Synthesis of pyrazine-phosphonates and -phosphine oxides from 2H-azirines or oximes

Article abstract of DOI:10.1021/ol0261534

(Matrix Presented) Tetrasubstituted pyrazines containing two phosphonate groups 2 in positions 2 and 5 and trisubstituted pyrazines containing a phosphonate 5 or a phosphine oxide group 7 in position 2 are obtained by thermal treatment of 2H-azirine-2-pho

Full text of DOI:10.1021/ol0261534

ORGANIC
LETTERS
2002
Vol. 4, No. 14
2405-2408
Synthesis of Pyrazine-phosphonates and
-Phosphine Oxides from 2H-Azirines or
Oximes
,†
Francisco Palacios,* Ana Mar´ıa Ochoa de Retana, Jose´ Ignacio Gil, and
Rafael Lo´pez de Munain
Facultad de Farmacia, UniVersidad del Pa´ıs Vasco, Apartado 450,
01080 Vitoria, Spain
qoppagaf@Vc.ehu.es
Received May 8, 2002
ABSTRACT
Tetrasubstituted pyrazines containing two phosphonate groups 2 in positions 2 and 5 and trisubstituted pyrazines containing a phosphonate
5 or a phosphine oxide group 7 in position 2 are obtained by thermal treatment of 2H-azirine-2-phosphonates 1 and -phosphine oxides 6.
These pyrazines can also be prepared from â-ketoxime tosylates 9 and 10 or from oxime derived from phosphine oxide 11.
Pyrazines are widely used intermediates in medicinal chem-
istry and for functional transformations.1,2 Pyrazines and
especially 2,5-disubstituted pyrazines, which are biosynthe-
sized from amino acids, are common units in a wide variety
of marine natural products with cytostatic and antitumor
properties,3 while pyrazinamide4 Ia (Figure 1, R ) NH2)
berculosis activity. Furthermore, it is known that phosphor
substituents regulate important biological functions6 and that
molecular modifications involving the introduction of orga-
nophosphorus functionalities could increase their biological
activity, in a manner similar to that reported for other
pharmaceuticals.6 For these reasons, pyrazines containing one
(1) For recent reviews on pyrazines see: (a) McCullough, K. L. In
Heterocyclic Compounds. Rodd’s Chemistry of Carbon Compounds, 2nd
ed., 2nd supplement; Sainsbury, M., Ed.; Elsevier: Amsterdam, 2000; Vol.
4, Parts I-J, pp 99-171. (b) Urban, S.; Hickford, S. J. H.; Blunt, J. W.;
Munro, M. H. G. Curr. Org. Chem. 2000, 4, 765. (c) Ohta, A.; Aoyagi, Y.
ReV. Heteroat. Chem. 1998, 18, 141. (d) Sato, N. In ComprehensiVe
Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W., Boulton, A. J.,
Eds.; Elsevier: Oxford, 1996; Vol. 6, pp 233-278.
(2) For recent contributions see: (a) Gohlke, H.; Gundisch, D.; Schwarz,
S.; Seitz, G.; Tilotta, M. C.; Wegge, T. J. Med. Chem. 2002, 45, 1065. (b)
Ragnarsson, U.; Grehn, L.; Maia, H. L.; Monteiro, L. S. Org. Lett. 2001,
3, 2021. (c) Liu, W.; Wise, D. S.; Townsend, L. B. J. Org. Chem. 2001,
66, 4783. (d) Cavalier, J. F.; Burton, M.; Dussart, F.; Marchand, F.; Rees,
J. F.; Marchant-Brynaert, J. Bioorg. Med. Chem. 2001, 9, 1037. (e) Shibata,
K.; Fukuwatari, T.; Sugimoto, E. Biochemistry 2001, 65, 1339.
Figure 1.
(3) (a) LaCour, T. G.; Guo, C.; Boyd, M. R.; Fuchs, P. L. Org. Lett.
