2-Amino-5,6-difluorophenyl-1 H-pyrazole-Directed PdII Catalysis: Arylation of Unactivated β-C(sp3)-H Bonds

Article abstract of DOI:10.1021/acs.joc.9b01276

Palladium-catalyzed arylation of unactivated β-C(sp³)-H bonds in carboxylic acid derivatives with aryl iodides is described for the first time using 2-amino-5,6-difluorophenyl-1H-pyrazole as an efficient and readily removable directing group. Two fluoro groups are installed at the 5- and 6-position of the anilino moiety in 2-aminophenyl-1H-pyrazole, clearly enhancing the directing ability of the auxiliary. In addition, the protocol employs Cu(OAc)₂/Ag₃PO₄ (1.2/0.3) as additives, evidently reducing the stoichiometric amount of expensive silver salts. Furthermore, this process exhibits high β-site selectivity, compatibility with diverse substrates containing α-hydrogen atoms, and excellent functional group tolerance.

Full text of DOI:10.1021/acs.joc.9b01276

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Article
2-Amino-5,6-Difluorophenyl-1H-Pyrazole-Directed PdII
Catalysis: Arylation of Unactivated #-C(sp3)-H Bonds
Jinyue Yang, Xiaopan Fu, Shibiao Tang, Kezuan Deng, Lili Zhang, Xian-Jin Yang, and Ya-Fei Ji
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01276 • Publication Date (Web): 17 Jul 2019
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Page 1 of 14
The Journal of Organic Chemistry
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2-Amino-5,6-Difluorophenyl-1H-Pyrazole-Directed PdII Catalysis:
Arylation of Unactivated β-C(sp3)−H Bonds
Jinyue Yang,† Xiaopan Fu,† Shibiao Tang,† Kezuan Deng,† Lili Zhang,† Xianjin Yang,*, ‡, § and Yafei Ji*, †
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† School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, P. R. China.
E-mail: jyf@ecust.edu.cn (Ji)
‡ Key Laboratory for Advanced Materials & Institute of Fine Chemicals, East China University of Science and Technology,
130 Meilong Road, Shanghai 200237, P. R. China. E-mail: yxj@ecust.edu.cn (Yang)
§ Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Science, 345
Lingling Road, Shanghai 200032, P. R. China.
N
H
R3
R2
R1
N
Ar
R3
R2
R1
cat. Pd(OAc)2
Cu(OAc)2 /Ag3PO4 (1.2/0.3)
N
N
H
H
F
F
N
F
F
N
p-xylene:DMF = 1:1
O
O
130 oC, 16 h
Ar-I
Compatible with substrates containing -hydrogen atoms

Readily removable directing group
41 examples, up to 78% yield
ABSTRACT: Palladium-catalyzed arylation of unactivated β-C(sp3)−H bonds in carboxylic acid derivatives with aryl iodides is
described for the first time using 2-amino-5,6-difluorophenyl-1H-pyrazole as an efficient and readily removable directing group.
Two fluoro groups are installed at the 5- and 6-position of the anilino moiety in 2-aminophenyl-1H-pyrazole, clearly enhance the
directing ability of the auxiliary. In addition, the protocol employs Cu(OAc)2/Ag3PO4 (1.2/0.3) as additives, evidently reducing the
stoichiometric amount of expensive silver salts. Furthermore, this process exhibits high β-site selectivity, compatibility with diverse
substrates containing α-hydrogen atoms, and excellent functional group tolerance.
Scheme 1. Directing Group Strategies for Unactivated
INTRODUCTION
C(sp3)−H Bond Arylation of Aliphatic Amides.
The immense potential of organic synthesis based on
transition-metal-catalyzed functionalization of C(sp2)−H
bonds has been extensively explored over the decades.1 In
comparison, direct functionalization of unactivated C(sp3)−H
bonds remains underdeveloped and continues to be highly
challenging because of the high bond dissociation enery and
the absence of stabilizing π-orbital interactions with the metal
center.2 However, directing-group-assisted strategy has
become a powerful and promising method for achieving
diverse transformations of inert C(sp3)−H bonds,3 such as
arylation,4 alkoxylation,5 alkenylation,6 alkynylation,7
carbonylation,8 amination,9 and others.10
Previous works
A) The first example of C(sp3)–H bond arylation via a bidentate directing group4a
O
O
Pd(OAc)2
AgOAc
R2
R1
R2
R1
+
N
Ar-I
N
H
H
N
no solvent
N
Ar
Ar = 4-MeOC6H4 or 4-AcC6H4
B) N,N-bidentate directing groups 13
Bn
N
N
N
O
O
N
N
S O
N
NH
NH
NH
NH
Shi13d, 2015
Ackermann13c, 2014
β-substituted carboxylic acid derivatives are frequently
found in a wide array of bioactive compounds.11 Therefore,
direct functionalization of their β-C(sp3)−H bonds is highly
appealing. According to previous reports, the bidentate
directing groups showed much better performance than the
monodentate ones.12 In 2005, Daugulis and co-workers first
demonstrated that 8-aminoquinoline could be employed as
bidentate directing group to promote β-arylation of aliphatic
amide derivatives (Scheme 1A).4a Following this pioneering
work, numerous N,N-bidentate directing groups have been
reasonably developed for the unactivated C(sp3)−H bond
arylation in aliphatic amide derivatives (Scheme 1B).13
Shi13a, 2013
Carretero13b, 2013
O
N
S
N
Me2N
O
N
N
NH
NH
NH
NH
Yu13h, 2018
Shi13e, 2015
Babu13g, 2016
Zhou13f, 2016
This work
N
N
H
O
R3
Ar
R3
R2
R1
Pd(OAc)2
Cu(OAc)2, Ag3PO4
N
N
H
H
C)
R2
F
F
N
F
F
N
Ar-I
R1
+
solvent
O
130 o
C
Despite all these great advances, some inherent limitations
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The Journal of Organic Chemistry
Page 2 of 14
also remain. For instance, arylation of secondary C(sp3)−H
group at the 5-position offered a lower yield than the
1
2
3
4
5
6
7
8
bond or various substrates containing α-hydrogen atoms can
unmodified directing group (3a, 3b). To our delight, the
addition of a fluoro substituent group at the anilino moiety
improved the yield of the arylated product 3c. When two
fluoro groups were separately installed at the 5- and 6-position,
the yield of 3d evidently increased to 58%. However, with
more fluoro groups, the yield of 3e was slightly diminished.
Additionally, we also introduced a methoxy substituent group
at the 5-position, which offered a lower yield (3f). 2-Amino-
5,6-difluorophenyl-1H-pyrazole was ultimately opted as the
most effective directing group for further surveys.
not be tolerated,4d, e, 14 possibly because that the palladacycle
can undergo β-hydride elimination with the α-hydrogen atom,
4b
which inhibited the desired step.3a,
Additionally, strong
auxiliaries give thermodynamically stable palladacycles, as a
result, the subsequent functionalization steps are less reactive.
In contrast, the palladacycles are less stable with weakly
coordinating directing groups, which is unfavorable to C−H
15
cleavage step.1a, To break through these limitations, efforts
9
are still in high demand to develop new types of directing
groups.
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Table 2. Optimization of the Reaction Conditions. a
Recently, Li’s and Baidya’s groups presented 2-
aminophenyl-1H-pyrazole as an effective N,N-bidentate
auxiliaries to realize various C(sp2)−H functionalizations.16
Most recently, our groups reported ortho-arylation of aromatic
amides directed by 2-amino-5-chlorophenyl-1H-pyrazole with
general work conditions, broader substrate scope and wider
functional group tolerance.17 Compared to C(sp2)−H bond
activation, C(sp3)−H functionalizations directed by amino-
pyrazole auxiliaries deserve to be paid more attention.
Meanwhile, considering adjusting the coordination ability of
this auxiliary, we undertake to introduce halide substituents
which exert inductive and conjugation effects with the
benzene ring at the anilino moiety. Herein, we describe the
first palldium-catalyzed arylation of unactivated β-C(sp3)−H in
carboxylic acid derivatives using 2-amino-5,6-difluorophenyl-
1H-pyrazole as a bidentate auxiliary (Scheme 1C). Particularly,
the protocol can afford arylated product of carboxylic acid
derivatives that contain α-hydrogen atoms in moderate to good
yields, ortho-substituted aryl iodides are also tolerated.
OMe
I
N
N
H
Pd(OAc)2 (10 mol%)
Additive (n1 equiv)
N
N
H
N
H
F
F
F
F
N
+
Solvent (2.0 mL)
130 oC, 16 h
O
O
OMe
3d
1d
2a
Yield
(%)b
Entry
Additive (n1 equiv)
Solvent
1
2
Ag3PO4 (1.0)
AgOAc (2.0)
AgTFA (2.0)
Ag2CO3 (2.0)
Cu(OAc)2 (2.0)
Cu(acac)2 (2.0)
CuCl2 (2.0)
p-xylene
p-xylene
p-xylene
p-xylene
p-xylene
p-xylene
p-xylene
p-xylene
p-xylene
p-xylene
p-xylene
p-xylene
DMF
58
47
32
20
56
51
<5
71
72
64
55
64
58
55
45
78
70
63
3
4
5
6
7
8
Cu(OAc)2/Ag3PO4 (1.6/0.4)
Cu(OAc)2/Ag3PO4 (1.2/0.3)
Cu(OAc)2/Ag3PO4 (0.8/0.2)
Cu(OAc)2/Ag3PO4 (1.0/0.5)
Cu(OAc)2/Ag3PO4 (1.3/0.2)
9
RESULTS AND DISCUSSION
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20
21
22
a
Table 1. Influence of Substituent Electronegativity on
the Directing Groups.a,b
Cu(OAc)2/Ag3PO4 (1.2/0.3
Cu(OAc)2/Ag3PO4 (1.2/0.3
Cu(OAc)2/Ag3PO4 (1.2/0.3
)
)
)
OMe
DCE
I
Pd(OAc)2 (10 mmol%)
Ag3PO4 (1.0 equiv)
N
N
H
N
N
DMSO
H
H
N
N
+
p-xylene, 130 oC, 16 h
Cu(OAc)2/Ag3PO4 (1.2/0.3
)
p-xylene/DMF (1:1)
O
O
OMe
R
R
Cu(OAc)2/Ag3PO4 (1.2/0.3) p-xylene/DMF (3:1)
3
1
2a
Cu(OAc)2/Ag3PO4 (1.2/0.3
)
)
p-xylene/DMF (1:3)
OMe
OMe
OMe
Cu(OAc)2/Ag3PO4 (1.2/0.3
p-xylene/DMF (1:1) 67c (76d)
p-xylene/DMF (1:1) 0e (0f, 0g)
p-xylene/DMF (1:1) 0h (51i)
p-xylene/DMF (1:1) 36 (27i)
N
N
N
N
N
N
H
N
H
H
Cu(OAc)2/Ag3PO4 (1.2/0.3
Cu(OAc)2/Ag3PO4 (1.2/0.3
Ag3PO4 (0.3)
)
N
N
)
O
O
O
Cl
F
3a
, 43%
3b
, 33%
3c
, 46%
OMe
Reaction conditions: 1d (0.3 mmol), 2a (0.9 mmol),
Pd(OAc)2 (10 mol%), additive (n1 equiv), solvent (3.0 mL),
130 C, 16 h. Isolated yields of 3d. 120 C. 140 C. 4-
OMe
OMe
N
N
N
N
N
H
N
H
o
b
c
o
d
o
e
H
N
N
F
N
F
F
f
O
Bromoanisole instead of 4-iodoanisole.
4-Chloroanisole
4-Methoxyphenylboronic acid
O
O
MeO
F
g
instead of 4-iodoanisole.
F
instead of 4-iodoanisole. h No Pd(OAc)2. i No Ag3PO4.
3f
, 31%
3d
, 58%
3e
, 52%
a
Reaction conditions: 1 (0.3 mmol), 2a (0.9 mmol),
With the optimized directing group in hand, We attempted
to improve the yield of the arylated product by changing the
reaction conditions (Table 2). We first screened various Ag
salts, and Ag3PO4 was considered as the best one (entries 1−4).
Pd(OAc)2 (10 mol%), Ag3PO4 (1.0 equiv), p-xylene (3.0
mL), 130 oC, 16 h. b Isolated yields of 3.
Initially, our efforts focused on substituent electronegativity
on the 2-aminophenyl-1H-pyrazole directing group. The
reaction was conducted in the presence of substrate 1 (0.3
mmol), Pd(OAc)2 (10 mol%), 4-iodoanisole 2a (3.0 equiv),
Inspired by previous literature,4d, we attempted to employ
18
Cu(OAc)2 as the single additive instead of expensive silver
salts, successfully obtaining 3d in 56% yield (entry 5). And
this is significant, since iodide scavenging is completed
without the need for silver salts. Notably, direct arylation of
C(sp3)−H aided by Cu salts is rather rare in bidentate directing
groups.4c, d, 14a, 19 Subsequently, we screened other copper (II)
o
Ag3PO4 (1.0 equiv) in p-xylene (3.0 mL) at 130 C for 16
hours (Table 1). And the target product 3a was obtained in
43% yield by the unmodified directing group. In fact, a chloro
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The Journal of Organic Chemistry
salts, and Cu(acac)2 resulted in inferior efficiency (entry 6) aliphatic amides derived from carboxylic acids with α-
1
2
3
4
5
6
7
8
while CuCl2 was almost inefficient (entres 7). Considering the
economy and reaction efficiency, we attempt to use Cu(OAc)2
(1.6 equiv) as the primary additive in concert with small
stoichiometric amount of Ag3PO4 (0.4 equiv) (entry 8), and the
yield of 3d was distinctly improved to 71%. Reducing the
mixed additives to 1.5 equiv had no adverse effect on the yield
(entry 9). But, further reducing additives lead to relative lower
yield (entry 10). Additionly, increasing or decreasing the
amount of Ag3PO4 in the common additives was detrimental
(entries 11 and 12). In contrast to our initial solvent choice of
p-xylene, DCE, DMF and DMSO were all diminished the
yield of 3d (entries 13−15). However, when p-xylene and
DMF was used as mixed solvent (p-xylene:DMF, 1:1, v/v), the
yield of the product 3d was improved to 78% (entry 16).
Changing the ratio of p-xylene and DMF, no better reaction
yields were observed. (entries 17 and 18). Inferior reaction
performance was observed in the reaction temperature of 120
quaternary centers or α-tertiary centers were examined. The
results are summarized in Table 3. The substrate 1g reacted
with 2a to afford the target β-monoarylated product 3g in 32%
yield and β,β-diarylated product 3g’ in 41% yield due to the
existence of two equivalent reactive β-C(sp3)−H sites. As for
substrate 1h, the corresponding product 3h of β-methyl
C(sp3)−H bond arylation was observed in 23% yield along
with 47% yield of β-methyl and β-methylene C(sp3)−H bonds
diarylated product 3h’. We then examined the site selectivity
of substrates containing β-methyl, linear β-methylene
C(sp3)−H bonds and γ-C(sp2)−H bonds. Arylation of the β-
methyl C(sp3)−H bonds was exclusively observed in moderate
to good yields, indicating the high selectivity of the directing
group (3d, 3i−3q). Additionally, we found that alkyl side
chains at the α-position had little effect on the yields of the
target products and substrates bearing aryl groups were less
reactive than those with aliphatic chains. Noteworthy,
aliphatic amides with α-hydrogen atoms all reacted smoothly.
Moreover, the arylation of β-methylene C(sp3)−H bond with
four-, five-, and six-membered cycloalkyl substituted aliphatic
amides was also tolerated, exclusively affording the
corresponding monoarylated products (3r−3t) in moderate
overall yields (51−55%), and no diarylated products were
obtained. For α-secondary substrate 1u, arylated product 3u
was successfully obtained in 41% yield. It should be noted that
the target products were obtained severally when employing
Cu(OAc)2 as the sole additive (3g, 3i, 3l, 3o, 3s), which has
economic advantage and potential application value in organic
synthetic chemistry.
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48
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50
51
52
53
54
55
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57
58
59
60
o
oC or 140 C (entry 19). Then several other arylation reagents
instead of 2a were not reactive (entry 20). Finally, control
experiments were conducted. No desired product was detected
without Pd(OAc)2, which demonstrated the essential role of
Pd(OAc)2 as catalyst (entry 21). Movever, 51% and 36%
isolated yield of 3d was separately obtained in the absence of
Ag3PO4 and without Cu(OAc)2, while Pd(OAc)2 alone was
only able to furnish 3d in 27% yield under similar conditions
(entries 21 and 22). It was proved that Cu(OAc)2 and Ag3PO4
played crucial roles and had a cooperative effect on promoting
the transformation. From the series of above examinations,
entry 16 was determined to be the optimal reaction conditions.
Table 3. Substrate Scope of the Aliphatic Amides.a,b
Table 4. Substrate Scope of Aryl Iodides.a,b
Pd(OAc)2 (10 mol%)
N
N
Ar
Pd(OAc)2 (10 mol%)
Cu(OAc)2 (1.2 equiv)
Ag3PO4 (0.3 equiv)
H
Cu(OAc)2 (1.2 equiv)
Ag3PO4 (0.3 equiv)
N
N
N
N
H
O
R3
R2
R1
Ar
H
N
R3
R2
R1
H
H
N
N
F
F
N
H
F
F
N
Ar-I
+
F
F
N
F
F
Ar =
p-xylene:DMF = 1:1
130 oC, 16 h
O
O
p-xylene:DMF = 1:1
130 oC, 16 h
Ar-I
O
OMe
1d
2
4
2a
1
3
R
4c
R = Me, , 75%
N
N
N
N
N
N
N
H
Ar
Ar
Ar
Ar
Ar
N
N
H
4d
R = CF3, , 68%
N
N
N
H
N
H
H
H
F
F
F
F
N
4e
R = F, , 69%
F
F
N
F
F
N
F
F
N
F
F
N
+
+
R = Cl, 4f, 67%
4g
R = COOEt, , 54%
R = COMe,
O
O
O
O
O
O
Ar
4h
69%
4b
47%
R
4c 4h
~
3g
73% ( , 32% and
3g'
, 41%)
(3h
3h'
, 47%)
70%
, 23% and
c
3g
3g'
41% ( , 10% and
, 31%)
R
N
N
Ar
Ar
N
Ar
N
N
N
N
N
4i
R = OMe, , 58%
H
H
N
H
n = 1, 3d, 78%
N
N
F
N
4j
4n
R = OMe, , 67%
F
F
Ar
R = Me, , 67%
F
F
N
H
N
+
H
3j
n = 2, , 64%
F
F
F
F
N
4k
R = CF3, , 63%
4o
R = F, , 64%
n
O
3k
O
n = 3, , 76%
O
4l
4p
R = COOMe, , 33%
R = COOMe, , 62%
F
c
O
O
3l
n = 4, , 70% (53%)
4m
, 60%
R = COMe,
3i
3i'
3i'
75% ( , 43% and , 32%)
3i
59% ( , 35% and , 24%)
3d 3j 3l
,
~
4i 4m
~
4n 4p
~
c
MeO
O
OMe
N
N
N
Ar
Ar
Ar
N
N
N
N
N
N
H
H
H
N
N
F
F
N
H
F
N
F
F
H
N
F
N
F
O
O
O
F
R
3o
3p
O
and
4q
, 67%
4r
, 62%
F
F
c
3o
R= 4-Me, , 43% (32%)
3p
R= 3-Cl, , 35%
3m
, 49%
3n
, 38%
Cl
F
F
Ar
N
N
Ar
Ar
N
N
N
N
N
N
N
H
H
N
N
H
N
N
Cl
N
F
F
H
N
N
H
F
H
N
F
F
F
F
F
N
F
F
n
O
O
O
F
OMe
O
O
O
3r 3t
~
F
3u,
3q
, 44%
41%
3r
n = 1, , 52%
3s
n = 2, , 55% (46%)
3t
n = 3, , 51%
4s
4u
, 57%
, NR
4t
, 59%
c
a
Reaction conditions: 1 (0.3 mmol), 2a (0.9 mmol), Pd(OAc)2
a
(10 mol%), Cu(OAc)2 (0.36 mmol), Ag3PO4 (0.09 mmol), p-
xylene (1.5 mL), DMF (1.5 mL), 130 oC, 16 h. b Isolated yields
of 4.
