A two-step synthesis of selected 1,2,3,4-tetrahydroquinoxaline derivatives from N -aryl-2-nitrosoanilines and arylidenecyanoacetic esters

Article abstract of DOI:10.1055/s-0033-1339467

Reaction of N-aryl-2-nitrosoanilines with alkyl arylidenecyanoacetates in the presence of Et₃N in MeCN leads to substituted 1,2,3,4-tetrahydroquinoxaline derivatives in reasonable yields. The reaction comprises nucleophilic addition of the nitrosoaniline to the Michael acceptor followed by cyclization involving the nitroso group. Since the reactive nitrogen groups in N-aryl-2-nitrosoanilines are of opposite character the reaction is regioselective and additionally it was found to be diastereoselective.

Full text of DOI:10.1055/s-0033-1339467

LETTER
▌1945
lAetteTr wo-Step Synthesis of Selected 1,2,3,4-Tetrahydroquinoxaline Derivatives
from N-Aryl-2-nitrosoanilines and Arylidenecyanoacetic Esters
Synthesis of 1,2,3,4-Tetrahydroquinoxaline Derivatives
Magdalena Królikiewicz,a Kacper Błaziak,b Witold Danikiewicz,b Zbigniew Wróbel*b
a
The Faculty of Chemistry, University of Warsaw, Pasteura 1, 02-093 Warsaw, Poland
b
Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44, 01-224 Warsaw 42, Poland
Fax +48(22)6326681; E-mail: zbigniew.wrobel@icho.edu.pl
Received: 10.06.2013; Accepted after revision: 21.06.2013
pleted by reduction of the hydroxyloamine formed
Abstract: Reaction of N-aryl-2-nitrosoanilines with alkyl aryl-
(Scheme 1).
idenecyanoacetates in the presence of Et3N in MeCN leads to sub-
stituted 1,2,3,4-tetrahydroquinoxaline derivatives in reasonable
yields. The reaction comprises nucleophilic addition of the nitro-
soaniline to the Michael acceptor followed by cyclization involving
the nitroso group. Since the reactive nitrogen groups in N-aryl-2-
nitrosoanilines are of opposite character the reaction is regioselec-
tive and additionally it was found to be diastereoselective.
H
EWG
N
EWG
NO
+
N
H
NH2
Key words: Michael addition, ring closure, condensation, hetero-
cycles, reduction
O
N
EWG
–
EWG
NO
+
The 1,2,3,4-tetrahydroquinoxaline scaffold is present in
numerous biologically active and pharmacologically im-
portant compounds.1 As an example compounds A, B, and
C have found applications as cholesteryl ester transfer
protein inhibitors,1b vasopressin V2 receptor antago-
nists,1c and prostaglandin D2 receptor antagonists,1d re-
spectively (Figure 1).
N
H
NH2
OH
N
H
N
EWG
EWG
N
H
N
H
OH
CF3
Scheme 1
O
N
N
H
Due to the opposite character of the nitrogen groups in the
starting nitrosoaniline this approach allows for regioselec-
tive annulation, which is particularly beneficial when oth-
er substituents are present in one or both reactants.
