Regiospecific synthesis of novel 6-amino-5-hydroxypyridazin-3(2H)-ones

Article abstract of DOI:10.1055/s-2008-1032157

The synthesis of a novel class of 6-amino-5-hydroxypyridazin-3(2H)-ones (3-oxo-2,3-dihydropyridazines) is described. These compounds also contain an ethoxycarbonyl moiety at the 4-position of the pyridazinone ring. They are prepared in good to moderate yi

Full text of DOI:10.1055/s-2008-1032157

610
PAPER
Regiospecific Synthesis of Novel 6-Amino-5-hydroxypyridazin-3(2H)-ones
S
ynthesis of
6
e
t
ydroxy
e
pyridazin-
3
r
(2
H
)-ones S. Dragovich,* Julie K. Blazel, Kimkim Dao, David A. Ellis, Lian-Sheng Li, Douglas E. Murphy,
Frank Ruebsam, Chinh V. Tran, Yuefen Zhou
Anadys Pharmaceuticals, 3115 Merryfield Row, San Diego, CA 92121, USA
Fax +1(858)5303648; E-mail: pdragovich@anadyspharma.com
Received 11 October 2007; revised 30 November 2007
Analysis of the desired molecules 6 suggested that they
Abstract: The synthesis of a novel class of 6-amino-5-hydroxy-
pyridazin-3(2H)-ones (3-oxo-2,3-dihydropyridazines) is described.
These compounds also contain an ethoxycarbonyl moiety at the
4-position of the pyridazinone ring. They are prepared in good to
could be prepared by acylation of amino(hydrazono)ace-
tates 4 with ethyl malonyl chloride (to give 5), followed
by Dieckmann cyclization under basic conditions
moderate yields (30–72%) by the condensation of disubstituted (Scheme 1, steps B and C, respectively). This sequence
amines with (alkylhydrazono)- or (arylhydrazono)(chloro)acetates
followed by subsequent acylation with ethyl malonyl chloride and
Dieckmann cyclization. An initial assessment of the scope and lim-
groups at the 6-position.5,6 The required amino(hydra-
itations of the new methodology is described along with the novel
synthesis of several (alkylhydrazono)(chloro)acetate substrates uti-
parallels our previously reported syntheses of similar 5-
hydroxypyridazin-3(2H)-ones bearing alkyl and aryl
zono)acetates 4 were envisioned to be derived from chlo-
ro(hydrazono)acetates 3 by reaction with an appropriate
amine (Scheme 1, step A).7 Encouragingly, a variety of
such chloro(phenylhydrazono)acetates 3 (R1 = aryl) are
readily accessible from the corresponding anilines via the
Japp–Klingemann reaction,8,9 and many of these com-
pounds are commercially available. However, we also
wished to examine alkyl groups at the 2-position of the
targeted 6-aminopyridazin-3(2H)-ones 6 (R1 = alkyl) to
better define the structure–activity relationships of the an-
tiviral agents under study. We therefore began the devel-
opment of our new methodology with the preparation of
several (alkylhydrazono)(chloro)acetates 3 (R1 = alkyl).10
lized in the pyridazinone preparations.
Key words: pyridazin-3(2H)-ones, Dieckmann cyclization, hydra-
zones, amino- and chloro(hydrazono)acetates, heterocycles
6-Aminopyridazin-3(2H)-ones (3-oxo-2,3-dihydropyrida-
zines) constitute an important class of biologically active
molecules with demonstrated binding affinity toward a1-
a2-adrenoceptors1 as well as the 5HT1A receptor.2 In the
course of our efforts to develop novel antiviral com-
pounds, we required a versatile synthesis to prepare 2-
substituted 6-amino-5-hydroxypyridazin-3(2H)-ones that
also contain an ester moiety at the 4-position (Figure 1,
structure 1). Unfortunately, existing literature methods for
the preparation of 6-aminopyridazin-3(2H)-ones do not
afford compounds containing the desired substituents at
the 4- and 5-positions. A majority provide access only to
molecules devoid of 4- or 5-substitution (e.g., structure 2,
Figure 1),1–3 while others afford pyridazin-3(2H)-ones
bearing halogens at these positions.4 Accordingly, we de-
veloped a new synthesis of 6-amino-5-hydroxypyridazin-
3(2H)-ones that also contain an ethoxycarbonyl moiety at
the 4-position. Below, we describe the details of this new
methodology along with an initial assessment of its scope
and limitations.
R2
N
OH
O
O
A. R3R2NH
Cl
R3
OEt
OEt
B. ClCOCH2CO2Et
N
N
N
O
HN
C. NaOEt
R1
R1
6
3
A
C
R3
O
R3
N
O
N
R2
R1
OEt
R2
OEt
B
N
N
N
O
HN
R1
R2
N
R2
N
OH
O
O
OEt
5
R3
4
R3
OR4
5
3
N
N
1
N
R1
O
N
O
Scheme 1
R1
1
2
As shown in Scheme 2, sequential treatment of Boc-pro-
tected hydrazone 7 (easily derived by the thermal conden-
sation of tert-butyl carbazate and ethyl glyoxylate) with
sodium hydride and 1-bromo-3-methylbutane followed
by heating at 50 °C provided the (alkylhydrazono)acetate
8a in good yield.11 This material was transformed into the
corresponding chloro(hydrazono)acetate 9a by treatment
with N-chlorosuccinimide at elevated temperature
Figure 1
SYNTHESIS 2008, No. 4, pp 0610–0616
Advanced online publication: 31.01.2008
DOI: 10.1055/s-2008-1032157; Art ID: M07607SS
© Georg Thieme Verlag Stuttgart · New York
x
x
.
x
x
.2
0
0
8

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Synthesis of 6-Amino-5-hydroxypyridazin-3(2H)-ones
611
O
O
[(acyl)(alkyl)hydrazono](amino)acetate 5a (cf. structure
5, Scheme 1).13 After a second basic workup, the crude
material thus obtained was briefly exposed to a slight ex-
cess of sodium ethoxide in ethanol at 50 °C to afford the
desired 6-aminopyridazin-3(2H)-one 6a (cf. structure 6,
Scheme 1) in good overall yield for the three-step process
(Table 1, entry 1). Several other 6-aminopyridazin-3(2H)-
ones 6b–i were also prepared in good to moderate yields
by analogous three-step transformations of chloro(hydra-
zono)acetate 3a and three equivalents of alternative disub-
stituted amines (Table 1, entries 2–9). The time and
temperature required to effect the first step in these pro-
cesses were somewhat dependent on the steric and elec-
tronic characteristics of the amine employed (Scheme 1,
step A). Accordingly, the transformation in which pyrro-
lidine was utilized required the lowest temperature and
shortest reaction time (Table 1, entry 5), while the reac-
tion of 3a with (less basic) morpholine proceeded much
more slowly over two days at a higher temperature
(Table 1, entry 9).
