Synthesis of N -(Hetero)arylconvolvine Derivatives through a Palladium-Catalyzed Buchwald-Hartwig Cross-Coupling

Article abstract of DOI:10.1055/s-0039-1690238

The present study describes the isolation of convolvine from the roots of the Tunisian plant Convolvulus dorycnium L. and its synthesis through a four-step sequence starting from tropine. Then, an efficient synthesis of N -(het)aryltropanes derivatives by

Full text of DOI:10.1055/s-0039-1690238

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2019, 51, A–J
paper
A
en
M. Hassine et al.
Paper
Synthesis
Synthesis of N-(Hetero)arylconvolvine Derivatives through a
Palladium-Catalyzed Buchwald–Hartwig Cross-Coupling
Manel Hassinea,b
R
H
N
N
N
Hichem Ben Jannet*b
NourEddine Ghermanic
Mouad Alamia
OMe
OMe
OMe
OMe
Br
+
cat.
FG
O
O
O
O
Buchwald–Hartwig
cross-coupling
Samir Messaoudi*a
Convolvine
from the Tunisian C. dorycnium
N-heteroaryl convolvine
analogues
a BioCIS-UMR 8076, Univ. Paris-Sud, CNRS, University Paris-
Saclay, Châtenay-Malabry, France
First Pd-catalyzed C(sp2)–N arylation of tropanone
Mild and operationally simple reaction conditions
Broad substrate scope and high FG tolerance
Antiproliferative activity
samir.messaoudi@u-psud.fr
N
b University of Monastir, Faculty of Science of Monastir,
Laboratory of Heterocyclic Chemistry, Natural Products
and Reactivity (LR11ES39), Team: Medicinal Chemistry and
Natural Products, Avenue of Environment, 5019 Monastir,
Tunisia
N
O
O
OMe
OMe
O
IC50 = 10 µM (HCT116)
hichem.bjannet@gmail.com
c Institut Galien UMR 8612, Univ. Paris-Sud, CNRS, University
Paris-Saclay, Châtenay-Malabry, France
Received: 02.10.2019
N
O
H
N
Accepted after revision: 14.10.2019
Published online: 05.11.2019
DOI: 10.1055/s-0039-1690238; Art ID: ss-2019-z0536-op
OH
N
O
OMe
OMe
O
O
O
O
O
O
L-Hyoscyamine
L-Cocaïne
(endo) Convolvine
Abstract The present study describes the isolation of convolvine from
the roots of the Tunisian plant Convolvulus dorycnium L. and its synthesis
through a four-step sequence starting from tropine. Then, an efficient
synthesis of N-(het)aryltropanes derivatives by a sequence of a palladi-
um-catalyzed N-arylationof convolvine has been established. This strat-
egy enabled access to unknown tropane scaffolds of biological inter-
ests.
O
O
N
O
Cl
N
O
NH2
Cl
HN
O
NH
O
N
Dichloropane
O
XL 888
Hsp90 inhibitor
I
F
Ioflupane
Key words convolvine, Buchwald–Hartwig reaction, palladium cataly-
sis, tropane
Figure 1 Tropane natural products and some semi-synthetic ana-
logues
Tropane is an important nitrogen bicyclic motif found in
many natural and synthetic compounds.1 Tropane deriva-
tives are among the economically most important pharma-
ceuticals.2 More than twenty active pharmaceutical ingre-
dients (APIs) containing the tropane moiety are manufac-
tured by pharmaceutical industries as antispasmodics,
anesthetics, antiemetrics, and bronchodilators.3
The biological importance of some Convolvulus species
and the high biological activity of the tropane alkaloids en-
couraged us to undertake a phytochemical study of Convol-
vulus dorycnium L. whose n-BuOH extract of the roots af-
forded an interesting tropane natural compound convolvine
(Figure 1), which was isolated for the first time from this
plant.
One of the interesting tropane compound currently un-
der clinical investigation is the tropanone-based inhibitor
XL888, which is reported as a potent and selective ATP-
competitive inhibitor of Hsp90.4 In preclinical studies,
XL888 inhibits the proliferation of a broad panel of human
tumor cell lines and induces marked degradation of HSP90
client proteins. In addition, XL888 is highly active in multi-
ple human tumor xenograft models in mice.
In the context of the development of new Hsp90 inhibi-
tors, we reported in a previous study that the 3-amidoquin-
olinone compound 6BrCaQ (Scheme 1)5,6 is a highly potent
Hsp90 inhibitor. This derivative displayed antiproliferative
activities ranging from 2 to 8 M against various cancer cell
lines (MCF7, MDA MB231, Caco2, IGROV-1, and ISHIKAWA).
Moreover, this lead compound is able to induce a significant
downregulation of several Hsp90 client proteins (HER2,
Raf-1, and cdk-4).
Because of the exciting activities of XL888 and 6BrCaQ,
we were interested to find out whether the combination of
the tropane core of XL888 and the quinoline nucleus of
6BrCaQ in one molecule may lead to more efficacious anti-
proliferative compounds of the type 5 (Scheme 1). Herein,
we planned to prepare a new series of N-(hetero)arylcon-
volvine analogues (Table 2), in which various chemical
modifications at the heteroaromatic nucleus were per-
formed in the aim to better understand the SAR in this nov-
el series. In this article, the synthesis and the biological
evaluation of novel (hetero)aryl convolvine analogues 5a–o
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–J
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
M. Hassine et al.
Paper
Synthesis
ant to note that the acylation reaction was also performed
in a gram scale (84 mmol, 12 g), and the product 3 was iso-
lated in a similar yield (66%).
O
N
N
OMe
O
H
N
Me
O
Br
NH2
HN
O
The X-ray crystal structure of N-methylconvolvine (3)11
depicted in Scheme 2 shows that the conformation of the
tropane scaffold and the aryl nucleus are not planar with an
dihedral angle around 90°. Moreover, the endo-stereochem-
istry of the tropine nucleus, which is corroborated with the
NMR data, was conserved during the acylation process as
confirmed by the X-crystal structure analysis of compound
3 (Scheme 2).
NH
N
O
XL888
H
N
6BrCaQ
OMe
IC50 = 4.1 nM (PI3K)
O
OMe
IC50 = 2 µM (MDA MDB 231)
O
Convolvine 2
Br
Hybride 6BrCaQ-Convolvine
With the N-methylconvolvine in our hand, we next
turned our attention to the deprotection of the nitrogen
atom in the intermediate 3. The challenge of this transfor-
mation is to achieve the demethylation while keeping intact
the ester function. Several methods are known for the de-
methylation of tropane derivatives12 such the use of ethyl
chloroformate or 2,2,2-trichloroethyl chloroformate as de-
methylating agents. These methods proceed through two
concomitant steps; (i) acylation/demethylation of the nitro-
gen and (ii) deacylation of the carbamate function. All our
attempts to synthesis the endo-convolvine (2) using these
two demethylating reagents, under several reported condi-
tions failed. At this stage, we decided to perform step by
step the protocol of the demethylation when 2,2,2-trichlo-
roethyl chloroformate was used. In the first step, the carba-
mate 4 resulting from acylation of the N-methylconvolvine
under microwave conditions followed by N-demethylation
of the ammonium intermediate, was obtained in a quanti-
tative yield (Scheme 2). Removal of the trichloroethoxycar-
bonyl group was then achieved using zinc dust in acetic
acid solution. Under these conditions the endo-convolvine
(2) was isolated in a 90% yield as a pure endo-conformer
without affecting the ester group. This sequence allows us
to obtain the convolvine (2) in 56% overall yield even when
achieving the synthesis on a gram scale (2 g).