MeO
CF3
N
N
O
O
N
H
In 2007, reassuming the Wohl–Aue reaction of ni-
troarenes with arylamines under basic conditions2 we
found that N-aryl-2-nitrosoanilines, postulated as unstable
intermediates, could be easily obtained in pure state, pro-
vided the reactions were carried out at low temperature
using an excess of strong base.3 Proximity and reverse
philicity of the nitroso and the amino functions makes N-
aryl-2-nitrosoanilines interesting starting materials for the
synthesis of nitrogen heterocyclic compounds. We
showed their versatility for the synthesis of phenazines,3a,4
benzimidazoles,5 quinoxalin-2(1H)-ones,6 or its 4-ox-
ides.7 Reaction of 4-amino-substituted N-aryl-2-nitro-
soanilines with two molecules of esters of cyanoacetic
acid led to dioxopyrroloquinoxalines.8 Having a variety of
N-aryl-2-nitrosoanilines available, we tried out the above-
mentioned synthetic path. First attempts were disappoint-
ing. N-Aryl-2-nitrosoanilines, bearing donor as well as ac-
ceptor substituents in both aromatic rings, subjected to the
reaction with methyl acrylate, acrylonitrile, 2-nitrosty-
rene, or ethyl benzylidenebenzoylacetate in various base–
EtO
O
CO2H
B
A
Me
N
N
O
O
N
Me
C
Figure 1
Retrosynthetic analysis of the 1,2,3,4-tetrahydroquinoxa-
line skeleton suggests that it could be synthesized directly
from appropriate 2-nitrosoaniline with unsaturated elec-
trophile via Michael addition of the amino group to the
activated C=C bond followed by aza-aldol reaction, com-
SYNLETT 21709013, 2415, 1945–1948
Advanced online publication: 09.08.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1339467; Art ID: ST-2013-D0537-L
© Georg Thieme Verlag Stuttgart · New York

1946
M. Królikiewicz et al.
LETTER
solvent systems either did not react or the reactions led to The reaction conditions were not optimized. From the
intractable mixtures. However, when 5-chloro-N-(4- stoichiometry angle, even a catalytic amount of a base
methylphenyl)-2-nitrosoaniline was reacted with ethyl should be enough for completion. However, in the appro-
benzylidenecyanoacetate in the presence of five equiva- priate experiment the expected product was formed so
lents of Et3N in MeCN at room temperature TLC control slowly that the rate of its destruction competed with that
showed slow disappearance of the starting substrates with of its formation, thus, the reaction led to an intractable
simultaneous formation of a new spot. Unfortunately, mixture of products.
upon standard purification on silica gel, the product un-
The addition–cyclization reaction seems to be sensitive to
derwent partial destruction, therefore its isolation in pure
a number of factors. The first one is the electronic effect
state was somewhat tricky. The 1H NMR and mass spectra
of the substituents in both aromatic rings of N-aryl-2-ni-
trosoaniline. Whereas the 4-halogen-substituted sub-
strates reacted smoothly, the reaction of those bearing
electron-donating substituents like OMe or NHR (Table 1,
allowed for resolving of its structure, consistent with the
expected N-hydroxy derivative of 1,2,3,4-tetrahydroqui-
noxaline 3a. Because of instability of such derivatives9
further transformation of 3a was performed without puri-
entries 4 and 15) did not proceed at all and only starting
fication. After the cyclization was complete the reaction
materials were observed after prolonged time at room
mixture was immediately subjected to reduction with zinc
temperature. Increase of the temperature resulted in some
destruction processes without formation of any defined
product. Apparently, substituents of +M effect, located
para to the nitroso group, lower its electron-withdrawing
in acetic acid9 from which tetrahydroquinoxaline 4a was
easily isolated as a stable compound in 68% yield. The
above procedure was then applied for the reactions of nu-
merous N-aryl-2-nitrosoanilines 1 with alkyl arylidene-
character, hence acidity of the aniline proton.
cyanoacetates 2 to determine scope, limitations, and main
features of the reaction (Table 1).10,11
Table 1 Two-Step Reaction of N-Aryl-2-nitrosoanilines with Arylidenecyanoacetic Esters Leading to Substituted 1,2,3,4-Tetrahydroquinox-
alines
NC
N
CO2R2
Ar2
NC
N
CO2R2
Ar2
H
HO
NO
H
NC
CO2R2
Ar2
N
Et3N
MeCN
N
Zn
AcOH
N
Ar1
Ar1
Ar1
+
R1
R1
R1
1
2
3
4
Entry
R1
Ar1
R2
Ar2
Time (h)
4
Yield (%)
1
2
Cl
F
4-MeC6H4
Et
Ph
Ph
Ph
Ph
Ph
48
2
4a
4b
–
68
4-ClC6H4
2,6-Me2C6H4
4-MeC6H4
4-Py
Et
67
3
Cl
OMe
Cl
Cl
Cl
Cl
Cl
Br
Ph
Cl
Cl
Cl
Et
48
48
0.3
24
1
n.r.a
n.r.a
59
4
Et
–
5
Et
4c
4d
4e
4f
4g
4h
4i
6
4-MeC6H4
4-Py
Me
Me
Et
2-thienyl
2-thienyl
Ph
33
7
56
8
4-ClC6H4
4-ClC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-ClC6H4
3.5
4
77
9
t-Bu
Et
Ph
91
10
11
12
13
14
15
Ph
24
48
48
24
72
48
78
Et
Ph
68
Me
Et
4-ClC6H4
4-ClC6H4
4j
4k
4l
38
74
Et
3,4-(MeO)2C6H3
Ph
71
NHMe
Et
–
n.r.a
a n.r. = no reaction.
