New highlights in the synthesis and reactivity of 1,4-dihydropyrazine derivatives

Article abstract of DOI:10.1016/j.tet.2008.06.080

In the course of our investigations on the synthesis of original nitrogen heterocyclic derivatives, we were interested in the synthesis and study of original 1,4-dihydropyrazine rings. To this aim the desired bisvinylphosphate derivative was prepared from N-Boc piperazine-2,5-dione and then was engaged in palladium catalyzed reactions (reduction, Suzuki and Stille cross-coupling reactions). The 1,4-dihydropyrazine and the corresponding 2,5-disubstituted derivatives were obtained in fair to good yields and were then functionalized under anionic conditions. Aromatization into 1,4-pyrazines was investigated in a second stage.

Full text of DOI:10.1016/j.tet.2008.06.080

Tetrahedron 64 (2008) 8059–8066
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
New highlights in the synthesis and reactivity of 1,4-dihydropyrazine derivatives
*
*
´
Mathilde Chaignaud, Isabelle Gillaizeau , Nouara Ouhamou, Gerard Coudert
ICOA, UMR CNRS 6005, Universite´ d’Orle´ans, BP 6759, 45067 Orle´ans Cedex 2, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 23 April 2008
Received in revised form 16 June 2008
Accepted 20 June 2008
Available online 25 June 2008
In the course of our investigations on the synthesis of original nitrogen heterocyclic derivatives, we were
interested in the synthesis and study of original 1,4-dihydropyrazine rings. To this aim the desired bis-
vinylphosphate derivative was prepared from N-Boc piperazine-2,5-dione and then was engaged in
palladium catalyzed reactions (reduction, Suzuki and Stille cross-coupling reactions). The 1,4-dihy-
dropyrazine and the corresponding 2,5-disubstituted derivatives were obtained in fair to good yields and
were then functionalized under anionic conditions. Aromatization into 1,4-pyrazines was investigated in
a second stage.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
H
N
R4
N
R1
N
H
N
Identifying improved methods for heterocycle synthesis and
essentially giving access to new heterocyclic scaffolds are of prime
importance.1 It is of prime importance to identify and improve the
methods that best allow to synthesize heterocycles, and to give
access to new heterocyclic scaffolds. As part of our interest in the
application of readily available enol phosphates in the synthesis of
new nitrogen heterocyclic compounds, we would like to report
herein the first results of our investigations on 1,4-dihydropyrazine
derivatives. The 1,4-dihydropyrazine ring system has attracted
much interest as a structural unit, this is mostly due to the fact that
Br
O
Br
N
R3
N
N
H
R2
N
H
O
Dragmacidin A R3 = Me, R4 = H
Dragmacidin B R3 = R4 = Me
1,5-Dihydroflavins
R3
O
N
O
H
N
N
N
B(OH)2
N
N
H
cyclic 8p-electron conjugation has the property to give rise to the
N
H
R6
R5
O
Ph
PS-341(Bortezomid)
proteasome inhibitor
so-called ‘antiaromatic’ character. 1,4-Dihydropyrazine derivatives
also constitute interesting electron donors in conducting charge-
transfer complexes and magnetic materials.2,4a,b This ring system
(Fig. 1) is a key structural feature of some redox-active biological
molecules such as 1,5-dihydroflavin coenzymes3 and of several
marine luciferins.4 This 1,4-diazine privileged scaffold is encoun-
tered as piperazine moieties5 in several marine natural products
showing cytotoxic and antitumor properties (i.e., dragmacidin A
and B) or as pyrazine units6 in some naturally occurring com-
pounds. Pyrazines have been widely used in the fields of medicinal
chemistry for the elaboration of the skeletons of biologically active
sites7 and in metal coordination chemistry as N,N0-bidentate
ligands.8 Despite the relevant potential of pyrazine, its chemistry9 is
Luciferins
Figure 1.
under-developed in comparison with that of its isomers and pyri-
dine. Given that a non-flexible dimerization approach is most often
reported for the preparation of substituted 1,4-dihydropyrazines10
and pyrazines, the development of new methods for their synthe-
ses is still a great challenge.
We have recently outlined the synthesis of various 1,4-dihy-
dropyridines A11a,b and 1,4-oxazines B11c (Fig. 2) from imide de-
rivatives by way of Pd-catalyzed coupling reactions of the
corresponding bisvinylphosphates. The first part of the work
reported here is devoted to the convenient use of our strategy in the
synthesis of 1,4-dihydropyrazines C (including R1¼R2¼H). Func-
tionalization of the latter under anionic conditions as well as
aromatization into pyrazines D is examined in a second stage.
* Corresponding authors. Fax: þ33 238 417 281.
E-mail addresses: isabelle.gillaizeau@univ-orleans.fr (I. Gillaizeau), gerard.
coudert@univ-orleans.fr (G. Coudert).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.06.080

8060
M. Chaignaud et al. / Tetrahedron 64 (2008) 8059–8066
COOR
N
With a view to valorize this 1,4-dihydropyrazine scaffold and to
R4
R3
O
N
N
N
R1
R1
access more complex heterocycles, we then focused on studying
their reactivity toward organometallic reagents. Taking into
account our previous results in the 1,4-oxazine series,11c we in-
vestigated the functionalization of these derivatives under anionic
conditions. This method, which offers the opportunity to easily
introduce various substituents onto these structures, should be
particularly useful to develop libraries for the development of
biologically relevant 1,4-diazine derivatives. Hence, we decided to
introduce various substituents at C-3 on the 2,5-diphenyl-1,4-
dihydropyrazine 4e, chosen as a model compound, or at C-2 on the
1,4-dihydropyrazine 5. The best results were obtained using LDA as
a base at ꢀ78 ꢁC in the presence or absence of HMPA.20 The 2-lithio
derivatives were trapped by a range of electrophiles (5 equiv)
leading to the required original trisubstituted derivatives 6a–e or
monosubstituted compound 7 in fair to good yields (Table 2). This
strategy allowed easy access to a great diversity of 1,4-dihy-
dropyrazines since further transformations of the resulting
compound 6 or 7 could easily be envisaged.
