An unexpected multi-component reaction to synthesis of 3-(5-amino-3-methyl- 1H-pyrazol-4-yl)-3-arylpropanoic acids in ionic liquid

Article abstract of DOI:10.1016/j.tetlet.2011.10.099

A new, one-pot, four-component condensation of 3-methyl-1H-pyrazol-5(4H)- one, ammonium acetate, aromatic aldehydes, and meldrum's acid in [bmim]BF ₄ as solvent is described for the synthesis of 3-(5-amino-3-methyl- 1H-pyrazol-4-yl)-3-arylpropanoic acid derivatives. This methodology resulting in excellent isolated yields in short reaction time is characterized by simple work up procedure and little environmental impact.

Full text of DOI:10.1016/j.tetlet.2011.10.099

Tetrahedron Letters 52 (2011) 7099–7102
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An unexpected multi-component reaction to synthesis of
3-(5-amino-3-methyl-1H-pyrazol-4-yl)-3-arylpropanoic acids in ionic liquid
⇑
⇑
Zhiyong Xiao, Min Lei , Lihong Hu
Shanghai Research Center for Modernization of Traditional Chinese Medicine, Shanghai Institute of Materia Medica, Shanghai 201203, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A new, one-pot, four-component condensation of 3-methyl-1H-pyrazol-5(4H)-one, ammonium acetate,
aromatic aldehydes, and meldrum’s acid in [bmim]BF4 as solvent is described for the synthesis of 3-(5-
amino-3-methyl-1H-pyrazol-4-yl)-3-arylpropanoic acid derivatives. This methodology resulting in
excellent isolated yields in short reaction time is characterized by simple work up procedure and little
environmental impact.
Received 11 August 2011
Revised 18 October 2011
Accepted 18 October 2011
Available online 21 October 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Green chemistry
Multi-component reaction
[bmim]BF4
Aldehyde
Meldrum’s acid
Multi-component reactions (MCRs) are attractive strategy for
organic synthesis due to their atom efficiency, operational simplic-
ity, and usually excellent productivity.1 In particular, MCRs have
been recognized as a powerful tool for the construction of the tar-
get products in a single operation without isolating the intermedi-
ates.2 Thus, the reaction time is reduced and both energy and raw
materials are saved. Therefore, development of novel, efficient, and
green MCRs focused on a target product from readily available re-
agents is one of the major challenges in organic synthesis.
In recent years, organic reactions in ionic liquid (IL) media have
received the considerable attention of synthetic organic chemists
not only because IL is an environmentally friendly solvent, but also
because IL exhibits unique reactivity different from those in
conventional organic solvents.3 As a part of our continual efforts
toward the development of novel, efficient, and green procedures
for multi-component reactions,4 we turned our attention toward
the four-component condensation of 3-methyl-1H-pyrazol-5(4H)-
one, ammonium acetate, aldehyde, and meldrum’s acid in
[bmim]BF4 as solvent. Herein, we describe a novel, efficient, and
green procedure for the synthesis of 3-(5-amino-3-methyl-1H-
pyrazol-4-yl)-3-arylpropanoic acid derivatives 4 via the four-com-
ponent condensation (Scheme 1).
acid 3 in IL (Scheme 2).5,6 b-Carbonyl enamine was regarded as
the key intermediate of the four-component condensation. As
shown in Scheme 3, Lipson and his co-workers7 reported that the
cyclization product
8
was obtained by
a
three-component
Ar
Ar CHO
OH
2
NH4OAc
+
N
N
O
O
N
H
[bmim]BF4
N
H
N
H
H
O
O
1
O
O
4
3
Scheme 1. Synthesis of 3-(5-amino-3-methyl-1H-pyrazol-4-yl)-3-arylpropanoic
acid derivatives 4.
