Study of reactivity in the 1,3-dipolar cycloaddition reactions leading to new triazolopyrrolopyrazine ring systems

Article abstract of DOI:10.1055/s-0030-1258532

The influence of the structural symmetry of the 2 double-reactive-sites component in the 1,3-dipolar cycloaddition reactions, involving nitrilimines as dipoles, was investigated. The experimental data showed that the loss of the symmetry leads to the form

Full text of DOI:10.1055/s-0030-1258532

LETTER
2067
Study of Reactivity in the 1,3-Dipolar Cycloaddition Reactions Leading to New
Triazolopyrrolopyrazine Ring Systems
Reactivity in the
1
n
,3-Dipolar
C
t
ycloadd
o
ition Reactio
n
ns ino Lauria, Annalisa Guarcello, Gaetano Dattolo, Anna Maria Almerico
Dipartimento Farmacochimico, Tossicologico e Biologico, Università di Palermo, Via Archirafi 32, 90123 Palermo, Italy
E-mail: lauria@unipa.it
Received 1 May 2010
quinoxaline derivatives of type 4 (Scheme 1). It was dem-
Abstract: The influence of the structural symmetry of the 2p dou-
onstrated that in the 1,3-DCR of the quinoxaline (5) with
ble-reactive-sites component in the 1,3-dipolar cycloaddition reac-
nitrilimines 6, the formation of the monocycloadduct 7
was never observed, even by using a large excess of dipo-
larophile,8 in contrast to literature data.10 In the case of the
reactions leading to the bistriazoloquinoxalines 4, both
possible biscycloadduct diastereomers (RR and RS), were
obtained. These findings confirm the lack of diastereose-
lectivity, at variance with the literature reports for other
symmetric diazine rings.9,11,12
tions, involving nitrilimines as dipoles, was investigated. The
experimental data showed that the loss of the symmetry leads to the
formation of the monocycloadduct in good yields.
Key words: 1,3-dipolar cycloaddition reactions, diazines, nitril-
imine dipoles, triazolopyrrolopyrazines
A large number of compounds bearing pyrrolopyrazine
and triazolopyrazine moieties showed appreciable activity
in many biological systems. Indolo[2,3-b]quinoxalines of
type 1 represent an important series of DNA intercalating
agents endowed with good antiviral and cytotoxic activi-
ties.1–3 The antiproliferative properties of the tricyclic in-
dolopyrazine system of type 2 have been demonstrated as
well.4 Moreover triazoloquinoxaline derivative 3 showed
antibacterial activity (Figure 1).5
N
R
R
N
N
N
N
N
Ar
Ar
N
N
5
+
R
N
Ar
N
N
N
7
R
N
N
Ar
6
4
N
R2
N
R1
N
NMe2
N
N
H2N
N
R3
N
Scheme 1 1,3-Dipolar cycloaddition reaction of nitrilimines and
quinoxaline
N
N
N
N
1
2
On the contrary, when the the dipolarophile component
was nonsymmetric, the reaction route changed. In fact, in
the case of the 1,3-DCR of nitrilimines 6 and the 5-meth-
ylquinoxaline (8) or quinazoline (9), the formation of the
monocycloadducts 10 and 11 was observed, although in
low yields (Scheme 2).13
N
H2N
3
Figure 1
To extend our previous studies on the synthesis of com-
pounds containing pyrrole,6 indole,7 or pyrazine8 core
structures, in this paper the synthesis of new triazolopyr-
rolopyrazines ring systems, strictly related with above de-
rivatives, was reported.
R
N
N
Ar
N
N
N
+
6
N
H
Azine or diazine heterocycles (pyridine, quinoxaline,
pyrazine) represented good reactants for the one-pot
building of complex ring systems through 1,3-dipolar cy-
cloaddition reactions (1,3-DCR) with nitrilimine dipoles.9
This reaction approach has been already employed with
success by us for the one-pot synthesis of the
1,12,12a,12b-tetrahydrobis-1,2,4-triazolo[4,3-a:3¢,4¢-c]-
10
8
R
N
N
Ar
N
N
+
6
N
N
9
11
Scheme 2 1,3-Dipolar cycloaddition reactions of nitrilimines and
nonsymmetric benzodiazines
SYNLETT 2010, No. 14, pp 2067–2070
Advanced online publication: 28.07.2010
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x
.x
x
.2
0
1
0
DOI: 10.1055/s-0030-1258532; Art ID: G12410ST
© Georg Thieme Verlag Stuttgart · New York

