Nickel-Catalyzed Defluorinative Reductive Cross-Coupling of gem

Aug 29, 2017 - Taking into account the potential of developing new alkene .... As shown in Table 3, a variety of gem-difluoroalkenes with diverse synt...
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Nickel-Catalyzed Defluorinative Reductive Cross-Coupling of gemDifluoroalkenes with Unactivated Secondary and Tertiary Alkyl Halides Xi Lu, Yan Wang, Ben Zhang, Jing-Jing Pi, Xiao-Xu Wang, Tian-Jun Gong,* Bin Xiao, and Yao Fu* Hefei National Laboratory for Physical Sciences at the Microscale, CAS Key Laboratory of Urban Pollutant Conversion, Anhui Province Key Laboratory of Biomass Clean Energy, iChEM, University of Science and Technology of China, Hefei 230026, China S Supporting Information *

ABSTRACT: Herein, we described a nickel-catalyzed monofluoroalkenylation through defluorinative reductive cross-coupling of gem-difluoroalkenes with alkyl halides. Key to the success of this strategy is the combination of C− F cleavage with alkyl halides activation. This reaction enables the convenient synthesis of a large variety of functionalized monofluoroalkenes under mild reaction conditions with broad functional group compatibility and excellent Z-selectivity. The combination of Ni catalysis with (Bpin)2/K3PO4 as terminal reductant promoted the efficient C(sp2)−C(sp3) formation especially the generation of all-carbon quaternary centers with high chemoselectivity.

1. INTRODUCTION The incorporation of fluorine atoms or fluorine-containing fragments into organic compounds could bring about unique biological and physical properties; for instance, it could effectively control lipid solubility, metabolic stability, and binding properties to biological targets.1 In recent years, monofluoroalkenes have been extensively used in the fields of medicinal chemistry and drug-discovery as they are ideal amidebond mimics with enhanced peptidases stability and stable conformation.2 Among the strategies developed for the synthesis of monofluoroalkenes, cross-coupling of gem-difluoroalkenes with diverse carbon nucleophiles has proved to be an efficient and prevailing method.3 The groups of Loh as well as those of Li and Wang independently realized the synthesis of monofluoroalkenes with C(sp2)−C(sp2) formation via C−H/ C−F activation.4 Besides the combination with C−H activation, Toste reported the palladium-catalyzed coupling of gem-difluoroalkenes with aryl boronic acids.5 Despite these successes, the development of general methods for the synthesis of monofluoroalkenes with C(sp2)−C(sp3) forming under mild conditions with readily available reagents is still desirable. On the other hand, reductive cross-coupling reactions gained substantial attentions as the direct coupling of two electrophiles represents a useful tool for selective construction of a diverse range of C−C bonds exhibiting high operational simplicity with safe handling.6 Over the past few years, reductive crosscoupling reactions involving carbon−halogen, carbon−oxygen, or carbon−nitrogen bond cleavage have achieved great advancements.7 Most recently, Gong and co-workers reported mild nickel-catalyzed reaction conditions for the challenging reductive cross-coupling reactions involving tertiary alkyl halides which were recognized as isomerization-prone in cross-coupling process.7g,8 However, in such an active field, © 2017 American Chemical Society

cross-coupling involving tertiary alkyl halides still remain undeveloped, and there is a lack of C−F bond cleavage involved processes. Taking into account the potential of developing new alkene functionalization reactions7l,9 and synthesis of fluorinated olefins,10 we envisioned that reductive cross-coupling reaction could be applied to the fluorine chemistry taking advantage of the precise combination of gem-difluoroalkenes C−F cleavage and nickel-catalyzed alkyl halides activation. Herein, we report the first defluorinative reductive cross-coupling that combines sterically hindered secondary and tertiary alkyl halides with gem-difluoroalkenes, which allows C(sp2)−C(sp3) formation under mild conditions with functional group toleration and excellent Z-selectivity (Scheme 1).