2000, 2, 33. (b) Basler, S.; Brunck, A.; Jautelat, R.; Winterfeldt, E. HelV.
Chim. Acta 2000, 83, 1854. (c) LaCour, T. G.; Guo, C.; Ma, S.; Jeong, J.
U.; Boyd, M. R.; Matsunaga, S.; Fusetani, N.; Fuchs, P. L. Bioorg. Med.
Chem. Lett. 1999, 9, 2587. (d) Guo, C.; Bhandaru, S.; Fuchs, P. L.; Boyd,
M. R. J. Am. Chem. Soc. 1996, 118, 10672.
and more recently pyrazinesters5 Ib (Figure 1, R ) OR) have
been successfully evaluated in vitro and in vivo for antitu-
† Fax: (+34) 945-013049.
10.1021/ol0261534 CCC: $22.00 © 2002 American Chemical Society
Published on Web 06/11/2002

(2-position; II, Figure 1) or two (2,5-positions; III, Figure
1) phosphorus substituents are expected to play a role similar
to that observed in their isosteric analogues I and could
possess biological activity and be used in the preparation of
new complex derivatives containing a pyrazine ring and
phosphorus substituents. However, as far as we know, no
examples of pyrazines containing phosphorus substituents
have been described.
Scheme 1
Recently, we reported the first asymmetric synthesis of
2H-azirines7 derived from phosphine oxides8 and the prepa-
ration of 3-substituted alkyl and aryl 2H-azirine-2-phospho-
nates9,10 by alkaloid-mediated Neber reaction of tosyl oximes.
A recent publication11 reporting the preparation and synthetic
use of chiral 2-aryl-2H-azirine-3-phosphonates prompted us
to report our own results concerning the synthesis of the until
now unknown pyrazines containing one (2-position; II,
Figure 2) or two (2,5-positions; III, Figure 2) phosphorus
took place when these azirines 1a,b were heated (2 h) at 80
°C without solvent to give in almost quantitative yields 3,6-
dialkyl pyrazines containing two phosphonate groups in 2,5-
positions 2 (Scheme 1, Table 1, entries 1 and 3).13 Spectro-
Table 1. Synthesis of Phosphorylated Pyrazines 2, 5 and 7
entry
compound
R
R1
yielda
1
2
3
4
5
6
7
8
9
2a
2a
2b
2b
5c
5c
7a
7a
7a
7b
OEt
OEt
OEt
OEt
OEt
OEt
Ph
Ph
Ph
Ph
Me
Me
Et
97b
61c
98b
68c
42d
90e
70e
74c
53f
68e
Figure 2.
substituents from easily available azirines derived from
phosphonates or phosphine oxides (IV, Figure 2) or from
their precursors (V, Figure 2). The key step is based on the
dimerization reaction of azirines.7a,12
Ring opening and selective dimerization of 3-alkyl-2H-
azirine phosphonates 1a (R1 ) CH3) and 1b (R1 ) C2H5)
Et
Ph
Ph
Me
Me
Me
Et
10
a Yields refer to isolated compounds. b From azirines 1a,b, 80 °C, 2 h.
c From tosyloximes 9a,b, 10a, rt, 14 h. d From azirine 1c, 120 °C, 2 h.
e From azirines 1c, 6a,b, refluxing toluene, 2 h. f One-pot procedure from
oxime 12a.
(4) (a) Suzuki, Y.; Suzuki, A.; Tamaru, A.; Katsukawa, C.; Oda, H. J.
Clin. Microbiol. 2002, 40, 501. (b) Zhang, Y.; Permar, S.; Sun, Z. J. Clin.
Microbiol. 2002, 40, 42. (c) Bothamley, G. Drug Saf. 2001, 24, 553. (d)
Zimhony, O.; Cox, J. S.; Welch, J. T.; Vilcheze, C.; Jacobs, W. R. Nat.
Med. (NY) 2000, 6, 1043.
