Ir-catalyzed borylation of C-H bonds in N-containing heterocycles: Regioselectivity in the synthesis of heteroaryl boronate esters

Article abstract of DOI:10.1002/anie.200503047

(Chemical Equation Presented) Blocking the way: Substitution at the 2-position in pyridines and other N-heterocycles blocks N-coordination to an Ir center. This steric hindrance provides a substrate-design criterion that allows the Ir-catalyzed borylation

Full text of DOI:10.1002/anie.200503047

Angewandte
Chemie
Synthesis Design
intrigued that GC–MS analysis of the borylation reaction
mixtures in situ did not show any borylation of the ligand 1A,
although 1A could be detected by itself. We envisaged three
possible reasons for this: 1) 1A is firmly attached to the Ir
center through the nitrogen atoms at all times; 2) it is simply
not a suitable substrate for the catalyst, even if it were to
dissociate; or 3) we would be unable to detect borylated 1A
by using our GC–MS method. We noted that pyridine itself is
a “poor” substrate for the borylation reaction,[9,10] whereas
pyrrole and quinoline are readily borylated;[11] however, 2,6-
chloropyridine and 2,6-dimethylpyridine were effectively
borylated at the 4-position,[5,12] and 5-bromo-2-cyanopyridine
was borylated at the 3- and 4-positions in a 2:1 ratio.[13]
To investigate the question of the borylation of 1A
further, rather than add a stoichiometric amount of 1A with
respect to the Ir center, 20 equivalents of the ligand and
40 equivalents of bis(pinacolato-O,O’)diboron (B2pin2) in
hexane (5 mL) were added to [Ir(cod)(m-OMe)]2 I (cod =
cyclooctadiene). GC–MS analysis of the reaction mixture
in situ after heating at 808C for 16 h showed borylation of 1A
was complete (100% conversion) and gave rise to a single
DOI: 10.1002/anie.200503047
À
Ir-Catalyzed Borylation of C H Bonds in
N-Containing Heterocycles: Regioselectivity in
the Synthesis of Heteroaryl Boronate Esters**
Ibraheem A. I. Mkhalid, David N. Coventry,
David Albesa-Jove, Andrei S. Batsanov,
Judith A. K. Howard, Robin N. Perutz, and
Todd B. Marder*
Aryl and heteroaryl boronates are very important, especially
as intermediates for Suzuki–Miyaura cross-coupling reac-
tions;[1] for the Cu-catalyzed C O and C N coupling
reactions developed by Chan, Lam, and co-workers;[2] and
for Rh-catalyzed conjugate additions to carbonyl com-
pounds.[3] The most attractive potential synthesis of these
À
À
À
boronate esters would be the direct borylation of C H bonds
1
in arenes or heteroarenes themselves. A very exciting recent
advance has been the development by Ishiyama et al.[4] and
Smith and co-workers[5] of in situ prepared, suitably ligated
analogues of the iridium tris(boryl) complexes discovered by
isomer, which H, 13C, and 2D NMR spectroscopic experi-
ments indicated to be 4,4’-tBu2-6,6’-(Bpin)2-2,2’-bipyridine
(2A) with the boryl group on the carbon atom adjacent to the
nitrogen atom (Scheme 1). Removal of the solvent in vacuo
us,[6] which catalyze the borylation of aromatic C H bonds
À
under mild conditions. Density functional theory (DFT)
calculations by Sakaki and co-workers,[7] in agreement with
proposals from the experimental data, suggest that the key
À
catalytic intermediate that leads to C H activation is the
sterically encumbered, five-coordinate [Ir(Bpin)3L2]species
(Bpin = B(OCMe2CMe2O)). This intermediate accounts for
the selectivity observed, as borylation typically avoids posi-
tions ortho to either substituents or to ring junctions. We have
taken advantage of this selectivity to prepare novel pyrene-
2,6-bis(boronate) and perylene-2,5,8,11-tetra(boronate)
esters amongst other polycyclic aryl boronates.[8] During the
course of our studies on the system developed by Ishiyama
et al. (L2 = 4,4’-tBu2-2,2’-bipyridine (dtbpy; 1A)), we were
[*] I. A. I. Mkhalid, Dr. D. N. Coventry, Dr. D. Albesa-Jove,
Dr. A. S. Batsanov, Prof. J. A. K. Howard, Prof. T. B. Marder
Department of Chemistry
Scheme 1. Borylation of 1A.
