Lithium Chloride Catalyzed Aza-Michael Addition of Pyrazoles to α,β-Unsaturated Imides

Article abstract of DOI:10.1055/s-0037-1611520

A lithium chloride catalyzed aza-Michael reaction of pyrazoles to α,β-unsaturated imides has been developed. A range of aromatic and aliphatic α,β-unsaturated imides are found to be suitable for the established method, providing the corresponding aza-Mich

Full text of DOI:10.1055/s-0037-1611520

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2019, 51, A–I
paper
A
en
H. Zhou et al.
Paper
Synthesis
Lithium Chloride Catalyzed Aza-Michael Addition of Pyrazoles to
,-Unsaturated Imides
Hongyan Zhou*a,b
Xiancheng Xiangb
Ben Mab
Ganggang Wangb
Zhixia Zhanga
R2
N
O
O
R2
N
O
O
R1
LiCl (10 mol%)
MeCN, reflux
R1
N
+
R
N
N
R
N
H
H
H
R = aryl, alkyl
up to 93% yield
Jingya Yang*b
0
0
0
0-0
0
0
2-
7
4
1
9-5
1
3
3
• cheap catalyst • broad substrate scope • high yields • easy to scale up
a College of Science, Gansu Agricultural University,
Lanzhou 730070, P. R. of China
zhouhy@gsau.edu.cn
b College of Chemistry and Chemical Engineering,
Northwest Normal University, Lanzhou 730070,
P. R. of China
yangjy@nwnu.edu.cn
Received: 23.01.2019
Accepted after revision: 01.04.2019
Published online: 17.04.2019
catalysis and coordination chemistry.6 Recently, the syn-
thetic methods for pyrazoles involving pyrazole ring syn-
thesis and modification have been comprehensively re-
viewed.7 From the standpoint of green chemistry, the aza-
Michael reaction of pyrazoles with activated olefins is an
ideal protocol with which to access N1-subtituted pyra-
zoles. Consequently, developing practical approaches to
conduct the reaction would be of general interest and of
high synthetic value.
DOI: 10.1055/s-0037-1611520; Art ID: ss-2019-h0044-op
Abstract A lithium chloride catalyzed aza-Michael reaction of pyra-
zoles to ,-unsaturated imides has been developed. A range of aro-
matic and aliphatic ,-unsaturated imides are found to be suitable for
the established method, providing the corresponding aza-Michael ad-
ducts in up to 93% yields. The inexpensive catalyst, good substrate tol-
erance, and ease of scale-up make this procedure highly practical.
In this regard, the aza-Michael reaction of pyrazole with
methyl acrylate,8 acrylonitrile,9 ,-unsaturated--keto es-
ters,10 nitroalkenes,11 ,-unsaturated ketones,12 and alke-
nyl sulfone3s have been developed. Recently, catalytic asym-
metric aza-Michael addition of pyrazole to ,-unsaturated
ketones were also reported.13 However, the aza-Michael ad-
dition of pyrazole to ,-unsaturated carboxylic acid is dif-
ficult to achieve because of the acid-base conflict of the re-
actants. In this context, only the reaction of aliphatic maleic
acid and crotonic acid have been realized on heating,14
while the aromatic carboxylic acid gave the corresponding
salt because of its steric bulk (Scheme 1).15
Key words Michael addition, ,-unsaturated imides, pyrazoles, nitro-
gen heterocycles, regioselectivity
The aza-Michael reaction is an essentially atom-eco-
nomic reaction that can be used to construct C–N bonds in
organic synthesis. It has been widely used in the synthesis
of N-heterocycles, -amino acids, -lactams, -amino alco-
hols, natural products, and pharmaceuticals.1 The aza-Mi-
chael reactions including catalytic asymmetric variants
have been extensively developed.2 Generally, strong bases
or Lewis acids are required to activate nucleophiles or Mi-
chael acceptors, and organocatalytic or metal catalytic
strategies are used for the asymmetric reactions. Though
numerous achievements have been made for aza-Michael
reactions, the intermolecular aza-Michael reactions of aro-
matic nitrogen heterocycles with less nucleophilicity are
still challenging and remain highly attractive.3
N
EWG
Michael acceptor
• Previous work:
N
N
+
R
N
H
EWG
R
Well-developed with:
Restricted with:
Pyrazoles are an important class of five-membered aro-
matic nitrogen heterocycles and often possess significant
bioactivities. Besides their use as herbicides, insecticides
and fungicides in agriculture,4 they have important applica-
tions in medicine because of their diverse pharmaceutical
activities such as anticancer, antibacterial, anti-inflamma-
tory, antidepressant, anticonvulsant, anti-obesity, and anti-
diabetic action.5 Moreover, pyrazoles are versatile ligands in
methyl acrylate
acrylonitrile
β,γ-unsaturated-α-keto esters
nitroalkenes
α,β-unsaturated ketones
alkenyl sulfone
α,β-unsaturated carboxylic acids
(limitted to aliphatic maleic acid
and crotonic acid)
• This work:
with α,β-unsaturated imides (previously undeveloped)
Scheme 1 The aza-Michael reactions of pyrazole
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–I

B
H. Zhou et al.
Paper
Synthesis
,-Unsaturated imides can be used as equivalents of
unsaturated carboxylic acids and represent an important
class of Michael acceptors. They have been used in asym-
metric conjugate cyanation16 and aza-Michael addition of
N-heterocycles (purine,3a 6-substituted purines,3a benzotri-
azole,3a 5-methyltetrazole,3a 5-phenyltetrazole3a,g). Howev-
er, to our knowledge, no aza-Michael reaction of pyrazole
with ,-unsaturated imides has been reported.
Table 1 Optimization of the Reaction Conditionsa
O
O
N
cat. (10 mol%)
N
O
O
N
+
N
Ph
N
Ph
solvent, temp, time
H
H
Ph
N
Ph
H
1a
2a
Entry
Catalyst
Solvent
Temp (°C)
Yield (%)b
In prior investigations, we have developed the cesium
carbonate catalyzed aza-Michael addition of pyrazole to
,-unsaturated ketones in dioxane.17 However, it was
found that the conditions were not suitable for ,-unsatu-
rated imides. In a continuation of our research program on
aza-Michael reaction of aromatic nitrogen heterocycles,17,18
we aimed to further explore aza-Michael addition of pyra-
zoles toward ,-unsaturated imides to generate valuable
pyrazole-containing products that would otherwise be dif-
ficult to access. Herein, we report our recent progress on
lithium chloride catalyzed aza-Michael reaction of pyra-
zoles with ,-unsaturated imides.
The investigation was started with N-cinnamoyl ben-
zamide (1a) and pyrazole (2a) as model substrates to opti-
mize the reaction conditions (Table 1). Initially, only trace
amounts of the aza-Michael adduct 3aa were observed un-
der catalyst-free conditions (entry 1). Various inorganic and
organic bases were then screened in acetonitrile at reflux
temperature (entries 2–8). Although they all showed a cer-
tain degree of catalytic activity, all gave unsatisfactory
yields. We then turned our attention to Lewis acids (entries
9–14). Among them, lithium chloride, an efficient catalyst
used in some aza-Michael reactions,19 displayed the best
catalytic performance and gave 3aa in 64% yield (entry 9).
