Indole as neutral leaving group in silver nitrate induced cyclization reactions of n-{2-[alkynyl(hetero)aryl]methylene}indolin-1-amines for the synthesis of annulated pyridine derivatives

Article abstract of DOI:10.1002/ejoc.200901471

N-(2-[Alkynyl(hetero)aryl]methylene}indolln-l-amines 3 undergo, upon treatment with silver nitrate in chloroform at 60 °C, electrophilic cyclization reactions to afford annulated pyridine derivatives 4. Mechanistically, the silver(I)-assisted 6-endo-dig r

Full text of DOI:10.1002/ejoc.200901471

FULL PAPER
DOI: 10.1002/ejoc.200901471
Indole as Neutral Leaving Group in Silver Nitrate Induced Cyclization
Reactions of N-{2-[Alkynyl(hetero)aryl]methylene}indolin-1-amines for the
Synthesis of Annulated Pyridine Derivatives
Nugzar Ghavtadze,*[a] Roland Fröhlich,[a] and Ernst-Ulrich Würthwein*[a]
Dedicated to Professor Christian Reichardt at the occasion of his 75th birthday
Keywords: Lewis acids / Cyclization / Nitrogen heterocycles / Silver / Quantum chemical calculations
N-{2-[Alkynyl(hetero)aryl]methylene}indolin-1-amines 3 un-
dergo, upon treatment with silver nitrate in chloroform at
60 °C, electrophilic cyclization reactions to afford annulated
pyridine derivatives 4. Mechanistically, the silver(I)-assisted
6-endo-dig ring-closure process of compounds 3 leads to the
formation of an intermediate pyridinium cation, which re-
leases – besides the products 4 – indole as unusual but ef-
ficient neutral leaving group after N–N bond cleavage. It is
shown that among the hydrazones studied, only the 1-amino-
indoline-derived substrates N-{2-[alkynyl(hetero)aryl]meth-
ylene}indolin-1-amines 3 are suitable to produce annulated
pyridine derivatives 4 in high yield. The reaction can be per-
formed in air and even in the presence of water in the reac-
tion medium. Since during the course of the reaction indole
is oxidized by the silver(I) ions, stoichiometric amounts of sil-
ver salt are required. Quantum chemical calculations have
been applied in order to gain additional information on the
reaction mechanism and the key reactive intermediates.
We have recently reported on a synthesis of 2H-pyrrole
derivatives by the aza-Nazarov reaction[3] from 1-amino-
indoline-derived azadienones, where 3H-indole acted as
neutral leaving group (Scheme 2).[4]
Introduction
Electrophilic substitution reactions at a nitrogen atom
usually involve a proton as leaving group (diazotization, N-
nitrosation or N-nitroso-dehydrogenation, formation of azo
compounds from amines, conversion of nitroso compounds
to azoxy compounds, N-halogenation or N-halo-dehydroge-
nation, and reactions of amines with CO or CO2)
(Scheme 1).[1]
Scheme 1.
In the present study we introduce indole as an efficient
neutral leaving group in electrophilic substitution reactions
at a nitrogen atom. To the best of our knowledge there is
only one other example of the use of a heterocyclic moiety
as a neutral leaving group, given by Katritzky et al.; they
utilized substituted pyridines as heterocyclic leaving
groups.[2]
Scheme 2. Aza-Nazarov synthesis of 2H-pyrroles.
We assumed that the driving force of this reaction is the
formation of the stable aromatic 1H-indole molecule from
the initial 3H-indole after cleavage of the N–N bond, along
with the exothermic 1,5-cyclization reaction.
Based on this discovery, one might expect that the basic
mechanism of this reaction sequence, namely the treatment
of 1-aminoindoline-derived hydrazones by suitable electro-
[a] Organisch-Chemisches Institut, Westfälische Wilhelms-Uni-
versität,
Corrensstrasse 40, 48149 Münster, Germany
Fax: +49-251-83-39772
E-mail: wurthwe@uni-muenster.de
ghavtadz@uni-muenster.de
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200901471.
Eur. J. Org. Chem. 2010, 1787–1797
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N. Ghavtadze, R. Fröhlich, E.-U. Würthwein
FULL PAPER
philes with subsequent N–N bond cleavage – liberating in-
dole – may find many other applications in organic nitrogen
chemistry (Scheme 3).
Scheme 6.
In contrast, cyclization reactions of phenylimines or ox-
imes of 2-(alkynyl)benzaldehydes or NЈ-(2-alkynylbenzyl-
idene)hydrazides are known to lead to N-phenyl-substituted
structures, N-oxides and isoquinolinium-2-yl amides,
respectively (however without cleavage of N–C, N–O or N–
N bonds).[9]
Scheme 3.
As part of our ongoing project establishing indole as an
efficient leaving group in electrophilic substitution reactions
at a nitrogen atom, we are pleased to report now the suc-
cessful application of this protocol for cyclization reactions
Results and Discussion
of
N-{2-[alkynyl(hetero)aryl]methylene}indolin-1-amines
Various examples of N-{2-[alkynyl(hetero)aryl]meth-
ylene}indolin-1-amines 3a–i can easily be obtained from o-
bromoarenecarbaldehydes 1 in a two-step procedure. The
first step is a Sonogashira cross-coupling reaction to afford
2-(alkynyl)arenecarbaldehydes 2. This step is followed by
condensation of the carbonyl function of 2 with N-amino-
indoline to give the hydrazones 3a–i in 66–93% yield. The
necessary N-aminoindoline was synthesized from indoline
by a nitrosation/reduction reaction sequence (Scheme 7,
Table 1).[10] We were able to obtain an X-ray diffraction
structure of compound 3a showing the conformation and
in particular the (E) configuration of the C=N bond in the
solid state (Figure 1).
leading to novel annulated pyridine derivatives.
In this context Larock et al. reported in a series of papers
the Lewis acid (Pd0, PdII, AgI, CuI) catalyzed synthesis of
isoquinoline derivatives from N-tert-butyl-2-(1-alkynyl)aryl-
aldimines, liberating isobutene as neutral leaving group
(Scheme 4).[5]
Scheme 4.
Upon treatment with 1.2 equiv. of AgNO3, hydrazones
3a–i underwent – in CHCl3 as solvent at 60 °C – a cycliza-
tion reaction leading to several quite different types of com-
pounds with an annulated pyridine moiety 4a–i (Scheme 8,
Table 2). The products were obtained in 44–98% yield after
purification by column chromatography. Interestingly, in all
experiments a silver mirror on the reaction flask was ob-
served. A second product, stemming from the indoline moi-
ety, was not detected (see below). Thus, we were able to
introduce several different substituents and heterocycles
(thiazole, imidazole, benzothiophene) into the hydrazone
Recently, Zhang et al. reported a synthesis of isoqinol-
ines from ortho-alkynylarenecarbaldehyde oxime derivatives
catalyzed by catalytic amounts of AgOTf. They postulated
that here an aldehyde acted as leaving group (Scheme 5).[6]
Scheme 5.
Liang et al. investigated the 2-alkynylbenzyl azide sys- system. Substituents at the 3-position of the formed ring
tem,[7] where – similarly to Yamamoto’s iodocyclization of can be alkyl, cycloalkyl, aryl or heteroaryl.
2-alkynylbenzyl azides – N2 acts as the leaving group to
For the compound 4i an X-ray diffraction structure was
obtained (Figure 2).
give substituted isoquinolines (Scheme 6).[8a–8c]
Scheme 7. Synthesis of N-(2-alkynylbenzylidene)indolin-1-amines 3.
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Indole as Leaving Group in the Synthesis of Annulated Pyridine Derivatives
Table 1. Structures and yields of N-{2-[alkynyl(hetero)aryl]meth-
ylene}indolin-1-amines 3.
Table 2. Structures and yields of the cyclization products 4.
Figure 2. Molecular structure of compound 4i in the solid state (X-
ray diffraction).[11]
Figure 1. Molecular structure of compound 3a in the solid state
(X-ray diffraction).[11]
The coinage metal assisted activation of triple bonds is
widely used in the synthesis of heterocyclic systems.[12] We
tested also other coinage metal salts [copper(I), gold(I), gol-
d(III)] and palladium(II) salts as catalysts for the cycliza-
tion of o-alkynylarenecarbaldehyde hydrazones 3 and some
other silver salts besides AgNO3. However, only silver ni-
trate gave good results. Acid treatment (catalytic amounts
of concd. HNO3) of 3 did not lead to cyclic products
(Scheme 9, Table 3).
Scheme 8. Silver nitrate assisted cyclization of N-{2-[alkynyl-
(hetero)aryl]methylene}indolin-1-amines 3 to give the pyridine de-
rivatives 4 (liberating indole as a leaving group).