2068
A. Lauria et al.
LETTER
N
N
Cl
N
Ar
+
N
H
Ph
N
R
H
6'a–d
12
R
R
N
R
R
N
N
N
N
Ar
N
Ar
N
N
Ar
Ar
N
N
N
11a
+
+
Ph
Ph
Ph
11b
N
H
N
N
N
N
H
N
H
14'
R
N
16a,b,d
13a–c
N
H
Ar
R
R
N
N
N
Ar
N
Ar
N
N
a R = COOMe, Ar = Ph
b R = COOEt, Ar = 4-ClC6H4
c R = COMe, Ar = Ph
d R = Ph, Ar = Ph
Ph
Ph
N
H
N
N
H
N
15a,b,d
14a–d
Scheme 3 1,3-Dipolar cycloaddition reaction of nitrilimines on pyrrolopyrazine ring as dipolarophile component
Thus, with the aim to explore further the influence of the 11a and H-11b (J = 7.4 Hz), that resulted in agreement
dipolarophile asymmetry in the 1,3-DCR, involving the with a trans configuration.8
pyrazine nucleus, 2-phenylpyrrolo[2,3-b]pyrazine (12)
On the contrary of our previous findings in the quinoxa-
was chosen as 2p component (Scheme 3).14 The synthesis
of 12 was performed according to a convenient method
that consists of the lithiation of methylpyrazine, followed
by an intramolecular Chichibabin-type reaction with ben-
zonitrile.15 The crucial point in this synthesis is represent-
ed by the use of an excess of strong base
lithiumdiisopropylamine by heating to 40 °C. A moderate
increase of yields was obtained by using 3–4 Å MS. The
regio- and site-selective 1,3-DCR of nitrilimines, generat-
ed from the chloroarylhydrazones 6¢a–d, to 2-phenylpyr-
rolo[2,3-b]pyrazine (12), allowed the synthesis, in ‘two
steps, one pot’, of the new ring system 1,11,11a,11b-
line series,8 in these reactions it was also possible to iso-
late, in good yields, as main component, the tricyclic
monoadduct pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine
14, which was directly collected by filtration. Moreover,
from the complex reaction mixture, other derivatives as
the monocycloadducts of type 15 and 16, obtained by the
addition on the pyrrole nitrogen by another molecule of
nitrilimine, were isolated. To optimize the yields, the ex-
perimental conditions were modulated as reported in
Table 1 (methods A–F).
It was possible to observe a slight increase of the yields
using two equivalents of chloroarylhydrazone (method
B). With a higher amount of it (3 equiv, method C) no in-
creased yield was observed, but the reaction mixture re-
sults more complex, and consequently the purification
became difficult. By analyzing the experimental data, it
tetrahydropyrrolo[2,3-e]bis[1,2,4]triazolo[3,4-c:4
qui-
noxaline,3¢-a]pyrazine of type 13. For these compounds it
was possible to estimate the coupling constant between H-
Table 1 Overall Results in Different Experimental Conditions
Method 6¢a (equiv)
Et3N (equiv) Time (h) Temp (°C) Solventa
Yield (%)b
12
5
13
6
14
42
60
n.i.
n.i.
6
15
16
5
Total
53
89
19
13
9
A
B
C
D
E
F
1
2
3
1
1
1
7
72
96
72
72
96
1
25
25
25
25
25
110
H
H
H
B
T
n.i.
10
8
n.i.
n.i.
2
13
9
6
4
n.i.
n.i.
n.i.
n.i.
10
8
7
5
1.5
1.5
n.i.
20
n.i.
4
3
T
13
3
20
a H: tetrahydrofuran; B: benzene; T: toluene.
b n.i.: not isolated.
Synlett 2010, No. 14, 2067–2070 © Thieme Stuttgart · New York

LETTER
Reactivity in the 1,3-Dipolar Cycloaddition Reactions
2069
appeared that the higher yields were achieved by using
two equivalents of chloroarylhydrazones in anhydrous
THF, at room temperature for four days, with an excess of
Et3N (method B). Therefore, by applying the optimized
experimental conditions to 1,3-DCR of 2-phenylpyrro-
lo[2,3-b]pyrazine (12) with the other chloroarylhydra-
zones 6¢b–d, the same reactivity trend, leading to the main
products, was observed (Table 2, Supporting Informa-
tion).14 Only in the case of the chloroarylhydrazone 6¢d
the biscycloadduct of type 13 was not isolated.
