Preparation of NH-pyrazoleacetic acid anilides from trilithiated acetoacetanilide, select aromatic esters, and hydrazine

Article abstract of DOI:10.1002/jhet.285

(Chemical Equation Presented) Acetoacetanilide was trilithiated with excess lithium diisopropylamide to form a reactive trianiontype intermediate. This was followed by a regioselective Claisen-type condensation of the trilithiated intermediate with a variety of aromatic esters to afford new C-acylated intermediates, 3,5-diketopentane-carboxanilides, that were not isolated but immediately condensed-cyclized with hydrazine to afford the NH- pyrazoleacetanilides, 5-aryl-1H-pyrazole-3-acetanilides, before these C-acylated intermediates had an opportunity to rearrange to anilino-pyranones, 4-anilino-6-aryl-2H-pyran-2-ones.

Full text of DOI:10.1002/jhet.285

January 2010
Preparation of NH-Pyrazoleacetic Acid Anilides from Trilithiated
Acetoacetanilide, Select Aromatic Esters, and Hydrazine
147
Ellyn A. Smith,a Chandra Potter,a Zachary C. Kennedy,a Andrew J. Puciaty,a
Amanda M. Acevedo-Jake,a Stephen D. Hersey,a Clyde R. Metz,a
William T. Pennington,b Donald G. VanDerveer,b and Charles F. Beama*
aDepartment of Chemistry and Biochemistry, College of Charleston, Charleston,
South Carolina 29424
bDepartment of Chemistry, Clemson University, Clemson, South Carolina 29434
*E-mail: beamc@cofc.edu
Received July 9, 2009
DOI 10.1002/jhet.285
Published online 5 January 2010 in Wiley InterScience (www.interscience.wiley.com).
Acetoacetanilide was trilithiated with excess lithium diisopropylamide to form a reactive trianion-
type intermediate. This was followed by a regioselective Claisen-type condensation of the trilithiated
intermediate with a variety of aromatic esters to afford new C-acylated intermediates, 3,5-diketopen-
tane-carboxanilides, that were not isolated but immediately condensed-cyclized with hydrazine to afford
the NH-pyrazoleacetanilides, 5-aryl-1H-pyrazole-3-acetanilides, before these C-acylated intermediates
had an opportunity to rearrange to anilino-pyranones, 4-anilino-6-aryl-2H-pyran-2-ones.
J. Heterocyclic Chem., 47, 147 (2010).
INTRODUCTION
mide (LDA), and other strong bases [6] was followed
by condensation with carboxy electrophiles, usually an
ester, and sometimes N-acylaziridines [7]. This afforded
C-acylated products 3, diketoesters, that could be iso-
lated and transformed by condensation-cyclization with
hydrazine into additional products, NH-pyrazoles 4.
Some of the dianion-type b-ketoester systems 2 have
been expanded to trianion-type b-ketoamide intermedi-
ates 6 that could be used in additional syntheses
(Scheme 2). Recently, acetoacetanilide 5 has been trili-
thiated with excess LDA, and these intermediates 6
were regioselectively condensed at the terminal carbon
atom with lithiated methyl thiosalicylate or a variety
of lithiated methyl salicylates to afford C-acylation
products 7 that were acid cyclized to 4H-1-benzothio-
pyran-4-ones (thiochromone-acetanilides) 8 [8] or 4H-1-
Pyrazoles of all substitution types continue to be pre-
pared and studied, either as stand alone molecular sys-
tems, or as part of a fused-ring group of compounds,
such as, indazoles and dihydrobenzindazoles [1]. NH-
Pyrazole-3-acetic acids and their derivatives have
received limited investigation [2], with a single recent
citation dealing with the preparation of NH-pyrazole-3-
acetanilides [3], and a single report for NH-pyrazole-3-
acetic acid hydrazides [4]. Of the possible pyrazole
substitution types, the NH-pyrazoles continue to receive
increasing interest, especially in ligand investigations [5]
(Scheme 1).
Claisen type strong base studies with b-ketoesters dia-
nions 2 resulting from deprotonation of 1 with alkali
metal amides (M ¼ Li, Na, or K), lithium diisopropyla-
benzopyran-4-ones (chromone-acetanilides)
9
[9],
respectively. When the trilithiated intermediates 6 were
condensed with other substituted benzoate esters, such
as, methyl 4-methoxybenzoate, rearrangement products
usually resulted and were identified as substituted 2-pyr-
anones, 4-anilino-6-aryl-2H-pyran-2-ones 10 [10].
Scheme 1. Syntheses with dimetalated b-ketoesters.
