Synthesis of 2-(1h-indol-2-yl)acetamides via br?nsted acid-assisted cyclization cascade

Article abstract of DOI:10.1021/acs.joc.0c01344

An efficient and straightforward Br?nsted-acid mediated cascade process was developed, involving cyclization of readily available β-ketonitriles into 2-aminofurans, and their subsequent recyclization into 2-(1H-indol-2-yl)acetamides is developed. This synthetic route opens a new avenue for an expeditious assembly of various isotryptamine derivatives for medicinal chemistry.

Full text of DOI:10.1021/acs.joc.0c01344

Subscriber access provided by EDINBURGH UNIVERSITY LIBRARY | @ http://www.lib.ed.ac.uk
Article
Synthesis of 2-(1H-Indol-2-yl)acetamides via
Bronsted Acid-Assisted Cyclization Cascade
Nicolai A Aksenov, Dmitrii A Aksenov, Anton A Skomorokhov, Lidiya A
Prityko, Alexander V. Aksenov, Georgii D Griaznov, and Michael Rubin
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01344 • Publication Date (Web): 03 Sep 2020
Downloaded from pubs.acs.org on September 4, 2020
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 26
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Synthesis of 2-(1H-Indol-2-yl)acetamides via Bronsted Acid-
Assisted Cyclization Cascade
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
†*
†
†
†
Nicolai A. Aksenov, Dmitrii A. Aksenov, Anton A. Skomorokhov, Lidiya A. Prityko,
†
‡
†,‡*
Alexander V. Aksenov, Georgii D. Griaznov, and Michael Rubin,
†
Department of Chemistry, North Caucasus Federal University, 1a Pushkin St., Stavropol 355009, Russia;
‡
Department of Chemistry, University of Kansas, 1567 Irving Hill Road, Lawrence, KS 66045, USA.
ABSTRACT: Efficient and straightforward Bronsted-acid mediated cascade process was developed, involving cyclization
of readily available -ketonitriles into 2-aminofurans and their subsequent recyclization into 2-(1H-indol-2-yl)acetamides
is developed. This synthetic route opens a new avenue for an expeditious assembly of various isotryptamine derivatives for
medicinal chemistry.
aries of drug-candidate compounds for medicinal
chemistry.
INTRODUCTION
It is hard to overstate importance of isotryptamine
scaffold for modern medicinal chemistry, so it is not
surprising, that molecules of this type attract a lot of
attention of many research groups around the world.
1-5
Among such structures are compound NVP LAQ-824,
investigated as pan-histone deacetylase inhibitor, dis-
rupting the chaperone function of HSP 90 and abandoned
after Phase I clinical trials in favor of more promising
tryptamine isomer Dacinostat. Also, an inhibitor of
6
anandamide uptake VDM-13, and selective cPLA2
7
-9
inhibitors Efipladip and Ecopladip should be menti-
oned (Figure 1). Arguably, isotryptamine-based struct-
1
0-13
ures 2 as well as related -carboline
be easily accessed by reduction of the corresponding 2-
1H-indol-2-yl)acetamide precursors 1 (Scheme 1). Sur-
derivatives 3 can
(
prisingly, the latter are not readily available, since there
are no reliable, general and straightforward methods for
their assembly. Herein we wish to disclose an account of
the discovery and development of unusual Brønsted acid-
assisted cascade cyclization of readily available 4-(2-
nitrophenyl)-4-oxo-2-arylbutanenitriles 4. According to
this straightforward, highly efficient and scalable prot-
ocol, acetamides 1 could be prepared in a manner
amenable for structural diversification, which should
make the featured approach attractive for building libr-
Figure 1. Biologically active isotryptamines
1
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 26
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
NH2
O
NH2
N
H
R
N
2
N
R
H
isotryptamines
1
N
H
R
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
O
R
3

-carbolines
CN
NH2
4
Scheme 1
RESULTS AND DISCUSSION
In the frame of the ongoing research in medicinal
chemistry of nitrogen-based heterocycles, our research
group gained an expertise in design and development of
Brønsted acid-assisted cascade transformations carried
out in polyphosphoric acid (PPA) medium. For example,
-aryl-2-(3-indolyl)acetohydroxamic acids 5 obtained
via PPA-assisted addition of indoles to nitrostyrenes
proved to serve as promising anti-tumor agents efficient
2
1
4-16
against several drug-resistant cancer cell lines.
To
perform a first series of SAR studies, synthetic appro-
aches towards 2-aryl-2-(3-indolyl)acetamides 6 and 2-
aryl-2-(3-indolyl)acetonitriles 7 were also developed
During the second stage of this project
we planned to test the activity of closely related 2-aryl-2-
17-19
(
Scheme 2).
Scheme 3
(2-indolyl)acetamides 1 (Scheme 1).
R3
R3
O
O
R1
R1
R2
CN
CN
R2
NO2
NH2
4
19
O
O
R1
R1
R3
R3
R2
R2
NH2
NO2
1
6
20
O
O
R1
R2
R3
R1
R2
R3
Scheme 2
+
CHO
18
+
CHO
NH2
NO2
We envisioned that target acetamide structure 1 could
be accessed via PPA-assisted cascade transformation as
shown in Scheme 3. It was imagined that upon treatment
with PPA 4-oxobutanenitrile 4 would be converted into
phosphorylated enolate 8, which would further undergo
-exo-dig cyclization involving enolate oxygen and
nitrile function to furnish phosphorylated 2-imino-2,3-
dihydro-1H-furan-1-ium intermediate 9. The latter
17
21
18
Scheme 4
would tautomerize into 2-amino-1H-furan-1-ium species
10, further dephosphorylated to furnish 2-aminofuran 11
(Scheme 3). Protonation of the furan ring would lead to
the formation of 5-amino-2H-furan-1-ium intermediate
5
2
ACS Paragon Plus Environment

Page 3 of 26
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
O
O
R1
R2
R1
R2
R3 CHO (18)
NaOH/EtOH
Procedure 1
R3
NH2
NH2
17
16
O
O
R1
R2
R1
R2
R3 CHO (18)
NaOH/EtOH
Procedure 1
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
R3
NO2
NO2
21
20
1
2
3
3
1
7a, 21a: R = R = H;
18a: R = Ph;
18i: R = 2-FC H ;
6 4
18j: R = 4-FC H ;
6 4
18k: R = 4-Me NC H ;
2 6 4
18l: R = 2-MeOC H ;
6 4
18m: R = 4-MeOC H ;
6 4
18n: R = 3,4-(MeO) C H ;
2 6 3
18o: R = 2-Py.
1
2
3
3
17b, 21b: R = R = OMe;
18b: R = 2-MeC H ;
6
4
1
2
3
3
17c, 21c: R R = OCH CH O;
7d: R = Br, R = H; R = Ph.
18c: R = 4-MeC H ;
2
2
6
4
1
2
3
3
3
1
18d: R = 4-EtC H ;
6
4
3
3
1
1
1
1
8e: R = 4-i-PrC H ;
6
4
3
3
8f: R = 2-ClC H ;
6
4
3
3
8g: R = 3-ClC H ;
6
4
3
8h: R = 4-ClC H ;
6
4
1
2
3
1
2
3
1
2
3
4
) 16aa: R = R = H; R = Ph, 60%
) 16ab: R = R = H; R = 2-MeC H , 78%;
) 16ac: R = R = H; R = 4-MeC H , 83%;
) 16ad: R = R = H; R = 4-EtC H , 67%;
5) 16ae: R = R = H; R = 4-i-PrC H , 71%;
6) 16af: R = R = H; R = 2-ClC H , 79%;
7) 16ag: R = R = H; R = 3-ClC H , 87%;
) 16ah: R = R = H; R = 4-ClC H , 81%;
) 16ai: R = R = H; R = 2-FC H , 82%;
0) 16aj: R = R = H; R = 4-FC H , 65%;
1) 16ak: R = R = H; R = 4-Me NC H , 50%;
2) 16al: R = R = H; R = 2-MeOC H , 89%;
3) 16am: R = R = H; R = 4-MeOC H , 86%;
14) 16an: R = R = H; R = 3,4-(MeO) C H , 74%;
1) 20aa: R = R = H; R = Ph, 96%
1
2
3
1
2
3
2) 20ab: R = R = H; R = 2-MeC H , 94%;
6 4
6
4
1
2
3
1
2
3
3) 20ac: R = R = H; R = 4-MeC H , 97%;
6 4
6
4
1
2
3
1
2
3
4) 20ad: R = R = H; R = 4-EtC H , 93%;
6 4
6
4
1
2
3
1
2
3
5) 20ae: R = R = H; R = 4-i-PrC H , 88%;
6 4
6
4
1
2
3
1
2
3
6) 20af: R = R = H; R = 2-ClC H , 93%;
6 4
6
4
1
2
3
1
2
3
7) 20ag: R = R = H; R = 3-ClC H , 90%;
6 4
6
4
1
2
3
1
2
3
8
9
1
1
1
1
8) 20ah: R = R = H; R = 4-ClC H , 98%;
6 4
6
4
1
2
3
1
2
3
9) 20ai: R = R = H; R = 2-FC H , 92%;
6 4
6
4
1
2
3
1
2
3
10) 20aj: R = R = H; R = 4-FC H , 91%;
6 4
6
4
1
2
3
1
2
3
11) 20ak: R = R = H; R = 4-Me NC H , 94%;
2 6 4
2
6
4
1
2
3
1
2
3
12) 20al: R = R = H; R = 2-MeOC H , 94%;
6 4
6
4
1
2
3
1
2
3
13) 20am: R = R = H; R = 4-MeOC H , 93%;
6 4
14) 20an: R = R = H; R = 3,4-(MeO) C H , 91%;
2 6 3
6
4
1
2
3
1
2
3
2
6
3
1
2
3
1
2
3
15) 16ao: R = R = H; R = 2-Py, 65%;
15) 20ba: R = R = OMe; R = Ph, 85%;
1
2
3
1
2
3
1
6) 16da: R = Br, R = H; R = Ph, 96%.
16) 20ca: R R = OCH CH O; R = Ph, 81%;
2 2
Scheme 5
1
2 activated towards nucleophilic attack with ortho-
aniline moiety. This 5-exo-trig attack would afford
a,8b-dihydro-4H-furo[3,2-b]indol-4-ium species 13,
which should exist in tautomeric equilibrium with
,3a,4,8b-tetrahydrofuro[3,2-b]indol-1-ium form 14
Scheme 3). Subsequent cleavage of C-O bond would
afford 2H-indol-1-ium species 15, which after deproton-
ation should provide the desired 1H-indole 1 bearing
acetamide substituent at C-2. It should be pointed out,
that conversion of bicyclic intermediate 14 accessed via
an alternative route into amide 1 was documented.
Acid-mediated cleavage of furan ring to trigger a
cyclization of indoles was also reported.
Evidently, successful implementation of this
approach would greatly depend on availability of struct-
urally diverse precursors 4. We envisioned that these 4-
oxonitrliles could be readily accessed via conjugate
addition of cyanide to ortho-aminochalcone 16, which, in
turn, could be assembled via aldol condensation of
acetophenone 17 with suitable aromatic aldehyde 18
(Scheme 4). Taken into account a high price tag for most
ortho-aminoacetophenones, an alternative pathway was
also planned, involving aldol condensation of much more
affordable ortho-nitroacetophenone precursors 21 to
access ortho-nitrochalcones 20. Subsequent conjugate
addition of cyanide would provide nitrile 19 that would
be subjected into reduction of ortho-nitro group to afford
the key precursor 4.
To implement this idea, ortho-aminoacetophenone
(17a) was subjected to the NaOH-assisted reaction with
benzaldehyde (18a) in an aqueous ethanol solution (see
Procedure 1 in Experimental part). The corresponding
chalcone 16aa was isolated in 60% yield (Scheme 5).
3
3
(
2
0
2
1
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 26
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Similarly, chalcone 20aa was obtained in 96% yield
starting from ortho-nitroacetophenone (21a) (Scheme 5).
In a similar manner 17a and 21a were converted into a
series of chalcones 16 and 20, respectively, employing a
variety of aromatic aldehydes 18b-o. Substituted aceto-
phenones 17b-d and 21b,c were also successfully
employed to furnish the corresponding chalcones
(Scheme 5). It should be pointed out that reactions
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
involving ortho-nitroacetophenone 21 provided consist-
ently better yields in these reactions (Scheme 5).
Next operation according to the plan included the
development of a protocol for the conjugate addition of
cyanide nucleophile to the chalcones. In our initial
attempt to carry out this transformation involving ortho-
nitrochalcones 20 we stumbled upon an unexpected side
process depicted in Scheme 6. It seemed like the ortho-
nitro group in the enolate 22, formed after the conjugate
addition was not an innocent substituent. Instead, it could
participate in an unusual intramolecular cyclization,
mechanistically related to the Baeyer-Drewson reaction,
and providing 3-oxo-3H-indole N-oxide 23, quickly
transforming into the thermodynamically more stable 1-
hydroxy-2-methyleneindolin-3-one form 24. The latter
Scheme 6
underwent spontaneous reductive transformation into
(E)-2-(3-oxoindolin-2-ylidene)-2-arylacetonitrile
25,
which was the only isolable product in this reaction, when
carried out in aqueous methanol in the presence of acetic
R3
O
O
R1
R1
R3
KCN/AcOH
DMSO
CN
R2
R2
NO2
NO2
Procedure 2
20
19
1
2
3
1
2
3
1
2
3
4
) 19aa, 20aa: R = R = H; R = Ph, 96%
9) 19ai, 20ai: R = R = H; R = 2-FC H , 99%;
6 4
10) 19aj, 20aj: R = R = H; R = 4-FC H , 74%;
6 4
11) 19ak, 20ak: R = R = H; R = 4-Me NC H , 48%;
2 6 4
12) 19al, 20al: R = R = H; R = 2-MeOC H , 98%;
6 4
13) 19am, 20am: R = R = H; R = 4-MeOC H , 76%;
6 4
14) 19an, 20an: R = R = H; R = 3,4-(MeO) C H , 91%;
2 6 4
15) 19ba, 20ba: R = R = OMe; R = Ph, 82%;
16) 19ca, 20ca: R R = OCH CH O; R = Ph, 81%;
2 2
1
2
3
1
2
3
) 19ab, 20ab: R = R = H; R = 2-MeC H , 66%;
6
4
1
2
3
1
2
3
) 19ac, 20ac: R = R = H; R = 4-MeC H , 85%;
6
4
1
2
3
1
2
3
) 19ad, 20ad: R = R = H; R = 4-EtC H , 72%;
6
4
1
2
3
1
2
3
5) 19ae, 20ae: R = R = H; R = 4-i-PrC H , 92%;
6
4
1
2
3
1
2
3
6
7
8
) 19af, 20af: R = R = H; R = 2-ClC H , 75%;
6
4
1
2
3
1
2
3
) 19ag, 20ag: R = R = H; R = 3-ClC H , 77%;
6
4
1
2
3
1
2
3
) 19ah, 20ah: R = R = H; R = 4-ClC H , 66%;
6
4
Scheme 7
R3
R3
O
O
R1
R1
R2
Fe/AcOH
Procedure 3
CN
CN
R2
NH2
NO2
4
19
1
2
3
1
2
3
1) 4aa, 19aa: R = R = H; R = Ph, 85%
9) 4ai, 19ai: R = R = H; R = 2-FC H , 98%;
6
4
1
2
3
1
2
3
2
3
4
5
) 4ab, 19ab: R = R = H; R = 2-MeC H , 82%;
10) 4aj, 19aj: R = R = H; R = 4-FC H , 72%;
6 4
11) 4ak, 19ak: R = R = H; R = 4-Me NC H , 94%;
2 6 4
12) 4al, 19al: R = R = H; R = 2-MeOC H , 99%;
6 4
13) 4am, 19am: R = R = H; R = 4-MeOC H , 84%;
6 4
14) 4an, 19an: R = R = H; R = 3,4-(MeO) C H , 88%;
2 6 4
15) 4ba, 19ba: R = R = OMe; R = Ph, 97%;
16) 4ca, 19ca: R R = OCH CH O; R = Ph, 95%.
2 2
6
4
1
2
3
1
2
3
) 4ac, 19ac: R = R = H; R = 4-MeC H , 88%;
6
4
1
2
3
1
2
3
) 4ad, 19ad: R = R = H; R = 4-EtC H , 93%;
6
4
1
2
3
1
2
3
) 4ae, 19ae: R = R = H; R = 4-i-PrC H , 91%;
6
4
1
2
3
1
2
3
6) 4af, 19af: R = R = H; R = 2-ClC H , 94%;
6
4
1
2
3
1
2
3
7
8
) 4ag, 19ag: R = R = H; R = 3-ClC H , 94%;
6
4
1
2
3
1
2
3
) 4ah, 19ah: R = R = H; R = 4-ClC H , 96%;
6
4
Scheme 8
4
ACS Paragon Plus Environment

Page 5 of 26
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
R3
O
O
R1
R2
R1
R3
KCN/AcOH
CN
DMSO
R2
NH2
NH2
Procedure 4
16
4
1
2
3
1
2
3
1
2
3
4
) 4aa, 16aa: R = R = H; R = Ph, 85%
9) 4ai, 16ai: R = R = H; R = 2-FC H , 91%;
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
6 4
1
2
3
1
2
3
) 4ab, 16ab: R = R = H; R = 2-MeC H , 93%;
10) 4aj, 16aj: R = R = H; R = 4-FC H , 93%;
6 4
11) 4ak, 16ak: R = R = H; R = 4-Me NC H , 78%;
2 6 4
6
4
1
2
3
1
2
3
) 4ac, 16ac: R = R = H; R = 4-MeC H , 90%;
6
4
1
2
3
1
2
3
) 4ad, 16ad: R = R = H; R = 4-EtC H , 94%;
12) 4al, 16al: R = R = H; R = 2-MeOC H , 89%;
6 4
6
4
1
2
3
1
2
3
5) 4ae, 16ae: R = R = H; R = 4-i-PrC H , 92%;
13) 4am, 16am: R = R = H; R = 4-MeOC H , 91%;
6 4
6
4
1
2
3
1
2
3
6) 4af, 16af: R = R = H; R = 2-ClC H , 87%;
14) 4an, 16an: R = R = H; R = 3,4-(MeO) C H , 86%;
2 6 4
15) 4ao, 16ao: R = R = H; R = 2-Py, 50%;
16) 4da, 16da: R = Br, R = H; R = Ph, 95%.
6
4
1
2
3
1
2
3
7
8
) 4ag, 16ag: R = R = H; R = 3-ClC H , 92%;
) 4ah, 16ah: R = R = H; R = 4-ClC H , 95%;
6
4
1
2
3
1
2
3
6
4
Scheme 9
acid. The detailed account on this unusual transformation
is disclosed in our recently published report.
substantial optimization of the reaction conditions, it was
found that below 30 C in solution DMSO in the presence
of acetic acid (see Procedure 2 in Experimental part) this
unwanted process was sufficiently suppressed, and
ketonitrile 19 could be isolated in good yields (Scheme
which made this modification impractical (entry 3). PPA
load of 2 g for 1 mmol scale reaction seems optimal, as
higher load leads to the dropped product yield (entry 4).
An attempt to charge the vessel with lower amount of
PPA resulted in incomplete reactions. It should be
pointed out that this reaction is sensitive to the acidic
medium and heavily relies on quite specific chemistry of
metaphosphoric acid. Thus, both sulfuric acid and
22
After
o
7
).
Next, we carried out reduction of aromatic nitro-
2 5 3
Eaton’s reagent (mixture of P O and MeSO H, 1:7) only
caused hydrolysis of nitrile function to provide amide
26aa (entries 5, 6).
group in keto-nitriles 19 into aniline function. To this
end, treatment with iron powder in acetic acid at room
temperature (see Procedure 3 in Experimental part)
afforded high yields of the corresponding ortho-anilines
4 (Scheme 8).
Alternatively, compounds 4 were accessed directly
from ortho-aminochalcones 16. Since side process
involving intramolecular Baeyer-Drewson nucleophilic
attack was not an issue in this case, the reaction was
Table 1. Optimization of the reaction conditions for the
designed transformation towards indoles 1
o
carried out at 50 C (see Procedure 4 in Experimental
part) to achieve faster complete conversion. Generally,
this reaction pathway provided high yields of target
products 4 (Scheme 9) and can be recommended as
method of the choice for small scale preparations,
provided that the corresponding ortho-aminoaceto-
phenone precursors 17 are available. However, for scale-
up application, the route involving more affordable and
highly crystalline nitro-derivatives seems more attractive.
With secured access to the key precursors in hand we
pursued our investigation towards the desired transform-
ation. To this end, ketonitrile 4aa was heated at 80 C in
molten polyphosphoric acid (80% PPA content, corresp-
4 2 7
onding to diphoshoric acid, H P O ) (Table 1, entry 1).
Disappointedly, no formation of indole product 1aa was
observed, instead hydrolysis of the nitrile function took
place, affording ketoamide 26aa in high yield. In PPA
#
1
Medium
PPA, 80%,
g/mmol
PPA, 87%,
2 g/mmol
PPA 87%,
g/mmol
PPA, 87%,
Temp.
80°C
Time Pdt (Yield)a
2h
26aa (92%)
1aa (70%)
1aa (72%)
1aa (67%)
26aa (86%)
2
2
3
4
5
80°C
60°C
80°C
r. t.
1.3h
6h
o
2
4h
8
H
(
g/mmol
SO , 98%,
300 mg/mmol),
2
4
0.5h
with 87% P
acid, (HPO
2
O
5
content (an equivalent of metaphosphoric
) the reaction of 4aa carried out at 80 C
proceeded smoothly to yield the desired indole 1aa in
good yield (entry 2). Slightly higher yield was obtained
AcOH
o
(200 mg/mmol)
3
)
n
6
Eaton`s reagent, 1/7, 80°C
g/mmol
a) Isolated yields are shown
3h
26aa (76%)
2
o
at 60 C, but at the expense of increased reaction time,
5
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 26
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
R3
O
R1
R3
R1
R2
PPA (87%)
CN
Me
R2
N
NH2
Procedure 5
H
NH2
O
1
4
Me
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
N
H
NH2
N
H
NH2
N
NH2
N
NH2
N
CONH2
H
H
H
O
O
O
O
1aa, 70%
1ab, 71%
1ac, 65%
1ad, 46%
1ae, 64%
Cl
F
Cl
Cl
F
N
H
NH2
N
H
CONH2
N
H
N
H
NH2
N
H
NH2
NH2
O
O
O
O
1
af, 88%
1ag, 78%
1ah, 62%
1ai, 53%
1aj, 50%
OMe
NMe2
OMe
MeO
MeO
N
NH2
N
H
NH2
N
H
NH2
H
N
NH2
O
O
O
H
O
1
al, 58%
1
am, 46%
1an, 38%
1
ak, 48%
MeO
MeO
O
O
Br
N
N
CONH2
N
N
N
CONH2
CONH2
CONH2
H
H
H
H
1
ao, 60%
1ba, 77%
1ca, 55%
1da, 52%
Scheme 10
With optimized reaction conditions in hand we
proceeded with investigation of the reaction scope and
limitations. First, reactivity of nitriles 4ab-ae derived
from alkyl substituted benzaldehydes 18b-e was tested.
These cyclizations proceeded smoothly, affording the
corresponding indoles 1ab-ae in moderate to good yields
cyclization well tolerates pyridine substituent. Thus,
amide 1ao can be furnished via this method in good yield
(entry 15). Finally, the possibility to assemble indoles
substituted at C-5 and C-6 was tested. To this end, nitrile
precursors 4ba, 4ca and 4da derived from the corresp-
onding substituted acetophenone were treated with PPA
under standard reaction conditions. Gratifyingly, these
cyclizations proceeded smoothly, affording the corresp-
onding indoles 1ba, 1ca and 1da as sole products in good
to moderate yields (Scheme 10, entries 16-18).
As was discussed above (Scheme 3) the proposed
mechanistic rationale presumes initial formation of 2-
aminofuran species 11 followed by nucleophilic attack
with ortho-amino group to furnish indole structure 1
(Scheme 11). It was reasoned, that in the absence of
aniline function, it would possible to intercept the furan
intermediate. To this end ketonitrile 27 was subjected to
the reaction in the presence of 87% PPA under standard
(
Scheme 10, entries 2-5). Next, cyclization of 4af-aj
derived from chloro- and fluorobenzaldehydes 18f-j were
examined. Indolylamides 1af-aj bearing halogenated
aryl substituents at C-2 were obtained with quite compar-
able efficiency (Scheme 10, entries 6-10). Preparation of
products bearing electron rich aryl substituent proved to
be more challenging. Reactions of dimethylamino-
(4ak), methoxy- (4al, 4am), and dimethoxy-substituted
(
4an) nitrile precursors proceeded smoothly, however,
increased solubility of the corresponding products 1ak-
an rendered isolation less efficient, which affected the
isolated yields (Scheme 10, entries 11-14). Also, the
6
ACS Paragon Plus Environment

