Darzens reaction in the synthesis of 3-(α-chloroalkyl)quinoxalin- 2(1H)-ones

Article abstract of DOI:10.1134/S1070428009080223

A two-stage method was developed for the synthesis of 3-(α- chloroalkyl- and α-chlorophenylalkyl)-quinoxalin-2(1H)-ones proceeding from methyl chloroalkyl- and chlorophenylalkylpyruvates obtained by Darzens reaction from methyl dichloroacetate and appropriate aldehydes in the presence of t-BuOK.

Full text of DOI:10.1134/S1070428009080223

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2009, Vol. 45, No. 8, pp. 1244−1247. © Pleiades Publishing, Ltd., 2009.
Original Russian Text © D.F. Saifina, V.R. Ganieva, V.A. Mamedov, 2009, published in Zhurnal Organicheskoi Khimii, 2009, Vol. 45, No. 8,
pp. 1252−1255.
Darzens Reaction
in the Synthesis of 3-(α-Chloroalkyl)quinoxalin-2(1H)-ones
D. F. Saifina, V. R. Ganieva, and V. A. Mamedov
Arbuzov Institute of Organic and Physical Chemistry, Kazan' Scientific Center, Russian Academy of Sciences,
Kazan', 420088 Russia
e-mail: mamedov@iopc.knC.ru
Received April 16, 2008
Abstract—A two-stage method was developed for the synthesis of 3-(α-chloroalkyl- and α-chlorophenylalkyl)-
quinoxalin-2(1H)-ones proceeding from methyl chloroalkyl- and chlorophenylalkylpyruvates obtained by Darzens
reaction from methyl dichloroacetate and appropriate aldehydes in the presence of t-BuOK.
DOI: 10.1134/S1070428009080223
methyl aryl or diaryl ketones [12–14], and aroyl or
heteroylpyruvic acids [10, 11].
The undying interest to quinoxalines and their deriva-
tives is primarily due to the appearance of their fragments
in the structure of versatile biologically and pharmaco-
logically important compounds, in particular, of agonists
and antagonists of various receptors [1–4], of substances
endowed with high antimicrobial action [5, 6] etc. [7–9].
We developed efficient preparation procedures for
3-(α-chloroalkyl- and α-chlorophenylalkyl)quinoxalin-
2(1H)-ones based on esters of chloroalkyl- and chloro-
phenylalkylpyruvic acids. The required α-oxoesters III
can be obtained by Darzens reaction from methyl
dichloroacetate and various aldehydes I (see the
scheme). The variation of aldehydes Ia–Ig used in the
reaction makes it possible to introduce into the position 3
of the quinoxalin-2(1H)-one substituents differing in the
length, in the character and possessing a chlorine atom
in the α-position.
Among the numerous procedures for the synthesis of
quinoxaline system the most commonly applied is the
condensation of ortho-phenylenediamine with various
substances supplying two-carbon fragments, like α-di-
carbonyl compounds [10–25], α-halocarbonyl compounds
[26, 27], and α-dihalides [28–30]. Besides the building
up of the quinoxaline ring is often performed in reactions
catalyzed by metal complexes thus extending the range
of suitable two-carbon synthons. For instance, α-hy-
droxyketones undergo an oxidative cyclization with
o-phenylendiamine in the presence of transition metals
(Mn, Pd, Ru, Cu) giving quinoxalines [31–33], and ketones
with a methylene group react with the o-phenylendiamine
in the presence of PEG-400 [34]. Epoxides also are
employed as two-carbon synthons in the reaction with o-
phenylendiamine catalyzed by bismuth [35]. Still the
dicarbonyl compounds are the most active: Reactions
involving them are as a rule one-stage processes, give
high yields, and do not require severe conditions and
expensive catalysts.
The reaction of methyl dichloroacetate with aldehydes
Ia–Ig in the presence of t-BuOK in THF proceeded with
the formation of oxiranes II, and the optimum temperature
of the reaction with aldehydes Ic–Ig proved to be –10°C,
and with aldehydes Ia and Ib , –40°C. The reaction
occurred stereoselectively affording predominantly a
single diastereomer [36], and the amount of the minor
isomer by the 1H NMR data did not exceed 2–3%. The
thermal isomerization of oxiranes IIa–IIg diastereomers
at 180°C provided the desired chloropyruvates IIIa–IIIg
in nearly quantitative yields. The characteristic indication
of the isomerization of oxiranes IIa–IIg into
chloropyruvates IIIa–IIIg is the downfield shift of the
1
signal of methine protons in the H NMR spectra by
In the published research the reactions with dicarbonyl
compounds were limited to dimethyl oxalate [18, 19],
~1.5 ppm to the region characteristic of chloropyruvates
1244

DARZENS REACTION
1245
Scheme.
