A novel tandem cyclization of condensed 2,3-dialkynylpyrazines into [1,2,3]triazolo[1′,5′;1,2]pyrido[3,4-b]pyrazines promoted by sodium azide

Article abstract of DOI:10.1016/j.tet.2009.11.039

6,7-Dialkynyl-1,3-dimethylpteridine-2,4(1H,3H)-diones and 2,3-dialkynylquinoxalines have been shown to react with sodium azide in DMF at room temperature giving rise 9,11-dimethyl-[1,2,3]triazolo[1′,5′;1,2]pyrido[4,3-g]pteridine-8,10(9H,11H)-diones and [1

Full text of DOI:10.1016/j.tet.2009.11.039

Tetrahedron 66 (2010) 146–151
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A novel tandem cyclization of condensed 2,3-dialkynylpyrazines into
[1,2,3]triazolo[10,50;1,2]pyrido[3,4-b]pyrazines promoted by sodium azide
,
a
a
a
b
A.V. Gulevskaya a , Shee Van Dang , A.S. Tyaglivy , A.F. Pozharskii , O.N. Kazheva ,
*
A.N. Chekhlov b, O.A. Dyachenko b
a Department of Chemistry, Southern Federal University, Zorge 7, Rostov-on-Don 344090, Russian Federation
b Institute of Problems of Chemical Physics, Russian Academy of Sciences, Semenov av. 1, 142432 Chernogolovka, Moscow Region, Russian Federation
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 13 July 2009
Received in revised form 22 October 2009
Accepted 5 November 2009
Available online 10 November 2009
6,7-Dialkynyl-1,3-dimethylpteridine-2,4(1H,3H)-diones and 2,3-dialkynylquinoxalines have been shown
to react with sodium azide in DMF at room temperature giving rise 9,11-dimethyl-[1,2,3]tri-
azolo[10,50;1,2]pyrido[4,3-g]pteridine-8,10(9H,11H)-diones and [1,2,3]triazolo[10,50;1,2]pyrido[3,4-b]qui-
noxalines. A novel tandem cyclization involves 1,3-dipolar cycloaddition of an azide ion to the
carbon–carbon triple bond followed by intramolecular nucleophilic addition of the intermediate
1,2,3-triazole N-anion to another C^C bond.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
the cyclization would provide a new synthesis of the alloxazine
nucleus (Scheme 2) as well as highlight some new aspects of the
Enediynes and structurally related compounds have attracted
much attention since the discovery of the natural enediyne anti-
biotics and the fascinating mode of their biochemical action.1 It is
supposed that the antitumour activity of these natural products is
based on the Bergman2 or Myers–Saito cyclizations3 involving the
formation of benzenoid diradical intermediates, which are able to
cleave DNA and to rupture the protein structure via oxidative
cleavage of the peptide bond. Not surprisingly, most of these
studies have focused on the synthesis of designed enediynes and on
the search for non-thermal ways to trigger their cycloaroma-
tization. Thus, several examples of nonradical cycloaromatization
of enediynes initiated by anion addition to the triple bond have
been reported.4 Cyclizations of this type find ever-increasing use in
synthetic organic chemistry as an effective route to phenan-
thridines, biphenyls, dibenzofurans, carbazoles etc.
enediyne chemistry.
Bu
Bu
N
Bu
Ar
NaN3
80oC
+
N
N
N
N
N
Ar
Ar
1
2
3
Bu
Bu
Bu
N
1,5-aryl-shif t
N3
Ar
1
Ar
N
N
N
Ar
N
N
N
N
N
1,5-aryl-shift
protonation
In this strategy, it has been recently reported5 that sodium azide
promotes a cascade cyclization of (Z)-1-arylhexa-3-en-1,5-diynes 1
into 1-aryl-1H-benzotriazoles 2,3 (Scheme 1). Following to our in-
terest in the chemistry of condensed pteridines6 we have attempted
to apply the above cyclization to 6,7-dialkynyl-1,3-dimethylpteri-
dine-2,4(1H,3H)-diones 4 (6,7-dialkynyl-1,3-dimethyllumazines).
We believed that as far as dialkynyllumazines 4 have the enediyne
moiety embedded into heterocyclic skeleton, the performance of
3
2
Scheme 1. Cyclization of (Z)-1-aryl-3-hexen-1,5-diynes into 1-aryl-1H-benzotriazoles.
O
R
6
7
Me
O
N
N
NaN3
N
N
R
N
N
N
R
N
N
+
Ph
N
Me
Ph
N
N
N
N
Ph
5
6
4
* Corresponding author. Tel.: þ7 863 2975 146.
Scheme 2. Target cyclization of 6,7-dialkynyl-1,3-dimethyllumazines into triazoloall-
oxazines.
E-mail address: agulevskaya@sfedu.ru (A.V. Gulevskaya).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.11.039

A.V. Gulevskaya et al. / Tetrahedron 66 (2010) 146–151
147
2. Results and discussion
R
N
O
R
O
9
8
O
7
6
5
N
Me
O
N
N
Me
N
R
Me
O
N
N
NaN3
N
N
N
N
With this aim, we first synthesized 6,7-dialkynyllumazines 4 by
the Sonogashira coupling of 6,7- dichlorolumazine 7 with terminal
alkynes (Scheme 3). The differential reactivity of the chlorine atoms
in 77 allows a stepwise introduction of alkynyl groups into position 6
and 7. Thus, treatment of dichloride 7 with one equivalent of phe-
nylacetylene in the Pd2dba3/CuI/K2CO3/DMF system at 25–30 ꢀC for
2 h gave 6-chloro-7-(phenylethynyl)lumazine 8 in 64% yield. The
use of two equivalents of phenylacetylene at 90–100 ꢀC led to 6,7-
dialkynyl derivative 4a in 33% yield. 6,7-Dialkynyllumazines 4b,c
were obtained in 37–54% yields by the coupling of 8 with the cor-
responding 1-alkynes at 90–100 ꢀC. For 4a X-ray analysis has been
4
+
3
10
N
DMF
N
Me
O
N
N
N
Ph
11 Me
Me
N
12
rt, 24 h
Ph
N
1
Ph
2
9a
4a-c
(45%)
9b (40%)
9c + 10c (84%, 2.6:1 ratio)
10a (25%)
10b (trace)
4,9 10
,
a
: R = Ph ( ), n-C6H13
b
c
( )
(
),
N
Scheme 4. Reaction of 6,7-dialkynyl-1,3-dimethyllumazines with sodium azide.
