Efficient and selective method for the synthesis of dihydrodipyridopyrazines based on the pd-catalysed animation of halopyridines

Article abstract of DOI:10.1002/ejoc.200900404

A novel methodology for the efficient: and selective synthesis of isomers A and B of N-substituted dihydrodipyridopyrazines was developed. The key step is the intermolecular coupling of aminopyridines and halonitropyridines/dihalopyr- idines in the presen

Full text of DOI:10.1002/ejoc.200900404

FULL PAPER
DOI: 10.1002/ejoc.200900404
Efficient and Selective Method for the Synthesis of Dihydrodipyridopyrazines
Based on the Pd-Catalysed Amination of Halopyridines
Oana-Irina Patriciu,[a,b] Adriana-Luminita Fînaru,[b] Stéphane Massip,[c]
¸
Jean-Michel Léger,[c] Christian Jarry,[c] and Gérald Guillaumet*[a]
Keywords: Dihydrodipyridopyrazines / Pd catalysis / Cross-coupling / Reduction / Cyclization
A novel methodology for the efficient and selective synthesis
of isomers A and B of N-substituted dihydrodipyridopyr-
azines was developed. The key step is the intermolecular
coupling of aminopyridines and halonitropyridines/dihalopyr-
idines in the presence of a catalyst system composed of
Pd(OAc)2/Xantphos. This system displays good functional
substituted N,NЈ-dipyridinylamines produces monosubsti-
tuted dihydrodipyridopyrazines, which can easily be alkyl-
ated to give a large variety of unsymmetrical 5,10-dialkyl-
5,10-dihydrodipyrido[2,3-b:2Ј,3Ј-e]pyrazines (isomers A) and
5,10-dialkyl-5,10-dihydrodipyrido[2,3-b:3Ј,2Ј-e]pyrazines
(isomers B).
group compatibility and the desired C–N bond-forming pro- (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
cess proceeds in good yields. Cyclization of suitable nitro-
Germany, 2009)
Introduction
A few years ago a new family of planar nitrogen hetero-
cycles – the dihydrodipyridopyrazines (DHDPPs) 1 and 2
(Figure 1) – was reported.[1,2]
Scheme 1.
Figure 1. Dihydrodipyridopyrazine isomers A and B.
Hetarynic cyclizations of the corresponding 2-alk-
ylamino-3-halogenopyridines 3 (Scheme 1) in the presence
of the complex base NaNH2/tBuONa make it possible to
synthesize many symmetrical dihydrodipyridopyrazines
without great difficulties of implementation, but with a
major disadvantage lying in the production of mixtures of
two isomers, together with total reaction yields that did not
exceed 50%.[2,3]
These compounds show interesting chemical proper-
ties[4–6] and give very encouraging results with regard to
their antitumor activity.[7] Wishing to avoid the disadvan-
tages described above, we set out to synthesize each isomer
separately.
In our efforts directed toward the construction of the di-
hydrodipyridopyrazine cycles (isomers A and B), we envi-
sioned a sequence in which in either case a palladium-cata-
lysed cross-coupling reaction or a nucleophilic aromatic
substitution would provide an intermediate that would then
be reduced and cyclized to give the desired dihydrodipyr-
idopyrazine (see Schemes 2 and 3).
[a] Institut de Chimie Organique et Analytique (ICOA), UMR
CNRS 6005, Université d’Orléans,
B. P. 6759, rue de Chartres, 45067 Orléans Cedex 2, France
Fax: +33-2-38417281
E-mail: gerald.guillaumet@univ-orleans.fr
[b] Laboratorul de Sinteza Organica si Analiza Structurala, Uni-
˘
˘ ¸
˘
˘
versitatea din Baca˘u,
In connection with our interest in the preparation of di-
hydrodipyridopyrazine isomers B we have recently reported
that the classical method through a nucleophilic displace-
ment of a leaving group in the presence of LiHMDS as the
157, Calea Maras¸es¸ti, 600115 Bacau, România
˘ ˘
˘
[c] EA 4138, Pharmacochimie, Université Victor Segalen Bordeaux 2,
146, rue Leo Saignat, 33076 Bordeaux Cedex, France
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200900404.
Eur. J. Org. Chem. 2009, 3753–3764
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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G. Guillaumet et al.
FULL PAPER
For these reasons, in the field of aromatic C–N bond
formation, we turned our attention to palladium-catalysed
amination.
This paper presents a mild method for the efficient and
selective synthesis of dihydrodipyridopyranizic isomers
based on Pd0-catalysed coupling of aminopyridines with
substituted halonitropyridines and/or of aminopyridines
with dihalopyridines.
The catalytic amination of aryl halides reported by Buch-
wald[9] and Hartwig[10] represents an alternative to classical
methods applied in the synthesis of a wide variety of poten-
tially useful compounds and has allowed the preparation of
compounds inaccessible by other known synthetic routes.[11]
There are some examples of Pd-catalysed N-arylations with
pyridinyl halides[12] achieved by use of DPPP, BINAP,
DPPF, P(tBu)3 or Xantphos as ligands. In the case of
electron-poor aminopyridines,[13] ligands such as
DCHPDMAB or Xantphos are required. The couplings in-
volving heteroaromatic cores represent a true challenge be-
cause the two partners involved are particularly deficient
in electrons. However, only a few examples of N-arylation
between two deactivated partners have been reported.[14]
This underlines the difficulty in coupling electron-poor ami-
nopyridines and hence shows the utility of particularly elec-
tron-rich ligands. On the other hand, our laboratory[15] has
recently reported very efficient conditions for the amination
of 2-chloropyridine with 3-amino-1,2,4-triazine in the pres-
ence of Pd(OAc)2 as palladium source, Xantphos as the li-
Scheme 2. Retrosynthetic analysis of the dihydrodipyridopyrazine
isomers A.
Scheme 3. Retrosynthetic analysis of the dihydrodipyridopyrazine
isomers B.
base and THF as the solvent led to the formation of the
compound resulting from oxidative nucleophilic substitu- gand and a large excess of K2CO3 as base in 1,4-dioxane
tion of hydrogen (ONSH).[8]
with good results.
Table 1. Palladium-catalysed N-arylation of aminopyridines with halo-nitropyridines.
[a] Method A: Pd(OAc)2 (10 mol-%), Xantphos (20 mol-%), K2CO3 (1.5 equiv.), 1,4-dioxane, nitropyridine (1 equiv.), aminopyridine
(1.2 equiv.). Method B: Pd(OAc)2 (15 mol-%), Xantphos (30 mol-%), K2CO3 (1.5 equiv.), 1,4-dioxane, nitropyridine (1 equiv.), aminopyr-
idine (1.2 equiv.). [b] 30% of starting amine was recovered.
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Pd-Catalysed Synthesis of Dihydrodipyridopyrazines
Table 2. Palladium-catalysed amination of dihalopyridines.
[a] Method A: Pd(OAc)2 (10 mol-%), Xantphos (20 mol-%), K2CO3 (1.5 equiv.), 1,4-dioxane, halopyridine (1 equiv.), aminopyridine
(1.2 equiv.). Method B: Pd(OAc)2 (15 mol-%), Xantphos (30 mol-%), K2CO3 (1.5 equiv.), 1,4-dioxane, halopyridine (1 equiv.), aminopyr-
idine (1.2 equiv.). Method C: Pd(OAc)2 (15 mol-%), Xantphos (30 mol-%), K2CO3 (1.5 equiv.), 1,4-dioxane, halopyridine (1.2 equiv.),
aminopyridine (1 equiv.). [b] Starting amine (65%) was recovered. [c] Starting amine (35%) was recovered. [d] Starting amine (84%) was
recovered. [e] Starting halopyridine (32%) was recovered. [f] Starting amine (75%) was recovered. [g] Starting amine (30%) was recovered.
[h] Starting halopyridine (20%) was recovered. [i] Starting amine (72%) was recovered. [j] Starting amine (40%) was recovered.
The best results were obtained with 3-aminopyridine (5,
Results and Discussion
Table 1, Entries 1 and 5), 3-amino-2-fluoropyridine (6a)[16]
and 3-amino-2-chloropyridine (6b, Table 1, Entries 2 and 3)
Palladium-Catalysed Synthesis of Substituted N,NЈ-Dipyr-
idinylamines
as amine source.
In the case of a coupling reaction with 3-amino-2-bro-
mopyridine (6c) under conditions similar to those pre-
viously used with 4, we observed the formation of the de-
sired N-arylation product 13c, but in poor yield (15%) and
accompanied by the recovery of a proportion of the starting
product. The reaction yield was not significantly improved
after an increase in the amount of Pd(OAc)2 to 15 mol-%
with the same Xantphos/Pd(OAc)2 ratio of 2:1 (Method B;
Table 1, Entry 4).
