A short preparation of pyrroloquinoxalinones via a cascade reaction of N -aryl-5-alkylamino-2-nitrosoanilines with methyl 2-cyanoalkanoates: Unexpected direction of nucleophilic substitution of hydrogen

Article abstract of DOI:10.1055/s-0032-1316903

N-Aryl-2-nitrosoanilines possessing 5-alkylamino groups undergo a bisheteroannulation reaction with anions of 2-cyanoalkanecarboxylates resulting in pyrroloquinoxalinone derivatives. The cascade reaction involves condensation of the cyanoester anions with

Full text of DOI:10.1055/s-0032-1316903

LETTER
▌973
lAetteSr hort Preparation of Pyrroloquinoxalinones via a Cascade Reaction of
N-Aryl-5-alkylamino-2-nitrosoanilines with Methyl 2-Cyanoalkanoates:
Unexpected Direction of Nucleophilic Substitution of Hydrogen
Synthesis of Pyrroloquinoxalinones
Magdalena Królikiewicz,a Piotr Cmoch,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, Poland
Fax +48(22)6326681; E-mail: zbigniew.wrobel@icho.edu.pl
Received: 18.01.2013; Accepted after revision: 17.03.2013
R2
Abstract: N-Aryl-2-nitrosoanilines
possessing
5-alkylamino
O
O
O
groups undergo a bisheteroannulation reaction with anions of 2-cy-
anoalkanecarboxylates resulting in pyrroloquinoxalinone deriva-
tives. The cascade reaction involves condensation of the cyanoester
anions with the nitroso group, unusual nucleophilic substitution of
hydrogen in the nitrosoaniline-derived intermediate with the second
carbanion molecule, and double intramolecular acylation of the
amino functions.
N
N
NHAr
+
N
CN
K2CO3
DMF
Ar
R2
CO2Me
R1
1
R1
3
2
Key words: carbanions, condensation, heterocycles, annulation,
nucleophilic aromatic substitution
Scheme 1
system, two products in ca. 2:3 ratio were formed (Table
1, entry 1). The more polar product was the expected qui-
noxalin-2(H)-one N-oxide 3a whereas the less polar, ac-
Cascade reactions have been the subject of intense re-
search during recent years since they make possible the
creation of complex molecules from simple and easily
available substrates in one-pot processes.1 Here we report
a multistep, three-component cascade reaction leading to
bisannulation of N-aryl-2-nitrosoanilines, providing a
new method for the synthesis of substituted fused oxin-
dole derivatives.
1
cording to H NMR and MS analyses, was a result of a
reaction of one molecule of 1 with two molecules of the
cyanoacetic ester. The first one formed a heterocyclic
ring, whereas the second was attached to the carbocyclic
ring.
Table 1 The Reactions of N-Aryl-2-nitrosoanilines with Methyl
2-Cyanobutanoates8
In 2007 we described a simple method for the preparation
of N-aryl-2-nitrosoanilines via nucleophilic substitution
of hydrogen in nitroarenes with anilines in the presence of
potassium tert-butoxide.2 Like prevailing SNHAr reactions
described earlier,3 this reaction proceeds faster than con-
ventional nucleophilic substitution of halogens. We have
also demonstrated that N-aryl-2-nitrosoanilines are versa-
tile educts in the synthesis of a variety of nitrogen hetero-
cyclic compounds such as phenazines,2a,4 benzimid-
azoles,5 and quinoxalin-2(H)-ones.6 Recently, we found
that in the reaction of N-aryl-2-nitroso-5-alkylanilines and
alkylated cyanoacetic esters 2 a number of quinoxalin-
2(H)-one N-oxides 3 can be obtained (Scheme 1).7
O
N
Ar
CN
MeO2C
R2
NH
N
R2
O
DBU
2
3
+
+
MeCN
R1
N
R1
Ar
1
4
Ar = 2,6-Me2C6H3
Entry R1
R2
Time
(h)
Yield of 3
Yield of 4
(%)a,b
(%)a,b
1
2
3
4
OMe
OMe
OMe
OBn
Et
5
3a 29 (65)
3b 33
4a 45 (0)
4b 37
n-Bu
i-Pr
Et
2
For R = F, Cl, Ph, OMe, and numerous aryl substituents
the reaction, carried out in DBU/MeCN or K2CO3/DMF
systems, proceeded smoothly and effectively and resulted
in the formation of the corresponding quinoxalinone ox-
ides 3 in moderate to excellent yields. However, when 5-
methoxy-2-nitroso-N-(4-methylphenyl)aniline (1: R1 =
OMe; Ar = 4-MeC6H4) was reacted with two equivalents
of methyl 2-cyanobutanoate 2 (R2 = Et) in DBU/MeCN
2.5
2.5
3c 22 (45)
3d 33
4c 52 (0)
4d 49
a Isolated yield.