O
O
R
RCHO, t-BuOK
Ia_Ig
O
Cl
Cl
+
C(O)OMe
MeO(O)C
H
THF
Cl2CH
OMe
H
R
SS,SR
RR,RS
IIa_IIg
NH2
Cl
Cl
O
N
D
NH2
AcOH
R
R
OMe
IIIa_IIIg
N
O
O
H
IVa_IVg
R = CH2Ph (a), (CH2)2Ph (b), Et (c), Pr (d), (CH2)5CH3 (e), (CH2)6CH3 (f), (CH2)9CH3 (g).
with an aliphatic substituent (~5.0 ppm).
(Ic–Ig) was slowly added an equimolar quantity of
powdered t-BuOK, the reaction mixture was kept for
2 h at–40...–50°C (Ia or Ib) or at –5...–10°C (Ic–Ig),
then it was warmed to room temperature and left standing
for 10 h. Then the reaction mixture was washed with
NaCl solution, extracted with toluene (3 × 50 ml). The
extract was dried with MgSO4 and evaporated in a
vacuum of a water-jet pump. Then the residue was
heated on an oil bath to 180°C for 2 h in a vacuum of
a water-jet pump. The obtained reaction mixture was
dissolved in acetic acid, the powder of o-phenylendiamine
was added in an amount calculated from the data of
1H NMR spectrum, the mixture was stirred for 5 h, the
separated crystals were filtered off and washed with
acetic acid.
Chloropyruvates IIIa–IIIg were used without
additional purification in the reaction with o-phenyl-
enediamine. The synthesis of 3-(α-chloroalkyl)quinoxalin-
2(1H)-ones IVa–IVg was carried out at room tempera-
ture in acetic acid.
IR spectra of all obtained chloroquinoxalines IVa–IVg
are characterized by the presence of the absorption band
of the C=O stretching vibrations at the frequency 1666 ±
5 cm–1 and of NH stretching vibrations in the region 2500–
1
3200 cm–1. H NMR spectra alongside the signals of
aromatic protons in the region 7.17–7.83, singlet signal
of the carbamoyl NH group in the region 12.47–12.65,
and multiplets of the aromatic protons in the range 0.89–
3.64 contain a doublet of doublets signal of the methine
proton at 5.39–5.72 ppm. In the spectrum of compound
IVa the protons of the group CHClCH2 appeared as
signals of AΒX system.
3-(α-Chlorophenylethyl)quinoxalin-2(1H)-one
(IVa) was obtained from 5 g (0.022 mol) of ester IIIa
and 2.38 g (0.022 mol) of o-phenylendiamine. Yield 5.12 g
(82%), mp 199–200°C. IR spectrum, ν, cm–1: 3157, 3065,
1661, 1609, 1599, 1577, 1498, 1482, 1432, 1031, 907, 761,
755, 709, 698, 589, 503. 1H NMR spectrum (DMSO-d6),
δ, ppm: 3.44 d.d (1H, CH2Ph, JAΒ 13.93, JAX 7.96 Hz),
3.69 d.d (1H, CH2Ph, JAΒ 13.93, JΒX 6.97 Hz), 5.67 d.d
(1H, CHCl, JAΒ 13.93 Hz), 7.20 d.d.d (1H, H6, J 7.29,
6.31, 1.99 Hz), 7.25–7.35 m (5H, C6H5), 7.37 d (1H, H8,
J 7.96 Hz), 7.57 d.d.d (1H, H7, J 8.30, 7.30, 1.32 Hz),
7.83 d (1H, H5, J 8.63 Hz), 12.48 br.s (1H, NH). Found,
%: C 67.31; H 4.45; Cl 12.38; N 9.97. C16H13ClN2O.
Calculated, %: C 67.49; H 4.60; Cl 12.45; N 9.84.
EXPERIMENTAL
..
Melting points were measured on a Boetius heating
block. IR spectra were recorded on a Fourier spectro-
photometer Bruker Vector-22 from mulls in mineral oil.
1H NMR spectra were registered on a spectrometer
Bruker MSL-400 at operating frequency 400.13 MHz
using the signal of residual protons of the deuterated
solvents as reference.