2. RESULTS AND DISCUSSION We commenced the study with 1a and 2a as the model substrates (Table 1) and systematically screened the influence of all reaction parameters (See Table S1 for more details). A frequently used nickel-bipyridine-reductant system7l was tested first, and (Bpin)2/K3PO4 performed best among various reductants (entries 1−4). We screened bipyridine family ligands (entries 5−7) and made a critical finding that L4 (entry 7) increased the yield to 55%. Further improvements came from the use of Ni(COD)2 (entry 8) and addition of iodocyclohexane in two separated batches (entry 9); the GC yield was increased to 77% with an isolated yield of 74% for product 3aa. These findings encouraged us to further examine the reactivity of tertiary alkyl halides. Gratifyingly, under the slightly modified reaction conditions, the GC yield of product Received: June 21, 2017 Published: August 29, 2017 12632

DOI: 10.1021/jacs.7b06469 J. Am. Chem. Soc. 2017, 139, 12632−12637

Article

Journal of the American Chemical Society Table 2. Substrate Scope of Alkyl Halidesa

Scheme 1. Nickel-Catalyzed Defluorinative Reductive CrossCoupling

Table 1. Optimization of the Reaction Conditionsa

entry

nickel source

ligand

reductant

yield (%)b

1 2 3 4 5 6 7 8 9d 10e

NiBr2·diglyme NiBr2·diglyme NiBr2·diglyme NiBr2·diglyme NiBr2·diglyme NiBr2·diglyme NiBr2·diglyme Ni(COD)2 Ni(COD)2 Ni(COD)2

L1 L1 L1 L1 L2 L3 L4 L4 L4 L4

Zn Mn DEMS/Na2CO3 (Bpin)2/K3PO4 (Bpin)2/K3PO4 (Bpin)2/K3PO4 (BPin)2/K3PO4 (Bpin)2/K3PO4 (Bpin)2/K3PO4 (Bpin)2/K3PO4

10 17 23 37 44 3 55 64 77 (74)c 94 (92)c

a

Isolated yield for 0.2 mmol scale reaction. Reaction conditions are the same as those for Table 1, entries 9 and 10. PMP = p-methoxyphenyl. Bz = benzoyl. Boc = t-butoxycarbonyl. Ts = tosyl. Cbz = carbobenzyloxy. bYield based on starting material recovery. c10% NiBr2·diglyme, 15% 4,7-dimethoxy-1,10-phenanthroline, 3 equiv of (Bpin)2/K3PO4, and alkyl iodide (one batch) were used. d10% NiBr2· diglyme, 15% L4, 3 equiv of (Bpin)2/K3PO4 and alkyl bromide (one batch) were used.

a

r.t. = room temperature. DEMS = diethoxymethylsilane. Diglyme = 2-methoxyethyl ether. DMAc = N,N-dimethylacetamide. COD = cis,cis-1,5-cyclooctadiene. (Bpin)2 = bis(pinacolato)diboron. bGC yield. Triphenylmethane as internal standard. cIsolated yield. d Iodocyclohexane was added in two batches. e2-Bromo-2-methylpropane was added in three batches; 3 equiv of (Bpin)2/K3PO4 and 2bromo-2-methylpropane were used.

bility with many synthetically relevant functional groups such as ether (3ae), ester (3af), acetal (3ag), carbamate (3ah, 3ak), amide (3ai), and sulfonamide (3aj). Heterocycles such as thiophene (3al) also survived during the transformation. It should be pointed out that substrate 3am selectively underwent the defluorinative reductive cross-coupling reaction without any side reaction at the terminal alkene group. Moreover, the tolerance of aldehyde group (3an) demonstrated that this reaction offers important advantages over the cross-coupling of gem-difluoroalkenes with alkyl organometallic reagents (e.g., Grignard reagents and lithium reagents).11 Finally, with slightly modified reaction conditions, this reaction could also be applied to the transformation of primary alkyl iodides (3co, 3ap) and 1bromo-1,1-difluoroalkanes (3aq). The applicability of this reaction was further examined by evaluating the substrate scope of gem-difluoroalkenes. As shown in Table 3, a variety of gem-difluoroalkenes with diverse synthetic valuable functional groups successfully converted to the desired products. For instance, those relatively robust ones

