Synthesis and Rotational Isomerism of 1-Substituted Methyl (S)-[5-(2-Nitrophenyl)-1H-pyrazole-4-carbonyl]alaninates

Article abstract of DOI:10.1021/acs.joc.5b02467

Seven title compounds 12a-g and the (S)-prolinate analogue 13 were prepared in five steps from 2-nitrobenzoic acid (7). Reduction of the nitro group followed by derivatization of the so formed anilines 14 gave the N-alkyl-(15a-c), N-acyl-(16a,b and 19), and N-vinyl derivative 20. NMR spectra of (S)-alanine and (S)-proline derived compounds 12, 13, 14-16, 19, and 20 exhibited two sets of signals corresponding to pairs of conformational diastereomers. The free energy barriers of rotation, ΔG^?₂₉₈ = 82-86 kJ mol^-1, were determined by ¹H NMR for 12a, 12d, 12f, and 12g and evaluated by DFT calculations.

Full text of DOI:10.1021/acs.joc.5b02467

Article
pubs.acs.org/joc
Synthesis and Rotational Isomerism of 1‑Substituted Methyl (S)‑[5-(2-
Nitrophenyl)‑1H‑pyrazole-4-carbonyl]alaninates
†
†
‡,§
†
†,‡,§
Marta Pock
̌
aj,†
̌
Luka Senica, Karmen Stopar, Miha Friedrich, Uros
̌
Grose
̌
lj, Janez Plavec,
†
†,‡
,†,‡
̌
̌
Crtomir Podlipnik, Bogdan Stefane, and Jurij Svete*
†
Faculty of Chemistry and Chemical Technology, University of Ljubljana, Vecn
̌
a pot 113, SI-1000 Ljubljana, Slovenia
Centre of Excellence EN-FIST, Trg Osvobodilne fronte 13, SI-1000 Ljubljana, Slovenia
§National Institute of Chemistry, Hajdrihova 19, SI-1000 Ljubljana, Slovenia
S Supporting Information
‡
*
ABSTRACT: Seven title compounds 12a−g and the (S)-prolinate
analogue 13 were prepared in five steps from 2-nitrobenzoic acid (7).
Reduction of the nitro group followed by derivatization of the so
formed anilines 14 gave the N-alkyl-(15a−c), N-acyl-(16a,b and 19),
and N-vinyl derivative 20. NMR spectra of (S)-alanine and (S)-
proline derived compounds 12, 13, 14−16, 19, and 20 exhibited two
sets of signals corresponding to pairs of conformational diaster-
‡
eomers. The free energy barriers of rotation, ΔG
= 82−86 kJ
298
−
1
1
mol , were determined by H NMR for 12a, 12d, 12f, and 12g and
evaluated by DFT calculations.
1. INTRODUCTION
Various heterocyclic systems are important scaffolds, which
found a widespread use and application as building blocks,
reagents, and ligands in synthetic and medicinal chemistry,
1
(
organo)catalysis, and material science.
An important new approach to drug discovery involves the
application of protein epitope mimetic (PEM) technology. The
β-hairpin is an especially interesting naturally occurring scaffold
used by many proteins for biomolecular recognition and thus is
an attractive tool for mimetic design. Within this context, a
variety of bi- and tricyclic systems can be envisaged as hairpin
mimetics, such as D-Pro-L-Pro (A), azabicycloalkane amino
acids B, 4,6-disubstituted dibenzo[b,d]furans and 9H-xanthenes
C, and 2-(2′-(aminomethyl)-[1,1′-biphenyl]-2-yl)acetic acid
(D). The last one is a particularly interesting PEM molecule
and secondary structure stabilizing template. Though quite
flexible at first glance, it is conformationally constrained due to
the restricted rotation around the C−C bond connecting the
2
,3
Figure 1. Examples of known PEM templates (hairpin mimetics) A−
aryl residues (Figure 1).
2,3
D, potential PEM template 1, and its nitro-masked precursor 2.
Rotational isomerism describes the phenomenon of rotation
4
about a single bond in a molecule. Atropisomerism, described
5
first by Christie and Kenner in 1922, is a type of rotational
8
many reagents and catalysts in asymmetric synthesis and as a
(
conformational) axial chirality-associated isomerism in which
6
decisive factor in pharmacological properties of bioactive
̅
the isomers can be isolated. As defined arbitrarily by Oki, the
9
compounds. Nowadays, the majority of known axially chiral
condition for the existence of atropisomerism is, that one of the
isolated isomers has a half-life time of at least 1000 s.
Accordingly, the minimum free energy barrier should be 109.6
compounds are based on carbocyclic biaryls (e.g. BINAP,
kJ mol− at 350 K. From initial ’academic curiosity’, axial
1
7
Received: October 26, 2015
Published: December 9, 2015
chirality has recently been recognized as a fundamental basis for
©
2015 American Chemical Society
146
DOI: 10.1021/acs.joc.5b02467
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Article
Scheme 1
a
Reaction conditions: (i) BuLi, THF, − 78 °C; (ii) ClCO Me or CO , −78 → 20 °C; (iii) KCN, NaI, CuI, toluene, reflux; (iv) CDI, THF, r.t., then
2
2
MeO CCH CO K, MgCl , 60 °C; (v) DMFDMA, toluene, reflux; (vi) RNHNH ·HCl (10a−l), n-PrOH or n-BuOH, reflux; (vii) 2 M NaOH,
MeOH, 35 °C; (viii) CDI, MeCN, r.t., then (S)-AlaOMe·HCl (11a) or (S)-ProOMe·HCl (11b), NMM.
2
2
2
2
2
8
QINAP, BINOL, etc.), whereas the field of hetarene-based
Table 1. Experimental Data for Compounds 2a−h, 5a−l,
10
analogues is somewhat less explored.
Recently, we published a simple synthesis and some further
transformations of 1-substituted 5-(2-aminophenyl)-1-phenyl-
H-pyrazoles. In extension, we thought that 5-(2-amino-
12a−g, and 13
yield (%)
1
1
compound
R
2
5
12
13
1
phenyl)-1-phenyl-1H-pyrazole-4-carboxylic acid (1), available
from the nitro-masked precursor 2, might be an interesting
axially chiral PEM template (cf. Figure 1). Additional
motivation for this research was based on the literature search
2a, 5a, 10a, 12a, 13
2b, 5b, 10b, 12b
2c, 5c, 10c, 12c
2d, 5d, 10d, 12d
2e, 5e, 10e, 12e
2f, 5f, 10f, 12f
2g, 5g, 10g, 12g
2h, 5h, 10h
Ph
96
97
100
84
92
53
96
45
−
48
98
26
40
77
84
82
72
58
63
24
85
72
72
71
75
87
69
85
−
−
−
−
−
54
−
−
−
−
−
−
−
−
−
−
−
cyclohexyl
tert-butyl
2-pyridyl
(
SciFinder Scholar), which revealed that the majority of known
,5-diaryl-1H-pyrazole-4-carboxamides were biologically active.
For example, they are potent central nicotinic acetylcholine
2-chlorophenyl
2,4,6-trichlorophenyl
4-methoxyphenyl
2-bromophenyl
Me
1
1
2
receptor antagonists useful in treating small cell lung
1
3−16
17
cancer,
they act as CB1 and histamine H3 receptor
5i, 10i
1
8
19
antagonists, as cannabinoid receptor modulators, as
5j, 10j
2,2,2-trifluoroethyl
−
−
−
20
21
inhibitors of NHE-1, and as fungicides. Consequently, the
above reasons triggered our decision to synthesize some
derivatives of 1 and 2 to study their rotational isomerism.
Herein, we report the synthesis and rotational isomerism of
derivatives of 1 and 2 including experimental determination of
rotation barriers by NMR spectroscopy.
5k, 10k
CH
CO
2
Et
2
5l, 10l
6-phenylpyridazin-3-yl
butanol gave the desired pyrazole derivatives 5a−l in 24−98%
yields over two steps. These were then hydrolyzed with 2 M
NaOH in methanol at 35 °C and the carboxylic acids 2a−h
were finally coupled with L-AlaOMe (11a) and L-ProOMe
(11b) to give the corresponding amides 12a−g and 13 in 54−
87% yields (Scheme 1, Table 1).
2. RESULTS AND DISCUSSION
Starting compounds 3 and 4 were prepared in two steps from
1
1
2
-nitroacetophenone following the literature procedure.
1
Attempted preparation of the key-intermediates 2a and 5a via
lithiation/carboxylation of 3 and 4 failed, whereas Cu-catalyzed
cyanation of 4 gave the cyano compound 6 in only 18% yield
To our great delight (although quite expectedly), the H and
C NMR spectra of compounds 12 and 13 exhibited two sets
1
3
of signals in a ratio of ∼1:1. This was in agreement with the
proposed formation of a mixture of conformational diaster-
eomers, presumably due to slow rotation around the C(5)−
C(1′) bond (Figure 2). Unfortunately, attempts to separate the
conformational diastereomers of 12 and 13 by preparative (CC,
MPLC) and analytical (TLC, HPLC) chromatographic
techniques failed.
(Scheme 1, Table 1). Therefore, another synthetic approach
was explored. Masamune-Claisen condensation of 2-nitro-
benzoic acid (7), followed by treatment of the β-keto ester 8a
with N,N-dimethylformamide dimethylacetal (DMFDMA), and
cyclization of the intermediate enaminone 9a with mono-
substituted hydrazines 10a−l in refluxing 1-propanol or 1-
1
47
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Article
1
Figure 2. Partial H NMR spectrum of compound 12a (CDCl , 300 MHz) exhibiting two sets of signals corresponding to the (S,M)-isomer and the
3
(S,P)-isomer.
Scheme 2
a
Reaction conditions: (i) H , Pd−C, MeOH, r.t.; (ii) 2-naphthaldehyde, EtOH, r.t., then NaBH , MeOH, r.t.; (iii) H , Pd−C, MeOH, acetone or
2
4
2
isobutyraldehyde, r.t.; (iv) H , Pd−C, AcOH, Ac O, r.t.; (v) PhCOCl, pyridine, 0 °C → r.t.; (vi) OCN−CH CO Et (17), CH Cl , r.t.; (vii) tert-butyl
2
2
2
2
2
2
(S)-(3-oxopent-4-yn-2-yl)carbamate (18), CH Cl , 0 °C → r.t.
2 2
1
48
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Our inability to separate the conformational diastereomers
by chromatography was explainable at best by isomerization
around the chiral axis being slow on the NMR chemical shift
time scale, yet too fast for preparative separation. We then
decided to carry out reduction of the nitro group followed by
derivatization of the so formed aniline. We hoped that
increased steric hindrance by bulky N-substituents in addition
to possible intramolecular hydrogen bonding between the NH
and CO groups might slow down rotation around the C(5)−
C(1′) bond. Catalytic hydrogenation of nitro compounds 12a−
c in the presence of Pd−C in methanol furnished the
corresponding anilines 14a−c in 71−87% yields, whereas
reductive alkylation of 12b with acetone and isobutyraldehyde
furnished the N-alkylated anilines 15a and 15b in 59% and 61%
yield, respectively (Scheme 2, Table 2). Reductive alkylation of
N-benzoyl analogue 16b in 72% yield. Addition of 14b to ethyl
isocyanatoacetate (17) and to tert-butyl (S)-(3-oxopent-4-yn-2-
yl)carbamate (18) led to the corresponding urea-(19) and
enaminone derivative 20. NMR spectra of the products 14−16,
19, and 20 exhibited two sets of signals, however, we were again
not able to separate the isomers (Scheme 2, Table 2).
Although existence of two conformational diastereomers in
solution due to slow rotation of the nonsymmetrical 2-
nitrophenyl group seemed obvious, also slow rotation of
substituents at positions N(1) and C(4), as well as cis/trans-
isomerization of the carboxamido group had to be taken into
account. To clarify this issue, some more derivatives with
different substitution pattern were synthesized. N-Methyl
carboxamides 21a,b and the (S)-1-phenylethyl ester 22 were
obtained by coupling of 2a with the corresponding
nucleophiles, while (S)-1-aryl-5-phenyl-1H-pyrazole-4-
carbonyl)alaninates 25a−c were synthesized from ethyl
benzoylacetate (8b) following standard synthetic protocol
22
Table 2. Experimental Data for Compounds 14−16, 19, and
20
(
Scheme 3, cf. Scheme 1). NMR spectra of compounds
compd.
R
R′
yield (%)
a
a
a
21a,b, 23a−c, 24a−c devoid of a chiral center and NMR
spectra of (S)-alaninates 25a−c with symmetrical phenyl group
at position 5 and a chiral center at the side chain exhibited
single sets of signals. Diastereotopicity of nuclei was observed
only in NMR spectra of (S)-1-phenylethyl ester 22 with a
nonsymmetrical nitrophenyl group at position 5 and a chiral
center at the side chain. This indicated, that anisochronicity of
nuclei resulted only from the combination of chiral center and
chiral axis due to slow rotation of the 5-nitrophenyl group,
whereas other aforementioned isomerisations were not relevant
in this respect (Scheme 3).
1
1
1
1
1
1
1
1
1
2
4a
4b
4c
5a
5b
5c
6a
6b
9
Ph
c-C H
72
87
71
59
61
36
75
72
72
74
6
11
t-butyl
a
i-Pr
a
a
i-Bu
2-C H CH
2
1
0
7
Ph
Me
c-C H
Ph
a
6
11
a
a
a
0
a
Not applicable.
3
. Structure Determination. The structures of novel
compounds 2a−h, 5a−l, 12a−g, 13, 14a−c, 15a−c, 16a,b, 19,
1
4b with 2-naphthaldehyde and NaBH gave 15c in 36% yield.
20, 21a,b, 22, 23b,c, 24b,c, and 25a−c were determined by
4
1
13
Next, catalytic hydrogenation of 12a in a mixture of acetic acid
and acetic anhydride gave the acetylamino derivative 16a in
spectroscopic methods (IR, H and C NMR, and MS) and by
elemental analyses for C, H, and N. Compounds 2c, 2d, 2g, 5h,
5k, 13, 14c, 15b, 16b, 19, 20, 22, 23b,c, and 24b,c were not
75% yield, whereas benzoylation of the aniline 14b afforded the
Scheme 3
a
Reaction conditions: (i) CDI, MeCN, r.t.; (ii) add MeNH ·HCl, NMM, r.t.; (iii) add 2 M Me NH in MeOH, r.t.; (iv) add (S)-1-phenylethanol, r.t.;
2
2
(
v) DMFDMA, toluene, reflux; (vi) RNHNH ·HCl (10a,e) or 2-O NC H NHNH ·HCl (10m), n-PrOH, reflux; (vii) 2 M NaOH, MeOH, 35 °C;
2
2
6
5
2
(
viii) add (S)-AlaOMe·HCl (11a), NMM.
1
49
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Article
Figure 3. Conformational isomerism and torsion angles Φ1−Φ4 in compounds 5, 12, 14−16, 19−22, and 25.
1
Figure 4. Partial H NMR spectrum of 12f (DMSO-d , 300 MHz) at 298−383 K showing the singlets for the OMe group. The coalescence
6
temperature (T ) is around 365 K.
c
2
f,g
obtained in analytically pure form. Their identities were
confirmed by 13C NMR and/or EI-HRMS.
requirements for β-turn minetics.
Crystal structures of
compounds 4, 6, 5e, 5f, and 25b are depicted in the Supporting
The structures of compounds 4, 6, 5e, 5f, and 25b were
Information.
determined by X-ray diffraction, which unambiguously
confirmed axial chirality of these compounds. Unfortunately,
the crystal structures were not compliant with structural
Rotational isomerism of compounds 5, 12, 13, 14−16, and
23
19−25 in solution was studied by NMR. In CDCl and DMSO-
3
d6 solution, all pyrazole derivatives 5, 12, 13, 14−16, and 19−
1
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1
Table 3. Selected Thermodynamic Parameters for Compounds 12a, 12d, 12f, and 12g Determined by H NMR in DMSO-d
6
Using CTM and CLA Approach
compound
entry
parameter
Δν (s−1)a
12a
11.8
12d
12f
12g
1
2
3
4
5
6
7
8
9
3.1
10.5
23.3
365
12.0
26.6
431
0
−
1
kc (s
)
b
26.1
6.91
375
95.1
91.1
51.1
48.2
T (K)
423
c
‡
c
ΔG (kJ/mol)
93.3
80.2
80.3
96.0
93.0
0.50
82.7
94.8
95.0
62.8
59.8
c
‡
d
ΔG c (kJ/mol)
93.4
b
E (kJ/mol)
70.8
a
‡
e
ΔH (kJ/mol)
67.8
‡
e
ΔS (J/mol K)
−0.88
85.9
−1.65
82.3
−1.18
84.2
‡
b
ΔG
(kJ/mol)
2
98
k298 (s−1)
b
5.5 × 10
−3
2.31 × 10
−2
1.97 × 10
−2
1.08 × 10
−2
10
a
b
c
Δν is chemical shift difference for OMe of each diastereomer in DMSO-d at 298 K. Obtained from k and plot of ln k against 1000/T. From
0
6
c
‡
−3
d
‡
e
ΔG = 19.1 × 10 ·T ·(9.97 + log T − log|Δν |). From ΔG = RT·(23.76 + ln T − ln k). Obtained from plot of ln(k/T) against 1000/T.
c
c
c
0
T
Figure 5. Comparison of π → π* interactions in compounds 12d, 12f and 12a, 12g.
2
5 with at least one nonsymmetrical substituent exist as
group was chosen as the reference signal. The coalescence of signals
was not reached for 12a and 12g, while the signals for 12d and 12f
interconverting mixtures of conformational isomers, due to
rotation around the following single bonds (Figure 3): N(1)−
C(1″) bond (torsion angle Φ1), C(5)−C(1′) bond (torsion
angle Φ2), C(4)−C(4′) bond (torsion angle Φ3), and the
amide or ester bond (torsion angle Φ4). Single sets of signals in
the NMR spectra of compounds 2, 5, 21, 23, and 24 devoid of
a stereogenic center are in agreement with conformational
enantiomers and isochronous enantiotopic nuclei (Figure 3,
right). Accordingly, introduction of a chiral center at the side
chain in compounds 12, 13, 14−16, 19, 20, 22, and 25 should
induce diastereotopicity to nuclei. However, anisochronicity of
diastereotopic nuclei was observed only for compounds 12, 13,
1
coalesced at ∼375 K and ∼365 K, respectively. H NMR spectrum of
2
3
compound 12f in region 3.45−3.75 ppm is depicted in Figure 4.
