Fluoro- or trifluoromethyl-substituted benzyl and phenethyl alcohols: Substrates for metal-mediated site-selective functionalization

Article abstract of DOI:10.1002/1099-0690(200208)2002:15<2508::AID-EJOC2508>3.0.CO;2-C

It was possible to functionalize the three fluorobenzyl alcohols and the three 2-(fluorophenyl)ethanols by metalation and subsequent carboxylation, the prototype electrophilic trapping reaction. Triisopropylsilyl (TIPS) outperformed methoxymethyl (MOM) as an O-protective group making seven new fluorobenzoic acids accessible in 63% average yield. Moreover, the TIPS group tolerates weakly basic and acidic media and, therefore, may facilitate further structural elaboration. The unprotected alcohols reacted more sluggishly and were unable to provide two of the targeted products (acids 1 and 2). The yield averaged only 46% in the five other cases (acids 3-7). The direct metalation of fluorinated benzyl and phenethyl alcohols remains nevertheless an attractive option because of its operational simplicity. All three (trifluoromethyl)benzyl alcohols and two of the three (trifluoromethyl)phenethyl alcohol isomers were successfully submitted to the metalation/functionalization sequence. These five starting materials gave rise to a total of nine new benzoic acids or lactones (compounds 8-14 and 17-18). Despite the poor yields (31% on average), the organometallic methods employed are, in general, extremely selective, economical and easy to perform. Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002.

Full text of DOI:10.1002/1099-0690(200208)2002:15<2508::AID-EJOC2508>3.0.CO;2-C

FULL PAPER
Fluoro- or Trifluoromethyl-Substituted Benzyl and Phenethyl Alcohols:
Substrates for Metal-Mediated Site-Selective Functionalization
Elena Marzi,[a] Andrea Spitaleri,[a] Florence Mongin,[b] and Manfred Schlosser*[a]
Keywords: Fluorinated substituents / Hydrogen-metal permutation / Regioselectivity / Organometallic reagents /
Protecting groups
It was possible to functionalize the three fluorobenzyl alco-
hols and the three 2-(fluorophenyl)ethanols by metalation
and subsequent carboxylation, the prototype electrophilic
trapping reaction. Triisopropylsilyl (TIPS) outperformed me-
thoxymethyl (MOM) as an O-protective group making seven
new fluorobenzoic acids accessible in 63% average yield.
Moreover, the TIPS group tolerates weakly basic and acidic
media and, therefore, may facilitate further structural elab-
oration. The unprotected alcohols reacted more sluggishly
and were unable to provide two of the targeted products (ac-
and phenethyl alcohols remains nevertheless an attractive
option because of its operational simplicity. All three (tri-
fluoromethyl)benzyl alcohols and two of the three (trifluoro-
methyl)phenethyl alcohol isomers were successfully submit-
ted to the metalation/functionalization sequence. These five
starting materials gave rise to a total of nine new benzoic
acids or lactones (compounds 8−14 and 17−18). Despite the
poor yields (31% on average), the organometallic methods
employed are, in general, extremely selective, economical
and easy to perform.
ids 1 and 2). The yield averaged only 46% in the five other ( Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany,
cases (acids 3−7). The direct metalation of fluorinated benzyl
2002)
A fluorine atom exerts the strongest and a trifluorome-
thyl group the weakest ortho-metalation promoting effect
among all halogenated substituents.[1] This, at first sight,
is in conflict with the rule-of-thumb according to which a
trifluoromethyl group has the same acidifying (or anion-
stabilizing) potential as a single fluorine. As an example,
one may quote the dissociation constants of fluoroacetic
acid (pKa 2.6) and 3,3,3-trifluoropropionic acid (pKa 2.9).[2]
However, metalation (hydrogen/metal permutation) reac-
tions are usually irreversible or, in other words, kinetically
controlled. As transition states are much more sensitive to
steric hindrance than ground states, the bulkiness of the tri-
fluoromethyl entity indeed impedes reactions in its
vicinity.[3Ϫ6]
ence reveals itself unequivocally in competition experi-
ments. When treated with sec-butyllithium, 3,5-difluoro-
benzotrifluoride [1,3-difluoro-5-(trifluoromethyl)benzene]
undergoes deprotonation at the fluorine-flanked position 16
times faster than 1,3,5-trifluorobenzene does (after statist-
ical correction), and 1-methoxymethoxy-4-(trifluorometh-
yl)benzene reacts with butyllithium 4.5 times faster than 1-
fluoro-4-(methoxymethoxy)benzene at the oxygen-adjacent
position.[9]
Besides in size, these two archetypal fluorine substituents
differ characteristically as far as the distance dependence
of their electronic effects is concerned. When moving the
deprotonation site from the ortho through the meta to the
para position, the activating effect of fluorine drops by
roughly half with each step,[7] whereas the effect of a trifluo-
romethyl group is almost position-invariant.[8] This differ-
Finally, fluorine and trifluoromethyl exhibit divergent be-
havior in yet another practically important respect. When
ortho-metalated, fluoroarenes do not suffer a 1,2-elimina-
tion of metal fluoride in general up to Ϫ50 °C, thus
avoiding the generation of energy-rich dehydroarene
(‘‘aryne’’) species. Metalated benzotrifluorides are stable up
to ϩ25 °C and beyond, unless they carry alkyl groups at
[a]
´
Section de Chimie et genie chimique, EPF BCh,
1015 Lausanne, Switzerland
[b]
´
Section de Chimie, Universite, BCh,
1015 Lausanne, Switzerland
2508
 WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002 1434Ϫ193X/02/0815Ϫ2508 $ 20.00ϩ.50/0 Eur. J. Org. Chem. 2002, 2508Ϫ2517

Substrates for Metal-Mediated Site-Selective Functionalization
FULL PAPER
the ortho- or para-positions. In this case they undergo an was isolated in 29% and 51% yield, respectively, when the
instantaneous 1,4- or 1,6-dehydrofluorination (and sub- MOM derivative was metalated with uncomplexed sec-bu-
sequent nucleophilic addition[10]), respectively, even at the tyllithium or the TIPS derivative with sec-butyllithium in
lowest temperatures, when exposed to organometallic re- the presence of both PMDTA and potassium tert-butoxide.
agents or metal amides.[11] Only meta-isomers such as 3-
(trifluoromethyl)toluene can be deprotonated at the
benzylic position[11] or, alternatively, at the 4-position,[12]
Table 1. Summary of the results obtained with 2-, 3- and 4-fluoro-
benzyl alcohols and their MOM- and TIPS-protected derivatives
depending on the base (Bs) employed.
The purpose of the present investigation was to explore
the possibility of preventing such 1,4- and 1,6-eliminations
of hydrogen fluoride. In particular, we wanted to find out
whether O-protected hydroxymethyl and β-hydroxyethyl
[a]
Protective groups: OMOM
ϭ
OCH2OCH3; OTIPS
ϭ
groups would be less prone to benzylic deprotonation than
simple alkyl groups are. Therefore, we have studied the
metalation and subsequent carboxylation of 2-, 3- and 4-
(trifluoromethyl)benzyl alcohols and of the 2-, 3- and 4-
isomers of 2-[(trifluoromethyl)phenyl]ethanol and, for com-
parison, of the corresponding monofluoroaryl analogs.
OSi(iC3H7)3.
Regiochemistry: ‘‘o-F’’ means metalation at a
[b]
position adjacent to fluorine but remote from the CH2OR group;
‘‘o,oЈ ’’ means metalation at the position flanked by both substitu-
ents. [c] Reaction conditions: metalation in a 7:3 mixture of tetrahy-
drofuran (THF) and hydrocarbons at Ϫ75 °C for 2 h unless stated
otherwise. Metalation reagents:
presence
(PMDTA).
potassium tert-butoxide.
[d]
sec-Butyllithium (LIS) in the
pentamethyldiethylenetriamine
of
N,N,NЈ,NЈЈNЈЈ
LIS alone. LIS in the presence of PMDTA and
[e]
[f]
Fluorobenzyl Alcohols, 2-(Fluorophenyl)ethanols and O-
Protected Derivatives as Substrates
The O-lithiated hydroxymethyl group is only a weak or-
tho-directing substituent.[12Ϫ17] Thus, we expected
metalation to occur next to the fluorine atom and remote
from the oxygen functional group whenever there were two
different sites available for deprotonation. This was found
to be true not only for the competition between fluorine
and the CH2OLi entity, but also between fluorine and the
methoxymethyl (MOM) or the triisopropylsilyl (TIPS) pro-
tected hydroxymethyl group.
The results are summarized below (see Table 1). The
MOM- or TIPS-protected 2- and 4-fluorobenzyl alcohols
afforded, after metalation, carboxylation and deprotection,
the 2-fluoro-3-(hydroxymethyl)benzoic acid (1, 36% or
61%) and the 2-fluoro-5-(hydroxymethyl)benzoic acid (4,
56% or 84%), respectively. The unprotected 2-fluorobenzyl
alcohol reacted sluggishly to produce an inseparable mix-
ture, whereas the 4-isomer again gave the acid 4 (49%). A
regiochemical alternative was encountered only with the 3-
fluorobenzyl alcohol. When this alcohol was treated with
sec-butyllithium in the presence of N,N,NЈ,NЈЈ,NЈЈ-penta-
methylethylenetriamine (PMDTA) in tetrahydrofuran for
2 h at Ϫ75 °C, 2-fluoro-4-(hydroxymethyl)benzoic acid (3;
47%) was obtained exclusively. The same product resulted,
although in lower yields (15% and 31%), when the MOM-
and TIPS-protected derivatives were the starting materials.
However, the lactone 2, the spontaneously formed dehydra-
tion product of the 2-fluoro-6-(hydroxymethyl)benzoic acid,
Eur. J. Org. Chem. 2002, 2508Ϫ2517
2509

E. Marzi, A. Spitaleri, F. Mongin, M. Schlosser
FULL PAPER
No such ‘‘optional site selectivity’’ [18Ϫ20] was achieved in with standard metalating reagents such as lithium diisopro-
the fluorophenethyl alcohol series (see Table 2). Depro- pylamide or lithium 2,2,6,6-tetramethylpiperidide with bu-
tonation with lithium 2,2,6,6-tetramethylpiperidide of each tyllithium, sec-butyllithium or tert-butyllithium either alone
of the three isomers, followed by carboxylation and neutral- or in combination with potassium tert-butoxide and
ization, afforded 2-fluoro-3-(2-hydroxyethyl)benzoic acid PMDTA. Only the best results are listed below (see Table 3
(5; 31%), 2-fluoro-4-(2-hydroxyethyl)benzoic acid (6; 61%) and text).
and 2-fluoro-5-(hydroxyethyl)benzoic acid (7; 43%). Em-
ploying the MOM- and TIPS-protected starting materials
and PMDTA-activated sec-butyllithium as the base gave,
after deprotonation, the same acids in 35% and 39%, 70%
and 67%, and 71% and 77% yield, respectively.
