An efficient 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU)-mediated synthesis of 5-(trifluoromethyl)-N-alkyl-1-(3- phenylisoquinoline-1-yl)-1H-pyrazole-4-carboxamides

Article abstract of DOI:10.1007/s11164-011-0375-y

A series of 5-(trifluoromethyl)-N-alkyl-1-(3-phenylisoquinoline-1-yl)- 1H-pyrazole-4-carboxamides 4 has been effectively achieved in high yield and purity from the reaction of pyrazole carboxylic acid 2 with amines 3 in the presence of TBTU as a catalyst

Full text of DOI:10.1007/s11164-011-0375-y

Res Chem Intermed (2012) 38:615–627
DOI 10.1007/s11164-011-0375-y
An efficient 2-(1H-benzotriazole-1-yl)-1,1,3,3-
tetramethyluronium tetrafluoroborate (TBTU)-
mediated synthesis of 5-(trifluoromethyl)-N-alkyl-
1-(3-phenylisoquinoline-1-yl)-1H-pyrazole-4-
carboxamides
•
K. Prabakaran F. Nawaz Khan Jong Sung Jin
•
Received: 2 August 2011 / Accepted: 25 August 2011 / Published online: 13 September 2011
Ó Springer Science+Business Media B.V. 2011
Abstract A series of 5-(trifluoromethyl)-N-alkyl-1-(3-phenylisoquinoline-1-yl)-
1H-pyrazole-4-carboxamides 4 has been effectively achieved in high yield and
purity from the reaction of pyrazole carboxylic acid 2 with amines 3 in the presence
of TBTU as a catalyst and diisopropyl ethylamine as a base in acetonitrile at room
temperature.
Keywords Isocoumarins Á TBTU Á Pyrazole-4-carboxamide Á 1,3-Disubstituted
isoquinoline
Introduction
Pyrazole derivatives are an important class of heterocyclic compounds [1], some of
which are depicted in Fig. 1. Pyrazoles with carboxamide moieties and trifluorom-
ethane group (e.g., pyrazosulfuron-ethyl, tebufenpyrad and tolfenpyrad, the active
pyrazole carboxamides) have demonstrated their potential in the agrochemical
industry [2–5]. Also, pyrazole carboxylic acids represent important building blocks
in organic and medicinal chemistry [6, 7]. For example, celecoxib, a first-to-market
drug of a number of selective cyclo-oxygenase 2 (COX-2) inhibitors, is a promising
Electronic supplementary material The online version of this article (doi:
10.1007/s11164-011-0375-y) contains supplementary material, which is available to authorized users.
K. Prabakaran Á F. N. Khan (&)
Organic and Medicinal Chemistry Research Laboratory, Organic Chemistry Division,
School of Advanced Sciences, VIT University, Vellore 632 014, Tamil Nadu, India
e-mail: nawaz_f@yahoo.co.in
F. N. Khan Á J. S. Jin
Division of High Technology Materials Research, Busan Center, Korea Basic Science Institute
(KBSI), Busan 618 230, Korea
e-mail: jsjin@kbsi.re.kr
123

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K. Prabakaran et al.
CH3
H3CO
CH3
(H3C)2N
H3C
H
N
N
N
N
N
N
O
N
O
N
S NH2
O
H3CO
N
H3C
CH3
(a)
(b)
(c)
Fig. 1 a Mepirizole, b difenamizole, c cyclooxygenase-2 (COX-2) inhibitor Celecoxib
anti-inflammatory and analgetic agent [8, 9]. Pyrazole-substituted epothilone
derivative showed strong anti-tumour activity through the stabilisation of micro-
tubules by binding with tubulin [10].
Isoquinolines are useful intermediates in organic synthesis, and have demon-
strated their potential in heterocycles construction [11–15] through palladium-
catalysed annulations, electrophilic cyclisations, etc. More importantly, 1,3-
disubstituted isoquinoline skeleton with pharmaceutically important properties
[16–20], such as chiral ligands for the transition metal catalysts [21], and their
iridium complexes in organic light emitting diodes (OLEDs) [22], has been
achieved. A number of methods have been developed for the synthesis of 1,3-
disubstituted isoquinolines, including palladium-catalysed cross-coupling [23],
copper-catalysed tandem reaction [24] and others [25–29]. Synthesis of disubsti-
tuted isoquinolines have been reported [30, 31] in which 1,3-disubstituted
derivatives showed an extensive range of biological activities including potent
thrombin inhibitory and anti-bacterial activity [32, 33]. In our continued research
interest on isocoumarins and isoquinolines [34–55], the present article envisioned
the efficient methodology for a series of 5-(trifluoromethyl)-N-alkyl-1-(3-phenyli-
soquinoline-1-yl)-1H-pyrazole-4-carboxamides in high yield and purity.
