PXPd-catalyzed borylation of aniline derivatives

Article abstract of DOI:10.2478/s11532-010-0076-1

Addition of pinacolborane (HBO₂C₂Me₄) to 2-iodoaniline can be catalyzed using a number of palladium complexes, including [(t-Bu)₂PCl]₂PdCl₂ (PXPd), to give the corresponding boronate ester 2-H₂NC₆H₄(BO₂C₂Me₄) in excellent yields. The PXPd system could also be used in the catalyzed borylation of substituted anilines to give the corresponding aminoboronate esters in moderate to high yields.

Full text of DOI:10.2478/s11532-010-0076-1

Cent. Eur. J. Chem. • 8(4) • 2010 • 725–731
DOI: 10.2478/s11532-010-0076-1
Central European Journal of Chemistry
PXPd-catalyzed borylation of aniline derivatives
Invited Paper
Susan L. Wheaton1, S. M. Humanayun Kabir1, Haiwen Zhang1,
Christopher M. Vogels1, Andreas Decken2†, Stephen A. Westcott1*
1 Department of Chemistry and Biochemistry, Mount Allison University,
Sackville, NB E4L 1G8, Canada
2 Department of Chemistry, University of New Brunswick,
Fredericton, NB E3B 5A3, Canada
Received 09 January 2010; Accepted 24 February 2010
Abstract: Addition of pinacolborane (HBO2C2Me4) to 2-iodoaniline can be catalyzed using a number of palladium complexes, including
[(t-Bu)2PCl]2PdCl2 (PXPd), to give the corresponding boronate ester 2-H2NC6H4(BO2C2Me4) in excellent yields. The PXPd system could
also be used in the catalyzed borylation of substituted anilines to give the corresponding aminoboronate esters in moderate to high
yields.
Keywords: Boron • Borylation • Catalysis • Cross-coupling • Palladium
© Versita Sp. z o.o.
1. Introduction
importance of these compounds in organic synthesis,
prompted us to examine alternate routes to boronated
Compounds containing boronic acids (RB(OH)2) or aniline derivatives.
boronate esters (RB(OR’)2) have received considerable
attention in catalyzed carbon-carbon bond formation
Cl
O P
O P
P O
P O
Cl
Pd Pd
Cl
reactions [1], solid-phase synthesis [2], macrocyclic
chemistry [3], organometallic and organic synthesis
[4], and as glucose sensors for diabetes therapy [5].
Interest in these compounds also arises from their
potent biological activities [6]. Traditionally, arylboron
compounds have been prepared by the transmetalation
between aryllithium or –magnesium reagents and
boron compounds that have good leaving groups
such as alkoxy moieties [7]. In recent years, however,
the use of palladium catalyzed borylations has proven
to be a more convenient procedure for preparing
arylboronate esters [8]. While reactive functional groups
such as primary amines have proven problematic,
elegant studies by Baudoin and co-workers [8b] have
shown that 2-bromoaniline can be converted into the
corresponding ortho boronate ester in good yields by
H
H
HO
P
Pd P OH
Cl
(a) POPd
(b) POPd1
HO
Cl
P
Cl
Cl
Cl
P
Pd
Cl
P Cl
Pd
Pd
Cl
Cl
P
OH
(c) POPd2
(d) PXPd
Figure 1.Structures of several palladium(II) complexes employed
in this study.
2. Experimental Procedure
addition of pinacolborane (HBpin, pin = O2C2Me4) using 2.1. Materials and measurements
a palladium catalyst system containing the monodentate Reagents and solvents were purchased from Aldrich
phosphine ligand 2-(dicyclohexylphosphino)biphenyl Chemicals. NMR spectra were recorded on a JEOL JNM-
(DCPB). Optimal yields for these reactions have been GSX270 FT spectrometer. 1H-NMR chemical shifts are
reported using dioxane as the solvent. Our interest in reportedinpartspermillion(ppm)andarereferencedtoresidual
generating aminoboron compounds, along with the solvent protons in deuterated solvent at 270 MHz. 11B-NMR
* E-mail: *swestcott@mta.ca
† adecken@unb.ca
725

PXPd-catalyzed borylation of aniline derivatives
chemicalshiftsarereportedinppmandarereferencedtoBF3.