Table 3. Summary of the major results obtained with 2-, 3- and 4-
(trifluoromethyl)benzyl alcohols
Table 2. Summary of the results obtained with 2-(2-, 3- and 4-
fluorophenyl)ethanols and their MOM- and TIPS-protected deriv-
atives
[a]
Protective groups: OMOM
ϭ OCH2OCH3; OTIPS ϭ
OSi(iC3H7)3. Regiochemistry: ‘‘o-CH2OR’’ means metalation at
a position adjacent to the O-deprotonated hydroxymethyl, but re-
mote from the trifluoromethyl group; ‘‘o-CF3’’ means the opposite.
[c] Reaction conditions: metalation in a 7:3 mixture of tetrahydrofu-
ran (THF) and hydrocarbons at Ϫ75 °C for 2 h unless stated other-
[b]
[a]
Protective groups: OMOM
ϭ
OCH2OCH3; OTIPS
ϭ
OSi(iC3H7)3.
Regiochemistry: ‘‘o-F’’ means metalation at a
[d]
[e]
[b]
wise. Metalation reagents:
paragraph of the general part preceding the Exp. Sect.). LIC in
Butyllithium (LIC).
See text (last
position adjacent to fluorine but remote from the CH2CH2OR
[f]
group. [c] Reaction conditions: metalation in a 7:3 mixture of tetra-
the presence of potassium tert-butoxide (KOR) and PMDTA.
hydrofuran (THF) and hydrocarbons at Ϫ75 °C for 2 h unless
[g]
[h]
[i]
tert-butyllithium (LIT).
LIC in the presence of KOR. LIS
[d]
stated otherwise. Metalation reagents:
methylpiperidide (LITMP).
Lithium 2,2,6,6-tetra-
in the presence of KOR and PMDTA.
[e]
sec-Butyllithium (LIS) in the pres-
ence of N,N,NЈ,NЈЈNЈЈ-pentamethyldiethylenetriamine (PMDTA).
The steric congestion caused by the trifluoromethyl
group offers a chance to the oxygen-functional substituent
to direct the metalation in its vicinity. Thus, 2-(trifluorome-
thyl)benzyl alcohol was attacked by butyllithium at the 6-
position as evidenced by the isolation of the lactone 8
(24%), spontaneously formed by dehydration of the 2-hy-
droxymethyl-3-(trifluoromethyl)benzoic acid. However,
when the same organolithium reagent was applied in the
presence of potassium tert-butoxide and PMDTA, depro-
tonation occurred at the CF3-adjacent site and ultimately
produced 3-hydroxymethyl-2-(trifluoromethyl)benzoic acid
(9; 33%).
Trifluoromethyl-Substituted Benzyl Alcohols and 2-Phenyl-
ethanols as Substrates
All three isomers of (trifluoromethyl)benzyl alcohol and
of 2-[(trifluoromethyl)phenyl]ethanol were allowed to react
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Eur. J. Org. Chem. 2002, 2508Ϫ2517

Substrates for Metal-Mediated Site-Selective Functionalization
FULL PAPER
3-(Trifluoromethyl)benzyl alcohol offered the rare pos- isomeric 3-(2-hydroxyethyl)-5-(trifluoromethyl)benzoic acid
sibility of threefold optional site selectivity. Whereas a pro- (16; 5%) were identified (see Table 4). The structure of the
ton was abstracted by tert-butyllithium from the CF3-re- latter compound was assigned on the basis of gas chroma-
mote 6-position, and by sec-butyllithium, if simultaneously tographic comparison with an authentic sample made by a
coordinated to potassium tert-butoxide and PMDTA, from multi-step sequence starting with 3-bromobenzotrifluoride
the CH2OM-remote 4-position, metalation was accomp- (for details, see Exp. Sect.). Finally, 2-[(4-trifluoromethyl)-
lished with butyllithium in the presence of potassium tert- phenyl]ethanol gave 5-(2-hydroxyethyl)-2-(trifluoromethyl)-
butoxide at the 2-position surrounded by the two substitu- benzoic acid (18; 13%) when treated consecutively with
ents. After carboxylation and neutralization the lactones 10 the butyllithium/potassium tert-butoxide/PMDTA complex
(12%) and 11 (47%) and 4-hydroxymethyl-2-(trifluoro- and dry ice (see Table 4).
methyl)benzoic acid (12; 25%) were isolated as pure com-
pounds.
Table 4. Summary of the major results obtained with 2-[2-, 3- and
4-(trifluoromethyl)phenyl]ethyl alcohols
[a]
Protective groups: OMOM
ϭ OCH2OCH3; OTIPS ϭ
OSi(iC3H7)3. [b] Regiochemistry: ‘‘m,mЈ’’ means metalation at a po-
sition remote from both substituents; ‘‘o-CF3’’ means metalation
4-(Trifluoromethyl)benzyl alcohol was found to obey the
same rules as its 2-isomer. When butyllithium was used as
the metalating reagent, the lactone 13 (29%) was formed,
whereas 5-hydroxymethyl-2-(trifluoromethyl)benzoic acid
(14; 36%) was obtained instead with sec-butyllithium simul-
taneously activated by potassium tert-butoxide and
PMDTA.
at a position adjacent to the trifluoromethyl but remote from the
[c]
O-deprotonated hydroxyethyl group.
Reaction conditions:
metalation in a 7:3 mixture of tetrahydrofuran (THF) and hydro-
[d]
carbons at Ϫ75 °C for 2 h unless stated otherwise. See text (last
[e]
paragraph of the general part preceding the Exp. Sect.).
The
[f]
isomers 16 and 17 were formed together in a 7:93 ratio. LIS ϩ
[g]
KOR ϩ PMDTA. LIC ϩ KOR ϩ PMDTA.
All attempts to convert 2-[(2-trifluoromethyl)phenyl]-
ethanol into a well-defined derivative failed. Several isomers
15 were produced simultaneously and in minor quantities.
The reaction between 2-[(3-trifluoromethyl)phenyl]ethanol
and sec-butyllithium in the presence of potassium tert-but-
oxide and PMDTA lacked the usually perfect regioselectiv-
ity. Along with the main product [4-(2-hydroxyethyl)-2-(tri-
fluoromethyl)benzoic acid (17; 64%)] small amounts of the
Eur. J. Org. Chem. 2002, 2508Ϫ2517
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E. Marzi, A. Spitaleri, F. Mongin, M. Schlosser
FULL PAPER
bromofluorobenzene or bromobenzotrifluoride isomer by bromine/
lithium permutation and subsequent reaction with paraformal-
dehyde or oxirane. The following working procedure is representat-
ive.
No evidence was gained suggesting extensive 1,4- or 1,6-
elimination of hydrogen fluoride (as proposed in the intro-
duction). The poor yields obtained with 2- and 4-trifluoro-
methyl-substituted benzyl and phenethyl alcohols are prob-
ably due to aggregate and mixed aggregate formation.
Alkyllithiums are known to combine with alkoxides to form
association complexes.[21Ϫ25] The latter may be too stable
to sustain an intramicellar hydrogen/metal transfer. In
agreement with this assumption, the metalating reagents
were found to be unconsumed to a large extent and most
of the starting material that did not show up as a new prod-
uct was recovered unchanged. Moreover, lithium alkoxides
tend to aggregate with themselves to form oligomeric or
polymeric clusters.[26Ϫ28] The oxygen-functionalized side
chain is thus converted into a huge and voluminous sub-
stituent that sterically shields the neighboring ortho posi-
tions. A comparison of the deprotonation efficiencies at the
6-position of 3-(trifluoromethyl)toluene,[12] lithium 3-(tri-
fluoromethylbenzyl alkoxide and lithium 2-[(3-trifluorome-
thyl)phenyl]ethoxide (see above) is quite revealing in this re-
spect.
2-(3-Fluorophenyl)ethanol: At Ϫ75 °C, 1-bromo-3-fluorobenzene
(11 mL, 18 g, 0.10 mol) and oxirane (4.8 mL, 4.2 g, 0.10 mol) were
added consecutively to a solution of butyllithium (0.10 mol) in
tetrahydrofuran (85 mL) and hexanes (65 mL). The mixture was
allowed to reach ϩ25 °C and the volatiles were then stripped off.
The residue was treated with an excess (0.20 mol) of 5.0  ethereal
hydrochloric acid (40 mL). A colorless liquid was collected upon
distillation; b.p. 70Ϫ71 °C/2 Torr (ref.:[32] b.p. 90 °C/3 Torr); n2D0
ϭ
1.5026; yield: 10.8 g (77%).
All MOM-protected benzyl and phenethyl alcohols were prepared
in the same way. Chloromethyl methyl ether[33] (4.6 m, 4.8 g,
60 mmol) was added dropwise, over 15 min, to a solution of the
alcohol (50 mmol) and N-ethyldiisopropylamine (‘‘Hünig’s base’’;
17 mL, 13 g, 0.10 mol) in dichloromethane (40 mL), kept at 0 °C.
After standing for 2 h at 25 °C, the mixture was poured into a 3.0
 aqueous solution (0.10 L) of sodium hydroxide and extracted
with diethyl ether (3 ϫ 25 mL). A colorless liquid was collected
upon distillation.
1-Fluoro-2-[(methoxymethoxy)methyl]benzene: From 2-fluorobenzyl
alcohol (5.3 mL, 6.3 g, 50 mmol); b.p. 42Ϫ43 °C/0.8 Torr; n2D0
ϭ
1.4871; d420 ϭ 1.178; yield: 6.1 g (72%). H NMR: δ ϭ 7.40 (t, J ϭ
7.4 Hz, 1 H), 7.3 (m, 1 H), 7.11 (t, J ϭ 7.5 Hz, 1 H), 7.05 (t, J ϭ
8.4 Hz, 1 H), 4.69 (s, 2 H), 4.64 (s, 2 H), 3.39 (s, 3 H) ppm. 13C
NMR: δ ϭ 160.8 (d, J ϭ 247 Hz), 130.2 (d, J ϭ 4 Hz), 129.5 (d,
J ϭ 8 Hz), 125.0 (d, J ϭ 1 4 Hz), 124.0 (d, J ϭ 4 Hz), 115.2 (d,
J ϭ 20 Hz), 95.3 (s), 62.9 (d, J ϭ 4 Hz), 55.2 (s) ppm. MS (c.i.):
m/z (%) ϭ 188 (49) [Mϩ ϩ NH4], 170 (8) [Mϩ], 130 (78), 109 (100).
