Suzuki reaction on pyridinium N-haloheteroarylaminides: regioselective synthesis of 3,5-disubstituted 2-aminopyrazines

Article abstract of DOI:10.1016/j.tet.2007.11.057

An extensive study of Suzuki-Miyaura cross-coupling processes on N-pyridinium bromoazinyl aminides has been performed. Mono- and disubstitution on 5- and 3,5-bromo derivatives produced the corresponding aryl derivatives. In the disubstituted compounds reg

Full text of DOI:10.1016/j.tet.2007.11.057

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 1351e1370
www.elsevier.com/locate/tet
Suzuki reaction on pyridinium N-haloheteroarylaminides: regioselective
synthesis of 3,5-disubstituted 2-aminopyrazines
*
´
Rafael Castillo, M. Jose Reyes, M. Luisa Izquierdo, Julio Alvarez-Builla
Departamento de Qu´ımica Orga´nica, Universidad de Alcala´, 28871 Alcala´ de Henares, Madrid, Spain
Received 1 October 2007; received in revised form 15 November 2007; accepted 16 November 2007
Available online 22 November 2007
Dedicated to Professor M. Yus on the occasion of his 60th birthday
Abstract
An extensive study of SuzukieMiyaura cross-coupling processes on N-pyridinium bromoazinyl aminides has been performed. Mono- and
disubstitution on 5- and 3,5-bromo derivatives produced the corresponding aryl derivatives. In the disubstituted compounds regioselective
substitution at the 3-position occurred, vicinal to the aminide nitrogen, and this was more evident in pyrazine derivatives. The commonly used
strategy involving N-alkylation and reduction of the NeN bond gave rise to a series of 2-alkylamino-3,5-disubstituted-pyrazines.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
allow the use of chlorinated substrates or avoid the use of
organic solvents.5
Polysubstituted heterocycles belong to the most important
class of organic compounds, they are widespread in nature
and many of them show interesting biological activities.1
Functionalization of halo- or metallated heteroaromatic com-
pounds through metal-mediated cross-coupling reactions has
become an important method for the preparation of different
multiple carbon-substituted heterocycles2 and, in recent years,
selective Pd-mediated reactions have been developed to
prepare highly functionalized heterocycles.3 The Suzukie
Miyaura cross-coupling reaction has proved to be a powerful
and versatile method for the formation of Csp2eCsp2 bonds.4
The process has important advantages over the other palla-
dium-catalyzed cross-coupling processes and these include
functional group compatibility, low toxicity of reagents and
intermediates, ready availability of boron derivatives, high
thermal stability and good tolerance against oxygen and aque-
ous solvents. Recently, efforts have been focused on the devel-
opment of efficient and selective catalytic systems that either
Pyridinium heteroaryl-stabilized aminides 1 (Fig. 1), in
which we have been interested for a number of years,6 are
a subgroup of mesomeric betaines7 with interesting reactivity8
due to their particular structure.8b
Regioselective halogenation8c at the iminoazine moiety
affords 3- or 3,5-halogenated aminides and these compounds
have been used in radical cyclization processes9 and, more
recently, preliminary results have been reported for the Suzuki
cross-coupling reaction of compounds 2a, 2b and 2d (Fig. 1)
with boronic acids.10
N
+
+ N
N–
N–
N
N
Y
Y
Br
W
W
1a Y=W=CH
1b Y=CH, W=N
1c Y=N, W=CH
2a Y=W=CH
2b Y=CH, W=N
2c Y=N, W=CH
2d Y=CBr, W=CH
2e Y=CBr, W=N
* Corresponding author. Tel.: þ34 91 885 46 06; fax: þ34 91 885 46 86.
E-mail address: julio.alvarez@uah.es (J. Alvarez-Builla).
Figure 1.
0040-4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.11.057

1352
R. Castillo et al. / Tetrahedron 64 (2008) 1351e1370
2. Results and discussion
2.1. Monosubstituted N-aminides
compound if steric effects were predominant in the process
(Scheme 2).10b
Monocoupling of N-aminides appeared to be even more
efficient in pyrazine derivatives 2ae2c. As a consequence,10b
a method involving a modification of method B was developed
in order to decrease the amount of boronic acids (1.1 mmol)
required with the aim of minimizing double coupling (Table
3). A series of 3-aryl or heteroaryl N-(5-bromopyrazin-2-yl)-
pyridinium aminides 10 were obtained. Although compounds
10 were obtained in fairly good yield, traces of diaryl aminides
7 and 50-aryl products were detected in the reaction mixture.
A reduction in the amount of catalyst from 5 to 1 mol %
minimized the insertion of Pd0 into the CeBr bond in the
50-position and, although the reaction took place slowly, a con-
siderable increase in selectivity and therefore in yield was
observed (Table 3, compounds 10a and 10c).
The reaction of pyridinium N-(5-bromoheteroaryl)aminides
2a, 2b and boronic acids worked effectively under standard
conditions: i.e., aminide (1 mmol), boronic acid (1.5 mmol),
Pd(PPh3)4 (5 mmol %) and Cs2CO3 (2 mmol) in refluxing tol-
uene/ethanol (20:1, v/v)10a (Table 1, method A) to afford the
substituted products 3 and 4. In all cases the process was
continued until substrate 2 had been consumed. In addition,
in the first attempt to prepare compound 3d it was found
that 4-(hydroxymethyl)phenylboronic acid had low solubility
in toluene and, as a result, the ratio of toluene/ethanol had
to be optimized, yielding 73% of 3d with a 4:1 mixture of tol-
uene/ethanol. Moreover, it is known that the base plays an
important role in the Suzuki process,4a with the amount and
base strength being two important factors in the transmetalla-
tion step in terms of increasing the conversion yields. As in
previous work, the use of hard bases10a did not increase the
yield of 3a but a softer base, such as K2CO3, was tested in
large excess11 in the coupling of aminide 2a with different
boronic acids. In most cases, the method (Table 1, method
B, with 10 mmol of base) produced high yields, often with
shorter reaction times, particularly in the case of 3d, which
was obtained in excellent yield (92%) (Scheme 1).
A model for the intermediate, in which the unshared pair of
the aminide nitrogen coordinates palladium to provide some
extra stability to the complex, has been proposed to explain
the observed selectivity (Scheme 3).10b
A similar type of behaviour has been reported in the liter-
ature for Pd-mediated processes involving 3,5-dibromopyra-
zines that contain substituents with an unshared electron pair
in the 2-position.3b,12 In addition, the recent regioselective
reduction of 3,5-dibromopyrazin-2-ylamine produced only
5-bromo-pyrazin-2-ylamine on using various hydride donors,
palladium sources, ligands, bases and solvents.12f The authors
suggest the participation of the neighbouring amino group as
a ligand as an explanation for the observed regioselectivity.
Once monocoupled aminides 10 had been prepared, a sec-
ond coupling on the remaining bromine in the 5-position was
achieved under previously described conditions (method B)
to give almost quantitative yields of the unsymmetrical
30,50-disubstituted pyrazin-2-ylaminides 11 (Scheme 4) re-
ported in Table 4.
+
R-B(OH)2 (1.5 equiv.)
+
N
N
N
N–
N
N–
Pd(PPh3)4
Base
Toluene/Ethanol
Y
Y
Br
W
R
W
Δ
2a-c
3 Y=W=CH
4 Y=CH, W=N
5 Y=N, W=CH
Scheme 1.
Two significant differences in chemical shifts can be obs-
1
erved in the H NMR spectra of N-(30,50-diarylpyrazin-2-yl)-
Results for derivatives of pyridine, pyrazine and pyrimidine
(compounds 3e5, respectively) are given in Table 1.
pyridinium aminides 7 and 10 in relation to the position of
the aryl (or heteroaryl) substituent on the diazine ring: (a) sub-
stituents in the 5-position exert a deshielding effect on H60
(w0.5 ppm) and (b) the signals for the a-protons of the group
in the 30-position appear at lower field than those for the same
substituent on the 50-position. Representative chemical shifts
for compounds 2d, 4a, 7a and 10a are given as examples in
Figure 2.
2.2. Disubstituted N-aminides
Dibromoaminide 2d8c was tested in a double Suzuki pro-
cess, using 3 equiv of boronic acid, 4 equiv of Cs2CO3 and
a mixture of toluene/ethanol (20:1, v/v) under reflux10a (Table
2, method A); alternatively, bearing in mind the previous
results (Table 1, method B) a double coupling was also tested
on pyridinium N-(3,5-dibromoazin-2-yl)aminides 2d and 2e
and several boronic acids, using 20 equiv of K2CO3 in a tolu-
ene/ethanol (4:1) solvent mixture under reflux (Table 2).
Yields were again higher on using method B and compounds
6 and 7 were obtained, as shown in Table 2.
Unexpectedly, 6h was obtained in low yield (18%) together
with the monosubstituted compound 8 as the main product
(48%) and 28% of the starting material 2d. This result indi-
cates a possible preference in the coupling process that gives
rise to compound 8 rather than its isomer 9dthe expected
3. Synthesis of 2-alkylaminoazines
The chemistry of pyridinium N-aminides has been well
developed in our research group, and several publications refer
to a regioselective N-alkylation and the subsequent reduction
of the NeN bond in order to obtain 2-alkylaminoazines.8b,e,g,i
The preparation of 2-aminoazines is interesting not only
because they are valuable intermediates in synthesis but also
due to their interesting properties.12 However, the preparation
of highly functionalized 2-aminopyrazines is not an easy
task.13,14 The present study could form the basis of a good

R. Castillo et al. / Tetrahedron 64 (2008) 1351e1370
1353
Table 1
Arylation of aminides 2aec with different arylboronic acidsa
4
3
2
5
6
1.5 equiv R-B(OH)2
+N
+N
N
N–
2'
Pd (PPh3)4
Base
6'
5'
N
N–
Y
Y
R
W
Br
W
2a-c
3, 4, 5
Ra
Compound
W
Y
Methodb
Time
(h)
Yield
(%)
Ra
Compound
W
Y
Methodb
Time
(h)
Yield
(%)
2'''
5'''
2'''
5'''
3'''
4'''
1'''
6'''
3'''
4'''
N
6'''
A
B
8
8
90
95
3a
CH
CH
3l
CH
CH
A
2
95
A
B
15
3
67
90
3b
3c
3d
3e
CH
CH
CH
CH
CH
CH
CH
CH
A
B
8
8
88
95
4a
4b
4c
4d
N
N
N
N
CH
CH
CH
CH
Me
HOH2C
B
2
87
MeO
O
A
B
12
12
25
92
A
B
24
1
45
84
HOH2C
MeO
Me
A
B
8
4
91
86
B
1
91
A
B
2
1
71
89
N
Me
N
3f
CH
CH
CH
CH
4e
5a
N
CH
N
Me
Cl
A
B
24
8
85
89
3g
CH
B
B
4
4
75
70
A
B
72
4
64
95
3h
CH
CH
5b
CH
N
HOC
Me
O
3i
3j
CH
CH
CH
CH
A
A
8
8
75
70
5c
CH
CH
N
N
B
B
5
4
81
73
MeO
Me
β
2'''
1'''
6'''
3'''
4'''
α
5d
5'''
4'''
3'''
3a'''
5'''
6'''
N
3k
CH
CH
B
8
89
5e
CH
N
B
2
95
2'''
7a''' O
7'''
a
Ring numbering employed in NMR analysis.
b
Method A: aminide (1 mmol), boronic acid (1.5 mmol), Cs2CO3 (2 mmol), Pd(PPh3)4 (5 mmol %), toluene/EtOH (20:1). Method B: aminide (1 mmol), boronic
acid (1.5 mmol), K2CO3 (10 mmol), Pd(PPh3)4 (5 mmol %), toluene/EtOH (4:1).

1354
R. Castillo et al. / Tetrahedron 64 (2008) 1351e1370
Table 2
Diarylation of aminides 2d,e with different boronic acids
+N
+N
N–
N
N–
R-B(OH)2
N
Br
W
2d, e
Br
R
W
6, 7
R
R
Compound
W
Methoda
A
Time (h)
8
Yield (%)
R
Compound
W
N
Methoda
Time (h)
Yield (%)
A
B
15
8
67
90
6a
CH
63
56
7a
6b
CH
A
8
7b
N
B
2
86
Me
MeO
O
A
B
24
8
45
95
6c
CH
CH
B
A
8
3
86
90
7c
N
N
HOH2C
Me
6d
7d
B
B
B
1
8
8
88
98
89
MeO
Me
6e
6f
CH
CH
B
A
8
8
70
78
7e
N
S
Me
Cl
7f
N
N
S
A
B
2
8
71
89
N
6g
6h
CH
CH
A
A
3
8
85
7g
N
18b
a
Method A: boronic acid (3 mmol), Cs2CO3 (4 mmol), Pd(PPh3)4 (5 mol %), toluene/ethanol (20:1). Method B: boronic acid (3 mmol), K2CO3 (20 mmol),
Pd(PPh3)4 (5 mol %), toluene/ethanol (4:1).
b
With 48% of aminide 8.
OH
B
OH
(3.0 mmol)
N
N+
N +
N–
N–
N+
N–
N +
N–
N
Pd(PPh3)4
K2CO3 (10 mmol)
Toluene/Ethanol
Δ
N
N
N
Br
Br
Br
Br
2d
N
N
8
6h
N
N
9
Scheme 2.
approach to produce 2-benzylamino-3,5-diarylpyrazines 13
with a high degree of variability, by reduction of salts 12
(Scheme 4).
In previous papers, we reported that the nuclear nitrogen on
N-pyridin-2-yl pyridinium aminides is partially blocked by an
intramolecular hydrogen bond, making the alkylation regiose-
lective on the exo-nitrogen8b (Fig. 3). Nevertheless, when this
process was applied to unsubstituted diazine-stabilized ami-
nides, where only one nitrogen can be blocked by the hydro-
gen bond, alkylation on the alternative nitrogen of the
diazine ring was also detected.8e In the case described here,
the presence of two bulky aryl substituents at the 30- and 50-po-
sition makes N40 less accessible, and only the exocyclic nitro-
gen alkylation product is successfully obtained (Fig. 3).
Alkylation of aminides 11 was performed in anhydrous ac-
etone and, once the solvent had been removed in vacuo, the
pyridinium salts 12 were isolated by treatment with ethyl ac-
etate, in which the excess alkylating agent and the unreacted
aminide 11 remained in solution. The pyridinium salts 12
were used in the next step without further purification. The
yields indicated in Table 5 are the result of the two steps:
N-alkylation and NeN reduction.

R. Castillo et al. / Tetrahedron 64 (2008) 1351e1370
1355
Table 3
Monoarylation of 30,50-dibromopyrazin-20-yl pyridinium N-aminide 2e
4. Conclusions
In conclusion, the peculiar reactivity of aminides 1, which
can be selectively mono- or dihalogenated,8c allows an easy
mono- or diarylation through the Suzuki reaction to produce
compounds 3e7 with a diverse range of 3- and 3,5-aryl and het-
eroaryl substituents, all obtained with excellent yields. In most
cases, the method employing an excess of K2CO3 (method B)
gives rise to better results than the use of Cs2CO3.10a
Moreover, the Suzuki process on dihalo derivatives of pyri-
dine, such as 2e, showed a regioselective arylationdpredomi-
nantly at the 30-position of the pyridine. The regioselectivity
was higher with pyrazine derivatives and this yielded 30-aryl
derivatives, which were subsequently substituted with a differ-
ent aryl group, thus yielding unsymmetrical pyridinium
N-(3,5-diarylpyrazin-2-yl)aminides 11 in high yields. Finally,
2-alkylaminopyrazines 13 were prepared by alkylation of ami-
nides 11 followed by NeN bond reduction of the correspond-
ing aminopyridinium salts 12.
N
N
R1-B(OH)2
+
+
N–
N
N
N–
N
N
Br
Br
Br
R1
2e
10
R1
Compound
Reaction time (h)
3 (48)a
Yield (%)
75 (87)a
10a
10b
10c
5
71
MeO
Me
8 (48)a
72 (85)a
Me
O
10d
8
65
In summary, the combination of the Suzuki arylation of
pyridinium N-(30-bromo or 30,50-dibromoazinyl)aminides and
conventional N-alkylation and NeN reduction allows the
preparation of differently functionalized 2-alkylaminopyr-
azines, and eventually pyridines or pyrimidines, with high effi-
ciency. Other Pd processes are currently being developed for
these broadly useful substrates.
Me
10e
10f
4
50
84
12
S
N
10g
12
81
S
5. Experimental
10h
10i
10j
2
4
65
77
60
5.1. General remarks
All melting points were determined in open capillary tubes
on Gallenkamp MFB-595-010 M, Electrothermal LA6304 or
Stuart Scientific SMP3 melting point apparatus and are uncor-
rected. IR spectra were obtained on a PerkineElmer FTIR
N
N
16
N
1
1725X spectrophotometer. H and 13C NMR spectra were re-
a
Pd(PPh3)4 (1 mol %).
corded on Varian Unity 300 or 500 MHz spectrometer or on
+
N
R1-B(OH)2 (1.1 equiv.)
+N
+
N
N–
N
N
N–
R1
N
N
N
N
N–
Pd(PPh3)4
K2CO3
Toluene/Ethanol
Δ
L
Br
Pd
Br
Br
Br
Br
L
10
2e
Scheme 3.
Br–
N
H
N
R3
Br
N
R3
Zn
R-B(OH)2 (1.5 equiv.)
N
N
+ N
N
+
+
N–
N
N–
R3
N
AcOH
Pd(PPh3)4
K2CO3
Acetone
R2
W
R1
R2
W
R1
Toluene/EtOH
Br
W
R1
10
R2
W
R1
Δ
11
12
13
Scheme 4.

