Straightforward access to pyrazines, piperazinones, and quinoxalines by reactions of 1,2-diaza-1,3-butadienes with 1,2-diamines under solution, solvent-free, or solid-phase conditions

Article abstract of DOI:10.1021/jo060450v

The preparation of tetrahydropyrazines, dihydropyrazines, pyrazines, piperazinones, and quinoxalines by 1,4-addition of 1,2-diamines to 1,2-diaza-1,3-butadienes bearing carboxylate, carboxamide, or phosphorylated groups at the terminal carbon and subseque

Full text of DOI:10.1021/jo060450v

Straightforward Access to Pyrazines, Piperazinones, and
Quinoxalines by Reactions of 1,2-Diaza-1,3-butadienes with
1,2-Diamines under Solution, Solvent-Free, or Solid-Phase
Conditions
Domitila Aparicio,‡ Orazio A. Attanasi,*,† Paolino Filippone,† Roberto Ignacio,‡
Samuele Lillini,† Fabio Mantellini,† Francisco Palacios,*,‡ and Jesu´s M. de los Santos‡
Istituto di Chimica Organica, UniVersita` degli Studi di Urbino “Carlo Bo”, Via Sasso 75, 61029 Urbino,
Italy, and Departamento de Qu´ımica Orga´nica I, Facultad de Farmacia, UniVersidad del Pa´ıs Vasco,
Apartado 450, 01080 Vitoria, Spain
attanasi@uniurb.it; qoppagaf@Vf.ehu.es
ReceiVed March 2, 2006
The preparation of tetrahydropyrazines, dihydropyrazines, pyrazines, piperazinones, and quinoxalines
by 1,4-addition of 1,2-diamines to 1,2-diaza-1,3-butadienes bearing carboxylate, carboxamide, or
phosphorylated groups at the terminal carbon and subsequent internal heterocyclization is described.
The solvent-free reaction of carboxylated 1,2-diaza-1,3-butadienes with the same reagents affords
piperazinones, while phosphorylated 1,2-diaza-1,3-butadienes yield phosphorylated pyrazines. The solid-
phase reaction of polymer-bound 1,2-diaza-1,3-butadienes with 1,2-diamines produces pyrazines.
Introduction
which are biosynthesized from amino acids, are common units
in a wide variety of marine natural products showing cytostatic
Pyrazines1,2 and quinoxalines3,4 are widely used intermediates
in medicinal chemistry. Furthermore, quinoxalines constitute the
skeleton of natural products and antibiotics,5 while pyrazines,
(3) (a) Porter, A. E. A. Pyrazines and their Benzo DeriVatiVes In
ComprehensiVe Heterocyclic Chemistry; Katritzky, A. R., Rees, C. W., Eds.;
Pergamon Press: New York, 1984; Vol. 3, p 191. (b) Cheeseman, G. W.
H.; Cookson, R. F. In The Chemistry of Heterocyclic Compounds, 2nd ed.;
Weissberger, A., Taylor, E. C., Eds.; Wiley: New York, 1979; p 1. (c)
Toshima, K.; Ozawa, T.; Kimura, T.; Matsumura, S. Bioorg. Med. Chem.
Lett. 2004, 14, 2777.
(4) (a) Jaso, A.; Zarranz, B.; Aldana, I.; Monge, A. J. Med. Chem. 2005,
48, 2019. (b) Piras, S.; Loriga, M.; Paglietti, G. Farmaco 2004, 59, 185.
(c) Carta, A.; Loriga, M.; Zanetti, S.; Sechi, L. A. Farmaco 2003, 58, 1251.
(d) Seitz, L. E.; Suling, W. J.; Reynolds, R. C. J. Med. Chem. 2002, 45,
5604. (e) Carta, A.; Paglietti, G.; Rhbarnikookar, M. E.; Sanna, P.; Sechi,
L.; Zanetti, S. Eur. J. Med. Chem. 2002, 37, 355.
† Universita` degli Studi di Urbino “Carlo Bo”.
‡ Universidad del Pa´ıs Vasco.
(1) For recent reviews of pyrazines, see: (a) Dembitsky, V. M.;
Gloriozova, T. A.; Poroikov, V. V. Mini-ReV. Med. Chem. 2005, 5, 319.
(b) Gryszkiewicz-Wojtkielewicz, A.; Jastrzebska, I.; Morzycki, J. W.;
Romanowska, D. B. Curr. Org. Chem. 2003, 7, 1257. (c) McCullough, K.
J.; Rodd’s Chemistry of Carbon Compounds, 2nd ed.; Sainsbury, M., Ed.;
Elsevier: Amsterdam, 2000; Vol. 4 (Parts I-J), pp 99-171. (d) Sato, N.
ComprehensiVe Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W.,
Boulton, A. J., Eds.; Elsevier: Oxford, 1996; Vol. 6, p 233.
(2) For recent contributions, see: (a) Buron, F.; Ple, N.; Turck, A.;
Queguiner, G. J. Org. Chem. 2005, 70, 2616. (b) Elmaaty, T. A.; Castle,
L. W. Org. Lett. 2005, 7, 5529. (c) Bonde, C. G.; Gaikwad, N. J. Bioorg.
Med. Chem. 2004, 12, 2151. (d) Gohlke, H.; Gundisch, D.; Schwarz, S.;
Seitz, G.; Tilotta, M. C.; Wegge, T. J. Med. Chem. 2002, 45, 1064.
(5) (a) Kim, Y. B.; Kim, Y. H.; Park, J. Y.; Kim, S. K. Bioorg. Med.
Chem. Lett. 2004, 14, 541. (b) Cornish, A.; Fox, K. R.; Waring, M. J.
Antimicrob. Agents Chemother. 1983, 23, 221. (c) Fox, K. R.; Waring, M.
J. Biochim. Biophys. Acta 1981, 654, 279. (d) Ueda, M.; Tanigawa, Y.;
Okami, Y.; Umezawa, H. J. J. Antibiot. 1954, 7, 125.
10.1021/jo060450v CCC: $33.50 © 2006 American Chemical Society
Published on Web 06/30/2006
J. Org. Chem. 2006, 71, 5897-5905
5897

Aparicio et al.
SCHEME 1
synthesis of different pyrazine esters and new pyrazinamides,
pyrazinephosphine oxides, and pyrazinephosphonates. We also
describe an efficient strategy for the preparation of unknown
functionalized tetrahydropyrazines15 III derived from R-amino
acid (R1 ) CO2R or R1 ) CONMe2) and new quinoxalines VI
(Scheme 1) derived from R-aminophosphorus mimetic com-
pounds (R1 ) POR2). Since in recent years combinatorial
synthesis of small organic molecules has received much
attention,16,17 we have reported in previous papers the construc-
tion of 1,2-diaza-1,3-butadienes bounded to polystyrene resins18,19a
or poly(ethylene glycol).20 In this work, we also investigated
the use of polymer-bound 1,2-diaza-1,3-butadienes as building
blocks for the facile solid-phase preparation of pyrazine deriva-
tives.
and antitumor properties,6 and pyrazinamides7 as well as
pyrazinesters8 have been successfully evaluated in vitro and in
vivo for antituberculosis activity. Therefore, the development
of new methods for synthesis of pyrazine and quinoxaline
derivatives acquired relevance in recent years.
Results and Discussion
The synthesis of carboxylate, carboxamide, phosphine oxide,
and phosphonate pyrazines 9 from 1,2-diaza-1,3-butadienes
1a-g and (1R,2R)-(+)-1,2-diphenyl-1,2-ethanediamine 2a,
(()-trans-2b, or (()-cis-1,2-diaminocyclohexane 2c is shown
in Schemes 2 and 3 and Table 1. 1,2-Diaza-1,3-butadienes 1a-e
reacted in acetonitrile at room temperature with diamine
compound 2a producing dihydropyrazines 6a-c (Scheme 2,
path a, Table 1). Under the same conditions, compounds 1b-e
reacted with 2b affording dihydropyrazines 6d-f (Scheme 2,
path a, Table 1). The reaction takes place by preliminary
nucleophilic attack of an amino group of 1,2-diamines 2 at the
terminal carbon of the heterodiene system 1 to give the 1,4-
adduct (Michael type) 3 that promptly affords piperazine 4 by
subsequent internal nucleophilic attack of the remaining amino
group at the carbon of the hydrazono moiety. Spontaneous
elimination of the hydrazine residue leads to substituted 1,4,5,6-
tetrahydropyrazines 5 isolable by fast purification with flash
chromatography only in the case of the reaction between 1b
and 2a. This product was identified as ethyl (5R,6R)-3-methyl-
5,6-diphenyl-1,4,5,6-tetrahydro-2-pyrazinecarboxylate 5a by 1H
NMR spectroscopy. In the other cases, spontaneous oxidation
of 5 gave rise directly to the corresponding 2-carboxylate or
2-carboxamide 5,6-dihydropyrazines 6a-f. 2-Carboxylate or
2-carboxamide pyrazines 9a-c,f-h were obtained from pure
products 6 or reaction mixtures by aromatization with phenyl-
trimethylammonium tribromide (PTAB) for compounds 9a,b
and 9f-h or by treatment with trifluoroacetic acid in acetonitrile
In a preliminary paper,9 carboxylated 1,2-diaza-1,3-buta-
dienes10,11 (I, R1 ) CO2R) have been used for the preparation
of pyrazinesters (IV, R1 ) CO2R) (Scheme 1) and interesting
piperazinones,12 while phosphorylated 1,2-diaza-1,3-butadienes
(I, R1 ) POR2) have been used for the preparation of
R-aminophosphonates13 and pyridazines.14 Here, we report the
(6) (a) Betancor, C.; Freire, R.; Perez-Martin, I.; Prange, T.; Suarez, E.
