Synlett 2021; 32(15): 1525-1530
DOI: 10.1055/s-0040-1706013
cluster
Modern Nickel-Catalyzed Reactions

Nickel-Catalyzed Cross-Electrophile Coupling of the Difluoromethyl Group for Fluorinated Cyclopropane Synthesis

,
Tristan M. McGinnis
,
,
Financial support from the Center for Scientific Review (NIH NIGMS R01GM100212) is gratefully acknowledged.
 


Abstract

Herein, we report a new strategy for fluorinated cyclopropane synthesis. Photocatalytic olefin difluoromethylation is coupled with a nickel-catalyzed intramolecular cross-electrophile coupling (XEC) reaction between a difluoromethyl moiety and a benzylic ether. To the best of our knowledge, this is the first example of a XEC reaction employing a difluoromethyl group as an electrophile. A plausible mechanism is highlighted, and DFT calculations are included to support the observed stereochemical outcome.


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Both cyclopropanes and fluorine atoms are frequently employed in medicinal chemistry to modify chemical, physical, and biological properties of drug candidates.[3] Fluo­rinated cyclopropanes are gaining attention as relevant building blocks in pharmaceutical design, as they combine the unique chemical and structural features of the two independent functional groups. For example, these moieties are present in medicinal agents bearing activity against several different indications, including depression, cancer, and bacterial infections (Scheme [1a]).[3] [4] [5] In the design of Zosuquidar, the fluorocyclopropane motif was installed to improve oral bioavailability by increasing chemical stability under acidic conditions.[5]

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Scheme 1 Synthesis and applications of fluorinated cyclopropanes

Due to the utility of fluorinated cyclopropanes in drug design, methods for the synthesis of these moieties are beginning to be developed (Scheme [1b]).[3] Two prominent approaches include addition of carbenes to fluoroalkenes and addition of fluorocarbenes to alkenes, both of which employ highly reactive diazo compounds or carbenoid equivalents.[3] [6] We envisioned a new strategy that would couple emerging methods in introduction of difluoromethyl groups[7] with an intramolecular cross-electrophile coupling (XEC) reaction (Scheme [1c]). Building upon our laboratory’s previously reported nickel-catalyzed XEC reaction of alkyl fluorides for cyclopropane synthesis, we conceived that a difluoromethyl group could be employed as an electrophile in a related XEC reaction for fluorinated cyclopropane synthesis.[8] The notion of engaging the carbon–fluorine bond of a difluoromethyl group in a XEC reaction presents a notable challenge: the strength of the C–F bond increases with each additional fluorine atom attached to the central carbon atom due to increased electrostatic forces.[9] This work describes a new approach for fluorinated cyclopropane synthesis, wherein the photocatalytic difluoromethylation of olefins is paired with a nickel-catalyzed intramolecular XEC reaction between benzylic ethers and difluoromethyl groups. Furthermore, the basis for the stereochemical outcome and a proposed mechanism of the XEC reaction are highlighted.

Owing to the importance of fluorinated compounds in drug development, chemists have spent the past several decades designing creative approaches for the introduction of fluorine atoms and fluorine-containing moieties into organic molecules.[10] While fluorination and trifluoromethylation reactions are well-established, the analogous difluoromethylation transformations remain a relatively nascent area of research. One contemporary approach for the efficient introduction of difluoromethyl groups is the radical difluoromethylation of olefins.[7] A variety of difluoromethyl radical precursors have been designed, influenced by related trifluoromethylation reagents such as Umemoto’s reagent and Langlois’ reagent.[7] [10] In these radical difluoromethylation reactions, the carbon-centered radical resulting from difluoromethyl addition can undergo diverse transformations, including hydroxylation,[11] etherification,[12] amination,[13] halogenation,[14] carboxylation,[15] arylation,[16] alkylation,[17] cyanation,[18] and hydrogenation.[19] [20]

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Scheme 2 Substrate synthesis

We employed the Qing laboratory’s oxydifluoromethylation procedure to synthesize benzylic alcohol 4 as a key intermediate for the synthesis of benzylic ether, thioether, and ester substrates for the nickel-catalyzed XEC reaction (Scheme [2a]).[11a] This synthetic route enables the efficient installation of both the benzylic C–O bond and the difluoromethyl group from commercially available 2-vinylnapthalene (2). Phosphonium salt 3 was generated in a straightforward three-step procedure from inexpensive starting materials.[21] [22] Although fac-Ir(ppy)3 is commercially available, the iridium catalyst could also be easily accessed in two steps from iridium(III) chloride hydrate.[23] Additionally, we synthesized benzylic ether 5 in a single step by replacing the H2O/acetone solvent with MeOH in the oxydifluoromethylation reaction to trap the intermediate carbocation (Scheme [2b]).

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Scheme 3 Optimization of the benzylic electrophile. Yield is determined by 1H NMR spectroscopy based on comparison to PhTMS as internal standard.

