Facile synthesis of spiro[benzo[e]indole-2,2′-piperidine] derivatives and their transformation to novel fluorescent scaffolds

Article abstract of DOI:10.1016/j.tet.2012.08.073

The reaction of azaheterocyclic enamines with acrylamide was employed for the preparation of novel fluorescent scaffolds possessing a benzo[e]indoline moiety. Reaction of 3-substituted 2-methylidene-1H-benzo[e]indole with acrylamide gave rise to spiro[ben

Full text of DOI:10.1016/j.tet.2012.08.073

Tetrahedron 68 (2012) 9260e9266
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Facile synthesis of spiro[benzo[e]indole-2,20-piperidine] derivatives and their
transformation to novel fluorescent scaffolds
a
,
,
Vida Buinauskaite b, Vytas Martynaitis b, Sven Mangelinckxc y, Gediminas Kreiza d, Norbert De Kimpe c,
_
a,b,
ꢀ
*
ꢀ
Algirdas Sackus
a
_
Institute of Synthetic Chemistry, Kaunas University of Technology, Radvilenu˛ pl. 19, LT-50254 Kaunas, Lithuania
b
_
Department of Organic Chemistry, Faculty of Chemical Technology, Kaunas University of Technology, Radvilenu˛ pl. 19, LT-50254 Kaunas, Lithuania
c Department of Sustainable Organic Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, B-9000 Ghent, Belgium
d
_
Institute of Applied Research, Vilnius University, Sauletekio 9-III, LT-10222 Vilnius, Lithuania
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 26 June 2012
Received in revised form 22 August 2012
Accepted 23 August 2012
Available online 31 August 2012
The reaction of azaheterocyclic enamines with acrylamide was employed for the preparation of novel
fluorescent scaffolds possessing a benzo[e]indoline moiety. Reaction of 3-substituted 2-methylidene-1H-
benzo[e]indole with acrylamide gave rise to spiro[benzo[e]indole-2,20-piperidin]-60-ones. Ring opening
reactions of the latter spiro compounds were investigated. Benzo[e]indoline derivatives possessing 2-(3-
carbamoylpropyl), 2-[3-(ethoxycarbonyl)propyl] and 2-(4-aminobutyl) side chains were synthesised. The
optical properties of the benzo[e]indoline derivatives were studied by UVevis and fluorescence
spectroscopy.
Keywords:
Benzo[e]indolines
Heterocyclic enamines
Acrylamide
Spiro[benzo[e]indole-2,20-piperidine]
Fluorescence
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
salts. For cyanine dye synthesis, the prepared salts were employed
as nucleophilic substrates for stepwise condensation with polyene-
During the last decade, there has been a significant increase in
the application of 1,1,2-trimethyl-1H-benzo[e]indole 1 as a pre-
cursor 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, probes for high-
contrast fluorescence imaging of biological tissues,1 novel fluo-
rophores for multiple-mode molecular logic systems2 and 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-sensitised solar cell applications.4
chain precursors.5
The present work deals with functionalisation of the 2-
methylidene-1H-benzo[e]indoles 3, prepared in two steps from
1,1,2-trimethyl-1H-benzo[e]indole 1, with acrylamide in order to
obtain novel functionalised fluorescent heterocyclic derivatives
that potentially can serve as fluorescent organic probes6 for bio-
molecular labelling and scaffolds for the synthesis of opto-
electronic materials.7 It is known, that such 2-methylidene bases,
derived from 1-alkyl-2,3,3-trimethyl-3H-indolium salts, act as C-
nucleophiles in reactions with haloalkanes,8 2-haloalkanols or
oxiranes9 and acrylamide.10 In the latter case, a carba-Michael ad-
dition of the enamine b-carbon atom across the a,b-unsaturated
The preparation protocols of these functional dyes usually in-
clude a step of N-alkylation of 1,1,2-trimethyl-1H-benzo[e]indole 1
with various alkylating agents, such as alkyl halides,1a,e,2,5a halo-
carboxylic acids,1a,d,f,4,5b,c and 1,4-butane sultone,5c to form the
corresponding N-substituted 1,1,2-trimethyl-1H-benzo[e]indolium
amide and subsequent cyclisation yielded spiro[indole[2,20]piper-
idine] derivatives. It is important to note also that structurally
similar spirocyclic ring systems, which possess a spiroannulated
piperidine ring at the indole C-3 atom, are frequently encountered
structural motifs in many medicinally valuable compounds.11
2. Results and discussion
* Corresponding author. Tel.: þ370 37 451401; e-mail addresses: Sven.Mange-
The starting iodides 2a2 and 2b12 were prepared from 1,1,2-
trimethyl-1H-benzo[e]indole 1 in accordance with the literature
ꢀ
ꢀ
linckx@UGent.be (S. Mangelinckx), algirdas.sackus@ktu.lt (A. Sackus).
y
Postdoctoral Fellow of the Research FoundationdFlanders (FWO), Belgium.
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.08.073

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V. Buinauskaite et al. / Tetrahedron 68 (2012) 9260e9266
9261
procedures. Treatment of iodides 2a,b with sodium hydroxide
O
OEt
H3C CH3
N
afforded enamines 3a,b, which were used in reactions without
further purification (purity >95% by 1H NMR/LCMS). For the
preparation of enamine 3c, benzo[e]indole 1 was alkylated with
benzyl iodide and then the obtained intermediate iodide 2c was
treated with triethylamine in dichloromethane. Heating of en-
amines 3aec with acrylamide in 1,2-ethanediol at 110 ꢀC resulted
in the formation of spiro[benzo[e]indole-2,20-piperidin]-60-ones
4aec (Scheme 1).
R
7a (R = Me, 72%)
7b (R = Et, 68%)
6M aq. HCl, EtOH
reflux, 4 h
O
Pd/C, H2 (20 bar)
AcOH, rt, 2-3 h
H3C CH3
NH2
H3C CH3
N
R
HN
N
R
H3C CH3
H3C CH3
CH3
RI, MeCN
O
6a (R = Me, 70%)
6b (R = Et, 66%)
4a,b
rt or reflux, 12-24 h
3 equiv LiAlH4
THF, reflux, 4 h
CH3
+
I-
N
1.5 equiv HClO4
EtOH, 0 °C, 2 h
N
R
NaOH/H2O, Et2O
or Et3N, CH2Cl2
rt, 0.5 h
1
NH2
H3C CH3
2a (R = Me)
2b (R = Et)
2c (R = Bn)
O
NH2
H3C CH3
N
R
H3C CH3
H3C CH3
+
H2C=CHCONH2
8a (R = Me, 77%)
8b (R = Et, 70%)
N
-
ClO4
4 equiv Ac2O or
2 equiv Boc2O
CH2Cl2, rt, 0.5-1.5 h
R
CH2
1,2-ethanediol
110 °C, 5-16 h
N
R
N
R
N
H
5a (R = Me, 74%)
5b (R = Et, 58%)
O
NHR1
H3C CH3
3a (R = Me)
3b (R = Et)
3c (R = Bn)
4a (R = Me, 79%)
4b (R = Et, 73%)
4c (R = Bn, 35%)
N
R
Scheme 1. Synthesis of spiro[benzo[e]indole-2,20-piperidin]-60-ones.
9a (R = Me, R1 = Ac, 78%)
9b (R = Me, R1 = Boc, 54%)
9c (R = Et, R1 = Ac, 83%)
9d (R = Et, R1 = Boc, 57%)
It can be assumed that the first stage of this reaction is the
formation of the appropriate Michael adducts, which then undergo
ring closure to the corresponding spiro compounds via the intra-
molecular addition of the amide nitrogen across the C-2 atom of the
indole ring system. The 1,2-ethanediol participates in the reaction
during proton transfer. In the 13C NMR spectra of 4aec, the signal of
the spiro-carbon atom resonates at ca. 87.0 ppm, and the signal of
the carbonyl carbon atom is present at around 173.0 ppm.
Scheme 2. Ring transformations of 3-alkylspiro[benzo[e]indole-2,20-piperidin]-60-
ones.
It is known that strong protic acids promote the cleavage of the
spiroindole-2,20-piperidinone ring system.10 The action of
perchloric acid on the 3-alkylspiro[benzo[e]indole-2,20-piperidin]-
60-ones 4a,b led to the opening of the piperidinone ring with for-
mation of the 2-(3-carbamoylpropyl)-1H-benzo[e]indolium per-
chlorates 5a,b (Scheme 2). The 13C NMR spectra of perchlorates 5a
and 5b contain signals at 196.5 and 196.7 ppm, respectively, which
can be attributed to the sp2-hybridised C-2 atom of the benzo[e]
indolium nuclei. When the spiro compounds 4a,b were dissolved in
acetic acid and subjected to hydrogenolysis by treatment with
hydrogen in the presence of catalytic palladium, ring opening of the
spiropiperidine ring was accompanied by reduction of the iminium
moiety to afford the novel benzo[e]indoline derivatives 6a,b, which
possess a 3-carbamoylpropyl side chain.
