Copper(I) or (II)-mediated conjugate addition or dimerisation of functionalised organolithium compounds

Article abstract of DOI:10.1016/S0040-4039(99)02336-9

The reaction of different functionalised organolithium intermediates 1- 3 with several electrophilic olefins 6 (2-cyclopentenone, 2-cyclohexenone, methyl vinyl ketone, benzylideneacetone, benzylideneacetophenone and ethyl acrylate) in the presence of copper(I) salts (bromide and iodide) in THF at -78°C gives, after hydrolysis with ammonium chloride, the expected products resulting from a conjugate addition. In the presence of copper(II) chloride intermediates 1-5 undergo dimerisation to yield the expected dimers. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(99)02336-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 1589–1592
Copper(I) or (II)-mediated conjugate addition or dimerisation of
functionalised organolithium compounds†
Isidro M. Pastor and Miguel Yus ∗
Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Alicante, Apdo 99, 03080 Alicante, Spain
Received 4 October 1999; accepted 16 December 1999
Abstract
The reaction of different functionalised organolithium intermediates 1–3 with several electrophilic olefins 6 (2-
cyclopentenone, 2-cyclohexenone, methyl vinyl ketone, benzylideneacetone, benzylideneacetophenone and ethyl
acrylate) in the presence of copper(I) salts (bromide and iodide) in THF at −78°C gives, after hydrolysis with
ammonium chloride, the expected products resulting from a conjugate addition. In the presence of copper(II)
chloride intermediates 1–5 undergo dimerisation to yield the expected dimers. © 2000 Elsevier Science Ltd. All
rights reserved.
Keywords: copper reagents; conjugate addition; dimerisation; functionalised organolithiums.
Organocopper reagents are important intermediates in synthetic organic chemistry not only from an
academic point of view, but also in industrial processes.1 The most important reactions of these reagents
are: (a) conjugate addition, (b) acylation, (c) alkylation/arylation, and (d) alkyne carbocupration. In
general, organocopper reagents are prepared by transmetallation from the corresponding magnesium
or, mainly, organolithium compounds. However, this approach is not generally applicable for func-
tionalised organocopper reagents2 due to the difficulty in obtaining stable functionalised organomag-
nesium or organolithium compounds. Examples of functionalised organocopper reagents prepared by
tin/copper transmetallation,3 direct reaction of halogenated compounds with activated Rieke copper,4 or
via organozinc5 or organozirconium6 reagents using copper cyanide or high order cyanocuprates, respec-
tively, can be found in the literature. In the last decade, we have been developing a new methodology to
prepare very reactive functionalised organolithium intermediates7 from halogenated8 or non-halogenated
materials9 and performing lithiation with lithium powder and a catalytic amount of an arene: naphthalene
and 4,40-di-tert-butylbiphenyl (DTBB) being the most commonly used.10–12 In this paper we describe
the reaction of functionalised organolithium derivatives with copper(I) or (II) salts in order to obtain
polyfunctionalised molecules through a conjugate addition to electrophilic olefins, or the corresponding
dimerisation, respectively.
∗
†
Corresponding author. Fax: 34 965903549; e-mail: yus@ua.es (M. Yus)
This paper is dedicated to the memory of Professor Raymond N. Castle.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02336-9
tetl 16264

1590
Fig. 1. Intermediates 1–5, olefins 6 and products 7–20
Intermediate 1 was prepared in THF by DTBB-catalysed lithiation of phthalan,7c,13 and was treated
with a copper(I) salt at −78°C and the corresponding electrophilic olefin 6 to give, after hydrolysis with
a saturated solution of ammonium chloride, the expected compounds 7–12, resulting from a conjugate
addition14 (Fig. 1 and Table 1, entries 1–12). Copper(I) bromide–dimethyl sulfide complex or copper(I)
Table 1
Preparation of compounds 7–15

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Table 2
Preparation of compounds 16–20
iodide were used either with or without an additive such as hexamethylphosphoramide (HMPA) or N,N0-
dimethylpropyleneurea (DMPU), as well as lithium bromide in the case of using ethyl acrylate as the
olefinic component. In general, the combination of copper(I) iodide and HMPA gave the best results.
The use of intermediate 2 (prepared by DTBB-catalysed lithiation of 2,3-dihydrobenzofuran15) and 3
(derived from isochroman by DTBB-catalysed lithiation7c,16) gave, under the same reaction conditions,
the expected products 13–15 (Fig. 1 and Table 1, entries 13–15).
In the second part of this study we considered the dimerisation of intermediates 1, 2, 3 and 4
(prepared by reaction of the corresponding chloroacetal with lithium naphthalene17) and 5 [prepared
from the corresponding alcohol by reaction with (1) nBuLi, THF, −78°C, and (2) lithium naphthalenide,
−78°C18] by means of copper(II) chloride in equimolar amounts at −78°C using THF as the solvent.
Thus, the expected dimers 16–20 were the only reaction products isolated after hydrolysis with saturated
ammonium chloride (Fig. 1 and Table 2, entries 1–7).
From a mechanistic point of view, in both processes mentioned above using copper(I) or copper(II)
salts, intermediates of the type RFGCu or (RFG)2Cu can be involved.1 However, radical-type reactions,
especially in the second case, cannot be ruled out.
General procedure for compounds 7–15: To a solution of anhydrous copper(I) iodide (2 mmol) and
the corresponding olefin 6 (1.1 mmol) in THF (4 ml) and HMPA (2 ml) was added a THF solution (6
ml) of the corresponding organolithium compound 1–3 (1 mmol) at −78°C. After 25 min stirring at the
same temperature the resulting mixture was hydrolysed with saturated NH4Cl (10 ml). After warming to
room temperature it was extracted with ether (5×8 ml), the organic layer dried over anhydrous MgSO4
and evaporated (15 Torr) giving a residue which was purified by column chromatography (silica gel,
hexane/ethyl acetate) to yield the title compounds.
General procedure for compounds 16–20: To a solution of copper(II) chloride (2 mmol) in THF (5
ml) was added a solution of the corresponding organolithium compound 1–5 (2 mmol) in THF (6 ml)

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at −78°C and the mixture was stirred for 45 min at the same temperature. Then it was hydrolysed and
worked up as described above for compounds 7–15.
Acknowledgements
This work was generously supported by the Dirección General de Enseñanza Superior (DGES) of the
Spanish Ministerio de Educación y Cultura (MEC) through the grant no. PB97-0133. I.M.P. thanks the
Generalitat Valenciana for a predoctoral fellowship.
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of copper(I) salt. For instance, in the reaction of intermediate 1 with 2-cyclohexenone (6b) or methyl vinyl ketone (6c) only
the corresponding 1,2-adducts were isolated: Pastor, I. M., unpublished results.
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