Synthesis of benzo[g]chrysenes
Graphical abstract
Introduction
The skeleton of benzo[g]chrysene (BgC) consists of one pentacyclic aromatic hydrocarbon (PAH).1, 2 It is produced by the combustion of fossil fuels and organic materials, and has been employed as a substrate in investigations of the mechanisms underlying the carcinogenicity of PAHs.3 Despite the importance of BgC as a cancer carcinogen, it is not readily yielded through synthesis. Common synthetic routes for making the skeleton of BgC include the double Grignard addition and aromatization (Harvey),4 Wittig olefination and photolysis (Hecht),5 Reformatsky reaction and Friedel–Crafts acylation (Lehr),6 Suzuki cross-coupling reaction and acid-mediated ring-closure (Kumar),7 and other approaches,8 as shown in Scheme 1.
Since palladium complex mediated Suzuki–Miyaura cross-coupling of an organoboron compound with a broad range of polyhalogenated substituents is useful for stereospecific carbon–carbon bond formation, most of the related literature on synthetic PAHs is focused on cross-coupling annulation. There have been extensive studies on the process for preparing functionalized PAHs, such as dibenzochrysenes,9 benzo[a]pyrenes,10 and other structures.11 However, as yet, there have been very few efficient syntheses of BgC skeletons bearing appropriate functional groups of different position. In continuation of our investigation with the application of 1a and 1b,12 a novel synthetic sequence of A→D→E→B→C approach (from one benzene ring to five fused benzene rings) is employed to construct 2 with 12,13-dimethoxy groups, via a series of simple and efficient functional group transformations of Claisen rearrangement, Grignard addition, base-promoted cyclodehydration and photolytic Scholl annulation (Scheme 2).
Section snippets
Results and discussion
The starting materials, compounds 4a–e, with the 2-cinnamyl group, were acquired from commercially available isovanillin (1a) and 3-hydroxybenzaldehyde (1b) with an A-ring motif, in moderate overall three-step yields according to the reported procedures in the standard sequence of O-allylation, Claisen rearrangement and O-alkylation as shown in Scheme 3.12
O-Allylation of two phenols, 1a or 1b, with trans-cinnamyl bromide (D ring, X=H, OMe) afforded ether product 3a, 3b or 3c in the presence of K
Conclusion
In summary, we have successfully presented a novel synthetic A→D→E→B→C ring formation through a sequence approach for the preparation of substituted benzo[g]chrysenes 2 via a series of simple and efficient functional group transformations of Claisen rearrangement, Grignard addition, base-promoted cyclodehydration, and photolytic Scholl annulation. This synthesis begins with simple starting materials and reagents, and provides a potential methodology for chemical biology research.
General
THF was distilled prior to use. All other reagents and solvents were obtained from commercial sources and used without further purification. Reactions were routinely carried out under an atmosphere of dry nitrogen with magnetic stirring. Products in organic solvents were dried with anhydrous magnesium sulfate before concentration in vacuo. Melting points were determined with a SMP3 melting apparatus. 1H and 13C NMR spectra were recorded on a Varian INOVA-400 spectrometer operating at 400 and at
Acknowledgements
The authors would like to thank the National Science Council of the Republic of China for its financial support.
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