O
NH2
H3C CH3
H3C CH3
Pd/C, H2 (20 bar)
AcOH, rt, 3 h
+
AcO-
N
HN
Bn
N
H H
O
4c
A
+
-
-NH4AcO
H3C CH3
N
H3C CH3
N
3 equiv LiAlH4
THF, reflux, 4 h
O
10 (55%)
11 (69%)
The 1H NMR spectra of 6a and 6b showed a characteristic
triplet for the H-2 proton at 2.34 and 2.31 ppm (3J¼7.1 Hz), re-
spectively, which is due to the coupling with protons of the ad-
jacent methylene group. The corresponding 13C NMR spectra
contained signals of the sp3-hybridised C-2 atom of 6a and 6b at
77.4 and 71.9 ppm, respectively. Heating of the amides 6a,b in
ethanol under reflux in the presence of hydrochloric acid afforded
the esters 7a,b, while the reduction of the amides 6 with lithium
aluminium hydride in THF gave the amines 8a,b. Acylation of the
latter with Ac2O and Boc2O yielded the amides 9a,c and the car-
bamates 9b,d, respectively.
Scheme 3. Recyclization of 3-benzylspiro[benzo[e]indole-2,20-piperidin]-60-one.
The reaction outcome can be explained by the palladium-
catalysed hydrogenolysis of the benzyl group,13 leading to the for-
mation of the intermediate product A, which underwent further
intramolecular transamidation14 to afford the condensed tetracy-
clic system 10.
It is important to note that the reduction of the lactam ring of
spiro compound 4a with lithium aluminium hydride was un-
successful, probably because of sterical hindrance, despite the
presence of a large excess of the reducing agent and stirring under
reflux in THF for 72 h. However, the lactam ring of compound 10 was
cleanly reduced with lithium aluminium hydride by reaction in THF
under reflux for 4 h to give the cyclic amine 11 in 69% isolated yield.
The single crystal X-ray structure of 11 (Fig. 1)15 shows that the
skeleton of the asymmetric unit contains the 8,9,10,11,11a,12-
However,
when
3-benzylspiro[benzo[e]indole-2,20-piper-
idinone] 4c was subjected to hydrogenolysis under analogous
conditions as compounds 4a,b, the reaction afforded the tetracyclic
10,11,11a,12-tetrahydrobenzo[e]pyrido[1,2-a]indol-8(9H)-one
10
(Scheme 3).

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V. Buinauskaite et al. / Tetrahedron 68 (2012) 9260e9266
9262
containing 1% (v/v) ethanol, the fluorescence of the latter com-
pounds underwent a red shift, showing emission at lem¼440 and
470 nm, respectively.
The fluorescence quantum yield (Ff) of the solutions in THF was
estimated by comparing the wavelength-integrated PL intensity of
the compound solution with that of the reference. Quinine sulfate
in 0.1 M H2SO4 with Ff¼53% at excitation wavelengths of
310e340 nm was used as a reference. Optical densities of the ref-
erence and the sample solutions were ensured to be below 0.05 to
avoid reabsorption effects. Estimated quantum yields were verified
by the integrating sphere method. In the case of benzoindolines 4a,
7a, 8a and 11, possessing the tertiary aromatic amine nitrogen
atom, the Ff values observed were between 22% (for 11) and 32%
(for 4a and 8a).
Fig. 1. ORTEP view of tetracyclic compound 11.
Additional studies will be mostly directed to the investigation of
the target properties of the synthesised compounds, with respect to
their applications as molecular probes for biomolecular labelling
and as fluorescent scaffolds for the synthesis of opto-electronic
materials.
hexahydrobenzo[e]pyrido[1,2-a]indole ring system. The pyrroline
ring of compound 11 is in an envelope conformation with C(12)
being out of the plane of the benzo[e]indole ring. The piperidine
ring is in a chair conformation with the hydrogen atom at C(12) in
the axial position. The sum of the valence bond angles around the
N(9) atom of 11 is 348.46ꢀ, which indicates that a pyramidal ge-
ometry exists at the sp3-hybridised nitrogen atom.16
The optical properties of 1,1,2-trimethyl-1H-benzo[e]indole 1
and the representative benzo[e]indoline derivatives 4a, 7a, 8a and
11 were investigated by UVevis spectroscopy, and the compounds
were subjected to fluorimetric measurements (Table 1).
It is known that structurally similar benzo[e]indol[1,2-a]py-
rimidine derivatives, possessing an annulated hexahydropyr-
imidine ring on the a-edge of the indoline ring, exhibit a strong blue
fluorescence with an emission maximum around 435 nm (in eth-
anol).3 First, the fluorescence spectra of the starting 1,1,2-trimethyl-
1H-benzo[e]indole 1, the spirobenzo[e]indole-2,20-piperidinone 4a
and the products derived from its reductive ring opening 7a, 8a and
11 were measured in a low polarity solvent such as tetrahydrofuran
(THF). Both the starting compound 1, possessing an azomethine
moiety, and the spiro compound 4a, bearing the electron-
withdrawing aminocarbonyl moiety attached to the C-2 atom of
the indole ring, displayed emission maxima (lem) at 424 nm.
However, the 2-substituted benzo[e]indolines 7a, 8a and 11
showed emission maxima (lem) varying between 440 and 445 nm
in the same solvent. When fluorescence spectra of compounds 4a
and 8a were measured in a polar solvent such as distilled water
3. Conclusions
In conclusion, a new method for the preparation of functional-
ised fluorescent derivatives of benzo[e]indoline was developed. The
reaction of 3-substituted 1,1-dimethyl-2-methylidene-2,3-dihydro-
1H-benzo[e]indole with acrylamide afforded spiro[benzo[e]indole-
2,20-piperidin]-60-ones via a carba-Michael addition of the enamine
b
-carbon atom across the
a
,
b
-unsaturated amide, and subsequent
-car-
nucleophilic addition of the amide nitrogen to the enamine
a
bon atom. The reductive ring opening of 3-alkylspiro[benzo[e]in-
dole-2,20-piperidin]-60-ones and further chemical transformations
gave fluorescent benzo[e]indoline derivatives, possessing reactive
2-[3-(ethoxycarbonyl)propyl] and 2-(4-aminobutyl) side chains. 3-
Benzyl[spirobenzo[e]indole-2,20-piperidin]-60-one
underwent
recyclisation to the benzo[e]pyrido[1,2-a]indole derivative under
similar reaction conditions. The wavelengths of the absorption and
emission maxima (labs/lem) for benzo[e]indoline derivatives 7a and
8a were at about 307/440 nm; the fluorescence quantum yields
were 25 and 32%, respectively.
4. Experimental
4.1. General
Reagents and solvents were purchased from commercial sup-
pliers and used without further purification unless indicated.
Dichloromethane was distilled from calcium hydride before use.
Tetrahydrofuran was dried over sodium. The purification of the
reaction mixtures was performed by flash chromatography using
a glass column with silica gel (0.035e0.070 nm, pore diameter ca.
6 nm). For thin layer chromatographic (TLC) analysis, Merck pre-
coated TLC plates (Silica gel 60 F254) were used. Melting points were
determined on a Melt-Temp (Capillary Melting point Apparatus)
and are uncorrected. 1H NMR (300 MHz) and 13C NMR (75 MHz)
spectra were recorded at rt with a Varian Unity Inova spectrometer
or with a Jeol Eclipse FT 300 NMR spectrometer. The chemical
shifts, expressed in parts per million, were relative to tetrame-
thylsilane (TMS). Infrared spectra were recorded on a Perkin Elmer
Spectrum One spectrometer using potassium bromide pellets or on
a PerkineElmer Spectrum BX FT-IR spectrometer in neat form with
an attenuated total reflectance (ATR) accessory. UVevis spectra
were recorded on a Perkin Elmer Lambda 35 UV/Vis spectrometer.
