Synthesis of diaminomethylidene derivatives of tetronic acid

Article abstract of DOI:10.1007/s11172-012-0221-4

Methyl 4-chloro-3-oxobutanoate reacts with benzoylcyanamide in the presence of catalytic amounts of Ni(acac)₂ to give the corresponding ketene N-benzoylaminal, which is transformed in boiling AcOH into 3-[(amino) (benzoylamino)methylidene]tetrahydrofuran-2,4-dione. Debenzoylation of the latter in the presence of EtONa in EtOH yields a N,N-unsubstituted diaminomethylidene derivative of tetronic acid. Cyclization of the adduct of methyl 4-chloro-3-oxobutanoate with benzoylcyanamide in the presence of triethylamine follows a different pathway leading to methyl 2-amino-1-benzoyl-4- oxo-4,5-dihydro-1H-pyrrole-3-carboxylate.

Full text of DOI:10.1007/s11172-012-0221-4

Russian Chemical Bulletin, International Edition, Vol. 61, No. 8, pp. 1640—1642, August, 2012
1640
Synthesis of diaminomethylidene derivatives of tetronic acid
M. A. Prezent and V. A. Dorokhov†
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (499) 135 5328. Eꢀmail: vador@ioc.ac.ru
Methyl 4ꢀchloroꢀ3ꢀoxobutanoate reacts with benzoylcyanamide in the presence of catalytic
amounts of Ni(acac)2 to give the corresponding ketene Nꢀbenzoylaminal, which is transformed
in boiling AcOH into 3ꢀ[(amino)(benzoylamino)methylidene]tetrahydrofuranꢀ2,4ꢀdione. Deꢀ
benzoylation of the latter in the presence of EtONa in EtOH yields a N,Nꢀunsubstituted
diaminomethylidene derivative of tetronic acid. Cyclization of the adduct of methyl 4ꢀchloroꢀ
3ꢀoxobutanoate with benzoylcyanamide in the presence of triethylamine follows a different
pathway leading to methyl 2ꢀaminoꢀ1ꢀbenzoylꢀ4ꢀoxoꢀ4,5ꢀdihydroꢀ1Hꢀpyrroleꢀ3ꢀcarboxylate.
Key words: methyl 4ꢀchloroꢀ3ꢀoxobutanoate, benzoylcyanamide, cyclization, diaminoꢀ
methylidene derivative of tetronic acid.
Scheme 1
Derivatives of tetronic acid (4ꢀhydroxyfuranꢀ2(5H)ꢀ
one) are known to be biologically important compounds
found in a number of living organisms (fungi, algae,
lichens, and tree fungi). They exhibit antiviral, antiꢀ
inflammatory, antibiotic, antitumor, and other types of
biological activity (see recent reviews1—4) and are very
popular as efficient reagents for the synthesis of various
furanꢀcontaining compounds (see, e.g., Refs 5—12).
Here we report on the synthesis of diaminomethylidene
derivatives of tetronic acid that are new promising buildꢀ
ing blocks for the design of heterocyclic systems.
Earlier,13—15 it has been found that ꢀoxo carboxylic
acid esters easily react with cyanamides in the presence of
catalytic amounts of Ni(acac)2 to give the corresponding
acyl(alkoxycarbonyl)ketene aminals, which were subseꢀ
quently employed in various approaches to the synthesis
of functionalized pyrimidines.15—18
Likewise, starting from methyl 4ꢀchloroꢀ3ꢀoxobuꢀ
tanoate (1) and benzoylcyanamide (2), we obtained ketene
aminal 3 in 70% yield (Scheme 1).
The 1H NMR spectrum of compound 3 in DMSOꢀd6
shows one set of signals because the barrier to rotation
about the C=C bond in such pushꢀpull systems is very
low.13,15,19
It is known that ꢀoxo carboxylic acid esters containꢀ
ing an appropriate substituent in the ꢀposition (Cl, Br,
OH, or OAc) can be employed as the starting materials in
the synthesis of tetronic acids (see Ref. 1). We found that
ketene aminal 3 in boiling acetic acid undergoes cyclizaꢀ
tion into Nꢀbenzoyldiaminomethylidenetetronic acid 4,
which is debenzoylated under the action of EtONa in
EtOH to give N,Nꢀunsubstituted compound 5. (Obviousꢀ
ly, the formation of furandione 4 is preceded by hydrolysis
of ester 3 to the corresponding acid.)
Crystalline products 4 and 5 are also ,ꢀdioxo ketene
aminals, which is confirmed by spectroscopic data (IR,
MS, and 1H and 13C NMR). As in the case of ketene
1
aminal 3, the H NMR spectrum (DMSOꢀd6) of comꢀ
† Deceased.
pound 4 shows one set of signals. The spectrum of diamiꢀ
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 8, pp. 1623—1625, August, 2012.
1066ꢀ5285/12/6108ꢀ1640 © 2012 Springer Science+Business Media, Inc.

