Metal-free ring expansion of indoles with nitroalkenes: A simple, modular approach to 3-substituted 2-quinolones

Article abstract of DOI:10.1039/c4ra14406f

3-Substituted 2-quinolones are obtained via a novel metal-free transannulation reaction of 2-nitroolefins with 2-substituted indoles in polyphosphoric acid. This acid-mediated cascade transformation operates via the ANRORC (Addition of Nucleophile, Ring Opening, and Ring Closure) mechanism and can be used in combination with the Fisher indole synthesis to offer a practical three-component hetero-annulation approach to 2-quinolones from arylhydrazines, 2-nitroalkenes, and acetophenone. An alternative entry to this chemistry employing the alkylation of electron-rich arenes and hetarenes with 1-(2-indolyl)-2-nitroalkene has also been demonstrated.

Full text of DOI:10.1039/c4ra14406f

View Article Online
View Journal
RSC Advances
This article can be cited before page numbers have been issued, to do this please use: A. V. Aksenov, A.
N. Smirnov, N. A. Aksenov, I. V. Aksenova, J. P. Matheny and M. Rubin, RSC Adv., 2014, DOI:
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. This Accepted Manuscript will be replaced by the edited,
formatted and paginated article as soon as this is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the Ethical guidelines still
apply. In no event shall the Royal Society of Chemistry be held
responsible for any errors or omissions in this Accepted Manuscript
or any consequences arising from the use of any information it
contains.
www.rsc.org/advances

Page 1 of 11
RSC Advances
View Article Online
DOI: 10.1039/C4RA14406F
RSC Advances
RSCPublishing
ARTICLE
Metal-Free Ring Expansion of Indoles with
Nitroalkenes: a Simple, Modular Approach to 3-
Substituted 2-Quinolones
Cite this: DOI: 10.1039/x0xx00000x
Alexander V. Aksenov,*a Alexander N. Smirnov,a Nicolai A. Aksenov,a
Inna V. Aksenova,a Jonathon P. Matheny,b and Michael Rubin*a,b
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
Abstract. 3ꢀSubstituted 2ꢀquinolones are obtained via a novel metalꢀfree transannulation
reaction of 2ꢀnitroolefins with 2ꢀsubstituted indoles in polyphosphoric acid. This acidꢀ
mediated cascade transformation operates via the ANRORC (Addition of Nucleophile, Ring
Opening, and Ring Closure) mechanism and can be used in a combination with the Fisher
indole synthesis to offer a practical threeꢀcomponent heteroꢀannulation approach to 2ꢀ
quinolones from arylhydrazines, 2ꢀ nitroalkenes, and acetophenone. An alternative entry to
this chemistry employing the alkylation of electronꢀrich arenes and hetarenes with 1ꢀ(2ꢀ
indolyl)ꢀ2ꢀnitroalkene has also been demonstrated.
www.rsc.org/
cyclization with a 1,2ꢀaryl shift, to produce 4ꢀunsubstituted
products.13 Recently, we communicated a new approach to a
range of 3ꢀarylꢀ and 3ꢀalkylsubstituted 2ꢀquinolones via a
Introduction
3ꢀSubstituted 2ꢀquinolones are attractive targets for medicinal
chemistry1ꢀ3 and important tools for material science.4ꢀ6
Figure
) shows a brief analysis of general approaches to 2ꢀquinolones
(
R3
1
R2
O
that include VilsmeierꢀHaack (a),3d,7 Knorr (b),8 and
Friedlander reactions (c).9 Along with transition metalꢀ
catalyzed versions of the above methods,10 and the recently
emerged carbonylative crossꢀcoupling reactions (d, f)11 and
RCM (e),12 the cumulative prior art provides access to a wide
variety of C3ꢀ and/or C4ꢀsubstituted 2ꢀquinolones. The two
classical methods, VilsmeierꢀHaack and Knorr, offer the
advantage of employing readily available monoꢀsubstituted
aromatic starting materials, whereas other described methods
rely on availability of the more advanced orthoꢀdisubstituted
aromatic synthons.
O
R2
O
R3
N
+
R
N
O
R1
R
NMe2
R1
(b)
Vilsmeier-
Haack
O
N
(a)
Knorr
R3
R1
R3
R
(c)
Friedlander
R2
R2
O
In contrast, approaches to 4ꢀunsubstituted analogs are much
less developed. Thus, general routes (aꢀc) provide poor results
in reactions involving aldehydes or formamide derivatives (R3
= H). Du and Zhao disclosed an elegant metalꢀfree approach to
3ꢀarylꢀ2ꢀquinolones (g) involving an iodine(III)ꢀmediated
N
O
R
R3
X
R1
(d)
Larock
+
NCO2Et
R1
R
R2
(g)
Du-Zhao
+ CO
(e)
RCM
R3
(f)
R2
R3
Willi
s
R1
N
R
R3
N
O
R
O
R1
R2
R2
+ R1NH2
+ CO
X
X
R
Figure 1
This journal is © The Royal Society of Chemistry 2013
RCS Adv., 2014, 00, 1-3 | 1

RSC Advances
Page 2 of 11
View Article Online
ARTICLE
Journal Name
DOI: 10.1039/C4RA14406F
metalꢀfree condensation reaction of readily available 2ꢀ The reaction appeared to be very sensitive to sterics at the
substituted indoles with βꢀnitroalkenes proceeding via an orthoꢀposition of the nitrostyrenes: both 2ꢀmethylꢀ (1a) and 2ꢀ
ANRORC (Addition of Nucleophile, Ring Opening, and Ring phenylindoles (1b) afforded low yield (entries 14ꢀ17) or no
Closure) pathway in polyphosphoric acid (PPA).14 We have product at all (entries 18, 19) with nitroalkenes bearing an
also probed a oneꢀpot preparation of 2ꢀquinolones from orthoꢀsubstituent (2l-o). Aliphatic nitroolefin 2p reacted
arylhydrazines by merging this new methodology with Fisher
indole synthesis. Herein we disclose a full account on this
unusual transformation.
Table 1. Reactions of 2ꢀsubstituted indoles with 2ꢀnitroalkenes in
PPA
R3
80% PPA
R1
+
Results and Discussion
NO2
N
R2
1
2
Reaction of indoles with nitroalkenes
R3
O
Our studies of the reactivity of nitro compounds with arenes in
polyphosphoric acid15 have brought us to the serendipitous
discovery of an unusual transannulation reaction of hydroxamic
+
R1 NH2
N
R2
O
6
7
acid
nitroolefins
assisted ringꢀopening of indole leading to 2(1
dihydroquinolinone
(
(
3
, formed upon electrophilic alkylation of indoles
1
with
2 (
Scheme 1).14 Instead of the anticipated acidꢀ
1
R1
R2
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
2
R3
6
Yield, %a
H
)ꢀ3,4ꢀ
1
2
3
4
5
6
7
8
9
1a Me
1b Ph
1a Me
1b Ph
1a Me
1a Me
1a Me
1a Me
1a Me
2a Ph
2a Ph
6aa
6aa
90
92
5
, the test reaction between 2ꢀphenylindole
1b) and βꢀnitrostyrene (2a) produced 3ꢀphenylꢀ2ꢀquinolone
6aa) lacking an acyl substituent at Cꢀ4. Evidently, after a
6 ring expansion, the reaction took an unexpected
2b 4ꢀMeOC6H4
2b 4ꢀMeOC6H4
2c 4ꢀiꢀPrC6H4
2d 3,4ꢀMe2C6H3
6ab 70
6ab 74
facile 5
ꢀ
turn: the R1 substituent of the indole together with the adjacent
carbon atom (Cꢀ2) was sacrificed to produce benzamide 7b as a
byproduct, together with quinolone 6aa isolated in high yield
6ac
89
(
Table 1, entry 2).
6ad 88
O
R3
2e 3,4ꢀ(MeO)2C6H3 6ae
78
79
68
NHOH
R1
2f 4ꢀEtOC6H4
2g 2ꢀFC6H4
6af
R3
R1
NO2
6ag
+
N
R2
N
R2
2
10 1a Me
11 1a Me
12 1a Me
13 1a Me
14 1a Me
15 1b Ph
16 1a Me
17 1b Ph
18 1a Me
19 1a Me
20 1a Me
21 1b Ph
22 1a Me
2h 3ꢀFC6H4
6ah 66
1
3
2i 4ꢀFC6H4
6ai
6aj
72
88
80% PPA
2j 3,4ꢀCl2C6H3
2k 3ꢀBrC6H4
2l 2ꢀC5H4N
2l 2ꢀC5H4N
2m 2ꢀNO2C6H4
2m 2ꢀNO2C6H4
2n 2ꢀBrC6H4
6ak 67
R3
O
6al
6al
49
46
NHOH
R1
N
O
R3
R2
6
O
R1
6am 36
6am 35
6an NR
O
+
R3
NR2
H
O
N
O
4
R1
NH2
2o 2,3ꢀ(MeO)2C6H3 6ao
NR
6ap 63
6ap 62
6aq 29
R2
7
5
2p nꢀPr
2p nꢀPr
Scheme 1
2q
2q
2q
H
H
H
23 1c
Me Me
Me
6cq
6cq
6ca
6ci
27
Subsequent optimization of the reaction conditions revealed
that best results are produced upon heating a mixture of the 2ꢀ
24 1d Ph
11
84b
74 (92)b
24 (89)b
3 (94)b
25 1c
26 1c
27 1e
Me Me
Me Me
2a Ph
substituted indole (
1) and the nitroalkene (2) in 80% PPA (a
composition corresponding to diphosphoric acid, H4P2O7) at
2i 4ꢀFC6H4
o
o
80ꢀ85 C for 30 min and then at 95ꢀ100 C for additional 2.5ꢀ3
hr. isoꢀSkatole (1a) has been identified as a more practical
model substrate because it provides comparable yields of 2ꢀ
quinolones (Table 1, compare entries 1ꢀ2, 3ꢀ4, 14ꢀ15, 16ꢀ17,
18ꢀ19, 20ꢀ21), but gives acetamide 7a as a byproduct, which is
easily removable by routine aqueous workup. Systematic
screening of various nitroolefins (Table 1) showed that
electronꢀdonating (entries 3ꢀ8) or weak electronꢀwithdrawing
groups (entries 9ꢀ13) on nitrostyrenes improve product yield.
Me nꢀBu 2a Ph
6ea
6ca
28 1d Ph
a) Isolated yields of purified 2ꢀquinolones.
Hydroxamic acids were obtained as sole products under standard
conditions. Their isolated yields are provided in parentheses.
Indicated yields of 2ꢀquinolones were obtained under forcing
reaction conditions at 130 oC.
Me 2a Ph
b)
2 | RCS Adv., 2014, 00, 1-3
This journal is © The Royal Society of Chemistry 2012

