Molecules 2012, 17(4), 4300-4312; doi:10.3390/molecules17044300

Article
Organocatalysis in Synthesis: L-Proline as an Enantioselective Catalyst in the Synthesis of Pyrans and Thiopyrans
Noha M. Hilmy Elnagdi * and Noura Saad Al-Hokbany
Women Students-Medical Studies & Sciences Sections, Chemistry Department, College of Science, King Saud University, Riyadh, KSA, P.O. Box 22452, Riyadh 11495, Saudi Arabia
*
Author to whom correspondence should be addressed; Email: elnagdinoha@yahoo.com; Tel.: +966-50-043-2102; Fax: +966-1-477-2245.
Received: 26 January 2012; in revised form: 19 March 2012 / Accepted: 20 March 2012 /
Published: 10 April 2012

Abstract

: The multicomponent reaction (MCR) of aromatic aldehydes 1 and malononitrile (2) with active methylenes 5a–h in the presence of L-proline produced pyrans and thiopyrans 6a–h stereospecifically and in good yields. Moreover a novel MCR of ethyl propiolate (8) with 1 and 2 in the presence of L-proline to afford (R)-polysubstituted pyran is also reported. X-ray structures, e.e. and optical activity of the synthesized compounds indicated that L-proline as a catalyst is responsible for the observed enantioselectivity in the studied reactions.
Keywords:
L-proline; pyran; assymetric synthesis; enantioselectivity; ethyl propiolate; optical activity

1. Introduction

Polyfunctionally substituted pyrans are no doubt an important class of heterocycles due to their great biological and pharmacological importance [1,2,3,4,5,6]. The addition of active methylene reagents to arylidenemalononitrile in the presence of homogeneous basic catalysts has been extensively used in the past for the synthesis of these compounds [7,8,9,10,11,12]. Interest in these reactions has recently been revived [13,14] with the aim of developing green laboratory reaction conditions [15,16], such as replacing homogeneous catalysis with heterogeneous ones [17,18,19,20], to synthesize enantiomerically pure pyrans for which diverse biological applications were noticed [21,22,23] and patented [24,25,26]. Many of these new approaches use multicomponent reactions and either an organocatalyst [27,28] or sometimes metal or nanoparticulated catalysts [29,30,31]. Although in plenty of these reactions a chiral center is being created only a few published works have discussed the exact stereochemistry of the synthesized compounds.

Since L-proline is a readily obtainable naturally occurring amino acid and is easy to obtain in high enantiomeric purity it has been reported as an eco-friendly catalyst for the synthesis of several heterocycles [32,33,34,35,36,37]. Recently Muramulla et al. reported the use of modularly designed organocatalysts (MDO) of L-proline in dichloromethane as a solvent for the synthesis of chiral pyranopyrazoles in moderate e.e. [38]. Gou et al. have also reacted aromatic aldehydes, malononitrile, and dimedone, in the presence of D,L-proline as a catalyst in the absence of solvent to obtain 2-amino-3-cyano-4-aryl-7,7-dimethyl-5,6,7,8-tetrahydrobenzo[b]pyran [27].

It seemed thus of value to see if the use of L-proline as a catalyst in the reaction of active methylene ketones with α,β-unsaturated nitriles in MCRs can be used to induce enantioselectivity of the synthesized pyrans. In this article the syntheses of pyrans, condensed pyrans and thiopyrans are reported. Moreover a novel pyran was prepared via the MCR of ethyl propiolate (8) with aldehydes and malononitrile in the presence of L-proline as a catalyst.

2. Results and Discussion

First in an attempt to synthesize the chiral pyranopyrazoles 4, we have reacted benzaldehyde (1), malononitrile (2) and pyrazolon-5-one (3) with 10% mol L-proline as the only catalyst. In contrast to Muramulla et al’s. findings that for the same reaction using L-proline alone as a catalyst under the reported reaction conditions no product was obtained, in our case after the reaction mixture was refluxed in ethanol for 4 h, the pyranopyrazole 4 was isolated in 81% yield (Scheme 1). To initially test if L-proline has induced any enantioselectivity in this reaction, compound 4 was tested for optical activity and found to be optically active with a specific rotation of +247.02 ([α]D, 25 °C, c = 1, DMF).

Molecules 17 04300 g001 200
Scheme 1. Synthesis of 6-amino-3,4-dimethyl-4-phenyl-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (4).

Click here to enlarge figure

Scheme 1. Synthesis of 6-amino-3,4-dimethyl-4-phenyl-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (4).
Molecules 17 04300 g001 1024

Next reacting benzaldehyde (1), malononitrile (2) and 3-oxo-3-phenylpropanenitrile (5g) in the presence of 10% L-proline as a catalyst afforded 2-amino-4,6-diphenyl-4H-pyran-3,5-dicarbonitrile (6g) in 83% yield and 70% e.e. (Scheme 2).

Molecules 17 04300 g002 200
Scheme 2. Synthesis of 2-amino-4,6-diphenyl-4H-pyran-3,5-dicarbonitrile (6g).

