2,2′-Dilithiobiphenyl by direct lithiation of biphenylene

Article abstract of DOI:10.1016/j.tetlet.2009.02.216

The reaction of biphenylene (1) with an excess of lithium powder (1:14 molar ratio) and a catalytic amount of DTBB (10 mol %) in THF at room temperature leads to the formation of the dilithiated species I by reductive opening of the four-membered ring. Further reaction of this intermediate with different electrophiles [Electrophile = H₂O, D₂O, Me₃SiCl, t-BuCHO, Et₂CO, n-Pr₂CO, (CH₂)₅CO, Ph₂CO and adamantanone] at 0 °C yields the corresponding products 2, after hydrolysis with water. Cyclisation of some representative examples of compounds 2 with H₃PO₄ gives the corresponding dibenzoxepines 3.

Full text of DOI:10.1016/j.tetlet.2009.02.216

Tetrahedron Letters 50 (2009) 2266–2269
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Tetrahedron Letters
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2,20-Dilithiobiphenyl by direct lithiation of biphenylene
*
*
Victor J. Lillo, Cecilia Gómez , Miguel Yus
Departamento de Química Orgánica, Facultad de Ciencias and Instituto de Síntesis Orgánica (ISO), Universidad de Alicante, Apdo. 99, 03080 Alicante, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
The reaction of biphenylene (1) with an excess of lithium powder (1:14 molar ratio) and a catalytic
amount of DTBB (10 mol %) in THF at room temperature leads to the formation of the dilithiated species
I by reductive opening of the four-membered ring. Further reaction of this intermediate with different
electrophiles [Electrophile = H2O, D2O, Me3SiCl, t-BuCHO, Et2CO, n-Pr2CO, (CH2)5CO, Ph2CO and ada-
mantanone] at 0 °C yields the corresponding products 2, after hydrolysis with water. Cyclisation of some
representative examples of compounds 2 with H3PO4 gives the corresponding dibenzoxepines 3.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 26 January 2009
Revised 24 February 2009
Accepted 27 February 2009
Available online 5 March 2009
Dedicated to Professor Armin de Meijere on
occasion of his 70th birthday.
Keywords:
Biphenylene
DTBB-catalysed lithiation
Lithium
Electrophiles
Dilithium intermediates
Oxepines
Li
Dilithium compounds are useful intermediates in synthetic
organic chemistry because their reaction with two equivalents
of an electrophile allows the direct introduction of two electro-
philic fragments in the organic skeleton of the organometallic
reagent in only one synthetic operation.1,2 Apart from transmet-
allation methodologies (mainly mercury- and tin-lithium ex-
change, only used in some unique cases), the most used
procedures for the generation of dilithium intermediates involve
deprotonation or halogen–lithium exchange.3 As an example, in
the case of 2,2-dilithiobiphenyl I, it has been generated by
using the two mentioned methodologies: (a) direct deprotona-
tion of biphenyl with n-BuLi/TMEDA,4 and bromine- or io-
dine–lithium exchange using n-BuLi or t-BuLi as lithiating
agent.5 However, and probably due to the general high instabil-
ity of dilithium intermediates,1 compound I was either obtained
with low yield4 or it was transmetallated into its zinc derivative
(by treatment with ZnCl2) in order to perform some further
transformations.4,5 Continuing with our interest in dilithium re-
agents6 we report here the generation of 2,2’-dilithiobiphenyl (I)
by direct lithiation of biphenylene using an arene-catalyst, a
methodology that has been extensively used in our group in
the last few years.7
Li
Li
Li
I
The reaction of commercially available biphenylene 1 with an
excess of lithium (1:14 molar ratio) and a catalytic amount of
4,40-di-tert-butylbiphenyl (DTBB; 1:0.2 molar ratio, 10% molar) in
THF at room temperature led, after 2 h, to a solution containing
the intermediate I, which was then treated with an electrophile
[1:2.2 molar ratio; Electrophile = H2O, D2O, Me3SiCl, t-BuCHO,
Et2CO, n-Pr2CO, (CH2)5CO, Ph2CO, adamantanone] at 0 °C for
30 min. After hydrolysis with water at temperatures ranging be-
tween 0 and 20 °C for 1 h the expected products 2 were isolated
(Scheme 1 and Chart 1).8
E
i-iii
E
1
2
Scheme 1. Reagents and conditions: (i) Li (1:14 molar ratio), DTBB (10% molar),
THF, rt, 2 h; (ii) electrophile = H2O, D2O, Me3SiCl, t-BuCHO, Et2CO, n-Pr2CO,
(CH2)5CO, Ph2CO, adamantanone (2.2 equiv), 0 °C, 30 min; (iii) H2O, 0 °C to rt, 1 h.
* Corresponding authors. Fax: + 34 965 903549 (M.Y.).
E-mail addresses: cgomez@ua.es (C. Gómez), yus@ua.es (M. Yus).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.02.216

