Regioselective Suzuki coupling on pyridinium N-(3,5-dibromoheteroar-2-yl)aminides

Article abstract of DOI:10.1016/j.tetlet.2006.06.097

A regioselective Suzuki-Miyaura cross-coupling reaction on 3′,5′-dibromo pyridinium N-(2′-azinyl)aminides is reported. A series of 3′-aryl(or heteroaryl)-5′-bromo-pyridinium N-(2′-pirazinyl)aminides were obtained in good yields. Two isomeric 3′,5′-diaryl

Full text of DOI:10.1016/j.tetlet.2006.06.097

Tetrahedron Letters 47 (2006) 6457–6460
Regioselective Suzuki coupling on pyridinium
N-(3,5-dibromoheteroar-2-yl)aminides
*
´
M. Jose Reyes, Rafael Castillo, M. Luisa Izquierdo and Julio Alvarez-Builla
Departamento de Quı´mica Orga´nica, Universidad de Alcala´, 28871 Alcala´ de Henares, Madrid, Spain
Received 27 April 2006; revised 19 June 2006; accepted 20 June 2006
Abstract—A regioselective Suzuki–Miyaura cross-coupling reaction on 30,50-dibromo pyridinium N-(20-azinyl)aminides is reported.
A series of 30-aryl(or heteroaryl)-50-bromo-pyridinium N-(20-pirazinyl)aminides were obtained in good yields. Two isomeric 30,50-
diaryl pyridinium N-(20-azinyl)aminides were also prepared.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Functionalization of heterocycles through Suzuki–
Miyaura palladium-catalyzed cross-coupling has been
established as a standard method for the synthesis of
biaryl and heterobiaryl systems.1 Substituted pyridines
and pyrazines are valuable intermediates in the pharma-
ceutical and flavour fields, so development of regioselec-
tive processes over both systems has an indubitable
interest. In the past years, our research programme
has been related with the synthetic utility of pyridinium
N-(20-azinyl)aminides 12 (Fig. 1) as building blocks in
the synthesis of azine derivatives,3 and we recently
reported preliminary results obtained in the cross-
coupling reaction between arylboronic acids and pyridi-
nium N-(50-bromoheteroar-20-yl)aminides 1a–c4 (Fig. 1).
The same double coupling methodology on 1c, employ-
ing 3-pyridylboronic acid (Scheme 1), produced a low
yield (18%) of the expected bis-heteroaryl aminide 2a,
while the monosubstituted ylide 3a appeared as the main
reaction product (48%), in addition to 28% of starting
material 1c that was recovered. Neither the use of a large
excess of 3-pyridylboronic acid and/or palladium cata-
lyst, nor longer reaction times, improved the yields of
compound 2a.
The structure elucidation of 3a was solved by compari-
1
son of its H NMR spectra with those of related com-
pounds. H60 of the 2-aminopyridine ring appears more
shielded when a bromine atom is in position 50-, than
when an arene is placed in the same position.3b,4 The
following data were obtained for dH60 (CD3OD) in
compounds 1c, 2a and 3a: 7.74 ppm, 8.03 ppm and
7.71 ppm, respectively. This result pointed out a consid-
erable degree of regioselectivity in the Suzuki process,
The promising results obtained from ylides 1a,b justified
broadening of the process over other aminides, such as
N-(30,50-dibromopyrid-20-yl)pyridinium aminide 1c.3c
On this substrate, a double Suzuki reaction was per-
formed, and different 3,5-disubstituted azines were
obtained.4
when
N-(30,50-dibromo-20-pyridin-20-yl)pyridinium
aminide 1c was reacted with pyridyl-3-boronic acid.
Regioselectivity in palladium cross-coupling reactions of
di-haloazines, having two identical halogen atoms in dif-
ferent positions of the ring, has not been often described
in the literature.5a On uncharged systems, 2,5-dibromo-
pyridine undergoes a regioselective palladium-catalyzed
coupling with terminal acetylenes and arylzinc halides,5b
and 2,5-dichloropyridine selectively reacts at 2-position
with phenylboronic acid.5c,d Moreover, the synthesis of
2-aryl-6-chloronicotinamides via Suzuki coupling of
2,6-dichloronicotinamide with aryl boronic acids has
also been described, and in this case, regioselectivity
N
N
+
N
N
+
1a W=CH, X=H
1b W=N, X=H
1c W=CH, X=Br
1d W=N, X=Br
-
-
N
N
Het
1
Br
X
W
Figure 1.
*
Corresponding author. Fax: +34 91 885 46 86; e-mail: julio.
alvarez@uah.es
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.06.097