O
O
Ar
Ar CHO
NH4OAc
IL
2
+
It was reported that 3,4-dihydropyridin-2(1H)-ones 6 could be
obtained via a four-component condensation of b-dicarbonyl
compounds 5, aldehydes 2, ammonium acetate, and meldrum’s
O
N
H
O
O
O
O
O
5
6
⇑
Corresponding authors.
E-mail addresses: mlei@mail.shcnc.ac.cn (M. Lei), simmhulh@mail.shcnc.ac.cn
3
(L. Hu).
Scheme 2. Synthesis of 3,4-dihydropyridin-2(1H)-ones 6.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.10.099

7100
Z. Xiao et al. / Tetrahedron Letters 52 (2011) 7099–7102
Table 1
Ar
Ar CHO
Synthesis of 3-(5-amino-3-methyl-1H-pyrazol-4-yl)-3-arylpropanoic acid derivatives 4a
2
MeOH
+
R
N
N
R
CHO
NH2
N
H
N
H
OH
N
H
O
O
O
2
NH4OAc
+
N
N
7
O
O
O
O
N
H
[bmim]BF4
N
H
8
O
O
N H
H
3
1
O
O
4
Scheme 3. Synthesis of 4,5-dihydro-1H-pyrazolo[3,4-b]pyridin-6(7H)-ones 8.
3
Entry
Ar
C6H5
4-CH3C6H4
4-CH3OC6H4
4-FC6H4
4-BrC6H4
2-ClC6H4
3-ClC6H4
Time (min)
Product 4
Yield (%)b
condensation of 3-methyl-1H-pyrazol-5-amine 7, aromatic alde-
hyde 2, and meldrum’s acid 3 in MeOH as solvent (Scheme 3).
Accordingly, we attempt to use 3-methyl-1H-pyrazol-5(4H)-one
1 replacing b-dicarbonyl compounds 5 in the synthesis of 4,5-dihy-
dro-1H-pyrazolo[3,4-b]pyridin-6(7H)-ones 8 via a four-component
condensation of 3-methyl-1H-pyrazol-5(4H)-one 1, aldehydes 2,
ammonium acetate, and meldrum’s acid 3 in IL.
Initially, we carried out the four-component condensation of 3-
methyl-1H-pyrazol-5(4H)-one 1, ammonium acetate, benzalde-
hyde 2a, and meldrum’s acid 3 in [bmim]BF4 as solvent at 100 °C.
After the reaction was completed as indicated by TLC, the reaction
mixture was cooled to room temperature, then water was added to
the mixture and stirred for 5 min. The solid was filtered and recrys-
tallized from EtOH/H2O (3:1) to afford the pure product. To our
surprise, this four-component condensation did not afford the
cyclization product 8a, while in contract, the products 3-(5-ami-
no-3-methyl-1H-pyrazol-4-yl)-3-phenylpropanoic acid derivatives
4a, shown in Scheme 1 and confirmed by NMR measurements,
were obtained in good yield (92%).
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
20
30
15
10
8
60
15
15
120
150
6
10
10
8
150
150
150
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
92, 90, 87c
90
94
94
94
82
92
87
82
88
93
90
93
90
4-ClC6H4
2,4-Cl2C6H3
2-NO2C6H4
3-NO2C6H4
4-NO2C6H4
4-CNC6H4
4-Pyridyl
CH3CH2
d
—
—
—
d
CH3CH2CH2
C6H5CH2
d
a
Reaction conditions: 3-methyl-1H-pyrazol-5(4H)-one 1 (5 mmol), ammonium
acetate (10 mmol), aromatic aldehyde 2 (5 mmol) and meldrum’s acid 3 (5 mmol),
[bmim]BF4 (2 mL), 100 °C.
b
Isolated yields.
[bmim]BF4 was recovered and reused three times.
Several side reactions were observed and the corresponding products failed to
c
d
The scope and generality of this four-component condensation
for the synthesis of 3-(5-amino-3-methyl-1H-pyrazol-4-yl)-3-aryl-
isolate.
