The indoleacetic acids in IMCRs: a three-component Ugi reaction involving TosMIC

Article abstract of DOI:10.1016/j.tet.2016.07.013

Isocyanide-based MCRs (IMCRs) involving for the first time the biological and pharmaceutical active indoleacetic acids are studied. In particular, the catalytic behavior of 2-acetyl-indoleacetic acid in the Ugi three-component reaction with TosMIC is emph

Full text of DOI:10.1016/j.tet.2016.07.013

Tetrahedron xxx (2016) 1e8
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The indoleacetic acids in IMCRs: a three-component Ugi reaction
involving TosMIC
a
,
b
b
*
Constantinos G. Neochoritis , Despina Livadiotou , Vassilios Tsiaras ,
a
b
Tryfon Zarganes-Tzitzikas , Evanthia Samatidou
Department of Pharmacy, University of Groningen, A. Deusinglaan 1, Groningen 9700AV, The Netherlands
Department of Chemistry, Aristotle University of Thessaloniki, Thessaloniki 54124, Macedonia, Greece
a
b
a r t i c l e i n f o
a b s t r a c t
Article history:
Isocyanide-based MCRs (IMCRs) involving for the first time the biological and pharmaceutical active
indoleacetic acids are studied. In particular, the catalytic behavior of 2-acetyl-indoleacetic acid in the Ugi
three-component reaction with TosMIC is emphasized. The reaction was optimized, revealing the cata-
lytic role of aromatic carboxylic acids as well, yielding a small library of a-aminoamides. Full assignment
of all 1H and C NMR chemical shifts has been unambiguously achieved.
Received 23 April 2016
Received in revised form 18 June 2016
Accepted 4 July 2016
Available online xxx
13
Ó 2016 Elsevier Ltd. All rights reserved.
Keywords:
Multi-component reactions
Ugi reaction
Passerini reaction
TosMIC
Indoleacetic acid
1. Introduction
component Ugi reactions (U-3CR).27e37 In this context, there are
few reports of Ugi reactions in which water acts as an internal
Multicomponent reactions (MCRs), involving at least three
starting materials in a one-pot reaction, remain amongst the most
nucleophile instead of a carboxylic acid (Scheme 1), leading to the
transformation of an aldehyde, a secondary amine, and an iso-
cyanide into an a-aminoamide. List et al. reported the first catalytic
U-3CR with primary amines, employing phenylphosphinic acid as
1,2
efficient method of rapidly introducing molecular diversity. They
provide access to highly functionalized molecules in simple and
straightforward one-step transformations and as such, they have
found widespread use in organic and diversity-oriented syn-
thesis.3 Among the known MCRs to date, the most valuable re-
actions are those based on isocyanides. Isocyanide-based
multicomponent reactions (abbreviated to IMCRs by Ugi and
D o€ mling) have attracted much attention especially in the field of
3
2
the best catalyst for this reaction. Some more applications using
3
8,39
phenylphosphinic acid as a U-3CR promoter are reported,
e5
40
41
whereas Lewis acids such as ZnCl
2
,
ZnO-nanoparticle and
4
2
43
44
boric acid, as well as pTsA and cellulose-SO
3
H
were also found
to catalyze U-3CR reaction among others.
combinatorial chemistry and high throughput screening, by virtue
of their synthetic potential, inherent atom efficiency, convergent
nature, ease of implementation and the generation of molecular
diversity.6
e12
The Ugi four-component reaction (U-4CR) is one of the
milestones in this field and great efforts have been devoted to the
exploration of the potential of this transformation.1,13e15 In recent
years several modifications of the classical U-4CR have been de-
1
6,17
scribed; these include in situ generation of isocyanides,
thesis of macrocycles
syn-
18e20
21e26
or diverse post-modifications.
There has also been much interest concerning the three-
Scheme 1. Ugi four and three-component reaction.
*
Corresponding author. E-mail address: k.neochoritis@rug.nl (C.G. Neochoritis).
http://dx.doi.org/10.1016/j.tet.2016.07.013
040-4020/Ó 2016 Elsevier Ltd. All rights reserved.
0
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2
C.G. Neochoritis et al. / Tetrahedron xxx (2016) 1e8
TosMIC, a multipurpose synthon that was introduced and
elaborated by van Leusen, is a unique and versatile isocyanide that
(10 mol %), where the desired compound was isolated in only 5%
yield with several unidentified, mainly polymerization products
(entry 3). To underscore the potential of our reaction we screened
other aromatic acids as catalysts (Table 1). Benzoic acid proved to
catalyze the reaction, yielding the desired compound in 39% (entry
9). Similar results were obtained using 2-phenylacetic acid as
a catalyst (38% yield, entry 8), whereas in the absence of acid only
the formation of the Schiff base between amine and aldehyde was
observed and the reaction did not proceed any further (entry 4).
4
5
leads to variety of products. Due to its nature, it can react either
from the active methylene or the isocyano group leading to dif-
ferent scaffolds (Fig. 1).4 The most common strategy that in-
corporates the active methylene functionality of TosMIC is the well-
known van Leusen three component reaction (vL-3CR) yielding
6
47e51
1,4,5-trisubstituted imidazoles.
Moreover, a wide range of
other heterocycles are reported such as quinoxalines, oxazolidi-
nones, oxazoles, thiazoles, indoles, triazoles, pyrroles, benzofurans,
and pyrrolopyrimidines5
2,53
besides natural product synthesis e.g.,
Table 1
5
4e56
Variolin B, Porphobilinogen and Mansouramycin B.
TosMIC
Screening of various catalysts and optimization conditions of the reaction
was also utilized, through its isocyano functionality, as a compo-
2
4,57e61
nent in the classical U-4CR
or the Ugi four component-five
center (U5C-4CR).6
2,63
Nevertheless, only in few reports TosMIC
has been demonstrated as a component in the U-3CR; List et al.
describe one example of the U-3CR of TosMIC using phenyl-
ꢀ
32
phosphinic acid in toluene at 80 C and Shaabani et al. using the
4
4
3
biopolymer catalyst cellulose-SO H.
We believe that the U-3CR is of immense importance and re-
quires more investigation in order to fully explore the scope and
limitations, especially at the isocyanide part. New catalysts, which
are easily accessible, cheap and with high functional group toler-
ance are urgently needed. Herein, we wish to report the catalytic
behavior of indoleacetic and other aromatic carboxylic acids in the
U-3CR involving TosMIC as isocyanide. Moreover, the incorporation
of indoleacetic acid, an important bioactive molecule, as a compo-
nent in other isocyanide-based MCRs is described.
Entry
1
R
Conditions
Compound 5d (yield %)
MeOH, rt, 24 ha
57
2
. Results and discussion
Our initial goal was to accomplish Ugi reactions involving
indoleacetic acids due to their biological interest64e66 and TosMIC.
These reactions could be also very easily used for various post-
modifications on account of the plethora of the characteristic
groups available, synthesizing vast libraries with pharmaceutical
interest. As a model reaction, p-methyl-benzaldehyde, p-methyl-
aniline, TosMIC and indoleacetic acid (entries 6 and 7) were allowed
to react in methanol at room temperature for 24 h. To our surprise,
we quickly determined that compound 5d, an U-3CR product, was
isolated in 28% yield instead of the expected Ugi product 6.
