Generation of allylic and benzylic organolithium compounds by fluorine-lithium exchange: Reaction with electrophiles

Article abstract of DOI:10.1016/S0022-328X(00)00770-1

The application of the naphthalene-catalysed lithiation methodology to allylic and benzylic fluorides 1 led to the corresponding allylic and benzylic organolithium reagents, which, in the presence of different electrophiles (Barbier-type reaction conditions), afforded the expected products 2 in moderate yields. The procedure was useful for the transformation of primary, secondary and tertiary benzylic fluorides into the corresponding lithium derivatives. When a two-step lithiation process was used (treatment of fluoride 1 with lithium and a catalytic amount of naphthalene, followed by addition of the electrophilic reagent), only Wurtz-type coupling products were formed.

Full text of DOI:10.1016/S0022-328X(00)00770-1

Journal of Organometallic Chemistry 624 (2001) 53–57
www.elsevier.nl/locate/jorganchem
Generation of allylic and benzylic organolithium compounds by
fluorine–lithium exchange: reaction with electrophiles
David Guijarro, Miguel Yus *
Departamento de Qu´ımica Orga´nica, Facultad de Ciencias, Uni6ersidad de Alicante, Apdo. 99, 03080 Alicante, Spain
Received 10 July 2000; accepted 10 October 2000
This paper is dedicated to Professor Jean F. Normant on the occasion of his 65th birthday
Abstract
The application of the naphthalene-catalysed lithiation methodology to allylic and benzylic fluorides 1 led to the corresponding
allylic and benzylic organolithium reagents, which, in the presence of different electrophiles (Barbier-type reaction conditions),
afforded the expected products 2 in moderate yields. The procedure was useful for the transformation of primary, secondary and
tertiary benzylic fluorides into the corresponding lithium derivatives. When a two-step lithiation process was used (treatment of
fluoride 1 with lithium and a catalytic amount of naphthalene, followed by addition of the electrophilic reagent), only Wurtz-type
coupling products were formed. © 2001 Elsevier Science B.V. All rights reserved.
Keywords: Allyllithium; Benzyllithium; Fluoro–lithium exchange; Lithiation
1. Introduction
lithium compounds [16] by chlorine–lithium exchange
or by ring opening of heterocycles [17], as well as
polylithiated synthons [18] starting from polychlorinated
materials under Barbier-type reaction conditions [19].
Recently, we have applied the above-mentioned
arene-catalysed lithiation to the generation of allylic and
benzylic organolithium compounds starting from the
corresponding mesylates [20], phosphates [21], alcohols
or their O-silylated derivatives [22] and carboxylic acid
derivatives (esters, amides, carbonates, carbamates and
ureas) [23]. In addition, when the same reaction is
quenched with water, this methodology is a useful
procedure for deallylation or debenzylation of oxygen-
or nitrogen-containing derivatives [24].
On the other hand, from a lithium chemistry point of
view, fluorinated materials are not adequate precursors
for the generation of organolithium compounds due to
the difficulty in cleaving the carbon–fluorine bond,
which is the strongest one that carbon can form [25].
Recently, we were able to generate aryllithium reagents
by a fluorine–lithium exchange using an arene as the
catalyst for the lithiation process [26]. In this paper, we
apply the methodology to the generation of allylic and
benzylic organolithium compounds from the corre-
sponding fluorinated precursors.
From a preparative point of view, the generation of
allylic and benzylic organolithium reagents cannot be
carried out using the general methodology for organo-
lithium compounds, i.e. the lithiation of allylic or ben-
zylic halides (mainly bromides and chlorides), because
the almost exclusive formation of Wurtz-type products
takes place [1–3]. Alternatives to overcome this prob-
lem, including (a) direct deprotonation with an alkyl-
lithium in the presence of a co-reactant (potassium
tert-butoxide [4,5] or an amine [6]), (b) mercury–lithium
or tin–lithium transmetallation [7–9] or (c) reductive
cleavage of allyl phenyl ether [10,11] are of limited
application.
Concerning lithiation procedures, in the last few years
we have been using an arene-catalysed lithiation [12–14]
to prepare very reactive organolithium compounds un-
der very mild reaction conditions. Thus, simple organo-
lithium compounds can be generated using
non-halogenated materials [15], functionalised organo-
* Corresponding author. Tel.: +34-965903548; fax: +34-
965903549; www.ua.es/dept.quimorg.
E-mail address: yus@ua.es (M. Yus).
0022-328X/01/$ - see front matter © 2001 Elsevier Science B.V. All rights reserved.
PII: S0022-328X(00)00770-1

