Hetarynic synthesis and chemical transformation of dihydrodipyridopyrazines

Article abstract of DOI:10.1016/S0040-4020(02)00310-1

Unprecedented dihydrodipyridopyrazines were easily obtained by hetarynic dimerization of 2-alkylamino-3-halogenopyridines in the presence of the complex base NaNH₂-tBuONa. Derivatizations of the new heterocycles are described. The anticancer ac

Full text of DOI:10.1016/S0040-4020(02)00310-1

TETRAHEDRON
Pergamon
Tetrahedron 58 <2002) 3513±3524
Hetarynic synthesis and chemical transformation
of dihydrodipyridopyrazines
a
Stephanie Blanchard, Ivan Rodriguez, Catherine Kuehm-Caubere, Pierre Renard,
a
b
b
Â
Á
Bruno Pfeiffer, Gerald Guillaumet and Paul Caubere
b
a,p
a,p
Â
Á
a
 Â
Institut de Chimie Organique et Analytique, ICOA, UMR-CNRS 6005, Universite d'Orleans, rue de Chartres, BP 6759,
Â
45067 Orleans Cedex 2, France
b
Â
ADIR, 1, rue Carle Hebert, Courbevoie, F-92415 Courbevoie Cedex, France
Received 27 November 2001; revised 30 January 2002; accepted 14 March 2002
AbstractÐUnprecedented dihydrodipyridopyrazines were easily obtained by hetarynic dimerization of 2-alkylamino-3-halogenopyridines
in the presence of the complex base NaNH2±tBuONa. Derivatizations of the new heterocycles are described. The anticancer activity of these
compounds is also mentioned. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
of 2-amino-3-halogeno pyridines 1 ought to lead to dihydro-
dipyridopyrazines <DHDPP) for which antitumor activity
could be expected. In the present paper, we report the results
obtained in this area. A few preliminary experiments have
been reported elsewhere.6
The active current researches for new antitumor agents are
due to the unfortunately limited capacity of existing drugs to
cure cancers. The huge amount of information gathered
during the last 20 years on the mechanism of tumor forma-
tion and development led to the identi®cation of several
targets to be reached by anticancer drugs.1 The diversity
of these targets explains the structural variety of substrates
with antitumor properties. Among them, planar polynuclear
nitrogen containing aromatic heterocycles form an
important anticancer family.1a,b,k±v,2
2. Cyclization of 2-N-alkylamino-3-bromopyridines
Exploratory experiments performed with 2-N-methylamino-
3-bromopyridine 1 <XˆBr) unexpectedly led to the forma-
tion, in equal amount, of two products possessing the same
molecular mass <Mˆ212) as it resulted from a GC/MS
analysis.
We have been involved for many years in programs dealing
with complex base <CB) initiated arynic reactions3 and their
application in medicinal chemistry.4 Studying hetarynic
reactions, we recently showed that amino pyridines could
be obtained by allowing amines to react with dehydro-
pyridines generated from appropriate halogenopyridines
and the CB NaNH2±tBuONa.5 We surmised that under
analogous conditions, head to tail intermolecular cyclization
One of the isomers easily led to single crystals which X-ray
diffraction data corresponded to the planar structure 2a
<Scheme 1, RˆMe). NMR spectra con®rmed this formula.
Only single crystals of very poor quality were obtained with
the second isomer. X-Ray diffraction analysis also
con®rmed a planar structure, however, the relative position
Scheme 1.
Keywords: dihydrodipyridopyrazines; formylation; nitration.
Corresponding authors. Tel.: 133-2-38-41-70-73; fax: 133-2-38-41-70-78; e-mail: gerald.guillaumet@univ-orleans.fr
p
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020<02)00310-1

3514
S. Blanchard et al. / Tetrahedron 58 52002) 3513±3524
Table 1. Cyclization of 1 <XˆBr) with NaNH2±tBuONa in THF
Finally, a few experiments performed with 1 <XˆCl)
showed that chloropyridine derivatives may be also used
in such reactions. Overall yields were lower <35%) than
with bromide but the reaction was very clean and 35% of
the starting material was easily recovered. In contrast, iodo
derivative 1 <XˆI) only led to very low yields due to the
large amount formation of tars.
Run
R
0
t <h)
Product
2/3a
Global yield <%)
1
2Et
3
Me
Bu
144
2a, 3a
2b, 3b
2c, 3c
2d
50/50
54/46
50/50
100/0
99/1
50
56
74
20
50
50
15c
12
72
72
96
168
96
4
5
6
7
MeCHPh
<CH2)2NMe2
<CH2)3NMe2
<CH2)2OTHP
2e, 3eb
2f, 3f
2g
52/48
100/0
3. Comments about the mechanisms
a
Determined by gas chromatography <GC) <capillary HP1, 6 m).
Not isolated, evidenced by GC/MS.
10% of monodealkoxyethyl product was also isolated <see Section 6 2h).
b
c
An arynic mechanism appeared as very likely. Indeed if
SNAr could explain the formation of 2 it cannot justify the
formation of 3. Moreover, the replacement of the complex
base by NaH led only to the starting material and in the
presence of HMPA, well known as favoring nucleophilic
substitution, no cyclization product was observed. In order
to obtain some insight into the mechanism, we studied
<Scheme 2) the behavior of halogenotrimethylsilyl pyridine
derivatives 4a and 4b in the presence of ¯uoride ions. Such
generation of arynes is well documented in the literature.7
of nitrogen of the pyridine rings was doubtful. A 2D NMR
analysis unambiguously attributed the unexpected structure
3a <Scheme 1, RˆMe) to the second isomer. Note that, for
both isomers, the planar formula indicates a strong electron
delocalization from the nitrogen of the pyrazine ring which
implies an appreciable formal positive charge on these
atoms. We will discuss further the formation of this
unexpected compound.
Irrespective of the reaction temperature <2208C to solvent
re¯ux), the same products were generated from the bromo-
pyridine derivative 4a and the starting material completely
disappeared after 1±3 h. The compounds 2 and 3 were
always formed in low but suf®cient amounts to be isolated,
separated and identi®ed. This result strongly supports the
hetarynic mechanism under the conditions of Scheme 1. The
formation of 5 and 1 <XˆBr) is reminiscent of the halogen
dance developed by Bunnett many years ago.8 Finally, 6
could be due to the reaction of 5 with the hetarynic inter-
mediate. Interestingly, when 6 was submitted to react with
the CB NaNH2±tBuONa, 2 was formed in 62% yield
con®rming the structure of this compound and supporting
its hetarynic formation. Note that reaction performed with
the corresponding chloroderivative 4b only led to the chloro
substrate 1 <XˆCl) in 80% yield. Thus, we tentatively
propose the mechanisms A and B reported in Scheme 3.
A systematic study <data not reported) showed that THF was
the most appropriate solvent, that the replacement of the CB
by NaNH2 alone was highly unfavorable to the progress of
the reaction, and that room temperature was more advisable.
Finally, since optimal ef®ciency of CB in arynic reactions is
obtained when NaNH2±tBuONa is 2/1,3 1 equiv. excess of
NaNH2 was necessary to furnish sodium amide 7. In Table 1
are reported the results obtained under the appropriate
conditions thus determined.
The low yield obtained in run 4 was due to a large destruc-
tion of the starting material certainly resulting from a proton
abstraction on the benzylic position. Replacement of the
phenethyl group by a benzyl or triphenylmethyl led only
to tar products. In the same way, the alkoxyethyl substituted
1 led to a large amount of by-products <run 7). The
monodealkoxylation observed <10%) was attributed to a
b-elimination.
The possible protonation of anionic intermediates such as 9
Scheme 2.

S. Blanchard et al. / Tetrahedron 58 52002) 3513±3524
3515
Scheme 3.
or 10 could be due to proton abstraction from the solvent. At
present, we are unable to give an explanation for the
variations of the 2/3 ratio with the nature of R. Assuming
8!10!11 takes place, both products 2 and 3 could be
rationalized as arising from the same intermediate 11 rather
than invoking competing mechanisms 8!9 versus 8!10.
This alternative might be offered as a possibility.
4. Chemical reactivity of dihydrodipyridopyrazines
To the best of our knowledge, compounds 3 are unknown
and only two DHDPP 2 have been incidentally mentioned in
the literature.9 Therefore, we decided to study the chemical
behavior of these substrates keeping in view our medicinal
chemistry purpose.
Scheme 4.

