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Fluorinated sulfoximines: syntheses, properties and applications Vincent Bizet,a Rafał Kowalczykb and Carsten Bolm*a The interest in fluorinated sulfoximines has rapidly increased over the past twenty years. As sulfoximines are analogues of sulfones where one of the two SQO units has been replaced by an SQN moiety, they can confer new reactivities and properties never observed for the respective sulfones. In this tutorial review, we present the specific properties of fluorinated sulfoximines (including important bioactivities) and describe
Received 25th November 2013
the syntheses and the applications of fluoromethyl transfer agents such as Johnson’s reagent. Furthermore,
DOI: 10.1039/c3cs60427f
we highlight the exceptional electronic effects induced by the presence of strongly electron-withdrawing fluoro-bearing sulfonimidoyl moieties, which allowed the development of remarkable super-acidifiers
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and super-acceptors with relevance in materials sciences.
Key learning points (1) (2) (3) (4)
Monofluoromethyl sulfoximines have a similar reactivity to Johnson’s reagent and can provide fluoroolefins, epoxides and cyclopropanes. Difluoromethyl and trifluoromethyl sulfoximines are electrophilic fluoromethyl transfer reagents. Fluorinated sulfonimidoyl groups are strong electron-withdrawing substituents applied in super-acidifiers and super-acceptors. Sulfoximines with fluorosubstituents can reveal interesting bioactivities.
Introduction The first sulfoximine was described by Bentley and co-workers in 1950.1 Formally, sulfoximines are monoaza analogues of sulfones where one of the sulfonyl oxygens is substituted by a nitrogen.2 This ‘‘one atom switch’’ has various advantages: first, the sulfur atom of the sulfonimidoyl group can be stereogenic, a property that has been utilised successfully in asymmetric synthesis.3,4 Second, the sulfoximine nitrogen can be functionalised, which allows introducing synthetic diversity, specific reactivity and unprecedent electronic properties. The replacement of hydrogen atoms by small and highly electronegative fluorine atoms has become an attractive tool to modify reactivities, properties and conformations of molecules.5 For the stereoselective introduction of fluorine atoms or fluoromethyl groups highly efficient methods have been reported.6 Initially, fluorinated sulfoximines have only been prepared as structural analogues of the corresponding sulfides, sulfoxides and sulfones.7 Soon, however, it became apparent that they
exhibited a significantly different reactivity. To illustrate this change, various fluoromethyl transfer reagents are depicted in Fig. 1. All fluorinated compounds shown in Fig. 1 are able to transfer fluoroalkyl (CH2F, CHF2 or CF3) groups. Noteworthy is, however, that fluoromethyl sulfones act as nucleophilic transfer agents (for CHF2 , –CF2–, QCF2 or CF3 ), while fluoromethyl sulfoximines 2–4 (as analogues of Johnson’s reagent 1) are
a
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany. E-mail: [email protected]; Fax: +49-241-809-2391; Tel: +49-241-809-4675 b Department of Organic Chemistry, Faculty of Chemistry, Wroclaw University of Technology, 50-370 Wroclaw, Poland
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Fig. 1
Comparison between fluoromethyl sulfones and sulfoximines.
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electrophilic (transferring CH2F, CHF2+, CHF2, or CF3+).8 This pronounced difference in reactivity allows the synthesis of a wide range of highly functionalised fluorinated molecules by carefully selecting the adequately substituted reagent. The possibility of introducing substituents on the sulfoximine nitrogen of fluorinated derivatives leads to additional opportunities. Thus, fluorinated sulfoximines can, for example, serve as materials for applications in electronics, where the acidity of the C–H bonds as well as the potential of aromatic compounds to undergo nucleophilic substitution reactions is fine-tuned by the N-substituent. Until recently, sulfoximines have been rather neglected in medicinal chemistry.9 However, growing interest can be noted, and the efficient synthetic methods summarised here will probably find applications in the synthesis of fluorinated drugs. Thus, the aim of this tutorial review is to give an overview of the high synthetic potential of sulfonimidoyl fluoride (S-F, Fig. 2) and fluorinated sulfoximines (S-CF, S-CF2, S-CF3 and S-Rf, Fig. 2). Accordingly, we discuss their properties, preparation and applications as key components of materials and bioactive agents.
Vincent Bizet
Vincent Bizet received his MSc in 2009 from the University of Caen, and completed his PhD in 2012 in UMR CNRS 6014 COBRA under the direction of Dr Cahard. He is currently a postdoctoral research associate with Professor Bolm at the RWTH Aachen University. As an Alexander von Humboldt postdoctoral fellow Vincent Bizet focusses on the asymmetric synthesis of fluorinated molecules and sulfoximines.
Rafał Kowalczyk received his PhD in 2006 from Wroclaw University of Technology under the supervision of Professor Skarzewski. In 2008 he was awarded a fellowship for postdoctoral research in the group of Professor Jurczak in the Institute of Organic Chemistry PAN. One year later he joined the group of Professor Bolm at RWTH Aachen University, where he was a postdoctoral associate until 2010. Currently, Rafał Kowalczyk is an Rafał Kowalczyk Associate Professor at the Wroclaw University of Technology. His research interest relates to asymmetric catalysis, organic synthesis, and organic chemistry of sulfur- and fluorine-containing compounds.
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Fig. 2
Sulfonimidoyl fluoride and fluorinated sulfoximines.
1. Preparation and use in organic synthesis Incorporation of a fluoroalkyl group (CF, CF2, CF3) into molecules is still a challenging task. Thus, methods allowing convenient fluoroalkylation of C-, O-, S-, N- and P-atoms are currently a subject of great interest. The development of fluorinated sulfoximines having an S-CF, S-CF2, S-CF3 or S-Rf bond gave a range of reagents with the ability to transfer a CFx group to another molecule. 1.1
S-F sulfonimidoyl fluorides
Sulfonimidoyl fluorides 7 can be prepared by treatment of sulfonimidoyl chlorides 6 with a fluoride source (sodium fluoride, potassium fluoride or tetrabutylammonium fluoride) in moderate to good yields (up to 89%; Scheme 1).10 They are relatively stable and can be purified by flash column chromatography. In synthesis, sulfonimidoyl fluorides have allowed
Scheme 1 Synthesis of sulfonimidoyl fluoride and behaviour of sulfonimidoyl halides in nucleophilic substitution reactions with organometallic reagents.
Carsten Bolm studied chemistry at the TU Braunschweig in Germany and at the University of Wisconsin in Madison (USA). In 1987 he finished his doctoral work with Professor Reetz in Marburg (Germany). After postdoctoral studies at MIT, Cambridge (USA), with Professor Sharpless, Carsten Bolm began to work on his habilitation in Basel (Switzerland) in the group of Professor Giese. In 1993 he Carsten Bolm became Professor of Organic Chemistry at the University of Marburg (Germany), and since 1996 he has been full professor of Organic Chemistry at the RWTH Aachen University (Germany). In 2012 he became an adjunct professor at WIT (Wuhan Institute of Technology), China.
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overcoming a serious limitation in the preparation of sulfoximines 8, where attempted nucleophilic substitution of sulfonimidoyl chlorides with organometallic reagents only afforded the corresponding sulfinamides 5. Sulfonimidoyl fluorides, in contrast, behave differently, providing the desired products in high yields (Scheme 1). For example, reactions of 7 with methyl- or butyllithium mainly lead to the corresponding sulfoximines (in yields up to 100%). It is noteworthy that applying Grignard reagents is less successful resulting in mixtures of both sulfoximines and sulfinamides. With anisole, a sulfonimidoyl fluoride was shown to undergo a Friedel–Crafts-type reaction affording the sulfoximine in 63% yield. When the corresponding sulfonimidoyl chloride was applied, the yield was only 36%.10 Similarly, 7 reacted with a-lithio isocyanides to give sulfoximines in yields up to 68%.11 Fluorination of N-trifluoromethylsulfonyl sulfonimidoyl chlorides 9 with CsF gave at best a 20% yield of fluorides 10. Good to excellent yields of 10 were achieved starting from sulfonimidoyl chlorides 9 or sulfonimidoyl ammonium salt 11 with trifluoride antimony or xenon difluoride, respectively (Scheme 2).12 1.2
S-CF sulfoximines
For preparing monofluoro olefins, epoxides and cyclopropanes, S-CF sulfoximines such as 16 are highly efficient reagents. The first synthesis of a S-CF sulfoximine was accomplished in a four-step reaction sequence with an overall yield of 52% (Scheme 3).13 Monofluoro sulfide 13 was obtained from the phenyl methyl sulfoxide (12) by fluorination with DAST. Oxidation of 13 with m-CPBA afforded S-CF sulfoxide 14, which was sequentially iminated and N-methylated using standard protocols elaborated by Johnson to give S-CF sulfoximine 16 via 15.14 Following Johnson’s strategy for the synthesis of olefins using sulfoximines (Scheme 4, top), 16 was shown to be a mild fluoromethylenation agent.13 Consequently, it was applied in
Scheme 2
Syntheses of N-trifluoromethylsulfonyl sulfonimidoyl fluorides 10.
Scheme 3
Syntheses of fluoromethyl sulfoximines 15 and 16.
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Scheme 4
Olefination of aldehydes and ketones with 16.
the preparation of 9-fluoromethylene analogues of prostaglandin E2 (PGE2), where the CQCHF moiety was expected to enhance the product stability in comparison to PGE2. In this manner, olefination of silyl-protected PGE2 derivative 19 with sulfoximine 16 led to PGE2 analogues 20 in 44% yield. Unfortunately, the E/Z ratio of the newly formed double bond was only 48/52 (Scheme 4, middle). This unsatisfying diastereoselectivity was also found in reactions of 16 with other ketones providing isomeric mixtures of olefins suggesting a rather limited synthetic applicability of this approach (Scheme 4, bottom). The N-tosyl analogue of 16, sulfoximine 26, has recently been described to be useful in monofluoromethylation of O-, S-, N-, and P-nucleophiles.15 The reagent was prepared starting from 13 by imination with chloramine-T to give sulfilimine 25, which was subsequently oxidized with H2O2 providing 26 in good overall yield (Scheme 5). Generally, treatment of deprotonated nucleophiles with 26 led to products such as 27–31 in very high yields. Mechanistically, electron transfer processes and the involvement of CH2F radicals were proposed. In contrast to the aforementioned synthetic approaches towards S-CF sulfoximines 16 and 26, which both started from monofluorosulfide 13,13,15 an alternative method has been developed for the monofluorination of S-aryl S-benzyl sulfoximines 32. This protocol involved a deprotonation of the benzylic position of 32 with sodium hydride and subsequent reaction of the resulting anion with N-fluorobenzenesulfonimide (NFSI) as an electrophilic fluorine source (Scheme 6). In this manner, fluorinated sulfoximines 33 were obtained in yields ranging from 61% to 83%.16 Applying fluorinated benzyl sulfoximines 33a–e in olefination reactions with nitrones like 34a gave a range of fluoroolefins such as 35b in moderate to excellent yields (29 to 94%) with good
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Scheme 5 Syntheses of fluoromethyl sulfoximine 26 and products obtained from it.
