A new route to ring-fused pyrazines: Imidazo[4,5-b]quinoxalines by a simple oxidation-annulation sequence

Article abstract of DOI:10.1055/s-0029-1217071

Novel tricyclic 4H-imidazo[4,5-b]quinoxalines were synthesized by a new orfto-annulation process starting from 4Himidazoles and cerammonium nitrate (CAN) as oxidation reagent in the presence of potassium carbonate as base. This reaction is interpreted as

Full text of DOI:10.1055/s-0029-1217071

PAPER
4049
A New Route to Ring-Fused Pyrazines: Imidazo[4,5-b]Quinoxalines
by a Simple Oxidation–Annulation Sequence
I
midazo[4,5-
bv
e
s
by a Sim
p
n
le
O
xidation
j
–Annu
a
lation Sequenc
e
Herzog,a Gunther Buehrdel,a Rainer Beckert,*a Susann Klimas,a Ernst-Ulrich Würthwein,*b Stefan Grimme,b
Helmar Görlsc
a
Institute of Organic and Macromolecular Chemistry, Friedrich-Schiller-University Jena, Humboldtstr. 10, 07743 Jena, Germany
Fax +49(3641)948212; E-mail: C6bera@uni-jena.de
Organic-Chemistry Institute, University Münster, Corrensstr. 40, 48149 Münster, Germany
b
Fax +49(251)8339772; E-mail: wurthwe@uni-muenster.de
Institute of Inorganic and Analytical Chemistry, Friedrich-Schiller-University Jena, Lessingstr. 8, 07743 Jena, Germany
c
Received 25 June 2009; revised 4 August 2009
tions have gained increasing interest. In the past, some
such cyclizations have been employed for the construc-
tion of phenazines, fluoflavines, fluorindines and other
ring-fused derivatives.7 Observations made by a cooperat-
Abstract: Novel tricyclic 4H-imidazo[4,5-b]quinoxalines were
synthesized by a new ortho-annulation process starting from 4H-
imidazoles and cerammonium nitrate (CAN) as oxidation reagent in
the presence of potassium carbonate as base. This reaction is inter-
preted as a multi-step reaction involving oxidative radical forma- ing group8a,b as well as our own experimental findings8c,d
tion, a radical aromatic substitution and a subsequent redox process.
inspired us to study such reactions in more detail.
The analysis is supported by high level DFT calculations. This nov-
el transformation opens the way for the construction of ring-fused
Our starting point was the observation that derivatization
reactions of the deep-red 4H-imidazoles of type 2 often
led to yellow, strongly fluorescent by-products. Since, ini-
tially, ring-annulation processes were suspected to cause
the formation of these by-products, first, the ortho-fluoro-
substituted derivative 2a was synthesized. The ortho-
fluorine atom should facilitate an intramolecular nu-
cleophilic substitution thus leading to tricycles of type 3.
derivatives of pyrazine. The new tricyclic products display strong
fluorescence in solution and, in addition, show reversible redox ac-
tivity.
Key words: amines, heterocycles, oxidations, radical reactions,
ring-closure
Ring-annulation reactions of nitrogen-containing systems
play an important role in the construction of pharmacolog-
ically active compounds as well as for new innovative ma-
terials. Besides ‘classical’ condensation reactions,
increasingly elegant pericyclic processes have been ap-
plied. As a result, laborious multi-step procedures with
low yields could therefore be replaced.
All compounds of type 2 were prepared by the standard
method developed in our group (Scheme 1) – the cycliza-
tion reaction of benzamidine hydrochloride and bis-
arylimidoyl chlorides 1.9 The bis-electrophiles of type 1
are easily accessible by a two-step, one-pot reaction.10
The new bis-arylimidoyl chloride 1j, which possesses
propargyl ether groups (Ar = C6H4OCH2C≡CH), was iso-
lated as yellow crystals in good yields. These newly intro-
duced functional groups offered the opportunity for
further modifications (e.g. cycloadditions and cross-
coupling reactions). The new derivatives 2h and 2o,
which possess n-octyl groups, were synthesized in order
to obtain compounds with better solubility in nonpolar
solvents (Scheme 1).
A special case among aza-heterocycles, however, are the
pyrazines where ring formation is based, almost without
exception, on condensation reactions. Cycloaddition reac-
tions of 1,4-diazadienes are quite rare and the results have
to be viewed critically.1 Particularly, intermediate elec-
tron-rich alkene substructures (ene-diamines) are capable
of undergoing subsequent redox processes. Other synthet-
ic approaches such as electrocyclization with subsequent
elimination2 applied to diazahexatriene systems mainly
resulted in the formation of pyrimidines3 and
quinazolines4 with only a few publications on the forma-
tion of pyrazines.5
+
NH2
Cl–
Ph
Ar
Ar
N
NH2
O
Cl
O
N
Cl
1) toluene r.t.
2) PCl5, 100 °C
N
MeCN, Et3N,
75 °C
ArNH2
Ph
+
The concept of electrocyclization of 1,n-dipoles and pos-
itively or negatively charged unsaturated systems was
successfully applied for azepines and larger ring systems.6
N
Cl
Cl
N
NH
Ar
1
2
Ar
Scheme 1 Synthesis of the 4H-imidazoles 2
Since vicinal diamines/diimines and the corresponding
hybrids are easily accessible, oxidative cyclization reac-
The starting compound 2a was isolated in good yields and
1
was characterized by elemental analysis, MS, H NMR
and 19F NMR data. Even during its synthesis, traces of a
strongly blue fluorescent substance were detected by
TLC, which could be isolated by column chromatogra-
SYNTHESIS 2009, No. 23, pp 4049–4057
x
x.
x
x
.
2
0
0
9
Advanced online publication: 22.10.2009
DOI: 10.1055/s-0029-1217071; Art ID: T12309SS
© Georg Thieme Verlag Stuttgart · New York

4050
S. Herzog et al.
PAPER
phy, in ~1% yield; this substance was identical to 3a. Sub- aminonitrones.12 Consequently, under these conditions
sequent treatment of 2a with various bases primarily (CAN, K2CO3, MeCN, r.t.), 2a exclusively gave 3b as the
formed the deep-purple anion of 2a which, however, main product. Analogously, oxidation reactions of all the
proved to be stable towards cyclization processes. In con- other 4H-imidazoles 2 resulted in the selective formation
trast, heating 2a in acetic acid under reflux formed a green of yellow cyclization products 3 (Scheme 3). Depending
solution which, upon work-up and purification, gave the on the substituents on the aryl residues, the yields varied
new derivative 3a in ~20% yield (Scheme 2). Compound from traces (3n and 3o) up to 90% (3d; Table 1). The low
3a was isolated as slightly yellow crystals which showed yield for 3n and 3o may be explained by the steric demand
strong blue fluorescence in solution. Most likely, in this exerted by the two neighboring trifluoromethyl/ester
reaction, the protonated cyanine-like form 2aH+ was gen- groups. The new derivatives were isolated in analytically
erated which easily undergoes an SNi-type reaction at the pure form after recrystallization/column chromatography.
aromatic core. However, all further attempts to improve Elemental analysis and MS data confirmed the loss of two
the yield of this ring-annulation reaction failed. In all hydrogen atoms. The 1H- and 13C NMR spectra of deriva-
cases, mixtures of decomposition products derived from tives 3 exhibited two sets of signals for the former aryl res-
the starting heterocycle 2a were obtained and the desired idues at the =N/NH-atoms, indicating an unsymmetrical
1
imidazoquinoxaline 3a was isolated only in low yield (1– structure. In the H NMR spectrum of derivative 3d, the
20%). Due to these experimental findings and in order to signal at d = 7.16 ppm was the key signal for this ortho-
introduce other functional groups into heterocycles 3, we annulation process. In the 13C NMR spectra, the C-2 of the
focused our further studies on a different synthetic strate- imidazole ring absorbs in the downfield region, similar to
gy.
the starting compounds (2: d = 189 ppm; 3: d = 181 ppm).
