Synthesis of new fluorescent building blocks via the microwave-assisted annulation reaction of 1,1,2-trimethyl-1H-benzo[e]indole with acrylic acid and its derivatives

Article abstract of DOI:10.1016/j.tet.2014.01.070

The reaction of 1,1,2-trimethyl-1H-benzo[e]indole with acrylic acid and its derivatives was employed for the preparation of novel fluorescent building blocks. Treatment of 1,1,2-trimethyl-1H-benzo[e]indole with acrylic acid, acrylamide or tert-butyl acrylate in an autoclave or a microwave reactor at 180-200 C afforded benzo[e]pyrido[1,2-a]indole derivatives. Various chemical transformations of the latter compounds have been performed to yield functionalized benzo[e]indole scaffolds. The structure assignments were based on data from ¹H and ¹³C NMR spectroscopy and single crystal X-ray analyses. The optical properties of the obtained benzo[e]indoline derivatives were studied by UV-vis and fluorescence spectroscopy.

Full text of DOI:10.1016/j.tet.2014.01.070

Accepted Manuscript
Synthesis of new fluorescent building blocks via the microwave-assisted annulation
reaction of 1,1,2-trimethyl-1H-benzo[e]indole with acrylic acid and its derivatives
Rasa Steponavičiūtė, Vytas Martynaitis, Aurimas Bieliauskas, Algirdas Šačkus
PII:
S0040-4020(14)00125-2
10.1016/j.tet.2014.01.070
TET 25244
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 3 December 2013
Revised Date: 15 January 2014
Accepted Date: 27 January 2014
Please cite this article as: Steponavičiūtė R, Martynaitis V, Bieliauskas A, Šačkus A, Synthesis of
new fluorescent building blocks via the microwave-assisted annulation reaction of 1,1,2-trimethyl-1H-
benzo[e]indole with acrylic acid and its derivatives, Tetrahedron (2014), doi: 10.1016/j.tet.2014.01.070.
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ACCEPTED MANUSCRIPT
Graphical Abstract
Leave this area blank for abstract info.
Synthesis of new fluorescent building blocks via the
microwave-assisted annulation reaction of
1,1,2-trimethyl-1H-benzo[e]indole with acrylic acid
and its derivatives
Rasa Steponavičiūtė,a Vytas Martynaitis,a Aurimas Bieliauskasa,b and Algirdas Šačkusa,b
aDepartment of Organic Chemistry, Kaunas University of Technology, Radvilėnų pl.19, LT-50254 Kaunas,
Lithuania
bInstitute of Synthetic Chemistry, Kaunas University of Technology, Radvilėnų pl. 19, LT-50254 Kaunas,
Lithuania

Tetrahedron
2
ACCEPTED MANUSCRIPT
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com
Synthesis of new fluorescent building blocks via the microwave-assisted annulation
reaction of 1,1,2-trimethyl-1H-benzo[e]indole with acrylic acid and its derivatives
Rasa Steponavičiūtė,a Vytas Martynaitis,a Aurimas Bieliauskasa,b and Algirdas Šačkusa,b,*
aDepartment of Organic Chemistry, Kaunas University of Technology, Radvilėnų pl.19, LT-50254 Kaunas, Lithuania
bInstitute of Synthetic Chemistry, Kaunas University of Technology, Radvilėnų pl. 19, LT-50254 Kaunas, Lithuania
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The reaction of 1,1,2-trimethyl-1H-benzo[e]indole with acrylic acid and its derivatives was
employed for the preparation of novel fluorescent building blocks. Treatment of 1,1,2-trimethyl-
1H-benzo[e]indole with acrylic acid, acrylamide or tert-butyl acrylate in an autoclave or a
microwave reactor at 180–200 °C afforded benzo[e]pyrido[1,2-a]indole derivatives. Various
chemical transformations of the latter compounds have been performed to yield functionalized
benzo[e]indole scaffolds. The structure assignments were based on data from 1H and 13C NMR
spectroscopy and single crystal X-ray analyses. The optical properties of the obtained
benzo[e]indoline derivatives were studied by UV–Vis and fluorescence spectroscopy.
Available online
Keywords:
1H-Benzo[e]indole
Acrylic acid
Microwave-assisted synthesis
Benzo[e]pyrido[1,2-a]indole
Fluorescence
2013 Elsevier Ltd. All rights reserved.
1. Introduction
When reacted with acrylamide, the structurally similar 2,3,3-
trimethyl-3H-indole serves as a N-nucleophile and affords
During the last decade, there has been a significant increase in
the use of 1,1,2-trimethyl-1H-benzo[e]indole 1 as a precursor for
the synthesis of fluorescent organic molecules that have wide
biomedical and technical applications. In particular, this starting
material was successfully used for the preparation of a number of
near-infrared fluorescence emitting dyes. These dyes were used
as labelling agents for biomolecules and probes for high-contrast
fluorescence imaging of biological tissues,1 as well as novel
fluorophores for multiple-mode molecular logic systems2 or
enzyme sensing in biological assays.3 Furthermore, blue organic
squaraine dyes containing the 1,1,2-trimethyl-1H-benzo[e]indole
nucleus were used for dye-sensitized solar cell applications.4 The
preparation methods for these functional dyes traditionally
include the alkylation of 1,1,2-trimethyl-1H-benzo[e]indole 1 to
form the corresponding 3-substituted 1,1,2-trimethyl-1H-
benzo[e]indolium salts.1-4 For cyanine dye synthesis, the
aforementioned salts were employed as nucleophilic substrates
for stepwise condensation with polyene-chain precursors.5,6
Recently, a significant number of alkylating agents, such as alkyl
halides,1a,e,2 propargyl bromide,1c haloalkanoic acids,1a,d,f,4,5a,b and
1,4-butane sultone5b were employed for the alkylation of 1,1,2-
trimethyl-1H-benzo[e]indole 1. However, the potentially useful
Michael addition adducts that can easily undergo intramolecular
cyclisation to form pyrimido[1,2-a]indole derivatives,7 which are
useful precursors of basic cyanine dyes.8 The corresponding 2-
methylidene bases, derived from 1-alkyl-2,3,3-trimethyl-3H-
indolium salts, act as C-nucleophiles when reacted with
acrylamide to yield spiro[indole-2,2’-piperidine] derivatives.9
Recently, the similar coupling of 2-methylidene-1H-
benzo[e]indole with acrylamide was utilized for the preparation
of novel fluorescent scaffolds.10 Finally, the condensation of
2,3,3-trimethyl-3H-indoles with 2,3-unsaturated aldehydes and
ketones provides pyrido[1,2-a]indolium salts that have been
applied to the synthesis of optical brighteners and dyes for
synthetic fibers,11 while their formylation afforded the
corresponding dialdehydes, as synthons for the preparation of 2-
(pyrazol-4-yl)-3H-indole derivatives.12 The aim of the present
work is the synthesis of fluorescent building blocks through the
reaction of 1,1,2-trimethyl-1H-benzo[e]indole with acrylic acid
and further chemical transformations of the obtained adducts.