Scheme 6 with NFSI.
Scheme 7
Syntheses of 33a–e through electrophilic fluorination of 32a–e Scheme 8
Olefination of nitrones with fluorinated sulfur reagents.
to excellent E/Z selectivities (E/Z: 26 : 74 to 0 : 100) in favour of the Z isomer.16 To gain further mechanistic insight, competition experiments with sulfoximine 32a, its fluorinated analog 33a and difluoro sulfone 36 were carried out (Scheme 7). Interestingly, the presence of the fluorine atom as in 33a improved the reactivity significantly leading to the corresponding olefin 35b in 87% yield, compared to only 34% yield for the non-fluorinated sulfoximine 35a. Moreover, the E/Z selectivity was excellent in both cases. (Note that both olefins had trans phenyl substituents and that the E/Z preference change was only a result of the CIP priority rules.) From the reaction of fluorinated sulfone 36 with nitrone 34b the expected olefin was never obtained but instead, the corresponding adduct 37 was isolated in 61% yield. The proposed mechanism is shown in Scheme 8. The reaction proceeds through the addition of sulfoximine anion 38 to nitrone 34a followed by an unusual 1,2-elimination of intermediate 39 to give product 35b, nitrosobenzene (40) and deprotonated N-tosyl-phenyl sulfonamide (41). The high level of
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Proposed mechanism for the olefination with nitrones.
stereoselectivity in favour of the Z isomer of 35b can be attributed to the formation of the pro-(Z)-adduct avoiding unfavourable interactions of the two aromatic rings as found in the pro-(E)-adduct.16 Another extension of Johnson’s early discoveries17 is the synthesis of monofluorinated epoxides through the addition of sulfoximine anions to carbonyl compounds (Scheme 9).19 Fluorinated S-aryl-S-alkyl sulfoximines 42 were prepared using the monofluorination method with NFSI, and products with S-ethyl, S-propyl, and S-pentyl chains were obtained in 69%, 71% and 54%, respectively. Deprotonation of 42 with n-butyllithium followed by reaction of the resulting anions with ketones 43 afforded monofluoroepoxides 44 in moderate to excellent yields (30 to 94%). Interestingly, aldehydes such as benzaldehyde could not be used in this reaction as they afforded complex product mixtures. Isolation of the rather unstable fluorinated epoxides was only possible for acetophenone derivatives with strong electron-withdrawing substituents. Essentially equimolar amounts of the diastereomers were obtained, which could be separated
Scheme 9
Epoxide formation through ketone addition.
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Scheme 11 Synthesis of 49 and its utilisation as a CHF2 transfer reagent. Scheme 10 Cyclopropanation of a,b-unsaturated Weinreb amides with enantiopure fluoro sulfoximines (R)-46.
by silica gel flash chromatography. Finally, a ring opening process was developed which allowed 1,2-fluorine shift reactions to occur converting epoxides 44 into a-fluorinated carbonyl compounds 45 with quaternary carbon atoms.18 Recently, enantiopure fluorosulfoximines (R)-26 and (R)-42 (where R1 = Me) have been applied in asymmetric syntheses of monofluorocyclopropanes of type 47 (Scheme 10).19 Both reagents were obtained by electrophilic fluorination of the corresponding enantiopure (S)-N-tosyl-S-alkyl-S-phenyl sulfoximines using a similar deprotonation/NFSI addition sequence as presented before. Treatment of fluoro-sulfoximines (R)-26 and (R)-42 with lithium hexamethyldisilazide (LiHMDS) in either THF or toluene followed by reaction of the resulting anions with a,b-unsaturated Weinreb amides 46 gave monofluorocyclopropanes 47 in high yields and with excellent stereoselectivities. In general, the diastereoisomeric ratios were higher when the reaction was performed in THF, while the use of toluene led to superior enantioselectivities. Accordingly, monofluorocyclopropanes 47a and 47b with (het)aryl substituents (R1) were obtained from 46 and (R)-26 with stereoselectivities of up to 99 : 1 dr and 98% ee in yields of 73–97%. The results for alkyl-substituted 47c were less satisfying as it was only formed as a mixture of three diastereomers in a ratio of 75 : 19 : 6 in 62% yield. Application of S-ethyl-substituted (R)-42 afforded products 47d and 47e in good yields (70–75%) with stereoselectivities of 87 : 13 dr and 76–87% ee. Finally, products 47 were transformed into other synthetically valuable compounds such as aldehydes, alcohols or ketones. Importantly, such reactions proceeded in good yields without racemization.19 Recently, the reactivity of S-CF sulfoximinium salts 2 has been under investigation. For a better understanding in a wider context, those results will be discussed in part 1.4.
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1.3
S-CF2 sulfoximines
Whereas S-CF2 sulfones7 have widely been used as nucleophilic difluoromethylation agents, S-CF2 sulfoximines such as 49 have served as electrophilic sources of CF2 allowing difluoroalkylation of C-, O-, S-, N- and P-nucleophiles (Scheme 11).20 The preparation of S-CF2 sulfoximine 49 started from the corresponding S-difluoromethyl sulfoxide 48, which was iminated by copper-catalyzed degradation of PhIQNTs to give 49 in 60% yield. Reactions with deprotonated aromatic and heteroaromatic thiols 50 as well as benzyl thiol provided the corresponding S-CHF2 derivatives 51 in moderate to good yields (57–94%). Notably, benzo[d]thiazole-2-thiol was difluoromethylated at both the sulfur and the nitrogen atom to give 52 and 53 in 44% and 27% yield, respectively. Under the same conditions, various other nitrogen-containing heterocycles 54 were reacted with 49 providing N-CHF2 products 55 in yields ranging from 40% to 72%. Also carbon nucleophiles were difluoromethylated as exemplified by reactions of arylacetylenes 56 with 49, which led to alkynes 57 in yields up to 87%. The application of sulfoximine 49 in the difluoromethylation of alkynes is an alternative to the common freon (CHF2Cl) based approach. Similar conditions for fluoromethylation of acetylenes were investigated with S-CF3, S-CF2Br and S-CFCl2 sulfoximines. Their low reactivity, however, led to only moderate yields (up to 53%) of the corresponding products.21 N,N-Dimethyl-S-difluoromethyl-S-phenyl-sulfoximinium tetrafluoroborate (3a), which is the difluoromethyl analogue of Johnson’s reagent 1 (Fig. 1),22 was prepared from thiophenol [50, where (Het)Ar is Ph] via difluoromethyl phenyl sulfoxide (48), which was iminated using a combination of oleum and sodium azide in DCM to give sulfoximine 58 in quantitative yield. Two subsequent methylations with trimethyloxonium tetrafluoroborate provided 3a via N-methyl derivative 59 in good overall yield (Scheme 12). Salt 3a formed in situ from 59 proved to be a highly active difluoromethyl transfer reagent for a wide range of N-, P-, S-,
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Scheme 12 Synthesis of 3a, the S-CHF2 analogue of Johnson’s reagent.
Scheme 14 Asymmetric syntheses of alcohols with terminal difluoromethyl groups.
1.4
Scheme 13 Application of in situ generated 3a as a CHF2 transfer reagent.
and O-nucleophiles (Scheme 13).23 In this manner, phosphonium salts 60 were obtained in yields of 35% to 57%, for both aliphatic or aromatic phosphines. Ammonium salts 61 were obtained in moderate to good yields (47–83%) starting from tertiary amines including triethylamine, N,N-dimethylaniline derivatives and N-phenylimidazol. The difluoromethylation of sodium thiophenolate led to 62 (with R = Ph) in 78% yield. Other sodium thiophenolates gave much lower yields of 62 (19–45%). Applying the same conditions to aliphatic alcohols gave the corresponding difluoromethyl ethers 63 in 25% to 48% yield. Deuterium labeling experiments provided mechanistic evidences of an electrophilic difluoromethylation pathway, and ruled out a pathway via a difluorocarbene. Recently, the synthetic potential of 49 as a nucleophilic difluoromethyl transfer agent has been investigated (Scheme 14).24 Unfortunately, deprotonation of 49 in the presence of an aldehyde or a ketone did not lead to any of the expected addition products 65 presumably due to the inherent instability of intermediately formed anion 64, which decomposed leading to difluorocarbene (66). However, replacing the electron-withdrawing tosyl group on the sulfoximine nitrogen of 49 by a tert-butyldimethylsilyl substituent afforded an alternative reagent 67, which proved significantly more stable in its deprotonated form (70). Reacting enantiopure (R)-70 with ketones followed by acidic desilylation led to NH-sulfoximines 68 with difluoromethylene groups in good yields and with moderate to high diastereoselectivities. Mild reductive desulfurisation of the major diastereomer of 68 with metallic magnesium provided optically pure tertiary alcohols 69 bearing terminal difluoromethyl groups in good yields.
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S-CF3 and S-Rf associated sulfoximines
Fluorinated sulfoximines with CF3 groups and Rf substituents are important reagents for trifluoromethylations25 and perfluoroalkylation reactions.26 Three synthetic methods have been developed for accessing such compounds. The pioneering work of the first stems from Shreeve, who obtained various S,S-perfluorosulfilimines and -sulfoximines27–29 starting from S,S-difluoroS,S-bis(perfluoroalkyl)sulfides or sulfoxides. As attempts to apply the standard protocol for sulfoxide iminations with sodium azide in sulfuric acid failed in cases of S-aryl S-CF3 derivatives, oleum (24%) was applied as solvent instead of sulfuric acid, and in this manner the desired S-aryl S-CF3 sulfoximines were accessed in up to 96% yield.30 A similar strategy was then applied to S-alkyl S-CF3 and S-alkyl S-C8F17 sulfoxides 71, which led to the corresponding sulfoximines 72 in high yields (Scheme 15).31 The procedure with sodium azide in oleum was also used for the syntheses of 1-oxo-1-trifluoromethyl-1l6-benzo[d]isothiazol3-one (73a), 1-trifluoro-methyl-benzo[1,3,2]dithiazole 1,3,3-trioxide (73b), and acyclic sulfoximines 74a and 74b (Scheme 16). Those S-CF3 sulfoximines were then applied for the introduction of CF3 groups through reactions with Grignard reagents (13–32%), sodium thiophenoxides (47–70%), and arylacetylene lithium salts (48–73%).32 The main drawback of the aforementioned methods for the synthesis of S-Rf sulfoximines is the use of the hazardous combination of sodium azide in sulfuric acid or oleum, as sodium azide is difficult to handle on a large scale and the in situ formation of HN3 presents a serious limitation for industrial applications.
Scheme 15
Syntheses of S-Rf sulfoximines 72 with sodium azide.
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Scheme 18
Scheme 16
Electrophilic trifluoromethylation of various nucleophiles.