Examining the scope and limitations of this reaction (Table 1),
we used the readily available 2-acetyl-indoleacetic acid, which gave
the best results (57% yield, entry 1), followed by the N-methylated
one (33% yield, entry 5). In addition, the reaction was repeated
under reflux, where 5d was isolated in a small yield (11% yield,
entry 2) and with catalytic amount of 2-acetyl-indoleacetic acid
2
MeOH, reflux, 24 ha
11c
3
4
5
MeOH, rt, 24 hb
>5c
d
d
MeOH, rt, 24 ha
MeOH, rt, 24 ha
33
6
7
MeOH, rt, 24 ha
MeOH, rt, 24 ha
28
28
8
9
MeOH, rt, 24 ha
MeOH, rt, 24 ha
38
39
1
1
0
1
H
2
O, 24 ha
d
Me
MeOH, rt, 24 ha
7c
a
b
c
Equimolar quantities of reactants.
Catalytical amount of acid 3.
Degradation and/or polymerization side products observed.
Fig. 1. TosMIC in MCR chemistry; the active methylene versus the
functionality.
a-addition
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C.G. Neochoritis et al. / Tetrahedron xxx (2016) 1e8
3
The reaction also did not progress when methanol was replaced
with water (entry 10). A non-aromatic carboxylic acid as acetic acid,
resulted in poor yields (7% yield, entry 11).
Having the optimized conditions in hand, we designed and
synthesized a library of U-3C derivatives involving aromatic alde-
hydes, amines and TosMIC with moderate to good yields (Scheme 2,
examined whereupon after stirring in MeOH at ambient tempera-
ture for 24 h, the U-4CR products 7a,b were isolated in 66% and 68%
yield, respectively as the only reaction products (Scheme 4). An
analogous reaction was observed when N-methyl-2-acetyl-indo-
leacetic acid 3b was used, leading to formation of the Ugi product
Scheme 4. U-4CR involving the indoleacetic moiety.
7c in 71% yield. It seems that the isocyanide functionality plays an
important role in determining the reaction route, yielding either
the U-4CR or the U-3CR adduct.
A three component, four center reaction (U-4C-3CR) was
attempted by using the indoleacetic acid 3b (as the acid and car-
bonyl component), aniline and cyclohexyl isocyanide, whereupon
the Ugi product 9 was isolated in 22% yield under reflux in toluene.
Amide 8 was isolated in low yield when the reaction performed in
refluxing methanol (Scheme 5).
Scheme 2. U-3CR catalyzed by the 2-acetyl-indoleacetic acid.
We thought that it would be also quite interesting to explore the
Passerini reaction (P-3CR) with the indoleacetic acids. So, the re-
action with p-methyl-benzaldehyde, indoleacetic acid 3a and
cyclohexyl isocyanide proceeded smoothly to give after stirring in
4
9e57%). These findings are of outmost importance, giving easy
access to derivatives 5, which can easily be subjected to post
6
7
2 2
CH Cl at ambient temperature for 24 h the Passerini product 10a in
modifications. The catalysts are easily prepared and the reaction
is scalable. A plausible mechanism is given in Scheme 3. This re-
action, to the best of our knowledge, is the first example of a three
component Ugi reaction catalyzed by indoleacetic acids.
59% yield as the only reaction product (Scheme 6). The reaction
Next, we wanted to expand the scope of the reaction utilizing
classical isocyanides. Thus, the Ugi reaction involving aniline,
benzaldehyde, indoleacetic acid 3a and cyclohexyl isocyanide was
Scheme 5. Example of the U-4C-3CR bearing the 2-acetyl-indole acetic acid leading to
a tetrahydro-1H-pyrido[3,4-b]indole.
Scheme 3. Plausible mechanism of the novel catalytic U-3CR.
Scheme 6. Investigation of the P-3CR involving indoleacetic acids 3.
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4
C.G. Neochoritis et al. / Tetrahedron xxx (2016) 1e8
2
00
with N-methyl-2-acetyl-indoleacetic acid 3b proceeded analo-
gously to give 10b in 54% yield. The reaction was also repeated
using TosMIC as the isocyanide component, in an attempt to isolate
the classical Passerini product, but unfortunately, the only isolated
H-2 gives COLOC correlation via a J with carbons at 131.9
d
(C-1 ),
000
d (C-1 ) and 168.9 d (1-CO), the H-5 via J with carbons at
2
140.6
107.8
d
0000
3
d
(C-3 ) and 172.0 d (C-4) and via J with the carbon at 127.9
(C-2 ). The protons of the methyl at 3.70
correlation with the carbons at 127.9
whereas the protons of the methyl at 2.22
0
000
3
d
(NeMe) show a
J
6
8
0000
0000
product was the TosMIC dimer compound 11 in 32% yield.
d
(C-2 ) and 136.8
d
(C-7a ),
2
d
(2-Me) show a J cor-
0
0
3
relation with the carbons at 137.8
d
(C-4 ) and J with the carbons at
2
.1. Structure assignments of the new compounds
0
0
00
0000
1
28.7
d
3
(C-3 , C-5 ). The H-4 at 7.30 show COLOC correlation via
d
2
0000 0000
3
J and J with the carbons at 121.4
with the carbons at 107.8
d (C-5 ), 127.6 d (C-3a ) and J
(C-3 ) and 136.8
correlates via J with the carbons at 118.8
The assigned molecular structures of the new compounds 5d,
b, and 10a were based on rigorous spectroscopic analysis in-
cluding IR, NMR ( H, C, HeH COSY, HeH NOESY, HMQC and
0
000
0000
0000
d
d
(C-7a ). The H-5
7
2
0000
1
13
d
(C-4 ) and 119.0
d
(C-
0
000
0000
2
6
d
), the H-6 at 6.99
d
correlates via J with the carbons at 108.9
(C-5 ), the H-2 at 6.80
HMBC), MS and elemental analysis data. The HMBC correlations of
2
3
4
0000
0000
0000
3
2
(C-7 ) and 121.4
d
d
correlates via
J
protons with carbons via J, J and J coupling are depicted in
Fig. 2AeC. Concerning the structure elucidation of the U-3CR ad-
ducts, the derivative 5d was studied. In IR, a strong absorption at
0
000
with the carbon at 107.8
d
(C-3 ) and J with the carbons at 127.6
(C-7a ). Finally, we detect NOESY in-
0
000
0000
d
(C-3a ) and 136.9
d
ꢁ
1
0000
0000
teractions between NeMe protons with the H-2 and H-7 and
8
11 cm was observed correlating to the p-substitution of the
ꢁ
1
0000
0000
.