Our approach to N,NЈ-dipyridinylamines was inspired by
the advances described above and is outlined in Tables 1
and 2.
Initially, halonitropyridines 4 and 7 react with aminopyr-
idines 5 and 6a–c (Table 1) in the presence of Pd(OAc)2
(10 mol-%) as the palladium source, Xantphos (20 mol-%)
as the ligand, K2CO3 (1.5 equiv.) as the base and 1,4-diox-
ane as the solvent (Method A).
It was possible to isolate single crystals of compounds
Reaction times varied between 3–24 h with yields ranging 13a and 15, thus permitting their analysis by X-ray crystal-
from 15 to 94%.
lography.
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G. Guillaumet et al.
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To complete our study of the palladium-catalysed amin- duction under Bellamy’s conditions[18] (SnCl2·2H2O, in eth-
ation, we also examined couplings of the dihalogenopyrid- anol at reflux for 5 h), but the corresponding amino deriva-
ines 8a and 8b[17] with a range of aminopyridines (5, 9a, tive was not isolated. We directly obtained the aromatiza-
9b, 10a, 10b and 11) under the same conditions. The most tion product 19 in yields ranging from 30 to 43%
interesting results are shown in Table 2.
(Scheme 4).
As would be expected, not all the dihalogenopyridines
behave identically under the reaction conditions used.
Treatment of 3-bromo-2-chloropyridine (8a) with 2-amino-
3-nitropyridine (10a) in the presence either of 10 mol-%
Pd(OAc)2 (Method A) or 15 mol-% Pd(OAc)2 (Method B)
(Table 2, Entry 3) gave the coupling product 13b in a mod-
erate yield (42%).
Optimization of these reactions was attempted. Chang-
ing the bromide atom for an iodine atom did not lead to a
higher yield of isolated 13b (Table 2, Entry 3 vs. 7,
Method A). To obtain the best results, high catalyst load-
ings [Pd(OAc)2 15 mol-%, Xantphos 30 mol-%] were used
(Method B), but we observed only a slight optimization of
the yield (Table 2, Entry 7). With use of an excess of haloge-
nated substrate [1 equiv. of 2-amino-3-nitropyridine (10a)
and 1.2 equiv. of 2-chloro-3-iodopyridine (8b)] with
Pd(OAc)2 (15 mol-%) as palladium source, Xantphos
(30 mol-%) as ligand and K2CO3 (1.5 equiv.) as base in 1,4-
dioxane (Method C), compound 13b – the potential precur-
sor of isomer A of DHDPP – was obtained in excellent
yield (90%, Table 2, Entry 7).
Under the same conditions (Method C), replacement of
2-amino-3-nitropyridine (10a) with 3-amino-2-nitropyridine
(11) as amine component gave compound 15, the potential
precursor of the dihydrodipyridopyrazine isomer B, in 85%
yield (Table 2, Entry 10).
We observed that the Pd-catalysed amination reactions
between 2-chloro-3-iodopyridine (8b) and the amino-nitro-
pyridines 10a and 11 led to 13b and 15 in yields higher than
those obtained in the coupling reactions of 4 with 6b and of
7 with 6b, respectively (Table 2, Entries 7 and 10 vs. Table 1,
Entries 3 and 6).
Scheme 4.
Amine 18 was isolated in 68% yield, however, when the
reduction of the nitro group of 13b in the presence of
SnCl2·2H2O in ethanol was carried out at room tempera-
ture for 44 h. The structure of 18 was also confirmed by X-
ray crystallography.
For the intramolecular cyclization, simple heating at re-
flux in ethanol was investigated. Under these conditions,
though, compound 19 was isolated in only 30% yield. Pd-
catalysed cyclization of 18 under the conditions of
Method A [Pd(OAc)2 (10 mol-%), Xantphos (20 mol-%),
K2CO3 (1.5 equiv.) in 1,4-dioxane], however, gave access to
19 in good yield (79%) (Scheme 4).
The unambiguous assignment of the structure of aroma-
tized compound 19 was established by X-ray crystallogra-
phy (Figure 2).
It should be noted that no reaction occurred when the N-
methylated aminopyridines 9b and 10b were used as amine
sources, with the starting materials being recovered
(Table 2, Entries 2, 4, 6 and 8).
This work confirms that both electron-withdrawing and
-donating substituents are tolerated under these conditions.
Compounds 13a–c and 15 are potential substrates for the
selective synthesis of dihydrodipyridopyrazine isomers A
and B, respectively.
Synthesis of DHDPP Isomers A
As a second part of our work, using 13 and 15 as starting
materials we examined the possibility of obtaining the N-
substituted dihydrodipyridopyrazine isomers A and B selec-
tively.
Figure 2. X-ray structure of compound 19.
In view of the above results, we reasoned that a prelimi-
nary N-alkylation would be the most convenient method to
Because the 20% yield of 13c made the use of this com- stabilize the molecule before the reduction step. We there-
pound rather unattractive, however, we decided to employ fore first allowed 13b to react with methyl iodide or butyl
13a and 13b as starting substrates.
iodide in the presence of sodium hydride in anhydrous
The nitro groups in 13a and 13b, the potential precursors DMF (Scheme 5). The alkylated products 20 and 21, iso-
of dihydrodipyridopyrazine isomers A, were subjected to re- lated in 93% and 73% yields, respectively, were than treated
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Pd-Catalysed Synthesis of Dihydrodipyridopyrazines
Scheme 5.
with SnCl2·2H2O in ethanol at reflux for 5 h to give the
Treatment of crude 22 with sodium hydride in DMF and
desired dihydrodipyridopyrazines 22 and 23. However, be- then with different halo derivatives resulted in the prepara-
cause these compounds seem to be unstable to column tion of the various 5,10-dialkyl-5,10-dihydrodipyrido[2,3-
chromatography, the monosubstituted isomers 22 and 23 b:2Ј,3Ј-e]pyrazines 26a–d (DHDPP isomers A) in excellent
were employed without preliminary purification in the next yields (Scheme 6).
reactions.
It should be noted that the monosubstituted isomers 22
and 23 each possessed a free amine, and so were easily sub-
stitutable for the preparation of unsymmetrically substi-
tuted N,N-dialkyl dihydrodipyridopyrazines.
Compounds 22 and 23 were subjected, without prior pu-
rification, to a classic acylation procedure (PivCl, Et3N,
dichloromethane at room temperature). The pivaloyl deriv-
atives 24 and 25 were synthesized in very good yields calcu-
lated over two steps (Scheme 5).
The structures of 21 and 24 were studied by X-ray crys-
tallography (Figure 3).
Scheme 6.
5,10-Dimethyl-5,10-dihydrodipyrido[2,3-b:2Ј,3Ј-e]pyrazine
(26a), obtained in 90% yield over two steps, has the same
spectroscopic data as those recorded for the compound iso-
lated by an arynic sequence.[2]
Synthesis of DHDPP Isomers B
In the case of compound 15, the potential precursor of
dihydrodipyridopyrazine isomers B, similar treatment with
SnCl2·2H2O, in ethanol at room temperature or at reflux
led directly to the corresponding aromatization product 27
in 55% and 69% yields, respectively (Scheme 7). In contrast
with the successful reaction of 13b at room temperature to
give 18, in the case of 15 the intermediate compound with
Figure 3. X-ray structure of compound 24.
Eur. J. Org. Chem. 2009, 3753–3764
a reduced nitro group was not detected.
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G. Guillaumet et al.
FULL PAPER
Scheme 7.
This result and our success in the synthesis of isomers A
encouraged us to proceed by the same methodology for the
synthesis of isomers B from the starting compound 15.
The 5,10-dialkyl-5,10-dihydrodipyrido[2,3-b:3Ј,2Ј-e]pyr-
azines 30a–d were prepared as outlined in Scheme 8. N-
Methylation of 15 with sodium hydride and methyl iodide
in DMF provided product 28 in 83% yield. The structure
of compound 28 was unambiguously established by X-ray
crystallography. The desired DHDPP B isomers 30a–d were
isolated in good yields after reduction/cyclization of 28 in
the presence of SnCl2·2H2O in ethanol at reflux for 5 h,
which was followed by N-alkylation of crude 29 with vari-
ous halo derivatives.
Figure 4. X-ray structure of compound 30d.
Conclusions
Specific syntheses of each of the unsymmetrically substi-
tuted dihydrodipyridopyrazine isomers A and B have been
The spectroscopic data for product 30a, obtained in 87% completed. The novel strategy that was developed for their
yield over two steps, are the same as those recorded for the syntheses featured Pd-catalysed reactions as key steps.