Next, the effect of solvent was evaluated by using lithium
chloride as the catalyst (entries 15–22). Except for metha-
nol and dimethyl sulfoxide (DMSO), other employed sol-
vents afforded the desired product 3aa with varying yields
but all were inferior to that in acetonitrile. Subsequent as-
sessment on the reaction temperature suggested that a
lower reaction temperature was unfavorable for the trans-
formation (entries 23–25). Further investigations showed
that shortening reaction time led to incomplete conversion
whereas extending the reaction time to over eighteen hours
did not bring about an improvement (entries 26 and 27).
Thus, the best reaction conditions were established as 10
mol% of lithium chloride as catalyst in acetonitrile at reflux
temperature.
1
2
–
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeOH
EtOH
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
120
trace
37
35
40
55
15
46
29
64
34
61
40
54
56
0
Cs2CO3
K2CO3
KOAc
K3PO4
NaOH
DBU
3
4
5
6
7
8
DMAP
LiCl
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26c
27d
BF3·OEt2
AlCl3
LiBr
LiI
LiOTf
LiCl
LiCl
27
trace
52
55
44
50
42
trace
48
57
65
48
LiCl
DMSO
CH2Cl2
1,4-dioxane
THF
LiCl
reflux
reflux
reflux
reflux
reflux
r.t.
LiCl
LiCl
LiCl
hexane
toluene
MeCN
MeCN
MeCN
MeCN
MeCN
LiCl
LiCl
LiCl
40
LiCl
60
LiCl
reflux
reflux
LiCl
a Reaction conditions: 1a (0.1 mmol ), 2a (0.12 mmol, 1.2 equiv), catalyst
(10 mol%), solvent (1 mL) at indicated temperature for 18 h.
b Isolated yield.
c 24 h.
d 12 h.
action was only slightly affected by the electronic effect of
the substituents, although a decreased reactivity was ob-
served with the NO2 substituent (3ea). It should be noted
that a longer reaction time was needed to complete the
transformation of the aromatic ,-unsaturated imides. In
contrast to the aromatic ,-unsaturated imides, the ali-
phatic ,-unsaturated imides reacted fast and gave the
corresponding products 3fa–sa with high to excellent
yields. This may be due to the lower steric hindrance of the
aliphatic substrates. Another possibility that causes this dif-
With the optimal reaction conditions in hand, the toler-
ance of the reaction towards ,-unsaturated imides was
then investigated (Scheme 2). To our delight, aromatic ,-
unsaturated imides with either electron-donating or elec-
tron-withdrawing substituents on their phenyl ring were
well tolerated and the corresponding products 3aa–ea were
obtained in moderate to high yields. The outcome of the re-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–I

C
H. Zhou et al.
Paper
Synthesis
ference may need to be considered; that is, the reaction rate
of the possible reverse reaction. To evaluate this possibility,
the stability of the product 3aa was investigated under the
standard conditions, and no reverse reaction was observed
even after 24 hours. Therefore, we can rule out the possibil-
ity of a reverse reaction.
zole reacted slightly slower and afforded the desired com-
pound 3ig with an inferior yield. In addition, ,-unsaturat-
ed imides 1t–w, bearing a substituent on the benzene ring
of the benzamide unit, showed similar reactivity to that of
unsubstituted 1i, affording the products 3ta–wa in satisfac-
tory yields.
R2
O
O
O
O
N
N
R1
R2
+
LiCl (10 mol%)
MeCN, reflux
N
O
O
N
O
O
N
LiCl (10 mol%)
MeCN, reflux
+
R1
N
N
H
R
N
H
Ph
Pr
Cl
N
N
H
R
N
Ph
Pr
NH
H
H
1a–s
2a
3aa–sa
1i,t–w
3
2a–g
Br
O2N
N
N
3ba: R' = 4-OMe, 18 h, 60%
3ca: R' = 4-Cl, 18 h, 73%
3da: R' = 4-F, 18 h, 79%
3ea: R' = 3-NO2, 18 h, 51%
N
O
O
N
O
O
R'
N
N
N
Ph
N
H
Ph
Ph
Ph
N
Ph
N
O
O
N
O
O
N
O
O
H
3aa, 18 h, 64%
Pr
N
Ph
Pr
N
Ph
Pr
N
Ph
H
H
H
3ib, 8 h, 91%
3ic, 8 h, 90%
3id, 10 h, 88%
N
N
N
N
O
O
N
O
O
N
O
O
Me
Me
N
Me
N
Et
N
Ph
i-Pr
N
Ph
Ph
Ph
Ph
H
H
H
N
N
Me
N
O
O
N
O
O
N
O
O
3fa, 7 h, 90%
3ga, 9 h, 85%
3ha, 8 h, 91%
Pr
N
Ph
Pr
N
Ph
N
Pr
N
Ph
H
H
H
N
N
N
3ie, 9 h, 93%
3if, 9 h, 91%
3ig, 13 h, 62%
N
O
O
N
O
O
N
O
O
Pr
N
i-Bu
N
Ph
Bu
N
H
H
H
N
N
N
O
O
O
O
Cl
3ia, 9 h, 92%
3ja, 9 h, 90%
3ka, 7 h, 85%
Br
Pr
N
Pr
N
H
H
N
N
N
N
O
O
N
O
O
N
O
O
3ta, 9 h, 90%
3ua, 10 h, 88%
amyl
octyl
N
Ph hexyl
N
Ph heptyl
N
H
H
H
3la, 7 h, 89%
3ma, 8 h, 87%
3na, 8 h, 92%
N
N
N
O
O
N
O
O
OEt
Pr
N
N
N
N
Pr
N
H
H
N
O
O
N
O
O
N
O
O
Cl
N
Ph nonyl
N
Ph decyl
N
3va, 10 h, 81%
3wa, 8 h, 78%
H
H
H
3oa, 8 h, 89%
3pa, 9 h, 88%
3qa, 7 h, 90%
Scheme 3 Scope of substituted pyrazoles and ,-unsaturated imides:
Reaction conditions: 1 (0.5 mmol), 2 (0.6 mmol, 1.2 equiv), LiCl (10
mol%) in MeCN (3 mL) at reflux temperature for given time. Isolated
yield are given.
N
N
N
N
O
O
O
O
undecyl
N
Ph
Ph
N
Ph
H
H
To illustrate the synthetic practicality of the established
method, a gram-scale aza-Michael reaction of pyrazole (2a)
with (E)-N-(but-2-enoyl)benzamide (1f) was performed
under the standard conditions. As shown in Scheme 4, the
reaction proceeded smoothly and afforded the product 3fa
in 90% isolated yield.
3ra, 8 h, 88%
3sa, 10 h, 87%
Scheme 2 Substrate scope for the reactions of pyrazole with ,-un-
saturated imides. Reaction conditions: 1 (0.5 mmol), 2a (0.6 mmol, 1.2
equiv), LiCl (10 mol%) in MeCN (3 mL) at reflux temperature for given
time. Isolated yield are given.
A number of substituted pyrazoles and ,-unsaturated
imides with a substituent on the benzene ring of the ben-
zamide unit were used to evaluated their compatibility
with the established method (Scheme 3). To our delight, 4-
chloro-, 4-bromo-, 4-nitro-, 4-methyl-, and 3,5-dimethyl-
substituted pyrazoles were well tolerated and gave the cor-
responding products 3ib–if in high to excellent yields; inda-
O
O
N
LiCl (10 mol%)
N
O
O
N
+
N
H
N
Ph
MeCN, reflux, 8 h
H
N
Ph
H
1f
2a
3fa
(8 mmol, 1.51 g)
(1.2 equiv)
(1.83 g, 89%)
Scheme 4 Gram-scale experiment
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–I

D
H. Zhou et al.
Paper
Synthesis
To further showcase the application of this strategy to
other Michael acceptors, the reaction of pyrazole (2a) with
nitrostyrene (4) was conducted under the established con-
ditions. To our delight, nitrostyrene was tolerated well and
furnished the desired aza-Michael adduct 5 with high yield
(Scheme 5).
rectly. Other reagents and solvents were commercially available, and
were used without further purification. The reaction mixtures were
purified by column chromatography over silica gel (PE/EtOAc).
