Monoprotection of Diols as a Key Step for the Selective Synthesis of Unequally Disubstituted Diamondoids (Nanodiamonds)

Abstract

The monoprotection (desymmetrization) of diamondoid, benzylic, and ethynyl diols has been achieved using fluorinated alcohols such as 2,2,2-trifluoroethanol (TFE) under acidic conditions. This practical acid-catalyzed S(N)1 reaction opens the door for the synthesis of novel bifunctional diamondoids. With diamantane as an example, we show that the resulting monoethers can be used to prepare selectively, for instance, amino or nitro alcohols and unnatural amino acids. These are important compounds in terms of the exploration of electronic, pharmacological, and material properties of functionalized nanodiamonds.

Selective Preparation of Diamondoid Fluorides[1]

“…[14] Recently we were able to demonstrate that the synthesis of unequally disubstituted diamantane derivatives, like amino alcohols and amino acids, is possible through the monoprotection of the corresponding diols by using fluorinated alcohols as solvent and reagent under acidic conditions. [15] This novel and currently only possibility of selectively preparing these unequally disubstituted derivatives encouraged us to synthesize difunctionalized diamondoids that also include fluorine substituents. Since it is known that the introduction of fluorine atoms into molecules can enhance or modify their properties or biological activities [16] we were particularly interested in the preparation of fluorinated unequally disubstituted polymantanes.…”

“…In order to prepare a fluoro alcohol we used our monoprotection method starting from diamantan-4,9-diol. [15] 9-(2,2,2-Trifluoroethoxy)-diamantan-4-ol (22) was converted into the corresponding bromide 23 using SOBr 2 (Scheme 1). The halogen exchange reaction with AgF was carried out in 86% yield to give the fluoro ether 24.…”

“…At this point we used trifluoroacetic acid to convert the ether into a base-labile ester function; this reaction worked very well in our recent preparation of amino alcohols. [15] To our suprise the fluorine atom was also substituted by a trifluoroacetoxy group (Scheme 1); the cleavage of a fluorine adamantane bond is known in literature, like for the preparation of amides [38] or the brominolysis of fluoroadamantane. [39] Unfortunately other cleavage procedures (e.g., with concentrated acetic acid or diluted acetic acid even at elevated temperatures) were also not successful and the ether function was retained even though the fluorine atom was not touched.…”

“…Since the amino function of 31 can be oxidized by m-chloroperbenzoic acid (m-CPBA) to the corresponding nitro alcohol [15] 34 we converted the alcohol function either by bromination and treatment with AgF or by direct fluorination utilizing DAST to afford 4-fluoro-9-nitrodiamantane (36) in high yields (Scheme 4). Next we reduced the nitro group by using a zinc/diluted HCl mixture at 40 8C and obtained the amino fluoride 33 with 73% yield (Scheme 4).…”

“…Monoether 22 can be transferred via a Ritter-type reaction with chloroacetonitrile to 2-chloro-N-[9-(2,2,2-trifluoro- (37). [15] By analogy to the synthesis of 9-fluorodiamantan-4-ol (30) we cleaved the trifluoroethoxy ether with BBr 3 in dichloromethane. Thereby we were able to isolate 2-chloro-N-[9-(bromo)diamantan-4-yl]acetamide (38) in 97% yield (Scheme 5).…”