Reaction of 4-oxocarboxylic acids and 5-substituted 3H-furan-2-ones with 1,2-binucleophiles of aromatic and alicyclic series

Article abstract of DOI:10.1134/S1070428010090198

Based on reactions of 5-substituted 3H-furan-2-ones or 4-oxocarboxylic acids with 1,2-binucleophiles of aromatic and aliphatic series methods were developed for the synthesis of tricyclic structures containing a pyrrolidine fragment fused with imidazolidine or oxazolidine ring. The pathways of the reactions are considered. It was demonstrated that the nature of the substrate did not affect the reaction direction, but changed the scheme of the interaction. The structures of compounds obtained for the first time were proved using IR and ¹H NMR spectra.

Full text of DOI:10.1134/S1070428010090198

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2010, Vol. 46, No. 9, pp. 1378−1382. © Pleiades Publishing, Ltd., 2010.
Original Russian Text © V.S. Grinev, O.A. Amal’chieva, A.Yu. Egorova, E.V. Lyubun’, 2010, published in Zhurnal Organicheskoi Khimii, 2010, Vol. 46, No. 9,
pp. 1376−1379.
Reaction of 4-Oxocarboxylic Acids
and 5-Substituted 3H-Furan-2-ones with 1,2-Binucleophiles
of Aromatic and Alicyclic Series
V. S. Grineva, O. A. Amal’chievab, A. Yu. Egorovab, and E. V. Lyubun’a
aInstitute of Biochemistry and Physiology of Plants and Bacteria,Russian Academy of Sciences
Saratov, 410049 Russia
e-mail: grinev@ibppm.sgu.ru
bChernyshevskii Saratov State University, Saratov, Russia
Received July 27, 2009
Abstract— Based on reactions of 5-substituted 3H-furan-2-ones or 4-oxocarboxylic acids with 1,2-binucleophiles
of aromatic and aliphatic series methods were developed for the synthesis of tricyclic structures containing
a pyrrolidine fragment fused with imidazolidine or oxazolidine ring. The pathways of the reactions are considered.
It was demonstrated that the nature of the substrate did not affect the reaction direction, but changed the scheme of
the interaction. The structures of compounds obtained for the first time were proved using IR and 1H NMR spectra.
DOI: 10.1134/S1070428010090198
The reactions of 3H-furan-2-ones containing aromatic
and aliphatic substituents in the position C5 with ethylene-
diamine and 2-aminoethanol was investigated before [1].
and applied possibilities of compounds obtained. We
also studied the reaction with an alicyclic binucleophile,
1,2-diaminocyclohexane.
Besides the 3H-furan-2-ones we used as initial com-
pounds 4-oxocarboxylic acids. Inasmuch as the 3H-furan-
2-ones are cyclic internal esters of 4-oxocarboxylic acids,
we have investigated the reactivity of these synthons and
have compared the effect of the open or cyclic form of ini-
tial compounds on the structure of the obtained products.
The target of this research is the study of reactions be-
tween 3H-furan-2-ones containing various substituents in
the position C5 with aromatic binucleophiles. We carried
out the reactions of furan-2-ones with 1,2-phenylenedi-
amine, 2-aminophenol, and 2-amino-4-methyphenol and
thus obtained new tricyclic compounds containing in their
structure an oxazolidine or imidazolidine ring fused with a
benzene ring. This fact considerably extends the synthetic
4-Oxocarboxylic acids Ia–Ic and 5-substituted 3H-
furan-2-ones IIa–IIc reacted with the aromatic 1,2-bi-
Scheme 1.
R
O
R
O
O
N
X
OH
H2N
HX
R'
Ia_Ic
or
+
R'
IIIa_IIIh
R
O
O
IIa_IIc
I, II, R = Ph (a), 4-MeC6H4 (b), 4-MeOC6H4 (c); III, R' = H, X = NH, R = Ph (a), 4-MeC6H4 (b), 4-MeOC6H4 (c); R' =
H, X = O, R = Ph (d), 4-MeC6H4 (e), 4-MeOC6H4 (f); R' = Me, X = O, R = Ph (g), 4-MeC6H4 (h).
