Synthesis of heteroarylogous 1H-indole-3-carboxamidines via a three-component interrupted Ugi reaction

Article abstract of DOI:10.1055/s-0034-1378921

A novel one-pot multicomponent synthesis of heteroarylogous 1H-indole-3-carboxamidines starting from readily available N-alkyl-N-(1H-indol-2-ylmethyl)amines, isocyanides, and carbonyl compounds is reported. The strategy exploits the ability of the indole nucleus to interrupt the classical Ugi reaction, by intercepting the nascent nitrilium ion.

Full text of DOI:10.1055/s-0034-1378921

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2015, 47, 489–496
paper
489
F. La Spisa et al.
Paper
Synthesis
Synthesis of Heteroarylogous 1H-Indole-3-carboxamidines via a
Three-Component Interrupted Ugi Reaction
Fabio La Spisaa
Fiorella Meneghettib
Beatrice Pozzia
Gian Cesare Tron*a
R3
+
N
R4
– C
N
R3
R2
O
H
MeOH
r.t.
N
R4
+
R1
a Dipartimento di Scienze del Farmaco, Università del Piemonte
Orientale ‘A. Avogadro’, Largo Donegani 2, 28100 Novara,
R1
NH
HN R2
N
H
Italy
+
3
9
0
(
3
2
1
3
)
7
5
6
2
1
giancesare.tron@unipmn.it
b Dipartimento di Scienze Farmaceutiche, Università degli Studi
di Milano, Via L. Mangiagalli 25, 20133 Milano, Italy
Received: 01.09.2014
Accepted after revision: 13.10.2014
Published online: 17.11.2014
been systematically searched for and found.8 Four main
strategies have been considered: i) the use of a secondary
amine and a nucleophile grafted in one of the four compo-
nents which allows for the interception of the formed imino
anhydride;9 ii) the use of electron-deficient phenols as car-
boxylic acid surrogates which can trigger a Smiles rear-
rangement in place of the Mumm-type rearrangement;10
iii) the identification of novel electrophiles, as substitutes
for the iminium ion, able to be attacked by the isocyanides
[acyl cyanides,11 trimethylsilanol,12 acyl isocyanates,13 (Z)-
chloro oximes14]; finally, iv) the intramolecular interception
of the nascent nitrilium ion by a nucleophile, avoiding, in
this case, the use of the carboxylic acid. The latter, three-
component reaction is usually referred to as the interrupted
Ugi reaction, and a series of transformations which have
followed this strategy have been disclosed. To date, reac-
tions with isocyanoacetamides,15 isocyano esters,15b,16 di-
amines,17 electron-rich anilines,18 2-aminophenols,19 2-
aminopyridines, and related heterocycles20 represent the
state of the art for the interrupted multicomponent Ugi re-
action (Scheme 2).
As shown in Scheme 2, it appears evident that despite
the fact that most of the above transformations have been
carried out using methanol as solvent, signs of the success-
ful formation of an imidate by the reaction between metha-
nol and the nitrilium ion have never been reported. This
result indicates either the reversibility of the process or the
inability of methanol to attack the nitrilium ion. In the
same way, the direct attack of the nitrilium ion by the
amine nitrogen to afford an aziridin-2-imine has never
been described.
DOI: 10.1055/s-0034-1378921; Art ID: ss-2014-t0538-op
Abstract A novel one-pot multicomponent synthesis of heteroarylo-
gous 1H-indole-3-carboxamidines starting from readily available
N-alkyl-N-(1H-indol-2-ylmethyl)amines, isocyanides, and carbonyl com-
pounds is reported. The strategy exploits the ability of the indole nucle-
us to interrupt the classical Ugi reaction, by intercepting the nascent
nitrilium ion.
Key words isocyanides, secondary amines, Ugi reaction, multicompo-
nent reactions, indoles
Although the Ugi reaction (Scheme 1) was discovered in
the late 1950s,1 this multicomponent transformation can
still be the starting point and the inspiration in the search
for novel and important multicomponent reactions (MCRs).
O
R1
O
R1NH2
R2
H
R4
R3
MeOH
N
1
2
+
H2O
N
H
R2
R4COOH
O
R3NC
3
4
5
Scheme 1 The four-component Ugi reaction
Indeed, following studies on the mechanism of the Ugi
reaction,2 different strategies have been disclosed over the
last decades for the identification of novel true isocyanide-
mediated MCRs.3 For example, shortly after the disclosure
of the four-component Ugi reaction, Ugi-like transforma-
tions using surrogates of amines (hydroxylamine,4 hydra-
zine5) or carboxylic acids (HN3,6 HNCO7) were reported,
affording novel molecular frameworks. Apart from the use
of bifunctionalized substrates in the Ugi reaction, only over
the past few years have intellectually deeper approaches
Stimulated by these results and aware that this strategy
has not been fully exploited yet, we started to consider
which nucleophile would be able to trap the ephemeral ni-
trilium ion in a productive manner. Firstly, we focused our
attention on the indole ring. Indeed, it is well known that its
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F. La Spisa et al.
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R3
R1
CN
R5
O
N
9
N
MeOH
r.t.
R2
N
R6
N
Me
N
R4
CHO
N
HN Me
H
8
R3
R4
N
NH
R1
N
R2
11
O
10
aldehyde
amine
isocyanide
R3
R1
O
Scheme 4 Three-component reaction
N
NH
R5
N
A
R4
R
HN
R3
EDG
N
O
R
N
N
N
H
R2
R1
R1
R2
N
H
HN
Scheme 2 Examples of interrupted multicomponent Ugi reactions; A =
alkyl chain
electron-rich nature makes electrophilic aromatic substitu-
tion (SEAr) at the C3 position extremely facile. To our sur-
prise, a preliminary search of the literature revealed to us
that this strategy had yet to be taken into consideration, de-
spite the undeniable importance of the indole nucleus in
several branches of chemistry. As proof of principle, we
therefore synthesized 1-(1H-indol-2-yl)-N-methylmethan-
amine (8) which is easily obtainable starting from the com-
mercially available 1H-indole-2-carboxylic acid (6) through
an amidation and a reduction reaction (Scheme 3).
