Efficient synthesis of 2-aryl-6-chloronicotinamides via PXPd2-catalyzed regioselective Suzuki coupling

Article abstract of DOI:10.1021/ol035188g

(Matrix presented) A short and convergent synthesis of 2-aryl-6-chloronicotinamides via regioselective Suzuki coupling of 2,6-dichloronicotinamide with aryl boronic acids is described. Regioselectivity was achieved by chelation of the palladium(0) species

Full text of DOI:10.1021/ol035188g

ORGANIC
LETTERS
2
003
Vol. 5, No. 17
131-3134
Efficient Synthesis of
-Aryl-6-chloronicotinamides via
3
2
PXPd2-Catalyzed Regioselective Suzuki
Coupling
Wu Yang,* Yufeng Wang, and James R. Corte
Bristol-Myers Squibb Pharmaceutical Research Institute, P.O. Box 5400,
Princeton, New Jersey 08543-5400
wu.yang@bms.com
Received June 26, 2003
ABSTRACT
A short and convergent synthesis of 2-aryl-6-chloronicotinamides via regioselective Suzuki coupling of 2,6-dichloronicotinamide with aryl
boronic acids is described. Regioselectivity was achieved by chelation of the palladium(0) species to an ester/amide group. The air-stable
palladium catalyst PXPd2, when used in reagent-grade methanol with K CO as the base, afforded the best regioselectivity and shortest
2 3
reaction times among the catalysts screened.
In the course of our investigations into suitable routes for
the preparation of 6-amino-2-arylnicotinamide analogues 1,
we sought a convergent approach where a variety of 2-aryl
and 6-amino groups could be installed late in the synthetic
sequence. To our surprise, only a limited number of
preparations of 6-amino-2-arylnicotinamides had been previ-
a Suzuki coupling to install the 2-aryl moiety. Alternatively,
the sequence could be reversed and route B would introduce
the 2-aryl moiety through the Suzuki coupling and then
subsequently incorporate the 6-amino group. The observed
regioselectivity for reaction of 4a/4b in either the S Ar or
N
Suzuki coupling would then be used to dictate which reaction
sequence would be chosen.
1
ously reported in the literature. Moreover, these existing
approaches were linear syntheses in which the aryl moieties
were incorporated early in the synthesis, making it difficult
to prepare a large number of analogues rapidly with variable
substitution at the 2-position.
It was necessary for us to develop a new and more
convergent method for the synthesis of 6-amino-2-arylnico-
tinamides. We envisioned two possible routes to nicotin-
amides 1 starting from readily available 2,6-dichloronicotinic
acid derivatives 4a or 4b (Scheme 1).
Our initial efforts focused on the nucleophilic aromatic
substitution sequence. Treating amide 4a with phenylethyl-
Scheme 1. Two Possible Routes to Nicotinamide 1
Route A would incorporate the 6-amino group, via a
nucleophilic aromatic substitution strategy and then employ
(
1) (a) Gompper, V. R.; Helnemann, U. Angew. Chem. 1980, 92, 208-
2
09. (b) Nuss, J. M.; Harrison, S. D.; Ring, D. B.; Boyce, R. S.; Johnson,
K.; Pfister, K. B.; Ramurthy, S.; Seely, L.; Wagman, A. S.; Desai, M.
Levine, B. H. WO 0220495.
1
0.1021/ol035188g CCC: $25.00 © 2003 American Chemical Society
Published on Web 07/30/2003

amine in THF at 60 °C gave 47% of the undesired, 2-amino
improve the regioselectivity for the Suzuki coupling by taking
advantage of the adjacent ester group to chelate the catalyti-
cally active Pd(0) species and direct its insertion into the
C2 carbon-chloride bond. Though Overman and Hallberg
have taken advantage of coordinating functional groups to
2
pyridine 5 as a single regioisomer along with 30% recovered
3
starting material 4a (eq 1). Since the S
N
Ar strategy afforded
6
the undesired regioisomer, we turned our attention to route
B with Suzuki coupling.