1
On the basis of the above temperature dependent H NMR data,
the experimental free energy of activation for rotation at the
‡
temperature of coalescence, ΔG , was determined for compounds
c
1
2a, 12d, 12f, and 12g using coalescence temperature method
24−27
(CTM).
The rates of rotation at T were determined using the
c
1/2
‡
equation for symmetrical exchange, k = π·Δν /2 , whereas the ΔG
values were determined from the modified Eyring equation. The
results are summarized in Table 3 (Entries 1−4).
thermodynamic parameters for the above compounds were
determined by the complete line shape analysis method
c
0
c
25
2
3
Next,
2
4,25,27
(CLA).
The rates of isomerization were determined from the
1
4−16, 19, 20, and 22 with a nonsymmetrical 2-nitropenyl
group at position 5 (Figure 3, left), whereas in compounds
5a−c with a symmetrical phenyl group at position 5 the nuclei
28
modified Eyring equations for the intermediate and fast exchange.
The coalescence temperature (T ), free energy of activation for
c
2
‡
rotation, ΔG , and activation energy for rotation (isomerization), E ,
were determined from Arrhenius plot of ln k against 1000/T. Since
the relative proportion of the two rotamers was close to 1:1, the ΔG
was determined from the modified Eyring equation for equally
The ΔH and the ΔS , were determined from
Arrhenius plot of ln(k/T) against 1000/T. The results are summarized
c
a
remained isochronous (Figure 3, right). In the presence of a
chiral center in compounds 25a−c, isochrony of nuclei is
explainable by fast rotation around Φ1, Φ3, and Φ4. This
clearly leads to the conclusion that diastereotopicity of nuclei in
compounds 12, 13, 14−16, 19, 20, and 22 is induced by a
combination of a chiral center at the side chain and chiral axis
formed by slow rotation around Φ2. On the other hand,
rotation around the other bonds is faster and, hence, does not
induce diastereotopicity (Figure 3).
29
‡
c
30,31
‡
‡
populated rotamers.
2
3
in Table 3 (Entries 5−10). The experimental free energy barriers of
‡
rotation at 298 K for compounds 12a, 12d, 12f, and 12g, ΔG
=
2
98
−1
82.3−85.9 kJ mol (Table 3, Entry 9), were below the arbitrary limit,
‡
−1
7
ΔG
> 93.5 kJ mol , defined by O
̅
ki.
H NMR data and thermodynamic parameters obtained by CLA
approach (cf. Table 3) reveal, that compounds 12d and 12f exhibit
300
1
4
. Experimental Determination of Rotational Barrier
1
1
through H NMR Data. The H NMR spectra of compounds 12a,
2d, 12f, and 12g were measured in DMSO-d6 at different
temperatures ranging from 298 to 393 K. The singlet for OMe
‡
1
slightly lower free energy of activation for rotation, ΔG
82.7 kJ mol at 298 K which is reflected in lower coalescence
= 82.3 and
298
−
1
1
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Article
Figure 6. GS1-global minimum (left) and GS2-local minimum (right) conformations of 12a.
temperature, Tc = 375 and 365 K (cf. Table 3). Accordingly,
Table 4. Total Energies and Relative Energies Obtained by
DFT Calculation for Compound 12a
−1
isomerization of 12d and 12f (k298 ∼ 0.02 s ) is faster than
−1
isomerization of 12a and 12g (k298 ≤ 0.01 s ). This difference is
explainable by the π → π* interactions between the aromatic rings.
Higher energy barrier of rotation in compounds 12a and 12g is in
agreement with stronger π → π* interactions between electron-poor
B3LYP/6−311+G(d,p)
a
EZPE (a.u.)
ΔE (kJ/mol) ΔG (kJ/mol)
GS1-global minimum
−1368.02465
−1368.02453
−1367.98766
−1367.98766
−1367.98303
−1367.98966
−1367.99265
−1367.99629
0
2-nitrophenyl group and electron-rich N-aryl groups. On the other
b
b
GS2-local minimum
0.33
97.1
97.1
0.32
hand, such π → π* interactions are weaker in compounds 12d and 12f
bearing electron-poor N-aryl groups (Figure 5).
TS1
TS2
TS3
TS4
TS5
TS6
104.2
104.2
119.1
102.4
86.5
5. Computational Determination of Rotational Barrier and
Modes of Rotation. Finally, the observations on the conformational
equilibrium were corroborated by quantum mechanical calculations at
the B3LYP/6-311G and B3LYP/6-311+G(d,p) level of theory in the
109.3
91.9
84.0
74.5
32
gas phase by means of the Gaussian 09 software. The stationary
points at the potential energy surface (PES) were determined and the
structure was characterized as minima or transition state based on the
number of imaginary frequencies (0 or 1). Pyrazole ring represented
the rigid part, while the aryl substituents and the amide moiety
exhibited conformational freedom. Torsion angles Φ1, Φ2, Φ3, and
Φ4 used to follow energetic changes induced by rotations are defined
on Figure 3. PES, obtained at the B3LYP/6-311G level of theory,
revealed the (P,S)-conformer as the GS1-global minimum with the
lowest energy and the (M,S)-conformer as the GS2-local minimum,
optimized with the B3LYP/6-311+G(d,p) level of theory, which is
marginally (0.33 kJ/mol) higher in energy in the gas phase. This result
is in excellent agreement with the experimental value, ΔG = 0.30 kJ/
75.6
a
Zero-point energy corrected values (EZPE) of B3LYP/6-311+G-
b
(d,p). A 53:47 ratio of conformational diastereomers of 12a in CDCl
3
at 298 K corresponds to energy difference, ΔG298 = 0.30 kJ/mol.
ring is for ΔE = 17.4 kJ/mol higher in energy than that of the
resonance stabilized amide bond. The obtained data support
conformational change form [GS1] to [GS2] via TS4 with ΔG
=
2
98
1
02.4 kJ/mol rotational barrier that is in fair agreement with the
experimental value.
2
98
6
. CONCLUSION
1
mol, determined by H NMR from the 53:47 ratio of conformational
In summary, methyl (1-substituted-5-(2-nitrophenyl)-1H-pyr-
azole-4-carbonyl)-L-alaninates 12a−g and their 5-(2-amino-
phenyl) analogues 14−16, 19, and 20 were prepared as
potential PEM templates in 4−6 steps from 2-nitrobenzoic acid
diastereomers of 12a in CDCl at 298 K. The PES scan also revealed
3
four possible transition state conformations. TS1 and TS2 correspond
to the conversion of [GS1] ↔ [TS1] ↔ [GS2] ↔ [TS2] ↔ [GS1] via
rotation around Φ1 and Φ2. They are of the same geometry and
energy ΔE is located 97.1 kJ/mol above the GS1. TS3 and TS4 were
found during simultaneous rotation of the nitrophenyl substituent
(
7). NMR spectra of compounds 12, 13, 14−16, 19, and 20
exhibit two sets of signals, which are due to slow rotation of 2-
nitrophenyl group. The axial chirality of these compounds was
additionally confirmed by their crystal structures. The
(
Φ2) and the amide side chain (Φ3). The respective energies (ΔE) of
TS3 and TS4, 109.3, and 91.9 kJ/mol, indicated that TS4 was 17.4 kJ/
mol more stable than TS3. Finally, TS5 and TS6 were identified upon
experimental free energy of rotation at T and at 350 K was
c
3
60° scan of the amide bond dihedral (Φ4) in the GS1-global
1
determined by H NMR for compounds 12a, 12d, 12f, and
minimum conformation. The sum of three bond angles around the
amide nitrogen (an index of sp character) in TS5 and TS6 was
3
33
12g. Our inability to separate the isomers is explainable by the
3
‡
3
39.7° and 334.6°, respectively. This indicated strong sp character on
experimental value for free energy of rotation, ΔG 298 = 82−86
−
1
‡
the amide nitrogen in allocated transition states TS5 and TS6. The
kJ mol , which is below the arbitrary limit, ΔG
> 93.5 kJ
3
00
−1
7
evaluated amide bond rotational barrier for the compound 12a (ΔE =
̅
mol , defined by Oki. Evaluation of the conformational
7
5.6 kJ/mol) was in the range of expectancy according to the literature
freedom in derivative 12a by DFT method was in agreement
with the experimental data indicating that rotational barrier of
nitrophenyl ring was higher in energy than that of resonance
stabilized amide bond. The experimental and computational
results also suggest that rotation of the nitrophenyl group
34
data. The fully optimized ground-state structures (GS1 and GS2) of
1
2a at B3LYP/6-311+G(d,p) level are shown in Figure 6. Total and
relative energies for 12a obtained by DFT calculations are given in
Table 4. The PES scans (obtained at the B3LYP/6-311G level of
theory) and geometries of transition states TS1−TS6 (optimized at
the B3LYP/6-311+G(d,p) level of theory) are given in the Supporting
Information.
(
atropisomerization) occurs in a molecular gear-type process
through simultaneous rotation of the 1-aryl, 5-(2-nitrophenyl),
and 4-carboxamido group. In terms of PEM, title compounds
are too rigid to be good mimics; however, increased flexibility
Thus, evaluation of the conformational freedom in derivative 12a by
DFT method demonstrated that the rotational barrier of nitrophenyl
1
52
DOI: 10.1021/acs.joc.5b02467
J. Org. Chem. 2016, 81, 146−161

The Journal of Organic Chemistry
Article
induced by replacement of the amino and carboxy groups with
aminomethyl and carboxymethyl groups could make the
template 1 a better β-turn mimic.
dried for 20 min over anh. Na
evaporated in vacuo to give 8a. Yield: 1.58 g (70%) of yellow oil. H
2
SO
4
, filtered, and the filtrate was
1
NMR (500 MHz, CDCl ) δ 3.73 (3H, s); 3.90 (2H, s); 7.53 (1H, dd, J
3
=
7.5, 1.3 Hz); 7.65 (1H, ddd, J = 8.1, 7.5, 1.2 Hz); 7.78 (1H, td, J =
.5, 1.3 Hz); 8.18 (1H, dd, J = 8.1, 1.2 Hz). 13C NMR (126 MHz,
CDCl ) δ 48.7, 52.5, 124.3, 128.1, 131.0, 134.6, 136.7, 145.3, 167.1,
7
7. EXPERIMENTAL SECTION
3
+
1
(
94.6. m/z (ESI) = 224 (MH ). m/z (HRMS) Found: 224.0556
7.1. General Methods. Melting points were determined on a
+
MH ). C H NO requires: m/z = 224.0565. ν (ATR) 2955, 1740
Kofler micro hot stage and on an automated melting point system.
The NMR spectra were recorded in CDCl and DMSO-d using TMS
10 10 5 max
−1
(
CO), 1526, 1437, 1345, 1203, 987, 699 cm .
3
6
7
.4. General Procedure for the Synthesis of 1-Substituted
as the internal standard on a 300 or 500 MHz instrument at 300 and
00 MHz for 1H and at 75.5 and 126 MHz for C nucleus,
13
Methyl 5-(2-nitrophenyl)-1H-pyrazole-4-carboxylates 5a−l. A
mixture of 8a (0.67 g, 3 mmol), anh. toluene (10 mL), and DMFDMA
5
respectively. Optical rotations were measured on polarimeter using 1
mL cell with a 10 cm path lenghth. Mass spectra were recorded on
TOF LC/MS spectrometer and IR spectra on a FTIR ATR
spectrophotometer. Microanalyses were performed by combustion
analysis on a CHN analyzer. Catalytic hydrogenations were carried out
on a hydrogenation apparatus (500 mL), always at room temperature
(0.5 mL, 3.3 mmol) was stirred under reflux for 4 h and volatile
components were evaporated in vacuo to give the crude enaminone 9
as a brown oily residue. The residue was dissolved in 1-propanol (10
mL) or 1-butanol (10 mL), hydrazine derivative 10a−l (3.6 mmol)
and 37% hydrochloric acid (6 drops) were added, and the mixture was
stirred under reflux for 3−32 h. Volatile components were evaporated
in vacuo and the residue was purified by FC (EtOAc/hexanes).
Fractions containing the product were combined and evaporated in
vacuo to give the crude products 5a−l. The solid products 5a−f,i,j,l
were suspended in Et O or i-Pr O (15 mL), the suspensions were
under 4 bar of H . Column chromatography (CC), flash column
2
chromatography (FC), and dry-vacuum flash chromatography
(
DVFC) were performed on silica gel (particle size 35−70 μm). 2-
Nitrobenzoic acid (7), CDI, potassium monomethyl malonate,
DMFDMA, hydrazine derivatives 10a−l, (S)-α-amino acid esters
hydrochlorides 11a,b, isobutyraldehyde, IBCF, and ethyl isocyanatoa-
cetate (17) are commercially available. 4-Bromo-5-(2-nitrophenyl)-1-
2
2
stirred at r.t. for 1 h, and the precipitates were collected by filtration
and washed with Et O or i-Pr O (2 × 5 mL) to give the purified
2
2
11
compounds 5a−f,i,j,l. The oily products 5g,h,k were purified by CC
EtOAc/hexanes). Fractions containing the product were combined
and evaporated in vacuo to give the crude products 5g,h,k.
.4.1. Methyl 5-(2-nitrophenyl)-1-phenyl-1H-pyrazole-4-carbox-
phenyl-1H-pyrazole (4) and tert-butyl (S)-(3-oxopent-4-yn-2-yl)-
2
2
(
carbamate (18) were prepared according to the literature
procedures.
7
The temperature dependent NMR data were acquired on 300 MHz
NMR spectrometer equipped with 5 mm 1H/19F/X PFG ATB
ylate (5a). Prepared from 8a (1.08 g, 4.8 mmol), DMFDMA (0.75
mL, 5 mmol), and phenylhydrazine hydrochloride 10a (0.84 g, 5.8
mmol) in 1-propanol, reflux for 4 h, FC (EtOAc/hexanes, 1:2),
1
Broadband Probe at 298 K. H spectra were obtained with a 5000 Hz
sweep width, 3.7 s acquisition time, 9.0 μs (90°) pulse width, 15 s
delay time and 16 scans. Chemical shifts were referenced to the
residual solvent signal of DMSO-d at δ 2.50 ppm. Temperature-
trituration with Et O. Yield: 744 mg (48%) of white crystals; mp 124−
2
1
1
26 °C. H NMR (500 MHz, CDCl ) δ 3.69 (3H, s), 7.18−7.22 (1H,
3
6
H
m), 7.26−7.33 (5H, m), 7.53−7.60 (2H, m), 8.11−8.16 (1H, m), 8.18
dependent measurements were carried out between 313 and 393 K
with steps of 10 K.
(
1H, s). 13C NMR (126 MHz, CDCl ) δ 51.4, 113.5, 124.6, 125.0,
3
1
1
28.5, 129.1, 130.5, 132.6, 133.0, 138.6, 141.6, 142.2, 142.2, 149.1,
7
.2. 5-(2-Nitrophenyl)-1-phenyl-1H-pyrazole-4-carbonitrile
+
62.9. m/z (ESI) = 324 (MH ). m/z (HRMS) Found: 324.0984
(
6). A 10 mL Schlenk flask was charged with 4-bromo-5-(2-
11
+
(MH ). C H N O requires: m/z = 324.0984. (Found: C, 63.07; H,
nitrophenyl)-1-phenyl-1H-pyrazole (4) (1.72 g, 5 mmol), NaI
150 mg, 1 mmol), CuI (95 mg, 0.5 mmol), and KCN (390 mg, 6
17 14
3
4
3
.84; N, 13.04. C H N O requires: C, 63.16; H, 4.05; N, 13.00.);
(
17 13 3 4
νmax (ATR) 3123, 2953, 1712 (CO), 1528, 1503, 1351, 1239, 773
mmol), the flask was evacuated, and filled with argon. Anhydrous
toluene (5 mL) and N,N-dimethylethylenediamine (0.54 mL, 5 mmol)
were added, the mixture was refluxed under argon for 24 h, and cooled
to room temperature. Aqueous ammonia (25%, 10 mL) was added and
the product was extracted with EtOAc (3 × 10 mL). The combined
organic phases were dried over anh. sodium sulfate, filtered, and the
filtrate was evaporated in vacuo. The residue was purified by DVFC
−
1
cm .
7
.4.2. Methyl 1-cyclohexyl-5-(2-nitrophenyl)-1H-pyrazole-4-car-
boxylate (5b). Prepared from 8a (1.58 g, 7.1 mmol), DMFDMA (1.2
mL, 8 mmol), and cyclohexylhydrazine hydrochloride 10b (1.20 g, 8
mmol) in 1-propanol, reflux for 14 h, FC (EtOAc), trituration with
1
Et O. Yield: 1.43 g (63%) of yellowish crystals; mp 167−169 °C. H
2
NMR (500 MHz, CDCl ) δ 1.10−1.30 (3H, m); 1.64 (1H, br d, J =
(
silica gel, EtOAc−hexanes, 1:1). Fractions containing the product
3
1
2.4 Hz); 1.79−2.09 (6H, m); 3.62 (3H, s); 3.70 (1H, tt, J = 11.5, 4.1
were combined and evaporated in vacuo. The residue was further
purified by MPLC (silica gel, EtOAc−hexanes, 1:2). Fractions
containing the product were combined and evaporated in vacuo to
Hz); 7.34 (1H, dd, J = 7.5, 1.6 Hz); 7.70 (1H, td, J = 7.8, 1.6 Hz); 7.76
(
1H, td, J = 7.5, 1.4 Hz); 8.00 (1H, s); 8.23 (1H, dd, J = 8.1, 1.4 Hz).
1
3
1
C NMR (126 MHz, CDCl ) δ 25.1, 25.5, 25.5, 32.5, 33.3, 51.3, 59.3,
give 6. Yield: 255 mg (18%) of yellowish crystals; mp 131−134 °C. H
3
NMR (500 MHz, CDCl ) δ 7.18 (2H, dd, J = 8.2, 1.4 Hz); 7.28−7.34
111.9, 125.0, 125.2, 130.8, 132.0, 133.4, 140.9, 140.9, 149.2, 163.3. m/z
3
+
+
(
3H, m); 7.58 (1H, dd, J = 7.6, 1.4 Hz); 7.69 (1H, td, J = 8.2, 1.4 Hz);
(ESI) = 330 (MH ). m/z (HRMS) Found: 330.1450 (MH ).
requires: m/z = 330.1448. (Found: C, 62.01; H, 5.65;
N, 12.65. C17 requires: C, 62.00; H, 5.81; N, 12.76.); νmax
7
.79 (1H, td, J = 7.6, 1.1 Hz); 8.08 (1H, s); 8.11 (1H, dd, J = 8.2, 1.2
C H N O
17 20 3 4
13
Hz). C NMR (126 MHz, CDCl ) δ 94.7, 112.8, 122.4, 124.3, 124.6,
H N O
19 3 4
3
−1
1
=
25.6, 129.1, 129.4, 131.7, 132.6, 134.1, 137.9, 142.6, 143.9. m/z (ESI)
(ATR) 2939, 2860, 1710 (CO), 1523, 1349, 1214, 782 cm .