Figure 1 ORTEP23 view of 11 and the relative atom-numbering scheme
(thermal ellipsoids at 40% probability)22
The overall molecular conformation of compound 11 is
determined by the tetrahydro-β-carboline-based tricyclic
framework having the side chain in the Z configuration and
the cyclohexane axially oriented. The 1H-indole ring sys-
tem is essentially planar and forms a dihedral angle of
77(1)° with the benzene ring attached to the tetrahydropy-
ridine fragment. The conformation of the six-membered
heterocyclic ring lies between the half-chair and envelope
conformation, as shown by the asymmetry parameters
QT = 0.593(1) Å, φ2 = –59(2)°, and θ = 69(1)°, while the cy-
clohexane adopts an almost perfect chair conformation,
Indole 8 was then reacted with cyclohexanecarboxalde-
hyde (10) and benzyl isocyanide (9) in methanol at room
temperature (Scheme 4). To our delight, after one hour we
observed the formation of a novel product which incorpo-
1
rated all three starting materials. H and 13C NMR analyses
revealed the structure 11, a novel scaffold unknown in the
literature. Compound 11, which was obtained in 74% yield,
can be considered as a sort of arylogous carboxamidine.21
In order to unequivocally confirm the molecular struc-
ture and, at the same time, to establish the spatial distribu-
tion of the functional groups, compound 11 was subjected
to X-ray crystal structure analysis.22 Its crystal structure is
represented in Figure 1, as an ORTEP23 drawing together
with the relative arbitrary atom-numbering scheme.
characterized
by
the
puckering
coordinates24
QT = 0.571(2) Å, φ2 = –168(1)°, and θ = 179(2)°. The crystal
packing is stabilized by intermolecular N–H···N- and
Cπ–H···N-type interactions and by π–π contacts between
the distal phenyl rings.
1) oxalyl chloride
DMF (cat.), CH2Cl2, r.t.
COOH
O
LiAlH4
N
H
HN Me
N
2) MeNH2, CH2Cl2
0 °C to r.t.
N
HN Me dioxane
reflux
H
H
6
8
7
Scheme 3 Synthesis of indole derivative 8
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Synthesis
It is important to highlight that the decision to use a
secondary amine in order to obtain the iminium ion under
neutral conditions was fundamental for the success of this
transformation. Indeed, when the same reaction was car-
ried out with the nor analogue of 8 and a Lewis or Brønsted
acid was used as catalyst to form the iminium ion, none of
the desired product could be detected. Furthermore, when
we performed the same reaction in the presence of a car-
boxylic acid (e.g., phenylacetic acid), we once again ob-
tained the interrupted Ugi product in low yield (28%), along
with the Passerini adduct (16%). No trace of the Ugi adduct
could be detected.
component transformation. Remarkably, even ketone 28
was able to react to produce a spiro compound, albeit in
modest yield. Finally, both indoles bearing electron-donat-
ing or electron-withdrawing groups maintain the ability to
intercept the nitrilium ion via the nucleophilic C3.
indoles
Me
HN
Cl
N
H
8
HN
HN
N
Our proposed, plausible mechanism for this novel MCR
is outlined in Scheme 5. The indole 8 reacts with the cyclo-
hexanecarboxaldehyde (10) to generate an iminium ion 12.
The iminium ion 12 cannot participate in a Pictet–Spengler
reaction with the indole nucleus as the closure would be 5-
endo-trig, disfavored by the Baldwin ring-closure rules. Ion
12 is, however, electrophilic enough to interact with the
isocyanide to form an electrophilic nitrilium ion 13. The lat-
ter is then intramolecularly intercepted by the C3 of the in-
dole nucleus.25 After a prototropic rearrangement, the final
product 11 is obtained. The intramolecular nitrilium trap-
ping should presumably happen in a stereoselective way,
yielding the E-isomer26 which isomerizes to the more stable
Z-isomer.
N
H
H
15
16
MeO
MeO
HN
N
17
H
isocyanides
NC
NC
NC
20
NC
O
9
18
19
NC
O
MeO
S
21
CN
O
22
aldehydes
O
O
O
CHO
H
+
H
HN Me
H
H
H
N
Me
23
10
24
Cl
+
O
25
O
O
N
O
N
12
H
H
NC
8
10
H
H
27
26
28
Figure 2 Building blocks used
N
11
H
+
In order to verify the amidine nature of these com-
pounds, we tested the hydrolytic stability of the imino moi-
ety of compound 11 under both acidic (6 M HCl, reflux) and
basic (6 M NaOH, dioxane, reflux) conditions. In both cases,
no sign of hydrolyzed products could be detected.
N
N
Me
N
Me
N
N
14
H
13
Scheme 5 Proposed mechanism for the formation of 11
In conclusion, heteroarylogous 1H-indole-3-carboxam-
idines, a new class of indole derivatives with four points of
diversity, were efficiently synthesized via a facile three-
component reaction. In this novel MCR, a new carbon–ni-
trogen bond, two carbon–carbon bonds, a carbon–nitrogen
double bond, and a six-membered ring are produced in one
pot in a single operation. The reaction proceeds under mild
conditions without requiring catalysts. As the indole ring
can be fully considered a privileged structure in agrochemi-
cals and drugs, these compounds may represent novel mo-
lecular scaffolds of importance. Furthermore, being
completely new and never reported, there are no intellectu-
In order to verify the generality of this novel transfor-
mation, we used different indoles (8, 15–17), isocyanides
(9, 18–22), and aldehydes (10, 23–28) (Figure 2); the final
compounds obtained are shown in Figure 3. The reaction
appears to be tolerant toward almost all types of isocya-
nides, both primary and secondary aliphatic and aromatic,
as well as less reactive isocyanides such as isocyanoacetate
21 and tosylmethyl isocyanide (TosMIC, 22). Formaldehyde,
and aliphatic and aromatic aldehydes, the latter requiring
longer reaction time, are able to participate in this multi-
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Synthesis
N
N
N
Cl
N
N
Me
N
Me
N
N
N
Me
N
N
H
H
H
N
H
32 35%
31 22%
30 83%
29 45%
Cl
N
N
N
N
N
N
N
N
H
N
NH
Me
N
H
36 68%
N
H
35 25%
33 50%
34 25%
OMe
O
O
N
S
O
N
N
Cl
N
Cl
N
N
N
Me
Me
N
H
N
N
N
H
H
N
H
39 20%
40 32%
38 55%
37 33%
N
N
N
MeO
MeO
N
N
N
Me
MeO
MeO
N
N
N
H
H
H
42 85%
41 55%
Figure 3 Arylogous 1H-indole-3-carboxamidines synthesized
43 72%
al property rights associated with these compounds, ren-
dering their exploitation valuable from an industrial point
of view. We anticipate that other neglected heterocyclic
rings (e.g., pyrroles,27 furans, thiophenes), when properly
functionalized, will be able to intercept the nitrilium ion,
channeling the MCR through an interrupted Ugi transfor-
mation. Studies with these heterocyclic ring systems are in
progress and the results will be reported in due course.