Reaction conditions: 1 (0.3 mmol), 2a (0.9 mmol), Pd(OAc)2
(10 mol%), Cu(OAc)2 (0.36 mmol), Ag3PO4 (0.09 mmol), p-
xylene (1.5 mL), DMF (1.5 mL), 130 oC, 16 h. b Isolated yields
of 3. c Cu(OAc)2 (0.6 mmol) in the absence of Ag3PO4.
Next, the scope of substrates bearing various substituents on the
iodoarene rings was examined (Table 4). para-Substituents
With the established reaction conditions, a series of
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including Me, CF3, F, Cl, Br, COOEt and COMe were tolerated to
iodides was carried out to futher probe the electronic effect, in
1
2
3
4
5
6
7
8
afford the target products 4c−4h in moderate to good yields
(54−75%), whereas the reaction of 1d with unsubstituted phenyl
iodide (2b) formed 4b in a lower yield (47%). meta-OMe, Me,
CF3, COOMe and COMe-subsitituded aryl iodides also reacted
well with 1d to yield the products 4i−4m in moderate yields
(58−67%). The reactions of 1d with ortho-methoxy and ortho-
fluoro-substituted aryl iodides generated the target products 4n
and 4o in 64−67% yields. Notably, an obvious diminution aroused
from ortho-COOMe substituent, and as a result 4p was only
obtained in 33% yield. In addition, disubstituted iodobenzene
derivatives reacted cleanly to give the arylated products (4q−4t)
with the moderate yields from 1d. However, when iodoethane was
used to reacted with 1d, arylated product 4u was not detected.
Electron-rich aryl iodides were found to give slightly higher
yields than electron-poor aryl iodides. The molecular structure of
the desired product 4k was further confirmed by the X-ray single
crystal structure (See Supporting Information). 20
order to collect some mechanistic information regarding the
arylation reaction.21 The mixture of 2a and 2e (1:1) was
treated with aliphatic amide derivative 1d under standard
reaction conditions. It was observed that 3d gave higher yield
than 4e (Scheme 3), which indicated that electron-donating
aryl groups would facilitate the reaction.
To gain insights into the reaction mechanism, a radical
quencher 2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO) was
added under standard conditions (Scheme 4A). It was found
that TEMPO have negligible effect on the yield, thus it was
unlikely to render a radical pathway. Additionally, we carried
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
out deuterium labelling experiments to investigate further
14a, 22
mechanism.13c,
When substrate 1d was exposed to the
standard consitions without 4-iodoanisole in AcOD, deuterium
was observed at beta position of aliphatic amide (Scheme 4B),
which indicated that the possibility of arylation of β-C(sp3)−H
bonds. Finally, deuterium labeling kinetic isotope effect (KIE,
kH/kD = 3.76) implied that the rate-determining step involved
breaking a C(sp3)−H bond (Scheme 4C).
Scheme 2. Further Study on Pd-Catalyzed C(sp3)−H
Arylation Reaction
A) Arylation of 1d with diiodobenzene
F
Scheme 4. The Effect of TEMPO and Deuterium Labelling
Experiments.
O
I
I
N
F
H
N
N
2v
(
, 0.2 mmol)
OMe
N
1d
N
N
N
H
2a
H
standard conditions
(0.6 mmol)
N
N
F
F
N
H
N
H
N
TEMPO
F
F
F
F
A)
O
standard conditions
O
O
5
, 58%
B) Gram-scale reaction
N
3d
1d
OMe
TEMPO
0
3 equiv
Yield (%)
78
74
N
H
N
H
N
2a
standard conditions
H
F
F
N
F
N
d-content
28%
O
O
N
without 4-iodoanisole
standard conditions
N
N
F
N
CD3
H
N
H
N
F
F
F
F
3d
69% (1.06 g)
OH
B)
1d
4 mmol (1.12 g)
C) Removal of the directing group
OMe
CH3COOD, 130 oC, 1.5 h
O
O
1d
1d
H/D-
89%
N
OMe
N
HCl (12 M)
H
(D)H
(D)H
N
N
N
F
F
N
4-iodoanisole
standard conditions
N
CD3
HO
Reflux
110 oC, 20h
H
N
H
F
F
F
N
O
1d
(0.1 mmol)
C)
+
130 oC, 1.5 h
O
O
O
3d
6
(0.25 mmol)
, 71%
F
kH/kD = 3.76
1d
[D3]-
3d and [D2]-3d
19%
(0.1 mmol)
In addition, we also tested the structural generality of the
reaction by using 1,4-diiodobenzene (2v) as an aryl iodide
under the optimized conditions (Scheme 2A). The result
displayed that the reaction of 1d (0.6 mmol) with 2v (0.2
mmol) proceeded smoothly to obtain the difunctionalized
product (5) in 58% yield. Reproducibility and scalability of
this protocol were successfully tested by proforming a gram-
scale reaction (Scheme 2B). Further, the directing group could
be effectively removed through treatment of arylated product
Scheme 5. Plausible Reaction Mechanism.
N
Ar
R3
R2
R1
N
R3
R2
R1
N
N
H
H
F
F
N
F
F
N
O
O
Pd(OAc)2
1
3
4
and
HOAc
L
I
L
o
N
Ar
with HCl (12 M) at 110 C to give the free arylated acid 6 in
OAc
PdII
N
PdII
N
R3
N
R3
R2
R1
R2
R1
F
F
N
71% yield (Scheme 2C). And aryl methyl ether is also
demethylated with the reaction.
F
N
O
O
IV
F
I
Scheme 3. Competition Experiment.
C
H
Reductive
elimination
Activation
R
HOAc
N
N
H
N
N
2a 2e
/
L
H
H
R3
L
PdIV
I
N
Ar
N
F
F
N
F
F
N
PdII
N
R3
R2
R1
standard conditions
N
F
F
N
O
O
R2
R1
F
F
N
Oxidative
addition
O
1d
3d 4e
/
= 2.1/1.0
O
3d
R = OMe, , 48%
II
4e
R = F, , 23%
III
ArI
A competition experiment with electronically biased aryl
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The Journal of Organic Chemistry
followed by Et3N (607.1 mg, 6 mmol). The corresponding acid
From the above experimental results and relevant literature
reports,4b, f, g, 13d, f, h a proposed mechanism for the reaction is
depicted in Scheme 5. The substrate 1d is probably
coordinated with Pd (II), to form N,N-chelated complex I,
which further undergoes β-C(sp3)–H bond activation via a
concerted metalation deprotonation passway to give
intermediate II. The next step involves oxidative addition of
aryl iodides generating Pd (IV) complex III. Subsequently,
accompanied by reductive elimination, the arylated product 3d
is furnished by exchanging ligand. Meanwhile, the active Pd
(II) catalyst is regenerated to accomplish the catalytic cycle.
We speculates that Cu and Ag salts play dual roles in this
transformation.19a, 23 First, CuII and AgI salts may be facilitate
oxidative addition of aryl iodides to PdII centers. Second, they
acts as iodide scavengers for success of the transformation.
chloride was added drop wise. Then the reaction was stirred at 0 °C
for 10 min, and then room temperture for 2 h. The mixture was
washed with saturated Na2CO3 and brine. Then the organic layer was
dried over MgSO4, filtered and concentrated in vacuo. The residue
was purified via a column chromatography on silica gel (eluents:
petroleum ether/ethyl acetate = 80:1 to 30:1) to supply the substrate 1.
N-(2-(1H-Pyrazol-1-yl)phenyl)-2-methylbutanamide (1a). White
solid; 1.08 g, 89% yield; m.p. 44.9–46.1 oC; 1H NMR (400 MHz,
CDCl3, ppm): δ 10.22 (s, 1H), 8.48 (dd, J1 = 8.4 Hz, J2 = 1.2 Hz, 1H),
7.81 (d, J = 1.6 Hz, 1H), 7.80 (d, J = 2.4 Hz, 1H), 7.38−7.30 (m, 2H),
7.15 (td, J1 = 7.6 Hz, J2 = 1.2 Hz, 1H), 6.50 (t, J = 2.4 Hz, 1H),
2.32−2.23 (m, 1H), 1.75−1.64 (m, 1H), 1.54−1.43 (m, 1H), 1.18 (d, J
= 6.8 Hz, 3H), 0.88 (t, J = 7.6 Hz, 3H); 13C{1H} NMR (100 MHz,
CDCl3, ppm): δ 175.1, 141.0, 131.8, 130.3, 129.1, 128.1, 123.8, 123.1,
122.5, 107.1, 44.5, 27.3, 17.2, 11.7; HRMS (EI): m/z [M+] calcd. for
C14H17N3O: 243.1372; found: 243.1371.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N-(4-Chloro-2-(1H-pyrazol-1-yl)phenyl)-2-methylbutanamide (1b).
o
Yellow solid; 1.21 g, 87% yield; m.p. 33.2–35.0 C; 1H NMR (400
CONCLUSION
MHz, CDCl3, ppm): δ 10.33 (s, 1H), 8.48 (d, J = 8.8 Hz, 1H),
7.81−7.80 (m, 2H), 7.29−7.26 (m, 2H), 6.51 (t, J = 2.4 Hz, 1H),
2.32−2.23 (m, 1H), 1.75−1.64 (m, 1H), 1.54−1.43 (m, 1H), 1.18 (d, J
= 6.8 Hz, 3H), 0.88 (t, J = 7.6 Hz, 3H); 13C{1H} NMR (100 MHz,
CDCl3, ppm): δ 175.2, 141.4, 130.4, 130.2, 129.6, 128.5, 127.8, 124.1,
122.2, 107.6, 44.5, 27.2, 17.1, 11.7; HRMS (EI): m/z [M+] calcd. for
C14H16N3OCl: 277.0982; found: 277.0980.
In summary, we have developed a Pd-catalyzed arylation of
unactivated β-C(sp3)–H bonds in carboxylic acid derivatives
via 2-amino-5,6-difluorophenyl-1H-pyrazole as an easily
removable auxiliary in the presence of Cu(OAc)2 and Ag3PO4
(1.2/0.3) as additives. These findings prove that the
transformation is significantly facilitated by introducing two
fluoro groups at initial directing group. This protocol exhibits
excellent β-site selectivity, which is compatible with diverse
substrates containing α-hydrogen atoms and arylation of
methylene C(sp3)−H bonds. Futher explorations of new
reactions with the novel modified N,N-bidentate directing
group are underway in our lab.
N-(4-Fluoro-2-(1H-pyrazol-1-yl)phenyl)-2-methylbutanamide (1c).
White solid; 0.82 g, 63% yield; m.p. 38.3–40.0 oC; 1H NMR (400
MHz, CDCl3, ppm): δ 10.23 (s, 1H), 8.44 (dd, J1 = 10.0 Hz, J2 = 5.6
Hz, 1H), 7.80 (d, J = 2.0 Hz, 1H), 7.78 (d, J = 2.8 Hz, 1H), 7.08−7.04
(m, 2H), 6.51 (dd, J1 = 2.4 Hz, J2 = 2.0 Hz, 1H), 2.31−2.22 (m, 1H),
1.74−1.63 (m, 1H), 1.53−1.43 (m, 1H), 1.17 (d, J = 6.8 Hz, 3H), 0.87
(t, J = 7.6 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3, ppm): δ 175.1,
158.3 (d, JCF = 242.9 Hz), 141.4, 130.2, 129.81 (d, JCF = 9.3 Hz),
127.9 (d, JCF = 3.1 Hz), 124.8 (d, JCF = 8.3 Hz), 114.4 (d, JCF = 21.3
Hz), 109.5 (d, JCF = 25.9 Hz), 107.6, 44.4, 27.3, 17.2, 11.7. HRMS
(EI): m/z [M+] calcd. for C14H16N3OF: 261.1277; found: 261.1278.
N-(3,4-Difluoro-2-(1H-pyrazol-1-yl)phenyl)-2-methylbutanamide
(1d). White solid; 0.58 g, 42% yield; m.p. 45.4–47.1 oC; 1H NMR
(400 MHz, CDCl3, ppm): δ 9.59 (s, 1H), 8.18−8.14 (m, 1H), 7.86 (d, J
= 1.6 Hz, 1H), 7.81 (dd, J1 = 4.0 Hz, J2 = 2.8 Hz, 1H), 7.19 (q, J = 9.2
Hz, 1H), 6.56 (t, J = 2.0 Hz, 1H), 2.26−2.17 (m, 1H), 1.70−1.59 (m,
1H), 1.50−1.40 (m, 1H), 1.14 (d, J = 6.8 Hz, 3H), 0.84 (t, J = 7.2 Hz,
3H); 13C{1H} NMR (100 MHz, CDCl3, ppm): δ 175.1, 146.9 (dd, JCF
= 244.8, 11.9 Hz), 143.8 (dd, JCF = 248.9, 15.5 Hz), 141.6, 133.1 (d,
JCF = 6.4 Hz), 129.8 (d, JCF = 3.2 Hz), 120.0 (d, JCF = 9.8 Hz), 118.0
(dd, JCF = 6.6, 4.6 Hz), 115.9 (d, JCF = 17.3 Hz), 107.5, 44.3, 27.2,
17.0, 11.6; HRMS (EI): m/z [M+] calcd. for C14H15N3OF2: 279.1183;
found: 279.1182.
2-Methyl-N-(3,4,5-trifluoro-2-(1H-pyrazol-1-yl)phenyl)butanamide
(1e). Yellow oil; 0.42 g, 28% yield; 1H NMR (400 MHz, CDCl3,
ppm): δ 9.57 (s, 1H), 8.30−8.25 (m, 1H), 7.87 (d, J = 2.0 Hz, 1H),
7.77 (dd, J1 = 4.0 Hz, J2 = 2.4 Hz, 1H), 6.57 (t, J = 2.4 Hz, 1H),
2.25−2.17 (m, 1H), 1.70−1.59 (m, 1H), 1.51−1.40 (m, 1H), 1.14 (d, J
= 6.8 Hz, 3H), 0.85 (t, J = 7.6 Hz, 3H); 13C{1H} NMR (100 MHz,
CDCl3, ppm): δ 174.1, 148.7 (ddd, JCF = 247.5, 9.8, 4.5 Hz), 143.9
(ddd, JCF = 248.9, 12.2, 5.3 Hz), 140.9, 135.2 (ddd, JCF = 248.2, 16.3,
14.4 Hz), 132.0 (d, JCF = 6.0 Hz), 128.5 (dd, JCF = 11.4, 3.6 Hz),
114.5 (dd, JCF = 10.9, 4.4 Hz), 106.6, 104.9 (dd, JCF = 23.6, 3.5 Hz),
43.3, 26.1, 15.9, 10.5; HRMS (EI): m/z [M+] calcd. for C14H14N3OF3:
297.1089; found: 297.1092.
EXPERIMENTAL SECTION
General Information. Unless otherwise indicated, all reagents
were obtained from commercial sources and used as received without
further purification. All solvents were only dried over 4 Å molecular
sieves. Reaction products were purified via column chromatography
on silica gel (100–200 mesh). Melting points were determined using
an open capillaries and uncorrected. NMR spectra were determined
on Bruker AV400 in CDCl3 with TMS as internal standard for 1H
NMR (400 MHz) and 13C NMR (100 MHz), respectively. HRMS
were measured on a QSTAR Pulsar I LC/TOF MS mass spectrometer
or Micromass GCTTM gas chromatograph-mass spectrometer.
General Procedure for the Preparation of Substrates. 16a , 24 To a
solution of fluorinated nitrobenzene (5 mmol) and DMSO (20.0 mL)
was slowly added NaOH (200.0 mg, 5 mmol), and pyrazole (408.5
mg, 6 mmol) in sequence. After the addition, the mixture was stirred
at room temperture for 4 h. Water (20 mL × 3) was added to the
mixture, then the product extracted with ethyl acetate (20 mL × 3).
The combined organic layer was dried over anhydrous MgSO4.
Finally, the solution was concentrated in vacuo to provide a crude
product. A mixture of iron powder (1.07 g, 19.1 mmol) and NH4Cl
(0.14 g, 2.6 mmol), in water (5.0 mL) was heated to 100 oC (oil bath)
for 15 min. Then the crude product of the previous step was quickly
added, and and stirred for corresponding time (TLC monitored). Upon
completion of the reaction, the mixture was cooled to room
temperature and neutralized with 5% NaHCO3 solution(V/V) and
extracted with ethyl acetate (20 mL × 3) and dryed with MgSO4.
Finally, the solution was concentrated in vacuo to provide a crude
product of 2-aminophenyl-1H-pyrazole derivatives.
N-(4-methoxy-2-(1H-pyrazol-1-yl)phenyl)-2-methylbutanamide (1f).
o
1
Yellow solid; 1.13 g, 83% yield; m.p. 60.4–62.0 C; H NMR (400
MHz, CDCl3, ppm): δ 9.88 (s, 1H), 8.30 (d, J = 9.2 Hz, 1H), 7.79 (d, J
= 1.6 Hz, 1H), 7.77 (d, J = 2.4 Hz, 1H), 6.90 (dd, J1 = 9.2 Hz, J2 = 2.8
Hz, 1H), 6.85 (d, J = 2.8 Hz, 1H), 6.48 (t, J = 2.0 Hz, 1H), 3.82 (s,
3H), 2.28−2.19 (m, 1H), 1.71−1.64 (m, 1H), 1.50−1.43 (m, 1H), 1.16
(d, J = 6.8 Hz, 3H), 0.85 (t, J = 7.6 Hz, 3H); 13C{1H} NMR (100 MHz,
CDCl3, ppm): δ 174.9, 155.9, 141.1, 130.4, 130.2, 125.0, 124.7, 112.6,
108.9, 107.2, 55.8, 44.3, 27.3, 17.2, 11.7; HRMS (EI): m/z [M+] calcd.
for C15H19N3O2: 273.1477; found: 273.1476.
