Synthesis of new substituted saturated γ -lactones from 2-(2,2-dimethyl-5-oxotetrahydrofuran-3-yl)acetyl chloride

Article abstract of DOI:10.1515/hc-2012-0017

New derivatives of substituted saturated γ -lactones were synthesized from 2-(2,2-dimethyl-5-oxotetrahydrofuran-3-yl) acetyl chloride. All new compounds were characterized by NMR and IR and elemental analysis. Copyright by Walter de Gruyter.

Full text of DOI:10.1515/hc-2012-0017

Heterocycl. Commun., Vol. 18(2), pp. 71–73, 2012 • Copyright © by Walter de Gruyter • Berlin • Boston. DOI 10.1515/hc-2012-0017
Synthesis of new substituted saturated γ-lactones from
2-(2,2-dimethyl-5-oxotetrahydrofuran-3-yl)acetyl chloride
Gayane Tokmajyan and Lusine Karapetyan*
Experimental section
Yerevan State University, Alex Manoogian 1, 0025,
Yerevan, Armenia
All solvents were dried by standard methods. Melting points were
measured with an Electrothermal 9100 apparatus. Elemental analy-
ses (C, H and N) were performed using a Heraeus CHN-O-Rapid
analyzer. IR spectra were recorded on a Specord 75 IR spectro-
meter with samples dispersed in mineral oil. 1H NMR and 13C NMR
spectra were recorded in DMSO-d6/CCl4 (1:3) solutions on a Varian
Mercury-300 VX spectrometer at 300 MHz and 75 MHz, respec-
tively. The purity of synthesized compounds was tested by means
of thin-layer chromatography (TLC) on Silufol UV-25 plates, eluent
acetone/benzene (1:2), visualization with iodine vapors.
*Corresponding author
e-mail: lousine_karapetyan@yahoo.com
Abstract
New derivatives of substituted saturated γ-lactones were syn-
thesized from 2-(2,2-dimethyl-5-oxotetrahydrofuran-3-yl)
acetyl chloride. All new compounds were characterized by
NMR and IR and elemental analysis.
Compound 1 was synthesized by using a published procedure
(Avetisyan and Ovsepyan, 1984).
General procedure for 5a–d
Keywords: amine; isothiocyanate; potassium thiocyanate;
saturated γ-lactone.
A mixture of 1 (0.41 g, 2.2 mmol) and excess potassium thiocyanate
(2) in anhydrous acetone (10 mL) was stirred at room temperature
for 30 min, then treated with amine 4a–d (4.4 mmol) and heated
under reflux for an additional 1 h. The solvent was removed under
reduced pressure and water was added to the residue. The precipi-
tated solid was filtered, washed with water and crystallized from
ethanol.
Introduction
Saturated γ-lactones are an important class of heterocyclic
compounds. They display a wide range of biological activities
and can be used in medicine, pharmacology, cosmetology, and
agriculture. Artemisinin and Santonin, endowed with valuable
biological activity, are compounds containing saturated lactone
rings (Dayson and Mey, 1964; Mashkovskiy, 1978; Shukla
et al., 1995; Arantes et al., 2009). Many compounds, such as
pilocarpine, a cholinergic drug, are also derivatives of lactones.
Synthesis of new derivatives of saturated lactones is thus of
great interest (Pinner et al., 1900, 1901; Davies et al., 2009).
2 - ( 2 , 2 - D i m e t hy l - 5 - oxo te t ra hyd ro f u ra n - 3 - y l ) - N -
(phenylcarbamothioyl)acetamide (5a) This compound was ob-
tained as a pale yellow solid; yield 84%; mp 188–189°C; Rf = 0.55;
IR: 1580, 1600, 1690, 1775, 3250, 3270 cm-1; 1H NMR: δH 1.35 and
1.50 (2s, 6H), 2.25–2.90 (m, 5H), 6.9–8.0 (m, 5H), 11.4 and 12.5
(2s, 2H); 13C NMR: δC 24.1, 33.8, 38.5, 40.2, 87.6, 126.8, 128.5,
131.1, 139.1, 177.2, 178.1, 179.5. Anal. Calcd for C15H18N2O3S: C,
58.80; H, 5.92; N, 9.14. Found: C, 58.83; H, 5.95; N, 9.21.
