Synthetic applications of fluorinated phenyllithiums preparation of fluorinated α-methylstyrenes, benzhydrols, benzophenones and aryltrimethylsilanes

ELSEVIER

Journal of Fluorine Chemistry 78 ( 1996) 113-l 19

Synthetic applications of fluorinated phenyllithiums Preparation of fluorinated a-methylstyrenes, benzhydrols, benzophenones and aryltrimethylsilanes Thomas David Yarwood, Anthony John Waring *, Paul Leslie Coe School

of Chemistry,

The University

ofBirmingham,

Edgbaston.

Binninghum

B15 27X

UK

Received 30 June 1995; accepted 9 February 1996

Abstract Regioselective preparations of a number of fluorinated phenyllithiums have recently been reported, which in some cases also contain one or more bromine substituents. These have now been applied to the synthesis of the corresponding halogenated 2-arylpropenes (a-methylstyrenes), benzhydrols, trifluoromethylbenzhydrols, benzophenones and aryltrimethylsilanes. Keywords:

Fluorinated phenyllithiums; Synthesis applications; NMR spectroscopy; Mass spectrometry

1. Introduction We recently reported studiesof the formation of phenyllithiums which contain one or morefluorine atoms,andsometimes bromine atoms also [ 11 ‘. This work extended other studies and enabled a number of such aryllithiums to be prepared in a regiospecific or highly regioselective manner. Moreover, the methodsandprinciples usedshouldbe directly transferableto many other substrates.Thus, for example, llithio-3,4-difluorobenzene was made by treating l-bromo3,4-difluorobenzene in ether with n-butyllithium/hexane. Similarly, 1-lithio-2,4-difluorobenzene was made from I bromo-2,4-difluorobenzene.The lithiated intermediateswere normally derivatized under mild conditions, usingacetoneto form the correspondinghalogenated2-arylpropan-2-01s(1) [ 11. We have now extended the synthetic applications of thesecompoundsand report the resultsin this paper.

2. Results and discussion The 2-arylpropan-2-01s1 have beendehydratedto produce the corresponding halogenated 2-arylpropenes [a-methylstyrenes] 2 (Scheme 1). For example, 2-( 3-bromo-4,6difluorophenyl) propan-2-01( 1; R, = Br, R, = R, = F) gave 72% of pure 2- (3-bromo-4,6-difluorophenyl) prop-2-ene(2; * Corresponding author. ’ The work described in this paper is taken, in part, from Ref. [2] 0022-l 139/96/$15.00 0 1996 Elsevier Science S.A. All rights reserved PIISOO22-1

139(96)03424-O

R, = Br, R, = R, = F) . A trace of hydroquinone wasaddedto the reaction mixtures to reducepolymerization. Better yields were obtained by using 85% orthophosphoric acid as dehydrating agent,rather than phosphoruspentoxide, andby using column chromatography to isolate the styrenes, rather than distillation from the reaction mixture as had been usedpreviously [3]. Details are given in the Experimental section and in Table 1. The 2- (2,4-difluorophenyl)propan-2-01 has beenmadepreviously from the reaction of 2,4-difluorophenylethan- 1-one (2,4-difluoroacetophenone) with methylmagnesiumiodide or methylmagnesiumbromide, but could not be converted into the corresponding a-methylstyrene [4]. However, a similar preparation published after our studies did give the a-methylstyrene [5]. The 2-(2,6-difluorophenyl)propan-2-01 has been made previously from methyl 2,6-difluorobenzoate with methylmagnesiumiodide [ 61: it and its I ( 13C) analoguehave also been made from 2,6-difluorophenylethan-l-one as above [71, and successfully (unpurified) 2-( 2,6-difluorodehydrated to form phenyl)propene (2; R2= R6= F) [ 6,7]. The two isomeric difluorophenyllithiums, made as describedabove by reacting the bromodifluorobenzene with butyllithium, were also allowed to react with 1 equiv. of benzaldehyde or 4-trifluoromethylbenzaldehyde in ether. Thus, 1-bromo-3,4-difluorobenzene(3) was lithiated to give 1-lithio-3,4-difluorobenzene (4). Reaction with 4-trifluoromethylbenzaldehyde followed by column chromatography gave 3,4-difluoro-4’-trifluoromethylbenzhydrol (5; R, =

114 Table 1 Dehydration

T.D. Yanvood

of 2-arylpropan-2-01s

et al. /.loumal

of Fluorine

Chemistry

Amt. of initial precursor (g)

Reagent,

2,4-Difluoro2,6-Difluoro3,4-Difluoro2-Bromo-4,5difluoro2-Bromo-5,6-difluoro3-Bromo-2,6-difluoro3-Bromo-4,6-difluoro-

5.0 5.0 5.0 8.0 5.0 5.0 5.0

P,% 1.7 g p205.3.0 g 85% H,PO,,, P,% 2.0 g 85% H,PG,, 85% H,PO,. 85% H,PO,,

at 20-25 “C. pure isolated products. Found: C, 46.7; H, 3.2%. C,H,BrF? Found: C, 46.1; H, 3.1%. C,H,BrF,

requires: requires:

of aryltrimethylsilanes,

Aryl substituents

3-Fluoro- ’ 2,4-Difluorod 2,6-Difluoro3,4-Difluoro3,4-Difluoro3-Bromo-4,6-difluoro-

in 7

ArSiMe,

amount ’

10 cm3 10 cm3 10 cm3 10 cm3

Time (h)

Yield h (%I

4 6 17 15 16 18 17

53 56 76 71 7oc 75 d 12

C, 46.4; H, 3.0%. C, 46.4; H, 3.0%.

%=F, Ar =4-CF,-C,H,-) in 70% yield. Reaction of the lithio compound with benzaldehyde gave 3,4-difluorobenzhydrol (5; R, = R, = F, Ar = C,H,-) (75%). Similarly, 1-lithio-2,4-difluorobenzene, made from l-bromo2,4-difluorobenzene, reacted with 4-trifluoromethylbenzaldehyde to give 2,4-difluoro-4’-trifluoromethylbenzhydrol (5: R, = RJ = F, Ar = 4-CF,-C,H,-) as a colourless oil in 48% yield, and with benzaldehyde to give 2,4-difluorobenzhydrol (5; R, = R, = F, Ar = C,H,-) ( 80%). In the same way, the two symmetrical dibromodifluorobenzenes were treated with butyllithium and then 4-trifluoromethylbenzaldehyde. Thus, n-butyllithium in ether converted I ,2-dibromo-4,5-difluorobenzene into 1-lithio-Z bromo-4,5-difluorobenzene which was allowed to react with 4-trifluoromethylbenzaldehyde to give 2-bromo-4,5difluoro-4’-trifluoromethylbenzhydrol (5; R, = Br, R, = R, = F, Ar = 4-CF,-C,H,-) (44%). 1,3-Dibromo-4,6difluorobenzene similarly gave 1-lithio-3-bromo-4,6-difluorobenzene and on reaction with 4-trifluoromethylbenzaldehyde gave 3-bromo-4,6-difluoro-4’-triTable 2 Preparation

113-119

2

1 to 2-arylpropenes

Aryl substituents in 1 and 2

a Reactions h Yields of ’ Analysis: d Analysis:

78 (1996)

(7)

Base: solvent

Yield (%)

B.p. a (“C)

Grignard: Et,0 “BuLi: hex., Et10 LDA: hex., THF “BuLi: hex., Et*0 Grignard: Et20 “BuLi: hex., Et,0

76 43 32 63 52 43

172-173 166167

’ e ‘ g ’ ’

177-178 176177 222-224

a Distillations at 747-752 mmHg. b From 3-fluorobromobenzene: see text, ’ Analysis: Found: C, 64.0; H, 7.8%. C&r,FSi requires: C, 64.2; H. 7.8%. ’ This compound has recently been reported [ 14,151. ‘Analysis: Found: C, 58.4; H, 6.4%. C9H,2FZSi requires: C, 58.1; H, 6.5%. f Analysis: Found: C, 58.4; H, 6.6%. C$IH,,F,Si requires: C, 58.1; H. 6.5%. g Analysis: Found: C. 57.8; H, 6.4%. &.H,,F,Si requires: C, 58.1; H, 6.5%. h Analysis: Found: C, 58.3; H, 6.4%. GH,2F2Si requires: C. 58.1; H, 6.5%. ’ Analysis: Found: C, 40.4; H, 4.0%. C&I, ,BrF,Sirequires: C, 40.7; H, 4.2%.

fluoromethylbenzhydrol (5; R-, = Br, R, = R, = F, Ar = 4-CF,-C,H,) (57%). Grignard reagents have been used previously to synthesize symmetrical and unsymmetrical polyfluorobenzhydrols which showed in vitro anti-fungal activity [ 81. We have prepared representative tetrafluorobenzhydrols by reaction of ethyl formate with 2 equiv. of 3,4- or 2,4-difluorophenyllithium, generated in ether. The yields, however, were modest, and the products had to be separated from the intermediate difluorobenzaldehydes (see Experimental details). Most of the preceding benzhydrols were oxidized to the corresponding benzophenones. For example 3,4-difluoro-4’trifluoromethylbenzhydrol was oxidized with excess chromic oxide in glacial acetic acid to give 3,4-difluoro-4’-trifluoromethylbenzophenone (6; R, = R, = F, Ar = 4-CFa-&H,--). Better yields were obtained using chromic acid in a two-phase ether/water medium (see Experimental details). Thus the present sequence of reactions offers good routes to (possibly further halogenated) fluorobenzophenones. Another potentially valuable application of the lithiated aromatics we have produced is in their reactions with chlorotrimethylsilane [ 91. This produces a series of aryltrimethylsilanes which should allow electrophilic ipso substitution in which the trimethylsilyl group is replaced by an electrophile. Since we have shown the possibility ofpreparing a wide range of halogenated phenyllithiums, there would be considerable scope for the preparation of benzenes with unusual substitution patterns. Some of the possibilities have been reviewed [ lo]. From our point of view, the most important application of these intermediates would be in the selective introduction of fluorine [ 111. Thus, 3,4-difluorophenyllithium (4)) made from 1-bromo-3,4-difluorobenzene (3) in ether, had an ethereal solution of chlorotrimethylsilane added at - 78 “C. The mixture was warmed to 20 “C overnight, and work-up gave pure 3,4-difluorophenyltrimethylsilane (7; R, = R, = F) in 63% yield. One may note that 1,2-elimination of lithium fluoride from this particular intermediate (4) cannot occur, so the scope for side-reactions is reduced. Other, similar reactions (see Table 2) gave 2,4-difluorophenyltri-

T.D. Ymwood

et ul. /Journal

of Fluorine

methylsilane in 43% yield and 3-bromo-4,6-difluorophenyltrimethylsilane (from 3-bromo-4,6-difluorophenyllithium). To test the generality of these reactions, 1,3-difluorobenzene was treated with lithium diisopropylamide (LDA) in THF at - 78 “C. The resulting 2,6-difluorophenyllithium [ 11 was reacted with chlorotrimethylsilane in ether at - 78 “C. However, there were many products containing trimethylsilyl groups, and the desired 2,6-difluorophenyltrimethylsilane (7; R, = R, = F) was isolated in only 32% yield. We believe the problem here is that chlorotrimethylsilane reacts slowly with 2,6-difluorophenyllithium at - 78 “C and that lithium fluoride can be eliminated to give an aryne during warming ‘. However, if there is no halogen substituent ortho to the lithium group, this elimination cannot be a competing reaction even at ambient temperature, and a Grignard reaction should be suitable for the preparation of the silanes. In accord with this, the Grignard reagent of 3-fluorobromobenzene was treated with chlorotrimethylsilane in ether at room temperature to form 3-fluorophenyltrimethylsilane (7; R, = F) in 76% yield. The Grignard reagent from 3,4-difluorobromobenzene similarly gave 3,4-difluorophenyltrimethylsilane (7; R, = R4 = F) in 52% yield.

3. Experimental

details

All solvents were purified and dried according to Vogel [ 131. n-Butyllithium was used as purchased as a 1.6 M solution in hexane unless otherwise stated. Analytical gas-liquid chromatography was run on Pye-Unicam series 304 or Shimadzu GC-RlA machines using silicone gum columns, SE30, on Celite. Column chromatography used silica (Sorbsil C60 for chromatography, 40-60 mesh, Phase Separations Ltd.) with CH2C12 as solvent unless otherwise stated. Melting points were taken on a Gallenkamp apparatus, and are uncorrected. Infrared spectra were run on a Perkin-Elmer series 1600 FT-IR machine. NMR spectra were run on a PerkinElmer R-12B machine at 60 MHz (‘H) and at 56.4 MHz (“F), on a JEOL FX-90Q machine at 90 MHz ( ‘H) or 84.26 MHz ( 19F) or on a JEOL GX-270 machine at 270 MHz (‘H only). The references used were TMS ( ‘H) and CFCl, ( 19F, chemical shifts as ppm upfield). Mass spectra were recorded on a Kratos MS80 instrument. 3.1. General (5)

procedure

for the preparation

of benzhydrols

n-Butyllithium, (1.6 M, in hexanes, 1 equiv.) was added in portions (l-2 cm3) to a stirred solution of the fluorinated arene( 1 equiv.) in dry ether (50 cm3) at - 78 “C during 3045 min. After 30 min at - 78 “C, the benzaldehyde( 1 equiv.) * Since our work, 2,6-difluorophenyllithium has been prepared from 1,3difluorobenzene and n-butyllithium in THF/TMEDA at - 70 “C and then trapped by chlorotrimethylsilane at - 70 “C to give 2.6-difluorophenyltrimethylsilane (7; Rz = R, = F) in 90% yield [ 121.

Chemistry

78 (1996)

113-119

115

was added in portions of l-2 cm3. After warming to room temperature,the productswere pouredinto 10% hydrochloric acid, extracted with ether, dried, the solvents removed and the product purified by column chromatography on silica. NMR data for the fluorinated benzhydrols (5) prepared are listed in Table 3. 3.1.1. Preparation benzhydrol

of 3,4-diJluoro-4’-tri$uoromethyl-

3,4-Difluorobromobenzene (10.0 g, 0.052 mol) was treated as above, then 4-trifluoromethylbenzaldehyde ( 10.0 g, 1 equiv.) was added in portions of ca. 2 cm’. Half of the oily product (14.3 g) was retained for oxidation and the remainder purified. Column chromatography gave: (i) an uncharacterized fluorescent oil (0.15 g) ; (ii) a blue oily unidentified aromatic compound (0.65 g) ; and (iii) 3,4difluoro-4’-trifluoromethylbenzhydrol(5; R, = R4= F, Ar = 4-CF&H,-) (5.1 g, 68%) (Analysis: Found: C, 58.2; H, 3.4%; m/z: 288 (M)+; 269 (M-F)+; 219 (M-CFs)+. Ci4H,F,0 requires: C, 58.3; H, 3.1%; M+ 288). 3.1.2. Preparation

of 3,4-difluorobenzhydrol

Benzaldehyde (5.5 cm3,0.052 mol) wasusedin a reaction otherwise identical to the preceding one. Chromatography separated pure 3,4-difluorobenzhydrol (5; R3= R4= F, Ar = C,H,-) (2.5 g, 22%). (Analysis: Found: C, 70.6; H, 4.8%. C,,H,,,FF,O requires:C, 70.9; H, 4.6%). Another fraction (5.5 g, 48%) was the sameproduct, containing a trace of unreactedbenzaldehyde (identified by GLC) . 3.1.3. Preparation benzhydrol

of 2,4-dsuoro-4’-trijluoromethyl-

1-Bromo-2,4-difluorobenzene ( 10.0 g, 0.052 mol) and 4trifluoromethylbenzaldehyde (7.7 g, 0.044 mol) gave the benzhydrol (5; R, = R4= F, Ar = 4-CF,-C,H,-), a colourlessoil (6.0 g, 47%) after column chromatography (Analysis:Found: C, 58.0; H, 2.9%. C,,H,F,O requires: C, 58.3; H, 3.1%). 3.1.4. Preparation

of 2,4-dijluorobenzhydrol

I-Bromo-2,4-difluorobenzene (10.0 g, 0.052 mol) and benzaldehyde (5.5 cm3,0.052 mol) were treated similarly to give 2,4-difluorobenzhydrol (5; R2= R4= F, Ar = C,H,-) (7.5 g, 66%) (Analysis:Found: C,71.1;H,4.3%.C,3H,c,FZ0 requires: C, 70.9; H, 4.6%), and a mixture ( 1.5 g, 13%) of this with a trace of unreactedbenzaldehyde. 3.1.5. Preparation methylbenzhydrol

of 2-bromo-4,.5-diJluoro-4’-trijuoro-

n-Butyllithium ( 11.5 cm3, 0.018 mol) was added to ,2dibromo-4,5-difluorobenzene (5.0 g, 0.018 mol) and the intermediate reacted with 4-trifluoromethylbenzaldehyde ( 3.15 g, 0.018 mol) . Chromatography separatedthree of the four components: (i) an unidentified green oil (0.7 g) ; (ii) 2-bromo-4,5-difluoro-4’-trifluoromethylbenzhydrol (5; R2= Br, R4= R5= F, Ar = 4-CF3-C6H4-) (3.0 g, 44%) con-

116

T.D. Yarwood

Table 3 NMR data for fluorinated

benzhydrols

R-2

R-3

F -c F 1118or 115.0 d F lll.Oor 114.5 d H 7.0-7.2 d

H 6.7-6.9 H 6.5-6.8

H 7.0-7.2

’

H 7.17d F 115.5 d H 7.36 *

H 6.8 d F 137.2 or 139.1 d F 130.7 or 140.0 J F 134.0 or 136.4 ’ H 6.86 k F 135.4 lJ

d d

et al. /Journal

of Fluorine

Chemistry

78 (1996)

113-l

5 (6 values a in CDCI,) R-4

R-5

F -c F 1118or 115.0 d F lll.Oor 114.5 d F 137.2 or 139.1 d F 130.2 or 140.0 d F 134.0 or 136.4’ F 103.6 d F 136.7 ’

H 6.7-6.9 H 6.66.8

R-6

d d

CF, b

H 7.35 e H 7.37 =

-c

H 6.8 d

H 7.36 d

H 7.0-7.2’

H 7.0-7.2

d

H 7.0-7.2

d

H 7.0-7.2

d

H 7.17 d

H 7.17d

Br

H 7.69 ’ Br

H 7.36’

63.1

taining a small amount of an unidentified impurity; and (iii) 4-trifluoromethylbenzoic acid (0.5 g) . of 3-bromo-4,6-diJuoro-4’-triJluoro-

1,3-Dibromo-4,6-difluorobenzene wasusedin an identical procedure to give the benzhydrol (5; R, = Br, Rd= R, = F, Ar = 4-CF,-C,H,-) (3.2 g, 48%) (Analysis: Found: C, 45.9; H, 2.2%. C,,HsBrF,O requires: C, 45.8; H, 2.2%). of 3,3’,4,4’-tetrajluorobenzhydrol n-Butyllithium in hexanes( 17.0cm3,27 mmol) wasadded in portions to stirred I-bromo-3,4-difluorobenzene (5.30 g, 27 mmol) in dry ether (50 cm3) at -78 “C during 30 min. After a further 30 min at - 78 “C, freshly distilled dry ethyl formate ( 1.1 cm3, 13.7 mmol) was addeddropwise over 10 min. After warming to 20 “C overnight, the product was acidified with 10% aq. HCl and extracted with ether. Workup andchromatography gave 3,3’,4,4’-tetrafluorobenzhydrol (2.73 g, 80% based on the bromodifluorobenzene) and 3.1.7. Preparation

Ar

CH, OH

7.46 f, 7.57 e Ph 7.2-7.3 d

6.07, 2.80

Symm.

h

6.24, 3.00

7.41 ‘, 7.58’ Ph 7.2-7.3 d

5.75, 2.79

Symm. h

5.68, 2.60 6.0 “, 2.8 6.1 “, 2.64

7.44, 7.60 m 7.47, 7.63 m

63.2 63.2

a References used were TMS ( ‘H) and CFCl, ( ‘T, chemical shift as ppm upfield) h The absence of an entry denotes a symmetrical benzhydrol (‘Symm.’ in the next column) or an arylphenylmethanol ’ Present but not recorded. d Complex m. e d, J= 8.6 Hz of d, J= 8.4 Hz (metu coupling to F-2 and F-4) of d, J= 6.6 Hz (orrho coupling to H-5). ‘d, J=8.2 Hz (H-Z’, H-6’ coupled to H-3’, H-5’). s d. J= 8.2 Hz (H-3’, H-5’ coupled to H-2’. H-6’). h Symmetrical benzhydrol. ’ d, J= 8.5 Hz (H-2’. H-6’). ‘d, J=8.5Hz (H-3’,H-5’). ‘d, J= 10.2 Hz of d, J=8.2 Hz (m-rho coupling to F-2 and F-4). ’ t, J= 8.0 Hz (metu coupling to F-2 and F-4). m d, J= 9.0 Hz (who coupling of H-2’ to H-3’ and H-5’ to H-6’). ” d, J= 4.4 Hz. ” d, J= 3.6 Hz.

3.1.6. Preparation methylbenzhydrol

19

(‘Ph’

5.95, 2.88

5.71, 2.49

in the next column).

3,4-difluorobenzaldehyde (0.22 g, 5.6%, based similarly). The compounds were identified by their ‘H NMR spectra. of 2,2’,4,4’-tetrajuorobenzhydrol In an identical experiment, 1-bromo-2,4-difluorobenzene gave 2,2’,4,4’-tetrafluorobenzhydrol (2.55 g, 74% basedon the bromodifluorobenzene) and 2,4-difluorobenzaldehyde (0.49 g, 12.8%,basedsimilarly). The compoundswere characterized by their ‘H NMR spectra. 3.1.8. Preparation

3.2. Preparation benzophenone

of 3,4-diJIuoro-4’-trij%oromethyl-

3,4-Difluoro-4’-trifluoromethylbenzhydrol (4.00 g, 13.9 mmol) in glacial acetic acid ( 10 cm3) was addedto a stirred mixture of chromium( VI) oxide (5.00 g, 50 mmol) in glacial acetic acid ( 15.0 cm3). The mixture was heatedto reflux for 30 min, then the products poured into iced water and left overnight. The white crystals which formed were collected, washedwith water and dried in vacua to give 3,4-difluoro-

T.D. Yarwood Table 4 NMR data for fluorinated

benzophenones

et ul. /Journal

c.f Fluorine

Chemistry

78 (1996)

113-l 19

117

6 (6 values a in CDCI,)

R-2

R-3

R-4

R-5

R-6

Ar”

CF,

F 102.6’ F 109.9 ’ H 7.70 k

H 6.92 d H 6.5-6.8 g F 129.7 ’ or 136.0 g F 130.2 or 136.0 e H 7.02 ’

F 105.2’ F 109.9 F 129.7 136.0 F 130.2 136.0 F 96.0 ’

H 7.04 f H 6.5-6.8 p H 7.30 m

H 7.67 8 H 7.65 j H 7.59 n

7.75 and 7.90 h Symm.

63.9

7.80 and 7.89”

63.6

H 7.30 “

H 7.56 ’

Symm.

-

Br

H 7.84-7.92

7.76 ” and 7.84-7.92 E

63.7

H 7.65 p F 106.5 ’

I ’ or f or B

E

a References used were TMS (‘H) and CFCl, (I?. chemical shift as ppm upfield). h ‘Symm.’ denotes a symmetrical benzophenone. ’ d, J= 9.1 Hz (mm coupling to F-4). d d, J= 10.1 Hz of d, J= 8.8 Hz (ortho coupling to F-2 and F-4) of d, J= 2.4 Hz (meta coupling to H-5). ’ q. J= 9.1 Hz (ortlzo coupling to H-3 and H-5, metu coupling to F-2). Id, J= 8.8 Hz (ortho coupling to F-4) of d. J=7.7 Hz (ortho coupling to H-6) of d, J= 2.4 Hz (meta coupling to H-3) of d, J=O.9 Hz 2). s Complex m. ‘d, J= 8.2 Hz (ortho coupling of H-2’ to H-3’ and H-S’ to H-6’). I Apparent t. ’ Apparent t, J= 8.6 Hz. ‘d, J= 10.4 Hz (ortho coupling of H-2 to F-3) of d, J= 7.7 Hz (meta coupling of H-2 to F-4) of d, J= 2.2 Hz (metu coupling of H-2 to ’ d of d, CJ = 21.4 Hz (ortho F-F and F-H couplings). m d, J= 9.7 Hz (ortho coupling to F-4) of d, J= 8.5 Hz (ortho coupling to H-6) of d, J= 7.6 Hz (meta coupling to F-3). “d, J= 8.5 Hz (ortlto coupling to H-5) of d, /=4.3 Hz (meta coupling to F-4) of d, J=2.2 Hz (meta coupling to H-2) of d, J= 1.3 Hz 3). “d, J= 8.0 Hz (ortko coupling of H-2’ to H-3’ and H-5’ to H-6’). p d, J= 10.4 Hz (ortho coupling of H-2 to F-3) of d, J= 7.5 Hz (metu coupling to F-4) of d, J=2.0 Hz (meta coupling to H-6). ‘I d, J= 9.7 Hz (o&o coupling to F-4) of d, J= 8.4 Hz (ortho coupling to H-6) of d, J= 7.5 Hz (meta coupling to F-3). r d, J= 8.4 Hz (ortho coupling to H-5) of d, J= 4.2 Hz (meta coupling to F-4) of d, J= 2.0 Hz (mera coupling to H-2) of d, J= 1.5 Hz 3). ’ Apparent q, J= 9.2 Hz (coupled to H-3, H-6, and F-4). ‘d,J=8.1 Hzofd.J=9,4Hz(coupledtoF-2andF-4). ” Apparent q, J= 9.2 Hz (coupled to H-3, H-6 and F-2). “d. J= 8.2 Hz (H-3’ and H-5’ coupling to H-2’ and H-6’).

4’-trifluoromethylbenzophenone (6; R, = Rd = F, Ar = 4CF,-C,H,-) (2.82 g, 71%) (Analysis: Found: C, 58.6; H, 2.4%. C,,H,F,O requires: C, 58.7; H, 2.5%). 3.3. Preparation benzophenone

of 2,4-dijuoro-4’-trijuoromethyl-

Sodium dichromate (1.4 g, 4.7 mmol) in cont. HZS04 (2.0 cm3) and water (10 cm3) wasaddedto 2,4-difluoro-4’trifluoromethylbenzhydrol ( 3.00 g, 10.4mmol) in ether (7.0 cm3) and the mixture stirred at room temperature for 2 h. Work-up (ether), washing (5% NaHCO,) and then chromatography (silica, CHC&) gave 2,4-difluoro-4’-trifluoromethylbenzophenone (6; R, = Rd= F, Ar = 4-CF,-C,H,-) (2.18 g, 73%) asa paleyellow oil (Analysis: Found: C, 59.0; H, 2.6%. C,,H,F,O requires: C, 58.7; H, 2.5%). 3.4. Preparation of 3-bromo-4,6-dijuoro-4’-tri’uoromethylbenzophenone

Sodium dichromate (0.63 g, 2.1 mmol) in 2 M H,S04 (5.0 cm3) wasaddedto a stirred solution of 3-bromo-4,6-difluoro-

(paru

coupling

to F-

(para

coupling

to F-

(paru

coupling

to F-

H-6).

4’-trifluoromethylbenzhydrol ( 1.75 g, 4.8 mmol) in ether (5.0 cm3). The mixture was stirred at reflux for 6 h and worked-up as above. Chromatography (silica, CHCl,) gave 3-bromo-4,6-difluoro-4’-trifluoromethylbenzophenone (6; R,=Br, R,=R,=F, Ar=4-CF,-C,H,-) (1.50 g, 86%), m.p. 93.8-94.9 “C (Analysis: Found: C, 46.1; H, 1.7%. C,,H,BrF,O requires: C, 46.0; H, 1.6%). NMR datafor the fluorinated benzophenones(6) prepared are listed in Table 4. 3.5. General

methods for the preparation

of 2-arylpropenes

(2) The two methods are exemplified below. Variations are given in Table 1. The 2-arylpropeneswere mostly characterized from their NMR spectra(Table 5). 3.5.1. Preparation

of 2-(3,4-dijluorophenyl)propene

2-( 3,4-Difluorophenyl)propan-2-01 (1; R, = Rd= F) (5.00 g, 0.029 mol), 85% orthophosphoric acid (10 cm3) and hydroquinone (0.5 g) were stirred at 20 “C for 17 h. The

T.D.

118 Table 5 NMR data for 2-aryl-2-methylpropenes R-2

R-3

F 110.7 or 112.6 b F 113.9 H 6.8-7.05 ’

H 6.6-6.9

Br Br F 105.4” or 114.1 n H 7.46 q

H 6.88 c F 140.1 or 143.0 l2 H 7.38 p H 7.30 ’ Br

Br

Yarwood

ef al. /Journal

of Fluorine

Chemistry

78 (1996)

113-119

2 ( 6 values ’ in CDCl,)

’

R-4

R-5

R-6

Me

=CH,

F 110.7 or 112.6 h H 7.18 f F 140.1 or 143.0 c F 135.9 c H 6.95 ’ H 7.41 I’

H 6.6-6.9”

H 7.25 d

2.13

5.20

H 6.88 e H 6.8-7.05

F 113.9 H 6.8-7.05

2.08

5.10. 5.40 4.83, 5.10

F 105.7 c

H 6.86 r

’

F 135.9 c F 135.9 * H 6.78 p

2.25 ’

H 7.01 h F 138.7 ’ F 105.4 m or 114.1 n F 111.6’

2.05

4.92, 5.22 5.00, 5.45 5.10, 5.41

2.05 2.03

2.13

5.21

a References used were TMS ( ‘H) and CFCI, ( ‘T. chemical shift as ppm upfield). h Apparent d, J= ca. 6.1 Hz. c Complex m. d d, J= 8.0 Hz (ortho coupled to H-5) oft, J= 6.1 Hz (mefa coupled to F-2 and F-4). e d, J= 15.0 Hz (orrho coupled to F-2 or F-6) of d, J= 7.0 Hz (ortho coupled to H-4). ’ t, J = 7.0 Hz (orfho coupled to H-3 and H-5) of d, .I = 2.0 Hz (mera coupled to F-2 and F-6). 8 d, J=9.5 Hz of d, J= 8.0 Hz (ortho and meta coupled to F). h d, J= 10.4 Hz of d. J= 8.0 Hz (orrho and mefu couplrd to F). ’ d, J=8.8 Hz (o&o coupled to H-4) of d. J=5.0 Hz (mera coupled to F-5) of d, J= 1.6 Hz (para coupled to F-6). ’ d, J= 8.8 Hz (orrho coupled to H-3) of d. J= 9.0 Hz (orfho coupled to F-5) of d, J= 8.0 Hz (coupled to F-6). ‘d, J=21.3 Hz (ortho coupled to F-6) of d, J=9.0 Hz (ortho coupled to H-4). ’ d, J = 21.3 Hz (orrho coupled to F-5). with extra broadening. m t, J= 8.0 Hz (meta coupled of F-2 and F-6). “t, J= 8.0 Hz (metu coupled of F-2 and F-6). “d, J= 8.2 Hz (orrho coupled to H-5) oft, J=5.5 Hz (meta coupled to F-2 and F-6). p t, J= 8.2 Hz (ortho coupled to H-4 and F-6) of d, J= 1.6 Hz (para coupled to F-2). q t, J= 8.2 Hz (mefa to F-4 and F-6). ‘d, J= 10.5 Hz ofd. J=9.0 Hz (coupled to F-4 and F-6).

mixture was poured into water (50 cm’) and extracted with ether (50 cm3). The washedand dried extract wasevaporated and the yellow oil (3.86 g) chromatographed on silica (CH,Cl,/ hexane, 1:1) to afford the substituted styrene (2; R,=R,=F) (3.4Og, 76%). of 2-(2,4-di$uorophenyl)propene 2- (2,4-Difluorophenyl) propan-2-01 (2; R2= R4= F) (5.00 g, 0.029 mol), phosphoruspentoxide ( 1.40 g, 9.9 mmol) and hydroquinone (0.35 g) were stirred together for 2 h at room temperature. Additional phosphoruspentoxide (0.3 g) was addedand the mixture stirred a further 2 h until IR spectroscopy indicated complete conversion. Work-up (ether) and chromatography gave 2-( 2,4-difluorophenyl)propene(2;R,=R,=F) (2.39g,53%),b.p. (Siwolobof’s method) 155-156 “C. 3.52. Preparation

3.6. Preparation

of 3,4-diJIuorophenyltrimethylsilane

n-Butyllithium in hexanes(32.5 cm3,0.052 mol) in ether (30 cm3) was addeddropwise to 1-bromo-3,4-difluoroben-

zene ( 10.0 g, 0.052 mol) in ether (50 cm3) at - 78 “C during 1h. After stirring 1 h further at - 78 “C, chlorotrimethylsilane (10.0 g, 0.092 mol) in ether was added during 1.5 h. The mixture was warmed to 20 “C overnight, filtered, washed (5% NaHCO,, then water) and dried. Distillation gave 3,4difluorophenyltrimethylsilane (7; R, = R, = F) (6.14 g, 63%) (see Table 2) and a resinousresidue ( 1.48 g) . 3.7. Preparation

of 2,6di@orophenyltrimethylsilane

1,3-Difluorobenzene (8.13 g, 0.070 mol) in dry THF (30 cm3) was added dropwise over 20 min at - 78 “C to LDA (0.070 mol) , made in the usual way in THF (75 cm3) and hexanes(44 cm”). Addition of chlorotrimethylsilane ( 10.85 g) in THF (30 cm3) and work-up as above gave 2,6-difluorophenyltrimethylsilane (7; R, = R, = F) (4.20 g, 32%) (seeTable 2) and a resinousresidue (5.4 g). 3.8. Preparation of 3-Jluorophenyltrimethylsilane Grignard reaction

by

1-Bromo-3-fluorobenzene ( 16.82 g, 0.096 mol) in ether ( 10 cm3) was addedto dry magnesiumturnings (2.4,0.099

T.D. Yanvood

Table 6 NMR data for fluorinated

aryltrimethylsilanes

et al. /Journal

ofFluorine

Chemistry

78 (1996)

119

113-119

7 ( S values a in CDCI,)

R-2

R-3

R-4

R-5

R-6

H 7.3 h F 97.8’ or 107.8 ’ F 97.8 H 6.95-7.38 H 7.50 k

F 114.5 h H 6.6-6.9 h

H 7.0 h F 97.8 ’ or 109.8 Cl H 7.30 p F 140.1’ F 102.4’or 99.0 h

H 7.3 h H 6.6-6.9

H 7.3 h H 7.3 c

h

H 6.78 ’ F 138.6 ’ Br

H 4.78 ’ H 6.95-7.38 H 6.80”

’

h

F 97.8 H 6.95-7.38 h F 102.4 I or 99.0 h

Me$i

0.26 0.30 b

0.36 h 0.26 0.31

a References used were TMS ( ‘H) and CFCI, ( ‘v, chemical shift as ppm upfield). h Complex m. ’ d, J= ca. 6.1 Hz (meta F-F coupling) with extra broadening. ’ d, J= 9.0 Hz (ortho H-F coupling) of d, J= 6.1 Hz (meta F-F coupling) e t, J= 9.0 Hz (mera coupling to F-2 and F-4) of d, J= 8.0 Hz (or&~ coupling to H-5). ‘t, J= 7.9 Hz (orrho coupling to F and H-4). r t, J= 7.9 Hz (orfho coupling to H-3 and H-5) oft, J= ca. 3 Hz (mera coupling to F-2 and F-6) h t, J= 1.5 Hz (coupling to F-2 and F-6). i d, J= 15 Hz (orrlro F-F coupling) of d, J= 9 Hz (orrho coupling to H-2). j d, J= 15 Hz (orrlto F-F coupling) oft, J= 9.0 Hz (meta coupling to H-2 and H-6). Ir d, J= 8.4 Hz of d, J=5.6 Hi (ieta coupling to F-4 and F-6i. I t. J= 9.0 Hz (meta coupling to F and ortho coupling to H). m t. J= 9 Hz (orrho coupling to F-4 and F-6)

mol) in ether at 20 “C. After 5.0 g of the aromatic had been added, the reaction was initiated with ultrasound and the remainder added during 1 h. Chlorotrimethylsilane ( 10.44 g, 0.096 mol) was added over 10 min and the mixture stirred for 16 h. Removal of the ether, filtration and distillation gave 3-fluorophenyltrimethylsilane (7; R, = F) ( 12.33 g, 76%) (see Table 2). NMR data for the fluorinated arylmethylsilanes (7) prepared are listed in Table 6. Acknowledgements We thank ICI Organics Division (now Zeneca Specialities) (Grangemouth) for funding this research, and Drs. J.D.R. Vass and J.D. McLean for their help and interest. We also thank a referee for helpful suggestions. References [ 11 P.L. Coe, A.J. Waring I, (1995) 2729.

and T.D. Yatwood,

J. Chem.

Sot.,

Perkin

Trans.

[21 T.D. Yarwood, Ph.D. thesis, University of Birmingham, 1992. [31 E. Nield, R. Stephens and J.C. Tatlow, J. Chem. Sot., (1959) 166. [41 M.G. Belshaw, A.R. Muir, M. Kinns, L. Phillips and Li-Ming Twanmoh, J. Chem. Sot., Perkin Trans. 2, ( 1974) 119. [5] Shen-Chun Kuo. D. Hou and Zheng-Yun Zhan, US Pat. 5 349 099, 1994. [61 T. Schaefer, R.P. Veregin, R. Laatikainen, R. Sebastian, K. Marat and J.L. Charlton, Can. J. Chem.. 60 ( 1982) 2611. [71 T. Schaefer, R. Sebastian, G.H. Penner and S.R. Salman, Can. J. Chem., 64 (1986) 1602. [SJ G.E. Ditchfield and A.E. Pedler. J. Fluorine Chem., IO (1977) 447. 191 D. Habich and F. Effenberger, Synfhesis. ( 1979) 841. [ 101 T.H. Chan and 1. Fleming, Synthesis, (1979) 761. [ 11 I M. Speranza. C.-Y. Shiue, A.P. Wolf, D.S. Wilbur and G. Angelini, J. Fluorine Chem., 30 (1985) 97. [ 121 B. Benneteau, F. Rajarisan, J. Dunogues and P. Babin, Tetrahedron, 49 (1993) 10 843. [131 A.I. Vogel, Textbook of Practical Organic Chemistry, 4th edn., Longman, London, 1978. [ 141 P. Babin, B. Bennetau and J. Dunogues. Fr. Demande 2 677 358,1992. [ 151 J.-N. Collard and J.-M. Homsperger, Eur. Pat. Appl., 611 769, 1994.