1356
R. Castillo et al. / Tetrahedron 64 (2008) 1351e1370
Table 4
Monoarylation of monocoupled aminides 10
dimensional H,H and H,C-correlation experiments, COSY,
HSQC, HMBC or related spectra. In order to identify the sig-
nals in the description of each product, positions of the pyridi-
nium ring are not labelled, positions of the azine ring are
labelled (0), positions of the 3-aryl substituent are labelled (00),
positions of the 5-aryl substituent (000) and positions of the
aryl belonging to the aryl ring of the N-benzyl substituent,
when present, are labelled (0000). Elemental analyses were carried
out on a Heraeus Rapid CHN analyzer and were within 0.4% of
the theoretical values for all the new compounds described.
Low resolution mass spectra (MS) were taken on a Hewlette
Packard 5988A (70 eV) spectrometer using chemical ionization
(CI) or electrospray (ESI) and high resolution analysis (FAB or
TOF) was performed on a VG AutoSPEC (Micromass Instru-
ment) or on an Agilent 6210 Time-of-flight LC/MS. All re-
agents and solvents were obtained from commercial sources,
except 3-pyridineboronic acid,15 and were used without further
purification. TLC analyses were performed on silica gel (Kie-
selgel 60 F254, MachereyeNagel) and spots were visualized un-
der UV light. Column chromatography was carried out with
silica gel 60 (40e63 mm, Merck) and/or employing Biotage
columns, using the mobile phase reported for each case.
R2-B(OH)2
+ N
N
+
N–
N
N
N–
R1
R2
N
R1
Br
N
10
11
R1a
R2b
Compound Reaction time (h) Yield (%)
Me
11a
11b
8
8
99
95
Me
Me
Me
S
11c
11d
11e
11f
8
8
1
1
89
S
84
92c
91c
N
5.2. General procedures for the preparation of
5-substituted N-(azin-2-yl)pyridinium aminides (3e5)
N
Method A. Aminides 2ae2c8c (1 mmol), the corresponding
boronic acid (1.5 mmol) and Cs2CO3 (2 mmol) were dissolved
in a toluene/ethanol mixture (20:1, 15 mL). Pd(PPh3)4 (5 mmol %)
was added and the mixture was stirred under argon and heated
under reflux for the reaction time indicated in Table 1.
Method B. Aminides 2ae2c8c (1 mmol), the corresponding
boronic acid (1.5 mmol) and K2CO3 (10 mmol) were dissolved
in a toluene/ethanol mixture (20:1, 15 mL). Pd(PPh3)4 (5 mmol %)
was added and the mixture was stirred under argon and heated
under reflux for the reaction time indicated in Table 1.
Me
11g
11h
8
8
90
82
S
Me
S
Me
Me
11i
11j
8
8
81
65
MeO
N
S
In both cases, the course of the reaction was followed by
1
TLC, HPLC and/or H NMR spectroscopy. Once the starting
S
S
material had been consumed, the system was allowed to reach
room temperature, the mixture was filtered through Celite or
silica gel and washed with acetonitrile until colour was no lon-
ger observed in the filtrate. The combined filtrates were eva-
porated to dryness. The crude product was purified by flash
chromatography on a silica gel column, with ethanol as the
mobile phase, and recrystallized from a suitable solvent. Com-
pound 3l was isolated as a yellow oil, while compounds 3a, 3c,
3g, 4c, 4e and 5ae5e were transformed into the corresponding
hydrobromides before purification.
11k
11l
8
8
90
86
N
N
N
S
N
11m
8
90
N
S
a
b
c
Positions labelled as (00) for NMR analysis.
Positions labelled as (000) for NMR analysis.
Yield has been improved in comparison to the first published results.10a
5.2.1. N-(5-Phenylpyridin-2-yl)pyridinium aminide (3a)
See Ref. 10a.
a Varian Mercury VX-300 system at room temperature. Chemi-
cal shifts are given in parts per million (d) downfield from
TMS. Coupling constants (J ) are in hertz (Hz) and signals
are described as follows: s, singlet; d, doublet; t, triplet; m,
multiplet; br, broad; ap, apparent. The tentative assignment
of proton and carbon resonances has been made on the basis
of double resonance, NOESY and TOCSY experiments, two-
5.2.2. N-[5-(4-Methylphenyl)pyridin-2-yl]pyridinium
aminide (3b)
Orange solid (300 mg, 88%, ethyl acetate/hexane), mp 141e
142 ꢀC; IR (KBr) nmax (cmꢁ1): 1594, 1468, 1376, 1287, 1130,
809, 670; 1H NMR (300 MHz, CD3OD): d 8.75 (2H, dd,

R. Castillo et al. / Tetrahedron 64 (2008) 1351e1370
1357
N
7.74 ppm
H
+
8.08 ppm
H
+ N
8.06 ppm
H
N–
+ N
+ N
7.58 ppm
H
N
N
N–
N
N
N
N
N–
N
N
N–
7.88 ppm
H
Br
Br
Br
H
H
H
7.78 ppm
8.23 ppm
7a
8.20 ppm
10a
2d
4a
Figure 2.
J¼7.0 and 1.3 Hz, H2(6)), 7.96 (1H, dd, J¼2.5 and 0.7 Hz,
H60), 7.91 (1H, tt, J¼7.7 and 1.3 Hz, H4), 7.71 (2H, dd,
J¼7.7 and 7.0 Hz, H3(5)), 7.65 (1H, dd, J¼8.9 and 2.5 Hz,
H40), 7.37 (2H, d, J¼8.0 Hz, H2000(6000)), 7.17 (2H, d,
J¼8.0 Hz, H3000(5000)), 6.61 (1H, dd, J¼8.9 and 0.7 Hz, H30),
2.34 (3H, s, CH3); 13C NMR (75 MHz, CD3OD): d 164.5
(C20), 144.5 (C60), 144.0 (C2(6)), 137.0 (C4), 137.0 (C1000 or
C4000), 136.9 (C1000 or C4000), 136.8 (C40), 130.5 (C3000(5000)),
128.2 (C3(5)), 126.3 (C2000(6000)), 125.5 (C50), 112.4 (C30),
21.1 (CH3). MS (CI, m/z): 262 (100, Mþ1), 261 (40), 185
(11). Anal. Calcd for C17H15N3$1/4H2O: C, 76.80; H, 5.88;
N, 15.81. Found: C, 76.69; H, 6.15; N, 15.69.
Table 5
Synthesis of 3,5-disubstituted aminopyrazines 13
5.2.3. N-[50-(3-Hydroxymethylphenyl)pyridin-2-yl]-
pyridinium aminide (3c)
H
Br–
R3-CH2Br
Red
N
N
N
R3
Red oil (263 mg, 95%), mp hydrobromide 187e188 ꢀC (yel-
lowish solid, ethanol); IR (KBr) nmax (cmꢁ1): 1597, 1469, 1377,
N
+ N
N
+
N
N
N–
N
R3
R2
R1
1
1299, 1150, 1000, 790; H NMR (300 MHz, CD3OD): d 8.78
R2
R1
R2
N
R1
12
(2H, dd, J¼7.0 and 1.2 Hz, H2(6)), 8.03 (1H, tt, J¼7.7 and
1.2 Hz, H4), 7.98 (1H, br d, J¼2.6 Hz, H60), 7.82 (2H, dd,
J¼7.7 and 7.0 Hz, H3(5)), 7.72 (1H, dd, J¼8.9 and 2.6 Hz,
H40), 7.52 (1H, m, H2000), 7.42 (1H, dt, J¼7.6 and 1.7 Hz,
H6000), 7.37 (1H, ap t, J¼7.3 Hz, H5000), 7.26 (1H, dt, J¼7.0
and 1.7 Hz, H4000), 6.62 (1H, d, J¼8.9 Hz, H30), 4.66 (2H, s,
11
13
R1a
R2b
R3c
Compound
Yield
78
Me
12a
13
CH2); C NMR (75 MHz, CD3OD): d 165.0 (C20), 144.9
Me
Me
(C2(6)), 144.5 (C60), 143.3 (C3000), 140.1 (C1000), 137.7 (C4),
137.1 (C40), 129.9 (C5000), 128.5 (C3(5)), 125.9 (C4000), 125.4
(C50), 125.4 (C6000), 125.0 (C2000), 112.3 (C30), 65.2 (CH2). MS
(CI, m/z): 278 (100, Mþ1), 277 (47), 260 (25), 201 (65).
Anal. Calcd for C17H15N3O$2HBr: C, 46.50; H, 3.90; N,
9.57. Found: C, 46.56; H, 3.69; N, 9.38.
12b
12c
70
68
Me
Me
Me
Me
12d
12e
79
5.2.4. N-[5-(4-Hydroxymethylphenyl)pyridin-2-yl]-
pyridinium aminide (3d)
See Ref. 8i.
S
81d
Br
S
S
Me
5.2.5. N-[5-(4-Methoxyphenyl)pyridin-2-yl]pyridinium
aminide (3e)
12f
78
62
Me
Me
Red solid (325 mg, 91%, dichloromethane/diethyl ether),
mp 151e152 ꢀC; IR (KBr) nmax (cmꢁ1): 1598, 1466, 1376,
1
1279, 1248, 1133, 817, 669; H NMR (300 MHz, CD3OD):
13a
Me
Me
Nucleophilic and
accessible N
13b
13c
57
63
H
+ N
N–
Blocked N
(H bond)
.
.
.
.
.
N
Me
N
S
a
b
c
d
Positions labelled as (00) for NMR analysis.
Positions labelled as (000) for NMR analysis.
Positions labelled as (0000) for NMR analysis.
Reaction time: 270 h.
Blocked N
(bulky fragments)
Figure 3.

1358
R. Castillo et al. / Tetrahedron 64 (2008) 1351e1370
d 8.78 (2H, dd, J¼7.0 and 1.3 Hz, H2(6)), 7.97 (1H, tt, J¼7.7
and 1.3 Hz, H4), 7.92 (1H, dd, J¼2.5 and 0.6 Hz, H60), 7.75
(2H, dd, J¼7.7 and 7.0 Hz, H3(5)), 7.64 (1H, dd, J¼8.8 and
2.5 Hz, H40), 7.41 (2H, d, J¼8.8 Hz, H2000(6000)), 6.95 (2H, d,
J¼8.8 Hz, H3000(5000)), 6.60 (1H, dd, J¼8.8 and 0.6 Hz, H30),
3.81 (3H, s, CH3); 13C NMR (75 MHz, CD3OD): d 164.4
(C20), 159.9 (C4000), 144.2 (C60), 144.2 (C2(6)), 137.2 (C4),
136.9 (C40), 132.5 (C1000), 128.4 (C3(5)), 127.6 (C2000(6000)),
125.5 (C50), 115.3 (C3000(5000)), 112.4 (C30), 55.7 (CH3). MS
(CI, m/z): 278 (100, Mþ1), 277 (71), 199 (9). Anal. Calcd
for C17H15N3O$1/4H2O: C, 72.45; H, 5.54; N, 14.91. Found:
C, 72.49; H, 5.51; N, 14.98.
7.88 (2H, dd, J¼7.7 and 6.8 Hz, H3(5)), 7.80 (1H, dd, J¼8.9
and 2.6 Hz, H40), 7.74 (2H, d, J¼8.4 Hz, H2000(6000)), 6.63
(1H, d, J¼8.9 Hz, H30); 13C NMR (75 MHz, CD3OD):
d 193.6 (CO), 165.7 (C20), 146.4 (C1000), 146.1 (C60), 145.0
(C2(6)), 138.6 (C4), 136.7 (C40), 135.6 (C4000), 131.5
(C3000(5000)), 128.7 (C3(5)), 126.3 (C2000(6000)), 123.2 (C50),
112.3 (C30). MS (CI, m/z): 276 (100, Mþ1), 275 (29), 199
(17). Anal. Calcd for C17H13N3O$1/4H2O: C, 72.96; H, 4.87;
N, 15.02. Found: C, 72.96; H, 5.17; N, 15.04.
5.2.9. N-[5-(4-Acetylphenyl)pyridin-2-yl]pyridinium
aminide (3i)
Orange solid (217 mg, 75%, dichloromethane), mp 188e
189 ꢀC; IR (KBr) nmax (cmꢁ1): 1671, 1582, 1458, 1374, 1267,
5.2.6. N-{5-[4-(N,N-Dimethylamino)phenyl]pyridin-2-yl}-
pyridinium aminide (3f)
1
1144, 818; H NMR (300 MHz, CD3OD): d 8.80 (2H, dd,
Red solid (250 mg, 86%, ethyl acetate), mp 156e157 ꢀC;
IR (KBr) nmax (cmꢁ1): 1612, 1598, 1471, 1381, 1302, 1138,
J¼7.0 and 1.2 Hz, H2(6)), 8.11 (1H, tt, J¼7.7 and 1.2 Hz,
H4), 8.10 (1H, dd, J¼2.6 and 0.8 Hz, H60), 8.03 (2H, d,
J¼8.6 Hz, H3000(5000)), 7.87 (2H, dd, J¼7.7 and 7.0 Hz, H3(5)),
7.79 (1H, dd, J¼8.9 and 2.6 Hz, H40), 7.67 (2H, d, J¼8.6 Hz,
H2000(6000)), 6.63 (1H, dd, J¼8.9 and 0.8 Hz, H30), 2.63 (3H, s,
CH3); 13C NMR (75 MHz, CD3OD): d 200.2 (CO), 165.7
(C20), 145.8 (C60), 145.1 (C1000), 145.0 (C2(6)), 138.5 (C4),
136.7 (C40), 135.7 (C4000), 130.3 (C3000(5000)), 128.7 (C3(5)),
126.0 (C2000(6000)), 123.5 (C50), 112.3 (C30), 26.5 (CH3). Anal.
Calcd for C18H15N3O: C, 74.72; H, 5.23; N, 14.52. Found: C,
74.69; H, 5.42; N, 14.49.
1
983, 815, 670; H NMR (300 MHz, CD3OD): d 8.79 (2H,
dd, J¼7.0 and 1.3 Hz, H2(6)), 7.96 (1H, tt, J¼7.7 and
1.3 Hz, H4), 7.92 (1H, dd, J¼2.6 and 0.7 Hz, H60), 7.77
(2H, dd, J¼7.7 and 7.0 Hz, H3(5)), 7.66 (1H, dd, J¼8.9 and
2.6 Hz, H40), 7.37 (2H, d, J¼9.0 Hz, H2000(6000)), 6.84 (2H, d,
J¼9.0 Hz, H3000(5000)), 6.61 (1H, dd, J¼8.9 and 0.7 Hz, H30),
2.95 (6H, s, CH3); 13C NMR (75 MHz, CD3OD): d 164.1
(C20), 151.0 (C4000), 144.0 (C2(6)), 143.7 (C60), 136.9 (C40),
136.7 (C4), 128.6 (C1000), 128.4 (C3(5)), 127.1 (C2000(6000)),
126.2 (C50), 114.6 (C3000(5000)), 112.5 (C30), 41.1 (CH3). MS
(CI, m/z): 291 (100, Mþ1), 290 (56), 214 (55), 108 (8), 80
(29). Anal. Calcd for C18H18N4$1/4H2O: C, 73.31; H, 6.33;
N, 19.01. Found: C, 73.60; H, 6.35; N, 18.89.
5.2.10. N-[5-(trans-2-Phenylvinyl)pyridin-2-yl]pyridinium
aminide (3j)
Red solid (191 mg, 70%, ethyl acetate/hexane), mp 159e
160 ꢀC; IR (KBr) nmax (cmꢁ1): 1589, 1483, 1468, 1386,
1
1345, 1156, 958, 755; H NMR (300 MHz, CD3OD): d 8.75
5.2.7. N-[5-(3-Chlorophenyl)pyridin-2-yl]pyridinium
aminide (3g)
(2H, dd, J¼7.0 and 1.2 Hz, H2(6)), 8.03 (1H, tt, J¼7.8 and
1.2 Hz, H4), 7.80 (2H, dd, J¼7.8 and 7.0 Hz, H3(5)), 7.76
(1H, m, H60), 7.74 (1H, m, H40), 7.49 (2H, m, H2000(6000)),
7.32 (2H, ap t, J¼7.6 Hz, H3000(5000)), 7.19 (1H, tt, J¼7.3 and
1.3 Hz, H4000), 7.01 (1H, ap d, J¼16.4 Hz, Ha), 6.88 (1H, ap
d, J¼16.4 Hz, Hb), 6.57 (1H, dd, J¼8.4 and 1.4 Hz, H30);
13C NMR (75 MHz, CD3OD): d 165.1 (C20), 147.0 (C60),
144.6 (C2(6)), 139.5 (C1000), 137.9 (C4), 134.8 (C40), 129.6
(C3000(5000)), 128.5 (C3(5)), 127.7 (C4000), 126.9 (C2000(6000)),
126.8 (Ca), 124.9 (Cb), 122.6 (C50), 112.8 (C30). MS (CI,
m/z): 274 (100, Mþ1), 273 (48), 197 (31). Anal. Calcd for
C18H15N3$1/4H2O: C, 78.24; H, 5.59; N, 15.21. Found: C,
78.31; H, 5.72; N, 15.21.
Orange oil (251 mg, 89%), mp hydrobromide 219e220 ꢀC
(yellowish solid, ethanol); IR (KBr) nmax (cmꢁ1): 1590, 1464,
1385, 1121, 694; 1H NMR (500 MHz, CD3OD): d 8.77
(2H, dd, J¼6.9 and 1.4 Hz, H2(6)), 7.99 (1H, tt, J¼7.7 and
1.4 Hz, H4), 7.95 (1H, d, J¼2.6 Hz, H60), 7.78 (2H, dd,
J¼7.7 and 6.9 Hz, H3(5)), 7.63 (1H, dd, J¼8.9 and 2.6 Hz,
H40), 7.48 (1H, t, J¼1.9 Hz, H2000), 7.39 (1H, ap dt, J¼7.8
and 1.5 Hz, H6000), 7.31 (1H, t, J¼7.8 Hz, H5000), 7.21 (1H,
m, H4000), 6.59 (1H, d, J¼8.9 Hz, H30); 13C NMR (125 MHz,
CD3OD): d 165.2 (C20), 145.2 (C60), 144.4 (C2(6)), 142.1
(C1000), 137.6 (C4), 136.6 (C40), 135.7 (C3000), 131.3 (C5000),
128.4 (C3(5)), 126.9 (C4000), 126.1 (C2000), 124.6 (C6000),
123.6 (C50), 112.3 (C30). MS (CI, m/z): 284/282 (37/100,
Mþ1), 283/281 (44/63), 246 (24), 205 (10). Anal. Calcd for
C16H12ClN3$HBr$1/4H2O: C, 52.34; H, 3.71; N, 11.44.
Found: C, 52.31; H, 3.79; N, 11.46.
5.2.11. N-[5-(Benzo[b]furan-2-yl)pyridin-2-yl]pyridinium
aminide (3k)
Orange solid (256 mg, 89%, ethyl acetate/hexane), mp
141e142 ꢀC; IR (KBr) nmax (cmꢁ1): 1619, 1487, 1451,
1
1395, 1137, 799, 744, 669; H NMR (300 MHz, CD3OD):
5.2.8. N-[5-(4-Formylphenyl)pyridin-2-yl]pyridinium
aminide (3h)
d 8.75 (2H, dd, J¼6.9 and 1.3 Hz, H2(6)), 8.22 (1H, br d,
J¼2.1 Hz, H60), 8.08 (1H, tt, J¼7.7 and 1.3 Hz, H4), 7.84
(2H, dd, J¼7.7 and 6.9 Hz, H3(5)), 7.81 (1H, dd, J¼8.9 and
2.4 Hz, H40), 7.51 (1H, m, H4000), 7.44 (1H, m, H7000), 7.19
(2H, m, H5000 and H6000), 6.84 (1H, d, J¼0.9 Hz, H3000), 6.59
(1H, dd, J¼8.9 and 0.6 Hz, H30); 13C NMR (75 MHz,
Orange solid (262 mg, 95%, ethanol/ethyl acetate), mp 163e
164 ꢀC; IR (KBr) nmax (cmꢁ1): 1691, 1584, 1470, 1393, 1305,
1166, 769; 1H NMR (300 MHz, CD3OD): d 9.97 (1H, s,
CHO), 8.80 (2H, dd, J¼6.8 and 1.3 Hz, H2(6)), 8.12 (1H, m,
H4), 8.10 (1H, m, H60), 7.93 (2H, d, J¼8.4 Hz, H3000(5000)),