Glass Oven B-585 Kugelrohr apparatus before being used. When
needed, the reactions were performed in flame- or oven-dried glass-
ware under a positive pressure of dry N2. NMR spectra were recorded
with a Jeol ECP 300 MHz spectrometer; the δ values are given in parts
per million. Mass spectra were recorded using a Thermo Finnigan LCQ
Deca XP Plus spectrometer equipped with an ESI source and an ion
trap detector. Infrared spectra were recorded on an FT-IR Thermo Ni-
colet Avatar spectrometer with absorption maxima (νmax) recorded in
wavenumbers (cm–1). Column chromatography was performed on sil-
ica gel (Merck Kieselgel, 0.063–0.200 mm, 70–230 mesh ASTM). TLC
was carried out on 5 × 20 cm plates with a layer thickness of 0.25 mm
(Merck silica gel 60 F254). When necessary, the plates were devel-
oped with KMnO4 or the Dragendorff reagent. Elemental analysis data
(C, H, N) are within ± 0.4% of the calculated values.
Commercially available reagents and solvents were purchased from
Sigma-Aldrich and Alfa Aesar, and were used without further purifi-
cation, unless otherwise noted. Liquid aldehydes were distilled with a
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Amines 8, 15, 16, and 17; General Procedure
Compounds 11 and 29–43; General Procedure
The corresponding carboxylic acid (1 equiv, 10 mmol) was dissolved
(0.3 M) in CH2Cl2 (ACS reagent, reag. ISO), and oxalyl chloride (1.6
equiv) and catalytic DMF (0.1 equiv) were added. The resulting sus-
pension was stirred at r.t. for 12 h, then the solvent was evaporated in
vacuo. The acyl chloride was then dissolved (0.2 M) in CH2Cl2 (ACS re-
agent, reag. ISO) and the corresponding primary amine (1.2 equiv)
was slowly added at 0 °C. The reaction mixture was stirred at r.t. over-
night, then washed with 2 M NaOH (100 mL), 2 M HCl (100 mL), and
brine (100 mL), then dried over Na2SO4. After evaporation of the sol-
vent in vacuo, the crude amide was directly used for the next step
without further purification. In a flame-dried flask, under N2 atmo-
sphere, LiAlH4 (3 equiv) was dissolved in anhyd dioxane (60 mL), then
the amide was added at 0 °C. The reaction mixture was refluxed over-
night, then the reaction was quenched with a sat. aq solution of
Na2SO4 (15 mL) at 0 °C; the resulting mixture was filtered. The filtrate
was basified with 2 M NaOH until pH 10, then it was extracted with
EtOAc (3 × 100 mL). The combined organic phases were washed with
brine (100 mL), then dried over Na2SO4 and concentrated to dryness.
The amine (1 equiv) was dissolved (0.2 M) in MeOH (ACS reagent,
reag. ISO, reag. Ph. Eur.), then the aldehyde (1 equiv) and the isocya-
nide (1 equiv) were subsequently added. The reaction mixture was
stirred at r.t. until completion (3 to 24 h). The solvent was evaporated
in vacuo and the product was purified by column chromatography.
N-[(4Z)-3-Cyclohexyl-2-methyl-2,3-dihydro-1H-pyrido[3,4-b]in-
dol-4(9H)-ylidene]-1-phenylmethanamine (11)
Prepared from 8 (100 mg, 0.62 mmol), 9 (70 mg, 0.62 mmol), and 10
(73 mg, 0.62 mmol) in 4 h. 11 was obtained as a yellow solid; yield:
170 mg (74%); mp 174–175 °C; Rf = 0.30 (EtOAc).
FT-IR (KBr): 2745, 2059, 1480, 978 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 8.31 (br s, 1 H), 7.55 (d, J = 4.0 Hz, 2 H),
7.38 (t, J = 4.0 Hz, 2 H), 7.31–7.21 (m, 3 H), 7.19–7.10 (m, 2 H), 4.85 (s,
2 H), 4.29 (d, J = 17.0 Hz, 1 H, AB), 3.62 (d, J = 10.0 Hz, 1 H), 3.48 (d,
J = 17.0 Hz, 1 H, AB), 2.47 (s, 3 H), 2.28–2.15 (m, 1 H), 1.85–1.48 (m, 5
H), 1.30–0.98 (m, 5 H).
13C NMR (75.4 MHz, CDCl3): δ = 164.3, 141.7, 137.1, 133.1, 128.5,
127.8, 126.5, 125.5, 122.4, 121.8, 121.2, 111.2, 109.4, 65.0, 54.5, 45.7,
43.9, 39.0, 32.0, 30.7, 26.6.
1-(1H-Indol-2-yl)-N-methylmethanamine (8)
Prepared from 1H-indole-2-carboxylic acid (6; 3 g, 20 mmol). 8 was
MS (ESI): m/z = 372 [M + H]+.
obtained as a brown solid; yield: 1.04 g (35%).
