Electrophilic Fluorination with 1-Fluoro-2,4,6

Organic and Medicinal Chemistry International Journal ISSN 2474-7610

Electrophilic Fluorination with 1-Fluoro-2,4,6- trimethylpyridinium tetrafluoroborate and NFSI (N-Fluorobenzenesulfonimide) reagents directed towards the synthesis of heterocycles ; Current Trends

Pankaj Sharma, Nutan Sharma, Amit Kumar and SunitaBhagat* Department of Chemistry, ARSD College, University of Delhi, India Submission: September 06, 2017; Published: September 19, 2017 *Corresponding author: SunitaBhagat, Department of Chemistry, ARSD College, University of Delhi, Dhaula Kuan, New Delhi-110021, Indias

Abstract Landolphiaowariensis

The phytochemical screening and the antidiarrhoeal activities of the crude extracts from Landolphiaowariensisthe leaves were carried out using standard methods. The results of the phytochemical screening showed thatLandolphiawariensis the plant contained alkaloids, saponins, tannins, flavonoids and glycosides. The results of the antidiarrhoeal screening of the crude extracts showed that exhibited zone of inhibition ranging from 15 mm to 35 mm against test microbes.Salmonella Ethyl-acetate Typhi, Shigelladysentriaeand extract of the Escherichaia Colirespectively being the most active fraction was subjected to column chromatography,1 leading13 to the isolation of single compound that showed a high activities (zone of inhibition from 8mm to 32mm) HNMR, CNMR against these causative agents of diarrhoea (Landolphiaowariensis ). Spectroscopic analysis of the isolated compound using , IR and GCMS showed that the compound was Cis-9-Octadecenoic acid. The result of this works therefore showed that the extract from the leaves of could be used for the treatment of diarrhoea and other diseases caused by targetedKeywords: microorganisms. Antidiarrheal; Landolphiaowariensis

; Isolation; Cis-9-Octadecenoic Acid

Introduction

located at a specific site, or often it is desirable to introduce The development of fluorination chemistry began more the element directly in order to obtain the desired chemical than 100 years ago with the first examples of nucleophilic and composition [12,13]. Electrophilic fluorination is one of the electrophilic fluorination reactions being reported in the second most direct methods for selective introduction of fluorine into half of the 19th century [1,2]. Fluorinated molecules plays a organic compounds [14]. In this respect, various reagents for significant role in pharmaceutical/medicinal [3,4] agrochemical electrophilic fluorination have been developed till now as shown [5,6] and material sciences [7] due to the unique properties in (Figure 1). Elemental fluorine itself is one of the most powerful of fluorine atom [8]. The introduction of fluorine atom can reagents [15]. modulate the properties of biologically active compounds, since 3 3 this may lead to changes in lipophilicity, chemical reactivity, However, fluoroxcompounds3 13 [16], such as CF OF, CF C(O) solubility, conformation, ability of hydrogen-bonding [9]. As a OF, CsSO4F, and CH C(O)OF some of which are generated result, 30-40% of agrochemicals and 20-25% of pharmaceuticals in situ, are exciting reagents for the introduction of fluorine on the market are estimated to contain fluorine [10]. electrophilically into a wide variety of organic compounds [17,18]. Most electrophilic fluorinating reagents are ultimately The efficacy of agrochemicals and pharmaceuticals derived from fluorine gas, the strongest elemental oxidant oftenly enhanced or it is due to the presence of fluorine atom known, which is synthesized by electrolysis of potassium in the structure [11]. Frequently, these type of compounds difluoride in hydrogen fluoride [19]. Electrophilic fluorination can be synthesized from small moieties in which fluorine is reactions with highly oxidizing fluorinating reagents [20] such Organic & Medicinal Chem IJ 3(4): OMCIJ.MS.ID.555620 (2017) 001 Organic and Medicinal Chemistry International Journal

as fluorine gas, hypofluorites, fluoroxysulfates, and perchloryl was crucial for the development of selective, functional-group- N+ fluoride are challenging to perform due to the high reactivity of tolerant fluorination methods. Another class of2 electrophilic3 the reagents. Xenon difluoride was developed as a more stable fluorinating reagents with the general structure R N-F or R -F electrophilic fluorination source, but its high oxidation potential began to gain popularity. In comparison to the previous reagents, still limits the tolerance of this reagent to functional groups [21]. these compounds were stable, safer, milder and less expensive N to produce. Furthermore, some of these compounds proved The development of crystalline, benchtop-stable fluorinating to be as reactive as established reagents in some cases, which reagents such as -fluorobis (phenyl) sulfonimide (NFSI) were also capable of a degree of selectivity that was previously [19] and related analogues [22,23], N-fluoropyridinium salts unattainable [26]. Efforts by Umemoto et al. led to the first [24], and 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo-[2.2.2] isolatable N-fluoropyridinium salts, which had good activity and octane bis(tetrafluoroborate) (Selectfluor, F-TEDABF4) [25] F were amenable to commercial production [27] (Figure 1). F O O F Xe O Cl O F N F F F O F OTf trifluoromethyl hypofluorite difluoroxenon hypofluorous perchloric 1-fluoroquinuclidin anhydride -1-ium