Click here to enlarge figure

Scheme 2. Synthesis of 2-amino-4,6-diphenyl-4H-pyran-3,5-dicarbonitrile (6g).
Molecules 17 04300 g002 1024

The 4H-pyran 6g was found to have 70% e.e. Confirmation that the 4H-pyran 6g indeed displayed an enantiomeric excess was obtained by performing 1H-NMR experiments with 6g in the presence of a chiral shift reagent (europium tris[3-heptafluoropropylhydroxymethylene]-(‏+)-camphorate). After making successive additions of this chiral shift reagent to a CDCl3 solution of 6g, the 4H-proton at δH 4.7 ppm appeared to resolve into two components (most obviously after the addition of 6 mg of the chiral shift reagent), and by calculation of the area under the chosen peak from the 1H-NMR that showed the maximum separation of the two components, 6g was found to be in 70% e.e. However at this stage, we cannot judge the predominance of the R or S enantiomers for this compound.

The above reported results encouraged us to prepare a series of polysubstituted 4H-pyrans. Pyrans 6a–h were all synthesized by the addition of benzaldehyde (1) and malononitrile (2) to active methylenes 5a–h using L-proline (10% mol) as a catalyst in a MCR to afford chiral pyrans 6a–h (Scheme 3). Active methylenes used are listed in Table 1. Structures and yields of the products 6a–h, as well as the reaction conditions are listed in Table 2.

Molecules 17 04300 g003 200
Scheme 3. Synthesis of enantioselective pyrans, benzopyrans, and thiopyrans 6a–h in a multicomponent reaction using L-proline as a catalyst.

Click here to enlarge figure

Scheme 3. Synthesis of enantioselective pyrans, benzopyrans, and thiopyrans 6a–h in a multicomponent reaction using L-proline as a catalyst.
Molecules 17 04300 g003 1024
Table Table 1. Compounds 5a–h.

Click here to display table

Table 1. Compounds 5a–h.
5aCH3COCH2COOEt5eEtCOOCH2COPh
5bCH3COCH2COCH35fPhCH2COOCH2COCH3
5cNCCH2CSNH25gPhCOCH2CN
5d Molecules 17 04300 i001 5h Molecules 17 04300 i002
Table Table 2. Compounds 6a–h and their yields.

Click here to display table

Table 2. Compounds 6a–h and their yields.
Compound aXR1R2Yield (%)
6aOCH3COOEt72
6bOCH3COCH360
6cSNH2CN92
6d *O Molecules 17 04300 i003 90
6eOPh COOEt87
6fOCH3COOCH2Ph65
6gOPhCN83
6h *O Molecules 17 04300 i004 78

a Compounds were characterized by their spectral data (IR, 13C-NMR, 1H-NMR). * These compounds could be prepared without a solvent at r.t. using grinding for 5 min. Compounds 6a, b, c, e, f, g were prepared using EtOH as a solvent and refluxing for 4 h.

Specific rotation measurements for some selected synthesized compounds revealed that these compounds are optically active, which supports the assumption that L-proline when used as a catalyst brings about enantioselectivity in such reactions. The specific rotation of some selected compounds is listed in Table 3.

Table Table 3. Specific rotation for some of the synthesized compounds.

Click here to display table

Table 3. Specific rotation for some of the synthesized compounds.
EntrySpecific rotation [α]D 25 °C, c = 1, DMF
6a+318.20
6e+198.81
6h+198.20
4+247.02
13+272.0

Structures proposed of the products 6a, b, d, e, h were well documented by X-ray crystallography as shown in Figure 1, Figure 2, Figure 3, Figure 4, Figure 5, Figure 6 [39]. It is worth mentioning that the 1H-NMR of the compound 6a has revealed the formation of two products in 2:1 ratio that could be separated by column chromatography. The first product could be shown by X-ray crystal structure (Figure 1) to be the 4H-pyran derivative (S)-ethyl 6-amino-5-cyano-2-methyl-4-phenyl-4H-pyran-3-carboxylate (6a), while the other product with molecular formula C22H22N2O4 and m/z = 378.2 is believed to be diethyl 5,5-dicyano-4,6-dimethyl-2-phenylcyclohexa-3,6-diene-1,3-dicarboxylate (7) as was proven by its spectroscopic data (Scheme 4).

Molecules 17 04300 g004 200
Figure 1. X-ray crystal structure of (S)-ethyl 5-cyano-2,6-dimethyl-4-phenyl-4H-pyran-3-carboxylate (6a).

Click here to enlarge figure

Figure 1. X-ray crystal structure of (S)-ethyl 5-cyano-2,6-dimethyl-4-phenyl-4H-pyran-3-carboxylate (6a).
Molecules 17 04300 g004 1024
Molecules 17 04300 g005 200
Figure 2. X-ray crystal structure of (R)-5-acetyl-2-amino-6-methyl-4-phenyl-4H-pyran-3-carbonitrile (6b).

Click here to enlarge figure

Figure 2. X-ray crystal structure of (R)-5-acetyl-2-amino-6-methyl-4-phenyl-4H-pyran-3-carbonitrile (6b).
Molecules 17 04300 g005 1024
Molecules 17 04300 g006 200
Figure 3. X-ray crystal structure of (S)-2-amino-7,7-dimethyl-5-oxo-4-phenyl-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile(6d).

