Intermolecular C-H Amidation of Alkenes with Carbon Monoxide and Azides via Tandem Palladium Catalysis

Article abstract of DOI:10.1055/a-1401-4486

An atom- and step-economic intermolecular multi-component palladium-catalyzed C-H amidation of alkenes with carbon monoxide and organic azides has been developed for the synthesis of alkenyl amides. The reaction proceeds efficiently without an ortho -directing group on the alkene substrates. Nontoxic dinitrogen is generated as the sole by-product. Computational studies and control experiments have revealed that the reaction takes place via an unexpected mechanism by tandem palladium catalysis.

Full text of DOI:10.1055/a-1401-4486

SYNTHESIS
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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart
2021, 53, A–K
special topic
A
Bond Activation – in Honor of Prof. Shinji
Z.-Y. Gu et al.
Special Topic
Synthesis
Intermolecular C–H Amidation of Alkenes with Carbon Monoxide
and Azides via Tandem Palladium Catalysis
Zheng-Yang Gu◊a,b
Yang Wu◊a
Feng Jinc
O
O
O
Pd(OAc)2 (5 mol%)
MeCN, 80 °C, 12 h
H
S
+
CO
(balloon)
+
R
SO2N3
+
N2
N
Xiaoguang Bao*c
R
H
37 examples, 44–91% yields
Ji-Bao Xia*a
0
0
0
0-0
0
0
2
-2
2
6
2
-
5
4
8
8
tandem Pd catalysis
no ortho-directing group
additive free
a State Key Laboratory for Oxo Synthesis and Selective Oxidation, Center for
Excellence in Molecular Synthesis, Suzhou Research Institute of LICP, Lan-
zhou Institute of Chemical Physics (LICP), University of Chinese Academy
of Sciences, Chinese Academy of Sciences, Lanzhou 730000, P. R. of China
jibaoxia@licp.cas.cn
b College of Textiles and Clothing & Key Laboratory for Advanced Technology
in Environmental Protection of Jiangsu Province, Yancheng Institute of
Technology, Yancheng, 224051, P. R. of China
c College of Chemistry, Chemical Engineering and Materials Science,
Soochow University, Suzhou, 215123, P. R. of China
xgbao@suda.edu.cn
◊ These authors contributed equally
Published as part of the Special Topic Bond Activation – in Honor of Prof. Shinji Murai
Corresponding Authors
Received: 07.02.2021
A. Natural products and drug candidates containing alkenyl amide as a key unit
Accepted after revision: 26.02.2021
Published online: 26.02.2021
DOI: 10.1055/a-1401-4486; Art ID: ss-2021-f0053-st
Me
NH
O
CO2H
Ph
Cl3C
MeO
O
N
S
H
N
H2N
Abstract An atom- and step-economic intermolecular multi-compo-
nent palladium-catalyzed C–H amidation of alkenes with carbon mon-
oxide and organic azides has been developed for the synthesis of alkenyl
amides. The reaction proceeds efficiently without an ortho-directing
group on the alkene substrates. Nontoxic dinitrogen is generated as the
sole by-product. Computational studies and control experiments have
revealed that the reaction takes place via an unexpected mechanism by
tandem palladium catalysis.
Me
N
barbamide, antifouling
tryptophan 4-aminocinnamamide
O
O
N
NHnPr HCl
H
H
N
H
O
O
H
N
H
H
H
Me
Me
OH
naucleofficine I, antiviral
antianoxia agent
B. Intermolecular amidation of alkenes with CO and amines
Key words C–H carbonylation, amidation, palladium, alkene, amides
well-developed
O
O
metal catalyst
N
H
H
The amide motif is undoubtedly one of the most im-
portant structural units in nature. It not only plays an es-
sential role in life as the backbone of proteins but also pres-
ents in numerous marketed drugs and materials.1 Among
them, the alkenyl amides are widely found in natural prod-
ucts and pharmaceuticals (Scheme 1A).2 In addition, alkenyl
amides are also reliable and versatile synthetic intermedi-
ates for the synthesis of a variety of useful chemicals, such
as amines, isonitriles, ketones, and hetorocycles.3 Conven-
tional route for the preparation of alkenyl amides relies on
condensation of carboxylic acids and amines in the pres-
ence of a stoichiometric ‘coupling’ reagent.4 However, the
production of large quantities of waste is the major concern
in this traditional amide synthesis.5 Therefore, the develop-
ment of catalytic, atom-economic, and efficient methods to
produce alkenyl amides are of great significance and re-
warding.
+
CO
+
NH2
N
H
unprecedented
C. Intermolecular C–H amidation of alkenes (This work)
O
H
CO
+
N3
Pd
+
N
H
Intermolecular three-component reaction
Tandem palladium catalysis
Without an ortho-directing group Mild conditions without any additive
Scheme 1 Intermolecular C–H amidation of alkenes
To overcome the low atom economy in traditional alke-
nyl amide synthesis, catalytic condensation of the alkenyl
carboxylic acids and amines has been developed using bo-
ronic acid as a catalyst.6 Recently, many strategies have
been developed for the catalytic synthesis of alkenyl amides
using other easily accessed raw materials other than car-
boxylic acids, such as hydroaminocarbonylation of alkynes
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–K
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
Z.-Y. Gu et al.
Special Topic
Synthesis
with carbon monoxide (CO) and amines.7 Use of inexpen-
sive and abundant CO gas for catalytic carbonylation is one
of the most straightforward and powerful strategies to pre-
pare carbonyl compounds.8 Aminocarbonylation of alkenyl
halides (pseudohalide) or alkenyl organometallic reagents
is another well-established methods for the synthesis of
alkenyl amides.9 Obviously, direct C–H carbonylation of
alkenes to produce alkenyl amides is much attractive and
atom-economic due to utilization of simple olefin as the
substrate. However, all of the reported C–H aminocarbon-
ylation of alkenes needed substrates bearing an NH func-
tionality as an intramolecuar ortho-directing group.10 Tran-
sition-metal-catalyzed intermolecular aminocarbonylation
of alkenes with free amines generally produced the corre-
sponding alkyl amides, which has been well developed
(Scheme 1B).11 Intermolecular C–H aminocarbonylation of
alkenes with free amines to produce alkenyl amides has not
been reported yet.12
Transition-metal-catalyzed C–N bond-forming reac-
tions via a metal-nitrene intermediate is a powerful meth-
od to prepare various N-containing chemicals.13 Readily
available organic azides are one class of convenient nitrene
precursors, which expel N2 as the sole byproduct in the ni-
trene transfer reactions.14 Catalytic carbonylation of azides
has been utilized for the synthesis of ureas and carbamates,
avoiding direct utilization of air- and moisture-sensitive
isocyanate compounds.15 We recently reported a conve-
nient approach for Rh-catalyzed C–H amidation of electron-
rich (hetero)arenes with CO and azides to produce aryl am-
ides.16 This finding inspired us that C–H amidation of
alkenes might be achieved with CO and azides via suitable
metal catalysis. We now report a Pd-catalyzed multi-com-
ponent intermolecular C–H amidation of alkenes with or-
ganic azides under 1 atm of CO (Scheme 1C). This method
has the advantages of synthetic simplicity, high efficiency,
atom- and step-economy, thus providing cost-efficient and
straightforward access to valuable alkenyl amides under
mild additive-free conditions.
Given the important role and wide presence of oxygen
heterocycles in pharmaceutical industry,17 we began by in-
vestigating the C–H amidation of dihydropyran (DHP, 1)
with CO (balloon pressure) and p-toluenesulfonyl azide (2)
in the presence of various metal catalysts. Both Pd(II) and
Pd(0) can catalyze this reaction. The desired amidation
product 3 was obtained in 78% yield with 5 mol% Pd(OAc)2
as the catalyst in MeCN at 80 °C (Table 1, entry 1). The use
of Pd(0) catalysts, Pd2(dba)3, or Pd(PPh3)4 were less effective
(entries 2, 3). No olefin aziridination product was observed
in the reaction.18 Moderate efficiency was observed when
[Rh(cod)Cl]2 was used as the catalyst (entry 4). The yield of
3 was increased to 90% when the amount of 2 was in-
creased to 1.5 equivalents (entry 7). A slightly lower yield
(81%) was obtained when the reaction temperature was de-
creased to 60 °C (entry 8). Lower yields were obtained
when other solvents were tested, such as toluene and THF
(entries 10, 11). The acetonitrile as solvent may serve as a
good coordinative ligand for palladium catalyst. Control ex-
periment showed that no reaction occurred without Pd cat-
alyst, demonstrating the essential role of the Pd catalyst in
promoting the reaction (entry 12).