6458
M. J. Reyes et al. / Tetrahedron Letters 47 (2006) 6457–6460
N
N
+
N
N
N
N
+
+
-
Pd(PPh3)4
CsCO3(4 eq.)
N
B(OH)2
-
-
N
N
+
+
1c (28%)
+
Br
Br
N
(3 eq.)
toluene/ethanol
(20:1) 8 hr reflux
N
N
N
Br
1c
3a (48%)
2a (18%)
Scheme 1.
was achieved by chelation of the palladium(0) species
by the amide group.5e Furthermore, Thompson et al.
obtained the 3,5-diheteroaryl product by Suzuki cou-
pling of 3,5-dibromopyridin-2-ylamine and 2-methoxy-
pyridin-3-yl boronic acid, but nothing appears in the
letter concerning the presence of monocoupled products
in the mixture.5f Regioselective Suzuki coupling has also
been reported in certain dihaloazine and -diazine sys-
tems, but only when the reactivity differences between
the two halogens was well defined.6
the best results with phenyl boronic acid, with a higher
yield and regioselectivity observed (Table 1, entries 5
and 6).
Although a model explaining the selectivity observed in
mono coupling reaction towards one of the bromine
groups in aminides 1 is not yet fully available, one
important factor should be the increased stability of
the palladium intermediate 5 (Fig. 2) with respect to
its opposite regioisomer. However, comparing results
between 1c and 1d, the regioselectivity is clearly higher
in the pyrazine derivative, so the second ring nitrogen
should have an additional influence. In a recent paper,
Yang and Jiang8 reported a similar selectivity for the
Suzuki coupling on 2,5-dibromo-3-methoxy pyrazine, a
non-charged substrate, which with one equivalent of
phenylboronic acid, yielded the 2-phenyl derivative in
a high yield.
The above cited results encouraged us to perform new
experiments to test the regioselectivity of the Suzuki
reaction of N-(30,50-dibromopyrid-20-yl)pyridinium ami-
nide 1c and N-(30,50-dibromopyrazin-20-yl)pyridinium
aminide 1d. Table 1 shows the results obtained for par-
allel coupling tests on 1c and 1d with three different
boronic acids, in the presence of Pd(PPh3)4 (5%), under
slightly different conditions (A and B) (Scheme 2). In all
cases the reaction mixtures, after 5 h reflux, were ana-
lyzed by HPLC/MS.7
In Table 2, the results obtained for the Suzuki coupling
of N-(30,50-dibromopyrazin-20-yl)pyridinium aminide 1d
with aryl and heteroarylboronic acids, following method
B are presented. In all cases a high degree of regioselec-
tivity for the 3-position was observed, with both aryl
and heteroarylboronic acids, and pyridinium N-(30-aryl
(or heteroaryl)-50-bromopyrazin-20-yl)aminides 3 were
obtained in good yields.9
The two aryl isomers 3 and 4 were detected together
with the corresponding 3,5-disubstituted aminide 2 and
a small quantity of starting material 1. In all cases, a
preference for substitution on position 30- was observed
(Scheme 2).
From these data, it appears that both the nature of the
aminide substrate and the boronic acid used are the
main factors influencing the degree of selectivity ob-
tained. Aminide 1d and, in this case, method B produced
The availability of aminides 3 allowed the synthesis of
two isomeric 30,50-disubstituted N-pyrazin-20-ylpyridi-
nium aminides 6d,h which were obtained when an addi-
tional Suzuki coupling was achieved on ylides 3d and 3h,
Table 1. Suzuki coupling of aminides 1c,d and R–B(OH)2: a regioselectivity study
N
+
N
N
N
N
N
+
+
N
N
+
-
-
-
-
N
N
N
N
Pd(PPh3)4
+
1c,d
+
+
R B(OH)2
+
5 hrs reflux
R
Y
R
R
Y
Br
Br
Y
R
Br
Y
Br
1c,d
2b-d
4b-d
3b-d
Entry
Aminide
Y
R
Methoda
2b–db Yield (%)
3b–db Yield (%)
4b–db Yield (%)
1c,db Yield (%)
1
2
3
4
5
6
1c
1c
1c
1c
1d
1d
CH
CH
CH
CH
N
Ph
Ph
p-Tol.
p-Tol.
Ph
A
B
A
B
A
B
14
10
22
29
8
52
36
36
32
61
67
16
23
27
30
26
3
18
31
15
10
5
N
Ph
25
5
a Method A: Cs2CO3 (4 equiv) as a base in toluene:ethanol (20:1). Method B: K2CO3 (10 equiv) as a base in toluene:ethanol (4:1).
b Yields determined by HPLC/MS.7