Page 3 of 11
Journal Name
RSC Advances
View Article Online
DOI: 10.1039/C4RAA14R4T0I6CFLE
uneventfully with both model indoles (entries 20, 21). Ar). Condensation of aliphatic aldehydes (R3 = Alk), unless
Employment of nitroethene (2q) gave poor yields of products carried out under much harsher conditions, often stops at the
6aq and 6cq lacking substituents at Cꢀ3 (entries 22ꢀ24). This stage of alcohol 10 (Scheme 3). Having faced this problem, we
can be attributed to the reduced stability of 2q at reasoned that nitroalcohol 10 could potentially be employed in
elevatedtemperatures. Very different results were obtained in
reactions of nitrostyrenes 2a
which upon exposure to standard reaction conditions
exclusively produced the corresponding hydroxamic acids
,i with Nꢀsubstituted indoles 1cꢀe,
Table 2. Threeꢀcomponent oneꢀpot synthesis of 2ꢀquinolones
R4
R4
3
O
80% PPA
100-110 oC
40 min
+
Ph
(entries 26ꢀ28; yields are shown in parentheses). Attempts to
force transannulation by increasing the reaction temperature to
Me
Ph
N
NHNH2
H
o
130 C resulted in good yields of products 6ca and 6ci starting
11
12
1
from 1,2ꢀdimethylindole (1c) (entries 25, 26). However, high
temperature reactions of indoles 1d and 1e, bearing a bulky
substituent at nitrogen atom or at C2, resulted in substantial
decomposition and poor yields of quinolones 6ca and 6ea
(entries 27, 28).
R4
R3
O
R3
NO2
2
N
H
6
80% PPA, heat
11
R4
H
H
H
H
H
H
H
H
H
H
H
H
H
2
R3
6
Yield, %a,b
Three-component coupling involving Fisher indole synthesis
1
11a
11a
11a
11a
11a
11a
11a
11a
11a
2a
H
6aa
6ab
6ac
6ad
6ae
6af
87
68
85
86
71
71
62
58
66
82
60
42
29
82
79
84
We envisioned a practical extension of this methodology in
directly accessing the quinolines from easily available
hydrazines by merging the Fisher indole synthesis16 with the
aboveꢀdescribed methodology in a oneꢀpot transformation.17
The Fisher indole synthesis is known to proceed efficiently at
elevated temperatures in orthophosphoric acid, so we
anticipated 80% PPA (diphosphoric acid) to serve as a suitable
medium for this reaction. Indeed, in our test experiment, a
2
3
4
5
6
7
8
9
2b 4ꢀMeOC6H4
2c 4ꢀiꢀPrC6H4
2d 3,4ꢀMe2C6H3
2e
2f
3,4ꢀ(MeO)2C6H3
4ꢀEtOC6H4
2g 2ꢀFC6H4
2h 3ꢀFC6H4
6ag
6ah
6ai
mixture of phenylhydrazine (11a) and acetophenone (12
)
heated in PPA at 100ꢀ110 oC quickly and cleanly produced
desired indole 1b. In this case acetophenone was chosen for its
high boiling point to alleviate material loss due to evaporation.
Upon completion of the first step, nitroalkene 2a was added and
subsequent heating of the reaction mixture afforded product 6aa
2i
2j
4ꢀFC6H4
10 11a
11 11a
12 11a
13 11a
3,4ꢀCl2C6H3
6aj
2k 3ꢀBrC6H4
2l 2ꢀC5H4N
6ak
6al
in high yield (Scheme 2
Table 2, entries 2ꢀ13) as well as paraꢀsubstituted hydrazines
11e Table 2, entries 14ꢀ16) subjected to the oneꢀpot
, Table 2, entry 1). Other nitroalkanes
(
ꢀ
g (
2m 2ꢀNO2C6H4
2a Ph
6am
6ha
6fa
transformation demonstrated efficiencies comparable to those
obtained with preꢀisolated indoles (Table 1).
14 11e Me
15 11f MeO 2a Ph
O
16 11g Cl 2a Ph
6ga
80% PPA
+
Ph
a) Isolated yields of purified products.
o
100-110 C
NHNH2
Me
Ph
N
40 min
H
11a
1b
12
H
R3
-H2O
PPA
base
R3
+
NO2
MeNO2
Ph
O
OH
80% PPA
8
9
10
Ph
1b
+
NO2
heat
87%
N
O
H
2a
Me
6aa
N
R2
R3
1
R3
NO2
N
O
80% PPA, heat
Scheme 2
R2
2
6
Reaction of indoles with 2-nitroethanols
1a: R2 = H; 1c: R2 = Me
2a, 8a, 10a: R3 = Ph
2c, 8c, 10c: R3 = 4-i-PrC6H4
2d, 8d, 10d: R3 = 3,4-Me2C6H3
2q, 8q, 10q: R3 = H
6aa: R2 = H, R3 = Ph; 81%
6ac: R2 = H, R3 = 4-i-PrC6H4; 88%
6ad: R2 = H, R3 = 3,4-Me2C6H3; 91%
6aq: R2 = H, R3 = H; 37%
The following modification of the standard protocol described
above addresses some limitations of the Henry reaction,18
which was employed in this study to prepare starting
nitroalkenes. The Henry reaction involves a baseꢀassisted
6cq: R2 = Me, R3 = H; 47%
condensation of nitrometh ane
9 with corresponding aldehydes
8
, and requires elimination of water in the last step, which
Scheme 3
proceeds smoothly for derivatives of aromatic aldehydes (R3 =
This journal is © The Royal Society of Chemistry 2012
RCS Adv., 2014, 00, 1-3 | 3

RSC Advances
Page 4 of 11
View Article Online
ARTICLE
Journal Name
DOI: 10.1039/C4RA14406F
the described transformation as a surrogate of nitroolefin
Indeed, at elevated temperatures, PPA should force elimination
of water producing in situ the required nitroalkene , which
would subsequently react with indoles Scheme ). formation of
Implementation of this idea afforded the corresponding 2ꢀ its subsequent acidꢀassisted solvolysis into the final product has
quinolones in yields matching or exceeding those obtained
2
.
hydrolytic cleavage gives rise to the amide byproduct
Scheme 5).
One of the possible alternative endꢀgames involving
ꢀacylaminoquinoline 26 as an intermediate and
7
(
2
1
(
3
N
6
via the original protocol (Scheme 3). This modification is
particularly useful for the preparation of quinolones
unsubstituted or alkylꢀsubstituted at Cꢀ3, for which the required
2ꢀnitroethanols are much more readily available than the
corresponding 2ꢀnitroalkenes.
Mechanistic rationale
While detailed mechanistic study is underway in our
laboratories, the ANRORC mechanism described below
(
Scheme 5) represents, in our opinion, the most plausible
scenario out of several mechanistic hypotheses that could
potentially account for the acquired body of empirical results,
and is backed by literature precedence for the related
elementary mechanistic steps.
The reaction commences with the initial electrophilic attack
by the nitroalkene at Cꢀ3 of indole to produce alkylideneazinic
acid 13
. In the presence of PPA this aciꢀspecies undergoes
rearrangement to hydroxamic acid anhydride 16, which upon
hydrolysis provides hydroxamic acid 3 19 Indeed, acids 3aa (R1
.
= Me, R3 = Ph, R2 = H) and 3ab (R1 = R3 = Ph, R2 = H) were
isolated as sole products after aqueous treatment of the
mixtures when the reactions were carried out below 80 oC.
When reꢀsubjected to the standard reaction conditions, both 3aa
and 3ab provided 2ꢀquinolone 6aa in high yield (Scheme 4).
Scheme 4
Subsequent steps involve intramolecular nucleophilic attack
by the oxime moiety at the iminium functionality in 16 to
afford tricyclic imine 17 (nucleophilic addition step of an
ANRORC sequence), which in the presence of acid
tautomerizes into enamine 18
. The latter undergoes a retroꢀ
DielsꢀAlder reaction to produce anilide 19 (Ringꢀopening step
of an ANRORC sequence). Next, migration of the acyl group
from aniline to the more nucleophilic imine nitrogen followed
by the nucleophilic attack by the aniline at the acyliminium
moiety in 20 (ring closure step of an ANRORC sequence)20
affords aminoquinoline species 21, which may cyclize into
Scheme 5
spiroꢀdioxaphosphazine 22. Finally, 2ꢀquinolone
6 is produced
after the extrusion of imide anhydride 23, which upon
4 | RCS Adv., 2014, 00, 1-3
This journal is © The Royal Society of Chemistry 2012

Page 5 of 11
Journal Name
RSC Advances
View Article Online
DOI: 10.1039/C4RAA14R4T0I6CFLE
been ruled out. Indeed, if this mechanism were operating, of two diastereomeric products resulted from alkylation of both
compound 20 possessing R1 = H would quickly undergo aromꢀ benzene rings.
atization into the thermodynamically more stable acylaminoꢀ
quinoline 26 (Scheme 6). We demonstrated, however, that
these compounds prepared by alternative methods do not show
the expected reactivity under the featured reaction conditions.
Conclusion
We have developed a new, convenient and general approach to
3ꢀsubstituted 2ꢀquinolones via a metalꢀfree cascade transformꢀ
ation starting from 2ꢀsubstituted indoles and 2ꢀnitroalkenes in
3-Aryl-2-quinolones via arylation of nitroolefins
We have also envisioned an alternative route to 3ꢀarylꢀ
substituted 2ꢀquinolones
6 via the electrophilic alkylation of
arenes 28 with easily available21 3ꢀindolyl nitroalkene 27. This
mode would proceed via the key intermediate 13 (Scheme 5)
and allow for easy diversification of an aromatic substituent R3
at the very last step of the synthesis. It would be particularly
advantageous for the rapid assembly of 3ꢀarylquinolone
Scheme 6
libraries22 as well as for efficient coupling of 2ꢀquinolones with
structurally advanced electronꢀrich aromatic fragments. To test
this approach, nitroolefin 27 was treated with PPA in the
presence of anisole under standard reaction conditions. We
were pleased to find that this transformation proceeded
Scheme 7
smoothly to give the expected product 6ab
Alkylation of other electronꢀrich arenes ( ꢀxylene, veratrol,
[1,3]ꢀbenzodioxole, phenetole, and tertꢀbutylbenzene) afforded
3ꢀarylsubstituted 2ꢀquinolones 6ad 6ae 6ar 6af, and 6as
respectively, in good yields (Scheme 7). Application of this
methodology for a singleꢀstep installation of a useful quinolone
chromophore into a complex aromatic structure was also
probed. Exposure of indole 27 and dibenzoꢀ18ꢀcrownꢀ6 ether to
PPA under standard reaction conditions provided desired
product 6at in 34% yield (Scheme 7), along with small amounts
(Scheme 7).
polyphosphoric acid. The unique features of PPA that serves as
a mild proton donor, a source for a good leaving group, a water
scavenger, and a highꢀboiling solvent, make it an ideal medium
for the described transformation. This uncatalyzed CꢀC bond
forming reaction operates via an unusual ANRORC transꢀ
annulation mechanism involving the extrusion of one carbon
atom of an indole and incorporation of two new carbon atoms
from a nitroolefin. This reaction was successfully combined
with the Fisher indole synthesis, which led to the
o
,
,
,
This journal is © The Royal Society of Chemistry 2012
RCS Adv., 2014, 00, 1-3 | 5

RSC Advances
Page 6 of 11
View Article Online
ARTICLE
Journal Name
DOI: 10.1039/C4RA14406F
developmentof an efficient, sequential, threeꢀcomponent A mixture of 3ꢀnitrovinylindole 27 (1 mmol), selected arene
heteroannulation methodology for the construction of the 3ꢀ (1.2 mmol) and PPA (2ꢀ3 g) was heated at 80ꢀ85 oC for 30 min.
arylꢀ2ꢀquinolone scaffold. This oneꢀpot method offers a The consumption of starting materials was monitored by TLC.
practical synthetic advantage over many known methods, After indole reacted completely, the temperature was increased
which rely on 1,2ꢀdisubstituted aromatic precursors. Indeed, to 95ꢀ100 °C and the reaction mixture was heated for 1 h, then
the featured methodology allows for the direct conversion of cooled to room temperature, poured into water (50 mL) and
arylhydrazines into substituted 2ꢀquinolones, which makes it neutralized with aqueous ammonia. The organic portion was
very attractive for diversity oriented synthesis. An alternative extracted twice with chloroform and filtered through silica gel.
entry to this transformation was explored, involving alkylation Concentration of the filtrate in vacuum followed recrystallꢀ
of electronꢀrich arenes with 2ꢀindolyl nitroalkenes. This direct, ization of the residue afforded the corresponding 2ꢀquinolones.
nonꢀcatalytic CꢀH functionalization offers the possibility for an
easy variability of the aromatic group at C3 of 2ꢀquinolone.
3-Phenylquinolin-2(1
°C (CH2Cl2/EtOH). H NMR (CDCl3) δ, ppm: 10.79 (bs, 1H),
H
)-one (6aa)
:
26 White solid, mp 234ꢀ235
1
7.92 (s, 1H), 7.79 (m, 2H), 7.61 (dd,
J = 6.6, 1.2 Hz, 1H), 7.52ꢀ
Experimental Section
7.47 (m, 3H), 7.43ꢀ7.39 (m, 1H), 7.30ꢀ7.22 (m, 2H); 13C NMR
(DMSOꢀd6) δ, ppm: 161.7, 139.1, 138.3, 137.0,132.2, 130.8,
129.4, 128.8, 128.6, 128.5, 122.5, 120.2, 115.4; The NMR
spectral data are consistent with published results.10a IR (KBr):
3456, 1647 cmꢀ1; HRMS calc`d for C15H11NONa (M+Na)+
244.0738, found 244.0736.
All reagents, solvents and catalysts were purchased from
commercial sources and used without purification. All reactions
were performed in ovenꢀdried flasks open to the atmosphere
and monitored by thin layer chromatography. Flash column
chromatography was performed on silica gel (32ꢀ63 ꢁm, 60 Å
pore size). Nitroalkenes 2a
from commercial sources, compounds 2c
were synthesized employing published procedures. Commercial
2ꢀnitroethanole 10q was used. 1ꢀArylꢀ2ꢀnitroethanoles
10a
were synthesized using standard literature procedure.25
,
b
,
e
,
g
,
h
,
j
,
k
,
m
,
,
d
n
,
,
f
o
were obtained
l23 and 2p q24
,
3-(4-Methoxyphenyl)quinolin-2(1
mp 259ꢀ261°C (CH2Cl2/EtOH). 1H NMR (CDCl3) δ, ppm:
11.57 (bs, 1 H), 7.86 (s, 1H), 7.76 (d, = 8.6 Hz, 2H), 7.60 (d,
= 7.8 Hz, 1H), 7.27 (m, 1H), 7.22 (t,
= 8.3 Hz, 2H), 3.88 (s, 3H); 13C
H)-one (6ab): White solid,
,
i
,
J
(
)
J
J
= 7.8 Hz, 1H), 7.47 (t,
= 7.6 Hz, 1H), 7.01 (d,
J
,c,d
J
NMR (DMSOꢀd6) δ, ppm: 161.2, 159.0, 138.1, 136.3, 131.0,
129.9, 129.8, 128.5, 127.8, 121.8, 119.7, 114.6, 113.3, 55.1;
The NMR spectral data are consistent with published results.10a
IR: 3480, 1661 cmꢀ1; HRMS calc`d for C16H13NO2Na (M+Na)+
274.0844, found 274.0838.
Reactions of 2-substituted indoles with 2-nitroalkenes in PPA
Method A: General Procedure for the Synthesis 6a-r
A mixture of indole
1 (1 mmol), nitrostyrol 2 (1.2 mmol) and
80% PPA (2ꢀ3 g) was heated at 80ꢀ85 oC for 30 min.
Consumption of starting indole was monitored by TLC. After
indole reacted completely the temperature was increased to 95ꢀ
100 °C and the reaction mixture was heated for 1 h, then cooled
to room temperature, poured into water (50 mL), and
neutralized with aqueous ammonia. Aqueous phase was
extracted with chloroform (2 x 15 mL) and filtered through a
short pad of silica gel. The solvent was removed by
evaporation, and the residual crude material was purified by
recrystallization.
3-(4-i-Propylphenyl)quinolin-2(1
H)-one (6ac): White solid,
mp 220ꢀ221 °C (CH2Cl2/EtOH). 1H NMR (CDCl3) δ, ppm:
11.46 (bs, 1H), 7.92 (s, 1H), 7.77 (d,
= 7.7 Hz, 1H), 7.50 (ddd, = 7.8, 7.7, 1.1 Hz, 1H), 7.37 (d,
8.7 Hz, 1H), 7.36 (d, = 8.2 Hz, 1H), 7.21 (dd,
1H), 3.02ꢀ2.94 (m, 1H), 1.31 (d,
= 6.9 Hz, 6H); 13C NMR
J
= 8.2 Hz, 2H), 7.62 (d,
J
J
J
=
J
J = 8.7, 7.7 Hz,
J
(CDCl3) δ, ppm: 162.5, 148.5, 137.4, 137.3,133.0, 131.9, 129.6,
128.3, 127.2, 125.9, 122.1, 119.9, 114.9, 33.5, 23.4 (2C); IR:
3445, 1652 cmꢀ1. EA: Calcd for C18H17NO: C, 82.10; H, 6.51;
N, 5.32. Found: C, 82.21; H, 6.46; N, 5.27. HRMS calc`d for
C18H17NONa (M+Na)+ 286.1208, found 286.1201.
Method B: Reaction of indoles with 2-nitroethanoles
A mixture of of indole
1 (1 mmol), nitroalcohol 10 (1.2 mmol)
and 80% PPA (2ꢀ3 g) was heated at 80ꢀ85 oC for 30 min.
Subsequently, the reaction was carried out and worked up in the
manner described for Method A (vide supra).
3-(3,4-Dimethyl)quinolin-2(1H)-one (6ad): White solid, mp
1
252ꢀ253 °C (CH2Cl2/EtOH). H NMR (CDCl3) δ, ppm: 11.71
(bs, 1H), 7.87 (s, 1H), 7.59ꢀ7.58 (m, 2H), 7.55 (d, = 7.8 Hz,
1H), 7.46 (dd, = 7.8, 7.7 Hz, 1H), 7.36 (d, = 8.2 Hz 1H),
7.24 (d, = 7.8 Hz, 1H), 7.20 (dd, = 8.2, 7.7 Hz, 1H), 2.35 (s,
J
J
J
Method C: Three-component coupling involving Fisher indole
synthesis
A mixture of arylhydrazone 11 (1.0 mmol), acetophenone 12
(1.0 mmol), and 80% PPA (2ꢀ3 g) was stirred at 100ꢀ110 °C for
40 min. When consumption of starting arylhydrazine 11 was
confirmed by TLC, the temperature was decreased to 80ꢀ85 °C
J
J
3H), 2.33 (s, 3H); 13C NMR (CDCl3) δ, ppm: 163.3, 138.0,
137.9, 136.9, 136.5, 133.9, 132.8, 130.2, 130.1, 129.7, 127.8,
126.5, 122.6, 120.8, 115.6, 20.6, 19.8; IR: 3442, 1656 cmꢀ1;
EA: Calcd for C17H15NO: C, 81.90; H, 6.06; N, 5.62. Found: C,
82.04; H, 6.01; N, 5.56; HRMS calc`d for C17H15NONa
(M+Na)+: 272.1051, found 272.1048.
and nitrostyrol
2 (1.2 mmol) was added in one portion. The
mixture was heated for additional 30 min, while consumption
of intermediate indole was monitored by TLC. After the indole
reacted completely, the temperature was increased to 95ꢀ100 °C
and the reaction mixture was heated for 1 h. The postꢀreaction
work up and isolation of the products is the same as in Method
A (vide supra).
3-(3,4-Dimethoxy)quinolin-2(1
H
)-one (6ae) 10a
:
White solid,
mp 209ꢀ210 °C (CH2Cl2/EtOH). H NMR (DMSOꢀd6) δ, ppm:
11.87 (bs, 1H), 8.09 (s, 1H), 7.71 (d, = 7.5 Hz, 1H), 7.48
(ddd, = 9.7, 7.7, 0.9 Hz, 1H), 7.42 (d, = 1.8 Hz, 1H), 7.38
(dd, = 8.4, 1.9 Hz, 1H), 7.34 (d, = 8.2 Hz, 1H), 7.19 (t, J =
1
J
J
J
J
J
7.4 Hz, 1H), 7.01 (d, J = 8.4 Hz, 1H), 3.81 (s, 3H), 3.80 (s, 3H);
Reaction of 3-nitrovinylindoles with arenes
13C NMR (DMSOꢀd6) δ, ppm: 161.1, 148.8, 148.1, 138.1,
136.5, 131.1, 129.8, 128.9, 127.9, 121.8, 121.3, 119.7, 114.6,
6 | RCS Adv., 2014, 00, 1-3
This journal is © The Royal Society of Chemistry 2012