chelate transient Pd(II) complexes and direct the regio-
7
selectivity in a variety of Heck reactions, chelation of the
Pd(0) species to direct the oxidative addition step in a
palladium-catalyzed process has not been previously re-
ported. To promote chelation of the ester and the Pd(0)
species, we reasoned that reduction of the ratio of ligand to
palladium, thereby making the palladium more coordinatively
unsaturated, might prove to be successful. Hartwig’s mecha-
8
Methyl ester 4b and phenyl boronic acid were initially
chosen as a model system to examine the regioselectivity in
the Suzuki coupling (Table 1). Refluxing 4b, phenyl boronic
nistic studies on Pd/P(t-Bu) -catalyzed aminations revealed
3
that a 1:1 ratio of Pd:P(t-Bu) was optimal, thus invoking a
monophosphine Pd(0) complex as the catalytically active
3
species. Indeed, treatment of 4b, phenyl boronic acid, and
9
KF, with Pd
2
(dba)
3
/[HP(t-Bu)
3
]BF
4
in THF at 50 °C,
afforded a 1.7:1 mixture of 2b:6b, favoring the desired 2-aryl
regioisomer (entry d). Use of Pd(PCy Cl as the catalyst
gave results almost identical to those seen with Pd (dba)
HP(t-Bu) ]BF , suggesting the active species was most likely
also a 1:1 ratio of Pd:PCy complex (entry e). Even though
Table 1. Regioselectivity for Suzuki Coupling with Different
Palladium Catalystsa
3
)
2
2
2
3
/
[
3
4
3
the bulky, electron-rich trialkylphosphines provided the
desired C2 aryl regioisomer as the major product, we sought
a catalyst system that did not require vigorous degassing and
therefore would be more amenable to parallel synthesis.
entry
Pd source (mol %)
Pd(PPh3)4 (5)
solvent 2b:6bb
a
b
c
d
e
f
THF
1:5c
10
Recently, Li demonstrated that air-stable 1:1 Pd/phosphi-
Pd(dppf)Cl2 (5)
THF
THF
THF
THF
MeOH
MeOH
1:2.9
1:1.8
1.7:1
1.7:1
trace
2.5:1
11
12
nous acid complexes such as POPd2 and PXPd2 are
efficient precatalysts for the Suzuki coupling of aryl chlo-
rides. Though the Suzuki coupling with POPd2 (entry f) led
to only a trace amount of product, PXPd2 in refluxing
Pd(OAc)2 (3)/(o-biphenyl)PCy2 (4.5)d
Pd2(dba)3 (1.5)/[HP(t-Bu)3]BF4 (3)e
Pd(PCy3)2Cl2 (5)
POPd2 (1)
PXPd2 (1)f
1
3
g
methanol (entry g) gave a 2.5:1 mixture of 2b:6b. In
addition to providing the best regioselectivity in the Suzuki
coupling reactions, the PXPd2 system provided an additional
advantage in that the coupling reactions could be run open
to the air without degassing the reaction mixture.
a
General reaction conditions: 1.0 equiv of 4b, 1.0 equiv of phenyl
b
boronic acid, 3.0 equiv of K2CO3, reflux, 16 h. Ratio determined by
reverse-phase analytical HPLC. Ratio determined by H NMR, since 2b
c
1
d
e
f
and Ph3PO overlapped in the HPLC. KF. KF, 50 °C. Reaction time:
0 min.
3
Encouraged by the preliminary results for the PXPd2-
catalyzed reaction, we chose to examine the effect of solvent
and base on the regioselectivity and reactivity of the coupling
(Table 2). In fact, the Suzuki coupling proceeded rapidly
even at room temperature, completely consuming the phenyl
boronic acid within 1 h (entry a). When anhydrous methanol
was used, the reaction was more sluggish, though the
2 3 3 4
acid, anhydrous K CO , and Pd(Ph P) in THF for 16 h gave
a 1:5 mixture of 2b:6b, with the undesired 6-aryl isomer
predominating (entry a). Similar results were observed when
4
bidentate ligands were employed (entries b and c). Presum-
ably, the regioselectivity for the Suzuki coupling is dictated
by the relative rates in oxidative addition for the two carbon-
chloride bonds. The undesired 6-aryl isomer predominated
since oxidative addition of the catalytically active phosphine
Pd(0) complex to the C6 carbon-chloride bond is less
sterically encumbered and thus favored. We sought to
5
(6) Precoordination of Pd(0) species to the π-system of sp2 carbon-halide
bonds has been proposed.
