The Use of Fluoromethanes in Organic Synthesis 1.Stephen Everett The Johns Hopkins University, Baltimore, MD 21205 Fluorocarbons are well-known for their commercial aonlications (1,Z). The chemical industry produces large quaitities for use as refrigerants (Freon-11, CFClJ. ". . aerosol propellants (Freon-12, C F ~ C ~and ~ ) fire , extinguishing agents (Freon-13-B-1. CBrFd. These com~oundsreadily satisfy basic requirements of minimal toxi&y and highstability. The chemical inertness of highly fluorinated compounds is derived from the strength of the C-F bond and the effective "shield" of electron density originating from the fluorine atoms. Even though fluoromethanes are relatively inert they have also found use as reagents in the selective fluoromethylation of oreanic molecules. Previous articles in this Journal have given excellent introductions to synthetic methods in organofluorine chemistry (31,biochemically significant fluorinated compounds (41, and a short history on the role of fluorine in chemistry (5). This article will review briefly the advances in selective fluorination, concentrating on the use of fluoromethanes as preformed fluorocarbon units for organic synthesis.' w
Survey of Selective Fluorination Processes ( 8 ) Fluorinated organic compounds have been successfully a o ~ l i e dto a ereat varietvof chemical and biochemical needs (i,*7). This itility can de attributed to the unique nature of the fluorine atom. because its small size and hieh electroneeativity set i t apart from the other halogens. 0&e attached an oreanic molecule. fluorine tends not to be used as a '.hand'iewfor further tranifmnations, as is usually the rnsc with ('I, Rr, or I. It bcwme.; an important suhsrirurnl 10 be wntained in the final target compounds, imparting desirable physical and chemical properties ro the nwlec~~le. In many respects selecti\ eiy fluorinnted analogs of natural substrates nrc ideal prohes 01l~iologicalsystems. The term "isoget~metr~c rransformntion" has been used to describe the incorporation o i fluorine in place uf hydrogen to modify a molerule with "m~nimaldisttmtion of ,gnorn~.tryand cmrur-
rent maximal effect on electron distribution" (8). This is a very important concept in the creation of slightly altered analogs of natural substrates. Increased lipophilicity, especially attributed to the presence of a trifluoromethyl moiety, can enhance the transport of a fluorinated molecule in a biological system. The effect of fluorine substitution might be manifest as an inhibition, alteration, or enhancement of a normal biological process (9). The highly toxic and reactive nature of most fluorinating reagents has restricted much of the work in the field of organofluorine chemistry to specialized industrial labs. In the nast decade the develonment of safer. selective reaeents has promoted organofluorine chemistry as a readily accessible comnonent in the arsenal of methods onen to all svnthetic organic chemists. Fluorine and hydrogen fluoride gases have been "tamed" by dilution. Controllable reactions are possible with a 5% mixture of Fz in nitrogen run at low temperatures (10). Seventy percent hydrogen fluoride in pyridine solution (11) has many advan CHB,F C1> Br, I. For example, CH~B;is a more potent alkylating agent than CH3CH2Br,which is approximately as reactive as CHzBrF, both of which are more reactive than CHzBrz. With fluorinated methylene halides X- is always displaced in preference to F-, while CH2F2 is essentially inert. Use of chlorofluoromethane, hromofluoromethane, and iodofluoromethane for fluoromethylations has been restrict-
>
144
lodofluoromethaneproduction (24)
1
Mechanlsrns The general term "fluoromethvlation" is used to denote any a~kylationinvolving the attachment of a single carhon unit containing one, two, or three fluorines, with or without other halogens or hydrogens present. Fluoromethylations are readily subdivided according to type of halomethane employed and mechanism of alkylation: CHzFyXz CHzFX CHF,X, CF,X,
Swarts's Readion 122)
15
a C h e m l ~ shin I in ppm upfleldfrom CFCI,. aFrom reaction a1 llvorinafed methane with nwmphilen. -Relative costs per mole of tlu~omemane.where t = $20/mole(DAST = 40 on this ale);N. A. = not available commercially.