Page 7 of 26
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
reaction conditions. Formation of furan 28 was detected
by HRMS and H NMR spectroscopy of the crude
reaction mixture. Isolation and purification of this comp-
ound, however, proved complicated, so the crude mixture
was treated with benzaldehyde to convert it into more
stable imine 29 that was isolated in 40% yield (Scheme
isomerize into acrylonitrile 31. The latter would undergo
intramolecular 5-exo-trig attack of nucleophilic aniline
function across the acrylonitrile acceptor moiety to afford
indoline 32. Subsequent elimination of polyphosphoric
acid residue and acid-assisted hydrolysis of nitrile
function would afford the final carboxamide product 1
(Scheme 12). This rationale seems quite reasonable at
the first glance, even though it requires anti-Markovnikov
protonation to produce intermediate carbocation 30. It
should be pointed out, however, that nitrile function is
typically quite stable in 87% PPA medium. In 80% PPA
hydrolysis would proceed much faster, but even then, it
would normally require heating for several hours at 100-
1
1
1). Of course, these experiments support the formation
of furan intermediate, although did not prove it. During
the revision stage one of the referees suggested an
alternative mechanistic rationale to consider, which is
depicted in Scheme 12. According to this reasoning,
starting material 4 after treatment with PPA would
provide phosphorylated enolate 8, which would
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
o
35
o
120 C.
formation of amide 1 would be sluggish, and intermediate
3 should be accumulating. However, this compound
Since our reaction is performed at 80 C,
3
was never observed in the reaction mixture. On the other
hand, unlike furan 28, which was successfully intercepted
(Scheme 11) most likely intermediate 11, originated from
substrate 4 bearing amine functionality, was also quite
elusive.
In order to gain better support of the proposed
rationale it was important to isolate aminofuran
intermediate, confirm its structure, and re-subject it to the
reaction conditions to obtain the final product 1. Since
we failed to accomplish this with substrate 4 bearing non-
protected aniline moiety, the next attempt was to employ
N-tosyl derivative. We reasoned, that sulfonamide
protection would moderate nucleophilic property of
aniline function, slowing down cyclization, and
stabilizing aminofuran structure. Furthermore, this group
can be later removed in the presence of 87% PPA,
regenerating an active form of aminofuran. To test this
idea, chalcone 16aa was subjected to the tosylation
reaction according to the standard procedure (Scheme
Scheme 11
3
6
13).
Hydrocyanation of the resulting sulfonamide 34
Scheme 13
Scheme 12
7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 26
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
compound was unambiguously confirmed by a single
crystal X-ray diffraction (CCDC #2022311, see SI for
details. Treatment of amine 38 with p-chlorobenz-
aldehyde in the presence of acetic acid triggered
cyclization into carboline, which was isolated in a form
of acetate salt 39. Subsequent acid-base extraction
afforded free base 40 (Scheme 15).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
CONCLUSION
In conclusion, an expeditious approach towards 2-
(1H-indol-2-yl)acetamides is developed. The featured
method entails a polyphosphoric acid-mediated cascade
process, consisting of cyclization of readily available -
ketonitriles into 2-aminofurans and their subsequent
recyclization. A series of variously substituted iso-
tryptamine derivatives were efficiently prepared.
Preparation of -carboline utilizing the featured synthetic
platform was also showcased.
Scheme 14
was carried out under conditions of Procedure 2 to afford
ketonitrile 35 in excellent overall yield (Scheme 13). To
ensure that removal of the sulfonyl protection takes place,
and the featured transformation proceeds smoothly
compound 35 was subjected to the reaction under
conditions of Procedure 5. Expectedly, normal product
EXPERIMENTAL PART
1
aa was formed, albeit in reduced yield (Scheme 13).
When the same reaction was quenched after 30 min, the
mixture contained furan 36 along with starting ketonitrile
General
1
H and 13C NMR spectra were recorded on a Bruker
3
5 and final indole product 1aa (Scheme 14). After
Avance-III spectrometer (400 or 100 MHz, respectively)
equipped with a BBO probe in CDCl or DMSO-d using
extraction, this crude material was treated with p-
methylbenzaldehyde in order to protect the second amine
function. The resulting imine 37 was isolated in low yield
in individual form and re-subjected to the reaction
conditions of Procedure 5 to afford the same product 1aa
3
6
TMS as an internal standard. High-resolution mass
spectra were registered with a Bruker Maxis spectrometer
(electrospray ionization, in MeCN solution, using
HCO Na−HCO H for calibration). Melting points were
2
2
(Scheme 14). Overall, we believe this investigation
measured with a Stuart smp30 apparatus. The reaction
progress and purity of isolated compounds were
controlled by TLC on Silufol UV-254 plates, with
hexanes/EtOAc mixtures used as eluents. Details on
preparation, physical and spectral data for chalcones
provides solid support on intermediacy of 2-aminofuran
structure in the featured transformation.
Lastly, in order to showcase the practicality of the
developed the synthetic methodology, a transformation
of carboxamide 1 into -carboline core was performed.
2
0aa-20ae, 20ag-20ak, 20am, and 20ba were described
To this end, amide function in 1aa was first reduced with
22
in our recent report. Syntheses of chalcones 16, 20af,
0al, 20an, 20ca, ketonitriles 4, 19 and indoles 1 are
37
LiAlH
4
according to the published procedure to provide
2
isotryptamine 38 (Scheme 15). The structure of this
described below. All other reagents and solvents were
purchased from commercial vendors and used as
received.
Preparation of chalcones
(
E)-1-(2-Nitrophenyl)-3-phenylprop-2-en-1-one
2
3
(20an), Typical Procedure 1: A stirred solution of 2'-
nitroacetophenone (21a) (1.65 g, 10.0 mmol) and 3,4-
dimethoxybenzaldehyde (18n) (1.65 g, 10.0 mmol) in
ethanol (20 mL) was treated with 10% NaOH aqueous
solution (40 mmol). The mixture was stirred at room
temperature for 12 h, while the reaction progress was
monitored by TLC. When completed, the mixture was
poured into an excessive amount of ice-cold water.
Formed solid precipitate was filtered off, dried on air, and
recrystallized from ethanol to afford the title compound
2
3
as yellow solid, mp 123.5–124.7 °C (EtOH), lit mp
1
20–122 °C, R
f
0.28 (EtOAc/hexanes, 1:2). Yield 2.848
Scheme 15
8
ACS Paragon Plus Environment

Page 9 of 26
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
1
-
g (9.1 mmol, 91%). H NMR (400 MHz, CDCl
3
) δ 8.18
128.5, 127.9, 127.5, 127.0, 124.2; FTIR (film, NaCl, cm
1
(dd, J = 8.2, 0.8 Hz, 1H), 7.81 – 7.73 (m, 1H), 7.70 – 7.60
(m, 1H), 7.50 (dd, J = 7.5, 1.2 Hz, 1H), 7.18 (d, J = 16.2
Hz, 1H), 7.06 (dd, J = 8.3, 1.7 Hz, 1H), 7.03 (d, J = 1.7
Hz, 1H), 6.89 (d, J = 16.2 Hz, 1H), 6.85 (d, J = 8.3 Hz,
H), 3.91 (s, 3H), 3.90 (s, 3H); C{ H} NMR (101 MHz,
CDCl ) δ 193.1, 152.0, 149.4, 146.9, 146.7, 136.7, 134.1,
30.6, 129.0, 127.0, 124.7, 124.4, 123.8, 111.1, 109.9,
): 3065, 1670, 1594, 1531, 1362, 1322, 1218; HRMS (ES
+
TOF m/z: (M+Na) Calcd for C15
Found 310.0238.
3
H10ClNNaO 310.0241;
(E)-1-(2-Aminophenyl)-3-phenylprop-2-en-1-one
1
3
1
25
1
(16aa): This compound was prepared according to
3
Typical Procedure 1 involving 2'-aminoacetophenone
(17a) (4.05 g, 30.0 mmol) and benzaldehyde (18a) (3.18
g, 30.0 mmol). The titled compound was obtained as
1
5
1
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
-1
6.2, 56.1; FTIR (film, NaCl, cm ): 3089, 2975, 2838,
2
5
630, 1528, 1508, 1356, 1257, 1148, 1023; HRMS (ES
orange solid, mp 65.6-67.0 °C, lit mp 71-72 °C
(MeOH), R 0.42 (EtOAc/hexanes, 1:4). Yield 4.014 g
(18 mmol, 60%). H NMR (400 MHz, CDCl
+
TOF) m/z: (M+Na) Calcd for C17
Found 336.0843.
H
15NNaO
5
336.0842;
f
1
3
) δ 7.87 (d,
((E)-3-(2-methoxyphenyl)-1-(2-nitrophenyl)prop-2-
J = 7.5 Hz, 1H), 7.75 (d, J = 15.6 Hz, 1H), 7.68 – 7.58
(m, 3H), 7.45 – 7.38 (m, 3H), 7.32 – 7.27 (m, 1H), 6.75 –
6.67 (m, 2H), 6.35 (br. s, 2H); C{ H} NMR (101 MHz,
CDCl ) δ 191.8, 151.1, 143.0, 135.4, 134.4, 131.1, 130.2,
129.0 (2C), 128.4 (2C), 123.2, 119.1, 117.4, 116.0; FTIR
2
4
en-1-one (20al):
This compound was prepared
1
3
1
according to Typical Procedure 1 involving 2'-nitroaceto-
phenone (21a) (825 mg, 5.00 mmol) and 2-methoxybenz-
aldehyde (18l) (680 mg, 5.00 mmol). The titled
compound was obtained as colorless solid, mp 80.4–82.8
3
-1
(film, NaCl, cm ): 3446, 3340, 1637, 1614, 1574, 1535,
1449, 1337, 1208, 1155, 977; HRMS (ES TOF m/z:
°
C (EtOH), R
f
0.28 (EtOAc/hexanes, 1:4). Yield 1.330 g
1
+
(
(
(
4.70 mmol, 94%). H NMR (400 MHz, CDCl
3
) δ 8.13
(M+Na) Calcd for C15
246.0892.
H13NNaO 246.0889; Found
d, J = 8.1 Hz, 1H), 7.73 (t, J = 7.2 Hz, 1H), 7.67 – 7.54
m, 2H), 7.49 (d, J = 7.6 Hz, 2H), 7.35 (t, J = 7.2 Hz, 1H),
.09 (d, J = 16.4 Hz, 1H), 6.94 (t, J = 7.5 Hz, 1H), 6.87
d, J = 8.3 Hz, 1H), 3.79 (s, 3H); C{ H} NMR (101
MHz, CDCl ) δ 193.6, 158.6, 146.9, 142.1, 136.5, 134.0,
132.5, 130.5, 129.2, 128.9, 126.7, 124.5, 122.9, 120.8,
11.3, 55.5; FTIR (film, NaCl, cm ): 3182, 1647, 1597,
571, 1535, 1498, 1281, 1244 1178; HRMS (ES TOF)
m/z: (M+Na) Calcd for C16
(E)-1-(2-Aminophenyl)-3-(o-tolyl)prop-2-en-1-one
26
7
(
(16ab): This compound was prepared according to
13
1
Typical Procedure 1 involving 2’-aminoacetophenone
(17a) (405 mg, 3.00 mmol) and 2-methylbenzaldehyde
(18b) (360 mg, 3.00 mmol). The title compound was
3
-1
1
obtained as orange crystals, mp 77.1-79.3 °C (EtOH), R
0.48 (EtOAc/hexanes, 1:4). Yield 555 mg (2.34 mmol,
f
1
+
1
H
13NNaO
4
306.0737; Found
3
78%). H NMR (400 MHz, CDCl ) δ 8.06 (d, J = 15.4
Hz, 1H), 7.96 – 7.86 (m, 1H), 7.71 (d, J = 7.6 Hz, 1H),
7.57 (d, J = 15.4 Hz, 1H), 7.38 – 7.22 (m, 4H), 6.73 (dd,
J = 7.6, 6.5 Hz, 2H), 6.38 (s, 2H), 2.51 (s, 3H); C{ H}
NMR (101 MHz, CDCl ) δ 191.8, 151.2, 140.7, 138.2
(2C), 134.4, 131.2, 131.0, 130.0, 126.5, 126.4, 124.4,
3
10.0734.
(
(
(E)-1-(2-Nitrophenyl)-3-phenylprop-2-en-1-one
20ca): This compound was prepared according to
Typical Procedure 1 employing 1-(7-nitro-2,3-dihydro-
benzo[b][1,4]dioxin-6-yl)ethan-1-one (21c) (1.115 g,
2
4
13
1
3
-1
5
.00 mmol) and benzaldehyde (18a) (530 mg, 5.00
mmol). The title compound was obtained as colorless
solid mp 110.1-111.6 °C (EtOH), R 0.13 (EtOAc/
hexanes, 1:4), R 0.44 (EtOAc/hexanes, 1:1). Yield 1.260
g (4.05 mmol, 81%). H NMR (400 MHz, CDCl
s, 1H), 7.53 – 7.44 (m, 2H), 7.40 – 7.34 (m, 3H), 7.24 (d,
J = 16.3 Hz, 1H), 7.01 – 6.86 (m, 2H), 4.43 – 4.30 (m,
H); C{ H} NMR (101 MHz, CDCl ) δ 192.6, 148.6,
3
45.7, 144.2, 140.2, 134.2, 131.0, 130.8 (2C), 129.1 (2C),
28.6, 126.7, 117.4, 114.5, 64.9, 64.4; FTIR (film, NaCl,
119.1, 117.4, 116.0, 20.0; FTIR (film, NaCl, cm ): 3433,
3320, 2938, 1743, 1638, 1571, 1244, 1162, 1046, 1016;
+
f
HRMS (ES TOF) m/z: (M+Na) Calcd for C16
260.1046; Found 260.1052.
H15NNaO
f
1
3
) δ 7.74
(E)-1-(2-Aminophenyl)-3-(p-tolyl)prop-2-en-1-one
2
7
(
(16ac): This compound was prepared according to
Typical Procedure 1 involving 2'-aminoacetophenone
(17a) (135 mg, 1.00 mmol) and 4-methylbenzaldehyde
(18c) (120 mg, 1.00 mmol). The titled compound was
1
3
1
4
1
1
28
obtained as yellow solid, mp 96.7-97.9 °C (EtOH), lit
cm-1): 3056, 2984, 1647, 1620, 1578, 1518, 1333, 1195,
mp 96-97 °C, R
f
0.44 (EtOAc/hexanes, 1:4). Yield 197
mg (0.83 mmol, 83%). H NMR (400 MHz, CDCl ) δ
+
1
1
112, 1056; HRMS (ES TOF) m/z: (M+Na) Calcd for
334.0686; Found 334.0693.
(E)-3-(2-Chlorophenyl)-1-(2-nitrophenyl)prop-2-en-
-one (20af): This compound was prepared according
to Typical Procedure 1 involving 2'-nitroacetophenone
21a) (825 mg, 5.00 mmol) and 2-chlorobenzaldehyde
18f) (700 mg, 5.00 mmol). The titled compound was
obtained as colorless solid, mp 81.7–82.4 °C (EtOH), R
.37 (EtOAc/hexanes, 1:4). Yield 1.335 g (4.65 mmol,
3%). H NMR (400 MHz, CDCl
3
C
17
H
13NNaO
5
7.88 (d, J = 7.5 Hz, 1H), 7.75 (d, J = 15.5 Hz, 1H), 7.59
(d, J = 15.5 Hz, 1H), 7.54 (d, J = 8.0 Hz, 2H), 7.32 – 7.26
(m, 1H), 7.22 (d, J = 7.9 Hz, 2H), 6.79 – 6.64 (m, 2H),
6.37 (s, 2H), 2.39 (s, 3H); C{ H} NMR (101 MHz,
CDCl ) δ 191.8, 151.0, 143.1, 140.6, 134.3, 132.5, 131.0,
129.7 (2C), 128.3 (2C), 122.1, 119.2, 117.3, 115.9, 21.6;
FTIR (film, NaCl, cm-1): 3436, 3309, 3054, 1648, 1578,
1541, 1511, 1478, 1337, 1209, 1200, 1156; HRMS (ES
2
4
1
1
3
1
(
(
3
f
0
9
1
1
+
3
) δ 8.16 (d, J = 8.1 Hz,
TOF) m/z: (M+Na) Calcd for C16
found 260.1049.
H15NNaO 260.1046;
H), 7.76 (t, J = 7.4 Hz, 1H), 7.70 – 7.56 (m, 3H), 7.51
d, J = 7.4 Hz, 1H), 7.39 – 7.18 (m, 3H), 6.94 (d, J = 16.3
Hz, 1H); C NMR (101 MHz, CDCl
141.2, 135.5, 134.8, 134.0, 131.7, 131.6, 130.7, 129.8,
(
(E)-1-(2-Aminophenyl)-3-(4-ethylphenyl)prop-2-en-
1
3
29
3
) δ 192.2, 146.4,
1-one (16ad): This compound was prepared according
to Typical Procedure 1 involving 2'-aminoacetophenone
9
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 26
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(
17a) (495 mg, 3.67 mmol) and 4-ethylbenzaldehyde
15.6 Hz, 1H), 7.85 (d, J = 7.6 Hz, 1H), 7.78 – 7.68 (m,
1H), 7.59 (d, J = 15.6 Hz, 1H), 7.46 – 7.39 (m, 1H), 7.36
– 7.27 (m, 3H), 6.76 – 6.65 (m, 2H), 6.38 (br. s, 2H);
(18d) (492 mg, 3.67 mmol). After Flash column chrom-
atography on Silica gel (eluting with EtOAc/hexanes,
2
9
13
1
1:4) the titled compound was obtained as yellow oil, lit
mp 34-36 °C (EtOH), R 0.61 (EtOAc/hexanes, 1:4).
Yield 323 mg (1.29 mmol, 35%). H NMR (400 MHz,
CDCl ) δ 7.87 (dd, J = 8.3, 1.0 Hz, 1H), 7.74 (d, J = 15.5
Hz, 1H), 7.64 – 7.52 (m, 3H), 7.35 – 7.21 (m, 3H), 6.71
dd, J = 7.7, 5.6 Hz, 2H), 6.33 (br. s, 2H), 2.69 (q, J = 7.6
3
C{ H} NMR (101 MHz, CDCl ) δ 191.5, 151.3, 138.8,
f
135.4, 134.6, 133.7, 131.2, 130.9, 130.4, 127.8, 127.1,
1
-1
125.9, 118.9, 117.5, 116.0; FTIR (film, NaCl, cm ):
3
3472, 3314, 3083, 1644, 1611, 1568, 1538, 1495, 1409,
1343, 1294, 1215, 1162, 1086; HRMS (ES TOF) m/z:
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
(
(M+Na) Calcd for C15
280.0498 (0.7 ppm).
H12ClNNaO 280.0500; Found
1
3
1
Hz, 2H), 1.26 (t, J = 7.6 Hz, 3H); C{ H} NMR (101
MHz, CDCl ) δ 191.9, 151.1, 147.0, 143.2, 134.3, 132.9,
31.1, 128.6 (2C), 128.5 (2C), 122.3, 119.3, 117.4, 116.0,
3
(E)-1-(2-Aminophenyl)-3-(3-chlorophenyl)prop-2-en-
27
1
1-one (16ag): This compound was prepared according
-1
29.0, 15.5; FTIR (film, NaCl, cm ): 3463, 3329, 2967,
1689, 1645, 1575, 1545, 1481, 1421, 1326, 1213, 1156,
1005; HRMS (ES TOF) m/z: (M+Na) Calcd for
to Typical Procedure 1 involving 2-aminoacetophenone
(17a) (135 mg, 1.00 mmol) and 3-chlorobenzaldehyde
(18g) (140 mg, 1.00 mmol). The title compound was
+
C
17
H
17NNaO 274.1202; Found 274.1204.
obtained as yellow solid, mp 95.9-98.0 °C (EtOH), R
0.53 (EtOAc/hexanes, 1:4). Yield 223 mg (0.87 mmol,
f
(E)-1-(2-Aminophenyl)-3-(4-isopropylphenyl)prop-2-
2
7
1
en-1-one (16ae):
This compound was prepared
3
87%). H NMR (400 MHz, CDCl ) δ 7.82 (d, J = 7.9 Hz,
according to Typical Procedure 1 involving 2-amino-
acetophenone (17a) (495 mg, 3.67 mmol) and 4-iso-
propylbenzaldehyde (18e) (543 mg, 3.67 mmol). After
Flash column chromatography on Silica gel (eluting with
EtOAc/hexanes, 1:4) the title compound was obtained as
1H), 7.68 – 7.51 (m, 3H), 7.45 (d, J = 6.3 Hz, 1H), 7.39
– 7.23 (m, 3H), 6.73 – 6.63 (m, 2H), 6.36 (br. s, 2H).
1
3
1
3
C{ H} NMR (101 MHz, CDCl ) δ 191.3, 151.2, 141.2,
137.2, 135.0, 134.6, 131.1, 130.2, 130.0, 127.8, 126.7,
-1
124.4, 118.9, 117.5, 116.1; FTIR (film, NaCl, cm ):
red oil, R
mmol, 71%). H NMR (400 MHz, CDCl
= 8.1 Hz, 1H), 7.72 (d, J = 15.5 Hz, 1H), 7.64 – 7.48 (m,
H), 7.33 – 7.16 (m, 3H), 6.72 – 6.60 (m, 2H), 6.23 (br.
s, 2H), 3.06 – 2.80 (m, 1H), 1.25 (d, J = 6.9 Hz, 6H).
f
0.53 (EtOAc/hexanes, 1:4). Yield 691 mg (2.60
3449, 3329, 3027, 1739, 1638, 1618, 1561, 1531, 1478,
1
+
3
): δ 7.84 (d, J
1417, 1303, 1196; HRMS (ES TOF) m/z: (M+Na) Calcd
for C15
H
12ClNNaO 280.0500; Found 280.0504.
3
(E)-1-(2-Aminophenyl)-3-(4-chlorophenyl)prop-2-en-
2
7
1-one (16ah): This compound was prepared according
to Typical Procedure 1 involving 2'-aminoacetophenone
(17a) (135 mg, 1.00 mmol) and 4-chlorobenzaldehyde
(18h) (140 mg, 1.00 mmol). The titled compound was
1
3
1
3
C{ H} NMR (101 MHz, CDCl ): δ 191.9, 151.6, 150.9,
1
1
43.2, 134.3, 133.0, 131.1, 128.5 (2C), 127.2 (2C), 122.3,
19.4, 117.5, 116.1, 34.2, 23.9 (2C). IR (film, NaCl,
-1
28
cm ): 3483, 3335, 2966, 1742, 1655, 1608, 1575, 1537,
1
Calcd for C18 19NNaO 288.1359; Found 288.1365.
Alternatively, purification can be performed via re-
crystallization of hydrochloride. To this end, a solution
of crude 16ae (530 mg, 2.00 mmol) in toluene (10 mL)
was combined with 20% HCl (5 mL). The resulting
solution was stirred at room temperature for 60 min. The
formed precipitate was filtered off and recrystallized
from EtOH. Hydrochloride was obtained as colorless
obtained as yellow solid, mp 94.7-96.1 °C, lit mp 94-95
+
514, 1480, 1330, 1209; HRMS (ES TOF) m/z: (M+Na)
°C, R
f
0.78 (EtOAc/hexanes, 1:1). Yield 208 mg (0.81
1
H
mmol, 81%). H NMR (400 MHz, CDCl ) δ 7.84 (d, J =
3
7.7 Hz, 1H), 7.68 (d, J = 15.6 Hz, 1H), 7.63 – 7.50 (m,
3H), 7.37 (d, J = 8.4 Hz, 2H), 7.32 – 7.27 (m, 1H), 6.80
1
3
1
– 6.63 (m, 2H), 6.36 (br. s, 2H); C{ H} NMR (101
MHz, CDCl ) δ 191.4, 151.2, 141.5, 136.0, 134.6, 133.9,
131.1, 129.5 (2C), 129.3 (2C), 123.6, 118.9, 117.4, 116.0;
3
-1
FTIR (film, NaCl, cm ): 3479, 3320, 3076, 1647, 1610,
1574, 1538, 1482, 1439, 1323, 1211, 1158; HRMS (ES
+
crystalline solid, m.p. 152.9-156.6 °C (EtOH). Yield 385
mg (1.28 mmol, 64%). H NMR (400 MHz, DMSO-d
δ 8.09 (d, J = 7.8 Hz, 1H), 7.86 (d, J = 15.5 Hz, 1H), 7.77
TOF) m/z: (M+Na) Calcd for C15
Found 280.0502.
H12ClNNaO 280.0500;
1
6
):
(E)-1-(2-Aminophenyl)-3-(2-fluorophenyl)prop-2-en-
23
(
(
d, J = 8.0 Hz, 2H), 7.63 (d, J = 15.5 Hz, 1H), 7.54 – 7.16
m, 6H), 6.98 (d, J = 8.2 Hz, 1H), 6.78 (t, J = 7.4 Hz, 1H),
1-one (16ai): This compound was prepared according
to Typical Procedure 1 involving 2'-aminoacetophenone
(17a) (1.35 g, 10.0 mmol) and 2-fluorobenzaldehyde
(18i) (1.24 g, 10.0 mmol). The titled compound was
1
3
1
3.00 – 2.82 (m, 1H), 1.21 (d, J = 6.9 Hz, 6H). C{ H}
NMR (101 MHz, DMSO-d ): δ 190.6, 151.1, 148.3,
42.7, 134.1, 132.6, 131.3, 128.9 (2C), 126.9 (2C), 122.4,
20.1, 118.5, 117.1, 33.4, 23.7 (2C). IR (film, NaCl,
6
2
3
1
1
obtained as orange solid, m.p. 91.0-93.2 °C (EtOH), lit
m.p. 91-93 °C (EtOH), R 0.32 (EtOAc/hexanes, 1:5).
Yield 1.976 g (8.2 mmol, 82%). H NMR (400 MHz,
CDCl ) δ 7.80 – 7.68 (m, 2H), 7.61 (d, J = 15.8 Hz, 1H),
7.50 (t, J = 7.5 Hz, 1H), 7.29 – 7.10 (m, 2H), 7.10 – 6.94
f
-1
1
cm ): 2886, 2624, 1748, 1662, 1591, 1514, 1324, 1226.
(E)-1-(2-Aminophenyl)-3-(2-chlorophenyl)prop-2-en-
3
3
0
1
-one (16af): This compound was prepared according
1
3
1
to Typical Procedure 1 involving 2'-aminoacetophenone
(m, 2H), 6.67 – 6.53 (m, 2H), 6.22 (br. s, 2H); C{ H}
NMR (101 MHz, CDCl ) δ 191.6, 161.6 (d, J = 253.8
(
(
17a) (135 mg, 1.00 mmol) and 2-chlorobenzaldehyde
18f) (168 mg, 1.20 mmol). The titled compound was
3
Hz), 151.2, 135.6 (d, J = 1.8 Hz), 134.5, 131.4 (d, J = 8.8
Hz), 131.1, 129.6 (d, J = 3.0 Hz), 125.7 (d, J = 7.0 Hz),
124.5 (d, J = 3.5 Hz), 123.4 (d, J = 11.5 Hz), 118.9, 117.4,
31
obtained as yellow solid, mp 86.2-88.3 °C, lit mp 87-89
°C, R 0.82 (EtOAc/hexanes, 1:1). Yield 203 mg (0.79
mmol, 79%). H NMR (400 MHz, CDCl
f
1
-1
3
) δ 8.12 (d, J =
116.3 (d, J = 22.0 Hz), 115.9; FTIR (film, NaCl, cm ):
10
ACS Paragon Plus Environment