54
D. Guijarro, M. Yus / Journal of Organometallic Chemistry 624 (2001) 53–57
2. Results and discussion
to the expected compounds 2aa–2af (Table 1, entries
1–6) in moderate yields. Other secondary or tertiary
starting materials, such as fluorides 1b and 1c respec-
tively, gave similar results (Table 1, entries 7 and 8, and
9 and 10 respectively). In the case of using an allylic
fluoride, such as the geranyl derivative 1d, we found a
different behaviour depending on the electrophile used.
With chlorotrimethylsilane, the expected compound 2da
was isolated (Table 1, entry 11 and table footnote c).
The reaction of benzyl fluoride (1a) with an excess of
lithium powder (1:10 molar ratio) and a catalytic
amount of naphthalene (1:0.16 molar ratio; 8 mol%), in
the presence of different electrophiles (Barbier-type
i
conditions; E=Me3SiCl, PrCHO, tBuCHO, Et2CO,
(CH2)5CO, Ph2CO), in THF, at temperatures ranging
between −30 and 0°C, led, after hydrolysis with water,
Table 1
Preparation of compounds 2 from fluorocompounds 1

D. Guijarro, M. Yus / Journal of Organometallic Chemistry 624 (2001) 53–57
55
However, with carbonyl compounds, the rearranged
3. Conclusions
products 2%dc and 2%dd were obtained (Table 1, entries
12 and 13). These results can be explained by taking
into account that the allyllithium derivative I initially
formed is in equilibrium with the corresponding less
stable tertiary one I%, and depending on the reactivity of
the electrophile gave different regioisomers. Chloro-
trimethylsilane (a hard electrophile) is very reactive and
reacts rapidly with intermediate I before equilibration
to I%. For less reactive carbonyl compounds (soft elec-
trophiles) the I“I% equilibration takes place prior to
reaction with the electrophile to give compounds 2%.1
This behaviour has previously been observed in other
similar cases [22,23]. In the case of using pivalaldehyde
with the starting material 1d, the expected mixture of
diastereoisomers (ca. 1:1) was obtained (Table 1, entry
12, table footnote e). On the other hand, the reaction
shown in Table 1 had to be performed in the presence
of the electrophile (Barbier-type conditions) in order to
avoid the decomposition of the in situ generated ben-
zylic or allylic organolithium intermediate. When the
reaction was carried out in the absence of the elec-
trophile (two-step process), only Wurtz-type coupling
products were isolated. Finally, the moderate yields
observed in the lithiation of fluorides 1 can be ex-
plained due to the formation to some extent of the
corresponding ‘reduced’ products RH as by-products;
the separation of these compounds is very easy by
column chromatography. Concerning a possible reac-
tion mechanism, an SET process is generally accepted
for the halogen–lithium exchange [13].
From the results described in this paper, we conclude
that allylic and benzylic fluorides can be used as start-
ing materials for the generation of the corresponding
organolithium derivatives, which are trapped with dif-
ferent electrophiles under Barbier-type reaction
conditions.
4. Experimental
4.1. General
For general information, see Ref. [27]. THF was
distilled from sodium–benzophenone under N2 before
use. All the commercially available reagents purchased
were of the best commercial grade (Aldrich, Acros) and
used without any further purification.
4.2. Preparation of fluorides 1a, 1b, and 1d
Fluorinated starting materials 1a, 1b and 1d were
prepared from the corresponding commercially avail-
able bromides (10.0 mmol) by reaction with
Bu4NF·3H2O (6.310 g, 20.0 mmol) in acetonitrile
(20 ml), according to a literature procedure [28]. When
the reaction was complete, water (5 ml) was added, the
mixture was extracted with pentane (5×10 ml) and the
combined organic layers were dried (Na2SO4). Com-
pound 1a was obtained in pure form by distillation of
pentane through a 10 cm long Vigreux column at atmo-
spheric pressure, in 76% yield. In the reaction per-
formed to synthesize 1b, a mixture of the expected
fluoride and the elimination product, styrene (ratio
1b/styrene: 1/0.8, 300 MHz 1H-NMR), was obtained,
which could not be separated. However, the presence of
the olefin did not interfere in the lithiation process of
1b. That mixture was separated from pentane as de-
scribed for fluoride 1a, giving a 75% combined yield.
Geranyl fluoride 1d was obtained in pure form by
evaporation of the solvent at reduced pressure
(15 Torr). Physical, spectroscopic and analytical data
for the aforementioned fluorides follow.
Benzyl fluoride (1a) [28]: Rf (hexane) 0.26; wmax(liquid
film) 3091, 3068, 3036, 1599, 1498, 985 cm−1; lH
(300 MHz, CDCl3) 7.46–7.30 (5 H, m, ArH), 5.36 (2H,
d, J=48.2 Hz, CH2); lC (75 MHz, CDCl3) 136.25 (d,
J=17.1 Hz), 128.7 (2C, d, J=3.7 Hz), 128.55, 127.5
(2C, d, J=4.9 Hz), 84.55 (d, J=166.0 Hz); m/z (EI)
112 (B1, M++2), 111 (4, M++1), 110 (54, M+), 109
(100), 83 (20), 51 (12); HRMS (EI) M+, found
110.0537. C7H7F requires 110.0532.
Starting fluorides 1a, 1b and 1d were prepared from
the corresponding bromides via a nucleophilic substitu-
tion reaction with hydrated tetrabutylammonium
fluoride in acetonitrile. The synthesis of the remaining
fluoride 1c was carried out by treatment of 3-phenyl-3-
pentanol (obtained by reaction between 3-pentanone
and
phenylmagnesium
bromide)
and
bis-(2-
methoxyethyl)aminosulfur trifluoride in CH2Cl2.
(1-Fluoroethyl)benzene (1b) [29]: Rf (hexane) 0.24;
wmax(liquid film) 3084, 3062, 3032, 1495, 1066 cm−1; lH
(300 MHz, CDCl3) 7.46–7.20 (5H, m, ArH), 5.60 (1H,
1 Another possible explanation for this different behaviour could be
that a chair-like transition state is operative when a carbonyl com-
pound is used as electrophile.

