Synthesis of pyrazole-3-carboxylates and pyrazole-1,5-dicarboxylates by one-pot cyclization of hydrazone dianions with diethyl oxalate

Article abstract of DOI:10.1016/j.tet.2007.12.024

The one-pot cyclization of hydrazone dianions with diethyl oxalate allows a convenient synthesis of pyrazole-3-carboxylates and pyrazole-1,5-dicarboxylates.

Full text of DOI:10.1016/j.tet.2007.12.024

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 2207e2215
www.elsevier.com/locate/tet
Synthesis of pyrazole-3-carboxylates and pyrazole-1,5-dicarboxylates
by one-pot cyclization of hydrazone dianions with diethyl oxalate
Tung T. Dang a, Tuan T. Dang a, Christine Fischer b, Helmar Gorls c, Peter Langer a,b,
*
¨
a Institut fu¨r Chemie, Universita¨t Rostock, Albert-Einstein-Strasse 3a, 18059 Rostock, Germany
b Leibniz-Institut fu¨r Katalyse e. V. an der Universita¨t Rostock, Albert-Einstein-Strasse 29a, 18059 Rostock, Germany
c Institut fu¨r Anorganische und Analytische Chemie, Universita¨t Jena, August-Bebel-Strasse 2, 07740 Jena, Germany
Received 15 October 2007; received in revised form 6 December 2007; accepted 10 December 2007
Available online 15 December 2007
Abstract
The one-pot cyclization of hydrazone dianions with diethyl oxalate allows a convenient synthesis of pyrazole-3-carboxylates and pyrazole-
1,5-dicarboxylates.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
Othersynthesesrelyoncyclizationsof1,3-diketoneswith hydra-
zine8 and on Michael reactions of hydrazines with a,b-unsat-
urated ketones.9 An interesting approach to pyrazoles relies
on the cyclization10 of hydrazone dianions, generated by
means of n-BuLi, with esters,11 acid chlorides12 and
nitriles.13 Pyrazolines have been prepared by cyclization of
dilithiated hydrazones with a-haloketones.14 Recently, the
synthesis of pyrazole-3-carboxylates by the reaction of
hydrazines with propiolates and Weinreb amides has been re-
ported.15 Ranatunge reported16 the synthesis of 5-arylpyra-
zole-3-carboxylates based on the condensation of
hydrazines with 4-aryl-2,4-dioxoesters. The products were
transformed into nitrate-substituted oximes which represent
potent and selective COX-1 and COX-2 inhibitors. We re-
ported the cyclization of oxime and hydrazone dianions
with epibromohydrin to give 1,2-oxazines and oxazolo[3,4-b]-
pyridazin-7-ones, respectively.17 The cyclization of oxime
dianions with diethyl oxalate, which provides a convenient
access to isoxazole-5-carboxylates, has also been studied.18
Recently, we reported a new and convenient approach to pyr-
azole-3-carboxylates by one-pot cyclizations of hydrazone
dianions with diethyl oxalate.19 Herein, we report full details
of these studies. In addition to our preliminary communica-
tion,19 pyrazole-1,5-dicarboxylates (i.e., carbamate-protected
pyrazole-3-carboxylates) have been prepared from the same
starting materials.
Pyrazole-3-carboxylic acid derivatives represent important
building blocks in organic and medicinal chemistry. In addi-
tion, they are of interest in their own right, due to their
pharmacological properties. For example, pyrazole-3-carboxy-
lic acids and pyrazolo[1,5-c]quinazoline-2-carboxylates are
nicotinic acid receptor agonists1 and excitatory amino acid
antagonists, respectively.2 It was shown that related bis(benzo-
[g]indazole-3-carboxamides) exhibit antiproliferative activity
against various cancer cell lines.3 Ethyl 5-propyl-1H-pyr-
azole-3-carboxylate is a key intermediate for the synthesis of
viagra.4 Celecoxib is the first-to-market drug of a number of
selective cyclo-oxygenase 2 (COX-2) inhibitors which are
promising anti-inflammatory and analgetic agents (without
the undesirable side effects associated with other non-steroidal
anti-inflammatories).5 Recently, Nicolaou et al.6 reported that
a pyrazole-substituted epothilone derivative shows a strong
antitumour activity through the stabilization of microtubules
by binding with tubulin. In fact, it is considered to be the
most potent epothilone derivative reported to date.
Pyrazoles are available by 1,3-dipolar cycloaddition reactions
of diazoalkanes with alkynes and related transformations.7
* Corresponding author. Tel.: þ49 381 4986410; fax: þ49 381 4986412.
E-mail address: peter.langer@uni-rostock.de (P. Langer).
0040-4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.12.024

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T.T. Dang et al. / Tetrahedron 64 (2008) 2207e2215
2. Results and discussion
(Scheme 2, Table 1). Likewise, the pyrazole-1,5-dicarboxy-
lates 4aei were obtained when TFA was employed. The cycli-
zation of diethyl oxalate with the dilithiated hydrazone of
p-nitroacetophenone was unsuccessful. The cyclization of
diethyl oxalate with the dianions of hydrazones 1j and 1k, pre-
pared from 3-methylbutan-2-one and pentan-2-one, afforded
the alkyl-substituted pyrazole-3-carboxylates 3j and 3k and
pyrazole-1,5-dicarboxylates 4j and 4k in good yields, respec-
tively. Pyrazoles 3l and 4l, containing a phenyl and a methyl
substituent, were prepared based on the cyclization of diethyl
oxalate with propiophenone-derived hydrazone 1l. The cycli-
zation of diethyl oxalate with the dianions of tetralone hydra-
zone 1m and of cycloalkanone-derived hydrazones 1neq
afforded, after dehydration and decarboxylation with PTSA,
the annulated pyrazole-3-carboxylates 3meq. The pyrazole-
1,5-dicarboxylates 4meq were isolated when the dehydration
was carried out using TFA. The yields of pyrazole-1,5-dicar-
boxylates 4 were in most cases slightly better than those of
pyrazole-3-carboxylates 3.
The reaction of a THF solution of diethyl oxalate (2) with
the dianion of acetophenone hydrazone 1a, generated by
n-butyllithium (2.5 equiv), and subsequent reflux of a toluene
solution of the crude product in the presence of p-toluenesul-
fonic acid (PTSA) afforded pyrazole-3-carboxylate 3a in up to
53% yield (Scheme 1). The best yields were obtained when the
reaction mixture was allowed to slowly warm from ꢀ78 to
20 ꢁC. The solvent was removed in vacuo without aqueous
work-up and a toluene solution of the residue was simply re-
fluxed in the presence of PTSA (4.0 equiv) for 8 h. Notably,
the use of oxalyl chloride or ethyl oxalyl chloride resulted in
polymerization. The employment of a tosyl- rather than carba-
mate-protected hydrazone was not successful (formation of
complex mixtures).
CO2Et
CO2Et
2.5 nBuLi
NH
Li
N
THF
N
N
Li
45 min, –78 °C
15 min, 20 °C
The structure of product 3b was independently confirmed
by X-ray crystal structure analysis (Fig. 1).20
Ph
Ph
1a
A
O
_
_
LiOEt
78 to 20 °C
16 h
OEt
+
EtO
N
CO2Et
HN
O
2
CO2Et
NH
R2
i, ii
R1
CO2Et
O
EtO2C
N
3a-q
NLi
R2
N
N
O
OEt
OLi
N
R1
OEt
CO2Et
1a-q
Ph
N
Ph
i, iii
+
O
CO2Et
N
C
B
EtO2C CO2Et
R2
R1
4a-q
2
TFA
p-TsOH
toluene,
CH2Cl2,
reflux, 8 h
reflux, 8 h
Scheme 2. Synthesis of pyrazole-3-carboxylates 3aeq and pyrazole-1,5-dicarb-
oxylates 4aeq. (i) (1) n-BuLi (2.5 equiv), THF, 45 min, ꢀ78 ꢁC; (2) 15 min,
20 ꢁC; (3) 2, ꢀ78/20 ꢁC, 16 h; (4) removal of THF; (ii) p-TsOH (4.0 equiv),
toluene, reflux, 8 h; (iii) TFA, CH2Cl2, reflux, 8 h.
CO2Et
N
O
O
N
HN
N
OEt
OEt
Ph
Ph
Table 1
Synthesis of 3aeq and 4aeq
3a (53%)
4a (59%)
Scheme 1. Mechanism of the formation of pyrazole-3-carboxylate 3a and of
pyrazole-1,5-dicarboxylate 4a.
3
R1
R2
3a (%)
4a (%)
a
b
c
d
e
f
C6H5
H
H
H
H
H
H
H
H
H
H
H
Me
53
57
61
45
db
45
38
42
47
69
72
62
54
43
40
38
31
59
61
48
47
42
db
db
54
41
72
70
69
49
44
47
42
65
4-MeC6H4
3-MeC6H4
4-(MeO)C6H4
2-(MeO)C6H4
1-Naphthyl
2-Naphthyl
4-ClC6H4
4-FC6H4
i-Pr
The formation of 3a can be explained by attack of the
carbon atom of dianion A onto 2 to give intermediate B, sub-
sequent cyclization by attack of the nitrogen atom onto the
carbonyl group (intermediate C), aromatization upon addition
of the acid and subsequent acid-mediated decarboxylation
(Scheme 1). Reflux of a CH2Cl2 solution of the crude product
in the presence of trifluoroacetic acid (TFA) afforded pyr-
azole-1,5-dicarboxylate 4a in up to 59% yield. This result
can be explained by the lower acidity of TFA compared to
PTSA. Noteworthy, both the protected and the non-protected
pyrazole-carboxylates were prepared from the same starting
material.
g
h
i
j
k
l
n-Pr
C6H5
m
n
o
p
q
C6H4(CH2)2
(CH2)4
(CH2)5
(CH2)6
(CH2)10
The cyclization of the dianions of hydrazones 1aei with
diethyl oxalate and subsequent dehydration with PTSA
afforded the aryl-substituted pyrazole-3-carboxylates 3aei
a
Yields of isolated products.
