Quinoxalino-fused sultines and their application in Diels-Alder reactions

Article abstract of DOI:10.1039/a606764f

The synthesis of 7,8-disubstituted quinoxalino[2,3-d]-[1,2λ⁴]oxathiine 2-oxides 7a-c, precursors for quinoxalino-o-quinodimethanes 3a-c, and their application in the Diels-Alder reactions are reported.

Full text of DOI:10.1039/a606764f

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Quinoxalino-fused sultines and their application in Diels–Alder reactions
Wen-Sheng Chung* and Jing-Horng Liu
Department of Applied Chemistry, National Chiao Tung University, Hsinchu, Taiwan 30050, R.O.C.
The synthesis of 7,8-disubstituted quinoxalino[2,3-d]-
[1,2l4]oxathiine 2-oxides 7a–c, precursors for quinoxalino-o-
quinodimethanes 3a–c, and their application in the Diels–
Alder reactions are reported.
sultines 7a–c all underwent extrusion of SO2 and the resulting
quinoxalino-o-quinodimethanes 3a–c were intercepted as the
1:1 adducts (12 and 13) in 69–89% yield. The reactions with
dimethyl acetylenedicarboxylate (DMAD) went similarly to
1:1 adducts and after loss of H2 gave 14a–c in 35–94%
yield.
In the absence of a dienophile, sultine 7a underwent thermal
extrusion of SO2 and formed the cyclobuta[1,2-b]quinoxaline
15a almost quantitatively. In contrast, 15a was reported5 to be
isolated only in low yield (10%) when the corresponding
sulfolene 4 was flash pyrolysed at 500 °C followed by addition
of excess N-phenylmaleimide (NPM). Thermolysis of 7a in the
presence of methanol or cyclohexa-1,4-diene, on the other hand,
gave 2,3-dimethylquinoxaline 11a in 89–99% yield. Inter-
The chemistry of heterocyclic o-quinodimethanes 1 has at-
tracted a great deal of attention recently.1 Various methods for
generating these highly reactive dienes have been developed.2
Among them, cheletropic elimination of SO2 from hetero-
aromatic-fused 3-sulfolenes 2 has drawn the most attention.1–3
Quinoxalines are important naturally occurring heterocycles
and are usually found to have biological and pharmaceutical
activity.4 Finding an easy, high-yield method for generating
quinoxalino-o-quinodimethanes 3 is thus of particular interest.
Although Chou et al. reported5 generating quinoxalino-o-
quinodimethanes 3a using SO2 extrusion of the quinoxalino-
fused sulfolene 4, all their attempts to isolate the Diels–Alder
adducts failed. Recently we described6 the generation of
nonclassical heteroaromatic o-quinodimethanes 5 by thermal
extrusion of SO2 from corresponding sultines 6. A significant
advantage of using sultines is that their thermolysis occurs at a
much lower temperature than that of corresponding sul-
folenes.6–8 We report here our work on the synthesis of
quinoxalino-fused sultines 7a–c and their applications in Diels–
Alder reactions with alkenes and alkynes.
Br
R
R
NH2
NH2
R
R
N
N
CH2Br
CH2Br
O
O
i
+
Br
8a R = H
b R = Me
c R = Cl
9
10a 92%
b 93%
c 90%
ii
iii
–
R
R
N
N
+
O
R
R
N
Previously unknown sultines 7a–c were synthesized in two
steps with good yields as shown in Scheme 1. Reaction of the
appropriate o-diamino-substituted benzene 8 with 1,4-dibro-
S
+
O
N
mobutane-2,3-dione
9
gave the known 2,3-bis(bro-
7a R = H 29%
b R = Me 25%
c R = Cl 30%
11a–c 56–67%
momethyl)quinoxaline 10a,9a 6,7-dimethylquinoxaline 10b,4,9b
and 6,7-dichloroquinoxaline 10c.4 The desired quinoxalino-
fused sultines 7a–c† and by-products 11 were obtained by the
use of Rongalite8 (sodium formaldehyde sulfoxylate) with the
corresponding dibromides 10a–c. Although the yields of
sultines 7a–c were only ca. 30%, fortunately the by-product 11
can be converted back to dibromide 10 via N-bromosuccinimide
bromination,4b which makes the syntheses of the sultines more
efficient.
Scheme 1 Reagents and conditions: i, benzene, reflux, 1 h; ii, Rongalite,
DMF, 0 °C, 7 h; iii, NBS
N
R
R
N
N
CO2Et
CO2Et
N
The Diels–Alder reactions of quinoxalino-fused sultines
7a–c with several dienophiles are presented in Scheme 2. When
heated in toluene (200 °C, sealed tube) in the presence of 3
equiv. of diethyl fumarate (EF) or dimethyl fumarate (MF), the
11a 89–99%
12a 89%
b 86%
c 74%
or
MeOH
EF
7a–c
PhMe, 200 °C
–SO2
R
N
R
R
N
N
R
R
N
N
CO2Me
CO2Me
N
N
MF
Het
Het
SO2
SO2
R
N
3a–c
2
3a R = H
b R = Me
c R = Cl
1
13a 84%
b 88%
c 69%
4
DMAD
– H2
no quencher
heat
N
R
R
N
CO2Me
CO2Me
N
N
–
O
•
•
+
15a 96%
14a 94%
b 35%
c 41%
S
a R = H
b R = Me
c R = Cl
X
X
O
5
6
Scheme 2
X = O, S and NR
Chem. Commun., 1997
205