7.4.3. Methyl 1-tert-butyl-5-(2-nitrophenyl)-1H-pyrazole-4-car-
boxylate (5c). Prepared from 8a (0.67 g, 3 mmol), DMFDMA (0.5
mL, 3.3 mmol), and tert-butylhydrazine hydrochloride 10c (0.47 g, 3.8
mmol) in 1-butanol, reflux for 32 h, FC (EtOAc/hexanes, 1:1),
+
+
291 (MH ). m/z (HRMS) Found: 291.0876 (MH ). C H N O
16 11 4 2
requires: m/z = 291.0877. (Found: C 65.82, H 3.28, N 18.87.
C H N O ·1/8H O requires: C 65.69, H 3.53, N 19.15.); ν
max
1
6
10
4
2
2
−1
(
ATR) 3130, 2232 (CN), 1524, 1496, 1347, 759, 691 cm .
.3. Synthesis of Methyl 3-(2-nitrophenyl)-3-oxopropanoate
8a). CDI (1.79 g, 11 mmol) was added to a solution of 2-nitrobenzoic
trituration with i-Pr O. Yield: 0.26 g (26%) of yellowish crystals; mp
7
2
1
(
106−108 °C. H NMR (500 MHz, CDCl ) δ 1.47 (9H, s, t-Bu), 3.59
3
acid (7) (1.68 g, 10 mmol) in acetonitrile (25 mL) and the mixture
was stirred at r.t. for 1 h. Then, a solid well homogenized mixture of
(3H, s), 7.40 (1H, dd, J = 7.4, 1.7 Hz), 7.66 (1H, td, J = 7.8, 1.7 Hz),
7.71 (1H, td, J = 7.5, 1.5 Hz), 7.96 (1H, s), 8.24 (1H, dd, J = 8.0, 1.5
Hz). 13C NMR (126 MHz, CDCl
) δ 30.7, 51.2, 63.2, 113.2, 125.0,
128.2, 130.5, 132.6, 133.0, 139.7, 141.1, 148.4, 163.3. m/z (ESI) = 304
powdered anh. MgCl (0.95 g, 10 mmol) and potassium monomethyl
3
2
malonate (2.34 g, 15 mmol) was added, and the mixture was stirred at
+
+
7
0 °C for 90 h. Volatile components were evaporated in vacuo, the
(MH ). m/z (HRMS) Found: 304.1294 (MH ). C H N O
15 18 3 4
residue was taken up in EtOAc (50 mL), and the so formed
requires: m/z = 304.1292. (Found: C, 59.70; H, 5.56; N, 13.77.
C H N O requires: C, 59.40; H, 5.65; N, 13.85.); ν (ATR) 2986,
suspension washed with 1 M NaHSO (3 × 50 mL), saturated aq.
4
15 17
3
4
max
−1
NaHCO (3 × 50 mL), and brine (70 mL). The organic phase was
2952, 1707 (CO), 1519, 1341, 1213, 1149, 1020, 758 cm .
3
1
53
DOI: 10.1021/acs.joc.5b02467
J. Org. Chem. 2016, 81, 146−161

The Journal of Organic Chemistry
Article
7
.4.4. Methyl 5-(2-nitrophenyl)-1-(2-pyridyl)-1H-pyrazole-4-car-
133.1, 133.6, 137.9, 142.2, 143.3, 148.9, 163.0. m/z (ESI) = 402, 404
+
+
boxylate (5d). Prepared from 8a (0.67 g, 3 mmol), DMFDMA (0.5
mL, 3.3 mmol), 2-hydrazinopyridine 10d (0.41 g, 3.8 mmol), and 37%
hydrochloric acid (6 drops) in 1-butanol, reflux for 24 h, FC (EtOAc/
(MH ). m/z (HRMS) Found: 402.0082 (MH ). C H BrN O
17 13 3 4
requires: m/z = 402.0084. νmax (ATR) 2951, 1711 (CO), 1525,
−1
1497, 1436, 1347, 1232, 1137, 755, 730 cm .
hexanes, 1:1), trituration with i-Pr O. Yield: 0.38 g (40%) of yellowish
crystals; mp 137−139 °C. H NMR (500 MHz, CDCl ) δ 3.69 (3H,
s); 7.11 (1H, ddd, J = 7.4, 4.9, 1.1 Hz); 7.36 (1H, dd, J = 7.3, 1.7 Hz);
.60 (1H, td, J = 7.5, 1.7 Hz); 7.64 (1H, td, J = 7.5, 1.6 Hz); 7.76 (1H,
ddd, J = 8.3, 7.4, 1.9 Hz); 7.86 (1H, dt, J = 8.2, 1.0 Hz); 8.00 (1H, ddd,
J = 4.8, 1.8, 0.8 Hz); 8.20 (1H, s); 8.25 (1H, dd, J = 8.0, 1.5 Hz). 13
NMR (126 MHz, CDCl ) δ 51.6, 115.0, 116.6, 122.6, 124.5, 127.1,
29.9, 132.3, 133.0, 138.7, 142.4, 142.6, 147.7, 148.4, 151.7, 162.9. m/z
ESI) = 325 (MH ). m/z (HRMS) Found: 325.0933 (MH ).
7.4.9. Methyl 1-methyl-5-(2-nitrophenyl)-1H-pyrazole-4-carbox-
ylate (5i). Prepared from 8a (0.67 g, 3 mmol), DMFDMA (0.5 mL,
3.3 mmol), methylhydrazine 10i (0.17 g, 3.8 mmol), and 37%
hydrochloric acid (6 drops) in 1-propanol, reflux for 4 h, FC (EtOAc/
2
1
3
7
hexanes, 3:1), trituration with i-Pr O. Yield: 0.45 g (58%) of yellowish
2
1
C
crystals; mp 114−116 °C. H NMR (500 MHz, CDCl ) δ 3.63 (3H,
3
s); 3.72 (3H, s, 1-Me); 7.40 (1H, dd, J = 7.5, 1.5 Hz, 6′-H); 7.70 (1H,
td, J = 7.8, 1.5 Hz, 5′-H); 7.77 (1H, td, J = 7.6, 1.3 Hz, 4′-H); 7.97
3
1
(
+
+
13
(1H, s); 8.23 (1H, dd, J = 8.1, 1.3 Hz, 3′-H). C NMR (126 MHz,
C H N O requires: m/z = 325.0931. (Found: C, 59.29; H, 3.42;
CDCl ) δ 37.4, 51.3, 112.9, 124.8, 125.0, 130.9, 132.2, 133.5, 140.9,
1
6
13
4
4
3
+
N, 17.40. C H N O requires: C, 59.26; H, 3.73; N, 17.28.); ν
142.0, 148.9, 163.1. m/z (ESI) = 262 (MH ). m/z (HRMS) Found:
16
12
4
4
max
+
(
ATR) 3122, 2950, 1707 (CO), 1517, 1345, 1290, 1240, 781, 759
262.0825 (MH ). C H N O requires: m/z = 262.0822. (Found: C,
12
12
3
4
−
1
cm .
55.15; H, 4.03; N, 16.03. C H N O requires: C, 55.17; H, 4.24; N,
12 11 3 4
−1
7
.4.5. Methyl 1-(2-chlorophenyl)-5-(2-nitrophenyl)-1H-pyrazole-
16.09.); νmax (ATR) 2951, 1707 (CO), 1529, 1355, 1215, 757 cm .
7.4.10. Methyl 5-(2-nitrophenyl)-1-(2,2,2-trifluoroethyl)-1H-pyra-
zole-4-carboxylate (5j). Prepared from 8a (0.67 g, 3 mmol),
DMFDMA (0.5 mL, 3.3 mmol), 2,2,2-trifluoroethylhydrazine 10j
(0.43 g, 3.8 mmol), and 37% hydrochloric acid (6 drops) in 1-butanol,
4
(
(
-carboxylate (5e). Prepared from 8a (2.23 g, 10 mmol), DMFDMA
1.5 mL, 10 mmol), and 2-chlorophenylhydrazine hydrochloride 10e
1.97 g, 11 mmol) in 1-propanol, reflux for 24 h, DVFC (EtOAc/
hexanes, 1:2), trituration with Et O. Yield: 2.75 g (77%) of white
crystals; mp 113−117 °C. H NMR (500 MHz, CDCl ) δ 3.70 (3H,
s); 7.20 (1H, td, J = 7.7, 0.9 Hz); 7.31 (1H, td, J = 7.9, 1.4 Hz); 7.35
2
1
reflux for 4 h, FC (EtOAc/hexanes, 1:1), trituration with i-Pr O. Yield:
3
2
1
0.67 g (63%) of yellowish crystals; mp 106−108 °C. H NMR (500
(
(
2H, dd, J = 7.8, 1.1 Hz); 7.45 (1H, dd, J = 8.0, 0.6 Hz); 7.50−7.57
MHz, CDCl ) δ 3.64 (3H, s); 4.41 and 4.70 (2H, 2 sextets, 1:1, J =
3
13
2H, m); 8.06−8.11 (1H, m); 8.22 (1H, s). C NMR (126 MHz,
16.2 Hz); 7.25 (1H, br d, J = 7.4 Hz); 7.75 (1H, td, J = 7.8, 1.6 Hz);
7.80 (1H, td, J = 7.5, 1.5 Hz); 8.08 (1H, s); 8.26 (1H, dd, J = 8.1, 1.5
CDCl ) δ 51.5, 113.1, 124.1, 124.6, 127.7, 129.6, 130.3, 130.6, 131.1,
3
Hz). 13C NMR (126 MHz, CDCl ) δ 50.9 (q, J = 35.6 Hz), 51.6,
1
3
32.1, 132.2, 133.0, 136.2, 142.3, 143.5, 148.8, 162.9. m/z (ESI) = 358,
60 (MH ). m/z (HRMS) Found: 358.0589 (MH ). C H ClN O
3
+
+
17
13
3
4
114.3, 122.6 (q, J = 280 Hz), 123.4, 125.2, 131.6, 132.8, 133.7, 142.4,
+
requires: m/z = 358.0589. (Found: C, 57.13; H, 3.29; N, 11.64.
C H ClN O requires: C, 57.07, H, 3.38, N, 11.75.); ν (ATR)
143.7, 148.8, 162.5. m/z (ESI) = 330 (MH ). m/z (HRMS) Found:
+
1
7
12
3
4
max
330.0694 (MH ). C H F N O requires: m/z = 330.0696. (Found:
13 11
3
3
4
−
1
2
950, 1712 (CO), 1522, 1498, 1346, 1237, 1136, 758 cm .
C, 47.71; H, 2.84; N, 12.56. C H F N O requires: C, 47.43; H, 3.06;
13 10 3 3 4
7
.4.6. Methyl 5-(2-nitrophenyl)-1-(2,4,6-trichlorophenyl)-1H-pyr-
N, 12.76.); ν (ATR) 2972, 1702 (CO), 1526, 1237, 1214, 1158,
785 cm .
max
−1
azole-4-carboxylate (5f). Prepared from 8a (2.23 g, 10 mmol),
DMFDMA (1.5 mL, 10 mmol), 2,4,6-trichlorophenylhydrazine 10f
7.4.11. Methyl 1-(2-ethoxy-2-oxoethyl)-5-(2-nitrophenyl)-1H-pyr-
(
2
2.33 g, 11 mmol), and 37% aq. HCl (0.7 mL) in 1-propanol, reflux for
4 h, DVFC (EtOAc/hexanes, 1:1), trituration with i-Pr O. Yield: 3.57
g (84%) of white crystals; mp 175−177 °C. H NMR (500 MHz,
CDCl ) δ 3.72 (3H, s); 7.31 (1H, d, J = 2.2 Hz); 7.33 (1H, dd, J = 7.5,
azole-4-carboxylate (5k). Prepared from 8a (0.67 g, 3 mmol),
DMFDMA (0.5 mL, 3.3 mmol), and ethyl 2-hydrazinoacetate
hydrochloride 10k (0.59 g, 3.8 mmol) in 1-butanol, reflux for 4 h,
2
1
1
3
FC (EtOAc/hexanes, 1:1). Yield: 0.23 g (24%) of yellow oil. H NMR
1.8 Hz); 7.44 (1H, d, J = 2.2 Hz); 7.54 (1H, td, J = 7.5, 1.6 Hz); 7.58
(500 MHz, CDCl ) δ 1.24 (3H, t, J = 7.1 Hz); 3.64 (3H, s); 4.17 and
3
(
1H, td, J = 7.8, 1.8 Hz); 8.20 (1H, dd, J = 7.9, 1.6 Hz); 8.28 (1H, s).
4.23 (2H, 2dq, 1:1, J = 10.8, 7.1 Hz); 4.56 and 4.93 (2H, 2d, 1:1, J =
17.4 Hz); 7.50 (1H, dd, J = 7.2, 1.8 Hz); 7.70 (1H, td, J = 7.6, 1.7 Hz);
1
3
C NMR (126 MHz, CDCl ) δ 51.7, 114.6, 123.1, 125.6, 128.8, 129.2,
3
1
1
4
31.1, 131.3, 133.1, 133.3, 135.5, 136.2, 137.0, 143.3, 143.8, 148.4,
7.73 (1H, td, J = 7.5, 1.5 Hz); 8.04 (1H, s); 8.21 (1H, dd, J = 7.9, 1.6
+
13
62.9. m/z (ESI) = 426, 428, 430 (MH ). m/z (HRMS) Found:
Hz). C NMR (126 MHz, CDCl
3
) δ 14.2, 51.5, 51.6, 62.3, 113.6,
+
25.9810 (MH ). C H Cl N O requires: m/z = 425.9810. (Found:
124.0, 124.9, 131.2, 132.6, 133.4, 141.8, 142.8, 149.0, 162.9, 167.3. m/z
17
11
3
3
4
+
+
C, 47.89; H, 2.34; N, 9.73. C H Cl N O requires: C, 47.86, H, 2.36,
(ESI) = 334 (MH ). m/z (HRMS) Found: 334.1030 (MH ).
requires: m/z = 334.1034. νmax (ATR) 2954, 1746
17
10
3
3
4
N, 9.85.); ν (ATR) 3094, 1709 (CO), 1530, 1352, 1230, 957,
C H N O
15 16 3 6
max
−
1
−1
8
07, 757 cm .
(CO), 1712 (CO), 1528, 1349, 1214, 1022, 783 cm .
7
.4.7. Methyl 1-(4-methoxyphenyl)-5-(2-nitrophenyl)-1H-pyra-
7.4.12. Methyl 5-(2-nitrophenyl)-1-(6-phenylpyridazin-3-yl)-1H-
pyrazole-4-carboxylate (5l). Prepared from 8a (0.67 g, 3 mmol),
DMFDMA (0.5 mL, 3.3 mmol), 3-hydrazino-6-phenylpyridazine 10l
(0.80 g, 3.8 mmol), and 37% hydrochloric acid (6 drops) in 1-butanol,
zole-4-carboxylate (5g). Prepared from 8a (0.67 g, 3 mmol),
DMFDMA (0.5 mL, 3.3 mmol), and 4-methoxyphenylhydrazine
hydrochloride 10g (0.63 g, 3.6 mmol) in 1-butanol, reflux for 16 h, FC
1
(
EtOAc/hexanes, 1:2). Yield: 0.868 g (82%) of brown oil. H NMR
reflux for 24 h, FC (EtOAc/hexanes, 1:1), trituration with i-Pr O.
2
1
(
500 MHz, CDCl ) δ 3.68 (3H, s); 3.76 (3H, s); 6.77−6.81 (2H, m);
Yield: 1.02 g (85%) of brownish crystals; mp 181−184 °C. H NMR
3
7
.19−7.23 (3H, m); 7.54−7.58 (2H, m); 8.10−8.13 (1H, m); 8.15
(500 MHz, CDCl ) δ 3.69 (3H, s); 7.45−7.49 (3H, m); 7.50 (1H, br
3
(
1H, s). 13C NMR (126 MHz, CDCl ) δ 51.4, 55.4, 113.2, 114.2,
dd, J = 7.6, 1.5 Hz); 7.64 (1H, td, J = 8.2, 1.5 Hz); 7.71 (1H, td, J =
3
1
1
3
2
24.6, 125.0, 126.4, 130.4, 131.7, 132.7, 133.0, 141.6, 141.9, 149.0,
7.5, 1.3 Hz); 7.92−7.96 (2H, m); 7.96 (1H, d, J = 9.2 Hz); 8.21 (1H,
+
13
59.4, 163.0. m/z (ESI) = 354 (MH ). m/z (HRMS) Found:
d, J = 9.2 Hz); 8.27 (1H, s); 8.28 (1H, br dd, J = 8.4, 1.1 Hz).
C
+
54.1098 (MH ). C H N O requires: m/z = 354.1084. ν (ATR)
NMR (126 MHz, CDCl ) δ 51.7, 115.8, 121.6, 125.0, 126.4, 126.7,
18
16
3
5
max
3
953, 1711 (CO), 1512, 1348, 1228, 1135, 1016, 834, 808, 781, 752
127.3, 129.2, 130.4, 130.4, 132.4, 133.4, 135.4, 142.9, 143.5, 147.8,
−1
+
cm .
154.4, 159.0, 162.6. m/z (ESI) = 402 (MH ). m/z (HRMS) Found:
+
7
.4.8. Methyl 1-(2-bromophenyl)-5-(2-nitrophenyl)-1H-pyrazole-
402.1197 (MH ). C H N O requires: m/z = 402.1197. (Found: C,
21
16
5
4
4
-carboxylate (5h). Prepared from 8a (446 mg, 2 mmol), DMFDMA
62.98; H, 3.50; N, 17.33. C H N O requires: C, 62.84; H, 3.77; N,
21 15 5 4
(
0.3 mL, 2 mmol), 2-bromophenylhydrazine 10h (492 mg, 2.2 mmol),
17.45.); νmax (ATR) 2952, 1716 (CO), 1535, 1350, 1244, 1131, 781,
740, 684 cm .