2. Results and discussion
The Michael addition of nucleophiles across active 2,3-
unsaturated carbonyl compounds are typically acid or base
catalyzed.13 A wide variety of acidic catalysts, mostly Lewis14
and protic15 acids, have been cited in the literature. Additionally,
the aza-Michael addition of cyclic azomethines, such as 3H-
indoles and 3,4-dihydroisoquinolines, across acrylamide can be
successfully carried out in acetic acid, which also acts as the
solvent when used in excess.7,16 However, when 1,1,2-trimethyl-
1H-benzo[e]indole 1 was treated with acrylic acid in refluxing
conjugate
addition
reactions
of
1,1,2-trimethyl-1H-
benzo[e]indole 1 with 2,3-unsaturated carbonyl derivatives
remain unexplored.
_______
*
Corresponding author. Tel.: +370 37451401; e-mail address:
algirdas.sackus@ktu.lt (A.Šačkus).

3
Table 1.
ACCEPTED MANUSCRIPT
Investigation of the reaction conditions for the coupling of 1,1,2-trimethyl-
1H-benzo[e]indole 1 with acrylic acid, acrylamide and tert-butyl acrylate
Reagents and
reaction conditions
(Method)
Ratio of products
Total yield of
products 2 and 3
Entry
2 and 3a
Acrylic acid, acetic
acid, autoclave, 180
°C, 19 h; (A)
1
2
3
4
7/3
2/3
1/2
7/2
51%
38%
21%
51%
Acrylic acid, o-
xylene, autoclave,
200 °C, 12 h; (B)
Acrylamide, acetic
acid, autoclave, 180
°C, 19 h; (C)
Acrylic acid, acetic
acid, microwave (100
W), 180 °C, 1 h; (D)
Acrylic acid, o-
xylene, microwave
(100 W), 180 °C, 1 h;
(E)
5
6
7
8
7/4
1/1
1/4
4/1
56%
67%
14%
56%
Scheme 1. Synthesis of benzo[e]pyrido[1,2-a]indolones 2 and 3
Acrylic acid, o-
xylene, microwave
(120 W), 200 °C, 1 h;
(F)
methylazomethines to 2,3-unsaturated carbonyl compounds
(Table 1, entry 8).
There is abundant evidence that cyclic α-C-methyl
azomethines exist in
a tautomeric equilibrium with the
tert-Butyl acrylate, o-
xylene, microwave
(120 W), 200 °C, 1 h
(G)
corresponding enamine form.18 Therefore, the formation of
tetracyclic compound 2 can be explained as a result of the acid-
catalysed aza-Michael addition reaction of 1 or its tautomer A
across the acrylic double bond, leading to the formation of the
intermediate adduct B, which undergoes further intramolecular
cyclisation. However, when the corresponding carba-Michael
addition reaction gives the intermediate adduct C, the cyclic
enamide 3 results.
tert-Butyl acrylate,
acetic acid,
microwave (100 W),
180 °C, 1 h (H)
aRatio determined for isolated products
The structural assignment of compounds 2 and 3 was based on
analysis of the spectral data. The 1H NMR spectrum of 2 revealed
two triplets of methylene protons at 4.07 and 4.55 ppm (J = 7.8
Hz) and a singlet at 5.29 ppm for the isolated methine proton,
which corresponded to the proton signals from the
CH2CH2C(=O)CH moiety. The spectrum of 3 showed a set of
signals attributable to the C(=O)CH2CH2CH moiety with
multiplets at 2.43–2.50 ppm and 2.65–2.72 ppm for the two
methylene groups and a triplet at 5.21 ppm (J = 4.2 Hz) for the
methine proton. The 13C NMR spectrum of 2 was characteristic
of enaminones and contained signals at 93.4 (N–C=CH), 175.5
(N–C=CH) and 190.3 (C=O) ppm.19 For enamide 3, the
corresponding carbon atom signals were present at 96.9, 151.3
and 168.2 ppm.20
glacial acetic acid or its mixture with hydrochloric acid, no
desired addition products were obtained, and only the starting
indole 1 was recovered. Heating the aforementioned reaction
mixture in an autoclave at 180 °C for 19 h afforded isomeric
pyrido[1,2-a]indolones 2 and 3 in isolated yields of 36% and
15%, respectively (Scheme 1 and Table 1, entry 1). When o-
xylene was used as the solvent instead of acetic acid, the total
yield of the reaction was only 38%, and compound 3 was the
major product (Table 1, entry 2). A mixture of products 2 and 3
was also obtained when acrylamide was used instead of acrylic
acid, but the total yield of the products decreased to 21% (Table
1, entry 3).
It is recognized that microwave irradiation efficiently
promotes Michael addition of heteronucleophiles to 2,3-
unsaturated carbonyl compounds.17 The reaction of 1,1,2-
trimethyl-1H-benzo[e]indole 1 and acrylic acid under microwave
irradiation in acetic acid and o-xylene gave a mixture of
compounds 2 and 3 within a short period of time (1 h) (Table 1,
entries 4, 5). The best total yield (67%) of products 2 and 3 was
achieved when the reaction was performed in a closed reaction
vessel at 200 °C using 120 W microwave irradiation power
(Table 1, entry 6). However, when tert-butyl acrylate was used as
the 2,3-unsaturated carbonyl substrate in similar reaction
conditions and the reaction was performed in o-xylene, the total
yield of the target products was miserable (Table 1, entry 7). The
last experiment was designed to assess the importance of acid
catalysis for this type of reaction. To this end, the aforementioned
reaction was performed in acetic acid. The obtained result – four-
fold increase of the total yield and change of the ratio between
products 2 and 3 in favour of the first – confirmed that acid
catalysis significantly stimulates aza-Michael addition of α-C-
Enaminones are versatile building blocks in organic
synthesis21 and are useful for the preparation of γ-
aminoalcohols22 and various heterocycles.23 To test the synthetic
Scheme 2. The synthetic application of enaminone 2

Tetrahedron
4
ACCEPTED MANUSCRIPT
Figure 1. ORTEP view of compound 4
potential of the enaminone 2, the reduction of it with NaBH4 and
condensation reactions with hydroxylamine and 1-methyl-1-
phenylhydrazine were investigated (Scheme 2). The reduction of
enaminones with NaBH4 gives γ-aminoalcohols,22d,e while the
condensation of enaminones with hydroxylamine forms isoxazole
derivatives.23d Treatment of compound 2 with NaBH4 in ethanol
at 60 °C afforded alcohol 4 as a single diastereomer after
recrystallisation from ethanol (Scheme 2).
The relative (10R*,11aS*)-configuration of compound 4 was
established by X-ray analysis (Figure 1).24 The piperidine ring of
the asymmetric, relatively rigid unit of 4 is in a chair
conformation with the hydroxyl group in an equatorial position.