5,10-dimethyl-5,10-dihydrodipyrido[2,3-b:3Ј,2Ј-e]pyrazine
We found that palladium-catalysed coupling reactions
between aminopyridines and either nitropyridines or di-
synthesized by the arynic sequence.[2]
The structure of 10-benzyl-5-methyl-5,10-dihydrodipyr- halopyridines in the presence of Pd(OAc)2 as catalyst and
ido[2,3-b:3Ј,2Ј-e]pyrazine (30d) was unambiguously estab- Xantphos as ligand, together with K2CO3 and dry 1,4-diox-
lished by X-ray crystallography. The ORTEP drawing of the ane, provided various N,NЈ-dipyridinylamines in good
crystal structure of compound 30d (Figure 4) shows that yields. This method has reasonable generality and compati-
two independent molecules exist in the unit. They present bility with base-sensitive functional group.
some differences in the plane angles’ values between pyr-
From suitable nitro-substituted N,NЈ-dipyridinylamines,
azine moiety and phenyl group [67.1(2)° for up molecule a substitution–reduction–cyclization–substitution sequence
and 71.6(2)° for down molecule].
allows easy and selective access to unsymmetrical 5,10-di-
Scheme 8.
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Pd-Catalysed Synthesis of Dihydrodipyridopyrazines
ether/ethyl acetate 10:0Ǟ9:1) to provide the desired compound 7
(0.54 mg, 30% yield) as yellow crystals; m.p. 100–101 °C. 1H NMR
(250 MHz, CDCl3, 27 °C): δ = 8.50 (dd, J = 4.6, 1.3 Hz, 1 H), 8.41
alkyl-5,10-dihydrodipyrido[2,3-b:2Ј,3Ј-e]pyrazines and 5,10-
dialkyl-5,10-dihydrodipyrido[2,3-b:3Ј,2Ј-e]pyrazines in very
good yields.
(dd, J = 7.9, 1.3 Hz, 1 H), 7.32 (dd, J = 7.9, 4.6 Hz, 1 H) ppm. 13
C
NMR (62.9 MHz, CDCl3, 27 °C): δ = 160.8 (Cq), 151.0 (CH),
147.9 (CH), 128.0 (CH), 81.6 (Cq) ppm. IR (ATR): ν = 1572,
˜
1528 cm–1. MS: m/z = 251.00 [M + H]+. HRMS: calcd. for
Experimental Section
C5H4IN2O2 [M + H]+ 250.9317; found 250.9321.
General: All air-sensitive experiments were performed under argon.
Dioxane was distilled from sodium benzophenone ketyl prior to
use. DMF was purified by distillation over CaH2 and stored under
an inert atmosphere over 4 Å molecular sieves. Dichloromethane
was distilled from calcium hydride under argon prior to use. Petro-
leum ether, where used, had a boiling range of 40–60 °C. All com-
mercially available reagents were used without further purification
unless otherwise noted. 1H and 13C NMR spectra were recorded on
a Bruker Avance DPX 250 spectrometer (at 250 MHz and 63 MHz,
N-Methyl-3-nitropyridin-2-amine (10b): A mixture of 2-chloro-
3-nitropyridine (0.3 g, 1.89 mmol) and methylamine (20 mL,
39.74 mmol) in ethanol (20 mL) was heated at 130 °C for 8 h in an
autoclave. The mixture was hydrolysed, extracted with ethyl acetate
and dried with MgSO4, and the solvent was removed under reduced
pressure to give the crude product. This residue was purified by
flash chromatography on silica gel (petroleum ether/ethyl acetate
8:2) and the desired product 10b (0.26 g, 90% yield) was obtained
1
respectively) or on
a Bruker Avance II 400 spectrometer (at
as yellow crystals. H NMR (250 MHz, CDCl3, 27 °C): δ = 8.44–
400 MHz and 100 MHz, respectively), with TMS as an internal
standard. Chemical shifts (δ) are reported in parts per million
(ppm) and the coupling constants (J) are reported in Hertz (Hz).
IR spectra were recorded on a Thermo-Nicolet AVATAR 320
AEK0200713 spectrometer by the ATR technique (germanium
crystal) and are reported in cm–1. Flash column chromatography
was carried out with Merck 40–70 nm (230–400 mesh) silica gel un-
der nitrogen pressure. Thin-layer chromatography (TLC) was car-
ried out on aluminium sheets precoated with silica gel (Merck
60 F254). Low-resolution mass spectra (MS) were recorded on a
Perkin–Elmer SCIEX AOI 300 spectrometer. High-resolution mass
spectra (ESI-TOF) were recorded on a Q-Tof micro waters spec-
trometer. Melting points were determined on a Büchi 510 melting
point apparatus in open capillaries and are uncorrected. X-ray
analyses were carried out on a Bruker Enraf Nonius CAD4 instru-
ment with a Cu sealed tube for compounds 15, 18, 21 and 28. Other
X-ray analyses were carried out on a MSC-Rigaku R-axis MM007
instrument with a Cu rotating anode and an image plate[19] as de-
tector for compounds 13a, 19, 24 and 30d. The Shelxs[20] and
Shelxl[21] programs were used for structures determination and re-
finement.
8.37 (m, 2 H), 8.19 (brs, 1 H, NH), 6.63 (dd, J = 8.3, 4.5 Hz, 1 H),
3.16 (d, J = 4.9 Hz, 3 H, CH3) ppm. 13C NMR (62.9 MHz, CDCl3,
27 °C): δ = 155.9 (CH), 153.3 (Cq), 135.3 (CH), 128.4 (Cq), 111.6
(CH), 28.3 (CH ) ppm. IR (ATR): ν = 3285, 1420 cm–1. MS: m/z
˜
3
= 154.3 [M + H]+. HRMS: calcd. for C6H8N3O2 [M + H]+
154.1466; found 154.1469.
General Procedure for the Palladium-Catalysed N-Arylations:
A
round-bottomed flask flushed with nitrogen was charged
with Xantphos (20 mol-%) and anhydrous 1,4-dioxane
(0.02 mmolmL–1). After degassing, Pd(OAc)2 (10 mol-%) was in-
troduced and the mixture was stirred under nitrogen for 10 min. In
a second round-bottomed flask, the heteroaryl halide (1 equiv.), the
amine (1.2 equiv.) and K2CO3 (1.5 equiv.) were poured into anhy-
drous 1,4-dioxane (0.05 mmol halide per mL). The Pd(OAc)2/
Xantphos solution was transferred by cannula and the resulted
mixture was subsequently heated at reflux under argon with vigor-
ous stirring. The progress of the reaction was monitored by TLC.
After cooling, the residue was filtered off through a Celite pad and
washed with CH2Cl2 and MeOH. The solvent was evaporated and
the residue was purified by flash chromatography on silica gel to
afford the desired N,NЈ-dipyridinylamines.
Starting Materials
Method A: Pd(OAc)2 (10 mol-%), Xantphos (20 mol-%), K2CO3
(1.5 equiv.), 1,4-dioxane, halogenopyridine (1 equiv.), aminopyr-
idine (1.2 equiv.).
Preparation of the Starting Materials: The halopyridines and ami-
nopyridines were either commercially available (4, 5, 6b, 6c, 8a, 9a,
9b, 10a, 11) or were easily prepared from commercially available
materials by literature procedures (6a,[16] 8b[17]).
Method B: Pd(OAc)2 (15 mol-%), Xantphos (30 mol-%), K2CO3
(1.5 equiv.), 1,4-dioxane, halogenopyridine (1 equiv.), aminopyr-
idine (1.2 equiv.).
3-Iodo-2-nitropyridine (7): Compound 7 was prepared by a pro-
cedure reported by Kuethe[17] starting from 3-amino-2-nitropyr-
idine (11). A 250 mL flask was charged with HCl (5 , 10 mL) and
3-amino-2-nitropyridine (1.0 g, 7.188 mmol). This reaction mixture
was cooled to –5 °C and sodium nitrite (0.744 g, 10.782 mmol) in
H2O (7 mL) was added dropwise while the internal temperature
was maintained below 5 °C. After 10 min at –5 °C, KI (2.625 g,
15.841 mmol) in water (7 mL) was added dropwise while the in-
ternal temperature was maintained below 10 °C over the course
of addition. The reaction mixture was allowed to warm to room
temperature and EtOAc (15 mL) was added. The pH of the aque-
ous layer was adjusted to 11 by addition of NaOH solution (6 ),
the layers were separated, and the organic layer was washed with
Na2S2O3 (0.3 , 15 mL). The EtOAc layer was concentrated under
reduced pressure and the residue was redissolved in DMF (10 mL).
Water (30 mL) was added dropwise to the brown/reddish mixture
and the slurry was stirred for 30 min and filtered. The filter cake
was washed with water (2ϫ10 mL) and dried under vacuum. The
crude product was purified by column chromatography (petroleum
Method C: Pd(OAc)2 (15 mol-%), Xantphos (30 mol-%), K2CO3
(1.5 equiv.), 1,4-dioxane, halogenopyridine (1.2 equiv.), aminopyr-
idine (1 equiv.).