H
H
N
OEt
OEt
a
N
R1
N
HN
Boc
Boc
8a–d
7
d
b
O
X
OEt
O
H
N
Cl
N
R1
OEt
R2
N
N
R1
10d X = H
3d X = Cl
e
9a–c R2 = Boc
3a–c R2 = H
c
a R1 = CH2CH2i-Pr
b R1 = CH2CH2t-Bu
c R1 = CH2CH2(cyclopropyl)
d R1 = CH2(4-FC6H4)
Unfortunately, attempts to prepare similar 6-aminopy-
ridazin-3(2H)-ones derived from monosubstituted amines
were unsuccessful. Although displacement of the chloride
present in 3a with propylamine proceeded uneventfully
(as evidenced by LCMS analysis), subsequent transfor-
mation of the resulting amino(hydrazono)acetate did not
cleanly afford the desired N-acyl intermediate or pyridazi-
none product. This outcome is likely due to the presence
of an alternative acylation site in the intermediate ami-
no(hydrazono)acetate (e.g., Scheme 1, 4, R3 = H) and ad-
ditional preparations of pyridazinones derived from
monosubstituted amines were not attempted.
Scheme 2 Reagents and conditions: (a) NaH, R1Br or R1OTs, DMF,
50 °C, 5–24 h, 64–95%; (b) NCS, EtOAc, 50 °C, 11–22 h, 76–85%;
(c) HCl, 1,4-dioxane, 23 °C, 5–18 h, 59–77%; (d) HCl, 1,4-dioxane,
23 °C, 2 h, 45%; (e) NCS, EtOAc, 60 °C, 30 min, 55%.
(Scheme 2). Removal of the Boc protecting group present
in 9a under acidic conditions then afforded the desired
chloro(hydrazono)acetate 3a in good yield following pu-
rification by flash chromatography.12 Two additional
(alkylhydrazono)(chloro)acetates 3b and 3c were pre-
pared analogously by independent alkylation of the sodi-
um salt of 7 with 1-bromo-3,3-dimethylbutane and the
tosylate derived from 2-cyclopropylethanol, respectively
(Scheme 2). Unfortunately, attempts to utilize secondary
halides [e.g., EtCH(X)Me, X = Br or I] to similarly de-
rivatize 7 did not afford significant amounts of the desired
alkylation products. In addition, although 4-fluorobenzyl
bromide smoothly coupled with the sodium salt of 7, the
resulting product (8d, Scheme 2) did not react with N-
chlorosuccinimide even after heating for extended periods
of time (24 h). Instead, chlorohydrazone 3d was obtained
after the Boc protecting group present in 8d was removed
under acidic conditions and the deprotected hydrazonoac-
etate 10d was chlorinated with N-chlorosuccinimide in
analogy with a literature precedent (Scheme 2).10
Instead, disubstituted amines were utilized to transform
chloro(hydrazono)acetates 3b and 3c into the correspond-
ing 6-aminopyridazin-3(2H)-one products 6j–l (Table 1,
entries 10–12) by a three-step processes analogous to that
described above for the derivatization of 3a. These trans-
formations proceeded smoothly and afforded the desired
pyridazinones 6j–l in good to moderate yields. Somewhat
surprisingly, similar derivatization of chloro(hydra-
zono)acetate 3d did not afford the pyridazinone product
6m (Table 1, entry 13). In this case, reaction of 3d with
pyrrolidine and acylation of the resulting intermediate
with ethyl malonyl chloride cleanly afforded the expected
[(acyl)(alkyl)hydrazono](amino)acetate 5m as evidenced
by LCMS analysis (Scheme 3). However, LCMS also in-
dicated that exposure of this entity to warm ethanolic so-
dium ethoxide resulted in cleavage of the N-acyl bond to
give 4m instead of the desired Dieckmann cyclization to
produce 6m (Scheme 3). The reasons for this alternate re-
activity are currently unknown, but may involve (a) the in-
creased susceptibility of the N-acyl linkage to hydrolysis
due to the presence of the 4-fluorobenzyl moiety, (b) an
unfavorable equilibrium between the E- and Z-isomers of
[(acyl)(alkyl)hydrazono](amino)acetate that precludes ef-
ficient Dieckmann cyclization, or (c) a combination of
both factors.
Having successfully prepared several (alkylhydra-
zono)(chloro)acetates 3, we next examined their transfor-
mation into the desired 6-aminopyridazin-3(2H)-ones 6
(Table 1). For example, treatment of 3a with three equiv-
alents of diethylamine at 100 °C in 1,4-dioxane for four
hours (Table 1, entry 1) resulted in its conversion into the
corresponding amino(hydrazono)acetate 4a as evidenced
by TLC and LCMS analysis of the reaction mixture (cf.
structure 4, Scheme 1). This intermediate was isolated in
crude form by a simple basic workup, and was subse-
quently condensed with ethyl malonyl chloride under
thermal conditions to provide the corresponding
Synthesis 2008, No. 4, 610–616 © Thieme Stuttgart · New York

