Synthesis and evaluation of novel 2,4-disubstituted arylthiazoles against T. BruceI

Article abstract of DOI:10.1039/c9md00478e

The design, synthesis and pharmacological evaluation of the 4-substituted-2-[3-(adamant-1-yl)-4-fluorophenyl]thiazoles 1a-j, the 4-substituted-2-[4-(adamant-1-yl)phenyl]thiazoles 2a-h, the 2-substituted-4-[4-(adamant-1-yl)phenyl]thiazoles 3a-e, the N-subs

Full text of DOI:10.1039/c9md00478e

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RESEARCH ARTICLE
Synthesis and evaluation of novel 2,4-
disubstituted arylthiazoles against T. brucei†
Cite this: DOI: 10.1039/c9md00478e
a
a
a
*
Markos-Orestis Georgiadis,
Violeta Kourbeli,
Ioannis P. Papanastasiou,
Andrew Tsotinis, a Martin C. Taylor b and John M. Kellyb
The design, synthesis and pharmacological evaluation of the 4-substituted-2-[3-(adamant-1-yl)-4-
fluorophenyl]thiazoles 1a–j, the 4-substituted-2-[4-(adamant-1-yl)phenyl]thiazoles 2a–h, the 2-substituted-
4-[4-(adamant-1-yl)phenyl]thiazoles 3a–e, the N-substituted 2-phenylthiazol-4-ethylamides 4a, b and the
N-substituted 4-phenylthiazol-2-ethylamides 4c, d is described. Compounds 1a and 2a exhibit trypanocidal
activity in the range of IC50 = 0.42 μM and IC50 = 0.80 μM, respectively. Both of these derivatives bear a li-
pophilic end, which consists of a 4-(1-adamantyl) phenyl or a 3-(1-adamantyl)phenyl moiety, a 1,3-thiazole
ring and a functional end, which comprises of an alkylamine and can be considered as promising candi-
dates for the treatment of Trypanosoma brucei infections.
Received 8th October 2019,
Accepted 22nd November 2019
DOI: 10.1039/c9md00478e
rsc.li/medchem
Research Foundation (GNF) have described the amide and
Introduction
urea derivatives of thiazolethylamines I, II and sulfonamides
The African sleeping sickness and the Chagas disease are two
of the major neglected tropical diseases (NTDs). The trypano-
somiases are vector-borne parasitic infections caused by flag-
ellated protozoa of the class Kinetoplastida.1 There are two
species of human-infectious trypanosomes, Trypanosoma
brucei, that causes human African trypanosomiasis (HAT),
and Trypanosoma cruzi, which is responsible for the Chagas
disease. HAT is prevalent in sub-Saharan Africa, transmitted
by the bite of a tsetse fly infected with one of the two subspe-
cies, Trypanosoma brucei gambiense or Trypanosoma brucei
rhodesiense. The Chagas disease is spread predominantly in
Latin and Central America by Triatominae bugs infected with
T. cruzi.2,3 Trypanosomiases, as with other NTDs, are becom-
ing public health problems in non-endemic countries, as a re-
sult of travel and migration. New drugs are urgently required,
as those that are currently available are characterized by side-
effects and treatment failures.4,5
III, shown in Fig. 1, as potent trypanocidals.6,7
Based on these findings and our involvement in the
adamantane chemistry,9–20 we report herein on the chemistry
and biology of thiazole derivatives of the general type scaffold
IV. The thiazole moiety is an important pharmacophore in many
compounds used against several tropical infectious diseases.21
Scaffold IV includes a 1,3-thiazole moiety, which is 2,4-
disubstituted. One substituent is the lipophilic end of the
scaffold, which consists of a phenyl ring bearing fluoro- and
1-adamantyl-functionalities. The 4-(1-adamantyl)phenyl sub-
stituent has been proven to be well tolerated and is endowed
with trypanocidal properties.22 The thiazole ring bears a vari-
ety of functional groups (Fig. 2).
2-Phenylthiazol-4-ethylamines 1a–d and 2a–d share the
same structural features, apart from the relative position of
the 1-adamantyl core and the addition of a fluoro-substituent
in series 1. Fluorine alters the biophysical and chemical prop-
erties, such as lipophilicity, acidity, as well as the reactivity
Various initiatives6–8 have led to the discovery of promis-
cuous trypanocidal derivatives from phenotypic high-
throughput screening of a number of compound libraries.
These have been further refined and optimized to enhance
drug-like properties. The Walter and Eliza Hall Institute
(WEHI), in partnership with the Drugs for Neglected Diseases
initiative (DNDi), and the Genomics Institute of the Novartis
a Division of Pharmaceutical Chemistry, Department of Pharmacy, School of Health
Sciences, National and Kapodistrian University of Athens, Panepistimioupoli-
Zografou, 157 84 Athens, Greece. E-mail: papanastasiou@pharm.uoa.gr
b Department of Pathogen Molecular Biology, London School of Hygiene and
Tropical Medicine, Keppel Street, London WC1 E7HT, UK
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c9md00478e
Fig. 1 General type scaffolds with trypanocidal activity.
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Compounds 4a, c bear the same thiazole ring substituents as
derivatives 2 and 3. Additionally, the adamantane core was
replaced in the camphor skeleton in adducts 4b, 4. The latter
molecules are sulfonamides in alignment with the scaffolds
of compounds III.7
Results and discussion
Synthesis
The 4-substituted-2ij3-(adamant-1-yl)-4-fluorophenyl]thiazoles
1a–j were synthesized as shown in Scheme 1. As starting mate-
rial, for the synthesis of thiazoles 1a–j, the (3-adamant-1-yl)-(4-
fluorophenyl)boronic acid (6) was used. The reported method
for the preparation of the boronic acid 6 (ref. 28) has been modi-
fied, by changing the reaction times. The synthetic route in-
volved a Suzuki–Miyaura palladium-catalyzed coupling between
the boronic acid 6 and the 2-thiazole bromide 7 (ref. 6) to pro-
vide the phthalimide protected adamantane derivative 8. The
hydrazinolysis of phthalimide derivative 8 led to the deprotected
parent compound 2-{2-[3-(adamant-1-yl)-4-fluorophenyl]thiazol-
4-yl}ethan-1-amine (1a), which was subsequently methylated, di-
methylated,29 acylated and carbamoylated to deliver adducts
1b–j, via the procedures shown in Scheme 1.
Fig. 2 Novel thiazole derivatives 1a–j, 2a–h, 3a–e, 4a–d.
The synthesis of the 4-substituted-2ij4-(adamant-1-
yl)phenyl]thiazoles 2a–d was realized following two synthetic
pathways, as illustrated in Scheme 2. The key-compound for
the preparation of the thiazoles 2a–h, the 2-{2-[(2-(adamant-1-
and conformation of the substituted derivatives.23 In 2018,
18 out of the 38 small drug molecules, that were approved by
the FDA, contain a fluorine atom.24,25 Derivatives 3 differ in
the thiazole moiety compared to adducts 1 and 2. The 2,4-
substituents of the thiazoles 2a, c have their positions
switched in derivatives 3c, d. The functionalization of the
amino-end of congeners 1 involves various amide (aromatic
and non-aromatic) and urea substituents. In adducts 2, the
polar heads were translocated to the functional end of the
general type scaffold IV. The length of the side chain of deriv-
atives 2e, 2g and 3e was kept at the distance of three atoms
(2C and 1N and vice versa), which in the derivatives I, II and
III was found to be the optimal length for enhanced
trypanocidal potency.6–8 The length of the R group is differ-
ent in adducts 2f, h and 3a, b. 2-Aminothiazole (adduct 3a),
is a frequent-hitting fragment in biophysical binding as-
says.26 Moreover, an analogous thiazole guanidinium system
of derivative 3e has been used as a substitute for other aro-
matic rings improving biological activity.27
yl)phenyl)thiazol-4-yl]ethyl}isoindoline-1,3-dione
(10)
was
obtained via two different synthetic routes. The first involves
a Suzuki–Miyaura30 palladium-catalysed coupling between
the 4,4,5,5-tetramethyl-2-[4-(adamant-1-yl)phenyl]-2H-1,3,2-di-
oxaborolane (9)31 and the 2-thiazole bromide 7, which led to
the protected precursor 10. The second synthetic approach,
towards the thiazole adduct 10, was based on the Hantzsch
condensation32 of thiobenzamide 14 with the α-bromoketone
15.6 Our lab has previously published the preparation of the
4-(adamant-1-yl)benzoic acid (12),31 which was now obtained
by a different transition metal ion catalyzed oxidation of
1-(4-tolyl)adamantane (11).33 The reported method of oxida-
tion34 was modified as the reaction mixture was bubbled with
oxygen gas and heated at 105 °C for 6 h. The benzoic acid 12
was subsequently converted to the corresponding benzamide
13 and the thiobenzamide 14. Comparing the two methods,
the first involves 5 steps (17% total yield), while the second 6
steps (25% total yield), a more facile work-up and cheaper
The relative position of the adamantane cage, the phenyl
ring and the thiazole moiety was altered in derivatives 4a, c.
Scheme 1 Reagents and conditions: (a) i. n-BuLi, THF, −78 °C, 20 min, ii. (i-PrO)3B, r.t. 18 h, 90%; (b) PdIJPPh3)4, Na2CO3, anh. toluene, 80 °C, 18 h,
80%; (c) H2NNH2.H2O, EtOH, reflux, 1 h; (d) i. ClCOOEt, NEt3, THF, r.t. 18 h, ii. LiAlH4, THF, reflux 4 h, iii. EtOH, H2O, NaOH 10%, 0 °C, 88% from 8;
(e) MeONa, CH3COOH, HCHO 38% in H2O, NaBH3CN, MeOH, r.t. 18 h, 75% from 8. (f) Benzoyl chloride (1f: 96% from 8) or 4-fluorobenzoyl chlo-
ride (1g: 93% from 8) or 1-piperidinecarbonyl chloride (1j: 36% from 8) or 1-pyrrolidinecarbonyl chloride (1i: 46% from 8), Et3N, EtOAc, r.t. 18 h; (g)
acetic anhydride (1d: 84% from 8) or butyric anhydride (1e: 92% for 8), Et3N, EtOAc, r.t. 48 h; (h) 3-methyl-furoic acid, EDCI, HOBt, DMAP, DMF/
DCM, 45 °C, 18 h, 29% from 8.
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Scheme 2 Reagents and conditions: (a) PdIJPPh3)4, Na2CO3, anh. toluene, 80 °C, 18 h, 87%; (b) O2, NaBr, MnIJOAc)2, CoIJOAc)2, AcOH/dioxane, 90
°C, 6 h, 89%; (c) i. SOCl2, 65 °C, 45 min, ii. aq. NH3, 25%, r.t. 1 h, 96%; (d) Lawesson's reagent, dioxane, 110 °C, 2 h, 50%; (e) i-PrOH, autoclave, 120
°C, 18 h, 65%; (f) H2NNH2·H2O, EtOH, reflux 1 h; (g) acetic anhydride, Et3N, EtOAc, r.t. 48 h, 53% from 10; (h) i. ClCOOEt, NEt3, THF, r.t. 18 h, ii.
LiAlH4, THF, reflux 4 h, iii. EtOH, H2O, NaOH 10%, 0 °C, 54% from 10; (i) MeONa, CH3COOH, HCHO 38% in H2O, NaBH3CN, MeOH, r.t. 18 h, 85%
from 10.
reagents. The parent thiazole 2a was methylated, dimethyl-
ated and acetylated to the respective congeners 2b–d, as pre-
viously shown.