Aza-Michael Addition of Pyrazoles to ,-Unsaturated Imides;
General Procedure
,-Unsaturated imide 1 (0.5 mmol), pyrazole 2 (0.6 mmol, 1.2 equiv),
LiCl (2.1 mg, 0.05 mmol, 10 mol%) and CH3CN (3.0 mL) was succes-
sively added into a dry Schlenk tube equipped with a cold finger. The
reaction mixture was stirred at reflux temperature until the reaction
was complete (monitored by TLC), then H2O (4 mL) was added and the
resulting mixture was extracted with EtOAc (2 × 8 mL). The combined
organic phase was washed with saturated brine, dried over anhy-
drous Na2SO4, and concentrated under reduced pressure. The crude
product was purified by column chromatography on silica gel using
petroleum ether/EtOAc as the eluent to afford the desired product 3.
N
NO2
N
LiCl (10 mol%)
N
+
NO2
N
MeCN, reflux, 15 h
H
4
5, 90%
Scheme 5 The aza-Michael reaction of pyrazole with nitrostyrene
-Amino acids are very important bioactive compounds
in life, biological, and chemical sciences.20 Integration of the
pyrazolyl group into amino acid molecules may enhance
their biological activity. However, for the foregoing reason,
-pyrazolyl amino acids are difficult to form by direct aza-
Michael reaction of pyrazole with ,-unsaturated carbox-
ylic acids. Therefore, the transformation of the aza-Michael
adducts 3aa and 3ia toward the corresponding amino acids
were conducted (Scheme 6). Gratifyingly, in the presence of
base, 3aa and 3ia were readily converted into 3-(1H-pyra-
zol-1-yl)butanoic acid (6aa) and 3-(1H-pyrazol-1-yl)hexa-
noic acid (6ia) in high yield.
N-(3-Phenyl-3-(1H-pyrazol-1-yl)propanoyl)benzamide (3aa)
Yield: 102.2 mg (64%); colorless solid; mp 165–167 °C.
1H NMR (CDCl3, 400 MHz):  = 9.16 (s, 1 H), 7.82–7.80 (m, 2 H), 7.59–
7.57 (m, 1 H), 7.54 (d, J = 1.2 Hz, 1 H), 7.47 (t, J = 7.8 Hz, 2 H), 7.43 (d,
J = 1.8 Hz, 1 H), 7.33–7.25 (m, 5 H), 6.24 (t, J = 1.8 Hz, 1 H), 5.97 (dd, J =
9.6, 4.2 Hz, 1 H), 4.31 (dd, J = 16.8, 9.6 Hz, 1 H), 3.62 (dd, J = 17.4,
4.2 Hz, 1 H).
13C NMR (100 MHz, CDCl3):  = 171.1, 165.5, 140.0, 139.3, 133.2,
132.6, 129.6, 128.9, 128.8, 128.2, 127.8, 126.6, 105.8, 61.2, 43.5.
HRMS (ESI): m/z [M + H]+ calcd for C19H18N3O2+: 320.1394; found:
320.1395.
N-(3-(4-Methoxyphenyl)-3-(1H-pyrazol-1-yl)propanoyl)ben-
zamide (3ba)
N
N
NaOH
N
O
N
O
O
THF, reflux, 2 h
Yield: 104.8 mg (60%); colorless solid; mp 169–170 °C.
R
OH
R
N
Ph
H
1H NMR (600 MHz, CDCl3):  = 9.02 (s, 1 H), 7.80 (d, J = 7.8 Hz, 2 H),
7.59 (t, J = 7.8 Hz, 1 H), 7.53 (s, 1 H), 7.48 (t, J = 7.8 Hz, 2 H), 7.41 (d, J =
1.8 Hz, 1 H), 7.23 (d, J = 9.0 Hz, 2 H), 6.85 (d, J = 8.4 Hz, 2 H), 6.23 (s,
1 H), 5.91 (q, J = 4.8 Hz, 1 H), 4.25 (dd, J = 17.4, 8.4 Hz, 1 H), 3.77 (s,
3 H), 3.61 (dd, J = 16.8, 4.8 Hz, 1 H).
3aa, R = Ph
3ia, R = Pr
6aa, 88%
6ia, 75%
Scheme 6 Transformations of the aza-Michael adducts 3aa and 3ia
13C NMR (150 MHz, CDCl3):  = 171.9, 165.4, 159.4, 139.3, 133.2,
132.6, 132.0, 129.4, 128.9, 128.0, 127.7, 114.2, 105.7, 60.8, 55.3, 43.6.
HRMS (ESI): m/z [M + H]+ calcd for C20H20N3O3+: 350.1499; found:
350.1496.
In summary, we have developed an efficient and practi-
cal strategy for the aza-Michael reaction of pyrazoles with
,-unsaturated imides. By using inexpensive and readily
available lithium chloride as catalyst, a variety of aromatic
and aliphatic ,-unsaturated imides were successfully con-
verted into the corresponding products with up to 93%
yields. The established protocol has advantages of high effi-
ciency, mild conditions, broad substrate scope, and ease of
scale-up. Furthermore, the products can be easily converted
into the corresponding -pyrazolyl amino acids, which po-
tentially possess important bioactivities.
N-(3-(4-Chlorophenyl)-3-(1H-pyrazol-1-yl)propanoyl)benzamide
(3ca)
Yield: 129.1 mg (73%); colorless solid; mp 170–172 °C.
1H NMR (400 MHz, CDCl3):  = 9.10 (s, 1 H), 7.82 (d, J = 7.6 Hz, 2 H),
7.62–7.45 (m, 5 H), 7.30–7.22 (m, 4 H), 6.26 (s, 1 H), 5.96 (dd, J = 8.8,
4.4 Hz, 1 H), 4.30 (dd, J = 17.6, 9.6 Hz, 1 H), 3.64 (dd, J = 17.2, 4.4 Hz,
1 H).
13C NMR (100 MHz, CDCl3):  = 172.0, 165.5, 139.5, 138.5, 134.1,
133.3, 132.5, 129.5, 129.0, 128.9, 128.1, 127.8, 106.0, 60.5, 43.4.
1H and 13C NMR spectra were recorded with a Varian Mercury-400
Plus or Agilent Technologies DD2 (600 MHz) spectrometer. High-reso-
lution mass spectra (HRMS) were performed with a Thermo Orbitrap
Elite instrument with an ESI source. Melting points were measured
with an XT4A apparatus (uncorrected). The ,-unsaturated imides
were prepared according to reported procedures.21 Anhydrous LiCl
(99%) and CH3CN (analytical reagent) were purchased and used di-
HRMS (ESI): m/z [M + H]+ calcd for C19H17ClN3O2+: 354.1004; found:
354.1001.
