Arene-catalysed lithiation of fluoroarenes

Article abstract of DOI:10.1016/S0040-4020(00)00013-2

The reaction of different fluoroarenes 1 with lithium and a catalytic amount (7%) of naphthalene in THF at -30°C affords the corresponding aryllithium intermediates which, by reaction with several electrophiles at temperatures ranging between -30 and 0°C, lead to the expected products 2, after hydrolysis. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00013-2

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 1135–1138
Arene-Catalysed Lithiation of Fluoroarenes
*
David Guijarro and Miguel Yus
†
´
´
Departamento de Quımica Organica, Facultad de Ciencias, Universidad de Alicante, Apdo 99, 03080 Alicante, Spain
´
This paper is dedicated to Professor Enrique Melendez on the occasion of his 65th birthday.
Received 7 October 1999; revised 2 December 1999; accepted 16 December 1999
Abstract—The reaction of different fluoroarenes 1 with lithium and a catalytic amount (7%) of naphthalene in THF at Ϫ30ЊC affords the
corresponding aryllithium intermediates which, by reaction with several electrophiles at temperatures ranging between Ϫ30 and 0ЊC, lead to
the expected products 2, after hydrolysis. ᭧ 2000 Elsevier Science Ltd. All rights reserved.
Introduction
to explore the possible synthetic applications of fluoroarenes
in a tandem lithiation electrophilic substitution reaction.15
The cleavage of the carbon–fluorine bond is not easy due to
its large bond energy, which makes this bond the strongest
one that carbon can form, and therefore very resistant to
chemical attack.1 However, this lack of reactivity, which
has been successfully used for technological and medical
applications, makes the degradation of fluoroderivatives
problematic, from an environmental point of view.2 In the
last years, several reports have appeared concerning the
activation of the carbon–fluorine bond, mainly using
organometallic complexes.3 The recent communication of
Angelici et al. reporting the hydrodefluorination of fluoro-
Results and Discussion
The reaction of fluorobenzene (1a) with an excess of lithium
powder (1:10 molar ratio) and a catalytic amount of naph-
thalene (1:0.14 molar ratio; 7 mol%) in THF at Ϫ30ЊC for
15 min gave a solution of phenyllithium, which upon treat-
ment with different electrophiles [iPrCHO, PhCHO, Et2CO,
(CH2)5CO, PhCOMe, Me3SiCl; 1:1.2 molar ratio] at
temperatures ranging between Ϫ30 and 0ЊC for ca. 3 h,
and final hydrolysis with water and hydrochloric acid,
afforded the expected products 2aa–af (see Table 1, entries
1–6). The reaction conditions were optimised using
the preparation of compound 2ac as the model reaction:
reactions at Ϫ78, Ϫ30 and 0ЊC, as well as processes in
the presence of the electrophile (Barbier-type conditions16),
were carried out, finding the best results working at Ϫ30ЊC
and in a two-step reaction. When the process was performed
without naphthalene as the electron carrier the yield was
substantially lower (see Table 1, entry 3 and footnote c).
It is worth noting that it is known that phenyllithium and
other organolithiums are able to metallate fluorobenzene to
give o-fluorophenyllithium,6,17 so it is important to find the
best reaction conditions in order to avoid this o-lithiation
process.
benzene using rhodium complexes supported on
a
palladium–silicon system4 prompted us to study the lithi-
ation of fluoroarenes. In general, fluorinated hydrocarbons
are not active towards different lithiating reagents.5 In the
case of fluorobenzene, its lithiation using non activated
lithium works in ether with less than 1% yield, after carbo-
nation.6 Better yields can be obtained using THF as solvent
and by activation of the metal using a stoichiometric amount
of an arene, such as naphthalene, being, to the best of our
knowledge, the reaction with carbon dioxide the only
process studied.7 In the last few years, we have been devel-
oping a new lithiation methodology which uses lithium
powder and a catalytic amount of an arene, naphthalene
and 4,40-di-tert-butylbiphenyl being the most commonly
used.8–10 This methodology has been shown to be useful
in the generation of (a) very reactive organolithium inter-
mediates under very mild reaction conditions starting from
non halogenated materials,11 (b) functionalised organo-
lithium compounds,12,13 or (c) polylithiated synthons.14 In
this paper we apply the mentioned arene catalysed lithiation
Other substituted fluoroarenes, such as methyl or methoxy
substituted fluorobenzenes, gave similar results to fluoro-
benzene (see Table 1, entries 7–14). Surprisingly, the
reaction did not work for a-fluoronaphthalene: in this
case, and using 3-pentanone as the electrophile, only
naphthalene (also coming from the arene catalyst) and
dihydronaphthalene (1:4 molar ratio) were isolated (tandem
GLC/MS) showing that the fluorine/lithium exchange took
place under the conditions assayed, but the corresponding
Keywords: aryl fluorides; lithiation; arene-catalysis; aryllithiums.