Results and discussion
Reactions of 5-(trifluoromethyl)-1-(3-phenylisoquinolin-1-yl)-1H-pyrazole-4-car-
boxylic acid 2 with primary amines 3 in the presence of TBTU as a catalyst and
N,N-diisopropylethylamine as a base in acetonitrile afforded 5-(trifluoromethyl)-
N-alkyl-1-(3-phenylisoquinolin-1-yl)-1H-pyrazole-4-carboxamides 4 (Scheme 1;
Tables 1, 2, 3, 4 and 5) in excellent yields (Table 5). Compound 2 was synthesised
in 97% yield from hydrolysis of 1 with sodium methoxide in methanol (Scheme 1).
The advantages of this reaction include low toxicity of by-products, ease of
separation of products and simple work-up. A proposed mechanism for the
formation of 4 is depicted in Scheme 2. The optimisation of reaction condition was
carried out by choosing acid 2 and amine 3a using different coupling reagents and
diisopropyl ethylamine in acetonitrile at room temperature. The result obtained is
recorded in Table 1. The reaction works very well in TBTU (entry 4). However,
123

An efficient 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium
617
EtO2C
F3C
HO2C
F3C
R-HNOC
F3C
N
N
N
N
N
N
N
N
3 a-n
RNH2
NaOH
methanol
TBTU/ACN
N
22-25 oC
15-20 min
Stirred at
50 oC/2h
2
1
4a-n
Scheme 1 Synthesis of 5-(trifluoromethyl)-N-alkyl-1-(3-phenylisoquinolin-1-yl)-1H-pyrazole-4-carbox-
amide 4
Scheme 2 A possible
mechanism for the amidation of
2 in the presence of TBTU
N
N
+
-
BF4
N
-O
N
O
C O
N
N
HO2C
F3C
N
O
N
+
N
N
N
N
-
BF
4 (TBTU)
N
N
F3C
N
base
N
Ph
Ph
2
R-HNOC
F3C
N
N
N
R-NH2
3
N
OH
N
O
O
N
+
N
N
N
Ph
F3C
N
N
4
N
Ph
N
N+
O-
N
N
N
O
N
+
N
+
N
N
-
N
BF4
-
BF4
coupling reagents such as HBTU and T3P produced moderate yields (Table 1,
entries 1 and 3), and other reagents were found to be less effective.
The quantities of both TBTU and DIPEA were varied to maximise the yield of 4a
from reaction of 2 with 3a (Table 2). The results indicated that the optimised condition
involves use of 1.1 equivalents of TBTU and atleast 2.0 equivalents of DIPEA (Table 2,
entry10). Theeffectofbaseonthereactionwasalsoinvestigated(Table 3). Itwasfound
that reactions involving the use of aliphatic amines such as methyl, ethyl, 1-phenyl ethyl
and n-hexyl amines do not require the use of diisopropylethyl amine as a base. However,
123

618
K. Prabakaran et al.
Yielda (%)
Table 1 Effect of coupling reagents in the amidation of 2 and 3a
Entry
Coupling reagent
1
2
3
4
5
HATU
72
48
70
90
52
EDC.HCl/HOBt
T3P
TBTU
DCC
Reaction conditions: a mixture of 2 (1.0 eq), amine 3 (1.1 eq), diisopropyl ethyl amine (2.0 eq, only for
acrylic and aromatic amines) and coupling reagent (1.1 eq) in acetonitrile solvent (8 mL) was stirred at
ambient temperature for 20–30 min
a
Isolated yield
Table 2 Effect of amount
Entry
TBTU (eq)
DIPEA (eq)
Yielda (%)
of TBTU and diisopropyl ethyl
amine loading in the amidation
of 2 and 3a
1
0.5
0.75
1.0
1.1
1.2
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.0
1.0
1.0
1.0
1.0
1.2
1.4
1.6
1.8
2.0
2.2
2.4
62
70
72
72
72
75
80
83
87
90
90
90
2
3
4
5
6
7
8
Reaction conditions: a mixture
of 2 (1.0 eq), amine 3 (1.1 eq)
in acetonitrile solvent (8 mL)
was stirred at ambient
9
10
11
12
temperature for 20–30 min
a
Isolated yield
it must be noted that the reaction completes within 15–20 min in every case and
therefore the effect of base in reactions 2 and 3i was also investigated (Table 3). The
results suggested that decreasing the quantity of base gradually increases the yield in
which aliphatic amine 3i itself acted as a base and facilitated the reaction. The effect of
solventinreactions2and3iwasinvestigatedandthe resultsarerecordedinTable 4. The
results revealed that solvents such as acetonitrile and tetrahydrofuran (Table 4, entries
1 and 2) gave good yields in comparison to solvents like 2-methyltetrahydrofuran,
dichloromethane and N,N-dimethyl formamide. Several amines 3 were tested in
reactions described inScheme 1 under the optimisedcondition. The yieldsof4a–nwere
in the range of 84–93% with high purity (Table 5). The products were characterised by
different spectral techniques including 1H NMR, 13C NMR, IR and MS.