two singlets of the N–CH3 protons (d 3.6 and 3.7), the set of the
signals belonging to the 1-Ph and 5-R substituents, and a charac-
teristic singlet peak at 7.5–7.7 ppm attributed to the aromatic
proton 6-H. Evidently, molecules 9 are well set up to lose N2 under
electron impact. Indeed, the mass spectra of all samples includes
peak [M-28]þ identified as [M-N2]þ. Only for triazole 9b a low in-
tensive peak of the molecular ion was observed. The structure of 9c
was unambiguously determined by single-crystal X-ray analysis
(Fig. 2).z The most fragment of the molecule including 1-phenyl
substituent is nearly planar.
performed (Fig. 1).y It revealed that the C( 0) distance equal to
b)-C(b
4.095 Å is 0.7–1.2 Å higher then it is commonly required for spon-
taneous room temperature Bergman cyclization.1a This means that
thermal cycloaromatization of 4, if it is possible at all, should pro-
ceed at elevated temperatures only.
β
O
O
O
R
α
Me
O
N
N
Cl
Me
O
N
N
Cl
Cl
Me
O
N
N
Ph
R
N
N
N
Cat.
Cat.
90-100oC
N
N
N
25-30oC
64%
α
'
Me
Ph
Me
Me
Ph
β'
33%
8
7
4a-c
Ph
Cat., 90-100oC, 37-54%
Cat. = Pd2dba3, CuI, K2CO3, DMF, argon
4: R = Ph (a), n-C6H13 (b), (c)
N
Scheme 3. Synthesis of 6,7-dialkynyl-1,3-dimethyllumazines.
Figure 2. ORTEP Plots for X-ray Crystal Structure of 9c.
Triazole 10a is yellow crystalline substance (lmax 387 nm). Its
NMR and IR spectral characteristics are quite similar to that of 9a.
The mass spectrum of 10a does not contain peak of the molecular
ion. However, it reveals peak [M-28]þ corresponding to the [M-
N2]þ ion.
A plausible mechanism for the formation of compounds 9 is
shown in Scheme 5. The process starts from [3þ2]-cycloaddition of
an azide ion to the C^C bond attached to the C-7 position of the
starting molecule.x This triple bond is a more sensitive to the nu-
cleophilic attack due to its conjugation with the uracil carbonyl
group as well as electron-withdrawing nature of its phenyl termi-
nus. The thus formed 1,2,3-triazole N-anion 11 undergoes hetero-
cyclization via N-anionic attack on the neighbouring alkyne bond
followed by protonation of the intermediate 12 during the work-up.
The same scheme can be proposed for the formation of isomeric
Figure 1. ORTEP Plots for X-ray Crystal Structure of 4a.
Then we treated 6,7-bis(phenylethynyl)lumazine 4a with sodium
azide in DMF and stirred the reaction mixture at room temperature
for 24 h. However, instead of the expected triazoloalloxazines 5 or 6,
[1,2,3]triazolo[10,50;1,2]pyrido[4,3-g]pteridine 9a together with iso-
meric product 10a were isolated in 45% and 25% yields, respectively
(Scheme 4). The reaction of 4b with NaN3 gave triazoles 9b (40%
isolated yield) and traces of 10b. When 4c was used as a starting
material, both isomeric products 9c and 10c were produced in 84%
total yield (2.6:1 ratio deduced by 1H NMR). Unfortunately, only
compound 9c could be isolated from this mixture in a pure state.
All triazoles 9 are orange solids with UV-absorption band cen-
tred at 429–445 nm. Their chloroform solutions show a green
fluorescence. Two characteristic bands of the carbonyl stretching
vibration in the 1667–1721 cmꢁ1 region were registrated in the IR
spectra of 9. The 1H NMR spectra of 9 are rather simple. They reveal
z
The following crystal structure has been deposited at the Cambridge Crystal-
lographic Data Centre and allocated the deposition number CCDC660803.
x
This assumption is in agreement with our earlier observation that the 7-alkynyl
y
The following crystal structure has been deposited at the Cambridge Crystal-
group of
4 is much more reactive towards nucleophile then this at the C-6
lographic Data Centre and allocated the deposition number CCDC738042.
position.6b

148
A.V. Gulevskaya et al. / Tetrahedron 66 (2010) 146–151
O
R
R
R
R
Me
N
N
R
N
N
N
N
N
N
N
R
N
N
N
H
N3
NaN3
N
9
N
N
N
DMF
O
N
N
Me
rt, 24 h
Ph
N
N
N
Ph
12
R
Ph
14a-c
17a
(77%)
4
11
17b (80%)
17c (10%)
Scheme 5. A plausible mechanism for the formation of triazolopyridopteridines 9.
14,17: R = Ph (a), p-Tol (b), n-C8H17 (c)
triazolopyridopteridine 10 with the only difference: the role of the
dipolarophile here is played by the 6-alkynyl group of 4.
To elucidate the scope and limitations of the discovered cycli-
zation we have also synthesized o-dialkynylarenes 14–16 and
studied their reactivity towards sodium azide. The preparation of
2,3-dialkynylquinoxalines 14 is outlined in Scheme 6. The Sono-
gashira cross–coupling reaction of 2,3-dichloroquinoxaline 13 with
1-alkynes using palladium as a catalyst gave 14a–c in moderate to
good yields. 4,5-Bis(phenylethynyl)imidazole 158 and 1,2-bis(phe-
nylethynyl)benzene 169 were obtained in accordance with the de-
scribed protocols.
Scheme 7. Reaction of 2,3-dialkynylquinoxalines with sodium azide.
R
N
N
Cl
Cl
N
N
R
Pd(PPh3)2Cl2
CuI/Et3N/DMF
R
Ar, rt, 4 h
14a (69%)
14b (84%)
14c (30%)
13
14: R = Ph (a), p-Tol (b), n-C8H17 (c)
Ph
Ph
Ph
N
N
Me
Ph
15
16
Figure 3. ORTEP Plots for X-ray Crystal Structure of 17a.
Scheme 6. Preparation of o-dialkynylarenes 14–16.