OEt2 as an external standard at 87 MHz. 13C-NMR chemical
N-(4-Methoxybenzyl)-3-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)benzenamine
1
shifts are reported in ppm and are referenced to solvent Yield: 79%; mp 105oC. H-NMR (CDCl3) d: 1.35 (s, 12H,
carbon resonances at 68 MHz. 19F-NMR spectra were pin), 3.80 (s, 3H, CH3), 3.82 (br s, 1H, NH), 4.29 (br s, 2H,
recorded on a Varian Mercury Plus 200 NMR spectrometer CH2), 6.74 (m, 1H, Ar), 6.91 (d, J = 8.2 Hz, 2H, Ar), 7.13
and are reported in ppm and referenced to CF3CO2H as an (s, 1H, Ar), 7.16-7.22 (ov m, 2H, Ar), 7.31 (d, J = 8.2 Hz,
external standard at 188 MHz. Multiplicities are reported as 2H, Ar). 11B-NMR (CDCl3) d: 30 (br). 13C{1H}-NMR (CDCl3)
singlet (s), doublet (d), triplet (t), multiplet (m), overlapping d: 24.8, 47.8, 55.3, 83.7, 114.0, 115.5, 119.2, 124.0, 128.7,
(ov), and broad (br). Infrared spectra were obtained using 128.9, 130 (br, CB), 131.4, 147.6, 158.8. FT-IR (Nujol):
a Mattson Genesis II FT-IR spectrometer and are reported 3398 (m, NH). Anal. Calcd. for C20H26BNO3 (339.28): C,
in cm-1. Melting points were measured uncorrected with a 70.80; H, 7.74 N, 4.13; Found: C, 71.22; H, 8.23; N, 4.02.
Mel-Temp apparatus. GC-MS analyses were conducted
using a Varian Saturn 2000 GC/MS/MS coupled to a
CP-3800 GC. The GC was equipped with the 1177 injection
port connected to a SPB-1 (Supelco) fused silica column
(30 m×0.25 mm i.d.×0.25 μm). The GC-MS spectrometer is
controlled by the Saturn Workstation software, Version 5.51.
Microanalyses for C, H, and N were carried out at Guelph
O
O
B
H
N
O
N-(4-Methoxybenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-
Chemical Laboratories (Guelph, Ontario). Imines and the dioxaborolan-2-yl)benzenamine
corresponding benzylamines were synthesized as reported Yield: 83%; mp 116-118oC. 1H-NMR (CDCl3) d: 1.30 (s, 12H,
previously [9].
pin), 3.80 (s, 3H, CH3), 4.15 (br s, 1H, NH), 4.26 (br s, 2H,
CH2), 6.59 (d, J = 8.4 Hz, 2H, Ar), 6.86 (d, J = 8.4 Hz, 2H,
Ar), 7.24 (d, J = 8.4 Hz, 2H, Ar), 7.62 (d, J = 8.4 Hz, 2H, Ar).
2.2. Synthesis
Underanatmosphereofdinitrogen, a1mLtoluenesolution 11B-NMR (CDCl3) d: 32 (br). 13C{1H}-NMR (CDCl3) d: 24.9,
of pinacolborane (380 mg, 3.00 mmol) was added to a 47.6, 55.4, 83.3, 112.3, 114.1, 129.0, 130 (br, CB), 130.8,
stirred 4 mL toluene solution of the appropriate iodoaniline 136.4, 150.3, 159.0. FT-IR (Nujol): 3373 (m, NH). Anal.
(1.00 mmol), triethylamine (400 mg, 4.00 mmol), and PXPd Calcd. for C20H26BNO3 (339.28): C, 70.80; H, 7.74; N, 4.13;
(12 mg, 0.02 mmol). The mixture was heated at reflux for Found: C, 70.31; H, 8.06; N, 4.16.
2 h. Following the addition of a 5 mL saturated aqueous
solution of NH4Cl, the aqueous phase was extracted with
three 10 mL portions of Et2O and the organic phase dried
over MgSO4. Upon filtration and removal of solvent under
vacuum, the resulting oil was dissolved in a minimum
amount of hexanes and stored at 0oC. The resulting
precipitate was collected by suction filtration.