Not carried out.
b

T.T. Dang et al. / Tetrahedron 64 (2008) 2207e2215
2209
(75 MHz, CDCl3): d¼14.2 (CH2CH3), 61.2 (OCH2CH3),
116.5 (CH, pyrazole), 125.9, 128.7, 129.2 (CH, ArH), 132.0
(C, Ar), 141.1, 148.5 (C, pyrazole), 161.2 (CO). IR (KBr,
cmꢀ1): ~n ¼ 3222 ðmÞ, 3200 (m), 3099 (m), 1802 (m), 1766
(m), 1745 (s), 1609 (s), 1600 (s), 1555 (s), 1432 (s), 1369
(m), 1253 (s), 1212 (s), 989 (s), 957 (m), 853 (s), 823 (m),
707 (m). MS (EI, 70 eV): m/z (%)¼216 (Mþ, 79), 171 (19),
170 (20), 114 (100), 104 (7), 89 (5), 77 (11). HRMS (EI,
70 eV): calcd for C12H12O2N2 (Mþ): 216.0893, found:
216.0892.
Figure 1. Crystal structure of 3b.
In conclusion, we have reported a convenient and regiose-
lective synthesis of pyrazole-3-carboxylates and pyrazole-
1,5-dicarboxylates based on cyclizations of hydrazone dianions
with diethyl oxalate. Noteworthy, both protected and non-
protected pyrazole-carboxylates are available from the same
starting materials.
3.2.2. Ethyl 5-(4-tolyl)-1H-pyrazole-3-carboxylate (3b)
Starting with a THF solution (20 mL) of hydrazone 1b
(2.0 mmol, 0.460 g), n-butyllithium (2.0 mL, 2.0 M solution
in hexane, 2.5 mmol), diethyl oxalate (0.3 mL, 2.2 mmol),
p-TsOH (8.0 mmol, 1.52 g) and 30 mL of toluene, 3b (57%,
262 mg) was isolated as a colourless solid, mp 145e147 ꢁC.
1H NMR (300 MHz, CDCl3): d¼1.21 (t, 3J¼7.2 Hz, 3H,
OCH2CH3), 2.37 (s, 3H, CH3), 4.25 (q, 3J¼7.2 Hz, 2H,
3. Experimental section
3.1. General comments
3
OCH2CH3), 6.95 (s, 1H, CH), 7.18 (d, J¼8.4 Hz, 2H, ArH),
3
7.59 (d, J¼8.4 Hz, 2H, ArH). 13C NMR (75 MHz, CDCl3):
All solvents were dried by standard methods and all reac-
tions were carried out under an inert atmosphere. For 1H
and 13C NMR spectra the deuterated solvents indicated were
used. Mass spectrometric data (MS) were obtained by electron
ionization (EI, 70 eV), chemical ionization (CI, H2O) or elec-
trospray ionization (ESI). For preparative scale chromatogra-
phy, silica gel (60e200 mesh) was used. Melting points are
uncorrected.
d¼12.1 (OCH2CH3), 19.3 (CH3), 58.8 (OCH2CH3), 102.7
(CH), 123.5, 127.5 (CH, ArH), 125.1, 136.5 (2C, Ar), 139.2,
145.1 (C, pyrazole), 159.3 (CO). IR (KBr, cmꢀ1): ~n ¼
3434 ðwÞ, 2985 (w), 1728 (s), 1447 (w), 1294 (s), 1248 (s),
1016 (w), 922 (w), 820 (s), 766 (m). MS (EI, 70 eV): m/z
(%)¼230 (Mþ, 100), 185 (13), 158 (9), 128 (86), 131 (8),
69 (21), 57 (8). HRMS (EI, 70 eV): calcd for C13H14O2N2
(Mþ): 230.1139, found: 230.1134.
3.2. Typical procedure for the synthesis of pyrazole-3-
carboxylates 3aeq
3.2.3. Ethyl 5-(3-tolyl)-1H-pyrazole-3-carboxylate (3c)
Starting with a THF solution (20 mL) of hydrazone 1c
(2.0 mmol, 0.460 g), n-butyllithium (2.0 mL, 2.0 M solution
in hexane, 2.5 mmol), diethyl oxalate (0.3 mL, 2.2 mmol),
p-TsOH (8.0 mmol, 1.52 g) and 30 mL of toluene, 3c (61%,
To a THF solution of hydrazones 1aeq (2.0 mmol) was
added n-butyllithium (2 mL, 2.5 M solution in hexane) at
ꢀ78 ꢁC. After stirring for 45 min at ꢀ78 ꢁC, the mixture was
stirred for 15 min at 20 ꢁC and, subsequently, diethyl oxalate
(2.2 mmol) was added at ꢀ78 ꢁC. After warming of the reac-
tion mixture to 20 ꢁC within 16 h, the solvent (THF) was
removed in vacuo. To the residue were added p-TsOH
(8.0 mmol, 1.52 g) and 30 mL of toluene. The mixture was
stirred under reflux for 8 h. After cooling to 20 ꢁC, a saturated
aqueous solution (20 mL) of NaHCO3 was added and the mix-
ture was stirred for 15 min at 20 ꢁC. The organic layer was sep-
arated, dried (Na2SO4) and filtered. The solvent of the filtrate
was removed in vacuo. The residue was purified by chromato-
graphy (silica gel, n-hexane/EtOAc¼10:1e2:1).
1
189 mg) was isolated as a yellow solid, mp 98e100 ꢁC. H
NMR (300 MHz, CDCl3): d¼1.22 (t, 3J¼7.2 Hz, 3H,
OCH2CH3), 2.27 (s, 3H, CH3), 4.26 (q, 3J¼7.2 Hz, 2H,
3
OCH2CH3), 7.05 (s, 1H, CH), 7.15 (d, J¼8.2 Hz, 1H, ArH),
7.23 (m, 2H, ArH), 7.52 (s, 1H, ArH), 8.21 (br s, NH). 13C
NMR (75 MHz, CDCl3): d¼14.2 (OCH2CH3), 21.5 (CH3),
61.3 (OCH2CH3), 105.4 (CH), 122.9, 126.5, 128.9, 129.5
(CH, ArH), 130.3, 138.7 (2C, Ar), 139.0, 148.8 (C, pyrazole),
160.9 (CO). IR (KBr, cmꢀ1): ~n ¼ 3254 ðsÞ, 3146 (m), 3120
(m), 2983 (m), 2924 (m), 1716 (s), 1916 (m), 1567 (m),
1480 (s), 1464 (s), 1386 (s), 1281 (s), 1170 (s), 998 (m),
848 (m), 794 (s), 779 (s), 697 (m). MS (EI, 70 eV): m/z
(%)¼230.1 (Mþ, 43), 185 (20), 184 (19), 128 (100), 127
(14), 102 (9), 91 (10). HRMS (EI, 70 eV): calcd for
C13H14O2N2 (Mþ): 230.1260, found: 230.1261.
3.2.1. Ethyl 5-phenyl-1H-pyrazole-3-carboxylate (3a)
Starting with a THF solution (20 mL) of hydrazone 1a
(2.0 mmol, 0.412 g), n-butyllithium (2.0 mL, 2.0 M solution
in hexane, 2.5 mmol), diethyl oxalate (0.3 mL, 2.2 mmol),
p-TsOH (8.0 mmol, 1.52 g) and 30 mL of toluene, 3a (53%,
3.2.4. Ethyl 3-(4-methoxyphenyl)-1H-pyrazole-3-
carboxylate (3d)
Starting with a THF solution (20 mL) of hydrazone 1d
(2.0 mmol, 0.472 g), n-butyllithium (2.0 mL, 2.0 M solution
in hexane, 2.5 mmol), diethyl oxalate (0.3 mL, 2.2 mmol),
p-TsOH (8.0 mmol, 1.52 g) and 30 mL of toluene, 3d (45%,
229 mg) was isolated as
a
colourless oil. 1H NMR
3
(300 MHz, CDCl3): d¼1.21 (t, J¼7.2 Hz, 3H, OCH2CH3),
3
4.21 (q, J¼7.2 Hz, 2H, OCH2CH3), 7.12 (s, 1H, CH), 7.35
(m, 3H, ArH), 7.75 (d, 3J¼8.2 Hz, 2H, ArH). 13C NMR

2210
T.T. Dang et al. / Tetrahedron 64 (2008) 2207e2215
221 mg) was isolated as a colourless solid, mp 130e132 ꢁC.
1H NMR (300 MHz, CDCl3): d¼1.61 (t, 3J¼7.2 Hz, 3H,
OCH2CH3), 3.71 (s, 3H, OCH3), 4.12 (q, 3J¼7.2 Hz, 2H,
3.2.7. Ethyl 5-(4-chlorophenyl)-1H-pyrazole-3-carboxylate
(3h)
Starting with a THF solution (20 mL) of hydrazone 1h
(2.0 mmol, 0.480 g), n-butyllithium (2.0 mL, 2.0 M solution
in hexane, 2.5 mmol) and diethyl oxalate (0.3 mL, 2.2 mmol),
p-TsOH (8.0 mmol, 1.52 g) and 30 mL of toluene, 3h (42%,
3
OCH2CH3), 6.79 (s, 1H, CH), 6.81 (d, J¼8.4 Hz, 2H, ArH),
7.51 (d, 3J¼8.4 Hz, 2H, ArH), 10.55 (br, 1H, NH). 13C
NMR (75 MHz, CDCl3): d¼14.0 (OCH2CH3), 55.2 (OCH3),
60.9, 62.2 (OCH2CH3), 104.2 (CH), 114.2, 127.0 (4CH,
ArH), 122.52, 159.81 (2C, Ar), 148.89, 158.65 (C, pyrazole),
161.47 (CO). IR (KBr, cmꢀ1): ~n ¼ 3241 ðmÞ, 3191 (m), 3142
(m), 2990 (m), 1752 (m), 1723 (s), 1699 (s), 1615 (s), 1511 (s),
1456 (s), 1309 (m), 1279 (s), 1243 (s), 995 (s), 964 (m), 832
(s), 811 (m), 722 (m). MS (EI, 70 eV): m/z (%)¼246 (Mþ,
83), 200 (22), 144 (100), 101 (11), 201 (11), 146 (6). HRMS
(EI, 70 eV): calcd for C13H14O3N2 (Mþ): 246.0995, found:
246.0998.