R. Castillo et al. / Tetrahedron 64 (2008) 1351e1370
1359
CD3OD): d 165.1 (C20), 156.1 (C2000), 155.3 (C7000a), 144.6
5.2.15. N-[5-(4-Acetylphenyl)pyrazin-2-yl]pyridinium
aminide (4c)
(C2(6)), 143.8 (C60), 138.2 (C4), 134.5 (C40), 130.7 (C3000a),
128.3 (C3(5)), 124.1 (C5000 or C6000), 123.6 (C5000 or C6000),
120.9 (C4000), 115.1 (C50), 111.9 (C30), 111.2 (C7000), 98.6
(C3000). MS (CI, m/z): 288 (100, Mþ1), 211 (38), 108 (10),
80 (60). Anal. Calcd for C18H13N3O$1/4H2O: C, 74.01; H,
4.66; N, 14.41. Found: C, 74.24; H, 4.83; N, 14.43.
Orange solid (244 mg, 84%), mp hydrobromide 210e211 ꢀC
(yellowish solid, ethanol/dichloromethane); IR (KBr) nmax
(cmꢁ1): 1672, 1601, 1578, 1521, 1495, 1467, 1400, 1263,
1
1146, 994, 828, 666; H NMR (300 MHz, CD3OD): d 8.86
(2H, dd, J¼6.9 and 1.3 Hz, H2(6)), 8.20 (1H, d, J¼
1.5 Hz, H60), 8.19 (1H, tt, J¼8.0 and 1.3 Hz, H4), 8.05 (2H,
d, J¼8.5 Hz, H2000(6000)), 7.99 (1H, d, J¼1.5 Hz, H30), 7.96
(2H, d, J¼8.5 Hz, H3000(5000)), 7.93 (2H, dd, J¼8.0 and 6.9 Hz,
H3(5)), 2.65 (3H, s, CH3); 13C NMR (75 MHz, CD3OD):
d 199.5 (CO), 160.8 (C20), 144.6 (C2(6)), 143.5 (C1000), 139.4
(C4), 139.2 (C60), 136.9 (C50), 136.6 (C30), 136.1 (C4000), 129.8
(C3000(5000)), 128.4 (C3(5)), 125.1 (C2000(6000)), 26.7 (CH3). MS
(CI, m/z): 291(100, Mþ1), 214(89), 108 (20), 80 (97). Anal.
Calcd for C17H14N4O$1/4H2O: C, 69.24; H, 4.96; N, 19.01.
Found: C, 69.44; H, 4.80; N, 19.17.
5.2.12. N-[5-(Pyridin-3-yl)pyridin-2-yl]pyridinium
aminide (3l)
Yellow oil (236 mg, 95%); IR (KBr) nmax (cmꢁ1): 1598,
1462, 1417, 1376, 1300, 1147, 1019, 804; 1H NMR
(500 MHz, CD3OD): d 8.80 (2H, dd, J¼7.0 and 1.2 Hz,
H2(6)), 8.70 (1H, dd, J¼2.4 and 0.7 Hz, H2000), 8.41 (1H,
dd, J¼4.8 and 1.5 Hz, H6000), 8.09 (1H, tt, J¼7.7 and 1.2 Hz,
H4), 8.00 (1H, dd, J¼2.5 and 0.7 Hz, H60), 7.98 (1H, ddd,
J¼8.0, 2.4 and 1.5 Hz, H4000), 7.86 (2H, dd, J¼7.7 and
7.0 Hz, H3(5)), 7.73 (1H, dd, J¼8.9 and 2.5 Hz, H40), 7.45
(1H, ddd, J¼8.0, 4.8 and 0.7 Hz, H5000), 6.64 (1H, dd, J¼8.9
and 0.7 Hz, H30); 13C NMR (125 MHz, CD3OD): d 165.7
(C20), 147.4 (C6000), 146.8 (C2000), 145.5 (C60), 144.9 (C2(6)),
138.3 (C4), 136.6 (C3000), 136.6 (C40), 134.6 (C4000), 128.6
(C3(5)), 125.4 (C5000), 121.1 (C50), 112.4 (C30). HRMS
(FAB) calcd for C15H13N4 [MþH]þ 249.1140, found
249.1149.
5.2.16. N-[5-(trans-2-Phenylvinyl)pyrazin-2-yl]pyridinium
aminide (4d)
Red solid (250 mg, 91%, ethanol), mp 180e181 ꢀC; IR
(KBr) nmax (cmꢁ1): 1568, 1501, 1396, 1146, 1004, 748; H
1
NMR (300 MHz, CD3OD): d 8.84 (2H, dd, J¼7.0 and 1.3 Hz,
H2(6)), 8.13 (1H, tt, J¼7.7 and 1.3 Hz, H4), 7.90 (1H, d,
J¼1.4 Hz, H60), 7.88 (2H, dd, J¼7.7 and 7.0 Hz, H3(5)), 7.72
(1H, d, J¼1.4 Hz, H30), 7.52 (2H, ap dd, J¼8.6 and 1.3 Hz,
H2000(6000)), 7.34 (2H, ap dd, J¼8.6 and 7.3 Hz, H3000(5000)), 7.23
(1H, d, J¼16.1 Hz, Hb), 7.22 (1H, tt, J¼7.3 and 1.3 Hz, H4000),
7.04 (1H, d, J¼16.1 Hz, Ha); 13C NMR (75 MHz, CD3OD):
d 160.3 (C20), 144.3 (C2(6)), 140.6 (C30), 139.1 (C50), 138.7
(C4), 137.5 (C1000), 137.0 (C60), 129.3 (C3000(5000)), 128.3
(C3(5)), 127.9 (C4000), 127.0 (C2000(6000)), 127.0 (Cb), 125.4
(Ca). Anal. Calcd for C17H14N4: C, 74.43; H, 5.14; N, 20.42.
Found: C, 74.16; H, 5.28; N, 20.21.
5.2.13. N-(5-Phenylpyrazin-2-yl)pyridinium aminide (4a)
Yellow solid (228 mg, 90%, dichloromethane/diethyl
ether), mp 171e172 ꢀC; IR (KBr) nmax (cmꢁ1): 1514, 1488,
1466, 1385, 1301, 1147, 992, 474; 1H NMR (300 MHz,
CD3OD): d 8.87 (2H, dd, J¼7.0 and 1.3 Hz, H2(6)), 8.14
(1H, tt, J¼7.7 and 1.3 Hz, H4), 8.08 (1H, d, J¼1.5 Hz, H60),
7.96 (1H, d, J¼1.5 Hz, H30), 7.89 (2H, dd, J¼7.7 and 7.0 Hz,
H3(5)), 7.78 (2H, ap dd, J¼8.5 and 1.3 Hz, H2000(6000)), 7.42
(2H, ap dd, J¼8.5 and 7.4 Hz, H3000(5000)), 7.30 (1H, tt, J¼7.4
and 1.3 Hz, H4000); 13C NMR (75 MHz, CD3OD): d 160.9
(C20), 144.8 (C2(6)), 139.4 (C50), 139.2 (C1000), 139.0 (C4),
138.7 (C60), 136.5 (C30), 129.7 (C3000(5000)), 128.6 (C3(5)),
128.2 (C4000), 125.9 (C2000(6000)). Anal. Calcd for C15H12N4:
C, 72.56; H, 4.87; N, 22.57. Found: C, 72.27; H, 5.03; N,
22.47.
5.2.17. N-[5-(Pyridin-3-yl)pyrazin-2-yl]pyridinium
aminide (4e)
Orange solid (217 mg, 89%, ethanol), mp 142e143 ꢀC; IR
(KBr) nmax (cmꢁ1): 1579, 1510, 1481, 1463, 1414, 1385,
1
1147, 996; H NMR (300 MHz, CD3OD): d 8.98 (1H, dd, J¼
2.3 and 0.7 Hz, H2000), 8.85 (2H, dd, J¼7.0 and 1.3 Hz, H2(6)),
8.43 (1H, dd, J¼4.8 and 1.6 Hz, H6000), 8.23 (1H, ddd, J¼8.1,
2.3 and 1.6 Hz, H4000), 8.17 (1H, tt, J¼7.8 and 1.3 Hz, H4),
8.13 (1H, d, J¼1.6 Hz, H60), 7.97 (1H, d, J¼1.6 Hz, H30),
7.91 (2H, dd, J¼7.8 and 7.0 Hz, H3(5)), 7.46 (1H, ddd, J¼8.1,
4.8 and 0.7 Hz, H5000); 13C NMR (75 MHz, CD3OD): d 161.0
(C20), 147.7 (C6000), 146.1 (C2000), 144.7 (C2(6)), 139.2 (C4),
138.9 (C60), 137.0 (C30), 135.3 (C3000), 135.2 (C50), 133.6
(C4000), 128.5 (C3(5)), 125.1 (C5000). MS (CI, m/z): 250 (100,
Mþ1). Anal. Calcd for C14H11N5$1.4H2O: C, 66.26; H, 4.57;
N, 27.60. Found: C, 66.58; H, 4.43; N, 27.31.
5.2.14. N-[5-(4-Methoxyphenyl)pyrazin-2-yl]pyridinium
aminide (4b)
Orange solid (242 mg, 87%, ethanol), mp 145e146 ꢀC; IR
(KBr) nmax (cmꢁ1): 1606, 1568, 1491, 1374, 1236, 1147, 992,
669; 1H NMR (300 MHz, CD3OD): d 8.86 (2H, dd, J¼7.0 and
1.3 Hz, H2(6)), 8.10 (1H, tt, J¼7.6 and 1.3 Hz, H4), 8.01 (1H,
d, J¼1.6 Hz, H60), 7.92 (1H, d, J¼1.6 Hz, H30), 7.86 (2H, dd,
J¼7.6 and 7.0 Hz, H3(5)), 7.69 (2H, d, J¼8.8 Hz, H2000(6000)),
6.97 (2H, d, J¼8.8 Hz, H3000(5000)), 3.84 (3H, s, CH3); 13C
NMR (75 MHz, CD3OD): d 160.2 (C4000), 159.9 (C20), 144.1
(C2(6)), 139.1 (C50), 138.2 (C4), 137.6 (C60), 135.9 (C30),
131.2 (C1000), 128.2 (C3(5)), 126.9 (C2000(6000)), 114.9
(C3000(5000)), 55.7 (CH3). Anal. Calcd for C16H14N4O: C,
69.05; H, 5.07; N, 20.13. Found: C, 68.69; H, 5.09; N, 20.00.
5.2.18. N-(5-Phenylpyrimidin-2-yl)pyridinium aminide (5a)
Yellow solid (186 mg, 75%), mp hydrobromide 222e
223 ꢀC (yellowish solid, ethanol/ethyl acetate); IR (KBr)
nmax (cmꢁ1): 1600, 1438; 1H NMR (300 MHz, CD3OD):
d 8.75 (2H, dd, J¼6.9 and 1.3 Hz, H2(6)), 8.40 (2H, s,

1360
R. Castillo et al. / Tetrahedron 64 (2008) 1351e1370
H40(60)), 8.19 (1H, tt, J¼7.8 and 1.3 Hz, H4), 7.91 (2H, dd,
J¼7.8 and 6.9 Hz, H3(5)), 7.49 (2H, dd, J¼8.4 and 1.4 Hz,
H2000(6000)), 7.41 (2H, dd, J¼8.4 and 7.2 Hz, H3000(5000)), 7.29
(1H, tt, J¼7.2 and 1.4 Hz, H4000); 13C NMR (75 MHz,
CD3OD): d 168.8 (C20), 157.2 (C40(60)), 145.7 (C2(6)),
139.8 (C4), 137.0 (C1000), 130.1 (C3000(5000)), 128.7 (C3(5)),
127.8 (C4000), 126.1 (C2000(6000)), 122.4 (C50). MS (CI, m/z): 249
(100, Mþ1), 200 (56), 172 (24). Anal. Calcd for
C15H12N4$HBr$H2O: C, 52.02; H, 4.37; N, 16.19. Found: C,
51.96; H, 3.98; N, 16.03.
123.3 (Ca), 119.4 (C50). MS (CI, m/z): 275 (100, Mþ1),
274 (26), 198 (84), 80 (79). Anal. Calcd for C17H14N4$HBr$
1/4H2O: C, 56.59; H, 4.63; N, 15.53. Found: C, 56.93; H,
4.36; N, 15.43.
5.2.22. N-[5-(Pyridin-3-yl)pyrimidin-2-yl]pyridinium
aminide (5e)
Yellow oil (236 mg, 95%), mp hydrobromide >300 ꢀC
(yellowish solid, ethanol); IR (KBr) nmax (cmꢁ1): 1602,
1
1446, 1307, 668; H NMR (300 MHz, CD3OD): d 8.77 (2H,
dd, J¼6.9 and 1.3 Hz, H2(6)), 8.69 (1H, dd, J¼2.4 and
0.9 Hz, H2000), 8.45 (1H, dd, J¼4.8 and 1.6 Hz, H6000), 8.44
(1H, s, H40(60)), 8.23 (1H, tt, J¼7.7 and 1.3 Hz, H4), 7.98
(1H, ddd, J¼8.1, 2.4 and 1.6 Hz, H4000), 7.94 (2H, dd, J¼7.7
and 6.9 Hz, H3(5)), 7.47 (1H, ddd, J¼8.1, 4.8 and 0.9 Hz,
5.2.19. N-[5-(4-Methylphenyl)pyrimidin-2-yl]pyridinium
aminide (5b)
Yellow solid (184 mg, 70%), mp hydrobromide 242e244 ꢀC
(yellowish solid, ethanol/ethyl acetate); IR (KBr) nmax (cmꢁ1):
1600, 1437; nmax (KBr/hydrobromide) 2813, 1619, 1594,
13
H5000); C NMR (75 MHz, CD3OD): d 168.6 (C20), 156.9
1
1468, 1431, 818, 773, 669; H NMR (300 MHz, CD3OD):
(C40(60)), 147.6 (C6000), 146.1 (C2000), 145.3 (C2(6)), 139.8 (C4),
134.1 (C4000), 133.5 (C3000), 128.4 (C3(5)), 125.2 (C5000), 118.1
(C50). MS (CI, m/z): 250 (100, Mþ1), 249 (19), 201 (70),
173 (34), 80 (34). Anal. Calcd for C14H11N5$2HBr$H2O: C,
39.19; H, 3.52; N, 16.32. Found: C, 39.74; H, 3.41; N, 15.99.
d 8.74 (2H, dd, J¼6.9 and 1.3 Hz, H2(6)), 8.36 (2H, s,
H40(60)), 8.17 (1H, tt, J¼7.8 and 1.3 Hz, H4), 7.89 (2H, dd, J¼
7.8 and 6.9 Hz, H3(5)), 7.36 (2H, d, J¼8.2 Hz, H2000(6000)), 7.22
(2H, d, J¼8.2 Hz, H3000(5000)), 2.36 (3H, s, CH3); 13C NMR
(75 MHz, CD3OD): d 168.6 (C20), 157.0 (C40(60)), 145.6
(C2(6)), 139.6 (C4), 137.7 (C4000), 134.1 (C1000), 130.7
(C3000(5000)), 128.7 (C3(5)), 126.0 (C2000(6000)), 122.5 (C50), 21.1
(CH3). MS (CI, m/z): 263 (35, Mþ1), 186 (89), 80 (100).
Anal. Calcd for C16H14N4$HBr$1/2H2O: C, 54.69; H, 4.31; N,
15.96. Found: C, 54.66; H, 4.41; N, 15.74.
5.3. Synthesis of symmetrical 3,5-disubstituted aminides
6 and 7: general procedure
Method A. Dibromoaminides 2d,e8c (1 mmol) and the corre-
sponding boronic acid (3 mmol) were dissolved in a toluene/eth-
anol mixture (20:1, 15 mL). Cs2CO3 (4 mmol) was added,
followed by Pd(PPh3)4 (5 mol %). After the addition, the mix-
ture was kept under argon with vigorous stirring for 5 min,
and then heated under reflux for the reaction time indicated in
Table 2.
Method B. Dibromoaminides 2d,e8c (1 mmol) and the corre-
sponding boronic acid (3 mmol) were dissolved in a toluene/eth-
anol mixture (4:1, 10 mL). K2CO3 (20 mmol) was added
followed by Pd(PPh3)4 (5 mol %). After the addition, the mix-
ture was kept under argon with vigorous stirring for 5 min,
and then heated under reflux for the reaction time indicated in
Table 2.
In both methods, as soon as the starting material has been
consumed, the system was allowed to reach room temperature,
the mixture was filtered through Celite or silica gel and the
residue washed with acetonitrile until colour was no longer
observed in the filtrate. The filtrates were combined, the sol-
vent evaporated to dryness and the residue purified by flash
chromatography through a silica gel column, using ethanol
as the mobile phase. Finally, the compounds were, if possible,
recrystallized from a suitable solvent. Compounds 6b and 6h
were isolated as yellow oils. Compounds 6a, 6e, 6f, 6g, 7b,
7d, 7e and 7f were transformed into the corresponding hydro-
bromides by adding aqueous hydrogen bromide (48%,
3 equiv) and the salts were isolated after removal of excess
acid. Ethyl acetate was then added and the aminide hydrobro-
mide was treated in an ultrasonic bath. The remaining solid
was filtered off and dried. Hydrobromides of compounds 6a,
6g, 7b and 7d were purified by recrystallization from ethanol.
To recover the free aminides 6e, 6f, 7e and 7f, the
5.2.20. N-[5-(4-Methoxyphenyl)pyrimidin-2-yl]pyridinium
aminide (5c)
Yellow solid (225 mg, 81%), mp hydrobromide 235e
236 ꢀC (yellowish solid, ethanol); IR (KBr) nmax (cmꢁ1):
1
1592, 1420, 1246, 820, 776; H NMR (300 MHz, CD3OD):
d 8.74 (2H, dd, J¼7.0 and 1.3 Hz, H2(6)), 8.33 (1H, s,
H40(60)), 8.16 (1H, tt, J¼7.7 and 1.3 Hz, H4), 7.89 (2H, dd,
J¼7.7 and 7.0 Hz, H3(5)), 7.39 (2H, d, J¼8.9 Hz, H2000(6000)),
6.97 (2H, d, J¼8.9 Hz, H3000(5000)), 3.82 (3H, s, CH3); 13C
NMR (75 MHz, CD3OD): d 168.2 (C20), 160.0 (C4000), 156.6
(C40(60)), 145.4 (C2(6)), 139.4 (C4), 129.3 (C1000), 128.5
(C3(5)), 127.2 (C2000(6000)), 122.3 (C50), 115.4 (C3000(5000)), 55.7
(CH3). MS (CI, m/z): 279 (100, Mþ1), 278 (32), 253 (33), 251
(34), 202 (57), 172 (20), 80 (34). Anal. Calcd for
C16H14N4O$HBr$1/4H2O: C, 52.83; H, 4.30; N, 15.40. Found:
C, 52.65; H, 4.08; N, 15.21.
5.2.21. N-[5-(trans-2-Phenylvinyl)pyrimidin-2-yl]-
pyridinium aminide (5d)
Yellow solid (200 mg, 73%), mp hydrobromide 227e229 ꢀC
(yellowish solid, ethanol/ethyl acetate); IR (KBr) nmax (cmꢁ1):
1591, 1438; 1H NMR (300 MHz, CD3OD): d 8.71 (2H, dd, J¼
6.8 and 1.2 Hz, H2(6)), 8.32 (2H, s, H40(60)), 8.16 (1H, tt, J¼7.8
and 1.2 Hz, H4), 7.87 (2H, dd, J¼7.8 and 6.8 Hz, H3(5)), 7.47
(2H, m, H2000(6000)), 7.31 (2H, ap t, J¼7.4 Hz, H3000(5000)), 7.20
(1H, tt, J¼7.4 and 1.3 Hz, H4000), 6.92 (2H, m, Ha and Hb);
13C NMR (75 MHz, CD3OD): d 168.1 (C20), 156.8 (C40(60)),
145.1 (C2(6)), 139.4 (C4), 138.6 (C1000), 129.3 (C3000(5000)),
128.3 (C3(5)), 127.8 (C4000), 126.8 (C2000(6000)), 125.5 (Cb),

