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. 14

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
1

Contact 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
MeLi

RFMgI]
PhMgBr

[RF.]

[R3P=CF2]
Zn

[:CF2]
KF

R3P+-CF2Br BrPR3 (R=Ph, Me2NH)

RFI
(RF=CnF2n+1)

n=1

CF3Br
Cu, Donor Solvent

CF2Br2

CF3

[CF3Cu]
N Br Br Br

CuI

CF3CO2Na(K)
S I

CF3

CF3 CF3 CF3

O

O N

Br AcO N
AcOOAc

N N NH2

O N N NH2

N F3C OAc O N

AcO OAc

Figure 1: Important uses for some simple perfluorinated alkyl halides

16

CF2=CFCl
CH2=CCl2

OH

CF3CH2F
2 x BuLi

FCl C MeONa CCl2 AcO AcO AcO FCl C CCl AcO AcO AcO

t-BuLi O

CF=CF2

F 2C

CF2=CFXO2H
XO2, X=C,S

Et3N

O OH OAc

[CF2=CFLi]
Me3SiCl

I2
CF3

CF2=CFI CF2=CFSiMe3

F2C

O NH2 OAc OCF2CHClF PhCHO

OH F F CF=CF2

KMnO4

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
HO
CF2CO2Et 4-ClC6H4CHO

Reformatsky Reaction
H3C

CHO

OH O BocNH CHO Cl HO
CF2CO2Et

NBoc CHO

H3C

CF2CO2Et

NBoc OH BocNH CF2CO2Et O CF2CO2Et OH

H2N HO2C

F N

NH2 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 gemDifluoromethylene compounds' by M.J. Tozer and T.F. Herpin, Tetrahedron, 1996, 52, 8619-8683).

CH(OH)CF3 SO2CF3 HO CF3

(85%)
NO2

(73%)

SO2F

CHO

(78%)

NO2

F- + CF3SiMe3 = CF3O BuO)2P

(93%)
(BuO)2P(=O)F O O H OH CF3 O O O

O N

CF3 OH F3C N CF3

CF3

(88%)
O

CF3 O

H CH3O

(62%)

HO

(91%)

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, 757786)

O CH=CHCH3 NO

F
O (C6F5)2S (C6F5)3B
BCl3 SCl2 HNO3

F
CH3CH=CHLi [H2N-]

F
HCO3H

NH2

F
[H-]

F
CF3CO3H

Li

H
BuLi

F
[Br+]

[NO2+]

NO2

BuLi

CH2CH2OH

Br

Cu
CuBr

F
O

F
CH2I2

CHO

MgBr

PhNMeCHO

C6F5CH2C6F5

>40oC

F
>0oC

F F F

F F

Figure 5

F F Hexafluorobenzene, pentafluorobenzene or bromopentafluorobenzene, provide access to an impressive and structurally wideranging 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)