Direct synthesis of hetero-biaryl compounds containing an unprotected NH2 group via Suzuki-Miyaura reaction

Article abstract of DOI:10.1016/j.tetlet.2005.03.053

Hetero-biaryl compounds were prepared via the Suzuki-Miyaura coupling reaction of hetero-aryl moieties containing an unprotected NH₂ group and arylboronic acids. D-t-BPF was found to be an efficient ligand for the cross-coupling of NH₂

Full text of DOI:10.1016/j.tetlet.2005.03.053

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 3573–3577
Direct synthesis of hetero-biaryl compounds containing an
unprotected NH2 group via Suzuki–Miyaura reaction
Takahiro Itoh* and Toshiaki Mase
Process Research, Process R&D, Banyu Pharmaceutical Co. Ltd, 9-1, Kamimutsuna 3-Chome, Okazaki, Aichi 444-0858, Japan
Received 16 February 2005; revised 8 March 2005; accepted 10 March 2005
Available online 5 April 2005
Abstract—Hetero-biarylcompounds were prepared via the Suzuki–Miyaura coupling reaction of hetero-arylmoieties containing an
unprotected NH2 group and arylboronic acids. D-t-BPF was found to be an efficient ligand for the cross-coupling of NH2-unpro-
tected hetero-aryl chlorides with phenylboronic acid.
Ó 2005 Elsevier Ltd. All rights reserved.
O2N
H2N
1 mol% Pd(OAc)2
1 mol% D-t-BPF
N
1. Introduction
O2N
H2N
N
(HO)2B
F
+
N
N
Cl
K2CO3, 1,4-dioxane
reflux, 10 hr
Biaryls are high value synthetic targets and can be found
as substructures in numerous pharmaceuticaland bio-
logical active compounds.1 A large number of synthetic
methods have been developed over the years for the
preparation of biaryls,2 however, the development of
palladium- and nickel-catalyzed cross-coupling strate-
gies has brought this methodology to the forefront of
biarylsynthesis. Indeed, the methods of choice for the
preparation of biaryls are cross-coupling reactions such
as Stille3 and Suzuki–Miyaura.4 A few direct cross-cou-
pling reactions involving NH2-unprotected hetero-aryl
moieties have been disclosed.5 It is common practice to
protection functionalgroups such as amines, aclohosl/
phenols, thiols/thiophenols and carboxylic acids6 prior
to the coupling step followed by deprotection later. In
this letter, we present the first highly efficient and general
Suzuki–Miyaura reaction between phenylboronic acid
and NH2-unprotected chloropyrimidines/pyridines.
F
1
2
3
y. 95%
Scheme 1.
Pd(OAc)2/dppf were found to be less effective than
Pd(OAc)2 with D-t-BPF. Since we envisioned that our
procedure would be applied in direct coupling of NH2-
unprotected hetero-aryl chlorides with arylboronic acids
providing structurally diversified hetero-biaryl amino
compounds, we have further investigated the role of
D-t-BPF. Thus, we report the scope and limitation of
this coupling reaction and the role of D-t-BPF in the
coupling reaction under anhydrous conditions.
These reaction conditions were applied to the synthesis
of an assortment of hetero-biarylcompounds having
unprotected NH2 group on the hetero-arylmoiety.
The results of the Suzuki–Miyaura cross-coupling reac-
tion employing D-t-BPF as ligand of the NH2-unpro-
tected various hetero-aryl chlorides with phenylboronic
acid under our typicalconditions are summarized in
Table 1. Arylation of the activated aminochloropyrimi-
dine afforded the corresponding biarylproducts in high
yield (entries 1 and 2). Coupling product of 4-amino-
5-nitro-6-methoxy-2-chloropyrimidine with phenyl-
boronic acid was also obtained in good yield (entry 3).
Recently, we reported 1,10-bis(di-tert-butylphosphino)-
ferrocene (D-t-BPF) was a highly effective ligand for
synthesis of 4-amino-2-arylpyrimidines via the direct
coupling of NH2-unprotected 4-amino-2-chloropyrim-
idine with arylboronic acids under anhydrous conditions
(Scheme 1).7 In this reaction, Pd(PPh3)2Cl2 or
Keywords: Suzuki–Miyaura reaction; Unprotected NH2 group; D-t-
BPF.