(
7) (a) Madin, A.; Overman, L. E. Tetrahedron Lett. 1992, 33, 4859. (b)
Nilsson, P.; Larhed, M.; Hallberg, A. J. Am. Chem. Soc. 2003, 125, 3430.
c) Olofsson, K.; Sahlin, H.; Larhed, M.; Hallberg, A. J. Org. Chem. 2001,
6, 544.
8) (a) Alcazar-Roman, L. M.; Hartwig, J. F. J. Am. Chem. Soc. 2001,
(
6
(
(
2) Regiochemistry was confirmed by NOE experiments. The amide
proton gave NOE when the peaks for CH2CH3 or CH2Ph were irradiated.
3) Hirokawa, Y.; Horikawa, T.; Kato, S. Chem. Pharm. Bull. 2000, 12,
847. Hirokawa obtained a mixture of regioisomers upon addition of amines
123, 12905. (b) Hartwig, J. F.; Kawatsura, M.; Haack, S. I.; Shaughnessy,
K. H.; Alcazar-Roman, L. M. J. Org. Chem. 1999, 64, 5575.
(9) Netherton, M. R.; Fu, G. C. Org. Lett. 2001, 3, 4295.
(10) (a) Li, G. Y.; Zheng, G.; Noonan, A. F. J. Org. Chem. 2001, 66,
8677. (b) Li, G. Y. Angew. Chem., Int. Ed. 2001, 40, 1513. (c) Li, G. Y. J.
Org. Chem. 2002, 67, 3643.
(
1
to 2,6-dichloronicotinic acid methyl ester, with the 2-amino regioisomer
predominating.
(
4) Wolfe, J. P.; Tomori, H.; Sadighi, J. P.; Yin, J.; Buchwald, S. L. J.
(11) POPd2, CAS #386706-32-7, was commercially available from
CombiPhos Catalysts, Inc. http://www.combiphos.com.
(12) PXPd2, CAS 386706-33-8, was available exclusively from Com-
biPhos Catalysts, Inc. http://www.combiphos.com.
(13) Methanol and ethanol are preferred solvents with the Pd/phosphinous
acid complexes. Li, G. Y. Personal communication.
Org. Chem. 2000, 65, 1158. The (o-biphenyl)PCy2 ligand can be thought
of as a bidentate ligand since Buchwald proposed participation of the
π-system of the ortho aromatic with the unoccupied d-orbital on palladium.
(
5) However, Hartwig has shown that the oxidative addition can be
reversible. Roy, A. H.; Hartwig, J. F. J. J. Am. Chem. Soc. 2001, 123, 1232.
3132
Org. Lett., Vol. 5, No. 17, 2003

Table 2. Solvent and Base Effects on PXPd2-Catalyzed Suzuki
Couplinga
Table 3. Suzuki Coupling of 2,6-Dichloronicotinamide
Catalyzed by PXPd2a
entry
solvent
base
2b:6bc
a
b
c
d
e
f
MeOH (reagent)b
MeOH (anhydrous)
MeOH (reagent)
MeOH (reagent)
THF, 65 °C
K2CO3
K2CO3
KF
Cs2CO3
K2CO3
K2CO3
K2CO3
1.8:1
2.7:1
1.4:1
hydrolysis of ester
1.8:1
1.8:1
1.1:1
toluene
DMF, 65 °C
g
a
General reaction conditions: 1.0 equiv of 4b, 1.0 equiv of phenyl
boronic acid, 3.0 equiv of base, room temperature, 16 h, 1% catalyst.
