Defluorinative Asymmetric Allylic Alkylations

Abstract

The introduction of allyl fluorides as alternative electrophiles in asymmetric allylic alkylation reactions has recently attracted significant interest. Despite the intrinsic thermodynamically demanding C–F bond-cleavage event, the fluorophilic nature of the silicon atom is key in assisting the activation and cleavage of the allylic C–F bond. Thus, the use of silylated compounds as unconventional nucleophiles, together with the Lewis basicity of fluorine when acting as a leaving group, enables the development of innovative chemical transformations within mild and selective catalytic schemes. This Synpacts article summarizes the diverse defluorinative asymmetric allylic alkylations with allyl fluorides reported to date under both chiral Lewis base and transition-metal catalysis.

Key words

C–F bond activation - defluorination - asymmetric catalysis - allylic alkylation - Lewis base catalysis - transition-metal catalysis

1

Introduction

Paula Rodríguez was born in Barcelona. She graduated in Chemistry from the University of Barcelona in 2022. In July 2023, she obtained her M. Sc. in Organic Chemistry at the University of Barcelona under the supervision of Dr. Xavier Companyó, and she is currently a PhD student in the same research group.
Jordi Duran was born in Caldes de Montbui, a town near Barcelona. He graduated in Chemistry from the University of Barcelona in 2021and obtained his M. Sc. in Organic Chemistry from the same university in 2022. He is currently a PhD student in the group of Dr. Xavier Companyó.
Martí Gisbert was born in Palamós, a town on the coast of Girona. He graduated in Chemistry from the University of Girona and obtained his M.Sc. in Organic Chemistry from the University of Barcelona. He is currently pursuing his PhD under the supervision of Dr. Xavier Companyó.
Dr. Xavier Companyó received his PhD in organic chemistry from the University of Barcelona in 2014. As part of his doctoral training, Xavier was a visiting researcher at the Center for Catalysis at Aarhus University (Denmark). In 2014, he moved to Imperial College London (United Kingdom) to carry out postdoctoral studies funded by a Marie Curie fellowship. Then, in 2016, Xavier joined the Department of Chemical Sciences at the University of Padova (Italy), where he received a STARS starting grant to begin his independent research. Since the autumn of 2020, Xavier has held a lectureship in organic chemistry at the University of Barcelona. His research focuses on the development of new reaction paradigms in sustainable asymmetric catalysis using a knowledge-driven approach.

The catalytic asymmetric allylic alkylation (AAA) reaction permits the regio- and stereoselective formation of new C–C or C–X bonds at an allylic position.[1] This fundamental synthetic transformation can be catalyzed either by transition-metal complexes[2] or by chiral Lewis bases (Scheme [1]A).[3] During recent decades, a myriad of novel cata­lytic methodologies have been developed under both catalytic approaches.[4] These protocols generally rely on the use of allylic substrates bearing a basic leaving group (LG), such as a carbonate or an acetate, in conjunction with stabilized nucleophiles.[4] Thus, the ionized LG acts as a Brønsted base to deprotonate the nucleophile in situ, which subsequently reacts with the corresponding electrophilic catalytic intermediate to forge the new bond at an allylic position (Scheme [1]A).

Scheme 1 (A) Conventional asymmetric allylic alkylations with Brønsted basic leaving groups and stabilized nucleophiles. (B) Defluorinative asymmetric allylic alkylations between allyl fluorides and silylated nucleophiles. LG: leaving group; M: transition metal; L*: chiral ligand; LB*: chiral Lewis base.

Recently, the introduction of nonstabilized nucleophiles into AAA schemes has been gaining significant attention.[5] The use of alternative activation pathways, including photochemical and electrochemical activation, permits an expansion of the portfolio of nucleophiles able to engage with classic allylic substrates within stereocontrolled catalytic transformations.[5]

A complementary approach to further broaden the synthetic performance of AAA reactions is the discovery of alternative allylic partners, such as allyl fluorides (Scheme [1]B). As the C–F bond is the strongest single bond that carbon forms,[6] its activation and cleavage under mild conditions is a challenging chemical process.[7] Therefore, harnessing the ability of these highly polarized bonds to participate in defluorinative catalytic processes is becoming a central topic in modern organic chemistry, as it unlocks reactivity schemes otherwise unattainable.[8]