3516
S. Blanchard et al. / Tetrahedron 58 52002) 3513±3524
Table 2. Formylation of 2 and 3
Formylation of 2
Run Substrate Solvent Reaction time <h)
Product
Conv.a <%)
12
R
Yieldb <%) 13
R
Yieldb <%)
1
2
3
2a
2c
2f
DCEa
DCEa
CFc
7
18
14
12a Me
12c Bu
12f <CH2)3NMe2
68
63
13a Me
13c Bu
25
8
44
95
30
83d
±
±
±
Formylation of 3
Run Substrate Solvent Reaction time <h)
Product
Yieldb <%)
Conv.a <%)
14
R
Yieldb <%) 15
R
16
R
Yieldb <%)
4
5
6
3a
3c
3f
DCEa
DCEa
CFc
18
8
14
14a Me
14c Bu
14f <CH2)3NMe2
90
70
±
±
15c Bu
±
±
±
16c
±
±
Bu
±
±
4
±
89
100
70
8
57e
±
±
POCl3 <10 equiv.)±DMF <23 equiv.) re¯ux then NaOH 3 M <36 equiv.) re¯ux 3 h.
a
This value arises from the following ratio: <initial reacting moles2residual moles)/initial reacting moles.
Based on converted materials.
CF: Chloroform.
Very highly unstable in solution, characterized by GC/MS and IR data.
Unstable characterized only by spectroscopic data.
b
c
d
e
4.1. Formylation of 2 and 3
4.2. Nitration of 2 and 3
We ®rst examined this electrophilic substitution which may
be performed under rather mild conditions and introduce a
carboxaldehyde function prone to further transformations.
The products which may be formed during this reaction are
reported in Scheme 4 and the best results obtained have
been gathered in Table 2.
Nitro group is of interest for further functionalization and in
the chemistry of antitumor agents.1 Our electron rich
substrates were very sensitive to usual electrophilic nitration
reagents and led only to untractable tars. So, we turned
towards nucleophilic nitration using the Ac2O±DMSO
10
reagent associated to KNO2 <method A). Preliminary
experiments showed that nitro compounds could be
obtained but some limitations were also observed. So, we
reasoned that since the key step of method A was a
nucleophilic attack of NO22 on a pyridine ring quaternized
by a Pummerer's reagent, it ought to be possible to replace
this latter by a proton. Exploratory experiments performed
using the oxalic salts showed that, as expected, they reacted
with KNO2 in nitromethane to lead to nitro derivatives
<method B). The reactions thus performed are summarized
in Scheme 5 and the best results obtained gathered in
Table 3.
Taking account of the recovered starting material, yields
based on converted materials may be considered as good
with both series. Irrespective of the starting substrate, selec-
tive formylation at the C2position was observed and
substrates 3 were more reactive than 2. At present, we are
unable to rationalize these observations. Finally, it appeared
that in a given series the reactivity also depended upon the
nature of the substituents R of the pyrazine ring <compare
runs 1±3 or 4±6). We attribute this property to a folding of
the planar structures due to the nature of the substituents R
with, as a consequence, a change in the delocalization of
the lone electron pairs of the nitrogens and thus of the
p-electron disponibility.
According to the pyridinium nature of the reaction inter-
mediates, the only products obtained were due to the
Scheme 5.

S. Blanchard et al. / Tetrahedron 58 52002) 3513±3524
3517
Table 3. Nitration of 2 and 3
Nitration of 2
Run Substrate Methoda <HOCO)2 <equiv.) KNO2 <equiv.) t <h)
Product
Conv.b <%)
17
R
Yieldc <%) 18
R
Yieldc <%)
1
2
3
4
5
6
7
2a
2a
2c
2c
2e
2f
A
B
A
B
B
B
B
±
1
±
1
5
5
5
6
22
6
2
3
2
17a
17a
17c
174c8
Me
Me
Bu0
Bu
97
60
62
94
71
67
97
±
±
18c
±
±
±
Bu
±
±
±
15
±
±
13
±
100
100
100
55
100
100
100
.5
2
6
2
2
17e <CH2)2NMe2
17f <CH2)30NMe2
17f <CH2)3NMe2
±
±
18f <CH2)3NMe2
3
5
2f
±
±
Nitration of 3
Run Substrate Methoda <HOCO)2 <equiv.) KNO2 <equiv.)
Product
Conv.b <%)
19
R
Yieldc <%) 20
R
Yieldc <%)
8
9
10
11
12
13
3a
3a
3c
3c
3f
A
B
A
B
B
B
±
3
±
1
5
5
6
3
6
2
3
5
18 19a
1.5 19a
Me
Me
±
88
5
±
90
73
71
20a
20a
20c
±
Me
Me
Bu
±
8
72100
90
±
±
21
100
2.5
±
197c2
100
100
90
Bu
2
2
19f <CH2)30NMe2
19f <CH2)3NMe2
±
20f <CH2)3NMe2
±
3f
100
a
Method A: Ac2O 6 equiv., DMSO 8 ml for 6 mM of Ac2O, room temperature; Method B: room temperature, sali®cation in CH2Cl2, nitration in CH3NO2.
This value arises from the following ratio: <initial reacting moles2residual moles)/initial reacting moles.
Based on converted materials.
b
c
nucleophilic attack of the carbon atom bonded to the
5. Conclusion
nitrogen of the pyridine rings. From the data of Table 3, it
appears that a large variety of nitro compounds may be
obtained. Methods A and B are complementary reactions
although method A appeared more limited than method B.
Thus, under the conditions of method A, 2e, 2f and 3f led
only to intractable mixture of products while method B led
to the expected compounds <runs 5±7, 12, 13).
In the present paper, we have shown that dihydrodipyrido-
pyrazines may be easily obtained by arynic intermolecular
cyclization of 2-aminoalkyl-3-halogenopyridines in the
presence of a complex base. These previously unknown
heterocycles have interesting chemical properties since
they may be functionalized with electrophilic or nucleo-
philic reagents. On the other hand, exploratory pharmaco-
logical investigations performed with L1210 showed that
these compounds constitute a new family of antiprolifera-
tive agents. Indeed, the IC50 of a number of the products
To the best of our knowledge, method B has never been
previously described and we propose the mechanism
reported in Scheme 6 to account of the reactions
observed. Aromatization of the assumed intermediate
must instantaneously take place in the reaction
medium.
presently described vary from 3 to 7 mM. More
interestingly, it was found that they are able to
interfere with the cell cycle at 5±25 mM, a good indication
Scheme 6.