3. Conclusions
In summary, we have presented
It was found that 2,3-bis(phenylethynyl)- and 2,3-bis(p-tolyl-
ethynyl)quinoxaline 14a,b smoothly reacted with sodium azide
in DMF at room temperature for 24 h to produce [1,2,3]tri-
azolo[10,50;1,2]pyrido[3,4-b]quinoxalines 17a,b in 77–80% yields
(Scheme 7). The structure of 17a has been proved by X-ray
measurements (Fig. 3).{ Reaction of 14c under the same conditions
proceeded reluctantly. Additional heating at 70 ꢀC for 2 h provided
17c in 10% yield. Both 4,5-bis(phenylethynyl)imidazole 15 and
1,2-bis(phenylethynyl)benzene 16 did not react with sodium azide
even at prolonged heating in DMF.
Comparing these results with the cyclization presented in
Scheme 1, one can assume that a driving force of the latter is the
benzene ring formation. Evidently, in the case of 1,2-di(phenyl-
ethynyl)benzene 16 the same reaction would lead to naphthalene
derivative. Energetically this process is less profitable. For the cy-
clization, the electrophilicity of the C^C bonds of o-dialkynylarene
seems to be its crucial factor. Indeed, the triple bonds of both re-
active o-dialkynylarenes 4 and 14 are influenced by electron-
withdrawing carbonyl or (and) aza groups. Due to this, the azide ion
adds readily to one of the C^C bonds even at room temperature.
The inertness of 4,5-bis(phenylethynyl)imidazole 15 may be
a consequence of the lower electrophilicity of its C^C bonds. An-
other retarding factor is that the alkyne groups of 15 are more
distant than in the cases of 4 and 14.
a
novel, sodium azide
promoted, tandem cyclization of 6,7-dialkynylpteridines and
2,3-dialkynylquinoxalines into hitherto unknown [1,2,3]triazolo-
[10,50;1,2]pyrido[4,3-g]pteridines and [1,2,3]triazolo[10,50;1,2]-
pyrido[3,4-b]quinoxalines, respectively. Its mechanism involves
1,3-dipolar cycloaddition of an azide ion to the C^C bond
followed by intramolecular nucleophilic addition of the
intermediate 1,2,3-triazole N-anion to another triple bond. Our
study has also demonstrated a huge difference in the reactivity
of acyclic enediynes (Scheme 1) and o-dialkynylarenes (Schemes
4 and 7) towards sodium azide. Though the exact reasons for
this difference are not quite understood, one can assume that
the electrophilicity of the C^C bond, the aromaticity of the
reaction products and the geometry of the transition state are
important factors. These findings have disclosed some new
aspects of enediyne chemistry, and provide a novel approach to
the condensed 1,2,3-triazoles with bridge-head nitrogen atom.
4. Experimental
4.1. General
Proton (1H) nuclear magnetic resonance (NMR) spectra were
recorded on a Bruker DPX-250 (250 MHz) spectrometers with
CDCl3 as a solvent. 13C NMR spectra were recorded on Varian Unity-
300 (75 MHz) and Bruker DPX-250 (62.9 MHz) spectrometers with
CDCl3 as a solvent. 1H and 13C NMR chemical shifts are in parts per
{
The following crystal structure has been deposited at the Cambridge Crystal-
lographic Data Centre and allocated the deposition number CCDC660802.

A.V. Gulevskaya et al. / Tetrahedron 66 (2010) 146–151
149
million relative to Me4Si. Coupling constants are in Hertz. The IR
4.4. Synthesis of 6-chloro-1,3-dimethyl-7-(phenylethynyl)-
spectra were recorded on a Specord IR-71 and Varian Excalibur
3100 FT-IR spectrometers using Nujol. Ultraviolet absorption (UV)
spectra were registered on a Specord M-40 and Cary 50 Probe
spectrophotometers with CHCl3 as a solvent. Mass spectra were
measured on a Finnigan MAT INCOS 50 spectrometer. CHN analysis
was accomplished by combustion analysis (Dumas and Pregl
method). Melting points were determined in glass capillaries using
a PTP device and are uncorrected. Flash column chromatography
was performed on silica gel and Al2O3 (III–IV activity, Brockman).
All commercial reagents (1-alkynes, palladium catalysts, PPh3,
DMF) were purchased from Acros and Aldrich and used without
additional purification.
pteridine-2,4(1H,3H)-dione 8
CuI (10 mg, 0.05 mmol), Pd2dba3 (18 mg, 0.02 mmol), PPh3
(42 mg, 0.16 mmol) and K2CO3 (103 mg, 0.75 mmol) were added to
6,7-dichloro-1,3-dimethyllumazine 7 (261 mg, 1 mmol) in DMF
(3 mL) under a slow stream of argon. The mixture was stirred and,
after 10 min, phenylacetylene (128 mg, 0.12 mL, 1.25 mmol) was
added. Stirring was continued for 2 h at room temperature under
argon. Then water (5 mL) was added to the reaction mixture. The
crude product was separated by filtration, rinsed with water and
dried. Crystallization from i-PrOH gave 8 (209 mg, 64%) as yellow
needles, mp 241–243 ꢀC; 1H NMR (CDCl3, 250 MHz)
3H, 3-Me), 3.71 (s, 3H, 1-Me), 7.46 (m, 3H, Ph), 7.69 (m, 2H, Ph); 13C
NMR (CDCl3, 62.9 MHz) ppm: 29.6, 30.3, 85.6, 102.3, 120.9, 124.7,
129.2, 131.3, 133.1, 142.2, 145.2, 146.6, 150.7, 159.0; IR (Nujol), cmꢁ1
1663 and 1727 (C]O), 2207 (C^C). UV (CHCl3), lmax (lg ), nm: 325
d ppm: 3.52 (s,
4.2. X-ray structure determination
d
:
Crystallographic data for 4a: at 120 K crystals of C24H16N4O2 are
monoclinic, space group P2(1)/n, a¼15.242(4), b¼8.631(2),
3
(3.93), 340 (3.98), 405 (4.46). Anal. calcd for C16H11ClN4O2: C, 58.82;
H, 3.39; Cl, 10.85; N, 17.15. Found: C, 58.65; H, 3.43; Cl, 11.05; N,
17.01.
c¼16.268(5) Å,
a
¼90ꢀ,
b
¼116.025(6)ꢀ,
g
¼90ꢀ, V¼1923.1(9) Å3, Z¼4,
M¼392.41, dcalcd¼1.355 g cmꢁ3
,
m
(MoKa)¼0.089 mmꢁ1, F(000)¼816.
Intensities of 15,260 reflections were measured with a SMART dif-
fractometer at 120 K and 5549 independent reflections (Rint¼0.0935)
were used in further refinement. The structures were solved by direct
method and refined by the full-matrix least squares against F2 in the
anisotropic-isotropic approximation. Hydrogen atoms were located
from the Fourier synthesis and refined in the isotropic approxima-
tion. The refinement converged to wR2¼0.1230 and GOF¼1.026 forall
independent reflections [R1¼0.0691 was calculated against F for
4.5. Synthesis of 1,3-dimethyl-6,7-bis(phenylethynyl)-
pteridine-2,4(1H,3H)-dione 4a
CuI (10 mg, 0.05 mmol), Pd2dba3 (18 mg, 0.02 mmol), PPh3
(42 mg, 0.16 mmol) and K2CO3 (207 mg, 1.5 mmol) were added to
6,7-dichloro-1,3-dimethyllumazine 7 (261 mg, 1 mmol) in DMF
(3 mL) under a slow stream of argon. The mixture was stirred and,
after 10 min, phenylacetylene (255 mg, 2.5 mmol) was added. Stir-
ring was continued for 2 h at 90–100 ꢀC under argon. The mixture
was then evaporated, treated with water (5 mL) and extracted with
chloroform (3ꢂ30 mL). The solvent was subsequently removed
under reduced pressure. The crude product was purified by flash
column chromatography on Al2O3 with CHCl3 as the eluent. The
yellow fraction with Rf 0.8 gave 4a. Crystallization from i-PrOH
yielded 4a (129 mg, 33%) as yellow needles, mp 225–227 ꢀC; 1H
observed 1797 reflections with I>2 s(I)].
Crystallographic data for 9c: at 293 K crystals of C29H32N8O2 are
triclinic, space group P-1, a¼8.989(2), b¼9.562(2), c¼15.079(3) Å,
a
¼94.78(3)ꢀ,
b
¼96.28(3)ꢀ,
g
¼99.97(3)ꢀ, V¼1261.9(4) Å3, Z¼2,
M¼524.63, dcalcd¼1.38 g cmꢁ3
, m
(MoKa)¼0.091 mmꢁ1, F(000)¼556.
Intensities of 4763 reflections were measured with a Enraf–Nonius
CAD-4 diffractometer at 293 K and 4451 independent reflections
(Rint¼0.0464) were used in further refinement. The structures were
solved by direct method and refined by the full-matrix least squares
against F2 in the anisotropic-isotropic approximation. Hydrogen
atoms were located from the Fourier synthesis and refined in the
isotropic approximation. The refinement converged to wR2¼0.1339
and GOF¼1.061 for all independent reflections [R1¼0.0477 was
NMR (CDCl3, 250 MHz)
d
ppm: 3.53 (s, 3H, 3-Me), 3.73 (s, 3H,1-Me),
ppm:
7.46 (m, 6H, Ph), 7.69 (m, 4H, Ph); 13C NMR (CDCl3, 75 MHz)
d
29.0, 29.5, 85.4, 86.3, 96.0, 99.9, 120.9, 121.6, 125.1, 128.5, 128.6,
129.6, 130.5, 132.0, 132.5, 137.0, 143.9, 145.5, 150.3, 158.9; IR (Nujol),
cmꢁ1: 1663 and 1714 (C]O), 2200 and 2213 cmꢁ1 (C^C); UV
calculated against F for observed 1797 reflections with I>2
s
(I)].
(CHCl3), lmax (lg 3), nm: 264 (4.42), 316 (4.45), 405 (4.28). Anal. calcd
Crystallographic data for 17a: at 100 K crystals of C24H15N5 are
triclinic, space group P-1, a¼8.954(2), b¼9.347(2), c¼11.107(3) (5) Å,
for C24H16N4O2: C, 73.46; H, 4.11; N, 14.28. Found: C, 73.56; H, 3.94;
N, 14.10.
a
¼82.163(5)ꢀ,
b
¼78.231ꢀ,
g
¼80.702(5)ꢀ, V¼892.9(3) Å3, Z¼2,
M¼373.41, dcalcd¼1.389 g cmꢁ3
,
m
(MoKa)¼0.086 mmꢁ1, F(000)¼388.
4.6. General procedure for 6,7-dialkynyllumazines 4b,c
Intensities of 11,376 reflections were measured with a SMART dif-
fractometer at 100 K and 5114 independent reflections (Rint¼0.0727)
were used in further refinement. The structures were solved by direct
method and refined by the full-matrix least squares against F2 in the
anisotropic-isotropic approximation. Hydrogen atoms were located
from the Fourier synthesis and refined in the isotropic approxima-
tion. The refinement converged to wR2¼0.0815 and GOF¼1.012 for all
independent reflections [R1¼0.0595 was calculated against F for
CuI (10 mg, 0.05 mmol), Pd2dba3 (18 mg, 0.02 mmol), PPh3
(42 mg, 0.16 mmol) and K2CO3 (103 mg, 0.75 mmol) were added to
6-chloro-1,3-dimethyl-7-(phenylethynyl)lumazine
8
(326.5 mg,
1 mmol) in DMF (3 mL) under a slow stream of argon. The mixture
was stirred for 10 min and alkyne (1.25 mmol) was added. Stirring
was continued for 2 h at 90–100 ꢀC under argon. Then the mixture
was evaporated, treated with water (5 mL) and extracted with
chloroform (3ꢂ30 mL). The solvent was subsequently removed
under reduced pressure. The crude product was purified by flash
column chromatography on Al2O3 with CHCl3 as the eluent. The
yellow fraction gave 4 (Rf 0.9 for 4b, Rf 0.5 for 4c). Crystallization
from i-PrOH yielded 4 as yellow crystals.
observed 2747 reflections with I>2 s(I)].
All calculations were performed using SHELXL-97 on a IBM PC
AT. Atomic coordinates, bond lengths, bond angles and thermal
parameters have been deposited at the Cambridge Crystallographic
Data Centre (CCDC) and allocated the deposition number
CCDC738042 (4a), 660803 (9c) and 660802 (17a).
4.6.1. 1,3-Dimethyl-6-(oct-1-ynyl)-7-(phenylethynyl)pteridine-
4.3. Synthesis of the starting compounds
2,4(1H,3H)-dione 4b. Yield 148 mg (37%). Yellow needles, mp 158–
160 ꢀC; 1H NMR (CDCl3, 250 MHz)
d
ppm: 0.83 (t, J¼6.9 Hz, 3H,
Compounds 77,10 and 1311 were synthesized in accordance with
known procedures. 1-(1-Ethynylcyclohexyl)piperidine was pre-
pared from 1-ethynylcyclohexanol by a literature procedure.12
(CH2)5CH3), 1.22–1.28 (m, 4H, (CH2)3(CH2)2CH3), 1.45 (m, 2H,
(CH2)2CH2C3H7), 1.65 (m, 2H, CH2CH2C4H9), 2.54 (t, J¼7.1 Hz, 2H,
CH2C5H11), 3.52 (s, 3H, 3-Me), 3.71 (s, 3H, 1-Me), 7.42 (m, 3H, Ph),

150
A.V. Gulevskaya et al. / Tetrahedron 66 (2010) 146–151
7.65 (m, 2H, Ph); 13C NMR (CDCl3, 62.9 MHz)
d
ppm: 14.4, 20.2, 22.9,
(4.18); MS m/z: 443 ([M]þ, 1), 415 ([M-N2]þ, 38), 401 (12), 347 (18),
28.6, 29.1, 29.5, 29.9, 31.7, 77.7, 86.8, 99.3, 99.7, 121.5, 125.4, 129.0,
272 (10), 77 (15), 67 (17), 55 (25), 43 (68), 41 (100). Anal. calcd for
C24H25N7O2: C, 65.00; H, 5.68; N, 22.11. Found: C, 65.13; H, 5.49; N,
22.22.
130.8, 132.9, 138.0, 144.3, 145.7, 150.9, 159.4; IR (Nujol), cmꢁ1: 1670
and 1710 (C]O), 2205 and 2240 (C^C); UV (CHCl3), lmax (lg 3), nm:
300 (4.34), 395 (4.35), 406 (4.36). MS m/z: 400 ([M]þ,100), 385 (16),
357 (35), 343 (30), 331 (52), 317 (11), 295 (11), 281 (16), 258 (10),
244 (32), 230 (20), 216 (29), 203 (25), 190 (40), 177 (15), 127 (19), 91
(19), 81 (35), 67 (17), 55 (22), 41 (55). Anal. calcd for C24H24N4O2: C,
71.98; H, 6.04; N, 13.99. Found: C, 72.11; H, 5.93; N, 14.12.
4.7.3. 9,11-Dimethyl-1-phenyl-5-(1-(piperidin-1-yl)cyclohexyl)-
[1,2,3]triazolo[10,50;1,2]pyrido[4,3-g]pteridine-8,10(9H,11H)-dione
9c. Yield 236 mg (45%). Orange crystals, mp 238–240 ꢀC; 1H NMR
(CDCl3, 250 MHz)
d ppm: 1.36–1.64 (m, 12H, 3CH2 cyclohexyl and
3CH2 piperidino), 2.40–2.70 (m, 8H, 2CH2 cyclohexyl and 2CH2
piperidino), 3.58 (s, 3H, 9-Me), 3.61 (s, 3H, 11-Me), 7.50 (m, 3H, Ph),
7.53 (s, 1H, 6-H), 8.18 (m, 2H, Ph); 13C NMR (CDCl3, 62.9 MHz)
4.6.2. 1,3-Dimethyl-7-(phenylethynyl)-6-((1-(piperidin-1-yl)cyclo-
hexyl)ethynyl)pteridine-2,4(1H,3H)-dione 4c. Yield 260 mg (54%).
Yellowish needles, mp 214–216 ꢀC; 1H NMR (CDCl3, 250 MHz)
d
ppm: 23.2, 25.4, 26.5, 27.9, 29.7, 30.6, 34.4, 48.3, 64.6, 115.6, 128.4,
d
ppm: 1.34 (m, 2H, CH2 cyclohexyl), 1.57 (m, 12H, 3CH2 cyclo-
128.5, 129.1, 129.7, 130.3, 130.8, 138.7, 139.0, 144.1, 145.5, 146.4,
hexylþ3CH2 piperidino), 2.13 (m, 2H, CH2 cyclohexyl), 2.66 (m, 4H,
150.7, 159.9; IR (Nujol), cmꢁ1: 1667 and 1721 (C]O); UV (CHCl3),
2CH2 piperidino), 3.53 (s, 3H, 3-Me), 3.71 (s, 3H, 1-Me), 7.42 (m, 3H,
lmax (lg 3
), nm: 317 (3.86), 429 (4.19); MS m/z: 496 ([M-N2]þ, 1), 413
Ph), 7.62 (m, 2H, Ph); 13C NMR (CDCl3, 62.9 MHz)
d
ppm: 23.2, 24.9,
([M-N2-C5H9N]þ, 62), 331 (33), 316 (57), 245 (11), 231 (14), 218 (11),
206 (13), 204 (18), 191 (13), 178 (11), 165 (31), 152 (13), 150 (31), 136
(25), 122 (26), 94 (12), 91 (15), 83 ([C5H9N]þ, 100), 76 (39), 69 (28),
66 (88), 43 (74). Anal. calcd for C29H32N8O2: C, 66.39; H, 6.15; N,
21.36. Found: C, 66.43; H, 5.98; N, 21.54.
26.0, 26.9, 29.5, 30.0, 36.0, 47.6, 59.8, 82.3, 86.8, 99.4, 99.8, 121.4,
125.5, 129.0, 130.7, 132.6, 137.6, 144.4, 145.7, 150.8, 159.5; IR (Nujol),
cmꢁ1: 1663 and 1710 (C]O), 2207 and 2233 (C^C); UV (CHCl3),
lmax (lg 3), nm: 299 (4.30), 385 (4.31). Anal. calcd for C29H31N5O2: C,
72.33; H, 6.49; N, 14.54. Found: C, 72.34; H, 6.31; N, 14.49.