Tetrahedron 2005, 61, 2803. (b) Li, W.; Fuchs, P. L. Org. Lett. 2003, 5,
2849. (c) LaCour, T. G.; Guo, C.; Boyd, M. R.; Fuchs, P. L. Org. Lett.
2000, 2, 33.
(7) (a) Fukuwatari, T.; Sugimoto, E.; Shibata, K. Biosc. Biotech. Biochem.
2002, 66, 1435. (b) Suzuki, Y.; Suzuki, A.; Tamaru, A.; Katsukawa, C.;
Oda, H. J. Clin. Microbiol. 2002, 40, 501. (c) Zhang, Y.; Permar, S.; Sun,
Z. J. Clin. Microbiol. 2002, 40, 42. (d) Bothamley, G. Drug Saf. 2001, 24,
553. (e) Zimhony, O.; Cox, J. S.; Welch, J. T.; Vilcheze, C.; Jacobs, W. R.
Nat. Med. (N. Y.) 2000, 6, 1043.
(8) (a) Milczarska, B.; Foks, H.; Zwolska, Z. Phosphorus, Sulfur and
Silicon and the Related Elements 2005, 180, 2255. (b) Cynamon, M. H.;
Speirs, R. J.; Welch, J. T. Antimicrob. Agents Chemother. 1998, 42, 462.
(c) Bergmann, K. E.; Cynamon, M. H.; Welch, J. T. J. Med. Chem. 1996,
39, 3394.
(9) Attanasi, O. A.; De Crescentini, L.; Favi, G.; Filippone, P.; Lillini,
S.; Mantellini, F.; Santeusanio, S. Synlett 2005, 1474.
(10) (a) Attanasi, O. A.; Caglioti, L. Org. Prep. Proced. Int. 1986, 18,
299. (b) Attanasi, O. A.; Filippone, P. Synlett 1997, 1128. (c) Attanasi, O.
A.; De Crescentini, L.; Filippone, P.; Mantellini, F.; Santeusanio, S. ArkiVoc
2002, xi, 274. (d) Attanasi, O. A.; De Crescentini, L.; Favi, G.; Filippone,
P.; Mantellini, F.; Santeusanio, S. J. Org. Chem. 2004, 69, 2686. (e) Attanasi,
O. A.; Baccolini, G.; Boga, C.; De Crescentini, L.; Filippone, P.; Mantellini,
F. J. Org. Chem. 2005, 70, 4033.
(11) (a) Figuereido, J. O.; Kascheres C. J. Org. Chem. 1997, 62, 1164.
(b) Caposcialli, N.; Novi, M.; Petrillo, G.; Tavani, C. Tetrahedron 1998,
54, 5315. (c) Schantl, J. R.; Na`denik, P. Synlett 1998, 786. (d) South, M.
S. J. Heterocycl. Chem. 1999, 36, 301. (e) Banert, K. In Targets in
Heterocyclic Systems-Chemistry and Properties; Attanasi, O. A., Spinelli,
D., Eds.; Societa` Chimica Italiana: Rome, 2000; Vol. 3, p 1. (f) Polanc, S.
In Targets in Heterocyclic Systems-Chemistry and Properties; Attanasi, O.
A., Spinelli, D., Eds.; Societa` Chimica Italiana: Rome, 2000; Vol. 3, p 33.
(g) Kuznetsov, M. A.; Kuznetsova L. M.; Schantl J. Russ. J. Org. Chem.
2000, 36, 836. (h) Boeckman, R. K., Jr.; Reed, J. E.; Ge, P. Org. Lett.
2001, 3, 3651. (i) Boeckman, R. K., Jr.; Ge, P.; Reed, J. E. Org. Lett. 2001,
3, 3647.
(15) SciFinder Scholar, CAS, American Chemical Society: Columbus,
Ohio, 2006.
(16) (a) Bunin, B. A. The Combinatorial Index; Academic Press, Ltd.:
London, 1998. (b) Obrecht, D.; Villalgordo, J. M. Solid-Supported Com-
binatorial and Parallel Synthesis of Small-Molecular-Weight Compound
Libraries; Elsevier Science, Ltd.: New York, 1998. (c) Combinatorial
Chemistry: Synthesis, Analysis, Screening; Jung, G., Ed.; Wiley-VCH:
Weinheim, 1999. (d) Combinatorial Chemistry and Molecular DiVersity in
Drug DiscoVery; Gordon, E. M., Kerwin, J. F., Jr., Eds.; John Wiley &
Sons, Ltd.: New York, 1998.
(12) (a) Benjahad, A.; Benhaddou, R.; Granet, R.; Kaouadji, M.; Krausz,
P.; Piekarski, S.; Thomasson, F.; Bosgiraud, C.; Delebasse´e, S. Tetrahedron
Lett. 1994, 9545. (b) Choi, S.-W.; Elmaleh, D. R.; Hanson, R. N.; Fischman,
A. J. J. Med. Chem. 1999, 42, 3647. (c) Zaleska, B.; Socha, R.; Karelus,
M.; Szneler, E.; Grochowski, J.; Serda, P. J. Org. Chem. 2003, 68, 2334
and references therein.
(13) (a) Palacios, F.; Aparicio, D.; Lo´pez, Y.; de los Santos, J. M.
Tetrahedron 2005, 61, 2815. (b) Palacios, F.; Aparicio, D.; de los Santos,
J. M.; Ignacio, R.; Lo´pez, Y. ArkiVoc 2005, Vi, 153. (c) Palacios, F.;
Aparicio, D.; Lo´pez, Y.; de los Santos, J. M. Tetrahedron Lett. 2004, 45,
4345.
(17) (a) Solid-Phase Organic Synthesis; Czarnik, A. V., Ed.; John Wiley
& Sons Ltd.: New York, 2001. (b) Solid-Phase Organic Synthesis; Burgess,
K., Ed.; John Wiley & Sons, Ltd.: New York, 2000.
(18) (a) Attanasi, O. A.; Filippone, P.; Guidi, B.; Hippe, T.; Mantellini,
F.; Tietze L. F. Tetrahedron Lett. 1999, 9277. (b) Attanasi, O. A.; De
Crescentini, L.; Filippone, P.; Mantellini, F.; Tietze L. F., Tetrahedron 2001,
57, 5855.
(19) (a) Attanasi, O. A.; De Crescentini, L.; Filippone, P.; Mantellini,
F.; Santeusanio, S. Synlett 2003, 1183. (b) Attanasi, O. A.; De Crescentini,
L.; Filippone, P.; Mantellini, F.; Santeusanio, S. HelV. Chim. Acta 2001,
84, 2379.
(14) Palacios, F.; Aparicio, D.; Lo´pez, Y.; de los Santos, J. M. Alonso,
C. Eur. J. Org. Chem. 2005, 1142.
(20) Attanasi, O. A.; De Crescentini, L.; Favi, G.; Filippone, P.; Lillini,
S.; Mantellini, F.; Santeusanio, S. Org. Lett. 2005, 7, 2469.
5898 J. Org. Chem., Vol. 71, No. 16, 2006

Straightforward Access to Pyrazines, Piperazinones, and Quinoxalines
SCHEME 2a
doublet for H-5 at δH 5.67 ppm (5JPH ) 4.0 Hz), while 8b gave
a well resolved doublet at δH 4.90 ppm (2JPH ) 23.7 Hz) for
H-2. The oxidation of 1,2-dihydropyrazine 7a with p-benzo-
quinone in dioxane under reflux led to the formation of pyrazine-
phosphine oxide 9d (Scheme 2, path b, Table 1), while the
aromatization of the mixture of isomeric dihydropyrazines 7b
and 8b can be performed under the same conditions producing
pyrazinephosphonate 9e (Scheme 2, path b, Table 1). Therefore,
this strategy affords an easy and efficient entry to phosphorylated
pyrazines. It is known that phosphorus substituents regulate
important biological functions,22 and the introduction of orga-
nophosphorus functionalities in simple synthons may afford the
development of new strategies for the preparation of phosphorus
substituted compounds.23 However, pyrazines directly substi-
tuted with phosphorus-containing functional groups have re-
ceived scarce attention, probably due to the lack of methods of
synthesis of these substrates. Only recently, the first synthesis
of phosphorylated analogues of pyrazinamides such as substi-
tuted pyrazines containing either one phosphorylated group at
2-position24 or two phosphonate groups at the 2,5-positions24,25
was reported.