The 1-adamantylcarbonylamides 4a, c and the ( )-10-
camphorsulfonyl amides 4b, d were obtained upon coupling
the commercially available 1-adamantylcarboxylic acid and
( )-10-camphorsulfonyl chloride with the 2-phenylthiazol-4-
ethylamine (22)6 and the 4-phenylthiazol-2-ethylamine (23),7
respectively. The acid reacted in the presence of the coupling
reagent HBTU, while the chlorides reacted without the aid of
any activating reagent (Scheme 5).
The functionalized thiazoles 2e–h were obtained by the
route shown in Scheme 3. The thiobenzamide 14 was con-
densed with 1,3-dichloroacetone and 4-chloroacetoacetate, un-
der Hantzsch reaction conditions, to give the chloro-
methylthiazole 15 and the thiazolethyl acetate 16, respectively.
Treatment of the choromethylthiazole 15 with KCN or KSCN
led to the respective cyanide 2e and the thiocyanide 2f. The
thiazolethyl acetate 16 was reduced to the corresponding alco-
hol 2g, which was then converted to the azide 2h, via activa-
tion of the methanesulphonyl derivative 17.
The synthesis of the 2-substituted-4-{4-(adamant-1-
yl)phenyl}thiazoles 3a–d and the guanidyl derivative 3e, is
shown in Scheme 4. (1-Phenyl)adamantane (18)4 was acylated
under Friedel–Crafts reaction conditions36 to deliver the cor-
responding α-bromoketone 19, which via a Hantzsch conden-
sation with the appropriate reagent, thiourea,37 thioamides
20,38 21 (ref. 7) and guanylthiourea provided the desired thia-
zoles 3a–c and 3e, respectively. The dimethylthiazole 3d was
prepared from the parent thiazole 3c, as shown before.
Pharmacology
The 27 new thiazole derivatives were tested for their activity
against the bloodstream form Trypanosoma brucei and the re-
sults are shown in Table 1.
It is apparent from the test results that the ethylamines
1a–c exhibit the highest activity among the new 2,4-
disubstituted arylthiazoles. Bulkier substituents than the
methyl group at the amino end have a negative impact on
trypanocidal activity. Amido adducts (alkyl 1d and 1c, the aro-
matic 1f and 1g and the heteroaromatic 1h) and the ureido
derivatives, 1i and 1j, have a non-significant activity. The
same pattern is also observed in the 2 series, as compounds
Scheme 3 Reagents and conditions: (a) 1,3-dichloroacetone, acetone, reflux, 18 h, 75%; (b) KCN, anh. DMF, 60 °C, 36 h (2e: 41%) or KSCN, EtOH,
45 °C, 18 h (2f: 67%); (c) 4-chloroacetoacetate, i-PrOH, autoclave, 120 °C, 18 h, 92%; (d) i. LiAlH4, THF, r.t. 2 h, ii. EtOH, H2O, NaOH 10%, 0 °C,
80%; (e) MsCl, Et3N, DCM, 0 °C then r.t. 18 h, 95%; (f) NaN3, anh. DMF, 60 °C, 2 h, 65%.
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Scheme 4 Reagents and conditions: (a) BrCOCH2Br, AlCl3, DCM, −10 °C then r.t. 18 h, 57%; (b) appropriate thiobenzamide 20 (3b: 36%), 21 (3c:
85%), i-PrOH, autoclave, 120 °C 18 h or thiourea (3a: 88%), EtOH, reflux, 18 h; (c) MeONa, CH3COOH, HCHO 38% in H2O, NaBH3CN, MeOH, r.t. 18
h, 85%; (d) guanylthiourea, EtOH, reflux, 18 h, 89%.
2a–c are ca. 20 times more active than their acetamido conge-
ner 2d. Comparing series 1 and 2, it becomes apparent that
the fluorine substitution has little positive effect on the activ-
ity. The dimethylamino isomeric thiazoles 2c and 3d present
almost the same potency, while the nor-derivatives, the iso-
meric thiazoles 2a and 3c, show a substantial difference in
potency. The 2-phenylthiazol-4-ethylamines 1a, c and 2a, c
seem to be, in general, more potent than their isomeric
4-phenylthiazol-2-ethylamines 3c and 3d. The decrease of the
length of the side chain does not enhance activity.
Methanamine 3b bears two atoms (carbon and nitrogen) in
its side chain and is twice as potent as the 2-aminothiazole
3a, which has only one nitrogen atom. The polar
functionalization of the side chain did not improve the
trypanocidal activity. The azido and cyano-tailored derivatives
2e and 2h are less potent, and the thiocyanate 2f, the ethanol
2g and the guanyl derivative 3e exhibit modest activity. The
change in the relative position of the adamantane cage, the
phenyl ring and the thiazole moiety, in adducts 4a and 4c,
did not lead to activity enhancement. Last, the replacement
of the adamantane skeleton by the camphorsulfonyl moiety
in derivatives 4b and 4d has not led to antitrypanosomal en-
hancement. The 2,4-disubstituted arylthiazole adamantane
derivatives, the ethylamines 1a–c and 2a–c, present a notable
pharmacological profile, which merits further investigation
in terms of activity and toxicity. These findings suggest that
an aliphatic amine moiety at the side chain is mandatory to
achieve notable trypanocidal activity. This amine group is
positively charged at the cytosolic pH, which is not the case
for all the other polar heads tested. The presence of this par-
ticular group might also enhance the cellular accumulation
into the protozoa, as it is reported in the case of bacteria.39,40
Thus, the ethylamines 1a–c and 2a–c seem to exhibit promis-
ing trypanocidal properties, although further optimisation
will be necessary to reduce their cytotoxicity and to develop a
more drug-like profile.
Conclusions
In this work, we describe the synthesis of a new series of
aromatic 2,4-disubstituted 1,3-thiazole analogues with
trypanocidal potency. Among their congeners, the
2-phenylthiazol-4-ethylamines 1a–c and 2a–c presented the
most significant trypanocidal activity against T. brucei. Ana-
logues 1a and 2a exhibit antitrypanosomal activity in the range
of IC50 = 0.42 μM and IC50 = 0.80 μM, respectively. Primary
amine 2a is less potent than its congener 1a, but exhibits
higher selectivity, which is a promising perspective for design-
ing new trypanocidals in the future. Both of these classes of
derivatives bear
a lipophilic end, which consists of a
4-(1-adamantyl)phenyl or a 3-(1-adamantyl)phenyl moiety, a
1,3-thiazole ring and a functional end, which comprises of an
alkylamine. The addition of the adamantane ring into the scaf-
fold of the thiazole reference compounds6,7 has not improved
their pharmacological profile, in terms of activity and toxicity.
On the other hand, the new congeners exhibit promising
trypanocidal properties that merit further investigation. These
tailored-made structural modifications will be implemented in
the future in the design of trypanocidal agents.
Experimental part
Biology
Cytotoxic activity against rat skeletal myoblast L6 cells. Cy-
totoxicity against mammalian cells was assessed using micro-
titre plates. Briefly, L6 cells (a rat skeletal muscle line) were
seeded at 1 × 104 mL−1 in 200 μL of growth medium
containing 7 different compound concentrations in a range
previously established to encompass both the IC50 and IC90
values. The plates were incubated for 6 days at 37 °C and 20
μL Alamar Blue (Biosource UK Ltd) was then added to each
well. After an additional 8 hours incubation, the fluorescence
was determined using a FLUOstar Omega fluorescent plate
reader (BMG Labtech). Inhibition of growth was calculated by
comparison with control values and IC50 and IC90 values were
determined in triplicate using linear regression analysis.
Scheme 5 Reagents and conditions: (a) appropriate chloride NEt3,
DCM or THF, r.t. 18 h, (4a: 49%, 4b: 50%, 4d: 81%); (b) 1-adamantane-
carboxylic acid HBTU, DIPEA, DCM/DMF, r.t. 24 h, 94%.
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Table 1 Screening of the new thiazole derivatives against T. brucei
S.I.b
a
Cmpd
T. brucei IC50 (μM)
T. brucei IC90a (μM)
L6 cells IC50a (μM)
1a
1b
1c
1d
1e
1f
0.42 0.01
0.90 0.01
0.79 0.02
15.3 0.2
>25
0.56 0.01
1.10 0.01
1.03 0.01
18.1 0.2
—
1.05 0.23
2.01 0.32
1.53 0.09
—
—
—
2.5
2.2
1.9
—
—
—
>20
—
1g
1h
1i
>20
>20
>20
—
—
—
—
—
—
—
—
—
1j
10.7 0.3
0.80 0.03
0.59 0.02
1.27 0.07
>20
12.6 0.2
1.17 0.01
0.79 0.01
1.60 0.22
—
—
—
—
—
30.5 4.5
12.8 0.2
4.40 0.07
3.58 0.05
—
18.7 0.4
31.1 0.3
13.1 0.2
31.5 0.6
<10.30
4.08 0.15
0.96 0.26
—
—
—
—
—
<1
5.1
1.6
—
—
—
—
—
—
<1
<1
1.5
2.3
—
—
—
—
—
2a
2b
2c
2d
2e
2f
2g
2h
3a
3b
3c
3d
3e
4a
4b
4c
4d
>20
∼10
∼10
>20
—
22.5 0.6
9.76 0.77
2.74 0.29
1.41 0.09
∼10
13.8 1.6
12.6 0.9
4.16 0.24
3.19 0.25
—
—
—
—
—
12.2 0.8
20.6 0.7
9.82 0.22
23.8 1.1
a
b
IC50 and IC90; concentration that inhibits growth by 50% and 90%. S.I.; selectivity index, the ratio of IC50 values obtained with L6 cells and
T. brucei respectively.
Trypanosoma brucei culturing and drug testing. Blood-
stream form T. brucei (strain 427) were cultured at 37 °C in
modified Iscove's medium. Trypanocidal activity was assessed
by growing parasites in microtiter plates in the presence of
various drug concentrations. Parasites were seeded at 0.25 ×
105 mL−1 in 200 μL of growth medium containing 7 different
compound concentrations in a range previously established
to encompass both the IC50 and IC90 values. The plates were
incubated for 48 hours at 37 °C and 20 μL Alamar Blue was
then added to each well. After an additional overnight incu-
bation, the fluorescence was determined. Inhibition of
growth was calculated by comparison with control values and
IC50 and IC90 values were determined in triplicate using lin-
ear regression analysis.
Biology, NHRF, Greece and the results obtained had a maxi-
mum deviation of 0.4% from the theoretical value.
3-{(1-Tricycloij3.3.1.13,7]decyl)-4-fluorophenyl}boronic acid
(6). n-BuLi (4 mL,1.6 M in hexanes, 6.4 mmol) was added in
one portion to a stirred solution of the bromide 5 (ref. 28)
(1.25 g, 4.04 mmol) in anhydrous THF (20 mL), at −73 °C, un-
der an argon atmosphere. The mixture was then stirred at
−80 °C for 25 min prior to addition of (i-PrO)3B (3 mL, 12.1
mmol). The reaction mixture was stirred for 35 min at the
same temperature and subsequently at ambient temperature
overnight. Next, dilute HCl (20 mL) was added dropwise at
0 °C, the mixture was stirred for 30 min at room temperature
and then extracted with EtOAc (3 × 20 mL). The combined or-
ganic layers were washed with water, dried over Na2SO4 and
the solvent evaporated under reduced pressure. The residue
was crystallized from n-hexane to give compound 6 (1.1 g,
90%) as a white solid, which was used directly in the next
step. 1H NMR (400 MHz, CDCl3) δ 8.18 (d, J = 8.7 Hz, 1H,
2-Har), 8.03 (dd, J = 8.4, 4.2 Hz, 1H, 6-Har), 7.12 (dd, J = 8.1,
7.8 Hz, 1H, 5-Har), 2.12 (bs, 3H, 3,5,7-Had), 2.06 (bs, 6H,
2,8,9-Had), 1.79 (br.s, 6H, 4,6,10-Had).