The spectroscopic data were in agreement with those reported in the
literature.28
Anal. Calcd for C25H29N3: C, 80.82; H, 7.87; N, 11.31. Found: C, 80.65;
H, 7.65; N, 11.20.
N-[(5-Chloro-1H-indol-2-yl)methyl]butan-1-amine (15)
N-(3-Isopropyl-2-methyl-2,3-dihydro-1H-pyrido[3,4-b]indol-
4(9H)-ylidene)pentan-1-amine (29)
Prepared from 5-chloro-1H-indole-2-carboxylic acid (2 g, 10 mmol).
15 was obtained as a brown oil; yield: 774 mg (32%); Rf = 0.10
(EtOAc–MeOH, 9:1).
Prepared from 8 (80 mg, 0.50 mmol), 20 (42 mg, 0.50 mmol), and 23
(36 mg, 0.50 mmol) in 3 h. 29 was obtained as a yellow solid; yield: 70
mg (45%); mp 125–126 °C; Rf = 0.15 (EtOAc–MeOH, 95:5).
FT-IR (liquid film): 3735, 2240, 1598, 643 cm–1
.
FT-IR (KBr): 3520, 2780, 1486, 954 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 10.05 (br s, 1 H), 7.57 (s, 1 H), 7.23–
7.01 (m, 3 H), 6.30 (s, 1 H), 3.85 (s, 2 H), 2.65 (t, J = 6.7 Hz, 2 H), 1.65–
1.15 (m, 5 H), 0.97 (t, J = 7.3 Hz, 3 H).
1H NMR (300 MHz, CDCl3): δ = 8.13 (br s, 1 H), 7.40–7.30 (m, 1 H),
7.28–7.08 (m, 3 H), 4.28 (d, J = 17.0 Hz, 1 H, AB), 3.65–3.35 (m, 4 H),
2.49 (s, 3 H), 1.85–1.70 (m, 3 H), 1.55–1.30 (m, 4 H), 1.15 (d, J = 4.6 Hz,
3 H), 1.00–0.8 (m, 6 H).
13C NMR (75.4 MHz, DMSO-d6): δ = 163.0, 137.9, 137.2, 125.7, 121.7
(2 C), 120.3, 111.6, 109.0, 65.1, 50.8, 45.4, 43.9, 31.8, 29.9, 29.3, 22.7,
21.6, 20.3, 14.6.
MS (ESI): m/z = 237 [M + H]+.
Anal. Calcd for C13H17ClN2: C, 65.95; H, 7.24; N, 11.83 Found: C, 66.30;
H, 7.52; N, 12.05.
N-(1H-Indol-2-ylmethyl)-1-phenylmethanamine (16)
MS (ESI): m/z = 312 [M + H]+.
Prepared from 1H-indole-2-carboxylic acid (6; 2 g, 12 mmol). 16 was
obtained as a brown oil; yield: 1.34 g (46%).
Anal. Calcd for C20H29N3: C, 77.12; H, 9.38; N, 13.49. Found: C, 77.41;
H, 9.12; N, 13.25.
The spectroscopic data were in agreement with those reported in the
literature.29
N-(3-Hexyl-2-methyl-2,3-dihydro-1H-pyrido[3,4-b]indol-4(9H)-
ylidene)naphthalen-2-amine (30)
N-[(5,6-Dimethoxy-1H-indol-2-yl)methyl]-2-phenylethanamine
(17)
Prepared from 8 (100 mg, 0.62 mmol), 18 (96 mg, 0.62 mmol), and 24
(71 mg, 0.62 mmol) in 6 h. 30 was obtained as a yellow solid; yield:
212 mg (83%); mp 110–111 °C; Rf = 0.25 (PE–EtOAc, 2:8).
Prepared from 5,6-dimethoxy-1H-indole-2-carboxylic acid (1 g, 4
mmol). 17 was obtained as a brown oil; yield: 320 mg (23%); Rf = 0.20
(EtOAc–MeOH, 9:1).
FT-IR (KBr): 3500, 2853, 1060, 967 cm–1
.
FT-IR (liquid film): 3726, 2360, 1608, 668 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 8.64 (br s, 1 H), 8.37 (t, J = 4.2 Hz, 1 H),
7.82 (d, J = 8.2 Hz, 2 H), 7.74 (d, J = 8.2 Hz, 1 H), 7.50–7.30 (m, 2 H),
7.30–7.10 (m, 5 H), 4.25 (d, J = 17.0 Hz, 1 H, AB), 3.62 (q, J = 4.5 Hz, 1
H), 3.51 (d, J = 17.0 Hz, 1 H, AB), 2.53 (s, 3 H), 1.78–1.40 (m, 2 H),
1.30–0.95 (m, 8 H), 0.72 (t, J = 7.0 Hz, 3 H).
13C NMR (75.4 MHz, CDCl3): δ = 165.5, 149.2, 139.0, 136.5, 134.4,
130.3, 128.8, 127.8, 127.3, 126.3, 125.0, 124.2, 122.9, 121.9, 121.8,
121.7, 115.6, 111.2, 109.0, 60.8, 45.6, 43.6, 31.5, 30.6, 28.9, 26.6, 22.5,
14.0.
1H NMR (300 MHz, CDCl3): δ = 8.56 (br s, 1 H), 7.35–7.15 (m, 5 H),
6.99 (s, 1 H), 6.80 (s, 1 H), 6.21 (s, 1 H), 3.91 (s, 2 H), 3.90 (s, 3 H), 3.88
(s, 3 H), 2.90 (t, J = 6.0 Hz, 2 H), 2.80 (t, J = 6.0 Hz, 2 H).
MS (ESI): m/z = 311 [M + H]+.
Anal. Calcd for C19H22N2O2: C, 73.52; H, 7.14; N, 9.03. Found: C, 73.43;
H, 7.01; N, 9.31.
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MS (ESI): m/z = 410 [M + H]+.