Results and discussion
N - ( B e n z y l c a r b a m o t h i o y l ) - 2 - ( 2 , 2 - d i m e t h y l - 5 -
oxotetrahydrofuran-3-yl)acetamide
(5b) This
compound
Here we report a general synthetic route to lactone derivatives
starting from readily available 2-(2,2-dimethyl-5-oxotetrahy-
drofuran-3-yl)acetyl chloride (1) (Avetisyan and Ovsepyan,
1984). Products 5a–d were obtained by reaction of compound
1 with potassium thiocyanate (2) followed by treatment of the
resultant intermediate product 3, without isolation, with ani-
line (4a), benzylamine (4b), cyclohexylamine (4c) or diethyl-
amine (4d). The overall yield of this one-pot synthesis is
82–84%. Amides 6a–d were synthesized by reaction of com-
pound 1 with amines 4a–d (Schemes 1 and 2).
Compounds 5 and 6 were tested for antibacterial activity
at the chemotherapy laboratory, A.L. Mndzhoyan Institute of
Fine Organic Chemistry, National Academy of Sciences of
the Republic of Armenia. These compounds showed a moder-
ate antibacterial activity in vitro, making it expedient to con-
duct further investigations in this area.
was obtained as a pale yellow solid; yield 83%; mp 195–196°C;
Rf = 0.53; IR: 1580, 1600, 1690, 3250, 3270 cm-1; 1H NMR: δH
1.35 and 1.50 (2s, 6H); 2.25–2.90 (m, 5H); 4.46 (d, 2H, J = 6.0 Hz)
6.9–8.0 (m, 5H); 11.4 (t, 1H, J = 6.0 Hz), 12.5 (s, 1H); 13C NMR: δC
24.1, 33.8, 38.5, 40.2, 52.9, 87.6, 128.8, 128.9, 130.6, 142.6, 177.2,
178,1, 189.5. Anal. Calcd for C16H20N2O3S: C, 59.98; H, 6.29;
N, 8.74. Found: C, 59.99; H, 6.31; N, 8.77.
N-(Cyclohexylcarbamothioyl)-2-(2,2-dimethyl-5-
oxotetrahydrofuran-3-yl)acetamide (5c) This compound was
obtained as a pale yellow solid; yield 84%; mp 182–183°C; Rf = 0.54;
IR: 1580, 1600, 1690, 1775, 3250, 3270 cm-1; 1H NMR: δH 1.35 and
1.50 (2s, 6H), 1.58–1.95 (m, 10H), 2.25–2.90 (m, 5H), 3.46–3.60
(m, 1H), 7.5 (d, 1H, J = 6.0 Hz), 12.5 (s, 1H); 13C NMR: δC 24.1,
25.5, 30.0, 33.8, 36.0, 38.5, 40.2, 56.3, 87.6, 177.2, 178,1, 189.5.
Anal. Calcd for C15H24N2O3S: C, 57.67; H, 7.74; N, 8.97. Found:
C, 57.74; H, 7.81; N, 8.99.
Brought to you by | Penn State - The Pennsylvania State University (Penn State - The Pennsylvania State University)
Authenticated | 172.16.1.226
Download Date | 5/19/12 8:34 PM

72 G. Tokmajyan and L. Karapetyan
R1
R2
N
S
O
HN
O
O
NCS
Cl
R1R2NH
4a-d
KSCN
2
H3C
H3C
H3C
H3C
H3C
O
O
O
O
3
O
O
H3C
1
5a-d
5a: R1 = H, R2 = C6H5; 5b: R1 = H, R2 = CH2C6H5;
5c: R1 = H, R2 = C6H11; 5d: R1 = R2 = C2H5.