Click here to enlarge figure

Figure 3. X-ray crystal structure of (S)-2-amino-7,7-dimethyl-5-oxo-4-phenyl-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile(6d).
Molecules 17 04300 g006 1024
Molecules 17 04300 g007 200
Figure 4. X-ray crystal structure of (S)-ethyl 6-amino-5-cyano-2,4-diphenyl-4H-pyran-3-carboxylate (6e).

Click here to enlarge figure

Figure 4. X-ray crystal structure of (S)-ethyl 6-amino-5-cyano-2,4-diphenyl-4H-pyran-3-carboxylate (6e).
Molecules 17 04300 g007 1024
Molecules 17 04300 g008 200
Figure 5. X-ray crystal structure of (R)-2-amino-5-oxo-4-phenyl-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (6h).

Click here to enlarge figure

Figure 5. X-ray crystal structure of (R)-2-amino-5-oxo-4-phenyl-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (6h).
Molecules 17 04300 g008 1024
Molecules 17 04300 g009 200
Figure 6. X-ray crystal structure of (R)-ethyl-6-amino-5-cyano-4-phenyl-4H-pyran-3-carboxylate 13.

Click here to enlarge figure

Figure 6. X-ray crystal structure of (R)-ethyl-6-amino-5-cyano-4-phenyl-4H-pyran-3-carboxylate 13.
Molecules 17 04300 g009 1024
Molecules 17 04300 g010 200
Scheme 4. Synthesis of the two products 6a and 7 in a 2:1 ratio.

Click here to enlarge figure

Scheme 4. Synthesis of the two products 6a and 7 in a 2:1 ratio.
Molecules 17 04300 g010 1024

In addition a novel synthesis of pyran 13 could be achieved by mixing benzaldehyde (1), and malononitrile (2) with ethyl propiolate (8) in ethanol and 10% L-proline as a catalyst. It is believed that initially L-proline (9) adds to ethyl propiolate (8) affording the enamine ester 10, while benzaldehyde (1) condenses with malononitrile (2) affording 2-benzylidenemalononitrile (11). This was followed by the addition of the electron rich β-carbon in the enamine ester to the electron poor π system in the benzylidine-malononitrile 11, affording an adduct. This adduct 12 is then hydrolyzed by H2O and cyclizes into 13 (Scheme 5). Compound 13 was also tested for optical activity and found to be optically active with a specific rotation of +272.0 ([α]D 25 °C, c = 1, DMF). The structure of 13 has been confirmed with certainty via X-ray crystal structure determination (Figure 6).

As shown in the X-ray structures (Figure 1, Figure 2, Figure 3, Figure 4, Figure 5, Figure 6), we have obtained the R-enantiomer in the case of compounds 9a, h, and 14, and the S-enantiomer in the cases of 9a, d, and e, but both enantiomers exist of course in the original product as a mixture.

Molecules 17 04300 g011 200
Scheme 5. Synthesis of (R)-ethyl-6-amino-5-cyano-4-phenyl-4H-pyran-3-carboxylate (13).

Click here to enlarge figure

Scheme 5. Synthesis of (R)-ethyl-6-amino-5-cyano-4-phenyl-4H-pyran-3-carboxylate (13).
Molecules 17 04300 g011 1024

3. Experimental

3.1. General

The 1H-NMR and 13C-NMR spectra were determined by using a Bruker DPX instrument at 400 MHz for 1H-NMR and 100 MHz for 13C-NMR. The chemical shifts are reported in ppm downfield to TMS (δ = 0) or DMSO-D6 (δ = 2.5) for 1H-NMR and relative to the central CDCl3 resonance (δ = 77.0) or DMSO-D6 (δ = 40.0) for 13C-NMR. The coupling constants J are given in Hz. Mass spectra were measured using a high resolution GC-MS (DFS) Thermo spectrometer with EI (70 EV). Column chromatography was performed using Acme’s silica gel (particle size 0.063–0.200 mm). IR spectra were recorded using KBr disks on a Perkin-Elmer System 2000 FT-IR spectrophotometer. Microanalyses were performed on a LECO CHNS-932 Elemental Analyzer. Optical rotations were measured on an Autopol IV (Rudolph Instruments) automatic polarimeter at 25 °C in DMF at concentration 1 mol. X-ray crystal structures were determined using a Single Crystal X-ray Crystallography-Rigaku Rapid II system and all the X-ray samples were prepared by recrystallization from hot ethanol. All melting points were recorded on a Griffin melting point apparatus and are reported uncorrected.

3.2. General Experimental Procedure for the Synthesis of Pyrans 6a–h and Compound 7

A mixture of benzaldehyde (1, 0.01 mol), malononitrile (2, 0.01 mol) and 10% mol L-proline was stirred at r.t. for 2 min. then active methylenes 5a–h (0.01 mol) were added. The mixture was refluxed in ethanol (10 mL) for 4–6 h followed by TLC. The crude compounds formed were recrystallized from ethanol and further purified using column chromatography using 2:1 petroleum ether/ethyl acetate as an eluent.

