Compounds 5a-5j. To a
solution of amine (5 mmol) in THF (50 mL), cooled to 0oC and
under nitrogen atmosphere, were successively added pyridine (1.8
equiv, 9 mmol) and a solution of 2-pyridylsulfonyl chloride (6
mmol, 1.2 equiv) in THF (2 mL). The resulting solution was
allowed to reach room temperature and it was stirred overnight
(precipitate was formed). The precipitate was removed by filtration.
To the filtrate was added water (20 mL), the mixture was
evaporated under reduced pressure to remove the THF. The
resulting suspension was filtered to obtain a white solid, the solid
was filtered, washed with toluene and dried under vacuum. The
solid (sulfonamide) was used without further purification in the
next step. A solution of sulfonamide(1 equiv), triarylbismuth (2
equiv), anhydrous Cu(OAc)2 (1.5 equiv), pyridine (1.5 equiv) in
CH2Cl2 (2.5 mL/mmol of substrate) was stirred at room
temperature overnight. The crude reaction mixture was
preabsorbed on silica gel and concentrated in vacuo. The residue
was purified by flash column chromatography to afford the desired
product.
Experimental Section
General Experimental Information: Unless otherwise noted, all
reagents were obtained from commercial suppliers and used as
received. Unless otherwise noted, all catalytic reactions were set up
in an argon atmosphere glovebox (Vigor, SGI800-750TS-F).
Unless otherwise noted, the substrates and reagents for catalytic
reactions were degassed and stored in the glovebox. All work-up
and purification procedures were carried out with reagent-grade
solvents in air. Thin Layer Chromatography analyses were
performed on silica gel coated glass plates (0.25 mm) with
fluorescence indicator UV254. For detection of spots, irradiation of
UV light at 254 nm or staining reagent using phosphomolybdic acid
solution was used. Flash column chromatography was conducted
with silica gel 60 (particle size 230–400 mesh, Huanghai) at room
temperature and under elevated pressure. Gas chromatography (GC)
analysis was conducted on a Shimadzu GC-2030 instrument
equipped with a Rtx-5 column (30 m  0.25 mm) with dodecane as
an internal standard. GC-MS analysis was conducted on an Agilent
5977B GC/MSD instrument equipped with a HP-5MS UI column
(30 m  0.25 mm). Melting points were measured with a micro
melting point apparatus. 1H NMR and 13C NMR spectra were
recorded at 400 MHz and at 101 MHz(or 151 MHz), respectively
in CDCl3 at room temperature. 1H NMR was reported as follows:
chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q =
quadruplet, m = multiplet), coupling constant (J values) in Hz and
integration. Chemical shifts (δ) were reported with respect to the
corresponding solvent residual peak at 7.26 ppm for CDCl3 for 1H
NMR. 13C NMR spectra (1H-broadband decoupled) were reported
in ppm using the central peak of CDCl3 (77.16 ppm). High-
resolution mass spectrometric measurements were provided by the
Department of The State Key Laboratory of Biotherapy, Sichuan
University. The molecular ion [M+H]+ and [M+Na]+ are given in
m/z units.
General Procedure for the Synthesis of Compounds 2a-2m: In
the glovebox, alkyl sulfonamide (0.2 mmol), Ni(COD)2 (10 mol%,
5.5 mg), IPrHCl (20 mol%, 17.0 mg), BPh3 (20 mol %, 9.7 mg),
and NaOtBu (2.0 equiv, 38.5 mg) were added into an oven-dried 4
ml vial with a magnetic stirring bar, followed by addition of
xylenes (1.0 mL). The vial was sealed and removed out of the
glovebox and heated to 60 °C in heating block. After 16 h, the vial
was cooled to room temperature. The mixture was concentrated in
vacuo and the residue was purified by flash column
chromatography to give the desired product.
General Procedure for the Synthesis of Pyridine-2-
Sulfonamides
Synthesis of pyridylsulfonyl chloride: Pyridylsulfonyl
chloride were synthesized according to procedures reported in the
literature15. 2-mercaptopyridine (2.22 g, 20 mmol) was dissolved
in conc. H2SO4 (56 mL) and cooled in ice bath. NaClO (roughly 5%
NaCIO, 220mL) was added dropwise to the solution. The resulting
mixture was stirred for 15 min at 0 °C before it was extracted with
CH2Cl2(3×30 mL). The combined organic phase was dried over
anhydrous Na2SO4 and concentrated to afford 2-pyridylsulfonyl
chloride as a pale-yellow oil. The compound is relatively unstable
4-(pyridin-2-yl)morpholine (2a). Isolated as pale-yellow oil
using petroleum ether/ethyl acetate (5:1) as eluent (25.9 mg, yield
78%). 1H NMR (400 MHz, CDCl3) δ 8.23-8.17 (m, 1H), 7.52-7.46
(m, 1H), 6.67-6.61 (m, 2H), 3.82 (t, J = 4.8 Hz, 4H), 3.49 (t, J = 4.8
Hz, 4H). 13C{1H} NMR (101 MHz, CDCl3) δ 159.6, 148.0, 137.5,
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113.8, 107.0, 66.8, 45.6. HRMS (ESI-TOF) m/z calculated for
4-(5-methylpyridin-2-yl)morpholine (2j). Isolated as a pale-
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C9H12N2O [M+H]+: 165.1022, found: 165.1026.
yellow oil using petroleum ether/diethyl ether (20:1) as eluent (25.0
mg, yield 70%). 1H NMR (400 MHz, CDCl3) δ 8.06-8.00 (m, 1H),
7.33 (dd, J = 8.8, 2.4 Hz, 1H), 6.57 (d, J = 8.8 Hz, 1H), 3.82 (t, J =
4.8 Hz, 4H), 3.43 (t, J = 4.8 Hz, 4H), 2.20 (s, 3H). 13C{1H} NMR
(101 MHz, CDCl3) δ 158.3, 147.8, 138.6, 123.1, 107.0, 66.9, 46.3,
17.5. HRMS (ESI-TOF) m/z calculated for C10H14N2O [M+H]+:
179.1179, found: 179,1181.
2-(piperidin-1-yl)pyridine (2b). Isolated as pale-yellow oil using
petroleum ether/dichloromethane (20:1) as eluent (27.4 mg, yield
85%). 1H NMR (400 MHz, CDCl3) δ 8.19-8.14 (m, 1H), 7.47-7.40
(m, 1H), 6.64 (d, J = 8.6 Hz, 1H), 6.58-6.50 (m, 1H), 3.55-3.50 (m,
4H), 1.66-1.61 (m, 6H). 13C{1H} NMR (101 MHz, CDCl3) δ 159.7,
147.9, 137.3, 112.4, 107.1, 46.4, 25.5, 24.7. HRMS (ESI-TOF) m/z
calculated for C10H14N2 [M+H]+: 163.1230, found: 163.1233.
4-(6-methylpyridin-2-yl)morpholine (2k). Isolated as yellow oil
using petroleum ether/ethyl acetate (10:1) as eluent (27.1 mg, yield
76%). 1H NMR (400 MHz, CDCl3) δ 7.39 (dd, J = 8.4, 7.6 Hz, 1H),
6.53 (d, J = 7.2 Hz, 1H), 6.42 (d, J = 8.4 Hz, 1H), 3.82 (t, J = 4.8
Hz, 4H), 3.49 (t, J = 4.8 Hz, 4H), 2.41 (s, 3H). 13C{1H} NMR (101
MHz, CDCl3) δ 159.3, 156.8, 137.9, 113.2, 103.6, 66.9, 45.8, 24.5.
HRMS (ESI-TOF) m/z calculated for C10H14N2O [M+H]+:
179.1179, found: 179.1186.
2-(pyrrolidin-1-yl)pyridine (2c). Isolated as pale-yellow oil
using petroleum ether/ethyl acetate (5:1) as eluent (23.4 mg, yield
79%). 1H NMR (400 MHz, CDCl3) δ 8.17-8.11 (m, 1H), 7.44-7.38
(m, 1H), 6.52-6.47 (m, 1H), 6.34 (d, J = 8.4 Hz, 1H), 3.46-3.42 (m,
4H), 2.02-1.95 (m, 4H). 13C{1H} NMR (101 MHz, CDCl3) δ 157.3,
148.1, 136.9, 111.0, 106.5, 46.7, 25.5. HRMS (ESI-TOF) m/z
calculated for C9H12N2 [M+H]+: 149.1073, found: 149.1077.