Cl N N F N F S N S O2N O O O O F 2BF4 2-fluoro-3,3-dimethyl-2,3- 2-fluoro-3,3-dimethyl-6-nitro-2,3- Seletfluor dihydrobenzo[d]isothiazole 1,1- dihydrobenzo[d]isothiazole 1,1-dioxide dioxide

F O O O O O N S S S S N F3C N CF3 O O O F BF4 F N,1,1,1-tetrafluoro-N- 1-fluoro-2,4,6-trimeth l ridin N-fluoro-N-(phenylsulfonyl) y py ((trifluoromethyl)sulfonyl)met benzenesulfonamide -1-ium tetrafluoroborate hanesulfonamide Figure 1: Electrophilic fluorinating reagents. Electrophilic Fluorinating Reagents The important role of the counter anion, which influences N-Fluoropyridinium tetrafluoroborate: (Scheme 1) the reactivity, selectivity, and stability of the reagent, was also N F demonstrated [28]. Des Marteau and co-workers later reported N the discovery of -fluorobis [(trifluoromethyl) sulfonyl] imide, BF4 accessed by the reaction of bis [(trifluoromethyl) ulfonyl]-imide F with fluorine gas [29,30]. The synthesis of this compound, which MgX LiCl 2 R R is still one of the most powerful sources of electrophilic fluorine, heptane, 1.5 h, 00C 3 1 was a step forward in the identification of a stable source of 30-83 % Yield electrophilic fluorine with desirable physical properties. One Scheme 1: Synthesis of aryl fluoride from Grignard reagents. major drawback is that it is not commercially available, so that the use of fluorine gas for its preparation in the laboratory is ultimately required. N O More recently, the development of the reagent NFSI O O F BF4 O presented a major advance for electrophilic fluorination, as it is a O THF, 00C, 30 min. F O 5 reliable, mild, stable, and effective source of electrophilic fluorine 4 rt, 48 h 58 %, 67 % ee that lends itself to large-scale synthesis and is commercially available. A number of reagents, each with its advantages and Scheme 2: Fluorination using N-Fluoropyridinium tetrafluoroborate. disadvantages, currently exist for the electrophilic incorporation of fluorine and have been the subject of several reviews [31-34]. In the present review, we give a comprehensive overview of the In (Scheme 1), Lagow and co. workers used literature reports emphasizing on two potential electrophilic N N-Fluoropyridinium tetrafluoroborate as fluorinating reagent fluorinating reagents 1-Fluoro-2,4,6-trimethylpyridinium among the N-fluoropyridinium salt series and can react as tetrafluoroborate and NFSI ( -Fluorobenzenesulfonimide). How to cite this article: Pankaj S, Nutan S, Amit K, SunitaB. Electrophilic Fluorination with 1-Fluoro-2,4,6-trimethylpyridinium tetrafluoroborate and 002 NFSI (N-Fluorobenzenesulfonimide) reagents directed towards the synthesis of heterocycles ; Current Trends. Organic & Medicinal Chem IJ. 2017; 3(4): 555620. DOI: 10.19080/OMCIJ.2017.03.555620. Organic and Medicinal Chemistry International Journal

ortho an electrophilic fluorine source. Exhibiting almost the same of organic molecules. The C-H activation/oxidative fluorination reactivity as other related N-fluoropyridinium salts, albeit with a process allows -fluorination of the aryl ring under kg somewhat−1 lower solubility, it has a high fluorine content (103 g microwave irradiation [38] (Scheme 4). ) [35] (Scheme 2). N (1.5 eq) BF4 CF N F 3 CF3 F BF4 N N 0 10 mol % Pd(OAc)2, C6H6, 110 C, 18 h 9 N 8 H F Pd OAC , ACN, PhCF N ( )2 3 82% 6 − 300 F µ wave ( W) 7 0 150 C, 2 h, 75 % Scheme 4: Palladium-catalyzed fluorination of Scheme 3: Palladium catalyzed fluorination of carbon-hydrogen 8-methylquinoline. bonds.

