Ugi/Smiles access to pyrazine scaffolds

Article abstract of DOI:10.1016/j.tetlet.2008.03.100

New pyrazine and quinoxaline scaffolds were obtained via an Ugi/Smiles four-component coupling of pyrazinone or quinoxalinone derivatives with isocyanides, aldehydes, and primary amines.

Full text of DOI:10.1016/j.tetlet.2008.03.100

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 3208–3211
Ugi/Smiles access to pyrazine scaffolds
*
*
´
Anaelle Barthelon, Aurelie Dos Santos, Laurent El Kaım , Laurence Grimaud
¨
Laboratoire Chimie et Proce´de´s, DCSO, UMR 7652, Ecole Nationale Supe´rieure de Techniques Avance´es, 32 Bd Victor, Paris 75015, France
Received 14 February 2008; revised 14 March 2008; accepted 19 March 2008
Available online 23 March 2008
Abstract
New pyrazine and quinoxaline scaffolds were obtained via an Ugi/Smiles four-component coupling of pyrazinone or quinoxalinone
derivatives with isocyanides, aldehydes, and primary amines.
Ó 2008 Elsevier Ltd. All rights reserved.
A few years ago, we reported a new Ugi-type four-com-
ponent coupling of isocyanides with aldehydes, primary
amines, and electron-deficient phenols.1 The key step of
this transformation involves a Smiles rearrangement of a
phenol imidate intermediate. We also showed that the
scope of this reaction could be extended to the use of acti-
vated pyridines as well as hydroxy- and mercapto-pyrim-
idines (Scheme 1).2 Now we report the results of our
study on pyrazinones and their benzo-fused analogues,
quinoxalinones.
Pyrazines represent an important class of heterocyclic
compounds.3 As several biosynthetic paths allow the
conversion of an amino acid into a pyrazine, this structural
unit is found in many natural products. They are important
flavor ingredients in food,4 and have shown interesting
anticancer5 as well as antituberculosis6 activities. Pyrazines
have been used widely as agrochemicals as well.7 These
properties prompted us to examine the potential of the
Ugi–Smiles coupling for the preparation of amino-
piperazine libraries and their benzo-fused analogues,
quinoxalines.
Different pyrazinones were prepared by condensing a-
dicarbonyl compounds with the corresponding a-amino
amides. These pyrazinones were treated with a stoichio-
metric amount of a carbonyl compound, an amine and
an isocyanide to perform the Ugi–Smiles coupling. The
expected amino-substituted pyrazines were obtained in
moderate to good yields as shown in Table 1.8 The best
yields were obtained in toluene at 100 °C. Under these con-
ditions, tert-butylisocyanide gave a poor yield of product
due to its low boiling point (Table 1, entry 4). The dimeth-
ylpyrazine derivatives 1d–f reacted sluggishly and gave low
yields of the desired adducts (Table 1, entries 9–11).
Next, quinoxalinones were investigated as potential
partners in this four-component coupling. Due to the poor
solubility of quinoxalinone 3, toluene had to be replaced by
DMSO as a solvent.9 Under these conditions, the desired
adducts were obtained albeit in poor yields (Scheme 2).
Afterwards, we envisioned the use of mercapto deriva-
tives to improve the efficiency of these couplings. Indeed,
O
R2
N
R1CHO
R4
+
R3NC
N
methanol
N
R4
R3HN
HO
60 °C
R1
N
R2NH2
N
R5
R5
R4
N
R4
N
N
N
R5
R5
H
O
Smiles
O
R3
H
R2
R3
N
R2
N
N
N
R1
R1
Scheme 1.
*
Corresponding authors. Tel.: +33 145525537; fax: +33 145528322
(L.E.K.).
E-mail addresses: laurent.elkaim@ensta.fr (L. E. Ka¨ım), laurence.
grimaud@ensta.fr (L. Grimaud).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.03.100

A. Barthelon et al. / Tetrahedron Letters 49 (2008) 3208–3211
3209
Table 1
Four-component formation of amino-pyrazines
R6
R5
N
OH
R4
R2
N
O
R1CHO
R3NC
R6
R5
N
N
R3
N
toluene
100
N
+
H
1
R1
R4
°
C
R2NH2
2
Entry
1
Pyrazinone
Time
Product
Yield (%)
92
O
Ph
Ph
N
N
OH
12 h
Ph
Ph
N
N
N
Bnp-OMe
N
H
i-Bu
1a
2a
O
Ph
Ph
N
N
N
Cy
N
H
2
3
4
1a
1a
1a
12 h
12 h
12 h
59
93
31
Et
2b
p-ClBn
O
Ph
Ph
N
N
N
Cy
N
H
i
-Bu
2c
O
Ph
Ph
N
N
N
t-Bu
N
H
Et
2d
MeO
N
O
Ph
Ph
N
Bnp-OMe
N
H
5
6
7
1a
12 h
76
73
29
N
Ph
2e
MeO
N
O
Ph
Ph
N
OH
Bn
Ph
Ph
N
NHBnp-OMe
6 d
i-Bu
N
N
Bn
1b
2f
O
Ph
Ph
N
N
N
NHBnp-Cl
1b
4 d
Et
Bn
2g
O
Ph
Ph
N
N
N
Ph
Ph
N
OH
NHCy
i
-Bu
8
2 d
43
N
SMe
1c
SMe
2h
(continued on next page)

