Expedient entry into 1,4-dihydroquinoxalines and quinoxalines via a novel variant of isocyanide-based MCR

Article abstract of DOI:10.1055/s-2008-1032106

A novel multicomponent reaction of o-phenylenediamines with aldehydes and isonitriles yields 1,4-dihydroquinoxalines. These intermediates are unstable under reaction conditions. They undergo oxidation with DDQ to furnish 33-54% isolated yields of the respective quinoxalines. This reaction is general for aromatic 1,2-diamines. Monoalkylated aryl 1,2-diamines lead to stable 1,4-dihydroquinoxalines. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1032106

LETTER
645
Expedient Entry into 1,4-Dihydroquinoxalines and Quinoxalines via a Novel
Variant of Isocyanide-Based MCR
E
ntry into 1, 4-Dihydro
i
quinox
k
aline
s
and
Q
h
uinoxaline
s
ail Krasavin,*,1 Vladislav Parchinsky
Chemical Diversity Research Institute, 2a Rabochaya St., Khimki, Moscow Reg., 114401, Russia
Fax +7(495)9954942; E-mail: myk@chemdiv.com
Received 12 September 2007
reactions of various aldehydo and keto acids,5,6 iii) aque-
Abstract: A novel multicomponent reaction of o-phenylenedi-
amines with aldehydes and isonitriles yields 1,4-dihydroquinoxa-
lines. These intermediates are unstable under reaction conditions.
They undergo oxidation with DDQ to furnish 33-54% isolated
yields of the respective quinoxalines. This reaction is general for ar-
omatic 1,2-diamines. Monoalkylated aryl 1,2-diamines lead to sta-
ble 1,4-dihydroquinoxalines.
ous-phase b-lactam synthesis from b-amino acids,7 and
many others.
In the course of our research on the Groebke-type reac-
tions,8,9 we explored the opportunities for other nitrogen
nucleophiles (e.g., free amino group) within the aldimine
moiety to intercept the initial reactive intermediate.10
Herein we would like to report that, according to this ra-
tionale, the use of o-phenylenediamine (1) in the reaction
with equimolar amounts of an aldehyde 2 and an isonitrile
3 leads to the formation of 1,4-dihydroquinoxalines 4
(Scheme 1).
Key words: combinatorial chemistry, dehydrogenations, multi-
component reactions, isocyanides, quinoxalines
Recent developments in the multicomponent reactions
(MCR)2 involving isocyanides and substrates containing
two reacting functionalities have further confirmed their
utility in generating complex scaffolds in a single chemi-
cal event. Notable examples include: i) Groebke reaction
of 2-aminoazines and azoles,3,4 ii) ring-forming Ugi-type
This reaction proceeded smoothly with a variety of reac-
tants (Table 1) in methanol at room temperature using
equimolar amount of HCl (concd) as a catalyst. In 18
hours, 1,4-dihydroquinoxalines 4a-h were detected as
major components of the reaction mixture by LCMS anal-
N
O
N
N
N
R2 N+ C–
+
R1
+
NH2
R1
H
N
NH
R2
acid catalyst
(a)
N
N
N
H
N
H
N+
H
H
–C
N
H
N
N+
H
R1
N+
R1
N
R2
R1
N+
R2
N
R2
H
H
N
N
NH2
O
H
R2
R2 N+ C–
R1
+
+
N
H
R1
NH2
1
4
3
2
(b)
acid catalyst
R2
H
N
R2
N
+N
NH2
N+
R2
NH2
–C
R1
H
R1
N
H
N
H
N+
H
R1
Scheme 1 The Groebke reaction of 2-aminopyrimidine (a) and the novel reaction of o-phenylenediamines described in this work (b).
SYNLETT 2008, No. 5, pp 0645–0648
x
x.
x
x.
2
0
0
8
Advanced online publication: 26.02.2008
DOI: 10.1055/s-2008-1032106; Art ID: D28507ST
© Georg Thieme Verlag Stuttgart · New York

646
M. Krasavin, V. Parchinsky
LETTER
Table 1 Quinoxalines 5a-h Synthesized in this Work
Entry Diamine 1
R1
Ph
Ph
Ph
N
R2
Yieldof
5 (%)c
NH2
1
2
3
4
5
6
54
50
53a
43
33
48
NH2
NH2
NH2
NH2
NH2
NH2
N
NH2
NH2
Figure 1 X-ray structure of the compound 5b.