between 5-CH
Compound 10a has similar structure to 7b (Fig. 2C). In H NMR
the equatorial protons of the cyclohexyl group (1.36e1.49 ) appear
at lower field than the axial (0.16e1.18 ). The NH appears as
a broad double peak at 5.58 , H-2 as single at 6.03 with its carbon
at 75.1 and the eCH appears as single at 3.80 with its carbon at
31.4 . The two methyl groups, (NeMe) and (4 -Me), appear at 3.70
(carbon at 32.5 ) and 2.30 (carbon at 21.1 ), respectively. The
protons H-4 and H-7 of the indole appear as double peaks at
7.66 and 7.32 , with their carbons at 118.7 and 109.5 , re-
spectively. H-5 and H-6 appear as double of doublets at 7.27 kai
2
protons with H-2 and H-4
aromatic ring. In addition, two absorptions at 3350 cm and one
1
ꢁ1
strong at 1689 cm for the two amino groups and the C]O re-
spectively, are observed. In NMR, the aromatic protons are well
defined through their 2J and J COLOC correlations as depicted in
Fig. 2A. The protons of the methyl group at 2.36
correlation with the carbon at 138.6
d
3
d
0
2
d
d
d
(4 -Me), show a J
0
3
d
d
d
(C-1 ) and J with the carbon
2
0
0
0 0
d
at 29.87
at 2.25
d (C-3 , C-5 ). Furthermore, the protons of the methyl group
0
0
2
d
d
d
d
d
(4 -Me) show a J correlation with the carbon at 128.9
d
(C-
3
00
00
0
00
000
0
0
4
) and J with the carbons at 129.93 d (C-3 , C-5 ). Finally, the
000
2
d
00
d
d
protons of the methyl group at 2.38 d (4 -Me) show a J correlation
3
0
000
000
with the carbon at 45.1 d (C-4 ) and J with the carbon at 129.8 d (C-
0
00
0
00
000
7.18
d
, with their carbons at 122.0
(carbon at 127.8
H-2 and H-6 appear as a triplet at 7.26 (carbon at 129.1
and H-3 and H-5 appear as triplet at 7.13 (carbon at 127.3
ꢂC).
d
and 119.7
d
, whereas the H-2
). In the phenyl ring,
, 2ꢂC)
3
d
, C-5 ). The H-2 gives a correlation with the carbons at 127.2
0
0
0
00
appears as a singlet at 7.00
d
d
(C-2 , C-6 ), 135.0
protons of the methylene group correlate via J with the tertiary
d
(C-1 ), 144.0
d
(C-1 ) and 171.5
d
(C-1). The
3
00
00
d
d
0
0
00
d
d,
carbon at 171.5
d (C-1).
Concerning compound 7b (Fig. 2B), in 1H NMR the equatorial
2
protons of the cyclohexyl group (1.45e1.90
d
) resonate at lower
0
field than the axial (0.85e1.37
d
). The H-4 (1.55e1.65, equitorial)
3. Conclusion
3
0
gives COLOC correlations via J with the carbons at 32.63
d
(C-2 )
0
and 32.59
d
(C-6 ). The NH appears as a broad double peak at 5.84
d
,
In conclusion, we have investigated the role and behaviour of
various indoleacetic acid derivatives in Ugi and Passerini reactions.
It was also emphasized that most possibly depending on the nature
whereas the H-2 as single at 6.06
d
with its carbon at 65.2
d. The 5-
CH appears as a single peak at 3.54
2
d
with its carbon at 31.6 d
. The
Fig. 2. Diagnostic COLOC correlations between protons and carbons (via 2
J
CeH, 3 CeH and 4
J JCeH) observed in compounds 5d (A), 7b (B) and 10a (C).
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C.G. Neochoritis et al. / Tetrahedron xxx (2016) 1e8
5
0
0
0
0
0
of isocyanide, indoleacetic acid derivatives could either play a cat-
alytic role driving the reaction to an U-3CR, or being incorporated
into an U-4CR and P-3CR, respectively. Useful insights to the cata-
lyzed U-3CR by various aromatic acids were also given by synthe-
sizing a small library. We believe that this study will add to the
TosMIC chemistry and can serve as a starting point for further
investigations.
7.32e7.38 (m, 5H, H-2 , H-6 , H-3 , H-5 , H-4 ), 7.54 (br t, 1H, 1-NH),
0
00
000 13
00
7.54 (d, J¼8.0 Hz, 2H, H-2 , H-6 ). C NMR (CDCl
3
)
d
20.5 (4 -Me),
0
0
00
00
00
21.7 (4 -Me), 60.1 (1-CH
2
), 64.5 (2-CH), 114.2 (C-2 , C-6 ), 127.3 (C-
0
000
000
0
00
0
2 , C-6 ), 128.7 (C-2 , C-6 ), 128.8 (C-4 ), 129.2 (C-4 ), 129.3 (C-3 ,
0
000
000
00
00
000
C-5 ), 129.9 (C-3 , C-5 ), 130.0 (C-3 , C-5 ), 134.0 (C-1 ), 137.9 (C-
0
00
000
ꢁ1
1 ), 143.9 (C-1 ), 145.2 (C-4 ), 171.3 (1-CO). IR (Nujol) cm 697,
759, 814, 1523, 1619, 1690. MS (LCMS) m/z (%) calcd for
þ
þ
C
23
24
H N
2
O
3
S, M þH: 409; found: 409 (31%, M þH), 431 (75%,
þ
þ
þ
4
4
. Experimental
M þNa), 447 (100%, M þK). HRMS (ESI) m/z calcd [MþH] :
þ
4
09.51326; found [MþH] : 409.51319.
.1. General
4
.2.3. 2-(Phenylamino)-2-(p-tolyl)-N-(tosylmethyl)acetamide
ꢀ
1
Column chromatography was carried out using Merck silica gel.
(5c). Brown crystals (0.200 g, 49% yield), mp 137e140 C; H NMR
0
0
0
0
TLC was performed using precoated silica gel glass plates 0.25 mm
containing fluorescent indicator UV254 purchased from Macherey-
Nagel using a 3:1 mixture of petroleum ether/ethyl acetate. Pe-
(CDCl
NH), 4.53 (dd, J¼6.5, 14.1 Hz, 1H, 1-CH), 4.66 (s, 1H, 2-CH), 4.75 (dd,
3
) d 2.36 (s, 3H, 4 -Me), 2.38 (s, 3H, 4 -Me), 4.39 (br s, 1H, 2-
00
00
J¼7.2, 14.1 Hz, 1H, 1-CH), 6.55 (dd, J¼0.9, 7.7 Hz, 2H, H-2 , H-6 ),
ꢀ
00
0
0
0
troleum ether refers to the fraction boiling between 60 and 80 C.
