Pyrrolo[1,2-a]quinoxalines: Novel synthesis via annulation of 2-alkylquinoxalines

Article abstract of DOI:10.1021/ol302348v

In an attempt to synthesize a novel homoleptic complex 3 from 2-methyl-3-phenylquinoxaline 1 and Ir(acac)₃ for application as a triplet emitter in OLEDs (organic light-emitting diodes) no cyclometalation was observed. Instead, an annulation to 1-methyl-4-phenylpyrrolo[1,2-a]quinoxaline 2 was observed. Since pyrroloquinoxalines are potentially bioactive and few paths for their synthesis are known, selected reactions and conditions were investigated, suggesting Ir(acac)₃ as catalyst and proving glycerol to be a reactant.

Full text of DOI:10.1021/ol302348v

ORGANIC
LETTERS
2012
Vol. 14, No. 19
5090–5093
Pyrrolo[1,2‑a]quinoxalines: Novel
Synthesis via Annulation of
2‑Alkylquinoxalines
Sven Ammermann,† Christian Hrib,‡ Peter G. Jones,‡ Wolf-Walther du Mont,‡
Wolfgang Kowalsky,† and Hans-Hermann Johannes*,†
Labor fu€r Elektrooptik am Institut fu€r Hochfrequenztechnik and Institut fu€r
€
Anorganische und Analytische Chemie, Technische Universitat Braunschweig,
Postfach 3329, 38023 Braunschweig, Germany
h2.johannes@ihf.tu-bs.de
Received August 22, 2012
ABSTRACT
In an attempt to synthesize a novel homoleptic complex 3 from 2-methyl-3-phenylquinoxaline 1 and Ir(acac)3 for application as a triplet emitter in
OLEDs (organic light-emitting diodes) no cyclometalation was observed. Instead, an annulation to 1-methyl-4-phenylpyrrolo[1,2-a]quinoxaline 2
was observed. Since pyrroloquinoxalines are potentially bioactive and few paths for their synthesis are known, selected reactions and conditions
were investigated, suggesting Ir(acac)3 as catalyst and proving glycerol to be a reactant.
The motif of pyrrolo[1,2-a]quinoxaline has attracted
attention because of its potential bioactivity. Derivatives
ofthismotif havebeeninvestigatedwithrespecttotheiruse
to inhibit microbial resistance to antibiotics,1 their poten-
tial antitumor activity,2 as specific high-affinity receptor
ligands,3,4 and as antileishmanial agents.5 To date, reviews
point out that only a few methods for synthesis of the
pyrrolo[1,2-a]quinoxaline motif are described in the
literature.6ꢀ8 Many of the known methods proceed either
via a cyclization starting from 1-arylpyrroles7,9ꢀ11 or
reaction paths involving 1,3-dipolar cycloaddition with
propiolates or N-ylides.12ꢀ15 Kaminskii et al.16 describe a
† Labor f€ur Elektrooptik am Institut f€ur Hochfrequenztechnik.
‡ Institut f€ur Anorganische und Analytische Chemie.
(1) Vidaillac, C.; Guillon, J.; Arpin, C.; Forfar-Bares, I.; Ba, B. B.;
Grellet, J.; Moreau, S.; Caignard, D.-H.; Jarry, C.; Quentin, C. Anti-
microb. Agents Chemother. 2007, 51, 831–838.
(6) Mamedov, V. A.; Kalinin, A. A.; Gubaidullin, A. T.; Litvinov,
I. A.; Azancheev, N. M.; Levin, Y. A. Russ. J. Org. Chem. 2004, 40, 114–
123.
ꢁ
(7) Harrak, Y.; Weber, S.; Gomez, A. B.; Rosell, G.; Pujol, M. D.
ARKIVOC 2007, iv, 251–259.
(8) Kalinin, A. A.; Mamedov, V. A. Chem. Heterocycl. Compd. 2011,
46, 1423–1442.
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Neamati, N. Bioorg. Med. Chem. 2007, 15, 288–294.
(9) Kobayashi, K.; Irisawa, S.; Matoba, T.; Matsumoto, T.; Yoneda,
K.; Morikawa, O.; Konishi, H. Bull. Chem. Soc. Jpn. 2001, 74, 1109–
1114.
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1987, 26, 1280–1281.
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(3) Campiani, G.; Morelli, E.; Gemma, S.; Nacci, V.; Butini, S.;
Hamon, M.; Novellino, E.; Greco, G.; Cagnotto, A.; Goegan, M.;
Cervo, L.; Dalla Valle, F.; Fracasso, C.; Caccia, S.; Mennini, T.
J. Med. Chem. 1999, 42, 4362–4379.
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D.; Kervran, A.; Rault, S. Eur. J. Med. Chem. 1998, 33, 293–308.
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M.; Thiolat, D.; Massip, S.; Tabourier, A.; Leger, J.-M.; Dufaure, B.;
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r
10.1021/ol302348v
Published on Web 09/19/2012
2012 American Chemical Society