3ac was found to be 94% (with a 92% isolated yield, entry 10). It should be pointed out that for the activation of tertiary alkyl halides (Bpin)2/K3PO4 exhibited much greater efficiency over other reductants such as Zn, Mn, or silane (see Table S2 for more details). With the optimized reaction conditions in hand, we sought to examine the scope of nickel-catalyzed defluorinative reductive cross-coupling reaction with a wide scope of unactivated secondary and tertiary alkyl halides. As shown in Table 2, these substrates could be converted to the desired products smoothly in all case of excellent Z-selectivity with modest to good isolated yields (40−92%). Both alkyl iodides (e.g., 3aa) and bromides (e.g., 3ac) could be transformed successfully; not only the cyclic (3ad) but also the acyclic (3ae) ones posed no problem. Under the mild reaction conditions, this reductive cross-coupling reaction showed good compati12633

DOI: 10.1021/jacs.7b06469 J. Am. Chem. Soc. 2017, 139, 12632−12637

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Journal of the American Chemical Society Table 3. Substrate Scope of gem-Difluoroalkenes.a

a

Isolated yield for 0.2 mmol scale reaction. Reaction conditions are the same as those for Table 1, entry 10. Ac = acetyl.

Scheme 2. Intramolecular Competitive Experimentsa

such as biphenyl structure (3be), ether (3cf and 3de), ester (3ee), fluoride (3ie), sulfonate (3je), and amine (3ne) were well-tolerated. This reaction could also conducted in the presence of some base-sensitive functional groups such as methyl ester (3ff), cyano group (3ge), and amide-possessing N−H bond (3hr). In addition, heterocycles such as dioxolane (3ke), furan (3le), dioxane (3me), pyridine (3oe), and benzothiophene (3pe) posed no problem during the crosscoupling process. An interesting substrate is 3qe, in which we observed a selective intermolecular cross-coupling with gemdifluoroalkene in the presence of an intramolecular terminal alkene group. To our delight, this reaction could even proceed smoothly in the presence of an acidic phenolic hydroxyl group (3rs, pKa ≈ 18, DMSO)12 which was sensitive to numerous alkyl organometallic reagents. Of note is that tetra-substituted gem-difluoroalkene (3se) could have been converted in this reaction with a satisfactory Z-selectivity, although further reaction conditions optimization was needed to improve the yield. Regarding to the chemoselectivity of this reaction, it exhibited that in the case of substrates with both tertiary and primary alkyl sites, the former are much more reactive.13 Thus, when 2s was treated with gem-difluoroalkene 1a (Scheme 2, eq 1), we observed only the carbon−carbon bond formation at the tertiary alkyl bromide, whereas the transformation at the primary alkyl sulfonate did not take place. The similar chemoselectivity was also found in substrate 2t with both tertiary alkyl bromide and primary alkyl bromide (Scheme 2, eq 2); the single product 3at was obtained. Moreover, in the intramolecular competitive experiments of tertiary with secondary alkyl sites, the generation of respective products 3au (Scheme 2, eq 3, tertiary alkyl bromide vs secondary alkyl sulfonate) and 3cv (Scheme 2, eq 4, tertiary alkyl bromide vs secondary alkyl bromide) further reflected the highly chemoselectivity of this reaction. In addition, the chemoselectivity of tertiary alkyl electrophiles over primary and secondary ones provided opportunities for further transformations through subsequent conventional cross-coupling reactions at the surviving primary and secondary alkyl sites. Finally, an intramolecular competitive experiment was carried out to

a Isolated yield for 0.2 mmol scale reaction. bYield based on starting material recovery. Reaction conditions are the same as those for Table 1, entry 10.

