Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Organocatalytic Nucleophilic Substitution Reaction of gemDifluoroalkenes with Ketene Silyl Acetals Azusa Kondoh,‡ Kazumi Koda,† and Masahiro Terada*,† †
Department of Chemistry, Graduate School of Science, Tohoku University, Aoba-ku, Sendai 980-8578, Japan Research and Analytical Center for Giant Molecules, Graduate School of Science, Tohoku University, Aoba-ku, Sendai 980-8578, Japan
‡
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ABSTRACT: An organocatalytic nucleophilic substitution reaction of gem-difluoroalkenes with ketene silyl acetals was developed. Phosphazene P4-tBu effectively catalyzed the reaction under mild conditions to provide monofluoroalkenes possessing an alkoxycarbonylmethyl group in high yields with high Z selectivities.
O
Scheme 1. Organocatalytic Nucleophilic Substitution Reaction of gem-Difluoroalkenes with Ketene Silyl Acetals
rganofluorine molecules are one of the privileged classes of molecules used in various research fields due to the distinctive properties of the fluorine atom.1 In particular, monofluoroalkenes are valuable as peptide bond isosteres possessing higher metabolic and conformational stability and increased lipophilicity in medicinal chemistry.2 They can also serve as fluorinated synthons in organic synthesis.3 Thus, considerable effort has been devoted to the development of efficient methods for the synthesis of monofluoroalkenes.4 One of the most general methodologies is the C−F functionalization of readily available gem-difluoroalkenes. A conventional approach based on this methodology is the nucleophilic substitution reaction using organometallic reagents, such as organolithium reagents and Grignard reagents, or anionic nucleophiles generated by using a stoichiometric amount of a Brønsted base, which proceeds through an addition−βelimination mechanism.5,6 In addition, transition-metal catalysis as well as photocatalysis have emerged as powerful tools for the C−F functionalization of gem-difluoroalkenes, and various types of reactions have been developed so far.7−9 Nevertheless, there still remains the issue of the limitation of scope of functional groups that can be directly introduced to the alkene moiety. Therefore, the development of a new reaction system that enables the expansion of the scope of introducible functional groups is highly anticipated. In this context, we envisioned the development of a new nucleophilic substitution reaction of gem-difluoroalkenes with silylated pronucleophiles, particularly ketene silyl acetals, by use of an organobase catalyst. Our reaction design is shown in Scheme 1. Ketene silyl acetal 2 is activated with the aid of an organobase catalyst to generate ester enolate A, which is the initiation step of the reaction.10 Subsequently, nucleophilic addition of the resulting enolate A to gem-difluoroalkene 1 followed by the βelimination of fluoride from B provides the desired product 3 along with a generated fluoride.11 The fluoride then directly © XXXX American Chemical Society
activates ketene silyl acetal 2, completing the catalytic cycle. Whereas catalytic SNAr reactions of silylated pronucleophiles with fluoroarenes, where the eliminated fluoride is utilized for the catalyst turnover, have been reported,12 the related catalytic substitution reaction of gem-difluoroalkenes is rare.13 Herein, we report that phosphazene P4-tBu effectively catalyzes the reaction under mild conditions to provide monofluoroalkenes possessing an alkoxycarbonylmethyl group in high yields with high Z selectivities. Our investigation commenced with a screening for the reaction conditions using gem-difluoroalkene 1a having a 2naphthyl group as the substrate and ketene silyl acetal 2a (Table 1). The initial experiment involved treatment of 1a with 2a in the presence of 10 mol % P4-tBu, which was previously utilized as an activator of silylated pronucleophiles in a catalytic SNAr reaction,12c,13 in toluene. As a result, desired product 3aa was obtained in high yield (entry 1).14 In addition, the reaction proceeded in a highly stereoselective manner, and Received: February 13, 2019
A
DOI: 10.1021/acs.orglett.9b00566 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Table 1. Screening for Reaction Conditionsa
Table 2. Scope of gem-Difluoroalkene 1a
yieldb (%) c
1a 0 76 86 38 36 0 0 27 7
entry
base
solvent
3aa
Z/E
1 2 3 4 5 6 7 8 9
P4-tBu P2-tBu P1-tBu iBu-PAP TBAF P4-tBu P4-tBu P4-tBu P4-tBu
toluene toluene toluene toluene toluene Et2O THF CH3CN DMF
96 (96) 3 0 42 57 78 72 40 60
98/2
95/5 94/6 98/2 98/2 98/2 97/3
entry
1
R1, R2
3
yieldb (%)
1 2 3 4 5 6e 7e 8e 9e 10 11e 12f
1b 1c 1d 1e 1f 1g 1h 1i 1j 1k 1l 1m
4-Br-C6H4, H 4-F3C-C6H4, H 4-NC-C6H4, H 4-MeO2C-C6H4, H 4-MeO-C6H4, H 3-F-C6H4, H 2-Cl-C6H4, H 1-naphthyl, H 2-thienyl, H 2-benzofuryl, H Ph, Ph Ph, OP(O)(OMe)2
3ba 3ca 3da 3ea 3fa 3ga 3ha 3ia 3ja 3ka 3la 3ma
84 81 80 72 89d 83 91 87 84 83 95 87
a
Reaction conditions: 1a (0.10 mmol), 2a (0.11 mmol), base (0.010 mmol), solvent (1.0 mL), rt, 13 h. bYields were determined by 1H NMR analysis of the crude mixture. Dibenzyl ether was used as the internal standard. Isolated yield is shown in parentheses. cDetermined by 1H NMR analysis of the crude mixture.
