A novel method for the synthesis of 3,4-disubstitutedpyrrole-2,5- dicarboxylates from hydrazones derived from α-diazo esters

Article abstract of DOI:10.1016/j.tet.2013.03.037

Hydrazones obtained from α-diazo esters were converted to pyrroles when heated with thionyl chloride in alcohol. Among hydrazones, those substituted with a benzene ring on the β-carbon to the ester are likely to give pyrroles in good yields.

Full text of DOI:10.1016/j.tet.2013.03.037

Tetrahedron xxx (2013) 1e6
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A novel method for the synthesis of 3,4-disubstitutedpyrrole-2,5-
dicarboxylates from hydrazones derived from a-diazo esters
,
b
,
b
a
b,
Eiko Yasui a , Masao Wada , Shinji Nagumo , Norio Takamura
*
*
a Department of Applied Chemistry, Kogakuin University, 2665-1 Nakano, Hachioji, Tokyo 192-0015, Japan
b Research Institute of Pharmaceutical Sciences, Musashino University, 1-1-20 Shinmachi, Nishitokyo, Tokyo 202-8585, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Hydrazones obtained from a-diazo esters were converted to pyrroles when heated with thionyl chloride
Received 11 December 2012
Received in revised form 7 March 2013
Accepted 9 March 2013
Available online xxx
in alcohol. Among hydrazones, those substituted with a benzene ring on the
likely to give pyrroles in good yields.
b-carbon to the ester are
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Pyrrole
PilotyeRobinson pyrrole synthesis
a
-Diazo ester
Hydrazone
1. Introduction
thus transformed to polyfunctional pyrroles through a 3,3-
sigmatropic rearrangement of divinylhydrazine (Scheme 1).8 In
this paper, we report detailed results on this pyrrole synthesis
method.
Nature abounds with compounds containing a pyrrole ring, such
as polycitone A,1 which inhibits retroviral reverse transcriptases
and cellular DNA polymerases, and storniamide A,2 which has
multidrug resistance reversal activity. Porphyrin, which is essential
for the maintenance of life activity, consists of four pyrroles. Re-
cently, porphyrins have been shown to cleave the DNA chain
through their photosensitizing effect. Therefore, interactions be-
tween porphyrins and DNA have been studied extensively. In par-
ticular, cationic porphyrin TMPyP4 is known to damage DNA and
induce apoptosis of cells.3 It has also attracted much attention from
chemical biologists since the late 1990s as it interacts with the G-
quadruplex.4 On the other hand, in the field of functional mole-
cules, a variety of calixpyrroles have been synthesized and their
anion binding has been discovered.5
2. Results and discussion
We first attempted installation of a vinyl group to a terminal
nitrogen of an a-diazo ester to obtain vinylhydrazone. However,
treatment of 1a with vinyl magnesium bromide or alkynyl lithiums
did not give the desired products (Scheme 2).
This result led us to prepare a diimine, which was expected to
isomerize to divinylhydrazine under acidic conditions. Reduction of
the a-diazo ester 1a was carried out according to a previously re-
ported method to give the corresponding hydrazone 2a.9 The ste-
reochemistry of the hydrazone 2a was determined from the
chemical shifts in the 1H NMR spectra.9,10 The signal for the ter-
minal hydrogens on the syn-hydrazone amine appeared at a lower
field than that for the anti-isomer due to hydrogen bonding with
the ester carbonyl group. The subsequent condensation of 2a with
phenylacetaldehyde generated diimine 3 in 78% yield. It was also
found that 1a reacted with 2-butanone when heated in the pres-
ence of tributylphosphine to afford diimine 5 directly in 88% yield.
Interestingly, treatment of both diimines 3 and 5 with thionyl
chloride in EtOH gave the symmetric pyrrole 4a rather than
unsymmetric pyrroles (Scheme 3). The formation of the symmetric
pyrrole is explained by beginning with alcoholysis at one C]N
bond far from the ester group, by which these diimines revert to
During our research on the reactivity of
are easily prepared from various
a-diazo esters 1, which
a
-amino acid esters,6 we reported
a modified synthesis method for polysubstituted indoles by com-
bining the classical Fischer reaction with our new reaction: the
facile formation of arylhydrazones by the coupling of 1 and various
arylmetal reagents.7 Fischer indole synthesis was well known to
involve a 3,3-sigmatropic rearrangement of hydrazine formed by
double bond isomerization of arylhydrazone. The mechanism
suggested to us a further application of a-diazo esters, which were
* Corresponding authors. E-mail address: bt13305@ns.kogakuin.ac.jp (E. Yasui).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.03.037
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2
E. Yasui et al. / Tetrahedron xxx (2013) 1e6
Scheme 1. Plausible mechanism for the synthesis of indole and pyrrole.
2f with 3,4,5-trimethoxyphenyl produced a polyfunctional pyrrole
4f in good yield. The reaction of 2g with a 4-chlorophenyl group
also proceeded readily to afford 4g in fairly good yield. Next, various
hydrazones without an aromatic ring at the b-position to the ester
were subjected to the same reaction conditions. Among them, only
hydrazones 2h and 2i derived from benzylcysteine and methionine
afforded polyfunctional pyrroles 4h and 4i in 60% and 21% yield,
respectively. On the other hand, treatment of hydrazones 2j and 2k
Scheme 2. Reactions of alpha-diazo ester with vinyl magnesium bromide or acetylide.