The sum of the angles between the covalent bonds around the
N(11) atom is 337.33°, which indicates that a pyramidal
geometry exists at the sp3-hybridised nitrogen atom.25 The length
of the C(2)–N(11) bond is slightly longer [1.409(2) Å] than that
in aniline (1.399; 1.385 Å)26 and 2-(4-cyanophenylacylidene)-
1,3,3-trimethyl-2,3-dihydro-1H-indole [1.402(4) Å].27 This
longer bond length may be explained by the disrupted
conjugation of the nitrogen lone electron pair with the π-system
of the aromatic ring.28 The C(12)–N(11) and C(16)–N(11) bond
lengths are 1.467(2) and 1.482(2) Å, respectively, and agree with
the known bond lengths of piperidines.29 The C(14)–O(18) bond
length [1.428(2) Å] is similar to those found in related alcohols.30
Condensation of 2 with hydroxylamine hydrochloride in
Scheme 3. The chemical transformations of enamide 3
important to note that the enamide moiety is a frequently
encountered structural motif in many medicinally valuable
compounds.39 When enamide 3 was treated with a methanolic
solution of HCl, generated by the addition of acetyl choride to
methanol, enaminone ring cleavage occurred to afford methyl 4-
(1,1-dimethyl-1 H-benzo[e]indol-2-yl)butanoate 8a in 86%
yield. The corresponding ethyl butanoate 8b was obtained in a
similar manner. Unexpectedly, the formation of esters 8a,b also
occurred when enamide 3 was alkylated with methyl or ethyl
iodide in DMF containing NaH, followed by a standard work-up
of the reaction mixture with water. The treatment of
benzo[e]indole derivative 8a with 48% tetrafluoroboric acid
afforded crystalline 1H-benzo[e]indolium tetrafluoroborate 9,
while alkylation with methyl iodide gave 2-(4-methoxy-4-
oxobutyl)-1,1,3-trimethyl-1H-benzo[e]indolium iodide 10.
It has previously been shown that 2-ethyl-3,3-dimethyl-3H-
indole easily autooxidises to 2-acetyl-3,3-dimethyl-3H-indole.40
We observed a similar tendency for oxidation of the 2-(3-
alkoxycarbonylpropyl) side-chain of compounds 8a,b. Heating
these compounds in DMSO, which is a weak oxidizer,41 at 50 °C
for 8 h afforded alkyl 4-(1,1-dimethyl-1H-benzo[e]indol-2-yl)-4-
oxobutanoates 11a,b in 96% and 88% yields, respectively. The
condensation of oxobutanoate 11a with phenylhydrazine afforded
phenylhydrazone 12 (Scheme 3).
The structure of compound 11a was confirmed by the
presence of the characteristic ketone carbonyl group absorption
band at 1674 cm-1 in the IR spectrum and a corresponding signal
at 196.1 ppm (ketone carbon) in the 13C NMR spectrum. Single
crystal X-ray analysis of 11a (Fig.2)42 indicated that the molecule
has a symmetry plane in which all skeletal atoms are positioned,
with the exception of the methyl carbons C(22) and C(22i).The
imino-carbonylic fragment [N(1)=C(2)–C(14)=O(15)] is in a s-
trans conformation. The ethylenic bridge connecting the two
carbonyl groups is in a staggered conformation, in which the
carbonyls are oriented in an anti-position. The ester group
possesses the Z-conformation.
1
ethanol in the presence of pyridine afforded the oxime 5. The H
NMR spectrum of 5, acquired in DMSO-d6 at 20 °C, revealed
two sets of proton signals attributed to the presence of a mixture
of the corresponding oxime Z- and E-isomers31 (5/1 ratio of
major/minor isomers) in solution. However, oxime 5 did not
undergo any further cyclisation to form an isoxazole derivative.
Fluorescent functionalised heterocycles are suitable building
blocks for the preparation of functional materials with various
photonic, electronic and optoelectronic applications.32 For
example, the condensation of 9-alkyl-9H-carbazole and 10-alkyl-
10H-phenothiazine derivatives, which possess a side-chain
aldehyde moiety, with phenylhydrazines resulted in the formation
of the corresponding hydrazones, which are efficient hole
transport materials.33 When compound 2 was heated with 1-
methyl-1-phenylhydrazine in ethanol, the condensation of the
enaminone carbonyl group with the hydrazine moiety occurred to
afford a mixture of Z- and E-hydrazones 6a and 6b, respectively,
in a ratio of 4/1. For the major isomer, the Z-configuration was
assigned on the basis of the NOE effect in the NMR spectrum of
the mixture of isomers.
Next, we investigated the chemical transformations of
compound 3, which possesses the cyclic enamide functionality
(Scheme 3). Enamides have been shown to have ambident
reactivity as they are simultaneously electrophilic at the α-carbon
and nucleophilic at the β-carbon. They are stable compounds
under neutral or basic conditions, but in acidic media,
protonation on the β-carbon atom occurs to form a reactive
acyliminium intermediate, which might undergo hydrolysis.34
Recently,
alkylation,35
arylation,36
alkenylation37
and
fluorination38 of enamides have been explored. Additionally, it is

5
Table 2.
ACCEPTED MANUSCRIPT
Absorption (λabs and ε) and fluorescence (λem and quantum yield Φf)
parameters for the benzo[e]indoline derivatives 1-7, 11a, 12 in THF and 9,10
in MeOH
ε×103
*
Entry
1
Compound
λabs
λem
Φf (%)
(dm3mol-1cm-1)
27.04
45.57
32.23
219
245
254
342
357
1
0.1
Figure 2. ORTEP view of compound 11a
31.94
14.34
21.66
212
239
261
2
3
2
3
402
382
30.7
0.6
The optical properties of benzo[e]indoline derivatives 1-7, 11a
and 12 in THF as well as 9 and 10 in MeOH were investigated by
UV–Vis spectroscopy, and the compounds were subjected to
fluorimetric measurements (Table 2). No significant difference
was observed between the three main absorption bands of
enaminone 2 and enamide 3.
However, the products of the condensation of enaminone 2
with hydroxylamine (5) and phenylhydrazine (6) showed a
significant bathochromic shift (74 and 127 nm, respectively)
compared to the starting compound; however, the bathochromic
shift in the case of the hydroxylic compound 4 did not exceed 46
nm. The absorption maxima of salts 9 and 10 were similar to
those of the 2,3,3-trimethyl-3H-indolium cations.43
The fluorescence spectra of products 2–7, 11a and 12 were
measured in THF, while those of salts 9 and 10 were measured in
methanol. The structurally similar benzo[e]indolo[1,2-
a]pyrimidine derivative exhibits a strong blue fluorescence with
an emission maximum at approximately 435 nm (in ethanol).3
The fluorescence spectra of products 2 and 3, measured in THF,
displayed emission maxima at 402 and 382 nm (Stokes shifts of
141 and 131 nm), respectively. The emission maximum exhibited
a marked displacement to longer wavelengths upon reduction of
the enaminone moiety or condensation with hydroxylamine
(Table 2, Entry 4 and 5, respectively). In contrast, hydrazone 6
exhibited a corresponding maximum at 377 nm with a ‘negative’
Stokes shift of 11 nm. The fluorescence spectra of the 3H-
indolium salts 9,10 exhibited two distinct maxima, a strong
emission band in the 440–470 nm region and a band of smaller
intensity near 380 nm.
The fluorescence quantum yield (Φf) of the solutions was
estimated by the integrating sphere method. It appeared that the
fluorescence quantum yield was sensitive to the structure of
compounds. With enaminone 2, which contains a tertiary
aromatic amine nitrogen atom, the observed Φf value was 30.7%.
However, the fluorescence quantum yield of the enamide 3 was
low and did not exceed 0.6%. The highest Φf value (37.5%) was
measured for hydroxyl-containing compound 4, while
hydrazones 6 and 12 emitted negligible fluorescence (Φf = 0.1%).