Experimental
All reagents were purchased from Sigma-Aldrich, Lancaster, and Qualigens, India,
and used without further purification. TBTU purchased from Spectrochem, India,
123

An efficient 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium
Table 3 Effect of loading of
diisopropylethyl amine in 2 and
619
Entry
DIPEA (eq)
Yielda (%)
3i
1
2
3
4
5
6
7
8
2.0
1.7
1.4
1.1
0.8
0.5
0.2
Nil
25
30
36
55
62
67
75
91
Reaction conditions: a mixture
of 2 (1.0 eq), amine 3 (1.1 eq),
diisopropylethyl amine and
TBTU (1.1 eq) in acetonitrile
solvent (8 mL) was stirred at
ambient temperature for
20–30 min
a
Isolated yield
Table 4 Effect of solvent in the amidation reaction of 2 and 3i
Entry
Solvent
Yielda (%)
1
2
3
4
5
Acetonitrile
91
88
85
76
70
Tetrahydrofuran
2-methyl THF
Dichloromethane
N,N-dimethyl formamide
Reaction conditions: a mixture of 2 (1.0 eq), amine 3 (1.1 eq), diisopropyl ethyl amine (2.0 eq, only for
acylic and aromatic amines) and TBTU (1.1 eq) in solvent (8 mL) was stirred at ambient temperature for
20–30 min
a
Isolated yield
and used as received. Infrared (IR) spectra were recorded using Avatar 330
equipped with DTGS detector. The NMR spectra were recorded on a Bruker
1
Spectrospin Avance DPX400 Ultrashield (400 MHz for H and 100 MHz for 13C).
Mass spectra were obtained using Agilent mass spectrometry. Melting points were
determined in open capillaries.
Synthesis of 5-(trifluoromethyl)-1-(3-phenylisoquinolin-1-yl)-1H-pyrazole-4-
carboxylic acid 2
A mixture of ethyl-5-(trifluoromethyl)-1-(3-phenylisoquinolin-1-yl)-1H-pyrazole-4-
carboxylate 1 (30 g, 72.97 mmol), sodium hydroxide (pellets, 3.21 g, 1.1 eq) in
methanol/water (3:1) mixture were stirred vigorously for 2 h. The reaction
completion was monitored by TLC analysis, the reaction mixture concentrated to
remove methanol and the remaining aqueous layer further diluted with 300 mL
water and the pH adjusted to 3–4 range. The solid precipitate was filtered off and
dried under high vacuum for 2 h at 50–55 °C to afford pure 5-(trifluoromethyl)-1-
(3-phenylisoquinolin-1-yl)-1H-pyrazole-4-carboxylic acid 2 (27 g, 96.6%) as light
1
yellow crystals: mp 209–210 °C; H NMR (400 MHz, CDCl3): d 13.55(bs, 1H),
8.80 (s, 1H), 8.46 (s, 1H), 8.26–8.24 (d, J = 8.4 Hz, 1H), 8.20–8.19 (d, J = 7.6 Hz,
2H), 7.97–7.93 (t, J = 6.8 Hz, 1H), 7.78–7.72 (q, 2H), 7.58–7.54 (t, J = 7.2 Hz,
2H), 7.50–7.47 (app. t, J = 7.2 Hz, 1H); 13C NMR (100 MHz, CDCl3): d 162.1,
123

620
K. Prabakaran et al.
Table 5 Synthesis of 4 according to Scheme 1
Yielda
(%)
Entry
Amines 3
Product 4
O
F3C
N
N
H
NH2
N
N
1
90
3a
4a
O
F3C
N
N
H
NH2
N
N
2
3
4
5
6
3b
89
92
88
84
87
4b
O
F3C
N
H
N
N
N
NH2
3c
4c
N
O
F3C
N
S
N
H
N
S
N
NH2
N
4d
3d
O
F3C
N
N
H
NH2
N
N
3e
4e
O
F3C
N
N
H
NH2
3f
N
N
4f
CH3
O
F3C
N
N
H
H3C
NH2
N
N
7
93
4g
3g
123

An efficient 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium
Table 5 continued
621
Yielda
(%)
Entry
Amines 3
Product 4
O
F3C
N
N
H
N
N
N
8
NH2
N
85
91
90
87
90
86
4h
3h
O
F3C
N
CH3
N
H
N
N
9
H3C NH2
3i
4i
O
F3C
CH3
N
H
N
N
N
10
11
12
13
H3C
3j
NH2
4j
O
F3C
N
OCH3
N
H
NH2
N
N
H3CO
3k
4k
H3C
O
F3C
N
N
H
N
N
CH3
NH2
4l
3l
O
F3C
N
n-hexyl
N
H
N
N
H3C
NH2
4m
3m
O
CF3
N
OCH3
3n
H
N
H3CO
N
N
14
H3CO
87
NH2
OCH3
4n
Reaction conditions: a mixture of 2 (1.0 eq), amine 3 (1.1 eq), diisopropyl ethyl amine (2.0 eq, only for
acylic and aromatic amines) and TBTU (1.1 eq) in acetonitrile solvent (8 mL) was stirred at ambient
temperature for 20–30 min.