N-(3-(4-Fluorophenyl)-3-(1H-pyrazol-1-yl)propanoyl)benzamide
(3da)
Yield: 133.2 mg (79%); colorless solid; mp 183–185 °C.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–I

E
H. Zhou et al.
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Synthesis
1H NMR (600 MHz, CDCl3):  = 9.00 (s, 1 H), 7.80 (t, J = 7.2 Hz, 2 H),
7.59 (t, J = 7.8 Hz, 1 H), 7.54 (s, 1 H), 7.48 (t, J = 7.8 Hz, 2 H), 7.43 (s,
1 H), 7.29–7.27 (m, 2 H), 7.00 (t, J = 8.4 Hz, 2 H), 6.24 (s, 1 H), 5.95 (q,
J = 4.8 Hz, 1 H), 4.29 (dd, J = 17.4, 9.6 Hz, 1 H), 3.63 (dd, J = 16.8,
4.2 Hz, 1 H).
13C NMR (150 MHz, CDCl3):  = 172.0, 165.5, 162.4 (d, J = 245.55 Hz),
139.5, 138.5 (q, J = 3.15 Hz), 133.3, 132.5, 129.5, 128.9, 128.5 (d, J =
8.10 Hz), 127.7, 115.7 (q, J = 21.60 Hz), 105.9, 60.5, 43.6.
N-(3-(1H-Pyrazol-1-yl)hexanoyl)benzamide (3ia)
Yield: 131.2 mg (92%); colorless solid; mp 104–106 °C.
1H NMR (400 MHz, CDCl3):  = 9.37 (s, 1 H), 7.38 (d, J = 7.2 Hz, 2 H),
7.59–7.41 (m, 5 H), 6.17 (s, 1 H), 4.75 (s, 1 H), 3.67 (dd, J = 16.7, 8.8 Hz,
1 H), 3.32 (d, J = 15.6 Hz, 1 H), 2.00 (br, 1 H), 1.79 (br, 1 H), 1.20–1.12
(m, 2 H), 0.88 (t, J = 6.8 Hz, 3 H).
13C NMR (150 MHz, CDCl3):  = 172.9, 165.6, 139.2, 133.0, 132.6,
129.5, 128.7, 127.8, 104.5, 57.9, 43.4, 37.3, 19.1, 13.4.
HRMS (ESI): m/z [M + H]+ calcd for C19H17FN3O2+: 338.1299; found:
338.1298.
HRMS (ESI): m/z [M + H]+ calcd for C16H20N3O2+: 286.1550; found:
286.1552.
N-(3-(3-Nitrophenyl)-3-(1H-pyrazol-1-yl)propanoyl)benzamide
(3ea)
N-(5-Methyl-3-(1H-pyrazol-1-yl)hexanoyl)benzamide (3ja)
Yield: 134.7 mg (90%); colorless solid; mp 102–104 °C.
Yield: 93.0 mg (51%); yellow solid; mp 171–172 °C.
1H NMR (600 MHz, CDCl3):  = 8.94 (br, 1 H), 7.80 (d, J = 7.2 Hz, 2 H),
7.59–7.40 (m, 5 H), 6.19 (s, 1 H), 4.87 (s, 1 H), 3.67 (dd, J = 16.4, 8.8 Hz,
1 H), 3.29 (d, J = 16.8 Hz, 1 H), 2.06 (br, 1 H), 1.61 (br, 1 H), 1.26 (br,
1 H), 0.94 (d, J = 5.2 Hz, 3 H), 0.85 (d, J = 5.2 Hz, 3 H).
13C NMR (150 MHz, CDCl3):  = 172.8, 165.5, 139.3, 133.1, 132.6,
129.6, 128.8, 127.8, 104.6, 56.3, 44.1, 43.8, 24.6, 22.9, 21.6.
1H NMR (600 MHz, DMSO-d6 ):  = 11.09 (s, 1 H), 8.18 (t, J = 1.8 Hz,
1 H), 8.14–8.13 (m, 1 H), 7.96 (d, J = 1.8 Hz, 1 H), 7.86 (dd, J = 7.8,
0.4 Hz, 2 H), 7.80 (d, J = 7.8 Hz, 1 H), 7.66–7.59 (m, 2 H), 7.52–7.48 (m,
3 H), 6.26 (t, J = 2.4 Hz, 1 H), 6.20 (dd, J = 9.0, 5.4 Hz, 1 H), 4.00 (dd, J =
17.4, 9.0 Hz, 1 H), 3.66 (dd, J = 16.8, 6.0 Hz, 1 H).
13C NMR (150 MHz, DMSO-d6):  = 171.3, 166.8, 148.2, 143.5, 139.7,
134.0, 133.5, 130.9, 130.6, 128.9, 128.8, 123.2, 120.0, 105.9, 59.7, 42.9.
HRMS (ESI): m/z [M + H]+ calcd for C17H22N3O2+: 300.1707; found:
300.1704.
HRMS (ESI): m/z [M + H]+ calcd for C19H17N4O4+: 365.1244; found:
365.1244.
N-(3-(1H-Pyrazol-1-yl)heptanoyl)benzamide (3ka)
Yield: 127.2 mg (85%); colorless solid; mp 99–100 °C.
N-(3-(1H-Pyrazol-1-yl)butanoyl)benzamide (3fa)
1H NMR (400 MHz, CDCl3):  = 9.30 (s, 1 H), 7.82 (d, J = 7.2 Hz, 2 H),
7.59 (t, J = 7.6 Hz, 1 H), 7.51–7.42 (m, 4 H), 6.18 (s, 1 H), 4.73 (t, J =
4.8 Hz, 1 H), 3.67 (dd, J = 16.8, 8.8 Hz, 1 H), 3.32 (dd, J = 17.2, 4.0 Hz,
1 H), 2.03–1.99 (m, 1 H), 1.86–1.80 (m, 1 H), 1.32–1.17 (m, 3 H), 1.05–
1.04 (m, 1 H), 0.84 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 172.9, 165.6, 139.3, 133.0, 132.6,
129.6, 128.7, 127.8, 104.6, 58.2, 43.4, 35.0, 28.0, 13.8.
Yield: 115.7 mg (90%); colorless solid; mp 115–116 °C.
1H NMR (600 MHz, CDCl3):  = 9.44 (s, 1 H), 7.82 (dd, J = 8.4, 1.2 Hz,
2 H), 7.57–7.54 (m, 1 H), 7.46–7.42 (m, 4 H), 6.16 (s, 1 H), 4.94–4.89
(m, 1 H), 3.64 (dd, J = 16.8, 7.8 Hz, 1 H), 3.30 (dd, J = 16.8, 4.8 Hz, 1 H),
1.57 (d, J = 6.6 Hz, 3 H).
13C NMR (150 MHz, CDCl3):  = 172.9, 165.7, 139.1, 133.1, 132.5,
128.7, 128.2, 127.8, 104.9, 53.5, 44.6, 21.2.
HRMS (ESI): m/z [M + H]+ calcd for C17H22N3O2+: 300.1707; found:
300.1704.
HRMS (ESI): m/z [M + H]+ calcd for C14H16N3O2+: 258.1237; found:
258.1233.
N-(3-(1H-Pyrazol-1-yl)octanoyl)benzamide (3la)
N-(3-(1H-Pyrazol-1-yl)pentanoyl)benzamide (3ga)
Yield: 139.5 mg (89%); colorless solid; mp 121–122 °C.
Yield: 115.2 mg (85%); colorless solid; mp 99–100 °C.