Ethyl-5-cyano-2,6-dimethyL-4-phenyl-4H-pyran-3-carboxylate (6a). White crystalline solid, Mp 189–190 °C; yield 72%, 1H-NMR [DMSO-d6], δ: ppm = 7.31 (t, 1H, Ar), 7.23 (m, 1H, Ar), 7.15 (d, J = 7.6 Hz, 1H, Ar), 6.94 (s, 2H, NH2), 4.29 (s, 1H), 3.94 (m, 2H, CH2), 2.30 (s, 3H, CH3), 1.03 (t, 3H, CH3); 13C-NMR: δ: ppm = 166 (O=C), 158.8 (C), 156.6 (C), 144.8 (CH), 128.5 (2C), 127.0 (2C), 126.9 (2C), 119.5 (CN), 107.0 (C), 60.0 (CH2), 58.8 (C), 19.6 (CH3), 17.0 (CH3); MS: m/z % 284.1 (M+100); Anal. calcd for C16H16N2O3 (284.30): C, 67.59; H, 5.67; N, 9.85; O, 16.882. Found: C, 67.63; H, 5.66; N, 9.71%.

5-Acetyl-2-amino-6-methyl-4-phenyl-4H-pyran-3-carbonitrile (6b). White crystalline solid, Mp 185–186 °C; yield 72%, 1H-NMR [DMSO-d6] δ 7.34 (m, 2H, Ar), 7.23 (m, 1H, Ar), 7.18 (m, 2H, Ar), 6.87 (s, 2H, NH2), 4.46 (s, 1H), 2.25 (s, 3H, CH3), 2.06 (s, 3H, CH3); 13C-NMR: [DMSO-d6], δ: ppm = 198 (O=C), 158.2 (C), 154.8 (C), 144.5 (CH), 128.7 (2C), 127.1 (2C), 126.9 (2C), 119.8 (CN), 114.9 (C), 57.7 (C), 29.8 (CH3), 18.4 (CH3); MS: m/z % 254.1 (M+100); Anal. calcd for C15H14N2O2 (254.1): C, 70.85; H, 5.55; N, 11.02; O, 12.58. Found: C, 71.40; H, 5.34; N, 10.98; O, 12.28%.

2,6-Diamino-4-phenyl-4H-thiopyran-3,5-dicarbonitrile (6c). Yellow crystalline solid, Mp 192–193 °C; yield 92%, 1H-NMR [DMSO-d6], δ: ppm = 7.35 (m, 2H, Ar), 7.26 (m, 3H, Ar), 6.93 (s, 4H, 2NH2), 4.26 (s, 1H); 13C-NMR: [DMSO-d6], δ: ppm = 151.2 (2C), 143.5 (C), 128.7 (2C), 127.1 (C), 126.6 (2C), 118.8 (2C, CN), 71.9 (2C), 43.3 (C); MS: m/z % 254.1 (M+100); Anal. calcd for C13H10N4S (255.31): C, 61.15; H, 4.34; N, 21.94; S, 12.55. Found: C, 61.14; H, 4.02; N, 21.50; S, 12.51%.

2-Amino-7,7-dimethyl-5-oxo-4-phenyl-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (6d). Faint yellow crystalline solid, Mp 228–230 °C; yield 90%, 1H-NMR [DMSO-d6], δ: ppm = 7.30 (m, 2H, Ar), 7.18 (m, 3H, Ar), 7.02 (s, 2H, NH2), 4.20 (s, 1H), 2.62 (m, 2H, CH2), 2.25 (m, 2H, CH2), 1.91 (m, 2H, CH2); 13C-NMR: [DMSO-d6], δ: ppm = 197.6 (C=O), 174.2 (C), 163.8 (C), 144.9 (C), 128.2 (2CH), 127.3 (2CH), 126.5 (CH), 119.4 (CN), 113.6 (C), 58.7 (C), 38.4 (CH2), 36.3 (C), 35.4 (CH2), 32.4 (C), 25.5 (2CH3); MS: m/z % 294.1 (M+100); Anal. calcd for C18H18N2O2 (294.3): C, 73.45; H, 6.16; N, 9.52; O, 10.87. Found: C, 73.67; H, 6.25; N, 9.34; O, 10.70%.

Ethyl 6-amino-5-cyano-2,4-diphenyl-4H-pyran-3-carboxylate (6e). Yellow crystalline solid, Mp 191–192 °C; yield 87%, 1H-NMR [DMSO-d6], δ 7.45 (m, 5H, Ar), 7.36 (m, 2H, Ar), 7.26 (m, 3H, Ar), 7.04 (s, 2H, NH2), 4.26 (s, 1H), 3.75 (q, 2H, CH2), 0.73 (t, 3H, CH3); 13C-NMR: [DMSO-d6], δ: ppm = 156.5 (C=O), 159.1 (C), 154.2 (C), 144.1 (C), 133.1 (C), 129.9 (CH), 128.6 (2CH), 128.4 (2CH), 128.0 (2CH), 127.3 (2CH), 127.1 (CH), 119.7 (CN), 108.9 (C), 60.19 (CH2), 56.9 (C), 40.1 (CH), 13.2 (CH3); MS: m/z % 346.1 (M+100); Anal. calcd for C21H18N2O3 (346.3): C, 72.82; H, 5.24; N, 8.09; O, 13.86. Found: C, 72.90; H, 5.28; N, 8.06; O, 13.76%.