6.82 (tt, J¼0.8, 7.4 Hz, 1H, H-4 ), 7.13e7.25 (m, 8H, H-2 , H-6 , H-3 ,
0
00
00
000
000
000
000
NMR spectra were recorded at room temperature on a Bruker AM
H-5 , H-3 , H-5 , H-3 , H-5 ), 7.54 (d, J¼8.2 Hz, 2H, H-2 , H-6 ),
1
13
13
0
3
00 spectrometer at 300 MHz for H and 75 MHz for C, re-
spectively, using CDCl as solvent. Chemical shifts are expressed in
values (ppm) relative to TMS as internal standard for H and
7.57 (br t, J¼6.5 Hz, 1H, 1-NH). C NMR (CDCl
3
) d 21.2 (4 -Me), 21.7
000 00 00 00
2
(4 -Me), 60.1 (1-CH ), 63.7 (2-CH), 114.1 (C-2 , C-6 ), 119.6 (C-4 ),
3
1
0 0 000 000 00 00
127.2 (C-2 , C-6 ), 128.7 (C-2 , C-6 ), 129.5 (C-3 , C-5 ), 129.85 (C-
d
1
3
000 000 0 0 000 0 0
3 , C-5 ),129.95 (C-3 , C-5 ),134.0 (C-1 ),134.8 (C-1 ),138.7 (C-4 ),
relative to TMS (0.00 ppm) or to CDCl
3
(77.05 ppm) for C NMR
n
1
00
000
ꢁ1
spectra. Coupling constants J are reported in Hz. Second order H
spectra in the aromatic region, where it was possible, were ana-
lysed by simulation.69 Low-resolution electron impact mass spectra
were recorded on a 6890N LC/MS system (Agilent Technology) and
high resolution mass spectra were recorded using a LTQ-Orbitrap-
XL (Thermo) at a resolution of 60000@m/z400. Structural assign-
ments of the derived compounds were established by analysis of
145.2 (C-1 ), 146.2 (C-4 ), 171.3 (1-CO). IR (Nujol) cm 691, 748,
811, 1509, 1604, 1686, 3350. MS (LCMS) m/z (%) calcd for
þ
þ
C
23
24
H N
2
O
3
S, M þH: 409; found: 409 (3%, M þH), 431 (59%,
þ
þ
þ
M þNa), 447 (100%, M þK). HRMS (ESI) m/z calcd [MþH] :
þ
409.51326; found [MþH] : 409.51310.
4.2.4. 2-(p-Tolyl)-2-(p-tolylamino)-N-(tosylmethyl)acetamide
1
13
ꢀ
1
their MS and NMR spectra ( H, C, DEPT, HeH COSY, HeH NOESY,
(5d). Yellow crystals (0.241 g, 57% yield), mp 171e173 C; H NMR
00 0 000
3
(CDCl ) d 2.25 (s, 3H, 4 -Me), 2.36 (s, 3H, 4 -Me), 2.38 (s, 3H, 4 -
HETCOR and COLOC).
Me), 4.22 (br s, 1H, 2-NH), 4.51 (dd, J¼6.4,14.2 Hz,1H,1-CH), 4.62 (s,
4
.2. General procedure for the U-3CR reaction with TosMIC
1H, 2-CH), 4.78 (dd, J¼7.3, 14.2 Hz, 1H, 1-CH), 6.47 (d, J¼8.2 Hz, 2H,
0
0
0
0
00
00
000
0
00
0
000
00
0
000
H-2 , H-6 ), 6.99 (d, J¼8.2 Hz, 2H, H-3 , H-5 ), 7.13 (d, J¼8.1 Hz, 2H,
To a stirred solution of the amines 1aed (1.0 mmol) in methanol
H-3 , H-5 ), 7.15 (d, J¼8.3 Hz, 2H, H-3 , H-5 ), 7.20 (d, J¼8.3 Hz, 2H,
(
8 mL), the corresponding aldehydes 2aed (1.0 mmol) were added
and the reaction mixture stirred at rt for 1 h. Then, the catalyst 3c
1.0 mmol) was added, the reaction mixture stirred for additional
5 min, followed by the addition of TosMIC (1.0 mmol). After 24 h at
H-2 , H-6 ), 7.54 (d, J¼8.1 Hz, 2H, H-2 , H-6 ), 7.54 (br t, J¼7.2 Hz,
13
00 0 000
1H, 1-NH). C NMR (CDCl
Me), 60.1 (1-CH ), 64.0 (2-CH), 114.1 (C-2 , C-6 ), 127.2 (C-2 , C-6 ),
3
) d 20.4 (4 -Me), 21.2 (4 -Me), 21.7 (4 -
0
0
00
0
0
(
1
2
000 000 00 000 000 0
128.7 (C-2 , C-6 ),128.9 (C-4 ),129.8 (C-3 , C-5 ),129.87 (C-3 , C-
0 00 00 000 0 0
5 ), 129.93 (C-3 , C-5 ), 134.0 (C-1 ), 135.0 (C-1 ), 138.6 (C-4 ), 144.0
rt, the solvent was removed and the resulting residue was sub-
jected to column chromatography on silica gel using petroleum
ether/AcOEt (7:1 and 3:1 for the derivatives 5aef and 5geh, re-
spectively) as eluent affording the compounds 5aeh.
0
0
000
ꢁ1
(C-1 ), 145.1 (C-4 ), 171.5 (1-CO). IR (Nujol) cm 811, 1524, 1619,
1689, 3350. MS (LCMS) m/z (%) calcd for C24
þ
H
26
N
2
O
3
S, M þH: 423;
þ
þ
þ
found: 423 (9%, M þH), 445 (62%, M þNa), 461 (100%, M þK).
þ
þ
HRMS (ESI) m/z calcd [MþH] : 423.53984; found [MþH] :
4
.2.1. 2-Phenyl-2-(phenylamino)-N-(tosylmethyl)acetamide
423.53955.
ꢀ
1
(5a). Yellow crystals (0.221 g, 56% yield), mp 158e159 C; H NMR
0
00
(
CDCl
3
)
d
2.38 (s, 3H, 4 -Me), 4.55 (dd, J¼6.5, 14.2 Hz, 1H, 1-CH),
4.2.5. 2-((4-Methoxyphenyl)amino)-2-(p-tolyl)-N-(tosylmethyl)
acetamide (5e). Yellow crystals (0.237 g, 54% yield), mp
4
.71 (s, 1H, 2-CH), 4.79 (dd, J¼7.3, 14.2 Hz, 1H, 1-CH), 6.57 (d,
0
0
00
00
ꢀ
1
0
000
J¼7.8 Hz, 2H, H-2 , H-6 ), 6.83 (t, J¼7.3 Hz, 1H, H-4 ), 7.13e7.22 (m,
135e136 C; H NMR (CDCl
3
)
d
2.36 (s, 3H, 4 -Me), 2.37 (s, 3H, 4 -
0
0
00
000
000
0
0
0
00
4
5
1
H, H-3 , H-5 , H-3 , H-5 ), 7.33e7.41 (m, 5H, H-2 , H-6 , H-3 , H-
Me), 3.73 (s, 3H, 4 -OMe), 4.17 (br s, 1H, 2-NH), 4.53 (dd, J¼6.5,
0
0
000
000
, H-4 ), 7.54 (d, J¼8.3 Hz, 2H, H-2 , H-6 ), 7.60 (br t, J¼7.3 Hz, 1H,
14.2 Hz, 1H, 1-CH), 4.59 (s, 1H, 2-CH), 4.75 (dd, J¼7.2, 14.2 Hz, 1H, 1-
-NH). 13C NMR (CDCl
)
d
21.7 (4 -Me), 60.1 (1-CH
000
), 64.0 (2-CH),
CH), 6.51 (d, J¼8.9 Hz, 2H, H-2 , H-6 ), 6.76 (d, J¼8.9 Hz, 2H, H-3 ,
00
00
00
0
000
0
3
2
0
0
00
00
0
0
000
000
00
0
000
000
000
114.0 (C-2 , C-6 ), 119.7 (C-4 ),127.3 (C-2 , C-6 ),128.6 (C-2 , C-6 ),
H-5 ),7.13 (d, J¼8.0 Hz, 2H, H-3 , H-5 ), 7.14 (d, J¼8.2 Hz, 2H, H-3 ,
0
0
0
00
00
000
0
0
128.9 (C-4 ), 129.3 (C-3 , C-5 ), 129.5 (C-3 , C-5 ), 129.9 (C-3 , C-
H-5 ), 7.20 (d, J¼8.2 Hz, 2H, H-2 , H-6 ), 7.53 (d, J¼8.2 Hz, 2H, H-2 ,
13
0
00
000
0
00
000
5
), 133.6 (C-1 ), 134.0 (C-1 ), 145.2 (C-1 ), 146.2 (C-4 ), 171.1 (1-
H-6 ), 7.60 (br t, J¼6.7 Hz, 1H, 1-NH). C NMR (CDCl
3
)
d
21.1 (4 -
000
2
Me), 21.7 (4 -Me), 60.1 (1-CH ), 64.5 (2-CH), 55.7 (4 -OMe), 115.0
ꢁ
1
00
CO). IR (Nujol) cm 694, 746, 1513, 1605, 1677. MS (LCMS) m/z
þ
þ
þ
00 00 00 00 0 0 000 000
(
(
3
%) calcd for C22
H
22
N
2
O
3
S, M þH: 395; found: 395 (5%, M þH), 417
(C-2 , C-6 ), 115.3 (C-3 , C-5 ), 127.1 (C-2 , C-6 ), 128.6 (C-2 , C-6 ),
þ
þ
000 000 0 0 000 0
129.79 (C-3 , C-5 ), 129.83 (C-3 , C-5 ), 134.1 (C-1 ), 135.0 (C-1 ),
100%, M þNa), 433 (18%, M þK). HRMS (ESI) m/z calcd [MþH] :
þ
0 00 000 00
138.5 (C-4 ), 140.3 (C-1 ), 145.1 (C-4 ), 153.6 (C-4 ), 171.6 (1-CO). IR
95.48668; found [MþH] : 395.48625.