1H NMR (400 MHz, CDCl3):  = 9.28 (s, 1 H), 7.82 (d, J = 6.4 Hz, 2 H),
7.59–7.41 (m, 5 H), 6.17 (s, 1 H), 4.72 (s, 1 H), 3.67 (dd, J = 16.8, 8.8 Hz,
1 H), 3.32 (d, J = 16.8 Hz, 1 H), 2.00 (br, 1 H), 1.82 (br, 1 H), 1.23–1.05
(m, 6 H), 0.83 (br, 3 H).
13C NMR (100 MHz, CDCl3):  = 172.7, 165.5, 139.4, 133.1, 132.7,
129.6, 128.8, 127.8, 104.6, 58.3, 43.5, 35.3, 31.2, 25.6, 22.4, 13.9.
1H NMR (400 MHz, CDCl3):  = 9.37 (s, 1 H), 7.83 (d, J = 7.2 Hz, 2 H),
7.60–7.57 (m, 1 H), 7.51–7.41 (m, 4 H), 6.17 (s, 1 H), 4.67–4.60 (m,
1 H), 3.68 (dd, J = 16.8, 8.8 Hz, 1 H), 3.33 (dd, J = 17.2, 4.0 Hz, 1 H),
2.06–1.87 (m, 2 H), 0.78 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 172.9, 165.6, 139.4, 133.1, 132.6,
129.7, 128.7, 127.8, 104.6, 59.7, 43.2, 28.5, 10.5.
HRMS (ESI): m/z [M + H]+ calcd for C18H24N3O2+: 314.1863; found:
314.1861.
HRMS (ESI): m/z [M + H]+ calcd for C15H18N3O2+: 272.1394; found:
272.1395.
N-(3-(1H-Pyrazol-1-yl)nonanoyl)benzamide (3ma)
N-(4-Methyl-3-(1H-pyrazol-1-yl)pentanoyl)benzamide (3ha)
Yield: 142.4 mg (87%); colorless solid; mp 116–117 °C.
Yield: 129.9 mg (91%); colorless solid; mp 102–103 °C.
1H NMR (400 MHz, CDCl3):  = 9.27 (s, 1 H), 7.82 (d, J = 6.4 Hz, 2 H),
7.59–7.42 (m, 5 H), 6.18 (s, 1 H), 4.72 (s, 1 H), 3.67 (dd, J = 16.8, 8.8 Hz,
1 H), 3.32 (d, J = 17.2 Hz, 1 H), 2.03–2.00 (m, 1 H), 1.82 (br, 1 H), 1.22
(br, 7 H), 1.04 (br, 1 H), 0.85 (br, 3 H).
13C NMR (100 MHz, CDCl3):  = 172.7, 165.5, 139.4, 133.1, 132.7,
129.6, 128.8, 127.8, 104.6, 58.3, 43.5, 35.4, 31.6, 28.7, 25.9, 22.5, 13.9.
1H NMR (600 MHz, CDCl3):  = 9.20 (s, 1 H), 7.78 (d, J = 8.4, 1.2 Hz,
2 H), 7.57–7.55 (m, 1 H), 7.47–7.44 (m, 3 H), 7.39 (d, J = 1.8 Hz, 1 H),
6.19 (s, 1 H), 6.15 (t, J = 1.8 Hz, 1 H), 4.42–4.39 (m, 1 H), 3.73 (dd, J =
16.8, 2.4 Hz, 1 H), 3.34 (dd, J = 16.8, 2.4 Hz, 1 H), 2.22–2.18 (m, 1 H),
1.01 (d, J = 6.6 Hz, 3 H), 0.72 (d, J = 6.6 Hz, 3 H).
13C NMR (150 MHz, CDCl3):  = 172.9, 165.5, 139.2, 133.0, 132.7,
130.4, 128.7, 127.8, 104.5, 64.1, 40.6, 33.4, 19.6, 19.0.
HRMS (ESI): m/z [M + H]+ calcd for C19H26N3O2+: 328.2020; found:
328.2021.
HRMS (ESI): m/z [M + H]+ calcd for C16H20N3O2+: 286.1550; found:
286.1548.
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Synthesis
N-(3-(1H-Pyrazol-1-yl)decanoyl)benzamide (3na)
HRMS (ESI): m/z [M + H]+ calcd for C24H36N3O2+: 398.2802; found:
398.2801.
Yield: 157.1 mg (92%); colorless solid; mp 114–115 °C.
1H NMR (400 MHz, CDCl3):  = 9.38 (s, 1 H), 7.82 (d, J = 7.6 Hz, 2 H),
7.59–7.41 (m, 5 H), 6.17 (s, 1 H), 4.72 (s, 1 H), 3.67 (dd, J = 16.8, 9.2 Hz,
1 H), 3.32 (d, J = 16.4 Hz, 1 H), 2.00 (br, 1 H), 1.82 (br, 1 H), 1.21 (br,
9 H), 1.05 (br, 1 H), 0.86 (br, 3 H).
13C NMR (100 MHz, CDCl3):  = 172.8, 165.5, 139.3, 133.1, 132.6,
129.7, 128.8, 127.8, 104.6, 58.3, 43.4, 35.3, 31.6, 29.0, 26.0, 22.5, 14.0.
N-(5-Phenyl-3-(1H-pyrazol-1-yl)pentanoyl)benzamide (3sa)
Yield: 151.1 mg (87%); colorless solid; mp 138–139 °C.
1H NMR (400 MHz, CDCl3):  = 9.09 (s, 1 H), 7.81 (d, J = 7.6 Hz, 2 H),
7.58–7.41 (m, 5 H), 7.28–7.10 (m, 5 H), 6.20 (s, 1 H), 4.73 (s, 1 H), 3.72
(dd, J = 17.2, 8.8 Hz, 1 H), 3.34 (d, J = 17.2 Hz, 1 H), 2.46–2.37 (m, 3 H),
2.16 (d, J = 9.2 Hz, 1 H).
13C NMR (100 MHz, CDCl3):  = 172.6, 165.5, 140.6, 139.7, 133.1,
132.6, 130.1, 128.8, 129.4, 128.3, 127.7, 126.0, 104.7, 57.3, 43.5, 36.5,
31.9.
HRMS (ESI): m/z [M + H]+ calcd for C20H28N3O2+: 342.2176; found:
342.2174.
N-(3-(1H-Pyrazol-1-yl)undecanoyl)benzamide (3oa)
HRMS (ESI): m/z [M + H]+ calcd for C21H22N3O2+: 348.1707; found:
348.1704.
Yield: 158.2 mg (89%); colorless solid; mp 112–113 °C.
1H NMR (400 MHz, CDCl3):  = 9.26 (s, 1 H), 7.82 (d, J = 7.6 Hz, 2 H),
7.59–7.42 (m, 5 H), 6.17 (s, 1 H), 4.73 (s, 1 H), 3.67 (dd, J = 16.8, 8.8 Hz,
1 H), 3.32 (d, J = 16.8 Hz, 1 H), 2.00 (br, 1 H), 1.82 (br, 1 H), 1.21 (br,
11 H), 1.05 (br, 1 H), 0.88–0.84 (m, 3 H).
N-(3-(1H-Pyrazol-1-yl)hexanoyl)-3-bromobenzamide (3ta)
Yield: 163.9 mg (90%); colorless solid; mp 97–99 °C.
