Regiospecific synthesis of 1,5-disubstituted-1H-pyrazoles containing differentiated 3,4-dicarboxylic acid esters via Suzuki coupling of the corresponding 5-trifluoromethane sulfonates

Article abstract of DOI:10.1016/j.tet.2006.11.053

A general procedure is described for the regiospecific preparation of 1-substituted-5-hydroxy-1H-pyrazoles containing differentiated ester moieties at the 3- and 4-positions. This process involves the coupling of monosubstituted benzyl carbazates with various malonyl chlorides or acids, deprotection of the coupling products via catalytic hydrogenation, and subsequent derivatization of the resulting hydrazides with monoalkyl oxalyl chlorides. The 5-hydroxy-1H-pyrazoles are readily transformed to the corresponding trifluoromethane sulfonates, which undergo palladium-mediated Suzuki coupling with a variety of boronic acids (aryl, heteroaryl, and alkenyl) in moderate to excellent yields (24-92%). The ester groups present in one of the resulting 1,5-disubstituted-1H-pyrazoles are further modified by selective hydrolysis or conversion to the corresponding dicarboxylic acid derivative followed by selective mono-esterification.

Full text of DOI:10.1016/j.tet.2006.11.053

Tetrahedron 63 (2007) 1154–1166
Regiospecific synthesis of 1,5-disubstituted-1H-pyrazoles
containing differentiated 3,4-dicarboxylic acid esters via Suzuki
coupling of the corresponding 5-trifluoromethane sulfonates
*
Peter S. Dragovich, Thomas M. Bertolini, Benjamin K. Ayida, Lian-Sheng Li,
Douglas E. Murphy, Frank Ruebsam, Zhongxiang Sun and Yuefen Zhou
Anadys Pharmaceuticals Inc, 3115 Merryfield Row, San Diego, CA 92121, United States
Received 15 October 2006; revised 18 November 2006; accepted 20 November 2006
Available online 14 December 2006
Abstract—A general procedure is described for the regiospecific preparation of 1-substituted-5-hydroxy-1H-pyrazoles containing differen-
tiated ester moieties at the 3- and 4-positions. This process involves the coupling of monosubstituted benzyl carbazates with various malonyl
chlorides or acids, deprotection of the coupling products via catalytic hydrogenation, and subsequent derivatization of the resulting hydrazides
with monoalkyl oxalyl chlorides. The 5-hydroxy-1H-pyrazoles are readily transformed to the corresponding trifluoromethane sulfonates,
which undergo palladium-mediated Suzuki coupling with a variety of boronic acids (aryl, heteroaryl, and alkenyl) in moderate to excellent
yields (24–92%). The ester groups present in one of the resulting 1,5-disubstituted-1H-pyrazoles are further modified by selective hydrolysis
or conversion to the corresponding dicarboxylic acid derivative followed by selective mono-esterification.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
this sequence afforded a 47% isolated yield of the 5-hydroxy-
1H-pyrazole1 4, which apparently arose from intramolecular
cyclization of 3 and subsequent dehydration. This result
suggested a novel approach to the regiospecific construction
of 1-substituted-3,4-diester-containing-5-hydroxy-1H-pyr-
azoles (6, Scheme 2) via the coupling of monosubstituted
benzyl carbazates (7) with malonyl chlorides or acids (8)
followed by Cbz removal and derivatization of the resulting
hydrazides with monoalkyl oxalyl chlorides (9).2 Subse-
quent Suzuki coupling of the corresponding 5-trifluorome-
thanesulfonyloxy-1H-pyrazoles3 would provide a general
method for the regiospecific synthesis of highly function-
alized 1,5-disubstituted-1H-pyrazoles bearing carboxylic
acids or esters at the 3- and 4-positions (5, Scheme 2) that
would complement the existing preparations of such
During the course of our recent efforts to develop novel
antiviral agents, we attempted to transform compound 1 to
the corresponding diacyl derivative 3 via removal of the
Cbz protecting group and treatment of the resulting hydr-
azide (2) with monoethyl oxalyl chloride (Scheme 1). Instead,
O
O
O
O
S
N
OMe
S
N
OMe
O
HN
O
HN
H
N
a
H2N
Cbz
N
N
1
2
b
O
O
O
O
O
O
O
O
R3O
R3O
O
N
S
N
OMe
S
OMe
3
HN
O
O
HN
OR2
OR2
EtO
H
4
N
N
N
N
R1
EtO
N
N
OH
1 N
R1
5
R4
N
O
OH
5
6
4
3
O
Scheme 1. Reagents and conditions: (a) H2, Pd on C, EtOAc, 23 ꢀC;
(b) ClC(O)CO2Et, i-Pr2NEt, CH2Cl2, 0/23 ꢀC, 47% from 1.
O
O
H
R1
H
Cl
+
+
N
N
R3O
X
OR2
Cbz
O
7
8
9
* Corresponding author. Tel.: +1 858 530 3648; e-mail: pdragovich@
anadyspharma.com
Scheme 2. X¼OH, Cl.
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.11.053

P. S. Dragovich et al. / Tetrahedron 63 (2007) 1154–1166
1155
heterocycles.4 Herein, we report our development of this new
approach to pyrazole synthesis including (1) the efficient
preparation of 1-substituted-5-hydroxy-1H-pyrazoles from
monosubstituted carbazates, (2) the optimization of reaction
conditions to effect Suzuki couplings with the corresponding
1-substituted-5-trifluoromethanesulfonyloxy-1H-pyrazoles,
and (3) the selective derivatization of the carboxylic acid
ester moieties present in one of the 1H-pyrazole Suzuki
coupling products.
in good yield and purity after chromatography on silica
gel.5 Similar derivatization of crude 13a with p-toluenesul-
fonyl chloride and triethylamine in the presence of catalytic
4-dimethylaminopyridine provided tosylate 15a in excellent
overall yield. Attempts to convert 13a to 5-chloro or 5-
bromopyrazoles via treatment with the corresponding phos-
phoryl halide or phosphorous trihalide (POX3 or PX3,
respectively) were unsuccessful and afforded numerous un-
identified decomposition products. Both triflate 14a and
tosylate 15a exhibited minimal decomposition by 1H NMR
after long-term (e.g., three months) storage as neat materials
at ꢁ20 ꢀC. However, 14a slowly decomposed to pyrazole
13a when left for extended periods of time on untreated
(dry) silica gel (approximately 10% conversion per day).
As detailed below, pyrazole triflates such as 14a that are
repeatedly exposed to atmospheric moisture during long-
term use and storage should be dried prior to utilizing
them in Suzuki coupling reactions.
2. Results and discussion
The optimized syntheses of several dimethyl-1-substituted-
3,4-dicarboxylate-1H-pyrazoles using our new methodology
are depicted in Scheme 3 along with their conversion to sev-
eral substrates suitable for use in Suzuki coupling reactions.
In one example, reductive coupling of benzyl carbazate and
isovaleraldehyde afforded monosubstituted carbazate 10a
[R1¼CH2CH2CH(CH3)2] in good yield. Acylation of 10a
with methyl malonyl chloride at elevated temperature then
provided intermediate 11a in excellent yield after basic
work-up and silica gel chromatography. The Cbz moiety
present in 11a was removed by hydrogenation and the crude
hydrazide thus obtained (12a) was treated with excess
monomethyl oxalyl chloride in the presence of N,N-diiso-
propylethylamine to give pyrazole 13a. Due to its polar
nature, it was difficult to completely separate this material
from minor impurities using flash chromatography. How-
ever, treatment of slightly impure 13a with excess trifluoro-
methanesulfonic anhydride in pyridine provided triflate 14a
As part of the above activities, considerable effort was spent
optimizing the transformation of hydrazide 12a to pyrazole
13a. A mechanism summarizing our current understanding
of this process is depicted in Scheme 4. Thus, hydrazide
12a reacts with one equivalent of monomethyl oxalyl chlo-
ride to afford acylated derivative 16. This intermediate
then undergoes rapid (and likely reversible) intramolecular
closure to give 17 (path A), which subsequently reacts
with a second equivalent of monomethyl oxalyl chloride to
provide intermediate 18. Elimination of monomethyl oxalic
acid ester from 18 then affords the observed pyrazole 13a.
This sequence is consistent with the observation that attemp-
ted conversion of 12a to 13a using fewer than 2 equiv of
monomethyl oxalyl chloride consistently resulted in incom-
plete consumption of the starting hydrazide.6 Intermediate
16 may conceivably undergo an alternate intramolecular clo-
sure to afford hemiketal 19 (path B) followed by dehydration
to provide pyridazinone 20 (a structural isomer of 13a).
However, the formation of significant amounts of cyclization
products via this alternate pathway was discounted by the in-
dependent synthesis of a Suzuki coupling product expected
to arise from the corresponding pyridazinone triflate 21
(see Scheme 5).7 In addition to undergoing the intramolecu-
lar closure described above, intermediate 16 may instead re-
act directly with a second equivalent of monomethyl oxalyl
chloride (Scheme 4, path C). The resulting bis-acylated ad-
duct (22) could, in fact, be detected in minor amounts by
LCMS and TLC analysis of the reaction mixture. However,
addition of pyridine or 4-dimethylaminopyridine to the reac-
tion medium greatly increased the amount of 22 formed rel-
ative to 13a. These results suggest that such additives
accelerate the acylation of 16 more than the corresponding
transformation of 17, and indicate that their use should be
avoided in the preparation of pyrazoles such as 13a.8
H
H2N
N
R1
g
P
H
R1
O
R1
H
b
N
N
O
a
Cbz
N N
H
R
H
OMe
10a-c
O
11a-c P = Cbz
12a-c P = H
c
d
O
N
O
N
O
O
MeO
MeO
e
OMe
OTf
OMe
N
N
OH
13a-c
R1
R1
14a-c
f
O
O
MeO
a R1 = CH2CH2CH(CH3)2
b R1 = CH2Cyclohexyl
c R1 = Phenyl
OMe
OTs
N
Having successfully prepared pyrazole triflate 14a, we then
examined its ability to participate in a Suzuki coupling reac-
tion with phenylboronic acid.9 We initially studied a litera-
ture protocol that had been successfully employed for the
Suzuki coupling of related pyrazole triflates (Table 1, entry
1).3 Somewhat surprisingly, we obtained only a modest yield
of the desired coupling product (23a) utilizing these reaction
conditions. We then surveyed several other literature proce-
dures that are reported to couple organotriflates and boronic
N
R1
15a
Scheme 3. Reagents and conditions: (a) CbzNHNH2, NaBH3CN, HOAc,
CH3OH, 0/23 ꢀC, 44–77%; (b) ClC(O)CH2CO2Me, 1,4-dioxane,
100 ꢀC, 89–98%; (c) H2, Pd on C, EtOAc, 23 ꢀC; (d) ClC(O)CO2Me,
i-Pr2NEt, CH2Cl2, 0/23 ꢀC, 95% (13a from 11a); (e) Tf2O, pyridine,
0 ꢀC, 86% (14a), 68% (14b from 11b), 77% (14c from 11c); (f) TsCl,
Et3N, DMAP, CH2Cl2, 23 ꢀC, 81% from 11a; (g) Ref. 17.