R1
R1
N
R2
COOR
R2
N
R2
R2
COOR
B
COOR
C
A
D
R = t-Bu, Ph
R1, R2 = aryl, heteroaryl, alcenyl, alcynyl, acyl, alkyl, hydroxyalkyl
R3, R4 = alkyl, allyl, hydroxyalkyl
Figure 2. Original substituted heterocycles accessible via our method.
2. Results and discussion
2.1. Synthesis and reactivity of 1,4-dihydropyrazines
In connection with our efforts to develop synthetic routes to
nitrogen containing derivatives, we have undertaken a research
program directed toward expanding the range of lactam-derived
enol phosphates available to the organist chemist.11,12 Taking ad-
vantage of our previous results, the original 1,4-dihydropyrazine
bisvinylphosphate 313 was efficiently synthesized in good yields
from piperazine-2,5-dione (Scheme 1). It is worth pointing out that
the presence of an electron withdrawing group on the nitrogen
atoms (tert-butoxycarbonyl group) facilitates the stabilization of
the 1,4-dihydropyrazine system. In these basic conditions at
ꢀ78 ꢁC, we didn’t observe any transannular rearrangement of the
enolate intermediate.14
2.2. Access to 2,5-disubstituted pyrazines
We next focused on pyrazines, which are widely used in-
termediates in medicinal chemistry.7 With the aim to prepare
various derivatives of this type, we examined the behavior of 1,4-
dihydropyrazine derivatives under acidic conditions (Table 3).
Treatment of 2,5-disubstituted dihydropyrazines with anhydrous
TFA in dichloromethane for 2 h afforded in fair to good yields the
corresponding pyrazines 8a–d, previously undescribed that could
not otherwise be easily accessible.21 By substituting TMSI for TFA,
the reaction time was improved (30 min instead of 2 h). However,
a low reactivity was encountered in some cases (Table 3, entries 2
and 4) during this deprotection/aromatization step, which was
probably due to the lack of solubility of some intermediates in
organic solvents.
Given that the fluorescence properties of pyrazines are
known,22 the photophysical properties of the previously synthe-
sized molecules were examined in CHCl3 solution by UV–vis and
fluorescence spectroscopies. The 2,5-disusbtituted pyrazines con-
sidered exhibited clear fluorescence properties that are reported in
Table 4. Further studies aiming to develop new molecular probes by
anchoring various substituted pyrazine units to more complex
molecules are currently being explored in our laboratory. This
approach should provide significant facts that could lead to the
development of highly selective and sensitive chemical sensors
with use of pyrazine derivatives.
Boc
N
R
N
O
P
O
O
PhO
PhO
LiHMDS, HMPA
O
P
OPh
OPh
(PhO)2P(O)Cl
(86%)
N
Boc
3
O
O
N
R
(Boc)2O
1 R = H
DMAP
(71%)
2 R = Boc
Scheme 1. Preparation of the 1,4-dihydropyrazine bisvinylphosphate 3.
In order to obtain ‘symmetrical’ 2,5-disubstituted 1,4-dihy-
dropyrazines, palladium coupling reactions were then investigated.
The Stille-coupling reaction was performed with various tin re-
agents in the presence of catalytic Pd(PPh3)4 and anhydrous LiCl in
refluxing THF for 1 h and afforded the desired compounds 4a–d in
fair to good yields (Table 1, entries 1–4).15 One of the attractive
features of our approach lies in its inherent versatility since a wide
range of reactants could be used. A Pd-catalyzed Suzuki–Miyaura
coupling reaction was then studied.16 By applying classic condi-
tions, a range of 2,5-disubstituted 1,4-dihydropyrazine 4e–h were
thus isolated in satisfying yields (Table 1, entries 5–8).
With these results in hand, it was deemed appropriate to
investigate the reduction of the vinyl phosphate groups. To the best
of our knowledge, so far, there has been no description of the 1,4-
dihydropyrazine 5 in the literature. By treatment of the bisvinyl-
phosphate 3 with triethylammonium formate, palladium acetate,
and triphenylphosphine in THF,11a the basic heterocyclic system 5
was isolated in moderate yield (45% yield). Fair yields (inferior to
20%) were also obtained by testing other conditions (different
sources of palladium(0) or various hydride sources: Et3Al/
Pd(PPh3)4,18 Et3SiH/Pd(PPh3)419). The slight instability of this non-
substituted 1,4-dihydropyrazine system could explain why the
yield was so moderate. However, the original derivative 5 might
hopefully find some useful applications as a building block in
heterocyclic and medicinal chemistry (Scheme 2).
3. Conclusion
To conclude, the procedures described here represent a con-
venient access to 1,4-dihydropyrazine and pyrazine derivatives
via vinyl phosphate intermediates. Few methods are available
for their syntheses, however, a review of the literature revealed
that if the parent molecules are easily prepared on the other
hand the corresponding substituted compounds are frequently
difficult to obtain. Subsequent to our study, it is worth noting
that the presence of different functional groups in many posi-
tions of these heterocycles makes such compounds useful for
further structural modifications and suitable as intermediates for
more complex structures or biologically active compounds. Be-
sides the mild and simple conditions of this procedure, its
versatility allows to access valuable combinatorial libraries.
Further studies are now underway in our laboratory with a view
to exploit the potentiality offered by this original heterocyclic
system.