1
211 mg) was isolated as a yellow solid, mp 179e181 ꢁC. H
NMR (300 MHz, CDCl3): d¼1.19 (t, 3J¼7.2 Hz, 3H,
OCH2CH3), 4.18 (q, 3J¼7.2 Hz, 2H, OCH2CH3), 6.90 (s,
3
3
1H, CH), 7.15 (d, J¼8.4 Hz, 2H, ArH), 7.55 (d, J¼8.4 Hz,
2H, ArH), 10.6 (br s, 1H, NH). 13C NMR (75 MHz, CDCl3):
d¼14.2 (OCH2CH3), 61.4 (OCH2CH3), 105.3 (CH), 127.00,
129.14 (CH, ArH), 129.6, 134.5 (2C, Ar), 139.1, 147.9 (C,
pyrazole), 160.7 (CO). IR (KBr, cmꢀ1): ~n ¼ 3132 ðmÞ, 2965
(s), 2939 (m), 2901 (m), 2873 (w), 1769 (s), 1734 (m), 1621
(m), 1444 (s), 1422 (s), 1331 (s), 1248 (s), 1182 (s), 942 (s),
865 (m), 824 (s), 773 (s), 728 (m). MS (EI, 70 eV): m/z
(%)¼252 [Mþ, 37Cl] (28), 250 [Mþ, 35Cl] (83), 206 (11),
204 (27), 148 (100), 113 (23), 75 (9). HRMS (EI, 70 eV):
calcd for C15H15O4N2Cl [Mþ, 35Cl]: 250.0503, found:
250.0502.
3.2.5. Ethyl 5-(naphth-1-yl)-1H-pyrazole-3-carboxylate (3f)
Starting with a THF solution (20 mL) of hydrazone 1f
(2.0 mmol, 0.568 g), n-butyllithium (2.0 mL, 2.0 M solution
in hexane, 2.5 mmol), diethyl oxalate (0.3 mL, 2.2 mmol),
p-TsOH (8.0 mmol, 1.52 g) and 30 mL of toluene, 3f (45%,
1
239 mg) was isolated as a yellow solid, mp 172e174 ꢁC. H
3.2.8. Ethyl 5-(4-fluorophenyl)-1H-pyrazole-3-carboxylate
(3i)
NMR (300 MHz, CDCl3): d¼1.20 (t, 3J¼7.2 Hz, 3H,
OCH2CH3), 4.39 (q, 3J¼7.2 Hz, 2H, OCH2CH3), 7.17 (s,
1H, CH), 7.57 (m, 3H, NaphH), 7.72 (d, 1H, NaphH), 7.96
(d, 2H, NaphH), 8.02 (s, 1H, NaphH). 13C NMR (75 MHz,
CDCl3): d¼18.9 (OCH2CH3), 65.6 (OCH2CH3), 114.0 (CH),
130.5, 130.6, 131.2, 131.8, 132.4, 133.5, 134.1 (CH), 135.0,
148.6, 149.1 (3C), 150.3, 159.0 (C, pyrazole), 160.8 (CO).
IR (KBr, cmꢀ1): ~n ¼ 3138 ðmÞ, 3058 (m), 2979 (m), 1732
(s), 1560 (m), 1382 (s), 1262 (s), 1244 (s), 1144 (s), 1100
(s), 1024 (s), 802 (s), 777 (s), 659 (m), 570 (m). MS (EI,
70 eV): m/z (%)¼266 (Mþ, 19), 221 (100), 193 (26), 139
(25), 127 (56), 73 (35), 45 (16). HRMS (EI, 70 eV): calcd
for C16H14O2N2 (Mþ): 266.1055, found: 266.1048.
Starting with a THF solution (20 mL) of hydrazone 1i
(2.0 mmol, 0.448 g), n-butyllithium (2.0 mL, 2.0 M solution
in hexane, 2.5 mmol), diethyl oxalate (0.3 mL, 2.2 mmol),
p-TsOH (8.0 mmol, 1.52 g) and 30 mL of toluene, 3i (47%,
1
228 mg) was isolated as a yellow solid, mp 188e189 ꢁC. H
NMR (300 MHz, CDCl3): d¼1.19 (t, 3J¼7.2 Hz, 3H,
OCH2CH3), 4.18 (q, 3J¼7.2 Hz, 2H, OCH2CH3), 6.86 (s,
3
3
1H, CH), 7.00 (t, J¼8.4 Hz, 2H, ArH), 7.60 (t, J¼8.4 Hz,
2H, ArH), 9.50 (br s, 1H, NH). 13C NMR (75 MHz, CDCl3):
d¼14.1 (OCH2CH3), 61.3 (OCH2CH3), 105.1 (CH), 115.7,
116.1 (d, 3JCF¼95 Hz, CH, Ar), 127.5, 127.6 (d, 2JCF¼109 Hz,
1
CH, Ar), 126.6 (C, Ar), 160.7, (d, JCF¼240 Hz, CF, Ar),
140.0, 137.6 (C, pyrazole), 164.8 (CO). IR (KBr, cmꢀ1):
~n ¼ 3437 ðwÞ, 3193 (m), 3133 (m), 3058 (m), 2985 (w),
1727 (s), 1612 (w), 1508 (s), 1449 (w), 1411 (m), 1275 (s),
1246 (s), 1197 (s), 994 (s), 840 (s), 824 (s), 779 (s), 615
(m). MS (EI, 70 eV): m/z (%)¼234 [Mþ, (73)], 189 (15),
188 (18), 134 (9), 133 (16), 132 (100). HRMS (EI, 70 eV):
calcd for C12H11O2N2F (Mþ): 234.0799, found: 234.0797.
3.2.6. Ethyl 3-(naphth-2-yl)-1H-pyrazole-3-carboxylate (3g)
Starting with a THF solution (20 mL) of hydrazone 1g
(2.0 mmol, 0.568 g), n-butyllithium (2.0 mL, 2.0 M solution
in hexane, 2.5 mmol), diethyl oxalate (0.3 mL, 2.2 mmol),
p-TsOH (8.0 mmol, 1.52 g) and 30 mL of toluene, 3g (38%,
202 mg) was isolated as a yellow solid, mp 172e174 ꢁC.
1H NMR (300 MHz, CDCl3): d¼1.35 (t, 3J¼7.2 Hz, 3H,
OCH2CH3), 4.37 (q, 3J¼7.2 Hz, 2H, OCH2CH3), 7.41 (s,
1H, CH), 7.57 (m, 2H, NaphH), 7.83e8.02 (m, 4H, NaphH),
8.49 (s, 1H, NaphH). 13C NMR (75 MHz, CDCl3): d¼14.4
(OCH2CH3), 60.2 (OCH2CH3), 105.4 (CH), 123.5, 124.2,
126.6, 127.0, 127.0, 128.2, 128.8 (CH), 135.0, 148.6, 149.1
(3C), 150.3, 159.0 (C, pyrazole), 160.8 (CO). IR (KBr,
cmꢀ1): ~n ¼ 3445 ðmÞ, 3433 (m), 3264 (s), 3137 (m), 2986
(m), 2926 (m), 1712 (s), 1559 (w), 1511 (s), 1481 (m), 1419
(m), 1384 (m), 1259 (s), 1184 (s), 1162 (s), 913 (w), 827 (m),
779 (m), 759 (m). MS (EI, 70 eV): m/z (%)¼266 (Mþ, 15),
220 (11), 165 (18), 164 (100), 163 (32), 127 (12), 126 (6).
HRMS (EI, 70 eV): calcd for C16H14O2N2 (Mþ): 266.1018,
found: 266.1048.
3.2.9. Ethyl 5-isopropyl-1H-pyrazole-3-carboxylate (3j)
Starting with a THF solution (20 mL) of hydrazone 1j
(2.0 mmol, 0.334 g), n-butyllithium (2.0 mL, 2.0 M solution
in hexane, 2.5 mmol), diethyl oxalate (0.3 mL, 2.2 mmol),
p-TsOH (8.0 mmol, 1.52 g) and 30 mL of toluene, 3j (72%,
1
262 mg) was isolated as a yellow solid, mp 61e63 ꢁC. H
3
NMR (300 MHz, CDCl3): d¼1.40 (m, J¼7.2 Hz, 9H, 3CH3),
3.27 (m, 3J¼7.2 Hz, 1H, (CH3)2CH), 4.48 (q, 3J¼7.2 Hz,
2H, OCH2CH3), 6.70 (s, 1H, CH). 13C NMR (75 MHz,
CDCl3): d¼13.5, 22.3 ((CH3)2CH), 32.2 (OCH2CH3), 61.0
(OCH2CH3), 104.6, 105.9 (CH), 142.0, 153.4 (C, pyrazole),
162.5 (CO). IR (KBr, cmꢀ1): ~n ¼ 2997 ðmÞ, 2968 (m), 2835
(m), 1809 (s), 1759 (s), 1534 (w), 1468 (s), 1386 (s), 1231

T.T. Dang et al. / Tetrahedron 64 (2008) 2207e2215
2211
(s), 1219 (s), 1011 (s), 1000 (m), 969 (m), 778 (m). MS (EI,
70 eV): m/z (%)¼182 (Mþ, 27), 121 (100), 107 (23), 79
(24), 67 (17), 29 (21). HRMS (EI, 70 eV): calcd for
C9H14O2N2 (Mþ): 182.1055, found: 182.1052.