R. Castillo et al. / Tetrahedron 64 (2008) 1351e1370
1361
corresponding hydrobromide was poured into acetone and ion
exchange resin Amberlite IRA-67 (3 equiv CE¼1.6 equiv/g)
was added. When equilibration was complete, the resin was
removed by filtration and the solvent evaporated to give the
desired aminide, which was used without further purification.
d 162.3 (C20), 159.8 (C4000), 159.6 (C400), 144.5 (C2(6)),
142.6 (C60), 136.8 (C40), 136.7 (C4), 133.0 (C100), 132.3
(C1000), 131.2 (C200(600)), 128.0 (C3(5)), 127.2 (C2000(6000)),
125.4 (C50), 124.5 (C30), 115.1 (C3000(5000)), 114.3 (C300(500)),
55.7 (OCH3). MS (CI, m/z): 384 (100, Mþ1), 383 (65), 307
(54), 305 (46), 108 (17), 80 (63). Anal. Calcd for
C24H21N3O2$H2O: C, 71.80; H, 5.77; N, 10.47. Found: C,
72.13; H, 5.51; N, 10.31.
5.3.1. N-(3,5-Diphenylpyridin-2-yl)pyridinium aminide (6a)
See Ref. 10a.
5.3.2. N-[3,5-Bis(4-methylphenyl)pyridin-2-yl]pyridinium
aminide (6b)
5.3.5. N-[3,5-Bis(3,5-dimethylphenyl)pyridin-2-yl]-
pyridinium aminide (6e)
Yellow oil (197 mg, 56%); IR (KBr) nmax (cmꢁ1): 1595,
Red solid (265 mg, 70%); mp 77e79 ꢀC; IR (KBr) nmax
(cmꢁ1): 2913, 1591, 1402, 1374, 1320, 1143, 1008, 845,
1
1435, 1380, 1308, 1165, 815; H NMR (300 MHz, CD3OD):
1
757, 698, 669; H NMR (500 MHz, CD3OD): d 8.69 (2H,
d 8.62 (2H, dd, J¼7.0 and 1.2 Hz, H2(6)), 7.92 (1H, tt, J¼7.8
and 1.2 Hz, H4), 7.90 (1H, d, J¼2.5 Hz, H60), 7.70 (2H, dd,
J¼7.8 and 7.0 Hz, H3(5)), 7.60 (2H, d, J¼8.1 Hz, H200(600)),
7.54 (1H, d, J¼2.5 Hz, H40), 7.39 (2H, d, J¼8.2 Hz,
H2000(6000)), 7.22 (2H, br d, J¼7.8 Hz, H300(500)), 7.18 (2H, br d,
J¼7.9 Hz, H3000(5000)), 2.37 (3H, s, CH3), 2.33 (3H, s, CH3);
13C NMR (125 MHz, CD3OD): d 162.9 (C20), 144.8 (C2(6)),
143.6 (C60), 138.1 (C100), 137.6 (C400), 137.3 (C40), 137.1 (C1000),
136.9 (C4), 136.9 (C4000), 130.5 (C3000(5000)), 130.4 (C200(600)),
129.8 (C300(500)), 128.2 (C3(5)), 126.3 (C2000(6000)), 125.6 (C50),
124.9 (C30), 21.3 (CH3), 21.1 (CH3). HRMS (FAB) calcd for
C24H22N3: [MþH]þ 352.1814, found: 352.1829.
dd, J¼7.0 and 1.2 Hz, H2(6)), 8.04 (1H, tt, J¼7.7 and
1.2 Hz, H4), 7.92 (1H, d, J¼2.4 Hz, H60), 7.81 (2H, dd,
J¼7.7 and 7.0 Hz, H3(5)), 7.55 (1H, d, J¼2.4 Hz, H40), 7.32
(2H, d, J¼1.6 Hz, H200(600)), 7.14 (2H, d, J¼1.6 Hz, H2000(6000)),
6.99 (1H, t, J¼1.6 Hz, H400), 6.92 (1H, t, J¼1.6 Hz, H4000), 2.38
(6H, s, CH3), 2.35 (6H, s, CH3); 13C NMR (125 MHz,
CD3OD): d 162.8 (C20), 145.4 (C2(6)), 144.0 (C60), 140.9
(C100), 140.0 (C1000), 139.6 (C4), 138.9 (C40), 138.0 (C3000(5000)),
137.8 (C300(500)), 129.7 (C400), 129.0 (C4000), 128.6 (C3(5)),
128.4 (C200(600)), 126.4 (C50), 125.5 (C30), 124.5 (C2000(6000)),
21.7 (CH3), 21.6 (CH3). MS(CI, m/z): 380 (7, Mþ1), 303
(40), 301 (100), 146 (23). Anal. Calcd for C26H25N3$1/2H2O:
C, 80.38; H, 6.75; N, 10.82. Found: C, 80.47; H, 6.51; N, 10.52.
5.3.3. N-[3,5-Bis(4-hydroxymethylphenyl)pyridin-2-yl]-
pyridinium aminide (6c)
Red solid (329 mg, 86%, ethanol/toluene); mp 205e206 ꢀC;
IR (KBr) nmax (cmꢁ1): 3169, 3112, 1599, 1442, 1419, 1384,
1321, 1041, 824, 678, 594, 517; 1H NMR (500 MHz,
CD3OD): d 8.72 (2H, dd, J¼7.0 and 1.2 Hz, H2(6)), 8.06 (1H,
tt, J¼7.8 and 1.2 Hz, H4), 7.96 (1H, d, J¼2.4 Hz, H60), 7.82
(2H, dd, J¼7.8 and 7.0 Hz, H3(5)), 7.73 (2H, d, J¼8.3 Hz,
H200(600)), 7.62 (1H, d, J¼2.4 Hz, H40), 7.53 (2H, d, J¼8.5 Hz,
H20000(60000)), 7.44 (2H, d, J¼8.4 Hz, H300(500)), 7.40 (2H, d, J¼
8.6 Hz, H3000(5000)), 4.68 (2H, s, CH2O), 4.64 (2H, s, CH2O);
13C NMR (125 MHz, CD3OD): d 161.3 (C20), 145.4 (C2(6)),
144.1 (C60), 141.5 (C400), 140.8 (C4000), 139.8 (C100), 139.0
(C1000), 138.2 (C4), 137.5 (C40), 130.4 (C200(600)), 128.7
(C3000(5000)), 128.5 (C3(5)), 127.9 (C300(500)), 126.4 (C2000(6000)),
125.8 (C50), 124.8 (C30), 65.1 (CH2O), 65.0 (CH2O). MS (CI,
m/z): 384 (4, Mþ1), 287 (27), 276 (25), 275 (100). Anal. Calcd
for C24H21N3O2$1/2H2O: C, 73.45; H, 5.65; N, 10.71. Found:
C, 73.34; H, 5.47; N, 10.60.
5.3.6. N-[3,5-Bis(3-chlorophenyl)pyridin-2-yl]pyridinium
aminide (6f)
Red solid (305 mg, 78%); mp 71e73 ꢀC; IR (KBr) nmax
(cmꢁ1): 1590, 1473, 1398, 1314, 1145, 1017, 785, 762, 695,
1
668; H NMR (500 MHz, CD3OD): d 8.68 (2H, dd, J¼7.0
and 1.3 Hz, H2(6)), 8.05 (1H, tt, J¼7.7 and 1.3 Hz, H4), 7.93
(1H, d, J¼2.6 Hz, H60), 7.81 (3H, m, H3(5) and H200), 7.62
(1H, ap dt, J¼7.7 and 1.6 Hz, H600), 7.55 (1H, d, J¼2.6 Hz,
H40), 7.52 (1H, ap t, J¼1.9 Hz, H2000), 7.43 (1H, ddd, J¼7.7,
1.6 and 1.0 Hz, H6000), 7.40 (1H, ap t, J¼7.7 Hz, H500), 7.34
(1H, ap t, J¼7.7 Hz, H5000), 7.31 (1H, ddd, J¼7.9, 1.9 and
1.0 Hz, H400), 7.23 (1H, ddd, J¼7.9, 1.9 and 1.0 Hz, H4000);
13C NMR (75 MHz, (CD3)2CO): d 161.8 (C20), 145.3 (C2(6)),
143.2 (C60), 143.2 (C100), 142.2 (C1000), 135.8 (C4), 135.1
(C3000), 134.5 (C40), 133.6 (C300), 131.1 (C5000), 130.3 (C500),
129.9 (C200), 128.7 (C600), 127.0 (C3(5)), 126.9 (C400), 126.2
(C4000), 125.5 (C2000), 124.2 (C6000), 122.4 (C50), 121.6 (C30).
MS (CI, m/z): 396/394/392 (1/8/11, Mþ1), 317/315/313 (30/
86/100), 278 (9), 146 (9). Anal. Calcd for C22H15Cl2N3$
1/2H2O: C, 65.85; H, 4.02; N, 10.47. Found: C, 65.66; H,
3.87; N, 10.12.
5.3.4. N-[3,5-Bis(4-methoxyphenyl)pyridin-2-yl]pyridinium
aminide (6d)
Red solid (345 mg, 90%, ethanol), mp 94e96 ꢀC; IR (KBr)
1
nmax (cmꢁ1): 1594, 1510, 1436, 1418, 1403, 1241; H NMR
(300 MHz, CD3OD): d 8.68 (2H, dd, J¼7.0 and 1.3 Hz,
H2(6)), 7.98 (1H, tt, J¼7.6 and 1.3 Hz, H4), 7.85 (1H, d, J¼
2.3 Hz, H60), 7.70 (2H, dd, J¼7.6 and 7.0 Hz, H3(5)), 7.66
(2H, d, J¼8.8 Hz, H200(600)), 7.53 (1H, d, J¼2.3 Hz, H40),
7.44 (2H, d, J¼8.8 Hz, H2000(6000)), 6.98 (2H, d, J¼8.8 Hz,
H300(500)), 6.96 (2H, d, J¼8.8 Hz, H3000(5000)), 3.85 (3H, s,
OCH3), 3.83 (3H, s, OCH3); 13C NMR (75 MHz, CD3OD):
5.3.7. N-[3,5-Bis(trans-2-phenylvinyl)pyridin-2-yl]-
pyridinium aminide (6g)
Yellow oil (319 mg, 85%), mp hydrobromide 187e189 ꢀC
(yellowish solid, ethanol); IR (KBr) nmax (cmꢁ1): 1619,
1
1584, 1451, 1388, 1148, 957, 741, 691; H NMR (300 MHz,
CD3OD): d 8.81 (2H, dd, J¼6.9 and 1.3 Hz, H2(6)), 8.27
(1H, tt, J¼7.7 and 1.3 Hz, H4), 8.10 (1H, d, J¼2.1 Hz, H60),

1362
R. Castillo et al. / Tetrahedron 64 (2008) 1351e1370
7.96 (2H, dd, J¼7.7 and 6.9 Hz, H3(5)), 7.75 (1H, d, J¼
2.1 Hz, H40), 7.62 (2H, m, H200(600)), 7.50 (2H, m, H2000(6000)),
1378, 1304, 1247, 748, 693, 663; 1H NMR (300 MHz,
CD3OD): d 8.76 (2H, dd, J¼6.9 and 1.3 Hz, H2(6)), 8.23
(2H, dd, J¼8.4 and 1.5 Hz, H200(600)), 8.14 (1H, tt, J¼7.7 and
1.3 Hz, H4), 8.03 (1H, s, H60), 7.88 (4H, m, H3(5) and
H2000(6000)), 7.48 (2H, tt, J¼7.2 and 1.6 Hz, H300(500)), 7.41 (3H,
m, H3000(5000) and H400), 7.28 (1H, tt, J¼7.3 and 1.3 Hz, H4000);
13C NMR (75 MHz, CD3OD): d 158.8 (C20), 145.3 (C2(6)),
1410.9 (C30), 139.8 (C100), 139.0 (C1000), 138.7 (C4), 138.4
(C500), 136.7 (C60), 130.0 (C200(600)), 129.3 (C3000(5000)), 129.0
(C4 ), 128.5 (C300(500)), 128.3 (C3(5)), 127.6 (C4000), 125.5
(C2000(6000). MS (CI, m/z): 325 (100, Mþ1), 324 (40), 248 (51),
246 (30), 80 (63). Anal. Calcd for C21H16N4$1/4H2O: C,
76.68; H, 5.06; N, 17.04. Found: C, 76.97; H, 4.84; N, 17.46.
00
00
7.49 (1H, d, J¼16.3 Hz, Ha ), 7.33 (1H, d, J¼16.3 Hz, Hb ),
7.34 (4H, m, H300(500) and H3000(5000)), 7.25 (1H, tt, J¼7.3 and
13
1.3 Hz, H400), 7.20 (1H, tt, J¼7.3 and 1.3 Hz, H4000), 7.05 (2H,
m, Hb and Ha ); C NMR (75 MHz, CD3OD): d 159.8 (C20),
000
000
0
00
145.9 (C2(6)), 144.4 (C4 ), 140.6 (C4), 131.5 (Cb ), 131.3
(C100), 131.1 (C60), 131.0 (C1000), 129.4 (C3000(5000) or C300(500)),
129.3 (C3000(5000) or C300(500)), 128.8 (C3(5)), 128.4 (C400), 127.8
(C4000), 127.4 (C200(600)), 126.9 0(C2000(6000)), 126.5 (Ca or Cb ),
000
000
0
000
000
00
125.8 (Cb or Ca ), 124.2 (C5 ), 124.0 (Ca ), 121.4 (C3 ). MS
(CI, m/z): 376 (5, Mþ1), 375 (9), 374 (12), 299 (59), 279 (9),
101 (33), 80 (100). Anal. Calcd for C26H21N3$2HBr: C, 58.12;
H, 4.31; N, 7.82. Found: C, 57.75; H, 4.32; N, 7.88.
5.3.10. N-[3,5-Bis(4-methoxyphenyl)pyrazin-2-yl]-
5.3.8. N-[3,5-Bis(pyridin-3-yl)pyridin-2-yl]pyridinium
aminide (6h) and N-[5-bromo-3-(pyridin-3-yl)-pyridin-
2-yl]pyridinium aminide (8)10b
Starting from dibromoaminide 2d and following general
procedure A, two main products were obtained and separated
by flash chromatography:
pyridinium aminide (7b)
Red solid (331 mg, 86%), mp hydrobromide 170e172 ꢀC
(yellowish solid, ethanol); IR (KBr) nmax (cmꢁ1): 1606,
1509, 1489, 1435, 1397, 1371, 1244, 1176, 1144, 1031, 836;
1H NMR (300 MHz, CD3OD): d 8.66 (2H, dd, J¼6.9 and
1.2 Hz, H2(6)), 8.18 (2H, d, J¼8.9 Hz, H200(600)), 8.01 (1H,
tt, J¼7.8 and 1.2 Hz, H4), 7.86 (1H, s, H60), 7.77 (2H, d, J¼
8.9 Hz, H2000(6000)), 7.76 (2H, dd, J¼7.8 and 6.9 Hz, H3(5)),
6.97 (2H, d, J¼8.9 Hz, H300(500)), 6.93 (2H, d, J¼8.9 Hz,
H3000(5000)), 3.83 (3H, s, OCH3), 3.79 (3H, s, OCH3); 13C
NMR (75 MHz, CDCl3): d 160.8 (C400), 160.0 (C4000), 158.2
(C20), 144.9 (C2(6)), 141.5 (C30), 138.5 (C50), 138.0 (C4),
135.2 (C60), 132.2 (C100), 131.8 (C1000), 131.5 (C200(600)),
128.1 (C3(5)), 126.8 (C2000(6000)), 114.7 (C3000(5000)), 113.9
(C300(500)), 55.7 (OCH3). MS (CI, m/z): 385 (43, Mþ1), 384
(24), 308 (100), 307 (26), 306 (24), 80 (64). Anal. Calcd for
C23H20N4O2$HBr$H2O: C, 57.15; H, 4.80; N, 11.59. Found:
C, 57.04; H, 4.80; N, 11.45.
N-[3,5-Bis(pyridin-3-yl)pyridin-2-yl]pyridinium
aminide
(6h): orange oil (59 mg, 18%); IR (KBr) nmax (cmꢁ1): 1598,
1446, 1402, 1314, 1146, 806, 712; 1H NMR (300 MHz,
CD3OD): d 8.95 (1H, br d, J¼2.2 Hz, H200), 8.75 (3H, m,
H2000 and H2(6)), 8.49 (1H, dd, J¼5.0 and 1.6 Hz, H600),
8.42 (1H, dd, J¼4.9 and 1.6 Hz, H6000), 8.27 (1H, dd, J¼8.0,
2.2 and 1.6 Hz, H400), 8.13 (1H, tt, J¼7.6 and 1.3 Hz, H4),
8.04 (1H, dd, J¼7.9, 2.3 and 1.6 Hz, H4000), 8.03 (1H, d,
J¼2.5 Hz, H60), 7.86 (2H, dd, J¼7.6 and 7.0 Hz, H3(5)),
7.72 (1H, d, J¼2.5 Hz, H40), 7.52 (1H, dd, J¼8.0, 5.0 and
0.7 Hz, H500), 7.47 (1H, dd, J¼7.9, 4.9 and 0.7 Hz, H5000);
13C NMR (75 MHz, CD3OD): d 163.2 (C20), 150.1 (C200),
147.7 (C600), 147.0 (C6000), 146.4 (C2000), 145.5 (C60), 145.3
(C2(6)), 138.8 (C400), 138.5 (C4), 137.1 (C300), 136.8 (C40),
136.0 (C3000), 134.4 (C4000), 128.3 (C3(5)), 125.2 (C5000), 124.6
(C500), 120.8 (C50), 120.2 (C30). HRMS (FAB) calcd for
C20H16N5: [MþH]þ 326.1406, found: 326.1402.
5.3.11. N-[3,5-Bis(4-acetylphenyl)pyrazin-2-yl]pyridinium
aminide (7c)
Red solid (274 mg, 95%, ethanol), mp 196e197 ꢀC; IR
(KBr) nmax (cmꢁ1): 1666, 1598, 1489, 1398, 1269, 1147,
1
N-[5-bromo-3-(pyridin-3-yl)pyridin-2-yl] pyridinium ami-
nide (8): orange oil (157 mg, 48%); IR (KBr) nmax (cmꢁ1):
1705, 1570, 1524, 1472, 1385, 1331, 1259, 1191, 1146,
841; H NMR (300 MHz, CD3OD): d 8.79 (2H, dd, J¼6.9
and 1.3 Hz, H2(6)), 8.52 (2H, d, J¼8.6 Hz, H200(600)), 8.23 (1H,
s, H60), 8.21 (1H, tt, J¼7.6 and 1.3 Hz, H4), 8.12 (2H, d,
J¼8.6 Hz, H300(500)), 8.10 (2H, d, J¼8.8 Hz, H2000(6000)), 8.06
(2H, d, J¼8.8 Hz, H3000(5000)), 7.93 (2H, dd, J¼7.6 and
6.9 Hz, H3(5)), 2.70 (3H, s, COCH3), 2.65 (3H, s, COCH3);
13C NMR (75 MHz, CDCl3): d 198.0 (CO), 197.7 (CO),
157.3 (C20), 143.6 (C30), 142.9 (C2(6)), 142.7 (C100), 139.3
(C50), 137.9 (C60), 136.5 (C1000), 136.4 (C4000), 135.3 (C400),
135.0 (C4), 129.7 (C2000(6000)), 129.1 (C300(500)), 128.0 (C3000(5000)
or C3(5)), 126.4 (C3(5) or C3000(5000)), 124.4 (C200(600)), 27.4
(CH3), 27.2 (CH3). MS (CI, m/z): 409 (7, Mþ1), 316 (17), 333
(39), 332 (100), 80 (86). Anal. Calcd for C25H20N4O2$1/4H2O:
C, 72.70; H, 5.01; N, 13.57. Found: C, 72.61; H, 4.95; N, 13.67.
1
1008, 900, 805, 712; H NMR (300 MHz, CD3OD): d 8.86
(1H, dd, J¼2.0 and 0.7 Hz, H200), 8.70 (2H, dd, J¼7.0 and
1.3 Hz, H2(6)), 8.48 (1H, dd, J¼4.9 and 1.6 Hz, H600), 8.17
(1H, dd, J¼8.0, 2.0 and 1.6 Hz, H400), 8.12 (1H, tt, J¼7.8
and 1.3 Hz, H4), 7.84 (2H, dd, J¼7.8 and 7.0 Hz, H3(5)),
7.71 (1H, d, J¼2.4 Hz, H60), 7.49 (1H, dd, J¼8.0, 4.9 and
0.7 Hz, H500), 7.46 (1H, d, J¼2.4 Hz, H40); 13C NMR
(75 MHz, CD3OD): d 161.7 (C20), 150.1 (C200), 148.2 (C600),
147.6 (C60), 145.5 (C2(6)), 140.5 (C40), 139.0 (C4), 138.7
(C400), 136.1 (C300), 128.4 (C3(5)), 124.8 (C500), 121.6 (C30),
105.2 (C50). HRMS (FAB) calcd for C15H7129BrN4: [MþH]þ
327.0245, found: 327.0238.
5.3.12. N-[3,5-Bis(trans-2-phenylvinyl)pyrazin-2-yl]-
pyridinium aminide (7d)
Red solid (331 mg, 88%), mp hydrobromide 207e209 ꢀC
(yellowish solid, ethanol); IR (KBr) nmax (cmꢁ1): 1733,
5.3.9. N-(3,5-Diphenylpyrazin-2-yl)pyridinium aminide (7a)
Red solid (240 mg, 74%, ethanol), mp 186e188 ꢀC; IR
(KBr) nmax (cmꢁ1): 1597, 1577, 1552, 1508, 1481, 1414,