Benzyl 6-amino-5-cyano-2-methyl-4-phenyl-4H-pyran-3-carboxylate (6f). White crystalline solid, Mp 199–200 °C; yield 65%, 1H-NMR [DMSO-d6], δ 7.26 (m, 6H, Ar), 7.13 (m, 2H, Ar), 7.08 (m, 2H, Ar), 6.95 (s, 2H, NH2), 5.02 (q, 2H, CH2), 4.34 (s, 1H), 2.34 (s, 3H, CH3); 13C-NMR: [DMSO-d6], δ: ppm = 156.3 (C=O), 158.3 (C), 157.4 (C), 144.8 (C), 135.7 (C), 128.5 (2CH), 128.2 (2CH), 127.8 (CH), 127.5 (2CH), 127.1 (2CH), 126.8 (CH), 119.7 (CN), 106.8 (C), 65.7 (CH2), 57.3 (C), 18.3 (CH3); MS: m/z % 346.2 (M+100); Anal. calcd for C21H18N2O3 (346.3): C, 72.82; H, 5.24; N, 8.09; O, 13.86. Found: C, 72.75; H, 5.13; N, 8.09; O, 14.03%.

2-Amino-4,6-diphenyl-4H-pyran-3,5-dicarbonitrile (6g). Yellow crystalline solid, Mp 162–163 °C; yield 83%, 1H-NMR [DMSO-d6], δ 7.80 (m, 2H, Ar), 7.57 (m, 3H, Ar), 7.45 (m, 2H, Ar), 7.37 (m, 2H, Ar), 7.32 (s, 2H, NH2), 3.44 (s, 1H); 13C-NMR: [DMSO-d6], δ: ppm = 158.5 (C), 157.6 (C), 142.2 (C), 131.7 (C), 130.0 (CH), 128.9 (2CH), 128.7 (2CH), 127.9 (CH), 127.8 (2CH), 127.7 (2CH), 118.9 (CN), 117.3 (CN), 55.6 (C); MS: m/z % 299.6 (M+100); Anal. calcd for C19H13N3O (299.3): C, 76.24; H, 4.38; N, 14.04; O, 5.35. Found: C, 76.84; H, 4.42; N, 14.01; O, 4.69%.

2-Amino-5-oxo-4-phenyl-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (6h). Yellow crystalline solid, Mp 172–173 °C; yield 78%, 1H-NMR [DMSO-d6], δ: ppm = 7.30 (m, 2H, Ar), 7.18 (m, 3H, Ar), 7.02 (s, 2H, NH2), 4.20 (s, 1H), 2.62 (m, 2H, CH2), 2.25 (m, 2H, CH2), 1.91 (m, 2H, CH2); 13C-NMR: [DMSO-d6], δ: ppm = 198.8 (C=O), 174.4 (C), 164.4 (C), 144.8 (C), 128.3 (2CH), 127.1 (2CH), 126.5 (CH), 119.7 (CN), 113.8 (C), 58.2 (C), 36.3 (C), 35.4 (CH2), 26.4 (CH2), 19.8 (CH2); MS: m/z % 266.1 (M+100); Anal. calcd for C16H14N2O2 (266.2): C, 72.16; H, 5.30; N, 10.52; O, 12.02. Found: C, 72.04; H, 5.54; N, 10.41; O, 11.98%.

Diethyl 5,5-dicyano-4,6-dimethyL-2-phenylcyclohexa-3,6-diene-1,3-dicarboxylate (7). Pale yellow crystalline solid, Mp 210 °C; yield 25%, 1H-NMR [DMSO-d6], δ: ppm = 7.60–7.42 (m, 5H, Ar), 7, 7.02 (s, 2H, NH2), 3.95 (s, 1H), 3.93 (m, 4H, 2CH2), 2.5 (S, 3H, CH3), 2.31 (S, 3H, CH3), 1.04 (m, 6H, 2CH3); 13C-NMR: [DMSO-d6], δ: ppm = 167.5 (2C=O), 137 (C), 136 (C), 129 (2C), 128 (C), 127 (C), 125 (C), 123 (2C), 117 (C), 116 (C), 61 (2C), 45 (C), 30 (C), 25 (2C), 15 (2C); MS: m/z % 378.4 (M+100); Anal. calcd for C22H22N2O4 (378.16): C, 69.83; H, 5.86; N, 7.40; O, 16.91. Found: C, 71.2; H, 5.80; N, 7.5; O, 16.31%.

3.3. Experimental Procedure for the Synthesis of 4

A mixture of benzaldehyde (1, 0.01 mol), malononitrile (2, 0.01 mol) and 10% mol L-proline, then pyrazolon-5-one (3, 0.01 mol) was added. The mixture was refluxed in ethanol (15 mL) for 4 h and followed by TLC. The crude compound formed was recrystallized from ethanol and further purified using column chromatography using ethyl acetate as eluent.

