Cobalt-Catalyzed Secondary Alkylation of Arenes and Olefins with Alkyl Ethers through the Cleavage of C(sp2)-H and C(sp3)-O Bonds

Article abstract of DOI:10.1021/acs.joc.8b02197

A novel cobalt-catalyzed C-H alkylation of arenes and olefins is achieved with (pyridin-2-yl)isopropyl amine as an N,N-bidentate directing group. Different linear, branched, and cyclic alkyl ethers were used as practical secondary alkylating reagents through cleavage of C(sp³)-O bond, providing an efficient approach to the synthesis of verstile o-alkylated arylamides and tetrasubstituted acrylamides. Mechanistic studies indicate that cleavage of the inert C(sp³)-O bond involves a cobalt-promoted radical process and that cleavage of the inert C(sp²)-H bond by a cobalt catalyst is a rate-limiting step.

Full text of DOI:10.1021/acs.joc.8b02197

Subscriber access provided by UNIV OF CAMBRIDGE
Article
Cobalt-Catalyzed Secondary Alkylation of Arenes and Olefins with
Alkyl Ethers through Cleavage of C(sp2)–H and C(sp3)–O Bonds
Xunqing Dong, Qun Li, Guigen Li, and Hongjian Lu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02197 • Publication Date (Web): 12 Oct 2018
Downloaded from http://pubs.acs.org on October 12, 2018
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 40
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Cobalt-Catalyzed Secondary Alkylation of Arenes and
Olefins with Alkyl Ethers through Cleavage of C(sp2)–H
and C(sp3)–O Bonds
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
Xunqing Dong, † Qun Li, † Guigen Li*,†,‡ and Hongjian Lu*,†
†Institute of Chemistry and BioMedical Sciences, School of Chemistry and Chemical
Engineering, Nanjing University, Nanjing, 210093, China
‡Department of Chemistry and Biochemistry, Texas Tech University, Lubbock,
TX 79409-1061, USA
cat. Co(acac)2
H
+
O
DTBP
PIP
CONH
PIP
CONH
C(sp2) C(sp3)
stable, ready available
secondary alkylating reagent
PIP = (pyridin-2-yl)
isopropyl
ABSTRACT: A novel cobalt-catalyzed C−H alkylation of arenes and olefins is
achieved with (pyridin-2-yl)isopropyl amine as a N,N-bidentate directing group.
Different linear, branched and cyclic alkyl ethers were used as practical secondary
alkylating reagents through cleavage of C(sp3)−O bond, providing an efficient
approach to the synthesis of verstile o-alkylated arylamides and tetrasubstituted
acrylamides. Mechanistic studies indicate that cleavage of the inert C(sp3)−O bond
involves a cobalt-promoted radical process and that cleavage of the inert C(sp2)−H
bond by a cobalt catalyst is a rate-limiting step.
Introduction
By avoiding the pre-functionalization of starting materials, transition metal
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 40
1
2
3
4
5
6
7
8
9
catalyzed C–H functionalization can be performed in a step- and atom-economic
manner, and this has attracted attention in organic synthesis.1 The alkylation
reaction of C(sp2)–H bond provides an efficient strategy for the construction of
C(sp2)–C(sp3) bonds.1,2 The most commonly encountered alkylating reagents
include nucleophilic organometallic reagents3 and electrophilic alkyl halides.4
These reagents have some disadvantages, such as the requirement of
pre-preparation, environmental unfriendliness, propensity for β-H elimination,
instability and high reactivity. To avoid these disadvantages, other alkylating
reagents have been developed. For example, the olefins have emerged as
efficient alkylating reagents.2b,5 However, it is generally necessary to use noble
metal catalysts or ligands to control the reactivity and the regioselectivity.
Alcohols and alkanes have been also promoted as green alkylating reagents.
Alcohols have a limited substance scope, require noble metal catalysts and have
been used infrequently.6 Alkanes have site-selective issues and low
regioselectivity were achieved in linear alkanes in most cases.7 Thus, cheap and
stable alkylating reagents with good site-selectivity still await development in
catalytic C–H alkylation reactions.
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
Alkyl ethers, common in industry and nature, are readily accessible chemicals
and often used as solvents in organic reactions. Thus, it is of interest to use alkyl
ethers as alkylating reagents formed by the cleavage of inert C(sp3)–O bonds.8
ACS Paragon Plus Environment

Page 3 of 40
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
But the C(sp3)–O bonds are extremely unreactive chemical bonds and are very
stable under basic and reductive conditions. Nevertheless, transition
metal-catalyzed cross-coupling reactions involving cleavage of C–O bonds have
potential utility and have seen remarkable progress.9 In most cases, aryl or
benzyl(allyl) ethers were used as aryl or benzyl(allyl) coupling partners, and
reactive organometallic reagents, such as organoboron, organozinc or Grignard
reagents, have to be used as a second coupling partner due to the low reactivity
of C–O bonds. Only a few examples have been provided in which unactivated
alkyl ethers have been used as alkyl coupling partners in reactions involving the
cleavage of C(sp3)–O bonds.10 Kakiuchi and Kochi have reported pioneering
work involving Ru-catalyzed C(sp2)–C(sp3) coupling of alkyl ethers with
triarylboroxines,10d and Shi has developed an Fe-promoted C(sp3)–C(sp3)
coupling of alkyl ethers with Grignard reagents10e (Scheme 1A). The substrate
scope of alkyl ethers in both cases is limited to 2-methoxyethyl aryl derivatives.
Thus, use of chemically stable and convenient counterparts, such as C(sp2)–H
bonds instead of organometallic reagents to couple with common alkyl ethers
would contribute significantly to the development of catalytic C(sp2)–C(sp3)
bond-forming methods. In this paper, we report a cobalt-catalyzed alkylation of
arylamides and acrylamides via inert C(sp2)–H and C(sp3)–O bond cleavages, in
which large excess amount of secondary alkyl ethers were used as alkylating
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 40
1
2
3
4
5
reagents (Scheme 1B).11
6
7
8
Scheme 1. Metal-catalyzed C–C formation using alkyl ethers as alkylating
9
reagents by cleavage of C(sp3)–O bonds
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
10d
and Shi10e
)
A
) Coupling reactions (Kakiuchi and Kochi,
[Ru]10d
120 0C
(Ar' BO)3
1Ar (CH2)2Ar
C(sp2) M partner
C(sp2) C(sp3) formation
MeO (CH2)2Ar
+
[Fe]10e
120 0C
MgCl
C(sp3) M partner
Alkyl
Alkyl (CH2)2Ar
C(sp3) C(sp3) formation
limited
1 alkylating reagent
2
B
This work
)
) Direct C(sp )-H alkylation (
[Co]
H
+
O
oxidant
DG
C(sp2) H partner
DG
(20 equiv or solvent)
2 alkylating reagent
C(sp2) C(sp3) formation
Results and Discussion
Cobalt-catalyzed C−H alkylation has met with remarkable success on account
of its economy, low toxicity and interesting reaction modes.12 Inspired by our
recent work on cobalt-catalyzed C−H bond functionalization,13,14 our study began
with the reaction between o-methylbenzamide 1a with (pyridin-2-yl)isopropyl (PIP)
amine as the bidentate directing group15 and isopropyl ether 2a as an alkylating
reagent to identify cobalt catalysts under oxidative conditions (Table 1). Both the
counteranion of the cobalt salt (entries 1-7) and oxidants (entries 8-10) play a
crucial role, and the valence state of cobalt complex has no influence on the
reaction (entries 3-4). After screening the solvents and temperatures (entries
ACS Paragon Plus Environment

Page 5 of 40
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
11-18), the optimal conditions were achieved with commercially available
Co(acac)2 and DTBP as catalyst and oxidant respectively (entry 3). Reducing the
catalyst loading, the yield of 3aa was decreased slightly (entries 19 and 20).
When the reaction was performed in 5.0 mmol scale, 3aa was still obtained in
78% isolated yield (entry 21). When 8-quinolinylbenzamide was used as
substrate, the reaction was complicated and few desired products (less than 10%)
could be observed.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 1. Optimization of Reaction Conditionsa
cat. [Co], peroxide
24 h, N2
H
+
PIP =
O
N
Me
Me
PIP
PIP
CONH
CONH
1a
2a
3aa
temp. (oC)
entry
cat.[Co]
peroxide
solvent
3aa yield (%)b
140
140
140
140
140
140
140
140
140
140
140
140
140
140
120
1
2
Co(OAc)2∙4H2O
CoCl2
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DCP
0
9
87c
Benzene
Benzene
Benzene
Benzene
Benzene
Benzene
Benzene
Benzene
Benzene
3
Co(acac)2
Co(acac)3
CoF3
4
85
5
trace
trace
0
6
Co(Cp*)(CO)I2
Co(TPP)Cl
Co(acac)2
Co(acac)2
Co(acac)2
Co(acac)2
Co(acac)2
Co(acac)2
Co(acac)2
Co(acac)2
7
8
42
9
DBHP
TBHP
DCP
6
10
11
12
13
14
16
trace
23
Benzene
PhCF3
DTBP
DTBP
DTBP
DTBP
t-BuPh
PhCl
66
55
PhCF3
Benzene
56
63
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 40
1
2
3
4
5
6
17
18
Co(acac)2
Co(acac)2
DTBP
DTBP
Benzene
Benzene
100
160
32
54
7
8
9
d
e
19
20
21f
Co(acac)2
Co(acac)2
DTBP
DTBP
DTBP
Benzene
Benzene
Benzene
140
140
140
84
69
78c
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
Co(acac)2
a
Reaction Conditions: 1a (0.2 mmol), 2a (4.0 mmol), [Co] (20 mol %), peroxide
b
1
(0.8 mmol), solvent (1.0 mL), N2, 24 h. Crude H NMR yield determined by
using CH2Br2 as an internal standard. c Isolated yield. d [Co] (10 mol %). e [Co] (5
f
mol %). 1a (5.0 mmol), 2a (75.0 mmol), Co(acac)2 (10 mol %), DTBP (15.0
mmol), benzene (25 mL), N2, 140 oC, 24 h.
Scheme 2. The scope of arylamidesa
ACS Paragon Plus Environment