a
Isolated yield
123

622
K. Prabakaran et al.
149.0, 148.5, 143.6, 139.5, 137.5, 133.1, 132.5, 129.8, 129.5, 128.1, 126.9, 124.5,
122.7, 119.5, 118.2; IR (cm-1) 3,366, 3,094, 2,921, 2,853, 2,249, 1,699, 1,638,
1,595, 1,505, 1,481, 1,413, 1,307, 1,227, 1,154, 1,100, 1,009, 922, 879, 850, 823,
743, 679, 631, 606, 549, 523, 503; LC–MS: m/z 384.2, C20H12F3N3O2 requires
383.09. Calcd C, 62.67; H, 3.16; N, 10.96%. Found: C, 62.59; H, 3.08; N, 10.87%.
General procedure for the synthesis of 5-(trifluoromethyl)-N-alkyl-1-(3-
phenylisoquinolin-1-yl)-1H-pyrazole-4-carboxamide 4
To a 20-mL vial TBTU (0.46 g, 1.43 mmol) and diisopropyl ethylamine (0.336 g;
2.60 mmol; in case of aliphatic amines not necessary to add additional base) were
added to a mixture of 2 (0.5 g; 1.30 mmol), amine 3 (1.43 mmol), acetonitrile
(8 mL) at room temperature under nitrogen atmosphere. This reaction mixture was
stirred vigorously for 20–30 min and its completion was monitored by TLC
analysis. The reaction mixture was quenched by the addition of water (15 mL) and
the solid precipitate was filtered off and dried under vacuum for 2 h to give 4a–4n in
high yields (Table 5).
The analysis data of 4a–n are given below.
4a. Yield: 90% of white solid; mp 206–207 °C; 1H NMR (400 MHz, DMSO-D6)
d 8.78 (s, 1H), 8.50 (d, J = 7.6 Hz, 1H), 8.33 (s, 1H), 8.26–8.20 (m, 3H), 7.95
(t, J = 8.4 Hz, 1H), 7.79–7.72 (m, 2H), 7.58–7.54 (t, J = 7.2 Hz, 2H), 7.49 (app. t,
J = 8.4 Hz, 1H), 3.78 (bs, 1H), 1.89–1.74 (m, 4H), 1.62 (d, J = 12.8 Hz, 1H),
1.39–1.15 (m, 5H); 13C NMR (100 MHz, DMSO-D6) d 159.6, 148.9, 148.4, 140.6,
139.5, 137.6, 132.46, 129.8, 129.7, 129.4, 128.2, 126.9, 124.6, 122.8, 122.5, 119.2,
48.7, 32.6, 25.6, 25.1; IR (cm-1) 3,225, 3,056, 2,983, 2,930, 2,854, 2,185, 1,984,
1,637, 1,585, 1,544, 1,493, 1,468, 1,407, 1,325, 1,289, 1,247, 1,158, 1,089, 1,043,
956, 887, 850, 750, 694, 566, 522, 452; LC–MS: m/z 465.1, 466.1. C26H23F3N4O
requires 464.18. Anal Calcd for C26H23F3N4O: C, 67.23; H, 4.99; N, 12.06%.
Found: C, 67.20; H, 4.99; N, 12.01%.
1
4b: Yield: 406 mg (89%) of white solid; mp 210–211 °C; H NMR (400 MHz,
DMSO-D6) d 8.78–8.75 (m, 2H), 8.36 (s, 1H), 8.26–8.20 (m, 3H), 7.95 (app. t,
J = 8.0 Hz, 1H), 7.79–7.72 (m, 2H), 7.58–7.54 (t, J = 8.4 Hz, 2H), 7.48 (app. t,
J = 7.2 Hz, 1H), 3.21–3.18 (t, J = 6.0 Hz, 2H), 1.06 (m, 1H), 0,51–0.46 (m, 2H),
0.29–0.27 (m, 2H); 13C NMR (100 MHz, DMSO-D6) d 160.4, 148.9, 148.4,140.6,
139.5, 137.6, 132.4, 129.8, 129.7, 129.5, 128.2, 126.9, 124.6, 122.8,122.2, 119.3,
43.7, 11.2, 3.7; IR (cm-1) 3,213, 3,055, 2,866, 1,666, 1,639, 1,589, 1,544, 1,490,
1,469, 1,406, 1,328, 1,279, 1,248, 1,164, 1,075, 1,043, 957, 886, 852, 749, 692; LC–
MS: m/z 437.1, 438.1. C24H19F3N4O requires 436.15. Anal Calcd for C24H19F3N4O:
C, 66.05; H, 4.39; N, 12.84%. Found: C, 66.02; H, 4.40; N, 12.81%.