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4-(5-(trifluoromethyl)pyridin-2-yl)morpholine (2l). Isolated as
a pale-yellow oil using petroleum ether/diethyl ether (20:1) as
eluent (20 mg, yield 43%). H NMR (400 MHz, CDCl3) δ 8.48-
N-benzyl-N-methylpyridin-2-amine (2d). Isolated as pale-
yellow oil using petroleum ether/ethyl acetate (5:1) as eluent (30.9
mg, yield 78%). 1H NMR (400 MHz, CDCl3) δ 8.24-8.15 (m, 1H),
7.46-7.41 (m, 1H), 7.33-7.28 (m, 2H), 7.26-7.20 (m, 3H), 6.59-6.54
(m, 1H), 6.51 (d, J = 8.4 Hz, 1H), 4.80 (s, 2H), 3.08 (s, 3H). 13C{1H}
NMR (101 MHz, CDCl3) δ 158.7, 147.7, 138.6, 137.5, 128.6, 127.0,
126.9, 111.8, 105.9, 53.3, 36.3. HRMS (ESI-TOF) m/z calculated
for C13H14N2 [M+H]+: 199.1230, found: 199.1232.
1
8.36 (m, 1H), 7.65 (dd, J = 8.8, 2.4 Hz, 1H), 6.63 (d, J = 9.2 Hz,
1H), 3.81 (t, J = 4.8 Hz, 4H), 3.60 (t, J = 4.8 Hz, 4H). 19F NMR
(376 MHz, CDCl3) δ -61.22 . 13C{1H} NMR (151 MHz, CDCl3) δ
160.7, 145.9(q, J = 4.2 Hz), 134.7(q, J = 2.7 Hz), δ 124.7 (q, J =
270.1 Hz), 115.9 (q, J = 33.0 Hz), 105.7, 66.7, 45.2. HRMS (ESI-
TOF) m/z calculated for C10H11F3N2O [M+H]+: 233.0896, found:
233.0900.
N,N-dibenzylpyridin-2-amine (2e). Isolated as a pale-yellow oil
using petroleum ether/diethyl ether (100:1) as eluent (20.3 mg,
yield 37%). 1H NMR (400 MHz, CDCl3) δ 8.23-8.13 (m, 1H), 7.37-
7.32 (m, 1H), 7.31-7.24 (m, 4H), 7.23-7.18 (m, 6H), 6.58-6.51 (m,
1H), 6.47-6.39 (m, 1H), 4.77 (s, 4H). 13C{1H} NMR (101 MHz,
CDCl3) δ 158.8, 148.1, 138.6, 137.6, 128.7, 127.2, 127.1, 112.4,
106.1, 51.0. HRMS (ESI-TOF) m/z calculated for C19H18N2
[M+H]+: 275.1543, found: 275.1544.
4-(isoquinolin-3-yl)morpholine (2m). Isolated as a pale-yellow
oil using petroleum ether/diethyl ether (20:1) as eluent (25.3 mg,
yield 59%). 1H NMR (400 MHz, CDCl3) δ 8.95 (s, 1H), 7.80 (d, J
= 8.4 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.55-7.46 (m, 1H), 7.33-
7.25 (m, 1H), 6.77 (s, 1H), 3.90 (t, J = 4.8 Hz, 4H), 3.55 (t, J = 4.8
Hz, 4H). 13C{1H} NMR (101 MHz, CDCl3) δ 157.0, 151.4, 138.8,
130.5, 127.8, 125.5, 124.1, 123.7, 99.1, 67.0, 46.8. HRMS (ESI-
TOF) m/z calculated for C13H14N2O [M+H]+: 215.1179, found:
215.1179.
N,N-dipropylpyridin-2-amine (2f). Isolated as yellow oil using
petroleum ether/ethyl acetate (50:1) as eluent (19.9 mg, yield 56%).
1H NMR (400 MHz, CDCl3) δ 8.14-8.09 (m, 1H), 7.46-7.35 (m,
1H), 6.49-6.40 (m, 2H), 3.39 (t, J =7.6 Hz, 4H), 1.66-1.58 (m, 4H),
0.93 (t, J = 7.6 Hz, 6H). 13C{1H} NMR (101 MHz, CDCl3) δ 158.0,
148.0, 136.9, 110.7, 105.6, 50.5, 20.8, 11.5. HRMS (ESI-TOF) m/z
calculated for C11H18N2 [M+H]+: 179.1543, found: 179.1546.
General Procedure for Compounds 4a-4p, 6a-6j: In the
glovebox, aryl pyridine sulfonamide (0.2 mmol), Ni(COD)2 (10
mol%, 5.5 mg), dcypt (12 mol%, 11.5 mg), BPh3 (20 mol %, 9.7
mg), and NaOtBu (1.5 equiv, 28.8 mg) were added into an oven-
dried 4 ml vial with a magnetic stirring bar, followed by addition
of xylenes (1.0 mL). The vial was sealed and removed out of the
glovebox and heated to 60 °C in heating block for 16 h. After
cooling the reaction mixture to room temperature, the mixture was
concentrated in vacuo and the residue was purified by flash column
chromatography to give the desired product.
N,N-dibutylpyridin-2-amine (2g). Isolated as white syrup liquid
using petroleum ether/ethyl acetate (50:1) as eluent (32.1 mg, yield
78%).1H NMR (400 MHz, CDCl3) δ 8.14-8.10 (m, 1H), 7.40-7.35
(m, 1H), 6.47-6.40 (m, 2H), 3.45-3.40 (m, 4H), 1.61-1.53 (m, 4H),
1.39-1.31 (m, 4H), 0.95 (t, J = 7.2 Hz, 6H). 13C{1H} NMR (101
MHz, CDCl3) δ 157.9, 148.0, 136.9, 110.6, 105.5, 48.4, 29.8, 20.4,
14.1. HRMS (ESI-TOF) m/z calculated for C13H22N2 [M+H]+:
207.1856, found: 207.1861.
N-methyl-N-phenylpyridin-2-amine (4a). Isolated as pale-
yellow syrup liquid using petroleum ether/dichloromethane (1:5)
as eluent (36.5 mg, yield 99%). 1H NMR (400 MHz, CDCl3) δ 8.27-
8.20 (m, 1H), 7.44-7.37 (m, 2H), 7.34-7.28 (m, 1H), 7.28-7.25 (m,
2H), 7.24-7.19 (m, 1H), 6.65-6.58 (m, 1H), 6.53 (d, J = 8.4 Hz,
1H), 3.49 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 158.8, 147.7,
146.8, 136.6, 129.7, 126.3, 125.5, 113.1, 109.2, 38.4. HRMS (ESI-
TOF) m/z calculated for C12H12N2 [M+H]+: 185.1073, found:
185.1076.
4-(3-methylpyridin-2-yl)morpholine (2h). Isolated as a pale-
yellow oil using petroleum ether/diethyl ether (20:1) as eluent (29.2
mg, yield 82%). 1H NMR (400 MHz, CDCl3) δ 8.20-8.14 (m, 1H),
7.44-7.40 (m, 1H), 6.87 (dd, J = 7.2, 4.8 Hz, 1H), 3.85 (t, J = 4.8
Hz, 4H), 3.15 (t, J = 4.8 Hz, 4H), 2.28 (s, 3H). 13C{1H} NMR (101
MHz, CDCl3) δ 161.5, 145.4, 139.6, 125.0, 118.3, 67.3, 50.2, 18.5.
HRMS (ESI-TOF) m/z calculated for C10H14N2O [M+H]+:
179.1179, found: 179.1179.
N-butyl-N-phenylpyridin-2-amine (4b). Isolated as pale-yellow
oil using petroleum ether/dichloromethane (1:1) as eluent (37.4 mg,
yield 83%). 1H NMR (400 MHz, CDCl3) δ 8.21-8.15 (m, 1H), 7.44-
7.38 (m, 2H), 7.28-7.22 (m, 4H), 6.58-6.53 (m, 1H), 6.35 (d, J =
8.4 Hz, 1H), 3.95 (t, J = 7.6 Hz, 2H), 1.67-1.58 (m, 2H), 1.41-1.31
(m, 2H), 0.91 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3)
δ 158.6, 147.6, 145.6, 136.6, 129.8, 127.7, 125.8, 112.7, 109.1, 49.9,
30.2, 20.2, 14.0. HRMS (ESI-TOF) m/z calculated for C15H18N2
[M+H]+: 227.1543, found: 227.1546.