Table 1 Catalytic C–H Amidation of Alkenea
O
Ts
catalyst (5 mol%)
N
+
CO
+
Ts N3
H
solvent, T, 12 h
O
(balloon)
O
1
2
3
Entry
Catalyst
Solvent
Temp (°C)
Yield (%)b
1
2
Pd(OAc)2
Pd2(dba)3
Pd(PPh3)4
[Rh(cod)Cl]2
Cu(OAc)2
Co2(CO)8
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
–
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
toluene
THF
80
80
80
80
80
80
80
60
25
80
80
80
78
48
3
44
4
55
5
trace
trace
90
6
7c
8c
9c
10c
11c
12c
81
12
trace
19
MeCN
0
a Reaction conditions: 1 (0.5 mmol), 2 (0.6 mmol), CO (balloon), catalyst
(5 mol%), MeCN (3 mL), 12 h.
b Determined by 1H NMR analysis using 1,1,2,2-tetrachloroethane as an
internal standard.
c With 0.75 mmol of 2.
With the optimal reaction conditions in hand, we first
investigated a wide range of alkenes in this C–H amidation
reaction under 1 atm of CO (Scheme 2). Overall, good to ex-
cellent yields of acrylamides were obtained. It was gratify-
ing to observe that 2-methoxy-DHP and 2-[(benzyl-
oxy)methyl]-DHP exhibited good reactivity producing the
corresponding products 4 and 5 in 80% and 86% yield, re-
spectively. Amidation of 2,3-dihydrofuran also occurred
smoothly affording the desired product 6 in 61% yield. A va-
riety of linear alkoxyethenes, such as ethoxy-, propoxy-, bu-
toxy-, isobutoxy-, cyclohexoxy-, and benzyloxyethene dis-
played moderate to good reactivity, furnishing the corre-
sponding products 7–12 in 44–82% yields. Remarkably,
amidation of (2-chloroethoxy)ethene produced chlorine-
containing acrylamide derivative 13 in 63% yield, which
could be easily functionalized for further transformation. It
should be noted that amidation of an E/Z mixture of 1-
ethoxy-1-propene gave E-alkenyl amide 14 in 76% yield as a
single stereoisomeric product. Excellent yield of (E)-15 was
obtained as the sole stereoisomeric product in the amida-
tion of 1,1-disubstituted olefin (2-ethoxy-1-propene). The
aryloxyethene can also be used as a substrate, delivering
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–K

C
Z.-Y. Gu et al.
Special Topic
Synthesis
the desired product 16 in moderate yield. However, no reac-
tion occurred with vinyl acetate, which might due to its
property of electron deficiency (→ 17, 0%). Notably, this C–H
amidation reaction is not restricted to vinyl ester sub-
strates, as stryene derivatives are also amenable to the reac-
tion. We found that electron-rich styrenes displayed good
reactivity in this reaction. For example, a variety of styrenes
bearing amino group all worked very well, and the corre-
sponding C–H amidation products 18–22 were isolated in
76–91% yields. Unfortunately, no reaction occurred when
simple aliphatic unactivated olefins, styrenes with elec-
tron-withdrawing groups, dienes, and simple cycloalkenes
were used under current conditions
We then investigated the scope of organic azides in the
amidation of DHP (1). It was found that arylsulfonyl azides
with both electron-donating group (Me, OMe), electron-
withdrawing group (CF3), or halogen substituents on the
benzene ring showed good reactivity, leading to the desired
products 24–29 in 71–83% yield. The reaction of naphthyl-
sulfonyl and heteroarylsulfonyl azides occurred smoothly
O
O
O
Pd(OAc)2 (5 mol%)
MeCN, 80 °C, 12 h
H
S
+
CO
+
R
SO2N3
+
N2
N
(balloon)
R
H
scope of alkenes with TsN3 (2)
O
O
O
O
O
O
Ts
O
Ts
Ts
N
Ts
Ts
Ts
Ts
N
N
N
Me
O
N
H
H
H
H
H
BnO
O
O
O
MeO
O
3, 82%
4, 80%
5, 86%
6, 61%
7, 54%
O
O
O
Me
Ts
Me
Cl
Ts
Ts
Ts
Ts
O
N
O
N
Me
O
N
H
Ph
O
N
H
O
N
H
H
H
Me
8, 59%
9, 44%
10, 52%
11, 82%
12, 70%
O
O
Me
O
O
O
O
Ts
Ts
Ts
Me
O
N
H
O
N
Me
O
N
O
N
H
Me
O
N
H
H
H
Me
13, 63%
14, 76%
15, 87%
16, 47%
17, 0%
O
O
O
O
Me
O
Ts
Ts
Ts
Ts
Ts
N
N
N
N
H
N
H
H
H
H
Me
Et
Me
N
N
N
N
N
N
O
Me
Et
Me
Me
18, 76%
19, 79%
20, 83%
21, 87%
22, 91%
scope of azides with DHP 1
O
Me
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
S
S
S
S
S
N
N
N
N
N
H
H
H
H
H
O
CF3
O
O
OMe
O
Me
Me
O
F
26, 82%
23, 73%
24, 82%
25, 81%
27, 71%
O
O
O
O
O
O
S
O
O
S
O
O
O
S
O
O
O
S
S
N
N
N
N
N
H
H
H
H
H
S
O
Cl
O
Br
O
O
O
28, 75%
29, 83%
30, 52%
31, 80%
32, 65%
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
S
Ph
S
S
Me
S
Me
S
N
N
Me
N
N
N
H
H
H
H
H
Me
O
O
O
O
O
33, 83%
34, 65%
35, 70%
36, 76%
37, 44%
amidation of complex molecules
Me
Me
Me
Ph
O
O
Me
Me
O
O
O
O
O
H
Me
Ph
O
S
S
N
N
H
H
H
H
Ph
O
O
Me
O
Me
from D-glucal
from stigmasterol
38, 67%
39, 53%
Scheme 2 Scope of C–H amidation of alkenes. Reagents and conditions: alkene (0.5 mmol), azide (0.75 mmol), CO (balloon), Pd(OAc)2 (5 mol%), MeCN
(3 mL), 80 °C, 12 h. Isolated yields are shown.
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–K

D
Z.-Y. Gu et al.
Special Topic
Synthesis
(→ 30–32). Furthermore, the alkylsulfonyl azides also ex-
hibited good reactivity in this transformation (→ 33–37).
Unfortunately, no reaction occurred with azidobenzene or
(azidomethyl)benzene as the substrate under the standard
conditions. Finally, late stage C–H amidation of olefin-con-
taining complex molecules was carried out. Amidation of
3,4,6-tri-O-benzyl-D-glucal occurred smoothly generating
the corresponding amide 38 in 67% yield. And selective C–H
amidation of vinyl ester derived from natural stigmasterol
produced the target product 39 in moderate yield, without
touching the other two double bonds in the molecule.
To demonstrate the synthetic utility of this method, a
scale-up reaction for C–H amidation of DHP (1) was carried
out. The desired product 3 was obtained in 86% yield
(Scheme 3a). Then, Ir-catalyzed alkenylation of 3 with
alkyne occurred smoothly generating functionalized 1,3-
diene 40 in good yield (Scheme 3b). Indole-containing het-
erocycles are widely present in pharmaceutical compounds
and biologically active molecules.19 We found that reaction
of alkenyl amide 7 with 1H-indole produced polycyclic in-
dole derivative 41 in good yield using AlCl3 as a Lewis acid
catalyst via transamidation and double addition reactions
(Scheme 3c). The product 15 could be easily converted to -
ketoamides 42 in excellent yield under acidic conditions at
room temperature (Scheme 3d). Antidiabetic Gliben-
clamide is a sulfonamide-containing small molecular drug,
one of the top 200 most prescribed medication in US
in2016.20 Amidation of DHP (1) with sulfonyl azide 43 pro-
duced the analogue 44 of Glibenclamide in 78% yield under
the standard conditions (Scheme 3e).