Page 11 of 26
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
3
470, 3329, 3061, 1645, 1615, 1568, 1484, 1457, 1330,
(E)-1-(2-Aminophenyl)-3-(4-methoxyphenyl)prop-2-
en-1-one (16am): This compound was prepared
+
25
1213, 1159, 1009; HRMS (ES TOF) m/z: (M+Na) Calcd
12FNNaO 264.0795; Found 264.0798.
(E)-(1-(2-aminophenyl)-3-(4-fluorophenyl)prop-2-en-
for C15
H
according to Typical Procedure 1 involving 2'-amino-
acetophenone (17a) (4.05 g, 30.0 mmol) and p-anisald-
ehyde (18a) (4.08 g, 30.0 mmol). The titled compound
was obtained as orange solid, mp 90.4-92.2 °C (MeOH),
2
3
1
-one (16aj): This compound was prepared according
to Typical Procedure 1 involving 2'-aminoacetophenone
2
5
(17a) (1.35 g, 10.0 mmol) and 4-fluorobenzaldehyde
lit mp 91-92 °C (MeOH), R
Yield 6.528 g (25.8 mmol, 86%). H NMR (400 MHz,
CDCl ) δ 7.84 (d, J = 8.1 Hz, 1H), 7.70 (d, J = 15.5 Hz,
f
0.28 (EtOAc/hexanes, 1:4).
1
(18j) (1.24 g, 10.0 mmol). The titled compound was
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
3
obtained as orange solid, mp 63.3-65.7 °C (EtOH), lit
3
mp 87-90 °C, R
g (6.5 mmol, 65%). H NMR (400 MHz, CDCl
d, J = 8.1 Hz, 1H), 7.70 (d, J = 15.6 Hz, 1H), 7.66 – 7.59
f
0.42 (EtOAc/hexanes, 1:4). Yield 1.567
1H), 7.56 (d, J = 8.7 Hz, 2H), 7.48 (d, J = 15.5 Hz, 1H),
7.30 – 7.23 (m, 1H), 6.91 (d, J = 8.7 Hz, 2H), 6.70 – 6.63
1
3
) δ 7.85
13
1
(
(m, 2H), 6.25 (br. s, 2H), 3.82 (s, 3H); C{ H} NMR
(101 MHz, CDCl ) δ 191.9, 161.4, 151.0, 142.9, 134.2,
(m, 2H), 7.54 (d, J = 15.6 Hz, 1H), 7.30 (t, J = 7.7 Hz,
1H), 7.10 (t, J = 8.6 Hz, 2H), 6.76 – 6.65 (m, 2H), 6.34
3
131.0, 130.1 (2C), 128.1, 120.9, 119.4, 117.4, 116.0,
1
3
1
-1
(br.s, 2H); C{ H} NMR (101 MHz, CDCl3) δ 191.6,
63.9 (d, J = 251.1 Hz), 151.1, 141.8, 134.5, 131.7 (d, J
3.1 Hz), 131.1, 130.2 (d, J = 8.5 Hz, 2C), 123.0 (d, J =
.3 Hz), 119.1, 117.5, 116.3, 116.1 (d, J = 2.5 Hz, 2C);
114.4 (2C), 55.5; FTIR (film, NaCl, cm ): 3459, 3327,
1
=
1
2831, 1647, 1568, 1508, 1287, 1251, 1215, 1158, 1033,
+
1010; HRMS (ES TOF) m/z: (M+Na) Calcd for
C
16
H
15NNaO
2
276.0995; Found 276.0997.
-1
FTIR (film, NaCl, cm ): 3464, 3322, 3047, 1642, 1618,
565, 1508, 1411, 1344, 1213, 1159, 1005, 985, 748;
(E)-1-(2-Aminophenyl)-3-(3,4-dimethoxyphenyl)-
2
3
1
prop-2-en-1-one (16an): This compound was prepared
according to Typical Procedure 1 involving 2'-amino-
acetophenone (17a) (1.35 g, 10.0 mmol) and 3,4-
dimethoxybenzaldehyde (18n) (1.66 g, 10.0 mmol). The
titled compound was obtained as orange crystals, m.p.
+
HRMS (ES TOF) m/z: (M+Na) Calcd for C15
64.0795; Found 264.0790.
E)-1-(2-Aminophenyl)-3-(4-(dimethylamino)phen-
H12FNNaO
2
(
32
yl)prop-2-en-1-one (16ak):
prepared according to Typical Procedure 1 involving 2’-
aminoacetophenone (17a) (135 mg, 1.00 mmol) and 4-
This compound was
2
3
93.3-94.5 °C (EtOH), lit m.p 84-86 °C (EtOH), R
f
0.57
(EtOAc/ hexanes, 1:4). Yield 2.094 g (7.4 mmol, 74%).
1
(
dimethylamino)benzaldehyde (18k) (149 mg, 1.00
mmol). The title compound was obtained as orange
crystals, mp 127.4-128.2 °C (EtOH), R 0.23 (EtOAc/
hexanes, 1:4). Yield 133 mg (0.5 mmol, 50%). H NMR
400 MHz, CDCl ) δ 7.77 (d, J = 8.0 Hz, 1H), 7.64 (d, J
15.4 Hz, 1H), 7.44 (d, J = 8.8 Hz, 2H), 7.33 (d, J = 15.4
Hz, 1H), 7.22 – 7.12 (m, 1H), 6.65 – 6.56 (m, 4H), 6.20
3
H NMR (400 MHz, CDCl ) δ 7.89 (d, J = 7.5 Hz, 1H),
7.72 (d, J = 15.5 Hz, 1H), 7.50 (d, J = 15.5 Hz, 1H), 7.35
– 7.26 (m, 1H), 7.23 (dd, J = 8.2, 1.5 Hz, 1H), 7.16 (d, J
= 1.5 Hz, 1H), 6.90 (d, J = 8.3 Hz, 1H), 6.72 (dd, J = 7.6,
4.9 Hz, 2H), 6.35 (br. s, 2H), 3.97 (s, 3H), 3.94 (s, 3H);
f
1
(
=
3
1
3
1
3
C{ H} NMR (101 MHz, CDCl ) δ 191.8, 151.1, 151.0,
149.2, 143.2, 134.2, 131.0, 128.3, 122.9, 121.0, 119.3,
117.4, 115.9, 111.2, 110.0, 56.04, 56.02; FTIR (film,
13
1
(
br.s, 2H), 2.92 (s, 6H); C{ H} NMR (101 MHz,
CDCl ) δ 192.0, 151.8, 150.7, 144.1, 133.8, 130.9, 130.2
(2C), 123.1, 119.9, 118.0, 117.3, 115.9, 112.0 (2C), 40.3
-1
3
NaCl, cm ): 3466, 3347, 1743, 1644, 1574, 1244, 1152,
+
1020, 977, 845, 733; HRMS (ES TOF) m/z: (M+Na)
Calcd for C17H17NNaO 306.1101; Found 306.1091.
3
-1
(2C); FTIR (film, NaCl, cm ): 3419, 3314, 1607, 1561,
518, 1432, 1353, 1208, 1158, 1013, 977; HRMS (ES
1
(E)-1-(2-Aminophenyl)-3-(pyridin-2-yl)prop-2-en-1-
+
33
TOF) m/z: (M+Na) Calcd for C17
Found 289.1311.
H
18
N
2
NaO 289.1311;
one (16ao): This compound was prepared according to
Typical Procedure 1 involving 2'-aminoacetophenone
(17a) (378 mg, 2.80 mmol) and picolinaldehyde (18o)
(300 mg, 2.8 mmol). The titled compound was obtained
(E)-1-(2-aminophenyl)-3-(2-methoxyphenyl)prop-2-
2
7
en-1-one (16al):
This compound was prepared
3
3
according to Typical Procedure 1 involving 2-amino-
acetophenone (17a) (495 mg, 3.67 mmol) and 2-
methoxybenzaldehyde (18l) (499 mg, 3.67 mmol).
Eluent: EtOAc/ hexanes, 1:2. The title compound was
as red crystalline solid, mp 107.4-109.0 °C (EtOH), lit
mp 112-115 °C, R 0.50 (EtOAc/hexanes, 1:2). Yield 408
mg (1.82 mmol, 65%). H NMR (400 MHz, CDCl
f
1
3
) δ
8.67 (d, J = 4.1 Hz, 1H), 8.21 (d, J = 15.1 Hz, 1H), 7.97
(d, J = 7.8 Hz, 1H), 7.74 – 7.68 (m, 1H), 7.69 (d, J = 15.1
Hz, 1H), 7.44 (d, J = 7.7 Hz, 1H), 7.34 – 7.22 (m, 2H),
obtained as orange oil, R
Yield 827 mg (3.26 mmol, 89%). H NMR (400 MHz,
CDCl ) δ 8.12 (d, J = 15.7 Hz, 1H), 7.89 (d, J = 7.5 Hz,
H), 7.74 (d, J = 15.7 Hz, 1H), 7.68 – 7.56 (m, 1H), 7.40
f
0.60 (EtOAc/hexanes, 1:1).
1
1
3
1
3
6.68 (t, J = 7.9 Hz, 2H), 6.43 (br. s, 2H); C{ H} NMR
(101 MHz, CDCl ) δ 191.8, 153.6, 151.3, 150.1, 141.0,
137.0, 134.7, 131.6, 127.0, 125.2, 124.2, 119.0, 117.3,
1
–
1
3
7.32 (m, 1H), 7.30 – 7.22 (m, 1H), 6.99 (t, J = 7.5 Hz,
H), 6.92 (d, J = 8.3 Hz, 1H), 6.77 – 6.65 (m, 2H), 6.43
-1
116.0; FTIR (film, NaCl, cm ): 3389, 3249, 1739, 1645,
1
3
1
(
s, 2H), 3.88 (s, 3H); C{ H} NMR (101 MHz, CDCl
δ 192.1, 158.5, 151.0, 138.3, 134.1, 131.3, 131.0, 128.8,
24.1, 123.6, 120.6, 119.1, 117.2, 115.7, 111.1, 55.4;
3
)
1614, 1571, 1541, 1478, 1427, 1337, 1216, 1172; HRMS
+
(ES TOF) m/z: (M+H) Calcd for C14
H
13
N
2
O 225.1022;
NaO
+
1
Found 225.1023; m/z: (M+Na) Calcd for C14
247.0842; Found 247.0843.
12 2
H N
-1
FTIR (film, NaCl, cm ): 3466, 3353, 3063, 2997, 1647,
577, 1518, 1492, 1304, 1241, 1188, 1162, 1066; HRMS
1
(E)-1-(2-Amino-5-bromophenyl)-3-phenylprop-2-en-
+
27
(ES TOF) m/z: (M+Na) Calcd for C16
276.0995; Found 276.0999.
H
15NNaO
2
1-one (16da): This compound was prepared according
to Typical Procedure 1 involving 2-amino-5-bromoaceto-
11
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 26
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
phenone (17d) (212 mg, 1.00 mmol) and benzaldehyde
(18a) (106 mg, 1.00 mmol). The titled compound was
1:1. The title compound was obtained as red oil, R
f
0.27
(EtOAc/ hexame, 1:2). Yield 1.164 g (3.96 mmol, 66%).
1
obtained as colorless solid, mp 122.3-123.7 °C (EtOH),
3
H NMR (400 MHz, CDCl ) δ 8.16 (d, J = 8.2 Hz, 1H),
3
4
lit. mp 150 °C (EtOH), R
f
0.62 (EtOAc/ hexanes, 1:2),
7.86 – 7.71 (m, 1H), 7.68 – 7.60 (m, 1H), 7.47 – 7.40 (m,
1H), 7.36 (dd, J = 7.5, 1.1 Hz, 1H), 7.27 – 7.20 (m, 3H),
4.70 (dd, J = 9.4, 4.7 Hz, 1H), 3.46 (dd, J = 18.0, 9.4 Hz,
0
9
1
2
3
1
.39 (EtOAc/hexanes, 1:4). Yield 289 mg (0.96 mmol,
6%). H NMR (400 MHz, CDCl ) δ 7.94 (d, J = 2.1 Hz,
3
1
1
3
1
H), 7.76 (d, J = 15.5 Hz, 1H), 7.65 (dd, J = 6.4, 2.8 Hz,
H), 7.52 (d, J = 15.5 Hz, 1H), 7.43 (dd, J = 5.0, 1.7 Hz,
H), 7.36 (dd, J = 8.8, 2.2 Hz, 1H), 6.64 (d, J = 8.8 Hz,
1H), 3.30 (dd, J = 18.0, 4.7 Hz, 1H), 2.44 (s, 3H); C{ H}
NMR (101 MHz, CDCl ) δ 197.9, 145.4, 136.8, 135.5,
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
134.9, 132.8, 131.4, 131.2, 128.7, 127.6, 127.4, 127.1,
124.7, 120.4, 47.0, 29.0, 19.3; FTIR (film, NaCl, cm ):
1
3
1
-1
H), 6.53 (br. s, 2H); C{ H} NMR (101 MHz, CDCl
3
):
δ 190.7, 149.9, 144.1, 137.0, 135.1, 133.2, 130.6, 129.1
2C), 128.6 (2C), 122.4, 120.4, 119.2, 107.0; FTIR (film,
3386, 2924, 2244, 1713, 1528, 1350, 1244, 1046; HRMS
+
(
(ES TOF) m/z: (M+Na) Calcd for C17
H
14
N
2
NaO
3
-1
NaCl, cm ): 3349, 3322, 3040, 1641, 1564, 1531, 1461,
1199, 1156; HRMS (ES TOF) m/z: (M+Na) Calcd for
317.0897; Found 317.0899.
4-(2-Nitrophenyl)-4-oxo-2-(p-tolyl)butanenitrile
(19ac): This compound was obtained via Typical
Procedure 2 from (E)-1-(2-nitrophenyl)-3-(p-tolyl)prop-
2-en-1-one (20ac) (1.602 g, 6.00 mmol). Eluent for
preparative column chromatography: EtOAc/hexane,
+
C
15
H
12BrNNaO 323.9994; Found 323.9998.
Preparation of 4-(2-nitrophenyl)-4-oxo-2-arylbut-
anenitriles
1
:3. The title compound was obtained as red oil, R
f
0.44
(
EtOAc/ hexane, 1:2). Yield 1.499 g (5.10 mmol, 85%).
4
-(2-Nitrophenyl)-4-oxo-2-phenylbutanenitrile
1
H NMR (400 MHz, CDCl
–
7
3
) δ 8.27 – 8.05 (m, 1H), 7.81
7.68 (m, 1H), 7.68 – 7.54 (m, 1H), 7.40 – 7.22 (m, 3H),
.18 (d, J = 7.9 Hz, 2H), 4.48 (dd, J = 8.4, 5.6 Hz, 1H),
(19aa), Typical procedure 2. A 50 mL round-bottomed
flask was charged with (E)-1-(2-nitrophenyl)-3-
phenylprop-2-en-1-one (20aa) (1.457 g, 6.00 mmol),
AcOH (360 mg, 6.00 mmol), and DMSO (18 mL) The
mixture was vigorously stirred and solution of KCN (750
mg, 11.5 mmol, 1.9 equiv.) in water (1.5 mL) was added
3.50 (dd, J = 18.0, 8.5 Hz, 1H), 3.32 (dd, J = 18.0, 5.6 Hz,
1
3
1
3
1H), 2.33 (s, 3H); C{ H} NMR (101 MHz, CDCl ) δ
197.7, 145.4, 138.4, 136.5, 134.7, 131.5, 131.2, 130.0
(2C), 127.33, 127.32 (2C), 124.6, 120.3, 48.1, 31.7, 21.1;
o
dropwise, maintaining the temperature below 20 C.
-1
FTIR (film, NaCl, cm ): 2931, 2858, 2251, 1709, 1521,
Then the reaction vessel was equipped with reflux
+
o
1356, 1251, 1211; HRMS (ES TOF) m/z: (M+Na) Calcd
condenser and the mixture was stirred at 30 C for 15-20
for C17
H
14
N
2
NaO
3
317.0897; Found 317.0899.
min, while the reaction progress was monitored by TLC.
It should be pointed out, that excessive reaction time has
highly detrimental effect on the reaction yield, as the
product can decompose under the reaction condition via
2
-(4-Ethylphenyl)-4-(2-nitrophenyl)-4-oxobutane-
nitrile (19ad): This compound was obtained via Typical
Procedure 2 from (E)-3-(4-ethylphenyl)-1-(2-nitrophen-
yl)prop-2-en-1-one (20ad) (1.686 g, 6.00 mmol). Eluent
2
2
subsequent intramolecular Baeyer-Drewson reaction.
for preparative column chromatography:
hexane, 1:4. The title compound was obtained as light-
brown oil, R 0.17 (EtOAc/hexane, 1:4), 0.71 (EtOAc/
hexane, 1:1). Yield 1.331 g (4.32 mmol, 72%). H NMR
400 MHz, CDCl ) δ 8.11 (dd, J = 8.2, 0.6 Hz, 1H), 7.77
7.67 (m, 1H), 7.67 – 7.58 (m, 1H), 7.42 – 7.28 (m, 3H),
EtOAc/
The reaction mixture was diluted with water (100 mL)
and extracted with dichloromethane (4 x 25 mL).
Combined organic extracts were washed with water (4 x
25 mL) and concentrated in vacuum. Typically, the
obtained prude products were sufficiently pure to be used
in the subsequent transformation, but for analytical
purposes they could be additionally purified by prepar-
ative column chromatography on Silica gel eluting with
EtOAc/hexane, 1:1. The title compound was obtained as
f
1
(
3
–
7
3
1
.21 (d, J = 8.1 Hz, 2H), 4.49 (dd, J = 8.5, 5.5 Hz, 1H),
.51 (dd, J = 18.0, 8.6 Hz, 1H), 3.32 (dd, J = 18.0, 5.5 Hz,
H), 2.63 (q, J = 7.6 Hz, 2H), 1.21 (t, J = 7.6 Hz, 3H);
13
1
C{ H} NMR (101 MHz, CDCl
136.5, 134.7, 131.8, 131.2, 128.8 (2C), 127.4 (2C), 127.3,
24.6, 120.3, 48.1, 31.8, 28.5, 15.5; FTIR (film, NaCl,
3
) δ 197.8, 145.4, 144.8,
red oil, R
f
0.51 (EtOAc/hexane, 1:1). Yield 1.613 g (5.76
1
mmol, 96%). H NMR (400 MHz, CDCl
3
) δ 8.10 (t, J =
0.0 Hz, 1H), 7.72 (t, J = 7.1 Hz, 1H), 7.68 – 7.56 (m,
1
1
1
3
1
-1
cm ): 2967, 2242, 1710, 1522, 1340, 1250, 1210, 996;
HRMS (ES TOF) m/z: (M+Na) Calcd for C18
331.1053; Found 331.1062.
H), 7.46 – 7.28 (m, 6H), 4.52 (dd, J = 8.4, 5.6 Hz, 1H),
.52 (dd, J = 18.0, 8.5 Hz, 1H), 3.34 (dd, J = 18.0, 5.6 Hz,
+
16 2 3
H N NaO
13
1
3
H); C{ H} NMR (101 MHz, CDCl ) δ 197.7, 145.3,
(2-(4-Isopropylphenyl)-4-(2-nitrophenyl)-4-oxobut-
136.4, 134.7, 134.6, 131.2, 129.3 (2C), 128.6, 127.5 (2C),
-1
anenitrile (19ae): This compound was obtained via
Typical Procedure 2 from (E)-3-(4-isopropylphenyl)-1-
(2-nitrophenyl)prop-2-en-1-one (20ae) (1.770 g, 6.00
mmol). Eluent for preparative column chromatography:
EtOAc/ hexane, 1:3. The title compound was obtained as
127.3, 124.6, 120.1, 48.0, 32.1; FTIR (film, NaCl, cm ):
070, 2924, 2251, 1957, 1710, 1528, 1343, 997; HRMS
3
+
12 2 3
(ES TOF) m/z: (M+Na) Calcd for C16H N NaO
3
4
03.0740; Found 303.0749 (-3.0 ppm).
-(2-Nitrophenyl)-4-oxo-2-(o-tolyl)butanenitrile
red oil, R
hexane, 1:2). Yield 1.777 g (5.52 mmol, 92%). H NMR
(400 MHz, CDCl ) δ 8.10 (dd, J = 8.2, 0.6 Hz, 1H), 7.71
(td, J = 7.5, 0.9 Hz, 1H), 7.64 – 7.58 (m, 1H), 7.37 – 7.29
f
0.19 (EtOAc/hexane, 1:4), 0.48 (EtOAc/
(
19ab): This compound was obtained via Typical
Procedure 2 from (E)-1-(2-nitrophenyl)-3-(o-tolyl)prop-
-en-1-one (20ab) (1.602 g, 6.00 mmol). Eluent for
preparative column chromatography: EtOAc/hexane,
1
3
2
12
ACS Paragon Plus Environment