H
N
NH2
N
R1
NH2
R1CHO (2), R2NC (3)
NH2
X
X
R2
Ph
concd HCl (1 equiv)
MeOH, r.t.
18 h, under Ar
N
H
N
H
NH2
O
NH2
1
4a–h
O
benzene, r.t.
1–3 h
DDQ (1 equiv)
7
8
35b
43
NH2 Ph
NH2
HO
N
R1
X
R2
NH2
NH2
N
N
H
S
O
5a–h
Scheme 2 Synthesis of quinoxalines 5a-h via intermediate forma-
tion of 1,4-dihydroquinoxalines 4a-h.
a The product was isolated chromatographically as 1:1 mixture of iso-
mers.
b The product was obtained as a single isomer after chromatography
(<5% of the other isomer was present in crude reaction mixture by
LCMS analysis).
flexibility with respect to functional group (e. g., 5g). To
the best of our knowledge, this new isocyanide-based
multicomponent reaction is the first example of the anilin-
ic amino group functioning as internal nucleophile to in-
tercept the isonitrile interacting with an aldimine moiety.
We further established that this two-step addition-oxida-
tion protocol can be extended to the synthesis of pyri-
do[2,3-b]pyrazine 8 from 2,3-dimiaminopyridine (6),16
albeit in low yield (Scheme 3).
c The yield for two steps (% from 1) after chromatography.
ysis, accompanied by minor byproducts.11 During at-
tempted chromatographic isolation of 4a-h, these
compounds were found to be unstable. Exposure of 4a-h
to air led to the formation of variable amounts of the re-
spective quinoxalines 5a-h. Efficient conversion of the
product mixture into a single isolable product was In order to confirm the intermediacy of 1,4-dihydroqui-
achieved by brief exposure of crude reaction mixtures noxalines 4 in the preparation of the isolated quinoxalines
containing 4a-h to DDQ/benzene system at room tem- 5, we tested the same multicomponent reaction using
monoalkylated diamines 9 and 11. Gratifyingly, the reac-
tion mixtures contained products 1017 and 1218 isolated in
moderate yields (Scheme 4). These heterocyclic com-
pounds are flavin analogues posing interest as molecular
probes19 and catalysts for biomimetic oxidations.20
perature. As expected, this furnished 5a-h (Scheme 2,
Table 1).12 The identity of synthesized quinoxalines 5 has
been confirmed by the X-ray analysis of a representative
compound 5b (Figure 1).13
Several relevant molecules have been reported as biolog-
ically active substances. A number of antifolate agents14
and kinase inhibitors15 based on this chemotype appeared
in the literature. Notably, their synthesis generally in-
volved multistep reaction sequences. The method report-
ed herein offers a convenient and conceptually new
alternative to combinatorial synthesis of 2-(alkylamino)-
3-arylquinoxalines. In addition, it offers considerable
In conclusion, we have discovered a novel variant of iso-
cyanide-based MCR involving aromatic 1,2-diamines and
demonstrated its preparative value in efficient two-step
synthesis of medicinally important 2-(alkylamino)-3-
arylquinoxalines 5a-h. This reaction could be extended
to the heterocyclic 1,2-diamines and N-monoalkylated di-
amines. The potential of this new ring-forming MCR war-
Synlett 2008, No. 5, 645–648 © Thieme Stuttgart · New York

LETTER
Entry into 1,4-Dihydroquinoxalines and Quinoxalines
647
References and Notes
NC
PhCHO
H
N
Ph
NH2
(1) New address: M. Krasavin, Department of Chemistry,
McGill University, Montreal, Quebec H3A 2K6, Canada.
(2) Dömling, A. Chem. Rev. 2006, 106, 17.
(3) Groebke, K.; Weber, L.; Mehlin, F. Synlett 1998, 661.
(4) Bienaymé, H.; Bouzid, K. Angew. Chem. Int. Ed. 1998, 37,
2234.