−1
and 37% aq. HCl (4 drops) in 1-propanol, reflux for 24 h, DVFC
1
(
(
(
EtOAc/hexanes, 1:2). Yield: 80 mg (72%) of brown oil. H NMR
500 MHz, CDCl ) δ 3.70 (3H, s); 7.23−7.27 (2H, m); 7.33−7.37
1H, m); 7.39−7.44 (1H, m); 7.51−7.58 (2H, m); 7.62−7.67 (1H,
7.5. General Procedure for the Synthesis of 1-Substituted 5-
(2-Nitrophenyl)-1H-pyrazole-4-carboxylic acids 2a−l. A mixture
of the ester 5 (2.7 mmol), methanol (30 mL), and 2 M aq. NaOH (5.9
mL, 11.8 mmol) was stirred at 50 °C for 24 h. Methanol was
evaporated in vacuo (40 mbar, 40 °C) and the aqueous solution was
3
13
m); 8.07−8.11 (1H, m); 8.23 (1H, s). C NMR (126 MHz, CDCl ) δ
5
3
1.5, 113.2, 122.1, 124.1, 124.6, 128.4, 129.6, 130.7, 131.3, 132.2,
1
54
DOI: 10.1021/acs.joc.5b02467
J. Org. Chem. 2016, 81, 146−161

The Journal of Organic Chemistry
Article
acidified with 1 M aq. HCl to pH ∼ 1. The precipitate was collected by
filtration and washed with water (2 × 5 mL) to give 2a−g.
Hz); 8.32 (1H, s); 12.75 (1H, br s). 13C NMR (126 MHz, DMSO-d6)
δ 114.8, 122.1, 125.3, 129.0, 129.1, 130.9, 131.6, 132.6, 133.7, 133.7,
135.4, 136.2, 142.8, 143.1, 147.6, 163.0. m/z (ESI) = 412, 414, 416
7
.5.1. 5-(2-Nitrophenyl)-1-phenyl-1H-pyrazole-4-carboxylic acid
+
+
(
2a). Prepared from 5a (3.23 g, 10 mmol). Yield: 2.977 g (96%) of
(MH ). m/z (HRMS) Found: 411.9653 (MH ). C H Cl N O
16 9 3 3 4
1
white crystals; mp 210−213 °C. H NMR (500 MHz, CDCl ) δ 7.19−
7
(
requires: m/z = 411.9653. (Found: C, 46.34; H, 1.90; N, 10.10.
C H Cl N O requires: C, 46.57; H, 1.59; N, 10.18.); ν (ATR)
3
.24 (1H, m); 7.25−7.32 (5H, m); 7.53−7.60 (2H, m); 8.09−8.15
1
6
8
3
3
4
max
13
−1
1H, m); 8.20 (1H, s); 9.86 (1H, br s). C NMR (126 MHz, CDCl )
2872, 1681 (CO), 1533, 1498, 1479, 1350, 1298, 856, 777 cm .
7.5.7. 1-(4-Methoxyphenyl)-5-(2-nitrophenyl)-1H-pyrazole-4-car-
boxylic acid (2g). Prepared from 5g (707 mg, 2 mmol). Yield: 651 mg
3
δ 113.0, 124.6, 124.8, 125.0, 128.6, 129.1, 130.6, 132.7, 133.1, 138.5,
+
1
42.5, 142.9, 148.7, 167.8. m/z (ESI) = 310 (MH ). m/z (HRMS)
+
1
Found: 310.0829 (MH ). C H N O requires: m/z = 310.0828.
(96%) of brown crystals; mp 115−120 °C. H NMR (500 MHz,
16
12
3
4
(
Found: C, 61.71; H, 3.64; N, 13.34. C H N O requires: C, 62.14;
CDCl ) δ 3.76 (3H, s); 6.76−6.80 (2H, m); 7.17−7.20 (2H, m);
16
11
3
4
3
H, 3.58; N, 13.59.); ν (ATR) 3412, 2876, 1672 (CO), 1532,
7.21−7.23 (1H, m); 7.53−7.58 (2H, m); 8.08−8.12 (1H, m); 8.17
max
−1
13
1
501, 1356, 783 cm .
(1H, s). C NMR (126 MHz, CDCl ) δ 55.4, 113.2, 114.2, 124.7,
3
7
.5.2. 1-Cyclohexyl-5-(2-nitrophenyl)-1H-pyrazole-4-carboxylic
125.0, 126.5, 130.3, 131.7, 132.8, 133.0, 142.0, 142.5, 148.8, 159.4,
+
acid (2b). Prepared from 5b (0.90 g, 2.7 mmol). Yield: 0.66 g
(
166.0. m/z (ESI) = 340 (MH ). m/z (HRMS) Found: 340.0938
1
+
78%) of white crystals; mp 235−238 °C. H NMR (500 MHz,
DMSO-d ) δ 1.07−1.19 (3H, m); 1.56 (1H, br s); 1.67−1.99 (6H, m);
.73 (1H, qt, J = 11.5, 4.0 Hz); 7.59 and 7.60 (1H, 2dd, 1;1, J = 7.6, 1.2
Hz); 7.80 and 7.84 (1H, 2td, J = 8.1 and 1.4 Hz); 7.88 and 7.90 (1H,
td, td, J = 7.5, 1.2 Hz); 7.92 and 7.99 (1H, 2s, 1:1); 8.23 and 8.26
1H, 2dd, J = 8.2, 1.3 Hz); 12.18 (1H, s). 13C NMR (126 MHz,
DMSO-d ) δ 24.7, 24.7, 32.2, 32.5, 58.1, 112.0, 124.2, 124.7, 131.1,
32.1, 133.8, 140.4, 148.7, 163.4. m/z (ESI) = 316 (MH ). m/z
HRMS) Found: 316.1294 (MH ). C H N O requires: m/z =
16.1292. (Found: C, 59.90; H, 5.28; N, 13.08. C H N O ·1/4H O
requires: C, 60.09; H, 5.52; N, 13.14.); ν (ATR) 2941, 2857, 1666
(MH ). C H N O requires: m/z = 340.0928. ν (ATR) 2929,
17
14
3
5
max
−
1
6
1703 (CO), 1513, 1441, 1350, 1301, 1240, 836, 767 cm .
7.5.8. 1-(2-Bromophenyl)-5-(2-nitrophenyl)-1H-pyrazole-4-car-
boxylic acid (2h). Prepared from 5h (402 mg, 1 mmol). Yield: 174
mg (45%) of white crystals; mp 224−227 °C. H NMR (500 MHz,
DMSO-d ) δ 7.30 (1H, br s, 1H of Ar); 7.38 (3H, dq, J = 7.3, 3.7 Hz);
3
1
2
(
6
6
7.65 (1H, td, J = 7.8, 1.6 Hz); 7.70 (1H, td, J = 7.6, 1.4 Hz); 7.78 (1H,
+
1
(
3
dd, J = 5.9, 3.4 Hz); 8.14 (1H, dd, J = 8.1, 1.3 Hz); 8.21 (1H, s); 12.61
+
13
16
18
3
4
(1H, br s). C NMR (126 MHz, DMSO-d ) δ 114.8, 122.1, 125.3,
6
16
17
3
4
2
129.0, 129.1, 130.9, 131.6, 132.6, 133.7, 133.7, 135.4, 136.2, 142.8,
+
max
143.1, 147.6, 163.0. m/z (ESI) = 388, 390 (MH ). m/z (HRMS)
−1
+
(
CO), 1531, 1346, 1224, 779, 695 cm .
.5.3. 1-tert-Butyl-5-(2-nitrophenyl)-1H-pyrazole-4-carboxylic
acid (2c). Prepared from 5c (0.53 g, 1.7 mmol). Yield: 0.51 g
Found: 387.9921 (MH ). C H BrN O requires: m/z = 387.9927.
16
11
3
4
7
(Found: C, 49.74; H, 2.69; N, 10.67. C H BrN O requires: C,
16 10 3 4
4
1
9.51; H, 2.60; N, 10.83.); νmax (ATR) 2867, 1707 (CO), 1525,
−
502, 1350, 1228, 1207, 1145, 775, 760 cm .
1
1
(
100%) of white crystals; mp 191−194 °C. H NMR (500 MHz,
DMSO-d ) δ 1.39 (9H, s); 7.62 (1H, dd, J = 7.5, 1.6 Hz); 7.77 (1H, td,
6
7.6. General Procedure for the Synthesis of Methyl (S)-(5-(2-
J = 7.8, 1.6 Hz); 7.82 (1H, td, J = 7.5, 1.4 Hz); 7.90 (1H, s); 8.22 (1H,
nitrophenyl)-1-substituted-1H-pyrazole-4-carbonyl)alaninates
12a−g and Methyl (S)-(5-(2-nitrophenyl)-1-phenyl-1H-pyra-
zole-4-carbonyl)prolinate (13). CDI (0.34 g, 2.1 mmol) was
added to a solution of carboxylic acid 2a−g (2 mmol) in anh. MeCN
(10 mL) and the mixture was stirred at r.t. for 2 h. Then, N-
methylmorpholine (0.22 mL) and (S)-amino ester hydrochloride
11a,b (2.2 mmol) were added and stirring at r.t. was continued for 40
h. Volatile components were evaporated in vacuo, the residue was
taken up in EtOAc (30 mL), and washed with 1 M HCl (3 × 20 mL),
dd, J = 8.2, 1.32 Hz); 12.07 (1H, s). 13C NMR (126 MHz, DMSO-d6)
δ 30.2, 62.6, 113.4, 124.7, 127.3, 130.9, 132.9, 133.4, 139.4, 140.5,
48.0, 163.4. m/z (ESI) = 290 (MH ). m/z (HRMS) Found:
90.1136 (MH ). C H N O requires: m/z = 290.1135. (Found: C,
8.15; H, 5.14; N, 14.27. C H N O requires: C, 58.13; H, 5.23; N,
+
1
2
5
1
+
14
16
3
4
14
15
3
4
4.53.); ν (ATR) 3459, 2989, 1694 (CO), 1521, 1354, 1231, 77
max
−
1
cm .
7
.5.4. 5-(2-Nitrophenyl)-1-(2-pyridyl)-1H-pyrazole-4-carboxylic
acid (2d). Prepared from 5d (1.55 g, 4.8 mmol). Yield: 1.30 g
aq. NaHCO (2 × 20 mL), and brine (20 mL). The organic phases
3
1
(
84%) of white crystals; mp 175−177 °C. H NMR (500 MHz,
DMSO-d ) δ 7.28 (1H, ddd, J = 7.4, 4.9, 1.1 Hz); 7.44 (1H, dd, J =
.1, 2.0 Hz); 7.70 (1H, td, J = 7.5, 1.9 Hz); 7.72 (1H, td, J = 7.4, 1.7
were combined, dried over anh. Na SO , filtered, and the filtrate was
2
4
evaporated in vacuo. The residue was purified by DVFC (silica gel,
EtOAc−hexanes) or MPLC (silica gel, EtOAc−hexanes). Fractions
containing the product were combined and evaporated in vacuo to
give 12a−g and 13.
6
7
Hz); 7.85 (1H, dt, J = 8.3, 1.0 Hz); 7.97 (1H, ddd, J = 8.9, 7.5, 1.9
Hz); 8.02 (1H, ddd, J = 4.8, 1.8, 0.8 Hz); 8.24 (1H, dd, J = 7.1, 2.0
Hz); 8.28 (1H, s); 12.60 (1H, s). 13C NMR (126 MHz, DMSO-d ) δ
7.6.1. Methyl (S)-(5-(2-nitrophenyl)-1-phenyl-1H-pyrazole-4-
carbonyl)alaninate (12a). Prepared from 2a (0.618 g, 2 mmol) and
methyl (S)-alaninate hydrochloride (11a) (0.31 g, 2.2 mmol), DVFC
(EtOAc−hexanes, 1:1). Yield: 0.567 g (72%) of white crystals; mp
6
1
1
(
15.5, 116.8, 123.1, 124.2, 126.5, 130.3, 132.3, 133.5, 139.5, 141.7,
42.6, 147.6, 147.9, 151.1, 163.2. m/z (ESI) = 311 (MH ). m/z
HRMS) Found: 311.0775 (MH ). C H N O requires: m/z =
11.0775. (Found: C, 57.78; H, 3.21; N, 17.89. C H N O requires:
+
+
15
11
4
4
2
2
1
3
178−179 °C; [α]
D
− 72.0 (c = 1.00, MeOH). H NMR (300 MHz,
15
10
4
4
C, 58.07; H, 3.25; N, 18.06.); ν (ATR) 2926, 1725 (CO), 1529,
CDCl
3
) δ 1.37 and 1.41 (3H, 2d, 1:1, J = 7.1 Hz); 3.72 and 3.73 (3H,
max
−1
1
435, 1349, 1238, 790, 774 cm .
2s, 1:1); 4.64 and 4.65 (1H, 2 quintets, 1:1, J = 7.2 Hz); 6.29 and 6.31
(1H, 2d, 1:1, J = 7.9 Hz); 7.20−7.33 (6H, m); 7.51−7.62 (2H, m);
7
.5.5. 1-(2-Chlorophenyl)-5-(2-nitrophenyl)-1H-pyrazole-4-car-
13
boxylic acid (2e). Prepared from 5e (1.79 g, 5 mmol). Yield: 1.58 g
8.03 and 8.06 (1H, 2s, 1:1); 8.07−8.14 (1H, m). C NMR (75.5
1
(
92%) of brownish crystals; mp 217−229 °C. H NMR (500 MHz,
MHz, CDCl ) δ 18.7, 18.8, 47.8, 47.9, 52.5, 52.5, 116.5, 116.6, 124.7,
3
DMSO-d ) δ 7.19 (1H, td, J = 7.7, 1.4 Hz); 7.27−7.38 (3H, m); 7.41−
124.8, 125.0, 125.1, 125.1, 125.1, 125.1, 128.4, 128.4, 129.1, 129.1,
130.4, 130.5, 132.9, 132.9, 133.0, 133.1, 138.7, 138.7, 138.8, 139.2,
140.1, 140.4, 149.1, 161.3, 161.4, 173.4, 173.5. m/z (ESI) = 395
6
7
.47 (1H, m); 7.47−7.53 (2H, m); 8.01−8.07 (1H, m); 8.23 (1H, s).
1
3
C NMR (126 MHz, DMSO-d ) δ 113.9, 124.3, 124.5, 127.6, 129.5,
6
+
+
1
1
(
30.3, 130.4, 131.0, 132.1, 132.1, 133.0, 136.3, 142.8, 143.3, 148.7,
64.2. m/z (ESI) = 344, 346 (MH ). m/z (HRMS) Found: 344.0433
MH ). C H ClN O requires: m/z = 344.0433. (Found: C, 56.19;
(MH ). m/z (HRMS) Found: 395.1354 (MH ). C H N O
20 19 4 5
+
requires: m/z = 395.1355. (Found: C, 60.78; H, 4.65; N, 14.12.
C H N O requires: C, 60.91; H, 4.60; N, 14.21.); ν (ATR) 3341,
+
16
11
3
4
20 18
4
5
max
H, 2.80; N, 12.26. C H ClN O requires: C, 55.91; H, 2.93; N,
1745 (CO), 1627 (CO), 1565, 1526, 1503, 1353, 1295, 1169,
16
10
3
4
−1
1
2.23.); νmax (ATR) 2865, 1709 (CO), 1526, 1504, 1229, 1206,
770 cm .
7.6.2. Methyl (S)-1-cyclohexyl-(5-(2-nitrophenyl)-1H-pyrazole-4-
−1
1
144, 777, 761 cm .
.5.6. 5-(2-Nitrophenyl)-1-(2,4,6-trichlorophenyl)-1H-pyrazole-4-
carboxylic acid (2f). Prepared from 5f (2.13 g, 5 mmol). Yield: 1.1 g
7
carbonyl)alaninate (12b). Prepared from 2b (0.631 g, 2 mmol) and
methyl (S)-alaninate hydrochloride (11a) (0.307 g, 2.2 mmol), DVFC
(EtOAc−hexanes, 2:1). Yield: 0.575 g (72%) of white crystals; mp
1
(
53%) of white crystals; mp 210−216 °C. H NMR (500 MHz,
2
2
1
DMSO-d ) δ 7.30 (1H, dd, J = 7.2, 1.8 Hz); 7.68−7.77 (2H, m); 7.83
196−198 °C; [α] − 57.8 (c = 0.50, MeOH). H NMR (500 MHz,
6
D
(
1H, d, J = 2.3 Hz); 8.00 (1H, d, J = 2.3 Hz); 8.23 (1H, dd, J = 7.9, 1.7
CDCl ) δ 1.10−1.30 (3H, m), 1.33 and 1.36 (3H, 2d, 1:1, J = 7.1 Hz);
3
1
55
DOI: 10.1021/acs.joc.5b02467
J. Org. Chem. 2016, 81, 146−161

The Journal of Organic Chemistry
Article
+
1
3
4
7
.63 (1H, br d, J = 12.5 Hz); 1.80−1.89 (3H, m); 1.90−2.06 (3H, m);
.66 (1H, tt, J = 11.8, 4.0 Hz); 3.70 and 3.71 (3H, 2s, 1:1); 4.58 and
.60 (1H, 2 quintets, 1:1, J = 7.2 Hz); 6.17 and 6.20 (1H, 2d, 1:1, J =
.3 Hz); 7.37 and 7.39 (1H, 2 dd, 1:1, J = 7.5, 1.5 Hz); 7.69 and 7.70
173.4, 173.5. m/z (ESI) = 429, 431 (MH ). m/z (HRMS) Found:
+
429.0958 (MH ). C H ClN O requires: m/z = 429.0960. (Found:
C, 56.04; H, 3.78; N, 13.24. C H ClN O requires: C, 56.02; H,
4.00; N, 13.07.); νmax (ATR) 3324, 1738 (CO), 1625 (CO),
20
18
4
5
20
17
4
5
−1
(
1H, 2 td, 1:1, J = 7.9, 1.5 Hz); 7.74 and 7.76 (1H, 2 td, 1:1, J = 7.5,
1566, 1524, 1501, 1352, 763 cm .