M. J. Reyes et al. / Tetrahedron Letters 47 (2006) 6457–6460
6459
+
N
N
N
N
N
+
+
N
L
-
-
Pd(PPh3)4
N
N
-
N
R' B(OH)2
+
Br
L
Y
R
N
Br
R
N
R'
Pd
6d,h
3d,h
Ar
5
Compd.
R
R'
Yield( %)
Figure 2.
6d
6h
Phenyl 3-Pyridyl
3-Pyridyl Phenyl
53
68
In conclusion, a regioselective Suzuki–Miyaura cross-
coupling process has been observed, on pyridinium
N-(30,50-dibromopirazyn-20-yl)aminides similar to 1d.
Although less evident, the phenomenon appears also in
their pyridine analogue. As a general methodology, the
process can be useful to selectively functionalize the 3-
position of the pyrazine ring. Two successive cross-cou-
pling reactions over 1d gave satisfactory yields in ami-
nides 6 with a non-symmetrical substitution (Scheme 2)
Scheme 2.
employing 4-pyridyl- and phenylboronic acids, respec-
tively10 (Scheme 2). In this way, the method provides a
straightforward strategy to obtain unsymmetrical 30,50-
disubstituted aminides 6, and not only the symmetrical
derivatives as has been described earlier.4
Table 2. Regioselective C–C coupling of aminide 1d and boronic acids
4
5
6
3
2
N
N
+
N
N
+
-
N
N
2'
-
6'
5'
Pd(PPh3)4 / K2CO3
N
+
B(OH)2
(1.1eq.)
R
toluene/ethanol (4:1)
reflux
3'
R
Br
Br
N
Br
1d
3d-h
Entry
1
Product
R
Reaction time (h)
3
Mp (ꢁC)
Yield (%)a
75
1''
3d
2''
3''
198–199
6''
5''
4''
2
3
3e
3f
4
5
200–202
182–183
50
71
H3C
H3C
O
O
4
3g
1
190–192
65
5
6
7
8
9
3h
3i
2
4
170–172
229–231
236–238
163–165
206–208
65
77
60
84
81
N
N
N
N
3j
16
12
12
3k
3l
S
S
a Isolated yield. Method B, as described in Table 1, was used.