1156
P. S. Dragovich et al. / Tetrahedron 63 (2007) 1154–1166
Me
O
Me
O
O
O
O
O
O
O
O
O
MeO
HO
HN
O
HN
MeO
OMe
OMe
A
HN
N
O
O
O
13a
12a
N
N
OMe
B
17
18
16
O
C
O
O
N
Me
O
O
O
MeO
O
MeO
O
O
MeO
MeO
HO
N
O
O
O
TfO
OMe
OMe
OMe
OMe
O
O
HN
HN
N
N
N
N
O
O
22
19
20
21
Scheme 4.
acids or esters in good yield (Table 1, entries 2–4).10 Unfor-
tunately, these procedures either completely failed to
provide the desired coupling product (entry 2) or did so in
relatively poor yield (entries 3 and 4).11 In all cases, we
observed significant amounts of pyrazole 13a by TLC and
LCMS analysis of the reaction mixtures suggesting that tri-
flate 14a underwent facile hydrolysis instead of the desired
coupling. A control experiment confirmed that 14a was
rapidly converted to pyrazole 13a when heated at 75 ꢀC in
DME/H2O (95:5) containing 2 equiv of Na2CO3 (100%
conversion after 4 h). This transformation proceeded more
slowly when conducted at the same temperature in anhy-
drous DME in the presence of 2 equiv of Na2CO3 (60%
conversion after 20 h)12 and did not occur at all in the ab-
sence of both added water and Na2CO3 (0% conversion after
48 h at 75 ꢀC). Accordingly, we examined anhydrous vari-
ants of several Suzuki coupling conditions [Pd(PPh3)4+
Na2CO3/K2CO3] and observed dramatically increased yields
of the desired product 23a (Table 1, entries 5 and 6). These
improved yields were somewhat dependent on the nature of
the carbonate base employed, as we obtained lower isolated
quantities of 23a using Cs2CO3 in place of Na2CO3 or
K2CO3 (entry 7). Hoping to reduce the water sensitivity of
the coupling reaction, we also examined coupling of tosylate
15a with phenylboronic acid using several conditions
reported in the literature (Table 1, entries 8–10).13 Unfortu-
nately, these experiments afforded none of the desired prod-
uct 23a either due to tosylate hydrolysis (entries 8 and 10) or
its complete lack of reactivity (entry 9). Since water has
a deleterious effect on the coupling reaction, we were not
surprised to observe a reduction in the coupling yield
when employing triflate 14a that had been repeatedly ex-
posed to the atmosphere during long-term use and storage
(especially when the compound was kept below 0 ꢀC).14
These variations could be easily avoided by azeotropically
drying the triflate (via concentration from toluene) prior to
conducting the coupling reactions.
entries 1–4). Use of ortho- and meta-substituted phenylbor-
onic acids also afforded the desired coupling products in
good yields (Table 2, entries 5 and 6). Several heterocyclic
boronic acids underwent the desired coupling as well, albeit
in lower yields than those observed for the phenylboronic
acid derivatives described above (Table 2, entries 7 and 8).
Certain heterocyclic boronic acids, however, failed to pro-
vide the desired coupling products when subjected to the
anhydrous reaction conditions (e.g., 3-pyridyl, 4-pyridyl,
2-furyl, and 3-furylboronic acids). All of these unreactive
substrates were highly insoluble in DME, even at elevated
temperatures. The addition of water as a co-solvent to in-
crease the solubility of these reagents was not examined
O
O
MeO
OEt
OTf
Cbz
HN
N
f, g, h
e
N
O
N
10a
OEt
28
29
O
i
O
OR
N
O
O
MeO
S
OEt
OEt
N
N
N
O
S
26 R = H
27 R = CH3
d
30
b,c
O
H
N
OH
HO
N
O
H
OEt
a
N
H2N
S
O
25
24
We next examined whether the anhydrous reaction condi-
tions described above could be utilized to couple triflate
14a with boronic acids and esters other than phenylboronic
acid. Good yields of the desired products were obtained
with phenylboronic acids bearing both electron-donating
and withdrawing substituents at the 4-position (Table 2,
Scheme 5. Reagents and conditions: (a) ethyl thiophene-2-glyoxylate,
NaOAc, EtOH, 80 ꢀC, 65%; (b) ClC(O)CH2CO2Et, 1,4-dioxane, 75 ꢀC;
(c) NaOEt, EtOH, 23 ꢀC, 64% from 25; (d) NaH, MeI, DMF, 23/45 ꢀC,
50%; (e) ClC(O)CH2CO2Et, 1,4-dioxane, 100 ꢀC, 91%; (f) H2, Pd on C,
EtOAc, 23 ꢀC; (g) ClC(O)CO2Me, i-Pr2NEt, CH2Cl2, 0/23 ꢀC; (h)
Tf2O, pyridine, 0 ꢀC, 25% from 28; (i) 2-thienylboronic acid, Na2CO3,
Pd(PPh3)4, DME, 75 ꢀC, 27%.

P. S. Dragovich et al. / Tetrahedron 63 (2007) 1154–1166
1157
Table 1. Optimization of coupling reaction conditions
O
N
O
O
N
O
MeO
OMe
MeO
OMe
Ph
23a
PhB(OH)2
conditions
X
N
N
14a or 15a
Entrya
X
PhB(OH)2 equiv Catalyst
Additive
Base (equiv)
Solvent
T (ꢀC) Timeb (h) Yieldc (%) Ref.
1
OTf 3.0
OTf 1.1
OTf 1.2
OTf 1.1
OTf 1.5
OTf 1.5
OTf 1.5
OTs 1.5
OTs 1.5
OTs 1.2
8% PdCl2(dppf)d 4% dppf
K3PO4 (3.0)
KF (3.3)
1,4-Dioxane
THF
8:1 DME/H2O
5:1 DME/H2O
DME
100
25
75
65
75
75
75
80
25
60
16
4
1.5
0.75
18
37
0
3
10a
10b,c
10d
—
—
—
13a
13b
13c
2
1% Pd(OAc2)
5% Pd(PPh3)4
2.4% Pd(PPh3)4
5% Pd(PPh3)4
5% Pd(PPh3)4
5% Pd(PPh3)4
3% Pd(OAc)2
3% Ni(COD)2
1% PCy3
None
None
None
None
None
3e
4
Na2CO3 (2.0)
K2CO3 (2.1)
Na2CO3 (2.0)
K2CO3 (2.0)
Cs2CO3 (2.0)
28
13
84
70
49
0
5
6
7
8
9
10
DME
DME
16
16
2
7% DCPTBf K3PO4$H2O (3.0) t-BuOH
12% PCy3
K3PO4 (3.0)
KF (8.0)
THF
1:1 THF/H2O
18g
22
0
0
5% PdCl2(PPh3)2 None
a
Reactions performed using approximately 0.50 mmol of starting OTf/OTs compound at 0.1 M concentration.
Time required for complete disappearance of starting OTf/OTs compound by TLC.
Isolated yield of purified coupling product after silica gel chromatography.
1:1 Complex with CH2Cl2.
OTf compound employed at 0.03 M concentration.
2-Dicyclohexylphosphino-20,40,60-triisopropylbiphenyl.
Starting OTs compound remained unchanged by TLC after 18 h.
b
c
d
e
f
g
due to the incompatibility of triflate 14a with basic, aqueous
10b and 10c were transformed to the corresponding pyrazole
triflates (14b and 14c, respectively) in good yields using
a reaction sequence analogous to that employed in the con-
version of 10a to 14a.18 As with the latter compound, both
14b and 14c were purified by silica gel chromatography
and were stable for extended periods of time when stored
as neat materials at ꢁ20 ꢀC. As illustrated in Table 3, triflates
14b and 14c readily participated in Suzuki coupling re-
actions with substituted phenylboronic acids using the anhy-
drous conditions described above to similarly transform
14a. Collectively, these results demonstrate the ability of
our methodology to regioselectively prepare a variety of 1-
substituted-3,4-diester-containing-5-hydroxy-1H-pyrazoles
and to transform them via the corresponding triflates to their
1,5-disubstituted analogs.
environments (see above).15 Instead, the pinacol ester of one
unreactive heterocyclic boronic acid (4-pyridyl) was suc-
cessfully coupled with 14a in moderate yield using the anhy-
drous reaction conditions (Table 2, entry 9). An unrelated
heterocyclic pinacol boronic ester was also coupled with
14a in similar yield using the identical reaction conditions
(Table 2, entry 10). The use of boronic esters may therefore
improve the yields of the desired coupling products in cases
where the coupling reaction is limited by poor solubility of
the corresponding boronic acids. Alkenyl boronic acids
participated in the coupling reaction with 14a and afforded
the corresponding products in yields that were somewhat
lower than those obtained with phenylboronic acids (Table
2, entries 11 and 12). Several alkyl boronic acid derivatives
were also examined in the coupling reaction with 14a (e.g.,
isobutyl, cyclobutyl, and cyclohexyl), but these failed to
provide any of the desired products. Collectively, the exper-
iments described above demonstrate that various 1,5-disub-
stituted-1H-pyrazoles can be prepared from triflate 14a in
good to moderate yields and also detail some of the limita-
tions associated with our methodology.16
As depicted in Scheme 4, treatment of hydrazide 12a with
monomethyl oxalyl chloride may conceivably produce pyr-
idazinone 20 instead of pyrazole 13a. The former entity
would likely be converted to the pyridazinone triflate 21
by the reaction conditions utilized to transform 5-hydroxy-
1H-pyrazoles such as 13a to their corresponding triflates
(cf. Scheme 3). In addition, the Suzuki coupling products
derived from 21 would be structural isomers of compounds
23a–m with identical molecular weights and potentially
Having determined that a variety of boronic acid derivatives
could be successfully coupled to triflate 14a under anhy-
drous conditions, we then explored whether other related
pyrazole triflates could be prepared using our new methodol-
ogy and subsequently utilized as Suzuki reaction substrates.
The synthesis of two such examples (14b and 14c) is illus-
trated in Scheme 3. Triflate 14b was prepared in a manner
analogous to that utilized to synthesize 14a, beginning
with the reductive coupling of cyclohexanecarboxaldehyde
and benzyl carbazate to produce 10b (R1¼CH2cyclohexyl).
In contrast, the monosubstituted benzyl carbazate required
for the preparation of triflate 14c (10c, R1¼phenyl) was
obtained via condensation of commercially available phe-
nylhydrazine and benzyl chloroformate.17 Intermediates
1
very similar H and/or 13C NMR characteristics. Although
the 13C NMR spectra of the Suzuki products described in
this work are consistent with their assignment as 1,5-disub-
stituted-3,4-diester-containing-1H-pyrazoles,19 we wished
to obtain additional evidence that our methodology did not
afford pyridazinone products.
Accordingly, we completed an independent synthesis of an
appropriately substituted 5-methoxy-3(2H)-pyridazinone
derivative and compared this entity with the corresponding
isomeric 1,5-disubstituted-1H-pyrazole (Scheme 5). Thus,
hydrazine 24 (oxalic acid salt) was converted to hydrazone

1158
P. S. Dragovich et al. / Tetrahedron 63 (2007) 1154–1166
Table 3. Suzuki coupling of triflates 14b and 14c
Table 2. Suzuki coupling of triflate 14a
O
O
O
O
O
O
O
N
O
R4B(OH)2 (1.5 eq)
Na2CO3 (2 eq)
MeO
OMe
OTf
MeO
OMe
R4
MeO
OMe
OTf
MeO
OMe
R4
23n-q
R4B(OH)2 (1.5 eq)
Na2CO3 (2 eq)
N
N
N
5% Pd(PPh3)4
DME, 75 °C
N
N
N
R1
N
R1
5% Pd(PPh3)4
DME, 75 °C
14b-c
Entrya
14a
23b-m
OTf
Product
#
Yieldb (%)
Entrya
1
R4
Product #
Yieldb (%)
79
O
O
MeO
Me2N
MeO
23b
23c
23d
23e
OMe
N
1
14b
23n
88
N
F
2
3
4
78
76
72
O
N
O
MeO
F3C
Cl
OMe
CN
N
2
14b
23o
56
O
O
MeO
5
6
7
23f
23g
23h
77
89
34
OMe
N
3
14c
23p
65
N
CN
O
S
O
MeO
OMe
N
4
14c
23q
66
N
Cl
8
23i
23j
33
26
NO2
S
a
N
9c,d
Reactions performed using approximately 1.0 mmol of starting OTf at
0.1 M concentration.
Isolated yield after purification on silica gel.
b
N
10c
11
23k
24
N
ether 27 in good yield.20 Separately, pyrazole triflate 29 was
synthesized from monosubstituted carbazate 10a by conden-
sation with ethyl malonyl chloride followed by removal of
the Cbz moiety, treatment with excess monomethyl oxalyl
chloride, and reaction of the resulting 5-hydroxy-1
H-pyrazole (not shown) with trifluoromethanesulfonic anhy-
dride (cf. Scheme 3). Triflate 29 was subsequently converted
to pyrazole 30 in 27% yield via Suzuki coupling with 2-thi-
enylboronic acid using the anhydrous reaction conditions
described above. Compounds 27 and 30 exhibit distinct
23l
40
30
12
23m
a
Reactions performed using approximately 0.50 mmol of 14a at 0.1 M
concentration.
Isolated yield after purification on silica gel.
The appropriate pinacol boronic ester was employed in lieu of the
corresponding boronic acid.
b
c
d
Use of 4-pyridylboronic acid did not afford any of the desired coupling
product.
1
TLC Rf values, LC retention times, and H and 13C NMR
spectral characteristics, clearly indicating that the major
products derived from the methodology described in this
work are not 6-substituted-3(2H)-pyridazinones.
25 (mixture of isomers) by thermal condensation with com-
mercially available ethyl thiophene-2-glyoxylate. A minor
amount of the corresponding amide condensation product
was also formed during this reaction and this material was
separated from the desired hydrazone via chromatography.
Intermediate 25 was then acylated at elevated temperature
with ethyl malonyl chloride and the resulting crude acyl-
hydrazone (mixture of isomers, not shown) was cyclized to
pyridazinone 26 by exposure to sodium ethoxide. Methyl-
ation of the enol moiety present in 26 then provided methyl
The preparation of pyrazole 30 described in Scheme 5
illustrates one example of the use of our methodology to
regiospecifically prepare 1,5-disubstituted-1H-pyrazoles
containing differentiated ester moieties at the 3- and 4-posi-
tions. Several additional syntheses of such differentiated 1,5-
disubstituted-1H-pyrazoles are depicted in Scheme 6. In one
instance, careful hydrolysis of the Suzuki coupling product
23a with aqueous LiOH gave monoacid 31 in good yield