1
4c: Yield: 406 mg (92%) of white solid; mp 223–224 °C; H NMR (400 MHz,
DMSO-D6) d 8.78 (s, 1H), 8.70 (d, J = 4.0 Hz, 1H), 8.33 (s, 1H), 8.26–8.20 (m,
3H), 7.94 (app. t, J = 7.2 Hz, 1H), 7.76 (app. t, J = 8.0 Hz, 1H), 7.70 (d,
J = 8.4 Hz, 1H), 7.58–7.54 (t, J = 7.6 Hz, 2H), 7.48 (app. t, J = 7.2 Hz, 1H), 2.87
(m, 1H), 0.78–0.73 (m, 2H), 0.61–0.57 (m, 2H); 13C NMR (100 MHz, DMSO-D6) d
161.1, 148.5, 148.0, 140.3, 139.1, 137.1, 132.0, 129.3, 129.3, 129.0, 127.8, 126.4,
124.1, 122.3, 121.6, 118.90, 22.8, 5.8; IR (cm-1), 3,226, 3,053, 2,921, 2,851, 2,267,
123

An efficient 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium
623
2,184, 2,139, 2,029, 2,013, 1,986, 1,960, 1,661, 1,636, 1,587, 1,549, 1,493, 1,470,
1,406, 1,380, 1,325, 1,292, 1,251, 1,162, 1,044, 1,022, 954, 888, 795, 751, 727, 694,
661, 564, 521, 500, 449; LC–MS: m/z 423.1, 424.1. C23H17F3N4O requires 422.14.
Anal Calcd for C23H17F3N4O: C, 65.40; H, 4.06; N, 13.26%. Found: C, 65.37; H,
4.06; N, 12.27%.
4d: Yield: 428 mg (88%) of yellow solid; mp 235–236 °C; 1H NMR (400 MHz,
DMSO-D6) d 12.99 (bs, 1H), 8.81 (s, 1H), 8.71 (s, 1H), 8.27 (d, J = 8.4 Hz, 1H),
8.23–8.21 (d, J = 8.4 Hz, 2H), 7.97 (app. t, J = 8.0 Hz, 1H), 7.81–7.73 (m, 2H),
7.62–7.55 (m, 3H), 7.49 (app. t, J = 7.2 Hz, 1H), 7.36 (d, J = 3.6 Hz, 1H); 13C
NMR (100 MHz, DMSO-D6) d 159.4, 148.8, 148.5, 141.5, 139.5, 137.5, 132.5,
129.8, 129.5, 128.2, 126.9, 124.5, 122.7, 119.5, 114.5; IR (cm-1), 3,459, 3,122,
3,017, 2,969, 2,944, 1,740, 1,676, 1,625, 1,552, 1,491, 1,463, 1,407, 1,286, 1,262,
1,224, 1,155, 1,039, 956, 917, 884, 858, 793, 758, 718, 685, 618, 521; LC–MS: m/z
466.0, 468.0. C23H14F3N5OS requires 465.09. Anal Calcd for C23H14F3N5OS: C,
59.35; H, 3.03; N, 15.05; S, 6.89%. Found: C, 59.32; H, 3.03; N, 15.07; S, 6.89%.
1
4e: Yield: 395 mg (84%) of white solid; mp 237–238 °C; H NMR (400 MHz,
DMSO-D6) d 8.78 (s, 1H), 8.58 (d, J = 7.2 Hz, 1H), 8.34 (s, 1H), 8.26–8.20 (m,
3H), 7.95 (app. t, J = 8.0 Hz, 1H), 7.79–7.71 (m, 2H), 7.58–7.55 (t, J = 7.6 Hz,
2H), 7.49 (app. t, J = 7.2 Hz, 1H), 4.23 (m, 1H), 1.96–1.92 (m, 2H), 1.78 (bs, 2H),
1.57 (bs, 4H); 13C NMR (100 MHz, DMSO-D6) d 160.1, 148.9, 148.4, 140.6, 139.5,
137.6, 132.4, 129.8, 129.7, 129.4, 128.2, 126.9, 124.6, 122.8, 122.5, 119.2, 51.3,
32.5, 24.0; IR (cm-1), 3,229, 3,052, 2,930, 2,852, 1,637, 1,585, 1,544, 1,493, 1,468,
1,407, 1,325, 1,289, 1,247, 1,169, 1,099, 1,045, 956, 889, 850, 754, 695, 566, 523,
452; LC–MS: m/z 451.1, 452.1. C25H21F3N4O requires 450.17. Anal. Calcd for
C25H21F3N4O: C, 66.66; H, 4.70; N, 12.44%. Found: C, 66.63; H, 4.69; N, 12.39%.
