A Quick Guide to the Synthesis of Organofluorine Compounds

A QUICK GUIDE TO THE SYNTHESIS OF ORGANOFLUORINE COMPOUNDS

by R. E. BANKS

Preamble

Approaching one million compounds containing one or more carbon-fluorine bonds are known, and since barely more than ten of those occur naturally, organofluorine chemistry is virtually a completely man-made branch of organic chemistry. Given these statistics, and the fact that none of the natural C-F compounds are isolated for utilisation, newcomers to the area will not be surprised to find that synthetic routes to a wide variety of fluoro-organic molecules have been developed, and that an impressive array of reagents exists for creating a C-F bond (the strongest single bond involving carbon, incidentally).

Basic Strategy

Two approaches are open to chemists planning routes to novel fluoro-organic targets: (A) purchase a starting material already containing the C-F bond(s) required (the `building block' method): and (B) create the C-F bond(s) at a convenient stage using the most appropriate of the numerous fluorinating agents available commercially (en-route fluorination). Depending on the target molecule, only one of these methods may be applicable; and sometimes both may be needed, as in the following route to the inhalation anaesthetic 'Sevoflurane':

(CF3)2CHOH + (CH3)2SO4/NaOH  (CF3)2CHOCH3

 (with Cl2/uv) (CF3)2CHOCH2Cl

 (with KF) (CF3)2CHOCH2F

It becomes necessary sometimes, of course, to face up to two challenges, the synthesis of a novel or non-commercial fluorinated building block and then its conversion to the final target molecule.

Buying C-F bonds in the form of `building blocks' or synthons (strategy A) is much more appealing than actually making C-F bonds (strategy B) to experimentalists who don't specialise in fluorine chemistry because often it avoids having to manipulate hazardous fluorinating agents and/or use unfamiliar techniques or special equipment. When en-route fluorination (B) is mandatory, the C-F bond(s) are preferentially constructed at as late a stage in the synthetic route as possible; this minimizes loss of fluorinated intermediates through side-reactions, purification procedures, etc.

Availability of Intermediates and Reagents

Very impressive ranges of both fluoro-organic building blocks and fluorinating agents are available commercially nowadays from companies like SynQuest Laboratories. Should any intermediate (or reagent) not be listed, SynQuest's chemists will make every effort to manufacture or locate it; perhaps even your target molecule can be provided!

Examples of the Building-Block Approach

Even a cursory glance through recent tomes such as Chemistry of Organic Fluorine Compounds II, (editors M. Hudlicky and A.E. Pavlath; (ACS Monograph 187, 1995) and Organofluorine Chemistry : Principles and Commercial Applications (editors R.E. Banks, B.E. Smart and J.C. Tatlow; Plenum Press, 1994) will reveal that a vast body of information bearing on the construction of fluoro-organic target molecules from already fluorinated precursors is available. The examples displayed here in Figures 1-5 can only scratch the surface of the subject. All of the building blocks/starting material shown are available from SynQuest Laboratories.

A concise structured account of mechanistic principles which underpin the synthesis and reactions of fluoro-organic building blocks can be found in chapter 11 (`A guide to Modern Organofluorine Chemistry') in Fluorine - The First Hundred Years, 1886-1986 (edited by R.E. Banks, D.W.A. Sharp and J.C. Tatlow; Elsevier Sequoia, 1986).

Common Selective Fluorination Methods

Important reaction types (e.g. C-H  C-F; C-Cl  C-F; C-OH  C-F; C=O  CF2; C=C  CH-CF) commonly used in the laboratory for producing C-F bonds at specific molecular sites are presented and exemplified in Table 1. Only reagents which any competent chemist ought to be able to use safely are listed; footnotes give information about equivalent reagents which properly-equipped well-practised fluorine chemists are happy to use (e.g HF, F2). All chemists working with fluorine and its compounds need to know about the hazards arising from contact with hydrogen fluoride (perhaps produced inadvertently); liquid HF (bp 19.5 oC), its vapour (to a lesser degree) and aqueous HF (hydrofluoric acid) can cause serious skin burns and sensible prior arrangements must be made for medical treatment.1

Information, such as the use of F2, high-valency metal fluorides (e.g. CoF3), and Simons electrochemical fluorination (ECF) for the synthesis of perfluorocarbons and their

1Contact SynQuest for information about dealing with HF burn treatments.

15 derivatives, can be found in Chemistry of Organic Fluorine Compounds II and Organofluorine Chemistry : Principles and Commercial Applications (see the section on the building-block approach to C-F compounds. `Hudlucky and Pavlath (Chemistry of Organofluorine Compounds II) presents a plethora of conventional synthetic uses for these synthons.

