Short communication
A Facile One-Pot Synthesis of Functionalized 4,8-Dihydropyrano[3,2-b]-pyran-4-ones
Sakineh Asghari* and Mohammad Ahmadipour
Department of Chemistry, Mazandaran University, P.O.Box 453, Babolsar, Iran.
* Corresponding author: E-mail: s.asghari@umz.ac.ir Fax: 00981125342350
Received: 04-05-2010
Abstract
The reactive intermediates generated by the addition of alkyl isocyanides and dialkyl acetylenedicarboxylates were trapped by 5-hydroxy-2-hydroxymethyl-4#-pyran-4-one (kojic acid) to yield functionalized 4,8-dihydropyrano[3,2-£]-pyran-4-ones at ambient temperature in good yields.
Keywords: Kojic acid, dialkyl acetylenedicarboxylate, tert-butyl isocyanide, cyclohexyl isocyanide, 4,8-dihydropyra-no[3,2-£]pyran-4-one.
1. Introduction
There has been particular attention in chromenes and their derivatives due to their application in industry, biology, and synthesis.1-3 Most interest arises because of the bicyclic ring in this system which has motivated many chemists to prepare this valuable compound through different routes.4-5 Recently, the synthesis of various derivatives of fused pyran-2-one has received much attention due to their utilization as HIV protease inhibitors in nonpepti-de human immunology.6 The fused pyran derivatives have been synthesized using a number of methods.7 Teimouri and coworkers8 reported a three-component reaction of 4-hydroxy-6-methyl-2#-pyran-2-one (1), a 2-pyrone derivative, with an acetylenic ester in the presence of an alkyl isocyanide to obtain the corresponding fused pyran. These results inspired us to study this type of reaction with kojic acid (5-hydroxy-2-hydroxymethyl-4#-pyran-4-one, 2), as a 4-pyrone derivative, which is an inexpensive naturally
O
HO
+ _ + R'—N=r +
O' 2
available compound. Additionally, as part of our current studies on the development of new routes to prepare hete-rocyclic systems,9-11 we performed this annulation reaction using kojic acid as a source of OH-acid.
2. Results and Discussion
When an equimolar amount of feri-butyl isocyanide was slowly added to a mixture of 1:1 molar ratio of kojic acid and dimethyl acetylenedicarboxylate at ambient tem-
Scheme 1
co2r
5a-e
perature, after 24 h compound 5a was obtained in 80% yield (Scheme 1). In order to determine the generality of this reaction the experiments were successfully repeated by using various derivatives of alkyl isocyanides and acetylenic esters as presented in Scheme 1.
On the basis of the well-established chemistry of isocyanides,1217 nucleophilic addition of alkyl isocyanide 3 to dialkyl acetylenedicarboxylate 4 leads to zwitterionic intermediate 6 which is protonated by kojic acid to give intermediate 7. This intermediate is attacked by kojic acid anion to produce ketenimine 8. 1,3-proton transfer in compound 8 and subsequent cyclization forms products 5a-e (Scheme 2).
The structures of compounds 5a-e were deduced from their 1H and 13C NMR, IR and mass spectra, and elemental analysis. The 1H NMR spectrum of 5a exhibited a singlet at 1.47 ppm for the tert-butyl group, two singlets at 3.69 and 3.72 ppm for two methoxy groups, a singlet at 4.61 ppm for methine proton (CHCO2Me) and two broad signals at 4.00 and 8.72 ppm for OH and NH protons, respectively. The proton-decoupled 13C NMR spectrum of 5a showed 15 distinct resonances in agreement with the proposed structure. Polarization of the C2-C3 double bond by the oxo and amino groups in the dihydropyrano ring led to appearance of C2 and C3 absorptions at 170.6 ppm and at 70.7 ppm, respectively. The IR spectrum of 5a displayed two absorption bands at 3450 and 3250 cm1 indicating the presence of amine and alcohol groups, and strong bands at 1733 and 1666 cm1 for C=O groups, respectively. The mass spectrum of 5a
displayed a molecular ion peak at m/z 367, which was consistent with the 1:1:1 adduct of tert-butyl isocyanide, dimethyl acetylenedicarboxylate and kojic acid.
The 1H and 13C NMR spectra of compounds 5b-e were similar to those of 5a, except for the ester and amine moieties, which exhibited characteristic signals with appropriate chemical shifts for the specific substitution patterns.
3. Conclusion
We have developed a convenient, one-pot method for preparing functionalized 4,8-dihydropyrano
[3,2-fc]pyran-4-ones. In the present method substrates react without any prior activation or modification. The simplicity of the procedure makes it an interesting alternative to complex multistep approaches.