contrast the reactivity of aliphatic and aryl gem-difluoroalkene (Scheme 2, eq 5). The coupling of 1t with 2c under standard conditions gave 3tc as the single product with a satisfactory 93% yield, which demonstrated the toleration of aliphatic gemdifluoroalkene during the transformation. Notably, this reaction was also executed successfully on gram-scale, delivering 3ae with a slightly decreased 71% isolated yield (Scheme 3). Meanwhile, fluoroalkene 3ae could be conveniently converted to corresponding fluoroalkane 4 through hydrogenation (with 78% isolated yield). Moreover, another gram-scale reaction product 3oe which possesses a pyridine cycle could be readily modified through C−H functionalization reactions such as fluoroalkenylation reaction4b and cyanation reaction.14 12634

DOI: 10.1021/jacs.7b06469 J. Am. Chem. Soc. 2017, 139, 12632−12637

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Journal of the American Chemical Society

Suzuki coupling might be a possible explanation for this reaction. However, both the coupling of alkyl borate 8 with 1a (Scheme 4, eq 8) and the coupling of alkenyl borate 9 with 2c (Scheme 4, eq 9) did not provide the desired products, which ruled out the mechanism of in situ borylation and subsequent Suzuki coupling. (See the Supporting Information for more details and discussion.) With the above observations, we proposed a radical-type mechanism (Figure 1).18 In this mechanism, the reaction was

Scheme 3. Gram-Scale Reactions and Synthetic Applicationsa

a

Isolated yield. Nickel-catalyzed reaction conditions are the same as those for Table 1, entry 10. See the Supporting Information for more details.

To examine the mechanism of nickel-catalyzed reductive cross-coupling of gem-difluoroalkenes with alkyl halides, we tested the radical clock experiment (Scheme 4, eq 6) using ((2Figure 1. Proposed mechanism.

Scheme 4. Mechanistic Probesa

initiated with the formation of NiI−Ln complex (A), followed by the generation of Ln−NiI−Bpin species (B) through a borylation process.7h,19 Then, NiI species B undergoes single electron transfer to alkyl halide 2, leading to the cage of alkyl radical and NiII intermediate (C). Radical addition to gemdifluoroalkene 1 afforded cage D and subsequently gave intermediate E via single electron transfer. Finally, desired product 3 was obtained with a β-F elimination process. Formed NiIII species F was reduced to the initial NiI−Ln complex (A) to finish the catalytic cycle. The excellent Z-selectivity might be caused by the formation of intermediate E.20 We exploited the synthetic application of this reaction for the modification of nature products (Scheme 5). As an example, hydroxyproline derivative 2x, which contained both carbamate and ester groups, performed well in the modification process (Scheme 5, eq 10). Another example, fructose derivative 1u reacted with alkyl bromide 2s smoothly to afford 3us, while tolerating both the sulfonate and ketal groups (Scheme 5, eq 11). Finally, we used this defluorinative reductive cross-coupling as an efficient tool for the synthesis of drug molecular analogues (Scheme 6). The coupling of gem-difluoroalkene 1v with alkyl iodide 2h resulted in the formation of monofluoroalkene 3vh with a 55% isolated yield. Through two more steps (i.e., deprotection and aromatic nucleophilic substitution), target pharmaceutical molecule 11 was made in 77% overall yield. Furthermore, LIM-kinase inhibitor mimic 3vy could be directly prepared through the coupling of 1v with complex alkyl bromide 2y in a satisfactory 43% yield.21

a Reactions were carried out on 0.2 mmol scale. See the Supporting Information for more details. Ar = 3,4-dimethoxy-phenyl.