. [RFLi RFMgI] [RF ] [R3P=CF2] [:CF2]

Zn KF MeLi PhMgBr + - R3P -CF2Br Br

PR3 (R=Ph, Me2NH) R I F n=1 CF3Br CF2Br2 (RF=CnF2n+1) Cu, Donor Solvent

CF 3 I CuI [CF3Cu] CF3CO2Na(K)

Br Br S I N Br

S CF3 O N CF 3 N N CF CF Br 3 3 AcO N N NH2 O

AcOOAc O

N N F3C N NH OAc N 2 O

AcO OAc

Figure 1: Important uses for some simple perfluorinated alkyl halides

16 OH CF2=CFCl CF3CH2F

CF=CF2 CH2=CCl2  t-BuLi 2 x BuLi

FCl O F2C C CF2=CFXO2H MeONa CCl2 XO2, X=C,S AcO [CF2=CFLi] AcO O Et3N AcO OH I CF =CFI OAc 2 2 FCl F C C AcO Me SiCl 2 CF3 3 AcO O CF2=CFSiMe3 CCl AcO NH2 PhCHO OCF CHClF OAc 2 OH

KMnO4 F F CF=CF2

HO2CCF2CClFCO2H N F

Figure 2 The `ozone friendly' CFC replacement 1,1,1,2-tetrafluoroethane (HFC-134a is proving to be a useful synthetic equivalent of the trifluorovinyl anion (J. Burdon et.al., J.Chem.Soc., Chem.Commun., 1996, 49-50; J.Fluorine Chem., 1997,85, 151-153). Chlorotrifluoroethylene (CTFE, commercially important in fluoropolymer circles) is a well-established precursor of trifluorovinyllithium and a host of other fluorinated intermediates and target molecules.

- Zn + BrCF2CO2Et = CF2CO2Et Reformatsky Reaction HO CF2CO2Et CHO

H3C 4-ClC6H4CHO OH O H C CF CO Et BocNH CHO NBoc 3 2 2 O Cl CHO

HO CF2CO2Et

NBoc OH O CF2CO2Et BocNH CF CO Et 2 2 OH

H2N FF NH2 N HO C 2 NH2

Figure 3 The Reformatsky reaction involving (most commonly) ethyl bromodifluoroacetate as a nucleophilic CF2 synthon (synthetic equivalent) is widely used in work on difluorinated biologically active compounds (see `Methods for the Synthesis of gem- Difluoromethylene compounds' by M.J. Tozer and T.F. Herpin, Tetrahedron, 1996, 52, 8619-8683).

CH(OH)CF3

SO2CF3 HO CF3

(85%) NO2 SO2F (73%) CHO O (78%)

NO2

- - OCF3 F + CF3SiMe3 = CF3 OH O N F3C CF3 O BuO)2P (BuO)2P(=O)F N O CF3 (93%) H O O O OH CF3 (88%)

O CF3

H H O (91%) HO O CH O (62%) 3

Figure 4 Examples of silicon-assisted trifluoromethylation of - electrophilic substrates via fluoride-triggered "CF3 " transfer from (trifluoromethyl)trimethlsilane (CF3TMS, Ruppert's Reagent). Tetrabutylammonium fluoride + (Bu4N F-, TBAF), often in `catalytic' amounts is generally used as the F- source. (For a recent detailed review, see G.K.S. Prakash and A.K Yudin, Chem.Rev. 1997, 97, 757- 786)

5 O

CH=CHCH3 NO F FF

O HNO3 CH3CH=CHLi HCO3H

- NH2 (C6F5)2S [H2N ] F F

(C6F5)3B SCl2 - [H ] CF3CO3H BCl3

Li HNO+ 2 BuLi [NO2 ] FFF

+ BuLi [Br ]

CH2CH2OH Br Cu CuBr FFF

CH2I2 CHO MgBr PhNMeCHO F F C6F5CH2C6F5

>40oC F F F F >0oC

F F F F Figure 5 Hexafluorobenzene, pentafluorobenzene or bromopentafluoro- benzene, provide access to an impressive and structurally wide- - ranging host of C6F5 derivatives, as contemplation of the reactions shown here should reveal. For a comprehensive account of the preparation and reactions of polyfluorinated aromatic and heteroaromatic compound, see G.M.Brookes' review in a recent issue of J.Fluorine Chem., (1997, 86, 1-76)