Negishi cross-coupling with functionalised organozinc compounds prepared by lithium-zinc transmetallation

Article abstract of DOI:10.1016/S0040-4039(01)01104-2

The reaction of some functionalised organolithium compounds 2 (easily prepared by DTBB-catalysed lithiation of isochroman, phthalan and 2,3-dihydrobenzofuran) with an equimolecular amount of zinc bromide followed by reaction with an aryl or alkenyl bromide in the presence of a catalytic amount of Pd(PPh₃)₄ or Pd(PPh₃)₂(OAc)₂ (5 mol%) under THF reflux overnight gave the expected cross-coupling compounds. These arylation or alkenylation processes, which work also with iodinated substrates, are not possible in the absence of the zinc or palladium compounds under the same reaction conditions.

Full text of DOI:10.1016/S0040-4039(01)01104-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 5721–5724
Negishi cross-coupling with functionalised organozinc compounds
prepared by lithium–zinc transmetallation
Miguel Yus* and Joaqu´ın Gomis
Departamento de Qu´ımica Orga´nica, Facultad de Ciencias, Universidad de Alicante, Apdo. 99, E-03080 Alicante, Spain
Received 14 June 2001; accepted 21 June 2001
Abstract—The reaction of some functionalised organolithium compounds 2 (easily prepared by DTBB-catalysed lithiation of
isochroman, phthalan and 2,3-dihydrobenzofuran) with an equimolecular amount of zinc bromide followed by reaction with an
aryl or alkenyl bromide in the presence of a catalytic amount of Pd(PPh3)4 or Pd(PPh3)2(OAc)2 (5 mol%) under THF reflux
overnight gave the expected cross-coupling compounds. These arylation or alkenylation processes, which work also with iodinated
substrates, are not possible in the absence of the zinc or palladium compounds under the same reaction conditions. © 2001
Elsevier Science Ltd. All rights reserved.
The use of functionalised organometallic compounds in
synthetic organic chemistry makes possible the direct
preparation of complex target molecules by reaction
with different electrophilic reagents.1 The stability of
the organometallic intermediate depends mainly on the
metal present in the molecule: an increase of the ionic
nature of the carbonꢀmetal bond increases the reactiv-
ity of the organometallic species and provokes less
tolerance towards the functional groups present in the
molecule. Thus, as expected, functionalised organo-
lithium reagents2 are far more reactive than the corre-
sponding organozinc derivatives3 and, consequently,
are limited concerning the functionality that they can
bear. On the contrary, functionalised organozinc com-
pounds react only with very reactive electrophiles (i.e.
allylic or benzylic halides) and frequently they should
be activated by transforming them into organocopper
compounds or mainly by means of a transition metal
catalyst such as nickel or palladium.3 In general, func-
tionalised organozinc reagents are prepared by iodine–
zinc or bromine–zinc interchange. Another classical
way, consisting of a lithium–zinc transmetallation, is
very limited due to the restricted stability of function-
alised organolithium compounds,2 which in many cases
have to be generated and used under Barbier-type
reaction conditions.4 In the last few years, we have been
using an arene-catalysed lithiation5–9 under very mild
reaction conditions in order to prepare functionalised
organolithium compounds, which by reaction with elec-
trophiles lead to the formation of polyfunctionalised
organic molecules. In this paper we describe the trans-
formation of some of these reactive organolithium
intermediates into the corresponding organozinc deriva-
tives followed by palladium-catalysed cross coupling
with sp2-hybridised halogenated materials, the so-called
Negishi reaction.10,11
A mixture of a THF filtered solution of the function-
alised organolithium intermediate 2a [2 mmol scale;
easily prepared by 4,4%-di-tert-butylbiphenyl (DTBB)-
catalysed reductive ring opening12 of isochroman (1a)13]
and dry zinc bromide (1:1 molar ratio) was treated with
different aryl bromides in the presence of a palladium
catalyst (1:0.05 molar ratio, 5% molar) and refluxed
overnight to give, after hydrolysis with hydrochloric
acid (see Table 1, footnote f), the expected compounds
3a–h (Scheme 1, Fig. 1 and Table 1, entries 1–9). As
catalyst, either commercially available tetrakis(tri-
phenylphosphine)palladium(0) (method A) or bis(tri-
phenylphosphine)palladium(II) acetate [method B; eas-
ily prepared by mixing palladium(II) acetate and
triphenylphosphine (1:2 molar ratio)] gave in both cases
comparable yields (Table 1, compare entries 1/2 and
14/15). The reaction works nicely with iodobenzene
(Table 1, entry 1 and footnote e) but failed for
chlorobenzene. In addition, aryl bromides containing
electron withdrawing (F, CF3, MeCO, CN, CO2Et) or
electron donating groups (MeO, Me2N) (Table 1,
entries 3–9) can be used for the coupling reaction as
well as naphthalene or heterocyclic derivatives (Fig. 1
and Table 1, entries 10–13).
Keywords: lithium–zinc transmetallation; functionalised organozinc
reagents; palladium-catalysed cross-coupling..
* Corresponding author. Fax: +34-96-5903549; e-mail: yus@ua.es
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01104-2

