An efficient synthesis of 3,3′-dipyridyl BINOL ligands

Article abstract of DOI:10.1016/j.tetlet.2009.04.092

Microwave-assisted Suzuki cross-coupling between 2,2′-bis(methoxymethyl)-3,3′-bis(potassium trifluoroboronato)BINOL and a series of 2-bromo- or 2-chloropyridines provides efficient access to 3,3′-dipyridyl BINOL ligands.

Full text of DOI:10.1016/j.tetlet.2009.04.092

Tetrahedron Letters 50 (2009) 3985–3987
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Tetrahedron Letters
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An efficient synthesis of 3,30-dipyridyl BINOL ligands
*
Anna Goldys, Christopher S. P. McErlean
School of Chemistry, University of Sydney, NSW 2006, Australia
a r t i c l e i n f o
a b s t r a c t
Microwave-assisted Suzuki cross-coupling between 2,20-bis(methoxymethyl)-3,30-bis(potassium triflu-
oroboronato)BINOL and a series of 2-bromo- or 2-chloropyridines provides efficient access to 3,30-dipyr-
idyl BINOL ligands.
Article history:
Received 16 March 2009
Revised 6 April 2009
Accepted 24 April 2009
Available online 3 May 2009
Ó 2009 Elsevier Ltd. All rights reserved.
The class of BINOL-derived ligands occupies a privileged posi-
tion in the arena of synthetic organic chemistry.1 Of particular
importance in this respect is the subset of ligands based on the
3,30-disubstituted BINOL scaffold. With an appropriate choice of
sterically demanding substituent at these flanking positions,
impressive levels of enantio- and diastereocontrol have been rea-
lised over a wide range of transformations.2
Gao and co-workers were the first to report 3,30-dipyridyl-
substituted BINOL variants.3 Recently, Snieckus and co-workers
have reported a general synthesis of this class and have employed
these compounds in highly enantioselective additions of alkyl zinc
reagents to aldehydes.4 Those authors present evidence that the
coordinating nitrogen atom on the pyridine ring leads to the for-
mation of a bi-functional catalyst coordinating more than one me-
tal centre.5 This is not the only mode of action available to such
ligands. It can be envisaged that the pendant nitrogen donor could
function as a Lewis acid, co-coordinating to a bound single metal
centre.6 We became interested in utilising this class of 3,30-dipyri-
dyl-substituted BINOL ligand for organocatalytic applications and
set about developing an efficient synthesis of these compounds.
The synthesis of 3,30-substituted BINOL 1 compounds can be
envisaged to arise through a palladium-mediated cross-coupling
between a metalated BINOL unit 2 and an aryl or heteroaryl halide
3 (Scheme 1). The metalated BINOL unit can be efficiently gener-
ated employing directed metalation groups (DMGs) such as an
OMOM, OMe or OCONEt2. However, the introduction of pyridyl
units in this way has proved troublesome due to the unwillingness
of halopyridines to participate in palladium-mediated reactions.
The initial attempts of Jørgensen and co-workers to couple BINOL
bis-boronic acid with halopyridines were unprofitable.7 In the first
reported synthesis of these compounds, Gao and co-workers used a
Suzuki cross-coupling between a bis-boronic pinacol ester and a
halopyridine to install the desired unit in yields ranging from 79
to 84%.3 Extended reactions times (24 h in refluxing toluene) were
Scheme 1. Retrosynthetic analysis.
required to effect the coupling which suffered from narrow scope.
Unfortunately, the synthesis of the bis-boronic pinacol ester has
proven capricious in our hands, with the compound being prone
to hydrolysis and consequently giving disappointing results in
the cross-coupling reactions with 2-bromopyridine.
After surveying alternatives, Snieckus settled upon the Negishi
coupling as the most efficient method to generate these com-
pounds.4 The readily available bis-MOM compound 4 underwent
* Corresponding author. Tel.: +61 2 9351 3970; fax: +61 2 3951 3329.
E-mail address: C.McErlean@chem.usyd.edu.au (C.S.P. McErlean).
Scheme 2. Snieckus’ route to 3,30-dipyridyl BINOL ligands.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.04.092