Scheme 1 Synthesis of 5a-d.
N - ( D i e t hy l c a r b a m o t h i o y l ) - 2 - ( 2 , 2 - d i m e t hy l - 5 -
N-Benzyl-2-(2,2-dimethyl-5-oxotetrahydrofuran-3-yl)acet-
amide (6b) This compound was obtained as a pale yellow solid;
yield 85%; mp 167–169°C; Rf = 0.58; IR: 1600, 1690, 1775, 3250
cm-1; 1H NMR: δH 1.35 and 1.50 (2s, 6H), 2.25–2.90 (m, 5H), 4.46
(d, 2H, J = 6.0 Hz), 6.9–8.0 (m, 5H), 9.88 (t, 1H, J = 6.0 Hz); 13C
NMR: δC 24.1, 33.8, 38.2, 40.5, 46.0, 87.6, 128.8, 128.90, 130.6,
143.6, 174.2, 178.1. Anal. Calcd for C15H19NO3: C, 68.94; H, 7.33;
N, 5.36. Found: C, 68.99; H, 7.42; N, 5.48.
oxotetrahydrofuran-3-yl)acetamide
(5d) This
compound
was obtained as a pale yellow solid; yield 82%; mp 131–132°C;
Rf = 0.58; IR: 1580, 1600, 1690, 1775, 3250, 3270 cm-1; 1H NMR:
δH 1.22 (t, 6H, J = 7 Hz); 1.35 and 1.50 (2s, 6H), 2.30–2.90 (m, 5H),
3.45 (q, 4H, J = 7 Hz), 10.18 (s, 1H). 13C NMR: δC 15.00, 24.11,
33.8, 38.50, 40.2, 49.9, 87.64, 177.2, 178.11, 189.5. Anal. Calcd for
C13H22N2O3S: C, 54.52; H, 7.74; N, 9.78. Found: C, 54.58; H, 7.79;
N, 9.82.
N-Cyclohexyl-2-(2,2-dimethyl-5-oxotetrahydrofuran-3-yl)ac-
etamide (6c) This compound was obtained as a pale yellow solid;
yield 85%; mp 142–143°C; Rf = 0.57; IR: 1600, 1690, 1775, 3250
cm-1; 1H NMR: δH 1.35 and 1.50 (s, 6H), 1.58–1.95 (m, 10H), 2.25–
2.90 (m, 5H), 3.45–3.60 (m, 1H), 7.50 (d, 1H, J = 8 Hz); 13C NMR:
δC 24.1, 24.9, 30.0, 33.8, 35.8, 38.4, 40.8, 49.4, 87.6, 174.3, 178.1.
Anal. Calcd for C14H23NO3: C, 66.37; H, 9.15; N, 5.53. Found: C,
66.39; H, 9.18; N, 5.59.
General procedure for 6a–d
To a precooled (0–5°C) solution of amine 4a–d (4.4 mmol) in anhy-
drous acetone (10 mL), compound 1 (0.41 g, 2.2 mmol) was added.
The mixture was stirred at room temperature for 30 min and heated
under reflux for an additional 1 h. The solvent was removed under
reduced pressure and water was added to the residue. The precipitate
solid was filtered, washed with water and crystallized from ethanol.
