Original synthesis of oxiranes via TDAE methodology: Reaction of 2,2-dibromomethylquinoxaline with aromatic aldehydes

Article abstract of DOI:10.1016/j.tetlet.2005.09.152

We report herein the reaction of 2,2-dibromomethylquinoxaline 2 with aromatic aldehydes 3a-g in the presence of TDAE. These reactions lead to a mixture of cis/trans-isomers of corresponding oxiranes 4a-g in good yields. The stereoselectivity of the reaction was sensitive to steric hindrance.

Full text of DOI:10.1016/j.tetlet.2005.09.152

Tetrahedron
Letters
Tetrahedron Letters 46(2005) 8373–8376
Original synthesis of oxiranes via TDAE methodology: reaction
of 2,2-dibromomethylquinoxaline with aromatic aldehydes
Marc Montana, Thierry Terme and Patrice Vanelle*
Laboratoire de Chimie Organique Pharmaceutique LCOP, UMR CNRS 6517, Universite´ de la Me´diterrane´e,
Faculte´ de Pharmacie, 27 Bd Jean Moulin, 13385 Marseille Cedex 05, France
Received 7 September 2005; revised 23 September 2005; accepted 26September 2005
Available online 11 October 2005
Abstract—We report herein the reaction of 2,2-dibromomethylquinoxaline 2 with aromatic aldehydes 3a–g in the presence of
TDAE. These reactions lead to a mixture of cis/trans-isomers of corresponding oxiranes 4a–g in good yields. The stereoselectivity
of the reaction was sensitive to steric hindrance.
ꢀ 2005 Elsevier Ltd. All rights reserved.
The quinoxaline derivatives show very interesting bio-
logical properties (antibacterial,1 antiviral, anticancer,2
antifungal, antihelmintic, antileishmanial,3 anti-HIV,3
insecticidal) and their interest in medicinal chemistry is
far to come to an end.4 Many drug candidates bearing
quinoxaline core structures are in clinical trials in antivi-
ral,1 anticancer, antibacterial,2 and CNS (central ner-
vous system) therapeutic areas. Among them, the
XK469 and the chloroquinoxaline sulfonamide (CQS)
were known as antineoplastic quinoxaline topoisomer-
ase II inhibitors (Fig. 1).
coccidiosis in poultry, rabbit, sheep, and cattle. CQS
was selected for clinical development based on good
activity against human tumor cells in the human tumor
colony-forming assay6 and subsequently has shown
activity against murine and human solid tumors.7
Moreover, oxiranes are versatile synthetic intermediates
frequently used in the synthesis of organic compounds.8
Their reactions generally involve cleavage of the
strained oxirane ring and include a wide range of
nucleophilic ring openings and acid- and base-induced
isomerizations.9
The XK469 or ( )-2-[4-(7-chloro-2-quinoxaliny)oxy]
phenoxy propionic acid, is an analog of the herbicide
Assureꢁ synthesized by DuPont Company, which pos-
sesses antitumor activity, especially against murine solid
tumors and human xenografts.5 CQS is a structural ana-
log of sulfoquinoxaline, a compound used to control
Tetrakis(dimethylamino)ethylene (TDAE) is a reducing
agent which reacts with halogenated derivatives to
generate an anion under mild conditions via a single
electron transfer (SET).10,11 In our research program
directed toward the development of original synthetic
methods using TDAE methodology in medicinal chem-
istry, we have developed many reactions between halo-
genated derivatives and electrophile compounds such
as aldehydes, ketones, a-keto-esters, a-ketolactams,
and ketomalonates.10–12
N
N
O
COOH
CH3
XK469
CQS
Cl
O
Cl
NH2
The interest of quinoxaline derivatives in medicinal
chemistry and the synthetic properties of oxiranes led
us to investigate the reaction of gem-dihalogenated
derivatives and electrophiles as aldehydes in the pres-
ence of TDAE. We report herein the reaction of 2,2-di-
bromomethylquinoxaline 2 with aromatic aldehydes
3a–g in the presence of TDAE. These reactions lead to
a mixture of cis/trans-isomers of corresponding oxiranes
4a–g. 2,2-Dibromomethylquinoxaline 2 was synthesized
in one step from 2-methylquinoxaline 1 by radical
N
N
O
S
N
H
O
Figure 1. Structures of XK469 and CQS.