1
4f: Yield: 397 mg (87%) of white solid; mp 236–237 °C; H NMR (400 MHz,
DMSO-D6) d 8.88 (d, J = 7.6 Hz, 1H), 8.77 (s, 1H), 8.37 (s, 1H), 8.26–8.19
(m, 3H), 7.94 (app. t, J = 8.0 Hz, 1H), 7.79–7.70 (m, 2H), 7.58–7.54 (t, J =
7.2 Hz, 2H), 7.48 (app. t, J = 7.2 Hz, 1H), 4.42 (m, 1H), 2.31–2.24 (m, 2H),
2.10–2.04 (m, 2H), 1.74–1.71 (m, 2H); 13C NMR (100 MHz, DMSO-D6) d 159.4,
148.9, 148.4, 140.6, 139.5, 137.5, 132.4, 129.8, 129.7, 129.5, 128.2, 126.9, 124.5,
122.7, 122.1, 119.3, 44.8, 30.4, 15.2; IR (cm-1), 3,228, 3,053, 2,928, 2,851, 2,028,
2,013, 1,985, 1,960, 1,660, 1,636, 1,586, 1,549, 1,493, 1,470, 1,406, 1,380, 1,325,
1,292, 1,251, 1,163, 1,045, 1,023, 954, 888, 852, 795, 751, 727, 694, 661, 564, 521,
500, 449; LC–MS: m/z 437.1, 438.1. C24H19F3N4O requires 436.15. Anal Calcd for
C24H19F3N4O: C, 66.05; H, 4.39; N, 12.84%. Found: C, 66.06; H, 4.36; N, 12.81%.
1
4g: Yield: 465 mg (93%) of white solid; mp 180–181 °C; H NMR (400 MHz,
DMSO-D6) d 8.78 (s, 1H), 8.47 (app. t, J = 9.0 Hz, 1H), 8.33 (s, 1H), 8.26–8.20
(m, 3H), 7.95 (app. t, J = 8.4 Hz, 1H), 7.80–7.71 (m, 2H), 7.59–7.54 (t,
J = 8.4 Hz, 2H), 7.49 (app. t, J = 7.6 Hz, 1H), 3.99–3.98 (bs, 1H), 1.90 (d,
J = 10.4 Hz, 1H), 1.74–1.70 (m, 2H), 1.62–1.54 (m, 3H), 1.53–1.31 (m, 2H), 1.07
(t, J = 7.2 Hz, 1H), 0.95–0.94 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, DMSO-
D6) d 160.1, 159.7, 148.9, 148.4, 140.7, 140.6, 139.5, 137.6, 132.4, 129.8, 129.7,
129.5, 128.2, 126.9, 124.6, 122.8, 119.2, 48.8, 46.5, 34.0, 32.5, 29.9, 28.7, 22.6; IR
(cm-1), 3,228, 3,058, 2,983, 2,935, 2,855, 1,637, 1,585, 1,545, 1,495, 1,468, 1,407,
1,322, 1,289, 1,247, 1,158, 1,089, 1,043, 956, 887, 852, 750, 694, 566, 522, 452;
123

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LC–MS: m/z 479.1, 480.2. C27H25F3N4O requires 478.2. Anal Calcd for
C27H25F3N4O: C, 67.77; H, 5.27; N, 11.7%. Found: C, 67.76; H, 5.27; N, 11.69%.
1
4h: Yield: 465 mg (85%) of white solid; mp 198–199 °C; H NMR (400 MHz,
DMSO-D6) d 9.32 (t, J = 6.0 Hz, 1H), 8.79 (s, 1H), 8.56 (d, J = 4.8 Hz, 1H), 8.48
(s, 1H), 8.26–8.20 (m, 3H), 7.95 (app. t, J = 8.0 Hz, 1H), 7.84–7.73 (m, 3H),
7.58–7.54 (t, J = 7.2 Hz, 2H), 7.50–7.42 (m, 2H), 7.31 (app. t, J = 7.2 Hz, 1H),
4.63–4.62 (d, J = 6.0 Hz, 2H); 13C NMR (100 MHz, DMSO-D6) d 160.6, 158.6,
149.4, 148.9, 148.5, 140.8, 139.5, 137.5, 137.2, 132.5, 132.1, 129.8, 129.5, 128.2,
126.9, 124.6, 122.7, 122.7, 121.7, 121.5, 121.2, 119.3, 118.5; IR (cm-1), 3,459,
3,019, 2,966, 1,742, 1,676, 1,625, 1,550, 1,492, 1,463, 1,407, 1,289, 1,262, 1,224,
1,150, 1,040, 956, 917, 884, 858, 793, 758, 718, 685, 618; LC–MS: m/z 474.1,
475.1. C27H25F3N4O requires 473.15. Anal Calcd for C26H18F3N5O: C, 65.96; H,
3.83; N, 14.79%. Found: C, 65.97; H, 3.83; N, 14.78%.