1
8
2
1
1
.5 Hz); 7.85 and 7.88 (1H, 2s, 1:1); 8.20 and 8.21 (1H, 2 dd, 1:1, J =
7.6.6. Methyl (S)-(5-(2-nitrophenyl)-1-(2,4,6-trichlorophenyl)-1H-
pyrazole-4-carbonyl)alaninate (12f). Prepared from 2f (825 mg, 2
mmol) and methyl (S)-alaninate hydrochloride (11a) (0.307 g, 2.2
mmol), DVFC (EtOAc−hexanes, 1:1). Yield: 687 mg (69%) of white
crystals; mp 186−190 °C; [α] − 36.0 (c = 0.50, MeOH). H NMR
(500 MHz, CDCl ) δ 1.40 and 1.42 (3H, 2d, 1:1, J = 7.4 Hz); 3.73 and
.1, 1.4 Hz). 13C NMR (126 MHz, CDCl ) δ 18.8, 18.9, 25.1, 25.1,
3
5.5, 25.6, 32.5, 33.4, 47.7, 47.8, 52.6, 52.6, 59.1, 59.1, 114.9, 115.0,
25.0, 125.1, 125.2, 125.2, 130.8, 130.9, 132.3, 132.3, 133.4, 133.4,
37.5, 137.8, 139.2, 139.5, 149.2, 149.2, 161.7, 161.7, 173.6, 173.7. m/z
2
2
1
D
+
+
(
ESI) = 401 (MH ). m/z (HRMS) Found: 401.1819 (MH ).
3
C H N O requires: m/z = 401.1822. (Found: C, 60.04; H, 5.98;
N, 13.93. C H N O requires: C, 59.99; H, 6.04; N, 13.99.); ν
3.73 (3H, 2s, 1:1); 4.64 and 4.65 (1H, 2 quintets, 1:1, J = 7.1 Hz); 6.45
and 6.48 (1H, 2d, 1:1, J = 7.3 Hz); 7.31 and 7.32 (1H, 2d, 1:1, J = 2.4
Hz); 7.37−7.43 and 7.37−7.43 (2H, 2m, 1:1); 7.52−7.61 and 7.52−
7.61 (2H, 2m, 1:1); 8.12−8.17 and 8.12−8.17 (1H, 2m, 1:1); 8.17 and
20
25
4
5
20
24
4
5
max
(
1
ATR) 3319, 2939, 2857, 1714 (CO), 1622 (CO), 1524, 1348,
−1
214, 782, 766 cm .
8.18 (1H, 2s, 1:1). 13C NMR (126 MHz, CDCl ) δ 18.7, 18.7, 48.0,
7
.6.3. Methyl (S)-1-tert-butyl-(5-(2-nitrophenyl)-1H-pyrazole-4-
3
carbonyl)alaninate (12c). Prepared from 2c (0.579 g, 2 mmol) and
methyl (S)-alaninate hydrochloride (11a) (0.31 g, 2.2 mmol), DVFC
4
1
1
8.1, 52.6, 52.6, 117.9, 118.0, 122.9, 123.0, 125.5, 125.5, 128.6, 128.7,
29.0, 129.0, 131.0, 131.1, 131.5, 131.7, 133.0, 133.1, 133.2, 133.2,
35.5, 135.5, 135.9, 136.0, 136.8, 136.8, 140.1, 140.5, 141.7, 141.9,
148.4, 148.4, 161.2, 161.2, 173.3, 173.5. m/z (ESI) = 497, 499, 501
(MH ). m/z (HRMS) Found: 497.0177 (MH ). C H Cl N O
requires: m/z = 497.0181. (Found: C, 48.25; H, 2.93; N, 11.15.
C H Cl N O requires: C, 48.26; H, 3.04; N 11.26.); ν (ATR)
344, 3065, 2951, 1720 (CO), 1650 (CO), 1618, 1572, 1555,
530, 1498, 1477, 1436, 1376, 1350, 1296, 1260, 1231, 1156, 1117,
044, 1009, 986, 959, 928, 885, 868, 854, 832, 822, 807, 784, 761, 749,
(
1
EtOAc−hexanes, 2:1). Yield: 0.532 g (71%) of white crystals; mp
22 1
D
54−156 °C; [α] − 48.3 (c = 0.80, MeOH). H NMR (500 MHz,
CDCl ) δ 1.29 and 1.31 (3H, 2d, J = 7.1 Hz, 1:1); 1.45 (9H, s); 3.67
+
+
3
20 16 3 4 5
and 3.68 (3H, 2s, 1:1); 4.53 and 4.54 (1H, 2 quintets, J = 7.2 Hz), 6.12
and 6.16 (1H, 2br d, 1:1, J = 7.3 Hz); 7.42 and 7.44 (1H, 2dd, 1:1, J =
20
15
3
4
5
max
7
7
.5, 1.6 Hz); 7.64 and 7.66 (1H, 2td, 1:1, J = 7.7, 1.6 Hz); 7.68 and
.70 (1H, 2td, 1:1, J = 7.5, 1.4 Hz); 7.81 and 7.83 (1H, 2s, 1:1); 8.19
3
1
1
7
13
and 8.20 (1H, 2dd, J = 8.0, 1.4 Hz). C NMR (126 MHz, CDCl ) δ
3
1
1
1
8.8, 18.9, 30.7, 30.7, 47.7, 47.7, 52.5, 52.6, 63.1, 63.1, 116.4, 116.5,
25.0, 125.0, 128.0, 128.1, 130.6, 130.7, 132.8, 132.9, 132.9, 133.0,
36.4, 136.7, 139.0, 139.4, 148.7, 148.7, 161.8, 161.8, 173.6, 173.7. m/z
−1
32, 708, 668, 652, 639, 614 cm .
7
.6.7. Methyl (S)-(1-(4-methoxyphenyl)-5-(2-nitrophenyl)-1H-pyr-
azole-4-carbonyl)alaninate (12g). Prepared from 2g (0.679 g, 2
mmol) and methyl (S)-alaninate hydrochloride (11a) (0.307 g, 2.2
+
+
(
ESI) = 375 (MH ). m/z (HRMS) Found: 375.1658 (MH ).
C H N O requires: m/z = 375.1663. (Found: C, 58.52; H, 5.83;
N, 14.43. C H N O requires: C, 57.75; H, 5.92; N, 14.96.); ν
18
23
4
5
mmol), DVFC (EtOAc−hexanes, 1:2). Yield: 720 mg (85%) of
18
22
4
5
max
22
brownish crystals; mp 127−131 °C; [α] − 52.4 (c = 0.50, MeOH).
D
(
1
ATR) 3308, 2984, 1751 (CO), 1627 (CO), 1520, 1341, 1201,
1
H NMR (500 MHz, CDCl ) δ 1.37 and 1.40 (3H, 2d, 1:1, J = 7.2
−
1
3
147, 757 cm .
Hz); 3.71 and 3.73 (3H, 2s, 1:1); 3.76 (3H, s); 4.64 and 4.64 (1H, 2
quintets, 1:1, J = 7.2 Hz); 6.35 and 6.39 (1H, 2d, 1:1, J = 7.4 Hz);
7
.6.4. Methyl (S)-(5-(2-nitrophenyl)-1-(2-pyridyl)-1H-pyrazole-4-
carbonyl)alaninate (12d). Prepared from 2d (0.621 g, 2 mmol) and
methyl (S)-alaninate hydrochloride (11a) (0.31 g, 2.2 mmol), DVFC
6
(
.76−6.80 and 6.76−6.80 (2H, 2m, 1:1); 7.16−7.20 and 7.16−7.20
2H, 2m, 1:1); 7.25−7.31 and 7.25−7.31 (1H, 2m, 1:1); 7.52−7.61
and 7.52−7.61 (2H, 2m, 1:1); 8.01 and 8.04 (1H, 2s, 1:1); 8.08−8.11
(
1
EtOAc−hexanes, 4:1). Yield: 0.593 g (75%) of white crystals; mp
22 1
D
44−146 °C; [α] − 37.5 (c = 0.60, MeOH). H NMR (500 MHz,
13
and 8.08−8.11 (1H, 2m, 1:1). C NMR (126 MHz, CDCl ) δ 18.6,
CDCl ) δ 1.30 and 1.33 (3H, 2d, 1:1 J = 7.1 Hz); 3.67 and 3.70 (3H,
3
3
1
1
1
1
8.7, 47.8, 47.8, 52.5, 52.5, 55.4, 55.4, 114.2, 114.2, 116.0, 116.1, 124.6,
24.7, 125.0, 125.1, 126.5, 126.5, 130.3, 130.4, 131.7, 131.7, 132.9,
32.9, 133.0, 133.1, 138.5, 138.8, 140.1, 140.5, 149.0, 149.0, 159.4,
2s, 1:1); 4.60 and 4.61 (1H, 2 quintets, 1:1, J = 7.1 Hz); 6.18 and 6.25
(
1H, 2d, 1:1, J = 7.2 Hz); 7.09 (1H, ddd, J = 7.4, 4.9, 1.0 Hz); 7.41 and
7
7
.43 (1H, 2dd, 1:1, J = 7.4, 2.0 Hz); 7.63 and 7.64 (1H, 2td, 1:1, J =
.5, 2.0 Hz); 7.65 and 7.68 (1H, 2td, 1:1, J = 7.5, 1.5 Hz); 7.74 (1H,
+
59.4, 161.4, 161.5, 173.4, 173.6. m/z (ESI) = 425 (MH ). m/z
+
(
HRMS) Found: 425.1456 (MH ). C H N O requires: m/z =
dddd, J = 8.2, 7.3, 1.8, 0.9 Hz); 7.86 (1H, dd, J = 8.2, 1.1 Hz); 7.98
1H, ddd, J = 4.9, 1.8, 0.9 Hz); 8.13 and 8.16 (1H, 2s, 1:1); 8.24 (1H,
21 21
4
6
4
25.1456. (Found: C, 59.37; H, 4.68; N, 12.96. C H N O requires:
C, 59.43; H, 4.75; N, 13.20.); νmax (ATR) 3339, 1758 (CO), 1626
(
21 20 4 6
13
dt, J = 8.3, 1.9 Hz). C NMR (126 MHz, CDCl ) δ 18.6, 18.8, 48.0,
3
−1
4
1
1
1
8.0, 52.6, 52.6, 116.3, 116.4, 118.7, 118.8, 122.4, 122.4, 124.5, 124.5,
26.6, 126.9, 130.2, 130.3, 132.4, 132.6, 133.1, 133.3, 138.7, 138.7,
39.2, 139.7, 140.4, 140.9, 147.5, 147.5, 149.0, 149.1, 151.8, 151.8,
(CO), 1514, 1254, 837, 753 cm .
7.6.8. Methyl (S)-(5-(2-nitrophenyl)-1-phenyl-1H-pyrazole-4-
carbonyl)prolinate (13). Prepared from 2a (0.618 g, 2 mmol) and
methyl (S)-prolinate hydrochloride (11b) (0.306 g, 2.2 mmol), FC
+
61.4, 161.5, 173.2, 173.4. m/z (ESI) = 396 (MH ). m/z (HRMS)
2
2
+
(
7
EtOAc/hexanes, 1:1). Yield: 0.450 g (54%) of greenish oil; [α] −
Found: 396.1298 (MH ). C H N O requires: m/z = 396.1302.
D
19
18
5
5
1
6.1 (c = 1.15, MeOH). H NMR (500 MHz, CDCl ) δ 1.86−2.01
(
Found: C, 57.72; H, 4.33; N, 17.71. C H N O requires: C, 57.72;
3
19
17
5
5
(
2H, m); 2.05−2.31 (2H, m); 3.46−3.90 (2H, m); 3.67 (3H, s); 4.50−
H, 4.33; N, 17.71.); νmax (ATR) 3341, 2947, 1753 (CO), 1620
−1
(
CO), 1562, 1519, 1476, 1349, 792, 759 cm .
4.62 (1H, m); 7.19−7.25 (2H, m); 7.26−7.32 (3H, m); 7.37−7.46
13
7
.6.5. Methyl (S)-1-(2-chlorophenyl)-5-(2-nitrophenyl)-1H-pyra-
(1H, m); 7.48−7.64 (2H, m); 7.94−8.06 (2H, m and 3-H). C NMR
zole-4-carbonyl)alaninate (12e). Prepared from 2e (0.687 g, 2
mmol) and methyl (S)-alaninate hydrochloride (11a) (0.307 g, 2.2
mmol), DVFC (EtOAc−hexanes, 1:2). Yield: 747 mg (87%) of white
(126 MHz, CDCl ) δ 25.3, 25.4, 29.1, 29.2, 48.8, 49.3, 52.2, 52.2, 59.0,
3
59.2, 117.4, 117.7, 124.6, 124.7, 125.0, 125.0, 125.0, 125.0, 128.3,
128.3, 129.1, 129.1, 130.2, 130.2, 133.0, 133.2, 133.3, 133.4, 138.6,
138.7, 139.2, 139.6, 140.0, 140.1, 148.5, 148.6, 162.5, 162.6, 172.4,
172.6. m/z (ESI) = 421 (MH ). m/z (HRMS) Found: 421.1506
(MH ). C H N O requires: m/z = 421.1506. ν (NaCl) 2966,
1742 (CO), 1620 (CO), 1528, 1500, 1351, 1198, 770, 694 cm .
7.7. General Procedure for the Preparation of Methyl 1-
Substituted (S)-(5-(2-Aminophenyl)-1H-pyrazole-4-carbonyl)-
alaninates 14a−d. A mixture of nitro compound 12 (1 mmol),
MeOH (50 mL), and 10% Pd−C (40 mg) was hydrogenated under 3
bar of H at r.t. for 4 h. The catalyst was removed by filtration through
a glass-sintered funnel and the filtrate was evaporated in vacuo. The
residue was purified by DVFC (silica gel, EtOAc−hexanes). Fractions
2
2
1
crystals; mp 135−138 °C; [α] − 57.7 (c = 1.05, MeOH). H NMR
D
+
(
500 MHz, CDCl ) δ 1.38 and 1.42 (3H, 2d, 1:1 J = 7.1 Hz); 3.72 and
3
+
3.74 (3H, 2s, 1:1); 4.65 and 4.65 (1H, 2 quintets, 1:1, J = 7.2 Hz); 6.35
22
21
4
5
max
−1
and 6.37 (1H, 2d, 1:1, J = 7.3 Hz); 7.20 and 7.21 (1H, 2t, 1:1, J = 7.7
Hz); 7.29−7.36 and 7.29−7.36 (2H, 2m, 1:1); 7.37−7.45 and 7.37−
7
8
.45 (2H, 2m, 1:1); 7.48−7.59 and 7.48−7.59 (2H, 2m, 1:1); 8.05 and
13
.07 (1H, 2t, 1:1, J = 2.1 Hz); 8.09 and 8.11 (1H, 2s, 1:1). C NMR
(
126 MHz, CDCl ) δ 18.7, 18.8, 47.8, 47.9, 52.5, 52.6, 116.1, 116.1,
3
1
1
1
24.0, 124.1, 124.6, 124.6, 127.6, 127.6, 129.6, 129.6, 130.3, 130.3,
30.6, 130.7, 131.0, 131.0, 132.2, 132.2, 132.3, 132.4, 133.0, 133.1,
36.2, 136.2, 139.1, 139.4, 141.8, 142.1, 148.8, 148.8, 161.2, 161.3,
2
1
56
DOI: 10.1021/acs.joc.5b02467
J. Org. Chem. 2016, 81, 146−161

The Journal of Organic Chemistry
Article
containing the product were combined and evaporated in vacuo to
give 14.
7.8. Synthesis of Methyl (S)-{1-cyclohexyl-5-[2-(alkylamino)-
phenyl]-1H-pyrazole-4-carbonyl}alaninates 15a,b. A mixture of
nitro compound 12b (400 mg, 1 mmol), MeOH (30 mL), acetone (20
mL, excess) or isobutyraldehyde (128 μL, 1.4 mmol), 2 M aq. HCl (1
drop, ∼20 mg), and 10% Pd−C (40 mg) was hydrogenated under 4
7
.7.1. Methyl (S)-(5-(2-aminophenyl)-1-phenyl-1H-pyrazole-4-
carbonyl)alaninate (14a). Prepared from 12a (0.394 g, 1 mmol).
22
1
Yield: 0.346 g (95%) of brown oil; [α] +13.6 (c = 1.10, MeOH). H
D
NMR (500 MHz, CDCl ) δ 1.21 and 1.26 (3H, 2d, 1:1, J = 7.1 Hz);
bar of H at r.t. for 8 h. The catalyst was removed by filtration through
2
3
3
.65 and 3.68 (3H, 2s, 1:1); 3.92 (2H, br s); 4.61 (1H, quintet, J = 7.2
a glass-sintered funnel and the filtrate was evaporated in vacuo. The
residue was purified by DVFC (EtOAc/hexanes, 1:2). Fractions
containing the product were combined and evaporated in vacuo to
give 15a,b.