O
O
O
Ar
O
O
Ar CHO
NH4OAc
O
O
O
NH4OAc
N
N
3
10
O
OH
[bmim]BF4
N
H
N
H
1
9
O
NH4OAc/H2O
O
Ar
Ar
O
Ar
O
OH
NH4OAc
NH4OAc/H2O
O
N
N
O
-CO2, -Acetone
N
O
O
N
N
O
N
H
O
O
12
H
H
NH2
11
13
NH4OAc
Ar
Intramolecular cyclization
-CO2, -Acetone
OH
Ar
N
N
O
N
H
H
N
H
N
4
N
H
O
H
8
Scheme 4. Plausible mechanism for the synthesis of 3-(5-amino-3-methyl-1H-pyrazol-4-yl)-3-arylpropanoic acid derivatives 4.

Z. Xiao et al. / Tetrahedron Letters 52 (2011) 7099–7102
7101
these conditions. This may explain why we only obtain the product
4 of the four-component condensation of 3-methyl-1H-pyrazol-
5(4H)-one 1, ammonium acetate, aldehyde 2 and meldrum’s acid
3 in [bmim]BF4 as solvent.
Ph
CN
Ph CHO
CN
N
HN
NH2
N
H
N
N
H
14
NH2
CN
In conclusion, we have described a four-component condensa-
tion reaction for the preparation of a variety of 3-(5-amino-3-
methyl-1H-pyrazol-4-yl)-3-arylpropanoic acid derivatives 4 from
3-methyl-1H-pyrazol-5(4H)-one 1, ammonium acetate, aldehyde
2, and meldrum’s acid 3 in [bmim]BF4 as a recyclable medium
and promoter. The process has several advantages from economi-
cal and environmental points of view, such as short reaction time,
high yields, and mild reaction conditions, which make it a useful
process for the synthesis of 3-(5-amino-3-methyl-1H-pyrazol-4-
yl)-3-arylpropanoic acid derivatives 4.11
7
Not formed
+
NH4OAc
N
O
N
H
1
Ph
CN
Ph CHO
CN
N
OH
HN
Acknowledgments
N
N
H
O
NH2
9
CN
15
This work was supported by the Chinese National Science and
Technology Major Project ‘Key New Drug Creation and Manufac-
turing Program’ (Grants 2009ZX09301-001, 2009ZX09102-022),
the National Natural Science Foundation of China (Grant
30925040).
Yield: 91%
Scheme 5. Multi-component condensation.
propanoic acid derivatives 4 were illustrated with different aro-
matic aldehydes and the results are summarized in Table 1.
The results of Table 1 clearly indicated the feasibility of this
four-component condensation in ionic liquid. The products 4 were
synthesized in excellent yields (82–94%) at 100 °C for 6–150 min.
Both the electron-rich and -deficient aldehydes as well as hetero-
cyclic aldehyde worked well leading to good yields of products 4.
We also examined this four-component condensation with 2-
substituted benzaldehydes, finding that the reaction time was
longer and yields were somewhat lower than other aldehydes
which were probably attributed to the steric hindrance (Table 1).
Aliphatic aldehydes like propionaldehyde, butylaldehyde, and phe-
nylacetaldehyde were also examined but their yields were not sat-
isfactory and the corresponding products failed to isolate, even
after stirring at 100 °C for 150 min.
Furthermore, the recyclable character of [bmim]BF4 was also
investigated (Table 1, entry 1). We obtained the desired product
4a in 92%, 90%, and 87% yields after 1–3 runs, respectively.
A tentative mechanism to rationalize the products 4 formation
is shown in Scheme 4, which is different from the reported
pathway. This reaction may occur via condensation, addition,
ring-opening, and amination mechanisms (Scheme 4).6–8 Initially,
3-methyl-1H-pyrazol-5-ol 9 is formed by the isomerization of
3-methyl-1H-pyrazol-5(4H)-one 1 and the intermediate 10 is
formed by Knoevenagel condensation of aldehyde 2 and meldrum’s
acid 3 by the action of ammonium acetate. Then, Michael addition
of 9 on 10 leads to the formation of 11, followed by ring-opening
promoted by ammonium acetate, affording the intermediate 12.