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N. Ghavtadze, R. Fröhlich, E.-U. Würthwein
Table 3. Optimization of the reaction conditions for the cyclization reaction of compound 3a leading to compound 4a.
FULL PAPER
Metal salt
Base
Solvent
T [°C]
t [h]
Yield [%]
10 mol-% CuI
10 mol-% PdCl2·(PhCN)2
10 mol-% PdCl2·(PPh3)2
5 mol-% AuCl3
10 mol-% CuBr
2 equiv. AgNO3
1.2 equiv. AgNO3
5 mol-% AuCl·PPh3
AgOAc
AgOTf
AgSbF6
–
–
1 equiv. K2CO3
1 equiv. K2CO3
1 equiv. K2CO3
1 equiv. Na2CO3
1 equiv. Na2CO3
–
–
–
DMF
DMF
DMF
DCE
100
100
50
50
50
60
60
60
60
60
60
70
6
4
5
5
5
3
3
5
3
4
4
5
3
no reaction
no reaction
no reaction
no reaction
no reaction
99
DCE
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
EtOH
CHCl3
98
no reaction
trace
trace
trace
no reaction
decomp.
–
–
–
1 equiv. K2CO3
cat. amount concd. HNO3
room temp.
Scheme 9.
Thus, we found the optimal conditions for this reaction
to be heating of the hydrazone 3 in CHCl3 at 60 °C in the
presence of 1.2 equiv. of silver nitrate. Catalytic amounts of
silver salt give only partial conversion. The reason for this
behaviour is discussed later in the text.
Scheme 10. Cyclization of 1,1-dimethyl-2-[2-(phenylethynyl)benzyl-
idene]hydrazine (5), 1-methyl-1-phenyl-2-[2-(phenylethynyl)benzyl-
idene]hydrazine (6), and N-[2-(phenylethynyl)benzylidene]-3,4-di-
hydroquinolin-1-amine (7).
It has to be underlined that neither the hydrazone-form-
ing step nor the cyclization reaction require absolute sol-
vents and inert conditions. The reactions can be carried out
in air, and the presence of water in the reaction medium
does not have any effect on the outcome of these reactions.
In order to be sure that exclusively N-aminoindoline-de-
rived hydrazones are suitable for the reaction, we also tested
the hydrazones 5 and 6, derived from 1,1-dimethylhydrazine
and 1-methyl-1-phenylhydrazine under the conditions dis-
cussed above. They gave only traces of the isoquinoline
product, the rest of the starting material was decomposed.
The N-aminotetrahydroquinoline-derived hydrazone 7 led
to the desired product 4a, but the reaction was much less
efficient, and the yield of 4a was only 15% (compared to
98% for the N-aminoindoline-derived analogue). In this ex-
periment the reaction mixture was heated in chloroform for
4 h in the presence of 1.2 equiv. of AgNO3, the remaining
substrate 7 was found to be decomposed (Scheme 10). We
were able to detect a peak at m/z = 132.0814 in the ESI
mass spectrum, which corresponds to the calculated mass
Iodine may also be used as electrophile[8,13] in these cycli-
zation reactions to afford the I-substituted product 8 in
35% yield (heating at 60 °C in chloroform for 8 h)
(Scheme 11).
Scheme 11. Iodocyclization of N-[2-(phenylethynyl)benzylidene]-
indolin-1-amine 3a.
We propose the following mechanism for the observed
of the protonated dihydroquinoline (m/z = 132.0813) silver(I)-induced reaction (Scheme 12). Silver(I) activation
formed in the reaction. However, we were not able to isolate at the alkyne moiety of the substrate is expected to initiate
it from the crude reaction mixture by column chromatog- a 6-endo-dig cyclization to afford a pyridinium cation,
raphy.
which in turn undergoes an N–N bond-fission reaction
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Indole as Leaving Group in the Synthesis of Annulated Pyridine Derivatives
Scheme 12. Proposed mechanism of the silver-assisted cycliaztion reaction of N-{2-[alkynyl(hetero)aryl]methylene}indolin-1-amines 3.
after removal of a proton from the indoline α-carbon atom, B3LYP/6-311G(d,p)-level[15] for the non-silver-containing
thereby releasing indole together with the annulated pyr- species and at the SCS-MP2/6-311G(d,p)&SDD//B3LYP/6-
idine derivatives 4.
311G(d,p)&SDD-level for silver-containing ones. The cal-
We were also able to clarify the fate of indole as the sec- culations of the silver(I) complex of N-[2-(prop-1-ynyl)-
ond product and the origin of the observed silver mirror. benzylidene]indolin-1-amine as model system (for simplicity
In principle, catalytic amounts of the silver salt should be we replaced larger groups by a methyl substituent at the
sufficient for the cyclization reaction, but under the reaction triple bond) in the gas phase without any solvation, show
conditions AgI is reduced to Ag0 by indole, which is formed that the cyclization step has an calculated activation barrier
after the N–N bond cleavage. The reduction process most of 34.7 kcal/mol (for this less reactive alkyl-substituted ex-
probably proceeds by a single-electron transfer mechanism, ample); the product formed is 5.6 kcal/mol lower in energy
and the intermediate indole radical undergoes uncontrolled compared to the silver substrate complex (Scheme 13, up-
polymerization. We performed a test reaction by treating per line). The N–N bond-fission step is calculated to be
1H-indole in chloroform with AgNO3 in the presence of exothermic as well. The sum of the energies of the proton-
nitrogen base (TEA, quinoline) at 60 °C. After 5 min, a sil- ated isoquinoline and 3H-indole is 8.1 kcal/mol lower in en-
ver mirror is formed, thus indicating the reduction of the ergy than that of the pyridinium cation (Scheme 13, middle
silver cation by indole.
line). By tautomerization of 3H-indole into 1H-indole an
The proposed mechanism is supported by quantum extra energy gain of 6.9 kcal/mol is achieved (Scheme 13,
chemical calculations[14] at the SCS-MP2/6-311G(d,p)// lower line).
Scheme 13. Calculated relative energies and activation barrier of the reactive species for the model system N-[2-(prop-1-ynyl)benzylidene]-
indolin-1-amine [SCS-MP2/6-311G(d,p)&SDD//B3LYP/6-311G(d,p)&SDD+ ZPE].
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Scheme 14. Results of the deuterium-labelling experiments.
According to the quantum chemical calculations, the sil- medium, which stems from dissociation of D2O. Further-
ver cation as a Lewis acid shows a significant affinity more, during the reaction H+ ions are also produced from
towards the C–C triple bond (π-electrophilicity) and also the indoline part of the substrate as it is oxidized to indole.
to the lone pair of the hydrazone nitrogen atom (σ-electro-
philicity).[16] Thus, the AgI ion in the pre-TS complex is
coordinated to both, the triple bond and the N1-hydrazone
nitrogen atom (Figure 3).
Conclusions
We have disclosed a useful second example of the use
of the indolyl substituent as leaving group from a nitrogen
moiety, provided as hydrazones of type 3. The silver nitrate
promoted cyclization reaction of N-{2-[alkynyl(hetero)-
aryl]methylene}indolin-1-amines 3 described here affords
several different annulated pyridine compounds 4 in good
to excellent yield. The hydrazones 3 might be considered as
stable alternatives to [2-alkynyl(hetero)aryl]methanimines.
Thus, in hydrazones 3 bearing an N-indolyl substituent in-
stead of a hydrogen atom as in imines, the indolyl fragment
may be considered to act as a “large hydrogen atom” under
our reaction conditions (Scheme 15).
Figure 3. Calculated σ,π-chelate structure of the silver(I) complex
based on the model system N-[2-(prop-1-ynyl)benzylidene]indolin-
1-amine [B3LYP/6-311G(d,p)&SDD].
Similarly to Larock et al.[5f] we tried to determine the
origin of the proton, which replaces the silver cation at the
4-position of the formed isoquinoline derivatives
(Scheme 14).
Scheme 15.
The transformations described here are very robust. They
can be performed in air and even in the presence of water.
When we performed the reaction in CHCl3 and quenched This is a significant advantage compared to procedures em-
the reaction mixture for the substrate 3c with D2O, the only ploying imines as substrates in similar types of reactions.
observed product was non-deuterated 4c. Similar results Some of the reaction substrates and products were charac-
were obtained then we performed the reaction in CDCl3 terized by X-ray diffraction.
and quenched with H2O or D2O. These experiments indi-
Quantum chemical calculations were used in order to
cate that the replacement of the AgI ion by the proton is support the proposed reaction mechanism and to identify
finished before the workup. However, in the presence of and characterize the key reactive intermediates at a high
50 equiv. D2O in CDCl3 as solvent for the cyclization reac- theoretical level.
tion of compound 3a we obtained a 1:1 mixture of non-
Further investigations to establish indole as neutral leav-
deuterated and deuterated product 4a. In this case a certain ing group in electrophilic substitution reactions at the nitro-
amount of D+ ions is assumed to be present in the reaction gen atom are underway in our laboratory.