Keywords: TDAE; Quinoxaline; Aromatic aldehydes; Oxiranes.
*
Corresponding author. Tel.: +33 4 91 83 55 80; fax: +33 4 91 79 46
77; e-mail: patrice.vanelle@pharmacie.univ-mrs.fr
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.09.152

8374
M. Montana et al. / Tetrahedron Letters 46 (2005) 8373–8376
1H NMR spectral studies reveal that oxiranes were iden-
N
N
N
Br2,
hν
tified as trans- or cis-isomers by their coupling constant.
Two distinct doublets appeared in the region at 4.13–
5.03 ppm with J = 1.6–1.9 Hz or J = 4.2–4.7 Hz each
of the signal corresponding to one proton. The small
value (1.6–1.8 Hz) of this coupling constant is consistent
with a trans-isomer as reported in the literature data15,16
and large value (4.3–4.5 Hz) indicates the cis-isomer of
oxirane.
Br
CCl4, 48 h
N
CH3
Br
1
2
93%
Scheme 1. Synthesis of 2,2-dibromomethylquinoxaline 2.
bromination using bromine in refluxing carbon tetra-
chloride and light catalysis (Scheme 1). Contrary to pre-
vious work,13 we have used an excess of bromine
(2.5 equiv) to support the formation of dibromide 2.
The formation of these oxiranes 4a–g may be explained
by nucleophilic addition of a-bromo carbanion, formed
by action of TDAE with 2,2-dibromomethylquinoxaline
2, on carbonyl group of aldehyde 3a–g followed by an
intramolecular nucleophilic substitution. The relative
cis/trans percentage of oxirane isomers reported in
Table 1 showed that the stereoselectivity of these reac-
tions was sensitive to steric hindrance. The reactions
with ortho-substituted aldehydes were most selective.
The reaction of 2,2-dibromomethylquinoxaline 2 with
3 equiv of aromatic aldehydes in the presence of TDAE
at À20 ꢂC for 1 h, followed by 2 h at room temperature,
led to a mixture of cis/trans-isomers of corresponding
oxiranes 4a–g in good yields, as shown in Scheme 2
and reported in Table 1.14
H
O
N
N
TDAE
Br
N
DMF, -20˚C
N
2
X
O
X
Br
cis/trans
3a-g
4a- g
Scheme 2. Reactions of 2,2-dibromomethylquinoxaline 2 with aromatic aldehydes in the presence of TDAE.
Table 1. Reactions of 2,2-dibromomethylquinoxaline 2 and aldehydes using TDAEa
Aldehyde 3
Oxirane 4
cis/trans-Isomers (%)b
Yield (%)c
83
N
NO2
4-Nitrobenzaldehyde 3a
4a
4b
4c
4d
4e
4f
47/53
N
N
O
O
Cl
4-Chlorobenzaldehyde 3b
45/55
48/52
50/50
20/80
30/70
45
79
38
48
42
N
N
N
CF3
CH3
4-Trifluoromethylbenzaldehyde 3c
4-Methylbenzaldehyde 3d
O
O
O
N
N
N
N
2-Trifluoromethylbenzaldehyde 3e
2-Methylbenzaldehyde 3f
CF3
CH3
N
N
O
N
N
2-Nitrobenzaldehyde 3g
4g
25/75
35
O
NO2
a All the reactions are performed using 3 equiv of aromatic aldehydes 3a–g, 1 equiv of dibromide 2, and 1 equiv of TDAE in anhydrous DMF.
b % Isomers determined on 1H NMR measurements from the crude product.
c % Yield relative to dibromide 2.