Quinazoline derivatives are important targets in the
pharmaceuticalindustry. The Suzuki–Miyaura reaction
at C-6,8 C-49 and C-89 positions of the quinazoline ring
*
Corresponding author. Tel.: +81 564 57 1726; fax: +81 564 51
7086; e-mail: takahiro_itoh@merck.com
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.03.053

3574
T. Itoh, T. Mase / Tetrahedron Letters 46 (2005) 3573–3577
(entries 6–812). The coupling of 4-amino-2-chloropyr-
idine with phenylboronic acid resulted in incomplete
reaction even after 48 h, and the product was obtained
in only 30% yield with remaining starting material (entry
9). These results suggested that the yield depends on
the basicity of aminochloropyridine. We infer that
the strongly basic 4-aminopyridine could increase the
propensity for coordination to palladium, which in turn
could result in a bis-(pyridine) complex, thus terminat-
ing the catalytic cycle.
Table 1. Coupling of NH2-unprotected aminochloropyrimidines/pyri-
dines with phenylboronic acid
(HO)2B
1.5 eq.
R
H2N
R
H2N
5 mol% Pd(OAc)2
N
N
or
or
Cl
Ph
5 mol% D-t-BPF
2 eq. K3PO4
1,4-dioxane, reflux
H2N
N
Cl
N
H2N
N
Ph
N
4a-i
Entry Substrates
Products
% Yielda
NC
NC
N
N
1
4a 91
H2N
F
N
Cl
Cl
H2N
F
N
Ph
Ph
Wagaw and Buchwald reported that the bidentate
ligand was an efficient for the amination of bromopyri-
dines.13 In the literature, he described that BINAP
prevents the formation of bis-(pyridine) complex
because of its bidentate nature (Scheme 2). Hamann
and Hartwig also reported that the sterically hindered
alkyl phosphines ligand D-t-BPF was efficient ligand
for amination due to the acceleration of oxidative
addition and reductive elimination.14
N
N
2
3
4b 88
H2N
N
H2N
N
OMe
N
OMe
N
O2N
H2N
O2N
H2N
4c 82
N
Cl
N
Ph
NH2
N
NH2
N
MeO
MeO
MeO
MeO
4
5
4d 89
4e 93
Lakshman et al.15 and Western et al.16 have observed
that the use of a non-chelating tert-butyl-substituted
phosphine in the Suzuki–Miyaura reaction of a pro-
tected 6- or 8-bromopurine nucleoside reduced the
activity of the metalcatayl st.
N
Cl
N
Ph
NH2
NH2
Ph
pKa 1.6
N
Cl
N
H2N
H2N
6
7
pKa 2.1
4f 82
4g 68
The selection of a ligand is one of the most important fac-
tors that affect the rate of oxidative addition and reduc-
tive elimination in the catalytic cycle. To facilitate
reductive elimination, there are three key factors, the
value of the bite angle P–Pd–P for bidentate ligands,
the length P–Pd and steric hindrance around ligands
including cone angles for monodentate ligands. For
instance, larger P–Pd–P (angle, D-t-BPF 104°, DPPF
96°, DPPP 91°, DPPE 85°)17 and longer P–Pd (length,
N
N
Cl
N
N
Ph
pKa 2.8
pKa 4.5
H2N
H2N
Cl
Cl
H2N
H2N
Ph
Ph
8
9
4h 72
N
N
˚
˚
˚
D-t-BPF 2.419 A, DPPF 2.292 A, DPPP 2.247 A, DPPE
NH2
NH2
˚
2.230 A) in the four complexes L2 PdRX (L2 = D-t-BPF,
pKa 4.8
4i 30
DPPF, DPPP, DPPE)18,19 are well translated to smooth
reductive elimination to form the coupling products.19
Since D-t-BPF is one of the most sterically hindered
analogues of ferrocenyl ligands, this ligand may generate
a more active catalyst compared to other ferrocenyl
ligands. In addition, the electron density of palladium is
also increased by coordination of alkyl phosphines rela-
tive to arylphosphines, therefore D- t-BFF is expected
to accelerate the rate of oxidative addition step. Further-
more, since P–C bonds of alkyl phosphines are stronger
than that of arylphosphines, D- t-BPF should provide
higher turnover numbers.20 For these reasons, the com-
plex resulting from Pd coordination to D-t-BPF exhibits
higher reactivity towards the arylation of aminopyrimi-
N
Cl
N
Ph
a Yields refer to the average isolated yield of two runs.
has been reported, but all examples reported do not
contain an unprotected NH2 group. As shown in entry
4, 4-amino-6,7-dimethoxy-2-chloroquinazoline was con-
verted to the corresponding 2-phenylquinazoline deriva-
tive in high yield.