(CH2), 61.1 (OCH2CH3), 122.6, 127.2, 128.6, 129.4 (CH),
120.1, 137.0 (2C), 128.3, 133.9, 145.8 (3C, pyrazole), 161.5
(CO). IR (KBr, cmꢀ1): ~n ¼ 3434 ðwÞ, 2985 (m), 2963 (m),
1724 (s), 1443 (w), 1294 (s), 1248 (s), 1016 (w), 928 (w),
820 (s), 761 (m). MS (EI, 70 eV): m/z (%)¼242 (Mþ, 16),
240 (100), 212 (6), 195 (24), 194 (31), 168 (43), 140 (43),
139 (22), 138 (95), 113 (8). HRMS (EI, 70 eV): calcd for
C14H14O2N2 (Mþ): 242.1049, found: 242.1047.
3.2.10. Ethyl 5-n-propyl-1H-pyrazole-3-carboxylate (3k)
Starting with a THF solution (20 mL) of hydrazone 1k
(2.0 mmol, 0.334 g), n-butyllithium (2.0 mL, 2.0 M solution
in hexane, 2.5 mmol), diethyl oxalate (0.3 mL, 2.2 mmol),
p-TsOH (8.0 mmol, 1.52 g) and 30 mL of toluene, 3k (63%,
3.2.13. Ethyl 4,5,6,7-tetrahydro-1H-indazole-3-
carboxylate (3n)
1
228 mg) was isolated as a yellow solid, mp 67e69 ꢁC. H
NMR (300 MHz, CDCl3): d¼0.79 (t, 3J¼7.2 Hz, 3H,
Starting with a THF solution (20 mL) of hydrazone 1n
(2.0 mmol, 0.368 g), n-butyllithium (2.0 mL, 2.0 M solution
in hexane, 2.5 mmol), diethyl oxalate (0.3 mL, 2.2 mmol),
p-TsOH (8.0 mmol, 1.52 g) and 30 mL of toluene, 3n (43%,
3
CH2CH2CH3), 1.19 (t, J¼7.2 Hz, 3H, OCH2CH3), 1.52 (m,
3J¼7.2 Hz, 2H, CH2CH2CH3), 2.54 (t, 3J¼7.2 Hz, 2H,
3
CH2CH2CH3), 4.20 (q, J¼7.2 Hz, 2H, OCH2CH3), 6.45 (s,
1H, CH). 13C NMR (75 MHz, CDCl3): d¼13.9 (CH2CH2CH3),
14.5 (OCH2CH3), 22.7, 29.4 (2CH2), 62.4 (OCH2CH3), 106.4
(CH), 142.4, 147.3 (C, pyrazole), 162.5 (CO). IR (KBr, cmꢀ1):
~n ¼ 2999 ðmÞ, 2964 (m), 2831 (m), 1803 (s), 1765 (s), 1523
(w), 1478 (s), 1389 (s), 1236 (s), 1212 (s), 1019 (s), 1003
(m), 969 (m), 778 (m). MS (EI, 70 eV): m/z (%)¼182 (Mþ,
18), 121 (100), 108 (51), 107 (23), 79 (14), 43 (15), 29 (11).
HRMS (EI, 70 eV): calcd for C9H14O2N2 (Mþ): 182.1055,
found: 182.1051.
167 mg) was isolated as a yellow oil, mp 116e118 ꢁC. H
1
NMR (300 MHz, CDCl3): d¼1.27 (t, 3J¼7.2 Hz, 3H,
OCH2CH3), 1.62e1.85 (m, 4H, CH2), 2.53e2.67 (m, 4H,
3
CH2), 4.27 (q, J¼7.2 Hz, 2H, OCH2CH3), 9.00 (br s, 1H,
NH). 13C NMR (75 MHz, CDCl3): d¼14.4 (OCH2CH3),
21.7, 22.1, 22.3, 22.5 (CH2), 60.9 (OCH2CH3), 120.3, 136.2,
145.6 (3C), 161.7 (CO). IR (KBr, cmꢀ1): ~n ¼ 3240 ðsÞ, 3216
(s), 147 (s), 3130 (s), 2986 (m), 2938 (s), 2859 (s), 2768
(m), 1727 (s), 1719 (s), 1446 (s), 1328 (s), 1262 (s), 1228
(s), 1176 (s), 1156 (s), 933 (s), 863 (s), 778 (s), 623 (s), 582
(s). MS (EI, 70 eV): m/z (%)¼194 (Mþ, 37), 165 (100), 149
(20), 121 (32), 94 (7), 67 (9). HRMS (EI, 70 eV): calcd for
C11H18O2N2 (Mþ): 194.1049, found: 194.1046.
3.2.11. Ethyl 4-methyl-5-phenyl-1H-pyrazole-3-
carboxylate (3l)
Starting with a THF solution (20 mL) of hydrazone 1l
(2.0 mmol, 0.438 g), n-butyllithium (2.0 mL, 2.0 M solution
in hexane, 2.5 mmol), diethyl oxalate (0.3 mL, 2.2 mmol),
p-TsOH (8.0 mmol, 1.52 g) and 30 mL of toluene, 3l (62%,
3.2.14. Ethyl 1,4,5,6,7,8-hexahydrocyclohepta[c]pyrazole-
3-carboxylate (3o)
1
251 mg) was isolated as a colourless oil. H NMR (300 MHz,
3
Starting with a THF solution (20 mL) of hydrazone 1o
(2.0 mmol, 0.396 g), n-butyllithium (2.0 mL, 2.0 M solution
in hexane, 2.5 mmol) and diethyl oxalate (0.3 mL,
2.2 mmol), 3o (40%, 167 mg) was isolated as a yellow solid,
mp 60e63 ꢁC. 1H NMR (300 MHz, CDCl3): d¼1.24
CDCl3): d¼1.22 (t, J¼7.2 Hz, 3H, OCH2CH3), 2.54 (s, 3H,
CH3), 4.25 (q, 3J¼7.2 Hz, 2H, OCH2CH3), 7.48 (m, 3H,
ArH), 7.63 (d, 3J¼8.2 Hz, 2H, ArH). 13C NMR (75 MHz,
CDCl3): d¼10.1 (CH2CH3), 14.5 (CH3), 60.8 (OCH2CH3),
128.0, 128.4, 129.0, 130.2, 130.8 (CH, ArH), 133.7 (C, Ar),
117.4, 138.3, 145.0 (C, pyrazole), 161.21 (CO). IR (KBr,
cmꢀ1): ~n ¼ 3221 ðwÞ, 3123 (m), 3099 (m), 3025 (m), 2956
(w), 1861 (s), 1821 (s), 1399 (s), 1365 (s), 1332 (s), 1299
(s), 1251 (s), 1989 (s), 1005 (s), 986 (s), 865 (m), 779 (m),
763 (m), 699 (m). MS (EI, 70 eV): m/z (%)¼231 (Mþ, 13),
230 (90), 185 (18), 184 (26), 183 (29), 129 (13), 128 (100),
77 (18). HRMS (EI, 70 eV): calcd for C13H14O2N2 (Mþ):
203.1055, found: 203.1057.
3
(t, J¼7.2 Hz, 3H, OCH2CH3), 1.58 (m, 4H, CH2), 1.73 (m,
3
2H, CH2), 2.67, 2.83 (mm, 4H, CH2), 4.28 (q, J¼7.2 Hz,
2H, OCH2CH3), 9.41 (br s, 1H, NH). 13C NMR (75 MHz,
CDCl3): d¼13.2 (OCH2CH3), 23.2, 26.1, 27.1, 28.7, 31.1
(CH2), 59.8 (OCH2CH3), 123.5, 133.6, 149.7 (3C), 160.6
(CO). IR (KBr, cmꢀ1): ~n ¼ 3179 ðsÞ, 3122 (s), 3074 (s),
2923 (s), 2850 (m), 1716 (s), 1581 (w), 1514 (w), 1443 (s),
1414 (s), 1259 (s), 1243 (s), 1158 (s), 1132 (s), 1044 (s), 956
(m), 886 (m), 791 (m), 722 (w). MS (EI, 70 eV): m/z
(%)¼208 (Mþ, 33), 179 (100), 161 (52), 135 (13), 133 (16).
HRMS (EI, 70 eV): calcd for C11H16O2N2 (Mþ): 208.1206,
found: 208.1201.
3.2.12. Ethyl 4,5-dihydro-1H-benzo[g]indazole-3-
carboxylate (3m)
Starting with a THF solution (20 mL) of hydrazone 1m
(2.0 mmol, 0.464 g), n-butyllithium (2.0 mL, 2.0 M solution
in hexane, 2.5 mmol), diethyl oxalate (0.3 mL, 2.2 mmol),
p-TsOH (8.0 mmol, 1.52 g) and 30 mL of toluene, 3m (54%,
261 mg) was isolated as a yellow solid, mp 153e156 ꢁC.
1H NMR (300 MHz, CDCl3): d¼1.21 (t, 3J¼7.2 Hz, 3H,
OCH2CH3), 2.91 (m, 4H, CH2), 4.14 (q, 3J¼7.2 Hz, 2H,
OCH2CH3), 7.17 (m, 3H, ArH), 7.72 (m, 1H, ArH). 13C
NMR (75 MHz, CDCl3): d¼14.7 (OCH2CH3), 19.9, 29.4
3.2.15. Ethyl 4,5,6,7,8,9-hexahydro-1H-cycloocta[c]pyrazole-
3-carboxylate (3p)
Starting with a THF solution (20 mL) of hydrazone 1p
(2.0 mmol, 0.426 g), n-butyllithium (2.0 mL, 2.0 M solution
in hexane, 2.5 mmol), diethyl oxalate (0.3 mL, 2.2 mmol),
p-TsOH (8.0 mmol, 1.52 g) and 30 mL of toluene, 3p (38%,
168 mg) was isolated as a yellow solid, mp 121e123 ꢁC.