INT2a can bind with CO to afford the isocyanate intermedi-
ate. The second pathway is that CO might coordinate with
Pd(II) and undergo migratory insertion with TsN3 via TS1b
followed by N2 dissociation to generate the isocyanate in-
termediate (path b). Computational results show that both
of the Pd(II)-catalyzed pathways have substantially high ac-
tivation barriers (larger than 30 kcal/mol, Figure S1). In ad-
dition, one may suggest that CO could reduce the Pd(II) cat-
alyst to Pd(0). When Pd(0) species is employed to catalyze
the reaction, the aforementioned pathways are also consid-
ered. It is interesting to find that the activation barrier cata-
lyzed by Pd(0) is significantly lowered than that catalyzed
by Pd(II) (Figure 1). Thus, computational results imply that
it is more feasible for Pd(0) species to promote the reaction
to form the isocyanate intermediate. We found that activa-
tion barrier of Pd(0)-catalyzed migratory insertion with
TsN3 to generate the isocyanate intermediate (Ts1b′, path b,
Figure 1) is much lower than that of Pd(0)-catalyzed de-
nitrogenation of TsN3 (Ts1a′, path a, Figure 1). Afterward,
the substrate ethoxyethene (1′) could undergo migratory
insertion with the formed isocyanate intermediate at the
Pd(0) site. Two possible regioselectivities are considered
and the corresponding transition states are shown as TS3a′
and TS3b′, respectively. The predicted activation barriers
indicate that the insertion of the terminal carbon of 1′ with
C atom of the isocyanate group is more favorable to occur.
This result could be rationalized by HOMO analysis of 1′
that the electron density of alkene moiety is more localized
at the terminal carbon due to the presence of O connected
with the alkenyl group (Figure 2). Similar character is also
found in the HOMO of 1. Therefore, the formation of INT4′
is more ready to occur. The subsequent -H elimination
could follow to produce INT6′. Finally, the reductive elimi-
nation of INT6′ could proceed to furnish the final product. It
should be noted that the formation of a -lactam interme-
diate is detected between DHP (1) and sulfonyl isocyanate
in the absence of Pd catalyst, which can be further trans-
formed into alkenyl amides under high temperature.21
Computational studies were carried out to gain a mech-
anistic insight into this reaction (see SI for detailed compu-
tational details). When Pd(OAc)2 is considered as an active
catalyst, the formation of the intermediate of isocyanate is
evaluated via two possible mechanistic pathways. The first
pathway is the Pd(II)-catalyzed denitrogenation of TsN3 via
TS1a to afford the palladium nitrene species (path a, Figure
S1 in Supporting Information). Subsequently, the generated
a) Scale-up reaction
b) Derivatization of alkenyl amide 3
O
O
O
Ph
Ph
Ts
N
Ts
Ts
(1.5 equiv)
Pd(OAc)2 (5 mol%)
MeCN, 80 °C, 12 h
H
N
N
+
CO
+
Ts N3
H
H
[Ir(cod)Cl]2 (2 mol%)
MeOH, 70 °C, 24 h
O
Ph
O
(balloon)
O
N
O
Ph
1 (2 mmol)
2
86%
3
3
64%
40
c) Derivatization of alkenyl amide 7
1H-indole (2.2 equiv)
AlCl3 (20 mol%)
d) Derivatization of alkenyl amide 15
NH
Me
15
O
O
O
O
O
1 M HCl
Ts
Ts
Ts
Cl
Me
O
N
Me
O
N
MeCN, rt, 1 h
toluene, 120 °C, 12 h
Me
N
H
H
H
O
7
67%
41
95%
Cl
42
e) Modification of Glibenclamide
Cl
O
O
O
MeO
HN
O
O
MeO
HN
O
O
Pd(OAc)2 (5 mol%)
MeCN, 80 °C, 12 h
S
S
Cy
S
+
CO
+
N3
MeO
N
O
N
N
O
H
O
(balloon)
H
H
N
O
O
H
Glibenclamide, antidiabetic drug
1
43
78%
44
Scheme 3 Synthetic applications
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–K

E
Z.-Y. Gu et al.
Special Topic
Synthesis
(kcal/mol) M06/6-311++G(d,p)-SDD/SMD//M06/6-31G(d)-LANL2DZ
G
L = MeCN
path a
path b
L2
24.4
L2
Pd
O
L2
Pd
TS1a'
Me
Pd
Ts
N
Ts
O
Ts
N
L2
C
N
Pd
C
1.89
C
O
O
1.91
1.95
N
O
9.7
O
Me
O
Me
N
N
TS1b'
1.63
Ts
TS3a'
TS3b'
TS3c'
4.2
3.4
INT2b'
L2
TS2b'
2.0
L2
Pd
0.0
INT1'
Pd
INT1b'
O
N
N
N
Tol
CO
–24.7
TS3c'
O
N
L
Tol
N
N
O
S
L
Ts
Pd
1.58
O
N
Ts
N2
S
N
N
Pd
O
PdL2
CO
N
N
H
C
H
Ts
–32.1
TS3b'
–38.9
TS3a'
O
C
Me
O
O
O
Me
N2
Me
O
–42.4
TS5'
–42.8
TS4'
H
Ts
1'
O
Me
–45.1
INT5'
N
–53.8
–54.1
INT6'
MeCN
O
Pd
L
–61.8
INT7'
INT3'
L2
Tol
O
Tol
L
O
L
Pd
S
Pd
H
S
O
MeCN
CO
Pd
O
N
C
L2
Pd
–68.2
INT4'
N
N
C
H
L2
Ts-N3
Ts
Pd
O
C
L2
Pd
N
O
O
Me
O
2.19
CO
O
N
Ts
product 7
Me
O
Me
N
N
N
H
Ts
N
N
Ts
C
–76.4
INT1'
O
TS1a'
TS1b'
Figure 1 Energy profiles for the Pd(0)-catalyzed C–H amidation of alkenes with CO and TsN3 (bond lengths are shown in Å)
However, the activation barriers is much higher than that of
Pd-catalyzed process (Figure 2, TS3c′ and Figure S3 in Sup-
porting Information).22 Nevertheless, the formation of -
lactam intermediate is not necessary in the presence of Pd
catalyst according to the computational studies.23
THP (1) with tosyl isocyanate (45) in the presence of
Pd(OAc)2/CO is much faster than that without Pd catalyst
(Scheme 4c). These results indicate that isocyanate should
a) Capture of isocyanate intermediate
Pd(OAc)2 (5 mol%)
N
C O
Ts N3
CO
Ts NH2
+
+
Ts
MeCN, 80 °C, 4 h
(balloon)
then analysis with GCMS
2
45, 23%
46, 77%
b) Control experiment with TsNH2
O
Ts
N
Pd(OAc)2 (5 mol%)
+
CO
+
Ts NH2
H
MeCN, 80 °C, 12 h
O
(balloon)
O
O
1
46
No reaction
3
c) Control experiment with TsNCO
O
Ts
N
N
C O
1'
1
+
Ts
MeCN, 80 °C, 3 h
H
O
Figure 2 Highest occupied molecular orbitals (HOMO) for alkene 1′
and 1
1
45
with Pd(OAc)2 (5 mol%)/CO (balloon) 3, 93%
without Pd(OAc)2
3, 42%
d) Kinetic isotope effect (KIE) experiment
O
Then, several control experiments were performed to
understand the reaction mechanism (Scheme 4). First, pal-
ladium-catalyzed carbonylation of tosyl azide (2) with CO
occurred smoothly affording tosyl isocyanate (45), which
was quickly converted into tosyl amine (46) by reaction
with water during analysis by GC-MS (Scheme 4a). We then
tested carbonylation of DHP (1) with CO and tosyl amine
(46), and no reaction occurred (Scheme 4b). Reaction of
Ts
Ts
Ph
D
O
CO (balloon)
Ph
O
N
H
Pd(OAc)2 (5 mol%)
12
+
Ts N3
MeCN, 80 °C
2
D
D
O
D
D D
kH/kD = 2.7
D
Ph
O
Ph
O
N
H
D
D
12-d4
Scheme 4 Control experiments
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–K

F
Z.-Y. Gu et al.
Special Topic
Synthesis
be the most possible reaction intermediate in the amidation
of alkene with CO and azide. Next, Pd2(dba)3 can also cata-
lyze the reaction albeit the reaction is slower than that with
Pd(OAc)2 as catalyst, demonstrating the Pd(0) might be the
active catalyst (Table 1, entry 2). In addition, when per-
forming the kinetic isotope effect (KIE) experiment with
benzyloxyethene and benzyloxyethene-d5, the KIE value
(kH/kD) was determined as 2.7 (Scheme 4d). This result indi-
cates that the terminal alkenyl C–H cleavage might be in-
volved in the rate-determining step, which is consistent
with the DFT calculations.