A single-crystal X-ray analysis of 3d allowed an unam-
biguous structural assignment of these compounds, as
shown in Figure 1. Hence, the cyclization products 3 have
the structure of 2-phenyl-4-aryl-4H-imidazo[4,5-b]quin-
oxalines. Compound 3d is a monomer in the solid state
with the bond lengths and angles being within the expect-
ed range. Typically, an alternation of bond lengths in the
4H-imidazol core was detected. The C2–C3 bond length
(1.46 Å) lies in the range of single carbon–carbon bonds
in a butadiene system. The π-system of the 4-tolyl ring is
nearly perpendicular with respect to the central 4H-imid-
azoquinoxaline functionality.
N
N
N
N
N
N
N
Ph
AcOH
Ph
120 °C
F
NH
F
– HF
F
Ar
NH+
3a
N
2a
Ph
N
2aH+
NH
Ar
Ar = 2-FC6H4
Scheme 2 Cyclization of ortho-fluoro-substituted 4H-imidazoles
Since radical cations were discussed as being alternative
intermediates in other cyclization reactions,11 oxidation
reactions were tested. Moreover, we recently demonstrat-
ed that oxygen is necessary in certain types of ortho-annu-
lation processes.8d
Several oxidants, combined with potassium carbonate
(the addition of a base results in shorter reaction times and
higher yields), were employed successfully in the ring-
forming reactions of compounds 2, e.g. cerammonium ni-
trate (CAN), lead(IV) acetate and potassium hexacyano-
ferrate(III). In these experiments, the combination of CAN
and potassium carbonate proved to be the best for this
transformation. This protocol is distinguished by short re-
action times, high yields and non-toxic by-products.
Figure 1 ORTEP plot (50% probability ellipsoids) of the solid-state
molecular structure (X-ray crystal structure analysis) of derivative 3d,
selected bond lengths in Å: N1–C1, 1.343(2); N1–C3, 1.372(2); N2–
C3, 1.3095(19); N2–C5, 1.379(2); N3–C1, 1.391(2); N3–C2,
1.3172(19); N4–C2, 1.3520(19); N4–C4, 1.4049(19); C2–C3,
1.461(2); C4–C5, 1.417(2).
The oxidation with lead(IV) acetate resulted in compara-
bly high yields but, due to the formation of toxic waste
products, this pathway was not pursued further. Using po-
tassium hexacyanoferrate(III), longer reaction times, ex-
cess of oxidant and higher temperatures were necessary in
order to obtain comparable yields. In a recent publication
we demonstrated that other oxidants able to transfer oxy-
gen (dimethyldioxirane, peroxyacids) selectively reacted
with 2 at the imino nitrogen atom with formation of b-
It is noteworthy that only a few literature reports on imi-
dazo[4,5-b]quinoxalines exist;13 2-substituted derivatives
with additional substituents at the pyrazine ring are un-
known.
Synthesis 2009, No. 23, 4049–4057 © Thieme Stuttgart · New York

PAPER
Imidazo[4,5-b]Quinoxalines by a Simple Oxidation–Annulation Sequence
4051
Ar
N
The new tricyclic compounds were well soluble in com-
mon solvents and proved to be stable towards air. In
contrast to the deep red-colored 4H-imidazoles (2d;
8
N
N
N
N
N
7
6
CAN, K2CO3, MeCN, r.t.
Ph
R1
Ph
N
l
max = 490 nm, shoulder 520 nm), their long-wavelength
NH
Ar
5
UV/Vis absorptions are shifted hypsochromically (Dl =
~100 nm; 3d: lmax = 385 nm, shoulder 400 nm). In addi-
tion, they display a strong blue fluorescence in solution
(3d: lEm = 488 nm) with Stokes shifts (n) of approximate-
ly 5500 cm–1 and quantum yields between 5 and 40%. The
bromo-substituted derivative 3k offers the preconditions
needed for subsequent modifications as exemplified here
for the Sonogashira cross-coupling method. Upon treat-
ment of 3k with triisopropylsilyl acetylene or phenyl acet-
ylene under standard Sonogashira conditions, the new,
highly fluorescent bis-acetylenes 3p and 3q were isolated
in high yields. It is noteworthy that all efforts to cross-
couple the parent compounds 2 itself failed so far. This
can be explained by the excellent chelating properties of
the 4H-imidazoles 2,14 which prevent the formation of cat-
alytically active palladium species.
Ar
2
3b–o
N
N
N
R2
Ph
N
Pd(PPh3)2Cl2 (10 mol%),
CuI (10 mol%),
Et3N, toluene, 80 °C
3p,q
R2
3k
3p: R2 = Si(i-Pr)3
3q: R2 = Ph
R2
Scheme 3 Synthesis of 4H-imidazo[4,5-b]quinoxalines and modifi-
cation by Sonogashira cross-coupling reaction
Due to their inherent merocyanine-type structures, com-
pounds 3 are likely to behave as multi-step redox systems
according to Scheme 4. We could recently demonstrate
that 4H-imidazoles 2 and other cross-conjugated systems
behave as electrophores that can easily be switched be-
tween oxidized and reduced forms.12,15,16 The cyclic vol-
tammograms, as well as difference pulse polarographic
measurements of 3d, revealed two reversible reduction
waves that correspond to two single-electron transfer
steps (3d; –0.728 V and –0.986 V). In the first step, it is
likely that the radical anion was generated. The second
electron-transfer step then leads to the formation of the di-
anion (3-Red), which can be protonated to yield the leuco
(3-Leuco) form (Scheme 4). The quasi-reversibility of the
reduction was confirmed by cyclovoltammetric measure-
ments (DE1RED,OX = 0.128 V and DE2RED,OX = 0.082 V).
3d-Leuco could also be obtained by the reduction of 3d in
tetrahydrofuran, in the presence of small amounts of aque-
ous sodium dithionite, however, this is rapidly reoxidized
by air. Furthermore, the cyclovoltammogram of 3d
showed two irreversible oxidation waves at 0.903 V and
1.372 V.
Table 1 Substitution Pattern of 2 and 3
2
Ar
R
Product Yield
(%)
2a
2a
2c
2d
2e
2f
2-FC6H4
H
3aa
3b
3c
3d
3e
3f
20
2-FC6H4
8-F
52
Ph
H
84
4-Tolyl
6-Me
92
4-(EtO2C)C6H4
4-F3CC6H4
4-t-BuC6H4
4-n-OctOC6H4
4-MeOC6H4
4-HC≡CCH2OC6H4
4-BrC6H4
6-EtO2C
6-F3C
6-t-Bu
6-n-OctO
6-MeO
6-HC≡CCH2O
6-Br
65
78
2g
2h
2i
3g
3h
3i
90
75
91
2j
3j
87
2k
2l
3k
3l
93
2-BrC6H4
8-Br
97
We postulate the following mechanism (Scheme 5) for the
formation of the imidazo[4,5-b]quinoxalines of type 3.
First, oxidation takes place through intermediate forma-
tion of the radical cation A derived from a secondary
amine. A relatively strong acidity has been predicted for
these radical cations and, consequently, deprotonation
may result in the aminyl radical B. Finally, radical B is
2m
2n
2o
3-F3CC6H4
3,5-(F3C)2C6H3
7-F3C
5,7-(F3C)2
3m
3n
3o
71
trace
trace
3,5-(n-OctO2C)2C6H3 5,7-(n-OctO2C)2
a Formed by SN-reaction on the ortho-F-position (Scheme 2).