ꢁ
1
(
Nujol) cm 813, 1085, 1513, 1597, 1689. MS (LCMS) m/z (%) calcd
þ
þ
4
.2.2. 2-Phenyl-2-(p-tolylamino)-N-(tosylmethyl)acetamide
for C24
H
26
N
2
O
4
S, M þH: 439; found: 439 (13%, M þH), 461 (55%,
ꢀ
1
þ
þ
þ
þ
(5b). Yellow crystals (0.200 g, 49% yield), mp 160e162 C; H NMR
M þNa), 477 (100%, M þK). HRMS (ESI) m/z calcd [MþH] :
00
000
(
CDCl
3
)
d
2.26 (s, 1H, 4 -Me), 2.38 (s, 3H, 4 -Me), 4.20 (br s, 1H, 2-
439.53924; found [MþH] : 439.53911.
NH), 4.51 (dd, J¼6.2, 14.3 Hz, 1H, 1-CH), 4.65 (s, 1H, 2-CH), 4.85 (dd,
00
00
J¼7.5, 14.3 Hz, 1H, 1-CH), 6.49 (d, J¼8.0 Hz, 2H, H-2 , H-6 ), 7.01 (d,
4.2.6. 2-(4-Methoxyphenyl)-2-(p-tolylamino)-N-(tosylmethyl) acet-
0
0
00
000
000
ꢀ
1
J¼8.0 Hz, 2H, H-3 , H-5 ), 7.14 (d, J¼7.8 Hz, 2H, H-3 , H-5 ),
amide (5f). Yellow crystals (0.232 g, 53% yield), mp 174e176 C; H
Please cite this article in press as: Neochoritis, C. G.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.07.013

6
C.G. Neochoritis et al. / Tetrahedron xxx (2016) 1e8
0
0
000
0
0
0
0
0
000
NMR (CDCl
4
4
3
)
d
2.24 (s, 3H, 4 -Me), 2.37 (s, 3H, 4 -Me), 3.79 (s, 3H,
H
ax-5 ), 1.53e1.62 (m, 1H, Heq-4 ), 1.79e1.90 (m, 2H, Heq-2 , Heq-6 ),
0
-OMe),4.22 (br s, 1H, 2-NH), 4.49 (dd, J¼6.4, 14.1 Hz, 1H, 1-CH),
3.56 (s, 2H, 5-CH
2
), 3.70 (s, 3H, NeMe), 3.78e3.87 (m, 1H, Hax-1 ),
0
.62 (s, 1H, 2-CH), 4.75 (dd, J¼7.2, 14.1 Hz, 1H, 1-CH), 6.46 (d,
5.73 (br d, J¼6.1 Hz,1H,1-NH), 6.06 (s, 1H, 2-CH), 6.83 (s, 1H, H-2 ),
0
0
00
00
00
00 00 00 00 00 000 000 000
J¼8.3 Hz, 2H, H-2 , H-6 ), 6.85 (d, J¼8.7 Hz, 2H, H-3 , H-5 ),6.97 (d,
6.99e7.28 (m, 13H, H-2 , H-3 , H-4 , H-5 , H-6 , H-2 , H-3 , H-4 ,
0
0
000
000
000
000
0000
0000
0
0000
0000 13
J¼8.0 Hz, 2H, H-3 , H-5 ), 7.13 (d, J¼8.1 Hz, 2H, H-3 , H-5 ), 7.22 (d,
H-5 , H-6 , H-5 , H-6 , H-7 ), 7.32 (d, J¼7.9 Hz, 1H, H-4 ).
C
0
0
000
000
0
0
J¼8.6 Hz, 2H, H-2 , H-6 ), 7.54 (d, J¼8.3 Hz, 2H, H-2 , H-6 ), 7.59 (br
NMR (CDCl
3
)
d
24.7 (C-5 ), 24.8 (C-3 ), 25.3 (C-4 ), 31.6 (5-CH
2
), 32.6
t, 1H, 1-NH). 13C NMR (CDCl
OMe), 60.2 (1-CH ), 63.6 (2-CH), 114.1 (C-2 , C-6 ), 114.6 (C-3 , C-5 ),
71.7 (1-CO), 128.5 (C-2 , C-6 ), 128.8 (C-4 ), 129.8 (C-3 , C-5 ),
)
d
20.4 (4 -Me), 21.6 (4 -Me), 55.3 (4 -
00
000
0
0
(NeMe), 32.6 (C-2 , C-6 ), 48.5 (C-1 ), 65.1 (2-CH), 107.5 (C-3 ),
0 0 0 0000
3
00
00
0
0000 0000 0000 0000
108.9 (C-7 ), 118.7 (C-4 ), 118.9 (C-6 ), 121.3 (C-5 ), 127.6 (C-
2
0
0
00
000
000
0000 000 0000 00 00 00
3a ), 127.8 (C-4 ), 128.0 (C-2 ), 128.1 (C-3 , C-5 ), 128.7 (C-1 ),
1
1
4
0
0
00
000
000
0
00
ꢁ1
000 000 000 000 00 00
129.1 (C-2 , C-6 ), 130.3 (C-3 , C-5 ), 130.4 (C-2 , C-6 ), 134.7 (C-
29.9 (C-3 , C-5 ), 130.1 (C-1 ), 134.2 (C-1 ), 144.0 (C-1 ), 160.0 (C-
), 128.7 (C-2 , C-6 ), 145.1 (C-4 ). IR (Nujol) cm 812, 1085,
510, 1618, 1686. MS (LCMS) m/z (%) calcd for C24
0
000
000
0000
00
000
7a ), 136.6 (C-4 ), 140.2 (C-1 ), 168.7 (1-CO), 172.1 (4-CO). MS
(LCMS) m/z (%) calcd for C31
þ
þ
þ
1
4
H
26
N
2
O
4
S, M þH:
H
33
N
3
O
2
, M þH: 480; found: 480 (8%,
þ
þ
þ
þ
þ
39; found 439 (4%, M þH), 461 (41%, M þNa), 477 (100%, M þK).