To a solution of the carboxylic acid (6 mmol) and DCM (15.0 mL)
at 0 oC (ice-water bath) was added 1–3 drops of DMF. After
effervescing subsided, oxalyl chloride (2.0 mL) was added drop wise.
o
After stirring and refluxing at 40 C (oil bath) for 10 h, the reaction
was concentrated in vacuo to give the acid chloride as an oil. It was
taken back with DCM (5 mL), cooled back 0°C. A solution of 2-
aminophenyl-1H-pyrazole derivatives in DCM (15.0 mL) was added,
N-(3,4-Difluoro-2-(1H-pyrazol-1-yl)phenyl)-2,2-dimethylbutanami-
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 14
o
1
de (1g). White solid; 0.59 g, 40% yield; m.p. 55.6–57.5 C; H NMR
(400 MHz, CDCl3, ppm): δ 9.71 (s, 1H), 8.17−8.13 (m, 1H), 7.86 (d, J
= 2.0 Hz, 1H), 7.80 (dd, J1 = 3.6 Hz, J2 = 2.4 Hz, 1H), 7.19 (q, J = 9.2
Hz, 1H), 6.56 (dd, J1 = 2.4 Hz, J2 = 2.0 Hz, 1H), 1.53 (q, J = 7.6 Hz,
2H), 1.14 (s, 6H), 0.76 (t, J = 7.6 Hz, 3H); 13C{1H} NMR (100 MHz,
CDCl3, ppm): δ 176.7, 146.8 (dd, JCF = 244.7, 11.9 Hz), 143.8 (dd,
1H), 7.74 (dd, J1 = 4.0 Hz, J2 = 2.4 Hz, 1H), 7.23−7.18 (m, 3H),
7.17−7.15 (m, 1H), 7.12−7.09 (m, 2H), 6.52 (t, J = 2.4 Hz, 1H), 2.99
(dd, J1 = 13.6 Hz, J2 = 7.2 Hz, 1H), 2.67 (dd, J1 = 13.6 Hz, J2 = 7.6
Hz, 1H), 2.61−2.52 (m, 1H), 1.17 (d, J = 6.8 Hz, 3H); 13C{1H} NMR
(100 MHz, CDCl3, ppm): δ 174.3, 146.9 (dd, JCF = 245.1, 12.1 Hz),
143.7 (dd, JCF = 248.8, 15.4 Hz), 141.6, 139.2, 133.1 (d, JCF = 6.7 Hz),
1
2
3
4
JCF = 248.9, 15.6 Hz), 141.6, 133.1 (d, JCF = 6.2 Hz), 130.1 (d, JCF
=
129.5 (d, JCF = 3.3 Hz), 128.8 (2C), 128.4 (2C), 126.4, 119.9 (d, JCF =
5
6
7
8
3.3 Hz), 120.1 (d, JCF = 10.1 Hz), 118.0 (dd, JCF = 6.6, 4.5 Hz), 115.9
(d, JCF = 17.4 Hz), 107.5, 43.6, 33.8, 24.7 (2C), 9.0; HRMS (EI): m/z
[M+] calcd. for C15H17N3OF2: 293.1340; found: 293.1339.
9.3 Hz), 117.9 (dd, JCF = 6.7, 4.8 Hz), 115.9 (d, JCF = 17.5 Hz), 107.5,
44.8, 40.2, 17.1; HRMS (EI): m/z [M+] calcd. for C19H17N3OF2:
341.1340; found: 341.1342.
N-(3,4-Difluoro-2-(1H-pyrazol-1-yl)phenyl)-1-methylcyclohexanec-
N-(3,4-Difluoro-2-(1H-pyrazol-1-yl)phenyl)-2-phenylpropanamide
(1n). Yellow oil; 0.52 g, 32% yield; 1H NMR (400 MHz, CDCl3,
ppm): δ 9.40 (s, 1H), 8.19−8.14 (m, 1H), 7.65 (dd, J1 = 3.6 Hz, J2 =
2.8 Hz, 1H), 7.52 (d, J = 1.6 Hz, 1H), 7.33−7.27 (m, 3H), 7.23−7.21
(m, 2H), 7.16 (q, J = 9.6 Hz, 1H), 6.41 (t, J = 2.4 Hz, 1H), 3.65 (q, J =
7.2 Hz, 1H), 1.54 (d, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz,
CDCl3, ppm): δ 173.0, 146.8 (dd, JCF = 244.9, 11.9 Hz), 143.8 (dd,
JCF = 248.8, 15.4 Hz), 141.6, 140.3, 132.7 (d, JCF = 6.2 Hz), 129.9 (d,
JCF = 3.2 Hz), 129.0 (2C), 127.8 (2C), 127.5, 119.9 (d, JCF = 10.2 Hz),
117.6 (dd, JCF = 6.6, 4.6 Hz), 115.8 (d, JCF = 17.4 Hz), 107.1, 48.4,
18.0; HRMS (EI): m/z [M+] calcd. for C18H15N3OF2: 327.1183; found:
327.1185.
N-(3,4-Difluoro-2-(1H-pyrazol-1-yl)phenyl)-2-(p-tolyl)propanami-
de (1o). Yellow solid; 0.58 g, 34% yield; m.p. 57.6–59.1 oC; 1H NMR
(400 MHz, CDCl3, ppm): δ 9.32 (s, 1H), 8.19−8.15 (m, 1H), 7.65 (dd,
J1 = 3.6 Hz, J2 = 2.8 Hz, 1H), 7.51 (d, J = 2.0 Hz, 1H), 7.16 (q, J = 9.2
Hz, 1H), 7.13−7.08 (m, 4H), 6.42 (t, J = 2.4 Hz, 1H), 3.61 (q, J = 7.2
Hz, 1H), 2.36 (s, 3H), 1.52 (d, J = 7.2 Hz, 3H); 13C{1H} NMR (100
MHz, CDCl3, ppm): δ 173.2, 146.8 (dd, JCF = 244.8, 11.9 Hz), 143.8
(dd, JCF = 248.8, 15.4 Hz), 141.5, 137.2, 137.0, 132.7 (d, JCF = 6.1
o
9
arboxamide (1h). White solid; 0.59 g, 37% yield; m.p. 53.6–54.4 C;
1H NMR (400 MHz, CDCl3, ppm): δ 9.73 (s, 1H), 8.18−8.14 (m, 1H),
7.85 (d, J = 2.0 Hz, 1H), 7.79 (dd, J1 = 3.6 Hz, J2 = 2.8 Hz, 1H), 7.19
(q, J = 9.2 Hz, 1H), 6.55 (6, J = 2.0 Hz, 1H), 1.96−1.93 (m, 2H),
1.50−1.44 (m, 3H), 1.32−1.27 (m, 5H), 1.12 (s, 3H); 13C{1H} NMR
(100 MHz, CDCl3, ppm): δ 176.6, 146.8 (dd, JCF = 244.6, 11.9 Hz),
143.9 (dd, JCF = 248.8, 15.5 Hz), 141.7, 133.1 (d, JCF = 6.1 Hz), 130.2
(d, JCF = 3.2 Hz), 120.1 (d, JCF = 10.1 Hz), 118.0 (d, JCF = 6.5, 4.6 Hz),
115.9 (d, JCF = 17.3 Hz), 107.5, 44.0, 35.5 (2C), 26.7, 25.6, 22.9 (2C);
HRMS (EI): m/z [M+] calcd. for C17H19N3OF2: 319.1496; found:
319.1497.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N-(3,4-Difluoro-2-(1H-pyrazol-1-yl)phenyl)isobutyramide
(1i).
White solid; 0.57 g, 43% yield; m.p. 76.5–78.3 oC; 1H NMR (400
MHz, CDCl3, ppm): δ 9.64 (s, 1H), 8.20−8.15 (m, 1H), 7.86 (d, J =
2.0 Hz, 1H), 7.8 (dd, J1 = 4.4 Hz, J2 = 2.8 Hz, 1H), 7.19 (q, J = 9.6 Hz,
1H), 6.56 (t, J = 2.4 Hz, 1H), 2.49−2.42 (m, 1H), 1.17 (s, 3H), 1.15 (s,
3H); 13C{1H} NMR (100 MHz, CDCl3, ppm): δ 175.5, 146.8 (dd, JCF
= 244.8, 12.0 Hz), 143.8 (dd, JCF = 248.8, 15.4 Hz), 141.6, 133.2 (d,
JCF = 6.5 Hz), 129.9 (d, JCF = 3.2 Hz), 119.9 (d, JCF = 10.2 Hz), 117.8
(dd, JCF = 6.6, 4.6 Hz), 115.9 (d, JCF = 17.1 Hz), 107.5, 36.9, 19.2
(2C); HRMS (EI): m/z [M+] calcd. for C13H13N3OF2: 265.1027; found:
265.1028.
Hz), 130.0 (d, JCF = 3.2 Hz), 129.7 (2C), 127.7 (2C), 119.9 (d, JCF
=
10.6 Hz), 117.5 (dd, JCF = 6.5, 4.6 Hz), 115.9 (d, JCF = 17.4 Hz),
107.0, 47.9, 21.1, 18.0; HRMS (EI): m/z [M+] calcd. for C19H17N3OF2:
341.1340; found: 341.1339.
N-(3,4-Difluoro-2-(1H-pyrazol-1-yl)phenyl)-2-methylpentanamide
(1j). White solid; 0.61 g, 42% yield; m.p. 62.1–63.4 oC; 1H NMR (400
MHz, CDCl3, ppm): δ 9.57 (s, 1H), 8.17−8.13 (m, 1H), 7.86 (d, J =
1.6 Hz, 1H), 7.80 (dd, J1 = 4.0 Hz, J2 = 2.8 Hz, 1H), 7.18 (q, J = 9.2
Hz, 1H), 6.55 (t, J = 2.0 Hz, 1H), 2.34−2.25 (m, 1H), 1.64−1.55 (m,
1H), 1.41−1.32 (m, 1H), 1.28−1.19 (m, 2H), 1.13 (d, J = 6.8 Hz, 3H),
0.84 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3, ppm): δ
175.2, 146.9 (dd, JCF = 244.9, 12.0 Hz), 143.8 (dd, JCF = 248.9, 15.5
Hz), 141.6, 133.1 (d, JCF = 6.4 Hz), 129.8 (d, JCF = 3.2 Hz), 120.0 (d,
JCF = 10.2 Hz), 118.0 (dd, JCF = 6.6, 4.6 Hz), 115.9 (d, JCF = 17.2 Hz),
107.4, 42.5, 36.4, 20.3, 17.5, 13.9; HRMS (EI): m/z [M+] calcd. for
C15H17N3OF2: 293.1340; found: 293.1341.
N-(3,4-Difluoro-2-(1H-pyrazol-1-yl)phenyl)-2-methylhexanamide
(1k). White solid; 0.55 g, 36% yield; m.p. 60.5–62.3 oC; 1H NMR
(400 MHz, CDCl3, ppm): δ 9.56 (s, 1H), 8.16−8.12 (m, 1H), 7.86 (d, J
= 2.0 Hz, 1H), 7.81 (dd, J1 = 3.6 Hz, J2 = 2.8 Hz, 1H), 7.19 (q, J = 9.2
Hz, 1H), 6.56 (t, J = 2.4 Hz, 1H), 2.32−2.23 (m, 1H), 1.65−1.56 (m,
1H), 1.43−1.34 (m, 1H), 1.32−1.88 (m, 4H), 1.13 (d, J = 6.8 Hz, 3H),
0.83 (t, J = 6.8 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3, ppm): δ
175.3, 146.9 (dd, JCF = 244.9, 11.9 Hz), 143.8 (dd, JCF = 248.9, 15.5
Hz), 141.7, 133.1 (d, JCF = 6.3 Hz), 129.8 (d, JCF = 3.3 Hz), 120.0 (d,
JCF = 9.3 Hz), 118.1 (dd, JCF = 6.7, 4.7 Hz), 115.9 (d, JCF = 17.4 Hz),
107.5, 42.7, 33.9, 29.3, 22.6, 17.5, 13.9; HRMS (EI): m/z [M+] calcd.
for C16H19N3OF2: 307.1496; found: 307.1494.
N-(3,4-Difluoro-2-(1H-pyrazol-1-yl)phenyl)-2-methylheptanamide
(1l). White solid; 0.59 g, 37% yield; m.p. 39.3–41.1 oC; 1H NMR (400
MHz, CDCl3, ppm): δ 9.58 (s, 1H), 8.17−8.13 (m, 1H), 7.85 (d, J =
1.6 Hz, 1H), 7.80 (dd, J1 = 4.0 Hz, J2 = 2.4 Hz, 1H), 7.18 (q, J = 9.6
Hz, 1H), 6.55 (t, J = 2.0 Hz, 1H), 2.32−2.23 (m, 1H), 1.64−1.55 (m,
1H), 1.42−1.33 (m, 1H), 1.97−1.25 (m, 6H), 1.13 (d, J = 6.8 Hz, 3H),
0.83 (t, J = 6.8 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3, ppm): δ
175.3, 146.9 (dd, JCF = 244.8, 12.1 Hz), 143.8 (dd, JCF = 248.9, 15.5
Hz), 141.6, 133.1 (d, JCF = 6.4 Hz), 129.8 (d, JCF = 3.2 Hz), 120.0 (d,
JCF = 9.8 Hz), 118.0 (dd, JCF = 6.6, 4.7 Hz), 115.9 (d, JCF = 17.3 Hz),
107.5, 42.8, 34.2, 31.7, 26.8, 22.5, 17.5, 14.0.; HRMS (EI): m/z [M+]
calcd. for C17H21N3OF2: 321.1653; found: 321.1650.
2-(3-Chlorophenyl)-N-(3,4-difluoro-2-(1H-pyrazol-1-yl)phenyl)pr-
o
opanamide (1p). White solid; 0.56 g, 31% yield; m.p. 72.5–73.3 C;
1H NMR (400 MHz, CDCl3, ppm): δ 9.50 (s, 1H), 8.18−8.14 (m, 1H),
7.70 (dd, J1 = 3.6 Hz, J2 = 2.4 Hz, 1H), 7.63 (d, J = 2.0 Hz, 1H),
7.28−7.26 (m, 1H), 7.25−7.23 (m, 2H), 7.21−7.17 (m, 1H), 7.14−7.12
(m, 1H), 6.46 (t, J = 2.0 Hz, 1H), 3.64 (q, J = 7.2Hz, 1H), 1.54 (d, J =
7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3, ppm): δ 172.1, 147.0
(dd, JCF = 245.2, 12.0 Hz), 143.7 (dd, JCF = 249.1, 15.5 Hz), 142.3,
141.6, 134.7, 132.8 (d, JCF = 6.5 Hz), 130.2, 129.6 (d, JCF = 3.2 Hz),
128.0, 127.7, 126.0, 119.9 (d, JCF = 9.9 Hz), 117.7 (dd, JCF = 6.5, 4.7
Hz), 115.8 (d, JCF = 17.4 Hz), 107.3, 48.0, 17.9; HRMS (EI): m/z [M+]
calcd. for C18H14N3OF2Cl: 361.0793; found: 361.0789.
N-(3,4-Difluoro-2-(1H-pyrazol-1-yl)phenyl)-2-(6-methoxynaphtha-
len-2-yl)propanamide (1q). Yellow solid; 0.61 g, 30% yield; m.p.
o
1
106.2–107.4 C; H NMR (400 MHz, CDCl3, ppm): δ 9.29 (s, 1H),
8.21−8.17 (m, 1H), 7.70 (d, J = 8.8 Hz, 1H), 7.66 (d, J = 8.4 Hz, 1H),
7.59 (s, 1H), 7.53 (dd, J1 = 3.6 Hz, J2 = 2.8 Hz, 1H), 7.26−7.24 (m,
1H), 7.20 (dd, J1 = 8.8 Hz, J2 = 2.4 Hz, 1H), 7.17−7.12 (m, 2H), 6.79
(d, J = 1.6 Hz, 1H), 6.14 (t, J = 2.0 Hz, 1H), 3.95 (s, 3H), 3.89 (q, J =
7.2 Hz, 1H), 1.83 (d, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz,
CDCl3, ppm): δ 173.3, 157.9, 146.8 (dd, JCF = 244.6, 11.6 Hz), 143.8
(dd, JCF = 248.8, 15.4 Hz), 141.3, 135.2, 134.0, 132.5 (d, JCF = 5.5
Hz), 130.0 (d, JCF = 3.1 Hz), 129.3, 129.1, 127.7, 126.7, 126.2, 119.8
(d, JCF = 9.1 Hz), 119.2, 117.4 (dd, JCF = 6.5, 4.7 Hz), 115.8 (d, JCF =
17.2 Hz), 106.9, 105.6, 55.4, 48.3, 17.8; HRMS (EI): m/z [M+] calcd.
for C23H19N3O2F2: 407.1445; found: 407.1447.
N-(3,4-Difluoro-2-(1H-pyrazol-1-yl)phenyl)cyclobutanecarboxami-
de (1r). Yellow solid; 0.54 g, 39% yield; m.p. 88.7–90.7 oC; 1H NMR
(400 MHz, CDCl3, ppm): δ 9.55 (s, 1H), 8.22−8.18 (m, 1H), 7.84 (d, J
= 2.0 Hz, 1H), 7.80 (dd, J1 = 4.0 Hz, J2 = 2.8 Hz, 1H), 7.18 (q, J = 9.6
Hz, 1H), 6.54 (t, J = 2.4 Hz, 1H), 3.13−3.05 (m, 1H), 2.29−2.16 (m,
4H), 2.01−1.90 (m, 1H), 1.87−1.80 (m, 1H); 13C{1H} NMR (100
MHz, CDCl3, ppm): δ 173.6, 146.8 (dd, JCF = 244.8, 12.0 Hz), 143.8
(dd, JCF = 248.7, 15.4 Hz), 141.6, 133.2 (d, JCF = 6.6 Hz), 129.8 (d,
JCF = 3.2 Hz), 119.7 (d, JCF = 10.1 Hz), 117.6 (dd, JCF = 6.0, 4.6 Hz),
115.9 (d, JCF = 17.3 Hz), 107.4, 41.1, 25.2 (2C), 17.9; HRMS (EI):
m/z [M+] calcd. for C14H13N3OF2: 277.1027; found: 277.1026.