Fluorescence spectra were recorded on a Hitachi MPF-4 spec-
trometer. Estimated quantum yields were verified using an in-
tegrating sphere setup, which consisted of wavelength-tunable
xenon light source with collimating optics serving as an excitation
Table 1
Absorption (labs and
the benzo[e]indoline derivatives 1, 4a, 7a, 8a, 11 in THF
3 ) and fluorescence (lem and quantum yield Ff) parameters for
Compound
labs (nm)
3
ꢁ103 (dm3 molꢂ1 cmꢂ1
)
lema (nm)
Ff (%)
1
219
245
254
27.04
45.57
32.23
424
45
4a
7a
8a
11
217
256
294
33.63
66.80
9.19
424
440
441
445
32
25
32
22
217
257
307
30.52
45.63
7.93
217
257
307
30.93
48.19
8.89
217
258
308
32.79
42.88
11.53
a
lex¼310 nm.

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V. Buinauskaite et al. / Tetrahedron 68 (2012) 9260e9266
9263
source and the integrating sphere (Sphere Optics) coupled to the
CCD spectrometer (Hamamatsu PMA-12) used for detection. Mass
spectra were recorded on a Waters Micromass ZQ 2000 (APCIþ,
20 V) instrument or on an Agilent 1100 series mass spectrometer
using a direct inlet system (electron spray, 4000 V). 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 Technol-
ogy, and were in good agreement (ꢃ0.4%) with the calculated
values. Diffraction data were collected on Bruker-Nonius KappaCCD
diffractometer at rt and also at ꢂ100 ꢀC. The crystal structures were
solved using known programs.17
pos mode), m/z (%): 309 (MþHþ, 100). Anal. Calcd for C20H24N2O
(%): C, 77.89; H, 7.84; N, 9.08. Found: C, 78.12; H, 8.20; N, 9.09.
4.2.3. 3-Benzyl-1,1-dimethyl-2,3-dihydro-60H-spiro[benzo[e]indole-
2,20-piperidin]-60-one (4c). To a solution of 1,1,2-trimethyl-1H-
benzo[e]indole 1 (2.09 g, 10 mmol) in acetonitrile (10 mL) was
added benzyl iodide (2.39 g, 11 mmol) and the mixture was heated
under reflux for 24 h. Upon cooling to rt, the solvent was removed
under reduced pressure and the residue was kept under high vac-
uum for 20 min to yield iodide 2c as a brown viscous substance,
which was used in the following reaction without further purifi-
cation. 1H NMR of 2c (300 MHz, CDCl3): dH 1.93 (s, 6H, 1-(CH3)2),
3.20 (s, 3H, 2-CH3), 6.05 (s, 2H, CH2), 7.26e7.30 (m, 2H, 2ꢁHbenzyl),
7.35e7.39 (m, 3H, 3ꢁHbenzyl), 7.64e7.78 (m, 2H, 7-H and 8-H), 7.70
(d, J¼8.9 Hz, 1H, 4-H), 8.02 (d, J¼7.9 Hz, 1H, 6-H), 8.04 (d, J¼8.9 Hz,
1H, 5-H), 8.12 (1H, d, J¼8.4 Hz, 9-H). To the obtained iodide 2c was
added a solution of triethylamine (3.03 g, 30 mmol) in dichloro-
methane (40 mL) and the mixture was stirred at rt for 1 h. The
organic solution was washed with water (2ꢁ50 mL), brine
(1ꢁ50 mL), dried over MgSO4 and concentrated under reduced
pressure. The residue (methylidene base 3c) was dissolved in eth-
ylene glycol (15 mL) and acrylamide (1.07 g, 15 mmol) was added to
the solution. The reaction mixture was stirred at 110 ꢀC for 16 h.
Then the reaction mixture was cooled to rt, diluted with water
(50 mL) and extracted with ethyl acetate (5ꢁ50 mL). The combined
organic layers were washed with brine (3ꢁ50 mL), dried over
MgSO4 and concentrated under reduced pressure. The residue was
subjected to flash chromatography on silica gel (dichloromethane/
methanol, 100:0/25:1 v/v) to yield the title compound 4c (1.28 g,
35%) as a light brown amorphous solid. 1H NMR (300 MHz, CDCl3):
dH 1.52 (3H, s,1-CH3),1.74 (s, 3H,1-CH3),1.89e2.08 (m, 3H, 30-Ha, 40-
CH2), 2.24e2.53 (m, 3H, 30-Hb, 50-CH2), 4.37 (d, J¼17.4 Hz, 1H, NC(H)
H), 4.55 (d, J¼17.4 Hz, 1H, NC(H)H), 6.08 (br s, 1H, NH), 6.70 (d,
J¼8.7 Hz, 1H, 4-H), 7.22 (ddd, J¼8.1, 6.9, 1.1 Hz, 1H, 7-H), 7.28e7.39
(m, 5H, 5ꢁCHbenzyl), 7.43 (ddd, J¼8.5, 6.9, 1.5 Hz, 1H, 8-H), 7.60 (d,
J¼8.7 Hz, 1H, 5-H), 7.73e7.76 (m, 1H, 6-H), 7.84e7.97 (m, 1H, 9-H);
13C NMR (75 MHz, CDCl3): dC 18.3 (C-40), 23.3 (1-CH3), 24.3 (1-CH3),
26.0 (C-30), 31.1 (C-50), 47.7 (NCH2), 50.4 (C-1), 87.4 (C-2), 110.5 (C-
4), 121.1 (C-9), 121.7 (C-7), 124.2 (Cquat), 126.1 (2ꢁC, CHbenzyl), 126.6
(C-8), 127.1, 128.7 (2ꢁC, CHbenzyl), 129.3 (Cquat), 129.6 (2ꢁC, C-5 and
C-6), 130.2 (Cquat), 139.4 (Cquat), 145.7 (Cquat), 172.8 (C]O); IR (neat,
nmax, cmꢂ1): 3163 (NeH), 3050, 2963, 1654 (C]O), 1620, 1591, 1519,
1451,1391,1349, 816, 744, 723, 697; MS (API-ES, pos mode), m/z (%):
371 (MþHþ,100). Anal. Calcd for C25H26N2O (%): C, 81.05; H, 7.07; N,
7.56. Found: C, 81.26; H, 6.82; N, 7.28.
4.2. Procedures for the preparation of 3-alkyl-1,1-dimethyl-
2,3-dihydro-60H-spiro[benzo[e]indole-2,20-piperidin]-60-ones
(4)
4.2.1. 1,1,3-Trimethyl-2,3-dihydro-60H-spiro[benzo[e]indole-2,20-pi-
peridin]-60-one (4a). To
a
suspension of iodide 2a2 (3.51 g,
10 mmol) in diethyl ether (50 mL) was added aqueous 1 M NaOH
solution (30 mL) and the reaction mixture stirred at rt for 0.5 h. The
organic layer was separated and the water layer was additionally
extracted with diethyl ether (2ꢁ25 mL). The combined organic
layers were washed with brine, dried over MgSO4 and concentrated
under reduced pressure. The residue was dissolved in ethylene
glycol (15 mL) and acrylamide (1.07 g, 15 mmol) was added to the
solution. The mixture was stirred at 110 ꢀC for 5 h. The reaction
mixture was cooled to rt, water (50 mL) was added and the mixture
was extracted with ethyl acetate (5ꢁ50 mL). The combined organic
layers were washed with brine (3ꢁ50 mL), dried over MgSO4 and
concentrated under reduced pressure. The residue was recrystal-
lised from ethyl acetate to give compound 4a (yield 2.34 g, 79%) as
grey crystals, mp 143e144.5 ꢀC. 1H NMR (300 MHz, CDCl3): dH 1.37
(s, 3H, 1-CH3), 1.62 (s, 3H, 1-CH3), 1.97e2.05 (m, 2H, 40-CH2),
2.13e2.17 (m, 2H, 30-CH2), 2.30 (dt, J¼17.3, 7.5 Hz, 1H, 50-Ha), 2.48
(dt, J¼17.3, 5.4 Hz, 1H, 50-Hb), 2.88 (s, 3H, NCH3), 5.91 (br s, 1H, NH),
6.89 (d, J¼8.7 Hz,1H, 4-H), 7.19e7.26 (m,1H, 7-H), 7.37e7.43 (m,1H,
8-H), 7.69 (d, J¼8.7 Hz, 1H, 5-H), 7.76 (d, J¼8.2 Hz, 1H, 6-H), 7.90 (d,
J¼8.6 Hz,1H, 9-H); 13C NMR (75 MHz, CDCl3): dC 18.7 (C-40), 22.5 (1-
CH3), 23.4 (1-CH3), 25.3 (C-30), 29.3 (NCH3), 31.4 (C-50), 50.1 (C-1),
87.1 (C-2), 110.2 (C-4), 121.0 (C-9), 121.7 (C-7),124.4 (Cquat), 126.5 (C-
8), 129.2 (Cquat), 129.5 and 129.6 (C-5 and C-6), 130.3 (Cquat), 145.9
(Cquat), 173.0 (C]O); IR (KBr, nmax, cmꢂ1): 3194 (NeH), 3052, 2973,
2959, 2894, 2874, 1655 (C]O), 1620, 1592, 1519, 1469, 1451, 1401,
1334, 1280, 1196, 1078, 1032, 953, 939, 811, 742; MS (API-ES, pos
mode), m/z (%): 295 (MþHþ, 100). Anal. Calcd for C19H22N2O (%): C,
77.52; H, 7.53; N, 9.52. Found: C, 77.31; H, 7.67; N, 9.78.