Michael addition of (()-trans-1,2-diaminocyclohexane 2b to
the heterodiene system of 1,2-diaza-1,3-butadiene 1f in meth-
ylene chloride at room temperature gave rise stereoselectively
to the formation of trans-2,3-dihydropyrazine-5-phosphine oxide
6g in 94% yield (Scheme 3, Table 1). In fact, the compound 6g
resulted only trans-isomer by NMR spectroscopy. The reaction
of 1,2-diaza-1,3-butadiene 1g with (()-trans-1,2-diaminocy-
clohexane 2b provided dihydropyrazine 6h in good yield
(Scheme 3, Table 1). Aromatization of dihydropyrazine 6g was
performed by oxidation with p-benzoquinone in dioxane under
reflux producing pyrazinephosphine oxide 9i (Scheme 3, Table
1). Unfortunately, the oxidation of dihydropyrazine 6h under
the same conditions did not lead to 2-phosphonylpyrazine 9,
but only to decomposition products. The stereoselectivity of the
process for the preparation of 2-phosphorylated dihydropyrazines
6 was also studied. For this reason, the reaction of 1,2-diaza-
1,3-butadienes 1f,g with (()-cis-1,2-diaminocyclohexane 2c was
explored giving rise to cis-dihydropyrazines 6i,j (Scheme 3,
Table 1). In this case, the oxidation readily occurred in the
reaction media (air atmosphere), and pyrazine 9i was easily
obtained from dihydropyrazine 6i (Table 1). However, pyrazine
9j was not possible to isolate, but its presence in the reaction
a Reagents and conditions: (i) for 1a-e + 2a and 1b-e + 2b, MeCN,
rt (path a); (ii) for 1f,g + 2a, CH2Cl2, rt (Path b); (iii) for 6a,b,d-f, PTAB,
CH2Cl2, rt, for 6c, CF3COOH, MeCN, reflux; (iv) p-benzoquinone, dioxane,
reflux.
SCHEME 3a
1
mixture was confirmed by H and 31P NMR together with the
dihydropyrazine 6j (Scheme 3, Table 1).
Pyrazine-2-carboxylate 9k has been directly obtained by
reaction of 1,2-diaza-1,3-butadienes 1a,b in ethanol with 1,2-
ethanediamine 2d. The reaction was allowed to stand at room
temperature until the complete disappearance of the reagents
and then refluxed in the presence of palladium on carbon
a Reagents and conditions: (i) CH2Cl2, rt; (ii) p-benzoquinone, dioxane,
reflux; (iii) CH2Cl2, rt.
under reflux for compound 9c (Scheme 2, path a, Table 1).
Similarly, the synthesis of pyrazine derivatives containing
phosphine oxide or phosphonate groups was achieved by
reaction of 1,2-diaza-1,3-butadienes 1f,g21 with 1,2-diphenyl-
1,2-ethanediamine 2a. In the case of 1f, the reaction at room
temperature led to substituted 4,5-dihydropyrazinephosphine
oxide 7a (Scheme 2, path b), while in the case of 1,2-diaza-
1,3-butadiene 1g, the reaction gave a mixture of isomeric
substituted 4,5- (7b) and 1,2-dihydropyrazine 8b (Scheme 2,
path b). These dihydropyrazines were characterized by 31P NMR
spectra, 7b showing one absorption at δP 18.3 ppm, while
absorption at δP 14.8 ppm was observed for dihydropyrazine
(21) These aza-alkenes 1f,g are prepared “in situ” by HCl elimination
of R-chlorohydrazones through base treatment.13
(22) For reviews, see: (a) Engel, R. In Handbook of Organophosphorus
Chemistry; Marcel Dekker, Inc.: New York, 1992. (b) Kafarski, P.; Lejezak,
B. Phosphorus Sulfur 1991, 63, 193. (c) Hoagland, R. E. In Biologically
ActiVe Natural Products; Culter, H. G., Ed.; ACS Symposium Series 380;
American Chemical Society: Washington, DC, 1988; p 182. (d) Toy, A.
D. F.; Walsh, E. N. In Phosphorus Chemistry in EVeryday LiVing; American
Chemical Society: Washington, DC, 1987; p 333.
(23) For an excellent review, see: Moneen, K.; Laureyn, I.; Stevens, C.
V. Chem. ReV. 2004, 104, 6177.
(24) Palacios, F.; Ochoa de Retana, A. M.; Gil, J. I.; Lo´pez de Munain,
R. Org. Lett. 2002, 4, 2405.
(25) Palacios, F.; Ochoa de Retana, A. M.; Mart´ınez de Marigorta, E.;
Rodr´ıguez, M.; Pagalday, J. Tetrahedron 2003, 59, 2617.
1
8b. Likewise, the H NMR spectra of 7b gave a well resolved
J. Org. Chem, Vol. 71, No. 16, 2006 5899

Aparicio et al.
yieldb (%)
TABLE 1. Yields of 1,4,5,6-Tetrahydropyrazines 5b-e, 5,6-Dihydropyrazines 6a-j, and Pyrazines 9a-l
1
R1
R2
2
R3
R4
R5
5
yielda (%)
6
yielda (%)
9
yielda (%)
1a
1b
1c
1d
1e
1f
1g
1b
1c
1d
1e
1f
1g
1f
1g
1a
1b
1f
CO2Et
CO2Et
Ot-Bu
NH2
NH2
Ot-Bu
NH2
OEt
OEt
NH2
NH2
Ot-Bu
NH2
OEt
OEt
OEt
OEt
Ot-Bu
NH2
OEt
O-t-Bu
O-t-Bu
O-t-Bu
O-t-Bu
2a
2a
2a
2a
2a
2a
2a
2b
2b
2b
2b
2b
2b
2c
2c
2d
2d
2d
2e
2e
2f
Ph
Ph
6a
6a
6b
6b
6c
66
62
68
61
52
9a
9a
9b
9b
9c
9d
9e
9f
9g
9g
9h
9i
60
56
62
58
40
92
70
36
46
43
13
67
86
87
86
91
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
5a
CO2Me
CO2Me
CONMe2
POPh2
PO(OEt)2
CO2Et
CO2Me
CO2Me
CONMe2
POPh2
PO(OEt)2
POPh2
PO(OEt)2
CO2Et
CO2Et
POPh2
CO2Et
trans-(CH2)4-
trans-(CH2)4-
trans-(CH2)4-
trans-(CH2)4-
trans-(CH2)4-
trans-(CH2)4-
cis-(CH2)4-
6d
6e
6e
6f
6g
6h
6i
51
49
45
60
94
82
c,d
f
73
90
93
41
9i
e
cis-(CH2)4-
6j
9j
9k
9k
9l
g,e
32
35
90
H
H
H
H
H
H
H
H
H
H
H
Me
Me
Pr
Pr
H
H
H
H
H
H
1a
1d
1a
1d
5b
5c
5d
5e
58
56
75
71
CO2Me
CO2Et
CO2Me
2f
a Yields of pure products are based on 1,2-diaza-1,3-butadienes 1a-g. b Yields of pure products are based on reagent 6. c Oxidation of dihydropyrazine
6i readily occurred, and pyrazine 9i was directly obtained. d This oxidation occurred at room temperature in the presence of air atmosphere. e Pyrazines 9i
and 9j were obtained in near quantitative yield. f A mixture of dihydropyrazine 6j and pyrazine 9j was obtained after purification of the crude compound 6j
1
in a ratio of 3.7/1. g Pyrazine 9j was not isolable, but its presence was confirmed by H and 31P NMR together with the dihydropyrazine 6j.
SCHEME 4a
SCHEME 5a
a Reagents and conditions: (i) for 1a,b + 2d, EtOH, rt; (ii) for 1a,d +
2e,f, MeCN, rt; (iii) for 1f + 2d, CH2Cl2, rt; (iv) for 1a,b + 2d, Pd/C,
EtOH, reflux; (v) for 1f + 2d, p-benzoquinone, dioxane, reflux.
a Reagents and conditions: (i) MeCN, rt; (ii) MeCN, CF3COOH, reflux.
TABLE 2. Yields of Hydrazones 11a,b and
5,6-Dicyano-3-methyl-2-pyrazinecarboxylates 9m,n
(Pd/C)26 (Scheme 4, Table 1). In a similar way, 1,2-diaza-1,3-
butadiene 1f reacted with 1,2-diaminoethane 2d in methylene
chloride at room temperature to give pyrazinephosphine oxide
9l in excellent yield by treatment of the reaction mixture with
p-benzoquinone in dioxane under reflux (Scheme 4, Table 1).
Unfortunately, all attempts to obtain dihydropyrazines 6a-j and
pyrazines 9a-l in good yields with the same procedure failed
likely because of the different substituents. For this reason, we
used the most suitable reaction conditions depending on the
nature of the substrate. To improve the scope of this synthetic
methodology, the reaction of N,N′-dimethylethylenediamine 2e
and N,N′-di-n-propylethylenediamine 2f with 1,2-diaza-1,3-
butadienes 1a,d in acetonitrile at room temperature was
1
R1
1b CO2Et
1c CO2Me NH2 11b
R2
11 yielda (%)
9
yielda (%) yieldb (%)
NH2 11a
62
55
9m
9n
58
74
78
87
a Yields of pure products are based on 1,2-diaza-1,3-butadienes 1b,c.
b Yields of pure products are based on reagent 11.
performed (Scheme 4). In these cases, the presence of alkyl
groups on both nitrogen atoms of diamine compounds 2e,f
prevents the final oxidation process giving new 1,4,5,6-
tetrahydropyrazine-2-carboxylates 5b-e in good yields (Scheme
4, Table 1).