Scheme 3. Production of symmetrical pyrrole from unsymmetric diimine.
hydrazone 2a. Subsequently, coupling by two molecules of 2a
concomitant with elimination of N2H4 generates the symmetric
diimine, so-called azine, which is further converted to 4a through
the same path as the PilotyeRobinson reaction:11 (i) isomerization
to divinyl hydrazine intermediate; (ii) 3,3-sigmatropic rearrange-
ment; (iii) cyclization of diimine intermediate concomitant with
elimination of NH3.
We thus examined the conversion of hydrazone itself into pyr-
role under the same conditions, as shown in Table 1. When treated
with thionyl chloride in EtOH at 90 ꢀC in a sealed tube, 2a was
converted to 4a in excellent yield. This remarkable result led us to
clarify the scope and limitation of this pyrrole formation using
hydrazones having various types of aromatic ring (entries 2e7). The
reaction of hydrazones 2bed derived from tyrosine, benzyl
tyrosine and methyl tyrosine, respectively, gave the corresponding
pyrroles 4bed in good yields. Although the yield was un-
satisfactory, pyrrole 4e with a 3,4-dimethoxyphenyl group was also
obtained. After the reaction of the hydrazone 2e, 1H NMR spectra of
crude mixture were examined. It contained several byproducts,
which were unstable to purify by silica gel column chromatogra-
phy. Considering from the chart, it seems that aromatic electro-
philic substitution occurred inter and intramolecularly and gave
complex mixture along with pyrrole 4e. The reaction of hydrazone
derived from benzylserine and leucine under the same conditions
resulted in their decomposition.
The reaction of hydrazones 2len derived from Cbz-lysine, aspartic
acid and glutamic acid are listed in Scheme 4. With its amine at the
sixth position from the iminic carbon, 2l was cyclized to afford the
compound 6 in 76% yield. As 2m and 2n contain a carbonyl group at
the fifth or sixth position from the amine of the hydrazone, intra-
molecular cyclization occurred faster than intermolecular conden-
sation. It seems that isomerization of the double bond occurred after
cyclization and gave 7 from 2m. Hydrazone 2n was obtained by re-
duction of diazo ester 1n with L-SelectrideÒ. When 1n was treated
with tributylphosphine, cyclic compound 9 was produced in 77%
yield.9 Further, 2n was gradually cyclized and gave 9 even though it
was stored in a refrigerator. When compound 9 was treated with
thionyl chloride in ethanol, compound 8 was produced (Scheme 5).
Considering these results, product 8 was obtained from 9 via cycli-
zation and subsequent oxidation.
The synthesis of pyrrole derivatives containing two different
aromatic rings is more difficult. There are two methods to obtain
unsymmetric 3,4-diarylpyrroles. The first introduces the different
aromatic rings one by one to dibromo or ditriflate pyrrole by
a coupling reaction.12 Lately, as its constructive application, Dau-
ban and Dodd et al. reported one-pot SuzukieMiyaura couplings
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E. Yasui et al. / Tetrahedron xxx (2013) 1e6
3
Table 1
of 3,4-dibromo-1H-pyrrole-2,5-dicarboxylate with two kinds of
Results of cyclization with various hydrazones
arylboronic acids, generating unsymmetrically substituted pyrrole
in moderate yield.13
A second method is to make 3,4-
diarylpyrroles through cyclization of a substrate having aromatic
substituents in advance.14 Steglich et al. reported the synthesis
of 3,4-diarylpyrrole-2,5-dicarboxylic acids and their ester
derivatives.15 In their method, pyrrole 4ab was synthesized from
sodium enolate of ethyl 3-(4-hydroxyphenyl) pyruvate, ethyl
3-bromo-3-phenylpyruvate and ammonia in 14% yield. We thus
challenged the synthesis of a pyrrole containing two different
aromatic rings by using our new method. Treatment of an
equivalent mixture of hydrazones 2a and 2b with thionyl chloride
in EtOH at 90 ꢀC in a sealed tube afforded unsymmetric pyrrole
4ab in moderate yield along with two symmetric pyrroles (4a:
30%; 4b: 19%) (Scheme 6). There is still room for improvement in
synthesizing unsymmetric pyrrole in good yield and further trials
are in progress.
Entry
R
R0
Yield (%)
1
2
Ph
(2a)
(2b)
Et
Et
94 (4a)
79 (4b)
3
4
(2c)
(2d)
Me
Me
74 (4c)
79 (4d)
5
6
7
(2e)
(2f)
(2g)
Me
Me
Me
37 (4e)
66 (4f)
80 (4g)
3. Conclusion
A new synthesis method for polyfunctional pyrroles has been
found. Various hydrazones obtained from
a-diazo esters were
converted to the corresponding pyrroles upon treatment with
thionyl chloride in alcohol. In particular, hydrazones having an
acidic proton on the b-carbon to the ester gave pyrrole derivatives
8
9
BnOe
(2j)
Me
Et
Complex mixture
Complex mixture
(CH3)2CHe
(2k)
in good yields. These ring formations should proceed through the
sequence of coupling of two molecular hydrazones concomitant
with elimination of hydrazine, isomerization to divinylhydrazine
intermediate, 3,3-sigmatropic rearrangement and cyclization
of the diimine intermediate concomitant with elimination of
NH3. This method would be applicable to the polyaromatic
systems that are widely found in various drugs and useful
materials.