P. S. Dragovich et al. / Tetrahedron 63 (2007) 1154–1166
1159
O
3. Experimental section
O
MeO
OtBu
Cbz
HN
3.1. General
N
e, f, g
d
N
O
N
10a
OTf
All reactions were performed in septum-sealed vials or
flasks under a slight positive pressure of dry nitrogen. All
commercial reagents were used as received from their
respective suppliers. 1,2-Dimethoxyethane (DME, >99%)
was purchased from Sigma–Aldrich and was used without
additional purification. All other solvents were purchased
from EMD in anhydrous form and were used without
additional purification. All employed solutions of reagents,
acids, and bases were aqueous in nature unless otherwise
indicated. Flash chromatography was performed on silica
gel using either self-packed glass columns (Merck silica
gel 60, 40–63 mM, manual elution) or commercially avail-
able cartridges (Analogix Superflash) and automated elution
systems. Preparative HPLC was performed using a Thomson
C18 ODSA column (5 micron, 50ꢂ21.2 mm ID). 1H NMR
and 13C NMR spectra were recorded at 400 and 100 MHz,
respectively. Chemical shifts are reported in parts per
million (d) using internal solvent signals as references and
coupling constants (when given) are reported in hertz (Hz).
OtBu
34
35
O
h
O
N
O
N
O
O
MeO
MeO
OH
OtBu
i
N
N
Ph
Ph
33
36
c
O
N
O
N
O
O
HO
HO
OH
OMe
Ph
b
a
N
N
23a
Ph
32
31
3.1.1. N0-(3-Methylbutyl)hydrazinecarboxylic acid
benzyl ester (10a). Benzyl carbazate (19.1 g, 115 mmol)
was added to a solution of isovaleraldehyde (9.56 g,
115 mmol) in CH3OH (300 mL) at 23 ꢀC. The reaction mix-
ture was stirred at 23 ꢀC for 30 min, then was cooled to 0 ꢀC.
Glacial acetic acid (12.5 mL) and sodium cyanoborohydride
(18.0 g, 286 mmol) were added sequentially and the mixture
was allowed to warm to 23 ꢀC. After stirring at 23 ꢀC for
17 h, the reaction mixture was concentrated under reduced
pressure to approximately 100 mL volume and was then
partitioned between half-saturated NaHCO3 and a 1:1 mix-
ture of EtOAc and hexanes. The organic layers were dried
over Na2SO4 and were concentrated. Purification of the
residue by chromatography (Superflash cartridge, gradient
elution, 5/50% EtOAc in hexanes) afforded 10a (10.3 g,
77%) as a white, waxy solid: mp¼45–46 ꢀC; Rf¼0.64
Scheme 6. Reagents and conditions: (a) LiOH, CH3OH, 23 ꢀC, 55%; (b)
BBr3, CH2Cl2, 0/23 ꢀC, 78%; (c) BBr3, CH2Cl2/CH3OH, 23 ꢀC, 54%
from 23a; (d) HO2CCH2CO2t-Bu, HATU, i-Pr2NEt, DMF, 23 ꢀC, 74%;
(e) H2, Pd on C, EtOAc, 23 ꢀC; (f) ClC(O)CO2Me, i-Pr2NEt, CH2Cl2,
0/23 ꢀC; (g) Tf2O, pyridine, 0 ꢀC, 73% from 34; (h) phenylboronic
acid, Na2CO3, Pd(PPh3)4, DME, 75 ꢀC, 92%; (i) TFA/CH2Cl2, 23 ꢀC, 92%.
after a simple work-up procedure. Alternatively, treatment of
23a with BBr3 afforded the diacid 32 in good yield following
an equally simple aqueous work-up. Adding methanol to the
crude hydrolysis reaction mixture obtained by exposing 23a
to BBr3 provided monoacid 33 in good yield and suggested
that diacid 32 could be selectively mono-esterified without
isolation.21 Although preparative HPLC methods were uti-
lized to obtain analytical samples of compounds 31–33,
the crude reaction products were relatively pure and could
likely be utilized directly in subsequent transformations
(e.g., amide formation).
1
(50% EtOAc in hexanes); H NMR (CDCl3) d: 0.90 (6H,
d, J¼7.1), 1.36 (2H, q, J¼7.2), 1.58–1.68 (1H, m), 2.88
(2H, t, J¼7.2), 5.13 (2H, s), 7.28–7.34 (5H, m); 13C NMR
(CDCl3) d: 22.6, 25.9, 36.5, 50.1, 66.9, 127.9, 128.0,
128.3, 135.9, 157.0; HRMS (ESI-TOF) calcd for
C13H21N2O2 [M+H]+: 237.1597; found: 237.1596.
The locations of the ester and acid moieties present in com-
pounds 31 and 33 were confirmed by an independent synthe-
sis of the latter molecule (Scheme 6). Thus, monosubstituted
carbazate 10a (Scheme 3) was coupled with commercially
available mono-tert-butyl malonate to afford intermediate 34
in good yield. This material was converted to triflate 35 in
excellent yield by a reaction sequence analogous to that
used to transform intermediate 11a to triflate 14a (cf. Scheme
3). Suzuki coupling of triflate 35 with phenylboronic acid
using the anhydrous reaction conditions described above pro-
ceeded uneventfully and provided compound 36 in 92% yield
after purification by flash chromatography. Selective cleav-
age of the tert-butyl ester present in 36 by exposure to tri-
fluoroacetic acid afforded a material whose crude 1H NMR
spectrum was identical to that of monoacid 33 (prepared
from 23a as described above) and clearly distinct from that
of monoacid 31. These results confirm the structural assign-
ments for compounds 31 and 33 and also illustrate the use of
malonate and oxalyl chloride derivatives containing orthog-
onally protected ester moieties in our new methodology.
3.1.2. N0-Cyclohexylmethylhydrazinecarboxylic acid
benzyl ester (10b). Benzyl carbazate (8.41 g, 50.6 mmol)
was added to a solution of cyclohexylcarboxaldehyde
(5.68 g, 50.6 mmol) in CH3OH (80 mL) at 0 ꢀC. The reaction
mixture was warmed to 23 ꢀC and stirred at that temperature
for 30 min, then was cooled back to 0 ꢀC. Glacial acetic acid
(8.0 mL) and sodium cyanoborohydride (7.95 g, 127 mmol)
were added sequentially and the mixture was allowed to
warm to 23 ꢀC. After stirring at 23 ꢀC for 16 h, the reaction
mixture was partitioned between half-saturated NaHCO3
and a 1:1 mixture of EtOAc and hexanes. The organic layers
were dried over Na2SO4 and were concentrated. Purification
of the residue by chromatography (gradient elution, 15/
40% EtOAc in hexanes) afforded 10b (12.0 g, 44%) as
a white solid: mp¼48–49 ꢀC; Rf¼0.69 (50% EtOAc
1
in hexanes); H NMR (CDCl3) d: 0.94 (2H, q, J¼11.3),