4-(4-methylpyridin-2-yl)morpholine (2i). Isolated as a pale-
yellow oil using petroleum ether/diethyl ether (15:1) as eluent (26.0
mg, yield 73%). 1H NMR (400 MHz, CDCl3) δ 8.06 (d, J = 5.2 Hz,
1H), 6.51 (d, J = 5.2 Hz, 1H), 6.45 (s, 1H), 3.81 (t, J = 4.8 Hz, 4H),
3.48 (t, J = 4.8 Hz, 4H), 2.27 (s, 3H). 13C{1H} NMR (101 MHz,
CDCl3) δ 160.0, 148.7, 147.7, 115.5, 107.6, 66.9, 45.9, 21.5.
HRMS (ESI-TOF) m/z calculated for C10H14N2O [M+H]+:
179.1179, found: 179.1185.
N-methyl-N-(naphthalen-2-yl)pyridin-2-amine (4c). Isolated
as white syrup liquid using petroleum ether/diethyl ether (30:1) as
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eluent (42.2 mg, yield 90%). 1H NMR (400 MHz, CDCl3) δ 8.33-
6.80-6.73 (m, 2H), 6.56-6.49 (m, 1H), 6.37 (d, J = 8.8 Hz, 1H),
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8.24 (m, 1H), 7.90-7.81 (m, 2H), 7.78 (d, J = 7.4 Hz, 1H), 7.69 (d,
J = 2.4 Hz, 1H), 7.53-7.44 (m, 2H), 7.41 (dd, J = 8.8, 2.0 Hz, 1H),
7.37-7.28 (m, 1H), 6.71-6.56 (m, 2H), 3.60 (s, 3H). 13C{1H} NMR
(101 MHz, CDCl3) δ 158.9, 147.9, 144.4, 136.9, 134.5, 131.4,
129.5, 127.8, 127.5, 126.5, 125.6, 125.4, 123.3, 113.6, 109.7, 38.7.
HRMS (ESI-TOF) m/z calculated for C16H14N2 [M+H]+: 235.1230,
found: 235.1234.
3.42 (s, 3H), 2.98(s, 6H). 13C{1H} NMR (101 MHz, CDCl3) δ
159.5, 149.1, 147.4, 136.6, 135.9, 128.1, 113.7, 112.1, 108.8, 40.9,
38.9. HRMS (ESI-TOF) m/z calculated for C14H17N3 [M+H]+:
228.1495, found: 228.1496.
N-(4-fluorophenyl)-N-methylpyridin-2-amine (4k). Isolated as
pale-yellow oil using petroleum ether/dichloromethane (1:5) as
eluent (38.0 mg, yield 94%). 1H NMR (400 MHz, CDCl3) δ 8.27-
8.17 (m, 1H), 7.34-7.29 (m, 1H), 7.25-7.19 (m, 2H), 7.13-7.06 (m,
N-methyl-N-(naphthalen-1-yl)pyridin-2-amine (4d). Isolated
as yellow oil using petroleum ether/ethyl acetate (10:1) as eluent
(45.1 mg, yield 96%). 1H NMR (400 MHz, CDCl3) δ 8.28-8.22 (m,
1H), 7.93 (d, J = 8.0 Hz, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.81 (d, J =
8.4 Hz, 1H), 7.56-7.49 (m, 2H), 7.48-7.41 (m, 2H), 7.22-7.15 (m,
1H), 6.62-6.54 (m, 1H), 6.02 (d, J = 8.4 Hz, 1H), 3.57 (s, 3H).
13C{1H} NMR (101 MHz , CDCl3) δ 159.4, 147.5, 143.0, 136.7,
135.2, 131.0, 128.6, 127.6, 126.7, 126.5, 126.4, 125.9, 123.4, 112.5,
108.7, 38.5. HRMS (ESI-TOF) m/z calculated for C16H14N2
[M+H]+: 235.1230, found: 235.1235.
2H), 6.64-6.58 (m, 1H), 6.42 (d, J = 8.4 Hz, 1H), 3.44 (s, 3H). 19
F
9
NMR (376 MHz, CDCl3) δ -116.37. 13C{1H} NMR (101 MHz,
CDCl3) δ 160.4 (d, J = 246.0 Hz), 158.9, 147.8, 142.9 (d, J = 3.1
Hz), 136.7, 128.4 (d, J = 8.4 Hz), 116.6 (d, J = 22.6 Hz), 113.1,
108.6, 38.6. HRMS (ESI-TOF) m/z calculated for C12H11FN2
[M+H]+: 203.0979, found: 203.0980.
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N-methyl-N-(4-(trifluoromethyl)phenyl)pyridin-2-amine (4l).
Isolated as a pale-yellow oil using petroleum ether/diethyl ether
(100:1) as eluent (29.8 mg, yield 59%). 1H NMR (400 MHz, CDCl3)
δ 8.32-8.25 (m, 1H), 7.65-7.55 (m, 2H), 7.49-7.39 (m, 1H), 7.37-
7.30 (m, 2H), 6.79 (d, J = 8.4 Hz, 1H), 6.77-6.73 (m, 1H), 3.52 (s,
3H). 19F NMR (376 MHz, CDCl3) δ -62.09. 13C{1H} NMR (151
MHz, CDCl3) δ 158.2, 150.1, 148.3, 137.3, 126.7 (q, J = 3.5 Hz),
125.8 (q, J = 32.7 Hz), 124.4 (q, J = 271.4 Hz), 123.9, 115.3, 111.0,
38.3. HRMS (ESI-TOF) m/z calculated for C13H11F3N2 [M+H]+:
253.0947, found: 253.0951.
N-([1,1'-biphenyl]-4-yl)-N-methylpyridin-2-amine
(4e).
Isolated as a pale-yellow oil using petroleum ether/diethyl ether
(10:1) as eluent (48.9 mg, yield 94%). 1H NMR (400 MHz, CDCl3)
δ 8.27-8.21 (m, 1H), 7.66-7.59 (m, 4H), 7.50-7.41 (m, 2H), 7.39-
7.31 (m, 4H), 6.69-6.61 (m, 2H), 3.52 (s, 3H). 13C{1H} NMR (101
MHz, CDCl3) δ 158.8, 147.9, 146.2, 140.6, 138.1, 136.8, 128.9,
128.4, 127.3, 127.0, 126.3, 113.5, 109.6, 38.5. HRMS (ESI-TOF)
m/z calculated for C18H16N2 [M+H]+: 261.1386, found: 261.1389.
4-(methyl(pyridin-2-yl)amino)benzonitrile (4m). Isolated as a
pale-yellow oil using petroleum ether/diethyl ether (15:1) as eluent
(34.3 mg, yield 82%). 1H NMR (400 MHz, CDCl3) δ 8.36-8.28 (m,
1H), 7.59-7.56 (m, 1H), 7.56-7.50 (m, 2H), 7.26-7.21 (m, 2H), 6.95
(d, J = 8.4 Hz, 1H), 6.90-6.82 (m, 1H), 3.52 (s, 3H). 13C{1H} NMR
(101 MHz, CDCl3) δ 157.8, 150.8, 148.6, 137.6, 133.4, 121.4,
119.4, 117.1, 113.3, 104.9, 38.0. HRMS (ESI-TOF) m/z calculated
for C13H11N3 [M+H]+: 210.1026, found: 210.1032.
N-methyl-N-(p-tolyl)pyridin-2-amine (4f). Isolated as pale-
yellow oil using petroleum ether/dichloromethane (1:5) as eluent
(34.9 mg, yield 88%). 1H NMR (400 MHz, CDCl3) δ 8.20-8.14 (m,
1H), 7.29-7.23 (m, 1H), 7.21-7.16 (m, 2H), 7.15-7.08 (m, 2H),
6.59-6.52 (m, 1H), 6.48-6.42 (m, 1H), 3.43 (s, 3H), 2.35 (s, 3H).
13C{1H} NMR (101 MHz, CDCl3) δ 158.8, 147.4, 144.1, 136.7,
135.5, 130.4, 126.5, 112.7, 109.0, 38.6, 21.0. HRMS (ESI-TOF)
m/z calculated for C13H14N2 [M+H]+:199.1230, found: 199.1238.