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M. Yus, J. Gomis / Tetrahedron Letters 42 (2001) 5721–5724
Table 1. Preparation of compounds 3
Entry
Organolithium intermediate
Brominated derivative
PhBr
Methoda
Product No.b
Yield (%)c
1
2
3
4
5
6
7
8
2a
A
B
B
A
A
B
A
B
B
A
A
A
B
A
B
B
B
3a
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3m
3n
3o
77 (83)d
74
69
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
4-FC6H4Br
4-CF3C6H4Br
67
4-MeOC6H4Br
4-Me2NC6H4Br
4-MeCOC6H4Br
4-NCC6H4Br
4-EtO2CC6H4Br
1-Bromonaphthalene
4-Bromopyridine
2-Bromothiophene
3-Bromofuran
Me2CꢁCHBr
63
38e
33
78e
49e
56
9
10
11
12
13
14
15
16
17
29e
59
30
58
64
43
2b
2c
PhBr
PhBr
49
a Method A: Pd(PPh3)4; method B: Pd(PPh3)2(OAc)2.
1
1
b All products 3 were ]95% pure (300 MHz H NMR and/or GLC) and were fully characterised by spectroscopic means (IR, H and 13C NMR,
and MS).
c Isolated yield after column chromatography (silica gel, hexane/ethyl acetate) based on the heterocyclic precursor of intermediates 2a–c
(isochroman, phthalan and 2,3-dihydrobenzofuran, respectively).
d Iodobenzene was used.
e Water was used for the final hydrolysis.
OLi
( )n
OH
( )n
( )n
O
( )m
ii-iv
i
+
ArBr
Li
( )m
Ar
( )m
1a: n = 2, m = 1
1b: n = m = 1
2a-c
3
1c: n = 0, m = 2
Scheme 1. Reagents and conditions: (i) Li, DTBB cat. (5 mol%), THF, 0 or 20°C, then filter off the excess of lithium; (ii) ZnBr2,
THF, 20°C, 30 min; (iii) Pd(PPh3)4 [method A] or Pd(PPh3)2(OAc)2 [method B] cat. (5 mol%), THF, 60°C, overnight; (iv)
HCl–H2O.
Concerning the mechanism of the reaction, three blank
experiments were carried out using the intermediate 2a
and bromobenzene as reagents under the same reaction
conditions shown in Scheme 1: (1) in the absence of
zinc bromide and the palladium catalyst, bromobenzene
(ꢀ90%) and 2-(2-methylphenyl)ethanol (>90%), result-
ing from a lithium–hydrogen exchange, were isolated;
(2) in the absence of zinc bromide and with method A,
2-(2-methylphenyl)ethanol (>90%) and biphenyl (91%)
were isolated; and (3) in the absence of any palladium
catalyst almost quantitative amounts of 2-(2-methyl-
phenyl)ethanol and bromobenzene were obtained. With
this information in hand, and considering the 2/zinc
bromide ratio used, an intermediate of type I can be
initially involved in the process, taking part in the
catalytic cycle generally accepted in the Negishi cross-
coupling reaction.10
The reaction shown in Scheme 1 is also applicable to
olefinic derivatives. Thus, for instance the reaction of
intermediate 2a with 1-bromo-2-methylpropene using
both methods A and B yielded the expected compound
3m (Fig. 1 and Table 1, entries 14 and 15).
Finally, and in order to check the cross-coupling reac-
tion with other functionalised organolithium com-
pounds, the reaction of intermediates 2b and 2c (easily
prepared by DTBB-catalysed lithiation of phthalan14
and 2,3-dihydrobenzofuran,15 respectively) with bro-
mobenzene under the same reaction conditions as for
intermediate 2a was studied, yielding compounds 3n
and 3o, respectively (Scheme 1, Fig. 1 and Table 1,
entries 16 and 17).16
In an attempt to generalise the reaction shown in
Scheme 1, we tried the same process with sp3- and
sp-hybridised brominated materials (such as cyclohexyl
bromide and 1-bromo-2-phenylacetylene), obtaining
only the reduced product, 2-(2-methylphenyl)ethanol
(>90%), without any detectable coupling product.
( )
n
O
Zn
( )m
I