synthesis via reaction of 1,2-diaminobenzene with various
2-hydroxy-1,5-diketones in ethanol and acetic acid, and
Blache et al.17 demonstrate the synthesis via condensation of
2-methylquinoxalines with alkyl bromopyruvates. To the
best of our knowledge, except for the 1,3-dipolar cycloaddi-
tion and the condensation reaction with alkyl bromopyr-
uvates, the five-membered pyrrole ring is always present in
the starting material and the six-membered pyrazine ring is
assembled. The reaction type described herein has not been
published elsewhere and demonstrates a unique path to
alkyl-substituted pyrrolo[1,2-a]quinoxalines.
The current literature contains few publications on the
application of quinoxalines for use as transport materials18
or as light-emitting compounds19,20 in OLEDs. Following
the widely used procedure for synthesis of homoleptic facial
metal complexes first described by Dedeian et al.,21 we
wished to synthesize a new emitting material 3. The reac-
tion repeatedly led to a yellow solid with unusually strong
fluorescence when excited at 366 nm. Analysis of the spectro-
scopic data provided no evidence for the successful synthesis
of 3, and we concluded that the product was a purely organic
compound arising via minor changes in the structure of 1.
the source of the incorporated C3 fragment, and does the
iridium play a role as catalyst.
In the course of a few simple reactions, which are
depicted in Scheme 1, we narrowed down the possibilities.
First, we added the base Na2CO3 as a possible promoter of
the cyclometalation, which formally depends on a depro-
tonation of the ligand 1. Then we reduced the amount of
Ir(acac)3 to test the catalytic activity and at the same time
lowered the reaction temperature, allowing a better com-
parisonwithsomeof thefollowing experiments. Inall cases
we obtained roughly the same yield of 2. In the absence of
Ir(acac)3, or after replacing glycerol by ethylene glycol, no
reaction took place. The use of IrCl3 nH2O, another
3
typical starting material for cyclometalation, with or with-
out addition of 2,4-pentanedione or silver trifluoroacetate,
led to the formation of a di-μ-chloro-bridged metal com-
plex 5. These metal complexes can be used to form suitable
products for application in OLEDs and are described
elsewhere.22 All in all, these reactions showed the necessity
for both Ir(acac)3 and glycerol, and we tentatively assumed
Ir(acac)3 to be the catalyst and glycerol to be the source of
the C3 fragment.
Scheme 1. First Simple Experiments
Figure 1. ORTEP representations of novel pyrrolo[1,2-a]-
quinoxalines 2 and 4 with thermal ellipsoids drawn at the 50%
probability level. Crystallized water is omitted in 2.
This was verified by X-ray analysis. The crystal structure
of 2 (obtained as a hemihydrate) is shown in Figure 1 and
reveals the unexpected and novel structure of a methyl-
substituted phenylpyrrolo[1,2-a]quinoxaline. This surpris-
ing structure prompted several questions: why does the
annulation of a five-membered pyrrole ring occur, what is
(14) Kim, H. S.; Kurasawa, Y.; Yoshii, C.; Masuyama, M.; Takada,
A.; Okamoto, Y. J. Heterocycl. Chem. 1990, 27, 1119–1122.
(15) Zhou, J.; Zhang, L.; Hu, Y.; Hu, H. J. Chem. Res., Synop. 1999,
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Heterocycl. Compd. 1992, 28, 97–100.
(17) Blache, Y.; Gueiffier, A.; Elhakmaoui, A.; Viols, H.; Chapat,
J.-P.; Chavignon, O.; Teulade, J.-C.; Grassy, G.; Dauphin, G.; Carpy, A.
J. Heterocycl. Chem. 1995, 32, 1317–1324.
(18) Thomas, K. R. J.; Lin, J. T.; Tao, Y.-T.; Chuen, C.-H. Chem.
Mater. 2002, 14, 2796–2802.
To testour preliminary conclusions, we conducteda new
series of reactions. A summary of the employed com-
pounds is given in Figure 2. First, we substituted Ir(acac)3
by the derivative Ir(acac-Me)3 6. As verified by NMR and
MS, we observed the synthesis of the already known
1-methyl-4-phenylpyrrolo[1,2-a]quinoxaline 2 in approxi-
mately the same yield of 38% without any evidence for the
(19) Hwang, F.-M.; Chen, H.-Y.; Chen, P.-S.; Liu, C.-S.; Chi, Y.;
Shu, C.-F.; Wu, F.-I.; Chou, P.-T.; Peng, S.-M.; Lee, G.-H. Inorg. Chem.
2005, 44, 1344–1353.
(20) Zhang, G. L.; Liu, Z. H.; Guo, H. Q. Chin. Chem. Lett. 2004, 15,
1349–1352.
(21) Dedeian, K.; Djurovich, P. I.; Garces, F. O.; Carlson, G.; Watts,
R. J. Inorg. Chem. 1991, 30, 1685–1687.
(22) Schneidenbach, D.; Ammermann, S.; Debeaux, M.; Freund, A.;
Zollner, M.; Daniliuc, C.; Jones, P. G.; Kowalsky, W.; Johannes, H.-H.
Inorg. Chem. 2010, 49, 397–406.
€
Org. Lett., Vol. 14, No. 19, 2012
5091

