Preparation of quinoxalines, dihydropyrazines, pyrazines and piperazines using tandem oxidation processes

Article abstract of DOI:10.1039/b307177b

α-Hydroxyketones undergo MnO₂-mediated oxidation followed by in situ trapping with aromatic or aliphatic 1,2-diamines to give quinoxalines or dihydropyrazines, respectively, in a one pot procedure which avoids the need to isolate the highly rea

Full text of DOI:10.1039/b307177b

Preparation of quinoxalines, dihydropyrazines, pyrazines and
piperazines using tandem oxidation processes
Steven A. Raw, Cecilia D. Wilfred and Richard J. K. Taylor*
Department of Chemistry, University of York, Heslington, York, UK YO10 5DD. E-mail: rjkt1@york.ac.uk;
Fax: +44(0)1904 434523; Tel: +44(0)1904 432606
Received (in Cambridge, UK) 23rd June 2003, Accepted 30th July 2003
First published as an Advance Article on the web 8th August 2003
a-Hydroxyketones undergo MnO2-mediated oxidation fol-
lowed by in situ trapping with aromatic or aliphatic
1,2-diamines to give quinoxalines or dihydropyrazines,
respectively, in a one pot procedure which avoids the need to
isolate the highly reactive 1,2-dicarbonyl intermediates.
Modifications of the procedure allow the formation of
pyrazines and piperazines.
observed under these conditions, but the addition of excess
methanol to the reaction mixture after dihydropyrazine forma-
tion gave the corresponding piperazines 5a–f in good yields
(Table 1).
As can be seen (Table 1), the procedure gave good to
excellent yields with aromatic (entries i–iii) and aliphatic
(entries iv–vi) a-hydroxyketones. In the reactions using
(±)-trans-1,2-diaminocyclohexane (entries ii–iv, vi), only one
Quinoxalines constitute the basis of many insecticides, fungi-
cides, herbicides and anthelmintics, as well as being important
in human health and as receptor antagonists.1,2 Dihydropyr-
azines, piperazines and pyrazines are also of great importance in
natural products and chemotherapeutic agents.2a,3
We have recently developed a number of manganese dioxide-
based tandem oxidation processes (TOPs) for the elaboration of
alcohols.4–6 As part of this programme, we discovered an in situ
oxidation–amine trapping process leading to imines.5 In
addition, we recently established that a-hydroxyketones un-
dergo in situ oxidation–trapping when treated with manganese
dioxide in the presence of stabilised Wittig reagents.6 We
therefore decided to investigate the conversion of a-hydrox-
yketones 1 into quinoxalines 2 or dihydropyrazines 3 by the use
of manganese dioxide along with suitable 1,2-diamino com-
pounds (Scheme 1).
Scheme 2 In situ formation of piperazines.13
Table 1 In situ piperazine formation13
Yielda
(%)
R
RA
Piperazine 5
i
Ph
H
5a
52
ii
Ph
(CH2)4
(CH2)4
5b
75
iii 2-Fur
5c
60b
iv C6H11
(CH2)4
5d
84
69
Scheme 1 Formation of quinoxalines and dihydropyrazines.8,9
We have shown these processes to be effective for a range of
a-hydroxyketones 1 and 1,2-diamines (Scheme 1).10 The
dihydropyrazines 3 were sometimes accompanied by N-acyl-
NA-formyl-trans-1,2-diaminocyclohexane byproducts 4. There
is an isolated example of the oxidative cleavage of bis-
hemiaminals11 and we propose a similar MnO2-mediated
process leading to 4.12
v
Hydrocortisone
H
5e
Having shown that it is possible to produce dihydropyrazines
3 in situ using TOP methodology, attention moved to extended
one-pot procedures. We recently reported the production of
secondary and tertiary amines from activated alcohols using a
MnO2 mediated one-pot oxidation imine-formation reduction
sequence.5 We envisaged a similar sequence leading from a-
hydroxyketones 1 to piperazines 5 (Scheme 2). Thus, the
dihydropyrazine-forming reactions described above were re-
peated using MnO2/NaBH4. No piperazine formation was
vi Hydrocortisone (CH2)4
5f 87c
a Yields refer to chromatographically pure product.9 b Compound 5c proved
sensitive to acid/base extraction; it was therefore isolated as the correspond-
ing diacetate. c Formed as a mixture (ca. 1 : 1) of diastereomers.