612
P. S. Dragovich et al.
PAPER
Table 1 Conversion of Chloro(hydrazono)acetates 3a–h into 6-Aminopyridazinones 6a–qa
Entry
1
Substrate 3 R1
(CH2)2i-Pr
NR2R3
Tempb (°C)
Time (h)b
Product 6
6a
Yieldc (%)
69
3a
3a
3a
3a
3a
3a
3a
3a
3a
3b
3b
3c
3d
3e
3f
NEt2
100
50
50
50
50
60
50
60
75
50
50
50
50
50
50
60
60
4
3
2
(CH2)2i-Pr
(CH2)2i-Pr
(CH2)2i-Pr
(CH2)2i-Pr
(CH2)2i-Pr
(CH2)2i-Pr
(CH2)2i-Pr
(CH2)2i-Pr
(CH2)2t-Bu
(CH2)2t-Bu
(CH2)2(cyclopropyl)
CH2(4-FC6H4)
Ph
N(Me)Pr
6b
6c
49
3
N(i-Pr)Me
4
54
4
N(t-Bu)Me
4
6d
6e
44
5
pyrrolidin-1-yl
2-methylpyrrolidin-1-yld
piperidin-1-yl
2-methylpiperidin-1-yld
morpholin-1-yl
pyrrolidin-1-yl
N(t-Bu)Me
2
54
6
2
6f
61
7
4
6g
30
8
2
6h
6i
47
9
48
3
72
10
11
12
13
14
15
16
17
6j
50
16
2
6k
6l
56
pyrrolidin-1-yl
pyrrolidin-1-yl
pyrrolidin-1-yl
N(Me)cyclohexyl
piperidin-1-yl
N(t-Bu)Me
35
2
6m
6n
6o
0e
1
38f
72
4-FC6H4
3
3g
2-O2N-4-MeOC6H3
3,5-Cl2C6H3
0.33
4
6p
64
3h
6q
62
a Reagents and conditions (cf. Scheme 1): (a) R3R2NH, 1,4-dioxane; (b) ClCOCH2CO2Et, 1,4-dioxane; (c) NaOEt, EtOH.
b Time and temperature required for the amine to effect consumption of the starting chloro(hydrazono)acetate 3a–h (Scheme 1, Step A).
c Isolated yield of 6-aminopyridazinone 6 after purification on silica gel (>90% purity).
d Racemic.
e Cleavage of acylated amino(hydrazono)acetate 5 observed in lieu of pyridazinone formation.
f Dieckmann cyclization (Scheme 1, Step C) conducted at 23 °C.
3e–h with disubstituted amines afforded the desired 6-
O
aminopyridazin-3(2H)-ones 6n–q in good to moderate
N
OEt
a
yields (Table 1, entries 14–17). These results suggest that
other readily available (arylhydrazono)(chloro)acetates
can also serve as efficient substrates for our new synthetic
methodology. Due to their polar nature, it was often diffi-
cult to remove all impurities from the aminopyridazinone
products described in this work by routine flash chroma-
tography on silica gel. However, this method typically af-
forded the desired materials in sufficient purity (>90%) to
enable their successful use in subsequent synthetic trans-
formations (e.g., ester derivatization). As described in the
experimental section below, the purity of several ami-
nopyridazinone products was further enhanced by prepar-
ative HPLC prior to their characterization.
3d
N
b
N
H
F
4m
c
O
O
OH
N
O
O
N
N
OEt
OEt
OEt
N
N
N
F
O
6m
5m
F
All reactions were performed in septum-sealed vials or flasks under
a slight positive pressure of anhyd N2. All commercial reagents
were used as received from their respective suppliers. Chloro(hy-
drazono)acetates 3e and 3h were purchased from Oakwood. Chlo-
ro(hydrazono)acetates 3f and 3g were purchased from Zerenex and
Bionet, respectively. All solvents were purchased from EMD in an-
hyd form and were used without additional purification. All em-
ployed solns of reagents, acids, and bases were aqueous, unless
Scheme 3 Reagents and conditions: (a) pyrrolidine, 1,4-dioxane,
50 °C, 2 h; (b) ClCOCH2CO2Et, 1,4-dioxane, 85 °C, 30 min;
(c) NaOEt, EtOH, 50 °C, 30 min.
Encouragingly, the three-step derivatization of several
commercially available (arylhydrazono)(chloro)acetates
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Synthesis of 6-Amino-5-hydroxypyridazin-3(2H)-ones
613
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 available cartridges
(Analogix Superflash) and automated elution systems. Preparative
HPLC was performed on a Luna C18(2) 100A Axia column (5 m,
50 × 21.2 mm ID). Chemical shifts d are reported relative to internal
solvent signals.
13C NMR (100 MHz, CDCl3): d = 14.5, 22.8, 26.2, 28.5, 37.7, 48.6,
63.9, 83.1, 128.2, 151.4, 159.7.
Anal. Calcd for C14H25ClN2O4: C, 52.41; H, 7.85; N, 8.73. Found:
C, 52.25; H, 7.60; N, 8.93.
Ethyl Chloro[(3-methylbutyl)hydrazono]acetate (3a)
A 4.0 M soln of HCl in 1,4-dioxane (30 mL) was added to a soln of
9a (8.80 g, 27.4 mmol) in 1,4-dioxane (5 mL) at 23 °C. The reaction
mixture was stirred at 23 °C and an additional portion of 4.0 M HCl
in 1,4-dioxane (10 mL) was added after 3 h. After stirring a total of
7 h at 23 °C, the reaction mixture was carefully partitioned between
half-saturated NaHCO3 soln (200 mL) and EtOAc (2 × 200 mL).
The combined organic layers were dried (Na2SO4) and concentrated
under reduced pressure. Purification of the residue by flash chroma-
tography (Superflash cartridge, gradient elution, 0→60% EtOAc–
hexanes) provided 3a.
Ethyl [(tert-Butoxycarbonyl)hydrazono]acetate (7)
A 45% soln of ethyl glyoxylate in toluene (11.5 mL, 50.7 mmol)
was added to a soln of tert-butyl carbazate (6.12 g, 46.3 mmol) in
1,4-dioxane (60 mL) at 60 °C. The reaction mixture was stirred at
60 °C for 10 min, then allowed to cool to 23 °C, and concentrated
under reduced pressure. The residue was purified by flash chroma-
tography (Superflash cartridge, gradient elution, 0→100% EtOAc–
hexanes); this afforded 7.
Yield: 8.50 g (85%); white solid; mp 101–104 °C.
1H NMR (400 MHz, CDCl3): d = 1.35 (t, J = 7.5 Hz, 3 H), 1.54 (s,
9 H), 4.26 (q, J = 6.9 Hz, 2 H), 6.82 (s, 1 H), 11.79 (br s, 1 H).
13C NMR (100 MHz, CDCl3): d = 14.5, 28.5, 61.7, 82.8, 134.2,
152.0, 163.7.
Yield: 4.68 g (77%); yellow oil.
1H NMR (400 MHz, CDCl3): d = 0.95 (d, J = 6.9 Hz, 6 H), 1.37 (t,
J = 7.1 Hz, 3 H), 1.51–1.56 (m, 2 H), 1.62–1.72 (m, 1 H), 3.52–3.56
(m, 2 H), 4.34 (q, J = 7.0 Hz, 2 H), 6.47 (br s, 1 H).