4. Experimental
Dialkyl acetylenedicarboxylates, ieri-butyl isocyanide, cyclohexyl isocyanide and kojic acid were obtained from Fluka and were used without further purification. Melting points were measured on an Electrothermal 9100 apparatus and are uncorrected. 'H and 13C, NMR spectra were measured with Bruker DRX-500 and 400 Avance spectrometers. Mass spectra were recorded on a Finnigan-Matt 8430 mass spectrometer operating at an ionization
+ - _
r'—n=c + ro„c—==—co^r
2 W 2
h	-,
r'-n^-M:
Co.
o
"h
+ // -co2R
r'—n^-
O
oh
c02r
O
co,r
R'.
O
^ O.
o
oh
ro2c
o
oh
ro,c h
8
1,3- proton transfer
co„r h
Scheme 2
cyclization
5a-e
potential of 70 eV. IR spectra were recorded on a Shimad-zu IR-470 spectrometer. Elemental analyses were performed using a Heraeus CHN-O Rapid analyzer.
Typical procedure for synthesis of dimethyl 2-(tert-butylamino)-6-(hydroxymethyl)-8-oxo-4,8-dihydrop-yrano[3,2-b]pyran-3,4-dicarboxylate ( 5a).
To a stirred solution of kojic acid (0.28 g, 2.0 mmol) and dimethyl acetylenedicarboxylate (0.24 ml, 2.0 mmol) in THF (10 ml) was dropwisely added tert-butyl isocyani-de (0.32 g, 2.0 mmol) at -10 °C over 10 min. The reaction mixture was then allowed to warm up to room temperature and stirred for 24 h. The solvent was removed under reduced pressure and the residue purified by column chro-matography (Merck Silica gel, 230-400 mesh) using he-xane:ethyl acetate (60:40) as eluent to give pure product 5a as a yellow powder in 80% yield.
4. 1. Analytical Data for Compounds 5a-e:
Dimethyl 2-(tert-butylamino)-6-(hydroxymethyl)-8-oxo-4,8-dihydropyrano [3,2-£]pyran-3,4-dicarboxylate (5a). Yellow powder, m.p. 160-163 °C, yield 80%, 1H NMR (500 MHz, CDCl3) 5 1.47 (9H, s, CMe3), 3.69 and 3.72 (6H, 2s, 2OMe), 4.00 (1H, bs, OH), 4.49 (2H, s, OCH2), 4.61 (1H, s, CH), 6.53 (1H, s, vinyl proton), 8.72 (1H, bs, NH); 13C NMR (125 MHz, CDCl3) 5 30.1 (CMe3), 41.6 (CH), 51.1 and 52.9 (2OMe), 53.3 (NCMe3), 60.6 (OCH2), 70.7 (C), 112.5 (CH), 137.9, 147.1, 160.1 and 170.6 (4C), 167.3 and 168.9 (2C=O, esters), 170.7 (C=O, ketone); IR (KBr) v 3450 (NH), 3250 (OH), 1733 and 1666 cm-1 (C=O); MS: m/z (%): 367 (M+, 4), 308 (85), 252 (100), 220 (28), 192 (9), 57 (10). Anal. Calcd. for C17H21NO8 (367.36): C, 55.58; H, 5.76; N, 3.81. Found: C, 55.45; H, 5.69; N, 3.77.
Diethyl 2-(tert-butylamino)-6-(hydroxymethyl)-8-oxo-4,8-dihydropyrano[3,2-£]pyran-3,4-dicarboxylate (5b). Yellow powder, m.p. 142-145 °C, yield 80%, 1H NMR (500 MHz, CDCl3) 5 1.24 (3H, t, 3JHH=7.1 Hz, CH3), 1.26 (3H, t, 3JHH=7.1 Hz, CH3), 1.47 (9H, s, CMe3), 3.5 (1H, bs, OH), 4.10-4.20 (4H, m, 2OCH2), 4.48 (2H, s, OCH2), 4.60 (1H, s, CH), 6.51 (1H, s, vinyl proton), 8.72 (1H, bs, NH); 13C NMR (125 MHz, CDCl3) 5 14.1 and 14.4 (2CH3) 30.1 (CMe3), 41.8 (CH), 53.2 (NCMe3), 59.7, 60.6 and 61.9 (3OCH2), 70.7 (C), 112.5 (CH), 137.8, 147.1, 159.9 and 170.5 (4C), 167.0 and 168.6 (2C=O, esters), 170.6 (C=O, ketone); IR (KBr) v 3413 (NH), 3276 (OH), 1744 and 1674 cm-1 (C=O); MS: m/z (%): 395 (M+., 3), 322 (81), 266 (100), 238 (19), 220 (25), 57 (21). Anal. Calcd. for C19H25NO8 (395.37): C, 57.72; H, 6.37; N, 3.54. Found: C, 557.61; H, 6.32; N, 3.50.