C9H11FO2 (170.19): calcd. C 63.52, H 6.52; found C 63.52, H 6.47.
1
Of course we had hoped to improve on the yields in the
CF3-substituted series by switching from the lithium alkox-
ides to O-protected benzyl and phenethyl alcohols. How-
ever, regardless of whether MOM- or TIPS-masked deriva-
tives were employed, the results were worse than those re-
ported above with the unprotected precursors. Presumably,
the benzyl ethers are too prone to α-deprotonation and sub-
sequent Wittig rearrangement, whereas the phenethyl ethers
appear to undergo a 1,2-elimination of H and OR, thus
releasing a styrene which polymerizes immediately.
1-Fluoro-3-[(methoxymethoxy)methyl]benzene: From 3-fluorobenzyl
alcohol (5.4 mL, 6.3 g, 50 mmol); b.p. 44Ϫ45 °C/1 Torr; n2D0
ϭ
1
1.4768; d420 ϭ 1.159; yield: 6.0 g (71%). H NMR: δ ϭ 7.30 (m, 1
H), 7.10 (m, 2 H), 6.96 (td, J ϭ 8.3, 2.7 Hz, 1 H), 4.70 (s, 2 H),
4.57 (s, 2 H), 3.39 (s, 3 H) ppm. 13C NMR: δ ϭ 163.0 (d, J ϭ
246 Hz), 140.7 (d, J ϭ 7 Hz), 129.9 (d, J ϭ 8 Hz), 123.1 (d, J ϭ 2
Hz), 114.5 (d, J ϭ 21 Hz), 95.8 (s), 68.4 (s), 55.4 (s) ppm. MS (c.i.):
m/z (%) ϭ 188 (16) [Mϩ ϩ NH4], 170 (21) [Mϩ], 109 (100).
C9H11FO2 (170.19): calcd. C 63.52, H 6.52; found C 63.78, H 6.56.
1-Fluoro-4-[(methoxymethoxy)methyl]benzene: From 4-fluorobenzyl
alcohol (5.4 mL, 6.3 g, 50 mmol); b.p. 76Ϫ77 °C/9 Torr (ref.[34] b.p.
55 °C/0.4 Torr); n2D0 ϭ 1.4789; d420 ϭ 1.183; yield: 5.8 g (68%). H
1
NMR: δ ϭ 7.32 (dd, J ϭ 8.2, 5.3 Hz, 2 H), 7.04 (t, J ϭ 8.2 Hz, 2
H), 4.71 (s, 2 H), 4.55 (s, 2 H), 3.41 (s, 3 H) ppm. 13C NMR: δ ϭ
162.4 (d, J ϭ 245 Hz), 133.7 (d, J ϭ 3 Hz), 129.7 (d, J ϭ 9 Hz, 2
C), 115.3 (d, J ϭ 21 Hz, 2 C), 95.7 (s), 68.5 (s), 55.4 (s) ppm. MS
(c.i.): m/z (%) ϭ 188 (21) [Mϩ ϩ NH4], 138 (29), 109 (100).
Experimental Section
Generalities: For laboratory routine and abbreviations, see previous
articles from this laboratory.[29Ϫ30] 1H and 13C NMR spectra were
recorded at 400 and 101 MHz, respectively, samples being dissolved
in deuteriochloroform unless stated otherwise. All mass spectra
were produced by chemical ionization (‘‘c.i.’’) in an ammonia
atmosphere at a potential of 96 eV and a source temperature of
100 °C.
1-Fluoro-2-[2-(methoxymethoxy)ethyl]benzene: From 2-(2-fluoro-
phenyl)ethanol (6.7 mL, 7.0 g, 50 mmol); b.p. 54Ϫ55 °C/0.7 Torr;
1
n2D0 ϭ 1.4755; d420 ϭ 1.151; yield: 4.5 g (67%). H NMR: δ ϭ 7.27
(t, J ϭ 8.4 Hz, 1 H), 7.19 (symm. m, 1 H), 7.05 (t, J ϭ 7.6 Hz, 1
H), 7.04 (t, J ϭ 9.2 Hz, 1 H), 4.51 (s, 2 H), 3.79 (t, J ϭ 7.1 Hz, 2
H), 3.31 (s, 3 H), 2.97 (t, J ϭ 7.1 Hz, 2 H) ppm. 13C NMR: δ ϭ
161.3 (d, J ϭ 245 Hz), 131.2 (d, J ϭ 5 Hz), 128.0 (d, J ϭ 8 Hz),
125.8 (d, J ϭ 16 Hz), 123.9 (d, J ϭ 3 Hz), 115.2 (d, J ϭ 22 Hz),
96.3 (s), 57.0 (s), 55.1 (s), 29.6 (s) ppm. MS (c.i.): m/z ϭ 202 (0)
[Mϩ ϩ NH4], 184 (4) [Mϩ], 154 (35), 122 (100), 109 (68).
C10H13FO2 (184.21): calcd. C 65.20, H 7.11; found C 65.20, H 6.94.
1. Starting Materials
All benzyl alcohols and 2-phenylethanols carrying a fluoro atom
or a trifluoromethyl group as a ring substituent are commercial,
though expensive. They can be readily prepared from the suitable
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Eur. J. Org. Chem. 2002, 2508Ϫ2517

Substrates for Metal-Mediated Site-Selective Functionalization
FULL PAPER
n2D0 ϭ 1.4798; yield: 12.8 g (86%). H NMR: δ ϭ 7.24 (td, J ϭ 6.8,
1
1-Fluoro-3-[2-(methoxymethoxy)ethyl]benzene: From 2-(3-fluoro-
phenyl)ethanol (6.3 mL, 7.0 g, 50 mmol); b.p. 50Ϫ52 °C/10 Torr; 1.8 Hz, 1 H), 7.16 (tdd, J ϭ 7.7, 5.5, 1.9 Hz, 1 H), 7.04 (td, J ϭ
1
n2D0 ϭ 1.4758; d420 ϭ 1.160; yield: 4.3 g (69%). H NMR: δ ϭ 7.24
7.0, 1.3 Hz, 1 H), 6.99 (ddd, J ϭ 10.5, 8.1, 1.1 Hz, 1 H), 3.88 (t,
(ddd, J ϭ 9.8, 8.1, 1.9 Hz, 1 H), 7.01 (d, J ϭ7.7 Hz, 1 H), 6.96 (td, J ϭ 6.6 Hz, 2 H), 2.89 (t, J ϭ 6.8 Hz, 2 H), 1.1 (m, 3 H), 1.01 (d,
J ϭ 9.8, 2.1 Hz, 1 H), 6.89 (td, J ϭ 8.6, 2.5 Hz, 1 H), 4.61 (s, 2 H),
3.75 (t, J ϭ 6.6 Hz, 2 H), 3.28 (s, 3 H), 2.89 (t, J ϭ 6.8 Hz, 2 H)
J ϭ 5.1 Hz, 18 H) ppm. 13C NMR: δ ϭ 161.4 (d, J ϭ 245 Hz),
131.7 (d, J ϭ 5 Hz), 127.8 (d, J ϭ 8 Hz), 126.0 (d, J ϭ 16 Hz),
ppm. 13C NMR: δ ϭ 162.9 (d, J ϭ 245 Hz), 141.6 (d, J ϭ 7 Hz), 123.7 (d, J ϭ 4 Hz), 115.1 (d, J ϭ 22 Hz), 63.2 (s), 32.9 (s), 17.8
129.7 (d, J ϭ 8 Hz), 124.5 (s), 115.8 (d, J ϭ 21 Hz), 113.1 (d, J ϭ (s), 11.8 (s) ppm. MS (c.i.): m/z (%) ϭ 315 (12) [Mϩ ϩ NH4], 298
21 Hz), 96.4 (s), 67.8 (s), 55.2 (s), 36.0 (s) ppm. MS (c.i.): m/z (%) ϭ
(77) [Mϩ ϩ 1], 297 (100) [Mϩ], 253 (100). C17H29FOSi (296.50):
202 (72) [Mϩ ϩ NH4], 130 (100), 122 (74), 109 (33). C10H13FO2 calcd. C 68.87, H 9.86; found C 68.66, H 9.81.
(184.21): calcd. C 65.20, H 7.11; found C 65.04, H 6.97.
[2-(3-Fluorophenyl)ethoxy]triisopropylsilane: From 2-(3-fluorophen-
1-Fluoro-4-[2-(methoxymethoxy)ethyl]benzene: From 2-(4-fluoro-
phenyl)ethanol (6.3 mL, 7.0 g, 50 mmol); b.p. 54Ϫ55 °C/0.6 Torr;
yl)ethanol (6.3 mL, 7.0 g, 50 mmol); b.p. 106Ϫ107 °C/0.71 Torr;
n2D0 ϭ 1.4795; yield: 12.6 g (85%). 1H NMR: δ ϭ 7.21 (dd, J ϭ
14.1, 7.6 Hz, 1 H), 6.98 (d, J ϭ 7.2 Hz, 1 H), 6.94 (d, J ϭ 10.1 Hz,
1
n2D0 ϭ 1.4769; d420 ϭ 1.085; yield: 6.7 g (73%). H NMR: δ ϭ 7.19
(ddd, J ϭ 7.6, 5.5, 1.8 Hz, 2 H), 6.98 (td, J ϭ 8.8, 1.8 Hz, 2 H), 1 H), 6.88 (td, J ϭ 8.8, 2.4 Hz, 1 H), 3.88 (t, J ϭ 6.6 Hz, 2 H),
4.61 (s, 2 H), 3.74 (t, J ϭ 6.7 Hz, 2 H), 3.29 (s, 3 H), 2.86 (t, J ϭ 2.84 (t, J ϭ 6.8 Hz, 2 H), 1.1 (m, 3 H), 1.03 (d, J ϭ 5.3 Hz, 18 H)
6.8 Hz, 2 H) ppm. 13C NMR: δ ϭ 161.5 (d, J ϭ 244 Hz), 134.7 (s), ppm. 13C NMR: δ ϭ 162.4 (d, J ϭ 244 Hz), 141.9 (d, J ϭ 7 Hz),
130.3 (d, J ϭ 8 Hz, 2 C), 115.1 (d, J ϭ 21 Hz, 2 C), 96.4 (s), 68.3
129.4 (d, J ϭ 8 Hz), 124.8 (s), 116.1 (d, J ϭ 21 Hz), 112.9 (d, J ϭ
21 Hz), 64.3 (s), 39.4 (s), 17.9 (s), 11.9 (s) ppm. MS (c.i.): m/z (%) ϭ
(s), 55.1 (s), 35.5 (s) ppm. MS (c.i.): m/z (%) ϭ 202 (0) [Mϩ
ϩ
NH4], 122 (100), 109 (76). C10H13FO2 (184.21): calcd. C 65.20, H 315 (2) [Mϩ ϩ NH4], 298 (33) [Mϩ ϩ 1], 297 (100) [Mϩ], 270 (47),
7.11; found C 65.24, H 7.10.