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CHEM. COMMUN., 2003, 2286–2287
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diastereomeric product was isolated and we have tentatively
assigned these as the all-equatorial adducts shown.14
We are grateful to the EPSRC for postdoctoral support
(ROPA, S.A.R.) and to Universiti Teknologi, Petronas, Ma-
laysia for a Ph. D. Scholarship (C. D. W.).
Finally, we investigated a TOP-aromatisation sequence
leading to pyrazines 6. To this end, the original dihydropyrazine
formation was repeated in THF and toluene at extended reflux
in the presence of excess MnO2 in order to effect the
aromatisation. However, under these conditions, only trace
amounts of pyrazines 6 were observed in the toluene reaction.
The use of co-oxidants, such as DDQ and CAN, in these
reactions resulted in complete degradation of the dihydropyr-
azines 5. We eventually established that the addition of ~ 0.4 M
KOH in methanol15 to the refluxing reaction mixture after the
formation of dihydropyrazines 5 resulted in production of the
corresponding pyrazines 6 (Scheme 3). It should be noted that
the addition of methanol alone did not achieve the desired
transformation. The results are summarised in Table 2. As is
apparent, the presence of an aromatic substituent facilitates
aromatisation.
Notes and references
1 G. Sakata, K. Makino and Y. Kurasawa, Heterocycles, 1988, 27,
2481.
2 (a) N. Sato, in Comprehensive Heterocyclic Chemistry II, Vol. 6, ed. A.
R. Katritzky, C. W. Rees and E. F. V. Scriven, Elsevier Science Ltd.,
Oxford, 1996, ch. 6.03; ; for more recent references see: (b) L. E. Seitz,
W. J. Suling and R. C. Reynolds, J. Med. Chem., 2002, 45, 5604; (c) A.
Gazit, H. App, G. McMahon, J. Chen, A. Levitzki and F. D. Bohmer, J.
Med. Chem., 1996, 39, 2170.
3 N. Sato, in Comprehensive Heterocyclic Chemistry II, Vol. 6, ed. A. R.
Katritzky, C. W. Rees and E. F. V. Scriven, Elsevier Science Ltd.,
Oxford, 1996, ch. 6.03; for more recent references see J. A. Bender, N.
A. Meanwell and T. Wang, Tetrahedron, 2002, 58, 3111; C. J. Dinsmore
and D. C. Beshore, Tetrahedron, 2002, 58, 3297; R. Gust, R. Keilitz and
K. Schmidt, J. Med. Chem., 2002, 45, 2325; L. E. Seitz, W. J. Suling and
R. C. Reynolds, J. Med. Chem., 2002, 45, 5604.
4 For oxidation–Wittig trapping see X. Wei and R. J. K. Taylor, J. Org.
Chem., 2000, 65, 616; L. Blackburn, H. Kanno and R. J. K. Taylor,
Tetrahedron Lett., 2003, 44, 115 and references therein.
5 (a) L. Blackburn and R. J. K. Taylor, Org. Lett., 2001, 3, 1637; (b) H.
Kanno and R. J. K. Taylor, Tetrahedron Lett., 2002, 43, 7337.
6 K. A. Runcie and R. J. K. Taylor, Chem. Commun., 2002, 974.
7 (a) H. Ihmels, M. Maggini, M. Prato and G. Scorrano, Tetrahedron
Lett., 1991, 32, 6215; (b) T. Caronna, A. Citterio, T. Crolla and F.
Minisci, J. Chem. Soc., Perkin Trans. 1, 1977, 865.
