Preparation of 1,2- and 1,4-dihydro derivatives of 6,7-dimethyl-2,3- diphenylquinoxaline via its dianion formed by reductive metallation

Article abstract of DOI:10.1007/s00706-007-0812-1

Treatment of 6,7-dimethyl-2,3-diphenylquinoxaline with sodium in tetrahydrofuran formed a monomeric dianion. The chemical behavior of this dianion was investigated by a variety of reagents. As the result, alkylation reactions gave 1,2-dihydro derivatives, while acylation reactions occured at 1,4-positions. Annulation of the pyrazine ring system was accomplished by treating the dianion with oligomethylene dichlorides, Cl(CH₂) _n Cl, n = 2-4.

Full text of DOI:10.1007/s00706-007-0812-1

Monatsh Chem 139, 669–672 (2008)
DOI 10.1007/s00706-007-0812-1
Printed in The Netherlands
Preparation of 1,2- and 1,4-dihydro derivatives of 6,7-dimethyl-2,3-
diphenylquinoxaline via its dianion formed by reductive metallation
Seniz Kaban, Feray Aydogan
Department of Chemistry, Yildiz Technical University, Davutpasa Campus, Esenler-Istanbul, Turkey
Received 12 September 2007; Accepted 22 September 2007; Published online 19 May 2008
# Springer-Verlag 2008
Abstract Treatment of 6,7-dimethyl-2,3-diphenylqui-
noxaline with sodium in tetrahydrofuran formed a
monomeric dianion. The chemical behavior of this
dianion was investigated by a variety of reagents. As
the result, alkylation reactions gave 1,2-dihydro de-
rivatives, while acylation reactions occured at 1,4-
positions. Annulation of the pyrazine ring system
was accomplished by treating the dianion with oligo-
methylene dichlorides, Cl(CH2)nCl, n ¼ 2–4.
gative arrangement with electron donating phenyl
groups and nitrogen atoms, is investigated.
Results and discussion
Treatment of 1 with excess sodium metal in tetra-
hydrofuran under an inert atmosphere gave a deep
purple colored solution of dianion 2. Under these
conditions 1 was converted to a monomeric dianion
2 which resonance structures can be thought as 2a,
2b, and 2c (Scheme 1).
Keywords Heterocycles; Reductions; Nucleophilic substitu-
tions; Annulation; Nitrogen anions.
However, in our opinion, the most probable reso-
nance structures are 2a and 2b in comparison with
2c. For determination of this expectation, the chem-
ical behavior of the dianion with several reagents
were investigated. To carry out these reactions, un-
reacted sodium was removed from the dianion so-
lution and the reagents were injected to alkylating
agents through a septum under argon atmosphere.
The reaction mixtures were stirred for 5–8 h. The
products 3–8 isolated from these reactions were
purified by chromatographic methods and charac-
terized by IR, NMR, and MS data and their puri-
ty was established by means of elemental analysis
(Scheme 2).
Introduction
The dianions formed by the reductive metallation
of unsaturated heterocyclic systems are very use-
ful intermediates in the synthesis of nonaromatic
dihydro derivatives of heteroaromatic compounds.
Moreover, these dianions are interesting due to their
vicinal anionic centers. Although the formation of
some heterocyclic dianions has been investigated
by NMR [1], their chemical behavior has not been
researched widely. So, our research group has stud-
ied on the alkylation and acylation reactions of the
dianions of fused heterocyclic compounds recently
[2–4].
From the alkylation reactions of 2, performed
at 25ꢀC, 1,2-dialkylation products were isolated as
main products, while small amounts of these prod-
ucts formed at ꢁ78ꢀC. 1,2-Di-hydro-1,2,6,7-tetra-
methyl-2,3-diphenylquinoxaline (3) was obtained by
the reaction with methyl iodide. 1H NMR spectra of
In this report, the reductive metallation of 6,7-di-
methyl-2,3-diphenylquinoxaline (1) having a conju-
Correspondence: Seniz Kaban, Department of Chemistry,
Yildiz Technical University, Davutpasa Campus, Esenler-
Istanbul 34220, Turkey. E-mail: skaban29@yahoo.com