N-(3,4-Difluoro-2-(1H-pyrazol-1-yl)phenyl)cyclopentanecarboxa-
N-(3,4-Difluoro-2-(1H-pyrazol-1-yl)phenyl)-2-methyl-3-phenylpro-
1
panamide (1m). Yellow oil; 0.68 g, 40% yield; H NMR (400 MHz,
CDCl3, ppm): δ 9.56 (s, 1H), 8.16−8.12 (m, 1H), 7.81 (d, J = 2.0 Hz,
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1
mide (1s). White solid; 0.62 g, 43% yield; m.p. 83.1–84.8 oC; 1H
namide (3c). Yellow oil; 50.7 mg, 46% yield; H NMR (400 MHz,
CDCl3, ppm): δ 9.99 (s, 1H), 8.33 (dd, J1 = 9.2 Hz, J2 = 5.6 Hz, 1H),
7.73 (d, J = 1.2 Hz, 1H), 7.67 (d, J = 2.0 Hz, 1H), 7.054 (dd, J1 = 9.2
Hz, J2 = 2.8 Hz, 1H), 7.03–7.00 (m, 3H), 6.70 (d, J = 8.4 Hz, 2H),
6.47 (s, 1H), 3.74 (s, 3H), 2.88 (dd, J1 = 13.6 Hz, J2 = 8.8 Hz, 1H),
2.70 (dd, J1 = 14.0 Hz, J2 = 6.0 Hz, 1H), 2.36–2.32 (m, 1H), 1.75–
1.68 (m, 1H), 1.60–1.53 (m, 1H), 0.87 (t, J = 7.6 Hz, 3H); 13C{1H}
NMR (100 MHz, CDCl3, ppm): δ 173.8, 158.5 (d, JCF = 243.0 Hz),
157.9, 141.3, 131.5, 130.0, 129.9, 129.7 (2C), 127.5 (d, JCF = 3.2 Hz),
125.1 (d, JCF = 8.4 Hz), 114.4 (d, JCF = 21.4 Hz), 113.7 (2C), 109.6 (d,
JCF = 25.8 Hz), 107.5, 55.1, 53.3, 38.0, 25.6, 11.9; HRMS (EI): m/z
[M+] calcd. for C21H22N3O2F: 367.1696; found: 367.1695.
NMR (400 MHz, CDCl3, ppm): δ 9.58 (s, 1H), 8.19−8.15 (m, 1H),
7.88 (d, J = 1.2 Hz, 1H), 7.81 (dd, J1 = 4.0 Hz, J2 = 2.8 Hz, 1H), 7.19
(q, J = 9.2 Hz, 1H), 6.57 (t, J = 2.0 Hz, 1H), 2.67−2.59 (m, 1H),
1.92−1.85 (m, 2H), 1.78−1.69 (m, 4H), 1.63−1.57 (m, 2H); 13C{1H}
NMR (100 MHz, CDCl3, ppm): δ 174.9, 146.8 (dd, JCF = 244.7, 11.9
Hz), 143.8 (dd, JCF = 248.8, 15.5 Hz), 141.6, 133.2 (d, JCF = 6.5 Hz),
133.0 (d, JCF = 3.2 Hz), 119.8 (d, JCF = 10.0 Hz), 117.8 (dd, JCF = 6.5,
4.6 Hz), 115.9 (d, JCF = 17.3 Hz), 107.4, 47.1, 30.1 (2C), 25.8 (2C);
HRMS (EI): m/z [M+] calcd. for C15H15N3OF2: 291.1183; found:
291.1182.
1
2
3
4
5
6
7
8
9
N-(3,4-Difluoro-2-(1H-pyrazol-1-yl)phenyl)cyclohexanecarboxami-
o
1
de (1t). White solid; 0.64 g, 42% yield; m.p. 92.1–93.6 C; H NMR
(400 MHz, CDCl3, ppm): δ 9.59 (s, 1H), 8.19−8.14 (m, 1H), 7.88 (d, J
= 1.6 Hz, 1H), 7.81 (dd, J1 = 4.0 Hz, J2 = 2.8 Hz, 1H), 7.18 (q, J = 9.2
Hz, 1H), 6.56 (t, J = 2.0 Hz, 1H), 2.20−2.13 (m, 1H), 1.86 (dd, J1 =
12.8 Hz, J2 = 2.0 Hz, 2H), 1.80−1.76 (m, 2H), 1.68−1.65 (m, 1H),
1.44−1.35 (m, 2H), 1.29−1.21 (m, 3H); 13C{1H} NMR (100 MHz,
CDCl3, ppm): δ 174.6, 146.8 (dd, JCF = 244.8, 12.0 Hz), 143.8 (dd,
N-(3,4-Difluoro-2-(1H-pyrazol-1-yl)phenyl)-2-(4-methoxybenzyl)b-
utanamide (3d). Yellow oil; 66.9 mg, 58% yield; 1H NMR (400 MHz,
CDCl3, ppm): δ 9.41 (s, 1H), 8.07–8.02 (m, 1H), 7.78 (d, J = 1.2 Hz,
1H), 7.70 (dd, J1 = 4.0 Hz, J2 = 2.4 Hz, 1H), 7.16 (q, J = 9.6 Hz, 1H),
6.98 (d, J = 8.8 Hz, 2H), 6.70 (d, J = 8.4 Hz, 2H), 6.51 (t, J = 2.4 Hz,
1H), 3.75 (s, 3H), 2.83 (dd, J1 = 14.0 Hz, J2 = 8.8 Hz, 1H), 2.67 (dd,
J1 = 13.6 Hz, J2 = 6.0 Hz, 1H), 2.32–2.24 (m, 1H), 1.71–1.63 (m, 1H),
1.57–1.51 (m, 1H), 0.84 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz,
CDCl3, ppm): δ 173.8, 158.0, 147.0 (dd, JCF = 245.0, 12.0 Hz), 143.8
(dd, JCF = 248.9, 15.5 Hz), 141.5, 133.0 (d, JCF = 6.4 Hz), 131.3,
129.6 (2C), 129.4 (d, JCF = 3.3 Hz), 120.1 (d, JCF = 10.9 Hz), 118.3
(dd, JCF = 6.7, 4.6 Hz), 115.8 (d, JCF = 17.5 Hz), 113.8 (2C), 107.4,
55.1, 53.2, 38.0, 25.6, 11.8; HRMS (EI): m/z [M+] calcd. for
C21H21N3O2F2: 385.1602; found: 385.1601.
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
JCF = 248.8, 15.5 Hz), 141.6, 133.2 (d, JCF = 6.5 Hz), 129.9 (d, JCF
=
3.2 Hz), 119.9 (d, JCF = 9.2 Hz), 117.9 (dd, JCF = 6.5, 4.7 Hz), 115.9
(d, JCF = 17.2 Hz), 107.5, 46.4, 29.3 (2C), 25.7, 25.6 (2C); HRMS
(EI): m/z [M+] calcd. for C16H17N3OF2: 305.1340; found: 305.1339.
N-(3,4-difluoro-2-(1H-pyrazol-1-yl)phenyl)propionamide
(1u).
o
1
Yellow soild; 0.47 g, 37% yield; m.p. 59.3–61.1 C; H NMR (400
MHz, CDCl3, ppm): δ 9.61 (s, 1H), 8.20−8.16 (m, 1H), 7.84 (d, J =
2.0 Hz, 1H), 7.81 (dd, J1 = 4.4 Hz, J2 = 2.8 Hz, 1H), 7.17 (q, J = 9.6
Hz, 1H), 6.54 (t, J = 2.0 Hz, 1H), 2.32 (q, J = 7.6 Hz, 2H), 1.15 (t, J =
7.6 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3, ppm): δ 172.3, 146.8
(dd, JCF = 244.8, 11.9 Hz), 143.8 (dd, JCF = 248.8, 15.6 Hz), 141.7,
133.2 (d, JCF = 6.7 Hz), 129.7 (d, JCF = 3.2 Hz), 119.7 (d, JCF = 10.2
Hz), 117.7 (dd, JCF = 6.5, 4.8 Hz), 115.9 (d, JCF = 17.4 Hz), 107.4,
31.0, 9.3; HRMS (EI): m/z [M+] calcd. for C12H11N3OF2: 251.0870;
found: 251.0869.
2-(4-Methoxybenzyl)-N-(3,4,5-trifluoro-2-(1H-pyrazol-1-
yl)phenyl-)butanamide (3e). Yellow oil; 62.7 mg, 52% yield; 1H NMR
(400 MHz, CDCl3, ppm): δ 9.37 (s, 1H), 8.20–8.14 (m, 1H), 7.79 (d, J
= 2.0 Hz, 1H), 7.65 (dd, J1 = 4.0 Hz, J2 = 2.8 Hz, 1H), 6.97 (d, J = 8.8
Hz, 2H), 6.70 (d, J = 8.8 Hz, 2H), 6.52 (t, J = 2.0 Hz, 1H), 3.75 (s,
3H), 2.82 (dd, J1 = 13.6 Hz, J2 = 8.8 Hz, 1H), 2.68 (dd, J1 = 13.6 Hz,
J2 = 6.0 Hz, 1H), 2.29–2.25 (m, 1H), 1.71–1.64 (m, 1H), 1.58–1.52
(m, 1H), 0.86 (t, J = 7.6 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3,
ppm): δ 173.9, 158.0, 149.6 (ddd, JCF = 247.5, 9.6, 4.5 Hz), 144.9
(ddd, JCF = 249.1, 12.0, 5.3 Hz), 141.8, 136.4 (ddd, 1JCF = 249.4, 2JCF
= 31.0, JCF = 14.9 Hz), 132.9 (d, JCF = 6.0 Hz), 131.1, 129.6 (2C),
129.0 (ddd, JCF = 11.8, 3.5, 1.9 Hz), 115.5 (dd, JCF = 10.7, 4.0 Hz),
113.8 (2C), 107.5, 106.1 (dd, JCF = 23.4, 3.4 Hz), 55.1, 53.4, 37.9,
25.5, 11.8; HRMS (EI): m/z [M+] calcd. for C21H20N3O2F3: 403.1508;
found: 403.1509.
General Procedure for Pd(II)-Catalyzed C(sp3)–H Bond
Arylation. A mixture of substrate 1 (0.3 mmol), aryl iodide 2 (0.9
mmol), Pd(OAc)2 (6.7 mg, 10 mol%), Cu(OAc)2 (65.4 mg, 0.36
mmol), Ag3PO4 (37.7 mg, 0.09 mmol), in p-xylene (1.5 mL) and
DMF (1.5 mL) was charged in a glass sealed-tube and stirred at 130
oC (oil bath) for 16 h. Upon completion of the reaction, saturated
brine (15 mL) and dichloromethane (15 mL) were added to the
mixture, then the aqueous layer was extracted with dichloromethane
(15 mL × 3). The combined organic layer was dried over anhydrous
MgSO4. Finally, the solution was concentrated in vacuo to provide a
N-(4-methoxy-2-(1H-pyrazol-1-yl)phenyl)-2-(4-methoxybenzyl)but-
anamide (3f). White solid; 35.3 mg, 44% yield; m.p. 134.2–135.4 oC;
1H NMR (400 MHz, CDCl3, ppm): δ 9.65 (s, 1H), 8.18 (d, J = 9.2 Hz,
1H), 7.71 (d, J = 1.6 Hz, 1H), 7.65 (d, J = 2.4 Hz, 1H), 7.02 (d, J =
8.8 Hz, 2H), 6.88 (dd, J1 = 9.2 Hz, J2 = 2.8 Hz, 1H), 6.81 (d, J = 2.8
Hz, 1H), 6.70 (d, J = 8.4 Hz, 2H), 6.43 (t, J = 2.0 Hz, 1H), 3.81 (s,
3H), 3.74 (s, 3H), 2.88 (dd, J1 = 13.6 Hz, J2 = 8.4 Hz, 1H), 2.67 (dd,
J1 = 13.6 Hz, J2 = 6.0 Hz, 1H), 2.35–2.27 (m, 1H), 1.73–1.64 (m, 1H),
1.57–1.51 (m, 1H), 0.85 (t, J = 7.6 Hz, 3H); 13C{1H} NMR (100 MHz,
CDCl3, ppm): δ 173.5, 157.9, 156.1, 141.0, 131.7, 130.6, 130.0, 129.7
(2C), 125.1, 124.5, 113.7 (2C), 112.6, 108.9, 107.1, 55.7, 55.1, 53.1,
38.0, 25.6, 11.8; HRMS (EI): m/z [M+] calcd. for C22H25N3O3:
379.1896; found: 379.1895.
N-(3,4-Difluoro-2-(1H-pyrazol-1-yl)phenyl)-2-(4-methoxybenzyl)-
2-methylbutanamide (3g). Yellow oil; 38.6 mg, 32% yield (11.5mg,
10% yield); 1H NMR (400 MHz, CDCl3, ppm): δ 9.57 (s, 1H),
8.14−8.10 (m, 1H), 7.74 (d, J = 2.0 Hz, 1H), 7.70 (dd, J1 = 4.0 Hz, J2
= 2.8 Hz, 1H), 7.20 (q, J = 9.6 Hz, 1H), 6.93 (d, J = 8.8 Hz, 2H), 6.68
(d, J = 8.8 Hz, 2H), 6.48 (t, J = 2.0 Hz, 1H), 3.75 (s, 3H), 2.95 (d, J =
13.6 Hz, 1H), 2.54 (d, J = 13.6 Hz, 1H), 1.87−1.78 (m, 1H),
1.43−1.34 (m, 1H), 1.06 (s, 3H), 0.79 (t, J = 7.2 Hz, 3H); 13C{1H}
NMR (100 MHz, CDCl3, ppm): δ 175.4, 158.1, 146.6 (dd, JCF = 244.9,
11.9 Hz), 143.8 (dd, JCF = 248.9, 15.5 Hz), 141.5, 132.9 (d, JCF = 6.3
Hz), 131.0 (2C), 129.7 (d, JCF = 3.2 Hz), 129.4, 120.2 (d, JCF = 9.9
Hz), 118.2 (dd, JCF = 6.7, 4.6 Hz), 115.9 (d, JCF = 17.4 Hz), 113.3
(2C), 107.4, 55.10, 48.7, 45.3, 32.6, 19.5, 8.9; HRMS (EI): m/z [M+]
calcd. for C22H23N3O2F2: 399.1758; found: 399.1759.
crude product, which was further purified via
a
column
chromatography on silica gel (eluents: petroleum ether/ethyl acetate =
70:1 to 20:1) to supply the desired products 3 and 4.
N-(2-(1H-pyrazol-1-yl)phenyl)-2-(4-methoxybenzyl)butanamide
(3a).Yellow oil; 45.1 mg, 43% yield; 1H NMR (400 MHz, CDCl3,
ppm): δ 10.34 (s, 1H), 8.38 (d, J = 8.0 Hz, 1H), 7.74 (d, J = 2.0 Hz,
1H), 7.69 (d, J = 2.4 Hz, 1H), 7.36–7.31 (m, 1H), 7.28 (d, J = 1.2 Hz,
1H), 7.16–7.12 (m, 1H), 7.03 (d, J = 8.4 Hz, 2H), 6.71 (d, J = 8.8 Hz,
2H), 6.46 (t, J = 2.0 Hz, 1H), 3.74 (s, 3H), 2.90 (dd, J1 = 13.6 Hz, J2 =
8.4 Hz, 1H), 2.70 (dd, J1 = 14.0 Hz, J2 = 6.4 Hz, 1H), 2.39–2.32 (m,
1H), 1.75–1.68 (m, 1H), 1.60–1.53 (m, 1H), 0.88 (t, J = 7.6 Hz, 3H);
13C{1H} NMR (100 MHz, CDCl3, ppm): δ 173.7, 157.9, 141.0, 131.6,
131.4, 130.1, 129.7 (2C), 129.2, 128.0, 124.0, 123.4, 122.5, 113.7
(2C), 107.1, 55.1, 53.3, 38.0, 25.6, 11.9; HRMS (EI): m/z [M+] calcd.
for C21H23N3O2: 349.1790; found: 349.1792.
N-(4-Chloro-2-(1H-pyrazol-1-yl)phenyl)-2-(4-methoxybenzyl)buta-
1
namide (3b). Yellow oil; 37.9 mg, 33% yield; H NMR (400 MHz,
CDCl3, ppm): δ 10.11 (s, 1H), 8.37 (d, J = 8.4 Hz, 1H), 7.73 (d, J =
1.2 Hz, 1H), 7.69 (d, J = 2.4 Hz, 1H), 7.30–7.26 (m, 2H), 7.01 (d, J =
8.4 Hz, 2H), 6.69 (d, J = 8.8 Hz, 2H), 6.47 (t, J = 2.4 Hz, 1H), 3.73 (s,
3H), 2.88 (dd, J1 = 13.6 Hz, J2 = 8.8 Hz, 1H), 2.70 (dd, J1 = 13.6 Hz,
J2 = 6.0 Hz, 1H), 2.37–2.33 (m, 1H), 1.76–1.68 (m, 1H), 1.60–1.54
(m, 1H), 0.89 (t, J = 7.6 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3,
ppm): δ 173.8, 157.9, 141.3, 131.4, 130.1, 130.0, 129.8, 129.7 (2C),
128.7, 127.7, 124.4, 122.2, 113.7 (2C), 107.5, 55.1, 53.4, 38.0, 25.6,
11.9; HRMS (EI): m/z [M+] calcd. for C21H22N3O2Cl: 383.1401; found:
383.1400.
N-(3,4-Difluoro-2-(1H-pyrazol-1-yl)phenyl)-2,2-bis(4-methoxyben-
zyl)butanamide (3g’). Yellow oil; 62.3 mg, 41% yield (46.5 mg, 31%
yield); H NMR (400 MHz, CDCl3, ppm): δ 9.42 (s, 1H), 8.12−8.08
1
N-(4-Fluoro-2-(1H-pyrazol-1-yl)phenyl)-2-(4-methoxybenzyl)buta-
(m, 1H), 7.59−7.57 (m, 2H), 7.20 (q, J = 9.2 Hz, 1H), 6.98 (d, J = 8.4
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Hz, 4H), 6.68 (d, J = 8.8 Hz, 4H), 6.37 (t, J = 2.0 Hz, 1H), 3.75 (s,
1H), 2.40−2.33 (m, 1H), 1.67−1.59 (m, 1H), 1.49−1.40 (m, 1H),
6H), 3.04 (d, J = 14.0 Hz, 2H), 2.74 (d, J = 14.0 Hz, 2H), 1.41 (q, J =
7.2 Hz, 2H), 1.04 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz,
CDCl3, ppm): δ 174.8, 158.0 (2C), 146.9 (dd, JCF = 244.9, 11.9 Hz),
143.7 (dd, JCF = 248.7, 15.3 Hz), 141.3, 132.6 (d, JCF = 6.3 Hz), 130.8
(4C), 129.4 (d, JCF = 3.2 Hz), 129.3 (2C), 120.2 (d, JCF = 9.4 Hz),
118.4 (dd, JCF = 6.6, 4.7 Hz), 115.8 (d, JCF = 17.4 Hz), 113.4 (4C),
107.3, 55.1 (2C), 53.1, 40.5 (2C), 22.6, 8.6; HRMS (EI): m/z [M+]
calcd. for C29H29N3O3F2: 505.2177; found: 505.2175.