8 General procedure for quinoxalines and dihydropyrazines: To a mixture
of a-hydroxyketone (0.50 mmol), 1,2-diamine (1.00 mmol) and
powdered 4 Å molecular sieves (0.50 g) in dry CH2Cl2 (25 mL) was
added activated MnO2 (0.435 g, 5.00 mmol) and the mixture heated to
reflux. With ethylenediamine, 2.0 M HCl in Et2O (1 eq. w.r.t. amine)
was also added to suppress formation of 4. After complete reaction, the
mixture was cooled to RT, filtered through Celite® and the residue
washed well with CH2Cl2. Concentration and purification of the crude
product by flash column chromatography on silica for quinoxalines or
deactivated, neutral alumina for dihydropyrazines gave the desired
product displaying consistent spectral data.
Scheme 3 In situ formation of pyrazines.16
Table 2 In situ pyrazine formation16
Yielda
(%)
R
RA
Pyrazine 6
i
Ph
H
6a17a
45
ii
Ph
(CH2)4
(CH2)4
6b
66
64
9 Known compounds gave data consistent with those published: novel
compounds were fully characterised.
10 Additional examples will be described in a full paper.
iii
iv
2-Fur
6c
11 H. Blitz, Justus Liebigs Ann. Chem., 1909, 36, 262.
12 The oxidative cleavage of 1,2-diols using MnO2 is well known: G.
Ohloff and W. Giersch, Angew. Chem., Int. Ed., 1973, 12, 401; H. S.
Outram, S. A. Raw and R. J. K. Taylor, Tetrahedron Lett., 2002, 43,
6185.
C6H11
H
H
6d17b
33
10
13 Piperazines: As described in ref. 8 but diamine reduced to 0.60 mmol
and NaBH4 (0.076 g, 2.00 mmol) included. After complete consumption
of substrate, MeOH (6 mL) added at RT and stirred for 20 h. Work up
and purification by acid/base extraction gave the desired product.
14 For precedent see K. Gollnick, S. Koegler and D. Maurer, J. Org.
Chem., 1992, 57, 229; L. W. Jenneskens, J. Mahy, E. M. M. de
Brabander-van den Berg, I. Van der Hoef and J. Lugtenburg, Recl. Trav.
Chim. Pays-Bas, 1995, 114, 97. Furthermore, the pertinent coupling
constants in the 1H NMR spectra of these compounds were in the range
indicative of trans-diaxial protons.
v
Hydrocortisone
6e
a Yields refer to chromatographically pure product.9
15 P. Darkins, M. Groarke, M. A. McKervey, H. M. Moncrieff, N.
McCarthy and M. Nieuwenhuyzen, J. Chem. Soc., Perkin Trans. 1,
2000, 381; A. Ohta, T. Watanabe, Y. Akita, M. Yoshida, S. Toda, T.
Akamatsu, H. Ohno and A. Suzuki, J. Heterocycl. Chem., 1982, 19,
1061.
16 Pyrazines: As described in ref. 8 but after consumption of substrate,
~ 0.4 M KOH in MeOH (5 mL) added and reflux continued for 20 h.
Work up and purification by flash column chromatography on silica
gave the desired product.
In conclusion, we have developed novel methodology for the
conversion of a-hydroxyketones 1 into the corresponding
quinoxalines 2 and dihydropyrazines 3 via a tandem oxidation
procedure with in situ trapping using 1,2-diamines. This
methodology has been successfully extended to allow the direct,
one-pot conversion of the dihydropyrazines into the corre-
sponding piperazines and pyrazines in fair to good yields.
Further work is continuing to optimise and apply this new
chemistry.
17 (a) G. J. Ellames, J. S. Gibson, J. M. Herbert and A. H. McNeill,
Tetrahedron, 2001, 57, 9487; and references therein; (b) A. Lablanche-
Combier and B. Plankaert, Bull. Soc. Chim. Fr., 1974, 225.
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