N-[3-(4-Chlorophenyl)-2-methyl-2,3-dihydro-1H-pyrido[3,4-b]in-
dol-4(9H)-ylidene]-1-phenylmethanamine (34)
Anal. Calcd for C28H31N3: C, 82.11; H, 7.63; N, 10.26. Found: C, 82.40;
H, 7.32; N, 10.54.
Prepared from 8 (100 mg, 0.62 mmol), 9 (73 mg, 0.62 mmol), and 25
(87 mg, 0.62 mmol) in 18 h. 34 was obtained as a yellow solid; yield:
62 mg (25%); mp 104–105 °C; Rf = 0.25 (PE–EtOAc, 1:9).
N-(2′-Methyl-1′,2′-dihydrospiro[cyclohexane-1,3′-pyrido[3,4-b]in-
dol]-4′(9′H)-ylidene)-1-phenylmethanamine (31)
FT-IR (KBr): 3320, 2831, 1184, 902 cm–1
.
1H NMR (300 MHz, DMSO-d6): δ = 11.44 (s, 1 H), 8.22 (d, J = 7.0 Hz, 1
H), 7.45–7.08 (m, 12 H), 5.16 (s, 1 H), 4.77 (d, J = 16.8 Hz, 1 H, AB), 4.28
(d, J = 16.8 Hz, 1 H, AB), 3.77 (d, J = 16.5 Hz, 1 H, AB), 3.55 (d, J = 16.5
Hz, 1 H, AB), 2.46 (s, 3 H).
Prepared from 8 (100 mg, 0.62 mmol), 9 (73 mg, 0.62 mmol), and 28
(61 mg, 0.62 mmol) in 14 h. 31 was obtained as a white solid; yield:
50 mg (22%); mp 189–190 °C; Rf = 0.15 (EtOAc).
FT-IR (KBr): 3425, 2363, 1653, 1140, 962 cm–1
.
13C NMR (75.4 MHz, DMSO-d6): δ = 162.4, 142.1, 141.1, 139.9, 134.2,
132.8, 131.2, 129.0, 128.7, 127.9, 126.7, 125.2, 122.4, 122.0, 121.0,
112.0, 109.7, 63.1, 53.6, 45.7, 42.6.
1H NMR (300 MHz, DMSO-d6): δ = 11.44 (br s, 1 H), 7.53 (d, J = 4.0 Hz,
1 H), 7.43–7.35 (m, 4 H), 7.33–7.27 (m, 1 H), 7.15–6.99 (m, 3 H), 5.02
(s, 2 H), 4.08 (s, 2 H), 2.32 (s, 3 H), 1.80–1.10 (m, 10 H).
13C NMR (75.4 MHz, DMSO-d6): δ = 163.5, 141.4, 138.6, 127.1, 126.5,
126.3, 125.0, 124.3, 119.9, 118.7, 110.5, 104.6, 61.4, 56.1, 47.1, 36.4,
25.2, 20.9.
MS (ESI): m/z = 400 [M + H]+.
Anal. Calcd for C25H22ClN3: C, 75.08; H, 5.54; N, 10.51. Found: C,
75.30; H, 5.67; N, 10.12.
MS (ESI): m/z = 358 [M + H]+.
N-(2-Benzyl-3-phenyl-2,3-dihydro-1H-pyrido[3,4-b]indol-4(9H)-
ylidene)cyclohexanamine (35)
Anal. Calcd for C24H27N3: C, 80.63; H, 7.61; N, 11.75. Found: C, 80.87;
H, 7.41; N, 11.41.
Prepared from 16 (100 mg, 0.42 mmol), 19 (46 mg, 0.42 mmol), and
26 (45 mg, 0.42 mmol) in 15 h. 35 was obtained as a yellow solid;
yield: 46 mg (25%); mp 84–85 °C; Rf = 0.20 (PE–EtOAc, 1:1).
N-(2-Butyl-6-chloro-3-cyclohexyl-2,3-dihydro-1H-pyrido[3,4-
b]indol-4(9H)-ylidene)naphthalen-2-amine (32)
FT-IR (KBr): 3520, 2231, 1114, 902 cm–1
.
Prepared from 15 (100 mg, 0.42 mmol), 10 (75 mg, 0.42 mmol), and
18 (78 mg, 0.42 mmol) in 6 h. 32 was obtained as a yellow solid; yield:
80 mg (35%); mp 187–188 °C; Rf = 0.30 (PE–EtOAc, 1:9).
1H NMR (300 MHz, DMSO-d6): δ = 11.20 (br s, 1 H), 8.32–8.26 (m, 1
H), 7.80–7.00 (m, 13 H), 5.09 (s, 1 H), 3.97 (d, J = 14.0 Hz, 1 H), 3.80–
3.20 (m, 4 H), 1.80–0.90 (m, 10 H).
FT-IR (KBr): 3400, 2115, 1022, 946 cm–1
.
13C NMR (75.4 MHz, DMSO-d6): δ = 158.5, 139.5, 137.5, 136.8, 129.2
(2 C), 128.9 (2 C), 128.8, 128.0, 127.7, 122.3, 122.1, 120.6, 112.3,
110.1, 61.3, 58.5, 57.6, 43.7, 35.2, 26.2, 24.5.
1H NMR (300 MHz, DMSO-d6): δ = 11.65 (br s, 1 H), 8.11 (s, 1 H), 7.83
(t, J = 7.5 Hz, 2 H), 7.72 (d, J = 8.2 Hz, 1 H), 7.55–7.30 (m, 3 H), 7.20–
7.00 (m, 3 H), 4.34 (d, J = 19.0 Hz, 1 H, AB), 3.80 (d, J = 19.0 Hz, 1 H,
AB), 2.80–2.70 (m, 2 H), 1.98–1.90 (m, 1 H), 1.60–0.80 (m, 18 H).
MS (ESI): m/z = 434 [M + H]+.
