Bromine-lithium exchange: An efficient tool in the modular construction of biaryl ligands

Article abstract of DOI:10.3762/bjoc.7.148

Regioselective bromine-lithium exchange reactions on polybrominated biaryls enable the modular synthesis of various polysubstituted biphenyls such as bis(dialkylphosphino)-, bis(diarylphosphino)- and dialkyl(diaryl) phosphinobiphenyls. All permutations of

Full text of DOI:10.3762/bjoc.7.148

Bromine–lithium exchange: An efficient tool in the
modular construction of biaryl ligands
Laurence Bonnafoux, Frédéric R. Leroux* and Françoise Colobert*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2011, 7, 1278–1287.
Laboratoire de stéréochimie, UMR 7509, CNRS-Université de
Strasbourg, ECPM, 25 rue Becquerel, F-67087 Strasbourg Cedex 02,
France
doi:10.3762/bjoc.7.148
Received: 01 June 2011
Accepted: 22 August 2011
Published: 14 September 2011
Email:
Laurence Bonnafoux - laurence.bonnafoux@gmail.com;
Frédéric R. Leroux* - frederic.leroux@unistra.fr; Françoise Colobert* -
francoise.colobert@unistra.fr
This article is part of the Thematic Series "Directed aromatic
functionalization".
* Corresponding author
Guest Editor: V. Snieckus
Keywords:
© 2011 Bonnafoux et al; licensee Beilstein-Institut.
License and terms: see end of document.
biaryl; bromine–lithium exchange; ligand; lithiation; phosphine
Abstract
Regioselective bromine–lithium exchange reactions on polybrominated biaryls enable the modular synthesis of various polysubsti-
tuted biphenyls such as bis(dialkylphosphino)-, bis(diarylphosphino)- and dialkyl(diaryl)phosphinobiphenyls. All permutations of
substituents at the ortho positions of the biphenyls are possible. In a similar manner, one can gain access to monophosphine
analogues. So far, such a process, based on the effective discrimination between bromine atoms as a function of their chemical
environment, has been observed only sporadically.
Introduction
Atropisomeric biaryls are important compounds in various and 6'-positions can affect the dihedral angle of the biphenyl
fields. In particular, pharmaceuticals and agrochemicals with backbone, one of the key factors for ligand efficiency. Both the
biaryl substructures are of general interest [1]. In addition, they aryl phosphorus substituents and the biphenyl backbone can be
have widespread applications as ligands in catalysis, or in ma- tailored in order to modify the stereoelectronic profile of a
terials sciences [2]. The atropisomeric C2-symmetric binaph- ligand.
thyl- or biphenyl-bridged diphosphine ligands BINAP [3],
H8-BINAP [4], BIPHEMP [5], MeO-BIPHEP [6], SEGPHOS Most frequently, biaryls are prepared through transition metal-
[7-9], P-Phos [10], SYNPHOS [11,12], Cn-TUNAPHOS [13] catalyzed reactions of suitable functionalized starting materials
and DIFLUORPHOS [14-16] and their analogues are well [17-22]. Although these methods are well established, alter-
known as highly efficient chiral ligands for a variety of tran- natives are investigated in order to avoid expensive transition
sition metal-catalyzed asymmetric transformations. The metals or ligands, which are especially required for the coupling
biphenyl backbone has the advantage that substituents at the 6- of deactivated or sterically hindered substrates.
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Beilstein J. Org. Chem. 2011, 7, 1278–1287.
Our group is developing new methods towards the synthesis of former role as one of the most important and versatile methods
highly functionalized atropisomeric biphenyls [23-32]. We seek in organic synthesis. New exchange reagents, such as isopropyl-
to perform their synthesis (a) in a modular way starting from a magnesium chloride, its LiCl complex [53-61] and lithium tri-
few common and easily available precursors; (b) with a high butylmagnesate [62,63], have been developed and allow reac-
degree of structural diversity; (c) in a straightforward, short, tions under noncryogenic conditions [64-66]. New access routes
reproducible manner; (d) in high yield and on multigram scale; to synthetically challenging aryl halide precursors have been
and, last but not least, (e) with a restricted use of transition devised.
metals and ligands.