Page 7 of 40
The Journal of Organic Chemistry
1
2
3
4
5
Standard
conditions
Ar/
Het
Ar/
Het
H
O
+
3
isolated
6
7
8
9
PIP
CONH
yield
PIP
CONH
1
Me
F
2a
3aa
87%
3ba
89%
3ca
52%
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
F3C
MeO
PIP
PIP
PIP
PIP
PIP
CONH
CONH
CONH
CONH
CONH
3da
73%
3ea
53%
3fa
88%
Cl
Br
PIP
CONH
CONH
3ha(mono)
58%
3ha(di)
MeO2C
F3C
3ga
72%
3ia
74%
PIP
PIP
CONH
PIP
CONH
21%
F
Cl
NC
3la(mono)
22%
3la(di)
3ja
74%
3ka
73%
52%
PIP
PIP
CONH
PIP
CONH
CONH
Me
Me
F
O
3ma
56%
PIP
3na
69%
3oa
41%
O
CONH
F
PIP
PIP
CONH
CONH
F
Cl
Cl
3pa
81%
3qa
71%
3ra
42%
S
PIP
CONH
Me
Me
PIP
CONH
PIP
CONH
a
Standard conditions: 1 (0.2 mmol), 2 (4.0 mmol), Co(acac)2 (20 mol %), DTBP
(0.8 mmol), benzene (1.0 mL), N2, 140 oC, 24 h.
Investigation of the scope of arylamides gave the results shown in Scheme 2. Both
electron-donating groups such as Me and OMe, and electron-withdrawing groups
such as CF3, F, Cl and Br in the o-position of benzamides were tolerated,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 40
1
2
3
4
5
6
7
8
9
producing the mono-alkylated products 3aa-fa in moderate to high yield. Due to
the electron density and steric effects, substituents in the m-position of
benzamides are able to control the reactivity and selectivity of substrates.16 When
there is CF3 group in the m-position, mono C−H alkylation takes place selectively
at the less-hindered position (3ga). Mixtures of the major mono-alkylated and the
minor di-alkylated compounds were produced when the m-position was
substituted by a CO2Me group (3ha). Benzamide or p-substituted benzamides
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
provided di-alkylated products
(3ia-ka), while p-cyanobenzamide gives a
mixture of mono- and di-alkylated compounds, the latter being predominant (3la).
Tetrasubstituted benzamides were obtained when trisubstituted substrates were
used (3ma-oa). When the halogen group was in the o-position relative to the
reaction site, the reaction still proceeded well (3pa-qa), showing that the
efficiency of the reaction is not influenced significantly by steric hindrance.
Heteroarylamides such as 5-chlorothiophene-1-carboxamide are also tolerated
(3ra).
Scheme 3. The scope of alkyl ethers
ACS Paragon Plus Environment

Page 9 of 40
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
Standard
Conditions
H
+
O
R
Me
Me
PIP
CONH
PIP
12
CONH
3
1a
2
isolated yield
9
cyclic alkyl ethers
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
3ad
66%b
3ab
68%a
3ac
80%a
6
7
non-cyclic alkyl ethers
3ae
3af
65%c
3ag
53%c
78%a (84%c)
3ah
48%c
3ai
60%a (79%c)
3aj
3ak
74%c
3al
59%c
3am
40%
43%a (67%c)
Ph
2 (2.0 mmol). 2d (0.6 mmol), benzene (2.0 mL), 48 h. c Using 2 (1.0 mL)
a
b
without benzene.
Next, the scope of alkyl ethers was examined (Scheme 3). Cyclic alkyl ethers
with varying ring size, such as cyclohexyl, cycloheptyl and even cyclododecyl
ethers can be used as efficient cyclic alkylating reagents, leading to the target
products 3ab-ad in good yields. Different linear alkyl ethers, such as 2-butyl and
2-pentyl ethers were tested, and the desired products 3ae-af were achieved, also
in good yields. This strategy can also be used with longer alkyl chain ethers such
as 2-nonyl and 2-tridecyl ethers (3ag-ah). More sterically hindered substrates,
such as 3-heptyl and 3-pentyl ethers were also compatible with the reaction
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 40
1
2
3
4
5
6
7
8
9
(3ai-aj). Branched alkyl ethers, whose tertiary C–H bonds could be easily broken
in radical reactions, were tolerated (3ak-al), showing the generality of this
reaction. It could be noted that the single desired product was afforded without
obvious sideproducts from cross-dehydrogenative coupling (CDC) reactions,8
and the yield was significantly improved when ether was used as the solvent
(Scheme 3, note c). When dibenzyl ether was used, the desired product 3am
was obtained only in moderate yield.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 4. Mechanistic studies of C(sp3)−O bond cleavage
ACS Paragon Plus Environment

Page 11 of 40
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
A) Identification of byproduct
1a 2i
n-Bu
n-Bu
Et
Et
Standard
Conditions
O
3ai
+
+
+
Eq 1
Et
4i,
n-Bu
46%
60%
GCMS
tBu
B) Radical trapping experiments
tBu
O
Standard
Et
Et
Et
n-Bu
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
Conditions
3ai
1a
+
2i
+
O
O
+
tBu
BHT
(4.0 equiv)
Eq 2
n-Bu
n-Bu
+tBu
6i,
[M+H]
not
+
5i
, [M+Na]
HRMS: 455.3866
Cal. 455.3865
observed
HRMS: 319.3003
Cal. 319.3002
Standard
2
N
1
Conditions
O
1a
2b
3ab
+
+
+
O N
TEMPO
(4.0 equiv)
Eq 3
3
O
not
observed
a
not
observed
7b-1
7b-2
7b-3
(6% yield )
(3% yield )
(6% yield )
a
a yield based on TEMPO.
a
C) Unsymmetric ether and dicyclobutyl ether
Standard
Conditions
O
1a
+
+
+
O
Eq 4
Me
CONHPIP
Me
CONHPIP
8an,
2n
68%
Me
not obtained
Me
Standard
Conditions
Me
Ph
Me
Et
O
1a
1a
+
Et
CONHPIP
Ph
Eq 5
Me
Me
CONHPIP
3ae'
no obtained
2o
3ae,
27%
Standard
O
Conditions
+
O
+
+
7
Eq 6
6
Me
Me
CONHPIP
CONHPIP
Me
CONHPIP
2p
+
+
3ab,
3ap',
[M+H]
[M+H]
HRMS: 337.2277
Cal. 337.2281
3ap,
32%
HRMS: 367.2748
Cal. 367.2750
A series of control experiments were performed in an effort to clarify the
mechanism of the C−O bond cleavage (Scheme 4). In the reaction of 1a with 2i,
the ketone 4i was obtained in 46% GC yield and the product from homocoupling
of alkyl radicals was observed by GCMS (Eq 1). When adding butylated
hydroxytoluene (BHT), a radical scavenger, to the reaction, the desired product
3ai was not observed but products 5i and 6i were detected by HRMS (Eq 2),
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 40
1
2
3
4
5
6
7
8
9
implying that both alkyl radical and α-alkyl radical of the ether may exist in the
reaction. When active radical scavenger (2,2,6,6-tetramethyl-piperidin-1-yl)oxyl
(TEMPO) was added, products 7b were obtained in 15% isolated yield, while
products arising from capture of the α-alkyl radical of ether were not detected by
either HRMS or GCMS possibly due to the steric hindrance in α-position of ether
2b (Eq 3). When cyclic butyl ether 2n was subjected to the reaction (Eq 4), no
obvious desired C−H alkylation product was observed and the product 8an was
isolated in good yield possibly due to the less sterically hindrance in α-position of
2n than that of other ethers. The asymmetric ether 2o was also used, the
alkylation product 3ae was obtained and 3ae' was not observed possibly due to
the steric hindrance and low reactivity of 1-phenylethyl radical if it was formed 14c
(Eq 5). When cyclohexyloctyl ether 2p was subjected to the reaction, the product
3ap formed from direct C−C coupling was isolated 14c and the alkylating products
3ab and 3ap' were only observed by HRMS (Eq 6).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 5. Mechanistic studies of C(sp2)−H bond cleavage
A) Competition reaction
Standard
Conditions
1b
1c
+
+
2a
(4.0 mmol)
Eq 6
F3C
MeO
3ca
PIP
CONH
PIP
CONH
3ba
, 13%
, 2%
B) One-pot and parallel KIE experiments
D
D
D
D
Standard Conditions
2a
(4.0 mmol)
3ia, ; D -3ia,
10%
and/or
D
D
D
1i
3ia
and/or
Eq 7,
Eq 8,
18%
KIE =
4
D
D
PIP
PIP
CONH
CONH
1.7
D -1i,
(>99% D)
D4-3ia
5
ACS Paragon Plus Environment

Page 13 of 40
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Several experiments were designed to reveal the mechanism of C(sp2)−H
bond cleavage (Scheme 5). The electronic effect on the phenyl ring was
investigated through the competition between 1b and 1c and it was found that the
electron-deficient benzamide 1b was more reactive (Eq 6). When the deuterated
benzamide D5-1i was subjected to the reaction for 6 h, 52% of D5-1i was
recovered without observation of obvious H/D exchange. Then, kinetic isotope
effects (KIE) were observed in competition experiments between substrates 1i
and D5-1i in one pot (3ia/D4-3ia = 1.8, Eq 7) or parallel experiments (KIE = 1.7,
Eq 8), implying that C(sp2)−H bond cleavage induced by cobalt is likely to be a
rate-limiting step.
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
Me
O
Me
O
H
1a
HX
HX
N
CoIII
N
Co(III)X3
CoIII
X
N
N
II
I
X
X
cobalt-catalyzed C-H cleavage
path b
Me
O
Me
O
t-BuO-
SET
a
3
HX
N
CoII
X
N
X
(II)
Co
2
CoIV
X
R1
N
N
path a
(t-BuO)2
2R
2R
IV
III
R1
= acac, t-BuO- or R-
X
cobalt-promoted C-O cleavage
2
4
t-BuOH
2R
1R
R2
R1
Intramolecular
2R
1R
R2
R1
H-shift
t-BuO
O
B
O
A
1R
R2
C
-alkyl radical
alkyl radicals
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 40
1
2
3
4
5
Figure 1. Possible Catalytic Cycles.
6
7
8
9
Based on these experimental results and previous reports,12 a conceivable
catalytic cycle involving high-valent Co-catalyzed C(sp2)–H cleavage and
Co-promoted C(sp3)–O cleavage is proposed (Figure 1). Initially, an
intermolecular single electron transfer (SET) process between Co(II)X2 and
DTBP provides a high-valent Co(III) species and the alkoxy radical t-BuO•.
Coordination of 1a with the Co(III) species by a ligand exchange process
generates intermediate I, and the subsequent C(sp2)−H cleavage forms
intermediate II. Meanwhile t-BuO• abstracts a hydrogen atom from the ether to
generate alkyl radicals A. Intramolecular hydrogen shift of A forms α-alkyl radical
B. Homolytic cleavage of B gives the ketone 4 and the active alkyl radical C. C is
promptly captured by the cobalt center of II to provide the Co(IV) species III. This
is followed by rapid reductive elimination of III as a result of the instability of
high-valent Co(IV), generating the Co(II) species IV (Path a).14 Alternatively, a
radical substitution reaction of radical C with Co(III) species II forms IV directly
(Path b).17 Finally, protonation of IV gives the product 3a and Co(II) species,
which can be re-oxidized to continue the catalytic cycle.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment

Page 15 of 40
The Journal of Organic Chemistry
1
2
3
4
5
Scheme 6. Synthesis of (Z) tetra- and tri-substituted acrylamides
6
7
8
9
1R
1R
2R
H
single
isomer
standard
conditions
path b
+
O
2R
PIP
CONH
PIP
CONH
1
2a
3
, isolated yield
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
path a
1R
X
1R
2R
trans/cis
mixture
oxidant
radical addition
to olefin
2R
PIP
CONH
PIP
CONH
PIP
CONH
PIP
CONH
PIP
PIP
CONH
CONH
3sa,
3ta,
3ua,
3va,
20%
82%
48%
38%
Based on this proposed mechanism, direct addition of the alkyl radical to the
double bond, which may lead to a trans- and cis-acrylamide mixture, would be a
major issue when acrylamides are used (path a, Scheme 6). In fact, when
(E)-2-methylbut-2-enamide was subjected to the reaction, (Z)-3sa alone was
obtained in high yield, showing that the alkyl radical B reacts with Co species II
(Figure 1) at a much faster rate than B reacts directly with double bonds. When
other trisubstituted and cyclic substrates were used, the desired tetrasubstituted
acrylamides 3ta-ua with Z configuration were produced, albeit in moderate yields.
The trisubstitued acrylamide 3va with a Z configuration could also be obtained,
but with low yield possibly due to the high reactivity of the double bond.
Conclusions
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 40
1
2
3
4
5
6
7
8
9
In summary, Co-catalyzed direct secondary alkylation of arenes and olefins
with alkyl ethers has been achieved. This reaction represents the first example of
the use of stable alkyl ethers as alkylating reagents in metal-catalyzed C−H
alkylation reactions through cleavage of inert C(sp3)−O bonds. It shows good
compatibility with synthetically relevant functional groups in arenes, and high site
selectivity with different alkylating reagents including linear, branched and cyclic
alkyl ethers. The reaction thus provides a novel practical tool for the preparation
of o-alkyl arylamides and tetrasubstituted acrylamides. Preliminary mechanistic
studies suggest that a high-valent cobalt species generated in situ catalyzes the
cleavage of C(sp2)−H bonds and cobalt promotes C(sp3)−O bond cleavage under
oxidative conditions via a radical process. The strategy developed here may lead
to new types of alkylation reaction which uses convenient alkyl ethers as
alkylating reagents.
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
EXPERIMENTAL SECTION
General Information. Thin layer chromatography (TLC) was performed on pre-coated silica
gel GF254 plates. Visualization of TLC was achieved by using UV light (254 nm). Column
chromatography was performed on silica gel (300-400 mesh) using a proper eluent. 1H NMR
was recorded on FT AM 400 (400 MHz). Chemical shifts were reported in parts per million
(ppm) referenced to chloroform-d (CDCl3) at 7.26 ppm. The following abbreviations were
ACS Paragon Plus Environment

Page 17 of 40
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
used to describe peak splitting patterns: br = broad, s = singlet, d = doublet, t = triplet, q =
quartet, dd = doublet of doublet, td = triplet of doublet, ddd = doublet of doublet of doublet, m
= multiplet. Coupling constants, J, were reported in hertz (Hz). The fully decoupled 13C NMR
was recorded on FT AM 400 (100 MHz). Chemical shifts were reported in ppm referenced to
the center of a triplet at 77.0 ppm of chloroform-d. Infrared (IR) spectra were recorded neat in
KBr cell. Frequencies are given in centimeter inverse (cm-1) and only selected absorbance is
reported. High resolution mass spectra were obtained by using the UHD Accurate-Mass Q-TOF
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
equipped with ESI or APCI.Unless otherwise mentioned, all commercial reagents and solvents were
obtained from commercial suppliers and used without further purification. Starting compounds
1a-1c,14c 1d,18a 1e-1j,14c 1k,18b 1l,14c 1m,14a 1n,18c 1o,14a 1p,14a 1r,14c 1s,18d 1u,14a and D5-1i14c were
known compounds, while 1q, 1t, 1v were unknown compounds, all of whose were prepared according
the general procedure. Starting compound 2b,18e 2c,18e 2d,18f 2j,18g 2o18h and 2p18e were known
compounds, while 2f, 2g, 2h, 2i, 2k, 2l, 2n were unknown compounds, all of whose were prepared
according the general procedure. 2a, 2e and 2m were commercial available.
General procedure for the synthesis of compounds 114c
Method one: To a 50 mL flask was added pre-prepared 2-(Pyridin-2-yl)isopropyl amine (PIPNH2) (2.0
mmol) and Et3N (2.2 mmol), then Substituted-benzoyl chloride (2.2 mmol) was added slowly at 0 oC.
The reaction was allowed to warm to room temperature and stirred overnight. The solvent was
removed under reduce pressure, then the residue was purified by column chromatography on silica gel
to afford product 1.
Method two: To a 50 mL flask was added HOBt (2.2 mmol), EDCI (2.2 mmol) and Substituted-
benzoic acid (2.2 mmol), after charged with nitrogen, DCM (20 mL), pre-prepared PIPNH2 (2.0 mmol)
was added, then the reaction was stirred at rt overnight. The solvent was removed under reduce
pressure, then the residue was purified by column chromatography on silica gel to afford product 1.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 40
1
2
3
4
5
6
7
8
9
5-chloro-2-methyl-N-(2-(pyridin-2-yl)propan-2-yl)benzamide (1q): TLC Rf = 0.5 (EtOAc/PE =
1:5); white solid, 473 mg, 82% (Method two); m.p.: 98-99 ℃; 1H NMR (400 MHz, CDCl3) δ 8.48 (d,
J = 4.3 Hz, 1H), 8.19 (s, 1H), 7.74 (td, J = 8.0, 1.7 Hz, 1H), 7.48–7.42 (m, 2H), 7.26 (t, J = 2.9 Hz,
1H), 7.20 (dd, J = 6.9, 5.1 Hz, 1H), 7.14 (d, J = 8.2 Hz, 1H), 2.42 (s, 3H), 1.88 (s, 6H); 13C{1H} NMR
(101 MHz, CDCl3) δ 167.8, 164.2, 147.6, 139.3, 137.2, 134.2, 132.2, 131.3, 129.3, 126.9, 122.0, 119.4,
57.1, 27.5, 19.3; IR (neat): 3012, 3005, 2988, 1647, 1473, 1275, 1260, 771, 763, 750 cm-1; HRMS
(ESI) Calcd. for C16H18ClN2O [M+H]+: 289.1108, found: 289.1110.
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
(E)-2-methyl-N-(2-(pyridin-2-yl)propan-2-yl)pent-2-enamide (1t): TLC Rf = 0.4 (EtOAc/PE = 1:3);
white solid, 450 mg, 97% (Method two); m.p.: 90-91 ℃; 1H NMR (400 MHz, CDCl3) δ 8.53 (d, J =
4.8 Hz, 1H), 8.14 (s, 1H), 7.72 (td, J = 7.9, 1.7 Hz, 1H), 7.42 (d, J = 8.1 Hz, 1H), 7.19 (dd, J = 6.9, 5.3
Hz, 1H), 6.42 (td, J = 7.2, 1.2 Hz, 1H), 2.18 (p, J = 7.4 Hz, 2H), 1.91 (s, 3H), 1.79 (s, 6H), 1.05 (t, J =
7.6 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 168.5, 165.0, 147.6, 137.1, 131.4, 121.8, 119.5, 56.4,
27.5, 21.7, 13.4, 12.6; IR (neat): 3349, 3000, 2971, 2933, 2873, 1663, 1507, 1275, 1260, 787, 765, 750
cm-1; HRMS (ESI) Calcd. for C14H21N2O [M+H]+: 233.1655, found: 233.1658.
(E)-N-(2-(pyridin-2-yl)propan-2-yl)but-2-enamide (1v): TLC Rf = 0.4 (EtOAc/PE = 1:2); white
solid, 379 mg, 93% (Method two); m.p.: 108-109 ℃; 1H NMR (400 MHz, CDCl3) δ 8.51 (d, J = 4.4
Hz, 1H), 7.81–7.66 (m, 2H), 7.41 (d, J = 8.1 Hz, 1H), 7.19 (dd, J = 6.9, 5.2 Hz, 1H), 6.81 (dq, J = 13.8,
6.8 Hz, 1H), 5.95 (d, J = 15.1 Hz, 1H), 1.85 (d, J = 5.9 Hz, 3H), 1.78 (s, 6H); 13C{1H} NMR (101
MHz, CDCl3) δ 165.1, 164.6, 147.6, 138.6, 137.1, 126.6, 121.8, 119.5, 56.4, 27.6, 17.6; IR (neat):
3305, 3005, 2987, 2937, 1634, 1474, 1275, 1260, 787, 750 cm-1; HRMS (ESI) Calcd. for C12H17N2O
[M+H]+: 205.1342, found: 205.1343.
General procedure for the synthesis of compounds 2:18e a solution of 2.0 mmol trimethylsilyl
triflate and 40.0 mmol triethylsilane in 20 mL of CH2C12 was added to a 100 mL flask with magnetic
stir bar after charged with nitrogen, then the ketone (20.0 mmol) in 20 mL of CH2C12 was added
slowly at 0 °C. Then the reaction was allowed to stir at room temperature for 2 hours. The solvent was
removed under reduce pressure, then the residue was purified by column chromatography on silica gel
to afford product 2.
ACS Paragon Plus Environment