O
H
N
O
B
O
N-(4-Fluorobenzyl)-2-(4,4,5,5-tetramethyl-1,3,2-
N-(4-Methoxybenzyl)-2-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzenamine
dioxaborolan-2-yl)benzenamine
Yield: 73%; mp 80-81oC. 1H-NMR (CDCl3) d: 1.32 (s, 12H,
Yield: 56% of a yellow oil. 1H-NMR (CDCl3) d: 1.32 (s, 12H, pin), 4.36 (d, J = 5.7 Hz, 2H, CH2), 6.31 (br t, J = 5.7 Hz, 1H,
pin), 3.80 (s, 3H, CH3), 4.33 (d, J = 5.2 Hz, 2H, CH2), 6.29 NH), 6.46 (d, J = 8.4 Hz, 1H,Ar), 6.63 (t, J = 6.7 Hz, 1H,Ar),
(br t, J = 5.2 Hz, 1H, NH), 6.52 (d, J = 8.2 Hz, 1H, Ar), 6.63 7.02 (m, 2H, Ar), 7.24 (t, J = 8.9 Hz, 1H, Ar), 7.32 (m, 2H,
(t of d, J = 7.4, 0.8 Hz, 1H, Ar), 6.87 (d, J = 8.7 Hz, 2H, Ar), 7.65 (d of d, J = 7.4, 1.7 Hz, 1H,Ar). 11B-NMR (CDCl3) d:
Ar), 7.24-7.31 (ov m, 3H, Ar), 7.65 (d of d, J = 7.4, 1.7 Hz, 30 (br). 13C{1H}-NMR (CDCl3) d: 25.0, 46.9, 83.6, 109.9, 110
1H, Ar). 11B-NMR (CDCl3) d: 31(br). 13C{1H}-NMR (CDCl3) (br, CB), 115.4 (d, JCF = 21 Hz), 116.0, 128.6 (d, JCF = 8 Hz),
d: 25.0, 47.0, 55.4, 83.6, 109.9, 110 (br, CB), 114.0, 115.8, 133.2, 135.6 (d, JCF = 3 Hz), 137.2, 154.3, 161.9 (d, JCF
=
128.2, 131.9, 133.2, 137.2, 154.5, 158.7. FT-IR (Nujol): 246 Hz, CF). 19F{1H}-NMR (CDCl3) d: -116.7. FT-IR (Nujol):
3404 (m, NH). Anal. Calcd. for C20H26BNO3 (339.28): C, 3415 (m, NH). Anal. Calcd. for C19H23BFNO2 (327.24): C,
70.80; H, 7.74 N, 4.13; Found: C, 71.15; H, 8.02; N, 3.97.
69.73; H, 7.10; N, 4.28; Found: C, 70.10; H, 6.86; N, 4.55.
F
O
H
N
H
N
O
B
O
B
O
O
726

S. L. Wheaton, et al.
N-(4-Fluorobenzyl)-3-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)benzenamine
3-(Trifluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)benzeneamine
Yield: 20%; mp 102-103oC. 1H-NMR (CDCl3): d 1.33
(s, 12H, pin), 3.94 (br s, 2H, NH2), 6.75 (dd, J = 8.0,
2.2 Hz, 1H, Ar), 6.94 (d, J = 2.2 Hz, 1H, Ar), 7.59 (d, J
= 8.0 Hz, 1H, Ar). 11B-NMR (CDCl3): d 30 (br). 13C{1H}-
NMR (CDCl3): d 25.1, 83.9, 112.0 (q, JCF = 5 Hz), 116.3
(br, CB), 116.4, 124.3 (q, JCF = 272, CF3), 135.8 (q, JCF
= 32 Hz), 137.4, 148.3. 19F{1H}-NMR (CDCl3): d -60.5.
FT-IR (Nujol): 3242 (m, NH), 3375 (m, NH), 3483 (m,
NH). Anal. Calcd. for C13H17NO2BF3 (287.12): C, 54.38;
H, 5.98; N, 4.88; Found: C, 54.83; H, 5.53; N, 4.39.
1
Yield: 83%; mp 64-66oC. H-NMR (CDCl3) d: 1.29 (s,
12H, pin), 3.94 (br s, 1H, NH), 4.30 (s, 2H, CH2), 6.68 (m,
1H, Ar), 7.00 (m, 2H, Ar), 7.11-7.18 (ov m, 3H, Ar), 7.31
(m, 2H, Ar). 11B-NMR d: 31 (br). 13C{1H}-NMR d: 25.0,
47.7, 83.8, 115.5 (d, JCF = 21 Hz), 115.6, 119.4, 124.3,
128.9, 129.2 (d, JCF = 8 Hz), 130 (br, CB), 135.3 (d, JCF
=
3 Hz), 147.5, 162.1 (d, JCF = 245 Hz, CF). 19F{1H}-NMR
d: -114.6. FT-IR (Nujol): 3361 (m, NH). Anal. Calcd. for
C19H23BFNO2 (327.24): C, 69.73; H, 7.10; N, 4.28; Found:
C, 69.43; H, 7.10; N, 4.50.