(5) (a) Cynamon, M. H.; Speirs, R. J.; Welch, J. T. Antimicrob. Agents
Chemother. 1998, 42, 462. (b) Bergmann, K. E.; Cynamon, M. H.; Welch,
J. T. J. Med. Chem. 1996, 39, 3394. (c) Speirs, R. J.; Welch, J. T.; Cynamon,
M. H. Antimicrob. Agents Chemother. 1995, 39, 1269.
(6) For reviews, see: (a) Engel, R. Handbook of Organophosphorus
Chemistry; Marcel Dekker, Inc.: New York, 1992. (b) Kafarski, P.; Lejczak,
B. Phosphorus Sulfur 1991, 63, 193-215. (c) Toy, A. D. F.; Walsh, E. N.
Phosphorus Chemistry in EVeryday LiVing; American Chemical Society:
Washington, DC, 1987; p 333.
(7) For recent reviews on azirines, see: (a) Palacios, F.; Ochoa de Retana,
A. M.; Martinez de Marigorta, E.; de los Santos, J. M. Org. Prep. Proced.
Int. 2002, 34, 219-269. (b) Gilchrist, T. L. Aldrichimica Acta 2001, 34,
51-55. (c) Palacios, F.; Ochoa de Retana, A. M.; Martinez de Marigorta,
E.; de los Santos, J. M. Eur. J. Org. Chem. 2001, 2401-2414.
(8) Palacios, F.; Ochoa de Retana, A. M.; Gil, J. I.; Ezpeleta, J. M. J.
Org. Chem. 2000, 65, 3213-3217.
(9) Palacios, F.; Ochoa de Retana, A. M.; Gil, J. I. Tetrahedron Lett.
2000, 41, 5363-5366.
(10) The asymmetric synthesis of diethyl 2-phenyl-2H-azirine-3-phos-
phonate (62%) and the isomeric 3-phenyl-2H-azirine-2-phosphonate (15%)
from chiral aziridines has been reported. Davis, F. A.; McCoull, W.
Tetrahedron Lett. 1999, 40, 249-252.
(11) The asymmetric synthesis of dimethyl 2-aryl-2H-azirine-3-phos-
phonates with a small proportion of the isomeric 3-aryl-2H-azirine-2-
phosphonate by Swern oxidation of chiral cis-aziridine phosphonates and
the use as a dienophile in cycloaddition reactions of 2H-azirine-3-
phosphonates have been recently reported. Davis, F. A.; Wu, Y.; Yan, H.;
Prasad, K. R.; McCoull, W. Org. Lett. 2002, 4, 655-658.
scopic data were in agreement with the assigned structure
of compounds 2. Mass spectrometry of 2a showed the
molecular ion peak (2%), while in the 31P NMR spectrum
the phosphonate group resonated at δP ) 9.7 ppm. The 13
C
NMR spectrum showed an absorption at δC ) 146.5 ppm
1
as a doublet with a coupling constant JPC ) 228.4 Hz for
carbon atoms directly bonded to the phosphorus (C-2 and
C-5) and a double doublet at δC ) 153.4 ppm with coupling
2
3
constants JPC ) JPC ) 23.0 Hz for both C-3 and C-6 of
the heterocycle.
(12) (a) Aurichio, S.; Grassi, S.; Malpezzi, L.; Sartori, A. S.; Truscello,
A. M. Eur. J. Org. Chem 2001, 1183-1187. (b) Alves, M. J.; Gilchrist, T.
L. J. Chem. Soc., Perkin Trans. 1 1998, 299-303. (c) Hugener, M.;
Heimgartner, H. HelV. Chim. Acta 1995, 78, 1490-1498. (d) Knittel, D.
Synthesis 1985, 186-188. (e) Alper, H.; Prickett, J. E.; Wollwitz, S. J.
Am. Chem. Soc. 1977, 99, 4330-4333. (f) Padwa, A. Acc. Chem. Res. 1976,
9, 371-378.