iodohept-6-en-1-yl)oxy)benzene (2w). We obtained only ringcyclized product 3aw′ in 24% isolated yield, which revealed the involvement of radical cyclization process.15 In addition, gemdifluoroalkane 7 was also subjected to the standard reaction conditions; desired product 3aa was not observed with 90% starting material recovery which could rule out the pathway of radical addition followed by sequential protonolysis and basemediated β-F elimination (Scheme 4, eq 7).5 Previously, Fu13a,16 reported the elegant nickel-catalyzed borylation of unactivated alkyl halides, and most recently Cao17 reported the stereoselective borylation of gem-difluoroalkenes. Thus, in suit

3. CONCLUSION We developed a nickel-catalyzed defluorinative reductive crosscoupling of gem-difluoroalkenes with sterically hindered secondary and tertiary alkyl halides involving C−F cleavage 12635

DOI: 10.1021/jacs.7b06469 J. Am. Chem. Soc. 2017, 139, 12632−12637

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Journal of the American Chemical Society Scheme 5. Synthetic Applications in Nature Productsa

temperature for 1 h. Then, the second batch of secondary alkyl halide (1.0 equiv) was added and stirred at room temperature for 15 h. The mixture was purified by column chromatography to afford the desired monofluoroalkene. Z/E ratio was determined by 1H and 19F NMR.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/jacs.7b06469. Detailed experimental procedures and spectra data for all compounds(PDF)

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AUTHOR INFORMATION

Corresponding Authors

*[email protected] *[email protected] ORCID a

Xi Lu: 0000-0002-9338-0780 Tian-Jun Gong: 0000-0001-5484-8531 Bin Xiao: 0000-0002-1200-6819 Yao Fu: 0000-0003-2282-4839

Reactions were carried out on 0.2 mmol scale. Reaction conditions are the same as those for Table 1, entries 9 and 10.

Scheme 6. Synthesis of LIM-Kinase Inhibitor Mimicsa

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are grateful for the support from National Natural Science Foundation of China (21325208, 21572212, 21502184, 21732006, 21702200), Ministry of Science and Technology of China (2017YFA0303500), Chinese Academy of Science (XDB20000000), Key Technologies R&D Programme of Anhui Province (1604a0702027), FRFCU, and PCSIRT. X.L. is grateful for the grants from China Postdoctoral Science Foundation (2016M600482 and 2017T100448).

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REFERENCES

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a

Isolated yield. Nickel-catalyzed reaction conditions are the same as those for Table 1, entries 9 and 10. See the Supporting Information for more details.

process. The present reaction provided convenient and efficient access to a large variety of functionalized monofluoroalkenes under mild reaction conditions which exhibited good functional groups compatibility with excellent Z-selectivity.22 The utilization of (Bpin)2/K3PO4 as final reductant promoted the successful construction of all-carbon quaternary centers with high chemoselectivity. Moreover, the present reaction would add new example for both fluorine chemistry and reductive cross-coupling reactions. Our next challenge is to develop the asymmetric version of this defluorinative reductive crosscoupling reaction.

4. EXPERIMENTAL SECTION 4.1. General Procedure A for Secondary Alkyl Halide Substrates. Ni(COD)2 (10 mol %), L4 (15 mol %), (Bpin)2 (2.0 equiv), and K3PO4 (2.0 equiv) were added to a Schlenk tube equipped with a stir bar. The Schlenk tube was evacuated and filled with argon (three cycles). To these solids, DMAc (0.2 M) was added under argon atmosphere. The reaction mixture was stirred at room temperature for 30 s. Next, the secondary alkyl halide (1.0 equiv) was added under a positive flow of argon and stirred at room temperature for another 30 s. The gem-difluoroalkene (1.0 equiv) was added and stirred at room 12636

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Zhang, Y.; Stouch, T. R.; Whitlock, N. A.; Gopinathan, S.; McKnight, B.; Wang, S.; Patel, N.; Wilson, A. G. E.; Hamman, B. D.; Rice, D. S.; Rawlins, D. B. ACS Med. Chem. Lett. 2015, 6, 84. (22) Alkynyl gem-difluoroalkene could have been converted in our reaction. For more details, see the Supporting Information.

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