13C NMR (100 MHz, CDCl3): d = 14.7, 22.8, 26.0, 38.9, 49.1, 62.6,
113.2, 160.0.
HRMS (ESI-TOF): m/z calcd for C9H16N2O4 [M + Na]+: 239.1002;
found: 239.0998.
Anal. Calcd for C9H17ClN2O2: C, 48.98; H, 7.76; N, 12.69. Found:
C, 48.77; H, 7.42; N, 12.39.
Ethyl [(tert-Butoxycarbonyl)(3-methylbutyl)hydrazono]ace-
tate (8a)
Ethyl [(tert-Butoxycarbonyl)(3,3-dimethylbutyl)hydrazono]ac-
etate (8b)
A 60% suspension of NaH in mineral oil (0.537 g, 13.4 mmol) was
added to a soln of 7 (2.42 g, 11.2 mmol) in DMF (50 mL) at 23 °C.
The resulting suspension was stirred for 15 min at 23 °C, and then
1-bromo-3-methylbutane (1.74 mL, 14.5 mmol) was added. The re-
action mixture was heated at 50 °C for 6 h, then allowed to cool to
23 °C, and concentrated under reduced pressure to a volume of
about 20 mL. The concentrate was partitioned between 0.5 M HCl
(200 mL) and an EtOAc–hexanes mixture (1:1, 2 × 150 mL). The
combined organic layers were dried (Na2SO4) and then concentrat-
ed under reduced pressure. Purification of the residue by flash chro-
matography (Superflash cartridge, gradient elution, 0→70%
EtOAc–hexanes) provided 8a.
To a stirred soln of 7 (9.5 g, 43.9 mmol) in anhyd DMF (60 mL) at
0 °C, a 60% dispersion of NaH in mineral oil (1.93 g, 48.3 mmol)
was added in portions. After stirring at 0 °C for 10 min, the reaction
mixture was allowed to warm to 23 °C and stirred at that tempera-
ture for 30 min. 1-Bromo-3,3-dimethylbutane (8.7 g, 52.7 mmol)
was added to the mixture, and stirring was continued at 50 °C for 24
h. The reaction mixture was allowed to cool to 23 °C, and then par-
titioned between 0.5 M HCl (200 mL) and EtOAc (2 × 200 mL).
The combined organic layers were washed with brine (100 mL),
dried (Na2SO4) and filtered. The filtrate was concentrated under re-
duced pressure and the residue was purified by flash chromatogra-
phy (Superflash cartridge, gradient elution, 0→100% EtOAc–
hexanes) to afford 8b.
Yield: 2.71 g (85%); colorless liquid.
1H NMR (400 MHz, CDCl3): d = 0.96 (d, J = 5.9 Hz, 6 H), 1.37 (t,
J = 7.0 Hz, 3 H), 1.39–1.45 (m, 2 H), 1.57 (s, 9 H), 1.60–1.65 (m, 1
H), 3.79–3.83 (m, 2 H), 4.31 (q, J = 7.3 Hz, 2 H), 7.12 (s, 1 H).
13C NMR (100 MHz, CDCl3): d = 14.5, 22.7, 26.4, 28.3, 34.2, 43.6,
61.5, 83.2, 128.9, 152.0, 163.8.
Yield: 8.4 g (64%); colorless oil.
1H NMR (400 MHz, CDCl3): d = 0.99 (s, 9 H), 1.39 (t, J = 7.2 Hz,
3 H), 1.44 (m, 2 H), 1.58 (s, 9 H), 3.82 (m, 2 H), 4.33 (q, J = 7.2 Hz,
2 H), 7.11 (s, 1 H).
Anal. Calcd for C14H26N2O4: C, 58.72; H, 9.15; N, 9.78. Found: C,
58.37; H, 8.75; N, 9.86.
13C NMR (100 MHz, CDCl3): d = 163.9, 14.5, 28.4, 28.5, 29.4, 30.3,
38.5, 41.9, 61.6, 83.3, 128.6, 152.0.
Ethyl [(tert-Butoxycarbonyl)(3-methylbutyl)hydrazono](chlo-
ro)acetate (9a)14
Ethyl [(tert-Butoxycarbonyl)(3,3-dimethylbutyl)hydra-
zono](chloro)acetate (9b)14
NCS (16.5 g, 123 mmol) was added to a soln of 8a (8.84 g, 30.9
mmol) in EtOAc (75 mL) at 23 °C. The reaction mixture was heated
at 50 °C for 11 h, then allowed to cool to 23 °C, and concentrated
under reduced pressure. The resulting white solid was triturated
with hexane and filtered through a medium frit. The collected solid
was washed with hexanes (3 ×). The combined filtrate and washings
were concentrated under reduced pressure. Purification of the re-
sulting yellow oil by flash chromatography (Superflash cartridge,
gradient elution, 0→50% EtOAc–hexanes) provided 9a.
To a 23 °C soln of 8b (8.5 g, 28.3 mmol) in EtOAc (80 mL), NCS
(15.4 g, 113.3 mmol) was added in portions. The resulting mixture
was stirred at 50 °C for 22 h, then allowed to cool to 23 °C, and con-
centrated under reduced pressure. The residue was suspended in
hexanes and filtered. The filtrate was concentrated under reduced
pressure and the residue was purified by flash chromatography (Su-
perflash cartridge, gradient elution, 0→50% EtOAc–hexanes) to af-
ford 9b.
Yield: 7.2 g (76%); yellow oil.
Yield: 8.40 g (85%); yellow liquid.
1H NMR (400 MHz, CDCl3): d = 0.97 (s, 9 H), 1.40 (t, J = 7.2 Hz,
3 H), 1.54 (s, 9 H), 1.57 (m, 2 H), 4.00 (m, 2 H), 4.38 (q, J = 7.2 Hz,
2 H).
1H NMR (400 MHz, CDCl3): d = 0.94 (d, J = 7.1 Hz, 6 H), 1.40 (t,
J = 7.1 Hz, 3 H), 1.53 (s, 9 H), 1.60–1.69 (m, 1 H), 3.95–3.98 (m, 2
H), 4.37 (q, J = 7.1 Hz, 2 H).
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P. S. Dragovich et al.
PAPER
Ethyl Chloro[(3,3-dimethylbutyl)hydrazono]acetate (3b)
To a 23 °C soln of 9b (5.9 g, 17.7 mmol) in anhyd 1,4-dioxane (10
mL), a 4.0 M soln of HCl in 1,4-dioxane (25 mL) was added slowly.