4.3. Procedures for the preparation of 3-alkyl-2-(4-amino-4-
oxobutyl)-1,1-dimethyl-1H-benzo[e]indolium perchlorates (5)
4.2.2. 3-Ethyl-1,1-dimethyl-2,3-dihydro-60H-spiro[benzo[e]indole-
2,20-piperidin]-60-one (4b). Compound 4b was obtained similarly to
4a from iodide 2b12 (3.65 g, 10 mmol). Yield 2.23 g (73%), light
brown crystals, mp 140.9e142.6 ꢀC (ethyl acetate). 1H NMR
(300 MHz, CDCl3): dH 1.27 (t, J¼7.3 Hz, 3H, CH2CH3), 1.37 (s, 3H, 1-
CH3), 1.63 (s, 3H, 1-CH3), 1.93e2.10 (m, 3H, 40-CH2 and 30-Ha),
2.16e2.25 (m,1H, 30-Hb), 2.34 (dt, J¼17.8, 6.6 Hz,1H, 50-Ha), 2.46 (dt,
J¼17.8, 6.3 Hz, 1H, 50-Hb), 3.23 (dq, J¼14.8, 7.3 Hz, 1H, C(H)HCH3),
3.35 (dq, J¼14.8, 7.5 Hz, 1H, C(H)HCH3), 5.95 (br s, 1H, NH), 6.87 (d,
J¼8.7 Hz, 1H, 4-H), 7.16e7.21 (m, 1H, 7-H), 7.35e7.41 (m, 1H, 8-H),
7.66 (d, J¼8.7 Hz, 1H, 5-H), 7.74 (d, J¼8.1 Hz, 1H, 6-H), 7.88 (d,
J¼8.5 Hz,1H, 9-H); 13C NMR (75 MHz, CDCl3): dC 15.5 (CH2CH3), 18.2
(C-40), 22.3 (1-CH3), 23.6 (1-CH3), 26.0 (C-30), 31.1 (C-50), 38.0
(CH2CH3), 50.2 (C-1), 87.0 (C-2), 109.7 (C-4), 120.9 (C-9), 121.3 (C-7),
123.6 (Cquat), 126.4 (C-8), 128.8 (Cquat), 129.4 and 129.5 (C-5 and C-
6), 130.3 (Cquat), 145.3 (Cquat), 172.5 (C]O); IR (KBr, nmax, cmꢂ1):
3192 (NeH), 3055, 2965, 2926, 2880, 1652 (C]O), 1618, 1592, 1516,
1466, 1368, 1340, 1189, 1048, 1033, 960, 932, 816, 745. MS (API-ES,
4.3.1. 2-(4-Amino-4-oxobutyl)-1,1,3-trimethyl-1H-benzo[e]indolium
perchlorate (5a). To a solution of compound 4a (294 mg,1 mmol) in
ethanol (10 mL), 74 wt % HClO4 (0.13 mL, 1.5 mmol) was added
dropwise and the solution was kept at 0 ꢀC for 2 h. The precipitated
crystalline material was filtered, washed with cold ethanol (1 mL)
and recrystallised from ethanol to give perchlorate 5a (291 mg,
74%) as white crystals, mp 171.3e172.2 ꢀC (with decomposition). 1H
NMR (300 MHz, DMSO-d6): dH 1.78 (s, 6H, 1-(CH3)2), 1.88e1.98 (m,
2H, COCH2CH2), 2.40 (t, J¼6.6 Hz, 2H, COCH2), 3.17e3.22 (m, 2H, 2-
CH2), 4.19 (s, 3H, NCH3), 6.98 (br s, 1H, N(H)H), 7.47 (br s, 1H, N(H)
H), 7.70e7.75 (m, 1H, 7-H), 7.76e7.82 (m,1H, 8-H), 8.08 (d, J¼8.9 Hz,
1H, 4-H), 8.20e8.23 (m, 1H, 6-H), 8.29 (d, J¼8.9 Hz, 1H, 5-H),
8.36e8.38 (m, 9-H); 13C NMR (75 MHz, DMSO-d6): dC 20.6 (2ꢁC, 1-
(CH3)2), 21.7 (COCH2CH2), 25.9 (2-CH2), 33.7 (COCH2), 35.2 (NCH3),
55.6 (C-1), 113.2 (C-4), 123.3 (C-9), 126.9 and 127.1 (C-7 and Cquat),
128.3 (C-8), 129.7 (C-6), 130.5 (C-5), 133.1 (Cquat), 136.4 (Cquat), 139.5
(Cquat), 173.3 (C]O), 196.5 (C]N); IR (KBr, nmax, cmꢂ1): 3423, 3305

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(NeH), 3157, 3079, 2984, 2974, 2947, 2876, 1686 (C]O), 1640, 1623,
1584, 1481, 1442, 1392, 1094, 819, 754, 623; MS (API-ES, pos mode),
m/z (%): 300 ðM ꢂ ClO4ꢂ; 100Þ. Anal. Calcd for C19H23ClN2O5 (%): C,
57.80; H, 5.87; N, 7.09. Found: C, 58.02; H, 6.10; N, 7.08.
6-H), 7.91e7.94 (m, 1H, 9-H); 13C NMR (75 MHz, CDCl3): dC 9.8
(CH2CH3), 21.1 (1-CH3), 23.5 (CH2), 28.3 (2ꢁC, 1-CH3 and CH2), 36.3
(COCH2), 39.8 (CH2CH3), 44.6 (C-1), 71.9 (C-2), 111.1 (C-4), 120.9 (C-
7), 121.3 (C-9), 125.9 (C-8), 127.7 (Cquat), 128.7 (2ꢁC, C-5 and Cquat),
129.3 (C-6), 130.3 (Cquat), 147.6 (Cquat), 175.2 (C]O); IR (neat, nmax
,
4.3.2. 2-(4-Amino-4-oxobutyl)-3-ethyl-1,1-dimethyl-1H-benzo[e]in-
dolium perchlorate (5b). Compound 5b was obtained similarly to 5a
from compound 4b (308 mg, 1 mmol). Yield 237 mg (58%), pink
crystals, mp 183.5e184.4 ꢀC (from ethanol, with decomposition). 1H
NMR (300 MHz, DMSO-d6): dH 1.57 (t, J¼7.2 Hz, 3H, CH2CH3),1.80 (s,
6H, 1-(CH3)2), 1.90e2.01 (m, 2H, COCH2CH2), 2.42 (t, J¼6.6 Hz, 2H,
COCH2), 3.17e3.23 (m, 2H, NCCH2), 4.70 (q, J¼7.2 Hz, 2H, NCH2),
6.99 (br s, 1H, N(H)H), 7.50 (br s, 1H, N(H)H), 7.72e7.83 (m, 2H, 7-H
and 8-H), 8.14 (d, J¼8.9 Hz, 1H, 4-H), 8.22e8.24 (m, 1H, 6-H), 8.30
(d, J¼8.9 Hz, 1H, 5-H), 8.37e8.40 (m, 9-H); 13C NMR (75 MHz,
DMSO-d6): dC 13.6 (CH2CH3), 20.9 (2ꢁC, 1-(CH3)2), 22.6
(COCH2CH2), 25.9 (2-CH2), 33.7 (COCH2), 43.5 (NCH2), 55.8 (C-1),
113.4 (C-4), 123.4 (C-9), 127.1 and 127.2 (Cquat and C-7), 128.3 (C-8),
129.7 (C-6), 130.6 (C-5), 133.1 (Cquat), 137.1 (Cquat), 138.0 (Cquat),
173.3 (C]O), 196.7 (C¼N); IR (KBr, nmax, cmꢂ1): 3423, 3319 (NeH),
3088, 2982, 2940, 2874, 1684 (C]O), 1652, 1583, 1479, 1465, 1393,
1100, 1089, 823, 755, 623; MS (API-ES, pos mode), m/z (%): 309
ðM ꢂ ClOꢂ4 ; 100Þ. Anal. Calcd for C20H25ClN2O5 (%): C, 58.75; H,
6.16; N, 6.85. Found: C, 59.10; H, 6.30; N, 6.79.