Upon completion of the synthesis of the convolvine, we
turned our attention to functionalization of the nitrogen
atom of convolvine through Pd-catalyzed cross coupling.
The main issue of this coupling is to maintain the benzoic
ester group intact during the cross coupling under basic
conditions. To this end, we examined the coupling of 3-bro-
mo-1-methylquinolinone (1a with convolvine (2) as a mod-
el study under various source of palladium/ligand catalysts,
bases, and solvents. Representative results from this study
are summarized in Table 1. The reaction of 1a (1 equiv)
with 2 (2 equiv) was first investigated under our previously
reported procedure [Pd(OAc)2. (5 mol%), XantPhos (5 mol%),
Cs2CO3, 1,4-dioxane, at 110 °C]13 (Table 1, entry 1). Unfortu-
nately, this coupling reaction failed and only the starting
materials were recovered unchanged. Using the monoden-
tate ligand XPhos instead of the bidentate XantPhos was
also unsuccessful (entry 2). Interestingly, switching from
Cs2CO3 as the base to the more basic t-BuONa, the coupling
reaction furnished 5a in a 12% yield (entry 3). This first re-
(5)
N
N
OMe
O
O
OMe
O
R
N
H
OMe
OMe
O
O
N-aryl convolvine
analogues of type 5
Scheme 1 General strategy to N-(hetero)aryl convolvine analogues
are described. Preliminary in vitro efficacy of these com-
pounds in terms of antiproliferative activity is reported.
Convolvine (Figure 1) was isolated as a white solid from
the n-BuOH extract from the roots of the Tunisian Convol-
vulus dorycnium. Its structure was evidenced through the
1H and 13C spectroscopy examination and by comparison
with literature data.7 We note that this same compound has
been also isolated from C. subhirsutus8 and C. krauseanus9
without specifying the corresponding stereochemistry.
To have at our disposal a sufficient quantity of con-
volvine as a starting material for the further modifications,
we envisioned to perform its synthesis in a gram scale rath-
er than its isolation from plant. Accordingly, the synthesis
commenced from O-acylation of tropine with the pre-
formed 2,3-dimethoxybenzoyl chloride (Scheme 2). Our
first attempt was performed according to the protocol of
Maksay et al.10 using NEt3 as a base in refluxing toluene. Un-
der these conditions, the desired N-methylconvolvine (3)
was isolated in yield, which never exceeded 20%. This result
is in concordance with the observation of Maksay et al.10
who has suggested that the acylation of tropine is usually
difficult because of the sterically hindered hydroxyl group.
To increase the yield of the O-acylation various reaction pa-
rameters were explored. Thus, when a solution of the
tropine and the freshly pre-formed 2,3-dimethoxybenzoyl
chloride in DCM was stirred at room temperature overnight
in the presence of triethylamine as a base and a catalytic
amount of DMAP, the N-methylconvolvine (3) was isolated
after purification in good 64% yield (Scheme 2). It is import-
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–J

C
M. Hassine et al.
Paper
Synthesis
OMe
OMe
HO
O
SOCl2
rt, 5 h
quantitative
Me
N
Me
N
OMe
OMe
OMe
OH
O
Cl
OMe
NEt3, DMAP
DCM, rt, 12 h
O
O
N-methylconvolvine 3
64%
12g scale, 66%
O
toluene, 140 °C, 4 h
MWI
O
Cl
quantitative
Cl
Cl
Cl
O
N
O
H
N
Zn dust, AcOH
OMe
OMe
OMe
OMe
80 °C, 2 h
90%
Cl
Cl Cl
O
O
O
O
4
Convolvine 2
X-ray of Convolvine 2
Scheme 2 Synthesis of convolvine (2)
sult indicates clearly that the reactivity of the amine of con-
volvine is far to be trivial. To increase the yield of 5a, we ex-
amined the influence of other reaction parameters. Pleas-
antly, when the coupling reaction was performed by using
the ratio of Pd/L = 1:2 [5 mol% Pd(OAc)2 and 10 mol% of
XPhos], the yield was improved up to 66% and the benzoic
ester was maintained intact (entry 5). By increasing the
amount of the base (from 1.5 equiv to 2 equiv), we managed
to isolate 95% of the desired product 5a (entry 6).
Table 1 Survey of Reaction Conditions for the N-Arylation of Con-
volvine (2) with 3-Bromoquinolinone 1aa
Pd cat.
L (10 mol%)
H
N
base (1.5 equiv)
N
OMe
OMe
N
OMe
OMe
1,4-dioxane
100 °C, 2 h
O
O
O
O
Br
O
O
5a
2
N
1a
Motivated by these results, we next explored the scope
of the coupling reaction of convolvine (2) with various (het-
ero)aryl bromides. Gratifyingly, all the N-arylations pro-
ceeded cleanly to give the substituted aryl N-convolvine an-
alogues 5a–o in good to excellent yields. As depicted in Ta-
ble 2, convolvine (2) was readily coupled with aryl
bromides having para and meta electron-withdrawing (F,
CF3, Cl, NO2, NC) or electron-donating (OMe) substituents to
give N-arylconvolvines 5b–f, 5j, 5l, and 5m in good yields.
In addition, the sterically demanding ortho substitution
pattern engaged in the coupling reaction of 2, furnished
compounds 5g and 5j having an ortho substituent group.
Interestingly, heteroarene such as 3-bromoquinolinone,
Entry
[Cu]
Pd(OAc)2
Base
Ligand
Yield (%)b
1
2
3
4
5
6c
Cs2CO3
XantPhos
XPhos
XPhos
–
0
Pd(OAc)2
Pd(OAc)2
Cs2CO3
0
t-BuONa
t-BuONa
t-BuONa
t-BuONa
12
10
66
95
PdG2XPhos
Pd(OAc)2
XPhos
XPhos
Pd(OAc)2
a Reaction conditions: 3-Bromoquinolinone 1a (1 equiv), convolvine (2; 2
equiv), [Pd(OAc)2] (5 mol%), ligand (5 mol%), base (1.5 equiv), 2 h, 100 °C,
[0.5 M].
b Yield of isolated 5a.
c Two equiv of the base were used.
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–J

D
M. Hassine et al.
Paper
Synthesis
5-bromoindole, and 3-bromopyridine were good substrates
in this reaction (compounds 5a, 5n,o). Of note, in the case
of coupling with dibromoquinolinone, only the bis-coupled
product 5o was isolated as the single product in 43% yield.
Upon completion of their syntheses, the in vitro activity
of convolvine derivatives 5a–o was evaluated by their
growth-inhibitory potency against a human colon carcino-
ma HCT-116 cells at the concentrations of 10–5 M. The
quantification of cell survival in this cell line was estab-
lished by using MTT assays after 72 hours exposure (Table
2), and GI50 values were determined at the concentration
required to produce 50% inhibition. Taxotere® was used as a
positive control (IC50 = 1 nM).