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D. Guijarro, M. Yus / Journal of Organometallic Chemistry 624 (2001) 53–57
4.4. Naphthalene-catalysed lithiation of fluorides 1 in
the presence of electrophiles. Isolation of compounds 2.
General procedure
dq, J=47.8, 6.4 Hz, CHF), 1.62 (3H, dd, J=23.9,
6.4 Hz, Me); lC (75 MHz, CDCl3) 141.9 (d, J=
17.5 Hz), 128.5, 128.15 (2C, d, J=2.3 Hz), 125.15 (2C,
d, J=6.8 Hz), 90.9 (d, J=167.3 Hz), 22.9 (d, J=
25.4 Hz); m/z (EI) 126 (B1, M++2), 125 (2, M++1),
124 (28, M+), 123 (10), 109 (100), 104 (21), 103 (14), 83
(11), 78 (16), 77 (14), 51 (29), 50 (16); HRMS (EI) M+,
found 124.0689. C8H9F requires 124.0688.
Geranyl fluoride (1d) [30]: Rf (hexane) 0.48;
wmax(liquid film) 1669, 1650, 976 cm−1; lH (300 MHz,
CDCl3) 5.56–5.43, 5.16–5.03 (1H each, 2m, 2×
HCꢀC), 4.89 (2H, dd, J=47.6, 7.3 Hz, CH2F), 2.21–
1.96 (4H, m, CH2CH2), 1.72 (3H, d, J=4.9 Hz,
MeCꢀCCH2F), 1.68, 1.60 (3H each, 2s, Me2C); lC
(75 MHz, CDCl3) 144.1 (d, J=12.2 Hz), 131.9, 123.6,
118.95 (d, J=17.1 Hz), 79.35 (d, J=156.3 Hz), 39.55,
26.2 (d, J=3.7 Hz), 25.6, 17.65, 16.4 (d, J=2.4 Hz);
m/z (EI) 156 (B1, M+), 113 (20), 112 (10), 69 (100), 67
(12), 53 (10), 41 (99); HRMS (EI) M+, found 156.1324.
C10H17F requires 156.1314.
To a green suspension of lithium powder (70 mg,
10.0 mmol) and naphthalene (20 mg, 0.16 mmol) in
THF (5 ml), under N2, was dropwise added a solution
of fluoride 1 (1.0 mmol) and the corresponding elec-
trophile E (1.5 mmol) in THF (2 ml), at −30°C, for ca.
20 min. The mixture was stirred for ca. 3 h and the
temperature allowed to rise to 0°C. The reaction was
then hydrolysed with water (10 ml), acidified with 2 M
HCl and extracted with ethyl acetate (3×20 ml). The
combined organic layers were washed successively with
a saturated solution of NaHCO3 (5 ml), water (5 ml)
and brine (5 ml), and then dried (Na2SO4). After evapo-
ration of the solvents (15 Torr) the resulting residue
was purified by column chromatography (silica gel,
hexane–ethyl acetate) to yield the title compounds 2.
Products 2aa [21], 2ab [20], 2ac [23], 2ad–af [20], 2ba–
bd [22a], 2da [22a], 2%dc [23] and 2%dd [22a], previously
prepared in our laboratory, were fully characterised by
comparison of their physical and spectroscopic data
with authentic samples. For unknown compounds 2ca
and 2cc, the corresponding physical, spectroscopic and
analytical data follow.
3-Phenyl-3-(trimethylsilyl)pentane (2ca): Rf (hexane)
0.45; wmax(liquid film) 3087, 3057, 3030, 3017, 1598,
1497, 1248, 834 cm−1; lH (300 MHz, CDCl3) 7.34–7.01
(5H, m, ArH), 2.12–1.82 (4H, m, 2×CH2), 0.90 (6H, t,
J=7.4 Hz, 2×MeCH2), −0.12 (9H, s, Me3Si); lC
(75 MHz, CDCl3) 145.8, 127.55, 127.25 (2C), 123.8,
35.25, 23.95 (2C), 9.0 (2C), −2.4 (3C); m/z (EI) 222