N-methyl-N-phenyl-5-(trifluoromethyl)pyridin-2-amine (4n).
Isolated as a pale-yellow oil using petroleum ether/diethyl ether
(100:1) as eluent (25.2 mg, yield 50%). 1H NMR (400 MHz, CDCl3)
δ 8.49-8.38 (m, 1H), 7.46-7.39 (m, 3H), 7.31-7.26 (m, 1H), 7.26-
7.21 (m, 2H), 6.43 (d, J = 8.8 Hz, 1H), 3.49 (s, 3H). 19F NMR (376
MHz, CDCl3) δ -61.19. 13C{1H} NMR (101 MHz, CDCl3) δ 160.4,
145.70, 145.68 (q, J = 3.9 Hz), 133.6 (q, J = 3.1 Hz), 130.2, 127.0,
126.9, 124.8 (q, J = 271.2 Hz), 115.5 (q, J = 33.0 Hz), 107.9, 38.8.
HRMS (ESI-TOF) m/z calculated for C13H11F3N2 [M+H]+:
253.0947, found: 253.0950.
N-methyl-N-(m-tolyl)pyridin-2-amine (4g). Isolated as pale-
yellow oil using petroleum ether/dichloromethane (1:5) as eluent
(37.3 mg, yield 94%). 1H NMR (400 MHz, CDCl3) δ 8.20-8.16 (m,
1H), 7.29-7.22 (m, 2H), 7.06-6.99 (m, 3H), 6.58-6.54 (m, 1H), 6.48
(d, J = 8.4 Hz, 1H), 3.43 (s, 3H), 2.33 (s, 3H).13C{1H} NMR (101
MHz, CDCl3) δ 158.9, 147.7, 146.8, 139.7, 136.5, 129.5, 127.0,
126.3, 123.4, 112.9, 109.2, 38.4, 21.4. HRMS (ESI-TOF) m/z
calculated for C13H14N2 [M+H]+: 199.1230, found: 199.1232.
N-methyl-N-(o-tolyl)pyridin-2-amine (4h). Prepared by general
procedure B at 80oC, isolated as yellow oil using petroleum
N-([1,1'-biphenyl]-4-yl)-N,3-dimethylpyridin-2-amine (4o).
Isolated as a pale-yellow oil using petroleum ether/diethyl ether
(50:1) as eluent (30.7 mg, yield 56%). 1H NMR (400 MHz, CDCl3)
δ 8.35 (dd, J = 4.8, 1.6 Hz, 1H), 7.59-7.52 (m, 2H), 7.51-7.45 (m,
3H), 7.43-7.35 (m, 2H), 7.31-7.26 (m, 1H), 7.02 (dd, J = 7.6, 4.8
Hz, 1H), 6.84-6.76 (m, 2H), 3.46 (s, 3H), 2.02 (s, 3H). 13C{1H}
NMR (101 MHz, CDCl3) δ 158.5, 148.1, 146.7, 141.0, 139.9, 133.2,
128.8, 128.3, 127.8, 126.64, 126.61, 119.8, 118.2, 39.6, 18.8.
HRMS (ESI-TOF) m/z calculated for C19H18N2 [M+H]+: 275.1543,
found: 275.1541.
1
ether/dichloromethane (1:1) as eluent (20.6 mg, yield 52%). H
NMR (400 MHz, CDCl3) δ 8.23-8.18 (m, 1H), 7.33-7.22 (m, 4H),
7.20-7.15 (m, 1H), 6.58-6.53 (m, 1H), 6.05 (d, J = 8.8 Hz, 1H),
3.40 (s, 3H), 2.15 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ
158.4, 147.5, 144.7, 136.9, 136.8, 131.5, 128.6, 127.7, 127.3, 112.1,
107.9, 37.4, 17.7. HRMS (ESI-TOF) m/z calculated for C13H14N2
[M+H]+: 199.1230, found: 199.1237.
N-(4-methoxyphenyl)-N-methylpyridin-2-amine (4i). Isolated
as a pale-yellow oil using petroleum ether/diethyl ether (100:1) as
eluent (22.3 mg, yield 52%). 1H NMR (400 MHz, CDCl3) δ 8.15-
8.09 (m, 1H), 7.24-7.16 (m, 1H), 7.13-7.05 (m, 2H), 6.91-6.82 (m,
2H), 6.53-6.45 (m, 1H), 6.30 (d, J = 8.8 Hz, 1H), 3.75 (s, 3H), 3.35
(s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 159.3, 157.8, 147.7,
139.8, 136.7, 128.4, 115.2, 112.6, 108.7, 55.6, 38.8. HRMS (ESI-
TOF) m/z calculated for C13H14N2O [M+H]+: 215.1179, found:
215.1187.
N-methyl-N-phenylisoquinolin-3-amine (4p). Isolated as a
pale-yellow oil using petroleum ether/diethyl ether (50:1) as eluent
(35.1 mg, yield 75%). 1H NMR (400 MHz, CDCl3) δ 8.90 (s, 1H),
7.70 (d, J = 8.0 Hz, 1H), 7.41-7.36 (m, 2H), 7.36-7.30 (m, 2H),
7.27-7.21 (m, 2H), 7.19-7.14 (m, 1H), 7.14-7.07 (m, 1H), 6.75 (s,
1H), 3.50 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 155.9, 151.3,
147.7, 138.6, 130.3, 129.7, 127.7, 125.3, 125.2, 124.6, 123.8, 123.4,
101.6, 38.9. HRMS (ESI-TOF) m/z calculated for C16H14N2
[M+H]+: 235.1230, found: 235.1238.
N1,N1,N4-trimethyl-N4-(pyridin-2-yl)benzene-1,4-diamine (4j).
Isolated as a white solid using petroleum ether/diethyl ether (50:1)
as eluent (20.5 mg, yield 45%, mp 91–92 oC). 1H NMR (400 MHz,
CDCl3) δ 8.23-8.15 (m, 1H), 7.28-7.22 (m, 1H), 7.15-7.07 (m, 2H),
N,N-diphenylpyridin-2-amine (6a). Isolated as pale-yellow
solid using petroleum ether/ethyl acetate (30:1) as eluent (44.3 mg,
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The Journal of Organic Chemistry
yield 90%, mp 94–95 oC). 1H NMR (400 MHz, CDCl3) δ 8.26-8.22
4-methyl-N,N-diphenylpyridin-2-amine (6h). Isolated as white
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5
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(m, 1H), 7.48-7.41 (m, 1H), 7.36-7.29 (m, 4H), 7.23-7.17 (m, 4H),
7.16-7.12 (m, 2H), 6.82-6.74 (m, 2H). 13C{1H} NMR (101 MHz,
CDCl3) δ 159.0, 148.3, 146.1, 137.3, 129.4, 126.3, 124.5, 116.1,
113.9. HRMS (ESI-TOF) m/z calculated for C17H14N2 [M+H]+:
247.1230, found: 247.1235.
solid using petroleum ether/ethyl acetate (30:1) as eluent (19.6 mg,
yield 38%, mp 85–87 oC). 1H NMR (400 MHz, CDCl3) δ 8.10 (d,
J = 4.8 Hz, 1H), 7.36-7.28 (m, 4H), 7.20-7.08 (m, 6H), 6.63 (d, J =
4.8 Hz, 1H), 6.59 (s, 1H), 2.20 (s, 3H). 13C{1H} NMR (101 MHz,
CDCl3) δ 159.2, 148.5, 147.9, 146.3, 129.3, 126.3, 124.4, 117.8,
114.5, 21.1. HRMS (ESI-TOF) m/z calculated for C18H16N2
[M+H]+: 261.1386, found: 261.1389.
N-([1,1'-biphenyl]-4-yl)-N-phenylpyridin-2-amine
(6b).
Isolated as white solid using petroleum ether/ethyl acetate (50:1) as
eluent (63.7 mg, yield 99%, mp 106–108 oC). 1H NMR (400 MHz,
CDCl3) δ 8.28-8.26 (m, 1H), 7.63-7.52 (m, 4H), 7.51-7.40 (m, 3H),
7.39-7.29 (m, 3H), 7.27-7.22 (m, 4H), 7.20-7.14 (m, 1H), 6.83-6.75
(m, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 158.9, 148.3, 146.0,
145.4, 140.7, 137.4, 137.1, 129.5, 128.7, 128.0, 127.0, 126.9, 126.5,
126.1, 124.8, 116.3, 114.1. HRMS (ESI-TOF) m/z calculated for
C23H18N2 [M+H]+: 323.1543, found: 323.1543.