Tomita, K. and Co workers used N In Scheme 4, Sanford and co workers used Palladium- -Fluoropyridinium catalyzed fluorination of 8-methylquinoline.2 Initial investigations tetrafluoroborate as fluorinating reagent as shown in (Scheme 2). focused on the Pd (OAc) -catalyzed benzylic fluorination of In this case of fluorination of 1-(trimethylsilyloxy) cyclohexene, 8-methylquinoline. This substrate was selected because it the yields and/or rates of reaction are not satisfactory, compared undergoes facile quinoline-directed C-H activation at Pd(II) to Cl to those of the triflateanalog,2 because2 of the reduced solubility of generate a 6-benzyl-Pd species and, as such, has been shown fluorinating reagents in CH . The same reactions performed to serve as an excellent+ substrate for related Pd-catalyzed C-H in acetonitrile, however, give similar results [36] and efficient activation/oxidative functionalization reactions [39,40]. An enantioselective electrophilic fluorination of β-ketoesters can be initial screen of F reagents2 under thermal reaction conditions achieved. It can be seen that use of NFPY (N-fluoropyridinium (10 mol % of Pd (OAc) , 110 °C, 13 h, benzene) revealed that tetrafluoroborate) resulted in moderate enantioselectivities. several conditions affected the desired benzylic C-H bond Interestingly, the addition of the electron-poor alcohol HFIP fluorination reaction, providing desired compound in modest However, N (1,1,1,3,3,3-hexafluoroisopropanol) as additive led to an increase 9-36% yields while using different+ fluorinating reagents [41]. in enantioselectivity to 67% ee [37](Scheme 3). -fluoro-2,4,6-trimethylpyridinium tetrafluoroborate served as a highly effective F source affording products in a 1-fluoro-2,4,6-trimethylpyridin-1-iumtetrafluoroborate was dramatically improved 82% isolated yield. Importantly, control selected as the best electrophilic fluorine donor for palladium- reactions in the absence of Pd catalyst showed none of the catalyzed fluorination on 2-arylpyridines. In Scheme 3, Takeru fluorinated product [42]. Furuya and Co-workers used Palladium catalysed fluorination

Scheme 5: Ligand-assisted Palladium(II)/(IV)o for sp3 C-H fluorination.

How to cite this article: Pankaj S, Nutan S, Amit K, SunitaB. Electrophilic Fluorination with 1-Fluoro-2,4,6-trimethylpyridinium tetrafluoroborate and 003 NFSI (N-Fluorobenzenesulfonimide) reagents directed towards the synthesis of heterocycles ; Current Trends. Organic & Medicinal Chem IJ. 2017; 3(4): 555620. DOI: 10.19080/OMCIJ.2017.03.555620. Organic and Medicinal Chemistry International Journal

F F N F CF3 F CF3 1 mol P T Me N O O 0 % ( d(O f)2( C )2 chiral Pd complexes, a variety of β-ketoesters reacted with 1.5 eq. oxidant R N F -fluorobenzenesulfonimide (NFSI) in an alcoholic solvent such R N F H H F F 20 mol % NMP, MeCN, 24 h, F H 15 as EtOH to afford the corresponding fluorinated products with 1200C 14 36-78 % excellent enantioselectivity (up to 94% ee). Various substrates

Oxidant = including cyclic and acyclic β-ketophosphonates underwent N OTf F the reaction with N-fluorobenzenesulfonimide (NFSI) in EtOH Scheme 6: N-Perfluorotolylamide-directed Pd-catalyzed to give the corresponding fluorinated products in a highly fluorination of arenes. enantioselective manner (94-98% ee). (Schemes 8 & 9) and (SchemeO 10) O O O Pd-cat 1 or 2 P OEt . e P OEt In Scheme 5, experimental investigation concludes a ( )2 NFSI (1 5 q) F ( )2 Solvent. rt 22 23 Scheme 9: Enantioselective electrophilic fluorination of cyclic change of rate limiting step using 8-aminoquinoline vs. β-ketoesters. 8-aminoquinoxaline as directing group by affecting the key Pd Scheme 9: Enantioselective electrophilic fluorination of cyclic β-ketoesters. (II) to Pd(IV) oxidation step. This finding led to the discovery of a simple ligand capable of lowering the activation energy for the O chiral bis (oxazoline)- O oxidation of Pd. This intriguing mechanistic journey provides O copper complexes O