Next, 12 is aminated by ammonium acetate to form the corre-
sponding products 4 (Scheme 4). All the reported papers pointed
out that the key intermediate was formed by the amination of
the carbonyl group.6–8 However, we believe that the aminated
intermediate is not formed in this system, and the directed evi-
dence comes from the fact shown in Scheme 5.9,10
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.10.099.
References and notes
1. (a) Zhao, L.; Cheng, G.; Hu, Y. Tetrahedron Lett. 2008, 49, 7364; (b) Wender, P. A.
Chem. Rev. 1996, 96, 1; (c) Yang, T.; Ferrali, A.; Campbellb, L.; Dixon, D. J. Chem.
Commum. 2008, 2923; (d) Tonogaki, K.; Itami, K.; Yoshida, J. J. Org. Chem. 2006,
8, 1419; (e) Bossharth, E.; Desbordes, P.; Monteiro, N.; Balme, G. Org. Lett. 2003,
5, 2441.
2. (a) Xiang, J.; Zheng, L.; Xie, H.; Hu, X.; Dang, Q.; Bai, X. Tetrahedron 2008, 64,
9101; (b) Ogura, Y.; Watanabe, H. Tetrahedron Lett. 2010, 51, 3294; (c) Litvinov,
V. P. Russ. Chem. Rev. 2003, 72, 69.
3. (a) Naik, P. U.; Harjani, J. R.; Nara, S. J.; Salunkhe, M. M. Tetrahedron Lett. 2004,
45, 1933; (b) Wang, C.; Guo, L.; Li, H.; Wang, Y.; Weng, J.; Wu, L. Green Chem.
2006, 8, 603; (c) Hemeon, I.; Singer, R. D. Chem. Commum. 2002, 1884; (d)
Welton, T. Chem. Rev. 1999, 99, 2071.
4. (a) Lei, M.; Ma, L.; Hu, L. Monatsh. Chem. 2010, 141, 1005; (b) Yu, C.; Lei, M.; Su,
W.; Xie, Y. Synth. Commum. 2007, 37, 3301; (c) Lei, M.; Ma, L.; Hu, L. Tetrahedron
Lett. 2009, 50, 6393; (d) Lei, M.; Ma, L.; Hu, L. Tetrahedron Lett. 2010, 51, 4746.
5. Fan, X. S.; Li, Y. Z.; Zhang, X. Y.; Qu, G. R.; Wang, J. J.; Hu, X. Y. Heteroat. Chem.
2006, 17, 382.
6. Tu, S.; Zhu, X.; Zhang, J.; Xu, J.; Zhang, Y.; Wang, Q.; Jia, R.; Jiang, B.; Zhang, J.;
Yao, C. Bioorg. Med. Chem. Lett. 2006, 16, 2925.
7. Lipson, V. V.; Desenko, S. M.; Shirobokova, M. G.; Shishkin, O. V.; Shishkina, S. V.
Russ. J. Org. Chem. 2006, 42, 1022.
8. Zhang, X. Y.; Li, Y. Z.; Fan, X. S.; Qu, G. R.; Hu, X. Y.; Wang, J. J. Chin. Chem. Lett.
2006, 17, 150.
9. Al-Matar, H. M.; Khalil, K. D.; Meier, H.; Kolshorn, H.; Elnagdi, M. H. ARKIVOC
2008, 288.
10. Nagarajan, A. S.; Reddy, B. S. R. Synlett 2009, 2002; Peng, Y.; Song, G.; Dou, R.
Green Chem. 2006, 8, 573.