1378

REACTION OF 4-OXOCARBOXYLIC ACIDS
1379
the use of synthons Ia–Ic the nucleophilic attack of the
nitrogen atom of the aromatic binucleophile is directed to
the more electron-deficient carbon atom of the carbonyl
group of the oxoacid (Scheme 3).
nucleophiles (1,2-phenylenediamine, 2-aminophenol, and
2-amino-4-methyphenol) in protic and aprotic solvents
(Scheme 1). The best results were obtained in benzene
at continuous azeotropic distillation of the formed water.
The stabilization of intermediate A probably occurs
through the attack of the second nucleophilic site on the
same carbon atom followed by intramolecular acyla-
tion and the formation of the tricyclic system IIIa–IIIc
(Scheme 3).
The physicochemical characteristics of compounds
IIIa–IIIh obtained using as initial substrates 4-oxoacids
or furanones were completely identical. Therefore the
synthesis of tricyclic systems from 4-oxoacids is more
favorable from the preparative viewpoint for it reduces
the process by one stage and eliminates the isolation of
the intermediate 3H-furan-2-ones.
Based on spectral data the structures of compounds
obtained were identified as 3a-substituted 2,3,3a,4-tetra-
hydro-1H-benzo[d]pyrrolo[1,2-a]-imidazol-1-ones IIIa–
IIIc, 3a-substituted 3,3a-dihydrobenzo[d]pyrrolo[2,1-b]
oxazol-1(2H)-ones IIId–IIIf, and 7-methyl-3a-substitut-
ed 3,3a-dihydro-benzo[d]pyrrolo[2,1-b]oxazol-1(2H)-
ones IIIg–IIIh.
The data of IR and 1H NMR spectra confirm the fact
of double heterocyclization. The IR spectra of tricyclic
IIIa–IIIh contain an absorption band of the C=O group
“Amide I” at 1690–1710 cm–1, a band of the C–N bond
vibrations at 1320–1330 cm–1, and in the spectra of com-
pounds IIIa–IIIc the absorption band of the N–H group
However the routes of the products formation are dif-
ferent. 3H-Furan-2-ones IIa–IIc contain in their structure
an electron-deficient carbon atom of the carbonyl group
which serves as the point of the attack of the nitrogen atom
of the binucleophile reagent resulting in the opening of
the lactone ring (Scheme 2).
The formation of the pyrrolidone ring with water
elimination results in the additional heterocyclization in
compounds IIIa–IIIh.
The substrate nature does not affect the direction of
the reaction, but the scheme of the interaction changes.At
Scheme 2.
O
R
X
R
C
C CH2CH2
R
O
H2N
HX
R'
NH
N
O
N
HO
HX
O
+
HX
_H2O
R
O
O
R'
IIIa_IIIh
IIa_IIc
Scheme 3.
NH2
O
XH
R
+
OH
O
R'
Ia_Ic
O
O
O
OH
R
R
X
R
R
X
OH
O
OH
N
HO
NH
N
NH
_H2O
HX
HX
R'
R'
IIIa_IIIh
R'
R'
A
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 9 2010

GRINEV et al.
1380
Scheme 4.
R
O
NH2
R
O
OH
H2N
O
N
HN
Id, Ie
or
+
_H2O
R
O
O
IVa, IVb, IVd, IVe
IIa, IIb
I, R = Me (d), Pr (e); IV, R = Ph (a), 4-MeC6H4 (b), Me (d), Pr (e).
appeared at 3290–3350 cm–1.
to those described above (Schemes 2, 3).
In the 1H NMR spectra of obtained compounds IIIa–
IIIh the multiplets of methylene protons at the atoms
C3 and C2 are observed at δ 2.05–2.60, 2.20–2.90 ppm
respectively, and the singlet of the proton of NH group, at
δ 4.20–4.38 ppm in the spectra of compounds IIIa–IIIc.
The proton signals from the fused benzene ring and the
benzene ring in the substituent in the position 3a appear at
δ 6.15–7.45 ppm
Hence it was demonstrated that 5-substituted 3H-
furan-2-ones and their precursors, 4-substituted 4-oxocar-
boxylic acids containing electron-deficient carbon atoms
readily reacted with 1,2-binucleophile reagents both
from alicyclic and aromatic series with the formation of
tricyclic imidazolidine and oxazolidine structures. Not-
withstanding different pathways of reactions involving
substituted 3H-furan-2-ones and 4-oxocarboxylic acids,
the final products have the same tricyclic structure.