F
O
O
H
B
N
B
O
O
H2N
CF3
N-(4-Fluorobenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)benzenamine
4-(Trifluoromethyl)-2-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)benzenamine
Yield: 85%; mp 137-138oC. 1H-NMR (CDCl3) d: 1.28 (s, Yield: 71%; mp 117-118oC. 1H-NMR (CDCl3): d 1.35 (s,
12H, pin), 4.22 (br t, J = 5.5 Hz, NH), 4.32 (d, J = 5.5 Hz, 12H, pin), 5.07 (br s, 2H, NH2), 6.59 (d, J = 8.6 Hz, 1H,
2H, CH2), 6.58 (d, J = 8.4 Hz, 2H, Ar), 7.00 (m, 2H, Ar), Ar), 7.41 (dd, J = 8.6, 2.4 Hz, 1H, Ar), 7.86 (d, J = 2.4
7.28 (m, 2H, Ar), 7.62 (d, J = 8.4 Hz, 2H, Ar). 11B-NMR Hz, 1H, Ar). 11B-NMR (CDCl3): d 30 (br). 13C{1H}-NMR
d: 30 (br). 13C{1H}-NMR d: 24.9, 47.1, 83.3, 112.0, 115.5 (CDCl3): d 25.4, 84.1, 110.3 (br, CB), 114.2, 118.6 (q, JCF
(d, JCF = 21 Hz), 129.0 (d, JCF = 8 Hz), 130 (br, CB), = 33 Hz), 125.1 (q, JCF = 271 Hz, CF3), 129.6 (q, JCF = 3
134.8 (d, JCF = 3 Hz), 136.5, 150.4, 162.2 (d, JCF = 246 Hz), 134.3 (q, JCF = 4 Hz), 156.2. 19F{1H}-NMR (CDCl3): d
Hz, CF). 19F{1H}-NMR d: -115.9. FT-IR (Nujol): 3363 (m, -61.5. FT-IR (Nujol): 3376 (m, NH), 3474 (m, NH). Anal.
NH). Anal. Calcd. for C19H23BFNO2 (327.24): C, 69.73; Calcd. for C13H17NO2BF3 (287.12): C, 54.38; H, 5.98; N,
H, 7.10; N, 4.28; Found: C, 69.30; H, 7.05; N, 4.46.
4.88; Found: C, 54.41; H, 6.10; N, 4.85.
F
NH2
H
N
O
F3C
B
O
O
B
O
2-(Trifluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)benzeneamine
5-(Trifluoromethyl)-2-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)benzenamine
Yield: 43%; mp 72-74oC. 1H-NMR (CDCl3): d 1.32 (s, 12H, Yield: 69%; mp 64-65oC. 1H-NMR (CDCl3): d 1.35 (s, 12H,
pin), 4.35 (br s, 2H, NH2), 6.70 (d, J = 8.2 Hz, 1H, Ar), 7.71 pin), 4.93 (br, 2H, NH2), 6.80 (s, 1H, Ar), 6.87 (d, J = 7.8 Hz,
(d, J = 8.2 Hz, 1H,Ar), 7.89 (s, 1H,Ar). 11B-NMR (CDCl3): d 1H, Ar), 7.70 (d, J = 7.8 Hz, 1H, Ar). 11B-NMR (CDCl3): d 30
30 (br). 13C{1H}-NMR (CDCl3): d 25.0, 83.9, 113.3 (q, JCF
=
(br). 13C{1H}-NMR (CDCl3): d 25.0, 84.2, 111.1 (q, JCF = 4
30 Hz), 115.5 (br, CB), 116.3, 125.3 (q, JCF = 272 Hz, CF3), Hz), 112.2 (br, CB), 113.1 (q, JCF = 4 Hz), 124.3 (q, JCF = 273
133.9 (q, JCF = 5 Hz), 139.5, 147.1 (q, JCF = 2 Hz). 19F{1H}- Hz, CF3), 134.5 (q, JCF = 32 Hz), 137.7, 153.9. 19F{1H}-NMR
NMR (CDCl3): d -62.9. FT-IR: 3240 (m, NH), 3367 (m, NH), (CDCl3): d -64.0. FT-IR (Nujol): 3398 (m, NH), 3460 (m, NH),
3494 (m, NH). Anal. Calcd. for C13H17NO2BF3 (287.12): C, 3504 (m, NH). Anal. Calcd. for C13H17NO2BF3 (287.12): C,
54.38; H, 5.98; N, 4.88; Found: C, 54.22; H, 6.20; N, 4.87. 54.38; H, 5.98; N, 4.88; Found: C, 54.49; H, 5.99; N, 4.89.
NH2
O
O
B
B
CF3
O
O
F3C
NH2
727

PXPd-catalyzed borylation of aniline derivatives
2.3. X-ray crystallography
Crystals of 2-APBpin suitable for an X-ray diffraction
study were grown from a saturated hexane solution at
5oC. Single crystals were coated with Paratone-N oil,
mounted using a glass fibre and frozen in the cold stream
of the goniometer. A hemisphere of data were collected
on a Bruker AXS P4/SMART 1000 diffractometer using
w and q scans with a scan width of 0.3o and exposure
time of 10 s. The detector distance was 5 cm. The data
were reduced [10a] and corrected for absorption [10b].