V. J. Lillo et al. / Tetrahedron Letters 50 (2009) 2266–2269
2267
D
Si
Me2
D
2a (91%)a
2c (50%)a
2b (86%)a,b
OH
OH
OH
HO
HO
HO
2d (63%)c
2e (54%)
2f (49%)
Ph
OH
OH
Ph
OH
HO
HO
HO
Ph
Ph
2i (54%)
2g (30%)
2h (47%)
Chart 1. Structures and isolated yields of pure compounds 2 (>95%, from GLC and/or 300 MHz 1H NMR), after column chromatography unless otherwise stated; (a) GLC yield;
this compound was impurified by small amounts of DTBB (<15%); (b) >95% Deuterium incorporation (tandem GLC–MS); (c) A 2:1 mixture of diastereomers was obtained,
which were separated by column chromatography.
Since the starting material 1 can act as electron carrier in the
lithiation step,7 the same process was performed in the absence
of DTBB as external arene: in this case we observed total conver-
sion of biphenylene in about the same reaction time. However,
the reaction is not clean and several by-products were obtained to-
gether with the expected ones 2, some of them resulting from the
partial reduction of the aromatic ring, which would be an indirect
proof of the participation of the arene 1 as electron transfer agent.
In addition, when the reaction shown in Scheme 1 was carried out
at lower temperatures (or removing the excess of lithium at the
end of the lithiation step), worst results were obtained, the corre-
sponding monosubstituted ones being the major products.9 Actu-
ally, in all cases compounds 2 were obtained together with small
amounts of the mentioned monosubstituted compounds (<10%),
which were easily separated from the desired product 2 by column
chromatography during the final isolation.
As Chart 1 shows, in the case of using Me3SiCl as electrophiles,
the expected product resulting from the incorporation of two sili-
con fragments was not obtained: instead, silafluorene 2c was the
only reaction product isolated. This behaviour was already de-
scribed in the literature5c and can be explained accepting the par-
ticipation of pentacoordinated organosilicon intermediates.10
When pivalaldehyde was used as electrophile the expected
mixture of diastereomers (2d, 2:1 after chromatographic isolation)
was obtained and separated by column chromatography. The
structure of the major diastereomer (R*,R*) was established by X-
ray analysis (Chart 2), the same technology being used for confirm-
ing the structure of the diol 2e (Chart 2).
2e
2d (major R*,R*)
Chart 2. X-ray structures of diols 2d (major) and 2e, derived from pivalaldehyde and 3-pentanone, respectively.