1160
P. S. Dragovich et al. / Tetrahedron 63 (2007) 1154–1166
1.12–1.28 (3H, m), 1.45–1.53 (1H, m), 1.66–1.78 (5H, m),
2.73 (2H, d, J¼5.9), 5.13 (2H, s), 7.31–7.38 (5H, m); 13C
NMR (CDCl3) d: 26.0, 26.6, 31.3, 36.2, 58.5, 67.1, 128.0,
128.1, 128.3, 135.9, 156.9; HRMS (ESI-TOF) calcd for
C15H23N2O2 [M+H]+: 263.1754; found: 263.1751.
(5.25 g, 98%) as a pale yellow oil: Rf¼0.28 (30% EtOAc in
1
hexanes); H NMR (CDCl3, mixture of rotational isomers)
d: 3.41 (br s, 2H), 3.71 (br s, 3H), 5.19 (s, 2H), 7.33–7.41
(m, 10H); 13C NMR (CDCl3, mixture of rotational isomers)
d: 40.5, 41.3, 41.9, 52.9, 68.3, 68.6, 127.8–129.2 (peaks are
broadened due to dynamic processes), 129.4, 129.9, 135.6,
140.8, 141.3, 155.1, 156.2, 165.8, 167.2, 167.8, 168.3;
Anal. Calcd for C18H18N2O5$0.10H2O: C, 62.82; H, 5.33;
N, 8.14. Found: C, 62.49; H, 5.68; N, 8.18.
3.1.3. 3-[N0-Benzyloxycarbonyl-N-(3-methylbutyl)-
hydrazino]-3-oxopropionic acid methyl ester (11a). Com-
pound 10a (12.0 g, 50.78 mmol) was dissolved in anhydrous
1,4-dioxane (300 mL), and methyl malonyl chloride (7.63 g,
55.86 mmol) was slowly added via syringe at 23 ꢀC. The
resulting solution was heated to 100 ꢀC for 1 h after which
time TLC analysis indicated completion of the reaction.
The mixture was allowed to cool to 23 ꢀC and then was
poured into half-saturated aqueous NaHCO3 solution. The
aqueous layer was extracted with a 1:1 mixture of EtOAc
in hexanes. The organic layers were dried over Na2SO4
and concentrated to afford a yellow oil. This residue was
purified by chromatography (gradient elution, 10/70%
EtOAc in hexanes) to provide 11a (7.76 g, 91%) as a pale
yellow oil, which subsequently solidified to a white, waxy
solid; mp¼49–50 ꢀC; Rf¼0.56 (50% EtOAc in hexanes);
1H NMR (DMSO-d6) d: 0.84 (6H, d, J¼6.1), 1.31–1.33
(2H, m), 1.49–1.56 (1H, m), 3.00–3.85 (7H, m), 5.13 (2H,
s), 7.31–7.36 (5H, m), 9.97 (1H, s); 13C NMR (CDCl3) d:
22.5, 25.8, 35.2, 40.7, 46.2, 52.5, 68.1, 128.1, 128.4,
128.5, 135.0, 154.6, 167.9; Anal. Calcd for C17H24N2O5:
C, 60.70; H, 7.19; N, 8.33. Found: C, 60.73; H, 7.19; N, 8.70.
3.1.6. 1-(3-Methylbutyl)-5-trifluoromethanesulfonyloxy-
1H-pyrazole-3,4-dicarboxylic acid dimethyl ester (14a).
Palladium on carbon (0.67 g, 5%) was added to a solution
of 11a (2.51 g, 7.46 mmol) in EtOAc (30 mL) at 23 ꢀC.
The resulting suspension was stirred under an atmosphere
of hydrogen (balloon) for 19 h, then was filtered through
Celite. The Celite was washed with EtOAc and the combined
washings and filtrate were concentrated under reduced pres-
sure to afford a yellow oil (crude 12a). This material was
dissolved in CH2Cl2 (80 mL) and was cooled to 0 ꢀC. N,
N-Diisopropylethylamine (5.7 mL, 32.76 mmol) and mono-
methyl oxalyl chloride (1.43 mL, 15.6 mmol) were then
added sequentially. The resulting dark brown solution was
stirred for 20 min at 0 ꢀC then was warmed to 23 ꢀC for 3 h
and partitioned between 1.0 M HCl and CH2Cl2. The com-
bined organic layers were dried over Na2SO4 and were
concentrated. The residue was purified by chromatography
(Superflash cartridge, gradient elution, 5% CH3OH in
CH2Cl2) to afford 13a (2.00 g, 95%) as a pale yellow liquid:
Rf¼0.22 (5% CH3OH in CH2Cl2); 1H NMR (DMSO-d6) d:
0.87 (6H, d, J¼6.2), 1.42–1.53 (3H, m), 3.50 (3H, s), 3.60–
3.63 (2H, m), 3.67 (3H, s). This material (1.4 g, 5.18 mmol)
was dissolved in pyridine (15 mL) at 0 ꢀC and trifluoro-
methanesulfonic anhydride (1.3 mL, 7.8 mmol) was added
dropwise via syringe. The mixture was allowed to stir for
2 h at 0 ꢀC then was partitioned between 1.0 M HCl and
a 1:1 mixture of EtOAc and hexanes. The combined organic
layers were dried over MgSO4 and concentrated. The residue
was purified by chromatography (Superflash cartridge, gradi-
ent elution, 0/100% EtOAc in hexanes) to provide 14a
(1.79 g, 86%) as a pale yellow oil: Rf¼0.46 (20% EtOAc in
3.1.4. 3-(N0-Benzyloxycarbonyl-N-cyclohexylmethyl-
hydrazino)-3-oxopropionic acid methyl ester (11b).
Compound 10b (7.00 g, 26.70 mmol) was dissolved in
anhydrous 1,4-dioxane (175 mL) and methyl malonyl chlo-
ride (4.01 g, 29.37 mmol) was slowly added via syringe at
23 ꢀC. The resulting solution was heated to 100 ꢀC for 1 h
after which time TLC analysis indicated completion of the
reaction. The mixture was allowed to cool to 23 ꢀC and
then was poured into half-saturated aqueous NaHCO3 solu-
tion. The aqueous layer was extracted with a 1:1 mixture of
EtOAc in hexanes. The organic layers were dried over
Na2SO4 and were concentrated to afford a yellow oil. This
residue was purified by chromatography (Superflash car-
tridge, gradient elution, 2/50% EtOAc in hexanes) to
provide 11b (8.56 g, 89%) as a white, waxy solid: mp¼96–
98 ꢀC; Rf¼0.33 (30% EtOAc in hexanes); 1H NMR
(CDCl3) d: 0.97–0.99 (2H, m), 1.17–1.23 (3H, m), 1.58–
1.73 (6H, m), 3.34–3.89 (7H, m), 5.20 (2H, s), 7.36–7.38
(5H, m); 13C NMR (CDCl3) d: 26.0, 26.6, 30.8, 35.7, 41.0,
52.7, 53.9, 68.4, 128.4, 128.6, 128.8, 135.3, 154.7, 168.4;
Anal. Calcd for C19H26N2O5: C, 62.97; H, 7.23; N, 7.73.
Found: C, 62.98; H, 6.96; N, 7.97.
1
hexanes); H NMR (CDCl3) d: 0.97 (6H, d, J¼7.0), 1.61
(1H, septet, J¼6.7), 1.79–1.84 (2H, m), 3.88 (3H, s), 3.96
(3H, s), 4.14 (2H, t, J¼8.1); 13C NMR (CDCl3) d: 22.4,
26.0, 37.9, 48.4, 52.5, 53.0, 105.2, 118.5 (q, J¼320), 140.8,
142.4, 159.8, 161.0; Anal. Calcd for C13H17F3N2O7S: C,
38.81; H, 4.26; N, 6.96. Found: C, 39.1; H, 4.17; N, 7.20.
3.1.7. 1-Cyclohexylmethyl-5-trifluoromethanesulfonyl-
oxy-1H-pyrazole-3,4-dicarboxylic acid dimethyl ester
(14b). Palladium on carbon (1.07 g, 5%) was added to
a solution of 11b (4.00 g, 11.0 mmol) in EtOAc (75 mL) at
23 ꢀC. The resulting suspension was stirred under an atmo-
sphere of hydrogen (balloon) for 2 h, and then was filtered
through Celite. The Celite was washed with EtOAc and
the combined washings and filtrate were concentrated under
reduced pressure to afford a clear oil. This material was
dissolved in CH2Cl2 (120 mL) and was cooled to 0 ꢀC. N,N-
Diisopropylethylamine (8.0 mL, 46.2 mmol) and mono-
methyl oxalyl chloride (2.0 mL, 22 mmol) were then added
sequentially. The resulting dark brown solution was stirred
for 30 min at 0 ꢀC then was warmed to 23 ꢀC for 4 h and
partitioned between 1.0 M HCl and EtOAc. The combined
3.1.5. 3-(N0-Benzyloxycarbonyl-N-phenylhydrazino)-3-
oxopropionic acid methyl ester (11c). Methyl malonyl
chloride (1.85 mL, 17.25 mmol) was added to a solution of
N0-phenylhydrazinecarboxylic acid benzyl ester17 (10c,
3.80 g, 15.68 mmol) in 1,4-dioxane (90 mL) at 23 ꢀC. The
mixture was refluxed for 1 h, then was cooled to 23 ꢀC and
was partitioned between saturated NaHCO3 and a 1:1 mix-
ture of EtOAc and hexanes. The combined organic layers
were dried over MgSO4 and concentrated. The residue was
purified by chromatography (Superflash cartridge, gradient
elution, 0/70% EtOAc in hexanes) to provide 11c

P. S. Dragovich et al. / Tetrahedron 63 (2007) 1154–1166
1161
organic layers were dried over Na2SO4 and were concen-
trated. The residue was purified by chromatography (Super-
flash cartridge, gradient elution, 5% CH3OH in CH2Cl2) to
afford 13b as a pale yellow solid. This material was dis-
solved in pyridine (20 mL) at 0 ꢀC and trifluoromethanesul-
fonic anhydride (1.7 mL, 10.13 mmol) was added dropwise
via syringe. The mixture was allowed to stir for 2 h at 0 ꢀC
then was partitioned between 1.0 M HCl and a 1:1 mixture
of EtOAc and hexanes. The combined organic layers were
dried over MgSO4 and concentrated. The residue was puri-
fied by chromatography (Superflash cartridge, gradient elu-
tion, 0/100% EtOAc in hexanes) to provide 14b (2.33 g,
68% from 11b) as a pale yellow oil: Rf¼0.54 (20% EtOAc
in hexanes); 1H NMR (CDCl3) d: 0.92–1.01 (2H, m),
1.11–1.27 (3H, m), 1.56 (2H, d, J¼11.0), 1.66–1.74 (3H,
m), 1.94–2.04 (1H, m), 3.87 (3H, s), 3.94–3.95 (5H, m);
13C NMR (CDCl3) d: 25.7, 26.1, 30.6, 38.1, 52.5, 53.0,
55.8, 105.1, 118.5 (q, J¼320), 141.3, 142.3, 159.9, 161.1;
Anal. Calcd for C15H19F3N2O7S: C, 42.06; H, 4.47; N,
6.54. Found: C, 42.29; H, 4.53; N, 6.82.
dissolved in CH2Cl2 (40 mL) and was cooled to 0 ꢀC. N,N-
Diisopropylethylamine (2.63 mL, 15.1 mmol) and mono-
methyl oxalyl chloride (0.622 mL, 7.20 mmol) were then
added sequentially. The resulting orange-red solution was
stirred for 20 min at 0 ꢀC then was warmed to 23 ꢀC for 2 h
and partitioned between 1.0 M HCl and EtOAc. The com-
bined organic layers were dried over Na2SO4 and were
concentrated to afford crude 13a as a brown oil. This mate-
rial was dissolved in CH2Cl2 (40 mL) at 23 ꢀC and 4-di-
methylaminopyridine (0.045 g, 0.37 mmol), p-toluenesulfonyl
chloride (1.03 g, 5.40 mmol), and triethylamine (0.802 mL,
5.75 mmol) were added sequentially. The reaction mixture
was stirred at 23 ꢀC for 1.75 h, then was partitioned between
half-saturated NaHCO3 and a 1:1 mixture of EtOAc and
hexanes. The combined organic layers were dried over
Na2SO4 and were concentrated. The residue was purified
by chromatography (Superflash cartridge, gradient elution,
0/65% EtOAc in hexanes) to provide 15a (1.24 g, 81%
from 11a) as a pale yellow oil: Rf¼0.53 (50% EtOAc in
1
hexanes); H NMR (CDCl3) d: 0.92 (d, 6H, J¼6.6), 1.48–
1.56 (m, 1H), 1.69–1.75 (m, 2H), 2.50 (s, 3H), 3.57 (s, 3H),
3.93 (s, 3H), 3.97–4.02 (m, 2H), 7.40 (d, 2H, J¼8.3), 7.80
(d, 2H, J¼8.3); 13C NMR (CDCl3) d: 22.2, 22.6, 26.1, 38.0,
48.1, 52.2, 52.9, 105.4, 129.1, 130.4, 131.5, 141.6, 142.9,
147.1, 160.8, 161.5; Anal. Calcd for C19H24N2O7S: C,
53.76; H, 5.70; N, 6.60. Found: C, 53.77; H, 5.70; N, 6.72.
3.1.8. 1-Phenyl-5-trifluoromethanesulfonyloxy-1H-pyr-
azole-3,4-dicarboxylic acid dimethyl ester (14c). Palla-
dium on carbon (0.70 g, 10%) was added to a solution of 11c
(5.17 g, 15.10 mmol) in EtOAc (100 mL) at 23 ꢀC. The
resulting suspension was stirred under an atmosphere of
hydrogen (balloon) for 8 h, and then was filtered through
Celite. The Celite was washed with EtOAc and the combined
washings and filtrate were concentrated under reduced
pressure to afford a pale yellow oil. This material was
dissolved in CH2Cl2 (120 mL) and was cooled to 0 ꢀC.
N,N-Diisopropylethylamine (11.05 mL, 63.42 mmol) and
monomethyl oxalyl chloride (2.78 mL, 30.20 mmol) were
then added sequentially. The resulting dark brown solution
was stirred for 20 min at 0 ꢀC then was warmed to 23 ꢀC
for 2 h and partitioned between 1.0 M HCl and CH2Cl2.
The combined organic layers were dried over MgSO4 and
were concentrated to afford crude 13c as a pale yellow solid.
This material was dissolved in pyridine (5.5 mL) at 0 ꢀC and
trifluoromethanesulfonic anhydride (0.547 mL, 3.26 mmol)
was added dropwise via syringe. The mixture was allowed
to stir for 1 h at 0 ꢀC then was partitioned between 1.0 M
HCl and a 1:1 mixture of EtOAc and hexanes. The combined
organic layers were dried over MgSO4 and concentrated.
The residue was purified by chromatography (Superflash
cartridge, gradient elution, 0/40% EtOAc in hexanes) to
provide 14c (0.68 g, 77% from 11c) as a white solid:
3.2. General procedure for Suzuki coupling of triflates
14a–c
The triflate (1 mmol) was dissolved in 10 mL anhydrous
DME and the desired boronic acid or ester (1.5 mmol),
Na2CO3, (2.0 mmol), and Pd(PPh3)4 (0.05 mmol) were
added sequentially. The resulting orange suspension was
purged with nitrogen for 3 min and then was heated at
75 ꢀC for 20 h. After cooling to 23 ꢀC, the reaction mixture
was filtered, concentrated in vacuo, and chromatographed on
silica gel (eluting with EtOAc in hexanes) to afford the
desired coupling products.22
3.2.1. 1-(3-Methylbutyl)-5-phenyl-1H-pyrazole-3,4-di-
carboxylic acid dimethyl ester (23a). Oil; Rf¼0.37 (30%
EtOAc in hexanes); 1H NMR (CDCl3) d: 0.78 (6H, d,
J¼6.2), 1.40–1.50 (1H, m), 1.63–1.69 (2H, m), 3.69 (3H,
s), 3.97 (3H, s), 4.02–4.06 (2H, m), 7.34–7.38 (2H, m),
7.46–7.50 (3H, m); 13C NMR (CDCl3) d: 22.5, 25.9, 39.3,
49.1, 52.2, 52.8, 114.4, 128.3, 128.7, 129.9, 142.3, 145.6,
162.5, 163.3; Anal. Calcd for C18H22N2O4$0.10H2O: C,
65.08; H, 6.73; N, 8.43. Found: C, 64.95; H, 6.36; N, 8.38.
1
mp¼105–106 ꢀC; Rf¼0.55 (30% EtOAc in hexanes); H
NMR (CDCl3) d: 3.94 (s, 3H), 4.00 (s, 3H), 7.54 (br s,
5H); 13C NMR (CDCl3) d: 52.7, 53.3, 106.5, 117.8 (q,
J¼321), 124.8, 129.8, 130.4, 135.5, 141.4, 143.5, 159.8,
161.1; Anal. Calcd for C14H11F3N2O7S: C, 41.18; H, 2.72;
N, 6.86. Found: C, 41.28; H, 3.01; N, 6.92.
3.2.2. 5-(4-Dimethylaminophenyl)-1-(3-methylbutyl)-
1H-pyrazole-3,4-dicarboxylic acid dimethyl ester (23b).
1
Oil; Rf¼0.13 (33% EtOAc in hexanes); H NMR (CDCl3)
d: 0.81 (6H, d, J¼6.6), 1.44–1.52 (1H, m), 1.64–1.73 (2H,
m), 3.06 (s, 6H), 3.72 (3H, s), 3.96 (3H, s), 4.03–4.09 (2H,
m), 6.91 (br s, 2H), 7.26 (2H, d, J¼8.8); 13C NMR
(CDCl3) d: 22.5, 26.0, 30.0, 39.2, 40.6, 48.9, 52.1, 52.6,
112.0, 113.9, 130.7, 142.0, 146.1, 150.7, 162.6, 163.7;
HRMS (ESI-TOF) calcd for C20H28N3O4 [M+H]+:
374.2074; found: 374.2070.
3.1.9. 1-(3-Methylbutyl)-5-(toluene-4-sulfonyloxy)-1H-
pyrazole-3,4-dicarboxylic acid dimethyl ester (15a).
Palladium on carbon (0.35 g, 5%) was added to a solution
of 11a (1.21 g, 3.60 mmol) in EtOAc (25 mL) at 23 ꢀC.
The resulting suspension was stirred under an atmosphere
of hydrogen (balloon) for 1.5 h, then was filtered through
Celite. The Celite was washed with EtOAc and the combined
washings and filtrate were concentrated under reduced pres-
sure to afford crude 12a as a colorless oil. This material was
3.2.3. 5-(4-Methoxyphenyl)-1-(3-methylbutyl)-1H-pyr-
azole-3,4-dicarboxylic acid dimethyl ester (23c). Oil;