Di-tert-butyl 2-(tert-butylamino)-6-(hydroxymethyl)-8-oxo-4,8-dihydropyra-no[3,2-£]pyran-3,4-dicarboxyla-te (5c). Yellow powder, m.p. 150-152 °C, yield 75%, 1H
NMR (500 MHz, CDCl3) 51.44, 1.47 and 1.48 (27H, 3s, 3CMe3), 4.09 (1H, bs, OH), 4.45 (1H, s, CH), 4.49 (2H, s, OCH23, 6.50 (1H, s, vinyl proton), 8.65 (1H, bs, NH); 13C NMR (125 MHz, CDCl3) 5 27.9, 28.5 and 30.2 (3CMe3), 43.3 (CH), 52.9 (NCMe3), 60.6 (OCH2), 72.3 (C), 79.8 and 82.1 (2OCMe3), 112.3 (CH), 137.7, 148.1, 159.8 and 169.7 (4C), 167.1 and 168.3 (2C=O, esters), 170.8 (C=O, ketone); IR (KBr) v 3509 (NH), 3250 (OH), 1739 and 1658 cm-1 (C=O); MS: m/z (%): 451 (M+, 2), 350 (46), 294 (92), 238 (100), 220 (13), 176 (16), 57 (60). Anal. Calcd. for C23H33NO8 (451.52): C, 61.18; H, 7.37; N, 3.10. Found: C, 61.10; H, 7.32; N, 3.06.
Dimethyl 2-(cyclohexylamino)-6-(hydroxymethyl)-8-oxo-4,8-dihydropyrano [3,2-£]pyran-3,4-dicarboxylate (5d). White powder, m.p. 158-161 °C, yield 75%, 1H NMR (400 MHz, CDCl3) 5 1.22-2.02 (10H, m, 5CH2), 3.09 (1H, bs, OH), 3.72 and 3.74 (6H, 2s, 2OMe), 3.90-3.99 (1H, m, CH), 4.52 (2H, s, OCH2), 4.63 (1H, s, CH), 6.53 (1H, s, CH), 8.64 (1H, bs, NH); 13C NMR (100 MHz, CDCl3) 5 24.2, 24.2, 25.4, 33.4 and 33.5 (5CH2),
41.7	(CH), 49.9 (NCH), 51.1 and 53.0 (2OCH3), 60.7 (OCH2), 70.0 (C), 112.7 (CH), 137.9, 147.1, 158.7 and 170.5 (4C), 166.6 and 168.8 (2C=O, esters), 170.8 (C=O, ketone); IR (KBr) v 3415 (NH), 3312 (OH), 1742 and 1684 cm-1 (C=O); MS: m/z (%): 393 (M+, 3), 334 (100), 252 (64), 220 (15), 192 (4), 83 (3). Anal. Calcd. for C19H23NO8 (393.40): C, 58.01; H, 5.89; N, 3.56. Found: C, 59.17; H, 6.01; N, 3.65.
Diethyl 2-(cyclohexylamino)-6-(hydroxymethyl)-8-oxo-4,8-dihydropyrano[3,2-£]pyran-3,4-dicarboxylate (5e). White powder, m.p. 133-136 °C, yield 75%, 1H NMR (400 MHz, CDCl3) 5 1.26 (3H, t, 3JHH=7.2 Hz, CH3), 1.27 (3H, t, 3Jhh=7.2 Hz, CH3), 1.31-2.02; (10H, m, 5CH2), 2.98 (1H, bs, OH), 3.94-3.97 (1H, m, CH), 4.10-4.25 (4H, m, 2OCH2), 4.51 (2H, s, OCH2), 4.62 (1H, s, CH), 6.52 (1H, s, CH), 8.64 (1H, bs, NH); 13C NMR (100 MHz, CDCl3) 5 14.1 and 14.4 (2CH2), 24.2, 24.2, 25.4, 33.4 and 33.5 (5CH2), 41.9 (CH), 49.8 (NCH), 59.6,
60.8	and 61.8 (3OCH2), 70.1 (C), 112.7 (CH), 137.8, 147.2, 158.6 and 170.5 (4C), 166.4 and 168.5 (2C=O, esters), 170.5 (C=O, ketone); IR (KBr) v 3411 (NH), 3336 (OH), 1743 and 1673 cm-1 (C=O); MS: m/z (%): 421 (M+., 3), 348 (100), 266 (86), 220 (27), 192 (7), 83 (13). Anal. Calcd. for C21H27NO8 (421.45): C, 59.86; H, 6.46; N, 3.32. Found: C, (51.01; H, 6.59; N, 3.39.
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Povzetek
V prispevku je predstavljena priprava substituiranih 4,8-dihidropiran[3,2-ft]-piran-4-onov z lovljenjem intermediatov, ki nastanejo pri adiciji alkil izocianidov in dialkil acetilendikarboksilatov na 5-hidroksi-2-hidroksimetil-4_ff-piran-4-on (kojsko kislino). Reakcija poteka pri sobni temperaturi z dobrimi izkoristki.