After stirring at 23 °C for 18 h, the reaction mixture was poured into
a sat. NaHCO3 soln (150 mL), and extracted with EtOAc (2 × 150
mL). The combined organic layers were washed with brine (100
mL), dried (Na2SO4), and filtered. The filtrate was concentrated un-
der reduced pressure and the residue was purified by flash chroma-
tography (Superflash cartridge, gradient elution, 0→60% EtOAc–
hexanes) to afford 3b.
the soln was concentrated under reduced pressure. The resulting
solid was triturated with hexanes and filtered. The collected solid
was washed with hexanes (3×) and the combined filtrate and wash-
ings were concentrated under reduced pressure. Flash column puri-
fication of the residue (gradient elution, 0→5% EtOAc–hexanes)
afforded 9c.
Yield: 0.479 g (85%); yellow oil.
1H NMR (400 MHz, CDCl3): d = 0.07–0.10 (m, 2 H), 0.43–0.47 (m,
2 H), 0.63–0.71 (m, 1 H), 1.38 (t, J = 7.0 Hz, 3 H), 1.49–1.58 (m, 11
H), 4.02–4.05 (m, 2 H), 4.36 (q, J = 7.1 Hz, 2 H).
13C NMR (100 MHz, CDCl3): d = 4.5, 8.4, 14.2, 28.3, 33.9, 49.8,
63.7, 83.0, 127. 5, 151.4, 159.7.
HRMS (ESI-TOF): m/z calcd for C14H23ClN2O4 [M + Na]+:
341.1238; found: 341.1254.
Yield: 2.46 g (59%); yellow oil.
1H NMR (400 MHz, CDCl3): d = 0.97 (s, 9 H), 1.38 (t, J = 7.2 Hz,
3 H), 1.57 (m, 2 H), 3.56 (m, 2 H), 4.35 (q, J = 7.2 Hz, 2 H), 6.43
(m, 1 H).
13C NMR (100 MHz, CDCl3): d = 14.7, 29.8, 30.2, 43.5, 47.6, 62.6,
113.4, 159.9.
Ethyl Chloro[(2-cyclopropylethyl)hydrazono]acetate (3c)
Compound 9c (0.35 g, 1.1 mmol) was dissolved in 1,4-dioxane (0.2
mL) at 23 °C. A 4.0 M soln of HCl in 1,4-dioxane (1.6 mL) was
added. The reaction mixture was stirred at 23 °C for 5 h, and then
partitioned between half-saturated NaHCO3 soln (30 mL) and
EtOAc (2 × 30 mL). The combined organic layers were dried
(MgSO4) and concentrated under reduced pressure. Flash column
purification of the residue (gradient elution, 0→15% EtOAc–hex-
anes) afforded 3c.
2-Cyclopropylethyl Toluene-4-sulfonate
2-Cyclopropylethanol (2.0 g, 23.3 mmol) was dissolved in CH2Cl2
(120 mL) at 23 °C. TsCl (4.9 g, 25.6 mmol), Et3N (4.21 mL, 30.2
mmol), and DMAP (0.293 g, 2.4 mmol) were added and the mixture
was stirred at 23 °C for 19 h. The mixture was washed with 1.0 M
HCl (300 mL) and the organic phase was passed through a plug of
silica gel. The filtrate was concentrated under reduced pressure to
afford the title compound.
Yield: 0.172 g (72%); yellow oil.
Yield: 5.14 g (92%); clear oil.
1H NMR (400 MHz, CDCl3): d = 0.08–0.12 (m, 2 H), 0.48–0.52 (m,
2 H), 0.66–0.76 (m, 1 H), 1.37 (t, J = 7.3 Hz, 3 H), 1.55 (q, J = 7.1
Hz, 2 H), 3.59–3.63 (m, 2 H), 4.35 (q, J = 7.2 Hz, 2 H), 6.65 (br s,
1 H).
13C NMR (100 MHz, CDCl3): d = 4. 6, 8. 6, 14.6, 35.0, 50.9, 62.6,
113.5, 159.9.
HRMS (ESI-TOF): m/z calcd for C9H15ClN2O2 [M + H]+: 219.0895;
found: 219.0890. A minor amount (0.012 g, 5%) of the other chlo-
ro(hydrazono)acetate isomer (more polar by TLC than 3c) was also
isolated.
1H NMR (400 MHz, CDCl3): d = 0.05–0.09 (m, 2 H), 0.47–0.52 (m,
2 H), 0.65–0.75 (m, 1 H), 1.43 (t, J = 7.1 Hz, 3 H), 1.70 (q, J = 7.0
Hz, 2 H), 3.92 (t, J = 7.0 Hz, 2 H), 4.46 (q, J = 7.0 Hz, 2 H).
1H NMR (400 MHz, CDCl3): d = 0.01–0.05 (m, 2 H), 0.40–0.44 (m,
2 H), 0.62–0.72 (m, 1 H), 1.55 (q, J = 6.8 Hz, 2 H), 2.45 (s, 3 H),
4.09 (t, J = 6.6 Hz, 2 H), 7.33 (d, J = 7.9 Hz, 2 H), 7.79 (d, J = 7.8
Hz, 2 H).
13C NMR (100 MHz, CDCl3): d = 4.4, 7.5, 21.9, 34.1, 70.8, 127.9,
129.8, 133.3, 144.6.
Anal. Calcd for C12H16O3S: C, 59.97; H, 6.71. Found: C, 60.02; H,
6.47.
Ethyl [(tert-Butoxycarbonyl)(2-cyclopropylethyl)hydra-
zono]acetate (8c)
Compound 7 (1.0 g, 4.63 mmol) was dissolved in anhyd DMF (20
mL), and a 60% suspension of NaH in mineral oil (0.222 g, 5.56
mmol) was added. The resulting yellow suspension was stirred for
15 min at 23 °C. 2-Cyclopropylethyl toluene-4-sulfonate (prepared
as described above, 1.44 g, 6.0 mmol) was added, and the reaction
mixture was heated at 50 °C for 5 h. After cooling to 23 °C, the soln
was partitioned between 0.5 M HCl (200 mL) and EtOAc–hexanes
(1:1, 2 × 150 mL). The combined organic layers were dried
(MgSO4) and concentrated under reduced pressure. Flash column
purification of the residue (EtOAc–hexanes, 1:9) afforded 8c.