23.56
32.41
25.34
206
224
251
33.28
53.87
9.50
217
258
296
307
4
5
4
5
438
450
377
37.5
15.9
0.1
10.52
48.46
30.10
35.00
221
266
335
46.08
27.99
20.06
19.70
213
265
351
388
6
7
6
7
28.71
54.42
8.45
216
252
293
304
430
13.8
8.14
27.57
21.39
19.96
16.52
219
246
256
264
377
468
8
9
9
0.5
55.91
17.27
18.14
220
266
276
379
444
10
21.2
37.87
25.27
28.33
12.88
222
274
283
335
376
442
10
11
11a
12
0.1
0.1
218
248
294
31.68
23.73
16.63
365
434
* λex = 310 nm
4. Experimental section
4.1. General
3. Conclusions
Reagents and solvents were purchased from commercial
suppliers and used without further purification unless indicated.
High temperature reactions were carried out in a high pressure
stainless steel laboratory autoclave Roth 1.4571 (Carl Roth
GmbH) equipped with a magnetic stirrer. Microwave reactions
were conducted using a CEM Discover Synthesis Unit (CEM
Corp., Matthews, NC) and performed in glass vessels (capacity
10 mL) sealed with a septum. The pressure was controlled by a
load cell connected to the vessel. The temperature of the contents
of the vessel was monitored using a calibrated infrared
temperature control mounted under the reaction vessel. All
experiments were performed using the stirring option. The
purification of the reaction mixtures was performed by flash
chromatography using a glass column with silica gel (0.035–
In conclusion, a new method for the preparation of new
functionalised fluorescent building blocks possessing the
benzo[e]indoline moiety has been developed. Treatment of 1,1,2-
trimethyl-1H-benzo[e]indole with acrylic acid and its derivatives
at elevated temperature afforded aza- or carba-Michael addition
adducts, which underwent further cyclisation to form isomeric
benzo[e]pyrido[1,2-a]indole derivatives possessing the reactive
enaminone and enamide structural units, respectively. Microwave
irradiation significantly expedited the aforementioned annulation
reaction. Herein, it was demonstrated that the enaminone and
enamide moieties annulated to the benzo[e]indoline nucleus may
serve as reactive sites for various chemical transformations
towards functionalised benzo[e]indoline derivatives possessing
intense fluorescence and significant Stokes shifts.
0.070 nm, pore diameter ca.
6 nm). For thin layer
chromatographic (TLC) analysis, Merck precoated TLC plates
(Silica gel F254) were used. Melting points were determined on a
Büchi B-540 capillary melting point apparatus and are
1
uncorrected. H NMR spectra were recorded at 300 MHz on a

Tetrahedron
6
Method A, to yield compounds 2 (842 mg, 32%) and 3 (921 mg,
35%).
Varian Unity Inova spectrometer and at 400 AMHCzCoEn Pa TBrEukDer MANUSCRIPT
Avance III spectrometer. 13C NMR spectra were collected using
the same instruments at 75 and 100 MHz, respectively. The
chemical shifts, expressed in ppm, were relative to
tetramethylsilane (TMS). Infrared spectra were recorded on a
Perkin Elmer Spectrum One spectrometer using potasium
bromide pellets. UV‒Vis spectra were recorded on a Perkin
Elmer Lambda 35 UV/Vis spectrometer. Fluorescence spectra
were recorded on a FL920 fluorescence spectrometer from
Edinburgh Instruments. The PL quantum yields were measured
from dilute THF or MeOH solutions by an absolute method using
the Edinburgh Instruments integrating sphere excited with Xe
lamp. Optical densities of the sample solutions were ensured to
be below 0.1 to avoid reabsorption effects. All optical
measurements were performed at room temperature under
ambient conditions. Mass spectra were recorded on a Waters
Micromass ZQ 2000 (APCI+, 20 V) instrument or on an Agilent
1100 series mass spectrometer using a direct inlet system
(electron spray, 4000 V). High-resolution ESI-TOF mass spectra
were measured on a Bruker maXis spectrometer. Diffraction data
were collected on Bruker-Nonius KappaCCD diffractometer at
room temperature and also at – 100 °C. The crystal structures
were solved using known programs.44 Elemental analyses (C, H,
and N) were recorded with a CE-440 elemental analyser, Model
440 CHN/O/S at the Microanalytical Laboratory, Department of
Organic Chemistry, Kaunas University of Technology.
Method G. To a solution of compound 1 (2.09 g, 10 mmol) in o-
xylene (10 mL), tert-butyl acrylate (1.79 g, 14 mmol) was added
and the mixture was heated in a microwave reactor (120 W) at
200 °C for 1 h Upon cooling to rt, the solvent was removed
under reduced pressure and the residue was purified according to
the Method A, to yield compounds 2 (79 mg, 3%) and 3 (289 mg,
11%).
Method H. To a solution of compound 1 (2.09 g, 10 mmol) in
glacial acetic acid (10 mL), tert-butyl acrylate (1.79 g, 14 mmol)
was added and the mixture was heated in a microwave reactor
(100 W) at 180 °C for 1 h. Standard workup and purification
according to the Method A yielded compounds 2 (1159 mg, 44%)
and 3 (316 mg, 12%).
4.2.1. 12,12-Dimethyl-8,9-dihydrobenzo[e]pyrido[1,2-a]indol-
10(12H)-one (2). Brownish crystals, mp 127–128 °C (ethyl
1
acetate). H NMR (300 MHz, DMSO-d6): δH 1.61 (s, 6H, 12-
(CH3)2), 4.07 (t, J=7.8 Hz, 2H, CH2), 4.55 (t, J=7.8 Hz, 2H,
CH2), 5.29 (s, 1H, CH), 7.33 (dd, J=8.0, 7.2 Hz, 1H, Ar-H), 7.42
(d, J=8.4 Hz, 1H, Ar-H), 7.51 (t, J=7.2 Hz, 1H, Ar-H), 7.92 (d,
J=8.4 Hz, 2H, Ar-H), 8.05 (d, J=8.7 Hz, 1H, Ar-H); 13C NMR
(75 MHz, DMSO-d6): δC 26.6 (2×C, 12-(CH3)2), 34.7 (CH2), 40.7
(CH2), 47.0 (C-12), 93.4 (C-11), 110.2, 121.8, 123.1, 127.2,
128.7, 128.8, 129.58, 129.64, 129.7, 140.8, 175.5 (C-11a), 190.3
(C=O); IR (KBr, νmax, cm-1): 3064 (CHarom), 2960 (CHaliph), 1642
(C=O), 1600, 1564, 1204, 813; MS (APCI+), m/z (%): 286
(M+Na+, 100). Anal. Calcd for C18H17NO (%): C, 82.10; H, 6.51;
N, 5.32. Found: C, 81.93; H, 6.57; N, 5.35.
4.2. Procedures for the preparation of benzo[e]pyrido[1,2-
a]indolone derivatives (2 and 3).
Method A. To a solution of 1,1,2-trimethyl-1H-benzo[e]indole (1)
(2.09 g, 10 mmol) in glacial acetic acid (10 mL), acrylic acid
(1.01 g, 14 mmol) was added and the reaction mixture was
heated in an autoclave at 180 °C for 19 h. Upon cooling to rt, the
reaction mixture was diluted with toluene and the solvents were
evaporated under reduced pressure. The residue was purified by
flash chromatography on silica gel (hexane/ethyl acetate,
8:1→ethyl acetate, v/v) to yield compounds 2 (947 mg, 36%) and
3 (395 mg, 15%).