cmꢂ1): 3331, 3185 (NeH), 3051, 2965, 2932, 2868, 2816, 1662 (C]
O), 1619, 1591, 1518, 1462, 1439, 1366, 1350, 1322, 1274, 1209, 1186,
1145, 1132, 1069, 807, 735, 672; MS (API-ES, pos mode), m/z (%): 311
(MþHþ, 100). Anal. Calcd for C20H26N2O (%): C, 77.38; H, 8.44; N,
9.02. Found: C, 77.21; H, 8.51; N, 9.23.
4.5. Procedures for the preparation of ethyl 4-(3-alkyl-1,1-
dimethyl-2,3-dihydro-1H-benzo[e]indol-2-yl)butanoates (7)
4.5.1. Ethyl
4-(1,1,3-trimethyl-2,3-dihydro-1H-benzo[e]indol-2-yl)
butanoate (7a). To a solution of amide 6a (148 mg, 0.5 mmol) in
ethanol (2 mL) 6 M HCl (4 mL) was added and the mixture was
stirred under reflux for 4 h. The reaction mixture was concentrated
under reduced pressure. The residue was dissolved in ethyl acetate,
washed with saturated NaHCO3 solution (2ꢁ10 mL). The organic
layer was separated, dried over MgSO4, filtered, concentrated under
reduced pressure and purified by flash chromatography on silica gel
(hexane/ethyl acetate, 3:1 v/v). Yield 117 mg (72%), a brown viscous
substance. 1H NMR (300 MHz, CDCl3): dH 1.30 (t, J¼7.1 Hz, 3H,
CH2CH3), 1.34 (s, 3H, 1-CH3), 1.71 (s, 3H, 1-CH3), 1.79e1.96 (m, 4H, 2-
CH2CH2), 2.44 (t, J¼6.9 Hz, 2H, CH2CO), 2.85 (s, 3H, NCH3), 2.91 (t,
J¼5.4 Hz, 1H, 2-H), 4.18 (q, J¼7.1 Hz, 2H, CH2CH3), 6.96 (d, J¼8.7 Hz,
1H, 4-H), 7.20 (ddd, J¼8.0, 6.9, 1.1 Hz, 1H, 7-H), 7.39 (ddd, J¼8.5, 6.9,
1.5 Hz, 1H, 8-H), 7.66 (d, J¼8.7 Hz, 1H, 5-H), 7.74e7.79 (m, 1H, 6-H),
7.96e7.99 (m, 1H, 9-H); 13C NMR (75 MHz, CDCl3): dC 14.3 (CH2CH3),
21.2 (1-CH3), 23.3 (CH2), 28.0 and 28.2 (1-CH3 and CH2), 34.9
(CH2CO), 35.9 (NCH3), 44.8 (C-1), 60.4 (CH2CH3), 77.4 (C-2), 111.5 (C-
4),121.4 (C-7),121.6 (C-9),126.0 (C-8),128.2 (Cquat),128.8 (C-5), 129.3
(Cquat), 129.4 (C-6), 130.1 (Cquat), 149.2 (C-3a), 173.4 (C]O); IR (KBr,
nmax, cmꢂ1): 3052, 2961, 2868, 2800, 1730 (C]O), 1621, 1592, 1518,
1459, 1363, 1292, 1191, 1121, 1025, 976, 806, 784, 744, 674; MS (API-
ES, pos mode), m/z (%): 326 (MþHþ, 100). Anal. Calcd for C21H27NO2
(%): C, 77.50; H, 8.36; N, 4.30. Found: C, 77.35; H, 8.44; N, 4.35.
4.4. Procedures for the preparation of 4-(3-alkyl-1,1-dimethyl-
2,3-dihydro-1H-benzo[e]indol-2-yl)butanamides (6)
4.4.1. 4-(1,1,3-Trimethyl-2,3-dihydro-1H-benzo[e]indol-2-yl)butana-
mide (6a). To a solution of compound 4a (1.47 g, 5 mmol) in glacial
acetic acid (5 mL) was added 10% Pd/C catalyst (74 mg, 5 wt % of
starting compound) under argon. The solution was hydrogenated
with H2 at 20 bar and rt for 2 h. The mixture was filtered through
a layer of CeliteÒ, the filter cake was washed with ethyl acetate and
the filtrate was concentrated under reduced pressure. The residue
was dissolved in ethyl acetate and washed with saturated aqueous
NaHCO3 solution (3ꢁ30 mL). The organic extract was dried over
Na2SO4, filtered and concentrated under reduced pressure. The
residue was subjected to flash chromatography on silica gel
(dichloromethane/methanol, 100:0/100:5 v/v) to afford the title
compound 6a (1.04 g, 70%) as white crystals, mp 118.0e119.6 ꢀC. 1H
NMR (300 MHz, CDCl3): dH 1.32 (s, 3H, 1-CH3), 1.70 (s, 3H, 1-CH3),
1.79e1.98 (m, 4H, COCH2CH2, 2-CH2), 2.34 (t, J¼7.1 Hz, 2H, COCH2),
2.84 (s, 3H, NCH3), 2.90e2.94 (m, 1H, 2-H), 5.52 (br s, 2H, NH2), 6.94
(d, J¼8.7 Hz,1H, 4-H), 7.16e7.21 (m,1H, 7-H), 7.35e7.40 (m, 1H, 8-H),
7.64 (d, J¼8.7 Hz, 1H, 5-H), 7.73e7.75 (m, 1H, 6-H), 7.94e7.97 (m, 1H,
9-H); 13C NMR (75 MHz, CDCl3): dC 21.2 (1-CH3), 23.7 (CH2), 28.1 and
28.2 (1-CH3 and CH2), 35.9 (NCH3), 36.3 (COCH2), 44.7 (C-1), 77.4 (C-
2),111.4 (C-4),121.3 and 121.5 (C-7 and C-9),126.0 (C-8),128.1 (Cquat),
128.8 (C-5), 129.2 and 129.3 (Cquat and C-6), 130.1 (Cquat), 149.3 (C-
3a),175.1 (C]O); IR (KBr, nmax, cmꢂ1): 3309, 3190 (NeH), 3048, 2961,
2866, 2794, 1686 (C]O), 1653, 1619, 1590, 1516, 1470, 1459, 1426,
1399, 1366, 1353, 1309, 1281, 1205, 1193, 1131, 977, 817, 750, 675; MS
(APCIþ), m/z (%): 297 (MþHþ, 100). Anal. Calcd for C19H24N2O (%): C,
76.99; H, 8.16; N, 9.45. Found: C, 76.59; H, 8.05; N, 9.38.
4.5.2. Ethyl 4-(3-ethyl-1,1-dimethyl-2,3-dihydro-1H-benzo[e]indol-
2-yl)butanoate (7b). Compound 7b was obtained similarly to 7a
from compound 6b (155 mg, 0.5 mmol). Yield 115 mg (68%),
a brown viscous substance. 1H NMR (300 MHz, CDCl3): dH 1.11 (t,
J¼7.1 Hz, 3H, NCH2CH3), 1.31 (t, J¼7.1 Hz, 3H, OCH2CH3), 1.35 (s, 3H,
1-CH3), 1.71 (s, 3H, 1-CH3), 1.80e2.00 (m, 4H, 2-CH2CH2), 2.44 (t,
J¼7.1 Hz, 2H, CH2CO), 3.29 (t, 1H, J¼5.2 Hz, 2-H), 3.29 (dq, J¼14.2,
7.1 Hz, 1H, NC(H)H), 3.53 (dq, J¼14.2, 7.1 Hz, 1H, NC(H)H), 4.20 (q,
J¼7.1 Hz, 2H, OCH2), 6.92 (d, J¼8.7 Hz,1H, 4-H), 7.17 (ddd, J¼8.0, 6.8,
1.1 Hz, 1H, 7-H), 7.37 (ddd, J¼8.5, 6.8, 1.4 Hz, 1H, 8-H), 7.64 (d,
J¼8.7 Hz, 1H, 5-H), 7.71e7.78 (m, 1H, 6-H), 7.95 (dd, J¼8.5, 6.8 Hz,
1H, 9-H); 13C NMR (75 MHz, CDCl3): dC 10.0 (NCH2CH3), 14.4
(OCH2CH3), 21.2 (1-CH3), 23.3 (CH2), 28.4 (2ꢁC, 1-CH3 and CH2),
35.1 (CH2CO), 40.0 (NCH2), 44.8 (C-1), 60.5 (OCH2), 72.2 (C-2), 111.3
(C-4), 121.1 and 121.5 (C-7 and C-9), 126.0 (C-8), 127.9 (Cquat), 128.9
and 129.0 (C-5 and Cquat), 129.5 (C-6), 130.5 (Cquat), 147.8 (C-3a),
173.5 (C]O); IR (neat, nmax, cmꢂ1): 3049, 2968, 2934, 2870, 2816,
1731 (C]O), 1620, 1591, 1518, 1465, 1439, 1369, 1349, 1274, 1184,
1069, 1025, 955, 806, 782, 742, 673; MS (API-ES, pos mode), m/z (%):
340 (MþHþ, 100). Anal. Calcd for C22H29NO2 (%): C, 77.84; H, 8.61;
N, 4.13. Found: C, 77.91; H, 8.56; N, 4.08.