* Corresponding author. Fax:ϩ34-965903549; e-mail: yus@ua.es
†
URL: www.ua.es/dept.quimorg/
0040–4020/00/$ - see front matter ᭧ 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00013-2

1136
D. Guijarro, M. Yus / Tetrahedron 56 (2000) 1135–1138
Table 1. Preparation of compounds 2
Producta
Entry
1
ArF (no.)
E
No.
Ar
X
Yield (%)b
38
iPrCHO
2aa
C6H5
iPrCHOH
2
3
4
5
6
(1a)
(1a)
(1a)
(1a)
(1a)
PhCHO
Et2CO
(CH2)5CO
PhCOMe
Me3SiCl
2ab
2ac
2ad
2ae
2af
C6H5
C6H5
C6H5
C6H5
C6H5
PhCHOH
Et2COH
(CH2)5COH
PhC(OH)Me
Me3Si
66
68 (38)c
72
52
50
7
8
PhCHO
Et2CO
2bb
2bc
2-MeC6H4
2-MeC6H4
PhCHOH
Et2COH
63
43
(1b)
9
PhCHO
Et2CO
2cb
2cc
3-MeC6H4
3-MeC6H4
PhCHOH
Et2COH
57
52
10
(1c)
(1d)
11
12
PhCHO
Et2CO
2db
2dc
4-MeC6H4
4-MeC6H4
PhCHOH
Et2COH
49
58
13
PhCHO
2eb
4-MeOC6H4
PhCHOH
61
48
14
15
(1e)
Et2CO
Et2CO
2ec
2fc
4-MeOC6H4
Et2COH
Et2COH
d
4-FC6H4
31ꢀ37†
a All compounds 2 were Ͼ95% pure (300 MHz 1H NMR and/or GLC).
b Isolated yield after column chromatography (silica gel, hexane/ethyl acetate) based on the starting fluoroarene 1.
c In parentheses, yield corresponding to the reaction carried out in absence of naphthalene.
d In parentheses, yield of compound 2aa.
a-lithionaphthalene abstracted a proton from the reaction
medium, probably from THF,18 giving the ‘reduced’
product. The same result was obtained working under
Barbier-type conditions at the three temperatures mentioned
above.
(see Table 1, entry 15 and footnote d). A similar result
was obtained performing the reaction in the presence of
the electrophile.
Finally, we tried the same reaction using 4-fluorophenol,
which was previously deprotonated with n-butyllithium. In
this case, after 24 h at room temperature, we isolated a ca.
1:1 mixture of phenol and the starting material, indicating
that the lithiation worked slowly and the lithium inter-
mediate formed decomposed under the reaction conditions
assayed.
When p-difluorobenzene was used as starting material and
using double the amount of 3-pentanone, a 31% yield was
obtained for the ‘monosubstitution’ product 2fc together
with 37% of compound 2ac, resulting from a second
fluorine/lithium exchange followed by proton abstraction

D. Guijarro, M. Yus / Tetrahedron 56 (2000) 1135–1138
1137
In conclusion, we have described here that fluoroarenes can
be used as starting materials for the generation of the corre-
sponding lithioarenes using naphthalene as an electron
carrier catalyst in the lithiation step.
127.45, 127.15 (2 C), 126.45, 123.6, 76.2, 21.4; m/z (EI) 200
(Ͻ1, Mϩϩ2), 199 (7, Mϩϩ1), 198 (49, Mϩ), 197 (14), 183
(19), 165 (17), 120 (12), 119 (71), 105 (100), 93 (46), 92
(70), 91 (62), 89 (13), 79 (23), 78 (18), 77 (69), 76 (11), 65
(23), 63 (11), 51 (28%); HRMS (EI) Mϩ, found 198.1027.
C14H14O requires 198.1045.
Experimental
General
3-(3-Methylphenyl)-3-pentanol (2cc). Rf (hexane/ethyl
acetate: 4:1) 0.39; nmax (liquid film) 3471, 3026, 1606,
1485 cmϪ1; dH (300 MHz, CDCl3) 7.29–7.11, 7.09–7.00
(3 H and 1 H, respectively, 2 m, ArH), 2.37 (3 H, s,
Me Ar), 1.95–1.73 (4 H, m, 2×CH2), 1.69 (1 H, s, OH),
0.77 (6 H, t, Jˆ7.6 Hz, 2×MeCH2); dC (75 MHz, CDCl3)
145.7, 137.4, 127.8, 126.95, 126.15, 122.5, 77.35, 34.9 (2
C), 21.65, 7.8 (2 C); m/z (EI) 179 (Ͻ1, Mϩϩ1), 178 (Ͻ1,
Mϩ), 150 (10), 149 (96), 91 (25), 65 (16), 57 (100), 43
(15%); HRMS (EI) Mϩ, found 178.1363. C12H18O requires
178.1358.