RESULTS AND DISCUSSION
During this investigation, 2-[3-(phenyl or substituted
phenyl)-1H-pyrazol-5-yl]-N-phenylacetamides, NH-pyrazole
C
V
2010 HeteroCorporation

148
E. A. Smith, C. Potter, Z. C. Kennedy, A. J. Puciaty, A. M. Acevedo-Jake, S. D. Hersey,
C. R. Metz, W. T. Pennington, D. G. VanDerveer, and C. F. Beam
Vol 47
Scheme 2. Syntheses with trilithiated acetoacetanilide including 5-aryl-1H-pyrazole-3-acetanilides 11a–l.
acetanilides, 11a–l were prepared by the immediate con-
densation-cyclization of 5-(phenyl or substituted phenyl)-
3,5-dioxo-N-phenylpentamides, diketopentanilides 7, (from
5 and 6) intermediate compounds with hydrazine. Interme-
diate diketopentanilides 7 were prepared by modification
and extension of some strong-base multiple anion proce-
dures where trianion 6 resulted from treatment of acetoac-
etanilide 5 with excess LDA to 6, and then condensed
with a variety of substituted benzoate esters, that did not
contain an ortho-substituted nucleophilic functional group
(e.g., thiophenol).
(CH carbon) resonance absorptions of the pyrazole ring
in all cases were noted d 101–107 ppm, which is in
accord with estimates and recent experimental data
reported by others [3,4]. DEPT taken after 5000 C-13
NMR scans on 11b followed by HMQC indicated the
presence of the methylene carbon absorptions at d 35.8
ppm, which was matched with H-1 NMR methylene
protons absorption at d 3.72 ppm; the C-13 NMR
absorption at d 102.5 ppm was matched with H-1 NMR
C4AH of the pyrazole ring absorption at d 6.61 ppm.
Other C-13 NMR absorptions were noted for the meth-
ylene carbons from d 32.9 to 40.2 ppm. LC-MS for all
compounds, (MþH)þ, were also satisfactory and com-
bustion analysis for the compounds were supportive.
The single crystal X-ray analysis obtained for product
11c indicated that a single tautomer in the keto form (I,
Fig. 1) with a hydrogen bonded to the nitrogen adjacent
to the pyrazole carbon also bonded to the methylene
(C3 in the ORTEP diagram illustrated in Fig. 2) and
that the pyrazole ring is nearly planar [12].
The purification of these diketopentanilide intermedi-
ates 7 presented a good possibility of rearrangements to
anilino-pyranones 10; consequently, they were treated
with excess hydrazine which resulted in the preferential
condensation of a hydrazine nitrogen with one of the two
carbonyl carbons of diketopentanilide intermediates 7 fol-
lowed by cyclodehydration to the targeted pyrazoleacetic
acid anilides 11a–l. Anilino-pyranones 10 were not found.
The pyrazole acetanilides 11a–l can be represented as
a molecular system with numerous tautomeric forms (I–
VI), including the keto-enol and annular tautomers with
the pyrazole NAH hydrogen bonded to either of the ad-
jacent nitrogen atoms (annular tautomers). IR carbonyl
absorptions from crystalline products were noted at
1651–1676 cmꢀ1. Proton magnetic spectra indicated pre-
dominantly or exclusively keto tautomer, with the meth-
ylene absorptions appearing as a singlet at d 3.44–3.78
ppm. The C4AH absorptions of the pyrazole ring were
noted at d 6.31ꢀ6.69 ppm. Carbon-13 NMR spectra
were indicative of structure but they were inconclusive.
Even after extensive scans, the projected number of car-
bon absorptions were usually not obtained [3]. The C4
Figure 1. 5-Aryl-1H-pyrazole-3-acetanilide tautomers I–VI.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

January 2010
Preparation of NH-Pyrazoleacetic Acid Anilides from Trilithiated Acetoacetanilide,
Select Aromatic Esters, and Hydrazine
149
[6g]. In addition to all products targeted and prepared
being new, they have the potential for use in agriculture
and medicine, applications in other syntheses, and for
spectral and theoretical studies.
EXPERIMENTAL
Melting points were obtained with a Mel-Temp II melting
point apparatus in open capillary tubes and are uncorrected.
Fourier transform infrared spectra were obtained with a Matt-
son Genesis II FTIR with Specac Golden Gate Accessory. Pro-
ton and C-13 nuclear magnetic resonance spectra were
obtained with a Varian Associates Mercury Oxford (300 MHz
for H-1 and 75 MHz for C-13) nuclear magnetic resonance
spectrometer, and chemical shifts are recorded in d ppm down-
field from an internal tetramethylsilane (TMS) standard. Com-
bustion analyses were performed by Quantitative Technologies,
Inc., P.O. Box 470, Whitehouse, NJ 08888. LCMS analyses
were measured on a Thermo-Finnigan LCQ Advantage system
with the Surveyor autosampler, Surveyor pump, and LCQ
Advantage Max mass spectral detector using electrospray ioni-
zation; 2 mg samples were prepared in 2 mL minꢀ1 of acetoni-
trile; 10 lL injections were pumped at 1.00 mL minꢀ1 iso-
cratically with 70% acetonitrile and 30% water, each buffered
with 0.1% formic acid by volume; 15 min runs were repro-
duced in positive MS modes. Data were collected at full scan
from 100 to 650 amu.