Method B. To a solution of compound 1 (2.09 mg, 10 mmol) in
o-xylene (10 mL), acrylic acid (1.01 g, 14 mmol) was added and
the reaction mixture was heated in an autoclave at 200 °C for 12
h. Upon cooling to rt, the solvent was removed under reduced
pressure and the residue was refined according to the Method A
to yield compounds 2 (368 mg, 14%) and 3 (631 mg, 24%).
Method C. To a solution of compound 1 (2.09 g, 10 mmol) in
glacial acetic acid (10 mL), acrylamide (1.0 g, 14 mmol) was
added and the reaction mixture was heated in an autoclave at 180
°C for 19 h. Standard workup and purification according to the
Method A afforded compounds 2 (184 mg, 7%) and 3 (368 mg,
14%).
Method D. To a solution of compound 1 (2.09 g, 10 mmol) in
glacial acetic acid (10 mL), acrylic acid (1.01 g, 14 mmol) was
added and the reaction mixture was heated in a microwave
reactor (100 W) at 180 °C for 1 h. Standard workup and
purification according to the Method A yielded compounds 2
(1026 mg, 39%) and 3 (316 mg, 12%).
Method E. To a solution of compound 1 (2.09 g, 10 mmol) in o-
xylene (10 mL), acrylic acid (1.01 g, 14 mmol) was added and
the reaction mixture was heated in a microwave reactor (100 W)
at 180 °C for 1 h. Upon cooling to rt, the solvent was removed
under reduced pressure and the residue was purified according to
the Method A to yield compounds 2 (921 mg, 35%) and 3 (553
mg, 21%).
4.2.2. 12,12-Dimethyl-10,12-dihydrobenzo[e]pyrido[1,2-a]indol-
8(9H)-one (3). Light brown crystals, mp 100–101 °C
1
(dichloromethane). H NMR (300 MHz, CDCl3): δH 2.32 (s, 6H,
12-(CH3)2), 2.43–2.50 (m, 2H, CH2), 2.65–2.72 (m, 2H, CH2),
5.21 (t, J=4.2 Hz, 1H, CH), 7.37 (ddd, J=8.2, 6.8, 1.2 Hz, 1H, Ar-
H), 7.47 (ddd, J=8.6, 6.8, 1.2 Hz, 1H, Ar-H), 7.78 (d, J=8.7 Hz,
1H, Ar-H), 7.83–7.88 (m, 1H, Ar-H), 8.04–8.09 (m, 1H, Ar-H),
8.56 (d, J=8.7 Hz, 1H, Ar-H); 13C NMR (75 MHz, CDCl3): δC
20.1 (CH2), 29.4 (2×C, 12-(CH3)2), 32.2 (CH2), 44.7 (C-12), 96.9
(C-11), 116.1, 122.9, 123.9, 126.2, 129.0, 129.1, 129.5, 129.9,
131.7, 137.4, 151.3 (C-11a), 168.2 (C=O); IR (KBr, νmax, cm-1):
3060 (CHarom), 2955 (CHaliph), 1694, 1671 (C=O), 1394, 818; MS
(APCI+), m/z (%): 286 (M+Na+, 100). Anal. Calcd for C18H17NO
(%): C, 82.10; H, 6.51; N, 5.32. Found: C, 81.83; H, 6.62; N,
5.46.
4.3. (10R*,11aS*)-12,12-Dimethyl-8,9,10,11,11a,12-
hexahydrobenzo[e]pyrido[1,2-a]indol-10-ol (4). To a solution of
compound 2 (267 mg, 1 mmol) in ethanol (3 mL), sodium
borohydride (114 mg, 3 mmol) was added and the reaction
mixture was heated at 60 °C for 2 h. Upon cooling to rt, reaction
mixture was quenched with water (10 mL) and extracted with
ethyl acetate (3×30 mL). The combined organic layers were dried
over Na2SO4, concentrated under reduced pressure. The crude
product was recrystallized from ethanol to give titled compound
4. Yield 134 mg (50%), white crystals, mp 175–176 °C (ethanol).
1H NMR (300 MHz, CDCl3): δH 1.27 (s, 3H, 12-CH3), 1.59 (q,
J=12.0 Hz, 1H, ½ CH2), 1.64 (s, 3H, 12-CH3), 1.68–1.78 (dq,
J=12.0, 5.1 Hz, 1H, ½ CH2), 1.94 (s, 1H, OH), 2.04–2.15 (m, 2H,
CH2), 2.64 (dt, J=12.0, 3.0 Hz, 1H, CHOH), 2.80 (dd, J=11.9, 2.3
Hz, 1H, ½ CH), 3.75–3.89 (m, 2H, CH2), 6.93 (d, J=8.4 Hz, 1H,
Ar-H), 7.21 (ddd, J=8.0, 6.8, 1.1 Hz, 1H, Ar-H), 7.40 (ddd,
J=8.4, 6.8, 1.4 Hz, 1H, Ar-H), 7.66 (d, J=8.6 Hz, 1H, Ar-H),
7.74–7.79 (m, 1H, Ar-H), 7.93–7.98 (m, 1H, Ar-H); 13C NMR
(75 MHz, CDCl3): δC 20.8 (12-CH3), 26.3 (12-CH3), 33.7 (CH2),
34.6 (CH2), 43.3 (C-12), 43.6 (CH2), 70.2 (CH), 73.2 (C-OH),
110.2, 121.4, 121.5, 126.1, 128.6, 128.7, 129.1, 129.4, 130.6,
147.4; IR (KBr, νmax, cm-1): 3396 (O-H), 3047 (CHarom) 2925
(CHaliph), 2814, 1519, 1298, 1074 (C-OH), 812; MS (APCI+), m/z
Method F. To a solution of compound 1 (2.09 g, 10 mmol) in o-
xylene (10 mL), acrylic acid (1.01 g, 14 mmol) was added and
the mixture was heated in a microwave reactor (120 W) at 200 °C
for 1 h. Upon cooling to rt, the solvent was removed under
reduced pressure and the residue was refined according to the

7
1
(%): 268 (M+H+, 100). Anal. Calcd for C18H21NO (%): C, 80.86;
H, 7.92; N, 5.24. Found: C, 81.19; H, 8.18; N, 5.43.
120–120.5 °C (acetonitrile). H NMR (300 MHz, CDCl3): δH
1.27 (s, 3H, 1-CH3), 1.44–1.55 (m, 2H, CH2), 1.65 (s, 3H, 1-
CH3), 1.67–1.77 (m, 4H, CH2), 3.16 (brs, 2H, NH, OH), 3.44–
3.50 (m, 1H, CH), 3.69–3.75 (m, 2H, CH2), 7.01 (d, J=8.5 Hz,
1H, Ar-H), 7.22 (ddd, J=8.1, 6.8, 1.1 Hz, 1H, Ar-H), 7.40 (ddd,
J=8.4, 6.8, 1.4 Hz, 1H, Ar-H), 7.59 (d, J=8.5 Hz, 1H, Ar-H),
7.74–7.78 (m, 1H, Ar-H), 7.94–7.99 (m, 1H, Ar-H); 13C NMR
(75 MHz, CDCl3): δC 21.0 (CH2), 24.1 (1-CH3), 27.2 (1-CH3),
28.8 (CH2), 32.8 (CH2), 45.2 (C-1), 62.6 (C-OH), 70.4 (CH),
113.3, 121.7, 121.9, 126.1, 128.7, 128.8, 129.4, 129.9, 130.7,
146.2; IR (KBr, νmax, cm-1): 3250 (O-H), 3071 (CHarom), 2940
(CHaliph), 2882, 1623, 1519, 810, 747; MS (ESI+), m/z (%): 270
(M+H+, 100). Anal. Calcd for C18H23NO (%): C, 80.26; H, 8.61;
N, 5.20. Found: C, 80.35; H, 8.69; N, 5.14.