1H NMR (400 MHz, CDCl3):  = 10.03 (s, 1 H), 7.97 (t, J = 2.0 Hz, 1 H),
7.76–7.73 (m, 1 H), 7.64–7.61 (m, 1 H), 7.44 (d, J = 1.6 Hz, 1 H), 7.33–
7.31 (m, 1 H), 7.30–7.26 (m, 1 H), 6.09 (t, J = 2.2 Hz,1 H), 4.72–4.66
(m, 1 H), 3.55 (dd, J = 16.8, 8.8 Hz, 1 H), 3.20 (dd, J = 17. 2, 4.0 Hz, 1 H),
1.97–1.87 (m, 1 H), 1.74–1.66 (m, 1 H), 1.17–0.97 (m, 2 H), 0.80 (t, J =
7.4 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 172.7, 165.5, 139.4, 133.1, 132.6,
129.6, 128.8, 127.8, 104.6, 58.3, 43.5, 35.3, 31.7, 29.3, 29.1, 26.0, 22.6,
14.0.
HRMS (ESI): m/z [M + H]+ calcd for C21H30N3O2+: 356.2333; found:
356.2330.
13C NMR (100 MHz, CDCl3):  = 173.0, 164.4, 139.2, 135.7, 134.5,
130.9, 130.0, 129.6, 126.6, 122.5, 104.5, 57.8, 43.3, 37.1, 19.0, 13.3.
HRMS (ESI): m/z [M + H]+ calcd for C16H19BrN3O2+: 364.0655; found:
364.0660.
N-(3-(1H-Pyrazol-1-yl)dodecanoyl)benzamide (3pa)
Yield: 162.6 mg (88%); colorless solid; mp 111–112 °C.
1H NMR (400 MHz, CDCl3):  = 9.24 (s, 1 H), 7.82 (d, J = 6.4 Hz, 2 H),
7.59–7.43 (m, 5 H), 6.18 (s, 1 H), 4.73 (s, 1 H), 3.68 (dd, J = 16.8, 8.8 Hz,
1 H), 3.32 (d, J = 16.4 Hz, 1 H), 2.00 (br, 1 H), 1.83 (br, 1 H), 1.22 (br,
13 H), 1.05 (br, 1 H), 0.87 (br, 3 H).
N-(3-(1H-Pyrazol-1-yl)hexanoyl)-2-chlorobenzamide (3ua)
Yield: 140.7 mg (88%); yellow oil.
13C NMR (100 MHz, CDCl3):  = 172.6, 165.4, 139.4, 133.1, 132.7,
129.7, 128.8, 127.8, 104.7, 58.4, 43.5, 35.3, 31.8, 29.4, 29.3, 29.2, 29.1,
26.0, 22.6, 14.0.
HRMS (ESI): m/z [M + H]+ calcd for C22H32N3O2+: 370.2489; found:
370.2485.
1H NMR (400 MHz, CDCl3):  = 9.54 (s, 1 H), 7.44–7.37 (m, 5 H), 7.32–
7.26 (m, 1 H), 6.15 (dd, J = 4.0, 2.0 Hz, 1 H), 4.74–4.62 (m, 1 H), 3.51
(dd, J = 16.8, 8.8 Hz, 1 H), 3.17 (dd, J = 17.2, 4.8 Hz, 1 H), 2.02–1.92 (m,
1 H), 1.78–1.69 (m, 1 H), 1.98–1.00 (m, 2 H), 0.86 (t, J = 7.3 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 171.6, 165.6, 139.2, 133.9, 131.9,
130.6, 130.0, 129.7, 129.2, 126.8, 104.4, 57.7, 43.2, 37.0, 19.0, 13.3.
HRMS (ESI): m/z [M + H]+ calcd for C16H19ClN3O2+: 320.1160; found:
320.1164.
N-(3-(1H-Pyrazol-1-yl)tridecanoyl)benzamide (3qa)
Yield: 172.6 mg (90%); colorless solid; mp 106–107 °C.
1H NMR (400 MHz, CDCl3):  = 9.26 (s, 1 H), 7.82 (d, J = 7.6 Hz, 2 H),
7.59–7.42 (m, 5 H), 6.18 (s, 1 H), 4.73 (s, 1 H), 3.67 (dd, J = 16.8, 9.2 Hz,
1 H), 3.32 (d, J = 16.8 Hz, 1 H), 2.00 (br, 1 H), 1.83 (br, 1 H), 1.22 (br,
15 H), 1.06 (br, 1 H), 0.89–0.86 (m, 3 H).
N-(3-(1H-Pyrazol-1-yl)hexanoyl)-4-chlorobenzamide (3va)
Yield: 129.1 mg (81%); yellow oil.
1H NMR (600 MHz, CDCl3):  = 9.59 (s, 1 H), 7.76 (dd, J = 6.6, 1.8 Hz,
2 H), 7.46 (d, J = 2.4 Hz, 1 H), 7.42–7.40 (m, 2 H), 7.37 (d, J = 2.4 Hz,
1 H), 6.14 (t, J = 2.4 Hz, 1 H), 4.71–4.67 (m, 1 H), 3.60 (dd, J = 16.8,
9.0 Hz, 1 H), 3.25 (dd, J = 16.8, 4.2 Hz, 1 H), 1.99–1.93 (m, 1 H), 1.78–
1.72 (m, 1 H), 1.19–1.15 (m, 1 H), 1.09–1.06 (m, 1 H), 0.84 (t, J =
7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 172.6, 165.4, 139.4, 133.1, 132.7,
129.7, 128.8, 127.8, 104.7, 58.3, 43.5, 35.4, 31.8, 29.5, 29.4, 29.3, 29.2,
29.1, 22.6, 14.1.
HRMS (ESI): m/z [M + H]+ calcd for C23H34N3O2+: 384.2646; found:
384.2643.
13C NMR (150 MHz, CDCl3):  = 172.9, 164.8, 139.5, 139.3, 131.0,
129.5, 129.4, 129.0, 104.7, 58.0, 43.4, 37.4, 19.1, 13.4.
HRMS (ESI): m/z [M + H]+ calcd for C16H19ClN3O2+: 320.1160; found:
320.1154.
N-(3-(1H-Pyrazol-1-yl)tetradecanoyl)benzamide (3ra)
Yield: 174.9 mg (88%); colorless solid; mp 81–82 °C.
1H NMR (400 MHz, CDCl3):  = 9.06 (s, 1 H), 7.81 (d, J = 8.0 Hz, 2 H),
7.61–7.57 (m, 1 H), 7.52–7.43 (m, 4 H), 6.18 (t, J = 2.0 Hz, 1 H), 4.77–
4.70 (m, 1 H), 3.67 (dd, J = 17.2, 9.2 Hz, 1 H), 3.32 (dd, J = 17.2, 4.0 Hz,
1 H), 2.07–2.00 (m, 1 H), 1.87–1.80 (m, 1 H), 1.22–1.06 (m, 18 H),
0.89–0.86 (m, 3 H).
N-(3-(1H-Pyrazol-1-yl)hexanoyl)-2-ethoxybenzamide (3wa)
Yield: 128.5 mg (78%); colorless solid; mp 136–137 °C.
1H NMR (600 MHz, CDCl3):  = 10.44 (s, 1 H), 8.13 (dd, J = 7.8, 1.8 Hz,
1 H), 7.49–7.47 (m, 3 H), 7.07 (t, J = 7.8 Hz, 1 H), 6.94 (d, J = 7.8 Hz,
1 H), 6.16 (t, J = 1.8 Hz, 1 H), 4.20 (dd, J = 13.8, 7.2 Hz, 2 H), 3.66 (dd,
13C NMR (100 MHz, CDCl3):  = 172.6, 165.4, 139.4, 133.2, 132.6,
129.7, 128.9, 127.7, 104.6, 58.3, 35.4, 31.9, 29.6, 29.5, 29.4, 29.3, 29.1,
26.0, 22.6, 14.1.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–I

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Synthesis
J = 18.0, 9.0 Hz, 1 H), 3.34 (dd, J = 17.4, 4.8 Hz, 1 H), 2.07–2.00 (m,
1 H), 1.82–1.78 (m, 1 H), 1.52 (t, J = 7.2 Hz, 3 H), 1.24–1.17 (m, 1 H),
1.13–1.09 (m. 1 H), 0.88 (t, J = 7.8 Hz, 3 H).