(13) General Procedure for the Preparation of Pyrazine Phospho-
nates (2a,b) from Azirines 1. The corresponding azirine (1a,b; 1 mmol)
was heated at 80 °C for 2 h under a N2 atmosphere. The crude product was
purified by chromatography using silica gel (hexane/ethyl acetate).
2406
Org. Lett., Vol. 4, No. 14, 2002

The formation of pyrazines 2 could be explained by
selective ring opening of azirines 1 involving the C-C single
bond and formation of unstable nitrile ylide dipoles 3,
followed by dimerization of the dipole7a,12f,14 and oxidation
of the resulting dihydropyrazines 4, although an alternative
mechanism with formation of vinyl nitrene intermediates by
C2-N ring opening of azirines 1, followed by dimerization7a,15
and oxidation of resulting dihydropyrazines 4, cannot be
totally excluded (Scheme 1).
bond, dimerization of the dipole intermediate, and aroma-
tization with the loss of diethyl phosphite (HPO(OEt)2) or
diphenyl phosphine oxide (HPOPh2) from resulting dihy-
dropyrazines 4 (R ) OEt) or 8 (R ) Ph) (Scheme 2).
Taking into account that phosphorylated azirines 1 (R )
OEt) and 6 (R ) Ph) can be easily prepared from oximes,8,9
we explored whether p-toluenesulfonyl oximes derived from
phosphonates 9 (R ) OEt) and phosphine oxides 10 (R )
Ph) or their oxime precursors 11 (R ) Ph) could also be
used as synthons for the preparation of phosphorus-
substituted pyrazines 2 and 7. Treatment of p-toluenesulfonyl
oximes derived from phosphonates 9 (R ) OEt) with primary
or secondary amines (R-methylbenzylamine, diethylamine,
piperidine) at room temperature gave pyrazines 2 (Scheme
3, Table 1, entries 2 and 4).17 Similarly, pyrazine phosphine
However, in the case of 3-phenyl-2H-azirine phosphonate
1c (R1 ) C6H5, R ) OEt), it was necessary to use more
drastic reaction conditions. First, azirine 1c was heated at
120 °C without solvent and (3,6-diphenyl pyrazin-2-yl)-
phosphonate 5c (R1 ) C6H5, R ) OEt) containing only one
phosphonate group in the 2-position was obtained in a
moderate yield (Scheme 2, Table 1, entry 5). However, the
Scheme 3a
Scheme 2
yield reached 90% when the reaction was performed in
refluxing toluene (Scheme 2, Table 1, entry 6). Spectroscopic
data were in agreement with pyrazine phosphonate 5c. Mass
spectrometry of 5c showed the molecular ion peak (27%).
In the 31P NMR spectrum, the phosphonate group resonated
a Reaction conditions: (i) R2NH, 25 °C; (ii) TsCl, Py.
1
at δP ) 10.1 ppm; in the H NMR spectrum, there appears
an absorption at δH ) 9.07 ppm as a doublet with a long-
5
range coupling constant JPH ) 4.6 Hz for H-4, while the
oxide 7a can be obtained from p-toluenesulfonyl oxime
derived from phosphine oxide 10a (R ) Ph) in the presence
of piperidine (Scheme 3, Table 1, entry 8). These results
suggest that in these cases, vinyl nitrene intermediates or
unstable nitrile ylide dipoles 3, generated from oximes 9 and
10, followed by dimerization7a,14 and oxidation of the
resulting dihydropyrazines 4, could explain the formation
of pyrazines 2 and 7. From a synthetic point of view, it is
noteworthy that pyrazine 7a can also be prepared in a one-
pot procedure from oxime derived from phosphine oxide 11a
(R ) Ph). The preparation of p-toluenesulfonyloxime 10a
(R ) Ph) was performed in situ by reaction of functionalized
â-oxime 11a (R ) Ph) with p-toluenesulfonyl chloride in
pyridine, and after filtration of the pyridinium salt, a
secondary amine (piperidine) was added to give substituted
pyrazine phosphine oxide 7 (Scheme 3, Table 1, entry 9).