Here, we summarize the defluorinative AAAs with allyl fluorides under asymmetric catalysis activation that have been reported to date, using either chiral Lewis bases or transition-metal complexes. The catalytic protocols in both activation strategies have in common the use of silylated nucleophiles (Scheme [1]B). Thus, silicon-assisted activation of the allylic C–F bond, together with the interplay of the chiral catalyst, prove to be crucial in achieving novel reactivity under mild catalytic conditions. This Synpacts article is primarily organized between organocatalytic and organometallic transformations. The operative catalytic conditions, their generality and limitations, and the proposed reaction mechanisms are discussed in detail for the various catalytic protocols. Overall, this article aims to provide the chemical community with insightful mechanistic information about the diverse asymmetric catalytic systems to achieve further progress in AAA reactions.

2

Lewis Base Catalyzed Methodologies

In 2014, Shibata and co-workers reported the first defluorinative AAA reaction (Scheme [2]).[9] This pioneering work tackled the kinetic resolution of allyl fluorides 5 through asymmetric allylic trifluoromethylation with the Ruppert–Prakash reagent (6) catalyzed by (DHQD)₂PHAL (9). The catalytic protocol simultaneously converts the racemic allyl fluoride 5 into a trifluoromethylated allylic compound 10 and the enantioenriched allyl fluoride (R)-5, thereby enabling the asymmetric construction of two chiral fluorinated compounds in a single catalytic process. Allyl fluorides 5 containing aromatic groups with different electronic properties are well tolerated, affording both the trifluoromethylated products 10 and the enantioenriched starting material (R)-5 in excellent yields (36–52%) and high enantioselectivities (92:8 to 99.5:0.5 er). Conversely, an alkyl-substituted allyl fluoride 5 significantly slows down the reaction, yielding the corresponding product 10 (R¹ = Cy) in 22% yield. In addition, the use of other silylated polyfluorinated nucleophiles, including 6 and 7, under the optimized catalytic conditions permits the enantioselective construction of structurally diverse polyfluorinated allylic compounds. The proposed reaction mechanism begins with the C–F bond activation of 5 by coordination with the silicon atom of 6 through Si–F interaction to form the enantiomeric complexes (S)- and (R)-11. Then, attack of the catalyst 9 on complex (S)-11 generates the electrophilic intermediate (E)-12 and the trifluoromethyl carbanion 13 through an S_N2′ process, with concomitant formation of Me₃Si–F (14). Finally, a second S_N2′ addition of carbanion 13 to species 12 forges the trifluoromethylated product 10 and releases ca­talyst 9. The fact that the chiral catalyst 9 reacts much faster with the complex (S)-11 than with (R)-11 accounts for the observed kinetic resolution of the allyl fluoride 5.

Scheme 2 Defluorinative asymmetric allylic trifluoroalkylation of allyl fluorides 5 with the Ruppert–Prakash reagent (6). R¹ = Ar or Cy; R² = Me or t-Bu.

Subsequently, in 2016, the Shibata group expanded on his pioneering discoveries by developing a defluorinative asymmetric allylic trichloromethylation of allyl fluorides 5 with chloroform (15) as trichloromethylating agent (Scheme [3]).[10] This elegant transformation, catalyzed by (DHQD)₂PHAL (9) and triggered by the Ruppert–Prakash reagent (6), forms diverse trichloromethylated products 16 in good to excellent yields (46–97%) and with good enantiocontrol (91:9 to 98.5:1.5 er). The methodology can be successfully expanded to other nucleophilic species, including the terminal alkyne 19a, the polyfluorinated arene 19b, and indene 19c, as well as the fluorinated disulfone 19d, furnishing products 21a–d in moderate yields (38–73%) and with a slightly decreased enantiocontrol (80.5:19.5 to 98.5:1.5 er). The lower yields in the formation of products 19a–d were ascribed to a competitive allylic trifluoromethylation reaction with carbanion 13. The proposed mechanism involves C–F bond activation through Si–F coordination and subsequent nucleophilic attack of catalyst 9 to generate the catalytic species 12 and the trifluoromethyl carbanion 13 (see Scheme [2]). Subsequently, 13 deproto­nates either chloroform or reagents 19a–d to generate the corresponding reactive carbanions in situ. Finally, stereocontrolled S_N2′ addition of these carbanions to the electrophilic intermediate 12 yields the enantioenriched products 16 and 21.

