Transition-metal-free atropo-selective synthesis of biaryl compounds based on arynes

Article abstract of DOI:10.1002/chem.201202739

A modular way towards biaryls: Highly enantioenriched biphenyls can be prepared based on a transition-metal-free aryl-aryl coupling followed by efficient desymmetrization or deracemization and chemoselective functionalization (see scheme). Copyright

Full text of DOI:10.1002/chem.201202739

COMMUNICATION
DOI: 10.1002/chem.201202739
Transition-Metal-Free Atropo-Selective Synthesis of Biaryl Compounds
Based on Arynes
Frꢀdꢀric R. Leroux,* Anaꢁs Berthelot, Laurence Bonnafoux, Armen Panossian, and
FranÅoise Colobert*[a]
The biaryl motif occupies an iconic role in chemistry,
being a key structural feature of natural products, biological-
ly active molecules, drugs, agrochemicals, and other novel
optical and mechanical materials.[1] Furthermore, the stereo-
genic axes provide rigid molecular frameworks for highly ef-
ficient tools in asymmetric synthesis.[2] With the continuously
increasing importance of axially chiral biaryl compounds as
chiral auxiliaries and ligands for asymmetric synthesis and
as a structurally decisive element in bioactive natural prod-
ucts, considerable efforts have been undertaken to develop
efficient methods for their atropo-selective synthesis.[3] Thus,
three issues are currently being addressed, namely the regio-
and stereoselective control in biaryl synthesis, as well as the
minimization of the amounts of metal used in these process-
es.
In recent years, classical methods for creating aryl–aryl
bonds[3b] have been supplanted by direct arylation methodol-
ogies in which the carbon–hydrogen bond is used as a func-
tional group.[4] However, in all these approaches the em-
ployment of heavy metals often causes contamination of the
products, which require purification for biological applica-
tions. Indeed, due to potentially toxic contamination of
pharmaceutical products, effective removal of the metal (Pt,
Pd, Ir, Rh, Ru, Os) in active pharmaceutical ingredients
(API) causes acute problems for pharmaceutical compa-
nies.[5]
coupling products, which can easily be functionalized further
on both phenyl rings.[7] Yet this approach represents an at-
tractive alternative to the important transition-metal-cata-
lyzed coupling reactions for different reasons: 1) no need
for transition metals; 2) no need for expensive ligands; 3)
the possibility to couple polybrominated aryls, difficult to re-
alize by Suzuki–Miyaura coupling; and 4) access to product
families through subsequent functionalization. This method-
ology has become a mature method for the synthesis of biar-
yls, and has been applied successfully to the preparation of
phosphorus ligands for catalysis.[8]
For instance, 2,2’,6-tribromobiphenyl (1a) and 2,2’-dibro-
mo-6-chlorobiphenyl (1b) can be obtained on multigram
scale through aryne coupling in almost quantitative yield
(Scheme 1).[9] We showed that the polybrominated scaffold
allows for regioselective, successive bromine/lithium inter-
conversions, which opens a route to a vast library of biar-
yls.[10]
We recently reported on an efficient transition-metal-free
aryl–aryl coupling protocol, the aryne coupling.[6] Starting
from haloarenes and alkyllithium reagents, it consists of the
reaction of in situ formed aryllithiums and arynes, with con-
comitant regeneration of a carbon–halogen bond. The aryne
coupling gives rise to a large number of diversely substituted
[a] Dr. F. R. Leroux, A. Berthelot, Dr. L. Bonnafoux, Dr. A. Panossian,
Prof. F. Colobert
Scheme 1. Synthesis of 2,2’,6-tribromo- and 2,2’-dibromo-6-chlorobiphen-
yls (1) as common building-blocks by aryne coupling.
Laboratoire de Chimie Molꢀculaire (UMR7509/CNRS/ECPM)
Universitꢀ de Strasbourg, 25 Rue Becquerel
67087 Strasbourg (France)
We disclose here an efficient route to the modular con-
struction of enantiopure biaryls based on the deracemization
or desymmetrization and subsequent regio- and chemoselec-
tive functionalization of some common building blocks.