6-Amino-3,4-dimethyl-4-phenyl-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (4). Yellow crystalline solid, Mp 225–226 °C; yield 81%, 1H-NMR [DMSO-d6], δ 12.1 (s, 1H, NH); 7.30 (m, 2H, Ar), 7.26 (m, 2H, Ar), 7.18 (d, J = 7.2 Hz, 1H, Ar), 6.78 (s, 2H, NH2), 1.79 (s, 3H, CH3), 1.76 (t, 3H, CH3); 13C-NMR: [DMSO-d6], δ: ppm = 159.9, 153.9, 147.3, 134.9, 128.0, 126.3, 126.0, 119.9, 116.3, 63.6, 30.1, 24.6, 13.6; MS: m/z % 266.1 (M+100); Anal. calcd for C15H14N4O (266.3): C, 67.65; H, 5.30; N, 21.04; O, 6.01. Found: C, 67.66; H, 5.01; N, 20.98, O, 6.33%.

3.4. Experimental Procedure for the Synthesis of 13

A mixture of benzaldehyde (1, 0.01 mol), malononitrile (2, 0.01 mol), ethyl propiolate (8, 0.01 mol), pyrazolon-5-one (3, 0.01 mol) and L-proline (9, 10% mol) was added together. The mixture was refluxed in ethanol (15 mL) for 4 h, followed by TLC. The crude compound formed was recrystallized from ethanol and further purified using column chromatography using ethyl acetate as eluent.

Ethyl-6-amino-5-cyano-4-phenyl-4H-pyran-3-carboxylate (13). White crystalline solid, Mp 227–230 °C; yield 65%, 1H-NMR [DMSO-d6], δ 7.71 (s, 1H), 7.32 (m, 2H, Ar), 7.24 (m, 1H, Ar), 7.22 (m, 2H, Ar), 7.02 (s, 2H, NH2), 4.23 (s, 2H, NH2), 4.01 (m, 2H, CH2), 1.07 (t, 3H, CH3); 13C-NMR: [DMSO-d6], δ: ppm = 164.5 (CH-pyran), 164.1 (C=O), 158.6 (C), 133.3 (CH), 130.5 (2CH), 128.4 (CH), 126.5 (CH), 119.6 (CN), 11.3 (C), 61.7 (CH2), 57.3 (C), 30.7 (CH), 14.1 (CH3); MS: m/z % 270.1 (M+100); Anal. calcd for C15H14N2O3 (270.28): C, 66.66; H, 5.22; N, 10.36; O, 17.76. Found: C, 66.73; H, 5.34; N, 10.35, O, 17.64%.

4. Conclusions

L-Proline could be used as a catalyst in the reaction of active methylene ketones with α,β-unsaturated nitriles in a multicomponent reaction that leads to creation of a chiral center, and bringing about enantioselectivity for the preparation of the produced pyrans and thiopyrans in good yields.

Acknowledgments

The authors extend their appreciation to the Deanship of Scientific Research at King Saud University for funding the work through the research group project NO. (RGP-VPP-041).