4. Experimental
4.1. General
1H and 13C NMR spectra were recorded on a JEOL JNN-ECX-400
spectrometer at 400 and 100 MHz, respectively. Chemical shifts
were expressed in
internal standard (
signals were referenced to CDCl3
abbreviations are used: s¼singlet, d¼doublet, t¼triplet, q¼quartet,
m¼multiplet and br¼broad. IR spectra were recorded on a JASCO
FT/IR-4100. Mass spectra were recorded on a JEOL JMS-GCmate II.
FAB and ESI-mass spectra were recorded on a JEOL JMS-700.
Melting points were determined on a Yanagimoto MP-S3 micro
melting point apparatus and were uncorrected.
d parts per million with tetramethylsilane as
d
¼0 ppm) for 1H NMR. Chemical shifts of carbon
(dC¼77.0 ppm). The following
4.2. Materials
Scheme 4. Production of heterocyclic compounds from hydrazones. Reagents and
conditions: (a) SOCl2, MeOH, 90 ꢀC (in a sealed tube); (b) SOCl2, EtOH, 90 ꢀC (in a sealed
tube).
All reagents and solvents were purchased from commercial
sources and used without further purification.
Scheme 5. Production of pyridazinone 8.
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4
E. Yasui et al. / Tetrahedron xxx (2013) 1e6
Scheme 6. Trial for the synthesis of unsymmetric pyrrole.
4.3. Synthesis of hydrazones
1247 cmꢁ1; HRMS (EI) calcd for C17H18N2O3 (Mþ) 298.1317, found
298.1320.
4.3.1. Typical experimental procedure for reduction with L-Selec-
trideÒ. Diazo ester 1a (204 mg, 1 mmol) was dissolved in THF (9 ml)
and stirred at ꢁ68 ꢀC under a nitrogen atmosphere. To this solution
was slowly added L-SelectrideÒ (1.0 ml, 1.0 M in THF). The reaction
mixture was stirred for 20 min at the same temperature, diluted
with saturated NH4Cl solution and extracted three times with ethyl
acetate. The combined organic phase was washed with brine, dried
over Na2SO4 and concentrated in vacuo. The resulting residue was
purified by silica gel column chromatography (hexane/ethyl
acetate¼2:1) to give 2a as pale-yellow crystals (172.9 mg, 84%).
4.3.2.5. Methyl
(E)-2-hydrazono-3-(4-methoxyphenyl)
pro-
7.10
pionate (2d). Mp 63e64 ꢀC; 1H NMR (CDCl3, 400 MHz)
d
(d, J¼8.0 Hz, 2H), 6.81 (d, J¼8.0 Hz, 2H), 6.04 (s, 2H), 3.84 (s, 3H),
2.06 (s, 2H), 2.94 (s, 3H); 13C NMR (CDCl3, 100 MHz)
d
165.78,
158.63, 138.23, 129.17, 126.59, 114.54, 55.36, 52.63, 29.68; IR (KBr)
3377, 3282, 3209, 1699 cmꢁ1; HRMS (EI) calcd for C11H14N2O3 (Mþ)
222.1004, found 222.1006.
4.3.2.6. Methyl (E)-2-hydrazono-3-(3,4-dimethoxyphenyl) pro-
pionate (2e). Mp 138e139 ꢀC; 1H NMR (CDCl3, 400 MHz)
4.3.2. Typical experimental procedure for reduction with tribu-
tylphosphine. Diazo ester 1a (427 mg, 2.09 mmol) was dissolved in
i-Pr2O (2.1 ml) and stirred at room temperature under a nitrogen
atmosphere. To this solution was added tributylphosphine (1.57 ml,
6.27 mmol). The reaction mixture was stirred for 150 min at the
same temperature, diluted with ethyl acetate (30 ml) and washed
with saturated NaHCO3 solution and brine. The organic phase was
dried over Na2SO4 and concentrated in vacuo. The resulting residue
was purified by silica gel column chromatography (hexane/ethyl
acetate¼10:1 to 1:1) to give 2a (401.5 mg, 93%) and its Z-isomer 2a0
(10.1 mg, 2%).
d
6.81e6.71 (m, 3H), 6.09 (s, 2H), 3.88 (s, 2H), 3.85 (s, 9H); 13C NMR
(CDCl3, 100 MHz)
d 165.67, 149.43, 147.99, 137.89, 126.93, 119.87,
111.39, 111.09, 55.83, 55.81, 52.53, 30.11; IR (KBr) 3402, 3290,
1695 cmꢁ1; HRMS (EI) calcd for C12H16N2O4 (Mþ) 252.1110, found
252.1103.