2268
V. J. Lillo et al. / Tetrahedron Letters 50 (2009) 2266–2269
References and notes
R
R
R
R
R
O
R
OH
1. For reviews, see: (a) Foubelo, F.; Yus, M. Trends Org. Chem. 1998, 7, 1–26; (b)
Foubelo, F.; Yus, M. Curr. Org. Chem. 2005, 9, 459–490; For a monograph, see:
(c) Strohmann, C.; Schildbach, D. In The Chemistry of Organolithium Compounds;
Rappoport, Z., Marek, I., Eds.; Wiley: Chichester, UK, 2004; pp 941–996.
2. Dilithium intermediates can be considered functionalised organolithium
compounds. For reviews, see: (a) Nájera, C.; Yus, M. Trends Org. Chem. 1991,
2, 155–181; (b) Nájera, C.; Yus, M. Org. Prep. Proced. Int. 1995, 27, 383–457; (c)
Nájera, C.; Yus, M. Recent Res. Dev. Org. Chem. 1997, 1, 67–96; (d) Yus, M.;
Foubelo, F. Rev. Heteroatom Chem. 1997, 17, 73–107; (e) Nájera, C.; Yus, M. Curr.
Org. Chem. 2003, 7, 867–926; (f) Nájera, C.; Sansano, J. M.; Yus, M. Tetrahedron
2003, 59, 9255–9303; (g) Chinchilla, R.; Nájera, C.; Yus, M. Chem. Rev. 2004, 104,
2667–2722; (i) See also the special issue of Tetrahedron Symposium-in-Print
(Nájera, C., Yus, M., Eds.) devoted to ‘Functionalised Organolithium
Compounds’, Tetrahedron. 2005, 61, 3139–3450.; (j) Yus, M.; Foubelo, F. In
Functionalised Organometallics; Knochel, P., Ed.; Wiley-VCH: Weinheim, 2005.
Chapter 2; (k) Foubelo, F.; Yus, M. Chem. Soc. Rev. 2008, 37, 2620–2633.
3. For general monographs on the preparation of organolithium compounds, see:
(a) Wakefield, B. J. Organolithium Methods; Academic: London, 1988; (b)Lithium
Chemistry: A Theoretical and Experimental Overview; Sapse, A. M., von Ragué
Schleyer, P., Eds.; J. Wiley & Sons: New York, NY, 1995; (c) Gray, M.; Tinkel, M.;
Sniekus, V.. In Comprehensive Organometallic Chemistry II; Abel, E. W., Stone, F.
G. A., Wilkinson, G., McKillop, A., Eds.; Pergamon: Oxford, 1995; Vol. 11, pp 1–
92; (d) Clayden, J. Organolithiums: Selectivity for Synthesis; Pergamon: Oxford,
2002; (e)The Chemistry of Organolithium Compounds; Rappopoprt, Z., Marek, I.,
Eds.; Wiley: Chichester, UK, 2004.
i
HO
R
R
3e (93%)
3i (85%)
2e, 2i
Scheme 2. Reagents and conditions: (i) 85% H3PO4, Et2O, rt, 1d (for 2e) or 4 h (for
2i).
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6. For the last paper on this topic from our laboratory, see: Lillo, V. J.; Gómez, C.;
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7. For reviews, see: (a) Yus, M. Chem. Soc. Rev. 1996, 25, 155–161; (b) Ramón, D. J.;
Yus, M. Eur. J. Org. Chem. 2000, 225–237; (c) Yus, M. Synlett 2001, 1197–1205;
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Cubana Quim. 2002, 14, 75–115; (f) Yus, M.. In The Chemistry of Organolithium
Compounds; Rappoport, Z., Marek, I., Eds.; J. Wiley & Sons: Chichester, 2004;
Vol. 1,. Part 2, Chapter 11 For mechanistic studies, see: (g) Yus, M.; Herrera, R.
P.; Guijarro, A. Tetrahedron Lett. 2001, 42, 3455–3458; (h) Yus, M.; Herrera, R.
P.; Guijarro, A. Chem. Eur. J. 2002, 8, 2574–2584; (i) Yus, M.; Herrera, R. P.;
Guijarro, A. Tetrahedron Lett. 2003, 44, 1309–1312; (j) Yus, M.; Herrera, R. P.;
Guijarro, A. Tetrahedron Lett. 2003, 44, 1313–1316; (k) Yus, M.; Herrera, R. P.;
Guijarro, A. Tetrahedron Lett. 2003, 44, 5025–5027; (l) Melero, C.; Guijarro, A.;
Baumann, V.; Pérer-Jiménez, A. J.; Yus, M. Eur. J. Org. Chem. 2007, 5514–5526;
(m) Melero, C.; Herrera, R. P.; Guijarro, A.; Yus, M. Chem. Eur. J. 2007, 13, 10096–
10107; For a polymer supported arene-catalysed version of this reaction, see:
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Gómez, C.; Ruiz, S.; Yus, M. Tetrahedron 1999, 55, 7017–7026; (p) Yus, M.;
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3i
Chart 3. X-ray structure of oxepine 3i.
In the second part of this study we carried out the dehydration
of some diols 2 in order to get the corresponding oxygen-contain-
ing heterocycles. Thus, treatment of diols 2e and 2i with 85% phos-
