Convenient synthesis of disubstituted tacrine derivatives via electrophilic and copper induced reactions

Article abstract of DOI:10.1016/j.tet.2016.07.012

The bromination of 2-aminobenzonitrile (2) with molecular bromine (2?equiv) furnished 2-amino-3,5-dibromobenzonitrile (7) in 98% yield. One-pot syntheses are described for dibromotacrine derivatives (6, 14–18) utilizing Friedl?nder reactions. A convenient route is described for disubstituted derivatives of tacrines from dibromotacrine 6 and 15 by various substitution reactions. Several disubstituted tacrines were synthesized by treatment of dibromo 6 and 15 derivatives with n-BuLi followed by trapping with an electrophile [Si(Me)₃Cl, S₂(Me)₂]. Both were converted to the corresponding cyano derivatives (21–23) via copper-assisted nucleophilic substitution reactions in moderate yields (30%, 50%, and 60%, respectively). Copper-induced nucleophilic substitution of dibromide 15 with NaOMe afforded mono methoxide 31 in 25% yield.

Full text of DOI:10.1016/j.tet.2016.07.012

Accepted Manuscript
Convenient synthesis of disubstituted tacrine derivatives via electrophilic and copper
induced reactions
Makbule Ekiz, Ahmet Tutar, Salih Ökten
PII:
S0040-4020(16)30635-4
10.1016/j.tet.2016.07.012
TET 27908
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 8 February 2016
Revised Date: 21 June 2016
Accepted Date: 4 July 2016
Please cite this article as: Ekiz M, Tutar A, Ökten S, Convenient synthesis of disubstituted tacrine
derivatives via electrophilic and copper induced reactions, Tetrahedron (2016), doi: 10.1016/
j.tet.2016.07.012.
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Graphical Abstract
Convenient Synthesis of Disubstituted Tacrine Derivatives via Electrophilic and Copper Induced
Reactions
Makbule Ekiz, Ahmet Tutar, Salih Ökten

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Convenient Synthesis of Disubstituted Tacrine Derivatives via Electrophilic
and Copper Induced Reactions
Makbule Ekiz,a,b Ahmet Tutar,*,b Salih Ökten*,c
aDepartment of Chemistry, Faculty of Art and Science, Düzce University, 81620, Düzce, Turkey
bDepartment of Chemistry, Faculty of Art and Science, Sakarya University, Serdivan, 54187, Sakarya, Turkey
cDepartment of Primary Education, Division of Science Education, Faculty of Education, Kırıkkale University,
Yahşihan, 71450, Kırıkkale, Turkey
*Corresponding Authors E-mail: atutar@sakarya.edu.tr, salihokten@kku.edu.tr Phone: +90 264 2956040; Fax:
+90 264 2955950

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Abstract: The bromination of 2-aminobenzonitrile (2) with molecular bromine (2 equiv)
furnished 2-amino-3,5-dibromobenzonitrile (7) in 98% yield. One-pot syntheses are described for
dibromotacrine derivatives (6, 14–18) utilizing Friedländer reactions. A convenient route is
described for disubstituted derivatives of tacrines from dibromotacrine 6 and 15 by various
substitution reactions. Several disubstituted tacrines were synthesized by treatment of dibromo 6
and 15 derivatives with n-BuLi followed by trapping with an electrophile [Si(Me)3Cl, S2(Me)2].
Both were converted to the corresponding cyano derivatives (21–23) via copper-assisted
nucleophilic substitution reactions in moderate yields (30%, 50%, and 60%, respectively). Copper-
induced nucleophilic substitution of dibromide 15 with NaOMe afforded mono methoxide 31 in
25% yield.
Keywords: Tacrine, bromotacrine, cyanotacrine, lithium-bromine exchange, thiomethyltacrine,
methoxytacrine.
1. Introduction
Acridine and its derivatives are in the class of well-known bioactive compounds that have
been commonly used as antimalarial and antibacterial agents.1-3 Moreover, tacrine (1, 9-amino-
1,2,3,4-tetrahydroacridine) is a reversible inhibitor of acetylcholinesterase, and it has been used as
a drug for treating Alzheimer’s disease4-7 since 1993. However, its serious side effects have
restricted its use against this disease.8,9 In recent years, studies have focused on using tacrines as
anticancer drugs10 due to the fact that tacrines and their derivatives can inhibit topoisomerase
enzymes and block the transcription of DNA.3
The importance of the synthesis of bioactive heterocyclic compounds such as indole,11
quinoline,12 acridine,13 and tacrine14 has led to the development of various synthetic methods such
as the Skraup, Friedländer, Doebner-von Millet, and Combes syntheses. The Friedländer
annulation reaction is one of the most well-known and straightforward approaches for the
synthesis of polysubstituted aromatic compounds with N functions.5,15-16 9-Amino-1,2,3,4-
tetrahydroacridine-1-ol, an effective anti-Alzheimer agent, has been prepared by a copper-assisted
Friedländer method.17 However, this method suffers from a long reaction time, low yields, harsh
reactions conditions, difficulties in work-up and expensive reagents.9,18 The reaction of
aminobenzonitriles and cyclic ketones may proceed in two possibilities: (i) Friedländer annulation
(cyclodehydration reaction) followed by intramolecular condensation or intramolecular imine

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formation,14,19 (ii) non Friedländer reaction via amide formation.15,19-21 Moreover, the Friedländer
method was performed in the presence of protic acids or various Lewis acids which effectively
promoted the cyclization reaction between anthranilonitrile and cyclohexanone.9 The catalyst has a
crucial effect on the conversion in the reactions. Lewis acids are more effective than Bronsted
acids15,19,22-23 and also Lewis acids directly effect the reaction mechanism and product variety. For
example, the normal Friedländer annulation products (quinoline, tacrine, acridine, etc.) were
furnished by AlCl3 while ZnCl3 gave quinazolinones.15,21
Halogenated aromatic compounds including a quinoline skeleton are used as precursors and
key compounds for numerous multifunctional heterocyclic compounds, undergoing metal-halogen
exchanges,12 couplings,24 and metal-assisted substitutions.12,25 This class of aromatic compounds
has been of interest to chemists16,24 due to its use as starting materials for numerous compounds
with pharmacological properties. For quinoline-based compounds, acridine, tacrine etc., ring
substitution by halogens is rather complex. In particular, direct bromination of N-functionalized
polycyclic aromatics is difficult because of their electron deficiencient nature and formation of N-
bromo complexes.23,25 Due to the difficulty in the preparation of bromotacrines, derivative
synthesis of them is often restricted.
Recent work has presented a novel approach to the synthesis of disubstituted tacrines, starting
from dibromo tacrines 6, 15 instead of Friedländer reaction between any 2-aminobezonitrile
substituted functional group and any ketone. Dibromo tacrines 6, 14–18 were prepared by
Friedländer quinoline reaction of several cyclic ketones (8–13) and brominated 2-
aminobenzonitrile (7) in the presence of different Lewis acids. The presence of the two bromine
atoms in tacrines (6, 15) makes them suitable candidates for further transformation through
transition metal-catalyzed or metal-halogen exchange to enable adequate diversity on the fused
benzo ring. The present study, to the best of our knowledge, is the first on brominated tacrine
derivatives. We describe convenient synthesis methods for dibromo-, methylthio-, cyano-,
trimethylsilyl-, and methoxytacrine derivatives.
2. Results and Discussion
The main goal of this work was to obtain polyfunctional bromo tacrine derivatives by
bromination of unsubstituted tacrines, because hetercyclic aromatics are key structures in a large
amount of pharmacological compounds. To achieve this goal, we first attempted to brominate 9-