b The yields reported earlier7 for the reaction carried out in
K2CO3/DMF are given in parentheses.
Initially, the assumed structure of this product was 5 (Fig-
ure 1), and the way of its formation seemed to be the oxi-
dative nucleophilic substitution of hydrogen (ONSH) in
3a with an anion of another molecule of cyanoacetic ester
SYNLETT 2013, 24, 0973–0976
Advanced online publication: 10.04.2013
DOI: 10.1055/s-0032-1316903; Art ID: ST-2013-D0062-L
© Georg Thieme Verlag Stuttgart · New York
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

974
M. Królikiewicz et al.
LETTER
at the expense of the oxygen of the nitrone function. Sim- and 5-aryl derivatives reacted with 2 leading exclusively
ilar intramolecular oxidative substitution reactions are to the quinoxalinones 3.
well known for quinoline N-oxide systems, although they
are limited to the substitution of hydrogen ortho to the N-
oxide function in the heterocyclic ring.9
O
–88.9 N
O
O
–58.0 N
NOE
N–224.2
H
N–216.0
H
H
Et
H
H
O
O
O
N
CN
N
H3C
H
H
CN
O
MeO2C
N
Et
N
O
CH3
CH3
NOE
MeO2C
3
4
Cl
NC
NH
OMe
Figure 2
O
5
6ox
The influence of the alkoxy group seems to be a result of
the conjugative electron-donating effect of this substitu-
ent.
Figure 1
In a separate experiment, however, it was found that 3a
did not react with 2 (R2 = Et) under the reaction conditions
thus, this possibility was unequivocally ruled out. More-
over, 1H NMR, 13C NMR, and 15N NMR spectra revealed
that the new product contained the cyanoacetic ester moi-
ety attached meta to the formerly present nitroso group
(Scheme 2).
A similar, and even more pronounced effect could be ex-
pected for nitrogen-based substituents such as alkylamino
groups, in addition capable of a subsequent in situ cycli-
zation with the adjacent ester function.11 This expectation
was fully confirmed by the reaction of 5-n-propylamino-
2-nitroso-N-(4-methylphenyl)aniline with two equiva-
lents of methyl 2-cyanobutanoate in the presence of an ex-
cess of DBU in acetonitrile which delivered
pyrroloquinoxalinone 6a in 67% yield (Scheme 2). The
exclusive formation of 6 definitely confirmed that the ad-
dition of the second molecule of the nucleophile took
place at the meta position to the position formerly occu-
pied by the nitroso group.
A structure of product of type 4 was confirmed by some
important NMR observations. A decrease in the 15N NMR
shielding of ca. 30 ppm regarding 3 confirms lack in the
oxygen atom at the sp2-hybridized nitrogen atom.10 Fur-
ther proof of the structure of 4 is the absence of the JH–H
coupling typical for aromatic systems. In case of 3 a 4JH–H
coupling is about 2.6 Hz, whereas in case of 4 JH–H is not
observed. It means that both aromatic protons (δ = 7.92
and 6.12 ppm) have to be in a para arrangement, where
5JH–H is usually less than 1 Hz. Additionally, using results
of NOESY 1D measurements both alkyl groups show
NOE with ring protons, and only one NOE is observed af-
ter irradiation of the methyl protons of the methoxy group
(Figure 2). If the substitution occurs ortho to the N-oxide
function irradiation of the protons corresponding to the
methyl of the methoxy group should lead to NOE en-
hancement at both aromatic protons. In this particular case
only one effect is observed and that is why the structure 5
with the cyanoacetate substituent in ortho position can be
excluded.