Based on the DFT calculations and control experiments,
the plausible reaction pathway has been proposed in
Scheme 5. Initially, Pd(II) precatalyst is reduced to the ac-
tive Pd(0) catalyst in the presence of CO, which may be sta-
bilized by acetonitrile as the ligand. The organic azide un-
dergoes ligand exchange with CO coordinated Pd(0) catalyst
to form intermediate I. Subsequently, migratory insertion of
CO into the azide generates palladacycle species II. After re-
lease of N2, palladium coordinated isocyanate species III is
formed. Next, coordination of alkene substrate and regiose-
lective migratory insertion generates palladacycle IV. The
following -H elimination produces amidopalladium inter-
mediate V. Finally, reductive elimination leads to the alke-
nyl amide and regenerates the Pd(0) catalyst.
tion mechanism involving tandem Pd-catalyzed in situ gen-
eration of isocyanate intermediate and subsequent cycload-
dition and -H elimination processes. However, no reaction
occurred when simple aliphatic unactivated olefins, sty-
renes with electron-withdrawing groups, dienes and sim-
ple cycloalkenes were tested under our current conditions.
And further investigations of C–H amidation of unactivated
olefins are currently under study in our laboratory.
All intermolecular amidation reactions were carried out under atmo-
spheric pressure of CO in oven-dried Schlenk tube. TLC analyses were
done on glass 0.25 mm silica gel plates. Flash chromatography col-
umns were packed with 200–300 mesh silica gel in PE (bp 60–90 °C).
High-resolution MS analyses were performed on Thermo Fisher Sci-
entific LTQ FT Ultra with DART Positive Mode or Agilent 6530 Accu-
rate–Mass Q-TOF LC/MS with ESI mode. NMR spectra were recorded
on a 400 MHz for 1H NMR and 100 MHz for 13C NMR, using TMS as an
internal reference DMSO-d6 and CDCl3 as solvent. Chemical shift val-
ues for protons are reported in parts per million (ppm,  scale) down-
field from TMS and are referenced to residual proton of DMSO-d6 ( =
2.50) and residual proton ( = 7.26) in CDCl3. Multiplicities are indi-
cated by standard abbreviations. 13C NMR spectra were recorded at
100 MHz. Chemical shifts for carbons are reported in parts per mil-
lion (ppm,  scale) downfield from TMS and are referenced to the car-
bon resonance of DMSO-d6 ( = 40.00) and CDCl3 ( = 77.00). Materi-
als were purchased from Tokyo Chemical Industry Co., Aldrich Inc.,
Alfa Aesar, Adamas, or other commercial suppliers and used as re-
ceived, unless otherwise noted. Sulfonyl azides were purchased, if
commercially available, or prepared from sulfonyl chlorides and NaN3
according to the well-established methods.
O
Pd(OAc)2
R
R'
N
CO
H
R
N3
Ln(CO)Pd0
The experimental procedures for synthetic applications (Scheme 3)
and control experiments (Scheme 4) are described in the Supporting
Information.
CO
O
CO
PdLn
R
N
R'
N
N
N
V
I
PdHLn
R
Amide Products; General Procedure
To an oven-dried Schlenk tube (10 mL) was added the organic azide
(0.75 mmol), Pd(OAc)2 (5.6 mg, 5 mol%). The tube was purged and
backfilled with CO (3 cycles) from a balloon. Anhyd MeCN (3.0 mL)
was injected into the tube, and then alkene (0.5 mmol) was injected
into the tube. After stirring at 80 °C for 12 h under CO atmosphere
(balloon), the mixture was concentrated under reduced pressure. The
residue was purified by column chromatography (PE/EtOAc 3:1–1:1)
to give the desired product.
Pd
O
Ln
Pd
C
O
R
N
N
N
N
R'
Pd
Ln
R
II
IV
Ln
Pd
N
C
N2
O
R'
R
III
Scheme 5 Plausible reaction pathway
N-Tosyl-3,4-dihydro-2H-pyran-5-carboxamide (3)
Yield: 115.3 mg (82%); white solid; mp 241.3–243.1 °C.
1H NMR (400 MHz, CDCl3):  = 8.71 (s, 1 H), 7.97 (d, J = 8.4 Hz, 2 H),
7.53 (s, 1 H), 7.33 (d, J = 8.2 Hz, 2 H), 4.00 (t, J = 5.2 Hz, 2 H), 2.43 (s, 3
H), 2.19 (t, J = 6.0 Hz, 2 H), 1.83 (tt, J = 6.0, 6.0 Hz, 2 H).
13C NMR (75 MHz, CDCl3):  = 164.7, 155.5, 144.8, 135.8, 129.5, 128.4,
106.9, 66.7, 21.7, 20.7, 18.8.
In summary, we have developed an atom- and step-eco-
nomic palladium-catalyzed intermolecular C–H amidation
of olefins to produce alkenyl amides from an inexpensive
and abundant carbonyl source (CO) and organic azides. This
protocol provides a simple and practical strategy for the
straightforward synthesis of alkenyl amides with a range of
substrates. Remarkably, neither directing group on the
alkenes or additive is needed for the reaction. Dinitrogen
(N2) is generated as the only by-product. The mechanistic
studies and control experiments have revealed a novel reac-
HRMS (ESI): m/z calcd for C13H16NO4S [M + H]+: 282.0795; found:
282.0787.
2-Methoxy-N-tosyl-3,4-dihydro-2H-pyran-5-carboxamide (4)
Yield: 124.5 mg (80%); Yellow oil.
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–K

G
Z.-Y. Gu et al.
Special Topic
Synthesis
1H NMR (400 MHz, CDCl3):  = 8.49 (s, 1 H), 7.97 (d, J = 8.4 Hz, 2 H),
7.39 (s, 1 H), 7.33 (d, J = 8.0 Hz, 2 H), 4.98 (t, J = 2.9 Hz, 1 H), 3.43 (s, 3
H), 2.43 (s, 3 H), 2.27–2.15 (m, 2 H), 1.96–1.90 (m, 1 H), 1.75–1.67 (m,
1 H).
1H NMR (400 MHz, CDCl3):  = 9.09 (s, 1 H), 7.94 (d, J = 8.4 Hz, 2 H),
7.61 (d, J = 12.2 Hz, 1 H), 7.31 (d, J = 8.4 Hz, 2 H), 5.30 (d, J = 12.2 Hz, 1
H), 3.82 (t, J = 6.4 Hz, 2 H), 2.42 (s, 3 H), 1.65–1.58 (m, 2 H), 1.39–1.30
(m, 2 H), 0.88 (t, J = 7.4 Hz, 3 H).
13C NMR (101 MHz, CDCl3):  = 164.4, 152.1, 144.8, 135.8, 129.5,
13C NMR (101 MHz, CDCl3):  = 164.8, 164.4, 144.7, 136.0, 129.5,
128.5, 107.9, 98.8, 56.2, 25.1, 21.6, 15.1.
128.1, 96.1, 71.9, 30.8, 21.6, 18.8, 13.5.
HRMS (ESI): m/z calcd for C14H17NO5SNa [M + Na]+: 334.0720; found:
HRMS (ESI): m/z calcd for C14H19NO4SNa [M + Na]+: 320.0927; found:
334.0719.
320.0920.
(E)-3-Isobutoxy-N-tosylacrylamide (10)
2-[(Benzyloxy)methyl]-N-tosyl-3,4-dihydro-2H-pyran-5-carbox-
amide (5)
Yield: 77.3 mg (52%); white solid; mp 186.7–188.2 °C.
1H NMR (400 MHz, CDCl3):  = 7.94 (d, J = 8.0 Hz, 2 H), 7.61 (d, J = 12.4
Hz, 1 H), 7.32 (d, J = 8.0 Hz, 2 H), 5.31 (d, J = 12.0 Hz, 1 H), 3.59 (d, J =
6.4 Hz, 2 H), 2.41 (s, 3 H), 1.97–1.86 (m, 1 H), 0.90 (d, J = 6.8 Hz, 6 H).
13C NMR (101 MHz, CDCl3):  = 165.0, 164.5, 144.6, 136.0, 129.5,
128.1, 96.1, 78.3, 27.9, 21.6, 18.7.
Yield: 172.6 mg (86%); Yellow oil.
1H NMR (400 MHz, CDCl3):  = 8.85 (s, 1 H), 7.97 (d, J = 8.4 Hz, 2 H),
7.54 (s, 1 H), 7.33–7.26 (m, 7 H), 4.54 (d, J = 2.0 Hz, 2 H), 4.07–4.01 (m,
1 H), 3.58 (dd, J = 10.4, 6.0 Hz, 1 H), 3.53 (dd, J = 10.4, 6.0 Hz, 1 H), 2.42
(s, 3 H), 2.30–2.24 (m, 1 H), 2.20–2.11 (m, 1 H), 1.94–1.87 (m, 1 H),
1.69–1.59 (m, 1 H).
