A. Lauria et al. / Tetrahedron Letters 50 (2009) 7333–7336
7335
(d), 128.5 (d), 131.2 (s), 133.4 (s), 141.8 (s), 142.2 (s), 143.9 (s), 158.3 (s), 164.0 (s).
Anal. Calcd for C27H24N6O4: C, 65.31; H, 4.87; N, 16.93. Found: C, 65.45; H, 4.82;
N, 16.82. In the case of the reaction with 2b, the first fraction eluted gave 1,12-(4-
chlorophenyl)-3,10-diethoxycarbonyl-12a-methyl-1,12,12a,12b-tetrahydrobis-
[1,2,4]triazolo[4,3-a:30,40-c]quinoxaline (7b): yield 25%; mp 115–117 °C; IR
cmꢀ1 1731 (C@O); 1H NMR: d 1.37 (s, 3H, CH3), 1.26–1.35 (m, 6H, 2 ꢁ CH3), 4.30–
4.77 (m, 4H, 2 ꢁ CH2), 5.90 (s, 1H, H-12b), 7.05–7.54 (m, 12H, H-6, H-7, H-5, H-8,
2 ꢁ o-C6H4Cl, 2 ꢁ m-C6H4Cl); 13C-NMR: d 13.6 (q), 13.8 (q), 14.7 (q), 62.3 (t), 63.1
(t), 75.2 (d), 78.4 (s), 115.4 (d), 119.0 (d), 123.0 (d), 123.1 (s), 123.5 (d), 123.8
(2 ꢁ d), 124.1 (s), 125.2 (s), 125.9 (s), 128.6 (d), 128.8 (d), 140.1 (s), 141.2 (s),
142.3 (s), 143.7 (s), 157.8 (s), 158.8 (s). Anal. Calcd for C29H26Cl2N6O4: C, 58.69; H,
4.42; N, 14.16. Found: C, 58.66; H, 4.48; N, 14.22. The second fraction eluted gave
Ar
N
H
N
N
a: R=COOCH3, Ar=C6H5;
c: R=COCH3, Ar=C6H5;
d: R=COC6H5, Ar=C6H5
+
N
R
Cl
2a,c,d
15
5
Ar
N
N
N
3a
R
Ar
N
diethyl
2,10-di-(4-chlorophenyl)-2,4,10,100a-tetrahydro-90H-spiro{pyrazolo-
N
10b N
3,100-[1,2,4]triazolo[4,3-a]quinoxaline}-30,5-dicarboxylate (8b): yield 15%; mp
170–172 °C, from ethanol; IR cmꢀ1 3322 (NH), 1731 and 1730 (C@O), 1590
(C@N); 1H NMR: d 1.20–1.27 (m, 6H, 2 ꢁ CH3), 2.27 (d, 1H, CH2, J = 19.1 Hz), 3.03
(d, 1H, CH2, J = 19.1 Hz), 4.22–4.25 (m, 4H, 2 ꢁ CH2), 5.25 (s, 1H, H-10a0), 6.67 (d,
2H, o-C6H4Cl, J = 7.4 Hz), 6.85–7.12 (m, 6H, m-C6H4Cl, H-50, H-60, H-70, H-80), 7.27
(d, 2H, o-C6H4Cl, J = 7.8 Hz), 7.37 (d, 2H, m-C6H4Cl, J = 7.8 Hz); 13C NMR: d 13.8
(q), 14.1 (q), 27.9 (t), 56.4 (d), 60.8 (t), 61.6 (t), 74.8 (s), 114.5 (d), 115.9 (d), 116.7
(d), 118.1 (s), 124.4 (d), 126.2 (d), 126.3 (s), 126.7 (d), 128.0 (d), 128.2 (d), 130.1
(s), 132.4 (s), 133.3 (s), 140.9 (s), 142.7 (s), 157.7 (s), 163.2 (s). Anal. Calcd for
C29H26Cl2N6O4: C, 58.69; H, 4.42; N, 14.16. Found: C, 58.66; H, 4.39; N, 14.22. In
the reaction with 2c, the residue was washed with ethanol (5 mL) and
chromatographed on a silica gel column using dichloromethane as eluent. The
first fraction eluted gave 3,10-diacetyl-1,12-diphenyl-12a-methyl-1,12,12a,
12b-tetrahydrobis[1,2,4]triazolo[4,3-a:30,40-c]quinoxaline (7c): yield 35%; mp
195–197 °C; IR cmꢀ1 1685 (C@O), 1595 (C@N); 1H NMR: d 1.45 (s, 3H, CH3), 2.66
(s, 3H, CH3), 2.70 (s, 3H, CH3), 5.54 (s, 1H, H-12b), 6.93 (t, 2H, p-C6H5, J = 7.0 Hz),
7.05–7.35 (m, 11H, Ar-H, H-5, H-8, H-7), 7.35 (m, 1H, H-6); 13C NMR: d 15.2 (q),
28.4 (q), 28.7 (q), 77.2 (d), 80.1 (s), 114.2 (d), 118.54 (d), 120.9 (d), 122.1 (d), 122.8
8(d), 123.3 (d), 122.9 (d), 124.6 (d), 124.6 (2 ꢁ s), 128.7 (d), 129.2 (d), 140.6 (s),
