Aliphatic organolithiums by fluorine-lithium exchange: n-octyllithium

Article abstract of DOI:10.1016/S0040-4039(03)01194-8

The reaction of 1-fluorooctane (1) with an excess of lithium powder (4-10 equiv.) and DTBB (2-4 equiv.) in THP at 0°C for 5 min gives a solution of the corresponding 1-octyllithium (2), which reacts then with different electrophiles at 0°C (D₂O, MeSiCl, Bu^tCHO, Et₂CO), or -78°C [ClCO₂Me, (PhCH₂S)₂] or -40°C (CO₂) to room temperature to give, after hydrolysis, the expected products (3). The same process applied to 2-fluorooctane gives mainly octane as reaction product, independently on the electrophile used, resulting from a proton abstraction by 2-lithiooctane formed from the reaction medium before addition of the electrophilic reagent.

Full text of DOI:10.1016/S0040-4039(03)01194-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 5025–5027
Aliphatic organolithiums by fluorine–lithium exchange:
n-octyllithium
Miguel Yus,* Raquel P. Herrera and Albert Guijarro
Departamento de Qu´ımica Orga´nica, Facultad de Ciencias, Universidad de Alicante, Apdo. 99, 03080 Alicante, Spain
Received 6 May 2003; accepted 8 May 2003
Dedicated to Professor Daniel Uguen on occasion of his 60th birthday
Abstract—The reaction of 1-fluorooctane (1) with an excess of lithium powder (4–10 equiv.) and DTBB (2–4 equiv.) in THP at
0°C for 5 min gives a solution of the corresponding 1-octyllithium (2), which reacts then with different electrophiles at 0°C (D2O,
MeSiCl, ButCHO, Et2CO), or −78°C [ClCO2Me, (PhCH2S)2] or −40°C (CO2) to room temperature to give, after hydrolysis, the
expected products (3). The same process applied to 2-fluorooctane gives mainly octane as reaction product, independently on the
electrophile used, resulting from a proton abstraction by 2-lithiooctane formed from the reaction medium before addition of the
electrophilic reagent. © 2003 Elsevier Science Ltd. All rights reserved.
The carbonꢀfluorine bond is the strongest that carbon
can form and therefore its cleavage is not an easy task.1
Two important consequences can be drawn from this
fact: (a) In recent times, fluorinated (especially
perfluorinated) solvents have been introduced mainly in
order to perform two-phase catalysis,2 and (b) the
degradation of fluoroderivatives in Nature is problem-
atic from an environmental point of view.3 The most
used methodology in order to perform defluorination
processes, excluding elimination reactions giving
olefins,4 involves the use of a metallic catalyst under
drastic reaction conditions.5 Recently we have been
studying the lithiation of fluoroderivatives using an
arene-catalysed methodology,6–8 naphthalene and 4,4%-
di-tert-butylbiphenyl (DTBB) being the electron-trans-
fer agents most commonly used.9 Thus, arylic10 and
benzylic or allylic11 fluorides could be converted into
the corresponding organolithium intermediates, and
after reaction with electrophiles the expected products
were obtained; in the second case (benzylic and allylic
starting materials) was necessary to work under Bar-
bier-type conditions (lithiation in the presence of the
electrophile)12 in order to avoid Wurtz-type side reac-
tions.13 However, when the same methodology (arene-
catalysed lithiation) was applied to aliphatic fluorides
the starting material remained unchanged. Very
recently, we could perform the defluorination of
fluoroalkanes using the reductive methodology men-
tioned in the presence of equimolecular amounts of
1,2-bis(trimethylsilyl)benzene as activating agent;14 this
procedure is however not appropriate to introduce an
electrophilic fragment (different than hydrogen) in the
molecule. In this paper we report for the first time on
the direct transformation of an alkyl fluoride into an
organolithium intermediate using a modification of the
mentioned arene-catalysed methodology.
The reaction of 1-fluorooctane (1) with an excess of
LiDTBB (4 equiv.) in tetrahydropyran (THP) at 0°C
for 5 min led to a solution of the corresponding 1-
lithiooctane (2), which after reaction with different
electrophiles (D2O, Me3SiCl, ButCHO, Et2CO) at the
same temperature and final hydrolysis with phosphate
buffer yielded the expected products 3 (Method A)
Scheme 1. Reagents and conditions: (i) LiDTBB (4 equiv.), THP, 0°C, 5 min (Method A) or Li excess, DTBB (2 equiv.), THP,
0°C, 5 min (Method B); (ii) E+=D2O, Me3SiCl, ButCHO, Et2CO, ClCO2Me, CO2, (PhCH2S)2 (5 equiv.), 0 or −78°C (or −40°C)
to 0°C; (iii) H2O.
Keywords: fluorine–lithium exchange; DTBB-catalysed lithiation; electrophiles; proton abstraction; organolithium compounds.
* Corresponding author. Fax: +34 965 903549; e-mail: yus@ua.es
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01194-8

