ELSEVIER Journal of Fluorine Chemistry 87 (1998) l-17

Review

SelectfluorTM reagent F-TEDA-BF, in action: tamed fluorine at your service ’

Ronald Eric Banks * Chrmisty Department, UMIST, Mcrnchrstrr M60 IQD, UK

Received 29 August 1997; accepted 15 October 1997

Abstract

This paper concerns the discovery, properties and applications in organic synthesis of 1 chloromethyl-4-fluoro- 1,4-diazoniabicy- clo [ 2.2.21 octane bis(tetrafluoroborate) (so-called F-TEDA-BF,), one of the best general-purpose user-friendly site-selective electrophilic fluorinating agents to have emerged from a vigorous search worldwide since 1980 for more generally acceptable (non-gaseous, less aggressive. non-explosive, less toxic, relatively inexpensive) reagents than perchloryl fluoride. O-F compounds like trifluoromethyl hypofluorite or caesium fluoroxysulfate, xenon difluoride or fluorine itself. The information presented is based on literature available prior to January 1997. 0 1998 Elsevier Science S.A.

Kqword.~: I-Chloromethyl-4-Auoro-1,4-diazoniabicyclo[ 2.2.2loctane bis(tetraAuoroborate); Electrophilic fluorination; N-Fluoro-compounds; Fluorinated biochemicals; F-TEDA-BF,

1. Introduction

What’s the connection between atomic power, refrigera- tion, toothpaste, aluminium, microelectronics, stain-resistant clothing, tire protection in aircraft and the Channel Tunnel (Eurotunnel), anticancer agents, non-stick cookware, retinal surgery and batteries for electronic watches and calculators? The answer is fluorine chemistry, commercial development of which has touched all our lives in more ways than even many chemists suspect. Of paramount importance to the growth of the fluorochemicals industry has been the realiza- tion that dramatic changes in the physical and biological properties and chemical reactivities of organic materials can be brought about by fluorination, as witnessed by today’s amazingly diverse and constantly expanding range of com- mercial products (agrochemicals, mediscal and healthcare products, surfactants, textile chemicals. dyes, liquid crystals, CFC and Halon replacements, polymers, inert oils and lubri- cants, ‘blood substitutes’ etc. [ I] ) containing one or more C-F bonds (see Fig. 1) .

Three primary factors (see Table 1) have led to the dis- tinction acquired by fluorine as a substituent in organic

* Corresponding author. ’ First published in the Proceedings of the BAlCS (British Association

for Chemical Specialities) Symposium held on th,: occasion of Chemspec Europe ‘97 (June 1997, Manchester, UK).

0022-l 139/98/$19.00 0 1998 Elsevier Science S.A. All rights reserved PllSOO22.1139(97)00127-9

molecules [ 241: (1) the great strength of the C-F bond (fluorine, the lightest halogen, forms the strongest single bond to carbon encountered in organic chemistry ) ; (2) the small size of bound fluorine (fluorine is the smallest subsrit- uent qfter hydrogen); and (3) fluorine (element 9) is extremely electronegative (excluding unusable neon, ele- ment 10,fluorine is the most electronegative of ull the chem- ical elements). F-Factor 3 ensures that fluorine is always electron-withdrawing ( -I effect) when bonded to carbon and that bonds will be strongly polarized (&‘C-F6-). F-Factors 1 and 2 made it possible long ago to contemplate complete replacement of hydrogen attached to carbon by Ru- orine in all hydrocarbons and theirfunctionalizedderivatives; furthermore, when stepwise conversion of hydrocarbons to their perfluorocarbon analogues is taken into account (e.g., CH,CO*H -+ CH?FCO?H -j CHF,CO,!H ---f CF3COZH), the inescapable conclusion is that a phenomenal number of fluoro-organic compounds can be modelled on known organic substances [6]. This situation, which contrasts so markedly with that involving chlorine, accounts for the exis- tence of the well-developed and rather specialised peduo- rucurbon sub-field of organofluorine chemistry (with strong technological connections [ 1 ] ) in which hydrogen is viewed as a substituent!

Overall, progress towards outstripping the list of known compounds based on C-H bonds has really been quite amaz-

CF,CttClBr

HALOTHAYE

CHFCICFIOCHF2

ENFLURANE

(inhalation onoe.~thcric.t)

CF,CHC10CHF2

ISOFLURANE

CFsBr CF,C’H,F

HALON 1301” HFC-t34a

(fire rrtinjpisliant) (re/rigeranf )

Fa+)H

cozrr

DIFLUNISAL

(onolgesic; anti-irtjlammotory; onri-pvrdic)

k FLU’CONAZOLE

FLUOXETINE’

(anti-dqwcrront)

B S-FLUOROURACIL (S-FU)

(onfi-cancer ap~l)

NH1

~mdioloh~flcd anti-parkinsonion) d

DERAMETHASONE FLUPREDNISOLONE

(Rlucocnrticoidr; onri-inflomma~r~rier)

cg-NHJ-NH+

\ F

Fig. I. Some familiar commercial orgauofluorine compounds

R.E. llanks/Journal of Fluorine Chemistry 87 (1998) I-I 7 3

Table I Fluorine (F) Factors

(1) Fluorine forms rhe strongest single bond to carbon found in organic chemistr?;. “AVERAGE” BOND DISSOCIATION ENERGIES (kJ/mol)

C-F C-Cl C-Br C-I 485 339 285 213 C-H c-o c-c C-N 413 358 346 301

(2) Fluorine is the second smallest subsriruent in organic molecules after hydrogen. “RECOMMENDED” INTERMOLECULAR VAN DER WAALS RADII (A) FOR VOLUME CALCULATIONS [5] H C N 0 F Cl Br I 1.20 I .70 I.55 I.52 I .4’ n I .I5 1.85 1.98 (” The best value for all C-F molecular environments except CH>F: for which 1.40 A is recommended.)