R. Castillo et al. / Tetrahedron 64 (2008) 1351e1370
1363
1595, 1547, 1489, 1372, 1145, 965, 744, 691; 1H NMR
(500 MHz, CD3OD): d 8.80 (2H, dd, J¼6.9 and 1.3 Hz,
H2(6)), 8.15 (1H, tt, J¼7.7 and 1.3 Hz, H4), 7.92 (1H, d,
(41), 245 (56). HRMS (ESI-TOF, CH3OH) calcd for
C25H17N4S2: [MþH]þ 437.08891, found: 437.09109.
00
J¼16.1 Hz, Hb ), 7.89 (2H, dd, J¼7.7 and 6.9 Hz, H3(5)),
5.3.15. N-[3,5-Bis(pyridin-3-yl)pyrazin-2-yl]pyridinium
aminide (7g)
00
7.71 (1H, d, J¼16.1 Hz, Ha ), 7.69 (2H, dd, J¼8.5 and
1.3 Hz, H200(600)), 7.64 (1H, s, H60), 7.56 (2H, dd, J¼8.6 and
Orange solid (212 mg, 65%, ethanol/diethyl ether), mp
220e221 ꢀC; IR (KBr) nmax (cmꢁ1): 1555, 1496, 1445,
1407, 1365, 1309, 1270, 1147, 709; 1H NMR (300 MHz,
CD3OD): d 9.55 (1H, d, J¼2.1 Hz, H200), 9.09 (1H, d, J¼
2.3 Hz, H2000), 8.85 (1H, ap dt, J¼8.1 and 2.1 Hz, H400), 8.80
(2H, dd, J¼6.9 and 1.3 Hz, H2(6)), 8.55 (1H, dd, J¼4.9 and
1.8 Hz, H600), 8.43 (1H, dd, J¼4.9 and 1.8 Hz, H6000), 8.37
(1H, ap dt, J¼8.1 and 2.3 Hz, H4000), 8.19 (1H, tt, J¼7.5 and
1.3 Hz, H4), 8.18 (1H, s, H60), 7.92 (2H, dd, J¼7.5 and
6.9 Hz, H3(5)), 7.55 (1H, dd, J¼8.1 and 4.9 Hz, H500), 7.48
(1H, dd, J¼8.1 and 4.9 Hz, H5000); 13C NMR (75 MHz,
CD3OD): d 159.4 (C20), 150.2 (C200), 148.5 (C6000), 147.4
(C600), 145.8 (C2000), 145.2 (C2(6)), 139.2 (C4), 138.5 (C60),
138.4 (C400), 137.7 (C30), 136.1 (C300), 135.3 (C3000), 134.6
(C50), 133.3 (C4000), 128.3 (C3(5)), 125.0 (C5000), 124.2 (C500).
MS (CI, m/z): 327 (7, Mþ1), 278 (10), 250 (60), 173 (10),
124 (10), 108 (17), 80 (100). Anal. Calcd for C19H14N6$
1/2H2O: C, 68.05; H, 4.51; N, 25.06. Found: C, 67.78; H,
4.42; N, 24.77.
1.3 Hz, H2000(6000)), 7.41 (2H, dd, J¼8.5 and 7.3 Hz,
H300(500)), 7.39 (1H, d, J¼16.1 Hz, Hb ), 7.35 (2H, dd,
000
J¼8.6 and 7.3 Hz, H3000(5000)), 7.31 (1H, tt, J¼7.3 and
1.3 Hz, H400), 7.24 (1H, tt, J¼7.3 and 1.3 Hz, H4000), 7.09
(1H, d, J¼16.1 Hz, Ha ); 13C NMR (125 MHz, CD3OD):
000
d 159.4 (C20), 145.7 (C2(6)), 140.1 (C30), 140.0 (C60), 139.5
000
00
0
00
(C1 ), 139.3 (C4), 139.1 (C1 ), 137.9 (C5 ), 134.9 (Cb ),
129.9 (C300(500)), 129.8 (C3000(5000)), 129.3 (C400), 128.8
(C3(5)), 128.3 (C200(600)), 128.2 (C4000), 127.5 (C2000(6000) and
000
000
00
Cb ), 126.6 (Ca ), 124.7 (Ca ). MS (CI, m/z): 377 (50,
Mþ1), 376 (21), 300 (100), 299 (29), 80 (20). Anal. Calcd
for C25H20N4$HBr: C, 65.65; H, 4.63; N, 12.25. Found: C,
65.26; H, 4.79; N, 12.17.
5.3.13. N-[3,5-Bis(thiophen-3-yl)pyrazin-2-yl]pyridinium
aminide (7e)
Red solid (328 mg, 98%), mp 82e84 ꢀC, mp hydrobromide
134e137 ꢀC (yellow solid); IR (KBr) nmax (cmꢁ1): 3108,
1
1529, 1488, 1426, 1383, 1367, 1244, 1178, 1145, 768; H
5.4. Synthesis of aminides 10: general procedure for the
selective coupling over N-(3,5-dibromopyrazin-2-yl)-
pyridinium aminide (2e)
NMR (500 MHz, (CD3)2CO): d 8.94 (3H, m, H2(6) and H200),
8.25 (1H, dd, J¼5.1 and 1.1 Hz, H400), 8.04 (1H, s, H60), 7.97
(1H, tt, J¼7.7 and 1.2 Hz, H4), 7.80 (2H, dd, J¼
7.7 and 7.0 Hz, H3(5)), 7.76 (1H, dd, J¼3.0 and 1.2 Hz, H2000),
7.66 (1H, dd, J¼5.0 and 1.2 Hz, H4000), 7.46 (1H, dd, J¼5.0
and 3.0 Hz, H5000), 7.41 (1H, dd, J¼5.1 and 3.0 Hz, H500); 13C
NMR (75 MHz, (CD3)2CO): d 157.1 (C20), 143.9 (C2(6)),
142.3 (C50), 141.4 (C30), 136.0 (C60), 135.9 (C4), 135.4 (C300),
134.6 (C3000), 129.8 (C400), 127.3 (C200), 127.2 (C3(5)), 126.5
(C5000), 126.0 (C4000), 123.8 (C500), 118.5 (C5000). MS (EI, m/z):
336 (64, Mþ), 257 (84), 121 (100), 79 (58). HRMS (ESI-TOF,
CH3OH) calcd for C17H13N4S2: [MþH]þ 337.05761, found:
337.05976.
Dibromoaminide 2e8b,c,h (330 mg, 1 mmol) and the corre-
sponding boronic acid (1.1 mmol) were dissolved in a tolu-
ene/ethanol mixture (4:1, 15 mL). K2CO3 (10 mmol) was
added followed by Pd(PPh3)4 (5 mol %). After the addition,
the mixture was kept under argon with vigorous stirring for
5 min, and then heated under reflux for the reaction time indi-
cated in Table 3 (i.e., until starting material was not detected
by TLC). The system was allowed to reach room temperature
and the mixture was filtered through Celite or silica gel. The
residue was washed with acetonitrile until colour was no
longer observed in the filtrates, which were combined and
evaporated to dryness. The residue was purified by flash chro-
matography on a silica gel column, using ethanol as eluent.
Finally, the bromo compounds 10 were, if possible, recrystal-
lized from a suitable solvent.
5.3.14. N-[3,5-Bis(benzo[b]thiophen-3-yl)pyraz-2-yl]-
pyridinium aminide (7f)
Orange solid (387 mg, 89%), mp 104e106 ꢀC; IR (KBr)
nmax (cmꢁ1): 1555, 1515, 1486, 1408, 1208, 1144, 862, 784,
1
758, 732, 700; H NMR (500 MHz, (CD3)2CO): d 9.28 (1H,
s, H200), 9.08 (1H, ddd, J¼8.2, 1.3 and 0.7 Hz, H400), 8.94
(2H, dd, J¼7.0 and 1.3 Hz, H2(6)), 8.56 (1H, ddd, J¼7.4,
1.4 and 0.7 Hz, H4000), 8.10 (1H, s, H60), 8.06 (1H, tt, J¼7.7
and 1.3 Hz, H4), 7.97 (2H, m, H7000 and H700), 7.87 (2H, dd,
J¼7.7 and 7.0 Hz, H3(5)), 7.82 (1H, s, H2000), 7.34 (4H, m,
H5000, H500, H6000 and H600); 13C NMR (125 MHz, (CD3)2CO):
d 158.0 (C20), 144.4 (C2(6), 141.7 (C7a000), 140.5 (C7a00),
140.1 (C3a00), 138.7 (C3a000), 138.2 (C60), 136.8 (C4), 136.3
(C30), 134.6 (C3000), 133.8 (C50), 132.0 (C300), 130.5 (C200),
127.6 (C3(5)), 127.3 (C400), 125.6 (C4000), 125.2 (C6000), 124.9
(C5000 and C500), 124.8 (C600), 123.5 (C700), 123.1 (C7000),
122.0 (C2000). MS (ESI, m/z): 437 (100, Mþ1), 358 (80), 277
5.4.1. N-(5-Bromo-3-phenylpyrazin-2-yl)pyridinium
aminide (10a)
See Ref. 10b.
5.4.2. N-[5-Bromo-3-(4-methoxyphenyl)pyrazin-
2-yl]pyridinium aminide (10b)
Orange solid (254 mg, 71%, ethyl acetate), mp 182e
183 ꢀC; IR (KBr) nmax (cmꢁ1): 1483, 1417, 1375, 1270,
1
1214, 969, 744, 671; H NMR (300 MHz, CD3OD): d 8.79
(2H, dd, J¼6.9 and 1.3 Hz, H2(6)), 8.28 (1H, tt, J¼7.8 and
1.3 Hz, H4), 8.12 (2H, d, J¼8.9 Hz, H200(600)), 7.96 (2H,
dd, J¼7.8 and 6.9 Hz, H3(5)), 7.64 (1H, s, H60), 7.03 (2H,