670
S. Kaban, F. Aydogan
Scheme 1
Scheme 2
3 showed four singlets belonging to 1-, 2-, 6-, and 7-
methyl groups at ꢀ ¼ 2.46, 1.81, 2.21, and 2.28 ppm.
This methylation showed that the alkylation of 2
proceeded stepwise, the first alkyl group being intro-
duced at the benzylic carbon followed by the second
at nitrogen.
Annulation to four-, five-, and six-membered ring
systems at 1,2-positions of 2 were accomplished
by the alkylation reactions with a series of oligo-
methylene dichlorides, Cl(CH2)nCl (n ¼ 2–4). These
azetidino- (4), pyrrolidino- (5), and piperidino- (6)
systems were performed through intramolecular exo-
tet ring closure in accordance with Baldwin’s rules
[5].
1
The H NMR spectra of 4–6 showed N–CH3 sig-
nals at 3.48–4.10 ppm and the other signals at 3.03–
3.61, 2.01–2.86, and 1.53–2.95 ppm as multiplets.
Acylation of 2 with methyl and ethyl chloro-
formate was executed at ꢁ78ꢀC. These reactions
occured on the negatively charged nitrogen atoms
with the formation of 1,4-dihydro derivatives 7 and
8 of 1. These structures were confirmed by 13C NMR
spectra of 7 in which C¼O group was observed at
155.35 ppm.