11. General procedure for the synthesis of compounds 4: a mixture of 3-methyl-
1H-pyrazol-5(4H)-one
1 (5 mmol), and ammonium acetate (10 mmol) in
[bmim]BF4 (2 mL) was heated to 100 °C under stirring for 10 min. Then,
aromatic aldehyde 2 (5.5 mmol) and meldrum’s acid 3 (5 mmol) were added to
the reaction mixture and it was stirred at 100 °C for the given time (Table 1).
After completion (by TLC), the reaction mixture was cooled to room
temperature, then water (5 mL) was added to the mixture and stirred for
5 min. The solid was filtered and recrystallized from EtOH/H2O (3:1) to afford
the pure products 4. The filtrate was concentrated under reduced pressure and
dried at 100 °C to recover the ionic liquid for subsequent use.
We carried out the reaction of 3-methyl-1H-pyrazol-5(4H)-one
1, and ammonium acetate in [bmim]BF4 as solvent at 100 °C for
2 h. Then, benzaldehyde 2a and malononitrile were added to the
reaction mixture and it was stirred at 100 °C for 10 min. As shown
in Scheme 5, the corresponding product 15 was obtained in 91%
yield, while in contract, the product 14 was not obtained at all. If
the intermediate 7 was formed in this system, the product 14
should be found. But in fact, the product 14 was not found which
meant that the aminated intermediate cannot be produced under
Compound 4a: White solid; mp: 235–237 °C; 1H NMR (400 MHz, DMSO-d6): d
2.03 (s, 3H), 2.71 (dd, J = 14.7, 7.4 Hz, 1H), 2.86 (dd, J = 14.7, 8.2 Hz, 1H), 4.21 (t,
J = 7.8 Hz, 1H), 6.67 (br s, 1H), 7.10 (t, J = 7.2 Hz, 1H), 7.22 (t, J = 7.6 Hz, 2H),
7.26 (br s, 1H), 7.30 (d, J = 7.5 Hz, 2H), 10.40 (br s, 2H); 13C NMR (100 MHz,
DMSO-d6):
d 10.70, 36.42, 40.37, 103.93, 126.01, 127.84, 128.42, 136.85,
145.78, 159.92, 173.51; MS (ESI): m/z 268 ([M+Na]+); Anal. Calcd for
C
13H15N3O2: C, 63.66; H, 6.16; N, 17.13. Found: C, 63.61; H, 6.15; N, 17.17.
Compound 4b: White solid; mp: 215–217 °C; 1H NMR (400 MHz, DMSO-d6): d
2.02 (s, 3H), 2.22 (s, 3H), 2.69 (dd, J = 14.7, 7.4 Hz, 1H), 2.83 (dd, J = 14.6, 8.2 Hz,
1H), 4.17 (t, J = 7.7 Hz, 1H), 6.68 (br s, 1H), 7.02 (d, J = 7.8 Hz, 2H), 7.18 (d,

7102
Z. Xiao et al. / Tetrahedron Letters 52 (2011) 7099–7102
J = 7.8 Hz, 2H), 7.25 (br s, 1H), 10.45 (br s, 2H); 13C NMR (100 MHz, DMSO-d6):
d 10.70, 21.01, 36.00, 40.47, 104.06, 127.71, 128.95, 134.80, 136.71, 142.76,
159.85, 173.54; MS (ESI): m/z 282 ([M+Na]+); Anal. Calcd for C14H17N3O2: C,
64.85; H, 6.61; N, 16.20. Found: C, 64.81; H, 6.57; N, 16.23.
136.84, 144.75, 159.83, 173.25; MS (ESI): m/z 302, 304 ([M+Na]+); Anal. Calcd
for C13H14ClN3O2: C, 55.82; H, 5.04; N, 15.02. Found: C, 55.79; H, 5.07; N, 15.00.