1364
R. Castillo et al. / Tetrahedron 64 (2008) 1351e1370
d, J¼8.9 Hz, H300(500)), 3.89 (3H, s, CH3); 13C NMR (75 MHz,
CDCl3): d 160.0 (C400), 156.6 (C20), 142.6 (C2(6)), 142.1
(C30), 139.5 (C60), 134.2 (C4), 131.0 (C200(600)), 130.2 (C100),
126.3 (C3(5)), 122.0 (C50), 113.4 (C300(500)), 55.7 (CH3).
Anal. Calcd for C16H13BrN4O: C, 53.80; H, 3.67; N, 15.68.
Found: C, 53.56; H, 3.84; N, 15.56.
5.4.6. N-[5-Bromo-3-(thiophen-3-yl)pyrazin-2-yl]-
pyridinium aminide (10f)
Red solid (279 mg, 84%, ethyl acetate/diethyl ether), mp
162e165 ꢀC; IR (KBr) nmax (cmꢁ1): 1526, 1484, 1409, 1369,
1349, 1242, 1190, 1146, 1106, 807, 768; 1H NMR (300 MHz,
(CD3)2CO): d 8.91 (1H, dd, J¼3.1 and 1.3 Hz, H200), 8.86
(2H, dd, J¼7.0 and 1.3 Hz, H2(6)), 8.12 (1H, tt, J¼7.7 and
1.3 Hz, H4), 7.98 (1H, dd, J¼5.1 and 1.2 Hz, H400), 7.90 (2H,
dd, J¼7.7 and 7.0 Hz, H3(5)), 7.53 (1H, s, H60), 7.41 (1H,
dd, J¼5.1 and 3.1 Hz, H500); 13C NMR (75 MHz, (CD3)2CO):
d 157.7 (C20), 144.4 (C2(6)), 140.3 (C60), 139.9 (C30), 137.4
(C4), 136.2 (C300), 129.2 (C400), 127.8 (C200), 127.6 (C3(5)),
124.3 (C500), 119.6 (C50). MS (CI, m/z): 335/333 (35/35,
Mþ1), 256/254 (67/64), 80 (100). Anal. Calcd for C13H9BrN4S:
C, 46.86; H, 2.72; N, 16.81, S, 9.62. Found: C, 46.90; H, 2.84;
N, 16.49; S, 9.71.
5.4.3. N-[5-Bromo-3-(3,5-dimethylphenyl)pyrazin-2-yl]-
pyridinium aminide (10c)
Brown solid (301 mg, 85%), mp 82e84 ꢀC (mp hydrobro-
mide 130e132 ꢀC, yellowish solid, ethanol); IR (KBr) nmax
(cmꢁ1): 2913, 1600, 1521, 1487, 1398, 1212, 1142, 852,
1
765, 697, 671; H NMR (300 MHz, (CD3)2CO): d 8.80 (2H,
dd, J¼7.0 and 1.3 Hz, H2(6)), 8.07 (1H, tt, J¼7.7 and
1.3 Hz, H4), 8.02 (2H, br s, H200(600)), 7.86 (2H, dd, J¼7.7
and 7.0 Hz, H3(5)), 7.51 (1H, s, H60), 6.97 (1H, br s, H400),
2.30 (6H, s, CH3); 13C NMR (75 MHz, (CD3)2CO): d 158.6
(C20), 144.4 (C2(6)), 141.0 (C60), 138.6 (C30), 137.2 (C4),
137,1 (C100), 130.4 (C300(500)), 127.8 (C3(5)), 127.8 (C200(600)),
123.3 (C400), 120.5 (C50), 21.5 (CH3). MS (CI, m/z): 357/355
(99/100, Mþ1), 278/276 (41/41). Anal. Calcd for
C17H15BrN4: C, 57.48; H, 4.26; N, 15.77. Found: C, 57.80;
H, 4.46; N, 15.50.
5.4.7. N-[3-(Benzo[b]thiophen-3-yl)-5-bromopyrazin-2-yl]-
pyridinium aminide (10g)
Orange solid (309 mg, 84%, ethyl acetate), mp 199e202 ꢀC;
IR (KBr) nmax (cmꢁ1): 1513, 1481, 1405, 1215, 1145, 855, 811,
782, 754, 730, 660, 514, 472; 1H NMR (300 MHz, (CD3)2CO):
d 9.39 (1H, s, H200), 9.07 (1H, m, H400), 8.86 (2H, dd, J¼7.0 and
1.3 Hz, H2(6)), 8.15 (1H, tt, J¼7.8 and 1.3 Hz, H4), 7.97 (1H,
m, H700), 7.92 (2H, dd, J¼7.8 and 7.0 Hz, H3(5)), 7.57 (1H, s,
H60), 7.46 (1H, ddd, J¼8.0, 7.0 and 1.3 Hz, H500 or H600), 7.39
(1H, ddd, J¼7.7, 7.4 and 1.5 Hz, H600 or H500); 13C NMR
(75 MHz, (CD3)2CO): d 158.4 (C20), 144.6 (C2(6)), 140.4
(C7a00), 140.1 (C60), 139.4 (C3a00), 137.8 (C4), 136.6 (C30),
132.0 (C300), 131.4 (C200), 127.7 (C3(5)), 126.8 (C400), 125.0
(C500 or C600), 125.0 (C600 or C500), 123.1 (C700), 118.8 (C50).
MS (CI, m/z): 385/383 (94/100, Mþ1), 306/304 (39/38), 113
(11). Anal. Calcd for C17H11BrN4S: C, 53.28; H, 2.89; N,
14.62; S, 8.37. Found: C, 53.55; H, 2.91; N, 14.45; S, 8.17.
5.4.4. N-[3-(4-Acetylphenyl)-5-bromopyrazin-2-yl]-
pyridinium aminide (10d)
Orange solid (240 mg, 65%, ethyl acetate), mp 190e
192 ꢀC; IR (KBr) nmax (cmꢁ1): 1664, 1602, 1473, 1428,
1
1399, 1359, 1274, 1162, 840, 759, 677; H NMR (300 MHz,
CD3OD): d 8.73 (2H, dd, J¼6.9 and 1.3 Hz, H2(6)), 8.38
(2H, d, J¼8.6 Hz, H200(600)), 8.17 (1H, tt, J¼7.7 and 1.3 Hz,
H4), 8.06 (2H, d, J¼8.6 Hz, H300(500)), 7.88 (2H, dd, J¼7.7
and 6.9 Hz, H3(5)), 7.63 (1H, s, H60), 2.67 (3H, s, CH3);
13C NMR (75 MHz, CDCl3): d 198.1 (CO), 157.1 (C20),
142.8 (C2(6)), 142.3 (C100), 141.6 (C60), 139.8 (C30), 136.5
(C400), 135.0 (C4), 129.5 (C200(600)), 128.0 (C300(500)), 126.5
(C3(5)), 121.8 (C50), 27.2 (CH3). Anal. Calcd for
C17H13BrN4O: C, 55.30; H, 3.55; N, 15.17. Found: C,
54.99; H, 3.71; N, 14.83.
5.4.8. N-[5-Bromo-3-(pyridin-3-yl)pyrazin-2-yl]pyridinium
aminide (10h)
Orange solid (204 mg, 65%, ethyl acetate/diethyl ether),
mp 170e172 ꢀC; IR (KBr) nmax (cmꢁ1): 1524, 1489, 1475,
1
1430, 1401, 1369, 812, 670; H NMR (300 MHz, CD3OD):
5.4.5. N-[5-Bromo-3-(trans-2-phenylvinyl)pyrazin-2-yl]-
pyridinium aminide (10e)
Orange solid (177 mg, 50%, ethyl acetate), mp 200e
202 ꢀC; IR (KBr) nmax (cmꢁ1): 1602, 1507, 1471, 1398,
1
1365, 1243, 1172, 1015, 842, 814, 654; H NMR (300 MHz,
d 9.44 (1H, dd, J¼2.3 and 0.8 Hz, H200), 8.74 (2H, dd, J¼
6.9 and 1.3 Hz, H2(6)), 8.73 (1H, ddd, J¼8.1, 2.3 and
1.7 Hz, H400), 8.51 (1H, dd, J¼4.9 and 1.7 Hz, H600), 8.15
(1H, tt, J¼7.8 and 1.3 Hz, H4), 7.87 (2H, dd, J¼7.8 and
6.9 Hz, H3(5)), 7.63 (1H, s, H60), 7.51 (1H, ddd, J¼8.1, 4.9
and 0.8 Hz, H500); 13C NMR (75 MHz, CD3OD): d 159.1
(C20), 150.0 (C200), 148.6 (C600), 145.1 (C2(6)), 142.8 (C60),
139.0 (C4), 138.0 (C400), 137.6 (C30), 135.0 (C300), 128.2
(C3(5)), 124.2 (C500), 120.9 (C50). HRMS (FAB) calcd for
CD3OD): d 8.77 (2H, dd, J¼6.9 and 1.3 Hz, H2(6)), 8.18
(1H, tt, J¼7.7 and 1.3 Hz, H4), 7.90 (2H, dd, J¼7.7 and
6.9 Hz, H3(5)), 7.80 (1H, d, J¼16.0 Hz, Hb), 7.65 (2H, m,
H200(600)), 7.55 (1H, d, J¼16.0 Hz, Ha), 7.53 (1H, s, H60),
7.39 (2H, m, H300(500)), 7.30 (1H, tt, J¼7.2 and 1.3 Hz,
C14H BrN5: [MþH]þ 328.0198, found: 328.0205.
79
11
13
H400); C NMR (75 MHz, CD3OD): d 158.7 (C20), 145.4
(C2(6)), 141.1 (C60), 140.0 (C30), 139.1 (C4), 138.3 (C100), 135.0
(Cb), 129.5 (C300(500)), 129.0 (C400), 128.3 (C3(5)), 127.9
(C200(600)), 123.0 (Ca), 121.7 (C50). MS (CI, m/z): 355/353 (39/
39, Mþ1), 278 (41), 276 (91), 274 (61), 196 (22), 108 (26),
80 (100). Anal. Calcd for C17H13BrN4$1/4H2O: C, 57.08; H,
3.80; N, 15.66. Found: C, 57.09; H, 3.81; N, 15.46.
5.4.9. N-[5-Bromo-3-(pyridin-4-yl)pyrazin-2-yl]pyridinium
aminide (10i)
Green solid (252 mg, 77%, toluene), mp 229e231 ꢀC; IR
(KBr) nmax (cmꢁ1): 1593, 1546, 1520, 1484, 1427, 1366,
1
1255, 1174, 1144, 823, 753, 658, 538; H NMR (300 MHz,
(CD3)2CO): d 8.82 (2H, dd, J¼7.0 and 1.3 Hz, H2(6)), 8.59

R. Castillo et al. / Tetrahedron 64 (2008) 1351e1370
1365
(2H, m, H200(600)), 8.44 (2H, m, H300(500)), 8.18 (1H, tt, J¼
7.7 and 1.3 Hz, H4), 7.94 (2H, dd, J¼7.7 and 7.0 Hz,
H3(5)), 7.65 (1H, s, H60); 13C NMR (75 MHz, (CD3)2CO):
d 159.3 (C20), 150.1 (C200(600), 145.5 (C400), 144.7 (C2(6)),
143.8 (C60), 140.4 (C30), 138.3 (C4), 128.0 (C3(5)), 123.5
(C300(500), 120.1 (C50). MS (CI, m/z): 330/328 (95/100, Mþ1),
249 (12), 248 (22). Anal. Calcd for C14H10BrN5$1/2H2O: C,
49.87; H, 3.29; N, 20.77. Found: C, 49.50; H, 3.54; N, 20.70.
(2H, dd, J¼7.0 and 1.3 Hz, H2(6)), 8.50 (2H, dd, J¼8.4 and
1.4 Hz, H200(600)), 8.13 (1H, s, H60), 8.04 (1H, tt, J¼7.7 and
1.3 Hz, H4), 7.86 (2H, dd, J¼7.7 and 7.0 Hz, H3(5)), 7.61
(2H, br s, H2000(6000)), 7.38 (3H, m, H300, 400 and 500), 6.89
(1H, br s, H4000), 2.32 (6H, s, CH3); 13C NMR (75 MHz,
(CD3)2CO): d 158.1 (C20), 144.0 (C2(6)), 140.4 (C3000(5000)),
139.3 (C100), 138.5 (C30), 138.1 (C1000), 136.8 (C60), 136.3
(C4), 132.7 (C50), 130.3 (C2000(6000)), 128.9 (C400), 128.4
(C300(500)), 128.0 (C3(5)), 127.5 (C4000), 123.1 (C2000(6000)), 21.5
(CH3). MS (ESI, m/z): 353 (66, Mþ1), 274 (100), 245 (16).
HRMS (ESI-TOF, CH3OH) calcd for C23H21N4: [MþH]þ
353.17607, found: 353.17960.
5.4.10. N-[5-Bromo-3-(pyrimidin-5-yl)pyrazin-2-yl]-
pyridinium aminide (10j)
Orange solid (197 mg, 60%, toluene), mp 234e236 ꢀC; IR
(KBr) nmax (cmꢁ1): 1614, 1527, 1476, 1463, 1414, 1204, 1042,
1
788, 749; H NMR (300 MHz, (CD3)2CO): d 9.74 (2H, s,
5.5.2. N-[3-(3,5-Dimethylphenyl)-5-phenylpyrazin-2-yl]-
pyridinium aminide (11b)
H4000(6000)), 9.07 (1H, s, H2000), 8.86 (2H, dd, J¼6.9 and
13
1.3 Hz, H2(6)), 8.19 (1H, tt, J¼7.7 and 1.3 Hz, H4), 7.95
Dark red solid (334 mg, 95%), mp hydrobromide 173e
175 ꢀC; IR (KBr) nmax (cmꢁ1): 3106, 1662, 1595, 1555,
1507, 1485, 1465, 1401, 1219, 855, 769, 760, 689, 667, 591;
1H NMR (300 MHz, (CD3)2CO): d 8.94 (2H, dd, J¼7.0 and
1.3 Hz, H2(6)), 8.14 (1H, s, H60), 8.07 (2H, br s, H200(600)),
8.05 (1H, tt, J¼7.7 and 1.3 Hz, H4), 7.98 (2H, dd, J¼8.4
and 1.3 Hz, H2000(6000)), 7.86 (2H, dd, J¼7.7 and 7.0 Hz,
H3(5)), 7.38 (2H, ap t, J¼7.7 Hz H3000(5000), 7.23 (1H, tt, J¼
7.3 and 1.3 Hz, H4000), 6.98 (1H, br s, H400), 2.35(6H, s
(2H, dd, J¼7.7 and 6.9 Hz, H3(5)), 7.65 (1H, s, H60);
C
NMR (75 MHz, DMSO-d6): d 157.5 (C20), 156.6 (C200),
155.5 (C400(600)), 143.4 (C2(6)), 142.4 (C60), 137.9 (C4),
132.2 (C500), 130.3 (C30), 127.0 (C3(5)), 118.3 (C50). MS
(EI, m/z): 330/328 (6/6, Mþ1), 202 (31), 160 (100). Anal.
Calcd for C13H9BrN6: C, 47.44; H, 2.76; N, 25.53. Found:
C, 47.20; H, 2.94; N, 25.80.
13
5.5. Synthesis of unsymmetrical disubstituted aminides
CH3); C NMR (75 MHz, (CD3)2CO): d 157.8 (C20), 144.1
11: general procedure
(C2(6)), 140.4 (C300(500)), 140.1 (C100 or C1000), 139.5 (C1000
or C100), 137.7 (C30), 137.1 (C60), 136.6 (C4), 136.5 (C50),
130.0 (C400), 129.3 (C3000(5000)), 128.2 (C3(5)), 127.5 (C200(600)),
127.2 (C4000), 125.1 (C2000(6000)), 21.6 (CH3). MS (ESI, m/z):
353(52, Mþ1), 302(10), 274(100), 245(8). HRMS (ESI-TOF,
CH3OH) calcd for C23H21N4: [MþH]þ 353.17607, found:
353.17911.
Pd(PPh3)4 (5 mol %), boronic acid (1.5 mmol), the corre-
sponding aminide 10 (1 mmol) and K2CO3 (10 mmol) were
stirred and heated under reflux under argon in a mixture of tol-
uene/ethanol (4:1, 15 mL) until starting material was no longer
detected by TLC (see Table 4). The system was then allowed
to reach room temperature, the mixture was filtered through
Celite or silica gel and the residue washed well with acetoni-
trile. The filtrates were combined and evaporated to dryness.
Aminide 11 was purified by flash chromatography on a silica
gel column, using ethanol as eluent, and recrystallized from
the appropriate solvent where possible. Compound 11j was
obtained as an oil. Compounds 11a, 11b, 11f and 11g were
treated with aqueous hydrobromic acid (48%) (3 equiv) and
the corresponding salt was isolated after removal of excess
acid. Ethyl acetate was then added and the aminide hydrobro-
mide was triturated in an ultrasonic bath. The remaining solid
was filtered off and dried. To recover the free aminides 11a,
11b and 11g, hydrobromide was poured into acetone and ion
exchange resin Amberlite IRA-67 (3 equiv CE¼1.6 equiv/g)
was added. When deprotonation was complete, the resin was
removed by filtration and the solvent evaporated to give the
desired aminide, which was used without further purification
for other synthetic steps. Compound 11f was purified as the
hydrobromide.
5.5.3. N-[5-(Benzo[b]thiophen-3-yl)-3-phenylpyrazin-2-yl]-
pyridinium aminide (11c)
Red solid (346 mg, 89%, ethyl acetate), mp 82e84 ꢀC; IR
(KBr) nmax (cmꢁ1): 3053, 1667, 1515, 1485, 1405, 1141, 760,
1
735, 696, 665, 535; H NMR (300 MHz, (CD3)2CO): d 9.05
(2H, dd, J¼7.0 and, 1.3 Hz, H2(6)), 8.68 (1H, m, H4000), 8.50
(2H, m, H200(600)), 8.20 (1H, tt, J¼7.7 and 1.3 Hz, H4), 8.19
(1H, s, H60), 7.97 (3H, m, H3(5) and 7000), 7.89 (1H, s, H2000),
7.43 (5H, m, H300(500), H400, H5000 and H6000); 13C NMR
(75 MHz, (CD3)2CO): d 155.9 (C20), 145.0 (C2(6)), 141.6
(C7a000), 140.1 (C3a000), 139.4 (C100), 138.7 (C4), 138.6 (C60),
137.8 (C30) , 137.8 (C50), 135.4 (C3000), 130.3 (C200(600)), 128.8
(C400), 128.4 (C300(500)), 127.9 (C3(5)), 125.5 (C4000), 125.2
(C6000), 125.1 (C5000), 123.5 (C7000), 123.1 (C2000). HRMS (ESI-
TOF, CH3OH) calcd for C23H17N4S: [MþH]þ 381.11684,
found: 381.12026.
5.5.4. N-[3-(Benzo[b]thiophen-3-yl)-5-phenylpyrazin-2-yl]-
pyridinium aminide (11d)
5.5.1. N-[5-(3,5-Dimethylphenyl)-3-phenylpyrazin-2-yl]-
pyridinium aminide (11a)
Red solid (338 mg, 89%, ethyl acetate), mp 90e92 ꢀC; IR
(KBr) nmax (cmꢁ1): 3055, 1483, 1448, 1412, 1368, 1209,
1145, 1019, 763, 734, 694, 665; 1H NMR (500 MHz,
(CD3)2CO): d 9.26 (1H, s, H200), 9.20 (1H, ddd, J¼8.2, 1.3
and 0.7 Hz, H400), 8.99 (2H, dd, J¼7.0 and 1.3 Hz, H2(6)),
Red solid (348 mg, 99%), mp 72e74 ꢀC; IR (KBr) nmax
(cmꢁ1): 3051, 2915, 1599, 1500, 1404, 1240, 1143, 1028, 848,
1
758, 695, 666, 542; H NMR (300 MHz, (CD3)2CO): d 8.95