VOLUMES (cm’/mol) OF ATOMS AND SIMPLE GROUPS BONDED TO CARBON [S] -H -F -Cl -Br -I 3.3 5.12 II .62 14.40 19.18

lcli / ‘CXl / 6.8 9.5 11.4 3.1 10.2 I I.7 15.3 -CH, -CH2F -CHF, -CF, 13.7 16.0 18.8 21.3 Note that the use of Pauling’s atomic van der Waals radii (H = I .20, F = 1.35 A) leads to the inappropriate conclusion that the CF group is very similar in size to the CH group. Bondi-derived [ 51 van der Walls volumes provide a proper comparison and reveal that it is the CF and CO groups which are very similar in size, both being significantly larger than CH. The widespread ability of CF to mimic CH, COH and COC groups in bioactive molecules plays a major role in drug design. Note also that the CF, group is much larger than CH,, and that the larger steric demand of CF2 indicates that use of this moiety to mimic ether oxygen (-0-) in biomolecules relies on an isopolar effect (fluorine mimicking the oxygen lone-pair electrons).

(3) Fluorine is rhe most electronrgariw element inc,q/ved in chemical bonding. PAULING ELECTRONEGATIVITIES H C N 0 F Cl 2. I 2.6 3.0 3.4 4.0 3.2 Fluorine’s powerful inductive effect (-I) markedly impacts upon the reactivity and physical properties of fluoro-organics. Where bioactive systems are concerned, much attention attaches to hydrogen bonding effects stemming from both direct (proton acceptance by negative F in a highly polar C-F bond) and indirect (proton donation through acidification of neighbouring hydrogen in CH bonds; or interference with H-acceptor sites through cT-inductive or field effects) consequences of changing from CH to CF.

ing since the first (and simplest) organic fluoride, methyl fluoride, was prepared in 1835 [ 7-91; ’ thus, by 1990 a stag- gering 6.2% of the 10 million compounds registeredin Chem- ical Abstracts contained one or more C-F bonds [ IO]. Since naturally-occurring organofluorine compounds are rare (Fig. 2) [ 1 l] and none are isolated for utilization, these statistics highlight the fact that fluoro-organic chemistry is virtually a man-made subject, underpinned by an impressive body of synthesis methodology. Where C-F bond introduc- tion is concerned (as distinct from buildling-block/synthon approaches to fluorinated target molecules [ 14]), apprecia- ble development is still underway, fuelled extensively by the increasingly important part that fluorine as a substituent is playing in medical [ 15-181 and agrochemical [ 18-201 research and development. From a commercial viewpoint, it was declared in 1992 [ 2 1 J that “conservative estimates call for more than US$SO billion/yr to be associated with this element [fluorine] in organic chemilstry alone.” More recently [ 181, it was pointed out that flldorinated pesticides represent 13% of all launched pesticides, with annual sales of US$4-5 billion for about 50 X IO” tonnes produced; sales

’ For a detailed account of the history of organofluorine chemistry, see Ref. [9].

of fluorinated drugs (including anaesthetics, diagnostic agents, etc.), which represent 8-9s of all synthetic drugs, were valued at US$20-25 billion/yr.

That ‘light’ strategic fluorination of organic compounds (i.e., the introduction of one or two fluorine substituents or a trifluoromethyl group at key molecular sites) can have pro- found and unexpected consequences where biological activ- ity is concerned first became apparent in the 193Os, but it was the landmark publications on 9a-fluorohydrocortisone ace- tate and 5-fluorouracil in the mid-1950s [9] which led to replacement of hydrogen or hydroxyl by fluorine becoming virtually sine qua non in medicinal and bio-organic research. The impressive (and growing) number and diversity of flu- orine-containing drugs now available in healthcare circles [ 181 attests to the great success of this policy of investigating fluorinated compounds in the search for improved pharma- ceuticals. Coupled with this, much current and projected research is aimed at improving our often poor understanding of why fluorine can play so special a role in chemotherapy. Some guidelines are provided in Table 1; readers seeking more information will find the concise accounts in Refs. [ 2,3.22] useful, while those looking for an authoritative in- depth discussion should consult Ref. [ 151.

R.1;. Bank.~/.lo~rnal of Fluorine Chemisry 87 (I 998) l-l 7

CH,FCO,H

CH,FCOCH3

HFC02H

b OH URJR)

P” CH,FC COIH

F” NH2

CH2F(CH2),C02H (x = 8,12, 14)

cis-CH2F(CH2),CH=CH(~*b~~O*H

(nucleoeidin)

KHzbCO~H CF/

” All the monotluondcs are plant mctabohtes (manly) or ~derive from bacteria (VIZ the aatibiotlc nuclcocldm and amno-acid fluo~othreomnel [II\

’ This potent greenhcose gas lb p. -I 28 “C. atmospheric hfet~me 5O.OtN yzws. GWP h.5OO (It10 \car time horizon: CO? = I)] / 121. aptly dubbed an ~nmlorml ,c:os. leas only recently been clamled to arise from nalural sources (natural gas and tluorspar contammi: tracts of uramum) [ 131 Anthropogmc sources of unnelcomc

CF, (maml) alunun~um production) are well known.

Fig. 2. Naturally-occurring organofluorine compounds. ”

Smooth progress on these fronts clearly requires chemists not specially trained in fluorine chemistry to have access to a range of easily-handled ( ‘user friendl,y’) selective (vegio and stereo) fhtorinating agents. That the already sizeable list of such agents available to organic chemists [ 141 continues to grow is a reflection of the fact that difficulties in the syn- thesis of C-F bonds persist, even for experts. Fluorinating agents can usefully be categorized according to the form (actual or incipient) in which they are viewed to ‘deliver’ fluorine to a suitably activated carbon sil.e, i.e.. fluorine atom (F’), fluoride ion (F-) or fluoronium ion (F’) [ 141. As explained later, neither free nor solvated F+ is actually involved, hence the common practice of using the symbol ‘F+‘.