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estingly, Diels–Alder adducts (such as 12–14a) were also
formed in excellent yield when the cyclobutene 15a was heated
in the presence of dienophiles at 200 °C, indicating that
cyclobutene 15a is also a good precursor of o-quinodimethane
3a.
Footnotes
† Cyclobuta[1,2-b]quinoxaline 15 has been reported in the literature (ref. 5)
and our samples correspond in all aspects with the reported properties.
Satisfactory spectral data were obtained for all products. Selected data for
7a: white solid, mp 137–138 °C; 1H NMR (300 MHz, CDCl3) d 8.08–8.03
(2 H, m), 7.82–7.77 (2 H, m), 5.63 (1 H, AB, J 16.1 Hz), 5.32 (1 H, AB, J
The reaction of 7a–c with excess NPM at 200 °C gave a pair
of new adducts 16 and 17 in 47–68% yields (Scheme 3). These
2:1 adducts showed similar spectral characteristics, consistent
with the cis and trans cyclooctaquinoxalines 16 and 17.‡ When
only 1 equiv. of NPM was used, the yield of 1:1 adduct 18b was
optimized to 72% and the 2:1 adducts (16 and 17) were present
in only trace amounts. Similar observation of these 2:1 adducts
in the trapping of pyrimidine o-quinodimethanes by NPM has
been reported recently by Tome´ et al.3a,c We were, however,
surprised to see that different adducts were reported10 when 10a
was heated with sodium iodide in the presence of NPM, even
though this method is generally assumed to give a synthetic
equivalent of o-quinodimethane 3a. The real reason for this
difference may be just as the authors described:10 the reaction of
10a and sodium iodide probably did not involve dehalogenation
to give a true o-quinodimethane 3a, but rather the adducts might
have been formed by a mechanism involving displacement of a
halogen atom by the dienophile.
Thus our results, obtained by pyrolysing 7,8-disubstituted
quinoxalino-fused sultines 7a–c, strongly support the formation
of quinoxalino-o-quinodimethanes 3a–c, which differ from the
products formed when sulfolene 4 is pyrolysed, or when 10a
and sodium iodide react.10 The easily synthesized sultines 7a–c
reacted under milder conditions (200 °C) than the correspond-
ing sulfolene 4 (!290 °C is required) and their reaction
products were different in many cases. When generated in the
presence of a dienophile, sultines 7a–c provided elegant
synthons for the formation of [4 + 2] cycloadducts. If no
trapping agents were used, the sultines gave cyclobuta[1,2-