University of Durham
South Road, Durham, DH13LE (England)
Fax: (+44)191-384-4737
E-mail: todd.marder@durham.ac.uk
followed by addition of 3 equivalents of PhI, 4 equivalents of
K3PO4·2H2O as the base, 10 mol% of [PdCl2(dppf)](dppf =
1,1’-bis(diphenylphosphino)ferrocene) as the catalyst, and dry
dimethylformamide (DMF) as the solvent and heating (808C,
6 h) gave 4,4’-tBu2-6,6’-Ph2-2,2’-bipyridine (3A) in 67% yield
of isolated product. The structure of this product was
confirmed by single-crystal X-ray diffraction (see the Sup-
porting Information).[14]
Interestingly, the same bis(borylated) dtbpy could be
converted cleanly into the monophenyl product 4A in 31%
yield of isolated product (also structurally characterized by X-
ray diffraction;[14] see the Supporting Information) under the
same conditions but using only 1.2 equivalents of PhI and
2 equivalents of K3PO4·2H2O as the base, thus indicating that
1) cross-coupling took place initially at one ring and 2) when
Prof. R. N. Perutz
Department of Chemistry
University of York
Heslington, YO105DD (England)
[**] We thank the EPSRC for support (T.B.M. andR.N.P.), the University
of Durham for a Sir Derman Christopherson Foundation Fellowship
(T.B.M.), One NorthEast (UK) for funding through the Nano-
technology UIC program (T.B.M. andJ.A.K.H.), the Saudi Arabia
Cultural Attache (London) for a postgraduate scholarship (I.A.I.M.),
Mrs. J. Dostal for the elemental analyses, andFrontier Scientific Inc.
andNetChem Inc. for generous gifts of bis(pinacolato- O,O’)di-
boron) (B2pin2).
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2006, 45, 489 –491
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
489

Communications
À
the PhI was depleted, hydrolysis of the remaining C B bond
was relatively facile under the reactions conditions.
cyanoarenes is given in reference [13]. Even though the
regioselectivity of the borylation of the two 4,4’-disubstituted
bipyridines (bpys) was different, what they have in common is
that bpy can be considered to be a 2-pyridyl substituted
pyridine, that is, that there is a bulky pyridine-substituent
ortho to the N atom that blocks N-coordination of either ring
because of the steric constraints of the key [Ir(Bpin)3(dtbpy)]
intermediate (see above). It cannot act as a bidentate ligand
because the Ir center is already five-coordinate, and it cannot
act as a monodentate pyridine (py) ligand because the ortho
py substitutent is too big to allow coordination at the N atom.
With that model in mind, we decided to examine 2-Ph-
pyridine (1C) which, along with its derivatives, has received
considerable attention as a C,N chelate on Ir centers for
electroluminescence in organic light-emitting diode (OLED)
devices.[15] We wondered whether a single 2-Ph group would
also inhibit N-coordination, thus allowing borylation of the
pyridine ring, and whether borylation of the phenyl or
pyridine groups would predominate. Indeed, borylation was
successful within 16 h at room temperature using 2.5 mol% of
I and 5 mol% of 1A, thus giving rise to equal amounts of 2-
Ph-4-(Bpin)-pyridine (2C(4)) and 2-Ph-5-(Bpin)-pyridine
(2C(5)). The solvent was removed from the crude mixture,
which was redissolved in 1,4-dioxane to which aqueous K2CO3
and [PdCl2(PPh3)2](5 mol%) were added. This mixture was
treated with 1-iodonaphthalene in a 20-mL crimp-top sealed
glass vessel and heated to 1508C for 1 h in a Biotage-Personal
Chemistry microwave reactor, thus giving 2-Ph-4-(1-Np)-
pyridine (3C(4)) and 2-Ph-5-(1-Np)-pyridine (3C(5)) in 61%
yield of the combined isolated products (Scheme 3). Com-
pounds 3C(4) and 3C(5) were separated chromatographi-
cally, identified spectroscopically, and their structures con-
firmed by single-crystal X-ray diffraction[14] (see the Support-
ing Information).