Ethyl [(tert-Butoxycarbonyl)(4-fluorobenzyl)hydrazono]ace-
tate (8d)
Compound 7 (2.47 g, 11.4 mmol) was dissolved in anhyd DMF (30
mL), and a 60% suspension of NaH in mineral oil (0.547 g, 13.7
mmol) was added. The resulting yellow suspension was stirred for
20 min at 23 °C. 4-Fluorobenzyl bromide (1.71 mL, 13.7 mmol)
was added and the reaction mixture was stirred at 23 °C for 18 h.
The volatiles were removed under reduced pressure and the residue
was partitioned between 0.5 M HCl (150 mL) and EtOAc (2 × 150
mL). The combined organic layers were dried (Na2SO4) and con-
centrated under reduced pressure. Purification of the residue by
flash chromatography (Superflash cartridge, gradient elution,
0→60% EtOAc–hexanes) afforded 8d.
Yield: 1.08 g (82%); clear oil.
1H NMR (400 MHz, CDCl3): d = 0.07–0.10 (m, 2 H), 0.45–0.50 (m,
2 H), 0.62–0.73 (m, 1 H), 1.36 (t, J = 7.0 Hz, 3 H), 1.46 (q, J = 7.3
Hz, 2 H), 1.56 (s, 9 H), 3.90 (t, J = 7.5 Hz, 2 H), 4.30 (q, J = 7.0 Hz,
2 H), 7.17 (s, 1 H).
13C NMR (100 MHz, CDCl3): d = 4.5, 8.7, 14.4, 28.2, 30.8, 45.0,
Yield: 3.50 g (95%); white solid; mp 87–89 °C.
61.4, 83.1, 128.9, 152.0, 163.8.
1H NMR (400 MHz, CDCl3): d = 1.31 (t, J = 7.3 Hz, 3 H), 1.57 (s,
9 H), 4.25 (q, J = 7.3 Hz, 2 H), 5.01 (s, 2 H), 6.98–7.02 (m, 2 H),
7.04 (br s, 1 H), 7.11–7.14 (m, 2 H).
HRMS (ESI-TOF): m/z calcd for C14H24N2O4 [M + Na]+: 307.1628;
found: 307.1641.
13C NMR (100 MHz, CDCl3): d = 14.5, 28.4, 48.7, 61.6, 84.0, 116.1
(d, J = 22.2 Hz), 128.3 (d, J = 7.7 Hz), 130.1 (d, J = 3.1 Hz), 130.7,
152.5, 162.2 (d, J = 245.4 Hz), 163.5-
Ethyl [(tert-Butoxycarbonyl)(2-cyclopropylethyl)hydra-
zono](chloro)acetate (9c)14
Compound 8c (0.5 g, 1.758 mmol) was dissolved in EtOAc (4.3
mL) at 23 °C and NCS (0.939 g, 7.03 mmol) was added. The reac-
tion mixture was heated at 50 °C for 16 h. After cooling to 23 °C,
Anal. Calcd for C16H21FO4N2: C, 59.25; H, 6.53; N, 8.64. Found: C,
59.45; H, 6.55, N, 8.90.
Synthesis 2008, No. 4, 610–616 © Thieme Stuttgart · New York

PAPER
Synthesis of 6-Amino-5-hydroxypyridazin-3(2H)-ones
615
Ethyl [(4-Fluorobenzyl)hydrazono]acetate (10d)
23 °C, and partitioned between half-saturated NaHCO3 soln (150
mL) and EtOAc (2 × 150 mL). The combined organic layers were
dried (Na2SO4) and then concentrated under reduced pressure. The
residue was dissolved in EtOH (15 mL) at 23 °C and a 21% wt/wt
soln of NaOEt in EtOH (1.59 mL, 4.91 mmol) was added. The re-
action mixture was heated at 50 °C for 20 min, then allowed to cool
to 23 °C, and partitioned between 0.5 M HCl (150 mL) and EtOAc
(2 × 150 mL). The combined organic layers were dried (Na2SO4)
and then concentrated under reduced pressure. Purification of the
residue by flash chromatography (Superflash cartridge, gradient
elution, 0→90% EtOAc–hexanes) provided the title compound.
A 4.0 M soln of HCl in 1,4-dioxane (15 mL) was added to a soln of
8d (2.55 g, 7.86 mmol) in 1,4-dioxane (15 mL) at 23 °C. The result-
ing soln was stirred at 23 °C for 2 h, and was then concentrated un-
der reduced pressure. The residue was partitioned between half-
saturated NaHCO3 soln (150 mL) and EtOAc (2 × 150 mL). The
combined organic layers were dried (Na2SO4) and then concentrat-
ed under reduced pressure. Purification of the residue by flash chro-
matography (Superflash cartridge, gradient elution, 0→60%
EtOAc–hexanes) afforded 10d.
Yield: 0.800 g (45%); yellow wax.
Yield: 0.914 g (69%); yellow-brown oil.
1H NMR (400 MHz, CDCl3): d = 1.29 (t, J = 6.9 Hz, 3 H), 4.01 (s,
2 H), 4.21 (q, J = 6.9 Hz, 2 H), 6.98–7.03 (m, 2 H), 7.48–7.52 (m, 2
H), 7.66 (s, 1 H).
13C NMR (100 MHz, CDCl3): d = 14.6, 51.4, 61.5, 115.7 (d,
J = 21.5 Hz), 128.0 (d, J = 8.4 Hz), 131.6 (d, J = 3.1 Hz), 139.3,
163.0 (d, J = 246.9 Hz), 171.4.
Additional purification by reverse-phase preparative HPLC
[30→70% MeCN–H2O (both containing 0.05% TFA), 4.5 min,
flow = 30 mL/min] afforded an analytical sample.
1H NMR (400 MHz, CDCl3): d = 0.95 (d, J = 6.3 Hz, 6 H), 1.16 (t,
J = 7.0 Hz, 6 H), 1.43 (t, J = 6.9 Hz, 3 H), 1.56–1.69 (m, 3 H), 3.36
(q, J = 7.0 Hz, 4 H), 4.04–4.08 (m, 2 H), 4.46 (q, J = 6.9 Hz, 2 H).
HRMS (ESI-TOF): m/z calcd for C11H13FN2O2 [M + H]+: 225.1034;
found: 225.1035.