This multistep, one-pot cascade reaction provides a new
method for the synthesis of substituted fused oxindole de-
rivatives. Some further examples of the reaction collected
in Table 2 show the scope of the reaction that proceeded
with 2-nitrosoanilines possessing variously substituted
primary alkylamino group at C-5.12 The last step of the re-
action sequence seems to be sterically tolerant as besides
primary alkyl groups, also secondary and even tertiary
substituents can be attached to the nitrogen atom without
negative influence on the product yield. On the other
hand, for at the moment unknown reasons, an unsubstitut-
ed amino group gave worse results (Table 2, entry 7) and
the desired product 6g (20%) was accompanied by its 4-
N-oxide 6ox (19%).
The unexpected formation of 4 was observed only for 5-
alkoxy-substituted 2-nitrosoanilines 1, while 5-halogen
Also the lower yields of product and more complicated re-
action course observed in some other cases (Table 2, en-
tries 6, 8, and 9) could not be rationalized. The reactions
R2
O
O
N
N
CN
R2
N
R2
O
NHAr
N
CN
DBU
Ar
R2
O
+
MeO2C
R2
MeCN
N
N
CO2Me
R1
NHR1
CN
NHR1
2
Ar
6
1
4
Scheme 2
Synlett 2013, 24, 973–976
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Pyrroloquinoxalinones
975
of 2 with 5-amino-substituted N-aryl-2-nitrosoanilines are tiously formulated (Scheme 3). Addition of the carbanion
much slower than with any other 5-substituted substrates, to the nitroso group of 1 leads to intermediate 7, which
including 5-alkoxy-2-nitrosoanilines.7 In some cases it eliminates cyanide anion to form nitrone 8.13 Mesomeric
took several days to complete the reaction but, neverthe- structures of 8 show possible conjugation of both the aryl-
less, the whole cascade was selective and efficient. The amino group and the substituent Y, provided the latter is a
most obvious reason is the deactivating effect of the lone +M substituent such as OR or NHR. This effect should
pair of the amino group conjugated with the para-located strongly favor the quinoid structures with partial negative
nitroso function. The same phenomenon, however, is ap- charge on the peripheral carbon atom, promoting a proton
parently responsible for subsequent addition of the cyano- transfer from the adjacent nitrogen atom. This process
acetate anion as well as for the bisannulation.
creates the quinoid structure 9,14 a crucial intermediate
making the 4-position of the initial nitrosoaniline suscep-
tible to the nucleophilic attack. If the conjugation of the
nitrone with Y does not exist simple intramolecular cycli-
zation of 8 produces 3.15 Multiple intermolecular and/or
intramolecular proton transfer leads to the elimination of
water from intermediate σH-adduct 10 providing 11 which
in turn undergoes intramolecular cyclization to 4 then, if
Y is an alkylamine group, to 6.15
Table 2 The Cascade Synthesis of Pyrroloquinoxalinones 68,12
Entry R1
Ar
R2
Time (d) Yield of 6 (%)a
1
2
n-Pr
4-MeC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-EtOC6H4
2,6-Me2C6H3
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-FC6H4
Et
10
1
6a 67
t-Bu
t-Bu
n-Bu
n-Bu
n-Bu
H
Et
6b 72
3
i-Pr
Et
14
5
6c 73
In conclusion, a new multistep reaction involving inter-
mediate-activated addition of a carbanion meta to the po-
sition occupied formerly by the activating nitroso group is
presented. It provides a simple method for the synthesis of
some pyrroloquinoxaline systems from simple starting
materials. The scope and limitations as well as a mecha-
nism of the reaction are now under investigation.
4
6d 71
5
Et
5
6e 63
6
Et
8
6f 28
7
i-Pr
Me
Me
n-Bu
7
6g 20 (19)b
6h 52 (24)c
6i 32
8
t-Bu
Me
1
9
6
Supporting Information for this article is available online at
10
i-Pr
3
6j 68
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
r
t
iornat
a Isolated yield.
b The yield of 6ox is given in parentheses
References and Notes
c The yield of 3e (R1 = Nt-Bu; R2 = Me; Ar = 4-ClC6H4) is given in
(1) Nicolaou, K. C.; Edmonds, D. J.; Bulger, P. G. Angew.
Chem. Int. Ed. 2006, 45, 7134.
parentheses.