13C NMR (150 MHz, CDCl3):  = 172.7, 163.6, 157.1, 139.2, 134.6,
132.8, 129.6, 121.6, 120.0, 112.6, 104.4, 65.2, 57.8, 44.0, 37.4, 19.2,
14.5, 13.5.
N-(3-(3,5-Dimethyl-1H-pyrazol-1-yl)hexanoyl)benzamide (3if)
Yield: 142.6 mg (91%); colorless solid; mp 139–140 °C.
1H NMR (600 MHz, CDCl3):  = 9.37 (br, 1 H), 7.75 (dd, J = 7.8, 1.2 Hz,
2 H), 7.54–7.52 (m, 1 H), 7.43 (t, J = 7.8 Hz, 2 H), 5.67 (s, 1 H), 4.56–
4.51 (m, 1 H), 3.55 (dd, J = 16.2, 9.6 Hz, 1 H), 3.08 (dd, J = 15.6, 9.6 Hz,
1 H), 2.19 (s, 3 H), 2.12 (s, 3 H), 1.95–1.92 (m, 1 H), 1.72–1.68 (m, 1 H),
1.20–1.10 (m, 1 H), 1.08–1.03 (m, 1 H), 0.84 (t, J = 7.2 Hz, 3 H).
HRMS (ESI): m/z [M + H]+ calcd for C18H23N3O3+: 330.1812; found:
13C NMR (150 MHz, CDCl3):  = 172.2, 165.3, 147.7, 139.9, 132.8,
330.1816.
128.6, 127.7, 104.5, 53.8, 43.4, 37.7, 19.2, 13.6, 13.5, 10.9.
N-(3-(4-Chloro-1H-pyrazol-1-yl)hexanoyl)benzamide (3ib)
HRMS (ESI): m/z [M + H]+ calcd for C18H24N3O2+: 314.1863; found:
Yield: 145.5 mg (91%); colorless solid; mp 137–139 °C.
314.1863.
1H NMR (600 MHz, CDCl3):  = 9.25 (s, 1 H), 7.83 (s, 1 H), 7.81 (d, J =
1.2 Hz, 1 H), 7.59 (t, J = 7.2 Hz, 1 H), 7.47 (t, J = 7.8 Hz, 2 H), 7.39 (d, J =
6.0 Hz, 2 H), 4.68 (t, J = 13.8 Hz, 1 H), 3.70 (dd, J = 18.0, 9.0 Hz, 1 H),
3.32 (dd, J = 17.4, 4.2 Hz, 1 H), 2.01–1.94 (m, 1 H), 1.78–1.72 (m, 1 H),
1.20–1.06 (m, 2 H), 0.87 (t, J = 7.2 Hz, 3 H).
13C NMR (150 MHz, CDCl3):  = 173.2, 165.8, 137.7, 133.3, 132.4,
128.9, 127.8, 127.7, 108.9, 58.5, 43.0, 37.1, 19.1, 13.5.
N-(3-(1H-Indazol-1-yl)hexanoyl)benzamide (3ig)
Yield: 104.0 mg (62%); colorless solid; mp 140–141 °C.
1H NMR (600 MHz, CDCl3):  = 9.04 (s, 1 H), 7.97 (s, 1 H), 7.72–7.70
(m, 2 H), 7.66 (d, J = 9.0 Hz, 1 H), 7.61 (d, J = 8.4 Hz, 1 H), 7.55 (t, J =
7.5 Hz, 1 H), 7.41 (t, J = 7.8 Hz, 2 H), 7.25–7.23 (m, 1 H), 7.06–7.03 (m,
1 H), 5.02–4.98 (m, 1 H), 3.85 (dd, J = 17.4, 9.6 Hz, 1 H), 3.41 (dd, J =
17.4, 3.6 Hz, 1 H), 2.22–2.15 (m, 1 H), 1.94–1.88 (m, 1 H), 1.26–1.20
(m, 1 H), 1.12–1.06 (m, 1 H), 0.88 (t, J = 7.5 Hz, 3 H).
HRMS (ESI): m/z [M + H]+ calcd for C16H19ClN3O2+: 320.1160; found:
320.1164.
13C NMR (150 MHz, CDCl3):  = 172.7, 165.3, 140.2, 133.5, 133.2,
132.6, 128.9, 127.6, 126.2, 123.6, 120.9, 120.6, 109.4, 54.1, 43.2, 37.4,
19.4, 13.6.
HRMS (ESI): m/z [M + H]+ calcd for C20H22N3O2+: 336.1707; found:
336.1710.
N-(3-(4-Bromo-1H-pyrazol-1-yl)hexanoyl)benzamide (3ic)
Yield: 163.9 mg (90%); colorless solid; mp 137–138 °C.
1H NMR (600 MHz, CDCl3):  = 8.98 (s, 1 H), 7.82–7.80 (m, 2 H), 7.60
(t, J = 7.8 Hz, 1 H), 7.50–7.47 (m, 1 H), 7.43 (d, J = 6.0 Hz, 2 H), 4.47–
4.70 (m, 1 H), 3.72 (dd, J = 18.0, 9.6 Hz, 1 H), 3.30 (dd, J = 18.0, 4.2 Hz,
1 H), 2.02–1.96 (m, 1 H), 1.80–1.74 (m, 1 H), 1.25–1.18 (m, 1 H), 1.14–
1.12 (m, 1 H), 0.88 (t, J = 7.2 Hz, 3 H).
13C NMR (150 MHz, CDCl3):  = 172.9, 165.6, 139.9, 133.3, 132.4,
129.8, 128.9, 127.8, 92.2, 58.6, 43.0, 37.1, 19.2, 13.4.
Procedure for Gram-Scale Synthesis of 3fa
(E)-N-(But-2-enoyl)benzamide (1f; 8 mmol, 1.51 g), pyrazole 2a (653
mg, 9.6 mmol, 1.2 equiv), LiCl (33.9 mg, 0.8 mmol, 10 mol%) and
CH3CN (20 mL) were successively added into a dry Schlenk tube
equipped with a cold finger. The reaction mixture was stirred at re-
flux temperature until the reaction was complete (monitored by TLC),
then H2O (20 mL) was added and the resulting mixture was extracted
with EtOAc (2 × 20 mL). The combined organic phase was washed
with saturated brine, dried over anhydrous Na2SO4, and concentrated
under reduced pressure. The crude product was purified by column
chromatography on silica gel using petroleum ether/EtOAc as the elu-
ent to afford the desired product 3fa (1.83 g, 89%).
HRMS (ESI): m/z [M + H]+ calcd for C16H19BrN3O2+: 364.0655; found:
364.0647.
N-(3-(4-Nitro-1H-pyrazol-1-yl)hexanoyl)benzamide (3id)
Yield: 145.3 mg (88%); colorless solid; mp 126–128 °C.