6460
M. J. Reyes et al. / Tetrahedron Letters 47 (2006) 6457–6460
that can undergo, as we have described earlier,3a,c either
an N–N reduction to produce 3,5-disubstituted 2-amino-
pyrazines3a,c or a regioselective alkylation process at the
exocyclic nitrogen followed by a similar N–N reduction,
to yield 3,5-disubstituted N-alkyl-2-aminopyrazines.3d,f,g
So, the whole approach might give access to useful
pyrazine intermediates. Efforts in this direction are in
progress in our laboratory.
6. (a) Gong, Y.; Pauls, H. W. Synlett 2000, 6, 829–831; (b)
Sotelo, E.; Ravina, E. Synlett 2002, 2, 223–226; (c)
˜
Bouillon, A.; Voisin, A. S.; Robie, A.; Lancelot, J.-C.;
Rault, S. J. Org. Chem. 2003, 68, 10178–10180; (d) Gong,
Y.; He, W. Heterocycles 2004, 62, 851–856.
7. HPLC conditions: Column, Luna C-18 (150 · 4.6 mm)
from Jasco Analitica; Eluent, HCOOH (4% in H2O)(A),
H2O(B) and CH3CN(C); Gradient, 93% B-4.5% B in
25 min, A = 2.5% t = 0–25 min; Flow, 1.0 mL/min; k, 280,
284 and 210 nm. Experiments were performed on an
Agilent 1100 HPLC/MS.
Acknowledgements
8. Yang, C.-G.; Jiang, B. J. Org. Chem. 2002, 67, 9392–9396.
9. General procedure for monocoupling: Pd(PPh3)4 (57 mg,
5% mmol), boronic acid (1.1 mmol), aminide 1d (330 mg,
1 mmol) and K2CO3 (10 mmol) were stirred under argon
and refluxed in a mixture of toluene:ethanol 4:1 (15 mL)
until no starting material was detected by TLC. The
mixture was filtered through celite and washed with
acetonitrile. The filtrates were combined and evaporated
to dryness. The residue was purified by flash chromatog-
raphy on a silica gel column using ethanol as eluent, and
recrystallized from the appropriate solvent.
´
The authors wish to thank the Comision Interministerial
´
de Ciencia y Tecnologıa (CICYT-BQU2001-1508) and
´
the Universidad de Alcala (UAH GC2005/006) for
´
financial support, and the Ministerio de Educacion y
Cultura (MEC) for two studentships (M.J.R. and R.C.).
References and notes
N-(50-Bromo-30-phenylpyraz-20-yl)pyridinium aminide (3d):
Orange solid (245 mg, 75%), mp 198–199 ꢁC (AcOEt), IR
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1
(KBr) mmax (cmꢀ1): 1484, 1404, 1372, 1239, 696 cmꢀ1; H
NMR (300 MHz, CD3OD): d (ppm) 8.71 (2H, dd, J = 7.0
and 1.3 Hz, H2(6)); 8.15 (1H, tt, J = 7.6 and 1.3 Hz, H4);
8.13 (2H, dd, J = 8.4 and 1.5 Hz, H200(600)); 7.87 (2H, dd,
J = 7.6 and 7.0 Hz, H3(5)); 7.58 (1H, s, H6’); 7.44 (3H, m,
H300(500) and H400); 13C NMR (75 MHz, CD3OD): d 156.4
(C20), 142.3 (C2(6)), 141.9 (C30), 140.0 (C60), 137.3 (C100),
134.1 (C4), 129.1 (C200(600)), 128.4 (C400), 127.7 (C300(500)),
126.0 (C3(5)), 121.7 (C50). Anal. Calcd for C15H11BrN4:
C, 55.07; H, 3.39; N, 17.12. Found: C, 55.28; H, 3.60; N,
16.93.
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´
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5% mmol), boronic acid (1.5 mmol), aminide 3 (1 mmol)
and K2CO3 (10 mmol) were stirred and refluxed under
argon, in a mixture of toluene:ethanol 4:1 (15 mL) until no
starting material was detected by TLC. The mixture was
filtered through celite and washed with acetonitrile. The
filtrates were combined and evaporated to dryness. The
residue was purified by flash chromatography on a silica
gel column using ethanol as eluent, and recrystallized from
the appropriate solvent.
´
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(b) Carceller, R.; Garcıa-Navıo, J. L.; Izquierdo, M. L.;
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N-[30-Phenyl-50-(300-pyridyl)pyraz-20-yl)pyridinium aminide
(6d): Orange solid (173 mg, 53%), mp 173–176 ꢁC (EtOH–
AcOEt), IR (KBr) mmax (cmꢀ1): 1554, 1501, 1468, 1401,
1368, 1303, 1252, 1142, 799, 754, 703, 664 cmꢀ1; 1H NMR
(300 MHz, CD3OD): d (ppm) 9.06 (1H, d, J = 2.2 Hz,
H2000); 8.71 (2H, dd, J = 6.8 y 1.3 Hz, H2(6)); 8.39 (1H, dd,
J = 4.8 and 1.7 Hz, H6000); 8.30 (1H, ddd, J = 8.1, 2.2
and 1.7 Hz, H4000); 8.26 (2H, dd, J = 8.4 and 1.6 Hz,
H200(600)); 8.13 (1H, tt, J = 7.5 y 1.3 Hz, H4); 8.06 (1H, s,
H60); 7.84 (2H, dd, J = 7.5 and 6.8 Hz, H3(5)); 7.44 (4H,
m, H300(500), H400 and H5000); 13C NMR (75 MHz. CD3OD):
d 159.3 (C20), 147.4 (C6000), 146.0 (C2000), 145.6 (C2(6)),
142.4 (C30), 139.7 (C100), 139.4 (C4), 137.5 (C60), 135.6
(C3000 or C50), 134.8 (C3000or C50), 133.5 (C4000), 130.2
(C200(600)), 129.3 (C400), 128.7 (C300(500)), 128.5 (C3(5)),
125.1 (C5000). Anal. Calcd for C20H15N5Æ1/2H2O: C,
71.84; H, 4.82; N, 20.94. Found: C, 71.80; H, 4.82; N,
20.63. MS (CI, m/z): 326 (57, M+1), 277 (20), 249 (100),
80 (43).
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