Table 2 Scope of the Coupling Reaction of Convolvine (2) with Various (Hetero)aryl Bromides and Cytotoxic Activity against HCT-116 Cellsa
Pd(OAc)2 (5 mol%)
Xphos (10 mol%)
H
N
N
(Het)Ar
t-BuONa (2 equiv)
OMe
OMe
OMe
OMe
FG
1,4-dioxane (2 mL)
100 °C, 2 h
O
O
FG
O
O
(Het)Ar
Br
5a–o
Electron-withdrawing groups
F
N
F3C
N
Cl
N
OMe
OMe
OMe
OMe
OMe
OMe
O
O
O
5b, 70%
5c, 57%
5d, 57%
Viab. [%]b = 47
O
O
O
O
1
Viab. [%]b = 68
2
Viab. [%]b = 43
4
CN
O2N
N
NC
N
N
OMe
OMe
OMe
OMe
OMe
O
O
OMe
5e, 58%
Viab. [%]b = 55
5f, 76%
Viab. [%]b = 50
5g, 30%
O
O
O
2
2
Viab. [%]b = 79
1
N
OMe
OMe
5h, 44%
Viab. [%]b = 40
GI50 = 98 µM
NC
2
5
O
O
Neutral and electron-donating groups
MeO
OMe
N
N
N
OMe
OMe
OMe
MeO
O
O
O
OMe
OMe
OMe
5i, 88%
Viab. [%]b = 55
5j, 96%
Viab. [%]b = 49
5k, 57%
O
O
4
O
1
Viab. [%]b = 55
2
N
OMe
OMe
5l, 68%
Viab. [%]b = 55
O
3
O
Heteroarenes
O
O
OMe
OMe
N
N
OMe
OMe
N
5o, 43%
Viab. [%]b = 54
5a, 95%
Viab. [%]b = 19
GI50 = 10 µM
Me
O
3
4
O
N
O
N
OMe
OMe
Me
O
N
O
O
N
N
N
OMe
OMe
Me
OMe
OMe
O
5m, 70%
Viab. [%]b = 57
GI50 = 63 µM
O
1
5n, 95%
Viab. [%]b = 58
O
1
2
O
a Reaction conditions: Convolvine (1 equiv), aryl bromide (2 equiv), Pd(OAc)2 (5 mol%), Xphos (10 mol%), t-BuONa (2 equiv), 1,4-dioxane at 100 °C, 2 h.
b Value of the anti-proliferative effect (% of viable cells compared to 100% untreated cells) of convolvine analogues in HCT-116 cell line at a concentration of 10–5
M (MTT method).
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–J

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M. Hassine et al.
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Synthesis
The results of this study, summarized in Table 2,
demonstrated that all tested compounds were able to de-
crease the cell viability in HCT-116 cells until 19–79% sur-
vivals compared to the reference compound 6BrCaQ (10%
survival) indicating the biological potential of convolvine
pharmacophore in this series. Interestingly, the combina-
tion of the quinolinone nucleus with convolvine moiety 5a
induced a significant decrease of the cell viability in HCT-
116 cells (19% survival) when compared with the reference
6BrCaQ (10% survival). Pleasantly, the growth inhibition
value GI50 for compound 5a (GI50 = 10 M) was measured
and was found to be approximatively the same that of the
reference 6BrCaQ (GI50 = 8 M). This result clearly validates
our initial strategy. Substitution of the nitrogen of the con-
volvine by an indole nucleus (compound 5m) did not pro-
duce a compound that inhibit cell growth more effectively
than the 5a (survival = 57%, GI50 = 63 M). Another import-
ant observation is that the disubstituted convolvine 5o af-
fects slightly the growth of HCT-116 cells (54% survival)
when compared with the monosubstituted convolvine 5a
(19% survival). These results clearly suggest that the pres-
ence of a bulky substituent at the C-7 position of the quino-
linone nucleus affect cell viability. It can be noted that con-
volvine (2) with free-NH is less cytotoxic since 60% of cells
survive when incubated with convolvine (2).
In conclusion, we have developed an efficient and prac-
tical protocol for the N-arylation of the tropane nucleus of
convolvine without affecting the benzoic ester part. This
transformation exhibited broad substrate scope with re-
spect to the aryl bromide partners. Through this methodol-
ogy, we designed and synthesized a series of N-(hete-
ro)arylconvolvines, and identified compound 5a displaying
the most stronger antiproliferative activity against HCT-116
cell lines. These preliminary results show the biological po-
tential of convolvine pharmacophore and suggest that
pharmaco-modulations of this compound may increase its
biological activity.
paratus and are uncorrected. High-resolution mass spectra (HR-MS)
were recorded on a Bruker MicroTOF spectrometer, using ESI with
MeOH as the carrier solvent. Nominal and exact m/z values are re-
ported in Daltons.
Plant Material
The roots of Convolvulus dorycnium L. were collected from the region
of Sidi Khelifa, Sousse (Tunisia) on June 2012. The plant was identified
by Prof. Fethia Harzallah-Skhiri in the Laboratory of Bioressources: In-
tegrative Biology and Valorization at Higher Institute of Biotechnolo-
gy of Monastir (Tunisia). A voucher specimen (CD-12) was deposited
in the herbarium of the above laboratory.
Extraction and Isolation
Dry roots of C. dorycnium (1.473 kg) were extracted twice with
MeOH/H2O mixture (7:3) for 2 days at rt. Then the aqueous solution
obtained after evaporation of solvent under vacuum was partitioned
with n-BuOH to yield 100 g (6.7%) of the corresponding extract. The
n-BuOH extract was subjected to RP-18 flash column chromatography
with gradient elution (H2O; H2O/MeOH, 90:10 to 30:70), yielding
twelve fractions (F1–F12) of which the fraction F9 appears to be of pure
convolvine (300 mg) according to TLC analysis.
8-Methyl-8-azabicyclo[3.2.1]octan-3-yl 3,4-Dimethoxybenzoate
(3)
To a solution of commercial endo-tropine (1 g, 7.08 mmol, 1 equiv) in
anhyd DCM were added 2,3-dimethoxybenzoyl chloride (1.562 g, 7.78
mmol, 1.1 equiv), NEt3 (2.961 mL, 21.2 mmol, 3 equiv), and 4-dime-
thylaminopyridine (0.951 g, 7.78 mmol, 1.1 equiv) under argon atmo-
sphere. The reaction mixture was stirred at rt overnight before being
cooled at 0 °C and quenched with sat. aq NH4Cl. The aqueous layer
was extracted with DCM (3 ×). The combined organic layers were
dried (MgSO4), filtered, and concentrated in vacuo. Purification by
flash column chromatography on silica gel yielded the desired prod-
uct (4.53 mmol) as a white solid; yield: 64% (4.53 mmol); mp 223–
224 °C; Rf = 0.58 (85:15 DCM/MeOH).
IR (neat): 2939, 2361, 1703, 1600, 1514, 1467, 1449, 1417, 1345,
1272, 1220, 1175, 1133, 1025, 877, 764, 632 cm–1
.