M þH), 502 (68%, M þNa), 518 (100%, M þK). HRMS (ESI) m/z
þ
þ
þ
þ
HRMS (ESI) m/z calcd [MþH] : 439.53924; found [MþH] :
calcd [MþH] : 480.61262; found [MþH] : 480.61258.
4
39.53922.
4.3.2. N-Cyclohexyl-2-(2-(1-methyl-1H-indol-3-yl)-N-phenyl acet-
4
.2.7. 2-((4-Chlorophenyl)amino)-2-(p-tolyl)-N-(tosylmethyl)acet-
amido)-2-(p-tolyl)acetamide (7b). Yellow oil (0.335 g, 68% yield);
ꢀ
1
1
0
0
amide (5g). Yellow crystals (0.239 g, 54% yield), mp 166e168 C; H
NMR (CDCl
H NMR (CDCl
3
)
d
0.85e1.00 (m, 2H, Hax-2 , Hax-6 ), 1.00e1.10 (m,
0
000
0
0
0
3
)
d
2.38 (s, 3H, 4 -Me), 2.40 (s, 3H, 4 -Me), 4.59 (dd,
1H, Hax-4 ), 1.20e1.37 (m, 2H, Hax-3 , Hax-5 ), 1.45e1.60 (m, 2H, Heq
-
-
0
0
0
0
0
J¼6.6, 14.2 Hz, 1H, 1-CH), 4.63 (s, 1H, 2-CH), 4.73 (dd, J¼6.8, 14.2 Hz,
3 , Heq-5 ), 1.55e1.65 (m, 1H, Heq-4 ), 1.72e1.90 (m, 2H, Heq-2 , Heq
0
000
0
00
000
00
1
H, 1-CH), 6.46 (d, J¼8.7 Hz, 2H, H-2 , H-6 ), 7.11 (d, J¼8.7 Hz, 2H,
6 ), 2.22 (s, 3H, 4 -Me), 3.54 (s, 2H, 5-CH
2
), 3.70 (s, 3H, NeMe),
0
0
00
0
H-3 , H-5 ),7.16 (d, J¼8.1 Hz, 2H, H-3 , H-5 ), 7.19 (d, J¼8.3 Hz, 2H,
3.70e3.82 (m, 1H, Hax-1 ), 5.84 (br d, J¼7.4 Hz, 1H, 1-NH), 6.06 (s,
0
0
0
0
0000
000
H-3 , H-5 ), 7.22 (d, J¼8.3 Hz, 2H, H-2 , H-6 ), 7.34 (br t, J¼6.6 Hz, 1H,
1H, 2-CH), 6.80 (s, 1H, H-2 ), 6.92 (t, J¼8.0 Hz, 1H, H-4 ), 6.94 (t,
0
00
000 13
00
00
0000
1
-NH), 7.52 (d, J¼8.2 Hz, 2H, H-2 , H-6 ). C NMR (CDCl
3
)
d
21.2
J¼7.0 Hz, 2H, H-3 , H-5 ), 6.99 (m, 1H, H-6 ), 7.01 (t, J¼8.0 Hz, 2H,
0
000
00
00
00 00 0000 000 000
(
4 -Me), 21.7 (4 -Me), 60.1 (1-CH
2
), 63.5 (2-CH), 115.1 (C-2 , C-6 ),
H-2 , H-6 ), 7.11 (m, 1H, H-5 ), 7.13 (m, 2H, H-3 , H-5 ), 7.16 (t,
0
0
0
0
000
000
00
000
000
0000
124.3 (C-4 ), 127.1 (C-2 , C-6 ), 128.6 (C-2 , C-6 ), 129.3 (C-3 , C-
J¼8.3 Hz, 2H, H-2 , H-6 ), 7.19 (d, J¼8.2 Hz, 1H, H-7 ), 7.30 (d,
0
0
000
000
0
0
000
000
0
0000 13
00
0
0
5
), 129.9 (C-3 , C-5 ), 130.1 (C-3 , C-5 ), 133.9 (C-1 ), 134.5 (C-1 ),
J¼7.9 Hz, 1H, H-4 ). C NMR (CDCl
3
)
d
21.0 (4 -Me), 24.6 (C-5 ),
0
00
0
0
139.0 (C-4 ), 144.7 (C-1 ), 145.3 (C-4 ), 170.9 (1-CO). IR (Nujol)
24.7 (C-3 ), 25.5 (C-4 ), 31.6 (5-CH
2
), 32.4 (NeMe), 32.59 (C-6 ),
ꢁ
1
0 0 0000 0000
cm
C
4
812, 1503, 1601, 1686. MS (LCMS) m/z (%) calcd for
32.63 (C-2 ), 48.5 (C-1 ), 65.2 (2-CH), 107.8 (C-3 ), 108.9 (C-7 ),
þ
þ
0000 0000 0000 0000
118.8 (C-4 ), 119.0 (C-6 ), 121.4 (C-5 ), 127.6 (C-3a ), 127.8 (C-
23
H23ClN
2
O
3
S, M þH: 443; found: 465/467 (81%, M þNa), 481/
þ
þ
000 0000 00 00 000 000
4 ), 127.9 (C-2 ), 128.7 (C-3 , C-5 ), 128.8 (C-2 , C-6 ), 130.2 (C-
83 (100%, M þK). HRMS (ESI) m/z calcd [MþH] : 443.95832;
þ
000 000 00 00 00 0000
3 , C-5 ), 130.5 (C-2 , C-6 ), 131.9 (C-1 ), 136.8 (C-7a ), 137.8 (C-
found [MþH] : 443.95825.
0
0
000
4
), 140.6 (C-1 ), 168.9 (1-CO), 172.0 (4-CO). MS (LCMS) m/z (%)
þ
þ
4
.2.8. 2-(4-Chlorophenyl)-2-(p-tolylamino)-N-(tosylmethyl)acet-
calcd for C32
H
35
N
3
O
2
, M þH: 494; found: 494 (7%, M þH), 516
ꢀ
1
þ
þ
þ
amide (5h). Yellow crystals (0.234 g, 53% yield), mp 179e181 C; H
NMR (CDCl
(70%, M þNa), 532 (100%, M þK). HRMS (ESI) m/z calcd [MþH] :
0
000
þ
3
)
d
2.25 (s, 3H, 4 -Me), 2.40 (s, 3H, 4 -Me), 4.81 (dd,
494.63920; found [MþH] : 494.63919.