b]quinoxaline 15 almost quantitatively, which again is a good
precursor of o-quinodimethanes 3. Further work to study the
mechanism by laser flash photolysis is in progress.
15.6 Hz), 4.59 (1 H, AABA, J 16.1 Hz) and 4.14 (1 H, AABA, J 16.1 Hz); 13
C
NMR (75.4 MHz, CDCl3), d 147.11 (Cq), 142.51 (Cq), 142.10 (Cq), 141.45
(Cq), 130.68 (CH), 130.39 (CH), 128.82 (CH), 128.77 (CH), 62.56 (CH2)
and 57.92 (CH2); m/z 220 (M+, 23%), 156 (M+ 2 SO2, 100), 129 (16), 102
(15). For 7b: white solid, mp 158–159 °C; 1H NMR d 7.79 (2 H, s), 5.61 (1
H, AB, J 15.6 Hz), 5.28 (1 H, AB, J 15.6 Hz), 4.57 (1 H, AABA, J 16.6 Hz),
4.08 (1 H, AABA, J 16.6 Hz) and 2.50 (6 H, s); 13C NMR, 145.98 (Cq), 141.55
(Cq), 141.43 (Cq), 141.12 (Cq), 140.83 (Cq), 140.43 (Cq), 127.68 (CH),
127.65 (CH), 62.64 (CH2), 57.93 (CH2), 20.39 (Me) and 20.36 (Me); m/z
248 (M+, 21), 184 (M+ 2 SO2, 100), 169 (38), 103 (9). For 7c: orange solid,
mp 205–206 °C, 1H NMR d 8.17 (2 H, s), 5.59 (1 H, AB, J 16.1 Hz), 5.30
(1 H, AB, J 16.1 Hz), 4.54 (1 H, AABA, J 16.5 Hz) and 4.13 (1 H, AABA, J 16.4
Hz); 13C NMR, 148.40 (Cq), 143.53 (Cq), 141.15 (Cq), 140.16 (Cq), 135.46
(Cq), 135.20 (Cq), 129.48 (CH), 129.43 (CH), 62.32 (CH2) and 57.76 (CH2);
m/z 288 (M+, 8), 224 (100), 226 (63), 189 (40), 154 (2).
‡ Selected data for a 1:1 mixture of 16a and 17a: 13C NMR d 178.93 (Cq),
177.22 (Cq), 176.13 (Cq), 175.90 (Cq), 151.80 (Cq), 151.12 (Cq), 141.51
(Cq), 140.69 (Cq), 132.23 (Cq), 131.35 (Cq), 130.26 (CH), 130.06 (CH),
129.17 (CH), 129.80 (CH), 128.96 (CH), 128.89 (CH), 128.82 (CH), 128.39
(CH), 126.47 (CH), 126.37 (CH), 42.42 (CH), 41.19 (CH), 39.64 (CH),
38.08 (CH), 34.27 (CH2), 32.48 (CH2); m/z 502 (M+, 36), 381 (54), 329 (M+
2 NPM, 52), 181 (100) (Found: M+, 502.1652. C30H22N4O4 requires M,
502.1641). Currently, stereochemistry cannot be assigned unambiguously.
References
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We thank the National Science Council of the Republic of
China for its financial support (Grant No. NSC 85-2113-M-
009-002).
O
R
R
N
N
i
7a–c
N
Ph
O
18a 66%
ii
b 72%
c 54%
i
O
O
O
O
Ph
Ph
N
N
N
N
R
R
N
N
R
+
N
N
O
O
O
O
R
Ph
Ph
16a
b
c
64%
68%
47%
17a
b
c
10 N. E. Alexandrou, G. E. Mertzanos, J. Stephanidou-Stephanatou,
C. A. Tsoleridis and P. Zachariou, Tetrahedron Lett., 1995, 36, 6777.
Scheme 3 Reagents and conditions: i, NPM (1 equiv.), toluene, 200 °C; ii,
NPM (3 equiv.), toluene, 200 °C
Received, 2nd October 1996; Com. 6/06764F
206
Chem. Commun., 1997