fluoromethanes methylene halides halofarms tetrahalomethanes
ed by their lack of commercial availability. Numerous syutheses are reported in the literature, but all require use of toxic materials and proceed in low y~elds:
Journal of Chemical Education
Nuc-
+ Br-CF2-Br
Nue- + :CF, Nuc-CF,- + CBr,F,
---
Nue-Br + :CF2+ BrF Nue-CF,Nuc-CF,Br + :CF, + Br-
(2) Single electron transfer can occur between the nucleophile and tetrahalomethane,creating radical anions in an S n ~ l
radical chain mechanism: Nuc-
+ CF,Br
CF,BrF' Nuc- + CF; Noc-CF,,-. + CF,Br
-
-
Nuc' + CF,BrF CF; + BrNuc-CF,-' Nuc-CF3 + CF,Br-
Wakselman and co-workers (27-31) have studied these processes, employing a variety of nucleophiles and fluoromethanes. The ionic chain mechanism appears to govern reactions of CBr2F2 with phenoxides, thiophenoxides (27), and carbanious (28),while the radical chain mechanism best explains results seen for CBr2Fz and enamines (291, CBrFB/ thiophenoxide and CCI2F2/thiophenoxide systems (30).
With the mixed halofluoromethane, CBrClFz, and thiophenoxides both processes compete for reaction control (31). Each case needs to he considered individually until clearer correlations between variables can he established. Applications Two popular targets for the attachment of fluoromethyl moieties have been malonic esters and protected amino acids. Most notable is the research hy Philippe Bey and coworkers (32,33,38, 39) a t the Merrell Dow Research Institute in Strashourg, France. There many biologically active fluorinated analogs have been synthesized for study as enzyme-activated irreversible inhibitors. The direct synthesis of n-halomethyl-a-amino acids is achieved by incorporation of a variety of halogenated methyl moieties onto the parent a-amino acids, using henzylidene protected amino ester a carhanions. These were designed to inhibit specific amino acid decarboxylases (32): I'OrMr (.,HsI.H-N
I I
(.-I1
H
('I1,Me
I
-% l'&lsC~H-N-~C-ll.
-
proach. Previous multistep processes are being supplanted by more direct routes, although a CF3+ intermediate or its equivalent still remains elusive. Trifluoromethyl iodide would he the reagent of choice if its reactivity paralleled that of methyl iodide. However, it does not act as a source of CFs+, since nucleophiles attack the iodine rather than the carbon of CF31. Photochemically or thermally induced homolytic cleavage of the carhon-iodine bond in trifluoromethyl iodide readily generates C F i for radical reactions. Trifluoromethylated imidazoles have been generated in this manner by Cohen (40). But most synthetically useful trifluoromethylation reactions employ organometallic reagents, trifluoromethyl copper (41) or zinc complexes (42). THF RX CF31+ Zn ultrasound' [CF3Zn11 ~d* RCF' The analogous Grignard reagent, CFsMgX, is difficult to prepare and gives low yields of trifluoromethylated product (7) ,-I.
CH.FVXI
Mi
COIMP
I
r6H5CH=N-C-R I
C'H,F,?(.->
Similarlv carhanions of malonic esters react with fluoromethanes."~lthou~h many suhstituted diethyl malonates are commerciallv available and allow easv attachment of fluoroproblems arise in the further manipulation methyl of the molecules. Diethyl fluoromethylated malonates are very resistant to aqueous acid hydrolysis and basic solutions promote elimination of fluoride ion. Therefore, the mixed ethyllt-hutyl diester or the di-t-hutyl malonic esters find greater synthetic utility in these cases. In this manner Bey has transformed difluoromethylated malonates into a-difluoromethylated acids, amines, and amino acids (33):
Chlorodifluoromethane was first used as a difluoromethylatingagent over 25 years ago (34). In addition to the work by Bey, CHCIF2 has been used to synthesize N-difluoromethyl vinylogous amides (34,35), fluorinated prostaglandins (36), and fluoromethylated amino acids from arninomalonates (37). Recently Bey has applied this strategy to the synthesis of fluoroallylamines, designed to inhibit monoamine oxidases (38):
As an alternative to use of CHKlF for the svnthesis of m,>notluoromrthplated rompmmds, a two-step prurehs using CHC'LF folluwrd hv tributvltin hydridr redurtiun works
New methods have appeared for the synthesis of compounds containing the trifluoromethyl group in response to increased interest in this unit which imparts special electronic effects and areater lipophilicitv to hiomolecules. The tritlll#~rornethyl m&ery rnnnol be incorporated t1.v thr methods descril~i>d ahow l ~ u trequires a difterenr synthetic ap-
