Different behavior of the reaction between 1,2-diaza-1,3-butadienes and 1,2-diamines under solvent or solvent-free conditions

Article abstract of DOI:10.1055/s-2005-868517

New piperazinones are obtained in satisfactory yields by reaction of 1,2-diaza-1,3-butadienes with 1,2-diamines under solvent-free conditions. In polar solvents, the same reagents give rise to interesting dihydropyrazines and then to pyrazines by oxidatio

Full text of DOI:10.1055/s-2005-868517

1474
LETTER
Different Behavior of the Reaction between 1,2-Diaza-1,3-butadienes and
1,2-Diamines under Solvent or Solvent-Free Conditions
Reactionbetween
r
1,2-Diaz
a
a-1,3-butad
z
ienes
a
nd1
i
,2-Dia
m
o
ines A. Attanasi, Lucia De Crescentini, Gianfranco Favi, Paolino Filippone,* Samuele Lillini, Fabio Mantellini,
Stefania Santeusanio
Istituto di Chimica Organica della Facoltà di Scienze Matematiche, Fisiche e Naturali, Università degli Studi di Urbino ‘Carlo Bo’,
Via Sasso 75, 61029 Urbino, Italy
E-mail: filippone@uniurb.it
Received 7 March 2005
O
COOMe
Abstract: New piperazinones are obtained in satisfactory yields by
reaction of 1,2-diaza-1,3-butadienes with 1,2-diamines under sol-
vent-free conditions. In polar solvents, the same reagents give rise
to interesting dihydropyrazines and then to pyrazines by oxidation
with PTAB or Pd/C.
H2N
N
R3
R2
R1
N
MeOOC
N
1a,b
solvent-free
N
H
+
HN
H2N
R2
NH2
R3
Key word: Michael additions, regioselectivity, heterocyclic com-
pounds, 1,2-diaza-1,3-butadienes, pyrazine derivatives
O
R1
3
2a–c
Pyrazines and piperazinones represent important classes
of heterocycle rings as they occur in many pharmacologi-
cally active substances. The piperazinone ring has proven
to be a valuable scaffold for the construction of biologi-
cally active molecules. Due in large part to their similarity
with amino acids, piperazinones have proven to be useful
tools for drug design and for evaluating interactions be-
tween natural ligands and macromolecules.1 Pyrazines are
useful for the treatment of obesity, psychiatric and neuro-
logical disorders.2 Based on our previous experience on
the chemistry of 1,2-diaza-1,3-butadienes,3 we report
herein a facile synthesis of pyrazine derivatives from
these starting materials under mild conditions.
H
N
H
N
R3
R2
O
R3
R2
O
O
O
N
N
R1
N
N
H
R1
N
H
N
H
5a,b
4a–c
Scheme 1
1,2-Diaza-1,3-butadienes 1a,b readily reacted under sol-
vent-free conditions with 1,2-ethanediamine (2a), ( )-
trans-1,2-diaminecyclohexane (2b), or (1R,2R)-(+)-1,2-
diphenyl-1,2-ethanediamine (2c) to give substituted
piperazinones 4a–c or 5a,b (see Scheme 1 and Table 1).
The first step of the reaction is the nucleophilic attack of
an NH2 group of compounds 2a–c at the terminal C-atom
of the azo-ene system of 1a,b with the formation of 1,4-
adducts 3. The subsequent nucleophilic attack of the
The reaction between 1,2-diaza-1,3-butadienes and 1,2-
diamines 2a–c has been carried out in MeCN or EtOH or
under solvent-free conditions showing an unexpected and
interesting different behaviour.
Table 1 Results for the Synthesis of Piperazinones 4 and 58
Entry
1,2-Diaza-1,3- R1
butadiene 1
Diamine 2
R2
R3
H
Product 4
Product 5
Yield (%)a Temp (°C)
1
2
3
4
5
1a
1a
1a
1b
1b
NH2
2a
2b
2c
2a
2b
H
4a
70
42
65
88
47
25
45
90
25
45
NH2
–(CH2)4–
–(CH2)4–
5a
NH2
Ph
H
Ph
H
4b
4c
Ot-Bu
Ot-Bu
5b
a Yield of pure isolated products based on 1,2-diaza-1,3-butadienes 1a,b.