H
N
N–
N
N
N
N
N
N
2 e
H+
2
R
R
R
N
H
N
N
N
Ar
Ar
Ar
3-Ox
3-Red
3-Leuco
Scheme 4 4H-Imidazo[4,5-b]quinoxalines 3 as two-electron redox systems
Synthesis 2009, No. 23, 4049–4057 © Thieme Stuttgart · New York

4052
S. Herzog et al.
PAPER
Ph
Ph
N
the double-hybrid functionals which have about 50%
Fock-exchange compared to 20% in B3LYP.
N
N
– H+
N
– e
Ph
Ph
2
Among other conceivable mechanisms compatible with
the reaction conditions (presence of base and oxidant at
room temperature), we took three possible pathways for
the cyclization reaction into account computationally
(Scheme 6). If the oxidation takes place first, a radical cat-
ion will be formed, which may either undergo the ring-
closure reaction or might be deprotonated to give the cor-
responding radical. Alternatively, initial oxidative remov-
al of a hydrogen atom may take place, producing the
radical, which will then cyclize. A third possibility in-
volves initial deprotonation by the base, whereby anionic
ring-closure reaction might occur. All three modes are ex-
pected to lead to the product observed after additional ox-
idation and deprotonation steps.
H
•
N
•
N
H+
+
N
A
N
B
Ph
Ph
N
N
•
N
N
+
– e
– H ,
C
3
Ph
H
Ph
C
Scheme 5 Proposed mechanism for the ortho-ring-annulation pro-
cess
able to attack the attached aromatic ring intramolecularly
to give 3 via C.
In order to investigate the mechanism of the ring-closure
reaction, high-level quantum chemical gas-phase calcula-
tions were performed using the program packages GAUS-
SIAN 03,17 employing the DFT B3LYP/6-311+G(d,p)
method for geometry optimization and energy determina-
tion including zero-point correction and TURBO-
MOLE,18 using the recently developed B2PLYP-D hybrid
functional,19 with the def2-TZVP-basis set,20 and the
B3LYP/6-311+G(d,p) geometries for the energy determi-
nations. Many DFT calculations of (charged) open-shell
species using standard hybrid functionals suffer from the
well-known problem of self-interaction error,21 that typi-
cally leads to reaction barriers that are too low and to over-
delocalization effects in unsaturated systems.22 These
problems can be significantly alleviated by increasing the
amount of Fock-exchange admixture as, for example, in
With respect to the cyclization reaction, the calculations
(B2PLYP-D data, B3LYP values in parentheses) clearly
favor the radical mechanism, which shows the lowest ac-
tivation barrier of 8.6 (18.1) kcal/mol, followed by the an-
ionic mechanism [25.1 (32.4) kcal/mol] and the radical
cation mode [42.3 (45.8) kcal/mol]. Thus, the radical
cyclization with its pronounced exothermicity [–12.1
(–11.3) kcal/mol] seems to be the favored mode of ring-
formation. In contrast, the energy-rich transition-state and
the product of the radical cation cyclization suffer signif-
icantly from a lack of resonance due to the four-coordi-
nate nitrogen atom present in these structures. The anionic
mechanism, despite its moderate energy barrier, seems to
be less likely since this mode is expected to require a
stronger base then is present in the reaction mixture.
Ph
N
N
N
N
TS
Ph
.
Ph
H
N+
.
+
H
N
N
N
42.3 (45.8)
H
Ph
Ph
36.6 (43.1)
– e–, – 2 H+
– e–
0.0
– H+
Ph
N
Ph
N
N
N
N
N
N
N
N
– e–, – H+
H
N
– e–, – H+
Ph
.
Ph
Ph
Ph
TS
.
N
N
N
N
N
N
8.6 (18.1)
H
Ph
Ph
Ph
Ph
–3.5 (6.8)
0.0
– H+
– e–
Ph
– 2 e–, – H+
N
N
N
N
N
N
–
Ph
TS
Ph
N–
Ph
N
25.1 (32.4)
H
Ph
17.5 (26.6)
0.0
Scheme 6 Overview of the three possible cyclization mechanisms studied using DFT-calculations. Relative energies (kcal/mol) at the
B2-PLYP-D/def2-TZVP//B3LYP/6-311+G(d,p)-level. Numbers in parentheses refer to B3LYP/6-311+G(d,p)//B3LYP/6-311+G(d,p)-
calculations.
Synthesis 2009, No. 23, 4049–4057 © Thieme Stuttgart · New York

PAPER
Imidazo[4,5-b]Quinoxalines by a Simple Oxidation–Annulation Sequence
4053
MS (EI): m/z (%) = 434 (1) [M+], 355/353 (70/50) [M – Br]+, 317
Thus, in good agreement with the experimental conditions
and the considerations discussed above, we suggest the
(50), 218/216 (100/90) [M/2+], 157/155 (60/70).
radical pathway for the cyclization reaction. The idea of a Anal. Calcd for C14H8Br2Cl2N2: C, 38.66; H, 1.85; N, 6.44. Found:
C, 39.07; H, 2.01; N, 6.44.
radical mechanism proceeding through a step-wise initial
oxidation to the radical cation, then deprotonation to the
radical seems especially attractive due to the enhanced
Bis[4-(propargyloxy)phenyl]oxaldiimidoyl Chloride (1j)
Yield: 83%; yellow crystals; mp 174–175 °C.
1H NMR (250 MHz, CDCl3): d = 7.29 (d, J = 8 Hz, 4 H, CH-Ar),
7.06 (d, J = 8 Hz, 4 H, CH-Ar), 4.74 (d, J = 2.4 Hz, 4 H, CH2), 2.56
acidity of nitrogen-containing radical cations in compari-
son to the neutral aromatic amines.23
In conclusion, starting from easily accessible 4H-imid-
azoles, a new synthesis of tricyclic imidazo[4,5-b]quin-
oxalines 3 has been developed. Their structure was
determined by elemental analysis, MS, NMR and, addi-
tionally, by X-ray crystal structural analysis. The com-
pounds are air-stable and well soluble in common solvents
and display a strong blue fluorescence in solution. These
features make them of interest as multifunctional dyes.
High-level quantum chemical DFT-calculations are in
good agreement with a radical cyclization mechanism,
which may operate after oxidation to the radical cation
and subsequent deprotonation to produce the intermediate
radical.
(t, J = 2.4 Hz, 2 H, C≡CH).
13C NMR (63 MHz, CDCl3): d = 156.7, 138.9, 136.7 (Cl-C=N),
123.5, 115.2, 78.2, 75.8, 56.1.
MS (EI): m/z (%) = 388/386/384 (10/40/70) [M+], 192 (100) [M/2+],
188 (60), 153 (20).
Anal. Calcd for C20H14Cl2N2O2: C, 62.35; H, 3.66; N, 7.27. Found:
C, 62.44; H, 3.86; N, 7.15.
2-Phenyl-4-arylamino-5-arylimino-4H-imidazoles (2); General
Procedure
A solution of the corresponding bis-aryloxaldiimidoyl chloride 1
(10 mmol), benzamidine hydrochloride (1.7 g, 11 mmol) and Et3N
(7.0 mL, 5.1 g, 50 mmol) in MeCN (50 mL) was heated under reflux
until no starting material 1 was detected (TLC; 2–5 h). The formed
Et3N·HCl was filtered off, the solvent was removed in vacuo and the
crude product was recrystallized or purified by column chromatog-
raphy on silica gel (CHCl3–n-heptane).