For general information see Ref. [19]. Fluorinated starting
materials and the electrophilic reagents were purchased of
the best commercial grade (Aldrich, Acros) and were used
without any further purification.
Naphthalene-catalysed lithiation of fluoroarenes 1 and
reaction with electrophiles. Isolation of compounds 2.
General procedure
3-(4-Methylphenyl)-3-pentanol (2dc).22 Rf (hexane/ethyl
acetate: 4:1) 0.34; nmax (liquid film) 3450, 3092, 3053,
3023, 1613, 1512 cmϪ1; dH (300 MHz, CDCl3) 7.25,7.13
(2 H each, 2 d, Jˆ7.9 Hz each, ArH), 2.33 (3 H, s, MeAr),
1.88–1.72 (4 H, m, 2×CH2), 1.67 (1 H, s, OH), 0.75 (6 H, t,
Jˆ7.3 Hz, 2×MeCH2); dC (75 MHz, CDCl3) 142.75,
135.65, 128.65 (2 C), 125.35 (2 C), 77.25, 34.8 (2 C),
20.9, 7.8 (2 C); m/z (EI) 178 (Ͻ1, Mϩ), 149 (78), 91 (19),
65 (11), 57 (100), 43 (13%); HRMS (EI) MϩϪH2O, found
160.1245. C12H16 requires 160.1252.
To a green suspension of lithium powder (70 mg,
10.0 mmol) and naphthalene (18 mg, 0.14 mmol) in THF
(5 mL), under N2, was dropwise added a solution of the
corresponding fluoroarene 1 (1.0 mmol) in THF (2 mL)
over ca. 20 min at Ϫ30ЊC. After 15 min stirring at the
same temperature [the starting material was consumed
(GLC)], the corresponding electrophile E (1.2 mmol) was
added and the mixture was stirred for ca. 3 h allowing the
temperature to rise to 0ЊC. The resulting mixture was then
hydrolysed with water (10 mL), acidified with 2 M hydro-
chloric acid and extracted with ethyl acetate (3×20 mL).
The organic layers were successively washed with a
saturated solution of NaHCO3 (5 mL), water (5 mL) and
saturated NaCl (5 mL), being then dried (Na2SO4). After
evaporation 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–
af, previously prepared in our laboratory,20 and compounds
2bb and 2db, commercially available (Aldrich), were fully
characterised by comparison of their physical and spectro-
scopic data with authentic samples. For the other known
compounds 2cb,21 2dc,22 2eb,23 2ec,24 and 2fc,25 partially
described in the literature, as well as for unknown
compounds 2bc and 2cc, the corresponding physical,
spectroscopic and analytical data follow.
(4-Methoxyphenyl)phenylmethanol (2eb).23 Rf (hexane/
ethyl acetate: 7:3) 0.29; nmax (liquid film) 3403, 3084,
3061, 3028, 1611, 1585, 1512, 1494 cmϪ1; dH (300 MHz,
CDCl3) 7.42–7.23, 6.92–6.84 (7 H and 2 H, respectively, 2
m, ArH), 5.79 (1 H, s, CHO), 3.79 (3 H, s, Me), 2.42 (1 H, br
s, OH); dC (75 MHz, CDCl3) 158.95, 144.0, 136.15, 128.35
(2 C), 127.85, 127.35 (2 C), 126.35 (2 C), 113.8 (2 C), 75.7,
55.2; m/z (EI) 215 (12, Mϩϩ1), 214 (42, Mϩ), 213 (15), 197
(12), 165 (12), 153 (11), 152 (13), 137 (32), 136 (12), 135
(60), 109 (100), 108 (37), 107 (13), 105 (64), 94 (20), 92
(12), 79 (16), 78 (16), 77 (83), 65 (13), 64 (12), 51 (28), 50
(12), 40 (25%); HRMS (EI) Mϩ, found 214.0967. C14H14O2
requires 214.0994.