Figure 2. ORTEP diagram (50% ellipsoids for nonhydrogen atoms),
C17H14 ClN3O 11c [11].
The molecular structure of 11c is shown in Figure 2
and selected bond distances and angles are listed in
Table 1. The bond lengths agree with the assignment of
the double bond shown between C1 and O1 for the keto
form (see ORTEP diagram for numbering of atoms).
The least squares best planes representing the rings
containing C6 and C5 are nearly coplanar with an angle
of 18.3ꢁ between them. There is likely some extended pi
bonding between these rings. Each molecule is hydrogen
bonded to four molecules: N3 to the H atom on N1, H
on N2 to O1, O1 to the H atom on N2, and H on N1 to
N3.
General procedure for the preparation of 5-aryl-1H-pyr-
azole-3-acetic acid anilides (11a–l). Ratio of reagents—Ace-
toacetanilide:LDA:ester, 1:4:1 for 11a–g, and 1:5:1 for 11h
and 11j. In a typical reaction sequence, LDA was prepared in
a round bottomed flask by the addition of 39–40 mL (50 mL
for 11h and 11j) of 1.60M n-butyllithium (0.0630 mol/0.0788
mol for 11h and 11j) in hexanes (e.g., 500 mL), equipped with
a nitrogen inlet tube, and a side-arm addition funnel (recom-
mended). The flask was cooled in an ice water bath, and 6.41
g (0.0630 mol) or 8.01 g (0.0788 mol for 11h and 11j) of dii-
sopropylamine (99.5%, Aldrich Chemical Co.), dissolved in
25–35 mL of dry THF was added from the addition funnel at
a fast drop wise rate during a 5 min period. The solution was
stirred for an additional 15–20 min, and then treated during 5
min with acetoacetanilide 6 (99.5%, Aldrich Chemical Co.),
The overall yields for the two-step synthesis may not
be optimal for an individual product, with the strong
base reactions usually having the greatest variance. A
practical side to the synthesis is the availability of start-
ing materials, the use of less toxic acylating reagents
(aromatic esters vs. acyl aziridines), a procedure that is
reproducible by someone not necessarily familiar with
strong base synthesis methods, and that the procedure is
conducive to making targeted products which can be
prepared in gram quantities after recrystallization from
common solvents. Although not investigated exten-
sively, tetramethylethylenediamine (TMEDA) did not
markedly increase the overall yield, on occasion ꢂ5%
Table 1
ꢁ
˚
Selected bond distances (A) and angles ( ), C17H14ClN3O 11c.
C1AO1
C1AN1
N1AC12
C1AC2
C2AC3
N2AC3
N3AN2
N3AC5
C4AC5
C3AC4
C6AC5
1.235(4)
1.341(4)
1.420(4)
1.519(4)
1.500(4)
1.345(4)
1.353(4)
1.347(4)
1.403(4)
1.375(5)
1.473(5)
C1AN1AC12
O1AC1AN1
O1AC1AC2
N1AC1AC2
C3AC2AC1
C4AC3AC2
C3AC4AC5
N3AC5AC4
C5AN3AN2
C3AN2AN3
N2AC3AC2
N2AC3AC4
C4AC3AC2AC1
C12AN1AC1AC2
128.5(3)
124.4(3)
120.9(3)
114.7(3)
108.7(3)
131.5(3)
105.8(3)
110.4(3)
104.7(2)
112.8(3)
122.1(3)
106.4(3)
50.5(5)
C11AC6AC5AC4
N1AC1AC2AC3
C1AN1AC12AC17
ꢀ18.3(5)
ꢀ103.2(3)
162.8(3)
174.5(3)
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

150
E. A. Smith, C. Potter, Z. C. Kennedy, A. J. Puciaty, A. M. Acevedo-Jake, S. D. Hersey,
C. R. Metz, W. T. Pennington, D. G. VanDerveer, and C. F. Beam
Vol 47
Table 2
Crystallographic data, C17H14ClN3O 11c.