Quinoxalines IVa–IVg. General procedure. To a mix-
ture of aldehyde Ia–Ig and methyl dichloroacetate in
anhydrous THF while stirring in an atmosphere of dry
argon at cooling to –53...–55 (Ia or Ib) or to –10°C [37]
3-(α-Chloro-γ-phenylpropyl)quinoxalin-2(1H)-
one (IVb) was obtained from 5 g (0.021 mol) of ester
IIIb and 2.25 g (0.021 mol) of o-phenylendiamine. Yield
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 8 2009

SAIFINA et al.
1246
5.32 g (85%), mp 201–203°C. IR spectrum, ν, cm–1: 3067,
3021, 2720, 1671, 1608, 1560, 1429, 1289, 906, 764, 751,
738, 701, 586. 1H NMR spectrum (DMSO-d6), δ, ppm:
2.75–2.83 m, 2.88–2.94 m (4H, CH2CH2), 5.40–5.45 m
(1H, CHCl), 7.20–7.40 m (7H, Ph + H6 and H8), 7.60 d.d
(1H, H7, J 7.96, 7.32 Hz), 7.82 d (1H, H5, J 7.96 Hz),
12.48 br.s (1H, NH). Found, %: C 68.13; H 4.93;
Cl 11.75; N 9.55. C17H15ClN2O. Calculated, %: C 68.34;
H 5.06; Cl 11.87; N 9.38.
1503, 1349, 903, 757, 591. 1H NMR spectrum (DMSO-
d6), δ, ppm: 0.89 t (3H, CH3, J 6.96 Hz), 1.28–1.54 m
[10H, (CH2)5], 2.13–2.29 m (2H, CH2CHCl), 5.45 d.d
(1H, CHCl, J 6.24, 6.2 Hz), 7.34–7.38 m (2H, H6, H8),
7.60 d.d.d (1H, H7, J 7.88, 7.68, 1.48 Hz), 7.82 d.d (1H,
H5, J 7.68, 0.72 Hz), 12.64 br.s (1H, NH). Found, %:
C 65.48; H 7.12; Cl 12.01; N 9.75. C16H21ClN2O.
Calculated, %: C 65.63; H 7.23; Cl 12.11; N 9.57.
3-(α-Chloroundecyl)quinoxalin-2(1H)-one (IVg)
was obtained from 1.4 g (5 mmol) of ester IIIg and
0.55 g (5 mmol) of o-phenylendiamine. Yield 1.27 g
(76%), mp 168–170°C. IR spectrum, ν, cm–1: 3104, 2717,
1666, 1609, 1558, 1502, 1239, 908, 758, 592. 1H NMR
spectrum (DMSO-d6 + CDCl3), δ, ppm: 0.86 t (3H, CH3,
J 6.97 Hz), 1.23–1.54 m [16H, (CH2)8], 2.13–2.27 m
(2H, CH2CHCl), 5.39 d.d (1H, CHCl, J 6.24, 6.24 Hz),
7.27 d.d.d (1H, H6, J 7.52, 7.52, 1.1 Hz), 7.34 d.d (1H,
H8, J 8.07, 0.73 Hz), 7.49 d.d.d (1H, H7, J 7.88, 7.52,
1.1 Hz), 7.76 d.d (1H, H5, J 8.07, 0.74 Hz), 12.52 br.s
(1H, NH). Found, %: C 67.98; H 8.02; Cl 10.41; N 8.50.
C19H27ClN2O. Calculated, %: C 68.14; H 8.13; Cl 10.59;
N 8.36.
3-(α-Chloropropyl)quinoxalin-2(1H)-one (IVc)
was obtained from 0.3 g (2 mmol) of ester IIIc and
0.20 g (2 mmol) of o-phenylendiamine.Yield 0.34 g (77%),
mp 209–211°C. IR spectrum, ν, cm–1: 3107, 2718, 1668,
1611, 1559, 1502, 1346, 910, 761, 590. 1H NMR spectrum
(DMSO-d6), δ, ppm: 1.07 t (3H, CH3, J 7.3 Hz), 2.18–
2.34 m (2H, CH2), 5.40 d.d (1H, CHCl, J 8.24 Hz), 7.34–
7.40 m (2H, H6, H8), 7.61 d.d.d (1H, H7, J 8.08, 7.30,
1.24 Hz), 7.83 d.d (1H, H5, J 7.76, 0.96 Hz). Found, %:
C 59.10; H 4.76; Cl 15.77; N 12.67. C11H11ClN2O.
Calculated, %: C 59.33; H 4.98; Cl 15.92; N 12.58.