R
R
N
N
N
1
N
Ar
N
Ar
Ar
N
N
N
N
N
2
6
6
3
N
N
4
R
17
19
18
H
N
N
N
6
N
Table 2 Optimized Experimental Conditions and Yields
N
Ar
N
Ar
N
N
6¢
Yield (%)a
R
R
20
21
13
14
60
50
55
35
15
10
10
n.i.
16
16
6
Total
89
Scheme
4
The prototropic-shift influence in the 1,3-dipolar
cycloaddition reactions
6¢a
6¢b
6¢c
6¢d
13
20
15
n.i.
6
86
this last case the enaminic form is more favorite that the
imine form (14¢ → 14), for this reason the monocyclo-
adduct is isolated from the reaction mixture in higher
yields.
n.i.
7
70
58
a n.i.: not isolated.
The application of 1,3-dipolar cycloaddition reactions on
the 2p component 2-phenylpyrrolo[2,3-b]pyrazine (12)
has permitted to isolate the new ring systems triazolo[3,4-
c:4¢,3¢-a]-3H-pyrrolo[2,3-e] pyrazine and pyrrole[2,3-
e][1,2,4]triazolo[4,3-a]pyrazine. It was demonstrated that
the asymmetry of the dipolarophile component influences
the reaction route. In fact it was possible to isolate, besides
the bisadduct 13 and, differently from what observed in
quinoxaline series, the monoadduct 14. From these exper-
imental results it is evident as the increase of the asymme-
try in the dipolarophile reactant leads to the formation of
the monocycloadduct.15,16,17
It must be emphasized that in the case of the symmetric di-
azine derivatives (pyrazine and quinoxaline),8 the mono-
cycloadducts were never isolated. This result can be due
to a higher reactivity of the monocycloadduct that prompt-
ly reacts with the second nitrilimine. Therefore, the exper-
imental evidences confirm that the first step is the rate-
limiting step for the formation of the biscycloadducts.
On the contrary, when in the dipolarophile component a
certain grade of asymmetry is present, the reaction route
changes: the monocycloadduct is less reactive, thus the
first cycloaddition often forbids the second one. This hy-
pothesis is corroborated by the case of the reaction of the
2-methylquinoxaline (17),13 in which the formation of the
biscycloadduct was observed (Scheme 4). It can be sup-
posed that the first cycloaddition involves the dipolaro-
phile center bearing the methyl group (1, 2).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
References and Notes
(1) Harmenberg, J.; Aakesson-Johansson, A.; Graeslund, A.;
Malmfors, T.; Bergman, J.; Wahren, B.; Aakerfeldt, S.;
Lundblad, L.; Cox, S. Antiviral Res. 1991, 15, 193.
(2) Harmenberg, J.; Wahren, B.; Bergman, J.; Akerfeldt, S.;
Lundblad, L. Antimicrob. Agents Chemother. 1988, 32,
1720.
(3) Skarin, T.; Rozell, B. L.; Bergman, J.; Toftagard, R.; Moller,
L. Chem. Biol. Interact. 1999, 122, 89.
(4) Arimondo, P. B.; Baldeyrou, B.; Laine, W.; Bal, C.;
Alphonse, F. A.; Routier, S.; Coudert, G.; Mérour, J. Y.;
Colson, P.; Houssier, C.; Bailly, C. Chem. Biol. Interact.
2001, 138, 59.
(5) Nasr, M.; Nasr, A. Arch. Pharm. Med. Chem. 2002, 8, 389.
(6) Lauria, A.; Diana, P.; Barraja, P.; Almerico, A. M.;
Cirrincione, G.; Dattolo, G. J. Heterocycl. Chem. 2000, 37,
747.
(7) Lauria, A.; Patella, C.; Dattolo, G.; Almerico, A. M. J. Med.
Chem. 2008, 51, 2037.
The cycloaddition leads to the monocycloadduct 19 in
which the prototropic shift is not possible. This last condi-
tion is essential for the second cycloaddition (19 → 18).
In fact if in the first cycloaddition the other dipolarophile
center (3, 4) was involved, the prototropic shift (20 → 21)
could have taken place forbidding the second cycloaddi-
tion (21 → 18).
This last consideration suggests that the prototropic shift
rate is comparable or even higher than that of the cycload-
dition reaction.