3210
A. Barthelon et al. / Tetrahedron Letters 49 (2008) 3208–3211
Table 1 (continued)
Entry
Pyrazinone
Time
3 d
Product
Yield (%)
45
N
N
OH
O
9
N
N
N
NHCy
NHCy
1d
i
-Bu
2i
O
N
OH
Bn
N
N
N
10
2 d
15
N
Et
Bn
1e
2j
O
N
N
OH
N
N
N
NHCy
i
-Bu
11
2 d
11
SMe
1f
SMe
2k
Table 2
N
N
OH
Thioamide formation from a mercaptopyrazinone and a mercapto-
quinoxalinone
R2
N
O
R1CHO
R3NC
N
N
R3
N
DMSO
Entry Mercapto
derivative
Time Product
(h)
Yield
(%)
H
+
R1
3
4 d, 100 °C
R2NH2
Ph
Ph
N
SH
S
R1
R2
R3
Cy
Cy
Yield (%)
1
2
3
4
12
12
12
12
76
36
31
9
Ph
Ph
N
N
N
Bnp-OMe
N
16
8
i
-Bu CH2CH2OMe
H
N
i-Bu
i
-Bu
Et
All
All
4a
5a
p
-MeOBn
9
S
Scheme 2.
Ph
Ph
N
N
N
Cy
N
4a
H
Et
5b
previous work on pyrimidines and benzo-fused hetero-
cycles, such as benzothiazoles and benzoxazoles, demon-
strated a higher reactivity of mercaptans over the
corresponding hydroxy derivatives.10 Mercaptopyrazinon-
es and quinoxalinones were obtained by the treatment of
the corresponding hydroxy derivatives with P2S5. When
submitted to the Ugi–Smiles coupling, these mercaptans
turned out to be less efficient than the corresponding
hydroxyl derivatives (Table 2).11 The higher solubility of
quinoxaline 4b allowed the reaction to be performed in
toluene, however the yields were not improved.
MeO
N
S
N
N
SH
N
NHCy
i-Bu
N
4b
5c
MeO
N
S
N
NHBnp-OMe
4b
i
-Bu
N
5d
To conclude, we have disclosed a new multicomponent
formation of aminopyrazines by an Ugi-type procedure.
The access to these new scaffolds confirms further the util-
ity of Ugi–Smiles couplings for the preparation of amino-
substituted nitrogen heterocycles. The extension of these
couplings to triazines and tetrazines as well as our efforts
to improve these additions with Lewis acids will be
reported in due course.
Acknowledgments
Financial support was provided by ENSTA. A.B.
`
thanks the ENS Cachan and the Ministere de l’enseigne-
´
ment superieur et de la recherche for a fellowship.

