Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Synthesis of Alkylated Monofluoroalkenes via Fe-Catalyzed Defluorinative Cross-Coupling of Donor Alkenes with gemDifluoroalkenes Ling Yang,‡ Wei-Wei Ji,‡ E Lin, Ji-Lin Li, Wen-Xin Fan, Qingjiang Li, and Honggen Wang* School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China S Supporting Information *
ABSTRACT: A reductive cross-coupling of gem-difluoroalkenes with diverse unactivated and heteroatom substituted olefins through a Fe-catalyzed hydrogen atom transfer (HAT) strategy is reported. Different from the previous HAT-type olefin crosscoupling reactions, the presence of a fluorine atom in the molecule results in a stereoselective β-F cleavage, leading to a C(sp2)−C(sp3) bond formation. A wide variety of alkylated monofluoroalkenes were obtained in good efficiency with excellent Z selectivity under air- and water-tolerant reaction conditions. A similar defluorinative coupling reaction of monofluoroalkenes was also realized.
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Scheme 1. Toward the Synthesis of Alkylated Monofluoroalkenes Starting from gem-Difluoroalkenes
onofluoroalkenes have found tremendous applications in medicinal chemistry, acting as peptide bond isosteres due to their ability to confer desired properties, such as higher metabolic and conformational stability, increased lipophilicity, and sometimes, better recognition.1 They can also serve as fluorinated synthons for organofluorine synthesis.2 Despite their great potential, only limited methods are available for their synthesis, and often a mixture of E/Z stereoisomers are obtained.3 There is therefore a great demand to develop a general and stereoselective method starting from readily available starting materials. gem-Difluoroalkenes are easily accessible2 and have emerged as an appealing class of synthetic intermediates to effect diverse C−C and C−X bond formation.2,4 Due to the profound electronegativity of fluorine atom and the repulsion effect from its lone-pair electrons, the C−C double bond is highly polarized.5 Therefore, it is not surprising that gem-difluoroalkenes can be attacked by diverse nucleophiles under basic conditions to give the α-substituted fluoroalkenes via an addition−elimination pathway.6 Recently, with the aid of a transition-metal catalyst, the defluorinative cross-coupling reactions toward the C(sp2)−C(sp2),7 C(sp2)− B,8 C(sp2)−Si,8b,9 and C(sp2)−H10 formation enriches the toolbox for monofluoroalkene synthesis. Nevertheless, the stereoselective C(sp2)−C(sp3) bond coupling, namely defluorinative alkylation, is still challenging. In this regard, Cao developed a copper-catalyzed cross-coupling of gem-difluoroalkenes with Grignard reagents (Scheme 1a).11 The use of strong nucleophile largely limits the functional group compatibility. Hashmi reported an elegant photocatalytic monofluoroalkenylation of alkyl amino compounds via dual C(sp3)−H/C(sp2)−F bond cleavages, but with moderate E/Z ratios being obtained (Scheme 1b).12 Fu recently extended this protocol by using α-amino acids as the alkyl sources.13 By using a reductive cross coupling strategy, Fu and Gong fulfilled efficient nickel-catalyzed coupling reactions of gem-difluoroalkenes with secondary and tertiary alkyl halides (Scheme 1c).14 © XXXX American Chemical Society
Recently, the catalytic hydrogen atom transfer (HAT) reaction wherein an earth-abundant metal such as Fe, Mn, or Co in combination of a hydrogen source promotes the hydrofunctionalization of alkenes has become an attractive strategy in organic synthesis.15 Advantages such as good regioselectivity and broad functional group tolerance are noteworthy. In particular, the strategy is well suited for the construction of quaternary carbon centers due to the ease and mildness of formation of tertiary alkyl radicals and their efficient engagement in radical reactions.16 In continuation of our interest in organofluorine synthesis by uncovering the reactivity Received: February 8, 2018
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DOI: 10.1021/acs.orglett.8b00471 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Scheme 2. Substrate Scope of Donor Alkenesa