3518
S. Blanchard et al. / Tetrahedron 58 52002) 3513±3524
for future anticancer agents. Details of the pharmacological
properties of the compounds synthesized as well as of a
number of their derivatives will be further published in
due course.
NH), 7.09 <d, Jˆ4.7 Hz, 1H, ArH), 1.37 <s, 9H, C<CH3)3),
0.41 <s, 9H, Si<CH3)3); 13C NMR d <ppm): 175.9 <CvO),
153.4, 149.2<2 £arom C), 146.4, 126.6 <2£arom CH), 125.5
<arom C), 40.2<C), 27.5 <3 £CH3), 21.1 <Si<CH3)3).
6.3.2. N-/3-Chloro-4-trimethylsilylpyridin-2-yl)-2,2-di-
methylpropanamide. The previous procedure gave the
title compound in 85% yield. Mp 1398C; MS <IS) 285
6. Experimental
1
<35Cl, M1H1), 287 <37Cl, M1H1); H NMR d <ppm):
6.1. General methods
8.36 <d, Jˆ4.7 Hz, 1H, ArH), 8.05 <s, 1H, NH), 7.13 <d,
Jˆ4.7 Hz, 1H, ArH), 1.37 <s, 9H, C<CH3)3), 0.40 <s, 9H,
Si<CH3)3); 13C NMR d <ppm): 175.8 <CvO), 150.4, 147.1
<2£arom C), 145.5, 128.8 <2£arom CH), 126.1 <arom C),
39.9 <C), 27.3 <3£CH3), 21.5 <Si<CH3)3).
Mps were determined on a Tottoli melting point apparatus
and are uncorrected. 1H and 13C NMR spectra were recorded
in CDCl3 with a Bruker AM 400 or a Bruker 250 MHz
spectrometer <Attached Proton Test method, APT) or a
Bruker instrument Avance DPX250 at 250.131 and
62.9 MHz, respectively. Chemical shifts <d values) were
reported in parts per million and coupling constants <J
values) in Hz. Me4Si was the internal standard. Infrared
spectra were recorded using NaCl ®lm or KBr pellets tech-
niques on a Perkin±Elmer spectrometer FT PARAGON
1000PC or on a Perkin Elmer 841 instrument. Elemental
analyses were performed by CNRS laboratory <Vernaison).
Mass spectra <MS) were recorded on a Perkin±Elmer mass
spectrometer SCIEX API 300 by ion spray <IS). Mass HR
spectra were recorded by `peak matching' with a Finnigan
MAT 95Q, BEQQ by the Institut de Recherches Servier
<Suresnes). TLC were performed with plates coated with
Kieselgel G <Merck). The silica gel used for ¯ash chromato-
graphy was Kieselgel of 0.04±0.063 mm particle size.
6.3.3. 2-Amino-3-bromo-4-trimethylsilylpyridine. The N-
<3-bromo-4-<trimethylsilyl)-2-pyridyl)-2,2-dimethylpro-
panamide <4.5 g, 0.014 mol) in HCl <6N) <50 ml) was
re¯uxed overnight. The mixture was basi®ed to pH 8
<KOH), extracted with CH2Cl2, dried over MgSO4 and the
solvent removed under reduced pressure to give quanti-
tatively the desired product. Mp 888C; MS <IS) 245 <79Br,
1
M1H1), 247 <81Br, M1H1); H NMR d <ppm): 7.96 <d,
Jˆ4.6 Hz, 1H, ArH), 6.95 <d, Jˆ4.7 Hz, 1H, ArH), 5.00 <s,
2H, NH2), 0.38 <s, 9H, Si<CH3)3); 13C NMR d <ppm): 155.1,
151.7 <2£arom C), 145.6, 119.9 <2£arom CH), 112.1 <arom
C), 21.1 <Si<CH3)3).
6.3.4. 2-Amino-3-chloro-4-trimethylsilylpyridine. The
previous procedure gave the title compound quantitatively.
Mp 928C; MS <IS) 201 <35Cl, M1H1), 203 <37Cl, M1H1);
1H NMR d <ppm): 7.93 <d, Jˆ4.6 Hz, 1H, ArH), 6.69 <d,
Jˆ4.7 Hz, 1H, ArH), 4.84 <s, 2H, NH2), 0.36 <s, 9H,
Si<CH3)3); 13C NMR d <ppm): 154.4, 148.6 <2£arom C),
144.9, 121.1 <2£arom CH), 119.4 <arom C), 21.4
<Si<CH3)3).
Sodium amide powder was obtained commercially <Merck).
Reagent-grade tetrahydrofuran <THF) was ®rst distilled
from potassium hydroxide and then from sodium benzo-
phenone ketyl and stored over sodium until used.
6.2. General procedure for the preparation of 2-alkyl-
amino-3-halogenopyridines 1
6.3.5. N-/3-Bromo-4-trimethylsilylpyridin-2-yl)-N-methyl-
amine 4a. To a suspension of 60% sodium hydride <0.56 g,
0.014 mol) in THF <25 ml) was added 2-amino-3-bromo-4-
trimethylsilylpyridine <3.3 g, 0.013 mol) in THF <25 ml)
under argon. The mixture was heated at 408C during
30 min, cooled to 2408C and methyl iodide <0.72ml,
0.014 mol) was added. The mixture was heated to room
temperature overnight and hydrolyzed, extracted with
CH2Cl2, dried over MgSO4 and the solvent removed under
reduced pressure to give a crude product which was puri®ed
by chromatography with EtOAc±hexane <5:95) as eluent.
Yield: 80%; mp 578C; 1H NMR d <ppm): 8.05 <d, Jˆ4.8 Hz,
1H, ArH), 6.54 <d, Jˆ4.8 Hz, 1H, ArH), 5.18 <br s, 1H, NH),
3.01 <d, Jˆ4.8 Hz, 3H, CH3), 0.37 <s, 9H, Si<CH3)3); 13C
NMR d <ppm): 154.6, 150.1 <2£arom C), 145.4, 118.4
<2£arom CH), 113.5 <arom C), 28.8 <CH3), 21.1
<Si<CH3)3); <Found: C, 41.53; H, 5.86; N, 10.63. C12H12N4
requires C, 41.70; H, 5.83; N, 10.81%).
2-Alkylamino-3-halogenopyridines
1
were prepared
according to a literature method11 using sodium hydride in
THF, from 2-amino-3-halogenopyridines. The latters were
synthesized by modi®cation of a literature procedure12
described by Turner. 1,2-Dibromoethane was used as
brominating agent to give 1a, hexachloroethane as chlori-
nating agent to afford 1b and iodine as iodinating agent to
give 1c.
6.3. General procedure for the preparation of 2-
methylamino-3-halogeno-4-trimethylsilylpyridines 4a,b
6.3.1. N-/3-Bromo-4-trimethylsilylpyridin-2-yl)-2,2-di-
methylpropanamide. The corresponding N-<3-bromo-2-
pyridyl)-2,2-dimethylpropanamide <4 g, 0.015 mol) in
THF <40 ml) was slowly added to a cold <2758C) solution
of LDA <0.060 mol) and Me3SiCl <7.89 ml, 0.060 mol) in
THF <40 ml). The resulting mixture was stirred for 2h at
2758C. The reaction was then hydrolyzed at room tempera-
ture, extracted with CH2Cl2. The extract was dried over
MgSO4 and the solvent removed under reduced pressure
to give a crude product which was puri®ed by chromato-
graphy with EtOAc±hexane <15:85) as eluent. Yield: 89%;
mp 1558C; MS <IS) 329 <79Br, M1H1), 331 <81Br, M1H1);
1H NMR d <ppm): 8.40 <d, Jˆ4.7 Hz, 1H, ArH),.11 <s, 1H,
6.3.6. N-/3-Chloro-4-trimethylsilylpyridin-2-yl)-N-methyl-
amine 4b. The previous procedure gave the title compound
1
in 79%. Oil; H NMR d <ppm): 8.03 <d, Jˆ4.7 Hz, 1H,
ArH), 6.59 <d, Jˆ4.7 Hz, 1H, ArH), 5.11 <br s, 1H, NH),
3.04 <d, Jˆ4.7 Hz, 3H, CH3), 0.36 <s, 9H, Si<CH3)3); 13C
NMR d <ppm): 154.2, 147.1 <2£arom C), 144.7, 121.9
<2£arom CH), 117.3 <arom C), 28.6 <CH3), 21.1