Thus this make the monocycloadduct 19 a suitable inter-
mediate for the second cycloaddition.
The same consideration can be extended to the case of
monocycloadduct 10 (Scheme 2), formed from the 5-methyl-
quinoxaline (8), and above all for the monocycloadducts
14 (Scheme 3) formed from the pyrrolopyrazine 12. In
(8) Lauria, A.; Guarcello, A.; Dattolo, G.; Almerico, A. M.
Tetrahedron Lett. 2008, 49, 1847.
Synlett 2010, No. 14, 2067–2070 © Thieme Stuttgart · New York

2070
A. Lauria et al.
LETTER
(9) (a) Aversa, M. C.; Bonaccorsi, P.; Giannetto, P.
J. Heterocycl. Chem. 1989, 26, 1619. (b) Grubert, L.;
Jugelt, W.; Breb, J.; Koppel, H.; Strietzel, U.; Dombrowski,
A. Liebigs Ann. Chem. 1992, 885.
(10) Dalla Croce, P. J. Heterocycl. Chem. 1975, 12, 1133.
(11) Grubert, L.; Patzel, M.; Jugelt, W.; Riemer, B.; Liebscher, J.
Liebigs Ann. Chem. 1994, 1005.
7.07–7.23 (m, 10 H, ArH), 7.35–7.43 (m, 2 H, 3-NC6H5),
7.55–7.59 (m, 2 H, 3-NC6H5), 10.77 (s, NH). 13C NMR [50.3
MHz, (CD3)2SO]: d = 52.8 (q), 53.0 (q), 73.3 (d), 74.6 (d),
97.5 (d), 110.0 (s), 113.1 (d), 113.2 (d), 115.0 (s), 120.8 (d),
120.9 (d), 123.2 (d), 124.9 (s), 125.9 (d), 128.8 (2 d), 128.9
(d), 132.2 (s), 140.6 (s), 142.8 (s), 143.4 (s), 144.2 (s), 158.4
(s), 158.6 (s). Anal. Calcd for C30H25N7O4: C, 65.80; H, 4.60;
N, 17.91. Found C, 65.76; H, 4.65; N, 18.02.
The second fraction eluted with CH2Cl2–EtOAc (98:2)gave
methyl 6-[methoxy-N-phenyl-2-oxoethanhydrazonyl]-3,7-
diphenyl-5,6-dihydro-3H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-
a]pyrazine-1-carboxylate (16a); yellow solid, yield 6%; mp
218–219 °C, from EtOH. IR: 3358–3021 (NH), 1739 (C=O),
1596 (C=N) cm–1. 1H NMR [200 MHz, (CD3)2SO]: d = 3.60
(s, 3 H, CH3), 3.95 (s, 3 H, CH3), 7.27 (s, 1 H, H-8), 7.37–
7.56 (m, 11 H, ArH), 7.65 (d, 2 H, 2-C6H5, J = 7.0 Hz), 7.72
(d, 2 H, 2-C6H5, J = 7.8 Hz), 8.32 (d, 2 H, 3-C6H5, J = 7.8
Hz), 8.48 (s, 1 H, H-4). 13C NMR (50.3 MHz, CDCl3): d =
52.8 (q), 52.9 (q), 108.3 (d), 110.9 (s), 120.0 (d), 120.9
(s)125.1 (d), 126.9 (d), 127.8 (d), 128.2 (d), 129.1 (d), 129.2
(d), 129.4 (d), 130.0 (d), 131.7 (s), 133.4 (d), 137.2 (s), 150.5
(s), 153.0 (s), 156.7 (s), 160.3 (s). Anal. Calcd for
(12) Nabih, K.; Baouid, A.; Hasnaoui, A.; Selkti, M.; Compain,
P. New J. Chem. 2003, 27, 1644.
(13) Lauria, A.; Guarcello, A.; Macaluso, G.; Dattolo, G.;
Almerico, A. M. Tetrahedron Lett. 2009, 50, 7333.