1H NMR (300 MHz, CDCl3):  = 7.56 (dd, J1 = 8.4 Hz, J2 = 1.9 Hz, 1 H,
H6′), 7.51 (d, J = 1.9 Hz, 1 H, H2′), 6.90 (d, J = 8.4 Hz, 1 H, H5′), 5.37 (m, 1
H, H3), 3.94 (s, 3 H, H7′), 3.92 (s, 3 H, H8′), 3.78 (br s, 2 H, H1,5), 2.77 (s, 3
H, H9), 2.55–2.25 (m, 6 H, H2,4,6,7), 2.20–2.05 (m, 2 H, H6,7).
13C NMR (75 MHz, CDCl3):  = 165.19 (C8), 153.53 (C4′), 149.06 (C3′),
123.14 (C6′), 122.38 (C1′), 112.10 (C2′), 110.53 (C5′), 65.19 (C3), 61.91
(C1,5), 56.22 (C7′), 56.15 (C8′), 40.21 (C9), 34.49 (C2,4), 24.95 (C6,7).
All reactions were conducted under an argon atmosphere. Solvents:
cyclohexane, pentane, EtOAc, DCM, and MeOH for extraction and
chromatography were of technical grade. The compounds were all
identified by usual physical methods, for example, 1D and 2D NMR
(COSY, HSQC, HMBC, and NOESY), IR, ES-HRMS. 1H and 13C NMR spec-
tra were measured in CDCl3 or acetone-d6 on a Bruker Avance 300 and
400 MHz spectrometers. 1H chemical shifts are reported in parts per
million from an internal standard TMS or of residual CHCl3 (7.27
ppm). Standard abbreviations are used to denote spin multiplicities.
13C chemical shifts are reported in parts per million from the central
peak of CDCl3 (77.14 ppm). IR spectra were recorded on a Bruker Vec-
tor 22 spectrophotometer and are reported in wave numbers (cm–1).
Rf values refer to TLC on 0.25 mm silica gel plates (60-F254). Flash
chromatography was performed on silica gel 60 (0.040–0.063 mm).
MS: m/z = 306.1705 ([M + H]+).
2,2,2-Trichloroethyl 3-[(3,4-Dimethoxybenzoyl)oxy]-8-azabicy-
clo[3.2.1]octane-8-carboxylate (4)
A Schlenk tube containing the N-Me convolvine (3; 0.1 g, 0.327 mmol,
1 equiv) was capped with a rubber septum, evacuated, and backfilled
with argon. This evacuation/backfill sequence was repeated one addi-
tional time. Anhyd toluene (2 mL) was added along with 2,2,2-trichlo-
roethyl chloroformate (0.135 mL, 0.982 mmol, 3 equiv). The septum
was replaced with a Teflon screwcap. The Schlenk tube was sealed,
and the mixture was stirred at 140 °C for 4 h under microwave irradi-
ation. The resulting suspension was cooled to rt and concentrated.
The desired product was obtained as a white solid; yield: quantitative
(0.32 mmol); mp 135–136 °C; Rf = 0.62 (6:4 cyclohexane/EtOAc).
Analytical TLC was performed on Merck precoated silica gel 60F
plates. Merck silica gel 60 (0.015–0.040 mm) was used for column
chromatography. Melting points were recorded on a Büchi B-450 ap-
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–J

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M. Hassine et al.
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Synthesis
IR (neat): 2937, 2361, 1713, 1702, 1601, 1514, 1465, 1414, 1313,
1289, 1270, 1248, 1221, 1178, 1102, 1078, 1023, 961, 942, 834, 762,
1H NMR (400 MHz, acetone-d6):  = 7.69 (dd, J1 = 8.4 Hz, J2 = 2.0 Hz, 1
H, H6′), 7.58 (d, J = 1.9 Hz, 1 H, H8′′), 7.53 (dd, J1 = 7.7 Hz, J2 = 1.3 Hz, 1
H, H7′′), 7.40 (d, J = 8.3 Hz, 1 H, H2′), 7.35–7.29 (m, 1 H, H5′′), 7.19–7.13
(m, 1 H, H3′′), 7.10 (d, J = 8.4 Hz, 1 H, H5′), 7.05 (s, 1 H, H4′′), 5.26 (m, 1
H, H3), 4.84 (br s, 2 H, H1,5), 3.91 (s, 3 H, H7′), 3.89 (s, 3 H, H8′), 3.73 (s, 3
H, H9′′), 2.40–2.34 (m, 2 H, H2,4), 2.32–2.27 (m, 2 H, H2,4), 2.15–2.11
(m, 2 H, H6,7), 1.84 (d, J = 14.4 Hz, 2 H, H6,7).
13C NMR (400 MHz, acetone-d6):  = 165.89 (C8), 159.55 (C2′′, 154.45
(C4′), 150.06 (C3′), 146.66 (C1′′), 137.94 (C8′′a), 136.19 (C4′′a), 127.07
(C5′′), 126.56 (C7′′), 124.00 (C6′′), 123.07 (C1′), 122.79 (C6′), 114.71 (C8′′),
114.46 (C2′), 113.00 (C5′), 111.92 (C4′′), 69.24 (C3), 56.23 (C7′), 56.12
(C8′), 55.01 (C1,5), 34.70 (C2,4), 31.58 (C9′′), 28.26 (C6,7).
713, 632 cm–1
.
1H NMR (300 MHz, CDCl3):  = 7.61 (dd, J1 = 8.4 Hz, J2 = 1.8 Hz, 1 H,
H6′), 7.52 (d, J = 1.8 Hz, 1 H, H2′), 6.89 (d, J = 8.4 Hz, 1 H, H5′), 5.33 (m, 1
H, H3), 4.84 (d, J = 12.0 Hz, 1 H, H10a), 4.66 (d, J = 12.0 Hz, 1 H, H10b),
4.41 (br s, 2 H, H1,5), 3.91 (s, 3 H, H7′), 3.90 (s, 3 H, H8′), 2.37–2.03 (m, 6
H, H2,4,6,7), 1.93 (m, 2 H, H6,7).
13C NMR (75 MHz, CDCl3):  = 165.45 (C8), 153.15 (C9), 151.40 (C4′),
148.81 (C3′), 123.24 (C6′), 122.96 (C1′), 111.98 (C2′), 110.45 (C5′), 95.92
(C11), 74.60 (C10), 67.84 (C3), 56.10 (C7′), 56.00 (C8′), 53.03 (C1), 52.90
(C5), 36.38 (C2), 35.61 (C4), 28.55 (C6), 27.70 (C7).
MS: m/z = 449.1559 ([M + H]+).
MS: m/z = 466.0526 ([M + H]+).
8-(4-Fluorophenyl)-8-azabicyclo[3.2.1]octan-3-yl 3,4-Dimethoxy-
benzoate (5b)
8-Azabicyclo[3.2.1]octan-3-yl 3,4-Dimethoxybenzoate [endo-Con-
volvine (2)]
Yield: 70% (0.70 mmol); yellow solid; mp 180–181 °C; Rf = 0.44 (cy-
clohexane/EtOAc 8:2).
A Schlenk tube was charged with the carbamate 4 (0.1 g, 0.214 mmol,
1 equiv) and Zc dust (0.042 g, 0.642 mmol, 3 equiv) in AcOH (2 mL).
The tube was capped with a rubber septum, evacuated, and backfilled
with argon. This evacuation/backfill sequence was repeated one addi-
tional time. The septum was replaced with a Teflon screwcap. The
Schlenk tube was sealed, and the mixture was stirred at 80 °C for 2 h.