N-(3-Nitropyridin-2-yl)-N-(pyridin-3-yl)amine (12): This compound
was obtained by the General Procedure for palladium-catalysed N-
arylations – Method A, with 2-chloro-3-nitropyridine (4, 200 mg,
1.26 mmol) and 3-aminopyridine (5, 142 mg, 1.51 mmol). Purifica-
tion by flash chromatography on silica gel (petroleum ether/ethyl
acetate 7:3Ǟ5:5) afforded product 12 (256 mg, 94% yield) as dark
orange crystals; m.p. 100–102 °C. 1H NMR (400 MHz, CDCl3,
25 °C): δ = 10.09 (brs, 1 H, NH), 8.85 (d, J = 2.5 Hz, 1 H), 8.55
(dd, J = 8.3, 1.8 Hz, 1 H), 8.49 (dd, J = 4.5, 1.8 Hz, 1 H), 8.40 (dd,
J = 4.7, 1.3 Hz, 1 H), 8.17–8.14 (m, 1 H), 7.33 (dd, J = 8.3, 4.7 Hz,
1 H), 6.91 (dd, J = 8.3, 4.5 Hz, 1 H) ppm. 13C NMR (62.9 MHz,
CDCl3, 27 °C): δ = 155.0 (CH), 149.9 (Cq), 145.5 (CH), 143.8
(CH), 135.6 (CH), 134.9 (Cq), 129.2 (CH), 129.1 (Cq), 123.5 (CH),
114.9 (CH) ppm. IR (ATR): ν = 3327, 1604, 1573, 1497, 1478,
˜
Eur. J. Org. Chem. 2009, 3753–3764
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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3759

G. Guillaumet et al.
FULL PAPER
756 cm–1. MS: m/z = 217.00 [M + H]+. HRMS: calcd. for
7.44–7.38 (m, 2 H) ppm. 13C NMR (62.9 MHz, CDCl3, 27 °C): δ
= 147.4 (CH), 146.2 (CH), 142.3 (Cq), 138.3 (CH), 138.1 (Cq),
134.7 (Cq), 131.7 (CH), 130.3 (CH), 125.3 (CH), 124.4 (CH) ppm.
C10H9N4O2 [M + H]+ 217.0726; found 217.0737.
N-(2-Fluoropyridin-3-yl)-N-(3-nitropyridin-2-yl)amine (13a): This
compound was obtained by the General Procedure for the palla-
dium-catalysed N-arylations – Method A, with 2-chloro-3-nitro-
pyridine (4, 1.07 g, 6.68 mmol) and 3-amino-2-fluoropyridine (6a,
0.91 g, 8.12 mmol). Purification by flash chromatography on silica
gel (petroleum ether/ethyl acetate 9:1) afforded product 13a (1.36 g,
86% yield) as orange crystals; m.p. 130 °C. 1H NMR (400 MHz,
CDCl3, 25 °C): δ = 10.30 (brs, 1 H, NH), 8.91 (ddd, J = 8.1, 7.9,
1.7 Hz, 1 H), 8.59 (dd, J = 8.3, 1.7 Hz, 1 H), 8.54 (dd, J = 4.5,
IR (ATR): ν = 3348, 1604, 1490, 1237 cm–1. MS: m/z = 217.00 [M
˜
+ H]+. HRMS: calcd. for C10H9N4O2 [M + H]+ 217.0726; found
217.0731.
N-(2-Chloropyridin-3-yl)-N-(2-nitropyridin-3-yl)amine (15): This
compound was obtained by the General Procedure for the palla-
dium-catalysed N-arylations – Method C, with 3-amino-2-nitropyr-
idine (11, 1.0 g, 7.19 mmol) and 2-chloro-3-iodopyridine (8b,
2.065 g, 8.63 mmol). Purification by flash chromatography on silica
1.7 Hz, 1 H), 7.93 (dt, J = 4.8, 1.7 Hz, 1 H), 7.23 (dd, J = 7.9, gel (petroleum ether/ethyl acetate 8:2Ǟ7:3) afforded product 15
1
4.8 Hz, 1 H), 6.98 (dd, J = 8.3, 4.6 Hz, 1 H) ppm. 13C NMR (1.53 g, 85% yield) as a yellow-orange solid; m.p. 160–162 °C. H
(100.6 MHz, CDCl3, 25 °C): δ = 154.7 (CH), 154.5 (d, Cq, J =
234.4 Hz), 149.4 (Cq), 140.7 (d, J = 14.1 Hz, CH), 135.7 (CH),
131.8 (d, J = 2.5 Hz, CH), 129.9 (Cq), 122.5 (d, J = 24.5 Hz, Cq),
NMR (400 MHz, CDCl3, 27 °C): δ = 9.19 (brs, 1 H, NH), 8.29
(dd, J = 4.7, 1.6 Hz, 1 H), 8.14 (dd, J = 4.1, 1.4 Hz, 1 H), 7.74 (dd,
J = 7.9, 1.6 Hz, 1 H), 7.61 (dd, J = 8.5, 1.4 Hz, 1 H), 7.48 (dd, J
= 8.5, 4.1 Hz, 1 H), 7.34 (dd, J = 7.9, 4.7 Hz, 1 H) ppm. 13C NMR
121.8 (d, J = 4.0 Hz, CH), 115.4 (CH) ppm. IR (ATR): ν = 3315,
˜
1610, 1429, 1227, 755 cm–1. MS: m/z = 235.5 [M + H]+. HRMS: (100.6 MHz, CDCl3, 27 °C): δ = 145.9 (Cq), 145.8 (CH), 143.3
calcd. for C10H8FN4O2 [M + H]+ 235.0631; found 235.0627.
(Cq), 139.2 (CH), 136.1 (Cq), 132.6 (Cq), 131.2 (CH), 130.2 (CH),
125.8 (CH), 123.2 (CH) ppm. IR (ATR): ν = 3323, 1601, 1493,
˜
N-(2-Chloropyridin-3-yl)-N-(3-nitropyridin-2-yl)amine (13b): This
compound was obtained by the General Procedure for the palla-
dium-catalysed N-arylations – Method C, with 2-amino-3-nitropyr-
idine (10a, 1.00 g, 7.19 mmol) and 2-chloro-3-iodopyridine (8b,
2.065 g, 8.63 mmol). Purification by flash chromatography on silica
gel (petroleum ether/ethyl acetate 9:1ǞCH2Cl2/ethyl acetate 10:0,
9:1) afforded product 13b (1.62 g, 90% yield) as a yellow-orange
powder; m.p. 160 °C. 1H NMR (400 MHz, CDCl3, 25 °C): δ =
1415, 1247, 795 cm–1. MS: m/z = 253.00 (37Cl) [M + H]+, 251.00
(35Cl) [M + H]+. HRMS: calcd. for C10H8N4O235Cl [M + H]+
251.0336; found 251.0339.
N-(2-Chloropyridin-3-yl)-N-(pyridin-2-yl)amine (16): This com-
pound was obtained by the General Procedure for the palladium-
catalysed N-arylations – Method B, with 2-chloro-3-iodopyridine
(8b, 150 mg, 0.63 mmol) and 2-aminopyridine (9a, 70.7 mg,
10.66 (brs, 1 H, NH), 8.96 (dd, J = 8.2, 1.7 Hz, 1 H), 8.60 (dd, J 0.75 mmol). Purification by flash chromatography on silica gel (pe-
= 8.3, 1.8 Hz, 1 H), 8.53 (dd, J = 4.6, 1.8 Hz, 1 H), 8.14 (dd, J = troleum ether/ethyl acetate 9:1Ǟ8:2Ǟ7:3) afforded product 16
4.6, 1.7 Hz, 1 H), 7.30 (dd, J = 8.2, 4.6 Hz, 1 H), 6.99 (dd, J = 8.3, (98 mg, 76% yield) as brown crystals; m.p. 120 °C (ref.[14e] 117 °C).