Page 7 of 11
Journal Name
RSC Advances
View Article Online
DOI: 10.1039/C4RAA14R4T0I6CFLE
112.6, 111.3, 55.6, 55.5; IR: 3462, 1651 cmꢀ1; HRMS calc`d 1H), 7.62 (d,
for C17H15NO3Na (M+Na)+: 304.0950, found 304.0946.
2H), 7.24 (t,
J
J
= 7.8 Hz, 1H), 7.55ꢀ7.51 (m, 2H), 7.36ꢀ7.33 (m,
= 7.7 Hz, 1H); 13C NMR (CDCl3) δ, ppm: 162.6,
139.0, 138.3, 138.2, 131.9, 131.3, 131.1, 130.9, 129.9, 128.2,
)-one (6af): White solid, 127.7, 123.0, 122.5, 120.3 115.6; IR: 3485, 1648 cmꢀ1; EA:
mp 215ꢀ217 °C (CH2Cl2/EtOH). 1H NMR (CDCl3) δ, ppm: Calcd for C15H10BrNO: C, 60.02; H, 3.36; N, 4.67. Found: C,
11.37 (bs, 1H), 7.87 (s, 1H), 7.77 (d, = 8.6 Hz, 2H), 7.59 (d, 60.16; H, 3.29; N, 4.59; HRMS calc`d for C15H10BrNONa
= 7.8 Hz, 1H) 7.47 (dd, = 7.8, 7.7 Hz, 1H), 7.33 (d,
= 8.2 (M+Na)+: 321.9843, found 321.9843.
Hz, 1H), 7.21 (dd, = 8.2, 7.8 Hz, 1H), 7.00 (d, = 8.6 Hz,
2H), 4.11 (q, = 7.0 Hz, 2H), 1.46 (t,
= 7.0 Hz, 3H); 13C 3-Pyridin-2-ylquinolin-2(1
NMR (CDCl3) δ, ppm: 163.2, 159.3, 137.8, 137.3, 132.2, 130.2, solid, mp 232ꢀ233 °C (1,4ꢀdioxane); H NMR (DMSOꢀd6) δ,
3-(4-Ethoxyphenyl) quinolin-2(1
H
J
J
J
J
J
J
J
J
H
)-one (6al) 27
:
Creamꢀcolored
1
130.0, 128.5, 127.8, 122.7, 120.7, 115.4, 114.5, 63.6, 15.0; IR: ppm: 12.07 (s, 1H), 8.78 (s, 1H), 8.69 (d,
3455, 1648 cmꢀ1; EA: Calcd for C17H15NO2: C, 76.96; H, 5.70; (d,
= 8.1 Hz, 1H), 7.86 (m, 2H), 7.55 (t,
N, 5.28. Found: C, 77.19; H, 5.61; N, 5.23; HRMS calc`d for (m, 2H), 7.23 (t,
J
= 4.6 Hz, 1H), 8.52
J
J = 8.3 Hz, 1H), 7.38
J
= 7.6 Hz, 1H); 13C NMR (DMSOꢀd6) δ,
C17H15NO2Na (M+Na)+: 288.1000, found 288.0991.
ppm: 161.1, 152.6, 149.2, 139.3, 138.8,136.2, 131.0, 128.8,
123.8, 123.0, 122.0, 119.2, 114.7; IR: 3475, 1645 cmꢀ1; HRMS
3-(2-Fluorophenyl)quinolin-2(1
H
)-one (6ag): White solid, mp calc`d for C14H10N2ONa (M+Na)+: 245.0691, found 245.0686.
233ꢀ235 °C (CH2Cl2/EtOH). H NMR (CDCl3) δ, ppm: 11.50
(bs, 1 H), 7.92 (s, 1H),7.63 (ddd, = 9.3, 7.5, 1.7 Hz, 1H), 7.59 3-(2-Nitro-phenyl)quinolin-2(1
(dd, = 7.8, 1.1 Hz, 1H), 7.50 (ddd,
7.42ꢀ7.37 (m, 1H), 7.35 (d, = 8.2 Hz, 1H), 7.28ꢀ7.18 (m, 3H); d6) δ, ppm: 12.00 (s, 1H), 8.17 (s, 1H), 8.06 (d,
13C NMR (CDCl3) δ, ppm: 162.5, 161.5, 159.5, 140.9, 138.4, 7.83 (t,
= 7.8 Hz, 1H), 7.78 (d,
131.9, 130.8, 130.1, 128.1, 127.8, 124.0 122.9, 120.0, 116.1, 7.8 Hz, 1H), 7.65 (d, = 7.8 Hz, 1H), 7.56 (t,
115.8. IR: 3502, 1650 cmꢀ1; EA: Calcd for C15H10NFO: C, 7.36 (d, = 7.8 Hz, 1H); 13C NMR
= 8.1 Hz, 1H), 7.25 (t,
1
J
H
)-one (6am) 28
:
Pale yellow
1
J
J = 7.8, 7.7, 1.3 Hz, 1H), solid, mp 317ꢀ318 °С (THF/diethyl ether); H NMR (DMSOꢀ
J
J
= 7.8 Hz, 1H),
J
J
= 7.8 Hz, 1H), 7.67 (t,
J =
J
J
= 8.1 Hz, 1H),
J
J
75.30; H, 4.21; N, 5.85. Found: C, 75.48; H, 4.16; N, 5.78; (DMSOꢀd6) δ, ppm: 133.6, 132.2, 131.0, 130.9, 130.6, 129.4,
HRMS calc`d for C15H10NFONa (M+Na)+: 262.0644, found 128.2, 123.9, 122.1, 119.3, 115.0; The NMR spectral data are
262.0639.
consistent with published results.28 IR: 2281 s, 1532 s, 1330 s
cmꢀ1; HRMS calc`d for C15H10N2O3Na (M+Na)+: 289.0589,
3-(3-Fluorophenyl)quinolin-2(1H)-one (6ah): White solid, found 289.0585.
mp 220ꢀ221 °C (CH2Cl2/EtOH). 1H NMR (CDCl3) δ, ppm:
29
12.22 (bs, 1H), 7.95 (s, 1H), 7.65ꢀ7.57 (m, 3H), 7.52 (dt,
7.7, 0.8 Hz, 1H), 7.48ꢀ7.39 (m, 2H), 7.24 (t,
(ddd,
= 8.4, 8.3, 2.3 Hz, 1H); 13C NMR (CDCl3) δ, ppm: (bs, 1H), 7.57 (s, 1H), 7.49ꢀ7.39 (m, 3H), 7.15 (ddd,
163.8, 163.1, 161.9, 139.1, 138.3, 131.1 130.9, 129.8, 128.1, 8,6 Hz, 1H), 2.67 (t, = 7 Hz, 2H), 1.75 (sextet, = 7 Hz, 2H),
124.6, 123.0, 120.3, 116.3, 115.8, 115.1; IR: 3495, 1648 cmꢀ1; 1.04 (t,
= 7 Hz, 3H); 13C NMR (CDCl3) δ, ppm: 164.5, 137.4,
J
=
3-
n
-Propylquinolin-2(1
H
)-one (6ap)
:
White solid, mp 142ꢀ
1
J
= 7.5, 1H), 7.12 143 °C (hexane/ethyl acetate); H NMR (CDCl3) δ, ppm: 12.77
= 2 and
J
J
J
J
J
EA: Calcd for C15H10NFO: C, 75.30; H, 4.21; N, 5.85. Found: 136.4, 133.7, 129.0, 126.7, 122.1, 120.1, 115.7, 32.3, 21.6,
C, 75.46; H, 4.17; N, 5.74; HRMS calc`d for C15H10NFONa 14.0. The NMR spectral data are consistent with published
(M+Na)+: 262.0644, found 262.0637.
results.27 IR: 3455, 1655 cmꢀ1; HRMS calc`d for C12H13NONa
(M+Na)+: 210.0885, found 210.0891.
3-(4-Fluorophenyl)quinolin-2(1
246ꢀ248 °C (CH2Cl2/EtOH). 1H NMR (DMSOꢀd6) δ, ppm: Quinolin-2(1
11.97 (bs, 1H), 8.11 (s, 1H), 7.85ꢀ7.81 (m, 2H), 7.72 (d, = 7.7 (CH2Cl2/EtOH). H NMR (CDCl3) δ, ppm: 7.85 (d,
Hz, 1H), 7.50 (dd, = 7.7, 7.6 Hz, 1H), 7.33 (d, = 8.2 Hz, 1H), 7.58 (d, = 8.0 Hz, 1H), 7.54 (d, = 8.4 Hz, 1H), 7.52ꢀ
1H), 7.17ꢀ7.28 (m, 3H); 13C NMR (DMSOꢀd6) δ, ppm: 163.1, 7.46 (m, 1H), 7.26ꢀ7.22 (m, 1H), 6.75 (d,
= 9.2 Hz, 1H), 2.14
H)-one (6ai): White solid, mp
H
)-one (6aq) 30
:
White solid, mp 197ꢀ199 °C
= 9.2 Hz,
1
J
J
J
J
J
J
J
161.0, 160.6, 138.4, 137.6, 132.6, 130.8, 130.3, 128.1, 122.0 (br. s, 1H). The NMR spectral data are consistent with
119.5, 114.9, 114.7; IR: 3588, 1651 cmꢀ1; EA: Calcd for published results.30 HRMS calc`d for C9H7NONa (M+Na)+:
C15H10NFO: C, 75.30; H, 4.21; N, 5.85. Found: C, 75.42; H, 168.0425, found 168.0420.
4.17; N, 5.73; HRMS calc`d for C15H10NFONa (M+Na)+:
262.0644, found 262.0640.
3-(Benzo[d][1,3]dioxol-5-yl)quinolin-2(1
H
)-one (6ar): White
solid, mp 215ꢀ218 °C (EtOH). H NMR (DMSOꢀd6) δ, ppm:
)-one (6aj): White solid, 11.88 (bs, 1H), 8.13 (s, 1H), 7.71 (d, = 7.49 Hz, 1H), 7.49
= 9.7, 7.7, 0.9 Hz, 1H), 7.43 (d, = 1.8 Hz, 1H), 7.40
= 8.4, 1.9 Hz, 1H), 7.37 (d, = 8.2 Hz, 1H), 7.19 (t,
= 8.4 7.4 Hz, 1H), 7.10 (d,
= 8.4 Hz, 1H), 5.95 (s, 2H); 13C NMR
= 8.2 Hz, 1H), (DMSOꢀd6) δ, ppm: 161.4, 146.3, 145.9, 138.0, 136.5, 131.2,
1
3-(3,4-Dichlorophenyl)quinolin-2(1
H
J
mp 298ꢀ299 °C (CH2Cl2/EtOH).1H NMR (DMSOꢀd6) δ, ppm: (ddd,
J
J
12.06 (bs, 1H), 8.27 (s, 1H), 8.11 (d,
= 8.4, 2.0 Hz, 1H), 7.74 (d, = 7.6 Hz, 1H), 7.70 (d,
Hz,1H), 7.53 (dd, = 7.7, 7.6, 1H), 7.34 (d,
7.21 (dd,
J
= 2.0 Hz, 1H), 7.80 (dd, (dd,
J
J
J =
J
J
J
J
J
J
J
= 8.2, 7.7 Hz, 1H); 13C NMR (DMSOꢀd6) δ, ppm: 129.8, 128.3, 127.9, 121.8, 121.5, 119.7, 114.6, 109.7, 107.4;
160.7, 138.7, 138.6, 136.8, 130.8, 130.6, 130.4, 130.3, 130.1, HRMS calc`d for C16H11NO3Na (M+Na)+: 288.0637, found
128.8, 128.5, 128.4, 122.1, 119.3 114.8; IR: 3495, 1648 cmꢀ1; 288.0635.
EA: Calcd for C15H9Cl2NO: C, 62.09; H, 3.13; N, 4.83. Found:
C, 62.28; H, 3.07; N, 4.72; HRMS calc`d for C15H9Cl2NONa 3-(4-tert-Butylphenyl)quinolin-2(1
H
)-one (6as): White solid,
mp 247ꢀ249 °C (EtOH). H NMR (CDCl3) δ, ppm: 11.84 (bs,
1H), 7.93 (s, 1H), 7.77 (d, = 8.3 Hz, 2H), 7.61 (dd, = 7.6,
)-one (6ak): White solid, 0.6 Hz, 1H), 7.51 (d, = 8.4 Hz, 2H), 7.40 (d, = 8.2 Hz, 1H),
mp 211ꢀ212 °C (CH2Cl2/EtOH). 1H NMR (CDCl3) δ, ppm: 7.23 (ddd,
= 7.6, 6.5, 0.7 Hz, 1H), 1.39 (s, 9H); 13C NMR
1
(M+Na)+: 311.9959, found 311.9954.
J
J
3-(3-Bromophenyl)quinolin-2(1
H
J
J
J
11.35 (bs, 1H), 7.96 (bs, 1 H), 7.92 (s, 1H), 7.75 (d,
J
= 7.7 Hz, (CDCl3) δ, ppm: 163.2, 151.4, 138.5, 137.8, 133.2, 132.3,
This journal is © The Royal Society of Chemistry 2012
RCS Adv., 2014, 00, 1-3 | 7