253 (44). C17H29FOSi (296.50): calcd. C 68.87, H 9.86; found C
68.62, H 9.80.
The TIPS-protected benzyl and phenethyl alcohols were also pre-
pared according to a general protocol. The alcohol (50 mmol),
[2-(4-Fluorophenyl)ethoxy]triisopropylsilane: From 2-(4-fluorophen-
chlorotriisopropylsilane (13 mL, 12 g, 60 mmol) and imidazole yl)ethanol (6.3 mL, 7.0 g, 50 mmol); b.p. 103Ϫ104 °C/0.8 Torr;
(8.8 g, 0.13 mol) were dissolved in N,N-dimethylformamide
(25 mL). After 20 h at 25 °C, the mixture was poured into water
n2D0 ϭ 1.4830; yield: 10.8 g (73%). 1H NMR: δ ϭ 7.16 (dd, J ϭ 8.6,
5.5 Hz, 2 H), 6.94 (t, J ϭ 8.9 Hz, 2 H), 3.84 (t, J ϭ 7.1 Hz, 2 H),
and extracted with dichloromethane (3 ϫ 20 mL). Distillation un- 2.81 (t, J ϭ 7.2 Hz, 2 H), 1.1 (m, 3 H), 1.04 (d, J ϭ 5.4 Hz, 18 H)
der reduced pressure gave a colorless liquid.
ppm. 13C NMR: δ ϭ 161.5 (d, J ϭ 244 Hz), 135.1 (d, J ϭ 3 Hz),
130.5 (d, J ϭ 8 Hz), 114.8 (d, J ϭ 21 Hz), 64.7 (s), 38.9 (s), 18.1
(s), 12.0 (s) ppm. MS (c.i.): m/z (%) ϭ 315 (17) [Mϩ ϩ NH4], 298
(87) [Mϩ ϩ 1], 297 (100) [Mϩ], 270 (45), 253 (52). C17H29FOSi
(296.50): calcd. C 68.87, H 9.86; found C 68.79, H 9.84.
(2-Fluorobenzyloxy)triisopropylsilane: From 2-fluorobenzyl alcohol
(5.3 mL, 6.3 g, 50 mmol); b.p. 113Ϫ115 °C/41 Torr; n2D0 ϭ 1.4857;
yield: 7.2 g (51%). 1H NMR: δ ϭ 7.57 (t, J ϭ 7.8 Hz, 1 H), 7.2 (m,
1 H), 7.14 (t, J ϭ 8 Hz, 1 H), 6.98 (t, J ϭ 9.8 Hz, 1 H), 4.90 (s, 2
H), 1.2 (m, 3 H), 1.08 (d, J ϭ 7.2 Hz, 18 H) ppm. 13C NMR: δ ϭ
159.6 (d, J ϭ 239 Hz), 128.8 (d, J ϭ 14 Hz), 128.1 (d, J ϭ 8 Hz),
127.8 (d, J ϭ 4 Hz), 124.0 (d, J ϭ 3 Hz), 114.5 (d, J ϭ 22 Hz),
59.1 (d, J ϭ 5 Hz), 18.1 (s), 12.1 (s) ppm. MS (c.i.): m/z (%) ϭ 300
(0) [Mϩ ϩ NH4], 283 (4) [Mϩ ϩ 1], 282 (2) [Mϩ], 256 (33), 239
(87), 91 (100). C16H27FOSi (282.47): calcd. C 68.03, H 9.63; found
C 68.13, H 9.54.
2. Reactions of Benzyl Alcohols and Derivatives Thereof
Methoxymethoxy (MOM)-Protected Benzyl Alcohols: The acetal
(25 mmol) was added to a solution of sec-butyllithium (25 mmol)
and N,N,NЈ,NЈЈ,NЈЈ-pentamethyldiethylenetriamine (PMDTA;
5.2 mL, 4.3 g, 25 mmol) in tetrahydrofuran (35 mL) and cyclohex-
ane (15 mL) kept in a dry ice bath. After 2 h at Ϫ75 °C, the mixture
was poured onto an excess of freshly crushed pieces of solid carbon
dioxide. After evaporation of the volatiles, the residue was taken
up in water and washed with dichloromethane (2 ϫ 25 mL). The
aqueous phase was acidified to pH 1 with hydrochloric acid (1.0
(3-Fluorobenzyloxy)triisopropylsilane: From 3-fluorobenzyl alcohol
(5.4 mL, 6.3 g, 50 mmol); b.p. 139Ϫ141 °C/25 Torr; n2D0 ϭ 1.4845;
1
yield: 11.7 g (83%). H NMR: δ ϭ 7.28 (td, J ϭ 7.7, 5.2 Hz, 1 H),
7.1 (m, 2 H), 6.91 (t, J ϭ 7.6 Hz, 1 H), 4.83 (s, 2 H), 1.2 (m, 3 H), ) and extracted with diethyl ether (3 ϫ 25 mL). The combined
1.09 (d, J ϭ 6.5 Hz, 18 H) ppm. 13C NMR: δ ϭ 163.1 (d, J ϭ
organic layers were dried and the solvents evaporated. The product
245 Hz), 144.5 (d, J ϭ 7 Hz), 129.5 (d, J ϭ 8 Hz), 121.0 (s), 113.4 was purified by crystallization.
(d, J ϭ 22 Hz), 112.5 (d, J ϭ 22 Hz), 64.4 (s), 17.9 (s), 12.1 (s)
2-Fluoro-3-(hydroxymethyl)benzoic Acid (1): From 1-fluoro-2-
ppm. MS (c.i.): m/z (%) ϭ 300 (0) [Mϩ ϩ NH4], 283 (5) [Mϩ ϩ 1],
282 (2) [Mϩ], 256 (69), 239 (100). C16H27FOSi (282.47): calcd. C
68.03, H 9.63; found C 67.97, H 9.63.
[(methoxymethoxy)methyl]benzene (3.6 mL, 4.3 g, 25 mmol); col-
orless needles; m.p. 135Ϫ136 °C (from toluene); yield: 1.5 g (36%).
1H NMR (CD3COCD3): δ ϭ 7.85 (td, J ϭ 7.6, 1.9 Hz, 1 H), 7.78
(tm, J ϭ 7.3 Hz, 1 H), 7.29 (t, J ϭ 7.7 Hz, 1 H), 4.79 (s, 1 H) ppm.
13C NMR (CD3COCD3): δ ϭ 165.6 (d, J ϭ 2 Hz), 160.0 (d, J ϭ
(4-Fluorobenzyloxy)triisopropylsilane: From 4-fluorobenzyl alcohol
(5.4 mL, 6.3 g, 50 mmol); b.p. 134Ϫ135 °C/53 Torr; n2D0 ϭ 1.4853;
yield: 13.1 g (93%). 1H NMR: δ ϭ 7.31 (dd, J ϭ 8.5, 5.7 Hz, 2 H), 259 Hz), 134.1 (d, J ϭ 6 Hz), 131.7 (d, J ϭ 15 Hz), 131.5 (s), 124.6
7.01 (7, J ϭ 8.6 Hz, 2 H), 4.79 (s, 2 H), 1.2 (m, 3 H), 1.08 (d, J ϭ
(d, J ϭ 4 Hz), 119.6 (d, J ϭ 10 Hz), 58.2 (d, J ϭ 6 Hz) ppm. MS
6.6 Hz, 18 H) ppm. 13C NMR: δ ϭ 161.9 (d, J ϭ 244 Hz), 137.3 (c.i.): m/z (%) ϭ 188 (100) [Mϩ ϩ NH4], 170 (6) [Mϩ], 123 (20).
(s), 127.2 (d, J ϭ 8 Hz), 114.9 (d, J ϭ 22 Hz), 64.4 (s), 18.0 (s),
12.0 (s) ppm. MS (c.i.): m/z (%) ϭ 300 (49) [Mϩ ϩ NH4], 283 (48)
[Mϩ ϩ 1], 282 (10) [Mϩ], 256 (72), 190 (100). C16H27FOSi (282.47):
calcd. C 68.03, H 9.63; found C 67.96, H 9.47.
C8H7FO3 (170.14): calcd. C 56.48, H 4.15; found C 56.46, H 4.29.
2-Fluoro-4-(hydroxymethyl)benzoic Acid (3): From 1-fluoro-3-
[(methoxymethoxy)methyl]benzene (3.7 mL, 4.2 g, 25 mmol);
colorless needles (from toluene); m.p. 173.5Ϫ175 °C; yield: 0.6 g
(15%). 1H NMR (CD3COCD3): δ ϭ 7.93 (t, J ϭ 7.7 Hz, 1 H), 7.28
[2-(2-Fluorophenyl)ethoxy]triisopropylsilane: From 2-(2-fluorophen-
yl)ethanol (6.7 mL, 7.0 g, 50 mmol); b.p. 105Ϫ106 °C/0.6 Torr; (d, J ϭ 7.3 Hz, 1 H), 7.26 (d, J ϭ 12.7 Hz, 1 H), 4.74 (s, 2 H) ppm.
Eur. J. Org. Chem. 2002, 2508Ϫ2517 2513

E. Marzi, A. Spitaleri, F. Mongin, M. Schlosser
FULL PAPER
13C NMR (CD3COCD3): δ ϭ 165.3 (d, J ϭ 4 Hz), 163.0 (d, J ϭ δ ϭ 7.3 (m, 2 H), 6.9 (m, 1 H), 4.80 (s, 2 H), 1.54 (hept, J ϭ 7.2 Hz,
258 Hz), 151.7 (d, J ϭ 8.0 Hz), 133.0 (s), 124.4 (d, J ϭ 3 Hz), 117.9
(d, J ϭ 11 Hz), 115.0 (d, J ϭ 23 Hz), 63.4 (s) ppm. MS (c.i.): m/z
3 H), 1.13 (d, J ϭ 7.3 Hz, 18 H) ppm. 13C NMR: δ ϭ 179.6 (s),
167.8 (d, J ϭ 240 Hz), 149.3 (d, J ϭ 5 Hz), 131.1 (d, J ϭ 10 Hz),
(%) ϭ 188 (100) [Mϩ ϩ NH4], 170 (19) [Mϩ], 123 (17). C8H7FO3 123.8 (s), 114.4 (d, J ϭ 30 Hz), 110.4 (d, J ϭ 24 Hz), 65.2 (s), 19.1
(170.14): calcd. C 56.48, H 4.15; found C 56.41, H 4.09.