A. Alexakis et al. recently achieved a significant breakthrough.
Polar organometallic chemistry [33-35] allows the performance They succeeded in the desymmetrization of prochiral poly-
of highly selective reactions. Therefore, it seemed to us the brominated [32,51] compounds by an asymmetric
ideal tool to reaching this goal. In this context, we recently bromine–lithium exchange in the presence of a stoichiometric
developed a novel transition metal-free aryl–aryl coupling amount of chiral diamines. An enantiomeric excess of up to
protocol, the "ARYNE-coupling", which allows the preparation 63% was obtained [67]. H. Kagan et al. reported the desym-
of di-, tri-, and even tetra-substituted ortho,ortho'-dibromo- metrization of prochiral aromatic or vinylic dihalide substrates
biphenyls [25,28,31,36-38]. These have the advantage that, by by halogen–metal exchange in the presence of a stoichiometric
means of successive or simultaneous bromine–lithium amount of diamines, with enantiomeric excess up to 26% [68].
exchanges, a huge panel of substituents can be introduced into Very recently, the Alexakis group achieved the catalytic
the biphenyl backbone.
bromine–lithium exchange allowing the preparation of biaryl-
atropisomers in quantitative yields and enantiomeric excesses
The bromine–lithium exchange reaction is certainly one of the up to 82% [69].
most fundamental synthetic transformations [39]. Although this
reaction was reported by C. S. Marvel in 1927 [40], G. Wittig Herein, we report on the preparation of C1 analogues of the
[41] and H. Gilman [42-44] were the first to apply it in organic most efficient and popular C2-symmetric biphenyl ligands. We
synthesis in the late thirties. Since then, this reaction has been will show that by means of regioselective bromine–lithium
considered as a mature method lacking both appeal and surprise exchanges all possible permutations of bis(diaryldiphosphino)-,
[33], and only new applications of this reaction or mechanistic bis(dialkylphosphino)- and dialkyl(diaryl)phosphinobiphenyls
studies have been reported [30,32,33,45-55]. However, in the become feasible. In a similar way, biphenyl-based monophos-
last few years, the halogen–metal permutation has recaptured its phine ligands were also obtained (Figure 1).
Figure 1: Modular synthesis of bis(diarylphosphino)-, bis(dialkylphosphino)- and dialkyl(diaryl)phosphinobiphenyls as well as monophosphino-
biphenyls by means of polar organometallic chemistry.
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Results and Discussion
Regioselective bromine–lithium exchange on
polybrominated biphenyls
subjected to lithiation, borylation with fluorodi-
methoxyborane·diethyl ether, followed by oxidation with
hydrogen peroxide and O-methylation with iodomethane in
acetone. 2,2'-Dibromo-6-methoxybiphenyl (1d) was finally
obtained in a very good global yield of 68% in 3 steps. Finally,
we proposed to introduce the phenyl ring (1f, 95%) by a regio-
selective Suzuki–Miyaura coupling via the iodo derivative
1e, the latter being obtained in 83% yield after trapping with
iodine.
Our group recently reported the efficient coupling of organo-
lithium intermediates with arynes, the so-called "ARYNE
coupling" [25,31,36]. This protocol is based on the formation of
a thermodynamically stable aryllithium intermediate and its
subsequent reaction with a 1,2-dibromobenzene derivative. The
transient benzyne adds the aryllithium derivative, followed by
in situ transfer of bromine between the resulting 2-biaryl-
lithium intermediate and another molecule of 1,2-dibromoben-
zene. Mono-, di- or even tetra-substituted ortho-bromobiaryls
can be obtained on a gram scale (Figure 2).
Similarly, as shown for 2,2',6-tribromobiphenyl (1a), when
6-substituted 2,2'-dibromobiphenyls 1b–e were treated with just
one equivalent of butyllithium in tetrahydrofuran at −78 °C,
another regioselective bromine–lithium exchange occurs on the
The intriguing question is whether one bromine would be functionalized ring (Scheme 2). Trapping with iodomethane
exchanged preferentially on the substrate when the bromine afforded the biphenyls 2 in high yield and perfect regioselec-
atoms are not activated by adjacent heteroatoms. An effective tivity, except for R = Ph (1f) and the benzodioxole derivative
discrimination between two bromine atoms as a function of (1i), where the regioselectivity was slightly lower (91:9 and
their chemical environment has so far been observed only 92:8, respectively).
sporadically in such processes [30,34,35,51,52,70-72].