In contrast, no borylation of 4-tBu-pyridine was observed
even after 2 days at 808C in hexane using 5 mol% of catalyst
prepared from dimer I and 2 equivalents of 1A; moreover,
10 mol% of the catalyst was required to achieve approx-
imately 6% conversion into the C H borylation product.
Presumably, 4-tBu-pyridine binds to the Ir center strongly
À
À
through the N atom, thus blocking the site needed for C H
activation.[10] Interestingly, the H NMR spectrum following
2
quenching with [2H]2O showed that borylation had taken
place ortho to the N atom. As we were unable to borylate 4-
tBu-pyridine effectively, we examined 4,4’-(MeO)2-2,2’-bipyr-
idine (1B) because of its similarity to 1A. A complete
reaction (100% conversion) of 1B was achieved after 16 h
using 2 equivalents of B2pin2 in hexane (5 mL), I (5 mol%),
and 1A (10 mol%) at 808C, as shown by in situ GC–MS
analysis. A single isomer of the bipyridyl bis(boronate) ester
(2B) was produced in approximately 85% yield plus approx-
1
imately 15% yield of the analogous monoboronate. H, 13C,
and 2D NMR spectroscopic experiments indicated that
borylation took place at the 5-position, ortho to the MeO
groups, in complete contrast with the borylation of dtbpy
(Scheme 2).
(Figure 1) confirmed the structure of the product.
A
single-crystal X-ray diffraction study[14]
Scheme 2. Borylation of 1B.
Finally, to test the generality of the process for the one-pot
synthesis of unusual heterocycles, to evaluate whether a single
CH3 group is sufficient to block N-coordination, and to direct
borylation ortho to the N atom, we carried out the borylation
of 2,3-dimethylpyrazine (1D) using I/1A under the same
conditions as for 1C. The product, 2,3-Me2-5-Bpin-pyrazine
(2D), was subsequently cross-coupled with 2-bromothio-
phene to give 2,3-Me2-5-(2-thienyl)-pyrazine (3D),[16] which
was isolated in 34% yield (and also structurally characterized
by X-ray diffraction;[14] see the Supporting Information).
Figure 1. Molecular structure of 2B.
It would, thus, appear that for electronic
reasons the borylation reactions will avoid posi-
tions ortho to the N atom in a pyridine ring unless
extreme steric hindrance makes other positions
inaccessible. Preliminary results of DFT calcula-
tions (B3LYP, 6-31G*) show that charges on the C
atom ortho to the N atom and the highest-
occupied molecular orbitals (HOMOs) and
lowest-unoccupied molecular orbitals (LUMOs)
of 1A and 1B are very similar. This example is the
first wherein purely electronic control leads to
exclusive borylation of aromatic compounds ortho
to a substituent (namely, OMe). A recent dis-
cussion of substituent effects in the borylation of
Scheme 3. Borylation of 1C.
490
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Angewandte
Chemie
[11]a) T. Ishiyama, J. Takagi, Y. Yonekawa, J. F. Hartwig, N.
In summary, we have shown that the catalyst will borylate
dtbpy unless it is already coordinated to the Ir center.
Moreover, we note that a single substituent ortho to the N
atom is sufficient to inhibit N-coordination to the Ir center,
thus “activating” the six-membered heteroarenes to boryla-
Miyaura, Adv. Synth. Catal. 2003, 345, 1103; b) T. Ishiyama, Y.
Nobuta, J. F. Hartwig, N. Miyaura, Chem. Commun. 2003, 2942.
[12]a) J.-Y. Cho, C. N. Iverson, M. R. Smith III, J. Am. Chem. Soc.
2000, 122, 12868; b) T. Tagata, M. Nishida, Adv. Synth. Catal.
2004, 346, 1655.
À
tion of C H bonds and providing a design criterion for
[13]G. A. Chotana, M. A. Rak, M. R. Smith, III, J. Am. Chem. Soc.