Page 13 of 26
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
(
m, 3H), 7.23 (d, J = 8.1 Hz, 2H), 4.49 (dd, J = 8.7, 5.4
m/z: (M+Na)+ Calcd for C16
Found 337.0347.
2 3
H11ClN NaO 337.0350;
Hz, 1H), 3.52 (dd, J = 18.0, 8.8 Hz, 1H), 3.33 (dd, J =
18.0, 5.4 Hz, 1H), 3.00 – 2.80 (m, 1H), 1.22 (d, J = 6.9
Hz, 6H); C{ H} NMR (101 MHz, CDCl
1
1
2-(2-Fluorophenyl)-4-(2-nitrophenyl)-4-oxobutane-
nitrile (19ai): This compound was obtained via Typical
Procedure 2 from (E)-3-(2-fluorophenyl)-1-(2-nitro-
phenyl)prop-2-en-1-one (20ai) (1.626 g, 6.00 mmol).
Eluent for preparative column chromatography: EtOAc/
hexane, 1:2. The title compound was obtained as red oil,
1
3
1
3
) δ 197.8,
49.3, 145.3, 136.4, 134.7, 131.8, 131.2, 127.34 (2C),
27.33 (2C), 127.31, 124.5, 120.3, 48.0, 33.7, 31.7, 23.8
-1
(2C); FTIR (film, NaCl, cm ): 2964, 2871, 2244, 1712,
1
528, 1350, 1247, 1201, 1059; HRMS (ES TOF) m/z:
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
(M+Na) Calcd for C19
H
18
N
2
Na
1
O
3
345.1210; Found
f
R 0.12 (EtOAc/hexane, 1:4), 0.62 (EtOAc/hexane, 1:1).
1
3
2
45.1216.
-(2-Chlorophenyl)-4-(2-nitrophenyl)-4-oxobutane-
Yield 1.770 g (5.94 mmol, 99%). H NMR (400 MHz,
CDCl ) δ 8.13 (d, J = 8.2 Hz, 1H), 7.75 (dd, J = 10.9, 4.1
3
nitrile (19af): This compound was obtained via Typical
Procedure 2 from (E)-3-(2-chlorophenyl)-1-(2-nitro-
phenyl)prop-2-en-1-one (20af) (1.722 g, 6.00 mmol).
Eluent for preparative column chromatography: EtOAc/
hexane, 1:2. The title compound was obtained as red oil,
R
7
1
Hz, 1H), 7.67 – 7.60 (m, 1H), 7.56 – 7.46 (m, 1H), 7.42
– 7.30 (m, 2H), 7.19 (t, J = 7.5 Hz, 1H), 7.14 – 7.06 (m,
1H), 4.72 (dd, J = 8.5, 5.4 Hz, 1H), 3.52 (dd, J = 18.1, 8.5
1
3
1
Hz, 1H), 3.39 (dd, J = 18.1, 5.4 Hz, 1H); C{ H} NMR
(101 MHz, CDCl ) δ 197.4, 160.1 (d, J = 248.4 Hz),
3
f
0.18 (EtOAc/hexane, 1:4). Yield 1.413 g (4.50 mmol,
145.4, 136.4, 134.8, 131.3, 130.8 (d, J = 8.4 Hz), 129.7
(d, J = 3.0 Hz), 127.4, 125.0 (d, J = 3.6 Hz), 124.7, 121.6
(d, J = 13.7 Hz), 119.1, 116.2 (d, J = 20.9 Hz), 46.0 (d, J
1
5%). H NMR (400 MHz, CDCl
3
) δ 8.12 (d, J = 7.9 Hz,
H), 7.79 – 7.72 (m, 1H), 7.69 – 7.58 (m, 2H), 7.46 – 7.36
-1
(m, 2H), 7.36 – 7.24 (m, 2H), 4.89 (dd, J = 8.7, 5.0 Hz,
= 1.1 Hz), 26.8 (d, J = 3.1 Hz); FTIR (film, NaCl, cm ):
1
3
1
1
H), 3.62 – 3.27 (m, 2H); C{ H} NMR (101 MHz,
) δ 197.4, 145.3, 136.3, 134.8, 132.7, 131.9, 131.3,
30.3, 130.1, 129.5, 127.8, 127.4, 124.6, 119.2, 45.8,
3070, 2985, 2246, 1714, 1531, 1344, 1241; HRMS (ES
+
CDCl
1
3
3
TOF) m/z: (M+Na) Calcd for
321.0646; Found 321.0645.
16 2 3
C H11FN NaO
-1
0.0; FTIR (film, NaCl, cm ): 3070, 2980, 2363, 2246,
2-(4-Fluorophenyl)-4-(2-nitrophenyl)-4-oxobutane-
+
1714, 1527, 1344, 1246; HRMS (ES TOF) m/z: (M+Na)
Calcd for C16 NaO 337.0350; Found 337.0353.
2-(3-Сhlorophenyl)-4-(2-nitrophenyl)-4-oxobutane-
nitrile (19aj): This compound was obtained via Typical
Procedure 2 from (E)-3-(4-fluorophenyl)-1-(2-nitro-
phenyl)prop-2-en-1-one (20aj) (1.626 g, 6.00 mmol).
Eluent for preparative column chromatography: EtOAc/
hexane, 1:1. The title compound was obtained as red oil,
H
11ClN
2
3
(
nitrile (19ag): This compound was obtained via Typical
Procedure 2 from (E)-3-(3-chlorophenyl)-1-(2-nitro-
phenyl)prop-2-en-1-one (20ag) (1.722 g, 6.00 mmol).
Eluent for preparative column chromatography: EtOAc/
hexane, 1:2. The title compound was obtained as red oil,
f
R 0.54 (EtOAc/hexane, 1:1).Yield 1.323 g (4.44 mmol,
1
3
74%). H NMR (400 MHz, CDCl ) δ 8.12 (d, J = 8.1 Hz,
1H), 7.73 (t, J = 7.3 Hz, 1H), 7.63 (t, J = 7.4 Hz, 1H),
7.40 (dd, J = 8.4, 5.1 Hz, 2H), 7.33 (d, J = 7.4 Hz, 1H),
7.06 (t, J = 8.5 Hz, 2H), 4.53 (dd, J = 7.5, 6.3 Hz, 1H),
3.50 (dd, J = 18.1, 8.0 Hz, 1H), 3.33 (dd, J = 18.1, 5.9 Hz,
R
f
0.14 (EtOAc/hexane, 1:4), R
:2). Yield 1.451 g (4.62 mmol, 77%). H NMR (400
MHz, CDCl ) δ 8.11 (d, J = 8.1 Hz, 1H), 7.74 (t, J = 7.3
f
0.46 (EtOAc/hexane,
1
1
3
1
3
1
Hz, 1H), 7.63 (t, J = 7.4 Hz, 1H), 7.41 (s, 1H), 7.36 (d, J
= 7.5 Hz, 1H), 7.34 – 7.28 (m, 3H), 4.52 (dd, J = 8.2, 5.7
Hz, 1H), 3.52 (dd, J = 18.2, 8.3 Hz, 1H), 3.33 (dd, J =
1
1
1
3
1H); C{ H} NMR (101 MHz, CDCl ) δ 197.5, 162.6 (d,
J = 248.0 Hz), 145.4, 136.3, 134.8, 131.3, 130.4 (d, J =
3.4 Hz), 129.4 (d, J = 8.3 Hz, 2C), 127.3, 124.7, 120.0,
116.3 (d, J = 21.9 Hz, 2C), 48.0, 31.4; FTIR (film, NaCl,
1
3
1
3
8.2, 5.6 Hz, 1H); C{ H} NMR (101 MHz, CDCl ) δ
-1
97.3, 145.3, 136.4, 136.2, 135.0, 134.8, 131.3, 130.7,
28.8, 127.7, 127.3, 125.8, 124.7, 119.6, 47.7, 31.6; FTIR
cm ): 3373, 3083, 2938, 2238, 1713, 1505, 1357, 1224,
+
1155; HRMS (ES TOF) m/z: (M+Na) Calcd for
C H11FN NaO 321.0646; Found 321.0648.
16 2 3
-1
(film, NaCl, cm ): 3089, 2944, 2257, 1709, 1528, 1485,
+
1
340, 1241, 1204; HRMS (ES TOF) m/z: (M+Na) Calcd
NaO 337.0350; Found 337.0350.
-(4-Chlorophenyl)-4-(2-nitrophenyl)-4-oxobutane-
2-(4-(Dimethylamino)phenyl)-4-(2-nitrophenyl)-4-
oxobutanenitrile (19ak): This compound was obtained
via Typical Procedure 2 from (E)-3-(4-(dimethylamino)-
phenyl)-1-(2-nitrophenyl)prop-2-en-1-one (20ak) (1.776
g, 6.00 mmol). Eluent for preparative column chroma-
tography: EtOAc/hexane, 1:1. The title compound was
for C16
2
H
11ClN
2
3
nitrile (19ah): This compound was obtained via Typical
Procedure 2 from (E)-3-(4-chlorophenyl)-1-(2-nitro-
phenyl)prop-2-en-1-one (20ah) (1.722 g, 6.00 mmol).
Eluent for preparative column chromatography: EtOAc/
hexane, 1:2. The title compound was obtained as red oil,
obtained as red oil, R
872 mg (2.70 mmol, 45%). H NMR (400 MHz, CDCl
f
0.44 (EtOAc/ hexane, 1:1). Yield
1
3
)
R
f
0.17 (EtOAc/hexane, 1:4). Yield 1.244 g (3.96 mmol,
6%). H NMR (400 MHz, CDCl ) δ 8.18 – 8.08 (m, 1H),
3
δ 8.14 (d, J = 7.5 Hz, 1H), 7.80 – 7.69 (m, 1H), 7.67 –
7.56 (m, 1H), 7.30 (dd, J = 7.5, 1.1 Hz, 1H), 7.25 – 7.21
(m, 2H), 6.70 (d, J = 8.5 Hz, 2H), 4.44 (dd, J = 8.3, 5.9
Hz, 1H), 3.46 (dd, J = 17.7, 8.4 Hz, 1H), 3.31 (dd, J =
1
6
7
5
.80 – 7.69 (m, 1H), 7.67 – 7.60 (m, 1H), 7.44 – 7.29 (m,
H), 4.53 (dd, J = 7.9, 6.0 Hz, 1H), 3.50 (dd, J = 18.1, 8.0
13
1
13
1
Hz, 1H), 3.32 (dd, J = 18.1, 5.9 Hz, 1H). C{ H} NMR
101 MHz, CDCl ) δ 197.4, 145.4, 136.3, 134.8, 134.6,
33.1, 131.3, 129.6 (2C), 129.0 (2C), 127.4, 124.7, 119.8,
17.7, 5.9 Hz, 1H), 2.95 (s, 6H); C{ H} NMR (101 MHz,
CDCl ) δ 198.1, 150.5, 145.5, 137.0, 134.7, 131.1, 128.3
(
1
3
3
(2C), 127.5, 124.7, 121.7, 120.8, 112.9 (2C), 48.5, 40.6,
31.5 (2C); FTIR (film, NaCl, cm ): 2905, 2244, 1713,
-1
-1
47.9, 31.5; FTIR (film, NaCl, cm ): 3103, 2938, 2864,
2244, 1716, 1528, 1495, 1409, 1343; HRMS (ES TOF)
13
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 26
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
614, 1521, 1340, 1201; HRMS (ES TOF) m/z: (M+H)+
Calcd for C18 324.1343; Found 324.1346.
4-(4,5-Dimethoxy-2-nitrophenyl)-4-oxo-2-phenylbut-
H
18
N
3
O
3
anenitrile (19ba): This compound was obtained via
Typical Procedure 2 from (E)-1-(4,5-dimethoxy-2-
nitrophenyl)-3-phenylprop-2-en-1-one (20ba) (1.878 g,
6.00 mmol). Eluent for preparative column chroma-
tography: EtOAc/hexane, 1:2. The title compound was
(2-(2-Methoxyphenyl)-4-(2-nitrophenyl)-4-oxobut-
anenitrile (19al): This compound was obtained via
Typical Procedure 2 from (E)-3-(2-methoxyphenyl)-1-
(2-nitrophenyl)prop-2-en-1-one (20al) (1.698 g, 6.00
mmol). Eluent for preparative column chromatography:
EtOAc/hexane, 1:2. The title compound was obtained as
red oil, R
obtained as light-yellow oil, R
f
0.27 (EtOAc/hexane, 1:2),
0.61 (EtOAc/hexane, 1:1). Yield 1.673 g (4.92 mmol,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
f
0.52 (EtOAc/hexane, 1:1). Yield 1.823 g (5.88
3
82%). H NMR (400 MHz, CDCl ): δ 7.59 (s, 1H), 7.41
1
mmol, 98%). H NMR (400 MHz, CDCl
3
) δ 8.10 (d, J =
.7 Hz, 1H), 7.78 – 7.69 (m, 1H), 7.67 – 7.57 (m, 1H),
.43 (dd, J = 7.5, 1.1 Hz, 1H), 7.37 (dd, J = 7.5, 0.9 Hz,
– 7.27 (m, 5H), 6.62 (s, 1H), 4.47 (dd, J = 8.5, 5.6 Hz,
1H), 3.93 (s, 3H), 3.89 (s, 3H), 3.43 (dd, J = 17.6, 8.6 Hz,
7
7
13
1
1H), 3.28 (dd, J = 17.6, 5.6 Hz, 1H); C{ H} NMR (101
MHz, CDCl ) δ = 197.9, 154.3, 149.9, 138.0, 134.6,
1H), 7.33 – 7.28 (m, 1H), 6.96 (dd, J = 11.0, 4.0 Hz, 1H),
6.90 (d, J = 8.2 Hz, 1H), 4.74 (t, J = 6.9 Hz, 1H), 3.86 (s,
3
131.2, 129.3 (2C), 128.5, 127.5 (2C), 120.3, 108.5, 106.8,
1
3
1
-1
3H), 3.45 – 3.31 (m, 2H); C{ H} NMR (101 MHz,
CDCl ) δ 198.3, 156.3, 145.5, 136.6, 134.6, 131.1, 130.0,
28.8, 127.5, 124.5, 122.3, 121.0, 120.1, 111.1, 55.6,
56.8, 56.6, 48.1, 32.5. IR (film, NaCl, cm ): 2946, 2839,
3
2248, 1708, 1574, 1514, 1468, 1330, 1277, 1223, 1176;
+
1
4
2
HRMS (ES TOF) m/z: (M+Na)
Na
Calcd for
-1
5.6, 27.6; FTIR (film, NaCl, cm ): 3076, 2937, 2845,
C
18
H
16
N
2
1
O
5
363.0951; Found 363.0958.
244, 1713, 1594, 1531, 1488, 1347 1248, 1023; HRMS
4-(7-Nitro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-4-
oxo-2-phenylbutanenitrile (19ca): This compound was
obtained via Typical Procedure 2 from (E)-1-(7-nitro-
2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-phenylprop-2-
en-1-one (20ca) (1.866 g, 6.00 mmol). Eluent for prepar-
ative column chromatography: EtOAc/hexane, 1:2. The
title compound was obtained as colorless solid, mp
+
(ES TOF) m/z: (M+Na) Calcd for C17
H
14
N
2
NaO
4
3
2
33.0846; Found 333.0849.
-(4-Methoxyphenyl)-4-(2-nitrophenyl)-4-oxobutane-
nitrile (19am): This compound was obtained via Typical
Procedure 2 from (E)-3-(4-methoxyphenyl)-1-(2-nitro-
phenyl)prop-2-en-1-one (20am) (1.790 g, 6.00 mmol).
Eluent for preparative column chromatography: EtOAc/
hexane, 1:2. The title compound was obtained as orange
f
101.1–104.2 °C, R 0.60 (EtOAc/hexane, 1:1), 0.09
(EtOAc/ hexane, 1:4). Yield 1.642 g (4.86 mmol, 81%).
1
oil, R
f
0.62 (EtOAc/hexane, 1:1). Yield 1.414 g (4.56
3
H NMR (400 MHz, CDCl ) δ 7.68 (s, 1H), 7.56 – 7.29
1
mmol, 76%). H NMR (400 MHz, CDCl
3
) δ 8.12 (d, J =
.2 Hz, 1H), 7.79 – 7.67 (m, 1H), 7.66 – 7.55 (m, 1H),
.36 – 7.28 (m, 3H), 6.89 (d, J = 8.7 Hz, 2H), 4.48 (dd, J
8.1, 6.0 Hz, 1H), 3.79 (s, 3H), 3.48 (dd, J = 17.9, 8.2
(m, 5H), 6.73 (s, 1H), 4.50 (dd, J = 8.3, 5.8 Hz, 1H), 4.45
– 4.20 (m, 4H), 3.41 (dd, J = 17.7, 8.4 Hz, 1H), 3.27 (dd,
8
7
=
1
3
1
3
J = 17.7, 5.7 Hz, 1H); C{ H} NMR (101 MHz, CDCl )
δ 197.0, 149.1, 144.6, 139.0, 134.8, 131.1, 129.4(2C),
13
1
Hz, 1H), 3.31 (dd, J = 17.9, 5.9 Hz, 1H); C{ H} NMR
101 MHz, CDCl ) δ 197.8, 159.7, 145.4, 136.6, 134.8,
31.2, 128.7 (2C), 127.4, 126.5, 124.7, 120.4, 114.7 (2C),
128.7, 127.6(2C), 120.3, 116.1, 114.6, 64.9, 64.4, 48.4,
-1
(
1
3
32.4; FTIR (film, NaCl, cm ): 3076, 2957, 2244, 1713,
1581, 1525, 1333, 1300, 1267, 1063; HRMS (ES TOF)
-1
+
55.4, 48.2, 31.4; FTIR (film, NaCl, cm ): 2997, 2238,
1767, 1716, 1528, 1508, 1347, 1241, 1182, 1030; HRMS
m/z: (M+Na) Calcd for C18
361.0805.
14 2 5
H N NaO 361.0795; Found
+
(ES TOF) m/z: (M+Na) Calcd for C17
H
14
N
2
NaO
4
3
2
33.0846; Found 333.0849.
-(3,4-Dimethoxyphenyl)-4-(2-nitrophenyl)-4-
Preparation of 4-(2-aminophenyl)-4-oxo-2-arylbut-
anenitriles
oxobutanenitrile (19an): This compound was obtained
via Typical Procedure 2 from (E)-3-(3,4-dimethoxy-
phenyl)-1-(2-nitrophenyl)prop-2-en-1-one (20an) (1.878
g, 6.00 mmol). Eluent for preparative column chroma-
tography: EtOAc/ hexane, 1:2. The title compound was
4
-(2-Aminophenyl)-4-oxo-2-phenylbutanenitrile
(4aa), Typical procedure 3. A 50 mL round-bottomed
flask was charged with 4-(2-nitrophenyl)-4-oxo-2-
phenylbutanenitrile (19aa) (1.680 g, 6.00 mmol), iron
powder (3.30 g, 59 mmol), AcOH (12 mL), water (16
mL), and EtOAc (4 mL). The mixture was stirred under
reflux for 1-3 h, while the reaction progress was
monitored by TLC. After completion of the reaction, the
mixture was neutralized with sodium bicarbonate and the
formed precipitate was filtered off. The filter cake was
washed with EtOAc (3 × 25 mL). The organic phase of
the combined filtrates was separated and the aqueous
layer was extracted with EtOAc (3 × 25 mL). Combined
obtained as colorless solid, mp 112.7-114.1 °C, R
f
0.58
(
EtOAc/ hexane, 1:1). Yield 1.856 g (5.46 mmol, 91%).
1
H NMR (400 MHz, CDCl
.72 (t, J = 7.3 Hz, 1H), 7.62 (t, J = 7.5 Hz, 1H), 7.31 (d,
J = 7.3 Hz, 1H), 6.95 (dd, J = 8.2, 1.5 Hz, 1H), 6.89 (d, J
1.5 Hz, 1H), 6.84 (d, J = 8.2 Hz, 1H), 4.49 (dd, J = 7.7,
.1 Hz, 1H), 3.88 (s, 3H), 3.86 (s, 3H), 3.49 (dd, J = 17.9,
3
) δ 8.13 (d, J = 8.1 Hz, 1H),
7
=
6
8
1
3
1
.2 Hz, 1H), 3.33 (dd, J = 17.9, 5.7 Hz, 1H); C{ H}
) δ 197.8, 149.5, 149.2, 145.4,
36.6, 134.8, 131.2, 127.4, 126.9, 124.7, 120.4, 119.8,
11.6, 110.5, 56.1, 56.0, 48.3, 31.8; FTIR (film, NaCl,
NMR (101 MHz, CDCl
1
1
3
2 4
organic extracts were dried with anhydrous Na SO and
-1
concentrated under reduced pressure. The residue was
purified by column chromatography eluting with
EtOAc/hexane, 1:4. Yield 1.275 g (5.10 mmol, 85%).
cm ): 2990, 2244, 1736, 1521, 1350, 1244, 1145, 1026;
HRMS (ES TOF) m/z: (M+Na) Calcd for C18
363.0951; Found 363.0949.
+
H
16
N
2
NaO
5
14
ACS Paragon Plus Environment