The second route towards perfluorinated sulfoximines 72 involves S-Rf sulfilimines such as 78, which require subsequent oxidations to give 72 (Scheme 17). For accessing S-Rf N-acyl sulfilimines 78 a convenient method has been developed, which starts from the corresponding S-Rf sulfoxides 71, which are activated by treatment with trifluoromethanesulfonic anhydride. Reactions of the resulting sulfonium salts 80 with (amides33,34 or) organonitriles35,36 lead to intermediates 81, which are hydrolysed upon aqueous work-up to give S-Rf N-acyl sulfilimines 78. While oxidation of 78 with potassium permanganate affords S-Rf N-acyl sulfoximines 79 in 40–95% yield, the same reaction in the presence of sodium hydroxide leads to S-Rf NH sulfoximines 72 in yields of 36–72%. To provide a more rapid and direct access to 72, a one-pot procedure was developed using a combination of the previously described conditions, which gave 72 in yields ranging from 63% to 94% (Scheme 17).35 Finally, the last approach towards S-Rf sulfoximines relies on the introduction of a trifluoromethyl group starting from sulfonimidoyl fluorides 7.12,37 Initially, Yagupolskii applied a combination of the Ruppert–Prakash reagent (TMSCF3) and a catalytic amount of tris(dimethylamino)sulfonium difluorotrimethylsiliconate
Scheme 17 Conversion of S-Rf sulfoxides into S-Rf sulfilimines and sulfoximines.
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Nucleophilic trifluoromethylation of sulfonimidoyl fluorides.
(TASF) for the nucleophilic trifluoromethylation of 7.12 Accordingly, the resulting N-protected S-CF3 sulfoximine 82 (with R1 = meta-fluorophenyl and R2 = SO2CF3) was obtained in 70% yield. Recently, this route has been modified by substituting TASF with tetrabutylammonium fluoride (TBAF). Yields of up to 79% were thereby realized in syntheses of S-CF3 sulfoximines 82 with various S-alkyl or S-aryl substituents (Scheme 18).37 The required sulfonimidoyl fluorides 7 were prepared in 35–89% yield from the corresponding chlorides 6 by reactions with KF or AgF in the presence of a catalytic amount of 18-crown-6. In order to increase the electron-withdrawing properties of the S-Rf sulfoximines, various N-functionalised derivatives were prepared.31 For this study, 72a served as a representative starting material, and groups such as trifluromethanesulfonyl (Tf), trimethylsilyl (TMS), nitro (NO2), perfluorobutanesulfonyl (SO2C4F9) or arenes substituted with cyano or nitro groups were introduced (Scheme 19). N-Arylation of fluorinated sulfoximines 84 has first been explored using palladium catalysis leading to moderate yields for a limited substrate scope. In contrast, copper-catalysed arylations proved more flexible allowing N-arylation of S-CF3 and S-C4F9 S-aryl sulfoximines in good to excellent yields starting from a wide range of bromo and iodoarenes substituted with both electron donating (Me, OMe) and electron withdrawing (CO2Et, NO2) groups. Even an aryl diiodide reacted well. As examples, N-pyridinyl, N-thionyl and N-naphthyl-substituted S-Rf sulfoximines 85a–c are depicted in Scheme 20.38
Scheme 19
N-Functionalisation of S-CF3 sulfoximine 72a.
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Copper-catalysed N-arylation of S-Rf sulfoximines. Scheme 22 reagent 1.
Synthesis and reactivity of 4a, the S-CF3 analogue of Johnson’s
Scheme 23
Electrophilic trifluoromethylation with 4a.
Scheme 21 N-Acylation and related reactions of S-Rf sulfoximines.
N-Acylation of fluorinated sulfoximines has been achieved by reacting NH sulfoximines 84 with acyl chlorides in the presence of triethylamine and a catalytic amount of DMAP. In this manner, a wide range of halomethyl and perfluoroalkyl sulfoximines could be converted providing the corresponding acylated products 86 (with Y = R and X = O) in yields up to 100% (Scheme 21).39 The use of diacyl chlorides led to C2-symmetric bissulfoximines in yield ranging from 54% to 79%. In analogy, 84 could be converted into carbamate-(64–100%), thiocarbamate(60%), urea-(64–82%), and thiourea-type (62%) structures 86 (with Y = OR, NHR and X = O, S). One of the main achievements in the chemistry of fluorinated sulfoximines is undoubtedly the development of reagents for the transfer of trifluoromethyl25 and perfluoroalkyl26 groups. Based on the seminal work by Johnson, who had shown that sulfoximinium salts such as 1 were potential methylene transfer reagents,22 trifluoromethyl analogue 4a was introduced (Scheme 22). Starting from trifluoromethyl phenyl sulfoxide (87) 4a was prepared in a four steps synthesis in 67% overall yield.40 Nitrogen transfer onto 87 using a combination of NaN3 in fuming H2SO4 led to NH sulfoximine 84a, which could be methylated with methyl iodide to give 88. Subsequent alkylation of 88 with methyl triflate gave trifluoromethansulfonate salt 4b, and counterion exchange from triflate to tetrafluoroborate led to 4a. As hypothesised on the basis of Johnson’s results, 4a proved to be an excellent electrophilic trifluoromethylation agent (CF3+ equivalent) that reacted with nucleophiles providing trifluoromethylated products 89 by elimination of dimethyl-benzenesulfinamide (90) in high yields (Scheme 22).40 The ability of 4a to serve as an electrophilic CF3-transfer agent was demonstrated in reactions with anions of b-ketoesters 91
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and in vinylogous trifluoromethylation of dicyanoalkylidenes 93, which provided trifluoromethylated products 92 and 94, respectively, in yields up to 93% (Scheme 23).41 In order to investigate the nature of trifluoromethylation reagent 4a in greater detail, a reaction was carried out in the presence of nitrobenzene, which is known as the radical scavenger. As no alteration of the process was observed, a radical or single electron transfer (SET) mechanism of the CF3 group transfer was excluded. In analogy to 4a (and Johnson’s reagent 1) S-CH2F sulfonate salts 2b and 2c were prepared (Scheme 24).41 With the goal to gain a deeper understanding of their electrophilic transfer properties, the reactivities of 2b and 2c were investigated in comparison to fluoromethyl transfer agents 3a, 4a and 49 (Scheme 25).41 Fluoroalkylation of b-ketoesters 91a providing mono-, di- and trifluoromethylated products 92a, 95–97 was chosen as a test reaction. Surprisingly, 2c showed an exclusive O-selectivity providing 95 as a single isomer. In contrast, 4a gave only
Scheme 24
Synthesis of 2c, the S-CH2F analogue of Johnson’s reagent 1.
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and 49 a dual radical and cationic pathway giving mixtures of O- and C-alkylation products was suggested. The original O-alkylation preference of 2c was extended to a range of other oxygen-containing functionalities such as carboxylic acids, phenols and sulfonic acids, leading to corresponding O-monofluoromethylated products 98–100 in good to excellent yields (Scheme 27).41
2. Electronic properties
Scheme 25
O/C-Selectivity in the fluoromethylation of b-ketoester 91a.
Scheme 26 Proposed mechanisms for fluoromethylation of enolates with S-CF sulfonate salt 2c (left) and S-CF3 sulfonate salt 4a (right).
C-alkylated product 92a. Less attractively, use of S-CHF2 transfer agents 3a or 49 afforded mixtures of C- and O-alkylated products 96 and 97 in varying ratios (ca. 1 : 1 to 2 : 1).42 Molecular orbital calculations revealed that the electrophilic nature (radical or cationic) of the examined fluoromethyl transfer agents was highly dependent on the number of fluorine atoms. A radical-like pathway was suggested for reactions with 2b (Scheme 26, left) involving an addition of the enolate oxygen onto the sulfur atom of 2c followed by a sequential homolytic cleavage of the resulting intermediate. Radical combination and elimination of phenylsulfinamide (90) gave 95. In contrast, the more electron-deficient character of the CF3 substituent of 4a involved an ionic SN2 mechanism of the carbon enolate onto the CF3 leading to 92a (Scheme 26, right).42 For reaction of 3a
Besides their applications in synthetic organic chemistry, fluorinated sulfoximines have gained interest as structural entities in super-acceptors and super-acidifiers.43 The possibility of modifying the electronic nature of molecules by N-substitution presents an advantage of sulfoximines over sulfones. Detailed studies on the modulation of the electron density in various aromatic compounds through the introduction of perfluroalkyl groups resulted in the development of super-strong electron-withdrawing substituents and super-strong acids. The sp-constants of the Hammet scale were used to identify the former. Accordingly, a higher sp-value indicated a stronger electron withdrawing capability of the analysed substituent (Table 1). For a long time, a nitro group was considered the most electron-withdrawing substituent. However, comparing its sp-value to the one found for a S(O)CF3 group shows that the latter also has a very strong electron-withdrawing power and that both are nearly identical (Table 1, entry 1 versus entry 3). While a SCF3 substituent has a smaller sp-value, those of fluorinated sulfimidoyl and sulfonyl groups are larger (Table 1, entries 2, 4 and 5, respectively). Replacing one oxygen of the sulfonyl moiety by an NH group leads to a substituent with lower electronwithdrawing capability (Table 1, entries 5 and 6). However, if the nitrogen bears a triflate instead of a hydrogen, the situation is reverse, and the very large sp-value of 1.39 indicates the exceptional electron-withdrawing power of this substituent (Table 1, entry 7), which corresponds to the relative strength of two nitro groups.43 The strong electron-withdrawing effects of fluorinated sulfonimidoyl substituents with N-triflyl groups was demonstrated experimentally in SNAr reactions starting from either sulfoximine 101 or sulfone 102. Whereas the former reacted smoothly with trifluoroethanol and aniline to provide high yields of the corresponding substitution products 103 and 104, the latter showed low reactivity with trifluoroethanol and none with aniline (Scheme 28).44
Table 1
Scheme 27
Scope of the O-monofluoromethylation with 2c.
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Comparison of the electron withdrawing properties
Entry
Substituenta
s ib
sRb
spb
1 2 3 4 5 6 7
NO2 SCF3 S(O)CF3 S(NSO2CF3)CF3 S(O)2CF3 S(O)(NH)CF3 S(O)(NSO2CF3)CF3
0.57 0.42 0.66 1.07 0.73 0.60 1.05
0.20 0.06 0.11 0.21 0.31 0.24 0.34
0.77 0.48 0.77 1.28 1.04 0.84 1.39
a
Substituent in a benzene ring.
b
Values obtained from 19F NMR spectra.
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Scheme 28 SNAr reactions with fluorinated sulfoximine 101 and sulfone 102.
Based on the soft–hard acid–base theory, it was concluded that the nature of the S(O)(NSO2CF3)CF3 group was hard, exhibiting low polarizability and activating aromatic systems primarily through electron withdrawal by powerful inductive effects. This assumption was in accord with the aformentioned studies (Table 1), which had revealed a significant inductive (si), but low conjugation effect (sR) of the S(O)(NSO2CF3)CF3 group. In order to further investigate the properties of highly fluorinated sulfur substituents, structural, thermodynamic and kinetic effects related to deprotonation of benzyltriflones 107–110 were studied using multinuclear NMR, pKa and Marcus intrinsic reactivity measurements.45 As expected, the S(O)(NSO2CF3)CF3 group in compound 110 had the strongest acidifying effect leading to a pKa value of 6.45 in DMSO (Scheme 29). The analogous data for unsubstituted benzyltriflone 107 was 8 pKa units higher. para-Nitro- and para-trifluoromethylsulfonylsubstituted derivatives 108 and 109 gave intermediate values.
