Synthesis of Stable Seleno[3,4-b]quinoxaline Derivatives

Article abstract of DOI:10.1021/ol035488y

(Equation presented) The unstable seleno[2,3-b]quinoxoline was generated and functionalized in situ to give the stable dialdehyde and diester derivatives. The dicyano compound was made in several steps from biscyanomethyl selenide and was found to be very

Full text of DOI:10.1021/ol035488y

ORGANIC
LETTERS
2
003
Vol. 5, No. 22
089-4092
Synthesis of Stable
Seleno[3,4-b]quinoxaline Derivatives
4
Emad Aqad, M. V. Lakshmikantham, and Michael P. Cava*
Department of Chemistry, UniVersity of Alabama,
Tuscaloosa, Box 870336, Alabama 35487-0336
mcaVa@bama.ua.edu
Received August 6, 2003
ABSTRACT
The unstable seleno[2,3-b]quinoxoline was generated and functionalized in situ to give the stable dialdehyde and diester derivatives. The
dicyano compound was made in several steps from biscyanomethyl selenide and was found to be very stable.
The highly reactive thieno[3,4-b]quinoxaline (1) has been
physical properties with the analogous sulfur heterocycles.
Moreover, studies aiming at the synthesis of this type of
novel compound should afford a valuable addition to the
scant synthetic methodology of selenophene chemistry. In
continuation of our efforts in the study of heteroaromatic
o-quinonoid molecular systems, we report in this paper the
synthesis of seleno[3,4-b]quinoxalines as well as further
chemistry of the selenoquinoxaline system. The electro-
chemical properties of the new electron deficient heterocycles
are also presented.
the object of chemical investigation for about two and half
1
decades. Theoretical analysis indicates that polymers derived
from the parent 1 should exhibit an exceptionally small band
2
gap, making this heterocycle attractive in the field of
conducting π-conjugated polymers. In earlier studies, the
transient formation of 1 was shown by trapping experiments
3
with N-phenylmaleimide. Recently, we reported the syn-
4
thesis of 1 by a base-catalyzed Pummerer reaction. Com-
pound 1 was obtained as acid-sensitive crystals which, when
protected from light and oxygen, were stable for several days.
Moreover, we have found that thieno[3,4-b]quinoxaline
bearing carboxaldehyde on the thiophene ring (2) is highly
4
stable. The selenium analogue of compound 1, seleno[3,4-
b]quinoxaline (3), as well as substituted products have
hitherto remained unknown. The synthesis of stable seleno-
[3,4-b]quinoxaline derivatives is of undoubted interest in
view of the possible comparison of their chemical and
Our goal in seleno[3,4-b]quinoxalines was the synthesis
of derivatives bearing small substituents with electron-
acceptor properties. Our objective was the synthesis of 1,3-
dicyanoseleno[3,4-b]quinoxaline (4), which we believe should
be stable to air and oligomerization. The multistep synthesis
of 4 is outlined in Scheme 1. Reaction of chloroacetonitrile
with sodium selenide generated in situ furnished the previ-
(
1) For a review on isomeric thienoquinoxaline, see: Moustafa, O. S.;
Yamada Y. J. Heterocycl. Chem. 2001, 38, 809.
(
(
2) Nayak, K.; Marynick, D. S. Macromolecules 1990, 23, 2237.
3) (a) MacDowell D. W. H.; Jeffries, A. T.; Meyers, M. B. J. Org. Chem.
1
1
971, 36, 1416. (b) Roland, M. M.; Anderson, R. C. J. Heterocycl. Chem.
977, 14, 541.
(4) Pohmer, J.; Lakshmikantham, M. V.; Cava, M. P., J. Org. Chem.
1
995, 60, 8283.
1
0.1021/ol035488y CCC: $25.00 © 2003 American Chemical Society
Published on Web 09/30/2003