M. Montana et al. / Tetrahedron Letters 46 (2005) 8373–8376
8375
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6. Shoemaker, R. H. Cancer Treat. Rep. 1986, 70, 9–12.
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Kris, M. G.; Orazem, J. P.; Young, C. W.; Warrell, R. P.,
Jr. Cancer Chemother. Pharmacol. 1995, 35, 483–488.
8. Erden, I. In Comprehensive Heterocyclic Chemistry II;
Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.;
Pergamon: Oxford, 1996; Vol. 1, pp 97–171.
A
B
O
O
Quinoxaline
H
H
H
H
Quinoxaline
R
R
Br
Br
9. Johnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric
Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley-VCH: New York,
2000; pp 231–285.
trans-oxirane
cis-oxirane
Scheme 3. Stereoselectivity of the oxirane formation.
´
10. Giuglio-Tonolo, G.; Terme, T.; Medebielle, M.; Vanelle,
P. Tetrahedron Lett. 2003, 44, 6433–6435.
´
11. Giuglio-Tonolo, G.; Terme, T.; Medebielle, M.; Vanelle,
Intramolecular substitution proceeds by a SN2 mecha-
nism. Two conformations are possible for the transition
state as shown in Scheme 3.
P. Tetrahedron Lett. 2004, 45, 5121–5124.
12. Amiri-Attou, O.; Terme, T.; Vanelle, P. Molecules 2005,
10, 545–551.
13. Goswami, S.; Dey, S.; Jana, S.; Adak, A. K. Chem. Lett.
2004, 33, 916–917; Maidwell, N. L.; Rezai, M. R.;
Roeschlaub, C. A.; Sammes, P. G. J. Chem. Soc., Perkin
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However, the one that predominates is often determined
by an eclipsing effect. In conformation A, the ortho-
substituted benzene ring is placed between a hydrogen
and a bromine atom, while in conformation B, it is
between quinoxaline ring and bromine atom. This means
that A is more stable, and most of the intramolecular
substitution should occur from this conformation. These
effects become larger while increasing size of the
substituents.
14. General procedure for the reaction of 2,2-dibromometh-
ylquinoxaline 2 and aldehydes using TDAE. Into a two-
necked flask equipped with a silica-gel drying tube and a
nitrogen inlet were added, under nitrogen at À20 ꢂC, 7 mL
of anhydrous DMF solution of 2 (0.3 g, 1 mmol) and
aldehyde 3a–g (3 mmol). The solution was stirred and
maintained at this temperature for 30 min and then TDAE
(0.3 g, 1.5 mmol) was added dropwise (via a syringe). A
red color immediately developed with the formation of a
white fine precipitate. The solution was vigorously stirred
at À20 ꢂC for 1 h and then warmed up to room temper-
ature for 2 h. After this time TLC analysis (dichlorometh-
ane) clearly showed that 2 was totally consumed. The
orange-red turbid solution was filtered (to remove the
octamethyloxamidinium dibromide) and hydrolyzed with
80 mL of H2O. The aqueous solution was extracted with
toluene (3 · 40 mL), the combined organic layers were
washed with H2O (3 · 40 mL), and dried over MgSO4.
Evaporation of the solvent left an orange viscous liquid as
crude product. Purification by silica gel chromatography
(dichloromethane) gave the corresponding mixture of cis/
trans-isomer oxiranes 4a–g as solids. New products: 4a cis-
isomer; 1H NMR (CDCl3) d 4.64 (d, J = 4.4 Hz, 1H); 4.73
(d, J = 4.4 Hz, 1H); 7.51 (d, J = 8.6Hz, 2H); 7.73 (m, 2H);
7.97 (m, 2H); 8.03 (d, J = 8.6Hz, 2H); 8.68 (s, 1H). 13C
NMR (CDCl3) 58.9; 59.1; 123.4 (2CH); 127.6(2CH);
128.8; 129.3; 130.2; 130.6; 140.4; 141.5; 142.0; 142.7; 147.6;
We have shown in this work that 2,2-dibromomethyl-
quinoxaline 2 formed an a-bromo carbanion using
TDAE methodology. Moreover, this anion reacted on
carbonyl group of aldehyde 3a–g to give oxirane deriv-
atives in good yields. The stereoselectivity of the reac-
tion was sensitive to steric hindrance.