Recently Burton and Wiemers (43) have reported the high-yield preparation of trifluoromethyl cadmium and zinc reagents emolovine . . . inexnensive dihalodifluoromethanes. This nwel transtormation rvquires participation 115. the solvrnl (dimeth\,lforrnamide) to generntt fluoride ion and convert CF2: to CF~-.Cuprous salts can then he used to prepare (trifluoromethyl) copper for the trifluoromethylation of aryl iodides (43): DMF Cd + CBr,F, +[CF,CdBr]
Use of dihromodifluoromethane to synthesize hromodifluoromethylated compounds has increased because the CFzBr unit can he transformed into a CF3 in one additional step. Reactions of enamines with CBr2F2followed by hydrolysis give a-CF2Br suhstituted ketones which are easily converted to trifluoromethylated compounds on attack by fluoride ion (29):
The hromodifluoromethyl unit attached to oxygen or sulfur is readily converted to CF3. Several groups have synthesized fluoromethylated phenoxides and thiophenoxides t,o study OCFs and SCF3 substituent effects (27,30,44):
Esters containing a trifluoromethyl group in the a-position can he synthesized by modifying the familiar pathway of malonic ester synthesis. After the attachment of a CF2Br unit to amonosuhstituted malonate, the product can then be transformed, by loss of one ester (dealkoxycarhonylation) and halogen exchange, to the desired trifluoromethylated compound by use of anhydrous K F in dimethyl sulfoxide (45):
This case is an interesting example of how a fluorinated Volume 64 Number 2
February 1987
145
unit can ereatlv influence or alter the "normal" course of subsequent ch&cal reactions. In malonic ester synthesis the normal sequence involves alkylation followed by acid or base hydrolysis to convert the geminal diester to a monoacid through deesterificatiun and decarhoxylation. With the bromodifluoromethyl substituted compounds these conditions lead to complete removal of the fluorinated unit, giving RCH2C02H.In addition to facile base-promoted loss of fluoride, these compounds show reduced reactivity of the carhonvl functionalities t o nucleonhilic attack due to the close pioximity and influence of thk fluoromethyl moiety. Through the efforts of Burton and co-workers (24,46,47) fluoromethanes have found great utility in Wittig reactions for the preparation of terminal vinvl fluorides. Tertiarv phosphines-and fluoromethanes readily form fluorinated phosphonium salts, sometimes in quantitative yields as in the case of triphenylphosphine and dihromodifluoromethane. These salts can he converted to phosphonium ylides with additional phosphine acting as a base. The fluoromethylene ylides can then undergo Wittig reactions with aldehydes and ketones (46):
+
-
Ph3P CBr,F, [Ph,PtCF,Br]BrPh P PhCHO [Ph3PtCF2-] + PhCH=CF,
a
Numerous combinations of tertiary phosphines, fluoromethanes, and carbonvl com~oundshave been exnlored. opening a synthetic route to many selectively fluorinated olefins (24,46,47,48), four of which are shown here:
With the exception of trifluoromethyl iodide, iodofluoromethanes are not commonlv emploved in svnthesis. Thev are inherently less stable than the analogous-brominated or chlorinated fluoromethanes and are not commercially available. CHoFI is desirable for fluoromethvlations.~,~ but its troublesome synthesis has limited its subsequent use. Current studies with difluurudiiodomethane point out its potential as a photochemical source of CFs and CF2I' (49). CF212can he svnthesized from CIAusine HeW. but it faces similar harriers to general utility as C H ~ F ~-': A final application of fluoromethanes in organic synthesis reemphasizes their importance in generating halocarhenes. In addition to their previously mentioned interaction with uucleophiles, fluorocmbenes &dergo insertions and cycloadditions, similar to, hut less vigorously than methylene (CH2:).One example from the recent literature is the cyclopropanation of vinyl ethers. Fluorine-19 NMR allows identification of all the isomeric products (50):
.
146
Journal of Chemical Education
~
~
~
~~~
Summary
Fluoromethanes are being used in organic synthesis to generate highly functionalized, selectively fluorinated intermediates which can he transformed into many fluoromethylated analogs not readily synthesized by other methods. These include u-mono-, di-i and triflu~iometh~lated carboxylic acids, esters, amines, and amino acids. Through the Wittig reaction fluoromethanes can be used to create monoand difluorinated terminal olefins. The use of fluoromethanes offers advantages of easy handling and low toxicity, and reactions can be run in simple glassware set-ups.