Derivatives of 6,7-dimethyl-2,3-diphenylquinoxaline
671
injection of 1 cm3 of methanol, the color changed to yellow and
the solution was extracted with diethyl ether (3ꢂ100 cm3).
The combined extracts were dried over sodium sulfate and
evaporated. The crude reaction product was chromatographed
on silica gel. Elution of column with toluene gave yellow
fluorescent crystals. Recrystallization from 40 to 60ꢀC pe-
troleum ether afforded 0.286g (84%) 3. Mp 176ꢀC; 1H NMR
(200MHz, CDCl3): ꢀ ¼ 1.81 (s, 2-CH3), 2.21 (s, 7-CH3),
2.28 (s, 6-CH3), 2.46 (s, 1-CH3), 6.39–7.53 (m, 12H, aro-
matic) ppm; IR (KBr): ꢁꢀ¼ 3080, 2970, 2850, 2740, 1625,
1497, 1446, 1344cmꢁ1; UV (chloroform): lmax ¼ 233,
258 nm; MS (70 eV): m=z (%) ¼ 341 (Mþ 1, 20), 340 (Mþ,
47), 325 (100), 263 (48), 236 (24), 118 (31), 103 (24), 77 (28).
The mass fragmentation and elemental analysis
results of all compounds supported the suggested
structures. In all experiments, some 1 was recovered,
probably because of only partial reduction of 1 to 2,
or conversion of 2 to 1 by traces of the oxygen in-
troduced into the system during the handling of the
reaction reagents.
Experimental
Melting points were measured in open capillaries with an
Electrothermal IA 9100 melting point apparatus. IR spectra
were recorded on a Philips PU 9714 and Mattson 1000 FTIR
spectrometer in KBr pellets. The NMR spectra were deter-
mined on a Varian 200 MHz Gemini in CDCl3 with TMS as
internal standart. UV spectra were recorded with Philips PU
8700 UV=VIS spectrometer using chloroform. Mass spectra
were obtained with Shimadzu GC=MS QP 2000 A. Elemental
analyses (C, H, and N) were carried out using Perkin-Elmer
240 B microanalyzer; their results were in favourable agree-
ment with the calculated values. Column chromatography was
performed with silica gel 60 (70–230 mesh) purchased from
E. Merck. Thin-layer chromatography (TLC) was effected with
Eastman Kodak Chromagram 13181 silica gel sheets with
fluorescent indicator. Tetrahydrofuran was purified by reflux-
ing for at least 8 h over LiAlH4 under N2, and when needed
the solvent was refluxed for 2 h and the required amount was
redistilled immediately before use. All reactions involving
alkali-metal compounds were conducted in an atmosphere of
purified and dried Ar. For determining of completion time
of reduction, the reductive metallation of 1 on a preparative
scale was performed. Removal of weighed aliquots of the
solution during the reaction between 1 and sodium in tetrahy-
drofuran, quenching the aliquots in 1:1 ¼ water:methanol, and
titrating with standardized HCl, demonstrated that formation
of deep purple solution of the dianion 2 was completed after
18h.
rac-6,7-Dimethyl-2a,3-diphenylazetidino[1,2-a]quinoxaline
(4, C24H22N2)
1,2-Dichloroethane (0.194g, 2.0 mmol) was added to the dia-
nion solution prepared by the procedure described for com-
pound 3, after 8 h stirring, the color of this resulting solution
was yellow. The crude reaction product was isolated and chro-
matographed on silica gel. Elution with toluene gave yellow
1
fluorescent oily product, 0.138g (40%). H NMR (200 MHz,
CDCl3): ꢀ ¼ 2.17 (s, 7-CH3), 2.23 (s, 6-CH3), 3.10 (m, 2-CHa),
3.54 (m, 2-CHb), 3.92 (m, 1-CHa), 4.06 (m, 1-CHb), 6.56–
7.80 (m, 12H, aromatic) ppm; IR (KBr): ꢁꢀ¼ 3080, 2980,
2850, 2770, 1610, 1590, 1480, 1440, 1312cmꢁ1; UV (chlo-
roform): lmax ¼ 268, 328nm; MS (70 eV): m=z (%) ¼ 339
(Mþ 1, 44), 338 (Mþ, 100), 337 (Mꢁ 1, 87), 323 (43), 310
(89), 309 (85), 261 (92), 234 (84), 206 (37), 103 (38), 77 (23).
rac-7,8-Dimethyl-3a,4-diphenylpyrrolidino[1,2-a]-
quinoxaline (5,C25H24N2)
The reaction described above was repeated with 1,3-dichloro-
propane (0.225g, 2.0 mmol) for 6 h. Chromatography (silica=
toluene) of crude product provides yellow needles, 0.266g
1
(75%). Mp 169ꢀC; H NMR (200MHz, CDCl3): ꢀ ¼ 2.01–
2.12 (m, 2-CH2), 2.18 (s, 8-CH3), 2.21 (s, 7-CH3), 2.43 (m,
3-CHa), 2.80 (m, 3-CHb), 3.48–3.69 (m, 1-CH2), 6.36–7.66
(m, 12H, aromatic) ppm; IR (KBr): ꢁꢀ¼ 3120, 2980, 2850,
2815, 1600, 1497, 1370, 1290 cmꢁ1; UV (chloroform):
lmax ¼ 257, 326 nm; MS (70 eV): m=z (%) ¼ 353 (Mþ 1,
35), 352 (Mþ, 81), 337 (22), 323 (26), 276 (100), 275 (64),
249 (38), 248 (96), 176 (38), 103 (35), 77 (41).
6,7-Dimethyl-2,3-diphenylquinoxaline (1) was prepared
from 4,5-dimethyl-1,2-phenylenediamine and 1,2-diphenyl-
ethanedione. Physical properties of 1 are comparable with
the data given in literature, e.g., mp 177ꢀC (Ref. [7] 173–
175ꢀC and [8] 172ꢀC); IR and NMR spectra were also found
to be similar to those of published in Refs. [7, 8].
rac-8,9-Dimethyl-4a,5-diphenylpiperidino[1,2-a]quinoxaline
(6, C26H26N2)
General procedure
The same reaction with compound 3 was performed with 1,4-
dichlorobutane (0.254 g, 2.0 mmol). Stirring was continued for
5 h. The crude product was chromatographed (silica=toluene)
rac-1,2-Dihydro-1,2,6,7-tetramethyl-2,3-diphenylquinoxaline
(3, C24H24N2)
1
Compound 1 (0.310g, 1.0 mmol) was placed in a specially
designed flask [6] equipped with a stirring bar and a septum,
the flask was evacuated and filled Ar. Then 100 cm3 of THF
was destilled and freshly cut sodium (ca. 1 g) was added.
Under an Ar atmosphere, the mixture was stirred about 18h
and the excess sodium was removed from the solution of 2.
Methyl iodide (0.284g, 2.0mmol) was injected through the
septum. This mixture was stirred for 5 h. The color of reac-
tion mixture changed from deep purple to deep brown. After
and yellow fluorescent oil (0.280g, 76%) was obtained. H
NMR (200MHz, CDCl3): ꢀ ¼ 1.53–1.78 (m, 3-CH2), 2.17 (s,
9-CH3), 2.25 (s, 8-CH3), 2.35 (t, 4-CH2), 2.83–2.95 (m, 2-
CH2), 3.58 (m, 1-CH2), 6.55–7.46 (m, 12H, aromatic) ppm;
IR (KBr): ꢁꢀ¼ 3120, 2980, 2850, 2780, 1625, 1497, 1446,
1344cmꢁ1; UV (chloroform): lmax ¼ 254 nm; MS (70 eV):
m=z (%) ¼ 367 (Mþ 1, 51), 366 (Mþ, 100), 365 (Mꢁ 1,
26), 310 (31), 309 (34), 290 (98), 289 (57), 263 (38), 262
(94), 247 (31), 234 (37), 207 (34), 183 (43), 103 (34), 77 (26).