3-(α-Chlorobutyl)quinoxalin-2(1H)-one (IVd)
was obtained from 1.46 g (8 mmol) of ester IIId and
0.88 g (8 mmol) of O-phenylendiamine. Yield 1.40 g
(74%), mp 205–206°C. IR spectrum, ν, cm–1: 2718, 1666,
1609, 1559, 1503, 907, 759, 711, 591. 1H NMR spectrum
(DMSO-d6), δ, ppm: 0.98 t (3H, CH3, J 7.52 Hz), 1.40–
1.63 m (2H, CH2CH3), 2.17–2.25 m (2H, CH2CHCl),
5.47 d.d (1H, CHCl, J 7.68, 6.96 Hz), 7.34–7.40 m (2H,
H6, H8), 7.61 d.d.d (1H, H7, J 8.24, 7.16, 1.12 Hz), 7.83
d.d (1H, H5, J 7.68, 0.72 Hz), 12.65 br.s (1H, NH). Found,
%: C 60.70; H 5.42; Cl 14.87; N 11.95. C12H13ClN2O.
Calculated, %: C 60.89; H 5.54; Cl 14.98; N 11.83.
REFERENCES
1. Prunier, H., Rault, S., and Lancelot, J.C., J. Med. Chem.,
1997, vol. 40, p. 1808.
2. Campiani, G., Cappelli, A., and Nacci, V., J. Med. Chem.,
1997, vol. 40, p. 3670.
3. Ohmori, J., Shimizu-Sasamata, M., and Okada, M., J. Med.
Chem., 1997, vol. 40, p. 2053.
4. Jacobsen, E.J., Stelzer, L.S., and Belonga, K.L., J. Med.
Chem., 1996, vol. 39, p. 3820.
3-(α-Chloroheptyl)quinoxalin-2(1H)-one (IVe)
was obtained from 0.3 g (1 mmol) of ester IIIe and 0.15 g
(1 mmol) of o-phenylendiamine. Yield 0.25 g (70%), mp
188–190°C. IR spectrum, ν, cm–1: 2717, 1666, 1609, 1560,
1502, 1430, 903, 756, 592. 1H NMR spectrum (DMSO-
d6), δ, ppm: 0.90 t (3H, CH3, J 6.42 Hz), 1.29–1.57 m
[8H, (CH2)4], 2.15–2.27 m (2H, CH2CHCl), 5.45 d.d (1H,
CHCl, J 6.6, 6.6 Hz), 7.33–7.40 m (2H, H6, H8), 7.61 d.d
(1H, H7, J 8.08, 7.32 Hz), 7.82 d (1H, H5, J 8.04 Hz),
12.64 br.s (1H, NH). Found, %: C 64.48; H 8.72;
Cl 12.57; N 10.15. C15H19ClN2O. Calculated, %: C 64.63;
H 6.87; Cl 12.72; N 10.05.
5. Padeiskaya, E.N., Novye khimioterapevticheskie
preparaty dlya lecheniya bol’nykh infektsionnymi
zabolevaniyami (New Therapeutic Chemicals for
Treatment of Infectious Diseases), Moscow, 1976.
6. Padeiskaya, E.N., Elina, A.S., and Pershin, G.N., Farm. &
Toks., 1967, p. 617.
7. Gazit,A.,App, H., McMahon, G., Chen, J., Levitzki,A., and
Bohmer, F.D., J. Med. Chem., 1996, vol. 39, 2170.
8. Sehlstedt, U., Aich, P., Bergman, J., Vallberg, H., Nor-
den, B., and Graslund,A., J. Mol. Biol., 1998, p. 278.
9. Cheeseman, G.W.H. and Cookson, R.F., Condensed
Pyrazines, Weissberger, A. and Taylor, E.C., Eds., New
York: Wiley-Interscience, 1979.
3-(α-Chlorooctyl)quinoxalin-2(1H)-one (IVf) was
obtained from 0.9 g (4 mmol) of ester IIIf and 0.41 g
(4 mmol) of o-phenylendiamine. Yield 0.88 g (75%), mp
173–175°C. IR spectrum, ν, cm–1: 2720, 1666, 1610, 1557,
10. Bozdyreva, K.S., Smirnova, I.V., and Maslivets, A.N., Zh.
Org. Khim., 2005, vol. 41, p. 1101.
11. Tolmacheva, I.A., Mashevskaya, I.V., and Maslivets,A.N.,
Zh. Org. Khim., 2002, vol. 38, p. 303.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRYVol. 45 No. 8 2009

DARZENS REACTION
2001, vol. 47, p. 217.