1366
R. Castillo et al. / Tetrahedron 64 (2008) 1351e1370
8.23 (1H, s, H60), 8.11 (1H, tt, J¼7.7 and 1.3 Hz, H4), 8.07
(2H, m, H2000(6000)), 8.03 (1H, ddd, J¼8.1, 1.3 and 0.7 Hz,
H700), 7.92 (2H, dd, J¼7.7 and 7.0 Hz, H3(5)), 7.51 (1H,
ddd, J¼7.6, 7.0 and 1.2 Hz, H500 or H600), 7.47 (2H, dd, J¼
8.2 and 7.4 Hz, H3000(5000), 7.46 (1H, m, H600 or H500), 7.31
(1H, tt, J¼7.4 and 1.2 Hz, H4000); 13C NMR (75 MHz,
(CD3)2CO): d 158.2 (C20), 144.4 (C2(6)), 140.4 (C7a00),
140.1 (C3a00), 139.7 (C1000), 136.8 (C4), 136.6 (C30 or C50),
136.5 (C50 or C30), 136.2 (C60), 133.7 (C300) 130.5 (C200),
129.4 (C3000(5000)) 127.5 (C3(5)), 127.1 (C4000 or C400), 126.9
(C400 or C4000), 125.1 (C2000(6000)), 125.0 (C500 or C600), 124.9,
(C600 or C500), 123.1 (C700). MS (ESI, m/z): 381(59, Mþ1), 303
(30), 302 (100). Anal. Calcd for C23H16N4S: C, 72.61; H, 4.24;
N, 14.73; S, 8.43. Found: C, 72.29; H, 4.41; N, 14.36; S, 8.08.
5.5.8. N-[3-(Benzo[b]thiophen-3-yl)-5-(3,5-dimethyl-
phenyl)pyrazin-2-yl]pyridinium aminide (11h)
Orange solid (335 mg, 82%, ethyl acetate), mp 77e79 ꢀC;
IR (KBr) nmax (cmꢁ1): 2913, 1600, 1492, 1406, 1360, 1205,
1
1145, 760, 733, 697, 667; H NMR (300 MHz, (CD3)2CO):
d 9.19 (1H, s, H200), 9.16 (1H, m, H400), 8.96 (2H, dd, J¼7.0
and 1.3 Hz, H2(6)), 8.16 (1H, s, H60), 8.06 (1H, tt, J¼7.7
and 1.3 Hz, H4), 7.98 (1H, m, H700), 7.88 (2H, dd, J¼7.7 and
7.0 Hz, H3(5)), 7.64 (2H, br s, H2000(6000)), 7.46 (1H, ddd,
J¼7.6, 7.0 and 1.4 Hz, H500 or H600), 7.39 (1H, ddd, J¼8.2,
7.0 and 1.4 Hz, H600 or H500), 6.91 (1H, br s, H4000), 2.34
13
(6H, s, CH3); C NMR (75 MHz, (CD3)2CO): d 157.7 (C20),
144.3 (C2(6)), 140.5 (C3000(5000)), 140.2 (C7a00), 139.6 (C3a00),
138.6 (C4), 137.3 (C1000), 136.8 (C30), 136.7 (C50), 136.1 (C60),
133.8 (C300), 130.4 (C200), 128.9 (C4000), 127.5 (C3(5)), 127.0
(C400), 124.9 (C500 or C600), 124.8 (C600 or 500), 123.3
(C2000(6000)), 123.2 (C700), 21.6 (CH3). MS (ESI, m/z): 409
(73, Mþ1), 331 (25), 330 (100), 277 (9), 245 (13). HRMS
(ESI-TOF, CH3OH) calcd for C25H21N4S: [MþH]þ
409.14814, found: 409.15118.
5.5.5. N-[3-Phenyl-5-(pyridin-3-yl)pyrazin-2-yl]pyridinium
aminide (11e)
See Ref. 10b.
5.5.6. N-[5-Phenyl-3-(pyridin-3-yl)pyrazin-2-yl]pyridinium
aminide (11f)
Orange solid (221 mg, 68%), mp hydrobromide 207e
209 ꢀC (yellowish solid, ethanol); IR (KBr) nmax (cmꢁ1):
1507, 1488, 1401, 1370, 1144, 757, 696, 665; 1H NMR
(300 MHz, CD3OD): d 9.52 (1H, d, J¼2.2 Hz, H200), 8.82
(1H, dt, J¼8.1 and 1.9 Hz, H600), 8.77 (2H, dd, J¼6.7 and
1.3 Hz, H2(6)), 8.52 (1H, dd, J¼5.0 and 1.6 Hz, H400), 8.11
(1H, tt, J¼7.6 and 1.3 Hz, H4), 8.09 (1H, s, H60), 7.91 (2H,
ap dd, J¼7.3 and 1.4 Hz, H2000(6000)), 7.85 (2H, dd, J¼7.6 and
6.7 Hz, H3(5)), 7.52 (1H, dd, J¼8.1 and 5.0 Hz, H500), 7.40
(2H, ap t, J¼7.3 Hz, H3000(5000)), 7.28 (1H, tt, J¼7.3 and
5.5.9. N-[5-(4-Methoxyphenyl)-3-(thiophen-3-yl)pyrazin-2-yl]-
pyridinium aminide (11i)
Red solid (292 mg, 81%, ether), mp 149e150 ꢀC; IR (KBr)
nmax (cmꢁ1): 3108, 2835, 1607, 1555, 1489, 1421, 1368, 1244,
1182, 1144, 1033, 834, 667; 1H NMR (300 MHz, (CD3)2CO):
d 8.99 (2H, dd, J¼7.0 and 1.2 Hz, H2(6)), 8.95 (1H, dd, J¼3.1
and 1.2 Hz, H200), 8.26 (1H, dd, J¼5.1 and 1.2 Hz, H400), 8.08
(1H, s, H60), 8.00 (1H, tt, J¼7.6 and 1.2 Hz, H4), 7.93 (2H, ap
d, J¼8.9 Hz, H2000(6000)), 7.84 (2H, dd, J¼7.7 and 7.0 Hz,
H3(5)), 7.41 (1H, dd, J¼5.1 and 3.1 Hz, H500), 6.97 (2H, ap
d, J¼8.9 Hz, H3000(5000)), 3.80 (3H, s, OCH3); 13C NMR
(75 MHz, (CD3)2CO): d 159.7 (C4000), 157.0 (C20), 143.8
(C2(6)), 141.6 (C30), 137.0 (C50), 136.7 (C300), 135.6 (C60 or
C4), 135.3 (C4 or C60), 132.3 (C1000), 129.8 (C400), 127.3
(C3(5)), 127.2 (C200), 126.4 (C2000(6000)), 123.8 (C500), 114.7,
(C3000(C5000)), 55.5 (CH3O). MS (CI, m/z): 361 (100, Mþ1),
360 (66), 284 (71), 282 (51), 80 (43). Anal. Calcd for
C20H16N4OS$1/2H2O: C, 65.02; H, 4.64; N, 15.26; S, 8.68.
Found: C, 64.66; H, 4.40; N, 14.96; S, 8.79.
13
1.4 Hz, H4000); C NMR (75 MHz, CD3OD): d 159.0 (C20),
150.5 (C200), 148.5 (C400), 145.2 (C2(6)), 138.9 (C1000), 138.7
(C4), 138.5 (C600), 138.2 (C50), 138.0 (C60), 137.3 (C30), 136.5
(C300), 129.5 (C3000(5000)), 128.3 (C3(5)), 127.8 (C4000), 125.5
(C2000(6000)), 124.3 (C500). MS (CI, m/z): 326 (100, Mþ1), 277
(18), 249 (83), 80 (39). Anal. Calcd for C20H17BrN5$1/2H2O:
C, 48.41; H, 3.66; N, 14.11. Found: C, 48.45; H, 3.76; N,
13.82.
5.5.7. N-[5-(Benzo[b]thiophen-3-yl)-3-(3,5-dimethyl-
phenyl)pyrazin-2-yl]pyridinium aminide (11g)
5.5.10. N-[3-(Benzo[b]thiophen-3-yl)-5-(trans-2-
Orange solid (367 mg, 90%), mp 69e71 ꢀC; IR (KBr) nmax
(cmꢁ1): 2917, 1600, 1515, 1470, 1397, 1210, 1140, 761, 735,
phenylvinyl)pyrazin-2-yl]pyridinium aminide (11j)
Red oil (264 mg, 65%); IR (KBr) nmax (cmꢁ1): 3111, 3055,
2923, 1548, 1485, 1421, 1379, 1227, 1200, 1145, 751, 692,
1
669; H NMR (300 MHz, (CD3)2CO): d 8.95 (2H, dd, J¼6.8
1
and 1.2 Hz, H2(6)), 8.68 (1H, m, H4000), 8.12 (2H, br s,
H200(600)), 8.09 (1H, s, H60), 8.05 (1H, tt, J¼6.8 and 1.2 Hz,
H4), 7.96 (1H, m, H7000), 7.87 (2H, dd, J¼7.6 and 6.8 Hz,
H3(5)), 7.80 (1H, s, H2000), 7.41 (2H, m, H5000 and 6000), 7.00
(1H, br s, H400), 2.35 (6H, s, CH3); 13C NMR (75 MHz,
(CD3)2CO): d 157.6(C20), 144.2 (C2(6)), 141.6 (C7a000),
140.1 (C300(500)), 140.0 (C3a000), 138.8 (C100), 138.6 (C4), 137.1
(C60), 136.4 (C30), 136.2 (C50), 136.1 (C3000), 130.0 (C400),
128.1 (C3(5)), 127.5 (C200(600)), 125.6 (C4000), 125.1 (C5000 or
C6000), 124.9 (C6000 or C5000), 123.4 (C7000), 121.9 (C2000), 21.6
(CH3). HRMS (ESI-TOF, CH3OH) calcd for C25H21N4S:
[MþH]þ 409.14814, found: 409.15105.
668; H NMR (300 MHz, (CD3)2CO): d 9.19 (1H, s, H200),
9.18 (1H, br d, J¼8.5 Hz, H400), 8.93 (2H, dd, J¼7.0 and
1.3 Hz, H2(6)), 8.08 (1H, tt, J¼7.6 and 1.3 Hz, H4), 7.98
(1H, br d, J¼7.9 Hz, H700), 7.88 (2H, dd, J¼7.6 and 7.0 Hz,
H3(5)), 7.70 (1H, s, H60), 7.57 (2H, m, H2000(6000)), 7.51 (1H,
ddd, J¼8.2, 7.0 and 1.3 Hz, H500), 7.42 (1H, d, J¼16.0 Hz,
Ha), 7.40 (1H, m, H600), 7.34 (2H, br t, J¼7.5 Hz, H3000(5000)),
7.23 (1H, d, J¼16.0 Hz, Hb), 7.19 (1H, tt, J¼7.5 and
1.3 Hz, H4000); 13C NMR (75 MHz, (CD3)2CO): d 158.3
(C20), 144.3 (C2(6)), 140.4 (C7a00), 140.2 (C3a00), 139.5 (C60),
139.2 (C1000), 137.7 (C30), 136.8 (C4), 135.8 (C50), 133.7
(C300), 130.7 (C200), 129.4 (C3000(5000)), 127.5 (C3(5)), 127.4

R. Castillo et al. / Tetrahedron 64 (2008) 1351e1370
1367
(C4000), 127.1 (C400), 127.0, (Cb), 126.9 (C2000(6000)), 125.5, (Ca),
124.9 (C500 and C600), 123.1 (C700). MS (ESI, m/z): 407 (81,
Mþ1), 329 (27), 328 (100), 277 (9), 245 (13), 133 (16).
HRMS (ESI-TOF, CH3OH) calcd for C25H19N4S: [MþH]þ
407.13249, found: 407.13536.
and 2.9 Hz, H5000); 13C NMR (75 MHz, (CD3)2CO): d 158.3
(C20), 157.7 (C200), 157.6 (C400(600)), 144.2 (C2(6)), 141.7
(C30), 138.9 (C60), 137.0 (C4), 135.6 (C50), 133.3 (C3000), 127.9
(C500), 127.6 (C3(5)), 126.7 (C4000), 126.0 (C2000), 119.0 (C5000).
MS (CI, m/z): 333 (100, Mþ1), 254 (51), 80 (9). HRMS (ESI-
TOF, CH3OH) calcd for C17H13N6S: [MþH]þ 333.09169,
found: 333.09588.
5.5.11. N-[3-(Benzo[b]thiophen-3-yl)-5-(pyrimidin-5-yl)-
pyrazin-2-yl]pyridinium aminide (11k)
Orange solid (344 mg, 90%, ethanol), mp 215e217 ꢀC; IR
(KBr) nmax (cmꢁ1): 3111, 3046, 1548, 1489, 1405, 1221,
5.6. Reaction of 3,5-disubstituted N-(pyrazin-20-yl)-
pyridinium aminides (11) with benzyl bromides
1
1146, 760, 734; H NMR (300 MHz, (CD3)2CO): d 9.30 (2H,
s, H4000(6000)), 9.24 (1H, s, H200), 9.05 (1H, br d, J¼7.7 Hz,
H400), 9.00 (1H, s, H2000), 8.91 (2H, dd, J¼7.0 and 1.3 Hz,
H2(6)), 8.27 (1H, s, H60), 8.20 (1H, tt, J¼7.7 and 7.0 Hz, H4),
7.98 (3H, m, H3(5) and H700), 7.50 (1H, ddd, J¼8.2, 7.0 and
General method. In a dried round-bottomed flask, a solution
of the corresponding aminide (0.5 mmol) in anhydrous ace-
tone (5 mL) was prepared. After addition of the corresponding
alkyl bromide (4 mmol), the mixture was stirred at room tem-
perature for the time indicated in Table 5, until starting ami-
nide was no longer detected by TLC. Once the reaction was
complete, the solvent was evaporated in vacuo and the remain-
ing crude product was triturated with ethyl acetate in an ultra-
sonic bath. The resulting suspension was filtered and the solid
washed well with ethyl acetate to remove the excess alkyl
bromide. The isolated salts 12 were used without further puri-
fication in the next step.
1.3 Hz, H500), 7.42 (1H, ddd, J¼8.1, 6.8 and 1.4 Hz, H600); 13
C
NMR (75 MHz, (CD3)2CO): d 159.2 (C20), 156.9 (C2000),
152.9 (C4000(6000)), 144.8 (C2(6)), 140.5 (C7a00), 139.9 (C3a00),
138.1 (C4), 137.4 (C60), 133.3 (C50), 132.9 (C30), 131.1 (C200),
130.3 (C300), 129.5 (C5000), 127.8 (C3(5)), 126.6 (C400), 125.1
(C500 or C600), 125.0 (C600 or C500), 123.3 (C700). MS (EI, m/z):
382 (24, Mþ), 303 (100), 275 (26), 171 (24), 79(50). HRMS
(ESI-TOF, CH3OH) calcd for C21H15N6S: [MþH]þ
383.10734, found: 383.11140. Anal. Calcd for C21H14N6S: C,
65.95; H, 3.69; N, 21.97; S, 8.38. Found: C, 65.75; H, 3.68;
N, 21.70; S, 8.34.
5.6.1. 1-{N-Benzyl-N-[5-(3,5-dimethyl)phenyl-3-
phenylpyrazin-2-yl]amino}pyridinium bromide (12a)
White solid (182 mg, 78%, ethanol), mp 182e184 ꢀC; IR
(KBr) nmax (cmꢁ1): 3103, 3033, 1616, 1467, 1416, 1371,
5.5.12. N-[5-(Benzo[b]thiophen-3-yl)-3-(pyrimidin-5-yl)-
pyrazin-2-yl]pyridinium aminide (11l)
1
1335, 1240, 1158, 1017, 861, 720, 700, 682, 481; H NMR
Orange solid (328 mg, 86%, ethanol/ethyl acetate), mp
217e220 ꢀC; IR (KBr) nmax (cmꢁ1): 3051, 1548, 1516,
1491, 1405, 1145, 759; 1H NMR (500 MHz, DMSO-d6):
d 9.78 (2H, s, H400(600)), 9.13 (1H, s, H200), 8.87 (2H, dd, J¼
7.0 and 1.2 Hz, H2(6)), 8.50 (1H, d, J¼8.2 Hz, H4000), 8.14
(1H, s, H60), 8.13 (1H, tt, J¼7.7 and 1.2 Hz, H4), 8.00 (1H,
d, J¼7.9 Hz, H7000), 7.92 (1H, s, H2000), 7.89 (2H, dd, J¼7.7
and 7.0 Hz, H3(5)), 7.44 (1H, ddd, J¼8.0, 7.1 and 1.2 Hz,
H5000), 7.40 (1H, ddd, J¼8.2, 6.9 and 1.3 Hz, H6000); 13C NMR
(75 MHz, DMSO-d6): d 157.3 (C20), 156.5 (C200), 156.0
(C400(600)), 143.6 (C2(6)), 140.2(C60), 139.8 (C7a000), 137.6 (C4),
136.8 (C3a000), 134.0 (C3000), 133.5 (C50), 131.9 (C30), 130.8
(C500), 127.0 (C3(5)), 124.2 (C5000 or C6000), 124.1 (C6000 or
C5000), 123.7 (C4000), 122.6 (C7000), 121.8 (C2000). MS (EI, m/z):
382 (100, Mþ), 303 (47), 275 (31), 172 (55), 79(50). Anal.
Calcd for C21H14N6S$1/2H2O: C, 64.43; H, 3.86; N, 21.47; S,
8.19. Found: C, 64.10; H, 3.61; N, 21.07; S, 8.07.
(300 MHz, CD3OD): d 8.96 (1H, s, H60), 8.92 (2H, dd, J¼6.8
and 1.3 Hz, H2(6)), 8.51 (1H, tt, J¼7.8 and 1.3 Hz, H4), 7.92
(2H, dd, J¼7.8 and 6.8 Hz, H3(5)), 7.79 (4H, m, H200(600) and
H2000(6000)), 7.54 (3H, m, H300(500) and H400), 7.30 (5H, ap s,
HePh0000), 7.18 (1H, br s, H4000), 5.12 (2H, s, CH2), 2.42 (6H,
s, CH3); 13C NMR (75 MHz, CD3OD): d 152.1, 150.6, 148.3,
148.2, 147.9, 140.0, 138.7, 137.8, 136.6, 134.3, 132.8, 130.9,
130.7, 130.1, 130.1, 130.1, 130.0, 129.7, 125.8, 60.5, 21.4. MS
(ESI, m/z): 443 (97, MþꢁBr), 364 (100). HRMS (ESI-TOF,
CH3OH) calcd for C30H27N4: [MꢁBr]þ 443.2236, found:
443.2228.
5.6.2. 1-{N-Benzyl-N-[3-(3,5-dimethyl)phenyl-5-
phenylpyrazin-2-yl]amino}pyridinium bromide (12b)
White solid (183 mg, 70%, ethanol), mp 181e183 ꢀC; IR
(KBr) nmax (cmꢁ1): 3000, 1615, 1529, 1467, 1399, 1374,
1
1226, 1184, 1158, 858, 766, 720, 692; H NMR (300 MHz,
CD3OD): d 8.96 (1H, s, H60), 8.92 (2H, dd, J¼6.7 and 1.3 Hz,
H2(6)), 8.54 (1H, tt, J¼7.8 and 1.3 Hz, H4), 8.16 (2H, dd,
J¼7.7 and 1.6 Hz, H2000(6000)), 7.96 (2H, dd, J¼7.8 and 6.7 Hz,
H3(5)), 7.55 (3H, m, H3000(5000) and H4000), 7.37 (2H, br s,
H200(600), 7.30 (5H, m, H20000(60000), H30000(50000) and H40000), 7.18
(1H, br s, H400), 5.13 (2H, s, CH2), 2.42 (6H, s, CH3); 13C
NMR (75 MHz, CD3OD): d 151.5, 150.8, 148.3, 148.2, 148.0,
140.1, 138.4, 137.7, 136.7, 134.3, 132.3, 131.8, 131.2, 130.5,
130.2, 130.1, 129.7, 128.0, 127.4, 61.5, 21.3. MS (ESI, m/z):
443 (20, MþꢁBr), 364 (100). HRMS (ESI-TOF, CH3OH) calcd
for C30H27N4: [MꢁBr]þ 443.2234, found: 443.2228.
5.5.13. N-[3-(Pyrimidin-5-yl)-5-(thiophen-3-yl)pyrazin-2-yl]-
pyridinium aminide (11m)
Red solid (299 mg, 90%, ethyl acetate), mp 183e185 ꢀC; IR
(KBr) nmax (cmꢁ1): 3105, 2923, 1546, 1531, 1497, 1451, 1397,
1336, 1253, 1162, 1143, 1017, 758, 662; 1H NMR (300 MHz,
(CD3)2CO): d 9.87 (2H, s, H400(600)), 9.07 (1H, s, H200), 8.96
(2H, dd, J¼7.0 and 1.3 Hz, H2(6)), 8.16 (1H, s, H60),
8.10 (1H, tt, J¼7.7 and 1.3 Hz, H4), 7.90 (2H, dd, J¼
7.7 and 7.0 Hz, H3(5)), 7.82 (1H, dd, J¼2.9 and 1.3 Hz, H2000),
7.68 (1H, dd, J¼5.1 and 1.3 Hz, H4000), 7.50 (1H, dd, J¼5.1