(s), 13.1 (s) ppm. MS (c.i.): m/z (%) ϭ 344 (11) [Mϩ ϩ NH4], 327
(14) [Mϩ ϩ 1], 301 (62), 300 (100).
2-Fluoro-5-(hydroxymethyl)benzoic Acid (4): From 1-fluoro-4-
[(methoxymethoxy)methyl]benzene (3.6 mL, 4.2 g, 25 mmol);
colorless needles (from hexanes); m.p. 136.5Ϫ138 °C; yield: 2.4 g
2-Fluoro-4-[(triisopropylsilyloxy)methyl]benzoic Acid (O-TIPS-pro-
tected acid 3): From (3-fluorobenzyloxy)triisopropylsilane (7.1 g,
25 mmol); colorless needles; m.p. 135Ϫ136 °C; yield: 2.5 g (31%;
raw material, according to gas chromatography: 51% and 29% of
O-TIPS protected acid 3 and hydrolysate of lactone 2, respectively).
1H NMR: δ ϭ 8.02 (t, J ϭ 8.1 Hz, 1 H), 7.21 (d, J ϭ 12.6 Hz, 1
H), 7.18 (d, J ϭ 7.8 Hz, 1 H), 4.88 (s, 2 H), 1.2 (m, 3 H), 1.09 (d,
J ϭ 6.6 Hz, 18 H) ppm. 13C NMR: δ ϭ 169.0 (s), 162.9 (d, J ϭ
262 Hz), 151.1 (d, J ϭ 8 Hz), 132.6 (s), 120.8 (d, J ϭ 3 Hz), 115.6
(d, J ϭ 10 Hz), 114.0 (d, J ϭ 23 Hz), 64.1 (s), 18.0 (s), 11.9 (s)
1
(56%). H NMR (CD3COCD3): δ ϭ 7.96 (dd, J ϭ 7.1, 2.4 Hz, 1
H), 7.6 (m, 1 H), 7.21 (dd, J ϭ 10.8, 8.5 Hz, 1 H), 4.68 (s, 2 H)
ppm. 13C NMR (CD3COCD3): δ ϭ 165.6 (d, J ϭ 2 Hz), 161.7 (d,
J ϭ 257 Hz), 139.4 (d, J ϭ 3 Hz), 133.6 (d, J ϭ 9 Hz), 131.0 (s),
119.4 (d, J ϭ 10 Hz), 117.4 (d, J ϭ 22 Hz), 63.5 (s) ppm. MS (c.i.):
m/z (%) ϭ 188 (100) [Mϩ ϩ NH4], 170 (7), [Mϩ], 123 (20).
C8H7FO3 (170.14): calcd. C 56.48, H 4.15; found C 56.25, H 4.58.
7-Fluoroisobenzofuran-1(3H)-one (2): The reaction was performed
with 1-fluoro-3-[(methoxymethoxy)methyl]benzene (3.7 mL, 4.2 g,
25 mmol) and sec-butyllithium (25 mmol) in the absence of any
additive and worked up as described above; colorless cubes (from
toluene); m.p. 164Ϫ166 °C (ref.[35] m.p. 166Ϫ167 °C); yield: 1.1 g
ppm. MS (c.i.): m/z (%) ϭ 344 (100) [Mϩ ϩ NH4], 327(28) [Mϩ
ϩ
1], 300 (52).
2-Fluoro-5-[(triisopropylsilyloxy)methyl]benzoic Acid (O-TIPS-pro-
tected acid 4): From (4-fluorobenzyloxy)triisopropylsilane (7.1 g,
1
1
(29%). H NMR: δ ϭ 7.69 (td, J ϭ 8.0, 4.5 Hz, 1 H), 7.28 (d, J ϭ
25 mmol); colorless prisms; m.p. 72Ϫ74 °C; yield: 6.9 g (84%). H
7.8 Hz, 1 H), 7.17 (t, J ϭ 7.9 Hz, 1 H), 5.33 (s, 2 H) ppm. 13C
NMR: δ ϭ 159.8 (d, J ϭ 264 Hz), 149.2 (s), 136.7 (d, J ϭ 8 Hz),
118.1 (d, J ϭ 4 Hz), 116.1 (d, J ϭ 19 Hz), 95.3 (s), 69.3 (s) ppm.
MS (c.i.): m/z (%) ϭ 170 (100) [Mϩ ϩ NH4], 153 (27), [Mϩ ϩ 1],
123 (51).
NMR: δ ϭ 8.00 (dd, J ϭ 7.1, 2.6 Hz, 1 H), 7.6 (m, 1 H), 7.15 (dd,
J ϭ 10.3, 8.2 Hz, 1 H), 4.89 (s, 2 H), 1.2 (m, 3 H), 1.09 (d, J ϭ
6.1 Hz, 18 H) ppm. 13C NMR: δ ϭ 170.0 (s), 161.6 (d, J ϭ 261 Hz),
137.6 (d, J ϭ 3 Hz), 132.9 (d. J ϭ 8 Hz), 129.8 (s), 117.1 (s), 116.9
(s), 63.9 (s), 17.9 (s), 12.1 (s) ppm. MS (c.i.): m/z (%) ϭ 344 (100)
[Mϩ ϩ NH4], 327(13) [Mϩ ϩ 1], 326 (6) [Mϩ].
Triisopropylsilyl (TIPS)-Protected Benzyl Alcohols: The reactions
were carried out as described above (see the preparation of acid 1)
unless stated otherwise. After evaporation of the volatiles, the alka-
line phase was treated with a 10% aqueous solution (20 mL) of
acetic acid and extracted with diethyl ether (3 ϫ 25 mL). The com-
bined organic layers were washed with brine (2 ϫ 25 mL), dried
and the solvents evaporated. Crystallization from a mixture of ethyl
acetate and hexanes or neat hexanes afforded the fluoro(triisoprop-
ylsilyloxymethyl)benzoic acids as colorless needles. Quantitative de-
protection was achieved by dissolving the product (15 mmol) in
dichloromethane (15 mL) and adding boron trifluoride diethyl
etherate (2.1 g, 1.9 mL, 15 mmol). After 1 h at 25 °C, methanol
(1 mL) was added and the solvents were evaporated to dryness. The
resulting benzoic acid or lactone was crystallized as specified above.
Unprotected Benzyl Alcohols: The reactions were carried out as de-
scribed for the preparation of acid 1 although with different
metalating reagents. The workup procedure was always the same
(as indicated above). The 2-fluorobenzyl alcohol failed to give any
useful result.
2-Fluoro-4-(hydroxymethyl)benzoic Acid (3): From 3-fluorobenzyl
alcohol (2.7 mL, 3.1 g, 25 mmol) with sec-butyllithium (50 mmol),
PMDTA (11 mL, 8.7 g, 50 mmol) and potassium tert-butoxide
(5.6 g, 50 mmol). According to gas chromatography (30 m, DB-
1701, 150 °C; 2 m, 5% SE-30 180 °C; internal standard: methyl
benzoate) the raw material isolated contained 12% of lactone 2
along with 71% of acid 3. The by-product was removed upon crys-
tallization from chloroform; yield: 2.0 g (47%).
2-Fluoro-3-[(triisopropylsilyloxy)methyl]benzoic Acid (O-TIPS pro-
tected acid 1): From (2-fluorobenzyloxy)triisopropylsilane (7.1 g,
2-Fluoro-5-(hydroxymethyl)benzoic Acid (4): From 4-fluorobenzyl
alcohol (2.7 mL, 3.1 g, 25 mmol) with butyllithium (75 mmol),
PMDTA (15.7 mL, 13.0 g, 75 mmol) and potassium tert-butoxide
(8.4 g, 75 mmol); yield: 2.1 g (49%).
1
25 mmol); colorless needles; m.p. 81Ϫ83 °C; yield: 5.0 g (61%). H
NMR: δ ϭ 7.91 (t, J ϭ 7.3 Hz, 1 H), 7.85 (t, J ϭ 7.1 Hz, 1 H), 7.2
(m, 1 H), 4.93 (s, 2 H), 1.2 (m, 3 H), 1.10 (d, J ϭ 7 Hz, 18 H) ppm.
13C NMR: δ ϭ 169.1 (s), 159.2 (d, J ϭ 261 Hz), 133.4 (d, J ϭ 6
Hz), 130.9 (s), 130.6 (d, J ϭ 14 Hz), 123.9 (d, J ϭ 4 Hz), 116.7 (d,
J ϭ 10 Hz), 58.8 (d, J ϭ 7 Hz), 18.0 (s), 11.9 (s) ppm. MS (c.i.):
m/z (%) ϭ 344 (1) [Mϩ ϩ NH4], 327 (12) [Mϩ ϩ 1], 326 (5) [Mϩ],
283 (100), 133 (76).
4-(Trifluoromethyl)isobenzofuran-1(3H)-one (8): From 2-(trifluoro-
methyl)benzyl alcohol (3.3 mL, 4.4 g, 25 mmol) in tetrahydrofuran
(50 mL) and butyllithium (75 mmol) in hexanes (50 mL); for 2 h at
ϩ25 °C; colorless prisms; m.p. 79Ϫ81 °C (after sublimation); yield:
1.2 g (24%). 1H NMR: δ ϭ 8.29 (d, J ϭ 7.8 Hz, 1 H), 8.09 (d, J ϭ
7.8 Hz, 1 H), 7.87 (t, J ϭ 7.8 Hz, 1 H), 5.58 (s, 2 H) ppm. 13C
NMR: δ ϭ 169.4 (s), 143.7 (s), 130.9 (q, J ϭ 4 Hz), 129.9 (s), 129.4
(s), 127.4 (s), 125.6 (q, J ϭ 34 Hz), 123.3 (q, J ϭ 272 Hz), 69.6 (s)
2-Fluoro-6-[(triisopropylsilyloxy)methylbenzoic Acid (O-TIPS-pro-
tected hydrolysis product of lactone 2): At Ϫ75 °C, (3-fluoro-
benzyloxy)triisopropylsilane (7.1 g, 25 mmol) was treated for 2 h
with sec-butyllithium (25 mmol) and PMDTA (5.2 mL, 4.3 g,
25 mmol) in the presence of potassium tert-butoxide (2.8 g,
25 mmol). According to gas chromatography (30 m, DB-1701, 180
°C; 2 m, 5% SE-30 200 °C; internal standard: methyl benzoate)
the raw material (yield: 85%) isolated after the usual workup (see
preparation of acid 1) contained small amounts of the TIPS-pro-
ppm. MS (c.i.): m/z (%) ϭ 220 (100) [Mϩ ϩ NH4], 203 (5) [Mϩ
ϩ
1], 202 (1) [Mϩ], 173 (40), 145 (63). C9H5F3O2 (202.13): calcd. C
53.48, H 2.49; found C 53.69, H 2.27.