The reaction of diaminomaleonitrile 10 with 1,2-diaza-1,3-
butadienes 1b,c in acetonitrile at room temperature was also
investigated (Scheme 5). The nucleophilic attack of amino group
of compound 10 at the terminal carbon of the heterodiene system
of 1,2-diaza-1,3-butadienes 1b,c led to hydrazone 1,4-adducts
11a,b isolated by chromatography on silica (Scheme 5, Table
(26) (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. (c) Merthes, M. P.; Lin, A. J. J. Med. Chem. 1970, 13, 77.
5900 J. Org. Chem., Vol. 71, No. 16, 2006

Straightforward Access to Pyrazines, Piperazinones, and Quinoxalines
TABLE 3. Solvent-Free Synthesis of Hydrazones 3a-d, Pyrazines-2-phosphorylates 9d,e,i, Piperazinones 14a-c, and
1,2,5,6-Tetrahydro-2-pyrazinones 15a-d
1
R1
R2
2
R3
R4
R5
3
yielda (%)
9
yielda (%)
14
yielda (%)
15
yielda,b (%) T (°C)
1c
1f
1g
1c
CO2Me
POPh2
PO(OEt)2 OEt
NH2
OEt
2a
2a
2a
2b
2b
2b
2d
Ph
Ph
Ph
Ph
Ph
Ph
14a
65
90
120
120
45
45
120
25
25
9d
9e
72
66
CO2Me
NH2
Ot-Bu
OEt
trans-(CH2)4-
trans-(CH2)4-
trans-(CH2)4-
15a
15b
42a
47a
1d CO2Me
1f
1c
1d CO2Me
1a CO2Et
1d CO2Me
1a CO2Et
1d CO2Me
POPh2
CO2Me
9i
93
NH2
H
H
H
H
H
H
H
14b
14c
70
88
15c
15d
62b
60b
O-t-Bu 2d
O-t-Bu 2e
O-t-Bu 2e
O-t-Bu 2f
O-t-Bu 2f
H
H
H
H
H
Me 3a
Me 3b
80
76
74
70
Pr
Pr
3c
3d
a Yields of pure products are based on 1,2-diaza-1,3-butadienes 1a,c,d,f,g. b Yields of pure products are based on reagents 14b,c.
SCHEME 6 a
2). 5,6-Dicyano-3-methyl-2-pyrazinecarboxylates 9m,n were
obtained by treatment of pure compounds 11a,b or the crude
reaction mixture with trifluoroacetic acid in acetonitrile under
reflux (Scheme 5 and Table 2). The cyclization process takes
place by further internal nucleophilic attack of the second amino
group at the hydrazone carbon giving the intermediate 12.
Spontaneous elimination of the hydrazine residue leads to
substituted 5,6-dicyano-3-methyl-1,4-dihydropyrazines 13 and
then to pyrazines 9m,n by oxidation with trifluoroacetic acid
in acetonitrile under reflux.
We have also studied the reactions of 1,2-diaza-1,3-butadienes
1c,d,f,g with diamine compounds 2a,b,d under solvent-free
conditions, in an attempt to obtain faster reaction times together
with simple and environmentally friendly procedures.27,28 To
obtain homogeneous reaction media, the reactions were carried
out at the melting point of diamines (Table 3). Surprisingly,
the reactions showed a different unexpected behavior. In fact,
1,2-diaza-1,3-butadienes 1c,d readily reacted with 6 equiv of
diamines 2a,d used as solvent and reagent to give substituted
piperazinones 14a-c (Scheme 6, path b, Table 3), while 1,2,5,6-
tetrahydro-2-pyrazinones 15a,b were directly collected in the
case of the reaction between 1,2-diaza-1,3-butadienes 1c,d
and (()-trans-1,2-diaminocyclohexane 2b (Scheme 6, path c,
a Reagents and conditions: (i) for 1a,d + 2e,f, solvent-free, for 1f,g +
2a, 1f + 2b (R1 ) POPh2, PO(OEt)2), solvent-free (path a), for 1c,d + 2d
and 1c + 2a (R1 ) CO2Me) (path b), for 1c,d + 2b (R1 ) CO2Me) (path
c); (ii) ) for 14b,c, NBS, MeOH, rt (path d).
Table 3).
The first step of this reaction is the nucleophilic attack of an
amino group of 1,2-diamines 2a,d at the terminal carbon atom
of the heterodiene system of 1,2-diaza-1,3-butadienes 1c,d with
the formation of hydrazone 1,4-adducts (Michael type) 3. The
subsequent nucleophilic attack of the second amino group at
the ester function with loss of an alcohol molecule produces
piperazinones 14a-c by ring closure (Scheme 6, path b, Table
3). In the case of the reaction between 1,2-diaza-1,3-butadienes
1c,d and (()-trans-1,2-diaminocyclohexane 2b, spontaneous
oxidation took place with the formation of 1,2,5,6-tetrahydro-
2-pyrazinones 15a,b without formation of the relevant products
14 (Scheme 6, path c). Oxidized compounds 15c,d were
obtained from 14b,c by treatment with N-bromosuccinimide
(NBS) in methanol at room temperature29,30 (Scheme 6, path
d). It is noteworthy that pyrazinephosphine oxides 9d,i and
pyrazinephosphonate 9e were directly prepared in good yields
by reaction of 1,2-diaza-1,3-butadienes 1f,g with 1,2-diamines
2a,b in solvent-free conditions (Scheme 6, path a, Table 3). In
these last cases, the absence of ester moiety at the terminal
carbon of the heterodiene system induces the ring closure by
attack of the second amino group at the hydrazone carbon of
(29) (a) Wisweswariah, S.; Prakash, G.; Bhushan, V.; Chandrasekaran,
S. Synthesis 1982, 309. (b) Attanasi, O. A.; Filippone, P.; Mei, A.; Serra-
Zanetti, F. J. Heterocycl. Chem. 1985, 22, 1341. (c) Attanasi, O. A.;
Filippone, P.; Guerra, P.; Serra-Zanetti, F. Synth. Commun. 1987, 17, 555.
(d) Attanasi, O. A.; Grossi, M.; Mei, A.; Serra-Zanetti, F. Org. Prep. Proced.
Int. 1988, 20, 405. (e) Dauben, W. G.; Warshawsky, A. M. Synth. Commun.
1988, 18, 1323. (f) Jacques, J.; Marquet, A. Organic Syntheses; Wiley:
New York, 1988; Collect. Vol. VI, p 175. (g) Attanasi, O. A.; Filippone,
P.; Fiorucci, C.; Foresti, E.; Mantellini, F. J. Org. Chem. 1998, 63, 9880.
(h) Attanasi, O. A.; Filippone, P.; Guidi, B.; Perrulli, F. R.; Santeusanio, S.
Heterocycles 1999, 51, 2423.
(27) (a) Varma, R. S. Green Chem. 1999, 43. (b) Metzger, J. O. Angew.
Chem., Int. Ed. 1998, 37, 2975. (c) Tanaka, K.; Toda, F. Chem. ReV. 2000,
100, 1025. (d) Varma, R. S. Pure Appl. Chem. 2001, 73, 193. (e) Cave, G.
W. V.; Raston, C. L.; Scott, J. L. Chem. Commun. 2001, 2159. (f) Tanaka,
K.; Toda, F. SolVent-free Organic Synthesis; Wiley-VCH: 2003.
(28) (a) Loh, T.-P.; Huang, J.-M.; Goh, S.-H.; Vittal, J. Org. Lett. 2000,
2, 1291. (b) Hajipour, A. R.; Arbabian, M.; Ruoho, A. E. J. Org. Chem.
2002, 67, 8622. (c) Xu, Z.-B.; Lu, Y.; Guo, Z.-R. Synlett 2003, 4, 564. (d)
Lee, J. C.; Bae, Y. H. Synlett 2003, 4, 507. (e) Yadav, L. D. S.; Singh, S.
Synthesis 2003, 1, 63. (f) Attanasi, O. A.; De Crescentini, L.; Favi, G.;
Filippone, P.; Mantellini, F.; Santeusanio, S. Synlett 2004, 3, 549.
(30) Cordonier, C. E. J.; Satake, K.; Atarashi, M.; Kawamoto, Y.;
Okamoto, H.; Kimura, M. J. Org. Chem. 2005, 70, 3425.
J. Org. Chem, Vol. 71, No. 16, 2006 5901

Aparicio et al.
SCHEME 7 a
SCHEME 8 a
a Reagents and conditions: (i) ) MeCN, rt.
TABLE 5. Yields of 5,6-Dihydropyrazines 6a-c,f Obtained in the
Solid Phase
1
R1
2
R2
R3
6
yielda (%)
1j
1k
1l
CO2Et
2a
2a
2a
2b
Ph
Ph
Ph
Ph
Ph
Ph
6a
6b
6c
6f
18
21
20
21
CO2Me
CONMe2
CONMe2
1l
trans-(CH2)4-
a Overall yields for the multistep process of pure isolated 6a-c,f with
respect to the starting polymer-bound p-toluenesulfonyl hydrazide.
a Reagents and conditions: (i) ) CH2Cl2, rt.