4.3.2.7. Methyl (E)-2-hydrazono-3-(3,4,5-trimethoxyphenyl) pro-
pionate (2f). Mp 133.5e134.5 ꢀC; 1H NMR (CDCl3, 400 MHz)
d
6.38
(s, 2H), 6.10 (s, 2H), 3.85 (s, 3H), 3.82 (s, 2H), 3.79 (s, 6H), 3.78
(s, 3H); 13C NMR (CDCl3, 100 MHz)
165.78, 153.79, 137.50, 136.98,
d
130.40,104.93, 60.92, 56.22, 52.70, 30.86; IR (KBr) 3402, 3244,1698,
1592, 1124 cmꢁ1; HRMS (EI) calcd for C13H18N2O5 (Mþ) 282.1216,
found 282.1223.
4.3.2.1. Ethyl (E)-2-hydrazono-3-phenylpropionate (2a). Mp
49e50 ꢀC; 1H NMR (CDCl3, 400 MHz)
d 7.32e7.20 (m, 5H), 6.05
(s, 2H), 4.33 (q, J¼7.2 Hz, 2H), 3.90 (s, 2H), 1.37 (t, J¼7.2 Hz, 3H); 13
C
4.3.2.8. Methyl (E)-2-hydrazono-3-(4-chlorophenyl) propionate
NMR (CDCl3, 100 MHz)
d
165.16, 137.98, 134.82, 128.96, 128.00,
(2g). Mp 62e63 ꢀC; 1H NMR (CDCl3, 400 MHz)
d
7.25 (d, J¼8.0 Hz,
126.85, 61.40, 30.39, 14.29; IR (KBr) 3386, 1698, 1559 cmꢁ1; HRMS
(EI) calcd for C11H14N2O2 (Mþ) 206.1055, found 206.1053.
2H), 7.12 (d, J¼8.0 Hz, 2H), 6.06 (s, 2H), 3.84 (s, 3H), 3.83 (s, 2H); 13
C
NMR (CDCl3, 100 MHz)
d 165.63, 137.14, 133.30, 132.89, 129.50,
129.24, 52.70, 29.72; IR (KBr) 3407, 1708, 1562 cmꢁ1; HRMS (EI)
calcd for C10H11ClN2O2 (Mþ) 226.0509, found 226.0509.
4.3.2.2. Ethyl (Z)-2-hydrazono-3-phenylpropionate (2a0). Mp
67e68 ꢀC; 1H NMR (CDCl3, 400 MHz)
d 8.17 (s, 2H), 7.29e7.18
(m, 5H), 4.14 (q, J¼7.2 Hz, 2H), 3.70 (s, 2H), 1.22 (t, J¼7.2 Hz, 3H); 13
C
4.3.2.9. Ethyl
(E)-2-hydrazono-3-benzylsulfinyl
propionate
NMR (CDCl3, 100 MHz)
d
162.73, 139.23, 130.38, 128.84, 128.13,
(2h). Mp 52e53 ꢀC; 1H NMR (CDCl3, 400 MHz)
d
7.35e7.24 (m, 5H),
126.07, 60.20, 39.48, 13.98; IR (KBr) 3455, 1693, 1676, 1576, 1540,
1211 cmꢁ1; HRMS (EI) calcd for C11H14N2O2 (Mþ) 206.1055, found
206.1065.
6.50 (s, 2H), 4.27 (q, J¼7.2 Hz, 2H), 3.75 (s, 2H), 3.58 (s, 2H), 1.33 (t,
J¼7.2 Hz, 3H); 13C NMR (CDCl3, 100 MHz)
d 164.44, 137.43, 134.40,
128.80, 128.58, 127.38, 61.45, 36.45, 23.88, 14.25; IR (KBr) 3426,
1690, 1551, 1188 cmꢁ1; HRMS (FAB pos.) calcd for C12H17N2O2S
(MþHþ) 253.1011, found 253.1007.
4.3.2.3. Ethyl (E)-2-hydrazono-3-(4-hydroxyphenyl) propionate
(2b). Mp 134e135 ꢀC; 1H NMR (DMSO-d6, 400 MHz)
d 9.18 (s, 1H),
7.69 (s, 2H), 6.97 (d, J¼8.8 Hz, 2H), 6.64 (d, J¼8.4 Hz, 2H), 4.09
4.3.2.10. Methyl (E)-2-hydrazono-4-methylsulfinyl butanoate
(q, J¼6.8 Hz, 2H), 3.62 (s, 2H), 1.19 (t, J¼6.8 Hz, 3H); 13C NMR
(2i). 1H NMR (CDCl3, 400 MHz)
d 6.36 (s, 2H), 3.83 (s, 3H), 2.80
(DMSO-d6, 100 MHz)
d
165.47, 155.59, 133.09, 129.21, 126.91, 115.11,
(t, J¼7.6 Hz, 2H), 2.68 (t, J¼7.6 Hz, 2H), 2.18 (s, 3H); 13C NMR (CDCl3,
59.78, 39.08, 14.28; IR (KBr) 3441, 1691, 1516 cmꢁ1; HRMS calcd for
100 MHz) d 165.11, 138.18, 52.27, 29.74, 24.45, 15.79; IR (film) 3410,
C
11H14N2O3 (Mþ) 222.1004, found 222.1016.
3318, 3225, 1705 cmꢁ1; HRMS (EI) calcd for C6H12N2O2S (Mþ)
176.0619, found 176.0631.