3986
A. Goldys, C. S. P. McErlean / Tetrahedron Letters 50 (2009) 3985–3987
such, we explored the synthesis and microwave-assisted cross-
coupling reactions of the bis(potassium trifluoroboronato)BINOL
compound 8.
Aryl, alkenyl and alkyl trifluoroborates have found increasing
use in synthesis as boron coupling partners in Suzuki reactions.8
Aryltrifluoroborates possess a number of properties that make
them very practical reagents. Unlike the corresponding boronic
acids, trifluoroborates exist as discrete species, avoiding compli-
cated acid-boroxine equilibria. They are inert towards many of
the standard reagents used by the synthetic chemist, acting as pro-
tected boronic acids under oxidative,9 alkylative10 and a variety of
other conditions.11 They are a much more atom economical source
of boron than pinacol or related esters, and they readily participate
in Suzuki coupling reactions without additives and in air. Impor-
tantly for our purposes, these solid compounds can be made in
an operationally simple manner following the procedure of
Vedejs.11
Scheme 3. Synthesis of 8.
Our synthesis began with the ortho-lithiation of the bis-MOM
compound 4, in the absence of TMEDA. Reaction with triisopropyl
borate delivered the readily hydrolysable boronic ester which was
converted into the corresponding bis(potassium trifluoroboronato)
complex by the action of KHF2. Simple filtration then delivered the
desired 2,20-bis(methoxymethyl)-3,30-bis(potassium trifluoroboro-
nato) BINOL compound 8 as a bench-stable, colourless solid in 99%
yield from 4 (Scheme 3).
Having achieved a simple and reliable synthesis of the boronate
coupling partner,12 we proceeded to investigate the Suzuki cou-
pling with 2-bromopyridines. Pleasingly, our initial attempt at
effecting a union between compound 8 and 2-bromopyridine 9
was successful. Irradiating a mixture of 8, 9, Pd(PPh3)4 (10 mol %)
and K2CO3 in DMF/water to 150 °C in a sealed microwave reactor,13
gave the desired adduct 10a as the sole product in 97% yield and in
just 15 min. Acid hydrolysis delivered the desired 3,30-dipyridyl-
BINOL 11a, quantitatively. To simplify the procedure further, the
MOM-protecting group could be removed during the reaction
work-up by treatment with acid. This simple protocol delivered
the desired 3,30-dipyridylBINOL 11a in an identical yield (Scheme
4).
Scheme 4. Suzuki coupling reaction of 8.
a double ortho-lithiation–iodination sequence. The purified bis-
iodo compound 5 underwent lithium–halogen exchange with
tert-butyllithium and transmetalation with ZnCl2 to give com-
pound 6. Palladium-mediated cross-coupling with a range of 2-
halopyridines in refluxing THF then delivered the desired 3,30-
dipyridyl-substituted BINOL ligands 7 in yields ranging from 42
to 75%. Attempts to generate the organo-zinc species 6 directly
from the initial doubly ortho-lithiated compound resulted in re-
duced yields (Scheme 2).
We next sought to explore the scope of the pyridyl coupling
partner. Snieckus had used 3-substituted-2-iodopyridines to illus-
trate the Negishi coupling methodology.4 We were confident that
We decided that a more operationally simple procedure was re-
quired, which would deliver the ligands in higher overall yield. As
Table 1
Synthesis of ligands 11a–h
Entry
Substrate 9
R1
R2
X
Yield of 10a (%)
Yield of 11a (%)
1
2
3
4
5
6
7
a
b
c
d
f
H
H
H
H
H
H
H
OMe
Br
Br
Br
Br
Br
Br
Cl
97
51
64
56
100
90
95
95
96
—
OBn
OC6H13
OC4H9
OTs
OH
27
g
h
n.d.b
63
H
92
a
Isolated yield after chromatography.
Not detected.
b