144.1 (s), 145.7 (s), 147.7 (s), 188.2 (s), 188.7 (s). Anal. Calcd for C27H24N6O2: C,
69.81; H, 5.21; N, 18.09. Found: C, 694.76; H, 5.15; N, 18.32. In the reaction with
2d, the first fraction eluted gave 3,10-dibenzoyl-1,12-diphenyl-12a-methyl-
1,12,12a,12b-tetrahydrobis[1,2,4]triazolo[4,3-a:30,40-c]quinoxaline (7d): yield
40%; mp 90–92 °C; IR cmꢀ1 1658 (C@O), 1596 (C@N); 1H NMR: d 1.64 (s, 3H, CH3),
5.67 (s, 1H, H-12b), 6.90–7.35 (m, 14H, Ar-H, H-5, H-6, H-7, H-8), 7.55–7.75 (m,
6H, m-COC6H5, p-COC6H5), 8.25 (4H, o-COC6H5); 13C NMR: d 15.3 (q), 77.6 (d),
79.4 (s) 114.5 (d), 118.7 (d), 119.6 (d), 121.9 (d), 122.7 (d), 123.4 (d), 122.9 (d),
123.0 (d), 124.2 (2 ꢁ s), 128.6 (d), 128.7 (d), 128.6 (d), 129.2 (d), 130.4 (d), 130.6
(d), 134.1 (d), 134.8 (d), 135.5 (s), 136.3 (s), 144.7 (s), 145.2 (2 ꢁ s), 141.2 (s),
145.4 (s), 183.1 (s), 183.5 (s). Anal. Calcd for C37H28N6O2: C, 75.49; H, 4.79; N,
14.28. Found: C, 75.66; H, 4.83; N, 14.32. The second fraction eluted gave 30,5-
dibenzoyl-2,10-diphenyl-2,4,10,10a0-tetrahydro-90H-spiro{pyrazolo-3,100-[1,2,4]-
triazolo[4,3-a]quinoxaline} (8d): yield 15%; mp 114–115 °C; IR cmꢀ1 1644
(C@O), 1596 (C@N); 1H NMR: d 2.70 (d, 1H, J = 19.3 Hz, CH2), 3.20 (d, 1H,
J = 19.3 Hz, CH2), 4.28 (s, 1H, NH) 5.32 (s, 1H, H-100a), 6.56 (d, 1H, J = 8.2 Hz, p-
C6H5), 6.81–7.59 (m, 19H, Ar-H), 7.80 (d, 1H, J = 8.2 Hz, H-80), 8.17 (d, 1H,
J = 8.2 Hz, H-50); 13C NMR: d 26.7 (t), 56.2 (d), 75.9 (s), 114.7 (d), 115.5 (d), 118.5
(d), 120.0 (s), 123.4 (d), 124.2 (d), 125.7 (d), 126.1 (d), 126.2 (d), 126.8 (d), 127.7
(d), 128.4 (d), 128.5 (d), 129.3 (d), 130.4 (d), 130.2 (d), 131.0 (s), 131.8 (s), 133.7
(d), 136.3 (s), 140.1 (s), 141.7 (s), 143.9 (s), 146.4 (s), 183.1 (s), 190.9 (s). Anal.
Calcd for C37H28N6O2: C, 75.49; H, 4.79; N, 14.28. Found: C, 75.56; H, 4.82; N,
14.23. General procedure for the 1,3-dipolar cycloaddition of 5-methyl-
quinoxaline (10) and chlorophenylhydrazones 2a,c. Triethylamine 1.15 mL
N
5
R
N
16a,c,d
17a
Scheme 4. Reactivity of quinazoline in the 1,3-DCRs with nitrilimine dipoles.
c]quinazoline (17a), was also isolated. It revealed the same site-
selectivity observed with the more nucleophile dipoles in pyrimi-
dine series (preferential cycloaddition on 1–2 position).10
The analysis of the experimental data showed that the cycload-
dition reactions, involving the dipole nitrilimines as dipoles and
the asymmetric benzodiazines as dipolarophiles, lead to a reaction
route different from that observed in the case of symmetric benzo-
diazines. First the reactivity lowers and also a certain grade of dia-
stereoselectivity emerged. In other words the asymmetric feature
‘generates’ a diastereoisomer simplification because the syn config-
uration partially is forbidden. In fact, only in the case of the dipole
higher reactive, the syn diastereoisomer was isolated.