2005, 127, 10539.
substrates for selective borylation. Complete regioselectivity
has been achieved through either electronic or steric control,
which allows, for the first time, borylation of pyridine
derivatives ortho to the N atom or ortho to a MeO substituent
(that is, meta to the N center). The compound 2-Ph-pyridine,
important in the design of triplet-emitting Ir complexes for
OLEDs,[15] can be further derivatized at the 4- and 5-positions
of the py ring in preference to the Ph ring, thus leading to
useful 4-(or 5-)-Ar’-2-Ar-pyridine derivatives. The compound
2,3-dimethylpyrazine was borylated ortho to the N atom and
cross-coupled with the electron-rich heteroarene 2-bromo-
thiophene. Finally, whilst some of the aryl pyridines, such as
3A and 4A, have been reported previously as ligands in Ru
and luminescent Ir and Pt complexes,[17] prepared by the
addition of PhLi to dtbpy followed by hydrolysis and
oxidation, our route is more general and inherently more
functional-group tolerant and does not require highly reactive
ArLi reagents. We expect this route to be of use in
applications that range from pharmaceuticals to new optical
and electronic materials.
[14]For synthetic and crystallization details and the molecular
structures, see the Supporting Information. X-ray diffraction
experiments were performed with SMART 1 K CCD area-
detector diffractometers using MoKa radiation (l = 0.71073 Š) at
T= 120(2) K; the structures were solved by direct methods
(SHELXTL; Bruker AXS, Inc., Madison, WI, USA). 3A·2C6F6:
C42H32F12N2, Mr = 792.70, orthorhombic, space group Pccn, a =
14.021(2), b = 19.509(3), c = 13.2267(19) Š, V= 3618.1(9) Š3,
Z = 4, 1calcd = 1.455 MgmÀ3, m = 0.128 mmÀ1, R (F; F2 > 2s) =
0.0550, Rw (F2, all data) = 0.1583, S = 1.297 for 5474 unique
data (q < 30.5) and 317 refined parameters; final difference
synthesis within Æ 0.54 eŠÀ3. 4A·C6F6: C30H28F6N2, Mr = 530.54,
orthorhombic, space group Pnma, a = 27.2125(17), b =
6.7353(5), c = 14.3175(10) Š, V= 2624.2(3) Š3, Z = 4, 1calcd
=
1.343 MgmÀ3, m = 0.108 mmÀ1, R (F; F2 > 2s) = 0.0508, Rw (F2,
all data) = 0.1346, S = 1.010 for 4319 unique data (q < 30.51) and
291 refined parameters; final difference synthesis within
Æ 0.34 eŠÀ3. 2B: C24H34B2N2O6, Mr = 468.15, monoclinic, space
group P21/n, a = 9.3567(6), b = 22.0270(13), c = 12.2764(8) Š,
b = 98.213(3)8, V= 2504.2(3) Š3, Z = 4, 1calcd = 1.242 MgmÀ3, m =
0.087 mmÀ1, R (F; F2 > 2s) 0.0717, Rw (F2, all data) = 0.2121, S =
1.069 for 7652 unique data (q < 30.508) and 317 refined
À3
parameters; final difference synthesis within Æ 0.64 eŠ
.
Received: August 26, 2005
Published online: December 2, 2005
3C(4): C21H15N, Mr = 281.34, monoclinic, space group P21, a =
6.7020(8), b = 7.6743(9), c = 14.6965(17) Š, b = 97.980(3)8, V=
748.57(15) Š3, Z = 2, 1calcd = 1.248 gcmÀ3, m = 0.072 mmÀ1, R (F;
F2 > 2s) = 0.0426, Rw (F2, all data) = 0.1261, S = 0.645 for 2165
unique data (q < 27.50) and 260 refined parameters; final
difference synthesis within Æ 0.33 eŠÀ3. 3C(5): C21H15N, Mr =
281.34, monoclinic, space group P21, a = 7.099(1), b = 12.943(2),
Keywords: boron · boronate esters · boronic acidheterocycles ·
.
À
C H activation · structure elucidation
c = 7.928(1) Š, b = 100.02(1)8, V= 717.33(18) Š3, Z = 2, 1calcd
=
1.303 gcmÀ3, m = 0.075 mmÀ1, R (F; F2 > 2s) = 0.0423, Rw (F2, all
data) = 0.1188, S = 1.069 for 2163 unique data (q < 29.98) and
259 refined parameters; final difference synthesis within
Æ 0.33 eŠÀ3. 3D: C10H10N2S, Mr = 190.26, monoclinic, space
group P21/n, a = 7.1352(19), b = 12.292(3), c = 11.175(3) Š, b =
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À3
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.
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Angew. Chem. Int. Ed. 2006, 45, 489 –491
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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