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Indole as Leaving Group in the Synthesis of Annulated Pyridine Derivatives
1
m.p. 201–202 °C. H NMR (300 MHz, CDCl3, 25 °C, TMS): δ =
3.00 (s, 6 H, CH3), 3.24 (t, J = 8.3 Hz, 2 H, CH2), 3.92 (t, J =
8.3 Hz, 2 H, CH2N), 6.69 (d, J = 8.5 Hz, 2 H, H-arom.), 6.82 (td,
J = 7.3, 1.1 Hz, 1 H, H-arom.), 7.12–7.31 (m, 5 H, H-arom.), 7.40–
7.49 (m, 3 H, H-arom.), 7.73 (s, 1 H, CH-imine), 8.08 (d, J =
7.9 Hz, 1 H, H-arom.) ppm. 13C NMR (75 MHz, CDCl3, 25 °C,
TMS): δ = 27.1 (CH2), 40.3 (CH3), 48.0 (CH2N), 85.3 (C-trip), 95.6
(C-trip), 109.0 (CH), 112.0 (CH), 120.3 (CH), 122.1, 123.9 (CH),
124.8 (CH), 127.1 (CH), 127.5, 127.76 (CH), 127.82 (CH), 131.91
(CH), 131.98 (CH), 132.6 (CH), 136.9, 147.9, 150.0 ppm. IR (neat):
Experimental Section
Melting points: Büchi Melting Point B-540, melting points are un-
corrected. 1H, 13C NMR spectroscopy: AMX 400, Bruker WM 300
spectrometer. TMS (1H: δ = 0.00 ppm) and CDCl3 (13C: δ =
77.0 ppm) were used as internal reference. IR: Varian 3100 FT-IR
(Excalibur Series). MS: Mass spectra were recorded with a Finni-
gan MAT 4200S, a Bruker Daltonics micrOTOF, a Waters-Micro-
mass Quatro LCZ (ESI). Elemental analysis: Elementar Vario EL
III. Column chromatography: Silica gel Merck 60 (0.040–
0.063 mm). TLC: Merck silica gel plates (silica gel 60 F254), detec-
tion with UV light.
ν = 3053 (w), 3021 (w), 2920 (w), 2899 (w), 2847 (w), 2801 (w),
˜
2203 (m), 1607 (m), 1595 (m), 1568 (m), 1524 (m), 1483 (s), 1464
(m), 1404 (s), 1366 (s), 1300 (m), 1267 (s), 1190 (s), 1153 (m), 1086
(w), 1065 (w), 1036 (w), 1013 (w), 945 (m), 885 (w), 866 (w), 816
(s), 748 (s), 586 (w), 563 (w), 550 (m), 509 (s) cm–1. HRMS (ESI):
calcd. for C25H23N3Na 388.1784; found 388.1787. C25H23N3
(365.48): calcd. C 82.16, H 6.34, N 11.50; found C 82.38, H 6.49,
N 11.45.
General Procedure for the Preparation of N-{2-[Alkynyl(hetero)-
aryl]methylene}indolin-1-amines 3: N-Indolin-1-amines 3a–i were
prepared from the corresponding o-alkynylarenecarbaldehydes 2[17]
and N-aminoindoline.[18] o-Alkynylarenecarbaldehyde 2 (1 mmol)
was dissolved in of ethanol (4 mL), and N-aminoindoline
(1.1 mmol) in ethanol (1 mL) was added slowly at 0 °C. Acetic acid
(1 equiv.) and a small amount of sodium acetate were added to the
reaction mixture in order to maintain a pH of 5–6. The reaction
mixture was stirred at room temp. for 4 h. The resulting product
was either separated by filtration and washed with water and cold
ethanol or purified by column chromatography after standard
aqueous workup.
N-[2-(Thiophen-3-ylethynyl)benzylidene]indolin-1-amine (3c): From
2-(thiophen-3-ylethynyl)benzaldehyde (0.280 g, 1.32 mmol) and N-
aminoindoline (0.195 g, 1.45 mmol) according to the general pro-
cedure. The subsequent chromatographic purification (Et2O/pen-
tane, 1:2) gave 0.340 g (1.04 mmol, 79%) of 3c as orange solid,
m.p.130–131 °C. 1H NMR (300 MHz, CDCl3, 25 °C, TMS): δ =
3.26 (t, J = 8.3 Hz, 2 H, CH2), 3.93 (t, J = 8.3 Hz, 2 H, CH2N),
6.84 (td, J = 7.3, 1.3 Hz, 1 H, H-arom.), 7.12–7.24 (m, 5 H, H-
arom.), 7.31–7.37 (m, 2 H, H-arom.), 7.49 (dd, J = 7.7, 0.9 Hz, 1
H, H-arom.), 7.53 (dd, J = 3.0, 1.2 Hz, 1 H, H-arom.), 7.87 (s, 1
H, CH-imine), 8.09 (dd, J = 8.0, 1.2 Hz, 1 H, H-arom.) ppm. 13C
NMR (75 MHz, CDCl3, 25 °C, TMS): δ = 27.1 (CH2), 47.9
(CH2N), 86.9 (C-trip), 89.5 (C-trip), 109.0 (CH), 120.5 (CH), 121.0,
122.2, 124.1 (CH), 124.8 (CH), 125.6 (CH), 127.1 (CH), 127.5,
127.9 (CH), 128.47 (CH), 128.51 (CH), 129.8 (CH), 131.3 (CH),
N-[2-(Phenylethynyl)benzylidene]indolin-1-amine (3a): From 2-
(phenylethynyl)benzaldehyde (0.420 g, 2.00 mmol) and N-amino-
indoline (0.295 g, 2.20 mmol) according to the general procedure.
The subsequent recrystallization from ethanol gave 0.600 g
(1.86 mmol, 93%) of 3a as a yellow solid, m.p. 133–134 °C. 1H
NMR (400 MHz, CDCl3, 25 °C, TMS): δ = 3.25 (t, J = 8.3 Hz, 2
H, CH2), 3.92 (t, J = 8.3 Hz, 2 H, CH2N), 6.83 (m, 1 H, H-arom.),
7.12–7.24 (m, 4 H, H-arom.), 7.31–7.39 (m, 4 H, H-arom.), 7.51–
7.55 (m, 3 H, H-arom.), 7.89 (s, 1 H, CH-imine), 8.11 (d, J =
8.0 Hz, 1 H, H-arom.) ppm. 13C NMR (100 MHz, CDCl3, 25 °C,
TMS): δ = 27.1 (CH2), 47.9 (CH2N), 87.4 (C-trip), 94.3 (C-trip),
109.0 (CH), 120.5 (CH), 121.0, 123.3, 124.0 (CH), 124.8 (CH),
127.1 (CH), 127.4, 127.8 (CH), 128.3 (CH), 128.4 (CH), 128.5
(CH), 131.3 (CH), 131.4 (CH), 132.3 (CH), 137.5, 147.8 ppm. IR
132.3 (CH), 137.4, 147.8 ppm. IR (KBr): ν = 3117 (w), 3094 (w),
˜
3055 (w), 3021 (w), 2212 (w), 1605 (m), 1566 (m), 1547 (m), 1479
(s), 1458 (m), 1447 (m), 1402 (s), 1354 (w), 1325 (w), 1300 (w), 1275
(w), 1258 (s), 1200 (m), 1188 (m), 1161 (m), 1126 (w), 1090 (w),
1076 (w), 1015 (w), 939 (w), 885 (w), 870 (m), 827 (m), 775 (s), 756
(s), 741 (s), 706 (w), 689 (m), 623 (s), 577 (m), 559 (w), 527 (m)
cm–1. HRMS (ESI): calcd. for C21H16N2SH 329.1107; found
329.1125.
(neat): ν = 3080 (w), 3057 (w), 3030 (w), 2991 (w), 2166 (w), 1609
˜
(m), 1593 (w), 1566 (m), 1547 (m), 1485 (s), 1464 (m), 1440 (m),
1402 (s), 1325 (w), 1300 (m), 1269 (m), 1254 (m), 1192 (m), 1169
(m), 1150 (w), 1086 (w), 1069 (w), 1011 (w), 912 (w), 883 (m), 872
(w), 849 (w), 752 (s), 687 (s), 669 (w), 571 (w), 523 (m) cm–1. HRMS
(ESI): calcd. for C23H18N2Na 345.1362; found 345.1368. C23H18N2
(322.41): calcd. C 85.68, H 5.63, N 8.69; found C 85.62, H 5.52, N
8.80.