3-(Hydroxymethyl)-2-(trifluoromethyl)benzoic Acid (9): From 2-(tri-
fluoromethyl)benzyl alcohol (3.3 mL, 4.4 g, 25 mmol) with butyl-
lithium (75 mmol) PMDTA (15.7 mL, 13.0 g, 75 mmol) and potas-
tected acid 3. This isomeric contamination was lost completely
1
upon crystallization; m.p. 65Ϫ67 °C; yield: 4.2 g (51%). H NMR: sium tert-butoxide (8.4 g, 75 mmol); colorless needles; m.p.
2514
Eur. J. Org. Chem. 2002, 2508Ϫ2517

Substrates for Metal-Mediated Site-Selective Functionalization
190Ϫ192 °C (from chloroform); yield: 1.8 g (33%). 1H NMR [Mϩ ϩ 1], 202 (8) [Mϩ], 173 (100), 145 (28). C9H5F3O2 (202.13):
FULL PAPER
(D3CCOCD3): δ ϭ 8.01 (d, J ϭ 7.9 Hz, 1 H), 7.73 (d, J ϭ 7.6 Hz,
1 H), 7.54 (d, J ϭ 7.6 Hz, 1 H), 4.89 (s, 2 H) ppm. 13C NMR
(D3CCOCD3): δ ϭ 168.7 (s), 142.3 (s), 133.8 (m), 131.9 (s), 129.4
(s), 126.6 (s), 124.3 (q, J ϭ 275 Hz), 60.1 (s) ppm. MS (c.i.): m/z
(%) ϭ 238 (100) [Mϩ ϩ NH4], 220 (8) [Mϩ], 134 (16). C9H9F3O3
(220.15): calcd. C 49.10, H 3.20; found C 49.07, H 3.00.
calcd. C 53.48, H 2.49, found C 53.42, H 2.44.
5-(Hydroxymethyl)-2-(trifluoromethyl)benzoic Acid (14): From 4-
(trifluoromethyl)benzyl alcohol (3.4 mL, 4.4 g, 25 mmol) as de-
scribed above for compound 12; colorless needles; m.p. 143Ϫ145
1
°C (from chloroform); yield: 2.0 g (36%). H NMR (CD3COCD3):
δ ϭ 7.89 (s, 1 H), 7.81 (d, J ϭ 8.4 Hz, 1 H), 7.71 (dm, J ϭ 8.4 Hz,
1 H), 4.81 (s, 2 H) ppm. 13C NMR (CD3COCD3): δ ϭ 167.0 (s),
147.4 (s), 131.7 (s), 128.6 (s), 127.7 (s), 126.6 (s), 126.5 (q, J ϭ 5
Hz, 2 C), 123.8 (q, J ϭ 272 Hz), 62.5 (s) ppm. MS (c.i.): m/z (%) ϭ
238 (100) [Mϩ ϩ NH4], 220 (40) [Mϩ], 151 (16). C9H9F3O3
(220.15): calcd. C 49.10, H 3.20; found C 49.04, H 3.08.
5-(Trifluoromethyl)isobenzofuran-1(3H)-one (10): From 3-(tri-
fluoromethyl)benzyl alcohol (3.4 mL, 4.4 g, 25 mmol) in tetrahy-
drofuran (60 mL) with tert-butyllithium (75 mmol) in pentanes
(65 mL). As revealed by gas chromatography (2 m, C-20M 180 °C;
2 m, 5% SE-30, 150 °C; internal standard: methyl benzoate). The
amount of 5-(trifluoromethyl)-2-benzofuran-1(3H)-one (10) and of
7-(trifluoromethyl)-2-benzofuran-1(3H)-one (11) formed was deter-
mined by comparison of their peak areas with that of the internal
standard. The yields found were 26% and 21% for 10 and 11, re-
spectively. The rest of the solution after evaporation of the solvents,
three crystallizations of the crude material from hexanes, and sub-
limation, gave colorless platelets; m.p. 65Ϫ67 °C (ref.[36] no physical
3. Reactions of Phenethyl Alcohols and Derivatives Thereof
Methoxymethoxy (MOM)-Protected 2-(Fluorophenyl)ethanols: The
acetal (25 mmol) was again treated with sec-butyllithium (25 mmol)
and PMDTA (5.4 mL, 4.3 g, 25 mmol) in tetrahydrofuran (35 mL)
and cyclohexane (16 mL) at Ϫ75 °C, but for 6 h. The quenching
with dry ice and the workup followed exactly the procedure estab-
lished for MOM-protected alcohols (see the first paragraph of Sec-
tion 2). The product was purified by recrystallization from hexanes
and sublimation.
1
constants or analysis reported); yield: 0.6 g (12%). H NMR: δ ϭ
8.21 (d, J ϭ 8.2 Hz, 1 H), 7.97 (d, J ϭ 10.4 Hz, 1 H), 7.96 (s, 1 H),
5.51 (s, 2 H) ppm. 13C NMR: δ ϭ 169.6 (s), 146.8 (s), 136.1 (q,
J ϭ 33 Hz), 129.0 (s), 126.6 (s), 126.5 (q, J ϭ 3 Hz), 123.4 (q, J ϭ
273 Hz), 119.7 (q, J ϭ 3 Hz), 69.6 (s) ppm. MS (c.i.): m/z (%) ϭ
220 (0) [Mϩ ϩ NH4], 203 (28) [Mϩ ϩ 1], 202 (6) [Mϩ], 173 (100),
145 (27), 125 (6). C9H5F3O2 (202.13): calcd. C 53.48, H 2.49; found
C 53.61, H 2.49.
2-Fluoro-3-(2-hydroxyethyl)benzoic Acid (5): From 1-fluoro-2-[2-
(methoxymethoxy)ethyl]benzene (4.0 mL, 4.6 g, 25 mmol); white
1
needles; m.p. 116Ϫ117 °C; yield: 1.6 g (35%). H NMR: δ ϭ 7.94
(t, J ϭ 6.4 Hz, 1 H), 7.58 (t, J ϭ 6.4 Hz, 1 H), 7.25 (t, J ϭ 7.9 Hz,
1 H), 3.89 (t, J ϭ 6.7 Hz, 2 H), 2.99 (t, J ϭ 6.6 Hz, 2 H) ppm. 13C
NMR: δ ϭ 166.4 (s), 160.4 (d, J ϭ 258 Hz), 135.7 (d, J ϭ 6 Hz),
130.4 (s), 127.4 (d, J ϭ 17 Hz), 123.4 (d, J ϭ 4 Hz), 119.2 (d, J ϭ
10 Hz), 61.6 (s), 32.5 (s) ppm. MS (c.i.): m/z (%) ϭ 202 (100) [Mϩ
ϩ NH4], 185 (6) [Mϩ ϩ 1], 164 (85), 109 (50). C9H9FO3 (184.17):
calcd. C 58.70, H 4.93; found C 58.78, H 4.77.
7-(Trifluoromethyl)-2-benzofuran-1(3H)-one (11): From 3-(trifluoro-
methyl)benzyl alcohol (3.4 mL, 4.4 g, 25 mmol) with potassium
tert-butoxide (5.6 g, 50 mmol) and butyllithium (from which the
commercial solvent was stripped off, 50 mmol) in tetrahydrofuran
(50 mL) at 0 °C for 2 h. Colorless needles, m.p. 112Ϫ114 °C (from
1
hexanes); yield: 2.4 g (47%). H NMR: δ ϭ 7.99 (d, J ϭ 7.3 Hz, 1
H), 7.96 (t, J ϭ 7.3 Hz, 1 H), 7.86 (d, J ϭ 7.6 Hz, 1 H), 5.47 (s, 2
H) ppm. 13C NMR: δ ϭ 166.9 (s), 148.9 (s), 134.0 (s), 128.8 (q,
J ϭ 36 Hz), 126.7 (q, J ϭ 5 Hz), 125.9 (s), 122.2 (q, J ϭ 273 Hz),
2-Fluoro-4-(2-hydroxyethyl)benzoic Acid (6): From 1-fluoro-3-2-
[(methoxymethoxy)ethyl]benzene (4.0 mL, 4.6 g, 25 mmol); color-
1
less platelets; m.p. 122Ϫ123 °C; yield: 1.6 g (39%). H NMR: δ ϭ
123.1 (s), 68.9 (s) ppm. MS (c.i.): m/z (%) ϭ 220 (100) [Mϩ
ϩ
7.78 (t, J ϭ 7.9 Hz, 1 H), 7.2 (m, 2 H), 3.64 (t, J ϭ 6.7 Hz, 2 H),
2.79 (t, J ϭ 6.8 Hz, 2 H) ppm. 13C NMR: δ ϭ 165.4 (d, J ϭ 3 Hz),
161.5 (d, J ϭ 256 Hz), 148.3 (d, J ϭ 8 Hz), 132.0 (s), 125.4 (d, J ϭ
3 Hz), 117.5 (d, J ϭ 22 Hz), 117.1 (d, J ϭ 10 Hz), 61.6 (s), 39.9
(s) ppm. MS (c.i.): m/z (%) ϭ 202 (1) [Mϩ ϩ NH4], 185 (15), [Mϩ
ϩ 1], 184 (48), [Mϩ], 154 (79), [Mϩ Ϫ COOH], 109 (100). C9H9FO3
(184.17): calcd. C 58.70, H 4.93; found C 58.67, H 4.76.
NH4], 203 (31) [Mϩ ϩ 1], 202 (10) [Mϩ], 173 (54). C9H5F3O2
(202.13): calcd. C 53.48, H 2.49; found C 53.62; H 2.57.