Scheme 1a
Scheme 2a
a
Key: (i) Na
2
Se/THF, 3 h (55%); (ii) iodobenzene diacetate,
THF, room temperature, 2.5 h; (iii) 2.2 equiv of n-BuLi at -78 °C
then addition of 2 equiv of ClCOOEt and stirring at room
temperature, overnight (28%).
dihydroseleno[3,4-b]quinoxaline (10) was achieved by an
6
alternate route. Thus, reaction of 2,3-bis(bromomethyl)-
a
Key: (i) Na
and NaBH
room temperature, 15 h; (iii) H
phenylenediamine, AcOH, reflux 30 min; (V) iodobenzene diacetate,
CH CI , room temperature, 4 h (60%).
2
Se was generated in situ from elemental selenium
quinoxaline (9) with sodium selenide generated in situ
furnished the dihydro derivative 10. Best results were
obtained when the dibromide 9 was added very slowly to a
dilute solution of a selenium reagent. Treatment of the
dihydro derivative with iodobenzene diacetate in THF
generates the fully aromatic quinoxaline derivative 3. At-
tempts to isolate 3 under an inert atmosphere using aqueous
workup and solvent extraction yield only a dark solid.
However, the generation of 3 under anhydrous conditions
in an inert atmosphere made its functionalization more
feasible. Thus, in situ dilithiation of the generated 3 with
excess n-butyllithium and subsequent reaction of the corre-
sponding dianion with ethyl chloroformate gave the diester
derivative 11 as yellow microcrystals. Interestingly enough,
the monosubstituted derivative was not formed in this
reaction. Similar to the dicyano derivative 4, compound 11
was found to be very stable.
4
2 2 5
in water under N ; (ii) diethyl oxalate, C H ONa/EtOH,
2
SO 35% at 0 °C; (iv) O-
4
2
2
ously unknown bis(cyanomethyl) selenide 5 in high yield.
The condensation of 5 with diethyl oxalate in the presence
of excess of sodium ethoxide leads to the formation of the
disodium salt of 2,5-dicyano-3,4-dihydroxyselenophene (6)
in moderate yield. Best results were obtained when the
reaction was carried out at room temperature for 15 h. The
disodium salt 6 is highly hygroscopic and was converted to
the corresponding dihydroxy derivative 7 immediately after
its filtration from the reaction mixture. We also noted that
the acidification of 6 was best achieved with aqueous solution
of 35% sulfuric acid at 0 °C. The overall yield of 7 under
these conditions was 35%-40%. In preliminary experiments,
we found that 7 reacts with o-phenylenediamine in refluxing
ethanol to give 8 in very low yield (12%). In the search for
better reaction conditions, we found that refluxing equimolar
amounts of 7 and o-phenylenediamine in acetic acid for 30
min increases the yield up to 80%. Compound 8 prepared
under these conditions crystallized as red-orange crystals up-
on cooling the reaction mixture. The formation of this pro-
duct indicates the presence to some extent of the diketo
tatumeric form 7′ under the reaction conditions. The dihy-
drodinitrile derivative 8 oxidized smoothly with iodobenzene
diacetate to the corresponding o-quinonoid derivative 4. Sim-
ilar oxidative aromatization of dihydrobenzo[c]selenophene
The selenide 10 treated under Vilsmeier conditions (DMF,
POCl in methylene chloride), afforded the diformyl com-
3
pound 12 (Scheme 3). The formation of this product implies
that the tautomeric form of 10 in which the selenophene ring
is aromatic (10′) must be present to some extent under the
reaction conditions, since this tautomer can react in a
Vilsmeier reaction. Related behavior has been observed in
4
the case of 1,3-dihydrothieno[3,4-b]quinoxaline and 2,3-
dimethylquinoxaline; the latter reacts in its tautomeric form
7
in a Diels-Alder reaction with maleic anhydride and
p-benzquinone. The dialdehyde 12 was oxidized smoothly
with iodobenzene diacetate to the corresponding o-quinonoid
dialdehyde 13, which forms stable orange red crystals.
Similar to derivatives 4 and 11, the stability of 13 is
exclusively attributed to electronic effects.
5
derivative was reported by us recently. Compound 4 forms
red stable microcrystals. The stability of 4 is due exclusively
to the electron-withdrawing effect of the nitrile groups.
The synthesis of the parent 3 was accomplished as outlined
in Scheme 2. The synthesis of the starting material 1,3-
(6) Compound 10 was prepared previously, via the reaction of 2,3-bis-
bromomethyl)quinoxaline with elemental selenium in the presence of a
large excess of sodium iodide and subsequent reduction of the corresponding
diiodoselenide. Abid, K. Y.; McWhinnie W. R. J. Organomet. Chem. 1987,
330, 337.
(
(5) Aqad, E.; Lakshmikantham, M. V.; Cava, M. P., Broker, G. A.,
Rogers, R. D. Org. Lett. 2003, 5, 2519
(7) Sch o¨ nberg, A., Mostafa, A. J. Chem. Soc. 1943, 654.
4090
Org. Lett., Vol. 5, No. 22, 2003