Compound 4i: White solid; mp: 230–232 °C; 1H NMR (400 MHz, DMSO-d6): d
2.07 (s, 3H), 2.76 (d, J = 7.8 Hz, 2H), 4.56 (t, J = 7.7 Hz, 1H), 6.72 (br s, 1H), 7.32
(br s, 1H), 7.36 (dd, J = 8.5, 1.9 Hz, 1H), 7.47 (d, J = 2.0 Hz, 1H), 7.63 (d,
J = 8.5 Hz, 1H), 10.54 (br s, 2H); 13C NMR (100 MHz, DMSO-d6): d 10.7, 32.65,
39.35, 101.60, 127.28, 128.77, 131.20, 131.31, 133.75, 137.17, 141.27, 160.04,
172.68; MS (ESI): m/z 336, 338 ([M+Na]+); Anal. Calcd for C13H3Cl2N3O2: C,
49.70; H, 4.17; N, 13.38. Found: C, 49.68; H, 4.20; N, 13.40.
Compound 4c: White solid; mp: 215–217 °C; 1H NMR (400 MHz, DMSO-d6): d
2.03 (s, 3H), 2.68 (dd, J = 14.6, 7.4 Hz, 1H), 2.82 (dd, J = 14.6, 8.3 Hz, 1H), 3.68 (s,
3H), 4.16 (t, J = 7.7 Hz, 1H), 6.68 (br s, 1H), 6.78 (d, J = 8.6 Hz, 2H), 7.21 (d,
J = 8.5 Hz, 2H), 7.25 (br s, 1H), 10.47 (br s, 1H); 13C NMR (100 MHz, DMSO-d6):
d 10.68, 35.62, 40.69, 55.38, 104.23, 113.78, 128.75, 136.69, 137.83, 157.66,
159.84, 173.59; MS (ESI): m/z 298 ([M+Na]+); Anal. Calcd for C14H17N3O3: C,
61.08; H, 6.22; N, 15.26. Found: C, 61.04; H, 6.20; N, 15.30.
Compound 4j: White solid; mp: 244–246 °C; 1H NMR (400 MHz, DMSO-d6): d
2.02 (s, 3H), 2.77–2.88 (m, 2H), 4.74 (t, J = 7.7 Hz, 1H), 6.74 (br s, 1H), 7.31 (br s,
1H), 7.36 (t, J = 7.7 Hz, 1H), 7.59 (t, J = 7.6 Hz, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.87
(d, J = 7.9 Hz, 1H), 10.62 (br s,2H); 13C NMR (100 MHz, DMSO-d6): d 10.37,
30.72, 39.48, 102.09, 123.84, 127.41, 130.39, 132.58, 137.40, 138.65, 149.91,
160.10, 172.66; MS (ESI): m/z 313 ([M+Na]+); Anal. Calcd for C13H14N4O4: C,
53.79; H, 4.86; N, 19.30. Found: C, 53.76; H, 4.88; N, 19.34.
Compound 4d: White solid; mp: 242–244 °C; 1H NMR (400 MHz, DMSO-d6): d
2.04 (s, 3H), 2.69 (dd, J = 14.7, 7.2 Hz, 1H), 2.86 (dd, J = 14.7, 8.4 Hz, 1H), 4.21 (t,
J = 7.8 Hz, 1H), 6.70 (br s, 1H), 7.04 (t, J = 8.9 Hz, 1H), 7.28 (br s, 1H), 7.32 (dd,
J = 8.5, 5.7 Hz, 2H), 10.51 (br s, 2H); 13C NMR (100 MHz, DMSO-d6): d 10.63,
35.76, 40.54, 103.77, 114.88 and 115.09 (2JCF = 20.7 Hz), 129.51 and 129.58
(3JCF = 7.8 Hz), 136.74, 141.91 and 141.94 (4JCF = 2.9 Hz), 159.65 and 162.05
(1JCF = 239.7 Hz), 159.80, 173.32; MS (ESI): m/z 286 ([M+Na]+; Anal. Calcd for
Compound 4k: White solid; mp: 261–263 °C; 1H NMR (400 MHz, DMSO-d6): d
2.09 (s, 3H), 2.72 (dd, J = 14.9, 6.9 Hz, 1H), 2.98 (dd, J = 14.9, 8.8 Hz, 1H), 4.35 (t,
J = 7.8 Hz, 1H), 6.76 (br s, 1H), 7.37 (br s, 1H), 7.54 (t, J = 7.9 Hz, 1H), 7.76 (d,
J = 7.7 Hz, 1H), 8.01 (dd, J = 8.1, 1.8 Hz, 1H), 8.19 (s, 1H), 10.54 (s, 2H); 13C NMR
(100 MHz, DMSO-d6): d 10.57, 36.26, 40.14, 102.79, 121.26, 122.39, 129.94,
134.98, 136.99, 148.05, 148.10, 159.81, 172.93; MS (ESI): m/z 313 ([M+Na]+);
Anal. Calcd for C13H14N4O4: C, 53.79; H, 4.86; N, 19.30. Found: C, 53.75; H,
4.89; N, 19.33.