The resulting suspension was cooled to rt and quenched with concd
aq NH4OH. The aqueous layer was extracted with DCM (3 ×). The
combined organic layers were dried (MgSO4), filtered, and concen-
trated in vacuo. Purification by flash column chromatography on sili-
ca gel afforded the desired product as a white solid; yield: 90% (0.192
mmol); mp 101–102 °C; Rf = 0.36 (8:2 CH2Cl2/MeOH).
IR (neat): 3050, 2956, 2937, 2915, 2838, 1702, 1601, 1589, 1517,
1504, 1465, 1442, 1416, 1377, 1358, 1345, 1328, 1291, 1270, 1249,
1227, 1211, 1175, 1132, 1107, 1085, 1033, 987, 948, 929, 880, 871,
819, 802, 764, 734, 707, 632 cm–1
.
1H NMR (300 MHz, CDCl3):  = 7.68 (dd, J1 = 8.4 Hz, J2 = 1.6 Hz, 1 H,
H6′), 7.58 (d, J = 1.6 Hz, 1 H, H2′), 7.02–6.81 (m, 3 H, H5′,5′′,3′′), 6.72 (m, 2
H, H2′′,6′′), 5.21 (m, 1 H, H3), 4.17 (br s, 2 H, H1,5), 3.95 (s, 3 H, H7′), 3.94
(s, 3 H, H8′), 2.46–2.09 (m, 6 H, H2,4,6,7), 1.76 (d, J = 15.2 Hz, 2 H,
H
6,7).
13C NMR (75 MHz, CDCl3):  = 165.73 (C8), 157.15 (C4′′), 153.17 (C4′),
148.90 (C3′), 142.92 (C1′′), 123.37 (C6′), 116.29 (C1′), 116.05 (C3′′,5′′),
116.00 (C2′′,6′′), 112.09 (C2′), 110.54 (C5′), 68.73 (C3), 56.17 (C7′), 56.08
(C8′), 53.63 (C1,5), 31.41 (C2,4), 28.32 (C6,7).
IR (neat): 2939, 2837, 1702, 1601, 1514, 1465, 1416, 1357, 1270,
1224, 1177, 1132, 1076, 1023, 875, 849, 765, 629 cm–1
.
13C NMR (75 MHz, CDCl3):  = 65.6, 152.9, 148.6, 123.3, 123.2, 111.9,
110.3, 68.5, 55.9, 53.4 (2 C), 37.6, 37.6, 29.4 (2 C).
MS: m/z = 292.1541 ([M + H]+).
MS: m/z = 386.1770 ([M + H]+).
8-[4-(Trifluoromethyl)phenyl]-8-azabicyclo[3.2.1]octan-3-yl 3,4-
Dimethoxybenzoate (5c)
Pd-Catalyzed Coupling of Convolvine (2) with Various Aryls and
Heteroaryls; General Procedure
Yield: 57% (0.57 mmol); white solid; mp 179–180 °C; Rf = 0.50 (cyclo-
A flame-dried resealable Schlenk tube was charged with Pd(OAc)2 (2
mg, 0.05 mmol, 5 mol%), Xphos (8 mg, 0.10 mmol, 10 mol%), the solid
reactant(s) [1.0 mmol of the 3-bromoquinolin-2(1H)-one/aryl/het-
eroaryl bromides, 2 mmol of convolvine (2)], and t-BuONa (33 mg, 2
mmol). The Schlenk tube was capped with a rubber septum, evacuat-
ed, and backfilled with argon; this evacuation/backfill sequence was
repeated one additional time. The solvent 1,4-dioxane (2 mL) was
added through the septum. The septum was replaced with a Teflon
screwcap. The Schlenk tube was sealed, and the mixture was stirred
at 100 °C for 2 h. The resulting suspension was cooled to rt and fil-
tered through Celite eluting with EtOAc, and the inorganic salts were
removed. The filtrate was concentrated and purification of the residue
by silica gel column chromatography gave the desired product.
hexane/EtOAc 7:3).
IR (neat): 2956, 2937, 2915, 2838, 1702, 1601, 1589, 1517, 1504,
1465, 1442, 1416, 1377, 1358, 1345, 1328, 1291, 1270, 1249, 1227,
1211, 1175, 1132, 1107, 1085, 1033, 987, 948, 929, 880, 871, 819,
802, 764, 734, 707, 632 cm–1
.
1H NMR (300 MHz, CDCl3):  = 7.69 (dd, J1 = 8.4 Hz, J2 = 1.6 Hz, 1 H,
H6′), 7.58 (d, J = 1.6 Hz, 1 H, H2′), 7.47 (d, J = 8.6 Hz, 2 H, H3′′,5′′), 6.94 (d,
J = 8.4 Hz, 1 H, H5′), 6.78 (d, J = 8.6 Hz, 2 H, H2′′,6′′), 5.22 (m, 1 H, H3),
4.30 (br s, 2 H, H1,5), 3.95 (s, 3 H, H7′), 3.94 (s, 3 H, H8′), 2.44–2.09 (m, 6
H, H2,4,6,7), 1.82 (d, J = 15.2 Hz, 2 H, H6,7).
13C NMR (75 MHz, CDCl3):  = 165.69 (C8), 153.24 (C1′′), 148.94 (C4′),
148.57 (C3′), 127.07 (C3′′), 127.02 (C5′′), 123.38 (C6′), 123.25 (C1′),
118.69 (C4′′), 118.26 (C7′′), 114.05 (C2′′,6′′), 112.11 (C2′), 110.56 (C5′),
68.59 (C3), 56.20 (C7′), 56.10 (C8′), 53.07 (C1,5), 31.94 (C2,4), 28.30 (C6,7).
8-(1-Methyl-2-oxo-1,2-dihydroquinolin-3-yl)-8-azabicyclo-
[3.2.1]octan-3-yl 3,4-Dimethoxybenzoate (5a)
MS: m/z = 436.1736 ([M + H]+).
Yield: 95% (0.97 mmol); yellow solid; mp 146–147 °C; Rf = 0.38 (CH-
Cl3/EtOAc 95:5).
8-(4-Chlorophenyl)-8-azabicyclo[3.2.1]octan-3-yl 3,4-Dimethoxy-
benzoate (5d)
IR (neat): 2958, 1702, 1632, 1592, 1563, 1514, 1463, 1416, 1379,
1359, 1342, 1309, 1289, 1270, 1248, 1219, 1177, 1167, 1132, 1107,
Yield: 57% (0.58 mmol); white solid; mp 170–171 °C; Rf = 0.61 (cyclo-
hexane/EtOAc 7:3).
1084, 1026, 979, 943, 872, 825, 764, 731, 701, 682, 647, 631 cm–1
.
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–J

G
M. Hassine et al.
Paper
Synthesis
IR (neat): 2957, 2935, 2916, 2837, 1710, 1703, 1596, 1514, 1494,
1464, 1443, 1416, 1379, 1358, 1345, 1329, 1296, 1270, 1248, 1225,
1216, 1176, 1133, 1098, 1082, 1032, 987, 948, 930, 881, 871, 814,
IR (neat): 2959, 2214, 1703, 1598, 1514, 1486, 1465, 1446, 1417,
1380, 1358, 1290, 1269, 1247, 1222, 1177, 1133, 1107, 1072, 1029,
935, 882, 814, 765, 733, 708, 631 cm–1
.