(B1, M++2), 221 (B1, M++1), 220 (4, M+), 146
(39), 135 (12), 117 (16), 91 (15), 74 (10), 73 (100), 45
(22), 43 (11); HRMS (EI) M+, found 220.1633.
C14H24Si requires 220.1647.
4.3. Synthesis of fluoride 1c
3-Pentanone (1.67 ml, 15.0 mmol) was added drop-
wise to a cooled (0°C) solution of phenylmagnesium
bromide (16.0 ml, 1.0 M solution in tetrahydrofuran,
16.0 mmol), under N2, for ca. 5 min. After 30 min
stirring at the same temperature, water (5 ml) was
added. The mixture was acidified with 2 M HCl (10 ml)
and extracted with ethyl acetate (3×20 ml). The com-
bined organic layers were washed with 1.0 M NaOH
(2×5 ml), water (5 ml) and brine (5 ml) and dried
(Na2SO4). After evaporation of the solvents (15 Torr),
the resulting residue was purified by column chro-
matography (silica gel, hexane–ethyl acetate), affording
3-phenyl-3-pentanol in 60% yield, whose physical and
spectroscopic data were in complete agreement with
those reported [31]. The alcohol obtained was trans-
formed into the corresponding fluoride by treatment
with bis-(2-methoxyethyl)aminosulfur trifluoride in
CH2Cl2, following a literature procedure [32]. Fluoride
1c was isolated by column chromatography (silica gel,
hexane) in 64% yield. Physical, spectroscopic and ana-
lytical data follow.
3-Fluoro-3-phenylpentane (1c): Rf (hexane) 0.40;
wmax(liquid film) 3090, 3060, 3029, 1606, 1496,
1031 cm−1; lH (300 MHz, CDCl3) 7.42–7.18 (5H, m,
ArH), 2.10–1.75 (4H, m, 2×CH2), 0.78 (6H, t, J=
7.4 Hz, 2×Me); lC (75 MHz, CDCl3) 142.8 (d, J=
22.0 Hz), 128.0 (2C, d, J=2.3 Hz), 126.75 (2C, d,
J=1.1 Hz), 124.65, 100.25 (d, J=176.3 Hz), 33.25 (2C,
d, J=24.3 Hz), 7.6 (2C, d, J=4.5 Hz); m/z (EI) 167 (2,
M++1), 166 (17, M+), 138 (11), 137 (100), 117 (48),
115 (29), 109 (15), 91 (29), 59 (12), 51 (12); HRMS (EI)
M+, found 166.1172. C11H15F requires 166.1158.
4-Ethyl-2,2-dimethyl-4-phenyl-3-hexanol (2cc): Rf
(hexane/ethyl acetate: 4/1) 0.45; wmax(liquid film) 3506,
3089, 3057, 1599, 1498 cm−1; lH (300 MHz, CDCl3)
7.48–7.09 (5H, m, ArH), 3.57 (1H, d, J=7.1 Hz,
CHO), 2.21–1.85 (4H, m, 2×CH2), 1.68 (1H, d, J=
7.1 Hz, OH), 0.87, 0.78 (3H each, 2t, J=7.4 Hz each,
2×MeCH2), 0.70 (9H, s, Me3C); lC (75 MHz, CDCl3)
144.95, 128.05 (2C), 127.7 (2C), 125.65, 83.75, 48.8,
37.55, 28.45 (3C), 26.35, 26.25, 8.65, 8.25; m/z (EI) 177
(10, M+−57), 148 (59), 119 (87), 117 (14), 105 (42), 91
(100), 87 (13), 69 (12), 57 (40), 45 (11), 43 (18), 41 (60);
HRMS (EI) M+, found 234.2000. C16H26O requires
234.1984.
Acknowledgements
This work was generously supported by the Direc-
cio´n General de Ensen˜anza Superior (DGES) of the

D. Guijarro, M. Yus / Journal of Organometallic Chemistry 624 (2001) 53–57
57
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