We investigated the reaction of compounds Id, Ie and
IIa, IIb with 1,2-binucleophile reagent of the alicyclic
series, 1,2-cyclohexanediamine (Scheme 4).
EXPERIMENTAL
The reaction with 1,2-cyclohexanediamine was
performed by boiling in benzene equimolar amounts of
reagents with azeotropic distillation of formed water.
The 1,2-cyclohexanediamine was used as a mixture of
cis- and trans-isomers.
IR spectra were recorded on a spectrophotometer
FSM 1201 from pellets with KBr. 1H NMR spectra were
registered on a spectrometer Bruker MSL-400 (operating
frequency 400 MHz), solvent CDCl3, internal reference
TMS. The purity of compounds was checked by TLC on
Silufol plates, eluent ethyl acetate–hexane–chloroform,
2:2:1, development in iodine vapor.
With substrates IIa, IIb we obtained 3a-substituted
decahydro-1H-benzo[d]pyrrolo[1,2-a]-imidazol-1-ones
IVa, IVb, IVd, IVe characterized by elemental analyses,
IR and 1H NMR spectra.
3a-Phenyl-2,3,3a,4-tetrahydro-1H-benzo[d]-
pyrrolo[1,2-a]imidazol-1-one (IIIa). A solution of 2 g
(11 mmol) of compound Ia [or 1.76 g (11 mmol) of
compound IIa] and 1.2 g (11 mmol) of 1,2-phenylenedi-
amine in 30 ml of anhydrous benzene was boiled while
continouosly distilling off azeotropic mixture with formed
water over 5 h. The separated precipitate was washed
with benzene, then with hexane, and reccrystallized
from acetone. Yield 2.12 g (75%), light-yellow crystals,
mp 156–159°C. IR spectrum, ν, cm–1: 3330 (NH), 1710
IR spectra of compounds IVa, IVb, IVd, IVe con-
tain the absorption bands of lactam carbonyl group in
the region 1690–1710 cm–1, of the secondary amino
group (3300–3350 cm–1), and of the cyclohexane ring
(2800–2920 cm–1).
In the 1H NMR spectra of compounds IVa, IVb, IVd,
IVe the multiplets of the protons at atoms C3 and C2 were
observed at δ 2.30–2.75, 2.55–2.95 ppm respectively,
the protons at the atoms of C8a and C4a of the imidazoli-
dine ring, at δ 2.22–2.45, 2.00–2.25 ppm, proton at the
nitrogen atom, at δ 4.10–4.35 ppm, and the multiplets
of the protons of the cyclohexane ring, in the region δ
1.29–2.10 ppm.
1
(C=O, “Amide-I”), 1320 (C–N). H NMR spectrum, δ,
ppm: 2.35–2.60 m (2H, C3H2 pyrrolidine.), 2.70–2.90 m (2H,
C2H2 pyrrolidine), 4.38 s (1H, NH), 6.50–6.90 m (4Harom),
7.25–7.60 m (5Harom, Ph). Found, %: C 76.56; H 5.73;
N 11.56. C16H14N2O. Calculated, %: C 76.80; H 5.60;
N 11.20.
The pathways of compounds IV formation are similar
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 9 2010

REACTION OF 4-OXOCARBOXYLIC ACIDS
1381
7-Methyl-3a-phenyl-3,3a-dihydrobenzo[d]
pyrrolo[2,1-b]oxazol-1(2H)-one (IIIg). Yield 1.57
g (35%), greenish-yellow crystals, mp 122–124°C.
IR spectrum, ν, cm–1: 1710 (C=O, “Amide-I”), 1326
(C–N). H NMR spectrum, δ, ppm: 2.13–2.35 m (2H,
C3H2 pyrrolidine), 2.32 s (3H, CH3), 2.40–2.60 m (2H, C2H2
Compounds IIIb–IIIh, IVa–IVe were obtained simi-
larly.
3a-(4-Methylphenyl)-2,3,3a,4-tetrahydro-1H-
benzo[d]pyrrolo[1,2-a]imidazol-1-one (IIIb). Yield
1.98 g (78%), light-yellow crystals, mp 158–160°C.