Next we evaluated the catalyst activity for the coupling
of NH2-unprotected chloropyridines with phenyl-
boronic acid (entries 5–9). Traditionally, the NH2 group
on the pyridine ring has to be protected prior to the
coupling reaction. The Pfizer group10 reported that the
protection of NH2 group is crucialfor the coupilng of
3-amino-2-chloropyridine with phenylboronic acid. On
the other hand, in our attempts, the direct coupling
of NH2-unprotected 3-amino-2-chloropyridine was suc-
Ar
P(o-tolyl)3
N
Ar Pd
N
X
X
Pd2(dba)3
ArX
Pd
Pd
X
8 P(o-tolyl)3
(o-tolyl)3P
Ar
XS
cessfulusing even 1 mo%l Pd(OAc)
and 1 mol%
2
N
D-t-BPF as ligand (entry 5).11 Reaction of 2- or 3-ami-
no-chloropyridine with phenylboronic acid afforded
the desired phenylpyridine in good to moderate yields
bis-(pyridine) complex
Scheme 2.

T. Itoh, T. Mase / Tetrahedron Letters 46 (2005) 3573–3577
Table 2. Influence of aminopyrimidine moiety for the cross-coupling
3575
O2N
H2N
N
L
L
5 mol% Pd(OAc)2
ligand
bidentate
ligand
O2N
H2N
N
Pd
N
fast
O2N
H2N
Cl
O2N
H2N
O2N
H2N
(HO)2B
+
N
N
K3PO4, 1,4-dioxane
reflux
Cl
O2N
N
Cl
N
Ar
N
5
6
with orwithout
slow
monodentate
ligand
H2N
N
L
Cl
H2
N
N
Pd
Liganda
4-Aminopyrimidine
None
% Yield of 6
L
Entry
1
bis-(amine) complex
D-t-BPF
92
Scheme 3.
P(t-Bu)2
2
None
91
2. Experimental
3
4
D-t-BPF
50 mol%
50 mol%
90
26
P(t-Bu)2
2.1. General
The arylboronic acids, Pd(OAc)2, ligands DPPF, D-t-
BPF (purchased from Johnson Matthey), K3PO4 and
anhydrous 1,4-dioxane, 2-MeTHF, were purchased
from commercialsources and were used without addi-
tionalpurification. Reactions were monitored by HPLC
and TLC (silica gel), and column chromatographic puri-
fications were performed on 300 mesh silica gel. Proton
and carbon NMR spectra were obtained at 500 MHz;
chemicalshifts ( d) were reported in parts per million,
and coupling constants (J) are in hertz. All experiments
were operated under a nitrogen atmosphere.
a 5 mol% of D- t-BPF, 10 mol% of monodentate phosphine ligand.
dine halides than complexes generated from DPPP,
DPPF or 1,10-bis(di-iso-propylphosphino)ferrocene (D-
i-PrPF). In addition, the particular properties of D-t-
BPF make it suitable for coupling of NH2-unprotected
pyrimidine/pyridine moieties.
In order to determine the coordination effect of the two
nitrogen atoms on the aminopyrimidine moiety during
the coupling reaction, aniline derivative 5 was coupled
with phenylboronic acid in the absence or presence of
4-aminopyrimidine (Table 2).
2.2. Typical procedure. The preparation of 4-amino-2-
phenylpyrimidine-5-carbonitrile (4a)
To a round-bottom flask were added chloropyrimidine
(1.0 g), the boronic acid (1.5 equiv), K3PO4 (2.0 equiv),
dry 1,4-dioxane (30 mL) or 2-MeTHF (30 mL). The
mixture was degassed by vacuum/N2 cycle three times.
Catalyst Pd(OAc)2 (5 mol%) and D- t-BPF (5 mol%)
were added and the mixture was degassed twice more.
The mixture was heated to reflux temperature
(ꢀ100 °C) for 4 h with vigorous stirring and HPLC con-
firmed the completion of the reaction. It was cooled to
ambient temperature then the slurry was filtered to
remove salt. The filter cake was washed with i-PrOAc.
The filtrate was concentrated under vacuum to ca.
40 mL. To the solution was added i-PrOAc and 1 N
NaOH aq to remove residualboronic acid. The organic
layer was separated and then washed with fresh 1 N
NaOH aq and 20% NaClaq successiveyl . After separa-
tion, the organic layer was evaporated to dryness. The
product was purified by column chromatography on sil-
ica gel or crystallization using appropriate solvents
(listed under individual compound headings, vide infra).