4.6 Hz, 1 H) ppm. 13C NMR (100.6 MHz, CDCl3, 25 °C): δ = 160.1 The spectroscopic data (IR and NMR) were in accordance with
(Cq), 154.5 (CH), 149.2 (Cq), 143.5 (CH), 141.9 (Cq), 135.8 (CH), the literature values.[14e]
132.9 (Cq), 130.1 (CH), 122.9 (CH), 115.6 (CH) ppm. IR (ATR):
N-(2-Chloropyridin-3-yl)-N-(pyridin-3-yl)amine (17): This com-
ν = 3299, 1606, 1590, 1502, 775 cm–1. MS: m/z = 253.00 (37Cl) [M
˜
pound was obtained by the General Procedure for the palladium-
catalysed N-arylations – Method C, with 3-aminopyridine (5,
40 mg, 0.42 mmol) and 2-chloro-3-iodopyridine (8b, 122.1 mg,
0.51 mmol). Purification by flash chromatography on silica gel (pe-
troleum ether/ethyl acetate 9:1Ǟ7:3Ǟ4:6) afforded product 17
(49 mg, 56% yield) as a red-brown gum. 1H NMR (400 MHz,
CDCl3, 25 °C): δ = 8.52 (s, 1 H), 8.36 (d, J = 4.7 Hz, 1 H), 7.94
(dd, J = 4.6, 1.5 Hz, 1 H), 7.51 (dd, J = 8.2, 1.0 Hz, 1 H), 7.46 (dd,
J = 8.1, 1.5 Hz, 1 H), 7.30 (dd, J = 8.2, 4.7 Hz, 1 H), 7.13 (dd, J
+ H]+, 251.00 (35Cl) [M + H]+. HRMS: calcd. for C10H8N4O235Cl
[M + H]+ 251.0336; found 251.0329.
N-(2-Bromopyridin-3-yl)-N-(3-nitropyridin-2-yl)amine (13c): This
compound was obtained by the General Procedure for the palla-
dium-catalysed N-arylations – Method B, with 2-chloro-3-nitropyr-
idine (4, 100 mg, 0.63 mmol) and 3-amino-2-bromopyridine (6c,
131 mg, 0.76 mmol). Purification by flash chromatography on silica
gel (petroleum ether/ethyl acetate 9:1Ǟ7:3) afforded product 13c
1
(37 mg, 20% yield) as a yellow powder: M.p. 83–85 °C. H NMR = 8.1, 4.6 Hz, 1 H), 6.26 (brs, 1 H, NH) ppm. 13C NMR
(250 MHz, CDCl3, 27 °C): δ = 10.60 (brs, 1 H, NH), 8.70 (dd, J =
8.1, 1.6 Hz, 1 H), 8.60 (dd, J = 8.3, 1.6 Hz, 1 H), 8.52 (dd, J = 4.6, (CH), 139.4 (Cq), 137.0 (Cq), 136.9 (Cq), 127.5 (CH), 124.1 (CH),
1.6 Hz, 1 H), 8.12 (dd, J = 4.6, 1.6 Hz, 1 H), 7.31 (dd, J = 8.1, 123.2 (CH), 121.8 (CH) ppm. IR (ATR): ν = 3407, 1582, 1485,
4.6 Hz, 1 H), 6.99 (dd, J = 8.3, 4.6 Hz, 1 H) ppm. 13C NMR 1216, 752 cm–1. MS: m/z = 208.00 (37Cl) [M + H]+, 206.00 (35Cl)
(62.9 MHz, CDCl3, 27 °C): δ = 154.5 (CH), 149.1 (Cq), 144.3 (CH),
[M + H]+. HRMS: calcd. for C10H9N335Cl [M + H]+ 206.0485;
143.6 (Cq), 135.9 (CH), 135.2 (Cq), 134.7 (Cq), 130.1 (CH), 123.1 found 206.0486.
(62.9 MHz, CDCl3, 25 °C): δ = 144.8 (CH), 143.0 (CH), 140.5
˜
(CH), 115.6 (CH) ppm. IR (ATR): ν = 3276, 1590, 1495, 1459,
˜
N2-(2-Chloropyridin-3-yl)pyridine-2,3-diamine (18): This compound
was obtained by the General Procedure for the reduction step, with
13b (100 mg, 0.40 mmol) and stannous chloride dihydrate (450 mg,
2.00 mmol) in absolute ethanol at room temperature. Purification
by flash chromatography on silica gel (petroleum ether/ethyl acetate
6:4) afforded product 18 (60 mg, 68% yield) as a beige-brown solid;
m.p. 119–121 °C. 1H NMR (250 MHz, CDCl3, 27 °C): δ = 8.44
(dd, J = 8.2, 1.6 Hz, 1 H), 7.90 (dd, J = 4.7, 1.6 Hz, 1 H), 7.83 (dd,
J = 5.0, 1.6 Hz, 1 H), 7.15 (dd, J = 8.2, 4.7 Hz, 1 H), 7.06 (dd, J
= 7.5, 1.6 Hz, 1 H), 6.90 (s, 1 H, NH), 6.80 (dd, J = 7.5, 5.0 Hz, 1
1425 cm–1. MS: m/z = 297.00 (81Br) [M + H]+, 295.00 (79Br) [M +
H]+. HRMS: calcd. for C10H8N4O279Br [M + H]+ 294.9831; found
294.9831.
N-(2-Nitropyridin-3-yl)-N-(pyridin-3-yl)amine (14): This compound
was obtained by the General Procedure for the palladium-catalysed
N-arylations – Method A, with 3-iodo-2-nitropyridine (7, 100 mg,
0.4 mmol) and 3-aminopyridine (5, 45 mg, 0.48 mmol). Purification
by flash chromatography on silica gel (petroleum ether/ethyl acetate
8:2Ǟ6:4) afforded product 14 (69 mg, 80% yield) as yellow crys-
tals; m.p. 128–129 °C. 1H NMR (400 MHz, CDCl3, 25 °C): δ = H), 3.49 (brs, 2 H, NH2) ppm. 13C NMR (62.9 MHz, CDCl3,
9.14 (brs, 1 H, NH), 8.61 (d, J = 2.5 Hz, 1 H), 8.53 (dd, J = 4.7, 27 °C): δ = 144.6 (Cq), 140.3 (CH), 139.1 (CH), 139.0 (Cq), 135.2
1.2 Hz, 1 H), 8.06 (dd, J = 4.0, 1.4 Hz, 1 H), 7.63–7.60 (m, 2 H), (Cq), 131.4 (Cq), 125.5 (CH), 124.6 (CH), 123.2 (CH), 118.4
3760
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 3753–3764

Pd-Catalysed Synthesis of Dihydrodipyridopyrazines
(CH) ppm. IR (ATR): ν = 3378, 3224, 1598, 1447, 751 cm–1. MS: General Procedure for Reduction/Cyclization/Alkylation: A mixture
˜
m/z = 223.5 (37Cl) [M + H]+, 221.5 (35Cl) [M + H]+. HRMS: calcd.
of N,NЈ-dipyridinylamines and SnCl2·2H2O (5 equiv.) in absolute
ethanol (0.07 gmL–1) was heated to reflux for 5 h. After reduction,
the starting material had disappeared and the solution was cooled
down and then poured into ice. The pH was made basic by addition
of a potassium carbonate solution before extraction with ethyl ace-
tate and washing with brine. The organic layer was dried with mag-
nesium sulfate and concentrated under reduced pressure. The ob-
tained product was used in the next alkylation step without further
purification by the General Procedure for alkylations (vide supra).
for C10H10N435Cl [M + H]+ 221.0594; found 221.0602.
Dipyrido[2,3-b:2Ј,3Ј-e]pyrazine (19): This compound was obtained
by the General Procedure for the reduction/cyclization step, with
13b (200 mg, 0.80 mmol) and stannous chloride dihydrate (900 mg,
4.00 mmol) at reflux in absolute ethanol. Purification by flash
chromatography on silica gel (CH2Cl2/MeOH 100:0Ǟ98:2Ǟ95:5)
afforded product 19 (62.5 mg, 43% yield) as a dark green solid;
1
m.p. Ͼ 250 °C. H NMR (250 MHz, CDCl3, 27 °C): δ = 9.40 (dd,
5-Methyl-5,10-dihydrodipyrido[2,3-b:2Ј,3Ј-e]pyrazine (22): This
compound was obtained by the General Procedure for the re-
duction/cyclization step with compound 20 (1.54 g, 5.82 mmol) and
stannous chloride dihydrate (6.56 g, 29.10 mmol) in absolute etha-
nol (25 mL). Product 22 (1.13 g), a yellow-green solid, was used in
the next step without further purification; m.p. 218–220 °C. 1H
NMR (400 MHz, [D6]DMSO, 25 °C): δ = 8.64 (brs, 1 H, NH),
7.23 (dd, J = 4.8, 1.6 Hz, 1 H), 7.16 (dd, J = 4.9, 1.3 Hz, 1 H), 6.42
(dd, J = 7.7, 1.3 Hz, 1 H), 6.39–6.32 (m, 3 H), 2.90 (s, 3 H,
CH3) ppm. 13C NMR (100.6 MHz, CDCl3, 25 °C): δ = 147.5 (Cq),
146.4 (Cq), 138.5 (CH), 138.0 (CH), 130.7 (Cq), 130.0 (Cq), 116.9
(CH), 116.5 (CH), 116.1 (CH), 115.6 (CH), 28.2 (CH3) ppm. IR
J = 3.8, 1.9 Hz, 2 H), 8.74 (dd, J = 8.8, 1.9 Hz, 2 H), 7.86 (dd, J
= 8.5, 4.1 Hz, 2 H) ppm. 13C NMR (62.9 MHz, CDCl3, 27 °C):
δ157.8 (2ϫCH), 149.9 (2ϫCq), 141.1 (2ϫCq), 139.4 (2ϫCH),
126.6 (2ϫCH) ppm. IR (ATR): ν = 1504 cm–1. HRMS: calcd. for
˜
C10H6N4Na [M + Na]+ 205.0490; found 205.0499.