TABLE 4. Yields of Phosphorylated Quinoxalines 19a-i
R1
1f POPh2
1g PO(OEt)2 OEt Me 16a
1h POPh2 OEt Ph 16a
1i PO(OEt)2 OEt Ph 16a
R2
R3
16
R4
R5
19 yielda (%)
attack of the second amino group at hydrazone carbon with loss
of a hydrazine carboxylate residue affords 2-phosphorylated
quinoxalines 19a-i (Scheme 7). This strategy affords a very
efficient entry to quinoxalinephosphine oxides 19a,c,e-h and
phosphonates 19b,d,i. Quinoxalines directly substituted with
phosphorus containing functional groups have received scarce
attention.31 To the best of our knowledge, the first synthesis of
quinoxalines with a phosphonate group at the 2-position of the
heterocyclic system is here described.
Based on the mild and simple conditions required from these
reactions in the liquid phase, we have investigated these
methodologies in solid-phase. Polymer-bound 1,2-diaza-1,3-
butadienes 1j-l prepared from polymer-bound p-toluenesulfonyl
hydrazide19a readily reacted with 3 equiv of diamines 2a,b in
acetonitrile at room temperature to afford directly substituted
5,6-dihydropyrazines 6a-c,f (Scheme 8, Table 5). The overall
yields for the multistep process of these solid-phase reactions
are comparable with the corresponding reactions in solution.
1
OEt Me 16a
H
H
H
H
H
H
H
H
19a
19b
19c
19d
19e
19f
81
83
91
>98
90
1f POPh2
1f POPh2
1h POPh2
1f POPh2
OEt Me 16b Me
OEt Me 16c Cl
OEt Ph 16c Cl
Me
Cl
Cl
93
19g
89
OEt Me 16d -(CHdCH)2- 19h
86
77
1g PO(OEt)2 OEt Me 16d -(CHdCH)2- 19i
a Yield of isolated purified compounds 19 based on 1,2-diaza-1,3-
butadienes 1f-i.
the intermediate 3. When the reaction between N,N′-dimethyl-
ethylenediamine 2e and N,N′-di-n-propylethylenediamine 2f with
1,2-diaza-1,3-butadienes 1a,d was carried out under solvent-
free conditions, only the hydrazone derivatives 3a-d were
formed in good yields (Scheme 6, Table 3). These latter
compounds directly crystallized in the reaction medium probably
avoiding the subsequent ring closure.
1,2-Diaza-1,3-butadienes containing a carboxylate group at
the terminal carbon have been used as starting materials for the
preparation of quinoxaline-2-carboxylates (Scheme 1, vide
supra).19 As a continuation of our work on the 1,4-addition
reaction (Michael type) of 1,2-diaza-1,3-butadienes and on the
chemistry of new phosphorus- and nitrogen-substituted hetero-
cycles, we explored also the behavior of 1,2-diaza-1,3-butadienes
derived from phosphine oxides and phosphonates, toward
aromatic 1,2-diamines, for the preparation of quinoxalines
containing a phosphine oxide or phosphonate moiety at the
2-position of the heterocyclic system (Scheme 1, vide supra).
1,2-Diaza-1,3-butadienes13 1f-i easily reacted in methylene
chloride at room temperature with 1,2-phenylendiamines 16a-d
to give quinoxaline-2-phosphine oxides and 2-phosphonates 19
in good to excellent yield (Scheme 7, Table 4). Addition of
1,2-phenylenediamine 16a to the heterodiene system of 1f led
to the formation of quinoxaline-2-phosphine oxide 19a in 81%
yield (Scheme 7, Table 4).
Conclusion
In summary, the procedures described here represent a
convenient entry to functionalized tetrahydropyrazines, dihy-
dropyrazines, pyrazines, piperazinones, quinoxaline-2-phosphine
oxides, and phosphonates by 1,4-addition (Michael type) of 1,2-
diamines to 1,2-diaza-1,3-butadienes in good yields. Although
a number of methods are available for the synthesis of pyrazines
and quinoxalines, a review of the literature revealed that the
parent molecules are easily prepared but the corresponding
substituted compounds are frequently difficult to obtain. The
presence of different functional groups in many positions of
these heterocycles is noteworthy making such compounds useful
for further interesting structural modifications and suitable as
intermediates for more complex structures or biologically active
compounds.1-8 Besides the mild and simple conditions of this
procedure permit the access to valuable combinatorial libraries.
The first step of the reaction is the nucleophilic attack of an
amino group of 1,2-phenylendiamines 16a-d on the terminal
carbon of the heterodiene system of 1,2-diaza-1,3-butadienes
1f-i with the formation of hydrazone 1,4-adduct intermediate
(Michael type) 17 (Scheme 7). The subsequent nucleophilic
(31) (a) Ito, Y.; Kojima, Y.; Suginome, M.; Murakami, M. Heterocycles
1996, 42, 597. (b) Sinou, D.; Percina-Pichon, N.; Konovets, A.; Iourtchenko,
A. ArkiVoc 2004, xiV, 103. (c) Imamoto, T.; Sugita, K, Yoshida, K. J. Am.
Chem. Soc. 2005, 127, 11934. (d) Acklin, P.; Allgeier, H.; Auberson, Y.
P.; Bischoff, S.; Ofner, S.; Sauer, D.; Schmutz, M. Bioorg. Med. Chem.
Lett. 1998, 8, 493.
5902 J. Org. Chem., Vol. 71, No. 16, 2006

Straightforward Access to Pyrazines, Piperazinones, and Quinoxalines
) 7.2 Hz, 3H), 2.91 (s, 3H), 4.50 (q, 3J ) 7.2 Hz, 2H), 7.28-7.32
(m, 6H), 7.48-7.51 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 14.1
(q), 22.6 (q), 61.8 (t), 128.1 (d), 128.2 (d), 128.6 (d), 129.0 (d),
129.5 (d), 129.6 (d), 137.6 (s), 137.8 (s), 140.1 (s), 149.1 (s), 151.3
(s), 153.0 (s), 165.0 (s); MS (EI) m/z 318 (52) [M+], 289 (8), 273
(4), 246 (100). Anal. Calcd for C20H18N2O2: C, 75.45; H, 5.70; N,
8.80. Found: C, 75.66; H, 5.59; N, 8.69.
In fact, many cyclic compounds previously obtained in solution
from these reagents may now be reached by solid-phase
reactions.
Experimental Section
General Methods. Reagent and solvent purification, workup
procedures, and analyses were performed in general as described
in the Supporting Information.
General Procedure for the Synthesis of Phosphorylated
Dihydropyrazines 6g-j, 7a,b, and 8b and Phosphorylated
Pyrazines 9d,e,i,j (See Scheme 2, Path b and Scheme 3). To a
stirred solution of 1,2-diaza-1,3-butadiene 1f,g (1 mmol) as a
mixture of E/Z isomers in CH2Cl2 (10 mL) was added dropwise
a solution of (1R,2R)-(+)-1,2-diphenyl-1,2-ethanediamine 2a,
(()-trans-1,2-diaminocyclohexane 2b, and (()-cis-1,2-diaminocy-
clohexane 2c (1 mmol) in CH2Cl2 (5 mL). The reaction mixture
was stirred at room temperature and followed by TLC (1-2 h).