8. Kollonitsch, J. Israel J . Chem. 1978, 17.53. 9. Walsh. C. Ad". Enzymologi, 1983.55, 197. 10. Purrington,S.T.:Kagen, B. S.:Pafrbk,T.B. Chem. Reu.,suhmitted. 1973,779and786.Olsh,G.A.;Welch, J. 11. Olah.G.A.;Nnjima,M.;Kereker.I.Synlhesis Svnthesir 1974,652. 12. Purrington,S.T.:Jones,W.A.J.Orp.Chem.1983,48,761.Purcington.S.T.:Jones,W. A. J. Fluorine Chem. 1984.26.43. 13. Barnette, W.E. J . Am. Chem.Soc. 1984.106.452, 14. Inman, C. E.: Oesterling. R. E.:Tyerkowski, E. A. J . Am. Chem. Sor. 1958.80.6533, Gershon, H.: Renwiek, J. A. A,; Wynn, W. K.; D'Ascoii, R. J. Org. Cham. 1966.31, 0,a
15. Smith,W. C. Ang~ui.C h r m 1nt.Ed. Engl. 1962.1.467. 16. Midd1atonW.JJ.Ow.Chem. 1975,40,574.Middleton, W.J.:Bingham,E.M. J.Org. Chrm. 1980.45.2883.
Compound8:Reinhold: New York, 1962. 20. Filler, R.lrrvalJ.Chrm. 1978,17,71. Shaeko1ford.S.A. J.Org. Chem. 1979.44.3485, 21. Hine. d.: Thomas. C. H.: Bhrenson, S. J. J. Am. Chem. Sor. 1955, 77,3886. Hine, J.; Ehrmaon,S.J.:Brsder.W. H. J A m Cham.Soe. 1956.78.2282, 22. Palets,0. Collect. Czech. C h m Commun. 1971,36,2062. 23. Haaze1dine.R. N. J . Chrm. Soc. 1962,4259. 24. Burton,D. J.;Greonlimh,P. E. J. Orp. Chem. 1975.40. 2796. 25. Hine,d.: Porter. J.J.J . Am.Chcm.Soc. 1957,79,5493and 5497. 26. Wheaton, G. A,:Burton, D. J. J . Org Chem. 1978.43.2643, 27. Rlcu. I.: Wakselman, C. Tetrahedron Lett. 1981, 22, 323. Rico, I.: Wakselman, C. Tntrnhrdrrin 1811197 6709
~~
. .~
37. ~ s u s h i r n aT.: , ~ a w a d s K. , ~ & h ~ d &~l . m 1985.26.2445. J.M~d.Chem. 38. Mcnonald. LA.: Lacate. J.M.;Bey.P.:Palfreyman,M.G.;Zreika,M. IJRS.28 IRE ~
~
39. Bey, P.; Dump. J. B.; Schiilin. D. Tetrahedron Lett. 1284.25.5657. 40. Kimotcl. H.: Fujii.S.;Cohen,L.A. J. Or& C h e m 1984.49.1080. 41. Kohsyashi,Y.:Ysmsmoto.K.:Kumadaki. I. TetrahedronLett. 1973.20.4071. 42. Kitarume,T.: Ishikawa, N. Chem.Leli. 1982, 137. 49. Rurton. D. J.:Wiemers, D. M. J . Am. C h e m Soc. 1985, 107,5014. Wiemem,D. M.:
Burion, D. 1 . J. Am. Chem. Soc. 1986,108,832. 44. Suda. M.; Hin0.C. TerrahedronLeil. 1981.22, 1997.
45. Everett, T. S.:Purrington,S. T.; Bumgardner, C . L.J . Org Cham. 1984.49.3702, 46. Burton, D. J. J.Fluon'nr Chem. 1983,23,339. 47. Hnyarhi. S.: Nskai,T.; Ishikawa. N.: Burton,D. J.;Naae.D. G.: K~r1ing.H.S. Chem. Left. 1979.988. 48. Suda.M. TetrahrdronL~tr.1981,22, 1421. 49. Elrhe1mer.S.; Dolbier, W. R.: Murls, M.; Seppelt,K.:Paproft,G. J . Orp. Chem. 1984. 49. 205. SO. Camps. F.: Coll, J.: Fabrias.G.:Guerrero,A.J . Nuoiinr Cham. 1985.23.261.