765, 736, 700, 682, 632 cm–1
.
1H NMR (300 MHz, CDCl3):  = 7.67 (dd, J1 = 8.4 Hz, J2 = 1.6 Hz, 1 H,
H6′), 7.57 (d, J = 1.6 Hz, 1 H, H2′), 7.52 (d, J = 7.7 Hz, 1 H, H3′′), 7.39 (t, J =
7.2 Hz, 1 H, H5′′), 6.98–6.77 (m, 3 H, H5′,4′′,6′′), 5.35 (m, 1 H, H3), 4.43 (br
s, 2 H, H1,5), 3.95 (s, 3 H, H7′), 3.94 (s, 3 H, H8′), 2.51–2.38 (m, 2 H,
1H NMR (300 MHz, CDCl3):  = 7.68 (dd, J1 = 8.4 Hz, J2 = 1.8 Hz, 1 H,
H6′), 7.58 (d, J = 1.8 Hz, 1 H, H2′), 7.19 (d, J = 8.8 Hz, 2 H, H3′′,5′′), 6.93 (d,
J = 8.4 Hz, 1 H, H5′), 6.70 (d, J = 8.9 Hz, 2 H, H2′′,6′′), 5.20 (m, 1 H, H3),
4.20 (br s, 2 H, H1,5), 3.95 (s, 3 H, H7′), 3.94 (s, 3 H, H8′), 2.42–2.06 (m, 6
H, H2,4,6,7), 1.76 (d, J = 15.2 Hz, 2 H, H6,7).
H
2,4), 2.28–2.24 (m, 2 H, H2,4), 2.12–2.06 (m, 2 H, H6,7), 2.00 (d, J =
16.4 Hz, 2 H, H6,7).
13C NMR (75 MHz, CDCl3):  = 165.71 (C8), 153.19 (C4′), 148.91 (C3′),
144.95 (C1′′), 129.55 (C3′′,5′′), 123.37 (C6′), 123.33 (C4′′), 121.88 (C1′),
116.21 (C2′′,6′′), 112.09 (C2′), 110.55 (C5′), 68.70 (C3), 56.18 (C7′), 56.09
(C8′), 53.26 (C1,5), 31.46 (C2,4), 28.33 (C6,7).
13C NMR (75 MHz, CDCl3):  = 165.68 (C8), 153.18 (C4′), 152.14 (C1′′),
148.90 (C3′), 135.29 (C5′′), 133.84 (C3′′), 123.37 (C6′), 123.29 (C1′),
119.79 (C7′′), 119.37 (C4′′), 116.61 (C6′′), 112.13 (C2′), 110.54 (C5′),
101.59 (C2′′), 68.23 (C3), 57.28 (C1,5), 56.18 (C7′), 56.10 (C8′), 36.15 (C2,4),
27.73 (C6,7).
MS: m/z = 402.1468 ([M + H]+).
MS: m/z = 393.1811 ([M + H]+).
8-(4-Nitrophenyl)-8-azabicyclo[3.2.1]octan-3-yl 3,4-Dimethoxy-
benzoate (5e)
8-(3-Cyanophenyl)-8-azabicyclo[3.2.1]octan-3-yl 3,4-Dimethoxy-
benzoate (5h)
Yield: 58% (0.58 mmol); yellow solid; mp 202–203 °C; Rf = 0.59 (cy-
clohexane/EtOAc 7:3).
Yield: 44% (0.44 mmol); white solid; mp 149–150 °C; Rf = 0.35 (cyclo-
hexane/EtOAc 7:3).
IR (neat): 2960, 2917, 2850, 2214, 1710, 1705, 1605, 1514, 1494,
1465, 1446, 1417, 1383, 1348, 1306, 1290, 1272, 1249, 1223, 1178,
1168, 1134, 1107, 1086, 1031, 988, 945, 930, 883, 871, 822, 766, 736,
IR (neat): 2958, 2838, 2359, 2227, 1705, 1598, 1571, 1515, 1492,
1466, 1438, 1417, 1379, 1338, 1305, 1290, 1272, 1218, 1177, 1133,
699, 632 cm–1
.
1109, 1083, 1033, 982, 942, 873, 765, 733, 682, 632 cm–1
.
1H NMR (300 MHz, CDCl3):  = 8.15 (d, J = 9.2 Hz, 2 H, H3′′,5′′), 7.67 (dd,
J1 = 8.4 Hz, J2 = 1.8 Hz, 1 H, H6′), 7.57 (d, J = 1.8 Hz, 1 H, H2′), 6.94 (d, J =
8.4 Hz, 1 H, H5′), 6.70 (d, J = 9.2 Hz, 2 H, H2′′,6′′), 5.26 (m, 1 H, H3), 4.39
(br s, 2 H, H1,5), 3.96 (s, 3 H, H7′), 3.95 (s, 3 H, H8′), 2.47–2.10 (m, 6 H,
H NMR (300 MHz, CDCl3):  = 7.68 (dd, J1 = 8.4 Hz, J2 = 1.6 Hz, 1 H, H6′),
7.57 (d, J = 1.6 Hz, 1 H, H2′), 7.30 (t, J = 7.9 Hz, 1 H, H5′′), 7.06–6.82 (m,
4 H, H4′′,6′′,2′′,5′), 5.22 (m, 1 H, H3), 4.24 (br s, 2 H, H1,5), 3.95 (s, 3 H, H7′),
3.94 (s, 3 H, H8′), 2.43–2.11 (m, 6 H, H2,4,6,7), 1.82 (d, J = 15.3 Hz, 2 H,
H
2,4,6,7), 1.92 (d, J = 15.2 Hz, 2 H, H6,7).
H6,7).
13C NMR (75 MHz, CDCl3):  = 165.63 (C8), 153.38 (C1′), 150.67 (C4′),
149.01 (C3′), 137.51 (C4′′), 126.86 (C3′′), 126.77 (C5′′), 123.40 (C6′),
123.04 (C1′), 112.82 (C2′′,6′′), 112.14 (C2′), 110.60 (C5′), 68.17 (C3), 56.24
(C7′), 56.15 (C8′), 53.61 (C1,5), 33.25 (C2,4), 28.20 (C6,7).
13C NMR (75 MHz, CDCl3):  = 165.66 (C8), 153.25 (C4′), 148.93 (C1′′),
146.47 (C3′), 130.48 (C5′′), 123.38 (C6′), 123.17 (C1′), 120.37 (C4′′),
119.63 (C7′′), 119.02 (C6′′), 117.64 (C2′′), 113.55 (C3′′), 112.09 (C2′),
110.56 (C5′), 68.40 (C3), 56.20 (C7′), 56.10 (C8′), 53.16 (C1,5), 31.74 (C2,4),
28.27 (C6,7).
MS (APCI positive): m/z = 413.1705 ([M + H]+).
MS: m/z = 393.1811 ([M + H]+).
8-(4-Cyanophenyl)-8-azabicyclo[3.2.1]octan-3-yl 3,4-Dimethoxy-
benzoate (5f)
8-(4-Methoxyphenyl)-8-azabicyclo[3.2.1]octan-3-yl 3,4-Dime-
thoxybenzoate (5i)
Yield: 76% (0.76 mmol); white solid; mp 206–207 °C; Rf = 0.40 (cyclo-
hexane/EtOAc 7:3).
Yield: 88% (0.88 mmol); white solid; mp 136–137 °C; Rf = 0.54 (cyclo-
hexane/EtOAc 7:3).
IR (neat): 3055, 2961, 2927, 2854, 1704, 1605, 1588, 1513, 1464,
1444, 1420, 1383, 1350, 1292, 1266, 1223, 1179, 1168, 1134, 1104,
1080, 1032, 986, 943, 870, 842, 822, 796, 766, 733, 702, 664, 630 cm–
IR (neat): 3051, 2960, 2933, 2854, 1710, 1707, 1603, 1510, 1465,
1445, 1418, 1381, 1360, 1291, 1266, 1242, 1224, 1215, 1179, 1132,
1108, 1086, 1034, 1004, 930, 879, 853, 821, 791, 767, 733, 702, 632
1
.
cm–1
.
1H NMR (300 MHz, CDCl3):  = 7.67 (dd, J1 = 8.4 Hz, J2 = 1.6 Hz, 1 H,
H6′), 7.57 (d, J = 1.6 Hz, 1 H, H2′), 7.49 (d, J = 8.8 Hz, 2 H, H3′′,5′′), 6.93 (d,
J = 8.4 Hz, 1 H, H5′), 6.74 (d, J = 8.8 Hz, 2 H, H2′′,6′′), 5.23 (m, 1 H, H3),
4.31 (br s, 2 H, H1,5), 3.95 (s, 3 H, H7′), 3.94 (s, 3 H, H8′), 2.42–2.09 (m, 6
H, H2,4,6,7), 1.86 (d, J = 15.3 Hz, 2 H, H6,7).
13C NMR (75 MHz, CDCl3):  = 165.65 (C8), 153.31 (C1′), 148.93 (C4′,3′),
134.13 (C3′′,5′′), 123.38 (C6′), 123.11 (C1′), 120.49 (C7′′), 114.21 (C2′),
112.11 (C5′), 110.58 (C2′′,6′′), 98.47 (C4′′), 68.33 (C3), 56.22 (C7′), 56.12
(C8′), 53.11 (C1,5), 32.52 (C2,4), 28.23 (C6,7).
1H NMR (300 MHz, CDCl3):  = 7.69 (dd, J1 = 8.4 Hz, J2 = 1.5 Hz, 1 H,
H6′), 7.59 (d, J = 1.5 Hz, 1 H, H2′), 6.93 (d, J = 8.4 Hz, 1 H, H5′), 6.86 (d, J =
8.9 Hz, 2 H, H2′′,6′′), 6.76 (d, J = 9.0 Hz, 2 H, H3′′,5′′), 5.22 (m, 1 H, H3), 4.18
(br s, 2 H, H1,5), 3.95 (s, 3 H, H7′), 3.94 (s, 3 H, H8′), 3.77 (s, 3 H, H7′′),
2.48–2.09 (m, 6 H, H2,4,6,7), 1.75 (d, J = 15.1 Hz, 2 H, H6,7).
13C NMR (75 MHz, CDCl3):  = 165.71 (C8), 153.09 (C4′), 151.89 (C4′′),
148.85 (C3′), 140.74 (C1′′), 123.41 (C6′), 123.33 (C1′), 116.35 (C2′′,6′′),
115.24 (C3′′,5′′), 112.06 (C2′), 110.51 (C5′), 68.86 (C3), 56.13 (C7′), 56.03
(C8′), 55.77 (C7′′), 53.71 (C1,5), 31.50 (C2,4), 28.25 (C6,7).
MS: m/z = 393.1815 ([M + H]+).
MS: m/z = 398.1968 ([M + H]+).
8-(2-Cyanophenyl)-8-azabicyclo[3.2.1]octan-3-yl 3,4-Dimethoxy-
benzoate (5g)
8-(2-Methoxyphenyl)-8-azabicyclo[3.2.1]octan-3-yl 3,4-Dime-
thoxybenzoate (5j)
Yield: 30% (0.30 mmol); white solid; mp 138–139 °C; Rf = 0.35 (cyclo-
hexane/EtOAc 7:3).
Yield: 96% (0.96 mmol); white solid; mp 129–130 °C; Rf = 0.42 (cyclo-
hexane/EtOAc 7:3).
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–J

H
M. Hassine et al.
Paper
Synthesis
IR (neat): 2956, 2836, 2255, 1704, 1601, 1516, 1498, 1466, 1453,
1417, 1378, 1356, 1291, 1271, 1221, 1177, 1130, 1108, 1069, 1030,
IR (neat): 2957, 1702, 1624, 1601, 1570, 1514, 1491, 1464, 1448,
1418, 1379, 1353, 1291, 1270, 1247, 1218, 1177, 1163, 1132, 1107,
933, 910, 881, 813, 766, 728, 648, 631 cm–1
.
1083, 1033, 941, 877, 822, 765, 728, 648, 631 cm–1
.
1H NMR (300 MHz, CDCl3):  = 7.69 (dd, J1 = 8.4 Hz, J2 = 1.8 Hz, 1 H,
H6′), 7.59 (d, J = 1.8 Hz, 1 H, H2′), 6.92 (d, J = 8.4 Hz, 1 H, H5′), 6.86–6.83
(m, 4 H, H3′′,4′′,5′′,6′′), 5.34 (m, 1 H, H3), 4.21 (br s, 2 H, H1,5), 3.94 (s, 6 H,
1H NMR (300 MHz, CDCl3):  = 7.76 (dd, J1 = 8.4 Hz, J2 = 1.8 Hz, 1 H,
H6′), 7.65 (d, J = 1.6 Hz, 1 H, H2′), 7.30 (d, J = 4.1 Hz, 1 H, H5′′), 7.06 (d, J =
1.7 Hz, 1 H, H4′′), 7.02 (d, J = 3.0 Hz, 1 H, H3′′), 6.98 (d, J = 8.4 Hz, 1 H,
H6′′), 6.93 (dd, J1 = 8.9 Hz, J2 = 1.9 Hz, 1 H, H7′′), 6.39 (d, J = 2.9 Hz, 1 H,
H2′′), 5.25 (m, 1 H, H3), 4.33 (br s, 2 H, H1,5), 4.00 (s, 6 H, H7′,8′), 3.79 (s, 3
H, H9′′), 2.54–2.49 (m, 2 H, H2,4), 2.39–2.21 (m, 4 H, H2,4,6,7), 1.82
(d, 2 H, J = 15.1 Hz, H6,7).
13C NMR (75 MHz, CDCl3):  = 165.80 (C8), 153.06 (C4′), 148.84 (C3′),
140.52 (C1′′), 131.15 (C4′′a), 129.69 (C4′′b), 129.16 (C6′′), 123.56 (C1′),
123.38 (C6′), 112.61 (C2′), 112.09 (C5′), 110.53 (C3′′), 110.20 (C2′′),
105.92 (C8′′), 99.96 (C7′′), 69.17 (C3), 56.17 (C7′), 56.07 (C8′), 54.17 (C1,5),
32.97 (C9′′), 31.82 (C2,4), 28.28 (C6,7).