The reagents were purchased from commercial sources and were
used directly unless otherwise stated in the text. All solvents were
of reagent grade and were dried according to common practice and
distilled prior to use. Reactions were monitored by TLC, carried out
on 0.2 mm Merck silica gel plates (60 F254). 1H and 13C NMR spec-
tra were recorded on Bruker AVANCE 250 and 400 spectrometers,
shifts (d) are given relative to signals arising from the solvent. Melt-
ing points were measured with a Galen III apparatus (Boëtius
system) or with a Kofler apparatus and are uncorrected. Electro-
chemical measurements were carried out in CH2Cl2 with a Metrohm
663 VA Stand using platinum electrodes (reference electrode SCE)
and tetrabutylammonium hexafluorophosphate as conductive salt.
2-Phenyl-4-(2-fluorophenylamino)-5-(2-fluorophenylimino)-
4H-imidazole (2a)
Yield: 62%; red crystals; mp 170–176 °C (CHCl3–n-heptane).
IR (ATR): 3391, 3369, 3069, 1592, 1496, 1434, 1341, 1245, 1230,
1086, 754, 716 cm–1.
1H NMR (250 MHz, CDCl3): d = 7.31–7.09 (m, 13 H, CH-Ar).
19F NMR (188 MHz, CDCl3): d = –125.4 (s, 2 F).
MS (EI): m/z (%) = 360 (35) [M+], 341 (25) [M – F]+, 136 (40), 121
(100), 103 (35).
Bis-aryloxaldiimidoyl Chlorides 1; General Procedure
UV/Vis (CHCl3): lmax (log e) = 481 nm (4.1).
To a solution of the corresponding aniline (0.1 mol) in toluene (50
mL), oxalyl chloride (4.6 mL, 6.6 g, 0.052 mol), dissolved in tolu-
ene (50 mL) was added within 10 min (a slurry of the corresponding
oxanilide was formed). The mixture was stirred for 20 min at r.t.
then PCl5 (22.0 g, 0.105 mol) was added. The mixture was heated
under reflux until no further hydrogen chloride was formed. The
dark-yellow reaction mixture was concentrated in vacuo to dryness
and the crude product was recrystallized from n-heptane/toluene.
Anal. Calcd for C21H14N4F2: C, 69.99; H, 3.92; N, 15.55. Found: C,
69.61; H, 3.87; N, 15.27.
2-Phenyl-4-(4-tolylamino)-5-(4-tolylimino)-4H-imidazole (2d)
Yield: 92%; red crystals; mp 209 °C (MeCN).9
1H NMR (250 MHz, CDCl3): d = 8.55 (m, 2 H, CH-Ph), 7.89 (d,
J = 8 Hz, 4 H, CH-Tol), 7.61–7.49 (m, 3 H, CH-Ph), 7.25 (d, J = 8
Hz, 4 H, CH-Tol), 2.39 (s, 6 H, CH-Tol).
13C NMR (63 MHz, CDCl3): d = 188.6 (C-2), 163.6, 139.5, 136.7,
133.6, 132.1, 130.5, 129.8, 128.5, 123.6, 21.2.
Bis(2-fluorophenyl)oxaldiimidoyl Chloride (1a)
Yield: 62%; yellow crystals; mp 105–107 °C.
1H NMR (250 MHz, CDCl3): d = 8.59–8.55 (m, 2 H, CH-Ar), 7.68–
7.51 (m, 2 H, CH-Ar), 7.32–7.12 (m, 4 H, CH-Ar).
19F NMR (188 MHz, CDCl3): d = –122.9 (s, 2 F).
MS (EI): m/z (%) = 312 (10) [M+], 156 (100) [M/2+].
2-Phenyl-4-(4-octanoxyphenylamino)-5-(4-octanoxyphenyl-
imino)-4H-imidazole (2h)
Yield: 67%; red crystals; mp 101–103 °C (CHCl3–n-heptane).
IR (ATR): 3369, 3304, 2956, 2920, 2853, 1614, 1574, 1533, 1504,
1237, 1168, 1031, 1000, 830 cm–1.
Anal. Calcd for C14H8Cl2F2N2: C, 53.70; H, 2.58; N, 8.95. Found:
C, 53.37; H, 2.72; N, 8.61.
1H NMR (250 MHz, CDCl3): d = 9.25 (s, 1 H, NH), 8.57 (m, 2 H,
CH-Ph), 8.02 (d, J = 8 Hz, 4 H, CH-Ar), 7.59–7.53 (m, 5 H, CH-
Ph), 6.98 (d, J = 8 Hz, 4 H, CH-Ar), 4.01 (t, J = 7 Hz, 4 H, OCH2),
1.85–1.78 (m, 4 H, CH2), 1.48–0.74 (m, 26 H, CH).
13C NMR (63 MHz, CDCl3): d = 187.5 (C-2), 162.6 (C-4), 135.2,
133.2, 132.3, 130.2, 128.4, 125.4, 121.2, 115.0, 68.3 (OCH2), 31.8,
30.1, 29.7, 29.1, 26.0, 22.6, 14.0.
Bis(2-bromophenyl)oxaldiimidoyl Chloride (1b)
Yield: 74%; yellow crystals; mp 182–183 °C.
1H NMR (250 MHz, CDCl3): d = 7.71–7.37 (m, 4 H, CH-Ar), 7.18–
7.11 (m, 2 H, CH-Ar), 7.07–7.04 (m, 2 H, CH-Ar).
13C NMR (63 MHz, CDCl3): d = 145.0, 141.1, 133.1, 127.9, 127.5,
120.1, 114.3.
MS (EI): m/z (%) = 580 (100) [M+], 467 (57), 451 (49).
Synthesis 2009, No. 23, 4049–4057 © Thieme Stuttgart · New York

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PAPER
UV/Vis (CHCl3): lmax (log e) = 423 (4.0), 508 (4.2), 538 nm (4.1).
13C NMR (63 MHz, CDCl3): d = 182.5 (C-2), 162.0, 159.3, 151.5
(1J = 440 Hz), 137.8, 132.8 (d, J = 11 Hz), 132.7, 132.6 (d, J = 2.5
Hz), 131.0, 130.1, 129.5, 129.2, 128.5, 128.4, 125.9, 125.7 (d, J = 4
Hz), 123.2 (d, J = 14 Hz), 117.5 (d, J = 18 Hz), 115.9.
Anal. Calcd for C37H48N4O2: C, 76.51; H, 8.33; N, 9.65. Found: C,
76.90; H, 8.74; N, 9.23.
2-Phenyl-4-[4-(propargyloxy)phenylamino]-5-[4-(propargyl-
oxy)phenylimino]-4H-imidazole (2j)
Yield: 74%; red crystals; mp 171 °C (CHCl3–n-heptane).
1H NMR (250 MHz, CDCl3): d = 8.58 (m, 2 H, CH-Ph), 8.05 (d,
J = 8 Hz, 4 H, CH-Ar), 7.62–7.51 (m, 3 H, CH-Ph), 7.08 (d, J = 8
Hz, 4 H, CH-Ar), 4.76 (d, J = 2.4 Hz, 4 H, OCH2), 2.56 (t, J = 2.4
Hz, 2 H, C≡CH).
19F NMR (188 MHz, CDCl3): d = –119.6 (s, 1 F).
MS (EI): m/z (%) = 340 (50) [M+], 321 (20) [M – F]+, 121 (80), 111
(100).