M. Yus, J. Gomis / Tetrahedron Letters 42 (2001) 5721–5724
5723
OH
OH
OH
OH
OH
F
CF3
3b
3c
3a
OH
OH
NMe2
OMe
COMe
3e
3d
3f
OH
OH
CO2Et
CN
3h
3i
3g
OH
OH
OH
N
O
S
3k
3j
3l
OH
OH
OH
3m
3n
3o
Figure 1. Compounds 3 prepared.
Finally, we can conclude that the palladium-catalysed
Negishi cross-coupling reaction can be applied to the in
situ generated functionalised organozinc reagents (pre-
pared from the corresponding functionalised organo-
lithium compounds by a lithium–zinc transmetallation
process), so in general an arylation reaction takes place
at the carbon attached to the metal, the process being
not possible with the starting lithiated species.
References
1. Boudier, A.; Bromm, L. O.; Lotz, M.; Knochel, P.
Angew. Chem., Int. Ed. 2000, 39, 4414–4435.
2. Reviews: (a) Na´jera, C.; Yus, M. Trends Org. Chem.
1991, 2, 155–181; (b) Na´jera, C.; Yus, M. Recent Res.
Devel. Org. Chem. 1997, 1, 67–96.
3. Reviews: (a) Knochel, P.; Singer, R. D. Chem. Rev.
1993, 93, 2117–2188; (b) Knochel, P. Synlett 1995, 393–
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1998, 54, 8275–8319; (d) Erdik, E. Organozinc Reagents
in Organic Synthesis; CRC Press: Boca Raton, 1996; (e)
Knochel, P. In Metal-catalysed Cross-coupling Reac-
tions; Diederich, F.; Stang, P. J., Eds.; Wiley-VCH:
Weinheim, 1998; (f) Organozinc Reagents, A Practical
Approach; Knochel, P.; Jones, P., Eds.; Oxford Univer-
sity Press: Oxford, 1999.
Acknowledgements
This work was financially generously supported by the
D.G.E.S. (no. PB97-0133) from the current Spanish
Ministerio de Educacio´n, Cultura y Deportes (MECD).
J.G. thanks the MECD for a fellowship.

5724
M. Yus, J. Gomis / Tetrahedron Letters 42 (2001) 5721–5724
4. Reviews: (a) Alonso, F.; Yus, M. Recent Res. Devel. Org.
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10. See, for instance: Negishi, E.; Liu, F. In Metal-catalysed
Cross-coupling Reactions; Diederich, F.; Stang, P. J.,
Eds.; Weinheim: Wiley-VCH, 1998.
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lithium compounds to a,b-unsaturated ketones and esters
in the presence of different Lewis acids, including zinc
halides, see: Yus, M.; Pastor, I. M.; Gomis, J. Tetra-
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16. Typical procedure for compounds 3: To a stirred green
suspension of lithium powder (70 mg, 10 mmol) and
DTBB (53 mg, 0.2 mmol) in THF (10 ml) was added
dropwise isochroman (1a) (0.25 ml, 2 mmol) at room
temperature and under an argon atmosphere. After the
addition the colour disappeared and after 30 min of
stirring the green colour appeared again. Then, the excess
of lithium was filtered off under an inert atmosphere and
the filtrate was added to a solution of dry zinc bromide
(450 mg, 2 mmol) in THF (5 ml). After 30 min of stirring,
to the resulting solution was added a solution of the
corresponding aryl bromide (2.2 mmol) and the palla-
dium catalyst (0.1 mmol for both methods A and B) in
THF (10 ml) and it was refluxed overnight. After cooling
to rt, the mixture was successively treated with 3 M
hydrochloric acid (4 ml) (see Table 1, footnote f) and
water (10 ml), and extracted with ether (3×10 ml). The
organic layer was dried (Na2SO4) and evaporated (15
torr) to give a residue, which was purified by column
chromatography (silica gel, hexane–ethyl acetate) to give
pure compounds 3.
12. Review: Yus, M.; Foubelo, F. Rev. Heteroatom. Chem.
1997, 17, 73–107.
.