SYNLETT 2005, No. 9, pp 1474–1476
0
1.
0
6.
2
0
0
5
Advanced online publication: 02.05.2005
DOI: 10.1055/s-2005-868517; Art ID: D06105ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Reaction between 1,2-Diaza-1,3-butadienes and 1,2-Diamines
1475
Table 2 Results for the Synthesis of Piperazine Derivatives 6 and 79,10
Entry
1,2-Diaza-1,3- R1
butadiene 1
R2
Diamine 2 R3
R4
Ph
Product 6 Yield (%)a Product 7 Yield (%)a
1
2
3
4
5
6
1a
1a
1b
1c
1d
1d
NH2
Me
Me
Me
Et
2b
–(CH2)4–
–(CH2)4–
6a
6b
6a
49
68
45
7a
7b
7a
7d
7d
7c
46
62
43
35
32
60
NH2
2c
2b
2a
2a
2c
Ph
Ot-Bu
NH2
H
H
Ot-Bu
Ot-Bu
Et
H
H
Et
Ph
Ph
6c
66
a Yield of pure isolated products based on 1,2-diaza-1,3-butadienes 1a–d.
second NH2 group at the ester function with loss of an The product 7d has been synthesized by the treatment of
alcohol molecule produces compounds 4a–c by ring intermediate 3 with Pd/C in EtOH under reflux6
closure.
(Scheme 2, Path b). Complicated crude mixture likely due
to degradation products has been observed for this reac-
tion and only formation of slight traces of 4a,c has been
detected by chromatography. Therefore, only product 7d
was isolated.
In the case of the reaction between 1,2-diaza-1,3-buta-
dienes 1a,b and 1,2-diamine 2b, a spontaneous oxidation
takes place with the formation of pyrazine derivatives
5a,b without the isolation of the relevant products 4.
In conclusion, this paper shows the different regioselec-
tivity in the reaction between 1,2-diaza-1,3-butadienes
and 1,2-diamines under solvent or solvent-free condi-
tions. In this way it is possible to obtain interesting new
pyrazines and piperazinones. Two known pyrazine
When the reaction between 1a–d and 2a–c was carried out
in polar solvents such as MeCN or EtOH, a different be-
haviour was observed. After the formation of the same
preliminary 1,4-adduct 3, the cyclization process occurs
by attack of the second NH2 group at the C=N hydrazone
carbon with successive loss of hydrazine molecule4 (see
Scheme 2 and Table 2). Then, an oxidative process af-
fords pyrazines 6a–c. The treatment of these compounds
with the brominating agent phenytrimethylammonium tri-
bromide (PTAB)5 easily furnished pyrazines 7a–c
(Scheme 2, Path a). No products 4 or 5 were detected in
the reaction mixture.
compounds,
methyl
3-methyl-5,6,7,8-tetrahydro-2-
quinoxalinecarboxylate7a (7a) and ethyl 3-methyl-2-
pyrazinecarboxylate7b (7d) used in the synthesis of bio-
logically active molecules have been also synthesized.
The advantage of this type of synthesis is the accessibility
of the starting materials and the simplicity of the experi-
mental procedures. Further explorations of the synthesis,
reaction, and biological activity of these compounds are in
progress.
O
COOR2
O
N
R1
N
Acknowledgment
R1
NH
N
COOR2
NH
1a–d
This work was supported by financial assistance from the M.I.U.R.-
Roma, and the Università di Urbino ‘Carlo Bo’.
MeCN
+
or EtOH
R3
H2N
R3
NH2
R4
H2N
R4
References
(1) (a) Dinsmore, C. J.; Beshore, D. C. Org. Prep. Proced. Int.