CCDC deposit number [14]
Color/shape
738,969
Yellow/chip
0.34 ꢃ 0.14 ꢃ 0.12
C17H14ClN3O
311.76
Crystal dimensions (mm)
Formula
Formula mass
T (K)
Crystal system
Space group
163
Monoclinic
P21/c
12.451(2)
9.642(2)
12.581(3)
104.884(7)
1459.8(5)
4
˚
a (A)
˚
b (A)
˚
c (A)
b(ꢁ)
3
˚
V (A )
Z
dcalc (g cmꢀ3
)
1.419
˚
k (A)
0.71073
0.267
648
l (mmꢀ1
F(000)
)
y range (ꢁ)
Reflections collected
2.70–25.15
9944
Miller indices
Unique reflections
ꢀ14 ꢅ h ꢅ 13, ꢀ10 ꢅ k ꢅ 11, ꢀ15 ꢅ l ꢅ 15
2605
1915
Unique reflections I > 2r(I)
Max and min transmission
Data, restraints, parameters
Final R indices I > 2r(I)
R indices all data
1.000, 0.932
2605, 0, 199
R1 ¼ 0.0613, wR2 ¼ 0.1425
R1 ¼ 0.0883, wR2 ¼ 0.1687
1.052
Goodness of fit on F2
˚
Largest diff peak and hole (e A
ꢀ3
)
0.322, ꢀ0.403
2.65 g (0.015 mol) dissolved in 40–60 mL of THF. After 3 h,
a solution of 0.0158 mol (5% molar excess) of substituted ben-
zoate ester dissolved in 25–35 mL of THF, was added, during
5 min, to the trilithiated intermediate 7, and the solution was
stirred overnight (N2) at room temperature. Finally, 100 mL of
3M hydrochloric acid was added all at once, followed by an
additional 100 mL of reagent grade ether, and the two-phase
mixture was separated, followed by extraction of the aqueous
layer with ether (2 ꢃ 50 mL). The combined organic fractions
were extracted with 25 mL of 5% sodium bicarbonate solution,
then 25 mL water. The resulting solution was dried (MgSO4),
decanted, and evaporated (if rotoevap. used, temperature of
water bath ꢂ40ꢁC). An oil usually resulted, which was taken
up in 50–75 mL of methanol followed by 6 mL of hydrazine
hydrate, 1 mL of acetic acid, and the solution heated under
reflux for 2–4 h. The resulting solution was allowed to evapo-
rate, and the resulting solid was recrystallized, usually from
common solvents to afford products 11a–l.
[13]: C, 65.02; H, 4.57; N, 13.38. Found: C, 64.97; H, 4.28;
N, 12.98.
2-[3-Phenyl-1H-pyrazol-5-yl]-N-phenylacetamide (11b). Com-
pound 11b was obtained in 31% yield, mp 222–224ꢁC (metha-
nol/benzene), from the two-step procedure for the condensa-
tion-cyclization of 6 and methyl benzoate. IR: 1668, 3195
1
cmꢀ1. H NMR (DMSO-d6): d 3.72 (s, 2H, CH2), 6.61 (s, 1H,
C4AH, pyrazole), 7.04 (t, 1H, ArH, J ¼ 7.5 Hz), 7.31–7.43
(m, 5H, ArH), 7.64 (d, 2H, ArH, J ¼ 7.5 Hz), 7.76 (d, 2H,
ArH, J ¼ 7.5 Hz), and 10.23 (NH). 13C NMR (DMSO-d6):
35.8, 102.6 (C4, pyrazole), 119.8, 124.0, 125.7, 128.2, 129.5,
132.6, 139.9, 168.4. LCMS, theor. exact mass, 277.12: exp.
(MþH)þ, 278.04. Anal. Calcd for C17H15N3O: C, 73.63; H,
5.45; N, 15.04. Found: C, 73.22; H, 5.47; N, 15.04.
2-[3-(3-Chlorophenyl)-1H-pyrazol-5-yl]-N-phenylacetamide
(11c). Compound 11c was obtained in 49% yield, mp 191–
194ꢁC (methanol), from the two-step procedure for the con-
densation-cyclization of 6 and methyl 3-chlorobenzoate. IR:
2-[3-(4-Chlorophenyl)-1H-pyrazol-5-yl]-N-phenylacetamide
(11a). Compound 11a was obtained in 34% yield, mp 234–
235ꢁC (methanol), from the two-step procedure for the con-
densation-cyclization of 6 and methyl 4-chlorobenzoate. IR:
753, 1655, 3132, and 3194 cmꢀ1 1H NMR (DMSO-d6): d
.
3.78 (s, 2H, CH2), 6.69 (s, 1H, C4AH, pyrazole), 7.06 (t, 1H,
ArH, J ¼ 7.8 Hz), 7.29–7.44 (m, 4H, ArH), 7.63 (d, 2H, ArH,
J ¼ 7.5 Hz), 7.76 (d, 2H, ArH, J ¼ 7.5 Hz), and 10.23 (s, 1H,
NH). 13C NMR (DMSO-d6): 34.59, 103.5 (C4, pyrazole),
119.5, 124.7, 125.7, 127.8, 129.1, 131.7, 134.5, 139.9. LCMS,
theor. exact mass, 311.08: exp. (MþH)þ, 312.01. Anal. Calcd
for C17H14 ClN3Oꢄ1/3 H2O [13]: C, 64.25; H, 4.65; N, 13.22.
