Expedient access to fused quinoxalines via Dess-Martin periodinane-mediated cyclization of unsymmetrical phenylenediamide derivatives

Article abstract of DOI:10.1016/j.tetlet.2009.11.080

One-pot cyclization of various 2-N-amido-homoallylanilides mediated by 4 equiv of Dess-Martin periodinane produced pyrrolo[1,2-a]quinoxalines (11 examples, up to 93% yield).

Full text of DOI:10.1016/j.tetlet.2009.11.080

Tetrahedron Letters 51 (2010) 1262–1264
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Tetrahedron Letters
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Expedient access to fused quinoxalines via Dess–Martin periodinane-mediated
cyclization of unsymmetrical phenylenediamide derivatives
b
a
a
a
ˇ a,
*
Cristian Dobrota , Jonathan Graeupner , Ioana Dumitru , Mihaela Matache , Codruta C. Paraschivescu
a University of Bucharest, Department of Chemistry, Sßoseaua Panduri, 90-92, Sector 5, 050657 Bucharest, Romania
b Technical University of Munich, Chemistry Dept, Lichtenbergstr, 4, 85747 Garching, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
One-pot cyclization of various 2-N-amido-homoallylanilides mediated by 4 equiv of Dess–Martin period-
inane produced pyrrolo[1,2-a]quinoxalines (11 examples, up to 93% yield).
Ó 2010 Published by Elsevier Ltd.
Received 21 October 2009
Accepted 17 November 2009
Available online 22 November 2009
The enormous potential of polyvalent iodine compounds as re-
agents for a wide variety of oxidative processes has been proven by
the large number of research papers published on this topic in
azepines. However, despite the wide range of biological activities
exhibited by functionalized quinoxalines,7 their preparation was
far less studied compared to the benzodiazepines.
recent years.1 Among them, the Dess–Martin periodinane2
1
To test the behavior of a homoallylic phenylenediamide in the
conditions of the Nicolaou reaction, we prepared a model substrate
that has two susceptible moieties able to undergo the oxidative
cyclization process, namely bis(N,N0-dipentenoyl)-1,2-phenylene-
diamine 5a. Thus, we submitted 5a to the action of an excess of
DMP in the conditions reported previously.4 Following the progress
of the reaction, we observed the formation of a single product that
we identified to be the hexahydropyrrolo[1,2-a]quinoxaline 6a
(36% yield, entry 1 in Table 1). This particular class of heterocycles
has been obtained before through the cyclization of quinoxalinyl-
propanoic acids.8
The formation of this type of products (i.e., quinoxalines 6) can
be explained following the general mechanistic pathway proposed
by Nicolaou.4 In this particular case, after the initial ligand ex-
change between DMP 1 and anilide 5, the vicinal amide moiety
probably plays an active part in the formation of the key hetero-
diene system, which by an intramolecular [4+2] cycloaddition
leads to the final product (Scheme 1).
(DMP–1,1,1-triacetoxy-1,2-benzoiodoxol-3-one) and its synthetic
precursor IBX 2 (1-hydroxy-1-oxo-1,2-benzoiodoxol-3-one) play
a key role, mainly due to their ability to effectively oxidize alcohols
to carbonyls under mild conditions. Moreover, various classes of
heterocycles have been lately reported as a result of the oxidative
transformations mediated by DMP and IBX.3
In this context, the formation of N-aryl pyrollidones 3 and re-
lated fused heterocycles, such as pyrrolo[1,2-a]benzoxazines 4 is
of particular interest (Fig. 1). This cascade oxidative cyclization of
unsaturated anilides in the presence of DMP or IBX (Scheme 1)
was discovered more than a decade ago by Nicolaou and his co-
workers during the synthesis of CP molecules.4
Exploring this new reaction, they reported related processes for
a large variety of anilides, urethanes, or ureas, proving the utility of
the complex structures thus obtained for the preparation of amino-
alcohols or aminosugars.5 We dare to name this transformation the
Nicolaou reaction. Soon thereafter, bis(trifluoroacetoxy)-iodoben-
zene (BTI) was discovered to mediate similar transformations.6
Mechanistic studies proved that the cascade process occurs via
an ortho-aza quinone intermediate, which leads to the final prod-
uct by a hetero-Diels cycloaddition. Moreover, it has been demon-
strated that vicinal groups may play a role in the outcome of the
Nicolaou reaction.4
Stimulated by this result, we decided to find the optimal condi-
tions and reagents for this transformation. Since in our case the
addition of water did not affect the yield,4 we performed all cycli-
zation reactions in dichloromethane, without any other additives.
We report herein an extension of this versatile reaction: the
one-pot preparation of fused quinoxaline derivatives starting from
various phenylenediamides bearing at least one homoallylic amide
moiety. The quinoxalines are interesting frameworks for drug
development, mainly due to their structural similarity to benzodi-
O
N
O
N
R
R
O
3
4
* Corresponding author.
ˇ
E-mail address: cdobrota@gw-chimie.math.unibuc.ro (C. Dobrota).
Figure 1. Heterocyclic scaffolds obtained from homoallylic benzamides.
0040-4039/$ - see front matter Ó 2010 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2009.11.080