S. Blanchard et al. / Tetrahedron 58 52002) 3513±3524
3519
<Si<CH3)3); <Found: C, 50.32; H, 7.18; N, 12.72. C12H12N4
requires C, 50.33; H, 7.04; N, 13.04%).
<q, Jˆ7 Hz, 2H, CH2), 3.32<q, Jˆ7 Hz, 2H, CH2), 1.21±
1.13 <m, 6H, 2£CH3); 13C NMR d <ppm): 147.4 <2£arom
C), 137.8 <2£arom CH), 130.7 <2£arom C), 116.5, 113.4
<4£arom CH), 38.2, 34.8 <2£CH2), 11.6, 9.2<2 £CH3);
<Found: C, 70.13; H, 6.82; N, 23.57. C14H16N4 requires C,
69.97; H, 6.71; N, 23.31%).
6.4. General procedure for arynic cyclization of 2-
alkylamino-3-bromopyridines 1 into dihydrodipyrido-
pyrazines 2 and 3
6.4.5. 5,10-Dibutyl-5,10-dihydrodipyrido[2,3-b:2,3-e]-
pyrazine 2c. Puri®ed by chromatography with EtOAc±
hexane <2:98) as eluent. Mp 948C; H NMR d <ppm): 7.33
The reactions were performed with the complex base
NaNH2±tBuONa.
1
<d, Jˆ4.5 Hz, 2H, ArH), 6.36 <m, 2H, ArH), 6.26 <d,
Jˆ7.5 Hz, 2H, ArH), 3.62 <t, Jˆ7 Hz, 4H, 2£CH2N),
1.60±1.52<m, 4H, 2 £CH2), 1.47±1.40 <m, 4H, 2£CH2),
0.99 <t, Jˆ7 Hz, 6H, 2£CH3); 13C NMR d <ppm): 145.2
<2£arom C), 137.9 <2£arom CH), 131.0 <2£arom C),
116.3, 114.7 <4£arom CH), 41.0 <2£CH2N), 26.9, 20.1
<4£CH2), 13.9 <2£CH3); <Found: C, 72.92; H, 8.21; N,
18.73. C18H24N4 requires C, 72.94; H, 8.16; N, 18.90%).
5a) Preparation of the complex base. To a magnetically
stirred suspension of 7 mol equiv. of NaNH2 <8.19 g,
210 mmol) in THF <20 ml) was dropwise added at room
temperature 2mol equiv. of tBuOH <4.44 g, 60 mmol) in
THF <1 ml) under nitrogen ¯ush. After completion of the
addition, the mixture was heated at 458C for 2h.
5b) Arynic cyclization. To the complex base thus prepared,
1 mol equiv. of 2-alkylamino-3-halogenopyridine <30 mmol)
in THF <60 ml) was dropwise added at 08C. The reaction
mixture was allowed to warm to room temperature and was
monitored by gas chromatography <GC) <capillary HP1,
6 m). After completion, the reaction mixture was hydrolyzed
at 08C, extracted with CH2Cl2, the extract dried over MgSO4,
and the solvent removed under reduced pressure.
6.4.6. 5,10-Dibutyl-5,10-dihydrodipyrido[2,3-b:3,2-e]-
pyrazine 3c. Puri®ed by chromatography with EtOAc±
hexane <2:98) as eluent. Mp 1158C; H NMR d <ppm):
1
7.35 <d, Jˆ5 Hz, 2H, ArH), 6.36 <dd, J1ˆ5 Hz,
J2ˆ7.6 Hz, 2H, ArH), 6.16 <d, Jˆ7.6 Hz, 2H, ArH), 3.93
<t, Jˆ7.5 Hz, 2H, CH2N), 3.18 <t, Jˆ8 Hz, 2H, CH2N),
1.62±1.58 <m, 2H, CH2), 1.54±1.50 <m, 2H, CH2), 1.44±
1.38 <m, 4H, 2£CH2), 1.02±0.93 <m, 6H, 2£CH3); 13C NMR
d <ppm): 147.8 <2£arom C), 137.9 <2£arom CH), 131.2
<2£arom C), 116.5, 113.7 <4£arom CH), 43.8, 39.7
<2£CH2N), 28.6, 25.8, 20.2, 20.0 <4£CH2), 14.0 <2£CH3);
<Found: C, 72.97; H, 8.25; N, 18.77. C18H24N4 requires C,
72.94; H, 8.16; N, 18.90%).
6.4.1. 5,10-Dimethyl-5,10-dihydrodipyrido[2,3-b:2,3-e]-
pyrazine 2a. Puri®ed by chromatography with EtOAc±
hexane <10:90) as eluent. Mp 1528C; H NMR d <ppm):
1
7.40 <d, Jˆ4.5 Hz, 2H, ArH), 6.45 <dd, J1ˆ4.5 Hz,
J2ˆ7 Hz, 2H, ArH), 6.30 <d, Jˆ7 Hz, 2H, ArH), 3.05 <s,
1
6H, 2£CH3); H NMR d <ppm): 147.7 <2£arom C), 138.2
<2£arom CH), 132.1 <2£arom C), 116.6, 115.2<4 £arom
CH), 28.7 <2£CH3N); <Found: C, 67.76; H, 5.53; N,
26.32. C12H12N4 requires C, 67.91; H, 5.70; N, 26.40%).
6.4.7. 5,10-Bis/1-phenylethyl)-5,10-dihydrodipyrido[2,3-
b:2,3-e]pyrazine 2d. Puri®ed by chromatography with
1
EtOAc±hexane <5:95) as eluent. Mp 1538C; H NMR d
<ppm): 7.46±7.25 <m, 12H, ArH), 6.40±6.17 <m, 6H,
4£ArH12£CH), 1.84 <t, Jˆ6.6 Hz, 6H, 2£CH3); 13C
NMR d <ppm): 149.4, 149.3, 140.8, 140.7 <4£arom C),
138.3, 138.3 <2£arom CH), 129.4, 129.3 <2£arom C),
128.6, 126.5, 126.1, 119.6, 119.5, 116.3 <14£arom CH),
50.6, 50.5 <2£CH), 14.9 <2£CH3); <Found: C, 79.48; H,
6.31; N, 14.36. C26H24N4 requires C, 79.56; H, 6.16; N,
14.27%).
6.4.2. 5,10-Dimethyl-5,10-dihydrodipyrido[2,3-b:3,2-e]-
pyrazine 3a. Puri®ed by chromatography with EtOAc±
hexane <5:95) as eluent. Mp 1508C; H NMR d <ppm):
7.45 <d, Jˆ4.5 Hz, 2H, ArH), 6.45 <dd, J1ˆ4.5 Hz,
J2ˆ7 Hz, 2H, ArH), 6.30 <d, Jˆ7 Hz, 2H, ArH), 3.25 <s,
3H, CH3N), 2.80 <s, 3H, CH3N); 13C NMR d <ppm): 148.6
<2£arom C), 138.2<2 £arom CH), 132.0 <2£arom C), 116.9,
114.4 <4£arom CH), 30.7, 27.7 <2£CH3N); <Found: C,
67.60; H, 5.61; N, 26.08. C12H12N4 requires C, 67.91; H,
5.70; N, 26.40%).
1
6.4.8. N,N-Dimethyl-2-{10-[2-/dimethylamino)ethyl]-5,
10-dihydrodipyrido[2,3-b:2,3-e]pyrazin-5-yl}-1-ethana-
mine 2e. Puri®ed by chromatography with Et3N±hexane
6.4.3. 5,10-Diethyl-5,10-dihydrodipyrido[2,3-b:2,3-e]-
pyrazine 2b. Puri®ed by chromatography with EtOAc±
1
<50:50) as eluent. Mp 1448C; H NMR d <ppm): 7.30 <dd,
1
hexane <3:97) as eluent. Mp 1458C; H NMR d <ppm):
J1ˆ1.8 Hz, J2ˆ4.3 Hz, 2H, ArH), 6.39 <m, 4H, ArH), 3.76
<t, Jˆ7.5 Hz, 4H, 2£CH2N), 2.45 <t, Jˆ7.5 Hz, 4H, 2£CH2),
3.32<s, 1H2, 4 £CH3); 13C13C NMR d <ppm): 146.7
<2£arom C), 138.2<2 £arom CH), 130.7 <2£arom C),
116.5, 114.8 <4£arom CH), 53.8 <2£CH2N), 45.7
<4£CH3), 39.8 <2£CH2N); <Found: C, 66.01; H, 7.95; N,
25.67. C18H26N6 requires C, 66.23; H, 8.03; N, 25.74%).
7.33 <d, Jˆ5 Hz, 2H, ArH), 6.37 <m, 2H, ArH), 6.30 <d,
Jˆ7.5 Hz, 2H, ArH), 3.69 <q, Jˆ7 Hz, 4H, 2£CH2), 1.16
<t, Jˆ7 Hz, 6H, 2£CH3); 13C NMR d <ppm): 146.9 <2£arom
C), 138.0 <2£arom CH), 130.7 <2£arom C), 116.4, 114.5
<4£arom CH), 36.0 <2£CH2), 10.3 <2£CH3); <Found: C,
70.04; H, 6.64; N, 23.29. C14H16N4 requires C, 69.97; H,
6.71; N, 23.31%).
6.4.9. N,N-Dimethyl-3-{10-[3-/dimethylamino)propyl]-
5,10-dihydrodipyrido[2,3-b:2,3-e]pyrazin-5-yl}-1-pro-
panamine 2f. Puri®ed by chromatography with Et3N as
6.4.4. 5,10-Diethyl-5,10-dihydrodipyrido[2,3-b:3,2-e]-
pyrazine 3b. Puri®ed by chromatography with EtOAc±
1
1
hexane <3:97) as eluent. Mp 1318C; H NMR d <ppm):
eluent. Mp 1008C; H NMR d <ppm): 7.28 <m, 2H, ArH),
6.34 <m, 4H, ArH), 3.64 <t, Jˆ7 Hz, 4H, 2£CH2), 2.35 <t,
7.37 <d, Jˆ5 Hz, 2H, ArH), 6.38 <dd, J1ˆ5 Hz,
Jˆ7 Hz, 4H, 2£CH2), 2.25 <s, 12H, 4£CH3), 1.75 <m, 4H,
J2ˆ7.4 Hz, 2H, ArH), 6.22 <d, Jˆ7.4 Hz, 2H, ArH), 4.00