Scheme 29 Electron withdrawing and carbanion stabilisation power of sulfur-containing substitutents.
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Scheme 30
Synthesis of liquid crystalline sulfoximine 117.
A similar trend was observed in pure water or in H2O–DMSO mixtures. For deprotonated 110, four resonance structures can be drawn (Scheme 29). Multinuclear NMR and kinetic studies showed that the highest charge density was located on the benzylic carbon and that the other resonance structures were less relevant. Based on all results, the S(O)(NSO2CF3)CF3 group was classified as a ‘‘super-acidifier’’. Because super-fluorinated materials are known to have a higher dielectric anisotropy (De) and thus a higher dipolar moment, the extraordinary electronic properties of the S(O)(NSO2CF3)CF3 moiety are attractive for the design of compounds applied in liquid crystalline displays (LCDs), organic light-emitting diodes (OLEDs) and organic field-effect transistors (OFETs). An example of a molecule that displays liquid crystallinity is shown in Scheme 30. The synthesis of 117 started from fluorinated hydrocarbon 111, which was converted into the target compound by a five-step reaction sequence. Whereas most steps proceed with satisfying yields, the oxidation of sulfide 113 giving 114 and the subsequent sulfoxide-tosulfilimine conversion of 114 providing 116 led to only low product yields.35 Unexpectedly, the dielectric anisotropy (Devirt) for sulfoximine 117 was significantly lower than the analogous value of sulfone 115. Conformational analysis provided an answer: free rotation of the N–SO2 bond of 117 resulted in three main conformers, which differed in energies in the range of 2.8 kcal mol 1. In each case, the triflic group of the protected nitrogen atom was located above the plane of the aromatic ring. Although all conformers had quite similar and high dipole moments (around 8.2 D), this vector was oblique to the direction of the long molecular axis of the molecule. As a result, the exact dielectric anisotropy of 117 was lower than expected. Recently, octupolar chromophores 120–123 with electronwithdrawing fluorinated sulfonimidoyl substituents have been prepared (Scheme 31). Their syntheses started from aryl
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the sulfur atom had a larger influence on the optical properties than the N–SO2Rf moiety.46
3. Bioactive S-CFx-containing sulfoximines The synthetic methods described above have also been applied in syntheses of bioactive molecules. Consequently, the S-CFx sulfoximine motif can be found in some patents, and three examples are presented in Fig. 3. Thus, S-CF3 sulfoximines 124 are inhibitors of HIF-Luciferase developed for the treatment of hyperproliferative and angiogenesis disorders,47 S-CF2Ar sulfoximine 125 has efficient herbicidal properties,48 and S-CHFAr sulfoximine 126 shows insecticidal features.49 With the goal of introducing conformational changes of the C,D-ring side-chain and to slow side-chain catabolism, fluorinated sulfoximine 129 was prepared as an analogue of hormone 1a,25-dihydroxyvitamin D3 (calcitriol, 130). The key step of the synthesis is shown in Scheme 32. Accordingly, Scheme 31 Synthesis of chromophores containing fluorinated sulfonimidoyl substituents.
bromides 118, which were accessed through a previously described procedure.35 Sonogashira couplings of 118 with tris[4-(ethynylphenyl)]amine (119) afforded 120–123 in moderate yields. Sulfoximines 120–123 showed strong absorptions in the near-UV and emissions in the visible region.46 Compounds with other electron-withdrawing substituents (S-Rf sulfoxides, sulfones and N-acyl sulfilimines) were also studied, and 13C NMR analysis revealed a linear correlation between the chemical shift difference (Dd) of the two acetylenic carbons and the Hammet constant (sp), which allowed a classification of the electron-withdrawing power of these groups. This analysis, however, could not be applied to fluorine-containing sulfoximines 120–123 because sp was unknown and Dd of the 13C NMR signals for the two acetylenic carbons was too small [Dd(120 and 121) = 10.2 ppm and Dd(122 and 123) = 10.3 ppm]. Compounds 120–123 showed an intense absorption band in the near-UV-blue-visible, and they were green emitters. An increase of Stokes shift was observed, which correlated with the electron-withdrawing properties of the substituents. All fluorinated sulfoximines were good fluorescence emitters (with fluorescence quantum yields F = 0.6–0.8) with red-shifted emissions from violet to green. This observation was regarded as evidence for core-to-periphery intramolecular charge-transfer transitions promoted by the strong peripheral electron-withdrawing groups. Finally, a linear correlation between the electronic gap (relaxed ground versus excited states) and the electron-withdrawing ability of the peripheral groups as revealed by the known sp constants was found. This correlation allowed the deduction of sp constants for sulfoximines 120 (sp = 1.35), 121 (sp = 1.35), 122 (sp = 1.44) and 123 (sp = 1.46), which showed that the perfluoroalkyl groups at
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Fig. 3
Examples of bioactive fluorinated sulfoximines.
Scheme 32
Synthesis of a 24-sulfoximine analogue of calcitriol.
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aldehyde 127 was treated with (S)-a-fluoro N-silylated sulfoximine 128, and subsequent elimination and desilylation afforded fluorine-containing sulfoximine 129 in moderate yield as a single diastereomer with E configuration at the newly formed double bond.50 Unfortunately, 129 showed no inhibitory activity against human cytochrome P450C24 (CYP24) hydroxylase enzyme (IC50 4 1000 nM), contrasting the behavior of a saturated (non-fluorinated) sulfoximine, which reached a 40-fold higher activity than the commonly used CYP24 inhibitor ketoconazole.
4. Conclusion and perspectives Fluorine-containing sulfoximines are multipurpose molecules with a variety of specific functions. Used as fluoromethyl transfer reagents, they provide access to a wide range of C-, O-, S-, N- and P-fluoroalkylated products. The strongly electronwithdrawing properties of fluorine-containing sulfonimidoyl moieties induce specific reactivities and selectivities, which cannot be achieved by other functional groups. Consequently, first applications have been reported in electronics and material sciences. Studies of bioactive sulfoximines with fluoro groups have been initiated, and with the growing interest in the general field,9 more results will lead to promising candidates in both crops science and medicinal chemistry. We believe that the future of fluorine-containing sulfoximines is bright and will lead to new discoveries affecting chemistry in a most positive manner.
Acknowledgements V.B. is grateful to the Alexander von Humboldt Foundation for a Postdoctoral Fellowship. The authors thank colleagues from Syngenta Crop Protection in Stein, Switzerland, for initial stimuli and acknowledge Dr Ingo Schiffers (RWTH Aachen University) for a careful proof-reading.
Notes and references 1 H. R. Bentley, E. E. McDermott, J. Pace, J. K. Whitehead and T. Moran, Nature, 1950, 165, 150–151. 2 M. Reggelin and C. Zur, Synthesis, 2000, 1–64. 3 H.-J. Gais, Heteroat. Chem., 2007, 18, 472–481. 4 C. Worch, A. C. Mayer and C. Bolm, in Organosulfur Chemistry in Asymmetric Synthesis, ed. T. Toru and C. Bolm, Wiley-VCH, Weinheim, 2008, pp. 209–232. 5 V. Bizet and D. Cahard, Chem. Soc. Rev., 2014, 43, 135–147. 6 J.-A. Ma and D. Cahard, Chem. Rev., 2008, 108, PR1–PR43. 7 G. K. S. Prakash and J. Hu, Acc. Chem. Res., 2007, 40, 921–930. 8 V. Gouverneur and O. Lozano, in Science of Synthesis, Stereoselective Synthesis, ed. J. G. De Vries, G. A. Molander and P. A. Evans, Georg Thieme, Stuttgart, 2011, vol. 3, pp. 851–930. ¨cking, Angew. Chem., Int. Ed., 2013, 52, 9399–9408. 9 U. Lu
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10 C. R. Johnson, K. G. Bis, J. H. Cantillo, N. A. Meanwell, M. F. D. Reinhard, J. R. Zeller and G. P. Vonk, J. Org. Chem., 1983, 48, 1–3. 11 D. Van Leusen and A. M. Van Leusen, Recl. Trav. Chim. Pays-Bas, 1984, 103, 41–45. 12 R. Y. Garlyauskajte, S. V. Sereda and L. M. Yagupolskii, Tetrahedron, 1994, 50, 6891–6906. 13 M. L. Boys, E. W. Collington, H. Finch, S. Swanson and J. F. Whitehead, Tetrahedron Lett., 1988, 29, 3365–3368. 14 C. R. Johnson, J. R. Shanklin and R. A. Kirchhoff, J. Am. Chem. Soc., 1973, 95, 6462–6463. 15 X. Shen, M. Zhou, C. Ni, W. Zhang and J. Hu, Chem. Sci., 2013, 5, 117–122. 16 W. Zhang, W. Huang and J. Hu, Angew. Chem., Int. Ed., 2009, 48, 9858–9861. 17 C. R. Johnson and E. R. Janiga, J. Am. Chem. Soc., 1973, 95, 7692–7700. 18 W. Zhang and J. Hu, Adv. Synth. Catal., 2010, 352, 2799–2804. 19 X. Shen, W. Zhang, L. Zhang, T. Luo, X. Wan, Y. Gu and J. Hu, Angew. Chem., Int. Ed., 2012, 51, 6966–6970. 20 W. Zhang, F. Wang and J. Hu, Org. Lett., 2009, 11, 2109–2112 Correction: Org. Lett., 2013, 15, 5613. 21 C. Urban, F. Cadoret, J.-C. Blazejewski and E. Magnier, Eur. J. Org. Chem., 2011, 4862–4867. 22 C. R. Johnson, E. R. Janiga and M. Haake, J. Am. Chem. Soc., 1968, 90, 3890–3891. 23 G. K. S. Prakash, Z. Zhang, F. Wang, C. Ni and G. A. Olah, J. Fluorine Chem., 2011, 132, 792–798. 24 X. Shen, W. Zhang, C. Ni, Y. Gu and J. Hu, J. Am. Chem. Soc., 2012, 134, 16999–17002. 25 N. Shibata, A. Matsnev and D. Cahard, Beilstein J. Org. Chem., 2010, 6, 65. ´ and E. Magnier, Eur. J. Org. Chem., 2012, 2479–2494. 26 Y. Mace 27 A. Sandhu, G. L. Gard, N. R. Patel, R. L. Kirchmeier and J. M. Shreeve, Inorg. Chem., 1993, 32, 3205–3208 and references therein. 28 T. Abe and J. M. Shreeve, Inorg. Chem., 1981, 20, 2432–2434. 29 T. Abe and J. M. Shreeve, Inorg. Chem., 1981, 20, 2894–2899. 30 N. V. Kondratenko, O. A. Radchenko and L. M. Yagupol’skii, Zh. Org. Khim., 1984, 20, 2250–2251. 31 E. Magnier and C. Wakselman, Synthesis, 2003, 565–569. 32 K. Adachi and S. Ishihara, Jpn. Kokai Tokkyo Koho, JP2005145917, Daikin Industries, Ltd., Japan, 2005. 33 N. V. Kondratenko, V. I. Popov, G. N. Timofeeva, N. V. Ignatiev and L. M. Yagupol’skii, Zh. Org. Khim., 1984, 20, 2599–2604. ¨hne and K.-P. Wanczek, 34 P. Kirsch, M. Lenges, D. Ku Eur. J. Org. Chem., 2005, 797–802. ´, C. Urban, C. Pradet, J. Marrot, J.-C. Blazejewski and 35 Y. Mace E. Magnier, Eur. J. Org. Chem., 2009, 3150–3153. ´, F. Cadoret, J.-C. Blazejewski and 36 C. Urban, Y. Mace E. Magnier, Adv. Synth. Catal., 2010, 352, 2805–2814. 37 R. Kowalczyk, A. J. F. Edmunds, R. G. Hall and C. Bolm, Org. Lett., 2011, 13, 768–771.