Page 15 of 26
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Typical procedure 4. A 50 mL round-bottomed flask
employing (E)-1-(2-aminophenyl)-3-(p-tolyl)prop-2-en-
1-one (16ac) (1.422 g, 6 mmol) in a yield of 1.426 g (5.40
mmol, 90%). Eluent for preparative column chromato-
was charged with (E)-1-(2-aminophenyl)-3-phenylprop-
2-en-1-one (16aa) (1.338 g, 6.00 mmol), acetic acid (360
mg, 6.0 mmol), and DMSO (18 mL). The mixture was
vigorously stirred and solution of KCN (750 mg, 11.5
mmol, 1.9 equiv.) in water (1.5 mL) was added dropwise.
Then the reaction vessel was equipped with reflux
graphy: EtOAc/hexane, 1:4. The title compound was
1
obtained as red oil, R
NMR (400 MHz, CDCl
f
0.69 (EtOAc/hexane, 1:2). H
3
) δ 7.57 (d, J = 8.0 Hz, 1H), 7.31
(d, J = 7.8 Hz, 2H), 7.26 (t, J = 7.7 Hz, 1H), 7.20 (d, J =
7.7 Hz, 2H), 6.65 (d, J = 8.2 Hz, 1H), 6.60 (t, J = 7.5 Hz,
1H), 6.34 (s, 2H), 4.48 (dd, J = 8.2, 5.7 Hz, 1H), 3.66 (dd,
J = 17.6, 8.6 Hz, 1H), 3.43 (dd, J = 17.6, 5.5 Hz, 1H),
o
condenser and the mixture was stirred at 50 C for 1 h,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
while the reaction progress was monitored by TLC.
Upon complete conversion the mixture was diluted with
water (100 mL) and extracted with dichloromethane (4 x
13
1
3
2.35 (s, 3H); C{ H} NMR (101 MHz, CDCl ) δ 196.3,
2
5 mL). Combined organic extracts were washed with
150.7, 138.2, 135.0, 132.5, 130.5, 129.9 (2C), 127.4 (2C),
121.3, 117.6, 116.7, 115.9, 44.9, 31.8, 21.1; FTIR (film,
water (4 x 25 mL) and concentrated in vacuum.
Typically, the obtained prude products were sufficiently
pure to be used in the subsequent transformation, but foe
analytical purposes they could be additionally purified by
preparative column chromatography on Silica gel eluting
with EtOAc/hexane, 1:4. Yield 1.380 g (5.52 mmol,
-1
NaCl, cm ): 3485, 3340, 3003, 2924, 2244, 1729,1650,
1577, 1551, 1511, 1449, 1248, 1218, 1155; HRMS (ES
+
TOF) m/z: (M+Na) Calcd for C17
Found 287.1151.
16 2
H N NaO 287.1155;
4-(2-Aminophenyl)-2-(4-ethylphenyl)-4-oxobutane-
nitrile (4ad): This compound was prepared via Typical
9
2%). The title compound was obtained as pale brown
1
oil, R
CDCl
f
0.59 (EtOAc/hexane, 1:4). H NMR (400 MHz,
Procedure
3
employing
2-(4-ethylphenyl)-4-(2-
3
) δ 7.53 (d, J = 8.0 Hz, 1H), 7.47 – 7.30 (m, 5H),
nitrophenyl)-4-oxobutanenitrile (19ad) (1.848 g, 6.00
mmol) or via Typical Procedure 4 employing (E)-1-(2-
aminophenyl)-3-(4-ethylphenyl)prop-2-en-1-one (16ad)
7
7
.28 – 7.18 (m, 1H), 6.64 (d, J = 8.3 Hz, 1H), 6.59 (t, J =
.5 Hz, 1H), 6.37 (s, 2H), 4.50 (dd, J = 8.6, 5.5 Hz, 1H),
3.65 (dd, J = 17.6, 8.7 Hz, 1H), 3.42 (dd, J = 17.6, 5.4 Hz,
(1.506 g, 6.00 mmol). Yields 1.551 g (5.58 mmol, 93%)
1
3
1
1H); C{ H} NMR (101 MHz, CDCl
3
) δ 196.0, 150.6,
and 1.568 g (5.64 mmol, 94%), respectively. The title
135.4, 134.8, 130.4, 129.1 (2C), 128.1, 127.4 (2C), 121.1,
compound was obtained as colorless crystals, mp 101.7-
-1
1
3
1
17.4, 116.4, 115.6, 44.6, 31.9; FTIR (film, NaCl, cm ):
472, 3353, 3037, 2244, 1644, 1611, 1584, 1548, 1241,
1
102.7 °C, R
CDCl
2H), 7.18 – 7.08 (m, 3H), 6.54 (d, J = 8.3 Hz, 1H), 6.52
6.46 (m, 1H), 6.23 (s, 2H), 4.38 (dd, J = 8.5, 5.6 Hz,
f
0.32 (EtOAc/Hex, 1:4). H NMR (400 MHz,
3
) δ 7.46 (d, J = 8.0 Hz, 1H), 7.23 (d, J = 8.1 Hz,
+
205, 1162; HRMS (ES TOF) m/z: (M+Na) Calcd for
C
16
H
14
N
2
NaO 273.0998; Found 273.0983.
-(2-Aminophenyl)-4-oxo-2-(o-tolyl)butanenitrile
4ab): This compound was prepared via Typical
–
4
1H), 3.56 (dd, J = 17.6, 8.6 Hz, 1H), 3.33 (dd, J = 17.6,
5.5 Hz, 1H), 2.55 (q, J = 7.6 Hz, 2H), 1.13 (t, J = 7.6 Hz,
(
1
3
1
Procedure A employing 4-(2-nitrophenyl)-4-oxo-2-(o-
tolyl)butanenitrile (19ab) (1.764 g, 6.00 mmol) or via
Typical Procedure 4 employing (E)-1-(2-aminophenyl)-
3
3H); C{ H} NMR (101 MHz, CDCl ) δ 196.3, 150.7,
144.5, 135.0, 132.7, 130.5, 128.7 (2C), 127.5 (2C), 121.3,
117.6, 116.7, 115.9, 44.9, 31.8, 28.5, 15.5; FTIR (film,
-1
3
-(o-tolyl)prop-2-en-1-one (16ab) (1.422 g, 6.00 mmol).
NaCl, cm ): 3472, 3343, 2967, 2237, 1639, 1545, 1161;
+
Yield 1.299 g (4.92 mmol, 82%) and 1.473 g (5.58 mmol,
93%), respectively. Eluent for preparative column
chromatography: EtOAc/hexane, 1:3. The title comp-
HRMS (ES TOF) m/z: (M+Na) Calcd for C18
H
18
N
2
NaO
301.1311; Found 301.1316.
4
-(2-Aminophenyl)-2-(4-isopropylphenyl)-4-oxo-
ound was obtained as brown oil, R
f
0.35 (EtOAc/hexane,
:4). H NMR (400 MHz, DMSO-d ) δ 7.79 (d, J = 7.9
Hz, 1H), 7.55 (d, J = 5.8 Hz, 1H), 7.36 – 7.19 (m, 6H),
.81 (d, J = 8.3 Hz, 1H), 6.53 (t, J = 7.4 Hz, 1H), 4.63
dd, J = 9.3, 5.0 Hz, 1H), 3.86 (dd, J = 17.9, 9.4 Hz, 1H),
butanenitrile (4ae): This compound was prepared via
Typical Procedure 3 employing 2-(4-isopropylphenyl)-4-
(2-nitrophenyl)-4-oxobutanenitrile (19ae) (1.932 g, 6.00
mmol) or via Typical Procedure 4 employing (E)-1-(2-
aminophenyl)-3-(4-isopropylphenyl)prop-2-en-1-one
1
1
6
6
(
3
1
3
1
.58 (dd, J = 17.9, 5.0 Hz, 1H), 2.40 (s, 3H); C{ H}
) δ 197.1, 151.4, 135.6,
34.6, 134.1, 131.4, 130.8, 128.0, 127.6, 126.6, 121.6,
17.0, 115.7, 114.5, 41.9, 28.3, 18.8; IR (film, NaCl,
(
9
16ae) (1.590 g, 6.00 mmol). Yields 1.594 g (5.46 mmol,
1%) and 1.612 g (5.52 mmol, 92%), respectively. Eluent
for preparative column chromatography: EtOAc/hexane,
:4. The title compound was obtained as reddish
NMR (101 MHz, DMSO-d
6
1
1
1
-1
cm ): 3479, 3347, 2984, 2238, 1736, 1644, 1614, 1581,
crystalline solid, mp 108.5-110.6 °C, R
f
0.64 (EtOAc/
) δ 7.59 (d, J =
1558, 1485, 1459, 1244, 1162, 1043; HRMS (ES TOF)
1
hexane, 1:2). H NMR (400 MHz, CDCl
3
+
m/z: (M+Na) Calcd for C17
H
16
N
2
O 287.1155; Found
8
.1 Hz, 1H), 7.35 (d, J = 8.1 Hz, 2H), 7.30 – 7.22 (m, 3H),
2
87.1164.
6.68 (d, J = 8.2 Hz, 1H), 6.62 (t, J = 7.6 Hz, 1H), 6.39 (s,
2H), 4.50 (dd, J = 8.5, 5.5 Hz, 1H), 3.69 (dd, J = 17.6, 8.6
Hz, 1H), 3.45 (dd, J = 17.6, 5.5 Hz, 1H), 3.04 – 2.80 (m,
4-(2-Aminophenyl)-4-oxo-2-(p-tolyl)butanenitrile
(4ac): This compound was prepared via Typical
Procedure 3 employing 4-(2-nitrophenyl)-4-oxo-2-(p-
tolyl)butanenitrile (19ac) (1.794 g, 6.00 mmol) in a yield
of 1.394 g (5.28 mmol, 88%). Alternatively, the same
compound was obtained via Typical Procedure 4
1
3
1
1H), 1.25 (d, J = 6.9 Hz, 6H); C{ H} NMR (101 MHz,
CDCl ) δ 196.4, 150.6, 149.2, 135.1, 132.9, 130.6, 127.6
(2C), 127.4 (2C), 121.3, 117.7, 117.0, 116.2, 45.1, 33.9,
3
-1
31.8, 24.0 (2C); FTIR (film, NaCl, cm ): 3478, 3353,
15
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 26
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
970, 2237, 1735, 1650, 1584, 1554, 1445, 1247, 1027,
J = 8.0 Hz, 1H), 7.56 (d, J = 8.5 Hz, 2H), 7.47 (d, J = 8.5
+
1161; HRMS (ES TOF) m/z: (M+Na) Calcd for
C
Hz, 2H), 7.35 – 7.16 (m, 3H), 6.78 (d, J = 8.3 Hz, 1H),
6.52 (t, J = 7.2 Hz, 1H), 4.61 (dd, J = 8.9, 5.2 Hz, 1H),
3.89 (dd, J = 17.9, 9.0 Hz, 1H), 3.61 (dd, J = 17.9, 5.3 Hz,
+
19
H
20
N
2
NaO (M+Na) 315.1468; Found 315.1471.
4
-(2-Aminophenyl)-2-(2-chlorophenyl)-4-oxo-
1
3
1
1
1
1
6
H); C{ H} NMR (101 MHz, DMSO-d ) δ 196.9,
butanenitrile (4af): This compound was prepared via
Typical Procedure 3 employing 2-(2-chlorophenyl)-4-(2-
nitrophenyl)-4-oxobutanenitrile (19af) (1.884 g, 6.00
mmol) or via Typical Procedure 4 employing (E)-1-(2-
aminophenyl)-3-(2-chlorophenyl)prop-2-en-1-one (16af)
51.3, 135.1, 134.6, 132.6, 131.3, 129.8 (2C), 128.8 (2C),
21.4, 117.0, 115.6, 114.5, 42.9, 30.8; FTIR (film, NaCl,
cm ): 3479, 3360, 3076, 2931, 2244, 1729, 1650, 1614,
584, 1548, 1492, 1452, 1413, 1370, 1248, 1208, 1164;
-1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
+
HRMS (ES TOF) m/z: (M+Na)
NaO 307.0609; Found 307.0604.
4-(2-Aminophenyl)-2-(2-fluorophenyl)-4-oxobut-
Calcd for
(1.542 g, 6.00 mmol). Yields 1.602 g (5.64 mmol, 94%)
C
16
H
11ClN
2
3
and 1.480 g (5.22 mmol, 87%), respectively. Eluent for
preparative column chromatography: EtOAc/Hex, 1:4.
The title compound was obtained as red oil, R
f
0.44
) δ 7.68
dd, J = 7.4, 1.6 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.44
anenitrile (4ai): This compound was prepared via
Typical Procedure 3 employing 2-(2-fluorophenyl)-4-(2-
nitrophenyl)-4-oxobutanenitrile (19ai) (1.788 g, 6.00
mmol) or via typical procedure 4 employing (E)-1-(2-
aminophenyl)-3-(2-fluorophenyl)prop-2-en-1-one (16ai)
(1.446 g, 6.00 mmol). Yields 1.576 g (5.88 mmol, 98%)
and 1.463 g (5.46 mmol, 91%), respectively. The title
1
(
(
EtOAc/hexane, 1:4). H NMR (400 MHz, CDCl
3
(dd, J = 7.6, 1.4 Hz, 1H), 7.40 – 7.31 (m, 2H), 7.28 (t, J
= 7.7 Hz, 1H), 6.68 (d, J = 8.3 Hz, 1H), 6.61 (t, J = 7.5
Hz, 1H), 6.38 (br. s, 2H), 4.90 (dd, J = 9.7, 4.2 Hz, 1H),
3
1
1
1
.64 (dd, J = 17.6, 9.8 Hz, 1H), 3.49 (dd, J = 17.6, 4.3 Hz,
H); C{ H} NMR (101 MHz, CDCl
35.1, 132.9, 132.7, 130.5, 130.3, 129.8, 129.4, 127.8,
20.2, 117.6, 116.5, 115.9, 42.8, 30.2; FTIR (film, NaCl,
1
3
1
3
) δ 195.9, 150.8,
f
compound was obtained as brown oil, R 0.34 (EtOAc/
1
hexane, 1:4), 0.71 (EtOAc/hexane, 1:1). H NMR (400
MHz, CDCl ) δ 7.47 – 7.40 (m, 2H), 7.24 (dd, J = 13.2,
3
-1
cm ): 3485, 3360, 2982, 2931, 2251, 1644, 1611, 1578,
551, 1479, 1452, 1363, 1248, 1224, 1162; HRMS (ES
6.3 Hz, 1H), 7.17 – 7.12 (m, 1H), 7.09 (t, J = 7.4 Hz, 1H),
7.04 – 6.96 (m, 1H), 6.55 (d, J = 8.3 Hz, 1H), 6.49 (t, J =
7.5 Hz, 1H), 6.26 (br. s, 2H), 4.60 (dd, J = 9.0, 4.9 Hz,
1H), 3.57 (dd, J = 17.6, 9.1 Hz, 1H), 3.36 (dd, J = 17.6,
1
+
TOF) m/z: (M+Na) Calcd for
07.0609; Found 307.0601.
-(2-Aminophenyl)-2-(3-chlorophenyl)-4-oxobut-
16 2
C H13ClN NaO
3
1
3
1
3
5.0 Hz, 1H); C{ H} NMR (101 MHz, CDCl ) δ 195.8,
4
159.8 (d, J = 248.0 Hz), 150.6, 134.9, 130.34, 130.25 (d,
J = 8.3 Hz), 129.4 (d, J = 3.0 Hz), 124.8 (d, J = 3.6 Hz),
anenitrile (4ag): This compound was prepared via
Typical Procedure 3 employing 2-(3-chlorophenyl)-4-(2-
nitrophenyl)-4-oxobutanenitrile (19ag) (1.884 g, 6.00
mmol) or via Typical Procedure 4 employing (E)-1-(2-
aminophenyl)-3-(3-chlorophenyl)prop-2-en-1-one
1
2
22.4 (d, J = 13.8 Hz), 120.0, 117.4, 116.3, 115.9 (d, J =
1.1 Hz), 115.7, 42.6, 26.7 (d, J = 3.0 Hz); FTIR (film,
-1
NaCl, cm ): 3479, 3360, 2251, 1614, 1492, 1241, 1158;
+
HRMS (ES TOF) m/z: (M+Na)
NaO 291.0904; Found 291.0900.
4-(2-Aminophenyl)-2-(4-fluorophenyl)-4-oxobut-
Calcd for
(
9
16ag) (1.542 g, 6.00 mmol). Yields 1.601 g (5.64 mmol,
4%) and 1.568 g (5.52 mmol, 92%), respectively. Eluent
for preparative column chromatography: EtOAc/hexane,
:4. The title compound was obtained as colorless solid,
16 2
C H13FN
1
anenitrile (4aj): This compound was prepared via
Typical Procedure 3 employing 2-(4-fluorophenyl)-4-(2-
nitrophenyl)-4-oxobutanenitrile (19aj) (1.788 g, 6.00
mmol) or via Typical Procedure B employing (E)-1-(2-
aminophenyl)-3-(4-fluorophenyl)prop-2-en-1-one (16aj)
(1.446 g, 6.00 mmol). Yields 1.158 g (4.32 mmol, 72%)
and 1.495 g (5.58 mmol, 93%), respectively. Eluent for
preparative column chromatography: EtOAc/hexane,
1
mp 157.0-159.4 °C, R
400 MHz, CDCl ) δ 7.55 (d, J = 7.7 Hz, 1H), 7.43 (s,
H), 7.35 – 7.30 (m, 3H), 7.27 (dd, J = 11.3, 4.0 Hz, 1H),
.65 (d, J = 8.3 Hz, 1H), 6.60 (t, J = 7.6 Hz, 1H), 6.30 (s,
f
0.59 (EtOAc/Hex, 1:2). H NMR
(
1
6
3
2H), 4.48 (dd, J = 8.2, 5.7 Hz, 1H), 3.66 (dd, J = 17.7, 8.4
1
3
1
Hz, 1H), 3.44 (dd, J = 17.7, 5.7 Hz, 1H); C{ H} NMR
(101 MHz, CDCl ) δ 195.6, 150.6, 137.4, 135.1, 134.9,
30.5, 130.4, 128.5, 127.7, 125.8, 120.5, 117.5, 116.4,
3
1
1
3
1
1:4. The title compound was obtained as light-brown
-1
1
15.8, 44.4, 31.6; FTIR (film, NaCl, cm ): 3472, 3333,
069, 2264, 1636, 1624, 1551, 1485, 1455, 1343, 1244,
207; HRMS (ES TOF) m/z: (M+Na) Calcd for
solid, mp 100.4-102.3 °C, R
NMR (400 MHz, CDCl
f
0.48 (EtOAc/Hex, 1:4). H
3
) δ 7.56 (dd, J = 8.1, 0.8 Hz, 1H),
+
7.45 – 7.33 (m, 2H), 7.29 – 7.22 (m, 1H), 7.12 – 6.99 (m,
2H), 6.65 (d, J = 8.3 Hz, 1H), 6.63 – 6.57 (m, 1H), 6.19
C
16
H
13ClN
2
NaO 307.0609; Found 307.0611.
(br. s, 2H), 4.50 (dd, J = 7.8, 6.2 Hz, 1H), 3.66 (dd, J =
4
-(2-Aminophenyl)-2-(2-chlorophenyl)-4-oxobut-
1
7.6, 8.1 Hz, 1H), 3.44 (dd, J = 17.6, 6.0 Hz, 1H);
C{ H} NMR (101 MHz, CDCl ) δ 195.9, 162.5 (d, J =
3
anenitrile (4ah): This compound was prepared via
Typical Procedure 3 employing 2-(4-chlorophenyl)-4-(2-
nitrophenyl)-4-oxobutanenitrile (19ah) (1.884 g, 6.00
mmol) or via Typical Procedure 4 employing (E)-1-(2-
aminophenyl)-3-(4-chlorophenyl)prop-2-en-1-one
(16ah) (1.542 g, 6.00 mmol). Yields 1.636 g (5.76 mmol,
96%) and 1.619 g (5.7 mmol, 95%), respectively. The
title compound was obtained as red oil, R
13
1
247.6 Hz), 150.7, 135.2, 131.4 (d, J = 3.2 Hz), 130.5,
129.4 (d, J = 8.4 Hz, 2C), 121.0, 117.7, 116.7, 116.4,
116.1 (d, J = 7.7 Hz, 2C), 44.8, 31.5; FTIR (film, NaCl,
-1
cm ): 3386, 2984, 2918, 2255, 1720, 1650, 1508, 1403,
350, 1228, 1158, 1092, 1046; HRMS (ES TOF) m/z:
1
+
2
(M+Na) Calcd for C16H13FN NaO 291.0904; Found
f
0.30 (EtOAc/
6
1
291.0915.
hexane, 1:4). H NMR (400 MHz, DMSO-d ) δ 7.74 (d,
16
ACS Paragon Plus Environment