incorporation of an additional methyl group. Then we
prepared 2,3,4-pentanetriol 7 and substituted it for glyc-
erol. To our surprise, the main product isolated from flash
chromatography was the already known quinoxaline 2,
but GC/MS analysis of other fractions clearly showed
M þ 14 and M þ 28 compounds that still support the idea
of the triol as the source of the C3 fragment for annulation.
A detailed GC/MS analysis can be found in the Supporting
Information.
Encouraged by these results, we performed a reaction
with glycerol-13C3 8 under the initial conditions to prove
the solvent to be the carbon source. After purification via
flash chromatography and recrystallization, we obtained a
yellowish solid in 16% yield with minor impurities which
were not removable, even by reversed-phase HPLC. Be-
cause of the low yield, which possibly is a consequence of a
kinetic isotope effect and the small scale of the reaction, we
could not perform a complete analysis, but 13C NMR and
the mass spectrum proved the incorporation of glycerol.
In analogy to the Skraup23,24 synthesis, we also per-
formed a reaction after replacing glycerol by acrolein 9
dissolved in ethylene glycol, which already proved to be
inert. Acrolein is a potential secondary product formed by
dehydration of glycerol and is believed to be the active
species in the Skraup synthesis. We initiated our reaction
with equimolar amounts and increased these gradually,
but found only very weak luminescence on the TLC,
suggesting acrolein is not the active species.
fluorescent compound were formed but could not be
isolated. Using reactant 12 we were confronted by a large
number of products, probably associated with the lack of
the phenyl group. Despite using HPLC a complete separa-
tion of all products was not successful, but the most
promising fraction could be isolated and then further
separatedand analyzedvia GC/MS. The mixture consisted
of two compounds, with little difference in retention time,
in the ratio of 1:4. Both compounds showed a similar mass
spectrum with the expected formula indicating isomers of
pyrrolo[1,2-a]quinoxaline.
Figure 3. Employed reactants.
According to the above experiments, an alkyl group in
the R-position to an imine (CdN) is mandatory for
efficient synthesis. Recently, Ir(I)-promoted reactions of
an alcohol with an activated methylene group in the
R-position to a nitrile were demonstrated.25,26 In general,
iridium, especially in a low oxidation state such as þI,
shows catalytic activity and is used for annulations27 and
activations of CꢀH groups.28 In the case of rhodium in low
oxidation state þI, a mechanism has been reported for the
annulation to a pyrrolidine ring from an intramolecular
alkene coupling with benzimidazole.29 We also considered
whether the opposite CdN-group has an influence when
iridium is coordinating to the nitrogen. Therefore we
synthesized 2-methyl-3-phenylquinoline 13, employed it
under the same conditions and observed evidence of the
synthesis of 1-methyl-4-phenylpyrrolo[1,2-a]quinoline 15
as expected in much lower yield. The result of this reaction
supports our assumption of an influence of the opposite
nitrogen and strengthens the idea of a catalytic pathway.
The different behavior of compounds 1 and 13 is depicted
in Scheme 2.
Figure 2. Other compounds used to substitute either Ir(acac)3 (6)
or glycerol (7ꢀ9).
In order to evaluate the scope of the reaction and for a
better understanding of the possible mechanism, we speci-
fically altered the quinoxaline body of 1 and performed
analogous reactions. A summary of the reactants is given
in Figure 3. We began with 2-ethyl-3-phenylquinoxaline 10
and found a compound 4 with a second methyl group.
Since it was not possible to determine the exact position of
the additional methyl group by NMR analysis, we verified
the structure of 4 by X-ray analysis. The structure is
depicted in Figure 1 and shows that the alkyl group of
our starting material is preserved in the product. Starting
from 2-phenylquinoxaline 11, a compound without a
methyl group, we expected and indeed found that almost
no reaction occurred. According to TLC only traces of a
Sinceourinitial intentionwas tocreate novelhomoleptic
metal complexes, we designed a reaction with the reactant
(25) Morita, M.; Obora, Y.; Ishii, Y. Chem. Commun. 2007, 2850–
2852.
€
(26) Lofberg, C.; Grigg, R.; Whittaker, M. A.; Keep, A.; Derrick, A.
J. Org. Chem. 2006, 71, 8023–8027.
(27) Ueura, K.; Satoh, T.; Miura, M. J. Org. Chem. 2007, 72, 5362–
5367.
(28) Feller, M.; Karton, A.; Leitus, G.; Martin, J. M. L.; Milstein, D.
J. Am. Chem. Soc. 2006, 128, 12400–12401.
(29) Wiedemann, S. H.; Lewis, J. C.; Ellman, J. A.; Bergman, R. G.
J. Am. Chem. Soc. 2006, 128, 2452–2462.
(23) Skraup, Z. H. Ber. Dtsch. Chem. Ges. 1880, 13, 2086–2087.
(24) Uff, B. C. Comprehensive Heterocyclic Chemistry; Pergamon:
Oxford, 1984; Vol. 2, pp 465ꢀ470.
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Org. Lett., Vol. 14, No. 19, 2012