new clues into oxidative C-H functionalization reactions. We P OEt P(OEt)2 NFSI (1.5 eq) F ( )2 expect these results will stimulate the development of new Solvent. rt 22 23 C-H functionalization reactions. It is being observed that if Scheme 10: Copper catalysed enantioselective electrophilic 8-aminoquinoline vs. 8-aminoquinoxaline are removed from the fluorination of cyclic β-ketoesters. reaction mixture the rate of reaction is affected and the overall yield of the reaction affected by 42 %. If the reaction performed without ligand the yield is only 15% and the yields vary with Dominique Cahard and Co workers developed a new different ligands [43] (Scheme 5) and (Scheme 6). efficient catalytic enantioselective electrophilic fluorination Double fluorination through two subsequent ortho of acyclic (Scheme 8) and (Scheme 9) cyclic β-ketoesters is ortho N fluorination events was addressed with a weakly coordinating developed [45]. As low as 1 mol% of chiral bis (oxazoline)- anionic -directing group -perfluorotolylamide derived copper triflate complexes catalyses the fluorination by from benzoic acid that allows for rapid displacement of the means of N-fluorobenzenesulfonimide (NFSI). The use of monofluorinated product by the substrate, thus affording high 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) is crucial for achieving selectivityElectrophilic for monofluorination fluorination (Scheme using 6). N-fluoro-N- high enantioselectivity [46]. Herein a new efficient catalytic (phenylsulfonyl) benzene sulphonamide (NFSI): enantioselective electrophilic fluorination of both cyclic and acyclic β-ketoesters by means of chiral bis (oxazoline)-copper complexes leading to enantio enriched fluorinated compounds in high yields and good enantioselectivities (scheme 10). The positive impact on the enantiomeric excess of achiral additives such as HFIP is alsoMgX reportedLiCl NFS [47,48]I (1.2 eq) (Scheme 11). F Het R 4:1 DCM/perfluorodecalin 2 h rt , 34-94 % Yield 24 25 Scheme 11: Synthesis of aryl fluorides from aryl Grignard reagents. Scheme 7: Enantioselective fluorination of β-ketoesters.

O O O O 1 mol % [Cu]* O O O R O O Ph Pd-cat. 1-5 mol % R2 R O 2 S F ( ) R1 O 1 F O N R O 1.5 eq. NFSI, R + or 1 R3 e . 3 R1 O EtOH IPA F 1 q HOCH(CF3)2, S R2 . o 27 R O O NFSI (1.5 eq) 26 Et2O, 0 5 h t 96 h, 2 rt 80-95% Ph 21 O 20 62-90% ee NFSI up to 94% ee R1= alkyl,Ar. u [C ]* = N O R = Et,Bn etc. Ph Scheme 8: Catalytic enantioselective fluorination of β-ketoesters. 2 Cu N R = alkyl 3 TfO OTf Ph Scheme12: Cu-catalyzed asymmetric α-fluorination of Mikiko Sodeoka co-workers reported a highly efficient β-ketoesters. catalytic enantioselective fluorination of β-ketoesters (Scheme 7) [44]. In the presence of a catalytic amount of

How to cite this article: Pankaj S, Nutan S, Amit K, SunitaB. Electrophilic Fluorination with 1-Fluoro-2,4,6-trimethylpyridinium tetrafluoroborate and 004 NFSI (N-Fluorobenzenesulfonimide) reagents directed towards the synthesis of heterocycles ; Current Trends. Organic & Medicinal Chem IJ. 2017; 3(4): 555620. DOI: 10.19080/OMCIJ.2017.03.555620. Organic and Medicinal Chemistry International Journal

2.5 mol % [Pd*] O O O O 1.5 eq. (Et3O)PF, 1.5 eq NFSI In (Scheme 11), fluorination of Grignard reagents with R O 1 F R1 O - electrophilic N-fluorinated reagents NFSI is the most reliable EtOH,18 72 h, R2 R2 0 -20 C to rt 49-96% method with simple aryl nucleophiles but is narrow in scope 32 83-94% ee = r. due to the basicity and nucleophilicity of the arylmagnesium R1 Alkyl,A 33 R2 = Alkyl,Ar. reagents [49,50]. Through appropriate choice of solvent and 1 P(Ar )2 r1 reagents, undesired protodemetallation products can be [Pd*] = P(A )2 minimized [51]. More recent work by Meng and Li demonstrated 1 the regioselective para fluorination of anilides with PhI(OPiv)2 Ar = 3,5-Dimethylphenyl Scheme 15: Pd-catalyzed asymmetric α-fluorination of β-ketoesters. and hydrogen fluoride/pyridine10 mol % N i[52](Scheme(ClO4)2. 6H2O 12). O O O 11 mol % L*, 1.2 e NFSI q R1 R2 X R R2 R2 . mo 2 R1 X -18 F 2 5 l % [Pd*] F 4 A MS, CH2Cl2,2 h, R H . e . . e R 3 29 1 5 q (Et3O)PF, 1 5 q NFSI 3 23 0C O O 71-93% N 28 N EtOH 18-72 h R1 83-99% ee R1 , , = oc r ar on . Boc - 0 o r Boc X, R1 O,NB ,A ,C b yl L* = 20 C t t 72-97% 34 R2 = tBu, Bn, etc. N 75-96% ee R = H, CF . R3 = Ar O Ph 1 3 35 O N R2 = Alkyl, Ar. Pd* Ph [ ] = 1 P(Ar )2 P Ar1 Scheme13: Ni-catalyzed asymmetric α-fluorination of β-ketoesters ( )2 and N-Boc oxindoles. Ar1 = 3,5-Dimethylphenyl Scheme 16: Pd-catalyzed asymmetric α-fluorination of oxindoles. 2-10 mol % [Ru*] O O O O 2 e . Et O PF, 1.2 e NFSI q ( 3 ) q R2 R1 O R O R2 F 1. 20 mol % catalyst* 5 eq NFSI 1 CH Cl ,24 h,23 0C. R 2 2 3 O 0 R3 9:1 THF/iPrOH, 10-12 h, 0 C R 36-96% R HO 30 H = 8-99% ee 7 F L* N 36 2. NaBH4, CH2Cl2 3 R1 = Alkyl,Ar. Cl 31 N Cl 54-96% R2 = Et,tBu,Bn, Aretc. u R P 91-99% ee R = Me, Bn. Ph2 3 PPh2 N O MacMillan catalyst* = N Ph HO CHCl H 2 Scheme 14: Ru-catalyzed asymmetric α-fluorination of β-ketoesters. Scheme 17: Organocatalytic asymmetric α-fluorination of aldehydes.