13C NMR (75.4 MHz, DMSO-d6): δ = 164.1, 149.4, 143.1, 135.6, 134.3,
130.1, 128.7, 128.2, 127.4, 126.8, 126.2, 125.7, 124.5, 122.8, 122.2,
120.6, 115.0, 113.6, 108.6, 63.0, 54.9, 44.8, 38.2, 31.7, 30.9, 26.4, 26.2,
20.2, 14.4.
Anal. Calcd for C30H31N3: C, 83.10; H, 7.21; N, 9.69. Found: C, 83.25; H,
7.45; N, 9.48.
N-(2-Benzyl-3-cyclohexyl-2,3-dihydro-1H-pyrido[3,4-b]indol-
4(9H)-ylidene)pentan-1-amine (36)
MS (ESI): m/z = 485 [M + H]+.
Prepared from 16 (100 mg, 0.42 mmol), 10 (47 mg, 0.42 mmol), and
20 (35 mg, 0.42 mmol) in 4 h. 36 was obtained as a yellow oil; yield:
123 mg (68%); Rf = 0.15 (PE–EtOAc, 6:4).
Anal. Calcd for C31H34ClN3: C, 76.92; H, 7.08; N, 8.68. Found: C, 76.69;
H, 6.88; N, 8.87.
N-(2-Benzyl-3-hexyl-2,3-dihydro-1H-pyrido[3,4-b]indol-4(9H)-
FT-IR (liquid film): 3517, 2145, 1090, 942 cm–1
.
ylidene)cyclohexanamine (33)
1H NMR (300 MHz, DMSO-d6): δ = 11.07 (br s, 1 H), 8.13 (d, J = 7.0 Hz,
1 H), 7.40–6.98 (m, 8 H), 4.31 (d, J = 20.0 Hz, 1 H, AB), 3.82–3.60 (m,
2 H), 3.54 (d, J = 10.0 Hz, 1 H), 3.38 (s, 2 H), 3.30–3.18 (m, 1 H), 2.35
(d, J = 10.0 Hz, 1 H), 1.80–0.90 (m, 16 H), 0.87 (t, J = 7.0 Hz, 3 H).
Prepared from 16 (100 mg, 0.42 mmol), 19 (46 mg, 0.42 mmol), and
24 (48 mg, 0.42 mmol) in 8 h. 33 was obtained as a brown solid; yield:
93 mg (50%); mp 96–97 °C; Rf = 0.40 (EtOAc).
FT-IR (KBr): 3509, 2926, 1140, 906 cm–1
.
13C NMR (75.4 MHz, DMSO-d6): δ = 162.5, 140.1, 138.2, 137.0, 129.0,
128.7, 127.8, 127.2, 126.0, 121.9, 120.0, 111.4, 109.1, 61.9, 59.2, 51.0,
41.5 (overlapped DMSO), 38.7, 32.0, 30.5, 30.0, 26.8, 26.5, 22.8, 14.3.
1H NMR (300 MHz, DMSO-d6): δ = 11.16 (br s, 1 H), 8.19 (t, J = 7.0 Hz,
1 H), 7.45–6.95 (m, 8 H), 4.26 (d, J = 17.0 Hz, 1 H), 3.85–3.60 (m, 4 H),
3.55–3.22 (m, 3 H), 1.90–1.10 (m, 18 H), 0.95–0.85 (m, 3 H).
MS (ESI): m/z = 428 [M + H]+.
13C NMR (75.4 MHz, DMSO-d6): δ = 161.5, 139.9, 138.6, 136.8, 129.1,
128.6, 127.5, 125.8, 122.3, 121.8, 120.3, 111.6, 108.8, 59.2, 57.3, 56.6,
43.5, 35.4, 31.8, 31.2, 30.3, 28.7, 26.4, 24.8, 22.7, 14.5.
Anal. Calcd for C29H37N3: C, 81.45; H, 8.72; N, 9.83. Found: C, 81.20; H,
8.45; N, 10.08.
MS (ESI): m/z = 442 [M + H]+.
N-(2-Butyl-6-chloro-2,3-dihydro-1H-pyrido[3,4-b]indol-4(9H)-
ylidene)naphthalen-2-amine (37)
Anal. Calcd for C30H39N3: C, 81.59; H, 8.90; N, 9.51. Found: C, 81.75; H,
9.05; N, 9.28.
Prepared from 15 (100 mg, 0.42 mmol), 18 (65 mg, 0.42 mmol), and
27 (13 mg, 0.42 mmol) in 6 h. 37 was obtained as a yellow solid; yield:
56 mg (33%); mp 109–110 °C; Rf = 0.30 (PE–EtOAc, 1:9).
FT-IR (KBr): 3394, 2929, 1651, 1491, 1164 cm–1
.
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1H NMR (300 MHz, CDCl3): δ = 8.34 (s, 1 H), 7.85–7.78 (m, 2 H), 7.72
(d, J = 8.0 Hz, 1 H), 7.49–7.35 (m, 2 H), 7.18 (s, 1 H), 7.15–6.99 (m, 2
H), 7.07 (d, J = 2.0 Hz, 1 H), 3.97 (s, 2 H), 3.40 (s, 2 H), 2.41 (t, J = 7.0
Hz, 2 H), 1.40–1.20 (m, 4 H), 0.83 (t, J = 7.3 Hz, 3 H).
13C NMR (75.4 MHz, CDCl3): δ = 160.7, 148.8, 143.8, 134.7, 134.3,
130.5, 128.9, 127.9, 127.5, 127.4, 126.4, 125.8, 124.4, 123.3, 121.8,
121.5, 115.9, 112.1, 110.8, 56.8, 54.2, 49.6, 29.1, 20.5, 14.0.
13C NMR (75.4 MHz, CDCl3): δ = 170.8, 144.8, 139.3, 136.5, 135.0,
129.6, 129.5, 125.0, 122.7, 122.1, 121.5, 111.2, 108.8, 73.0, 60.6, 45.1,
43.6, 31.8, 30.2, 29.3, 27.0, 22.7, 21.8, 14.2.
MS (ESI): m/z = 452 [M + H]+.
Anal. Calcd for C26H33N3O2S: C, 69.15; H, 7.36; N, 9.30. Found: C,
69.34; H, 7.21; N, 9.56.
MS (ESI): m/z = 402 [M + H]+.
N-(3-Isopropyl-2-methyl-2,3-dihydro-1H-pyrido[3,4-b]indol-
4(9H)-ylidene)cyclohexanamine (41)
Anal. Calcd for C25H24ClN3: C, 74.71; H, 6.02; N, 10.45. Found: C,
75.03; H, 5.77; N, 10.18.
Prepared from 8 (100 mg, 0.62 mmol), 19 (68 mg, 0.62 mmol), and 23
(45 mg, 0.62 mmol) in 4 h. 41 was obtained as a white solid; yield:
111 mg (55%); mp 210–211 °C; Rf = 0.30 (EtOAc–MeOH, 95:5).
Methyl 2-[(3-Cyclohexyl-2-methyl-2,3-dihydro-1H-pyrido[3,4-
b]indol-4(9H)-ylidene)amino]acetate (38)
FT-IR (KBr): 3477, 2146, 1147, 945 cm–1
.
Prepared from 8 (100 mg, 0.62 mmol), 10 (70 mg, 0.62 mmol), and 21
(60 mg, 0.62 mmol) in 8 h. 38 was obtained as a yellow oil; yield: 121
mg (55%); Rf = 0.35 (EtOAc).
1H NMR (300 MHz, DMSO-d6): δ = 11.08 (br s, 1 H), 8.05 (d, J = 8.2 Hz,
1 H), 7.30 (d, J = 7.5 Hz, 1 H), 7.06–7.02 (m, 2 H), 4.28 (d, J = 17 Hz, 1
H), 3.65–3.58 (m, 2 H), 3.45–3.35 (m, 1 H), 2.40 (s, 3 H), 1.90–1.20 (m,
11 H), 1.10 (d, J = 6.5 Hz, 3 H), 0.83 (d, J = 6.5 Hz, 3 H).
FT-IR (liquid film): 2927, 1740, 1612, 1449, 727 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 8.27 (br s, 1 H), 7.30–7.21 (m, 1 H),
7.20–7.05 (m, 3 H), 4.41 (s, 2 H), 4.30 (d, J = 17.0 Hz, 1 H, AB), 3.84 (s,
3 H), 3.52 (d, J = 17.0 Hz, 1 H, AB), 3.35 (d, J = 10.0 Hz, 1 H), 2.46 (s, 3
H), 2.21–2.15 (m, 1 H), 1.85–0.90 (m, 10 H).
13C NMR (75.4 MHz, CDCl3): δ = 172.1, 166.8, 137.2, 136.7, 125.3,
122.4, 121.8, 121.3, 111.0, 109.6, 65.3, 53.3, 52.1, 45.6, 43.9, 38.9,
31.8, 30.5, 26.5.
13C NMR (75.4 MHz, DMSO-d6): δ = 160.4, 138.0, 137.0, 125.7, 121.9
(2 C), 120.3, 111.6, 108.9, 65.2, 57.6, 45.3, 43.9, 35.4, 34.9, 28.7, 26.1,
24.7, 21.5, 20.1.
MS (ESI): m/z = 324 [M + H]+.
Anal. Calcd for C21H29N3: C, 77.97; H, 9.04; N, 12.99. Found: C, 78.14;
H, 8.86; N, 13.15.
MS (ESI): m/z = 354 [M + H]+.
N-(3-Cyclohexyl-6,7-dimethoxy-2-phenethyl-2,3-dihydro-1H-pyr-
ido[3,4-b]indol-4(9H)-ylidene)pentan-1-amine (42)
Anal. Calcd for C21H27N3O2: C, 71.36; H, 7.70; N, 11.89. Found: C,
71.45; H, 7.54; N, 11.67.
Prepared from 17 (100 mg, 0.32 mmol), 10 (36 mg, 0.32 mmol), and
20 (27 mg, 0.32 mmol) in 4 h. 42 was obtained as a yellow oil; yield:
137 mg (85%); Rf = 0.40 (PE–EtOAc, 1:1).
N-(2-Butyl-6-chloro-3-cyclohexyl-2,3-dihydro-1H-pyrido[3,4-
b]indol-4(9H)-ylidene)pentan-1-amine (39)
FT-IR (liquid film): 3215, 2341, 1652, 1488, 1207, 750 cm–1
.
Prepared from 15 (100 mg, 0.42 mmol), 10 (47 mg, 0.42 mmol), and
20 (35 mg, 0.42 mmol) in 12 h. 39 was obtained as a yellow solid;
yield: 36 mg (20%).; mp 147–148 °C; Rf = 0.15 (PE–EtOAc, 1:9).
1H NMR (300 MHz, DMSO-d6): δ = 10.78 (br s, 1 H), 7.62 (s, 1 H), 7.30–
7.10 (m, 5 H), 6.87 (s, 1 H), 4.22 (d, J = 17.0 Hz, 1 H, AB), 3.75 (s, 3 H),
3.72 (s, 3 H), 3.63 (d, J = 17.0 Hz, 1 H, AB), 3.50–3.23 (m, 3 H), 2.80–
2.60 (m, 4 H), 2.13 (d, J = 11.6 Hz, 1 H), 1.75–0.93 (m, 16 H), 0.86 (t,
J = 7.0 Hz, 3 H).
13C NMR (75.4 MHz, DMSO-d6): δ = 162.9, 146.6, 145.3, 140.8, 137.0,
131.5, 129.2, 128.6, 126.3, 118.5, 109.6, 104.7, 96.1, 62.3, 57.3, 56.4,
56.2, 50.7, 44.5, 38.9, 35.4, 32.0, 31.9, 30.6, 30.1, 26.6, 22.8, 14.7.
FT-IR (KBr): 3214, 2258, 1100, 896 cm–1
.