4.4.2. 4-(3-Ethyl-1,1-dimethyl-2,3-dihydro-1H-benzo[e]indol-2-yl)
butanamide (6b). Compound 6b was obtained similarly to 6a from
compound 4b (1.54 g, 5 mmol). Yield 1.023 g (66%), brown viscous
substance. 1H NMR (300 MHz, CDCl3): dH 1.07 (t, J¼7.2 Hz, 3H,
CH2CH3), 1.32 (s, 3H, 1-CH3), 1.68 (s, 3H, 1-CH3), 1.74e1.96 (m, 4H,
COCH2CH2 and 2-CH2), 2.31 (t, J¼7.1 Hz, 2H, COCH2), 3.26 (dq,
J¼14.6, 7.2 Hz, 1H, C(H)HCH3), 3.27e3.29 (m, 1H, 2-H), 3.50 (dq,
J¼14.6, 7.2 Hz, 1H, C(H)HCH3), 5.54 (br s, 1H, N(H)H), 5.80 (br s, 1H,
N(H)H), 6.89 (d, J¼8.7 Hz, 1H, 4-H), 7.12e7.17 (m, 1H, 7-H),
7.32e7.38 (m, 1H, 8-H), 7.62 (d, J¼8.7 Hz,1H, 5-H), 7.71e7.73 (m,1H,
4.6. Procedures for the preparation of 4-(3-alkyl-1,1-dimethyl-
2,3-dihydro-1H-benzo[e]indol-2-yl)butan-1-amines (8)
4.6.1. 4-(1,1,3-Trimethyl-2,3-dihydro-1H-benzo[e]indol-2-yl)butan-
1-amine (8a). A solution of the amide 6a (296 mg, 1 mmol) in dry

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tetrahydrofuran (2 mL) was added to a suspension of LiAlH4
(114 mg, 3 mmol) in dry tetrahydrofuran (3 mL) under nitrogen
atmosphere. The reaction mixture was stirred under reflux under
nitrogen atmosphere for 4 h. After cooling to 0 ꢀC, an aqueous 3 M
NaOH solution (5 mL) was added and the mixture stirred at rt for
3 h. Then the reaction mixture was filtered over CeliteÒ, the filter
cake was washed with ethyl acetate and the filtrate was extracted
with ethyl acetate (3ꢁ20 mL). The organic layers were combined,
washed with brine (3ꢁ15 mL), dried over Na2SO4, filtered and
concentrated under reduced pressure and purified by flash chro-
matography on silica gel (dichloromethane/methanol, 10:1 v/v) to
afford the title compound 8a (yield 217 mg, 77%) as a yellow viscous
substance. 1H NMR (300 MHz, CDCl3): dH 1.40 (s, 3H, 1-CH3),
1.57e1.73 (m, 4H, CH2CH2CH2NH2), 1.76 (s, 3H, 1-CH3), 1.81e1.95
(m, 2H, 2-CH2), 2.56 (br s, 2H, NH2), 2.77e2.84 (m, 2H, CH2NH2),
2.86 (s, 3H, NCH3), 2.97 (t, J¼5.8 Hz, 1H, 2-H), 7.00 (d, J¼8.7 Hz, 1H,
4-H), 7.22e7.29 (m, 1H, 7-H), 7.42e7.47 (m, 1H, 8-H), 7.70 (d,
J¼8.7 Hz, 1H, 5-H), 7.81 (d, J¼8.2 Hz, 1H, 6-H), 8.04 (d, J¼8.7 Hz, 1H,
9-H); 13C NMR (75 MHz, CDCl3): dC 21.0 (1-CH3), 25.0 (CH2), 28.0
and 28.3 (1-CH3 and 2-CH2), 33.8 (CH2), 35.6 (NCH3), 41.6 (CH2NH2),
44.5 (C-1), 77.3 (C-2), 111.2 (C-4), 121.0 and 121.3 (C-7 and C-9),
125.7 (C-8), 127.9 (Cquat), 128.5 (C-5), 129.0 (Cquat), 129.2 (C-6), 130.0
(Cquat), 149.2 (C-3a); IR (neat, nmax, cmꢂ1): 3301 (NeH), 3053, 2934,
2864, 2800, 1666, 1621, 1592, 1518, 1458, 1360, 1353, 1292, 1206,
1145, 1055, 907, 806, 729, 683, 672; MS (APCIþ, pos mode), m/z (%):
283 (MþHþ, 100). Anal. Calcd for C19H26N2$0.7H2O (%): C, 77.35; H,
9.36; N, 9.49. Found: C, 77.46; H, 9.13; N, 9.11.
1H, 4-H), 7.15e7.20 (m, 1H, 7-H), 7.34e7.40 (m, 1H, 8-H), 7.63 (d,
J¼8.7 Hz, 1H, 5-H), 7.72e7.75 (m, 1H, 6-H), 7.94e7.96 (m, 1H, 9-H);
13C NMR (75 MHz, CDCl3): dC 21.2 (1-CH3), 23.3 (COCH3), 25.2 (CH2),
28.3 (2ꢁC, 1-CH3 and 2-CH2), 30.5 (CH2), 36.0 (NCH3), 39.5
(CH2NH), 44.8 (C-1), 77.5 (C-2), 111.5 (C-4), 121.3 (C-7), 121.6 (C-9),
126.0 (C-8), 128.2 (Cquat),128.8 (C-5),129.3 (Cquat),129.4 (C-6),130.2
(Cquat), 149.4 (C-3a), 170.2 (C]O); IR (neat, nmax, cmꢂ1): 3288
(NeH), 3073, 3057, 2960, 2936, 2865, 2802,1650 (C]O),1621,1592,
1519, 1458, 1363, 1292, 1206, 1122, 995, 908, 807, 727, 673, 684; MS
(API-ES, pos mode), m/z (%): 325 (MþHþ, 100). Anal. Calcd for
C21H28N2O (%): C, 77.74; H, 8.70; N, 8.63. Found: C, 77.59; H, 8.77; N,
8.71.
4.7.2. tert-Butyl [4-(1,1,3-trimethyl-2,3-dihydro-1H-benzo[e]indol-2-
yl)butyl]carbamate (9b). To a solution of compound 4a (141 mg,
0.5 mmol) in dry dichloromethane (5 mL), di-tert-butyl dicarbonate
(218 mg, 1 mmol) was added and the mixture was stirred at rt for
30 min. Then the reaction mixture was diluted with dichloro-
methane (10 mL) and washed with saturated aqueous NaHCO3
(2ꢁ10 mL). The organic extract was dried over MgSO4, filtered and
concentrated under reduced pressure. The residue was purified by
flash chromatography on silica gel (petroleum ether/diethyl ether,
4:1/2:1 v/v) to afford the title compound 9b (103 mg, 54%) as
a brown viscous substance. 1H NMR (300 MHz, CDCl3): dH 1.31 (s,
3H, 1-CH3), 1.46 (s, 9H, C(CH3)3), 1.58e1.61 (m, 4H, CH2CH2CH2NH),
1.68 (s, 3H, 1-CH3), 1.77e1.81 (m, 2H, 2-CH2), 2.83 (s, 3H, NCH3),
2.89 (t, J¼5.7 Hz, 1H, 2-H), 3.12e3.27 (m, 2H, CH2NH), 4.58 (br s, 1H,
NH), 6.95 (d, J¼8.7 Hz, 1H, 4-H), 7.16e7.21 (m, 1H, 7-H), 7.35e7.40
(m, 1H, 8-H), 7.64 (d, J¼8.7 Hz, 1H, 5-H), 7.72e7.75 (m, 1H, 6-H),
7.94e7.97 (m, 1H, 9-H); 13C NMR (75 MHz, CDCl3): dC 21.2 (1-CH3),
25.1 (CH2), 28.3 (2ꢁC, 1-CH3 and 2-CH2), 28.4 (3ꢁC, C(CH3)3), 31.0
(CH2), 36.0 (NCH3), 40.4 (CH2NH), 44.8 (C-1), 77.6 (C-2), 79.2
(C(CH3)3), 111.6 (C-4), 121.4 and 121.6 (C-7 and C-9), 126.0 (C-8),
128.4 (Cquat), 128.8 (C-5), 129.4 (2ꢁC, Cquat and C-6), 130.2 (Cquat),
149.4 (C-3a), 156.0 (C]O); IR (neat, nmax, cmꢂ1): 3351 (NeH), 3057,
2971, 2933, 2865, 2798, 1691 (C]O), 1622, 1592, 1517, 1456, 1364,
1282, 1249, 1168, 909, 807, 730, 673; MS (API-ES, pos mode), m/z
(%): 383 (MþHþ, 100). Anal. Calcd for C24H34N2O2 (%): C, 75.35; H,
8.96; N, 7.32. Found: C, 75.24; H, 9.01; N, 7.38.
4.6.2. 4-(3-Ethyl-1,1-dimethyl-2,3-dihydro-1H-benzo[e]indol-2-yl)
butan-1-amine (8b). Compound 8b was obtained similarly to 8a
from amide 6b (310 mg, 1 mmol). Yield 207 mg (70%), a yellow oily
substance. 1H NMR (300 MHz, CDCl3): dH 1.06 (t, J¼7.2 Hz, 3H,
CH2CH3), 1.30 (s, 3H, 1-CH3), 1.57e1.64 (m, 4H, CH2CH2CH2NH2),
1.67 (s, 3H, 1-CH3), 1.73e1.82 (m, 2H, 2-CH2), 2.55 (br s, 2H, NH2),
2.78e2.82 (2H, m, CH2NH2), 3.19e3.31 (2H, m, 2-H and C(H)HCH3),
3.49 (dq, J¼14.7, 7.2 Hz, 1H, C(H)HCH3), 6.88 (d, J¼8.7 Hz, 1H, 4-H),
7.14 (ddd, J¼8.0, 6.9, 1.2 Hz, 1H, 7-H), 7.34 (ddd, J¼8.5, 6.9, 1.5 Hz,
1H, 8-H), 7.61 (1H, d, J¼8.7 Hz, 5-H), 7.70e7.73 (m, 1H, 6-H),
7.91e7.94 (m, 1H, 9-H); 13C NMR (75 MHz, CDCl3): dC 9.9 (CH2CH3),
21.1 (1-CH3), 25.2 (CH2), 28.4 and 28.7 (1-CH3 and 2-CH2), 34.0
(CH2), 39.9 (CH2CH3), 41.9 (CH2NH2), 44.6 (C-1), 72.2 (C-2), 111.2 (C-
4), 120.9 (C-7), 121.4 (C-9), 125.9 (C-8), 127.8 (Cquat), 128.8 (2ꢁC, C-5
4.7.3. N-[4-(3-Ethyl-1,1-dimethyl-2,3-dihydro-1H-benzo[e]indol-2-
yl)butyl]acetamide (9c). Compound 9c was obtained similarly to 9a
from compound 8b (148 mg, 0.5 mmol). Yield 140 mg (83%),
a brown viscous substance. 1H NMR (300 MHz, CDCl3): dH 1.07 (t,
J¼7.3 Hz, 3H, CH2CH3), 1.30 (s, 3H, 1-CH3), 1.52e1.63 (m, 4H,
CH2CH2CH2NH), 1.67 (s, 3H, 1-CH3), 1.73e1.80 (m, 2H, 2-CH2), 1.99
(s, 3H, COCH3), 3.18e3.33 (m, 4H, CH2NH, 2-H and C(H)HCH3), 3.49
(dq, J¼14.7, 7.3 Hz, 1H, C(H)HCH3), 5.61 (br s, 1H, NH), 6.89 (d,
J¼8.7 Hz, 1H, 4-H), 7.12e7.17 (m, 1H, 7-H), 7.35 (ddd, J¼8.4, 6.9,
1.5 Hz, 1H, 8-H), 7.61 (d, J¼8.7 Hz, 1H, 5-H), 7.70e7.73 (m, 1H, 6-H),
7.91e7.94 (m, 1H, 9-H); 13C NMR (75 MHz, CDCl3): dC 9.9 (CH2CH3),
21.1 (1-CH3), 23.4 (COCH3), 25.1 (CH2), 28.4 and 28.5 (1-CH3 and 2-
CH2), 30.6 (CH2), 39.6 and 39.9 (CH2CH3 and CH2NH), 44.6 (C-1),
72.1 (C-2), 111.2 (C-4), 120.9 (C-7), 121.3 (C-9), 125.9 (C-8), 127.8
(Cquat), 128.8 (C-5), 129.4 (2ꢁC, Cquat and C-6),130.4 (Cquat), 147.7 (C-
3a), 170.1 (C]O); IR (neat, nmax, cmꢂ1): 3278 (NeH), 3073, 2966,
2932, 2866, 1649 (C]O), 1621, 1591, 1555, 1518, 1473, 1462, 1438,
1366, 1275, 1209, 1186, 1146, 1133, 1066, 958, 909, 806, 782, 730,
684, 673; MS (API-ES, pos mode), m/z (%): 339 (MþHþ, 100). Anal.
Calcd for C22H30N2O (%): C, 78.06; H, 8.93; N, 8.28. Found: C, 78.34;
H, 9.08; N, 8.40.
and Cquat), 129.4 (C-6), 130.4 (Cquat), 147.8 (C-3a); IR (neat, nmax
,
cmꢂ1): 3363 (NeH), 3184 (NeH), 3049, 2965, 2932, 2866, 1620,
1591, 1518, 1471, 1439, 1366, 1349, 1324,1274, 1209, 1186, 1145, 1133,
1067, 956, 806, 737, 672; MS (API-ES, pos mode), m/z (%): 297
(MþHþ, 100). Anal. Calcd for C20H28N2 (%): C, 81.03; H, 9.52; N, 9.45.
Found: C, 81.24; H, 9.38; N, 9.49.
4.7. Procedures for the preparation of N-[4-(1-alkyl-1,1-
dimethyl-2,3-dihydro-1H-benzo[e]indol-2-yl)butyl]acet-
amides and the corresponding carbamates (9)
4.7.1. N-[4-(1,1,3-Trimethyl-2,3-dihydro-1H-benzo[e]indol-2-yl)bu-
tyl]acetamide (9a). A solution of acetic anhydride (204 mg,
2 mmol) and amine 8a (141 mg, 0.5 mmol) in dry dichloromethane
(5 mL) was stirred at rt for 1.5 h. The reaction mixture was diluted
with dichloromethane (10 mL) and washed with saturated aqueous
NaHCO3 solution (2ꢁ10 mL), the organic layer was separated, dried
over MgSO4, filtered and concentrated under reduced pressure. The
residue was purified by flash chromatography on silica gel
(dichloromethane/methanol,100:3 v/v). Yield 126 mg (78%), yellow
oil. 1H NMR (300 MHz, CDCl3): dH 1.30 (s, 3H, 1-CH3), 1.52e1.63 (m,
4H, CH2CH2CH2NH), 1.67 (s, 3H, 1-CH3), 1.76e1.82 (m, 2H, 2-CH2),
1.98 (s, 3H, COCH3), 2.81 (s, 3H, NCH3), 2.88 (t, J¼5.9 Hz, 1H, 2-H),
3.29 (q, J¼6.2 Hz, 2H, CH2NH), 5.69 (br s, 1H, NH), 6.93 (d, J¼8.7 Hz,
4.7.4. tert-Butyl [4-(3-ethyl-1,1-dimethyl-2,3-dihydro-1H-benzo[e]in-
dol-2-yl)butyl]carbamate (9d). Compound 9d was obtained simi-
larly to 9b from amine 8b (148 mg, 0.5 mmol). Yield 113 mg (57%),
brown viscous substance. 1H NMR (300 MHz, CDCl3): dH 1.06 (t,

_
V. Buinauskaite et al. / Tetrahedron 68 (2012) 9260e9266
9266
J¼7.2 Hz, 3H, CH2CH3), 1.30 (s, 3H, 1-CH3), 1.46 (s, 9H, C(CH3)3),
1.51e1.62 (m, 4H, CH2CH2CH2NH), 1.67 (s, 3H, 1-CH3), 1.72e1.79 (m,
2H, 2-CH2), 3.06e3.30 (m, 4H, CH2NH, 2-H and C(H)HCH3), 3.49 (dq,
J¼14.7, 7.2 Hz, 1H, C(H)HCH3), 4.61 (br s, 1H, NH), 6.88 (d, J¼8.7 Hz,
1H, 4-H), 7.11e7.16 (m, 1H, 7-H), 7.34 (ddd, J¼8.4, 6.9, 1.2 Hz, 1H, 8-
H), 7.61 (d, J¼8.7 Hz, 1H, 5-H), 7.70e7.73 (m, 1H, 6-H), 7.91e7.94 (m,
1H, 9-H); 13C NMR (75 MHz, CDCl3): dC 9.8 (CH2CH3), 21.0 (1-CH3),
24.9 (CH2), 28.2 (2ꢁC, 1-CH3 and 2-CH2), 28.4 (3ꢁC, C(CH3)3), 31.0
(CH2), 39.7 (CH2CH3), 40.3 (CH2NH), 44.5 (C-1), 72.0 (C-2), 79.2
(C(CH3)3), 111.1 (C-4), 120.8 (C-7), 121.3 (C-9), 125.8 (C-8), 127.7
(Cquat), 128.7 (2ꢁC, C-5 and Cquat), 129.3 (C-6), 130.3 (Cquat), 147.7 (C-
3a), 155.9 (C]O); IR (neat, nmax, cmꢂ1): 3346 (NeH), 3057, 2969,
2933, 2866, 1691 (C]O), 1621, 1591, 1518, 1474, 1439, 1364, 1274,
1249, 1169, 908, 806, 781, 740, 672; MS (API-ES, pos mode), m/z (%):
397 (MþHþ, 100). Anal. Calcd for C25H36N2O2 (%): C, 75.72; H, 9.15;
N, 7.06. Found: C, 75.53; H, 9.28; N, 7.14.