N-(3,4-Difluoro-2-(1H-pyrazol-1-yl)phenyl)-1-(4-methoxybenzyl)c-
yclohexanecarboxamide (3h). Yellow oil; 29.0 mg, 23% yield; 1H
NMR (400 MHz, CDCl3, ppm): δ 9.53 (s, 1H), 8.18−8.16 (m, 1H),
7.71 (s, 2H), 7.19 (q, J = 9.2 Hz, 1H), 6.87 (d, J = 8.4 Hz, 2H), 6.63
(d, J = 8.4 Hz, 2H), 6.48 (s, 1H), 3.74 (s, 3H), 2.68 (s, 2H), 1.99 (d, J
= 11.2 Hz, 2H), 1.59−1.52 (m, 4H), 1.35−1.30 (m, 2H), 1.25−1.22 (m,
2H); 13C{1H} NMR (100 MHz, CDCl3, ppm): δ 174.7, 158.1, 146.8
(dd, JCF = 244.7, 11.9 Hz), 143.8 (dd, JCF = 248.7, 15.5 Hz), 141.5,
132.8 (d, JCF = 6.3 Hz), 130.8 (2C), 129.8 (d, JCF = 3.1 Hz), 128.7,
1.29−1.16 (m, 2H), 0.84 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz,
CDCl3, ppm): δ 173.9, 158.0, 147.0 (dd, JCF = 245.0, 11.9 Hz), 143.8
(dd, JCF = 248.9, 15.4 Hz), 141.6, 133.0 (d, JCF = 6.3 Hz), 131.3,
129.6 (2C), 129.3 (d, JCF = 3.2 Hz), 120.1 (d, JCF = 10.2 Hz), 118.3
(dd, JCF = 6.5, 4.6 Hz), 115.8 (d, JCF = 17.4 Hz), 113.8 (2C), 107.4,
55.1, 51.4, 38.3, 34.7, 20.6, 14.0; HRMS (EI): m/z [M+] calcd. for
C22H23N3O2F2: 399.1758; found: 399.1759.
1
2
3
4
5
6
7
8
N-(3,4-Difluoro-2-(1H-pyrazol-1-yl)phenyl)-2-(4-methoxybenzyl)h-
exanamide (3k). Yellow oil; 93.8 mg, 76% yield; 1H NMR (400 MHz,
CDCl3, ppm): δ 9.40 (s, 1H), 8.05−8.01 (m, 1H), 7.78 (d, J = 1.2 Hz,
1H), 7.70 (dd, J1 = 3.2 Hz, J2 = 2.8 Hz, 1H), 7.16 (q, J = 9.2 Hz, 1H),
6.99 (d, J = 8.4 Hz, 2H), 6.71 (d, J = 8.4 Hz, 2H), 6.51 (t, J = 2.0 Hz,
1H), 3.75 (s, 3H), 2.84 (dd, J1 = 14.0 Hz, J2 = 9.2 Hz, 1H), 2.67 (dd,
J1 = 13.6 Hz, J2 = 6.0 Hz, 1H), 2.38−2.31 (m, 1H), 1.69−1.60 (m, 1H),
1.52−1.43 (m, 1H), 1.26−1.21 (m, 2H), 1.19−1.13 (m, 2H), 0.81 (t, J
= 6.8 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3, ppm): δ 173.9,
157.9, 147.0 (dd, JCF = 244.9, 11.8 Hz), 143.8 (dd, JCF = 249.1, 15.5
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
120.0 (d, JCF = 9.8 Hz), 117.9 (d, JCF = 6.8, 4.6 Hz), 115.8 (d, JCF
=
Hz), 141.6, 132.9 (d, JCF = 6.4 Hz), 131.3, 129.6 (2C), 129.3 (d, JCF =
17.3 Hz), 113.2 (2C), 107.3, 55.1, 49.3, 35.3, 33.9, 25.8, 25.7, 23.1,
23.0; HRMS (EI): m/z [M+] calcd. for C24H25N3O2F2: 425.1915; found:
425.1916.
3.2 Hz), 120.1 (d, JCF = 10.4 Hz), 118.3 (dd, JCF = 6.6, 4.6 Hz), 115.8
(d, JCF = 17.3 Hz), 113.8 (2C), 107.4, 55.2, 51.7, 38.3, 32.4, 29.5,
22.6, 14.0; HRMS (EI): m/z [M+] calcd. for C23H25N3O2F2: 413.1915;
found: 413.1913.
N-(3,4-Difluoro-2-(1H-pyrazol-1-yl)phenyl)-1-(4-methoxybenzyl)-
2-(4-methoxyphenyl)cyclohexanecarboxamide (3h’). Yellow oil; 74.3
N-(3,4-Difluoro-2-(1H-pyrazol-1-yl)phenyl)-2-(4-methoxybenzyl)h-
1
1
mg, 47% yield; H NMR (400 MHz, CDCl3, ppm): δ 9.18 (s, 1H),
ptanamide (3l). Yellow oil; 89.1 mg, 70% yield (67.9 mg, 53%); H
7.99−7.95 (m, 1H), 7.61 (dd, J1 = 3.6 Hz, J2 = 2.8 Hz, 1H), 7.55 (d, J
= 1.6 Hz, 1H), 7.14 (d, J = 8.0 Hz, 2H), 7.10 (q, J = 8.8 Hz, 1H), 6.82
(d, J = 8.4 Hz, 2H), 6.71 (d, J = 8.8 Hz, 2H), 6.61 (d, J = 8.4 Hz, 2H),
6.40 (t, J = 2.4 Hz, 1H), 3.76 (s, 3H), 3.71 (s, 3H), 3.03 (d, J = 13.6Hz,
1H), 2.88−2.84 (m, 2H), 2.02−1.91 (m, 2H), 1.86−1.81 (m, 2H),
1.73−1.71 (m, 2H), 1.50−1.45 (m, 2H); 13C{1H} NMR (100 MHz,
CDCl3, ppm): δ 173.5, 158.1, 157.9, 146.7 (dd, JCF = 244.6, 12.0 Hz),
143.7 (dd, JCF = 248.5, 15.5 Hz), 141.4, 135.2, 132.6 (d, JCF = 6.4 Hz),
NMR (400 MHz, CDCl3, ppm): δ 9.39 (s, 1H), 8.04−8.00 (m, 1H),
7.79 (d, J = 2.0 Hz, 1H), 7.70 (dd, J1 = 3.6 Hz, J2 = 2.4 Hz, 1H), 7.16
(q, J = 9.2 Hz, 1H), 6.99 (d, J = 8.4 Hz, 2H), 6.71 (d, J = 8.8 Hz, 2H),
6.51 (t, J = 2.4 Hz, 1H), 3.75 (s, 3H), 2.84 (dd, J1 = 14.0 Hz, J2 = 9.2
Hz, 1H), 2.66 (dd, J1 = 13.6 Hz, J2 = 5.6 Hz, 1H), 2.38−2.31 (m, 1H),
1.69−1.60 (m, 1H), 1.47−1.43 (m, 1H), 1.19−1.17 (m, 6H), 0.88−0.81
(m, 3H); 13C{1H} NMR (100 MHz, CDCl3, ppm): δ 174.0, 157.9,
147.0 (dd, JCF = 245.0, 11.8 Hz), 143.7 (dd, JCF = 249.0, 15.5 Hz),
141.6, 132.9 (d, JCF = 6.4 Hz), 131.3, 129.6 (2C), 129.3 (d, JCF = 3.2
Hz), 120.1 (d, JCF = 9.6 Hz), 118.4 (dd, JCF = 6.6, 4.6 Hz), 115.8 (d,
JCF = 17.4 Hz), 113.7 (2C), 107.4, 55.1, 51.7, 38.3, 32.6, 31.8, 27.1,
22.5, 14.0; HRMS (EI): m/z [M+] calcd. for C24H27N3O2F2: 427.2071;
found: 427.2072.
2-Benzyl-N-(3,4-difluoro-2-(1H-pyrazol-1-yl)phenyl)-3-(4-methox-
yphenyl)propanamide (3m). Brown oil; 69.6 mg, 49% yield; 1H NMR
(400 MHz, CDCl3, ppm): δ 9.24 (s, 1H), 7.98−7.95 (m, 1H), 7.68 (d, J
= 1.2 Hz, 1H), 7.58 (dd, J1 = 3.6 Hz, J2 = 2.4 Hz, 1H), 7.18 (q, J = 6.8
Hz, 2H), 7.14−7.12 (m, 1H), 7.12−7.09 (m, 3H), 6.99 (d, J = 8.4 Hz,
2H), 6.70 (d, J = 8.8 Hz, 2H), 6.45 (t, J = 2.0 Hz, 1H), 3.75 (s, 3H),
2.98 (dd, J1 = 13.2 Hz, J2 = 8.8 Hz, 1H), 2.92 (dd, J1 = 14.0 Hz, J2 =
9.6 Hz, 1H), 2.80 (dd, J1 = 13.6 Hz, J2 = 5.6 Hz, 1H), 2.75 (dd, J1 =
14.0 Hz, J2 = 6.0 Hz, 1H), 2.65−2.59 (m, 1H); 13C{1H} NMR (100
MHz, CDCl3, ppm): δ 173.0, 158.0, 147.0 (dd, JCF = 245.0, 12.2 Hz),
143.6 (dd, JCF = 249.0, 15.6 Hz), 141.4, 139.0, 132.8 (d, JCF = 6.4 Hz),
130.9, 129.7 (2C), 129.0 (d, JCF = 3.3 Hz), 128.7 (2C), 128.5 (2C),
126.4, 119.9 (d, JCF = 10.2 Hz), 118.2 (dd, JCF = 6.5, 4.7 Hz), 115.7 (d,
JCF = 17.3 Hz), 113.8 (2C), 107.3, 55.1, 53.8, 38.7, 38.0; HRMS (EI):
m/z [M+] calcd. for C26H23N3O2F2: 447.1758; found: 447.1759.
N-(3,4-Difluoro-2-(1H-pyrazol-1-yl)phenyl)-3-(4-methoxyphenyl)-
2-phenylpropanamide (3n). Yellow oil; 49.2 mg, 38% yield; 1H NMR
(400 MHz, CDCl3, ppm): δ 9.49 (s, 1H), 8.11−8.07 (m, 1H), 7.63 (t, J
= 3.2 Hz, 1H), 7.60 (d, J = 1.6 Hz, 1H), 7.29−7.27 (m, 1H), 7.25−7.23
(m, 2H), 7.19 (dd, J1 = 7.6 Hz, J2 = 2.0 Hz, 2H), 7.15 (q, J = 10.0 Hz,
1H), 6.96 (d, J = 8.8 Hz, 2H), 6.70 (d, J = 8.4 Hz, 2H), 6.42 (t, J = 2.0
Hz, 1H), 3.74 (s, 3H), 3.63 (t, J = 7.2 Hz, 1H), 3.48 (dd, J1 = 14.0 Hz,
J2 = 7.6 Hz, 1H), 2.97 (dd, J1 = 13.6 Hz, J2 = 7.2 Hz, 1H); 13C{1H}
NMR (100 MHz, CDCl3, ppm): δ 171.6, 158.0, 146.9 (dd, JCF = 245.3,
12.0 Hz), 143.7 (dd, JCF = 249.0, 15.4 Hz), 141.6, 138.7, 132.8 (d, JCF
= 6.5 Hz), 131.2, 129.9 (2C), 129.6 (d, JCF = 3.3 Hz), 128.8 (2C),
128.2 (2C), 127.5, 119.9 (d, JCF = 9.7 Hz), 117.9 (dd, JCF = 6.6, 4.4
Hz), 115.8 (d, JCF = 17.3 Hz), 113.7 (2C), 107.2, 56.9, 55.2, 38.1;
HRMS (EI): m/z [M+] calcd. for C25H21N3O2F2: 433.1602; found:
433.1604.
130.8 (2C), 130.6 (2C), 129.3 (d, JCF = 3.1 Hz), 128.8, 119.9 (d, JCF
=
9.4 Hz), 118.1 (dd, JCF = 6.5, 4.5 Hz), 115.7 (d, JCF = 17.3 Hz), 113.3
(2C), 113.1 (2C), 107.2, 55.1, 52.0 (2C), 51.0, 44.0, 30.8, 30.0, 24.1,
22.4; HRMS (EI): m/z [M+] calcd. for C31H31N3O3F2: 531.2333; found:
531.2329.
N-(3,4-Difluoro-2-(1H-pyrazol-1-yl)phenyl)-3-(4-methoxyphenyl)-
2-methylpropanamide (3i). Brown oil; 47.6 mg, 43% yield (38.8 mg,
35% yield); 1H NMR (400 MHz, CDCl3, ppm): δ 9.53 (s, 1H),
8.14−8.10 (m, 1H), 7.80 (d, J = 1.6 Hz, 1H), 7.74 (dd, J1 = 4.0 Hz, J2
= 2.4 Hz, 1H), 7.17 (q, J = 9.6 Hz, 1H), 7.00 (d, J = 8.8 Hz, 2H), 6.73
(d, J = 8.4 Hz, 2H), 6.52 (t, J = 2.0 Hz, 1H), 3.76 (s, 3H), 2.90 (dd, J1
= 13.6 Hz, J2 = 7.2 Hz, 1H), 2.61 (dd, J1 = 13.6 Hz, J2 = 7.2 Hz, 1H),
2.56−2.47 (m, 1H), 1.16 (d, J = 6.4 Hz, 3H); 13C{1H} NMR (100
MHz, CDCl3, ppm): δ 174.4, 158.0, 146.9 (dd, JCF = 245.1, 12.2 Hz),
143.7 (dd, JCF = 248.9, 15.6 Hz), 141.6, 133.0 (d, JCF = 6.6 Hz), 131.2,
129.8 (2C), 129.5 (d, JCF = 3.2 Hz), 119.9 (d, JCF = 10.1 Hz), 117.9
(dd, JCF = 6.6, 4.8 Hz), 115.8 (d, JCF = 17.4 Hz), 113.8 (2C), 107.4,
55.2, 45.1, 39.4, 17.1; HRMS (EI): m/z [M+] calcd. for C20H19N3O2F2:
371.1445; found: 371.1444.
N-(3,4-Difluoro-2-(1H-pyrazol-1-yl)phenyl)-2-(4-methoxybenzyl)-
3-(4-methoxyphenyl)propanamide (3i’). Brown oil; 45.6 mg, 32%
1
yield (34.5 mg, 24%); H NMR (400 MHz, CDCl3, ppm): δ 9.22 (s,
1H), 7.96−7.92 (m, 1H), 7.68 (d, J = 1.6 Hz, 1H), 7.59 (dd, J1 = 3.6
Hz, J2 = 2.4 Hz, 1H), 7.12 (q, J = 9.2 Hz, 1H), 7.00 (d, J = 8.4 Hz,
4H), 6.70 (d, J = 8.8 Hz, 4H), 6.45 (t, J = 2.0 Hz, 1H), 3.75 (s, 6H),
2.90 (dd, J1 = 13.6 Hz, J2 = 9.2 Hz, 2H), 2.73 (dd, J1 = 13.6 Hz, J2 =
5.6 Hz, 2H), 2.60−2.54 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3,
ppm): δ 172.1, 157.0 (2C), 145.9 (dd, JCF = 245.0, 12.0 Hz), 142.6 (dd,
JCF = 249.0, 15.3 Hz), 140.4, 131.7 (d, JCF = 6.7 Hz), 130.0 (2C),
128.6 (4C), 128.0 (d, JCF = 3.1 Hz), 118.9 (d, JCF = 9.7 Hz), 117.2 (dd,
JCF = 6.7, 4.2Hz), 114.6 (d, JCF = 17.3 Hz), 112.8 (4C), 106.2, 54.1
(2C), 53.0, 36.9 (2C); HRMS (EI): m/z [M+] calcd. for C27H25N3O3F2:
477.1864; found: 477.1866.
N-(3,4-Difluoro-2-(1H-pyrazol-1-yl)phenyl)-2-(4-methoxybenzyl)p-
entanamide (3j). Yellow oil; 77.1 mg, 64% yield; 1H NMR (400 MHz,
CDCl3, ppm): δ 9.39 (s, 1H), 8.05−8.01 (m, 1H), 7.79 (d, J = 1.6 Hz,
1H), 7.71 (t, J = 2.8 Hz, 1H), 7.16 (q, J = 9.2 Hz, 1H), 6.98 (d, J = 8.4
Hz, 2H), 6.70 (d, J = 8.0 Hz, 2H), 6.51 (s, 1H), 3.75 (s, 3H), 2.84 (dd,
J1 = 13.6 Hz, J2 = 8.8 Hz, 1H), 2.66 (dd, J1 = 13.6 Hz, J2 = 6.0 Hz,
N-(3,4-Difluoro-2-(1H-pyrazol-1-yl)phenyl)-3-(4-methoxyphenyl)-
2-(p-tolyl)propanamide (3o). Brown oil, 61.3 mg, 43% yield (45.8 mg,
32% yield); 1H NMR (400 MHz, CDCl3, ppm): δ 9.43 (s, 1H),
8.12−8.07 (m, 1H), 7.63 (t, J = 2.8 Hz, 1H), 7.59 (d, J = 1.6 Hz, 1H),
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1
7.15 (t, J = 9.2 Hz, 1H), 7.13−7.10 (m, 1H), 7.08 (s, 3H), 6.96 (d, J =
137.1–138.6 C; H NMR (400 MHz, CDCl3, ppm): δ 8.98 (s, 1H),
8.00−7.97 (m, 1H), 7.72 (d, J = 1.2 Hz, 1H), 7.58 (dd, J1 = 3.6 Hz, J2
= 2.8 Hz, 1H), 7.10 (q, J = 9.2 Hz, 1H), 7.04 (d, J = 8.4 Hz, 2H), 6.63
(d, J = 8.4 Hz, 2H), 6.46 (s, 1H), 3.72 (s, 3H), 2.87−2.82 (m, 1H),
2.61 (d, J = 3.2 Hz, 1H), 2.40−2.30 (m, 1H), 1.99−1.89 (m, 3H),
1.73−1.66 (m, 2H), 1.53 (dd, J1 = 8.4 Hz, J2 = 4.0 Hz, 1H), 1.39 (dd,
J1 = 24.0 Hz, J2 = 11.6 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3,
ppm): δ 173.0, 157.7, 146.7 (dd, JCF = 248.4, 15.5 Hz), 143.7 (dd, JCF
= 248.7, 15.3 Hz), 141.5, 136.1, 132.8 (d, JCF = 6.3 Hz), 129.5 (d, JCF
= 3.2 Hz), 128.3 (2C), 119.8 (d, JCF = 10.1 Hz), 117.8 (dd, JCF = 6.6,
4.7 Hz), 115.7 (d, JCF = 17.4 Hz), 113.5 (2C), 107.2, 55.1, 49.0, 44.4,
28.9, 27.2, 25.7, 21.7; HRMS (EI): m/z [M+] calcd. for C23H23N3O2F2:
411.1758; found: 411.1756.