HRMS (ESI): m/z calcd for C14H19NO4SNa [M + Na]+: 320.0927; found:
320.0931.
13C NMR (101 MHz, CDCl3):  = 164.7, 154.9, 144.8, 137.5, 135.9,
129.5, 128.4, 127.8, 127.7, 107.0, 75.7, 73.4, 71.2, 22.7, 21.6, 18.5.
HRMS (ESI): m/z calcd for C21H24NO5S [M + H]+: 402.1370; found:
402.1358.
(E)-3-(Cyclohexyloxy)-N-tosylacrylamide (11)
Yield: 132.6 mg (82%); white solid; mp 242.2–243.4 °C.
1H NMR (400 MHz, CDCl3):  = 8.24 (s, 1 H), 7.94 (d, J = 8.4 Hz, 2 H),
7.58 (d, J = 12.0 Hz, 1 H), 7.32 (d, J = 8.0 Hz, 2 H), 5.32 (d, J = 12.0 Hz, 1
H), 3.90 (tt, J = 8.8, 3.8 Hz, 1 H), 2.43 (s, 3 H), 1.86–1.82 (m, 2 H), 1.72–
1.71 (m, 2 H), 1.48–1.40 (m, 2 H), 1.31–1.25 (m, 4 H).
13C NMR (101 MHz, CDCl3):  = 164.9, 163.6, 144.7, 136.1, 129.5,
128.2, 96.9, 82.1, 31.7, 25.0, 23.2, 21.6.
N-Tosyl-4,5-dihydrofuran-3-carboxamide (6)
Yield: 81.5 mg (61%); white solid; mp 227.6–228.8 °C.
1H NMR (400 MHz, CDCl3):  = 9.32 (s, 1 H), 7.96 (d, J = 7.2 Hz, 2 H),
7.39–7.33 (m, 3 H), 4.50 (t, J = 9.8 Hz, 2 H), 2.80 (t, J = 9.6 Hz, 2 H), 2.43
(s, 3 H).
13C NMR (101 MHz, CDCl3):  = 161.6, 157.8, 144.9, 135.8, 129.5,
128.3, 110.5, 73.3, 27.4, 21.6.
HRMS (ESI): m/z calcd for C16H21NO4SNa [M + Na]+: 346.1083; found:
346.1089.
HRMS (ESI): m/z calcd for C12H14NO4S [M + H]+: 268.0638; found:
268.0636.
(E)-3-(Benzyloxy)-N-tosylacrylamide (12)
Yield:116.0 mg (70%); white solid; mp 208.1–209.9 °C.
1H NMR (400 MHz, CDCl3):  = 7.92 (d, J = 8.4 Hz, 2 H), 7.68 (d, J = 12.0
Hz, 1 H), 7.36–7.27 (m, 7 H), 5.42 (d, J = 12.4 Hz, 1 H), 4.88 (s, 2 H),
2.42 (s, 3 H).
13C NMR (101 MHz, CDCl3):  = 164.6, 163.7, 144.8, 135.9, 134.7,
129.5, 128.7, 128.6, 128.1, 127.8, 97.3, 73.7, 21.6.
(E)-3-Ethoxy-N-tosylacrylamide (7)
Yield: 72.7 mg (54%); white solid; mp 214.5–216.3 °C.
1H NMR (400 MHz, CDCl3):  = 9.32 (s, 1 H), 7.93 (d, J = 8.0 Hz, 2 H),
7.61 (d, J = 12.2 Hz, 1 H), 7.29 (d, J = 8.4 Hz, 2 H), 5.34 (d, J = 12.2 Hz, 1
H), 3.87 (q, J = 7.2 Hz, 2 H), 2.40 (s, 3 H), 1.26 (t, J = 7.2 Hz, 3 H).
13C NMR (101 MHz, CDCl3):  = 165.0, 164.0, 144.6, 136.1, 129.4,
128.1, 96.4, 67.6, 21.5, 14.3.
HRMS (ESI): m/z calcd for C17H17NO4SNa [M + Na]+: 332.0951; found:
332.0957.
HRMS (ESI): m/z calcd for C12H16NO4S [M + H]+: 270.0795; found:
270.0785.
(E)-3-(2-Chloroethoxy)-N-tosylacrylamide (13)
Yield: 95.7 mg (63%); white solid; mp 192.7–193.9 °C.
1H NMR (400 MHz, CDCl3):  = 9.20 (s, 1 H), 7.92 (d, J = 8.4 Hz, 2 H),
7.62 (d, J = 12.4 Hz, 1 H), 7.32 (d, J = 8.2 Hz, 2 H), 5.40 (d, J = 12.0 Hz, 1
H), 4.09 (t, J = 5.6 Hz, 2 H), 3.67 (t, J = 6.0, 2 H), 2.42 (s, 3 H).
13C NMR (101 MHz, CDCl3):  = 164.5, 163.5, 145.0, 135.9, 129.7,
128.2, 97.5, 71.7, 41.5, 21.7.
(E)-3-Propoxy-N-tosylacrylamide (8)
Yield: 83.6 mg (59%); white solid; mp 199.5–200.9 °C.
1H NMR (400 MHz, CDCl3):  = 8.99 (s, 1 H), 7.94 (d, J = 8.4 Hz, 2 H),
7.62 (d, J = 12.4 Hz, 1 H), 7.32 (d, J = 8.0 Hz, 2 H), 5.32 (d, J = 12.0 Hz, 1
H), 3.78 (t, J = 6.4 Hz, 2 H), 2.42 (s, 3 H), 1.71–1.62 (m, 2 H), 0.91 (t, J =
7.4 Hz, 3 H).
HRMS (ESI): m/z calcd for C12H14ClNO4SNa [M + Na]+: 326.0224;
found: 326.0231.
13C NMR (101 MHz, CDCl3):  = 164.8, 164.4, 144.8, 136.0, 129.5,
128.1, 96.2, 73.6, 22.2, 21.6, 10.1.
HRMS (ESI): m/z calcd for C13H18NO4S [M + H]+: 284.0951; found:
284.0961.
(E)-3-Ethoxy-2-methyl-N-tosylacrylamide (14)
Yield: 107.7 mg (76%); colorless oil.
1H NMR (400 MHz, CDCl3):  = 9.00 (br s, 1 H), 7.96 (d, J = 8.4 Hz, 2 H),
7.34–7.30 (m, 3 H), 3.96 (q, J = 7.2 Hz, 2 H), 2.40 (s, 3 H), 1.67 (d, J = 1.2
Hz, 3 H), 1.22 (t, J = 7.2 Hz, 3 H).
(E)-3-Butoxy-N-tosylacrylamide (9)
Yield: 65.4 mg (44%); white solid; mp 191.3–193.5 °C.
13C NMR (101 MHz, CDCl3):  = 166.1, 157.7, 144.6, 136.0, 129.4,
128.2, 106.6, 70.2, 21.5, 15.1, 8.7.
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–K

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Z.-Y. Gu et al.
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Synthesis
HRMS (ESI): m/z calcd for C13H18NO4S [M + H]+: 284.0951; found:
(E)-3-[4-(4-Methylpiperazin-1-yl)phenyl]-N-tosylacrylamide (21)
284.0962.
Yield: 173.8 mg (87%); yellow solid; mp 294.7–295.5 °C.
1H NMR (400 MHz, DMSO-d6):  = 7.81 (d, J = 8.4 Hz, 2 H), 7.41–7.36
(m, 5 H), 6.94 (d, J = 8.4 Hz, 2 H), 6.35 (d, J = 15.6 Hz, 1 H), 3.30–3.28
(m, 4 H), 2.63–2.60 (m, 4 H), 2.37 (s, 3 H), 2.35 (s, 3 H).
13C NMR (101 MHz, DMSO-d6):  = 165.5, 152.3, 143.6, 143.0, 138.6,
129.9, 129.6, 127.9, 124.6, 116.9, 115.1, 54.3, 46.9, 45.4, 21.5.
(E)-3-Ethoxy-N-tosylbut-2-enamide (15)
Yield: 123.2 mg (87%); colorless oil. The stereochemistry of 15 was
confirmed by 2D NOESY analysis.