Acknowledgment
This work was supported by the Centre National de la
Recherche Scientifique. We express our thanks to
1
M. Noailly for H and 13C NMR spectra recording.
References and notes
1. Naylor, M. A.; Stephen, M. A.; Nolan, J.; Sutton, B.;
Tocher, J. H.; Fielden, E. M.; Adams, J. E.; Strafford, I.
Anticancer Drug Des. 1993, 8, 439–461.
148.7. trans-Isomer; 1H NMR (CDCl3)
d 4.28 (d,
J = 1.6Hz, 1H); 4.40 (d, J = 1.6Hz, 1H); 7.58 (d, J =
8.7 Hz, 2H); 7.82 (m, 2H); 8.11 (m, 2H); 8.28 (d,
J = 8.7 Hz, 2H); 8.89 (s, 1H). 13C NMR (CDCl3) 60.5;
62.2; 124.0 (2CH); 126.6 (2CH); 129.2; 129.5; 130.5; 130.8;
141.8; 142.2; 142.8; 143.2; 148.2; 150.1. Anal. Calcd for
C16H11N3O3 (293.28): C, 65.53; H, 3.78; N, 14.33. Found:
2. Harmenberg, J.; Akesson-Johansson, A.; Graslund, A.;
Malmfors, T.; Bergman, J.; Wahren, B.; Akerfeldt, S.;
Lundblad, L.; Cox, S. Antiviral Res. 1991, 15, 193–204.
3. Fournet, A.; Mahieux, R.; Fakhfakh, M. A.; Franck, X.;
Hocquemiller, R.; Figadere, B. Bioorg. Med. Chem. Lett.
2003, 13, 891–894; Munos, M.-H.; Mayrargue, J.; Four-
net, A.; Gantier, J.-C.; Hocquemiller, R.; Moskowitz, H.
Chem. Pharm. Bull. 1994, 42, 1914–1916.
4. Cheeseman, G. W. H.; Cookson, R. F. In The Chemistry
of Heterocyclic Compounds; Weissberger, A., Taylor, E.
C., Eds.; John Wiley and Sons: New York, 1979; Vol. 35,
p 1.
5. Corbett, T. H.; Lorusso, P. M.; Demchick, L.; Simpson,
C.; Pugh, S.; White, K.; Kushner, J.; Polin, L.; Meyer, J.;
Czarnecki, J.; Heilbrun, L.; Horwitz, J. P.; Gross, J. L.;
Behrens, C. H.; Harrison, B. A.; McRipley, R. J.; Trainor,
G. Invest. New Drugs 1998, 16, 129–139; Lorusso, P. M.;
Parchment, R.; Demchik, L.; Knight, J.; Polin, L.;
1
C, 65.59; H, 3.66; N, 14.33. Compound 4b cis-isomer; H
NMR (CDCl3) d 4.56(d, J = 4.4 Hz, 1H); 4.65 (d,
J = 4.4 Hz, 1H); 7.15 (d, J = 8.7 Hz, 2H); 7.25 (d, J =
8.7 Hz, 2H); 7.75 (m, 2H); 8.03 (m, 2H); 8.62 (s, 1H). 13C
NMR (CDCl3) 59.0; 59.3; 128.1 (2CH); 128.6(2CH);
128.8; 129.4; 130.0; 130.4; 131.7; 134.1; 141.6; 142.0;
143.0; 149.6. trans-Isomer; 1H NMR (CDCl3) d 4.23 (d,
J = 1.8 Hz, 1H); 4.25 (d, J = 1.8 Hz, 1H); 7.36(m, 4H);
7.79 (m, 2H); 8.11 (m, 2H); 8.86(s, 1H). 13C NMR
(CDCl3) 61.2; 61.9; 127.1 (2CH); 128.9 (2CH); 129.1;
129.4; 130.1;130.6; 134.5; 134.7; 141.8; 142.2; 142.6; 150.9.