General Procedure for Alkylations: The appropriate N,NЈ-dipyrid-
inylamine (1 equiv.) in DMF was added under argon at 0 °C to a
suspension of sodium hydride (60%, 1.1 equiv.) in DMF. The mix-
ture was stirred at room temperature for 20 min and cooled to
–78 °C, and the halo derivative (1.2 equiv.) was added dropwise.
The reaction mixture was allowed to warm slowly to room tem-
perature and stirred until the end of the reaction. The reaction was
monitored by TLC for the disappearance of starting materials. The
mixture was hydrolysed, extracted with ethyl acetate and dried with
MgSO4, and the solvent was removed under reduced pressure to
give the crude product, which was purified by flash chromatog-
raphy on silica gel to afford the desired product.
(ATR): ν = 3155, 1459, 1444 cm–1. MS: m/z = 199.5 [M + H]+.
˜
HRMS: calcd. for C11H11N4 [M + H]+ 199.0984; found 199.0978.
5-Butyl-5,10-dihydrodipyrido[2,3-b:2Ј,3Ј-e]pyrazine (23): This com-
pound was obtained by the General Procedure for the reduction/
cyclization step, with compound 21 (1.41 g, 4.60 mmol) and stan-
nous chloride dihydrate (5.19 g, 23.00 mmol) in absolute ethanol
(20 mL). Product 23 (1.08 g), a green solid, was used in the next
step without further purification; m.p. 180–182 °C. 1H NMR
(250 MHz, [D6]DMSO, 80 °C): δ = 8.33 (brs, 1 H, NH), 7.23–7.12
(m, 2 H), 6.38–6.30 (m, 4 H), 3.57 (t, J = 7.7 Hz, 2 H, CH2), 1.52–
1.32 (m, 4 H, 2 CH2), 0.93 (t, J = 7.2 Hz, 3 H, CH3) ppm. 13C
NMR (62.9 MHz, [D6]DMSO, 80 °C): δ = 147.2 (Cq), 145.9 (Cq),
137.9 (CH), 137.7 (CH), 129.54 (Cq), 129.47 (Cq), 116.3 (CH),
116.0 (CH), 115.7 (CH), 115.0 (CH), 39.8 (CH2), 26.7 (CH2), 19.1
N-(2-Chloropyridin-3-yl)-N-methyl-N-(3-nitropyridin-2-yl)amine
(20): This compound was obtained by the General Procedure for
alkylations, with compound 13b (1.60 g, 6.38 mmol) and methyl
iodide (476.9 µL, 7.66 mmol). The solution was stirred for 2 h at
room temperature. Purification by flash chromatography on silica
gel (petroleum ether/ethyl acetate 8:2) afforded product 20 (1.57 g,
93 % yield) as a yellow solid; m.p. 79 °C. 1H NMR (250 MHz,
CDCl3, 27 °C): δ = 8.48 (dd, J = 4.7, 1.6 Hz, 1 H), 8.28 (dd, J =
4.7, 1.9 Hz, 1 H), 7.92 (dd, J = 8.2, 1.6 Hz, 1 H), 7.51 (dd, J = 7.8,
1.9 Hz, 1 H), 7.19 (dd, J = 7.8, 4.7 Hz, 1 H), 6.91 (dd, J = 8.1,
4.7 Hz, 1 H), 3.54 (s, 3 H, CH3) ppm. 13C NMR (62.9 MHz,
CDCl3, 27 °C): δ = 151.6 (CH), 150.7 (Cq), 149.1 (Cq), 147.6 (CH),
140.1 (Cq), 135.7 (CH), 135.0 (Cq), 134.8 (CH), 123.5 (CH), 115.1
(CH ), 13.3 (CH ) ppm. IR (ATR): ν = 3150, 1453, 748 cm–1. MS:
˜
2
3
m/z = 241.00 [M + H]+. HRMS: calcd. for C14H17N4 [M + H]+
241.1453; found 241.1455.
5-(2,2-Dimethylpropanoyl)-10-methyl-5,10-dihydrodipyrido[2,3-
b:2Ј,3Ј-e]pyrazine (24): Triethylamine (263 µL, 1.89 mmol,
1.25 equiv.) was added under argon to a solution of non-purified
compound 22 (300 mg, 1.51 mmol), resulting from the reduction/
cyclization step, in dichloromethane (30 mL). After the mixture has
been stirred for 5 min at room temperature, pivaloyl chloride
(205 µL, 1.66 mmol, 1.1 equiv.) was added at 0 °C. After 60 h of
stirring at room temperature, the reaction medium was hydrolysed,
extracted with ethyl acetate and dried with MgSO4, and the solvent
was removed under reduced pressure to give the crude product.
This residue was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate 9:1) and the desired product 24
(CH), 39.9 (CH ) ppm. IR (ATR): ν = 1512, 1407, 757 cm–1. MS:
˜
3
m/z = 267.00 (37Cl) [M + H]+, 265.00 (35Cl) [M + H]+. HRMS:
calcd. for C11H10N4O235Cl [M + H]+ 265.0492; found 265.0489.
N-Butyl-N-(2-chloropyridin-3-yl)-N-(3-nitropyridin-2-yl)amine (21):
This compound was obtained by the General Procedure, with com-
pound 13b (1.60 g, 6.38 mmol) and butyl iodide (875 µL,
7.66 mmol). The solution was stirred for 48 h at room temperature.
Purification by flash chromatography on silica gel (petroleum ether/
ethyl acetate 9:1) afforded product 21 (1.43 g, 73% yield) as a yel-
1
low solid; m.p. 101–102 °C. H NMR (250 MHz, CDCl3, 27 °C): δ
= 8.47 (dd, J = 4.4, 1.9 Hz, 1 H), 8.27 (dd, J = 4.7, 1.6 Hz, 1 H), (400 mg, 92% yield calculated over two steps) was obtained as a
1
7.92 (dd, J = 8.2, 1.9 Hz, 1 H), 7.50 (dd, J = 7.8, 1.6 Hz, 1 H), 7.25
(dd, J = 7.8, 4.7 Hz, 1 H), 6.89 (dd, J = 8.2, 4.4 Hz, 1 H), 4.01 (t,
J = 7.8 Hz, 2 H, CH2), 1.73–1.61 (m, 2 H, CH2), 1.43–1.29 (m, 2
H, CH2 ), 0.92 (t, J = 7.2 Hz, 3 H, CH3) ppm. 13 C NMR
yellow-green solid; m.p. 149–151 °C. H NMR (250 MHz, CDCl3,
27 °C): δ = 7.94–7.88 (m, 3 H), 7.06–7.05 (m, 2 H), 6.83 (dd, J =
7.7, 5.0 Hz, 1 H), 3.37 (s, 3 H, CH3), 1.20 (s, 9 H, 3 CH3-Piv) ppm.
13C NMR (62.9 MHz, CDCl3, 27 °C): δ = 181.6 (Cq, C=O), 150.0
(62.9 MHz, CDCl3, 27 °C): δ = 151.5 (CH), 150.3 (Cq), 148.8 (Cq), (Cq), 143.8 (Cq), 142.8 (CH, Cpy), 139.8 (CH, Cpy), 135.3 (Cq),
147.3 (CH), 138.6 (Cq), 137.0 (CH), 135.3 (Cq), 134.7 (CH), 123.4 128.4 (CH, Cpy), 125.8 (Cq), 121.9 (CH, Cpy), 119.1 (CH, Cpy),
(CH), 114.9 (CH), 51.9 (CH2), 29.6 (CH2), 20.2 (CH2), 13.9 117.2 (CH, Cpy), 42.9 (Cq, C-Piv), 30.0 (CH3), 28.6 (3 ϫ CH3-
(CH ) ppm. IR (ATR): ν = 754, 1422, 1480 cm–1. MS: m/z = 309.50
Piv) ppm. IR (ATR): ν = 1666, 1433 cm–1. MS: m/z = 283.50 [M
˜
˜
3
(
37Cl) [M + H]+, 307.50 (35Cl) [M + H]+. HRMS: calcd. for + H]+. HRMS: calcd. for C16H19N4O [M + H]+ 283.1559; found
C14H16N4O235Cl [M + H]+ 307.0962; found 307.0966.