M. Chaignaud et al. / Tetrahedron 64 (2008) 8059–8066
8061
Table 1
Suzuki and Stille coupling reactions on the bisvinylphosphate 3
O
PhO
P
Boc
N
Boc
N
O
R
PhO
O
P
RSnBu3 or RB(OH)2
Pd0
OPh
OPh
N
Boc
3
N
Boc
4a-h
R
O
Entry
Reagents
Products (yield %)
O
O
Boc
N
Bu3Sn
O
O
1a
4a (80)
O
N
Boc
O
Boc
N
2a
4b (68)
4c (41)
Bu3Sn
N
Boc
Ph
Boc
N
3a
Ph
Bu3Sn
N
Boc
Ph
MeO
Boc
N
H
N
Bu3Sn
N
H
4a
4d (25)
H
N
N
OMe
Boc
OMe
Boc
N
(HO)2B
5b
6b
7b
4e (72)
4f (87)
4g (94)
4h (61)
N
Boc
Boc
N
(HO)2B
S
S
S
N
Boc
Boc
N
(HO)2B
O
O
O
S
N
Boc
Boc
N
(OH)2B
S
S
8b
N
Boc
a
Conditions: 10 mol % Pd(PPh3)4, 5 equiv RSnBu3, 6 equiv LiCl, THF, 1 h, reflux.17
Conditions: (i) 10 mol % PdCl2(PPh3)2, THF, rt, 15 min; (ii) 5 equiv RB(OH)2, 3 equiv Na2CO3 2 M, EtOH, reflux, 2 h.
b
4. Experimental part
O
P
Boc
N
Boc
N
PhO
PhO
HCOOH, Et3N
4.1. General
O
O
P
Pd(OAc)2, PPh3
OPh
OPh
THF, reflux
(45%)
N
Boc
5
N
Boc
3
O
All the solvents used for reactions were distilled prior to use
according to the standard procedures. THF was distilled from so-
dium/benzophenone ketyl immediately prior to use. Dichloro-
methane was distilled over CaH2 and methanol from magnesium
Scheme 2. Catalyzed palladium reduction of the bisvinylphosphate 3.

8062
M. Chaignaud et al. / Tetrahedron 64 (2008) 8059–8066
Table 2
Table 3
Functionalization of the 1,4-dihydropyrazines 4e and 5
Access to 2,5-disubstituted pyrazines 8a–da
Boc
N
Boc
N
Boc
N
Ph
R
Ph
R1
Ph
R
N
1) LDA, THF, -78 °C
2) Electrophile
TFA, CH2Cl2, RT
or TMSI, CH2Cl2
N
Boc
4e
N
Boc
4e,f,h
Ph
R
N
Boc
6a-h
N
R
8a-d
Boc
N
Boc
N
Entry
1
Reagents
Products (Yield %)
1) LDA, THF, -78 °C
2) Electrophile
N
Boc
5
N
Boc
7
R1
N
N
4e
8a18 (100)
Entry
1a
Electrophiles
Bu3SnCl
Products (Yield %)
N
Boc
S
S
2
3
4f
8b (64)
Ph
Ph
N
SnBu3
Ph
S
N
6a (62)
6b (63)
6c (75)
6d (85)
6e (60)
N
Boc
N
Boc
N
4h
8c (80)
SiMe3
Ph
S
N
2a
3a
5a
6a
Me3SiCl
N
Boc
MeO
Boc
N
CHO
Boc
N
OH
Ph
OMe
OMe
N
H
H
4
4d
8d (20)
N
N
Boc
MeO
OMe
OMe
N
Boc
Ph
OMe
OMe
Boc
N
a
Conditions: 10 equiv TFA, CH2Cl2, rt, 2 h or 5 equiv TMSI, CH2Cl2, rt, 30 min.
Ph
CHO
Ph
DMF
N
Boc
Table 4
Relative fluorescence intensities of pyrazines 8a–c: maximum absorption wave-
length (labs), molar absorption coefficients ( ), maximum emission wavelength
lem), and fluorescence quantum yield (Ff
Boc
N
3
Ph
CO2Me
Ph
(
)
NCCO2Me
Entry
Compounds
labs nm
3
103
M
ꢀ1 cmꢀ1
log
3
lem nm
Ff
N
1a
2a
3a
8a
8b
8c
326
367
390
12
4.1
5.0
3.9
374
417
418
433
0.05
0.15
0.40
Boc
94.2
8.30
Boc
N
7b
NCCO2Me
7 (65)
Solution in CHCl3: 8a: c¼7.76ꢂ10ꢀ5 mol Lꢀ1
;
8b: c¼8.20ꢂ10ꢀ6 mol Lꢀ1
;
8c:
a
c¼5.23ꢂ10ꢀ5 mol Lꢀ1
.
N
Boc
COOMe
a
Conditions: (i) 2.5 equiv LDA, THF, ꢀ78 ꢁC, 1 h; (ii) 2 equiv HMPA, ꢀ78 ꢁC,
4.2. Preparation of the N,N-bis-(tert-butoxycarbonyl)-2,5-bis-
(diphenyloxy-phosphoryloxy)-[1,4]-dihydropyrazine (3)
10 min; (iii) 5 equiv electrophile, ꢀ78 ꢁC, 30 min.
b
Conditions: (i) 1.2 equiv LDA, THF, ꢀ78 ꢁC, 20 min; (ii) 5 equiv electrophile,
ꢀ78 ꢁC, 30 min.
A solution of LiHMDS (1 M in hexane, 7.9 mL, 7.95 mmol,
2.5 equiv) in THF (20 mL) was cooled to ꢀ78 ꢁC under argon. Sub-
sequently, a solution of N,N-bis-(tert-butoxycarbonyl)-piperazine-
2,5-dione 223 (1.00 g, 3.18 mmol, 1 equiv) in THF (5 mL), distilled
diphenyl chlorophosphate (1.40 mL, 6.67 mmol, 2.1 equiv), and
distilled HMPA (1.50 mL, 8.90 mmol, 2.8 equiv) were added drop-
wise over 5 min. After 1 h at ꢀ78 ꢁC, water (50 mL) was added and
the mixture was extracted with EtOAc. The organic layer was dried
over anhydrous MgSO4 and concentrated in vacuo. The residue was
purified by flash column chromatography on silica gel (petroleum
ether/EtOAc, 7:3) to give 3 (2.13 g, 86%) as a white solid; mp¼75–
turnings. The reactions were monitored by thin-layer chromato-
graphy (TLC) analysis using silica gel (60 F254) plates. The com-
pounds were visualized by UV irradiation and/or spraying with
a solution of potassium permanganate, followed by charring at
150 ꢁC. Column chromatography was performed on silica gel 60
(230–400 mesh, 0.040–0.063 mm). Melting points (mp [ꢁC]) were
taken on samples in open capillary tubes and are uncorrected. The
infrared spectra of the compounds were recorded on an Infrared
Fourier Transform spectrophotometer using NaCl plates or KBr
pellets. 1H and 13C NMR spectra were recorded on a spectrometer at
250 MHz or at 400 MHz. Chemical shifts are given in parts per mil-
lion from tetramethylsilane (TMS) as an internal standard. Either an
ionspray or an electronic impact method was used to record mass
spectra. Petroleum ether (P.E.) had a 40–60 ꢁC boiling point range.