IR spectrum, ν, cm–1: 3350 (NH), 1690 (C=O,
“Amide-I”), 1330 (C–N). 1H NMR spectrum, δ, ppm:
2.25 s (3H, CH3), 2.40–2.55 m (2H, C3H2 pyrrolidine),
2.50–2.70 m (2H, C2H2 pyrrolidine), 4.35 s (1H, NH),
6.50–6.85 m (4Harom), 7.15–7.35 d.d (4Harom). Found,
%: C 76.16; H 6.15; N 10.10. C17H16N2O. Calculated,
%: C 75.69; H 6.06; N 10.61.
1
pyrrolidine), 6.70–6.95 m (3Harom), 7.10–7.38 m (5Harom
,
Ph). Found, %: C 76.56; H 5.35; N 5.17. C17H15NO2.
Calculated, %: C 76.96; H 5.70; N 5.28.
7-Methyl-3a-(4-methylphenyl)-3,3a-dihydro-
benzo[d]pyrrolo[2,1-b]oxazol-1(2H)-one (IIIh). Yield
1.43 g (32%), greenish-yellow crystals, mp 123–124°C.
IR spectrum, ν, cm–1: 1705 (C=O, “Amide-I”), 1327
3a-(4-Methoxyphenyl)-2,3,3a,4-tetrahydro-1H-
benzo[d]pyrrolo[1,2-a]imidazol-1-one (IIIc). Yield 1.42
g (46%), orange crystals, mp 109–112°C. IR spectrum, ν,
cm–1: 3330 (NH), 1700 (C=O, “Amide-I”), 1330 (C–N).
1H NMR spectrum, δ, ppm: 2.40–2.59 m (2H, C3H2
pyrrolidine), 2.50–2.70 m (2H, C2H2 pyrrolidine), 3.35 s (3H,
OCH3), 4.20 s (1H, NH), 6.40–6.90 m (4Harom), 7.20–
7.65 d.d (4Harom). Found, %: C 72.53; H 6.12; N 9.68.
C17H16N2O2. Calculated, %: C 72.86; H 5.71; N 10.00.
1
(C–N). H NMR spectrum, δ, ppm: 2.15–2.37 m (2H,
C3H2 pyrrolidine), 2.42–2.67 m (2H, C2H2 pyrrolidine), 2.62 s
(3H, CH3), 2.36 s (3H, CH3), 6.60–7.05 m (3Harom),
7.10–7.45 m (4Harom). Found, %: C 77.15; H 5.97; N 4.91.
C18H17NO2. Calculated, %: C 77.40; H 6.13; N 5.01.
3a-Phenyldecahydro-1H-benzo[d]pyrrolo[1,2-
a]-imidazol-1-one (IVa). Yield 1.35 g (48%), light-
brown crystals, mp 165°C (decomp.). IR spectrum, ν,
cm–1: 3330 (NH), 1710 (C=O, “Amide-I”), 1H NMR
spectrum, δ, ppm: 1.35–1.89 m (8H, 4 CH2), 2.00 m
(1H), 2.22 m (1H), 2.42–2.60 m (2H, C3H2 pyrrolidine),
2.70–2.85 m (2H, C2H2 pyrrolidine), 4.39 s (1H, NH),
7.20–7.60 m (5Harom). Found, %: C 74.85; H 8.05;
N 11.12. C16H20N2O. Calculated, %: C 75.00; H 7.81;
N 10.94.
3a-Phenyl-3,3a-dihydrobenzo[d]pyrrolo[2,1-b]-
oxazol-1(2H)-one (IIId). Yield 1.71 g (62%), yellow
crystals, mp 153–155°C. IR spectrum, ν, cm–1: 1710
1
(C=O, “Amide-I”), 1326 (C–N). H NMR spectrum, δ,
ppm: 2.18–2.35 m (2H, C3H2 pyrrolidine), 2.30–2.48 m (2H,
C2H2 pyrrolidine), 6.50–6.90 m (4Harom), 7.10–7.30 m (5Ha-
rom, Ph). Found, %: C 76.10; H 4.98; N 5.12. C16H13NO2.
Calculated, %: C 76.49; H 5.18; N 5.58.