672
S. Kaban, F. Aydogan
2830, 1730, 1510, 1464, 1371, 1336 cmꢁ1; UV (chloroform):
lmax ¼ 243 nm; MS (70 eV): m=z (%) ¼ 457 (Mþ 1, 82), 456
(Mþ, 68), 455 (Mꢁ 1, 34), 383 (57), 339 (82), 310 (55), 309
(100), 233 (64), 207 (36), 192 (31), 104 (49), 77 (33).
Dimethyl 1,4-dihydro-6,7-dimethyl-2,3-diphenylquinoxaline-
1,4-dicarboxylate (7, C26H24O4N2)
The solution of dianion 2 was cooled ꢁ78ꢀC and methyl
chloroformate (0.189 g, 2 mmol) was injected. The reac-
tion mixture was stirred for 4.5 h, and then allowed warming
to room temperature. The crude product obtained after 1 h
stirring as described for 3 was chromatographed on silica
gel. After elution of 1 with toluene, 7 was obtained by
elution of the column with chloroform as colorless bright
small plates, 0.285 g (66%). Mp 195ꢀC; 1H NMR (200 MHz,
CDCl3): ꢀ ¼ 2.33 (s, 6-CH3, 7-CH3), 3.62 (s, 1-CO2CH3, 4-
CO2CH3), 7.15–7.47 (m, 12H, aromatic) ppm; 13C NMR
(50 MHz, CDCl3): ꢀ ¼ 21.71 (CH3), 54.92 (COOCH3),
126.23–137.27 (C¼C, aromatic 18C), 155.35 (COOCH3)
ppm; IR (KBr): ꢁꢀ¼ 3110, 3010, 2970, 2830, 1727, 1497,
1446, 1344 cmꢁ1; UV (chloroform): lmax ¼ 250 nm; MS
(70 eV): m=z (%) ¼ 429 (Mþ 1, 100), 428 (Mþ, 51), 427
(Mꢁ 1, 47), 370 (92), 310 (59), 309 (99), 233 (54), 207 (33),
103 (48), 77 (26).
Acknowledgements
We are grateful to Research Foundation of Yildiz Technical
University (Project Number: 94-B-01-02-02) and Turkish
Scientific and Technical Research Council (TBAG=14) for
financial support.
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Diethyl 1,4-dihydro-6,7-dimethyl-2,3-diphenylquinoxaline-
1,4-dicarboxylate (8, C28H28O4N2)
The procedure described for 7 was repeated with ethyl
chloroformate (0.217 g, 2.0 mmol). The reaction mixture was
stirred at ꢁ78ꢀC for 3.5 h, and then at room temperature for
2 h. Chromatographic separation on silica gel with toluene
followed by chloroform gave colorless crystals, 0.245 g
(54%). Mp 206–207ꢀC; 1H NMR (200 MHz, CDCl3): ꢀ ¼
1.03 (t, 1-CO2CH2CH3, 4-CO2CH2CH3), 2.32 (s, 6-CH3, 7-
CH3), 4.05 (q, 1-CO2CH2CH3, 4-CO2CH2CH3), 7.14–7.52
(m, 12H, aromatic) ppm; IR (KBr): ꢁꢀ¼ 3110, 3005, 2970,