4.3.2.4. Methyl (E)-2-hydrazono-3-(4-benzyloxyphenyl) pro-
pionate (2c). Mp 96.0e96.5 ꢀC; 1H NMR (CDCl3, 400 MHz)
4.3.2.11. Methyl
(E)-2-hydrazono-3-benzyloxy
propionate
d
7.42e7.30 (m, 5H), 7.11 (d, J¼8.8 Hz, 2H), 6.90 (d, J¼8.8 Hz, 2H),
6.03 (s, 2H), 5.02 (s, 2H), 3.85 (s, 3H), 3.82 (s, 2H); 13C NMR (CDCl3,
100 MHz) 165.65, 157.75, 138.14, 136.85, 129.09, 128.55, 127.96,
127.41, 126.78, 115.40, 70.01, 52.51, 29.59; IR (KBr) 3429, 1701, 1510,
Please cite this article in press as: Yasui, E.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.03.037
(2j). 1H NMR (CDCl3, 400 MHz)
d
7.40e7.27 (m, 5H), 7.05 (s, 2H),
4.61 (s, 2H), 4.48 (s, 2H), 3.82 (s, 3H); 13C NMR (CDCl3, 100 MHz)
d
d
164.93, 137.04, 133.06, 128.54, 128.19, 128.09, 72.68, 63.57, 52.32;
IR (film) 3424, 3310, 3229, 2951, 2862, 1694, 1566, 1441 cmꢁ1
;

E. Yasui et al. / Tetrahedron xxx (2013) 1e6
5
HRMS (FAB pos.) calcd for C11H15N2O3 (MþHþ) 223.1083, found
(d, J¼8.4 Hz, 4H), 5.02 (s, 4H), 3.77 (s, 6H); 13C NMR (CDCl3,
223.1108.
100 MHz) d 160.75, 157.83, 136.98, 131.93, 131.20, 128.51, 127.91,
125.35, 121.08, 113.79, 69.87, 51.75; IR (KBr) 3263, 1703,
1212 cmꢁ1; HRMS calcd for C34H29NO6 (Mþ) 547.1995, found
547.1994.
4.3.2.12. Ethyl (E)-2-hydrazono-4-methyl pentanoate (2k). 1H
NMR (CDCl3, 400 MHz)
d
6.03 (s, 2H), 4.28 (q, J¼7.2 Hz, 2H), 2.37
(d, J¼7.6 Hz, 2H), 2.03 (septet, J¼7.2 Hz, 1H), 1.35 (t, J¼7.2 Hz, 3H),
0.96 (d, J¼6.8 Hz, 6H); 13C NMR (CDCl3, 100 MHz)
d
165.20, 140.23,
4.4.1.4. Dimethyl 3,4-bis(4-methoxyphenyl)-1H-pyrrole-2,5-di-
61.13, 32.60, 25.88, 22.88, 14.29; IR (film) 3412, 1701, 1140 cmꢁ1
;
carboxylate (4d). Mp 198e199 ꢀC; 1H NMR (CDCl3, 400 MHz)
d
9.79
HRMS calcd for C8H16N2O2 (Mþ) 172.1212, found 172.1210.
(br s, 1H), 7.04 (d, J¼8.8 Hz, 4H), 6.76 (d, J¼9.2 Hz, 4H), 3.77 (s, 12H);
13C NMR (CDCl3, 100 MHz)
d 160.76, 158.50, 131.89, 131.25, 125.08,
4.3.2.13. Methyl (E)-2-hydrazono-6-benzyloxycarbonylamino
hexanoate (2l). 1H NMR (CDCl3, 400 MHz)
7.40e7.28 (m, 5H),
121.08, 112.88, 55.05, 51.73; IR (KBr) 3348, 1705 cmꢁ1; HRMS calcd
for C22H21NO6 (Mþ) 395.1369, found 395.1365.
d
6.21 (s, 2H), 5.08 (s, 2H), 4.86 (br s, 1H), 3.78 (s, 3H), 3.28
(q, J¼6.4 Hz, 2H), 2.50 (t, J¼8.0 Hz, 2H), 1.56 (q, J¼6.4 Hz, 2H), 1.49
4.4.1.5. Dimethyl 3,4-bis(3,4-dimethoxyphenyl)-1H-pyrrole-2,5-di-
(m, 1H); 13C NMR (CDCl3, 100 MHz)
d
165.53, 156.99, 138.55, 136.51,
carboxylate (4e). Mp 171e171.5 ꢀC; 1H NMR (CDCl3, 400 MHz)
d
9.80
(br s,1H), 6.74 (m, 4H), 6.62 (d, J¼1.2 Hz, 2H), 3.86 (s, 6H), 3.80 (s, 6H),
3.64 (s, 6H); 13C NMR (CDCl3, 100 MHz)
160.75, 148.04, 147.88,
128.51, 128.13, 127.93, 66.72, 52.20, 39.48, 30.15, 22.99, 20.80; IR
(film) 3410, 3318, 2947, 2862, 1708, 1535, 1443, 1207 cmꢁ1; HRMS
calcd for C15H21N3O4 (Mþ) 307.1532, found 307.1532.
d
131.25, 125.37, 123.40, 121.07, 114.32, 110.29, 55.74, 51.83; IR (KBr)
3310, 1721, 1682, 1535, 1466, 1319, 1250 cmꢁ1; HRMS (EI) calcd for
4.3.2.14. Ethyl
(E)-2-hydrazono
succinate
(2m). Mp
C
24H25NO8 (Mþ) 455.1580, found 455.1566.