of gem-difluoroalkenes,7a,b,8b we envisioned the electron-rich alkyl radical I, generated via HAT from olefin, might regioselectively add to the double bond of gem-difluoroalkenes (Scheme 1d). Thereafter, the one-electron reduction of the newly formed radical II would result in an anion III. In the previous olefin cross-coupling reactions, this anion was found to be protonated by the solvent.15d,17 We reasoned the presence of a β fluorine atom in the adduct might trigger a β-F elimination, leading to an alkylated monofluoroalkene. Herein, we report an iron-cataylzed coupling reaction of a series of “donor” alkenes with gem-difluoroalkenes as acceptor via HAT strategy. The protocol offers an unprecedented opportunity for the synthesis of structurally diverse alkyl monofluoroalkenes, including fluorinated allyl alcohol and amine derivatives, with excellent Z-selectivity under air- and water-tolerant reaction conditions. We commenced the study by investigating the reaction of gem-difluoroalkene 1a with vinyl acetate 2a (Table 1). An initial Table 1. Optimization of the Reaction Conditionsa
entry
catalyst (10 mol %)
hydrogen source
solvent (0.2 M)
temp (°C)
yieldb (%)
1 2 3 4 5 6 7 8 9 10 11c 12 13
Fe(dibm)3 Fe(acac)3 Co(dibm)2 Fe(dibm)3 Fe(dibm)3 Fe(dibm)3 Fe(dibm)3 Fe(dibm)3 Fe(dibm)3 Fe(dibm)3 Fe(dibm)3 Fe(dibm)3 Fe(dibm)3
PhSiH3 PhSiH3 PhSiH3 Ph3SiH Et3SiH Et2MeSiH NaBH4 PhSiH3 PhSiH3 PhSiH3 PhSiH3 PhSiH3 PhSiH3
EtOH EtOH EtOH EtOH EtOH EtOH EtOH DCE THF i-PrOH EtOH EtOH EtOH
60 60 60 60 60 60 60 60 60 60 60 40 80
32 28 trace trace trace trace trace trace 12 26 62 29 28
a
Conditions: 1 (0.4 mmol, 1.0 equiv), 2 (1.2 mmol, 3.0 equiv), Fe(dibm)3 (10 mol %), PhSiH3 (6.0 equiv), EtOH (2.0 mL), 60 ̊C, under air, 18 h. bPhSiH3 was added in two portions. c1 mmol scale.
be used, although decreased yields were found (3gc and 3ad). Endocyclic enol ethers could also be coupled (3ae−ag), as highlighted by the efficient reaction of glucose derived olefin with 1a, leading to a C-glycoside (3ah) in good yield with excellent Z/E selectivity and diastereoselectivity. Additionally, enecarbamates could undergo reaction efficiently, thus allowing a facile synthesis of fluorinated allyl amine derivative (3ai, 3aj). The reaction of vinyl thioether was effective (3ak). Not surprisingly, 1,1-disubstituted donor olefins were competent coupling partners, leading to the alkylated products (3al−aq) with an all-carbon quaternary center. However, while the use of terminal alkyl olefin did give the desired product 3ar, the use of styrene only delivered the reductive homodimerization product, probably due to the high stability of the resulting benzyl radical, which leads to the radical addition to gem-difluoroalkene less favored. The substrate scope on the gem-difluoroalkene part was also investigated (Scheme 3). It was found that a series of para(3bb−hb), meta- (3ib−nb), and ortho-substituted (3ob and 3pb) substrates were applicable to the reaction. In general, aryl gem-difluoroalkenes bearing electron-withdrawing substituent showed better reactivity. This tendency is in contrast to the nickel-catalyzed defluorinative reductive cross-coupling reaction, wherein alkyl radical was proposed to be involved as an intermediate, but electron-rich aryl gem-difluoroalkenes were better acceptors.14 Thus, substituents, such as ester (3bb and 3 lb), CF3 (3cb and 3jb), amide (3eb), cyano (3aa, and 3ib), fluoro (3nb), chloro (3kb and 3ob), and bromo (3mb and 3pb), gave the corresponding products in moderate to good yields. The reaction of biphenyl (3db), 4-(tert-butyl)phenyl
a
Conditions: 1a (0.2 mmol, 1.0 equiv), 2a (0.3 mmol, 3.0 equiv). The yield was determined by 1H NMR using p-iodoanisole as internal standard. cPhSiH3 (6.0 equiv) was used; isolated yields. b
survey demonstrated the use of Fe(dibm)3 (10 mol %, dibm, diisobutyrylmethane) as catalyst; PhSiH3 (3.0 equiv) as hydrogen source in EtOH at 60 °C under air gave the desired product 3aa as a single Z stereoisomer in 31% yield (entry 1). The use of other iron- or cobalt-based catalysts led to lower yields (entries 2 and 3). PhSiH3 was found to be critical, as other hydrogen sources, such as Ph3SiH, Et3SiH, Et2MeSiH, or NaBH4, showed almost no reactivity (entries 4−7). The screening of solvents demonstrated that original EtOH was the best of choice (entries 8−10). To our delight, by doubling the loading of PhSiH3 to 6 equiv, the yield could be significantly increased to 62% (entry 11). Of note, PhSiH3 was completely consumed after the reaction as detected by GC−MS, and a significant amount of PhSi(OEt)3 was formed. The increase of temperature was unproductive (entries 12 and 13). With the optimized conditions in hand, we sought to exam the scope of reaction by employing a wide variety of donor olefins (Scheme 2). It was found that in addition to vinyl ester (3aa), aryl vinyl ether was also compatible with the reaction conditions (3ab). Remarkably, the silyl enol ethers could also B