Emission (CHCl3): l = 450 nm; l = 470 nm.
Anal. Calcd for C21H13N4F: C, 74.11; H, 3.85; N, 16.46. Found: C,
73.81; H, 3.61; N, 16.16.
13C NMR (63 MHz, CDCl3): d = 188.0 (C-2), 156.2, 133.4, 132.1,
2-Phenyl-4-aryl-4H-imidazo[4,5-b]quinoxalines (3); General
Procedure
130.4, 128.5, 125.5, 125.4, 125.3, 115.5, 78.3, 75.8, 56.1.
+
MS (EI): m/z (%) = 432 (40) [M+], 393 (60) [M – C3H3 ], 158 (20),
A mixture of the corresponding 2-phenyl-4H-imidazole 2 (2 mmol),
K2CO3 (1.4 g, 10 mmol) and CAN (3.3 g, 6 mmol) in MeCN (50
mL) was stirred at r.t. (less reactive/less soluble derivatives of type
2 at 50 °C) until no starting material 2 could be detected (TLC, 0.5–
4 h; in the case of 2l and 2m even after 24 h only a conversion of
25% could be observed). Most of the solvent was removed in vacuo
and the residue was added to H2O (100 mL). The crude product was
extracted with CHCl3 (3 × 100 mL), the insoluble solid was filtered
off and washed with MeOH. The organic layers were combined and
dried (Na2SO4). After removing the solvent in vacuo, the product
was purified by column chromatography on silica gel (CHCl3–
MeOH).
133 (100).
Anal. Calcd for C27H20N4O2: C, 74.99; H, 4.66; N, 12.95. Found: C,
74.58; H, 4.42; N, 12.46.
2-Phenyl-4-(2-bromophenylamino)-5-(2-bromophenylimino)-
4H-imidazole (2l)
Yield: 84%; red crystals; mp 214 °C (MeCN).
IR (ATR): 3301, 3062, 1615, 1592, 1566, 1538, 1423, 1327, 1267
1060, 1022, 747 cm–1.
1H NMR (250 MHz, CDCl3): d = 9.51 (s, 1 H, NH), 8.60–8.58 (m,
2 H, CH-Ph), 7.70–7.47 (m, 7 H, CH-Ar), 7.27–7.13 (m, 4 H, CH-
Ar).
2-Phenyl-4-(2-fluorophenyl)-8-fluoro-4H-imidazo[4,5-b]quin-
oxaline (3b)
Yield: 52%; yellow crystals; mp 256 °C.
1H NMR (400 MHz, CDCl3): d = 8.61–8.58 (m, 2 H, CH-Ph), 7.75–
7.38 (m, 9 H, CH-Ar), 7.11 (m, 1 H, CH-Ar).
MS (DEI): m/z (%) = 484/482/480 (5/10/5) [M+], 403/401 (80/100)
[M – Br]+, 300 (35).
UV/Vis (CHCl3): lmax (log e) = 405 (4.0), 491 nm (4.2).
Anal. Calcd for C21H14N4Br2: C, 52.31; H, 2.93; N, 11.62. Found:
C, 52.07; H, 2.65; N, 11.31.
19F NMR (188 MHz, CDCl3): d = –119.6 (s, 1 F), –119.8 (s, 1 F).
MS (EI): m/z (%) = 358 (100) [M+], 339 (22) [M – F]+, 255 (32).
Emission (CHCl3): lmax = 496 nm.
2-Phenyl-4-[3,5-di(carboxyoctyl)phenylamino]-5-[3,5-di(car-
boxyoctyl)phenylimino]-4H-imidazole (2o)
Yield: 76%; red solid; mp 60–65 °C.
1H NMR (250 MHz, acetone-d6): d = 8.69 (s, 4 H, CH-Ar), 8.30–
8.23 (m, 4 H, CH-Ar), 7.57–7.35 (m, 3 H, CH-Ph), 4.32–4.22 (m,
8 H, OCH2), 1.77–1.74 (m, 8 H, CH2), 1.40–1.30 (m, 40 H, CH2),
0.89–0.87 (m, 12 H, CH3).
13C NMR (63 MHz, acetone-d6): d = 189.1, 165.0, 134.3, 132.0,
131.8, 131.0, 128.8, 65.6 (OCH2), 32.2, 29.6, 28.6, 28.4, 26.3, 22.9,
14.1 (CH3).
Anal. Calcd for C21H12N4F2: C, 70.39; H, 3.38; N, 15.63. Found: C,
70.06; H, 3.11; N, 15.33.
2-Phenyl-4-phenyl-4H-imidazo[4,5-b]quinoxaline (3c)
Yield: 84%; yellow crystals; mp 304 °C (dec).
IR (ATR): 3073, 1596, 1566, 1454, 1431, 1345, 1245, 1136, 1096,
1064, 917, 753, 716, 689 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.60 (m, 2 H, CH-Ph), 8.38 (d,
J = 8 Hz, 1 H, CH-Ar), 7.78–7.38 (m, 11 H, CH-Ar).
13C NMR (100 MHz, CDCl3): d = 182.5 (C-2), 162.0, 148.3, 138.0,
135.7, 133.0, 132.4, 130.9, 130.4, 130.3, 130.0, 128.9, 128.8, 128.5,
127.6, 125.8, 116.6.
MS (ESI, MeOH/CHCl3): m/z (%) = 971 (100) [M + Na+], 949 (60)
[M + H+].
Anal. Calcd for C57H80N4O8: C, 72.12; H, 8.49; N, 5.90. Found: C,
71.81; H, 8.34; N, 5.99.
MS (EI): m/z (%) = 322 (73) [M+], 321 (100) [M – H+].
2-Phenyl-4-(2-fluorophenyl)-4H-imidazo[4,5-b]quinoxaline
(3a)
UV/Vis (CHCl3): lmax (log e) = 379 nm (4.5).
Anal. Calcd for C21H14N4: C, 78.24; H, 4.38; N, 17.38. Found: C,
77.83; H, 4.21; N, 17.11.
A solution of 2a (1.0 g, 2.7 mmol) in glacial AcOH (10 mL) was
heated to 120 °C until no starting material 2a could be detected
(TLC; ~4 h). A green solution formed. Most of the solvent was re-
moved in vacuo and the residue was added to H2O (50 mL). After
neutralization with Na2CO3, the crude product was extracted with
CHCl3 (3 × 50 mL) and the organic layer was dried (Na2SO4). After
removing the solvent in vacuo, the product was purified by column
chromatography on silica gel (CHCl3–MeOH).
2-Phenyl-4-tolyl-6-methyl-4H-imidazo[4,5-b]quinoxaline (3d)
Yield: 92%; yellow crystals; mp 296 °C (dec).
IR (ATR): 3047, 2983, 2953, 2927, 1592, 1563, 1514, 1480, 1431,
1342, 814, 713 cm–1.
1H NMR (250 MHz, CDCl3): d = 8.57 (m, 2 H, CH-Ph), 8.25 (d,
J = 8 Hz, 1 H, CH-8), 7.56–7.42 (m, 8 H, CH-Ar), 7.16 (s, 1 H, CH-
5), 2.59 (s, 3 H, CH3), 2.49 (s, 3 H, CH3).
Yield: 20%; yellow crystals; mp 257 °C (dec).
1H NMR (250 MHz, CDCl3): d = 8.59–8.57 (m, 2 H, CH-Ph), 8.38–
8.35 (m, 1 H, CH-Ar), 7.77–7.44 (m, 9 H, CH-Ar), 7.30 (m, 1 H,
CH-Ar).
Synthesis 2009, No. 23, 4049–4057 © Thieme Stuttgart · New York

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Imidazo[4,5-b]Quinoxalines by a Simple Oxidation–Annulation Sequence
4055
13C NMR (63 MHz, CDCl3): d = 181.4, 161.1, 148.2, 140.6, 139.9,
136.5, 133.2, 133.1, 132.2, 130.9, 130.5, 129.9, 129.0, 128.4, 127.7,
127.3, 116.2, 22.1, 21.5.
13C NMR (100 MHz, CDCl3): d = 181.5 (C-2), 161.5, 153.6, 152.8,
148.3, 136.4, 133.3, 133.0, 132.1, 130.3, 129.9, 128.7, 128.4, 127.1,
127.0, 124.2, 112.6, 35.4, 35.1, 31.3, 31.0.
MS (EI): m/z (%) = 350 (100) [M+], 335 (70).
MS (EI): m/z (%) = 434 (100) [M+], 419 (85), 403 (10), 377 (20),
202 (20), 188 (20), 174 (10).
MS (micro-ESI): m/z (%) = 373 (100) [M + Na+], 351 (20) [M +
H+].
UV/Vis (CDCl3): lmax (log e) = 385 nm (4.4).
Emission (CHCl3): lmax = 487 nm.
HRMS: m/z calcd for C24H19N4: 351.161; found: 351.163.
UV/Vis (CHCl3): lmax (log e) = 385 (4.5) nm.
Emission (CHCl3): lmax = 488 nm.
Anal. Calcd for C29H30N4: C, 80.15; H, 6.96; N, 12.89. Found: C,
79.73; H, 6.56; N, 12.66.
Anal. Calcd for C23H18N4: C, 78.83; H, 5.18; N, 15.99. Found: C,
78.52; H, 5.06; N, 15.76.
2-Phenyl-4-(4-octyloxyphenyl)-6-octyloxy-4H-imidazo[4,5-
b]quinoxaline (3h)
Yield: 79%; yellow crystals; mp 243–244 °C.
2-Phenyl-4-(4-ethoxycarbonylphenyl)-6-ethoxycarbonyl-4H-
imidazo[4,5-b]quinoxaline (3e)
Yield: 65%; yellow crystals; mp 265 °C.
1H NMR (400 MHz, CDCl3): d = 8.56 (m, 2 H, CH-Ph), 8.22 (d,
J = 8 Hz, 1 H, CH-8), 7.48–7.45 (m, 5 H, CH-Ar), 7.22 (m, 3 H,
CH-Ar), 6.75 (d, J = 2 Hz, 1 H, CH-5), 4.14 (t, J = 7.1 Hz, 2 H,
OCH2), 3.90 (t, J = 7.1 Hz, 2 H, OCH2), 1.92–1.73 (m, 4 H, CH2),
1.54–0.73 (m, 26 H, CH2).
IR (ATR): 3395, 2987, 2930, 2852, 1717 (C=O), 1664, 1592, 1531,
1437, 1345, 1273, 1229, 1101, 1021, 919, 851, 765 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.56–8.36 (m, 5 H, CH-Ar), 8.25–
8.06 (m, 3 H, CH-Ar), 7.74–7.45 (m, 4 H, CH-Ar), 4.52 (q, J = 7.1
Hz, 2 H, OCH2), 4.39 (q, J = 7.1 Hz, 2 H, OCH2), 1.50 (q, J = 7.1
Hz, 3 H, CH3), 1.40 (q, J = 7.1 Hz, 3 H, CH3).
13C NMR (100 MHz, CDCl3): d = 168.8, 162.7, 161.3, 146.0, 143.2,
135.6, 134.8, 132.3, 132.2, 131.8, 131.2, 129.2, 128.5, 127.4, 126.9,
126.2, 120.8, 116.2, 115.1, 99.0, 69.4, 68.8, 31.8, 31.7, 29.6, 29.3,
29.2, 28.8, 26.0, 25.9, 22.6, 14.0.
13C NMR (100 MHz, CDCl3): d = 184.1 (C-2), 165.2 (C=O), 163.3
(C=O), 161.5, 148.7, 140.2, 140.1, 138.7, 133.1, 132.8, 132.5,
131.7, 131.1, 130.4, 128.6, 127.8, 126.0, 119.0, 118.4, 61.8, 60.9,
14.4.
MS (EI): m/z (%) = 578 (30) [M+], 353 (10), 248 (20), 221 (11), 135
(48), 109 (86), 28 (100).
Anal. Calcd for C37H46N4O2: C, 76.78; H, 8.01; N, 9.68. Found: C,
76.19; H, 7.75; N, 9.46.
MS (EI): m/z (%) = 466 (59) [M+], 437 (23), 409 (20), 393 (43), 365
(36), 320 (12).
2-Phenyl-4-(4-methoxyphenyl)-6-methoxy-4H-imidazo[4,5-
b]quinoxaline (3i)
Yield: 91%; yellow crystals; mp 270–274 °C.
1H NMR (250 MHz, CDCl3): d = 8.56 (m, 2 H, CH), 8.26 (d, J = 8
Hz, 1 H, CH-8), 7.51–7.22 (m, 8 H, CH-Ar), 6.77 (d, J = 2 Hz, 1 H,
CH-5), 3.99 (s, 3 H, OCH3), 3.81 (s, 3 H, OCH3).
13C NMR (50 MHz, DMSO-d6): d = 180.0 (C-2), 160.8, 160.2,
148.3, 133.4, 133.3, 132.1, 130.8, 129.7, 128.6, 128.4, 128.3, 115.7,
115.5, 98.6, 55.8, 55.7.
UV/Vis (CDCl3): lmax (log e) = 387 nm (4.3).
Anal. Calcd for C27H22N4O4: C, 69.52; H, 4.75; N, 14.01. Found: C,
69.15; H, 4.54; N, 13.64.
2-Phenyl-4-(4-trifluoromethylphenyl)-6-trifluoromethyl-4H-
imidazo[4,5-b]quinoxaline (3f)
Yield: 78%; yellow crystals; mp 190–192 °C.
IR (ATR): 3395, 3298, 2927, 2855, 1670, 1599, 1530, 1508, 1442,
1411, 1321, 1250, 1109, 1067, 1019, 833, 719 cm–1.
MS (EI): m/z (%) = 382 (100) [M+], 344 (10), 248 (20).
1H NMR (400 MHz, CDCl3): d = 8.60 (m, 2 H, CH-Ph), 8.51 (d,
3J = 8 Hz, 1 H, CH-8), 8.10 (d, J = 8 Hz, 2 H, CH-Ar), 7.91 (dd,
3J = 8 Hz, 4J = 2 Hz, 1 H, CH-7), 7.80 (m, 2 H, CH-Ar), 7.61–7.49
(m, 4 H, CH-Ar).
19F NMR (188 MHz, CDCl3): d = –62.48 (s, 3 F), –63.21 (s, 3 F).
MS (EI): m/z (%) = 458 (20) [M+], 389 [M – CF3]+, 376 (100), 188
Anal. Calcd for C23H18N4O2: C, 72.24; H, 4.74; N, 14.65. Found: C,
71.89; H, 4.52; N, 14.35.
2-Phenyl-4-(4-propargyloxyphenyl)-6-propargyloxy-4H-imi-
dazo[4,5-b]quinoxaline (3j)
Yield: 87%; yellow crystals; mp 289 °C (dec).
1H NMR (200 MHz, DMSO-d6): d = 8.35 (m, 2 H, CH), 8.22 (d,
J = 8 Hz, 1 H, CH-8), 7.70 (d, J = 8 Hz, 2 H, CH-Ar), 7.54–7.51 (m,
(73), 161 (85), 145 (46).
