Letter pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Arynes in the Monoarylation of Unprotected Carbohydrate Amines Kumar Bhaskar Pal,† Mukul Mahanti,† and Ulf J. Nilsson* Centre for Analysis and Synthesis Department of Chemistry, Lund University, Box 124, 221 00 Lund, Sweden S Supporting Information *
ABSTRACT: A CsF-mediated method has been developed for the N-arylation of amino sugars that affords good to excellent yields of arylated products under mild conditions involving the in situ generation of arynes. The reaction conditions tolerate a variety of common carbohydrate protecting groups and also performs exceptionally well on unprotected amino sugar derivatives. The reactions are scalable in moderate to good yields with broad scope.
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Hence, we hypothesized that amines, being the more reactive nucleophile in amino sugar derivatives, O-protected or even unprotected, would react selectively with arynes to yield N-aryl derivatives. Herein, we report a room temperature methodology to functionalize carbohydrate amines with an aryl group using in situ generated arynes as the aryl source (Scheme 1). Initially, the condition dependence of the reaction of 6-amino6-deoxy-1,2:3,4-di-O-isopropylidene-α-D-galactopyranose 1a with benzyne generated in situ from 2-(trimethylsilyl)phenyl triflate 2a was investigated. Treating 1a with precursor 2a and 2 equiv of CsF in CH3CN at room temperature afforded the monoarylated product 6-deoxy-1,2:3,4-di-O-isopropylidene-6-N-phenylaminoα-D-galactopyranoside 3a in 90% isolated yield (Table 1, entry 1) within 2 h. Interestingly, when the amount of CsF was increased up to 3 equiv, the yield was similar (entry 2), while increasing the amount of aryne precursor (entries 3 and 5) or the reaction temperature (entry 4) gave lower yields mainly due to competing formation of di-N-arylated product. When the amount of 2a used (for entry 3 and 5) was 1 and 1.1 equiv, 4% and 16% of diN-arylated were obtained, respectively. Elevation of the temperature10p up to 60 °C (entry 4) yielded 22% of di-N-arylated product, while the choice of THF10r as the solvent was detrimental (entry 6). Using KF10e,m (entries 7−9) in the presence of 18-crown-6 (entries 7, 8) as the fluoride source proved to be less efficient and gave lower yields, while tetrabutylammonium fluoride (TBAF)10j gave yields comparable with those of CsF as a fluoride source (entries 10, 11). With optimized reaction conditions for the selective mono N-arylation of 1a with benzyne (Table 1), the amino sugar scope was investigated. A panel of furanose and pyranose structures with different protecting groups, both acid and base sensitive, were reacted under the optimized conditions to give the corresponding unsubstituted phenyl derivatives in good to high yields (Scheme 2). Noteworthy is the reaction sensitivity to the nitrogen nucleophilicity, this being reflected in the fact that amino sugars having electron-withdrawing groups (i.e., to give 3g, 3l, and 3m) reacted slowly with the benzyne, whereas electron-donating groups (i.e., to give 3h, 3i, and 3k) accelerated
he functionalization of carbohydrates is essential in the synthesis of glycomimetics,1 glycobiological2 studies, and natural product synthesis. While chemical O-functionalization of carbohydrates and glycoconjugates is central and extensively developed, N-functionalization is less developed despite the common occurrence of biologically active N-functionalized carbohydrate structures.3 Chemical modifications at aminosugar N-positions mainly involve N-acylation,4 alkylation,5 azidation,6 and Schiff base formation,7 while N-arylation8 has been sparingly studied. Nevertheless, carbohydrate N-arylation is of significant interest to carbohydrate sciences as the O/NH isosteric relationship can be used for structure−activity relationship investigations of protein−glycan interactions, solubility can be improved in a weakly basic N-analogue, and the extra valency of the N-analogue can be used to introduce additional affinity and/or selectivity, enhancing structural moieties into a protein-binding glycomimetic compound. A limited number of literature reports on carbohydrate N-arylation present varying yields and typically require a careful choice among a limited number of possible O-protecting groups. Metal-catalyzed C−N cross coupling with amino sugars requires a catalyst8 or elevated temperature9 (Scheme 1) Arynes10 are Scheme 1. Approaches To Introduce Aryl Functional Groups at Carbohydrate Amines
highly electrophilic in nature, and the highly strained carbon− carbon triple bond reacts rapidly with nucleophiles like alcohols,11 amines,12 amides,13 aldehydes,14 thiols,15 and carboxylic acids10,16 with a high sensitivity toward the nucleophilicity of the nucleophile. © XXXX American Chemical Society
Received: December 1, 2017
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DOI: 10.1021/acs.orglett.7b03741 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Table 1. Reaction Conditions Optimization of Mono-Nphenylation of 6-Amino-6-deoxy-1,2:3,4-di-Oisopropylidene-α-D-galactopyranose 1a
Scheme 2. Selective Mono-N-phenylation of Different Amino Sugars (1a−q) with 2aa
isolated yield (%) entry
F− source (equiv)
solvent
2a (equiv)
time (h)
3a
7a
1 2 3 4a 5 6 7 8 9 10 11
CsF (2) CsF (3) CsF (2) CsF (2) CsF (2) CsF (2) KF/18-Crown-6 (2) KF/18-Crown-6 (2) KF (2) TBAF (2) TBAF (2)
CH3CN CH3CN CH3CN CH3CN CH3CN THF THF CH3CN CH3CN CH3CN THF
0.98 0.98 1 0.98 1.1 0.98 0.98 0.98 0.98 0.98 0.98
2 4 2 1 2 12 24 24 24 4 4
90 94 80 45 65