b
c
Reaction time: 30 min. Ratio determined by reverse-phase analytical
HPLC.
regioselectivity was improved compared with results obtained
in the identical reaction carried out in reagent-grade methanol
(entry b). This observation suggested that trace amounts of
water present in standard reagent-grade methanol might play
a role in accelerating the reaction. This acceleration might
possibly be a result of solvolytic transformation of PXPd2
to a more active catalyst such as that seen in the examples
14
reported by Bedford or due to more efficient solubilization
of the inorganic base. Switching the base to potassium
fluoride afforded a similar ratio of regioisomers, though the
reaction proceeded at a slower rate (entry c). Replacement
of potassium carbonate with cesium carbonate resulted in
rapid hydrolysis of the methyl ester to the corresponding acid,
and only a trace amount of product was observed by HPLC
(entry d). Finally, with other solvents such as THF, DMF,
and toluene, the reactions proceeded more slowly than those
with methanol and therefore required elevated temperatures
and/or prolonged reaction times (entries e-g).
Having identified a catalyst system that provided the
desired regioselectivity, we turned our attention to the target
substrate 4a for the Suzuki coupling. If the observed
improvement in regioselectivity is in fact attributable to
chelation of the ester group to the Pd(0) species, then amide
a
General reaction conditions: 1.0 equiv of 4b, 1.2 equiv of phenyl
b
boronic acid, 3.0 equiv of K2CO3, 55 °C, 1 h, 2% catalyst. Isolated yields
after purification. c Based on 10-20% recovered starting material. EtOH
d
was used as solvent.
9
4
:1 mixture of 2-aryl:6-aryl isomer (Table 3, entry a). Amide
a was also found to be less reactive toward Suzuki coupling
4a with enhanced coordinating ability relative to the ester
than ester 4b but at the same time more prone to nucleophilic
substitution by methanol or water at the 2-position. As a
result, the coupling reactions generally gave greater yields
with heating and higher catalyst loading (2%). This method
was subsequently applied to the preparation of a variety of
should lead to even greater regioselectivity. Indeed, subject-
1
5
ing amide 4a to the optimized Suzuki conditions led to a
(14) Bedford, R. B.; Hazelwood, S. L.; Limmert, M. E.; Brown, J. M.;
Ramdeehul, S.; Cowley, A. R.; Coles, S. J.; Hursthouse, M. B. Organo-
metallics 2003, 22, 1364.
2
-aryl-6-chloronicotinamides 2a (Table 3). This optimized
(15) Representative experimental procedures for the preparation of
combination of directing group, catalyst, and reaction condi-
tions worked consistently well with both electron-rich (entries
b and c) and electron-deficient (entries d and f) boronic acids,
compounds 2a and 6a are as follows: amide 4a (228 mg, 0.73 mmol),
boronic acid (107 mg, 0.88 mmol), and K2CO3 (302 mg, 2.19 mmol) were
mixed in MeOH (1.5 mL), and PXPd2 (10.5 mg, 0.015 mmol) was added.
The reaction mixture was heated at 55 °C for 1 h, after which the reaction
mixture was concentrated and partitioned between water (10 mL) and EtOAc
(
10 mL). The aqueous layer was extracted again with EtOAc (2 × 10 mL),
10.4 Hz, 2H), 4.12 (t, J ) 5.2 Hz, 2H), 6.86 (dd, J ) 0.9, 8.7 Hz, 2H),
6.91 (t, J ) 7.4 Hz, 1H), 7.11 (brs, 1H), 7.18-7.25 (m, 2H), 7.36-7.43
(m, 3H), 7.53 (d, J ) 8.0 Hz, 1H), 7.93-7.96 (m, 2H), 8.13 (d, J ) 8.0
Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 40.2, 66.8, 115.0, 119.2, 121.7,
127.6, 128.9, 129.3, 130.0, 130.7, 137.1, 141.3, 147.3, 158.8, 159.6, 165.1.