1. 1 mol % catalyst*, 1 eq NFSI O MTBE, 12-28 h, 230C R R HO H 0 Several methods have exploited the two-point binding 2. NaBH4, MeOH, 23 C F 38 39 55-95% of dicarbonyl compounds to chiral lewis acid complexes to F C 3 91-97% ee control enantioselective fluorination. Asymmetric fluorination CF3 Jorgensen catalyst* = OTMS of β-ketoesters was achieved with Cu (II)- (Scheme-12) and N H (Scheme 13) [53]. Several methods have exploited the two-point CF3 F C binding of dicarbonyl compounds to chiral lewis acid complexes 3 Scheme 18: Organocatalytic asymmetric α-fluorination of aldehydes. to control enantioselective fluorination. Asymmetric fluorination of β-ketoesters was achieved with Ni (II)-BOX complexes (Scheme 13) [54] by Cahard and Shibata/Toru, respectively (Scheme 14). Chiral Pd-BINAP complexes developed by Sodeoka shown Chiral bis (imino) bis (phosphine) ruthenium (II) complex in (Scheme 15) and (Scheme 16) catalyzes the enantioselective by Togni (Scheme 14) [55] and scandium binapthyl phosphate fluorination of α-ketoesters [59], β-ketoesters (Scheme 11), complexes by Inanaga [56]. The Ni-catalyzed reaction, using [60] β-ketophosphonates, [61] oxindoles, [62] and α-ester lactones/lactams [63]. The use of chiral palladium complexes a 10 mol% catalyst loading, has demonstrated the broadest tert substrate scope so far, and allows for α-fluorination of a variety was particularly successful for the α-fluorination of acyclic of β-ketoesters and N-Boc-protected amides [52] in 71-93% α-ketoesters, cyclic and acyclic -butyl β-ketoester as well yield and 83-99% ee, respectively. The catalytic enantioselective as oxindoles α-substituted with an electronically diverse range α-fluorination of α-substituted methyl, tert-butyl malonate was of aryl and alkylgroups [59-62] (Scheme 17). The aldehyde accomplished via chiral lewis acid catalysis with Zn (II) acetate, α-fluorination method described by MacMillan demonstrates a (R,R)-4,6-dibenzofurandiyl-2,2’-bis(4-phenyloxazoline) ligand, broader substrate scope, (Scheme 17) [64]. These fluorinated and NFSI. This approach was specifically optimized for the compounds are useful for the synthesis of different biological malonate substrate en route to the enantioselective synthesis of active heterocycles [65]. Jørgensen and co workers used NFSI fluorinated β-lactams [57,58]. and organocatalytic α-fluorination of aldehydes. (Scheme 18) How to cite this article: Pankaj S, Nutan S, Amit K, SunitaB. Electrophilic Fluorination with 1-Fluoro-2,4,6-trimethylpyridinium tetrafluoroborate and 005 NFSI (N-Fluorobenzenesulfonimide) reagents directed towards the synthesis of heterocycles ; Current Trends. Organic & Medicinal Chem IJ. 2017; 3(4): 555620. DOI: 10.19080/OMCIJ.2017.03.555620. Organic and Medicinal Chemistry International Journal

[66] While the method described the utilization of lower loadings bond. The formation C-F bonds at sp carbon centers by reductive of catalyst and electrophilic fluorinating reagent. Branched elimination from high-valent transition-metal complexes has aldehydes constitute difficult substrates for enantioselective also been investigated with Pt (IV) complexes [73,74]. α-fluorination;1. nonetheless. mol to 1 e catal st* O 30 % q y R1 1.2 e NFSI R2 Enantiopure (R)-silyl ketones were prepared by R q HO H 2 diastereoselective silylation of the (S)-or (R)-1-amino-2- F 0 R1 2. DMF or THF ,22 h, 23 C 54-96% methoxy methylpyrrolidine (SAMP/RAMP) hydrazone and used - ee 40 91 97% as substrates in diastereoselective electrophilic fluorinations 41 in which the silyl group acts as a traceless directing group. O O O H catal st* = OH OTIPS Lithium enolates of chiral compound generated by LDA were y N N N N fluorinated with enantiopure (R)-silyl ketones were prepared NH NH N N N Ph H H by diastereoselective silylation of the (S)-or(R)-1-amino-2- Scheme 19: Organocatalytic asymmetric α-fluorination of methoxymethylpyrrolidine (SAMP/RAMP) hydrazone and used α-branched aldehydes. as substrates in diastereoselective electrophilic fluorinations in O O LDA or LHMDS which- theu e silyl group acts as a traceless directing group [75]. t B M 2Si t-BuMe2Si F