Synlett 2013, 24, 1945–1948
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of 1,2,3,4-Tetrahydroquinoxaline Derivatives
1947
H
H
O2N
CN
N
O
N
HN
MeO2C
NC
CO2Me
Et3N
NO
H
MeO2C
MeO2C
HO
N
Zn
AcOH
N
HN
HN
+
N
N
51%
40%
N
NO2
Cl
Cl
Cl
Cl
5
6
Scheme 2
Although less pronounced, the effect of substituents in ethoxycarbonyl group. Coupling constants were calculat-
Ar1 is also visible. More electron-withdrawing groups en- ed using Karplus-type equation for the dihedral angle
hance the reactivity of 1 making the reaction faster (Table formed by atoms 1, 2, 3, and 4 (Figure 2) in the models ob-
1, entry 1 vs. entries 8 and 9). Remarkable acceleration of tained by DFT calculations (for details see Supporting In-
the reaction was observed when the benzene ring was re- formation). These constants were equal to 2.2 Hz and 7.8
placed with strongly electronegative pyridine (Table 1, Hz for isomers 4a-1 and 4a-2, respectively. Taking into
entries 5 and 7).
account that the measured coupling constant was equal to
1.3 Hz, isomer 4a-1 shows much better fit.
On the other hand, two ortho-methyl groups in the 2,6-di-
methylaniline moiety of 1 make the nitrosoaniline unreac- The above supposition was then confirmed by the reaction
tive (Table 1, entry 3), which seems to be a result of steric of methyl (2-nitrobenzylidene)cyanoacetate with 5-chlo-
hindrances in the addition step rather then of the electron- ro-N-(4-methylphenyl)-2-nitrosoaniline under standard
donating effect of these substituents.
conditions. The crude product was treated with zinc in
AcOH to remove the N-hydroxyl group and to reduce the
nitro group to the amino group.
With regard to arylidenecyanoacetates 2, there are higher
yields observed in the reactions of ethyl and, especially,
tert-butyl esters then in those of methyl esters (Table 1, As a result of a subsequent cyclization of the latter with
entries 13 vs. 12 and 9 vs. 8). Thus, the use of higher esters the cis-cyanide substituent, polycyclic amidine 5 was
2 supposedly can improve the yields of the reactions of formed (Scheme 2). While it was a stable compound12 it
other substrates.
could be easily hydrolyzed to the corresponding lactam 6.
Products 4 were obtained as essentially single diastereo- In conclusion, a new way for the synthesis of nitrogen het-
mers. The relative configuration of the substituents on erocyclic systems from N-aryl-2-nitrosoanilines is pre-
carbon atoms of the tetrahydroquinoxaline ring (atoms 2 sented. The reaction makes use of the opposite character
and 3 in Figure 2) has been established on the basis of of the nitrogen functions in the nitrosoanilines for the re-
NMR measurements accompanied with theoretical calcu- gioselective and diastereoselective synthesis of 1,2,3,4-
lations.
tetrahydroquinoxaline derivatives. It is believed to pro-
ceed via initial nucleophilic addition of the deprotonated
N-aryl-2-nitrosoaniline to the Michael acceptor. Nucleo-
philic reactivity of N-aryl-2-nitrosoanilines has not been
observed earlier.