Page 17 of 26
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
4
-(2-Aminophenyl)-2-(4-(dimethylamino)phenyl)-
6.66 (d, J = 8.3 Hz, 1H), 6.60 (t, J = 7.5 Hz, 1H), 6.44 (s,
2H), 4.46 (dd, J = 8.3, 5.7 Hz, 1H), 3.80 (s, 3H), 3.65 (dd,
J = 17.6, 8.5 Hz, 1H), 3.43 (dd, J = 17.6, 5.7 Hz, 1H);
4-oxobutanenitrile (4ak): This compound was prepared
via Typical Procedure 3 employing 2-(4-(dimethylam-
ino)phenyl)-4-(2-nitrophenyl)-4-oxobutanenitrile (19ak)
1.938 g, 6.00 mmol) or via Typical Procedure B
employing (E)-1-(2-aminophenyl)-3-(4-(dimethylam-
1
3
1
3
C{ H} NMR (101 MHz, CDCl ) δ 196.2, 159.3, 150.6,
(
134.9, 130.4, 128.6 (2C), 127.3, 121.3, 117.4, 116.5,
-
115.7, 114.5 (2C), 55.3, 44.7, 31.2; IR (film, NaCl, cm
1
ino)phenyl)prop-2-en-1-one (16ak) (1.596 g, 6.00
mmol). Yields 1.652 g (5.64 mmol, 94%) and 1.371 g
): 3466, 3340, 2251, 1733, 1644, 1611, 1574, 1545,
+
1512, 1254, 1165, 1030; HRMS (ES TOF) m/z: (M+Na)
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
4.68 mmol, 78%), respectively. The title compound was
obtained as dark brown oil, R 0.18 (EtOAc/Hex, 1:4),
.64 (EtOAc/Hex, 1:1). H NMR (400 MHz, CDCl ) δ
.59 (d, J = 7.7 Hz, 1H), 7.32 – 7.21 (m, 3H), 6.76 – 6.68
(m, 2H), 6.65 (d, J = 8.4 Hz, 1H), 6.61 (t, J = 7.6 Hz, 1H),
6.30 (br.s, 2H), 4.42 (dd, J = 8.5, 5.7 Hz, 1H), 3.65 (dd, J
= 17.5, 8.6 Hz, 1H), 3.42 (dd, J = 17.5, 5.6 Hz, 1H), 2.95
Calcd for C17
-(2-Aminophenyl)-4-oxo-2-phenylbutanenitrile
4an): This compound was prepared via Typical
16 2 2
H N NaO 303.1104; Found 303.1103.
f
4
1
0
7
3
(
Procedure A employing 2-(3,4-dimethoxyphenyl)-4-(2-
nitrophenyl)-4-oxobutanenitrile (19an) (2.040 g, 6.00
mmol) or via Typical Procedure B employing (E)-1-(2-
aminophenyl)-3-(3,4-dimethoxyphenyl)prop-2-en-1-one
(16an) (1.698 g, 6.00 mmol). Yields 1.637 g (5.28 mmol,
88%) and 1.600 g (5.16 mmol, 86%), respectively. Eluent
for preparative column chromatography: EtOAc/hexane,
1
3
1
(
1
1
(
1
s, 6H); C{ H} NMR (101 MHz, CDCl
3
) δ 196.8, 150.7,
50.4, 135.0, 130.6, 128.3 (2C), 122.7, 121.7, 117.6,
17.0, 116.0, 112.9 (2C), 45.2, 40.6 (2C), 31.3; FTIR
-1
film, NaCl, cm ): 3472, 3353, 2931, 2244, 1614, 1521,
1
:4. The title compound was obtained as yellow
crystalline solid, m.p. 133.3-135.7°C, R 0.25 (EtOAc/
) δ 7.61 (dd, J =
+
356, 1165; HRMS (ES TOF) m/z: (M+Na) Calcd for
NaO 316.1420; Found 316.1418.
-(2-Aminophenyl)-2-(2-methoxyphenyl)-4-oxobut-
f
C
18
H
19
N
3
1
hexane, 1:4). H NMR (400 MHz, CDCl
3
4
8.2, 0.9 Hz, 1H), 7.33 – 7.27 (m, 1H), 6.98 (dd, J = 8.2,
2.0 Hz, 1H), 6.93 (d, J = 1.9 Hz, 1H), 6.87 (d, J = 8.3 Hz,
1H), 6.68 (d, J = 8.4 Hz, 1H), 6.66 – 6.60 (m, 1H), 6.34
(br.s, 2H), 4.50 (dd, J = 8.3, 5.8 Hz, 1H), 3.92 (s, 3H),
3.90 (s, 3H), 3.70 (dd, J = 17.5, 8.4 Hz, 1H), 3.48 (dd, J
anenitrile (4al): This compound was prepared via
Typical Procedure 3 employing 2-(2-methoxyphenyl)-4-
2-nitrophenyl)-4-oxobutanenitrile (19al) (1.860 g, 6.00
(
mmol) or via Typical Procedure 4 employing (E)-1-(2-
aminophenyl)-3-(2-methoxyphenyl)prop-2-en-1-one
(16al) (1.518 g, 6.00 mmol). Yields 1.663 g (5.94 mmol,
99%) and 1.495 g (5.34 mmol, 89%), respectively. Eluent
for preparative column chromatography: EtOAc/hexane,
:3. The title compound was obtained as light-green
solid, mp 119.2-120.5 °C, R 0.25 (EtOAc/hexane, 1:4).
H NMR (400 MHz, DMSO-d ) δ 7.76 (d, J = 8.0 Hz,
H), 7.49 (d, J = 7.3 Hz, 1H), 7.36 (t, J = 7.3 Hz, 1H),
.30 – 7.19 (m, 3H), 7.08 (d, J = 8.2 Hz, 1H), 7.00 (t, J =
.4 Hz, 1H), 6.78 (d, J = 8.3 Hz, 1H), 6.52 (t, J = 7.4 Hz,
H), 4.65 (dd, J = 9.4, 4.6 Hz, 1H), 3.96 – 3.79 (m, 4H),
3.49 (dd, J = 17.8, 4.7 Hz, 1H); C{ H} NMR (101
MHz, DMSO-d ) δ 197.3, 156.2, 151.3, 134.6, 131.3,
129.6, 128.6, 123.2, 121.2, 120.8, 117.0, 115.7, 114.5,
1
3
1
3
= 17.5, 5.7 Hz, 1H); C{ H} NMR (101 MHz, CDCl ) δ
196.4, 150.8, 149.5, 149.0, 135.1, 130.6, 127.9, 121.3,
119.8, 117.6, 116.8, 116.0, 111.6, 110.6, 56.1, 56.1, 45.1,
-1
31.8; FTIR (film, NaCl, cm ): 3472, 3353, 2950, 2251,
1
1713, 1617, 1525, 1452, 1254, 1145, 1023; HRMS (ES
+
f
TOF) m/z: (M+Na) Calcd for C18
Found 333.1200.
18 2 3
H N NaO 333.1210;
1
6
1
7
7
1
4
-(2-Aminophenyl)-4-oxo-2-(pyridin-2-yl)butane-
nitrile (4ao): This compound was prepared via Typical
Procedure 4 employing (E)-1-(2-aminophenyl)-3-(pyr-
idin-2-yl)prop-2-en-1-one (16ao) (1.344 g, 6.00 mmol).
Eluent for preparative column chromatography:
EtOAc/hexane, 1:3. The title compound was obtained as
1
3
1
6
red crystalline solid, mp 127.2-129.9 °C, R
f
0.44
-1
1
3
1
(
3
11.5, 55.8, 41.0, 26.3; FTIR (film, NaCl, cm ): 3466,
353, 3056, 2997, 2245, 1690, 1617, 1587, 1492, 1462,
290, 1248, 1158, 1109, 1033; HRMS (ES TOF) m/z:
M+Na) Calcd for C17
(EtOAc/hexane, 1:2). Yield 753 mg (3.00 mmol, 50%).
1
3
H NMR (400 MHz, CDCl ) δ 8.50 (d, J = 4.1 Hz, 1H),
7.67 (t, J = 7.7 Hz, 1H), 7.58 (d, J = 8.1 Hz, 1H), 7.48 (d,
J = 7.8 Hz, 1H), 7.23 – 7.12 (m, 2H), 6.60 (d, J = 8.3 Hz,
+
H
16
N
2
NaO
2
303.1104; Found
03.1112.
1
H), 6.53 (t, J = 7.6 Hz, 1H), 6.21 (br.s, 2H), 4.58 (t, J =
4
-(2-Aminophenyl)-2-(4-methoxyphenyl)-4-oxobut-
6.7 Hz, 1H), 3.80 (dd, J = 17.7, 6.0 Hz, 1H), 3.68 (dd, J
1
3
1
anenitrile (4am): This compound was prepared via
Typical Procedure 3 employing 2-(4-methoxyphenyl)-4-
2-nitrophenyl)-4-oxobutanenitrile (19am) (1.860 g, 6.00
mmol) or via Typical Procedure 4 employing (E)-1-(2-
aminophenyl)-3-(4-methoxyphenyl)prop-2-en-1-one
(16am) (1.518 g, 6.00 mmol). Yields 1.411 g (5.04
mmol, 84%) and 1.529 g (5.46 mmol, 91%), respectively.
Eluent for preparative column chromatography: EtOAc/
3
= 17.7, 7.5 Hz, 1H); C{ H} NMR (101 MHz, CDCl ) δ
196.2, 154.2, 150.7, 149.7, 137.4, 134.8, 130.5, 123.1,
122.6, 120.2, 117.4, 116.5, 115.7, 42.1, 34.0; FTIR (film,
(
-1
NaCl, cm ): 3483, 3335, 2933, 2248, 1748, 1641, 1621,
1594, 1541, 1447, 1430, 1350, 1320; HRMS (ES TOF)
+
m/z: (M+Na) Calcd for C15
274.0953.
13 3
H N NaO 274.0951; Found
4
-(2-Amino-4,5-dimethoxyphenyl)-4-oxo-2-phenyl-
hexane, 1:4. The title compound was obtained as light-
butanenitrile (4ba): This compound was prepared via
Typical Procedure 3 employing 4-(4,5-dimethoxy-2-
nitrophenyl)-4-oxo-2-phenylbutanenitrile (19ba) (2.040
g, 6.00 mmol). Eluent for preparative column chromato-
1
brown solid, R
MHz, CDCl
Hz, 2H), 7.26 (t, J = 7.2 Hz, 1H), 6.92 (d, J = 8.7 Hz, 2H),
f
0.67 (EtOAc/hexane, 1:4). H NMR (400
3
) δ 7.57 (d, J = 7.6 Hz, 1H), 7.34 (d, J = 8.6
17
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 26
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
graphy: EtOAc/hexane, 1:2. The title compound was
obtained as colorless solid, mp 178.5-180.8 °C, R 0.19
(EtOAc/hexane, 1:2), R 0.54 (EtOAc/hexane, 1:1). Yield
1.804 g (5.82 mmol, 97%). H NMR (400 MHz, DMSO-
with
4-(2-aminophenyl)-4-oxo-2-phenylbutanenitrile
f
(4aa) (250 mg, 1.00 mmol) and polyphosphoric acid (2.0
g, 87% P O content). The reaction mixture was
2 5
f
1
thoroughly mixed and the vessel was placed in an oil bath
heated to 80°C. Stirring was continued for 1.3 h, while
the reaction progress was monitored by TLC. After
completion the reaction mixture is poured into water (20
mL), and thoroughly triturated. To reach full hydrolysis
of polyphosphoric acid the resulting solution was brought
to a boiling for 1 min. After that, the mixture was cooled
down and extracted with EtOAc (4 × 25 mL). Combined
organic extracts were concentrated in vacuo and the
residue was purified by column y chromatography
eluting with EtOAc/hexane, 1:1. The title compound was
d
6
) δ 7.52 (d, J = 7.3 Hz, 2H), 7.41 (t, J = 7.4 Hz, 2H),
7
.34 (t, J = 7.2 Hz, 1H), 7.18 (s, 2H), 7.10 (s, 1H), 6.33
(s, 1H), 4.55 (dd, J = 8.9, 5.2 Hz, 1H), 3.80 (dd, J = 8.9,
5
5
1
1
.2 Hz, 1H), 3.75 (s, 3H), 3.68 (s, 3H), 3.50 (dd, J = 17.7,
.2 Hz, 1H); C{ H} NMR (101 MHz, DMSO-d ) δ
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
3
1
94.3, 155.6, 149.0, 139.1, 136.2, 128.9 (2C), 127.9 (3C),
21.8, 113.1, 107.9, 98.8, 56.3, 55.3, 43.0, 31.6; FTIR
-1
(film, NaCl, cm ): 3490, 3343, 2980, 2242, 1742, 1632,
1585, 1508, 1458, 1397, 1250, 1120, 1153; HRMS (ES
+
TOF) m/z: (M+Na) Calcd for C18
Found 333.1214.
18 2 3
H N NaO 333.1210;
obtained as colorless solid, mp 163.5-164.6 °C, R
f
0.24
0.62 (EtOAc). Yield 175 mg
0.70 mmol, 70%). H NMR (400 MHz, DMSO-d ) δ
), 7.44 (d, J =
.7 Hz, 1H), 7.41 – 7.29 (m, 5H), 7.27 – 7.21 (m, 1H),
.18 (br. s, 1H, CONH ), 7.01 (t, J = 7.1 Hz, 1H), 6.93 (t,
(
(
1
7
7
EtOAc/ hexane, 1:1), R
f
4-(7-Amino-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-
4-oxo-2-phenylbutanenitrile (4ca): This compound was
prepared by typical procedure 3 employing 4-(7-nitro-
1
6
0.93 (br. s, 1H), 7.76 (br. s, 1H, CONH
2
2
,3-dihydrobenzo[b][1,4]dioxin-6-yl)-4-oxo-2-phen-
2
ylbutanenitrile (19ca) (2.028 g, 6.00 mmol). Eluent for
preparative column chromatography: EtOAc/hexane,
1
3
1
J = 7.1 Hz, 1H), 6.28 (s, 1H), 5.06 (s, 1H); C{ H} NMR
(101 MHz, DMSO-d
6
) δ 172.1, 139.5, 137.6, 136.4, 128.3
1
0
9
5
:2. The title compound was obtained as yellow oil, R
.15 (EtOAc/hexane, 1:4). Yield 1.756 g (5.70 mmol,
f
(2C), 128.2 (2C), 127.6, 126.9, 120.6, 119.5, 118.7,
-1
1
111.2, 100.2, 50.8; FTIR (film, NaCl, cm ): 3418, 3164,
2761, 1652, 1496, 1402, 1295, 1250; HRMS (ES TOF)
m/z: (M+Na) Calcd for C16
5%). H NMR (400 MHz, CDCl
3
) δ 7.47 – 7.28 (m,
H), 7.06 (s, 1H), 6.11 (s, 1H), 6.04 (br. s, 2H), 4.50 (dd,
+
H
14
N
2
NaO 273.0998; Found
J = 8.5, 5.7 Hz, 1H), 4.32 – 4.22 (m, 2H), 4.16 (dd, J =
5.1, 2.2 Hz, 2H), 3.57 (dd, J = 17.4, 8.6 Hz, 1H), 3.34 (dd,
2
73.0992.
1
3
1
2-(1H-Indol-2-yl)-2-(o-tolyl)acetamide (1ab): This
compound was prepared via Typical Procedure 5 from 4-
J = 17.4, 5.6 Hz, 1H); C{ H} NMR (101 MHz, CDCl
3
)
δ 194.2, 150.4, 147.4, 135.7, 134.7, 129.3 (2C), 128.3,
(2-aminophenyl)-4-oxo-2-(o-tolyl)butanenitrile
(4ab)
1
3
1
27.6 (2C), 121.2, 117.8, 111.4, 103.7, 65.3, 64.0, 44.7,
2.2; FTIR (film, NaCl, cm ): 3492, 3373, 2931, 2248,
-1
(264 mg, 1.00 mmol); the heating was continued for 1 h.
Eluent for column chromatography: EtOAc. The title
compound was obtained as yellow amorphous solid, R
f
644, 1611, 1574, 1551, 1479, 1449, 1251, 1162; HRMS
+
(ES TOF) m/z: (M+Na) Calcd for C18
H
16
N
2
NaO
3
0
7
.27 (EtOAc/hexane, 1:1). Yield 187 mg (0.71 mmol,
3
31.1053; Found 331.1054.
-(2-Amino-5-bromophenyl)-4-oxo-2-phenyl-
butanenitrile (4da): This compound was prepared by
Typical Procedure employing (E)-1-(2-amino-5-
bromophenyl)-3-phenylprop-2-en-1-one (16da) (1.806 g,
.00 mmol). Eluent for preparative column chromato-
1
1%). H NMR (400 MHz, DMSO-d
), 7.44 (d, J = 7.7 Hz, 1H),
7.32 (d, J = 7.9 Hz, 1H), 7.28 – 7.11 (m, 5H), 7.01 (t, J =
.1 Hz, 1H), 6.93 (t, J = 7.1 Hz, 1H), 6.16 (s, 1H), 5.22
6
) δ 10.93 (br. s,
4
1H), 7.67 (br. s, 1H, CONH
2
4
7
1
3
1
(s, 1H), 2.36 (s, 3H); C{ H} NMR (101 MHz, DMSO-
6
d
1
4
1
6
) δ 172.0, 137.7, 137.6, 136.4, 136.0, 130.0, 128.2,
27.7, 126.7, 125.8, 120.5, 119.5, 118.7, 111.1, 100.4,
7.8, 19.4; FTIR (film, NaCl, cm ): 3437, 2997, 1767,
graphy: EtOAc/hexane, 1:4. The title compound was
obtained as light-brown crystalline solid, mp 136.7-138.7
-1
°C, R
1:1). Yield 1.870 g (5.70 mmol, 95%). H NMR (400
MHz, CDCl ) δ 7.65 (d, J = 2.2 Hz, 1H), 7.47 – 7.30 (m,
H), 6.59 (d, J = 8.9 Hz, 1H), 6.39 (br.s, 2H), 4.48 (dd, J
f f
0.25 (EtOAc/hexane, 1:4), R 0.58 (EtOAc/hexane,
686, 1460, 1379, 1247, 1049; HRMS (ES TOF) m/z:
1
+
(M+Na) Calcd for C17
H
16
N
2
NaO 287.1155; Found
3
2
2
87.1147.
-(1H-Indol-2-yl)-2-(p-tolyl)acetamide (1ac): This
6
=
8.8, 5.3 Hz, 1H), 3.66 (dd, J = 17.7, 8.8 Hz, 1H), 3.41
compound was prepared via Typical Procedure 5 from 4-
(2-aminophenyl)-4-oxo-2-(p-tolyl)butanenitrile (4ac)
264 mg, 1.00 mmol). Eluent for column chromato-
1
3
1
(
dd, J = 17.7, 5.3 Hz, 1H); C{ H} NMR (101 MHz,
CDCl ) δ 195.4, 149.4, 137.8, 135.3, 132.7, 129.4 (2C),
28.5, 127.6 (2C), 120.9, 119.6, 118.1, 107.1, 45.1, 32.2;
3
(
1
graphy: EtOAc/hexane, 1:1. The title compound was
obtained as colorless crystalline solid, mp 176.5-177.4
-1
FTIR (film, NaCl, cm ): 3449, 3329, 2248, 1742, 1655,
614, 1584, 1551, 1484, 1421, 1240, 1193, 1163; HRMS
1
°
1
d
C, R
f
0.17 (EtOAc/hexane, 1:1), R
f
0.64 (EtOAc). Yield
72 mg (0.65 mmol, 65%). H NMR (400 MHz, DMSO-
) δ 10.89 (br. s, 1H), 7.70 (br. s, 1H, CONH ), 7.42 (d,
+
(ES TOF) m/z: (M+Na) Calcd for C16
2
H13BrN NaO
1
351.0103; Found 351.0105.
6
2
J = 7.7 Hz, 1H), 7.33 (d, J = 7.9 Hz, 1H), 7.26 (d, J = 7.9
Hz, 2H), 7.14 (br. s, 1H, CONH ), 7.12 (d, J = 7.9 Hz,
H), 7.00 (t, J = 7.2 Hz, 1H), 6.92 (t, J = 7.2 Hz, 1H),
Preparation of (2-(1H-indol-2-yl)-2-arylacetamides
2
2
1
3
1
2
-(1H-Indol-2-yl)-2-phenylacetamide (1aa): Typical
6.24 (s, 1H), 5.00 (s, 1H), 2.27 (s, 3H); C{ H} NMR
(101 MHz, DMSO-d ) δ 172.3, 137.9, 136.5, 136.4,
procedure 5. A 5 mL round-bottomed flask was charged
6
18
ACS Paragon Plus Environment

Page 19 of 26
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
1294, 1228, 1155, 1043; HRMS (ES TOF) m/z: (M+Na)+
Calcd for C16H13ClN NaO 307.0609; Found 307.0616.
2 3
2-(3-Chlorophenyl)-2-(1H-indol-2-yl)acetamide
(1ag): This compound was prepared via Typical
Procedure 5 from 4-(2-aminophenyl)-2-(3-chlorophen-
yl)-4-oxobutanenitrile (4ag) (284 mg, 1.00 mmol).
Eluent for column chromatography: EtOAc/Hex, 1:1.
1
35.9, 128.8 (2C), 128.2 (2C) 127.6, 120.5, 119.5, 118.7,
-1
111.2, 100.1, 50.5, 20.7; FTIR (film, NaCl, cm ): 3450,
3396, 3188, 1742, 1642, 1447, 1414, 1401, 1250, 1113;
HRMS (ES TOF) m/z: (M+Na) Calcd for C17
+
H
16
N
2
NaO
2
2
87.1155; Found 287.1157.
-(4-Ethylphenyl)-2-(1H-indol-2-yl)acetamide (1ad):
This compound was prepared via Typical Procedure 5
from 4-(2-aminophenyl)-2-(4-ethylphenyl)-4-oxobutane-
nitrile (4ad) (278 mg, 1.00 mmol). Eluent for column
chromatography: EtOAc/hexane, 1:1. The title comp-
ound was obtained as colorless crystals, m.p. 158.2-159.3
The title compound was obtained as light-yellow oil. R
0.31 (EtOAc/hexane, 1:1). Yield 222 mg (0.78 mmol,
f
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
78%). H NMR (400 MHz, CDCl
7.54 (d, J = 7.7 Hz, 1H), 7.37 – 7.14 (m, 6H), 7.13 – 7.06
(m, 1H), 6.27 (s, 1H), 6.16 (br. s, 1H, CONH ), 5.84 (br.
), 4.95 (s, 1H); C NMR (101 MHz,
) δ 173.5, 139.8, 136.5, 134.9 (2C), 130.3, 128.7,
128.2, 128.1, 126.7, 122.3, 120.5, 120.2, 111.4, 102.5,
3
) δ 9.08 (br. s, 1H),
°
C. R
128 mg (0.46 mmol, 46%). H NMR (400 MHz, DMSO-
) δ 10.89 (br. s, 1H), 7.71 (br. s, 1H, CONH ), 7.43 (d,
f
0.26 (EtOAc/hexane, 1:1), 0.68 (EtOAc). Yield
2
1
13
s, 1H, CONH
CDCl
2
d
6
2
3
J = 7.7 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.27 (d, J = 7.7
Hz, 2H), 7.20 – 7.10 (m, 3H), 7.00 (t, J = 7.3 Hz, 1H),
6
1
6
51.7; H NMR (400 MHz, DMSO-d ) δ 11.98 (s, 1H),
.92 (t, J = 7.2 Hz, 1H), 6.25 (s, 1H), 5.01 (s, 1H), 2.56
7.80 (s, 1H), 7.46 (d, J = 7.7 Hz, 1H), 7.42 (s, 1H), 7.39
– 7.30 (m, 4H), 7.25 (s, 1H), 7.02 (t, J = 7.2 Hz, 1H), 6.94
1
3
1
(
q, J = 7.4 Hz, 2H), 1.15 (t, J = 7.5 Hz, 3H); C{ H}
NMR (101 MHz, DMSO-d ) δ 172.3, 142.3, 137.8,
36.8, 136.4, 128.2 (2C), 127.61, 127.58 (2C), 120.5,
19.5, 118.7, 111.2, 100.1, 50.5, 27.8, 15.8; FTIR (film,
1
3
1
6
(t, J = 7.1 Hz, 1H), 6.32 (s, 1H), 5.10 (s, 1H); C{ H}
NMR (101 MHz, DMSO-d ) δ 171.5, 141.8, 136.9,
1
1
6
136.4, 132.8, 130.1, 128.1, 127.6, 127.1, 126.9, 120.8,
-1
-1
NaCl, cm ): 3386, 3155, 2971, 1650, 1455, 1406, 1251;
119.7, 118.8, 111.2, 100.3, 50.3; FTIR (film, NaCl, cm ):
+
HRMS (ES TOF) m/z: (M+Na) Calcd for C18
01.1311; Found 301.1312.
H
18
N
2
NaO
3362, 2926, 1745, 1668, 1594, 1574, 1460, 1421, 1384,
+
3
1290, 1246; HRMS (ES TOF) m/z: (M+Na) Calcd for
16 2
C H13ClN NaO 307.0609; Found 307.0614.
2-(1H-Indol-2-yl)-2-(4-isopropylphenyl)acetamide
(1ae): This compound was prepared via Typical Proc-
edure 5 from 4-(2-aminophenyl)-2-(4-isopropylphenyl)-
2-(4-Chlorophenyl)-2-(1H-indol-2-yl)acetamide
(1ah): This compound was prepared via Typical
Procedure 5 from 4-(2-aminophenyl)-2-(4-chlorophen-
yl)-4-oxobutanenitrile (4ah) (284 mg, 1.00 mmol).
Eluent for column chromatography: EtOAc/hexane, 1:1.
The title compound was obtained as colorless solid, mp
4
-oxobutanenitrile (4ae) (292 mg, 1.00 mmol). Eluent for
column chromatography: EtOAc/hexane, 1:1. The title
compound was obtained as yellowish oil, R 0.53
EtOAc). Yield 187 mg (0.64 mmol, 64%). H NMR (400
f
1
(
MHz, CDCl
3
) δ 9.04 (br. s, 1H), 7.41 (d, J = 7.7 Hz, 1H),
75.5-77.2 °C, R
(0.62 mmol, 62%). H NMR (400 MHz, CDCl ) δ 8.98
f
0.38 (EtOAc/hexane, 1:1). Yield 177 mg
1
7
.16 (d, J = 8.0 Hz, 1H), 7.13 (d, J = 7.8 Hz, 2H), 7.07
d, J = 8.1 Hz, 2H), 7.05 – 7.00 (m, 1H), 6.97 (t, J = 7.1
Hz, 1H), 6.21 (br.s, 1H, CONH ), 6.13 (s, 1H), 5.72 (br.s,
1H, CONH ), 4.84 (s, 1H), 2.91 – 2.65 (m, 1H), 1.13 (d,
J = 6.9 Hz, 6H); C{ H} NMR (101 MHz, CDCl
3
(
(br. s, 1H), 7.45 (d, J = 7.7 Hz, 1H), 7.32 – 7.14 (m, 5H),
7.11 – 7.05 (m, 1H), 7.01 (t, J = 7.1 Hz, 1H), 6.17 (s, 1H),
2
2
5.94 (br. s, 1H, CONH
(s, 1H); C{ H} NMR (101 MHz, CDCl ) δ 173.5,
2
), 5.73 (br. s, 1H, CONH
2
), 4.91
1
3
1
13
1
3
): δ
74.6, 148.6, 136.4, 136.1, 135.1, 128.5 (2C), 128.1,
27.2 (2C), 121.9, 120.3, 119.9, 111.2, 102.0, 51.7, 33.8,
4.0 (2C); FTIR (film, NaCl, cm ): 3343, 2967, 1752,
675, 1514, 1454, 1417, 1293, 1240, 1052; HRMS (ES
3
1
1
2
1
136.43, 136.35, 135.1, 134.0, 129.9 (2C), 129.3 (2C),
128.0, 122.3, 120.5, 120.1, 111.3, 102.4, 51.3; FTIR
-1
-1
(film, NaCl, cm ): 3340, 3056, 1650, 1614, 1584, 1518,
+
1492, 1347, 1300, 1092; HRMS (ES TOF) m/z: (M+Na)
+
TOF) m/z: (M+Na) Calcd for C19
Found 315.1472.
2
This compound was prepared via Typical Procedure 5
from 4-(2-aminophenyl)-2-(2-chlorophenyl)-4-oxobut-
anenitrile (4af) (284 mg, 1.00 mmol). Eluent for column
chromatography: EtOAc/hexane, 2:1. The title comp-
ound was obtained as colorless solid, mp 74.5–77.1 °C.
H
20
N
2
NaO 315.1468;
2 3
Calcd for C16H13ClN NaO 307.0609; Found 307.0600.
2-(2-Fluorophenyl)-2-(1H-indol-2-yl)acetamide (1ai):
This compound was prepared via Typical Procedure 5
from 4-(2-aminophenyl)-2-(2-fluorophenyl)-4-oxobut-
anenitrile (4ai) (268 mg, 1.00 mmol). Eluent for column
chromatography: EtOAc/hexane, 1:1. The title
-(2-Chlorophenyl)-2-(1H-indol-2-yl)acetamide (1af):
compound was obtained as brown amorphous solid, R
0.29 (EtOAc/hexane, 1:1), 0.71 (EtOAc). Yield 142 mg
f
1
R
8
7
f
0.34 (EtOAc/hexane, 1:1). Yield 250 mg (0.88 mmol,
(0.53 mmol, 53%). H NMR (400 MHz, DMSO-d
6
) δ
1
8%). H NMR (400 MHz, CDCl
3
) δ 9.19 (br. s, 1H),
11.02 (br. s, 1H), 7.77 (br. s, 1H, CONH ), 7.47 (d, J =
2
.53 (d, J = 7.8 Hz, 1H), 7.45 – 7.33 (m, 3H), 7.28 – 7.21
7.7 Hz, 1H), 7.37 – 7.24 (m, 4H), 7.22 – 7.17 (m, 1H),
(m, 2H), 7.17 (t, J = 7.3 Hz, 1H), 7.09 (t, J = 7.4 Hz, 1H),
7.14 (t, J = 7.4 Hz, 1H), 7.07 – 7.01 (m, 1H), 6.96 (t, J =
1
3
1
6
.30 (s, 1H), 5.92 (br. s, 1H, CONH
2
), 5.86 (br. s, 1H,
7.1 Hz, 1H), 6.25 (s, 1H), 5.35 (s, 1H). C{ H} NMR
(101 MHz, DMSO-d ): δ 171.2, 159.9 (d, J = 244.8 Hz),
13
1
CONH
2
), 5.56 (s, 1H); C{ H} NMR (101 MHz, CDCl
3
)
6
δ 172.9, 136.3, 136.0, 134.6, 133.8, 130.2, 130.0, 129.4,
28.2, 127.7, 122.2, 120.5, 120.1, 112.3, 102.4, 48.5;
136.4, 136.3, 130.3 (d, J = 3.5 Hz), 128.9 (d, J = 8.2 Hz),
127.7, 126.4 (d, J = 14.6 Hz), 124.2 (d, J = 3.2 Hz), 120.8,
119.7, 118.9, 115.0 (d, J = 21.8 Hz), 111.2, 100.6, 43.8
1
-1
FTIR (film, NaCl, cm ): 3459, 3400, 1673, 1591, 1459,
-1
(d, J = 2.7 Hz). FTIR (film, NaCl, cm ): 3334, 1925,
19
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 26
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1294, 1251, 1109, 1026; HRMS (ES TOF) m/z: (M+Na)+
Calcd for C17H N NaO 303.1104; Found 307.1107.
16 2 2
1
667, 1615, 1579, 1492, 1460, 1369, 1298, 1233; HRMS
+
(ES TOF) m/z: (M+Na) Calcd for C16
291.0904; Found 291.0902.
H
13FN
2
NaO
2-(1H-Indol-2-yl)-2-(4-methoxyphenyl)acetamide
(1am): This compound was prepared via Typical
Procedure 5 from 4-(2-aminophenyl)-2-(4-methoxyphen-
yl)-4-oxobutanenitrile (4am) (280 mg, 1.00 mmol).
Eluent for column chromatography: EtOAc/hexane, 1:1.
The title compound was obtained as yellow amorphous
2-(4-Fluorophenyl)-2-(1H-indol-2-yl)acetamide (1aj):
This compound was prepared via Typical Procedure 5
from 4-(2-aminophenyl)-2-(4-fluorophenyl)-4-oxobut-
anenitrile (4aj) (268 mg, 1.00 mmol). Eluent for column
chromatography: EtOAc. The title compound was
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
obtained as yellow amorphous solid, R
f
0.46 (EtOAc).
Yield 134 mg (0.50 mmol, 50%). H NMR (400 MHz,
DMSO-d ) δ 10.94 (br. s, 1H), 7.77 (br. s, 1H, CONH ),
.49 – 7.36 (m, 3H), 7.34 (d, J = 8.0 Hz, 1H), 7.21 (br. s,
1H, CONH ), 7.16 (t, J = 8.8 Hz, 2H), 7.02 (t, J = 7.2 Hz,
1H), 6.94 (t, J = 7.2 Hz, 1H), 6.28 (s, 1H), 5.08 (s, 1H);
solid, R
mmol, 46%). H NMR (400 MHz, DMSO-d
(br. s, 1H), 7.68 (br. s, 1H, CONH ), 7.42 (d, J = 7.7 Hz,
1H), 7.35 – 7.25 (m, 3H), 7.13 (br. s, 1H, CONH ), 7.00
(t, J = 7.1 Hz, 1H), 6.95 – 6.85 (m, 3H), 6.23 (s, 1H), 4.98
f
0.47 (EtOAc/hexane, 1:1). Yield 129 mg (0.46
1
1
6
) δ 10.88
6
2
2
7
2
2
1
3
1
(s, 1H), 3.72 (s, 3H); C{ H} NMR (101 MHz, DMSO-
) δ 172.4, 158.2, 138.1, 136.3, 131.5, 129.3 (2C), 127.6,
120.5, 119.5, 118.7, 113.6 (2C), 111.2, 100.0, 55.1, 50.0;
1
3
1
C{ H} NMR (101 MHz, DMSO-d
J = 242.7 Hz), 137.6, 136.4, 135.6 (d, J = 2.9 Hz), 130.2
d, J = 8.1 Hz, 2C), 127.6, 120.7, 119.6, 118.8, 114.9 (d,
J = 21.2 Hz, 2C), 111.2, 100.2, 50.0; FTIR (film, NaCl,
6
) δ 172.0, 161.3 (d,
d
6
-1
(
FTIR (film, NaCl, cm ): 3386, 3188, 1677, 1508, 1455,
+
1290, 1248, 1175, 1030; HRMS (ES TOF) m/z: (M+Na)
-1
cm ): 3426, 1680, 1508, 1007; HRMS (ES TOF) m/z:
16 2 2
Calcd for C17H N NaO 303.1104; Found 303.1111.
+
(M+Na) Calcd for C16
H
13FN
2
NaO 291.0904; Found
2-(3,4-Dimethoxyphenyl)-2-(1H-indol-2-yl)acetamide
(1an): This compound was prepared via Typical
Procedure 5 from 4-(2-aminophenyl)-2-(3,4-dimethoxy-
phenyl)-4-oxobutanenitrile (4an) (310 mg, 1.00 mmol);
the heating was continued for 2 hours. Eluent for column
chromatography: EtOAc. The title compound was
2
2
91.0915.
-(4-(Dimethylamino)phenyl)-2-(1H-indol-2-yl)acet-
amide (1ak): This compound was prepared via Typical
Procedure 5 from 4-(2-aminophenyl)-2-(4-(dimethyl-
amino)phenyl)-4-oxobutanenitrile (4ak) (293 mg, 1.00
mmol). Eluent for column chromatography: EtOAc/
hexane, 1:1. The title compound was obtained as light
obtained as yellow amorphous solid, R
f
0.46 (EtOAc).
Yield 118 mg (0.38 mmol, 38%). H NMR (400 MHz,
DMSO-d ) δ 10.90 (br. s, 1H), 7.66 (br. s, 1H, CONH ),
7.42 (d, J = 7.7 Hz, 1H), 7.33 (d, J = 8.0 Hz, 1H), 7.13
(br.s, 1H, CONH ), 7.04 (s, 1H), 7.00 (t, J = 7.3 Hz, 1H),
6.96 – 6.86 (m, 3H), 6.24 (s, 1H), 4.97 (s, 1H), 3.72 (s,
1
pink solid, mp 189.4-190.1 °C (benzene), R
f
0.57
6
2
1
(EtOAc). Yield 141 mg (0.48 mmol, 48%). H NMR (400
MHz, DMSO-d
6
) δ 10.83 (br. s, 1H), 7.61 (br. s, 1H,
2
CONH
2
), 7.41 (d, J = 7.7 Hz, 1H), 7.32 (d, J = 8.0 Hz,
H), 7.19 (d, J = 8.7 Hz, 2H), 7.07 (br. s, 1H, CONH ),
.99 (t, J = 7.1 Hz, 1H), 6.91 (t, J = 7.1 Hz, 1H), 6.67 (d,
1
3
1
1
6
2
6
6H); C{ H} NMR (101 MHz, DMSO-d ) δ 172.4,
148.4, 147.9, 138.1, 136.4, 131.9, 127.6, 120.6, 120.5,
119.5, 118.7, 112.2, 111.7, 111.2, 100.0, 55.6, 55.5, 50.4;
J = 8.7 Hz, 2H), 6.21 (br. s, 1H), 4.90 (s, 1H), 2.85 (s,
13
1
-1
6
H); C{ H} NMR (101 MHz, DMSO-d
6
) δ 172.8,
FTIR (film, NaCl, cm ): 3510, 1768, 1454, 1387, 1236,
+
149.5, 138.6, 136.3, 128.8 (2C), 127.6, 127.2, 120.3,
119.4, 118.6, 112.3 (2C), 111.1, 99.8, 50.0, 40.3 (2C);
1062, 1029; HRMS (ES TOF) m/z: (M+Na) Calcd for
C
18
H
18
N
2
NaO
3
333.1210; Found 333.1216.
-1
FTIR (film, NaCl, cm ): 3406, 3301, 2885, 2799, 1690,
654, 1614, 1525, 1459, 1353, 1231, 1195, 1063; HRMS
2-(1H-Indol-2-yl)-2-(pyridin-2-yl)acetamide
(1ao):
1
This compound was prepared via Typical Procedure 5
from 4-(2-aminophenyl)-4-oxo-2-(pyridin-2-yl)butane-
nitrile (4ao) (251 mg, 1.00 mmol); the heating was
continued for 2 hours. Prior to extraction the mixture was
basified with 20% aqueous solution of ammonia (10 mL).
+
19 3
(ES TOF) m/z: (M+Na) Calcd for C18H N NaO
3
2
16.1420; Found 316.1421.
-(1H-Indol-2-yl)-2-(2-methoxyphenyl)acetamide
(1al): This compound was prepared via Typical
Procedure 5 from 4-(2-aminophenyl)-2-(2-methoxy-
phenyl)-4-oxobutanenitrile (4al) (280 mg, 1.00 mmol);
the heating was continued for 7 hours. Eluent for column
chromatography: EtOAc/Hex, 1:1. The title compound
Eluent for column chromatography: CH
60:3:1. The title compound was obtained as light-yellow
oil, R 0.14 (EtOAc), R 0.29 (CH Cl /EtOH/Et N,
60:3:1), R 0.52 (EtOAc/EtOH, 4:1). Yield 151 mg (0.60
mmol, 60%). H NMR (400 MHz, CDCl
2 2 3
Cl /EtOH/Et N,
f
f
2
2
3
f
1
was obtained as slightly pink amorphous solid, R
f
0.16
3
) δ 9.74 (br. s,
(
EtOAc/hexane, 1:1). Yield 162 mg (0.58 mmol, 58%).
1H), 8.59 (d, J = 4.2 Hz, 1H), 7.64 (t, J = 7.7 Hz, 1H),
7.53 (d, J = 7.8 Hz, 1H), 7.37 – 7.29 (m, 2H), 7.25 – 7.04
1
H NMR (400 MHz, DMSO-d
br. s, 1H, CONH ), 7.43 (d, J = 7.7 Hz, 1H), 7.31 (d, J =
.9 Hz, 1H), 7.27 – 7.20 (m, 1H), 7.12 – 7.06 (m, 2H),
6
) δ 10.90 (br. s, 1H), 7.49
(
2
(m, 4H), 6.35 (s, 1H), 6.22 (br. s, 1H, CONH
2
), 5.23 (s,
1
3
1
7
7
7
1H); C{ H} NMR (101 MHz, CDCl ) δ 172.8, 157.6,
3
.04 – 6.97 (m, 2H), 6.93 (t, J = 7.3 Hz, 1H), 6.86 (t, J =
149.1, 137.8, 136.5, 134.7, 128.1, 124.4, 122.9, 122.1,
-
.4 Hz, 1H), 6.17 (s, 1H), 5.33 (s, 1H), 3.81 (s, 3H);
120.4, 120.0, 111.4, 102.1, 53.8; FTIR (film, NaCl, cm
13
1
1
C{ H} NMR (101 MHz, DMSO-d
6
) δ 172.1, 156.5,
): 3349, 3174, 1742, 1581, 1460, 1434, 1374, 1243,
1
1
37.5, 136.3, 129.1, 128.1, 127.7, 127.6, 120.5, 120.1,
19.5, 118.7, 111.1, 110.7, 100.4, 55.5, 44.6; FTIR (film,
14 3
1146, 1045; HRMS (ES TOF) calc`d for C15H N O
+
(M+H) 252.1131, found 252.1134 (-0.9 ppm), HRMS
-1
+
NaCl, cm ): 3347, 3056, 2838, 1667, 1578, 1488, 1465,
(ES TOF) m/z: (M+Na) Calcd for C15
274.0951; Found 274.0958.
13 3
H N NaO
20
ACS Paragon Plus Environment