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´, B. Pe ´got, R. Guillot, C. Bournaud, M. Toffano, 38 Y. Mace G. Vo-Thanh and E. Magnier, Tetrahedron, 2011, 67, 7575–7580. ´, C. Constant-Urban, S. Bouvet, B. Pe ´got, 39 Y. Mace C. Bournaud, M. Toffano, G. Vo-Thanh, P. Diter and E. Magnier, Synthesis, 2013, 1505–1512. 40 S. Noritake, N. Shibata, S. Nakamura, T. Toru and M. Shiro, Eur. J. Org. Chem., 2008, 3465–3468. 41 Y. Nomura, E. Tokunaga and N. Shibata, Angew. Chem., Int. Ed., 2011, 50, 1885–1889. 42 Y.-D. Yang, X. Lu, G. Liu, E. Tokunaga, S. Tsuzuki and N. Shibata, ChemistryOpen, 2012, 1, 221–226. 43 L. M. Yagupol’skii, J. Fluorine Chem., 1987, 36, 1–28 and references therein. 44 V. N. Boiko, N. V. Kirii and L. M. Yagupolskii, J. Fluorine Chem., 1994, 67, 119–123.
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45 F. Terrier, E. Magnier, E. Kizilian, C. Wakselman and E. Buncel, J. Am. Chem. Soc., 2005, 127, 5563–5571. ´, S. Clift, O. Mongin, 46 C. Rouxel, C. Le Droumaguet, Y. Mace E. Magnier and M. Blanchard-Desce, Chem.–Eur. J., 2012, 18, 12487–12497. 47 M. Haerter, H. Beck, P. Ellinghaus, K. Berhoerster, S. Greschat, K.-H. Thierauch and F. Suessmeier, German Pat., WO 2010054764, 2010. 48 A. Plant, J. E. Boehmer and A. L. Peace, GB Pat., WO 2006037945, 2006. 49 Y. Zhu, R. B. Rogers and J. X. Huang, US Pat., US 20050228027, 2005. 50 M. Kahraman, S. Sinishtaj, P. M. Dolan, T. W. Kensler, S. Peleg, U. Saha, S. S. Chuang, G. Bernstein, B. Korczak and G. H. Posner, J. Med. Chem., 2004, 47, 6854–6863.
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Cite this: DOI: 10.1039/c3cs60427f
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Fluorinated sulfoximines: syntheses, properties and applications Vincent Bizet,a Rafał Kowalczykb and Carsten Bolm*a The interest in fluorinated sulfoximines has rapidly increased over the past twenty years. As sulfoximines are analogues of sulfones where one of the two SQO units has been replaced by an SQN moiety, they can confer new reactivities and properties never observed for the respective sulfones. In this tutorial review, we present the specific properties of fluorinated sulfoximines (including important bioactivities) and describe
Received 25th November 2013
the syntheses and the applications of fluoromethyl transfer agents such as Johnson’s reagent. Furthermore,
DOI: 10.1039/c3cs60427f
we highlight the exceptional electronic effects induced by the presence of strongly electron-withdrawing fluoro-bearing sulfonimidoyl moieties, which allowed the development of remarkable super-acidifiers
www.rsc.org/csr
and super-acceptors with relevance in materials sciences.
Key learning points (1) (2) (3) (4)
Monofluoromethyl sulfoximines have a similar reactivity to Johnson’s reagent and can provide fluoroolefins, epoxides and cyclopropanes. Difluoromethyl and trifluoromethyl sulfoximines are electrophilic fluoromethyl transfer reagents. Fluorinated sulfonimidoyl groups are strong electron-withdrawing substituents applied in super-acidifiers and super-acceptors. Sulfoximines with fluorosubstituents can reveal interesting bioactivities.
Introduction The first sulfoximine was described by Bentley and co-workers in 1950.1 Formally, sulfoximines are monoaza analogues of sulfones where one of the sulfonyl oxygens is substituted by a nitrogen.2 This ‘‘one atom switch’’ has various advantages: first, the sulfur atom of the sulfonimidoyl group can be stereogenic, a property that has been utilised successfully in asymmetric synthesis.3,4 Second, the sulfoximine nitrogen can be functionalised, which allows introducing synthetic diversity, specific reactivity and unprecedent electronic properties. The replacement of hydrogen atoms by small and highly electronegative fluorine atoms has become an attractive tool to modify reactivities, properties and conformations of molecules.5 For the stereoselective introduction of fluorine atoms or fluoromethyl groups highly efficient methods have been reported.6 Initially, fluorinated sulfoximines have only been prepared as structural analogues of the corresponding sulfides, sulfoxides and sulfones.7 Soon, however, it became apparent that they
exhibited a significantly different reactivity. To illustrate this change, various fluoromethyl transfer reagents are depicted in Fig. 1. All fluorinated compounds shown in Fig. 1 are able to transfer fluoroalkyl (CH2F, CHF2 or CF3) groups. Noteworthy is, however, that fluoromethyl sulfones act as nucleophilic transfer agents (for CHF2 , –CF2–, QCF2 or CF3 ), while fluoromethyl sulfoximines 2–4 (as analogues of Johnson’s reagent 1) are
a
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany. E-mail: [email protected]; Fax: +49-241-809-2391; Tel: +49-241-809-4675 b Department of Organic Chemistry, Faculty of Chemistry, Wroclaw University of Technology, 50-370 Wroclaw, Poland
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Fig. 1
Comparison between fluoromethyl sulfones and sulfoximines.
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electrophilic (transferring CH2F, CHF2+, CHF2, or CF3+).8 This pronounced difference in reactivity allows the synthesis of a wide range of highly functionalised fluorinated molecules by carefully selecting the adequately substituted reagent. The possibility of introducing substituents on the sulfoximine nitrogen of fluorinated derivatives leads to additional opportunities. Thus, fluorinated sulfoximines can, for example, serve as materials for applications in electronics, where the acidity of the C–H bonds as well as the potential of aromatic compounds to undergo nucleophilic substitution reactions is fine-tuned by the N-substituent. Until recently, sulfoximines have been rather neglected in medicinal chemistry.9 However, growing interest can be noted, and the efficient synthetic methods summarised here will probably find applications in the synthesis of fluorinated drugs. Thus, the aim of this tutorial review is to give an overview of the high synthetic potential of sulfonimidoyl fluoride (S-F, Fig. 2) and fluorinated sulfoximines (S-CF, S-CF2, S-CF3 and S-Rf, Fig. 2). Accordingly, we discuss their properties, preparation and applications as key components of materials and bioactive agents.
Vincent Bizet
Vincent Bizet received his MSc in 2009 from the University of Caen, and completed his PhD in 2012 in UMR CNRS 6014 COBRA under the direction of Dr Cahard. He is currently a postdoctoral research associate with Professor Bolm at the RWTH Aachen University. As an Alexander von Humboldt postdoctoral fellow Vincent Bizet focusses on the asymmetric synthesis of fluorinated molecules and sulfoximines.
Rafał Kowalczyk received his PhD in 2006 from Wroclaw University of Technology under the supervision of Professor Skarzewski. In 2008 he was awarded a fellowship for postdoctoral research in the group of Professor Jurczak in the Institute of Organic Chemistry PAN. One year later he joined the group of Professor Bolm at RWTH Aachen University, where he was a postdoctoral associate until 2010. Currently, Rafał Kowalczyk is an Rafał Kowalczyk Associate Professor at the Wroclaw University of Technology. His research interest relates to asymmetric catalysis, organic synthesis, and organic chemistry of sulfur- and fluorine-containing compounds.
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Fig. 2
Sulfonimidoyl fluoride and fluorinated sulfoximines.
1. Preparation and use in organic synthesis Incorporation of a fluoroalkyl group (CF, CF2, CF3) into molecules is still a challenging task. Thus, methods allowing convenient fluoroalkylation of C-, O-, S-, N- and P-atoms are currently a subject of great interest. The development of fluorinated sulfoximines having an S-CF, S-CF2, S-CF3 or S-Rf bond gave a range of reagents with the ability to transfer a CFx group to another molecule. 1.1
S-F sulfonimidoyl fluorides
Sulfonimidoyl fluorides 7 can be prepared by treatment of sulfonimidoyl chlorides 6 with a fluoride source (sodium fluoride, potassium fluoride or tetrabutylammonium fluoride) in moderate to good yields (up to 89%; Scheme 1).10 They are relatively stable and can be purified by flash column chromatography. In synthesis, sulfonimidoyl fluorides have allowed
Scheme 1 Synthesis of sulfonimidoyl fluoride and behaviour of sulfonimidoyl halides in nucleophilic substitution reactions with organometallic reagents.
Carsten Bolm studied chemistry at the TU Braunschweig in Germany and at the University of Wisconsin in Madison (USA). In 1987 he finished his doctoral work with Professor Reetz in Marburg (Germany). After postdoctoral studies at MIT, Cambridge (USA), with Professor Sharpless, Carsten Bolm began to work on his habilitation in Basel (Switzerland) in the group of Professor Giese. In 1993 he Carsten Bolm became Professor of Organic Chemistry at the University of Marburg (Germany), and since 1996 he has been full professor of Organic Chemistry at the RWTH Aachen University (Germany). In 2012 he became an adjunct professor at WIT (Wuhan Institute of Technology), China.