phoric acid in ether at room temperature gave the expected
dibenzoxepines 3e and 3i, respectively (Scheme 2).11,12
The structure of compound 3i was confirmed by X-ray analysis
(Chart 3).
In summary, we have described herein the easy generation of a
2,20-dilithiobiphenyl using a very simple methodology, the DTBB-
catalysed lithiation of commercially available biphenylene. This
dianion has been trapped with different electrophiles, especially
carbonyl compounds affording interesting diols that were easily
cyclised under acidic conditions to yield the expected oxepines.
Compared to other possible methodologies (transmetallation,
deprotonation or halogen–lithium exchange), the here reported
generation of the dilithiated species I is the most convenient one
concerning the atom-economy philosophy.13
8. General procedure for compounds 2: To a dark green suspension of lithium
powder (49 mg, 7 mmol) and DTBB (13 mg, 0.05 mmol) in THF (1 mL) was
added dropwise a solution of biphenylene (77 mg, 0.5 mmol) in THF (2 mL) and
the mixture was stirred for 2 h at rt. The corresponding electrophile (1.1 mmol,
except for compound 2a and 2b, where direct work-up or 0.5 ml of D2O was
used, respectively) was then added at 0 °C and it was stirred at the same
temperature for 30 min. The resulting mixture was hydrolysed with water
(5 mL) allowing the temperature to rise to rt. The mixture was extracted with
EtOAc (3 ꢀ 10 mL), the organic layer dried with MgSO4 and solvents were
evaporated in vacuo to yield
a residue that was purified by column
chromatography (silica gel, hexane–EtOAc) to afford the title products.
9. The monosubstituted products (2, with one E = H) would be formed by
abstraction of one hydrogen from the reaction medium (probably from THF at
Acknowledgements
the a-position; see, for instance: Clayden, J.; Yasin, S. A. New J. Chem. 2002, 26,
191–192), before or after quenching with one molecule of the electrophile.
10. (a) Ishikawa, M.; Tabohashi, T.; Sugisawa, H.; Nishimura, K.; Kumada, M. J.
Organomet. Chem. 1983, 250, 109–119; For additional reactions involving
pentaorganosilicates, see: (b) Maercker, A.; Stötzel, R. Chem. Ber. 1987, 120,
1695–1706; (c) Vedejs, E.; Daugulis, O.; Diver, S. T.; Powell, D. R. J. Org. Chem.
1998, 63, 2338–2341; (d) van Klink, G. P. M.; de Boer, H. J. R.; Schat, G.;
Akkerman, O. S.; Bickelhaupt, F.; Spek, A. L. Organometallics 2002, 21, 2119–
2135. .
This work was generously supported by the Spanish Ministerio
de Educación y Ciencia (MEC; grants CTQ2007-65218/BQU and
Consolider Ingenio 2010, CSD2007-00006). V. L. thanks the Univer-
sity of Alicante for a predoctoral fellowship. We also thank Medal-
chemy S.L. for a gift of chemicals, especially lithium powder.
_
Supplementary data
+
Supplementary data (analytical, physical and spectroscopic data
for compounds 2 and 3, as well as the corresponding literature ref-
erences for known compounds) associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2009.02.216.
Li
Si
Me3
II

V. J. Lillo et al. / Tetrahedron Letters 50 (2009) 2266–2269
2269
11. General procedure for compounds 3: A solution of the pure diol 2 (0.1 mol) in
ether (1 mL) was treated with 85% H3PO4 (1 mL) and it was stirred at rt until
the starting material was consumed (TLC; 1 d for 2e and 4 h for 2i). Then it was
extracted with EtOAc (3 ꢀ 10 mL), the organic layer dried with MgSO4 and
evaporated in vacuo to afford the pure oxepines 3.
1998, 54, 656–659; (b) Majetich, G.; Hicks, R.; Okha, F. New. J. Chem. 1999,
129–131; (c) Azzena, U.; Demartis, S.; Pilo, L.; Piras, E. Tetrahedron 2000, 56,
8375–8382.
13. (a) Trost, B. M. Science 1991, 254, 1471–1477; (b) Trost, B. M. Angew.
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12. For reports leading to oxepines of type 3 following different methodologies
see, for instance: (a) Nieger, M.; Hupfer, H.; Bolte, M. Acta Crystallogr., Sect C