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2a–c
3
EtOH,
Pd/C 5%
(from 2a)
Path a
N
Path b
R2OOC
R3
R4
R2OOC
R3
R4
N
CH2Cl2,
PTAB (2 equiv)
N
N
Weissberger, A.; Taylor, E. C., Eds.; Wiley Interscience:
Chichester, 1982, 8–10. (d) In The Chemistry of
7a–d
6a–c
Scheme 2
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Synlett 2005, No. 9, 1474–1476 © Thieme Stuttgart · New York

1476
O. A. Attanasi et al.
LETTER
(3) (a) Attanasi, O. A.; De Crescentini, L.; Favi, G.; Filippone,
P.; Mantellini, F.; Santeusanio, S. ARKIVOC 2002, xi, 274;
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Santeusanio, S. J. Org. Chem. 2004, 69, 2686. (c) Attanasi,
O. A.; De Crescentini, L.; Favi, G.; Filippone, P.; Mantellini,
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(5) (a) Wisweswariah, S.; Prakash, G.; Bhushan, V.;
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51, 2423.
1738, 1717, 1697, 1531 cm–1. 1H NMR (400 MHz, DMSO-
d6): d = 1.23 (m, 4 H), 1.43 (s, 9 H), 1.68 (m, 2 H), 1.87 (m,
1 H), 1.95 (s, 3 H), 2.17 (m, 1 H), 2.98 (m, 1 H), 3.06 (m, 1
H), 8.45 (s, 1 H), 9.87 (s, 1 H). 13C NMR (100 MHz, DMSO-
d6): d = 14.34, 23.15, 24.65, 27.97, 29.99, 31.23, 53.46,
62.49, 79.65, 147.01, 152.72, 156.55, 161.53.
MS: m/z (%) = 307 (2) [M+ – 1], 293 (2), 279 (2), 252 (2),
235 (2), 207 (4), 191 (4), 179 (10), 167 (10), 137 (10), 123
(10), 111 (16), 97 (28), 83 (30), 69 (44), 57 (100). Anal.
Calcd for C15H24N4O3: C, 58.42; H, 7.84; N, 18.17. Found:
C, 58.50; H, 7.79; N, 18.23.
(9) General Procedure for the Synthesis of Substituted 5,6-
Dihydropyrazines 6a–c and Substituted Pyrazines 7a–c.
A stoichiometric amount of 1,2-diaza-1,3-butadiene 1a,b,d
(1.0 mmol) was slowly added to a solution of 1,2-diamines
2b,c (1.0 mmol) in MeCN (50 mL). The reaction was
allowed to stand at r.t. with magnetic stirring until complete
disappearance of 1,2-diaza-1,3-butadiene (monitored by
silica gel TLC, 1 h). The solvent was removed under reduced
pressure and the products 6a–c were purified by
chromatography on silica, (elution mixture: cyclohexane–
EtOAc, 30:70). In order to obtain the oxidized products
7a–c, the crude mixture was dissolved with CH2Cl2 (150
mL) and PTAB (2 mmol) was slowly added. The crude
reaction mixture was washed with H2O (2 × 30 mL), the
organic layer was dried over anhyd Na2SO4 and the solvent
was evaporated under reduced pressure. The products 7a–c
were purified by chromatography on silica (elution mixture:
cyclohexane–EtOAc, 60:40).
Data for methyl (5R,6R)-3-methyl-5,6-diphenyl-5,6-
dihydro-2-pyrazinecarboxylate (6b): 1H NMR (400 MHz,
CDCl3): d = 2.41 (d, 5J = 2.4 Hz, 3 H), 3.95 (s, 3 H), 4.29 (dq,
3J = 14.8 Hz, 5J = 2.4 Hz, 1 H), 4.37 (d, 3J = 14.8 Hz, 1 H),
6.95 (m, 4 H), 7.19 (m, 6 H). 13C NMR (100 MHz, CDCl3):
d = 22.87, 53.05, 65.27, 66.13, 126.55, 126.85, 127.34,
127.40, 128.13, 128.21, 139.35, 140.03, 153.24, 155.58,
164.36. MS: m/z (%) = 306 (100) [M+].
(6) (a) Adlington, R. M.; Baldwin, J. E.; Catterick, D.; Pritchard,
G. J. J. Chem. Soc., Perkin Trans. 1 2000, 299.
(b) Adlington, R. M.; Baldwin, J. E.; Catterick, D.;
Pritchard, G. J. J. Chem. Soc., Perkin Trans. 1 2001, 668.