1H NMR (400 MHz, CDCl3):  = 9.03 (s, 1 H), 7.95 (d, J = 8.4 Hz, 2 H),
7.31 (d, J = 8.0 Hz, 2 H), 5.03 (s, 1 H), 3.72 (q, J = 7.0 Hz, 2 H), 2.42 (s, 3
H), 2.20 (s, 3 H), 1.25 (t, J = 7.0 Hz, 3 H).
HRMS (ESI): m/z calcd for C21H26N3O3S [M + H]+: 400.1689; found:
400.1693.
13C NMR (101 MHz, CDCl3):  = 174.8, 164.5, 144.5, 136.3, 129.5,
128.0, 90.9, 64.2, 21.6, 19.6, 14.0.
HRMS (ESI): m/z calcd for C13H18NO4S [M + H]+: 306.0770; found:
306.0771.
(E)-3-[4-(Dimethylamino)phenyl]-N-tosylbut-2-enamide (22)
Yield: 163.1 mg (91%); yellow solid; mp > 300 °C.
1H NMR (400 MHz, DMSO-d6):  = 11.78 (br s, 1 H), 7.84 (d, J = 8.0 Hz,
2 H), 7.43–7.38 (m, 4 H), 6.70 (d, J = 8.4 Hz, 2 H), 6.21 (s, 1 H), 2.93 (s,
6 H), 2.39 (s, 3 H), 2.37 (s, 3 H).
(E)-3-(Naphthalen-2-yloxy)-N-tosylacrylamide (16)
Yield: 86.3 mg (47%); white solid; mp 238.2–239.6 °C.
13C NMR (101 MHz, DMSO-d6):  = 164.6, 156.0, 151.7, 144.3, 137.5,
129.9, 128.0, 127.7, 127.7, 112.5, 112.1, 40.2, 21.5, 16.9.
HRMS (ESI): m/z calcd for C19H22N2O3SNa [M + Na]+: 367.1087; found:
367.1088.
1H NMR (400 MHz, CDCl3):  = 7.96–7.93 (m, 3 H), 7.81 (d, J = 8.4 Hz, 2
H), 7.74 (d, J = 8.0 Hz, 1 H), 7.51–7.43 (m, 2 H), 7.39 (d, J = 2.8 Hz, 1 H),
7.31 (d, J = 8.0 Hz, 2 H), 7.17 (dd, J = 8.8, 2.4 Hz, 1 H), 5.69 (d, J = 12 Hz,
1 H), 2.34 (s, 3 H).
13C NMR (101 MHz, CDCl3):  = 164.1, 160.4, 153.3, 145.0, 135.8,
133.8, 130.9, 130.3, 129.6, 128.3, 127.8, 127.4, 127.0, 125.6, 118.2,
113.5, 102.0, 21.7.
HRMS (ESI): m/z calcd for C20H18NO4S [M + H]+: 368.0951; found:
368.0962.
N-(Phenylsulfonyl)-3,4-dihydro-2H-pyran-5-carboxamide (23)
Yield: 97.6 mg (73%); white solid; mp 202.3–204.1 °C.
1H NMR (400 MHz, CDCl3):  = 8.91 (s, 1 H), 8.09 (d, J = 7.8 Hz, 2 H),
7.64–7.52 (m, 4 H), 3.99 (t, J = 5.2 Hz, 2 H), 2.19 (t, J = 6.4 Hz, 2 H),
1.84–1.81 (m, 2 H).
13C NMR (101 MHz, CDCl3):  = 164.9, 155.6, 138.9, 133.7, 128.8,
128.3, 106.9, 66.7, 20.7, 18.7.
HRMS (ESI): m/z calcd for C12H14NO4S [M + H]+: 268.0638; found:
268.0640.
(E)-3-[4-(Dimethylamino)phenyl]-N-tosylacrylamide (18)
Yield: 130.9 mg (76%); yellow solid; mp > 300 °C.
1H NMR (400 MHz, CDCl3):  = 7.99 (d, J = 8.4 Hz, 2 H), 7.61 (d, J = 15.2
Hz, 1 H), 7.36 (d, J = 8.8 Hz, 2 H), 7.32 (d, J = 8.0 Hz, 2 H), 6.62 (d, J = 9.2
Hz, 2 H), 6.19 (d, J = 15.6 Hz, 1 H), 3.01 (s, 6 H), 2.41 (s, 3 H).
N-[(4-Methoxyphenyl)sulfonyl]-3,4-dihydro-2H-pyran-5-carbox-
amide (24)
The other spectral and analytical data are in accordance with the lit-
erature.1
Yield: 121.9 mg (82%); white solid; mp 238.9–240.1 °C.
1H NMR (400 MHz, CDCl3):  = 8.70 (s, 1 H), 8.02 (d, J = 8.6 Hz, 2 H),
7.53 (s, 1 H), 6.99 (d, J = 8.4 Hz, 2 H), 4.00 (t, J = 4.8 Hz, 2 H), 3.86 (s, 3
H), 2.19 (t, J = 6.0 Hz, 2 H), 1.86–1.81 (m, 2 H).
13C NMR (101 MHz, CDCl3):  = 164.8, 163.7, 155.4, 130.7, 130.2,
114.0, 106.9, 66.7, 55.6, 20.7, 18.8.
(E)-3-[4-(Diethylamino)phenyl]-N-tosylacrylamide (19)
Yield: 147.1 mg (79%); yellow solid; mp > 300 °C.
1H NMR (400 MHz, CDCl3):  = 8.63 (br s, 1 H), 8.00 (d, J = 8.4 Hz, 2 H),
7.60 (d, J = 15.6 Hz, 1 H), 7.35–7.30 (m, 4 H), 6.58 (d, J = 8.8 Hz, 2 H),
6.18 (d, J = 15.2 Hz, 1 H), 3.37 (q, J = 7.2 Hz, 4 H), 2.41 (s, 3 H), 1.17 (t,
J = 7.2 Hz, 6 H).
HRMS (ESI): m/z calcd for C13H16NO5S [M + H]+: 298.0744; found:
298.0753.
13C NMR (101 MHz, CDCl3):  = 164.1, 149.9, 146.7, 144.7, 136.2,
130.7, 129.5, 128.3, 120.7, 111.2, 110.5, 44.5, 21.6, 12.5.
HRMS (ESI): m/z calcd for C20H24N2O3SNa [M + Na]+: 395.1400; found:
395.1403.
N-(Mesitylsulfonyl)-3,4-dihydro-2H-pyran-5-carboxamide (25)
Yield: 125.3 mg (81%); white solid; mp 268.6–269.3 °C.
1H NMR (400 MHz, CDCl3):  = 8.85 (s, 1 H), 7.53 (s, 1 H), 6.97 (s, 2 H),
4.02 (t, J = 5.2 Hz, 2 H), 2.72 (s, 6 H), 2.29 (s, 3 H), 2.20 (t, J = 6.0 Hz, 2
H), 1.88–1.83 (m, 2 H).
13C NMR (101 MHz, CDCl3):  = 165.3, 155.2, 143.4, 140.3, 132.7,
132.0, 106.9, 66.6, 22.8, 21.0, 20.8, 18.9.
(E)-3-(4-Morpholinophenyl)-N-tosylacrylamide (20)
Yield: 160.4 mg (83%); yellow solid; mp > 300 °C.
1H NMR (400 MHz, DMSO-d6):  = 11.99 (br s, 1 H), 7.85 (d, J = 8.4 Hz,
2 H), 7.47–7.41 (m, 5 H), 6.95 (d, J = 8.8 Hz, 2 H), 6.38 (d, J = 15.6 Hz, 1
H), 3.72–3.70 (m, 4 H), 3.22–3.19 (m, 4 H), 2.39 (s, 3 H).
HRMS (ESI): m/z calcd for C15H19NO4SNa [M + Na]+: 332.0927; found:
332.0939.
13C NMR (101 MHz, DMSO-d6):  = 164.2, 153.0, 144.6, 144.5, 137.2,
130.1, 130.0, 128.1, 124.3, 114.69, 114.66, 66.3, 47.6, 21.5.
HRMS (ESI): m/z calcd for C20H23N2O4S [M + H]+: 387.1373; found:
387.1373.
N-{[4-(Trifluoromethyl)phenyl]sulfonyl}-3,4-dihydro-2H-pyran-
5-carboxamide (26)
Yield: 145.7 mg (82%); white solid; mp 254.4–255.8 °C.
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–K

I
Z.-Y. Gu et al.