1
4i: Yield: 377 mg (91%) of white solid; mp 218–219 °C; H NMR (400 MHz,
DMSO-D6) d 8.78 (s, 1H), 8.65 (d, J = 4.0 Hz, 1H), 8.35 (s, 1H), 8.26–8.20 (m,
3H), 7.95 (app. t, J = 7.2 Hz, 1H), 7.79–7.70 (m, 2H), 7.58–7.47 (m, 3H),
2.84–2.83 (d, J = 4.4 Hz, 3H); 13C NMR (100 MHz, DMSO-D6) d 160.8, 148.9,
148.5, 140.7, 139.5, 137.6, 132.4, 129.8, 129.7, 129.5, 128.2, 126.9, 124.5, 122.7,
122.1, 119.3, 118.5, 26.9; IR (cm-1), 3,230, 3,054, 2,930, 2,851, 2,029, 2,015,
1,984, 1,636, 1,660, 1,588, 1,549, 1,495, 1,470, 1,405, 1,380, 1,325, 1,295, 1,251,,
1,163, 1,023, 954, 852, 795, 751, 727, 694, 661, 564, 521, 500; LC–MS: m/z 397.1,
398.1. C21H15F3N4O requires 396.12. Anal Calcd for C21H15F3N4O: C, 63.63; H,
3.81; N, 14.14%. Found: C, 63.66; H, 3.81; N, 14.12%.
1
4j: Yield: 377 mg (90%) of white solid; mp 208–209 °C; H NMR (400 MHz,
DMSO-D6) d 8.78 (bs, 1H), 8.67 (t, J = 5.6 Hz, 1H), 8.35 (bs, 1H), 8.32–8.20 (m,
3H), 7.95 (app. t, J = 8.4 Hz, 1H), 7.79–7.71 (m, 2H), 7.58–7.54 (t, J = 7.2 Hz,
2H), 7.48 (app. t, J = 7.2 Hz, 1H), 3.35–3.29 (q, 2H), 1.19–1.15 (t, J = 7.2 Hz,
3H); 13C NMR (100 MHz, DMSO-D6) d 160.2, 148.9, 148.4, 140.6, 139.5, 137.6,
132.4, 129.8, 129.7, 129.5, 128.2, 126.9,124.5, 122.7, 122.3, 119.3, 34.4, 15.0; IR
(cm-1), 3,232, 3,055, 2,932, 2,852, 1,636, 1,588, 1,549, 1,495, 1,470, 1,405, 1,380,
1,325, 1,295, 1,251,, 1,163, 1,023, 954, 852, 795, 751, 727, 694, 661, 564, 521, 500;
LC–MS: m/z 411.1, 412.1. C22H17F3N4O requires 410.14. Anal Calcd for
C22H17F3N4O: C, 64.39; H, 4.18; N, 13.65%. Found: C, 64.39; H, 4.19; N, 13.66%.
1
4k: Yield: 400 mg (87%) of white solid; mp 135–137 °C; H NMR (400 MHz,
DMSO-D6) d 8.78–8.75 (m, 2H), 8.37 (s, 1H), 8.26–8.20 (q, 3H), 7.95 (app. t,
J = 6.8 Hz, 1H), 7.79–7.71 (m, 2H), 7.58–7.54 (t, J = 7.2 Hz, 2H), 7.49 (app. t,
J = 7.2 Hz, 1H), 3.52–3.46 (m, 4H), 3.32 (s, 3H); 13C NMR (100 MHz, DMSO-D6)
d 160.5, 148.9, 148.4, 140.7, 139.5, 137.6, 132.4, 129.8, 129.7, 129.5, 128.2,126.9,
124.5, 122.8, 122.0, 119.3, 70.8, 58.4; IR (cm-1), 3,726, 3,623, 3,345, 2,984, 2,904,
2,190, 2,153, 1,964, 1,713, 1,625, 1,563, 1,468, 1,397, 1,326, 1,270, 1,240, 1,150,
1,041, 958, 903, 842, 753, 716, 688, 605, 539, 453, 403; LC–MS: m/z 441.1, 442.1.
C23H19F3N4O2 requires 440.15. Anal Calcd for C23H19F3N4O2: C, 62.72; H, 4.35;
N, 12.72%. Found: C, 62.69; H, 4.33; N, 12.72%.