C13H14FN3O2: C, 59.31; H, 5.36; N, 15.96. Found: C, 59.26; H, 5.32; N, 15.99.
Compound 4e: White solid; mp: 229–231 °C; 1H NMR (400 MHz, DMSO-d6): d
2.05 (s, 3H), 2.70 (dd, J = 14.8, 7.1 Hz, 1H), 2.88 (dd, J = 14.8, 8.5 Hz, 1H), 4.20 (t,
J = 7.8 Hz, 1H), 6.74 (br s, 1H), 7.26 (d, J = 8.5 Hz, 2H), 7.32 (br s, 1H), 7.42 (d,
J = 8.4 Hz, 2H), 10.59 (br s, 2H); 13C NMR (100 MHz, DMSO-d6): d 10.64, 35.96,
40.18, 103.39, 119.06, 130.15, 131.25, 136.91, 145.15, 159.86, 173.28; MS (ESI):
m/z 346, 348 ([M+Na]+); Anal. Calcd for C13H14BrN3O2: C, 48.17; H, 4.35; N,
12.96. Found: C, 48.14; H, 4.38; N, 12.98.
Compound 4l: Yellow solid; mp: 253–255 °C; 1H NMR (400 MHz, DMSO-d6): d
2.08 (s, 3H), 2.74 (dd, J = 14.4, 6.2 Hz, 1H), 2.98 (dd, J = 14.1, 8.7 Hz, 1H), 4.35 (t,
J = 7.5 Hz, 1H), 6.78 (br s, 1H), 7.38 (br s, 1H), 7.56 (d, J = 7.8 Hz, 2H), 8.11 (d,
J = 7.6 Hz, 2H), 10.59 (s, 2H); 13C NMR (100 MHz, DMSO-d6): d 10.58, 36.48,
39.68, 102.62, 123.72, 129.07, 137.10, 146.04, 153.79, 159.85, 172.96; MS (ESI):
m/z 313 ([M+Na]+); Anal. Calcd for C13H14N4O4: C, 53.79; H, 4.86; N, 19.30.
Found: C, 53.82; H, 4.84; N, 19.33.
Compound 4f: White solid; mp: 226–228 °C; 1H NMR (400 MHz, DMSO-d6): d
2.06 (s, 3H), 2.74 (dd, J = 14.8, 7.2 Hz, 1H), 2.81 (dd, J = 14.9, 8.3 Hz, 1H), 4.61 (t,
J = 7.7 Hz, 1H), 6.70 (br s, 1H), 7.16 (t, J = 7.8 Hz, 1H), 7.26 (t, J = 7.4 Hz, 1H),
7.28 (br s, 1H), 7.33 (d, J = 7.8 Hz, 1H), 7.63 (d, J = 6.9 Hz, 1H), 10.46 (br s, 2H);
13C NMR (100 MHz, DMSO-d6): d 10.78, 32.97, 39.50, 102.06, 127.17, 127.78,
129.45, 129.94, 132.83, 137.17, 142.13, 160.13, 172.91; MS (ESI): m/z 302, 304
([M+Na]+); Anal. Calcd for C13H14ClN3O2: C, 55.82; H, 5.04; N, 15.02. Found: C,
55.78; H, 5.01; N, 15.06.