N-[2-(Oct-1-ynyl)benzylidene]indolin-1-amine (3d): From 2-(oct-1-
ynyl)benzaldehyde (0.400 g, 1.87 mmol) and N-aminoindoline
(0.278 g, 2.06 mmol) according to the general procedure. The subse-
quent chromatographic purification (Et2O/pentane, 1:5) gave
1
0.530 g (1.61 mmol, 86%) of 3d as a brown viscous oil. H NMR
(400 MHz, CDCl3, 25 °C, TMS): δ = 0.88–0.93 (m, 3 H, CH3),
1.31–1.35 (m, 4 H, CH2), 1.49–1.51 (m, 2 H, CH2), 1.61–1.66 (m, 2
H, CH2), 2.49 (t, J = 6.9 Hz, 2 H, CH2), 3.24 (t, J = 8.3 Hz, 2 H,
CH2), 3.88 (t, J = 8.3 Hz, 2 H, CH2N), 6.82 (td, J = 7.3, 1.3 Hz, 1
H, H-arom.), 7.12–7.29 (m, 5 H, H-arom.), 7.37 (dd, J = 7.7, 1.0 Hz,
1 H, H-arom.), 7.82 (s, 1 H, CH-imine), 8.06 (dd, J = 8.0, 1.0 Hz,
1 H, H-arom.) ppm. 13C NMR (100 MHz, CDCl3, 25 °C, TMS): δ
= 14.1 (CH3), 19.6 (CH2), 22.6 (CH2), 27.0 (CH2), 28.7 (CH2), 28.9
(CH2), 31.5 (CH2), 48.0 (CH2N), 78.5 (C-trip), 95.5 (C-trip), 109.0
(CH), 120.3 (CH), 122.1, 123.8 (CH), 124.8 (CH), 127.1 (CH), 127.4
(CH), 127.7 (CH), 127.8 (CH), 132.0 (CH), 132.3 (CH), 137.2,
X-ray Crystal Structure Analysis of 3a:[11] Empirical formula
C23H18N2, M = 322.39, yellow crystal 0.45ϫ0.30ϫ0.08 mm, a =
34.5200(2), b = 6.6330(1), c = 15.6070(10) Å, β = 102.501(4)°, V
= 3448.8(2) Å3, ρcalcd. = 1.228 gcm–3, µ = 0.556 mm–1, empirical
absorption correction (0.788ՅTՅ0.957), Z = 8, monoclinic, space
group C2/c (No. 15), λ = 1.54178 Å, T = 223(2) K, ω and φ scans,
14013 reflections collected (Ϯh, Ϯk, Ϯl), [(sinθ)/λ] = 0.60 Å–1, 3076
independent (Rint
= 0.054) and 2651 observed reflections
[IՆ2σ(I)], 226 refined parameters, R = 0.045, wR2 = 0.134, max.
(min.) residual electron density 0.12 (–0.16) eÅ–3, hydrogen atoms
calculated and refined as riding atoms.
147.9 ppm. IR (neat): ν = 3055 (w), 3024 (w), 2953 (m), 2926 (m),
˜
N-{2-[4-(Dimethylamino)phenylethynyl]benzylidene}indolin-1-amine
2852 (m), 2224 (w), 1609 (m), 1568 (m), 1547 (m), 1483 (s), 1468
(s), 1445 (m), 1406 (s), 1328 (m), 1300 (m), 1260 (m), 1246 (m),
1211 (w), 1188 (m), 1171 (m), 1152 (w), 1096 (w), 1013 (w), 978
(w), 949 (w), 883 (m), 827 (w), 802 (w), 756 (s), 743 (s), 704 (w),
667 (w), 588 (w) 561 (m), 527 (s) cm–1. HRMS (ESI): calcd. for
(3b):
From
2-[4-(dimethylamino)phenylethynyl]benzaldehyde
(0.060 g, 0.24 mmol) and N-aminoindoline (0.035 g, 0.26 mmol) ac-
cording to the general procedure. The subsequent recrystallization
from ethanol gave 0.082 g (0.22 mmol, 93%) of 3b as a yellow solid,
Eur. J. Org. Chem. 2010, 1787–1797
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1793

N. Ghavtadze, R. Fröhlich, E.-U. Würthwein
C23H26N2H 331.2169; found 331.2177. C23H26N2 (330.47): calcd. C (w), 3019 (w), 2967 (w), 2949 (w), 2920 (w), 2849 (w), 2212 (w),
FULL PAPER
83.59, H 7.93, N 8.48; found C 83.19, H 7.96, N 8.30.
1607 (m), 1587 (m), 1524 (m), 1481 (s), 1468 (s), 1439 (m), 1414
(m), 1383 (w), 1369 (w), 1294 (m), 1260 (m), 1204 (m), 1184 (s),
1159 (s), 1042 (w), 1024 (w), 974 (w), 912 (w), 897 (w), 880 (w),
860 (w), 772 (m), 750 (s), 714 (m), 702 (s), 689 (s), 629 (w), 559
(m), 528 (m) cm–1. HRMS (ESI): calcd. for C27H22N4H 403.1917;
found 403.1921. C27H22N4 (402.50): calcd. C 80.57, H 5.51, N
13.92; found C 80.23, H 5.58, N 13.82.
N-[2-(Cyclopentylethynyl)benzylidene]indolin-1-amine (3e): From 2-
(cyclopentylethynyl)benzaldehyde (0.265 g, 1.34 mmol) and N-
aminoindoline (0.198 g, 1.47 mmol) according to the general pro-
cedure. The subsequent chromatographic purification (Et2O/pen-
tane, 1:5) gave 0.360 g (1.15 mmol, 86%) of 3e as a yellow solid,
m.p. 80–81 °C. 1H NMR (300 MHz, CDCl3, 25 °C, TMS): δ =
1.61–1.77 (m, 6 H, CH2), 1.99–2.09 (m, 2 H, CH2), 2.92 (m, 1 H,
N-[(2-Phenyl-4-(phenylethynyl)thiazol-5-yl)methylene]indolin-1-
CH), 3.26 (t, J = 8.3 Hz, 2 H, CH2), 3.88 (t, J = 8.3 Hz, 2 H, amine (3h): From 2-phenyl-4-(phenylethynyl)thiazole-5-carbal-
CH2N), 6.82 (td, J = 7.2, 1.4 Hz, 1 H, H-arom.), 7.13–7.29 (m, 5
H, H-arom.), 7.36 (dd, J = 7.7, 1.1 Hz, 1 H, H-arom.), 7.81 (s, 1
H, CH-imine), 8.05 (dd, J = 8.0, 1.2 Hz, 1 H, H-arom.) ppm. 13C
NMR (75 MHz, CDCl3, 25 °C, TMS): δ = 25.0, 27.1, 31.0, 34.1,
dehyde (0.080 g, 0.28 mmol) and N-aminoindoline (0.045 g,
0.33 mmol) according to the general procedure. The subsequent
chromatographic purification (Et2O/pentane, 1:10) gave 0.080 g
(0.20 mmol, 71%) of 3h as an orange solid, m.p.196–197 °C. 1H
47.9 (CH2N), 78.0 (C-trip), 99.8 (C-trip), 109.0 (CH), 120.3 (CH), NMR (300 MHz, CDCl3, 25 °C, TMS): δ = 3.29 (t, J = 8.2 Hz, 2
122.1, 123.8 (CH), 124.8 (CH), 127.1 (CH), 127.4 (CH), 127.7 H, CH2), 3.99 (t, J = 8.2 Hz, 2 H, CH2N), 6.89 (m, 1 H, H-arom.),
(CH), 127.8 (CH), 132.06 (CH), 132.1 (CH), 137.2, 147.9 ppm. IR 7.15–7.22 (m, 3 H, H-arom.), 7.38 (m, 3 H, H-arom.), 7.46 (m, 3
(neat): ν = 3055 (w), 2959 (m), 2864 (w), 2224 (w), 1607 (m), 1570 H, H-arom.), 7.61 (m, 2 H, H-arom.), 7.64 (s, 1 H, CH-imine) 8.02–
(m), 1549 (m), 1481 (s), 1445 (m), 1398 (s), 1298 (m), 1269 (m), 8.04 (m, 2 H, H-arom.) ppm. 13C NMR (75 MHz, CDCl3, 25 °C,
˜
1250 (m), 1186 (m), 1163 (m), 1097 (w), 1036 (w), 1015 (w), 980
(w), 891 (m), 881 (w), 835 (w), 802 (w), 745 (s), 706 (m), 577 (m),
TMS): δ = 27.0 (CH2), 48.1 (CH2N), 82.6 (C-trip), 94.3 (C-trip),
109.3 (CH), 121.3 (CH), 122.5, 124.4 (CH), 125.0 (CH), 126.8
525 (m) cm–1. HRMS (ESI): calcd. for C22H22N2H 315.1856; found (CH), 127.7, 128.0 (CH), 128.4 (CH), 128.8 (CH), 129.0 (CH),
315.1865.