1
4l: Yield: 400 mg (90%) of white solid; mp 175–176 °C; H NMR (400 MHz,
DMSO-D6) d 9.11–9.09 (d, J = 8.0 Hz, 2H), 8.78 (bs, 1H), 8.45 (bs, 1H), 8.26–8.20
(m, 3H), 7.94 (app. t, J = 7.6 Hz, 1H), 7.79–7.72 (m, 2H), 7.58–7.54 (t,
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An efficient 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium
625
J = 7.6 Hz, 2H), 7.49 (d, J = 7.2 Hz, 1H), 7.46–7.44 (d, J = 7.6 Hz, 2H),
7.39–7.36 (t, J = 7.6 Hz, 2H), 7.27 (app. t, J = 7.2 Hz, 1H), 5.18 (t, J = 7.2 Hz,
1H), 1.52–1.50 (d, J = 7.2 Hz, 3H); 13C NMR (100 MHz, DMSO-D6) d 159.7,
148.9, 148.5, 144.7, 140.8, 139.5, 137.6, 132.4, 129.8, 129.7, 129.4, 128.7, 128.2,
127.2, 126.9, 126.5, 124.6, 122.8, 122.1, 119.3, 48.9, 22.7; IR (cm-1), 3,283, 3,185,
3,054, 2,922, 1,949, 1,595, 1,617, 1,565, 1,504, 1,422, 1,378, 1,325, 1,441, 1,183,
1,140, 1,073, 1,030, 960, 914, 842, 818, 797, 766, 747, 683, 642, 574, 520, 411;
LC–MS: m/z 487.1, 488.1. C28H21F3N4O requires 486.17. Anal Calcd for
C28H21F3N4O: C, 69.13; H, 4.35; N, 11.52%. Found: C, 69.13; H, 4.33; N, 11.49%.
1
4m: Yield: 400 mg (86%) of white solid; mp 143–144 °C; H NMR (400 MHz,
DMSO-D6) d 8.78 (bs, 1H), 8.65 (t, J = 5.6 Hz, 1H), 8.34 (bs, 1H), 8.26–8.24
(d, J = 8.0 Hz, 1H), 8.22–8.20 (d, J = 8.8 Hz, 2H), 7.95 (app. t, J = 8.0 Hz, 1H),
7.79–7.72 (m, 2H), 7.58–7.54 (t, J = 7.2 Hz, 2H), 7.48 (app. t, J = 7.2 Hz, 1H),
3.32–3.26 (m, 2H), 1.58–1.51 (q, 2H), 1.38–1.23 (m, 6H), 0.91–0.87 (t, J = 6.8 Hz,
3H); 13C NMR (100 MHz, DMSO-D6) d 160.3, 148.9, 148.4, 140.6, 139.5, 137.6,
132.4, 131.6, 129.8, 129.7, 129.49, 128.2, 126.9, 124.6, 122.7, 122.3, 121.2, 119.3,
31.4, 29.3, 26.5, 22.5, 14.3; IR (cm-1), 3,233, 3,058, 2,936, 2,851, 2,026, 2,015,
1,984, 1,636, 1,650, 1,588, 1,549, 1,495, 1,470, 1,405, 1,388, 1,325, 1,295, 1,251,
1,163, 1,023, 954, 852, 795, 751, 727, 694, 661, 564, 521, 500; LC–MS: m/z 467.1,
468.1. C26H25F3N4O requires 466.2. Anal Calcd for C26H25F3N4O: C, 66.94; H,
5.40; N, 12.0%. Found: C, 66.92; H, 5.39; N, 11.99%.
1
4n: Yield: 400 mg (87%) of yellow liquid; H NMR (400 MHz, DMSO-D6) d
8.78–8.74 (m, 2H), 8.31 (s, 1H), 8.26–8.20 (m, 3H), 7.95 (app. t, J = 8.0 Hz, 1H),
7.79–7.70 (m, 2H), 7.58–7.55 (t, J = 7.6 Hz, 2H), 7.49 (app. t, J = 7.6 Hz, 1H),
6.91–6.87 (m, 2H), 6.80 (d, J = 8.0 Hz, 1H), 3.77–3.72 (m, 8H), 2.83–2.80 (m,
2H); 13C NMR (100 MHz, DMSO-D6) d 160.3, 149.1, 148.9, 148.5, 147.8, 140.6,
139.5, 137.5, 132.4, 132.2, 129.8, 129.5, 128.2, 126.9, 124.5, 122.7, 122.2, 121.0,
119.3, 113.0, 112.4, 56.0, 55.8, 41.3, 38.7, 34.9; IR (cm-1), 3,292, 3,037, 2,330,
2,290, 2,251, 2,198, 2,222, 2,181, 2,160, 2,142, 2,119, 2,059, 2,025, 2,013, 1,986,
1,968, 1,963, 1,955, 1,942, 1,896, 1,861, 1,833, 1,616, 1,561, 1,520, 1,461, 1,407,
1,321, 1,237, 1,200, 1,143, 1,104, 964, 893, 828, 793, 749, 653, 596, 564; LC–MS:
m/z 547.1. C30H25F3N4O3 requires 546.19. Anal Calcd for C30H25F3N4O3: C, 65.93;
H, 4.61; N, 10.25%. Found: C, 65.91; H, 4.59; N, 10.22%.
Conclusion
An efficient, simple and high yielding method for the synthesis of various
5-(trifluoromethyl)-N-alkyl-1-(3-phenylisoquinoline-1-yl)-1H-pyrazole-4-carbox-
amides from pyrazole carboxylic acid and primary amines in the presence of TBTU
was established. The procedure involves simple work-up, ease of separation of
products and low toxicity of by-products.
Acknowledgment The authors wish to express their gratitude to the Management, VIT University,
India for their support and facilities.
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