(7) (a) Gybaeck, H.; Johansson, M.; Minidis, A.; Nordvall, G.;
Raboisson, P.; Wensbro, D. PCT Int. Appl. WO
2004069813, 2004. (b) Merthes, M. P.; Lin, A. J. J. Med.
Chem. 1970, 13, 77.
(8) General Procedure for the Synthesis of Piperazinones
5a,b and 4a–c.
1,2-Diaza-1,3-butadienes 1a,b (0.5 mmol) were slowly
added to a solution of 1,2-diamines 2a–c (3 mmol) heated in
an oil bath (for temperatures, see Table 1) with magnetic
stirring. After the complete disappearance of 1,2-diaza-1,3-
butadiene (monitored by silica gel TLC, 20 min) the crude
reaction mixture was purified by chromatography on silica
gel (elution mixture: EtOAc–MeOH, 90:10) for the products
5a,b and 4b. The excess of 1,2-diamine 2a was evaporated
under reduced pressure and the crude reaction mixture was
purified by crystallization from EtOAc–MeOH for the
products 4a,c.
Data for methyl 3-methyl-5,6-diphenyl-2-
pyrazinecarboxylate (7b) yellow powder, mp 102–104 °C.
IR (nujol): nmax = 1728, 1402, 1312 cm–1. 1H NMR (400
MHz, CDCl3): d = 2.93 (s, 3 H), 4.01 (s, 3 H), 7.29 (m, 6 H),
7.48 (m, 4 H). 13C NMR (100 MHz, CDCl3): d = 22.73,
52.77, 128.21, 128.25, 128.64, 129.07, 129.58, 129.62,
137.59, 137.66, 139.40, 149.16, 151.91, 153.31, 165.87.
MS: m/z (%) = 304 (100) [M+]. Anal. Calcd for C19H16N2O2:
C, 74.98; H, 5.30; N, 9.20. Found: C, 74.89; H, 5.25; N, 9.14.
(10) General Procedure for Synthesis of Ethyl 3-Methyl-
pyrazine-2-carboxylate (7d).
Data for tert-butyl 2-[1-(3-oxo-2-piperazinyl)ethylidene]-1-
hydrazinecarboxylate (4c): white powder, mp 187–188 °C.
IR (nujol): nmax = 3229, 1723, 1698, 1659, 1541 cm–1. 1H
NMR (400 MHz, DMSO-d6): d = 1.43 (s, 9 H), 1.70 (s, 3 H),
2.76 (m, 1 H), 2,79 (br s, 1 H), 2.92 (m, 1 H), 3.04 (m, 1 H),
A solution of 1,2-diaza-1,3-butadienes 1c,d (1 mmol) in
EtOH (10 mL) was added dropwise to a magnetically stirred
solution of 1,2-ethanediamine 2a (1.0 mmol) in EtOH (50
mL). The reaction was allowed to stand at r.t. until complete
disappearance of 1,2-diaza-1,3-butadiene (monitored by
silica gel TLC, 1 h). The reaction was then treated with Pd/
C (110 mg, 5%) with magnetic stirring and was refluxed for
14 h. The mixture was filtered and the solvent evaporated
under reduced pressure. Product 7d was purified by
chromatography on silica gel (elution mixture:
3.19 (m, 1 H), 3.80 (s, 1 H), 7.76 (s, 1 H), 9.47 (s, 1 H). 13
C
NMR (100 MHz, DMSO-d6): d = 13.55, 28.04, 41.21, 41.81,
66.07, 79.01, 150.82, 153.00, 167.82. MS: m/z (%) = 256 (2)
[M+], 239 (1), 200 (5), 183 (2), 139 (26), 126 (8), 110 (8), 98
(30), 83 (16), 69 (24), 57 (100). Anal. Calcd for C11H20N4O3:
C, 51.55; H, 7.87; N, 21.86. Found: C, 51.64; H, 7.81; N,
21.79.
Data for tert-butyl 2-[1-(3-oxo-3,4,4a,5,6,7,8,8a-octahydro-
2-quinoxalinyl)ethylidene]-1-hydrazinecarboxylate (5b):
white powder, mp 195–197 °C. IR (nujol): nmax = 3223,
cyclohexane–EtOAc, 70:30).
Synlett 2005, No. 9, 1474–1476 © Thieme Stuttgart · New York