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5-methyl-N,N-diphenylpyridin-2-amine (6i). Isolated as pale-
yellow solid using petroleum ether/ethyl acetate (10:1) as eluent
(35.4 mg, yield 68%, mp 71–73 oC). 1H NMR (400 MHz, CDCl3)
δ 8.11-8.06 (m, 1H), 7.34-7.27 (m, 5H), 7.18-7.12 (m, 4H), 7.12-
7.07 (m, 2H), 6.73 (d, J = 8.4 Hz, 1H), 2.25 (s, 3H). 13C{1H} NMR
(101 MHz, CDCl3) δ 157.1, 148.2, 146.4, 138.3, 129.3, 125.8,
125.7, 124.0, 114.6, 17.6. HRMS (ESI-TOF) m/z calculated for
C18H16N2 [M+H]+: 261.1386, found: 261.1386.
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N-phenyl-N-(p-tolyl)pyridin-2-amine (6c). Isolated as pale-
yellow oil using petroleum ether/ethyl acetate (20:1) as eluent (51.5
mg, yield 99%). 1H NMR (400 MHz, CDCl3) δ 8.25-8.21 (m, 1H),
7.46-7.39 (m, 1H), 7.35-7.28 (m, 2H), 7.23-7.18 (m, 2H), 7.18-7.08
(m, 5H), 6.81-6.71 (m, 2H), 2.36 (s, 3H). 13C{1H} NMR (101 MHz,
CDCl3) δ 159.1, 148.2, 146.2, 143.5, 137.3, 134.5, 130.2, 129.3,
126.7, 126.0, 124.3, 115.8, 113.4, 21.0. HRMS (ESI-TOF) m/z
calculated for C18H16N2 [M+H]+: 261.1386, found: 261.1384.
6-methyl-N,N-diphenylpyridin-2-amine (6j). Isolated as white
syrup liquid using petroleum ether/ethyl acetate (50:1) as eluent
(48.3 mg, yield 93%). 1H NMR (400 MHz, CDCl3) δ 7.35 (d, J =
1.6 Hz, 1H), 7.32-7.26 (m, 4H), 7.21-7.14 (m, 4H), 7.13-7.06 (m,
2H), 6.67 (d, J = 7.6 Hz, 1H), 6.51 (d, J = 8.4 Hz, 1H), 2.39 (s,
3H).13C{1H} NMR (101 MHz, CDCl3) δ 158.5, 157.2, 146.3, 137.6,
129.1, 126.0, 124.0, 115.9, 111.5, 24.4. HRMS (ESI-TOF) m/z
calculated for C18H16N2 [M+H]+: 261.1386, found: 261.1390.
N-(4-fluorophenyl)-N-phenylpyridin-2-amine (6d). Isolated as
white syrup liquid using petroleum ether/ethyl acetate (20:1) as
eluent (47.9 mg, yield 91%). 1H NMR (400 MHz, CDCl3) δ 8.23-
8.20 (m, 1H), 7.47-7.41 (m, 1H), 7.36-7.29 (m, 2H), 7.21-7.10 (m,
5H), 7.07-6.99 (m, 2H), 6.81-6.75 (m, 1H), 6.71 (d, J = 8.4 Hz,
1H). 19F NMR (376 MHz, CDCl3) δ -117.72. 13C{1H} NMR (101
MHz, CDCl3) δ 159.8 (d, J = 245.3 Hz), 158.9, 148.2, 145.9, 142.0
(d, J = 3.1 Hz), 137.4, 129.5, 128.2 (d, J = 8.3 Hz), 126.1, 124.7,
116.3, 116.1 (d, J = 7.6 Hz), 113.2. HRMS (ESI-TOF) m/z
calculated for C17H13FN2 [M+H]+: 265.1136, found: 265.1137.
Gram Scale of the Desulfitative Cross-Coupling Reaction
Gram-scale synthesis of compound 2a: In the glovebox, 4-
(pyridin-2-ylsulfonyl)morpholine (4.5 mmol, 1.03 g), Ni(COD)2
(10 mol%, 123.8 mg), IPr ·HCl (20 mol%, 382.5 mg), BPh3 (20
mol%, 217.9 mg), and NaOtBu (2.0 equiv, 865.0 mg) were added
into an oven-dried 75 mL screw cap Teflon-sealed tube with a
magnetic stirring bar, followed by addition of xylenes (22.5 mL).
The tube was closed and removed out of the glovebox and heated
to 60 °C in heating block. After 16 h, the tube was cooled to room
temperature. The solvent was removed under reduced pressure and
the residue was purified by flash column chromatography to give
the desired product 2a. Isolated as yellow oil using petroleum ether/
ethyl acetate (15:1) as eluent (528 mg, yield 72%).
N-phenyl-N-(4-(trifluoromethyl)phenyl)pyridin-2-amine (6e).
Prepared by general procedure B at 100oC, isolated as yellow syrup
liquid using petroleum ether/dichloromethane (3:1) as eluent (24.0
mg, yield 39%). 1H NMR (400 MHz, CDCl3) δ 8.33-8.24 (m, 1H),
7.55-7.47 (m, 3H), 7.41-7.35 (m, 2H), 7.25-7.16 (m, 5H), 6.91-6.86
(m, 1H), 6.80 (d, J = 8.4 Hz, 1H). 19F NMR (376 MHz, CDCl3) δ -
62.00. 13C{1H} NMR (101 MHz, CDCl3) δ 158.5, 149.2, 148.4,
145.4, 137.7, 129.9, 127.1, 126.2 (q, J = 3.8 Hz), 125.7, 124.9 (q,
J = 32.7 Hz), 124.3 (q, J = 272.4 Hz), 124.1, 117.5, 115.2. HRMS
(ESI-TOF) m/z calculated for C18H13F3N2 [M+H]+: 315.1104,
found: 315.1106.
Gram-scale synthesis of compound 4a: In the glovebox, N-
methyl-N-phenylpyridine-2-sulfonamide (4.5 mmol, 1.12 g),
Ni(COD)2 (10 mol%, 123.8 mg), dcypt (12 mol%, 257.2 mg), BPh3
(20 mol%, 217.9 mg), and NaOtBu (1.5 equiv, 648.7 mg) were
added into an oven-dried 75 mL screw cap Teflon-sealed tube with
a magnetic stirring bar, followed by addition of xylenes (22.5 mL).
The tube was closed and removed out of the glovebox and heated
to 60 °C in heating block. After 16 h, the tube was cooled to room
temperature. The solvent was removed under reduced pressure and
the residue was purified by flash column chromatography to give
the desired product 4a. Isolated as yellow oil using petroleum ether/
dichloromethane (1:5) as eluent (730 mg, yield 88%).
N-(p-tolyl)-N-(4-(trifluoromethyl)phenyl)pyridin-2-amine
(6f). Prepared by general procedure B at 80oC, isolated as yellow
oil using petroleum ether/dichloromethane (3:1) as eluent (25.4 mg,
yield 39%). 1H NMR (400 MHz, CDCl3) δ 8.30-8.22 (m, 1H), 7.54-
7.44 (m, 3H), 7.24-7.15 (m, 4H), 7.11-7.05 (m, 2H), 6.90-6.83 (m,
1H), 6.77 (d, J = 8.4 Hz, 1H), 2.37 (s, 3H). 19F NMR (376 MHz,
CDCl3) δ -61.95. 13C{1H} NMR (101 MHz, CDCl3) δ 158.5, 149.2,
148.2, 142.7, 137.7, 135.8, 130.6, 127.3, 126.1 (q, J = 3.8 Hz),
124.7 (q, J = 32.6 Hz), 124.3 (q, J = 272.5 Hz), 123.8, 117.2, 114.9,
21.0. HRMS (ESI-TOF) m/z calculated for C19H15F3N2 [M+H]+:
329.1260, found: 329.1260.