the combined EtOAc layers were dried over MgSO4, filtered, and condensed
to yield a yellow semisolid. Reverse-phase HPLC purification provided
compounds 2a (158 mg, 61%), 6a (18 mg, 7%), and bis-phenyl product
(
55 mg, 19%), all as a white solid. The structures of these three compounds
1
1
were confirmed by HMQC experiments. Compound 2a. H NMR (400
MHz, CDCl3): δ 3.53 (dd, J ) 5.4, 10.4 Hz, 2H), 3.73 (t, J ) 5.0 Hz, 2H),
5
Bis-phenyl Compound. H NMR (400 MHz, CDCl3): δ 3.59 (dd, J )
5.4, 10.4 Hz, 2H), 3.74 (t, J ) 5.0 Hz, 2H), 5.99 (brs, 1H), 6.63 (d, J ) 7.9
Hz, 2H), 6.90 (t, J ) 7.4 Hz, 1H), 7.18-7.27 (m, 5H), 7.41-7.45 (m, 3H),
7.61 (d, J ) 8.4 Hz, 2H), 7.76 (d, J ) 8.1 Hz, 1H), 7.94-7.96 (m, 2H),
.81 (brs, 1H), 6.61 (d, J ) 7.9 Hz, 2H), 6.88 (t, J ) 7.4 Hz, 1H), 7.12-
.22 (m, 5H), 7.26 (d, J ) 8.1 Hz, 1H), 7.53 (d, J ) 7.1 Hz, 2H), 7.88 (d,
7
13
13
J ) 8.1 Hz, 2H). C NMR (100 MHz, CDCl3): δ 39.8, 66.2, 114.8, 121.6,
1
1
8.18 (d, J ) 8.2 Hz, 1H). C NMR (100 MHz, CDCl3): δ 40.0, 66.0,
23.0, 129.0, 129.2, 129.8, 130.1, 130.2, 137.9, 140.4, 152.4, 157.2, 158.6,
114.8, 119.9, 121.6, 127.9, 129.0, 129.3, 129.4, 129.8, 130.1, 130.6, 137.4,
137.8, 139.7, 156.1, 158.4, 158.5, 168.8.
1
67.8. Compound 6a. H NMR (400 MHz, CDCl3): δ 3.84 (dd, J ) 5.5,
Org. Lett., Vol. 5, No. 17, 2003
3133

with isolated yields all above 50%. When a sterically
hindered boronic acid such as 2-methoxyphenyl boronic acid
was used (entry e), the reaction was sluggish even in
refluxing reagent-grade ethanol and the yield was lower due
to competing reaction of the 2-chloro group with water.
The synthesis of target 6-amino-2-arylnicotinamide 1 was
accomplished by treatment of 2a with amines at 140 °C as
exemplified in eq 2.
tivity in Suzuki couplings of 2,6-dichloronicotinamides was
discovered. The air-stable palladium catalyst PXPd2 was
found to catalyze the Suzuki coupling of 2,6-dichloronico-
tinamide with aryl boronic acids to give the 2-aryl-6-
chloronicotinamides 2a in moderate to good yields. This
methodology offers a short (three steps) and convergent
synthesis 6-amino-2-arylnicotinamides from commercially
available 2,6-dichloronicotinic acid. Furthermore, this method
could be easily adapted to high-throughput parallel synthesis.
Acknowledgment. We thank Ms. Yixin Li for performing
NMR experiments on compounds 2b and 6b. We are
thankful to Dr. Lawrence Hamann for valuable suggestions
and Drs. Ruth Wexler and Karnail Atwal for helpful
comments.
Supporting Information Available: Experimental pro-
cedure and characterization for compounds 1, 2b, 6b, and
5
, entries a-f in Table 3. This material is available free of
In summary, a novel method using the ester/amide moiety
to direct the insertion of the catalytically active Pd(0) species
to the C2 carbon-chloride bond to control the regioselec-
charge via the Internet at http://pubs.acs.org.
OL035188G
3134
Org. Lett., Vol. 5, No. 17, 2003