283.1563.
Eur. J. Org. Chem. 2009, 3753–3764
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3761

G. Guillaumet et al.
5-Butyl-10-(2,2-dimethylpropanoyl)-5,10-dihydrodipyrido[2,3-b:2Ј,3Ј-e]- 7.34 (dd, J = 5.0, 1.6 Hz, 2 H), 6.44–6.27 (m, 4 H), 5.87–5.74 (m,
FULL PAPER
pyrazine (25): Triethylamine (217 µL, 1.56 mmol, 1.25 equiv.) was
added under argon to a solution of non-purified compound 23
(300 mg, 1.25 mmol), resulting from the reduction/cyclization step,
in dichloromethane (30 mL). After the mixture had been stirred for
5 min at room temperature, pivaloyl chloride (169 µL, 1.37 mmol,
1.1 equiv.) was added at 0 °C. After 60 h of stirring at room tem-
perature, the reaction medium was hydrolysed, extracted with ethyl
acetate and dried with MgSO4, and the solvent was removed under
reduced pressure to give the crude product. This residue was puri-
fied by flash chromatography on silica gel (petroleum ether/ethyl
acetate 10:0Ǟ9:1) and the desired product 25 (385 mg, 93% yield
calculated over two steps) was obtained as a brown-green solid;
m.p. 111–113 °C. 1H NMR (250 MHz, CDCl3, 27 °C): δ = 7.89
(dd, J = 4.9, 1.6 Hz, 1 H), 7.85–7.80 (m, 2 H), 7.03–7.01 (m, 2 H),
6.79 (dd, J = 7.8, 4.9 Hz, 1 H), 4.00 (t, J = 7.5 Hz, 2 H, CH2),
1.76–1.64 (m, 2 H, CH2), 1.5–1.37 (m, 2 H, CH2), 1.18 (s, 9 H,
3ϫCH3-Piv), 0.97 (t, J = 7.2 Hz, 3 H, CH3-Bu) ppm. 13C NMR
(62.9 MHz, CDCl3, 27 °C): δ = 181.7 (Cq, C=O), 149.5 (Cq), 143.9
(Cq), 142.8 (CH, Cpy), 139.6 (CH, Cpy), 134.2 (Cq), 128.2 (CH,
Cpy), 125.6 (Cq), 121.7 (CH, Cpy), 119.2 (CH, Cpy), 117.1 (CH,
Cpy), 42.9 (Cq, C-Piv), 41.7 (CH2), 28.6 (3 CH3), 28.1 (CH2), 20.3
1 H, CH), 5.29–5.17 (m, 2 H, CH2b), 4.28 (t, J = 2.2 Hz, 2 H,
CH2a), 3.04 (s, 3 H, CH3) ppm. 13C NMR (62.9 MHz, CDCl3,
27 °C): δ = 147.5 (Cq), 147.0 (Cq), 138.4 (CH, Cpy), 138.2 (CH,
Cpy), 131.9 (Cq), 131.6 (CH), 131.1 (Cq), 117.0 (CH, Cpy), 116.6
(CH2b), 116.2 (CH, Cpy), 115.4 (2ϫCH, 2ϫCpy), 44.2 (CH2a), 28.9
(CH ) ppm. IR (ATR): ν = 1597, 1434 cm–1. MS: m/z = 239.00 [M
˜
3
+ H]+. HRMS: calcd. for C14H15N4 [M + H]+ 239.1297; found
239.1297.
5-Benzyl-10-methyl-5,10-dihydrodipyrido[2,3-b:2Ј,3Ј-e]pyrazine
(26d): This compound was obtained by the General Procedure for
reduction/cyclization/alkylation, with non-purified compound 22
(90 mg, 0.45 mmol), resulting from the reduction/cyclization step,
and benzyl chloride (63 µL, 0.54 mmol). The solution was stirred
overnight at room temperature. Purification by flash chromatog-
raphy on silica gel (petroleum ether/ethyl acetate 8:2) afforded
product 26d (119 mg, 89% yield calculated over two steps) as a
green solid; m.p. 131–133 °C. 1H NMR (250 MHz, CDCl3, 27 °C):
δ = 7.37–7.19 (m, 7 H, 2 Hpy and 5 Harom), 6.47 (dd, J = 7.5,
5.0 Hz, 1 H, Hpy), 6.40 (dd, J = 7.5, 1.3 Hz, 1 H, Hpy), 6.25 (dd, J
= 7.5, 5.0 Hz, 1 H, Hpy), 6.14 (dd, J = 7.5, 1.2 Hz, 1 H, Hpy), 4.96
(s, 2 H, CH2), 3.11 (s, 3 H, CH3) ppm. 13C NMR (62.9 MHz,
CDCl3, 27 °C): δ = 147.6 (Cq), 147.4 (Cq), 138.8 (CHpy), 137.8
(CHpy), 136.4 (Cq), 131.7 (Cq), 131.4 (Cq), 128.8 (2ϫCHarom),
127.1 (CHarom), 126.6 (2 ϫ CHarom), 117.4 (CHpy), 116.7
(2ϫCHpy), 116.0 (CHpy), 45.7 (CH2), 29.3 (CH3) ppm. IR (ATR):
(CH ), 14.0 (CH ) ppm. IR (ATR): ν = 1728, 1433 cm–1. MS: m/z
˜
2
3
= 325.61 [M + H]+. HRMS: calcd. for C19H25N4O [M + H]+
325.2028; found 325.2030.
5,10-Dimethyl-5,10-dihydrodipyrido[2,3-b:2Ј,3Ј-e]pyrazine (26a):
This compound was obtained by the General Procedure for re-
duction/cyclization/alkylation, with non-purified compound 22
(90 mg, 0.45 mmol), resulting from the reduction/cyclization step,
and methyl iodide (34 µL, 0.54 mmol). The solution was stirred
overnight at room temperature. Purification by flash chromatog-
raphy on silica gel (petroleum ether/ethyl acetate 8:2) afforded
product 26a (89 mg, 90% yield calculated over two steps) as a green
solid; m.p. 152–153 °C (ref.[2] 152 °C). The spectroscopic data (IR
and NMR) were in accordance with the literature values.[2]
ν = 1454, 1434, 750 cm–1. MS: m/z = 289.50 [M + H]+. HRMS:
˜
calcd. for C18H17N4 [M + H]+ 289.1453; found 289.1465.
Dipyrido[2,3-b:3Ј,2Ј-e]pyrazine (27): This compound was obtained
by the General Procedure for the reduction/cyclization step, with
15 (100 mg, 0.80 mmol) and stannous chloride dihydrate (450 mg,
2.00 mmol) in absolute ethanol (10 mL) at reflux. Purification by
flash chromatography on silica gel (CH2Cl2/MeOH 100:0Ǟ98:2)
afforded product 27 (50 mg, 69% yield) as a green solid; m.p. Ͼ
250 °C. 1H NMR (250 MHz, CD3OD, 27 °C): δ = 9.41 (dd, J =
3.8, 1.9 Hz, 2 H), 8.73 (dd, J = 8.8, 1.9 Hz, 2 H), 8.01 (dd, J = 8.8,
3.8 Hz, 2 H) ppm. 13C NMR (62.9 MHz, CDCl3, 27 °C): δ158.2
(2ϫCH), 150.7 (2 ϫCq), 140.3 (2 ϫCq), 138.5 (2 ϫCH), 126.3
5-Butyl-10-methyl-5,10-dihydrodipyrido[2,3-b:2Ј,3Ј-e]pyrazine (26b):
This compound was obtained by the General Procedure for re-
duction/cyclization/alkylation, with non-purified compound 22
(90 mg, 0.45 mmol), resulting from the reduction/cyclization step,
and butyl bromide (60 µL, 0.54 mmol). The solution was stirred
overnight at room temperature. Purification by flash chromatog-
raphy on silica gel (petroleum ether/ethyl acetate 8:2) afforded
product 26b (104 mg, 88% yield calculated over two steps) as a
(2ϫCH) ppm. IR (ATR): ν = 778 cm–1. MS: m/z = 183.00 [M +
˜
H]+. HRMS: calcd. for C10H6N4Na [M + Na]+ 205.0490; found
205.0492.