Regrettably, from the viewpoint of general organic chem- ists, the legendary reactivity of elemental fluorine (easily the most reactive of all the elements) precludes free-and-easy routine direct use of F, (b.p. - 188°C; highly toxic) as a selective fluorinating agent of the radical (F’) or electrophilic (‘F+ ‘) type. This came as quite a blow to Moissan [9]. who isolated fluorine at a time ( 1886) when chlorination meth- odology based on Cl, was already well established [23] but failed to make hoped-for extensive contributions to organo- fluorine chemistry owing to the uncontrollable violence of reactions between neat hydrocarbon-based materials and the lighter halogen. Fluorine has been ‘tamled’ during the past 60 years in terms of producing perfluorocarbon compounds on both laboratory and commercial scales [ 1 ] ; but while great strides have been made since 1980 in the selective direct fluorination of organic molecules through the important ‘Fi’ mode [21.24-281. FL cannot yet be viewed as a general laboratory alternative to so-called positive fluorine carriers [ 14,29-361, particularly those of the N-F class [ 341.

This paper reviews the discovery, properties and reactions of the commercially-available N-F reagent widely known as

F-TEDA-BF, (1). An N-fuoroammonium salt, this has proved to be one of the best general-purpose user-friendly site-selective electrophilic fluorinating agents to have emerged from a vigorous search worldwide since 1980 for more generally acceptable (non-gaseous, less aggressive, non-explosive, less toxic, relatively inexpensive) ‘F+’ trans- fer reagents than perchloryl fluoride [ 321, O-F compounds like trifluoromethyl hypofluorite or caesium fluoroxysulfate [ 29,30,33,36], xenon difluoride [ 3 1,35 ] or fluorine itself [21,28].

2. Discovery, synthesis and properties of F-TEDA- BF,tl)

2. I. Background

The potential of compounds containing N-F bonds to act as electrophilic fluorinating agents was first signalled more than 30 years ago by Banks and Williamson [ 371. Inspired by reports in the late 1950s on the first ‘F+’ carrier,perchloryl fluoride (FC103, an extremely hazardous gas [ 32,38]), they showed that perfluoro-N-fluoropiperidine (2) will convert the sodium salts of 2-nitropropane and diethyl malonate to 2-fluoro-2-nitropropane and diethyl dihuoromalonate respec- tively. These conversions were rationalized on the basis of nucleophilic displacement on the fluorine of the NF group in 2 (Scheme I, pathway A) [ 37,391, although later [ 40,4 1 ] an alternative electron-transfer mechanism was introduced (Scheme I I pathway B). ’ Interestingly, debate continues about the mechanism of fluorination with NF reagents: nec- essarily of no concern here, readers seeking a detailed dis- cussion should consult Ref. [ 34). Note clearly that neither

’ See also Ref. [42].

R.E. Banks / Joumul of Fluorine Chemistry 87 (1998) I-I 7

BYPRODUCTS

t

-/--hFbaFl A” W3hCN02 - (CH,),CFNO, +

Ni+

e-OF2 Fz F, Na+ Fz Fz

Bc ‘3 - Fl

Ntt F2 F2

‘The same mtchanisms apply when an N-fluoroammonium salt like F-TEDA-BF, (I) is involved (Nu = nucleophile):

N;- + FiJ(CH2CH2)&-CH2Cl A” NuF + N(CH2CHZ)$&CH2Cl

+ NuF + N(CH2CH2)3N-CH2Cl

bA = SN2 pathway

‘B = e? (SE’T) path-cay

Scheme 1. ‘F+’ Delivery mechanisms exemplified.

free nor solvated fluoronium (F+ ) ions are implicated in any of the reactions carried out with NF reaglents or their alter- natives; this is not unexpected in view of the high value of the molar enthalpy of formation of gaseous F+ (1760 kJ/ mol) compared with the values for the other halonium ions (Cl+, 1370; Br+, 1260; If, 1120 kJ/mol).

Fl F2 F2 ,i2 F,

(2) (3)

X-= TW. BFT

(CF,SO,),NF

(7) (8) X-=TfO-,BF;,P&

R = CH,, C& Cd&,, CH,CI, CH,CF,

X-= TEO; BFT, PF;

! +

0 X-

N

Although perfluoro-N-fluoropiperidine (2) (an easily- handled liquid, b.p. 49~5°C) has been developed further as a useful site-selective fluorinating agent of the ‘F+’ delivery

1?. E. Banks /Journal qf Fluorinr Chemistry 87 (I 99X) I-I 7

F,/N,, MetX

CH,CN.-35 CD k

X-

A

MetX = alkali metal (Li, Na, K) salt

X= TfO-(ie. CF,SO,). BF, PF;

In the absence of M&X, X E F - Scheme 2. Preparation of N-fluoroquinuclidinium salts [42,43,49,51]

class, especially where polarizable (resonance-stabilized) carbanions are concerned [ 441, this prototypical reagent of the NF class has never achieved any real status. This stems not only frolm its low-yield specialized method of preparation (Simons ECF of pyridine in HF), but also because it was eclipsed almost at birth by the onset of extensive work with hazardous OF reagents [30], starting with CF,OF (b.p. - 97°C) and then with easily-handled xenon difluoride (subl. 114°C) [31,35].