M. Schlosser and J. Gorecka-Kobylinska recently reported on
Fortunately, the reaction occurred exclusively on the doubly the relative basicities of aryllithiums bearing methoxy, chlorine,
halogenated ring when 2,2',6-tribromobiphenyl [28,38], fluorine, trifluoromethyl and trifluoromethoxy substituents
obtained almost quantitatively by the ARYNE coupling at the ortho, meta, and para positions. Equilibration studies of
protocol, was submitted to the bromine–lithium exchange reac- two aryllithiums of comparable basicity with the corresponding
tion. When 2,2',6-tribromobiphenyl (1a) [28] was treated at bromo- or iodoarenes allowed them to determine the "basicity"
−78 °C with BuLi and the intermediate aryllithium trapped with (protodelithiation) increments ∆∆G, derived from the
iodomethane, 2,2'-dibromo-6-methylbiphenyl (1b) was obtained equilibrium constants. The authors showed that the basicity
in an excellent yield of 96%. Analogously, when benzenesul- increments are linearly correlated with the relative
fonylazide was used as an electrophile, 2-azido-2',6-dibromo- protonation enthalpies of the corresponding aryl anions in
biphenyl was obtained. The use of lithium aluminium hydride in the gas phase. Compared with "naked" aryl anions, the
ether at reflux for 4.5 h gave exclusively 2-amino-2',6-dibromo- basicity of aryllithiums mirrors the effects of ortho,
biphenyl, which was submitted to a reductive methylation by meta, and para substituents to the extent of 36%, 30%, and
means of formaldehyde and sodium cyanoborohydride. 2-N,N- 25%, respectively [73].
Dimethylamino-2',6-dibromobiphenyl (1c) was obtained in an
overall yield of 79% in 3 steps (Scheme 1). To introduce the These results explain the difference in regioselectivity of the
methoxy group, 2,2',6-tribromobiphenyl (1a) was successively bromine–lithium exchange, between a bromine atom residing
Figure 2: ARYNE coupling.
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Beilstein J. Org. Chem. 2011, 7, 1278–1287.
Scheme 1: Functionalization of 2,2',6-tribromobiphenyl (1a) by regioselective bromine–lithium exchange.
Scheme 2: Functionalization of 2,2'-dibromobiphenyls (1b–e) by regioselective bromine–lithium exchange.
on a phenyl ring that bears a "stabilizing" substituent at a equivalent of butyllithium in tetrahydrofuran at −78 °C (condi-
remote meta position and a bromine atom on an "unstabilized" tions a) or in toluene at 0 °C (conditions b). After cooling to
phenyl ring.
−78 °C, the lithiated intermediate was then allowed to react
with a solution of ClPCy2, or ClPPh2 in toluene. In these cases,
the monophosphines 3 were obtained in good yields
Biaryl mono- and diphosphines
In the following section we will show how a large family of (Scheme 3).
biaryl mono- and diphosphines becomes readily accessible
through these common building-blocks. The general access is Single crystal X-ray analyses [74] of one ligand of each family
depicted in Figure 3.
(R1 = NMe2 (3a, Figure 4), OMe (3b, see Supporting Informa-
tion File 3), Ph (3d, see Supporting Information File 4), OCH2O
(3f, see Supporting Information File 5)) were performed in
Biarylmonophosphines: Path A
From the methylated intermediates 2a–d, new monophosphines order to confirm their structure. Thus, we confirmed the selec-
became accessible in one additional step (Scheme 3). The tivity of the different halogen–metal exchange reactions
bromine–lithium exchange was either performed with just one performed throughout the synthesis.
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Beilstein J. Org. Chem. 2011, 7, 1278–1287.