A. Goldys, C. S. P. McErlean / Tetrahedron Letters 50 (2009) 3985–3987
3987
Table 2
deprotection protocol. Enantioselective HPLC analysis of the prod-
uct 3,30-dipyridyl BINOL compounds 11b–d and 11h demonstrated
unambiguously that the stereochemical integrity of the biaryl bond
was not compromised during the coupling protocol (Table 2).
In summary, we have disclosed an efficient route to 3,30-dipyr-
idyl-substituted BINOL ligands based on a microwave-assisted
Suzuki coupling reaction between the bis(potassium trifluoroboro-
nato)BINOL compound 8 and a series of 2-halopyridines. Applica-
tions of these ligands in catalytic settings will be reported in due
course.
Synthesis of enantiomerically enriched ligands 11a–d
Entry
Compound
eea
Observed ½a 2D0
ꢀ
Supplementary data
1
2
3
4
11a
11b
11c
11d
—
ꢁ45.8
ꢁ48.9
ꢁ37.0
ꢁ34.5
>98%
>98%
>98%
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.04.092.
a
Determined on a Diacel AD-H column, eluting with 50% hexane–isopropanol.
References and notes
1. Brunel, J. M. Chem. Rev. 2005, 105, 857–897.
the less reactive 2-bromopyridines would participate in the micro-
wave-assisted Suzuki couplings. Gratifyingly, 3-benzyloxy,14 3-
hexyloxy and 3-butyloxy-2-bromopyridine15 reacted under the
conditions listed above to give the desired compounds in 51%,
64% and 56% yields, respectively (Table 1, entries 2–4). The use
2. Examples include, hydrogenation: Minnaard, A. J.; Feringa, B. L.; Lefort, L.; De
Vries, J. G. Acc. Chem. Res. 2007, 40, 1267–1277; halocyclisation of
polyprenoids: Sakakura, A.; Ukai, A.; Ishihara, K. Nature 2007, 445, 900–903;
organo-zinc additions to aldehydes: Harada, T.; Hiraoka, Y.; Kusukawa, T.;
Marutani, Y.; Matsui, S.; Nakatsugawa, M.; Kanda, K. Org. Lett. 2003, 5, 5059–
5062; cycloaddition reactions: Nakashima, D.; Yamamoto, H. J. Am. Chem. Soc.
2006, 128, 9626–9627; conjugate addition reactions: Wu, T. R.; Chong, J. M. J.
Am. Chem. Soc. 2007, 129, 4908–4909; reductive aminations: Storer, R. I.;
Carrera, D. E.; Ni, Y.; MacMillan, D. W. C. J. Am. Chem. Soc. 2006, 128, 84–86.
3. Jin, R.-Z.; Bian, Z.; Kang, C.-q.; Guo, H.-q.; Gao, L. Z. Synth. Commun. 2005, 35,
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2007, 9, 4403–4406.
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of readily available bromopyridines represents
improvement to the current methods.
a significant
The bifunctional coupling partner 3-tosyl-2-bromo-pyridine16
also underwent coupling with the bis-boronate, albeit in a much
reduced yield (entry 5). The reaction was not restricted to bromo-
pyridines. 2-Chloro-5-methoxypyridine could be utilised effec-
tively as the coupling partner to give the desired product in 63%
yield (entry 7). In each case, acid-catalysed removal of the MOM-
protecting group was uneventful and delivered the free diol in a
straightforward manner. As the reaction was conducted in aqueous
media, we thought that alcohol-protecting groups on the pyridine
core may be superfluous. However, attempts to couple the parent
2-bromo-3-pyridinol under the standard conditions were uni-
formly unsuccessful (entry 6).
Whilst these initial reactions defined the scope of the pyridyl
coupling partner, they were performed on racemic BINOL sub-
strates. We next sought to ascertain whether or not the microwave
conditions were suitable for the generation of a single enantio-
meric series. As such, (S)-4 was converted into the corresponding
bis(potassium trifluoroboronato)BINOL (S)-8 in the manner
described above. The bis(potassium trifluoroboronato)BINOL (S)-8
was then subjected to the microwave-assisted Suzuki coupling–
12. This reaction has been carried out several times on gram scale.
13. The microwave-assisted reactions were conducted in quartz reactor vessels
using a Milestone MicroSYNTH laboratory microwave.
14. Genin, M. J.; Poel, T. J.; Yagi, Y.; Biles, C.; Althaus, I.; Keiser, B. J.; Kopta, L. A.;
Friis, J. M.; Reusser, F.; Adams, W. J.; Olmsted, R. A.; Voorman, R. L.; Thomas, R.
C.; Romero, D. L. J. Med. Chem. 1996, 39, 5267–5275.
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16. Hodgson, R.; Kennedy, A.; Nelson, A.; Perry, A. Synlett 2007, 1043–1046.