Electrophilic cyclizations of 2,3-dialkynylquinoxalines and 1, 2-dialkynylbenzenes: A comparative study

Article abstract of DOI:10.1016/j.tet.2012.10.098

The reactivity of 2,3-dialkynylquinoxalines towards electrophiles (Br ₂, I₂, ICI, NBS, HBr) has been studied. All tested reactions, except one with HBr, start with the addition of an electrophile to the carbon-carbon triple bond that promotes further 5-exo-dig carbocyclization ultimately yielding a mixture of stereoisomeric cyclopenta[b]quinoxaline derivatives. The nature of substituents on the C=C bonds of the starting molecule influence the stereochemical result of the reaction. The ratio of isomeric cyclization products also depends on the electrophile used. ortho-Dialkynylbenzenes and ortho-dialkynylquinoxalines demonstrate rather similar reactivity towards halogen electrophiles, but differ in their reactions with hydrobromic acid, which is caused by the basic nature of the aza group of the quinoxaline substrate.

Full text of DOI:10.1016/j.tet.2012.10.098

Tetrahedron 69 (2013) 910e917
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Electrophilic cyclizations of 2,3-dialkynylquinoxalines and
1,2-dialkynylbenzenes: a comparative study
*
Anna V. Gulevskaya , Roman Yu Lazarevich, Alexander F. Pozharskii
Department of Organic Chemistry, Southern Federal University, Zorge 7, Rostov-on-Don 344090, Russian Federation
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 24 July 2012
Received in revised form 17 September 2012
Accepted 5 October 2012
Available online 12 November 2012
The reactivity of 2,3-dialkynylquinoxalines towards electrophiles (Br2, I2, ICl, NBS, HBr) has been studied.
All tested reactions, except one with HBr, start with the addition of an electrophile to the carbonecarbon
triple bond that promotes further 5-exo-dig carbocyclization ultimately yielding a mixture of stereo-
isomeric cyclopenta[b]quinoxaline derivatives. The nature of substituents on the C^C bonds of the
starting molecule influence the stereochemical result of the reaction. The ratio of isomeric cyclization
products also depends on the electrophile used. ortho-Dialkynylbenzenes and ortho-dialkynylquinoxa-
lines demonstrate rather similar reactivity towards halogen electrophiles, but differ in their reactions
with hydrobromic acid, which is caused by the basic nature of the aza group of the quinoxaline substrate.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Enediynes
Electrophilic cyclizations
2,3-Dialkynylquinoxalines
Cyclopenta[b]quinoxalines
1. Introduction
radicals (Scheme 2, A),4 nucleophiles (Scheme 2, B),5 transition
metal complexes (Scheme 2, C),6 frustrated Lewis pair (Scheme 2,
Alkynes find ever-increasing use in synthetic organic and ma-
terial chemistry.1 One prominent group of alkynes is enediynes,
because of the presence of the (Z)-hexa-3-en-1,5-diyne fragment in
some naturally occurring antibiotics.2 It is supposed that the anti-
tumour and antibacterial activity of enediyne antibiotics is based
on the Bergman cyclization,3 which generates benzene-1,4-
diradicals (Scheme 1), which are able to cleave DNA and rupture
the protein structure via oxidative cleavage of the peptide bond.
D)7 and so on. In addition, substituents at the alkyne termini can
also be involved in the cyclization process leading to polynuclear
products (Scheme 2, E and F).8,9
Despite significant recent advances in this area, the synthetic
potential of enediynes seems to be underestimated. To date, most of
the research on the above cyclizations deals with acyclic and ben-
zoannelated enediynes as substrates. Unfortunately, there are only
a few reports on the reactivity of ortho-dialkynyl hetarenes. There is
no doubt that the enediyne moiety incorporated into the hetero-
cyclic skeleton may possess a reactivity that is more diverse than
that of acyclic and benzofused counterparts. It may create a new
opportunity for the synthesis of polynuclear heterocyclic
compounds.
Recently, we reported several nucleophilic cyclizations of 2,3-
dialkynylquinoxalines and some other condensed pyrazines.10 It
has been found that their reactivity towards nucleophiles differs
from that of acyclic enediynes and ortho-dialkynylbenzenes. Due to
Scheme 1.
The challenging chemical structures of enediyne antibiotics and
their fascinating mode biochemical action have attracted consid-
erable scientific attention.2f Most of the work on enediyne chem-
istry is focused on the synthesis of designed enediynes, their
thermal reactivity modulation and anticancer activity evaluation.
Meanwhile, besides thermal or photochemical Bergman reaction,
cyclizations of enediynes can be induced by various reagents:
the high
p-deficiency of the azine ring, ortho-dialkynylpyrazines
react readily even with neutral nucleophiles and undergo un-
prompted or base-induced cascade cyclizations with direct partic-
ipation of the added nucleophile and the aza group.
The revealed specificity in the reactivity of ortho-dialkynylpyr-
azines encouraged us to turn our attention to electrophilic cycli-
zations of heterocyclic enediynes. Herein, we present reactions of
2,3-dialkynylquinoxalines with electrophiles (Br2, I2, ICl, NBS and
HBr) and compare them with those of ortho-dialkynylbenzenes.
* Corresponding author. Tel.: þ7 863 297 5146; fax: þ7 863 297 5151; e-mail
addresses: agulevskaya@sfedu.ru, anvasgul@gmail.com (A.V. Gulevskaya).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.10.098

A.V. Gulevskaya et al. / Tetrahedron 69 (2013) 910e917
911
2 in the reaction products was attributed to the sterically less
hindered attack of the bromide ion on the cation 4. Subsequently,
another mechanism was proposed, based on DFT calculations.11d
According to this, the electrophilic cyclization of 1 to give 2 can
be rationalized by the formation of the stabilized cation 6 (Scheme
4, route B). The cyclization to give an aromatic six-membered ring
(6-endo-dig cyclization) would yield a highly unfavourable naph-
thyl cation. The bromovinyl cation 5 is a true minimum (at B3LYP6-
31G*) with a classic, nonbridging structure.
Scheme 4.
It should be noted that there are no data on the effect of the
alkyne substituents on the cyclization process. Meanwhile, in both
articles5b,11d the formation of a resonance-stabilized carbenium ion
6 as an intermediate is emphasized.
With this in mind, we synthesized 2,3-dialkynylquinoxalines
7aed, with various substituents (Ph, p-Tol, n-Bu, SiMe3) on the
C^C bond, via a Sonogashira coupling in accordance with reported
procedures.10b
The reaction of 2,3-bis(phenylethynyl)quinoxaline 7a with bro-
mine in dry chloroform at room temperature in the dark afforded
a mixture of isomeric 3-bromo-1-(bromo(phenyl)methylene)-2-
phenyl-1H-cyclopenta[b]quinoxalines 8a and 9a in nearly quanti-
tative total yield and in a 2.6:1 ratio (1H NMR spectroscopic data)
(Scheme 5, Table 1, entry 1). Flash column chromatography and
subsequent recrystallization gave pure product 8a. Compound 7b
reacted with bromine in a completely analogous manner (Scheme 5,
Table 1, entry 1).
Scheme 2.
2. Results and discussion
Only limited studies on the electrophilic cyclizations of ene-
diynes have been reported. In the majority of studies, benzoanne-
lated enediynes have been used as substrates.5b,11 There are no data
on the reactivity of acyclic and heterocyclic12 enediynes.
The reaction of 1,2-bis(phenylethynyl)benzene with bromine
was reported to produce isomeric benzofulvene derivatives 2 and 3
in a w4:1 ratio (Scheme 3).5b,11a,11d Reactions of 1 with other
electrophiles (I2, HBr, H2SO4) proceeded in analogous manner.5b
Scheme 5.
Scheme 3.
The reaction of 7a with iodine in chloroform proceeded gave
only traces of the desired product. The use of nitromethane as the
solvent gave a better result (Scheme 5, Table 1, entry 3). The X-ray
crystal structure of the major reaction product 8c supported the
In the original work,11a,5b a concerted mechanism of electro-
philic additiond5-exo-dig cyclization for this transformation was
proposed (Scheme 4, route A). The predominance of the (E)-isomer

912
A.V. Gulevskaya et al. / Tetrahedron 69 (2013) 910e917
The 1H NMR spectra of the aryl substituted products 8aed and
9aed provided a highly satisfactory method of defining their ste-
reochemistry. In the 1H NMR spectra of products 8aed, the protons
corresponding to the two aryl groups were seen as multiplets at
Table 1
Halogen-promoted electrophilic cyclizations of 2,3-dialkynylquinoxalines
Entry
R
Eþ Xꢀ
Solvent,
reaction time
8:9 Ratio
(NMR data)
Yield (%)
1
2
3
4
5
6
Ph
Br2
Br2
I2
CHCl3
2 h
CHCl3
2 h
CH3NO2
24 h
CHCl3
24 h
CHCl3
20 h
CHCl3
20 h
2.6:1
2.6:1
2.8:1
1.5:1
d
64 (8a)
63 (8b)
59 (8c)
d
6.7e7.2 ppm, while those of 9aed were seen as multiplets at
7.4e7.7 ppm (Fig. 3).
2,3-Dialkynylquinoxalines 7c,d bearing non-aromatic sub-
d
p-Tol
Ph
stituents on the C^C bonds are also able to react with bromine in
chloroform, although extended reaction times are required
(Scheme 5, Table 1, entries 5 and 6). In both cases, the isomer 9 was
the only reaction product.
The structural assignment for compound 9e, apart from ele-
mental analysis, was based on the following evidence. The IR and
13C NMR spectra reveal the absence of the C^C bond in this mol-
ecule. For comparison, in the 13C NMR spectrum of the starting
compound 7c the C^C bond carbons manifest themselves as peaks
Ph
ICl
Br2
Br2
45 (8d)
31 (9d)
73 (9e)
n-Bu
SiMe3
d
57 (9f)
at
peaks at
d
79.0 and 98.2 ppm. In the 13C NMR spectrum of 9e eight upfield
structural assignment (Fig. 1). The peripheral phenyl groups are
coplanar to each other with a separation between their centroids of
about 3.54 A and are perpendicular to the fully conjugated cyclo-
d
14e40 ppm (sp3 C) and twelve peaks at
d 112e152 ppm
(sp2 C) are observed. The 1H NMR spectrum of 9e displays signals of
ꢀ
protons belonging to two different butyl groups (Fig. 4). The
a
pentaquinoxaline moiety.
-methylene protons of one of them resonate as a broad multiplet
at 2.3e2.5 ppm, whereas those of the other butyl group show
d
a broad doublet of multiplets at
d 2.6e3.2 ppm. The proposed
structure 9e was also confirmed by the 1He1H NOESY experiment,
which indicated the absence of the spatial interaction between
protons of the above a-methylene groups.
The structure 9f was proved by a combination of mass spec-
trometry, IR, 1H and 13C NMR spectroscopic measurements. The
chemical shifts of the aromatic protons H(6) and H(7)
(d
7.79e7.87 ppm), H(5) and H(8) (
d
8.06e8.20 ppm) in the 1H NMR
spectrumof 9fare similar tothose of9eprovidingevidence to suggest
a similarity in their stereo structures. The 13C NMR spectra of both
compounds (excluding the sp3 carbons region) are also very similar.
Returning to the mechanism, previously proposed for electro-
philic cyclization of 1,2-bis(phenylethynyl)benzene 1, and taking
into account the above experimental data, one can conclude that
the resonance stabilization of the intermediate carbenium ion 6
(see, Scheme 4) is not a crucial factor for the cyclization. However,
the nature of the substituents on the alkyne termini influences the
stereochemical result of the reaction. In the case of an aryl sub-
stituent, the stabilized cation 10 serves as an intermediate
(Scheme 6). It can be attacked by the halide ion from the less
hindered left side (to provide the major product 8) or from the right
side (to yield the minor isomer 9). The ratio of the cyclization
products depends on the electrophile used (to be more precise, its
counterion). The attack of a chloride ion on intermediate 10 (from
the right side) affording compound 9d is less sterically demanding
than in the cases of bromide or iodide ions. As a consequence, the
yield of the minor isomer 9d increases. Reactions of 2,3-
dialkynylquinoxaline 7c or 7d, with non-aromatic substituents on
the C^C bonds, with electrophiles, evidently, proceed via the vinyl
cation 11 with an intrinsically more stable geometry affording the
corresponding compound 9 as a single product.
Fig. 1. ORTEP Plots for X-ray crystal structure of 8c.
The use of iodine chloride as the electrophile changed the 8:9
ratio strongly, though isomer 8d prevailed as before (Scheme 5,
Table 1, entry 4). Both (Z)-isomer 8d and (E)-isomer 9d were iso-
lated in pure form. The structure of the minor product 9d was
unambiguously secured by X-ray crystal structure analysis (Fig. 2).
In the next experiment, N-bromosuccinimide was used as an
electrophile. Treatment of 7a with NBS in glacial acetic acid gave
dibromo ketone 13 in 57% yield (Scheme 7). The mass spectrum of
13 shows a combination of peaks m/z 508 [Mþ2]þ, 506 [M]þ, 504
[Mꢀ2]þ with w1:2:1 relative intensities, which are typical for
dibromo compounds. Its IR and 13C NMR spectra indicate the
presence of a C]O bond (nC
]
1656 cmꢀ1
, d 192.4 ppm). The
O
structure of 13 was also proved by X-ray crystal structure analysis
(Fig. 5). Presumably, compound 13 is formed by a mechanism
analogous to that shown in Scheme 6. However, during the course
of the reaction acetic acid serves as the source of a nucleophile after
the carbocyclization step (10/12). The acetoxy compound 12 un-
Fig. 2. ORTEP Plots for X-ray crystal structure of 9d.
dergoes further electrophilic addition of a bromonium ion

A.V. Gulevskaya et al. / Tetrahedron 69 (2013) 910e917
913
Fig. 3. The 1H NMR spectra of compounds 8d and 9d (CDCl3).
accompanied by deacetylation as depicted in Scheme 7. As reported
previously,5b 1,2-bis(phenylethynyl)benzene reacts with bromine
in methanol to yield (1,1-dibromo-2-phenyl-1H-inden-3-
yl)(phenyl)methanone as the major product. Thus, both sub-
strates 1 and 7a demonstrate rather similar reactivity towards
halogen electrophiles.
The different behaviour of benzofused and heterocyclic ene-
diynes towards electrophiles is illustrated by their reactions with
hydrobromic acid. The interaction of 1,2-bis(phenylethynyl)ben-
zene 1 with HBr proceeds in agreement with Scheme 4 to afford
a mixture of isomeric 1-(bromo(phenyl)methylene)-2-phenyl-1H-
indenes.5b While, 2,3-bis(phenylethynyl)quinoxaline 7a under the
Fig. 4. The 1H NMR spectrum of compound 9e (CDCl3).

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A.V. Gulevskaya et al. / Tetrahedron 69 (2013) 910e917
same conditions forms only the addition product 16 (Scheme 8).
The main reason for this difference is the basic nature of the aza
group. Evidently, the reaction starts with its protonation to give
a cation 14. Subsequent nucleophilic attack of the bromide ion on
the C^C bond provides an allene intermediate 15, that rearranges
into adduct 16. The IR spectrum indicates the absence of C^C
bonds in this molecule. The 1H NMR spectrum of 16 also confirmed
its symmetrical structure.
Scheme 6.
Scheme 8.
Comparing the reactivity of benzofused and heterocyclic ene-
diynes, we should also mention another important point. In case of
1,2-bis(phenylethynyl)benzene 1 both nucleophilic5b and electro-
philic5b attacks are directed on the same carbon atom of the C^C
bond resulting in 5-exo-dig cyclizations (Scheme 9, A and B).13 The
polarity of the triple bonds of dialkynylquinoxalines 7 causes dif-
ferences in the reaction sites10a as well in the modes of subsequent
cyclizations (Scheme 9, C and D).
A
B
Scheme 7.
C
D
Scheme 9.
3. Conclusion
In summary, we have found that ortho-dialkynylbenzenes and
ortho-dialkynylquinoxalines demonstrate rather similar reactivity
towards halogen electrophiles. All tested reactions of ortho-dia-
lkynylquinoxalines with Br2, I2, ICl, NBS start with the addition of an
electrophile to the carbonecarbon triple bond that promotes fur-
ther 5-exo-dig carbocyclization ultimately yielding a mixture of
Fig. 5. ORTEP Plots for X-ray crystal structure of 13.

A.V. Gulevskaya et al. / Tetrahedron 69 (2013) 910e917
915
isomeric cyclopenta[b]quinoxaline derivatives. The presence of an
aryl substituent on the alkyne termini of ortho-dialkynylquinoxa-
line is not crucial for this cyclization. At the same time, the nature of
substituents on the C^C bonds influence the stereochemical result
of the reaction. The ratio of isomeric cyclization products depends
also on the electrophile used.
was stirred for 24 h at 70 ꢂC under argon. The reaction mixture
was then evaporated to dryness under reduced pressure. The
residue was purified by flash column chromatography on silica gel
(3ꢁ15 cm) with CH2Cl2 as the eluent. The colourless fraction Rf 0.6
(CH2Cl2) gave 7d (138 mg, 43%) as colourless crystals, mp
118e121 ꢂC; 1H NMR (CDCl3, 250 MHz)
d
ppm: 0.33 (s, 18H,
ortho-Dialkynylbenzenes and ortho-dialkynylquinoxalines differ
in their reactivity towards hydrobromic acid due to the basic nature
of the aza group of the quinoxaline substrate.
2SiMe3), 7.69e7.79 (m, 2H, H(6) and H(7)), 7.99e8.07 (m, 2H, H(5)
and H(8)); 13C NMR (CDCl3, 62.9 MHz)
d ppm: 0.1, 101.2, 102.8,
129.3, 131.5, 140.6, 140.8; IR, cmꢀ1: 1556, 2182 (C^C). MS m/z: 322
([M]þ, 16), 308 (11), 307 (39), 146 (15), 73 (100). Anal. Calcd for
4. Experimental
4.1. General
C18H22N2Si2: C, 67.03; H, 6.87; N, 8.68; Si, 17.41. Found: C, 66.89; H,
6.97; N, 8.51.
4.4. Synthesis of (Z)-3-bromo-1-(bromo(phenyl)methylene)-
2-phenyl-1H-cyclopenta[b]quinoxaline 8a
Proton (1H) nuclear magnetic resonance (NMR) spectra were
recorded on a Bruker DPXꢀ250 (250 MHz) spectrometer. 13C NMR
spectra were recorded on Bruker DPX-250 (62.9 MHz) spectrom-
eter. 1H and 13C NMR chemical shifts are in parts per million rel-
ative to Me4Si. Coupling constants are in Hertz. The IR spectra
were recorded on a Varian Excalibur 3100 FT-IR spectrometer
using Nujol. Mass spectra were measured on a Finnigan MAT
INCOS 50 spectrometer. CHN analysis was accomplished by com-
bustion analysis (Dumas and Pregl method). Melting points were
determined in glass capillaries using a Stuart SMP30 device and
are uncorrected. Flash column chromatography was performed on
silica gel. All commercial reagents (1-alkynes, palladium catalysts,
NBS) were purchased from Acros and Aldrich.
To a stirred solution of 2,3-bis(phenylethynyl)quinoxaline 7a
(165 mg, 0.499 mmol) in CHCl3 (5 mL) under argon, solution of
bromine (1 mL, 0.5 M in CHCl3, 0.5 mmol) was added drop wise. The
reaction was allowed to stir at room temperature for 2 h in the dark.
The reaction mixture was diluted with CH2Cl2 (30 mL), washed with
a saturated aqueous solution of Na2SO3 and then with water. The
solvent was evaporated under reduced pressure and the residue was
purified by flash column chromatography on silica gel (3.5ꢁ20 cm)
using CH2Cl2 as the eluent. The yellow fraction with Rf 0.6 (CH2Cl2)
was separated. The crude product was crystallized from heptane/
CHCl3 (5:1, v/v) yielding 8a (156 mg, 64%) as yellow needles, mp
192e194 ꢂC; 1H NMR (CDCl3, 250 MHz)
2Ph), 7.09e7.17 (m, 2H, 2Ph), 7.69e7.83 (m, 2H, H(6) and H(7)),
8.18e8.29 (m, 2H, H(5) and H(8)); 13C NMR (CDCl3, 62.9 MHz)
ppm:
124.9,127.8,127.9,128.2,129.5,129.8,129.9,130.0,130.5,130.7,130.8,
d ppm: 6.87e7.06 (m, 8H,
4.2. X-ray structure determination
d
Atomic coordinates, bond lengths, bond angles and thermal
parameters have been deposited at the Cambridge Crystallographic
Data Centre (CCDC) and allocated the deposition numbers CCDC
893084 (8c), CCDC 893085 (9d) and CCDC 893086 (13).
133.5, 133.7, 133.9, 140.6, 141.4, 142.1, 150.3, 151.1, 152.9; IR, cmꢀ1
:
1554,1577; MS m/z: 492 ([Mþ2]þ, 2.4), 490 ([M]þ, 5.1), 488 ([Mꢀ2]þ,
2.6), 409 (4), 330 ([MꢀBr2]þ, 100), 301 (4), 227 (5), 200 (5), 164 (13).
Anal. Calcd for C24H14Br2N2: C, 58.81; H, 2.88; Br, 32.60; N, 5.71.
Found: C, 58.63; H, 3.00; Br, 32.68; N, 5.58.
4.3. Synthesis of the starting compounds
Starting 2,3-dialkynylquinoxalines 7a,b,10b were synthesized in
accordance with known procedures.
4.5. Synthesis of (Z)-3-bromo-1-(bromo(p-tolyl)methylene)-
2-p-tolyl-1H-cyclopenta[b]quinoxaline 8b
4.3.1. Synthesis of 2,3-di(hex-1-ynyl)quinoxaline 7c. CuI (10.0 mg,
0.05 mmol), PdCl2(PPh3)2 (20.0 mg, 0.03 mmol) and Et3N (4 mL)
were added to 2,3-dichloroquinoxaline14 (199 mg, 1.0 mmol) in dry
DMF (4 mL) under a slow stream of argon. After 20 min stirring
The reaction of 2,3-bis(p-tolylethynyl)quinoxaline 7b (179 mg,
0.499 mmol) with bromine was carried out in accordance with the
procedure described in Section 4.4. Compound 8b (164 mg, 63%)
was obtained as yellow needles, mp 206e207 ꢂC; 1H NMR (CDCl3,
under argon,1-hexyne (179 mg, 250
m
L, 2.18 mmol) was added drop
250 MHz)
d
ppm: 2.18 (s, 3H, Me), 2.21 (s, 3H, Me), 6.71 (d, J¼7.9 Hz,
wise. Stirring was continued for 24 h at room temperature. The
reaction mixture was then treated with a saturated aqueous solu-
tion of NH4Cl (10 mL) and extracted with CH2Cl2 (3ꢁ30 mL). The
solvent was evaporated under reduced pressure. The residue was
purified by flash column chromatography on silica gel (3ꢁ20 cm)
with CH2Cl2 as the eluent. The yellowish fraction Rf 0.5 (CH2Cl2)
gave 7c (197 mg, 68%) as yellowish oil; 1H NMR (CDCl3, 250 MHz)
2H, p-Tol), 6.79 (d, J¼7.9 Hz, 2H, p-Tol), 6.88 (d, J¼8.2 Hz, 2H, p-Tol),
6.99 (d, J¼8.2 Hz, 2H, p-Tol), 7.68e7.79 (m, 2H, H(6) and H(7)),
8.19e8.26 (m, 2H, H(5) and H(8)); 13C NMR (CDCl3, 62.9 MHz)
d
ppm: 21.5 (7), 21.5 (9), 123.9, 128.3, 128.5, 129.4, 129.9, 130.0,
130.3, 130.7, 130.8 (5), 130.8 (7), 131.0, 133.3, 134.1, 137.9, 140.2,
141.4, 142.1, 150.6, 151.2, 152.9; IR, cmꢀ1: 1557, 1580, 1607; MS m/z:
520 ([Mþ2]þ, 6), 518 ([M]þ, 13), 516 ([Mꢀ2]þ, 6), 437 (8), 358
([MꢀBr2]þ, 100), 343 (78), 259 (6), 240 (6), 211 (5), 179 (9), 171 (32),
164 (5), 140 (12), 114 (5). Anal. Calcd for C26H18Br2N2: C, 60.26; H,
3.50; Br, 30.84; N, 5.41. Found: C, 60.09; H, 3.61; Br, 31.03; N, 5.55.
d
ppm: 0.91 (t, J¼7.3 Hz, 6H, 2(CH2)3Me), 1.42e1.70 (m, 8H,
2CH2(CH2)2Me), 2.52 (t, J¼7.0 Hz, 4H, 2CH2CH2CH2Me), 7.59e7.67
(m, 2H, H(6) and H(7)), 7.89e7.97 (m, 2H, H(5) and H(8)); 13C NMR
(CDCl3, 62.9 MHz)
d ppm: 14.0, 19.8, 22.5, 30.6, 79.0, 98.2, 129.0,
130.7, 140.6, 141.5; IR, cmꢀ1: 1530, 1556, 2230 (C^C). MS m/z: 290
([M]þ, 43), 262 (5), 261 (20), 248 (34), 247 (52), 234 (14), 233 (65),
219 (78), 205 (53), 182 (11), 167 (7), 154 (34), 140 (17), 127 (17), 113
(27), 102 (18), 89 (14), 77 (100). Anal. Calcd for C20H22N2: C, 82.72;
H, 7.64; N, 9.65. Found: C, 82.88; H, 7.51; N, 9.49.
4.6. Synthesis of (Z)-3-iodo-1-(iodo(phenyl)methylene)-2-
phenyl-1H-cyclopenta[b]quinoxaline 8c
To a stirred solution of 2,3-bis(phenylethynyl)quinoxaline 7a
(66.0 mg, 0.199 mmol) in CH3NO2 (3 mL) under argon, a solution of
iodine (254 mg, 1.0 mmol) in CH3NO2 (6 mL) was added drop wise.
The reaction was allowed to stir at room temperature for 24 h in the
dark. The reaction mixture was diluted with CH2Cl2 (30 mL),
washed with a saturated aqueous solution of Na2SO3 and then with
water. The solvent was evaporated under reduced pressure and the
4.3.2. Synthesis of 2,3-bis((trimethylsilyl)ethynyl)quinoxaline 7d. A
mixture of CuI (10.0 mg, 0.05 mmol), PdCl2(PPh3)2 (20.0 mg,
0.03 mmol), 2,3-dichloroquinoxaline14 (199 mg, 1.0 mmol), tri-
methylsilylacetylene (206 mg, 300 mL, 2.10 mmol) and Et3N (4 mL)

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A.V. Gulevskaya et al. / Tetrahedron 69 (2013) 910e917
residue was purified by flash column chromatography on silica gel
(3.5ꢁ20 cm) using CH2Cl2 as the eluent. The yellow fraction with Rf
0.6 (CH2Cl2) was separated. The crude product was crystallized
from heptane/CHCl3 (5:1, v/v) yielding 8c (69.0 mg, 59%) as orange
washed with a saturated aqueous solution of Na2SO3 and then with
water. The solvent was evaporated under reduced pressure and the
residue was purified by flash column chromatography on silica gel
(3.5ꢁ20 cm) using CHCl3 as the eluent. The yellowish fraction with
Rf 0.6 (CH2Cl2) gave 9e (165 mg, 73%) as yellowish oil; 1H NMR
crystals, mp 214e216 ꢂC; 1H NMR (CDCl3, 250 MHz)
d ppm:
6.81e7.10 (m, 10H, 2Ph), 7.69e7.81 (m, 2H, H(6) and H(7)),
(CDCl3, 250 MHz)
d
ppm: 0.79 (t, J¼7.3 Hz, 3H, (CH2)3Me), 1.00 (t,
8.19e8.31 (m, 2H, H(5) and H(8)); 13C NMR (CDCl3, 62.9 MHz)
J¼7.3 Hz, 3H, (CH2)3Me), 1.17e1.32 (m, 2H, (CH2)2CH2Me), 1.43e1.62
(m, 2H, (CH2)2CH2Me), 1.64e1.78 (m, 4H, 2CH2CH2CH2Me),
2.31e2.45 (m, 2H, CH2CH2CH2Me), 2.90 (br dm, J¼63.8 Hz, 2H,
CH2CH2CH2Me), 7.79e7.89 (m, 2H, H(6) and H(7)), 8.05e8.19 (m,
d
ppm: 104.4, 109.8, 127.6, 127.9, 128.1, 129.2, 129.4, 130.0, 130.2 (8),
130.3 (3), 130.5, 130.9, 136.5, 138.4, 140.8, 142.7, 145.4, 150.6, 155.5,
156.3; IR, cmꢀ1: 1554, 1573; MS m/z: 584 ([M]þ, 4), 457 (5), 330
([MꢀI2]þ, 100), 301 (12), 292 (14), 252 (11), 227 (20), 201 (20), 176
(12), 165 (89), 151 (21), 137 (10), 127 (51), 100 (20). Anal. Calcd for
2H, H(5) and H(8)); 13C NMR (CDCl3, 62.9 MHz)
d ppm: 14.2, 14.4,
22.3, 22.5, 29.7, 31.4, 40.2, 40.7, 111.8, 117.1, 128.7, 129.8, 129.9, 131.7,
131.8, 138.0, 141.2, 141.5, 150.5, 152.9; IR, cmꢀ1: 1562, 1614. Anal.
Calcd for C20H22Br2N2: C, 53.36; H, 4.93; Br, 35.50; N, 6.22. Found: C,
53.45; H, 5.07; Br, 35.29; N, 6.33.
C
24H14I2N2: C, 49.34; H, 2.42; I, 43.45; N, 4.80. Found: C, 49.48; H,
2.32; I, 43.62; N, 4.77.
4.7. Synthesis of (Z)-1-(chloro(phenyl)methylene)-3-iodo-2-
phenyl-1H-cyclopenta[b]quinoxaline 8d and (E)-1-(chloro-
(phenyl)methylene)-3-iodo-2-phenyl-1H-cyclopenta[b]qui-
noxaline 9d
4.9. Synthesis of (Z)-3-bromo-1-(bromo(trimethylsilyl)meth-
ylene)-2-(trimethylsilyl)-1H-cyclopenta[b]quinoxaline 9f
To a stirred solution of 2,3-bis((trimethylsilyl)ethynyl)quinoxa-
line 7d (80.0 mg, 0.248 mmol) in CHCl3 (3 mL) under argon, solu-
tion of bromine (1 mL, 0.75 M in CHCl3, 0.75 mmol) was added drop
wise. The reaction was allowed to stir at room temperature for 20 h
in the dark. The reaction mixture was diluted with CH2Cl2 (30 mL),
washed with a saturated aqueous solution of Na2SO3 and then with
water. The solvent was evaporated under reduced pressure and the
residue was purified by flash column chromatography on silica gel
(3.5ꢁ20 cm) using CH2Cl2 as the eluent. The colourless fraction
with Rf 0.6 (CH2Cl2) gave 9f (69 mg, 57%) as yellowish oil; 1H NMR
To a stirred solution of 2,3-bis(phenylethynyl)quinoxaline 7a
(132 mg, 0.399 mmol) in CHCl3 (5 mL) under argon, solution of
iodine chloride (1 mL, 0.4 M in CHCl3, 0.4 mmol) was added drop
wise. The reaction was allowed to stir at room temperature for 24 h
in the dark. The reaction mixture was diluted with CH2Cl2 (30 mL),
washed with a saturated aqueous solution of Na2SO3 and then with
water. The solvent was evaporated under reduced pressure and the
residue was purified by flash column chromatography on silica gel
(3.5ꢁ30 cm) using CH2Cl2 as the eluent. The yellow fraction with Rf
0.6 (CH2Cl2) gave (Z)-1-(chloro(phenyl)methylene)-3-iodo-2-phenyl-
1H-cyclopenta[b]quinoxaline 8d. The yellow fraction with Rf 0.5
(CH2Cl2) gave (E)-1-(chloro(phenyl)methylene)-3-iodo-2-phenyl-1H-
cyclopenta[b]quinoxaline 9d. Both crude products were crystallized
from heptane/CHCl3 (5:1, v/v).
(CDCl3, 250 MHz)
d
ppm: ꢀ0.08 (s, 9H, SiMe3), 0.47 (s, 9H, SiMe3),
7.79e7.87 (m, 2H, H(6) and H(7)), 8.06e8.20 (m, 2H, H(5) and H(8));
13C NMR (CDCl3, 62.9 MHz)
d
ppm: 0.4, 0.5,118.2,122.0,127.2, 129.8,
129.9, 131.8, 131.9, 140.3, 140.8, 141.3, 150.1, 152.3; IR, cmꢀ1: 1558,
1611; MS m/z: 411 ([Mþ2ꢀSiMe3]þ, 9), 409 ([MꢀSiMe3]þ, 19), 407
([Mꢀ2ꢀSiMe3]þ, 9), 329 ([MꢀBrSiMe3]þ, 3), 139 (22), 73 (100).
Anal. Calcd for C18H22Br2N2Si2: C, 44.82; H, 4.60; Br, 33.13; N, 5.81;
Si, 11.65. Found: C, 44.66; H, 4.45; Br, 32.96; N, 6.00.
Compound 8d was obtained (88.0 mg, 45%) as yellow needles,
mp 182e184 ꢂC; 1H NMR (CDCl3, 250 MHz)
d ppm: 6.87e7.09 (m,
8H, 2Ph), 7.10e7.19 (m, 2H, 2Ph), 7.67e7.82 (m, 2H, H(6) and H(7)),
8.18e8.31 (m, 2H, H(5) and H(8)); 13C NMR (CDCl3, 62.9 MHz)
d
ppm: 105.5, 128.0, 128.8, 128.9 (8), 129.0 (3), 129.5, 129.7, 129.9,
4.10. Synthesis of (1,1-dibromo-2-phenyl-1H-cyclopenta[b]
130.2, 130.7, 130.8, 132.2, 138.0, 138.7, 141.3, 142.2, 142.4, 149.2,
153.5, 156.5; IR, cmꢀ1: 1563, 1586; MS m/z: 494 ([Mþ2]þ, 7), 492
([M]þ, 20), 365 (13), 363 (13), 330 ([MꢀICl]þ, 99), 329 (100), 301
(12), 292 (14), 252 (11), 246 (14), 227 (16), 202 (22), 182 (21), 175
(9), 164 (69), 151 (20), 137 (10), 127 (32), 102 (21). Anal. Calcd for
quinoxalin-3-yl)(phenyl)methanone 13
To a stirred solution of 2,3-bis(phenylethynyl)quinoxaline 7a
(165 mg, 0.499 mmol) in glacial acetic acid (3 mL), a solution of NBS
(178 mg, 1.0 mmol) in glacial acetic acid (5 mL) was added drop
wise. The reaction was allowed to stir at room temperature for 20 h
in the dark. The reaction mixture was filtered. The crude product
was crystallized from heptane/CHCl3 (5:1, v/v) yielding 13 (143 mg,
57%) as yellowish crystals, mp 168e170 ꢂC (decomp.); 1H NMR
C
24H14ClIN2: C, 58.50; H, 2.86; Cl, 7.20; I, 25.75; N, 5.69. Found: C,
58.32; H, 3.03; IþCl, 33.07; N, 5.83.
Compound 9d was obtained (61.0 mg, 31%) as orange crystals,
mp 183e186 ꢂC; 1H NMR (CDCl3, 250 MHz)
d ppm: 7.39e7.68 (m,
13H, 2Ph, H(6), H(7) and H(8)), 8.14 (dm, J¼7.9 Hz, 1H, H(5)); 13C
(CDCl3, 250 MHz)
7.69e7.82 (m, 2H), 7.86e7.97 (m, 4H), 8.02e8.10 (m, 1H), 8.22e8.29
(m,1H); 13C NMR (CDCl3, 62.9 MHz)
ppm: 53.7,128.9 (6),129.0 (4),
d ppm: 7.32e7.43 (m, 5H), 7.48e7.57 (m, 1H),
NMR (CDCl3, 62.9 MHz)
d ppm: 103.9, 127.9, 128.0, 128.2, 129.4,
129.9, 130.0, 130.1, 130.3, 130.5 (5), 130.5 (7), 132.9, 136.1, 138.5,
141.9, 142.3, 142.8, 151.0, 154.7, 155.2; IR, cmꢀ1: 1549, 1581; MS m/z:
494 ([Mþ2]þ, 24), 492 ([M]þ, 72), 365 (11), 363 (11), 330 ([MꢀICl]þ,
100), 329 (99), 301 (12), 252 (11), 246 (15), 227 (21), 202 (19), 182
(15), 164 (53), 151 (16), 137 (7), 127 (20), 102 (10). Anal. Calcd for
d
129.2,129.3,130.0,130.1, 130.2,130.7, 131.1, 131.4, 133.9,134.9,136.0,
141.3, 143.2, 149.9, 153.9, 159.0, 192.4; IR, cmꢀ1: 1656 (C]O); MS
m/z: 508 ([Mþ2]þ, 2), 506 ([M]þ, 4), 504 ([Mꢀ2]þ, 2), 427 (16), 426
([MꢀBr]þ,12), 425 (14), 399 (14), 397 (13), 347 (8), 318 (71), 270 (5),
241 (24), 214 (24), 189 (13), 173 (16), 159 (11), 139 (9), 113 (18), 105
(100). Anal. Calcd for C24H14Br2N2O: C, 56.95; H, 2.79; Br, 31.57; N,
5.53; O, 3.16. Found: C, 57.13; H, 2.95; Br, 31.44; N, 5.72.
C
24H14ClIN2: C, 58.50; H, 2.86; Cl, 7.20; I, 25.75; N, 5.69. Found: C,
58.65; H, 2.70; IþCl, 32.75; N, 5.61.
4.8. Synthesis of (E)-3-bromo-1-(1-bromopentylidene)-2-
butyl-1H-cyclopenta[b]quinoxaline 9e
4.11. Synthesis of 2,3-bis((Z)-2-bromo-2-phenylvinyl)qui-
noxaline 16
To
a stirred solution of 2,3-di(hex-1-ynyl)quinoxaline 7c
(145 mg, 0.499 mmol) in CHCl3 (3 mL) under argon, solution of
bromine (1 mL, 0.5 M in CHCl3, 0.5 mmol) was added drop wise. The
reaction was allowed to stir at room temperature for 20 h in the
dark. The reaction mixture was diluted with CH2Cl2 (30 mL),
HBr gas prepared from KBr (500 mg, 4.20 mmol) and concd
H2SO4 (4 mL) was passed through a stirred solution of 2,3-
bis(phenylethynyl)quinoxaline 7a (165 mg, 0.499 mmol) in glacial
acetic acid (5 mL). The reaction was allowed to stir at room

A.V. Gulevskaya et al. / Tetrahedron 69 (2013) 910e917
917
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temperature for 1 h in the dark. The solvent was evaporated under
reduced pressure and the residue was purified by flash column
chromatography on silica gel (3.5ꢁ20 cm) using CH2Cl2 as the
eluent. The yellowish fraction with Rf 0.6 (CH2Cl2) gave 16 (211 mg,
86%) as yellowish crystals, mp 108e109 ꢂC; 1H NMR (CDCl3,
4. (a) Kovalenko, S. V.; Peabody, S.; Manoharan, M.; Clark, R. J.; Alabugin, I. V.
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250 MHz)
d ppm: 7.43e7.42 (m, 6H, 2Ph), 7.60 (s, 2H), 7.66e7.74 (m,
4H, 2Ph), 7.76e7.83 (m, 2H, H(6) and H(7)), 8.12e8.19 (m, 2H, H(5)
and H(8)); 13C NMR (CDCl3, 62.9 MHz)
d ppm: 126.7, 128.3, 128.9,
5. (a) Wu, M.-J.; Lin, C.-F.; Lu, W.-D. J. Org. Chem. 2002, 67, 5907e5912; (b)
Whitlock, H. W.; Sandvick, P. E.; Overman, L. E.; Reichardt, P. B. J. Org. Chem.
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1993, 115, 12627e12628; (e) Wu, M.-J.; Lin, C.-F.; Chen, S.-H. Org. Lett. 1999, 1,
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2012, 48, 82e94.
129.5, 130.1, 130.8, 131.9, 139.8, 141.2, 151.0; IR, cmꢀ1: 1616; MS m/z:
492 ([M]þ, 0.1), 413 (10), 411 (11), 332 (31), 331 (67), 330 (7), 255
(21), 229 (8), 204 (28), 176 (9), 165 (30), 128 (16), 102 (100), 77 (42).
Anal. Calcd for C24H16Br2N2: C, 58.56; H, 3.28; Br, 32.47; N, 5.69.
Found: C, 58.40; H, 3.35; Br, 32.63; N, 5.48.
€
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Acknowledgements
We gratefully acknowledge the Russian Foundation for Basic
Research for financial support of this research (grant No 11-03-
00079-a). We also thank Zoya Starikova, Anna Tkachuk and Oleg
Burov for assistance.
€
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Supplementary data
11. (a) Whitlock, H. W.; Sandvick, P. E. J. Am. Chem. Soc. 1966, 88, 4525e4526; (b)
Whitlock, B. J.; Whitlock, H. W. J. Org. Chem. 1972, 37, 3559e3561; (c) Zhou, Q.;
Carroll, P. J.; Swager, T. M. J. Org. Chem. 1994, 59, 1294e1301; (d) Schreiner, P. R.;
Prall, M.; Lutz, V. Angew. Chem., Int. Ed. 2003, 42, 5757e5760; (e) Werner, C.;
Hopf, H.; Grunenberg, J.; Jones, P. G. Eur. J. Org. Chem. 2010, 4027e4034; (f)
Chase, D. T.; Rose, B. D.; McClintock, S. P.; Zakharov, L. N.; Haley, M. M. Angew.
Chem., Int. Ed. 2011, 50, 1127e1130.
12. There is one exception, e.g., interaction of 2,3-bis((2-methoxyphenyl)ethynyl)
benzo[b]thiophene with iodine producing 2,20-(benzo[b]thiophene-2,3-diyl)
bis(3-iodobenzofuran) [Mehta, S.; Larock, R. C. J. Org. Chem. 2010, 75,1652e1658].
However, in this transformation the alkynyl groups react with an electrophile
independently to each other.
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2012.10.098.
These data include MOL files and InChiKeys of the most important
compounds described in this article.
References and notes
ꢁ
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H. F. Chem. Rev. 2000, 100, 1605e1644.
13. Types of cyclizations in this Scheme are pointed in accordance with the ex-
tended classification of cyclization modes by Gilmore, K.; Alabugin, I. V. Chem.
Rev. 2011, 111, 6513e6556.
2. For review, see: (a) Nicolaou, K. C.; Dai, W. M. Angew. Chem., Int. Ed. Engl. 1991,
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