3520
S. Blanchard et al. / Tetrahedron 58 52002) 3513±3524
2£CH2); 13C NMR d <ppm): 147.1 <2£arom C), 138.1
<2£arom CH), 131.1 <2£arom C), 116.5, 114.8 <4£arom
CH), 57.0 <2£CH2N), 45.5 <4£CH3), 39.6 <2£CH2N), 23.2
<2£CH2); <Found: C, 67.64; H, 8.64; N, 23.64. C20H30N6
requires C, 67.76; H, 8.53; N, 23.71%).
6.70 <dd, Jˆ5.3, 1.2Hz, 1H, ArH), 6.54 <dd, Jˆ1.2Hz,
1H, ArH), 5.23 <br s, 1H, NH), 2.87 <d, Jˆ5.0 Hz, 3H,
CH3); <Found: C, 38.83; H, 3.86; N, 14.74. C6H7BrN2
requires C, 38.53; H, 3.77; N, 14.98%).
6.5.2. N-/3-Bromopyridin-2-yl)-N-methylamine 1a. 1H
NMR d <ppm): 8.09 <dd, Jˆ5.0, 1.5 Hz, 1H, ArH), 7.59
<dd, Jˆ7.6, 1.5 Hz, 1H, ArH), 6.44 <dd, Jˆ7.6, 5.0 Hz,
1H, ArH), 5.03 <br s, 1H, NH), 3.03 <d, Jˆ4.7 Hz, 3H,
6.4.10. N,N-Dimethyl-3-{10-[3-/dimethylamino)propyl]-
5,10-dihydrodipyrido[2,3-b:3,2-e]pyrazin-5-yl}-1-pro-
panamine 3f. Puri®ed by chromatography with Et3N as
1
1
eluent. Mp 848C; H NMR d <ppm): 7.33 <d, Jˆ5 Hz, 2H,
CH3); H NMR d <ppm): 154.9 <arom C), 146.4, 138.9,
ArH), 6.38±6.33 <dd, J1ˆ5 Hz, J2ˆ7 Hz, 2H, ArH), 6.28±
6.26 <d, Jˆ7 Hz, 2H, ArH), 3.96 <t, Jˆ7.5 Hz, 2H, 2£CH2),
3.28 <t, Jˆ7.5 Hz, 2H, CH2), 2.43±2.28 <m, 4H, 2£CH2),
2.26 <s, 6H, 2£CH3), 2.24 <s, 6H, 2£CH3), 1.84 <m, 2H,
CH2), 1.67 <m, 2H, CH2); 13C NMR d <ppm): 147.6
<2£arom C), 138.0 <2£arom CH), 131.2<2 £arom C),
116.6, 113.8 <4£arom CH), 57.3, 56.5 <2£CH2N), 45.5,
45.4 <4£CH3), 41.9, 38.2<2 £CH2N), 24.4, 22.3 <2£CH2);
<Found: C, 67.67; H, 8.45; N, 23.64. C20H30N6 requires C,
67.76; H, 8.53; N, 23.71%).
112.6 <3£arom CH), 105.3 <arom C), 28.4 <CH3); <Found:
C, 38.40; H, 3.91; N, 15.11. C6H7BrN2 requires C, 38.53; H,
3.77; N, 14.98%).
6.5.3. N-/4-Bromopyridin-2-yl)-N-methyl-N-[2-/methyl-
amino)pyridin-3-yl]amine 6. Oil; H NMR d <ppm): 8.17
1
<dd, Jˆ5.0, 1.5 Hz, 1H, ArH), 8.03 <d, Jˆ5.3 Hz, 1H, ArH),
7.27 <dd, Jˆ1.3, 1.5 Hz, 1H, ArH), 6.79 <dd, Jˆ5.3, 1.3 Hz,
1H, ArH), 6.63 <dd, Jˆ7.3, 5.0 Hz, 1H, ArH), 6.37 <d,
Jˆ1.3 Hz, 1H, ArH), 4.70 <br s, 1H, NH), 3.31 <s, 3H,
CH3), 3.00 <d, Jˆ4.7 Hz, 3H, CH3); 13C NMR d <ppm):
159.1, 156.0 <2£arom C), 148.6, 147.2, 135.4 <3£arom
CH), 133.1, 126.2 <2£arom C), 116.8, 112.7, 110.9
<3£arom CH), 36.9, 28.2 <2£CH3); <Found: C, 49.54; H,
4.66; N, 18.63. C12H13BrN4 requires C, 49.16; H, 4.47; N,
19.11%).
6.4.11. 5,10-Bis[2-/tetrahydro-2Hpyran-2-yloxy)ethyl]-
5,10-dihydrodipyrido[2,3-b:2,3-e]pyrazine 2g. Puri®ed
by chromatography with EtOAc±hexane <30:70). Mp
1
1108C; H NMR d <ppm): 7.30 <d, Jˆ4.5 Hz, 2H, ArH),
6.60 <d, Jˆ8 Hz, 2H, ArH), 6.37 <dd, J1ˆ4.5 Hz,
J2ˆ8 Hz, 2H, ArH), 4.64 <m, 2H, CHO), 3.91±3.84 <m,
8H, aliph H), 3.72±3.64 <m, 2H, aliph H), 3.53±3.47 <m,
2H, aliph H), 1.80±1.51 <m, 12H, aliph H); 13C NMR d
<ppm): 146.7 <2£arom C), 138.0 <2£arom CH), 131.2
<2£arom C), 116.4, 115.7, 98.8, 98.7 <4£arom CH12£aliph
CH), 63.6, 61.9, 61.9, 41.7, 30.3, 25.2, 19.1 <12£CH2);
<Found: C, 65.03; H, 7.33; N, 12.93. C24H32N4O4 requires
C, 65.43; H, 7.32; N, 12.72%).
6.5.4. N-/3-Chloropyridin-2-yl)-N-methylamine 1b. The
previous procedure with 4b gave only the title compound
1
in 80% yield. Oil; H NMR d <ppm): 8.05 <dd, Jˆ5.0,
1.5 Hz, 1H, ArH), 7.41 <dd, Jˆ7.5, 1.5 Hz, 1H, ArH),
6.50 <dd, Jˆ7.5, 5.0 Hz, 1H, ArH), 5.01 <br s, 1H, NH),
3.04 <d, Jˆ4.7 Hz, 3H, CH3); 13C NMR d <ppm): 154.6
<arom C),146.0, 137.5, 115.4 <3£arom CH), 112.4 <arom
C), 28.4 <CH3); <Found: C, 50.22; H, 4.67; N, 19.63.
C6H7BrN2 requires C, 50.54; H, 4.95; N, 19.65%).
6.4.12. 5-[2-/Tetrahydro-2Hpyran-2-yloxy)ethyl]-5,10-
dihydrodipyrido[2,3-b:2,3-e]pyrazine 2h. Puri®ed by
chromatography with EtOAc±hexane <50:50). H NMR d
1
6.6. Formylation of 2 and 3
<ppm): 7.31 <d, Jˆ4.5 Hz, 1H, ArH), 7.18 <d, Jˆ4.5 Hz, 1H,
ArH), 6.60 <d, Jˆ7.5 Hz, 1H, ArH), 6.39±6.28 <m, 2H,
ArH), 6.17 <d, Jˆ7.5 Hz, 1H, ArH), 4.65 <t, Jˆ1 Hz, 1H,
aliph CH), 3.95±3.82<m, 4H, aliph H), 3.69±3.62<m, 1H,
aliph H), 3.55±3.47 <m, 1H, aliph H), 1.84±1.53 <m, 6H,
aliph H); 13C NMR d <ppm): 147.7, 146.5 <2£arom C),
138.9, 137.3 <2£arom CH), 131.3, 129.3 <2£arom C),
116.7, 116.7, 116.5, 116.2<4 £arom CH), 99.0 <aliph CH),
63.98, 62.17, 41.85, 30.54, 25.38, 19.35 <6£CH2); <HRMS
calcd for C17H20N4O2 312.1581, found: 312.1569).
5a) Preparation of the Vilsmeier reagent. POCl3 <9.32ml,
100 mmol) was added dropwise at 08C to DMF <17.7 ml,
230 mmol) under magnetic stirring and nitrogen
atmosphere. Then, the mixture was allowed to warm quickly
to room temperature and stirred for 15 min.
5b) Formylation. The Vilsmeier reagent thus prepared was
added to a re¯uxing solution of dihydrodipyridopyrazine 2
or 3 <10 mmol) in 1,2-dichloroethane or chloroform
<100 ml). After completion, the reaction mixture was cooled
at 08C and KOH 3 M <120 ml) was added dropwise. The
mixture was heated to re¯ux for 3 h, then diluted with water
<200 ml) and extracted with CH2Cl2. The extract was
washed with water and the organic layer dried over
MgSO4. The solvent was removed under reduced
pressure.
6.5. Reactions of 4a,b with ¯uoride ions
To a solution of Bu4NF <1 M in THF) <1.3 or 2.5 equiv.) in
Ê
THF <6 ml/1 mmol) under molecular sieves 4 A was added
dropwise 4a or 4b <1 equiv.) in THF <6 ml/1 mmol). The
mixture was stirred 1 h at 2208C, 08C or room temperature,
diluted with ethyl acetate and washed with NaHCO3 <sat).
The organic phase was dried over MgSO4 and the solvent
removed under reduced pressure to give a mixture of several
products. Compounds 2 and 3 were obtained as traces and
identi®ed.
6.6.1. 5,10-Dimethyl-5,10-dihydrodipyrido[2,3-b:2,3-e]-
pyrazine-2-carbaldehyde 12a. Puri®ed by chromato-
graphy with EtOAc±hexane <30:70) as eluent. Mp 1768C;
1
IR <KBr), nmax1682<C vO) cm21; H NMR d <ppm): 9.61
<s, 1H, CHO), 7.46 <d, Jˆ4.5 Hz, 2H, ArH), 7.16 <d,
Jˆ8.1 Hz, 1H, ArH), 6.56 <dd, J1ˆ4.5 Hz, J2ˆ7.6 Hz, 1H,
ArH), 6.44 <d, Jˆ7.6 Hz, 1H, ArH), 6.36 <d, Jˆ8.1 Hz, 1H,
6.5.1. N-/4-Bromopyridin-2-yl)-N-methylamine 5. Mp
888C; H NMR d <ppm): 6.87 <d, Jˆ5.3 Hz, 1H, ArH),
1