Z/Ec 99/1 99/1 >99/1 >99/1 83/17 98/2 97/3 96/4 95/5 99/1 1/>99g
a
Reaction conditions: 1 (0.10 mmol), 2a (0.11 mmol), P4-tBu (0.010 mmol), toluene (1.0 mL), rt, 13 h. bIsolated yield of major isomer unless otherwise noted. cDetermined by 1H NMR analysis of the crude mixture. dIsolated yield of a mixture of isomers. e2.0 equiv of 2a (0.20 mmol) was used. fReaction was performed with 2.0 equiv of 2a (0.20 mmol) at −40 °C. gEstimated on the basis of experimental evidence and DFT calculations. See the SI for details.
Z-isomer was obtained as the major isomer. 15 Other phosphazenes, such as P2-tBu and P1-tBu, did not catalyze the reaction, suggesting the basicity of phosphazenes was important (entries 2 and 3). Proazaphosphatrane (iBu-PAP), which was also utilized in the catalytic SNAr reaction12d and the catalytic Mukaiyama aldol reaction with ketene silyl acetal,16 was then tested (entry 4). In this case, the reaction proceeded, but the yield of the product was moderate. Furthermore, the Z selectivity was slightly decreased. Tetrabutylammonium fluoride (TBAF) was also examined and found to be less effective than P4-tBu (entry 5). These results imply that a countercation of anionic species formed in situ, such as an enolate, a benzyl anion, and a fluoride, is influential on both catalyst turnover and stereoselectivity. The solvent effect was then investigated (entries 1 and 6−9). As a result, less polar solvents were suitable for this reaction, and toluene was the solvent of choice (entry 1). With the optimized reaction conditions in hand, the scope of gem-difluoroalkenes was investigated (Table 2). In this reaction, a variety of monoaryl-substituted substrates were applicable. In the case of substrates having an electronwithdrawing group at the para-position of the aryl group, the reaction proceeded smoothly to provide the corresponding products in good yields with almost perfect Z selectivities (entries 1−4). In contrast, in the case of 1f having an electrondonating methoxy group at the para-position, the Z selectivity was decreased (entry 5). We assume that generation of more stabilized benzyl anion intermediate (B in Scheme 1) would facilitate the β-elimination of fluoride to provide thermodynamically favorable (Z)-product with higher selectivity. 3Fluorophenyl- and 2-chlorophenyl-substituted 1g and 1h underwent the reaction without any problem to provide the corresponding 3ga and 3ha in good yields with high Z selectivities (entries 6 and 7). Owing to the mildness of the reaction conditions, a wide range of functional groups on the aryl group, such as halo, trifluoromethyl, methoxycarbonyl, and cyano groups, were compatible. The reaction of heteroarylsubstituted 1j and 1k also proceeded smoothly to afford 3ja and 3ka, respectively. However, alkyl-substituted substrates
were not suitable for this reaction, and a complex mixture was obtained. In this reaction, diphenyl-substituted 1l was also applicable, and corresponding 3la was obtained in high yield (entry 11). Furthermore, alkenylphosphate 1m provided corresponding 3ma in high yield as a single isomer (entry 12). Next, the scope of ketene silyl acetals was examined (Scheme 2). Dialkyl-substituted 2b provided 3ab in moderate Scheme 2. Scope of Ketene Silyl Acetals 2
yield with high Z selectivity. The reaction of phenoxysubstituted 2c also proceeded to provide 3ac. Monosubstituted 2d was also tested, but the desired product was formed only in low yield (