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overcoming a serious limitation in the preparation of sulfoximines 8, where attempted nucleophilic substitution of sulfonimidoyl chlorides with organometallic reagents only afforded the corresponding sulfinamides 5. Sulfonimidoyl fluorides, in contrast, behave differently, providing the desired products in high yields (Scheme 1). For example, reactions of 7 with methyl- or butyllithium mainly lead to the corresponding sulfoximines (in yields up to 100%). It is noteworthy that applying Grignard reagents is less successful resulting in mixtures of both sulfoximines and sulfinamides. With anisole, a sulfonimidoyl fluoride was shown to undergo a Friedel–Crafts-type reaction affording the sulfoximine in 63% yield. When the corresponding sulfonimidoyl chloride was applied, the yield was only 36%.10 Similarly, 7 reacted with a-lithio isocyanides to give sulfoximines in yields up to 68%.11 Fluorination of N-trifluoromethylsulfonyl sulfonimidoyl chlorides 9 with CsF gave at best a 20% yield of fluorides 10. Good to excellent yields of 10 were achieved starting from sulfonimidoyl chlorides 9 or sulfonimidoyl ammonium salt 11 with trifluoride antimony or xenon difluoride, respectively (Scheme 2).12 1.2
S-CF sulfoximines
For preparing monofluoro olefins, epoxides and cyclopropanes, S-CF sulfoximines such as 16 are highly efficient reagents. The first synthesis of a S-CF sulfoximine was accomplished in a four-step reaction sequence with an overall yield of 52% (Scheme 3).13 Monofluoro sulfide 13 was obtained from the phenyl methyl sulfoxide (12) by fluorination with DAST. Oxidation of 13 with m-CPBA afforded S-CF sulfoxide 14, which was sequentially iminated and N-methylated using standard protocols elaborated by Johnson to give S-CF sulfoximine 16 via 15.14 Following Johnson’s strategy for the synthesis of olefins using sulfoximines (Scheme 4, top), 16 was shown to be a mild fluoromethylenation agent.13 Consequently, it was applied in
Scheme 2
Syntheses of N-trifluoromethylsulfonyl sulfonimidoyl fluorides 10.
Scheme 3
Syntheses of fluoromethyl sulfoximines 15 and 16.
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Scheme 4
Olefination of aldehydes and ketones with 16.
the preparation of 9-fluoromethylene analogues of prostaglandin E2 (PGE2), where the CQCHF moiety was expected to enhance the product stability in comparison to PGE2. In this manner, olefination of silyl-protected PGE2 derivative 19 with sulfoximine 16 led to PGE2 analogues 20 in 44% yield. Unfortunately, the E/Z ratio of the newly formed double bond was only 48/52 (Scheme 4, middle). This unsatisfying diastereoselectivity was also found in reactions of 16 with other ketones providing isomeric mixtures of olefins suggesting a rather limited synthetic applicability of this approach (Scheme 4, bottom). The N-tosyl analogue of 16, sulfoximine 26, has recently been described to be useful in monofluoromethylation of O-, S-, N-, and P-nucleophiles.15 The reagent was prepared starting from 13 by imination with chloramine-T to give sulfilimine 25, which was subsequently oxidized with H2O2 providing 26 in good overall yield (Scheme 5). Generally, treatment of deprotonated nucleophiles with 26 led to products such as 27–31 in very high yields. Mechanistically, electron transfer processes and the involvement of CH2F radicals were proposed. In contrast to the aforementioned synthetic approaches towards S-CF sulfoximines 16 and 26, which both started from monofluorosulfide 13,13,15 an alternative method has been developed for the monofluorination of S-aryl S-benzyl sulfoximines 32. This protocol involved a deprotonation of the benzylic position of 32 with sodium hydride and subsequent reaction of the resulting anion with N-fluorobenzenesulfonimide (NFSI) as an electrophilic fluorine source (Scheme 6). In this manner, fluorinated sulfoximines 33 were obtained in yields ranging from 61% to 83%.16 Applying fluorinated benzyl sulfoximines 33a–e in olefination reactions with nitrones like 34a gave a range of fluoroolefins such as 35b in moderate to excellent yields (29 to 94%) with good
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Scheme 5 Syntheses of fluoromethyl sulfoximine 26 and products obtained from it.
Scheme 6 with NFSI.
Scheme 7
Syntheses of 33a–e through electrophilic fluorination of 32a–e Scheme 8
Olefination of nitrones with fluorinated sulfur reagents.
to excellent E/Z selectivities (E/Z: 26 : 74 to 0 : 100) in favour of the Z isomer.16 To gain further mechanistic insight, competition experiments with sulfoximine 32a, its fluorinated analog 33a and difluoro sulfone 36 were carried out (Scheme 7). Interestingly, the presence of the fluorine atom as in 33a improved the reactivity significantly leading to the corresponding olefin 35b in 87% yield, compared to only 34% yield for the non-fluorinated sulfoximine 35a. Moreover, the E/Z selectivity was excellent in both cases. (Note that both olefins had trans phenyl substituents and that the E/Z preference change was only a result of the CIP priority rules.) From the reaction of fluorinated sulfone 36 with nitrone 34b the expected olefin was never obtained but instead, the corresponding adduct 37 was isolated in 61% yield. The proposed mechanism is shown in Scheme 8. The reaction proceeds through the addition of sulfoximine anion 38 to nitrone 34a followed by an unusual 1,2-elimination of intermediate 39 to give product 35b, nitrosobenzene (40) and deprotonated N-tosyl-phenyl sulfonamide (41). The high level of
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Proposed mechanism for the olefination with nitrones.
stereoselectivity in favour of the Z isomer of 35b can be attributed to the formation of the pro-(Z)-adduct avoiding unfavourable interactions of the two aromatic rings as found in the pro-(E)-adduct.16 Another extension of Johnson’s early discoveries17 is the synthesis of monofluorinated epoxides through the addition of sulfoximine anions to carbonyl compounds (Scheme 9).19 Fluorinated S-aryl-S-alkyl sulfoximines 42 were prepared using the monofluorination method with NFSI, and products with S-ethyl, S-propyl, and S-pentyl chains were obtained in 69%, 71% and 54%, respectively. Deprotonation of 42 with n-butyllithium followed by reaction of the resulting anions with ketones 43 afforded monofluoroepoxides 44 in moderate to excellent yields (30 to 94%). Interestingly, aldehydes such as benzaldehyde could not be used in this reaction as they afforded complex product mixtures. Isolation of the rather unstable fluorinated epoxides was only possible for acetophenone derivatives with strong electron-withdrawing substituents. Essentially equimolar amounts of the diastereomers were obtained, which could be separated
Scheme 9
Epoxide formation through ketone addition.
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Scheme 11 Synthesis of 49 and its utilisation as a CHF2 transfer reagent. Scheme 10 Cyclopropanation of a,b-unsaturated Weinreb amides with enantiopure fluoro sulfoximines (R)-46.
by silica gel flash chromatography. Finally, a ring opening process was developed which allowed 1,2-fluorine shift reactions to occur converting epoxides 44 into a-fluorinated carbonyl compounds 45 with quaternary carbon atoms.18 Recently, enantiopure fluorosulfoximines (R)-26 and (R)-42 (where R1 = Me) have been applied in asymmetric syntheses of monofluorocyclopropanes of type 47 (Scheme 10).19 Both reagents were obtained by electrophilic fluorination of the corresponding enantiopure (S)-N-tosyl-S-alkyl-S-phenyl sulfoximines using a similar deprotonation/NFSI addition sequence as presented before. Treatment of fluoro-sulfoximines (R)-26 and (R)-42 with lithium hexamethyldisilazide (LiHMDS) in either THF or toluene followed by reaction of the resulting anions with a,b-unsaturated Weinreb amides 46 gave monofluorocyclopropanes 47 in high yields and with excellent stereoselectivities. In general, the diastereoisomeric ratios were higher when the reaction was performed in THF, while the use of toluene led to superior enantioselectivities. Accordingly, monofluorocyclopropanes 47a and 47b with (het)aryl substituents (R1) were obtained from 46 and (R)-26 with stereoselectivities of up to 99 : 1 dr and 98% ee in yields of 73–97%. The results for alkyl-substituted 47c were less satisfying as it was only formed as a mixture of three diastereomers in a ratio of 75 : 19 : 6 in 62% yield. Application of S-ethyl-substituted (R)-42 afforded products 47d and 47e in good yields (70–75%) with stereoselectivities of 87 : 13 dr and 76–87% ee. Finally, products 47 were transformed into other synthetically valuable compounds such as aldehydes, alcohols or ketones. Importantly, such reactions proceeded in good yields without racemization.19 Recently, the reactivity of S-CF sulfoximinium salts 2 has been under investigation. For a better understanding in a wider context, those results will be discussed in part 1.4.
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1.3
S-CF2 sulfoximines
Whereas S-CF2 sulfones7 have widely been used as nucleophilic difluoromethylation agents, S-CF2 sulfoximines such as 49 have served as electrophilic sources of CF2 allowing difluoroalkylation of C-, O-, S-, N- and P-nucleophiles (Scheme 11).20 The preparation of S-CF2 sulfoximine 49 started from the corresponding S-difluoromethyl sulfoxide 48, which was iminated by copper-catalyzed degradation of PhIQNTs to give 49 in 60% yield. Reactions with deprotonated aromatic and heteroaromatic thiols 50 as well as benzyl thiol provided the corresponding S-CHF2 derivatives 51 in moderate to good yields (57–94%). Notably, benzo[d]thiazole-2-thiol was difluoromethylated at both the sulfur and the nitrogen atom to give 52 and 53 in 44% and 27% yield, respectively. Under the same conditions, various other nitrogen-containing heterocycles 54 were reacted with 49 providing N-CHF2 products 55 in yields ranging from 40% to 72%. Also carbon nucleophiles were difluoromethylated as exemplified by reactions of arylacetylenes 56 with 49, which led to alkynes 57 in yields up to 87%. The application of sulfoximine 49 in the difluoromethylation of alkynes is an alternative to the common freon (CHF2Cl) based approach. Similar conditions for fluoromethylation of acetylenes were investigated with S-CF3, S-CF2Br and S-CFCl2 sulfoximines. Their low reactivity, however, led to only moderate yields (up to 53%) of the corresponding products.21 N,N-Dimethyl-S-difluoromethyl-S-phenyl-sulfoximinium tetrafluoroborate (3a), which is the difluoromethyl analogue of Johnson’s reagent 1 (Fig. 1),22 was prepared from thiophenol [50, where (Het)Ar is Ph] via difluoromethyl phenyl sulfoxide (48), which was iminated using a combination of oleum and sodium azide in DCM to give sulfoximine 58 in quantitative yield. Two subsequent methylations with trimethyloxonium tetrafluoroborate provided 3a via N-methyl derivative 59 in good overall yield (Scheme 12). Salt 3a formed in situ from 59 proved to be a highly active difluoromethyl transfer reagent for a wide range of N-, P-, S-,
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Scheme 12 Synthesis of 3a, the S-CHF2 analogue of Johnson’s reagent.
Scheme 14 Asymmetric syntheses of alcohols with terminal difluoromethyl groups.