References and Notes

  1. McGlacken, G.P.; Fairlamb, I.J.S. 2-Pyrone natural products and mimetics: Isolation, characterisation and biological activity. Nat. Prod. Rep. 2005, 22, 369–385, doi:10.1039/b416651p.
  2. Danishefsky, S.J.; Pearson, W.H.; Segmuller, B.E. Total synthesis of (.+-.)-3-deoxy-D-manno-2-octulopyranosate. J. Am. Chem. Soc. 1985, 107, 1280–1285, doi:10.1021/ja00291a030.
  3. Pandey, G.; Singh, R.P.; Gary, A.; Singh, V.K. Synthesis of Mannich type products via a three component coupling reaction. Tetrahedron Lett. 2005, 46, 2137–2140, doi:10.1016/j.tetlet.2005.01.118.
  4. Danishefsky, S.J.; Selnick, H.G.; Zelle, R.E.; DeNinno, M.P. Total synthesis of zincophorin. J. Am. Chem. Soc. 1988, 110, 4368–4378, doi:10.1021/ja00221a043.
  5. Danishefsky, S.J.; DeNinno, M.P. Totally synthetic routes to the higher monosaccharides. Angew. Chem. Int. Ed. Engl. 1987, 26, 15–23, doi:10.1002/anie.198700151.
  6. Williams, D.R.; Heidebrecht, R.W. Total synthesis of (+)-4,5-deoxyneodolabelline. J. Am. Chem. Soc. 2003, 125, 1843–1850, doi:10.1021/ja0279803.
  7. Ghozlan, S.A.; Abdelhamid, I.A.; Gaber, H.; Elnagdi, M.H. Studies with functionally substituted enamines: Synthesis of new aminoazolo-pyrimidines and -1,2,4-triazines. J. Chem. Res. 2004, 12, 789–793.
  8. Lingaiah, B.P.V.; Reddy, G.V.; Yakaiah, T.; Narsaiah, B.; Reddy, S.N.; Yadla, R.; Rao, P.S. Efficient and convenient method for the synthesis of poly functionalised 4H-pyrans. Synth. Commun. 2004, 34, 4431–4437, doi:10.1081/SCC-200039502.
  9. Balalaie, S.; Ramezanpour, S.; Bararjanian, M.; Gross, J.H. DABCO-catalyzed efficient synthesis of naphthopyran derivatives via one-pot three-component condensation reaction at room temperature. Synth. Commun. 2008, 38, 1078–1089, doi:10.1080/00397910701862865.
  10. Abdel-Galil, F.M.; Abdel-Motaleb, R.M.; Elnagdi, M.H. Nitriles in heterocyclic synthesis: The reaction of acetophenonylidenemalononitrile with some active methylene reagents and acrylonitrile derivatives. An. Quim. Ser. C 1988, 84, 19–21.Chem. Abstr. 1989, 110, 75387.
  11. Stoyanov, E.V.; Ivanov, I.C.; Heber, D. General method for the preparation of substituted 2-amino-4H,5H-pyrano[4,3-b]pyran-5-ones and 2-amino-4H-pyrano[3,2-c]pyridine-5-ones. Molecules 2000, 5, 19–32, doi:10.3390/50100019.
  12. Nagarajan, A.S.; Reddy, B.S. Synthesis of substituted pyranopyrazoles under neat conditions via a multicomponent reaction. Synlett 2009, 12, 2002–2004.
  13. Al-Matar, H.M.; Khalil, K.D.; Adam, A.Y.; Elnagdi, M.H. Green one pot solvent-free synthesis of pyrano[2,3-c]-pyrazoles and pyrazolo[1,5-a]pyrimidines. Molecules 2010, 15, 6619–6629, doi:10.3390/molecules15096619.
  14. Al-Zaydi, K.M.; Borik, R.M.; Mekheimer, R.A.; Elnagdi, M.H. Green chemistry: A facile synthesis of polyfunctionally substituted thieno[3,4-c]pyridinones and thieno[3,4-d]pyridazinones under neat reaction conditions. Ultrason. Sonochem. 2010, 17, 909–915, doi:10.1016/j.ultsonch.2009.12.008.
  15. Mosaddegh, E.; Hassankhani, A.; Mansouri, G. An efficient, simple and green Zn(Phen)2Cl2 complex catalyzed synthesis of 4-H-benzo[b]pyrans in water at ambient temperature. E J. Chem. 2011, 8, 529–534, doi:10.1155/2011/684937.
  16. Al-Mousawi, S.M.; Moustafa, M.S.; Elnagdi, M.H. Green synthetic approaches: Solventless synthesis of polyfunctional substituted aromatics as potential versatile building blocks in organic synthesis utilizing enaminones and enaminonitriles as precursors. Green Chem. Lett. Rev. 2011, 4, 185–193, doi:10.1080/17518253.2010.528049.
  17. Subba Reddy, B.V.; Divya, B.; Swain, M.; Rao, T.P.; Yadav, J.S.; Vishnu Vardhan, M.V.P.S. A domino Knoevenagel hetero-Diels-Alder reaction for the synthesis of polycyclic chromene derivatives and evaluation of their cytotoxicity. Bioorg. Med. Chem. Lett. 2012, 22, 1995–1999, doi:10.1016/j.bmcl.2012.01.033.
  18. O’Reilly, M.C.; Lindsley, C.W. Enantioselective synthesis of C2-functionalized, N-protected morpholines and orthogonally N,N'-protected piperazines via organocatalysis. Tetrahedron Lett. 2012, 53, 1539–1542, doi:10.1016/j.tetlet.2011.12.063.
  19. Naziroglu, H.N.; Durmaz, M.; Bozkurt, S.; Demir, A.S.; Sirit, A. Application of L-prolinamides as highly efficient organocatalysts for the asymmetric Michael addition of unmodified aldehydes to nitroalkenes. Tetrahedron Asymmetry 2012, 23, 164–169, doi:10.1016/j.tetasy.2012.01.008.
  20. Gu, L.; Zhou, Y.; Zhang, J.; Gong, Y. A highly chemo- and enantioselective nitroaldol reaction of haloenals: Preparation of chiral functionalized allylic alcohols. Tetrahedron Asymmetry 2012, 23, 124–129, doi:10.1016/j.tetasy.2012.01.011.
