JOURNAL OF CHEMICAL RESEARCH 2015
VOL. 39
SEPTEMBER, 499–501
RESEARCH PAPER 499
An efficient synthesis of bis-purine derivatives by a PPh3 -catalysed double addition of dialkylated xanthine derivatives to alkyl propiolates Nasim Shamsa, Mohammad Hossein Mosslemina* and Hossein Anaraki-Ardakanib a
Department of Chemistry, Yazd Branch, Islamic Azad University, PO Box 89195-155, Yazd, Iran Department of Chemistry, Mahshahr Branch, Islamic Azad University, Mahshahr, Iran
b
Reaction between 5,7-dialkylated xanthine derivatives (2 equiv.) and an alkyl propiolate in the presence of catalytic amounts of triphenyl phosphine yields alkyl 2,3-bis(1,3-dialkyl-2,6-dioxo/oxothio-2,3-dihydro-1H -purin-7(6H)-yl)propanoates in excellent yield. Keywords: purine, xanthines, alkyl propiolates, triphenyl phosphine
In 1884, Emil Fischer1,2 had recognised the fused heterocyclic system, imidazo[4,5-d]pyrimidine as a purine and in 1889, he accomplished its first synthesis.3 In his pioneering work, he had also explored a versatile transformation on purine resembling the naturally occurring guanine, adenine, xanthine, uric acid, and caffeine.4 Purine is the most ubiquitous nitrogen-containing heterocycle in nature and is the core structure of adenine and guanine in RNA and DNA.5,6 In medicinal chemistry, purine motifs have attracted a great deal of attention due to their preponderance in pharmaceutically important compounds.7 For example, therapeutically, purines are interferon inducers, sulfotransferase inhibitors, phosphodiesterase inhibitors, microtubule assembly inhibitors, leukotriene A4 hydrolase inhibitors, cysteine protease cathepsin K inhibitors, corticotropin-releasing hormone receptor (CRH-R1) modulators and nucleoside transport inhibitors. Purine containing kinase inhibitors such as Src tyrosine kinase,8 P38a MAP kinase,9 inositol-1,4,5-trisphosphate-3-kinase,10 protein kinase11 and cyclin-dependent kinase (CDK)12,13 have also been broadly exploited. For example, olomoucine, roscovitine and purvalanol A are the most potent kinase inhibitors; indeed, roscovitine is currently in clinical trials. Furthermore, purine-based heat shock protein (Hsp90) inhibitors, BIIB021 have also entered into clinical development,14-16 and purines play a vital role in neurotransmission and neuromodulation, with their effects mediated by purine and pyrimidine17,18 receptor subfamilies, P1, P2X, and P2Y. In the area of infectious diseases, such as tuberculosis,19 numerous purine nucleosides were found to be selective against mycobacterium tuberculosis. The lead compound, 2-methyl adenosine,20 is active against proliferating and non-proliferating bacteria due to its ability to inhibit protein synthesis. Xanthine is a common structural component in medicinal chemistry and new chemical entities (NCEs) development.21 Xanthine-based lead molecules have been exploited in numerous therapeutic areas, for instance, Alzheimer’s disease, 22 diabetes,23 asthma,24 Parkinson’s disease25 and cancer.26 Furthermore, xanthine derivatives are one of the most abundant chemical classes of adenosine receptor antagonists.27 Caffeine is the most prevalent xanthine and is used as a CNS stimulant drug globally.28 In continuation of our work on PPh3-catalysed addition of heterocycles to acetylenic esters,29,30 we now report an efficient synthetic route to alkyl 2,3-bis(1,3-dialkyl-2,6-dioxo/thio-2,3dihydro-1H-purin-7(6H)-yl)propanoates.