1162
P. S. Dragovich et al. / Tetrahedron 63 (2007) 1154–1166
Rf¼0.45 (33% EtOAc in hexanes); 1H NMR (CDCl3) d: 0.80
(6H, d, J¼6.6), 1.44–1.50 (1H, m), 1.64–1.70 (2H, m), 3.71
(3H, s), 3.88 (3H, s), 3.97 (3H, s), 4.03–4.07 (2H, m), 6.99–
7.01 (2H, dt, J¼8.8, 2.2), 7.28–7.30 (2H, dt, J¼8.8, 2.2); 13C
NMR (CDCl3) d: 22.4, 25.9, 39.2, 48.9, 52.1, 52.7, 55.5,
114.1, 116.1, 120.1, 131.2, 142.1, 145.4, 160.5, 162.5,
163.4; Anal. Calcd for C19H24N2O5: C, 63.32; H, 6.71; N,
7.77. Found: C, 63.17; H, 6.91; N, 7.82.
Anal. Calcd for C17H22N2O4S: C, 58.27; H, 6.33; N, 7.99.
Found: C, 58.60; H, 6.26; N, 8.08.
3.2.9. 5-(5-Chlorothiophen-2-yl)-1-(3-methylbutyl)-1H-
pyrazole-3,4-dicarboxylic acid dimethyl ester (23i). Oil;
1
Rf¼0.30 (20% EtOAc in hexanes); H NMR (CDCl3) d:
0.83 (6H, d, J¼6.6), 1.50 (1H, septet, J¼6.6), 1.69 (2H, q,
J¼8.2), 3.75 (3H, s), 3.96 (3H, s), 4.09–4.13 (2H, m), 6.99
(2H, d, J¼4.3), 7.16 (1H, dd, J¼6.1, 1.2), 7.45–7.50 (2H,
m); 13C NMR (CDCl3) d: 22.4, 26.0, 39.3, 49.3, 52.3,
52.7, 116.2, 125.4, 126.5, 130.1, 133.8, 136.9, 141.9,
161.8, 162.8; HRMS (ESI-TOF) calcd for C16H20ClN2O4S
[M+H]+: 371.0827; found: 371.0821.
3.2.4. 1-(3-Methylbutyl)-5-(4-trifluoromethylphenyl)-
1H-pyrazole-3,4-dicarboxylic acid dimethyl ester (23d).
1
Oil; Rf¼0.22 (20% EtOAc in hexanes); H NMR (CDCl3)
d: 0.78 (6H, d, J¼6.2), 1.40–1.50 (1H, m), 1.63–1.69 (2H,
m), 3.69 (3H, s), 3.97 (3H, s), 4.02–4.06 (2H, m), 7.34–
7.38 (2H, m), 7.46–7.50 (3H, m); 13C NMR (CDCl3) d:
22.4, 25.9, 39.1, 49.2, 52.2, 52.8, 114.5, 123.7 (q,
J¼271.7), 125.6 (q, J¼3.8), 130.4, 131.9, 131.9 (q,
J¼33.0), 142.6, 144.1, 162.2, 162.8; Anal. Calcd for
C19H21F3N2O4: C, 57.28; H, 5.31; N, 7.03. Found: C,
57.22; H, 5.49; N, 7.21.
3.2.10. 1-(3-Methylbutyl)-5-pyridin-4-yl-1H-pyrazole-
3,4-dicarboxylic acid dimethyl ester (23j). Oil; Rf¼0.56
1
(5% CH3OH in CH2Cl2); H NMR (CD3OD) d: 0.83 (6H,
d, J¼6.3), 1.46 (1H, septet, J¼6.6), 1.66 (2H, q, J¼7.3),
3.69 (3H, s), 3.95 (3H, s), 4.14 (2H, t, J¼7.3), 7.55 (2H, d,
J¼5.3), 8.75 (2H, br s); 13C NMR (CD3OD) d: 22.6, 26.8,
39.9, 50.3, 52.6, 53.2, 115.2, 126.3, 138.6, 144.0, 150.6,
163.8, 163.9; HRMS (ESI-TOF) calcd for C17H21N3O4
[M+H]+: 332.1605; found: 332.1601.
3.2.5. 5-(4-Chlorophenyl)-1-(3-methylbutyl)-1H-pyr-
azole-3,4-dicarboxylic acid dimethyl ester (23e). Oil;
1
Rf¼0.27 (20% EtOAc in hexanes); H NMR (CDCl3) d:
0.79 (6H, d, J¼6.6), 1.46 (1H, septet, J¼6.6), 1.66 (2H, q,
J¼7.0), 3.69 (3H, s), 3.96 (3H, s), 4.00–4.04 (2H, m), 7.30
(2H, dt, J¼8.6, 2.3), 7.46 (2H, dt, J¼8.2, 1.6); 13C NMR
(CDCl3) d: 22.4, 25.8, 39.1, 49.1, 52.1, 52.7, 114.3, 126.5,
128.9, 131.1, 136.1, 142.4, 144.3, 162.3, 163.0; Anal. Calcd
for C18H21ClN2O4: C, 59.26; H, 5.80; N, 7.68. Found: C,
59.39; H, 6.04; N, 7.92.
3.2.11. 10-Methyl-2-(3-methylbutyl)-2H,10H-[3,40]bipyr-
azolyl-4,5-dicarboxylic acid dimethyl ester (23k). Oil;
1
Rf¼0.13 (33% EtOAc in hexanes); H NMR (CDCl3) d:
0.85 (6H, d, J¼6.6), 1.49 (1H, septet, J¼6.6), 1.67 (2H, dt,
J¼7.8, 6.6), 3.72 (3H, s), 3.89 (3H, s), 3.97 (3H, s), 4.15–
4.19 (2H, m), 7.67 (1H, s), 7.94 (1H, s); 13C NMR
(CDCl3) d: 22.6, 26.1, 30.0, 39.2, 49.2, 52.3, 52.7, 114.2,
131.6, 137.5, 142.2, 162.3, 163.7; HRMS (ESI-TOF) calcd
for C16H23N4O4 [M+H]+: 335.1714; found: 335.1709.
3.2.6. 1-(3-Methylbutyl)-5-o-tolyl-1H-pyrazole-3,4-
dicarboxylic acid dimethyl ester (23f). Oil; Rf¼0.37
1
(20% EtOAc in hexanes); H NMR (CDCl3) d: 0.77 (6H,
3.2.12. 1-(3-Methylbutyl)-5-propenyl-1H-pyrazole-3,4-
dicarboxylic acid dimethyl ester (23l). Oil; Rf¼0.19
d, J¼6.5), 1.44 (1H, septet, J¼6.6), 1.57–1.68 (2H, m),
2.13 (3H, s), 3.65 (3H, s), 3.77–3.84 (1H, m), 3.92–3.95
(1H, m), 3.98 (3H, s), 7.16 (1H, d, J¼7.7), 7.28–7.33 (2H,
m), 7.37–7.41 (1H, m); 13C NMR (CDCl3) d: 19.7, 22.1,
25.5, 38.7, 48.5, 51.7, 52.5, 113.8, 125.6, 127.7, 129.7,
129.8, 130.0, 137.5, 142.3, 145.2, 162.3, 162.6; Anal. Calcd
for C19H24N2O4: C, 66.26; H, 7.02; N, 8.13. Found: C,
66.06; H, 7.16; N, 8.22.
1
(20% EtOAc in hexanes); H NMR (CDCl3) d: 0.96 (6H,
d, J¼6.6), 1.57–1.66 (1H, m), 1.74 (2H, q, J¼7.0), 1.96
(3H, d, J¼5.0), 3.86 (3H, s), 3.93 (3H, s), 4.16 (2H, t,
J¼7.8), 6.26–6.36 (2H, m); 13C NMR (CDCl3) d: 19.6,
22.6, 26.1, 30.0, 39.0, 49.3, 52.3, 52.6, 113.0, 116.5,
136.3, 141.7, 142.0, 162.4, 164.3; Anal. Calcd for
C15H22N2O4: C, 61.21; H, 7.53; N, 9.52. Found: C, 61.29;
H, 7.41; N, 9.55.
3.2.7. 1-(3-Methylbutyl)-5-m-tolyl-1H-pyrazole-3,4-
dicarboxylic acid dimethyl ester (23g). Oil; Rf¼0.37
(20% EtOAc in hexanes); 1H NMR (CDCl3) d: 0.79 (6H, d,
J¼6.9), 1.46 (1H, septet, J¼6.6), 1.65–1.70 (2H, m), 2.42
(3H, s), 3.70 (3H, s), 3.96 (3H, s), 4.03 (2H, t, J¼7.8), 7.15
(2H, d, J¼7.2), 7.28 (1H, d, J¼8.0), 7.36 (1H, t, J¼7.7);
13C NMR (CDCl3) d: 21.5, 22.2, 25.7, 39.0, 48.8, 51.9,
52.5, 114.1, 126.7, 127.9, 128.3, 130.0, 130.3, 138.1,
141.8, 145.5, 162.2, 163.1; Anal. Calcd for C19H24N2O4:
C, 66.26; H, 7.02; N, 8.13. Found: C, 66.43; H, 6.78; N, 8.48.
3.2.13. 5-Cyclopent-1-enyl-1-(3-methylbutyl)-1H-pyr-
azole-3,4-dicarboxylic acid dimethyl ester (23m). Oil;
1
Rf¼0.22 (20% EtOAc in hexanes); H NMR (CDCl3) d:
0.94 (6H, d, J¼6.6), 1.59 (1H, septet, J¼6.6), 1.70–1.76
(2H, m), 2.07 (2H, quintet, J¼7.4), 3.83 (3H, s), 3.94 (3H,
s), 4.09–4.13 (2H, m), 2.56–2.61 (2H, m), 2.62–2.67 (2H,
m), 5.98 (1H, quintet, J¼1.9); 13C NMR (CDCl3) d: 22.6,
24.0, 26.1, 31.1, 33.8, 36.2, 49.2, 52.1, 52.6, 113.6, 131.3,
136.0, 142.0, 142.9, 162.4, 163.5; Anal. Calcd for
C17H24N2O4: C, 63.73; H, 7.55; N, 8.74. Found: C, 63.56;
H, 7.86; N, 9.05.
3.2.8. 1-(3-Methylbutyl)-5-(4-methylthiophen-3-yl)-1H-
pyrazole-3,4-dicarboxylic acid dimethyl ester (23h). Oil;
1
Rf¼0.20 (20% EtOAc in hexanes); H NMR (CDCl3) d:
3.2.14. 1-Cyclohexylmethyl-5-(4-fluorophenyl)-1H-pyr-
azole-3,4-dicarboxylic acid dimethyl ester (23n). Oil;
0.81 (6H, d, J¼6.6), 1.46 (1H, septet, J¼6.6), 1.64 (2H, q,
J¼7.0), 2.07 (3H, s), 3.82–4.10 (2H, br s), 3.70 (3H, s),
3.98 (3H, s), 7.09 (1H, m), 7.30 (1H, d, J¼3.1); 13C NMR
(CDCl3) d: 14.7, 22.4, 25.8, 39.1, 48.9, 52.0, 52.7, 114.3,
122.2, 127.1, 128.7, 137.4, 141.1, 142.6, 162.4, 162.8;
1
Rf¼0.66 (30% EtOAc in hexanes); H NMR (CDCl3) d:
0.69–0.78 (2H, m), 1.00–1.20 (3H, m), 1.45 (2H, d,
J¼10.8), 1.61–1.63 (3H, m), 1.87–1.93 (1H, m), 3.67 (3H,
s), 3.83 (2H, d, J¼7.0), 3.95 (3H, s), 7.14–7.18 (2H, m),