N-(3,4-difluoro-2-(1H-pyrazol-1-yl)phenyl)-3-(4-methoxyphenyl)p-
ropanamide (3u). Yellow oil, 43.6 mg, 41% yield; 1H NMR (400
MHz, CDCl3, ppm): δ 9.62 (s, 1H), 8.19−8.14 (m, 1H), 7.82 (d, J =
1.6 Hz, 1H), 7.80 (dd, J1 = 4.4 Hz, J2 = 2.8 Hz, 1H), 7.18 (q, J = 9.6
Hz, 1H), 7.08 (d, J = 8.4 Hz, 2H), 6.79 (d, J = 8.4 Hz, 2H), 6.54 (t, J
= 2.4 Hz 1H), 3.77 (s, 3H), 2.91 (t, J = 7.6 Hz, 2H), 2.57 (t, J = 8.0 Hz
2H); 13C{1H} NMR (100 MHz, CDCl3, ppm): δ 170.7, 158.1, 146.9
(dd, JCF = 245.1, 12.0 Hz), 143.7 (dd, JCF = 248.8, 15.5 Hz), 141.7,
133.2 (d, JCF = 6.6 Hz), 132.3, 129.5 (d, JCF = 3.2 Hz), 129.2 (2C),
8.4 Hz, 2H), 6.70 (d, J = 8.8 Hz, 2H), 6.43 (t, J = 2.0 Hz, 1H), 3.74 (s,
3H), 3.60 (t, J = 7.6 Hz, 1H), 3.47 (dd, J1 = 14.0 Hz, J2 = 7.6 Hz, 1H),
2.95 (dd, J1 = 14.0 Hz, J2 = 7.6 Hz, 1H), 2.32 (s, 3H); 13C{1H} NMR
(100 MHz, CDCl3, ppm): δ 171.9, 158.0, 146.9 (dd, JCF = 244.8, 11.6
Hz), 143.8 (dd, JCF = 248.8, 15.3 Hz), 141.5, 137.1, 135.6, 132.8 (d,
JCF = 6.3 Hz), 131.4, 129.9 (2C), 129.7 (d, JCF = 3.2 Hz), 129.5 (2C),
128.0 (2C), 119.9 (d, JCF = 9.8 Hz), 117.8 (dd, JCF = 5.9, 5.3 Hz),
115.8 (d, JCF = 17.3 Hz), 113.7 (2C), 107.1, 56.4, 55.2, 38.0, 21.1;
HRMS (EI): m/z [M+] calcd. for C26H23N3O2F2: 447.1758; found:
447.1759.
2-(3-Chlorophenyl)-N-(3,4-difluoro-2-(1H-pyrazol-1-yl)phenyl)-3-
(4-methoxyphenyl)propanamide (3p). Yellow oil; 48.7 mg, 35% yield;
1H NMR (400 MHz, CDCl3, ppm): δ 9.57 (s, 1H), 8.07−8.04 (m, 1H),
7.67−7.65 (m, 2H), 7.21 (s, 1H), 7.21−7.17 (m, 2H), 7.14 (t, J = 8.4
Hz, 1H), 7.11−7.08 (m, 1H), 6.97 (d, J = 8.8 Hz, 2H), 6.72 (d, J = 8.8
Hz, 2H), 6.45 (t, J = 2.4 Hz, 1H), 3.74 (s, 3H), 3.61 (t, J = 7.6 Hz, 1H),
3.46 (dd, J1 = 13.6 Hz, J2 = 7.6 Hz, 1H), 2.95 (dd, J1 = 13.6 Hz, J2 =
7.2 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3, ppm): δ 170.9, 158.1,
147.1 (dd, JCF = 245.5, 12.0 Hz), 143.7 (dd, JCF = 249.2, 15.5 Hz),
141.5, 140.7, 134.6, 132.8 (d, JCF = 6.6 Hz), 130.7, 130.0, 129.8 (2C),
129.3 (d, JCF = 3.3 Hz), 128.3, 127.7, 126.3, 120.0 (d, JCF = 10.3 Hz),
118.0 (dd, JCF = 6.3, 4.8 Hz), 115.8 (d, JCF = 17.5 Hz), 113.8 (2C),
107.4, 56.5, 55.2, 38.0; HRMS (EI): m/z [M+] calcd. for
C25H20N3O2F2Cl: 467.1212; found: 467.1214.
N-(3,4-Difluoro-2-(1H-pyrazol-1-yl)phenyl)-2-(6-methoxynaphthal-
en-2-yl)-3-(4-methoxyphenyl)propanamide (3q). Yellow solid; 68.1
mg, 44% yield; m.p. 82.8–84.2 oC; 1H NMR (400 MHz, CDCl3, ppm):
δ 9.41 (s, 1H), 8.15−8.11 (m, 1H), 7.66 (d, J = 3.6 Hz, 1H), 7.64 (d, J
= 2.8 Hz, 1H), 7.54−7.52 (m, 2H), 7.28 (dd, J1 = 8.4 Hz, J2 = 1.6 Hz,
1H), 7.18−7.14 (m, 2H), 7.11 (d, J = 2.0 Hz, 1H), 7.08 (d, J = 1.6 Hz,
1H), 6.98 (d, J = 8.4 Hz, 2H), 6.69 (d, J = 8.8 Hz, 2H), 6.20 (t, J = 2.4
Hz, 1H), 3.93 (s, 3H), 3.79 (t, J = 8.4 Hz, 1H), 3.93 (s, 3H), 3.60 (dd,
J1 = 14.0 Hz, J2 = 6.8 Hz, 1H), 3.08 (dd, J1 = 14.0 Hz, J2 = 8.0 Hz,
1H); 13C{1H} NMR (100 MHz, CDCl3, ppm): δ 171.9, 157.9, 157.8,
146.9 (dd, JCF = 245.5, 12.3 Hz), 143.7 (dd, JCF = 248.8, 15.2 Hz),
141.3, 134.0, 133.5, 132.6 (d, JCF = 6.2 Hz), 131.3, 129.9 (2C), 129.7
1
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4
5
6
7
8
9
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13
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18
19
20
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23
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25
26
27
28
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30
31
32
33
34
35
36
37
38
39
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42
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46
47
48
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53
54
55
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59
60
119.8 (d, JCF = 9.6 Hz), 117.8 (dd, JCF = 6.1, 4.8 Hz), 115.9 (d, JCF
=
17.5 Hz), 114.0 (2C), 107.4, 55.3, 39.9, 30.4; HRMS (EI): m/z [M+]
calcd. for C19H17N3O2F2: 357.1289; found: 357.1287.
2-Benzyl-N-(3,4-difluoro-2-(1H-pyrazol-1-yl)phenyl)butanamide
o
1
(4b). Yellow solid; 50.1 mg, 47% yield, m.p. 63.2–64.8 C; H NMR
(400 MHz, CDCl3, ppm): δ 9.42 (s, 1H), 8.07−8.03 (m, 1H), 7.80 (d, J
= 1.6 Hz, 1H), 7.70 (dd, J1 = 4.0 Hz, J2 = 2.8 Hz, 1H), 7.20−7.17 (m,,
2H), 7.15−7.12 (m, 2H), 7.09 (d, J = 6.8 Hz, 2H), 6.51 (t, J = 2.4 Hz,
1H), 2.92 (dd, J1 = 13.6 Hz, J2 = 8.8 Hz, 1H), 2.74 (dd, J1 = 13.6 Hz,
J2 = 6.0 Hz, 1H), 2.37−2.30 (m, 1H), 1.72−1.64 (m, 1H), 1.59−1.52
(m, 1H), 0.84 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3,
ppm): δ 173.7, 147.0 (dd, JCF = 244.9, 12.0 Hz), 143.8 (dd, JCF
249.0, 15.0 Hz), 141.6, 139.3, 133.0 (d, JCF = 6.4 Hz), 129.3 (d, JCF
=
=
3.2 Hz), 128.7 (2C), 128.4 (2C), 126.3, 120.1 (d, JCF = 3.7 Hz), 118.3
(d, JCF = 3.6 Hz), 115.9 (d, JCF = 17.3 Hz), 107.5, 52.9, 38.8, 25.6,
11.7; HRMS (EI): m/z [M+] calcd. for C20H19N3OF2: 355.1496; found:
355.1497.
(d, JCF = 3.2 Hz), 129.4, 129.0, 127.6, 127.5, 126.4, 119.9 (d, JCF
=
9.4 Hz), 119.1, 117.7 (dd, JCF = 6.5, 4.5 Hz), 115.8 (d, JCF = 17.4 Hz),
113.7 (2C), 107.0, 105.6, 56.7, 55.4, 55.1, 37.7; HRMS (EI): m/z [M+]
calcd. for C30H25N3O3F2: 513.1864; found: 513.1859.
N-(3,4-Difluoro-2-(1H-pyrazol-1-yl)phenyl)-2-(4-methylbenzyl)but-
1
anamide (4c). Yellow oil; 82.8 mg, 75% yield; H NMR (400 MHz,
N-(3,4-Difluoro-2-(1H-pyrazol-1-yl)phenyl)-2-(4-methoxyphenyl)c-
yclobutanecarboxamide (3r). Brown oil; 59.2 mg, 52% yield; 1H
NMR (400 MHz, CDCl3, ppm): δ 9.20 (s, 1H), 7.84 (d, J = 1.6 Hz,
1H), 7.80−7.75 (m, 1H), 7.66 (dd, J1 = 4.0 Hz, J2 = 2.4 Hz, 1H), 7.05
(q, J = 9.2 Hz, 1H), 6.96 (d, J = 8.4 Hz, 2H), 6.64 (d, J = 8.8 Hz, 2H),
6.54 (t, J = 2.0 Hz, 1H), 3.91−3.85 (m, 1H), 3.70 (s, 3H), 3.44−3.38
(m, 1H), 2.54−2.48 (m, 1H), 2.47−2.40 (m, 1H), 2.33−2.28 (m, 1H),
2.20−2.15 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3, ppm): δ 171.1,
158.0, 146.6 (dd, JCF = 244.6, 12.4 Hz), 143.6 (dd, JCF = 248.4, 15.5
Hz), 141.5, 133.1 (d, JCF = 6.6 Hz), 132.4, 129.3 (d, JCF = 3.2 Hz),
128.2 (2C), 119.6 (d, JCF = 10.8 Hz), 117.7 (dd, JCF = 6.9, 4.7 Hz),
115.7 (d, JCF = 17.2 Hz), 113.5 (2C), 107.3, 55.2, 47.6, 42.6, 24.9,
20.0; HRMS (EI): m/z [M+] calcd. for C21H19N3O2F2: 383.1445; found:
383.1443.
CDCl3, ppm): δ 9.42 (s, 1H), 8.08−8.03 (m, 1H), 7.80 (d, J = 2.0 Hz,
1H), 7.70 (dd, J1 = 4.0 Hz, J2 = 2.8 Hz, 1H), 7.18 (q, J = 9.6 Hz, 1H),
6.70 (d, J = 1.2 Hz, 4H), 6.51 (t, J = 2.4 Hz, 1H), 2.87 (dd, J1 = 14.0
Hz, J2 = 8.8 Hz, 1H), 2.69 (dd, J1 = 13.6 Hz, J2 = 6.4 Hz, 1H),
2.35−2.31 (m, 1H), 2.27 (s, 3H), 1.71−1.63 (m, 1H), 1.58−1.51 (m,
1H), 0.84 (t, J = 7.6 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3, ppm):
δ 173.8, 147.0 (dd, JCF = 245.2, 11.8 Hz), 143.8 (dd, JCF = 247.4, 16.4
Hz), 141.6, 136.2, 135.6, 132.9 (d, JCF = 7.0 Hz), 129.4, 129.1 (2C),
128.6 (2C), 120.1 (d, JCF = 10.2 Hz), 118.3, 115.8 (d, JCF = 17.0 Hz),
107.3, 53.0, 38.4, 25.6, 21.1, 11.7; HRMS (EI): m/z [M+] calcd. for
C21H21N3OF2: 369.1653; found: 369.1652.
N-(3,4-Difluoro-2-(1H-pyrazol-1-yl)phenyl)-2-(4-(trifluoromethyl)-
benzyl)butanamide (4d). White solid; 86.5 mg, 68% yield; m.p. 80.4–
81.8 oC; 1H NMR (400 MHz, CDCl3, ppm): δ 9.50 (s, 1H), 8.03−8.00
(m, 1H), 7.75 (d, J = 2.0 Hz, 1H), 7.67 (dd, J1 = 4.0 Hz, J2 = 2.8 Hz,
1H), 7.39 (d, J = 8.0 Hz, 2H), 7.20−7.13 (m, 3H), 6.49 (t, J = 2.0 Hz,
1H), 2.95 (dd, J1 = 14.0 Hz, J2 = 9.2 Hz, 1H), 2.78 (dd, J1 = 13.6 Hz,
J2 = 5.6 Hz, 1H), 2.37−2.29 (m, 1H), 1.78−1.68 (m, 1H), 1.61−1.55
(m, 1H), 0.89 (t, J = 7.6 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3,
ppm): δ 172.0, 146.1 (dd, JCF = 245.4, 11.9 Hz), 142.4, 142.6 (dd, JCF
= 249.3, 15.6 Hz), 140.4, 132.0 (d, JCF = 6.5 Hz), 127.9 (2C), 127.9,
N-(3,4-Difluoro-2-(1H-pyrazol-1-yl)phenyl)-2-(4-methoxyphenyl)c-
yclopentanecarboxamide (3s). Yellow solid; 65.2 mg, 55% yield
o
1
(54.9, 46% yield); m.p. 86.5–87.9 C; H NMR (400 MHz, CDCl3,
ppm): δ 9.21 (s, 1H), 7.85−7.83 (m, 1H), 7.81 (d, J = 1.2 Hz, 1H),
7.64 (dd, J1 = 4.0 Hz, J2 = 2.8 Hz, 1H), 7.05 (q, J = 9.6 Hz, 1H), 6.95
(d, J = 8.4 Hz, 2H), 6.59 (d, J = 8.4 Hz, 2H), 6.53 (t, J = 2.0 Hz, 1H),
3.69 (s, 3H), 3.32 (dd, J1 = 15.6 Hz, J2 = 8.4 Hz, 1H), 2.92 (dd, J1 =
14.4 Hz, J2 = 8.0 Hz, 1H), 2.19−2.13 (m, 1H), 2.10−2.05 (m, 2H),
2.01−1.91 (m, 2H), 1.75−1.67 (m, 1H); 13C{1H} NMR (100 MHz,
CDCl3, ppm): δ 172.8, 157.8, 146.6 (dd, JCF = 244.5, 12.1 Hz), 143.5
(dd, JCF = 248.4, 15.5 Hz), 141.4, 133.0 (d, JCF = 6.4 Hz), 133.0,
129.4 (d, JCF = 3.2 Hz), 128.6 (2C), 119.5 (d, JCF = 9.8 Hz), 117.5 (dd,
JCF = 6.6, 4.6 Hz), 115.6 (d, JCF = 17.3 Hz), 113.4 (2C), 107.2, 55.1,
52.9, 49.0, 31.5, 28.3, 24.7; HRMS (EI): m/z [M+] calcd. for
C22H21N3O2F2: 397.1602; found: 397.1599.
127.4 (d, JCF = 32.2 Hz), 124.2 (q, JCF = 3.7 Hz, 2C), 123.2 (q, JCF
=
270.2 Hz), 119.0 (d, JCF = 9.6 Hz), 117.2 (dd, JCF = 6.8, 4.7 Hz),
114.8 (d, JCF = 17.2 Hz), 106.5, 51.8, 37.5, 25.0, 10.7; HRMS (EI):
m/z [M+] calcd. for C21H18N3OF5: 423.1370; found: 423.1367.
N-(3,4-Difluoro-2-(1H-pyrazol-1-yl)phenyl)-2-(4-fluorobenzyl)but-
1
anamide (4e). Yellow oil; 77.0 mg, 69% yield; H NMR (400 MHz,
CDCl3, ppm): δ 9.43 (s, 1H), 8.04−8.00 (m, 1H), 7.76 (d, J = 1.6 Hz,
1H), 7.71 (dd, J1 = 4.4 Hz, J2 = 2.8 Hz, 1H), 7.16 (q, J = 9.6 Hz, 1H),
7.01 (dd, J1 = 8.4 Hz, J2 = 5.2 Hz, 2H), 6.82 (t, J = 8.8 Hz, 2H), 6.52
(t, J = 2.4 Hz, 1H), 2.85 (dd, J1 = 13.6 Hz, J2 = 9.2 Hz, 1H), 2.70 (dd,
N-(3,4-Difluoro-2-(1H-pyrazol-1-yl)phenyl)-2-(4-methoxyphenyl)c-
yclohexanecarboxamide (3t). White solid, 62.8 mg, 51% yield; m.p.
ACS Paragon Plus Environment

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Page 10 of 14
J1 = 13.6 Hz, J2 = 5.6 Hz, 1H), 2.31−2.23 (m, 1H), 1.74−1.66 (m, 1H),
1.59−1.52 (m, 1H), 0.86 (t, J = 7.6 Hz, 3H); 13C{1H} NMR (100 MHz,
CDCl3, ppm): δ 173.5, 161.4 (d, JCF = 242.6 Hz), 147.0 (dd, JCF
245.1, 11.8 Hz), 143.7 (dd, JCF = 249.1, 15.5 Hz), 141.6, 134.9 (d, JCF
= 3.1 Hz), 133.0 (d, JCF = 6.5 Hz), 130.0 (d, JCF = 7.8 Hz, 2C), 129.1
(d, JCF = 3.3 Hz), 120.1 (d, JCF = 10.5 Hz), 118.3 (dd, JCF = 6.8, 4.8
Hz), 115.8 (d, JCF = 17.5 Hz), 115.2 (d, JCF = 21.0 Hz, 2C), 107.4,
53.3, 38.0, 25.9, 11.8; HRMS (EI): m/z [M+] calcd. for C20H18N3OF3:
373.1402; found: 373.1401.
8.8 Hz, 1H), 2.69 (dd, J1 = 13.6 Hz, J2 = 6.4 Hz, 1H), 2.33−2.30 (m,
1H), 2.27 (s, 3H), 1.71−1.63 (m, 1H), 1.58−1.51 (m, 1H), 0.83 (t, J =
7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3, ppm): δ 173.8, 147.0
(dd, JCF = 245.0, 11.8 Hz), 143.8 (dd, JCF = 249.0, 15.5 Hz), 141.5,
139.2, 137.9, 133.0 (d, JCF = 6.4 Hz), 129.6, 129.4 (d, JCF = 3.2 Hz),
128.3, 127.1, 125.7, 120.1 (d, JCF = 10.2 Hz), 118.2 (dd, JCF = 6.5, 4.4
Hz), 115.9 (d, JCF = 17.5 Hz), 107.4, 52.9, 38.7, 25.6, 21.4, 11.7;
HRMS (EI): m/z [M+] calcd. for C21H21N3OF2: 369.1653; found:
369.1652.