In order to control the axial chirality, we decided to intro-
duce a traceless chiral auxiliary after the first bromine/lithi-
um exchange. The sulfinyl group has advantages that can
Fax : (+33)3-68-85-27-42
E-mail: frederic.leroux@unistra.fr
francoise.colobert@unistra.fr
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201202739. It contains experi-
mental protocols, characterization data and copies of H, 13C and
1
31P NMR spectra for all compounds; copies of SFC or GC spectra
proving the enantiomeric purity of compounds.
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hardly be improved by other chiral auxiliaries:[11] 1) its high
optical stability; 2) the existence of a large number of sulfi-
nylating agents in both enantiomeric forms; 3) the known
ortho-directing ability of the sulfinyl group and its efficiency
as a carrier of chiral information; 4) electronic properties,
which enhance the contrast between the physical properties
of the two stereoisomers, mainly because of dipole orienta-
tion;[11c] and 5) they are very useful as traceless resolving
agents, as they may undergo sulfoxide/lithium exchange[10c]
affording new organometallic intermediates, which can sub-
sequently be trapped by various electrophiles.[12]
When 2,2’,6-tribromobiphenyl (1a) or the analogous 2,2’-
dibromo-6-chlorobiphenyl (1b) were submitted to the regio-
selective bromine/lithium interconversion[10a,b] followed by
trapping with enantiomerically pure (1R,2S,5R)-(À)-menth-
yl-(S)-p-toluenesulfinate,[13] the atropo-diastereomeric biar-
ylsulfoxides 2 were obtained in excellent yields. Simple crys-
tallization allowed for the separation of both atropo-diaster-
eoisomers affording 2a-SaR and 2a-SaS in 54 and 70%
yield, respectively, based on the theoretically possible yield
of each diastereoisomer (Scheme 2).
Figure 1. ORTEP representation of the structure of 2a-SaR (for 2a-SaS
see reference [14]); thermal ellipsoids at the 50% probability level.
lithium or tert-butyllithium) were employed, no chemoselec-
tivity between both types of substituents was observed. In
contrast, when employing Knochelꢂs iPrMgCl·LiCl reagent,
a clean sulfoxide/magnesium interconversion was observed
at À508C. However, when the intermediate biaryl Grignard
reagent was treated with iodomethane as the electrophile,
the temperature had to be raised to 08C, which caused parti-
al racemization of the biaryl axis. Thus, we had to find an
exchange reagent 1) which allows the discrimination be-
tween the sulfoxide group and the bromine atom(s) and 2)
which leads to an intermediate which is reactive enough for
trapping at lower temperature. PhLi appeared to be the re-
agent of choice fulfilling all these requirements. It has been
rarely employed in this kind of exchange reaction.[15]
When the atropo-diastereomeric biaryl sulfoxides 2 were
treated with PhLi at À788C, a clean sulfoxide/Li intercon-
version occurred within 10 min. Subsequent trapping with
various electrophiles afforded enantioenriched biaryls with
excellent e.r.ꢂs (ꢀ96:4, Table 1). For example, starting from
biaryl 2a-SaR, the methyl derivative 3a-aR was obtained
upon treatment with iodomethane (Table 1, entry 1), the al-
dehyde 3b-aR was obtained after trapping of the lithiated
intermediate
with
N,N-dimethylformamide
(Table 1,
entry 3), and the acid 3c-aR was obtained after pouring
onto freshly crushed dry ice (Table 1, entry 4). The iodo de-
rivative 3d-aS was obtained in a similar way after addition
of iodine (Table 1, entry 5). After treatment of the lithiated
intermediate with fluorodimethoxyborane diethyl etherate
and oxidative treatment, the phenol was obtained and im-
mediately converted into the methyl ether 3e-aR (Table 1,
entry 6).