4-(Hydroxymethyl)-2-(trifluoromethyl)benzoic Acid (12): From 3-
(trifluoromethyl)benzyl alcohol (3.4 mL, 4.4 g, 25 mmol) with sec-
butyllithium (75 mmol), N,N,NЈ,NЈЈ,NЈЈ-pentamethyldiethylenetri-
amine (15.7 mL, 13.0 g, 75 mmol) and potassium tert-butoxide
(8.4 g, 75 mmol) in tetrahydrofuran (70 mL) and cyclohexane
2-Fluoro-5-(2-hydroxyethyl)benzoic Acid (7): From 1-fluoro-4-[2-
(55 mL) colorless needles were obtained; m.p. 129Ϫ131 °C; yield:
(methoxymethoxy)ethyl]benzene (4.2 mL, 4.6 g, 25 mmol); color-
1
1
1.4 g (25%). H NMR (CD3COCD3): δ 7.91 (d, J ϭ 7.9 Hz, 1 H), less needles; m.p. 133Ϫ134.5 °C; yield: 3.2 g (70%). H NMR: δ ϭ
7.86 (s, 1 H), 7.74 (dd, J ϭ 8.1, 0.7 Hz, 1 H), 4.91 (s, 2 H) ppm.
7.83 (dd, J ϭ 7.1, 2.2 Hz, 1 H), 7.39 (ddd, J ϭ 7.1, 4.6, 2.2 Hz, 1
13C NMR (CD3COCD3): δ ϭ 166.8 (s), 146.6 (s), 130.4 (s), 130.0 H), 7.06 (td, J ϭ 10.3, 8.2 Hz, 1 H), 3.83 (t, J ϭ 6.6 Hz, 2 H), 2.86
(s), 129.6 (s), 127.9 (q, J ϭ 32 Hz), 124.2 (q, J ϭ 5 Hz), 123.7 (q, (t, J ϭ 6.6 Hz, 2 H) ppm. 13C NMR: δ ϭ 166.2 (s), 160.7 (d, J ϭ
J ϭ 273 Hz), 62.6 (s) ppm. MS (c.i.): m/z (%) ϭ 238 (100) [Mϩ
ϩ
257 Hz), 135.1 (d, J ϭ 4 Hz), 134.8 (d, J ϭ 8 Hz), 132.5 (s), 118.9
NH4], 220 (11) [Mϩ], 151 (45), 127 (43). C9H9F3O3 (220.15): calcd. (d, J ϭ 10 Hz), 116.6 (d, J ϭ 22 Hz), 62.8 (s), 38.1 (s) ppm. MS
C 49.10, H 3.20; found C 48.81, H 3.13.
(c.i.): m/z (%) ϭ 202 (0) [Mϩ ϩ NH4], 184 (11) [Mϩ], 154 (100)
[Mϩ Ϫ COOH], 133 (31), 109 (73). C9H9FO3 (184.17): calcd. C
58.70, H 4.93; found C 58.75, H 5.13.
6-(Trifluoromethyl)isobenzofuran-1(3H)-one (13): From 4-(tri-
fluoromethyl)benzyl alcohol (3.4 mL, 4.4 g, 25 mmol) in tetrahy-
drofuran (50 mL) and butyllithium (75 mmol) in hexanes; for 2 h Triisopropylsilyl(TIPS)-Protected 2-(Fluorophenyl)ethanols: The re-
at ϩ25 °C; white powder; m.p. 88Ϫ90 °C (after sublimation); yield:
action, workup and deprotection conditions were identical to those
specified above for TIPS-protected benzyl alcohols as the substrates
1
1.5 g (29%). H NMR: δ ϭ 8.36 (s, 1 H), 8.10 (dd, J ϭ 8.1, 1 Hz,
1 H), 7.82 (d, J ϭ 8.3 Hz, 1 H), 5.51 (s, 2 H) ppm. 13C NMR: δ ϭ (PMDTA-activated sec-butyllithium in a 2:1 mixture of tetrahy-
169.5 (s), 149.7 (s), 132.2 (q, J ϭ 33 Hz), 130.9 (q, J ϭ 2 Hz), 126.7
drofuran and cyclohexane for 2 h at Ϫ75 °C, carboxylation, extrac-
(s), 123.2 (q, J ϭ 3 Hz), 123.1 (q, J ϭ 3 Hz), 123.4 (q, J ϭ 272 Hz), tion, treatment with boron trifluoride and recrystallisation from
69.6 (s) ppm. MS (c.i.): m/z (%) ϭ 220 (37) [Mϩ ϩ NH4], 203 (37) ethyl acetate and hexanes).
Eur. J. Org. Chem. 2002, 2508Ϫ2517
2515

E. Marzi, A. Spitaleri, F. Mongin, M. Schlosser
FULL PAPER
2-Fluoro-3-[(triisopropylsilyloxy)ethyl]benzoic Acid (O-TIPS pro-
tected acid 5): From [2-(2-fluorophenyl)ethoxy]triisopropylsilane
°C; internal standard: methyl benzoate) of the methyl esters (after
exhaustive reaction with diazomethane), the principal product 17
(7.4 g, 25 mmol); colorless prisms; m.p. 75Ϫ76 °C; yield: 5.7 g (64%) was accompanied by small amounts of the isomer 16 (5%)
(67%). 1H NMR: δ ϭ 7.88 (td, J ϭ 7.8, 1.9 Hz, 1 H), 7.52 (td, J ϭ
which was identified by comparison of its retention times with
7.7, 2.1 Hz, 1 H), 7.15 (t, J ϭ 7 Hz, 1 H), 3.91 (t, J ϭ 6.5 Hz, 2 those of an authentic sample (see below). Colorless stars; m.p.
H), 2.94 (td, J ϭ 7.1, 1.3 Hz, 2 H), 1.1 (m, 3 H), 1.00 (d, J ϭ 116Ϫ118 °C (from ethyl acetate and hexanes); yield: 2.1 g (36%).
5.6 Hz, 18 H) ppm. 13C NMR: δ ϭ 169.9 (s), 160.9 (d, J ϭ 261 Hz),
1H NMR (D3CCOCD3): δ ϭ 7.83 (d, J ϭ 8.1 Hz, 1 H), 7.75 (s, 1
137.6 (d, J ϭ 6 Hz), 130.7 (s), 128.0 (d, J ϭ 17 Hz), 123.4 (d, J ϭ H), 7.65 (d, J ϭ 8.1 Hz, 1 H), 3.84 (t, J ϭ 6.3 Hz, 2 H), 2.96 (t,
4 Hz), 117.3 (d, J ϭ 11 Hz), 62.8 (s), 32.7 (s), 17.9 (s), 11.9 (s) J ϭ 6.3 Hz, 2 H) ppm. 13C NMR (D3CCOCD3): δ ϭ 166.9 (s),
ppm. MS (c.i.): m/z (%) ϭ 358 (89) [Mϩ ϩ NH4], 342 (55) [Mϩ
ϩ
144.2 (s), 132.7 (s), 130.3 (s), 129.3 (s), 126.6 (s), 127.8 (q, J ϭ 32
Hz), 127.3 (q, J ϭ 5 Hz), 123.7 (q, J ϭ 273 Hz), 62.0 (s), 38.6 (s)
ppm. MS (c.i.): m/z (%) ϭ 253 (100), 252 (90) [Mϩ ϩ NH4], 234
(3) [Mϩ], 186 (23). C9H9F3O3 (234.17): calcd. C 53.48, H 2.49;
found C 53.69, H 2.27.
1], 341 (100) [Mϩ].
2-Fluoro-4-[(triisopropylsilyloxy)ethyl]benzoic Acid (O-TIPS pro-
tected acid 6): From [2-(3-fluorophenyl)ethoxy]triisopropylsilane
(7.4 g, 25 mmol); colorless platelets; m.p. 102Ϫ103 °C; yield: 6.0 g
1
(71%). H NMR: δ ϭ 7.94 (t, J ϭ 7.8 Hz, 1 H), 7.11 (dd, J ϭ 9.4,
5-(2-Hydroxyethyl)-2-(trifluoromethyl)benzoic Acid (18): From 2-[4-
(trifluoromethyl)phenyl]ethanol (3.9 mL, 4.7 g, 25 mmol) with bu-
tyllithium (75 mmol), PMDTA (15.7 mL, 13.0 g, 75 mmol) and
potassium tert-butoxide (8.4 g, 75 mmol). Colorless needles; m.p.
99Ϫ101 °C (from chloroform); yield: 0.78 g (13%). 1H NMR
(D3CCOCD3): δ ϭ 7.80 (s, 1 H), 7.76 (d, J ϭ 7.8 Hz, 1 H), 7.66
(d, J ϭ 7.9 Hz, 1 H), 3.85 (t, J ϭ 5.9 Hz, 2 H), 2.96 (t, J ϭ 5.9 Hz,
2 H) ppm. 13C NMR (D3CCOCD3): δ ϭ 167.2 (s), 144.9 (s), 131.8
(s, 2 C), 130.8 (s), 126.4 (q, J ϭ 6 Hz), 125.6 (q, J ϭ 32 Hz), 121.2
(q, J ϭ 272 Hz), 61.9 (s), 38.4 (s) ppm. MS (c.i.): m/z (%) ϭ 252
(33) [Mϩ ϩ NH4], 217 (19), 186 (44), 164 (100). C9H9F3O3
(234.17): calcd. C 53.48, H 2.49; found C 53.69, H 2.27.
1.6 Hz, 1 H), 7.07 (d, J ϭ 12.1 Hz, 1 H), 3.92 (t, J ϭ 6.1 Hz, 2 H),
2.88 (t, J ϭ 6.5 Hz, 2 H), 1.1 (m, 3 H), 1.01 (d, J ϭ 5.8 Hz, 18 H)
ppm. 13C NMR: δ ϭ 169.1 (s), 162.6 (d, J ϭ 262 Hz), 149.0 (d,
J ϭ 9 Hz), 132.4 (s), 125.1 (d, J ϭ 3 Hz), 117.6 (d, J ϭ 22 Hz),
115.1 (d, J ϭ 10 Hz), 63.6 (s), 39.4 (s), 17.9 (s), 11.9 (s) ppm. MS
(c.i.): m/z (%) ϭ 358 (39) [Mϩ ϩ NH4], 341 (36) [Mϩ], 297 (100).
2-Fluoro-5-[(triisopropylsilyloxy)ethyl]benzoic Acid (O-TIPS pro-
tected acid 7): From From [2-(4-fluorophenyl)ethoxy]triisopropyl-
silane (7.4 g, 25 mmol); colorless needles; m.p. 57Ϫ59 °C; yield:
1
6.6 g (77%). H NMR: δ ϭ 7.89 (dd, J ϭ 7.3, 2.4 Hz, 1 H), 7.45
(ddd, J ϭ 7.1, 4.7, 2.3 Hz, 1 H), 7.07 (dd, J ϭ 10.5, 8.1 Hz, 1 H),
3.89 (t, J ϭ 6.6 Hz, 2 H), 2.85 (t, J ϭ 6.4 Hz, 2 H), 1.0 (m, 3 H),
1.01 (d, J ϭ 5.1 Hz, 18 H) ppm. 13C NMR: δ ϭ 169.5 (s), 161.3
(d, J ϭ 261 Hz), 136.5 (d, J ϭ 9 Hz), 135.6 (d, J ϭ 5 Hz), 133.1
(s), 116.9 (d, J ϭ 10 Hz), 116.7 (d, J ϭ 22 Hz), 64.1 (s), 38.6 (s),
17.9 (s), 11.9 (s) ppm. MS (c.i.): m/z (%) ϭ 358 (100) [Mϩ ϩ NH4],
341 (46) [Mϩ], 314 (24).