We began our evaluation of the nickel-catalyzed XEC reaction for fluorinated cyclopropane synthesis by assessing the efficacy of various benzylic electrophiles (Scheme [3]). In related cross-coupling (XC) and XEC reactions of benzylic ethers, Lewis acidic Mg(II) species have played an important role in facilitating the initial oxidative addition of the C–O bond.[24] Specifically, MgI2, which is present in methylmagnesium iodide solutions due to the Schlenk equilibrium, has been identified as an important component of these XC and XEC reactions.[25] Accordingly, we designed a range of substrates containing pendant Lewis basic heteroatoms that could promote the binding of Lewis acidic MgI2, and in turn facilitate oxidative addition of the benzylic electrophile.[26] Unfortunately, substrates 7 and 8 bearing pendant pyridine functionalities did not afford fluorinated cyclopropane cis-6 when subjected to the reaction conditions. Benzylic ester 9 containing a pendant thioether moiety was also unable to generate the desired cyclopropane product. We next hypothesized that commonly utilized electrophiles such as pivalates and tosylates could improve the results, but 10 and 11 did not produce cyclopropane cis-6. Finally, we were pleased to observe that thioether 12 engaged in the desired XEC reaction, albeit in low yield and with poor diastereoselectivity. We aimed to improve the yield of the XEC reaction by designing a substrate containing a 2-methoxyethylether appendage, which has previously been employed as a traceless directing group for related Ni-catalyzed Kumada XC reactions.[26] We were delighted to observe that substrate 13 afforded the desired product in 22% yield and 3:1 dr. Ultimately, we found that simple methyl ether 5, without any pendant Lewis basic functionalities, afforded the best results, generating fluorinated cyclopropane cis-6 in 39% yield and 5:1 dr. At this point, we concluded that methyl ethers are adequate benzylic electrophiles for this transformation and proceeded to evaluate the other key components of the XEC reaction.

Table 1 Evaluation of Reductants

Entry

Reductant

cis-6 (%)a

dr (cis/trans)

1

MeMgI

39

5:1

2

AlMe3

<2

3

ZnEt2

<2

4

B2Pin2

<2

a Yield determined by 1H NMR spectroscopy based on comparison to PhTMS as internal standard.

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Scheme 4 Evaluation of ligands and transition-metal catalysts.a Yield determined by 1H NMR based on comparison to PhTMS as internal standard. b Reaction was run for 24 h. c Ligand = rac-BINAP. d 5 mol% of each catalyst were used.

After identifying methyl ethers as optimal benzylic leaving groups, we next evaluated reductants (Table [1]). First, we hypothesized that methylmagnesium iodide could be replaced with alternative alkylmetal reagents. Unfortunately, AlMe3 and ZnEt2 did not yield fluorinated cyclopropane 6 when employed in the XEC reaction (entries 2 and 3). Moving forward, we were inspired by the Gong group’s application of B2Pin2 as a reductant in nickel-catalyzed alkyl-alkyl XEC reactions.[27] However, when utilized in our nickel-catalyzed XEC reaction, B2Pin2 did not afford the desired cyclopropane product (entry 4). Based on these observations, the distinct reactivity of methylmagnesium iodide is key for the success of the XEC reaction.

With the optimal leaving group and reductant identified, we decided to evaluate different ligands (Scheme [4]). First, we found that nitrogen-based ligands and NHC ligands only afforded recovered starting material, with no generation of cis-6. We next evaluated a series of monodentate phosphine ligands. Although PCy3, PPh3, and BrettPhos resulted solely in starting material, tris-(4-fluorophenyl)phosphine generated 8% of olefin byproduct 15. Presumably, 15 is formed via oxidative addition of the nickel catalyst to the benzylic ether, β-hydride elimination, and then Kumada cross-coupling between the resulting allylic C–F bonds and methylmagnesium iodide. After observing some reactivity with a monodentate phosphine ligand, we transitioned to bidentate phosphine ligands. Although dppe and Xantphos afforded only recovered starting material, dppm, (R,R)-isopropyl-Duphos, dppb, DPEPhos, and 1,3-bis(di-tert-butylphosphinomethyl)benzene all generated at least one identifiable byproduct. Along with previously observed olefin 15, byproduct 14 was also seen as a result of competitive Kumada cross-coupling between benzylic ether 5 and methylmagnesium iodide. Finally, we found that biphep, (R)-C3-Tunephos, (R)-Tol-BINAP, (S,S)-Duphos-Me, (R)-DM-BINAP, o-Tol-BINAP, and rac-BINAP all afforded cis-6. (R)-C3-Tunephos generated the fluorinated cyclopropane product in 20:1 dr, albeit in only 17% yield. Overall, rac-BINAP remained the optimal choice of ligand due to the superior yield and good diastereoselectivity.