130.6 (CH), 131.8 (CH), 132.7, 133.6, 140.6, 146.7, 165.2 ppm. IR
(neat): ν = 3053 (w), 3030 (w), 2992 (w), 2959 (w), 2924 (w), 2850
˜
N-[(6-(Phenylethynyl)benzo[d][1,3]dioxol-5-yl)methylene]indolin-1-
amine (3f): From 6-(phenylethynyl)benzo[d][1,3]dioxole-5-carbal-
dehyde (0.220 g, 0.88 mmol) and N-aminoindoline (0.130 g,
0.97 mmol) according to the general procedure. The subsequent
recrystallization from ethanol gave 0.260 g (0.71 mmol, 81%) of 3f
as a yellow solid, m.p. 169–170 °C. 1H NMR (300 MHz, CDCl3,
25 °C, TMS): δ = 3.23 (t, J = 8.3 Hz, 2 H, CH2), 3.88 (t, J = 8.3 Hz,
(w), 2208 (w), 1734 (w), 1665 (w), 1611 (w), 1599 (m), 1541 (m),
1503 (m), 1485 (s), 1462 (m), 1439 (m), 1402 (m), 1356 (w), 1298
(m), 1260 (m), 1227 (w), 1188 (w), 1175 (w), 1163 (w), 1094 (w),
1016 (m), 978 (w), 907 (w), 854 (w), 802 (w), 746 (s), 708 (w), 687
(s), 679 (s), 635 (w), 604 (m), 547 (w), 540 (m) cm–1. HRMS (ESI):
calcd. for C26H19N3SH 406.1372; found 406.1362.
2 H, CH2N), 5.98 (d, J = 0.9 Hz, 2 H, OCH2O), 6.82 (m, 1 H, H- N-[(2-(Phenylethynyl)benzo[b]thiophen-3-yl)methylene]indolin-1-
arom.), 6.92 (s, 1 H, H-arom.), 7.11–7.22 (m, 3 H, H-arom.), 7.34– amine (3i): From 2-(phenylethynyl)benzo[b]thiophene-3-carbal-
7.40 (m, 3 H, H-arom.), 7.48–7.52 (m, 2 H, H-arom.), 7.56 (s, 1 H, dehyde (0.262 g, 1.00 mmol) and N-aminoindoline (0.148 g,
H-arom.), 7.84 (s, 1 H, CH-imine) ppm. 13C NMR (75 MHz, 1.10 mmol) according to the general procedure. The subsequent
CDCl3, 25 °C, TMS): δ = 27.1 (CH2), 48.0 (CH2N), 87.4 (C-trip),
93.2 (C-trip), 101.4 (OCH2O), 103.8 (CH), 108.9 (CH), 111.0 (CH),
114.8, 120.3 (CH), 123.4, 124.8 (CH), 127.4, 127.8 (CH), 128.2
recrystallization from ethanol gave 0.250 g (0.66 mmol, 66%) of 3i
as an orange solid, m.p. 184–185 °C. H NMR (400 MHz, CDCl3,
25 °C, TMS): δ = 3.29 (t, J = 8.3 Hz, 2 H, CH2), 3.97 (t, J = 8.3 Hz,
1
(CH), 128.4 (CH), 131.3 (CH), 131.5 (CH), 133.5, 147.1, 147.9, 2 H, CH2N), 6.86 (td, J = 7.1, 1.6 Hz, 1 H, H-arom.), 7.16 (d, J =
148.6 ppm. IR (neat): ν = 3055 (w), 3005 (w), 2901 (w), 1886 (w), 7.2 Hz, 1 H, H-arom.), 7.22–7.29 (m, 2 H, H-arom.), 7.38–7.45 (m,
˜
2207 (w), 1607 (m), 1601 (m), 1558 (m), 1491 (m), 1474 (s), 1441 4 H, H-arom.), 7.50 (ddd, J = 8.2, 7.2, 1.2 Hz, 1 H, H-arom.), 7.56–
(m), 1412 (m), 1377 (w), 1298 (w), 1267 (w), 1242 (s), 1209 (s), 1153 7.58 (m, 2 H, H-arom.), 7.76 (d, J = 7.7 Hz, 1 H, H-arom.), 7.93
(m), 1138 (w), 1034 (s), 937 (m), 910 (w), 889 (s), 860 (m), 841 (w), (s, 1 H, CH-imine), 8.98 (d, J = 7.8 Hz, 1 H, H-arom.) ppm. 13C
799 (w), 762 (s), 752 (s), 687 (s), 637 (w), 608 (w), 538 (w) cm–1.
HRMS (ESI): calcd. for C24H18N2O2Na 389.1260; found 389.1265.
C24H18N2O2 (366.42): calcd. C 78.67, H 4.95, N 7.65; found C
78.49, H 4.90, N 7.58.
NMR (100 MHz, CDCl3, 25 °C, TMS): δ = 27.1 (CH2), 47.4
(CH2N), 82.5 (C-trip), 99.9 (C-trip), 109.0 (CH), 120.5 (CH), 121.0,
121.9 (CH), 122.7, 124.9 (CH), 125.2 (CH), 125.9 (CH), 126.0
(CH), 127.6, 128.0 (CH), 128.5 (CH), 128.8 (CH), 129.7 (CH),
131.5 (CH), 135.77, 135.80, 139.5, 147.8 ppm. IR (neat): ν = 3053
˜
N-[(1-Methyl-2-phenyl-4-(phenylethynyl)-1H-imidazol-5-yl)methyl-
ene]indolin-1-amine (3g): From 1-methyl-2-phenyl-4-(phenyleth-
ynyl)-1H-imidazole-5-carbaldehyde (0.110 g, 0.38 mmol) and N-
aminoindoline (0.060 g, 0.46 mmol) according to the general pro-
cedure. The subsequent recrystallization from ethanol gave 0.130 g
(0.32 mmol, 84%) of 3g as a yellow solid, m.p. 222–223 °C. 1H
NMR (300 MHz, CDCl3, 25 °C, TMS): δ = 3.28 (t, J = 8.2 Hz, 2
(w), 3021 (w), 3001 (w), 2930 (w), 2866 (w), 2847 (w), 2197 (w),
1607 (m), 1562 (m), 1547 (m), 1483 (w), 1458 (m), 1412 (m), 1366
(m), 1298 (w), 1271 (m), 1252 (s), 1202 (m), 1076 (w), 1017 (w),
868 (m), 839 (w), 806 (w), 754 (s), 737 (s), 729 (s), 689 (s), 642 (w),
575 (m), 542 (s), 529 (m) cm–1. HRMS (ESI): calcd. for
C25H18N2SNa 401.1083; found 401.1088.
H, CH2), 3.92 (t, J = 8.2 Hz, 2 H, CH2N), 4.05 (s, 3 H, CH3), 6.85 1,1-Dimethyl-2-[2-(phenylethynyl)benzylidene]hydrazine (5): From 2-
(td, J = 7.3, 0.8 Hz, 1 H, H-arom.), 7.04 (m, 1 H, H-arom.), 7.16 (phenylethynyl)benzaldehyde (0.155 g, 0.75 mmol) and 1,1-dimeth-
(m, 2 H, H-arom.), 7.33–7.35 (m, 3 H, H-arom.), 7.46–7.49 (m, 3
H, H-arom.), 7.54–7.59 (m, 3 H, H-arom.), 7.68–7.71 (m, 2 H, H- cedure. The subsequent chromatographic purification (Et2O/pen-
arom.) ppm. 13C NMR (75 MHz, CDCl3, 25 °C, TMS): δ = 27.0 tane, 1:5) gave 0.170 g (0.69 mmol, 91%) of 5 as a brown oil. 1H
ylhydrazine (0.048 g, 0.80 mmol) according to the general pro-
(CH2), 35.8 (CH3), 47.5 (CH2N), 82.5 (C-trip), 93.5 (C-trip), 108.6 NMR (400 MHz, CDCl3, 25 °C, TMS): δ = 3.02 (s, 6 H, CH3),
(CH), 120.6 (CH), 123.2, 123.5 (CH), 125.0 (CH), 127.5, 127.8 7.17 (td, J = 7.7, 1.1 Hz, 1 H, H-arom.), 7.28 (m, 1 H, H-arom.),
(CH), 128.1 (CH), 128.3 (CH), 128.5 (CH), 129.2 (CH), 129.3
7.31–7.37 (m, 3 H, H-arom.), 7.47–7.53 (m, 3 H, H-arom.), 7.80 (s,
(CH), 131.4 (CH), 133.5, 147.6, 149.9 ppm. IR (neat): ν = 3059
1 H, CH-imine), 7.93 (dd, J = 8.0, 0.4 Hz, 1 H, H-arom.) ppm. 13
C
˜
1794
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 1787–1797

Indole as Leaving Group in the Synthesis of Annulated Pyridine Derivatives
NMR (100 MHz, CDCl3, 25 °C, TMS): δ = 42.7 (CH3), 87.5 (C-
trip), 94.1 (C-trip), 120.7, 123.4, 123.8 (CH), 126.7 (CH), 128.3
(CH), 128.4 (CH), 128.5 (CH), 131.4 (CH), 132.1 (CH), 137.9 ppm.
chromatographic purification (Et2O/pentane, 1:3) gave 0.050 g
(0.24 mmol, 98%) of 4a as a brown solid, m.p. 91–92 °C. 1H NMR
(400 MHz, CDCl3, 25 °C, TMS): δ = 7.42 (td, J = 9.2, 4.3 Hz, 1
H, H-arom.), 7.51 (t, J = 7.5 Hz, 2 H, H-arom.), 7.58 (dd, J = 11.1,
IR (neat): ν = 3055 (w), 2995 (w), 2859 (w), 2789 (w), 2212 (w),
˜
1599 (m), 1566 (m), 1545 (m), 1491 (m), 1462 (m), 1445 (m), 1423 4.0 Hz, 1 H, H-arom.), 7.69 (m, 1 H, H-arom.), 7.87 (d, J = 8.3 Hz,
(w), 1402 (w), 1273 (m), 1260 (m), 1159 (w), 1132 (w), 1096 (w), 1 H, H-arom.), 7.99 (d, J = 8.2 Hz, 1 H, H-arom.), 8.07 (s, 1 H,
1057 (s), 1042 (m), 978 (m), 922 (m), 856 (m), 816 (w), 752 (s), 692 H-arom.), 8.13 (d, J = 8.5 Hz, 2 H, H-arom.), 9.34 (s, 1 H, CHN)
(s), 629 (m), 577 (m), 554 (w), 522 (m) cm–1. HRMS (ESI): calcd. ppm. 13C NMR (100 MHz, CDCl3, 25 °C, TMS): δ = 116.5 (CH),
for C17H16N2H 249.1386; found 249.1387.
126.9 (CH), 127.0 (CH), 127.1 (CH), 127.6 (CH), 127.7, 128.5
(CH), 128.8 (CH), 130.5 (CH), 136.6, 139.6, 151.3, 152.4 (CHN)
ppm. HRMS (ESI): calcd. for C15H11NH 206.0964; found
206.0962.
1-Methyl-1-phenyl-2-[2-(phenylethynyl)benzylidene]hydrazine
(6):
From 2-(phenylethynyl)benzaldehyde (0.155 g, 0.75 mmol) and 1-
methyl-1-phenylhydrazine (0.098 g, 0.80 mmol) according to the ge-
neral procedure. The subsequent chromatographic purification
(Et2O/pentane, 1:5) gave 0.215 g (0.69 mmol, 92%) of 6 as a yellow
solid. m.p. 119–120 °C. 1H NMR (400 MHz, CDCl3, 25 °C, TMS):
δ = 3.44 (d, J = 0.6, 3 H, CH3), 6.94 (td, J = 7.3, 0.7 Hz, 1 H, H-
arom.), 7.21(td, J = 7.5, 1.0 Hz, 1 H, H-arom.), 7.29–7.41 (m, 8 H,
H-arom.), 7.50–7.55 (m, 3 H, H-arom.), 8.06 (s, 1 H, CH-imine),
8.09 (d, J = 8.0 Hz, 1 H, H-arom.) ppm. 13C NMR (100 MHz,
CDCl3, 25 °C, TMS): δ = 33.2 (CH3), 87.5 (C-trip), 94.4 (C-trip),
115.5 (CH), 120.8 (CH), 121.3, 123.3, 124.3 (CH), 127.2 (CH),
128.35 (CH), 128.43 (CH), 128.6 (CH), 129.0 (CH), 130.4 (CH),
4-(Isoquinolin-3-yl)-N,N-dimethylaniline (4b): From compound 3b
(0.050 g, 0.14 mmol) according to the general procedure. The sub-
sequent chromatographic purification (Et2O/pentane, 1:1) gave
0.022 g (0.09 mmol, 65%) of 4b as a yellow solid, m.p. 139–140 °C.
1H NMR (400 MHz, CDCl3, 25 °C, TMS): δ = 3.03 [s, 6 H,
N(CH3)2], 6.84 (dd, J = 9.5, 2.4 Hz, 2 H, H-arom.), 7.50 (m, 1 H,
H-arom.), 7.64 (m, 1 H, H-arom.), 7.81 (d, J = 8.3 Hz, 1 H, H-
arom.), 7.94 (d, J = 9.3 Hz, 1 H, H-arom.), 7.95 (s, 1 H, H-arom.),
8.05 (d, J = 9.0 Hz, 2 H, H-arom.), 9.28 (s, 1 H, CHN) ppm. 13C
NMR (100 MHz, CDCl3, 25 °C, TMS): δ = 40.4 [N(CH3)2], 112.4
(CH), 114.2 (CH), 126.1 (CH), 126.6 (CH), 127.1, 127.4, 127.6
(CH), 127.8 (CH), 130.3 (CH), 136.9, 150.8, 151.6, 152.1 (CHN)
131.4 (CH), 132.3 (CH), 137.7, 147.7 ppm. IR (neat): ν = 3076 (w),
˜
3057 (w), 3024 (w), 2216 (w), 1595 (m), 1568 (m), 1551 (m), 1493
(s), 1443 (m), 1379 (m), 1317 (m), 1275 (m), 1192 (m), 1179 (m),
1145 (m), 1090 (m), 1028 (m), 993 (m), 914 (w), 887 (m), 845 (w),
754 (s), 746 (s), 689 (s), 640 (w), 584 (m), 534 (m) cm–1. HRMS
(ESI): calcd. for C22H18N2Na 333.1362; found 333.
ppm. IR (neat): ν = 2922 (w), 2853 (w), 2804 (w), 1605 (s), 1580
˜
(s), 1524 (s), 1481 (w), 1441 (s), 1354 (s), 1321 (w), 1261 (w), 1225
(m), 1194 (s), 1167 (m), 1123 (m), 1063 (w), 1013 (w), 941 (m), 883
(s), 862 (m), 818 (s), 764 (s), 729 (m), 683 (m), 667 (m), 611 (w),
551 (m), 532 (m) cm–1. HRMS (ESI): calcd. for C17H16N2H
249.1386; found 249.1380.
