Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Synthesis of α‑Fluorinated Imides via Direct Fluorohydroxylation of Ynamides Ji-Lin Li, E. Lin, Xiang-Lei Han, Qingjiang Li,* and Honggen Wang* Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
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ABSTRACT: A practical synthesis of α-fluorinated imides via the catalyst-free fluorohydroxylation of ynamides is developed. The reaction employs commercially available Selectfluor (F-TEDA-BF4) and H2O as the fluorine and hydroxyl sources, respectively. A broad range of aryl- or alkyl-substituted ynamides were well applicable to the reaction with good functional group tolerance under simple and mild reaction conditions. The synthetic utility of the α-fluoroimide products was demonstrated by several value-added transformations. Preliminary mechanistic studies were conducted.
T
ylation of alkynes under mild reaction conditions. The poor regioselectivity observed when electronically unbiased alkynes were used represents a major limitation. With the aid of a preinstalled carbonyl or hydroxyl directing group, the regioselective fluorohydroxylation of alkynes was feasible under silver catalysis2e,f or catalyst-free conditions.2g Interestingly, Zupan found that 1-phenyl-substituted acetylenes could react directly with Selectfluor and H2O in refluxing acetonitrile, but the reaction delivered α,α-difluoro ketone products predominantly (Scheme 1b).5 We reasoned that ynamides,6 a type of readily accessible unsaturated system with a protected nitrogen atom directly attached to the carbon−carbon triple bond, may be intriguing substrates toward fluorohydroxylation, thereby leading to αfluorinated imide products. First, ynamides are generally more electron rich than typical alkynes, which should confer increased reactivity when electrophilic F+ sources7 are employed. Second, the bias of electron distribution on the triple bond should render a high level of regioselectivity. Third, overfluorination, a potential side reaction as observed by Zupan,5 may be suppressed due to the reluctance of initially formed αfluorinated amides to undergo enolization compared to their ketone counterparts. Previously, the reaction of ynamides with nucleophilic F− sources mainly led to hydrofluorination products (Scheme 1c).8 In conjunction with our continuing interest in the new chemistry of a heteroatom-activated unsaturated system,9,10 herein, we report a regioselective fluorohydroxylation of ynamides by using Selectfluor and H2O as the fluorine and hydroxyl sources, respectively (Scheme 1d). The high reactivity of ynamides in this chemistry eliminates the use of catalyst, thereby offering an operationally simple and efficient route to α-fluoroimide products.8a,11 Not only aryl ynamides but also alkyl ynamides are applicable to the reaction.
he difunctionalization of alkynes by simultaneous introduction of two functional groups into a molecule represents an attractive synthetic tool in complex molecule synthesis.1 In this respect, the 1,2-fluorohydroxylation of alkynes allows a convenient route to α-fluorinated carbonyl compounds,2 which can serve as valuable building blocks for organofluorine synthesis3 and themselves are useful in medicinal chemistry (Scheme 1a).4 In this respect, elegant independent works from Nevado2a and Xu and Hammond2b−d showed that gold is an effective catalyst to promote the 1,2-fluorohydroxScheme 1. Bioactive α-Fluorinated Carbonyl Compounds and Fluorination of Alkynes
Received: April 24, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01428 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
of varying amounts of H2O all led to inferior results (entries 14 and 15). Finally, the attempt to suppress the formation of 3a by using steric hindered base 2,6-di-tert-butylpyridine was unexpectedly unsuccessful (entry 16). With the optimized reaction conditions established (Table 1, entry 3), we next investigated the substrate scope of the reaction. The effect of R1 substituent on the triple bond was first examined (Scheme 2). For aryl-substituted ynamides, a number of
The imide functionality in the product serves as a valuable handle for further transformations. Classically, the α-fluoroamide products could be accessed via electrophilic fluorination of amides under drastic reaction conditions11a−e or nucleophilic fluorination of amides by using an Umpolung strategy.12 Initially, the direct 1,2-fluorohydroxylation of N-methyl-N(phenylethynyl)methanesulfonamide (1a) with Selectfluor (2.0 equiv) and H2O (5.0 equiv) was studied. Under the catalysis of π-acidic PPh3AuCl or Lewis acid Zn(OTf)2 in acetonitrile at 60 °C for 3 h, the desired 1,2-fluorohydroxylation product 2a was formed in moderate yield. The direct hydration product 3a was detected as the minor side product, and no overfluorination product was detected (Table 1, entries 1 and 2). Surprisingly,
Scheme 2. Substrate Scope on R1
Table 1. Optimization of Reaction Conditionsa
yield (%) entry
F
catalyst (10 mol %)
solvent
2a
3ab
1 2 3 4 5 6 7 8 9 10c 11d 12e 13f 14g 15h 16i
Selectfluor Selectfluor Selectfluor Selectfluor II NFSI FTMP-OTfc Selectfluor Selectfluor Selectfluor Selectfluor Selectfluor Selectfluor Selectfluor Selectfluor Selectfluor Selectfluor
PPh3AuCl Zn(OTf)2
MeCN MeCN MeCN MeCN MeCN MeCN THF DCE PhMe MeCN MeCN MeCN MeCN MeCN MeCN MeCN
54 62 73 68 8 trace 8 6 5 44 60 74