ACCEPTED MANUSCRIPT
4.4. 12,12-Dimethyl-8,9-dihydrobenzo[e]pyrido[1,2-a]indol-
10(12H)-hydroxyimine (5). To a solution of compound 2 (267
mg, 1 mmol) in ethanol (3 mL), pyridine (158 mg, 2 mmol) and
hydroxylamine hydrochloride (145 mg, 2.1 mmol) were added
and the reaction mixture was stirred at rt for 24 h. Then the
reaction mixture was quenched with water (10 mL) and extracted
with ethyl acetate (3×10 mL). The combined organic layers were
dried over Na2SO4, concentrated under reduced pressure. The
residues were refined by flash chromatography on silica gel
(dichloromethane/ethyl acetate 5:1, v/v, saturated with gaseous
NH3) to afford the title compound 5. Yield 235 mg (84%),
1
yellowish crystals, mp 210–211 °C (ethanol). H NMR (300
MHz, DMSO-d6): δH 1.61 (s, 6H, 12-(CH3)2), 2.57–2.61 (m, 2H,
CH2) (major isomer), 2.79 (t, J=7.0 Hz, 2H, CH2) (minor isomer),
3.69 (t, J=7.0 Hz, 2H, CH2) (minor isomer), 3.78–3.85 (m, 2H,
CH2) (major isomer), 5.36 (s, 1H, CH) (minor isomer), 5.75 (s,
1H, CH) (major isomer), 7.22–7.30 (m, 2H, Ar-H), 7.44 (ddd,
J=8.3, 6.8, 1.2 Hz, 1H, Ar-H), 7.84 (t, J=9.0 Hz, 2H, Ar-H),
7.97–8.00 (m, 1H, Ar-H), 10.03 (s, 1H, OH) (major isomer),
10.26 (s, 1H, OH) (minor isomer); 13C NMR (75 MHz, DMSO-
d6): δC 26.9, 27.8 (2×C, 12-(CH3)2), 28.0, 40.6, 45.5, 45.8, 82.6,
109.6, 109.8, 121.4, 122.6, 126.8, 127.0, 127.1, 129.1, 129.2,
129.3, 129.6, 141.8, 148.3, 151.2, 163.6; IR (KBr, νmax, cm-1):
3232 (O-H), 3086 (CHarom), 2953 (CHaliph), 1609 (C=N), 1518,
1352, 928, 812; MS (APCI+), m/z (%): 263 (M+H+, 100). Anal.
Calcd for C18H18N2O (%): C, 77.67; H, 6.52; N, 10.06. Found: C,
77.37; H, 6.62; N, 9.83.
4.7. Preparation of alkyl 4-(1,1-dimethyl-1H-benzo[e]indol-2-
yl)butanoate derivatives (8a,b)
Method A. To a solution of compound 3 (267 mg, 1 mmol) in dry
alcohol (4 mL), acetyl chloride (157 mg, 2 mmol) was added
dropwise and the reaction mixture was stirred under reflux under
argon atmosphere for 1.5 h. After cooling, solvent was removed
under reduced pressure, the reaction mixture quenched with
water, neutralized with Na2CO3 and extracted with diethyl ether
(3×15 mL). The combined organic layers were dried over
Na2SO4 and concentrated under reduced pressure. The residue
was refined by flash chromatography on silica gel (hexane/ethyl
acetate 5:1, v/v) to afford compounds 8a,b.
Method B. To a solution of compound 3 (267 mg, 1 mmol) in dry
N,N-dimethylformamide (1 mL), sodium hydride (60%
dispersion in mineral oil, 40 mg, 1 mmol) was added portion
wise under argon atmosphere. The reaction mixture was stirred at
60 °C under argon atmosphere until complete dissolution of
sodium hydride. Then, alkyl halide (2 mmol) was added
dropwise to the reaction mixture and the mixture was stirred at rt
for 2 h. Then the reaction mixture was quenched with water (10
mL) and extracted with diethyl ether (3×15 mL). The combined
organic layers were dried over Na2SO4 and concentrated under
reduced pressure. The residue was refined according to the
Method A to yield compounds 8a,b.
4.5. 12,12-Dimethyl-10-(2-methyl-2-phenylhydrazinylidene)-
8,9,10,12-tetrahydrobenzo[e]pyrido[1,2-a]indole (6). To
a
solution of compound 2 (267 mg, 1 mmol) in toluene (3 mL) 1-
methyl-1-phenylhydrazine (257 mg, 2.1 mmol) and catalytic
amount of glacial acetic acid were added and the reaction mixture
was refluxed for 3 h. After cooling, toluene was removed under
reduced pressure. The residue was purified by flash
chromatography on silica gel (dichloromethane/ethyl acetate 5:1,
v/v, saturated with gaseous NH3) to give titled compound 6 as a
mixture of Z- and E-isomers. Yield 290 mg (79%), yellow resin.
1H NMR (400 MHz, CDCl3): δH 1.67 (s, 6H, 2×CH3) (major
isomer), 1.75 (s, 6H, 2×CH3) (minor isomer), 2.92 (t, J=7.1 Hz,
2H, CH2) (minor isomer), 2.96–3.03 (m, 2H, CH2) (major
isomer), 3.12 (s, 3H, N-CH3) (minor isomer), 3.13 (s, 3H, N-
CH3) (major isomer), 3.73 (t, J=7.1 Hz, 2H, CH2) (minor isomer),
3.91–3.97 (m, 2H, CH2) (major isomer), 5.69 (s, 1H, CH) (minor
isomer), 5.74 (s, 1H, CH) (major isomer), 6.80–6.98 (m, 3H, Ar-
H), 7.03–7.13 (m, 1H, Ar-H), 7.22–7.34 (m, 3H, Ar-H), 7.43–
7.51 (m, 1H, Ar-H), 7.74–7.86 (m, 2H, Ar-H), 7.93–8.00 (m, 1H,
Ar-H); 13C NMR (100 MHz, CDCl3): δC 24.8, 27.9 (2×C), 28.1
(2×C), 29.9, 40.5, 41.1, 41.2, 42.8, 46.8, 47.0, 85.3 (CH), 90.9
(CH), 109.0, 109.2, 114.8 (2×C), 115.2 (2×C), 119.1, 119.5,
121.81, 121.83, 122.7, 122.91, 126.96, 127.0, 128.4, 128.6, 128.8
(2×C), 128.95 (2×C), 129.58, 129.69, 129.71, 129.83, 129.84,
129.87, 129.9, 130.0, 141.3, 141.8, 151.59, 151.63, 162.9, 165.8,
166.9, 168.5; IR (KBr, νmax, cm-1): 3053 (CHarom), 2962 (CHaliph),
1625, 1595 (C=N), 1570, 1207, 752; HRMS (ESI TOF): [M+H+],
found 368.2125. [C25H25N3+H+] requires 368.2121.