Soon afterwards, the same group reported a defluorinative asymmetric allylic alkynylation of allyl fluorides 5 with silylated alkynes 22 catalyzed by (DHQD)₂PHAL (9) (Scheme [4]).[11] A series of chiral 1,4-enynes 23 are formed in moderate to excellent yields (35–93%) and with good to excellent enantioselectivities (92.5:7.5 to 97.5:2.5 er) under the optimized catalytic conditions. Whereas allyl fluorides 5 with electron-deficient aromatic moieties afford the products in high yields (66–93%), the use of allyl fluorides with electron-rich aryls leads to a decrease in reactivity (55–74% yield). Increasing the steric hindrance on either the ester of 5 (R² = t-Bu) or the trialkylsilyl group (R³ = i-Pr) of 22 severely reduces the reactivity, resulting in the formation of the corresponding products in trace amounts. Based on the kinetic observation that the first 50% of reaction conversion is achieved much faster (~12 h) than reaction completion (~3 d), the authors proposed that the transformation proceeds through dynamic kinetic resolution (DKR) of the racemic allyl fluoride 5, in which only (S)-5 produces product 23. This stereochemical outcome is rationalized by invoking a catalyst-controlled S_Ni substitution of (S)-5 by the silylated nucleophile 22 through the cyclic four-membered transition state 25 to form product 23 with retention of configuration. Furthermore, (R)-5 does not react with 22 but, instead, undergoes rate-limiting racemization to ge­nerate the reactive (S)-5, thereby allowing the reaction to proceed to completion.

Scheme 3 Enantioselective allylic trichloromethylation of allyl fluorides 5 with chloroform (15) assisted by the Ruppert–Prakash reagent (6) under Lewis base catalysis. R¹ = Ar; R² = Me, Et, or t-Bu.

Scheme 4 Enantioselective alkynylation of allyl fluorides 5 with silylated alkynes 22 under Lewis base catalysis through dynamic kinetic resolution of the allyl fluoride. R¹ = Ar, or Cy; R² = Me, Et, or t-Bu; R³ = Me, Et, or i-Pr.

In 2017, the Shibata group developed a catalytic asymmetric synthesis of chiral (tetrazolyl)methyl-containing acrylates 27 via defluorinative AAA of allyl fluorides 5 with silylated tetrazoles 26 catalyzed by (DHQD)₂PHAL (9) (Scheme [5]).[12] The catalytic methodology relies on the kinetic resolution of 5, enabling the formation of product 27 with moderate to excellent yields (21–63%) and good to excellent enantioselectivities (92.5:7.5 to 99.5:0.5 er), along with the recovery of enantioenriched starting material (R)-5 (21–41% yield, 87.5:12.5 to 99.5:0.5 er). The authors propose a reaction mechanism in which (S)-5 reacts with substrate 26 through a cyclic transition state via S_Ni substitution under the interplay of catalyst 9 (see Scheme [4]). In this scenario, product 27 is formed with retention of configu­ration from (S)-5, whereas substrate (R)-5 remains unreacted, allowing its recovery in enantioenriched form. In addition, the authors found that products 27 induce spontaneous apoptosis of human monocytic leukemia cells (U937), demonstrating the potential of defluorinative AAA for the synthesis of new chiral products with relevant biological activities.

Scheme 5 Enantioselective allylic alkylation of allyl fluorides 5 with 2-[(trimethylsilyl)methyl]-2H-tetrazoles 26 by Lewis base catalyzed kinetic resolution. R¹ = Ar, or Cy; R² = Me, or t-Bu.