Found: C, 64.34; H, 4.84; N, 13.04.
1
1651, 3217, and 3332 cmꢀ1. H NMR (DMSO-d6): d 3.78 (s,
2H, CH2), 6.63 (s, 1H, C4AH, pyrazole), 7.05 (t, 1H, ArH,
J ¼ 7.5 Hz), 7.31 (t, 2H, ArH, J ¼ 7.8 Hz), 7.45 (m, 2H,
ArH), 7.63 (d, 2H, ArH, J ¼ 7.8 Hz), 7.79 (m, 2H, ArH),
10.22 (s, 1H, NH), and 12.86 (s, 1H, NH). 13C NMR (DMSO-
d6): 31.37, 102.78 (C4, pyrazole), 119.8, 124.0, 127.4, 129.4,
139.8, 147.3, 174.1, 178.5. LCMS, theor. exact mass, 311.08:
exp. (MþH)þ 312.0. Anal. Calcd for C17H14 ClN3Oꢄ1/8 H2O
Single crystal X-ray structure determination. Yellow crys-
tals of C17H14ClN3O 11c were recrystallized from an ethanol-
water solution in order to give satisfactory crystals for X-ray
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

January 2010
Preparation of NH-Pyrazoleacetic Acid Anilides from Trilithiated Acetoacetanilide,
Select Aromatic Esters, and Hydrazine
151
determination. Crystal data for X-ray studies were collected at
20ꢁC on a Mercury CCD area detector coupled with a Rigaku
AFC8 diffractometer with graphite monochromated Mo-K
radiation. Data were collected in 0.5ꢁ oscillations in x with 40
s exposures. A sweep of data was done using x oscillations
from ꢀ40.0ꢁ to 90.0ꢁ at v ¼ 45ꢁ and / ¼ 0.0ꢁ; a second
sweep was performed using x oscillations from ꢀ30.0ꢁ to
80.0ꢁ at v ¼ 45ꢁ and / ¼ 90.0ꢁ. The crystal-to-detector dis-
tance was 27.7789 mm. Details of the data collection are
reported in Table 2. Data were collected, processed, and cor-
rected for Lorentz polarization and for absorption using Crys-
talClear (Rigaku) [15].
The nonhydrogen atoms were refined anistropically. Ideal
hydrogen atom coordinates for the rings containing C6 and
C12 (see numbering of atoms in ORTEP diagram, Fig. 2) were
calculated and the hydrogen atoms were allowed to ride on
their respective carbon atoms. The hydrogen atoms on N1, N2,
C2, and C4 were located by difference and then ideal coordi-
nates were calculated and these hydrogen atoms were allowed
to ride on their respective atoms. The temperature factors of
all hydrogen atoms were varied isotropically. Structure solu-
tion, refinement, and the calculation of derived results were
performed using the SHELX-97 [16] package of computer pro-
grams. Neutral atom scattering factors were those of Cromer
and Waber [16], and the real and imaginary anomalous disper-
sion corrections were those of Cromer [17].
142.2, 149.9, 172.2. LCMS, theor. exact mass 355.03: exp.
(MþH)þ, 355.98. Anal. Calcd for C17H14 BrN3O: C, 57.32; H,
3.96; N, 11.85. Found: C, 56.94; H, 3.89; N, 11.83.
2-[3-(4-Methoxyphenyl)-1H-pyrazol-5-yl]-N-phenylacetamide
(11g). Compound 11g was obtained in 40% yield, mp 201–
203ꢁC (methanol), from the two-step procedure for the con-
densation-cyclization of 6 and methyl 4-methoxybenzoate. IR:
1
1
1660, 3283 cmꢀ1. H NMR (CDCl3): d H NMR (DMSO-d6):
d 3.66 (s, 2H, CH2), 3.75 (s, 3H, OCH3), 6.47 (s, 1H, C4AH,
pyrazole), 6.94–7.05 (m, 3H, ArH), 7.24–7.31 (m, 2H, ArH),
7.58–7.67 (m, 4H, ArH) and 10.16 (s, NH). 13C NMR
(DMSO-d6): 36.01, 54.86, 78.36, 100.94 (C4, pyrazole), 113.8,
119.2, 123.1, 126.3, 128.4, 129.4, 138.9, 158.8, 167.8. LCMS,
theor. exact mass, 307.13: exp. (MþH)þ, 308.06. Anal. Calcd
for C18H17N3O2: C, 70.34; H, 5.58; N, 13.67. Found: C,
70.11; H, 5.55; N, 13.51.