* Correspondent. E-mail:
[email protected]
Results and discussion Our synthetic route is shown in Scheme 1 and was validated by the addition of theophylline 1 (R = Me, X = O) (2 equiv.) to methyl propiolate 2 (R’ = Me) in the presence of a catalytic amount of triphenyl phosphine (0.2 mol%) to yield bis-derivative 3a (R, R’= Me; X = O) in 95% yield. Various 5,7-dialkylated xanthines 1 (R = Me, Et; X = O, S) (2 equiv.) were then added to methyl and other alkyl propiolates 2 (R’ = Me, Et, But) in the presence of a catalytic amount of triphenyl phosphine (0.2 mol%) to yield six other bis-derivatives 3b–g (R = Me, Et; R’ = Me, Et, But; X = O, S) in 87–93% yield (Scheme 1). The structures of all the compounds were deduced from their IR, 1H NMR, 13C NMR and mass spectra and by elemental analysis. For example, the IR spectrum of 3a showed absorptions at 1732, 1698 and 1666 cm-1 indicating the presence of C=O groups. The 1H NMR spectrum of 3a exhibited four singlets for the (N–CH3) group at δ 3.38–3.57 ppm and another singlet for the carbomethoxy group at δ 3.85 and ppm; also two doublet of doublets at δ 5.06 and 5.25 with (2 JHH =15 Hz, 3 JHH = 10 Hz) and (1H, d,d, 2 JHH = 15 Hz, 3 JHH = 5 Hz) for the diastereotopic hydrogens of the methylene group are observable. In addition, a doublet of doublets appear at δ 6.01 with (1H, d,d, 3 JHH =10 Hz, 3 JHH = 5 Hz, CH) for the methine group. Finally, two singlets appear at δ 7.35, 7.48 ppm due to two aromatic hydrogen atoms. The 1H decoupled 13C NMR spectrum of 3a showed 17 resonances as expected. A plausible mechanism for the formation of compound 3 is shown in Scheme 2. On the basis of the well-established chemistry of trivalent phosphorus nucleophiles,31–33 it is reasonable to assume that compound 4 results from the initial addition of triphenylphosphine to propiolate and protonation of which by xanthine 1 yields 5. Then, the positively charged ion intermediate 5 is attacked by the conjugate anion of xanthine 6 to form the ylide 7 which is protonated by another xanthine to yield 8. Then 8 is attacked by the conjugate anion of xanthine 6 to produce compound 3 by loss of triphenylphosphine (Scheme 2).
Conclusion In conclusion, an efficient and novel one-pot synthesis of alkyl 2,3-bis(1,3-dialkyl-2,6-dioxo/thio-2,3-dihydro-1H-purin-7(6H)-yl) propanoates from simple and readily available starting materials under mild conditions has been developed. It is hoped that this approach could be of value in the preparation of novel synthetic fragments with unique properties for medicinal chemistry programs.
500 JOURNAL OF CHEMICAL RESEARCH 2015
R X O R 2
H
CO2R'
N
N
PPh3 (0.2 mol%)
+
R
N
N
R
N O
CH3CN, r.t, 2h
N
N
X
N
H
R'O2C
N
H 1
3
2 3
R
R'
X
Yield (%)*
a
Me
Me
O
95
b
Me
Et
O
92
c
Me
t-Bu
O
93
d
Me
Me
S
90
e
Me
Et
S
88
f
Et
Me
O
91
g
Et
Et
O
87
O N
N
N
R X
R
*Isolated yields. Scheme 1 O PPh3
R +
H
CO2R
H N
N
X
N
N R
4
+ PPh3
H
H
CO2R'
O N
N
N
N 6
5
1
R X
R
R X O R X
R'O2C N
N
H + PPh3
N
N
+
N
N
N
N
R 7
R
O
H
1
N N
R'O2C
X
R
+ PPh3
N O
R
N
8
-PPh3 O
H H
3
N
R
N
X 6 R
Scheme 2
Experimental Melting points were determined with an Electrothermal 9100 apparatus. Elemental analyses were performed using a Costech ECS 4010 CHNS–O analyser at the analytical laboratory of Islamic Azad University Yazd branch. Mass spectra were recorded on a Finnigan-Mat 8430 mass spectrometer operating at an ionisation potential of 70 eV. IR spectra were recorded on a Shimadzu IR-470 spectrometer. NMR spectra were obtained on a Bruker DRX-500 Avance spectrometer (1H NMR at 500 Hz, 13C NMR at 125 Hz) in CDCl3 using TMS as an internal standard. Chemical shifts (δ) are given in ppm and coupling constants (J) are
given in Hz. The chemicals used in this work were purchased from Fluka (Buchs, Switzerland) and were used without further purification. General procedure A solution of theophylline (2 mmol) and methyl propiolate (1 mmol) in the presence of a catalytic amount of triphenyl phosphine (0.2 mmol) in CH3CN (10 mL) was stirred for 2h at room temperature. After completion of the reaction (monitored by TLC), the solvent was removed under reduced pressure and the precipitate obtained was washed with diethyl ether to yield a pure product.