Interest in NF reagents was finally aroused with a ven- geance in the early 1980s with the appearance of publications concerning .N-fluoropyridin-2( 1 H) -one (3; Purrington’s rea- gent) [ 451 and N-fluoro-N-alkylsulfonamides (4; Bamette reagents) [46], which were followecl closely by reports on N-fluoropyridinium salts (Umemolo reagents, e.g., 5) [47,48] and N-fluoroquinclidinium fluoride (6; a UMIST reagent) [ 491 (both more reactive than 3 and 4) and to the introduction of the most powerful ‘F” delivery agent of the NF class, N-fluorobis( trifluoromethy lsulfonyl) imide (7; DesMarteau’s reagent) [ 501. All of these regents were pro- duced by direct fluorination of the corresponding amines, e.g., the bridgehead tertiary monoamine quinuclidine in the case of 6 and its congeners 8 (see Scheme 2 )

2.2. Invention of F-TEDA reagents (1, 11)

The serendipitous discovery of N-lluoroquinuclidinium fluoride (6) by Du Boisson and Morton and its subsequent development as a user-friendly ‘F+’ delivery agent by Banks et al. [ 5 11, including improved method:s of synthesis and the introduction of virtually non-hygroscopic variants (El) [ 42,431, inspired work at UMIST on the direct fluorination of commercial 1,4-diazabicyclo [ 2.2.21 octane, known in the polyurethane foam industry as TEDA (triethylenediamine) , which is much cheaper and more readily available than qui- nuclidine, its monoamine analogue. Not only, it was reasoned, should a bis-analogue (9) of a quinuclidine-based reagents (6, 8) be more cost-effective (greater wt.‘% of available ‘F+‘), but also it would provide a more powerful means of site-selective fluorination by virtue of the powerful electron- withdrawing effect of the second +NF group. In practice, bis( NF)TE;DA salts (9) proved difficult to isolate and when eventually (obtained [ 52,531 were found to deliver only one- half of the theoretically available ‘F+’ per molecule. These features can be rationalized by self-defluorination [ 53,541 of the mono-NF entity (10) visualized as ,117 intermediate in the

FZ * (SET process)

F- F

HF + NuF

(9) * see also reference [53]. b NuH = electron-rich substrate (Nu = nucleophile).

Scheme 3. Proposed mechanisms ’ associated with the instability of mono( NF)TEDA salts (from Ref. 1541). D

direct fluorination of TEDA [ 541, or in ‘F+ ’ delivery reac- tions of 9 [ 53,541 (Scheme 3). 4

Since quinuclidine readily yieldedN-fluoroquinuclidinium salts (see Scheme 2) when treated with elemental fluorine in the presence of passive ( ‘non-nucleophilic’, oxidation-resis- tant counter-anions) under carefully controlled conditions [ ‘polar mode’; dilute fluorine ( 10% F, in N2) ; liquid phase (well-stirred cold CFC13 or CH$N as diluent) ] to eliminate hot spots and hence the onset of highly exothermic cata- strophic reactions arising from the ease of homolysis of the surprisingly weak F-F bond ( 159 kJ/mol)] [9,28], it was argued that the same technique ought to work in the TEDA series if electronic equivalence was first established by qua- temizing just one of the bridgehead nitrogens prior to fluor- ination. This simple strategy worked splendidly, for not only did it provide a range of easily-isolated NF-TEDA salts (1, ll), but also it enabled the fluorinating power to be ‘tuned’ through variation in the electronegativity ( - Zeffect) of the quatemizing group R [ 551.

2.3. Routes to F-TEDA reagents and their ‘F+ ’ delivery potential

Details of the synthesis methodology employed at UMIST to prepare TEDA monoquats ( 12) [ 561 and convert them to user-friendly (solid) NF-TEDA reagents (1, 11) [ 55,571 are shown in Schemes 4 and 5 respectively; Scheme 6 dis- plays the fluorinations carried out with these reagents toestab-

4 Detailed mechanisms were first recorded by I. Sharif, PhD Thesis, Uni- versity of Manchester. 1992; see also M.K. Besheesh, UMIST PhD Thesis, 1994.

R.E. Banks/found of Fluorine Chemist? 87 (1998) I-l 7

RY, KOTf, CH&N, 20 oC

R = CH,, C2HS: Y= Cl (X-= TfC-) /-r I\, R = n-C8H,,; Y = Br

sCF,CH,OTf, CH,CN

-10 to 20 oc

\ (X -= TfO-)

” TtU = triflate (tritluoromethanesulfonate. CRSO0). h Details of the laboratory synthesis of this hygroscopic monoquat chloride on a 100 g scale (95% yield) can be

found in reference [57). The monoquat tetrafluoroborate 12 (R = CHKl. X- = BF,). casdy obtainable from the chloride + NaBF, in at least 95% yield 1571, is the immediate precursor of F-TEDA-BFI (I) (see Scheme

5). r Laboratory yields of all the monoquat salts (purified samples) ranged from good to excellent W-98%)

Scheme 4. Synthesis of TEDA monoquats ” (F-TEDA diquat precursors) [56]

b

Fz,‘792

CH3C.V, r -($y MetXorLA ,

F,/N,, MetX, CH,CN, -35 oCc

1: 1 F21sF,, CH,CN, -35 OC W)

(12) (R = CH,CI, X-= BF; )d

A

MetX = NaBF,, NaPF6, LiOTf etc; LA = Lewis acid := Xv- F-(for X-=BF;, LA = BF,; PF, gives PFC salts)

* Yields (pure products) range from X1-97%. b Not Isolated ’ This is the best routine laboratov method. and IS easily run on ihe 100 g scale d Carried out in a special closed Pyrex system with neat FI 1511.

Scheme 5. Synthesis of F-TEDA salts ” (LA = Lewis acid) in simple glass flow systems [ 571.

lish their potential to become important iluorinating agents of the electrophilic class. No persuasive evidence for a counter-anion effect (increased specificity; yield enhance- ment) was noted and since fluoride salts were avoided on grounds of hygroscopicity and the ability of F- to trigger undesired side-reactions, the tetrafluoroborate salts emerged as the best for commercialisation from the viewpoint of cost- effectiveness. Fluorinating power within the series was found to increase with increasing electron-withdrawing power of

the alkylating group R (CH,, C2H,, CRH,, <CHJl < CF,CH,) [ 55,571 as anticipated from the outset, hence the ‘tunability’ of the series.