Gram-scale synthesis of compound 6a: In the glovebox, N,N-
diphenylpyridine-2-sulfonamide (3.5 mmol, 1.09 g), Ni(COD)2 (10
mol%, 96.3 mg), dcypt (12 mol%, 200.2 mg), BPh3 (20 mol%,
169.5 mg), and NaOtBu (1.5 equiv, 504.5 mg) were added into an
oven-dried 75 mL screw cap Teflon-sealed tube with a magnetic
stirring bar, followed by addition of xylenes (17.5 mL). The tube
was closed and removed out of the glovebox and heated to 60 °C
in heating block. After 16 h, the tube was cooled to room
temperature. The solvent was removed under reduced pressure and
the residue was purified by flash column chromatography to give
the desired product 6a. Isolated as pale yellow solid using
petroleum ether/ ethyl acetate (30:1) as eluent (776 mg, yield 90%).
3-methyl-N,N-diphenylpyridin-2-amine (6g). Isolated as a pale-
yellow oil using petroleum ether/diethyl ether (10:1) as eluent (25.0
mg, yield 48%). 1H NMR (400 MHz, CDCl3) δ 8.25-8.20 (m, 1H),
7.46-7.40 (m, 1H), 7.21-7.10 (m, 4H), 6.97 (dd, J = 7.2, 4.8 Hz,
1H), 6.95-6.83 (m, 6H), 1.89 (s, 3H). 13C{1H} NMR (101 MHz,
CDCl3) δ 157.8, 147.3, 146.9, 140.6, 129.7, 129.3, 123.0, 122.7,
120.8, 18.6. HRMS (ESI-TOF) m/z calculated for C18H16N2
[M+H]+: 261.1386, found: 261.1387.
Synthesis of compound 8: In the glovebox, N-benzyl-N-(2-
(dimethylamino)ethyl)pyridine-2-sulfonamide
(0.2
mmol),
Ni(COD)2 (10 mol%, 5.5 mg), IPrHCl (20 mol%, 17.0 mg), BPh3
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Page 8 of 10
S. M. Structure-Based Discovery of BM-957 as a Potent Small-
(20 mol %, 9.7 mg), and NaOtBu (2.0 equiv, 38.5 mg) were added
into an oven-dried 4 mL vial with a magnetic stirring bar, followed
by addition of xylenes (1.0 mL). The vial was sealed and removed
out of the glovebox and heated to 60 °C in heating block. After 16
h, the vial was cooled to room temperature. The mixture was
concentrated in vacuo and the residue was purified by flash column
chromatography to give the desired product N1-benzyl-N2,N2-
dimethyl-N1-(pyridin-2-yl)ethane-1,2-diamine 8. Isolated as
yellow oil using methanol/dichloromethane/triethylamine
Molecule Inhibitor of Bcl-2 and Bcl-xL Capable of Achieving
Complete Tumor Regression. J. Med. Chem. 2012, 55, 8502-8514.
(b) Gosmini, R.; Nguyen, V. L.; Toum, J.; Simon, C.; Brusq, J. M.
G.; Krysa, G.; Mirguet, O.; Riou-Eymard, A. M.; Boursier, E. V.;
Trottet, L.; Bamborough, P.; Clark, H.; Chung, C. W.; Cutler, L.;
Demont, E. H.; Kaur, R.; Lewis, A. J.; Schilling, M. B.; Soden, P.
E.; Taylor, S.; Walker, A. L.; Walker, M. D.; Prinjha, R. K.;
Nicodeme, E. The Discovery of I-BET726 (GSK1324726A), a
Potent Tetrahydroquinoline ApoA1 Up-Regulator and Selective
BET Bromodomain Inhibitor. J. Med. Chem. 2014, 57, 8111-8131.
(c) Zhou, H. B.; Chen, J. F.; Meagher, J. L.; Yang, C. Y.; Aguilar,
A.; Liu, L.; Bai, L. C.; Gong, X.; Cai, Q.; Fang, X. L.; Stuckey, J.
A.; Wang, S. M. Design of Bcl-2 and Bcl-xL Inhibitors with
Subnanomolar Binding Affinities Based upon a New Scaffold. J.
Med. Chem. 2012, 55, 4664-4682. (d) Li, G. Y.; Zhou, H.; Jiang, Y.;
Keim, H.; Topiol, S. W.; Poda, S. B.; Ren, Y.; Chandrasena, G.;
Doller, D. Design and Synthesis of 4-Arylpiperidinyl Amide and N-
Arylpiperdin-3-yl-cyclopropane Carboxamide Derivatives as Novel
Melatonin Receptor Ligands. Bioorg. Med. Chem. Lett. 2011, 21,
1236-1242.
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(20:1:0.1) as eluent (25.0 mg, yield 49%). H NMR (400 MHz,
CDCl3) δ 8.20-8.10 (m, 1H), 7.40-7.36 (m, 1H), 7.33-7.27 (m, 2H),
7.25-7.19 (m, 3H), 6.56-6.51 (m, 1H), 6.45 (d, J = 8.8 Hz, 1H),
4.77 (s, 2H), 3.67 (t, J = 7.6 Hz, 2H), 2.52 (t, J = 7.6 Hz, 2H), 2.27
(s, 6H). 13C{1H} NMR (101 MHz, CDCl3) δ 158.1, 148.1, 138.8,
137.2, 128.5, 127.0, 126.9, 111.9, 105.8, 56.7, 52.0, 46.6, 45.7.
HRMS (ESI-TOF) m/z calculated for C16H21N3 [M+H]+: 256.1808,
found: 256.1807.
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Procedure of Cross-over Experiment between 3f and 3o.
In the glovebox, compound 3f (0.1 mmol), 3o (0.1 mmol),
Ni(COD)2 (10 mol%, 5.5 mg), dcypt (12 mol%, 11.5 mg), BPh3 (20
mol %, 9.7 mg), and NaOtBu (1.5 equiv, 28.8 mg) were added into
an oven-dried 4 ml vial with a magnetic stirring bar, followed by
addition of xylenes (1.0 mL). The vial was sealed and removed out
of the glovebox and heated to 60 °C in heating block for 16 h. After
cooling the reaction mixture to room temperature, the mixture was
passed through a short silica gel pad with EtOAc. The compounds
and the yields were detected by GC-MS and GC.
3. Jawale, D. V.; Pratap, U. R.; Mane, R. A. An Alternative Synthetic
Route for an Antidiabetic Drug, Rosiglitazone. Bioorg. Med. Chem.
Lett. 2012, 22, 924-928.
4. (a) Abiko, Y.; Matsumura, A.; Nakabayashi, K.; Mori, H.
Thermoresponsive Core–Shell Nanoparticles with Cross-Linked π-
Conjugate Core Based on Amphiphilic Block Copolymers by RAFT
Polymerization and Palladium-Catalyzed Coupling Reactions.
Polymer 2014, 55, 6025-6035. (b) Murakami, H.; Nishiide, R.;
Ohira, S.; Ogata, A. Synthesis of MDI and PCL-Diol-Based
Polyurethanes Containing [2] and [3] Rotaxanes and Their
Properties. Polymer 2014, 55, 6239-6244. (c) Ourari, A.;
Ouennoughi, Y.; Aggoun, D.; Mubarak, M. S.; Pasciak, E. M.;
Peters, D. G. Synthesis, Characterization, and Electrochemical
Study of a New Tetradentate Nickel(II)-Schiff Base Complex
ASSOCIATED CONTENT
Supporting Information
1H, 13C, 19F NMR spectra of compounds found in the Supporting
Information. This material is available free of charge via the
Internet at http://pubs.acs.org.
Derived
from
Ethylenediamine
and
5′-(N-methyl-N-
phenylaminomethyl)-2′-hydroxyacetophenone. Polyhedron 2014,
67, 59-64. (d) Ferrando-Soria, J.; Pardo, E.; Ruiz-Garcia, R.; Cano,
J.; Lloret, F.; Julve, M.; Journaux, Y.; Pasan, J.; Ruiz-Perez, C.
Synthesis, Crystal Structures and Magnetic Properties of
MIICuIIChains (M=Mn and Co) with Sterically Hindered
Alkyl‐Substituted Phenyloxamate Bridging Ligands. Chem.-Eur. J.
2011, 17, 2176-2188.