P. S. Dragovich et al. / Tetrahedron 63 (2007) 1154–1166
1163
7.30–7.34 (2H, m); 13C NMR (CDCl3) d: 25.7, 26.3, 30.6,
38.5, 52.1, 52.8, 56.3, 114.3, 115.9 (d, J¼20), 124.2,
132.2, 142.4, 145.3, 162.4, 163.1, 163.4 (d, J¼250); Anal.
Calcd for C20H23FN2O4: C, 64.16; H, 6.19; N, 7.48. Found:
C, 64.06; H, 6.54; N, 7.51.
3.2.19. [(3-Methylbutyl)hydrazono]thiophen-2-yl-acetic
acid ethyl ester (25). A suspension of hydrazine oxalate
24 (6.91 g, 36 mmol), ethyl thiophene-2-glyoxylate (5.53 g,
30 mmol), and sodium acetate (3.69 g, 45 mmol) in absolute
ethanol (100 mL) was stirred at 80 ꢀC under a nitrogen
atmosphere for 40 h. The mixture was cooled to 23 ꢀC,
then was diluted with water and EtOAc and extracted with
EtOAc. The combined organic layers were washed with
brine and dried over Na2SO4. The solvents were removed
in vacuo and the residue was purified by chromatography
(Superflash cartridge, gradient elution, 0/100% EtOAc in
hexanes) to afford 25 as a mixture of two isomers (oil;
5.23 g, 65%): (major isomer) Rf¼0.75 (20% EtOAc in hex-
anes); 1H NMR (CDCl3) d: 0.97 (6H, d, J¼6.8), 1.43 (3H, t,
J¼7.2), 1.57 (2H, m), 1.72 (1H, m), 3.56 (2H, m), 4.35 (2H,
q, J¼7.2), 6.96 (1H, dd, J¼5.2, 4.0), 7.11 (1H, dd, J¼5.2,
1.2), 7.34 (1H, dd, J¼4.0, 1.2); LCMS (ESI+): m/e 269.2
[M+1]+, 537.4 [2M+1]+, 559.0 [2M+Na]+ (exact MS:
268.12).
3.2.15. 5-(3-Cyanophenyl)-1-cyclohexylmethyl-1H-pyr-
azole-3,4-dicarboxylic acid dimethyl ester (23o). Oil;
1
Rf¼0.44 (30% EtOAc in hexanes); H NMR (CDCl3) d:
0.66–0.78 (2H, m), 1.01–1.20 (3H, m), 1.45 (2H, d,
J¼10.8), 1.61–1.63 (3H, m), 1.87–1.94 (1H, m), 3.69 (3H,
s), 3.82 (2H, d, J¼7.2), 3.94 (3H, s), 7.58–7.64 (3H, m),
7.78–7.79 (1H, m); 13C NMR (CDCl3) d: 25.7, 26.3, 30.6,
38.6, 52.3, 52.9, 56.5, 113.2, 114.4, 117.9, 129.6, 129.8,
133.3, 133.6, 134.6, 142.8, 143.9, 162.2, 162.6; HRMS
(ESI-TOF) calcd for C21H23N3O4 [M+H]+: 382.1761;
found: 382.1756.
3.2.16. 5-(4-Cyanophenyl)-1-phenyl-1H-pyrazole-3,4-di-
carboxylic acid dimethyl ester (23p). Purified by reverse
phase HPLC (20–100% CH3CN in H2O; 22 mL/min); oil;
3.2.20. 5-Hydroxy-2-(3-methylbutyl)-3-oxo-6-thiophen-
2-yl-2,3-dihydropyridazine-4-carboxylic acid ethyl ester
(26). Compound 25 (2.08 g, 7.76 mmol) was dissolved in
anhydrous 1,4-dioxane (20 mL), and ethyl malonyl chloride
(1.32 mL, 9.31 mmol) was slowly added via syringe at
23 ꢀC. The reaction mixture was stirred at 100 ꢀC for
20 min, then was cooled to 23 ꢀC. The mixture was diluted
with EtOAc, washed with saturated NaHCO3 and brine,
and dried over Na2SO4. The solvents were removed in vacuo
to give the crude acylhydrazone intermediate. This residue
was dissolved in EtOH (25 mL) at 23 ꢀC, and sodium
ethoxide solution (3.50 mL of a 21 wt % solution in EtOH,
9.31 mmol) was added. The reaction mixture was stirred
for 30 min at 23 ꢀC, then aqueous HCl (5%, 6.3 mL) was
added slowly, and the resulting suspension was extracted
with EtOAc. The combined organic layers were washed
with brine and were dried over Na2SO4. The solvents were
removed in vacuo and the residue was purified by chromato-
graphy (Superflash cartridge, gradient elution, 0/100%
EtOAc in hexanes) to afford 26 (1.67 g, 64%) as yellow
solid: Rf¼0.3 (50% EtOAc in hexanes); 1H NMR (DMSO-
d6) d: 0.91 (6H, d, J¼6.0), 1.27 (3H, t, J¼6.8), 1.51–1.61
(3H, m), 4.03 (2H, t, J¼7.2), 4.26 (2H, q, J¼7.2), 7.11
(1H, dd, J¼5.2, 3.6), 7.59 (1H, dd, J¼4.8, 1.2), 7.78 (1H,
dd, J¼3.6, 1.2); 13C NMR (CDCl3) d: 14.4, 22.7, 26.0,
37.4, 50.9, 63.3, 103.3, 127.4, 127.8, 128.3, 134.9, 135.9,
156.7, 163.8, 171.5; Anal. Calcd for C16H20N2O4S: C,
57.12; H, 5.99; N, 8.33. Found: C, 56.75; H, 6.29; N, 8.36.
1
Rf¼0.25 (30% EtOAc in hexanes); H NMR (CDCl3) d:
3.78 (s, 3H), 3.99 (s, 3H), 7.19 (d, 2H, J¼7.9), 7.33–7.35
(m, 3H), 7.38 (d, 2H, J¼8.0), 7.61 (d, 2H, J¼8.1); 13C
NMR (CDCl3) d: 52.7, 53.1, 113.6, 116.0, 118.1, 125.8,
129.3, 129.5, 131.0, 132.2, 132.5, 138.1, 143.0, 143.9,
162.0, 162.9; HRMS (ESI-TOF) calcd for C20H15N3O4
[M+H]+: 362.1135; found: 362.1130.
3.2.17. 5-(4-Nitrophenyl)-1-phenyl-1H-pyrazole-3,4-
dicarboxylic acid dimethyl ester (23q). Yellow solid;
1
mp¼138–139 ꢀC; Rf¼0.30 (30% EtOAc in hexanes); H
NMR (CDCl3) d: 3.76 (s, 3H), 3.97 (s, 3H), 7.19 (d, 2H,
J¼7.7), 7.29–7.34 (m, 3H), 7.44 (d, 2H, J¼8.6), 8.15 (d,
2H, J¼8.6); 13C NMR (CDCl3) d: 52.7, 53.1, 115.8, 116.1,
123.6, 125.7, 129.4, 131.4, 134.3, 138.1, 142.7, 143.9,
148.3, 162.0, 162.8; Anal. Calcd for C19H15N3O6: C,
59.84; H, 3.96; N, 11.02. Found: C, 59.65; H, 4.31; N, 10.99.
3.2.18. (3-Methylbutyl)hydrazine, oxalic acid salt (24).
This compound was prepared following the method of
Anderson et al.23 A solution of ethyl carbazate (22.0 g,
211 mmol) and isovaleraldehyde (18.2 g, 211 mmol) in
i-PrOH (120 mL) was refluxed for 2 h, then cooled to 23 ꢀC
and let stand overnight. The volatiles were removed under
reduced pressure and the residue was dissolved in EtOH
(100 mL). Platinum on carbon (4.0 g, 5%) was added and the
resulting suspension was stirred at 23 ꢀC under an atmosphere
of hydrogen (balloon) for 55 h. The reaction mixture was
filtered through Celite and then concentrated under reduced
pressure. The residue was suspended in aqueous NaOH
(140 mL of a 30 wt %/wt solution) and heated at 100 ꢀC for
2 h. The reaction mixture was cooled to 23 ꢀC, then was di-
luted with water and extracted with CH2Cl2. The combined
organic layers were dried over Na2SO4, then were transferred
to a large beaker. Solid oxalic acid (18.2 g, 202 mmol) was
added at 23 ꢀC and the mixture was vigorously stirred for
30 min. The resulting precipitate was collected by filtration
and was washed with CH2Cl2 and Et2O to afford (after drying
3.2.21. 5-Methoxy-2-(3-methylbutyl)-3-oxo-6-thiophen-
2-yl-2,3-dihydropyridazine-4-carboxylic acid ethyl ester
(27). Compound 26 (0.726 g, 2.16 mmol) was dissolved in
anhydrous DMF (8 mL), and NaH (60% in mineral oil,
0.259 g, 6.48 mmol) was added in three portions at 23 ꢀC un-
der a nitrogen atmosphere. The reaction mixture was stirred
at 23 ꢀC for 15 min, then was heated to 45 ꢀC and stirred for
15 min. Methyl iodide (1.34 mL, 21.6 mmol) was added and
stirring was continued at 45 ꢀC for 24 h. The mixture was
cooled to 23 ꢀC, quenched with water (10 mL), and ex-
tracted with EtOAc. The combined organic layers were
washed with brine and dried over Na2SO4. The solvent
was removed in vacuo and the residue was purified by
chromatography (Superflash cartridge, gradient elution,
1
in the air) 28.7 g (74%) of 24 as a white solid: H NMR
(DMSO-d6) d: 0.86 (6H, d, J¼6.8), 1.41 (2H, m), 1.60 (1H,
m), 2.88 (2H, m), 8.07 (3H, br s); 13C NMR (DMSO-d6)
d: 22.3, 25.3, 33.3, 48.9, 164.6.