85.5e86.0 ꢀC; 1H NMR (CDCl3, 400 MHz)
d
6.60 (s, 2H), 4.31
(q, J¼7.2 Hz, 2H), 4.17 (q, J¼7.2 Hz, 2H), 3.63 (s, 2H), 1.36 (t, J¼7.2 Hz,
4.4.1.6. Dimethyl 3,4-bis(3,4,5-trimethoxyphenyl)-1H-pyrrole-2,5-
3H), 1.26 (t, J¼7.2 Hz, 3H); 13C NMR (CDCl3, 100 MHz)
d
168.80,
dicarboxylate (4f). Mp 168.0e168.5 ꢀC; 1H NMR (CDCl3, 400 MHz)
d
164.31, 132.26, 61.69, 61.65, 31.50, 14.30, 14.06; IR (KBr) 3410, 3298,
1716, 1697 cmꢁ1; HRMS (FAB pos.) calcd for C8H15N2O4 (Mþ)
203.1032, found 203.1033.
9.85 (br s, 1H), 6.36 (s, 4H), 3.81 (s, 12H), 3.64 (s, 12H); 13C NMR
(CDCl3, 100 MHz) 160.71, 152.44, 137.34, 131.22, 128.19, 121.10,
d
108.50, 60.98, 56.15, 52.04; IR (KBr) 3276, 2942, 1702, 1239,
1125 cmꢁ1; HRMS (EI) calcd for C26H29NO10 (Mþ) 515.1791, found
515.1750.
4.3.2.15. Ethyl (E)-2-hydrazono glutarate (2n). 1H NMR (CDCl3,
400 MHz)
d
6.68 (s, 2H), 4.28 (q, J¼7.2 Hz, 2H), 4.13 (q, J¼7.2 Hz, 2H),
2.74 (t, J¼6.4 Hz, 2H), 2.62 (t, J¼6.4 Hz, 2H), 1.35 (t, J¼7.2 Hz, 3H),1.26
4.4.1.7. Dimethyl 3,4-bis(4-chlorophenyl)-1H-pyrrole-2,5-dicarbox-
(t, J¼7.2 Hz, 3H); 13C NMR (CDCl3, 100 MHz)
d
174.11, 164.77, 138.44,
ylate (4g). Mp 182e183 ꢀC; 1H NMR (CDCl3, 400 MHz)
d 9.90 (br s,
61.13, 61.08, 30.69, 19.09, 14.28, 14.07; IR (film) 3418, 2986, 2932,
1H), 7.19 (d, J¼8.0 Hz, 4H), 7.02 (d, J¼8.0 Hz, 4H), 3.77 (s, 6H); 13C
1720cmꢁ1; HRMScalcd for C9H16N2O4 (Mþ)216.1110, found 216.1094.
NMR (CDCl3, 100 MHz) d 160.54, 133.36, 132.13, 131.10, 130.18,
127.93, 121.48, 52.05; IR (KBr) 2952, 1710, 1297, 1247 cmꢁ1; HRMS
calcd for C12H13N3O2 (Mþ) 403.0378, found 403.0378.
4.4. Synthesis of pyrroles
4.4.1. Typical experimental procedure for pyrrole 4a. Hydrazone 2a
(176.1 mg, 0.85 mmol) was dissolved in ethanol (2 ml) in a sealed
tube. To this solution was slowly added thionyl chloride (0.62 ml,
8.50 mmol) diluted in ethanol (3 ml) at 0 ꢀC and stirred for 45 min
at 90 ꢀC. After cooling to room temperature, the reaction mixture
was slowly poured into saturated aqueous NaHCO3 solution (30 ml)
and extracted with ethyl acetate (10 ml) three times. The organic
phase was dried over Na2SO4 and concentrated under reduced
pressure. The resulting residue was purified by silica gel column
chromatography (hexane/ethyl acetate¼3:1) to give 4a as colour-
less crystals (145.5 mg, 94%).
4.4.1.8. Diethyl 3,4-bis(benzylsulfinyl)-1H-pyrrole-2,5-dicarbox-
ylate (4h). 1H NMR (CDCl3, 400 MHz)
d 9.84 (br s, 1H), 7.23e7.10 (m,
10H), 4.31 (q, J¼7.2 Hz, 4H), 3.96 (s, 4H), 1.37 (t, J¼7.2 Hz, 3H); 13C
NMR (CDCl3, 100 MHz)
d 159.22, 137.78, 128.98, 128.15, 126.93,
126.60, 126.07, 61.39, 40.49, 14.26; IR (film) 3271, 1705, 1273 cmꢁ1
;
HRMS calcd for C24H25NO4S2 (Mþ) 455.1225, found 455.1225.