  21. Babu, N.S.; Pasha, N.; Rao, K.T.; Prasad, P.S.; Lingaiah, N. A heterogeneous strong basic Mg/La mixed oxide catalyst for efficient synthesis of polyfunctionalized pyrans. Tetrahedron Lett. 2008, 49, 2730–2733, doi:10.1016/j.tetlet.2008.02.154.
  22. Zamocka, J.; Misikova, E.; Durinda, J. Preparation, structure elucidation and activity of some [(5-hydroxy- or 5-methoxy-4-oxo-4H-pyran-2-yl) methyl]-2-alkoxycarbanilates. Pharmazie 1991, 46, 610.
  23. Urbahns, K.; Horvath, E.; Stasch, J.P.; Mauler, F. 4-Phenyl-4H-pyrans as IKCa channel blockers. Bioorg. Med. Chem. Lett. 2003, 13, 2637–2639, doi:10.1016/S0960-894X(03)00560-2.
  24. Touati, E.; Krin, E.; Quillardet, P.; Hofnung, M. 7-Methoxy-2-nitronaphtho(2, l-b)furan (R7000)-induced mutation spectrum in the lacI gene of Escherichia coli: Influence of SOS mutagenesis. Carcinogenesis 1996, 17, 2543–2550, doi:10.1093/carcin/17.12.2543.
  25. Witte, E.C.; Neubert, P.; Roesch, A. 7-(Piperazinylpropoxy)-2H-1-benzopyran-2-ones. DE Patent 3427985.
  26. Press, J.B.; Sanfilippo, P.J.; Urbanski, M. Process for the preparation of enantiomerically pure thienopyran derivatives. US Patent US5457212.
  27. Gou, S.; Wang, S.; Li, J. D,L-Proline-catalyzed one-pot synthesis of pyrans and pyrano[2,3-c]pyrazole derivatives by a grinding method under solvent-free conditions. Synth. Commun. 2007, 37, 2111–2120, doi:10.1080/00397910701396906.
  28. Al-Matar, H.; Khalil, K.; Meier, H.; Kolshorn, H.; Elnagdi, M. Chitosan as heterogeneous catalyst in Michael additions: The reaction of cinnamonitriles with active methylene moieties and phenols. ARKIVOC 2008, xvi, 288–301.
  29. Kumar, D.; Reddy, V.B.; Sharad, S.; Dube, U.; Kapur, S. A facile one-pot green synthesis and antibacterial activity of 2-amino-4H-pyrans and 2-amino-5-oxo-5,6,7,8-tetrahydro-4H-chromenes. Eur. J. Med. Chem. 2009, 44, 3805–3809, doi:10.1016/j.ejmech.2009.04.017.
  30. Banerjee, S.; Horn, A.; Khatri, H.; Sereda, G. A green one-pot multicomponent synthesis of 4H-pyrans and polysubstituted aniline derivatives of biological, pharmacological, and optical applications using silica nanoparticles as reusable catalyst. Tetrahedron Lett. 2011, 52, 1878–1881, doi:10.1016/j.tetlet.2011.02.031.
  31. Menz, H.; Kirsch, S.F. Synthesis of stable 2H-pyran-5-carboxylates via a catalyzed Propargyl-Claisen rearrangement/Oxa-6π electrocyclization strategy. Org. Lett. 2006, 8, 4795–4797, doi:10.1021/ol061856x.
  32. Mecadon, H.; Rumum, Md.; Kharbangar, I.; Laloo, B.M.; Kharkongor, I.; Rajbangshi, M.; Myrboh, B. L-Proline as an efficient catalyst for the multi-component synthesis of 6-amino-4-alkyl/aryl-3-methyl-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitriles in water. Tetrahedron Lett. 2011, 52, 3228–3231, doi:10.1016/j.tetlet.2011.04.048.
  33. Mukhopadhyay, C.; Tapaswi, P.K.; Butcher, R.J. L-Proline-catalyzed one-pot expeditious synthesis of highly substituted pyridines at room temperature. Tetrahedron Lett. 2010, 51, 1797–1802, doi:10.1016/j.tetlet.2010.01.106.
  34. Hernández, J.G.; García-López, V.; Juaristi, E. Solvent-free asymmetric aldol reaction organocatalyzed by (S)-proline-containing thiodipeptides under ball-milling conditions. Tetrahedron 2012, 68, 92–97, doi:10.1016/j.tet.2011.10.093.
  35. Pandey, J.; Anand, N.; Tripathi, R.P. L-Proline catalyzed multicomponent reaction of 3,4-dihydro-(2H)-pyran, urea/thiourea, and aldehydes: Diastereoselective synthesis of hexahydropyrano pyrimidinones (thiones). Tetrahedron 2009, 65, 9350–9356, doi:10.1016/j.tet.2009.09.002.
  36. Shi, C.; Chen, H.; Shi, D. An Efficient one-pot three-component synthesis of tetrahydrofuro[3,4-b]quinoline-1,8(3H,4H)-dione derivatives catalyzed by L-proline. J. Heterocycl. Chem. 2012, 49, 125, doi:10.1002/jhet.782.
  37. Raghuvanshi, D.S.; Singh, K.N. An efficient protocol for multicomponent synthesis of spirooxindoles employing L-proline as catalyst at room temperature. J. Heterocycl. Chem. 2010, 47, 1323–1327, doi:10.1002/jhet.451.
  38. Muramulla, S.; Zhao, C. A new catalytic mode of the modularly designed organocatalysts (MDOs): Enantioselective synthesis of dihydropyrano[2,3-c]pyrazoles. Tetrahedron Lett. 2011, 52, 3905–3908, doi:10.1016/j.tetlet.2011.05.092.
  39. CCDC 850090-850094 and 851560 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via “http://www.ccdc.cam.ac.uk/data_request/cif”.
  • Sample Availability:Samples of the compounds 6a–h, 4 and 13 are available from the authors.
Molecules EISSN 1420-3049 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert