Synthesis of thieno[2,3-b]quinoxalines and pyrrolo[1,2-a]-quinoxalines from 2-haloquinoxalines

Article abstract of DOI:10.1039/b101458g

The palladium(0)-catalysed coupling of 2-haloquinoxalines with functionally substituted alkynes, addition of one mol equivalent of bromine to the 2-alkynylquinoxalines thus produced and then reaction of the resulting dibromides with disodium trithiocarbon

Full text of DOI:10.1039/b101458g

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Synthesis of thieno[2,3-b]quinoxalines and pyrrolo[1,2-a]-
quinoxalines from 2-haloquinoxalines
Montserrat Armengol and John A. Joule*
1
Department of Chemistry, The University of Manchester, Manchester, UK M13 9PL
Received (in Cambridge, UK) 14th February 2001, Accepted 20th March 2001
First published as an Advance Article on the web 10th April 2001
The palladium(0)-catalysed coupling of 2-haloquinoxalines with functionally substituted alkynes, addition of one
mol equivalent of bromine to the 2-alkynylquinoxalines thus produced and then reaction of the resulting dibromides
with disodium trithiocarbonate produced 2-hydroxymethyl- and 2-(diethoxymethyl)thieno[2,3-b]quinoxalines.
Addition of bromine to some 6-substituted-2-(3,3-diethoxypropyn-1-yl)quinoxalines gave pyrrolo[1,2-a]quinoxalines.
Treatment of a 3-(1,2-dibromoalkenyl)quinoline, a 3-(1,2-dibromoalkenyl)pyrazine, and a 5-(1,2-dibromoalkenyl)-
pyrimidine with disodium trithiocarbonate failed to induce thiophene ring formation.
Introduction
We have previously described1 a route (Scheme 1) to thieno-
[2,3-b]quinoxalines in which a 2-haloquinoxaline is cross-
coupled with an alkyne, one mole of bromine is added across
the triple bond and the resulting 1,2-dibromoalkene reacted
with disodium trithiocarbonate2 resulting in a cyclising ring
closure to a thieno[2,3-b]quinoxaline with the loss of both
bromine atoms. We have shown that the process works well for
simple alkyl- and a range of aryl-alkynes, resulting in the
2,6-Dichloroquinoxaline3 1c was coupled with propargyl
corresponding 2-substituted heterocycles, and discussed the
alcohol tetrahydropyranyl ether4 giving 2c and this was reacted
with bromine. We were surprised to find that the two stereo-
isomeric products each contained three bromine atoms—two
had added as usual to the triple bond but a third had been
incorporated elsewhere. 1H-NMR analysis showed that the
benzene ring still had three protons and thus the third bromine
had to reside on the protecting group. Consideration of the
possible mechanism whereby a bromine atom could have
become incorporated into the tetrahydropyran ring (via a ring-
opened enol ether), the presence of signals for only four protons
at δ < 2.10, and the observation that the tetrahydropyran C-2
proton was now a clear doublet (in one of the stereoisomers)
lead us to suggest structure 3b for these products. A search of
the literature shows that this bromination of a tetrahydro-
pyranyl ether is unprecedented. Reaction of the 1,2-dibromo-
alkenes 3b with disodium trithiocarbonate brought about the
desired ring-closure and formation of 4a, aqueous acidic
hydrolysis of which produced the alcohol 4b.
mechanism for the transformation.1 In this paper we describe
our further studies into the generality of the thiophene
ring-closing process, the synthesis of thieno[2,3-b]quinoxalines
with functionalised 2-alkyl side-chains, and the synthesis of
pyrrolo[1,2-a]quinoxalines.
Scheme 1
At a higher oxidation level, we were unable to cross-couple
methyl propiolate with 2-iodoquinoxaline and so resorted to
using an ortho ester as surrogate. Coupling 3,3,3-triethoxy-
propyne5 with 2-chloroquinoxaline gave 2d and brief treatment
with toluene-p-sulfonic acid monohydrate converted this into
the ester 2e. Addition of bromine to this was unexceptional,
producing a mixture of double bond isomers 3c, however on
attempted thieno[2,3-b]quinoxaline formation, the reaction in
methanol solution took an alternative course and 1,3-dithiole-
3-thione 5, as a mixture of methyl and ethyl esters, was formed
efficiently. One can speculate that the Michael-type trithio-
carbonate addition to this alkene, which is believed to be the
initiating step in the thieno[2,3-b]quinoxaline synthesis,1 is in
this case governed by conjugation to the ester (rather than the
ring imine) preventing the sequence which leads to the tricycle
and allowing the alternative mode of reaction.6
Results and discussion
Our route (Scheme 1) to thieno[2,3-b]quinoxalines begins with
the construction of a 2-alkynylquinoxaline 2 by a cross-
coupling reaction for which 2-chloro- or 2-iodoquinoxalines 1
can be used.1 Coupling 2-iodoquinoxaline 1b with propargyl
alcohol (prop-2-ynyl alcohol) produced 2a but attempted
addition of bromine did not proceed smoothly and the
complex mixture of products obtained was not further exam-
ined. Since it seemed likely that the alcohol function was
responsible for the complexity of the product mixture, it was
protected as a benzoate 2b and then bromine addition pro-
ceeded smoothly giving 3a. However attempted application of
the (basic) ring-closing conditions again led to complex
mixtures—clearly the choice of an ester for protection was not
well advised.
978
J. Chem. Soc., Perkin Trans. 1, 2001, 978–984
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b101458g

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Scheme 3
as shown in Scheme 3, thus addition of bromine gives typically
the trans product, which is in equilibrium via a tautomer with
the cis isomer; ring-closure of the cis isomer then loss of
ethanol provides the observed tricyclic product.
It seemed extraordinary that the presence of an apparently
remote chlorine substituent should influence the course of the
reaction between the alkynyl acetal 2g and its unsubstituted
prototype, 2f. Accordingly we decided to prepare an altern-
atively 6-substituted quinoxalinylalkyne and examine its reac-
tion with bromine. The interaction of 1,2-diaminobenzenes
with glyoxylic acid esters is well known to give rise to
quinoxalin-2(1H)-ones, and these in turn can be transformed
into the corresponding 2-haloquinoxalines suitable for coup-
ling; unsymmetrically substituted 1,2-diaminobenzenes give
mixtures of quinoxalinone regioisomers. The use of glyoxylic
acid, instead of the ester, with 4-substituted 1,2-diamino-
benzenes was shown to produce a larger proportion of the
6-substituted-quinoxalin-2(1H)-one.7 The reaction between
1,2-diamino-4-methoxybenzene and butyl glyoxylate gave a
mixture of the quinoxalin-2(1H)-ones which were converted
into the chlorides and these were separated by fractional
crystallisation; the identities of these two halides have not been
established.8 We repeated the ring synthesis with this diamine,
but using glyoxylic acid, and obtained a mixture of methoxy-
quinoxalin-2(1H)-ones, richer in one isomer than the other.
The mixture was converted into the chlorides, from which pure
samples of the major and the minor halides could be isolated by
chromatography. On the basis of the earlier work,7 we assign
to the major halide structure 1d while the less abundant halide
is 1e.
Each of these halides was separately coupled with 3,3-
diethoxypropyne giving 2h and 2i respectively and these were
then treated with bromine. In analogy with the reaction
observed with the 6-chloro-alkyne 2g, 2h was transformed into
a pyrrolo[1,2-a]quinoxaline; early experiments made it clear
that a third bromine atom was being incorporated into the
product so 2 mole equivalents were used and the product 6b was
isolated in high yield, the position of the benzene ring halogen
following from the 1H-NMR spectrum of the product. The
isomer 2i on the other hand did not produce a pyrrolo-
quinoxaline, but simply a mixture containing straightforward
bromine adducts, one with the acetal intact and one with an
aldehyde, which were not fully characterised. The role of the
6-substituent remains something of a mystery until further
experiments can be carried out.
Working at an intermediate oxidation level, 2-iodoquin-
oxaline was coupled with 3,3-diethoxypropyne giving 2f,
addition of bromine then gave 3d and our standard ring-closing
conditions produced the diethyl acetal 4c of 2-formylthieno-
[2,3-b]quinoxaline. However, when the 6-chloro-analogue 2g
was prepared by a comparable cross-coupling and subjected to
bromine, a product C13H9Br2ClN2O was formed in which it was
evident that one ethoxy group had been lost while two bromine
atoms had been incorporated. Additionally, the typical
quinoxaline low field singlet signal was still present, though
shifted somewhat to a higher field at δ 8.68. To this product we
assigned structure 6a and confirmed this assignment by a
simple borohydride reduction when dihydro-derivative 7, an
N-arylpyrrole, was formed, lacking the quinoxaline singlet but
having a CH2NH system (Scheme 2).
We speculate that this pyrrolo[1,2-a]quinoxaline 6a is formed
Scheme 2
J. Chem. Soc., Perkin Trans. 1, 2001, 978–984
979

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Returning to the mechanism by which the thieno[2,3-b]-
quinoxalines are formed, we speculated that there may be two
essential criteria for a successful sequence: (1) there must be a
ring imine, in conjugation with the dibromoalkene, in order to
encourage correctly oriented dithiocarbonate addition and (2)
there must be another ring imine unit to encourage the intra-
molecular cyclising sulfur addition; both of these requirements
are satisfied in the quinoxaline series. We sought confirmation
of these ideas by preparing a quinoline analogue of the cyclis-
ation substrates, thus 3-bromoquinoline was coupled to give 8
and bromine was added to produce 9. On exposure of 9 to
disodium trithiocarbonate no reaction occurred at room tem-
perature and at reflux, only elimination to return the alkyne 8.
in parts per million downfield from tetramethylsilane. Peak
multiplicities are denoted by s (singlet), br s (broad singlet),
d (doublet), t (triplet), q (quartet) and m (multiplet) or by a
combination of these e.g. dd (double doublet), with coupling
constants (J) given in Hz. 13C-NMR spectra were recorded on
a Bruker AC 300 spectrometer operating at 75 MHz. Mass
spectra were recorded on a Fisons VG Trio 2000 for electron
impact (EI) and chemical ionization (CI) modes. Accurate mass
measurements were made on a Kratos Concept. Melting points
were recorded on a Reichert heated stage microscope and are
uncorrected. Petroleum ether refers to the fraction bp 40–60 ЊC.
Solutions were degassed by bubbling nitrogen for 10 min.
2-(3-Hydroxypropyn-1-yl)quinoxaline 2a
A mixture of 2-iodoquinoxaline (1.5 g, 5.8 mmol), propargyl
alcohol (0.4 ml, 6.9 mmol), bis(triphenylphosphine)-
palladium() chloride (100 mg, 0.14 mmol), copper() iodide
(50 mg, 0.26 mmol), and triethylamine (12 ml) was heated at
60 ЊC and under nitrogen for 6 h. After evaporation of the tri-
ethylamine, the residue was diluted with 1 M hydrochloric acid
and extracted with dichloromethane. The organic extract was
purified by column chromatography over silica gel, eluting with
ethyl acetate to afford 2-(3-hydroxypropyn-1-yl)quinoxaline 2a
(700 mg, 66%) as a yellow solid, mp 140–141 ЊC. 1H-NMR (300
MHz, CDCl3): δ 2.17 (t, J = 6.3 Hz, 1H), 4.67 (d, J = 6.3 Hz,
2H), 7.84 (m, 2H), 8.14 (m, 2H), 8.97 (s, 1H). 13C-NMR (300
MHz, CDCl3): δ 51.2, 82.9, 92.0, 129.0, 129.1, 130.6, 130.7,
138.7, 141.1, 141.9, 146.8. MS (CI): 185 (M + 1, 100%), 169 (48).
Calcd. for: C11H8N2O: 184.0636. HRMS: found: M+, 184.0635.
2-(3-Benzoyloxypropyn-1-yl)quinoxaline 2b
To a solution of 2-(3-hydroxypropyn-1-yl)quinoxaline 2a (100
mg, 0.55 mmol) in dichloromethane (5 ml) and triethylamine
(0.08 ml) at room temperature, benzoyl chloride (0.07 ml, 0.6
mmol) was added, under nitrogen. The mixture was stirred for
2 h. The reaction was quenched with aqueous saturated sodium
hydrogencarbonate and extracted with dichloromethane. The
combined organic extracts were dried and concentrated to give
a brown oil which was purified by flash column chromato-
graphy over silica gel, eluting with dichloromethane to give
2-(3-benzoyloxypropyn-1-yl)quinoxaline 2b (135 mg, 85%) as a
brown solid, mp 94–97 ЊC. 1H-NMR (300 MHz, CDCl3): δ 5.32
(s, 2H), 7.53 (m, 2H), 7.65 (m, 1H), 7.85 (m, 2H), 8.14 (m, 4H),
8.93 (s, 1H). 13C-NMR (300 MHz, CDCl3): δ 52.6, 83.8,
87.3, 128.4, 129.1, 129.8 (2 × C), 130.7 (2 × C), 133.3, 138.3,
141.1, 141.9, 146.8, 165.6. MS (CI): 289 (M + 1, 100%), 169
(52). Calcd. for: C18H12N2O2: 288.0898. HRMS: found: M+,
288.0893.
We then considered whether the benzenoid ring is an
essential component of the cyclising procedure and prepared
pyrazinylalkyne 109 and from it the dibromoalkene 11.
Exposure of this dihalide to the conditions which, in the quin-
oxaline series, lead to cyclisation resulted only in debromination
and a return to the pyrazinylalkyne 10; no thieno[2,3-b]pyrazine
was formed. Similarly, the pyrimidinylalkyne 1210 was prepared
and converted into dibromoalkene 13. For this substrate,
criterion (1) above is not met, though the double bond is
activated in an inductive sense in the required direction by the
electron-deficient heterocycle; criterion (2) is satisfied. However,
once again exposure to disodium trithiocarbonate resulted only
in debromination and a return to alkyne 12.
We conclude that the formation of thieno[2,3-b]quinoxalines
described previously1 and in this paper requires both imine
units and the fused benzene ring. The factor which allows
success is the retention of an aromatic ring during the cyclising
sequence in which the heterocyclic ring temporarily loses its
aromatic status.
(E)- and (Z)-2-(3-Benzoyloxy-1,2-dibromoprop-1-en-1-yl)-
quinoxaline 3a
A solution of bromine (0.12 ml, 2.3 ml) in dichloromethane (10
ml) was added dropwise to a stirred solution of 2-(3-benzoyl-
oxypropyn-1-yl)quinoxaline 2b (600 mg, 2.08 mmol) dissolved
in dichloromethane (25 ml). The resultant mixture was stirred
for 2 h at room temperature. Addition of aqueous sodium
metabisulfite and dichloromethane was followed by separation,
drying, and evaporation of the organic phase under reduced
pressure to give a brown oil. Purification of this by column
chromatography over silica gel, eluting with dichloromethane–
petroleum ether (8:2), gave the minor dibromoalkene 3a
Experimental
General
Thin layer chromatography was carried out on Merck silica gel
F254 0.255 mm plates, and spots were visualised, where
appropriate, by ultraviolet fluorescence at 254 or 297 nm. Flash
column chromatography was performed using Merck Kiesel gel
60 (230–400 mesh). Tetrahydrofuran was dried by distillation
from potassium–benzophenone; dichloromethane was dried by
distillation from calcium hydride. All other chemicals were
purified using standard procedures as required. Organic solu-
tions were dried over anhydrous magnesium sulfate. IR spectra
were recorded on an ATI Mattson Genesis Series FTIR
spectrometer and absorption data are given in cmϪ1. 1H-NMR
spectra were recorded on a Varian AC 300E NMR spectro-
meter operating at 300 MHz. All chemical shifts are reported
1
(assumed to be Z) (300 mg, 32%) as a brown gum. H-NMR
(300 MHz, CDCl3): δ 5.23 (s, 2H), 7.45 (m, 2H), 7.60 (m,
1H), 7.87 (m, 2H), 8.04 (m, 2H), 8.15 (m, 2H), 9.20 (s, 1H).
13C-NMR (300 MHz, CDCl3): δ 65.4, 125.0, 128.3, 129.1, 129.2,
129.4, 129.5, 129.7, 130.9, 131.7, 133.3, 140.7, 141.4, 145.3,
150.3, 165.4. MS (CI): 447, 449, 451 (M + 1, 50, 100, 50%), 289
(90), 169 (75). Calcd. for: C18H1279Br2N2O2: 446.9344. HRMS:
980
J. Chem. Soc., Perkin Trans. 1, 2001, 978–984

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found: M+, 446.9349. Eluting with dichloromethane gave the
major dibromoalkene 3a (assumed to be E) (460 mg, 49%) as a
white solid, mp 140–143 ЊC. 1H-NMR (300 MHz, CDCl3):
δ 5.55 (s, 2H), 7.47 (m, 2H), 7.65 (m, 1H), 7.90 (m, 2H), 8.20 (m,
4H), 9.05 (s, 1H). 13C-NMR (300 MHz, CDCl3): δ 66.7, 125.0,
128.3, 128.9, 129.4, 129.5, 129.7, 130.0, 130.9, 131.7, 134.3,
140.7, 141.5, 145.2, 150.1, 165.4. MS (CI): 447, 449, 451
(M + 1, 50, 100, 50%), 289 (40). Calcd. for: C18H1279Br2N2O2:
446.9344. HRMS: found: M+, 446.9344.
1.5 ml) was added to a hot solution of (E)-6-chloro-2-[1,2-
dibromo-3-(3-bromotetrahydropyran-2-yloxy)prop-2-en-1-yl]-
quinoxaline (E)-3b (320 mg, 0.69 mmol) in methanol (20 ml)
with stirring. The resulting solution was cooled to room tem-
perature and stirred for a further 1 h. After evaporation of the
methanol, water and dichloromethane were added. The organic
layer was separated, dried, and evaporated under reduced pres-
sure to give a red solid. Purification of this by column chrom-
atography over silica gel, eluting with dichloromethane, gave
thienoquinoxaline 4a (85 mg, 30%) as a yellow solid, mp 106–
108 ЊC. 1H-NMR (300 MHz, CDCl3): δ 1.52 (m, 1H), 1.90 (m,
2H), 2.40 (m, 1H), 3.57 (m, 1H), 3.95 (m, 2H), 4.76 (d, J = 4.4
Hz, 1H), 4.91 (d, J = 14.0 Hz, 1H), 5.06 (d, J = 14.0 Hz, 1H),
7.39 (s, 1H), 7.65 (dd, J = 2.3 and 9.1 Hz, 1H), 8.03 (d, J = 9.1
Hz, 1H), 8.06 (d, J = 2.3 Hz, 1H). 13C-NMR (300 MHz,
CDCl3): δ 23.0, 29.7, 48.3, 62.8, 65.3, 100.4, 119.7, 127.3, 130.3,
130.4, 135.0, 139.4, 140.1, 150.7, 151.6. MS (CI): 413, 415,
417 (M + 1, 75, 100, 35%), 335 (40), 235 (60). Calcd. for:
C16H1479Br35ClN2O2S: 412.9727. HRMS: found: (M + H)+,
412.9727.
6-Chloro-2-[3-(tetrahydropyran-2-yloxy)propyn-1-yl]quinoxaline
2c
To a degassed solution of 2,6-dichloroquinoxaline (1.5 g, 7.5
mmol) and 3-(tetrahydropyran-2-yloxy)prop-1-yne4 (1.1 g,
8.25 mmol) in acetonitrile (40 ml) and triethylamine (7.5 ml),
palladium() acetate (130 mg, 0.57 mmol), copper() iodide
(182 mg, 0.95 mmol), and triphenylphosphine (200 mg, 0.76
mmol) were added, under nitrogen. The mixture was heated at
60 ЊC for 4 h. After evaporation of the organic solvents, the
residue was diluted with water and extracted with dichloro-
methane. The dichloromethane extract was purified by column
chromatography over silica gel, eluting with petroleum ether–
diethyl ether (8:2) to give 6-chloro-2-[3-(tetrahydropyran-2-
yloxy)propyn-1-yl]quinoxaline 2c (1.29 g, 56%) as a pale yellow
coloured oil. 1H-NMR (300 MHz, CDCl3): δ 1.60–1.95 (m,
6H), 3.64 (m, 1H), 3.94 (m, 1H), 4.61 (d, J = 16.3 Hz, 1H), 4.66
(d, J = 16.3 Hz, 1H), 4.97 (apparent triplet, J = 3.4 Hz, 1H),
7.77 (dd, J = 2.3 and 9.0 Hz, 1H), 8.05 (d, J = 9.0 Hz, 1H), 8.13
(d, J = 2.3 Hz, 1H), 8.90 (s, 1H). 13C-NMR (300 MHz, CDCl3):
δ 18.8, 25.2, 30.1, 54.4, 61.9, 82.9, 90.6, 97.2, 128.1, 130.3,
131.6, 136.3, 138.9, 140.4, 141.1, 147.8. MS (EI): 305 (M+, 37Cl,
30), 303 (M+, 35Cl, 100). Calcd. for: C16H1535ClN2O2: 303.0900.
HRMS: found: M+, 303.0907.
7-Chloro-2-hydroxymethylthieno[2,3-b]quinoxaline 4b
A solution of 6-chloro-2-(3-bromotetrahydropyran-2-yloxy-
methyl)thieno[2,3-b]quinoxaline 4a (20 mg, 0.05 mmol) in
methanol (1 ml) was added to an aqueous solution of 4 M
hydrochloric acid with stirring. The solution was heated for a
further 24 h at 70 ЊC. The mixture was concentrated in vacuo
and then basified with sodium carbonate and extracted with
dichloromethane. The dichloromethane extract was purified by
column chromatography over silica gel, eluting with dichloro-
methane, giving 6-chloro-2-hydroxymethylthieno[2,3-b]quin-
oxaline 4b (6.5 mg, 52%) as a yellow solid. 1H-NMR (300 MHz,
d6-DMSO): δ 5.92 (s, 2H), 7.73 (s, 1H), 7.96 (dd, J = 2.3 and 9.0
Hz, 1H), 8.28 (d, J = 9.0 Hz, 1H), 8.31 (d, J = 2.3 Hz, 1H). MS
(CI): 251 (M + 1, 37Cl, 40%), 249 (M + 1, 35Cl, 100%), 235 (70).
(E)- and (Z)-6-Chloro-2-[1,2-dibromo-3-(3-bromotetrahydro-
pyran-2-yloxy)prop-1-en-1-yl]quinoxaline 3b
2-(3,3,3-Triethoxypropyn-1-yl)quinoxaline 2d
A solution of bromine (0.13 ml, 2.43 mmol) in dichloro-
methane (5 ml) was added dropwise to a stirred solution of
6-chloro-2-[3-(tetrahydropyran-2-yloxy)propyn-1-yl]quinoxaline
2c (700 mg, 2.3 mmol) dissolved in dichloromethane (15 ml).
The resultant mixture was stirred for 2 h at room temperature.
Addition of aqueous sodium metabisulfite and dichloro-
methane followed by separation, drying, and evaporation of the
organic phase under reduced pressure gave a brown oil. Purifi-
cation of this by column chromatography over silica gel, eluting
with dichloromethane, gave the major dibromoalkene 3b
(assumed to be E) as a brown oil (320 mg, 25%). 1H-NMR (300
MHz, CDCl3): δ 1.60 (m, 1H), 2.10 (m, 2H), 2.50 (m, 1H), 3.76
(m, 1H), 4.13 (m, 2H), 4.94 (m, 3H), 7.80 (dd, J = 2.2 and 8.8
Hz, 1H), 8.11 (d, J = 8.8 Hz, 1H), 8.18 (d, J = 2.2 Hz, 1H), 9.00
(s, 1H). 13C-NMR (300 MHz, CDCl3): δ 22.4, 29.2, 48.4, 62.4,
70.8, 100.2, 115.8, 123.2, 128.1, 130.7, 131.7, 137.0, 140.1,
141.8, 145.7, 152.0. MS (CI): 539, 541, 543, 545 (M + 1, 12, 29,
32, 20%), 385 (35), 383 (100), 381 (80), 303 (30). And the minor
dibromoalkene 3b (assumed to be Z) as a brown oil (220 mg,
To a degassed solution of 2-chloroquinoxaline (1 g, 6 mmol)
and 3,3,3-triethoxypropyne5 (1.13 g, 6.6 mmol) in acetonitrile
(14 ml) and triethylamine (7 ml), palladium() acetate (40 mg,
0.18 mmol), copper() iodide (69 mg, 0.36 mmol), and tri-
phenylphosphine (95 mg, 0.36 mmol) were added under nitro-
gen. The mixture was heated at 70 ЊC for 3 h. After evaporation,
the residue was diluted with aqueous sodium carbonate and
extracted with dichloromethane. The organic extract was puri-
fied by column chromatography over silica gel, eluting with
dichloromethane–ethyl acetate (1:1) to give 2-(3,3,3-tri-
ethoxypropyn-1-yl)quinoxaline 2d (1.7 g, 97%) as an orange oil.
1H-NMR (300 MHz, CDCl3): δ 1.34 (t, J = 7.1 Hz, 9H), 3.87
(q, J = 7.1 Hz, 6H), 7.82 (m, 2H), 8.18 (m, 2H), 8.95 (s, 1H).
13C-NMR (300 MHz, CDCl3): δ 14.83, 59.3, 81.9, 87.2, 109.0,
129.2, 129.3, 130.7, 130.8, 130.5, 141.8, 142.2, 147.1. MS (EI):
255 (MϪEtO, 100%), 227 (50), 181 (40).
Ethyl quinoxalin-2-ylpropiolate 2e
1
17%). H-NMR (300 MHz, CDCl3): δ 1.60 (m, 1H), 1.95 (m,
A mixture of the 2-(3,3,3-trimethoxypropyn-1-yl)quinoxaline
2d (4.8 g, 16 mmol), toluene-p-sulfonic acid monohydrate
(4.5 g, 24 mmol), and benzene was stirred at room temperature
for 1 h. The organic layer was separated and the aqueous layer
extracted with ether. The combined organic extracts were dried
and evaporated in vacuo to give a residue which was purified by
column chromatography over silica gel, eluting with petroleum
ether–ethyl acetate (8:2), to give ethyl quinoxalin-2-ylpropiolate
2H), 2.37 (m, 1H), 3.42 (m, 1H), 3.78 (m, 1H), 4.02 (m, 1H),
4.45 (d, J = 17.5 Hz, 1H), 4.65 (d, J = 17.5 Hz, 1H), 4.76
(d, J = 3.0 Hz, 1H), 7.82 (dd, J = 2.3 and 9.9 Hz, 1H), 8.07
(d, J = 9.0 Hz, 1H), 8.17 (d, J = 2.3 Hz, 1H), 9.09 (s, 1H).
13C-NMR (300 MHz, CDCl3): δ 22.3, 29.1, 48.1, 62.2, 68.7,
99.6, 114.9, 123.9, 128.1, 130.7, 132.0, 137.0, 139.4, 141.7,
146.1, 150.6. MS (CI): 539, 541, 543, 545 (M + 1, 8, 22, 29,
15%), 385 (30), 383 (100), 381 (70), 303 (50).
2e (2.8 g, 79%) as a yellow solid. IR (NaCl): 1717, 2341 cmϪ1
.
1H-NMR (300 MHz, CDCl3): δ 1.43 (t, J = 7.1 Hz, 3H), 4.39
(d, J = 7.1 Hz, 2H), 7.88 (m, 2H), 8.1 (m, 2H), 9.04 (s, 1H).
13C-NMR (300 MHz, CDCl3): δ 13.9, 62.6, 81.9, 82.3, 129.3,
129.5, 131.0, 131.6, 136.6, 141.9, 142.1, 146.9, 152.7. MS (CI):
7-Chloro-2-(3-bromotetrahydropyran-2-yloxymethyl)thieno-
[2,3-b]quinoxaline 4a
An aqueous solution of disodium trithiocarbonate2 (33%,
J. Chem. Soc., Perkin Trans. 1, 2001, 978–984
981

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227 (M + 1, 100%). Calcd. for: C13H10N2O2: 226.0742. HRMS:
found: M+, 226.0740.
(12 ml) was added dropwise to a stirred solution of 2-(3,3-
diethoxypropyn-1-yl)quinoxaline 2f (750 mg, 2.9 mmol) dis-
solved in dichloromethane (24 ml). The resultant mixture was
stirred over 2 h at room temperature. Addition of aqueous
sodium metabisulfite and dichloromethane followed by separ-
ation, drying, and evaporation of the organic phase under
reduced pressure gave an orange oil. Purification of this by
column chromatography with dichloromethane yielded 2-(1,2-
dibromo-3,3-diethoxypropen-1-yl)quinoxaline 3d (715 mg,
59%) as a pale yellow oil. 1H-NMR (300 MHz, CDCl3): δ 1.37
(t, J = 7.0 Hz, 6H), 3.77 (m, 2H), 3.90 (m, 2H), 5.67 (s, 1H),
7.82 (m, 2H), 8.19 (m, 2H), 9.00 (s, 1H). 13C-NMR (300 MHz,
CDCl3): δ 15.0, 63.3, 129.2, 129.5, 130.5, 130.9, 144.9. MS (CI):
415, 417, 419 (M + 1, 20, 30, 20%), 275 (100). Calcd. for:
C15H1679Br2N2O2: 414.9657. HRMS: found: M+, 414.9654.
Ethyl 2,3-dibromo-3-(quinoxalin-2-yl)prop-2-enoate 3c
A solution of bromine (0.18 ml, 3.6 mmol) in dichloromethane
(10 ml) was added dropwise to a stirred solution of ethyl
quinoxalin-2-ylpropiolate 2e (1 g, 3.3 mmol) dissolved in
dichloromethane (20 ml). The resultant mixture was stirred for
12 h at room temperature. Addition of aqueous sodium meta-
bisulfite and dichloromethane followed by separation, drying,
and evaporation of the organic phase under reduced pressure
gave an orange oil. Purification of this by column chromato-
graphy over silica gel, eluting with petroleum ether–diethyl
ether (8:1), gave the dibromoalkene 3c as a mixture of stereo-
isomers (822 mg, 64%) in a ratio of ca. 2:3, as a yellow oil. IR
1
(NaCl): 1732 cmϪ1. H-NMR (300 MHz, CDCl3): δ 0.98 (t,
2-(Diethoxymethyl)thieno[2,3-b]quinoxaline 4c
J = 7.1 Hz, 1.8H), 1.47 (t, J = 7.1 Hz, 1.2H), 4.10 (q, J = 7.1
Hz, 1.2H), 4.48 (t, J = 7.1 Hz, 0.8H), 7.88 (m, 2H), 8.18 (m,
2H), 9.07 (s, 1H). 13C-NMR (300 MHz, CDCl3): δ 13.5, 13.9,
62.7, 63.1, 116.1, 118.3, 119.1, 122.0, 128.4, 129.1, 129.2, 129.3,
129.6, 130.1, 130.8, 130.9, 131.0, 131.1, 131.3, 131.6, 141.6,
144.2, 144.2, 144.8, 163.2, 163.8. MS (CI): 385, 387, 389 (M+,
40, 80, 40%), 227 (100). Calcd. for: C13H1079Br2N2O2: 383.911.
HRMS: found: (M + H)+, 383.9111.
An aqueous solution of disodium trithiocarbonate2 (33%, 1.6
ml) was added to a solution of the 2-(1,2-dibromo-3,3-
diethoxypropen-1-yl)quinoxaline 3d (415 mg, 1 mmol) in
methanol (16 ml) with stirring. The resulting solution was
stirred for a further 2 h. After evaporation of methanol, the
residue was diluted with water and extracted with dichloro-
methane. The organic extract was dried, and evaporated under
reduced pressure to give a brown oil which was purified by
column chromatography over silica gel, eluting with dichloro-
methane to obtain 2-(diethoxymethyl)thieno[2,3-b]quinoxaline
4c (154 mg, 53%) as a yellow oil. 1H-NMR (300 MHz, CDCl3):
δ 1.23 (t, J = 7.0 Hz, 6H), 3.63 (m, 4H), 5.80 (s, 1H), 7.47 (s,
1H), 7.47 (m, 2H), 8.10 (m, 2H). 13C-NMR (300 MHz, CDCl3):
δ 15.0, 61.7, 98.7, 120.0, 128.4 (2 × C), 129.1 (2 × C), 140.1,
140.9, 150.6, 153.1, 156.5. MS (CI): 289 (M + 1, 100). Calcd.
for: C15H16N2O2S: 288.0932. HRMS: found: M+, 288.0928.
4-Ethoxycarbonyl-5-(quinoxalin-2-yl)-1,3-dithiole-2-thione 5 and
4-methoxycarbonyl-5-(quinoxalin-2-yl)-1,3-dithiole-2-thione
An aqueous solution of disodium trithiocarbonate2 (33%,
3.8 ml) was added to a hot solution of ethyl 2,3-dibromo-3-
(quinoxalin-2-yl)prop-2-enoate (1.5 g, 3.8 mmol) in methanol
(38 ml) with stirring. The resulting solution was cooled to room
temperature and stirred for a further 1 h. After evaporation of
methanol, the residue was diluted with water and extracted with
dichloromethane. The organic extract was dried, and evapor-
ated under reduced pressure to give a black solid. Purification
of this by column chromatography over silica gel, eluting with
dichloromethane, gave a red solid, which was recrystallised
from methanol to give a mixture of ethyl ester 5 and the corre-
sponding methyl ester (800 mg, 63%) in a ratio of ca. 3:2, as a
yellow solid. IR (NaCl): 1707, 1087 cmϪ1. 1H-NMR (300 MHz,
CDCl3): δ 1.28 (t, J = 7.1 Hz, 0.6 × 3H), 3.85 (s, 0.4 × 3H), 4.32
(J = 7.1 Hz, 0.6 × 2H), 7.90 (m, 2H), 8.17 (m, 2H), 9.20 (s, 1H).
13C-NMR (300 MHz, CDCl3): δ 13.8 (CH3CH2O), 53.4
(CH3O), 63.0 (CH3CH2O), 129.2, 129.5, 130.9, 131.5, 144.6.
MS (CI): 335 (M + 1, 45%), 321 (M + 1, 100%).
6-Chloro-2-(3,3-diethoxypropyn-1-yl)quinoxaline 2g
To a degassed solution of 2,6-dichloroquinoxaline (500 mg, 2.5
mmol) and 3,3-diethoxypropyne (0.42 ml,
3 mmol) in
acetonitrile (6.25 ml) and triethylamine (2.5 ml), palladium()
acetate (50 mg, 0.22 mmol), copper() iodide (70 mg, 0.36
mmol), and triphenylphosphine (80 mg, 0.30 mmol) were
added. The mixture was heated at 80 ЊC for 1 h 30 min. After
evaporation of the solvent the residue was diluted with water
and extracted with dichloromethane. The organic extract was
purified by column chromatography over silica gel, eluting with
petroleum ether–diethyl ether (6:4) to yield 6-chloro-2-(3,3-
diethoxypropyn-1-yl)quinoxaline 2g (500 mg, 70%) as a white
2-(3,3-Diethoxypropyn-1-yl)quinoxaline 2f
1
solid, mp 76–78 ЊC. H-NMR (300 MHz, CDCl3): δ 1.43 (t,
J = 7.0 Hz, 6H), 3.80 (m, 2H), 3.92 (m, 2H), 5.61 (s, 1H), 7.78
(dd, J = 2.2 and 9.0 Hz, 1H), 8.06 (d, J = 9.0 Hz, 1H), 8.14 (d,
J = 2.2 Hz, 1H), 8.98 (s, 1H). 13C-NMR (300 MHz, CDCl3):
δ 15.0, 61.4, 81.9, 88.9, 91.5, 128.1, 130.4, 131.8, 136.6, 138.4,
140.5, 141.3, 147.8. MS (CI): 293 (M + 1, 37Cl, 30), 291 (M + 1,
35Cl, 100), 216 (20). Calcd. for: C15H1535ClN2O2: 290.0822.
HRMS: found: M+, 290.0822. Calcd. for: C15H15ClN2O2: C,
61.97; H, 5.20; N, 9.64; Cl, 12.19%. Anal.: found: C, 62.11; H,
4.99; N, 9.58; Cl, 12.28%.
To a degassed solution of 2-iodoquinoxaline (500 mg, 1.9
mmol) and 3,3-diethoxypropyne (0.33 ml, 2.3 mmol) in
acetonitrile (4.6 ml) and triethylamine (2.3 ml), palladium()
acetate (13 mg, 0.057 mmol), copper() iodide (21 mg, 0.114
mmol), and triphenylphosphine (30 mg, 0.114 mmol) were
added under nitrogen. The mixture was heated at 80 ЊC for 1 h
30 min. After evaporation of organic solvents the residue was
diluted with water and extracted with dichloromethane. The
organic extract was purified by column chromatography over
silica gel, eluting with petroleum ether–diethyl ether (60:40) to
give 2-(3,3-diethoxypropyn-1-yl)quinoxaline 2f (398 mg, 82%)
as a yellow oil. 1H-NMR (300 MHz, CDCl3): δ 1.33 (t, J = 7.1
Hz, 6H), 3.75 (m, 2H), 3.91 (m, 2H), 5.62 (s, 1H), 7.82 (m, 2H),
8.11 (m, 2H), 8.95 (s, 1H). 13C-NMR (300 MHz, CDCl3): δ 15.0,
61.3, 100.2, 136.0, 82.2, 88.2, 91.5, 129.2, 129.3, 130.6, 130.7,
138.3, 141.1, 142.0, 147.0. MS (CI): 257 (M + 1, 25), 211 (100),
183 (65). Calcd. for: C15H16N2O2 + H, 257.1289. HRMS: found:
(M + H)+, 257.1293.
2,3-Dibromo-7-chloro-1-ethoxypyrrolo[1,2-a]quinoxaline 6a
A solution of bromine (0.5 ml, 1.03 mmol) in dry dichloro-
methane (2.5 ml) was added dropwise to a stirred solution of
6-chloro-2-(3,3-diethoxypropyn-1-yl)quinoxaline 2g (250 mg,
0.86 mmol) dissolved in dry dichloromethane (5 ml). The
resultant mixture was stirred for 2 h at room temperature under
nitrogen. Addition of aqueous sodium metabisulfite and
dichloromethane followed by separation, drying, and evapor-
ation of the organic phase, then purification by column chrom-
atography over silica gel, eluting with dichloromethane, and
then recrystallisation from ethanol gave the 2,3-dibromo-7-
2-(1,2-Dibromo-3,3-diethoxypropen-1-yl)quinoxaline 3d
A solution of bromine (0.16 ml, 3.2 mmol) in dichloromethane
982
J. Chem. Soc., Perkin Trans. 1, 2001, 978–984

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chloro-1-ethoxypyrrolo[1,2-a]quinoxaline 6a (200 mg, 58%) as
yellow needles, mp (dec.) 120 ЊC. 1H-NMR (300 MHz, CDCl3):
δ 1.60 (t, J = 7.1 Hz, 3H), 4.52 (q, J = 7.1 Hz, 2H), 7.52 (dd,
J = 2.3 and 9.0 Hz, 1H), 7.96 (d, J = 2.3 Hz, 1H), 8.48 (d,
J = 9.0 Hz, 1H), 8.68 (s, 1H). 13C-NMR (300 MHz, CDCl3):
δ 15.3, 71.6, 94.2, 97.2, 117.0, 117.2, 125.8, 127.5, 129.0, 131.0,
137.4, 141.9, 144.1. MS (CI): 403, 405, 407 (M + 1, 40, 100,
60%). Calcd. for: C13H979Br235ClN2O: 401.8771. HRMS: found:
M+, 401.8772. Calcd. for: C13H9Br2ClN2O: C, 38.60; H, 2.24; N,
6.93; Cl, 8.76; Br, 39.51%. Anal.: found: C, 38.67; H, 2.27; N,
6.85; Cl, 8.44; Br, 39.71%.
(200 mg, 1 mmol) and 3,3-diethoxypropyne (0.17 ml, 1.23
mmol) in acetonitrile (4 ml) and triethylamine (2 ml),
palladium() acetate (12 mg, 0.05 mmol), copper() iodide (14
mg, 0.05 mmol), and triphenylphosphine (20 mg, 0.1 mmol)
were added under nitrogen. The mixture was stirred under
nitrogen at 70 ЊC for 2 h. After evaporation, the residue was
diluted with aqueous sodium bicarbonate and extracted with
dichloromethane. The organic extract was purified by column
chromatography over silica gel, eluting with diethyl ether–
petroleum ether (1:1) to yield 6-methoxy-2-(3,3-diethoxy-
propyn-1-yl)quinoxaline 2h (167 mg, 57%) as a white solid. 1H-
NMR (300 MHz, CDCl3): δ 1.25 (t, J = 7.1 Hz, 6H), 3.75 (m,
2H), 3.90 (m, 2H), 4.02 (s, 3H), 5.60 (s, 1H), 7.37 (d, J = 2.7 Hz,
1H), 7.45 (dd, J = 2.7 and 9.2 Hz, 1H), 7.96 (d, J = 9.2 Hz, 1H),
8.85 (s, 1H). 13C-NMR (300 MHz, CDCl3): δ 15.0, 55.8, 61.2,
82.3, 87.3, 91.5, 106.5, 124.1, 130.2, 135.5, 138.2, 142.9, 147.1,
161.4. MS (CI): 287 (M + 1, 100%). Calcd. for: C16H18N2O3:
286.1317. HRMS: found: M+, 286.1313.
2,3-Dibromo-7-chloro-1-ethoxy-4,5-dihydropyrrolo[1,2-a]-
quinoxaline 7
A solution of 2,3-dibromo-7-chloro-1-ethoxypyrrolo[1,2-a]-
quinoxaline 6a (55 mg, 0.13 mmol) and sodium borohydride
(30 mg, 0.78 mmol) in tetrahydrofuran (3 ml) was stirred for 24 h
at room temperature. The solvent was removed under reduced
pressure and the residue was diluted with water and extracted
with dichloromethane to obtain the 2,3-dibromo-7-chloro-1-
ethoxy-4,5-dihydropyrrolo[1,2-a]quinoxaline 7 (45 mg, 85%) as
7-Methoxy-2-(3,3-diethoxypropyn-1-yl)quinoxaline 2i
To a degassed solution of 2-chloro-7-methoxyquinoxaline 1e
(47 mg, 0.24 mmol) and 3,3-diethoxypropyne (0.04 ml, 0.28
mmol) in acetonitrile (1 ml) and triethylamine (0.5 ml),
palladium() acetate (2.6 mg, 0.012 mmol), copper() iodide
(4.5 mg, 0.024 mmol), and triphenylphosphine (6.3 mg, 0.024
mmol) were added under nitrogen. The mixture was stirred
under nitrogen at room temperature overnight. After evapor-
ation, the residue was diluted with aqueous solution of sodium
bicarbonate and extracted with dichloromethane. The organic
extract was purified by column chromatography over silica
gel, eluting with diethyl ether–petroleum ether (1:1) to yield
7-methoxy-2-(3,3-diethoxypropyn-1-yl)quinoxaline 2i (46 mg,
1
yellow needles, mp (dec.) 140 ЊC (from methanol). H-NMR
(300 MHz, CDCl3): δ 1.31 (t, J = 7.1 Hz, 3H), 3.92 (br s, 1H),
4.62 (q, J = 7.1 Hz, 2H), 4.16 (s, 2H), 6.67 (d, J = 2.3 Hz,
1H), 6.71 (dd, J = 2.3 and 8.6 Hz, 1H), 7.73 (d, J = 8.6 Hz, 1H).
13C-NMR (300 MHz, CDCl3): δ 15.2, 39.9, 71.2, 86.3,
93.1, 115.4, 117.2, 118.5, 119.3, 123.5, 125.4, 130.3, 138.1.
MS (CI): 405, 407, 409 (M + 1, 45, 100, 45%). Calcd. for:
C13H1179Br2ClN2O: 403.8927. HRMS: found: M+, 403.8928.
Calcd. for: C13H11Br2ClN2O: C, 38.41; H, 2.73; N, 6.89%. Anal.:
found: C, 38.77; H, 2.41; N, 6.83%.
1
6- and 7-Methoxyquinoxalin-2(1H)-ones
67%) as a white solid. H-NMR (300 MHz, CDCl3): δ 1.33 (t,
J = 7.1 Hz, 6H), 3.76 (m, 2H), 3.91 (m, 2H), 4.02 (s, 3H), 5.62
(s, 1H), 7.37 (d, J = 2.7 Hz, 1H), 7.45 (dd, J = 2.7 and 9.2 Hz,
1H), 7.98 (d, J = 9.2 Hz, 1H), 8.80 (s, 1H). 13C-NMR (300
MHz, CDCl3): δ 15.0, 55.7, 61.3, 82.1, 87.9, 91.5, 106.2, 124.2,
130.0, 137.4, 138.1, 143.8, 144.5, 161.7. MS (CI): 287 (M + 1,
100%). Calcd. for: C16H18N2O3: M+, 86.1317. HRMS: found:
286.1314.
A solution of glyoxylic acid (3 g, 33.6 mmol) in water (12 ml)
was added dropwise to a stirred solution of 1,2-diamino-4-
methoxybenzene (3.3 g, 24 mmol) in methanol (6 ml) and acetic
acid (3 ml) at Ϫ15 ЊC. The reaction mixture was allowed to
warm to room temperature, and stirred for 1 h. A voluminous
precipitate was formed which was filtered and washed with
water and methanol. The resulting solid was recrystallised from
ethanol to afford a mixture of 6-methoxyquinoxalin-2(1H)-one
and 7-methoxyquinoxalin-2(1H)-one (2.1 g, 50%) as a brown
solid. MS (CI): 177 (M + 1, 100%).
2,3,6-Tribromo-1-ethoxy-7-methoxypyrrolo[1,2-a]quinoxaline
6b
A solution of bromine (0.036 ml, 0.7 mmol) in dry dichloro-
romethane (0.5 ml) was added dropwise to a stirred solution of
6-methoxy-2-(3,3-diethoxypropyn-1-yl)quinoxaline 2h (100 mg,
0.35 mmol) dissolved in dry dichloromethane (4 ml). The
resultant mixture was stirred for 2 h at room temperature
under nitrogen. Addition of aqueous sodium metabisulfite and
dichloromethane followed by separation, drying, and evapor-
ation of the organic phase under reduced pressure gave an
orange solid. Purification of this by recrystallisation from
ethanol gave the 2,3,6-tribromo-1-ethoxy-7-methoxypyrrolo-
[1,2-a]quinoxaline 6b (84 mg, 50%) as an orange solid, mp
2-Chloro-6-methoxyquinoxaline 1d and 2-chloro-7-methoxy-
quinoxaline 1e
A solution of 6- and 7-methoxyquinoxalin-2(1H)-ones (500
mg, 2.8 mmol) in phosphoryl chloride (20 ml) was heated at
reflux for 1 h. The reaction mixture was concentrated in vacuo
and then poured onto ice and basified with sodium carbonate.
The organic material was extracted with ethyl acetate. The
organic layer was washed with brine, dried, and evaporated
to give a mixture of 2-chloro-6-methoxy- and 2-chloro-7-
methoxyquinoxalines (300 mg, 55%) in a ratio of ca. 3:1 which
were separated by chromatography, eluting with petroleum
ether–ethyl acetate (95:5). 2-Chloro-6-methoxyquinoxaline: 1H-
NMR (300 MHz, CDCl3): δ 3.90 (s, 3H), 7.31 (d, J = 2.7 Hz,
1H), 7.37 (dd, J = 2.7 and 9.2 Hz, 1H), 7.82 (d, J = 9.2 Hz, 1H),
8.63 (s, 1H). 13C-NMR (300 MHz, CDCl3): δ 55.8, 106.7, 123.7,
124.2, 129.2, 130.4, 138.2, 142.7, 144.6. MS (CI): 197 (M + 1,
37Cl, 31%), 195 (M + 1, 35Cl, 100%). 2-Chloro-7-methoxy-
quinoxaline: 1H-NMR (300 MHz, CDCl3): δ 3.89 (s, 3H), 7.22
(d, J = 2.7 Hz, 1H), 7.33 (m, 1H), 7.91 (d, J = 9.2 Hz, 1H), 8.55
(s, 1H). MS (CI): 197 (M + 1, 37Cl, 31%), 195 (M + 1, 35Cl,
100%).
1
(dec.) 130 ЊC. H-NMR (300 MHz, CDCl3): δ 1.59 (t, J = 7.1
Hz, 3H), 4.0 (s, 3H), 4.48 (q, J = 7.1 Hz, 2H), 7.16 (d, J = 9.3
Hz, 1H), 8.55 (d, J = 9.3 Hz, 1H), 8.74 (s, 1H). 13C-NMR (300
MHz, CDCl3): δ 15.3, 56.8, 71.5, 94.0, 97.1, 102.3, 111.1, 115.3,
117.3, 122.0, 149.1, 144.2, 154.3. MS (CI): 477, 479, 481, 483
(M + 1, 30, 100, 98, 30%). Calcd. for: C14H1179Br3N2O2:
475.8372. HRMS: found: M+, 475.8370.
3-(4-Chlorophenylethynyl)quinoline 8
To a degassed solution of 3-bromoquinoline (500 mg, 2.4
mmol) and 4-chlorophenylacetylene (327 mg, 2.4 mmol) in
acetonitrile (10 ml) and triethylamine (5 ml), palladium()
acetate (27 mg, 0.12 mmol), copper() iodide (46 mg, 0.24
mmol), and triphenylphosphine (60 mg, 0.24 mmol) were added
6-Methoxy-2-(3,3-diethoxypropyn-1-yl)quinoxaline 2h
To a degassed solution of 2-chloro-6-methoxyquinoxaline 1d
J. Chem. Soc., Perkin Trans. 1, 2001, 978–984
983

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under nitrogen. The mixture was stirred under nitrogen at 80 ЊC
for 24 h. After evaporation, the residue was diluted with aque-
ous sodium bicarbonate and extracted with dichloromethane.
The organic extract was purified by column chromatography
over silica gel, eluting with dichloromethane. Recrystallisation
from methanol gave 3-(4-chlorophenylethynyl)quinoline 8 (315
mg, 50%) as a white solid, mp 130–132 ЊC. 1H-NMR (300 MHz,
CDCl3): δ 7.39 (d, J = 8.7 Hz, 2H), 7.55 (d, J = 8.7 Hz, 2H),
7.62 (m, 1H), 7.77 (m, 1H), 7.84 (m, 1H), 8.15 (d, J = 8.5 Hz,
1H), 8.34 (s, 1H), 9.03 (s, 1H). 13C-NMR (300 MHz, CDCl3):
δ 87.4, 91.3, 117.0, 121.0, 127.1, 127.2, 127.5, 128.7, 129.3,
130.1, 132.8, 134.8, 138.2, 146.8, 151.8. MS (CI): 266 (M + 1,
37Cl, 40%), 264 (M + 1, 35Cl, 100%). Calcd. for: C17H1035ClN:
263.0501. HRMS: found: M+, 263.0503. Calcd. for: C17H10ClN:
C, 77.42; H, 3.82; N, 5.31%. Anal.: found: C, 76.91; H, 3.73; N,
5.14%.
Hz, 3H), 1.51 (m, 2H), 1.75 (m, 2H), 2.94 (t, J = 6.8 Hz, 2H),
8.55 (br s, 1H), 8.66 (br s, 1H), 8.74 (br s, 1H). 13C-NMR (300
MHz, CDCl3): δ 13.8, 21.7, 29.3, 40.6, 143.6, 143.9, 145.5. MS
(CI): 319, 321, 323 (M + 1, 46, 85, 43%), 161 (100%). Calcd.
for: C16H1279BrN2 + H: 318.9446. HRMS: found: (M + H)+:
318.9450.
5-(Hex-1-yn-1-yl)pyrimidine 12
A mixture of 5-bromopyrimidine (2 g, 12.5 mmol), hex-1-yne
(1.4 ml, 25 mmol), bis(triphenylphosphine)palladium() chlor-
ide (263 mg, 0.37 mmol), copper() iodide (143 mg, 0.75 mmol)
and triethylamine (20 ml) was heated at 80 ЊC overnight under
nitrogen atmosphere. The residue was diluted with water and
extracted with dichloromethane and the organic extract was
washed with 1 M hydrochloric acid. Separation, drying and
evaporation of the organic phase under reduced pressure gave
an oil. Purification of this by column chromatography over
silica gel eluting with dichloromethane–ethyl acetate (95:5),
gave 5-(hex-1-yn-1-yl)pyrimidine 12 (1.85 g, 92%) as an orange
oil with spectroscopic data identical to those reported
previously.10
3-[1,2-Dibromo-2-(4-chlorophenyl)ethenyl]quinoline 9
A solution of bromine (0.10 ml, 2 mmol) in dichloromethane
(5 ml) was added dropwise to a stirred solution of 2-(4-chloro-
phenylethynyl)quinoline 8 (500 mg, 1.89 mmol) dissolved in
dichloromethane (11 ml). The resultant mixture was stirred for
4 h at room temperature. Addition of aqueous sodium meta-
bisulfite and dichloromethane followed by separation, drying,
and evaporation of the organic phase under reduced pressure
gave an orange solid. Purification of this by column chromato-
graphy over silica gel, eluting with dichloromethane, then
recrystallisation from methanol, gave the 3-[1,2-dibromo-2-(4-
chlorophenyl)ethenyl]quinoline 9 (536 mg, 68%) as white
5-(1,2-Dibromohex-1-en-1-yl)pyrimidine 13
A solution of bromine (0.17 ml, 3.41 mmol) in dichloro-
methane (6 ml) was added dropwise to a stirred solution of
5-(hex-1-yn-1-yl)pyrimidine 12 (500 mg, 3.4 mmol) dissolved in
dichloromethane (16 ml). The resultant mixture was stirred for
16 h at room temperature. Addition of aqueous sodium
metabisulfite and dichloromethane followed by separation,
drying, and evaporation of the organic phase under reduced
pressure gave a yellow oil. Purification of this by column
chromatography over silica gel, eluting with dichloromethane–
ethyl acetate (95:5), gave 5-(1,2-dibromohex-1-en-1-yl)-
1
crystals, mp 135–138 ЊC. H-NMR (300 MHz, CDCl3): δ 7.47
(d, J = 8.7 Hz, 2H), 7.57 (d, J = 8.7 Hz, 2H), 7.65 (m, 1H), 7.83
(m, 1H), 7.93 (d, J = 8.2 Hz, 1H), 8.20 (d, J = 8.5 Hz, 1H), 8.37
(s, 1H), 9.15 (s, 1H). 13C-NMR (300 MHz, CDCl3): δ 115.7,
119.5, 127.3, 128.1, 128.7, 130.4, 130.5, 135.1, 136.4, 138.5. MS
(CI): 422, 424, 425, 428 (M + 1, 14, 32, 22, 45%), 266 (32), 264
(100). Calcd. for: C17H1079Br235ClN: 420.8869. HRMS: found:
M+, 420.8862. Calcd. for: C17H10Br2ClN: C, 48.32; H, 2.14; N,
3.31; Cl, 8.39; Br, 37.82%. Anal.: found: C, 47.93; H, 2.33; N,
3.55; Cl, 8.12; Br, 37.17%.
1
pyrimidine 13 (839 mg, 84%) as a colorless oil. H-NMR (300
MHz, CDCl3): δ 1.04 (t, J = 7.2 Hz, 3H), 1.50 (m, 2H), 2.17
(m, 2H), 2.92 (t, J = 7.4 Hz, 2H), 8.79 (s, 2H), 9.18 (s, 1H).
13C-NMR (300 MHz, CDCl3): δ 13.8, 21.7, 29.4, 40.8, 108.6,
127.9, 156.9, 157.7 (2 × C). MS (CI): 319, 321, 323 (M + 1, 15,
20, 13%), 161 (100). Calcd. for: C10H1279Br2N2: 317.9368.
HRMS: found: M+: 317.9362.
2-(Hex-1-yn-1-yl)pyrazine 10
Acknowledgements
To a degassed solution of 2-chloropyrazine (1 g, 8.7 mmol) and
hex-1-yne (1 ml, 10.4 mmol) in acetonitrile (16 ml) and triethyl-
amine (8 ml), palladium() acetate (98 mg, 0.43 mmol),
copper() iodide (166 mg, 0.87 mmol), and triphenylphosphine
(288 mg, 0.87 mmol) were added under nitrogen. The mixture
was stirred under nitrogen at 80 ЊC for 4 h. After evaporation,
the residue was diluted with an aqueous solution of sodium
bicarbonate and extracted with dichloromethane. The organic
extract was purified by column chromatography over silica gel,
eluting with dichloromethane–ethyl acetate (95:5) to yield
2-(hex-1-yn-1-yl)pyrazine 10 (990 mg, 71%) as an orange oil
with spectroscopic properties identical with those reported
previously.9
The work described in this paper was made possible by funding
from the Nissan Chemical Company, Tokyo, Japan, through the
intermediacy of Dr Kenzi Makino of that company. We are
most grateful to the Nissan Chemical Company for financial
support and for a studentship (M. A.), and to Dr Makino for
his interest in this work and for many stimulating chemical
discussions throughout our collaboration.
References
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3 We thank the Nissan Chemical Company for a generous supply of
2,6-dichloroquinoxaline.
2-(1,2-Dibromohex-1-en-1-yl)pyrazine 11
4 R. W. Bates, D. Diez-Martin, W. J. Kerr, J. G. Knight, S. V. Ley and
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A solution of bromine (0.28 ml, 6.16 mmol) in dichloro-
methane (12 ml) was added dropwise to a stirred solution of
2-(hex-1-yn-1-yl)pyrazine 10 (900 mg, 5.6 mmol) dissolved in
dichloromethane (24 ml). The resultant mixture was stirred
for 3 h at room temperature. Addition of aqueous sodium
metabisulfite and dichloromethane followed by separation, dry-
ing, and evaporation of the organic phase under reduced pres-
sure gave an oil. Purification of this by column chromatography
over silica gel, eluting with dichloromethane–ethyl acetate
(95:5) gave the 2-(1,2-dibromohex-1-en-1-yl)pyrazine 10 (1.4 g,
78%) as an oil. 1H-NMR (300 MHz, CDCl3): δ 1.03 (t, J = 6.4
10 T. Studemann, M. Ibrahim-Ouaii and P. Knochel, Tetrahedron,
1998, 54, 1299.
984
J. Chem. Soc., Perkin Trans. 1, 2001, 978–984