UV/Vis (CDCl3): lmax (log e) = 380 nm (4.3).
Emission (CHCl3): lmax = 503 nm.
3
4
3 H, CH-Ph), 7.45 (dd, J = 8 Hz, J = 2 Hz, 1 H, CH-7), 7.35 (d,
J = 8 Hz, 2 H, CH-Ar), 6.80 (d, J = 2 Hz, 1 H, CH-5), 4.98 (d,
J = 2.4 Hz, 2 H, OCH2), 4.84 (d, J = 2.4 Hz, 2 H, OCH2), 3.67 (t,
J = 2.4 Hz, 1 H, C≡CH), 3.59 (t, J = 2.4 Hz, 1 H, C≡CH).
Anal. Calcd for C23H12F6N4: C, 60.27; H, 2.64; N, 12.22. Found: C,
59.84; H, 2.25; N, 12.01.
1H NMR (250 MHz, CDCl3): d = 8.58–8.26 (m, 3 H, CH-Ar), 7.75–
6.69 (m, 9 H, CH-Ar), 4.87 (d, J = 2.4 Hz, 2 H, OCH2), 4.71 (d,
J = 2.4 Hz, 2 H, OCH2), 2.65 (t, J = 2.4 Hz, 1 H, C≡CH), 2.53 (d,
J = 2.4 Hz, 1 H, C≡CH).
2-Phenyl-4-(4-tert-butylphenyl)-6-tert-butyl-4H-imidazo[4,5-
b]quinoxaline (3g)
Yield: 90%; yellow crystals; mp 243–245 °C.
13C NMR (50 MHz, DMSO-d6): d = 178.7 (C-2), 159.8, 158.2,
157.5, 148.2, 133.2, 133.0, 132.0, 131.4, 130.7, 128.9, 128.8, 128.7,
116.1, 115.9, 100.5, 79.2, 78.9, 78.7, 78.2, 56.2, 55.9.
IR (ATR): 3065, 2959, 2908, 2867, 1595, 1565, 1482, 1423, 1341,
1248, 1154, 1091, 919, 823, 718 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.59 (m, 2 H, CH-Ph), 8.31 (d,
J = 8 Hz, 1 H, CH-8), 7.74 (m, 3 H, CH-Ar), 7.53–7.46 (m, 5 H,
CH-Ar), 7.37 (d, J = 2 Hz, 1 H, CH-5), 1.50 (s, 9 H, CH3), 1.32 (s,
9 H, CH3).
+
MS (EI): m/z (%) = 430 (100) [M+], 391 (80) [M – C3H3 ], 352 (50),
207 (40), 83 (80).
Anal. Calcd for C27H18N4O2: C, 75.39; H, 4.21; N, 13.02. Found: C,
75.05; H, 3.96; N, 12.76.
Synthesis 2009, No. 23, 4049–4057 © Thieme Stuttgart · New York

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S. Herzog et al.
PAPER
2-Phenyl-4-(4-bromophenyl)-6-bromo-4H-imidazo[4,5-b]quin-
oxaline (3k)
Yield: 93%; yellow crystals; mp 350 °C (dec).
ing acetylene (3 mmol) and Et3N (5 mL, 36 mmol). The mixture was
stirred at 80 °C for 4 h under argon, then the mixture was filtered
and the solvent was removed in vacuo. The crude product was puri-
fied by column chromatography on silica gel (CHCl3–MeOH).
IR (ATR): 3050, 1675, 1589, 1560, 1468, 1425, 1338, 1238, 820
cm–1.
1H NMR (250 MHz, DMSO-d6): d = 8.39 (m, 2 H, CH-Ph), 8.23 (d,
J = 8 Hz, 1 H, CH-Ar), 8.03–7.93 (m, 4 H, CH-Ar), 7.74 (d, J = 8
Hz, 1 H, CH-Ar), 7.56–7.53 (m, 3 H, CH-Ar), 7.40 (d, J = 2 Hz,
1 H, CH-5).
2-Phenyl-4-(4-triisopropylsilylethynylphenyl)-6-triisopropyl-
silylethynyl-4H-imidazo[4,5-b]quinoxaline (3p)
Yield: 95%; yellow crystals; 238 °C (dec).
1H NMR (400 MHz, CDCl3): d = 8.70 (m, 2 H, CH-Ph), 7.97–7.44
(m, 10 H, CH-Ar), 1.22–1.15 (m, 42 H, i-Pr).
13C NMR (100 MHz, CDCl3): d = 171.8, 149.4, 144.6, 139.5, 135.4,
133.9, 133.4, 132.4, 132.0, 131.9, 129.7, 129.3, 128.4, 127.5, 127.2,
126.8, 120.1, 105.3, 105.2, 99.2, 95.0, 18.7, 18.6, 11.4, 11.3.
MS (EI): m/z (%) = 482/480/478 (30/70/30) [M+], 401/399 (40/45)
[M – Br]+, 217 (40), 193 (40), 165 (30).
UV/Vis (CHCl3): lmax (log e) = 387 (4.5), 403 nm (4.5).
MS (DEI): m/z (%) = 683 (10) [M + H+], 277 (75), 183 (100).
UV/Vis (CDCl3): lmax (log e) = 422 (4.5), 448 nm (4.6).
Emission (CHCl3): lmax = 473 nm.
Anal. Calcd for C21H12N4Br2: C, 52.53; H, 2.50; N, 11.67. Found:
C, 52.24; H, 2.68; N, 11.72.
2-Phenyl-4-(2-bromophenyl)-8-bromo-4H-imidazo[4,5-b]quin-
oxaline (3l)
Yield: 97%; yellow crystals; mp 377 °C (dec).
1H NMR (400 MHz, DMSO-d6): d = 8.44 (m, 2 H, CH-Ph), 8.16–
8.09 (m, 2 H, CH-Ar), 7.93–7.76 (m, 3 H, CH-Ar), 7.67–7.56 (m,
4 H, CH-Ar), 7.20 (m, 1 H, CH-Ar).
Anal. Calcd for C43H54N4Si2: C, 75.61; H, 7.97; N, 8.26. Found: C,
75.14; H, 7.55; N, 7.95.
2-Phenyl-4-(4-phenylethynylphenyl)-6-phenylethynyl-4H-imi-
dazo[4,5-b]quinoxaline (3q)
Yield: 93%; yellow crystals; mp 218 °C.
13C NMR (100 MHz, DMSO-d6): d = 182.7 (C-2), 162.5, 148.2,
135.1, 135.0, 134.5, 133.6, 133.3, 132.8, 130.5, 130.4, 129.9, 129.8,
129.5, 129.0, 128.5, 125.1, 121.0, 117.0.
MS (EI): m/z = 482/480/478 (6/13/7) [M+], 402/401/399 (3/13/14),
217 (43), 103 (22).
1H NMR (400 MHz, CDCl3): d = 8.59 (m, 2 H, CH-Ph), 8.32 (d,
J = 8 Hz, 1 H, CH-8), 7.94 (d, J = 8 Hz, 2 H, CH-Ar), 7.77–7.37 (m,
17 H, CH-Ar).
13C NMR (100 MHz, CDCl3): d = 162.1, 137.7, 134.7, 133.5, 133.1,
132.8, 132.7, 132.1, 132.0, 131.8, 131.0, 130.1, 128.9, 128.5, 128.4,
127.8, 126.1, 124.1, 122.6, 122.3, 119.2, 93.0, 92.1, 88.6, 87.9.
Anal. Calcd for C21H12N4Br2: C, 52.53; H, 2.50; N, 11.67. Found:
C, 52.19; H, 2.27; N, 11.42.