RSC Advances
Page 8 of 11
View Article Online
ARTICLE
Journal Name
DOI: 10.1039/C4RA14406F
130.4, 128.7 (2C), 127.9, 125.5 (2C), 123.0, 120.7, 115.8, 34.8,
31.5; HRMS calc`d for C19H19NONa (M+Na)+: 300.1364, 6-Chloro-3-phenylquinolin-2(1 )-one (6ga) 29
H : White solid,
1
found 300.1357.
mp 249ꢀ250 °C (hexane/EtOAc); H NMR (DMSOꢀd6) δ, ppm:
12.06 (br. s, 1H), 8.11 (s, 1H), 7.86 (d, = 2.0 Hz, 1H), 7.77 (d,
= 7.1 Hz, 2H), 7.56 (dd, = 9.3, 2.0 Hz, 1H), 7.50ꢀ7.42 (m,
= 9.0 3H), 7.38 (d,
= 9.3 Hz, 1H); 13C NMR (DMSOꢀd6) δ, ppm:
J = 8.1 Hz, 1H), 7.36 160.7, 136.9, 136.4, 135.8, 132.7, 129.9, 128.6, 128.0, 127.9,
J
29
1-Methylquinolin-2(1
°C (hexane/EtOAc); H NMR (CDCl3) δ, ppm: 7.66 (d,
Hz, 1H), 7.56 (t,
H
)-one (6cq)
:
White solid, mp 75ꢀ76
J
J
1
J
J
J
= 8.0 Hz, 1H), 7.55 (d,
= 8.1 Hz, 1H), 6.71 (d, J = 9.0 126.9, 125.6, 120.6, 116.5. The NMR spectral data are
(d, = 8.0 Hz, 1H), 7.23 (t,
J
J
Hz, 1H), 3.72 (s, 3H); 13C NMR (CDCl3) δ, ppm: 162.2, 139.9, consistent with published results.29 IR: 3455, 1650 cmꢀ1;
138.8, 130.5, 128.6, 122.0, 121.6, 120.6, 114.0, 29.4. IR: 1650 HRMS calc`d for C15H10NClONa (M+Na)+: 278.0349, found
cmꢀ1. HRMS calc`d for C10H9NONa (M+Na)+: 182.0582, found 278.0345.
182.0577.
3-(6,7,9,10,17,18,20,21-Octahydro-5,8,11,16,19,22-hexaoxa-
29
1-Methyl-3-phenylquinolin-2(1
H
)-one (6ca)
:
White solid, dibenzo[a,j]cyclooctadecen-2-yl)-1H-quinolin-2-one (6at): A
mp 140ꢀ142 °C (ligroin); 1H NMR (CDCl3) δ, ppm: 7.58 (s, mixture of 3ꢀnitrovinylindole (1.0 mmol), dibenzoꢀ18ꢀcrownꢀ6
o
1H), 7.70 (d,
J
= 8.1 Hz, 2H), 7.59 (d,
J
= 8.2 Hz, 1H), 7.55 (t, ether (1 mmol), and PPA (2ꢀ3 g) was heated at 80ꢀ85 C for 30
J
= 8.1 Hz, 1H), 7.43 (t,
J = 8.2 Hz, 2H), 7.39ꢀ7.34 (m, 2H), min. Reaction progress was monitored by TLC. When all
7.24 (t, J = 8.0 Hz, 1H), 3.79 (s, 3H); 13C NMR (CDCl3) δ, indole was consumed, the reaction temperature was increased
ppm: 161.4, 139.5, 136.7, 132.4, 130.2, 128.9, 128.7,128.0, to 95ꢀ100 °C and the mixture was heated for 1 h, then cooled to
127.9, 122.1, 120.6, 113.9, 30.0, one carbon signal is missing room temperature, poured into water (50 mL), and neutralized
due to overlap; IR: 1645 cmꢀ1. The NMR and IR spectral data by aqueous ammonia. The aqueous phase was extracted twice
are consistent with published results.29,31,32 HRMS calc`d for with chloroform, concentrated, and isolated by flash chromꢀ
C16H13NONa (M+Na)+: 258.0895, found 258.0888.
atography (eluent EtOAc/petroleum ether). The compound was
finally purified by recrystallization from EtOAc. White solid,
1
1-Methyl-3-(4-Fluorophenyl)quinolin-2(1
H
)-one (6ci): White mp 208ꢀ209 °C (EtOAc); H NMR (DMSOꢀd6) δ, ppm: 11.86
1
solid, mp 172ꢀ173 °C (ligroin); H NMR (CDCl3) δ, ppm: 7.78 (br. s, 1H), 8.10 (s, 1H), 7.70 (d,
(s, 1H), 7.72ꢀ7.68 (m, 2H), 7.63ꢀ7.57 (m, 2H), 7.39 (d, = 1.6 8.3 Hz, 1H), 7.40ꢀ7.37 (m, 2H), 7.32 (d,
Hz, 1H), 7.28ꢀ7.25 (m, 2H), 7.12 (t, = 7.6 Hz, 1H), 7.00 (d,
J
= 7.7 Hz, 1H), 7.47 (t,
= 8.2 Hz, 1H), 7.18
J = 8.3 Hz, 1H), 6.99ꢀ6.95 (m, 2H),
J =
J
J
J
= 8.6 Hz, 2H), 3.8 (s, (t,
J
3H); 13C NMR (CDCl3) δ, ppm: 164.0, 161.6 (2C), 139.7, 6.89ꢀ6.86 (m, 2H), 4.18ꢀ4.10 (m, 4H), 4.10ꢀ4.04 (m, 4H), 3.92ꢀ
136.8, 132.9 (2C), 131.6, 130.9, 130.8, 130.5, 129.0, 122.4, 3.81 (m, 8H); 13C NMR (DMSOꢀd6) δ, ppm: 161.1, 148.0,
120.8, 115.3, 115.1, 114.2, 30.2; HRMS calc`d for 147.9 (2C), 147.3, 138.0, 136.5, 131.0, 129.8, 128.7, 127.8,
C16H12NFONa (M+Na)+: 276.0801, found 276.0797.
121.8, 121.3, 120.7 (2C), 119.6, 114.5, 113.1, 112.5 (2C),
111.9, 68.9 (4C), 67.9, 67.8, 67.6 (2C); HRMS calc`d for
1-Butyl-3-phenylquinolin-2(1
H
)-one (6ea): White solid, mp C29H29NO7Na (M+Na)+: 526.1842, found 526.1834.
1
154ꢀ153 °C (ligroin); H NMR (CDCl3) δ, ppm: 7.81 (s, 1H),
7.73 (d, = 7.2 Hz, 1H), 7.62 (d, = 7.7 Hz, 1H), 7.56 (ddd,
= 7.9, 7.8, 1.2 Hz, 1H), 7.45ꢀ7.42 (m, 2H), 7.39ꢀ7.37 (m, 2H),
J
J
J
Experiments on isolation of intermediate hydroxamic acid and
its further conversion into 2-quinolone
7.24ꢀ7.22 (m, 1H), 4.36 (t,
1.55ꢀ1.50 (m, 2H), 1.02 (t,
J
J
= 7.8 Hz, 2H), 1.83ꢀ1.75 (m, 2H),
= 7.3 Hz, 3H); 13C NMR (CDCl3)
A mixture of indole 1a,d,c,e (1.0 mmol), βꢀnitrostyrene 2a,i
(1.2 mmol) and PPA (4 g) was stirred at 70ꢀ75°C for 30 min.
The reaction mixture was cooled down to room temperature,
poured into water (50 ml), and neutralized by aqueous
ammonia to pH~8. The formed precipitate was filtered off and
recrystallized.
δ, ppm: 161.4, 139.0, 136.9 (2C), 132.6, 130.3, 129.2 (3C),
128.3 (2C), 128.2, 122.1, 121.2, 114.2, 43.0, 29.7, 20.6, 14.0;
HRMS calc`d for C19H19NO2Na (M+Na)+: 300.1364, found
300.1358.
33
6-Methyl-3-phenylquinolin-2(1
H)-one (6ha)
:
White solid,
Hydroxamic acids 3aa,ab,db,ci,ea obtained as described above
(1 mmol) were stirred in PPA at 95ꢀ100°C for 3 h. The
mixtures were cooled down, poured into water (50 mL), and
neutralized with aqueous ammonia to pH~8. The aqueous
portions were extracted with chloroform (2 x 50 mL) and
combined organic phases were filtered through a short pad of
Silica gel (32ꢀ63 ꢁm, 60 Å pore size). The filtrates were
concentrated in vacuum to afford samples of quinolones
mp 218ꢀ219 °С (EtOH); 11.87 (s, 1H), 8.02 (s, 1H,), 7.75ꢀ7.73
(m, 2H), 7.51 (s, 1H), 7.44ꢀ7.41 (m, 2H), 7.37 (d, = 7.22 Hz,
= 8.37 Hz, 1H), 2.35
J
1H), 7.34 (d,
J = 8.3 Hz, 1H), 7.24 (d, J
(s, 3H); 13C NMR (100 MHz, DMSOꢀd6) δ, ppm: 160.9, 137.4,
136.4, 131.5 (2C), 130.8, 128.7 (2C), 127.9 (2C), 125.7, 127.5,
119.5, 114.6, 99.5, 20.4. The NMR spectral data are consistent
with published results.32 IR: 3450, 1660 cmꢀ1; HRMS calc`d for
C16H13NONa (M+Na)+: 258.0895, found 258.0887.
6aa
,
cq,
ci
,
ea identical to the material described above.
10b
6-Methoxy-3-phenyl(1H)quinolin-2(1
H
)-one (6fa)
:
Pale
yellow solid, mp 248ꢀ249 °C (CHCl3/EtOAc); 1H NMR
(CDCl3) δ, ppm: 10.89 (br. s, 1H), 7.86 (s, 1H), 7.8 (s, 1H),
N
-Hydroxy-2-(2-methyl-1
H
-indol-3-yl)-2-phenylacetamide
1
(3aa): White solid, mp 110ꢀ112 °C (toluene); H NMR (400
MHz, DMSOꢀd6) δ, ppm: 10.86 (br. s, 1H), 10.79 (br. s, 1H),
7.79 (s, 1H), 7.48 (m, 2H), 7.42 (m, 1H), 7.23 (d,
J
= 9.0 Hz,
8.86 (br. s, 1H), 7.52 (d,
7.20 (m, 5H), 6.94 (ddd,
(t,
J
= 7.9 Hz, 1H), 7.37 (s, 1H), 7.26ꢀ
1H), 7.14 (dd,
J = 6.1, 2.7 Hz, 1H), 7.04 (d, J = 2.7 Hz, 1H),
3.88 (s, 3H); 13C NMR (DMSOꢀd6) δ, ppm: 160.7, 154.3,
137.4, 136.6, 133.1, 132.0, 128.8, 128.0, 127.9, 120.3, 119.6,
116.1, 109.6, 55.6. The NMR spectral data are consistent with
published results.10b IR: 3445, 1642 cmꢀ1; HRMS calc`d for
C16H13NO2Na (M+Na)+: 274.0844, found 274.0838.
J
= 7.45, 7.37 and 0.64 Hz, 1H), 6.83
J
= 7.2 Hz, 1H), 4.93 (s, 1H), 2.30 (s, 3H); 13C NMR (100
MHz , DMSOꢀd6) δ, ppm: 168.7, 140.5, 135.1, 133.2, 128.1
(2C), 127.9 (2C), 127.7, 126.1, 119.9, 119.8, 118.0, 110.2,
108.5, 45.3, 11.9; HRMS calc`d for C17H16N2O2Na (M+Na)+:
303.1109, found 303.1105. Yield 238 mg (0.85 mmol, 85%).
8 | RCS Adv., 2014, 00, 1-3
This journal is © The Royal Society of Chemistry 2012

Page 9 of 11
Journal Name
RSC Advances
View Article Online
DOI: 10.1039/C4RAA14R4T0I6CFLE
Farr, J. R. Fozard, D. Janus, E. M. Rosethorne, D. A. Sandham, D. A.
Sykes, A. Trifilieff, K. L. Turner, and E. Wissler, Bioorg. Med.
Chem. Lett. 2012, 22, 6280ꢀ6285.
N
-Hydroxy-2-(2-phenyl-1H-indol-3-yl)-2-phenylacetamide
(3ab): White solid, mp 220ꢀ221 °C (toluene). The NMR
spectral data are consistent with published results.14 HRMS
calc`d for C22H18N2O2Na (M+Na)+: 365.1266, found 365.1260.
Yield 329 mg (0.96 mmol, 96%).
3
(a) A. DoléansꢀJordheim, J. B. Veron, O. Fendrich, E. Bergeron, A.
MontagutꢀRomans, Y. S. Wong, B. Furdui, J. Freney, C. Dumontet,
and A. Boumendjel, ChemMedChem 2013,
8, 652ꢀ657. (b) S. E.
N
-Hydroxy-2-(1-methyl-2-phenyl-1H-indol-3-yl)-2-phen-
1
Wolkenberg, Z. Zhao, C. Thut, J. W. Maxwell, T. P. McDonald, F.
Kinose, M. Reilly, C. W. Lindsley, and G. D. Hartman, J. Med.
Chem. 2011, 54, 2351ꢀ2358. (c) P. V. Chaturvedula, S. E. Mercer, S.
S. Pin, G. Thalody, C. Xu, C. M. Conway, D. Keavy, L. Signor, G. H.
Cantor, N. Mathias, P. Moench, R. Denton, R. Macci, R. Schartman,
V. Whiterock, C. Davis, J. E. Macor, and G. M. Dubowchik, Bioorg.
Med. Chem. Lett. 2013, 23, 3157ꢀ3161. (d) B. Joseph, F. Darro, A.
Behard, B. Lesur, F. Collignon, C. Decaestecker, A. Frydman, G.
Guillaumet, and R. J. Kiss, J. Med. Chem. 2002, 45, 2543ꢀ2555.
See for example: W. M. F. Fabian, K. S. Niederreiter, G. Uray, and
W. Stadlbauer, J. Mol. Struct. 1999, 477, 209ꢀ220.
ylacetamide (3db): White solid, mp 152ꢀ155 °C (toluene). H
NMR (DMSOꢀd6) δ, ppm: 10.64 (br. s, 1H), 8.08 (br. s, 1H),
7.70 (d,
J
= 8.0 Hz, 1H), 7.54ꢀ7.47 (m, 3H), 7.45ꢀ7.37 (m, 3H),
= 7.5 Hz, 1H),
7.23ꢀ7.19 (m, 2H), 7.15ꢀ7.12 (m, 4H), 6.94 (t,
J
4.76 (s, 1H), 3.53 (s, 3H); 13C NMR (DMSOꢀd6) δ, ppm: 168.5,
140.6, 138.9, 136.9, 130.9, 130.6 (2C), 128.5 (2C), 128.4,
127.9 (2C), 127.8 (2C), 126.4, 126.1, 122.2, 121.2, 118.8,
110.3, 109.6, 46.3, 30.7. HRMS calc`d for C23H20N2O2Na
(M+Na)+: 379.1422, found 379.1415. Yield 335 mg (0.94
mmol, 94%).
4
5
2-(4-Fluoro-phenyl)-N-hydroxy-2-(1-methyl-2-phenyl-1H-
indol-3-yl)-acetamide (3ci): White solid, mp 174ꢀ175 °C
(toluene). H NMR (DMSOꢀd6) δ, ppm: 10.65 (br. s, 1H), 8.82
See for example: M. S. Tremblay, M. Halim, and D. Sames, J. Am.
Chem. Soc. 2007, 129, 7570ꢀ7577.
1
(br. s, 1H), 7.69 (d,
J = 8.0 Hz, 1H), 7.53ꢀ7.49 (m, 3H), 7.45 (d,
6
7
L. Clima and W. Bannwarth, Helv. Chim. Acta 2008, 91, 165ꢀ175.
See, for example: (a) Y. Zhang, Y. Fang, H. Liang, H. Wang, K. Hu,
X. Liu, X. Yi, and Y. Peng, Bioorg. Med. Chem. Lett. 2013, 23, 107ꢀ
111. (b) M. A. Alonso, M. M. Blanco, C. Avendano, and J. C.
Menendez, Heterocycles 1993, 36, 2315ꢀ2325.
J
= 8.3 Hz, 1H),7.39ꢀ7.37 (m, 2H), 7.17ꢀ7.10 (m, 3H), 7.05ꢀ
7.01 (m, 2H), 6.96 (t,
J = 7.5 Hz, 1H), 4.74 (s, 1H), 3.53 (s,
3H); 13C NMR (DMSOꢀd6) δ, ppm: 168.4, 161.8, 159.4, 139.0,
136.9, 136.7 (2C), 130.8, 130.6 (2C), 129.7 (2C), 128.5 (2C),
128.4, 126.3, 121.8, 121.3, 119.0, 114.7, 114.5, 110.2, 109.7,
45.6, 30.7; HRMS calc`d for C23H19N2FO2Na (M+Na)+:
397.1328, found 397.1323. Yield 344 mg (0.92 mmol, 92%).
8
9
See, for example: (a) X. Liu, X. Xin, D. Xiang, R. Zhang, S. Kumar,
F. Zhou, and D. Dong, Org. Biomol. Chem. 2012, 10, 5643ꢀ5646. (b)
G. Uray, K. S. Niederreiter, F. Belaj, and W. M. F. Fabian, Helv.
Chim. Acta 1999, 82, 1408ꢀ1417.
2-(1-Butyl-2-phenyl-1H-indol-3-yl)-N-hydroxy-2-phenyl-
acetamide (3ea): White solid, mp 132ꢀ134 °C (CH2Cl2/EtOH).
1H NMR (DMSOꢀd6) δ, ppm: 10.64 (br. s, 1H), 8.82 (br. s, 1H),
See, for example: (a) S.ꢀY. Han, J. W. Choi, J. Yang, C. H. Chae, J.
Lee, H. Jung, K. Lee, J. D. Ha, H. R. Kim, and S. Y. Cho, Bioorg.
Med. Chem. 2012, 22, 2837ꢀ2844. (b) K. K. Park and J. Y. Jung,
Heterocycles 2005, 65, 2095ꢀ2105.
7.71 (d,
7.15ꢀ7.12 (m, 4H), 6.92 (t,
J
= 8.0 Hz, 1H), 7.51ꢀ7.38 (m, 6H), 7.22ꢀ7.19 (m, 2H),
= 7.5 Hz, 1H), 4.70 (s, 1H), 4.02ꢀ
J
3.96 (m, 2H), 1.49ꢀ1.45 (m, 2H), 1.07ꢀ1.02 (m, 2H), 0.67 (t, J =
7.24 Hz, 3H); 13C NMR (DMSOꢀd6) δ, ppm: 168.6, 140.6,
138.7, 136.1, 136.2, 130.7, 128.5 (2C), 128.4 (2C), 127.9 (2C),
127.8 (2C), 126.6, 126.1, 122.4, 121.2, 118.7, 110.6, 109.8,
46.2, 42.8, 31.4, 19.2, 13.3; HRMS calc`d for C26H26N2O2Na
(M+Na)+: 421.1892, found 421.1887. Yield 355 mg (0.89
mmol, 89%).
10 (a) P. J. Manley and M. T. Bilodeau, Org. Lett. 2004, 6, 2433ꢀ2435.
(b) L. Fu, X. Huang, D. Wang, P. Zhao, and K. Ding, Synthesis 2011,
1547ꢀ1574.
11 (a) J.ꢀR. Chen, J. Liao, and W.ꢀJ. Xiao, Can. J. Chem. 2010, 88, 331ꢀ
337. (b) D. V. Kadnikov and R. C. Larock, J. Organomet. Chem.
2003, 687, 425ꢀ435. (c) A. C. Tadd, A. Matsuno, M. R. Fielding, and
M. C. Willis, Org. Lett. 2009, 11, 583ꢀ586.
Acknowledgements
This work was supported by the Russian Science Foundation
(grant #14ꢀ23ꢀ00068).
12 J. Minville, J. Poulin, C. Dufresne, and C. F. Sturino, Tetrahedron
Lett. 2008, 49, 3677ꢀ3681.
13 L. Liu, H. Lu, H. Wang, C. Yang, X. Zhang, D. ZhangꢀNegrerie, Y.
Du, and K. Zhao, Org. Lett. 2013, 15, 2906ꢀ2909.
Notes and references
14 A. V. Aksenov, A. N. Smirnov, N. A. Aksenov, I. V. Aksenova, L. V.
Frolova, A. Kornienko, I. V. Magedov, and M. Rubin, Chem.
Commun. 2013, 49, 9305ꢀ9307.
1
2
For recent reviews, see: (a) C. B. M. Poulie and L. Bunch,
ChemMedChem 2013, , 205ꢀ215. (b) S. Heeb, M. P. Fletcher, S. R.
8
Chhabra, S. P. Diggle, P. Williams, and M. Camara, FEMS
Microbiol. Rev. 2011, 35, 247ꢀ274.
15 For review, see: (a) A. N. Smirnov, N. A. Aksenov, I. V. Malikova,
and A. V. Aksenov, Chem. Heterocycl. Comp. 2014, 50, 594ꢀ618.
For recent studies, see: (b) S. V. Shcherbakov, D. A. Lobach, M.
Rubin, and A. V. Aksenov, Chem. Heterocycl. Comp. 2014, 50, 757ꢀ
760. (c) A. V. Aksenov, N. A. Aksenov, A. E. Tsys', V. I.
Goncharov, and S. N. Ovcharov, Russ. Chem. Bull. 2013, 62, 1127ꢀ
1128. (d) N. A. Aksenov, A. V. Aksenov, I. V. Aksenova, and Yu. I.
Smushkevich, Chem. Heterocycl. Comp. 2013, 49, 645ꢀ647. (e) A.
V. Aksenov, N. A. Aksenov, O. N. Nadein, and I. V. Aksenova,
For recent examples, see: (a) D. A. Sabbah, N. A. Simms, W. Wang,
Y. Dong, E. L. Ezell, M. G. Brattain, J. L. Vennerstrom, and H. A.
Zhong, Bioorg. Med. Chem. 2012, 20, 7175ꢀ7183. (b) N. Kumar, V.
P. Raj, B. S. Jayshree, S. S. Kar, A. Anandam, S. Thomas, P. Jain, A.
Rai, and C. M. Rao, Chem. Biol. Drug Des. 2012, 80, 291ꢀ299. (c) A.
A. AlꢀAmiery, R. I. H. AlꢀBayati, K. Y. Saour, and M. F. Radi, Res.
Chem. Intermed. 2012, 38, 559ꢀ569. (d) D. Beattie, D. Beer, M. E.
Bradley, I. Bruce, S. J. Charlton, B. M. Cuenoud, R. A. Fairhurst, D.
This journal is © The Royal Society of Chemistry 2012
RCS Adv., 2014, 00, 1-3 | 9