4.7.1. Methyl 4-(1,1-dimethyl-1H-benzo[e]indol-2-yl)butanoate
(8a). Method A: treatment of 3 with a mixture of acetyl chloride
and absolute methanol; yield 254 mg (86%). Method B: treatment
of 3 with methyl iodide (284 mg, 2 mmol); yield 268 mg (91%).
1
Yellow resin. H NMR (400 MHz, CDCl3): δH 1.53 (s, 6H, 1-
(CH3)2), 2.27 (p, J=7.4 Hz, 2H, CH2), 2.55 (t, J=7.2 Hz, 2H,
CH2), 2.71 (t, J=7.5 Hz, 2H, CH2), 3.69 (s, 3H, OCH3), 7.44
(ddd, J=8.1, 6.9, 1.1 Hz, 1H, Ar-H), 7.54 (ddd, J=8.3, 6.8, 1.3
Hz, 1H, Ar-H), 7.83 (q, J=8.5 Hz, 2H, Ar-H), 7.94 (d, J=7.8 Hz,
1H, Ar-H), 8.01 (d, J=8.4 Hz, 1H, Ar-H); 13C NMR (100 MHz,
CDCl3): δC 21.7, 22.7 (2×C, 1-(CH3)2), 27.7, 33.6, 51.7, 55.6,
120.1, 122.7, 124.5, 126.4, 128.7, 128.9, 129.7, 132.4, 138.6,
150.8, 173.9 (C=O), 191.6 (C=N); IR (KBr, νmax, cm-1): 3060
(CHarom), 2964 (CHaliph), 1745, 1728 (C=O), 1567, 1169 (C-O),
752. HRMS (ESI TOF): [M+H+], found 296.1650.
[C19H21NO2+H+] requires 296.1645. Anal. Calcd for C19H21NO2
(%): C, 77.26; H, 7.17; N, 4.74. Found: C, 77.16; H, 7.34; N,
5.04.
4.7.2. Ethyl
4-(1,1-dimethyl-1H-benzo[e]indol-2-yl)butanoate
4.6. 4-(1,1-Dimethyl-2,3-dihydro-1H-benzo[e]indol-2-yl)butan-
1-ol (7). To a solution of compound 3 (267 mg, 1 mmol) in
ethanol (3 mL), sodium borohydride (114 mg, 3 mmol) was
added and the reaction mixture was heated at 60 °C for 5 h. Upon
cooling to rt, water (10 mL) was added and reaction mixture was
extracted with ethyl acetate (3×10 mL). The combined organic
layers were dried over Na2SO4 and concentrated under reduced
pressure. The residue was refined by flash chromatography on
silica gel (hexane/ethyl acetate, 4:1→ethyl acetate, v/v) to yield
the title compound 7. Yield 243 mg (90%), grey crystals, mp
(8b). Method A: treatment of 3 with a mixture of acetyl chloride
and absolute ethanol; yield 232 mg (75%). Method B: treatment
of 3 with ethyl iodide (312 mg, 2 mmol); yield 124 mg (40%).
1
Yellow resin. H NMR (400 MHz, CDCl3): δH 1.26 (t, J=7.2 Hz,
3H, CH2CH3), 1.52 (s, 6H, 1-(CH3)2), 2.23–2.31 (m, 2H, CH2),
2.53 (t, J=7.2 Hz, 2H, CH2), 2.71 (t, J=7.5 Hz, 2H, CH2), 4.15 (q,
J=7.1 Hz, 2H, CH2CH3), 7.43 (ddd, 1H, J=8.1, 6.9, 1.2 Hz, 1H,
Ar-H), 7.53 (ddd, J=8.3, 6.8, 1.3 Hz, 1H, Ar-H), 7.83 (q, J=8.5
Hz, 2H, Ar-H), 7.93 (d, J=6.3 Hz, 1H, Ar-H), 7.99 (d, J=8.2 Hz,

Tetrahedron
1H, Ar-H); 13C NMR (100 MHz, CDCl3): δC 14.3, 21.7, 22.6
8
2934 (CHaliph), 1757 (C=O), 1674 (C=O), 1163 (C-O), 832, 748;
HRMS (ESI TOF): [M+H+], found 310.1440. [C19H19NO3+H+]
requires 310.1438.
ACCEPTED MANUSCRIPT
(2×C, 1-(CH3)2), 27.7, 33.9, 55.6, 60.4, 120.1, 122.7, 124.5,
126.3, 128.7, 128.9, 129.7, 132.4, 138.6, 150.7, 173.4 (C=O),
191.6 (C=N); IR (KBr, νmax, cm-1): 3045 (CHarom), 2973 (CHaliph),
1676 (C=O), 1333, 1163 (C-O), 822, 752; MS (ESI+), m/z (%):
310 (M+H+, 100). Anal. Calcd for C20H23NO2 (%): C, 77.64; H,
7.49; N, 4.53. Found: C, 77.85; H, 7.54; N, 4.50.
4.10.2. Ethyl
4-(1,1-dimethyl-1H-benzo[e]indol-2-yl)-4-
oxobutanoate (11b). Compound 8b (0.31 g, 1 mmol) was used to
prepare 11b according to the general procedure. Yield 282 mg
(88%), yellow crystals, mp 126–127 °C (ethanol). 1H NMR (400
MHz, CDCl3): δH 1.27 (t, J=7.1 Hz, 3H, CH3), 1.72 (s, 6H, 1-
(CH3)2), 2.76 (t, J=6.6 Hz, 2H, CH2), 3.51 (t, J=6.6 Hz, 2H,
CH2), 4.17 (q, J=7.1 Hz, 2H, CH2), 7.53–7.58 (m, 1H, Ar-H),
7.60 (ddd, J=8.4, 6.9, 1.5 Hz, 1H, Ar-H), 7.91–7.97 (m, 2H, Ar-
H), 7.97–8.00 (m, 1H, Ar-H), 8.11 (d, J=7.8 Hz, 1H, Ar-H); 13C
NMR (100 MHz, CDCl3): δC 14.2, 22.4 (2×C, 1-(CH3)2), 28.2,
33.9, 55.4, 60.6, 121.6, 123.6, 126.1, 126.7, 128.2, 129.5, 129.7,
133.9, 143.1, 149.4, 172.7, 180.5 (C=O), 195.9 (C=O); IR (KBr,
νmax, cm-1): 3068 (CHarom), 2930 (CHaliph), 1747 (C=O), 1677
(C=O), 1333, 1163, 1119, 822, 754; MS (ESI+), m/z (%): 324
(M+H+, 100). Anal. Calcd for C20H21NO3 (%): C, 74.28; H, 6.55;
N, 4.33. Found: C, 74.06; H, 6.85; N, 4.42.