13C NMR (100 MHz, CDCl3): d = 13.1, 14.3, 22.7, 26.0, 37.3, 44.6,
50.4, 63.2, 145.3, 157.5, 158.7, 163.0, 171.6.
Ethyl Chloro[(4-fluorobenzyl)hydrazono]acetate (3d)
NCS (0.524 g, 3.92 mmol) was added to a soln of 10d (0.800 g, 3.57
mmol) in EtOAc (15 mL) at 23 °C. The mixture was heated at 60 °C
for 30 min, then allowed to cool to 23 °C, and concentrated under
reduced pressure. The residue was triturated with hexanes (10 mL)
and filtered through a cotton plug. Purification of the filtrate by
flash chromatography (Superflash cartridge, gradient elution,
0→30% EtOAc–hexanes) afforded 3d.
HRMS (ESI-TOF): m/z calcd for C16H27N3O4 [M + H]+: 326.2074;
found: 326.2075.
Ethyl 5-Hydroxy-2-(3-methylbutyl)-3-oxo-6-pyrrolidin-1-yl-
2,3-dihydropyridazine-4-carboxylate (6e)
Pyrrolidine (1.02 mL, 12.2. mmol) was added to a soln of 3a (0.90
g, 4.08 mmol) in 1,4-dioxane (12 mL) at 23 °C. The reaction mix-
ture was heated at 50 °C for 2 h, then allowed to cool to 23 °C, and
partitioned between half-saturated NaHCO3 soln (150 mL) and
EtOAc (2 × 150 mL). The combined organic layers were dried
(Na2SO4) and then concentrated under reduced pressure. The resi-
due was dissolved in 1,4-dioxane (8 mL) at 23 °C, and ethyl malo-
nyl chloride (0.624 mL, 4.89 mmol) was added. The reaction
mixture was heated at 85 °C for 30 min, then allowed to cool to
23 °C, and partitioned between half-saturated NaHCO3 soln (150
mL) and EtOAc (2 × 150 mL). The combined organic layers were
dried (Na2SO4) and then concentrated under reduced pressure. The
residue was dissolved in EtOH (40 mL) at 23 °C, and a 21% wt/wt
soln of NaOEt in EtOH (1.59 mL, 4.91 mmol) was added. The re-
action mixture was heated at 50 °C for 30 min, then allowed to cool
to 23 °C, and partitioned between 0.5 M HCl (150 mL) and EtOAc
(2 × 150 mL). The combined organic layers were dried (Na2SO4)
and then concentrated under reduced pressure. Purification of the
residue by flash chromatography (Superflash cartridge, gradient
elution, 0→80% EtOAc–hexanes) provided the title compound.
Yield: 0.511 g (55%); yellow oil.
1H NMR (400 MHz, CDCl3): d = 1.30 (t, J = 3.5 Hz, 3 H), 4.12 (s,
2 H), 4.21 (q, J = 6.9 Hz, 2 H), 6.20 (br s, 1 H), 7.01–7.06 (m, 2 H),
7.75–7.80 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 14.6, 51.9, 61.5, 115.5 (d,
J = 22.2 Hz), 126.0, 128.6 (d, J = 8.4 Hz), 130.8 (d, J = 3.1 Hz),
163.4 (d, J = 249.2 Hz), 171.0.
HRMS (ESI-TOF): m/z calcd for C11H12ClFN2O2 [M + H]+:
259.0644; found: 259.0642.
6-Amino-5-hydroxypyridazin-3(2H)-ones 6; Typical Proce-
dures
Three representative procedures for the synthesis of 6-amino-5-hy-
droxypyridazin-3(2H)-ones 6 from chloro(hydrazono)acetates 3 are
provided below. They differ primarily in the time and temperature
utilized for the amination of the latter materials (Scheme 1, step A).
In addition, a slightly greater excess of ethyl malonyl chloride was
used during the acylation of the amino(hydrazono)acetates 4 de-
rived from (arylhydrazono)(chloro)acetates 3e–h relative to that
employed for the derivatization of the corresponding alkylhydra-
zono intermediates. The described 6-amino-5-hydroxypyridazin-
3(2H)-ones were isolated in approximately 90% purity (as assessed
by 1H NMR and LCMS analysis) and were further purified by pre-
parative HPLC prior to their final characterization.
Yield: 0.718 g (54%); yellow-brown oil.
Additional purification by reverse-phase preparative HPLC
[45→100% MeCN in H2O (both containing 0.05% TFA), 6.5 min,
flow = 30 mL/min] afforded an analytical sample.
1H NMR (400 MHz, CDCl3): d = 0.96 (d, J = 6.2 Hz, 6 H), 1.43 (t,
J = 7.1 Hz, 3 H), 1.57–1.68 (m, 3 H), 1.89–1.92 (m, 4 H), 3.58–3.62
(m, 4 H), 3.99–4.03 (m, 2 H), 4.45 (q, J = 7.0 Hz, 2 H).
13C NMR (100 MHz, CDCl3): d = 14.4, 22.8, 25.6, 26.1, 37.1, 49.5,
Ethyl 6-(Diethylamino)-5-hydroxy-2-(3-methylbutyl)-3-oxo-
2,3-dihydropyridazine-4-carboxylate (6a)
50.5, 63.1, 133.0, 157.6, 158.7, 163.2, 171.9.
HRMS (ESI-TOF): m/z calcd for C16H25N3O4 [M + H]+: 324.1918;
found: 324.1904.
Et2NH (1.26 mL, 12.2. mmol) was added to a soln of 3a (0.90 g,
4.08 mmol) in 1,4-dioxane (15 mL) at 23 °C. The reaction mixture
was heated at 100 °C for 4 h, then allowed to cool to 23 °C, and par-
titioned between half-saturated NaHCO3 soln (150 mL) and
EtOAc–hexanes (1:1, 2 × 150 mL). The combined organic layers
were dried (Na2SO4) and concentrated under reduced pressure. The
residue was dissolved in 1,4-dioxane (15 mL) at 23 °C and ethyl
malonyl chloride (0.624 mL, 4.89 mmol) was added. The reaction
mixture was heated at 85 °C for 30 min, then allowed to cool to
Ethyl 5-Hydroxy-2-(4-methoxy-2-nitrophenyl)-3-oxo-6-piperi-
din-1-yl-2,3-dihydropyridazine-4-carboxylate (6p)
Piperidine (0.923 mL, 9.34 mmol) was added to a soln of 3g (0.94
g, 3.11 mmol) in 1,4-dioxane (70 mL) at 23 °C. The reaction mix-
ture was heated at 60 °C for 20 min, then allowed to cool to 23 °C,
and partitioned between half-saturated NaHCO3 soln (150 mL) and
Synthesis 2008, No. 4, 610–616 © Thieme Stuttgart · New York