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C. Dobrota et al. / Tetrahedron Letters 51 (2010) 1262–1264
1263
OAc
I
O
O
O
O
O
-
O
AcO
O
N
NH
I
N
N
N
N
R
O
N
N
H
DMP (1)
O
O
OAc
N
N
- AcOH
H
O
H
6
5
R
O
ref 4
O
R
OAc
R
O
R
Scheme 1. Plausible mechanism for the formation of quinoxaline derivatives in the oxidative cyclization of unsymmetrical homoallylic phenylenediamides.
Table 1
The benzoyl derivative 5b led to the desired product 6b in a
higher yield of 66% (Table 1, entry 6), proving the superiority of
arylamides as vicinal groups in the substrates. A further increase
of the electronic density on the aryl ring in the vicinal amide
(i.e., use of the 4-methoxyphenyl-carboxamide, PMP–CO–) resulted
in the formation of the tricyclic compound 6c in 81% (Table 1,
entry 7), while the attempt to employ a secondary diarylamine
(substrate 5d) in the process failed (Table 1, entry 8).
Oxidative cyclization of 5a–d to pyrrolo[1,2-a]quinoxalines10 6a–d in presence of
DMP 1
O
O
OAc
OAc
I
AcO
N
N
conditions
H
H
O
N
R
N
R
O
1
Endocyclic olefins are known to be better substrates for the Nico-
laou reaction compared to their acyclic counterparts.4 Therefore, we
synthesized the series of ortho-substituted methylcyclopent-2-eno-
ylbenzamides 5e–l bearing various substituents on the nitrogen
atom and submitted it to the action of 4 equiv of DMP (Table 2). This
scoping ensures not only retrieval of the best conditions for the
cyclization process, but would also provide the desirable methodo-
logical flexibility in organic synthesis.9 Satisfactorily, all the sub-
strates tested were completely converted in the presence of DMP
1 and they all yielded the desired tetracyclic structures 6e–k as ma-
jor products, with one notable exception, which led to an unex-
pected product (substrate 5l, vide infra, Scheme 2).
This series of fused quinoxalines is structurally similar to the
benzoxazine derivatives prepared in almost identical conditions
by the group of Nicolaou.4 Indeed, the proton NMR spectra of quin-
oxalines 6a–k are very similar to those of the corresponding re-
ported benzoxazines. Based on this fact as well as bidimensional
NMR correlation experiments, we also propose the syn junction
for all the cycles of the fused quinoxaline derivatives obtained by
cascade cyclizations in the presence of DMP.10
5a-d
6a-d
Entry
Substrate
R
Conditionsa
Yieldc (%)
1
2
3
4
5
6
7
8
5a
5a
5a
5a
5a
5b
5c
5d
CH2@CH–(CH2)2–CO–
CH2@CH–(CH2)2–CO–
CH2@CH–(CH2)2–CO–
CH2@CH–(CH2)2–CO–
CH2@CH–(CH2)2–CO–
Ph-CO–
4 equiv of 1
4 equiv of 1
6 equiv of 1
4 equiv BTIb
4 equiv PIDA
4 equiv of 1
4 equiv of 1
4 equiv of 1
36
37d
40
e
—
—
e
66
81
4-MeO–C6H4–CO–
Ph
e
—
a
b
c
20 h under argon at rt in dry dichloromethane.
6 h in the same conditions.
Isolated yields.
2 equiv of water was added.
Decomposition of the substrate under the reaction conditions.
d
e
A ratio of 4:1 DMP/substrate was found to be optimal with respect
to the cyclization product yield (entries 2–5 in Table 1). Moreover,
use of trivalent iodine-containing reagents (BTI or PIDA—iodoben-
zenediacetate) in the same reaction conditions led to substrate
decomposition.
Interestingly, the attempt to use a substrate having a urea moi-
ety (i.e., 5l) led to the formation of an unexpected product.
O
H
O
N
O
N
N
N
N
O
4 eq. DMP
4 eq. DMP
CH2Cl2, 20h, r.t.
55%
H
H
N
N
CH2Cl2, 20h, r.t.
H
N
O
O
N
H
5l
7
H
N
O
O
AcO
O
I
O
N
O
H
N
N
N
OAc
N
HN
N
O
O
- AcOH
O
H
NH
AcO
Scheme 2. Preparation of benzotriazine derivative 7 by oxidative cyclization of urea-substituted benzamide 5l.