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amino-1,2,3,4-tetrahdyroacridine (tacrine, 1) with Br2 under photolytic conditions. For irradiation,
an immersion photochemical apparatus with a projector lamp (50–650 W, visible light) was used.
However, tacrine 1 initially reacted with Br2 and produced bromine salt 5 (Scheme 1). The attempt
at bromination after protection of the N atom in the tacrine cycle treating with methyl iodine also
failed (Scheme 1).
Scheme 1. Attempts at bromination of 9-amino-1,2,3,4-tetrahydroacridine (1) to get bromotacrine
derivatives.
Due to problems with the direct bromination of tacrine to get polyfunctional brominated
tacrine derivatives, bromination of 2-aminobenzonitrile (2) was undertaken. Bromination of 2-
aminobenzonitrile (7) was reported with NBS in 77% yield.26 However, we treated 2-
aminobenzonitrile (2) with 2.2 eq Br2 in AcOH at 15–20 °C according to the literature.27 This
reaction furnished 2-amino-3,5-dibromobenzonitrile (7) in 98% yield as a sole product (Scheme
2).
Scheme 2. Bromination of 2-aminobenzonitrile 2 with molecular bromine. Reagents and
conditions. (a) Br2 (2.2 eq), AcOH, 15-20 °C, 10 min.

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In order to synthesize bromotacrine derivatives (6, 14–18), Friedländer reactions between 2-
amino-3,5-dibromobenzonitrile (7) and cyclic ketones (8–13) in the presence of some Lewis acids
were accomplished (Scheme 3, Table 1). The cyclodehydration reaction under toluene reflux was
further evaluated with several ketones and 2-amino-3,5-dibromobenzonitrile in the presence of
different Lewis acids. Cyclopentanone (8) and cyclohexanone (9) furnished lower yields of
products 14 (39%, conversion 74%) and 16 (68%, conversion 86%), respectively, compared to the
seven-membered ring product 15 (92%, conversion 100%) (Table 1, Entries 1, 3 and 5).
Furthermore, cyclic 1,3 diones (11–13) with 2-amino-3,5-dibromobenzonitrile under the same
reaction conditions furnished tacrine-1-one derivatives (16–18) with low yields (8%, 54%, and
14%, respectively) and low to good conversions (47%, 78% and 34%, respectively) (Table 1,
Entries 2, 4 and 6).
Scheme 3. Novel approach to synthesize bromotacrine derivatives (6, 14–18).
In this type of reaction, non Friedländer products can be formed according to the nature of
catalyst and reagents.15,19 2-Aminobenzonitriles with electron-withdrawing substituents on the
aromatic ring reacted with cyclic ketones to give the corresponding tacrines in lower yields but
also produced quinazolinone derivatives (i.e. 19 and 20) (Scheme 4) as non-Friedländer products
in higher yields than electron-donating substituted 2-aminobenzonitriles.15 The yields of some
products, especially cyclopentanone and cyclopentadione derivatives (14, 16) was low.
However, we did not obtain possible side products after the isolation process possibly due to the
fact that the reaction mixture was only extracted with CHCl3 for product isolation and also no
further purification was conducted. It is possible that the side products were not soluble in CHCl3.
Because, in the literature15,19 the reaction residue was dissolved in polar solvents such as acetone,
ethyl acetate, and then colomn chromatograpy was applied for isolation of the products.
Interestingly, 7-membered bromo tacrine derivative 15 was produced in higher yield (92%)
compared 14 and 6. Increasing the size of the cyclic ketone could suppress formation of the non
Friedländer product, quinazolinone derivatives (19 and 20) due to steric hinderance to formation

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of the amide cycle (Scheme 4), whereas 5-membered cyclic ketone may have facilitated the
formation of 19. Thus, all attempts to get 5-memebered tacrines (14 and 16) from cyclopentadione
11 and cyclopentanone 8 gave low yields.
Scheme 4. Synthesized 5 and 7 membered bromotacrines (14 and 15) and possible side products
(19 and 20).
Generally un-catalysed reaction process may lead to the non-Friedländer product,
quinazolinone,15 but the metal salt Lewis acids could control selectivity of formation of the
Friedländer or the non- Friedländer product.19 Lewis acids activated the ketones via coordination
and imine–enamine tautomerism may have occurred in the Friedländer reaction progress.9,19 In the
next step, Lewis acids can activate the nitrile group for intramolecular attack of the emanine
carbon to nitrile group. To determine the efficiencies of Lewis acids for our reaction, In(III),
Bi(III), Fe(III), Al(III) and Zn(II) chlorides were tested. Among the tested metal cholorides, the
most promising results were obtained with InCl3 for all tacrine derivatives (6, 14–18). Especially
the rection promoted with InCl3 afforded 15 in 92% yield with 100% conversion. The ability of
the Lewis acids to effectively promote the cyclodehydration between 2-amino-3,5-
dibromobenzonitrile (7) and cyclic ketones (8–13) was found to be the following order: InCl3 >
BiCl3 > FeCl3 > AlCl3 > ZnCl2 (Table 1).
Table 1. Reaction conditions for the synthesis of brominated tacrine derivatives (6, 14–18), yields
(%) and conversion (%)
Entry
Ketone Solvent Lewis Acid Conversion* Product, Yield
(%)
(%)
BiCl3
InCl3
14, 18
14, 39
1
toluene
74

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AlCl3
ZnCl2
BiCl3
InCl3
16, 0
16, 3
16, 5
16, 8
2
3
toluene
toluene
47
86
FeCl3
BiCl3
InCl3
6, 55
6, 58
6, 68
4
toluene
FeCl3
BiCl3
InCl3
17, 38
17, 42
17, 54
78
BiCl3
InCl3
15, 20
15, 92
5
6
toluene
toluene
100
BiCl3
18, 14
34
*Conversion was calculated for the highest product yield of each entry
13
Structures of all bromotacrines (6, 14–18) were determined by 1H NMR, C NMR, and FT-
IR spectroscopy and high resolution mass spectrometry. 1H NMR spectra of compounds 6, 14–15
1
consist of aryl Hs, alkyl Hs, and NH signals. The H NMR spectra of 6, 14, and 15 clearly show
dibromo structures due to two aryl signals with meta coupling constants (4J = 1.8 Hz). Three
aliphatic and NH shifts [3.18 (t), 2.88 (t), 2.27–2.17 (m), 4.53 (brs, NH)] are recorded for 14. In
13
the C NMR spectra of compounds 6, 14–15, the seven quaternary carbon resonances in the sp2
region are also in agreement with the proposed structure.
Preparation of dibromotacrine analogues (16–18) from cyclic diones (11–13) led to lower
yields (8%, 54%, and 14%, respectively) than the yields of dibromotacrines (6, 14-15) from mono
1
cyclic ketones (8-10). The H NMR spectra of 16, 17, and 18, which consisted of two meta
4
coupled (4J = 2.1 Hz and J = 1.8 Hz) aryl signals, matched quite well with the suggested
structures. Furthermore, the 13C NMR spectra of 16, 17, and 18 consisting of 10 aromatic signals
with C=O signals (δ 205.8, 202.0, and 207.0 ppm, respectively), were also in good agreement with
the proposed structures.
Bromo substituted tacrine derivatives are polyfunctional starting materials and precursors for
numerous substituted tacrine compounds. Moreover, to evaluate this potential we investigated the
metal-halogen exchange and the copper induced reactions of 6 and 15.