In 2019, Vilotijevic and co-workers developed an enantioselective methodology using nitrogen-centered silylated pronucleophiles, representing the first report of a defluorinative asymmetric allylic amination (Scheme [6]).[13] The reaction between allyl fluorides 5 and N-silyl pyrroles, indoles, or carbazoles 28 as N-silylated nucleophiles catalyzed by (DHQD)₂PHAL (9) permits the construction of various chiral allylated N-heterocyclic compounds 29. The use of the bulky tert-butyl(dimethyl)silyl group in 28 was revealed to be instrumental in avoiding competitive C-alkylation and favoring N-alkylation toward 29. Both electron-withdrawing and electron-donating substituents were well tolerated in the aromatic rings of 5 and 28, providing the corresponding allylated products 29 in good to excellent yields (62–98%) and with high enantioselectivities (83:17 to 99:1 er). The authors proposed that the reaction catalyzed by DABCO proceeds through two consecutive S_N2′ mechanisms. Subsequently, the same group further expanded this methodology to the construction of disubstituted pyrrolizinones 31 (Scheme [6], bottom).[14] Catalytic hydrogenation of the allylic moiety of the pyrrole-derived products 29 and subsequent BBr₃-promoted Friedel–Crafts cyclization furnished pro­ducts 31 in moderate overall yields (14–60%). Interestingly, although the hydrogenation of 29 formed an inseparable mixture of diastereoisomers 30 (3.1:1 to 1.3:1 dr), their cyclization afforded bicyclic products 31 with a fully trans configuration.

Scheme 6 Enantioselective defluorinative allylic amination of allyl fluorides 5 with silylated pyrroles, indoles, and carbazoles 28 catalyzed by a chiral Lewis base, and product derivatization for the synthesis of disubstituted pyrrolizinones 31. R = Ar or Cy.

In 2020, Vilotijevic and co-workers reported a defluorinative asymmetric allylic phosphonyldifluoromethylation of allyl fluorides 5 catalyzed by (DHQD)₂PHAL (9) (Scheme [7]A).[15] The equimolar reaction between 5 and 32 proceeds through kinetic resolution of the allyl fluorides with selectivity factors ranging from 5–81. The phosphonyldifluoromethylated allylic products 33 can be isolated in good yields (30–55%) and with excellent enantiocontrol (90:10 to 98:2 er), together with the recovery of the unreacted fluorinated electrophile 5 in an enantioenriched R form (25–52% yield; 91:9 to 99:1 er)

Scheme 7 (A) Defluorinative asymmetric allylic phosphonyldifluoromethylation by Lewis base catalyzed kinetic resolution of the allyl fluoride 5. R¹ = Ar; R² = Me, Et, Bu, Bn, or t-Bu. (B) Defluorinative asymmetric allylic ethoxycarbonyldifluoromethylation by Lewis base catalyzed dynamic kinetic resolution of the allyl fluoride 5. R¹ = Ar; R² = Me, Et, or t-Bu.

In the same year, Shibata and co-workers reported a closely related methodology, consisting of a defluorinative asymmetric ethoxycarbonyldifluoromethylation of allyl fluorides 5 catalyzed by (DHQD)₂PHAL (9) (Scheme [7]B).[16] In this case, the authors determined that the reaction proceeds through dynamic kinetic resolution of 5, permitting full consumption of the allyl fluoride and forming the enantioenriched fluorinated products 36 in moderate to good yields (24–85%) and with good enantioselectivities (87.5:12.5 to 96.5:3.5 er). The methodology can be extended to difluorinated nucleophiles bearing diverse functional groups, such as phenylsulfanyl (35) or phosphonyl (32). Based on evidence from a series of experimental kinetic studies, the authors proposed that the reaction proceeds by a stepwise S_N2′–S_N2′ mechanism (see Scheme [2]), while slow catalyst-promoted racemization of 5 accounts for the observed DKR process.

In 2023, Companyó and co-workers developed an asymmetric defluorinative allylation of α-substituted silyl enol ethers (SEE) 37 with allyl fluorides 5 under Lewis base catalysis, representing the first defluorinative AAA able to forge more than one stereogenic carbon in a single catalytic event (Scheme [8]A).[17] The methodology permits the construction of α-allyl ketones bearing two contiguous stereocenters in a regio-, diastereo-, and enantioselective fashion. A wide range of cyclic SEEs 37 were successfully allylated in the presence of (DHQD)₂PHAL catalyst (9), affording the corresponding ketones 38 in moderate to good yields (38–88%), excellent diastereocontrol (16:1 to 20:1 dr) and with good to excellent enantiocontrol (89:11 to 96:4 er). The protocol is also amenable to the allylation of acyclic substituted and nonsubstituted SEEs, as well as ketone-derived biorelevant natural products, including (+)-camphor, pregnenolone, and estrone. A series of electroanalytic and spectroscopic experiments permitted the identification of a Si–F interaction between the silylated nucleophile 37 and the allyl fluoride 5 in complex 39. Further kinetic studies revealed that the reaction proceeds through dynamic kine­tic resolution of the allyl fluoride 5 with an initial fast regime in which only (S)-5 is consumed to produce 38, followed by a second slower regime ascribed to (R)-5 racemization. The authors proposed that the formation of the highly organized six-membered transition state 40 governs the regio- and diastereochemical outcome of the catalytic process. In this scenario, the catalyst-controlled S_Ni substitution of the fluorine leaving group in 40 takes place with retention of configuration, furnishing the α-allyl ketone 38 with a syn configuration of the newly forged stereogenic carbons.