References and notes
1. Aversa, M. C.; Bonaccorsi, P.; Giannetto, P. J. Heterocycl. Chem. 1989, 26, 1619–
1922.
2. Grubert, L.; Patzel, M.; Jugelt, W.; Riemer, B.; Liebscher, J. Liebigs Ann. Chem.
1994, 1005–1011.
3. Grubert, L.; Jugelt, W.; Breb, J.; Koppel, H.; Strietzel, U.; Dombrowski, A. Liebigs
Ann. Chem. 1992, 885–894.
4. Grassi, G.; Risitano, F.; Foti, F. Tetrahedron 1995, 51, 11855–11862.
5. Dalla Croce, P. J. Heterocycl. Chem. 1975, 12, 1133.
6. Lauria, A.; Guarcello, A.; Dattolo, G.; Almerico, A. M. Tetrahedron Lett. 2008, 49,
1847–1850.
7. Nabih, K.; Baouid, A.; Hasnaoui, A.; Selkti, M.; Compain, P. New J. Chem. 2003,
27, 1644–1648.
8. Experimental data: All melting points were taken on a Buchi-Tottoli capillary
apparatus and are uncorrected; IR spectra were determined in bromoform with a
Jasco FT/IR 5300 spectrophotometer; 1H and 13C NMR spectra were measured in
CDCl3 solution (TMS as internal reference) at 200 and 50.3 MHz, respectively,
using a Bruker AC-E series 200 MHz spectrometer. 13C NMR spectra are reported,
indicating the multiplicity, (s, singlet; d, doublet; t, triplet; q, quartet) assigned
by DEPT135 experiments. Column chromatography was performed with Merck
silica gel 230–400 mesh ASTM or with a Biotage FLASH40i chromatography
module (prepacked cartridge system). General procedure for the 1,3-dipolar
cycloaddition of 2-methylquinoxaline (6) and chlorophenylhydrazones 2a–d.
Triethylamine 1.15 mL (8.3 mmol) was added to a solution of 2-methylqui-
noxaline (3.47 mmol) and chlorophenylhydrazones (6.93 mmol) in anhydrous
tetrahydrofuran (20 mL). The mixture was stirred at room temperature for
appropriate time (2a,b, 60 h; 2c,d, 72 h). The chlorohydrate of triethylamine was
removed by filtration and the solution was evaporated under reduced pressure.
The residue was washed with ethanol (5 mL) and chromatographed on a silica gel
column using dichloromethane as the eluent. In the reaction with 2a, the first
fraction eluted gave 3,10-dimethoxycarbonyl-1,12-diphenyl-12a-methyl-
1,12,12a,12b-tetrahydrobis[1,2,4]triazolo[4,3-a:30,40-c]quinoxaline (7a): yield
30%; mp 187–188 °C; IR cmꢀ1 1735 (CO); 1H NMR: d 1.32 (s, 3H, CH3), 3.88 (s, 3H,
CH3), 3.95 (s, 3H, CH3), 5.85 (s, 1H, H-12b), 6.80–6.95 (m, 2H, H-5, H-8), 7.12–7.21
(m, 10H, Ar-H), 7.45–7.60 (m, 2H, H-6, H-7);13C NMR: d 14.7 (q), 52.9 (q), 53.7 (q),
75.6 (d), 78.5 (s), 114.0 (d), 118.2 (d), 119.0 (d), 121.5 (d), 122.4 (d), 122.9 (d),
123.3 (s), 123.6 (d), 123.8 (d), 124.3 (s), 128.7 (d), 129.0 (d), 141.2 (s), 141.3 (s),
141.8 (s), 145.2 (s), 158.5 (s), 158.8 (s). Anal. Calcd for C27H24N6O4: C, 65.31; H,
4.87; N, 16.93. Found: C, 65.66; H, 4.83; N, 17.00. The second fraction eluted gave
dimethyl 2,10-diphenyl-2,4,10,10a0-tetrahydro-90H-spiro{pyrazolo-3,100-[1,2,4]
triazolo[4,3-a]quinoxaline}-30,5-dicarboxylate (8a): yield 20%; mp 222–224 °C,
from ethanol; IR cmꢀ1 3330 (NH), 1729 and 1720 (C@O); 1594 (C@N). 1H NMR: d