RSC Advances
Page 10 of 11
View Article Online
ARTICLE
Journal Name
DOI: 10.1039/C4RA14406F
Synth. Commun. 2012, 42, 541ꢀ547. (f) A. V. Aksenov, N. A.
Aksenov, O. N. Nadein, and I. V. Aksenova, Synlett 2010, 2628ꢀ
2630.
16 For reviews, see; (a) B. Robinson, Chem, Rev. 1969, 69, 227ꢀ250. (b)
B. Robinson, Chem. Rev. 1963, 63, 373ꢀ401. (c) G. W. Gribble, J.
Chem. Soc., Perkin Trans. 1, 2000, 1045ꢀ1075. (d) G. R. Humphrey
and J. T. Kuethe, Chem. Rev. 2006, 106, 2875ꢀ2911.
17 An alternative mode of cascade combining the Fisher indolization
with the ANRORC reaction featured herein, was recently communꢀ
icated, see: A. V. Aksenov, A. N. Smirnov, N. A. Aksenov, I. V.
Aksenova, A. S. Bijieva, and M. Rubin, Org. Biomol. Chem. DOI:
10.1039/ c4ob02131b
18 (a) C. Palomo, M. Oiarbide, and A. Laso, Eur. J. Org. Chem.
2007, 2561ꢀ2574. (b) F. A. Luzzio, Tetrahedron 2001, 57, 915ꢀ945.
19 For alkylation of arenes with 2ꢀnitrostyrenes to afford hydroxamic
acids, see: A. D. Grebenyuk, A. K. Tashmukhamedova, Chem.
Heterocycl. Compd., 2006, 42, 732ꢀ734.
20 Apparently,
EꢀZ isomerization of an olefin moiety should
accompany this cyclization. We believe this process can occur easily
due to reversible conjugate addition of any adventurous nucleophilic
species across this double bond.
21 L. Canoira, J. Gonzalo Rodriguez, J. B. Subirats, J. A. Escario, I.
Jimenez, and A. R. MartinezꢀFernandez, Eur. J. Med. Chem. 1989,
24, 39ꢀ42.
22 For screening of 3ꢀarylꢀ2ꢀquinolone library to evaluate their antiꢀ
tumor activity, see: M. Mehta, J. W. Keisinger, X. P. Zhang, M. L.
Lerner, D. J. Brackett, R. W. Brueggemeier, P.ꢀK. Li, and J. T.
Pento, Anticancer Res. 2010, 30, 4883ꢀ4889.
23 (a) D. E. Worral J. Am. Chem. Soc. 1938, 60, 2841. (b) K. W.
Rosenmund Chem. Ber. 1909, 42, 4778. (c) А. В. Eltsov, Russ. J.
Gen. Chem. 1962, 32, 1525.
24 (a) E. Schmidt and G. Rutz, Chem. Ber. 1928, 61, 2142ꢀ2148. (b) G.
D. Buckley and C. W. Scaife, J. Chem. Soc. 1947, 1471ꢀ1472.
25 O. Snow, Psychoactive Synthesis Series. Amphetamine Syntheses.
Overview & Reference Guide for Professionals. Thoth Press, USA,
1998, 1, 82.
26 K. Hino, Y. Nagai, and H. Uno, Chem. Pharm. Bull. 1987, 35, 2819ꢀ
2824.
27 D. H. Hey and J. M. Williams, J. Chem. Soc. 1950, 1678ꢀ1683.
28 P. M. Fresneda, P. Molina, and S. Delgado, Tetrahedron 2001, 57
,
6197ꢀ6202.
29 K. K. Park and J. Y. Jung, Heterocycles 2005, 65, 2095ꢀ2105.
30 Y.ꢀJ. Cherng, Tetrahedron 2002, 58, 1125ꢀ1129.
31 C. E. Kaslow and B. Buncher, J. Org. Chem. 1958, 23, 271ꢀ276.
32 H. Ahlbrecht and C. Vonderheid, Ber. 1975, 108, 2300ꢀ2311.
33 T. Eicher and V. Schneider, Synthesis, 1989, 372ꢀ378.
10 | RCS Adv., 2014, 00, 1-3
This journal is © The Royal Society of Chemistry 2012