3-(4-Methoxyphenyl)-3-pentanol (2ec).24 Rf (hexane/ethyl
acetate: 1:1) 0.57; nmax (liquid film) 3404, 3071, 3059, 3037,
1612, 1511 cmϪ1; dH (300 MHz, CDCl3) 7.29, 6.87 (2 H
each, 2 d, Jˆ8.9 Hz each, ArH), 3.80 (3 H, s, MeO),
1.90–1.72 (4 H, m, 2×CH2), 1.69 (1 H, br s, OH), 0.76 (6
H, t, Jˆ7.6 Hz, 2× MeCH2); dC (75 MHz, CDCl3) 157.95,
137.85, 126.6 (2 C), 113.25 (2 C), 77.05, 55.15, 34.85 (2 C),
7.8 (2 C); m/z (EI) 195 (Ͻ1, Mϩϩ1), 194 (3, Mϩ), 176 (12),
165 (92), 147 (15), 91 (11), 77 (14), 57 (100), 43 (11%);
HRMS (EI) Mϩ, found 194.1284. C12H18O2 requires
194.1307.
3-(2-Methylphenyl)-3-pentanol (2bc). Rf (hexane/ethyl
acetate: 4:1) 0.38; nmax (liquid film) 3472, 3059, 3016,
1601, 1485 cmϪ1; dH (300 MHz, CDCl3) 7.47–7.44, 7.21–
7.12 (1 H and 3 H, respectively, 2 m, ArH), 2.51 (3 H, s,
Me Ar), 2.14–1.98, 1.94–1.79 (2 H each, 2 m, 2×CH2), 1.71
(1 H, s, OH), 0.79 (6 H, t, Jˆ7.3 Hz, 2× Me CH2); dC
(75 MHz, CDCl3) 142.75, 135.0, 132.4, 127.3, 126.55,
125.4, 78.75, 33.25 (2 C), 22.45, 8.0 (2 C); m/z (EI) 178
(Ͻ1, Mϩ), 150 (13), 149 (100), 119 (10), 91 (32), 65 (20), 57
(93), 43 (25%); HRMS (EI) MϩϪH2O, found 160.1251.
C12H16 requires 160.1252.
3-(4-Fluorophenyl)-3-pentanol (2fc).25 Rf (hexane/ethyl
acetate: 4:1) 0.38; nmax (liquid film) 3462, 3086, 3061,
3029, 1604, 1509 cmϪ1; dH (300 MHz, CDCl3) 7.40–7.28,
7.05–6.95 (2 H each, 2 m, ArH), 1.92–1.70 (4 H, m,
2×CH2), 1.69 (1 H, s, OH), 0.75 (6 H, t, Jˆ7.3 Hz,
2×Me); dC (75 MHz, CDCl3) 161.4 (d, Jˆ244 Hz), 141.35
(d, Jˆ2 Hz), 127.1 (2 C, d, Jˆ7 Hz), 114.6 (2 C, d,
(3-Methylphenyl)phenylmethanol (2cb).21 Rf (hexane/
ethyl acetate: 7:3) 0.38; nmax (liquid film) 3383, 3085,
3060, 3028, 1606, 1590, 1493 cmϪ1; dH (300 MHz,
CDCl3) 7.44–7.05 (9 H, m, ArH), 5.80 (1 H, s, CHO),
2.36 (3 H, s, Me), 2.30 (1 H, br s, OH); dC (75 MHz,
CDCl3) 143.8, 143.7, 138.1, 128.4 (2 C), 128.35, 128.25,

1138
D. Guijarro, M. Yus / Tetrahedron 56 (2000) 1135–1138
11. (a) For a review, see: Guijarro, D.; Yus, M. Recent Res. Devel.
Org. Chem. 1998, 2, 713–744. (b) Previous paper on this topic
Jˆ21 Hz), 77.1, 35.0 (2 C), 7.7 (2 C); m/z (EI) 164 (3,
MϩϪ18), 153 (81), 135 (21), 57 (100), 43 (62), 40 (12%);
HRMS (EI) MϩϪH2O, found 164.1019. C11H13F requires
164.1001.
´
from our laboratory: Alonso, E.; Guijarro, D.; Martınez, P.;
´
Ramon, D. J.; Yus, M. Tetrahedron 1999, 55, 11027–11038.
´
12. For reviews, see: (a) Najera, C.; Yus, M. Trends Org. Chem.
´
1991, 1, 155–181. (b) Najera, C.; Yus, M. Recent Res. Devel. Org.
Acknowledgements
Chem. 1997, 1, 67–96. (c) Yus, M.; Foubelo, F. Rev. Heteroatom.
Chem. 1999, 17, 73–107.