Page 21 of 26
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
2
-(5,6-Dimethoxy-1H-indol-2-yl)-2-phenylacetamide
mixed, placed in an oil bath pre-heated to 80 °C, and
stirred for 2 hours. When TLC control indicated the
reaction completion, the mixture was poured into water
and thoroughly triturated. The mixture was neutralized
(1ba): This compound was prepared via Typical
Procedure 5 from 4-(2-amino-4,5-dimethoxyphenyl)-4-
oxo-2-phenylbutanenitrile (4ba) (310 mg, 1.00 mmol).
Eluent for column chromatography: EtOAc/Hex, 1:1.
4
with 20% NH OH solution (10 ml) and extracted with
The title compound was obtained as pale-yellow oil, R
f
EtOAc (4 × 25 mL), concentrated in vacuo and purified
by column chromatography (Eluent: EtOAc/Hex, 2:1).
Yield 247 mg (0.92 mmol, 92%). Method B: 4-(2-
aminophenyl)-4-oxo-2-phenylbutanenitrile (4aa) (250
0
7
7
.47 (EtOAc/hexane, 1:1). Yield 240 mg (0.77 mmol,
1
7%). H NMR (400 MHz, CDCl
.28 (s, 5H), 6.94 (s, 1H), 6.75 (s, 1H), 6.30 (br. s, 1H,
), 6.10 (s, 1H), 5.97 (br. s, 1H, CONH ), 4.95 (s,
H), 3.84 (s, 3H), 3.77 (s, 3H); C{ H} NMR (101 MHz,
3
) δ 9.08 (br. s, 1H),
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
CONH
1
2
2
2 4
mg, 1.00 mmol), H SO (300 mg) and AcOH (200 mg)
13
1
were placed in a 5 mL round bottom flask equipped with
a magnetic stirring bar. The reaction mixture was
vigorously stirred for 30 minutes at room temperature,
after which the reaction mixture was poured into water
3
CDCl ) δ 174.6, 146.9, 145.1, 138.2, 134.3, 130.8,
129.0(2C), 128.5(2C), 127.8, 120.7, 102.1, 101.9, 94.7,
56.4, 56.1, 52.0; FTIR (film, NaCl, cm ): 3356, 2946,
2832, 1665, 1481, 1451, 1344, 1243, 1203, 1143, 1123;
HRMS (ES TOF) m/z: (M+Na) Calcd for C18
3
2
phenylacetamide (1ca): This compound was prepared
via Typical Procedure 5 from 4-(7-amino-2,3-dihydro-
benzo[b][1,4]dioxin-6-yl)-4-oxo-2-phenylbutanenitrile
-1
4
(20 mL). The mixture was neutralized with 20% NH OH
+
H
18
N
2
NaO
3
solution (10 mL), extracted with EtOAc (4 × 25 mL),
concentrated in vacuo, and purified by column
chromatography (Eluent: EtOAc/Hex, 2:1). Yield 230 mg
(0.86 mmol, 86%). The titled compound was obtained as
33.1210; Found 333.1216.
-(2,3-Dihydro-6H-[1,4]dioxino[2,3-f]indol-7-yl)-2-
colorless solid, mp 145.1-148.0 °C (EtOH), R
f
0.15
0.34 (EtOAc). H NMR (400 MHz,
) δ 7.83 (d, J = 8.0 Hz, 1H), 7.53 (br.s, 1H,
), 7.41 (d, J = 7.4 Hz, 2H), 7.31 (t, J = 7.4 Hz,
2H), 7.23 (t, J = 7.2 Hz, 2H), 7.17 (br.s, 2H), 6.83 (br.s,
1H, CONH ), 6.75 (d, J = 8.3 Hz, 1H), 6.53 (t, J = 7.4 Hz,
1H), 4.07 (dd, J = 9.7, 3.4 Hz, 1H), 3.83 (dd, J = 17.4,
1
(EtOAc/Hex, 1:1), R
DMSO-d
CONH
f
(
4ca) (308 mg, 1.00 mmol. Eluent for column chromato-
graphy: EtOAc/hexane, 1:1. The title compound was
obtained as colorless solid, mp 207.9 – 209.3 °C. R 0.17
(EtOAc/hexane, 1:1). Yield 169 mg (0.55 mmol, 55%).
6
2
f
2
1
H NMR (400 MHz, DMSO-d
br. s, 1H, CONH ), 7.37 – 7.27 (m, 4H), 7.26 – 7.19 (m,
H), 7.14 (br. s, 1H, CONH ), 6.85 (s, 1H), 6.78 (s, 1H),
.07 (s, 1H), 4.97 (s, 1H), 4.24 – 4.08 (m, 4H); C{ H}
) δ 172.2, 139.7, 139.6,
38.2, 137.1, 131.6, 128.21 (2C), 128.15 (2C), 126.8,
21.9, 105.5, 99.4, 98.2, 64.1, 63.8, 50.8; FTIR (film,
6
) δ 10.49 (br. s, 1H), 7.71
1
3
1
(
1
6
2
10.1 Hz, 1H), 3.10 (dd, J = 17.4, 3.5 Hz, 1H); C{ H}
NMR (101 MHz, DMSO-d ) δ 199.8, 174.3, 151.0,
140.9, 134.1, 131.3, 128.3 (2C), 127.9 (2C), 126.6, 116.9,
2
6
1
3
1
-1
NMR (101 MHz, DMSO-d
6
116.5, 114.5, 46.4, 42.0; FTIR (film, NaCl, cm ): 3490,
3362, 3040, 1748, 1665, 1634, 1578, 1541, 1450, 1400,
1
1
+
1229, 1206; HRMS (ES TOF) m/z: (M+Na) Calcd for
-1
NaCl, cm ): 3466, 3386, 3175, 2878, 1647, 1465, 1416,
1
Calcd for C18 NaO 331.1053; Found 331.1056.
2-(5-Bromo-1H-indol-2-yl)-2-phenylacetamide (1da):
This compound was prepared via Typical Procedure 5
from
butanenitrile (4da) (328 mg, 1.00 mmol); the heating was
continued for 3 hours. Eluent for column chromato-
graphy: EtOAc/CH
was obtained as colorless solid, mp 189.3-191.8 °C, R
0
5
1
16 16 2 2
C H N NaO 291.1104; Found 291.1109.
+
343, 1264, 1178, 1069; HRMS (ES TOF) m/z: (M+Na)
3,5-Diphenylfuran-2-amine (28): 5 mL round-bottomed
flask equipped with mechanical stirring was charged with
4-oxo-2,4-diphenylbutanenitrile (4aa) (235 mg, 1.00
mmol) and 87% PPA (2.00 g). The reaction mixture was
thoroughly stirred and placed in the oil bath preheated to
60 °C. The stirring was continued for 1 hr, while the
reaction progress was monitored by TLC analysis. Upon
completion, the mixture was poured into water (20 mL),
thoroughly triturated, and neutralized with 20% aqueous
ammonia solution. Then, the mixture was diluted with
water (100 mL), extracted with EtOAc (4 × 25 mL) and
concentrated in vacuum. The obtained crude product
contained about 90% of the titled compound, but it could
not be purified by preparative column chromatography,
as it rapidly decomposed upon contact with silica gel.
The spectra and properties listed below were measured
H
16
N
2
3
4-(2-amino-5-bromophenyl)-4-oxo-2-phenyl-
2 2
Cl , 1:2 to 1:1. The title compound
f
.47 (EtOAc/CH
2
Cl
2%). H NMR (400 MHz, DMSO-d
H), 7.78 (br. s, 1H, CONH ), 7.64 (s, 1H), 7.47 – 7.17
2
, 1:1). Yield 171 mg (0.52 mmol,
1
6
) δ 11.17 (br. s,
2
(m, 7H), 7.12 (d, J = 8.0 Hz, 1H), 6.28 (s, 1H), 5.07 (s,
1
3
1
1H); C{ H} NMR (101 MHz, DMSO-d
139.3, 139.2, 135.1, 129.5, 128.30 (2C), 128.26 (2C),
27.0, 123.0, 121.7, 113.2, 111.3, 100.0, 50.7; FTIR
6
) δ 171.9,
1
-1
(film, NaCl, cm ): 3430, 3188, 2933, 1742, 1658, 1461,
for the crude material. Pale brown oil, R
(EtOAc/hexanes, 1:4). H NMR (400 MHz, CDCl
3
f
0.43
): δ
7.57 – 7.50 (m, 2H), 7.40 – 7.29 (m, 3H), 7.18 (s, 1H),
+
1
1
417, 1387, 1307, 1253; HRMS (ES TOF) m/z: (M+Na)
Calcd for C16 NaO 351.0103; Found 351.0102.
H
13BrN
2
1
3
1
7
.16 – 7.06 (m, 1H), 6.12 (s, 2H); C{ H} NMR (101
(
(
4-(2-aminophenyl)-4-oxo-2-phenylbutanamide
26aa): Method A: 4-(2-aminophenyl)-4-oxo-2-phenyl-
MHz, CDCl ) δ 153.2, 142.1, 134.0, 130.7, 128.7 (2C),
3
128.5 (2C), 125.4 (2C), 124.9, 124.1, 121.5 (2C), 107.4,
98.7; FTIR (film, NaCl, cm-1): 3340, 3063, 1957, 1885,
1630, 1597, 1251, 1172.
N-(3,5-diphenylfuran-2-yl)-1-phenylmethanimine
(29): To the crude product 28 obtained from 1.00 mmol
butanenitrile (4aa) (250 mg, 1.00 mmol) and
polyphosphoric acid (2 g, 80% P content) were placed
into a 5 mL round bottom flask equipped with a
mechanical stirring bar. The contents were thoroughly
2
O
5
21
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 26
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
of 4-oxo-2,4-diphenylbutanenitrile (4aa) was added
ethanol (5 mL) and freshly distilled benzaldehyde (106
mg, 1.00 ммоль). The mixture was stirred for 1 hr at
room temperature. The formed precipitate was collected
on a sintered funnel, washed with cold ethanol, and dried
on air. The title compound was obtained as yellow solid,
3
g (5.64 mmol, 94%). H NMR (400 MHz, CDCl ) δ 11.17
(s, 1H), 7.78 – 7.59 (m, 4H), 7.47 (t, J = 7.9 Hz, 1H), 7.43
– 7.32 (m, 5H), 7.22 (d, J = 8.0 Hz, 2H), 7.04 (t, J = 7.7
Hz, 1H), 4.46 (dd, J = 8.2, 5.7 Hz, 1H), 3.66 (dd, J = 18.0,
8.2 Hz, 1H), 3.43 (dd, J = 18.1, 5.7 Hz, 1H), 2.36 (s, 3H);
C{ H} NMR (101 MHz, CDCl ) δ 198.4, 144.2, 140.5,
3
136.4, 135.7, 134.9, 130.8, 129.9 (2C), 129.5 (2C), 128.7,
127.6 (2C), 127.4 (2C), 122.9, 121.3, 120.4, 119.5, 45.5,
1
3
1
mp 158.3-159.2 °C, R
29 mg, (0.40 mmol, 40%). H NMR (400 MHz, CDCl
δ 8.83 (s, 1H), 8.02 (d, J = 7.3 Hz, 2H), 7.98 – 7.91 (m,
H), 7.79 (d, J = 7.4 Hz, 2H), 7.53 – 7.39 (m, 7H), 7.32
f
0.67 (EtOAc/hexanes, 1:4). Yield
1
1
3
)
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
-1
32.0, 21.7; FTIR (film, NaCl, cm ): 3124, 2245, 1652,
2
1601, 1575, 1493, 1449, 1339, 1160, 1092; HRMS (ES
13
1
+
(t, J = 7.3 Hz, 2H), 7.07 (s, 1H); C{ H} NMR (101
TOF) m/z: (M+Na) C23
427.1080.
20 2 3
H N NaO S 427.1087; Found
MHz, CDCl ) δ 153.1, 150.0, 137.1, 132.7, 131.0, 130.4,
3
128.93 (2C), 128.90 (2C), 128.8 (2C), 128.6 (2C), 128.14
(2C), 128.07, 127.2, 124.1 (2C), 121.6, 107.3; FTIR
4-Methyl-N-(2-(5-((4-methylbenzylidene)amino)-4-
phenylfuran-2-yl)phenyl)benzenesulfonamide (37): A
5 mL round-bottomed flask was charged with N-(2-(3-
cyano-3-phenylpropanoyl)phenyl)-4-methylbenzene-
sulfonamide (35) (404 mg, 1.00 mmol), and
-1
(film, NaCl, cm ): 3063, 2997, 2357, 1957, 1894, 1809,
767, 1601, 1528, 1488, 1455, 1251, 1125, 1059; HRMS
1
+
(ES TOF) m/z: (M+Na) Calcd for C23H17NNaO
3
46.1202; Found 346.1204.
2 5
polyphosphoric acid (2.0 g, 87% P O content). The
N-(2-Сinnamoylphenyl)-4-methylbenzenesulfon-
reaction mixture was thoroughly mixed and the vessel
was placed in an oil bath preheated to 80°C. Stirring was
continued for 30 min. Then, the reaction mixture was
poured into a mixture of water (20 mL) and crushed ice
(10 g), and thoroughly triturated. After homogenization,
3
8
amide (34):
Prepared according to the modified
3
6
procedure adopted from literature. 4-Toluenesulfonyl
chloride (2.286 g, 12.0 mmol) and pyridine (6.4 mL, 80
mmol) were added to a stirred solution of (E)-1-(2-
aminophenyl)-3-phenylprop-2-en-1-one (16aa) (10
3
the mixture was neutralized with NaHCO (5 g in 50 mL
mmol, 2.23 g) in CH
2
Cl
2
(20 mL) at 0 °C. The mixture
of water) and extracted with dichloromethane (4 x 15
mL). Combined organic phases were concentrated
vacuum and the residue was placed in 25 mL round-
bottomed flask. 4-Methylbenzaldehyde (120 mg, 1.00
mmol), EtOH (4 mL) and AcOH (30 mg, 0.50 mmol)
were added and the resulting mixture was heated at reflux
for 2 h. After this period the mixture was allowed to cool
down and the formed precipitate was filtered off. Solid
phase was separated by column chromatography on
Silica gel, eluting with EtOAc/Hexane (gradient from 1:4
to 1:2) to obtain 39 mg of 4-methyl-N-(2-(5-((4-methyl-
benzylidene)amino)-4-phenylfuran-2-yl)phenyl)benz-
enesulfonamide (37) and 25 mg of starting material (35).
Mother liquor was evaporated, and the residue was also
chromatographed, to afford 83 mg of compound 37 and
140 mg of starting material (35) along with other
unreacted components such as p-tolualdehyde. Total
yield of furan 37 was 122 mg (0.24 mmol, 24%) and 165
mg of unreacted N-(2-(3-cyano-3-phenylpropanoyl)-
phenyl)-4-methylbenzenesulfonamide (35) (0.41 mmol,
was stirred at room temperature for 6-8 hours until the
reaction was complete (TLC). The reaction was quenched
with water (20 mL) and the aqueous phase extracted with
CH
washed subsequently with water (3 × 20 mL), 10%
aqueous HCl (3 × 10 mL), 5% NaHCO (2 × 20 mL),
dried with anhydrous Na SO , filtered, and concentrated
2 2
Cl (3 × 20 mL). The combined organic phases were
3
2
4
under reduced pressure. The resulting solid was
recrystallized from ethanol to afford the title compound
as yellow solid, mp 133.7-135.0 °C (EtOH), R
(EtOAc/hexane, 1:4). Yield 3.66 g (9.7 mmol, 97%). H
NMR (400 MHz, CDCl ) δ 11.04 (s, 1H), 7.83 (dd, J =
.0, 1.6 Hz, 1H), 7.74 (dd, J = 8.4, 1.2 Hz, 1H), 7.70 –
f
0.44
1
3
8
7
2
.66 (m, 2H), 7.63 (d, J = 15.6 Hz, 1H), 7.59 (dd, J = 6.7,
.9 Hz, 2H), 7.48 (ddd, J = 8.5, 7.3, 1.6 Hz, 1H), 7.43 (dd,
J = 5.1, 1.9 Hz, 3H), 7.32 (d, J = 15.6 Hz, 1H), 7.18 –
1
3
1
7
.09 (m, 3H), 2.21 (s, 3H); C{ H} NMR (101 MHz,
CDCl ) δ 193.0, 146.1, 143.9, 139.9, 136.4, 134.5, 134.4,
31.2, 130.7, 129.7 (2C), 129.2 (2C), 128.7 (2C), 127.4
2C), 125.2, 123.3, 122.3, 121.1, 21.5; FTIR (film, NaCl,
3
1
(
1
6
41%) were recovered. H NMR (400 MHz, DMSO-d ) δ
-1
cm ): 3044, 1643, 1590, 1571, 1493, 1445, 1386, 1325,
1277, 1202, 1150; HRMS (ES TOF) m/z: (M+Na) Calcd
9.80 (s, 1H), 8.91 (s, 1H), 8.00 – 7.94 (m, 2H), 7.89 (d, J
= 7.9 Hz, 2H), 7.84 (dd, J = 7.8, 1.6 Hz, 1H), 7.58 – 7.47
(m, 4H), 7.41 – 7.28 (m, 6H), 7.23 (d, J = 8.0 Hz, 2H),
7.08 (dd, J = 7.9, 1.4 Hz, 1H), 2.40 (s, 3H), 2.22 (s, 3H);
+
for C22
H
19NNaO
3
S 400.0978; Found 400.0976.
(N-(2-(3-Cyano-3-phenylpropanoyl)phenyl)-4-meth-
1
3
1
ylbenzenesulfonamide (35). This material was obtained
according to the Typical procedure 4, starting from N-(2-
6
C{ H} NMR (101 MHz, DMSO-d ) δ 154.7, 149.6,
146.5, 142.8, 141.6, 138.0, 133.9, 132.2, 132.1, 129.7
(2C), 129.5 (2C), 128.6 (4C), 128.5 (2C), 127.5, 127.4
(2C), 127.3, 127.14, 127.08, 126.4 (2C), 119.4, 111.3,
21.3, 20.9; FTIR (film, NaCl, cm ): 3373, 3249, 2923,
2846, 1740, 1601,1493, 1454, 1401, 1325, 1158, 1090;
cinnamoylphenyl)-4-methylbenzenesulfonamide
(34)
(2.262 g, 6.00 mmol). The crude product was purified by
-1
preparative column chromatography on Silica gel, eluting
with EtOAc/Hex, 1:3. The title compound was obtained
+
as white solid, mp 193.7-195.0°C, R
f
0.51 (EtOAc/Hex,
HRMS (ES TOF) m/z: (M+Na)
529.1556, found 529.1548.
31 26 2 3
C H N NaO S
1
:2). Yield 2.278 g (5.64 mmol, 94%). Alternatively, this
material can be purified by trituration with benzene
followed by re-crystallization from ethanol. Yield 2.278
22
ACS Paragon Plus Environment