76 ꢁC. IR (cmꢀ1): 2980, 1735, 1596, 1489, 1346 cmꢀ1 1H NMR
.
(400 MHz, CDCl3)
d
: 1.43 (s, 18H), 6.36 (d, JH–P¼2.5 Hz, 2H), 7.16 (t,
J¼7.5 Hz, 4H), 7.24–7.33 (m, 16H). 13C NMR (100.6 MHz, CDCl3)
d:
27.7 (q), 83.2 (s), 107.7 (d, J3 ¼5 Hz), 107.9 (d), 119.7 (d), 119.8 (d),
C–P
125.6 (d),129.7 (d),134.8 (s, J2 ¼10.5 Hz),135.0 (s),148.9 (s),149.8
C–P

M. Chaignaud et al. / Tetrahedron 64 (2008) 8059–8066
8063
(s, J2 ¼7.5 Hz), 150.0 (s). HRMS (TOF ESþ) m/z [MþNa]þ calcd for
HRMS (TOF ESþ) m/z [MþNa]þ calcd for C32H36N4O263Na: 595.2532;
C–P
23
C
38H40N2O NaP2: 801.1954; found 801.1948.
found 595.2538.
12
4.4. General procedure (B) for Suzuki–Miyaura-type
coupling reactions
4.3. General procedure (A) for Stille-type coupling reactions
4.3.1. N,N-Bis-(tert-butoxycarbonyl)-2,5-di(benzo[b][1,4]dioxin-
3-yl)-[1,4]-dihydropyrazine (4a)
4.4.1. N,N-Bis-(tert-butoxycarbonyl)-2,5-diphenyl-[1,4]-
dihydropyrazine (4e)
To a stirred solution of bisvinylphosphate 3 (0.30 g, 0.38 mmol,
1 equiv) in THF (5 mL), benzodioxin-2-yl-tributyltin (0.561 g,
1.90 mmol, 5 equiv) and LiCl (0.096 g, 2.28 mmol, 6 equiv) were
added under argon. Then, the flask was evacuated and backfilled
with argon three times. Under argon, Pd(PPh3)4 (0.048 g,
0.04 mmol, 10 mol %) was added, and the mixture was refluxed for
1 h. After cooling, the reaction mixture was filtered through Celite
and was washed with EtOAc. The organic layer was washed with
brine, dried over anhydrous MgSO4, and concentrated in vacuo. The
residue was purified by flash column chromatography on silica gel
(petroleum ether/EtOAc, 98:2) to give 4a (0.166 g, 80%) as a yellow
To a solution of bisvinylphosphate 3 (0.300 g, 0.38 mmol,
1 equiv) in THF (5 mL) under argon, PdCl2(PPh3)2 (0.027 g,
0.04 mmol, 10 mol %) was added. The flask was evacuated and
backfilled with argon three times, and the mixture was stirred for
15 min. Then, phenylboronic acid (0.231 g, 1.90 mmol, 5 equiv),
Na2CO3 2 M (1.35 mL, 2.7 mmol, 3 equiv), and a few drops of EtOH
were added. The mixture was refluxed for 2 h. After cooling, the
reaction mixture was filtered through Celite and was washed with
EtOAc. The organic layer was washed with brine, dried over anhy-
drous MgSO4, and concentrated in vacuo. The residue was purified
by flash column chromatography on silica gel (petroleum ether/
EtOAc, 98:2) to give 4e (0.133 g, 72%) as a white solid; mp¼188–
189 ꢁC. IR: 2980, 1708, 1670, 1489 cmꢀ1. 1H NMR (250 MHz, CDCl3)
oil. IR (cmꢀ1): 3432, 1705, 1494 cmꢀ1. 1H NMR (250 MHz, CDCl3)
1.43 (s, 18H), 6.13 (s, 2H), 6.49 (s, 2H), 6.64–6.68 (m, 4H), 6.81–6.85
(m, 4H). 13C NMR (62.9 MHz, CDCl3)
: 28.0 (q), 83.0 (s), 109.5 (d),
d:
d
d
: 1.07 (s, 18H), 6.46 (s, 2H), 7.20–7.35 (m, 10H). 13C NMR (62.9 MHz,
116.2 (d), 118.2 (d), 122.5 (d), 124.3 (d), 124.7 (d), 131.8 (s), 142.0 (s),
142.4 (s), 146.2 (s), 149.7 (s). MS (IS): m/z¼547 [MH]þ, 569
[MþNa]þ.
CDCl3) d: 28.0 (q), 81.9 (s), 118.3 (d), 126.1 (d), 127.7 (d), 128.3 (d),
131.5 (s), 135.5 (s), 150.5 (s). HRMS (TOF ESþ) m/z [MþNa]þ calcd for
C
26H30N2O243Na: 457.2103; found 457.2104.
4.3.2. N,N-Bis-(tert-butoxycarbonyl)-2,5-di(vinyl)-[1,4]-
dihydropyrazine (4b)
4.4.2. N,N-Bis-(tert-butoxycarbonyl)-2,5-bis-(benzo[b]thiophen-
2-yl)-[1,4]-dihydropyrazine (4f)
Compound 4b was prepared according to the general procedure
(A) reported for 4a starting from 3 (0.300 g, 0.38 mmol, 1 equiv)
and tributylvinyltin (0.610 mL, 1.90 mmol, 5 equiv). Flash column
chromatography on silica gel (petroleum ether/EtOAc, 9:1) afforded
4b as a white solid; mp¼119–120 ꢁC. IR: 3434, 1702, 1643, 1368,
Compound 4f was prepared according to the general procedure
(B) reported for 4e starting from 3 (0.300 g, 0.38 mmol,1 equiv) and
benzo[b]thiophen-2-boronic acid (0.252 g, 1.90 mmol, 5 equiv).