Page 19 of 40
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Oxydicyclohexane (2b): TLC Rf = 0.6 (EtOAc/PE = 1:50); colorless oil, 561 mg, 62%; 1H NMR (400
MHz, CDCl3) δ 3.29 (dt, J = 8.9, 4.0 Hz, 1H), 1.86 (m, 2H), 1.73 (m, 2H), 1.53 (m, 1H), 1.19 (m, 5H);
13C{1H} NMR (101 MHz, CDCl3) δ 74.8, 33.5, 26.0, 24.7; HRMS (ESI) Calcd. for C12H23O [M+H]+:
183.1749, found: 183.1747.
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
Oxydicycloheptane (2c): TLC Rf = 0.5 (EtOAc/PE = 1:20); colorless oil, 1.40 g, 67%; 1H NMR (400
MHz, CDCl3) δ 3.37 (tt, J = 8.4, 4.2 Hz, 1H), 1.85–1.73 (m, 2H), 1.67–1.55 (m, 2H), 1.55–1.43 (m,
6H), 1.37–1.24 (m, 2H); 13C{1H} NMR (101 MHz, CDCl3) δ 77.4, 34.8, 28.2, 23.1; HRMS (ESI)
Calcd. for C14H27O [M+H]+: 211.2063, found: 211.2057.
1
Oxydicyclododecane (2d): TLC Rf = 0.6 (EtOAc/PE = 1:40); colorless oil, 3.19 g, 91%; H NMR
(400 MHz, CDCl3) δ 3.50–3.41 (m, 1H), 1.65–1.52 (m, 2H), 1.49–1.23 (m, 20H); 13C{1H} NMR (101
MHz, CDCl3) δ 73.9, 30.0, 24.5, 23.9, 23.5, 23.3, 21.1; HRMS (ESI) Calcd. for C24H46NaO [M+Na]+:
373.3447, found: 373.3437.
1
2-(pentan-2-yloxy)pentane (2f): TLC Rf = 0.5 (CH2Cl2/PE = 1:20); colorless oil, 820 mg, 52%; H
NMR (400 MHz, CDCl3) δ 3.40 (dt, J = 11.9, 6.0 Hz, 1H), 1.50–1.25 (m, 4H), 1.09 (dd, J = 11.0, 6.1
Hz, 3H), 0.89 (t, J = 6.7 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 73.2, 72.6, 39.8, 39.5, 21.1,
20.4, 19.0, 18.9, 14.23, 14.16; HRMS (ESI) Calcd. for C10H22NaO [M+Na]+: 181.1569, found:
181.1575.
1
2-(nonan-2-yloxy)nonane (2g): TLC Rf = 0.6 (PE); colorless oil, 2.30 g, 85%; H NMR (400 MHz,
CDCl3) δ 3.39 (dt, J = 11.9, 6.0 Hz, 1H), 1.45 (dd, J = 13.2, 6.3 Hz, 1H), 1.39–1.21 (m, 11H), 1.09 (dd,
13
J = 10.1, 6.1 Hz, 3H), 0.87 (t, J = 6.6 Hz, 3H); C{1H} NMR (101 MHz, CDCl3) δ 73.4, 72.9, 37.5,
37.2, 31.9, 29.78, 29.74, 29.3, 25.9, 25.7, 22.7, 21.1, 20.4, 14.1; HRMS (ESI) Calcd. for C18H39O
[M+H]+: 271.3002, found: 271.3001.
1
2-(tridecan-2-yloxy)tridecane (2h): TLC Rf = 0.4 (PE); colorless oil, 3.60 g, 94%; H NMR (400
MHz, CDCl3) δ 3.39 (dt, J = 11.9, 6.1 Hz, 1H), 1.51–1.43 (m, 1H), 1.40–1.20 (m, 19H), 1.09 (dd, J =
10.2, 6.1 Hz, 3H), 0.87 (t, J = 6.8 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 73.4, 72.9, 37.6, 37.2,
31.9, 29.83, 29.79, 29.70, 29.68, 29.66, 29.37, 29.36, 25.9, 25.7, 22.7, 21.1, 20.5, 14.1; HRMS (ESI)
Calcd. for C26H55O [M+H]+: 383.4254, found: 383.4260.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 40
1
2
3
4
5
6
7
8
9
1
3-(heptan-3-yloxy)heptane (2i): TLC Rf = 0.6 (CH2Cl2/PE = 1:30); colorless oil, 2.05 g, 95%; H
NMR (400 MHz, CDCl3) δ 3.24–3.12 (m, 1H), 1.54–1.36 (m, 4H), 1.36–1.20 (m, 4H), 0.95–0.81 (m,
6H); 13C{1H} NMR (101 MHz, CDCl3) δ 78.21, 78.16, 33.6, 33.5, 27.8, 27.6, 26.8, 26.7, 23.0, 14.1,
9.7, 9.6; HRMS (ESI) Calcd. for C14H30NaO [M+Na]+: 237.2195, found: 237.2200.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
3-(pentan-3-yloxy)pentane (2j): TLC Rf = 0.6 (CH2Cl2/PE = 1:10); colorless oil, 1.30 g, 82%; H
NMR (400 MHz, CDCl3) δ 3.14 (m, 1H), 1.52–1.42 (m, 4H), 0.89 (t, J = 7.4 Hz, 6H); 13C{1H} NMR
(101 MHz, CDCl3) δ 79.5, 26.4, 9.7; HRMS (ESI) Calcd. for C10H22NaO [M+Na]+: 181.1569, found:
181.1577.
2-methyl-4-((4-methylpentan-2-yl)oxy)pentane (2k): TLC Rf = 0.7 (EtOAc/PE = 1:40); colorless oil,
1
1.04 g, 56%; H NMR (400 MHz, CDCl3) δ 3.48 (ddd, J = 9.6, 6.9, 4.8 Hz, 1H), 1.76–1.64 (m, 1H),
1.43 (td, J = 13.8, 7.2 Hz, 1H), 1.18–1.03 (m, 4H), 0.88 (dd, J = 9.8, 4.8 Hz, 6H); 13C{1H} NMR (101
MHz, CDCl3) δ 71.8, 70.5, 47.2, 47.0, 24.52, 24.45, 23.0, 22.9, 22.85, 22.6, 21.6, 20.6; HRMS (ESI)
Calcd. for C12H26NaO [M+Na]+: 209.1882, found: 209.1880.
2-methyl-5-((5-methylhexan-2-yl)oxy)hexane (2l): TLC Rf = 0.4 (PE); colorless oil, 1.93 g, 91%; 1H
NMR (400 MHz, CDCl3) δ 3.38 (dq, J = 13.1, 6.4 Hz, 1H), 1.57–1.41 (m, 2H), 1.41–1.31 (m, 1H),
1.30–1.20 (m, 1H), 1.20–1.05 (m, 4H), 0.88 (t, J = 10.2 Hz, 6H); 13C{1H} NMR (101 MHz, CDCl3) δ
73.7, 73.2, 35.3, 35.0, 34.9, 34.8, 28.16, 28.15, 22.69, 22.66, 22.56, 21.1, 20.4; HRMS (ESI) Calcd.
for C14H30NaO [M+Na]+: 237.2195, found: 237.2197.
1
Oxydicyclobutane (2n): TLC Rf = 0.6 (CH2Cl2/PE = 1:10); colorless oil, 718 mg, 57%; H NMR
(400 MHz, CDCl3) δ 3.87 (p, J = 7.4 Hz, 1H), 2.20–2.08 (m, 2H), 1.90 (qd, J = 10.3, 2.7 Hz, 2H),
1.65 (q, J = 10.1 Hz, 1H), 1.45 (qt, J = 10.7, 8.0 Hz, 1H); C{1H} NMR (101 MHz, CDCl3) δ 70.8,
13
30.8, 12.8; HRMS (ESI) Calcd. for C8H15O [M+H]+: 127.1124, found: 127.1126.
(Octyloxy)cyclohexane (2p):18e To a 100 mL flask with magnetic stir bar was added 30.0 mmol
1-Octanol, 60.0 mmol Imidazole and 30 mL of CH2C12, then 36.0 mmol TMSCl was added slowly at
0 °C. The reaction was allowed to stir at room temperature for 2 hours. The solvent was removed
under reduce pressure, then the residue was purified by column chromatography on silica gel to afford
trimethyl(octyloxy)silane. To a 100 mL two-neck flask with magnetic stirring bar, and nitrogen inlet
ACS Paragon Plus Environment