A. Barthelon et al. / Tetrahedron Letters 49 (2008) 3208–3211
3211
of allylamine (0.8 mmol, 1 equiv), 88 lL of isobutyraldehyde
(0.8 mmol, 1 equiv), and 120 lL of para-methoxybenzylisonitrile
(0.8 mmol, 1 equiv). The resulting mixture was stirred at 110 °C for
12 h. The solvent was then removed in vacuo. The crude product was
purified by flash chromatography on silica gel (DCM/AcOEt: 95:5) to
give 383 mg (92%) of 2a as a white solid. Mp 116–117 °C. 1H
NMR (400 MHz, CDCl3) d 8.11 (s, 1H), 7.36–7.23 (m, 10H), 6.96 (d,
J = 8.6 Hz, 2H), 6.83 (t, J = 5.3 Hz, 1H), 6.71 (d, J = 8.6 Hz,
2H), 5.87 (ddt, J = 15.6, 10.4, 5.1 Hz, 1H), 5.42 (t, J = 7.1 Hz, 1H),
5.30 (dd, J = 17.2, 10.6 Hz, 2H), 4.29–4.28 (m, 2H), 4.23–4.21 (m,
1H), 4.10–4.06 (m, 1H), 3.76 (s, 3H), 2.02–1.95 (m, 1H), 1.84–1.77
(m, 1H), 1.69–1.62 (m, 1H), 0.98 (d, J = 6.8 Hz, 3H), 0.97 (d,
J = 6.8 Hz, 3H). 13C NMR (100.6 MHz, CDCl3) d 171.8, 159.2, 152.2,
148.8, 141.5, 139.4, 139.3, 134.1, 130.4, 129.9, 129.8, 129.7, 129.2,
128.7, 128.5, 128.5, 127.8, 118.0, 114.4, 56.1, 55.6, 48.1, 43.3,
37.7, 25.3, 22.9. HRMS: calcd for C33H36N4O2 520.2838. Found
520.2839.
References and notes
1. (a) El Ka¨ım, L.; Grimaud, L.; Oble, J. Angew. Chem., Int. Ed. 2005,
44, 7961; (b) El Ka¨ım, L.; Gizolme, M.; Grimaud, L.; Oble, J. J. Org.
Chem. 2007, 72, 4169.
2. El Ka¨ım, L.; Gizolme, M.; Grimaud, L.; Oble, J. Org. Lett. 2006, 8,
4019.
3. 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. In Rodd’s Chemistry of Carbon Compounds, 2nd ed.; Sainsbury,
M., Ed.; Elsevier: Amsterdam, 2000; Vol. 4, pp 99–171. Parts I–J; (d)
Sato, N. In Comprehensive Heterocyclic Chemistry II; Katritzky, A. R.,
Rees, C. W., Boulton, A. J., Eds.; Elsevier: Oxford, 1996; Vol. 6, p 233.
4. (a) Maga, J. A. Food Rev. Int. 1992, 8, 479; (b) Buchbauer, G.; Klein,
C. T.; Wailzer, B.; Wolschann, P. J. Agric. Food Chem. 2000, 48, 4273.
5. (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.
9. The reaction was performed as well in MeOH, CH3CN and in
a 10:1 mixture of toluene:water without any improvement in the
yield.
10. El Ka¨ım, L.; Gizolme, M.; Grimaud, L. Synlett 2007, 465.
11. Typical procedure for 5b: To a solution of 264 mg (1 mmol, 1 equiv) of
5,6-diphenylpyrazine-2-thiol 4a in 1 mL of toluene were added 75 lL
of allylamine (1 mmol, 1 equiv), 108 lL of propanal (1 mmol,
1 equiv), and 110 lL of cyclohexylisonitrile (1 mmol, 1 equiv). The
resulting mixture was stirred at 110 °C for 3 days. The solvent was
then removed in vacuo. The crude product was purified by flash
chromatography on silica gel (DCM/petroleum ether: 60:40) to give
´
Lett. 2000, 2, 33; (d) Buron, F.; Ple, N.; Turck, A.; Gueguiner, G. J.
Org. Chem. 2005, 70, 2616.
6. (a) Fukuwatari, T.; Sugimoto, E.; Shibata, K. Biosci. 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)
Milczarska, B.; Foks, H.; Zwolska, Z. Phosphorus, Sulfur Silicon
Relat. Elem. 2005, 180, 2255; (e) Cynamon, M. H.; Speirs, R. J.;
Welch, J. T. Antimicrob. Agents Chemother. 1998, 42, 462.
7. (a) Fales, H. M.; Blum, M. S.; Southwick, E. W.; William, D. L.;
Roller, P. P.; Don, A. W. Tetrahedron 1988, 44, 5045; (b) Tecle, B.;
Sun, C. M.; Borphy, J. J.; Toia, R. F. J. Chem. Ecol. 1987, 13, 1811;
(c) Wheeler, J. W.; Avery, J.; Olubajo, O.; Shamim, M. T.; Storm, C.
B. Tetrahedron 1982, 38, 1939; (d) Brown, W. V.; Moore, B. P. Insect
Biochem. 1979, 9, 451; (e) Oldham, N. J.; Morgan, E. D. J. Chem.
Soc., Perkin Trans. 1 1993, 2713.
1
169 mg (36%) of 5b as an orange oil. H NMR (400 MHz, CDCl3) d
9.40 (br s, 1H), 8.13 (s, 1H), 7.40–7.26 (m, 10H), 5.96–5.87 (m, 1H),
5.33–5.27 (m, 2H), 5.08 (br s, 1H), 4.52 (dd, J = 18.2, 4.8 Hz, 1H),
4.20–4.07 (m, 2H), 2.47–2.37 (m, 1H), 2.15–2.04 (m, 1H) 1.78–1.60
(m, 2H), 1.43–1.27 (m, 3H), 1.20–1.10 (m, 2H) 1.00 (dd, J = 7.6,
7.0 Hz, 3H), 0.86–0.77 (m, 1H), 0.70–0.60 (m, 1H), 0.52–0.43 (m, 1H).
13C NMR (100.6 MHz, CDCl3) d 200.5, 152.1, 148.1, 141.4, 139.8,
138.9, 134.3, 130.5, 129.9, 129.8, 129.0, 128.8, 128.5, 127.9, 117.7,
67.3, 53.6, 49.0, 31.3, 30.8, 25.4, 24.8, 24.4, 11.7. HRMS: calcd for
8. Typical procedure for 2a: To a solution of 198 mg (0.8 mmol, 1 equiv)
of 5,6-diphenylpyrazin-2-ol 1a in 1 mL of toluene were added 60 lL
C
29H34N4S 470.2504. Found 470.2509.