4.4.1.9. Dimethyl 3,4-bis(methylsulfinyl)-1H-pyrrole-2,5-dicarbox-
ylate (4i). Mp 91e92 ꢀC; 1H NMR (CDCl3, 400 MHz)
9.50 (br s, 1H),
4.06 (s, 4H), 3.91 (s, 6H), 2.05 (s, 6H); 13C NMR (CDCl3, 100 MHz)
d
d
160.67, 127.44, 122.38, 51.85, 26.48, 15.21; IR (KBr) 3321, 1697,
1282, 1273 cmꢁ1; HRMS calcd for C12H18NO4S2 (MþHþ) 304.0677,
4.4.1.1. Diethyl 3,4-bis(4-phenyl)-1H-pyrrole-2,5-dicarboxylate (4a).
found 304.0647.
Mp 151e151.8 ꢀC; 1H NMR (CDCl3, 400 MHz)
d
9.86 (br s,1H), 7.21e7.16
(m, 6H), 7.15e7.09 (m, 4H), 4.22 (q, J¼8.0 Hz, 4H),1.17 (t, J¼8.0 Hz, 6H);
4.4.1.10. Diethyl 3-(4-hydroxyphenyl)-4-phenyl-1H-pyrrole-2,5-di-
13C NMR (CDCl3, 100 MHz)
d
160.55, 133.14, 131.46, 130.93, 127.34,
carboxylate (4ab). Mp 186.0e186.4 ꢀC; 1H NMR (CDCl3, 400 MHz)
127.00, 121.64, 60.97, 14.09; IR (KBr) 3325, 1703, 1302, 1242 cmꢁ1
;
d 9.85 (br s, 1H), 7.20e7.18 (m, 3H), 7.13e7.11 (m, 2H), 6.99e6.95
HRMS calcd for C22H21NO4 (Mþ) 363.1471, found 363.1477.
(m, 2H), 6.66e6.62 (m, 2H), 4.25 (q, J¼7.2 Hz, 2H), 4.22 (q,
J¼7.2 Hz, 2H), 1.22 (t, J¼7.2 Hz, 3H), 1.16 (t, J¼7.2 Hz, 3H); 13C
4.4.1.2. Diethyl 3,4-bis(4-hydroxyphenyl)-1H-pyrrole-2,5-dicarboxy-
late (4b). Mp 227e228 ꢀC; 1H NMR (CD3OD, 400 MHz)
6.88 (d,
NMR (CDCl3, 100 MHz) d 160.56, 160.53, 155.05, 133.21, 132.02,
d
131.39, 131.32, 130.84, 127.23, 126.81, 124.83, 121.49, 121.38,
114.38, 60.85, 14.06, 13.94; IR (KBr) 3348, 3210, 1690, 1474, 1435,
1296, 1250 cmꢁ1; HRMS calcd for C22H21NO6 (Mþ) 379.1420,
found 379.1419.
J¼8.8 Hz, 2H), 6.60 (d, J¼8.8 Hz, 2H), 4.17 (q, J¼7.2 Hz, 2H), 1.15 (t,
J¼7.2 Hz, 3H); 13C NMR (CD3OD, 100 MHz)
d 162.43, 157.27, 133.20,
132.67, 126.34, 123.18, 115.06, 61.61, 14.35; IR (KBr) 3526, 3402,
3271, 1697, 1481, 1427, 1296, 1242 cmꢁ1; HRMS calcd for C22H21NO6
(Mþ) 395.1369, found 395.1367.
4.5. Synthesis of heterocyclic compounds in Schemes 4 and 5
4.4.1.3. Dimethyl 3,4-bis(4-benzyloxyphenyl)-1H-pyrrole-2,5-di-
4.5.1. Experimental procedure for compounds in Scheme 4. Hydrazone
was dissolved in alcohol in a sealed tube. To this solution was
slowly added thionyl chloride diluted in the same alcohol at 0 ꢀC
carboxylate (4c). Mp 172e173 ꢀC; 1H NMR (CDCl3, 400 MHz)
d
9.79 (br s, 1H), 7.45e7.30 (m, 10H), 7.05 (d, J¼8.4 Hz, 4H), 6.84
Please cite this article in press as: Yasui, E.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.03.037

6
E. Yasui et al. / Tetrahedron xxx (2013) 1e6
and stirred for 45 min at 90 ꢀC. After cooling to room temperature,
the reaction mixture was slowly poured into saturated aqueous
NaHCO3 solution and extracted with ethyl acetate three times. The
organic phase was washed with brine, dried over Na2SO4 and
concentrated under reduced pressure. The resulting residue was
purified by silica gel column chromatography to give heterocyclic
compounds.
(q, J¼7.2 Hz, 2H), 2.93 (t, J¼8.4 Hz, 2H), 2.57 (t, J¼8.4 Hz, 2H), 1.38
(t, J¼7.2 Hz, 3H); 13C NMR (CDCl3, 100 MHz)
d 166.88, 162.94,
142.89, 62.20, 25.69, 21.02, 14.11; IR (KBr) 1713, 1624, 1288,
1202 cmꢁ1; HRMS (EI) calcd for C7H10N2O3 (Mþ) 170.0691, found
170.0692.