0 O R1 R2 NFSI, THF, -78 C to rt R1 R2 5 eq NFSI 47 O F 46 R O R PhH, 4 min. 16 h, 1100C OSiMe O O 42 43 3 LDA or LHMDS F - u e t-BuMe Si F - u e - t B M 2Si NFSI 2 t B M 2Si R= CH2Ph, (CH2)2CH2Ph, CHPhMe 24 98% + THF, -78 0C to rt Scheme 20: Fluorination of tert-butyl alkylperoxoates with NFSI. 48 49 50 Contains 5 % 72 % 28 % of the regioisomers Scheme 22: Electrophilic fluorination of (R)-silyl ketones. Barbas (Scheme 19) [67] accomplished the enantioselective organocatalytic α-fluorination of aldehydes. Similarly, Lithium enolates of compound generated by LDA enantioselective α-fluorination of ketones is possible using ee were fluorinated with NFSI in good yields and with high enaminecatalysis [68]. Barbas reported a promising 98-99% diastereomeric excesses. Interestingly, LiHMDS allowed reverse yield and 45-66% for this class of substrates. The fluorinated diastereoselectivity to be obtained. The diastereoselectivity aldehyde products are especially useful for the synthesis of was found to reflect the ratio of enolate stereomers, with NFSI enantiopure β-fluoroamines, which can be obtained by a chiral reacting only from the less sterically hindered enolate face. sulfinyl imine condensation, directed reduction sequence of the This concept was also applied to silyl enol ether; however, the enantioenriched fluorinated aldehyde [69] (Scheme 20). The fluorination gave rise to a significant amount of regioisomers N-F bonds in electrophilic fluorinating reagents have relatively O O O (Scheme 22) [76]. O LiHMDS THF low bond dissociation energies (2.84 eV for N-fluorosultam) O N , tert O N [70]. Under photolysis or thermolysis conditions, a variety of -7 0 NF I Bn 8 C, S F Bn -butyl alkyl peroxoates afforded the corresponding alkyl 50 51 78 % fluorides upon treatment with NFSI (Scheme 20) [71]. Primary > 98 % de alkyl fluoride formation was not efficient, which supports the Scheme 23: Fluorination of oxazolidinone. N(SO2Ph)2 mechanism hypothesis5 mol % of P dradicalOAc , intermediates. ( )2 O 7.5 mol % bathocu roine F O O p F O R R R1 NFSI, 10 mol % Cu (OTf)2, O R 2.5 eq NFSI, dioxane, 10 h, 45 R O R 0 ClCH CH Cl 1 50 C - 2 2 R 44 37 88% 800C, 8h 2 52 53 Scheme 21: Intermolecular aminofluorination of styrenes with NFSI. yield upto 95 % Trans / Cis :upto > 49:1 Scheme 24: Catalytic tandem Nazarov cyclization/sequential fluorination trapping. The intermolecular amino fluorination of styrene’s (Scheme 21) [72] can be facilitated by the use of palladium catalysts as described by Liu. Although reactions accomplish amino A chiral oxazolidinone auxiliary was also used by Stauton fluorination of alkenes, different approaches were employed and co-workers to direct the addition of a fluorine atom in the and different reaction mechanisms proposed for each case. preparation of fluoro analogue as a biosynthetic precursor of the Intermolecular amino fluorination is thought to occur via fluoro- ionophore antibiotic tetronasin (Scheme 23) [77]. A new catalytic palladation involving substrate, NFSI and the active palladium stereo selective tandem transformation via Nazarov cyclization/ complex, followed by oxidation to a putative Pd (IV) species, and electrophilic fluorination has been accomplished (Scheme 24). subsequent reductive elimination to form a carbon–nitrogen This sequence is efficiently catalyzed by a Cu (II) complex to