Flash column chromatography on silica gel (petroleum ether/
EtOAc, 98:2) afforded 4f (0.180 g, 87%) as a yellow solid; mp¼168–
1340, 1163, 1133, 765 cmꢀ1
.
1H NMR (250 MHz, CDCl3)
d: 1.49 (s,
169 ꢁC. IR: 3018, 1706, 1640 cmꢀ1. 1H NMR (250 MHz, CDCl3)
d: 1.28
18H), 5.10 (d, J¼11.0 Hz, 2H), 5.30 (d, J¼17.0 Hz, 2H), 6.22 (dd, J¼17.0
(s, 18H), 6.74 (s, 2H), 7.26 (s, 2H), 7.27–7.35 (m, 4H), 7.69–7.79 (m,
and 11.0 Hz, 2H), 6.38 (s, 2H). 13C NMR (62.9 MHz, CDCl3)
d: 28.3 (q),
4H). 13C NMR (62.9 MHz, CDCl3)
d
: 27.9 (q), 82.9 (s), 120.1 (d), 121.7
82.4 (s), 113.7 (t),118.7 (d), 128.7(s), 128.9 (s), 129.7 (d), 150.2 (s). MS
(IS): m/z¼335 [MH]þ, 357 [MþNa]þ. Anal. Calcd for C18H26N2O3: C,
64.65; H, 7.84; N, 8.38. Found: C, 64.74; H, 7.79; N, 8.19.
(d), 122.3 (d), 123.5 (d), 124.6 (d), 124.7 (d), 125.8 (s), 137.4 (s), 139.1
(s), 139.5 (s), 150.1 (s). MS (IS): m/z¼569 [MþNa]þ. Anal. Calcd for
C30H30N2O4S2: C, 65.91; H, 5.53; N, 5.12. Found: C, 65.95; H, 5.38; N,
5.04.
4.3.3. N,N-Bis-(tert-butoxycarbonyl)-2,5-bis-(2-phenylethynyl)-
[1,4]-dihydropyrazine (4c)
4.4.3. N,N-Bis-(tert-butoxycarbonyl)-2,5-bis-(benzofuran-2-yl)-
[1,4]-dihydropyrazine (4g)
Compound 4c was prepared according to the general procedure
(A) reported for 4a starting from 3 (0.300 g, 0.38 mmol, 1 equiv)
and tributylphenyltin (0.460 mL, 0.65 mmol, 5 equiv). Flash column
chromatography on silica gel (petroleum ether/EtOAc, 98:2) affor-
ded 4c (0.051 g, 41%) as a yellow solid; mp¼160–161 ꢁC. IR: 2979,
Compound 4g was prepared according to the general procedure
(B) reported for 4e starting from 3 (0.300 g, 0.38 mmol,1 equiv) and
benzo[b]furan-2-boronic acid (0.221 g, 1.90 mmol, 5 equiv). Flash
column chromatography on silica gel (petroleum ether/EtOAc,
98:2) afforded 4g (0.180 g, 87%) as a beige solid; mp¼168–169 ꢁC.
1724, 1369, 1289, 1153, 1105, 756 cmꢀ1. 1H NMR (250 MHz, CDCl3)
d
:
1.40 (s, 18H), 6.56 (s, 2H), 7.18–7.21 (m, 5H), 7.30–7.34 (m, 5H). 13
NMR (62.9 MHz, CDCl3)
C
IR: 3018, 1713, 1454 cmꢀ1. 1H NMR (250 MHz, CDCl3)
d: 1.25 (br s,
d
: 28.3 (s), 82.1 (s), 83.0 (s), 90.3 (s), 111.3
18H), 6.74 (s, 2H), 6.91 (s, 2H), 7.18–7.30 (m, 4H), 7.42 (d, J¼8.0 Hz,
(s),122.7 (s), 125.0 (d),128.4 (s), 128.5 (s),133.7 (s),151.1 (s). MS (IS):
2H), 7.53 (dd, J¼6.5 and 1.5 Hz, 2H). 13C NMR (62.9 MHz, CDCl3)
d:
m/z¼483 [MH]þ, 495 [MþNa]þ.
27.8 (q), 82.8 (s), 104 (d), 111.0 (d), 120.2 (s), 120.3 (s), 120.4 (s), 121.0
(d), 121.9 (s), 123.1 (d), 124.6 (d), 128.4 (d), 149.6 (s), 149.9 (s), 154.4
(s). MS (IS): m/z¼515 [MH]þ, 537 [MþNa]þ.
4.3.4. N,N-Bis-(tert-butoxycarbonyl)-2,5-bis-(5-methoxy-1H-
indol-2-yl)-[1,4]-dihydropyrazine (4d)
Compound 4d was prepared according to the general procedure
(A) reported for 4a starting from 3 (0.149 g, 0.19 mmol, 1 equiv) and
4.4.4. N,N-Bis-(tert-butoxycarbonyl)-2,5-di(thiophen-2-yl)-[1,4]-
dihydropyrazine (4h)
5-methoxy-1H-indol-2-yl-tributyltin
5 equiv). Flash column chromatography on silica gel (petroleum
(0.420 mL,
0.96 mmol,
Compound 4h was prepared according to the general procedure
(B) reported for 4e starting from 3 (0.300 g, 0.38 mmol,1 equiv) and
thiophen-2-boronic acid (0.338 g,1.90 mmol, 5 equiv). Flash column
chromatography on silica gel (petroleum ether/EtOAc, 98:2) affor-
ded 4h (0.180 g, 87%) as a yellow oil. IR (cmꢀ1): 2980, 1707, 1368,
ether/EtOAc, 98:2) afforded 4d (0.027 g, 25%) as a yellow solid;
mp¼155–156 ꢁC. IR: 3404, 1681, 1640 cmꢀ1
.