4.5.3. Experimental procedure for compound 8 from 9. The com-
pound 9 (103.5 mg, 0.61 mmol) was slowly added thionyl chloride
(0.440 ml, 6.10 mmol) diluted in ethanol (4 ml) and stirred for
60 min at 90 ꢀC in a sealed tube. After cooling to room temperature,
the reaction mixture was slowly poured into saturated aqueous
NaHCO3 solution and extracted with ethyl acetate three times. The
organic phase was washed with brine, dried over Na2SO4 and
concentrated under reduced pressure. The resulting residue was
purified by silica gel column chromatography (hexane/ethyl
acetate¼1:2) to give the compound 8 (41.9 mg, 0.25 mmol, 41%).
4.5.1.1. 1,2-(4H)-Pyridinedicarboxylic acid,5,6-dihydro-2-methyl
1-(phenylmethyl) ester (6). 1H NMR (CDCl3, 400 MHz)
d 7.27e7.37
(m, 5H), 6.08 (t, J¼3.6 Hz, 1H), 5.14 (s, 2H), 3.66 (t, J¼5.6 Hz, 2H),
3.54 (br s, 3H), 2.24 (dt, J¼6.8, 3.6 Hz, 2H),1.83 (quint, J¼6.8 Hz, 2H);
13C NMR (CDCl3, 100 MHz)
d 165.10, 153.98, 135.74, 132.31, 128.42,
128.14, 128.12, 123.14, 67.91, 51.86, 43.62, 22.83, 22.61; IR (film)
1713, 1396, 1335, 1273, 1258, 1234 cmꢁ1; HRMS (EI) calcd for
C
15H17NO4 (Mþ) 275.1158, found 275.1157.
4.5.1.2. Ethyl 2,5-dihydro-5-oxo-1H-pyrazole-3-carboxylate (7).
Acknowledgements
Mp 185 ꢀC; 1H NMR (CDCl3, 400 MHz)
d 6.21 (s, 1H), 4.44 (q,
J¼7.2 Hz, 2H), 1.42 (t, J¼7.2 Hz, 3H); 13C NMR (CDCl3, 100 MHz)
This work was financially supported by Uehara Memorial
Foundation.
d
161.43, 161.39, 134.28, 92.90, 62.28, 14.12; IR (KBr) 3356, 1720,
1504, 1443, 1381, 1281 cmꢁ1; HRMS (EI) calcd for C6H8N2O3 (Mþ)
156.0535, found 156.0532.
References and notes
4.5.1.3. Ethyl 3-pyridazinone-6-carboxylate (8). Mp 122e123 ꢀC;
1. (a) Rudi, A.; Goldberg, I.; Stein, Z.; Frolow, F.; Benayahu, Y.; Schleyer, M.;
Kashman, Y. J. Org. Chem. 1994, 59, 999e1003; (b) Loya, S.; Rudi, A.; Kashman,
Y.; Hizi, A. Biochem. J. 1999, 344, 85e92.
2. Palermo, J. A.; Rodriguez Brasco, M. F.; Seldes, A. M. Tetrahedron 1996, 52,
2727e2734.
1H NMR (CDCl3, 400 MHz)
d
7.94 (d, J¼10 Hz, 1H), 7.04 (d, J¼10 Hz,
1H), 4.46 (q, J¼7.2 Hz, 2H), 1.43 (t, J¼7.2 Hz, 3H); 13C NMR (CDCl3,
100 MHz)
d 162.12, 161.43, 137.51, 132.55, 129.92, 62.51, 14.15; IR
(KBr) 2847, 1713, 1288, 1142 cmꢁ1; HRMS (EI) calcd for C7H8N2O3
(Mþ) 168.0535, found 168.0528.
3. Tada-Oikawa, S.; Oikawa, S.; Hirayama, J.; Hirakawa, K.; Kawanishi, S. Photo-
chem. Photobiol. 2009, 85, 1391e1399.
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1998, 120, 3261e3262.
ꢀ
5. Gale, P. A.; Sessler, J. L.; Kral, V. Chem. Commun. 1998, 1e8.
4.5.2. Experimental procedure for compound 9. Diazo ester 1n
(285 mg, 1.33 mmol) was dissolved in i-Pr2O (1.3 ml) and stirred at
room temperature under a nitrogen atmosphere. To this solution
was added tributylphosphine (1.00 ml, 3.95 mmol). The reaction
mixture was stirred for 60 min at the same temperature, diluted
with ethyl acetate (30 ml) and washed with saturated NaHCO3
solution and brine. The organic phase was dried over Na2SO4, and
concentrated in vacuo. The resulting residue was purified by silica
gel column chromatography (hexane/ethyl acetate¼6:1 to 1:1) to
give 9 (175 mg, 77%) and its Z-hydrazone 2n0 (18.4 mg, 6%).
6. (a) Takamura, N.; Mizoguchi, T.; Koga, K.; Yamada, S. Tetrahedron 1975, 31,
227e230; (b) Takamura, N.; Mizoguchi, T.; Koga, K.; Yamada, S. Tetrahedron Lett.
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4.5.2.1. Ethyl 6-oxo-1,4,5,6-tetrahydropyridazine-3-carboxylate
(9). Mp 133e134 ꢀC; 1H NMR (CDCl3, 400 MHz)
d
9.10 (s, 1H), 4.36
15. Hinze, C.; Kreipl, A.; Terpin, A.; Steglich, W. Synthesis 2007, 608e612.
Please cite this article in press as: Yasui, E.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.03.037