1H NMR (300 MHz, CDCl3): d¼1.20 (t, 3J¼7.2 Hz, 3H,

2212
T.T. Dang et al. / Tetrahedron 64 (2008) 2207e2215
OCH2CH3), 1.25e1.40 (m, 4H, 2CH2), 1.50e1.60 (m, 4H,
TFA (1 mL) and 30 mL of CH2Cl2, 4a (59%, 339 mg) was
1
3
CH2), 2.68, 2.75 (mm, 4H, 2CH2), 4.19, 4.30 (q, J¼7.2 Hz,
isolated as a yellow oil. H NMR (300 MHz, CDCl3): d¼
2H, OCH2CH3). 13C NMR (75 MHz, CDCl3): d¼12.9
(OCH2CH3), 20.4, 23.7, 24.5, 24.6, 27.4, 28.9 (6CH2), 59.6
(OCH2CH3), 121.9, 134.6, 146.9 (3C), 160.9 (CO). IR (KBr,
cmꢀ1): ~n ¼ 3183 ðmÞ, 3125 (m), 2928 (m), 2853 (m), 1717
(s), 1456 (s), 1445 (s), 1270 (s), 1245 (s), 1151 (s), 1095 (s),
1043 (s), 948 (m), 865 (m), 779 (m), 732 (m). MS (EI,
70 eV): m/z (%)¼222 (Mþ, 46), 194 (14), 193 (86), 177
(12), 176 (25), 175 (100), 149 (13), 147 (12), 121 (12), 120
(12). HRMS (EI, 70 eV): calcd for C12H18O2N2 (Mþ):
222.1362, found: 222.1358.
1.28e1.39 (tt, J¼7.2 Hz, 6H, 2OCH2CH3), 4.29e4.59 (qq,
3
3J¼7.2 Hz, 4H, 2OCH2CH3), 7.06 (s, 1H, CH), 7.39 (m, 3H,
ArH), 7.87 (d, 3J¼8.2 Hz, 2H, ArH). 13C NMR (75 MHz,
CDCl3): d¼14.4, 14.7 (2CH2CH3), 62.0, 65.6 (2OCH2CH3),
110.4 (CH, pyrazole), 126.8, 127.1, 128.4, 129.1, 129.8 (CH,
ArH), 130.9 (C, Ar), 138.8, 149.4 (C, pyrazole), 154.4,
160.6 (2CO). IR (KBr, cmꢀ1): ~n ¼ 3201 ðmÞ, 3012 (s), 2956
(m), 2931 (w), 1798 (s), 1731 (s), 1615 (m), 1565 (m), 1538
(m), 1465 (s), 1321 (s), 1254 (s), 935 (s), 865 (m), 732 (m).
MS (EI, 70 eV): m/z (%)¼288 (Mþ, 56), 171 (100), 170
(15), 142 (23), 114 (29), 104 (8), 89 (29), 77 (18). HRMS
(EI, 70 eV): calcd for C15H16O4N2 (Mþ): 288.1110, found:
288.1115.
3.2.16. Ethyl 4,5,6,7,8,9,10,11,12,13-decahydro-1H-cyclo-
dodeca[c]pyrazole-3-carboxylate (3q)
Starting with a THF solution (20 mL) of hydrazone 1q
(2.0 mmol, 0.536 g), n-butyllithium (2.0 mL, 2.0 M solution
in hexane, 2.5 mmol), diethyl oxalate (0.3 mL, 2.2 mmol),
p-TsOH (8.0 mmol, 1.52 g) and 30 mL of toluene, 3q (34%,
3.3.2. Diethyl 3-(4-tolyl)-1H-pyrazole-1,5-dicarboxylate
(4b)
Starting with a THF solution (20 mL) of hydrazone 1b
(2.0 mmol, 0.46 g), n-butyllithium (2.0 mL, 2.0 M solution
in hexane, 2.5 mmol), diethyl oxalate (0.3 mL, 2.2 mmol),
TFA (1 mL) and 30 mL of CH2Cl2, 4b (61%, 368 mg) was iso-
1
189 mg) was isolated as a yellow solid, mp 121e123 ꢁC. H
NMR (300 MHz, CDCl3): d¼1.09 (t, 3J¼7.2 Hz, 3H,
OCH2CH3), 1.05e1.42 (m, 12H, CH2), 1.63 (m, 4H, CH2),
2.59 (m, 4H, CH2), 4.15 (q, 3J¼7.2 Hz, 2H, OCH2CH3),
9.92 (br s, 1H, NH). 13C NMR (75 MHz, CDCl3): d¼14.0
(OCH2CH3), 20.5, 21.0, 22.1, 22.9, 24.0, 25.1, 25.2, 25.2,
27.3, 28.1 (CH2), 60.3 (OCH2CH3), 121.9, 137.4, 145.9
(3C), 162.0 (CO). IR (KBr, cmꢀ1): ~n ¼ 3419 ðwÞ, 3178 (m),
3120 (m), 2957 (s), 2930 (s), 2848 (m), 1720 (s), 1577 (w),
1470 (m), 1440 (m), 1410 (m), 1296 (m), 1260 (m), 1161
(s), 1182 (s), 1094 (m), 964 (w), 793 (w), 728 (w). MS (EI,
70 eV): m/z (%)¼278 (Mþ, 69), 235 (23), 232 (37), 205
(100), 168 (28), 149 (21), 122 (39), 121 (20). HRMS (EI,
70 eV): calcd for C16H26O2N2 (Mþ): 278.2115, found:
278.2113.
1
lated as a yellow oil. H NMR (300 MHz, CDCl3): d¼1.31,
1.39 (tt, 3J¼7.2 Hz, 6H, 2OCH2CH3), 2.31 (s, 3H, CH3),
4.25, 4.47 (qq, 3J¼7.2 Hz, 4H, 2OCH2CH3), 6.94 (s, 1H,
3
3
CH), 7.17 (d, J¼8.3 Hz, 2H, ArH), 7.67 (d, J¼8.3 Hz, 2H,
ArH). 13C NMR (75 MHz, CDCl3): d¼14.1, 14.2 (OCH2CH3),
21.4 (CH3), 62.4, 65.3 (OCH2CH3), 110.0 (CH), 126.4, 129.6
(CH, ArH), 128.1, 139.6 (2C, Ar), 138.1, 147.9 (C, pyrazole),
154.2, 160.0 (CO). IR (KBr, cmꢀ1): ~n ¼ 3140 ðmÞ, 2984 (s),
2939 (m), 2871 (w), 1770 (s), 1739 (s), 1616 (m), 1558 (m),
1522 (m), 1403 (s), 1371 (s), 1293 (s), 947 (s), 861 (m), 720
(m). MS (EI, 70 eV): m/z (%)¼302 (Mþ, 60), 229 (19),
203.1 (56), 185 (29), 184 (25), 158 (21), 128 (100), 29.2
(15), 91.1 (10). HRMS (EI, 70 eV): calcd for C16H18O4N2
(Mþ): 302.1260, found: 302.1261.
3.3. Typical procedure for the synthesis of pyrazole-1,5-
carboxylates 4aeq
To a THF solution of hydrazones 1aeq (2.0 mmol) was
added n-butyllithium (2 mL, 2.5 M solution in hexane) at
ꢀ78 ꢁC. After stirring for 45 min at ꢀ78 ꢁC, the mixture
was stirred for 15 min at 20 ꢁC and, subsequently, diethyl oxa-
late (2.2 mmol) was added at ꢀ78 ꢁC. After warming of the
reaction mixture to 20 ꢁC within 16 h, the solvent (THF) was
removed in vacuo. To the residue were added TFA (1 mL) and
30 mL of CH2Cl2. The mixture was stirred under reflux for
8 h. After cooling to 20 ꢁC, a saturated solution (20 mL) of
NaHCO3 was added and the mixture was stirred for 15 min
at 20 ꢁC. The combined organic layers were dried (Na2SO4),
filtered and the solvent of the filtrate was removed in vacuo.
The residue was purified by chromatography (silica gel,
n-hexane/EtOAc¼10:1e2:1).
3.3.3. Diethyl 3-(3-tolyl)-1H-pyrazole-1,5-dicarboxylate
(4c)
Starting with a THF solution (20 mL) of hydrazone 1c
(2.0 mmol, 0.461 g), n-butyllithium (2.0 mL, 2.0 M solution
in hexane, 2.5 mmol), diethyl oxalate (0.3 mL, 2.2 mmol),
TFA (1 mL) and 30 mL of CH2Cl2, 4c (48%, 289 mg) was iso-
lated as a colourless oil. 1H NMR (300 MHz, CDCl3): d¼1.35,
3
1.40 (tt, J¼7.2 Hz, 3H, OCH2CH3), 2.35 (s, 3H, CH3), 4.35,
3
4.47 (qq, J¼7.2 Hz, 2H, OCH2CH3), 6.97 (s, 1H, CH), 7.13,
7.53 (dd, 3J¼8.2 Hz, 2H, ArH), 7.20 (m, 1H, ArH), 7.61
(s, 1H, ArH). 13C NMR (75 MHz, CDCl3): d¼14.2, 14.3
(OCH2CH3), 21.5 (CH3), 62.5, 65.4 (OCH2CH3), 110.3
(CH), 123.8, 127.2, 128.8, 130.4 (CH, ArH), 130.9, 138.7
(2C, Ar), 138.1, 149.6 (C, pyrazole), 154.9, 160.4 (CO). IR
(KBr, cmꢀ1): ~n ¼ 3138 ðwÞ, 3053 (w), 2983 (m), 2938 (m),
2872 (w), 1767 (s), 1739 (s), 1558 (m), 1466 (s), 1446 (s),
1338 (s), 1293 (s), 1155 (s), 963 (s), 862 (s), 791 (s), 771
(s), 705 (m). MS (EI, 70 eV): m/z (%)¼302 (Mþ, 76), 229
(21), 185 (13), 184 (12), 129 (14), 128 (100), 102 (6).