Figure 3: General access to biaryl mono- and diphosphine ligands; (Cy = cyclohexyl).
Scheme 3: Synthesis of monophosphines 3; (Cy = cyclohexyl).
Mixed dialkyl(diaryl)phosphinobiphenyls:
Path B
tion. We started from the same dibromobiaryls 1 as before, but
submitted them now to just one equivalent of butyllithium in
In order to synthesize mixed diphosphines, we took advantage THF. The aryllithium intermediate was then trapped with one
of the non-equivalence of the two phenyl rings towards lithia- equivalent of ClPCy2. The resulting monophosphine 4 was
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Beilstein J. Org. Chem. 2011, 7, 1278–1287.
Figure 4: Molecular structure of compound 3a (crystallized from ethyl acetate/hexane) [74].
Scheme 4: Preparation of mixed dialkyl(diaryl)phosphinobiphenyls 5 via successive bromine–lithium exchange.
isolated and then submitted to a second bromine–lithium yields for biaryls carrying α-fluorinated ether substituents, such
exchange in toluene followed by addition of ClPPh2 as OCF2O (53%; Table 1, entry 9) or OCF3 (33%; Table 1,
(Scheme 4). The lithiation–phosphination sequence was not entry 14), in comparison with their nonfluorinated counterparts,
substrate-dependent and reaction conditions were the same for OCH2O (70%; Table 1, entry 8) and OMe [30] (74%; Table 1,
all the different ortho substituents. In this way, pure ligands entry 5).
were obtained on a gram scale.
In the case of 2-N,N-dimethylamino-2',6-dibromobiphenyl (1c),
Bis(dialkyl)phosphinobiphenyls: Path C
higher yields were obtained when the double bromine–lithium
In order to gain access to bis(dicyclohexylphosphino)biphenyls exchange was realized successively instead of simultaneously.
3, a double bromine–lithium exchange was performed on the Indeed, the double phosphination in THF or toluene gave the
2,2'-dibromobiaryls 1. A screening of the reaction conditions corresponding ligand in a very poor yield (Table 1, entries 3 and
revealed higher yields for the double phosphination when the 4). When the first Br–Li exchange was carried out in THF at
bromine–lithium exchange and trapping with ClPCy2 were −78 °C, followed by trapping with ClPCy2, the corresponding
carried out in toluene rather than in THF and at higher tempera- monophosphine 7 was obtained in a good yield of 63%. The
ture. For example, with R1 = Me, OCF2O, and OCF2CF2O, the second Br–Li exchange was performed in toluene at 0 °C,
corresponding diphosphines were obtained in a yield of 54% (in affording ligand 6c in a moderate yield of 44% after trapping
toluene) versus 12% (in THF), 53% versus 36% and 73% with ClPCy2 (Scheme 5).
versus 35%, respectively (Table 1, entries 1, 2, 9, 10, 11 and
12). A series of bis(dicyclohexylphosphino)biphenyls 6 Single crystal X-ray analysis of 6c was performed (see
was obtained in good yield. However, we noticed lower Supporting Information File 6) [74].
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Beilstein J. Org. Chem. 2011, 7, 1278–1287.
Table 1: Synthesis of bis(dicyclohexylphosphino)biphenyls 6.
Entry
R1
X
RLi
n
Solvent
T [° C]
t
T' [°C]
t'
Ligand Yield
1
Me
Br
Br
Br
Br
Br
Br
Br
Br
I
BuLi
BuLi
t-BuLi
BuLi
BuLi
t-BuLi
BuLi
BuLi
BuLi
BuLi
BuLi
BuLi
BuLi
BuLi
2
2
4
2
2
4
2
2
3
3
3
3
2
2
toluene
THF
110
−78
−78
0
1 h
1 h
1 h
50
2 h
1 h
1 h
1 h
1 h
1 h
1 h
2 h
2 h
1 h
2 h
1 h
1 h
2 h
6b
6b
6c
6c
6d
6f
54%
12%
22%
30%
74%
66%
49%
70%
53%
36%
73%
35%
79%
33%
2
Me
−78
−78
3
NMe2
NMe2
OMe [30]
Ph
THF
4
toluene
THF
15 min −78
5
−78
−78
−78
110
25
1 h
1 h
1 h
1 h
1 h
1 h
1 h
1 h
−78
−78
−78
50
6
THF
7
Cl
THF
6g
6h
6i
8
OCH2O
OCF2O
OCF2O
O(CF2)2O
O(CF2)2O
F
toluene
toluene
THF
9
25
10
11
12
13
14
I
−78
25
−78
25
6i
I
toluene
THF
6j
I
−78
−78
110
−78
6j
Br
Br
THF
15 min −78
1 h 50
6k
6l
OCF3
toluene
Scheme 5: Stepwise bromine–lithium exchange on 1c.