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M. Yus et al. / Tetrahedron Letters 44 (2003) 5025–5027
(Scheme 1 and Table 1, entries 1, 3, 5 and 7). Alterna-
tively, the lithiation can be performed using an excess
of lithium powder (ca. 10 equiv.) and a stoichiometric
amount of DTBB (2 equiv.) also in THP at 0°C during
5 min for the same electrophiles as above (Method B)
(Table 1, entries 2, 4, 6 and 8). In the case of using
methyl chloroformate or dibenzyl disulfide the reaction
with the electrophile worked better at temperatures
ranging between −78°C and room temperature; for
carbon dioxide −40°C to room temperature are the best
reaction conditions (Table 1, entries 9–11).
carrier by reductive alkylation.16 Differences between
Methods A and B lie on the possible participation of a
dilithium–arene when an excess of lithium is used
(Method B). This has been studied for the case of
naphthalene,7,16 and it is currently under investigation
for biphenyl derivatives such as DTBB. We then tried
the lithiation of a secondary fluoroalkane such as 2-
fluorooctane using Method B, which in general works
better than Method A (see Table 1) under the same
reaction conditions as shown in Scheme 1. Using the
same electrophiles (D2O, Me3SiCl, ButCHO, Et2CO) at
0°C we obtained >94% yield of octane. It seems that the
expected 2-lithiooctane is formed, but under the reac-
tion conditions assayed it does not survive long enough
to take up a proton from the reaction medium before
the reaction with the electrophile.
Up to date, the preparation of alkyllithium reagents
from alkyl fluorides has been an elusive task.10,11,14
Several reasons prevented this apparently simple target:
(a) The relentless tendency of alkyl fluorides to undergo
ET reactions at low temperature, (b) the reactivity
towards ethereal solvents of the alkyllithium reagents at
higher temperatures,15 (c) the apparent nucleophilic
reactivity displayed by lithium–arene species other than
DTBB toward primary alkyl fluorides,16 and (d) the
reactivity toward the solvent of the lithium–arene spe-
cies themselves.7b While alkyl fluorides are not reduced
by Li–arenes in any appreciable amount at −78°C, the
reduction takes place at room temperature or 0°C at a
convenient rate (less than 5 min). Unfortunately, alkyl-
lithium reagents are stable in THF (the most commonly
used solvent in lithium chemistry)13,17 or THP at
−78°C, but readily abstract a proton from THF at 0°C
or higher temperatures;15 THP is a better behaving
solvent.7b Even in THP at 0°C, which proved to be the
temperature of choice, short reaction times are manda-
tory. With substoichiometric DTBB at 0°C, arene
catalysed cycles are too slow and long reaction times
are required, allowing alkyllithium reagents to react
with the solvent. After addition of the electrophile, the
main reaction product was the alkane. The use of a
substoichiometric amount of arene catalysts other than
DTBB is precluded due to their inactivation as electron
In conclusion, we report in this paper the preparation
for the first time of a primary organolithium compound
(1-lithiooctane) by fluorine–lithium exchange and its
reaction with different electrophiles.18 The reaction with
a secondary fluoroalkane (2-fluorooctane) gives the cor-
responding 2-lithiooctane that takes a proton from the
reaction medium giving octane; this renders impossible
its reaction with other electrophiles.
Acknowledgements
This work was generously supported by the Direccio´n
General de Ensen˜anza Superior (DGES) of the current
Spanish Ministerio de Ciencia y Tecnolog´ıa (grant no.
PB97-0133) and the Generalitat Valenciana (grant no.
CTIDIB/2002/318). R.P.H. thanks the University of
Alicante for financial support. We also thank
MEDALCHEMY S.L. for a gift of chemicals, espe-
cially lithium powder.
Table 1. Preparation of compounds 3
Entry
Method
Electrophile
E+
Temperature
Producta
SE (°C)
No.
E
Yield (%)b
1
2
3
4
5
6
7
8
A
B
A
B
A
B
A
B
B
B
B
D2O
D2O
0
0
0
0
0
0
0
0
3a
3a
3b
3b
3c
3c
3d
3d
3e
3f
D
D
Me3Si
Me3Si
96c
98d
78
85
63
85
64
65
59
60
53
Me3SiCl
Me3SiCl
ButCHO
ButCHO
Et2CO
Et2CO
ClCO2Me
CO2
ButCHOH
ButCHOH
Et2COH
Et2COH
CO2Me
9
10
11
−78“0
−40“0
−78“0
CO2H
PhCH2S
(PhCH2S)2
3g
a All compounds 3 were >95% pure (GLC and/or 300 MHz 1H NMR) and were fully characterised by spectroscopic means (IR, 1H and 13C NMR,
and MS).
b Isolated yield determined by quantitative GLC (using decane as internal standard for compounds 3a–d) or 300 MHz 1H NMR (using
N,N-diphenylformamide as internal standard for compounds 3e–g) based on the starting 1-fluorooctane (1).
c >99% deuterium incorporation (mass spectrometry).
d 97% deuterium incorporation (mass spectrometry).

M. Yus et al. / Tetrahedron Letters 44 (2003) 5025–5027
5027
15. See, for instance: (a) Bates, R. B.; Kroposki, L. M.;
Potter, D. E. J. Org. Chem. 1972, 37, 560; (b) Mills, N.
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P. Chem. Commun. 2001, 1640; (d) Clayden, J.; Kenwor-
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18. Typical procedure: A suspension of lithium powder19
[Method A: 14 mg (2 mmol); Method B: 70 mg (10
mmol)] and DTBB [Method A: 559 mg (2.1 mmol);
Method B: 266 mg (1 mmol) in THP (10 mL) was stirred
for 2 h at room temperature. After cooling at 0°C, to the
resulting mixture was added dropwise a mixture of 1-
fluorooctane [Method A: 33 mg (0.25 mmol); Method B:
66 mg (0.5 mmol)] and decane [Method A: 35.5 mg (0.25
mmol); Method B: 71 mg (0.5 mmol)] as internal stan-
dard (for D2O, Me3SiCl, ButCHO, Et2CO as elec-
trophiles. After 5 min stirring [the starting material was
consumed (GLC)] the corresponding electrophile (5
mmol) was added at the same temperature and after 20
min the mixture was hydrolysed with phosphate tampon
(5 mL), extracted with Et2O (3×20 mL), dried over
Na2SO4 and evaporated. For D2O, Me3SiCl, ButCHO
and Et2CO yields were determined by quantitative GLC.
When ClCO2Me or (PhCH2S)2 were used as electrophiles,
after lithiation the mixture was cooled at −78°C and
pentane (5 mL) was added before adding the electrophile,
allowing then the temperature to rise to room tempera-
ture with stirring, being then hydrolysed as it was before
described. For CO2, after lithiation through the mixture
cooled at −40°C was bubbled CO2 gas for 5 min allowing
then the temperature to rise to room temperature before
acidic extraction and work-up as described above. For
the last three electrophiles [ClCO2Me, (PhCH2S)2 and
CO2] yields were determined by quantitative 1H NMR
using N,N-diphenylformamide as internal standard.
Characterisation of compounds 3 was made by spectro-
1
scopic means (IR, H and 13C NMR, and MS).
19. Lithium powder was prepared as described before: Yus,
M.; Mart´ınez, P.; Guijarro, D. Tetrahedron 2001, 57,
10119.