DOI: 10.1021/acs.orglett.8b00471 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Scheme 3. Substrate Scope of gem-Difluoroalkenesa
indicate that hydrogen atom transfer from PhSiH3 to the donor olefin was involved. In addition, the reaction was completely inhibited by radical scavenger TEMPO (Scheme 4c). Furthermore, the coupling of diallyl amide gave a cyclized product 3as (Scheme 4d). Therefore, a radical-based process might be involved in the mechanism. In all, the above observations are consistent with the mechanism depicted in Scheme 1d. Synthetic transformations were performed to showcase the utility of the product (Scheme 5). The acetyl group in 3aa Scheme 5. Synthetic Transformations of the Products
a
Conditions: 1 (0.4 mmol, 1.0 equiv), 2 (1.2 mmol, 3.0 equiv), Fe(dibm)3 (10 mol %), PhSiH3 (6.0 equiv), EtOH (2.0 mL), under air, 60 ̊C, 18 h. bPhSiH3 was added in two portions.
(3fb), 4-methyloxy (3gb), and 4-methyl sulfide (3hb) gemdifluoroalkenes, however, gave lower yields. The above success supports our hypothesis that the β-F elimination, rather than the protonation, is a favored process (Scheme 1d). Thus, the use of monofluoroalkene as acceptor might offer a new opportunity to access alkyl-substituted alkenes. Indeed, we found that the reaction of (Z)-4a with 2,3dihydrofuran under the standard conditions delivered the defluorinative alkylation product in 48% yield as a single E isomer (eq 1). Interestingly, the reaction of either (E)-4b or (Z)-4b gave the same isomeric product 5bb (eq 2), implicating the reaction is not stereospecific, and the same reaction intermediate was involved.
could be easily hydrolyzed under acidic conditions to give a 2fluoroallylic alcohol 6, which proved to be a useful intermediate for diverse transformations. For instance, a copper-catalyzed nucleophilic displacement gave a 2-fluoroallyic azide 7.18 The free alcohol could be oxidized to a fluorinated α,β-unsaturated ketone 8 in good yield with MnO2. With a copper-catalyzed dehydration reaction, the fluorinated 1,3-butadiene 9 could be efficiently obtained. Finally, an Appel reaction converted the alcohol to the corresponding bromide 10. In summary, with an iron-catalyzed hydrogen atom transfer (HAT) strategy, we realized an efficient defluorinative crosscoupling of diverse donor alkenes with gem-difluoroalkenes. The protocol provided a wide variety of alkylated monofluoroalkenes, including fluorinated allyl alcohol and amine derivatives, with excellent Z-selectivity under air- and watertolerant reaction conditions. By following a similar protocol, the coupling reactions of donor alkenes with monofluoroalkenes to give alkylated alkenes were also demonstrated. The product obtained could be transformed to structurally diverse fluorinecontaining molecules. Mechanistic studies were conducted, and a tentative reaction mechanism has been proposed.
To gain more mechanistic insight into the reaction, experimental studies were conducted. The use of PhSiD3 instead of PhSiH3 resulted in the formation of a deuterated adduct (Scheme 4a), whereas the use of EtOD or CD3CD2OD led to no deuterium incorporation (Scheme 4b). These results
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Scheme 4. Mechanistic Studies
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b00471. Experimental procedures and full analytical data (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Qingjiang Li: 0000-0001-5535-6993 Honggen Wang: 0000-0002-9648-6759 Author Contributions ‡
L.Y. and W.-W.J. contributed equally.
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DOI: 10.1021/acs.orglett.8b00471 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Notes
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The authors declare no competing financial interest.
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ACKNOWLEDGMENTS Generous financial support from the Key Project of Chinese National Programs for Fundamental Research and Development (2016YFA0602900), the National Natural Science Foundation of China (21472250), and the “1000-Youth Talents Plan” are gratefully acknowledged.
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DOI: 10.1021/acs.orglett.8b00471 Org. Lett. XXXX, XXX, XXX−XXX