Page 21 of 40
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
was added powdered iodine (0.70 mmol) and hexamethyldisilane (0.77 mmol) in 14 mL of CH2C12.
The solution was stirred at room temperature for 10 min and then cooled to 0 °C and a solution of
Cyclohexanone (14.0 mmol) and trimethyl(octyloxy)silane (14.0 mmol) in 20 mL of CH2C12 was
added via syringe. The reaction was stirred for 10 min more at 0 °C, then triethylsilane was added
slowly via syringe until the color changes from violet to red-gold, during of which the solution was
warmed from 0 °C to 24 °C, and then the reaction was stirred at room temperature for 2 hours. The
solvent was removed under reduce pressure, then the residue was purified by column chromatography
on silica gel to afford product 2p as colorless oil, 1.98 g, 31% (based on 1-Octanol); TLC Rf = 0.5
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
(AcOEt/PE = 1:50); H NMR (400 MHz, CDCl3) δ 3.42 (t, J = 6.8 Hz, 2H), 3.24–3.13 (m, 1H),
1.94–1.85 (m, 2H), 1.73 (m, 2H), 1.53 (m, 2H), 1.36–1.18 (m, 16H), 0.87 (t, J = 6.9 Hz, 3H); 13C{1H}
NMR (101 MHz, CDCl3) δ 77.4, 68.0, 32.4, 31.8, 30.3, 29.5, 29.3, 26.3, 25.9, 24.3, 22.7, 14.1; HRMS
(ESI) Calcd. for C14H28NaO [M+Na]+: 235.2038, found: 235.2034.
General procedure for the synthesis of compounds 3: A screw capped 25 mL oven-dried Schlenk
tube was charged with Teflon spinbar, benzamide 1 (0.2 mmol) and Co(acac)2 (10.3 mg, 0.04 mmol,
20 mol %), then ether 2 (4.0 mmol), DTBP (117.0 mg, 0.8 mmol, 4.0 equiv) and benzene (1.0 mL)
were injected by syringe behind the tube was evacuated and filled with N2. The reaction mixture was
o
stirred intensively at 140 C for 24 h. Then the reaction mixture was cooled to room temperature,
disposed under reduced pressure and the residue was purified by chromatography on silica gel
(EtOAc/PE) to give the desired product 3.
2-isopropyl-6-methyl-N-(2-(pyridin-2-yl)propan-2-yl)benzamide (3aa): TLC Rf = 0.5 (EtOAc/PE
= 1:5); white solid; 51.5 mg, yield: 87%; m.p.: 118-119 ℃; 1H NMR (400 MHz, CDCl3) δ 8.42 (d, J =
4.3 Hz, 1H), 8.10 (s, 1H), 7.73 (td, J = 7.9, 1.7 Hz, 1H), 7.46 (d, J = 8.1 Hz, 1H), 7.23 (d, J = 7.6 Hz,
1H), 7.17 (dd, J = 5.0, 4.1 Hz, 2H), 7.03 (d, J = 7.3 Hz, 1H), 3.16 (dt, J = 13.7, 6.8 Hz, 1H), 2.37 (s,
13
3H), 1.92 (s, 6H), 1.26 (d, J = 6.8 Hz, 6H); C{1H} NMR (101 MHz, CDCl3) δ 169.3, 164.3, 147.5,
145.2, 137.9, 137.1, 134.0, 128.5, 127.5, 122.8, 121.9, 119.4, 57.1, 30.6, 27.4, 24.4, 19.3.; IR (neat):
3333, 3063, 2963, 2929, 2868, 1660, 1594, 1501, 788, 764 cm-1; HRMS (ESI) Calcd. for C19H25N2O
[M+H]+: 297.1968, found: 297.1973.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 40
1
2
3
4
2-isopropyl-N-(2-(pyridin-2-yl)propan-2-yl)-6-(trifluoromethyl)benzamide (3ba): TLC Rf = 0.7
5
6
1
(EtOAc/PE = 1:5); white solid; 62.3 mg, yield: 89%; m.p.: 73-74 ℃; H NMR (400 MHz, CDCl3) δ
7
8
9
8.41 – 8.39 (m, 1H), 8.35 (s, 1H), 7.73 (td, J = 7.9, 1.7 Hz, 1H), 7.56 (d, J = 7.8 Hz, 1H), 7.51 (d, J =
7.0 Hz, 1H), 7.45 (dd, J = 7.6, 7.0 Hz, 2H), 7.19 – 7.15 (m, 1H), 3.27 (dt, J = 13.7, 6.8 Hz, 1H), 1.91
(d, J = 20.2 Hz, 6H), 1.27 (t, J = 7.2 Hz, 6H); 13C{1H} NMR (101 MHz, CDCl3) δ 166.0, 164.0, 147.5,
147.3, 137.2, 135.5, 129.5, 128.8, 126.8 (q, 2JC-F = 30 Hz), 125.4, 123.5 (q, 3JC-F = 5 Hz), 122.7, 120.7
(d, 1JC-F = 251 Hz, CF3), 57.3, 30.2, 27.1, 26.8, 24.6, 24.1; 19F NMR (376 MHz, CDCl3) δ -58.47; IR
(neat): 3324, 3058, 2969, 2933, 2872, 1669, 1594, 1505, 1128, 765, 750 cm-1; HRMS (ESI) Calcd. for
C19H22F3N2O [M+H]+: 351.1685, found: 351.1684.
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
2-isopropyl-6-methoxy-N-(2-(pyridin-2-yl)propan-2-yl)benzamide (3ca): TLC Rf = 0.4 (EtOAc/PE
= 1:5); white solid; 33.1 mg, yield: 53%; m.p.: 121-122 ℃; 1H NMR (400 MHz, CDCl3) δ 8.45 – 8.40
(m, 1H), 7.76 (s, 1H), 7.71 – 7.65 (m, 1H), 7.51 (d, J = 8.1 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.19 –
7.11 (m, 1H), 6.93 (d, J = 7.9 Hz, 1H), 6.74 (d, J = 8.2 Hz, 1H), 3.79 (s, 3H), 3.17 (dt, J = 13.5, 6.8 Hz,
1H), 1.25 (d, J = 6.8 Hz, 6H); 13C{1H} NMR (101 MHz, CDCl3) δ 167.2, 164.5, 155.9, 147.6, 147.4,
136.9, 129.6, 127.5, 121.7, 119.5, 117.7, 108.4, 57.4, 55.9, 30.3, 27.7, 24.2; IR (neat): 3308, 3065,
2967, 2868, 2837, 1655, 1596, 1514, 787, 752 cm-1; HRMS (ESI) Calcd. for C19H25N2O2 [M+H]+:
313.1917, found: 313.1916.
2-fluoro-6-isopropyl-N-(2-(pyridin-2-yl)propan-2-yl)benzamide (3da): TLC Rf = 0.6 (EtOAc/PE =
1:5); white solid; 43.8 mg, yield: 73%; m.p.: 91-92 ℃; 1H NMR (400 MHz, CDCl3) δ 8.45 (d, J = 4.6
Hz, 1H), 8.12 (s, 1H), 7.73 (td, J = 8.0, 1.6 Hz, 1H), 7.47 (d, J = 8.1 Hz, 1H), 7.34 – 7.28 (m, 1H),
7.18 (dd, J = 7.0, 5.2 Hz, 1H), 7.13 (d, J = 7.8 Hz, 1H), 6.93 (t, J = 8.6 Hz, 1H), 3.24 (dt, J = 13.7, 6.9
Hz, 1H), 1.90 (s, 6H), 1.27 (d, J = 6.9 Hz, 6H); 13C{1H} NMR (101 MHz, CDCl3) δ 164.5, 164.1,
158.9 (d, 1JC-F = 246 Hz), 148.8 (d, 4JC-F = 3 Hz), 147.5, 137.1, 130.1 (d, 3JC-F = 9 Hz), 125.8 (d, 2JC-F
= 18 Hz), 121.9, 121.2 (d, 4JC-F = 3 Hz), 119.4, 112.8 (d, 2JC-F = 22 Hz), 57.4, 30.32, 30.31, 27.5, 24.1;
19F NMR (376 MHz, CDCl3) δ -117.33；IR (neat): 3321, 2967, 2931, 2870, 1666, 1614, 1504, 1472,
787, 750 cm-1; HRMS (ESI) Calcd. for C18H22FN2O [M+H]+: 301.1717, found: 301.1718.
ACS Paragon Plus Environment