3.3.1. Diethyl phenylpyrazole-1,5-dicarboxylate (4a)
Starting with a THF solution (20 mL) of hydrazone 1a
(2.0 mmol, 0.412 g), n-butyllithium (2.0 mL, 2.0 M solution
in hexane, 2.5 mmol), diethyl oxalate (0.3 mL, 2.2 mmol),

T.T. Dang et al. / Tetrahedron 64 (2008) 2207e2215
2213
HRMS (EI, 70 eV): calcd for C16H18O4N2 (Mþ): 302.1260,
found: 302.1262.
138.6, 148.9 (C, pyrazole), 152.9, 160.0 (CO). IR (KBr,
cmꢀ1): ~n ¼ 3139 ðmÞ, 2984 (s), 2939 (m), 2907 (m), 2873
(w), 1763 (s), 1739 (m), 1602 (m), 1449 (s), 1427 (s), 1337
(s), 1244 (s), 1180 (s), 948 (s), 861 (m), 827 (s), 770 (s),
738 (m). MS (EI, 70 eV): m/z (%)¼324 [Mþ, 37Cl] (30),
322 [Mþ, 35Cl] (54), 250 (74), 205 (37), 148 (100), 113
(33), 75 (9). HRMS (EI, 70 eV): calcd for C15H15O4N2Cl
[Mþ, 35Cl]: 322.0720, found: 322.0724.
3.3.4. Diethyl 3-(4-methoxyphenyl)-1H-pyrazole-1,5-
dicarboxylate (4d)
Starting with a THF solution (20 mL) of hydrazone 1d
(2.0 mmol, 0.472 g), n-butyllithium (2.0 mL, 2.0 M solution
in hexane, 2.5 mmol), diethyl oxalate (0.3 mL, 2.2 mmol),
TFA (1 mL) and 30 mL of CH2Cl2, 4d (47%, 302 mg) was iso-
lated as a colourless oil. 1H NMR (300 MHz, CDCl3): d¼1.31,
1.40 (t, 3J¼7.2 Hz, 3H, OCH2CH3), 3.78 (s, 3H, OCH3), 4.33,
4.47 (q, 3J¼7.2 Hz, 2H, OCH2CH3), 6.85 (s, 1H, CH), 6.90 (d,
2H, ArH), 7.67 (d, 2H, ArH). 13C NMR (75 MHz, CDCl3):
d¼13.9, 14.0 (OCH2CH3), 55.2 (OCH3), 62.1, 65.0
(OCH2CH3), 109.6 (CH), 114.0, 127.7 (CH, ArH), 123.6,
154.6 (2C, Ar), 138.7, 148.7 (C, pyrazole), 157.9, 162.8
(CO). IR (KBr, cmꢀ1): ~n ¼ 3138 ðwÞ, 2983 (m), 2938 (m),
2838 (w), 1761 (s), 1739 (s), 1613 (s), 1524 (m), 1456 (m),
1433 (s), 1371 (s), 1293 (s), 948 (m), 861 (m), 770 (m). MS
(EI, 70 eV): m/z (%)¼318 (Mþ, 75), 246 (45), 231 (10), 200
(33), 200 (22), 144 (100), 174 (14), 146 (10), 29 (16).
HRMS (EI, 70 eV): calcd for C16H18O5N2 (Mþ): 318.1210,
found: 318.1216.
3.3.7. Diethyl 3-(4-fluorophenyl)pyrazole-1,5-
dicarboxylate (4i)
Starting with a THF solution (20 mL) of hydrazone 1i
(2.0 mmol, 0.448 g), n-butyllithium (2.0 mL, 2.0 M solution
in hexane, 2.5 mmol), diethyl oxalate (0.3 mL, 2.2 mmol),
TFA (1 mL) and 30 mL of CH2Cl2, 4i (41%, 250 mg) was
isolated as a colourless oil. 1H NMR (300 MHz, CDCl3):
d¼1.22e1.38 (tt, 3J¼7.2 Hz, 6H, 2OCH2CH3), 4.26e4.49
3
(qq, J¼7.2 Hz, 4H, 2OCH2CH3), 6.89 (s, 1H, CH), 7.00 (t,
3J¼8.3 Hz, 2H, ArH), 7.70 (t, 3J¼8.3 Hz, 2H, ArH). 13C
NMR (75 MHz, CDCl3): d¼14.4, 14.4 (2CH3), 62.7, 65.4
3
(2CH2), 110.1 (CH), 116.1, 116.3 (d, JCF¼95 Hz, CH, Ar),
2
127.5, 127.8 (d, JCF¼109 Hz, CH, Ar), 127.5 (C, Ar),
1
153.4, 160.4 (d, J¼240 Hz, CF, Ar), 138.9, 149.3 (C, pyr-
azole), 162.2, 165.5 (CO). IR (KBr, cmꢀ1): ~n ¼ 3139 ðwÞ,
3067 (w), 2985 (s), 2940 (m), 2908 (w), 1763 (s), 1739 (s),
1608 (s), 1455 (s), 1433 (s), 1371 (s), 1244 (s), 1159 (s),
949 (s), 831 (s), 770 (s). MS (EI, 70 eV): m/z (%)¼306
[Mþ, (45)], 235 (10), 234 (75), 233 (26), 189 (47), 188 (39),
162 (23), 134 (16), 133 (25), 132 (100). HRMS (EI, 70 eV):
calcd for C15H15O4N2F (Mþ): 306.1016, found: 306.1011.
3.3.5. Diethyl 3-(3-methoxyphenyl)-1H-pyrazole-1,5-
dicarboxylate (4e)
Starting with a THF solution (20 mL) of hydrazone 1e
(2.0 mmol, 0.472 g), n-butyllithium (2.0 mL, 2.0 M solution
in hexane, 2.5 mmol), diethyl oxalate (0.3 mL, 2.2 mmol),
TFA (1 mL) and 30 mL of CH2Cl2, 4e (42%, 254 mg) was
isolated as a colourless oil. 1H NMR (300 MHz, CDCl3):
3
d¼1.27, 1.38 (t, J¼7.2 Hz, 3H, 2OCH2CH3), 3.82 (s, 3H,
3.3.8. Diethyl isopropylpyrazole-1,5-dicarboxylate (4j)
Starting with a THF solution (20 mL) of hydrazone 1j
(2.0 mmol, 0.344 g), n-butyllithium (2.0 mL, 2.0 M solution
in hexane, 2.5 mmol), diethyl oxalate (0.3 mL, 2.2 mmol),
TFA (1 mL) and 30 mL of CH2Cl2, 4j (72%, 365 mg) was iso-
lated as a yellow oil. 1H NMR (300 MHz, CDCl3): d¼1.15 (d,
3J¼7.2 Hz, 6H, (CH3)2CH), 1.22e1.34 (tt, 3J¼7.2 Hz, 6H,
2OCH2CH3), 2.95 (m, 3J¼7.2 Hz, 1H, (CH3)2CH), 4.19e
4.43 (qq, 3J¼7.2 Hz, 4H, 2OCH2CH3), 6.49 (s, 1H, CH).
13C NMR (75 MHz, CDCl3): d¼14.2, 28.0 (2OCH2CH3),
22.2 ((CH3)2CH), 62.4, 65.7 (2CH2), 110.1, 110.2 (2CH),
149.3, 160.8 (C, pyrazole), 138.2, 162.1 (2CO). IR (KBr,
cmꢀ1): ~n ¼ 2973 ðmÞ, 2938 (w), 2876 (w), 1776 (s), 1739
(s), 1657 (s), 1479 (s), 1373 (s), 1292 (s), 1235 (s), 1064 (s),
1017 (m), 981 (m), 771 (m). MS (EI, 70 eV): m/z (%)¼254
(Mþ, 38), 209 (12), 182 (16), 181 (62), 167 (30), 137 (38),
136 (26), 135 (70), 121 (100), 67 (12), 29 (31). HRMS (EI,
70 eV): calcd for C12H18O4N2 (Mþ): 254.1261, found:
254.1258.
3
OCH3), 4.32, 4.45 (q, J¼7.2 Hz, 2H, 2OCH2CH3), 7.20 (s,
1H, CH), 6.81e6.96 (m, 2H, ArH), 7.92 (m, 1H, ArH). 13C
NMR (75 MHz, CDCl3): d¼14.2, 14.2 (2OCH2CH3), 55.3
(OCH3), 62.0, 64.9 (OCH2CH3), 111.1 (CH), 114.0, 120.7,
129.2, 130.5 (CH, ArH), 119.9, 151.7 (2C, Ar), 136.5, 148.3
(C, pyrazole), 157.5, 162.0 (CO). IR (KBr, cmꢀ1): ~n ¼
2983 ðmÞ, 2939 (s), 2909 (m), 2839 (w), 1761 (s), 1736 (s),
1604 (m), 1586 (m), 1504 (m), 1470 (s), 1439 (s), 1342 (s),
1294 (s), 948 (s), 861 (m), 829 (m), 758 (m). MS (EI, 70 eV):
m/z (%)¼318 (Mþ, 100), 201 (35), 145 (30), 144 (32), 134
(18), 132.1 (37), 114 (28), 29 (32). HRMS (EI, 70 eV): calcd
for C16H18O4N2 (Mþ): 318.1210, found: 318.1217.