The structures were solved by direct methods and
refined by full-matrix least squares on F2 [10c]. All non-
hydrogen atoms were refined anisotropically. Hydrogen
atoms were found in Fourier difference maps and
refined isotropically.
Figure 2.The molecular structure of 2-APBpin with displacement
ellipsoids shown at 30% probability level. Selected bond
distances (Å) and angles (o): B-O(8) 1.3690(16), B-O(9)
1.3705(16), B-C(3) 1.5467(18), N(1)-C(2) 1.3622(18),
B-N(1) 2.974(2); O(8)-B-O(9) 112.76(11), O(8)-B-C(3)
123.99(11), O(9)-B-C(3) 123.22(11).
3. Results and Discussion
These borylation reactions are believed to proceed
via initial reduction of the palladium(II) salt, by the
Recently, Li [11] demonstrated that air-stable Pd/ borane, to an active palladium(0) species [1]. Once
phosphinous acid complexes [(t-Bu)2P(OH)]2PdCl2 reduced, oxidative addition of the aryl halide followed
(abbreviated POPd, Fig. 1a) and {[(t-Bu)2PO...H...OP(t- by transmetallation of the borane with the Pd-X moiety
Bu)2]PdCl}2 (abbreviated POPd1, Fig. 1b) are efficient gives a palladium boryl (Pd-B(OR)2) intermediate, which
catalysts for the Suzuki-Miyaura cross coupling of aryl must isomerize before reductive elimination can give the
chlorides. These compounds have also shown recent desired aryl boronate ester product (Scheme 1). It has
utility as catalysts in a number of reactions [12] including also been postulated that once the palladium(0) species
the NaOH-promoted cross-coupling of arylsiloxanes with is present, oxidative addition of the dialkoxyborane
aryl chlorides and bromides in water [12a]. We have found species occurs first to give a reactive palladium hydrido
that reactions of commercially-available 2-iodoaniline with boryl intermediate. This transient species can rapidly go
HBpin using these catalyst systems, without additional through a transmetallation of the aryl halide, followed
phosphine ligands, also gave good yields of the boron- by isomerization and reductive elimination to give the
containinganilinederivative2-(4,4,5,5-tetramethyl-[1,3,2]- desired product.
Pd(II)
dioxaborolan-2-yl)phenylamine (2-APBpin) (Table 1,
HB(OR)2
entries 4 & 6, respectively) [8b,d]. As seen in the seminal
ArX
work by Baudoin and co-workers [8b], optimal yields were
ArB(OR)2
Pd(0)
achieved using 3 equivalents of HBpin and 4 equivalents
of triethylamine as the base. The synthesis of aminoboron
derivatives is of singular interest, as these compounds
are remarkably potent enzyme inhibitors [6j] and many
have been investigated extensively for their application
in boron neutron capture therapy [6c]. The formation of
2-APBpin in these catalyzed borylations was confirmed
by melting point, multinuclear NMR spectroscopy and
GC-MS data. The structural analysis of this aminoboron
compound was carried out by an X-ray diffraction study
(Fig. 2) and crystallographic data presented in Table 2.
Ar
Pd(II)
Ar
X
Pd(II)
B(OR)2
HB(OR)2
NEt3
/
Pd(II)
Ar
B(OR)2
NEt3HX
Scheme 1.A plausible catalytic cycle for the borylation of aryl
halides.
While yields are moderate for reactions using the
The B–O bond distances of 1.3690(16) and 1.3705(16) palladium-phosphinous acid complexes, excess HBpin
Å are typical for those observed in other Bpin structures is required to facilitate this reaction. This is presumably
where the boron is three coordinate [13]. The molecule due to HBpin reacting with the polar P-OH groups.
showed no appreciable intra- or intermolecular interaction Indeed, we have found that stoichiometric addition of
between the Lewis acidic boron atom and the basic HBpin to these compounds led to extensive degradation
amine group. Such interactions may be responsible for of the borane to give H2 and pinBOBpin [14]. Further work
observed antimicrobial properties in related diaminoboron is needed, however, to elucidate the fate of the palladium
compounds [6f].
complexes in these reactions. As deleterious reaction
728

S. L. Wheaton, et al.
yields of the desired boronate ester compounds.