Page 23 of 40
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
2-chloro-6-isopropyl-N-(2-(pyridin-2-yl)propan-2-yl)benzamide (3ea): TLC Rf = 0.6 (EtOAc/PE =
1:5); primrose solid; 33.5 mg, yield: 53%; m.p.: 100-101 ℃; 1H NMR (400 MHz, CDCl3) δ 8.43 (d, J
= 4.3 Hz, 1H), 8.19 (s, 1H), 7.73 (td, J = 8.0, 1.7 Hz, 1H), 7.47 (d, J = 8.1 Hz, 1H), 7.26 (dd, J = 6.2,
3.1 Hz, 2H), 7.22 (dd, J = 7.0, 2.1 Hz, 1H), 7.20 – 7.16 (m, 1H), 3.18 (dt, J = 13.7, 6.8 Hz, 1H), 1.92
(s, 6H), 1.26 (d, J = 6.9 Hz, 6H); 13C{1H} NMR (101 MHz, CDCl3) δ 166.2, 164.1, 147.9, 147.4,
137.2, 136.9, 130.5, 129.7, 126.8, 124.0, 121.9, 119.5, 57.4, 30.9, 27.3, 24.3; IR (neat): 3322, 3058,
2966, 2931, 2870, 1664, 1592, 1472, 788, 750 cm-1; HRMS (ESI) Calcd. for C18H22ClN2O [M+H]+:
317.1421, found: 317.1426.
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
2-bromo-6-isopropyl-N-(2-(pyridin-2-yl)propan-2-yl)benzamide (3fa): TLC Rf = 0.7 (EtOAc/PE =
1:5); primrose solid; 63.3 mg, yield: 88%; m.p.: 95-96 ℃; 1H NMR (400 MHz, CDCl3) δ 8.43 (d, J =
4.6 Hz, 1H), 8.20 (s, 1H), 7.73 (td, J = 7.9, 1.6 Hz, 1H), 7.47 (d, J = 8.1 Hz, 1H), 7.40 (d, J = 7.9 Hz,
1H), 7.29 (d, J = 7.8 Hz, 1H), 7.20 (t, J = 7.9 Hz, 2H), 3.17 (dd, J = 13.8, 6.9 Hz, 1H), 1.93 (s, 6H),
1.26 (d, J = 6.8 Hz, 6H); 13C{1H} NMR (101 MHz, CDCl3) δ 167.0, 164.1, 148.1, 147.4, 138.8, 137.2,
130.0, 124.6, 122.8, 121.9, 119.6, 119.5, 57.4, 31.1, 27.3, 24.3; IR (neat): 3323, 2966, 2931, 2867,
1665, 1592, 1502, 787, 764, 750 cm-1; HRMS (ESI) Calcd. for C18H22BrN2O [M+H]+: 361.0916,
found: 361.0918.
2-isopropyl-N-(2-(pyridin-2-yl)propan-2-yl)-5-(trifluoromethyl)benzamide (3ga): TLC Rf = 0.7
1
(EtOAc/PE = 1:5); white solid; 50.4 mg, yield: 72%; m.p.: 85-86 ℃; H NMR (400 MHz, CDCl3) δ
8.47 – 8.41 (m, 1H), 8.27 (s, 1H), 7.74 (td, J = 8.1 Hz, 1H), 7.64 (s, 1H), 7.63-7.60 (d, J =12.0 Hz,
1H), 7.47 (t, J = 8.8 Hz, 2H), 7.20 (dd, J = 6.9, 5.1 Hz, 1H), 3.45 (dt, J = 13.7, 6.8 Hz, 1H), 1.90 (s,
6H), 1.29 (d, J = 6.9 Hz, 6H); 13C{1H} NMR (101 MHz, CDCl3) δ 168.3, 164.0, 150.5, 147.5, 138.0,
2
3
3
137.3, 128.0 (q, JC-F = 32 Hz), 126.6, 126.2 (q, JC-F = 3 Hz), 125.4, 123.8 (q, JC-F = 3 Hz), 122.7,
120.7 (d, 1JC-F = 266 Hz, CF3), 57.2, 30.0, 27.4, 24.0; 19F NMR (376 MHz, CDCl3) δ -62.37; IR (neat):
3315, 3061, 2970, 2933, 2873, 1664, 1617, 1473, 1125, 837, 750 cm-1; HRMS (ESI) Calcd. for
C19H22F3N2O [M+H]+: 351.1685, found: 351.1688.
methyl 4-isopropyl-3-((2-(pyridin-2-yl)propan-2-yl)carbamoyl)benzoate (3ha(mono)): TLC Rf =
1
0.7 (EtOAc/PE = 1:5); primrose solid; 44.2 mg, yield: 58%; m.p.: 88-89 ℃; H NMR (400 MHz,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 40
1
2
3
4
5
6
7
8
9
CDCl3) δ 8.44 (d, J = 4.3 Hz, 1H), 8.19 (s, 1H), 8.05 (d, J = 1.6 Hz, 1H), 8.01 (dd, J = 8.2, 1.6 Hz,
1H), 7.73 (td, J = 8.0, 1.7 Hz, 1H), 7.44 (t, J = 8.7 Hz, 2H), 7.20 – 7.15 (m, 1H), 3.90 (s, 3H), 3.45 (dt,
J = 13.7, 6.8 Hz, 1H), 1.89 (s, 6H), 1.27 (d, J = 6.9 Hz, 6H); 13C{1H} NMR (101 MHz, CDCl3) δ
168.7, 166.6, 164.1, 151.9, 147.6, 137.7, 137.2, 130.5, 128.0, 127.6, 126.2, 122.0, 119.4, 57.2, 52.1,
30.1, 27.4, 23.9; IR (neat): 3324, 3057, 2967, 2870, 1723, 1664, 1473, 1255, 786, 750 cm-1; HRMS
(ESI) Calcd. for C20H25N2O3 [M+H]+: 341.1866, found: 341.1868.
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
methyl 2,4-diisopropyl-3-((2-(pyridin-2-yl)propan-2-yl)carbamoyl)benzoate (3ha(di)): TLC Rf =
1
0.5 (EtOAc/PE = 1:5); primrose solid; 16.0 mg, yield: 21%; m.p.: 93-94 ℃; H NMR (400 MHz,
CDCl3) δ 8.40 (d, J = 4.2 Hz, 1H), 8.29 (s, 1H), 7.73 (td, J = 8.0, 1.7 Hz, 1H), 7.43 (d, J = 8.2 Hz, 2H),
7.22 (d, J = 8.1 Hz, 1H), 7.18 (dd, J = 7.0, 5.3 Hz, 1H), 3.89 (s, 3H), 3.37 (dt, J = 14.3, 7.1 Hz, 1H),
3.14 (dt, J = 13.6, 6.8 Hz, 1H), 1.91 (s, 6H), 1.39 (d, J = 7.2 Hz, 3H), 1.33 (d, J = 7.1 Hz, 3H), 1.25 (d,
J = 6.8 Hz, 3H), 1.22 (d, J = 6.8 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 170.9, 168.7, 164.0,
148.3, 147.4, 142.5, 138.6, 137.2, 130.1, 129.6, 123.1, 122.0, 119.4, 57.2, 52.2, 31.8, 30.7, 27.2, 27.1,
24.6, 23.9, 22.6, 21.8; IR (neat): 3326, 2965, 2931, 2867, 1728, 1660, 1471, 1275, 1123, 750 cm-1;
HRMS (ESI) Calcd. for C23H31N2O3 [M+H]+: 383.2335, found: 383.2338.
2-isopropyl-N-(2-(pyridin-2-yl)propan-2-yl)benzamide (3ia): TLC Rf = 0.7 (EtOAc/PE = 1:5);
Colorless crystal; 47.9 mg, yield: 74%; m.p.: 140-141 ℃; 1H NMR (400 MHz, CDCl3) δ 8.42–8.38 (m,
1H), 8.16 (s, 1H), 7.72 (m, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.34 (t, J = 8.0 Hz, 1H), 7.19 (d, J = 8.0 Hz,
2H), 7.16 (m, 1H), 3.17 (m, 2H), 1.93 (s, 6H), 1.27 (m, 12H); 13C{1H} NMR (101 MHz, CDCl3) δ
169.3, 164.3, 147.4, 145.0, 137.1,137.0, 128.8, 122.8, 121.9, 119.4, 57.1, 30.6, 27.3, 24.8, 24.2; IR
(neat): 3333, 3063, 2964, 2929, 2868, 1660, 1594, 1501, 764, 750 cm-1; HRMS (ESI) Calcd. for
C21H29N2O [M+H]+: 325.2281, found: 325.2285.
4-fluoro-2,6-diisopropyl-N-(2-(pyridin-2-yl)propan-2-yl)benzamide (3ja): TLC Rf
=
0.6
(EtOAc/PE = 1:5); white solid; 50.6 mg, yield: 74%; m.p.: 103-104 ℃; 1H NMR (400 MHz, CDCl3) δ
8.42 (d, J = 4.5 Hz, 1H), 8.24 (s, 1H), 7.77–7.71 (m, 1H), 7.46 (d, J = 8.1 Hz, 1H), 7.19 (dd, J = 6.9,
5.3 Hz, 1H), 6.86 (d, J = 10.2 Hz, 2H), 3.18 (dt, J = 13.4, 6.7 Hz, 2H), 1.92 (s, 6H), 1.28–1.23 (m,
12H); 13C{1H} NMR (101 MHz, CDCl3) δ 168.6, 164.1, 163.3 (d, 1JC-F = 245 Hz), 148.0 (d, 3JC-F = 7
ACS Paragon Plus Environment