CHb and 9-CH2), 2.00 (dp, J¼12.7, 2.9 Hz, 1H, 10-Hb), 2.56 (dt, J¼3.1,
11.5 Hz,1H, 8-Ha), 2.71 (dd, J¼2.5, 11.5 Hz, 1H, 11a-H), 3.76e3.80 (m,
1H, 8-Hb), 6.92 (d, J¼8.6 Hz, 1H, 6-H), 7.14e7.19 (m, 1H, 3-H),
7.33e7.39 (m,1H, 2-H), 7.62 (d, J¼8.6 Hz,1H, 5-H), 7.72e7.75 (m,1H,
4-H), 7.92e7.95 (m, 1H,1-H); 13C NMR (75 MHz, CDCl3): dC 20.8 (12-
CH3), 24.1 (C-11), 24.6 (C-10), 25.3 (C-9), 26.5 (12-CH3), 43.6 (C-12),
46.5 (C-8), 75.5 (C-11a),110.2 (C-6),121.1 (C-1),121.6 (C-3),125.9 (C-
2), 128.3 (Cquat), 128.5 (C-5), 129.1 (Cquat), 129.4 (C-4), 130.6 (Cquat);
IR (KBr, nmax, cmꢂ1): 3076, 3050, 2968, 2928, 2852, 2798,1619,1589,
1519, 1473, 1440, 1373, 1341, 1299, 1252, 1205, 1143, 1078, 986, 832,
806, 737, 680; MS (API-ES, pos mode), m/z (%): 252 (MþHþ, 100).
Anal. Calcd for C18H21N$0.8H2O (%): C, 81.34; H, 8.57; N, 5.27.
Found: C, 81.13; H, 8.17; N, 5.44.
Acknowledgements
This work was partly supported by the European Social Fund
Agency under the project ‘Synthesis, investigation and application
of high tech materials’. The authors are also indebted to the Re-
search FoundationdFlanders (FWO-Vlaanderen) for financial sup-
port of this research.
4.8. Procedure for the preparation of 12,12-dimethyl-10,
11,11a,12-tetrahydrobenzo[e]pyrido[1,2-a]indol-8(9H)-one (10)
To a solution of compound 4c (740 mg, 2 mmol) in glacial acetic
acid (2 mL) was added 10% Pd/C catalyst (37 mg, 5 wt % of starting
compound) under argon. The solution was hydrogenated with H2 at
20 bar and rt for 3 h. The mixture was filtered through a layer of
CeliteÒ, the filter cake was washed with ethyl acetate and the fil-
trate was concentrated under reduced pressure. The residue was
dissolved in ethyl acetate and washed with saturated aqueous
NaHCO3 solution (3ꢁ30 mL). The organic extract was dried over
Na2SO4, filtered and concentrated under reduced pressure. The
product was purified by flash chromatography on silica gel
(dichloromethane/methanol, 100:0/100:1 v/v) to afford the title
compound 10 (291 mg, 55%) as brown crystals, mp 123e125 ꢀC. 1H
NMR (300 MHz, CDCl3): dH 1.28 (s, 3H, 12-CH3), 1.73 (s, 3H, 12-CH3),
1.66e1.90 (m, 2H, 10-Ha and 11-Ha), 2.05e2.18 (m, 2H, 10-Hb and
11-Hb), 2.47e2.59 (m, 1H, 9-Ha), 2.65e2.74 (m, 1H, 9-Hb), 3.85 (dd,
J¼3.3, 11.5 Hz, 1H, 11a-H), 7.38 (ddd, J¼8.1, 6.9, 1.3 Hz, 1H, 3-H), 7.47
(ddd, J¼8.5, 6.9, 1.5 Hz, 1H, 2-H), 7.75 (d, J¼8.8 Hz, 1H, 5-H),
7.84e7.87 (m, 1H, 4-H), 8.07e8.11 (m, 1H, 1-H), 8.50 (d, J¼8.8 Hz,
1H, 6-H); 13C NMR (75 MHz, CDCl3): dC 20.7 (C-10), 22.4 (2ꢁC, C-11-
CH2 and 1-CH3), 26.1 (1-CH3), 32.8 (C-9), 44.4 (C-12), 71.1 (C-11a),
117.6 (C-6), 122.9 (C-1), 123.9 (C-3), 126.1 (C-2), 128.6 (C-5), 129.4
(2ꢁC, C-4 and Cquat), 131.9 (Cquat), 132.4 (Cquat), 139.2 (Cquat), 168.5
(C]O); IR (KBr, nmax, cmꢂ1): 3057, 2982, 2962, 2934, 2869, 1643
(C]O), 1590, 1471, 1462, 1425, 1407, 1336, 1310, 1220, 1178, 1149,
820, 741; MS (API-ES, pos mode), m/z (%): 266 (MþHþ, 100). Anal.
Calcd for C18H19NO (%): C, 81.47; H, 7.22; N, 5.28. Found: C, 81.62; H,
7.16; N, 5.26.
Supplementary data
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2012.08.073.
These data include MOL files and InChiKeys of the most important
compounds described in this article.
References and notes
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4.9. Procedure for the preparation of 12,12-dimethyl-
8,9,10,11,11a,12-hexahydrobenzo[e]pyrido[1,2-a]indole (11)
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To a suspension of LiAlH4 (114 mg, 3 mmol) in dry tetrahydro-
furan (3 mL), a solution of compound 10 (265 mg, 1 mmol) in dry
tetrahydrofuran (2 mL) was added and the reaction mixture was
stirred under nitrogen at reflux temperature for 4 h. After the re-
action mixture was cooled to rt, 3 M NaOH (1 mL) was added
dropwise to the reaction mixture. A finely suspended solid was
filtered off using a fritted glass Buchner funnel and the filter cake
was washed with ethyl acetate. The filtrate was extracted with ethyl
acetate (3ꢁ20 mL), the combined organic layers were washed with
brine (3ꢁ15 mL), dried over Na2SO4 and concentrated under re-
duced pressure. The residue was subjected to flash chromatography
on silica gel (dichloromethane) to afford the title compound 11
(173 mg, 69%), as grey crystals, mp 142.5e144.0 ꢀC. 1H NMR
(300 MHz, CDCl3): dH 1.21 (s, 3H, 12-CH3), 1.30e1.45 (m, 1H, 10-Ha),
1.50e1.59 (m, 1H, 11-Ha), 1.62 (3H, s, 12-CH3), 1.64e1.83 (m, 3H, 11-
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ꢁ
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and references cited therein.
15. The CCDC deposition number of 12,12-dimethyl-8,9,10,11,11a,12-hexahy-
drobenzo[e]pyrido[1,2-a]indole 11 is 867552; formula: C18H21N1; unit cell pa-
ꢂ
rameters: a 22.0448(7), c 11.7136(4) A, space group I41/a.
16. Gilli, G.; Bertolasi, V.; Bellucci, F.; Ferretti, V. J. Am. Chem. Soc. 1986, 108, 2420.
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