1164
P. S. Dragovich et al. / Tetrahedron 63 (2007) 1154–1166
0/100% EtOAc in hexanes) to afford 27 (0.38 g, 50%) as
a colorless oil: Rf¼0.45 (20% EtOAc in hexanes); 1H
NMR (CDCl3) d: 0.99 (6H, d, J¼6.0), 1.45 (3H, t, J¼7.2),
1.64–1.78 (3H, m), 4.07 (3H, s), 4.19 (2H, m), 4.47 (2H,
q, J¼7.2), 7.08 (1H, dd, J¼5.2, 3.6), 7.39 (1H, dd, J¼4.8,
0.8), 7.68 (1H, dd, J¼3.6, 1.2); 13C NMR (CDCl3) d: 14.4,
22.7, 26.1, 37.3, 50.5, 58.6, 62.9, 115.3, 127.5, 127.8,
128.2, 136.1, 136.8, 153.6, 158.7, 164.6; Anal. Calcd for
C17H22N2O4S: C, 58.27, H, 6.33; N, 7.99. Found: C,
58.02; H, 6.67; N, 8.12.
J¼7.0), 1.60 (1H, septet, J¼6.6), 1.77–1.83 (2H, m), 3.94
(3H, s), 4.10–4.14 (2H, m), 4.35 (2H, q, J¼7.0); 13C NMR
(CDCl3) d: 14.2, 22.3, 26.0, 37.9, 48.2, 52.9, 61.8, 105.5,
118.4 (q, J¼321), 140.6, 142.3, 159.5, 161.1; Anal. Calcd
for C14H19F3N2O7S: C, 40.38; H, 4.60; N, 6.73. Found: C,
40.60; H, 4.75; N, 7.00.
3.2.24. 1-(3-Methylbutyl)-5-thiophen-2-yl-1H-pyrazole-
3,4-dicarboxylic acid 4-ethyl ester 3-methyl ester (30).
This compound was prepared in 27% isolated yield after
chromatography by coupling triflate 29 with 2-thienyl-
boronic acid using the anhydrous reaction conditions de-
3.2.22. 3-[N0-Benzyloxycarbonyl-N-(3-methylbutyl)-
hydrazino]-3-oxopropionic acid ethyl ester (28). Com-
pound 10a (12.5 g, 53 mmol) and ethyl malonyl chloride
(8.1 mL, 64 mmol) were dissolved in anhydrous 1,4-dioxane
(100 mL) and heated to 100 ꢀC for 30 min. The reaction
was cooled to room temperature, quenched with saturated
aqueous NaHCO3, and diluted with water until clear. This
aqueous solution was extracted twice with EtOAc and the
combined organic layers were dried over Na2SO4, filtered,
concentrated in vacuo, and chromatographed (Superflash
cartridge, gradient elution, 0/50% EtOAc in hexanes) to
give 28 (16.9 g, 91%) as a clear yellow oil: Rf¼0.24
1
scribed above: oil; Rf¼0.50 (20% EtOAc in hexanes); H
NMR (CDCl3) d: 0.86 (6H, d, J¼6.8), 1.21 (3H, t, J¼7.2),
1.56 (1H, m), 1.73 (2H, m), 3.97 (3H, s), 4.16 (1H, m),
4.22 (2H, q, J¼7.2), 7.16 (1H, dd, J¼4.8, 3.6), 7.22 (1H,
dd, J¼3.6, 0.8), 7.55 (1H, dd, J¼5.2, 1.2); 13C NMR
(CDCl3) d: 14.2, 22.5, 26.1, 39.4, 49.5, 52.7, 61.3, 116.5,
127.0, 127.4, 128.9, 130.7, 138.1, 141.9, 162.1, 162.7;
Anal. Calcd for C17H22N2O4S: C, 58.27; H, 6.33; N, 7.99.
Found: C, 58.65; H, 6.73; N, 8.21.
3.2.25. 1-(3-Methylbutyl)-5-phenyl-1H-pyrazole-3,4-di-
carboxylic acid 4-methyl ester (31). Compound 23a
(0.11 g, 0.333 mmol) was dissolved in CH3OH (8 mL) at
23 ꢀC. A 2.0 M, aqueous solution of LiOH (2 mL) was
added and the mixture was stirred at 23 ꢀC for 30 min. The
mixture was then partitioned between 1.0 M HCl and
EtOAc. The organic layers were dried over MgSO4 and
filtered. The filtrate was concentrated in vacuo to a faintly
yellow oil. Purification by reverse phase HPLC (20–100%
CH3CN in H2O; 22 mL/min) followed by lyophilization
from a mixture of 1:5 1,4-dioxane and H2O (5 mL) afforded
31 (0.057 g, 55%) as a white solid: mp¼74–75 ꢀC; Rf¼0.2–
0.3 (100% EtOAc); 1H NMR (CDCl3) d: 0.76 (6H, d, J¼6.1),
1.45 (1H, septet, J¼6.7), 1.68 (2H, q, J¼7.5), 3.63 (3H, s),
3.99–4.03 (2H, m), 7.28–7.30 (2H, m), 7.49–7.55 (3H, m);
13C NMR (CDCl3) d: 22.3, 25.9, 39.0, 49.6, 53.2, 110.5,
128.6, 129.4, 130.0, 143.6, 148.2, 160.3, 167.5; HRMS
(ESI-TOF) calcd for C17H20N2O4 [M+H]+: 317.1496;
found: 317.1489.
1
(30% EtOAc in hexanes); H NMR (CDCl3) d: 0.91 (6H,
d, J¼6.2), 1.27 (3H, t, J¼7.0), 1.43 (2H, q, J¼6.6),
1.55–1.62 (1H, m), 3.2–3.6 (4H, br s), 4.16 (2H, q, J¼7.0),
5.20 (2H, s), 7.09 (1H, br s), 7.36–7.38 (5H, m); 13C
NMR (CDCl3) d: 14.4, 22.7, 26.0, 35.4, 41.2, 46.3, 61.8,
68.3, 128.4, 128.3, 128.7, 168.1; Anal. Calcd for
C18H26N2O5: C, 61.70; H, 7.48; N, 7.99. Found: C, 61.74;
H, 7.56; N, 8.09.
3.2.23. 1-(3-Methylbutyl)-5-trifluoromethanesulfonyl-
oxy-1H-pyrazole-3,4-dicarboxylic acid 4-ethyl ester 3-
methyl ester (29). Compound 28 (16.9 g, 48.2 mmol) was
dissolved in EtOH (200 mL) and to this solution was added
palladium on carbon (3.5 g, 5%). The atmosphere in the flask
was removed under reduced pressure and back-filled with
H2; this process was repeated twice. The resulting slurry
was stirred under a slight positive pressure of H2 for 12 h,
upon which it was filtered through Celite and concentrated
in vacuo to give 10.4 g of a clear yellow oil. This material
was dissolved in CH2Cl2 (160 mL) and cooled to 0 ꢀC. To
this solution was added sequentially N,N-diisopropylethyl-
amine (20.1 mL, 120.5 mmol) and monomethyl oxalyl chlo-
ride (5.8 mL, 62.7 mmol). After 1 h at 0 ꢀC, the reaction was
warmed to 23 ꢀC and stirred an additional 2 h, whereupon it
was partitioned between 1.0 M HCl and EtOAc. The com-
bined organic layers were dried over Na2SO4, filtered, and
concentrated. The residue was filtered through a plug of sil-
ica gel that was rinsed well with 10% CH3OH in CH2Cl2.
The filtrate was concentrated under reduced pressure to
give a colorless liquid. This material was dissolved in anhy-
drous pyridine (10 mL) and cooled to 0 ꢀC. To this solution
was added dropwise trifluoromethanesulfonic anhydride
(10 mL). After stirring 30 min at 0 ꢀC and 30 min at
23 ꢀC, the reaction was partitioned between 1.0 M HCl
and EtOAc. The combined organic layers were dried over
MgSO4, filtered, and concentrated. The residue was purified
by chromatography (Superflash cartridge, gradient elution,
0/100% EtOAc in hexanes) to give 29 (5.1 g, 25% from
28) as a clear yellow oil: Rf¼0.4 (25% EtOAc in hexanes);
1H NMR (CDCl3) d: 0.96 (6H, d, J¼6.6), 1.36 (3H, t,
3.2.26. 1-(3-Methylbutyl)-5-phenyl-1H-pyrazole-3,4-di-
carboxylic acid (32). Compound 23a (0.064 g, 0.194 mmol)
was dissolved in CH2Cl2 (1.16 mL) at 23 ꢀC. The mixture
was chilled to 0 ꢀC and boron tribromide (1.16 mL of
a 1.0 M solution in CH2Cl2, 1.16 mmol) was added drop-
wise. The ice bath was removed and the mixture stirred at
23 ꢀC for 5 h. Water (5 mL) was added dropwise and the
mixture was stirred at 23 ꢀC for 5 min then was partitioned
between EtOAc and H2O. The organic layer was washed
with brine, then was dried over MgSO4, filtered, and con-
centrated in vacuo to a brown oil. Purification by reverse
phase HPLC (20–100% CH3CN in H2O; 22 mL/min) fol-
lowed by lyophilization from a mixture of 1:5 1,4-dioxane
and H2O (5 mL) afforded 32 (0.046 g, 78%) as a white solid:
mp¼91–94 ꢀC; Rf¼0.05 (100% EtOAc); 1H NMR (CDCl3)
d: 0.76 (6H, d, J¼6.4), 1.44 (1H, septet, J¼6.5), 1.64 (2H, q,
J¼7.3), 4.02 (2H, t, J¼8.0), 7.30–7.36 (2H, m), 7.46–7.55
(3H, m); 13C NMR (CDCl3) d: 22.3, 25.8, 38.0, 49.5,
112.6, 128.0, 128.7, 129.6, 130.1, 141.2, 150.0, 164.3,
165.0; HRMS (ESI-TOF) calcd for C16H18N2O4 [M+H]+:
303.1339; found: 303.1332.