The solvent was evaporated under vacuum, and the crude products
6g-j were purified by flash chromatography (silica gel, ethyl
acetate/methanol 90:10), and crude products 7a,b and 8b were
purified by flash chromatography (silica gel, ethyl acetate). Products
7b and 8b were obtained as a mixture of isomeric dihydropyridines
in 70% yield. An example of pure 8b was obtained after chroma-
tography. In the case of reaction between 1f and 2c, only the
pyrazine 9i was isolated. In the case of the reaction between 1g
and 2c, a mixture of dihydropyrazine 6j and pyrazine 9j was
obtained after purification of the crude compound 6j in a ratio of
General Procedure for the Synthesis of Ethyl (5R,6R)-3-
Methyl-5,6-diphenyl-1,4,5,6-tetrahydro-2-pyrazinecarboxylate
5a, Substituted 5,6-Dihydropyrazines 6a-f, and Substituted
Pyrazines 9a-c,f-h (See Scheme 2, Path a). A stoichiometric
amount of 1,2-diaza-1,3-butadiene 1a-e (1 mmol) as a mixture of
E/Z isomers32 was slowly added to a solution of (1R,2R)-(+)-1,2-
diphenyl-1,2-ethanediamine 2a (1 mmol) in MeCN (50 mL). Under
the same conditions, compounds 1b-e reacted with (()-trans-1,2-
diaminocyclohexane 2b. The reaction was allowed to stand at room
temperature (rt) with magnetic stirring until complete disappearance
of 1,2-diaza-1,3-butadiene (monitored by silica gel TLC, 1 h). The
solvent was then removed under reduced pressure, and the products
6a-f were purified by chromatography on silica (elution mixture:
cyclohexanes/ethyl acetate, 30:70). To obtain the oxidized products
9a,b,f-h, the crude mixture or pure products 6a,b,d-f (1 mmol)
were dissolved with CH2Cl2 (150 mL), and PTAB (2 mmol) was
slowly added. The reaction mixture was washed with H2O (2 × 30
mL), the organic layer was dried over anhydrous Na2SO4, and the
solvent was evaporated under reduced pressure. The products 9a,b
and 9f-h were purified by chromatography on silica (elution
mixture: cyclohexane/ethyl acetate, 60:40), and 9a,b were crystal-
lized from ethyl acetate-light petroleum ether (at 40-60 °C). To
obtain product 9c, the solution of 1,2-diaza-1,3-butadiene 1e (1
mmol) and 1,2-diamine 2a (1 mmol) was stirred until complete
disappearance of the reagents (monitored by TLC). Trifluoroacetic
acid was then added to the mixture until pH 1, and the solution
was refluxed for 34 h. The solvent was removed under reduce
pressure, and the crude was dissolved in ethyl acetate and washed
with a saturated solution of Na2CO3 (2 × 15 mL). The organic
layer was dried over anhydrous Na2SO4. The product 9c was
purified by chromatography on silica (elution mixture: cyclohexane/
ethyl acetate, 60:40) and crystallized from ethyl acetate-light
petroleum ether (at 40-60 °C). In the case of the reaction between
1b and 2a, along with 6a, product 5a was isolated as a yellow oil
by flash chromatography on silica gel and was immediately
1
3.7/1. Products 6j and 9j were immediately subjected to H and
31P analysis because of their instability. Pyrazine 9i was obtained
by oxidation of dihydropyrazine 6g or 6i (0.5 mmol) with
p-benzoquinone (0.5 mmol, 54 mg) in dioxane (5 mL). The mixture
was stirred and refluxed for 16 h. In the same way, oxidation of
dihydropyrazines 7a (0.5 mmol) and the mixture of dihydropyra-
zines 7b, 8b (0.5 mmol) with p-benzoquinone (0.5 mmol, 54 mg)
in refluxing dioxane (5 mL) gave pyrazines 9d and 9e, respectively.
The product 9d was purified by flash chromatography (silica gel,
ethyl acetate/hexanes 30:70), and products 9e,i were purified by
flash-chromatography (silica gel, ethyl acetate).
5-(Diphenylphosphinoyl)-6-methyl-2,3-diphenyl-1,2-dihydro-
pyrazine (7a): yellow oil; IR (NaCl) νmax 3196, 3052, 2919, 1722,
1658, 1514, 1493, 1434, 1172 cm-1; 1H NMR (400 MHz, CDCl3)
δ 2.13 (s, 3H), 5.66 (d, 5JPH ) 4.2 Hz, 1H), 7.14-7.93 (m, 20H);
13C NMR (100 MHz, CDCl3) δ 16.9, 51.4, 110.3 (d, 1JPC ) 166.6
Hz), 126.1, 126.9, 127.7, 127.8, 127.8, 127.8, 127.9, 128.2, 128.4,
128.5, 130.7, 130.7, 130.8, 130.8, 131.6, 131.7, 131.8, 131.9, 134.1,
134.7, 135.2, 135.7, 137.1, 139.9, 141.3 (d, 3JPC ) 17.8 Hz), 145.4
(d, 2JPC ) 27.4 Hz); 31P NMR (120 MHz, CDCl3) δ 27.7; MS (CI)
m/z 449 (M+ + 1, 100). Anal. Calcd for C29H25N2OP: C, 77.66;
H, 5.62; N, 6.25. Found: C, 77.72; H, 5.59; N, 6.28.
1
subjected to H NMR analysis because of its poor stability.
Ethyl (5R,6R)-3-methyl-5,6-diphenyl-1,4,5,6-tetrahydro-2-
pyrazinecarboxylate (5a): yellow oil; 1H NMR (400 MHz, CDCl3)
3
3
δ 1.21 (t, J ) 7.2 Hz, 3H), 1.76 (s, 3H), 4.19 (q, J ) 7.2 Hz,
3
3
Diethyl (3-methyl-5,6-diphenyl-4,5-dihydropyrazin-2-yl)phos-
2H), 5.22 (t, J ) 8.4 Hz, 1H), 5.32 (t, J ) 8.4 Hz, 1H), 7.12-
7.26 (m, 10H), 8.61 (d, J ) 8.4 Hz, 1H), 9.47 (d, J ) 8.4 Hz,
1H).
phonate (7b): 1H NMR (400 MHz, CDCl3) δ 1.03-1.40 (m, 6H),
3
3
5
2.34 (s, 3H), 3.88-4.29 (m, 4H), 5.67 (d, JPH ) 4.0 Hz, 1H),
7.27-7.82 (m, 10H); 31P NMR (160 MHz, CDCl3) δ 18.3.
Diethyl (3-methyl-5,6-diphenyl-1,2-dihydropyrazin-2-yl)phos-
phonate (8b): colorless oil; IR (NaCl) νmax 3228, 2983, 1744, 1450,
1402, 1247, 1028 cm-1; 1H NMR (400 MHz, CDCl3) δ 1.01-1.41
(m, 6H), 2.32 (d, 4JPH ) 2.4 Hz, 3H), 4.09-4.87 (m, 4H), 4.90 (d,
2JPH ) 23.7 Hz, 1H), 7.27-7.79 (m, 10H), 10.08 (br s, 1H); 13C
NMR (100 MHz, CDCl3) δ 13.7, 14.1, 14.4, 16.2, 16.2, 16.3, 16.4,
16.4, 21.0, 59.3 (d, 1JPC ) 146.8 Hz), 62.2, 62.3, 62.4, 63.1, 63.4,
63.5, 127.3, 127.6, 128.1, 128.2, 128.4, 128.7, 129.2, 130.4, 134.8
Ethyl (5R,6R)-3-methyl-5,6-diphenyl-5,6-dihydro-2-pyrazine-
carboxylate (6a): yellow oil; IR (Nujol) νmax 1742, 1677, 1564
1
3
cm-1; H NMR (400 MHz, CDCl3) δ 1.41 (t, J ) 7.2 Hz, 3H),
5
3
5
2.39 (d, J ) 2.4 Hz, 3H), 4.28 (dq, J ) 14.8 Hz, J ) 2.4 Hz,
1H), 4.36 (d, 3J ) 14.8 Hz, 1H), 4.43 (q, 3J ) 14.8 Hz, 2H), 6.93-
6.98 (m, 4H), 7.17-7.21 (m, 6H); 13C NMR (100 MHz, CDCl3) δ
14.1 (q), 22.8 (q), 62.4 (t), 65.4 (d), 66.0 (d), 127.3 (d), 127.4 (d),
127.8 (d), 128.1 (d), 128.2 (d), 128.3 (d), 139.4 (s), 140.2 (s), 153.7
(s), 155.5 (s), 164.2 (s); MS (EI) m/z 320 (67) [M+], 291 (74), 275
(62), 247 (100). Anal. Calcd for C20H20N2O2: C, 74.98; H, 6.29;
N, 8.74. Found: C, 75.16; H, 6.21; N, 8.63.
4
2
(d, JPC ) 2.7 Hz), 150.8, 153.1, 154.3 (d, JPC ) 9.1 Hz); 31P
NMR (160 MHz, CDCl3) δ 14.8; MS (EI) m/z 384 (M+, 5). Anal.
Calcd for C21H25N2O3P: C, 65.61; H, 5.56; N, 7.29. Found: C,
65.71; H, 5.51; N, 7.27.
Ethyl 3-methyl-5,6-diphenyl-2-pyrazinecarboxylate (9a): yel-
low powder; mp 67-71 °C; IR (Nujol) νmax 1727, 1578, 1473,
1404, 1384, 1304 cm-1; 1H NMR (400 MHz, CDCl3) δ 1.46 (t, 3J
2-(Diphenylphosphinoyl)-3-methyl-5,6-diphenylpyrazine (9d):
yellow oil; IR (NaCl) νmax 1653, 1434, 1391, 1183 cm-1; 1H NMR
(400 MHz, CDCl3) δ 2.94 (s, 3H), 7.13-7.89 (m, 20H); 13C NMR
(100 MHz, CDCl3) δ 22.0, 127.2, 127.3, 127.3, 127.5, 127.7, 127.9,
128.1, 128.2, 128.3, 128.4, 128.6, 128.8, 128.9, 129.1, 129.2, 129.3,
(32) (a) Attanasi, O. A.; Filippone, P.; Mei, A.; Santeusanio, S. Synthesis
1984, 671. (b) Attanasi, O. A.; Filippone, P.; Mei, A.; Santeusanio, S.
Synthesis 1984, 873.
J. Org. Chem, Vol. 71, No. 16, 2006 5903

Aparicio et al.