Electrochemical measurements [ 581, well supported by our own practical experience and that of the team led by Dr. G.P. Pez at Air Products and Chemicals ( APCI), indicate that the fluorinating power of F-TEDA-BF, (1) approaches closely that of the most active (though still non-commercial) ‘F+’ delivery agent of the N-F class, N-fluorobis(tri-

.P. E. Banks/Journal of Fluorirle Chemistry 87 (1998) 1-I 7

(n:p =-co. 3:2)

3 (

!‘I\ /

2 4 OH

i 1 +

C,H,CWO,C,H,), - (1

5 w-1, - + ,+, F. .F

J GWW (- 100%)

(o:p=co. 1:l)

(o:p = co. 62:38)

* Molar ranos of tluorinating agent:substrate close to I: I were employed. Yrclds of all products fell in the 72- 100% range.

D Loss of “F‘” from each F-TEDA reagent regenerates its tnonoquat precursor X- R-‘N(CHCH?hN. whtcb can be recovered as a pro on salt. R-‘N(CHCH,),N’-H 2X. and recycled or disposed of by author&d methods.

REAGENTS- 1 CH4?(COzCrHr)~ Na’ in THF, -10 to 20 “C. 2 I-morpholinoc~clohe~ene in CHG. -1Y6 to 20 “C. then HCI aq.. 3 C,H50H in CH,OH. 21) “C. 4 l-HOCtoHq (co 50% excess) in CHIOH. -IY6 to 21) “C. S 2- HOCloH- in CH,OH -196 to 20 “C: h GHNHCOCH, (100% excess) in boiling CHCN: 7 C,H<OCH, in vet CHCN. 10 “C: 8 C,Hl!;02Na tn CHCN. 20 “C.

Scheme 6. Pioneering electrophilic fluorinations [ 571 effected with F-TEDA-salt reagents (1, 11) “.’

(-100%~ (-100%)” 0 NMR yields: ,~-fluoroquinuclldlnium terrafluomborate can be rsolated chralnatographicall~ with at least Y7%

efficmcy

Scheme 7. Transfer fluorination of quinuclidine with F-TEDA-BF, [59]

fluoromethylsulfonyl) imide (7) [ 341. All of the F-TEDA reagents are more powerful than N-fluoroquinuclidinium salts (6,8) or N-lluoropyridinium triflak (5, X = TfO ~ ) and its 2,4,6-trimethyl analogue, as nicely ‘demonstrated by the ability of F-TEDA-BF, to ‘transfer N-fluorinate’ quinucli- dine, pyridine and 2,4,6trimethylpyridine at ring nitrogen (see Scheme 7) [ 591.

Details of the process employed by Air Products ( APCI) to manufacture the general-purpose coc,t-effective l-chloro-

methyl-bfluoro- 1,4-diazoniabicyclo [ 2.2.21 octane reagent ( 1) at its Hometown Facility in Pennsylvania (US) are pro- prietary. Known widely as F-TEDA-BF,, this member of the company’s Selectfluor family of selective fluorinating agents was in use commercially by the end of 1993 [ 60,611, prin- cipally for the production of fluorosteroids. Since then it has been used in R & D worldwide to fluorinate a fair range of electron-rich substrates under mild conditions with high selectivity and (often) efficiency, as exemplified in the

9

remainder of this article. No special appar,atus or handling techniques are required and the spent reagent is readily degradable to manageable waste products (see footnote b, Scheme 6).

Interestingly, the manufacture of SelNectorTM reagent F-TEDA-BFI (1) on a multitonne/yr scale from the corre- sponding TEDA monoquat provides only the second example of the use of elemental fluorine at plant level to effect site- selective monofluorination of a ‘complex’ organic substrate, the other being the production of the well known anticancer agent 5fluorouracil (see Fig. 1) from uracil [ 181. In the case of the NF compound, the fluorine is safely stored ready for delivery in F’ mode at suitably activated carbon sites (overt or masked carbanions) in a wide variety of organic mole- cules, as exemplified later.

2.4. Properties of F-TEDA-BF, (1) /57,62 / s

SelectfluorTM reagent F-TEDA-BF, is a white, free-flow- ing, virtually non-hydroscopic, high melting (apparent m.p. 190°C) crystalline solid, the X-ray structure of which has been reported [ 631. Its thermal behaviour is complicated. In gram quantities, highly purified material ( :> 99.5%) is stable to about 2OO”C, but impurities (notably F- sources) can noticeably lower the onset temperature of autothermal decomposition. In large-scale tests, 100 kg of commercial F-TEDA-BF4 (purity > 95%) contained in a 55 gal drum was found to exhibit no self-heating or changes in composi- tion when kept at 56°C for 7 days. Conservatively, it is rec- ommended that the bulk solid reagent should be stored in a cool dry place and not heated above 80°C. A solution of F- TEDA-BF, (ca. 2 g) in dry acetonitrile (510 cm3, i.e., typical conditions for reactions at the research level) loses less than 10% of its activity ( ‘F+’ transfer capability ) when heated under refhtx (82°C) for 1 day [ 577.

Like all the F-TEDA salts of type 11, F-TEDA-BF, (1) is very soluble in cold water ( 176 g/I at 20°C hence providing the opportunity to carry out certain fluorinations in this medium) or dilute hydrochloric acid [note that Cl- is not oxidized at 20°C to chlorine, whereas Br- :md (very rapidly) I- do give the parent elements]. It is decomposed by dilute sodium hydroxide and reacts with cold DMSO (rapidly and exothermically) and with DMF (slowly on heating) to give products still under investigation. It is reasonably soluble in acetonitrile (50 g/l) but only slightly so in lower alcohols or acetone. Reactions in these solvents can often be accelerated by adding small quantities of water or acid (CFCO,H, for example in Ref. [ 571) which not only i’mproves solubility but also, especially in the presence of acids, presumably impacts upon fluorination mechanisms.

i An MSDS (Material Safety Data Sheet) can be obtainedfromDr. Reiner Taege, Air Products SA, Special Gases Group (Europe). Zoning Industriel de Keumiee. rue de la Spinette 37. B-5 140 Sombreffe, Belgium; fax: + 32- 71-81-65-99. In the US, contact Gary Saba. Air Products and Chemicals. 7201 Hamilton Boulevard, Allentown, PA 18195-1501; fax: + l-610-481- 3765.