3a-(4-Methylphenyl)decahydro-1H-benzo[d]
pyrrolo[1,2-a]imidazol-1-one (IVb). Yield 1.54 g (52%),
light-brown crystals, mp 177°C (decomp.). IR spectrum,
ν, cm–1: 3300 (NH), 1710 (C=O, “Amide-I”), 1H NMR
spectrum, δ, ppm: 1.40–2.00 m (8H, 4 CH2), 2.25 m
(1H), 2.30–2.42 m (2H, C3H2 pyrrolidine), 2.45 m (1H),
2.55 s (3H, CH3), 2.55–2.75 m (2H, C2H2 pyrrolidine), 4.25
s (1H, NH), 7.30–7.60 m (4Harom). Found, %: C 75.37;
H 8.00; N 10.61. C17H22N2O. Calculated, %: C 75.56;
H 8.15; N 10.37.
3a-(4-Methylphenyl)-3,3a-dihydrobenzo[d]-
pyrrolo[2,1-b]oxazol-1(2H)-one (IIIe). Yield 2.27 g
(78%), greenish-yellow crystals, mp 116–117°C. IR
spectrum, ν, cm–1: 1700 (C=O, “Amide-I”), 1325
1
(C–N). H NMR spectrum, δ, ppm: 2.29–2.50 m (2H,
C3H2 pyrrolidine), 2.45–2.65 m (2H, C2H2 pyrrolidine), 2.60 s
(3H, CH3), 6.39–6.85 m (4Harom), 7.10–7.45 m (4Harom).
Found, %: C 77.20; H 5.41; N 5.09. C17H15NO2. Calcu-
lated, %: C 76.98; H 5.66; N 5.28.
3a-Methyldecahydro-1H-benzo[d]pyrrolo[1,2-a]-
imidazol-1-one (IVd). Yield 1.26 g (59%), light-brown
crystals, mp 152°C (decomp.). IR spectrum, ν, cm–1:
3350 (NH), 1700 (C=O, “Amide-I”), 1H NMR spectrum,
δ, ppm: 1.50–2.10 m (8H, 4 CH2), 2.35 m (3H, CH3),
2.40 m (1H), 2.50 m (1H), 2.55–2.75 m (2H, C3H2 pyr-
rolidine), 2.60–2.95 m (2H, C2H2 pyrrolidine), 4.15 s (1H,
NH). Found, %: C 67.95; H 9.59; N 14.68. C11H18N2O.
Calculated, %: C 68.04; H 9.28; N 14.43.
3a-(4-Methoxyphenyl)-3,3a-dihydrobenzo[d]-
pyrrolo[2,1-b]oxazol-1(2H)-one (IIIf). Yield 1.24
g (40%), greenish-yellow crystals, mp 110–112°C.
IR spectrum, ν, cm–1: 1695 (C=O, “Amide-I”), 1320
(C–N). 1H NMR spectrum, δ, ppm: 2.05–2.30 m (2H,
C3H2 pyrrolidine), 2.70–2.90 m (2H, C2H2 pyrrolidine), 3.36 s
(3H, OCH3), 6.15–6.60 m (4Harom), 7.25–7.55 m (4Harom).
Found, %: C 75.39; H 5.91; N 4.77. C17H15NO3. Calcu-
lated, %: C 74.93; H 5.34; N 4.98.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 9 2010

GRINEV et al.
1382
3a-Propyldecahydro-1H-benzo[d]pyrrolo[1,2-a]-
C13H22N2O. Calculated, %: C 70.27; H 9.91; N 12.61.
imidazol-1-one (IVe). Yield 1.34 g (55%), light-brown
crystals, mp 159°C (decomp.). IR spectrum, ν, cm–1:
The study was carried out under a financial support
of the Russian Foundation for Basic Research (grant no.
10-03-00640-a).
1
3335 (NH), 1695 (C=O, “Amide-I”), H NMR spec-
trum, δ, ppm: 0.90–1.65 m (7H, C3H7), 1.50–2.10 m
(8H, 4 CH2), 2.29 m (1H), 2.35 m (1H), 2.45–2.60 m
(2H, C3H2 pyrrolidine), 2.70–2.85 m (2H, C2H2 pyrrolidine),
4.15 s (1H, NH). Found, %: C 70.08; H 10.16; N 12.82.
REFERENCES
1. Amaml’chieva, O.A. and Egorova, A.Yu., Zh. Org Khim.,
2006, vol. 42, p. 1358.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 9 2010