D. Sherman et al. / Tetrahedron Letters 48 (2007) 8943–8946
8945
X
N
N
R
Cl
N
N
Br
Ar
N
N
Br
i
ii
i
i or iii
N
N
R
N
N
N
R
N
R
S
S
S
S
S
S
S
O
H
N
N
N
Cl
N
R1
N
N
N
16
15
17; R1 = Me
18; R1 = Et
19; R1 = CN
12; X= OH; R = Br
23; X = Cl;
24
25; Ar = pyridin-3-yl
R=
O
O
O
B
O
N O
iii
R =
O
N O
O
26
O
Scheme 6. Reagents and condtions: (i) 5-formyl-2-thiopheneboronic
acid, PdCl2(dppf), K2CO3, H2O, 1,4-dioxane, reflux (or microwave at
110 °C); (ii) RMgI, Fe(acac)3, THF, NMP, rt (low yield); (iii)
Pd(Ph3P)4, Zn(CN)2, DMF, 100 °C, microwave (50–60%).
Ar
N
N
O
S
N
N
27; Ar = pyridin-3-yl
28; Ar = pyrimidin-5-yl
29; Ar = 1-methyl-pyrazol-4-yl
of Zn(CN)2 was used to incorporate a nitrile group,
giving 19 in good yield. Other methods for nitrile forma-
tion, such as displacement with NaCN, KCN, or CuCN,
did not yield any product. Indeed, the choice of catalyst
for this reaction proved to be of crucial importance, as
PdCl2(dppf)2 failed to yield any of the desired nitrile
19 upon reaction with Zn(CN)2.
Scheme 8. Reagents and condtions: (i) POCl3 (30%); (ii) ArB(OH)2 or
boronic ester, PdCl2(dppf)2, K2CO3, H2O, 1,4-dioxane, microwave at
110 °C (30–40%); (iii) 26, PdCl2(dppf)2, K2CO3, 1,4-dioxane, micro-
wave at 110 °C (60%).
reactions could be utilized to obtain isomerically pure
2,3,7-triaryl or 3-alkyl-2,7-diaryl compounds, respec-
tively. The general approach outlined in this Letter will
likely be of interest to those working in the fields of
medicinal or materials chemistry, where the quinoxaline
and pyridopyrazine nuclei have demonstrated
usefulness.
Displacement reactions of 15, using either nitrogen or
oxygen nucleophiles, were also successful (Scheme 7).
The latter were reacted via their DBU salts15 when dis-
placed with a secondary alcohol, such as tetrahydrothio-
phen-3-ol,16 to give 21. Reaction with primary alcohols
to give adducts such as 22 was accomplished using a
Pd(0)-mediated coupling17 in toluene as a solvent.18
Preparation of regioisomeric analogues proved to be
more of a challenge as all attempts to synthesize 23
failed. Instead, a three-step procedure from lactam 12
was devised (Scheme 8). First, 12 was reacted with POCl3
to give chloride 24. A series of Suzuki reactions were then
undertaken to prepare the desired regioisomeric pyrido-
pyrazines. For example, 24 was cross-coupled with pyr-
dine-3-boronic acid to give the mono-pyridyl adduct 25
in moderate yield (30–40%). The bromide in 25 was then
coupled further using boronic ester 26 to give the final
2,3,7-triaryl derivative 27. The same general strategy
was also used to prepare related regio-defined 2,3,7-tri-
aryl derivatives 28 and 29 using an identical reaction
sequence.
References and notes
1. For recent reviews see: (a) Groziak, M. P. Prog. Hetero-
cycl. Chem. 2005, 17, 304–336; (b) Gobec, S.; Urleb, U.
Sci. Synth. 2004, 16, 845–911; (c) Sako, M. Sci. Synth.
2004, 16, 1269–1290.