N-[2-(Phenylethynyl)benzylidene]-3,4-dihydroquinolin-1(2H)-amine
(7): From 2-(phenylethynyl)benzaldehyde (0.260 g, 1.26 mmol) and
1-amino-1,2,3,4-tetrahydroquinoline (0.205 g, 1.39 mmol) accord-
ing to the general procedure. 0.215 g (0.69 mmol, 92%) of 7 as a
yellow solid, m.p. 144–145 °C. 1H NMR (400 MHz, CDCl3, 25 °C,
TMS): δ = 2.19 (m, 2 H, CH2), 2.77 (m, 2 H, CH2), 3.73 (t, J =
6.2 Hz, 2 H, CH2N), 6.82 (td, J = 7.3, 1.1 Hz, 1 H, H-arom.), 7.03
(dd, J = 7.4, 1.0 Hz, 1 H, H-arom.), 7.17–7.22 (m, 2 H, H-arom.),
7.33–7.40 (m, 4 H, H-arom.), 7.51–7.56 (m, 3 H, H-arom.), 7.80
(d, J = 8.3 Hz, 1 H, H-arom.), 8.08 (s, 1 H, CH-imine), 8.12 (dd,
J = 8.0, 0.7 Hz, 1 H, H-arom.) ppm. 13C NMR (100 MHz, CDCl3,
25 °C, TMS): δ = 21.9 (CH2), 27.0 (CH2), 44.9 (CH2), 87.5 (C-trip),
94.2 (C-trip), 114.7 (CH), 119.9 (CH), 121.2, 123.3, 123.9, 124.3
(CH), 127.1 (CH), 127.4 (CH), 128.2 (CH), 128.3 (CH), 128.4
(CH), 128.6 (CH), 129.2 (CH), 131.5 (CH), 132.4 (CH), 138.0,
3-(Thiophen-3-yl)isoquinoline (4c): From compound 3c (0.131 g,
0.40 mmol) according to the general procedure. The subsequent
chromatographic purification (Et2O/pentane, 1:3) gave 0.070 g
(0.33 mmol, 83%) of 4c as a red solid, m.p. 90–91 °C. 1H NMR
(300 MHz, CDCl3, 25 °C, TMS): δ = 7.43 (dd, J = 5.0, 3.1 Hz, 1 H,
H-arom.), 7.56 (d, J = 7.1 Hz, 1 H, H-arom.), 7.66 (t, J = 7.5 Hz, 1
H, H-arom.), 7.73 (dd, J = 5.1, 1.2 Hz, 1 H, H-arom.), 7.82 (d, J =
8.2 Hz, 1 H, H-arom.), 7.92 (s, 1 H, H-arom.), 7.94 (d, J = 8.3 Hz, 1
H, H-arom.), 8.03 (dd, J = 3.0, 1.2 Hz, 1 H, H-arom.), 9.26 (s, 1
H, CHN) ppm. 13C NMR (75 MHz, CDCl3, 25 °C, TMS): δ =
115.8 (CH), 123.1 (CH), 126.0 (CH), 126.3 (CH), 126.7 (CH), 126.8
(CH), 127.59, 127.61 (CH), 130.6 (CH), 136.6, 142.2, 147.5, 152.5
(CHN) ppm. IR (neat): ν = 3103 (w), 3053 (w), 2922 (w), 2855 (w),
˜
142.8 ppm. IR (neat): ν = 3057 (w), 3028 (w), 2938 (w), 2926 (w),
˜
1622 (m), 1582 (m), 1530 (w), 1485 (w), 1437 (m), 1379 (m), 1339
(w), 1300 (m), 1277 (m), 1229 (m), 1196 (m), 1167 (w), 1140 (w),
1013 (w), 962 (m), 945 (m), 908 (w), 881 (m), 837 (m), 804 (s), 746
(s), 691 (s), 654 (m), 617 (m), 514 (m) cm–1. HRMS (ESI): calcd. for
C13H9NSH 212.0528; found 212.0526. C13H9NS (211.28): calcd. C
73.90, H 4.29, N 6.63; found C 73.46, H 4.44, N 7.04.
2839 (w), 2141 (w), 1601 (w), 1566 (m), 1549 (w), 1485 (s), 1460
(w), 1445 (m), 1393 (s), 1277 (w), 1221 (m), 1194 (m), 1161 (s),
1074 (w), 1057 (m), 1034 (w), 1022 (w), 935 (w), 876 (w), 800 (w),
750 (s), 689 (s), 650 (w), 571 (w), 524 (m) cm–1. HRMS (ESI):
calcd. for C24H20N2Na 359.1519; found 359.1531. C24H20N2
(336.44): calcd. C 85.68, H 5.99, N 8.33; found C 85.57, H 6.07, N
8.38.
3-Hexylisoquinoline (4d): From compound 3d (0.066 g, 0.20 mmol)
according to the general procedure. The subsequent chromato-
graphic purification (Et2O/pentane, 1:3) gave 0.022 g (0.10 mmol,
General Procedure for the Silver Nitrate Assisted Cyclization of N-
{2-[Alkynyl(hetero)aryl]methylene}indolin-1-amines 3 into Annulated
Pyridine Derivatives 4: The respective N-{2-[alkynyl(hetero)aryl]-
methylene}indolin-1-amine 3 (1 mmol) was dissolved in CHCl3
(5 mL); silver nitrate (1.2 mmol; 1.2 equiv.) was added to the solu-
tion in one portion. The reaction mixture was heated at 60 °C for
the time indicated in Table 2. After cooling to room temperature,
the reaction mixture was diluted with chloroform and washed with
water. The organic phase was separated, dried with magnesium sul-
fate and purified by column chromatography.
1
52%) of 4d as an orange oil. H NMR (400 MHz, CDCl3, 25 °C,
TMS): δ = 0.88 (t, J = 7.0 Hz, 3 H, CH3.),1.31–1.41 (m, 6 H, CH2),
1.77–1.85 (m, 2 H, CH2), 2.93 (m, 2 H, CH2), 7.47 (s, 1 H, H-
arom.), 7.51–7.55 (m, 1 H, H-arom.), 7.62–7.67 (m, 1 H, H-arom.),
7.75 (d, J = 8.2 Hz, 1 H, H-arom.), 7.93 (d, J = 8.2 Hz, 1 H, H-
arom.), 9.20 (s, 1 H, CHN) ppm. 13C NMR (100 MHz, CDCl3,
25 °C, TMS): δ = 14.1 (CH3), 22.6 (CH3), 29.1 (CH3), 30.0 (CH3),
31.8 (CH3), 38.2 (CH3), 117.9 (CH), 126.1 (CH), 126.2 (CH), 127.0,
3-Phenylisoquinoline (4a):[19] From compound 3a (0.081 g, 127.5 (CH), 130.2 (CH), 152.0 (CHN), 155.9 ppm. IR (neat): ν =
˜
0.25 mmol) according to the general procedure. The subsequent
3055 (w), 2926 (m), 2855 (m), 1630 (m), 1591 (m), 1582 (m), 1491
Eur. J. Org. Chem. 2010, 1787–1797
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1795

N. Ghavtadze, R. Fröhlich, E.-U. Würthwein
FULL PAPER
(w), 1456 (m), 1377 (w), 1275 (w), 1167 (w), 1140 (w), 1015 (w), (m), 864 (m), 802 (m), 756 (s), 745 (m), 681 (s), 667 (s), 610 (s), 540
949 (m), 878 (m), 851 (w), 746 (m), 630 (s), 534 (s) cm–1. HRMS
(ESI): calcd. for C15H19NH 214.1590; found 214.1598.
(m), 513 (m) cm–1. HRMS (ESI): calcd. for C18H12N2SH 289.0794;
found 289.0786.
3-Phenylbenzo[4,5]thieno[3,2-c]pyridine (4i): From compound 3i
(0.150 g, 0.40 mmol) according to the general procedure. The sub-
sequent chromatographic purification (Et2O/pentane, 2:5) gave
0.050 g (0.19 mmol, 48%) of 4i as a yellow solid, m.p. 167–168 °C.
1H NMR (400 MHz, CDCl3, 25 °C, TMS): δ = 7.44 (m, 1 H, H-
arom.), 7.49–7.52 (m, 4 H, H-arom.), 7.88 (m, 1 H, H-arom.), 8.10
(m, 2 H, H-arom.), 8.20 (d, J = 0.8 Hz, 1 H, H-arom.), 8.27 (m, 1
H, H-arom.), 9.47 (s, 1 H, CHN) ppm. 13C NMR (100 MHz,
CDCl3, 25 °C, TMS): δ = 114.4 (CH), 121.7 (CH), 122.9 (CH),
125.4 (CH), 127.2 (CH), 127.7 (CH), 128.9 (CH), 129.1 (CH),
3-Cyclopentylisoquinoline (4e): From compound 3e (0.126 g,
0.40 mmol) according to the general procedure. The subsequent
chromatographic purification (Et2O/pentane, 2:5) gave 0.036 g
(0.18 mmol, 46%) of 4e as a brown solid, m.p. 145–146 °C. 1H
NMR (300 MHz, CDCl3, 25 °C, TMS): δ = 1.77–1.92 (m, 6 H,
CH2), 2.21–2.29 (m, 2 H, CH2), 3.48 (m, 1 H, CH), 7.61–7.66 (m,
2 H, H-arom.), 7.76–7.86 (m, 2 H, H-arom.), 8.04 (d, J = 8.2 Hz,
1 H, H-arom.), 9.34 (s, 1 H, CHN) ppm. 13C NMR (75 MHz,
CDCl3, 25 °C, TMS): δ = 25.6 (CH2), 33.6 (CH2), 46.1 (CH), 118.2
(CH), 126.4 (CH), 126.7, 127.5 (CH), 128.3 (CH), 132.3 (CH),
130.5, 133.4, 139.1, 142.7 (CHN), 149.5, 153.5 ppm. IR (neat): ν =
˜
137.5, 149.9 (CHN), 156.0 ppm. IR (neat): ν = 2949 (m), 2862 (m),
˜
3053 (w), 3022 (w), 2963 (w), 1595 (w), 1574 (m), 1528 (w), 1470
(w), 1454 (w), 1441 (m), 1435 (m), 1368 (m), 1321 (w), 1300 (m),
1246 (m), 1225 (m), 1086 (m), 1070 (m), 1018 (m), 989 (w), 932
(w), 918 (w), 860 (m), 822 (m), 781 (m), 752 (s), 721 (s), 687 (s),
629 (s), 557 (w), 534 (w) cm–1. HRMS (ESI): calcd. for C17H11NSH
262.0685; found 262.0672.