Page 11 of 11
RSC Advances
View Article Online
DOI: 10.1039/C4RA14406F
RSC Advances
RSCPublishing
ARTICLE
Metal-Free Ring Expansion of
Indoles with Nitroalkenes: a Simple,
Modular Approach to 3-Substituted
2-Quinolones
Alexander V. Aksenov,*a Alexander N. Smirnov,a
Nicolai A. Aksenov,a
Inna V. Aksenova,a
Jonathon P. Matheny,b and Michael Rubin*a,b
Abstract. 3ꢀSubstituted 2ꢀquinolones are obtained via a novel metalꢀ
free transannulation reaction of 2ꢀnitroolefins with 2ꢀsubstituted
indoles in polyphosphoric acid. This acidꢀmediated cascade
transformation operates via the ANRORC (Addition of Nucleophile,
Ring Opening, and Ring Closure) mechanism and can be used in a
combination with the Fisher indole synthesis to offer a practical threeꢀ
component heteroꢀannulation approach to 2ꢀquinolones from
arylhydrazines, 2ꢀ nitroalkenes, and acetophenone. An alternative
entry to this chemistry employing the alkylation of electronꢀrich
arenes and hetarenes with 1ꢀ(2ꢀindolyl)ꢀ2ꢀnitroalkene has also been
demonstrated.
TOC graphics
R3
O
R1 NH2
R3
80% PPA
R1
+
+
NO2
N
N
O
R2
R2
NO2
80% PPA
R3-H
+
R1
N
R2
80% PPA
R2 = H
O
R3
+
+
NO2
Me
R1
NHNH2
This journal is © The Royal Society of Chemistry 2013
RCS Adv., 2014, 00, 1-3 | 11