The oral toxicity of SelectfluorT” F-TEDA-BF, is mod- erate (male rat oral LD,,, = 640 mg/kg) . The rat acute lethal dermal dose is >2g/kg of body weight. An MSDS is available. ’

3. Applications of F-TEDA-BFJ (1) in C-F bond synthesis

The rapid commercialization of F-TEDA-BF, [ 60,6 I ] fol- lowing the synthesis of the first sample at UMIST early in 1990 (by Banks and Sharif) [ 55,631 coupled with the gen- erous provision of free samples by APCI to numerous inves- tigators, has resulted in a steady stream of research publications concerning its reactions since 1992. Examples of the conversions reported are presented below, together with brief commentaries. For previous reviews, see Refs. [ 34,62.64].

3 1. Ekctrophilic~uorination of hmzene derivatives and

related aromatic carbocycles

Benzene resists attack by F-TEDA-BF, under reasonable conditions. The introduction of electron-releasing ( + I, -L M) ring substituents facilitates fluorination [ 55,57,64-671 and under appropriate conditions difluorination can be achieved, e.g. (see also Scheme 6).

(65%) (32%)

CsHs 24 h - C+H5& + ‘GHseF

(36”/.,) (29%)

For information on the fluorination of biphenyl, naphtha- lene, anthracene and phenanthrene and their derivatives with F-TEDA-BF,. see Refs. [ 66-681. Also Scheme 6 contains information on the fluorination of naphthols [ 571. Regiose- lective fluorination of anthraquinones with F-TEDA-BF, has proved of interest in connection with research on non-stero- idal anti-inflammatory drugs for the treatment of osteoarthri-

’ Use of CF,CO,H as solvent enhanced the rate of fluorination, virtually the same results being obtained in 4 h [ 67 1.

10 4X. Banks/Journal of Fluorirw Chemist? 87 (1998) 1-I 7

tis, as indicated by work on the somewhat deactivated substrate methyl 4,5-dimethoxy-9,10-anthraquinone-2-car- boxylate [ 691:

(ZY”)

3.2. Fluorination of nucleoside bases and nucleosides

uracil, R = H thgmine. R = CH,

(R = H. 82%;rr~n,viis= 8:I) 5.fluorouracil

(R = CH3. 95%)

F-TEDA-BF, (2 equiv.l CH,CNICHxOH

retlux (under N,) 4 h

U

(I) F-TEDA-BFJ m

CHJCN (under Nz) RT, 15 min. (2) (CzHshN

U = urncil (5 !%; SIR = 9515)

As above )

G = N’~‘,N2-tribenzoylguanine (46%; Rls = 66134)

The ploy of modifying the reactivity of biologically-active compounds through replacement of H or OH substituents by F has been especially rewarding in tb: field of nucleoside chemistry, yielding compounds of greeter therapeutic value (e.g. the anti-cancer agent 5-fluorouracil). The value of

F-TEDA-BF4 to researchers in this field has been signalled through recent work on the synthesis of 5-fluorinated pyrim- idine bases [ 701 and 2’-, 3’-, and 5’-fluoronucleosides [ 7 11.

The latter piece of work was based on research with mode1 compounds [ 651, namely preparation of cY-fluorinated sulf- oxides and sulfones through a-fluorination of sulfides via in situ fluoro-Pummerer rearrangement of an intermediate sul- fonium salt with a nitrogenous base: RSCH,R’ + F-TEDA- BF, + RS +FCH2R’ + RSCHFR’ -+ RS( 0)CHFR’ (x= l,2), e.g.

I. F-TEDA-BF,

n-CpH,&Ha CH,CN, RT. 10 min. c n-C,HI~O&H~F (35%) 2. TEA 3. m-CPBA

1. F-TEDA-BF4 CH&N, RT, 10 min. c

2. TEA 3. NBS

I F-TEDA-BF,

CH,SCH,C02 CH,CH, CHsCN, RT,‘IO min.

2. TEA 3. m-CPBA

3.3. Fluorination of steroids

0

OAc

(13)

X = H, F, Cl, Br, I

CH,SOzCHFC02 CH*CH, (58%

The ability of a single fluorine substituent to enhance remarkably the therapeutic activity of a steroid was estab- lished in the 1950s [ 91 when Fried and Sabo compared the glucocorticoid activities of 9a-halogen0 derivatives of hydrocortisone acetate (13, X = H) and established that the order of increasing potency was X= I(O.l) <Br(0.28) < Cl(4) <F( II) (values relative to H= 1) [72]. Since then. a large number of fluorinated steroidal derivatives have appeared in the pharmaceutical marketplace [ 18,721 and medicinal chemists have continuously been on the lookout for new C-F bond forming reactions to accelerate research in the area or with which to replace inferior production methods.

Fluorination with ‘F+’ carriers impacts importantly on the introduction of a fluorine substituent at position 6 or 16 in steroids [ 721. F-TEDA is highly effective for creating C-F bonds selectively at these positions via electrophilic attack on enol acetate or silyl enol derivatives [ 651, e.g.,

R.1:. Banks/Journal of Fluorirw Chemistp 87 (1998) I-17 II

bydrocortisone enol acetate

AcO

&

OAc

-0Ac

0 /

F

(88%; a/p = 47/53)

0

OAc

F-TEDA-BF4

CH&N, UT, 15 mi?

prednisolnne rnol acetate

OAc

(X5%; lx/g = 57/13)

OR

\ CP F-TEDA-BF4

CH,CN. RT. + Zh(R=Ac)

Ad 15 min (R = SiMc3)

(from androsteronc acetate)

Ad

(>!W%; a/p = 9515)

Note the efficiency and ease of fluorination (reactions generally are instantaneous at room temperature; yields and regioselectivities can be high; and the reagent tolerates a wide variety of functionalities). Consideration of the relative reactivities of a range of ‘F +’ carriers for the fluorination of testosterone enol acetate reveals the attractiveness of F-TEDA-BF, ( see Table 2) 1721.