O
O
OEt
Ph
H1
OEt
H1
4 C
4 C
NC
NC
HN
3
3
HN
2
Ph
2
N
N
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
r
t
iornat
Cl
Cl
References and Notes
4a-1
4a-2
(1) (a) For a review of recent advances in the synthesis of
quinoxalines and medicinal compounds containing a
quinoxaline moiety, see: Mamedov, V. A.; Zhukova, N. A.
Prog. Heterocycl. Chem. 2012, 24, 55. (b) Eary, C. T.;
Jones, Z. S.; Groneberg, R. D.; Burgess, L. E.; Mareska, D.
A.; Drew, M. D.; Blake, J. F.; Laird, E. R.; Balachari, D.;
O’Sullivan, M.; Allen, A.; Marsh, V. Bioorg. Med. Chem.
Lett. 2007, 17, 2608. (c) Ohtake, Y.; Naito, A.; Hasegawa,
H.; Kawano, K.; Morizono, D.; Taniguchi, M.; Tanaka, Y.;
Matsukawa, H.; Naito, K.; Oguma, T.; Ezure, Y.; Tsuriya, Y.
Bioorg. Med. Chem. 1999, 7, 1247. (d) Torisu, K.;
Figure 2
All the results were consistent with the structure 4a-1 in
which the phenyl group is cis to the cyano group. Accord-
ing to DFT calculations this isomer is approximately 20
kJ/mol more stable than compound 4a-2. Providing that
the reaction is controlled thermodynamically this differ-
ence is large enough to shift the equilibrium completely
towards the more stable isomer. The second proof for the
structure 4a-1 was obtained from the comparison of the
Kobayashi, K.; Iwahashi, M.; Nakai, Y.; Onoda, T.;
Sugimoto, I.; Okada, Y.; Matsumoto, R.; Nanbu, F.;
Ohuchida, S.; Nakai, H.; Toda, M. Bioorg. Med. Chem.
3
measured and calculated JC–H coupling constants be-
tween hydrogen atom 1 and carbonyl carbon atom from
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 1945–1948

1948
M. Królikiewicz et al.
LETTER
2004, 12, 5361. (e) Sikorski, J. A. J. Med. Chem. 2006, 49,
1. (f) Jacobsen, E. J.; Stelzer, L. S.; Belonga, K. L.; Carter,
D. B.; Im, W. B.; Sethy, V. H.; Tang, A. H.;
VonVoigtlander, P. F.; Petke, J. D. J. Med. Chem. 1996, 39,
3820. (g) Barrows, T. H.; Farina, P. R.; Chrzanowski, R. L.;
Benkovic, P. A.; Benkovic, S. J. J. Am. Chem. Soc. 1976, 98,
3678.
10 mmol) was added. The mixture was stirred for 30 min at
r.t. and evaporated to dryness in vacuo. The residue was
treated with EtOAc (30 mL) and aq NaHCO3, filtered
through a Celite pad, and extracted with EtOAc (3 × 20 mL).
The extract was dried (Na2SO4), the solvent was evaporated,
and the product was isolated by column chromatography
(SiO2, hexane–EtOAc).
(2) (a) Wohl, A.; Aue, W. Ber. Dtsch. Chem. Ges. 1901, 34,
2442. (b) Wohl, A. Ber. Dtsch. Chem. Ges. 1903, 36, 4135.
(c) Serebryanyi, S. B. Ukrain. Khim. Zhur. 1955, 21, 350.
(3) (a) Wróbel, Z.; Kwast, A. Synlett 2007, 1525. (b) Wróbel,
Z.; Kwast, A. Synthesis 2010, 3865.
(4) Kwast, A.; Stachowska, K.; Trawczyński, A.; Wróbel, Z.
Tetrahedron Lett. 2011, 6484.