Synthetic procedures. All chemicals and solvents were
obtained from commercial suppliers and used without fur-
ther purification. Reactions were monitored by thin layer
chromatography. Melting points were determined on a Büchi
530 apparatus and are uncorrected. Infrared (IR) spectra were
1
recorded on a Perkin-Elmer 833 spectrophotometer. H-NMR
spectra recorded on a Bruker DRX 400 (400 MHz) spectrome-
ter and 13C-NMR spectra were taken at 50 MHz on Bruker AC
200 (200 MHz) spectrometer and at 150 MHz on Bruker
Avance 600 spectrometer (600 MHz). All NMR spectra were
taken in deuterochloroform or hexadeuterodimethyl sulfoxide
and the chemical shifts are reported in ppm. Elemental anal-
yses (C, H, N) were carried out by the Institute of Chemical
2-{2-[2-((1-Tricycloij3.3.1.13,7]decyl)-4-fluorophenyl)thiazol-
4-yl]ethyl}isoindoline-1,3-dione (8). Argon was bubbled for 20
min through a stirred mixture of boronic acid 6 (250 mg, 0.9
mmol), the 2-thiazole bromide 7 (ref. 6) (161 mg, 0.45 mmol),
toluene (5 mL) and Na2CO3 (2 M, 5 mL). The reaction mixture
was then heated to 80 °C, under an argon atmosphere,
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PdIJPPh3)4 (107 mg) was added and heating was continued
overnight. After cooling, the reaction mixture was extracted
with EtOAc (3 × 25 mL) and the combined organics were
washed with water dried over Na2SO4 and the solvent removed
in vacuo. The residue was purified by column chromatography.
Elution with 10–20% EtOAc in hexanes afforded compound
anol, water and a NaOH (10%) solution were sequentially
added. The resulting suspension was then filtered, the filtrate
was evaporated in vacuo and the resulting residue was treated
with water and a HCl (5%) solution. The aqueous phase was
then washed with Et2O and solid Na2CO3 was added until pH
= 10. The aqueous phase was then extracted with DCM and
the combined organic phase was dried over Na2CO3 and the
solvent evaporated in vacuo to afford compound 1b, as a vis-
cous oil (170 mg, 88% from compound 8). M.p. (dihydro-
chloride): 221–223 °C (EtOH/Et2O). 1H NMR (400 MHz,
DMSO-d6) δ 9.26 (br.s, 1H, NHth), 7.97 (bs, 2H, NH2), 7.86–
7.76 (m, 2H, 2,6-Har), 7.53 (s, 1H, 5-Hth), 7.24 (dd, J = 12.8,
8.3 Hz, 1H, 5-Har), 3.24 (d, J = 4.7 Hz, 2H, NCH2), 3.17 (d, J =
7.5 Hz, 2H, CH2), 2.57 (t, J = 5.4 Hz, 3H, CH3), 2.07 (s, 3H,
3,5,7-Had), 2.02 (s, 6H, 2,8,9-Had), 1.74 (s, 6H, 4,6,10-Had).
13C NMR (150 MHz, DMSO-d6) δ 166.5 (2-Cth), 162.7 (d, J =
251.7 Hz, 4-Car), 152.7 (4-Cth), 137.4 (d, J = 11.1 Hz, 3-Car),
129.3 (1-Car), 126.0 (d, J = 10.2 Hz, 2-Car), 124.9 (d, J = 7.1
Hz, 6-Car), 117.4 (d, J = 26.5 Hz, 5-Car), 116.1 (5-Cth), 47.2
(NCH2), 40.4 (2,8,9-Cad), 36.2 (4,6,10-Cad), 36.0 (1-Cad), 32.4
(CH3), 28.1 (3,5,7-Cad), 27.4 (CH2). Anal. calcd for
C22H31FCl2N2S: C, 58.59; H, 6.59; N, 6.32 found C, 58.71; H,
6.25; N, 6.09.
1
8 as a foamy solid (175 mg, 80%). H NMR (400 MHz, CDCl3)
δ 7.85–7.79 (m, 2H, 3′,4′-Har), 7.76 (dd, J = 7.7, 2.2 Hz, 1H,
2-Har), 7.73–7.68 (m, 2H, 2′,5′-Har), 7.64–7.58 (m, 1H, 6-Har),
6.71 (s, 1H, 5-Hth), 6.96 (dd, J = 12.7, 8.3 Hz, 1H, 5-Har), 4.11
(t, J = 7.0 Hz, 2H, CH2N), 3.23 (t, J = 7.0 Hz, 2H, CH2), 2.10 (br.
s, 3H, 3,5,7-Had), 2.04 (bs, 6H, 2,8,9-Had), 1.79 (br.s, 6H,
4,6,10-Had). 13C NMR (150 MHz, DMSO-d6) δ 167.2 (CO),
166.6 (2-Cth), 162.8 (d, J = 251.9 Hz, 4-Car), 152.8 (4-Cth),
137.5 (d, J = 11.4 Hz, 3-Car), 132.9 (1′,6′-Car), 132.8 (3′,4′-Car),
129.2 (1-Car), 126.2 (d, J = 8.4 Hz, 2-Car), 125.1 (6-Car), 122.2
(2′,5′-Car) 117.5 (d, J = 25.4, 5-Car), 116.4 (5-Cth), 40.5 (2,8,9-
Cad), 38.4 (NCH2), 36.2 (1-Cad), 36.0 (4,6,10-Cad), 28.8 (CH2),
28.2 (3,5,7-Cad). Anal. calcd for C29H27FN2O2S: C, 71.58; H,
5.59; N, 5.76 found C, 71.35; H, 5.41; N, 5.54.
2-{2-[3-(1-Tricycloij3.3.1.13,7]decyl)-4-fluorophenyl]thiazol-4-
yl}ethan-1-amine (1a). A solution of phthalimide 8 (600 mg,
1.23 mmol) and hydrazine hydride (2 mL) in EtOH (20 mL)
was refluxed for 1 h and then cooled to 0 °C. The resulting
suspension was filtered and the filtrate evaporated. The resi-
due (crude amine 1a) was used in the next steps without fur-
ther purification. M.p. (dihydrochloride): 246–248 °C (EtOH/
Et2O). 1H NMR (600 MHz, DMSO-d6) δ 8.35 (bs, 1H, NHth),
7.83–7.73 (m, 2H, 2.6-Har), 7.50 (s, 1H, 5-Hth), 7.18 (dd, J =
12.7, 8.4 Hz, 1H, 5-Har), 6.10 (br.s, 4H, NH4), 3.31–2.93 (m,
4H, CH2, NCH2), 2.01 (br.s, 3H, 3,5,7-Had), 1.96 (br.s, 6H,
2,8,9-Had), 1.69 (br.s, 6H, 4,6,10-Had). 13C NMR (151 MHz,
DMSO-d6) δ 166.6 (s, 2-Cth), 162.8 (d, J = 251.9 Hz, 4-Car),
152.8 (4-Cth), 137.5 (d, J = 11.4 Hz, 3-Car), 129.2 (1-Car),
126.2 (d, J = 8.4 Hz, 2-Car), 125.1 (6-Car), 117.5 (d, J = 25.4
Hz, 5-Car), 116.4 (5-Cth), 40.5 (2,8,9-Cad), 38.4 (NCH2), 36.2
(1-Cad), 36.0 (4,6,10-Cad), 28.8 (CH2), 28.2 (3,5,7-Cad). Anal.
calcd for C21H29FCl2N2S: C, 58.74; H, 6.34; N, 6.52 found C,
58.51; H, 6.44; N, 6.68.
2-{2-[3-(1-Tricycloij3.3.1.13,7]decyl)-4-fluorophenyl]thiazol-4-
yl}-N,N-dimethylethyl-1-amine (1c). A solution of MeONa (0.1
mL, 30% in MeOH, 0.52 mmol) was added to a stirred solu-
tion of compound 1a dihydrochloride (220 mg, 0.52 mmol)
in MeOH (8 mL) and the resulting mixture was stirred for 10
min in ambient temperature. Then acetic acid (0.12 mL, 2
mmol) and NaCNBH3 (65 mg, 1.01 mmol) were added into
the reaction mixture. Subsequently, a solution of aq. HCHO
(38%, 0.1 mL, 1.20 mmol) dissolved in MeOH (2.5 mL) was
added dropwise over the course of 30 min and the reaction
mixture was stirred at ambient temperature, overnight. The
solvent was removed in vacuo and an aqueous solution of
NaOH (4N, 5 mL) was added. The resulting mixture was then
extracted with EtOAc (3 × 20 mL) and the combined organic
phases were washed with brine, dried over MgSO4 and the
solvent evaporated to afford compound 1c, as a yellow vis-
cous oil (150 mg, 75% from compound 8). M.p. (dihydro-
chloride): 280–282 °C (EtOH/Et2O). 1H NMR (400 MHz,
DMSO-d6) δ 10.89 (s, 1H, NHTh), 7.86–7.76 (m, 2H, 2,6-Har),
7.53 (s, 1H, 5-Hth), 7.25 (dd, J = 12.7, 8.2 Hz, 1H, 5-Har), 6.05
(s, 1H, NH), 3.52–3.36 (m, 2H, NCH2), 3.30–3.19 (m, 2H,
CH2), 2.81 (d, J = 4.9 Hz, 6H, CH3), 2.07 (s, 3H, 3,5,7-Had),
2.02 (s, 6H, 2,8,9-Had), 1.75 (s, 6H, 4,6,10-Had). 13C NMR (150
MHz, DMSO-d6) δ 166.9 (2-Cth), 163.1 (d, J = 251.8 Hz, 4-Car),
153.0 (4-Cth), 137.9 (d, J = 11.1 Hz, 3-Car), 129.8 (d, J = 2.8
Hz, 1-Car), 126.4 (d, J = 9.8 Hz, 2-Car), 125.3 (d, J = 5.4 Hz,
6-Car), 117.8 (d, J = 25.6 Hz, 5-Car), 116.6 (5-Cth), 55.8
(NCH2), 42.5 (CH3), 40.9 (2,8,9-Cad), 36.6 (4,6,10-Cad), 36.4
(1-Cad), 28.5 (3,5,7-Cad), 26.4 (CH2). Anal. calcd for
C23H33FCl2N2S: C, 60.39; H, 6.83; N, 6.12 found C, 60.50; H,
6.91; N, 6.41.
2-{2-[3-(1-Tricycloij3.3.1.13,7]decyl)-4-fluorophenyl]thiazol-4-
yl}-N-methylethan-1-amine (1b). Ethyl chloroformate (0.1 mL,
1.01 mmol) and Et3N (0.15 mL) were added to a stirred solu-
tion of the amine 1a (180 mg, 0.51 mmol) in anhydrous THF
(3 mL), at 0 °C, under an argon atmosphere. The reaction
mixture was stirred for 5 min at 0 °C and then at ambient
temperature, overnight. Next, water was added into the mix-
ture, which was then extracted with EtOAc. The organic
phase was washed with water dried over MgSO4 and the sol-
vent evaporated. The resulting residue was used in the next
step without further purification.
A solution of the crude amide (220 mg, 0.51 mmol) in an-
hydrous THF (5 mL) was added dropwise to a stirred suspen-
sion of LiAlH4 (100 mg, 2.52 mmol) in anhydrous THF (5
mL), under an argon atmosphere. The mixture was stirred at
ambient temperature for 25 min and then refluxed for 4 h.
Next, the reaction mixture was cooled in an ice bath, and eth-
General method for the preparation of amides 1d–g, i, j
and 2d. A stirred solution of amine 1a or 2a (1 eq.) and Et3N
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(0.5 mL) in EtOAc (7 mL) was cooled to 0 °C and the appro-
priate acid chloride or anhydride (2–3 eq.) was added under
an argon atmosphere. The reaction mixture was stirred at
ambient temperature for 24–48 h. Water was added into the
mixture, which was then extracted with EtOAc. The combined
organic layers were washed with water, dried over Na2SO4,
the solvent evaporated and the residue was purified by col-
umn chromatography.
2.98 (t, J = 6.3 Hz, 2H, CH2), 2.09 (br.s, J = 14.7 Hz, 9H, 3,5,7-
Had, 2,8,9-Had), 1.80 (bs, 6H, 4,6,10-Had). 13C NMR (50 MHz,
CDCl3) δ 166.1 (2-Cth), 166.0 (CO), 164.5 (d, J = 349.7 Hz,
4-Car), 155.5 (4-Cth), 138.3 (d, J = 11.2 Hz, 3-Car), 131.3 (4′-
Car), 129.6 (1-Car), 128.5 (3′,5′-Car), 127.0 (2′,6′-Car), 125.8 (d,
J = 2.9 Hz, 6-Car), 125.6 (2-Car), 117.2 (d, J = 25.8 Hz, 5-Car),
114.3 (5-Cth), 41.1 (2,8,9-Cad), 39.2 (CH2N), 36.9 (4,6,10-Cad),
36.7 (1-Cad), 31.0 (CH2), 28.9 (3,5,7-Cad). M.p. (fumarate): 305
°C (dec) (MeOH/Et2O). Anal. calcd for C32H33FN2O5S: C,
66.65; H, 5.77; N, 4.86 found C, 65.39; H, 5.90; N, 4.72.
N-{2-[2-(3-(1-Tricycloij3.3.1.13,7]decyl)-4-fluorophenyl]-
thiazol-4-yl]ethyl}acetamide (1d). Acetamide 1d was prepared,
as described in the general method, using acetic anhydride (3
eq.). Elution with EtOAc afforded compound 1d as a foamy
solid (140 mg, 84% from compound 8). 1H NMR (400 MHz,
CDCl3) δ 7.85 (dd, J = 7.7, 2.2 Hz, 1H, 2-Har), 7.70 (ddd, J =
8.2, 4.3, 2.2 Hz, 1H, 6-Har), 7.04 (dd, J = 12.4, 8.4 Hz, 1H,
5-Har), 6.95 (s, 1H, 5-Hth), 6.49 (br.s, 1H, NH), 3.64 (q, J = 6.3
Hz, 2H, CH2N), 2.98 (t, J = 6.3 Hz, 2H, CH2), 2.09 (br.s, J =
14.7 Hz, 9H, 3,5,7,2,8,9-Had), 1.99 (s, 3H, CH3), 1.80 (br.s, 6H,
4,6,10-Had). 13C NMR (50 MHz, CDCl3) δ 170.1 (CO), 166.1
(2-Cth), 164.5 (d, J = 349.7 Hz, 4-Car), 155.5 (4-Cth), 138.6 (d,
J = 11.2 Hz, 3-Car), 129.6 (1-Car), 125.8 (d, J = 2.9 Hz, 6-Car),
125.6 (2-Car), 117.2 (d, J = 25.8 Hz, 5-Car), 114.2 (5-Cth), 41.1
(d, J = 3.5 Hz, 2,8,9-Cad), 39.1 (CH2N), 36.9 (4,6,10-Cad), 36.7
(1-Cad), 31.0 (CH2), 28.9 (3,5,7-Cad), 23.5 (CH3). M.p. (fuma-
rate): 143-145 °C (MeOH/Et2O). Anal. calcd for C27H31FN2O5S:
C, 63.03; H, 6.07; N, 5.44 found C, 62.89; H, 6.01; N, 5.21.
N-{2-[2-(3-(1-Tricycloij3.3.1.13,7]decyl)-4-fluorophenyl)-
thiazol-4-yl]ethyl}butylamide (1e). Butylamide 1e was pre-
pared, as described in general method, using butyric anhy-
dride (3 eq.). Elution with 50% EtOAc in hexanes afforded
compound 1e as a foamy solid (165 mg, 92% from 8). 1H
NMR (400 MHz, CDCl3) δ 7.85 (dd, J = 7.7, 2.2 Hz, 1H, 2-Har),
7.70 (ddd, J = 8.2, 4.3, 2.2 Hz, 1H, 6-Har), 7.04 (dd, J = 12.4,
8.4 Hz, 1H, 5-Har), 6.95 (s, 1H, 5-Hth), 6.49 (br.s, 1H, NH),
3.64 (q, J = 6.3 Hz, 2H, CH2N), 2.98 (t, J = 6.3 Hz, 2H, CH2),
2.09 (br.s, J = 14.7 Hz, 9H, 3,5,7,2,8,9-Had), 2.18 (t, J = 6.9 Hz,
2H, CH2CO), 1.80 (br.s, 6H, 4,6,10-Had), 1.67 (h, J = 6.9 Hz,
2H, CH2), 0.94 (t, J = 7.4 Hz, 3H, CH3). 13C NMR (50 MHz,
CDCl3) δ 170.2 (CO), 166.1 (2-Cth), 164.5 (d, J = 349.7 Hz,
4-Car), 155.5 (4-Cth), 138.3 (d, J = 11.2 Hz, 3-Car), 129.6
(1-Car), 125.8 (d, J = 2.9 Hz, 6-Car), 125.6 (2-Car), 117.2 (d, J =
25.8 Hz, 5-Car), 114.3 (5-Cth), 41.1 (2,8,9-Cad), 39.2 (CH2N),
36.9 (4,6,10-Cad), 36.7 (1-Cad), 31.0 (CH2), 28.9 (3,5,7-Cad),
28.9 (CH2), 19.3 (CH2), 13.9 (CH3). M.p. (fumarate): 291–293
°C (MeOH/Et2O). Anal. calcd for C29H35FN2O5S: C, 64.19; H,
6.50; N, 5.16 found C, 64.38; H, 6.61; N, 5.33.
N-{2-[2-(3-(1-Tricycloij3.3.1.13,7]decyl)-4-fluorophenyl)-
thiazol-4-yl]ethyl}-4-fluorobenzamide (1g). 4-Fluorobenzamide
1g was prepared, as described in general method, using
4-fluorobenzoyl chloride (3 eq.). Elution with 50% EtOAc in
hexanes afforded compound 1g as a foamy solid (185 mg,
1
93% from compound 8). H NMR (400 MHz, DMSO-d6) δ 8.05
(br.s, 1H, NH), 7.80 (m, 2H, 2′,6′-Har), 7.75 (dd, J = 7.7, 2.0
Hz, 1H, 2-Har), 7.68 (dd, J = 7.7, 8.9 Hz, 1H, 6-Har), 7.12–6.96
(m, 4H, 5-Har, 5-Hth, 3′,5′-Har), 3.70 (q, J = 5.8 Hz, 2H,
CH2N), 3.05 (t, J = 6.7 Hz, 2H, CH2), 2.03 (s, 3H, 3,5,7-Had),
1.99 (s, 6H, 2,8,9-Had), 1.72 (s, 6H, 4,6,10-Had). 13C NMR (50
MHz, CDCl3) δ 166.1 (2-Cth), 166.0 (CO), 164.5 (d, J = 349.7
Hz, 4-Car), 163.9 (d, J = 348.6 Hz, 4′-Car) 155.5 (4-Cth), 138.3
(d, J = 11.2 Hz, 3-Car), 130.1 (d, J = 3 Hz, 1′-Car), 129.6
(1-Car), 128.3 (d, J = 7 Hz, 2′,6′-Car), 125.8 (d, J = 2.9 Hz,
6-Car), 125.6 (2-Car), 117.2 (d, J = 25.8 Hz, 5-Car), 116.1 (d, J =
18 Hz, 3′,5′-Car) 114.3 (5-Cth), 41.1 (d, J = 3.5 Hz, 2,8,9-Cad),
39.2 (CH2N), 36.9 (4,6,10-Cad), 36.7 (1-Cad), 31.0 (CH2), 28.9
(3,5,7-Cad). M.p. (fumarate): 226–227 °C (MeOH/Et2O). Anal.
calcd for C32H32F2N2O5S: C, 64.63; H, 5.42; N, 4.71 found C,
64.44; H, 5.73; N, 4.88.
N-{2-[2-(3-(1-Tricycloij3.3.1.13,7]decyl)-4-fluorophenyl)-
thiazol-4-yl] ethyl}-3-methylfuran-2-ylcarboxamide (1h). DMAP
(57 mg, 0.46 mmol), EDCI (90 mg, 0.46 mmol) and HOBt (65
mg 0.41 mmol) were added to a stirred mixture of the amine 1a
(150 mg, 0.41 mmol) and 3-methylfuroic acid (52 mg, 0.41
mmol) in anhydrous DMF (2 mL) and anhydrous DCM (1
mL) at 0 °C, under an argon atmosphere. The reaction mix-
ture was stirred at the same temperature for 1 h and then at
45 °C, overnight. Water was added into the mixture, which
was then extracted with EtOAc. The organic phase was
washed with water dried over Na2SO4 and the solvent evapo-
rated in vacuo. The residue was purified by column chroma-
tography. Elution with EtOAc afforded compound 1h as a
foamy solid (50 mg, 29% from compound 8).1H NMR (400
MHz, CDCl3) δ 7.85 (dd, J = 7.7, 2.2 Hz, 1H, 2-Har), 7.70 (ddd,
J = 8.2, 4.3, 2.2 Hz, 1H, 6-Har), 7.30 (d, J = 0.9 Hz, 1H, 5-Hfur)
7.04 (dd, J = 12.4, 8.4 Hz, 1H, 5-Har), 6.95 (s, 1H, 5-Hth), 6.49
(bs, 1H, NH), 6.35 (d, J = 1.0 Hz, 1H, 4-Hfur), 3.64 (q, J = 6.3
Hz, 2H, CH2N), 2.98 (t, J = 6.3 Hz, 2H, CH2), 2.40 (s, 3H,
CH3), 2.09 (br.s, J = 14.7 Hz, 9H, 3,5,7,2,8,9-Had), 1.80 (br.s,
6H, 4,6,10-Had). 13C NMR (50 MHz, CDCl3) δ 166.1 (2-Cth),
164.5 (d, J = 349.7 Hz, 4-Car), 160.6 (CO), 155.5 (4-Cth),
142.7 (4-Cfur), 141.1 (1-Cfur), 138.3 (d, J = 11.2 Hz, 3-Car),
129.6 (1-Car), 125.8 (d, J = 2.9 Hz, 6-Car), 125.6 (2-Car), 117.2
(d, J = 25.8 Hz, 5-Car), 115.6 (2-Cfur), 115.2 (5-Cth), 114.3
N-{2-[2-(3-(1-Tricyclo[3.3.1.13,7]decyl)-4-fluorophenyl)-
thiazol-4-yl] ethyl}benzamide (1f). Benzamide 1f was pre-
pared, as described in general method, using benzoyl chlo-
ride (2 eq.). Elution with 30% EtOAc in hexanes afforded
compound 1f as a foamy solid (186 mg, 96%, from 8). 1H
NMR (400 MHz, CDCl3) δ 7.91–7.82 (m, 2H, 2′,6′-Har), 7.85
(dd, J = 7.7, 2.2 Hz, 1H, 2-Har), 7.70 (ddd, J = 8.2, 4.3, 2.2 Hz,
1H, 6-Har), 7.59–7.51 (m, 1H, 4′-Har), 7.46–7.36 (m, 2H, 3′,5′-
Har), 7.04 (dd, J = 12.4, 8.4 Hz, 1H, 5-Har), 6.95 (s, 1H,
5-Hth), 6.49 (br.s, 1H, NH), 3.64 (q, J = 6.3 Hz, 2H, CH2N),
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(3-Cfur), 41.1 (2,8,9-Cad), 39.2 (CH2N), 36.9 (4,6,10-Cad), 36.7
(1-Cad), 31.0 (CH2), 28.9 (3,5,7-Cad), 11.0 (CH3). M.p. (fuma-
rate): 260 (dec) °C (MeOH/Et2O). Anal. Calcd for
C31H32FN2O6S: C, 64.12; H, 5.73; N, 4.82 found C, 64.44; H,
5.54; N, 4.98.
2H, 3,5-Har), 7.46 (d, J = 8.5 Hz, 2H, 2,6-Har), 2.12 (s, 3H,
3,5,7-Had), 1.94 (s, 6H, 2,8,9-Had), 1.78 (d, J = 7.1 Hz, 6H,
4,6,10-Had).
4-(1-Tricyclo[3.3.1.13,7]decyl)benzamide (13). A solution of
4-(adamant-1-yl)benzoic acid (12) (2 g, 6.17 mmol) in SOCl2
(12 ml) was heated at 65 °C for 45 min. The excess of SOCl2
was removed under reduced pressure and subsequently by
azeotropic distillation with benzene. The resulting precipitate
was then dissolved in anhydrous THF (10 mL) and added to
a stirred solution of NH3 (25%) in water (50 mL), dropwise,
at 0 °C. The reaction mixture was stirred for 30 min at ambi-
ent temperature and extracted with EtOAc. The organic layer
dried over MgSO4 and the solvent evaporated to afford com-
pound 13 as an off white solid (1.9 g, 96%). 1H NMR (400
MHz, CDCl3) δ 7.83 (d, J = 8.5 Hz, 2H, 3,5-Har), 7.64 (br.s, 2H,
NH2), 7.39 (d, J = 8.5 Hz, 2H, 2,6-Har), 2.11 (s, 3H, 3,5,7-Had),
1.90 (br.s, 6H, 2,8,9-Had), 1.77 (q, J = 12.2 Hz, 6H, 4,6,10-
Had). Anal. calcd for C17H21NO: C, 79.96; H, 8.29 found C,
79.77; H, 8.57.
N-(2-(2-(3-(1-Tricycloij3.3.1.13,7]decyl)-4-fluorophenyl)-
thiazol-4-yl) ethyl)pyrrolidin-1-yl-carboxamide (1i). Carboxa-
mide 1i was prepared, as described in general method, using
1-pyrrolidinecarbonyl chloride (2 eq.). Elution with 75%
EtOAc in hexanes afforded compound 1i as a foamy solid (80
mg, 46% from compound 8). 1H NMR (400 MHz, CDCl3) δ
7.85 (dd, J = 7.7, 2.2 Hz, 1H, 2-Har), 7.70 (ddd, J = 8.2, 4.3, 2.2
Hz, 1H, 6-Har), 7.04 (dd, J = 12.4, 8.4 Hz, 1H, 5-Har), 6.95 (s,
1H, 5-Hth), 5.24 (br.s, 1H, NH), 3.64 (q, J = 6.3 Hz, 2H,
CH2N), 3.46–3.26 (m, 4H, 2,5-Hpy) 2.98 (t, J = 6.3 Hz, 2H,
CH2), 2.09 (br.s, 9H, 3,5,7,2,8,9-Had), 1.94–1.85 (m, 4H,
3,4-Hpy), 1.80 (br.s, 6H, 4,6,10-Had). 13C NMR (50 MHz,
CDCl3) δ 166.1 (2-Cth), 164.5 (d, J = 349.7 Hz, 4-Car), 156.9
(CO), 155.5 (4-Cth), 138.3 (d, J = 11.2 Hz, 3-Car), 129.6
(1-Car), 125.8 (d, J = 2.9 Hz, 6-Car), 125.6 (2-Car), 117.2 (d, J =
25.8 Hz, 5-Car), 114.3 (5-Cth), 45.4 (2,5-Cpy), 41.1 (d, J = 3.5
Hz, 2,8,9-Cad), 39.2 (CH2N), 36.9 (4,6,10-Cad), 36.7 (1-Cad),
31.0 (CH2), 28.9 (3,5,7-Cad), 25.6 (3,4-Cpy). M.p. (fumarate):
301 °C (dec) (MeOH/Et2O). Anal. calcd for C30H36FN3O5S: C,
63.25; H, 6.37; N, 7.38 found C, 63.09; H, 6.14; N, 7.19.
N-{2-[2-(3-(1-Tricycloij3.3.1.13,7]decyl)-4-fluorophenyl)-
thiazol-4-yl}ethyl)piperidine-1-yl-carboxamide (1j). Carboxa-
mide 1j was prepared, as described in general method, using
1-piperidinecarbonyl chloride (2 eq.). Elution with 50% EtOAc
in hexanes afforded compound 1j as a foamy solid (50 mg,
36% from compound 8). 1H NMR (400 MHz, CDCl3) δ 7.85
(dd, J = 7.7, 2.2 Hz, 1H, 2-Har), 7.70 (ddd, J = 8.2, 4.3, 2.2 Hz,
1H, 6-Har), 7.04 (dd, J = 12.4, 8.4 Hz, 1H, 5-Har), 6.95 (s, 1H,
5-Hth), 5.24 (br.s, 1H, NH), 3.64 (q, J = 6.3 Hz, 2H, CH2N),
3.51–3.20 (m, 4H, 2,6-Hpi) 2.98 (t, J = 6.3 Hz, 2H, CH2), 2.09
(br.s, J = 14.7 Hz, 9H, 3,5,7,2,8,9-Had), 1.80 (bs, 6H, 4,6,10-
Had), 1.66–1.39 (m, 6H, 3,4,5-Hpi). 13C NMR (150 MHz,
CDCl3) δ 166.6 (2-Cth), 162.8 (d, J = 251.9 Hz, 4-Car), 156.9
(CO), 152.8 (4-Cth), 137.5 (d, J = 11.4 Hz, 3-Car), 129.2
(1-Car), 126.2 (d, J = 8.4 Hz, 2-Car), 125.1 (6-Car), 117.5 (d, J =
25.4, 5-Car), 116.4 (5-Cth), 43.9 (2,6-Cpi), 40.5 (2,8,9-Cad),
38.4 (NCH2), 36.2 (1-Cad), 36.0 (4,6,10-Cad), 28.8 (CH2), 28.2
(3,5,7-Cad), 24.8 (3,5-Cpi), 23.5 (4-Cpi). Anal. calcd for
C27H34FN3OS: C, 69.35; H, 7.33; N, 8.99 found C, 69.55; H,
7.39; N, 9.12.
4-(1-Tricyclo[3.3.1.13,7]decyl)thiobenzamide
(14).
Lawesson's reagent (1.2 g) was added to a stirred solution of
benzamide 13 (1.5 g, 6.17 mmol) in dioxane (15 mL) and the
reaction mixture was heated to 110 °C, overnight. The solvent
was removed in vacuo and the crude residue was crystallised
from DCM. The filtrate of the recrystallisation still contained
benzamide 13, thus it was purified by column chromatogra-
phy. Elution with DCM afforded compound 14 as a yellow
solid (780 mg, 50%). M.p.: 201–202 °C 1H NMR (400 MHz,
CDCl3) δ 7.83 (d, J = 8.5 Hz, 2H, 3,5-Har), 7.64 (br.s, 1H, NH),
7.39 (d, J = 8.5 Hz, 2H, 2,6-Har), 7.20 (s, 1H, NH), 2.11 (s, 3H,
3,5,7-Had), 1.90 (br.s, 6H, 2,8,9-Had), 1.77 (q, J = 12.2 Hz, 6H,
4,6,10-Had). 13C NMR (150 MHz, CDCl3) δ 202.6 (CS), 156.0
(1-Car), 136.4 (4-Car), 126.9 (2,6-Car), 125.1 (3,5-Car), 42.9
(2,8,9-Cad), 36.7 (4,6,10-Cad), 36.6 (1-Cad), 28.8 (3,5,7-Cad).
C17H21NS: C, 75.23; H, 7.80 found C, 75.07; H, 7.99.
2-{2-[2-(1-Tricycloij3.3.1.13,7]decyl)phenyl]ethyl}isoindoline-
1,3-dione (10)
Method A. Phthalimide 10 was prepared in a similar way
as for compound 8 using pinacolborane 9 (ref. 31) (300 mg,
0.88 mmol) and bromothiazole 7 (ref. 6) (250 mg, 0.73 mmol)
as starting materials. Elution with 10–20% EtOAc in hexanes
afforded compound 10 as a white solid (300 mg, 87%).
Method B. The bromoketone 15 (ref. 6) (200 mg, 0.66
mmol) was added to a stirred solution of the thiobenzamide
14 (180 mg, 0.66 mmol) in EtOH (4 mL) and the reaction
mixture was refluxed overnight. The resulting suspension was
filtered and the precipitate was washed with Et2O and dried
over MgSO4 to afford compound 10, as a white solid (200 mg,
4-(1-Tricyclo[3.3.1.13,7]decyl)benzoic acid (12). Oxygen gas
was bubbled into a stirred solution of 1-(4-tolyl)adamantane
(11)33 (1.4 g, 6.17 mmol), CoIJOAc)2 (73 mg, 0.31 mmol),
MnIJOAc)2 (9 mg, 0.03 mmol) and NaBr (35 mg, 0.32 mmol) in
AcOH (26 mL)/dioxane (2.8 mL)/H2O (0.7 mL) for 6 h, at 105
°C. The resulting mixture was cooled to ambient temperature
and water was added into the mixture. The residue obtained
was filtered and washed with water. The resulting solid was
then dried in vacuo, in the presence of P2O5, overnight to af-
ford compound 12, as a white solid (1.4 g, 89%). 1H NMR
(400 MHz, CDCl3) δ 12.30 (br.s, 1H, OH) 8.04 (d, J = 8.4 Hz,
1
65%) M.p.: 213–214 °C. H NMR (600 MHz, CDCl3) δ 7.81 (dt,
J = 6.8, 3.4 Hz, 2H, 2′,5′-Har), 7.73 (d, J = 8.4 Hz, 2H, 2,6-Har),
7.66 (dt, J = 6.8, 3.4 Hz, 2H, 3′,4′-Har), 7.34 (d, J = 8.4 Hz, 2H,
3,5-Har), 6.94 (s, 1H, 5-Hth), 4.10 (t, J = 7.1 Hz, 2H, NCH2),
3.21 (t, J = 7.1 Hz, 2H, CH2), 2.12 (br.s, 3H, 3,5,7-Had), 1.91
(br.s, 6H, 2,8,9-Had), 1.78 (dd, J = 25.4, 12.1 Hz, 6H, 4,6,10-
Had). 13C NMR (150 MHz, CDCl3) δ 168.4 (CO), 168.2
(2-Cth), 154.2 (4-Cth), 153.4 (1-Car), 133.9 (3′,4′-Car), 132.3
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(1′,6′-Car), 131.1 (4-Car), 126.4 (2,6-Car), 125.4 (3,5-Car), 123.3
(2′,5′-Car), 114.2 (5-Cth), 43.1 (2,8,9-Cad), 37.7 (NCH2), 36.9
(4,6,10-Cad), 36.5 (1-Cad), 30.2 (CH2), 29.0 (3,5,7-Cad).
C29H28N2O2S: C, 74.33; H, 6.02; N, 5.98 found C, 74.64; H,
6.12; N, 6.21.
0.42 mmol) and acetic anhydride (0.15 ml, 1.42 mmol). Elu-
tion with 10% MeOH in DCM afforded compound 2d as a
white solid (100 mg, 53% from compound 10). M.p. (fuma-
rate): 164–166 °C (MeOH/Et2O). 1H NMR (600 MHz, DMSO-
d6) δ 13.12 (s, 1H, NHTh), 7.95 (s, 1H NHCO), 7.84 (d, J =
8.2 Hz, 2H, 2,6-Har), 7.46 (d, J = 8.2 Hz, 2H, 3,5-Har), 7.34 (s,
1H, 5-Hth), 6.63 (s, 2H, CH-Fum), 3.39 (dt, J = 13.3, 6.7 Hz,
2H, NCH2), 2.88 (t, J = 7.2 Hz, 2H, CH2), 2.06 (s, 3H, 3,5,7-
Had), 1.88 (s, 6H, 2,8,9-Had), 1.80 (s, 3H, CH3), 1.74 (br.s, 6H,
4,6,10-Had). 13C NMR (75 MHz, DMSO-d6) δ 169.1 (NCO),
166.5 (2-Cth), 166.0 (CO, fum), 155.2 (4-Cth), 153.0 (1-Car),
134.0 (CH-fum), 130.7 (4-Car), 125.9 (2,6-Car), 125.5 (3,5-Car),
114.6 (5-Cth), 42.4 (2,8,9-Cad), 38.2 (NCH2), 36.1 (4,6,10-Cad),
36.0 (1-Cad), 31.3 (CH2), 28.3 (3,5,7-Cad), 22.7 (CH3). Anal.
calcd for C27H32N2O5S: C, 65.30; H, 6.50; N, 5.64 found C,
65.27; H, 6.33; N, 5.45.
2-{2-[4-(1-Tricycloij3.3.1.13,7]decyl)phenyl]thiazol-4-yl}ethan-
1-amine (2a). The amine 2a was prepared in a similar way as
the amine 1a, using phthalimide 10 as starting material to af-
ford 2a as a green solid. M.p. (dihydrochloride): 225 °C (dec)
(MeOH/Et2O). 1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H,
NHth), 7.86 (d, J = 8.3 Hz, 2H, 2,6-Har), 7.52 – 7.44 (m, 3H,
3,5-Har, 5-Hth), 6.75 (s, 3H, NH3), 3.20–3.07 (m, 4H, CH2,
NCH2), 2.06 (s, 3H, 3,5,7-Had), 1.88 (s, 6H, 2,8,9-Had), 1.74 (s,
6H, 4,6,10-Had).13C NMR (75 MHz, DMSO-d6) δ 167.5 (2-Cth),
153.6 (4-Cth), 153.4 (1-Car), 130.9 (4-Car) 126.4 (2,6-Car),
126.0 (3,5-Car), 116.1 (5-Cth), 42.8 (2,8,9-Cad), 38.6 (NCH2),
36.5 (4,6,10-Cad), 36.4 (1-Cad), 29.2 (CH2), 28.7 (3,5,7-Cad).
Anal. calcd for C21H27Cl2N2S: C, 61.31; H, 6.86; N, 6.81 found
C, 61.19; H, 6.95; N, 6.69.
2-[4-(1-Tricycloij3.3.1.13,7]decyl)phenyl]-4-(chloromethyl)-
thiazole (15). Thiobenzamide 14 (200 mg, 0.74 mmol) was
added to a stirred solution of 1-3-dichloroacetone (125 mg,
0.99 mmol) in acetone (4 mL) and the reaction mixture was
refluxed overnight. The solvent was removed in vacuo and
the resulting residue was dissolved in conc. H2SO4 (5 mL),
stirred for 30 min and subsequently poured onto a mixture
of water and ice. The resulting suspension was the filtered
and the precipitate was washed with water to afford com-
pound 15 as a yellow-white solid (190 mg, 75%), which was
used in the next step without further purification.
2-{2-[4-(1-Tricyclo[3.3.1.13,7]decyl)phenyl]thiazol-4-yl}-N-
methylethan-1-amine (2b). The amine 2b was prepared in a
similar way as the methylamine 1b, using the amine 2a (180
mg, 0.51 mmol) as starting material to afford compound 2b
as yellow solid (95 mg, 54% from 10). M.p. (difumarate): 147–
149 °C (EtOH/Et2O). 1H NMR (600 MHz, DMSO-d6) δ 7.89–
7.83 (d, J = 8.2 Hz, 2H, 2,6-Har), 7.46 (m, 3H, 5-Hth, 3,5-Har),
6.57 (s, 4H, Hfum), 3.31–3.22 (m, 2H, NCH2), 3.17–3.08 (m,
2H, CH2), 2.68 (br.s, 2H, NH2), 2.60 (s, 3H, CH3), 2.06 (br.s,
3H, 3,5,7-Had), 1.87 (br.s, 6H, 2,8,9-Had), 1.75 (br.s, 6H,
4,6,10-Had). 13C NMR (150 MHz, DMSO-d6) δ 167.2 (2-Cth),
167.0 (CO, fum), 153.2 (1-Car), 152.9 (4-Cth), 134.6 (C-fum),
130.5 (4-Car), 126.0 (2,6-Car), 125.6 (3,5-Car), 115.7 (5-Cth),
47.4 (NCH2), 42.4 (2,8,9-Cad), 36.1 (4,6,10-Cad), 36.0 (1-Cad),
32.5 (CH3), 28.3 (3,5,7-Cad), 27.6 (CH2). Anal. calcd for
C30H36N2O8S: C, 61.63; H, 6.21; N, 4.79 found C, 61.47; H,
6.08; N, 5.01.
2-{2-[4-(1-Tricycloij3.3.1.13,7]decyl)phenyl]thiazol-4-yl}-
acetonitrile (2e). A solution of the chloride 15 (180 mg, 0.52
mmol) and KCN (260 mg, 5.24 mmol) in anhydrous DMF (2
mL), was heated at 60 °C under an argon atmosphere for 36
h and then chilled to room temperature. Water was then
added into the reaction mixture, which was extracted with
EtOAc. The organic layer was washed with water and brine,
dried over MgSO4, and then the solvent was evaporated in
vacuo. The solid residue was then purified by column chro-
matography. Elution with 20% EtOAc in hexanes afforded
compound 2e as a yellow crystalline solid (70 mg, 41%). M.p.:
2-{2-[4-(1-Tricycloij3.3.1.13,7]decyl)phenyl]thiazol-4-yl}-N,N-
dimethylethan-1-amine (2c). Dimethylamine 2c was prepared
in a similar way as the dimethylamine 1c, using the amine 2a
(220 mg, 0.64 mmol), as starting material to afford com-
pound 2c as yellow solid (150 mg, 85% from 10). M.p.
(difumarate): 302 °C (dec) (EtOH/Et2O). 1H NMR (400 MHz,
DMSO-d6) δ 7.89–7.83 (d, J = 8.2 Hz, 2H, 2,6-Har), 7.46 (m,
3H, 5-Hth, 3,5-Har), 6.57 (s, 4H, Hfum), 3.31–3.22 (m, 2H,
NCH2), 3.17–3.08 (m, 2H, CH2), 2.68 (br.s, 2H, NH), 2.46 (s,
6H, CH3), 2.06 (br.s, 3H, 3,5,7-Had), 1.87 (br.s, 6H, 2,8,9-Had),
1.75 (br.s, 6H, 4,6,10-Had). 13C NMR (150 MHz, DMSO-d6) δ
167.5 (4-Cth), 166.6 (CO, fum), 153.7 (4-Cth), 134.7 (1-Car),
134.6 (CH, fum), 130.9 (4-Car), 126.4 (2,6-Car), 126.0 (3,5-
Car), 116.0 (5-Cth), 56.4 (CH2N), 43.0 (CH3), 42.9 (2,8,9-Cad),
36.6 (4,6,10-Cad), 36.5 (1-Cad), 28.7 (3,5,7-Cad), 27.0 (CH2).
Anal. calcd for C31H38N2O8S: C, 62.19; H, 6.40; N, 4.68 found
C, 62.31; H, 6.64; N, 4.14.
1
159–160 °C. H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 8.5 Hz,
2H, 2,6H-ar), 7.44 (d, J = 8.4 Hz, 2H, 3,5-Har), 7.26 (s, 1H,
5-Hth), 3.95 (s, 2H, CH2), 2.12 (s, 3H, 3,5,7-Had), 1.93 (d, J =
2.1 Hz, 6H, 2,8,9-Had), 1.79 (q, 6H, 4,6,10-Had). 13C NMR
(150 MHz, CDCl3) δ 169.7 (2-Cth), 154.2 (1-Car), 145.6 (4-Cth),
130.4 (4-Car), 126.4 (2,6-Car), 125.6 (3,5-Car), 116.9 (CN),
115.6 (5-Cth), 43.0 (2,8,9-Cad), 36.7 (4,6,10-Cad), 36.5 (1-Cad),
28.9 (3,5,7-Cad), 20.7 (CH2). Anal. calcd for C21H22N2S: C,
75.41; H, 6.63; N, 8.38 found C, 74.34; H, 6.29; N, 8.51.
2-[4-(1-Tricyclo[3.3.1.13, 7 ]decyl)phenyl]-4-(thio-
cyanatemethyl)thiazole (2f). A solution of the chloride 15 (250
mg, 0.73 mmol) and KSCN (100 mg, 1.34 mmol) in EtOH (4
ml), was heated to 45 °C under an argon atmosphere over-
night. The reaction mixture was then poured onto a mixture
of ice and water and the resulting suspension was filtered.
The residue obtained was crystallized from EtOH to afford
compound 2f as a white solid (250 mg, 67%). M.p.: 169–170
N-{2-[2-(4-(1-Tricycloij3.3.1.13,7]decyl)phenyl)thiazol-4-yl]-
ethyl}acetamide (2d). The acetamide 2d was prepared as de-
scribed in the general method, using the amine 2a (150 mg,
1
°C. H NMR (600 MHz, CDCl3) δ 7.85 (d, J = 8.4 Hz, 2H, 2,6H-
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ar), 7.41 (d, J = 8.4 Hz, 2H, 3,5-Har), 7.23 (s, 1H, 5-Hth), 4.29
(s, 2H, CH2), 2.09 (s, 3H, 3,5,7-Had), 1.91 (d, 6H, 2,8,9-Had),
1.76 (q, 6H, 4,6,10-Had). 13C NMR (150 MHz, CDCl3) δ 169.7
(2-Cth), 154.2 (1-Car), 149.7 (4-Cth), 130.4 (4-Car), 126.5 (2,6-
Car), 125.6 (3,5-Car), 117.5 (5-Cth), 112.0 (SCN), 43.0 (2,8,9-
Cad), 36.7 (4,6,10-Cad), 36.50 (1-Cad), 33.9 (CH2), 28.9 (3,5,7-
Cad). Anal. calcd for C21H22N2S2: C, 68.81; H, 6.05; N, 7.64
found C, 68.81; H, 6.09; N, 7.59.