AUTHOR INFORMATION
Corresponding Author
*E-mail: lianzhong@scu.edu.cn
ORCID
5. (a) Weber, P.; Scherpf, T.; Rodstein, I.; Lichte, D.; Schar, L. T.;
Goossen, L. J.; Gessner, V. H.
Ylide‐Functionalized Phosphine for
A
Highly Active
Søren Kramer: 0000-0001-6075-9615
Zhong Lian: 0000-0003-2533-3066
Author Contributions
Palladium‐Catalyzed
Aminations of Aryl Chlorides. Angew. Chem. Int. Ed. 2019, 58,
3203-3207. (b) Inatomi, T.; Fukahori, Y.; Yamada, Y.; Ishikawa, R.;
Kanegawa, S.; Koga, Y.; Matsubara, K. Ni(I)–Ni(III) Cycle in
Buchwald–Hartwig Amination of Aryl Bromide Mediated by NHC-
Ligated Ni(I) Complexes. Catal. Sci. Technol. 2019, 9, 1784-1793. (c)
Dorel, R.; Grugel, C. P.; Haydl, A. M. The Buchwald–Hartwig
Amination After 25 Years. Angew. Chem. Int. Ed. 2019, 58, 17118-
17129. (d) Inoue, F.; Kashihara, M.; Yadav, M. R.; Nakao, Y.
Buchwald-Hartwig Amination of Nitroarenes. Angew. Chem. Int.
Ed. 2017, 56, 13307-13309. (e) Ayothiraman, R.; Rangaswamy, S.;
Maity, P.; Simmons, E. M.; Beutner, G. L.; Janey, J.; Treitler, D. S.;
Eastgate, M. D.; Vaidyanathan, R. Zinc Acetate-Promoted
Buchwald-Hartwig Couplings of Heteroaromatic Amines. J. Org.
Chem. 2017, 82, 7420-7427. (f) Zhang, Y.; Cesar, V.; Storch, G.;
Lugan, N.; Lavigne, G. Skeleton Decoration of NHCs by Amino
Groups and its Sequential Booster Effect on the
Palladium‐Catalyzed Buchwald–Hartwig Amination. Angew.
Chem. Int. Ed. 2014, 53, 6482-6486. (g) Wagner, P.; Bollenbach,
M.; Doebelin, C.; Bihel, F.; Bourguignon, J. J.; Salome, C.; Schmitt,
M. t-BuXPhos: a Highly Efficient Ligand for Buchwald–Hartwig
Coupling in Water. Green Chem. 2014, 16, 4170-4178. (h) Al-Amin,
M.; Honma, T.; Hoshiya, N.; Shuto, S.; Arisawa, M. Ligand‐Free
Buchwald–Hartwig Aromatic Aminations of Aryl Halides
Catalyzed by Low‐Leaching and Highly Recyclable
Sulfur‐Modified Gold‐Supported Palladium Material. Adv. Synth.
Catal. 2012, 354, 1061-1068. (i) Charles, M. D.; Schultz, P.;
⊥J.L. and X.J. contributed equally.
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
This work is supported by funding from National Natural Science
Foundation (Nos. 21901168), and start-up funding from Sichuan
University. S.K. thank the Lundbeck Foundation (Grant No. R250-
2017-1292) and the Technical University of Denmark for generous
financial support.
REFERENCES
1. (a) Kanokmedhakul, S.; Kanokmedhakul, K.; Lekphrom, R.
Bioactive Constituents of the Roots of Polyalthia cerasoides. J. Nat.
Prod. 2007, 70, 1536-1538. (b) Ma, D. W.; Zhang, Y. D.; Yao, J.
C.; Wu, S. H.; Tao, F. G. Accelerating Effect Induced by the
Structure of α-Amino Acid in the Copper-Catalyzed Coupling
Reaction of Aryl Halides with α-Amino Acids. Synthesis of
Benzolactam-V8. J. Am. Chem. Soc. 1998, 120, 12459-12467.
2. (a) Chen, J. F.; Zhou, H. B.; Aguilar, A.; Liu, L.; Bai, L. C.;
McEachern, D.; Yang, C. Y.; Meagher, J. L.; Stuckey, J. A.; Wang,
8
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1
The Journal of Organic Chemistry
Buchwald, S. L. Efficient Pd-Catalyzed Amination of Heteroaryl
Halides. Org. Lett. 2005, 7, 3965-3968.
Rhodium(I)‐Catalyzed C-C Bond Cleavage Directed by a Pyridine
Group. Angew. Chem. Int. Ed. 2012, 51, 2690-2694. (i) Murakami,
M.; Amii, H.; Ito, Y. Selective Activation of Carbon–Carbon Bonds
Next to a Carbonyl Group. Nature 1994, 370, 540-541.
6. (a) Ley, S. V.; Thomas, A. W. Modern Synthetic Methods for
Copper‐Mediated C(aryl)-O, C(aryl)-N, and C(aryl)-S Bond
Formation. Angew. Chem. Int. Ed. 2003, 42, 5400-5449. (b) Ferlin,
F.; Trombettoni, V.; Luciani, L.; Fusi, S.; Piermatti, O.; Santoro, S.;
Vaccaro, L. A Waste-Minimized Protocol for Copper-Catalyzed
Ullmann-Type Reaction in a Biomass Derived Furfuryl Alcohol/Water
Azeotrope. Green Chem. 2018, 20, 1634-1639. (c) Rovira, M.;
Jasikova, L.; Andris, E.; Acuna-Pares, F.; Soler, M.; Guell, I.;
Wang, M. Z.; Gomez, L.; Luis, J. M.; Roithova, J.; Ribas, X. A
CuI/CuIII Prototypical Organometallic Mechanism for the Deactivation of
an Active Pincer-like CuI Catalyst in Ullmann-Type Couplings. Chem.
Commun. 2017, 53, 8786-8789. (d) De, S.; Yin, J.; Ma, D. Copper-
Catalyzed Coupling Reaction of (Hetero)Aryl Chlorides and
Amides. Org. Lett. 2017, 19, 4864-4867. (e) Yoo, W. J.; Tsukamoto,
T.; Kobayashi, S. Visible Light-Mediated Ullmann-Type C–N
Coupling Reactions of Carbazole Derivatives and Aryl Iodides. Org.
Lett. 2015, 17, 3640-3642. (f) Ziegler, D. T.; Choi, J.; Munoz-
Molina, J. M.; Bissember, A. C.; Peters, J. C.; Fu, G. C. A Versatile
Approach to Ullmann C–N Couplings at Room Temperature: New
Families of Nucleophiles and Electrophiles for Photoinduced,
Copper-Catalyzed Processes. J. Am. Chem. Soc. 2013, 135, 13107-
13112. (g) Zhou, F.; Guo, J.; Liu, J.; Ding, K.; Yu, S.; Cai, Q.
Copper-Catalyzed Desymmetric Intramolecular Ullmann C–N
Coupling: An Enantioselective Preparation of Indolines. J. Am.
Chem. Soc. 2012, 134, 14326-14329. (h) Monnier, F.; Taillefer, M.
Catalytic C-C, C-N and C-O Ullmann‐Type Coupling Reactions:
Copper Makes a Difference. Angew. Chem. Int. Ed. 2008, 47, 3096-
3099. (i) Zhao, Y.; Wang, Y.; Sun, H.; Li, L.; Zhang, H. Ullmann
2
3
4
5
6
7
8
9
9. Nishizawa, A.; Takahira, T.; Yasui, K.; Fujimoto, H.; Iwai, T.;
Sawamura, M.; Chatani, N.; Tobisu, M. Nickel-Catalyzed
Decarboxylation of Aryl Carbamates for Converting Phenols into
Aromatic Amines. J. Am. Chem. Soc. 2019, 141, 7261-7265.