1.4
Scheme 13 Application of in situ generated 3a as a CHF2 transfer reagent.
and O-nucleophiles (Scheme 13).23 In this manner, phosphonium salts 60 were obtained in yields of 35% to 57%, for both aliphatic or aromatic phosphines. Ammonium salts 61 were obtained in moderate to good yields (47–83%) starting from tertiary amines including triethylamine, N,N-dimethylaniline derivatives and N-phenylimidazol. The difluoromethylation of sodium thiophenolate led to 62 (with R = Ph) in 78% yield. Other sodium thiophenolates gave much lower yields of 62 (19–45%). Applying the same conditions to aliphatic alcohols gave the corresponding difluoromethyl ethers 63 in 25% to 48% yield. Deuterium labeling experiments provided mechanistic evidences of an electrophilic difluoromethylation pathway, and ruled out a pathway via a difluorocarbene. Recently, the synthetic potential of 49 as a nucleophilic difluoromethyl transfer agent has been investigated (Scheme 14).24 Unfortunately, deprotonation of 49 in the presence of an aldehyde or a ketone did not lead to any of the expected addition products 65 presumably due to the inherent instability of intermediately formed anion 64, which decomposed leading to difluorocarbene (66). However, replacing the electron-withdrawing tosyl group on the sulfoximine nitrogen of 49 by a tert-butyldimethylsilyl substituent afforded an alternative reagent 67, which proved significantly more stable in its deprotonated form (70). Reacting enantiopure (R)-70 with ketones followed by acidic desilylation led to NH-sulfoximines 68 with difluoromethylene groups in good yields and with moderate to high diastereoselectivities. Mild reductive desulfurisation of the major diastereomer of 68 with metallic magnesium provided optically pure tertiary alcohols 69 bearing terminal difluoromethyl groups in good yields.
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S-CF3 and S-Rf associated sulfoximines
Fluorinated sulfoximines with CF3 groups and Rf substituents are important reagents for trifluoromethylations25 and perfluoroalkylation reactions.26 Three synthetic methods have been developed for accessing such compounds. The pioneering work of the first stems from Shreeve, who obtained various S,S-perfluorosulfilimines and -sulfoximines27–29 starting from S,S-difluoroS,S-bis(perfluoroalkyl)sulfides or sulfoxides. As attempts to apply the standard protocol for sulfoxide iminations with sodium azide in sulfuric acid failed in cases of S-aryl S-CF3 derivatives, oleum (24%) was applied as solvent instead of sulfuric acid, and in this manner the desired S-aryl S-CF3 sulfoximines were accessed in up to 96% yield.30 A similar strategy was then applied to S-alkyl S-CF3 and S-alkyl S-C8F17 sulfoxides 71, which led to the corresponding sulfoximines 72 in high yields (Scheme 15).31 The procedure with sodium azide in oleum was also used for the syntheses of 1-oxo-1-trifluoromethyl-1l6-benzo[d]isothiazol3-one (73a), 1-trifluoro-methyl-benzo[1,3,2]dithiazole 1,3,3-trioxide (73b), and acyclic sulfoximines 74a and 74b (Scheme 16). Those S-CF3 sulfoximines were then applied for the introduction of CF3 groups through reactions with Grignard reagents (13–32%), sodium thiophenoxides (47–70%), and arylacetylene lithium salts (48–73%).32 The main drawback of the aforementioned methods for the synthesis of S-Rf sulfoximines is the use of the hazardous combination of sodium azide in sulfuric acid or oleum, as sodium azide is difficult to handle on a large scale and the in situ formation of HN3 presents a serious limitation for industrial applications.
Scheme 15
Syntheses of S-Rf sulfoximines 72 with sodium azide.
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Scheme 18
Scheme 16
Electrophilic trifluoromethylation of various nucleophiles.
The second route towards perfluorinated sulfoximines 72 involves S-Rf sulfilimines such as 78, which require subsequent oxidations to give 72 (Scheme 17). For accessing S-Rf N-acyl sulfilimines 78 a convenient method has been developed, which starts from the corresponding S-Rf sulfoxides 71, which are activated by treatment with trifluoromethanesulfonic anhydride. Reactions of the resulting sulfonium salts 80 with (amides33,34 or) organonitriles35,36 lead to intermediates 81, which are hydrolysed upon aqueous work-up to give S-Rf N-acyl sulfilimines 78. While oxidation of 78 with potassium permanganate affords S-Rf N-acyl sulfoximines 79 in 40–95% yield, the same reaction in the presence of sodium hydroxide leads to S-Rf NH sulfoximines 72 in yields of 36–72%. To provide a more rapid and direct access to 72, a one-pot procedure was developed using a combination of the previously described conditions, which gave 72 in yields ranging from 63% to 94% (Scheme 17).35 Finally, the last approach towards S-Rf sulfoximines relies on the introduction of a trifluoromethyl group starting from sulfonimidoyl fluorides 7.12,37 Initially, Yagupolskii applied a combination of the Ruppert–Prakash reagent (TMSCF3) and a catalytic amount of tris(dimethylamino)sulfonium difluorotrimethylsiliconate
Scheme 17 Conversion of S-Rf sulfoxides into S-Rf sulfilimines and sulfoximines.
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Nucleophilic trifluoromethylation of sulfonimidoyl fluorides.
(TASF) for the nucleophilic trifluoromethylation of 7.12 Accordingly, the resulting N-protected S-CF3 sulfoximine 82 (with R1 = meta-fluorophenyl and R2 = SO2CF3) was obtained in 70% yield. Recently, this route has been modified by substituting TASF with tetrabutylammonium fluoride (TBAF). Yields of up to 79% were thereby realized in syntheses of S-CF3 sulfoximines 82 with various S-alkyl or S-aryl substituents (Scheme 18).37 The required sulfonimidoyl fluorides 7 were prepared in 35–89% yield from the corresponding chlorides 6 by reactions with KF or AgF in the presence of a catalytic amount of 18-crown-6. In order to increase the electron-withdrawing properties of the S-Rf sulfoximines, various N-functionalised derivatives were prepared.31 For this study, 72a served as a representative starting material, and groups such as trifluromethanesulfonyl (Tf), trimethylsilyl (TMS), nitro (NO2), perfluorobutanesulfonyl (SO2C4F9) or arenes substituted with cyano or nitro groups were introduced (Scheme 19). N-Arylation of fluorinated sulfoximines 84 has first been explored using palladium catalysis leading to moderate yields for a limited substrate scope. In contrast, copper-catalysed arylations proved more flexible allowing N-arylation of S-CF3 and S-C4F9 S-aryl sulfoximines in good to excellent yields starting from a wide range of bromo and iodoarenes substituted with both electron donating (Me, OMe) and electron withdrawing (CO2Et, NO2) groups. Even an aryl diiodide reacted well. As examples, N-pyridinyl, N-thionyl and N-naphthyl-substituted S-Rf sulfoximines 85a–c are depicted in Scheme 20.38
Scheme 19
N-Functionalisation of S-CF3 sulfoximine 72a.
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Scheme 20
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Copper-catalysed N-arylation of S-Rf sulfoximines. Scheme 22 reagent 1.
Synthesis and reactivity of 4a, the S-CF3 analogue of Johnson’s
Scheme 23
Electrophilic trifluoromethylation with 4a.
Scheme 21 N-Acylation and related reactions of S-Rf sulfoximines.
N-Acylation of fluorinated sulfoximines has been achieved by reacting NH sulfoximines 84 with acyl chlorides in the presence of triethylamine and a catalytic amount of DMAP. In this manner, a wide range of halomethyl and perfluoroalkyl sulfoximines could be converted providing the corresponding acylated products 86 (with Y = R and X = O) in yields up to 100% (Scheme 21).39 The use of diacyl chlorides led to C2-symmetric bissulfoximines in yield ranging from 54% to 79%. In analogy, 84 could be converted into carbamate-(64–100%), thiocarbamate(60%), urea-(64–82%), and thiourea-type (62%) structures 86 (with Y = OR, NHR and X = O, S). One of the main achievements in the chemistry of fluorinated sulfoximines is undoubtedly the development of reagents for the transfer of trifluoromethyl25 and perfluoroalkyl26 groups. Based on the seminal work by Johnson, who had shown that sulfoximinium salts such as 1 were potential methylene transfer reagents,22 trifluoromethyl analogue 4a was introduced (Scheme 22). Starting from trifluoromethyl phenyl sulfoxide (87) 4a was prepared in a four steps synthesis in 67% overall yield.40 Nitrogen transfer onto 87 using a combination of NaN3 in fuming H2SO4 led to NH sulfoximine 84a, which could be methylated with methyl iodide to give 88. Subsequent alkylation of 88 with methyl triflate gave trifluoromethansulfonate salt 4b, and counterion exchange from triflate to tetrafluoroborate led to 4a. As hypothesised on the basis of Johnson’s results, 4a proved to be an excellent electrophilic trifluoromethylation agent (CF3+ equivalent) that reacted with nucleophiles providing trifluoromethylated products 89 by elimination of dimethyl-benzenesulfinamide (90) in high yields (Scheme 22).40 The ability of 4a to serve as an electrophilic CF3-transfer agent was demonstrated in reactions with anions of b-ketoesters 91
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and in vinylogous trifluoromethylation of dicyanoalkylidenes 93, which provided trifluoromethylated products 92 and 94, respectively, in yields up to 93% (Scheme 23).41 In order to investigate the nature of trifluoromethylation reagent 4a in greater detail, a reaction was carried out in the presence of nitrobenzene, which is known as the radical scavenger. As no alteration of the process was observed, a radical or single electron transfer (SET) mechanism of the CF3 group transfer was excluded. In analogy to 4a (and Johnson’s reagent 1) S-CH2F sulfonate salts 2b and 2c were prepared (Scheme 24).41 With the goal to gain a deeper understanding of their electrophilic transfer properties, the reactivities of 2b and 2c were investigated in comparison to fluoromethyl transfer agents 3a, 4a and 49 (Scheme 25).41 Fluoroalkylation of b-ketoesters 91a providing mono-, di- and trifluoromethylated products 92a, 95–97 was chosen as a test reaction. Surprisingly, 2c showed an exclusive O-selectivity providing 95 as a single isomer. In contrast, 4a gave only
Scheme 24
Synthesis of 2c, the S-CH2F analogue of Johnson’s reagent 1.
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and 49 a dual radical and cationic pathway giving mixtures of O- and C-alkylation products was suggested. The original O-alkylation preference of 2c was extended to a range of other oxygen-containing functionalities such as carboxylic acids, phenols and sulfonic acids, leading to corresponding O-monofluoromethylated products 98–100 in good to excellent yields (Scheme 27).41
2. Electronic properties
Scheme 25
O/C-Selectivity in the fluoromethylation of b-ketoester 91a.
Scheme 26 Proposed mechanisms for fluoromethylation of enolates with S-CF sulfonate salt 2c (left) and S-CF3 sulfonate salt 4a (right).