Scheme 8 (A) Diastereo- and enantioselective defluorinative allylation of α-substituted silyl enol ethers 37 with allyl fluorides 5. R¹ = Ar; R² = Me, Et, hexyl. (B) Enantioselective defluorinative allylation of nonsubstituted silyl enol ethers 42 with allyl fluorides 5. R¹ = Ar or alkyl; R² = Me, t-Bu, Bn, Et, or Bu.

Almost simultaneously, Vilotijevic and co-workers reported a related transformation for the defluorinative allylation of methyl ketone-derived SEE 42 with allyl fluorides 5 catalyzed by (DHQD)₂PHAL (9) (Scheme [8]B).[18] The method provides allylated ketones 43 with a single chiral center in moderate to excellent yields (13–98%) and excellent enantioselectivities (86:14 to 99:1 er).

3

Transition-Metal Catalyzed Methodologies

There are recent reports of transition-metal catalyzed defluorinative AAAs using structurally distinct allyl fluorides, demonstrating that this type of reactivity is not restricted to Morita–Baylis–Hillman fluorides 5 and Lewis base catalysis. In 2019, Trost and co-workers developed the first palladium-catalyzed defluorinative AAA (Scheme [9]A).[19] The reaction between cyclic allyl fluorides 44 and the Ruppert–Prakash reagent (6) catalyzed by a cyclopentadienyl allyl palladium catalyst 46 with a chiral bidentate diamidophosphite ligand 47 affords a large variety of allylic trifluoromethylated products 48 in moderate to excellent yields (43–95%) and with excellent enantioselectivities (91:9 to 97:3 er). The method permits the trifluoromethylation of diverse six-membered cyclic allyl fluorides 44 bearing aromatic, alkynyl, alkenyl, or nitrogenated substituents, as well as seven-membered allyl fluorides. Besides the trifluoromethyl group, other polyfluorinated moieties were efficiently installed at the allylic position, such as pentafluoroethyl (7), pentafluorophenyl (8), and heptafluoropropyl (45), yielding the corresponding perfluorinated compounds with good results (45–94% yield; 80:20 to 97:3 er). To study the reaction mechanism, the trans-disubstituted allyl fluoride 49 was subjected to the optimized reaction conditions, yielding the corresponding trifluoromethylated product trans-50 with overall retention of the stereochemistry. Previous studies on palladium-catalyzed defluorinative allylic alkylations showed an inversion mechanism during the ionization event.[20] Accordingly, the authors proposed a double-inversion process consisting of ionization and nucleophilic addition, which accounts for the overall retention of configuration observed in product 50.

In 2021, Trost and co-workers reported another palladium-catalyzed defluorinative AAA between allyl fluorides 44 and silylated alkyl sulfones 51 catalyzed by the palladium complex 46 and the chiral ligand 47 (Scheme [9]B).[21] As α-sulfonyl carbanions are hard nucleophiles, their activation through deprotonation requires the use of strong bases. Such reaction conditions complicate the implementation of these substrates within catalytic asymmetric manifolds. Therefore, the authors leveraged the fluorophilicity of the silylated alkyl sulfones 51 to activate such substrates under milder catalytic conditions toward an asymmetric synthesis of homoallylic sulfones 52. Whereas aromatic sulfones afford products 52 in good to excellent yields (65–91%) and with high enantioselectivities (90.5:9.5 to 98.5:1.5 er), alkyl-substituted sulfones generate the corresponding products 52 in lower yields and with poorer enantiocontrol (57–66% yield and 90.5:9.5 to 93:7 er). A wide variety of six-membered cyclic allyl fluorides 44 were successfully employed, affording the corresponding homoallyl sulfones 52 in yields of 57–88% and with 73.5:26.5 to 97.5:2.5 er