S. Blanchard et al. / Tetrahedron 58 52002) 3513±3524
3521
1
ArH), 3.14 <s, 3H, CH3N), 3.13 <s, 3H, CH3N); 13C NMR d
<ppm): 190.8 <CHO), 147.5, 145.9, 143.0 <3£arom C), 138.7
<arom CH), 137.2, 131.7 <2£arom C), 120.5, 118.1, 116.3,
113.9 <4£arom CH), 29.1, 28.7 <2£CH3); <Found: C, 65.07;
H, 5.14; N, 22.91. C13H12N4O requires C, 64.99; H, 5.03; N,
23.32%).
3H, CH3N), 2.88 <s, 3H, CH3N); H NMR d <ppm): 190.7
<CHO), 148.2, 147.7, 142.7 <3£arom C), 139.7 <arom CH),
136.6, 130.3 <2£arom C), 120.2, 117.1, 115.9, 113.0
<4£arom CH), 31.2, 27.6 <2£CH3); <Found: C, 65.28; H,
5.00; N, 23.63. C13H12N4O requires C, 64.99; H, 5.03; N,
23.32%).
6.6.2. 5,10-Dimethyl-5,10-dihydrodipyrido[2,3-b:2,3-e]-
pyrazine-3-carbaldehyde 13a. Puri®ed by chromato-
graphy with EtOAc±hexane <30:70) as eluent. Mp 1798C;
IR <KBr), nmax 1673 <CvO) cm21; 1H NMR d <ppm): 9.62
<s, 1H, CHO), 7.77 <d, Jˆ1 Hz, 1H, ArH), 7.50 <dd,
J1ˆ2Hz, J2ˆ4 Hz, 1H, ArH), 6.62<s, 1H, ArH), 6.49 <m,
2H, ArH), 3.17 <s, 3H, CH3), 3.09 <s, 3H, CH3); 13C NMR d
<ppm): 188.7 <CHO), 151.8 <arom C), 147.7 <arom C), 146.8
<arom C), 140.2 <arom CH), 132.7, 129.9, 127.2 <3£arom
C), 117.2, 116.7, 109.6 <3£arom CH), 29.2, 28.7 <2£CH3);
<Found: C, 65.11; H, 5.22; N, 23.20. C13H12N4O requires C,
64.99; H, 5.03; N, 23.32%).
6.6.7. 5,10-Dibutyl-5,10-dihydrodipyrido[2,3-b:3,2-e]-
pyrazine-2-carbaldehyde 14c. Puri®ed by chromatography
with EtOAc±hexane <30:70) as eluent. Mp 1088C; IR <KBr),
1
nmax 1689 <CvO) cm21; H NMR d <ppm): 9.58 <s, 1H,
CHO), 7.45 <d, Jˆ4.5 Hz, 1H, ArH), 7.11 <d, Jˆ8.1 Hz,
1H, ArH), 6.41 <dd, J1ˆ4.5 Hz, J2ˆ7.6 Hz, 1H, ArH),
6.30 <d, Jˆ7.6 Hz, 1H, ArH), 6.17 <d, Jˆ8.1 Hz, 1H,
ArH), 3.99 <t, Jˆ7.6 Hz, 2H, CH2N), 3.24 <t, Jˆ7.6 Hz,
2H, CH2N), 1.68±1.39 <m, 8H, 4£CH2), 1.03±0.95 <m,
6H, 2£CH3); 13C NMR d <ppm): 191.2<CHO), 147.6,
147.3, 142.8 <3£arom C), 139.7 <arom CH), 136.0, 129.6
<2£arom C), 119.2, 116.8, 115.5, 112.5 <4£arom CH), 44.1,
39.7, 28.3, 26.0, 20.1, 19.9 <6£CH2), 13.9, 13.7 <2£CH3);
<Found: C, 70.51; H, 7.38; N, 17.02. C19H24N4O requires C,
70.34; H, 7.46; N, 17.27%).
6.6.3. 5,10-Dibutyl-5,10-dihydrodipyrido[2,3-b:2,3-e]-
pyrazine-2-carbaldehyde 12c. Puri®ed by chromatography
with EtOAc±hexane <20:80) as eluent. Mp 958C; IR <KBr),
1
nmax 1690 <CvO) cm21; H NMR d <ppm): 9.57 <s, 1H,
6.6.8. 5,10-Dibutyl-5,10-dihydrodipyrido[2,3-b:3,2-e]-
pyrazine-2,7-dicarbaldehyde 15c. Puri®ed by chromato-
graphy with EtOAc±hexane <30:70) as eluent. Mp 1598C;
IR <KBr), nmax 1682<C vO) cm21; 1H NMR d <ppm): 9.63
<s, 1H, CHO), 9.62<s, 1H, CHO), 7.85 <s, 1H, ArH), 7.25 <d,
Jˆ7.9 Hz, 1H, ArH), 6.62<s, 1H, ArH), 6.36 <d, Jˆ7.9 Hz,
1H, ArH), 4.09 <t, Jˆ7 Hz, 2H, CH2N), 3.31 <t, Jˆ7 Hz, 2H,
CH2N), 1.67±1.39 <m, 8H, 4£CH2), 1.06±0.96 <m, 6H,
2£CH3); 13C NMR d <ppm): 190.8, 188.5 <CHO), 152.0
<arom C), 148.5 <arom CH), 145.5, 142.9, 135.4, 130.3,
127.1 <5£arom C), 119.9, 114.2, 110.1 <3£arom CH),
44.3, 40.6 <2£CH2N), 28.2, 25.7, 20.0, 19.8 <4£CH2),
13.8, 13.6 <2£CH3); <Found: M, 352.1894. C20H24N4O2
requires M, 352.1894).
CHO), 7.38 <d, Jˆ4.5 Hz, 1H, ArH), 7.10 <d, Jˆ7.6 Hz,
1H, ArH), 6.47 <dd, J1ˆ4.5 Hz, J2ˆ7.6 Hz, 1H, ArH),
6.36 <d, Jˆ7.6 Hz, 1H, ArH), 6.26 <d, Jˆ7.6 Hz, 1H,
ArH), 3.86 <m, 4H, 2£CH2), 1.56 <m, 4H, 2£CH2), 1.43
<m, 4H, 2£CH2), 1.00 <m, 6H, 2£CH3); 13C NMR d
<ppm): 191.0 <CHO), 147.0, 145.5, 142.7 <3£arom C),
138.4 <arom CH), 136.3, 130.8 <2£arom C), 119.4,
118.0, 115.8, 113.4 <4£arom CH), 41.5, 41.0, 26.9, 26.8,
20.0 <6£CH2), 13.8 <2£CH3); <Found: C, 70.78; H, 7.65;
N, 17.52. C19H24N4O requires C, 70.34; H, 7.46; N,
17.27%).
6.6.4. 5,10-Dibutyl-5,10-dihydrodipyrido[2,3-b:2,3-e]-
pyrazine-3-carbaldehyde 13c. Puri®ed by chromatography
with EtOAc±hexane <20:80) as eluent. Mp 1178C; IR <KBr),
6.6.9. 5,10-Dibutyl-5,10-dihydrodipyrido[2,3-b:3,2-e]-
pyrazine-2,8-dicarbaldehyde 16c. Puri®ed by chromato-
graphy with EtOAc±hexane <30:70) as eluent. Mp 1568C;
IR <KBr), nmax 1686 <CvO) cm21; 1H NMR d <ppm): 9.63
<s, 2H, 2£CHO), 7.16 <d, Jˆ8.1 Hz, 2H, ArH), 6.34 <d,
Jˆ8.1 Hz, 2H, ArH), 4.07 <t, Jˆ7.6 Hz, 2H, CH2N), 3.31
<t, Jˆ7.6 Hz, 2H, CH2N), 1.67±1.42<m, 8H, 4 £CH2), 1.05±
0.98 <m, 6H, 2£CH3); 13C NMR d <ppm): 191.3 <2£CHO),
147.4, 144.0, 134.4 <6£arom CH), 118.5, 114.6 <4£arom
CH), 44.6, 39.9, 28.1, 26.1, 20.1, 19.9 <6£CH2), 13.9, 13.7
<2£CH3); <Found: C, 67.78; H, 6.94; N, 15.57. C20H24N4O2
requires C, 68.16; H, 6.86; N, 15.90%).
1
nmax 1682<C vO) cm21; H NMR d <ppm): 9.55 <s, 1H,
CHO), 7.68 <s, 1H, ArH), 7.43 <m, 1H, ArH), 6.51 <s, 1H,
ArH), 6.40 <m, 2H, ArH), 3.67±3.59 <m, 4H, 2£CH2N),
1.55 <m, 4H, 2£CH2), 1.42<m, 4H, 2 £CH2), 0.98 <m, 6H,
2£CH3); 13C NMR d <ppm): 188.5 <CHO), 151.6 <arom C),
147.8 <arom CH), 146.6 <arom C), 140.1 <arom CH), 131.7,
128.8, 127.1 <3£arom C), 116.8, 116.5, 109.0 <3 arom CH),
41.8, 41.3 <2£CH2N), 27.1, 26.6, 20.0 <6£CH2), 13.8, 13.7
<2£CH3); <Found: C, 70.32; H, 7.51; N, 17.42. C19H24N4O
requires C, 70.34; H, 7.46; N, 17.27%).
6.6.5. 5,10-Bis[3-/dimethylamino)propyl]-5,10-dihydro-
dipyrido[2,3-b:2,3-e]pyrazine-2
Puri®ed by chromatography with Et3N as eluent. Oil; IR
<thin ®lm), nmax 1681 <CvO) cm21; m/z <CI, CH4) 383
<M11).
carbaldehyde
12f.
6.6.10. 5,10-Bis[3-/dimethylamino)propyl]-5,10-dihydro-
dipyrido[2,3-b:3,2-e]pyrazine-2-carbaldehyde 14f. Puri-
®ed by chromatography with Et3N as eluent. Oil; IR <thin
®lm), nmax 1688 <CvO) cm1; 1H NMR d <ppm): 9.58 <s, 1H,
CHO), 7.44±6.34 <m, 5H, ArH), 4.03 <m, 2H, CH2), 3.37
<m, 2H, CH2), 2.44 <m, 2H, CH2), 2.35 <m, 2H, CH2), 2.28
<s, 6H, 2£CH3), 2.22 <s, 6H, 2£CH3), 1.83 <m, 2H, CH2),
1.68 <m, 2H, CH2); 13C NMR d <ppm): 190.8 <CHO), 143.2,
146.8, 142.5 <3£arom C), 139.6 <arom CH), 136.0, 129.4
<2£arom C), 119.3, 116.8, 115.5, 112.6 <4£arom CH), 57.0,
55.9 <2£CH2), 45.4, 45.1 <4£CH3), 41.9, 38.3, 23.8, 22.3
<4£CH2); m/z <CI, CH4) 383 <M11).
6.6.6. 5,10-Dimethyl-5,10-dihydrodipyrido[2,3-b:3,2-e]-
pyrazine-2-carbaldehyde 14a. Puri®ed by chromato-
graphy with EtOAc±hexane <50:50) as eluent. Mp 1578C;
IR <KBr), nmax 1684 <CvO) cm21; 1H NMR d <ppm): 9.63
<s, 1H, CHO), 7.53 <d, Jˆ5 Hz, 1H, ArH), 7.17 <d, Jˆ8 Hz,
1H, ArH), 6.49 <dd, J1ˆ5 Hz, J2ˆ7.6 Hz, 1H, ArH), 6.39 <d,
Jˆ7.6 Hz, 1H, ArH), 6.28 <d, Jˆ8 Hz, 1H, ArH), 3.32<s,