X-ray Crystal Structure Analysis of 4i:[11] Empirical formula
C17H11NS, M = 261.33, light yellow crystal 0.25ϫ0.15ϫ0.03 mm,
a = 8.7552(1), b = 5.8014(1), c = 24.4634(1) Å, β = 97.434(1)°, V
= 1232.11(3) Å3, ρcalcd. = 1.409 gcm–3, µ = 2.168 mm–1, empirical
absorption correction (0.613ՅTՅ0.938), Z = 4, monoclinic, space
group P21/c (No. 14), λ = 1.54178 Å, T = 223(2) K, ω and φ scans,
8954 reflections collected (Ϯh, Ϯk, Ϯl), [(sinθ)/λ] = 0.60 Å–1, 2161
2488 (m), 1645 (m), 1626 (m), 1614 (m), 1580 (m), 1562 (w), 1489
(m), 1450 (m), 1389 (w), 1254 (w), 1207 (w), 1155 (m), 962 (m),
914 (m), 885 (s), 777 (s), 750 (s), 696 (w), 563 (m), 532 (m) cm–1.
HRMS (ESI): calcd. for C14H15NH 198.1277; found 198.1277.
7-Phenyl-[1,3]dioxolo[4,5-g]isoquinoline (4f):[5f] From compound 3f
(0.104 g, 0.28 mmol) according to the general procedure. The sub-
sequent chromatographic purification (Et2O/pentane, 2:3) gave
0.035 g (0.14 mmol, 50%) of 4f as a red solid. m.p. 117–118 °C. 1H
NMR (300 MHz, CDCl3, 25 °C, TMS): δ = 6.09 (s, 2 H, CH2),
7.11 (s, 1 H, H-arom.), 7.20 (s, 1 H, H-arom.), 7.40 (m, 1 H, H-
arom.), 7.49 (m, 2 H, H-arom.), 7.89 (s, 1 H, H-arom.), 8.07 (m, 2
H, H-arom.), 9.06 (s, 1 H, CHN) ppm. 13C NMR (75 MHz, CDCl3,
25 °C, TMS): δ = 101.6 (CH2), 102.8 (CH), 103.1 (CH), 116.4
(CH), 125.0, 126.8 (CH), 128.3 (CH), 128.7 (CH), 135.0, 139.6,
148.3, 150.1 (CHN), 150.5, 151.1 ppm. HRMS (ESI): calcd. for
C16H11NO2H 250.0863; found 250.0862.
independent (Rint
= 0.058) and 1779 observed reflections
[IՆ2σ(I)], 176 refined parameters, R = 0.054, wR2 = 0.138, max.
(min.) residual electron density 0.20 (–0.19) eÅ–3, disorder refined
with a ratio of 88:12, hydrogen atoms calculated and refined as
riding atoms.
3-Methyl-2,6-diphenyl-3H-imidazo[4,5-c]pyridine (4g): From com-
pound 3g (0.028 g, 0.07 mmol) according to the general procedure.
The subsequent chromatographic purification (Et2O) gave 0.015 g
(0.05 mmol, 76%) of 4g as a yellow solid, m.p. 169–170 °C. 1H
NMR (300 MHz, CDCl3, 25 °C, TMS): δ = 4.02 (s, 3 H, CH3),
6.98 (s, 1 H, H-arom.), 7.38–7.44 (m, 1 H, H-arom.), 7.49–7.54 (m,
2 H, H-arom.), 7.58–7.60 (m, 2 H, H-arom.), 7.81–7.84 (m, 2 H,
H-arom.), 8.05–8.08 (m, 2 H, H-arom.), 8.14 (d, J = 1.0 Hz, 1 H,
H-arom.), 8.93 (d, J = 1.0 Hz, 1 H, H-arom.) ppm. 13C NMR
(75 MHz, CDCl3, 25 °C, TMS): δ = 32.3(CH3), 111.2 (CH), 127.1
(CH), 128.2 (CH), 128.8 (CH), 129.0 (CH), 129.1, 129.6 (CH),
130.7 (CH), 132.4 (CH), 133.7, 140.1, 149.3, 151.1, 157.3 ppm. IR
4-Iodo-3-phenylisoquinoline (8):[5c] From compound 3a (0.100 g,
0.30 mmol) by addition of I2 (6 equiv., 0.450 g, 1.80 mmol) in of
CHCl3 (5 mL). The reaction mixture was stirred at 60 °C for 8 h.
After aqueous workup and extraction with CHCl3, chromato-
graphic purification (Et2O/pentane, 2:3) gave 0.035 g (0.11 mmol,
35%) of 8 as a yellow oil. 1H NMR (400 MHz, CDCl3, 25 °C,
TMS): δ = 7.44–7.53 (m, 3 H, H-arom.), 7.61–7.65 (m, 2 H, H-
arom.), 7.69 (ddd, J = 8.0, 7.0, 1.0 Hz, 1 H, H-arom.), 7.84 (ddd,
J = 8.5, 7.0, 1.3 Hz, 1 H, H-arom.), 7.97 (d, J = 8.1 Hz, 1 H, H-
arom.), 8.24 (dd, J = 8.5, 0.8 Hz, 1 H, H-arom.), 9.17 (s, 1 H,
CHN) ppm. HRMS (ESI): calcd. for C15H10INH 331.9931; found
331.9939.
(neat): ν = 3055 (w), 3030 (w), 2955 (w), 2924 (m), 2853 (m), 1734
˜
(w), 1670 (w), 1607 (m), 1570 (w), 1520 (w), 1476 (s), 1466 (s), 1441
(s), 1381 (m), 1344 (m), 1287 (w), 1261 (m), 1213 (w), 1190 (w),
1117 (m), 1074 (w), 1016 (m), 972 (w), 916 (m), 899 (w), 866 (m),
858 (w), 843 (w), 779 (s), 760 (s), 721 (m), 696 (s), 675 (s), 610
(w), 602 (m), 522 (w) cm–1. HRMS (ESI): calcd. for C19H15N3H
286.1339; found 286.1340.
Supporting Information (see footnote on the first page of this arti-
cle): 1H and 13C NMR spectra for the new compounds, deuterium-
labelling NMR spectra. Quantum chemical calculations: Cartesian
coordinates,
SCS-MP2/6-311G(d,p)//B3LYP/6-311G(d,p)&
SDD+ZPE energies (au). Thermal ellipsoid plots for the crystal
structures (ellipsoid probability contours 50%).
2,6-Diphenylthiazolo[5,4-c]pyridine (4h): From compound 3h
(0.080 g, 0.20 mmol) according to the general procedure. The sub-
sequent chromatographic purification (Et2O/pentane, 1:3) gave
0.025 g (0.09 mmol, 44%) of 4h as an orange solid, m.p. 147–
Acknowledgments
1
148 °C. H NMR (300 MHz, CDCl3, 25 °C, TMS): δ = 7.47–7.59
This work was supported by the International Research Training
(m, 6 H, H-arom.), 8.10–8.13 (m, 2 H, H-arom.), 8.16–8.19 (m, 2
Group IRTG, Münster-Amsterdam-Leiden 1444, the Deutsche
H, H-arom.), 8.39 (d, J = 0.7 Hz, 1 H, H-arom.), 9.31(s, 1 H, CHN) Forschungsgemeinschaft (DFG, Bad Godesberg) and the Fonds
ppm. 13C NMR (75 MHz, CDCl3, 25 °C, TMS): δ = 114.6 (CH), der Chemischen Industrie (Frankfurt).
120.6, 127.3 (CH), 128.3 (CH), 129.2 (CH), 129.4 (CH), 129.8
(CH), 130.9, 132.5, 132.7 (CH), 142.3 (CH), 147.6, 148.5,
[1] M. B. Smith, J. March, in March’s Advanced Organic Chemis-
161.3 ppm. IR (neat): ν = 3057 (w), 3028 (w), 2963 (w), 2851 (w),
˜
try: Reactions, Mechanisms, and Structure, 5th ed., John
Wiley & Sons, Inc., New York, 2001, pp. 815–820 and refer-
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1587 (m), 1523 (w), 1506 (m), 1476 (m), 1437 (s), 1420 (m), 1260
(m), 1240 (m), 1198 (w), 1096 (w), 1072 (w), 1018 (m), 962 (s), 905
1796
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 1787–1797

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[18] N-Aminoindoline was prepared from commercially available
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Received: December 16, 2009
Published Online: February 10, 2010
Eur. J. Org. Chem. 2010, 1787–1797
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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