Anal. Calcd for C16H11ClN2O (282.72): C, 67.97; H, 3.92;
N, 9.91. Found: C, 67.91; H, 3.95; N, 9.63. Compound 4c

8376
M. Montana et al. / Tetrahedron Letters 46 (2005) 8373–8376
1
cis-isomer; H NMR (CDCl3) d 4.63 (d, J = 4.4 Hz, 1H);
4.70 (d, J = 4.4 Hz, 1H); 7.46(m, 4H); 7.74 (m, 2H); 8.02
(m, 2H); 8.66 (s, 1H). 13C NMR (CDCl3) 59.1; 59.4; 123.5;
125.3 (2CH); 126.8; 127.1 (2CH); 129.0; 129.4; 130.1;
127.1; 129.4; 129.7; 129.8; 130.3; 130.6; 130.8; 130.9; 131.7;
132.9; 140.9; 141.8; 143.3; 144.1. Anal. Calcd for
C17H11F3N2O (316.28): C, 64.56; H, 3.51; N, 8.86. Found:
C, 64.40; H, 3.72; N, 8.49. Compound 4f cis-isomer;1H
NMR (CDCl3) d 2.21 (s, 3H); 4.55 (d, J = 4.4 Hz, 1H);
4.70 (d, J = 4.4 Hz, 1H); 6.92 (m, 1H); 7.10 (m, 2H); 7.56
(m, 1H); 7.71 (m, 2H); 8.00 (m, 2H); 8.44 (s, 1H). 13C
NMR (CDCl3) 18.7; 58.7; 59.5; 125.6; 127.1; 128.2; 128.8;
129.3; 129.7 (2CH); 130.1; 131.3; 136.0; 141.5; 141.9;
142.8; 150.2. trans-Isomer; 1H NMR (CDCl3) d 2.38 (s,
3H); 4.18 (d, J = 1.9 Hz, 1H); 4.37 (d, J = 1.9 Hz, 1H);
7.22 (m, 3H); 7.39 (m, 1H); 7.80 (m, 2H); 8.12 (m, 2H);
8.90 (s, 1H). 13C NMR (CDCl3) 18.9; 60.2; 61.0; 124.2;
126.3; 128.3; 129.2; 129.4; 130.0; 130.1; 130.5; 134.3; 136.2;
141.9; 142.3; 142.6; 151.5. Anal. Calcd for C17H14N2O
(262.31): C, 77.84; H, 5.38; N, 10.68. Found: C, 78.23; H,
5.49; N, 10.56. Compound 4g cis-isomer; 1H NMR
(CDCl3) d 4.84 (d, J = 4.7 Hz, 1H); 5.03 (d, J = 4.7 Hz,
1H); 7.35 (m, 1H); 7.70 (m, 2H); 7.80 (m, 3H); 7.97 (m,
2H); 8.54 (s, 1H). 13C NMR (CDCl3) 58.9; 59.3; 124.5;
127.6; 129.1; 129.2; 129.3; 130.0; 130.3; 132.3; 133.7;
1
130.5; 137.5; 141.5; 142.0; 142.8; 149.8. trans-Isomer; H
NMR (CDCl3) d 4.27 (d, J = 1.7 Hz, 1H); 4.35 (d, J =
1.7 Hz, 1H); 7.55 (d, J = 8.7 Hz, 2H); 7.66 (d, J = 8.7 Hz,
2H); 7.81 (m, 2H); 8.12 (m, 2H); 8.88 (s, 1H). 13C NMR
(CDCl3) 61.0; 62.0; 123.7; 125.7 (2CH); 126.1 (2CH);
126.6; 129.1; 129.4; 130.3; 130.7; 139.9; 141.8; 142.2; 142.7;
150.6. Anal. Calcd for C17H11F3N2O (316.28): C, 64.56;
H, 3.51; N, 8.86. Found: C, 65.13; H, 3.77; N, 8.25.