Similarly, when performing the reaction with the other
atropoisomer 2a-SaS, as exemplified in entry 2 of Table 1,
the enantiomer 3a-aS was obtained in excellent yield and
e.r. after trapping with iodomethane. The chlorobiphenyl 2b
was functionalized in a similar way as shown in entries 7–10
of Table 1. The absolute configuration of the biaryl axes in
3a-aR, 3b-aR, 3d-aS, 4a-aR and 4d-aS was confirmed by
single-crystal X-ray diffraction analysis (Figure 2).[14]
Scheme 2. Desymmetrization of achiral 1a and deracemization of race-
mic 1b by means of enantiomerically pure p-tolylsulfoxide as chiral auxil-
iary.
The chlorobiphenyl 1b gave the corresponding diaster-
eoisomers in 60 and 54% yield, respectively. The structures
of these compounds and the absolute configuration of 2a-
SaR, 2a-SaS, and 2b-SaR were determined by single-crystal
X-ray diffraction analysis (Figure 1).[14]
The most challenging part is now the chemoselective func-
tionalization of the atropo-diastereomerically pure biaryls
without racemization. Both substitutents, the sulfoxide
group as well as the bromine atoms, may undergo exchange
reactions. When standard organolithium reagents (n-butyl-
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Coupling Reactions
COMMUNICATION
Table 1. Chemoselective sulfoxide/lithium interconversion towards enan-
tiopure biaryls 3.[a]
Scheme 3. Example for a modular biaryl construction.
Precursor
Product
X
Yield
[%]
e.r.
X
EI
1
2
3
4
5
6
7
8
9
2a-SaR
2a-SaS
2a-SaR
2a-SaR
2a-SaR
2a-SaR
2b-SaR
2b-SaR
2b-SaR
2b-SaR
Br
Br
Br
Br
Br
Br
Cl
Cl
Cl
Cl
3a-aR
3a-aS
3b-aR
3c-aR
3d-aS
3e-aR
4a-aR
4b-aR
4c-aR
4d-aS
Br
Br
Br
Br
Br
Br
Cl
Cl
Cl
Cl
Me
Me
95
96
81
86
92
72
95
69
84
90
98:2
98:2
99:1
>99:1
>99:1
97:3
96:4
99:1
>99:1
97:3
position. The biphenyl 5 was obtained in 92% yield and e.r.
>99:1 (Scheme 3). The third substituent, a carboxylic group,
was then introduced after another bromine/lithium intercon-
version followed by pouring onto freshly crushed dry ice.
When the bromine/lithium exchange was performed at
À788C during 5 min, the carboxylic acid 6 was obtained in
60% yield and 85:15 e.r. When the biaryl lithium intermedi-
ate was kept for 45 min at À788C before trapping, a 70:30
e.r. was obtained (85:15 e.r. after 5 min). In contrast, when
performing the exchange at À1008C for 5 min, a 91:9 e.r.
was achieved. These results underline the configurational
stability of the intermediate biaryl lithium.
CHO
COOH
I
OMe
Me
CHO
COOH
I
10
[a] * in the structures of the products indicates the element of chirality.
In another model reaction, we decided to apply our re-
cently developed catalytic phosphination[16] on the enantio-
merically pure biphenyl 4d-aS (Table 1, entry 10). Although
this trisubstituted biphenyl had to be heated at 1308C for
3 h, the diphosphine 7 was obtained with an e.r. of 92:8
(Scheme 4). The absolute configuration of the biaryl axes
Figure 2. ORTEP representation of the structure of 3a-aR (for 3b-aR,
3d-aR, 4a-aR, 4d-aS see reference [14]); thermal ellipsoids at the 50%
probability level.
Scheme 4. Example for a Pd-catalyzed phosphination on enantiopure bi-
phenyl 4d-aS.
In order to show the scope of this approach, we decided
to perform a complete functionalization of the biaryl
through subsequent sulfoxide- and bromine/lithium inter-
conversions. First the atropo-diastereoisomer 2a-SaR was
converted into the methoxy derivative as already shown in
Table 1, entry 6. In the next step, a regioselective bromine/
lithium interconversion followed by trapping with iodome-
thane allowed the introduction of a methyl group at the 2’-
was confirmed by single-crystal X-ray diffraction analysis.[14]
Similarly, we could show that iodobiaryl 3d-aS can be ef-
ficiently submitted to a catalytic amination in order to intro-
duce an NH2 substituent (Scheme 5). The aminobiphenyl
3 f-aR was obtained in 49% yield and with 94:6 e.r.