Page 25 of 40
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
Hz), 147.4, 137.2, 133.1 (d, 4JC-F = 3 Hz), 122.0, 119.4, 109.8 (d, 2JC-F = 22 Hz), 57.1, 30.7, 27.3, 24.6,
24.0; 19F NMR (376 MHz, CDCl3) δ -112.50; IR (neat): 3334, 2965, 2932, 2871, 1660, 1597, 1470,
1167, 786, 749 cm-1; HRMS (ESI) Calcd. for C21H28FN2O [M+H]+: 343.2186, found: 343.2189.
9
4-chloro-2,6-diisopropyl-N-(2-(pyridin-2-yl)propan-2-yl)benzamide (3ka): TLC Rf
=
0.7
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
(EtOAc/PE = 1:5); white solid; 52.3 mg, yield: 73%; m.p.: 150-151 ℃; 1H NMR (400 MHz, CDCl3) δ
8.40 (d, J = 4.4 Hz, 1H), 8.25 (s, 1H), 7.73 (dd, J = 11.1, 4.4 Hz, 1H), 7.44 (d, J = 8.1 Hz, 1H), 7.17
(dd, J = 6.9, 5.4 Hz, 1H), 7.13 (s, 2H), 3.12 (dq, J = 13.5, 6.7 Hz, 2H), 1.90 (s, 6H), 1.24 (dd, J = 6.4,
4.6 Hz, 12H); 13C{1H} NMR (101 MHz, CDCl3) δ 168.4, 164.0, 147.4,147.3, 137.2, 135.4, 134.7,
123.3, 122.0, 119.4, 57.1, 30.7, 27.3, 24.6, 24.0; IR (neat): 3325, 2964, 2932, 2870, 1661, 1580, 1500,
900, 764, 749 cm-1; HRMS (ESI) Calcd. for C21H28ClN2O [M+H]+: 359.1891, found: 359.1893.
4-cyano-2-isopropyl-N-(2-(pyridin-2-yl)propan-2-yl)benzamide (3la(mono)): TLC Rf = 0.5
1
(EtOAc/PE = 1:5); primrose solid; 13.5 mg, yield: 22%; m.p.: 180-181 ℃; H NMR (400 MHz,
CDCl3) δ 8.44 (d, J = 4.3 Hz, 1H), 8.35 (s, 1H), 7.76 (td, J = 7.9, 1.7 Hz, 1H), 7.65 (s, 1H), 7.54–7.47
(m, 2H), 7.45 (d, J = 8.1 Hz, 1H), 7.21 (dd, J = 6.7, 5.0 Hz, 1H), 3.42 (dt, J = 13.7, 6.9 Hz, 1H), 1.89
(s, 6H), 1.27 (d, J = 6.9 Hz, 6H); 13C{1H} NMR (101 MHz, CDCl3) δ 167.8, 163.8, 147.8, 147.5,
141.5, 137.4, 130.2, 129.4, 127.6, 122.2, 119.5, 118.7, 113.3, 57.2, 29.9, 27.4, 23.9; IR (neat): 3251,
3054, 2970, 2921, 2851, 2231, 1640, 1592, 1543, 750 cm-1; HRMS (ESI) Calcd. for C19H22N3O
[M+H]+: 308.1764, found: 308.1769.
4-cyano-2,6-diisopropyl-N-(2-(pyridin-2-yl)propan-2-yl)benzamide (3la(di)): TLC Rf = 0.7
(EtOAc/PE = 1:5); white solid; 36.3 mg, yield: 52%; m.p.: 149-150 ℃; 1H NMR (400 MHz, CDCl3) δ
8.40 (d, J = 4.6 Hz, 1H), 8.35 (s, 1H), 7.75 (dd, J = 11.1, 4.3 Hz, 1H), 7.44 (d, J = 8.1 Hz, 3H), 7.19
(dd, J = 6.9, 5.4 Hz, 1H), 3.15 (dt, J = 13.6, 6.8 Hz, 2H), 1.90 (s, 6H), 1.25 (dd, J = 6.6, 3.9 Hz, 12H);
13C{1H} NMR (101 MHz, CDCl3) δ 167.30, 163.7, 147.4, 146.6, 140.9, 137.4, 127.1, 122.1, 119.4,
119.2, 112.8, 57.3, 30.6, 27.3, 24.5, 23.9; IR (neat): 3320, 2966, 2933, 2871, 2229, 1663, 1594, 1503,
1470, 764, 750 cm-1; HRMS (ESI) Calcd. for C22H28N3O [M+H]+: 350.2233, found: 350.2234.
6-isopropyl-N-(2-(pyridin-2-yl)propan-2-yl)-2,3-dihydrobenzo[b][1,4]dioxine-5-carboxamide
1
(3ma): TLC Rf = 0.3 (EtOAc/PE = 1:5); primrose oil; 38.1 mg, yield: 56 %; H NMR (400 MHz,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 40
1
2
3
4
5
6
7
8
9
CDCl3) δ 8.45 (dd, J = 4.8, 0.7 Hz, 1H), 7.94 (s, 1H), 7.71 (td, J = 7.9, 1.8 Hz, 1H), 7.49 (d, J = 8.1
Hz, 1H), 7.19–7.15 (m, 1H), 6.83 (dd, J = 20.3, 8.5 Hz, 2H), 4.25 (m, 4H), 3.10 (m, 1H), 1.89 (s, 6H),
1.22 (d, J = 6.9 Hz, 6H); 13C{1H} NMR (101 MHz, CDCl3) δ 166.4, 164.4, 147.5, 141.3, 139.9, 139.1,
137.0, 127.3, 121.8, 119.5, 118.0, 117.5, 64.5, 64.1, 57.4, 29.8, 27.6, 24.4; IR (neat): 3326, 3053, 2969,
2931, 2874, 1655, 1590, 1487, 1286, 1086, 750 cm-1; HRMS (ESI) Calcd. for C20H25N2O3 [M+H]+:
341.1866, found: 341.1868.
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
2-isopropyl-4,6-dimethyl-N-(2-(pyridin-2-yl)propan-2-yl)benzamide (3na): TLC Rf
=
0.6
1
(EtOAc/PE = 1:5); white solid; 42.8 mg, yield: 69%; m.p.: 80-81 ℃; H NMR (400 MHz, CDCl3) δ
8.41 (d, J = 4.3 Hz, 1H), 8.08 (s, 1H), 7.72 (td, J = 8.0, 1.7 Hz, 1H), 7.45 (d, J = 8.1 Hz, 1H), 7.17 (dd,
J = 7.0, 5.3 Hz, 1H), 6.98 (s, 1H), 6.86 (s, 1H), 3.15 (dt, J = 13.7, 6.8 Hz, 1H), 2.34 (s, 3H), 2.33 (s,
13
3H), 1.92 (s, 6H), 1.25 (d, J = 6.9 Hz, 6H); C{1H} NMR (101 MHz, CDCl3) δ 169.6, 164.4, 147.5,
145.2, 138.1, 137.1, 135.3, 134.0, 128.3, 123.3, 121.9, 119.4, 57.0, 30.5, 27.4, 24.4, 21.4, 19.2; IR
(neat): 3336, 2964, 2927, 2868, 1656, 1609, 1501, 1470, 877, 749 cm-1; HRMS (ESI) Calcd. for
C20H27N2O [M+H]+: 311.2124, found: 311.2126.
2,4-difluoro-6-isopropyl-N-(2-(pyridin-2-yl)propan-2-yl)benzamide (3oa): TLC Rf
=
0.6
1
(EtOAc/PE = 1:5); white solid; 26.1 mg, yield: 41 %; m.p.: 84-85 ℃; H NMR (400 MHz, CDCl3) δ
8.43 (d, J = 4.2 Hz, 1H), 8.19 (s, 1H), 8.07 (m, 1H), 7.71 (td, J = 8.0, 1.7 Hz, 1H), 7.44 (d, J = 8.1 Hz,
1H), 7.18 (dt, J = 14.4, 6.3 Hz, 1H), 6.89–6.81 (m, 1H), 3.26 (dt, J = 13.6, 6.6 Hz, 1H), 1.85 (s, 6H),
4
1.23 (d, J = 6.9 Hz, 6H); 13C{1H} NMR (101 MHz, CDCl3) δ 164.1, 163.7, 151.0 (d, JC-F = 4 Hz),
150.9 (d, 4JC-F = 4 Hz), 147.6, 137.3, 120.8 (d, 1JC-F = 256 Hz), 108.7 (d, 4JC-F = 3 Hz), 108.5 (d, 4JC-F
= 3 Hz), 101.7, 101.44, 101.18, 57.5, 30.5, 27.5, 24.0; 19F NMR (376 MHz, CDCl3) δ -108.74, -108.76,
-113.34, -113.36; IR (neat): 3330, 3057, 2976, 2934, 2871, 1664, 1593, 1473, 1108, 768, 749 cm-1;
HRMS (ESI) Calcd. for C18H21F2N2O [M+H]+: 319.1623, found: 319.1621.
3-fluoro-2-isopropyl-6-methyl-N-(2-(pyridin-2-yl)propan-2-yl)benzamide (3pa): TLC Rf = 0.5
(EtOAc/PE = 1:5); white solid; 50.9 mg, yield: 81%; m.p.: 111-112 ℃; 1H NMR (400 MHz, CDCl3) δ
8.43 (d, J = 4.3 Hz, 1H), 8.15 (s, 1H), 7.73 (td, J = 8.0, 1.6 Hz, 1H), 7.45 (d, J = 8.1 Hz, 1H),
7.21–7.15 (m, 1H), 6.98 (dd, J = 8.3, 5.0 Hz, 1H), 6.90 (dd, J = 11.5, 8.4 Hz, 1H), 3.11 (dt, J = 14.0,
ACS Paragon Plus Environment