7.8.1. Methyl (S)-{1-cyclohexyl-5-[2-(isopropylamino)phenyl]-1H-
pyrazole-4-carbonyl}-alaninate (15a). Prepared from 12b (400 mg,
Hz); 6.01 and 6.38 (1H, 2d, 1:1, J = 7.2 Hz); 6.71−6.85 (2H, m); 6.92
and 6.97 (1H, dd, J = 1.6, 7.7 Hz); 7.21−7.36 (6H, m); 8.25 and 8.26
(
1H, 2s, 1:1). 13C NMR (126 MHz, CDCl ) δ 18.2, 18.2, 47.8, 47.9,
3
5
1
1
1
2.3, 52.3, 113.4, 113.6, 115.9, 116.3, 118.0, 118.0, 119.0, 119.1, 124.2,
24.2, 127.9, 127.9, 128.9, 128.9, 131.00, 131.1, 131.6, 131.6, 138.5,
38.5, 139.1, 139.1, 142.0, 142.1, 145.3, 145.6, 161.9, 161.9, 173.0,
1
mmol) and acetone (20 mL, excess). Yield: 0.242 g (59%) of white
22
1
+
solid; mp 118−121 °C; [α] + 16.6 (c = 0.85, MeOH). H NMR
(500 MHz, CDCl ) δ 1.08 and 1.11 (6H, 2d, 1:1, J = 7.2 Hz); 1.14 and
73.2. m/z (ESI) = 365 (MH ). m/z (HRMS) Found: 365.1629
D
+
(
MH ). C H N O requires: m/z = 365.1614. ν (ATR) 3344,
3
20
21
4
3
max
−1
1.15 (3H, 2d, 1:1, J = 7.2 Hz); 1.17−1.26 and 1.17−1.26 (3H, 2m,
1
741 (CO), 1646 (CO), 1545, 1499, 1212, 760 cm . The
1:1); 1.59−1.65 and 1.59−1.65 (1H, 2m, 1:1); 1.75−1.84 and 1.75−
1.84 (4H, 2m, 1:1); 1.85−1.95 and 1.85−1.95 (1H, 2m, 1:1); 1.96−
2.05 and 1.96−2.05 (1H, 2m, 1:1); 3.21 and 3.21 (1H, 2 br s, 1:1);
3.61 and 3.62 (3H, 2s, 1:1); 3.63−3.72 and 3.63−3.72 (2H, 2m, 1:1);
4.53 and 4.53 (1H, 2 quintets, 1:1, J = 7.3 Hz); 6.01 and 6.06 (1H, 2d,
hydrochloride salt of 14a was obtained in the following way. The free
amine 14a (0.267 g, 0.7 mmol) was dissolved in EtOAc (15 mL), 2 M
HCl−EtOAc (1 mL, 2 mmol) was added, and the mixture was stirred
at r.t. for 16 h. The precipitate was collected by filtration and washed
with EtOAc (5 mL) to give 14a·HCl. Yield: 0.060 g (21%) of white
2
2
1
1:1, J = 7.3 Hz); 6.76−6.84 and 6.76−6.84 (2H, 2m, 1:1); 7.03 and
solid; mp 130−136 °C; [α] − 13.3 (c = 0.15, MeOH). H NMR
D
7
.09 (1H, 2 dd, 1:1, J = 7.6, 1.7 Hz); 7.39−7.44 and 7.39−7.44 (1H,
(
500 MHz, DMSO-d ) δ 1.35 and 1.40 (3H, 2d, 1:1, J = 7.2 Hz); 3.58
6
13
m); 8.14 and 8.14 (1H, 2s, 1:1). C NMR (126 MHz, CDCl ) δ 18.4,
3
and 3.66 (3H, s); 4.48 (1H, quintet J = 7.2 Hz); 6.87−6.93 (1H, m);
1
8.4, 22.6, 22.7, 23.0, 23.0, 25.1, 25.1, 25.5, 25.5, 25.5, 25.5, 32.9, 33.0,
6
8
1
1
1
.97−7.10 (1H, m); 7.26−7.57 (7H, m); 8.40 and 8.47 (1H, 2s, 1:1);
.93 and 9.02 (1H, 2br s, 1:1). 13C NMR (126 MHz, DMSO-d ) δ
33.4, 33.4, 43.9, 44.0, 47.8, 47.9, 52.3, 52.4, 58.3, 58.4, 111.8, 112.0,
6
1
1
12.7, 112.7, 115.8, 115.9, 117.1, 117.3, 131.0, 131.1, 132.0, 132.0,
6.9, 16.9, 47.9, 48.0, 52.0, 52.1, 116.9, 117.0, 125.5, 125.5, 125.7,
25.7, 128.2, 128.2, 128.8, 128.8, 130.7, 130.8, 132.3, 132.3, 138.8,
38.8, 140.0, 140.1, 163.2, 163.3, 172.6, 172.8. m/z (ESI) = 365
37.5, 137.6, 141.3, 141.3, 145.9, 146.1, 162.2, 162.2, 173.1, 173.2. m/z
+
+
(
ESI) = 413 (MH ). m/z (HRMS) Found: 413.2543 (MH ).
requires: m/z = 413.2547. (Found: C, 67.02; H, 8.11;
N, 13.61. C H N O requires: C, 66.96; H, 7.82; N, 13.58.); ν
max
+
+
C H N O
23 33 4 3
(
MH ). m/z (HRMS) Found: 365.1608 (MH ). C H N O
20 21 4 3
23
32
4
3
requires: m/z = 365.1614. (Found: C, 60.55; H, 5.18; N, 13.46.
C H ClN O requires: C, 59.92; H, 5.28; N, 13.98.); ν (ATR)
3
(
1
ATR) 3394, 3320, 2931, 2857, 1744 (CO), 1652 (CO), 1540,
2
0
21
4
3
max
−1
514, 1170, 747 cm .
−1
446, 1739 (CO), 1630 (CO), 1500, 1458, 1218, 766 cm .
.7.2. Methyl (S)-(5-(2-aminophenyl)-1-cyclohexyl-1H-pyrazole-
-carbonyl)alaninate (14b). Prepared from 12b (0.400 g, 1 mmol),
7
.8.2. Methyl (S)-{1-cyclohexyl-5-[2-(isobutylamino)phenyl]-1H-
pyrazole-4-carbonyl}-alaninate (15b). Prepared from 12b (400 mg,
mmol) and isobutyraldehyde (128 μL, 1.4 mmol). Yield: 0.260 g
7
4
1
FC (EtOAc/hexanes, 1:3). Yield: 0.323 g (87%) of white crystals; mp
1
CDCl ): 1.14−1.26 and 1.14−1.26 (3H, 2m, 1:1); 1.17 and 1.21 (3H,
22
D
(61%) of white solid; mp 107−110 °C; [α] + 17.6 (c = 0.50,
2
2
1
41−146 °C; [α] + 28.2 (c = 0.50, MeOH). H NMR (500 MHz,
1
D
MeOH). H NMR (500 MHz, CDCl ) δ 0.81 and 0.81 (6H, 2d, 1:1, J
3
3
=
6.8 Hz); 1.09 and 1.11 (3H, 2d, 1:1, J = 5.3 Hz); 1.12−1.22 and
2
1
1
3
d, 1:1, J = 7.1 Hz); 1.60−1.67 and 1.60−1.67 (1H, 2m, 1:1); 1.78−
.89 and 1.78−1.89 (4H, 2m, 1:1); 1.89−2.03 and 1.89−2.03 (2H, 2m,
:1); 3.64 and 3.66 (3H, 2s, 1:1); 3.72 (2H, br s); 3.52−3.68 and
.70−3.86 (1H, 2m, 1:1); 4.57 and 4.57 (1H, 2 quintets, 1:1, J = 7.1
1
1
.12−1.22 (3H, 2m, 1:1); 1.54−1.61 and 1.54−1.61 (1H, 2m, 1:1);
.68−1.83 and 1.68−1.83 (5H, 2m, 1:1); 1.84−2.02 and 1.84−2.02
(2H, 2m, 1:1); 2.82−2.92 and 2.82−2.92 (2H, 2m, 1:1); 3.48−3.56
and 3.48−3.56 (1H, 2 br s, 1:1); 3.57 and 3.57 (3H, 2s, 1:1); 3.63−
.73 and 3.63−3.73 (1H, 2m, 1:1); 4.48 and 4.49 (1H, 2 quintets, 1:1,
J = 7.2 Hz); 5.98 and 6.05 (1H, 2d, 1:1, J = 7.3 Hz); 6.70−6.83 and
Hz); 6.08 and 6.12 (1H, 2d, 1:1, J = 7.4 Hz); 6.83−6.95 (2H, 2m,
3
1
7
:1); 7.07 and 7.12 (1H, 2dd, 1:1, J = 7.6, 1.6 Hz); 7.33−7.38 and
13
.33−7.38 (1H, 2m, 1:1); 8.11 and 8.12 (1H, s). C NMR (126 MHz,
6
.70−6.83 (2H, 2m, 1:1); 6.99 and 7.05 (1H, 2 dd, 1:1, J = 7.6, 1.7
CDCl ) δ 18.3, 18.3, 25.0, 25.0, 25.4, 25.4, 32.8, 33.2, 47.7, 47.7, 52.3,
3
Hz); 7.34−7.40 and 7.34−7.40 (1H, m); 8.09 and 8.09 (1H, 2s, 1:1).
5
1
1
2.3, 58.3, 58.3, 113.1, 113.2, 115.7, 115.7, 115.9, 116.3, 119.0, 119.0,
30.6, 130.7, 131.6, 131.6, 137.6, 137.6, 140.7, 140.8, 145.4, 145.6,
13
C NMR (126 MHz, CDCl ) δ 18.2, 18.4, 20.2, 20.3, 20.3, 20.3, 25.0,
3
2
5
1
1
5.0, 25.4, 25.4, 25.4, 25.4, 27.8, 27.8, 32.8, 32.8, 33.3, 33.3, 47.7, 47.7,
1.2, 51.2, 52.2, 52.2, 58.2, 58.2, 111.0, 111.3, 112.4, 112.4, 115.7,
15.8, 117.1, 117.2, 130.6, 130.7, 131.9, 131.9, 137.4, 137.5, 141.0,
41.0, 146.8, 147.0, 162.0, 162.0, 172.9, 173.0. m/z (ESI) = 427
+
62.2, 162.2, 173.2, 173.3. m/z (ESI) = 371 (MH ). m/z (HRMS)
+
Found: 371.2075 (MH ). C H N O requires: m/z = 371.2078.
20
27
4
3
(
Found: C, 63.39; H, 7.29; N, 14.71. C H N O ·1/2H O requires:
20 26 4 3 2
C, 63.31; H, 7.17; N, 14.77.); νmax (ATR) 3394, 2928, 2857, 1747
+
+
(MH ). m/z (HRMS) Found: 427.2697 (MH ). C H N O
2
4
35
4
3
−1
(
CO), 1653 (CO), 1629, 1543, 1201, 1141, 828, 751 cm .
.7.3. Methyl (S)-(5-(2-aminophenyl)-1-tert-butyl-1H-pyrazole-4-
carbonyl)alaninate (14c). Prepared from 12c (0.374 g, 1 mmol), FC
requires: m/z = 427.2704. (Found: C, 66.65; H, 8.03; N, 12.81.
C H N O ·1/3H O requires: C, 66.64; H, 8.08; N, 12.95.); ν
max
7
24
34
4
3
2
(
1
ATR) 3399, 3321, 2932, 2854, 1747 (CO), 1652 (CO), 1509,
(
1
EtOAc/hexanes, 1:3). Yield: 0.140 g (39%) of yellow solid, mp 162−
−1
201, 1168, 734 cm .
2
2
1
64 °C; [α] + 12.1 (c = 1.00, MeOH). H NMR (500 MHz, CDCl )
D
3
7.9. Synthesis of Methyl (1-cyclohexyl-5-{2-[(naphthalen-1-
δ 1.08 and 1.12 (3H, 2d, 1:1, J = 7.2 Hz); 1.50 (9 H, br s); 3.62 and
3
4
yl)methyl]amino}-phenyl)-1H-pyrazole-4-carbonyl)-L-alaninate
(15c). A mixture of amino compound 14b (370 mg, 1 mmol), EtOH
(10 mL) and 2-naphthaldehyde (156 mg, 1 mmol) was stirred at r.t.
for 120 h. The solvent was evaporated and the resulting imine was
.65 (3H, 2s, 1:1); 3.68 and 3.75 (2H, 2d, 1:1, J = 5.2 Hz); 4.50 and
.54 (1H, d, J = 8.0 and 7.2 Hz); 5.82 and 5.87 (1H, 2d, 1:1, J = 7.2
Hz); 6.78−6.86 and 6.86−6.93 (1H, 2m, 1:1); 7.13 (1H, d, J = 7.6
Hz); 7.20 (1H, d, J = 9.0 Hz); 7.33 and 7.35 (1H, 2m, 1:1); 8.08 (1H,
dissolved in MeOH (10 mL) and NaBH (50 mg, 1.3 mmol) was
4
br s). 13C NMR (126 MHz, CDCl ) δ 18.1, 18.1, 30.3, 30.3, 47.6, 47.7,
3
added at 0 °C. The reaction mixture was stirred at 0 °C for 2 h.
Volatile components were evaporated in vacuo, the residue was taken
up in Et O (100 mL), and washed with aq. NaHCO (50 mL). The
5
1
1
2.2, 52.2, 62.5, 62.5, 115.7, 115.8, 116.1, 116.3, 117.6, 117.7, 118.6,
18.6, 131.2, 131.3, 131.5, 131.6, 137.6, 137.6, 139.6, 139.7, 145.4,
2
3
+
45.6, 162.2, 162.2, 173.1, 173.3. m/z (ESI) = 345 (MH ). m/z
organic phases were combined, dried over anh. Na SO , filtered, and
2 4
+
(
HRMS) Found: 345.1918 (MH ). C H N O requires: m/z =
the filtrate was evaporated in vacuo. The residue was purified by CC
(silica gel, EtOAc−hexanes, 1:1). Fractions containing the product
were combined and evaporated in vacuo to give 15c. Yield: 184 mg
18
25
4
3
3
45.1921. νmax (ATR) 3403, 3332, 2924, 1748 (CO), 1637 (C
−1
O), 1537, 1455, 1196, 1144, 752 cm .
1
57
DOI: 10.1021/acs.joc.5b02467
J. Org. Chem. 2016, 81, 146−161

The Journal of Organic Chemistry
Article
2
2
13
(
36%) of white crystals; mp 135−138 °C; [α] + 3.3 (c = 0.60,
8.1 Hz); 9.14 and 9.27 (1H, 2s, 1:1). C NMR (126 MHz, CDCl ) δ
D
3
1
MeOH). H NMR (500 MHz, CDCl ) δ 1.10 and 1.18 (3H, 2d, 1:1, J
7.1 Hz); 1.20−1.31 and 1.20−1.31 (3H, 2m, 1:1); 1.61−1.68 and
.61−1.68 (1H, 2m, 1:1); 1.78−2.08 and 1.78−2.08 (6H, 2m, 1:1);
.56 and 3.63 (3H, 2s, 1:1); 3.74−3.83 and 3.74−3.83 (1H, 2m, 1:1);
.14 and 4.17 (1H, 2t, 1:1, J = 5.8 Hz); 4.49 and 4.52 (2H, 2d, 1:1, J =
.1 Hz); 4.55 and 4.59 (1H, 2 quintets, 1:1, J = 7.2 Hz); 5.99 and 6.08
1H, 2d, 1:1, J = 7.2 Hz); 6.79 and 6.81 (1H, 2d, 1:1, J = 9.3 Hz); 6.85
and 6.88 (1H, 2t, 1:1, J = 6.4 Hz); 7.09 and 7.15 (1H, 2dd, 1:1, J = 7.5,
.6 Hz); 7.31−7.38 and 7.31−7.38 (2H, 2m, 1:1); 7.42−7.49 and
.42−7.49 (2H, 2m, 1:1); 7.68 and 7.70 (1H, 2s, 1:1); 7.75 and 7.75
1H, 2 br d, 1:1, J = 7.6 Hz); 7.78 and 7.78 (1H, 2dd, 1:1, J = 8.5, 2.8
18.4, 18.5, 25.1, 25.1, 25.4, 25.4, 25.5, 25.5, 33.1, 33.1, 33.2, 33.3, 48.2,
48.3, 52.7, 52.8, 58.6, 58.6, 115.9, 115.9, 122.1, 123.0, 125.3, 126.1,
125.3, 125.7, 127.3, 127.3, 127.3, 127.3, 128.7, 128.7, 128.8, 128.8,
130.4, 130.5, 131.2, 131.2, 131.9, 132.0, 134.2, 134.4, 137.6, 137.7,
138.4, 138.6, 139.0, 139.1, 163.5, 163.5, 165.6, 165.8, 173.4, 173.5. m/z
(ESI) = 475 (MH ). m/z (HRMS) Found: 475.2333 (MH ).
C H N O requires: m/z = 475.2340. (Found: C, 68.09; H, 6.52;
N, 11.58. C H N O requires: C, 68.34; H, 6.37; N, 11.81); ν
3
=
1
3
4
5
+
+
(
27
31
4
4
27
30
4
4
max
1
7
(
(
7
ATR) 3272, 2932, 2856, 1743 (CO), 1637 (CO), 1508, 1205,
−1
60, 707 cm .
7
.12. Synthesis of Methyl (S)-(1-cyclohexyl-5-{2-[3-(2-
Hz); 7.81 and 7.81 (1H, 2 br d, 1:1, J = 7.9 Hz); 8.15 and 8.15 (1H, 2s,
ethoxy-2-oxoethyl)ureido]-phenyl}-1H-pyrazole-4-carbonyl)-
alaninate (19). Ethyl isocyanatoacetate (17) (400 μL, 3.6 mmol) was
added to a solution of aniline 14b (185 mg, 0.5 mmol) in anh.
dichloromethane (10 mL) and the mixture was stirred at r.t. for 24 h.
Volatile components were evaporated in vacuo to give 19. Yield: 0.180
1
3
1
1
1
1
:1). 13C NMR (126 MHz, CDCl ) δ 18.2, 18.4, 25.0, 25.4, 25.5, 25.5,
3
3.0, 33.3, 47.7, 47.8, 47.8, 47.8, 52.2, 52.3, 58.3, 58.3, 111.7, 111.9,
12.9, 113.0, 115.8, 115.9, 117.8, 117.9, 125.0, 125.1, 125.5, 125.6,
25.8, 125.9, 126.2, 126.3, 127.6, 127.6, 127.7, 127.7, 128.5, 128.5,
30.6, 130.7, 131.9, 131.9, 132.7, 132.8, 133.4, 133.4, 136.1, 136.2,
37.4, 137.4, 141.0, 141.1, 146.3, 146.6, 162.0, 162.1, 173.0, 173.1. m/z
ESI) = 511 (MH ). m/z (HRMS) Found: 511.2701 (MH ).
C H N O requires: m/z = 511.2704. (Found: C, 73.23; H, 6.58;
g (72%) of white crystals; [α]2 − 5.2 (c = 0.95, MeOH). H NMR
2
D
1
(
500 MHz, CDCl ) δ 0.96−1.13 and 0.96−1.13 (3H, 2m, 1:1); 1.18
3
+
+
(
and 1.18 (3H, 2d, 1:1, J = 7.1 Hz); 1.26 and 1.29 (3H, 2d, 1:1, J = 7.1
Hz); 1.50−1.57 and 1.50−1.57 (1H, 2m, 1:1); 1.57−1.74 and 1.57−
1.74 (4H, 2m, 1:1); 1.76−1.89 and 1.76−1.89 (2H, 2m, 1:1); 3.50−
31
35
4
3
N, 10.98. C H N O requires: C, 72.92; H, 6.71; N, 10.97.); ν
ATR) 3387, 3342, 2933, 2856, 1747 (CO), 1643 (CO), 1505,
31
34
4
3
max
(
8
3
.57 and 3.50−3.57 (1H, 2m, 1:1); 3.58 and 3.58 (3H, 2s, 1:1); 3.77
and 3.80 (2H, 2d, 1:1, J = 5.5 Hz); 4.08 and 4.08 (2H, 2q, 1:1, J = 7.1
Hz); 4.34 and 4.35 (1H, 2 quintets, 1:1, J = 7.2 Hz); 7.07 and 7.09
−
1
26, 747 cm .