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4
5
6
7
8
=
2-(4-Chlorobenzyl)-N-(3,4-difluoro-2-(1H-pyrazol-1-yl)phenyl)but-
N-(3,4-Difluoro-2-(1H-pyrazol-1-yl)phenyl)-2-(3-(trifluoromethyl)-
benzyl)butanamide (4k). White solid; 79.8 mg, 63% yield; m.p. 83.6–
84.9 oC; 1H NMR (400 MHz, CDCl3, ppm): δ 9.50 (s, 1H), 8.04−8.00
(m, 1H), 7.75 (d, J = 2.0 Hz, 1H), 7.70 (dd, J1 = 4.0 Hz, J2 = 2.4 Hz,
1H), 7.39−7.37 (m, 1H), 7.35 (s, 1H), 7.30−7.27 (m, 2H), 7.17 (q, J =
9.6 Hz, 1H), 6.49 (t, J = 2.4 Hz, 1H), 2.97 (dd, J1 = 13.6 Hz, J2 = 9.6
Hz, 1H), 2.78 (dd, J1 = 13.6 Hz, J2 = 5.6 Hz, 1H), 2.35−2.27 (m, 1H),
1.76−1.68 (m, 1H), 1.60−1.53 (m, 1H), 0.86 (t, J = 7.2 Hz, 3H);
o
anamide (4f). Yellow solid, 78.2 mg, 67% yield; m.p. 95.8–97.6 C;
1H NMR (400 MHz, CDCl3, ppm): δ 9.41 (s, 1H), 8.04−8.00 (m, 1H),
7.75 (d, J = 1.6 Hz, 1H), 7.70 (dd, J1 = 4.0 Hz, J2 = 2.4 Hz, 1H), 7.16
(q, J = 9.2 Hz, 1H), 7.09 (d, J = 8.4 Hz 2H), 6.97 (d, J = 8.4 Hz 2H),
6.54 (t, J = 2.4 Hz, 1H), 2.84 (dd, J1 = 13.6 Hz, J2 = 9.2 Hz, 1H), 2.70
(dd, J1 = 13.6 Hz, J2 = 5.2 Hz, 1H), 2.31−2.23 (m, 1H), 1.75−1.68 (m,
1H), 1.59−1.52 (m, 1H), 0.87 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100
MHz, CDCl3, ppm): δ 173.3, 147.1 (dd, JCF = 245.2, 12.1 Hz), 143.7
(dd, JCF = 249.0, 15.5 Hz), 141.5, 137.7, 133.0 (d, JCF = 6.5 Hz),
9
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19
20
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24
25
26
27
28
29
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31
32
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37
38
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60
13C{1H} NMR (100 MHz, CDCl3, ppm): δ 173.1, 147.1 (dd, JCF
=
245.5, 12.2 Hz), 143.6 (dd, JCF = 249.2, 15.7 Hz), 141.5, 140.3, 133.0
(d, JCF = 6.7 Hz), 132.2, 130.6 (d, JCF = 31.7 Hz), 129.0 (d, JCF = 3.3
Hz), 128.8, 125.4 (q, JCF = 3.8 Hz), 124.1 (q, JCF = 266.8 Hz), 123.3
(q, JCF = 3.7 Hz), 120.1 (d, JCF = 10.1 Hz), 118.3 (dd, JCF = 6.7, 4.5
Hz), 115.8 (d, JCF = 17.4 Hz), 107.5, 53.0, 38.6, 25.9, 11.7; HRMS
(EI): m/z [M+] calcd. for C21H18N3OF5: 423.1370; found: 423.1372.
Methyl 3-(2-((3,4-difluoro-2-(1H-pyrazol-1-yl)phenyl)carbamoyl)-
butyl)benzoate (4l). Yellow solid; 76.5 mg, 62% yield; m.p. 89.6–91.2
132.0, 130.0 (2C), 129.1 (d, JCF = 3.3 Hz), 128.5 (2C), 120.1 (d, JCF
=
9.9 Hz), 118.3 (dd, JCF = 6.5, 4.5 Hz), 115.8 (d, JCF = 17.4 Hz), 107.5,
53.1, 38.2, 25.8, 11.8; HRMS (EI): m/z [M+] calcd. for
C20H18N3OF2Cl: 389.1106; found: 389.1108.
Ethyl 4-(2-((3,4-difluoro-2-(1H-pyrazol-1-yl)phenyl)carbamoyl)bu-
tyl)benzoate (4g). Yellow oil; 68.9 mg, 54% yield; 1H NMR (400
MHz, CDCl3, ppm): δ 9.46 (s, 1H), 8.02−7.98 (m, 1H), 7.82 (d, J =
8.0 Hz, 2H), 7.75 (d, J = 1.6 Hz 1H), 7.67 (dd, J1 = 4.0 Hz, J2 = 2.4
Hz, 1H), 7.16 (q, J = 9.6 Hz, 1H), 7.12 (d, J = 8.0 Hz 2H), 6.48 (t, J =
2.0 Hz, 1H), 4.36 (q, J = 7.2 Hz, 2H), 2.94 (dd, J1 = 13.6 Hz, J2 = 9.6
Hz, 1H), 2.78 (dd, J1 = 13.6 Hz, J2 = 5.6 Hz, 1H), 2.37−2.29 (m, 1H),
1.76−1.69 (m, 1H), 1.60−1.53 (m, 1H), 1.39 (t, J = 7.2 Hz, 3H), 0.87
(t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3, ppm): δ 172.2,
165.5, 146.0 (dd, JCF = 245.3, 11.9 Hz), 143.6, 142.6 (dd, JCF = 249.1,
1
oC; H NMR (400 MHz, CDCl3, ppm): δ 9.47 (s, 1H), 8.05−8.00 (m,
1H), 7.80−7.78 (m, 2H), 7.75 (d, J = 2.0 Hz 1H), 7.68 (dd, J1 = 4.0 Hz,
J2 = 2.4 Hz, 1H), 7.27 (d, J = 8.4 Hz 1H), 7.23 (t, J = 7.6 Hz, 1H),
7.15 (q, J = 9.2 Hz, 1H), 6.47 (t, J = 2.4 Hz, 1H), 3.90 (s, 3H), 2.94
(dd, J1 = 13.6 Hz, J2 = 9.2 Hz, 1H), 2.78 (dd, J1 = 13.6 Hz, J2 = 5.6
Hz, 1H), 2.37−2.29 (m, 1H), 1.74−1.66 (m, 1H), 1.58−1.51 (m, 1H),
0.84 (t, J = 7.6 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3, ppm): δ
173.3, 167.0, 147.0 (dd, JCF = 245.1, 11.9 Hz), 144.1 (dd, JCF = 249.0,
15.5 Hz), 141.5, 139.7, 133.5, 133.0 (d, JCF = 6.6 Hz), 130.2, 129.8,
129.1 (d, JCF = 3.2 Hz), 128.4, 127.7, 120.1 (d, JCF = 9.3 Hz), 118.3
(dd, JCF = 6.6, 4.8 Hz), 115.8 (d, JCF = 17.4 Hz), 107.4, 52.9, 52.1,
38.6, 25.7, 11.7; HRMS (EI): m/z [M+] calcd. for C22H21N3O3F2:
413.1551; found: 413.1549.
15.7 Hz), 140.5, 131.9 (d, JCF = 6.6 Hz), 128.6 (2C), 127.9 (d, JCF
3.3 Hz), 127.6 (2C), 127.5, 119.0 (d, JCF = 10.5 Hz), 117.3 (dd, JCF
=
=
6.6, 4.5 Hz), 114.7 (d, JCF = 17.5 Hz), 106.4, 59.8, 51.8, 37.8, 24.9,
13.4, 10.7; HRMS (EI): m/z [M+] calcd. for C23H23N3O3F2: 427.1707;
found: 427.1708.
2-(4-Acetylbenzyl)-N-(3,4-difluoro-2-(1H-pyrazol-1-yl)phenyl)but-
1
anamide (4h). Yellow oil; 82.3 mg, 69% yield; H NMR (400 MHz,
2-(3-Acetylbenzyl)-N-(3,4-difluoro-2-(1H-pyrazol-1-yl)phenyl)but-
o
CDCl3, ppm): δ 9.53 (s, 1H), 8.03−7.99 (m, 1H), 7.76 (d, J = 2.0 Hz,
2H), 7.74 (s, 1H), 7.68 (dd, J1 = 4.4 Hz, J2 = 2.8 Hz, 1H), 7.19−7.12
(m, 3H), 6.48 (t, J = 2.4 Hz, 1H), 2.96 (dd, J1 = 13.6 Hz, J2 = 9.2 Hz,
1H), 2.79 (dd, J1 = 13.2 Hz, J2 = 5.6 Hz, 1H), 2.54 (s, 3H), 2.38−2.31
(m, 1H), 1.76−1.68 (m, 1H), 1.60−1.53 (m, 1H), 0.86 (t, J = 7.2 Hz,
3H); 13C{1H} NMR (100 MHz, CDCl3, ppm): δ 197.7, 173.1, 148.3
(dd, JCF = 245.3, 12.0 Hz), 145.1, 143.6 (dd, JCF = 249.3, 15.7 Hz),
141.5, 135.3, 132.9 (d, JCF = 6.7 Hz), 129.0 (d, JCF = 3.4 Hz), 128.9
(2C), 128.5 (2C), 120.0 (d, JCF = 10.4 Hz), 118.3 (dd, JCF = 6.6, 4.6
Hz), 115.8 (d, JCF = 17.4 Hz), 107.4, 52.7, 38.7, 26.6, 25.9, 11.7;
HRMS (EI): m/z [M+] calcd. for C22H21N3O2F2: 397.1602; found:
397.1601.
N-(3,4-Difluoro-2-(1H-pyrazol-1-yl)phenyl)-2-(3-methoxybenzyl)b-
utanamide (4i). Yellow solid, 67.3 mg, 58% yield; m.p. 78.8–80.5 oC;
1H NMR (400 MHz, CDCl3, ppm): δ 9.42 (s, 1H), 8.09−8.05 (m, 1H),
7.79 (d, J = 1.6 Hz, 1H), 7.71 (dd, J1 = 3.6 Hz, J2 = 2.4 Hz, 1H), 7.16
(q, J = 9.2 Hz, 1H), 7.10 (t, J = 7.6 Hz, 1H), 6.69−6.65 (m, 3H), 6.50
(t, J = 2.4 Hz, 1H), 3.73 (s, 3H), 2.89 (dd, J1 = 13.2 Hz, J2 = 8.4 Hz,
1H), 2.70 (dd, J1 = 13.6 Hz, J2 = 6.0 Hz, 1H), 2.35−2.30 (m, 1H),
1.71−1.62 (m, 1H), 1.60−1.51 (m, 1H), 0.83 (t, J = 7.2 Hz, 3H);
13C{1H} NMR (100 MHz, CDCl3, ppm): δ 173.7, 159.5, 147.0 (dd,
JCF = 245.0, 12.0 Hz), 143.8 (dd, JCF = 249.1, 15.5 Hz), 141.6, 140.9,
133.0 (d, JCF = 6.4 Hz), 129.4, 129.3, 121.1, 120.1 (d, JCF = 9.2 Hz),
118.2 (dd, JCF = 6.6, 4.6 Hz), 115.8 (d, JCF = 17.5 Hz), 114.4, 111.7,
107.4, 55.1, 52.8, 38.9, 25.6, 11.7; HRMS (EI): m/z [M+] calcd. for
C21H21N3O2F2: 385.1602; found: 385.1601.
anamide (4m). White solid; 71.6 mg, 60% yield; m.p. 92.3–94.0 C;
1H NMR (400 MHz, CDCl3, ppm): δ 9.51 (s, 1H), 8.06−8.02 (m, 1H),
7.76 (d, J = 2.0 Hz, 1H), 7.72−7.69 (m, 3H), 7.37−7.26 (m, 2H), 7.15
(q, J = 9.2 Hz, 1H), 6.48 (t, J = 2.0 Hz, 1H), 2.97 (dd, J1 = 13.6 Hz, J2
= 9.2 Hz, 1H), 2.79 (dd, J1 = 13.6 Hz, J2 = 6.0 Hz, 1H), 2.54 (s, 3H),
2.38−2.30 (m, 1H), 1.74−1.66 (m, 1H), 1.59−1.52 (m, 1H), 0.85 (t, J
= 7.6 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3, ppm): δ 198.1,
173.3, 147.0 (dd, JCF = 245.3, 12.0 Hz), 143.6 (dd, JCF = 249.0, 15.4
Hz), 141.6, 139.9, 137.2, 133.6, 133.0 (d, JCF = 6.7 Hz), 129.1 (d, JCF
= 3.3 Hz), 128.6, 128.4, 126.6, 120.0 (d, JCF = 9.0 Hz), 118.2 (dd, JCF
= 6.6, 4.6 Hz), 115.8 (d, JCF = 17.4 Hz), 107.4, 52.9, 38.6, 26.7, 25.8,
11.7; HRMS (EI): m/z [M+] calcd. for C22H21N3O2F2: 397.1602; found:
397.1600.
N-(3,4-Difluoro-2-(1H-pyrazol-1-yl)phenyl)-2-(2-methoxybenzyl)b-
utanamide (4n). White solid; 77.7 mg, 67% yield; m.p. 114.9–115.5
1
oC; H NMR (400 MHz, CDCl3, ppm): δ 9.28 (s, 1H), 8.08−8.04 (m,
1H), 7.79 (d, J = 1.6 Hz, 1H), 7.70 (dd, J1 = 4.0 Hz, J2 = 2.8 Hz, 1H),
7.19−7.11 (m, 2H), 7.01 (dd, J1 = 7.6 Hz, J2 = 2.0 Hz, 1H), 6.79−6.75
(m, 2H), 6.51 (t, J = 2.4 Hz, 1H), 3.80 (s, 3H), 2.81 (dd, J1 = 8.0 Hz,
J2 = 4.4 Hz, 2H), 2.46−2.39 (m, 1H), 1.71−1.63 (m, 1H), 1.54−1.48
(m, 1H), 0.82 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3,
ppm): δ 174.3, 157.3, 146.8 (dd, JCF = 244.8, 11.9 Hz), 143.9 (dd, JCF
= 248.8, 15.2 Hz), 141.5, 133.0 (d, JCF = 6.1 Hz), 130.7, 129.7 (d, JCF
= 3.2 Hz), 127.7, 127.5, 120.3, 120.0 (d, JCF = 9.2 Hz), 118.1 (dd, JCF
= 6.3, 4.8 Hz), 115.9 (d, JCF = 17.1 Hz), 110.2, 107.4, 55.2, 50.5, 33.9,
25.5, 11.8; HRMS (EI): m/z [M+] calcd. for C21H21N3O2F2: 385.1602;
found: 385.1600.
N-(3,4-Difluoro-2-(1H-pyrazol-1-yl)phenyl)-2-(2-fluorobenzyl)bu-
tanamide (4o). Yellow solid; 71.7 mg, 64% yield; m.p. 59.6–61.4 oC;
1H NMR (400 MHz, CDCl3, ppm): δ 9.52 (s, 1H), 8.06−8.02 (m, 1H),
7.81 (d, J = 1.6 Hz, 1H), 7.71 (dd, J1 = 4.0 Hz, J2 = 2.8 Hz, 1H), 7.17
(t, J = 9.6 Hz, 1H), 7.09 (q, J = 7.6 Hz, 2H), 6.96−6.90 (m, 2H), 6.51
N-(3,4-Difluoro-2-(1H-pyrazol-1-yl)phenyl)-2-(3-methylbenzyl)but-
1
anamide (4j). Yellow oil; 74.1 mg, 67% yield; H NMR (400 MHz,
CDCl3, ppm): δ 9.41 (s, 1H), 8.08−8.04 (m, 1H), 7.80 (d, J = 2.0 Hz,
1H), 7.71 (dd, J1 = 4.0 Hz, J2 = 2.4 Hz, 1H), 7.17 (q, J = 9.2 Hz, 1H),
6.08 (t, J = 7.2 Hz, 1H), 6.94 (d, J = 7.6 Hz, 1H), 6.91 (s, 1H), 6.89 (d,
J = 7.6 Hz, 1H), 6.51 (t, J = 2.4 Hz, 1H), 2.88 (dd, J1 = 13.6 Hz, J2 =
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(t, J = 2.4 Hz, 1H), 2.86 (d, J = 7.6 Hz, 2H), 2.44−2.36 (m, 1H),
= 2.8 Hz, 1H), 7.18 (q, J = 9.6 Hz, 1H), 7.09 (t, J = 1.6 Hz, 1H), 6.96
(s, 1H), 6.95 (s, 1H), 6.51 (t, J = 2.4 Hz, 1H), 2.84 (dd, J1 = 13.6 Hz,
J2 = 9.6 Hz, 1H), 2.66 (dd, J1 = 13.6 Hz, J2 = 5.2 Hz, 1H), 2.30−2.22
(m, 1H), 1.75−1.67 (m, 1H), 1.58−1.51 (m, 1H), 0.86 (t, J = 7.6 Hz,
3H); 13C{1H} NMR (100 MHz, CDCl3, ppm): δ 172.8, 147.1 (dd, JCF
= 245.3, 12.0 Hz), 143.6 (dd, JCF = 249.1, 15.5 Hz), 142.7, 141.5,
134.7 (2C), 132.9 (d, JCF = 6.9 Hz), 128.9 (d, JCF = 3.3 Hz), 127.2
(2C), 126.8, 120.2 (d, JCF = 10.2 Hz), 118.4 (dd, JCF = 6.7, 4.8 Hz),
115.8 (d, JCF = 17.5 Hz), 107.5, 52.8, 38.2, 25.9, 11.7; HRMS (EI):
m/z [M+] calcd. for C20H17N3OF2Cl2: 423.0717; found: 423.0719.
General Procedure for Arylation of 1d with Diiodobenzene. A
mixture of substrate 1d (167.6 mg, 0.6 mmol), 1,4-diiodobenzene 2v
(66.0 mg, 0.2 mmol), Pd(OAc)2 (13.5 mg, 10 mol%), Cu(OAc)2
(130.8 mg, 0.72 mmol), Ag3PO4 (75.3 mg, 0.18 mmol) in p-xylene
(1.5 mL) and DMF (1.5 ml) was charged in a glass sealed-tube and
stirred at 130 oC (oil bath) for 16 h. Upon completion of the reaction,
saturated brine (15 mL) and dichloromethane (15 mL) were added to
the mixture, then the aqueous layer was extracted with
dichloromethane (15 mL × 3). The combined organic layer was dried
over anhydrous MgSO4. Finally, the solution was concentrated in
vacuo to provide a crude product, which was further purified via a
column chromatography on silica gel (eluents: petroleum ether/ethyl
1.74−1.66 (m, 1H), 1.58−1.51 (m, 1H), 0.84 (t, J = 7.2 Hz, 3H);
13C{1H} NMR (100 MHz, CDCl3, ppm): δ 173.5, 161 (d, JCF = 243.5
Hz), 147.0 (dd, JCF = 244.8, 12.0 Hz), 143.7 (dd, JCF = 248.9, 15.5
Hz), 141.6, 132.9 (d, JCF = 6.6 Hz), 131.3 (d, JCF = 4.8 Hz), 129.3 (d,
JCF = 3.2 Hz), 128.2 (d, JCF = 8.1 Hz), 126.1 (d, JCF = 15.6 Hz), 123.9
(d, JCF = 3.5 Hz), 120.1 (d, JCF = 9.1 Hz), 118.2 (dd, JCF = 6.6, 4.6 Hz),
115.8 (d, JCF = 17.4 Hz), 115.2 (d, JCF = 21.8 Hz), 107.4, 51.1, 32.4,
25.6, 11.7; HRMS (EI): m/z [M+] calcd. for C20H18N3OF3: 373.1402;
found: 373.1401.