Fluorination of enamines of A’- or A I.“-3-ketosteroids with F-TEDA-BF4 produces a mixture of 4 and 6-fluorinated products [65]. (Note the model reaction in Scheme 6:

Table 2 Comparison of the 64uorination of testosterone enol acetate with a range of ‘F+’ carriers [ 721

,,co&Ac eodAc F

Reagent Temp.

(“C) Time (h)

Yield (%I

Q/P Ratio

FCIO, 20 I 58 113 CF,OF -70 38 I13 ‘Wet’ CFICt O)ONa/F? ’ -78 0.25 70 31.5 CH,C(O)OF -78 0.25 61 II2 FP-TSOO ’ 40 IO 71 II2 F-TED.4BF4 20 0.15 95 213

’ This system generates mainly the perfluoroacyl hypofluorite CF,C( 0)OF 1301. ” N-fluoropyridinium triflate (5; X = TfO )

conversion of 1 -morpholinocyclohexene to 2-fluorocyclo- hexanone).

Electrophilic fluorodestannylation of steroidal trimethyl- stannyl derivatives with F-TEDA-BF, has been investigated during research connected with the development of rapid methods for the synthesis of 18F labelled compounds for PET scanning (see footnote d, Fig. 1). 4-Fluoroandrost-4-ene- 3,17-dione ( 14) and 17-O-benzoyl-4-fluorotestosterone were prepared using both F-TEDA-BF, and the solid OF reagent caesium fluoroxysulfate. Cs‘ FOSO; [ 731; the latter, which is potentially explosive [ 331, gave better yields.

Sn(CH,), b

(14)

3.4. Fluorination of carborl-metal bonds

Fluorodemetallation of vinylstannanes withF-TEDA-BF,, illustrated in the previous section, was first disclosed in work associated with interests in the design of mechanism-based enzyme inhibitors and other bioactive molecules [ 741, e.g.,

1” F-TEDA-BF, H

(CGH&(S=C\ CH&N. 80 ‘JC

c (C6H&C=C’

SWGbh ‘F ( 7 I “A )

12 I?.E. Banks/Journal qf Fluorine Chemist? 87 (1998) 1-17

,C02C2Hs CQCzHs

C&C,- Na+ F-TEDA-BFI

) CSh

CO2CzHs THF/DMF, RT, 30 min. CF

651 CWJzh

(94%)

0 0 0 0

R

DMF,-5OoCtoRT ) @

F-TEDA-BFJ

(10 min. at RT) =I FR

R = (-)-menthyl 1821 (94%)

K+ H PKQW2Hsh F-TEDA-BF4

F NVKGHs)2 -

i so2w5

DMF/t-BuOH. RT - x IO min. H S02Ws

1651 (61%)

F-TEDA-BFJ, 3.2 equiv.

GH5 WXk CHFN, 40 oC 27 d

c A&

(91%)

C6H5 NV-Sk

I F F

A

I (see Clcheme 9)

RT, 27 h F-TEDA-BFJ (73%)

0 0 NaH, THF

0 .o

W&k Iat1 NW3h

Scheme 8. Examples of the fluorination of stabilized carhanions with F-TEDA-BF, [ h5,8 1,82]_

and the method has also been employed to prepare 2- and 3-fluorinated indoles (caesium fluoroxysulfate gave higher yields of product, as in the work on steroidal analogues) 1751, e.g.,

-sn(cw3 F-TEDA-BF, F

CH,,CN, RT, 12 h

(Ts =ptoluenesulfonyl) (40% I

Grignard reagents react slowly aith suspensions of F-TEDA-BE, in dry diethyl ether or THF at 20°C to provide monofluorides [65], e.g.,

F-TEDA-BFa

C6MWr - &H,F (61%) (CZH~)~O. RT. 16 h

5-Fluorocyclopentadiene (of interest in anti-viral research involving the synthesis of carbocyclic analogues of nucleo-

sides) ’ can be generated (for in situ trapping) from F-TEDA-BF, and cyclopentadienylthallium [ 761, e.g.

F-TEDA-BF,

0 to 20 oc R (35%)

(R = CO*CH,)

3.5. Fluorination of stabilized curbanions

Quite a lot of attention has been paid to applications of F-TEDA-BF, in this field and some of the results are dis- played in Schemes 8 and 9. Important work from the view- point of applications in research on bioactive molecules [ 641 is that on selective fluorination of P-dicarbonyl compounds and the synthesis of fluoromethylphosphonates.

’ This follows from the use of CHF and CF, moieties as mimics for the oxygen atom of the sugar components (see Table I ).

0 0

C,H, (78%)

(87Y”)

NV3,)2

(91”/,)

CH,CN, 40 ‘KY, 647 h WWz

GHs=CzHs

CH,

0

F-TEDA-Bk’,

CH#ZN, RT, 19 h

0 0 ” F-TEDA-RF, (I equiv.)

CH,CN, RT, 54 h ) * G&S f-)CZH?

b x

X = H (87%). F (4%)

a The “qano eqwalent” ol this comersion proceeds in e~celleni ! leld at JO “C: CJKH(CN)CO:CIH, + F-TEDA-BFI (1.5 equiv I + C,HSCF(CN)COIC!HS (92%) [Xl]. Slgniiicant applications m s$xsis arc expected IO follow from iha result

Scheme 9. Direct (i.e. under neutral conditions) conversion of I ,3dicarhonyl compounds to mono- and di-fluoro derivati\eh using F-TEDA-BF, 18 I I.