JOURNAL OF CHEMICAL RESEARCH 2015 501 Methyl 2,3-bis(1,3-dimethyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl) propanoate (3a): White powder; yield 95%; m.p. 162–164°C; IR (KBr) (νmax, cm-1): 1732, 1698, 1666 (C=O); 1H NMR δ 3.43–3.57 (12H, 4s, 4NCH3), 3.85 (3H, 1s, OCH3), 5.06 (1H, d,d, 2JHH =15, 10 Hz, CH), 5.25 (1H, d,d, 2JHH =15 Hz, 3JHH =5 Hz, CH), 6.01 (1H, d,d, 3JHH =10, 5 Hz, CH), 7.35, 7.48 (2H, s, 2CH aromatic). 13C NMR: δ 28.5–30.3 (4NCH3), 48.4 (CH2), 54.0 (OCH3), 59.6 (CH), 106.7, 106.9, 142.7, 143.1, 149.9, 150.0 (aromatic carbons), 153.1, 155.5, 155.9 and 167.0 (C=O)ppm; MS (m/z,%): 444 (M.+, 25). Anal. calcd for C18H20N8O6: C, 48.65; H, 4.54; N, 25.21; found: C, 48.98; H, 4.84; N, 24.88%. Ethyl 2,3-bis(1,3-dimethyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)yl)propanoate (3b): White powder; yield 92%; m.p. 168–170°C; IR (KBr) (νmax, cm-1): 1730, 1703, 1659 (C=O); NMR: 1H NMR: δ 1.27 (3H, t, 3 JHH = 7.5 Hz, CH3), 3.40–3.56 (12H, 4s, 4 NCH3), 4.31 (2H, m, OCH2), 5.06 (1H, d,d, 2 JHH =15, 10 Hz, CH), 5.24 (1H, d,d, 2 JHH =15, 5 Hz, CH), 5.98 (1H, d,d, 3 JHH =10, 5 Hz, CH), 7.34, 7.47 (2H, s, 2CH aromatic); 13C NMR: δ 14.4 (CH3), 28.5–30.3 (4NCH3), 48.4 (CH2), 59.6 (CH), 63.4 (OCH2), 106.7, 106.9, 142.7, 143.1, 149.9, 150.0 (aromatic carbons), 151.7, 155.5, 155.9 and 166.4 (C=O) ppm; MS (m/z,%): 458 (M.+, 20). Anal. calcd for C19H22N8O6: C, 49.78; H, 4.84; N, 24.44; found: C, 50.10; H, 4.94; N, 24.20%. t-Butyl 2,3-bis(1,3-dimethyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)yl)propanoate (3c): White powder; yield 93%; m.p. 175–177°C; IR (KBr) (νmax, cm-1): 1735, 1698, 1663 (C=O); 1H NMR δ 1.41 (9H, s, C(CH3)3), 3.42–3.54 (12H, 4s, 4 NCH3), 5.08 (1H, d,d, 2 JHH =15,10 Hz, CH), 5.22 (1H, d,d, 2 JHH =15,5 Hz, CH), 6.02 (1H, d,d, 3 JHH =10,5 Hz, CH), 7.34, 7.49 (2H, s, 2CH aromatic); 13C NMR δ 27.7 (C(CH3)3), 28.5–30.4 (4NCH3), 48.4 (CH2), 59.6 (CH), 80.3 (OC(CH3)3), 106.6, 106.9, 142.6, 143.0, 149.9, 150.0 (aromatic carbons), 151.8, 155.5, 155.8 and 166.9 (C=O) ppm; MS (m/z,%): 486 (M.+, 26). Anal. calcd for C21H26N8O6: C, 51.85; H, 5.39; N, 23.03; found: C, 51.60; H, 5.64; N, 23.33%. Methyl 2,3-bis(1,3-dimethyl-6-oxo-2-thioxo-2,3-dihydro-1H-purin7(6H)-yl)propanoate (3d): White powder; yield 90%; m.p. 145–147°C; IR (KBr) (νmax, cm-1): 1729, 1705 (C=O); 1H NMR δ 3.39–3.56 (12H, 4s, 4 NCH3), 3.81 (3H, 1s, OCH3), 5.07(1H, d,d, 2JHH =15, 10 Hz, CH), 5.29 (1H, d,d, 2JHH =15 Hz, 5 Hz, CH), 6.06 (1H, d,d, 3JHH =10, 5 Hz, CH), 7.33, 7.47 (2H, s, 2CH aromatic). 13C NMR δ 28.50–30.31 (4NCH3), 48.39 (CH2), 53.98 (OCH3), 59.67 (CH), 106.63, 106.89, 142.58, 143.07, 145.02, 149.95(aromatic carbons), 155.55, 155.77 and 166.89 (3C=O),178.41 (C=S) ppm. MS (m/z,%): 476 (M.