Phosphafluorenes and
still contaminated with varying amounts of phosphafluorenes 9
bis(diarylphosphino)biphenyls: Path D and E
and triphenylphosphine (Table 2).
When the ortho,ortho'-dibromobiphenyls 1 were submitted to a
double bromine–lithium exchange in THF followed by trapping Conclusion
with two equivalents of ClPPh2, whatever the nature of the In the present work, we showed how completely regioselective
ortho substituent (R = Me, OMe, NMe2, Cl, OCF3, Ph, OCH2O, bromine–lithium exchange reactions on polybrominated
OCF2O, OCF2CF2O, H, F), the formation of an intramolecular biphenyls allow the construction of a new family of di- and
cyclization product, a dibenzophosphole, was exclusively monophosphine ligands. The required polybrominated
observed. This is consistent with the observations of O. biphenyls can be easily obtained through an efficient transition
Desponds et al. [75]. However, when THF was replaced by metal-free aryl–aryl coupling protocol developed by our group.
toluene, the outcome of the reaction could be modified in favor The regioselectivity can be explained by recent equilibration
of the 2,2'-bis(diphenylphosphino)biphenyls 8 [27] which were studies of M. Schlosser et al. which allowed the determination
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Beilstein J. Org. Chem. 2011, 7, 1278–1287.
Table 2: Synthesis of bis(diphenylphosphino)biphenyls 8.
Cpd.
R
X'
n [equiv]
Ta [°C]
T' b [°C]
Yield 8c
8b
8c
8d
8f
Me
Br
Br
Br
Br
Br
Br
I
2
2
2
2
2
2
3
3
2
110
110
110
110
110
110
25
50
50
50
50
50
50
25
25
50
30%
44%
17%
24%
23%
18%
47%
34%
10%
NMe2
OMe
Ph
8g
8h
8i
Cl
OCH2O
OCF2O
OCF2CF2O
OCF3
8j
I
25
8l
Br
110
aTemperature for the halogen/metal exchange; bTrapping temperature; cIsolated yield of 8 after flash-chromatography on silica gel.
of ∆∆G increments for substituents at the ortho, meta, and para
Supporting Information File 4
positions.
Crystal structure data for 3d.
[http://www.beilstein-journals.org/bjoc/content/
Overall, the methodology presented in this study offers the
supplementary/1860-5397-7-148-S4.pdf]
possibility to consider new pathways for the synthesis of more
sophisticated biaryl scaffolds. Catalytic studies as well as the
Supporting Information File 5
control of biaryl axial chirality are currently underway and will
Crystal structure data for 3f.
be reported in due course.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-7-148-S5.pdf]
Supporting Information
Supporting Information File 6
Supporting Information File 1
Crystal structure data for 6c.
Experimental details and spectroscopic data for new
[http://www.beilstein-journals.org/bjoc/content/
compounds.
supplementary/1860-5397-7-148-S6.pdf]
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-7-148-S1.pdf]
Supporting Information File 2
Crystal structure data for 3a.
Acknowledgements
We thank the CNRS and the Ministère de la Recherche of
[http://www.beilstein-journals.org/bjoc/content/
France. We are very grateful to LONZA AG, Switzerland for a
supplementary/1860-5397-7-148-S2.pdf]
PhD grant for L.B. We also thank Dr. Lydia Brelot, Université
de Strasbourg, for single crystal X-ray analysis.
Supporting Information File 3
Crystal structure data for 3b.
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