For this study, we carried out the cross-coupling of
3-chloro-6-nitroaniline and phenylboronic acid with/
without 4-aminopyrimidine. The coupling reaction pro-
ceeded smoothly in high yield regardless of the ligand
used in the absence 4-aminopyrimidine (entries 1 and
2). These data suggests that the weak basicity of aniline
should not detrimentally impact the coupling reaction.
Next we examined the coupling reaction under the same
conditions in the presence of 50 mol% of 4-aminopyr-
imidine. The presence of 4-aminopyrimidine does not
affect the coupling when using D-t-BPF as ligand (entry
3), however dramatic affects with the monodentate
ligand were observed (entry 4). These results showed
that the addition of 4-aminopyrimidine significantly
influences the catalytic activity due to its strong basicity
when using the monodentate ligand. On the other hand,
the bidentate nature of D-t-BPF coupled with its
high electron density and bulkiness effectively sup-
presses coordination of 4-aminopyrimidine to the
metal.
1
Compound 4a: H NMR (500 MHz, DMSO-d6): d 8.74
Taken together, we propose that the efficiency of this
catalyst system (Pd(OAc)2, D-t-BPF) is due to the abil-
ity of the chelating bis-(phosphine) ligand to inhibit the
formation of bis-(amine) complex (Scheme 3).
(s, 1H, pyrimidine-H), 8.33 (d, J = 6.8, 8.5 Hz, 2H, Ar–
H), 7.94 (br s, 2H, NH2), 7.57–7.50 (m, 3H, Ar–H); 13C
NMR (125 MHz, DMSO-d6): d 165.19, 162.98, 161.97,
136.83, 131.92, 128.90, 128.64, 116.11, 87.95; HRMS
calcd for C11H8N4 (M++H), 197.0827. Found, 197.0819.
In conclusion, the titled biaryls could be obtained in
generally good yields and without any protection of
the amino functional group using sterically hindered
and electron rich alkyl bidentate phosphine ligand D-t-
BPF with Pd(OAc)2 under anhydrous conditions.
1
Compound 4b: H NMR (500 MHz, DMSO-d6): d 8.25
(dd, J = 6.4, 8.8 Hz, 1H, Ar–H), 8.25 (dd, J = 7.8,
8.8 Hz, 1H, Ar–H), 8.25 (dd, J = 5.5, 7.8 Hz, 1H,
Ar–H), 7.46 (d, J = 6.4 Hz, 1H, Ar–H), 7.45 (s, 1H,

3576
T. Itoh, T. Mase / Tetrahedron Letters 46 (2005) 3573–3577
pyrimidine-H), 7.45 (d, J = 5.5 Hz, 1H, Ar–H), 7.33 (s,
2H, NH2); 13C NMR (125 MHz, DMSO-d6): d 159.07,
159.02, 153.94, 153.85, 145.89, 143.85, 139.97, 139.82,
137.70, 130.20; HRMS calcd for C10H8FN3 (M++H),
190.0780. Found, 190.0805.
6.46 (dd, J = 2.1, 5.5 Hz, 1H, pyridine-H), 6.05
(s, 2H, NH2); 13C NMR (125 MHz, DMSO-d6) d
156.09, 155.01, 149.39, 139.68, 128.35, 128.26, 126.08,
107.76, 104.88; HRMS calcd for C11H10N2 (M++H),
171.0922. Found, 171.1002.
1
Compound 6: crystallized from i-PrOAc/n-heptane. H
1
Compound 4c: crystallized from i-PrOAc/n-heptane. H
NMR (500 MHz, CDCl3): d 8.18 (d, J = 8.9 Hz, 1H,
Ar–H), 7.57 (d, J = 7.7, 8.8 Hz, 2H, Ar–H), 7.18–7.40
(m, 3H, Ar–H), 6.98 (d, J = 1.9 Hz, 1H, Ar–H), 6.93
(dd, J = 1.9, 8.9 Hz, 1H, Ar–H), 6.15 (s, 2H, NH2);