Reactions of bulky ortho iodoanilines (entries 4 & 7)
gave lower yields than their meta and para counterparts
presumably due to the increased steric bulk in these
systems. Substitution on the benzyl group did not have
a significant effect on yields. While similar yields were
obtained with the analogous bromides, we did not
observe any significant product formation for reactions
with the corresponding chlorides. Benzylamines
containing boron groups have been examined recently
for potential antifungal properties [9].
We then examined the borylation of commercially-
available aniline derivatives containing electron-
withdrawing trifluoromethyl groups. The generation of
the corresponding boronate ester compounds has been
of recent interest in the preparation of MRI probes [15],
electroactive luminophores [16], and in the preparation
of pharmaceutically relevant dihydroquinolones [17].
As shown in Scheme 2, yields of isolated product are
moderate if the bromide is ortho to the amine group,
where the position of the CF3 has little effect. Yields are
much lower, however, if the bromide group is para to the
amine where the lowest yield was found in the case where
the CF3 is ortho to the leaving group. Attempts to improve
yields using other metal complexes proved unsuccessful.
of the HBpin with the phosphinous acid groups led to
degradation of the borane and catalyst, we decided to
examine the analogous reactions using the structurally
related phosphine chloride complexes. Remarkably,
we found that reactions using [(t-Bu)2PCl]2PdCl2
(abbreviated PXPd, Fig. 1d) gave near quantitative
conversion of 2-iodoaniline to 2-APBpin (entries 1 & 2)
without significant decomposition of either the catalyst
or the dialkoxyborane. Reactions run in toluene gave
slightlygreateryieldsthanthosereactionsrunindioxane.
Unfortunately, significantly lower yields of the desired
product were obtained in reactions run in THF (entry 9)
or those using the dimeric complex {[(t-Bu)2PCl]PdCl}2
(abbreviated PxPd2, entry 3). Interestingly, reactions
with the bulky DCPB/Pd(OAc)2 system (entry 7),
also gave low yields and attempts to use a phosphine
free catalyst system (Pd(OAc)2) afforded none of the
desired products (entry 10). Not surprisingly, attempts
to catalyze this reaction using other metal complexes,
such as Ni(OAc)2 and RhCl(PPh3)3, proved unsuccessful
(entries 11 & 12, respectively).
Encouraged by these results, we then decided to
investigate the borylation of other iodoaniline derivatives
(Table 3). Reactions using 3 equivalents of HBpin and
the PXPd precatalyst in toluene gave good to excellent
Table 1. Metal catalyzed borylation of 2-iodoaniline with
Table 2. Crystallographic data collection parameters for 2-APBpin.
pinacolborane.
CCDC deposit no.
241954
C12H18BNO2
219.08
H2N
O
B
Chemical formula
H2N
I
5 mol% Pd, NEt3
Formula mass
O
Crystal system
monoclinic
P2(1)/c
O
BH
O
Space group
a (Å)
10.0970(13)
9.9124(13)
13.2168(18)
109.795(2)
1244.6(3)
4
b (Å)
c (Å)
b (o)
V (Å3)
Entry
Catalyst
Solvent
Yielda,b
1
2
PXPd
PXPd
toluene
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
THF
>95
95
75
75
75
65
30
30
10
0
Z
Dcalcd (mg m-3)
Crystal dimensions (mm3)
T (K)
1.169
3
PXPd2
POPd
0.40×0.225×0.20
198(1)
4
Radiation
m (mm-1)
MoKa (l = 0.71073)
0.077
5
Pd(OAc)2 + 4PPh3
POPd1
6
Total reflections collected
Total unique reflections
No. of variables
Rint
8345
2799
7
Pd(OAc)2 + 4DCPB
POPd2
217
8
0.0256
q (o)
2.14 to 27.49
0.209 and -0.168
1.073
9
PXPd
Largest diff peak & hole (e Å-3)
GoF on F2
10
11
12
Pd(OAc)2
dioxane
dioxane
dioxane
Ni(OAc)2
0
R1a [I>2s(I)]
0.0404
wR2b (all data)
0.1111
RhCl(PPh3)3
0
a R1 = Σ||Fo|–|Fc||/Σ|Fo|.
a Yields of products as determined by GC-MS and analysis of integrated
1H-NMR spectra.
2
b wR2 = (Σ[w(Fo -Fc2)2]/Σ[wFo4])1/2, where w = 1/[s2(Fo2) + (0.0498 * P)2 +
b Products are characterized by spectral analysis (1H- and 11B-NMR and
GC-MS) and compared with authentic sample.
(0.1942 * P)] where P = (max (Fo2, 0) + 2 * Fc2)/3.
729

PXPd-catalyzed borylation of aniline derivatives
Table 3. PXPd catalyzed borylation of substituted iodoanilines.