1H NMR (400 MHz,
acetone-d6) d: 1.19 (s, 18H), 3.80 (s, 6H), 6.45 (s, 2H), 6.46 (s, 2H),
6.76 (dd, J¼9.0 and 2.5 Hz, 2H), 7.05 (d, J¼2.50 Hz, 2H), 7.28 (d,
1335. 1H NMR (250 MHz, CDCl3)
d
: 1.29 (s,18H), 6.57 (s, 2H), 6.96 (dd,
J¼5.0 and 3.5 Hz, 2H), 7.02 (dd, J¼3.5 and 1.0 Hz, 2H), 7.23 (dd, J¼5.0
and 1.0 Hz, 2H). 13C NMR (62.9 MHz, CDCl3)
: 27.8 (q), 82.4 (s),118.7
(d), 124.6 (d), 125.1 (d), 125.9 (d), 126.8 (s), 137.4 (s), 150.2 (s). HRMS
J¼9.0 Hz, 2H), 10.35 (se, 2H, NH). 13C NMR (100.6 MHz, acetone-d6)
d: 28.8 (q), 59.7 (q), 83.3 (s), 102.4 (d), 103.4 (d), 113.4 (d), 114.0 (d),
d
120.3 (d), 126.9 (s), 130.7 (s), 133.7 (s), 134.3 (s), 151.8 (s), 156.2 (s).

8064
M. Chaignaud et al. / Tetrahedron 64 (2008) 8059–8066
(TOF ESþ) m/z [MþNa]þ calcd for C22H26N2O423NaS2: 469.1231; found
4.6.3. N,N-Bis-(tert-butoxycarbonyl)-2-(hydroxy(3,4,5-
469.1243.
trimethoxy)-methyl)-3,6-diphenyl-[1,4]-dihydropyrazine (6c)
Compound 6c was prepared according to the general procedure
(C) reported for 6a starting from 4e (0.080 g, 0.18 mmol, 1 equiv)
and 3,4,5-trimethoxybenzaldehyde (0.177 g, 0.90 mmol, 5 equiv).
Flash column chromatography on silica gel (petroleum ether/
EtOAc/Toluene, 5:3:2) afforded 6c (0.085 g, 75%) as a white solid;
mp¼91–92 ꢁC. IR (cmꢀ1): 3378, 2979, 1715, 1625. 1H NMR
4.5. Preparation of the N,N-bis-(tert-butoxycarbonyl)-[1,4]-
dihydropyrazine (5)
To a solution of bisvinylphosphate 3 (1.00 g, 1.28 mmol, 1 equiv)
in DME (5 mL), Pd(OAc)2 (0.023 g, 0.10 mmol, 8 mol %) and PPh3
(0.053 g, 0.21 mmol, 0.16 equiv) were added under argon. Then, the
flask was evacuated and backfilled with argon three times and was
stirred for 5 min. At room temperature, this solution was then
transferred dropwise into a degassed solution of formic acid
(0.240 mL, 6.40 mmol, 5 equiv) and triethylamine (1.10 mL,
7.68 mmol, 6 equiv) in DME (5 mL). The reaction mixture was
refluxed for 2 h. After cooling, the mixture was filtered through
Celite and was washed with EtOAc. The organic layer was washed
with brine, dried with MgSO4, filtered, and concentrated in vacuo.
The residue was purified by flash column chromatography on silica
gel (petroleum ether/EtOAc, 98:2) to give 5 (0.165 g, 45%) as a white
(400 MHz, acetone-d6) d: 1.07 (s, 9H), 1.13 (s, 9H), 3.63 (s, 6H), 3.75
(3H), 5.29 (d, J¼10.5 Hz, 1H), 6.54 (s, 1H), 6.57–6.59 (m, 2H), 6.66 (d,
J¼10.5 Hz, 1H), 7.10–7.20 (m, 6H), 7.47–7.56 (m, 4H). 13C NMR
(100.6 MHz, acetone-d6) d: 28.7 (q), 28.7 (q), 57.4 (q), 61.8 (q), 73.5
(d), 84.1 (s), 84.4 (s), 104.9 (d), 122.2 (d), 126.6 (d), 129.1 (d), 129.8
(d), 130.3 (d), 130.4 (s), 130.8 (d), 132.7 (s), 136.5 (s), 137.3 (s),
139.6 (s), 140.4 (s), 140.6 (s), 151.8 (s), 155.5 (s), 156.1 (s). HRMS (TOF
ESþ) m/z [MþNa]þ calcd for C36H42N2O283Na: 653.2838; found
653.2847.
4.6.4. N,N-Bis-(tert-butoxycarbonyl)-2-formyl-3,6-diphenyl-[1,4]-
dihydropyrazine (6d)
solid; mp¼104–105 ꢁC. 1H NMR (400 MHz, CDCl3)
d: 1.45 (s, 18H),
Compound 6d was prepared according to the general pro-
cedure (C) reported for 6a starting from 4e (0.080 g, 0.18 mmol,
1 equiv) and DMF (0.070 mL, 0.90 mmol, 5 equiv). Flash column
chromatography on silica gel (petroleum ether/EtOAc, 8:2) affor-
ded 6d (0.096 g, 85%) as a yellow solid; mp¼145–146 ꢁC. IR
5.77 (s, 2H), 5.89 (br s, 2H), 5.94 (br s, 2H), 6.04 (s, 2H). 13C NMR
(100.6 MHz, CDCl3) d: 28.3 (q), 81.8 (s), 81.9 (s), 110.5 (d), 111.0 (d),
111.6 (d), 112.0 (d), 148.4 (s), 148.5 (s). HRMS (TOF ESþ) m/z
[MþNa]þ calcd for C14H22N2O243Na: 305.1477; found 305.1482.
(cmꢀ1): 2980, 1815, 1720, 1364. 1H NMR (400 MHz, CDCl3)
d: 1.14
(s, 9H), 1.25 (br s, 9H), 7.09 (s, 1H), 7.27–7.57 (m, 10H), 9.32 (br s,
4.6. General procedure (C) for the preparation of
trisubstituted derivatives 6a–6e
1H). 13C NMR (100.6 MHz, CDCl3)
d
: 27.5 (q), 27.9 (q), 82.0 (s), 84.2
(s), 125.3 (d), 125.5 (s), 128.0 (d), 128.4 (d), 128.7 (d), 129.8 (d),
130.5 (d), 131.7 (s), 131.9 (s), 149.8 (s), 151.3 (s), 186.0 (s). HRMS
(TOF ESþ) m/z [MþNa]þ calcd for C27H30N2O253Na: 485.2052; found
485.2049.