1247
12. Guillon, J., Boulouard, M., Lisowski, V., Stiebing, S., Le-
long, V., Dallemagne, P., and Rault, S., J. Pharm.
Pharmacol., 2000, vol. 52, p. 1369.
24. Lawrence, D.S., Copper, J.E., and Smith, C.D., J. Med.
Chem., 2001, 44, p. 594.
25. More, S.V., Sastry, M.N.V., Wang, Ch., and Yao, Ch.-F.,
Tetrahedron Lett., 2005, vol. 46, p. 6345.
26. Csikós, É., Gönczi, C., Podányi, B., Tóth, G., and Her-
mecz, I., J. Chem. Soc., Perkin Trans. 1, 1999, p. 1789.
27. Insuasty, B., Fernandez, F., Quiroga, J., and Moreno, R.J.
Heterocycl. Chem., 1998, vol. 35, p. 977.
28. Juncai, F., Yang, L., Qinghua, M., and Bin, L., Synth.
Commun., 1998, vol. 28, p. 193.
13. Leonard, N.J. and Boyer, J.H., J. Am. Chem. Soc., 1950,
vol. 72, p. 2980.
14. Ocal, N., Turgut, Z., Kaban, S., J. Heterocycl. Chem., 1998,
3 vol. 5, p. 1349.
..
..
15. Gonczi, C., Csikos, E., Podanyi, B., Nusser, T., Bocs-
key, Z., and Hermecz, I., J. Chem. Soc., Perkin Trans. 1,
2000, p. 1417.
16. Kirkovits, G.J., Zimmerman, R.S., Huggins, M.T.,
Lynch, V.M., and Sessler, J.L., Eur. J. Org. Chem., 2002,
p. 3768.
29. Barluenga, J.,Aznar, F., Liz, R., and Cabal, M.P., Synthesis,
1985, p. 313.
30. Petukhov, P.A. and Tkachev, A.V., Tetrahedron, 1997,
vol. 53, p. 9761.
31. Raw, S.A., Wilfred, C.D., and Taylor, R.J.K., Chem.
Commun., 2003, p. 2286.
32. Kim, S.Y., Park, K.H., and Chung, Y.K., Chem. Commun.,
2005, p. 1321.
33. Marques, C.S., Moura, N., and Burke, A.J., Tetrahedron
Lett., 2006, vol. 47, p. 6049.
34. Cho, C.S., Ren, W.X., and Shim, S.C., Tetrahedron Lett.,
2007, vol. 48, p. 4665.
35. Antoniotti, S. and Dunach, E., Tetrahedron Lett., 2002, vol.
43, p. 3971.
36. Mamedov, V.A., Berdnikov, E.A., Tsuboi, S., Khamamo-
to, Kh., Komiyama, T., Gorbunova, E.A., Gubaidullin,A.T.,
and Litvinov, I.A., Izv. Akad. Nauk, Ser. Khim., 2006,
p. 1402.
37. Komiyama, T., Takaguchi, Y., Tsuboi S., Synthesis, 2006,
vol. 24, p. 4115.
17. Adlington, R.M., Baldwin, J.E., Catterick, D., and Prit-
chard, G.J., J. Chem. Soc., Perkin Trans. 1, 2000, p. 299.
18. Touzani, R., Ben-Hadda, T., Elkadiri, S., Ramdani, A.,
Maury, O., Le, Bozec, H., Toupet, L., and Dixneuf, P.H.,
New J. Chem., 2001, vol. 25, p. 391.
19. Li, J.J., Carson, K.G., Trivedi, B.K., Yue, W.S., Ye, Q.,
Glynn, R.A., Millerv, S.R., Connor, D.T., Roth, B.D.,
Luly, J.R., Low, J.E., Heilig, D.J., Yang, W., Qin, S., and
Hunt, S., Bioorg. Med. Chem., 2003, vol. 11, p. 3777.
20. Duffy, K.J., Haltiwanger, C., Huang,Y., Konialian-Beck,A.,
and Luengo, J.I., Tetrahedron Lett., 1998, p. 8017.
21. Jigajinni, V.B., Preston, P.N., Shah, V.K., Simpson, S.W.,
Soutar, I., and Stewart, N.J. High, Perform. Polym., 1993,
vol. 5, p. 239.
22. Reddy, G.V., Rama, Rao, V.N.S., Maitraie, D., Ravikanth, S.,
Yadla, R., Reddy, S.N., and Rao, P.S., J. Fluorine Chem.,
2003, p. 203.
23. Klein, D.J., Kim, B.-S., and Harris, F.W., Polymer Bull.,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 8 2009