C6H5CH=CH2 F-TEDA-BFa

b (48%) CH3CN, HzO, RT GHSFH--CH*F

OH WI

C6H5, F-TEDA-BFJ 7H3

,CSCHI

a3 CH3CN, CH30H, RT

) C,Hs-y-CH*F (98%)

1651 oc113

F-TEDA-BFd P C&H&=CC~HS CH3CN, HZO, reflux

. C6H+Z-CF2C6H5 (51”/o)

F-TEDA-BFd B C6H,CZCCH3 * C,HsC-CFzCH3

CH$N, HzO, reflux (51%)

1841

F-TEDA-BFJ

CH3CN, CHsOH, RT

1831

(+ traces of the syn-isomer)

” For a detaded discussion of tncch;~nist~clkinetic/stercocl~en~icnl aspects of rcactlons bctuccn F-TEDA-BFI and phen$substituled alkcnes. see refercncc 185 1.

Scheme IO. Some examples of the electrophilic Huorination of activated alkenes and .dkynes with F-TEDA-BF4 in the presence of carbocation traps. ”

14 X.E. Banks / Jounzal qf Fluorinr Chemists 87 (1998) l-l 7

3.6. Miscellaneous reactions:jluorinat.;on of alkenes and alkynes; jluorodecarboxylation offurans and pyrroles; solvent participation; oxidative wes of F-TEDA-BF, in general organic synthesis

Examples of some other types of selective electrophilic fluorination achieved using F-TEDA-EIF, are displayed in Schemes l&13. Note the use of solvent systems to capture fluorocarbocationic intermediates in Sck emes 10 and 11. The most intriguing example of solvent participation involves remote functionalization of ( - )-menthol [77], a process which leaves no fluorine in the final Toduct (Scheme 11)

and points to the potential of F-TEDA-BF, as a reagent in general organic synthesis. Another example of this involves the efficient oxidation of substituted benzylic alcohols and aromatic aldehydes to the corresponding aldehydes and ben- zoic acids respectively; the latter conversion proceeds via benzoyl fluorides - a situation which enables the aldehydes to function as acylating agents in a one-pot procedure (see Scheme 12) [78].

Finally, the ‘enabling’ virtues of F-TEDA-BF, as a reagent for the promotion of advances in research on fluorinated ana- logues of biologically-active molecules have been nicely exemplified recently though the development of fluorode-

F-TISDA-BFI (2.2 NaOH aq.

C H,CN (retlux), 16 h CA2CI,, RT. 16 h OH

(CHdzCH 3

(-)-menthol

I:-TEDA-BFa (1 equiv.) wk~=CAz -

CH&N (reflur), 24 h

y Based on (-)-menthol in a reaction where the oxazinium tetrafluortirate was not isolated 1771. ’ This FWer-type fluor,,functionalization procedure has also been observed m work with the Sclccttl~or~”

“look-alike” reagent HO-+N(CHKH>),N’-F (BFr)? (Accufluor “’ NFTh. an Allied-Signal product) 1871.

Scheme Il. Examples of solvent incorporation during reactions involving F-TEDA-BF4 [77,86]

F-TEDA-BF, I. F-TEDA-BF.,

CHJYN (reflux) CH3CN (rellux)

X 2. Hz0 X

(X = H, 2-Cl, 4-C& 2-NO*, 4-N02) (X = H, 4-C& 4-NO*, 4.CN)

F-TEDA-BF, (I .3 equiv.)

,/FzG-

F

(1) F-TEDA-BF4 (1.4 equiv.) I CH$JN (retlur), 70 h

*

-; “‘:;;I&~~~,~

(2) CHJOH, RT

(64%)

u Troublesome to isolate owing to inadvertent hydrolqsrs to p-CIC,H,C02H and attack on glass b? the HF thus pdUCd.

Scheme 12. Oxidative functional group interconversions using F-TEDA-BF, [ 781.

R.E. Banks /Journal @‘Fluorine Clremistp 87 11998) I-17 15

F-TEDA-BF, (1 equiv.)

CCIJNaHC03 aq. ZOW,lSh

(27%)

C&H

F-TEDA-BF4

CsH12/NaHCOx aq.

(27% overall)

F-TEDA-BF? CH&&/NaHCO~ aq.

RT, 20 min.

F-TEDA-BF4

CH2Cl2/NaHCO3 aq.

RT

KOH aq.

” 2-Fluoroporphobilinogen lactam methyl ester * F-PBG. a new potential suicide Inhibitor of prophmoblhnogen deaminase

Scheme 13. Fluorodecarboxylation with F-TEDA-BF, 179,801.

carboxylation routes to Auorofurans and fluoropyrroles (Scheme 13) [79,80]. The work on the synthesis of mono- fluorinated furans via fluorodecarboxylation of bromofuroic acids, for example, was carried out in connection with sem- isynthetic antibacterials [ 791. Hitherto, fluorofurans have been viewed as rare compounds, despite being much sought after by medicinal and pesticide chemist;. That situation and the corresponding pyrrole case [ 801 may well change mark- edly now that ‘tamed’ fluorine, in the guise of an NF function, is at the service of research chemists.

Acknowledgements

I am deeply indebted to quite a few highly-talented young researchers for helping me to pursue work on site-selective

Auorinating reagents of the N-F class at UMIST. On this occasion, I want to particularly thank Dr. Iqbal Sharif (who actually prepared the first sample of F-TEDA-BF4, in fact the first F-TEDA reagent of any type [ 57 ] ) , Dr. Soad Mohialdin- Khaffaf and Dr. Mohamed Besheesh for firmly establishing preparative routes to NF reagents based on TEDA and also carrying out pioneering ‘F” transfer experiments. Much of their work was financed by Air Products and Chemicals (USA) and our gratitude for that support cannot be over- stated. At Air Products in Allentown, the crucial task of bring- ing F-TEDA-BF, to the marketplace was undertaken by a team energetically directed by Dr. Guido Pez. Research Chemists Dr. Robert Syvret (process R & D/scale up) and Dr. Sankar La1 (applications of F-TEDA-BF4 in the pharmaceutical industry) played vitally important roles.

Vignettes of these highly-motivated chemists can be found in Ref. [ 341. My thanks go also to Mrs. liita Berry (UMIST) and Dr. Balii Abdo (InfoChem, Manchester) for applying their considerable skills (typing and artwork/typesetting, respectively) so successfully to my handwritten manuscript.

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