Scheme 3a
Scheme 4
a
Key: (i) POCl
etate, CH Cl , room temperature 3 h, (56%); (iii) 2-thiophenecar-
boxaldehyde, t-BuOK/Et O, room temperature, overnight.
3 2 2
/DMF/CH Cl , (46%); (ii) iodobenzene diac-
2
2
2
The similar reactivity of the selenide 10 and 2,3-dimeth-
ylquinoxaline suggests that the methylene protons in 10
should be readily deprotonated with the strong base potas-
sium amide, as shown by alkylation to give 2,3-dipropy-
8
lquinoxaline. In the present case, we found that compound
10 reacts with 2-thiophenecarboxaldehyde in a Knovenagel
reaction with the formation of the unsaturated condensation
product 14. Several different approaches were studied, but
best results (65-70%) were obtained under basic conditions
groups, is the strongest electron acceptor in this series.
As expected, the weakest acceptor is derivative 13 incorpo-
rating carbethoxy groups in the selenophene ring. The
reversibility of the two reduction processes indicates the
stability of the anion radical and dianion under the CV
experimental conditions. The relatively large differences of
potentials between the first and second reduction potential
∆E value for compound 4 is similar to the ∆E value for
tetracyanoquinodimethane (TCNQ) under the same experi-
mental conditions. The large ∆E in the case of 4 suggests
enhanced stability of its derived dianion 16. Formally, the
dianion 16 could be presented in more than one meso-
meric structure. The mesomeric structure 16′ incorporating
the aromatic pyrazine moiety and two negative charges
adjanced to electron-withdrawing groups describes better the
nature of bonding of the dianion and explains its enhanced
stability.
(potassium tert-butoxide/diethyl ether). The Z,Z-configuration
for the condensation product based on NMR spectroscopy
is described for analogous products.9
The electron-accepting properties of the stable thieno[3,4-
b]quinoxaline derivatives 4, 11, and 13 were studied by cyclic
voltammetry (CV). The voltammograms of the three deriva-
tives exhibit two reversible one-electron reduction waves
corresponding to the generation of the anion radical and the
dianion, respectively (Scheme 4). A representative voltam-
The strong electron-accepting ability of derivative 4 is
similar to that of 2,2-biindanylidene-1,3,1′,3′-tetraone,10
chloranil, and other strong electron acceptors derived from
the p-benzoquinone parent system. The latter class of
acceptors was widely employed in the synthesis of donor-
1
1
acceptor charge-transfer complexes. Compound 4 can
be thus considered as a parent for a new series of reversible
two-stage one-electron systems with strong electron-accept-
ing abilities and is a promising candidate as an acceptor
component of conducting donor-acceptor complexes.
(
(
8) Ogg, R. A., Jr.; Bergstrom, F. W. J. Am. Chem. Soc. 1931, 53, 1846.
9) Hieber, G.; Hanak, M.; Wurst, K.; Strahle, J. Chem. Ber. 1991, 124,
-
4
Figure 1. Cyclic voltammetry of 4 (5 × 10 M in acetonitrile).
1
597.
(
10) Khodorkovsky, V.; Ellern, A.; Neilands, O. Tetrahedron Lett. 1994,
5, 2955.
3
(
11) Khodorkovsky, V.; Becker Y. J. In Organic Conductors, Funda-
mogram is shown in Figure 1. Judging from the first
mentals and Applications; Farges, J. P., Ed.; Marcel Dekker: New York,
reduction potential (Table 1), derivative 4, bearing cyano
1994; Chapter 3, p 75.
Org. Lett., Vol. 5, No. 22, 2003
4091

noxalines bearing electron-withdrawing groups are stable and
exhibit strong electron-accepting abilities. Effort aimed at
the use of these electron-deficient and electroactive com-
pounds in the fabrication of new materials is underway.
a
Table 1. Electrochemical Data for 4, 11, 13, and TCNQ
compd
E1 red (V)
E2 red (V)
∆E (V)
4
1
1
-0.05
-0.22
-0.31
0.27
-0.66
-0.78
-0.80
-0.31
0.61
0.56
0.49
0.58
1
3
Acknowledgment. This work was supported by a grant
from the National Science Foundation (No. CHE-9910177).
TCNQ
a
-4
5
× 10 M in acetonitrile, Bu4NPF6 supporting elecrolyte, SCE
reference electrode, Pt working electrode, 100 m V/s scan rate.
Supporting Information Available: Experimental de-
tails. This material is available free of charge via the Internet
at http://pubs.acs.org.
In conclusion, the first synthesis of seleno[3,4-b]quinoxa-
line derivatives has been achieved, and seleno[3,4-b]qui-
OL035488Y
4092
Org. Lett., Vol. 5, No. 22, 2003