3.3.6. Diethyl 3-(4-chlorophenyl)-1H-pyrazole-1,5-
dicarboxylate (4h)
Starting with a THF solution (20 mL) of hydrazone 1h
(2.0 mmol, 0.481 g), n-butyllithium (2.0 mL, 2.0 M solution
in hexane, 2.5 mmol), diethyl oxalate (0.3 mL, 2.2 mmol),
TFA (1 mL) and 30 mL of CH2Cl2, 4h (54%, 347 mg) was
isolated as a colourless oil. 1H NMR (300 MHz, CDCl3):
d¼1.23, 1.32 (tt, 3J¼7.2 Hz, 6H, 2OCH2CH3), 4.27, 4.39
3.3.9. Diethyl n-propylpyrazole-1,5-dicarboxylate (4k)
Starting with a THF solution (20 mL) of hydrazone 1k
(2.0 mmol, 0.344 g), n-butyllithium (2.0 mL, 2.0 M solution
in hexane, 2.5 mmol), diethyl oxalate (0.3 mL, 2.2 mmol),
TFA (1 mL) and 30 mL of CH2Cl2, 4k (70%, 365 mg) was
isolated as a yellow oil. 1H NMR (300 MHz, CDCl3):
3
(qq, J¼7.2 Hz, 4H, 2OCH2CH3), 6.88 (s, 1H, CH), 7.24 (d,
3J¼8.3 Hz, 2H, ArH), 7.68 (d, 3J¼8.3 Hz, 2H, ArH). 13C
NMR (75 MHz, CDCl3): d¼14.1 (2CH3), 62.4, 65.4 (2CH2),
109.8 (CH), 127.8, 129.0 (CH, ArH), 135.4, 138.6 (2C, Ar),

2214
T.T. Dang et al. / Tetrahedron 64 (2008) 2207e2215
d¼0.85 (t, 3J¼7.2 Hz, 3H, CH2CH2CH3), 1.24e1.40 (tt,
3J¼7.2 Hz, 6H, 2OCH2CH3), 1.61 (m, 3J¼7.2 Hz, 2H,
3.3.12. Diethyl 4,5,6,7-tetrahydroindazole-1,5-
dicarboxylate (4n)
3
CH2CH2CH3), 2.55 (t, J¼7.2 Hz, 2H, CH2CH2CH3), 4.24e
Starting with a THF solution (20 mL) of hydrazone 1n
(2.0 mmol, 0.481 g), n-butyllithium (2.0 mL, 2.0 M solution
in hexane, 2.5 mmol), diethyl oxalate (0.3 mL, 2.2 mmol),
TFA (1 mL) and 30 mL of CH2Cl2, 4n (44%, 234 mg) was iso-
lated as a colourless oil. 1H NMR (300 MHz, CDCl3): d¼1.35,
1.41 (t, 3J¼7.2 Hz, 6H, 2OCH2CH3), 1.63e1.84 (m, 4H,
4.48 (qq, 3J¼7.2 Hz, 4H, 2OCH2CH3), 6.49 (s, 1H, CH).
13C NMR (75 MHz, CDCl3): d¼14.5 (CH2CH2CH3), 22.6,
30.7 (2OCH2CH3), 62.5, 65.3 (2CH2), 111.7 (CH), 149.2,
160.8 (C, pyrazole), 132.9, 158.3 (2CO). IR (KBr, cmꢀ1):
~n ¼ 2964 ðmÞ, 2936 (m), 2874 (m), 1775 (s), 1739 (s), 1558
(w), 1471 (s), 1374 (s), 1297 (s), 1237 (s), 1064 (s), 1018
(m), 986 (m), 770 (m). MS (EI, 70 eV): m/z (%)¼254 (Mþ,
4), 226 (27), 209 (10), 182 (21), 154 (83), 137 (42), 136
(17), 121 (24), 108 (100), 107 (14), 79 (21). HRMS (EI,
70 eV): calcd for C12H18O4N2 (Mþ): 254.1261, found:
254.1264.
3
CH2), 2.66, 2.72 (tt, J¼6.8 Hz, 4H, 2CH2), 4.35, 4.49 (q,
3J¼7.2 Hz, 4H, 2OCH2CH3). 13C NMR (75 MHz, CDCl3):
d¼12.8, 12.9 (OCH2CH3), 19.3, 21.0, 21.2, 22.9 (CH2),
60.4, 63.2 (OCH2CH3), 120.0, 136.9, 146.5 (3C), 152.3,
160.4 (CO). IR (KBr, cmꢀ1): ~n ¼ 2967 ðmÞ, 2935 (s), 2857
(s), 2763 (m), 1725 (s), 1718 (s), 1444 (s), 1326 (s), 1176
(s), 933 (s), 868 (s), 774 (s), 622 (s), 587 (s). MS (EI,
70 eV): m/z (%)¼266 (Mþ, 24), 221 (15), 193 (54), 165
(100), 149 (53), 121 (48), 91 (17), 79 (14), 67 (15). HRMS
(EI, 70 eV): calcd for C13H18O4N2 (Mþ): 266.1267, found:
266.1269.
3.3.10. Diethyl 4-methyl-5-phenylpyrazole-1,5-
dicarboxylate (4l)
Starting with a THF solution (20 mL) of hydrazone 1l
(2.0 mmol, 0.412 g), n-butyllithium (2.0 mL, 2.0 M solution
in hexane, 2.5 mmol), diethyl oxalate (0.3 mL, 2.2 mmol),
TFA (1 mL) and 30 mL of CH2Cl2, 4l (69%, 416 mg) was iso-
3.3.13. Diethyl 4,5,6,7,8-pentahydrocyclohepta[c]pyrazole-
1,5-dicarboxylate (4o)
1
lated as a yellow oil. H NMR (300 MHz, CDCl3): d¼1.30e
1.40 (tt, 3J¼7.2 Hz, 6H, 2OCH2CH3), 2.20 (s, 3H, CH3),
Starting with a THF solution (20 mL) of hydrazone 1o
(2.0 mmol, 0.396 g), n-butyllithium (2.0 mL, 2.0 M solution
in hexane, 2.5 mmol), diethyl oxalate (0.3 mL, 2.2 mmol),
TFA (1 mL) and 30 mL of CH2Cl2, 4o (47%, 263 mg) was iso-
lated as a colourless oil. 1H NMR (300 MHz, CDCl3): d¼1.35,
1.41 (tt, 3J¼7.2 Hz, 6H, 2OCH2CH3), 1.53e1.77 (m, 4H,
CH2), 1.76e1.91 (m, 2H, CH2), 2.59, 2.81 (2ꢂm, 4H, 2CH2),
4.37, 4.44 (2ꢂq, 3J¼7.2 Hz, 2H, OCH2CH3). 13C NMR
(75 MHz, CDCl3): d¼12.0, 12.2 (2OCH2CH3), 22.2, 25.0,
27.6, 28.2, 30.0 (CH2), 62.6, 63.9 (2OCH2CH3), 125.3,
131.8, 147.0 (3C), 156.8, 159.4 (CO). IR (KBr, cmꢀ1): ~n ¼
2923 ðsÞ, 2850 (m), 1716 (s), 1581 (w), 1514 (w), 1443 (s),
1414 (s), 1259 (s), 1243 (s), 1158 (s), 1132 (s), 1044 (s),
956 (m), 886 (m), 791 (m), 722 (w). MS (EI, 70 eV): m/z
(%)¼280 (Mþ, 35), 234 (43), 207 (53), 179 (78), 161 (100),
91 (12), 79 (17), 67 (17). HRMS (EI, 70 eV): calcd for
C14H20O4N2 (Mþ): 280.1417, found: 280.1418.
3
4.30e4.59 (qq, J¼7.2 Hz, 4H, 2OCH2CH3), 7.30 (m, 3H,
ArH), 7.59 (d, 3J¼8.2 Hz, 2H, ArH). 13C NMR (75 MHz,
CDCl3): d¼9.8, 14.5 (2CH2CH3), 15.6 (CH3), 62.9, 65.4
(2OCH2CH3), 128.7, 128.9, 129.3 (CH, ArH), 131.9 (C, Ar),
120.8, 136.1, 149.5 (C, pyrazole), 155.0, 161.6 (2CO). IR
(KBr, cmꢀ1): ~n ¼ 3063 ðwÞ, 2982 (m), 2964 (m), 2953 (m),
2873 (w), 1771 (s), 1758 (s), 1444 (s), 1371 (s), 1345 (s),
1302 (s), 1244 (s), 1216 (s), 1083 (s), 1047 (s), 860 (m),
774 (m), 763 (m), 700 (m). MS (EI, 70 eV): m/z
(%)¼302 (Mþ, 60), 230 (47), 229 (23), 207 (13), 185 (47),
184 (45), 128 (100), 104 (22), 77 (22), 29 (26). HRMS (EI,
70 eV): calcd for C16H18O4N2 (Mþ): 302.1261, found:
302.1263.