3-(2-Hydroxyethyl)-5-(trifluoromethyl)benzoic Acid (16): 2,2,6,6-
Tetramethylpiperidine (25 mL, 21 g, 0.15 mol) and 3-bromobenzo-
trifluoride (21 mL, 34 g, 0.15 mol) were added consecutively to a
solution of butyllithium in tetrahydrofuran (0.20 L) and hexanes
(90 mL) cooled to Ϫ100 °C. After 2 h at Ϫ100 °C, the mixture was
treated with iodine (38 g, 0.15 mol) in tetrahydrofuran (50 mL).
Distillation afforded 2-bromo-1-iodo-4-(trifluoromethyl)benzene,
Unprotected 2-(Fluorophenyl)ethanols: 2,2,6,6-Tetramethylpiperid-
ine (8.4 mL, 7.1 g, 50 mmol) and the alcohol (25 mmol) were added which eventually crystallized as colorless needles; m.p. 31Ϫ33 °C;
1
consecutively to a solution of butyllithium (50 mmol) in tetrahy-
drofuran (40 mL) and hexanes (30 mL) cooled in a dry ice/meth-
b.p. 80Ϫ82 °C/10 Torr; yield: 43.1 g (82%). H NMR: δ ϭ 8.00 (d,
J ϭ 8.1 Hz, 1 H), 7.86 (d, J ϭ 1.4 Hz, 1 H), 7.24 (dd, J ϭ 8.2,
anol bath and kept at Ϫ75 °C for 6 h. The carboxylation, isolation 1.5 Hz, 1 H) ppm. 13C NMR: δ ϭ 140.8 (s), 144.9 (s), 132.0 (q,
and purification of the final products were accomplished as de-
scribed at the beginning of Section 2.
J ϭ 33 Hz), 130.5 (s), 129.4 (q, J ϭ 4 Hz), 129.4 (q, J ϭ 4 Hz),
124.9 (q, J ϭ 3 Hz), 123.0 (q, J ϭ 273 Hz), 106.0 (s) ppm. MS
(c.i.): m/z (%) ϭ 370 (0) [Mϩ ϩ NH4], 368 (0) [Mϩ ϩ NH4], 353
(14) [Mϩ ϩ 1], 352 (93) [Mϩ], 351 (12) [Mϩ ϩ 1], 350 (100) [Mϩ],
144 (36). C7H3BrF3I (350.91): calcd. C 23.96, H 0.86; found C
24.11, H 1.11. Diisopropylamine (14 mL, 10 g, 0.10 mol) and 2-
bromo-1-iodo-4-(trifluoromethyl)benzene (35 g, 0.10 mol) were ad-
ded consecutively to a solution of butyllithium in tetrahydrofuran
(0.14 L) and hexanes (60 mL) cooled to Ϫ100 °C and kept at that
temperature for 2 h. After neutralization and distillation, 1-bromo-
3-iodo-5-(trifluoromethyl)benzene was collected as a colorless li-
quid; m.p. Ϫ20 to Ϫ15 °C; b.p. 64Ϫ66 °C/2 Torr; n2D0 ϭ 1.5584;
yield: 23.2 g (66%). 1H NMR: δ ϭ 8.04 (s, 1 H), 7.88 (s, 1 H), 7.33
(s, 1 H) ppm. 13C NMR: δ ϭ 143.2 (s), 133.6 (q, J ϭ 34 Hz), 133.0
(q, J ϭ 4 Hz), 128.0 (q, J ϭ 4 Hz), 123.3 (s), 122.0 (q, J ϭ 274 Hz),
94.3 (s) ppm. MS (c.i.): m/z (%) ϭ 370 (5) [Mϩ ϩ NH4], 368 (30)
[Mϩ ϩ NH4], 352 (69) [Mϩ], 350 (69) [Mϩ], 288 (57), 287 (52).
C7H3BrF3I (350.91): calcd. C 23.96, H 0.86; found C 23.83, H 0.96.
At Ϫ75 °C, 1-bromo-3-iodo-5-(trifluoromethyl)benzene (18 g,
50 mmol) in precooled tetrahydrofuran (70 mL) was added to bu-
tyllithium (50 mmol) in hexanes (30 mL). Immediately afterwards,
the mixture was poured onto an excess of freshly crushed dry ice.
2-Fluoro-3-(2-hydroxyethyl)benzoic Acid (5): From 2-(2-fluorophen-
yl)ethanol (3.4 mL, 3.5 g, 25 mmol); yield: 1.6 g (31%).
2-Fluoro-4-(2-hydroxyethyl)benzoic Acid (6): From 2-(3-fluorophen-
yl)ethanol (3.1 mL, 3.5 g, 25 mmol); yield: 2.8 g (61%).
2-Fluoro-5-(2-hydroxyethyl)benzoic Acid (7): From 2-(4-fluorophen-
yl)ethanol (3.1 mL, 3.5 g, 25 mmol); yield 2.0 (43%).
Unprotected 2-[Tri(fluoromethyl)phenyl]ethanols: The metalation
was brought about by butyllithium or sec-butyllithium simultane-
ously activated by PMDTA and potassium tert-butoxide in tetrahy-
drofuran (90 mL) and cyclohexane (35 mL) or hexanes (35 mL) at
Ϫ75 °C for 2 h. Carboxylation and isolation followed the standard
procedure (see at the beginning of Section 2). The ortho isomer
gave a mixture of three unidentified products formed in roughly
equal amounts and in a total yield of 46% (by gas chromato-
graphy).
4-(2-Hydroxyethyl)-2-(trifluoromethyl)benzoic Acid (17): From 2-[3-
(trifluoromethyl)phenyl]ethanol (3.8 mL, 4.7 g, 25 mmol); with sec-
butyllithium (50 mmol), PMDTA (10.4 mL, 8.7 g, 50 mmol) and Extraction into the alkaline phase, acidification, extraction with
potassium tert-butoxide (5.6 g, 50 mmol). According to gas chro-
matography (30 m, DB-1701, 150 °C isotherm; 2 m, 5% SE-30, 200
diethyl ether and crystallization afforded 3-bromo-5-(trifluorome-
thyl)benzoic acid as colorless platelets; m.p. 133Ϫ135 °C (from hex-
2516
Eur. J. Org. Chem. 2002, 2508Ϫ2517

Substrates for Metal-Mediated Site-Selective Functionalization
FULL PAPER
S. Takagishi, M. Schlosser, Synlett 1991, 119Ϫ121.
M. Schlosser, H. Geneste, Chem. Eur. J. 1998, 4, 1969Ϫ1973.
H. O. House, T. M. Bare, W. E. Hanners, J. Org. Chem. 1969,
34, 2209Ϫ2217.
[11]
[12]
[13]
1
anes); yield: 10.9 g (81%). H NMR: δ ϭ 8.43 (s, 1 H), 8.30 (s, 1
H), 8.01 (s, 1 H) ppm. 13C NMR: δ ϭ 169.6 (s), 136.4 (s), 133.6
(q, J ϭ 4 Hz), 132.6 (q, J ϭ 34 Hz), 131.8 (s), 125.8 (q, J ϭ 4 Hz),
123.2 (s), 122.6 (q, J ϭ 273 Hz) ppm. MS (c.i.): m/z (%) ϭ 288 (16)
[Mϩ ϩ NH4], 286 (17) [Mϩ ϩ NH4], 270 (42) [Mϩ], 268 (43) [Mϩ],
253 (91), 251 (100). C8H4BrF3O2 (269.17): calcd. C 35.72, H 1.50;
found C 35.44, H 1.60. 3-Bromo-5-(trifluoromethyl)benzoic acid
(6.7 g, 25 mmol) was introduced slowly, in the course of 45 min,
[14]
[15]
D. W. Slocum, W. Ackermann, J. Chem. Soc., Chem. Commun.
1974, 968Ϫ969.
M. Uemura, S. Tokuyama, T. Sakan, Chem. Lett. 1975,
1195Ϫ1198; Chem. Abstr. 1976, 84, 16906v.
N. Meyer, D. Seebach, Chem. Ber. 1980, 113, 1304Ϫ1319.
M. Schlosser, G. Simig, H. Geneste, Tetrahedron 1998, 54,
9023Ϫ9032.
[16]
[17]
and with vigorous stirring into
a solution of butyllithium
(50 mmol) in tetrahydrofuran (20 mL) and hexanes (30 mL). After
the addition of oxirane (1.2 mL, 1.1 g, 25 mmol), the temperature
was allowed to rise slowly to ϩ25 °C. The mixture was then treated
with 2.0  ethereal hydrogen chloride before being evaporated to
dryness. Crystallization from chloroform gave the acid 16 as color-
less needles; m.p. 163Ϫ164 °C; yield: 0.61 g (9%). 1H NMR
(D3CCOCD3): δ ϭ 8.21 (s, 1 H), 8.18 (s, 1 H), 7.88 (s, 1 H), 3.85
(t, J ϭ 6.2 Hz, 2 H), 3.05 (t, J ϭ 6.2 Hz, 2 H) ppm. 13C NMR
(D3CCOCD3): δ ϭ 166.5 (s), 143.4 (s), 134.9 (s), 132.4 (s), 130.9
(q, J ϭ 4 Hz), 131.1 (q, J ϭ 32 Hz), 124.6 (q, J ϭ 4 Hz), 125.0 (q,
J ϭ 272 Hz), 63.0 (s), 39.4 (s) ppm. MS (c.i.): m/z (%) ϭ 252 (100)
[Mϩ ϩ NH4], 234 (13) [Mϩ], 204 (26), 159 (23). C10H9F3O3
(269.17): calcd. C 51.15, H 3.77; found C 51.29, H 3.87.
[18]
G. Katsoulos, S. Takagishi, M. Schlosser, Synlett 1991,
731Ϫ732.
[19]
[20]
M. Schlosser, Eur. J. Org. Chem. 2001, 3975Ϫ 3984.
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Acknowledgments
This work was financially supported by the Schweizerische Na-
tionalfonds zur Förderung der wissenschaftlichen Forschung, Bern
(grant 20-55Ј303-98) and the Bundesamt für Bildung und Wissen-
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Received February 6, 2002
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