How to cite this article: Pankaj S, Nutan S, Amit K, SunitaB. Electrophilic Fluorination with 1-Fluoro-2,4,6-trimethylpyridinium tetrafluoroborate and 006 NFSI (N-Fluorobenzenesulfonimide) reagents directed towards the synthesis of heterocycles ; Current Trends. Organic & Medicinal Chem IJ. 2017; 3(4): 555620. DOI: 10.19080/OMCIJ.2017.03.555620. Organic and Medicinal Chemistry International Journal

afford fluorine-containing 1-indanone derivatives with two with NFSI, compared to 82% de with NFOBS, was attributed new stereocenters with high diastereoselectivity (trans/cis up to the greater steric bulk of NFSI. The reaction provided a nice to 49/1). Three examples of catalytic enantioselective tandem example of deconjugative electrophilic fluorination. The acyclic Br Br Br M l Li l transformationiprM gareCl Li Cpresentedl [78]gC (SchemeC NFSI 25).(1.2 eq) Br F fluoro compound was employed in the synthesis of fluoro THF,00C, 1h carbohydrates [81,82] (Scheme 28). Baoming and co workers N N Solvent. rt, 2h N reports in (Scheme 28) that a convenient and efficient method 54 55 56 for fluorination of methylene cyclopropanes is reported. This Scheme 25: Synthesis of aryl fluorides from aryl Grignard reagents. is exemplified in the stereo selective preparation of N-[(E)-3- fluorobut-3-en-1-yl]-benzene sulfonimides by the reaction of H O methylene cyclopropanes with N-fluorobenzene sulfonimide Amine (S)-A or (S)-B O NH R O Benzaldehyde (1 eq) (NFSI) in goodR to excellent yields [83]. 1 (1 eq , Solvent N 1 NFSI (1.2 eq) Ph H N(SO2Ph)2 Ph H 18 MeOH rt 20 min. [ F]NFSI 18 , , Ph H 0 R 57 F R THF, 60 C 2 r m n. 18F 2 63 t, 20 i 58 59 o - 18 62 12 t 36 h o e (S) [ F] 18 65 t 90 % Yi ld (S)-[ F] O Ar N DCA Ar R1 = H, 4-MeC6H4, 4-OMeC6H4,C6H5 r : - - N Ph N OTMS A 3,5 CF3 Ph R = H 4-Me H 4- Me H H H H 1 , C6 4, O C6 4,C6 5 - (S)-A (S) B Scheme 28: Stereoselective fluorination of methylene cyclopropanes Scheme 26: Organomediated enantioselective 18F fluorination using NFSI. for PET applications. O Ph L-proline 30 mol % R2 S O ( ) 2-OH-C H CO H 60 mol % R CHO + F N 6 4 2 ( ) 2 R1 CHO F S O THF 0.1 M , rt F In (Scheme 25), Paul Knochel and co-workers developed 64 ( ) R1 Ph a simple, convenient and highly versatile one-pot method for O 65 E major (E/Z = > 20:1 = - - - e e c. converting aromatic and heteroaromatic bromides or iodides R1 H, 4 FC6H4, 4 ClC6H4, 4 OM C6H4,Ph t α-position only R = H, Me,Et etc. into the corresponding fluorides by choosing an optimized 2 Scheme 29: Stereoselective α,α-difluoro of γ,γ-disubstituted different solvent mixture. This procedure allows a direct access butenals. to fluorinated pyridines, thiophenes, pyrroles and isoquinolines NHC as well as to sterically congested fluorine-substituted benzenes, R LG 1 NHC, NFSI R2 COOEt which are otherwise difficult to prepare. Further investigations R2 O NaHCO R N F 3 1 N EtOH, rt 67 N F of this potentially practical synthetic method are currently 66 H up to 98 % yield underway [79] (Scheme 26). O BF F F O LG = OCOOMe 4 O F O O C -F bond formation O LiHMDS, THF N sp2 N mild reaction conditions BnO Ph Ph NFSI, -780C F Scheme 30: Catalytic α-fluoro allenoate synthesis. BnO 60 61 76 % Yield 1 ee 00 % The allylic moieties has been found in many bioactive Scheme 27: Diastereoselective fluorination of α, β-unsaturated chiral compounds and medicines, and compounds with a fluorine oxazolidinone. atom at the α-position of an allylic moiety, allylic fluorides, have exhibited excellent enhancement of the bioactivity of 18 have served as versatile intermediates in the synthesis of a their parent compounds [84,85]. Furthermore, allyl fluorides The first organomediated asymmetric F fluorination 18 N has been accomplished using a chiral imidazolidinone and large number of fluorinated compounds [86,87] motivating the

[ F] -fluorobenzenesulfonimide in (Scheme 26). This18 development of numerous synthetic methods with controlled method provides access to enantioenriched18F-labeled -regio and stereoselectivity for allylic fluorides in (scheme 29) α-fluoroaldehydes (>90% ee), which are versatile chiral F and (Scheme 30) [88,89]. synthons for the synthesis of radiotracers. The utility of this The first catalytic α-fluoro allenoate synthesis is described process is demonstrated with the synthesis of the PET (positron by complete the structure with a suitable combination of emission tomography) tracer (2S,4S)-4-[18F] fluoroglutamic N-heterocyclic carbine precatalyst, base, and fluorine reagent, acid [80](Scheme 27). the reaction proceeded smoothly to yield a wide range of α-fluoro Diastereoselective fluorination of α,β-unsaturated chiral allenoates with excellent chemoselectivity (Scheme 30). These oxazolidinone was conducted by reaction of LiHMDS followed substituted α-fluorinated allenoates have been synthesized for by addition of NFSI to produce a single diastereomer in 76% the first time, and they are versatile synthetic intermediates yield (Scheme 27).The complete diastereoselectivity reached toward other useful fluorine-containing building blocks [90].