1H NMR (300 MHz, DMSO-d6): δ = 11.29 (br s, 1 H), 8.03 (s, 1 H), 7.33
(d, J = 8.2 Hz, 1 H), 7.07 (d, J = 8.2 Hz, 1 H), 4.23 (d, J = 18.0 Hz, 1 H,
AB), 3.70 (d, J = 18.0 Hz, 1 H, AB), 3.55–3.50 (m, 1 H), 2.55–2.35 (m, 2
H), 2.17 (d, J = 11.0 Hz, 1 H), 1.80–0.80 (m, 28 H).
13C NMR (75.4 MHz, DMSO-d6): δ = 162.6, 144.8, 136.3, 126.7, 125.0,
121.5, 120.7, 113.3, 109.2, 62.0, 54.6, 50.9, 44.5, 31.8, 30.8, 30.5, 30.0,
26.8, 26.6, 22.6, 20.3, 14.6, 14.4.
MS (ESI): m/z = 502 [M + H]+.
Anal. Calcd for C32H43N3O2: C, 76.61; H, 8.64; N, 8.38. Found: C, 76.45;
H, 8.34; N, 8.56.
MS (ESI): m/z = 428 [M + H]+.
N-(3-Hexyl-6,7-dimethoxy-2-phenethyl-2,3-dihydro-1H-pyri-
do[3,4-b]indol-4(9H)-ylidene)-1-phenylmethanamine (43)
Anal. Calcd for C26H38ClN3: C, 72.95; H, 8.95; N, 9.82. Found: C, 72.67;
H, 8.57; N, 10.04.
Prepared from 17 (100 mg, 0.32 mmol), 9 (37 mg, 0.32 mmol), and 24
(36 mg, 0.32 mmol) in 4 h. 43 was obtained as a yellow oil; yield: 121
mg (72%); Rf = 0.25 (PE–EtOAc, 1:9).
N-(3-Hexyl-2-methyl-2,3-dihydro-1H-pyrido[3,4-b]indol-4(9H)-
ylidene)-1-tosylmethanamine (40)
Prepared from 8 (100 mg, 0.62 mmol), 22 (121 mg, 0.62 mmol), and
24 (71 mg, 0.62 mmol) in 7 h. 40 was obtained as a brown oil; yield:
90 mg (32%); Rf = 0.30 (EtOAc).
FT-IR (liquid film): 2929, 2344, 1477, 1300, 733 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.88 (br s, 1 H), 7.55 (d, J = 7.3 Hz, 2 H),
7.36 (t, J = 7.6 Hz, 2 H), 7.30–7.10 (m, 5 H), 7.08 (d, J = 7.6 Hz, 1 H),
6.77 (s, 1 H), 4.80 (s, 2 H), 4.23 (d, J = 17.0 Hz, 1 H, AB), 3.98–3.77 (m,
8 H, 2 × OMe and 2 H overlapped), 3.63 (d, J = 17.0 Hz, 1 H, AB), 2.85–
2.60 (m, 4 H), 1.70–1.20 (m, 9 H), 0.89 (t, J = 6.4 Hz, 3 H).
13C NMR (75.4 MHz, DMSO-d6): δ = 165.4, 147.0, 145.5, 142.8, 140.7,
137.7, 129.9, 129.0, 128.7, 127.9, 126.5, 118.4, 108.8, 104.6, 96.2, 58.0,
57.3, 56.5, 56.2, 52.9, 35.2, 32.0, 29.6, 28.9, 26.6, 14.2.
FT-IR (liquid film): 2910, 1863, 1450, 964, 762 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 8.91 (br s, 1 H), 7.93 (t, J = 5.5 Hz, 3 H),
7.33–7.25 (m, 3 H), 7.20–7.02 (m, 2 H), 5.03 (q, J = 14.0 Hz, 2 H, AB),
4.25 (d, J = 17.0 Hz, 1 H, AB), 3.65–3.50 (m, 2 H), 2.41 (s, 3 H), 2.33 (s,
3 H), 1.60–1.15 (m, 10 H), 0.87 (t, J = 6.5 Hz, 3 H).
MS (ESI): m/z = 524 [M + H]+.
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Anal. Calcd for C34H41N3O2: C, 77.98; H, 7.89; N, 8.02. Found: C, 78.20;
H, 7.58; N, 8.33.
(16) Lalli, C.; Bouma, M. J.; Bonne, D.; Masson, G.; Zhu, J. Chem. Eur. J.
2011, 17, 880.
(17) (a) Kysil, V.; Khvat, A.; Tsirulnikov, S.; Tkachenko, S.; Williams,
C.; Churakova, M.; Ivachtchenko, A. Eur. J. Org. Chem. 2010,
1525. (b) Keung, W.; Bakir, F.; Patron, A.; Rogers, D.; Priest, C. D.;
Darmohusodo, V. Tetrahedron Lett. 2004, 45, 733.
Acknowledgment
(18) (a) Deyrup, J. A.; Vestling, M. M.; Hagan, W. V.; Yun, H. Y. Tetra-
hedron 1969, 25, 1467. (b) Schneekloth, J. S.; Kim, J.; Sorensen,
E. J. Tetrahedron 2009, 65, 3096. (c) Kim, J.; Schneekloth, J. S.;
Sorensen, E. J. Chem. Sci. 2012, 3, 2849.
Financial support from Università del Piemonte Orientale is gratefully
acknowledged.
Supporting Information
(19) Varadi, A.; Palmer, T. C.; Notis, P. R.; Redel-Traub, G. N.; Afonin,
D.; Subrath, J. J.; Pasternak, G. W.; Hu, C.; Sharma, I.; Majumdar,
S. Org. Lett. 2014, 16, 1668.
(20) (a) Bienaymé, H.; Bouzid, K. Angew. Chem. 1998, 110, 2349.
(b) Groebke, K.; Weber, L.; Mehlin, F. Synlett 1998, 661.
(c) Blackburn, B.; Guan, P.; Fleming, K.; Shiosaki, S.; Tsai, S. Tet-
rahedron Lett. 1998, 39, 3635.
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1378921.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 489–496