NH2
O
B
NH2
RHN
RHN
Br
5 mol% PXPd, NEt3
5 mol% PXPd, NEt3
O
O
I
B
O
BH
O
O
R2
O
R2
BH
R = H, CH2Ar
O
R1
R1
Entry
R
I
Yielda
R1 = H, R2 = CF3: 69%
R1 = CF3, R2 = H: 70%
1
2
3
4
5
6
7
8
9
H
ortho
meta
para
>95
95
83
56
79
83
73
83
85
H
NH2
NH2
R1
H
R1
R2
5 mol% PXPd, NEt3
4-MeOC6H4CH2
4-MeOC6H4CH2
4-MeOC6H4CH2
4-FC6H4CH2
4-FC6H4CH2
4-FC6H4CH2
ortho
meta
para
O
BH
O
R2
Br
B
O
O
ortho
meta
para
R1 = H, R2 = CF3: 20%
R1 = CF3, R2 = H: 43%
a Reactions were conducted in toluene and products were characterized by
1H-, 11B-, 13C-, and 19F-NMR spectroscopy, FT-IR, and elemental analysis.
Scheme 2.Borylation of aniline derivatives containing
trifluoromethyl groups.
4. Conclusions
using diboron sources in an effort to improve atom
economy, the results of which will be published in due
In summary, we have shown that PXPd can be used course.
to effectively catalyze the borylation of various aniline
derivatives with excess pinacolborane to give the Acknowledgements
corresponding boron containing aniline derivatives. The authors thank the Natural Science and Engineering
Although other Pd/phosphinous acid complexes could Research Council of Canada (SAW), the Canada Research
be used to catalyze this transformation, reactions with Chairs Program/Canadian Foundation for Innovation/Atlantic
PXPd gave the best yields and less decomposition Innovation Foundation and Mount Allison University for
of the starting borane. No additional phosphine is financial support. We also thank Dr. George Li (CombiPhos
needed to facilitate these reactions. Future work in Catalysts, Inc.) for the most generous gift of palladium
this area will be to examine the analogous reactions catalysts and anonymous reviewers for helpful comments.
References
[1] (a) N. Miyaura, A. Suzuki, Chem. Rev. 95, 2457 [4] (a) J. Tailor, D.G. Hall, Org. Lett. 2, 3715 (2000);
(1995); (b) A. Suzuki, Proc. Jpn. Acad., Ser. 80, 359
(2004); (c) C. Christophersen, M. Begtrup, S. Ebdrup,
H. Petersen, P. Vedsø, J. Org. Chem. 68, 9513
(b) N.A. Petasis, I.A. Zavialov, J. Am. Chem. Soc.
120, 11798 (1998); (b) R.A. Batey, D.B. MacKay,
V. Santhakumar, J.Am. Chem. Soc. 121, 5075 (1999)
(2003); (d) F. Bellina, A. Carpita, R. Rossi, Synthesis [5] (a) M. Yamamoto, M. Takeuchi, S. Shinkai,
15, 2419 (2004); (e) A. Suzuki, J. Organomet. Chem.
576, 147 (1999); (f) J. Ramirez, V. Lillo,A.M. Segarra,
E. Fernández, Curr. Org. Chem. 12, 405 (2008); (g)
Tetrahedron 54, 3125 (1998); (b) L. Zhang,
J.A. Kerszulis, R.J. Clark. T. Ye, L. Zhu, Chem.
Commun. 2151 (2009)
R.A. Gossage, H.A. Jenkins, P.N.Yadav,Tetrahedron [6] (a) W. Yang, X. Gao, B. Wang, Med. Res. Rev. 23,
Lett. 45, 7689 (2004)
346 (2003); (b) C. Morin, Tetrahedron 50, 12521
(1994) ; (c) A.H. Soloway et al., Chem. Rev.
98, 1515 (1998); (d) R. Smoum, A. Rubinstein,
M. Srebnik, Bioorg. Chem. 31, 464 (2003); (e)
W.T. Barranco, C.D. Eckhert, Cancer Lett. 216,
21 (2004); (f) A.M. Irving et al., New J. Chem.
27, 1419 (2003); (g) C.W. Gray Jr., B.T. Walker,
[2] B. Carboni, C. Pourbaix, F. Carreaux, H. Deleuze,
B. Maillard, Tetrahedron Lett. 40, 7979 (1999)
[3] (a) N. Farfán et al., J. Organomet. Chem. 581, 70
(1999); (b) H. Höpfl, J. Organomet. Chem. 581,
129 (1999); (c) H. Höpfl, Struct. Bonding 103, 1
(2002)
730

S. L. Wheaton, et al.
R.A. Foley, T.A. Houston, Tetrahedron Lett. [11] (a) G.Y. Li, J. Org. Chem. 67, 3643 (2002);(b)
44, 3309 (2003); (h) G. Rana, K. Vyakaranam,
G.Y. Li, G. Zheng, A.F. Noonan, J. Org. Chem. 66,
8677 (2001); (c) G.Y. Li, Angew. Chem. Int. Ed. Engl.