Scheme 9 (A) Palladium-catalyzed defluorinative asymmetric allylic fluoroalkylation of allyl fluorides 44. R = Ar, alkynyl, or alkenyl. (B) Palladium-catalyzed defluorinative synthesis of chiral homoallylic sulfones 52. R = Ar, alkenyl, or Bn.

Scheme 10 Iridium-catalyzed desymmetrization of allylic gem-difluorides 53 with activated methylene compounds 54 and silyl ketene acetals­ 59. R¹ = Ar, CH₂OBz, or CH₂Np; ; R² = alkyl, allyl, or OMOM; R³ = Me, or Et; R⁴ = alkyl, or H; EWG = CO₂Et, CO₂PMB, or CN. Np = 2-naphthyl

In 2020, the Hartwig group developed a desymmetrization of geminal allyl difluorides 53 for the construction of enantioenriched fluorinated quaternary stereocenters through an iridium-catalyzed defluorinative AAA (Scheme [10]).[22] Two different types of nucleophiles can be successfully employed (54 or 59). On the one hand, malonates, malononitriles, and β-keto esters 54 are activated by deprotonation with a strong base to form the corresponding enolate 62 in situ. Interestingly, the reactions with sodium and potassium enolates proceed at much lower rates than the corresponding reaction with the lithium enolate, demonstrating the key role of the lithium cation in assisting the oxidative addition of the C–F bond. Hence, the combination of a chiral iridium phosphoramidite catalyst (56 or 57) together with t-BuOLi (55) as a fluorophilic activator permits the selective cleavage of a single C–F bond in 53 to form the tetrasubstituted fluorinated product 58. On the other hand, silyl ketene acetals 59 also engage in a defluorinative AAA with geminal allyl difluorides 53, leveraging the Si–F interaction to selectively activate a single C–F bond. In both cases, the corresponding monosubstituted fluorinated products 58 and 61 are formed in good to excellent yields (71–99%) and with high enantioselectivities (82:18 to 99:1). The authors proposed that the cationic Ir(III) allyl precatalyst (56 or 57) reacts rapidly with the lithiated nucleophile 62, releasing the allyl group in the catalyst as the allyl nucleophile 63, and binds to one equivalent of the starting allyl difluoride 53 to generate the catalytically-active Ir(I) olefin complex 65. This complex undergoes a lithium-assisted oxidative addition, by an outer-sphere mechanism, to generate Ir(III)–π-allyl complex 66 and lithium fluoride (67). This π-allyl complex is rapidly intercepted by the nucleophile 62 to generate intermediate 68. Finally, dissociative ligand substitution releases product 58 and regenerates the catalytic species 65 for a subsequent turnover.

4

Summary and Outlook

This Synpacts article outlines the various asymmetric allylic alkylation reactions reported to date that use allyl fluorides as electrophilic counterparts under both chiral Lewis base activation and transition-metal catalysis. The catalytic reaction mechanisms of the diverse transformations are discussed in detail with the aim of providing the chemical community with a toolbox for further advancement in the field of AAAs. The use of silylated pronucleo­philes is essential for activation of the strong allylic C–F bond through Si–F interaction. The bond is subsequently cleaved under mild conditions with the concomitant interplay of the chiral catalyst. Hence, in contrast to classical AAA reactions in which the nucleophile is activated by deprotonation, the silylated pronucleophiles in defluorinative AAA are activated through a Lewis acid–base interaction, unlocking novel reactivities within mild and selective catalytic schemes. Overall, this Synpacts article shows how the adoption of unconventional reagent partners in classical organic transformations, such as the AAA, permits the expansion of the synthetic boundaries of these venerable reactions toward otherwise unattainable reactivity schemes.

Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

Professor Albert Moyano is acknowledged for proofreading the manuscript.

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Publication History

Received: 03 November 2023

Accepted after revision: 15 November 2023

Accepted Manuscript online:
15 November 2023

Article published online:
02 January 2024