We next evaluated alternative transition-metal catalysts. Because iron and cobalt complexes have been widely successful catalysts for cross-electrophile coupling reactions, we selected FeCl3 and CoBr2 as potential catalysts (Scheme [4]).[28] Unfortunately, XEC reactions employing these iron and cobalt catalysts did not afford any fluorinated cyclopropane cis-6, and instead resulted in recovered starting material. Additionally, CoBr2 in combination with Ni(cod)2 or FeCl3 did not yield the desired cyclopropane product. We concluded that Ni(cod)2 is the optimal catalyst for the intramolecular XEC reaction.

Alternative substrates bearing aryl substituents, also reacted to provide the desired fluorocyclopropanes in modest yields (Scheme [5]). As anticipated based on our prior work, naphthylic or heterocyclic substituents were sufficient in activating the benzylic position. In related XEC reactions, we have determined that benzylic sulfonamides react similarly to benzylic ethers.[29] This is the case for the XEC to form fluorinated cyclopropanes as well. For example, generation of 6 from the corresponding ether or sulfonamide provides similar yield and diastereoselectivity, and cyclopropanes 16 and 17 could be prepared from the corresponding sulfonamides.

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Scheme 5 Reaction scope. Yield is determined by 1H NMR spectroscopy based on comparison to PhTMS as internal standard. a 24 h. b X = NTs. c X = OMe. d Yield based on recovered starting material.

Based on experimental and computational studies of related nickel-catalyzed XEC reactions,[24] [30] Scheme [6] shows a plausible catalytic cycle. After binding to the arene, the nickel catalyst first undergoes oxidative addition with the benzylic ether to generate benzylnickel species 22. Next, transmetallation between intermediate 22 and methylmagnesium iodide affords Ni(II) complex 25. The nucleophilic benzylnickel species then reacts with the alkyl fluoride in an intramolecular SN2-type reaction, affording a 5:1 mixture of cis-6 and trans-6. Finally, the second equivalent of methylmagnesium iodide engages in transmetallation with Ni(II) species 26, which ultimately undergoes reductive elimination to release ethane. We were intrigued to observe that the nickel-catalyzed XEC reaction showed selectivity for cis-6 over trans-6 and hypothesized that cis-6 is thermodynamically more stable than trans-6 due to stereoelectronic effects. To determine the relative stabilities, we calculated the energy of the two diastereomers in a density functional theory (DFT) study at the B3LYP level employing the 6–31G (d) basis set.[31] [32] [33] The results of the DFT experiments demonstrated that cis-6 is thermodynamically more stable than trans-6 by 1.29 kcal/mol. Presumably, a stronger hyperconjugation interaction exists between σC–H and σ*C–F in cis-6 when compared with the corresponding interaction between σC–C and σ*C–F in trans-6.[34] This stereochemical outcome is notable because it allows for the diastereoselective synthesis of disubstituted cyclopropanes.

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Scheme 6 Possible catalytic cycle

In conclusion, we have developed a new approach for fluorinated cyclopropane synthesis.[35] This strategy relies on emerging methods in photocatalytic olefin difluoromethylation coupled with an intramolecular nickel-catalyzed XEC reaction of the difluoromethyl group. Although our laboratory has previously established XEC reactions of alkyl fluorides, this work, to the best of our knowledge, represents the first example of an XEC reaction employing the difluoromethyl group as an electrophile. This advancement is particularly noteworthy due to the trend of C–F bond strengths in fluorinated alkanes, where –CF3 > –CF2H > –CFH2. DFT calculations confirm the greater thermodynamic stability of the cis diastereomer relative to the trans diastereomer of the fluorinated cyclopropane product of the XEC reaction, consistent with the observed stereoselectivity. Ultimately, this newly established reactivity of low-valent nickel catalysts will aid in the future development of XC and XEC reactions of geminal dihalides and other sluggish electrophiles.


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Acknowledgment

Dr. Felix Grun is acknowledged for mass spectrometry data.

Supporting Information


Corresponding Author

Elizabeth R. Jarvo
Department of Chemistry, University of California-Irvine
4114 Natural Sciences I, Irvine, CA 92697-2925
USA   

Publication History

Received: 29 July 2020

Accepted after revision: 30 December 2020

Article published online:
28 January 2021

© 2021. Thieme. All rights reserved

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany


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Scheme 1 Synthesis and applications of fluorinated cyclopropanes
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Scheme 2 Substrate synthesis
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Scheme 3 Optimization of the benzylic electrophile. Yield is determined by 1H NMR spectroscopy based on comparison to PhTMS as internal standard.
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Scheme 4 Evaluation of ligands and transition-metal catalysts.a Yield determined by 1H NMR based on comparison to PhTMS as internal standard. b Reaction was run for 24 h. c Ligand = rac-BINAP. d 5 mol% of each catalyst were used.
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Scheme 5 Reaction scope. Yield is determined by 1H NMR spectroscopy based on comparison to PhTMS as internal standard. a 24 h. b X = NTs. c X = OMe. d Yield based on recovered starting material.
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Scheme 6 Possible catalytic cycle