N
NH2
concd HCl (1 equiv)
MeOH, r.t., 3 d
under Ar
N
N
H
N
H
6
7
(5) Ilyn, A. P.; Loseva, M. V.; Vvedensky, V. Y.; Putsykina, E.
B.; Tkachenko, S. E.; Kravchenko, D. V.; Khvat, A. V.;
Krasavin, M. Y.; Ivachtchenko, A. V. J. Org. Chem. 2006,
71, 2811.
benzene, r.t.
3 h
DDQ (1 equiv)
(6) Mironov, M. A.; Ivantsova, M. N.; Mokrushin, V. S. Mol.
Diversity 2003, 6, 193.
N
(7) (a) Pirrung, M. C.; Das Sharma, K. J. Am. Chem. Soc. 2004,
126, 444. (b) Kanizsai, I.; Gyónfalvi, S.; Szakonyi, Z.;
Sillanpää, R.; Fülöp, F. Green Chem. 2007, 9, 357.
(8) Parchinsky, V. Z.; Shuvalova, O.; Ushakova, O.;
Kravchenko, D. V.; Krasavin, M. Tetrahedron Lett. 2006,
47, 947.
N
N
N
H
8 12%
Scheme 3
(9) Parchinsky, V. Z.; Koleda, V. V.; Shuvalova, O.;
Kravchenko, D. V.; Krasavin, M. Tetrahedron Lett. 2006,
47, 6891.
H
N
NH2
(10) (a) One example of an aliphatic diamine participating in the
intramolecular Ugi-type MCR has been reported in:Keung,
W.; Bakir, F.; Patron, A. P.; Rogers, D.; Priest, C. D.;
Darmohusodo, V. Tetrahedron Lett. 2004, 45, 733. (b) An
account of the use of ethylene diamines appeared in print
when the present manuscript was in preparation: Kysil, V.;
Tkachenko, S.; Khvat, A.; Williams, C.; Tsirulnikov, S.;
Churakova, M.; Ivachtchenko, A. Tetrahedron Lett. 2007,
48, 6239.
PhCHO, c-HeptNC
concd HCl (1 equiv)
MeOH, r.t.
NH
N
N
H
18 h
9
10 44%
H
N
NH2
PhCHO, c-HeptNC
(11) (a) One of the redundant byproducts was identified as 2-
(R1)-substituted benzimidazole, presumably formed from
the oxidative cyclization of the intermediate aldimine. This
observation is in accordance with our previous results, see
ref. 11b. The unwanted benzimidazole formation could be
minimized by thorough exclusion of air from the reaction
medium. (b) Krasavin, M.; Kobak, V. V.; Bondarenko, T.
Y.; Kravchenko, D. V. Heterocycles 2005, 65, 2189.
(12) Analytical Data for Selected Compounds
Compound 5b: pale yellow solid, mp 156-157ºC. 1H NMR
(300 MHz, DMSO-d6): d = 7.50-7.59 (m, 7 H), 7.21-7.31
(m, 5 H), 6.34 (s, 1 H, NH), 3.64 (unresolved dd, 2 H,
NHCH2), 2.93 (unresolved t, 2 H, NHCH2CH2), 2.37 (s, 3
H), 2.33 (s, 3 H). 13C NMR (75 MHz, DMSO-d6): d = 150.0,
145.7, 140.3, 140.1, 139.6, 137.3, 135.5, 133.5, 129.6, 129.2
(two signals overlapped), 128.9, 128.8, 128.2, 126.4, 125.7,
42.9, 34.7, 20.2, 19.7. LCMS: m/z = 354 [M + 1]. HRMS
(EI): m/z calcd for C24H23N3: 353.4710; found: 353.4711.