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C. Dobrota et al. / Tetrahedron Letters 51 (2010) 1262–1264
Table 2
Supplementary data
Oxidative cyclization of 5e–k to pyrrolo[1,2-a]quinoxalines10 6e–k in the presence of
DMP 1
Supplementary data (detailed experimental procedures for the
preparation of substrates 5a–l and products 6a–k and 7, as well
as copies of NMR spectra of all the compounds) associated with
this article can be found, in the online version, at doi:10.1016/
j.tetlet.2009.11.080.
O
O
H
N
N
H
N
R
4 eq. DMP
H
H
CH2Cl2, 20h, r.t.
N
R
H
References and notes
5e-k
6e-k
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Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277–7287.
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Lett. 2001, 42, 5167–5170; (e) Nicolaou, K. C.; Baran, P. S.; Zhong, Y.-L.; Fong, K.
C.; Choi, H.-S. J. Am. Chem. Soc. 2002, 124, 2190–2201; (f) Janza, B.; Studer, A. J.
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71, 8261–8263; (h) Dobrota, C.; Paraschivescu, C. C.; Dumitru, I.; Matache, M.;
Baciu, I.; Ruta, L. L. Tetrahedron Lett. 2009, 50, 1886–1888.
Entry
Substrate
R
Yielda (%)
1
2
3
4
5
6
7
5e
5f
5g
5h
5i
2-(Cyclopent-2-enyl)acetyl
Ph-CO–
4-MeO–C6H4–CO–
4-O2N–C6H4–CO–
4-Me-C6H4–SO2–
EtO-CO–
60
78
93
63
75
71
49
5j
5k
(EtO)2PO–
a
Isolated yields.
4. (a) Nicolaou, K. C.; Zhong, Y.-L.; Baran, P. S. Angew. Chem., Int. Ed. 2000, 39, 622–
625; (b) Nicolaou, K. C.; Sugita, K.; Baran, P. S.; Zhong, Y.-L. Angew. Chem., Int.
Ed. 2001, 40, 207–210; (c) Nicolaou, K. C.; Baran, P. S.; Zhong, Y.-L.; Sugita, K. J.
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2000, 39, 2525–2529; (b) Nicolaou, K. C.; Baran, P. S.; Zhong, Y.-L.; Barluenga,
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Corey, E. J.; Cheng, X.-M. Logic of Chemical Synthesis, 1st ed.; Wiley-VCH, 1995.
10. See Supplementary data for details.
Although the progress of the reaction was similar, with complete
conversion of the substrate toward a major compound, the polarity
of the product isolated was much lower compared to that of the
other fused tetracyclic quinoxalines. This product was identified
as the benzo[e][1,2,4]triazine derivative 7 (Scheme 2). Its forma-
tion may be explained by the attack of the far-sided nitrogen of
the urea moiety on the imidoester, thus closing the six-membered
triazine ring.
In conclusion, we described an original and effective access to
fused quinoxaline derivatives, via a cascade cyclization process
mediated by an excess of Dess–Martin periodinane. Further inves-
tigation of this versatile process is currently under study and will
be reported in due course.