1368
R. Castillo et al. / Tetrahedron 64 (2008) 1351e1370
5.6.3. 1-{N-[5-(3,5-Dimethylphenyl)-3-phenylpyrazin-2-yl]-
N-[(3-methyl)benzyl]amino}pyridinium bromide (12c)
5.6.6. 1-{N-[3-(Benzo[b]thiophen-3-yl)-5-(3,5-
dimethylphenyl)pyrazin-2-yl]-N-benzylamino} pyridinium
bromide (12f)
White solid (182 mg, 68%, ethanol), mp 187e189 ꢀC; IR
(KBr) nmax (cmꢁ1): 3104, 3031, 2917, 1616, 1471, 1411,
1370, 1240, 1160, 1017, 859, 765, 745, 725, 700, 682, 656;
1H NMR (300 MHz, CD3OD): d 8.96 (1H, s, H60), 8.92 (2H,
dd, J¼6.8 and 1.3 Hz, H2(6)), 8.51 (1H, tt, J¼7.8 and 1.3 Hz,
H4), 7.93 (2H, dd, J¼7.8 and 6.8 Hz, H3(5)), 7.81 (2H,
m, H200(600)), 7.78 (2H, br s, H2000(6000), 7.55 (3H, m, H300(500)
and H400), 7.16 (3H, m, H40000, H50000 and H60000), 7.06 (1H, br s,
H4000), 7.03 (1H, br s, H20000), 5.06 (2H, s, CH2), 2.42 (6H, s,
CH3), 2.27 (3H, s, CH3); 13C NMR (75 MHz, CD3OD):
d 152.3, 150.9, 148.6, 148.6, 148.2, 140.5, 140.2, 139.0, 138.1,
136.8, 134.4, 133.1, 131.6, 131.2, 131.1, 130.4, 130.3, 130.0,
130.0, 128.0, 126.1, 60.9, 21.7, 21.6. MS (ESI, m/z): 457
(100, MþꢁBr), 378 (66). HRMS (ESI-TOF, CH3OH) calcd
for C31H29N4: [MꢁBr]þ 457.2392, found: 457.2384.
Yellow solid (226 mg, 78%, ethanol), mp >129 ꢀC (dec);
IR (KBr) nmax (cmꢁ1): 3004, 1613, 1532, 1471, 1430, 1371,
1
1334, 1237, 1179, 1042, 854, 763, 732, 700, 669; H NMR
(300 MHz, CD3OD): d 9.10 (1H, s, H60), 8.55 (2H, dd, J¼
6.8 and 1.3 Hz, H2(6)), 8.28 (1H, tt, J¼7.7 and 1.3 Hz, H4),
8.00 (1H, m, H400), 7.98 (1H, s, H200), 7.79 (2H, br s,
H2000(6000)), 7.73 (2H, dd, J¼7.7 and 6.8 Hz, H3(5)), 7.69
(1H, m, H700), 7.47 (2H, m, H500 and H600), 7.23 (6H, m,
H20000(60000), H30000(50000), H40000 and H4000), 5.20 (2H, s, CH2),
2.42 (6H, s, CH3); 13C NMR (75 MHz, CD3OD): d 152.0,
151.6, 147.8, 147.6, 143.2, 141.3, 140.0, 139.3, 139.2, 138.2,
136.5, 134.3, 133.0, 132.8, 130.9, 130.2, 130.1, 129.6, 126.6,
126.0, 125.8, 124.1, 123.9, 60.5, 21.4. MS (ESI, m/z): 499 (37,
MþꢁBr), 420 (100).
5.7. Preparation of unsymmetrical benzyl(3,5-diaryl-
pyrazin-2-yl)amines (13)
5.6.4. 1-{N-[5-(Benzo[b]thiophen-3-yl)-3-phenylpyrazin-
2-yl]-N-benzylamino}pyridinium bromide (12d)
White solid (201 mg, 79%, ethanol), mp 165e166 ꢀC; IR
(KBr) nmax (cmꢁ1): 3009, 2931, 1615, 1512, 1471, 1456,
General method. Zinc dust (500 mg) was added to a solution
of the corresponding pyridinium salt 12 (100 mg) in glacial
acetic acid (25 mL) and the mixture was stirred at room tem-
perature for 48 h. During this period a slight change in the col-
our of the solution was observed. Once the reaction had
finished, the remaining solid was removed by filtration and
the solvent evaporated. The residue was dissolved in a mixture
of ethyl acetate (10 mL) and an aqueous solution of sodium
hydroxide (20%) (5 mL). The organic layer was separated
and the aqueous phase was re-extracted with ethyl acetate
(2ꢂ5 mL). The combined organic layers were extracted with
hydrochloric acid (20%) (2ꢂ5 mL) and the aqueous phase,
containing the aminoazine hydrochloride, was then basified
to pH¼10 using solid sodium hydroxide. The free amine
was extracted using ethyl acetate (3ꢂ10 mL). The combined
organic phases were washed with brine, dried over MgSO4, fil-
tered and evaporated to dryness. The residue was purified by
column chromatography on silica gel, using dichloromethane
as eluent, and the corresponding benzyl(3,5-diarylpyrazin-
2-yl)amine 13 was crystallized from a suitable solvent.
1
1428, 1408, 1163, 1058, 760, 732, 702; H NMR (500 MHz,
CD3OD): d 8.94 (2H, J¼6.9 and 1.3 Hz, H2(6)), 8.80 (1H, s,
H60), 8.59 (1H, dd, J¼6.1 and 2.8 Hz, H4000), 8.43 (1H, tt, J¼
7.8 and 1.3 Hz, H4), 8.30 (1H, s, H2000), 7.87 (3H, m, H3(5)
and 7000), 7.77 (2H, dd, J¼8.0 and 1.5 Hz, H200(600)), 7.51 (2H,
tt, J¼7.3 and 1.5 Hz, H300(500)), 7.46 (1H, tt, J¼7.3 and 1.5 Hz,
H400), 7.33 (2H, m, H6000 and 7000), 7.25 (5H, m, H20000(60000),
30000(50000) and 40000), 4.99 (2H, s, CH2); 13C NMR (75 MHz,
CD3OD): d 157.2, 149.6, 149.1, 148.1, 148.0, 147.1, 141.9,
140.1, 140.1, 138.0, 137.5, 134.0, 132.7, 130.9, 130.6, 130.2,
130.0, 129.9, 129.6, 126.0, 125.9, 125.5, 123.7, 60.4. HRMS
(ESI-TOF, CH3OH) calcd for C30H23N4S: [MꢁBr]þ
471.1643, found: 471.1634.
5.6.5. 1-{N-[3-(Benzo[b]thiophen-3-yl)-5-phenylpyrazin-
2-yl]-N-[(2-bromo)benzyl]amino}pyridinium bromide (12e)
Yellow solid (255 mg, 81%, ethanol), mp >130 ꢀC (dec); IR
(KBr) nmax (cmꢁ1): 3053, 1728, 1612, 1532, 1471, 1416, 1332,
1
1175, 1027, 766, 739, 694, 508, 472; H NMR (300 MHz,
5.7.1. N-Benzyl-N-[5-(3,5-dimethyl)phenyl-3-phenyl-
pyrazin-2-yl]amine (13a)
CD3OD): d 9.24 (1H, s, H60), 8.38 (2H, dd, J¼6.7 and 1.5 Hz,
H2(6)), 8.23(1H, tt, J¼7.7 and 1.5 Hz, H4), 8.20(2H, dd, J¼
7.9 and 1.8 Hz, H2000(6000)), 7.94 (1H, m, H400), 7.82 (1H, s,
H200), 7.65 (2H, dd, J¼7.7 and 6.7 Hz, H3(5)), 7.62(1H, m,
H700), 7.55 (4H, m, H3000(5000), H4000 and H30000), 7.44 (1H, ddd,
J¼8.5, 7.3 and 1.5 Hz, H500 or H600), 7.37 (1H, ddd, J¼8.2,
7.3 and 1.5 Hz, H600 or H500), 7.28 (3H, m, H40000, H50000 and
H60000), 5.40 (2H, s, CH2); 13C NMR (75 MHz, CD3OD):
d 151.9, 151.8, 147.9, 147.5, 143.6, 141.1, 139.5, 138.2, 136.5,
134.7, 134.0, 133.7, 132.7, 132.2, 131.4, 130.2, 129.8, 129.7,
129.4, 128.1, 126.6, 126.3, 126.0, 124.0, 123.7, 60.2. MS (ESI,
m/z): 551/549 (100/86, MþꢁBr), 472/470 (51/46). HRMS (ESI-
TOF, CH3OH) calcd for C30H22BrN4S: [MꢁBr]þ 551.0728/
549.0749, found: 551.0718/549.0734.
White solid (43 mg, 62%, ethyl acetate/hexane) mp 102e
104 ꢀC, IR (NaCl) nmax (cmꢁ1): 3435, 3028, 2917, 1668,
1604, 1580, 1506, 1359, 1218, 1163, 1027, 850, 742, 699;
1H NMR (300 MHz, CDCl3): d 8.45 (1H, s, H60), 7.74 (2H,
dd, J¼8.2 and 1.8 Hz, H200(600)), 7.53 (2H, br s, H2000(6000)),
7.46 (3H, m, H300(500) and H400), 7.28 (5H, m, HePh0000), 6.97
(1H, br s, H4000), 5.28 (1H, t, J¼5.9 Hz, NH ), 4.67 (2H,
d, J¼5.9 Hz, CH2), 2.36 (6H, s, CH3); 13C NMR (75 MHz,
CDCl3): d 150.6 (C20), 141.3 (C50), 140.3 (C30), 139.1 (C10000),
138.2 (C60), 137.7 (C3000(5000)), 137.3 (C1000 or C100), 137.2 (C100
or C1000), 129.5 (C4000), 129.2 (C300(500)), 129.0 (C400), 128.6
(C30000(50000)), 128.5 (C200(600)), 127.5 (C20000(60000)), 127.3
(C40000), 123.5 (C2000(6000)), 45.4 (CH2), 21.4 (CH3). HRMS

R. Castillo et al. / Tetrahedron 64 (2008) 1351e1370
1369
(ESI-TOF, CH3OH) calcd for C25H24N3: [MþH]þ 366.1970,
Rev. 2003, 103, 1875e1916; (d) de Meijere, A.; Diederich, F.; Metal-
Catalysed Cross-Coupling Reactions, 2nd ed.; Wiley-VCH: Weinheim,
2004; Vols. 1 and 2; (e) Kirch, G.; Hesse, S.; Comel, A. Curr. Org.
Synth. 2004, 1, 47e63; (f) Corbet, J.-P.; Mignani, G. Chem. Rev.
2006, 106, 2651e2710.
found: 366.1992.
5.7.2. N-Benzyl-N-[3-(3,5-dimethyl)phenyl-5-
3. (a) Collins, I. J. Chem. Soc., Perkin Trans. 1 2002, 1921e1940; (b)
Schroter, S.; Christoph, S.; Bach, T. Tetrahedron 2005, 61, 2245e2267;
phenylpyrazin-2-yl]amine (13b)
White solid (39 mg, 57%, ethyl acetate/hexane) mp 91e
93 ꢀC, IR (NaCl) nmax (cmꢁ1): 3432, 3030, 2920, 1602, 1513,
¨
(c) Large, J. M.; Clarke, M.; Williamson, D. M.; McDonald, E.; Collins,
I. Synlett 2006, 861e864.
1
1488, 1195, 1163, 1028, 856, 764, 695; H NMR (300 MHz,
4. (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457e2495; (b) Suzuki,
A. J. Organomet. Chem. 1999, 576, 147e168; (c) Kotha, S.; Lahiri, L.;
Kashinath, D. Tetrahedron 2002, 58, 9633e9695.
CDCl3): d 8.45 (1H, s, H60), 7.93 (2H, dd, J¼7.8 and 1.5 Hz,
H2000(6000)), 7.41 (3H, m, H3000(5000) and H4000), 7.32 (7H, m,
H200(600) and HePh0000), 7.05 (1H, br s, H400), 5.33 (1H, t, J¼
5.5 Hz, NH ), 4.67 (2H, t, J¼5.5 Hz, CH2), 1.23 (6H, s, CH3);
13C NMR (75 MHz, CDCl3): d 150.8 (C20), 140.9 (C50 or
C10000), 140.8 (C10000 or C50), 139.2 (C30), 138.8 (C60), 137.4
(C300(500) and C1000 or C100), 137.0 (C100 or C1000), 130.7 (C400),
128.7 (C3000(5000) or C30000 (50000)), 128.6 (C30000 (50000) or
C3000(5000)), 127.7 (C4000), 127.4 (C2000(6000)), 127.2 (C40000), 126.1
(C2000(6000) or C2 0000 (60000)), 125.6 (C20000(60000) or C2000(6000)), 45.4
(CH2), 21.4 (CH3). HRMS (ESI-TOF, CH3OH) calcd for
C25H24N3: [MþH]þ 366.1970, found: 366.1987.
´
´
5. (a) Najera, C.; Gil-Molto, J.; Karlstrom, S. Adv. Synth. Catal. 2004,
´
¨
346, 1798e1811; (b) Lu, G.; Fanzen, R.; Zahng, Q.; Xu, Y. Tetra-
hedron Lett. 2005, 46, 4255e4259; (c) Leadbeater, N. E. Chem. Commun.
2005, 2881e2902; (d) Li, J.-H.; Zhu, Q.-M.; Xie, Y.-X. Tetrahedron
2006, 62, 10888e10895; (e) Kudo, N.; Perseghini, M.; Fu, G. C. Angew.
Chem., Int. Ed. 2006, 45, 1282e1284; (f) Billingsley, K. L.; Anderson,
K. W.; Buchwald, S. L. Angew. Chem., Int. Ed. 2006, 45, 3484e
3488.
6. Vaquero, J. J.; Alvarez-Builla, J. Advances in Nitrogen Heterocycles; JAI:
Stamford, 2000; Vol. 4, pp 159e250.
7. Ollis, D. W.; Stanforth, S. P. Tetrahedron 1985, 41, 2239e2329.
´
8. (a) Carceller, R.; Garcıa-Navıo, J. L.; Izquierdo, M. L.; Alvarez-Builla, J.
Tetrahedron Lett. 1993, 34, 2019e2020; (b) Carceller, R.; Garcıa-Navıo,
´
´
´
´
J. L.; Izquierdo, M. L.; Alvarez-Builla, J.; Fajardo, M.; Gomez-Sal, P.;
Gago, F. Tetrahedron 1994, 50, 4995e5012; (c) Burgos, C.; Delgado,
5.7.3. N-[5-(Benzo[b]thiophen-3-yl)-5-phenylpyrazin-2-yl]-
N-benzylamine (13c)
´
F.; Garcıa-Navıo, J. L.; Izquierdo, M. L.; Alvarez-Builla, J. Tetrahedron
´
Yellow oil (45 mg, 63%); IR (NaCl): nmax (cmꢁ1): 3434,
3059, 2921, 1577, 1524, 1494, 1452, 1425, 1349, 1218,
1161, 1027, 759, 734, 700; 1H NMR (500 MHz, CDCl3):
d 8.45 (1H, s, H60), 8.42 (2H, m, H4000), 7.88 (1H, m, H7000),
7.78 (2H, m, H200(600)), 7.51 (2H, m, H300(500)), 7.44 (1H, m,
H400), 7.38 (2H, m, H5000 and H6000), 7.35 (4H, m, H20000(60000)
and H30000(50000)), 7.27 (1H, m, H40000), 5.36 (1H, t, J¼5.6 Hz,
NH ), 4.70 (2H, d, J¼5.6 Hz, CH2); 13C NMR (75 MHz,
CDCl3): d 150.5 (C20), 140.8 (C7a000), 140.2 (C30), 139.3
(C60), 139.0 (C3000), 138.7 (C3a000), 137.4 (C100), 137.0 (C10000),
134.0 (C50), 129.2 (C200(600) or 300(500)), 129.1 (C400), 128.6
(C300(500) or C200(600)), 128.3 (C20000(60000) or C30000(50000)), 127.5
(C30000(50000) or C20000(60000)), 127.3 (C40000), 124.4 (C4000 or C6000),
124.4 (C6000 or C4000), 124.0 (C2000 or C5000), 123.8, (C5000 or
C2000), 122.7 (C7000), 45.4 (CH2). HRMS (APCI-TOF, CH3OH)
calcd for C25H20N3S: [MþH]þ 394.1378, found: 394.1388.
´
1995, 51, 8649e8654; (d) Garcıa de Viedma, A.; Martinez-Barrasa, V.;
Burgos, C.; Izquierdo, M. L.; Alvarez-Builla, J. J. Org. Chem. 1999, 64,
´
´
1007e1010; (e) Martınez-Barrasa, V.; Delgado, F.; Burgos, C.; Garcıa-
Navıo, J. L.; Izquierdo, M. L.; Alvarez-Builla, J. Tetrahedron 2000, 56,
´
2481e2490; (f) De la Rosa, R.; Martinez-Barrasa, V.; Burgos, C.;
Alvarez-Builla, J. Tetrahedron Lett. 2000, 41, 5837e5840; (g) Reyes,
M. J.; Delgado, F.; Izquierdo, M. L.; Alvarez-Builla, J. Tetrahedron
2002, 58, 8573e8579; (h) Reyes, M. J.; Burgos, C.; Izquierdo, M. L.;
Alvarez-Builla, J. Tetrahedron 2004, 60, 1093e1097; (i) Castillo, R.;
Izquierdo, M. L.; Alvarez-Builla, J. Tetrahedron Lett. 2007, 48, 5899e
5903.
´
9. (a) Matınez-Barrasa, V.; Garcıa de Viedma, A.; Burgos, C.; Alvarez-
´
~
´
Builla, J. Org. Lett. 2000, 2, 3933e3935; (b) Nunez, A.; Garcıa de
´
Viedma, A.; Martınez-Barrasa, V.; Burgos, C.; Alvarez-Builla, J. Syn-
lett 2002, 1093e1096; (c) Nunez, A.; Sanchez, A.; Burgos, C.;
´
~
´
Alvarez-Builla, J. Tetrahedron 2004, 60, 6217e6224; (d) Sanchez,
~
A.; Nunez, A.; Alvarez-Builla, J.; Burgos, C. Tetrahedron 2004, 60,
´
~
11843e11850; (e) Sanchez, A.; Nunez, A.; Burgos, C.; Alvarez-
~
Builla, J. Tetrahedron Lett. 2006, 47, 8343e8346; (f) Nunez, A.;
´
Sanchez, A.; Burgos, C.; Alvarez-Builla, J. Tetrahedron 2007, 63,
6774e6783.
Acknowledgements
10. (a) Reyes, M. J.; Izquierdo, M. L.; Alvarez-Builla, J. Tetrahedron Lett.
2004, 45, 8713e8715; (b) Reyes, M. J.; Castillo, R.; Izquierdo, M. L.;
Alvarez-Builla, J. Tetrahedron Lett. 2006, 47, 6457e6460.
´
The authors wish to thank the Comision Interministerial de
Ciencia y Tecnologıa (CICYT-BQU2001-1508 and CTQ2005-
11. (a) Sadighi, J. P.; Singer, R. A.; Buchwald, S. L. J. Am. Chem. Soc. 1998,
120, 4960e4976; (b) Garnier, E.; Audoux, J.; Pasquinet, E.; Suzenet, F.;
Poullain, D.; Lebret, B.; Guillaumet, G. J. Org. Chem. 2004, 69, 7809e
7815.
´
´
08902) and the Universidad de Alcala (UAH GC2005/006)
for financial support and the Ministerio de Educacion y Cien-
´
cia (MEC) for two studentships (M.J.R. and R.C.). We also
thank Professor Mijail Galajov for his assistance in the
NMR study.
12. (a) Nakamura, H.; Aizawa, M.; Takeuchi, D.; Murai, A.; Shimoura, O.
Tetrahedron Lett. 2000, 41, 2185e2188; (b) Wu, C.; Nakamura, H.;
Murai, A.; Shimoura, O. Tetrahedron Lett. 2001, 42, 2997e3000; (c)
Jiang, B.; Yang, C.-G.; Xiong, W.-N.; Wang, J. Bioorg. Med. Chem.
2001, 9, 1149e1154; (d) Adamczyk, M.; Akireddy, S. R.; Johnson,
D. D.; Mattingly, P. G.; Pan, Y.; Reddy, R. E. Tetrahedron 2003, 59,
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