(2) (a) Wróbel, Z.; Kwast, A. Synlett 2007, 1525. (b) Wróbel,
Z.; Kwast, A. Synthesis 2010, 3865.
(3) (a) Mąkosza, M. Chem. Soc. Rev. 2010, 39, 2855.
(b) Mąkosza, M.; Wojciechowski, K. Chem. Rev. 2004, 104,
2631. (c) Mąkosza, M. Synthesis 2011, 2341.
On the basis of the tentative mechanism of the reaction of
alkylated cyanoacetates, proposed in our previous work,7
the following pathway for the formation of 4 can be cau-
3
R1
R1
R1
–
R1
CO2Me
CN
NHAr
–O
–O
+
N
–O
–O
–
+
N
+
N
N
CO2Me
NHAr
CO2Me
+NHAr
CO2Me
NHAr
DBU
+
1
2
– CN–
MeCN
+Y
Y
Y
Y
7
8
Y = OR, NHR
R1
BH
R1
R1
H
CO2Me
H
–O
–O
+
N
CO2Me
B–
CO2Me
N
N
N
N
NHAr
Ar
2–
– H2O
Y = NHR
Ar
H
4
6
NC
NC
MeO2C
MeO2C
R1
Y
10
R1
Y
11
Y
2–
9
Scheme 3 Proposed mechanism for the bisheteroannulation of N-aryl-2-nitrosoanilines with 2-cyanoalkanoates
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 973–976

976
M. Królikiewicz et al.
LETTER
(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, DOI: 10.1002/hlca.201200304.
(7) Królikiewicz, M.; Wróbel, Z. J. Heterocycl. Chem. 2013, in
press.
(17), 364 (19), 363 (27), 337 (21), 336 (20), 335 (43). HRMS
(EI): m/z calcd for C25H25N4O2Cl: 448.1666; found:
448.1687.
(9) Some illustrative examples: (a) Shuman, R. T.; Ornstein, P.
L.; Paschal, J. W.; Gesellchen, P. D. J. Org. Chem. 1990, 55,
738. (b) Yousif, M. M.; Saeki, S.; Hamana, M. Chem.
Pharm. Bull. 1982, 30, 2326. (c) Tagawa, Y.; Nomura, M.;
Yamashita, H.; Goto, Y.; Hamana, M. Heterocycles 1999,
51, 2385. (d) Yousif, M. M.; Saeki, S.; Hamana, M. J.
Heterocycl. Chem. 1980, 17, 305. (e) Douglass, J. E.;
Gebhart, M. A. J. Heterocycl. Chem. 1990, 27, 1433.
(10) Witanowski, M.; Stefaniak, L.; Webb, G. A. Nitrogen NMR
Spectroscopy, In Annual Reports on NMR Spectroscopy;
Webb, G. A., Ed.; Academic Press: London, 1982, 1–486
Part B, Vol. 11.
(11) (a) Fife, T. H.; Duddy, N. W. J. Am. Chem. Soc. 1983, 105,
74. (b) RajanBabu, T. V.; Chenard, B. L.; Petti, M. A. J.
Org. Chem. 1986, 51, 1704. (c) Karp, G. M.; Condon, M. E.
J. Heterocycl. Chem. 1994, 31, 1513. (d) Tichenor, M. S.;
Kastrinsky, D. B.; Boger, D. L. J. Am. Chem. Soc. 2004, 26,
8396.
(8) Analytical Data for Representative New Products
Compound 3e: yellow crystals; mp 246 °C (dec.; hexane–
EtOAc). 1H NMR (400 MHz, CDCl3): δ = 1.24 (s, 9 H), 2.54
(s, 3 H), 4.15 (s, 1 H), 5.77 (d, J = 2.1 Hz, 1 H), 6.59 (dd,
J = 9.2, 2.1 Hz, 1 H), 7.26-7.29 (m, 2 H), 7.58–7.61 (m, 2 H),
8.17 (d, J = 9.2 Hz, 1 H). 13C NMR (100 MHz, CDCl3): δ =
11.7, 29.4, 51.4, 97.7, 112.3, 121.5, 122.6, 130.1, 130.5,
134.6, 134.8, 135.4, 135.9, 149.5, 157.2. ESI-MS: m/z = 380
[M + Na]+, 358 [M + H]+. ESI-HRMS: m/z calcd for
C19H21N3O235Cl [M + H]+: 358.1322; found: 358.1234.