1H NMR (600 MHz, CDCl3):  = 8.93 (s, 1 H), 8.21 (s, 1 H), 8.03 (s, 1 H),
7.82 (d, J = 7.8 Hz, 2 H), 7.61 (t, J = 7.2 Hz, 1 H), 7.49 (t, J = 7.8 Hz, 2 H),
4.78–4.75 (m, 1 H), 3.82 (dd, J = 18.6, 9.6 Hz, 1 H), 3.41 (dd, J = 18.0,
3.0 Hz, 1 H), 2.08–2.02 (m, 1 H), 1.84–1.79 (m, 1 H), 1.24–1.19 (m,
1 H), 1.15–1.09 (m, 1 H), 0.90 (t, J = 7.2 Hz, 3 H).
13C NMR (150 MHz, CDCl3):  = 172.7, 165.6, 135.9, 135.0, 133.6,
132.1, 129.5, 129.0, 127.7, 59.4, 42.5, 36.6, 19.1, 13.4.
Procedure for Aza-Michael Addition of Pyrazole to Nitrostyrene
Nitrostyrene 4 (74.5 mg, 0.5 mmol), pyrazole (40.9 mg, 0.6 mmol, 1.2
equiv), LiCl (2.1 mg, 0.05 mmol, 10 mol%) and CH3CN (3.0 mL) were
successively added into a dry Schlenk tube equipped with a cold fin-
ger. The reaction mixture was stirred at reflux temperature until the
reaction was complete (monitored by TLC), then H2O (4 mL) was add-
ed and the resulting mixture was extracted with EtOAc (2 × 8 mL).
The combined organic phase was washed with saturated brine, dried
over anhydrous Na2SO4, and concentrated under reduced pressure.
The crude product was purified by column chromatography on silica
gel using petroleum ether/EtOAc as the eluent to afford the desired
product 5 (97.7 mg, 90%).
HRMS (ESI): m/z [M + H]+ calcd for C16H19N4O4+: 331.1401; found:
331.1404.
N-(3-(4-Methyl-1H-pyrazol-1-yl)hexanoyl)benzamide (3ie)
Yield: 139.2 mg (93%); colorless solid; mp 143–145 °C.
1H NMR (600 MHz, CDCl3):  = 9.31 (s, 1 H), 7.81 (d, J = 6.6 Hz, 2 H),
7.57 (s, 1 H), 7.45 (s, 2 H), 7.27 (s, 1 H), 7.17 (s, 1 H), 4.63 (s, 1 H), 3.59
(dd, J = 16.2, 7.2 Hz, 1 H), 3.25 (d, J = 16.2 Hz, 1 H), 1.99 (s, 3 H), 1.97–
1.89 (br, 1 H), 1.75 (m, 1 H), 1.19–1.11 (m, 2 H), 0.86 (s, 3 H).
1-(2-Nitro-1-phenylethyl)-1H-pyrazole (5)11b,17
13C NMR (150 MHz, CDCl3):  = 172.7, 165.6, 139.7, 133.0, 132.7,
Yield: 97.7 mg (90%); yellow oil.
128.7, 128.4, 127.8, 115.1, 57.8, 43.5, 37.4, 19.2, 13.5, 8.8.
HRMS (ESI): m/z [M + H]+ calcd for C17H22N3O2+: 300.1707; found:
300.1710.
1H NMR (600 MHz, CDCl3):  = 7.58 (d, J = 1.8 Hz, 1 H), 7.42 (d, J =
2.4 Hz, 1 H), 7.37–7.34 (m, 3 H), 7.29–7.28 (m, 2 H), 6.28 (t, J = 1.8 Hz,
1 H), 6.12 (q, J = 4.8 Hz, 1 H), 5.61 (dd, J = 14.4, 9.6 Hz, 1 H), 4.86 (dd,
J = 13.8, 4.8 Hz, 1 H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–I

H
H. Zhou et al.
Paper
Synthesis
13C NMR (150 MHz, CDCl3):  = 140.0, 135.7, 129.7, 129.1, 129.0,
126.7, 106.4, 77.1, 62.1.
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HRMS (ESI): m/z [M + H]+ calcd for C11H12N3O2+: 218.0924; found:
218.0922.
Transformations of the Aza-Michael Products 3aa and 3ia; Typical
Procedure (6aa)
Compound 3aa (319.4 mg, 1 mmol) was dissolved in THF (8 mL) and
cooled to 0 °C. A solution of NaOH (1 N, 2.0 mL, 2.0 mmol) was added
dropwise over 1 min and the mixture was then stirred at 0 °C for 30
min. The mixture was stirred at reflux temperature for 2 h. The reac-
tion mixture was cooled to r.t., then saturated NaHCO3 (2 mL) was
added. The aqueous phase was washed with CH2Cl2 (3 × 5 mL), acidi-
fied to pH 2–3 and extracted with CH2Cl2 (5 × 5 mL). The combine or-
ganic layer was washed with saturated brine, dried over anhydrous
Na2SO4 and concentrated under reduced pressure. The residue was
purified by column chromatography (petroleum ether/EtOAc, 2:1) to
afford the desired product 6aa (190.3 mg, 88%) contaminated with ca.
10% benzoic acid and a small amount of unknown impurities.
3-Phenyl-3-(1H-pyrazol-1-yl)propanoic Acid (6aa)
[CAS Reg. No. 1310308-63-4]
Yield: 190.3 mg (88%); colorless solid; mp 105–107 °C.
1H NMR (600 MHz, DMSO-d6):  = 12.47 (br, 1 H), 7.84 (d, J = 1.8 Hz,
1 H), 7.47 (t, J = 1.8 Hz, 1 H), 7.32–7.21 (m, 5 H), 6.22 (s, 1 H), 5.88–
5.85 (m, 1 H), 3.48–3.43 (m, 1 H), 3.18–3.14 (m, 1 H).
13C NMR (150 MHz, DMSO-d6):  = 171.8, 141.1, 139.1, 130.0, 128.9,
128.2, 127.1, 105.7, 61.5, 40.0.
HRMS (ESI): m/z [M + H]+ calcd for C12H13N2O2+: 217.0972; found:
217.0972.
3-(1H-Pyrazol-1-yl)hexanoic Acid (6ia)
The product 6ia was contaminated with ca. 6% benzoic acid.
Yield: 68.3 mg (75%); colorless solid; mp 75–77 °C.
1H NMR (600 MHz, CDCl3):  = 11.34 (s, 1 H), 7.56 (d, J = 1.2 Hz, 1 H),
7.43–7.42 (m, 1 H), 6.18 (t, J = 2.1 Hz, 1 H), 4.62–4.59 (m, 1 H), 3.02
(dd, J = 16.5, 8.3 Hz, 1 H), 2.81 (dd, J = 16.5, 5.1 Hz, 1 H), 1.96–1.92 (m,
1 H), 1.76–1.71 (m, 1 H), 1.17–1.13 (m, 1 H), 1.10–1.00 (m, 1 H), 0.85
(t, J = 7.2 Hz, 3 H).
13C NMR (150 MHz, CDCl3):  = 174.7, 139.4, 129.9, 104.8, 58.6, 40.2,
36.9, 19.2, 13.4.
HRMS (ESI): m/z [M + H]+ calcd for C9H15N2O2+: 183.1128; found:
183.1126.
Funding Information
This work was supported by the National Natural Science Foundation
of China (21362034), the Special Funds for Discipline Construction of
Gansu Agricultural University (GAU-XKJS-2018-133), and the Pro-
gram for Improving Scientific Research Ability of Young Teachers of
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Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1611520.
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