40, 1513 (2001); (d) G.Y. Li, J. Organomet. Chem.
653, 63 (2002); (e) POPd2, PXPd2, PXPd, POPd, and
POPd1 are commercially available from CombiPhos
Catalysts, Inc. http://www.combiphos.com.
S.C. Ledger, S.L. Delaney, J.A. Maguire,
N.S. Hosmane, Appl. Organomet. Chem. 17,
361 (2003); (i) N.S. Hosmane, J.A. Maguire,
Eur. J. Chem. 3989 (2003); (j) J. Adams, Cancer
Treat Rev. 29, 3 (2003); (k) I.B. Sivaev, V.V.
Bregadze, Eur. J. Inorg. Chem. 1433 (2009); [12] (a) C. Wolf, R. Lerebours, Org. Lett. 6, 1147 (2004);
(l) T. Watanabe et al., Bioorg. Med. Chem. Lett.
19, 2343 (2009); (m) D.S. Matteson, Med. Res.
Rev. 28, 233 (2008)
(b) R. Lerebours, C. Wolf, Synthesis 2287 (2005);
(c) C. Wolf, R. Lerebours, J. Org. Chem. 68, 7077
(2003); (d) C. Wolf, R. Lerebours, E. H. Tanzini,
Synthesis 2069 (2003); (e) C. Wolf, R. Lerebours,
J. Org. Chem. 68, 7551 (2003); (f) C. Wolf,
R. Lerebours, Org. Biomol. Chem. 2, 2161 (2004);
(g) W. Yang, Y. Wang, J.R. Corte, Org. Lett. 5, 3131
(2003); (g) G. Miao, P. Ye, L. Yu, C.M. Baldino,
J. Org. Chem. 70, 2332 (2005); (h) R.R. Poondra,
P.M. Fischer, N.J. Turner, J. Org. Chem. 69, 6920
(2004); (i) G.E. Tumambac, C. Wolf, J. Org. Chem.
69, 2048 (2004); (j) S.P. Khanapure, D.S. Garvey,
Tetrahedron Lett. 45, 5283 (2004)
[7] N. Miyaura, K. Maruoka, In S. Komiya (Ed.),
Synthesis of Organometallic Compounds (Wiley,
New York, 1997) 345
[8] (a) M. Murata, T. Oyama, S. Watanabe, Y. Masuda,
J. Org. Chem. 65, 164 (2000); (b) O. Baudoin,
D. Guénard, F. Guéritte, J. Org. Chem. 65, 9268
(2000); (c) H. Fuwa et al., Tetrahedron Lett 45, 2323
(2004); (d) A. Herrbach, A. Marinetti, O. Baudoin,
D. Guénard, F. Guéritte, J. Org. Chem. 68, 4897
(2003); (e) P.-E. Broutin, I. Čerňa, M. Campaniello,
F. Leroux, F. Colobert, Org. Lett. 6, 4419 (2004); [13] (a) S. Hawkswood, D.W. Stephan, Dalton Trans.
(f) H. Fang, G. Kaur, J. Yan, B. Wang, Tetrahedron
Lett. 46, 1671 (2005)
2182 (2005); (b) R.B. Coapes et al., J. Chem. Soc.
Dalton Trans. 1201 (2001)
[9] C.M. Vogels et al., Can. J. Chem. 79, 1115 (2001)
[10] (a) SAINT 6.02 (Bruker AXS, Inc., Madison,
Wisconsin, 1997-1999); (b) G.M. Sheldrick,
[14] C.M. Vogels, P.E. O’Connor, T.E. Phillips,
K.J. Watson, M.P. Shaver, P.G. Hayes,
S.A. Westcott, Can. J. Chem. 79, 1898 (2001)
SADABS (Bruker AXS, Inc., Madison, Wisconsin, [15] Y. Hattori et al., Bioorg. Med. Chem. 15, 2198 (2007)
1999); (c) G.M. Sheldrick, SHELXTL 5.1 (Bruker [16] B.D. Liddle et al., J. Org. Chem. 72, 5637 (2007)
AXS, Inc., Madison, Wisconsin, 1997)
[17] J. Horn et al., Tetrahedron 65, 9002 (2009)
731