P. S. Dragovich et al. / Tetrahedron 63 (2007) 1154–1166
1165
3.2.27. 1-(3-Methylbutyl)-5-phenyl-1H-pyrazole-3,4-
dicarboxylic acid 3-methyl ester (33). Compound 23a
(0.1 g, 0.303 mmol) was dissolved in CH2Cl2 (1.82 mL) at
23 ꢀC. The mixture was chilled to 0 ꢀC and boron tribromide
(1.82 mL of a 1.0 M solution in CH2Cl2, 1.82 mmol) was
added dropwise. The ice bath was removed and the mixture
was stirred at 23 ꢀC for 4 h. TLC analysis indicated complete
hydrolysis to produce intermediate 32. CH3OH (5 mL) was
then added dropwise to the reaction mixture and the solution
was stirred at 23 ꢀC for 2.5 h. The mixture was diluted with
EtOAc and washed sequentially with H2O and brine. The
organic phase was dried over MgSO4, filtered, and was con-
centrated in vacuo to a brown oil. Purification by reverse
phase HPLC (20–100% CH3CN in H2O; 22 mL/min) fol-
lowed by lyophilization from a mixture of 1:5 1,4-dioxane
and H2O (5 mL) afforded 33 (0.052 g, 54%) as a white,
(50 mL) at 23 ꢀC. The resulting suspension was stirred under
an atmosphere of hydrogen (balloon) for 1.5 h then was fil-
tered through Celite. The Celite was washed with EtOAc and
the combined washings and filtrate were concentrated under
reduced pressure to afford a clear oil. This material was dis-
solved in CH2Cl2 (75 mL) and was cooled to 0 ꢀC. N,N-Di-
isopropylethylamine (5.63 mL, 32.3 mmol) and monomethyl
oxalyl chloride (1.42 mL, 15.4 mmol) were then added se-
quentially. The resulting dark brown solution was stirred
for 20 min at 0 ꢀC then was warmed to 23 ꢀC for 2.5 h and
partitioned between 1.0 M HCl and CH2Cl2. The combined
organic layers were dried over Na2SO4 and were concen-
trated. The red/brown residue was dissolved in pyridine
(50 mL) at 0 ꢀC and trifluoromethanesulfonic anhydride
(1.37 mL, 8.10 mmol) was added dropwise via syringe.
The mixture was allowed to stir for 1.5 h at 0 ꢀC then was
partitioned between 1.0 M HCl and a 1:1 mixture of EtOAc
and hexanes. The combined organic layers were washed
with saturated NaHCO3, then dried over Na2SO4, and con-
centrated. The residue was purified by chromatography
(Superflash cartridge, gradient elution, 0/50% EtOAc in
hexanes) to provide 35 (2.38 g, 73% from 34) as a pale yel-
low oil: Rf¼0.61 (30% EtOAc in hexanes); 1H NMR
(CDCl3) d: 0.96 (6H, d, J¼6.5), 1.56 (9H, s), 1.58–1.63
(1H, m), 1.77–1.82 (2H, m), 3.94 (3H, s), 4.09–4.13 (2H,
m); 13C NMR (CDCl3) d: 22.4, 26.1, 28.2, 38.1, 48.2,
52.9, 83.4, 107.3, 118.6 (q, J¼320.5), 140.2, 142.1, 159.1,
161.4; Anal. Calcd for C16H23F3N2O7S: C, 43.24; H, 5.22;
N, 6.30. Found: C, 43.29; H, 5.37; N, 6.40.
1
waxy, solid: mp¼93–95 ꢀC; Rf¼0.65 (100% EtOAc); H
NMR (CDCl3) d: 0.78 (6H, d, J¼6.2), 1.45 (1H, septet,
J¼6.6), 1.62–1.68 (2H, m), 4.02–4.06 (2H, m), 4.13 (3H,
s), 7.30–7.33 (2H, m), 7.49–7.53 (3H, m); 13C NMR
(CDCl3) d: 22.3, 25.8, 39.1, 49.5, 54.2, 115.1, 128.3,
128.6, 129.6, 129.9, 138.5, 150.4, 160.5, 166.6; HRMS
(ESI-TOF) calcd for C17H20N2O4 [M+H]+: 317.1496;
found: 317.1493.
3.2.28. 1-(3-Methylbutyl)-5-phenyl-1H-pyrazole-3,4-
dicarboxylic acid 3-methyl ester (33) (alternate prepara-
tion). Compound 36 (0.037 g, 0.099 mmol) was dissolved in
CH2Cl2 (4 mL) at 23 ꢀC. Trifluoroacetic acid (3 mL) was
added and the reaction mixture was stirred at 23 ꢀC for
20 min. Toluene (8 mL) was added and the volatiles were
removed under reduced pressure. Toluene (8 mL) was added
to the residue and the volatiles were again removed under
reduced pressure to afford crude 33 (0.029 g, 92%) as
3.2.31. 1-(3-Methylbutyl)-5-phenyl-1H-pyrazole-3,4-di-
carboxylic acid 4-tert-butyl ester 3-methyl ester (36).
Compound 35 (0.439 g, 0.998 mmol) was dissolved in
10 mL anhydrous DME and phenylboronic acid (0.181 g,
1.48 mmol), Na2CO3 (0.209 g, 1.97 mmol), and Pd(PPh3)4
(0.057 g, 0.049 mmol) were added sequentially. The result-
ing orange suspension was purged with nitrogen for 3 min
and then was heated at 75 ꢀC for 18 h. The reaction mixture
was filtered through Celite and the Celite was washed with
EtOAc. The combined filtrate and washings were concen-
trated in vacuo and purified by chromatography (Superflash
cartridge, gradient elution, 0/40% EtOAc in hexanes) to
provide 36 (0.338 g, 92%) as a colorless oil: Rf¼0.58
1
a colorless oil: H NMR data in CDCl3 identical to those
described above.
3.2.29. 3-[N0-Benzyloxycarbonyl-N-(3-methylbutyl)-
hydrazino]-3-oxopropionic acid tert-butyl ester (34).
Compound 10a (2.57 g, 10.9 mmol) was dissolved in DMF
(60 mL) at 23 ꢀC and mono-tert-butyl malonate (1.67 mL,
10.8 mmol), HATU (4.13 g, 10.9 mmol), and N,N-diisopro-
pylethylamine (4.17 mL, 23.9 mmol) were added sequen-
tially. The reaction mixture was stirred at 23 ꢀC for 1 h,
then the volatiles were removed under reduced pressure.
The residue was partitioned between 0.5 M HCl and a 1:1
mixture of EtOAc and hexanes. The combined organic
layers were dried over Na2SO4 and were concentrated. Puri-
fication of the residue by chromatography (Superflash
cartridge, gradient elution, 0/60% EtOAc in hexanes) pro-
vided 34 (3.06 g, 74%) as a light pink solid: mp¼111–
112 ꢀC; Rf¼0.49 (30% EtOAc in hexanes); 1H NMR
(CDCl3) (mixture of isomers) d: 0.90–0.92 (m), 1.45 (br s),
1.58 (br s), 3.25–3.52 (m), 5.20 (br s), 7.11 (br s), 7.34–
7.39 (m); 13C NMR (CDCl3) d: 22.9, 26.2, 28.4, 35.6,
42.6, 46.4, 68.3, 82.5, 128.4, 128.8, 128.9, 135.5, 154.9,
167.3, 168.7; Anal. Calcd for C20H30N2O5: C, 63.47; H,
7.99; N, 7.40. Found: C, 63.68; H, 8.23; N, 7.61.
1
(30% EtOAc in hexanes); H NMR (CDCl3) d: 0.78 (6H,
d, J¼6.7), 1.33 (9H, s), 1.44–1.47 (1H, m), 1.62–1.68 (2H,
m), 3.96 (3H, s), 3.99–4.03 (2H, m), 7.33–7.35 (2H, m),
7.46–7.48 (3H, m); 13C NMR (CDCl3) d: 22.5, 25.9, 28.2,
39.3, 49.0, 52.6, 81.4, 116.2, 128.6, 128.8, 129.7, 129.9,
142.2, 145.1, 161.8, 162.6; Anal. Calcd for C21H28N2O4:
C, 67.72; H, 7.58; N, 7.52. Found: C, 67.87; H, 7.83; N, 7.75.
Acknowledgements
The authors would like to thank Dr. Stephen Webber for his
support and encouragement during the course of this work.
References and notes
3.2.30. 1-(3-Methylbutyl)-5-trifluoromethanesulfonyl-
oxy-1H-pyrazole-3,4-dicarboxylic acid 4-tert-butyl ester
3-methyl ester (35). Palladium on carbon (0.70 g, 5%)
was added to a solution of 34 (2.78 g, 7.34 mmol) in EtOAc
1. Where applicable, the pyrazole compounds described in this
work are arbitrarily drawn as their 5-hydroxy tautomers.
2. For other preparations of 1-substituted-5-hydroxy-1H-pyr-
azoles containing carboxylic esters or acids at the 3- and

1166
P. S. Dragovich et al. / Tetrahedron 63 (2007) 1154–1166
4-positions, see: (a) Ruhemann, S. J. Chem. Soc. 1907, 91, 1359;
(b) Ruhemann, S. Proc. Chem. Soc., London 1908, 23, 195.
Flegeau, E. F.; Popkin, M. E.; Greaney, M. F. Org. Lett. 2006,
8, 2495.
3. Dvorak, C. A.; Rudolph, D. A.; Ma, S.; Carruthers, N. I. J. Org.
Chem. 2005, 70, 4188.
12. The hydrolysis observed in this example is most likely due to
trace amounts of water present in the Na2CO3 and the small
scale of the experiment.
4. For other syntheses of 1,5-disubstituted-1H-pyrazoles contain-
ing carboxylic esters or acids at the 3- and 4-positions, see: (a)
Vicentini, C. B.; Mazzanti, M.; Morelli, C. F.; Manfrini, M.
J. Heterocycl. Chem. 2000, 37, 175; (b) Washizuka, K.-I.;
Nagai, K.; Minakata, S.; Ryu, I.; Komatsu, M. Tetrahedron
Lett. 1999, 40, 8849; (c) Veronese, A. C.; Callegari, R.;
Morelli, C. F.; Vicentini, C. B. Tetrahedron 1997, 42, 14497;
(d) Kano, K.; Scarpetti, D.; Warner, J. C.; Anselme, J.-P.;
Springer, J. P.; Arison, B. H. Can. J. Chem. 1986, 64, 2211;
(e) Schultz, A. G.; Ravichandran, R. Tetrahedron Lett. 1981,
22, 1771.
5. O-Triflation is inferred by the subsequent transformation of 14a
to the corresponding Suzuki coupling products 23a–m. No at-
tempt was made to quantitate any minor amounts of the corre-
sponding N-triflation product that may also have been formed
during the conversion of 13a to 14a.
13. (a) Nguyen, H. N.; Huang, X.; Buchwald, S. L. J. Am. Chem.
Soc. 2003, 125, 11818; (b) Tang, Z.-Y.; Hu, Q.-S. J. Am.
Chem. Soc. 2004, 126, 3058; (c) Wu, J.; Zhu, Q.; Wang, L.;
Fathi, R.; Yang, Z. J. Org. Chem. 2003, 68, 670.
14. For example, the yield of 23a was reduced to 38% when using
coupling conditions identical to those listed in Table 1, entry 5
but employing 14a that had been stored at ꢁ20 ꢀC and exposed
to the atmosphere five times.
15. The use of DMF as solvent was also examined to improve the
coupling of insoluble heterocyclic boronic acids with 14a.
However, this modification did not afford any of the desired
products.
16. Initial attempts to couple amines to triflate 14a using known lit-
erature conditions did not afford any of the desired products:
˚
(a) Ahman, J.; Buchwald, S. L. Tetrahedron Lett. 1997, 38,
6. This observation also suggests that the acylation of 17 is not
dramatically slower than that of 12a.
7. No attempt was made to quantitate minor amounts of any pyr-
idazinone cyclization products that may have been produced
during the conversion of 12a to 13a.
8. Adduct 22 was not isolated and rigorously characterized.
However, the assignment depicted in Scheme 4 is consistent
with: (a) the molecular weight observed by LCMS, (b) the be-
lief that structure 22 is more likely to be detected by TLC anal-
ysis than other reaction intermediates or side products which
share the same chemical formula (e.g., 18), and (c) the inability
to convert 22 to 13a by its prolonged exposure to the pyrazole-
forming reaction conditions.
6363; (b) Louie, J.; Driver, M. S.; Hamann, B. C.; Hartwig,
J. F. J. Org. Chem. 1997, 62, 1268; (c) Wolfe, J. P.; Buchwald,
S. L. J. Org. Chem. 1997, 62, 1264.
17. Pirkle, W. H.; Gravel, P. L. J. Org. Chem. 1976, 23, 3763.
18. Intermediate 13c was not purified by chromatography prior to
its conversion to triflate 14c.
19. For example, compound 23a exhibits the following 13C reso-
nances in CDCl3: 114.4, 142.3, 145.6 (pyrazole carbon atoms),
162.5, and 163.3 (ester carbonyl carbon atoms) ppm. The
related 1,5-dimethyl-1H-pyrazole-3,4-dicarboxylic acid 3-
ethyl ester 4-methyl ester4c exhibits corresponding resonances
at 112.0, 143.1, 143.6, 162.5, and 163.5 ppm in the same
solvent.
9. For reviews of the Suzuki reaction, see: (a) Kotha, S.; Lahiri,
K.; Kashinath, D. Tetrahedron 2002, 58, 9633; (b) Suzuki, A.
J. Organomet. Chem. 1999, 576, 147; (c) Miyaura, N.;
Suzuki, A. Chem. Rev. 1995, 95, 2457.
10. (a) Littke, A. F.; Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2000, 122,
4020; (b) Aldous, D. J.; Bower, S.; Moorcroft, N.; Todd, M.
Synlett 2001, 150; (c) Fu, J.-M.; Snieckus, V. Tetrahedron
Lett. 1990, 31, 1665; (d) Roppe, J.; Smith, N. D.; Huang, D.;
Tehrani, L.; Wang, B.; Anderson, J.; Brodkin, J.; Chung, J.;
Jiang, X.; King, C.; Munoz, B.; Varney, M. A.; Prasit, P.;
Cosford, N. D. P. J. Med. Chem. 2004, 47, 4645.
20. Methylation of the enol oxygen atom present in 26 is inferred
1
by the close similarity of this molecule’s H and 13C NMR
spectra with those of 27. It is expected that other possible meth-
ylation products (e.g., methylation of the ester or amide oxygen
atoms or the enol carbon atom) would exhibit greater spectral
differences when compared with 26.
21. The formation of an anhydride intermediate following treat-
ment of 23a with BBr3 cannot be excluded.
22. The coupling procedure has also been successfully performed
in parallel using a Bodan mini-block XT under a nitrogen
atmosphere.
11. An additional example of OTf/RB(OH)2 coupling was
reported after our optimization work had been completed:
23. Anderson, F. E.; Kaminsky, D.; Dubnick, B.; Klutchko, S. R.;
Cetenko, W. A.; Gylys, J.; Hart, J. A. J. Med. Chem. 1962, 5, 221.