13C NMR spectrum of 5c showed doublets at δC ) 136.6
ppm (1JPC ) 185.3 Hz) for C-2, 141.7 ppm (4JPC ) 3.5 Hz)
for C-5, 149.4 ppm (2JPC ) 17.1 Hz) for C-3, and 155.6
ppm (3JPC ) 26.1 Hz) for C-6. The scope of the reaction
was not limited to azirines derived from phosphonate 1c,
given that thermal heating of 3-alkyl azirine phoshine oxides
6a (R1 ) CH3) and 6b (R1 ) C2H5) in refluxing toluene led
to the formation of pyrazine phosphine oxides 7a,b (Scheme
2, Table 1, entries 7 and 10).16 However, 3-phenyl azirine
phosphine oxides 6c (R1 ) C6H5) seem to be somewhat more
stable than the corresponding alkyl-substituted azirines 6a,b,
since heating 3-phenyl azirine 6c in refluxing toluene did
not give the pyrazine and the starting product 6c was
recovered instead. The formation of pyrazines 5 (R ) OEt)
and 7 (R ) Ph) could be explained, as before, by selective
ring opening of azirines 1c and 6 involving the C-C single
(17) General Procedure for Preparation of Pyrazine Phosphonate
(2a,b) and Pyrazine Phosphine Oxides (7a,b) from Tosyloximes (9, 10).
To a well-stirred solution of the corresponding tosyloxime (1 mmol) (9a,b,
10a) in dry benzene or EtOH was added under a N2 atmosphere a secondary
amine (1.2 mmol) (diethylamine, piperidine). The reaction was allowed to
stay at room temperature for 14 h. The resulting mixture was washed three
times with distilled water (5 mL), extracted with CH2Cl2, dried over
anhydrous MgSO4, and evaporated under vacuum. The crude product was
purified by chromatography using silica gel (hexane/ethyl acetate).
(14) Chandrasekhar, S.; Gopalaiah, K. Tetrahedron Lett. 2001, 42, 8123-
8125.
(15) Smolinsky, G.; Pride, C. A. J. Org. Chem. 1968, 33, 2411-2416.
(16) General Procedure for Preparation of Pyrazine Phosphonate
(5c) and Pyrazine Phosphine Oxides (7a,b) from Azirines 1c, 6a,b. A
solution of the corresponding azirine (1 mmol) in dry toluene (5 mL) was
refluxed for 2 h under a N2 atmosphere. The crude product was purified by
chromatography using silica gel (hexane/ethyl acetate).
Org. Lett., Vol. 4, No. 14, 2002
2407

In conclusion, the first synthesis of phosphorylated
analogues of pyrazinamides such as substituted pyrazines
containing two phosphonate groups (2,5-positions) 2 and
pyrazines containing one phosphonate group (2-position) 5
or a phosphine oxide group (2-position) 7 is described. The
process could imply thermal ring opening of 2H-azirines
derived from phosphonates 1 or phosphine oxides 6 and
dimerization of unstable nitrile ylide intermediates. Pyrazines
2 and 7 can also be obtained in a one-pot procedure from
tosyloximes 9 and 10 or from oxime 11. Phosphorylated
pyrazines may be important synthons in organic synthesis
and for the preparation of biologically active compounds of
interest to medicinal chemistry.3-5
Acknowledgment. The present work has been supported
by the Direccio´n General de Investigacio´n del Ministerio de
Ciencia y Tecnolog´ıa (MCYT, Madrid DGI, BQU2000-0217)
and by the Universidad del Pa´ıs Vasco (UPV, G11/99). J.I.G.
and R.L.M. thank the Universidad del Pa´ıs Vasco and the
Ministerio de Educacio´n y Cultura (Madrid) for predoctoral
fellowships.
Supporting Information Available: General procedures
and characterization data of compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL0261534
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Org. Lett., Vol. 4, No. 14, 2002