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Scheme 5. Synthesis of cyano tacrines (21–23). Reagents and conditions. (a) CuCN (6 eq), DMF,
4 h, 150 °C. (b) CuCN (9 eq), DMF, 6 h, 150 °C.
First the copper-induced cyanation of dibromotacrines (6 and 15) was investigated (Scheme
5). Compound 6 was reacted with CuCN in refluxing DMF to afford a mixture of cyanotacrines 21
and 22 (Scheme 5, Entry 1). The effect of equivalents of CuCN on the product ratio was
investigated and it was observed that 6 equivalents of CuCN gave a mixture of two cyanotacrine
derivatives, 21 and 22, that formed in a 32:50 ratio (conversion 82%, Entry 1), as assigned by 1H
NMR spectroscopy, whereas further equivalents of CuCN (9 equivalents) furnished dicyanide 23
in moderate yield (60%, Entry 3) as the sole product.
The structures of compounds 21, 22, and 23 and the position of the CN group were confirmed
1
13
by H and C NMR, HRMS, FT-IR, and 2D NMR (HMBC, HETCOR) analysis. In the HMBC
experiment of 21, a strong correlation (3JCH) was observed between the cyano carbon atom (δC
114.1 ppm) and the aromatic proton at H-3 (δH 7.98 ppm) while it (δC 114.1 ppm) was not
correlated with H-1 (δH 7.91 ppm), confirming the attachment of the cyano group at C-4. In the
FT-IR spectra of 9-amino-5,7-dicyano-1,2,3,4-tetrahydroacridine 22, a characteristic CN
1
stretching signal was observed at 2250 cm-1. Moreover, in the H NMR spectra of 9-amino-5,7-
dicyano-1,2,3,4-tetrahydroacridine 22, a downfield shift for H-3 (δH 9.04 ppm) was observed with
13
low coupling constant (4J = 1.6 Hz) and the doublet of H-1 was shown at δH 8.44 ppm. The C
NMR spectra of 22 consisted of nine aromatic carbons, and two sp resonances.
When 11-amino-2,4-dibromo-7,8,9,10-tetrahydro-6H-cyclohepta[b]quinoline (15) was treated
1
with CuCN in refluxing DMF, the H NMR spectrum indicated the formation of 11-amino-2,4-

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dicyano-7,8,9,10-tetrahydro-6H-cyclohepta[b]quinoline (23) as the sole product in 60% yield
(Scheme 5, Entry 3). In the 1H NMR spectrum of 23, signals for the aromatic protons H-1 and H-3
(δH 9.04 and 8.49, respectively) were shifted downfield when compared to signals of the starting
material 15 (H-1 and H-3; δH 7.99 and 7.79, respectively). Finally, the 13C NMR of 23 consisted of
nine sp2 resonances and two cyano resonances, as well as five sp3 resonances. Characteristic CN
carbon signals (δC 117.5 and 117.1) in the 13C NMR spectra and the stretching signal (2234 cm-1)
in the FT-IR spectra helped to confirm the structure of 23.
To demonstrate the value of 6 and 15 as starting materials for numerous useful compounds,
we investigated the metal-halogen exchange reaction of 6 and 15. After treatment with n-BuLi, the
reaction mixture in THF at -78 °C were trapped with dimethyl disulfide, trimethylsilyl chloride
and DMF respectively (Scheme 6). Trapping with dimethyl disulfide furnished 9-amino-7-bromo-
5-(methylthio)-1,2,3,4-tetrahydroacridine (24, 45%) as the sole product, while a mixture of 9-
amino-7-bromo-5-(trimethylsilyl)-1,2,3,4-tetrahydroacridine (25, 30%) and 9-amino-5,7-
bis(trimethylsilyl)-1,2,3,4-tetrahydroacridine (26, 11%) was obtained in low yields. However, the
carbaldehyde 27 product was not observed. To prevent deprotonation of the NH2 group, metal-
halogen exchange reactions wwere conducted at -78 °C. On the contrary, the amine could be
deprotonated with n-BuLi at moderate temperatures (10–22 °C), in literature,28 it was reported that
deprotonation of an NH2 group was not observed at lower temperatures (< -60 °C).
Scheme 6. Metal halogen exchange reactions of 6. Reagents and conditions. (a) n-BuLi (4.5 eq) in
THF, -78 °C, 1 h; (b) S2(CH3)2 (2.5 eq), 2 h, -78 °C, then 1 h, rt; (c) Si(CH3)3Cl (2.5 eq), 3 h, -78
°C, then 1 h, rt; (d) DMF (2.5 eq), 2 h, -78 °C, then 1 h, rt.

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1
The H NMR spectra confirmed the formation of compounds 24–26 by showing two silyl
signals in 26, one silyl signal in 25, and one thiomethyl signal in 24. In the 1H NMR spectrum, 25
displays the same signal system as dibromide 6, except with lower field shifting. In addition, 2D
NMR spectra provided information about the position of thiomethyl and trimethylsilyl substitution
occurring in which position in 25 and 26. In the HBMC spectra of 25, the thiomethyl H- atoms (δH
2.49 ppm) correlated with a quaternary C atom at δC 142.5 ppm, which showed that the thiomethyl
group was bonded to the C-5 atom in compound 24. In the HBMC spectra of 24, the C atom at δC
142.5 ppm correlated with a doublet at δH 7.23 ppm (H-6) but did not correlate with H-8 (δH 7.55
ppm), confirming that the thiomethyl group was substituted at C-5. In the HBMC spectra of 25,
the trimethylsilyl H atoms (δH 0.33 ppm) correlated with a quaternary C atom at δC 143.8 ppm.
Moreover, the C atom at δC 143.8 ppm correlated with a doublet at δH 7.62 ppm (H-6) but did not
correlate with H-8 (δH 8.04 ppm), which confirmed that the trimethylsilyl group was bonded to the
C-5 atom in compound 25.
Scheme 7. Metal halogen exchange reactions of 15. Reagents and conditions. (a) n-BuLi (4.5 eq)
in THF, -78 °C, 1 h; (b) S2(CH3)2 (2.5 eq), 2 h, -78 °C, then 1 h, rt; (c) Si(CH3)3Cl (2.5 eq), 3 h, -
78 °C, then 1 h, rt; (d) DMF (2.5 eq), 2 h, -78 °C, then 1 h, rt.
When 5,7-dibromide 15 was treated with n-BuLi in THF at -78 °C and then trapping with
S2(CH3)2, the NMR spectrum of 29 indicated the formation of mono thiomethyl substituted
tacrine 29. However, trapping with Si(CH3)3Cl furnished only bistrimethlysilyl substituted tacrine
1
28. In the H NMR spectrum, 2,4-bis(trimethylsilyl) 28 shows the same signal system as 2,4-
dibromide 15, except with upfield shifting. Moreover, the similarities of the signal systems for
compound 28 with those of 2,4-dibromide 15 were quite helpful in the identification of the
1
structures (Scheme 7). The H NMR spectrum of 28 consists of two doublet signals of aromatic

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protons H-1 and H-3 (δH 8.13 and 7.75 ppm, respectively) with meta coupling and also two
singlets (δH 0.27, 0.36) for two silyl groups.
The 1H NMR spectra of 29, which consisted of two aromatic signals (δH 7. 54 and 7.24 ppm),
four aliphatic multiplet signals of H- atoms (δH 3.11–3.14 (2H), 2.70–2.73 (2H), 1.84–1.88 (2H),
1.65–1.77 (4H)), and a singlet at δH 2.49 ppm (SCH3), matched quite well with the suggested
structure. Structural characterization of 29 was further confirmed by HRMS spectroscopy and 2D
2
NMR spectra. Compound 29 supported JCH couplings through an HMBC correlation, and
confirmed the positions of the SCH3 group (2- or 4-thiomethyl) and the aromatic protons H-1 and
H-3. The fact that C-4 (δC 142.4 ppm) correlated with both a singlet of SCH3 (δH 2.49 ppm) and a
meta coupled doublet (H-3, 4J= 2.1 Hz; δH 7.24) confirmed that the SCH3 group was substituted in
C-4, which is in agreement with the proposed structure for 29. In addition, the 13C NMR spectrum
of 29, consisting of fifteen signals, was also in good agreement with the proposed structure
(Scheme 7).
Lastly, treatment of dibromides (6 and 15) with MeONa was performed in the presence of CuI
in DMF at ca. 150 °C according to the literature method (Scheme 8).12 While the copper-induced
reaction of 15 resulted in the formation of mono methoxide 31 (25%), compound 6 did not react
with NaOMe.
Scheme 8. Synthesis of methoxytacrine (32). Reagents and conditions. (a) CH3ONa (30 eq), CuI
(0.5 eq), DMF, 150 °C, 24 h.
Structural characterization of the methoxide compound 31 was further confirmed by HRMS
2
and 2D NMR spectra. Methoxy derivative 31 provided JCH couplings through an HMBC
correlation, and confirmed the positions of the MeO group (2- or 4-methoxide) and the aromatic
protons H-1 and H-3. The fact that C-4 (δC 150.1 ppm) correlated with H-3 (δH 7.55 ppm, 4J= 1.7

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Hz) and characteristic OCH3 protons (δH 4.06 ppm) but not with H-1 (δH 8.31 ppm) confirmed that
the OCH3 group was attached to C-4.
3. Conclusions
We have developed a simple and convenient route to a variety of disubstituted tacrines by
Friedländer reactions starting with 2-amino-3,5-dibromobenzonitrile, which are difficult to
synthesize by direct bromination of tacrines due to the formation of N-bromo complexes and their
electron-deficient nature. Our study demonstrated a novel, and convenient approach to prepare
novel compounds 6, 14–18 expanding on the restricted studies in the literature to obtain
substituted tacrine derivatives. The novel synthesized compounds were fully characterized.
We started with 2-amino-3,5-dibromobenzonitrile (7) to prepare dibromotacrines (6, 14–18)
using the Friedländer method5,9 in the presence of Lewis acids. These compounds are synthetically
useful intermediates and functional compounds for substituted tacrines. InCl3 was found to be best
catalyst for cyclization reactions. Application of lithium-halogen exchange and copper-assisted
substitution reactions furnished disubstituted 22, 23, 26, 28, or monosubstitute
monobromotacrines 21, 24, 25, 28, and 31. The compounds 21, 24, 25, 28, and 31 can potentially
be converted to other disubstituted tacrines due to their bromine groups.
In conclusion, we have reported for the first time the synthesis of bromine-substituted tacrines
starting from 2-amino-3,5-dibromobenzonitrile (7). This paper presents a novel synthetic approach
to prepare disubstituted derivatives. Compounds 21–26, 28–29 and 31 may have anti-Alzheimer or
anticancer activity, in light of tacrine derivatives, commercially used for anti-Alzheimer drugs.
Recently, preliminary studies of anti-Alzheimer acvivites of disubstituted tacrines have been in
progress and we have obtained some promising results. If the bioactive potential of 21–26, 28–29
and 31 can be evaluated comprehensively, the results may contribute to cures for some illnesses
(Alzheimers’ disease, cancer etc.) in the future.
4. Experimental Section
General Experimental Methods. Thin layer chromatography was carried out on Merck silica F254
0.255 mm plates, and spots were visualized by UV at 254 nm. Flash column chromatography was
performed using Merck 60 (70–230 mesh) silica gel. Melting points were determined on a MPM-
H1 capillary melting points apparatus. Solvents were concentrated at reduced pressure. IR spectra

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were recorded on a Shimadzu Prestige-21 (200 VCE) FT/IR instrument. Mass spectra were
recorded on a Agilent 6530 Accurate-Mass spectrometer under electron-impact (EI) and chemical
1
ionization conditions. NMR spectra were recorded on a Varian Infinity Plus at 300 MHz for H
and at 75 MHz for 13C NMR and on an Agilent at 600 MHz for 2D NMR experiments.
4.1. Synthesis of 2-Amino-3,5-dibromobenzonitrile (7)
Bromine (3.52 g, 0.022 mol) was added dropwise to a magnetically stirred, cooled (ice-water bath)
solution of 2-aminobenzonitrile 2 (1.18 g, 0.01 mol) in acetic acid (30 mL) at 15–20 °C over 10
min. The reaction mixture was stirred at room temperature for 5 h, then added to ice-water (100
mL), and the white precipitate was collected by filtration. The precipitate was washed thoroughly
with water, and dried on Na2SO4 at room temperature to afford a white solid mass 7 (98%), mp =
155–156 °C (Lit27, 156 °C); Rf (30% EtAcO/hexane) = 0.37. 1H NMR (300 MHz, CDCl3): δ 7.73
(d, 4J = 2.3 Hz, 1 H), 7.48 (d, 4J = 2.3 Hz, 1 H), 4.90 (brs, 2 H) ppm. 13C NMR (75 MHz, CDCl3):
δ 146.4, 139.6, 133.8, 115.8, 109.9, 108.4, 98.1 ppm. All data were identical to that reported in the
literature.27
4.2. Synthesis of dibromotacrine derivatives
General Procedure for Tacrine Analogs. To a mixture of 2-amino-3,5-dibromobenzonitrile (1.0
mmol) and ketone (1.10 mmol) in toluene (12 mL) placed in a round bottom flask connected to a
reflux condenser was added Lewis acid (1.20 mmol). The mixture was heated at 120 °C for 24 h
under stirring. After cooling to room temperature, the remaining solids were treated with NaOH
solution (2 mol L-1, 12 mL) and this mixture was heated at reflux for 24 h. On cooling to room
temperature, the reaction mixture was extracted with CHCl3 (3 × 25 mL), and the organic layers
were combined and dried over Na2SO4. The solvent was evaporated under reduced pressure to
give the desired product. The procedures were performed under an argon atmosphere in the
presence of ZnCl2, InCl3, FeCl3, and BiCl3. The isolated products appeared to be sufficiently clean
and no further purification was conducted.
4.2.1. 9-Amino-5,7-dibromo-2,3-dihydro-1H-cyclopenta[b]quinoline (14). White solid (133 mg,
1
39%, isolated yield); m.p = 272-274 °C; Rf (10% MeOH/CHCl3) = 0.52. H NMR (300 MHz,
4
4
CDCl3): δ 8.01 (d, J = 1.8 Hz, 1 H, H-8), 7.82 (d, J = 1.8 Hz, 1 H, H-6), 4.53 (brs, 2 H, NH2),
3.18 (t, 3J = 6.0 Hz, 2 H, CH2, H-3), 2.88 (t, 3J = 6.0 Hz, 2 H, CH2, H-1), 2.27- 2.17 (m, 2 H, CH2,

ACCEPTED MANUSCRIPT
15
H-2). 13C NMR (75 MHz, CDCl3): δ 169.0 (C), 145.6, 144.8, 134.1 (CH), 125.0 (C), 124.2 (CH),
120.1 (C), 116.1, 115.4, 35.7 (CH2), 27.7 (CH2), 22.7 (CH2). HRMS (ESI) m/z: Calcd for
C12H1179Br2N2 [M + H]+ 340.9289; Found: 340.8948. IR (cm-1): 3456, 3338, 3222, 3081, 2956,
2050, 1980, 1738, 1635, 1477, 1359, 856, 778, 738, 666.
4.2.2. 9-Amino-5,7-dibromo-1,2,3,4-tetrahydroacridine (6). Yellow cubic crystals (241 mg,
1
68%, isolated yield); m.p = 174-175 °C; Rf (5% MeOH/CHCl3) = 0.25. H NMR (300 MHz,
4
4
CDCl3): δ 7.97 (d, J = 1.8 Hz, 1 H, H-8), 7.78 (d, J = 1.8 Hz, 1 H, H-6), 4.64 (brs, 2 H, NH2),
3
3
3.05 (t, J = 6.0 Hz, 2 H, CH2, H-4), 2.58 (t, J = 6.0 Hz, 2 H, CH2, H-1), 1.94-1.82 (m, 4 H, 2
CH2, H-1, H-3). 13C NMR (75 MHz, CDCl3): δ 160.6, 146.1, 142.6, 134.8, 125.9 (CH), 122.6,
119.2 (CH), 116.4, 112.3, 34.6 (CH2), 24.0 (CH2), 22.8 (2 CH2). HRMS (ESI) m/z: Calcd for
C13H1379Br2N2 [M + H]+ 354.9445; Found: 354.9002. FT-IR (cm–1): 3475, 3338, 3237, 3079,
2936, 2864, 1647,1478, 1350, 855, 733.
4.2.3. 11-Amino-6,8-dibromo-2,3,4,5-tetrahydro-1H-cyclohepta[1,2-b]quinoline (15). White
1
solid (339 mg, 92%, isolated yield); m.p = 194-196 °C; Rf (5% MeOH/CHCl3) = 0.38. H NMR
(300 MHz, CDCl3): δ 7.99 (d, 4J = 1.8 Hz, 1 H, H-1), 7.79 (d, 4J = 1.8 Hz, 1 H, H-3), 4.59 (brs, 2
H, NH2), 3.17 (t, 4J = 6.0 Hz, 2 H, CH2, H-6), 2.74 (t, 4J = 6.0 Hz, 2 H, CH2, H-6), 1.65-1.88 (m, 6
H, 3 CH2, H-7, H-8, H-9). 13C NMR (75 MHz, CDCl3): δ 166.6, 144.6, 142.5, 134.7, 126.2, 123.0,
120.2, 117.8, 117.1, 40.3, 32.2, 27.6, 27.0, 26.9. HRMS (ESI) m/z: Calcd for C14H1579Br2N2 [M +
H]+ 368.9602; Found: 368.9245. IR (cm-1): 3054, 3347, 3233, 2944, 2912, 2848, 1736, 1629,
1574, 1468, 1367, 786, 729, 691.
4.2.4. 9-Amino-5,7-dibromo-2,3-dihydro-1H-cyclopenta[b]quinolin-1-one (16). White solid (28
1
mg, 8%, isolated yield); m.p = 228-230 °C; Rf (10% MeOH/CHCl3) = 0.60. H NMR (300 MHz,
4
4
CDCl3): δ 8.18 (d, J = 2.1 Hz, 1 H, H-8), 7.94 (d, J = 2.1 Hz, 1 H, H-6), 4.89 (brs, 2H, NH2),
3.28-3.32 (m, 2 H, CH2, H-3), 2.78-2.82 (m, 2 H, CH2, H-2). 13C NMR (75 MHz, CDCl3): δ 205.8,
174.1, 151.4, 147.1, 138.1, 127.0, 125.1, 120.0, 116.9, 109.3, 35.8, 28.9. HRMS (ESI) m/z: Calcd
79
for C12H9 Br2N2O [M + H]+ 354.9082; Found: 354.9851. IR (cm-1): 3327, 3072, 3046, 2924,
1640, 1574, 1489, 1382, 1201, 1039, 823, 748.

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4.2.5. 9-Amino-5,7-dibromo-3,4-dihydroacridin-1(2H)-one (17). Light yellow cubic cyrstals
1
(199 mg, 54%, isolated yield); m.p = 158-160 °C; Rf (10% MeOH/CHCl3) = 0.72. H NMR (300
4
MHz, CDCl3): δ 8.11 (d, 4J = 1.8 Hz, 1 H, H-8), 7.90 (d, J = 1.8 Hz, 1 H, H-6), 3.17 (t, 3J = 6.0
Hz, 2 H, CH2, H-4), 2.74 (t, 3J = 6.0 Hz, 2 H, CH2, H-2), 2.15 (t, 3J = 6.0 Hz, 2 H, CH2, H-3), 1.67
(brs, 2 H, NH2). 13C NMR (75 MHz, CDCl3): δ 202.0, 165.5, 153.5, 144.6, 138.2, 126.2, 123.6,
120.1, 117.6, 107.3, 40.1, 35.0, 21.7. HRMS (ESI) m/z: Calcd for C13H1179Br2N2O [M + H]+
368.9238; Found: 368.8902. FT-IR (cm–1) 3334, 3186, 2948, 2874, 1644, 1532, 1478, 1008, 795,
670.
4.2.6. 11-Amino-2,4-dibromo-8,9-dihydro-6H-cyclohepta[b]quinolin-10(7H)-one (18). White
1
solid (54 mg, 14%, isolated yield); m.p = 132-134 °C; Rf (10% MeOH/CHCl3) = 0.75. H NMR
(300 MHz, CDCl3): δ 8.09 (d, 4J = 1.8 Hz, 1 H, H-1), 7.89 (d, 4J = 1.8 Hz, 1 H, H-3), 7.55 (brs, 2
H, NH2), 3.24 (t, 3J = 6.0 Hz, 2 H, CH2, H-6), 2.86 (t, 3J = 6.0 Hz, 2 H, CH2, H-9), 1.81-1.86 (m, 2
H, CH2, H-7), 1.97-2.01 (m, 2 H, CH2, H-8), 13C NMR (75 MHz, CDCl3): δ 207.0, 164.7, 152.5,
143.8, 137.7, 126.3, 123.5, 120.0, 117.7, 110.9, 42.7, 37.7, 24.1, 21.5. HRMS (ESI) m/z: Calcd for
C14H13N2 Br2O [M + H]+ 382.9395; Found: 382.9043. IR (cm–1) 3300, 3201, 2941, 2864, 2164,
79
2050, 1981, 1738, 1637,1610, 1533, 1457, 1402, 1189, 1047, 944, 861, 743, 656.
4.3. Synthesis of 5-cyano- and 5,7-dicyano-1,2,3,4-tetrahydroacridine derivatives
9-Amino-5,7-dibromo-1,2,3,4-tetrahydroacridine 6 (0.40 g, 1.12 mmol) was dissolved in freshly
distilled DMF (30 mL) and mixed with cuprous cyanide (0.60 g, 6.72 mmol, 6 eq). The reaction
mixture was stirred magnetically at reflux (~ca. 160 °C) under N2 for 4 h. The resulting solution
was cooled to room temperature and added to a stirred mixture of aqueous NH3 solution (d: 0.88
g/cm3, 28-30% (w/w), 30 mL) and ice (90 mL). The resulting mixture was stirred for 15 min. The
solid that separated was collected by filtration, washed with water (60 mL), and stirred with
dichloromethane (60 mL) for 30 min. The resulting suspension was filtered and the filtrate was
washed once with a small volume of water, dried (Na2SO4), and the solvent was evaporated. NMR
analysis of the residue indicated the formation 21 and 22 in a ratio of 32:50, respectively, and the
reaction conversion was 82%. The compounds were isolated with silica gel column
chromatography using AcOEt/hexane (1:4). 9-Amino-7-bromo-5-cyano-1,2,3,4-tetrahydroacridine
(21) was collected as the first eluent (51 mg, 30%), and then the solvent polarity was increased to

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a ratio of 1:2 (AcOEt/hexane). 9-amino-5,7-dicyano-1,2,3,4-tetrahydroacridine (22) (69 mg, 50%)
was isolated in pure form.
4.3.1. 9-Amino-7-bromo-5-cyano-1,2,3,4-tetrahydroacridine (21). Yellow needles (51 mg, 30%,
1
isolated yield); m.p = 142-144 °C; Rf (3% MeOH/CHCl3) = 0.68. H NMR (300 MHz, CDCl3) δ
7.98 (d, 4J = 2.1 Hz, 1 H, H-3) 7.91 (d, 4J = 2.1 Hz, 1 H, H-1), 4.70 (brs, 2H), 2.98 (t, 3J = 6.0 Hz,
2 H, CH2), 2.54 (t, 3J = 6.0 Hz, 2 H, CH2), 1.82-1.89 (m, 4 H, 2 CH2). 13C NMR (75 MHz, CDCl3)
δ 162.1, 146.1, 145.1, 137.2, 127.9, 118.7, 116.9, 115.2, 114.1 (CN), 112.9, 34.5, 24.0, 22.6 (2
CH2). HRMS (ESI) m/z: Calcd for C14H1379Br N3 [M + H]+ 302.0293; Found: 302.0021. IR (cm-1)
3482, 3390, 3344, 3244, 3010, 2951, 2856, 2233, 2051, 1980, 1739, 1637, 1491, 1365, 1350,
1228, 1216, 861,746.
4.3.2. 9-Amino-5,7-dicyano-1,2,3,4-tetrahydroacridine (22). Yellow needles (69 mg, 50%,
isolated yield); mp = 184-186 °C; Rf (3% MeOH/CHCl3) = 0.48. 1H NMR (300 MHz, DMSO-d6):
δ 9.04 (d, 4J = 1.6 Hz, 1 H, H-3), 8.44 (d, 4J = 1.6 Hz, 1 H, H-1), 7.09 (brs, 2 H, NH2), 3.30 (brs, 2
H, CH2, H-5), 2.86 (brs, 2 H, CH2, H-8), 2.49 (d, 3J = 6 Hz, 4 H, 2 CH2, H-6, H-7). 13C NMR (75
MHz, CDCl3) δ 163.1, 150.2, 147.3, 136.2, 134.5, 118.6, 117.2 (CN), 117.0 (CN), 112.4, 111.9,
104.2, 34.3, 24.0, 22.5, 22.3. HRMS (ESI) m/z: Calcd for C15H13N4 [M + H]+ 249.2905; Found:
249.1140. IR (cm-1) 3455, 3377, 3260, 3073, 2929, 2854, 2233, 1708, 1654, 1567, 1364, 1283,
980, 883, 789.
4.4. Synthesis of 11-amino-6,8-dicyano-2,3,4,5-tetrahydro-1H-cyclohepta[1,2-b]quinoline
(23)
11-Amino-6,8-dibromo-2,3,4,5-tetrahydro-1H-cyclohepta[1,2-b]quinoline 15 (0.50 g, 1.35 mmol)
was dissolved in freshly distilled DMF (33 mL) and mixed with cuprous cyanide (1.09 g, 12.2
mmol, 9 eq). The reaction mixture was stirred magnetically at reflux (appx. 160 °C) under N2 for 8
h. The resulting solution was cooled to room temperature and added to a stirred mixture of
aqueous NH3 solution (d: 0.88 g/cm3, 28-30% (w/w), 30 mL) and ice (90 mL). The resulting
mixture was stirred for 15 min. The solid that separated was collected by filtration, washed with
water (60 mL), and stirred with dichloromethane (60 mL) for 30 min. The resulting suspension