How to cite this article: Pankaj S, Nutan S, Amit K, SunitaB. Electrophilic Fluorination with 1-Fluoro-2,4,6-trimethylpyridinium tetrafluoroborate and 007 NFSI (N-Fluorobenzenesulfonimide) reagents directed towards the synthesis of heterocycles ; Current Trends. Organic & Medicinal Chem IJ. 2017; 3(4): 555620. DOI: 10.19080/OMCIJ.2017.03.555620. Organic and Medicinal Chemistry International Journal

Scheme 31: Fluorination of azolium enolates generated from simple aliphatic aldehydes

F O Ph R R R 2 S O AgNO3 (20 mol %) R2 Guosheng Liu and co workers reported a novel silver- + F N R K CO 2 eq , Et O N 1 S O 2 3 ( ) 2 R1 NHTs s catalyzed intramolecular amino fluorination of allenes for O Ph T 73 74 the synthesis of 4-fluoro-2,5-dihydropyrroles, in which the NFSI (1.5 eq) vinyl C-Ag bond is cleaved using NFSI to afford vinyl C-F Scheme 32: Silver-catalyzed intramolecular amino fluorination of bonds [93]. In addition, further convenient aromatization of allenes. fluorinated dihydropyrroles readily afforded the corresponding 4-fluoropyrrole derivatives (Scheme 33). In Scheme 33, Prochiral indole 75 was also subjected to the optimized fluorocyclization The asymmetric fluorination of azolium enolates that are conditions, which afforded the difluorinated tricyclic tetrahydro generated from readily available simple aliphatic aldehydes oxazolo [3,2-a]O indole 76 in 50% yield, 60% ee [94] (Scheme 34). or α-chloro aldehydes and N-heterocyclic carbenes (NHCs) is NFSI (1MOL %) F described in (Scheme 31). The process significantly expands the O O synthetic utility of NHC-catalyzed fluorination and provides facile R R P(OMe)2 access to a wide range of α-fluoro esters, amides, and thioesters 79 77 N with excellent enantioselectivity [91]. Catalytic systems that 2 45 % to 75 % Yield are based on N-heterocyclic carbenes (NHCs) have proven to be 78 versatile in particular for establishing the α-stereogenic center = e of esters via key azolium enolate intermediates [92](Scheme 32). R yi ld Bn, 56 % (CH2)7CH3 67 % p(OMe)-C6H4CH2 65 % p(Br)-C6H4CH2 69 % Scheme 34: One-pot synthesis of optically active propargylic fluorides.

In (Scheme 34), Jørgensen and co-workers reported a simple, direct one-pot organocatalytic approach to the formation of optically active propargylic fluorides 79. This consists homologation with the Ohira-Bestman reagent 78, providing of organocatalytic α-fluorination of aldehydes followed by Scheme 33: Enantioselective fluorocyclization of prochiral indoles. optically active propargylic fluorides [95,96].

How to cite this article: Pankaj S, Nutan S, Amit K, SunitaB. Electrophilic Fluorination with 1-Fluoro-2,4,6-trimethylpyridinium tetrafluoroborate and 008 NFSI (N-Fluorobenzenesulfonimide) reagents directed towards the synthesis of heterocycles ; Current Trends. Organic & Medicinal Chem IJ. 2017; 3(4): 555620. DOI: 10.19080/OMCIJ.2017.03.555620. Organic and Medicinal Chemistry International Journal

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How to cite this article: Pankaj S, Nutan S, Amit K, SunitaB. Electrophilic Fluorination with 1-Fluoro-2,4,6-trimethylpyridinium tetrafluoroborate and 0010 NFSI (N-Fluorobenzenesulfonimide) reagents directed towards the synthesis of heterocycles ; Current Trends. Organic & Medicinal Chem IJ. 2017; 3(4): 555620. DOI: 10.19080/OMCIJ.2017.03.555620. Organic and Medicinal Chemistry International Journal

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How to cite this article: Pankaj S, Nutan S, Amit K, SunitaB. Electrophilic Fluorination with 1-Fluoro-2,4,6-trimethylpyridinium tetrafluoroborate and 0011 NFSI (N-Fluorobenzenesulfonimide) reagents directed towards the synthesis of heterocycles ; Current Trends. Organic & Medicinal Chem IJ. 2017; 3(4): 555620. DOI: 10.19080/OMCIJ.2017.03.555620.