In conclusion, we have developed an efficient protocol for
the modular construction of enantioenriched biphenyl deriv-
atives based on 1) an almost quantitative access to polybro-
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F. R. Leroux, F. Colobert et al.
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minated precursors by means of a transition-metal-free aryl–
aryl coupling, 2) the regioselective introduction of a trace-
less chiral auxiliary (an enantiopure p-tolylsulfinyl group) al-
lowing the separation of atropo-diastereoisomers by simple
crystallization, 3) the chemoselective functionalization of
this auxiliary, and 4) subsequent regioselective functionaliza-
tion of the remaining bromine atoms. During all these trans-
formations, the configuration of the biaryl axes is main-
tained and no racemization occurs.
Experimental Section
At À788C, n-butyllithium (1 equiv) was added dropwise to a solution of
the substrate (1 equiv) in THF (2 mLmmolÀ1 substrate). At 08C, this sol-
ution was added through a cannula to a stirred solution of (À)-(S)-
menthyl-p-toluenesulfinate (1 equiv) in toluene (6.7 mLmmolÀ1 (À)-(S)-
menthyl-p-toluenesulfinate). The reaction mixture was allowed to reach
RT over 12 h. Water (4 mLmmolÀ1 substrate) was added. The layers were
separated and the aqueous layer was extracted with dichloromethane (3ꢃ
4 mLmmolÀ1 substrate). The combined organic layers were dried, filtered
and evaporated. The crude material was purified by column chromatog-
raphy to yield the desired compound.
General procedure for sulfoxide/lithium exchange and trapping with an
electrophile (iodomethane or iodine): A pre-cooled solution of the sub-
strate (1 equiv) in THF (10 mLmmolÀ1 substrate) was added to a solution
of PhLi (2 equiv; prepared by adding tBuLi (2.0 equiv) to idobenzene
(1 equiv) in diethyl ether (4 mLmmolÀ1 iodobenzene) and stirring for
30 min at 08C) at À788C. After 10 min, the electrophile (3 equiv) was
added and the mixture was warmed to r.t. Water (4 mLmmolÀ1 substrate)
was added. The layers were separated and the aqueous layer was extract-
ed with ethyl acetate (3ꢃ4 mLmmolÀ1 substrate). The combined organic
layers were dried over Na2SO4, filtered and evaporated. The crude mate-
rial was purified by column chromatography to yield the desired com-
pound.
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This work was supported by the CNRS (Centre National de la Recherche
Scientifique) and the “Ministꢄre de l’Education Nationale et de la Re-
cherche”. A.B. thanks the “Ministꢄre de l’Education Nationale et de la
Recherche” (France) for an MENRT Ph.D. grant. L.B. is much indebted
to LONZA AG (Switzerland) for a Ph.D. grant. We are very much grate-
ful to J. Graff and Prof. A. Alexakis, University of Geneva (Switzerland)
for SFC and GC analysis.
Keywords: biaryls
· chirality · selectivity · sulfoxide ·
synthetic methods
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Coupling Reactions
COMMUNICATION
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Received: July 2, 2012
Revised: August 16, 2012
Published online: && &&, 0000
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F. R. Leroux, F. Colobert et al.
Coupling Reactions
F. R. Leroux,* A. Berthelot,
L. Bonnafoux, A. Panossian,
F. Colobert* ................... &&&& — &&&&
Transition-Metal-Free Atropo-Selec-
tive Synthesis of Biaryl Compounds
Based on Arynes
A modular way towards biaryls:
by efficient desymmetrization or dera-
cemization and chemoselective func-
tionalization (see scheme).
Highly enantioenriched biphenyls can
be prepared based on a transition-
metal-free aryl–aryl coupling followed
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ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
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