10. (a) Markovic, T.; Rocke, B. N.; Blakemore, D. C.; Mascitti, V.;
Willis, M. C. Pyridine Sulfinates as General Nucleophilic Coupling
Partners in Palladium-Catalyzed Cross-Coupling Reactions with
Aryl Halides. Chem. Sci. 2017, 8, 4437-4442. (b) Markovic, T.;
Rocke, B. N.; Blakemore, D. C.; Mascitti, V.; Willis, M. C. Catalyst
Selection Facilitates the Use of Heterocyclic Sulfinates as General
Nucleophilic Coupling Partners in Palladium-Catalyzed Coupling
Reactions. Org. Lett. 2017, 19, 6033-6035. (c) Knauber, T.;
Chandrasekaran, R.; Tucker, J. W.; Chen, J. M.; Reese, M.; Rankic,
D. A.; Sach, N.; Helal, C. Ru/Ni dual Catalytic Desulfinative
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
Photoredox Csp2–Csp Cross-Coupling of Alkyl Sulfinate Salts and
3
Aryl Halides. Org. Lett. 2017, 19, 6566-6569. (d) Markovic, T.;
Murray, P. R. D.; Rocke, B. N.; Shavnya, A.; Blakemore, D. C.;
Willis, M. C. Heterocyclic Allylsulfones as Latent Heteroaryl
Nucleophiles in Palladium-Catalyzed Cross-Coupling Reactions. J.
Am. Chem. Soc. 2018, 140, 15916-15923. (e) Wei, J.; Liang, H.; Ni,
C.; Sheng, R.; Hu, J. Transition-Metal-Free Desulfinative Cross-
Coupling of Heteroaryl Sulfinates with Grignard Reagents. Org.
Lett. 2019, 21, 937-940.
11. (a) Takahashi, F.; Nogi, K.; Yorimitsu, H. Intramolecular
Desulfitative Coupling: Nickel-Catalyzed Transformation of Diaryl
Sulfones into Biaryls via Extrusion of SO2. Org. Lett. 2018, 20,
6601-6605. (b) Yu, T. Y.; Zheng, Z. J.; Bai, J. H.; Fang, H.; Wei, H.
Nickel-Catalyzed Intramolecular Coupling of Sulfones via the
Extrusion of Sulfur Dioxide. Adv. Synth. Catal. 2019, 361, 2020-
2024. (c) Kamigata, N.; Ozaki, J.; Kobayashi, M. Reaction of
Alkenesulfonyl Chlorides with Olefins Catalyzed by a Ruthenium
(II) Complex. A Novel Method for Synthesis of (E, E)-1,4-Diaryl-
1,3-Butadienes. J. Org. Chem. 1985, 50, 5045-5050.
Reaction in Tetraethyl Orthosilicate:
a Novel Synthesis of
Triarylamines and Diaryl Ethers. Chem. Commun. 2007, 3186-3188.
7. (a) Lee, S. C.; Liao, H. H.; Chatupheeraphat, A.; Rueping, M.
Nickel‐Catalyzed C−S Bond Formation via Decarbonylative
Thioetherification of Esters, Amides and Intramolecular
Recombination Fragment Coupling of Thioesters. Chem.-Eur. J.
2018, 24, 3608-3612. (b) Liu, X. Q.; Yue, H. F.; Jia, J. Q.; Guo, L.;
Rueping, M. Synthesis of Amidines from Amides Using a
Nickel‐Catalyzed Decarbonylative Amination through CO
Extrusion Intramolecular Recombination Fragment Coupling.
Chem.-Eur. J. 2017, 23, 11771-11775. (c) Morioka, T.; Nishizawa,
A.; Furukawa, T.; Tobisu, M.; Chatani, N. Nickel-Mediated
Decarbonylation of Simple Unstrained Ketones through the
Cleavage of Carbon-Carbon Bonds. J. Am. Chem. Soc. 2017, 139,
1416-1419. (d) Zhao, T. T.; ; Xu, W. H.; Zheng, Z. J.; Xu, P. F.;
Wei, H. Directed Decarbonylation of Unstrained Aryl Ketones via
Nickel-Catalyzed C-C Bond Cleavage. J. Am. Chem. Soc. 2018,
140, 586-589.
8. (a) Malapit, C. A.; Ichiishi, N.; Sanford, M. S. Pd-Catalyzed
Decarbonylative Cross-Couplings of Aroyl Chlorides. Org. Lett.
2017, 19, 4142-4145. (b) Somerville, R. J.; Martin, R. Forging C−C
Bonds Through Decarbonylation of Aryl Ketones. Angew. Chem.
Int. Ed. 2017, 56, 6708-6710. (c) Takise, R.; Isshiki, R.; Muto, K.;
Itami, K.; Yamaguchi, J. Decarbonylative Diaryl Ether Synthesis by
Pd and Ni Catalysis. J. Am. Chem. Soc. 2017, 139, 3340-3343. (d)
Ichiishi, N.; Malapit, C. A.; Wozniak, L.; Sanford, M. S. Palladium-
and Nickel-Catalyzed Decarbonylative C–S Coupling to Convert
Thioesters to Thioethers. Org. Lett. 2018, 20, 44-47. (e) Morioka,
T.; Nakatani, S.; Sakamoto, Y.; Kodama, T.; Ogoshi, S.; Chatani,
N.; Tobisu, M. Nickel-Catalyzed Decarbonylation of N-acylated N-
heteroarenes. Chem. Sci. 2019, 10, 6666-6671. (f) Zheng, Z. J.;
Jiang, C.; Shao, P. C.; Liu, W. F.; Zhao, T. T.; Xu, P. F.; Wei, H.
Controlled Ni-Catalyzed Mono- and Double-Decarbonylations of α-
Ketothioesters. Chem. Commun. 2019, 55, 1907-1910. (g)
Dermenci, A.; Whittaker, R. E.; Gao, Y.; Cruz, F. A.; Yu, Z. X.;
Dong, G. B. Rh-Catalyzed Decarbonylation of Conjugated Ynones
via Carbon–Alkyne Bond Activation: Reaction Scope and
Mechanistic Exploration via DFT Calculations. Chem. Sci. 2015, 6,
3201-3210. (h) Lei, Z. Q.; Li, H.; Li, Y.; Zhang, X. S.; Chen, K.;
Wang, X.; Sun, J.; Shi, Z. J. Extrusion of CO from Aryl Ketones:
12. Chen, X. M.; Xiao, X.; Sun, H. T.; Li, Y.; Cao, H. L.; Zhang, X.
M.; Yang, S. Y.; Lian, Z. Transition-Metal-Catalyzed
Transformation of Sulfonates via S–O Bond Cleavage: Synthesis of
Alkyl Aryl Ether and Diaryl Ether. Org. Lett. 2019, 21, 8879-8883.
13. For an elegant transition-metal-free approach using stoichiometric
magnesium amides, see: (a) Balkenhohl, M.; Francois, C.; Roman,
D. S.; Quinio, P.; Knochel, P. Transition-Metal-Free Amination of
Pyridine-2-Sulfonyl Chloride and Related N-Heterocycles Using
Magnesium Amides. Org. Lett. 2017, 19, 536-539. (b) Balkenhohl,
M.; Valsamidou, V.; Knochel, P. Amination of 2-Pyridinesulfonic
and 8-Quinolinesulfonic Acids with Magnesium Amides. Eur. J.
Org. Chem. 2019, 5165-5168.
14. When Dcypt was utilized as ligand instead of IPr·HCl for the
dialkyl sulfonamide 1a, only 12% yield of 2b was obtained.
15. Garcia-Rubia, A.; Urones, B.; Gomez Arrayas, R.; Carretero, J. C.
PdII‐Catalyzed C-H Olefination of N‐(2‐Pyridyl)sulfonyl Anilines
and Arylalkylamines. Angew. Chem. Int. Ed. 2011, 50, 10927-10931.
16. Balkenhohl, M.; Francois, C.; Sustac Roman, D.; Quinio, P.;
Knochel, P. Transition-Metal-Free Amination of Pyridine-2-
sulfonyl Chloride and Related N-Heterocycles Using Magnesium
Amides. Org. Lett. 2017, 19, 536-539
17. Goulaouic-Dubois, C.; Guggisberg, A.; Hesse, M. Protection of
Amines by the Pyridine-2-Sulfonyl Group and Its Cleavage under
Mild Conditions (SmI2 or Electrolysis). J. Org. Chem. 1995, 60,
5969-5972.
18. Chan, D. M. T. Promotion of Reaction of N-H Boths with
Triarylbismuth and Cupric Acetate. Tetrahedron lett. 1996, 37,
9013-9016.
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O O
S
R1
R2
Ni cat.
R1, R2 = alkyl and aryl
N
R1
N
Ar
N
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Ar
R2
N
-SO2
Cheap
Easily Accessible
Versatile



Mild conditions (60 °C)
High functional group tolerance
Broad scope (39 examples, up to 99% yield)



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