Page 27 of 40
The Journal of Organic Chemistry
1
2
3
4
7.0 Hz, 1H), 2.32 (s, 3H), 1.91 (s, 6H), 1.35 (d, J = 7.0 Hz, 6H); 13C{1H} NMR (101 MHz, CDCl3) δ
5
6
4
1
3
168.3 (d, JC-F = 3 Hz), 164.1, 160.4 (d, JC-F = 246 Hz), 147.5, 139.4(d, JC-F = 6 Hz), 137.2, 131.4,
7
8
9
4
3
2
131.2, 129.7 (d, JC-F = 3 Hz), 128.8 (d, JC-F = 8 Hz), 122.0, 119.4, 116.0 (d, JC-F = 23 Hz), 57.1,
30.3, 27.3, 21.6, 18.7; 19F NMR (376 MHz, CDCl3) δ -117.47; IR (neat): 3323, 2974, 2932, 2875,
1663, 1563, 1502, 1473, 814, 749 cm-1; HRMS (ESI) Calcd. for C19H24FN2O [M+H]+: 315.1873,
found: 315.1874.
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
3-chloro-2-isopropyl-6-methyl-N-(2-(pyridin-2-yl)propan-2-yl)benzamide (3qa): TLC Rf = 0.5
(EtOAc/PE = 1:5); white solid; 46.8 mg, yield: 71%; m.p.: 120-121 ℃; 1H NMR (400 MHz, CDCl3) δ
8.42 (d, J = 4.8 Hz, 1H), 8.17 (s, 1H), 7.73 (td, J = 8.0, 1.7 Hz, 1H), 7.44 (d, J = 8.1 Hz, 1H),
7.23–7.16 (m, 2H), 6.96 (d, J = 8.1 Hz, 1H), 3.39 (d, J = 6.0 Hz, 1H), 2.32 (s, 3H), 1.91 (s, 6H), 1.43
(dd, J = 6.9, 4.5 Hz, 6H); 13C{1H} NMR (101 MHz, CDCl3) δ 168.6, 164.0, 147.4, 140.6, 140.3, 137.2,
133.3, 131.2, 130.9, 128.9, 122.0, 119.4, 57.1, 32.3, 27.2, 20.7, 20.4, 19.0; IR (neat): 3321, 2974, 2931,
2873, 1663, 1593, 1501, 1472, 1125, 749 cm-1; HRMS (ESI) Calcd. for C19H24ClN2O [M+H]+:
331.1578, found: 331.1580.
5-chloro-3-isopropyl-N-(2-(pyridin-2-yl)propan-2-yl)thiophene-2-carboxamide (3ra): TLC Rf =
1
0.7 (EtOAc/PE = 1:5); primrose solid; 27.1 mg, yield: 42 %; m.p.: 74-75 ℃; H NMR (400 MHz,
CDCl3) δ 8.56 (s, 1H), 8.51 (d, J = 4.8 Hz, 1H), 7.75 (td, J = 7.9, 1.7 Hz, 1H), 7.43 (d, J = 8.1 Hz, 1H),
7.22 (dd, J = 7.2, 5.2 Hz, 1H), 6.86 (s, 1H), 3.70 (m, 1H), 1.84 (s, 6H), 1.26 (d, J = 6.9 Hz, 6H);
13C{1H} NMR (101 MHz, CDCl3) δ 164.2, 161.2, 150.7, 147.4, 137.4, 131.5, 131.5, 126.6, 122.0,
119.4, 57.3, 28.3, 27.5, 23.7; IR (neat): 3302, 2969, 2926, 2869, 2379, 2316, 1655, 1484, 848, 786
cm-1; HRMS (ESI) Calcd. for C16H20ClN2OS [M+H]+: 323.0986, found: 323.0980.
(Z)-2,3,4-trimethyl-N-(2-(pyridin-2-yl)propan-2-yl)pent-2-enamide (3sa): TLC Rf
=
0.5
1
(EtOAc/PE = 1:5); white solid; 42.6 mg, yield: 82 %; m.p.: 83-84 ℃; H NMR (400 MHz, CDCl3) δ
8.48 (d, J = 4.8 Hz, 1H), 7.77–7.68 (m, 2H), 7.41 (d, J = 8.1 Hz, 1H), 7.17 (dd, J = 7.3, 4.9 Hz, 1H),
2.94 (dt, J = 13.6, 6.8 Hz, 1H), 1.84 (s, 3H), 1.79 (s, 6H), 1.57 (s, 3H), 1.00 (d, J = 6.8 Hz, 6H);
13C{1H} NMR (101 MHz, CDCl3) δ 172.0, 164.6, 147.5, 139.2, 137.0, 127.4, 121.8, 119.4, 56.5, 32.1,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 40
1
2
3
4
5
6
27.5, 21.0, 16.3, 11.2; IR (neat): 3336, 2963, 2871, 2374, 2362, 2339, 2320, 1657, 1468, 871 cm-1;
HRMS (ESI) Calcd. for C16H25N2O [M+H]+: 261.1968, found: 261.1966.
7
8
9
(Z)-3-ethyl-2,4-dimethyl-N-(2-(pyridin-2-yl)propan-2-yl)pent-2-enamide (3ta): TLC Rf = 0.5
(EtOAc/PE = 1:3); Colorless oil; 26.3 mg, yield: 48 %; 1H NMR (400 MHz, CDCl3) δ 8.48 (d, J = 4.8
Hz, 1H), 7.74–7.64 (m, 2H), 7.40 (d, J = 8.1 Hz, 1H), 7.17 (dd, J = 7.3, 5.0 Hz, 1H), 2.94 (dt, J = 13.6,
6.8 Hz, 1H), 2.02 (q, J = 7.6 Hz, 2H), 1.86 (s, 3H), 1.79 (s, 6H), 1.03 (dd, J = 13.5, 7.2 Hz, 9H);
13C{1H} NMR (101 MHz, CDCl3) δ 172.1, 164.6, 147.5, 144.6, 137.0, 128.2, 121.7, 119.4, 56.5, 32.5,
27.5, 21.4, 19.5, 16.0, 14.2; IR (neat): 3343, 3053, 2967, 2933, 2873, 1652, 1499, 1472, 787, 749 cm-1;
HRMS (ESI) Calcd. for C17H27N2O [M+H]+: 275.2124, found: 275.2120.
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
2-isopropyl-N-(2-(pyridin-2-yl)propan-2-yl)cyclohex-1-enecarboxamide (3ua): TLC Rf = 0.5
1
(EtOAc/PE = 1:4); white solid; 21.8 mg, yield: 38 %; m.p.: 85-86 ℃; H NMR (400 MHz, CDCl3) δ
8.51–8.47 (m, 1H), 7.75–7.67 (m, 2H), 7.40 (d, J = 8.1 Hz, 1H), 7.19–7.15 (m, 1H), 2.95 (dt, J = 13.7,
6.8 Hz, 1H), 2.25 (d, J = 2.0 Hz, 2H), 1.98 (d, J = 1.9 Hz, 2H), 1.79 (s, 6H), 1.64–1.58 (m, 4H), 1.00
(d, J = 6.9 Hz, 6H); 13C{1H} NMR (101 MHz, CDCl3) δ 171.6, 164.7, 147.5, 140.9, 137.0, 129.6,
121.8, 119.4, 56.5, 31.3, 27.5, 27.3, 22.51, 22.49, 22.1, 21.0; IR (neat): 3344, 2961, 2931, 2867, 2837,
1648, 1498, 1471, 787, 748 cm-1; HRMS (ESI) Calcd. for C18H27N2O [M+H]+: 287.2124, found:
287.2123.
(Z)-3,4-dimethyl-N-(2-(pyridin-2-yl)propan-2-yl)pent-2-enamide (3va): TLC Rf = 0.5 (EtOAc/PE
1
= 1:3); white solid; 9.9 mg, yield: 20 %; m.p.: 43-44 ℃; H NMR (400 MHz, CDCl3) δ 8.50 (d, J =
4.8 Hz, 1H), 7.70 (td, J = 7.9, 1.7 Hz, 1H), 7.55 (s, 1H), 7.41 (d, J = 8.1 Hz, 1H), 7.17 (dd, J = 7.0, 5.3
Hz, 1H), 5.66 (d, J = 29.8 Hz, 1H), 3.90 (dt, J = 13.7, 6.9 Hz, 1H), 1.77 (s, 6H), 1.74 (d, J = 1.1 Hz,
3H), 1.04 (dd, J = 14.8, 6.9 Hz, 6H); 13C{1H} NMR (101 MHz, CDCl3) δ 166.3, 164.8, 157.3, 147.6,
137.0, 121.7, 119.6, 119.5, 56.4, 28.8, 27.7, 20.8, 18.6; IR (neat): 3325, 3044,2987, 1655, 1502, 1473,
1275, 1261, 764, 750 cm-1; HRMS (ESI) Calcd. for C15H23N2O [M+H]+: 247.1811, found: 247.1808.
2-cyclohexyl-6-methyl-N-(2-(pyridin-2-yl)propan-2-yl)benzamide (3ab): TLC Rf = 0.6 (EtOAc/PE
= 1:5); primrose solid; 45.7 mg, yield: 68 %; m.p.: 75-76 ℃; 1H NMR (400 MHz, CDCl3) δ 8.42 (d, J
= 4.7 Hz, 1H), 8.02 (s, 1H), 7.76–7.70 (m, 1H), 7.47 (d, J = 8.1 Hz, 1H), 7.23 (t, J = 7.6 Hz, 1H),
ACS Paragon Plus Environment

Page 29 of 40
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
7.20–7.16 (m, 1H), 7.14 (d, J = 7.7 Hz, 1H), 7.03 (d, J = 7.4 Hz, 1H), 2.75 (ddd, J = 11.7, 7.5, 3.1 Hz,
1H), 2.37 (s, 3H), 1.93 (s, 6H), 1.92–1.87 (m, 2H), 1.76 (s, 2H), 1.67 (s, 2H), 1.43 (dd, J = 24.2, 12.1
Hz, 2H), 1.27–1.23 (m, 2H); 13C{1H} NMR (101 MHz, CDCl3) δ 169.3, 164.3, 147.5, 144.2, 138.1,
137.1, 134.1, 128.4, 127.4, 123.5, 121.9, 119.4, 57.0, 41.2, 27.4, 27.0, 26.2, 19.3; IR (neat): 3326,
2927, 2852, 1659, 1593, 1472, 1275, 1124, 786, 764, 750 cm-1; HRMS (ESI) Calcd. for C22H29N2O
[M+H]+: 337.2281, found: 337.2283.
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
2-cycloheptyl-6-methyl-N-(2-(pyridin-2-yl)propan-2-yl)benzamide (3ac): TLC Rf
=
0.7
1
(EtOAc/PE = 1:5); white solid; 56.0 mg, yield: 80 %; m.p.: 95-96 ℃; H NMR (400 MHz, CDCl3) δ
8.42 (d, J = 4.8 Hz, 1H), 8.05 (s, 1H), 7.73 (td, J = 7.9, 1.7 Hz, 1H), 7.47 (d, J = 8.1 Hz, 1H),
7.24–7.16 (m, 2H), 7.12 (d, J = 7.7 Hz, 1H), 7.01 (d, J = 7.4 Hz, 1H), 2.95–2.80 (m, 1H), 2.36 (s, 3H),
1.93 (s, 6H), 1.77–1.37 (m, 12H); 13C{1H} NMR (101 MHz, CDCl3) δ 169.3, 164.3, 147.5, 146.3,
137.2, 137.1，134.0, 128.5, 127.1, 123.6, 121.9, 119.5, 57.0, 42.8, 27.8, 27.5, 27.4, 19.3; IR (neat):
3334, 2926, 2855, 1659, 1593, 1500, 1471, 1123, 764, 750 cm-1; HRMS (ESI) Calcd. for C23H31N2O
[M+H]+: 351.2437, found: 351.2440.
2-cyclododecyl-6-methyl-N-(2-(pyridin-2-yl)propan-2-yl)benzamide (3ad): TLC Rf
=
0.6
(EtOAc/PE = 1:3); primrose solid; 55.5 mg, yield: 66 %; m.p.: 83-84 ℃; 1H NMR (400 MHz, CDCl3)
δ 8.43 (d, J = 4.2 Hz, 1H), 8.16 (s, 1H), 7.75 (td, J = 7.9, 1.7 Hz, 1H), 7.48 (d, J = 8.1 Hz, 1H), 7.24 (t,
J = 7.6 Hz, 1H), 7.22–7.16 (m, 2H), 7.04 (d, J = 7.3 Hz, 1H), 3.06 (p, J = 6.6 Hz, 1H), 2.38 (s, 3H),
1.98 (s, 6H), 1.78 (s, 2H), 1.55 (dd, J = 13.0, 6.9 Hz, 2H), 1.44–1.20 (m, 18H); 13C{1H} NMR (101
MHz, CDCl3) δ 169.4, 164.3, 147.4, 144.2, 138.9, 137.1, 134.1, 128.3, 127.4, 124.4, 121.9, 119.4,
57.0, 36.5, 32.1, 27.3, 24.1, 23.9, 23.3, 23.2, 19.4; IR (neat): 3336, 3062, 2931, 2861, 1659, 1499,
1470, 1444, 765, 749 cm-1; HRMS (ESI) Calcd. for C28H40N2NaO [M+Na]+: 443.3039, found:
443.3038.
2-(sec-butyl)-6-methyl-N-(2-(pyridin-2-yl)propan-2-yl)benzamide (3ae): TLC Rf = 0.6 (EtOAc/PE
= 1:5); primrose solid; 52.1 mg, yield: 84 %; m.p.: 91-92 ℃; 1H NMR (400 MHz, CDCl3) δ 8.41 (d, J
= 4.4 Hz, 1H), 8.07 (s, 1H), 7.72 (td, J = 8.0, 1.7 Hz, 1H), 7.45 (d, J = 8.1 Hz, 1H), 7.23 (t, J = 7.7 Hz,
1H), 7.16 (dd, J = 6.9, 5.3 Hz, 1H), 7.11 (d, J = 7.8 Hz, 1H), 7.02 (d, J = 7.4 Hz, 1H), 2.87 (dd, J =
ACS Paragon Plus Environment