Scheme 2. Depiction of Supposed Influence of Opposite Nitro-
gen in Compound 1 in Comparison to Compound 13
Scheme 3. Proposed Preliminary Mechanism
14. We already knew that in case of the unexpected
annulation the alkyl group in R-position to the imine
remains in the molecule and took into consideration that
CꢀF bonds are thermodynamically stable. Even though
Harrak et al.7 have shown that aromatic CꢀF bonds can
undergo an intramolecular nucleophilic displacement to
form pyrrolo[1,2-a]quinoxalines we expected the CF3
group to remain inert. To our considerable surprise we
could only isolate the already known quinoxaline 2 in 37%
yieldwithnoevidenceofany fluorineatominthestructure.
Since the conversion of 14 to 2 was inconsistent with our
model, we investigated the reaction more closely. We
planned a parallel experiment based on the original setup
with reactants 1 and 14. Both reactions were performed for
76 h at temperatures starting from 160 °C and increasing
stepwise every 18ꢀ20 h by 10 °C to a final temperature of
190 °C. Samples were taken and analyzed via TLC before
increasing the temperature. We found that the reaction
with 1 already occurs at 160 °C, whereas 14 needs 180 °C
for a clear conversion. Also we noticed an intriguing spot
on the TLC of the reaction with 14, which appeared before
final product 2, vanishing at the same time that 2 was
forming. Since the position of the spot corresponded
exactly to the retention factor of 1 we analyzed a sample
by GC/MS. Indeed, we could prove the presence of 1 in the
reaction mixture. Together with the higher temperature
needed for conversion of 14 we can assume that a second,
as yet unknown, mechanism primarily forms 1 which then
converts to 2. Presumably, the reaction proceeds via an
insertion of iridium into the CꢀF bonds. Very recently,
Chan and Leong investigated an iridium CO complex
activating an aromatic CꢀF bond together with water.30
As proved by our own research, the appearance of a CO
molecule in an iridium complex is feasible.31 From the sum
of the presented reactions we propose the preliminary
mechanism shown in Scheme 3. Because of the excess of
glycerol, one 2,4-pentanedione ligand is exchanged, creat-
ing the catalytically active complex. In the following steps,
water from glycerol is eliminated, possibly explaining the
presence of water in the single crystals of 2, and finally
CꢀC and CꢀN bonds are established.
In summary, we have prepared various novel, potentially
bioactive, methyl-substituted pyrrolo[1,2-a]quinoxalines from
2-alkylquinoxalines via a new route. Ir(acac)3 probably reacts
as a catalyst and glycerol represents the carbon source for the
annulation of a pyrrole ring. We have proven the structure
of our products by complete analysis including two X-ray
structures, proposed a preliminary mechanism for the reaction
and supported our conjectures by experiments.
Acknowledgment. We thank Dr. Jahn (Technische Uni-
€
€
versitat Braunschweig) and Dr. Zollner (TU-BS) for help-
ful discussions and Dr. Beuerle (TU-BS) for GC/MS
analysis. We also thank BMBF for financial support
(FKZ 01 BD 0687).
Supporting Information Available. Experimental proce-
dures, spectral and crystallographic data of described com-
pounds, and discussed HPLC, GC/MS, and TLC results.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(30) Chan, P. K.; Leong, W. K. Organometallics 2008, 27, 1247–1253.
(31) Ammermann, S.; Daniliuc, C.; Jones, P. G.; du Mont, W.-W.;
Kowalsky, W.; Johannes, H.-H. Dalton Trans. 2008, 4095–4098.
The authors declare no competing financial interest.
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