Compound 5g: grey solid, mp 203 °C (decomp.). 1H NMR
(400 MHz, DMSO-d6): d = 12.95 (br s, 1 H, COOH), 8.33 (d,
J = 1.5 Hz, 1 H), 8.04 (dd, J = 8.6, 1.8 Hz, 1 H), 7.74 (m, 2
H), 7.64 (d, J = 8.6 Hz, 1 H), 7.55 (m, 3 H), 6.61 (d, J = 6.6
Hz, 1 H, NH), 4.46 (m, 1 H, NHCH), 2.00 (m, 2 H), 1.65 (m,
2 H), 1.54 (m, 4 H). 13C NMR (75 MHz, DMSO-d6): d =
167.5 (COOH), 150.9, 148.2, 144.3, 136.7, 135.6, 130.8,
130.1, 129.8, 129.3, 128.9, 126.1, 125.8, 52.9, 32.2, 24.0.
LCMS: m/z = 334 [M + 1]. HRMS (EI): m/z calcd for
C20H19N3O2: 333.3933; found: 333.3932.
concd HCl (1 equiv)
MeOH, r.t.
N
NH
N
N
N
H
18 h
MeO
11
12 25%
OMe
Scheme 4 Air-stable 1,4-dihydroquinoxaline 10 and 1,4-dyhydro-
pyrido[2,3-b]pyrazine 12 prepared from monoalkylated diamines (9
and 11, respectively).
rants future studies to expand scope and optimize yields of
the target compounds.
The starting diamine 1 (10 mmol) was dissolved in anhyd MeOH
(50 mL) and the solution was thoroughly degassed by freeze-thaw
technique. Concentrated HCl (10 mmol) and equimolar amounts of
aldehyde 2 and isonitrile 3 were added to the resulting solution. The
reaction mixture was stirred at r.t. for 18 h under argon. Methanol
was evaporated in vacuo. The residue was partitioned between sat.
aq NaHCO3 and CHCl3. Aqueous layer was further extracted with
CHCl3. Combined organic extracts were dried over anhyd MgSO4,
filtered, and concentrated in vacuo. Crude product was washed with
dry benzene (ca. 100 mL) and a solution of DDQ in 5 mL of ben-
zene was added dropwise. The resulting mixture was stirred at r.t.
for 1-3 h. The precipitate of hydroquinone was filtered off and
washed with toluene. The combined filtrate and washings were con-
centrated in vacuo. Quinoxalines 5a-h were isolated chromato-
graphically (SiO2) using EtOAc-hexane mixtures as eluent.
Compound 5h: yellow sticky solid, mp 68–69 °C. 1H NMR
(400 MHz, DMSO-d6): d = 7.86 (dd, J = 3.8, 0.9 Hz, 1 H),
7.83 (dd, J = 5.1, 0.9 Hz, 1 H), 7.78 (dd, J = 8.2, 1.1 Hz, 1
H), 7.62 (dd, J = 8.4, 1.1 Hz, 1 H), 7.55 (ddd, J = 8.4, 6.8, 1.1
Hz, 1 H), 7.37 (ddd, J = 8.2, 6.8, 1.3 Hz, 1 H), 7.27 (dd,
J = 5.1, 3.8 Hz, 1 H), 6.87 (t, J = 5.3 Hz, NHCH2), 3.70 (dt,
Jd = 5.3, Jt = 5.1 Hz, 2 H, NHCH2), 3.62 (t, J = 5.1 Hz, 2 H,
MeOCH2), 3.31 (s, 3 H, OCH3). 13C NMR (75 MHz, DMSO-
Acknowledgment
The authors thank Dr. Volodymyr Kysil of ChemDiv, Inc. (San
Diego, CA) for helpful discussions regarding this work.
Synlett 2008, No. 5, 645–648 © Thieme Stuttgart · New York

648
M. Krasavin, V. Parchinsky
LETTER
d6): d = 149.4, 140.9, 140.8, 140.0, 136.4, 130.3, 130.0,
128.7, 128.4, 128.2, 125.9, 124.8, 70.3, 58.4, 40.7. LCMS:
m/z = 286 [M + 1]. HRMS (EI): m/z calcd for C15H15N3OS:
285.3703; found: 285.3703.