3522
S. Blanchard et al. / Tetrahedron 58 52002) 3513±3524
6.7. Nitration of 2 and 3
as eluent. Mp 1108C; IR <KBr), nmax 1516, 1486, 1441
1
<NO2) cm21; H NMR d <ppm): 7.45 <m, 1H, ArH), 7.42
<d, Jˆ8.1 Hz, 1H, ArH), 6.52<m, H2, ArH), 6.34 <d,
Jˆ8.1 Hz, 1H, ArH), 3.83 <m, 4H, 2£CH2), 2.42±2.33 <m,
16H, 2£CH2, 4£CH3); 13C NMR d <ppm): 148.4 <arom C±
NO2), 145.6, 145.0 <2£arom C), 139.5 <arom CH), 137.3,
128.9 <2£arom C), 118.6, 116.8, 144.1 <4£arom CH), 53.9,
53.7 <2£CH2), 45.7 <4£CH3), 40.8, 40.1 <2£CH2); <Found:
C, 58.03; H, 6.91; N, 26.34. C18H25N7O2 requires C, 58.21;
H, 6.78; N, 26.40%).
Method A. The reactions were performed according to the
literature.10
Method B. <a) Salt formation. To a solution of 1 mol equiv.
of 2 or 3 in CH2Cl2 <50 ml for 6 mmol) was added the
amount of oxalic acid indicated in Table 3. After stirring
during 20 h the salt was either ®ltered or the solvent
removed under vacuum and the solid used without other
puri®cation.
6.7.5. N1,N1-Dimethyl-2-{10-[2-/dimethylamino)propyl]-
2-nitro-5,10-dihydrodipyrido[2,3-b:2,3-e]pyrazin-5-yl}-
1-propanamine 17f. Puri®ed by chromatography with Et3N
as eluent. Mp 958C; IR <KBr), nmax 1517, 1485, 1440
<b) Nitration. The salt thus prepared was placed in CH3NO2
<50 ml for 6 mmol) and the amount of KNO2 indicated in
Table 3 was added. The reaction was monitored by TLC or
gas chromatography. After completion KOH 1 M <150 ml
for 6 mmol) was added and the mixture extracted with
CH2Cl2. The organic layer was dried over Na2SO4 and the
solvent removed under reduced pressure.
1
<NO2) cm21; H NMR d <ppm): 7.41 <m, 2H, ArH), 6.54±
6.39 <m, 3H, ArH), 3.70 <m, 4H, 2£CH2N), 2.41±2.33 <m,
4H, 2£CH2N), 2.26 <s, 6H, 2£CH3), 2.24 <s, 6H, 2£CH3),
1.74 <m, 4H, 2£CH2); 13C NMR d <ppm):148.1 <arom C±
NO2), 145.4, 144.8 <2£arom C), 139.0 <arom CH), 137.3,
129.8 <2£arom C), 118.2, 116.5, 113.9, 113.6 <4£arom CH),
59.5, 56.3 <2£CH2N), 45.2<4 £CH3), 40.2<2 £CH2N), 22.9,
22.6 <2£CH2); <Found: M, 399.2369. C20H29N7O2 requires
M, 399.2377).
6.7.1. 5,10-Dimethyl-2-nitro-5,10-dihydrodipyrido[2,3-
b:2,3-e]pyrazine 17a. Puri®ed by chromatography with
EtOAc±hexane <30:70) as eluent. Mp 2128C; IR <KBr),
1
nmax 1545, 1522, 1491 <NO2) cm21; H NMR d <ppm):
7.49 <d, Jˆ5 Hz, 1H, ArH), 7.47 <d, Jˆ8 Hz, 1H, ArH),
6.58 <dd, J1ˆ5 Hz, J2ˆ7.6 Hz, 1H, ArH), 6.48 <d,
Jˆ7.6 Hz, 1H, ArH), 6.28 <d, Jˆ8 Hz, 1H, ArH), 3.13 <s,
3H, CH3N), 3.14 <s, 3H, CH3N); 13C NMR d <ppm): 148.6
<C±NO2), 147.4, 147.1 <2£arom C), 140.3 <arom CH),
137.9, 130.2<2 £arom C), 117.8, 116.7, 114.3, 113.5
<4£arom CH), 31.8, 28.1 <2£CH3); <Found: C, 55.77; H,
4.44; N, 27.00. C12H11N5O2 requires C, 56.03; H, 4.31; N,
27.22%).
6.7.6. N1,N1-Dimethyl-2-{10-[2-/dimethylamino)propyl]-
2,7-dinitro-5,10-dihydrodipyrido[2,3-b:2,3-e]pyrazin-5-
yl}-1-propanamine 18f. Puri®ed by chromatography with
Et3N±methanol <70:30) as eluent. Oil; IR <thin ®lm), nmax
1
1513, 1473, 1448 <NO2) cm21; H NMR d <ppm): 7.52<d,
Jˆ8.1 Hz, 2H, ArH), 6.71 <d, Jˆ8.1 Hz, 2H, ArH), 3.80 <m,
4H, 2£CH2), 2.43±2.35 <m, 4H, 2£CH2), 2.26 <s, 12H,
4£CH3), 1.80 <m, 4H, 2£CH2); 13C NMR d <ppm): 148.8
<arom C±NO2), 145.2<2 £arom C), 136.5 <2£arom CH),
116.6 <2£arom C), 115.0 <4£arom CH), 56.4 <2£CH2),
45.3 <4£CH3), 40.4 <2£CH2), 22.9 <2£CH2); <Found: C,
53.87; H, 6.58; N, 24.92. C20H28N8O4 requires C, 54.04;
H, 6.35; N, 25.21%).
6.7.2. 5,10-Dibutyl-2-nitro-5,10-dihydrodipyrido[2,3-b:
2,3-e]pyrazine 17c. Puri®ed by chromatography with
EtOAc±hexane <20:80) as eluent. Mp 1118C; IR <KBr),
1
nmax 1517, 1485, 1438 <NO2) cm21; H NMR d <ppm):
7.41±7.38 <m, 2H, ArH), 6.54±6.49 <dd, J1ˆ4.9 Hz,
J2ˆ7.9 Hz, 1H, ArH), 6.43 <d, Jˆ7.9 Hz, 1H, ArH), 6.20
<d, Jˆ8.6 Hz, 1H, ArH), 3.67 <m, 4H, 2£CH2N), 1.61±1.38
<m, 8H, 4£CH2), 1.00 <m, 6H, 2£CH3); 13C NMR d <ppm):
148.2<arom C±NO 2), 145.8, 145.2<2 £arom C), 139.1
<arom CH), 137.3, 129.9 <2£arom C), 118.3, 116.6, 114.0,
113.6 <4£arom CH), 41.8, 41.4 <2£CH2N), 26.8 <2£CH2),
20.0 <2£CH2), 13.8 <2£CH3); <Found: C, 63.27; H, 6.83; N,
20.39. C18H23N5O2 requires C, 63.32; H, 6.79; N, 20.51%).
6.7.7. 5,10-Dimethyl-2-nitro-5,10-dihydrodipyrido[2,3-
b:3,2-e]pyrazine 19a. Puri®ed by chromatography with
EtOAc±hexane <40:60) as eluent. Mp 2068C; IR <KBr),
1
nmax 1513, 1444 <NO2) cm21; H NMR d <ppm): 7.56 <d,
Jˆ5 Hz, 1H, ArH), 7.49 <d, Jˆ8.6 Hz, 1H, ArH), 6.56 <dd,
J1ˆ5 Hz, J2ˆ8 Hz, 1H, ArH), 6.46 <d, Jˆ8 Hz, 1H, ArH),
6.24 <d, Jˆ8.6 Hz, 1H, ArH), 3.32<s, 3H, CH N), 2.93 <s,
3
3H, CH3N); 13C NMR d <ppm): 140.4 <arom C), 137.9,
130.2<4 £arom CH), 117.9, 116.8, 114.4, 113.5 <4£arom
C), 31.8, 28.1 <2£CH3); <Found: C, 55.72; H, 4.54;
N, 26.94. C12H11N5O2 requires C, 56.03; H, 4.31; N,
27.22%).
6.7.3. 5,10-Dibutyl-2,7-nitro-5,10-dihydrodipyrido[2,3-
b:2,3-e]pyrazine 18c. Puri®ed by chromatography with
EtOAc±hexane <20:80) as eluent. Mp 2218C; IR <KBr),
1
nmax 1520, 1469, <NO2) cm21; H NMR d <ppm): 7.54 <d,
6.7.8. 5,10-Dimethyl-2,8-dinitro-5,10-dihydrodipyrido-
[2,3-b:3,2-e]pyrazine 20a. Puri®ed by chromatography
with EtOAc±hexane <40:60) as eluent. Mp .2708C; IR
Jˆ8.1 Hz, 2H, ArH), 6.47 <d, Jˆ8.1 Hz, 2H, ArH), 3.97 <t,
Jˆ7 Hz, 4H, 2£CH2N), 1.70±1.45 <m, 8H, 4£CH2), 1.04 <t,
Jˆ7 Hz, 6H, 2£CH3); 13C NMR d <ppm): 149.2<2 £arom
C±NO2), 144.9, 136.6 <4£arom C), 116.7, 115.4 <4£arom
CH), 42.9 <2£CH2N), 27.2, 20.4 <4£CH2), 14.1 <2£CH3);
<Found: C, 55.79; H, 5.85; N, 21.45. C18H22N6O4 requires C,
55.95; H, 5.74; N, 21.75%).
1
<KBr), nmax 1528, 1447 <NO2) cm21; H NMR d <ppm):
7.58 <d, Jˆ8.3 Hz, 2H, ArH), 6.67 <d, Jˆ8.3 Hz, 2H,
ArH), 3.12<s, 6H, 2 £CH3); <Found: M, 302.0756.
C12H10N6O4 requires M, 302.0758).
6.7.9. 5,10-Dibutyl-2-nitro-5,10-dihydrodipyrido[2,3-b:
3,2-e]pyrazine 19c. Puri®ed by chromatography with
EtOAc±hexane <30:70) as eluent. Mp 1288C; IR <KBr),
6.7.4. N1,N1-Dimethyl-2-{10-[2-/dimethylamino)ethyl]-
2-nitro-5,10-dihydrodipyrido[2,3-b:2,3-e]pyrazin-5-yl}-
1-ethanamine 17e. Puri®ed by chromatography with Et3N