4.7.4. 8,10-Dimethyl-1,5-diphenyl-[1,2,3]triazolo[10,50;1,2]pyrido[3,4-
4.7. General procedure for the triazolopyridopteridines
9 and 10
g]pteridine-9,11(8H,10H)-dione 10a. Yield 109 mg (25%). Yellow
needles, mp 255–257 ꢀC; 1H NMR (CDCl3, 250 MHz)
d
ppm: 3.49 (s,
3H, 10-Me), 3.58 (s, 3H, 8-Me), 7.42–7.61 (m, 7H, 6-H, Ph and Ph0),
8.00–8.09 (m, 2H, Ph), 8.24–8.33 (m, 2H, Ph0); IR (Nujol), cmꢁ1
To a stirred solution of 6,7-dialkynyllumazine 4 (0.5 mmol) in
DMF (5 mL), sodium azide (49 mg, 0.75 mmol) was added. The
reaction mixture was stirred at room temperature for 24 h. A so-
lution of NH4Cl (27 mg, 0.5 mmol) in water (5 mL) was added. The
mixture was extracted with chloroform (3ꢂ20 mL) and concen-
trated in vacuo. Flash column chromatography on Al2O3 with CHCl3
as the eluent gave a yellow fraction Rf 0.7–0.9 containing both
products 9 and 10.
:
1727 and 1740 (C]O); UV (CHCl3), lmax (lg 3), nm: 330 (3.98), 387
(4.28); MS m/z: 407 ([M-N2]þ, 2), 379 (100), 366 (27), 364 (30), 291
(10), 149 (21), 140 (11), 128 (19), 114 (10), 103 (10), 82 (15), 77 (35),
67 (21), 55 (27), 43 (40). Anal. calcd for C24H17N7O2: C, 66.20; H,
3.94; N, 22.52. Found: C, 66.24; H, 3.76; N, 22.70.
4.8. General procedure for 2,3-dialkynylquinoxalines 14
The mixture of 9a and 10a was separated by additional flash
column chromatography on Al2O3 with CHCl3 as the eluent. The
yellow fraction with Rf 0.75 gave 10a, the dark yellow fraction with
Rf 0.65 gave 9a. Both 9a and 10a were crystallized from i-PrOH.
Additional flash column chromatography (Al2O3, CHCl3) of the
mixtures 9b and 10b, 9c and 10c gave the only corresponding tri-
azole 9 in a pure state.
CuI (19 mg, 0.1 mmol), Pd(Ph3P)2Cl2 (35 mg, 0.05 mmol) and
Et3N (2 mL) were added to 2,3-dichloroquinoxaline 13 (199 mg,
1 mmol) in DMF (5 mL) under a slow stream of argon. The mixture
was stirred for 10 min and alkyne (2.5 mmol) was added dropwise.
Stirring was continued for 4 h at room temperature under argon
(reaction with 1-decyne needed additional heating at 70–80 ꢀC for
2 h). Then the mixture was evaporated, treated with water (5 mL)
and extracted with CH2Cl2 (3ꢂ20 mL). The solvent was sub-
sequently removed under reduced pressure. The crude product was
purified by flash column chromatography on silica with CH2Cl2/
hexane (10:1, v/v) as the eluent (Rf 0.75 for 14a, Rf 0.79 for 14b, Rf
0.92 for 14c). Additional purification of 14c was carried out by flash
column chromatography on silica with CHCl3 as the eluent.
4.7.1. 9,11-Dimethyl-1,5-diphenyl-[1,2,3]triazolo[10,50;1,2]pyrido[4,3-
g]pteridine-8,10(9H,11H)-dione 9a. Yield 196 mg (45%). Orange
needles, mp 273–275 ꢀC; 1H NMR (CDCl3, 250 MHz)
d ppm: 3.59 (s,
3H, 9-Me), 3.66 (s, 3H, 11-Me), 7.52 (m, 3H, Ph), 7.61 (m, 3H, Ph0),
7.69 (s,1H, 6-H), 8.03 (m, 2H, Ph), 8.20 (m, 2H, Ph0); 13C NMR (CDCl3,
62.9 MHz)
d ppm: 29.7, 30.6, 115.4, 127.9, 128.5, 129.2, 129.3, 129.9,
130.0, 130.2, 130.6, 131.1,131.4,138.9,139.5,140.9,146.4,146.7,150.7,
159.7; IR (Nujol), cmꢁ1: 1673 and 1713 (C]O); UV (CHCl3), lmax
4.8.1. 2,3-Bis(phenylethynyl)quinoxaline 14a. Yield 228 mg (69%).
(lg
3
), nm: 319 (4.03), 445 (4.23); MS m/z: 409 (53), 407 ([M-N2]þ,
Off-white needles, mp 128–129 ꢀC (MeOH), lit.13 128–130 ꢀC (ben-
100), 394 (16), 392 ([M-HN3]þ, 24), 282 (12), 280 (11), 140 (10), 82
(10), 77 (17), 55 (10), 43 (17). Anal. calcd for C24H17N7O2: C, 66.20;
H, 3.94; N, 22.52. Found: C, 66.02; H, 4.15; N, 22.38.
zene/light petroleum); 1H NMR (CDCl3, 250 MHz)
d pm: 7.37 (m,
6H, Ph and Ph0), 7.68 (m, 4H, Ph and Ph0), 7.75 (m, 2H, 6-H and 7-H),
8.06 (m, 2H, 5-H and 8-H); IR (Nujol), cmꢁ1: 2206 (C^C); UV
(CHCl3), lmax (lg 3), nm: 270 (4.49), 280 (4.47), 305 (4.54), 390
4.7.2. 5-Hexyl-9,11-dimethyl-1-phenyl-[1,2,3]triazolo[10,50;1,2]-
pyrido[4,3-g]pteridine-8,10(9H,11H)-dione 9b. Yield 177 mg (40%).
Orange needles, mp 209–211 ꢀC; 1H NMR (CDCl3, 250 MHz)
(4.24); MS m/z: 330 ([M]þ, 60), 203 (62), 176 (23), 165 (38), 127 (81),
100 (41), 87 (13), 76 (87), 63 (25), 50 (100), 39 (37). Anal. calcd for
C24H14N2: C, 87.25; H, 4.27; N, 8.48. Found: C, 87.07; H, 4.44; N, 8.60.
d
ppm: 0.88 (t, J¼6.9 Hz, 3H, (CH2)5CH3), 1.28–1.43 (m, 4H,
(CH2)3(CH2)2CH3), 1.53 (m, 2H, (CH2)2CH2(CH2)2CH3), 1.98 (m, 2H,
CH2CH2(CH2)3CH3), 3.38 (t, J¼7.3 Hz, 2H, CH2(CH2)4CH3), 3.58 (s,
3H, 9-Me), 3.66 (s, 3H, 11-Me), 7.45 (s, 1H, 6-H), 7.52 (m, 3H, Ph),
4.8.2. 2,3-Bis(p-tolylethynyl)quinoxaline 14b. Yield 300 mg (84%).
Off-white needles, mp 183–185 ꢀC (hexane); 1H NMR (CDCl3,
250 MHz)
7.57 (d, J¼8.1 Hz, 4H, p-Tol), 7.73 (m, 2H, 6-H and 7-H), 8.04 (m, 2H,
5-H and 8-H); 13C NMR (CDCl3, 62.9 MHz)
ppm: 22.1, 86.9, 96.7,
119.0, 129.3, 129.8, 131.1, 132.8, 140.7, 140.8, 141.5; IR (Nujol), cmꢁ1
2205 (C^C); UV (CHCl3), lmax (lg ), nm: 270 (4.65), 285 (4.72), 300
d
ppm: 2.37 (s, 6H, 2CH3), 7.17 (d, J¼8.1 Hz, 4H, p-Tol),
8.23 (m, 2H, Ph); 13C NMR (CDCl3, 62.9 MHz)
d
ppm: 14.5, 23.0, 26.8,
29.3, 29.7, 30.6, 30.9, 31.9, 113.2, 127.2, 128.4, 128.8, 129.8, 130.0,
130.6, 138.4, 139.3, 142.6, 146.1, 146.7, 150.7, 159.7; IR (Nujol), cmꢁ1
1667 and 1713 (C]O); UV (CHCl3), lmax (lg ), nm: 313 (3.90), 440
d
:
:
3
3

A.V. Gulevskaya et al. / Tetrahedron 66 (2010) 146–151
151
(4.76), 384 (4.40); MS m/z: 358 ([M]þ, 72), 343 ([M-CH3]þ,72), 216
(72), 289 (24), 179 (19), 140 (100), 114 (34), 76 (17), 50 (14). Anal.
calcd for C26H18N2: C, 87.12; H, 5.06; N, 7.82. Found: C, 86.93; H,
5.25; N, 8.01.
11-H), 8.57 (d, J¼8.4 Hz, 2H, p-Tol); 13C NMR (CDCl3, 62.9 MHz)
d
ppm: 22.0, 115.5, 128.1, 128.4, 128.8, 129.1, 129.4, 129.8, 130.0(9),
130.1(1), 130.1(3), 131.0, 131.5, 138.0, 139.5, 141.6, 141.7, 142.4, 143.4,
143.7, 146.3; UV (CHCl3), lmax (lg 3), nm: 270 (4.57), 315 sh (4.14),
435 (4.04); MS m/z: 373 ([M-N2]þ, 100), 358 (50), 232 (14), 187 (23),
140 (13), 128 (10), 115 (40), 102 (23), 91 (36), 77 (26), 65 (30), 51
(21), 39 (27). Anal. calcd for C26H19N5: C, 77.79; H, 4.77; N, 17.44.
Found: C, 77.96; H, 4.58; N, 17.40.
4.8.3. 2,3-Bis(dec-1-ynyl)quinoxaline 14c. Yield 120 mg (30%). Off-
white crystals, mp 35–36 ꢀC (MeOH/H2O); 1H NMR (CDCl3,
250 MHz)
d ppm: 0.86 (m, 6H, 2CH3), 1.30 m (16H, 8CH2), 1.50 (m,
4H, 2CH2), 1.68 (m, 4H, 2CH2), 2.55 (t, J¼7.3 Hz, 4H, 2CH2), 7.68 (m,
2H, 6-H and 7-H), 7.98 (m, 2H, 5-H and 8-H); 13C NMR (CDCl3,
4.9.3. 1,5-Dioctyl-[1,2,3]triazolo[50,10;1,2]pyrido[3,4-b]quinoxaline
62.9 MHz)
d
ppm: 14.5, 20.2, 23.1, 28.7, 29.4, 29.5, 29.6, 32.3, 79.0,
17c. Yield 22 mg (10%). Yellow needles, mp 59–61 ꢀC (decomp.,
98.4, 129.0, 130.8, 140.6, 141.6; IR (Nujol), cmꢁ1: 2210 (C^C); UV
MeOH); 1H NMR (CDCl3, 250 MHz)
d ppm: 0.86 (m, 6H, 2CH3), 1.30–
(CHCl3), lmax (lg
3
), nm: 268 (4.73), 354 (4.12), 363 (4.00), 372
1.60 (m, 20H, 10CH2), 1.97 (m, 4H, 2CH2), 3.34 (t, J¼7.4 Hz, 2H, CH2),
3.53 (t, J¼7.7 Hz, 2H, CH2), 7.19 (t, J¼1.1 Hz, 1H, 6-H), 7.85 (m, 2H, 9-
H and 10-H), 8.13–8.28 (m, 2H, 8-H and 11-H); 13C NMR (CDCl3,
(4.21); MS m/z: 402 ([M]þ, 9), 261 (32), 247 (21), 235 (39), 219 (38),
205 (18), 181 (10), 154 (10), 77 (31), 55 (31), 50 (10), 41 (100). Anal.
calcd for C28H38N2: C, 83.53; H, 9.51; N, 6.96. Found: C, 83.73; H,
9.64; N, 7.12.
62.9 MHz)
d ppm: 14.4(9), 14.5(1), 23.0(5), 23.0(9), 27.0, 27.2, 29.3,
29.6, 29.6(8), 29.7(1), 29.7(3), 29.8, 29.9, 31.0, 32.2, 32.3, 113.1,
128.2, 129.6, 130.0, 130.7, 131.1, 138.4, 142.3, 142.9, 143.3, 143.8,
4.9. General procedure for [1,2,3]triazolo[50,10;1,2]pyrido-
[3,4-b]quinoxalines 17
148.0; UV (CHCl3), lmax (lg 3), nm: 254 (4.75), 396 (4.31), 415 (4.32);
MS m/z: 417 ([M-N2]þ, 31), 333 (100), 319 (13), 260 (12), 246 (31),
233 (58), 220 (33), 209 (16), 193 (10), 102 (11), 77 (13), 55 (31), 41
(100). Anal. calcd for C24H15N5: C, 75.46; H, 8.82; N, 15.72. Found: C,
C, 75.63; H, 8.72; N, 15.61.