2.27 (d, 1H, CH2, J = 19.1 Hz), 2.98 (d, 1H, CH2, J = 19.1 Hz), 3.73 (s, 3H, CH3), 3.77
(s, 3H, CH3), 5.27 (s, 1H, H-10a0), 6.67 (d, 1H, H-50, J = 8.2 Hz), 6.72 (d, 1H, p-C6H5),
6.95–7.02 (m, 9H, Ar-H), 7.17–7.22 (m, 2H, H-70, H-60), 7.39 (d, 1H, H-80,
J = 8.2 Hz); 13C NMR: d 27.7 (t), 52.0 (q), 52.4 (q), 56.9 (d), 74.7 (s), 114.5 (d), 115.6
(d), 115.9 (d), 118.1 (s), 122.5 (d), 122.7 (d), 125.7 (d), 126.1 (d), 126.7 (d), 128.1
(8.3 mmol) was added to
a solution of 5-methylquinoxaline (4.57 mmol,
0.66 g) and chlorophenylhydrazones (9.15 mmol) in anhydrous tetrahydro-
furan (20 mL). The mixture was stirred at room temperature for 72 h (36 h in the
case of the reaction with 2c). The chlorohydrate of triethylamine was removed by
filtration. The solution was evaporated under reduced pressure. The residue was
washed with ethanol (5 mL) and chromatographed on a silica gel column. In the
reaction with 2a, using cyclohexane/ethyl acetate (9:1) as the eluent, the first
fraction eluted gave 2-anilino-5-methylquinoxaline-1(4H)-carbonitrile (14):
yield 22%; mp 174–175 °C; IR cmꢀ1 2242 (CN); 1H NMR: d 2.54 (s, 3H, CH3), 7.01
(m, 2H, p-C6H5, H-8), 7.18–7.45 (m, 6H, Ar-H), 8.12 (s, 1H, H-3). 13C NMR: d 17.2
(q), 104.5 (s), 112.5 (d), 121.2 (d), 125.0 (d), 127.4 (d), 128.3 (2 ꢁ s), 129.4 (d),
131.30 (s), 131.35 (d), 139.6 (s), 141.6 (d), 145.07 (s). Anal. Calcd for C16H14N4: C,
73.26; H, 5.38; N, 21.36. Found: C, 73.67; H, 5.43; N, 21.53. The second fraction
eluted gave 3,10-dimethoxycarbonyl-1,12-diphenyl-5-methyl-1,12,12a,12b-
tetrahydrobis[1,2,4]triazolo[4,3-a:30,40-c]quinoxaline (11a): yield 20%; mp
219–222 °C, from ethanol; IR cmꢀ1 1735 (C@O), 1598 (C@N); 1H NMR: d 2.13
(s, 3H, CH3), 3.82 (s, 3H, CH3), 3.91 (s, 3H, CH3), 5.83 (d, 1H, H-12a, J = 7.6 Hz), 5.86
(d, 1H, H-12b, J = 7.6 Hz), 6.76 (m, 2H, H-6, H-7), 7.03–7.18 (m, 11H, H-8, Ar-H);
13C NMR: d 18.2 (q), 52.9 (q), 53.3 (q), 70.9 (d), 71.7 (d), 113.0 (d), 113.3 (d), 116.9
(d), 120.4 (s), 120.8 (d), 124.0 (d), 125.1 (d), 126.6 (s), 128.7 (d), 128.8 (d), 132.0
(s), 141.6 (s), 141.8 (s), 142.7 (s), 143.8 (s), 157.8 (s), 159.0 (s). Anal. Calcd for
C27H24N6O4: C, 65.31; H, 4.87; N, 16.93. Found: C, 65.26; H, 4.93; N, 17.02. Further
fraction eluted afforded methyl 6-methyl-3-phenyl-3,5-dihydro[1,2,4]triaz-
olo[4,3-a]quinoxaline-1-carboxylate (12a): yield 12%; mp 202–204 °C, from
ethanol; IR cmꢀ1 3250 (N–H), 1715 (C@O), 1650 (C@N); 1H NMR: d 2.65 (s, 3H,
CH3), 3.86 (s, 3H, CH3), 6.77 (d, 1H, H-9, J = 8.3 Hz), 7.05 (1H, p-C6H5), 7.20–7.45
(m, 6H, Ar-H), 8.18 (s, 1H, H-4), 8.39 (s, 1H, N–H). 13C NMR: d 17.6 (q), 53.0 (q),
111.8 (d), 114.9 (d), 119.0 (s), 131.3 (s), 123.7 (d), 126.6 (d), 129.5 (d), 131.8 (d),
139.0 (s), 139.8 (s), 141.5 (s), 148.9 (d), 153.3 (s). Anal. Calcd for C18H16N4O2: C,
67.49; H, 5.03; N, 17.49. Found: C, 67.54; H, 5.13; N, 17.32. In the reaction with 2c,