616
P. S. Dragovich et al.
PAPER
EtOAc (2 × 150 mL). The combined organic layers were dried
(Na2SO4) and then concentrated under reduced pressure. The resi-
due was dissolved in 1,4-dioxane (30 mL) at 23 °C and ethyl malo-
nyl chloride (0.676 mL, 5.30 mmol) was added. The reaction
mixture was heated at 85 °C for 2 h, then allowed to cool to 23 °C
and partitioned between half-saturated NaHCO3 soln (150 mL) and
EtOAc (2 × 150 mL). The combined organic layers were dried
(Na2SO4) and then concentrated under reduced pressure. The resi-
due was dissolved in EtOH (40 mL) at 23 °C and a 21% wt/wt soln
of NaOEt in EtOH (1.21 mL, 3.73 mmol) was added. The reaction
mixture was heated at 50 °C for 30 min, then allowed to cool to
23 °C, and partitioned between 1.0 M HCl (150 mL) and EtOAc
(2 × 150 mL). The combined organic layers were dried (Na2SO4)
and then concentrated under reduced pressure. Purification of the
residue by flash chromatography (Superflash cartridge, gradient
elution, 0→8% MeOH–CH2Cl2) provided the title compound.
(5) Li, L.-S.; Zhou, Y.; Zhao, J.; Dragovich, P. S.; Stankovic,
N.; Bertolini, T. M.; Murphy, D. E.; Sun, Z.; Tran, C. V.;
Ayida, B. K.; Ruebsam, F.; Webber, S. E. Synthesis 2007,
3301.
(6) Murphy, D. E.; Dragovich, P. S.; Ayida, B. K.; Bertolini, B.
M.; Li, L.-S.; Ruebsam, F.; Stankovic, N. S.; Sun, Z.; Zhao,
J.; Zhou, Y. Tetrahedron Lett. 2008, 49, 811.
(7) Frohberg, P.; Kupfer, C.; Stenger, P.; Baumeister, U.; Nuhn,
P. Arch. Pharm. (Weinheim, Ger.) 1995, 328, 505.
(8) Phillips, R. R. Org. React. 1959, 10, 143.
(9) For a recent use of the Japp–Klingemann reaction to prepare
a chloro(phenylhydrazono)acetate, see: Catarzi, D.; Colotta,
V.; Varano, F.; Lenzi, O.; Filacchioni, G.; Trincavelli, L.;
Martini, C.; Montopoli, C.; Moro, S. J. Med. Chem. 2005,
48, 7932.
(10) For the preparation of similar (alkylhydrazono)(chloro)ace-
tates, see: (a) Conti, P.; Grazioso, G.; di Ventimiglia, S. J.;
Pinto, A.; Roda, G.; Madsen, U.; Bräuner-Osborne, H.;
Nielsen, B.; Costagli, C.; Galli, A. Chem. Biodiversity 2005,
2, 748. (b) Bach, K. K.; El-Seedi, H. R.; Jensen, H. M.;
Nielsen, H. B.; Thomsen, I.; Torssell, K. B. G. Tetrahedron
1994, 50, 7543.
(11) Unless otherwise noted, all hydrazones described in this
work were isolated and characterized as single isomers. No
attempt was made to assign hydrazone stereochemistry (E or
Z) or to rigorously identify any minor amounts of alternate
isomers that may have been formed during a given synthetic
transformation.
Yield: 0.836 g (64%); dark red oil.
Additional purification by reverse-phase preparative HPLC
[0→100% MeCN–H2O (both containing 0.05% TFA), 7.0 min,
flow = 30 mL/min] afforded an analytical sample.
1H NMR (400 MHz, CDCl3): d = 1.42 (t, J = 7.1 Hz, 3 H), 1.60–1.62
(m, 2 H), 1.66–1.71 (m, 4 H), 3.17–3.20 (m, 4 H), 3.91 (s, 3 H), 4.46
(q, J = 7.0 Hz, 2 H), 7.19 (dd, J = 2.9, 9.0 Hz, 1 H), 7.46 (d, J = 9.3
Hz, 1 H), 7.56 (d, J = 2.4 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 14.2, 24.6, 25.8, 50.2, 56.4, 63.6,
103.8, 110.2, 119.6, 127.8, 130.8, 145.7, 146.5, 157.7, 159.7, 163.9,
171.2.
(12) Reversing the order of the chlorination and Boc-
deprotection steps also afforded 3a, but in significantly
lower yield.
HRMS (ESI-TOF): m/z calcd for C19H22N4O7 [M + H]+: 419.1561;
found: 419.1549.
(13) The major amino(hydrazono)acetate acylation products
described in this work are inferred to be those depicted in
Scheme 1 (structure 5) by their successful conversion into 6-
aminopyridazin-3(2H)-ones in reasonable yields (Scheme 1,
structure 6). Significant amounts of alternate acylation
products were not detected by LCMS analysis of the reaction
mixtures and no other attempts were made to identify and/or
quantify such entities.
(14) The reaction was performed in an open flask. We have
observed that the chlorination rate and yield can vary with
the source of the N-chlorosuccinimide employed in the
reaction.
References
(1) Corsano, S.; Strappaghetti, G.; Barbaro, R.; Giannaccini, G.;
Betti, L.; Lucacchini, A. Bioorg. Med. Chem. 1999, 7, 933.
(2) Corsano, S.; Strappaghetti, G.; Leonardi, A.; Rhazri, K.;
Barbaro, R. Eur. J. Med. Chem. 1997, 32, 339.
(3) Corsano, S.; Vezza, R.; Scapicchi, R.; Foresi, S.;
Strappaghetti, G.; Nenci, G. G.; Gresele, P. Eur. J. Med.
Chem. 1995, 30, 627.
(4) Park, J.-W.; Kim, J.-J.; Kim, H.-K.; Kang, Y.-J.; Lee, W. S.;
Yoon, Y.-J. J. Heterocycl. Chem. 2000, 37, 1603.
Synthesis 2008, No. 4, 610–616 © Thieme Stuttgart · New York