Compound 4m: White solid; mp: 248–250 °C; 1H NMR (400 MHz, DMSO-d6): d
2.06 (s, 3H), 2.70 (dd, J = 14.9, 7.0 Hz, 1H), 2.94 (dd, J = 14.9, 8.6 Hz, 1H), 4.29 (t,
J = 7.7 Hz, 1H), 6.75 (br s, 1H), 7.35 (br s, 1H), 7.49 (d, J = 8.2 Hz, 2H), 7.71 (d,
J = 8.1 Hz, 2H), 10.55 (br s, 2H); 13C NMR (100 MHz, DMSO-d6): d 10.58, 36.64,
39.72, 102.80, 108.88, 119.53, 128.93, 132.46, 137.00, 151.56, 159.83, 173.00;
MS (ESI): m/z 293 ([M+Na]+); Anal. Calcd for C14H14N4O2: C, 62.21; H, 5.22; N,
20.73. Found: C, 62.18; H, 5.20; N, 20.74.
Compound 4g: White solid; mp: 239–241 °C; 1H NMR (400 MHz, DMSO-d6): d
2.06 (s, 3H), 2.68 (dd, J = 14.8, 6.9 Hz, 1H), 2.91 (dd, J = 14.7, 8.6 Hz, 1H), 4.22 (t,
J = 7.6 Hz, 1H), 6.74 (br s, 1H), 7.14–7.29 (m, 3H), 7.32 (br s, 1H), 7.35 (s, 1H),
10.55 (br s, 2H); 13C NMR (100 MHz, DMSO-d6): d 10.60; 36.25, 40.13, 103.27,
126.05, 126.67, 127.64, 130.29, 133.06, 136.93, 148.32, 159.82, 173.16; MS
(ESI): m/z 302, 304 ([M+Na]+); Anal. Calcd for C13H14ClN3O2: C, 55.82; H, 5.04;
N, 15.02. Found: C, 55.80; H, 5.00; N, 15.07.
Compound 4n: White solid; mp: 258–260 °C; 1H NMR (400 MHz, DMSO-d6): d
2.07 (s, 3H), 2.70 (dd, J = 14.9, 7.1 Hz, 1H), 2.94 (dd, J = 14.9, 8.4 Hz, 1H), 4.22 (t,
J = 7.7 Hz, 1H), 6.78 (br s, 1H), 7.29 (d, J = 5.7 Hz, 2H), 7.37 (br s, 1H), 8.41 (d,
J = 5.7 Hz, 2H), 10.60 (br s, 2H); 13C NMR (100 MHz, DMSO-d6): d 10.59, 35.76,
39.70, 102.49, 123.33, 137.09, 149.69, 154.22, 159.89, 173.04; MS (ESI): m/z
269 ([M+Na]+); Anal. Calcd for C12H14N4O2: C, 58.53; H, 5.73; N, 22.75. Found:
C, 58.50; H, 5.71; N, 22.79.
Compound 4h: White solid; mp: 234–236 °C; 1H NMR (400 MHz, DMSO-d6): d
2.05 (s, 3H), 2.69 (dd, J = 14.8, 7.1 Hz, 1H), 2.88 (dd, J = 14.8, 8.5 Hz, 1H), 4.21 (t,
J = 7.8 Hz, 1H), 6.72 (br s, 1H), 7.26–7.33 (m, 5H), 10.54 (br s, 2H); 13C NMR
(100 MHz, DMSO-d6): d 10.63, 35.90, 40.24, 103.45, 128.32, 129.72, 130.58,