13C NMR (125 MHz, CDCl3): d 148.57, 144.87,
138.93, 131.44, 128.98, 128.89, 127.17, 126.85, 116.55,
116.41; HRMS calcd for C12H10N2O2 (M++H),
215.0821. Found, 215.0829.
NMR (500 MHz, DMSO-d6): d 8.36 (d, J = 7.1 Hz, 2H,
Ar–H), 8.35 (br s, 2H, NH2), 7.59 (dd, J = 7.0, 7.4 Hz,
1H, Ar–H), 7.54 (dd, J = 7.0, 7.4 Hz, 2H, Ar–H), 4.12
(s, 3H, OMe); 13C NMR (125 MHz, DMSO-d6): d
164.02, 162.98, 158.87, 136.07, 132.32, 128.96, 128.90,
114.26, 55.21; HRMS calcd for C11H10N4O3 (M++H),
247.0831. Found, 247.0857.
i
1
Compound 4d: crystallized from PrOAc/n-heptane. H
NMR (500 MHz, CDCl3) d 8.45 (d, J = 8.8 Hz, 1H,
Ar–H), 8.44 (d, J = 7.9 Hz, 1H, Ar–H), 7.50–7.42 (m,
3H, Ar–H), 7.31 (s, 1H, quinazoline-H), 6.92 (s, 1H, quin-
azoline-H), 5.56 (s, 3H, OMe), 4.02 (s, 3H, OMe); 13C
NMR (125 MHz, CDCl3): d 160.12, 159.82, 155.01,
148.95, 148.40, 138.75, 129.81, 128.38, 128.02, 107.95,
106.92, 100.21, 56.27, 56.16; HRMS calcd for
C10H11N3O2 (M++H), 282.1243. Found, 282.1238.
Acknowledgements
Dr. M. Palucki and Dr. N. Yasuda, Merck & Co., Inc.,
are acknowledged for critical reading of this manuscript.
We thank Mr. M. Ishikawa for HRMS analysis.
References and notes
1
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Compound 4e: H NMR (500 MHz, CDCl3): d 8.16–
8.13 (m, 1H), 7.71–7.67 (m, 2H), 7.53–7.28 (m, 3H),
7.11–7.02 (m, 2H), 3.84 (br s, 2H, NH2); 13C NMR
(125 MHz, CDCl3): d 145.43, 140.44, 140.33, 139.05,
129.20, 128.86, 128.62, 123.45, 123.06; HRMS calcd
for C11H10N2 (M++H), 171.0922. Found, 171.0938.
1
Compound 4f: H NMR (500 MHz, DMSO-d6): d 8.15
´
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(d, J = 2.7 Hz, 1H, Ar–H), 8.09 (d, J = 9.0 Hz, 1H,
Ar–H), 8.00 (d, J = 3.3 Hz, 1H, Ar–H), 8.00 (d,
J = 7.2 Hz, 1H, Ar–H), 7.74 (dd, J = 2.7 Hz, 1H, Ar–
H), 7.59–7.52 (m, 3H, Ar–H); 13C NMR (125 MHz,
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1
Compound 4g: H NMR (500 MHz, DMSO-d6): d 6.98
(d, J = 8.5 Hz, 1H, Ar–H), 3.50 (br s, 2H, NH2); 13C
NMR (125 MHz, DMSO-d6): d 155.90, 144.33, 131.42,
129.61, 127.55, 112.14, 110.39; HRMS calcd for
C11H10N2 (M++H), 171.0922. Found, 171.0948.
1
Compound 4h: H NMR (500 MHz, CDCl3): d 8.32 (d,
J = 2.4 Hz, 1H, pyridine-H), 7.67 (dd, J = 8.5 Hz, 1H,
pyridine-H), 7.51 (d, J = 8.7 Hz, 1H, Ar–H), 7.50 (d,
J = 7.8 Hz, 1H, Ar–H), 7.43 (d, J = 7.6 Hz, 1H, Ar–
H), 7.41 (d, J = 7.9 Hz, 1H, Ar–H), 7.31 (t, J = 7.4 Hz,
1H, Ar–H), 6.58 (d, J = 8.5 Hz, 1H, pyridine-H), 4.50
(s, 2H, NH2); 13C NMR (125 MHz, CDCl3): d 157.60,
146.43, 138.33, 136.57, 128.90, 127.43, 126.90, 126.30,
108.50; HRMS calcd for C11H10N2 (M++H), 171.0922.
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1
Compound 4i: H NMR (500 MHz, DMSO-d6): d 8.09
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1H, Ar–H), 7.91 (d, J = 7.1 Hz, 1H, Ar–H), 7.45–7.36
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T. Itoh, T. Mase / Tetrahedron Letters 46 (2005) 3573–3577
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