Compound 4d cis-isomer; 1H NMR (CDCl3) d 2.20 (s,
3H); 4.57 (d, J = 4.2 Hz, 1H); 4.62 (d, J = 4.2 Hz, 1H);
6.98 (d, J = 8.7 Hz, 2H); 7.19 (d, J = 8.7 Hz, 2H); 7.71 (m,
2H); 8.01 (m, 2H); 8.60 (s, 1H). 13C NMR (CDCl3) 21.1;
59.2; 60.0; 126.6 (2CH); 128.9; 129.0 (2CH); 129.3; 129.8;
130.0; 130.1; 137.9; 141.6; 141.9; 143.2; 150.3. trans-
Isomer; 1H NMR (CDCl3) d 2.38 (s, 3H); 4.22 (d,
J = 1.8 Hz, 1H); 4.28 (d, J = 1.8 Hz, 1H); 7.25 (m, 4H);
7.79 (m, 2H); 8.11 (m, 2H); 8.87 (s, 1H). 13C NMR
(CDCl3) 21.2; 61.8; 62.1; 125.7 (2CH); 129.1; 129.3; 129.4
(2CH); 130.0; 130.5; 132.9; 138.7; 141.8; 142.3; 142.5;
151.4. Anal. Calcd for C17H14N2O (262.31): C, 77.84; H,
5.38; N, 10.68. Found: C, 77.34; H, 5.59; N, 10.56.
Compound 4e cis-isomer; 1H NMR (CDCl3) d 4.74 (d,
J = 4.5 Hz, 1H); 4.80 (d, J = 4.5 Hz, 1H); 7.30 (m, 1H);
7.47 (m, 2H); 7.71 (m, 2H); 7.79 (m, 1H); 8.00 (m, 2H);
8.52 (s, 1H). 13C NMR (CDCl3) 58.2; 59.5; 124.0; 125.8;
128.4; 128.6; 129.1; 129.2; 129.5; 129.9; 130.2; 131.5;
1
141.6; 141.9; 142.6; 148.0; 149.1. trans-Isomer; H NMR
(CDCl3) d 4.17 (d, J = 1.9 Hz, 1H); 4.93 (d, J = 1.9 Hz,
1H); 7.56(m, 1H); 7.80 (m, 4H); 8.15 (m, 2H); 8.24 (m,
1H); 8.92 (s, 1H). 13C NMR (CDCl3) 59.7; 61.0; 124.9;
127.1; 129.2; 129.3; 129.4; 130.2; 130.6; 133.0; 134.5; 142.0;
142.3; 142.8; 147.6; 150.3. Anal. Calcd for C16H11N3O3
(293.28): C, 65.53; H, 3.78; N, 14.33. Found: C, 65.68; H,
3.48; N, 13.92.
15. Price, C.; Carmelite, D. D. J. Am. Chem. Soc. 1966, 88,
4039–4044.
1
131.6; 141.7; 141.9; 142.6; 149.3. trans-Isomer; H NMR
(CDCl3) d 4.13 (d, J = 1.6Hz, 1H); 4.61 (d, J = 1.6Hz,
1H); 7.48 (m, 1H); 7.65 (m, 2H); 7.79 (m, 3H); 8.13 (m,
2H); 8.87 (s, 1H). 13C NMR (CDCl3) 61.1; 62.0; 124.0;
16. Williams, D. H.; Fleming, I. In Spectroscopic Methods in
Organic Chemistry, 4th ed.; Mc Graw-Hill: New York,
1991; pp 76–101.