Special Topic
Synthesis
1H NMR (400 MHz, CDCl3):  = 8.77 (s, 1 H), 8.23 (d, J = 8.4 Hz, 2 H),
7.81 (d, J = 8.0 Hz, 2 H), 7.56 (s, 1 H), 4.03 (t, J = 5.2 Hz, 2 H), 2.20 (t, J =
6.4 Hz, 2 H), 1.89–1.83 (m, 2 H).
N-(Naphthalen-2-ylsulfonyl)-3,4-dihydro-2H-pyran-5-carboxam-
ide (31)
Yield: 127.0 mg (80%); white solid; mp 298.5–299.9 °C.
13C NMR (101 MHz, CDCl3):  = 164.9, 156.0, 142.4, 135.3 (q, J = 32.7
Hz), 129.0, 126.0 (q, J = 3.5 Hz), 123.1 (q, J = 271.6 Hz), 106.8, 66.8,
20.7, 18.8.
1H NMR (400 MHz, DMSO-d6):  = 11.68 (s, 1 H), 8.60 (d, J = 2.0 Hz, 1
H), 8.21 (d, J = 8.0 Hz, 1 H), 8.13 (d, J = 8.8 Hz, 1 H), 8.04 (d, J = 8.0 Hz,
1 H), 7.91 (dd, J = 8.8, 2.0 Hz, 1 H), 7.75–7.66 (m, 3 H), 3.97 (t, J = 4.8
Hz, 2 H), 2.01 (t, J = 6.4 Hz, 2 H), 1.73–1.67 (m, 2 H).
HRMS (ESI): m/z calcd for C13H13F3NO4S [M + H]+: 336.0512; found:
13C NMR (101 MHz, DMSO-d6):  = 166.0, 155.8, 137.6, 135.0, 131.9,
336.0502.
129.9, 129.7, 129.6, 128.3, 128.2, 123.1, 108.3, 66.8, 20.9, 18.8.
N-[(4-Fluorophenyl)sulfonyl]-3,4-dihydro-2H-pyran-5-carboxam-
ide (27)
HRMS (ESI): m/z calcd for C16H15NO4SNa [M + Na]+: 340.0614; found:
340.0613.
Yield: 101.3 mg (71%); white solid; mp 208.9–210.3 °C.
1H NMR (400 MHz, CDCl3):  = 8.61 (s, 1 H), 8.14–8.09 (m, 2 H), 7.53
(s, 1 H), 7.24–7.18 (m, 2 H), 4.02 (t, J = 5.2 Hz, 2 H), 2.19 (t, J = 6.4 Hz, 2
H), 1.86 (tt, J = 10.8, 5.2 Hz, 2 H).
N-(Thiophen-2-ylsulfonyl)-3,4-dihydro-2H-pyran-5-carboxamide
(32)
Yield: 88.8 mg (65%); white solid; mp 182.7–183.3 °C.
13C NMR (101 MHz, CDCl3):  = 165.7 (d, J = 255.1 Hz), 164.7, 155.7,
134.7 (d, J = 3.3 Hz), 131.4 (d, J = 9.7 Hz), 116.2 (d, J = 22.9 Hz), 106.8,
66.8, 20.7, 18.8.
1H NMR (400 MHz, CDCl3):  = 8.80 (s, 1 H), 7.91 (dd, J = 4.0, 1.2 Hz, 1
H), 7.67 (dd, J = 4.8, 1.2 Hz, 1 H), 7.57 (s, 1 H), 7.10 (dd, J = 4.8, 4.0 Hz,
1 H), 4.03 (t, J = 4.8 Hz, 2 H), 2.22 (t, J = 6.0 Hz, 2 H), 1.89–1.84 (m, 2
H).
HRMS (ESI): m/z calcd for C12H13FNO4S [M + H]+: 286.0544; found:
13C NMR (101 MHz, CDCl3):  = 164.8, 155.7, 139.1, 135.0, 133.7,
286.0547.
127.3, 106.9, 66.8, 20.7, 18.8.
N-[(4-Chlorophenyl)sulfonyl]-3,4-dihydro-2H-pyran-5-carboxam-
ide (28)
HRMS (ESI): m/z calcd for C10H12NO4S2 [M + H]+: 274.0202; found:
274.0207.
Yield: 113.1 mg (75%); white solid; mp 295.6–297.1 °C.
1H NMR (400 MHz, DMSO-d6):  = 11.67 (br s, 1 H), 7.92 (d, J = 8.6 Hz,
2 H), 7.68 (d, J = 8.8 Hz, 3 H), 3.98 (t, J = 5.2 Hz, 2 H), 2.03 (t, J = 6.4 Hz,
2 H), 1.75–1.69 (m, 2 H).
13C NMR (101 MHz, DMSO-d6):  = 166.0, 156.0, 139.4, 138.7, 130.1,
129.7, 108.2, 66.9, 20.9, 18.8.
N-(Benzylsulfonyl)-3,4-dihydro-2H-pyran-5-carboxamide (33)
Yield: 116.7 mg (83%); white solid; mp 183.7–184.5 °C.
1H NMR (400 MHz, CDCl3):  = 7.97 (s, 1 H), 7.51 (s, 1 H), 7.38–7.26
(m, 5 H), 4.65 (s, 2 H), 4.10–4.03 (t, J = 5.2 Hz, 2 H), 2.18 (t, J = 6.4 Hz, 2
H), 1.90–1.85 (m, 2 H).
13C NMR (101 MHz, CDCl3):  = 166.0, 155.9, 130.7, 129.1, 128.8,
128.1, 106.8, 66.8, 59.0, 20.7, 18.7.
HRMS (ESI): m/z calcd for C12H12ClNO4SNa [M + Na]+: 324.0068;
found: 324.0078.
HRMS (ESI): m/z calcd for C13H16NO4S [M + H]+: 282.0795; found:
282.0801.
N-[(4-Bromophenyl)sulfonyl]-3,4-dihydro-2H-pyran-5-carboxam-
ide (29)
Yield: 143.7 mg (83%); white solid; mp 192.1–194.1 °C.
N-(Propylsulfonyl)-3,4-dihydro-2H-pyran-5-carboxamide (34)
1H NMR (400 MHz, DMSO-d6):  = 11.68 (s, 1 H), 7.86–7.81 (m, 4 H),
7.67 (s, 1 H), 3.98 (t, J = 4.8 Hz, 2 H), 2.03 (t, J = 6.0 Hz, 2 H), 1.75–1.69
(m, 2 H).
13C NMR (101 MHz, DMSO-d6):  = 166.0, 156.0, 139.9, 132.6, 130.1,
127.7, 108.2, 66.8, 20.9, 18.8.
Yield: 75.8 mg (65%); white solid; mp 184.4–186.1 °C.
1H NMR (400 MHz, CDCl3):  = 8.60 (br s, 1 H), 7.58 (s, 1 H), 4.05 (t, J =
5.2 Hz, 2 H), 3.48–3.44 (m, 2 H), 2.24 (t, J = 6.0 Hz, 2 H), 1.91–1.81 (m,
4 H), 1.04 (t, J = 7.6 Hz, 3 H).
13C NMR (101 MHz, CDCl3):  = 166.0, 155.8, 107.0, 66.7, 55.2, 20.7,
18.7, 16.9, 12.6.
HRMS (ESI): m/z calcd for C12H12BrNO4SNa [M + Na]+: 367.9563;
found: 367.9560.
HRMS (ESI): m/z calcd for C9H16NO4S [M + H]+: 234.0795; found:
234.0805.
N-(Naphthalen-1-ylsulfonyl)-3,4-dihydro-2H-pyran-5-carboxam-
ide (30)
N-(Butylsulfonyl)-3,4-dihydro-2H-pyran-5-carboxamide (35)
Yield: 82.5 mg (52%); white solid; mp > 300 °C.
Yield: 86.6 mg (70%); white solid; mp 197.1–199.4 °C.
1H NMR (400 MHz, DMSO-d6):  = 11.92 (s, 1 H), 8.69 (d, J = 8.6 Hz, 1
H), 8.34 (d, J = 7.6 Hz, 1 H), 8.28 (d, J = 8.4 Hz, 1 H), 8.11 (d, J = 8.0 Hz,
1 H), 7.80–7.65 (m, 4 H), 3.95 (t, J = 4.8 Hz, 2 H), 1.97 (t, J = 6.0 Hz, 2
H), 1.70–1.64 (m, 2 H).
13C NMR (101 MHz, DMSO-d6):  = 165.7, 155.6, 135.2, 135.1, 134.1,
131.6, 129.7, 128.7, 127.9, 127.3, 125.0, 124.3, 108.2, 66.7, 20.8, 18.8.
