Banks Organofluorine Quick Guide

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A QUICK GUIDE TO THE SYNTHESIS OF ORGANOFLUORINECOMPOUNDS

by R. E. BANKS

Preamble

Approaching one million compounds containing one or more carbon-fluorine bondsare known, and since barely more than ten of those occur naturally, organofluorinechemistry is virtually a completely man-made branch of organic chemistry. Given thesestatistics, 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 offluoro-organic molecules have been developed, and that an impressive array of reagentsexists 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-organictargets: (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 themost appropriate of the numerous fluorinating agents available commercially (en-routefluorination). Depending on the target molecule, only one of these methods may beapplicable; and sometimes both may be needed, as in the following route to the inhalationanaesthetic '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 ofa novel or non-commercial fluorinated building block and then its conversion to the finaltarget molecule.

Buying C-F bonds in the form of `building blocks' or synthons (strategyA) is muchmore appealing than actually making C-F bonds (strategy B) to experimentalists who don'tspecialise in fluorine chemistry because often it avoids having to manipulate hazardousfluorinating agents and/or use unfamiliar techniques or special equipment. When en-routefluorination (B) is mandatory, the C-F bond(s) are preferentially constructed at as late astage in the synthetic route as possible; this minimizes loss of fluorinated intermediatesthrough side-reactions, purification procedures, etc.


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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 everyeffort 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 FluorineCompounds II, (editors M. Hudlicky and A.E. Pavlath; (ACS Monograph 187, 1995) andOrganofluorine 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 informationbearing 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 thesurface of the subject. All of the building blocks/starting material shown are available fromSynQuest Laboratories.

A concise structured account of mechanistic principles which underpin the synthesisand reactions of fluoro-organic building blocks can be found in chapter 11 ( A guide toModern 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 specificmolecular sites are presented and exemplified in Table 1. Only reagents which anycompetent chemist ought to be able to use safely are listed; footnotes give informationabout equivalent reagents which properly-equipped well-practised fluorine chemists arehappy to use (e.g HF, F2). All chemists working with fluorine and its compounds need toknow about the hazards arising from contact with hydrogen fluoride (perhaps producedinadvertently); liquid HF (bp 19.5 oC), its vapour (to a lesser degree) and aqueous HF(hydrofluoric acid) can cause serious skin burns and sensible priorarrangements must bemade for medical treatment.1

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

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


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

[CF3Cu]

CF3Br

[RF.]

RFI

(RF=CnF2n+1)

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

CF2Br2

R3P+-CF2Br Br

-

PR3 (R=Ph, Me2NH

KFZnMeLi PhMgBr

CF3

N CF3

N BrBrBr

CF3CF3

I

Cu, Donor Solvent

CF3CO2Na(K)CuI

S CF3

S I

N

N N

N

O

O

NH2

OAcAcO

OAc

F3C

N

N N

N

O

O

NH2

OAcAcO

AcOBr

Figure 1: Important uses for some simple perfluorinated alkyl halides

n=1


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OH

CF=CF2

O

OH

CF=CF2

N

CF3

NH2

O

OCF2CHClFOAc

AcOAcO

AcO

O

OHOAc

AcOAcO

AcO

CF2=CFI

[CF2=CFLi]

CF3CH2FCF2=CFCl

CF2=CFXO2H

Me3SiCl

F2CFClC

CCl2 XO2, X=C,S

I2

CF2=CFSiMe3PhCHO

F2CFClC

CCl

MeONa

CH2=CCl2

HO2CCF2CClFCO2H

KMnO4

Et3N

2 x BuLit-BuLi

F

F

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 fluoropolymercircles) is a well-established precursor of trifluorovinyllithium and a host of otherfluorinated intermediates and target molecules.

Zn + BrCF2CO2Et =-CF2CO2Et

Reformatsky ReactionHO

Cl

CF2CO2Et

HO CF2CO2Et

BocNH

OH

CF2CO2Et

BocNH CHO H3C

OH

CF2CO2Et

H3C

CHO

ONBoc

CHO

ONBoc

OH

CF2CO2Et

HO2C

N

NH2

NH2

F FH2N

O

4-ClC6H4CHO

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 activecompounds (see Methods for the Synthesis ofgem-Difluoromethylene compounds' by M.J . Tozer and T.F. Herpin,Tetrahedron, 1996, 52, 8619-8683).


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F- + CF3SiMe3 = CF3-

SO2CF3

NO2

CH(OH)CF3

HO CF3

NCF3

OH

F3C

CH3O

H H

OHCF3

OCF3

HO

O

O

BuO)2P

O

CF3

SO2F

NO2

CHO O

N

O CF3

O

OO

OH

O(BuO)2P(=O)F

(93%)

(73%)

(85%)

(78%)

(88%)

(91%)

(62%) 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 generallyused as the F- source. (For a recent detailed review, seeG.K.S. Prakash and A.K Yudin, Chem.Rev. 1997, 97, 757-786)


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O

O

(C6F5)2S

(C6F5)3B

Li

CH=CHCH3 NO

HNO3 CH3CH=CHLi

[H2N-

]

NH2

HCO3H

SCl2

BCl3

H NO2

CH2CH2OH Br Cu

CHO MgBr

FF

F

F

FF

F

F

>40oC

>0oC

O

C6F5CH2C6F5

CH2I2

PhNMeCHO

BuLi

BuLi [NO2+]

CuBr

[H-]

[Br+]

CF3CO3H

F F F

F F

F F F

FF 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 reactionsshown here should reveal. For a comprehensive account of thepreparation and reactions of polyfluorinated aromatic and

heteroaromatic compound, see G.M.Brookes' review in a recentissue ofJ.Fluorine Chem., (1997, 86, 1-76)

Banks Organofluorine Quick Guide

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