Modular, Metal-Catalyzed Cycloisomerization Approach to Angularly Fused Polycyclic Aromatic Hydrocarbons and Their Oxidized Derivatives

Palladium-catalyzed cross-coupling
reactions of 2-bromobenzaldehyde
and 6-bromo-2,3-dimethoxybenzaldehyde with 4-methyl-1-naphthaleneboronic
acid and acenaphthene-5-boronic acid gave corresponding o-naphthyl benzaldehydes. Corey–Fuchs olefination followed
by reaction with n-BuLi led to various 1-(2-ethynylphenyl)­naphthalenes.
Cycloisomerization of individual 1-(2-ethynylphenyl)­naphthalenes to
various benzo­[c]­phenanthrene (BcPh) analogues was accomplished smoothly with catalytic PtCl2 in PhMe. In the case of 4,5-dihydrobenzo­[l]­acephenanthrylene,
oxidation with DDQ gave benzo­[l]­acephenanthrylene.
The dimethoxy-substituted benzo­[c]­phenanthrenes were
demethylated with BBr3 and oxidized to the o-quinones with PDC. Reduction of these quinones with NaBH4 in THF/EtOH in an oxygen atmosphere gave the respective dihydrodiols.
Exposure of the dihydrodiols to N-bromoacetamide
in THF-H2O led to bromohydrins that were cyclized with
Amberlite IRA 400 HO– to yield the series 1 diol
epoxides. Epoxidation of the dihydrodiols with mCPBA
gave the isomeric series 2 diol epoxides. All of the hydrocarbons
as well as the methoxy-substituted ones were crystallized and analyzed
by X-ray crystallography, and these data are compared to other previously
studied BcPh derivatives. The methodology described
is highly modular and can be utilized for the synthesis of a wide
variety of angularly fused polycyclic aromatic hydrocarbons and their
putative metabolites and/or other derivatives.

钯催化交叉偶联反应（Palladium-catalyzed cross-coupling reactions）可实现2-溴苯甲醛（2-bromobenzaldehyde）与6-溴-2,3-二甲氧基苯甲醛（6-bromo-2,3-dimethoxybenzaldehyde）分别与4-甲基-1-萘硼酸（4-methyl-1-naphthaleneboronic acid）和苊-5-硼酸（acenaphthene-5-boronic acid）的偶联，得到相应的邻萘基苯甲醛类产物。
经科里-富克斯烯烃化反应（Corey–Fuchs olefination）后，再与正丁基锂（n-BuLi）反应，可得到多种1-(2-乙炔基苯基)萘类化合物。
各1-(2-乙炔基苯基)萘类化合物在甲苯（PhMe）中以二氯化铂（PtCl₂）为催化剂，可顺利发生环异构化反应，生成多种苯并[c]菲（benzo[c]phenanthrene, BcPh）类似物。
针对4,5-二氢苯并[l]苊蒽（4,5-dihydrobenzo[l]acephenanthrylene），经2,3-二氯-5,6-二氰对苯醌（DDQ）氧化后可得到苯并[l]苊蒽（benzo[l]acephenanthrylene）。
二甲氧基取代的苯并[c]菲类化合物可通过三溴化硼（BBr₃）实现脱甲基修饰，再经重铬酸吡啶鎓盐（PDC）氧化得到邻醌类化合物。
将上述醌类化合物在氧气氛围下，于四氢呋喃/乙醇（THF/EtOH）混合溶剂中用硼氢化钠（NaBH₄）还原，即可得到对应的二氢二醇类产物。
将该二氢二醇与N-溴代乙酰胺在THF-H₂O混合溶剂中反应，生成溴代醇中间体，随后经Amberlite IRA 400 氢氧根型树脂（Amberlite IRA 400 HO–）环化，得到系列1二醇环氧化物。
若以间氯过氧苯甲酸（mCPBA）对二氢二醇进行环氧化反应，则可得到异构体系列2二醇环氧化物。
所有烃类衍生物及甲氧基取代衍生物均经结晶纯化，并通过X射线晶体衍射分析（X-ray crystallography）完成表征，同时将这些实验数据与此前已报道的其他苯并[c]菲衍生物进行了对比。
本研究所述合成方法具有高度的模块化特性，可用于合成多种角稠合多环芳烃及其推定代谢物或其他衍生物。