2-[3-[4-(Dimethylamino)phenyl]-1H-pyrazol-5-yl]-N-
phenylacetamide (11h). Compound 11h was obtained in a
19% yield, mp 272–275ꢁC (DMF), from the two-step proce-
dure for the condensation-cyclization of 6 and methyl 4-dime-
thylaminobenzoate. IR: 1610, 1670, 3184 cmꢀ1 1H NMR
.
(DMSO-d6): d 2.92 (s, 6H, CH3), 3.67(s, 2H, CH2), 6.38 (s,
1H, C4AH, pyrazole), 6.72 (d, 2H, ArH, J ¼ 9.0 Hz), 7.02 (t,
1H, ArH, J ¼ 7.2 Hz), 7.27 (t, 2H, J ¼ 7.8 Hz, ArH), 7.55 (d,
2H, ArH, J ¼ 8.7 Hz), 7.62 (d, 2H, ArH, J ¼ 7.5 Hz), 8.17
(d, 2H, ArH), 10.09 (s, 1H, NH). 13C NMR (DMSO-d6): 36.5,
44.0, 87.6, 101.0 (C4, pyrazole), 113.0, 119.8, 123.9, 126.6,
129.4, 139.2, 149.7, 139.9, 150.5. LCMS, theor. exact mass,
320.38: exp. (MþH)þ, 321.09. Anal. Calcd for C19H20N4Oꢄ1/4
H2O [13]: C, 70.24; H, 6.36; N, 17.34. Found: C, 70.30; H,
6.40; N, 17.49.
2-[3-(4-Methylphenyl)-1H-pyrazol-5-yl]-N-phenylacetamide
(11d). Compound 11d was obtained in 40% yield, mp 196–
198ꢁC (methanol), from the two-step procedure for the con-
densation-cyclization of 6 and methyl 4-methylbenzoate. IR:
1
1338, 1660 cmꢀ1. H NMR (DMSO-d6): d 2.51 (s, 2H, CH3),
3.72 (s, 2H, CH2), 6.56 (s, 1H, C4AH, pyrazole), 7.05 (t, 1H,
ArH, J ¼ 7.5 Hz), 7.20–7.34 (m, 4H, ArH), 7.62–7.66 (m, 4H,
ArH), 10.22 (s, 1H, NH). 13C NMR (DMSO-d6): d 25.79,
26.23, 39.51, 54.04, 106.98 (C4, pyrazole), 124.6, 128.7,
130.4, 134.2, 134.4, 134.8, 142.3, 144.6, 173.3. LCMS, theor.
exact mass 291.14: exp. (MþH)þ, 292.08. Anal. Calcd for
C18H17N3Oꢄ1/2 H2O [13]: C, 71.90; H, 6.04; N, 13.99. Found:
C, 72.01; H, 6.26; N, 14.38.
2-[3-(3,5-Dimethylphenyl)-1H-pyrazol-5-yl]-N-phenylacetamide
(11i). Compound 11i was obtained in a 40% yield, 222–224ꢁC
(ethanol/benzene), from the two-step procedure for the conden-
sation-cyclization of 6 and methyl 3,5-dimethylbenzoate. IR:
1
1660, 3238 cmꢀ1. H NMR (DMSO-d6): d 2.29 (s, 6H, CH3),
3.38 (s, 2H, CH2), 6.55 (s, 1H, C4AH, pyrazole), 6.92 (s, 1H,
ArH), 7.05 (t, 1H, ArH, J ¼ 7.5 Hz), 7.31 (t, 2H, ArH, J ¼
7.5 Hz), 7.37 (s, 1H, ArH), 7.61 (s, 2H, ArH), 7.64 (d, 2H,
ArH, J ¼ 1.2 Hz), 10.19 (s, 1H, NH). 13C NMR (DMSO-d6):
21.7, 37.6, 102.5 (C4, pyrazole), 107.0, 112.7, 119.8, 123.5,
123.9, 129.4, 130.0, 138.6, 139.9, 160.8. LCMS, theor. exact
mass, 305.15: exp. (MþH)þ, 306.17. Anal. Calcd for
C19H19N3O: C, 74.73; H, 6.27; N, 13.76. Found: C, 74.34; H,
6.34; N, 13.66.
2-[3-(4-(1,1-Dimethylethyl)phenyl)-1H-pyrazol-5-yl]-N-
phenylacetamide (11e). Compound 11e was obtained in
37% yield, mp 262–265ꢁC (methanol), from the two-step pro-
cedure for the condensation-cyclization of 6 and methyl 4-
(1,1-dimethylethyl)benzoate. IR: 1676, 3128 cmꢀ1 1H NMR
.