+, 15). Anal. calcd for C18H20N8O4S2: C, 45.37; H, 4.23; N, 23.51; S, 13.46%; found: C, 45.60; H, 4.01; N, 23.19; S, 13.79%. Ethyl 2,3-bis(1,3-dimethyl-6-oxo-2-thioxo-2,3-dihydro-1H-purin-7 (6H)-yl)propanoate (3e): White powder; yield 88%; m.p. 150–152°C; IR (KBr) (νmax, cm-1): 1731, 1700 (C=O); 1H NMR δ 1.25 (3H, t, 3 JHH =7.5 Hz, CH3), 3.38–3.55 (12H, 4s, 4 NCH3), 4.29 (2H, q, 3JHH = 7.5 Hz, OCH2), 5.03(1H, d,d, 2JHH =15, 10 Hz, CH), 5.21 (1H, d,d, 2JHH =15, 5 Hz, CH), 6.08 (1H, d,d, 3JHH =10, 5 Hz, CH), 7.32, 7.50 (2H, s, 2CH aromatic); 13C NMR δ 14.4 (CH3), 28.5–30.4 (4NCH3), 48.8 (CH2), 59.6 (CH),63.4 (OCH2), 106.7, 106.9, 142.6, 143.1, 149.9, 150.0 (aromatic carbons), 154.7, 155.8 and 166.7 (3C=O), 178.3 (C=S) ppm; MS (m/z,%): 490 (M.+, 19). Anal. calcd for C19H22N8O4S2: C, 46.52; H, 4.52; N, 22.84; S, 13.07; found: C, 46.21; H, 4.41; N, 23.10; S, 13.39%. Methyl 2,3-bis(1,3-diethyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)yl)propanoate (3f): White powder; yield 91%; m.p. 181–183°C; IR (KBr) (νmax, cm-1): 1736, 1702, 1665 (C=O); NMR data: 1H NMR δ 1.17–1.28 (12H, 4t,3 JHH = 7.1 Hz, 4CH3), 3.81 (3H, 1s, OCH3), 3.98–4.23 (12H, 4m, 3 JHH =7.1 Hz, 4NCH2), 5.09(1H, d,d, 2 JHH =15,10 Hz, CH), 5.20 (1H, d,d, 2 JHH =15, 5 Hz, CH), 6.04 (1H, d,d, 3 JHH =10, 5 Hz, CH), 7.29, 7.39 (2H, s, 2CH aromatic). 13C NMR δ 12.8–13.9 (4CH3), 38.4–42.6 (4NCH2), 48.3 (CH2), 53.8 (OCH3), 59.986 (CH), 106.7, 106.9, 141.8, 144.1, 149.7, 150.1 (aromatic carbons), 151.9, 154.9, 155.4 and 167.3 (C=O); MS (m/z,%): 500 (M.+, 31). Anal. calcd for C22H28N8O6: C, 52.79; H, 5.64; N, 22.39; found: C, 53.01; H, 5.36; N, 22.18%.
Ethyl 2,3-bis(1,3-diethyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl) propanoate (3g): White powder; yield 87%; m.p. 199–201°C; IR (KBr) (νmax, cm-1): 1728, 1698, 1670 (C=O); 1H NMR: δ 1.15–1.25 (12H, 4t, 3JHH = 7.1 Hz, 4CH3), 1.29 (3H, t, 3JHH =7.5 Hz, CH3), 3.99–4.20 (12H, 4m, 3 JHH = 7.1 Hz, 4NCH2), 4.33 (2H, m, OCH2), 5.10(1H, d,d, 2JHH =15,10 Hz, CH), 5.19 (1H, d,d, 2JHH =15,5 Hz, CH), 6.03 (1H, d,d, 3JHH =10,5 Hz, CH), 7.30, 7.38 (2H, s, 2CH aromatic); 13C NMR: δ 12.9–14.5 (5CH3), 38.7–42.6 (4NCH2), 48.3 (CH2), 59.8 (CH), 62.3(OCH2), 106.7, 106.8, 141.8, 144.1, 149.7, 150.2 (aromatic carbons), 151.9, 154.9, 155.4 and 167.3 (C=O). MS (m/z,%): 514 (M.+, 29). Anal. calcd for C23H30N8O6: C, 53.69; H, 5.88; N, 21.78%; found: C, 53.95; H, 5.60; N, 22.04%.
Received 10 July 2015; accepted 1 August 2015 Paper 1503482 doi: 10.3184/174751915X14396278385301 Published online: 1 September 2015
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