7
.10. Synthesis of Methyl (S)-(5-(2-acetylaminophenyl)-1-
phenyl-1H-pyrazole-4-carbonyl)alaninate (16a). A mixture of
nitro compound 12a (0.197 g, 0.5 mmol), AcOH (10 mL), Ac O (5
mL), and 10% Pd−C (20 mg) was hydrogenated under 3 bar of H at
r.t. for 4 h. Then, hydrogenation was stopped, MeOH (10 mL) was
added, and the mixture was left at r.t. for 2 h to solvolize excess Ac O.
The catalyst was removed by filtration through a glass-sintered funnel
and the filtrate was evaporated in vacuo. The residue was purified by
FC (EtOAc/hexanes, 1:1). Fractions containing the product were
combined and evaporated in vacuo to give 16a. Yield: 0.153 g (75%)
of yellowish solid; mp 86−91 °C; [α] − 19.4 (c = 0.20, MeOH). H
NMR (500 MHz, CDCl ) δ 1.35 and 1.38 (3H, 2d, 1:1, J = 7.2 Hz);
(
1H, 2t, 1:1, J = 6.0 Hz); 7.04−7.09 and 7.04−7.09 (2H, 2m, 1:1);
2
7
7
=
.36−7.42 and 7.36−7.42 (1H, 2m, 1:1); 7.51 and 7.60 (1H, 2s, 1:1);
2
.89−7.92 and 7.89−7.92 (1H, 2m, 1:1); 7.92 and 8.09 (1H, 2d, 1:1, J
13
7.2 Hz); 8.14 and 8.16 (1H, 2s, 1:1). C NMR (126 MHz, CDCl )
3
2
δ 14.1, 14.1, 17.0, 17.1, 24.9, 24.9, 32.0, 32.2, 32.9, 33.0, 41.2, 41.2,
7.3, 47.4, 51.8, 51.8, 57.3, 57.3, 60.3, 60.3, 115.8, 115.9, 120.3, 120.5,
22.0, 122.0, 122.3, 122.4, 129.5, 129.6, 130.7, 131.1, 138.2, 138.4,
38.4, 138.5, 139.4, 139.6, 155.3, 155.3, 161.7, 161.8, 170.6, 170.7,
173.1, 173.2. m/z (ESI) = 500 (MH ). m/z (HRMS) Found:
4
1
1
+
2
2
1
D
+
5
3
1
00.2498 (MH ). C H N O requires: m/z = 500.2504. ν (ATR)
25 34 5 6 max
3
401, 3319, 2933, 2858, 1747 (CO), 1704 (CO), 1633 (CO),
2
(
.02 and 2.03 (3H, 2s, 1:1); 3.74 and 3.76 (3H, 2s, 1:1); 4.63 and 4.65
1H, 2 quintets, 1:1, J = 7.2 Hz); 6.29 and 6.56 (1H, 2d, 1:1, J = 7.0
Hz); 6.96 (1H, br t, J = 6.4 Hz); 7.08 (1H, br q, J = 7.9 Hz); 7.14−
−1
586, 1542, 1197, 767 cm .
.13. Synthesis of Methyl (S)-{5-[2-({(S,Z)-4-[(tert-
butoxycarbonyl)amino]-3-oxopent-1-en-1-yl}amino)phenyl]-
-cyclohexyl-1H-pyrazole-4-carbonyl}alaninate (20). A solution
7
7
.21 (1H, m); 7.22−7.34 (4H, m); 7.39−7.46 (1H, m); 7.73 and 7.79
1
(
1H, 2 br d, J = 8.0 Hz); 8.10 (1H, br s); 8.62 and 8.86 (1H, 2s, 1:1).
of aniline 14b (370 mg, 1 mmol) in anh. dichloromethane (5 mL) was
added to a cold (0 °C) solution of tert-butyl (S)-(3-oxopent-4-yn-2-
yl)carbamate (18) in anh. dichloromethane (5 mL) and the mixture
was stirred at r.t. for 16 h. Volatile components were evaporated in
vacuo and the residue was purified by CC (silica gel, EtOAc/hexanes,
3:2). Fractions containing the product were combined and evaporated
in vacuo to give 20. Yield: 0.420 g (74%) of white crystals; mp 91−95
1
3
C NMR (126 MHz, CDCl ) δ 18.0, 18.2, 23.8, 24.0, 48.1, 48.3, 52.6,
3
5
1
1
1
4
6
2.7, 117.6, 117.8, 123.1, 123.9, 124.7, 124.8, 125.5, 125.9, 126.0,
26.7, 128.0, 128.0, 129.0, 129.0, 130.7, 130.8, 131.3, 131.4, 137.1,
37.2, 138.9, 138.9, 139.3, 139.7, 139.7, 140.1, 163.2, 163.3, 169.1,
69.3, 173.2, 173.6. m/z (ESI) = 407 (MH ). m/z (HRMS) Found:
07.1723 (MH ). C H N O requires: m/z = 407.1719. (Found: C,
4.09; H, 5.22; N, 13.07. C H N O ·1/3AcOH requires: C, 63.84;
H, 5.52; N, 13.14.); νmax (KBr) 3467, 1741 (CO), 1639 (CO),
+
+
22
23
4
4
22
22
4
4
22
D
1
°
C; [α] + 20.4 (c = 1.05, MeOH). H NMR (500 MHz, CDCl ) δ
3
−1
1.07−1.24 and 1.07−1.24 (3H, 2m, 1:1, 3H of C
3H, 2d, 1:1, J = 7.0 Hz); 1.27 and 1.30 (3H, 2d, 1:1, J = 7.1 Hz); 1.45
6
H11); 1.26 and 1.26
1
586, 1500, 1390, 1307, 764 cm .
(
7
.11. Synthesis of Methyl (S)-[5-(2-benzamidophenyl)-1-
and 1.45 (9H, 2s, 1:1); 1.59−1.66 and 1.59−1.66 (1H, 2m, 1:1);
cyclohexyl-1H-pyrazole-4-carbonyl]alaninate (16b). Benzoyl
chloride (64 μL, 0.55 mmol) was added to a cold (0 °C) solution
of aniline 14b (185 mg, 0.5 mmol) in anh. pyridine (10 mL) and the
mixture was stirred at r.t. for 24 h. Volatile components were
evaporated in vacuo and the residue was purified by DVFC (silica gel,
EtOAc/hexanes, 1:2). Fractions containing the product were
combined and evaporated in vacuo to give 16b. Yield: 0.170 g
1
(
(
4
7
2
.72−1.88 and 1.72−1.88 (4H, 2m, 1:1); 1.90−2.06 and 1.90−2.06
2H, 2m, 1:1); 3.60−3.67 and 3.60−3.67 (1H, 2m, 1:1); 3.67 and 3.69
3H, 2s, 1:1); 4.24 and 4.24 (1H, 2 quintets, 1:1, J = 7.0 Hz); 4.59 and
.62 (1H, 2 quintets, 1:1, J = 7.0 Hz); 5.29 and 5.30 (1H, 2d, 1:1, J =
.8 Hz); 5.41 and 5.44 (1H, 2d, 1:1, J = 7.2 Hz); 6.08 and 6.08 (1H,
d, 1:1, J = 5.5 Hz); 7.21−7.35 and 7.21−7.35 (4H, 2m, 1:1); 7.53−
2
2
(
72%) of white crystals; mp 77−83 °C; [α] +6.8 (c = 3.8, MeOH).
H NMR (500 MHz, CDCl ) δ 1.09−1.24 and 1.09−1.24 (3H, 2m,
7.59 and 7.53−7.59 (1H, 2m, 1:1); 8.12 and 8.15 (1H, 2s, 1:1); 11.04
D
1
13
and 11.07 (1H, 2d, 1:1, J = 8.5 Hz). C NMR (126 MHz, CDCl
) δ
8.8, 18.8, 19.4, 19.6, 25.1, 25.1, 25.5, 25.5, 25.6, 25.6, 28.5, 28.5, 32.5,
2.5, 33.4, 33.4, 47.9, 47.9, 52.5, 52.5, 53.8, 54.0, 58.7, 58.8, 79.4, 79.4,
3
3
1
3
1
:1); 1.35 and 1.38 (3H, 2d, 1:1, J = 7.2 Hz); 1.51−1.64 and 1.51−
.64 (2H, 2m, 1:1); 1.65−1.72 and 1.65−1.72 (1H, 2m, 1:1); 1.74−
.87 and 1.74−1.87 (2H, 2m, 1:1); 1.91−2.04 and 1.91−2.04 (2H, 2m,
:1); 3.69 and 3.74 (3H, 2s, 1:1); 3.75−3.84 and 3.75−3.84 (1H, 2m,
:1); 4.62 and 4.65 (1H, 2 quintets, 1:1, J = 7.2 Hz); 6.23 and 6.27
1H, 2d, 1:1, J = 7.2 Hz); 7.22−7.25 and 7.22−7.25 (1H, 2m, 1:1);
.31−7.36 and 7.31−7.36 (1H, 2m, 1:1); 7.37−7.43 and 7.37−7.43
2H, 2m, 1:1); 7.46−7.50 and 7.46−7.50 (1H, 2m, 1:1); 7.57−7.62
and 7.57−7.62 (1H, 2m, 1:1); 7.69−7.76 and 7.69−7.76 (2H, 2m,
:1); 7.93 and 7.96 (1H, 2s, 1:1); 8.10 and 8.19 (1H, 2 br d, 1:1, J =
1
1
1
1
(
7
95.4, 95.7, 115.1, 115.4, 116.3, 116.4, 118.3, 118.5, 123.9, 124.0, 131.5,
131.7, 131.7, 131.8, 137.1, 137.4, 139.7, 139.9, 139.8, 140.1, 143.3,
143.9, 155.3, 155.4, 161.9, 162.0, 173.5, 173.5, 198.4, 198.6. m/z (ESI)
= 568 (MH ). m/z (HRMS) Found: 568.3122 (MH ). C30
requires: m/z = 568.3130. (Found: C, 63.22; H, 7.44; N, 12.28.
requires: C, 63.47; H, 7.28; N, 12.34.); νmax (ATR) 3304,
2932, 2857, 1720 (CO), 1627 (CO), 1585, 1454, 1278, 1161,
+
+
H N O
42 5 6
(
C H N O
30 41 5 6
−
1
1
753 cm .
1
58
DOI: 10.1021/acs.joc.5b02467
J. Org. Chem. 2016, 81, 146−161

The Journal of Organic Chemistry
Article
7
.14. Synthesis of N-Methyl 5-(2-nitrophenyl)-1-phenyl-1H-
mmol), and phenylhydrazine hydrochloride 10a (0.80 g, 5.5 mmol),
FC (EtOAc/hexanes, 1:2). Yield: 1.32 g (90%) of brownish crystals.
Physical and spectral data of pyrazole 23a were in agreement with the
pyrazole-4-carboxamides 21a,b. CDI (0.17 g, 1.05 mmol) was
added to a solution of carboxylic acid 2a (1 mmol) in anh. MeCN (5
mL) and the mixture was stirred at r.t. for 2 h. Then amine (2 mmol)
was added and stirring at r.t. was continued for 40 h. Volatile
components were evaporated in vacuo and the residue was purified by
DVFC (silica gel, EtOAc−hexanes). Fractions containing the product
were combined and evaporated in vacuo to give 21.
3
5
literature data.
7.16.2. Ethyl 1-(2-chlorophenyl)-5-phenyl-1H-pyrazole-4-carbox-
ylate (23b). Prepared from 8b (0.96 g, 5 mmol), DMFDMA (0.8 mL,
5.3 mmol), and 2-chlorophenylhydrazine hydrochloride 10e (0.98 g,
5.5 mmol), FC (EtOAc/hexanes, 1:2). Yield: 1.50 g (92%) of
1
7
.14.1. N-Methyl-5-(2-nitrophenyl)-1-phenyl-1H-pyrazole-4-car-
brownish oil. H NMR (500 MHz, CDCl ) δ 1.23 (3H, t, J = 7.1 Hz);
3
boxamide (21a). Prepared from 2a (310 mg, 1 mmol) and MeNH
4.22 (2H, q, J = 7.1 Hz); 7.22−7.33 (8H, m); 7.36−7.41 (1H, m), 8.23
2
(1H, s). 13C NMR (126 MHz, CDCl ) δ 14.2, 60.2, 113.1, 127.3,
(
0
2 M in MeOH, 1 mL, 2 mmol), DVFC (EtOAc/hexanes, 1:2). Yield:
3
1
.138 g (43%) of white solid; mp 214−216 °C. H NMR (500 MHz,
127.7, 128.1, 129.2, 130.0, 130.2, 130.3, 130.6, 132.4, 137.0, 142.7,
+
CDCl ) δ 2.82 (3H, d, J = 4.8 Hz); 5.95 (1H, br q, J = 3.9 Hz); 7.25−
147.5, 162.9. m/z (ESI) = 327, 329 (MH ). m/z (HRMS) Found:
3
+
7
.31 (6H, m); 7.52−7.58 (2H, m); 7.93 (1H, s); 8.08−8.12 (1H, m).
327.0890 (MH ). C H ClN O requires: m/z = 327.0895. νmax
18
16
2
2
1
3
C NMR (126 MHz, CDCl ) δ 26.2, 116.8, 124.6, 125.0, 125.2, 128.3,
(ATR) 3063, 2981, 1708 (CO), 1555, 1499, 1444, 1224, 1127,
3
−
1
1
=
29.1, 130.3, 132.9, 133.0, 138.5, 138.7, 140.2, 149.1, 162.7. m/z (ESI)
323 (MH ). m/z (HRMS) Found: 323.1139 (MH ). C H N O
760, 695 cm .
+
+
17
15
4
3
7.16.3. Ethyl 1-(2-nitrophenyl)-5-phenyl-1H-pyrazole-4-carboxy-
late (23c). Prepared from 8b (0.96 g, 5 mmol), DMFDMA (0.8 mL,
5.3 mmol), 2-nitrophenylhydrazine hydrochloride 10m (0.84 g, 5.5
requires: m/z = 323.1139. (Found: C, 63.39; H, 4.30; N, 17.15.
C H N O requires: C, 63.35; H, 4.38; N, 17.38.); ν (ATR) 3306,
1
7
14
4
3
max
−1
3
098, 1621 (CO), 1573, 1525, 1501, 1342, 961, 767 cm .
mmol), and 37% aq. HCl (11 drops), FC (EtOAc/hexanes, 1:2).
1
7
.14.2. N,N-Dimethyl-5-(2-nitrophenyl)-1-phenyl-1H-pyrazole-4-
Yield: 1.32 g (78%) of brown oil. H NMR (500 MHz, CDCl
3
) δ 1.23
carboxamide (21b). Prepared from 2a (310 mg, 1 mmol) and
(3H, t, J = 7.1 Hz); 4.23 (2H, q, J = 7.1 Hz); 7.24 (1H, dd, J = 7.6, 1.7
Me NH (2 M in MeOH, 1 mL, 2 mmol), DVFC (EtOAc/hexanes,
Hz); 7.28−7.37 (5H, m); 7.48−7.56 (2H, m); 7.91 (1H, dd, J = 7.8,
2
1
13
1
(
:3). Yield: 0.172 g (51%) of white solid; mp 159−163 °C. H NMR
1.8 Hz); 8.20 (1H, s). C NMR (126 MHz, CDCl ) δ 14.2, 60.3,
3
500 MHz, CDCl ) δ 2.96 and 3.08 (6H, 2 br s, 1:1); 7.20−7.25 (2H,
114.1, 125.2, 127.6, 128.1, 129.5, 129.7, 129.7, 130.4, 132.7, 133.2,
3
+
m), 7.27−7.32 (3H, m); 7.46 (1H, dd, J = 7.6, 1.5 Hz); 7.54 (1H, td, J
143.5, 145.9, 146.8, 162.6. m/z (ESI) = 338 (MH ). m/z (HRMS)
+
=
7.8, 1.6 Hz); 7.60 (1H, td, J = 7.5, 1.4 Hz); 7.86 (1H, s); 7.99 (1H,
Found: 338.1143 (MH ). C H N O requires: m/z = 338.1135. ν
18
16
3
4
max
13
dd, J = 8.1, 1.3 Hz). C NMR (126 MHz, CDCl ) δ 35.3, 39.0, 117.6,
24.7, 124.8, 124.9, 128.2, 129.1, 130.3, 133.1, 133.1, 138.7, 138.8,
39.2, 148.8, 164.4. m/z (ESI) = 337 (MH ). m/z (HRMS) Found:
37.1294 (MH ). C H N O requires: m/z = 337.1295. (Found: C,
(ATR) 3386, 2987, 2781, 1714 (CO), 1524, 1451, 1350, 782, 771,
3
−
1
1
1
3
6
4
7
749, 65 cm .
+
7.17. General Procedure for the Synthesis of 1-Substituted
5-Phenyl-1H-pyrazole-4-carboxylic acids 24a−c. A mixture of
the ester 23 (3 mmol), methanol (30 mL), and 2 M aq. NaOH (6.6
mL, 13.2 mmol) was stirred at 50 °C for 24 h. Methanol was
evaporated in vacuo (40 mbar, 40 °C) and the aqueous solution was
acidified with 1 M aq. HCl to pH ∼ 1 and the product 24 was either
collected by filtration and washed with water (2 × 5 mL) or taken up
in EtOAc (50 mL) when oily acid was formed. The organic phase was
dried for 20 min over anh. Na SO , filtered, and the filtrate was
+
18
17
4
3
3.85; H, 4.76; N, 16.11. C H N O ·1/8H O requires: C, 63.85; H,
18
16
4
3
2
.84; N, 16.55.); ν (ATR) 2926, 1619 (CO), 1525, 1498, 1345,
max
−1
74, 763 cm .