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Methyl 2-(2-((3,4-difluoro-2-(1H-pyrazol-1-yl)phenyl)carbamoyl)-
butyl)benzoate (4p). Yellow solid; 40.9 mg, 33% yield; m.p. 82.0–
84.2 oC; 1H NMR (400 MHz, CDCl3, ppm): δ 9.28 (s, 1H), 8.07−8.03
(m, 1H), 7.85 (dd, J1 = 8.0 Hz, J2 = 1.2 Hz, 1H), 7.73 (d, J = 2.0 Hz,
1H), 7.66 (dd, J1 = 4.0 Hz, J2 = 2.8 Hz, 1H), 7.31−7.27 (m, 1H), 7.20
(d, J = 6.0 Hz, 1H), 7.16 (d, J = 5.6 Hz, 1H), 7.13 (t, J = 4.4 Hz, 1H),
6.47 (t, J = 2.0 Hz, 1H), 3.89 (s, 3H), 3.21 (dd, J1 = 12.8 Hz, J2 = 6.0
Hz, 1H), 3.09 (dd, J1 = 12.8 Hz, J2 = 8.8 Hz, 1H), 2.50−2.53 (m, 1H),
1.77−1.69 (m, 1H), 1.59−1.53 (m, 1H), 0.83 (t, J = 7.6 Hz, 3H);
13C{1H} NMR (100 MHz, CDCl3, ppm): δ 174.0, 167.6, 146.9 (dd,
JCF = 244.8, 11.6 Hz), 143.9 (dd, JCF = 250.3, 16.4 Hz), 141.6, 141.4,
132.8 (d, JCF = 6.2 Hz), 132.0, 131.9, 131.1, 129.5 (d, JCF = 3.2 Hz),
128.9, 126.5, 120.1 (d, JCF = 10.6 Hz), 118.2 (dd, JCF = 6.2, 4.8 Hz),
115.8 (d, JCF = 17.3 Hz), 107.3, 52.2, 52.0, 37.9, 25.7, 11.8; HRMS
(EI): m/z [M+] calcd. for C22H21N3O3F2: 413.1551; found: 413.1548.
N-(3,4-Difluoro-2-(1H-pyrazol-1-yl)phenyl)-2-(2,4-dimethoxybenz-
yl)butanamide (4q). Yellow solid; 83.3 mg, 67% yield; m.p. 95.0–
97.1 oC; 1H NMR (400 MHz, CDCl3, ppm): δ 9.26 (s, 1H), 8.10−8.06
(m, 1H), 7.78 (d, J = 1.6 Hz, 1H), 7.69 (dd, J1 = 4.0 Hz, J2 = 2.8 Hz,
1H), 7.16 (q, J = 9.6 Hz, 1H), 6.89 (d, J = 8.0 Hz, 1H), 6.51 (t, J = 2.4
Hz, 1H), 6.34(d, J = 2.4 Hz, 1H), 6.28 (dd, J1 = 8.4 Hz, J2 = 2.4 Hz,
1H), 3.76 (s, 3H), 3.75 (s, 3H), 2.73 (d, J = 7.6 Hz, 2H), 2.41−2.33 (m,
1H), 1.69−1.62 (m, 1H), 1.53−1.47 (m, 1H), 0.82 (t, J = 7.6 Hz, 3H);
13C{1H} NMR (100 MHz, CDCl3, ppm): δ 174.4, 159.5, 158.2, 146.8
(dd, JCF = 244.7, 11.8 Hz), 143.8 (dd, JCF = 248.7, 15.3 Hz), 141.5,
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acetate
= 30:1 to 10:1) to supply the product 5. 2,2'-(1,4-
Phenylenebis(methyle-ne))bis(N-(3,4-difluoro-2-(1H-pyra-zol-1-
yl)phenyl)butanamide) (5). Yellow gum; 73.3 mg, 58% yield; 1H
NMR (400 MHz, CDCl3, ppm): δ 9.42 (s, 2H), 8.03−7.97 (m, 2H),
7.78 (t, J = 2.4 Hz, 2H), 7.71−7.69 (m, 2H), 7.14 (q, J = 9.6 Hz, 2H),
6.91 (d, J = 1.6 Hz, 4H), 6.51 (t, J = 2.0 Hz, 2H), 2.83 (dd, J1 = 13.6
Hz, J2 = 8.4 Hz, 2H), 2.68−2.61 (m, 2H), 2.31−2.23 (m, 2H),
1.66−1.58 (m, 2H), 1.53−1.46 (m, 2H), 0.79 (td, J1 = 7.6 Hz, J2 = 2.8
Hz, 6H); 13C{1H} NMR (100 MHz, CDCl3, ppm): δ 173.7, 173.6,
147.0 (dd, JCF = 245.1, 11.3 Hz, 2C), 143.8 (dd, JCF = 241.5, 17.5 Hz,
2C), 141.5 (2C), 137.1 (2C), 133.0 (t, JCF = 6.3 Hz, 2C), 129.3 (t, JCF
= 3.3 Hz, 2C), 128.8 (2C), 128.7 (2C), 120.0 (d, JCF = 9.6 Hz, 2C),
118.2 (2C), 115.8 (d, JCF = 17.7 Hz, 2C), 107.4 (2C), 52.8, 52.6, 38.3
(2C), 25.6, 25.5, 11.7 (2C); HRMS (EI): m/z [M+] calcd. for
C34H32N6O2F4: 632.2523; found: 632.2521.
General Procedure for Gram-Scale Reaction. A mixture of
substrate 1d (1.12 g, 4 mmol), 4-iodoanisole 2a (2.81 g, 12 mmol),
Pd(OAc)2 (111.7 mg, 10 mol%), Cu(OAc)2 (871.8 mg, 4.8 mmol),
Ag3PO4 (502.3 mg, 1.2 mmol), in p-xylene (20 mL) and DMF (20
mL) was charged in a round-bottomed flask (100 mL) and stirred at
130 oC (oil bath) for 16 h. Upon completion of the reaction, saturated
brine (100 mL) and dichloromethane (100 mL) were added to the
mixture, then the aqueous layer was extracted with dichloromethane
(30 mL × 3). The combined organic layer was dried over anhydrous
MgSO4. Finally, the solution was concentrated in vacuo to provide a
132.9 (d, JCF = 6.1 Hz), 130.9, 129.7 (d, JCF = 3.2 Hz), 120.0 (d, JCF
=
10.9 Hz), 119.9, 118.1 (dd, JCF = 6.3, 4.6 Hz), 115.9 (d, JCF = 17.6
Hz), 107.3, 103.6, 98.5, 55.3, 55.2, 50.8, 33.3, 25.5, 11.8; HRMS (EI):
m/z [M+] calcd. for C22H23N3O3F2: 415.1707; found: 415.1708.
N-(3,4-Difluoro-2-(1H-pyrazol-1-yl)phenyl)-2-(3,5-
1
dimethylbenzyl-)butanamide (4r). Brown oil; 70.7 mg, 62% yield; H
NMR (400 MHz, CDCl3, ppm): δ 9.39 (s, 1H), 8.09−8.05 (m, 1H),
7.80 (d, J = 1.6 Hz, 1H), 7.72 (dd, J1 = 4.0 Hz, J2 = 2.8 Hz, 1H), 7.17
(q, J = 9.6 Hz, 1H), 6.76 (s, 1H), 6.71 (s, 2H), 6.51 (t, J = 2.4 Hz, 1H),
2.84 (dd, J1 = 13.2 Hz, J2 = 8.4 Hz, 1H), 2.64 (dd, J1 = 13.6 Hz, J2 =
6.4 Hz, 1H), 2.32−2.28 (m, 1H), 2.22 (s, 6H), 1.70−1.62 (m, 1H),
1.57−1.51 (m, 1H), 0.82 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz,
CDCl3, ppm): δ 173.9, 147.0 (dd, JCF = 245.0, 11.9 Hz), 143.8 (dd,
JCF = 249.0, 15.4 Hz), 141.5, 139.2, 137.7 (2C), 132.9 (d, JCF = 6.4
Hz), 129.4 (d, JCF = 3.2 Hz), 128.0, 126.6 (2C), 120.1 (d, JCF = 9.2
Hz), 118.2 (dd, JCF = 6.5, 4.6 Hz), 115.8 (d, JCF = 17.3 Hz), 107.4,
53.0, 38.7, 25.6, 21.3 (2C), 11.7; HRMS (EI): m/z [M+] calcd. for
C22H23N3OF2: 383.1809; found: 383.1810.
crude product, which was further purified via
a
column
chromatography on silica gel (eluents: petroleum ether/ethyl acetate =
60:1 to 30:1) to supply the desired product 3d (1.06 g, 69%).
General Procedure for the Removal of the Directing Group.
The reaction was performed in an air atmosphere. A mixture of the
arylated producted 3d (96.4 mg, 0.25 mmol) and HCl (5 mL, 12 M)
o
N-(3,4-Difluoro-2-(1H-pyrazol-1-yl)phenyl)-2-(2,4-difluorobenzyl)-
butanamide (4s). Yellow solid; 67.0 mg, 57% yield; m.p. 105.5–107.7
were added to a round-bottomed flask (25 mL) and stirred at 110 C
(oil bath) for 20 h. Upon completion of the reaction, water (20 mL)
and was slowly added to the mixture, then the aqueous layer was
extracted with ethyl acetate (20 mL × 5). The combined organic layer
was dried over anhydrous MgSO4. Finally, the solution was
concentrated in vacuo to provide a crude product, which was further
1
oC; H NMR (400 MHz, CDCl3, ppm): δ 9.54 (s, 1H), 8.04−8.00 (m,
1H), 7.78 (d, J = 1.6 Hz, 1H), 7.72 (dd, J1 = 4.0 Hz, J2 = 2.4 Hz, 1H),
7.16 (q, J = 9.6 Hz, 1H), 7.04−6,99 (m, 1H), 6.68−6.61 (m, 2H), 6.52
(t, J = 2.4 Hz, 1H), 2.80 (d, J = 8.0 Hz, 2H), 2.38−2.30 (m, 1H),
1.75−1.68 (m, 1H), 1.58−1.51 (m, 1H), 0.86 (t, J = 7.6 Hz, 3H);
purified via
a column chromatography on silica gel (eluents:
13C{1H} NMR (100 MHz, CDCl3, ppm): δ 173.3, 161.6 (dd, JCF
245.3, 11.7 Hz), 160.9 (dd, JCF = 246.1, 11.7 Hz), 147.1 (dd, JCF
=
=
dichloromethane/ methanol = 200:1 to 100:1) to supply the free acid 6.
1
2-(4-hydroxybenz-yl)butanoic acid (6). Yellow oil; 34.4 mg, 71%; H
245.3, 11.9 Hz), 143.7 (dd, JCF = 249.0, 15.6 Hz), 141.6, 132.9 (d, JCF
= 6.8 Hz), 131.8 (dd, JCF = 9.3, 6.4 Hz), 129.1 (d, JCF = 3.2 Hz), 122.0
(dd, JCF = 15.7, 3.7 Hz), 120.0 (d, JCF = 9.4 Hz), 118.3 (dd, JCF = 6.7,
4.6 Hz), 115.8 (d, JCF = 17.2 Hz), 110.9 (dd, JCF = 20.6, 3.5 Hz),
107.4, 103.7 (t, JCF = 25.5 Hz), 51.3, 31.8, 25.7, 11.7; HRMS (EI):
m/z [M+] calcd. for C20H17N3OF4: 391.1308; found: 391.1307.
NMR (400 MHz, CDCl3, ppm): δ 6.97 (d, J = 8.0 Hz, 2H), 6.64 (d, J
= 8.4 Hz, 2H), 2.80 (dd, J1 = 14.0 Hz, J2 = 9.6 Hz, 1H), 2.71 (dd, J1 =
14.0 Hz, J2 = 6.0 Hz, 1H), 2.58−2.51 (m, 1H), 1.70−1.55 (m, 2H),
0.96 (t, J = 7.6 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3, ppm): δ
180.6, 152.9, 130.0, 128.9 (2C), 114.4 (2C), 48.6, 36.1, 24.1, 10.7;
HRMS (EI): m/z [M+] calcd. for: C11H14O3: 194.0943; found:
194.0942.
General Procedure for Competition Experiment. A mixture of
substrate 1d (83.8 mg, 0.3 mmol), 1-iodo-4-methoxybenzene 2a
(105.3 mg, 0.45 mmol), 1-fluoro-4-iodobenzene 2e (99.9 mg, 0.45
2-(3,5-Dichlorobenzyl)-N-(3,4-difluoro-2-(1H-pyrazol-1-
yl)phenyl-)butanamide (4t). Yellow solid; 75.0 mg, 59% yield; m.p.
91.0–92.4 oC; 1H NMR (400 MHz, CDCl3, ppm): δ 9.54 (s, 1H),
8.04−8.00 (m, 1H), 7.78 (d, J = 2.0 Hz, 1H), 7.75 (dd, J1 = 4.4 Hz, J2
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mmol), Pd(OAc)2 (6.7 mg, 10 mol%), Cu(OAc)2 (65.4 mg, 0.36
The Supporting Information is available free of charge on the
mmol), Ag3PO4 (37.7 mg, 0.09 mmol), in p-xylene (1.5 mL) and
DMF (1.5 mL) was charged in a glass sealed-tube and stirred at 130
oC (oil bath) for 16 h. Upon completion of the reaction, saturated
brine (15 mL) were added to the mixture, then the aqueous layer was
extracted with dichloromethane (15 mL × 3). The combined organic
layer was dried over anhydrous MgSO4. Finally, the solution was
concentrated in vacuo to provide a crude product, which was further
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ACS Publications website.
Spectral data for all new compounds (PDF)
Crystallographic data for 4k (CIF)
AUTHOR INFORMATION
Corresponding Author
purified via
a column chromatography on silica gel (eluents:
*E-mail: jyf@ecust.edu.cn (Ji).
*E-mail: yxj@ecust.edu.cn (Yang).
petroleum ether/ethyl acetate = 70:1 to 30:1) to supply the desired
product 3d (28.3 mg, 23%) and 4e (52.7 mg, 48%).
9
General Procedure for Deuterium Labelling Experiments. A
mixture of substrate 1d (55.8 mg, 0.2 mmol), Pd(OAc)2 (4.5 mg, 10
mol%), Cu(OAc)2 (43.6 mg, 0.24 mmol), Ag3PO4 (25.1 mg, 0.06
mmol), in p-xylene (1.0 mL), DMF (1.0 mL) and AcOD (1.0 mL) was
charged in a glass sealed-tube and stirred at 130 oC (oil bath) for 1.5 h.
After the reaction, saturated brine (15 mL) was added to the mixture,
then the aqueous layer was extracted with dichloromethane (15 mL ×
3). The combined organic layer was dried over anhydrous MgSO4 and
concentrated in vacuo to provide a crude product, which was further
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Yafei Ji: 0000-0002-3562-6703
XianJin Yang: 0000-0002-1368-3643
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
purified via
a column chromatography on silica gel (eluents:
We gratefully thank the National Natural Science Foundation of
China (Project Nos. 21676088 and 21476074) for financial
support.
petroleum ether/ethyl acetate = 50:1 to 30:1) to supply the product
H/D-1d (49.7 mg, 89%). The 1H NMR of H/D-1d was 1H NMR (400
MHz, CDCl3, ppm): δ 9.58 (s, 1H), 8.18−8.14 (m, 1H), 7.86 (s, 1H),
7.81 (d J = 3.2 Hz, 1H), 7.18 (q, J = 9.6 Hz, 1H), 6.55 (t, J = 2.4 Hz,
0.82H), 2.24−2.17 (m, 1H), 1.67−1.60 (m, 1H), 1.48−1.41 (m, 1H),
1.13 (d, J = 6.8 Hz, 2.16H), 0.84 (t, J = 7.2 Hz, 3H).
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The preparation of [D3]-1d. Under the atmosphere of N2, to a
stirred solution of lithium diisopropylamide (LDA) (20 mL, 2.0 M/L
o
in THF) cooled at -15 C (ice salt bath) was added dropwise butyric
acid (0.80 g, 9.0 mmol). After 30 min, 1,3-dimethylpropyleneurea
(DMPU) (1.15 g, 9.0 mmol) was added drop by drop. Then, the
mixture was stirred at room temperture for 1 h and cooled again at -15
oC, CD3I (2.84 g, 20 mmol) in 10 mL of anhydrous THF was added
dropwise. Then, the reaction mixture was raised to room temperature
and stirred for 3 h. Finally, the reaction was neutralized by ice cold
20% H2SO4. The aqueous layer was extracted with ethyl acetate (15
mL × 3). The combined organic layer was washed with water and
brine, dried over anhydrous MgSO4, and concentrated in vacuo to
afford 2-[2H3]methylbutyric acid (0.71 g, 75%).25 The following steps
are same as those for the substrates. [D3]-1d was obtained in 40%
yield (0.56 g). The 1H NMR of [D3]-1d was 1H NMR (400 MHz,
CDCl3, ppm): δ 9.57 (s, 1H), 8.18−8.14 (m, 1H), 7.86 (d, J = 2.0 Hz,
1H), 7.81 (dd, J1 = 4.0 Hz, J2 = 2.4 Hz, 1H), 7.19 (q, J = 9.2 Hz, 1H),
6.56 (t, J = 2.4 Hz, 1H), 2.20 (t, J = 6.8 Hz, 1H), 1.67−1.59 (m, 1H),
1.48−1.41 (m, 1H), 0.84 (t, J = 7.6 Hz, 3H).
A mixture of substrate [D3]-1d (28.2 mg, 0.1 mmol), 1d (27.9 mg,
0.1 mmol), 4-iodoanisole (140.4 mg, 0.6 mmol), Pd(OAc)2 (4.5 mg,
10 mol%), Cu(OAc)2 (43.6 mg, 0.24 mmol), Ag3PO4 (25.1 mg, 0.06
mmol), in p-xylene (1.0 mL) and DMF (1.0 mL) was charged in a
glass sealed-tube and stirred at 130 oC (oil bath) for 1.5 h. Upon
completion of the reaction, saturated brine (15 mL) was added to the
mixture, then the aqueous layer was extracted with dichloromethane
(15 mL × 3). The combined organic layer was dried over anhydrous
MgSO4. Finally, the solution was concentrated in vacuo to provide a
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crude product, which was further purified via
a
column
chromatography on silica gel (eluents: petroleum ether/ethyl acetate =
70:1 to 30:1) to supply the product 3d and [D2]-3d (14.9 mg, 19%).
1
1
The H NMR of 3d and [D2]-3d was H NMR (400 MHz, CDCl3,
ppm): δ 9.40 (s, 1H), 8.06−8.02 (m, 1H), 7.79 (d, J = 1.6 Hz, 1H),
7.70 (dd, J1 = 3.6 Hz, J2 = 2.4 Hz, 1H), 7.16 (q, J = 9.6 Hz, 1H), 6.98
(d, J = 8.8 Hz, 2H), 6.70 (d, J = 8.8 Hz, 2H), 6.51 (t, J = 2.0 Hz, 1H),
3.75 (s, 1H), 2.84 (dd, J1 = 13.6 Hz, J2 = 8.8 Hz, 0.79H), 2.67 (dd, J1
= 13.6 Hz, J2 = 6.0 Hz, 0.79H), 2.30−2.26 (m, 1H), 1.65−1.57 (m,
1H), 1.56−1.51 (m, 1H), 0.84 (t, J = 7.2 Hz, 3H). The 1H NMR
analysis showed that the ratio of 3d to [D2]-3d is 3.76.
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