S. Blanchard et al. / Tetrahedron 58 52002) 3513±3524
3523
n
max 1518, 1493, 1448 <NO2) cm21; 1H NMR d <ppm): 7.48
Institut de Recherches Servier <Suresnes) are gratefully
acknowledged for assistance with the mass analyses. We
thank Professor M. Nardelli <Parma University), Professor
<d, Jˆ4.9 Hz, 1H, ArH), 7.38 <d, Jˆ8.5 Hz, 1H, ArH), 6.46
<m, 1H, ArH), 6.37 <d, Jˆ7.3 Hz, 1H, ArH), 6.12<d,
Jˆ8.5 Hz, 1H, ArH), 3.95 <t, Jˆ6.5 Hz, 2H, CH2), 3.26 <t,
Jˆ6.5 Hz, 2H, CH2), 1.64±1.38 <m, 8H, 4£CH2), 1.05±0.94
<m, 6H, 2£CH3); 13C NMR d <ppm): 148.0, 146.3, 146.2
<3£arom C), 140.0 <arom CH), 136.9, 129.1 <2£arom C),
117.4, 116.1, 114.1, 112.5 <4£arom CH), 44.3, 40.0, 27.8,
25.8, 19.9, 19.7 <6£CH2), 13.6, 13.5 <2£CH3); <Found: C,
63.60; H, 6.67; N, 20.46. C18H23N5O2 requires C, 63.32; H,
6.79; N, 20.51%).
Â
J. M. Leger <Bordeaux II University) and Professor C. Jarry
<Bordeaux II University) for considerable help in structural
determination.
References
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[2,3-b:3,2-e]pyrazine 20c. Puri®ed by chromatography
with EtOAc±hexane <30:70) as eluent. Mp 2028C; IR
1
<KBr), nmax 1521, 1461 <NO2) cm21; H NMR d <ppm):
7.47 <d, Jˆ8 Hz, 2H, ArH), 6.37 <d, Jˆ8 Hz, 2H, ArH),
4.03 <t, Jˆ7.3 Hz, 2H, CH2N), 3.35 <t, Jˆ7.3 Hz, 2H,
CH2N), 1.69±0.97 <m, 14H, aliph H); 13C NMR d <ppm):
149.6 <arom C±NO2), 146.0, 135.4 <4£arom C), 115.9,
114.2<4 £arom CH), 45.5, 41.2<2 £CH2N), 27.9, 26.2,
20.1, 20.1 <4£CH2), 13.9, 13.8 <3£CH3); <Found: C,
55.81; H, 5.85; N, 21.60. C18H22N6O4 requires C, 55.95;
H, 5.74; N, 21.75%).
6.7.11. N1,N1-Dimethyl-2-{10-[2-/dimethylamino)pro-
pyl]-2-nitro-5,10-dihydrodipyrido[2,3-b:3,2-e]pyrazin-
5-yl}-1-propanamine 19f. Puri®ed by chromatography
with Et3N as eluent. Mp 1238C; IR <KBr), nmax 1526,
1
1449 <NO2) cm21; H NMR d <ppm): 7.46 <d, Jˆ4.5 Hz,
1H, ArH), 7.36 <d, Jˆ8 Hz, 1H, ArH), 6.53 <d, Jˆ7.6 Hz,
1H, ArH), 6.48 <m, 1H, ArH), 6.33 <d, Jˆ8 Hz, 1H, ArH),
3.97 <t, Jˆ7.5 Hz, 2H, CH2N), 3.38 <t, Jˆ7.5 Hz, 2H,
CH2N), 2.40 <t, Jˆ7 Hz, 2H, CH2), 2.33 <t, Jˆ7 Hz, 2H,
CH2), 2.26 <s, 6H, 2£CH3), 2.24 <s, 6H, 2£CH3), 1.80 <m,
2H, CH2), 1.69 <m, 2H, CH2); 13C NMR d <ppm): 147.9
<arom C±NO2), 146.1, 145.9 <2£arom C), 139.9 <arom
CH), 137.1, 129.1 <2£arom C), 117.4, 116.2, 114.1, 112.7
<4£arom CH), 56.9, 55.7 <2£CH2N), 45.1, 45.1 <4£CH3),
42.1, 38.8 <2£CH2N), 23.5, 22.2 <2£CH2); <Found: C,
60.41; H, 7.52; N, 24.28. C20H29N7O2 requires C, 60.13;
H, 7.32; N, 24.54%).
Â
Curr. Pharm. Des. 1997, 3, 265. <s) Pierre, A.; Atassi, G.;
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6.7.12. N1,N1-Dimethyl-2-{10-[2-/dimethylamino)pro-
pyl]-2,8-dinitro-5,10-dihydrodipyrido[2,3-b:3,2-e]pyra-
zin-5-yl}-1-propanamine 20f. Puri®ed by chromatography
with Et3N as eluent. Mp 160±1708C; IR <KBr), nmax1529,
1
1462<NO ) cm21; H NMR d <ppm): 7.47 <d, Jˆ8.1 Hz,
2
2H, ArH), 6.64 <d, Jˆ8.1 Hz, 2H, ArH), 4.05 <t,
Jˆ6.1 Hz, 4H, 2£CH2), 3.51 <t, Jˆ7.1 Hz, 2H, CH2N),
2.46 <m, 2H, CH2), 2.35 <m, 2H, CH2), 2.29 <s, 6H,
2£CH3), 2.26 <s, 6H, 2£CH3), 1.85 <m, 2H, CH2), 1.73
<m, 2H, CH2); 13C NMR d <ppm): 148.8 <arom C±NO2),
144.2, 136.5 <4£arom CH), 116.6 <2£arom C), 115.0
<2£arom C), 56.4 <2£CH2), 45.3 <4£CH3), 40.4
<2£CH2N), 22.9 <2£CH2); <Found: M, 444.2233.
C20H28N8O4 requires M, 444.2228).
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Acknowledgements
The Orleans group thanks ADIR <Courbevoie) for ®nancial
support. Dr P. H. Lambert and Dr J. P. Volland from the

3524
S. Blanchard et al. / Tetrahedron 58 52002) 3513±3524
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