2. (a) Li, J.; Chen, J.; Zhang, L.; Wang, F.; Gui, C.; Zhang,
L.; Qin, Y.; Xu, Q.; Liu, H.; Nan, F.; Shen, J.; Bai, D.;
Chen, J.; Shen, X.; Jiang, H. Bioorg. Med. Chem. 2006, 14,
5527–5534; (b) Li, J.; Zhang, J.; Chen, J.; Luo, X.; Zhu,
W.; Shen, J.; Liu, H.; Shen, X.; Jiang, H. J. Comb. Chem.
2006, 8, 326–337.
3. Zhang, L.; Qiu, B.; Xiong, B.; Li, X.; Li, J.; Wang, X.; Li,
J.; Shen, J. Bioorg. Med. Chem. Lett. 2007, 17, 2118–2122.
4. (a) Takano, Y.; Shiga, F.; Asano, J.; Ando, N.; Uchiki,
H.; Anraku, T. Bioorg. Med. Chem. Lett. 2003, 13, 3521–
3535; (b) Catarzi, D.; Colotta, V.; Varano, F.; Calabri, F.
R.; Filacchioni, G.; Galli, A.; Costagli, C.; Carla, V. J.
Med. Chem. 2004, 47, 262–272.
5. Kim, K. S.; Qian, L. G.; Bird, J. E.; Dickinson, K. E. J.;
Moreland, S.; Schaeffer, T. R.; Waldron, T. L.; Delaney,
C. L.; Weller, H. N.; Miller, A. V. J. Med. Chem. 1993, 36,
2335–2342.
In conclusion, we have shown that differential reactivity
between two amino groups in an aromatic 1,2-diamine
starting material can be exploited to obtain a number
of regio-defined unsymmetrical 2,3,6-quinoxaline, or
2,3,7-pyridopyrazine derivatives. Our approach to
2,3,7-pyridopyrazines is particularly noteworthy, as the
use of palladium- and iron-mediated cross-coupling
6. (a) Barnett, S. F.; Bilodeau, M. T.; Lindsley, C. W. Curr.
Top. Med. Chem. 2005, 5, 109–125; (b) Bilodeau, T. M.;
Duggan, M. E.; Hartnett, J. C.; Lindsley, C. W.; Manley,
P. J.; Wu, Z.; Zhao, Z. WO 2003086394; (c) Lindsley, C.
W.; Zhao, Z.; Leister, W. H.; Robinson, R. G.; Barnett, S.
F.; Defeo-Jones, D.; Jones, R. E.; Hartman, G. D.; Huff,
J. R.; Huber, H. E.; Duggan, M. E. Bioorg. Med. Chem.
Lett. 2005, 15, 761–764.
i
ii or iii
N
N
R
N
N
R
N
N
R
S
S
S
1 O
R
N
N
O
Cl
N
N
O
20
15
21; R1 =
22; R1 = CH2CH2OMe
S
R=
N
O
7. Baxter, A.; Kindon, N.; Stocks, M. WO 2005021513.
8. (a) He, W.; Myers, M. R.; Hanney, B.; Spanda, A. P.;
Bilder, G.; Galzcinski, H.; Amin, D.; Needele, S.; Page,
K.; Jayyosi, Z.; Perrone, M. H. Bioorg. Med. Chem. Lett.
2003, 13, 3097–3100; (b) Myers, M. R.; He, W.; Hanney,
B.; Setzer, N.; Maguire, M. P.; Zulli, A.; Bilder, G.;
Scheme 7. Reagents and condtions: (i) morpholine, iPrOH, 100 °C (ca.
70%); (ii) (a) DBU, DMSO, rt, (b) NaH, tetrahydrothiophen-3-ol,
THF, 0 °C to reflux (ca. 30%); (iii) HOCH2CH2OMe, Pd(OAc)2,
Cs2CO3, 2-(di-tert-butylphosphino)-1,10-binaphthyl, toluene, 70 °C,
microwave (ca. 50%).