129.4, 129.5, 129.6, 130.9, 131.0, 131.2, 131.3, 131.6, 131.8, 131.8,
was then removed under reduced pressure, and the products 11a,b
were purified by chromatography on silica, (elution mixture:
cyclohexanes/ethyl acetate, 30:70). To obtain 5,6-dicyanopyrazine-
3-methyl-2-carboxylates 9m,n, the crude mixtures, or pure products
11a,b (1 mmol), were dissolved with MeCN (30 mL), and
trifluoroacetic acid was added until pH 1. The solution was refluxed
for 30 h. The reaction mixture was neutralized with Na2CO3 and
filtered, and the solvent was evaporated under reduced pressure.
The products 9m,n were purified by chromatography on silica
(elution mixture: cyclohexane/ethyl acetate, 60:40).
1
132.0, 132.1, 132.3, 132.7, 137.4, 137.8, 145.4 (d, JPC ) 129.0
3
4
Hz), 148.0 (d, JPC ) 15.4 Hz), 151.8 (d, JPC ) 2.89 Hz), 155.2
(d, 2JPC ) 21.4 Hz); 31P NMR (160 MHz, CDCl3) δ 25.8; MS (EI)
m/z 446 (M+, 100). Anal. Calcd for C29H23N2OP: C, 78.01; H,
5.19; N, 6.27. Found: C, 78.00; H, 5.22; N, 6.26.
General Procedure for the Synthesis of 1,4,5,6-Tetrahydro-
pyrazine-3-methyl-2-carboxylates 5b-e and Ethyl 3-Meth-
ylpyrazine-2-carboxylate 9k (See Scheme 4). A stoichiometric
amount of 1,2-diaza-1,3-butadiene 1a,d (1 mmol) as a mixture of
E/Z isomers was slowly added to a solution of N,N′-dimethyleth-
ylenediamine 2e or N,N′-di-n-propylethylenediamine 2f (1 mmol)
in MeCN (50 mL). The reaction was allowed to stand at room
temperature (rt) with magnetic stirring for 14 h. The solvent was
then removed under reduced pressure and the products 5b-e were
purified by chromatography on silica, (elution mixture: cyclohex-
anes/ethyl acetate, 70:30).
To obtain ethyl 3-methylpyrazine-2-carboxylate 9k, a solution
of 1,2-diaza-1,3-butadienes 1a,b (1 mmol) as a mixture of E/Z
isomers in EtOH (10 mL) was added dropwise to a magnetically
stirred solution of 1,2-diaminoethane 2d (1 mmol) in EtOH (50
mL). The reaction was allowed to stand at rt 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 refluxed for 14 h. The mixture was
filtered and the solvent evaporated under reduced pressure. Product
9k was purified by chromatography on silica gel (elution mixture:
cyclohexane/ethyl acetate 70:30) and crystallized from ethyl
acetate-light petroleum ether (at 40-60 °C).
Ethyl 5,6-dicyano-3-methyl-2-pyrazinecarboxylate (9m): white
powder; mp 83-85 °C; IR (Nujol) νmax 2242, 1743 cm-1; 1H NMR
(400 MHz, CDCl3) δ 1.44 (t, 3J ) 7.2 Hz, 3H), 2.93 (s, 3H), 4.50
3
(q, J ) 7.2 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 13.9 (q),
23.2 (q), 63.5 (t), 112.3 (s), 112.4 (s), 129.9 (s), 133.4 (s), 145.9
(s), 158,5 (s), 162.4 (s); MS (EI) m/z 216 (35) [M+], 188 (70), 170
(89), 144 (100). Anal. Calcd for C10H8N4O2: C, 55.56; H, 3.73;
N, 25.91. Found: C, 55.50; H, 3.72; N, 25.88.
Ethyl 3-[2-(aminocarbonyl)hydrazono]-2-[(2-amino-1,2-dicy-
anovinyl)amino]butanoate (11a): white powder; mp 111-113 °C
dec; IR (Nujol) νmax 3486, 3374, 2220, 1746, 1688 cm-1; 1H NMR
3
(400 MHz, DMSO-d6) δ 1.19 (t, J ) 7.2 Hz, 3H), 1.86 (s, 3H),
4.17 (q, 3J ) 7.2 Hz, 2H), 4.54 (d, 3J ) 9.6 Hz, 1H), 5.54 (d, 3J )
9.6 Hz, 1H), 6.10 (s, 2H), 6.37 (br s, 2H), 9.39 (s, 1H); 13C NMR
(100 MHz, DMSO-d6) δ 14.0 (q), 14.4 (q), 61.4 (t), 63.9 (d), 104.2
(s), 112.0 (s), 115.9 (s), 116.1 (s), 142.2 (s), 157.0 (s), 169.4 (s);
MS (EI) m/z 293 (27) [M+], 277 (29), 265 (32), 248 (25), 236
(100). Anal. Calcd for C11H15N7O3: C, 45.05; H, 5.15; N, 33.43.
Found: C, 45.09; H, 5.14; N, 33.46.
Ethyl 1,3,4-trimethyl-1,4,5,6-tetrahydro-2-pyrazinecarboxy-
late (5b): yellow oil; IR (Nujol) νmax 1688, 1574, 1456 cm-1;1H
NMR (400 MHz, CDCl3) δ 1.15 (t, 3J ) 7.2 Hz, 3H), 2.22 (s, 3H),
2.24 (s, 3H), 2.64-2.66 (m, 4H), 2.89 (s, 3H), 3.08-3.10 (m, 4H),
General Procedure for the Synthesis of R-{Methyl[2-
(methylamino)ethyl]amino}hydrazones 3a-d by Solvent-Free
Reactions (See Scheme 6). 1,2-Diaza-1,3-butadiene 1a,d (1 mmol)
as a mixture of E/Z isomers was slowly added to 1,2-diamine 2e,f
(2 mmol). The reaction mixture was allowed to stand at room
temperature (rt) with magnetic stirring until complete disappearance
of 1,2-diaza-1,3-butadiene (monitored by silica gel TLC, 1 h). Pure
hydrazones 3a-d were crystallized from acetate-ethyl ether.
tert-Butyl 2-(3-ethoxy-1-methyl-2-methyl[2-(methylamino)-
ethyl]amino-3-oxopropylidene)-1-hydrazinecarboxylate (3a): white
powder; mp 145-147 °C; IR (Nujol) νmax 3238, 3165, 1748, 1707
cm-1; 1H NMR (400 MHz, DMSO-d6) δ 1.17 (t, 3J ) 6.8 Hz, 3H),
1.41 (s, 9H), 1.82 (s, 3H), 2.20 (s, 3H), 2.48 (s, 3H), 3.30 (br s,
1H), 3.89 (s, 1H), 3.84-4.12 (m, 2H), 9.61 (s, 1H); 13C NMR (100
MHz, DMSO-d6) δ 13.9 (q), 14.1 (q), 28.0 (q), 38.9 (q), 51.5 (t),
59.8 (t), 73.4 (d), 79.2 (s), 149.6 (s), 152.8 (s), 169.7 (s); MS (EI)
m/z 329 (4) [M+ - 1], 300 (5), 286 (17), 243 (13), 230 (100).
Anal. Calcd for C15H30N4O4: C, 54.53; H, 9.15; N, 16.91. Found:
C, 54.48; H, 9.13; N, 16.89.
General Procedure for the Synthesis of Phosphorylated
Pyrazines 9d,e,i and Piperazinones 14a-c and 15a-d by
Solvent-Free Reactions (See Scheme 6, Paths a-d). Phospho-
rylated pyrazines 9d,e,i were also obtained by solvent-free condi-
tions when diamine 2a or 2b (1 mmol) was added dropwise to
1,2-diaza-1,3-butadiene 1f,g (1 mmol). The reaction mixture was
heated at 120 °C for 3 h, and the crude product 9d was purified by
flash chromatography (silica gel, ethyl acetate/hexanes 30:70);
products 9e,i were purified by flash chromatography (silica gel,
ethyl acetate).
3
3.98 (q, J ) 7.2 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 14.5
(q), 15.4 (q), 38.5 (q), 43.3 (q), 44.3 (t), 47.8 (t), 58.0 (t), 110.5
(s), 143.8 (s), 166.1 (s); MS (EI) m/z 198 (100) [M+]. Anal. Calcd
for C9H16N2O2: C, 58.67; H, 8.75; N, 15.21. Found: C, 58.72; H,
8.77; N, 15.23.
General Procedure for the Synthesis of 2-(Diphenylphosphi-
noyl)-3-methylpyrazine 9l (See Scheme 4). To a magnetically
stirred solution of 1,2-diaza-1,3-butadiene 1f (1 mmol) as a mixture
of E/Z isomers in CH2Cl2 (10 mL) was added dropwise a solution
of 1,2-diaminoethane 2d (1.2 mmol) in CH2Cl2 (10 mL) at room
temperature and under a nitrogen atmosphere. The reaction mixture
was stirred at room temperature until complete disappearance of
starting materials (1 h). The solvent was evaporated under vacuum.
The crude product was unstable, and the dihydropyrazine was
directly oxidized with 1,4-benzoquinone (1 mmol, 108 mg) in
refluxing dioxane (10 mL). The reaction was washed with water
(20 mL) and extracted with CH2Cl2 (2 × 10 mL). The organic phase
was evaporated under vacuum, and product 9l was purified by flash
chromatography (silica gel, ethyl acetate).