1H NMR (400 MHz, CDCl3):  = 8.55 (br s, 1 H), 7.59 (s, 1 H), 4.06 (t, J =
5.2 Hz, 2 H), 3.51–3.47 (m, 2 H), 2.25 (t, J = 6.4 Hz, 2 H), 1.92–1.86 (m,
2 H), 1.82–1.74 (m, 2 H), 1.49–1.40 (m, 2 H), 0.93 (t, J = 7.2 Hz, 3 H).
13C NMR (101 MHz, CDCl3):  = 165.9, 155.8, 107.0, 66.8, 53.3, 25.1,
21.2, 20.7, 18.8, 13.5.
HRMS (ESI): m/z calcd for C10H18NO4S [M + H]+: 248.0951; found:
248.0954.
HRMS (ESI): m/z calcd for C16H15NO4SNa [M + Na]+: 340.0614; found:
340.0605.
N-(Isopropylsulfonyl)-3,4-dihydro-2H-pyran-5-carboxamide (36)
Yield: 88.6 mg (76%); white solid; mp 189.7–191.4 °C.
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–K

J
Z.-Y. Gu et al.
Special Topic
Synthesis
1H NMR (400 MHz, CDCl3):  = 8.51 (br s, 1 H), 7.59 (s, 1 H), 4.05 (t, J =
5.2 Hz, 2 H), 3.97–3.90 (hept, J = 7.2 Hz, 1 H), 2.25 (t, J = 6.0 Hz, 2 H),
1.92–1.86 (m, 2 H), 1.39 (d, J = 6.8 Hz, 6 H).
13C NMR (101 MHz, CDCl3):  = 165.9, 155.7, 107.1, 66.7, 53.9, 20.7,
18.8, 15.9.
1H NMR (400 MHz, CDCl3):  = 8.88 (br s, 1 H), 8.12 (d, J = 2.8 Hz, 1 H),
8.01 (d, J = 8.0 Hz, 2 H), 7.88–7.84 (m, 1 H), 7.56 (s, 1 H), 7.39 (d, J = 8.0
Hz, 2 H), 7.37–7.34 (m, 1 H), 6.86 (d, J = 8.8 Hz, 1 H), 4.01 (t, J = 5.2 Hz,
2 H), 3.77–3.72 (m, 5 H), 3.00 (t, J = 7.2 Hz, 2 H), 2.18 (t, J = 6.4 Hz, 2
H), 1.87–1.81 (m, 2 H).
13C NMR (101 MHz, CDCl3):  = 165.1, 164.2, 155.9, 155.5, 145.6,
137.4, 132.4, 131.7, 129.3, 128.6, 126.5, 122.4, 112.9, 107.2, 66.7, 56.2,
40.5, 35.5, 20.7, 18.7.
HRMS (ESI): m/z calcd for C9H16NO4S [M + H]+: 234.0795; found:
234.0802.
HRMS (ESI): m/z calcd for C22H23ClN2O6SNa [M + Na]+: 501.0858;
found: 501.0847.
N-[(1-Allylcyclopropyl)sulfonyl]-3,4-dihydro-2H-pyran-5-carbox-
amide (37)
Yield: 59.7 mg (44%); white solid; mp 210.2–211.5 °C.
1H NMR (400 MHz, CDCl3):  = 7.98 (br s, 1 H), 7.57 (s, 1 H), 5.73 (ddt,
J = 17.2, 10.0, 7.2 Hz, 1 H), 5.17–5.08 (m, 2 H), 4.08 (t, J = 5.2 Hz, 2 H),
2.65 (d, J = 6.8 Hz, 2 H), 2.26 (t, J = 6.4 Hz, 2 H), 1.95–1.89 (m, 2 H),
1.74–1.70 (m, 2 H), 1.01–0.97 (m, 2 H).
Conflict of Interest
The authors declare no conflict of interest.
13C NMR (101 MHz, CDCl3):  = 164.6, 155.4, 132.8, 118.9, 107.1, 66.7,
40.0, 35.3, 20.8, 19.1, 11.7.
Funding Information
HRMS (ESI): m/z calcd for C12H18NO4S [M + H]+: 272.0951; found:
272.0946.
We acknowledge financial support from NSFC (21772208, 22001226,
21633013), Natural Science Foundation of Jiangsu Province
(BK20201183), Key Research Program of Frontier Sciences of CAS
(QYZDJSSW-SLH051), The Natural Science Foundation of the Jiangsu
Higher Education Institutions of China (20KJB150016), and Funding
for School-Level Research Projects of Yancheng Institute of Technolo-
(2S,3R,4S)-3,4-Di(benzyloxy)-2-[(benzyloxy)methyl]-N-tosyl-3,4-
dihydro-2H-pyran-5-carboxamide (38)
Yield: 205.6 mg (67%); colorless oil.
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1H NMR (400 MHz, CDCl3):  = 8.91 (s, 1 H), 7.84 (d, J = 8.4 Hz, 2 H),
7.55 (s, 1 H), 7.39–7.24 (m, 17 H), 4.66 (s, 2 H), 4.57–4.44 (m, 5 H),
4.32 (d, J = 4.0 Hz, 1 H), 4.09 (t, J = 4.4 Hz, 1 H), 3.75–3.65 (m, 2 H),
2.41 (s, 3 H).
Supporting Information
13C NMR (101 MHz, CDCl3):  = 163.7, 156.6, 144.6, 137.4, 137.0,
136.1, 135.9, 129.3, 128.9, 128.6, 128.5, 128.43, 128.39, 128.37, 128.2,
127.9, 127.7, 105.8, 77.0, 73.4, 72.2, 70.8, 70.5, 70.0, 67.0, 21.6.
Supporting information for this article is available online at
https://doi.org/10.1055/a-1401-4486. Su
p
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ortingInformationS
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HRMS (ESI): m/z calcd for C35H36NO7S [M + H]+: 614.2207; found:
614.2214.
References
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(E)-3-({(3S,8S,9S,10R,13R,14S,17R)-17-[(2R,5S,E)-5-Ethyl-6-methyl-
hept-3-en-2-yl]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-
tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl}oxy)-N-tosyl-
acrylamide (39)
Yield: 67.4 mg (53%), with 0.2 mmol alkene substrate; colorless oil.
1H NMR (400 MHz, CDCl3):  = 7.94 (d, J = 8.4 Hz, 2 H), 7.57 (d, J = 11.6
Hz, 1 H), 7.31 (d, J = 8.0 Hz, 2 H), 5.36–5.33 (m, 2 H), 5.15 (dd, J = 15.2,
8.4 Hz, 1 H), 5.02 (dd, J = 15.2, 8.4 Hz, 1 H), 3.79–3.71 (m, 1 H), 2.42 (s,
3 H), 2.31 (d, J = 7.6 Hz, 2 H), 2.07–1.84 (m, 6 H), 1.61–1.42 (m, 11 H),
1.28–1.13 (m, 6 H), 1.02 (d, J = 6.8 Hz, 3 H), 0.98 (s, 3 H), 0.85–0.79 (m,
9 H), 0.69 (s, 3 H).
13C NMR (101 MHz, CDCl3):  = 164.9, 163.3, 144.6, 138.9, 138.2,
136.3, 129.5, 129.3, 128.2, 123.2, 97.3, 83.4, 56.8, 55.9, 51.2, 50.0,
42.2, 40.4, 39.6, 38.5, 36.7, 36.5, 31.8, 28.8, 28.1, 25.4, 24.3, 21.6, 21.2,
21.0, 19.2, 19.0, 12.2, 12.0.
HRMS (ESI): m/z calcd for C39H58NO4S [M + H]+: 636.4081; found:
636.4080.
N-({4-[2-(5-Chloro-2-methoxybenzamido)ethyl]phenyl}sulfonyl)-
3,4-dihydro-2H-pyran-5-carboxamide (44)
Yield: 186.8 mg (78%); white powder; mp 190.5–192.1 °C.
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–K

K
Z.-Y. Gu et al.
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Synthesis
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(22) The transition state leading to the formation of -lactam inter-
mediate is located as TS3c′, which is much higher in energy
than the pathway via TS3a′ (Figure 1).
(23) After the formation of the isocyanate intermediate, a possible
Pd(II)-catalyzed pathway to afford the final product is also con-
sidered (Figure S2 in Supporting Information). The main mech-
anistic difference for Pd(II)-catalyzed pathway is that the
acetate ligand could serve as a proton shuttle to assist the H-
migration to yield the final product.
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