(14) General Procedure for the 1,3-Dipolar Cycloaddition
Reactions of 2-Phenyl[1H]pyrrolo[2,3-b]pyrazine15 (12)
and Chlorophenylhydrazones16,17 6¢a–d (Method B)
Triethylamine (20.48 mmol) was added to a solution of
2-phenyl[1H]pyrrolo[2,3-b]pyrazine (12, 2.56 mmol,
0.5 g) and chlorophenylhydrazones 6¢a–d (5.12 mmol) in
anhydrous THF (20 mL). The mixture was stirred at r.t. for
96 h. In the case of the reaction of 12 and 6¢a, methyl 3,7-
diphenyl-5,6-dihydro-3H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-
a]pyrazine-1-carboxylate (14a) was directly filtered from
the mixture; yield 60%; mp 188–189 °C, from EtOH. IR:
3430–3093 (NH), 1731 (C=O), 1556 (C=N) cm–1. 1H NMR
[200 MHz, (CD3)2SO]: d = 3.82 (s, 3 H, CH3), 6.82 (s, 1 H,
H-8), 7.04 (t, 1 H, 4-NC6H5, J = 6.6 Hz), 7.25–7.46 (m, 6 H,
ArH), 8.03–8.05 (m, 1 H, 4-C6H5), 8.21–8.25 (m, 3 H, ArH,
H-4), 10.82 (s, N H). 13C NMR [50.3 MHz, (CD3)2SO]: d =
52.8 (q), 89.1 (d), 114.8 (d), 120.7 (s), 121.6 (s), 123.2 (d),
127.7 (d), 128.7 (d), 129.3 (d), 129.7 (d), 130.2 (d), 130.8 (s),
135.3 (s), 142.4 (s), 160.4 (s), 168.7 (s). Anal. Calcd for.
C21H17N5O2: C, 67.91; H, 4.61; N, 18.86. Found: C, 67.96;
H, 4.68; N, 18.92.
C30H25N7O4: C, 65.80; H, 4.60; N, 17.91. Found: C, 65.73;
H, 4.57; N, 18.05.
Further fraction eluted with CH2Cl2–EtOAc (95:5), afforded
methyl 3,7-diphenyl-3H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-
a]pyrazine-1-carboxylate (15a); very bright orange solid,
yield 10%; mp 254–255 °C, from EtOH. IR: 1735 (C=O),
1552 (C=N) cm–1. 1H NMR [200 MHz, (CD3)2SO]: d = 3.99
(s, 3 H, CH3), 7.51 (s, 1 H, H-8), 7.61–7.72 (m, 5 H, ArH),
7.75 (d, 2 H, 2-NC6H5, J = 6.6 Hz), 8.04 (d, 2 H, 3-C6H5,
J = 7.3 Hz), 8.45–8.47 (m, 2 H, ArH, H-4). 13C NMR [50.3
MHz, (CD3)2SO]: d = 53.0 (q), 91.4 (d), 124.3 (2 d), 129.0
(2 d), 129.9 (d), 130.5 (d), 132.4 (d), 133.9 (s), 134.5 (s),
142.4 (s), 144.6 (s), 162.8 (s), 163.2 (s), 177.1 (s). Anal.
Calcd for C21H15N5O2: C, 68.28; H, 4.09; N, 18.96. Found:
C, 68.36; H, 4.16; N, 19.03. For the experimental details of
all reactions see Supporting Information.
The solution was evaporated under reduced pressure, the
residue was washed with EtOH (5 mL) and chromatog-
raphed on a silica gel column using CH2Cl2 as the eluent.
The first fraction eluted gave 3,9-dimethoxycarbonyl-
1,6,11-triphenyl(1,11,11a,11b-tetrahydrobis-1,2,4-
triazolo[3,4-c:4¢,3¢-a]-3H-pyrrolo[2,3-e]pyrazine) (13a);
yellow solid, yield 13%; mp 214–215 °C, from EtOH. IR:
3407–3166 (NH), 1733, 1708 (C=O), 1594 (C=N) cm–1. 1H
NMR [200 MHz, (CD3)2SO]: d = 3.91 (s, 3 H, CH3), 3.96
(s, 3 H, CH3), 5.83 (d, 1 H, H-11a, J = 7.6 Hz), 5.95 (d, 1 H,
H-11b, J = 7.6 Hz), 6.75–6.77 (m, 3 H, H-5, 4-NC6H5),
(15) Davis, M. L.; Wakefield, B. J.; Wardell, J. A. Tetrahedron
1992, 48, 939.
(16) Dieckmann, W.; Platz, L. Chem. Ber. 1905, 38, 2986.
(17) Ghiglieri-Bertez, C.; Coquelet, C.; Alazet, A.; Bonne, C.
Eur. J. Med. Chem. 1987, 147.
Synlett 2010, No. 14, 2067–2070 © Thieme Stuttgart · New York