Page 23 of 26
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Preparation of 1aa from furan 37: (E)-4-Methyl-N-(2-
aldehyde (84.3 mg, 0.60 mmol), EtOH (2 mL), and
AcOH (36 mg, 0.60 mmol). The mixture was heated at
reflux for 3 h, then cooled down to room temperature.
The formed precipitate was filtered off and washed twice
with EtOH to afford the titled compound in a form of
(5-((4-methylbenzylidene)amino)-4-phenylfuran-2-
yl)phenyl)benzenesulfonamide (37) (116 mg, 0.23
mmol) was subjected to the reaction with 87% PPA under
conditions of Typical Procedure 5. After standard
aqueous work up, isolation and purification, 2-(1H-indol-
acetate (39), colorless solid, mp 204.0-207.6 °C (EtOH).
1
2
3
-yl)-2-phenylacetamide (1aa) was obtained in a yield of
0 mg (0.12 mmol, 52%).
6
H NMR (400 MHz, DMSO-d ) δ 10.66 (s, 1H), 7.50 –
7.14 (m, 11H), 6.93 (t, J = 7.5 Hz, 1H), 6.75 (t, J = 7.5
Hz, 1H), 6.65 (d, J = 7.9 Hz, 1H), 5.25 (s, 1H), 4.31 (t, J
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Preparation of 1aa from furan 35 (Control
experiment): (N-(2-(3-Cyano-3-phenylpropanoyl)phen-
yl)-4-methylbenzenesulfonamide (35) (404 mg, 1.00
mmol) was subjected to the reaction with 87% PPA under
conditions of Typical Procedure 5. Full conversion was
=
6.3 Hz, 1H), 3.34 (dd, J = 12.4, 5.3 Hz, 1H), 2.86 (dd,
13
1
J = 12.3, 7.2 Hz, 1H), 1.91 (s, 3H); C{ H} NMR (101
MHz, DMSO-d ) δ 172.1, 143.3, 142.6, 136.1, 136.0,
6
131.4, 130.4 (2C), 128.4 (2C), 128.4 (2C), 128.0 (2C),
126.6, 125.1, 120.3, 118.3, 118.1, 111.4, 111.2, 56.1,
o
achieved in 120 min at 80 C. After standard aqueous
-1
51.0, 41.3, 21.1; FTIR (film, NaCl, cm ): 3044, 2564,
619, 1493, 1452, 1408, 1337, 1311, 1238, 1086, 1013.
This salt was quantitively converted into a free base by
partitioning it between saturated solution of NaHCO (20
work up, isolation and purification, 2-(1H-indol-2-yl)-2-
phenylacetamide (1aa) was obtained in a yield of 145 mg
(0.58 mmol, 58%).
1
3
Control experiment, reaction between p-tolualdehyde
mL) and chloroform (20 mL). Organic layer was
concentrated in vacuo to afford 1-(4-chlorophenyl)-4-
phenyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (40)
as transparent colorless crystals, mp 143.8-147.9 °C
and
N-(2-(3-cyano-3-phenylpropanoyl)phenyl)-4-
methylbenzenesulfonamide (35): This experiment was
performed to exclude the possibility of formation of furan
3
5
7 directly from ketonitrile 35 during protection step. A
mL round-bottomed flask was charged with N-(2-(3-
(
EtOH), R
f
0.56 (EtOAc/Hex, 1:1). Yield 168 mg (47
1
mmol, 94%). H NMR (400 MHz, CDCl
3
) δ 7.82 (s, 1H),
cyano-3-phenylpropanoyl)phenyl)-4-methylbenzene-
sulfonamide (35) (404 mg, 1.00 mmol), p-tolualdehyde
7.42 – 7.27 (m, 7H), 7.21 (td, J = 6.2, 3.0 Hz, 3H), 7.09
(ddd, J = 8.2, 7.0, 1.2 Hz, 1H), 6.91 (ddd, J = 8.0, 7.1, 1.0
Hz, 1H), 6.80 (d, J = 7.9 Hz, 1H), 5.34 (d, J = 2.1 Hz,
(120 mg, 1.00 mmol), EtOH (4 mL) and AcOH (30 mg,
0
.50 mmol). The mixture was heated at reflux for 2
1
H), 4.31 (td, J = 5.7, 2.7 Hz, 1H), 3.53 (dd, J = 12.6, 5.4
hours. After this period the mixture was analyzed for
1
3
1
Hz, 1H), 3.10 (dd, J = 12.6, 8.5 Hz, 1H); C{ H} NMR
101 MHz, CDCl ) δ 141.8, 141.2, 136.1, 135.9, 133.4,
30.1 (2C), 129.0 (2C), 128.8 (2C), 128.7 (2C), 127.5,
25.7, 121.7, 119.6, 119.4, 112.6, 110.9, 57.5, 52.0, 42.6;
1
presence of compound 37 by TLC and H NMR. The
(
1
1
3
mixture contained only unreacted N-(2-(3-cyano-3-phen-
ylpropanoyl)phenyl)-4-methylbenzenesulfonamide (35)
and tolualdehyde with no detectable traces of compound
-1
FTIR (film, NaCl, cm ): 3395, 2926, 2853, 1491, 1454,
1
C H20ClN
23 2
3
7.
+
308, 1238, 1087, 1011; HRMS (ES TOF) m/z: (M+H)
359.1310; Found 359.1302.
2
-(1H-Indol-2-yl)-2-phenylethan-1-amine (38): This
material was prepared by reduction with LiAlH
according to the general procedure, described in
4
ASSOCIATED CONTENT
Supporting Information
3
8
literature, starting with 2-(1H-indol-2-yl)-2-phenylacet-
amide (1aa) (500 mg, 2.00 mmol). The titled compound
1
1
was obtained as yellow solid, mp 183.4-184.4 °C, R
EtOAc/EtOH/Et N, 20:1:1), R 0.11 (EtOAc). Yield 227
mg (0.96 mmol, 48%). H NMR (400 MHz, CDCl ) δ
.04 (br. s, 1H), 7.56 (d, J = 7.9 Hz, 1H), 7.39 – 7.19 (m,
f
0.31
H and 13C{ H} NMR spectral charts, HRMS spectral
(
3
f
charts for all new compounds. X-Ray crystallography data.
1
3
The Supporting Information is available free of charge on
the ACS Publications website.
9
6
6
7
H), 7.13 (t, J = 7.5 Hz, 1H), 7.08 (t, J = 7.3 Hz, 1H),
.29 (s, 1H), 4.17 (t, J = 6.5 Hz, 1H), 3.46 (dd, J = 12.3,
AUTHOR INFORMATION
Corresponding Authors
NA: E-mail: naksenov@ncfu.ru; phone: +7(8652) 33-0856;
MR: E-mail: mrubin@ku.edu; fax: +1(785) 864-5396;
phone: +1 (785) 864-5071
.2 Hz, 1H), 3.32 (dd, J = 12.4, 5.7 Hz, 1H), 1.56 (s, 2H);
1
3
1
C{ H} NMR (101 MHz, CDCl
3
) δ 141.2, 140.9, 136.0,
128.9(2C), 128.4(2C), 128.4, 127.2, 121.4, 120.2, 119.7,
-
1
1
3
10.8, 100.1, 47.7, 47.0; FTIR (film, NaCl, cm ): 3187,
069, 2934, 2864, 1740, 1489, 1458, 1290, 1242; HRMS
+
(ES TOF) m/z: (M+H)
C
16
H
17
N
2
237.1386; Found
2
37.1379; X-Ray diffraction: CCDC #2022311, see SI
ORCID
for details.
Nicolai A. Aksenov: 0000-0002-7125-9066
Dmitrii A. Aksenov: 0000-0002-0727-9652
Anton A. Skomorokhov: 0000-0003-1525-9800
Lidiya A. Prityko: 0000-0002-3982-2533
Alexander V. Aksenov: 0000-0002-6644-9949
Georgii D. Griaznov: 0000-0001-9236-866X
1
-(4-Chlorophenyl)-4-phenyl-2,3,4,5-tetrahydro-
1
H-pyrido[4,3-b]indole (40): A 5mL round-bottomed
flask was charged with 2-(1H-indol-2-yl)-2-phenylethan-
-amine (38) (118 mg, 0.50 mmol), 4-chlorobenz-
1
23
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 26
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Michael Rubin: 0000-0002-1668-9311
Tam, S.; Shen, M. W. H.; Khor, S.; Xu, X.; Goodwin,
D. G.; Ramarao, M. K.; Nickerson-Nutter, C.;
Donahue, F.; Ku, M. S.; Clark, J. D.; McKew, J. C.,
Discovery of Ecopladib, an Indole Inhibitor of
Cytosolic Phospholipase A2α. J. Med. Chem. 2007,
50 (6), 1380-1400.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
Funding Sources
9. McKew, J. C.; Lee, K. L.; Shen, M. W. H.; Thakker,
P.; Foley, M. A.; Behnke, M. L.; Hu, B.; Sum, F.-W.;
Tam, S.; Hu, Y.; Chen, L.; Kirincich, S. J.; Michalak,
R.; Thomason, J.; Ipek, M.; Wu, K.; Wooder, L.;
Ramarao, M. K.; Murphy, E. A.; Goodwin, D. G.;
Albert, L.; Xu, X.; Donahue, F.; Ku, M. S.; Keith, J.;
Nickerson-Nutter, C. L.; Abraham, W. M.; Williams,
C.; Hegen, M.; Clark, J. D., Indole Cytosolic
Phospholipase A2 α Inhibitors: Discovery and in
Vitro and in Vivo Characterization of 4-{3-[5-Chloro-
2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1-
(diphenylmethyl)-1H-indol-3-yl]propyl}benzoic
Acid, Efipladib. J. Med. Chem. 2008, 51 (12), 3388-
3413.
10. (a) Dong, H.; Latka, R. T.; Driver, T. G., Ruthenium-
Catalyzed γ-Carbolinium Ion Formation from Aryl
Azides; Synthesis of Dimebolin. Org. Lett. 2011, 13
(10), 2726-2729. (b) Zakurdaev, E. P.; Balenkova, E.
S.; Nenajdenko, V. G. Mild and Regioselective
Straightforward Synthesis of Isomelatonin Analogs.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
This work was supported by the Russian Science
Foundation (grant # 19-73-00091)
REFERENCES
1. Bali, P.; Pranpat, M.; Bradner, J.; Balasis, M.;
Fiskus, W.; Guo, F.; Rocha, K.; Kumaraswamy, S.;
Boyapalle, S.; Atadja, P.; Seto, E.; Bhalla, K.,
Inhibition of Histone Deacetylase 6 Acetylates and
Disrupts the Chaperone Function of Heat Shock
Protein 90: a novel basis for antileukemia activity of
histone deacetylase inhibitors. J. Biol. Chem. 2005,
2
80 (29), 26729-26734.
2
.
Bradner, J. E.; West, N.; Grachan, M. L.; Greenberg,
E. F.; Haggarty, S. J.; Warnow, T.; Mazitschek, R.,
Chemical Phylogenetics of Histone Deacetylases.
Nat. Chem. Biol. 2010, 6 (3), 238-243.
3
4
.
.
Dokmanovic, M.; Clarke, C.; Marks, P. A., Histone
Deacetylase Inhibitors: Overview and Perspectives.
Mol. Cancer Res. 2007, 5 (10), 981-989.
Lahm, A.; Paolini, C.; Pallaoro, M.; Nardi, M. C.;
Jones, P.; Neddermann, P.; Sambucini, S.;
Bottomley, M. J.; Lo Surdo, P.; Carfi, A.; Koch, U.;
De Francesco, R.; Steinkuehler, C.; Gallinari, P.,
Unraveling the Hidden Catalytic Activity of
Vertebrate Class IIa Histone Deacetylases. Proc.
Natl. Acad. Sci. U. S. A. 2007, 104 (44), 17335-
Mendeleev Commun. 2006, 4, 213-215.
(c)
Voznesenskaia, N. G.; Shmatova, O. I.; Nenajdenko,
V. G. Pictet-Spengler Synthesis of Perfluoroalkyl-
ated Tetrahydro-γ-carbolines and Tetrahydro-
pyrrolopyrazines. Synthesis 2020, 52, 263-272.
11. Lee, Y.-M.; Klausen, R. S.; Jacobsen, E. N., Thiourea-
Catalyzed Enantioselective Iso-Pictet-Spengler
Reactions. Org. Lett. 2011, 13 (20), 5564-5567.
12. Yang, W.-L.; Li, C.-Y.; Qin, W.-J.; Tang, F.-F.; Yu, X.;
Deng, W.-P., Cu(I)-Catalyzed Chemoselective and
Stereoselective [3 + 3] Cycloaddition of Azomethine
Ylides with 2-Indolylnitroethylenes: Facile Access to
Highly Substituted Tetrahydro-γ-Carbolines. ACS
Catal. 2016, 6 (9), 5685-5690.
13. Zheng, L.; Bin, Y.; Wang, Y.; Hua, R., Synthesis of
Natural Product-like Polyheterocycles via One-Pot
Cascade Oximation, C-H Activation, and Alkyne
Annulation. J. Org. Chem. 2016, 81 (19), 8911-8919.
14. Aksenov, A. V.; Smirnov, A. N.; Aksenov, N. A.;
Aksenova, I. V.; Frolova, L. V.; Kornienko, A.;
Magedov, I. V.; Rubin, M., Metal-Free Trans-
annulation Reaction of Indoles with Nitrostyrenes:
a Simple Practical Synthesis of 3-Substituted 2-
Quinolones. Chem. Commun. (Cambridge, U. K.)
2013, 49 (81), 9305-9307.
1
7340.
5. Scott, G. K.; Mattie, M. D.; Berger, C. E.; Benz, S.
C.; Benz, C. C., Rapid Alteration of MicroRNA Levels
by Histone Deacetylase Inhibition. Cancer Res.
2006, 66 (3), 1277-1281.
6. De Petrocellis, L.; Bisogno, T.; Davis, J. B.; Pertwee,
R. G.; Di Marzo, V., Overlap between the Ligand
Recognition Properties of the Anandamide
Transporter and the VR1 Vanilloid Receptor:
Inhibitors of Anandamide Uptake with Negligible
Capsaicin-Like Activity. FEBS Lett. 2000, 483 (1), 52-
5
6.
7
.
Chen, L.; Wang, W.; Lee, K. L.; Shen, M. W. H.;
Murphy, E. A.; Zhang, W.; Xu, X.; Tam, S.;
Nickerson-Nutter, C.; Goodwin, D. G.; Clark, J. D.;
McKew, J. C., Reactions of Functionalized
Sulfonamides with Application to Lowering the
Lipophilicity of Cytosolic Phospholipase A2α
Inhibitors. J. Med. Chem. 2009, 52 (4), 1156-1171.
Lee, K. L.; Foley, M. A.; Chen, L.; Behnke, M. L.;
Lovering, F. E.; Kirincich, S. J.; Wang, W.; Shim, J.;
15. Aksenov, A. V.; Smirnov, A. N.; Magedov, I. V.;
Reisenauer, M. R.; Aksenov, N. A.; Aksenova, I. V.;
Pendleton, A. L.; Nguyen, G.; Johnston, R. K.;
Rubin, M.; De Carvalho, A.; Kiss, R.; Mathieu, V.;
8
.
24
ACS Paragon Plus Environment

Page 25 of 26
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Lefranc, F.; Correa, J.; Cavazos, D. A.; Brenner, A.
26. Zhang, X.; Song, X.; Li, H.; Zhang, S.; Chen, X.; Yu,
X.; Wang, W., An Organocatalytic Cascade Approach
toward Polysubstituted Quinolines and Chiral 1,4-
Dihydroquinolines-Unanticipated Effect of N-
Protecting Groups. Angew. Chem., Int. Ed. 2012, 51
(29), 7282-7286.
27. Chelghoum, M.; Bahnous, M.; Bouraiou, A.;
Bouacida, S.; Belfaitah, A., An Efficient and Rapid
Intramolecular aza-Michael Addition of 2'-
Aminochalcones using Ionic Liquids as Recyclable
Reaction Media. Tetrahedron Lett. 2012, 53 (32),
4059-4061.
28. Santos, M. B.; Pinhanelli, V. C.; Garcia, M. A. R.;
Silva, G.; Baek, S. J.; Franca, S. C.; Fachin, A. L.;
Marins, M.; Regasini, L. O., Antiproliferative and
Pro-apoptotic Activities of 2'- and 4'-
Aminochalcones against Tumor Canine Cells. Eur. J.
Med. Chem. 2017, 138, 884-889.
29. Kozlowska, J.; Potaniec, B.; Baczynska, D.;
Zarowska, B.; Aniol, M., Synthesis and Biological
Evaluation of Novel Aminochalcones as Potential
Anticancer and Antimicrobial Agents. Molecules
2019, 24 (22), 4129.
J.; Bryan, B. A.; Rogelj, S.; Kornienko, A.; Frolova,
L. V., Activity of 2-Aryl-2-(3-indolyl)acetohydr-
oxamates against Drug-Resistant Cancer Cells. J.
Med. Chem. 2015, 58 (5), 2206-2220.
16. Segat, G. C.; Moreira, C. G.; Santos, E. C.; Heller,
M.; Schwanke, R. C.; Aksenov, A. V.; Aksenov, N.
A.; Aksenov, D. A.; Kornienko, A.; Marcon, R.;
Calixto, J. B., A New Series of Acetohydroxamates
Shows in vitro and in vivo Anticancer Activity against
Melanoma. Invest. New Drugs 2019, Ahead of Print,
DOI:10.1007/s10637-019-00849-6
7. Aksenov, A. V.; Aksenov, N. A.; Dzhandigova, Z. V.;
Aksenov, D. A.; Rubin, M., Nitroalkenes as
Surrogates for Cyanomethylium Species in a One-
Pot Synthesis of Non-Symmetric Diarylacetonitriles.
RSC Adv. 2015, 5 (129), 106492-106497.
8. Aksenov, A. V.; Aksenov, N. A.; Dzhandigova, Z. V.;
Aksenov, D. A.; Voskressensky, L. G.; Nenajdenko,
V. G.; Rubin, M., Direct Reductive Coupling of
Indoles to Nitrostyrenes en route to (Indol-3-
yl)acetamides. RSC Adv. 2016, 6 (96), 93881-93886.
9. Aksenov, A. V.; Aksenov, N. A.; Dzhandigova, Z. V.;
Aksenova, I. V.; Voskressensky, L. G.; Smirnov, A.
N.; Rubin, M. A., An Efficient Synthesis of (3-Indol-
yl)acetonitriles by Reduction of Hydroxamic Acids.
Chem. Heterocycl. Compd. 2016, 52 (5), 299-302.
0. Borger, M.; Frederich, J. H., Pyridazine N-Oxides as
Precursors to 2-Aminofurans: Scope and Limitations
in Complexity Building Cascade Reactions. Org. Lett.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
1
1
30. Wang, Z.; Xu, X.; Gu, Z.; Feng, W.; Qian, H.; Li, Z.;
Sun, X.; Kwon, O., Nazarov Cyclization of 1,4-
Pentadien-3-ols: Preparation of Cyclopenta[b]-
indoles and Spiro[indene-1,4'-quinoline]s. Chem.
Commun. (Cambridge, U. K.) 2016, 52 (13), 2811-
2814.
2
2
31. Bunce, R. A.; Nammalwar, B., (±)-2-Aryl-2,3-
2
019, 21 (7), 2397-2401.
dihydro-4(1H)-quinolinones
by
a
Tandem
1. Butin, A. V.; Smirnov, S. K.; Stroganova, T. A.;
Bender, W.; Krapivin, G. D., Simple Route to 3-(2-
Indolyl)-1-propanones via a Furan Recyclization
Reaction. Tetrahedron 2007, 63 (2), 474-491.
22. Aksenov, N. A.; Aksenov, D. A.; Arutiunov, N. A.;
Aksenova, D. S.; Aksenov, A. V.; Rubin, M.,
Unexpected Cyclization of ortho-Nitrochalcones
into 2-Alkylideneindolin-3-ones. RSC Advances
2020, 10 (31), 18440-18450.
3. Zhao, F.; Zhao, Q.-J.; Zhao, J.-X.; Zhang, D.-Z.; Wu,
Q.-Y.; Jin, Y.-S., Synthesis and cdc25B Inhibitory
Activity Evaluation of Chalcones. Chem. Nat.
Compd. 2013, 49 (2), 206-214.
4. Lin, Z.; Hu, Z.; Zhang, X.; Dong, J.; Liu, J.-B.; Chen,
D.-Z.; Xu, X., Tandem Synthesis of Pyrrolo[2,3-
b]quinolones via Cadogen-Type Reaction. Org. Lett.
Reduction-Michael Addition Reaction. J. Heterocycl.
Chem. 2011, 48 (3), 613-619.
32. Fosso, M. Y.; LeVine, H., III; Green, K. D.; Tsodikov,
O. V.; Garneau-Tsodikova, S., Effects of Structural
Modifications on the Metal Binding, Anti-Amyloid
Activity, and Cholinesterase Inhibitory Activity of
Chalcones. Org. Biomol. Chem. 2015, 13 (36), 9418-
9426.
33. Abonia, R.; Cuervo, P.; Castillo, J.; Insuasty, B.;
Quiroga, J.; Nogueras, M.; Cobo, J., Unexpected
Intramolecular Cyclization of Some 2'-Amino-
chalcones to Indolin-3-ones Mediated by
Amberlyst-15. Tetrahedron Lett. 2008, 49 (34),
5028-5031.
34. Tokes, A. L.; Janzso, G., Reactions of 2'-Amino-
chalcone. Synth. Commun. 1989, 19 (18), 3159-68.
35. Snyder, H. R.; Elston, C. T., Polyphosphoric Acid as a
Reagent in Organic Chemistry. VI. The Hydrolysis of
Nitriles to Amides. J. Am. Chem. Soc. 1954, 76,
3039-3040.
36. Wang, Z.; Xu, X.; Gu, Z.; Feng, W.; Qian, H.; Li, Z.;
Suna, X.; Kwon, O., Nazarov Cyclization of 1,4-
Pentadien-3-ols: Preparation of Cyclopenta[b]-
2
2
2
2
017, 19 (19), 5284-5287.
5. Xia, Y.; Yang, Z.-Y.; Xia, P.; Bastow, K. F.;
Tachibana, Y.; Kuo, S.-C.; Hamel, E.; Hackl, T.; Lee,
K.-H., Antitumor Agents. 181. Synthesis and
Biological Evaluation of 6,7,2',3',4'-Substituted-
1
,2,3,4-tetrahydro-2-phenyl-4-quinolones as a New
Class of Antimitotic Antitumor Agents. J. Med.
Chem. 1998, 41 (7), 1155-1162.
25
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 26
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
indoles and Spiro[indene-1,4′-quinoline]s. Chem.
Commun. 2016, 52, 2811-2814.
3
7. Fernández García, C.; Marco, J. L.; Alvarez, E. F.,
Synthesis of α- and β-methyl derivatives of 2-[(5-
methoxy-1-methyl)indol-2-yl]ethylamine as selec-
tive inhibitors of monoamine oxidases A and B.
Tetrahedron 1992, 48, 6917-6928.
38. Kim, J.; Chang, S., Iridium-Catalyzed Direct C-H
Amidation with Weakly Coordinating Carbonyl
Directing Groups under Mild Conditions. Angew.
Chem. Int. Ed. 2014, 53 (8), 2203-2207.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
26
ACS Paragon Plus Environment