3.3.11. Diethyl 4,5-dihydrobenzo[g]indazole-1,5-
carboxylate (4m)
Starting with a THF solution (20 mL) of hydrazone 1m
(2.0 mmol, 0.464 g), n-butyllithium (2.0 mL, 2.0 M solution
in hexane, 2.5 mmol), diethyl oxalate (0.3 mL, 2.2 mmol),
TFA (1 mL) and 30 mL of CH2Cl2, 4m (49%, 339 mg) was
isolated as a yellow solid, mp 131e133 ꢁC. 1H NMR
(300 MHz, CDCl3): d¼1.36e1.51 (tt, 3J¼7.2 Hz, 6H,
3.3.14. Diethyl 4,5,6,7,8,9-hexahydrocycloocta[c]pyrazole-
1,5-dicarboxylate (4p)
Starting with a THF solution (20 mL) of hydrazone 1p
(2.0 mmol, 0.424 g), n-butyllithium (2.0 mL, 2.0 M solution
in hexane, 2.5 mmol), diethyl oxalate (0.3 mL, 2.2 mmol),
TFA (1 mL) and 30 mL of CH2Cl2, 4p (42%, 247 mg) was iso-
lated as a colourless oil. 1H NMR (300 MHz, CDCl3): d¼1.36,
1.37 (t, 3J¼7.2 Hz, 6H, 2OCH2CH3), 1.32e1.54 (m, 4H,
2CH2), 1.63e1.79 (m, 4H, CH2), 2.59, 2.82 (mm, 4H,
2CH2), 4.39, 4.49 (q, 3J¼7.2 Hz, 4H, 2OCH2CH3). 13C
NMR (75 MHz, CDCl3): d¼14.4, 14.52 (2OCH2CH3), 21.6,
25.5, 25.7, 25.8, 30.0, 30.0 (6CH2), 62.4, 65.0 (2OCH2CH3),
126.5, 134.1, 149.4 (3C), 158.3, 161.6 (CO). IR (KBr,
cmꢀ1): ~n ¼ 3481 ðwÞ, 2982 (m), 2930 (s), 2855 (m), 1753
(s), 1732 (s), 1482 (s), 1459 (s), 1384 (s), 1374 (s), 1235 (s),
1157 (s), 1051 (s), 969 (w), 862 (m), 831 (m), 765 (m). MS
(EI, 70 eV): m/z (%)¼294 (Mþ, 22), 248 (31), 221 (33), 193
3
2OCH2CH3), 2.94 (m, 4H, CH2), 4.20e4.58 (qq, J¼7.2 Hz,
4H, 2OCH2CH3), 7.29 (m, 3H, ArH), 8.03 (m, 1H, ArH).
13C NMR (75 MHz, CDCl3): d¼14.2, 19.152 (2OCH2CH3),
29.4, 31.9 (2CH2), 62.0, 64.9 (2OCH2CH3), 124.0, 127.1,
128.5, 129.5 (CH), 127.4, 137.6 (2C), 127.4, 129.5, 151.4
(3C, pyrazole), 149.5, 160.5 (CO). IR (KBr, cmꢀ1): ~n ¼
3434 ðwÞ, 3412 (m), 3142 (m), 2956 (m), 1856 (s), 1567
(w), 1354 (s), 1198 (s), 1101 (w), 899 (w), 856 (s), 785 (m).
MS (EI, 70 eV): m/z (%)¼314 (Mþ, 100), 242 (36), 241
(20), 213 (37), 196 (49), 195 (65), 169 (80), 168 (59), 140
(88), 139 (63), 115 (35). HRMS (EI, 70 eV): calcd for
C17H18O4N2 (Mþ): 314.1261, found: 314.1262.

T.T. Dang et al. / Tetrahedron 64 (2008) 2207e2215
2215
3. Pinna, G. A.; Pirisi, M. A.; Mussino, J.-M.; Murineddu, G.; Loriga, G.;
Pau, A.; Grella, G. E. Il Farmaco 2003, 58, 749.
(29), 193 (29), 177 (23), 176 (53), 175 (100), 161 (20), 122
(23). HRMS (EI, 70 eV): calcd for C15H22O4N2 (Mþ):
294.0118, found: 294.0116.
4. Clayden, J.; Geeves, N.; Warren, S. Organic Chemistry; Oxford University
Press: Oxford, 2000.
5. (a) Dannhardt, G.; Laufer, S. Curr. Med. Chem. 2000, 7, 1101; (b) Carty,
T. J.; Marfat, A. Curr. Opin. Anti-Inflamm. Immunomod. Invest. Drugs
1999, 1, 89.
3.3.15. Diethyl 4,5,6,7,8,9,10,11,12,13-decahydro-
cyclododeca[c]pyrazole-1,5-dicarboxylate (4q)
´
6. Nicolaou, K. C.; Pratt, B. A.; Arseniyadis, S.; Wartmann, M.; OBrate, A.;
Starting with a THF solution (20 mL) of hydrazone 1q
(2.0 mmol, 0.536 g), n-butyllithium (2.0 mL, 2.0 M solution
in hexane, 2.5 mmol), diethyl oxalate (0.3 mL, 2.2 mmol),
TFA (1 mL) and 30 mL of CH2Cl2, 4q (65%, 227.5 mg) was
isolated as a colourless oil. 1H NMR (300 MHz, CDCl3):
Giannakakou, P. ChemMedChem 2006, 1, 41.
7. (a) The Chemistry of Heterocyclic Compounds; Grunanger, P., Vita-Finzi,
P., Eds.; John Wiley: New York, NY, 1991; Vol. 49, Part 1; (b) Aggarwal,
V. K.; de Vincente, J.; Bonnert, R. V. J. Org. Chem. 2003, 68, 5381; (c)
Deng, X.; Mani, N. S. Org. Lett. 2006, 8, 3505.
3
8. (a) Handbook of Heterocyclic Chemistry; Katritzky, A. R., Pozharskii,
A. F., Eds.; Elsevier Sciences: Amsterdam, 2000; (b) Heller, S. T.;
Natarajan, S. R. Org. Lett. 2006, 8, 2675; (c) Humphries, P. A.; Finefield,
J. M. Tetrahedron Lett. 2006, 47, 2443.
d¼1.36, 1.37 (t, J¼7.2 Hz, 6H, 2OCH2CH3), 1.32e1.54 (m,
12H, 6CH2), 1.63, 1.79 (m, 4H, CH2), 2.51, 2.68 (t, 4H,
3
2CH2), 4.39, 4.49 (q, J¼7.2 Hz, 4H, 2OCH2CH3). 13C NMR
(75 MHz, CDCl3): d¼13.7, 13.9 (2OCH2CH3), 20.1, 22.7,
22.8, 23.0, 24.7, 24.9, 25.5, 25.6, 27.4, 27.9 (10CH2), 61.68,
64.39 (2OCH2CH3), 125.9, 134.61, 149.0 (3C), 156.8, 161.7
(CO). IR (KBr, cmꢀ1): ~n ¼ 3485 ðwÞ, 2989 (m), 2927 (s),
2855 (m), 1749 (s), 1736 (s), 1485 (s), 1459 (s), 1381 (s),
1374 (s), 1235 (s), 1157 (s), 1049 (s), 969 (w), 862 (m), 831
(m), 765 (m). MS (EI, 70 eV): m/z (%)¼350 (Mþ, 22), 278
(19), 277 (100), 240 (17), 231 (21), 205 (11), 121 (10).
HRMS (EI, 70 eV): calcd for C15H22O4N2 (Mþ): 350.2200,
found: 350.2195.
9. (a) Bishop, B. C. Synthesis 2004, 43; (b) Ahmed, S. M.; Kobayashi, K.;
Mori, A. Org. Lett. 2005, 7, 4487.
10. For a review of cyclization reactions of dianions in organic synthesis, see:
Langer, P.; Freiberg, W. Chem. Rev. 2004, 104, 4125.
11. Matsumura, N.; Kunigihara, A.; Yoneda, S. Tetrahedron Lett. 1983,
24, 3239.
12. Matsumura, N.; Kunigihara, A.; Yoneda, S. Tetrahedron Lett. 1984,
25, 4529.
13. Duncan, D. C.; Trumbo, T. A.; Almquist, C. D.; Lentz, T. A.; Beam, C. F.
J. Heterocycl. Chem. 1987, 24, 555.
14. Beam, C. F.; Reames, D. C.; Harris, C. E.; Dasher, I. W.; Hollinger, W. M.;
Shealy, N. L.; Sandifer, R. M.; Perkins, M.; Hauser, C. R. J. Org. Chem.
1975, 40, 514.
Acknowledgements
15. Persson, T.; Nielsen, J. Org. Lett. 2006, 8, 3219.
16. Ranatunge, R. R.; Augustyniak, M.; Bandarage, U. K.; Earl, R. A.; Ellis,
J. L.; Garvey, D. S.; Janero, D. R.; Letts, L. G.; Martino, A. M.; Murty,
M. G.; Richardson, S. K.; Schroeder, J. D.; Shumway, M. J.; Tam,
S. W.; Trocha, A. M.; Young, D. V. J. Med. Chem. 2004, 47, 2180.
17. Dang, T. T.; Albrecht, U.; Gerwien, K.; Siebert, M.; Langer, P. J. Org.
Chem. 2006, 71, 2293.
Financial support from the Ministry of Education and
Training of Vietnam (scholarships for T.T.D. and T.T.D.) is
gratefully acknowledged.
References and notes
18. Dang, T. T.; Albrecht, U.; Langer, P. Synthesis 2006, 2515.
19. Dang, T. T.; Dang, T. T.; Langer, P. Tetrahedron Lett. 2007, 48, 3591.
20. CCDC-670182 (3b) contains all crystallographic details of this publica-
tion and are available free of charge at www.ccdc.cam.ac.uk/conts/
retrieving.html or can be ordered from the following address: Cambridge
Crystallographic Data Centre, 12 Union Road, GB-Cambridge CB21EZ;
fax: (þ44)1223-336-033; or deposit@ccdc.cam.ac.uk.
1. van Herk, T.; Brussee, J.; van den Nieuwendijk, A. M. C. H.; van der
Klein, P. A. M.; Ijzerman, A. P.; Stannek, C.; Burmeister, A.; Lorenzen,
A. J. Med. Chem. 2003, 46, 3945.
2. Varano, F.; Catarzi, D.; Colotta, V.; Filacchioni, G.; Galli, A.; Costagli, C.;
`
Carla, V. J. Med. Chem. 2002, 45, 1035.