MS (DEI): m/z (%) = 522 (78) [M+], 521 (90) [M – H+], 277 (100),
2-Phenyl-4-(3-trifluoromethylphenyl)-7-trifluoromethyl-4H-
imidazo[4,5-b]quinoxaline (3m)
Note: the isomeric 5-trifluoromethyl derivative was only detected in
261 (30).
UV/Vis (CHCl3): lmax (log e) = 410 (4.6), 428 nm (4.6).
Emission (CHCl3): lmax = 483 nm; lmax = 502 nm.
trace amounts (TLC).
Anal. Calcd for C37H22N4: C, 85.04; H, 4.24; N, 10.72. Found: C,
84.59; H, 4.01; N, 10.42.
Yield: 71%; yellow crystals; mp 252 °C.
1H NMR (400 MHz, CDCl3): d = 8.57 (d, J = 2 Hz, 1 H, CH-8), 8.48
(m, 2 H, CH-Ph), 8.07–7.92 (m, 4 H, CH-Ar), 7.75 (dd, J = 8 Hz,
J = 2 Hz, 1 H, CH), 7.55–7.53 (m, 1 H, CH-Ph), 7.47–7.39 (m, 3 H,
CH-5).
X-ray Crystal Structure Determination for 3d
The intensity data for the compound was collected on a Nonius
Kappa CCD diffractometer, using graphite-monochromated Mo-Ka
radiation. Data were corrected for Lorentz and polarization effects,
but not for absorption effects.24 The structure was solved by direct
methods (SHELXS),25 and refined by full-matrix least squares tech-
niques against Fo2 (SHELXL-97).26 The hydrogen atoms for the
molecule were located by difference Fourier synthesis and refined
isotropically. Only the hydrogen atoms of the 6-methyl group were
included at calculated positions with fixed thermal parameters. All
other hydrogen atoms were included at calculated positions with
fixed thermal parameters. All non-hydrogen atoms were refined
anisotropically.26 XP (SIEMENS Analytical X-ray Instruments,
Inc.) was used for structure representations.
13C NMR (100 MHz, CDCl3): d = 183.8 (C-2), 162.7, 148.7, 137.0,
2
2
135.7, 133.5, 133.3 (q, J = 32 Hz, CCF3), 133.0 (q, J = 32 Hz,
3
CCF3), 132.4, 131.4, 130.3, 129.1, 128.7, 128.1, 127.8 (q, J = 4
3
3
Hz), 127.5, 125.0 (q, J = 4 Hz), 124.9 (q, J = 4 Hz), 123.5 (q,
1J = 270 Hz), 123.2 (q, 1J = 270 Hz), 117.1.
19F NMR (188 MHz, CDCl3): d = –62.4 (s, 3 F), –63.1 (s, 3 F).
MS (EI): m/z (%) = 458 (100) [M+], 439 (10) [M – F]+, 389 (80) [M
– CF3]+, 229 (60), 145 (80).
UV/Vis (CDCl3): lmax (log e) = 378 nm (4.6).
Emission (CHCl3): lmax = 492 nm.
CCDC-735167 (for 3d) contains the supplementary crystallograph-
ic data for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/conts/retrieving.html [or from the Cambridge
Crystallographic Data Centre, 12, Union Road, Cambridge CB2
1EZ, UK; fax: +44(1223)336033; or deposit@ccdc.cam.ac.uk].
Anal. Calcd for C23H12F6N4: C, 60.27; H, 2.64; N, 12.22. Found: C,
60.01; H, 2.43; N, 12.42.
2-Phenyl-4-[3,5-bis(trifluoromethyl)phenylamino]-5,7-bis(tri-
fluoromethyl)-4H-imidazo[4,5-b]quinoxaline (3n)
MS (EI): m/z (%) = 595/594 (50/100) [M+], 575 (10) [M – F]+, 526/
525 (20/90) [M – CF3]+, 300 (90), 229 (60), 213 (50).
X-ray Crystal Data for 3d
Empirical formula: C23H18N4; Mr = 350.41 gmol–1; yellow prism;
crystal size 0.05 × 0.05× 0.05 mm3; monoclinic; space group P21/n;
unit cell dimensions: a = 9.0370(4) Å, b = 12.2704(6) Å,
c = 15.6333(5) Å, b = 94.637(3)°; V = 1727.86(13) Å3; T = –90 °C;
Z = 4; rcalcd. = 1.347 g/cm3; m(Mo-Ka) = 0.82 cm–1; F(000) = 736;
12078 reflections in h(–11/11), k(–15/15), l(–20/20), measured in
Sonogashira Cross-Coupling Reaction with 3k; General Proce-
dure
To a suspension of 4H-imidazo[4,5-b]quinoxaline 3k (2 mmol),
Pd(PPh3)2Cl2 (73 mg, 0.1 mmol), Ph3P (55 mg, 0.2 mmol) and CuI
(20 mg, 0.1 mmol) in degassed toluene, was added the correspond-
Synthesis 2009, No. 23, 4049–4057 © Thieme Stuttgart · New York

PAPER
Imidazo[4,5-b]Quinoxalines by a Simple Oxidation–Annulation Sequence
4057
the range 2.11° £ Q £ 27.47°, completeness Qmax = 99.7%, 3947 in-
dependent reflections, Rint = 0.0447, 2774 reflections with Fo
(14) (a) Blumhoff, J.; Beckert, R.; Walther, D.; Rau, S.; Rudolph,
M.; Görls, H.; Plass, W. Eur. J. Inorg. Chem. 2007, 481.
(b) Blumhoff, J.; Beckert, R.; Rau, S.; Losse, S.; Matschke,
M.; Günther, W.; Görls, H. Eur. J. Inorg. Chem. 2009, 2162.
(15) (a) Gebauer, T.; Beckert, R.; Weiß, D.; Knop, K.;
Käpplinger, C.; Görls, H. Chem. Commun. 2004, 1860.
(b) Matschke, M.; Beckert, R. Molecules 2007, 12, 723.
(16) (a) Matschke, M.; Käpplinger, C.; Weiß, D.; Beckert, R.
Tetrahedron Lett. 2005, 8249. (b) Matschke, M.;
Käpplinger, C.; Beckert, R. Tetrahedron 2006, 62, 8586.
(c) Matschke, M.; Blumhoff, J.; Beckert, R. Tetrahedron
2008, 7815.
>4s(Fo); 305 parameters,
0
restraints, R1obs = 0.0495,
wR2obs = 0.1184, R1all = 0.0796, wR2all = 0.1334, GOOF = 1.034,
largest difference peak and hole: 0.306/–0.269 e Å–3.
Acknowledgment
We are grateful to the Friedrich Schiller University Jena for finan-
cial support of the work of G. Buehrdel by a grant. E.-U.W. thanks
Prof. Hans J. Schäfer, Münster, for helpful discussions.
(17) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J. R.; Montgomery, J. A. Jr.;
Vreven, T.; Kudin, K. N.; Burant, J. C.; Millam, J. M.;
Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi,
M.; Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.;
Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.;
Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.;
Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.;
Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.;
Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.;
Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.;
Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V.
G.; Dapprich, S.; Daniels, A. D.; Strain, M. C.; Farkas, O.;
Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman,
J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.;
Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.;
Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith,
T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.;
Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen, W.;
Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian 03,
Revision C.02; Gaussian, Inc.: Wallingford CT, 2004,
Details of the quantum chemical calculations may be
obtained from E.-U. Würthwein upon request..
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Synthesis 2009, No. 23, 4049–4057 © Thieme Stuttgart · New York