3ꢀDiaminomethylidenetetrahydrofuranꢀ2,4ꢀdione
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 8, August, 2012
1641
3ꢀ(Diaminomethylidene)tetrahydrofuranꢀ2,4ꢀdione (5). Benzoꢀ
yl derivative 4 (1.46 g, 6 mmol) was added to a solution of metalꢀ
lic sodium (0.138 g, 6 mmol) in ethanol (20 mL). The reaction
mixture was stirred at room temperature for 5 h, neutralized with
HCl (0.216 g) in ethanol (10 mL), and concentrated. The resiꢀ
due was recrystallized from acetonitrile, washed with a small
amount of water, and dried. The yield of compound 5 was 0.477
g (56%), m.p. >300 C (MeCN). Found (%): C, 42.47; H, 4.45;
N, 19.42. C5H6N2O3. Calculated (%): C, 42.26; H, 4.25;
N, 19.71. IR, /cm–1: 3420, 3300 (NH), 1620, 1600 (CO). MS,
m/z: 142 [M]+. 1H NMR (DMSOꢀd6), : 4.30 (s, 2 H, CH2);
7.50 (br.s, 2 H, NH2); 7.80 (br.s, 2 H, NH2). 13C NMR
(DMSOꢀd6), : 70.4 (C(5)); 80.0 (C(3)); 159.6 (NH2—C—NH2);
174.5 (C(2)); 193.3 (C(4)).
Methyl 2ꢀaminoꢀ1ꢀbenzoylꢀ4ꢀoxoꢀ4,5ꢀdihydroꢀ1Hꢀpyrroleꢀ
3ꢀcarboxylate (6). A mixture of ketene aminal 3 (2.07 g, 7 mmol)
and triethylamine (0.71 g, 7 mmol) in MeCN (10 mL) was reꢀ
fluxed for 2 h and kept for 16 h. The precipitate that formed was
filtered off, washed with water, and dried. The yield of compound
6 was 1.36 g (75%), m.p. 230—232 C (MeCN). Found (%):
C, 59.87; H, 4.95; N, 10.83. C13H12N2O4. Calculated (%):
C, 60.00; H, 4.65; N, 10.76. IR, /cm–1: 3544—3220 (NH),
1700, 1680, 1660 (CO). MS, m/z: 260 [M]+, 229 [M – MeO]+,
155 [M – PhCO]+. 1H NMR (DMSOꢀd6), : 3.70 (s, 3 H, MeO);
4.00 (s, 2 H, CH2); 7.30—7.70 (m, 3 H, Ph); 7.95 (d, 2 H, Ph,
J = 7.0 Hz); 8.50—9.30 (br.s, 2 H, NH2).
nomethylidenetetronic acid 5 contains no signals for aroꢀ
matic protons.
Interestingly, the cyclization of ketene aminal 3 under
basic conditions (in the presence of an equivalent amount
of TEA) follows a different route leading to methyl
2ꢀaminoꢀ1ꢀbenzoylꢀ4ꢀoxoꢀ4,5ꢀdihydroꢀ1Hꢀpyrroleꢀ3ꢀ
carboxylate (6); i.e., the ring closure involves the fragꢀ
ments PhCONH and ClCH2. The mass spectrum of comꢀ
pound 6 contains a molecular ion peak with m/z 260; the
1H NMR spectrum (DMSOꢀd6) show signals for MeO
( 3.70) and for the aromatic protons of the benzoyl
substituent.
The diaminomethylidene derivatives of tetronic acid (4)
and (5) we obtained for the first time are of certain interꢀ
est as potential reagents for heterocyclic synthesis. In
this context, N,Nꢀunsubstituted aminal 5 seems to
be more promising because such ,ꢀdioxo ketene
aminals are highly efficient in heterocyclization proꢀ
cesses.18
Experimental
1
H and 13C NMR spectra were recorded on a Bruker AMꢀ300
instrument (300 and 75 MHz, respectively) at 25 C. Mass spectra
were measured on a Kratos MSꢀ30 instrument (EI, 70 eV). IR
spectra were recorded on a Specord Mꢀ82 instrument (KBr pellets).
Benzoylcyanamide was prepared as described earlier.20 Nickel
acetylacetonate (Aldrich) was recrystallized from MeOH and
dried in vacuo. Methyl 4ꢀchloroꢀ3ꢀoxobutanoate (Aldrich), comꢀ
mercial anhydrous ethanol, glacial acetic acid, acetonitrile, and
THF were also used.
Methyl 2ꢀ[(amino)(benzoylamino)methylidene]ꢀ4ꢀchloroꢀ3ꢀ
oxobutanoate (3). A solution of cyanamide 2 (1.46 g, 10 mmol),
methyl 4ꢀchloroꢀ3ꢀoxobutanoate (1.5 g, 10 mmol), and Ni(acac)2
(0.128 g, 0.5 mmol) in THF (20 mL) was refluxed for 1 h and
concentrated. The residue was recrystallized from MeOH. The
yield of compound 3 was 2.07 g (70%), m.p. 121—122 C
(MeOH). Found (%): C, 52.66; H, 4.44; N, 9.47. C13H13ClN2O4.
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Received October 19, 2011;
in revised form March 27, 2012