4.6.1. N,N-Bis-(tert-butoxycarbonyl)-2-(tributylstannyl)-3,6-
diphenyl-[1,4]-dihydropyrazine (6a)
Lithium diisopropylamide 1.8 M in THF/heptane/ethylbenzene
(0.250 mL, 0.54 mmol, 2.5 equiv) was added dropwise, at ꢀ78 ꢁC, to
4.6.5. N,N-Bis-(tert-butoxycarbonyl)-2-methoxycarbonyl-3,6-
diphenyl-[1,4]-dihydropyrazine (6e)
a
solution of N,N-bis-(tert-butoxycarbonyl)-2,5-diphenyl-[1,4]-
dihydropyrazine 4e (0.080 g, 0.18 mmol, 1 equiv) in THF (4 mL).
After stirring for 1 h at ꢀ78 ꢁC, distilled HMPA (0.060 mL,
0.36 mmol, 2 equiv) was added and then dropwise a solution of
tributyltin chloride (0.240 mL, 0.90 mmol, 5 equiv) in THF (1 mL).
After 1 h, the mixture was diluted with EtOAc and quenched with
water. The organic layer was separated, and the aqueous solution
was extracted with EtOAc. The combined organic phases were dried
with MgSO4, filtered, and concentrated in vacuo. The residue was
purified by flash column chromatography on silica gel (petroleum
ether/EtOAc, 98:2) to give 6a (0.081 g, 62%) as a yellow oil. IR: 2955,
Compound 6e was prepared according to the general procedure
(C) reported for 6a starting from 4e (0.1 g, 0.23 mmol, 1 equiv) and
methyl cyanoformate (0.070 mL, 1.15 mmol, 5 equiv). Flash column
chromatography on silica gel (petroleum ether/EtOAc, 8:2) afforded
6e (0.067 g, 60%) as a yellow solid; mp¼65–66 ꢁC. IR (cmꢀ1): 2970,
1732, 1634, 1360. 1H NMR (400 MHz, CDCl3)
d: 1.10 (br s, 18H), 3.69
(s, 3H), 6.69 (br s, 1H), 7.27–7.36 (m, 6H), 7.51 (m,4H). 13C NMR
(100.6 MHz, CDCl3) : 27.4 (q), 51.8 (q), 81.8 (s), 83.1 (s), 119.3 (d),
d
125.4 (s), 128.0 (d), 128.4 (d), 128.6 (d), 129.9 (d), 130.5 (d), 131.7 (s),
131.8 (s), 135.0 (s), 141.1 (s), 142.9 (s), 151.9 (s), 163.3 (s). MS (IS):
m/z¼515 [MþNa]þ.
1710, 1358 cmꢀ1. 1H NMR (400 MHz, CDCl3)
1.09 (s, 9H), 1.10 (s, 9H), 1.15–1.46 (m, 18H), 9.81 (s, 1H), 7.19–7.43
(m, 10H). 13C NMR (100.6 MHz, CDCl3)
: 12.2 (t), 13.8 (q), 27.5 (t),
d: 0.84 (t, J¼8.0 Hz, 9H),
d
4.7. N,N-Bis-(tert-butoxycarbonyl)-2-methoxycarbonyl-[1,4]-
27.8(q), 27.9 (q), 29.0 (t), 81.0 (s), 81.8 (s), 119.4 (d), 124.8 (d), 126.0
(d), 127.2 (d), 128.0 (d), 128.2 (d), 131.0 (s), 131.0 (s), 136.7 (s), 138.4
(s), 141.2 (s), 152.0 (s). HRMS (TOF ESþ) m/z [MþNa]þ calcd for
dihydropyrazine (7)
Lithium diisopropylamide 1.8 M in THF/heptane/ethylbenzene
(0.140 mL, 0.25 mmol, 1.2 equiv) was added dropwise at ꢀ78 ꢁC, to
a solution of N,N-bis-(tert-butoxycarbonyl)-[1,4]-dihydropyrazine 5
(0.060 g, 0.21 mmol, 1 equiv) in THF (2 mL). After 15 min of stirring
at ꢀ78 ꢁC, the solution of methyl cyanoformate (0.833 mL,
1.05 mmol, 5 equiv) in THF (1 mL), previously dried over molecular
sieves (4 Å), was added dropwise. After 2 h of stirring, the mixture
was diluted with EtOAc and quenched with water. The organic layer
was separated, and the aqueous phase was extracted with EtOAc.
The combined organic phases were dried with MgSO4, filtered, and
concentrated in vacuo. The residue was purified by flash column
chromatography on silica gel (petroleum ether/EtOAc, 98:2) to give
7 (0.072 g, 65%) as a yellow oil. IR (cmꢀ1): 2980, 1732, 1634,
C
38H56N2O423Na120Sn: 747.3159; found 747.3183.
4.6.2. N,N-Bis-(tert-butoxycarbonyl)-2-(trimethylsilyl)-3,6-
diphenyl-[1,4]-dihydropyrazine (6b)
Compound 6b was prepared according to the general procedure
(C) reported for 6a starting from 4e (0.100 g, 0.23 mmol, 1 equiv)
and trimethylsilyl chloride (0.145 mL, 1.15 mmol, 5 equiv). Flash
column chromatography on silica gel (petroleum ether/EtOAc, 8:2)
afforded 6b (0.073 g, 63%) as an oil. IR: 2980,1694, 1588 cmꢀ1
.
1H
: 0.07 (s, 9H), 1.07 (br s, 18H), 6.99 (s, 1H),
7.34 (m, 10H). 13C NMR (100.6 MHz, CDCl3)
: 0.9 (q), 1.2 (2C, t), 27.5
NMR (400 MHz, CDCl3)
d
d
(q), 27.9 (q), 81.1 (s), 82.1 (s), 125.3 (d), 125.5 (s), 128.0 (d), 128.4 (d),
128.7 (d), 129.6 (s), 132.6 (s), 138.3 (s), 145.6 (s), 151.6 (s). HRMS
(TOF ESþ) m/z [MþNa]þ calcd for C29H38N2O423NaSi: 529.2486;
found 529.2511.