2-(Diphenylphosphinoyl)-3-methylpyrazine (9l): white solid;
mp 136-137 °C; IR (KBr) νmax 1434, 1183, 1114 cm-1; 1H NMR
(300 MHz, CDCl3) δ 2.87 (s, 3H), 7.27-7.79 (m, 10H), 8.46-
4
3
8.48 (m, 1H), 8.54 (dd, JPH ) 3.9 Hz, JHH ) 2.4 Hz, 1H); 13C
NMR (75 MHz, CDCl3) δ 23.0, 128.6, 128.7, 129.2, 129.3, 131.0,
3
131.1, 132.2, 132.3, 132.5, 141.4 (d, JPC ) 15.6 Hz), 145.1 (d,
4JPC ) 3.5 Hz), 150.3 (d, 1JPC ) 126.2 Hz), 159.6 (d, 2JPC ) 20.6
Hz); 31P NMR (120 MHz, CDCl3) δ 27.2; MS (EI) m/z 294 (M+,
70). Anal. Calcd for C17H15N2OP: C, 69.38; H, 5.14; N, 9.52.
Found: C, 69.46; H, 5.12; N, 9.55.
1,2-Diaza-1,3-butadienes 1c,d (0.5 mmol) were slowly added to
1,2-diamines 2a,b,d (3 mmol) heated in an oil bath (for tempera-
tures, see Table 2) with magnetic stirring. After the complete
disappearance of 1,2-diaza-1,3-butadiene (monitored by silica gel
TLC, 20 min), the crude mixture was purified by chromatography
on silica gel (elution mixture: ethyl acetate/methanol, 90:10) for
the products 14a and 15a,b. For products 14b,c, the excess 1,2-
diamine 2d was evaporated under reduced pressure and the crude
reaction mixture was crystallized from ethyl acetate-methanol.
To a magnetically stirred solution of piperazinones 14b,c (0.5
mmol) in methanol (20 mL) was slowly added a stoichiometric
General Procedure for the Synthesis of R-[(2-Amino-1,2-
dicyanovinyl)amino]hydrazones 11a,b and 5,6-Dicyanopyrazine-
3-methyl-2-carboxylates 9m,n (See Scheme 5). A stoichiometric
amount of 1,2-diaza-1,3-butadiene 1b,c (1 mmol) as a mixture of
E/Z isomers was slowly added to a solution of diaminomaleonitrile
10 (3 mmol) in MeCN (30 mL). The reaction was allowed to stand
at room temperature (rt) with magnetic stirring for 96 h. The solvent
5904 J. Org. Chem., Vol. 71, No. 16, 2006

Straightforward Access to Pyrazines, Piperazinones, and Quinoxalines
amount of NBS (0.5 mmol). The conversion into pertinent 1,2,5,6-
tetrahydro-2-pyrazinones 15a,b occurred in 2 h. The solvent was
evaporated under reduced pressure, and the crude reaction mixture
was purified by chromatography on silica gel (elution mixture: ethyl
acetate/methanol, 90:10) and was crystallized from ethyl acetate-
methanol.
2-[1-(3-Oxo-2-piperazinyl)ethylidene]-1-hydrazinecarbox-
amide (14b): white powder; mp 149-152 °C; IR (Nujol) νmax 3450,
3291, 3199, 1704, 1661, 1590 cm-1; 1H NMR (400 MHz, DMSO-
d6) δ 1.74 (s, 3H), 2.69-2.76 (m, 2H), 2.88-2.93 (m, 1H), 3.01-
3.07 (m, 1H), 3.16-3.23 (m, 1H), 3.82 (s, 1H), 6.28 (s, 2H), 7.77
(br s, 1H), 9.09 (s, 1H); 13C NMR (100 MHz, DMSO-d6) δ 14.0
(q), 41.1 (t), 42.0 (t), 65.6 (d), 146.8 (s), 157.2 (s), 168.1 (s); MS
(EI) m/z 199 (3) [M+], 182 (7), 169 (17), 149 (13), 139 (25), 123
(15), 111 (22), 97 (50), 83 (63), 69 (90), 57 (100). Anal. Calcd for
C7H13N5O2: C, 42.20; H, 6.58; N, 35.16. Found: C, 42.39; H, 6.50;
N, 35.31.
19d was purified by flash chromatography (silica gel, ethyl acetate/
hexanes 90:10).
2-(Diphenylphosphinoyl)-3-methylquinoxaline (19a): brown
solid; mp 159-160 °C; IR (KBr) νmax 1540, 1434, 1188, 1122 cm-1
;
1H NMR (300 MHz, CDCl3) δ 3.00 (s, 3H), 7.27-8.05 (m, 14H);
13C NMR (100 MHz, CDCl3) δ 23.7, 128.3, 128.4, 128.5, 128.6,
128.8, 128.9, 129.3, 129.9, 130.6, 130.7, 131.1, 131.8, 132.0, 132.1,
132.2, 132.5, 139.8 (d, 3JPC ) 17.6 Hz), 141.6 (d, 4JPC ) 2.3 Hz),
1
2
151.1 (d, JPC ) 124.0 Hz), 156.6 (d, JPC ) 22.2 Hz); 31P NMR
(160 MHz, CDCl3) δ 27.2; MS (EI) m/z 344 (M+, 100). Anal. Calcd
for C21H17NOP: C, 73.25; H, 4.96; N, 8.14. Found: C, 73.16; H,
4.92; N, 8.13.
General Procedure for the Synthesis of 3-Methyl-5,6-dihy-
dropyrazine-2-carboxylate 6a-c,f in Solid Phase (See Scheme
8). To NdN-polymer-bound 1,2-diaza-1,3-butadienes19a 1j-l in
MeCN (20 mL) was added (1R,2R)-(+)-1,2-diphenyl-1,2-ethanedi-
amine 2a or (()-trans-1,2-diaminocyclohexane 2b (3 equiv). The
reaction mixture was allowed to stand at room temperature in MeCN
under magnetic stirring for 4-6 h furnishing 3-methyl-5,6-
dihydropyrazine-2-carboxylates 6 in solution. The resin was washed
with MeCN (5 × 5 mL) and CH2Cl2 (5 × 5 mL). After evaporation
of the solvent under reduced pressure, the residue was purified by
chromatography on a silica gel column (cyclohexane/ethyl acetate,
60:40) to give 6a-c,f as yellow oils.
2-[1-(3-Oxo-3,4,5,6-tetrahydro-2-pyrazinyl)ethylidene]-1-hy-
drazinecarboxamide (15c): white powder; mp 188-190 °C; IR
1
(Nujol) νmax 3409, 3276, 3190, 1693, 1673, 1591, 1541 cm-1; H
NMR (400 MHz, DMSO-d6) δ 1.94 (s, 3H), 3.21-3.25 (m, 2H),
3.67 (t, 3J ) 6.0 Hz, 2H), 6.21 (br s, 2H), 8.35 (br s, 1H), 9.66 (s,
1H); 13C NMR (100 MHz, DMSO-d6) δ 12.4 (q), 37.9 (t), 48.1 (t),
142.2 (s), 155.9 (s), 156.7 (s), 161.0 (s); MS (EI) m/z 197 (6) [M+],
181 (7), 169 (33), 151 (25), 125 (36), 111 (59), 97 (92), 83 (100).
Anal. Calcd for C7H11N5O2: C, 42.64; H, 5.62; N, 35.51. Found:
C, 42.81; H, 5.49; N, 35.59.
Acknowledgment. The Italian authors thank the Ministero
dell’Universita`, dell’Istruzione e della Ricerca (MIUR)-Roma,
and the Universita` degli Studi di Urbino and the Spanish authors
thank the Direccio´n General de Investigacio´n del Ministerio de
Ciencia y Tecnolog´ıa (MCYT, Madrid DGI, BQU2000-0217)
and the Universidad del Pa´ıs Vasco (UPV, GS/02) for supporting
this work. J.M.S. and R.I. thank the Ministerio de Ciencia y
Tecnolog´ıa (Madrid) for financial support through the Ramo´n
y Cajal Program and for a predoctoral fellowship, respectively.
General Procedure for the Synthesis of 2-Phosphorylated
Quinoxalines 19a-i (See Scheme 7). To a magnetic stirred solution
of 1,2-diaza-1,3-butadienes 1f-i (1 mmol) as a mixture of E/Z
isomers in CH2Cl2 (10 mL) was added dropwise a solution of
o-phenylendiamine 16a, 4,5-dimethyl-o-phenylendiamine 16b, 4,5-
dichloro-o-phenylendiamine 16c, 2,3-diaminonaphthalene 16d (1.2
mmol) in CH2Cl2 (10 mL) at room temperature and under a nitrogen
atmosphere. The reaction mixture was stirred at room temperature
until complete disappearance of starting materials (1-3 h). The
solvent was evaporated under vacuum and products 19a,f,h were
recrystallized from ethyl acetate, 19b,e,i were purified by flash
chromatography (silica gel, ethyl acetate), 19c,g were purified by
flash chromatography (silica gel, ethyl acetate/hexanes 50:50), and
Supporting Information Available: General experimental
procedures and characterization data for all new compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
JO060450V
J. Org. Chem, Vol. 71, No. 16, 2006 5905