(DMSO-d6): d 1.26 (s, 9H, CH3), 3.44 (s, 2H, CH2), 6.55 (s,
1H, C4AH, pyrazole), 7.03 (t, 1H, ArH, J ¼ 7.5 Hz), 7.29 (t,
2H, ArH, J ¼ 8.1 Hz), 7.40 (d, 2H, ArH, J ¼ 8.4 Hz), 10.20
(s, 1H, NH). 13C NMR (DMSO-d6): 26.6, 31.8, 35.0, 102.3
(C4, pyrazole), 113.1, 119.9, 123.9, 125.5, 125.2, 126.2, 129.4,
139.9. LCMS, theor. exact mass 333.18: exp. (MþH)þ,
334.10. Anal. Calcd for C20H23N3O: C, 75.65; H, 6.95; N,
12.60. Found: C, 75.28; H, 7.01; N, 12.54.
2-[3-(4-Aminophenyl)-1H-pyrazol-5-yl]-N-phenylacetamide
(11j). Compound 11j was obtained in a 32% yield, 178–180ꢁC
(ethanol), from the two-step procedure for the condensation-
cyclization of 6 and methyl 4-aminobenzoate. IR: 1662, 2777,
3322 cmꢀ1 1H NMR (DMSO-d6): d 3.62 (s, 2H, CH2), 5.32
.
(s, 1H, NH), 6.32 (s, 1H, C4AH, pyrazole), 6.53 (s, 2H, NH),
6.58 (d, 2H, ArH, J ¼ 7.2 Hz), 7.02 (t, 1H, ArH, J ¼ 7.5 Hz),
7.28 (t, 2H, ArH), 7.36 (d, 2H, ArH, J ¼ 8.7 Hz), 7.61 (d, 2H,
ArH, J ¼ 7.5 Hz), 10.18 (s, 1H, NH). 13C NMR (DMSO-d6):
39.5, 100.8 (C4, pyrazole), 113.2, 115.1, 119.8, 120.8, 121.7,
123.9, 125.9, 126.7, 129.4, 130.1, 139.9, 168.9. LCMS, theor.
exact mass, 292.34: exp. (MþH)þ 293.04. Anal. Calcd for
C17H16N4Oꢄ1/4 H2O [13]: C, 68.79; H, 5.60; N, 18.87. Found:
C, 68.85; H, 5.49; N, 18.26.
2-[3-(4-Bromophenyl)-1H-pyrazol-5-yl]-N-phenylacetamide
(11f). Compound 11f was obtained in 19% yield, mp 246–
249ꢁC (methanol), from the two-step procedure for the con-
densation-cyclization of 6 and methyl 4-bromobenzoate. IR:
1
1651, 3209 cmꢀ1. H NMR (DMSO-d6): d 3.44 (s, 2H, CH2),
6.54 (s, 1H, C4AH, pyrazole), 7.03 (d, 1H, ArH, J ¼ 8.3 Hz),
7.31 (t, 2H, ArH, J ¼ 5.4 Hz), and 7.57–7.62 (m, 4H, ArH)
and 10.20 (s, 1H, NH). 13C NMR (DMSO-d6): d 34.3, 102.6
(C4, pyrazole), 119.8, 124.0, 127.7, 129.4, 132.2, 139.0, 139.8,
2-[3-(3,4-Dimethoxyphenyl)-1H-pyrazol-5-yl]-N-phenylacetamide
(11k). Compound 11k was obtained in a 19% yield, 198–
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

152
E. A. Smith, C. Potter, Z. C. Kennedy, A. J. Puciaty, A. M. Acevedo-Jake, S. D. Hersey,
C. R. Metz, W. T. Pennington, D. G. VanDerveer, and C. F. Beam
Vol 47
200ꢁC (methanol), from the two-step procedure for the con-
[2] (a) Bouveault, L.; Bongert, A.Bull Soc Chim Fr 1902, 27,
1095; (b) Claisen, L. Ber Deutschen Chem Gesellschaft 1903, 36,
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Jones, R. G.; Mann, M. J. J Am Chem Soc 1953, 75, 4048.
[3] (a) Sviridov, S. I.; Vasil’ev, A. A.; Shorshnev, S. V. Tetra-
hedron 2007, 63, 12195; (b) Their compound 2b (d ¼ 103.5 ppm) rela-
tive to this report made the statement that the signals of the rest of the
carbon atoms were missing.
densation-cyclization of 6 and methyl 3,4-dimethoxybenzoate.
IR: 1655, 2931, 3193 cmꢀ1 1H NMR (DMSO-d6): d 3.68 (s,
.