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18
was filtered and the filtrate was washed once with a small volume of water, dried (Na2SO4), and
the solvent was evaporated. The compounds were isolated with silica gel column chromatography
using AcOEt/hexane (1:2). 11-Amino-6,8-dicyano-2,3,4,5-tetrahydro-1H-cyclohepta[1,2-
b]quinoline (23) (210 mg, 60%) was isolated in pure form.
4.4.1. 11-Amino-6,8-dicyano-2,3,4,5-tetrahydro-1H-cyclohepta[1,2-b]quinoline (23). Yellow
cubic cyrstals (210 mg, 60%, isolated yield); m.p = 190-191 °C; Rf (3% MeOH/CHCl3) = 0.58. 1H
NMR (600 MHz, DMSO-d6) δ 9.04 (d, 4J = 1.5 Hz, 1 H, H-1), 8.49 (d, 4J =1.5 Hz, 1 H, H-3), 7.08
(brs, 2 H, NH2), 3.02-3.05 (m, 2 H, CH2), 2.79-2.82 (m, 2 H, CH2), 1.79-1.83 (m, 2 H, CH2), 1.62-
1.65 (m, 2 H, CH2), 1.52-1.56 (m, 2 H, CH2). 13C NMR (150 MHz, DMSO-d6) δ 169.7, 149.0,
147.5, 136.0, 134.6, 118.5, 118.0, 117.5, 117.1, 112.4, 105.0, 31.8, 27.4, 27.1, 26.6, 25.6. HRMS
(ESI) m/z: Calcd for C16H15N4 [M + H]+ 263.1297, Found: 263.1027. IR (cm–1) 3478, 3434, 3378,
3272, 3063, 2923, 2848, 2234, 1704, 1650, 1569, 1489, 1437, 1346, 1070, 802, 712.
4.5. Synthesis of 9-amino-7-bromo-5-(thiomethyl)-1,2,3,4-tetrahydroacridine (24)
n-Butyl lithium (1.18 mL, 2.5 M, 3.02 mmol, 4.5 eq) was added to a vacuum-dried ask containing
dibromide 6 (0.24 g, 0.67 mmol) in THF (15 mL) at -78 °C for 5 min and stirred for 90 min. Next,
S2(CH3)2 (0.15 mL, 1.68 mmol, 2.5 eq) was added to the mixture in the flask at -78 °C and the
final mixture was stirred at -78 °C for 120 min and then at 25 °C for 1 h. The mixture was
quenched with water (10 mL) and then the aqueous layer was extracted with diethyl ether (3 × 20
mL). The combined organic parts were washed sequentially with water (2 × 20 mL) and dried
over Na2SO4. The solvent was removed by reduced pressure, and the crude product was purified
using short silica gel column chromatography. The reaction mixture was applied to a short silica
gel chromatography column eluting with hexane/AcOEt (3:1). Compound 24 was iolated as a pale
yellow solid (49 mg, 25%).
4.5.1. 9-Amino-7-bromo-5-(thiomethyl)-1,2,3,4-tetrahydroacridin (24). Pale yellow solid (49
mg, 25%, isolated yield); m.p = 189-191 °C; Rf (3% MeOH/CHCl3) = 0.55. 1H NMR (300 MHz,
4
4
CDCl3) δ 7.55 (d, J = 1.5 Hz, 1 H, H-8), 7.23 (d, J = 1.5 Hz, 1 H, H-6), 4.54 (brs, 2 H, NH2),
3
3
3.03 (t, J = 6.0 Hz, 2 H, CH2, H-4), 2.58 (t, J = 6.0 Hz, 2 H, CH2, H-1), 2.49 (s, 3 H, SCH3),
1.89-1.92 (m, 4 H, 2 CH2, H-2, H-3). 13C NMR (75 MHz, CDCl3) δ 158.1, 145.8, 142.5 (C-5),
142.3, 124.3, 118.1, 117.7, 117.6 (C-8), 112.2 (C-6), 34.3 (C-4), 24.0 (C-1), 22.9 (C-2), 22.8 (C-
79
3), 14.5 (SCH3). HRMS (ESI) m/z: Calcd for C14H17N2 BrS [M + H]+ 323.0218; Found:

ACCEPTED MANUSCRIPT
19
322.9937. IR (cm–1) 3459, 3412, 3186, 2934, 2856, 2050, 1648, 1618, 1476, 1369, 1288, 978, 818,
710.
4.6. Synthesis of 5-trimethylsilyl- and 5,7-bis(trimethylsilyl)-1,2,3,4-tetrahydroacridine
derivatives
n-Butyl lithium (0.85 mL, 2.5 M, 8.87 mmol, 4.5 eq) was added to a vacuum-dried ask containing
dibromide 6 (0.24 g, 0.67 mmol) in THF (15 mL) at -78 °C for 5 min and stirred for 60 min. Next,
SiMe3Cl (0.54 mL, 4.93 mmol, 2.5 eq) was added to the mixture in the flask at -78 °C, and the
final mixture was stirred at -78 °C for 180 min and then at 25 °C for 1 h. The mixture was
quenched with water (10 mL) and then the aqueous layer was extracted with diethyl ether (4 × 40
mL). The combined organic parts were washed sequentially with water (2 × 20) and dried over
Na2SO4. The solvent was removed by reduced pressure, and the crude product was purified using
short silica gel column chromatography. The reaction mixture was applied to a short silica gel
chromatography column eluting with hexane/AcOEt (20:1). 25 (102 mg) 30% and 26 (37 mg)
11% were isolated in pure forms.
4.6.1. 9-Amino-7-bromo-5-(trimethylsilyl)-1,2,3,4-tetrahydroacridine (25). Colorless needles
(102 mg, 30%, isolated yield); m.p = 136-138 °C; Rf (20% CHCl3/hexane) = 0.90. 1H NMR (300
4
4
3
MHz, CDCl3) δ 8.04 (d, J = 2.4 Hz, 1 H, H-8), 7.62 (d, J = 2.1 Hz, 1 H, H-6), 2.96 (t, J = 6.0
Hz, 2 H, CH2, H-4), 2.74 (t, 3J = 6.0 Hz, 2H, CH2, H-1), 1.80-1.88 (m, 2 H, CH2, H-3), 1.70-1.78
13
(m, 2 H, CH2, H-2), 1.20 (brs, 2 H, NH2), 0.33 (s, 9 H, Si(CH3)3). C NMR (75 MHz, CDCl3) δ
158.7, 150.5, 149.8, 143.8 (C-5), 136.9 (C-6), 129.1, 129.0, 128.1 (C-8), 118.9, 33.8 (C-4), 27.0
(C-1), 22.9 (2 CH2, C-3, C-2), 2.24 (3 CH3, Si(CH3)3). HRMS (ESI) m/z: Calcd for
C16H2279BrN2Si [M + H]+ 349.0736, Found: 349.0622. IR (cm–1) 3748, 2952, 2856, 2163, 2087,
1567, 1543, 1454, 1327, 1251, 1147, 1093, 930, 828, 680.
4.6.2. 9-amino-5,7-bis(trimethylsilyl)-1,2,3,4-tetrahydroacridine (26). Colorless needles (37 mg,
1
11%, isolated yield); m.p = 121-122 °C; Rf (20% CHCl3/hexane) = 0.73. H NMR (300 MHz,
CDCl3) δ 8.15 (d, 4J = 1.5 Hz, 1 H, H-8), 7.77 (d, 4J = 0.9 Hz, 1 H, H-6), 3.01 (t, 3J = 6.0 Hz, 2 H,
CH2, H-4), 2.78 (t, 3J = 6.0 Hz, 2 H, CH2, H-1), 1.95-1.90 (m, 2 H, CH2, H-2), 1.86-1.80 (m, 2 H,
CH2, H-3), 1.20 (brs, 2 H, NH2), 0.37 (s, 9H, Si(CH3)3), 0.29 (s, 9 H, Si(CH3)3). 13C NMR (75
MHz, CDCl3) δ 159.3, 152.7, 152.0, 139.5, 138.9, 135.6, 133.2, 129.1, 127.4, 34.7, 27.8, 23.9 (2

ACCEPTED MANUSCRIPT
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CH2), 3.17 (6 CH3). HRMS (ESI) m/z: Calcd for C19H31N2Si2 [M + H]+ 343.2026, Found:
343.8971. IR (cm–1) 3749, 2949, 2898, 2843, 2086, 1735, 1546, 1452, 1256, 1247, 1058, 922, 812.
4.7. Synthesis of 11-amino-6,8-bis(trimethylsilyl)-2,3,4,5-tetrahydro-1H-cyclohepta[1,2-
b]quinoline (28)
n-Butyl lithium (2.40 mL, 2.5 M, 6.08 mmol, 4.5 eq) was added to a vacuum-dried ask containing
dibromide 15 (0.50 g, 1.35 mmol) in THF (15 mL) at -78 °C for 5 min and stirred for 60 min.
Next, SiMe3Cl (0.43 mL, 3.38 mmol, 2.5 eq) was added to the mixture in the flask at -78 °C, the
final mixture was stirred at -78 °C for 180 min and then 25 °C for 1 h. The mixture was quenched
with water (10 mL) and the aqueous layer was extracted with diethyl ether (4 × 40 mL). The
combined organic parts were washed sequentially with water (2 × 20) and dried over Na2SO4.
After removing the solvent under reduced presure, the crude product was applied to column
chromatography eluting with hexane. Compound 28 was isolated as a white solid (156 mg, 65%).
4.7.1. 11-Amino-6,8-bis(trimethylsilyl)-2,3,4,5-tetrahydro-1H-cyclohepta[1,2-b]quinoline (28).
1
White solid (156 mg, 65%, isolated yield); m.p = 99-100 °C; Rf (20% CHCl3/hexane) = 0.80. H
4
4
NMR (300 MHz, CDCl3) δ 8.13 (d, J = 1.2 Hz, 1 H, H-1), 7.75 (d, J =1.2 Hz, 1 H, H-3), 3.08-
3.12 (m, 2 H, CH2), 2.93-2.97 (m, 2 H, CH2), 1.58-1.80 (m, 6 H, 3 CH2), 1.20 (brs, 2 H, NH2),
0.27 (s, 9 H, 3 CH3, Si(CH3)3), 0.36 (s, 9 H, 3 CH3, Si(CH3)3). 13C NMR (75 MHz, CDCl3) δ
164.7, 152.4, 150.6, 139.8, 138.8, 135.9, 134.0, 133.8, 127.4, 41.6 (CH2), 33.1 (CH2), 29.5 (CH2),
28.0 (2 CH2), 2.70 (6 CH3). HRMS (ESI) m/z: Calcd for C20H33N2Si2 [M + H]+ 357.2182; Found:
357.2062. IR (cm–1) 3749, 2949, 2898, 2843, 2086, 1735, 1546, 1452, 1256, 1247, 1058, 922, 822.
4.8. Synthesis
of
the
11-amino-8-bromo-6-(thiomethyl)-2,3,4,5-tetrahydro-1H-
cyclohepta[1,2-b]quinoline (29)
n-Butyl lithium (2.40 mL, 2.5 M, 6.08 mmol, 4.5 eq) was added to a vacuum-dried ask containing
dibromide 15 (0.50 g, 1.35 mmol) in THF (30 mL) at -78 °C for 5 min and stirred for 60 min.
Next, 1,2-dimethyldisulfite S2(CH3)2 (0.28 mL, 3.38 mmol, 2.5 eq) was added to the mixture at -
78 °C, and the final mixture was stirred at -78 °C for 120 min and then at 25 °C for 2 h. The
mixture was quenched with water (10 mL) the aqueous layer was extracted with diethyl ether (3 ×
20 mL). The combined organic parts were washed sequentially with water (3 × 20 mL) and dried

ACCEPTED MANUSCRIPT
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over Na2SO4. After removing the solvent under reduced presure, the crude product was applied to
column chromatography eluting with hexane/AcOEt (5:1). Compound 29 was obtained as white
solid (319 mg, 70%).
4.8.1. 11-Amino-8-bromo-6-(thiomethyl)-2,3,4,5-tetrahydro-1H-cyclohepta[1,2-b]quinoline
(29). White solid (319 mg, 70%, isolated yield); m.p = 211-213 °C; Rf (3% MeOH/CHCl3) = 0.75.
4
4
1H NMR (300 MHz, CDCl3) δ 7.54 (d, J = 2.1 Hz, 1 H, H-3), 7.24 (d, J = 2.1 Hz, 1 H, H-1),
4.60 (brs, 2H, NH2), 3.11-3.14 (m, 2 H, CH2, H-6), 2.70-2.73 (m, 2 H, CH2, H-10), 2.49 (s, 3 H,
13
SCH3), 1.84-1.88 (m, 2 H, CH2, H-8), 1.65-1.77 (m, 4 H, 2 CH2, H-7, H-9). C NMR (75 MHz,
CDCl3) δ 164.4, 144.6, 142.4 (C-4), 142.1 (C-2), 124.4 (C-1), 118.7, 118.6, 118.3 (C-3) , 117.7,
40.1 (C-6), 32.3 (C-8), 27.7 (C-9), 27.1 (C-7), 26.8 (C-10), 14.6 (SCH3). HRMS (ESI) m/z: Calcd
for C15H1879BrN2S [M + H]+ 337.0374; Found: 337.0267. IR (cm–1) 3501, 3413, 3020, 2910, 2845,
2042, 1738, 1617, 1578, 1471, 1370, 1217, 1051, 956, 832, 789.
4.9. Synthesis of 11-amino-8-bromo-6-methoxy-2,3,4,5-tetrahydro-6H-cyclohepta[1,2-
b]quinoline (31)
Freshly cut Na (0.50 g, 30 mmol) was added to dry MeOH (15 mL) under nitrogen atmosphere.
After Na in MeOH fully remelted, DMF and vacuum-dried CuI (0.13 g, 0.68 mmol) were added
to
the
reaction
mixture.
Next,
11-amino-2,4-dibromo-7,8,9,10-tetrahydro-6H-
cyclohepta[b]quinoline (15) (0.50 g, 1.35 mmol) in DMF (15 mL) was added to the mixture,
which was stirred magnetically under N2 atmosphere at reflux (ca. 150 °C) for 24 h. The reaction
progress was monitored by TLC. After cooling to rt, H2O (30 mL) was added to the mixture, and
the aqueous layer was extracted with CHCl3 (3 × 50 mL). The organic layers were combined,
washed with H2O (3 × 25 mL), and dried (Na2SO4). After filtration and removal of the solvent, the
mixture was purified by short silica gel (SiO2) column chromatography, eluting with
AcOEt/hexane (9:1). Methoxide 31 was obtained as white cubic crystals (108 mg, 25%).
4.9.1. 11-Amino-8-bromo-6-methoxy-2,3,4,5-tetrahydro-6H-cyclohepta[1,2-b]quinoline (31).
White cubic crystals (108 mg, 25%, isolated yield); m.p = 225-227 °C; Rf (25% MeOH/CHCl3) =
1
0.75. H-NMR (300 MHz, CDCl3): δ 8.31 (d, 4J = 1.7 Hz, 1 H, H-1), 7.55 (d, 4J = 1.7 Hz, 1 H, H-
3), 4.06 (s, OCH3), 3.25-3.23 (m, 2 H, CH2, H-6), 2.86-2.85 (m, 2 H, CH2, H-10), 2.49 (brs, 2 H,
NH2), 1.52-1.79 (m, 6 H, 3 CH2, H-7, H-8, H-9) ppm. 13C NMR (75 MHz, CDCl3): δ 158.6, 153.9,

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150.1, 127.6, 119.4, 118.0, 117.4 (C-1), 116.7, 115.4 (C-3), 57.7 (OCH3), 32.4 (C-6), 31.2 (C-7),
26.2 (C-8), 25.5 (C-9), 25.0 (C-10) ppm. HRMS (ESI) m/z: Calcd for C15H1879BrN2O [M + H]+
321.0603; Found: 321.0481. IR (cm–1) 3623, 3258, 3113, 3013, 2920, 2852, 1736, 1664, 1576,
1501, 1268, 1071, 840, 673.
5. Acknowledgements
This study was supported by grants from the Sakarya University Research Fund (Project number:
2014-02-04-008).
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