Compound 4a: white crystals; mp 179–180 °C (hexane–
EtOAc). IR (KBr): 2236 (CN), 1755, 1672, 1621 cm–1. 1H
NMR (400 MHz, CDCl3): δ = 1.17 (t, J = 7.4 Hz, 3 H), 1.35
(t, J = 7.4 Hz, 3 H), 2.38–2.45 (m, 2 H), 2.46 (s, 3 H), 2.96
(q, J = 7.4 Hz, 2 H), 3.64 (s, 3 H), 3.78 (s, 3 H), 6.11 (s, 1 H),
(12) General Procedure for the Synthesis of Pyrrolo-
quinoxalinones 6a–j
5-Amino-N-aryl-2-nitrosoaniline (0.5 mmol) and methyl 2-
cyanoalkanoate (1.1 mmol) were dissolved in dry MeCN (5
mL). DBU (0.4 mL, 2.68 mmol) was added in one portion,
and the mixture was stirred at r.t. for the time specified in
Table 2. The mixture was poured into sat. NH4Cl (10 mL)
and H2O (10 mL), extracted with EtOAc (3 × 20 mL), dried
with Na2SO4, and the crude product was chromatographed.
(13) (a) Aurich, G. Chem. Ber. 1965, 98, 3917. (b) Mąkosza, M.;
Jagusztyn-Grochowska, M.; Ludwikow, M.; Jawdosiuk, M.
Tetrahedron 1974, 30, 3723. (c) Jawdosiuk, M.; Ostrowska,
B.; Mąkosza, M. J. Chem. Soc. D 1971, 548.
(14) (a) Conant, J. B.; Fieser, L. F. J. Am. Chem. Soc. 1924, 46,
1858. (b) Pethig, B. R.; Gascoyne, P. R. C.; Mclaughlin, J.
A.; Szent-Gyorgyi, A. Proc. Natl. Acad. Sci. U.S.A. 1983,
80, 129.
(15) Ritzmann, G.; Ienaga, K.; Kiriasis, L. Chem. Ber. 1980, 113,
1535.
7.14–7.18 (m, 1 H), 7.38–7.43 (m, 1 H), 7.92 (s, 1 H). 13
C
NMR (100 MHz, CDCl3): δ = 9.7, 10.8, 21.3, 27.1, 28.5,
50.0, 54.5, 56.0, 97.7, 118.1, 120.6, 126.9, 127.7, 127.8,
128.6, 130.9, 131.0, 132.9, 135.8, 139.7, 154.8, 156.9,
160.4, 168.7. MS (EI): m/z 420 (16), 419 (57), 390 (10), 361
(27), 360 (100), 333 (12). HRMS (EI): m/z calcd for
C24H25N3O4: 419.1845; found: 419.1841.
Compound 6b: yellow crystals; mp 148–151 °C (hexane–
EtOAc). IR (KBr): 2241 (CN), 1731, 1670, 1627 cm–1. 1H
NMR (400 MHz, CDCl3): δ = 0.95 (t, J = 7.4 Hz, 3 H), 1.36
(t, J = 7.4 Hz, 3 H), 1.51 (s, 9 H), 2.18–2.30 (m, 2 H), 2.93–
3.02 (m, 2 H), 6.51 (s, 1 H), 7.25–7.29 (m, 2 H), 7.61–7.65
(m, 2 H), 7.85 (s, 1 H). 13C NMR (100 MHz, CDCl3): δ = 8.0,
10.5, 27.0, 28.7, 31.6, 47.2, 59.3, 99.9, 117.0, 121.6, 124.9,
128.3, 129.5, 129.6, 130.6, 130.7, 134.2, 135.0, 135.8,
144.1, 154.4, 160.9, 170.9. MS (EI): m/z (%) = 450 (16), 449
(17), 448 (34), 395 (15), 394 (47), 393 (40), 392 (100), 365
Synlett 2013, 24, 973–976
© Georg Thieme Verlag Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not be copied or
emailed to multiple sites or posted to a listserv without the copyright holder's express written permission.
However, users may print, download, or email articles for individual use.