2-(2,2-Dimethyl-5-oxotetrahydrofuran-3-yl)-N,N-diethylacet-
amide (6d) This compound was obtained as a light brown solid;
yield 81%; mp 144–145°C; Rf = 0.58; IR: 1600, 1690, 1775, 3250
2-(2,2-Dimethyl-5-oxotetrahydrofuran-3-yl)-N-phenyl-
acetamide (6a) This compound was obtained as a pale yellow
solid; yield 82%; mp 135–136°C; Rf = 0.56; IR: 1600, 1690, 1775,
3250 cm-1; 1H NMR: δH 1.35 and 1.50 (2s, 6H), 2.25–2.90 (m, 5H),
6.9–8.1 (m, 5H), 9.75 (s, 1H); 13C NMR: δC 24.1, 33.8, 38.5, 40.2, 9.6,
123.6, 126.4, 131.0, 140.1, 175.2, 178.1. Anal. Calcd for C14H17NO3:
C, 67.99; H, 6.93; N, 5.66. Found: C, 68.08; H, 6.98; N, 5.72.
1
cm-1; H NMR: δH 1.22 (t, 6H, J = 7 Hz), 1.35 and 1.50 (2s, 6H),
2.30–2.90 (m, 5H), 3.45 (q, 4H, J = 7 Hz); 13C NMR: δC 15.0,
24.1, 33.8, 38.5, 40.2, 49.9, 87.6, 177.2, 178.1. Anal. Calcd for
C12H21NO3: C, 63.41; H, 9.31; N, 6.16. Found: C, 63.44; H, 9.34;
N, 69.19.
Acknowledgment
R1
R2
We are grateful to Dr. Henrik Panosyan for NMR analyses (Molecular
Structure Research Centre, Yerevan, Armenia).
O
N
Cl
O
R1R2NH
4a-d
-R1R2NH·HCl
References
H3C
H3C
H3C
O
O
O
Arantes, F. F. P.; Barbosa, L. C. A.; Alvarenga, E. S.; Demuner, A. J.;
Bezerra, D. P.; Ferreira, J. R. O.; Costa-Lotufo, L. V.; Pessoa, C.;
Moraes, M. O. Synthesis and cytotoxic activity of α-santonin
derivatives. Eur. J. Med. Chem. 2009, 44, 3739–3745.
Avetisyan, A. A.; Ovsepyan, V. V. Some chemical transformations of
carboxysubstituted tetrahydro-2-furanons. Arm. Khim. Zh. 1984,
37, 122–123.
O
H3C
1
6a-d
6a: R1 = H, R2 = C6H5 ; 6b: R1 = H, R2 = CH2C6H5;
6c: R1 = H, R2 = C6H11 ; 6d: R1 = R2 = C2H5.
Scheme 2 Synthesis of 6a-d.
Brought to you by | Penn State - The Pennsylvania State University (Penn State - The Pennsylvania State University)
Authenticated | 172.16.1.226
Download Date | 5/19/12 8:34 PM

New derivatives of saturated γ-lactones 73
Davies, S. G.; Roberts, P. M.; Stephenson, P. T.; Storr, H. R.;
Thomson, J. E. A practical and scaleable total synthesis of
the jaborandi alkaloid (+)-pilocarpine. Tetrahedron 2009, 65,
8283–8296.
Dayson, G.; Mey, P. Chemistry of Synthetic Drugs; Mir: Moscow,
1964, pp. 579.
Pinner, A.; Kohlhammer, E. Ueber pilocarpin. Chem. Ber. 1901, 34,
727–736.
Shukla, K. L.; Gund, T. M.; Meshnick, S. R. Molecular modeling
studies of the artemisinin (qinghaosu)-hemin interaction: dock-
ing between the antimalarial agent and its putative receptor.
J. Mol. Graph. 1995, 13, 215–222.
Mashkovskiy, M. D. Drugs; Meditsina publishers: Moscow, 1978;
Vol. 1, pp. 204.
Pinner, A.; Kohlhammer, E. Ueber pilocarpin. Chem. Ber. 1900, 33,
2357–2363.
Received January 24, 2012; accepted March 11, 2012
Brought to you by | Penn State - The Pennsylvania State University (Penn State - The Pennsylvania State University)
Authenticated | 172.16.1.226
Download Date | 5/19/12 8:34 PM