J¼7.4, 14.2 Hz, 1H, 1-CH), 4.51 (dd, J¼6.2, 14.2 Hz, 1H, 1-CH), 4.66 (s,
0
0
1
3
2
H, 2-CH), 7.25 (d, J¼8.7 Hz, 2H, H-2 , H-6 ), 7.31 (d, J¼8.6 Hz, 2H, H-
4.3.3. 2-(2-Acetyl-1-methyl-1H-indol-3-yl)-N-(2-(cyclohexylamino)-
0
0
00
00
, H-5 ), 4.27 (br s, 1H, 2-NH), 2.25 (s, 3H, 4 -Me), 6.47 (d, J¼8.3 Hz,
2-oxo-1-(p-tolyl)ethyl)-N-phenylacetamide
(0.380 g, 71% yield), mp 225 C; H NMR (CDCl
(7c). White
solid
0
0
00
00
000
ꢀ
1
H, H-2 , H-6 ), 6.99 (d, J¼8.1 Hz, 2H, H-3 , H-5 ), 2.39 (s, 3H, 4 -
3
)
d
0.91e1.05 (m, 2H,
0
00
000
000
0
0
0
0
Me), 7.53 (d, J¼8.2 Hz, 2H, H-2 , H-6 ), 7.15 (d, J¼8.0 Hz, 2H, H-3 ,
H
H
ax-2 , Hax-6 ), 1.08e1.12 (m, 1H, Hax-4 ), 1.24e1.34 (m, 2H, Hax-3 ,
0
00 13
00
000
0
000
0
0
0
0
H-5 ). C NMR (CDCl
3
)
d
20.4 (4 -Me), 21.7 (4 -Me), 60.0 (1-CH
2
),
ax-5 ), 1.57e1.61 (m, 2H, Heq-3 , Heq-5 ), 1.65 (m, 1H, Heq-4 ),
0
0
00
0
000
0
0
0000
6
6
3.4 (2-CH),114.1 (C-2 , C-6 ), 128.57 (C-2 , C-6 ), 128.63 (C-2 , C-
1.80e1.90 (m, 2H, Heq-2 , Heq-6 ), 2.26 (s, 3H, 2 -Me), 2.56 (s, 3H,
4 -Me), 3.73e3.79 (m, 1H, Hax-1 ), 3.81 (s, 2H, 5-CH
0
00
00
0
0
000
00
00
0
),129.2 (C-4 ), 129.3 (C-3 , C-5 ), 129.8 (C-3 , C-5 ),130.0 (C-3 ,
2
), 3.92 (s, 3H,
0
0
000
0
0
00
C-5 ), 133.9 (C-1 ), 134.7 (C-1 ), 136.4 (C-4 ), 143.6 (C-1 ), 145.3 (C-
4
m/z (%) calcd for C23
NeMe), 5.60 (br d, J¼7.8 Hz, 1H, 1-NH), 6.02 (s, 1H, 2-CH), 6.96 (t,
0
00
ꢁ1
000
00
00
), 171.0 (1-CO). IR (Nujol) cm 815, 1522, 1618, 1686. MS (LCMS)
J¼8.3 Hz, 1H, H-4 ), 6.99 (t, J¼8.2 Hz, 2H, H-3 , H-5 ), 7.08 (t,
þ
00
00
0000
H
23ClN
2
O
3
S, M þH: 443; found: 465/467 (53%,
J¼7.9 Hz, 2H, H-2 , H-6 ), 7.09 (ddd, J¼2.3, 8.0, 8.1 Hz, 1H, H-6 ),
þ
þ
þ
000 000 000 000 0000 0000
M þNa), 481/483 (100%, M þK). HRMS (ESI) m/z calcd [MþH] :
7.25e7.35 (m, 6H, H-2 , H-3 , H-5 , H-6 , H-5 , H-7 ), 7.50 (d,
þ
0000 13
0000
00
4
43.95832; found [MþH] : 443.95799.
J¼8.0 Hz, 1H, H-4 ). C NMR (CDCl
3
)
d
15.2 (2 -Me), 21.0 (4 -Me),
0
0
0
0
2
4.8 (C-3 , C-5 ), 25.5 (C-4 ), 30.8 (NeMe), 32.7 (C-6 ), 32.8 (5-CH
2
),
0 0 0000 0000
4
.3. General procedure for the U-4CR reaction with cyclohexyl
32.8 (C-2 ), 48.7 (C-1 ), 65.3 (2-CH), 110.2 (C-7 ), 116.1 (C-3 ),
0000 0000 0000 0000
120.2 (C-4 ), 120.6 (C-6 ), 125.6 (C-5 ), 127.1 (C-3a ), 128.3 (C-
isocyanide
0
00
00 00 000 000 000 000
),129.0 (C-3 , C-5 ),129.1 (C-2 , C-6 ),130.3 (C-3 , C-5 ),130.5
4
00 00 00 0000 0000 00
To a stirred solution of the amine 1a (1.0 mmol) in methanol
1 mL), the corresponding aldehydes 2a,b (1.0 mmol) were added
(C-2 , C-6 ), 131.6 (C-1 ), 134.8 (C-2 ), 138.1 (C-7a ), 138.7 (C-4 ),
000 0000
140.2 (C-1 ), 168.7 (1-CO), 170.5 (2-CO), 192.6 (2 -CO). IR (Nujol)
(
ꢁ
þ
1
and the reaction mixture stirred at rt for 1 h. Then, the indole
carboxylic acids 3a,b (1.0 mmol) were added, the reaction mixture
stirred for additional 10 min, followed by the addition of cyclohexyl
isocyanide (1.0 mmol). After 24 h at rt, the solvent was removed
and the resulting residue was washed with ether affording com-
pounds 7aec.
cm 1493, 1594, 1650. MS (LCMS) m/z (%) calcd for C34H N O ,
37 3 3
þ
þ
M þH: 536; found: 536 (10%, M þH), 558 (100%, M þNa), 574
þ
þ
(65%, M þK). HRMS (ESI) m/z calcd [MþH] : 536.67588; found
þ
[MþH] : 536.67541.
4.4. Synthesis of 2-(2-acetyl-1-methyl-1H-indol-3-yl)-N-
phenylacetamide (8)
4
.3.1. N-Cyclohexyl-2-(2-(1-methyl-1H-indol-3-yl)-N-phenyl acet-
1
amido)-2-phenylacetamide (7a). Yellow oil (0.316 g, 66% yield); H
NMR (CDCl
H
To a stirred solution of the amine 1a (1.0 mmol) in methanol
(2 mL), the indole acetic acid 3b (1.0 mmol) and cyclohexyl iso-
cyanide (1.0 mmol) were added and the reaction mixture refluxed
0
0
0
3
)
d
0.89e1.01 (m, 2H, Hax-2 , Hax-6 ), 1.04e1.15 (m, 1H,
0
0
0
ax-4 ), 1.23e1.38 (m, 2H, Heq-3 , Heq-5 ), 1.24e1.38 (m, 2H, Hax-3 ,
Please cite this article in press as: Neochoritis, C. G.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.07.013

C.G. Neochoritis et al. / Tetrahedron xxx (2016) 1e8
7
000 000 000 000 000
3 ), 109.5 (C-7 ), 118.7 (C-4 ), 119.7 (C-6 ), 122.0 (C-5 ), 127.2 (C-
3a ), 127.3 (C-3 , C-5 ), 127.8 (C-2 ), 129.1 (C-2 , C-6 ), 132.7 (C-
for 3 h. The solvent was removed and the resulting residue was
subjected to column chromatography on silica gel using petroleum
ether/AcOEt (5:1) affording compound 8.