C-alkylated product 92a. Less attractively, use of S-CHF2 transfer agents 3a or 49 afforded mixtures of C- and O-alkylated products 96 and 97 in varying ratios (ca. 1 : 1 to 2 : 1).42 Molecular orbital calculations revealed that the electrophilic nature (radical or cationic) of the examined fluoromethyl transfer agents was highly dependent on the number of fluorine atoms. A radical-like pathway was suggested for reactions with 2b (Scheme 26, left) involving an addition of the enolate oxygen onto the sulfur atom of 2c followed by a sequential homolytic cleavage of the resulting intermediate. Radical combination and elimination of phenylsulfinamide (90) gave 95. In contrast, the more electron-deficient character of the CF3 substituent of 4a involved an ionic SN2 mechanism of the carbon enolate onto the CF3 leading to 92a (Scheme 26, right).42 For reaction of 3a
Besides their applications in synthetic organic chemistry, fluorinated sulfoximines have gained interest as structural entities in super-acceptors and super-acidifiers.43 The possibility of modifying the electronic nature of molecules by N-substitution presents an advantage of sulfoximines over sulfones. Detailed studies on the modulation of the electron density in various aromatic compounds through the introduction of perfluroalkyl groups resulted in the development of super-strong electron-withdrawing substituents and super-strong acids. The sp-constants of the Hammet scale were used to identify the former. Accordingly, a higher sp-value indicated a stronger electron withdrawing capability of the analysed substituent (Table 1). For a long time, a nitro group was considered the most electron-withdrawing substituent. However, comparing its sp-value to the one found for a S(O)CF3 group shows that the latter also has a very strong electron-withdrawing power and that both are nearly identical (Table 1, entry 1 versus entry 3). While a SCF3 substituent has a smaller sp-value, those of fluorinated sulfimidoyl and sulfonyl groups are larger (Table 1, entries 2, 4 and 5, respectively). Replacing one oxygen of the sulfonyl moiety by an NH group leads to a substituent with lower electronwithdrawing capability (Table 1, entries 5 and 6). However, if the nitrogen bears a triflate instead of a hydrogen, the situation is reverse, and the very large sp-value of 1.39 indicates the exceptional electron-withdrawing power of this substituent (Table 1, entry 7), which corresponds to the relative strength of two nitro groups.43 The strong electron-withdrawing effects of fluorinated sulfonimidoyl substituents with N-triflyl groups was demonstrated experimentally in SNAr reactions starting from either sulfoximine 101 or sulfone 102. Whereas the former reacted smoothly with trifluoroethanol and aniline to provide high yields of the corresponding substitution products 103 and 104, the latter showed low reactivity with trifluoroethanol and none with aniline (Scheme 28).44
Table 1
Scheme 27
Scope of the O-monofluoromethylation with 2c.
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Comparison of the electron withdrawing properties
Entry
Substituenta
s ib
sRb
spb
1 2 3 4 5 6 7
NO2 SCF3 S(O)CF3 S(NSO2CF3)CF3 S(O)2CF3 S(O)(NH)CF3 S(O)(NSO2CF3)CF3
0.57 0.42 0.66 1.07 0.73 0.60 1.05
0.20 0.06 0.11 0.21 0.31 0.24 0.34
0.77 0.48 0.77 1.28 1.04 0.84 1.39
a
Substituent in a benzene ring.
b
Values obtained from 19F NMR spectra.
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Scheme 28 SNAr reactions with fluorinated sulfoximine 101 and sulfone 102.
Based on the soft–hard acid–base theory, it was concluded that the nature of the S(O)(NSO2CF3)CF3 group was hard, exhibiting low polarizability and activating aromatic systems primarily through electron withdrawal by powerful inductive effects. This assumption was in accord with the aformentioned studies (Table 1), which had revealed a significant inductive (si), but low conjugation effect (sR) of the S(O)(NSO2CF3)CF3 group. In order to further investigate the properties of highly fluorinated sulfur substituents, structural, thermodynamic and kinetic effects related to deprotonation of benzyltriflones 107–110 were studied using multinuclear NMR, pKa and Marcus intrinsic reactivity measurements.45 As expected, the S(O)(NSO2CF3)CF3 group in compound 110 had the strongest acidifying effect leading to a pKa value of 6.45 in DMSO (Scheme 29). The analogous data for unsubstituted benzyltriflone 107 was 8 pKa units higher. para-Nitro- and para-trifluoromethylsulfonylsubstituted derivatives 108 and 109 gave intermediate values.
Scheme 29 Electron withdrawing and carbanion stabilisation power of sulfur-containing substitutents.
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Scheme 30
Synthesis of liquid crystalline sulfoximine 117.
A similar trend was observed in pure water or in H2O–DMSO mixtures. For deprotonated 110, four resonance structures can be drawn (Scheme 29). Multinuclear NMR and kinetic studies showed that the highest charge density was located on the benzylic carbon and that the other resonance structures were less relevant. Based on all results, the S(O)(NSO2CF3)CF3 group was classified as a ‘‘super-acidifier’’. Because super-fluorinated materials are known to have a higher dielectric anisotropy (De) and thus a higher dipolar moment, the extraordinary electronic properties of the S(O)(NSO2CF3)CF3 moiety are attractive for the design of compounds applied in liquid crystalline displays (LCDs), organic light-emitting diodes (OLEDs) and organic field-effect transistors (OFETs). An example of a molecule that displays liquid crystallinity is shown in Scheme 30. The synthesis of 117 started from fluorinated hydrocarbon 111, which was converted into the target compound by a five-step reaction sequence. Whereas most steps proceed with satisfying yields, the oxidation of sulfide 113 giving 114 and the subsequent sulfoxide-tosulfilimine conversion of 114 providing 116 led to only low product yields.35 Unexpectedly, the dielectric anisotropy (Devirt) for sulfoximine 117 was significantly lower than the analogous value of sulfone 115. Conformational analysis provided an answer: free rotation of the N–SO2 bond of 117 resulted in three main conformers, which differed in energies in the range of 2.8 kcal mol 1. In each case, the triflic group of the protected nitrogen atom was located above the plane of the aromatic ring. Although all conformers had quite similar and high dipole moments (around 8.2 D), this vector was oblique to the direction of the long molecular axis of the molecule. As a result, the exact dielectric anisotropy of 117 was lower than expected. Recently, octupolar chromophores 120–123 with electronwithdrawing fluorinated sulfonimidoyl substituents have been prepared (Scheme 31). Their syntheses started from aryl
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the sulfur atom had a larger influence on the optical properties than the N–SO2Rf moiety.46
3. Bioactive S-CFx-containing sulfoximines The synthetic methods described above have also been applied in syntheses of bioactive molecules. Consequently, the S-CFx sulfoximine motif can be found in some patents, and three examples are presented in Fig. 3. Thus, S-CF3 sulfoximines 124 are inhibitors of HIF-Luciferase developed for the treatment of hyperproliferative and angiogenesis disorders,47 S-CF2Ar sulfoximine 125 has efficient herbicidal properties,48 and S-CHFAr sulfoximine 126 shows insecticidal features.49 With the goal of introducing conformational changes of the C,D-ring side-chain and to slow side-chain catabolism, fluorinated sulfoximine 129 was prepared as an analogue of hormone 1a,25-dihydroxyvitamin D3 (calcitriol, 130). The key step of the synthesis is shown in Scheme 32. Accordingly, Scheme 31 Synthesis of chromophores containing fluorinated sulfonimidoyl substituents.
bromides 118, which were accessed through a previously described procedure.35 Sonogashira couplings of 118 with tris[4-(ethynylphenyl)]amine (119) afforded 120–123 in moderate yields. Sulfoximines 120–123 showed strong absorptions in the near-UV and emissions in the visible region.46 Compounds with other electron-withdrawing substituents (S-Rf sulfoxides, sulfones and N-acyl sulfilimines) were also studied, and 13C NMR analysis revealed a linear correlation between the chemical shift difference (Dd) of the two acetylenic carbons and the Hammet constant (sp), which allowed a classification of the electron-withdrawing power of these groups. This analysis, however, could not be applied to fluorine-containing sulfoximines 120–123 because sp was unknown and Dd of the 13C NMR signals for the two acetylenic carbons was too small [Dd(120 and 121) = 10.2 ppm and Dd(122 and 123) = 10.3 ppm]. Compounds 120–123 showed an intense absorption band in the near-UV-blue-visible, and they were green emitters. An increase of Stokes shift was observed, which correlated with the electron-withdrawing properties of the substituents. All fluorinated sulfoximines were good fluorescence emitters (with fluorescence quantum yields F = 0.6–0.8) with red-shifted emissions from violet to green. This observation was regarded as evidence for core-to-periphery intramolecular charge-transfer transitions promoted by the strong peripheral electron-withdrawing groups. Finally, a linear correlation between the electronic gap (relaxed ground versus excited states) and the electron-withdrawing ability of the peripheral groups as revealed by the known sp constants was found. This correlation allowed the deduction of sp constants for sulfoximines 120 (sp = 1.35), 121 (sp = 1.35), 122 (sp = 1.44) and 123 (sp = 1.46), which showed that the perfluoroalkyl groups at
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Fig. 3
Examples of bioactive fluorinated sulfoximines.
Scheme 32
Synthesis of a 24-sulfoximine analogue of calcitriol.
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aldehyde 127 was treated with (S)-a-fluoro N-silylated sulfoximine 128, and subsequent elimination and desilylation afforded fluorine-containing sulfoximine 129 in moderate yield as a single diastereomer with E configuration at the newly formed double bond.50 Unfortunately, 129 showed no inhibitory activity against human cytochrome P450C24 (CYP24) hydroxylase enzyme (IC50 4 1000 nM), contrasting the behavior of a saturated (non-fluorinated) sulfoximine, which reached a 40-fold higher activity than the commonly used CYP24 inhibitor ketoconazole.
4. Conclusion and perspectives Fluorine-containing sulfoximines are multipurpose molecules with a variety of specific functions. Used as fluoromethyl transfer reagents, they provide access to a wide range of C-, O-, S-, N- and P-fluoroalkylated products. The strongly electronwithdrawing properties of fluorine-containing sulfonimidoyl moieties induce specific reactivities and selectivities, which cannot be achieved by other functional groups. Consequently, first applications have been reported in electronics and material sciences. Studies of bioactive sulfoximines with fluoro groups have been initiated, and with the growing interest in the general field,9 more results will lead to promising candidates in both crops science and medicinal chemistry. We believe that the future of fluorine-containing sulfoximines is bright and will lead to new discoveries affecting chemistry in a most positive manner.
Acknowledgements V.B. is grateful to the Alexander von Humboldt Foundation for a Postdoctoral Fellowship. The authors thank colleagues from Syngenta Crop Protection in Stein, Switzerland, for initial stimuli and acknowledge Dr Ingo Schiffers (RWTH Aachen University) for a careful proof-reading.
Notes and references 1 H. R. Bentley, E. E. McDermott, J. Pace, J. K. Whitehead and T. Moran, Nature, 1950, 165, 150–151. 2 M. Reggelin and C. Zur, Synthesis, 2000, 1–64. 3 H.-J. Gais, Heteroat. Chem., 2007, 18, 472–481. 4 C. Worch, A. C. Mayer and C. Bolm, in Organosulfur Chemistry in Asymmetric Synthesis, ed. T. Toru and C. Bolm, Wiley-VCH, Weinheim, 2008, pp. 209–232. 5 V. Bizet and D. Cahard, Chem. Soc. Rev., 2014, 43, 135–147. 6 J.-A. Ma and D. Cahard, Chem. Rev., 2008, 108, PR1–PR43. 7 G. K. S. Prakash and J. Hu, Acc. Chem. Res., 2007, 40, 921–930. 8 V. Gouverneur and O. Lozano, in Science of Synthesis, Stereoselective Synthesis, ed. J. G. De Vries, G. A. Molander and P. A. Evans, Georg Thieme, Stuttgart, 2011, vol. 3, pp. 851–930. ¨cking, Angew. Chem., Int. Ed., 2013, 52, 9399–9408. 9 U. Lu
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