To a stirred solution of 2,3-dialkynylquinoxaline 14 (0.5 mmol)
in DMF (6 mL), sodium azide (49 mg, 0.75 mmol) was added. The
reaction mixture was stirred at room temperature for 24 h (in the
case of 14c reaction needed additional heating at 70 ꢀC for 2 h). A
solution of NH4Cl (27 mg, 0.5 mmol) in water (5 mL) was added.
The crude product was separated by filtration. Flash column chro-
matography on silica with CHCl3 as the eluent (yellow fraction, Rf
0.22 for 17a, Rf 0.18 for 17b, Rf 0.34 for 17c) followed by crystalli-
zation from MeOH gave 17.
References and notes
1. For review, see: (a) Kar, M.; Basak, A. Chem. Rev. 2007, 107, 2861–2890; (b)
Rawat, D. S.; Zaleski, J. M. Synlett 2004, 0393–0421; (c) Wenk, H. H.; Winkler,
M.; Sander, W. Angew. Chem., Int. Ed. 2003, 42, 502–528; (d) Basak, A.; Mandal,
S.; Beg, S. S. Chem. Rev. 2003, 103, 4077–4094; (e) Nicolaou, K. C.; Dai, W.-M.
Angew. Chem., Int. Ed. Engl. 1991, 30, 1387–1530.
2. Jones, R. R.; Bergman, R. G. J. Am. Chem. Soc. 1972, 94, 660–661.
3. Nagata, R.; Yamanaka, H.; Okazaki, E.; Saito, I. Tetrahedron Lett. 1989, 30, 4995–
4998.
4. (a) Lee, C. Y.; Lin, C. F.; Lee, J. L.; Chiu, C. C.; Lu, W. D.; Lu, W. D.; Wu, M. J. J. Org.
Chem. 2004, 69, 2106–2110; (b) Wu, M. J.; Lin, C. F.; Lu, W. D. J. Org. Chem. 2002,
67, 5907–5912; (c) Wu, M. J.; Lee, C. J.; Lin, C. F. Angew. Chem., Int. Ed. 2002, 41,
4077–4079; (d) Wu, M. J.; Lin, C. F.; Chen, S. H. Org. Lett. 1999, 1, 767–768; (e)
Magnus, P.; Eisenbeis, S. A. J. Am. Chem. Soc. 1993, 115, 12627–12628; (f)
Sugiyama, H.; Yamashita, K.; Nishi, M.; Saito, I. Tetrahedron Lett. 1992, 33,
515–518.
4.9.1. 1,5-Diphenyl-[1,2,3]triazolo[50,10;1,2]pyrido[3,4-b]quinoxaline
17a. Yield 144 mg (77%). Bright yellow needles, mp 213–215 ꢀC
(decomp., i-PrOH); 1H NMR (CDCl3, 250 MHz)
d ppm: 7.51 (s, 1H, 6-
H), 7.55 (m, 6H, Ph and Ph0), 7.85 (m, 2H, 9-H and 10-H), 8.04 (m, 2H,
Ph), 8.18 (m, 2H, 8-H and 11-H), 8.61 (m, 2H, Ph0); 13C NMR (CDCl3,
62.9 MHz)
d ppm: 116.1, 128.4, 128.6, 128.7, 129.1, 129.5, 129.6, 130.0,
130.1(9), 130.2(2), 130.9, 131.2, 131.6, 131.7, 137.9, 141.7, 142.2, 143.4,
5. Chen, Zh.-Y.; Wu, M.-J. Org. Lett. 2005, 7, 475–477.
143.5,146.1; UV (CHCl3), lmax (lg 3), nm: 427 (4.23); MS m/z: 345 ([M-
6. (a) Gulevskaya, A. V.; Dang, V. S.; Pozharskii, A. F. Russ. Chem. Bull., Int. Ed. 2003,
52, 1403–1410; (b) Dang, V. S.; Gulevskaya, A. V.; Pozharskii, A. F.; Kotelevskaya,
R. V. Chem. Heterocycl. Compd. (Engl. Transl.) 2005, 41, 124–135; (c) Gulevskaya,
A. V.; Dang, V. S.; Pozharskii, A. F. J. Heterocycl. Chem. 2005, 42, 413–419.
7. Heckel, A.; Pfleiderer, W. Helv. Chim. Acta 1986, 69, 708–717.
8. Zhao, Zh.; Peacock, J. G.; Gubler, D. A.; Peterson, M. A. Tetrahedron Lett. 2005, 46,
1373–1375.
9. Kauffman, J. F.; Turner, J. M. J. Phys. Chem. A 2006, 110, 241–251.
10. Blike, F. F.; Godt, H. C. J. Am. Chem. Soc. 1954, 76, 2798–2800.
11. Stevens, J. R.; Pfister, K.; Wolf, F. J. J. Am. Chem. Soc. 1946, 68, 1035–1039.
12. Hehhion, G. F.; Nelson, K. W. J. Am. Chem. Soc. 1957, 79, 2142–2145.
13. Ames, D. E.; Brohi, M. I. J. Chem. Soc., Perkin Trans 2 1980, 1384–1389.
N2]þ, 100), 317 (16), 218 (15), 172 (57), 159 (20), 114 (22), 101 (29), 87
(10), 76 (41), 63 (29), 51 (56), 39 (31). Anal. calcd for C24H15N5: C,
77.20; H, 4.05; N, 18.76. Found: C, 77.13; H, 3.95; N, 18.96.
4.9.2. 1,5-Di(p-tolyl)-[1,2,3]triazolo[50,10;1,2]pyrido[3,4-b]quinoxa-
line 17b. Yield 160 mg (80%). Bright yellow prisms, mp 266–268 ꢀC
(decomp., MeOH); 1H NMR (CDCl3, 250 MHz)
d ppm: 2.53 (s, 6H,
2CH3), 7.45 (d, J¼8.4 Hz, 4H, p-Tol), 7.52 (s, 1H, 6-H), 7.90 (m, 2H,
9-H and 10-H), 7.99 (d, J¼8.4 Hz, 2H, p-Tol), 8.23 (m, 2H, 8-H and