0
00
00
00
000
00
00
0
0
000
00
1 ), 136.9 (C-7a ), 138.5 (C-4 ), 167.0 (1-CO), 169.6 (2-CO). MS
þ
(
LCMS) m/z (%) calcd for C26
H
30
N
2
O
3
, M þH: 419; found: 419 (5%,
þ
þ
þ
4
.4.1. 2-(2-Acetyl-1-methyl-1H-indol-3-yl)-N-phenylacetamide
M þH), 441 (100%, M þNa), 457 (88%, M þK). HRMS (ESI) m/z
1
þ
þ
(8). Yellow oil (0.055 g, 18% yield); H NMR (CDCl
3
)
d
2.71 (s, 3H, 2-
calcd [MþH] : 419.52800; found [MþH] : 419.52750.
Me), 3.97 (s, 3H, NeMe), 4.02 (s, 2H, 3-CH
2
), 7.01 (t, J¼7.4 Hz, 1H, H-
0
0
0
0
4
), 7.22 (m, 2H, H-2 , H-6 ), 7.34e7.45 (m, 5H, H-5, H-6, H-7, H-3 ,
4.6.2. 2-(Cyclohexylamino)-2-oxo-1-(p-tolyl)ethyl-2-(2-acetyl-1-
methyl-1H-indol-3-yl)acetate (10b). Yellow oil (0.271 g, 59% yield);
0
13
H-5 ), 7.84 (d, J¼8.1 Hz, 1H, H-4), 8.54 (br s, 1H, NH). C NMR
1
000
00
(
CDCl
3
)
d
31.0 (2-Me), 33.0 (NeMe), 35.4 (3-CH
2
), 110.5 (C-7), 116.9
H NMR (CDCl
3
)
d
2.30 (s, 1H, 2 -Me), 2.63 (s, 3H, 4 -Me),
0
0
0
(
C-3), 119.7 (C-5), 121.3 (C-2 , C-6 ), 121.4 (C-6), 124.0 (C-4), 126.8 (C-
3.54e3.57 (m, 1H, Hax-1 ), 3.96 (s, 3H, NeMe), 4.13 (d, J¼2.4 Hz, 2H,
0
0
0
0
4
7
C
), 128.9 (C-3 , C-5 ), 136.0 (C-3a),138.3 (C-1 ), 138.3 (C-2), 139.2 (C-
5-CH
2
), 5.66 (br d, J¼8.0 Hz, 1H, 1-NH), 5.99 (s, 1H, 2-CH), 7.10 (t,
0
0
00
00
00
000
a), 168.5 (3-CO), 193.3 (2-CO). MS (LCMS) m/z (%) calcd for
J¼7.9 Hz, 2H, H-3 , H-5 ), 7.19 (t, J¼7.7 Hz, 2H, H-2 , H-6 ), 7.21 (m,
þ
þ
000
000
19
H
18
N
2
O
2
, M þH: 307; found: 307 (6%, M þH), 329 (100%,
1H, H-6 ), 7.36 (m, 1H, H-5 ), 7.41 (d, J¼8.5 Hz, 1H, H-7 ), 7.72 (d,
þ
þ
þ
000 13
000
M þNa), 345 (94%, M þK), 361 (28%, M þNaþMeOH). HRMS (ESI)
J¼8.1 Hz, 1H, H-4 ). C NMR (CDCl
3
)
d
14.0 (2 -Me), 22.7 (s, 3H,
þ
þ
00
0
0
m/z calcd [MþH] : 307.35842; found [MþH] : 307.35800.
4 -Me), 24.9 (5-CH
2
), 25.4 (C-4 ), 31.9 (NeMe), 32.4 (C-6 ), 24.7 (C-
0
0
0 0 0 000
3
, C-5 ), 32.5 (C-2 ), 47.7 (C-1 ), 75.8 (2-CH), 110.6 (C-7 ), 114.0 (C-
00
000
000
000
000
4
2
.5. Synthesis of N-cyclohexyl-1,9-dimethyl-3-oxo-2-phenyl-
,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-carboxamide (9)
3 ), 120.6 (C-4 ), 121.2 (C-6 ), 126.3 (C-5 ), 126.6 (C-3a ), 127.4
(C-3 , C-5 ),129.3 (C-2 , C-6 ), 132.8 (C-1 ), 134.8 (C-7a ), 138.7 (C-
4
0
0
00
00
00
00
000
0
0
000
000
), 138.8 (C-2 ), 167.0 (1-CO), 168.6 (2-CO), 192.2 (2 -CO). MS
þ
To a stirred solution of the amine 1a (1.0 mmol) in toluene
(LCMS) m/z (%) calcd for C28
H
32
N
2
O
4
, M þH: 461; found: 461 (3%,
þ
þ
þ
(
4 mL), the indole acetic acid 3b (1.0 mmol) and cyclohexyl iso-
M þH), 483 (100%, M þNa), 499 (50%, M þK). HRMS (ESI) m/z
þ
þ
cyanide (1.0 mmol) were added and the reaction mixture refluxed
for 2 h. The solvent was removed and the resulting residue was
washed with ether affording compound 9.
calcd [MþH] : 461.56468; found [MþH] : 461.56457.
Acknowledgements
4
1
.5.1. N-Cyclohexyl-1,9-dimethyl-3-oxo-2-phenyl-2,3,4,9-tetrahydro-
The authors sincerely want to acknowledge Prof. Ioulia
Stephanidou-Stephanatou and Prof. Constantinos Tsoleridis for
their support.
H-pyrido[3,4-b]indole-1-carboxamide (9). Yellow oil (0.091 g, 22%
1
00
00
00
yield); H NMR (CDCl
3
)
d
0.91e1.10 (m, 3H, H-2 ax, H-6 ax, H-4 ax),
00 00 00 00
1.23e1.35 (m, 3H, H-1 ax, H-3 ax, H-5 ax), 1.48e1.61 (m, 3H, H-3 eq,
0
0
00
00
00
H-5 eq, H-4 eq), 1.76e1.79 (m, 2H, H-2 eq, H-6 eq), 2.63 (s, 3H, 1-
Me), 2.71 (s, 2H, 4-CH ), 3.69e3.78 (m, 1H, H-1 eq), 3.97 (s, 3H,
References and notes
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2
0
0
0
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1
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0
0
(
1
2
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2
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29
H N
3
O
2
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4
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.6. General procedure for the P-3CR reaction with cyclohexyl
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1
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1
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0
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d
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H
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0
0
0
0
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0
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00
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000 13
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0
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0
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0
0
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Please cite this article in press as: Neochoritis, C. G.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.07.013