(5) Wróbel, Z.; Stachowska, K.; Grudzień, K.; Kwast, A. Synlett
2011, 1439.
(6) Wróbel, Z.; Stachowska, K.; Kwast, A.; Gościk, A.;
Królikiewicz, M.; Pawłowski, R.; Turska, I. Helv. Chim.
Acta 2013, 96, 956.
(7) Wróbel, Z.; Królikiewicz, M. J. Heterocycl. Chem. 2013, 50,
in press.
(11) Analytical Data for Representative Products
Compound 3a: grey crystals; mp 132–134 °C (Et2O–
hexane). 1H NMR (500 MHz, DMSO-d6): δ = 0.95 (t, J = 7.0
Hz, 3 H), 2.20 (s, 3 H), 4.00–4.06 (m, 2 H), 5.60 (s, 1 H),
6.10 (s, 1 H), 6.84 (dd, J = 8.5, 1.1 Hz, 1 H), 7.10 (s, 5 H),
7.45 (d, J = 8.5 Hz, 1 H), 7.22–7.28 (m, 3 H), 7.33–7.40 (m,
2 H), 10.52 (s, 1 H). 13C NMR (125 MHz, DMSO-d6):
δ = 13.4, 20.5, 63.0, 66.2, 70.9, 113.2, 114.2, 117.6, 118.5,
126.6, 128.1, 128.8, 129.1, 129.2, 130.2, 132.9, 133.9,
136.4, 137.4, 139.6, 162.8. Anal. Calcd for C25H22ClN3O3:
C, 67.04; H, 4.95; N, 9.38. Found: C, 67.08; H, 5.03; N, 9.28.
Compound 4a: white crystals; mp 185–187 °C (EtOH). 1H
NMR (500 MHz, DMSO-d6): δ = 1.01 (t, J = 7.0 Hz, 3 H),
2.24 (s, 3 H), 4.06–4.17 (m, 2 H), 5.25 (s, 1 H), 6.27 (d,
J = 2.3 Hz, 1 H), 6.74 (dd, J = 8.5, 2.3 Hz, 1 H), 6.81 (d,
J = 8.5 Hz, 1 H), 6.89–6.92 (m, 2 H), 7.11–7.15 (m, 2 H),
7.32 (s, 5 H), 7.76 (s, 1 H). 13C NMR (125 MHz, DMSO-d6):
δ = 14.1, 20.9, 60.2, 63.7, 64.8, 114.2, 116.2, 116.4, 119.5,
123.1, 126.3, 128.7, 128.9, 129.2, 130.6, 130.8, 133.6,
135.8, 136.9, 142.1, 165.4. MS (EI): m/z = 433 (36), 432
(29), 431 (100), 406 (13), 405 (10), 404 (35), 360 (28), 359
(23), 358 (81), 333 (21), 332 (18), 331 (58), 330 (13), 329
(30), 328 (12), 327 (54). Anal. Calcd for C25H22ClN3O2: C,
69.52; H, 5.13; N, 9.73. Found: C, 69.60; H, 5.19; N, 9.79.
(12) Comesse, S.; Sanselme, M.; Daich, A. J. Org. Chem. 2007,
73, 5566.
(8) Królikiewicz, M.; Cmoch, P.; Wróbel, Z. Synlett 2013, 24,
973.
(9) Instability of similar hydroxylamines was reported: López-
Cantarero, J.; Cid, M. B.; Poulsen, T. B.; Bella, M.; Ruano,
J. L. G.; Jørgensen, K. A. J. Org Chem. 2007, 72, 7062.
(10) General Procedure for the Synthesis of Compound 4
To a solution of N-aryl-2-nitrosoaniline 1 (1 mmol) and
arylidenecyanoacetic ester 2 (1.2 mmol) in dry MeCN (10
mL) was added Et3N (0.73 mL, 5 mmol). The mixture was
stirred until the reaction was complete (TLC control, times
shown in Table 1). The mixture was then evaporated to
dryness, treated with AcOH (10 mL), then Zn dust (650 mg,
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