´
This work was generously supported by the Direccion
General de Ensen˜anza Superior (DGES) of the Spanish
13. Previous paper on this topic from our laboratory: Ortiz, J.;
Guijarro, A.; Yus, M. Tetrahedron 1999, 55, 4831–4842.
14. (a) For a review, see: Foubelo, F.; Yus, M. Trends Org. Chem.
1998, 7, 1–26. (b) Previous paper on this topic from our laboratory:
Foubelo, F.; Yus, M. Tetrahedron Lett. 1999, 40, 743–746.
15. The application of this methodology to 4-fluorophenylmethyl
methyl ether at low temperatures does not allow the fluorine/
lithium exchange: Azzena, U.; Carta, S.; Melloni, G.; Sechi, A.
Tetrahedron 1997, 53, 16205–16212.
´
Ministerio de Educacion y Cultura (grant. no. PB97-
´
0133). We thank Dr C. Gomez for HRMS measurements.
References
1. Hudlicky, M. Chemistry of Organic Fluorine Compounds,
Prentice-Hall: New York, 1992 (p. 175).
2. (a) Banks, R. E.; Smart, B. E.; Tatlow, J. C., Eds. Organo-
fluorine Chemistry: Principles and Commercial Applications;
Plenum: New York, 1994. (b) Hudlicky, M.; Pavlath, A. E., Eds.
Chemistry of Organic Fluorine Compounds II. A Critical Review;
ACS Monography 187; ACS: Washington, DC, 1995.
3. For a review, see: Kiplinger, J. L.; Richmond, T. G.; Osterberg,
C. E. Chem. Rev. 1994, 94, 373–431.
4. Yang, H.; Gao, H.; Angelici, R. J. Organometallics 1999, 18,
2285–2287 and references cited therein.
5. Wakefield, B. J. Organolithium Methods, Academic Press:
London, 1988 (p.21).
16. (a) For a monograph, see: Blomberg, C. In The Barbier
Reaction and Related One-Step Processes; Hafner, K.;
Rees, C. W.; Trost, B. M.; Lehn, J.-M.; Schleyer, P. von R.;
Zahvadnik, R., Eds., Springer: Berlin, 1993. (b) For a review,
see: Alonso, F.; Yus, M. Recent Res. Devel. Org. Chem. 1997, 1,
397–436.
17. Schlosser, M. Organometallics in Synthesis; Schlosser, M.
Ed.; Wiley: Chichester, 1994, p 85.
18. See, for instance: Bates, R. B.; Kroposki, L. M.; Potter, D. E.
J. Org. Chem. 1972, 37, 560–562.
19. Choudhury, P. K.; Foubelo, F.; Yus, M. Tetrahedron 1999, 55,
10779–10788.
6. Gilman, H.; Soddy, T. S. J. Org. Chem. 1957, 22, 1121–1122.
7. (a) Eisch, J. J. J. Org. Chem. 1963, 28, 707–710. (b) Screttas, C.
G. J. Chem. Soc., Chem. Commun. 1972, 752–753.
20. Guijarro, D.; Yus, M. Tetrahedron 1994, 50, 3447–3450.
21. Smirnova, T.S.; Mostova, M.I.; Ioffe, D.V. Zh. Org. Khim.
1974, 10, 1466–1469; Chem. Abstr. 1974, 81, 90813s.
22. Asanuma, T.; Ito, M.; Jpn. Kokai Tokkyo Koho. JP63,126,834;
Chem. Abstr. 1988, 109, 210679y.
23. Chen, D.-W.; Takai, K.; Ochiai, M. Tetrahedron Lett. 1997,
38, 8211–8214.
24. Collins, D. J.; Jacobs, H. A. Aust. J. Chem. 1987, 40, 1989–
2004; Chem. Abstr. 1988, 109, 109920v.
8. For reviews, see: (a) Yus, M. Chem. Soc. Rev. 1996, 155–161.
´
(b) Ramon, D. J.; Yus, M. Eur. J. Org. Chem., in press.
´
9. (a) First account on this reaction: Yus, M.; Ramon, D. J.
J. Chem. Soc., Chem. Commun. 1991, 398–400. (b) Previous
paper on this topic from our laboratory: Foubelo, F.; Gutierrez,
A.; Yus, M. Synthesis 1999, 503–514.
10. For a polymer-supported version of this process, see: (a)
´
Gomez, C.; Ruiz, S.; Yus, M. Tetrahedron Lett. 1998, 39, 1397–
25. Kelly, D. P.; Jenkins, M. J.; Mantello, R. A. J. Org. Chem.
1981, 46, 1650–1653.
´
1400. (b) Gomez, C.; Ruiz, S.; Yus, M. Tetrahedron 1999, 55,
7017–7026.