N-(2-Chloropyridin-3-yl)-N-methyl-N-(2-nitropyridin-3-yl)amine
(28): This compound was obtained by the General Procedure for
alkylations, with compound 15 (500 mg, 1.99 mmol) and methyl
iodide (149 µL, 2.39 mmol). The solution was stirred for overnight
at room temperature. Purification by flash chromatography on sil-
ica gel (petroleum ether/ethyl acetate 5:5) afforded product 28
(438 mg, 83 % yield) as a yellow solid; m.p. 130 °C. 1H NMR
(250 MHz, CDCl3, 27 °C): δ = 8.19 (dd, J = 4.7, 1.7 Hz, 1 H), 8.06
(dd, J = 4.3, 1.4 Hz, 1 H), 7.56 (dd, J = 8.3, 1.4 Hz, 1 H), 7.51–
7.45 (m, 2 H), 7.21 (dd, J = 7.9, 4.7 Hz, 1 H), 3.30 (s, 3 H,
CH3) ppm. 13C NMR (62.9 MHz, CDCl3, 27 °C): δ = 150.1 (Cq),
147.8 (Cq), 146.6 (CH), 140.4 (CH), 140.3 (Cq), 137.0 (Cq), 134.9
(CH), 130.8 (CH), 128.2 (CH), 123.4 (CH), 41.0 (CH3) ppm. IR
1
green solid; m.p. 68–69 °C. H NMR (250 MHz, CDCl3, 27 °C): δ
= 7.33–7.31 (m, 2 H), 6.38–6.33 (m, 2 H), 6.28–6.23 (m, 2 H), 3.60
(t, J = 7.3 Hz, 2 H, CH2), 2.99 (s, 3 H, CH3), 1.59–1.46 (m, 2 H,
CH2), 1.43–1.34 (m, 2 H, CH2), 0.95 (t, J = 7.2 Hz, 3 H, CH3) ppm.
13C NMR (62.9 MHz, CDCl3, 27 °C): δ = 147.8 (Cq), 147.4 (Cq),
138.4 (CH), 138.1 (CH), 132.1 (Cq), 131.3 (Cq), 116.6 (2ϫCH),
115.1 (2ϫCH), 41.1 (CH2), 28.8 (CH3), 27.1 (CH2), 20.2 (CH2),
14.0 (CH -Bu) ppm. IR (ATR): ν = 1598, 1466 cm–1. MS: m/z =
˜
3
255.50 [M + H]+. HRMS: calcd. for C15H19N4 [M + H]+ 255.1610;
found 255.1615.
5-Allyl-10-methyl-5,10-dihydrodipyrido[2,3-b:2Ј,3Ј-e]pyrazine (26c):
This compound was obtained by the General Procedure for re-
duction/cyclization/alkylation, with non-purified compound 22
(90 mg, 0.45 mmol), resulting from the reduction/cyclization step,
and allyl bromide (47 µL, 0.54 mmol). The solution was stirred
overnight at room temperature. Purification by flash chromatog-
raphy on silica gel (petroleum ether/ethyl acetate 8:2) afforded
(ATR): ν = 1422, 802 cm–1. MS: m/z = 267.00 (37Cl) [M + H]+,
˜
265.00 (35Cl) [M + H]+. HRMS: calcd. for C11H10N4O235Cl [M +
H]+ 265.0492; found 265.0485.
5-Methyl-5,10-dihydrodipyrido[2,3-b:3Ј,2Ј-e]pyrazine (29): This
compound was obtained by the General Procedure for the re-
duction/cyclization step, with compound 28 (360 mg, 1.36 mmol)
product 26c (101 mg, 91% yield calculated over two steps) as a and stannous chloride dihydrate (1.53 mg, 6.80 mmol) in absolute
green solid; m.p. 62 °C. 1H NMR (250 MHz, CDCl3, 27 °C): δ =
ethanol (25 mL). Product 29 (265 mg), a green-brown powder, was
3762
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 3753–3764

Pd-Catalysed Synthesis of Dihydrodipyridopyrazines
used in the next step without further purification; m.p. 115–118 °C.
NMR (62.9 MHz, [D6]acetone, 27 °C): δ = 148.6 (2ϫCq), 140.2
1H NMR (400 MHz, CDCl3, 25 °C): δ = 7.34 (dd, J = 5.2, 0.8 Hz, (Cq, Carom), 138.7 (2ϫCHpy), 132.8 (2ϫCq), 128.8 (2ϫCHarom),
2 H), 6.49 (dd, J = 7.1, 5.2 Hz, 2 H), 6.34 (d, J = 7.1 Hz, 2 H),
128.4 (2ϫCHarom), 127.1 (CHarom), 118.4 (2ϫCHpy), 116.1
2.84 (s, 3 H, CH ) ppm. IR (ATR): ν = 3155, 1459, 1444 cm–1. MS: (2ϫCHpy), 43.0 (CH ), 31.3 (CH ) ppm. IR (ATR): ν = 1425,
˜
˜
3
2
3
m/z = 199.5 [M + H]+. HRMS: calcd. for C11H11N4 [M + H]+
740 cm–1. MS: m/z = 289.00 [M + H]+. HRMS: calcd. for C18H17N4
199.0984; found 199.0989.
[M + H]+ 289.1453; found 289.1465.
X-ray Crystallography: CCDC-720326 (for 13a), -720327 (for 15),
-720328 (for 18), -720329 (for 19), -720330 (for 21), -720331 (for
24), -720332 (for 28) and -720333 (for 30d) contain the supplemen-
tary crystallographic data for this paper. These data can be ob-
tained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
5,10-Dimethyl-5,10-dihydrodipyrido[2,3-b:3Ј,2Ј-e]pyrazine (30a):
This compound was obtained by the General Procedure for re-
duction/cyclization/alkylation, with non-purified compound 29
(85 mg, 0.43 mmol), resulting from the reduction/cyclization step,
and methyl iodide (32 µL, 0.51 mmol). The solution was stirred
overnight at room temperature. Purification by flash chromatog-
raphy on silica gel (petroleum ether/ethyl acetate 8:2) afforded
product 30a (80 mg, 87% yield calculated over two steps) as a yel-
low powder; m.p. 150–152 °C (ref.[2] 150 °C). The spectroscopic
data (IR and NMR) were in accordance with the literature values.[2]
Supporting Information (see also the footnote on the first page of
1
this article): H and 13C NMR spectra for compounds 7, 10b, 12,
13a–13c, 14, 15, 17, 18–25, 26b–26d, 27, 28, 30b–30d and 1H NMR
spectrum for compound 29; crystal data and structure refinement
data for 13a, 15, 18, 19, 21, 24, 28 and 30d.
10-Butyl-5-methyl-5,10-dihydrodipyrido[2,3-b:3Ј,2Ј-e]pyrazine (30b):
This compound was obtained by the General Procedure for re-
duction/cyclization/alkylation, with non-purified compound 29
(90 mg, 0.45 mmol), resulting from the reduction/cyclization step,
and butyl bromide (60 µL, 0.54 mmol). The solution was stirred
overnight at room temperature. Purification by flash chromatog-
raphy on silica gel (petroleum ether/ethyl acetate 7:3) afforded
product 30b (96 mg, 82% yield calculated over two steps) as a green
solid; m.p. 61 °C. 1H NMR (250 MHz, [D6]acetone, 27 °C): δ =
7.34 (dd, J = 4.4, 2.2 Hz, 2 H), 6.48–6.43 (m, 4 H), 3.93 (t, J =
7.5 Hz, 2 H, N–CH2), 2.84 (s, 3 H, CH3), 1.63–1.53 (m, 2 H, CH2),
1.41–1.32 (m, 2 H, CH2), 0.91 (t, J = 7.2 Hz, 3 H, CH3) ppm. 13C
NMR (62.9 MHz, [D6]acetone, 27 °C): δ = 148.8 (2ϫCq), 138.8
(2 ϫ CH), 132.8 (2 ϫ Cq), 117.9 (2 ϫ CH), 115.7 (2 ϫ CH), 40.1
(CH2), 31.2 (CH3), 29.4 (CH2), 20.9 (CH2), 14.3 (CH3-Bu) ppm.
Acknowledgments
We are grateful to the French Embassy in Romania for partial fin-
ancial support through the PAI Brancusi programme.
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˜
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This compound was obtained by the General Procedure for re-
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(90 mg, 0.45 mmol), resulting from the reduction/cyclization step,
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7.33 (d, J = 3.1 Hz, 2 H), 6.48 (d, J = 3.1 Hz, 4 H), 5.97–5.83 (m,
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J = 10.3, 1.6 Hz, 1 H, CHb “cis”), 4.63–4.61 (m, 2 H, N–CH2),
2.87 (s, 3 H, CH3) ppm. 13C NMR (62.9 MHz, [D6]acetone, 27 °C):
δ = 148.4 (2ϫCq), 138.8 (2ϫCHpy), 134.9 (CH), 132.8 (2ϫCq),
118.1 (2ϫCHpy), 116.0 [CH2, CH2(a+b)], 115.9 (2ϫCHpy), 42.1
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G. Guillaumet et al.
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Published Online: June 16, 2009
3764
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 3753–3764