2H, CH2), 3.78 (s, 3H, OCH3), 3.80 (s, 3H, OCH3), 5.28 (s,
1H, NH), 6.35 (s, 1H, C4AH, pyrazole), 6.54–6.76 (m, 3H,
ArH) 6.94–7.18 (m, 3H, ArH), 7.49–7.57 (m, 3H, ArH), and
9.22 (s, 1H, NH); 13C NMR (DMSO-d6): 37.9, 56.2, 87.5,
102.1 (C4, pyrazole), 109.4, 112.6, 118.1, 119.8, 123.9, 129.4,
139.9, 147.9, 149.6, 168.0. LCMS, theor. exact mass, 337.37:
exp. (MþH)þ 338.08. Anal. Calcd for C19H19N3O3ꢄ1/4 H2O
[13]: C, 66.75; H, 5.75; N, 12.29. Found: C, 67.11; H, 5.62;
N, 12.23.
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2-[3-(3-Chloro-4-methoxyphenyl)-1H-pyrazol-5-yl]-N-
phenylacetamide (11l). Compound 11l was obtained in a
30% yield, 215–218ꢁC (ethanol) from the two-step procedure
for the condensation-cyclization of 6 and methyl 3-chloro-4-
[6] (a) Huckin, S. N.; Weiler, L. Tetrahedron Lett 1972, 2405;
(b) Sandifer, R. M.; Bhattacharya, A. K.; Harris, T. M. J Org Chem
1981, 46, 2260; (c) Boatman, S.; Hauser, C. R. J Org Chem 1966,
31, 1785; (d) Boatman, S.; Harris, T. M.; Hauser, C. R. J Am Chem
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1
methoxybenzoate. IR: 1502, 1600, 1667, 2839, 3263 cmꢀ1. H
NMR (DMSO-d6): d 3.77 (s, 2H, CH2), 3.85 (s, 3H, CH3O),
5.41 (s, 1H, NH) 6.56 (s, 1H, C4AH, pyrazole), 7.03 (t, 1H,
ArH, J ¼ 7.2 Hz), 7.14 (d, 1H, ArH, J ¼ 8.4 Hz), 7.31 (t, 2H,
ArH, J ¼ 7.5 Hz), 7.60 (d, 1H, ArH, J ¼ 1.8 Hz), 7.69 (d,
2H, ArH, J ¼ 1.8 Hz), 7.80 (s, 1H, ArH), 12.74 (s, 1H, NH).
13C NMR (DMSO-d6): 26.2, 40.2, 56.8, 103.3 (C4, pyrazole),
113.7, 119.8, 122.0, 124.0, 125.6, 126.9, 129.4, 139.8, 154.5,
167.9. LCMS, theor. exact mass, 341.09: exp. (MþH)þ,
342.01. Anal. Calcd for C18H16ClN3O2: C, 63.25; H, 4.72; N,
12.29. Found: C, 62.91; H, 4.79; N, 12.19.
[7] (a) Schmidt, D.; Conrad, J.; Klaiber, I.; Beifuss, U. Chem
Commun 2006, 4732; (b) Lygo, B. Tetrahedron 1995, 51, 12859.
[8] Angel, A. J.; Finefrock, A. E.; French, K. L.; Hurst, D. R.;
Williams, A. R.; Rampey, M. E.; Studer-Martinez, S. L.; Beam, C. F.
Can J Chem 1999, 77, 94.
Acknowledgments. The authors thank the following sponsors:
the Research Corporation, the National Science Foundation
grants CHE # 9708014 and # 0212699 for Research at Undergrad-
uate Institutions, and the United States Department of Agricul-
ture, NRICGP # 2003-35504-12853. The College of Charleston
awarded single summer grants through its Summer Undergradu-
ate Research Forum (SURF-2008) to E. A. Smith (also 2009), A.
M. Acevedo-Jake, A. J. Puciaty, and Z. C. Kennedy.
[9] Hurst, D. R.; French, K. L.; Angel, A. J.; Williams, A. R.;
Rampey, M. E.; Guion, T. S.; Chan, K. W.; Kassis, C. M.; Studer-
Martinez, S. L.; Beam, C. F. J Heterocycl Chem 1998, 35, 1357.
[10] Downs, J. R.; Grant, S. P.; Townsend, J. D.; Schady, D. A.;
Pastine, S. J.; Embree, M. C.; Metz, C. R.; Pennington, W. T.; Bailey
Walsch, R. D.; Beam, C. F. Can J Chem, 2004, 82, 659.
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[12] Ramos, M.; Alkorta, I.; Elguero, J. Tetrahedron 1997, 53,
1403.
[13] The incorporation of water and other molecules in recrystal-
lized and pure azoles, especially pyrazoles, has been noted in many
investigations. While the 8:1 ratio of water:product for 1a is unlikely,
analytical crystals of 1a gave the combustion analysis presented. See
also: ref. 1d and references cited therein.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet