Synthesis of the farnesyl ether 2,3,5-trifluoro-6-hydroxy-4-[(E,E)-3,7,11-trimethyldodeca-2,6,10-trien-1-yloxy] nitrobenzene, and related compounds containing a substituted hydroxytrifluorophenyl residue: Novel inhibitors of protein farnesyltransferase, geranylgeranyltransferase I and squalene synthase

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Synthesis of the farnesyl ether 2,3,5-triﬂuoro-6-hydroxy-4-[(E,E)-

3,7,11-trimethyldodeca-2,6,10-trien-1-yloxy]nitrobenzene, and

related compounds containing a substituted hydroxytriﬂuorophenyl

residue: novel inhibitors of protein farnesyltransferase,

geranylgeranyltransferase I and squalene synthase

1

Jonathan H. Marriott,^aAmelia M. Moreno Barber,^aIan R. Hardcastle,^a†

Martin G. Rowlands,^aRachel M. Grimshaw,^aStephen Neidle^band Michael Jarman*^a

^aCRC Centre for Cancer Therapeutics, The Institute of Cancer Research, 15 Cotswold Road,

Sutton, Surrey, UK SM2 5NG

^bCRC Biomolecular Structure Unit, Chester Beatty Laboratories,

Institute of Cancer Research, Fulham Road, London, UK SW3 6JB

Received (in Cambridge, UK) 1st September 2000, Accepted 27th October 2000

First published as an Advance Article on the web 30th November 2000

Pentaﬂuoronitrobenzene was converted via two successive phase-transfer catalysed S_NAr reactions with (E,E)-

farnesol or geraniol followed by hydroxide ion into the 2,3,6-triﬂuoro-5-hydroxy-4-nitrophenyl farnesyl ether

3a and the geranyl ether 3b. Analogues containing a cyano (3c) or carbamoyl (3d) group in place of nitro or an

epoxygeranyl (3e) group as the prenyl (3-methylbut-2-enyl) containing residue were similarly prepared. Those

containing a sulfonic acid (35a, 35b) or a methyl sulfone (41) group were made by modiﬁcations of this approach

involving the use of protecting groups. The synthesis of carboxy analogues (27a, 27b) involved the alkylation of

a protected ﬂuorinated ortho-hydroxybenzoic acid derivative (25) with (E,E)-farnesyl or geranyl bromide. The

non-ﬂuorinated compound 18 was analogously prepared via compound 17a. Mitsunobu reactions were used in the

synthesis of 15, a dihydroxylated analogue of 3b, and of 8, the non-ﬂuorinated analogue of 3a. The nitro compounds

3a and 3b were moderate inhibitors of both farnesyl transferase and geranylgeranyl transferase I, the geranyl carboxy

derivative 27b of the latter enzyme and the farnesyl sulfonic acid derivative 35a of squalene synthase.

phenyl group. As previously reported,⁶compound 3a is an

inhibitor of FTase and GGTase I. We subsequently prepared

further, related compounds to elucidate eﬀects of structure

within the substituted phenyl group on activity against these

enzymes. The choice of compounds reﬂects our interest in the

eﬀect of the nature of the group para to the isoprenoid-bearing

oxygen (a nitro group in compound 3a). Certain compounds

were also prepared to gain information on the eﬀect of the

Introduction

The enzyme protein farnesyl transferase (FTase) plays a pivotal

role in the cell-signalling pathway from a cell surface receptor to

the nucleus.¹The enzyme farnesylates the Ras protein, using

farnesyl diphosphate as the source of the farnesyl group. This

step is a necessary precursor to association of Ras with the cell

membrane, where it can interact with its signalling partners.

Ras possesses GTPase activity and functions as a molecular

ortho hydroxy group and the ﬂuorination within the phenyl

switch cycling between the active, GTP-bound and the inactive,

group. Compounds containing a geranyl group were also pre-

GDP bound states. Ras is frequently found mutated or over-

pared, either in addition to or in place of the corresponding

expressed in many cancers and so inhibitors of Ras function,

(E,E)-farnesyl compound. In addition to the syntheses, we

report results of inhibition assays for the target enzymes FTase

e.g. of FTase, are attractive targets for novel cancer therapies.²

Also a potentially important target is the geranylgeranyl

and GGTase I, and also for the enzyme squalene synthase

diphosphate-utilising enzyme geranylgeranyl transferase I

(SqSase), which is critically involved in cholesterol synthesis,

(GGTase I) which can mediate geranylgeranylation and activ-

and which, like FTase, uses farnesyl diphosphate as a substrate.

ation of one form of Ras, Ki-Ras, even in the presence of

The substituted aryl groups in the compounds described

an inhibitor of FTase.³GGTase I also mediates the geranyl-

here may be compared with those in a series of inhibitors of

geranylation of Rho family proteins of potential importance in

ATP-dependent EGF-receptor tyrosine kinase reported by Liu

controlling cell motility and invasion.⁴

et al.,⁷which contain a benzene ring with a carboxylic acid,

After a preliminary modelling study⁵in which certain sub-

nitro, amide or sulfonic acid group ortho to a hydroxy group.

stituted aryl groups, bearing a hydroxy substituent, were

compared with di- or tri-phosphate groups (in relation to

Results and discussion

Synthesis

selection of possible analogues of guanosine 5Ј-triphosphate),

we synthesised the farnesyl compound 2,3,5-triﬂuoro-6-

hydroxy-4-[(E,E)-3,7,11-trimethyldodeca-2,6,10-trien-1-yloxy]-

nitrobenzene (3a), in which the diphosphate group of farnesyl

diphosphate is replaced by a 2,3,6-triﬂuoro-5-hydroxy-4-nitro-

The target compounds synthesised are listed in Table 1.

A general approach which has been used to synthesise several

of the target compounds is sequential S_NAr reactions of per-

ﬂuoroarenes with the appropriate alkoxide ion followed by

hydroxide ion (Scheme 1). Thus, pentaﬂuoronitrobenzene (1a)

† Present address: Department of Chemistry, Bedson Building, Uni-

versity of Newcastle, Newcastle upon Tyne, UK NE1 7RU.

DOI: 10.1039/b007101n

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This journal is © The Royal Society of Chemistry 2000

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Table 1 Inhibition studies^a

R

W

X

Y

Z

FTase^b

GGTase I^c

>100

12.5 2.0

6.2

80

>100

7.5 0.8

>100

45 12

8.5 1.1

>100

150

114

30

SqSase^d

Nd

2b

3a

3b

3c

3d

3e

8

15

18

27a

27b

30

Geranyl

Farnesyl^e

Geranyl

Farnesyl

Epoxygeranyl ^f

Farnesyl

Geranyl

Farnesyl

Geranyl

Farnesyl

Geranyl

F

H

F

H

F

H

OH

H

F

NO₂

CN

CONH₂

NO₂

>100

6.3 1.11

2.9

64

>100

45 12

>100

125

>100

25

O^ϪNa^ϩ

OH

F

69

>100

90

7

NO₂

CO₂H

CO₂^ϪNa^ϩ

SO₃^ϪNa^ϩ

SO₂Me

8

>100

12

35a

35b

41

OH

2

4

34

F

Nd

α-Hydroxyfarnesylphosphonic acid

2.6 0.24

2.5 0.5

25

40

5

7

9.2 3.5

100 18

Chaetomellic acid A

^aFor assay procedures, see ref. 34 (FTase, GGTase I) and ref. 35 (SqSase). ^bFarnesyl transferase. ^cGeranylgeranyl transferase I. ^dSqualene synthase

(values are for inhibition of squalene formation). ^eFarnesyl = (E,E)-farnesyl. ^fEpoxygeranyl = 2,3-epoxygeranyl. Nd = not determined; IC₅₀values

are the mean of three independent determinations sd, except where no sd is given; >100 means no signiﬁcant inhibition at highest concentration

tested, 100 µM.

Scheme 1 Reagents and conditions: i, ROH, 1 M aq. NaOH, Bu₄N^ϩHSO₄^Ϫ, CH₂Cl₂; ii, 50% w/w aq. NaOH, Bu₄N^ϩHSO₄^Ϫ(ϩ (C₆H₁₃)₄N^ϩHSO₄^Ϫfor

2d→3d), PhMe; iii, for 3a: NaOH, Et₂O; for 3b: Amberlite IRC50 (Na^ϩform).

has been reported⁸to undergo mono-substitution by meth-

oxide ion preponderantly at the para-position. To generate the

corresponding alkoxides from (E,E)-farnesol or geraniol

needed for their analogous reactions with 1a (Scheme 1), phase-

transfer catalysis (PTC) was used. The reaction of a variety of

alcohols and phenols with reactive perﬂuoroarenes was con-

veniently conducted at ambient temperature in a two-phase

system comprising dilute aqueous sodium hydroxide with

dichloromethane as the organic phase and tetra-n-butyl-

ammonium hydrogen sulfate as the phase-transfer catalyst.⁹

After puriﬁcation, solutions in toluene of the intermediate

farnesyl and geranyl ethers, respectively 2a and 2b, were treated

in a second PTC step with 50% aqueous sodium hydroxide

and tetra-n-butylammonium hydrogen sulfate to introduce the

hydroxy group ortho to the nitro substituent. Hydroxy deriv-

atives 3a and 3b were converted into their respective solid

sodium salts since the parent phenols tended to decompose

during storage. The choice of phase-transfer conditions for the

second step also has literature precedents, including previous

work from this laboratory. In concentrated aqueous alkaline

solutions (50% NaOH or 60% KOH) hydroxide ions are

minimally solvated, and unhydrated anions can be transferred

from the aqueous to the organic phase under PTC conditions.¹⁰

It has been proposed^11athat hydroxide ion itself is extracted

from such concentrated alkaline solutions into the organic

phase with a limited number of water molecules in its hydration

sphere and is thus highly nucleophilic. The formation of

phenols from 1,2,3,4-tetraﬂuorobenzene and hexaﬂuoro-

benzene under such conditions has been described,^11a,band the

potential advantage of the phase-transfer methodology over

other methods for the synthesis of polyﬂuorophenols was

discussed.^11bWe have also used such conditions to prepare 4,4Ј-

dihydroxyoctaﬂuoroazobenzene from decaﬂuoroazobenzene,¹²

whereas the use of potassium hydroxide in tert-butyl alcohol

had aﬀorded only mono-substitution products.^12,13

Pentaﬂuorobenzonitrile 1b has also been shown to react

with one equivalent of sodium methoxide in methanol to give

predominantly the para-substituted product.¹⁴Analogously,

application of the foregoing ﬁrst PTC reaction conditions to

nitrile 1b (Scheme 1), using geraniol as the alcohol, gave pre-

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Scheme 2 Reagents and conditions: i, (E,E)-farnesol, 1 M aq. NaOH, Bu₄N^ϩHSO₄^Ϫ, CH₂Cl₂; ii, 50% w/w aq. NaOH, Bu₄N^ϩHSO₄; iii, chrom-

Ϫ

atography; iv, (E,E)-farnesol, DEAD, PPh₃, THF.

dominantly geranyl ether 2c. It is of interest that the nitrile

function survived the harsher PTC conditions required to per-

form the second step, from 2c to the hydroxy derivative 3c,

given that prolonged treatment of starting nitrile 1b with

aqueous sodium hydroxide is known to hydrolyse the nitrile

function to produce tetraﬂuoro-4-hydroxybenzoic acid.¹⁴An

analogous route from pentaﬂuorobenzamide 1c, with farnesol

as the alcohol, likewise aﬀorded the amide 3d (Scheme 1),

though both steps needed longer reaction times, at elevated

temperatures, reﬂecting the lesser activating eﬀect of the carb-

amoyl substituent. Also in contrast to the other pentaﬂuoro-

arene starting materials, which gave product yields of 50% or

better in the ﬁrst PTC step, with strong regioselectivity for

para-substitution, amide 1c gave a poor yield of a mixture of

the ortho-substituted (4) and para-substituted (2d) farnesyl

ethers in the ﬁrst step with preponderance (19% yield) of the

former. It is possible that hydrogen bonding between the amide

carbonyl function and hydroxide ion directs ortho-substitution,

by analogy with the observation that a nitro group can direct

ortho-substitution by an amine.⁸However the carbamoyl func-

tion withstood well the conditions of the second PTC step,

possibly because of ionisation of the –NH function, and a 50%

yield of the hydroxy derivative 3d was obtained from the inter-

mediate tetraﬂuoro derivative 2d.

An unﬂuorinated analogue of 3a, compound 8, was prepared

(Scheme 2, (a)) by the general methods described above,

using 2,4-diﬂuoronitrobenzene 5 and (E,E)-farnesol as the

starting materials. In contrast to 1a though, the reaction of 5

with (E,E)-farnesol was not regioselective, producing an

inseparable mixture of the desired intermediate para-

substituted farnesyl ether 6 and the presumed ortho-substituted

analogue 7 in ca. 1:1 ratio. This lack of regioselectivity is also

in contrast to the 5:1 bias in favour of the para-substituted

product reported for the reaction of 2,4,5-triﬂuoronitrobenzene

with the alkoxide of Boc-piperidin-4-ol.¹⁵It would appear from

these results that it is the additional activating eﬀect of the

5-ﬂuoro substituent which favours 4- over 2-substitution in

this triﬂuoronitrobenzene and the presence of two (as opposed

to only one) adjacent ﬂuorine substituents which favours 4-

substitution in the case of 1a. Fortunately the second PTC step,

applied to the mixture of 6 and 7, gave two easily separable

products. To conﬁrm which of these products was the desired

2-hydroxy derivative 8, the second step was repeated on

pure 2-ﬂuoro derivative 6 prepared (Scheme 2, (b)) by a

Mitsunobu reaction between 3-ﬂuoro-4-nitrophenol 9 and

(E,E)-farnesol, unambiguously producing the correct regio-

isomer 8.

In view of the strongly deactivating inﬂuence of the O^Ϫ

substituent¹⁶towards further nucleophilic substitution reac-

tions, the direct introduction of a second hydroxy group into 3b

by nucleophilic displacement under strongly basic conditions

was not explored as a potential route to the 2,6-dihydroxynitro

compound 15. The alternative approach adopted (Scheme 3)

was suggested by the known ready conversion of pentaﬂuoro-

nitrobenzene 1a into 2,4,6-trialkoxy derivatives by reaction with

sodium methoxide⁸or sodium ethoxide.¹⁷However methoxy

or ethoxy derivatives were not precursors of choice for the

synthesis of the target intermediate trihydroxy derivative 14 as

the strongly deactivating nitro substituent was thought likely

to impede cleavage of these alkoxy groups by Lewis acids. Thus

4-methoxytetraﬂuoronitrobenzene was only partly demethyl-

ated¹⁸by aluminium chloride under conditions known to fully

demethylate 2,3,5,6-tetraﬂuoroanisole.¹⁹Also, the powerful

Lewis acid aluminium triiodide was needed to cleave the

strongly deactivated methoxy substituents in 4,4Ј-dimethoxy-

octaﬂuoroazobenzene in one route to the 4,4Ј-dihydroxy deriv-

ative.¹²It was thought that tribenzyl derivative 13 might be

cleaved under milder conditions and this compound was

therefore targeted as a potential intermediate to 14. Thus 1a

and benzyl alcohol reacted (Scheme 3) under PTC conditions to

give mainly the 4-substituted product 10 in 72% isolated yield,

together with minor amounts of the 2-isomer 11 (3%) and the

2,4-disubstituted product 12 (1.5%). The 2- and 6-ﬂuorine sub-

stituents in 10 were then displaced by treatment with a solution

generated from benzyl alcohol and potassium tert-butoxide in

THF¹⁵to give the trisubstituted derivative 13 in 52% isolated

yield together with disubstituted derivative 12 (2.6%). The

product 13 was debenzylated using TFA–pentamethylbenz-

ene,²⁰to give the trihydroxynitro compound 14. The subsequent

reaction of 14 with geraniol under Mitsunobu conditions was

suﬃciently regioselective to aﬀord the desired regioisomer 15 in

moderate (37%) yield. A precedent for such a regioselective

Mitsunobu reaction comes from the work of Dushin and

Danishefsky,²¹who described the speciﬁc benzylation of the

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Scheme 3 Reagents and conditions: i, BnOH, 1 M aq. NaOH, Bu₄N^ϩHSO₄^Ϫ, CH₂Cl₂; ii, BnOH, KOBu^t, THF; iii, pentamethylbenzene, TFA; iv,

geraniol, DIAD, PPh₃, THF.

4-hydroxy group of the isopropylidene derivative of 2,4,6-

trihydroxybenzoic acid.

adapted to introduce the more sensitive farnesyl and geranyl

groups, so an alternative synthetic strategy was adopted.

Analogues of 3a, 3b and 8 which contain a carboxy group

in place of nitro are particularly interesting targets. The 2-

hydroxybenzoic acid (salicyl) residue is present in several inhib-

itors of ATP-dependent EGF receptor tyrosine kinase,^7,22,23

where its role may be to compete with ATP for chelation of the

Mg^2ϩion present in the active site of the EGF receptor.^22,23

Magnesium ion is also required by FTase where it probably

coordinates to and activates the diphosphate leaving group of

farnesyl diphosphate.²⁴Analogous inhibition of FTase by com-

pounds containing farnesyl appropriately attached to a salicyl

group might therefore be envisaged. The route chosen for

the synthesis of the present target compounds was suggested

by the aforementioned²¹use of the isopropylidene group to

protect simultaneously a carboxy and ortho-hydroxy function.

Analogously (Scheme 4), protection of these functionalities

An appropriate dihydroxylated precursor to the target

compounds was obtained (Scheme 5) by ﬁrst dibenzylating

commercially available 4-hydroxytetraﬂuorobenzoic acid 19

using benzyl bromide and caesium carbonate in dimethyl-

formamide,²⁶then treating the product benzyl ether 20 with

a solution prepared from benzyl alcohol and potassium tert-

butoxide in THF¹⁵to give 2,4-bis(benzyloxy) derivative 21

with the 2,4,6-trisubstituted derivative 22 as a minor product.

The transformation of 20 into 21 may be regarded as analogous

to the reported reaction of methyl 2,3,5,6-tetraﬂuoro-4-meth-

oxybenzoate with sodium methoxide to give a 2,4-dimethoxy

derivative.²⁵Catalytic hydrogenation of 21 gave the ﬂuorinated

dihydroxy acid 23 in 53% overall yield from monohydroxy

acid 19. Attempts to use the isopropylidene group to protect

the carboxy and adjacent hydroxy functions in 23, as had

been successful with the unﬂuorinated dihydroxy acid 16

(Scheme 4), gave only very low yields of material believed to

be the desired product (results not shown). However a base-

promoted reaction of phenyl salicylates with a variety of

aliphatic aldehydes has been described²⁷and from the poten-

tial protecting groups exempliﬁed, methylene was chosen.

Dihydroxy acid 23 was ﬁrst converted into its crude penta-

ﬂuorophenyl ester 24 by reaction with pentaﬂuorophenyl

triﬂuoroacetate.²⁸Application of the aforementioned reaction

conditions²⁷to 24, using paraformaldehyde, produced the

selectively protected derivative 25 albeit in modest yield (24%).

Reaction of 25 with (E,E)-farnesyl bromide–caesium carbonate

in dimethylformamide produced protected farnesyl ether 26. If

the time allowed for this step was extended, spontaneous in situ

cleavage of the methylene protecting group ensued to give the

target farnesyl derivative, isolated after passing through an

ion-exchange column as its crystalline sodium salt 27a. Spon-

taneous deprotection was also observed after geranylation of 25

to give the corresponding geranyl derivative, also isolated as the

sodium salt 27b. To assess the inﬂuence of the phenolic func-

tion in the triﬂuorinated carboxylate 27a on enzyme inhibitory

activity, its tetraﬂuorinated analogue was needed. This was pre-

pared in three steps from hydroxy acid 19 (Scheme 6). Ester 28

had previously been made from ethyl pentaﬂuorobenzoate,

using sodium nitrite to introduce the 4-hydroxy group.²⁹Alk-

aline hydrolysis of the product (29) of farnesylation of 28

aﬀorded the sodium salt 30 in 33% overall yield from 19.

Scheme 4 Reagents and conditions: i, Me₂CO, TFAA, TFA; ii, (E,E)-

farnesyl bromide, NaH, THF, 60 ЊC, 3 h; iii, 48% aq. KOH, DMSO,

60 ЊC, then 1 M aq. HCl.

in 2,4-dihydroxybenzoic acid 16, to give the isopropylidene

derivative 17a, then treatment with (E,E)-farnesyl bromide–

sodium hydride, gave farnesyl ether 17b. Alkaline hydrolysis of

17b gave the target unﬂuorinated hydroxy acid 18 in 19% yield

overall from 16.

In relation to the preparation of ﬂuorinated analogues of 18,

it was noted that a compound having the desired substitution

pattern, namely 3,5,6-triﬂuoro-2-hydroxy-4-methoxybenzoic

acid²⁵is known. However, its synthesis involves heating 2,3,4,5-

tetraﬂuorophenol with sodium methoxide in sulfolane at

140 ЊC, prior to treatment of the resulting 4-methoxy derivative

with n-butyllithium and carbon dioxide to introduce the

carboxy group. It seemed unlikely that the ﬁrst step could be

The synthesis of compounds containing the sulfonic acid

substituent (Scheme 7) was envisaged as proceeding via an ester

of pentaﬂuorobenzenesulfonic acid. The ester function needed

to be suﬃciently base-stable to withstand the conditions of the

two PTC reactions used to insert the prenyl containing and

hydroxy functions, but labile enough to be removed at the end

of the reaction sequence without cleavage of the farnesyl or

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Scheme 5 Reagents and conditions: i, BnBr, Cs₂CO₃, DMF; ii, BnOH, KOBu^t, THF; iii, H₂, Pd–C, MeOH–H₂O; iv, pentaﬂuorophenyl triﬂuoro-

acetate, pyridine, CH₂Cl₂; v, paraformaldehyde, DABCO, DMF; vi, (E,E)-farnesyl bromide, Cs₂CO₃, DMF; vii, RBr, Cs₂CO₃, DMF, then Amberlite

IRC50 (Na^ϩform).

Scheme 6 Reagents and conditions: i, EtOH, H₂SO₄; ii, (E,E)-farnesyl

bromide, Cs₂CO₃, DMF; iii, NaOH, EtOH–H₂O.

geranyl moiety. The 2,2-dimethylpropan-1-yl (neopentyl) pro-

tecting group, developed for arylsulfonic acids,³⁰was explored

ﬁrst. Commercially available pentaﬂuorobenzenesulfonyl

chloride 31 was converted (Scheme 7) into the neopentyl ester

32a. Application of the previously described two phase-transfer

steps, using geraniol in the ﬁrst step, produced successively the

geranyl ether 33a and the hydroxy derivative 34a. However,

attempts to remove the neopentyl group selectively from 34a, by

heating with tetramethylammonium iodide in acetonitrile at

40–50 ЊC or with sodium iodide in (CD₃)₂SO at 50–60 ЊC

appeared to remove the geranyl group (results not shown).

We therefore turned to the 2-methylpropan-1-yl (isobutyl)

protecting group which has been used³¹in the synthesis of

sulfonate-containing nucleosides. Despite the expected greater

lability of this group towards hydroxide ion, it withstood the

strongly basic conditions of the second phase-transfer step

suﬃciently to yield the required protected farnesyl derivative

(34b) in 50% yield from its precursor 33b. The lower isolated

yield of the geranyl derivative 34c from the corresponding

step (19%) reﬂects at least in part the fact that a portion of

the product formed was discarded owing to the presence of a

by-product which had been incompletely separated during

Scheme 7 Reagents and conditions: i, ROH, pyridine, Et₂O; ii, R¹OH,

1 M aq. NaOH, Bu₄N^ϩHSO₄^Ϫ, CH₂Cl₂; iii, 50% w/w aq. NaOH, Bu₄N^ϩ-

HSO₄^Ϫ, PhMe; iv, for 34b: NaI, MeCN; for 34c: Me₄N^ϩI^Ϫ, MeCN,

then Bio-Rad AG50W X-4 (Na^ϩform).

chromatography. The deprotection of 34b was carried out with

sodium iodide in acetonitrile, which reacted smoothly at room

temperature and gave the sodium salt 35a directly. The isobutyl

group was removed from 34c by warming with tetramethyl-

ammonium iodide in acetonitrile; a subsequent ion-exchange

step produced the sodium salt 35b.

The ﬁnal variable ring-substituent exempliﬁed was the methyl

sulfone moiety. The route to the relevant target compound, the

sulfone 41, is shown in Scheme 8. Pentaﬂuorothiophenol (36a)

was converted into the known thiomethyl derivative (36b),

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Scheme 8 Reagents and conditions: i, methyl toluene-p-sulfonate, 1 M aq. NaOH, Bu₄N^ϩHSO₄^Ϫ, CH₂Cl₂; ii, 30% w/w aq. H₂O₂, AcOH, 100 ЊC, 2 h;

iii, geraniol, 1 M aq. NaOH, Bu₄N^ϩHSO₄^Ϫ, CH₂Cl₂; iv, 2-(trimethylsilyl)ethanol, KOBu^t, THF; v, 1 M Bu₄N^ϩF^Ϫ, THF then Bio-Rad AG50W-X4

(H^ϩform).

using methyl toluene-p-sulfonate, thereby avoiding the pre-

viously used,³²potentially hazardous diazomethane. Oxidation

to the known sulfone (37),³²followed by the usual phase-

transfer catalysed reaction, with geraniol, aﬀorded geranyl

ether 38. However, the second phase-transfer reaction to insert

the hydroxy function, which had previously been successful in

the presence of nitro, cyano, carbamoyl and sulfonate ester sub-

stituents, failed when applied to the methyl sulfone derivative

38, giving an intractable mixture from which the desired

product 41 could not be recovered. An alternative strategy, in

which the hydroxy group was introduced in a protected form,

was envisaged. The benzyl protecting group had been success-

fully used for this purpose during syntheses of the dihydroxy

nitro derivative 15 and the carboxy derivatives 27a and 27b.

However, its removal in these cases preceded introduction of

the farnesyl or geranyl substituent, which would not be the case

in the presently envisaged route to 41. It seemed unlikely that

the geranyl group would survive either the hydrogenolysis or

TFA deprotection methods used to remove a benzyl substitu-

ent. Therefore, 2-(trimethylsilyl)ethyl, originally developed for

the protection of carboxy functions,³³was chosen as an altern-

ative protecting group, removable under mild conditions that

would spare the geranyl function. Tetraﬂuoro derivative 38 was

treated with a solution prepared from 2-(trimethylsilyl)ethanol

and potassium tert-butoxide in THF to give the (trimethyl-

silyl)ethyl ether (39) (69% yield) together with a minor prop-

ortion of the bis[(trimethylsilyl)ethyl] derivative (40) (15%).

Deprotection of 39 using tetra-n-butylammonium ﬂuoride

followed by treatment with acidic ion-exchange resin aﬀorded

the desired hydroxy derivative 41 in 51% yield from 39 and 26%

overall from pentaﬂuorophenyl methyl sulfone 37.

farnesylation with IC₅₀6.3 µM (Table 1). Replacement of the

farnesyl group by a geranyl group (3b) reduced the FTase IC₅₀

to 2.9 µM. Compounds 3a and 3b each inhibited GGTase I

with about half the potency they displayed against FTase. In the

SqSase assay, the (E,E)-farnesyl compound 3a had weak activ-

ity, while the geranyl compound 3b was inactive. As a working

hypothesis we considered that 3a acts as an analogue of

farnesyl diphosphate, so the greater activity of the geranyl

derivative 3b compared with the farnesyl derivative 3a in the

FTase assay was surprising, and encouraged the synthesis of

further geranyl derivatives for evaluation. Attempts to prepare

the geranylgeranyl analogue of 3a, as a potential inhibitor

of the geranylgeranyl diphosphate-utilising enzyme GGTase I,

were frustrated by the lipophilic character conferred by the

geranylgeranyl substituent.³⁷

The farnesyl carboxy derivative 27a had much weaker activ-

ity than its nitro analogue 3a against GGTase I, and did not

inhibit FTase. However, as with the nitro compounds, replace-

ment of the (E,E)-farnesyl group in 27a with geranyl improved

potency against GGTase I, here to such an extent that the

geranyl carboxy derivative 27b was almost as good an inhib-

itor of this enzyme (IC₅₀8.5 µM) as the corresponding nitro

derivative 3b (IC₅₀6.2 µM).

The unﬂuorinated farnesyl nitro and farnesyl carboxy com-

pounds, respectively 8 and 18, the geranyl tetraﬂuoro nitro

compound 2a and the farnesyl tetraﬂuoro carboxy compound

30 were all inactive against both FTase and GGTase I. Thus,

ring ﬂuorination and the presence of the ring –OH group

together appear to contribute vitally to activity against these

enzymes. Compound 15, containing two ring –OH groups, was

however also inactive in all the assays.

The other substituted phenoxy groups evaluated all had the

2,3,5-triﬂuoro-6-hydroxy substitution pattern, and exempliﬁed

further variations at the ring position para to the isoprenoid-

bearing O atom. The farnesyl carbamoyl compound 3d was

inactive in all three assays. The geranyl cyano compound 3c

showed slight inhibition of FTase and GGTase I. The geranyl

sulfone derivative 41 was a moderate inhibitor but showed little

selectivity between FTase and GGTase I. The (E,E)-farnesyl

and geranyl sulfonic acid sodium salts 35a and 35b showed very

weak or no activity against FTase and GGTase I, but in the

SqSase assay they were the two most active among the com-

pounds evaluated. The greater potency towards SqSase of the

farnesyl analogue 35a (IC₅₀12 µM) compared with the geranyl

compound 35b (IC₅₀34 µM) is in this case consistent with a

compound acting as a substrate analogue.

Enzyme inhibition studies

Compounds were tested for their ability to inhibit the FTase

and GGTase I activities of the cytosolic fraction of rat brain

(which contains both these activities), using a previously pub-

lished procedure from this laboratory.³⁴Inhibition of the

SqSase activity of rat liver microsomes was also determined

using a published procedure³⁵except that a substrate con-

centration of 10 µM farnesyl diphosphate with 0.06 µCi

[1-³H]farnesyl diphosphate was used, and 2 mM dithiothreitol

was added to the assay buﬀer. Inhibitory activities (see Table 1)

were compared with those of standard inhibitors of FTase,

namely α-hydroxyfarnesylphosphonic acid and chaetomellic

acid A, which have been identiﬁed as competitive inhibitors

of FTase with respect to farnesyl diphosphate.³⁶As had been

reported previously,⁶the nitro derivative 3a inhibited H-Ras

In the FTase-catalysed reaction, a bond is formed between

the sulfur atom of the carboxy terminal cysteine residue of the

4270

J. Chem. Soc., Perkin Trans. 1, 2000, 4265–4278

View Article Online

protein substrate and C-1 of farnesyl diphosphate and diphos-

phate ion is released.³⁸The 2,3-epoxygeranyl compound 3e was

made with the possibility in mind that, if 3e could occupy the

binding site of farnesyl diphosphate, it might prevent farnesyl-

ation of the Ras protein by alkylating its terminal cysteine –SH

group. 2,3-Epoxygeraniol is readily obtained by regioselective

epoxidation of geraniol using 3-chloroperoxybenzoic acid.³⁹

The epoxide functionality withstood the conditions of the

two PTC reactions starting from pentaﬂuoronitrobenzene 1a

(Scheme 1) to aﬀord successively intermediate 2e and target

epoxygeranyl nitro derivative 3e. Remarkably, and in marked

contrast to its geranyl counterpart 3b which was the most

potent inhibitor of FTase (IC₅₀2.9 µM) among the compounds

described here, epoxygeranyl derivative 3e did not inhibit

FTase, but was a selective inhibitor of GGTase I, with IC₅₀

7.5 µM similar to that of 3b.

(2 F, m), Ϫ146.99 (2 F, m); m/z (ESI, Ϫve ion mode) 346

(M Ϫ H)^Ϫ, 210 (M Ϫ geranyl)^Ϫ.

4-[(E)-3,7-Dimethylocta-2,6-dien-1-yloxy]-2,3,5-triﬂuoro-6-

hydroxynitrobenzene 3b. (Phase-transfer catalysed hydrolysis:

general procedure B)

A mixture of 2b (0.695 g, 2.0 mmol), toluene (5.3 cm³) and 50%

w/w aqueous sodium hydroxide (1 cm³) and tetra-n-butyl-

ammonium hydrogen sulfate (0.68 g, 2.0 mmol) was stirred

rapidly at 50 ЊC for 1 h. The mixture was cooled and partitioned

between toluene (25 cm³) and water (15 cm³) with acidiﬁcation

(1 M hydrochloric acid) of the aqueous phase to pH 4–5. The

aqueous phase was extracted with diethyl ether (4 × 20 cm³)

and the combined organic phases were washed with water

(5 × 10 cm³), dried (MgSO₄) and evaporated. Chromatography

[Merck 7729 silica; hexane–dichloromethane (1:1), dichloro-

methane, and dichloromethane–ethanol (99:1 then 98:2) in

succession] gave the geranyl nitro derivative 3b (0.395 g, 57%)

(orange oil) (Found: C, 56.0; H, 5.45; N, 3.9; F, 16.2;

C₁₆H₁₈F₃NO₄requires C, 55.65; H, 5.25; N, 4.1; F, 16.5%);

δ_H[(CD₃)₂SO] 1.54 (3 H, s), 1.61 (3 H, s), 1.66 (3 H, d, J 0.6)

(3 × Me), 2.02 (4 H, m, 4,5-H), 4.82 (2 H, d, J 7.3, 1-H), 5.00

(1 H, m, 6-H), 5.42 (1 H, t, J 7.3, 2-H), 12.0 (1 H, br, OH);

δ_F[(CD₃)₂SO] Ϫ162.57 (1 F, d, J 23.7), Ϫ151.86 (1 F, dd, J 6.6,

23.7), Ϫ151.02 (1 F, d, J 8.5).

Concluding remarks

In summary, eﬃcient methods have been described for the

preparation of compounds containing isoprenoid residues

attached to 2,3,6-triﬂuoro-5-hydroxy-4-X-phenoxy groups,

where X represents a variety of substituents. The relative

potency of inhibition towards FTase, GGTase I and SqSase

varied with the nature of the substituent X and with that of the

attached isoprenoid residue. The synthetic methods described

should allow the introduction of a wide range of substitu-

ents other than farnesyl and geranyl. The chemistry described

also extends the variety of methods available for introducing

one or even two hydroxy substituents into a polyﬂuorinated

aromatic ring.

Sodium salt of 3b

A solution of 3b (0.282 g, 0.82 mmol) in methanol–water (4:1)

was passed through a column (17 cm³bed volume) of Amber-

lite IRC50 ion-exchange resin (Na^ϩform). The column was

eluted with further methanol–water (4:1) until the eluate was

almost colourless, and the eluate was evaporated. The sodium

salt of 3b (0.142 g, 47%) gave small yellow needles, mp 130–

132 ЊC (from water: heating should be minimised) (Found: C,

52.05; H, 4.7; N, 3.7; F, 15.3; C₁₆H₁₇F₃NNaO₄requires C, 52.3;

H, 4.7; N, 3.8; F, 15.5%); δ_H[(CD₃)₂SO] 1.55 (3 H, s), 1.62 (6 H,

s) (3 × Me), 2.01 (4 H, m, 4,5-H), 4.59 (2 H, d, J 7.1, 1-H), 5.04

(1 H, m, 6-H), 5.39 (1 H, t, J 7.1, 2-H); δ_F[(CD₃)₂SO] Ϫ182.96

(1 F, dd, J 8.6, 25.3), Ϫ155.98 (1 F, t, J 8.4), Ϫ154.72 (1 F, dd,

J 8.5, 25.6); m/z (ESI, Ϫve ion mode) 344 (M Ϫ Na)^Ϫ.

Experimental

Melting points were determined with a Reichert micro-hot-

stage apparatus, and are uncorrected. NMR spectra were

1

recorded on a Bruker AC250 spectrometer at 250 MHz for H

spectra and at 235 MHz for ¹⁹F spectra. The residual signal for

undeuterated solvent was used as internal standard for ¹H

spectra. For ¹⁹F spectra, chemical shifts are relative to FCCl₃

(δ_F= 0). IR spectra were recorded on a Perkin-Elmer 1720X

spectrometer. Elemental analyses were carried out by C.H.N.

Analysis Ltd, Leicester, England or Butterworth Laboratories

Ltd, Teddington, England. ESI mass spectra were obtained on

a Finnigan MAT TSQ700 triple quadrupole mass spectrometer

or a Finnigan LCQ ion trap mass spectrometer. FAB mass

spectra were obtained at the School of Pharmacy, London

University. Dried solvents were used for reactions where

appropriate.

2,3,5,6-Tetraﬂuoro-4-[(E,E)-3,7,11-trimethyldodeca-2,6,10-

trien-1-yloxy]nitrobenzene 2a

From 1a (1.065 g, 5 mmol) and (E,E)-farnesol using general

procedure A. Chromatography [Merck 15111 silica; hexane–

dichloromethane (gradient: 20:1, 10:1, 6:1, 4:1)] gave 2a (1.16

g, 56%) as a yellow oil (Found: C, 60.7; H, 6.1; N, 3.3; F, 18.2;

C₂₁H₂₅F₄NO₃requires C, 60.7; H, 6.1; N, 3.4; F, 18.3%); δ_H

(CDCl₃) 1.59 (6 H, s), 1.68 (3 H, d, J 0.8), 1.74 (3 H, d, J 0.8)

(4 × Me), 2.09 (8 H, m, 4,5,8,9-H), 4.92 (2 H, d, J 7, 1-H), 5.07

(2 H, m, 6, 10-H), 5.46 (1 H, t, J 7, 2-H); δ_F(CDCl₃) Ϫ158.21

(2-F, m), Ϫ151.56 (2 F, m); m/z (FAB) 414.1695 (M Ϫ H)^ϩ(calc

for (M Ϫ H)^ϩ, 414.1692).

4-[(E)-3,7-Dimethylocta-2,6-dien-1-yloxy]-2,3,5,6-tetraﬂuoro-

nitrobenzene 2b. (Phase-transfer catalysed formation of ethers:

general procedure A)

Pentaﬂuoronitrobenzene 1a (3.20 g, 15 mmol), geraniol (2.31 g,

15 mmol), dichloromethane (30 cm³), 1 M aqueous sodium

hydroxide (30 cm³), and tetra-n-butylammonium hydrogen

sulfate (0.51 g, 1.5 mmol) were stirred together rapidly at

ambient temperature for 1 h. The mixture was cooled in ice and

suﬃcient 1 M sulfuric acid was added dropwise to render the

aqueous layer neutral (pH 7). The dichloromethane layer was

separated and the aqueous layer extracted with dichloro-

methane (3 × 10 cm³). The combined dichloromethane solution

was washed with water (3 × 25 cm³), dried (MgSO₄) and

evaporated. Chromatography (Merck 9385 silica) with hexane–

dichloromethane (4:1) as eluant gave the geranyl derivative 2b

(2.645 g, 50%) as a yellow oil (Found: C, 55.45; H, 5.0; N, 3.95;

F, 21.6; C₁₆H₁₇F₄NO₃requires C, 55.3; H, 4.9; N, 4.0; F, 21.9%);

δ_H[(CD₃)₂SO] 1.55 (3 H, s), 1.62 (3 H, s), 1.69 (3 H, d, J 0.8)

(3 × Me), 2.04 (4 H, m, 4,5-H), 4.96 (2 H, d, J 7.3, 1-H), 5.02

(1 H, m, 6-H), 5.45 (1 H, t, J 7.3, 2-H); δ_F[(CD₃)₂SO] Ϫ154.56

2,3,5-Triﬂuoro-6-hydroxy-4-[(E,E)-3,7,11-trimethyldodeca-

2,6,10-trien-1-yloxy]nitrobenzene 3a

From 2a (0.26 g, 0.626 mmol) using general procedure B.

Chromatography [Merck 15111 silica; hexane–ethyl acetate

(5:1)] gave the title compound 3a (0.149 g, 57%) as an unstable

yellow oil; δ_H(CDCl₃) 1.59 (6 H, s), 1.68 (3 H, d, J 0.6), 1.75

(3 H, d, J 0.6) (4 × Me), 1.93–2.09 (8 H, m, 4,5,8,9-H), 4.98

(2 H, d, J 7.2, 1-H), 5.07 (2 H, m, 6,10-H), 5.48 (1 H, t, J 7.2,

2-H), 10.5 (1 H, s, OH); δ_F(CDCl₃) Ϫ165.95 (1 F, d, J 22.2),

Ϫ159.31 (1 F, d, J 7.7), Ϫ150.52 (1 F, dd, J 7.2, 23.1); m/z (ESI,

Ϫve ion mode) 412 (M Ϫ H)^Ϫ.

Sodium salt of 3a

A solution of 3a (0.32 g, 0.77 mmol) in dry diethyl ether (4 cm³)

J. Chem. Soc., Perkin Trans. 1, 2000, 4265–4278

4271

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was added to powdered sodium hydroxide (0.08 g, 2 mmol) and

the mixture was stirred under argon for 30 min, then evap-

orated. The residue was dissolved in the minimum of warm

diethyl ether and the insoluble solid removed by ﬁltration. The

material that separated from the ﬁltrate on cooling was isolated

by centrifugation. Recrystallisation from diethyl ether, and

isolation of the solid by centrifugation, gave the sodium salt of

3a (0.120 g, 36%) as an orange powder, mp 132–135 ЊC; δ_H

[(CD₃)₂SO] 1.54 (6 H, s), 1.62 (6 H, s) (4 × Me), 1.91–2.08 (8 H,

m, 4,5,8,9-H), 4.57 (2 H, d, J 7.2, 1-H), 5.06 (2 H, m, 6,10-H),

5.39 (1 H, t, J 7.2, 2-H); δ_F[(CD₃)₂SO] Ϫ183.04 (1 F, dd, J 8.7,

25.0), Ϫ156.06 (1 F, m), Ϫ154.77 (1 F, dd, J 8.6, 25.1); m/z

(FAB) 458.1540 (calc for (M ϩ Na)^ϩ, 458.1531).

2.03 (8 H, m, 4,5,8,9-H), 4.78 (2 H, d, J 7.2, 1-H), 5.05 (2 H, m,

6,10-H), 5.44 (1 H, t, J 7.2, 2-H), 8.01 (1 H, br s, NH), 8.19 (1 H,

br s, NH); δ_F[(CD₃)₂SO] Ϫ155.49 (2 F, m), Ϫ143.49 (2 F, m);

m/z (FAB) 436 (M ϩ Na)^ϩ.

2,3,5-Triﬂuoro-6-hydroxy-4-[(E,E)-3,7,11-trimethyldodeca-

2,6,10-trien-1-yloxy]benzamide 3d

From 2d (0.145 g, 0.35 mmol) using general procedure B,

except that the initial reaction was for 24 h, then tetra-n-

hexylammonium hydrogen sulfate (0.016 g, 0.035 mmol) was

added, and the reaction was continued at 50 ЊC for 2 d and at

room temperature for a further 5 d. Chromatography [Merck

15111 silica; hexane–ethyl acetate (9:1 followed by 8:2)] gave

amide 3d (0.072 g, 50%), mp 109–110 ЊC (from ethanol) (Found:

C, 64.0; H, 6.8; N, 3.4; F, 13.8; C₂₂H₂₈F₃NO₃requires C, 64.2;

H, 6.9; N, 3.4; F, 13.85%); δ_H(CDCl₃) 1.56 (3 H, s), 1.59 (3 H,

s), 1.68 (3 H, d, J 0.8), 1.73 (3 H, s) (4 × Me), 1.96–2.08 (8 H, m,

4,5,8,9-H), 4.85 (2 H, d, J 7.1, 1-H), 5.08 (2 H, m, 6,10-H), 5.49

(1 H, t, J 7.1, 2-H), 5.80 (1 H, br s, NH), 6.82 (1 H, br s, NH),

12.98 (1 H, s, OH); δ_F(CDCl₃) Ϫ165.83 (1 F, d, J 23.7), Ϫ156.91

(1 F, d, J 10.1), Ϫ143.76 (1 F, m); m/z (ESI, Ϫve ion mode) 410

(M Ϫ H)^Ϫ.

4-[(E)-3,7-Dimethylocta-2,6-dien-1-yloxy]-2,3,5,6-tetraﬂuoro-

benzonitrile 2c

From pentaﬂuorobenzonitrile 1b (10 g, 52 mmol) and geraniol

using general procedure A. Chromatography [Merck 9385

silica; hexane–dichloromethane (4:1)] gave nitrile 2c (purity

90–95%, by NMR; the remainder being the presumed ortho-

isomer) (14.09 g, ca. 77%) (oil) (Found: C, 62.4; H, 5.2; N, 4.3;

F, 23.3; C₁₇H₁₇F₄NO requires C, 62.4; H, 5.2; N, 4.3; F, 23.2%);

δ_H[(CD₃)₂SO] 1.55 (3 H, s), 1.62 (3 H, s), 1.68 (3 H, s) (3 × Me),

2.04 (4 H, m, 4,5-H), 4.95 (2 H, d, J 7.3, 1-H), 5.01 (1 H, m,

6-H), 5.44 (1 H, t, J 7.3, 2-H); δ_F[(CD₃)₂SO] Ϫ154.02 (2 F, m),

Ϫ135.19 (2 F, m) (minor signals for presumed ortho-isomer, all

multiplets, ca. equal intensity; Ϫ161.30, Ϫ152.68, Ϫ145.59,

Ϫ133.8); m/z (FAB) 326 (M Ϫ H)^ϩ.

4-(3,7-Dimethyl-2,3-epoxyoct-6-en-1-yloxy)-2,3,5,6-tetraﬂuoro-

nitrobenzene 2e

From 1a (0.801 g, 3.76 mmol) and 2,3-epoxygeraniol³⁹using

general procedure A. Chromatography [Merck 15111 silica,

hexane–dichloromethane (5:3)] gave epoxygeranyl derivative 2e

(0.693 g, 51%) as a yellow oil (Found: C, 52.9; H, 4.7; N, 3.9; F,

21.0; C₁₆H₁₇F₄NO₄requires C, 52.9; H, 4.7; N, 3.9; F, 20.9%);

δ_H[(CD₃)₂SO] 1.26 (3 H, s, Me), 1.45 (m, 4-H), 1.58 (3 H, s,

Me), 1.65 (3 H, s, Me), 2.04 (2 H, m, 5-H), 3.17 (1 H, dd, J 3.6,

7.3, 2-H), 4.42 (1 H, dd, J 7.3, 11.4, 1-H), 4.73 (1 H, dd, J 3.6,

11.4, 1-H), 5.09 (1 H, m, 6-H); δ_F[(CD₃)₂SO] Ϫ154.74 (2 F,

m), Ϫ147.07 (2 F, m); m/z (FAB) 362 (M Ϫ H)^ϩ.

4-[(E)-3,7-Dimethylocta-2,6-dien-1-yloxy]-2,3,5-triﬂuoro-6-

hydroxybenzonitrile 3c

From 2c (2.616 g, 8 mmol) using general procedure B. Chrom-

atography [Merck 9385 silica; dichloromethane–ethanol (98:2,

97:3 and 95:5 in succession)] gave nitrile 3c (purity ca. 90%, by

NMR; 2.117 g, ca. 81%) (yellow solid). Further puriﬁcation of

a portion of this material [Merck 9385 silica; hexane–diethyl

ether (1:3), diethyl ether, and diethyl ether–methanol (98:2

then 95:5) in succession] gave pure 3c, mp 62–64 ЊC (Found: C,

63.1; H, 5.7; N, 4.2; F, 17.05; C₁₇H₁₈F₃NO₂requires C, 62.8; H,

5.6; N, 4.3; F, 17.5%); ν_max(ﬁlm)/cm^Ϫ12250; δ_H[(CD₃)₂SO] 1.54

(3 H, s), 1.61 (3 H, s), 1.65 (3 H, s) (3 × Me), 2.01 (4 H, m, 4,5-

H), 4.83 (2 H, d, J 7.3, 1-H), 4.99 (1 H, br s, 6-H), 5.40 (1 H, t,

J 7.3, 2-H), 12.07 (1 H, br s, OH); δ_F[(CD₃)₂SO] Ϫ162.16 (1 F,

d, J 23.0), Ϫ151.88 (1 F, d, J 8.0), Ϫ137.93 (1 F, dd, J 9.8, 23.4);

m/z (ESI, Ϫve ion mode) 324.5 (M Ϫ H)^Ϫ.

4-(3,7-Dimethyl-2,3-epoxyoct-6-en-1-yloxy)-2,3,5-triﬂuoro-6-

hydroxynitrobenzene 3e

From 2e (0.645 g, 1.78 mmol) using general procedure B except

that reaction was for 30 min at room temperature. Chrom-

atography [Merck 7729 silica; hexane–dichloromethane,

dichloromethane, dichloromethane–ethanol (99:1, 98:2, 97:3)

in succession] gave as a yellow oil which solidiﬁed on cooling,

epoxygeranyl derivative 3e (0.304 g, 48%), mp 72–74 ЊC (from

hexane) (Found: C, 53.35; H, 5.0; N, 3.9; F, 15.8; C₁₆H₁₈F₃NO₅

requires C, 53.2; H, 5.0; N, 3.9; F, 15.8%); δ_H[(CD₃)₂SO] 1.24

(3 H, s, Me), 1.44 (m, 4-H), 1.57 (3 H, s, Me), 1.64 (3 H, d, J 0.9,

Me), 2.02 (2 H, m, 5-H), 3.13 (1 H, dd, J 3.9, 7.1, 2-H), 4.29

(1 H, dd, J 7.1, 11.5, 1-H), 4.55 (1 H, dd, J 3.9, 11.5, 1-H), 5.09

(1 H, m, 6-H); δ_F[(CD₃)₂SO] Ϫ163.07 (1 F, d, J 22.2), Ϫ151.87

(1 F, dd, J 7.4, 23.7), Ϫ151.40 (1 F, d, J 6.7); m/z (FAB) 360

(M Ϫ H)^ϩ.

2,3,5,6-Tetraﬂuoro-4-[(E,E)-3,7,11-trimethyldodeca-2,6,10-

trien-1-yloxy]benzamide 2d and 2,3,4,5-tetraﬂuoro-6-[(E,E)-

3,7,11-trimethyldodeca-2,6,10-trien-1-yloxy]benzamide 4

From pentaﬂuorobenzamide 1c (3.021 g, 14.3 mmol) and

(E,E)-farnesol using general procedure A, except that the

reaction was conducted under argon at room temperature for

26 h and then under reﬂux for 45 h. Chromatography [Merck

7729 silica; hexane–ethyl acetate (gradient, 100:0 to 5:1)] gave

ﬁrst the ortho-isomer 4 (1.129 g, 19%), mp 46–48 ЊC (from

hexane) (Found: C, 63.8; H, 6.6; N, 3.35; C₂₂H₂₇F₄NO₂requires

C, 63.9; H, 6.6; N, 3.4%); δ_H[(CD₃)₂SO] 1.56 (6 H, s) (2 × Me),

1.63 (6 H, s) (2 × Me), 2.03 (8 H, m, 4,5,8,9-H), 4.63 (2 H, d,

J 7.1, 1-H), 5.06 (2 H, m, 6,10-H), 5.42 (1 H, t, J 7.1, 2-H), 7.91

(1 H, br s, NH), 8.06 (1 H, br s, NH); δ_F[(CD₃)₂SO] Ϫ162.96

(1 F, t, J 23.7), Ϫ156.38 (1 F, t, J 22.0), Ϫ153.77 (1 F, dd, J 8.8,

22.0), Ϫ143.53 (1 F, dd, J 8.6, 25.3); m/z (FAB) 436 (M ϩ Na)^ϩ.

An impure fraction eluted (0.406 g) next from which further

chromatography [Merck 9385 silica; hexane–ethyl acetate (2:1)]

aﬀorded pure para-isomer 2d (0.203 g, 3%), mp 106–108 ЊC

(from hexane) (Found: C, 63.8; H, 6.6; N, 3.4; F, 18.4;

C₂₂H₂₇F₄NO₂requires C, 63.9; H, 6.6; N, 3.4; F, 18.4%); δ_H

[(CD₃)₂SO] 1.55 (6 H, s), 1.63 (3 H, s), 1.66 (3 H, s) (4 × Me),

2-Hydroxy-4-[(E,E)-3,7,11-trimethyldodeca-2,6,10-trien-1-

yloxy]nitrobenzene 8

(a) From 2,4-diﬂuoronitrobenzene (5). The reaction of 5

(1.591 g, 10 mmol) with (E,E)-farnesol using general procedure

A but with overnight reaction, followed by chromatography

[Merck 15111 silica; hexane–ethyl acetate (40:1 then 30:1)]

gave a 1:1 mixture (shown by the presence of two signals in the

¹⁹F NMR spectrum at δ_F(CDCl₃) Ϫ113.23 (m) and Ϫ101.47

(m)), (2.475 g, 68%) (oil) containing 2-ﬂuoro-4-[(E,E)-3,7,11-

trimethyldodeca-2,6,10-trien-1-yloxy]nitrobenzene

6 as one

component. Using general procedure B, but with reaction time

2 h, this mixture (1.412 g, 3.91 mmol) was converted into

hydroxy nitro derivative 8 (0.660 g, 47% based on 5), a yellow

solid, mp 38–39 ЊC (Found: C, 70.12; H, 8.07; N, 3.94;

C₂₁H₂₉NO₄requires C, 70.17; H, 8.13; N, 3.9%); δ_H(CDCl₃)

4272

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1.60 (6 H, s), 1.68 (3 H, d, J 0.7), 1.76 (3 H, s) (4 × Me), 1.92–

2.20 (8 H, m, 4,5,8,9-H), 4.60 (2 H, d, J 6.6, 1-H), 5.10 (2 H, m,

6,10-H), 5.45 (1 H, m, 2-H), 6.53 (2 H, m, Ar-H), 8.02 (1 H, d,

J 10.1, Ar-H), 11.05 (1H, s, OH); m/z (ESI, Ϫve ion mode) 358

(M Ϫ H)^Ϫ.

dichloromethane solution washed with brine (40 cm³), dried

(MgSO₄) and evaporated. Chromatography [Merck 9385 silica;

hexane–dichloromethane (7:4)] gave ﬁrst 12 (0.068 g, 2.6%)

(from hexane; identiﬁed by mp and NMR), then tris-

(benzyloxy) derivative 13 (1.667 g, 52%), mp 77–79 ЊC (from

hexane) (Found: C, 67.9; H, 4.5; N, 2.9; F, 8.0; C₂₇H₂₁F₂NO₅

requires C, 67.9; H, 4.4; N, 2.9; F, 8.0%); δ_H[(CD₃)₂SO] 5.15

(4 H, s, 2,6-OCH₂), 5.30 (2 H, s, 4-OCH₂), 7.38 (15 H, m,

3 × Ph); δ_F[(CD₃)₂SO] Ϫ145.28 (s); m/z (FAB) 476 (M Ϫ H)^ϩ.

(b) From 3-ﬂuoro-4-nitrophenol (9). DEAD (0.833 g, 4.8

mmol) was added dropwise during 5 min to a stirred, cooled

(ice–water bath) solution of 9 (0.677 g, 4.3 mmol), (E,E)-

farnesol (0.957 g, 4.3 mmol) and triphenylphosphine (1.248 g,

4.8 mmol) in dry THF (8 cm³) under argon. After a further 5

min the reactants were allowed to warm to room temperature

and after 26 h, the mixture was evaporated. Chromatography

[Merck 9385 silica; hexane–diethyl ether (15:1)] gave farnesyl

ether 6 (0.323 g, 21%) as an oil (Found: C, 69.9; H, 7.9; N, 3.8;

F, 5.2; C₂₁H₂₈FNO₃requires C, 69.8; H, 7.8; N, 3.9; F, 5.3%);

δ_H(CDCl₃) 1.59 (6 H, s), 1.67 (3 H, s), 1.76 (3 H, s) (4 × Me),

1.98 (4 H, m), 2.12 (4 H, m) (farnesyl 4,5,8,9-H), 4.61 (2 H, d,

J 6.6, farnesyl 1-H), 5.08 (2 H, m, farnesyl 6,10-H), 5.44 (1 H,

t, J 6.6, farnesyl 2-H), 6.73 (2 H, m, Ar-H), 8.08 (1 H, t, J 9.3,

Ar-H); δ_F(CDCl₃) Ϫ113.19 (t, J 11.7); m/z (FAB) 384.1940

(M ϩ Na)^ϩ(calc for (M ϩ Na)^ϩ384.1951). The reaction of 6

(0.142 g, 0.39 mmol) with 50% w/w aqueous sodium hydroxide

followed the conditions used to prepare 3b and gave after

chromatography [Merck 9385 silica; hexane–diethyl ether

(19:1)] the hydroxy nitro derivative 8 (0.117 g, 83%), mp

37–39 ЊC, with NMR spectrum as for the corresponding

product prepared from compound 5.

3,5-Diﬂuoro-2,4,6-trihydroxynitrobenzene 14

A mixture of 13 (1.500 g, 3.14 mmol), pentamethylbenzene (7.0

g, 47 mmol), and TFA (75 cm³) was stirred at room temperature

under argon in the dark for 26 h, then evaporated to dryness.

The residue was partitioned between 0.1 M aqueous sodium

hydroxide (150 cm³) and dichloromethane (100 cm³). The

aqueous layer was extracted with dichloromethane (3 × 15 cm³)

and the combined dichloromethane solution extracted with

0.1 M aqueous sodium hydroxide (20 cm³). The combined

aqueous phase was acidiﬁed with 1 M hydrochloric acid (100

cm³) and extracted with diethyl ether (6 × 50 cm³). The com-

bined diethyl ether solution was washed with water (20 cm³),

dried (MgSO₄), and evaporated and the residue sublimed in

vacuo to give trihydroxy derivative 14 (0.441 g, 68%) as a deep

red solid, mp 162–164 ЊC (Found: C, 34.7; H, 1.6; N, 6.7;

F, 18.3; C₆H₃F₂NO₅requires C, 34.8; H, 1.5; N, 6.8; F, 18.35%);

δ_H[(CD₃)₂SO] 10.72 (s); δ_F[(CD₃)₂SO] Ϫ164.52; m/z (ESI,

Ϫve ion mode) 206 (M Ϫ H)^Ϫ.

4-Benzyloxy-2,3,5,6-tetraﬂuoronitrobenzene 10, 2-benzyloxy-

3,4,5,6-tetraﬂuoronitrobenzene 11, and 2,4-bis-(benzyloxy)-

3,5,6-triﬂuoronitrobenzene 12

4-[(E)-3,7-Dimethylocta-2,6-dien-1-yloxy]-3,5-diﬂuoro-2,6-

dihydroxynitrobenzene 15

Diisopropyl azodicarboxylate (DIAD) (0.195 g, 0.96 mmol)

was added dropwise to a stirred, cooled (ice–water bath) solu-

tion of 14 (0.183 g, 0.88 mmol), geraniol (0.150 g, 0.97 mmol),

and triphenylphosphine (0.255 g, 0.97 mmol) in THF (4.4 cm³)

under nitrogen. The mixture was allowed to warm to room

temperature during 2 h. After a further 3 h, further geraniol

(0.053 g, 0.34 mmol), triphenylphosphine (0.073 g, 0.28 mmol)

and DIAD (0.071 g, 0.35 mmol) were added. After 23 h (total

time) the mixture was partitioned between dichloromethane (50

cm³) and brine (20 cm³). The aqueous layer was extracted with

dichloromethane (10 cm³) and the combined dichloromethane

solution dried (Na₂SO₄) and evaporated. Chromatography

[Merck 9385 silica; hexane–dichloromethane (1:1 then 1:2)

then dichloromethane] gave geranyl derivative 15 (0.112 g,

37%) as an orange solid (Found: C, 53.9; H, 5.5; N, 4.0;

C₁₆H₁₉F₂NO₅ؒ0.75H₂O requires C, 53.85; H, 5.8; N, 3.9%).

Crystallisation from n-pentane without heating above room

temperature gave orange ﬂakes (0.081 g), mp 42–45 ЊC;

δ_H[(CD₃)₂SO] 1.55 (3 H, s), 1.63 (3 H, s), 1.65 (3 H, s) (3 × Me),

2.01 (4 H, m, 4,5-H), 4.70 (2 H, d, J 7.2, 1-H), 5.03 (1 H, br s,

6-H), 5.41 (1 H, t, J 7.2, 2-H), 10.95 (2 H, s, 2 × OH); δ_F

[(CD₃)₂SO] Ϫ159.06; m/z (ESI, Ϫve ion mode) 342 (M Ϫ H)^Ϫ.

From 1a (8.52 g, 40 mmol) and benzyl alcohol using general

procedure A but with reaction time 3.5 h. Chromatography

[Merck 9385 silica; petroleum spirit (bp 60–80 ЊC)–ethyl acetate

(25:1 or 19:1)] gave slightly impure 4-benzyloxy derivative

10 (6.095 g, from light petroleum (bp 80–100 ЊC) then from

hexane). Chromatography [Merck 15111 silica; petroleum spirit

(bp 60–80 ЊC)–dichloromethane (2:1)] of the concentrated

mother liquors gave further 10 (2.567 g, from hexane; total yield

8.662 g, ca. 72%), along with 2-benzyloxy derivative 11 (0.388 g,

3%, from hexane) and 2,4-bis(benzyloxy) derivative 12 (0.229

g, 1.5%, after re-chromatography). For 10 (sublimed sample):

mp 72–74 ЊC (Found: C, 51.75; H, 2.4; N, 4.6; F, 25.5;

C₁₃H₇F₄NO₃requires C, 51.8; H, 2.3; N, 4.65; F, 25.2%); δ_H

[(CD₃)₂SO] 5.49 (2 H, s, CH₂), 7.46 (5 H, m, Ph); δ_F[(CD₃)₂SO]

Ϫ154.43 (2 F, m), Ϫ146.80 (2 F, m); m/z (FAB) 300 (M Ϫ H)^ϩ.

For 11: mp 74–75 ЊC (Found: C, 51.75; H, 2.4; N, 4.6; F, 25.5;

C₁₃H₇F₄NO₃requires C, 51.8; H, 2.3; N, 4.65; F, 25.2%);

δ_H[(CD₃)₂SO] 5.32 (2 H, d, J 1.4, CH₂), 7.41 (5 H, s, Ph);

δ_F[(CD₃)₂SO] Ϫ160.06 (1 F, t, J 23.6), Ϫ151.02 (1 F, dd, J 6.9,

21.9), Ϫ149.33 (1 F, t, J 21.4), Ϫ148.47 (1 F, m). For 12: mp 45–

47 ЊC (Found: C, 61.6; H, 3.7; N, 3.6; F, 14.9; C₂₀H₁₄F₃NO₄

requires C, 61.7; H, 3.6; N, 3.6; F, 14.6%); δ_H[(CD₃)₂SO] 5.22

(2 H, d, J 0.6, CH₂), 5.39 (2 H, s, CH₂), 7.39 (10 H, m, 2 × Ph);

δ_F[(CD₃)₂SO] Ϫ154.21 (1 F, d, J 23.7), Ϫ149.84 (1 F, dd, J 9.0,

23.7), Ϫ144.38 (1 F, d, J 6.8); m/z (FAB) 388 (M Ϫ H)^ϩ.

2,2-Dimethyl-7-hydroxy-4H-1,3-benzodioxin-4-one 17a

TFAA (6 cm³) and acetone (1.2 cm³) were added to a stirred

suspension of 2,4-dihydroxybenzoic acid 16 (1.0 g, 6.49 mmol)

in TFA (10 cm³) at 0 ЊC. After 24 h at room temperature the

yellow solution obtained was concentrated. The residue was

added to saturated aqueous NaHCO₃(50 cm³) and the products

extracted with ethyl acetate (3 × 50 cm³). The combined ethyl

acetate solution was washed with water (50 cm³) and brine

(50 cm³), dried (MgSO₄) and concentrated. Chromatography

[Merck 15111 silica; hexane–ethyl acetate (gradient: 8:2, 7:3,

6:4)] gave isopropylidene derivative 17a (0.592 g, 47%), mp 203–

204 ЊC (from ethyl acetate) (Found: C, 61.8; H, 5.2; C₁₀H₁₀O₄

requires C, 61.85; H, 5.2%); ν_max(KBr disc)/cm^Ϫ11613, 1694;

δ_H[(CD₃)₂SO] 1.65 (6 H, s, 2 × Me), 6.37 (1 H, d, J 2.3, 8-H),

2,4,6-Tris(benzyloxy)-3,5-diﬂuoronitrobenzene 13

Dry benzyl alcohol (1.7 cm³, 16 mmol) was added to a stirred,

cooled (ice–water bath) suspension of potassium tert-butoxide

(1.64 g, 14.6 mmol) in dry THF (65 cm³) under nitrogen. After

30 min a solution of 10 (2.00 g, 6.64 mmol) in THF (7 cm³) was

added rapidly by syringe. After a further 90 min, at room tem-

perature, the mixture was cooled in ice and glacial acetic acid

(1.2 cm³) was added. The mixture was evaporated and the

residue partitioned between dichloromethane (60 cm³) and

saturated aqueous NaHCO₃(60 cm³). The aqueous layer was

extracted with dichloromethane (5 × 10 cm³) and the combined

J. Chem. Soc., Perkin Trans. 1, 2000, 4265–4278

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6.59 (1 H, dd, J 2.3, 8.7, 6-H), 7.68 (1 H, d, J 8.7, 5-H), 10.85

(1 H, s, OH); m/z (FAB) 195 (M ϩ H)^ϩ.

Samples of the minor product, the more polar tris(benzyloxy)

derivative 22 (oil) were isolated from other preparations

(Found: C, 74.2; H, 5.1; F, 6.75; C₃₅H₂₈F₂O₅requires C, 74.2; H,

5.0; F, 6.7%); δ_H(CDCl₃) 5.00 (4 H, s, 2,6-OCH₂), 5.18 (2 H, s),

5.20 (2 H, s) (4-OCH₂, CO₂CH₂), 7.31 (20 H, m, 4 × Ph);

δ_F(CDCl₃) Ϫ147.93 (s); m/z (FAB) 565 (M Ϫ H)^ϩ.

2-Hydroxy-4-[(E,E)-3,7,11-trimethyldodeca-2,6,10-trien-1-

yloxy]benzoic acid 18

A solution of 17a (0.20 g, 1.03 mmol) in THF (3 cm³) was

added to a suspension of sodium hydride (60% dispersion;

0.049 g, 1.23 mmol) in THF (4 cm³). When eﬀervescence had

ceased (after 1 min), (E,E)-farnesyl bromide (0.28 cm³, 1.03

mmol) was added dropwise. The resulting mixture was stirred at

room temperature for 48 h and at 60 ЊC for a further 3 h. Water

(10 cm³) was added and the mixture extracted with ethyl acetate

(3 × 20 cm³). The combined ethyl acetate solution was dried

(MgSO₄) and evaporated. Chromatography [Merck 15111

silica; hexane–ethyl acetate (9:1)] gave 2,2-dimethyl-7-[(E,E)-

3,7,11-trimethyldodeca-2,6,10-trien-1-yloxy]-4H-1,3-benzo-

dioxin-4-one 17b (0.195 g, 47.5%) (oil); δ_H(CDCl₃) 1.60, 1.68,

1.72, 1.75 (4 × s, total 18H, 6 × Me), 1.93–2.17 (8 H, m,

farnesyl 4,5,8,9-H), 4.57 (2 H, d, J 6.6, farnesyl 1-H), 5.10 (2 H,

m, farnesyl 6,10-H), 5.46 (1 H, m, farnesyl 2-H), 6.42 (1 H, d,

J 2.3, 8-H), 6.64 (1 H, dd, J 2.3, 8.8, 6-H), 7.85 (1 H, d, J 8.8,

5-H). A solution of 17b (0.192 g, 0.482 mmol) in DMSO (3 cm³)

was treated with 48% w/v aqueous potassium hydroxide (0.7

cm³) and the mixture was heated at 60 ЊC for 30 min. The result-

ing mixture was cooled, acidiﬁed (1 M hydrochloric acid) to ca.

pH 5, and extracted with ethyl acetate (2 × 20 cm³). The com-

bined ethyl acetate solution was washed successively with water

(25 cm³) and brine (25 cm³), then evaporated. Chromatography

[Merck 15111 silica; hexane–ethyl acetate (4:1)] gave title com-

pound 18 (0.153 g, 88%), mp 83–84 ЊC (from hexane) (Found: C,

73.6; H, 8.4; C₂₂H₃₀O₄requires C, 73.7; H, 8.4); δ_H(CDCl₃) 1.60

(6 H, s), 1.68 (3 H, s), 1.75 (3 H, s) (4 × Me), 1.93–2.19 (8 H, m,

farnesyl 4,5,8,9-H), 4.58 (2 H, d, J 6.6, farnesyl 1-H), 5.10 (2 H,

m, farnesyl 6,10-H), 5.47 (1 H, t, J 6.6, farnesyl 2-H), 6.46–6.51

(2 H, m, 3,5-H), 7.80 (1 H, d, J 8.5, 6-H), 10.66 (1 H, s, OH);

m/z (ESI, Ϫve ion mode) 357 (M Ϫ H)^Ϫ; m/z (FAB) 381.2050

(M ϩ Na)^ϩ; calc for (M ϩ Na)^ϩ, 381.2042.

2,3,5-Triﬂuoro-4,6-dihydroxybenzoic acid 23

A mixture of 21 (13.592 g, 28.4 mmol), methanol (345 cm³),

water (1.4 cm³), and 10% Pd–C (1.73 g) was degassed and

stirred under H₂at room temperature for 5.5 h. The catalyst was

removed by ﬁltration through Celite, the ﬁltrate evaporated,

and the residue crystallised from water to give dihydroxy acid 23

(5.444 g, 92%, in 2 crops), mp 215–225 ЊC (sublimes) (Found: C,

40.3; H, 1.35; F, 27.4; C₇H₃F₃O₄requires C, 40.4; H, 1.45;

F, 27.4%); δ_H[(CD₃)₂SO] 11.8 (br s); δ_F[(CD₃)₂SO] Ϫ168.83

(1 F, d, J 23.5), Ϫ161.98 (1 F, d, J 10.1), Ϫ139.63 (1 F, dd,

J 10.1, 23.7); m/z (FAB) 209 (M ϩ H)^ϩ.

Pentaﬂuorophenyl 2,3,5-triﬂuoro-4,6-dihydroxybenzoate 24

Pentaﬂuorophenyl triﬂuoroacetate (0.92 cm³, 5.4 mmol) was

added to a stirred mixture of 23 (1.073 g, 5.2 mmol), dry

dichloromethane (39 cm³) and dry pyridine (1.29 cm³, 15.9

mmol) at room temperature. After 4 h further pentaﬂuoro-

phenyl triﬂuoroacetate (0.7 cm³, 4 mmol) was added and after

a further 12 h the clear solution was diluted with dichloro-

methane (100 cm³), washed successively with 0.1 M hydrochloric

acid (3 × 30 cm³) and water (2 × 30 cm³), dried (MgSO₄) and

evaporated to dryness. The residue was triturated with hexane

and dried thoroughly (oil pump) to give pentaﬂuorophenyl ester

24 (1.813 g, ca. 94%) as a white solid which was used without

further puriﬁcation; mp 122–128 ЊC; δ_F[(CD₃)₂SO] Ϫ167.20

(1 F, d, J 23.2), Ϫ161.74 (2 F, t, J 21.1), Ϫ157.74 (1 F, d, J 8.6),

Ϫ156.95 (1 F, t, J 22.6), Ϫ152.51 (2 F, d, J 21.0), Ϫ140.80 (1 F,

dd, J 9.4, 23.5); m/z (FAB) 374.9920 (M ϩ H)^ϩ; calc for

(M ϩ H)^ϩ, 374.9904.

5,6,8-Triﬂuoro-7-hydroxy-4H-1,3-benzodioxin-4-one 25

Benzyl 4-benzyloxy-2,3,5,6-tetraﬂuorobenzoate 20

Paraformaldehyde (0.234 g, equivalent to 7.8 mmol formalde-

hyde) and DMF (4.5 cm³) were stirred together at room tem-

perature for 25 min. Compound 24 (0.579 g, 1.5 mmol) and

DABCO (0.349 g, 3.1 mmol) were then added successively and

stirring continued for 21 h followed by ﬁltration and concen-

tration. A solution of the residue in methanol (5 cm³) was

passed through a column (bed volume 12.5 cm³) of Bio-Rad

AG50W X-4 100–200 mesh cation-exchange resin (H^ϩform),

which was eluted with methanol and concentrated. Chrom-

atography (Merck 9385 silica; gradient from 0 to 20% ethanol

in dichloromethane) followed by concentration of appropriate

fractions and passage of a solution in methanol–water (4:1)

through another column (6 cm³bed volume) of Bio-Rad

AG50W X-4 100–200 mesh cation-exchange resin (H^ϩform)

using further methanol–water (4:1) for elution aﬀorded, on

concentration the methylene derivative 25, a white solid (0.083 g,

24%), mp 214 ЊC (Found: C, 43.5; H, 1.3; F, 25.95; C₈H₃F₃O₄

requires C, 43.7; H, 1.4; F, 25.9%); ν_max(KBr disc)/cm^Ϫ11647,

1715; δ_H[(CD₃)₂SO] 5.84 (s, CH₂); δ_F[(CD₃)₂SO] Ϫ163.21 (1 F,

m), Ϫ159.77 (1 F, m), Ϫ140.36 (1 F, dd, J 10.7, 21.1); m/z (FAB)

221 (M ϩ H)^ϩ.

Caesium carbonate (48.33 g, 0.148 mol) was added to a rapidly

stirred, cooled (ice–water bath) mixture of 2,3,5,6-tetraﬂuoro-

4-hydroxybenzoic acid 19 (hydrate, 15.057 g, 0.07 mol), benzyl

bromide (18.9 cm³, 0.159 mol), and DMF (127 cm³). The

mixture was allowed to warm to room temperature. After 3 d

the mixture was evaporated and the residue partitioned between

ethyl acetate (250 cm³) and water (125 cm³). The aqueous layer

was extracted with ethyl acetate (3 × 40 cm³) and the combined

ethyl acetate solution washed with half-saturated brine (3 × 40

cm³), dried (MgSO₄) and evaporated to give benzyl ester 20

(25.0 g, 91.5%), mp 64–66 ЊC (from hexane) (Found: C, 64.6; H,

3.7; F, 19.5; C₂₁H₁₄F₄O₃requires C, 64.6; H, 3.6; F, 19.5%);

δ_H[(CD₃)₂SO] 5.40 (4 H, s, 2 × CH₂), 7.43 (10 H, s, 2 × Ph);

δ_F[(CD₃)₂SO] Ϫ155.12 (2 F, m), Ϫ140.30 (2 F, m); m/z (FAB)

389 (M Ϫ H)^ϩ.

Benzyl 2,4-bis(benzyloxy)-3,5,6-triﬂuorobenzoate 21 and benzyl

2,4,6-tris(benzyloxy)-3,5-diﬂuorobenzoate 22

The procedure, using 20 (24.5 g, 63 mmol), benzyl alcohol (9.74

cm³, 94 mmol) and potassium tert-butoxide (8.77 g, 78 mmol)

was essentially that used to prepare compound 13, except that

extraction was with diethyl ether. Chromatography [Merck

7729 silica; n-pentane–diethyl ether (stepwise gradient: 99:1,

98.5:1.5, 98:2, 97:3, 95:5)] gave bis(benzyloxy) derivative 21

(19.6 g, 65%) (oil) (Found: C, 70.6; H, 4.6; F, 11.6; C₂₈H₂₁F₃O₄

requires C, 70.3; H, 4.4; F, 11.9%); δ_H(CDCl₃) 5.02 (2 H, s),

5.25 (2 H, s), 5.29 (2 H, s) (3 × CH₂), 7.35 (15 H, m, 3 × Ph);

δ_F(CDCl₃) Ϫ155.86 (1 F, d, J 23.1), Ϫ147.45 (1 F, d, J 9.9),

Ϫ141.97 (1 F, dd, J 10.1, 23.5); m/z (FAB) 479 (M ϩ H)^ϩ.

5,6,8-Triﬂuoro-7-[(E,E)-3,7,11-trimethyldodeca-2,6,10-trien-1-

yloxy]-4H-1,3-benzodioxin-4-one 26

(E,E)-Farnesyl bromide (0.15 g, 0.53 mmol) was added to a

stirred mixture of 25 (0.075 g, 0.34 mmol), caesium carbonate

(0.167 g, 0.51 mmol), and dry DMF (0.75 cm³) under argon at

room temperature in the dark. After 2 h the mixture was evap-

orated and toluene (15 cm³) was added and evaporated.

Chromatography [Merck 7729 silica; hexane–ethyl acetate

4274

J. Chem. Soc., Perkin Trans. 1, 2000, 4265–4278

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(stepwise gradient: 100:0, 99.5:0.5, 99:1, 97:3, 95:5)] gave

the farnesyl derivative 26 (0.083 g, 57%) (oil) (Found: C, 64.8;

H, 6.5; F, 13.3; C₂₃H₂₇F₃O₄requires C, 65.1; H, 6.4; F, 13.4%);

δ_H[(CD₃)₂SO] 1.55 (6 H, s), 1.63 (3 H, s), 1.68 (3 H, s) (4 × Me),

2.04 (8 H, m, farnesyl 4,5,8,9-H), 4.91 (2 H, d, J 7.1, farnesyl

1-H), 5.04 (2 H, m, farnesyl 6,10-H), 5.45 (1 H, t, J 7.1, farnesyl

2-H), 5.88 (2 H, s, 2-H); δ_F[(CD₃)₂SO] Ϫ158.73 (1 F, d, J 22.9),

Ϫ154.51 (1 F, d, J 11.2), Ϫ139.63 (1 F, dd, J 11.9, 22.0); m/z

(FAB) 447 (M ϩ Na)^ϩ.

to prepare 26 except that the reaction time was 16 h. Work-up

essentially as for 20 then chromatography [Merck 15111 silica;

hexane–dichloromethane (stepwise gradient: 9:1, 3:1, 2:1)]

gave the farnesyl derivative 29 (0.794 g, 85%) (oil) (Found: C,

65.35; H, 6.9; F, 16.9; C₂₄H₃₀F₄O₃requires C, 65.15; H, 6.8; F,

17.2%); δ_H(CDCl₃) 1.39 (3 H, t, J 7.1, CH₃CH₂), 1.59 (6 H, s),

1.68 (3 H, s), 1.71 (3 H, s) (4 × farnesyl Me), 2.07 (8 H, m,

4,5,8,9-H), 4.42 (2 H, q, J 7.1, CH₃CH₂), 4.84 (2 H, d, J 7.2,

1-H), 5.07 (2 H, m, 6,10-H), 5.47 (1 H, t, J 7.2, 2-H); δ_F(CDCl₃)

Ϫ156.26 (2 F, m), Ϫ141.05 (2 F, m); m/z (FAB) 442 (M^ϩ).

Sodium 2,3,5-triﬂuoro-6-hydroxy-4-[(E,E)-3,7,11-trimethyl-

dodeca-2,6,10-trien-1-yloxy]benzoate 27a

Sodium 2,3,5,6-tetraﬂuoro-4-[(E,E)-3,7,11-trimethyldodeca-

2,6,10-trien-1-yloxy]benzoate 30

The foregoing reaction was set up again, using (E,E)-farnesyl

bromide (0.16 g, 0.56 mmol), 25 (0.100 g, 0.45 mmol), caesium

carbonate (0.183 g, 0.56 mmol) and DMF (0.95 cm³). After

21 h, the mixture was evaporated. Chromatography [Merck

7729 silica; dichloromethane–ethanol (stepwise gradient: 100:0,

98:2, 97:3, 95:5, 90:10, 85:15)], dissolution of the concentrate

from pure fractions in ethanol–water (4:1) (TLC with

chloroform–methanol–acetic acid, 95:5:3) and passage

through a column (10 cm length × 5 mm diameter) of

Amberlite IRC50 cation-exchange resin (Na^ϩform), using

further ethanol–water (4:1) as eluant aﬀorded, on trituration

of the concentrates with cold diethyl ether, the hydroxytri-

ﬂuoro derivative 27a as a white solid (0.064 g, 33%), which gave

crystals mp 202–203 ЊC (from water) (Found: C, 60.55; H, 6.0;

F, 13.2; S, 10.7; C₂₂H₂₆F₃NaO₄requires C, 60.8; H, 6.0; F,

13.1; S, 10.5%); δ_H[(CD₃)₂SO] 1.55 (6 H, s), 1.63 (6 H, s)

(4 × Me), 2.01 (8 H, m, 4,5,8,9-H), 4.64 (2 H, d, J 7.2, 1-H),

5.06 (2 H, m, 6,10-H), 5.41 (1 H, t, J 7.2, 2-H), 11.47 (s, OH);

δ_F[(CD₃)₂SO] Ϫ172.14 (1 F, d, J 22.4), Ϫ159.99 (1 F, t, J 6.8),

Ϫ144.90 (1 F, dd, J 13.1, 24.0); m/z (ESI, Ϫve ion mode)

411 (M Ϫ Na)^Ϫ.

A 20% aqueous solution of sodium hydroxide (0.1 cm³) was

added to a rapidly stirred solution of 29 (0.115 g, 0.26 mmol) in

ethanol (1.1 cm³) and water (0.1 cm³) at room temperature with

protection from light. After 2.5 h the mixture was diluted with

water (6 cm³), cooled in ice, and centrifuged. The supernatant

was pipetted oﬀ and the precipitated solid washed with water

(2 × 6 cm³) by resuspension and centrifugation, then crystal-

lised from water (5 cm³) to give sodium salt 30 (0.062 g, 55%),

mp 224–226 ЊC (Found: C, 59.8; H, 5.87; F, 17.3; C₂₂H₂₅F₄-

NaO₃ؒ0.25H₂O requires C, 59.9; H, 5.8; F, 17.2%); δ_H[(CD₃)₂SO]

1.56 (6 H, s), 1.62 (3 H, s), 1.63 (3 H, s) (4 × Me), 2.02 (8 H, m,

4,5,8,9-H), 4.64 (2 H, d, J 7.2, 1-H), 5.07 (2 H, m, 6,10-H), 5.42

(1 H, t, J 7.2, 2-H); δ_F[(CD₃)₂SO] Ϫ156.76 (2 F, m), Ϫ145.37 (2

F, m); m/z (ESI, Ϫve ion mode) 413.2 (M Ϫ Na)^Ϫ.

2,2-Dimethylpropan-1-yl pentaﬂuorobenzenesulfonate 32a

A solution of 2,2-dimethylpropan-1-ol (2.498 g, 28.3 mmol)

and pyridine (2.3 cm³, 28 mmol) in dry diethyl ether (2 cm³)

was added to a stirred solution of pentaﬂuorobenzenesulfonyl

chloride 31 (5.005 g, 18.8 mmol) in diethyl ether (30 cm³) at 8 ЊC

under argon. After 30 min at 8 ЊC then 46 h at room temper-

ature the mixture was ﬁltered and the solids washed with diethyl

ether (3 × 20 cm³). The combined ﬁltrate and washings were

washed successively with 2 M hydrochloric acid (2 × 10 cm³)

and saturated aqueous NaHCO₃(10 cm³), dried (MgSO₄) and

evaporated. Chromatography [Merck 9385 silica; light petrol-

eum (bp 60–80 ЊC)–dichloromethane (successively 5:1, 4:1 and

3:1)] gave ester 32a (3.568 g, 60%), mp 85 ЊC (from hexane)

(Found: C, 41.4; H, 3.4; F, 29.8; S, 10.3; C₁₁H₁₁F₅O₃S requires

C, 41.5; H, 3.5; F, 29.85; S, 10.1%); δ_H[(CD₃)₂SO] 0.91 (9 H, s,

CMe₃), 4.00 (2 H, s, OCH₂); δ_F[(CD₃)₂SO] Ϫ158.76 (2 F, m),

Ϫ144.50 (1 F, m), Ϫ136.02 (2 F, m).

Sodium 4-[(E)-3,7-dimethylocta-2,6-dien-1-yloxy]-2,3,5-

triﬂuoro-6-hydroxybenzoate 27b

The procedure, starting from geranyl bromide (0.156 g, 0.72

mmol) and 25 (0.100 g, 0.45 mmol), was essentially that used to

prepare the farnesyl analogue 27a, with the following changes:

the reaction time was 7 h; elution with dichloromethane–

ethanol was followed by dichloromethane–ethanol–glacial

acetic acid (170:30:3); methanol–water (4:1) was the solvent

and eluant for ion-exchange column chromatography. The

geranyl derivative 27b a white solid (0.084 g, 51%) gave colour-

less ﬂakes, mp 205 ЊC (from water) (Found: C, 55.8; H, 5.0;

C₁₇H₁₈F₃NaO₄requires C, 55.8; H, 4.95%); δ_H[(CD₃)₂SO] 1.54

(3 H, s), 1.62 (6 H, s) (3 × Me), 2.00 (4 H, m, 4,5-H), 4.65 (2 H,

d, J 7.3, 1-H), 5.03 (1 H, m, 6-H), 5.40 (1 H, t, J 7.3, 2-H),

11.47 (1 H, s, OH); δ_F[(CD₃)₂SO] Ϫ171.98 (1 F, dd, J 6.2, 23.8),

Ϫ159.89 (1 F, d, J 6.9), Ϫ144.84 (1 F, dd, J 13.2, 23.9); m/z

(ESI, Ϫve ion mode) 343 (M Ϫ Na)^Ϫ.

2,2-Dimethylpropan-1-yl 4-[(E)-3,7-dimethylocta-2,6-dien-1-

yloxy]-2,3,5,6-tetraﬂuorobenzenesulfonate 33a

From 32a (0.955 g, 3 mmol) and geraniol using general pro-

cedure A. Chromatography [Merck 9385 silica; ﬁrst with

hexane–dichloromethane (2:1), then with hexane–dichloro-

methane (3:1 and 2:1 in succession)] gave tetraﬂuoro derivative

33a (0.751 g, 55%) (oil) (Found: C, 55.8; H, 6.25; F, 16.9; S, 7.1;

C₂₁H₂₈F₄O₄S requires C, 55.7; H, 6.2; F, 16.8; S, 7.1%); δ_H

[(CD₃)₂SO] 0.90 (9 H, s, CMe₃), 1.55 (3 H, s), 1.62 (3 H, s), 1.69

(3 H, s) (3 × geranyl Me), 2.04 (4 H, m, 4,5-H), 3.95 (2 H, s,

SO₃CH₂), 4.96 (2 H, d, J 7.2, 1-H), 5.02 (1 H, m, 6-H), 5.46

(1 H, t, J 7.2, 2-H); δ_F[(CD₃)₂SO] Ϫ154.01 (2 F, m), Ϫ138.11

(2 F, m).

Ethyl 2,3,5,6-tetraﬂuoro-4-hydroxybenzoate²⁹28

The preparation from 2,3,5,6-tetraﬂuoro-4-hydroxybenzoic

acid 19 hydrate (2 g, 9 mmol) followed essentially the literature

procedure⁴⁰for ethyl 2,3,4,5-tetraﬂuoro-6-hydroxybenzoate

except that chromatography [Merck 15111 silica; dichloro-

methane–ethanol (stepwise gradient: 100:0, 99:1, 250:6,

250:8, 250:13, 9:1)] was used to give the ester 28 (1.473 g,

69%), mp 108–110 ЊC (lit.²⁹mp, 107–109 ЊC; δ_H(CDCl₃) 1.39

(3 H, t, J 7.1, CH₃), 4.42 (2 H, q, J 7.1, CH₂), 6.3 (1 H, br s,

OH); δ_F(CDCl₃) Ϫ163.12 (2 F, m), Ϫ140.54 (2 F, m); m/z (FAB)

239 (M ϩ H)^ϩ.

2,2-Dimethylpropan-1-yl 4-[(E)-3,7-dimethylocta-2,6-dien-1-

yloxy]-2,3,5-triﬂuoro-6-hydroxybenzenesulfonate 34a

From 33a (0.23 g, 0.5 mmol) using procedure B but with reac-

tion at room temperature. Chromatography [Merck 7729 silica;

hexane–dichloromethane (1:1) then dichloromethane, then on

Merck 9385 silica with hexane–dichloromethane (1:1)] gave

hydroxytriﬂuoro derivative 34a (0.083 g, 36%) (oil) (Found: C,

56.2; H, 6.5; F, 12.6; S, 7.2; C₂₁H₂₉F₃O₅S requires C, 56.0; H,

Ethyl 2,3,5,6-tetraﬂuoro-4-[(E,E)-3,7,11-trimethyldodeca-

2,6,10-trien-1-yloxy]benzoate 29

The reaction conditions using 28 (0.50 g, 2.1 mmol) and (E,E)-

farnesyl bromide (0.66 g, 2.3 mmol) were essentially those used

J. Chem. Soc., Perkin Trans. 1, 2000, 4265–4278

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6.5; F, 12.65; S, 7.1%); δ_H[(CD₃)₂SO] 0.89 (9 H, s, CMe₃), 1.55

(3 H, s), 1.62 (3 H, s), 1.65 (3 H, s) (3 × geranyl Me), 2.01 (4 H,

m, 4,5-H), 3.82 (2 H, s, SO₃CH₂), 4.85 (2 H, d, J 7.2, 1-H), 5.02

(1 H, m, 6-H), 5.42 (1 H, t, J 7.2, 2-H), 11.44 (1 H, br s, OH);

δ_F[(CD₃)₂SO] Ϫ162.69 (1 F, d, J 23.5), Ϫ151.97 (1 F, d, J 8.8),

Ϫ139.97 (1 F, dd, J 9.2, 24.1); m/z (ESI, Ϫve ion mode) 449

(M Ϫ H)^Ϫ.

Ϫ164.93 (1 F, d, J 24.9), Ϫ155.88 (1 F, d, J 9.9), Ϫ141.84 (1 F,

dd, J 10.1, 27.0); m/z (ESI, Ϫve ion mode) 447 (M Ϫ Na)^Ϫ.

2-Methylpropan-1-yl 4-[(E)-3,7-dimethylocta-2,6-dien-1-yloxy]-

2,3,5,6-tetraﬂuorobenzenesulfonate 33c

From recrystallised 32b (1.217 g, 4 mmol) and geraniol using

general procedure A. Chromatography [Merck 9385 silica,

hexane–dichloromethane (3:2) then hexane–dichloromethane

(2:1)] gave in later fractions pure geranyl derivative 33c (oil)

(0.219 g) preceded by impure material (1.119 g) (ca. 90% pure

by NMR) (total yield ca. 1.2 g, 68%) (Found: C, 54.7; H, 6.0; F,

17.5; S, 7.5; C₂₀H₂₆F₄O₄S requires C, 54.8; H, 6.0; F, 17.3; S,

7.3%); δ_H[(CD₃)₂SO] 0.88 (6 H, d, J 6.8, Me₂CH), 1.55 (3 H, s),

1.62 (3 H, s), 1.68 (3 H, s) (3 × geranyl Me), 1.96 (1 H, m,

Me₂CH), 2.03 (4 H, m, 4,5-H), 4.07 (2 H, d, J 6.3, SO₃CH₂),

4.95 (2 H, d, J 7.2, 1-H), 5.02 (1 H, m, 6-H), 5.45 (1 H, t, 2-H);

δ_F[(CD₃)₂SO] Ϫ154.03 (2 F, m), Ϫ138.23 (2 F, m); m/z (ESI, Ϫve

ion mode) 436 (M Ϫ H)^Ϫ.

2-Methylpropan-1-yl pentaﬂuorobenzenesulfonate 32b

The reaction of 2-methylpropan-1-ol (8 cm³, 87 mmol) with

31 (15 g, 56 mmol) following essentially the method used to

prepare 32a except that the reaction duration, at room tem-

perature, was 17 h. Chromatography [hexane–dichloromethane

(stepwise gradient: 5:1, 4:1, 3:1 and 2.5:1)] gave ester 32b

(11.0 g, 64%) mp 47–49 ЊC (from hexane) (Found: C, 39.5; H,

3.0; F, 31.4; S, 10.7; C₁₀H₉F₅O₃S requires C, 39.5; H, 3.0; F,

31.2; S, 10.5%); δ_H[(CD₃)₂SO] 0.90 (6 H, d, J 6.7, 2 × Me), 1.97

(1 H, m, Me₂CH), 4.12 (d, J 6.3, OCH₂); δ_F[(CD₃)₂SO]

Ϫ158.75 (2 F, m), Ϫ144.53 (1 F, m), Ϫ136.02 (2 F, m). Note: the

title compound appears unstable in (CD₃)₂SO, since NMR

spectra also contain a second set of signals that increase in

intensity with time relative to those of 32b.

2-Methylpropan-1-yl 4-[(E)-3,7-dimethylocta-2,6-dien-1-yloxy]-

2,3,5-triﬂuoro-6-hydroxybenzenesulfonate 34c

From 33c (purity ca. 90%; 0.522 g, 1.2 mmol) using general

procedure B but with reaction at room temperature. Chrom-

atography [Merck 9385 silica; hexane–dichloromethane (1:1)

then a gradient to neat dichloromethane; next with hexane–

dichloromethane (5:4 then 1:3) then neat dichloromethane]

gave title compound 34c (0.098 g, 19%) (oil) (Found: C, 55.0; H,

6.2; F, 13.2; S, 7.2; C₂₀H₂₇F₃O₅S requires C, 55.0; H, 6.2; F, 13.1;

S, 7.3%); δ_H[(CD₃)₂SO] 0.87 (6 H, d, J 6.6, Me₂CH), 1.54 (3 H,

s), 1.61 (3 H, s), 1.65 (3 H, d, J 0.7) (3 × geranyl Me), 1.92 (1 H,

m, Me₂CH), 2.01 (4 H, m, 4,5-H), 3.94 (2 H, d, J 6.3, SO₃CH₂),

4.84 (2 H, d, J 7.2, 1-H), 5.01 (1 H, m, 6-H), 5.42 (1 H, t, J 7.2,

2-H), 11.43 (1 H, br s, OH); δ_F[(CD₃)₂SO] Ϫ162.60 (1 F, d,

J 24.2), Ϫ151.90 (1 F, d, J 8.7), Ϫ140.02 (1 F, dd, J 10.0, 23.7);

m/z (ESI, Ϫve ion mode) 435 (M Ϫ H)^Ϫ.