7
.15. Synthesis of (S)-1-Phenylethyl 5-(2-nitrophenyl)-1-
phenyl-1H-pyrazole-4-carboxylate (22). Carboxylic acid 2a (155
mg, 0.5 mmol) was dissolved in thionyl chloride (4 mL), the mixture
was heated under reflux for 4 h, and the volatile components were
evaporated in vacuo. The residue was dissolved in anh. CH Cl (5
2
4
2
2
evaporated in vacuo to give 24a−c.
mL), (S)-(−)-1-phenylethanol (60 μL, 0.5 mmol) was added, and
stirring at r.t. was continued for 24 h. The reaction mixture was
concentrated in vacuo and the residue was purified by DVFC (silica
gel, EtOAc/hexanes, 1:3). Fractions containing the product were
combined and evaporated in vacuo to give 22. Yield: 77 mg (37%) of
7.17.1. 1,5-Diphenyl-1H-pyrazole-4-carboxylic acid (24a). Pre-
pared from 23a (877 mg, 3 mmol). Yield: 753 mg (95%) of brownish
crystals. Physical and spectral data of carboxylic acid 24a were in
3
6
agreement with the literature data.
7.17.2. 1-(2-Chlorophenyl)-5-phenyl-1H-pyrazole-4-carboxylic
colorless oil; [α]2 + 66.0 (c = 0.15, MeOH). H NMR (500 MHz,
2
D
1
acid (24b). Prepared from 23b (980 mg, 3 mmol). Yield: 788 mg
1
CDCl ) δ 1.42 and 1.43 (3H, 2d, 53:47, J = 6.6 Hz); 5.87 and 5.92
(88%) of brownish oil. H NMR (500 MHz, CDCl ) δ 7.22−7.33
3
3
(
1H, 2q, 47:53, J = 6.7 Hz); 6.99−7.04 and 6.99−7.04 (1H, 2m);
(8H, m); 7.38 (1H, dd, J = 8.1, 1.4 Hz); 8.26 (1H, s); 8.83 (1H, br s).
C NMR (126 MHz, CDCl ) δ 112.1, 127.3, 127.6, 127.8, 129.3,
13
7
2
4
.18−7.33 and 7.18−7.33 (10H, 2m); 7.51−7.59 and 7.51−7.59 (2H,
m); 8.08−8.15 and 8.08−8.15 (1H, 2m); 8.22 and 8.23 (1H, 2s,
6:54). 13C NMR (126 MHz, CDCl ) δ C NMR (126 MHz, CDCl )
3
129.9, 130.1, 130.3, 130.7, 132.3, 136.7, 143.5, 148.1, 168.1. m/z (ESI)
13
+
+
3
3
= 299, 301 (MH ). m/z (HRMS) Found: 299.0583 (MH ).
C H ClN O requires: m/z = 299.0582. ν (ATR) 2914, 1721
δ 21.8, 22.1, 72.3, 72.5, 124.7, 124.7, 125.0, 125.0, 125.0, 125.0, 125.9,
16
12
2
2
max
−
1
1
1
1
=
25.9, 125.9, 125.9, 127.7, 127.8, 128.3, 128.3, 128.4, 128.4, 128.5,
28.5, 129.1, 129.1, 129.1, 129.1, 130.4, 130.4, 132.6, 132.8, 133.0,
33.0, 138.7, 138.7, 141.2, 141.4, 142.3, 142.6, 161.6, 161.7. m/z (ESI)
(CO), 1550, 1502, 1224, 1202, 1137, 778, 763, 696 cm .
7.17.3. 1-(2-Nitrophenyl)-5-phenyl-1H-pyrazole-4-carboxylic acid
(24c). Prepared from 23c (1.01 g, 3 mmol). Yield: 751 mg (81%) of
+
+
1
414 (MH ). m/z (HRMS) Found: 414.1444 (MH ). C H N O
brownish oil. H NMR (500 MHz, CDCl ) δ 7.23 (1H, dd, J = 7.5, 1.7
24
20
3
4
3
requires: m/z = 414.1448. νmax (ATR) 2929, 1708 (CO), 1525,
Hz); 7.25−7.32 (4H, m); 7.33−7.38 (1H, m); 7.48−7.56 (2H, m);
−1
13
1
498, 1347, 1223, 1135, 1007, 960, 754, 693 cm .
7.91 (1H, dd, J = 7.7, 1.8 Hz); 8.24 (1H, s). C NMR (126 MHz,
7
.16. General Procedure for the Synthesis of 1-Substituted
CDCl ) δ 113.0, 125.2, 127.1, 128.2, 129.7, 129.7, 129.9, 130.3, 132.5,
3
+
Ethyl 5-phenyl-1H-pyrazole-4-carboxylates 23a−c. A mixture of
1
(
33.3, 144.2, 145.7, 147.6, 167.9. m/z (ESI) = 310 (MH ). m/z
HRMS) Found: 310.0826 (MH ). C H N O requires: m/z =
+
8
b (0.96 g, 5 mmol), anh. toluene (15 mL), and DMFDMA (0.8 mL,
16 12 3 4
5.3 mmol) was stirred under reflux for 4 h and volatile components
3
7
10.0822. νmax (ATR) 3065, 1681 (CO), 1530, 1500, 1349, 1243,
−
1
were evaporated in vacuo. The residue was dissolved in 1-butanol (15
mL), hydrazine derivative 10a,e,m (5.5 mmol) and 37% hydrochloric
acid (11 drops) were added, and the mixture was stirred under reflux
for 16 h. Volatile components were evaporated in vacuo and the
residue was purified by FC (EtOAc/hexanes). Fractions containing the
product were combined and evaporated in vacuo to give the crude
products 23a−c.
78, 726, 695 cm .
.18. General Procedure for the Synthesis of Methyl 1-
7
Substituted (S)-(5-Phenyl-1H-pyrazole-4-carbonyl)alaninates
25a−c. CDI (0.34 g, 2.1 mmol) was added to a solution of carboxylic
acid 24a−c (2 mmol) in anh. MeCN (10 mL) and the mixture was
stirred at r.t. for 2 h. Then, N-methylmorpholine (0.22 mL) and L-
alanine methyl ester hydrochloride (11a) (0.31 g, 2.2 mmol) were
added and stirring at r.t. was continued for 40 h. Volatile components
were evaporated in vacuo, the residue was taken up in EtOAc (30 mL),
7
.16.1. Ethyl 1,5-diphenyl-1H-pyrazole-4-carboxylate (23a).
Prepared from 8b (0.96 g, 5 mmol), DMFDMA (0.8 mL, 5.3
1
59
DOI: 10.1021/acs.joc.5b02467
J. Org. Chem. 2016, 81, 146−161

The Journal of Organic Chemistry
Article
and washed with 1 M HCl (3 × 20 mL), aq. NaHCO (2 × 20 mL),
3
ACKNOWLEDGMENTS
■
and brine (20 mL). The organic phases were combined, dried over
We thank the Slovenian Research Agency for the financial
support through grants P1-0179 and P1-0242.
anh. Na SO , filtered, and the filtrate was evaporated in vacuo. The
2
4
residue was purified by DVFC (silica gel, EtOAc−hexanes). Fractions
containing the product were combined and evaporated in vacuo to
give 25a−c.
REFERENCES
■
7
.18.1. Methyl (S)-(1,5-diphenyl-1H-pyrazole-4-carbonyl)-
(
1) Joule, J. A.; Mills, K. In Heterocyclic Chemistry, 5th ed.; Wiley-
Blackwell, 2010; Chapters 30−33, pp 587−664.
2) (a) Vagner, J.; Qu, H.; Hruby, V. J. Curr. Opin. Chem. Biol. 2008,
alaninate (25a). Prepared from 24a (0.529 g, 2 mmol) and methyl
(
(
1
S)-alaninate hydrochloride (11a) (0.31 g, 2.2 mmol), DVFC
(
1
EtOAc−hexanes, 1:1). Yield: 0.538 g (77%) of white crystals; mp
2
2
1
2, 292−296. (b) Robinson, J. A.; DeMarco, S.; Gombert, F.; Moehle,
09−111 °C; [α] − 18.0 (c = 0.50, MeOH). H NMR (500 MHz,
D
K.; Obrecht, D. Drug Discovery Today 2008, 13, 944−951.
CDCl ) δ 1.26 (3H, d, J = 7.2 Hz); 3.68 (3H, s); 4.64 (1H, quintet, J =
3
(
(
(
c) Robinson, J. A. Acc. Chem. Res. 2008, 41, 1278−1288.
d) Hanessian, S.; Auzzas, L. Acc. Chem. Res. 2008, 41, 1241−1251.
e) Wells, J. A.; McClendon, C. L. Nature 2007, 450, 1001−1009.
7
.2 Hz); 5.94 (1H, d, J = 7.3 Hz); 7.18−7.22 (2H, m); 7.25−7.30 (3H,
13
m); 7.33−7.37 (2H, m); 7.41−7.48 (3H, m); 8.20 (1H, s). C NMR
(
126 MHz, CDCl ) δ 18.3, 47.9, 52.4, 117.3, 125.1, 127.9, 128.7,
3
1
=
28.8, 129.1, 129.8, 130.4, 139.1, 141.5, 141.8, 162.0, 173.2. m/z (ESI)
(f) Hutchinson, E. G.; Thornton, J. M. Protein Sci. 1994, 3, 2207−
2216. (g) Gallo, E. A.; Gellman, S. H. J. Am. Chem. Soc. 1993, 115,
9774−9788.
+
+
350 (MH ). m/z (HRMS) Found: 350.1513 (MH ). C H N O
20 20 3 3
requires: m/z = 350.1499. (Found: C, 68.79; H, 5.41; N, 11.95.
C H N O requires: C, 68.75; H, 5.48; N, 12.03.); ν (ATR) 3307,
(3) (a) Hanessian, S.; McNaughton-Smith, G.; Lombart, H.-G.;
Lubell, W. D. Tetrahedron 1997, 53, 12789−12854. (b) Halab, L.;
Gosselin, F.; Lubell, W. D. Biopolymers 2000, 55, 101−122.
(c) Cluzeau, J.; Lubell, W. D. Biopolymers 2005, 80, 98−150.
(4) Eliel, E. L.; Wilen, S. H.; Mander, L. N. In Stereoisomers in
Stereochemistry of Organic Compounds; John Wiley and Sons: New
York, 1994; pp 49−70.
20
19
3
3
max
1
732 (CO), 1636 (CO), 1561, 1496, 1386, 1304, 1224, 762, 695
−1
cm .
7
.18.2. Methyl (S)-(1-(2-chlorophenyl)-5-phenyl-1H-pyrazole-4-
carbonyl)alaninate (25b). Prepared from 24b (0.597 g, 2 mmol)
and methyl (S)-alaninate hydrochloride (11a) (0.31 g, 2.2 mmol),
DVFC (EtOAc−hexanes, 1:2). Yield: 0.537 g (70%) of brownish oil;
2
2
1
[
(
(
(
α] − 15.6 (c = 2.0, MeOH). H NMR (500 MHz, CDCl ) δ 1.27
(5) Christie, G. H.; Kenner, J. J. Chem. Soc., Trans. 1922, 121, 614−
620.
D
3
3H, d, J = 7.1 Hz); 3.68 (3H, s); 4.65 (1H, quintet, J = 7.2 Hz); 6.01
1H, d, J = 7.3 Hz); 7.22−7.26 (1H, m); 7.28−7.40 (8H, m); 8.23
(6) Eliel, E. L.; Wilen, S. H.; Mander, L. N. In 14−5. Biphenyls.
Atropisomerism in Stereochemistry of Organic Compounds; John Wiley
and Sons: New York, 1994; pp 1142−1155.
1H, s). 13C NMR (126 MHz, CDCl ) δ 18.3, 47.9, 52.4, 116.4, 127.3,
27.8, 128.7, 129.8, 130.0, 130.1, 130.2, 130.7, 132.5, 136.8, 141.7,
3
1
+
143.9, 161.9, 173.2. m/z (ESI) = 384, 386 (MH ). m/z (HRMS)
̅
(7) Oki, M. Recent Advances in Atropisomerism. In Topics in
+
Found: 384.1118 (MH ). C H ClN O requires: m/z = 384.1119.
Stereochemistry; Allinger, N. L., Eliel, N. L., Wilen, S. H., Eds.; John
Wiley and Sons: New York, 1983; Vol. 14, pp 1−81.
20
19
3
3
(
Found: C, 60.64; H, 4.48; N, 13.98. C H N O requires: C, 60.91;
20 18 4 5
H, 4.60; N, 14.21.); νmax (ATR) 3315, 2952, 1740 (CO), 1644
(8) (a) Rosini, C.; Franzini, L.; Raffaelli, A.; Salvadori, P. Synthesis
1992, 1992, 503−517. (b) McCarthy, M.; Guiry, P. J. Tetrahedron
2001, 57, 3809−3844. (c) Bringmann, G.; Price Mortimer, A.; Keller,
P. A.; Gresser, M. J.; Garner, J.; Breuning, M. Angew. Chem., Int. Ed.
(
6
CO), 1557, 1518, 1498, 1488, 1446, 1207, 1166, 912, 762, 727,
−
1
96 cm .
7
.18.3. Methyl (S)-(1-(2-nitrophenyl)-5-phenyl-1H-pyrazole-4-
carbonyl)alaninate (25c). Prepared from 24c (0.619 g, 2 mmol)
and methyl (S)-alaninate hydrochloride (11a) (0.31 g, 2.2 mmol),
DVFC (EtOAc−hexanes, 1:2). Yield: 0.426 g (54%) of brownish
2
(
005, 44, 5384−5427.
9) Bringmann, G.; Gunther, C.; Ochse, M.; Schupp, O.; Tasler, S. In
̈
Biaryls in Nature in Progress in the Chemistry of Organic Natural
Products; Herz, W., Falk, H., Kirby, G. W., Moore, R. E., Eds.;
Springer: Vienna, 2001; Vol. 82, pp 1−249.
2
2
1
crystals; mp 154−159 °C; [α] − 9.0 (c = 0.50, MeOH). H NMR
D
(
500 MHz, CDCl ) δ 1.29 (3H, d, J = 7.1 Hz); 3.69 (3H, s); 4.65 (1H,
3
quintet, J = 7.2 Hz); 6.01 (1H, d, J = 7.2 Hz); 7.23 (1H, dd, J = 7.3, 2.0
Hz); 7.36−7.46 (5H, m); 7.52 (2H, pd, J = 7.6, 1.7 Hz); 7.91 (1H, dd,
(
10) Alkorta, I.; Elguero, J.; Roussel, C.; Vanthuyne, N.; Piras, P. Adv.
Heterocycl. Chem. 2012, 105, 1−188.
11) Janjic, M.; Prebil, R.; Grose
Golobic, A.; Stare, K.; Dahmann, G.; Stanovnik, B.; Svete, J. Helv.
Chim. Acta 2011, 94, 1703−1717.
12) Peng, Y.; Zhang, Q.; Snyder, G. L.; Zhu, H.; Yao, W.; Tomesch,
J = 7.8, 1.8 Hz); 8.19 (1H, s). 13C NMR (126 MHz, CDCl ) δ 18.4,
3
̌
̌ ̌ ̌
lj, U.; Kralj, D.; Malavasic, C.;
(
́
4
1
8.0, 52.4, 117.4, 125.2, 127.3, 129.1, 129.6, 129.7, 130.2, 130.3, 132.5,
33.2, 142.5, 143.3, 145.9, 161.5, 173.1. m/z (ESI) = 395 (MH ). m/z
̌
+
+
(
HRMS) Found: 395.1345 (MH ). C H N O requires: m/z =
20
19
4
5
(
3
95.1350. (Found: C, 60.64; H, 4.48; N, 13.98. C H N O requires:
20 18 4 5
J.; Papke, R. L.; O’Callaghan, J. P.; Welsh, W. J.; Wennogle, L. P.
C, 60.91; H, 4.60; N, 14.21.); νmax (ATR) 3301, 1733 (CO), 1635
Bioorg. Med. Chem. Lett. 2010, 20, 4825−4830.
−1
(
CO), 1563, 1536, 1361, 1303, 766, 748, 698 cm .
(13) Udagawa, S.; Yamamoto, M.; Aoki, T.; Oosumi, K.; Hayashi, K.
WO 2014069554.
14) Peng, Y.; Wennogle, L. P.; Zhang, Q.; Tomesch, J. WO
012178057.
15) Li, P.; Peng, Y.i; Tomesch, J.; Wennogle, L. P.; Zhang, Q. WO
012178112.
16) Peng, Y.; Wennogle, L.; Zhang, Q.; Tomesch, J. WO
ASSOCIATED CONTENT
(
2
(
2
■
* Supporting Information
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.5b02467.
(
Crystal data. (CIF)
2012177263.
Copies of the NMR spectra, X-ray diffraction data,
DNMR spectra, computational details, additional tables
and figures. (PDF)
(17) Menozzi, G.; Fossa, P.; Cichero, E.; Spallarossa, A.; Ranise, A.;
Mosti, L. Eur. J. Med. Chem. 2008, 43, 2627−2638.
(18) Bailey, N.; Bamford, M. J.; Dean, D. K.; Pickering, P. L.; Wilson,
D. M.; Witherington, J. WO 2005058837.
(
(
19) Pendri, A.; Gerritz, S.; Dodd, D. S.; Sun, C. US 20050080087.
20) Hamanaka, E. S.; Guzman-Perez, A.; Ruggeri, R. B.; Wester, R.
AUTHOR INFORMATION
Corresponding Author
Tel.: +386 1 4798 562. Fax: +386 1 2419 144. E-mail: jurij.
svete@fkkt.uni-lj.si.
■
*
T.; Mularski, C. J. WO 9943663.
21) Pepin, R.; Schmitz, C.; Lacroix, G. B.; Dellis, P.; Veyrat, C. EP
60701.
(
3
(
̌
̌ ̌ ̌
22) Senica, L.; Groselj, U.; Kasunic, M.; Kocar, D.; Stanovnik, B.;
Notes
Svete, J. Eur. J. Org. Chem. 2014, 2014, 3067−3071.
(23) For details, see Supporting Information.
The authors declare no competing financial interest.
1
60
DOI: 10.1021/acs.joc.5b02467
J. Org. Chem. 2016, 81, 146−161

The Journal of Organic Chemistry
Article
(
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̈
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(
1
(
(
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(
(
Reynolds, W. F. Molecules 2012, 17, 7914−7926. (b) Zimmer, K. D.;
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(
9
(
31) Shanan-Atidi, H.; Bar-Eli, K. H. J. Phys. Chem. 1970, 74, 961−
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32) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
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P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.;
Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima,
T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, J. A., Jr.;
Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin,
K. N.; Staroverov, V. N.; Keith, T.; Kobayashi, R.; Normand, J.;
Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.;
Cossi, M.; Rega, N.; Millam, J. M.; Klene, M.; Knox, J. E.; Cross, J. B.;
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