4.8. 2-(4-Methoxy-4-oxobutyl)-1,1-dimethyl-1H-
benzo[e]indolium tetrafluoroborate (9). To
a solution of
compound 8a (295 mg, 1 mmol) in diethyl ether (5 mL) 48%
solution of tetrafluoroboric acid was added dropwise and the
reaction mixture was kept at +5 °C for 1 h. The formed salt was
filtered and recrystallized from ethanol to give the title compound
9. Yield 156 mg (41%), brownish crystals, mp 114–115 °C
1
(ethanol). H NMR (400 MHz, DMSO-d6): δH 1.64 (s, 6H, 1-
(CH3)2), 2.14 (p, J=7.5 Hz, 2H, CH2), 2.57 (t, J=7.5 Hz, 2H,
CH2), 3.05 (t, J=7.5 Hz, 2H, CH2), 3.64 (s, 3H, OCH3), 6.97
(br.s., 1H, NH), 7.61 (t, J=7.2 Hz, 1H, Ar-H), 7.69 (dd, J=11.7,
4.5 Hz, 1H, Ar-H), 7.81 (d, J=8.6 Hz, 1H, Ar-H), 8.08–8.15 (m,
2H, Ar-H), 8.25 (d, J=8.4 Hz, 1H, Ar-H); 13C NMR (100 MHz,
DMSO-d6): δC 20.6, 21.8 (2×C, 1-(CH3)2), 27.2, 32.5, 51.4, 55.6,
116.3, 116.4, 123.0, 126.1, 127.7, 127.8, 129.7, 129.9, 132.5,
137.8, 172.9, 197.0; IR (KBr, νmax, cm-1): 3574, 3506 (N-H),
3114 (CHarom), 2953 (CHaliph), 1739, 1197, 1059, 822; MS (ESI+)
m/z (%): 296 (M-BF4)+, 100). Anal. Calcd for C19H22BF4NO2
(%): C, 59.55; H, 5.79; N, 3.66. Found: C, 59.37; H, 5.81; N,
3.64.
4.11. Methyl
phenylhydrazinylidene)butanoate (12). To
4-(1,1-dimethyl-1H-benzo[e]indol-2-yl)-4-(2-
solution of
a
compound 11a (0.31 g, 1 mmol) in ethanol (4 mL) phenyl
hydrazine (0.22 g, 2 mmol) was added and the reaction mixture
was refluxed for 3 h. Upon cooling to rt, water (10 mL) was
added and the reaction mixture was extracted with diethyl ether
(3×15 mL). The combined organic layers were dried over
Na2SO4 and concentrated under reduced pressure. The residue
was refined by flash chromatography on silica gel (hexane/ethyl
acetate, 6:1, v/v) to afford compound 12. Yield 328 mg (82%),
4.9. 2-(4-Methoxy-4-oxobutyl)-1,1,3-trimethyl-1H-
benzo[e]indolium iodide (10). A solution of compound 8a (295
mg, 1 mmol) in methyl iodide (6,84 g, 48 mmol, 3 mL) was
stirred at rt for 4 h. After termination, the reaction mixture was
kept at +5 °C for another 2 h. The formed salt was filtered and
recrystallized from acetonitrile to give the title compound 10.
Yield 220 mg (50%), grey crystals, 181–182 °C (acetonitrile). 1H
NMR (400 MHz, CDCl3): δH 1.79 (s, 6H, 1-(CH3)2), 1.92–2.01
(m, 2H, CH2), 2.69 (t, J=7.0 Hz, 2H, CH2), 3.21–3.30 (m, 2H,
CH2), 3.66 (s, 3H, CH3), 4.18 (s, 3H, CH3), 7.70–7.76 (m, 1H,
Ar-H), 7.76–7.82 (m, 1H, Ar-H), 8.09 (d, J=8.9 Hz, 1H, Ar-H),
8.22 (d, J=7.8 Hz, 1H, Ar-H), 8.30 (d, J=8.9 Hz, 1H, Ar-H), 8.38
(d, J=8.4 Hz, 1H, Ar-H); 13C NMR (100 MHz, DMSO-d6): δC
20.7 (2×C, 1-(CH3)2), 21.4, 25.7, 32.7, 35.5, 51.6, 55.7, 113.4,
123.5, 127.0, 127.2, 128.4, 129.8, 130.5, 133.2, 136.5, 139.6,
172.9 (C=O), 196.1 (N+=C); IR (KBr, νmax, cm-1): 3057 (CHarom),
2950 (CHaliph), 1723 (C=O), 1428, 1192 (C-O), 821; MS (ESI+),
m/z (%): 310 (M-I)+, 100). Anal. Calcd for C20H24INO2 (%): C,
54.93; H, 5.53; N, 3.20. Found: C, 54.78; H, 5.34; N, 3.42.
1
brown resin. H NMR (400 MHz, CDCl3): δH 1.89 (s, 6H, 1-
(CH3)2), 2.84–2.90 (m, 2H, CH2), 3.22–3.29 (m, 2H, CH2), 3.72
(s, 3H, CH3), 6.94–7.04 (m, 1H, Ar-H), 7.29–7.34 (m, 2H, Ar-H),
7.36–7.41 (m, 2H, Ar-H), 7.46 (ddd, J=8.0, 6.9, 1.1 Hz, 1H, Ar-
H), 7.56 (ddd, J=8.3, 6.8, 1.3 Hz, 1H, Ar-H), 7.87 (s, 2H, Ar-H),
7.95 (dd, J=8.2, 0.5 Hz, 1H, Ar-H), 8.18 (d, J=8.4 Hz, 1H, Ar-H),
9.70 (s, 1H, NH); 13C NMR (100 MHz, CDCl3): δC 19.8, 25.5
(2×C, 1-(CH3)2), 31.8, 52.5, 55.4, 113.8 (2×C), 120.2 (2×C),
121.5 (2×C), 123.0, 124.8, 126.4, 128.5, 129.1, 129.6 (2×C),
129.9, 132.8, 141.4, 144.4, 176.2, 183.3 (C=O); IR (KBr, νmax
,
cm-1): 3273 (NH), 3059 (CHarom), 2934 (CHaliph), 1716 (C=O),
1602, 1496, 1246, 1167 (C-O), 820, 751; MS (ESI+), m/z (%):
400 (M+H+, 100). Anal. Calcd for C25H25N3O2 (%): C, 75.16; H,
6.31; N, 10.52. Found: C, 74.93; H, 6.45; N, 10.63.
Acknowledgments
This work was partly supported by the European Social Fund
Agency under the project ‘Synthesis, investigation and
application of high tech materials.’
4.10. Procedure for preparation of alkyl 4-(1,1-dimethyl-1H-
benzo[e]indol-2-yl)-4-oxobutanoate derivatives (11a,b).
A
solution of compound 8a,b (1 mmol) in dimethyl sulfoxide (2
mL) was stirred at 50 °C for 8 h. Then the reaction mixture was
diluted with ethyl acetate (10 mL) and washed with brine (3×10
mL), the organic layer was separated, dried over Na2SO4, filtered
and concentrated under reduced pressure. The crude product was
recrystallized from ethanol to give the title compounds 11a,b.
References and notes
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4.10.1. Methyl
4-(1,1-dimethyl-1H-benzo[e]indol-2-yl)-4-
oxobutanoate (11a). Compound 8a (295 mg, 1 mmol) was used
to prepare 11a according to the general procedure. Yield 298 mg
1
(96%), yellow crystals, mp 133.5–134.5 °C (ethanol). H NMR
(400 MHz, CDCl3): δH 1.72 (s, 6H, 1-(CH3)2), 2.77 (t, J=6.6 Hz,
2H, CH2), 3.52 (t, J=6.6 Hz, 2H, CH2), 3.71 (s, 3H, OCH3), 7.55
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9
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4
is
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