2-Methylpropan-1-yl 2,3,5,6-tetraﬂuoro-4-[(E,E)-3,7,11-

trimethyldodeca-2,6,10-trien-1-yloxy]benzenesulfonate 33b

From 32b (2.43 g, 8 mmol) and (E,E)-farnesol using general

procedure A, but initiating the reaction at 10 ЊC. Chrom-

atography [Merck 9385 silica; hexane–dichloromethane (2:1)]

gave the slightly impure title compound 33b (2.44 g, 60%) as an

oil [Found (for material from the purest fraction of the eluate):

C, 59.5; H, 6.8; F, 15.1; S, 6.4; C₂₅H₃₄F₄O₄S requires C, 59.3; H,

6.8; F, 15.0; S, 6.3%]; δ_H[(CD₃)₂SO] 0.88 (6 H, dd, J 0.7, 6.8,

Me₂CH), 1.55 (6 H, s), 1.63 (3 H, s), 1.69 (3 H, s) (4 × farnesyl

Me), 2.04 (9 H, m, Me₂CH, 4,5,8,9-H), 4.07 (2H, m, SO₃CH₂),

4.95 (2 H, d, J 7.1, 1-H), 5.05 (2 H, m, 6,10-H), 5.46 (1 H, t,

J 7.1, 2-H); δ_F[(CD₃)₂SO] Ϫ154.03 (2 F, m), Ϫ138.21 (2 F, m);

m/z (ESI) 529 (M ϩ Na)^ϩ.

Sodium 4-[(E)-3,7-dimethylocta-2,6-dien-1-yloxy]-2,3,5-

triﬂuoro-6-hydroxybenzenesulfonate 35b

2-Methylpropan-1-yl 2,3,5-triﬂuoro-6-hydroxy-4-[(E,E)-3,7,11-

trimethyldodeca-2,6,10-trien-1-yloxy]benzenesulfonate 34b

Compound 34c (0.141 g, 0.323 mmol), tetramethylammonium

iodide (0.078 g, 0.388 mmol) and acetonitrile (2 cm³) were

stirred together for 3 h at room temperature, then for 66 h at

37 ЊC. The mixture was evaporated and the residue chromato-

graphed [Merck 7729 silica; dichloromethane then dichloro-

methane–methanol (stepwise gradient: 95:5 and 90:10) in

succession]. A suspension of the product in methanol–water

(4:1) was applied to a column (bed volume 8 cm³) of Bio-Rad

AG50W X-4 100–200 mesh cation-exchange resin (Na^ϩform)

which was eluted with methanol–water (4:1) and the eluate

evaporated to dryness. The residue was extracted by trituration

with acetonitrile and the extracts concentrated, giving the

crystalline title compound 35b as colourless ﬂakes (0.030 g,

23%), mp 260 ЊC (decomp.) (Found: C, 47.7; H, 4.5; F, 14.2;

C₁₆H₁₈F₃NaO₅S requires C, 47.8; H, 4.5; F, 14.2%);

δ_H[(CD₃)₂SO] 1.54 (3 H, s), 1.62 (6 H, s) (3 × Me), 2.00 (4 H, m,

4,5-CH₂), 4.69 (2 H, d, J 7.3, 1-H), 5.03 (1 H, m, 6-H), 5.40

(1 H, t, J 7.3, 2-H), 11.28 (1 H, s, OH); δ_F[(CD₃)₂SO] Ϫ164.92

(1 F, d, J 24.7), Ϫ155.88 (1 F, d, J 9.8), Ϫ141.85 (1 F, dd, J 9.8,

26.2); m/z (ESI, Ϫve ion mode) 378 (M Ϫ Na)^Ϫ.

From slightly impure 33b (1.55 g, 3.06 mmol) using general

procedure B, but at ice-bath temperature initially, then at room

temperature. Chromatography [Merck 9385 silica with hexane–

dichloromethane (stepwise gradient: 3:2, 1:1) then dichloro-

methane] gave farnesyl ether 34b (0.77 g, 50%) (oil) (Found: C,

59.1; H, 67.0; F, 11.6; S, 6.3; C₂₅H₃₅F₃O₅S requires C, 59.5; H,

7.0; F, 11.3; S, 6.35%); δ_H[(CD₃)₂SO] 0.87 (6 H, d, J 6.8,

Me₂CH), 1.54 (6 H, s), 1.62 (3 H, s), 1.66 (3 H, s) (4 × farnesyl

Me), 1.94 (m), 2.02 (m) (overlapping, total 9H, Me₂CH, 4,5,8,9-

H), 3.94 (2 H, d, J 6.3, SO₃CH₂), 4.84 (2 H, d, J 7.3, 1-H), 5.05

(2 H, m, 6,10-H), 5.42 (1 H, t, J 7.3, 2-H), 11.4 (1 H, br s, OH);

δ_F[(CD₃)₂SO] Ϫ162.61 (1 F, d, J 24.0), Ϫ151.92 (1 F, d, J 8.1),

Ϫ140.02 (1 F, dd, J 8.2, 24.6); m/z (ESI, Ϫve ion mode) 503

(M Ϫ H)^Ϫ.

Sodium 2,3,5-triﬂuoro-6-hydroxy-4-[(E,E)-3,7,11-trimethyl-

dodeca-2,6,10-trien-1-yloxy]benzenesulfonate 35a

A solution of 34b (0.303 g, 0.6 mmol) and sodium iodide (0.096

g, 0.64 mmol) in acetonitrile (2.5 cm³) was stirred under argon

at room temperature in the dark. After 20 h the mixture was

cooled in ice and the precipitate collected by ﬁltration and

washed with the minimum volume of cold acetonitrile to give

title compound 35a (0.201 g, 72%), mp 270 ЊC (decomp.) (from

acetonitrile) (Found: C, 52.95; H, 5.5; F, 12.4; S, 7.0; C₂₁H₂₆-

F₃NaO₅Sؒ0.25H₂O requires C, 53.1; H, 5.6; F, 12.0; S, 6.75%);

δ_H[(CD₃)₂SO] 1.54 (6 H, s, 2 × Me), 1.62 (6 H, s, 2 × Me), 2.01

(8 H, m, 4,5,8,9-H), 4.68 (2 H, d, J 7.2, 1-H), 5.06 (2 H, m, 6,10-

H), 5.41 (1 H, t, J 7.2, 2-H), 11.28 (1 H, s, OH); δ_F[(CD₃)₂SO]

Methyl pentaﬂuorophenyl sulﬁde³²36b

Argon was bubbled through a mixture of pentaﬂuorothio-

phenol 36a (10.56 g, 52.8 mmol), dichloromethane (105 cm³),

and methyl toluene-p-sulfonate (9.89 g, 53.1 mmol). Aqueous

sodium hydroxide (1 M; 105 cm³) and tetra-n-butylammonium

hydrogen sulfate (1.80 g, 5.3 mmol) were then added succes-

sively and the mixture was stirred rapidly under argon with

cooling (ice–water bath) for 65 min. The dichloromethane layer

was separated and the aqueous layer extracted with dichloro-

4276

J. Chem. Soc., Perkin Trans. 1, 2000, 4265–4278

View Article Online

methane (3 × 25 cm³). The combined dichloromethane solution

was washed with water (4 × 100 cm³), dried (MgSO₄) and con-

centrated to leave a liquid. Samples of 36b were puriﬁed by ﬁrst

chromatography (Merck 9385 silica; neat hexane) to separate

a by-product more polar than the required product, then dis-

tilling under water pump vacuum (bp = 79–82 ЊC); δ_H(CDCl₃)

2.48; δ_F(CDCl₃) Ϫ161.74 (2 F, m), Ϫ154.24 (1 F, t, J 20.6),

Ϫ134.05 (2 F, dd, J 6.9, 23.9).

S, 8.5%); δ_H[(CD₃)₂SO] 1.55, 1.62, 1.66 (3 × s, each 3 H, 3 ×

geranyl Me), 2.02 (4 H, m, 4,5-H), 3.38 (3 H, s, SO₂Me), 4.82

(2 H, d, J 7.1, 1-H), 5.03 (1 H, m, 6-H), 5.43 (1 H, t, J 7.1, 2-H),

11.4 (br, OH); δ_F[(CD₃)₂SO] Ϫ162.82 (1 F, d, J 22.1), Ϫ152.42

(1 F, d, J 9.8), Ϫ142.83 (1 F, dd, J 9.7, 23.8); m/z (ESI, Ϫve ion

mode) 377 [(M Ϫ H)^Ϫ]; m/z (FAB) 379.1170 (M ϩ H)^ϩ(calc for

(M ϩ H)^ϩ, 379.1191).

Methyl pentaﬂuorophenyl sulfone³²37

Acknowledgements

This work was supported by Programme Grant SP2330/0201

from the Cancer Research Campaign (CRC). Support from

Cancer Research Campaign Technology (to J. H. M.) and the

award of a CRC studentship (to A. M. M. B.) are also acknow-

ledged. We thank Dr B. P. Nutley of this Institute for ESI mass

spectra and the School of Pharmacy, London University, for

FAB mass spectra.

This compound was prepared from 36 by the literature pro-

cedure; mp 93–95 ЊC (lit.³²85–86 ЊC); δ_H[(CD₃)₂SO] 3.51 (s);

δ_F[(CD₃)₂SO] Ϫ159.42 (2 F, m), Ϫ145.51 (1 F, m), Ϫ137.56

(2 F, m).

4-[(E)-3,7-Dimethylocta-2,6-dien-1-yloxy]-2,3,5,6-tetraﬂuoro-

phenyl methyl sulfone 38

From 37 (1.50 g, 6.1 mmol) and geraniol, using general pro-

cedure A. Chromatography [Merck 9385 silica; hexane–diethyl

ether (2:1)] gave the title compound 38 (1.738 g, 75%) as an oil

which solidiﬁed on cooling, mp 36–38 ЊC (Found: C, 53.7; H,

5.3; F, 19.9; S, 8.5; C₁₇H₂₀F₄O₃S requires C, 53.7; H, 5.3; F, 20.0;

S, 8.4%); δ_H[(CD₃)₂SO] 1.56, 1.63, 1.69 (3 × s, each 3 H, 3 × ger-

anyl Me), 2.04 (4 H, m, 4,5-H), 3.46 (s, 3 H, SO₂Me), 4.93 (2 H,

d, J 7.2, 1-H), 5.03 (1 H, m, 6-H), 5.45 (1 H, t, J 7.2, 2-H);

δ_F[(CD₃)₂SO] Ϫ154.57 (2 F, m), Ϫ139.71 (2 F, m); m/z (FAB)

513.0144 (M ϩ Cs)^ϩ(calc for (M ϩ Cs)^ϩ, 513.0124).

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The procedure using 38 (0.751 g, 1.97 mmol), 2-(trimethyl-

silyl)ethanol (0.333 g, 2.82 mmol) and potassium tert-butoxide

(0.260 g, 2.32 mmol) followed essentially that used to prepare

compound 13. Chromatography [Merck 9385 silica; hexane–

diethyl ether (4:1)] gave bis(trimethylsilylethoxy) derivative 40

(0.178 g, 15%) and mono(trimethylsilylethoxy) derivative 39

(0.652 g, 69%) as colourless oils; for 40 (Found: C, 56.3; H, 8.0;

F, 6.6; S, 5.4; C₂₇H₄₆F₂O₅SSi₂requires C, 56.2; H, 8.0; F, 6.6; S,

5.6%); δ_H[(CD₃)₂SO] 0.03 (18 H, s, SiMe₃), 1.16 (4 H, t, J 8.5,

CH₂Si), 1.54, 1.61, 1.64 (3 × s, each 3 H, 3 × geranyl Me), 2.00

(4 H, m, 4,5-H), 3.31 (3 H, s, SO₂Me), 4.11 (4 H, t, J 8.5,

CH₂CH₂Si), 4.80 (2 H, d, J 7.2, 1-H), 5.01 (1 H, m, 6-H), 5.40

(1 H, t, J 7.2, 2-H); δ_F[(CD₃)₂SO] Ϫ146.74 (s); m/z (FAB)

649.3020 (M ϩ Me₃Si)^ϩ(calc for (M ϩ Me₃Si)^ϩ, 649.3046); for

39 (Found: C, 55.0; H, 6.9; F, 11.8; S, 6.8; C₂₂H₃₃F₃O₄SSi

requires C, 55.2; H, 6.95; F, 11.9; S, 6.7%); δ_H[(CD₃)₂SO] 0.04

(9 H, d, J 0.7, SiMe₃), 1.19 (2 H, dd, J 8.3, 9.0, CH₂Si), 1.54, 1.62,

1.66 (3 × s, each 3 H, 3 × geranyl Me), 2.02 (4 H, m, 4,5-H),

3.38 (3 H, s, SO₂Me), 4.20 (2 H, dd, J 8.3, 9.0, CH₂CH₂Si), 4.86

(2 H, d, J 7.2, 1-H), 5.01 (1 H, m, 6-H), 5.42 (1 H, t, J 7.2, 2-H);

δ_F[(CD₃)₂SO] Ϫ155.58 (1 F, d, J 23.7), Ϫ146.10 (1 F, d, J 9.1),

Ϫ141.16 (1 F, dd, J 10.0, 23.7); m/z (FAB) 551.2265

(M ϩ Me₃Si)^ϩ(calc for (M ϩ Me₃Si)^ϩ, 551.2294).

4-[(E)-3,7-Dimethylocta-2,6-dien-1-yloxy]-2,3,5-triﬂuoro-6-

hydroxyphenyl methyl sulfone 41

Tetra-n-butylammonium ﬂuoride (1 M solution in THF; 1.12

cm³) was added to 39 (0.268 g, 0.56 mmol) and the resulting

mixture was stirred at room temperature for 50 min. Methanol–

water (4:1) was added and the solution applied to a column (2.5

cm³) (bed volume 16 cm³) of Bio-Rad AG50W-X4 100–200

mesh cation-exchange resin (H^ϩform). Further methanol–

water (4:1) was allowed to percolate through the column and

from the eluate was recovered in two crops the crystalline title

compound 41 (0.109 g, 51%) mp 46–48 ЊC (Found: C, 54.0; H,

5.6; F, 15.1; S, 8.6; C₁₇H₂₁F₃O₄S requires C, 54.0; H, 5.6; F, 15.1;

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