1371 cmꢀ1. 1H NMR (400 MHz, DMSO-d6)
3.71 (s, 3H), 6.07 (d, J¼3.5 Hz, 1H), 6.31 (d, J¼3.5 Hz, 1H), 7.02 (s,
1H). 13C NMR (100.6 MHz, DMSO-d6)
: 27.4 (q), 27.5 (q), 51.8 (q),
d: 1.39 (s, 9H), 1.47 (s, 9H),
d

M. Chaignaud et al. / Tetrahedron 64 (2008) 8059–8066
8065
81.6 (s), 83.2 (s), 113.7 (d), 114.9 (d), 125.1 (d), 148.0 (s), 149.3 (s),
163.1 (s). HRMS (TOF ESþ) m/z [MþNa]þ calcd for C16H24N2O263Na:
363.1532; found 363.1528.
standard method using quinine sulfate in 0.5 N H2SO4 solution as
reference. The refractive index of the solution was taken into
account in the calculation (Figs. 3 and 4).
4.8. General procedure (D) for the preparation
of the pyrazines
4.8.1. 2,5-Diphenylpyrazine (8a)
Method 1: to a solution of N,N-bis-(tert-butoxycarbonyl)-2,5-
diphenyl-[1,4]-dihydropyrazine 4e (0.080 g, 1.80 mmol, 1 equiv) in
CH2Cl2 (5 mL) was added trifluoroacetic acid (1.00 mL, 1.80 mmol,
10 equiv) with fast stirring at room temperature for 2–4 h (TLC
control). The reaction mixture was then diluted with CH2Cl2 and
was quenched with saturated NaHCO3 solution. The organic layer
was separated, and the aqueous phase was extracted with CH2Cl2.
The combined organic phases were dried with MgSO4, filtered,
and concentrated in vacuo. The residue was washed with Et2O,
filtered, and concentrated to afford 8a as a beige solid (0.041 g,
100%).
Method 2: to a solution of 4e (0.080 g, 1.80 mmol, 1 equiv) in
CH2Cl2 (5 mL) was added trimethylsilyl iodide (1.30 mL, 1.10 mmol,
4.8 equiv) at room temperature. After 30 min of stirring, the
reaction mixture was quenched with saturated NaHCO3 solution.
The compound 8a (0.037 g, 73%) was isolated by using the same
work-up as described in method 1.
Figure 3. Normalized absorption spectra of compounds 8a, 8b, and 8c in CHCl3.
Mp¼195–196 ꢁC. IR (cmꢀ1): 3382, 1652, 1636, 1106, 1078 cmꢀ1
.
1H NMR (400 MHz, CDCl3)
d: 7.45–7.55 (m, 6H), 8.06 (m, 4H), 9.08
(s, 2H). 13C NMR (100.6 MHz, CDCl3)
d: 126.9 (d), 129.2 (d), 129.9 (d),
136.4 (s), 141.4 (d),150.8 (s). HRMS (EI) m/z [M]þ calcd for C16H12N2:
232.1000; found 232.0985.
4.8.2. 2,5-Dithiophenylpyrazine (8b)
Compound 8b was prepared according to the method described
for 8a. Yellow solid isolated in 64% yield; mp¼93 ꢁC. 1H NMR
(250 MHz, CDCl3)
d
: 7.17 (t, 2H, J¼4.5 Hz), 7.48 (d, 2H, J¼4.8 Hz),
7.68 (d, 2H, J¼3.6 Hz), 8.88 (s, 2H). HRMS (EI) m/z [M]þ calcd for
C
12H8N2S2: 244.0128; found 244.0132.
4.8.3. 2,5-Dibenzothiophenylpyrazine (8c)
Compound 8c was prepared according to the method described
for 8a. Orange solid isolated in 80% yield; mp >250 ꢁC. 1H NMR (250
MHz, CDCl3) d: 7.38–7.42 (m, 3H), 7.85 (m, 5H), 7.97 (s, 1H), 9.07 (s,
1H). HRMS (EI) m/z [M]þ calcd for C20H12N2S2: 344.0441; found
344.0430.
Figure 4. Normalized fluorescence spectra of compounds 8a, 8b, and 8c in CHCl3.
4.8.4. 2,5-Bis-(5-methoxy-1H-indol-2-yl)-pyrazine (8d)
Compound 8d was prepared according to the method described
for 8a. Brown solid isolated in 20% yield; mp >250 ꢁC. 1H NMR
Acknowledgements
(250 MHz, DMSO-d6)
d
: 3.78 (s, 6H), 6.80 (dd, 2H, J¼2.2 and 9 Hz),
7.08 (d, 2H, J¼2 Hz), 7.25 (br s, 2H), 7.37 (d, 2H, J¼9 Hz), 9.21 (s, 2H),
11.68 (br s, 2H). HRMS (EI) m/z [M]þ calcd for C22H18N4O2:
370.4102; found 370.4104.
´
We thank ‘La Ligue Contre le Cancer Comite du Loiret’ and ‘La
Fe´de´ration pour la Recherche Me´dicale Comite´ d’Orle´ans’ for their
financial support. The authors thank Sandrine Villette, Centre de
Biophysique Mole´culaire CNRS UPR4301 Orle´ans, for her help in the
study of the photophysical properties of pyrazine derivatives.
4.9. Fluorescence study
Absorption spectra were obtained with an UVIKON XL Double
Beam ultraviolet–visible (UV/VIS) spectrophotometer (Secomam,
France). Stock solutions for absorption measurements were
prepared in CHCl3 and diluted at absorbance 0.01–0.05 for fluo-
rescence measurements to minimize the ‘inner-filter effect’. Fluo-
rescence emission spectra (excitation wavelength 326 nm for 8a,
367 nm for 8b, 390 nm for 8c, and 2 nm bandwidth) were recorded
at room temperature in silica cells of 1 cm pathlength using a Jobin-
Yvon Fluoromax 2 spectrofluorimeter. Emission spectra were
corrected with the computer program supplied with the in-
strument. Fluorescence quantum yields were determined by the
Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2008.06.080.
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