DMSO-d6): d = 7.24 (m, 3 H), 7.15 (m, 2 H), 6.86 (m, 1 H),
6.83 (m, 1 H), 6.72 (ddd, J = 7.6, 7.5, 1.6 Hz, 1 H), 6.53 (dd,
J = 7.5, 1.6 Hz, 1 H), 5.47 (s, 1 H, dihydroquinaxoline-NH),
4.24 (br s, 1 H, NH-cycloC7H13), 3.52 (s, 3 H, NCH3), 3.48
(m, 1 H, NHCH), 1.72-1.82 (m, 2 H), 1.44-1.67 (m, 8 H),
1.18-1.35 (m, 2 H). 13C NMR (75 MHz, DMSO-d6): d =
149.8, 140.5, 132.1, 132.0, 128.8, 127.7, 126.4, 120.3,
119.9, 114.5, 113.0, 58.7, 53.4, 37.2, 36.6, 30.6, 28.3, 28.1,
24.7, 24.5. LCMS: m/z = 334 [M + 1]. HRMS (EI): m/z calcd
for C22H27N3: 333.4806; found: 333.4803.
(13) Crystallographic data (excluding structure factors) for the
structure 5b have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication
number CCDC 671798. Copies of the data can be obtained
free of charge, on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK [fax: +44 (1223)336033 or e-
mail: deposit@ccdc.cam.ac.uk].
(18) Characterization Data for 12
(14) Loriga, M.; Fiore, M.; Sanna, P.; Paglietti, G. Il Farmaco
1995, 50, 289.
(15) Ding, S.; Gray, N. S.; Wu, X.; Ding, Q.; Schultz, P. G. J. Am.
Chem. Soc. 2002, 124, 1594.
Brown viscous oil. 1H NMR (400 MHz, DMSO-d6): d = 8.33
(dd, J = 4.9, 1.3 Hz, 1 H), 7.89 (dd, J = 7.6, 1.3 Hz, 1 H),
7.56 (m, 2 H), 7.51 (m, 3 H), 7.07 (dd, J = 4.9, 7.6 Hz, 1 H),
4.55 (t, J = 6.3 Hz, 2 H, MeOCH2), 3.65 (t, J = 6.3 Hz, 2 H,
NHCH2), 3.30 (s, 3 H, OCH3), 3.24 (m, 1 H, NHCH), 1.44
(m, 2 H), 1.30-1.40 (m, 6 H), 1.21 (m, 2 H), 0.95 (m, 2 H).
13C NMR (75 MHz, DMSO-d6): d = 154.2, 149.0, 146.1,
139.8, 139.5, 136.1, 130.0, 129.0, 127.4, 117.1, 114.2, 68.3,
58.4, 58.0 (one signal obscured by DMSO sept). LCMS:
m/z = 379 [M + 1]. HRMS (EI): m/z calcd for C23H30N4O:
378.5218; found: 378.5221.
(16) Characterization Data for 8
Brown oil. 1H NMR (300 MHz, DMSO-d6): d = 8.79 (dd,
J = 5.1, 1.8 Hz, 1 H), 8.50 (d, J = 7.3 Hz, 1 H), 7.73 (br s, 1
H, NH), 7.64 (m, 2 H), 7.53-7.59 (m, 4 H), 7.28-7.35 (m, 4
H), 7.22 (m, 1 H), 3.72 (dd, J = 14.2, 7.2 Hz, 2 H,
NHCH2CH2), 2.98 (t, J = 7.2 Hz, 2 H, NHCH2CH2). 13
C
NMR (75 MHz, DMSO-d6): d = 158.4, 151.6, 147.0, 142.1,
136.7, 135.0, 134.9, 133.6, 130.1, 129.6, 128.5, 127.9,
127.2, 126.4, 125.8, 43.6, 35.2. LCMS: m/z = 327 [M + 1].
HRMS (EI): m/z calcd for C21H18N4: 326.4044; found:
326.4047.
(19) Kajiki, T.; Moriya, H.; Hoshino, K.; Kuroi, T.; Kondo, S.;
Nabeshima, T.; Yano, Y. J. Org. Chem. 1999, 61, 9679.
(20) Linden, A. A.; Johansson, M.; Hermanns, N.; Bäckvall, J.-E.
J. Org. Chem. 2006, 71, 3849.
(17) Characterization Data for 10
Off-white solid, mp 110–112 °C. 1H NMR (300 MHz,
Synlett 2008, No. 5, 645–648 © Thieme Stuttgart · New York

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