°C, for 2 h. The reaction mixture was then extracted with
EtOAc and the organic layer was dried over MgSO4 and
evaporated in vacuo. The resulting residue was then puri-
fied by column chromatography. Elution with 20% EtOAc
in hexanes afforded compound 2h as a white solid (100
1
mg, 65%). H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 8.6 Hz,
2H, 2,6H-ar), 7.42 (d, J = 8.5 Hz, 2H, 3,5-Har), 6.99 (s, 1H,
5-Hth), 3.70 (t, J = 6.9 Hz, 2H, CH2N), 3.09 (t, J = 7.1 Hz,
2H, CH2), 2.12 (s, 3H, 3,5,7-Had), 1.93 (d, 6H, 2,8,9-Had),
1.85–1.71 (m, 6H, 4,6,10-Had). 13C NMR (75 MHz, CDCl3) δ
168.5 (2-Cth), 154.0 (4-Cth), 153.7 (1-Car) 131.1 (4-Car),
126.5 (2,6-Car), 125.6 (3,5-Car), 114.6 (5-Cth), 50.7
(CH2N3), 43.2 (2,8,9-Cad), 36.9 (4,6,10-Cad), 36.6 (1-Cad),
31.5 (CH2), 29.0 (3,5,7-Cad). Anal. calcd for C21H24N4S: C,
69.20; H, 6.64; N, 15.37 found C, 69.08; H, 6.47; N, 14.99.
2-Bromo-1-[4-(1-Tricycloij3.3.1.13,7]decyl)phenyl]ethanone
(19). To a stirred solution of (1-phenyl)adamantane (18)35
(1.00 g, 4.71 mmol) and AlCl3 (700 mg, 5.10 mmol) in anhy-
drous DCM (10 mL) was added a solution of BrCOCH2Br (0.5
mL, 4.71 mmol) in anhydrous DCM (10 mL) under an argon
atmosphere, at −10 °C. The reaction mixture was then heated
to room temperature and stirred under an argon atmosphere
overnight. Then the reaction mixture was poured onto ice-wa-
ter, extracted with DCM and the organic layer was dried over
MgSO4 and the solvent evaporated under vacuum. The
resulting crude residue was purified by gradient column
chromatography. Elution with EtOAc 3–5% in hexanes
afforded compound 19 as a white solid (900 mg, 57%). M.p.:
Ethyl 2-{2-[4-(1-Tricycloij3.3.1.13,7]decyl)phenyl]thiazol-4-yl}-
acetate (16). 4-Chloroacetoacetate (700 mg, 2.43 mmol) was
added to a stirred mixture of thiobenzamide 14 (1 g, 3.68
mmol) in i-PrOH (8 mL), and the reaction mixture was stirred
overnight, at 110 °C, in an autoclave. The solvent was then re-
moved in vacuo and the resulting residue was dissolved in
EtOAc and washed with water, a saturated aqueous solution
of NaHCO3 and brine. The organic layer was then dried over
MgSO4 and the solvent evaporated under vacuum. The
resulting oil was triturated with EtOAc/hexanes to afford com-
pound 16 as a light orange solid (1.3 g, 92%) which was used
in the next step without further purification.
2-{2-[4-(1-Tricycloij3.3.1.13,7]decyl)phenyl]thiazol-4-yl}ethan-
1-ol (2g). To a stirred suspension of LiAlH4 (85 mg, 2.23
mmol) in anhydrous THF (5 mL), was added dropwise a solu-
tion of compound 16 (170 mg, 0.44 mmol) in anhydrous THF
(3 mL), under an argon atmosphere and then the reaction
mixture was stirred at ambient temperature for 2 h. Next, the
mixture was cooled in an ice bath and ethanol, water and a
NaOH (10%) solution were added in order. The resulting sus-
pension was then filtered, the filtrate was evaporated in vacuo
and extracted with DCM. The organic layer was then washed
with water, dried over MgSO4 and the solvent evaporated to
afford compound 2g as an off white solid (120 mg, 80%). M.
1
94–96 °C (EtOAc/Hex). H NMR (400 MHz, CDCl3) δ 7.94 (d, J
= 8.6 Hz, 2H, 2,6-Har), 7.48 (d, J = 8.6 Hz, 2H, 3,5-Har), 4.45
(s, 2H, CH2), 2.12 (s, 3H, 3,5,7-Had), 1.92 (d, J = 2.5 Hz, 6H,
2,8,9-Had), 1.83–1.75 (br.s, 6H, 4,6,8-Had). 13C NMR (75 MHz,
CDCl3) δ 191.0 (CO), 158.0 (1-Car), 129.0 (2,6-Cad), 127.5
(4-Cad), 125.6 (3,5-Car), 42.9 (2,8,9-Cad), 36.9 (1-Cad), 36.8
(3,6,10-Cad), 31.1 (CH2), 28.8 (3,5,7-Cad). Anal. calcd for
C18H21BrO: C, 64.87; H, 6.35 found C, 64.63; H, 6.46.
1
p.: 93–94 °C. H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 8.4 Hz,
2H, 2,6H-ar), 7.42 (d, J = 8.4 Hz, 2H, 3,5-Har), 6.94 (s, 1H,
5-Hth), 3.99 (s, 2H, CH2OH), 3.68 (s, 1H, OH), 3.02 (t, J = 5.5
Hz, 2H, CH2), 2.12 (s, 3H 3,5,7-Had), 1.95 (d, J = 11.0 Hz, 6H,
2,8,9-Had), 1.83–1.73 (m, 6H, 4,6,10-Had). 13C NMR (150
MHz, CDCl3) δ 168.5 (2-Cth), 155.7 (4-Cth), 153.8 (1-Car),
130.7 (4-Car), 126.3 (2,6-Car), 125.5 (3,5-Car), 113.4 (5-Cth),
62.1 (CH2OH), 43.0 (2,8,9-Cad), 36.7 (4,6,10-Cad), 36.4 (1-Cad),
33.8 (CH2), 28.9 (3,5,7-Cad). Anal. calcd for C21H25NOS: C,
74.30; H, 7.42; N, 4.13 found C, 74.53; H, 7.31; N, 3.95.
4-[4-(1-Tricycloij3.3.1.13,7]decyl)phenyl]thiazol-2-amine
hydrobromide (3a). A solution of the bromoketone 19 (130
mg, 0.39 mmol) and thiourea (30 mg, 0.39 mmol) in EtOH (3
mL) was heated at 80 °C, in an autoclave, overnight. The reac-
tion mixture was then cooled to room temperature, treated
with Et2O and the resulting precipitate was filtered to afford
compound 3a hydrobromide as a white solid (150 mg, 88%).
2-{2-[4-(1-Tricycloij3.3.1.13,7]decyl)phenyl]thiazol-4-yl)ethyl}-
methanesulfonate (17). To a stirred solution of the alcohol 2g
(170 mg, 0.50 mmol) and Et3N (85 μL) in DCM (2 mL), MsCl
(50 μL) was added dropwise at 0 °C. The reaction mixture
was stirred at ambient temperature overnight. 1 M hydrochlo-
ride solution was added, into the reaction mixture, which
was then extracted with EtOAc and the organic layer was
dried over MgSO4 and the solvent evaporated to afford com-
pound 17 as a yellow solid (170 mg, 95%), which used in the
next step without further purification.
1
M.p. (hydrobromide): 345 °C (dec) (EtOH/Et2O). H NMR (400
MHz, DMSO-d6) δ 8.84 (br.s, 3H, NH3), 7.66 (d, J = 8.5 Hz, 2H,
2,6-Har), 7.47 (d, J = 8.5 Hz, 2H, 3,5-Har), 7.18 (d, J = 5.1 Hz,
1H, 5-Hth), 2.07 (d, J = 8.1 Hz, 3H, 3,5,7-Had), 1.87 (br.s, 6H,
2,8,9-Had), 1.74 (s, 6H, 4,6,10-Had). 13C NMR (150 MHz,
DMSO-d6) δ 170.1 (4-Cth), 152.2 (2-Cth), 127.2 (1-Car), 125.7
(4-Car), 125.6 (2.6-Car), 125.3 (3,5-Car), 101.9 (5-Cth), 42.3
(2,8,9-Cad), 36.1 (4,6,10-Cad), 35.9 (1-Cad), 28.2 (3,5,7-Cad).
Anal. calcd for C19H22BrN2S: C, 58.31; H, 5.92; N, 7.16 found
C, 58.12; H, 5.85; N, 6.98.
2-[4-(1-Tricyclo[3.3.1.13,7]decyl)phenyl]-4-(2-azidoethyl)-
thiazole (2h). To a stirred solution of the mesylate 17 (180
mg, 0.42 mmol) in anhydrous DMF (2 mL), was added
NaN3 (40 mL) and the reaction mixture was heated at 60
2-{4-[4-(1-Tricycloij3.3.1.13,7]decyl)phenyl]thiazol-2-yl}-
methanamine difumarate (3b). A solution of the bromo-
ketone 19 (1.10 g, 3.30 mmol) and amide 20 (ref. 38) (750 mg,
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3.60 mmol) in i-PrOH (12 mL) was heated at 120 °C, in an au-
toclave, overnight. The reaction mixture was then cooled to
room temperature, treated with Et2O and the resulting pre-
cipitate was filtered to afford compound 3b (480 mg, 36%).
M.p. (difumarate): 172 °C (dec) (EtOH/Et2O). 1H NMR (400
MHz, DMSO-d6) δ 8.02 (s, 1H, 5-Hth), 7.90 (d, J = 8.5 Hz, 2H,
2,6-Har), 7.42 (d, J = 8.5 Hz, 2H, 3,5-Har), 6.57 (s, 4H, Hfum),
4.33 (s, 2H, CH2), 2.06 (s, 3H, 3,5,7-Had), 1.88 (d, J = 2.2 Hz,
6H, 2,8,9-Had), 1.74 (s, 6H, 4,6,10-Had). 13C NMR (75 MHz,
DMSO-d6) δ 167.7 (2-Cth), 166.8 (CO, fum), 151.0 (4-Cth),
134.5 (CH2fum), 131.4 (1-Car), 127.1 (4-Car), 125.9 (2,6-Car),
125.2 (3,5-Car), 114.5 (5-Cth), 42.6 (2,8,9-Cad), 40.8 (CH2N),
36.3 (4,6,10-Cad), 35.8 (1-Cad), 28.4 (3,5,7-Cad). Anal. calcd for
C28H32N2O8S: C, 60.62; H, 5.79; N, 5.03 found C, 60.33; H,
6.02; N, 4.89.
1H, 5-Hth), 7.41 (d, J = 8.4 Hz, 2H, 3,5-Har), 2.06 (s, 3H, 3,5,7-
Had), 1.87 (s, 6H, 2,8,9-Had), 1.74 (s, 6H, 4,6,10-Had). 13C
NMR (75 MHz, DMSO-d6) δ 160.2 (2-Cth), 154.0 (4-Cth), 151.1
(1-Car), 130.9 (4-Car), 125.8 (2,6-Car) 125.1 (3,5-Car), 107.4
(5-Cth), 42.9 (2,8,9-Cad), 36.1 (4,6,10-Cad), 35.7 (1-Cad), 28.3
(3,5,7-Cad). Anal. calcd for C20H25BrN4S: C, 55.43; H, 5.81; N,
12.93 found C, 55.31; H, 5.89; N, 13.23.
N-(2-(2-Phenylthiazol-4-yl)ethyl)IJ1-tricycloij3.3.1.13,7]-
decane)carboxamide (4a). A solution of 1-adamantylcarbonyl
chloride (450 mg, 2.26 mmol) in anhydrous THF (8 mL) was
added dropwise, at 0 °C onto a stirred solution of the
2-phenylthiazol-4-ethylamine (22)6 (308 mg, 1.51 mmol) and
Et3N (0.45 mL, 3.23 mmol) in THF (8 mL) and the reaction
mixture was stirred at ambient temperature under an argon
atmosphere overnight. The mixture was extracted with DCM
and the organic phase was then washed with water, dried
over MgSO4 and the solvent evaporated under reduced pres-
sure. The resulting residue was purified with column chro-
matography. Elution with 50% EtOAc in hexanes afforded
compound 4a as a white solid (270 mg, 49%). M.p.: 135–136
2-{4-[4-(1-Tricycloij3.3.1.13,7]decyl)phenyl]thiazol-2-yl}-
ethanamine hydrobromide (3c). Ethanamine 3c was prepared
in a similar way as the amine 3b, using the bromoketone 19
(800 mg, 2.40 mmol) and derivative 21 (ref. 7) (550 mg, 2.69
mmol) as starting materials to afford compound 3c hydro-
bromide as a white solid (850 mg, 85%). M.p. (hydro-
bromide): 261–263 °C (EtOH/Et2O). 1H NMR (400 MHz,
DMSO-d6) δ 7.98 (s, 1H, 5-Cth), 7.94–7.85 (m, 5H, NH3,
2,6-Har), 7.42 (d, J = 8.4 Hz, 2H, 3,5-Har), 3.34–3.26 (m, 4H,
NCH2, CH2), 2.07 (s, 3H, 3,5,7-Had), 1.88 (s, 6H, 2,8,9-Had),
1.74 (s, 6H, 4,6,10-Had). 13C NMR (150 MHz, DMSO-d6) δ
165.5 (4-Cth), 154.1 (2-Cth), 150.8 (1-Car), 125.9 (2,6-Car),
1245.0 (3,5-Car), 113.5 (5-Cth), 42.5 (2,8,9-Cad), 38.1 (NCH2),
36.1 (4,6,10-Cad), 35.7 (1-Cad), 30.3 (CH2), 28.3 (3,5,7-Cad).
Anal. calcd for C21H27BrN2S: C, 60.14; H, 6.49; N, 6.68 found
C, 60.38; H, 6.59; N, 6.45.
1
°C. H NMR (400 MHz, CDCl3) δ 7.99–7.91 (m, 2H, 2,6-Har),
7.46–7.38 (m, 3H, 3,4,5-Har), 6.96 (s, 1H, 5-Cth), 6.86 (br.s,
1H, NH), 3.60 (dd, J = 12.0, 5.6 Hz, 2H, CH2NH), 2.91 (t, J =
9,51 Hz 2H, CH2), 2.05 (br.s, 3H, 3,5,7-Had), 1.88 (s, 6H, 2,8,9-
Had), 1.70 (q, J = 12.1 Hz, 6H 4,6,10-Had). 13C NMR (150
MHz, CDCl3) δ 177.88 (CO), 168.2 (2-Cth), 155.9 (4-Cth),
133.5 (1-Car), 130.0 (4-Car), 128.8 (2,6-Car), 126.3 (3,5-Car),
114.2 (5-Cth), 40.5 (CH2N), 39.3 (2,8,9-Cad), 38.8 (1-Cad), 36.5
(4,6–10-Cad), 30.7 (CH2), 28.1 (3,5,7-Cad). Anal. calcd for
C22H26N2OS: C, 72.08; H, 7.15; N, 7.64 found C, 72.31; H,
7.09; N, 7.88.
2-{4-[4-(1-Tricycloij3.3.1.13,7]decyl)phenyl]thiazol-2-yl}-N,N-
dimethylethan-1-amine dihydrochloride (3d). Dimethylamine
3d was prepared in a similar way as the amine 1c, using the
derivative 3c (200 mg, 0.48 mmol) as starting material to af-
ford compound 3d as a white solid (150 mg, 85%). M.p. (di-
1-((1R,4R)-7,7-Dimethyl-2-oxobicycloij2.2.1]hept-1-yl)-N-(2-
(2-phenylthiazol-4-yl)ethyl)methanesulfonamide (4b). The
carboxamide 4b was prepared in a similar way as the deriva-
tive 4a, using 2-phenylthiazol-4-ethylamine (22)6 (339 mg, 1.66
mmol) and ( )-10-camphorsulfonyl chloride (623 mg, 2.49
mmol) as starting materials in DCM (7 mL), to afford 4b as a
viscous liquid (350 mg, 50%). M.p (hydrochloride): 144–145
1
hydrochloride): 200–202 °C (EtOH/Et2O). H NMR (400 MHz,
DMSO-d6) δ 10.84 (s, 1H, NHTh), 7.97 (br.s, 1H, 5-Hth), 7.88
(d, J = 8.4 Hz, 2H, 2,6-Har), 7.42 (d, J = 8.5 Hz, 2H, 3,5-Har),
5.16 (br.s, 1H, NH), 3.55 (s, 4H, CH2, NCH2), 2.83 (d, J = 4.9
Hz, 6H, 3,5,7-Had), 2.07 (s, 3H), 1.88 (d, J = 2.3 Hz, 6H, 2,8,9-
Had), 1.74 (s, 6H, 4,6,10-Had). 13C NMR (150 MHz, DMSO-d6)
δ 165.0 (4-Cth), 154.0 (2-Cth), 150.8 (1-Car), 131.3 (4-Car),
125.9 (2,6-Car), 125.0 (3,5-Car), 113.6 (5-Cth), 54.9 (NCH2),
42.5 (2,8,9-Cad), 42.2 (CH3), 36.2 (4,6,10-Cad), 35.7 (1-Cad),
28.3 (3,5,7-Cad), 27.6 (CH2). Anal. calcd for C23H3Cl2N2S: C,
62.86; H, 7.34; N, 6.37 found C, 62.72; H, 7.23; N, 6.11.
1
°C. H NMR (400 MHz, DMSO-d6) δ 7.93 (dd, J = 7.3, 2.2 Hz,
2H, 2,6-Har), 7.54–7.43 (m, 4H, 3,4,5-Har, 5-Hth), 7.24 (br.s,
1H, NH), 3.45–3.32 (m, 3H, CH2NH), 3.26 (d, J = 14.9 Hz, 1H,
CH2S), 2.97 (t, J = 7.2 Hz, 2H, CH2), 2.85 (d, J = 14.9 Hz, 1H,
CH2S), 2.30 (m, 2H, 3-Hcamexo, 6-Hcamexo), 2.00 (t, J = 4.4 Hz,
1H, 5-Hcam), 1.95–1.81 (m, 2H, 4-Hcamexo, 6-Hcamendo), 1.50
(ddd, J = 13.7, 9.3, 4.5 Hz, 1H, 3-Hcarendo), 1.39–1.30 (m, 1H,
4-Hcarendo), 0.96 (s, 3H, CH3), 0.73 (s, 3H, CH3). 13C NMR
(150 MHz, DMSO-d6) δ 215.0 (CO), 167.2 (2-Cth), 155.0
(4-Cth), 133.4 (1-Car), 130.7 (4-Car), 129.7 (2,6-Car), 126.6
(3,5-Car), 116.3 (5-Cth), 58.3 (2-Ccam), 48.2 (CH2), 48.0
(7-Ccam), 42.7 (6-Ccam), 42.5 (5-Ccam), 42.5 (CH2N), 32.2
(CH2), 26.7 (4-Ccam), 25.0 (3-Ccam), 19.8 (CH3), 19.7 (CH3).
Anal. calcd for C21H27ClN2O3S: C, 55.43; H, 5.98; N, 6.16
found C, 55.21; H, 6.11; N, 6.02.
1-{2-[4-(1-Tricycloij3.3.1.13,7]decyl)phenyl]thiazol-4-
yl}guanidine (3e). A stirred solution of the bromoketone 19
(200 mg, 0.60 mmol) and guanylthiourea (80 mg, 0.66 mmol)
in EtOH (4 mL) was refluxed overnight. The reaction mixture
was then cooled to room temperature, Et2O was added and
the resulting suspension was filtered to afford compound 3e
hydrobromide (200 mg, 89%). M.p. (hydrobromide): 358–359
°C. 1H NMR (400 MHz, DMSO-d6) δ 11.98 (s, 1H, NH), 8.22
(br.s, 4H, 2 × NH2), 7.85 (d, J = 8.4 Hz, 2H, 2,6-Har), 7.68 (s,
N-[2-(4-Phenylthiazol-2-yl)ethyl]IJ1-tricycloij3.3.1.13,7]decane)-
carboxamide (4c). To a stirred solution of the 4-phenylthiazol-
2-ethylamine hydrobromide (23)7 (300 mg, 1.05 mmol) in
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DMF/DCM 1 : 1 (10 mL), was added 1-adamantanecarboxylic
acid (227 mg, 1.26 mmol), HBTU (478 mg, 1.26 mmol), and
DIPEA (474 mg, 3.68 mmol) and the reaction mixture was
stirred at ambient temperature under an argon atmosphere,
overnight. The mixture was then partitioned between DCM
and an aqueous solution of citric acid (10%) and the aqueous
phase was extracted with DCM. The combined organic phase
was then washed with water and brine, dried over MgSO4
and the solvent evaporated under reduced pressure. The
resulting residue was purified with gradient column chroma-
tography. Elution with 10% to 50% EtOAc in hexanes
afforded compound 4a as a white solid (330 mg, 94%). M.p.:
107–108 °C. 1H NMR (400 MHz, CDCl3) δ 8.01–7.84 (m, 2H,
2,6-Har), 7.54–7.28 (m, 3,4,5-Har, 5-Hth), 6.92 (s, 1H, NH),
3.69 (dd, J = 11.8, 5.7 Hz, 3H, CH2N), 3.20 (t, J = 7.4 Hz, 3H,
CH2), 2.02 (s, 3H, 3,5,7-Had), 1.87 (d, J = 2.3 Hz, 6H, 2,8,9-
Had), 1.70 (q, J = 12.2 Hz, 6H, 4,6,10-Had).13C NMR (150
MHz, CDCl3) δ 177.9 (CO), 168.2 (2-Cth), 155.9 (4-Cth),
133.5 (1-Car), 130.0 (4-Car), 128.8 (2,6-Car), 126.3 (3,5-Car),
114.2 (5-Cth), 40.5 (CH2N), 39.3 (2,8,9-Cad), 38.8 (1-Cad), 36.5
(4,6–10-Cad), 30.7 (CH2), 28.1 (3,5,7-Cad). Anal. calcd for
C22H26N2OS: C, 72.09; H, 7.15; N, 7.64 found C, 72.27; H,
7.23; N, 7.92.
1-((1R,4R)-7,7-Dimethyl-2-oxobicycloij2.2.1]hept-1-yl)-N-(2-
(4-phenylthiazol-2-yl)ethyl)methanesulfonamide hydrochlo-
ride (4d). The sulfonamide 4d was prepared in a similar way
as the derivative 4b, using 4-phenylthiazol-2-ethylamine (23)7
(210 mg, 1.03 mmol) and ( )-10-camphorsulfonyl chloride
(400 mg, 1.59 mmol) as starting materials, to afford com-
pound 4d as a viscous liquid (300 mg, 70%). M.p. (hydrochlo-
ride): 130–131 °C. 1H NMR (400 MHz, DMSO-d6) δ 8.01 (s,
1H, 5-Hth), 7.95 (d, J = 7.5 Hz, 2H, 2,6-Har), 7.54–7.20 (m,
3H, 3,4,5-Har), 5.26 (s, 2H, NH), 3.46 (s, 2H, CH2N), 3.30 (d, J
= 14.9 Hz, 1H, CH2S), 3.24 (t, J = 6.9 Hz, 2H, CH2), 2.90 (d, J =
Dr. Kyriakos C. Prousis, (Institute of Chemical Biology, Na-
tional Hellenic Research Found) for NMR experiments.
Notes and references
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6-Hcamexo), 2.01 (t, J = 4.4 Hz, 1H, 5-Hcam), 1.95–1.83 (m,
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Conflicts of interest
There are no conflicts to declare.
Acknowledgements
We thank Dr. Dimitra Benaki (Division of Pharmaceutical
Chemistry, Department of Pharmacy, School of Health Sci-
ences, National and Kapodistrian University of Athens) and
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