H
H
7′,8′), 3.86 (s, 3 H, H7′′), 2.52–2.35 (m, 2 H, H2,4), 2.28–2.02 (m, 4 H,
2,4,6,7), 1.91 (d, J = 14.8 Hz, 2 H, H6,7).
13C NMR (75 MHz, CDCl3):  = 165.75 (C8), 153.01 (C4′), 151.22 (C2′′),
148.80 (C3′), 138.72 (C1′′), 123.55 (C1′), 123.35 (C6′), 121.14 (C4′′),
120.92 (C3′′), 116.85 (C6′′), 112.09 (C2′), 111.94 (C5′′), 110.49 (C5′), 68.77
(C3), 56.44 (C7′), 56.12 (C8′), 56.04 (C7′′), 55.61 (C1,5), 36.36 (C2,4), 27.65
(C6,7).
MS: m/z = 398.1968 ([M + H]+).
MS: m/z = 421.2122 ([M + H]+).
8-(3-Methoxyphenyl)-8-azabicyclo[3.2.1]octan-3-yl 3,4-Dime-
thoxybenzoate (5k)
8-(Pyridin-3-yl)-8-azabicyclo[3.2.1]octan-3-yl 3,4-Dimethoxyben-
zoate (5n)
Yield: 57% (0.57 mmol); white solid; mp 123–124 °C; Rf = 0.44 (cyclo-
hexane/EtOAc 7:3).
Yield: 95% (0.95 mmol); white solid; mp 140–141 °C; Rf = 0.45
(CH2Cl2/EtOAc 4:6).
IR (neat): 2958, 2836, 2253, 1710, 1610, 1600, 1573, 1515, 1494,
1465, 1417, 1359, 1290, 1271, 1222, 1178, 1164, 1133, 1108, 1081,
1032, 983, 941, 909, 872, 765, 727, 688, 648 cm–1
.
IR (neat): 2957, 2838, 2360, 1703, 1601, 1580, 1515, 1487, 1465,
1418, 1378, 1349, 1302, 1290, 1272, 1248, 1218, 1177, 1133, 1108,
1H NMR (300 MHz, CDCl3):  = 7.69 (dd, J1 = 8.4 Hz, J2 = 1.8 Hz, 1 H,
H6′), 7.58 (d, J = 1.8 Hz, 1 H, H2′), 7.17 (t, J = 8.1 Hz, 1 H, H5′′), 6.93 (d, J =
8.4 Hz, 1 H, H5′), 6.42 (dd, J1 = 8.1 Hz, J2 = 1.7 Hz, 1 H, H6′′), 6.38–6.19
(m, 2 H, H2′′,4′′), 5.22 (m, 1 H, H3), 4.23 (br s, 2 H, H1,5), 3.94 (s, 3 H, H7′),
3.93 (s, 3 H, H8′), 3.80 (s, 3 H, H7′′), 2.44–2.05 (m, 6 H, H2,4,6,7), 1.76 (d,
J = 15.2 Hz, 2 H, H6,7).
13C NMR (75 MHz, CDCl3):  = 165.78 (C8), 161.21 (C3′′), 153.16 (C4′),
148.91 (C3′), 147.65 (C1′′), 130.49 (C5′′), 123.39 (C6′), 112.12 (C2), 111.19
(C1′), 110.56 (C5′), 108.15 (C4′′), 101.99 (C6′′), 101.72 (C2′′), 68.98 (C3),
56.21 (C7′), 56.11 (C8′), 55.32 (C7′′), 53.16 (C1,5), 31.68 (C2,4), 28.36 (C6,7).
1087, 1032, 986, 948, 930, 823, 798, 765, 730, 707, 632, 614 cm–1
.
1H NMR (300 MHz, CDCl3):  = 8.19 (br s, 1 H, H2′′), 7.98 (br s, 1 H, H4′′),
7.67 (dd, J1 = 8.4 Hz, J2 = 1.4 Hz, 1 H, H6′), 7.56 (d, J = 1.4 Hz, 1 H, H2′),
7.12–7.16 (m, 1 H, H5′′), 7.04 (d, J = 8.4 Hz, 1 H, H6′′), 6.92 (d, J = 8.4 Hz,
1 H, H5′), 5.20 (m, 1 H, H3), 4.26 (br s, 2 H, H1,5), 3.93 (s, 3 H, H7′), 3.92
(s, 3 H, H8′), 2.42–2.07 (m, 6 H, H2,4,6,7), 1.80 (d, J = 15.2 Hz, 2 H,
H
6,7).
13C NMR (75 MHz, CDCl3):  = 165.62 (C8), 153.18 (C4′), 148.87 (C3′),
142.29 (C1′′), 138.48 (C4′′), 137.57 (C2′′), 124.06 (C1′), 123.33 (C6′),
123.19 (C5′′), 121.49 (C6′′), 112.05 (C2′), 110.52 (C5′), 68.44 (C3), 56.15
(C7′), 56.05 (C8′), 52.83 (C1,5), 31.58 (C2,4), 28.18 (C6,7).
MS: m/z = 398.1968 ([M + H]+).
MS: m/z = 369.1811 ([M + H]+).
8-Phenyl-8-azabicyclo[3.2.1]octan-3-yl 3,4-Dimethoxybenzoate
(5l)
8-(6-{(1R,3R,5S)-3-[(3,4-dimethoxybenzoyl)oxy]-8-azabicyclo-
[3.2.1]octan-8-yl}-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)-8-
azabicyclo[3.2.1]octan-3-yl 3,4-Dimethoxybenzoate (5o)
Yield: 68% (0.68 mmol); white solid; mp 183–184 °C; Rf = 0.48 (cyclo-
hexane/EtOAc 7:3).
IR (neat): 2360, 2341, 2330, 1704, 1597, 1511, 1460, 1418, 1387,
1321, 1303, 1271, 1226, 1193, 1174, 1140, 1114, 1086, 1029, 872,
Yield: 43% (0.43 mmol); white solid; mp 118–119 °C; Rf = 0.51
(CH2Cl2/EtOAc 9:1).
831, 766, 752, 724 cm–1
.
IR (neat): 2958, 2917, 2851, 1703, 1633, 1604, 1589, 1514, 1465,
1439, 1417, 1380, 1346, 1290, 1271, 1249, 1222, 1178, 1168, 1133,
1107, 1085, 1031, 987, 944, 931, 880, 872, 821, 798, 765, 734, 701,
1H NMR (300 MHz, CDCl3):  = 7.70 (dd, J1 = 8.4 Hz, J2 = 1.8 Hz, 1 H,
H6′), 7.59 (d, J = 1.8 Hz, 1 H, H2′), 7.29 (s, 1 H, H3′′), 7.23 (s, 1 H, H5′′),
6.94 (d, J = 8.4 Hz, 1 H, H5′), 6.80 (d, J = 8.5 Hz, 2 H, H2′′,6′′), 6.72 (t, 1 H,
J = 7.3 Hz, H4′′), 5.22 (m, 1 H, H3), 4.27 (br s, 2 H, H1,5), 3.96 (s, 3 H, H7′),
3.95 (s, 3 H, H8′), 2.48–2.04 (m, 6 H, H2,4,6,7), 1.77 (d, J = 15.1 Hz, 2 H,
632 cm–1
.
1H NMR (300 MHz, acetone-d6):  = 7.69 (dd, J1 = 8.4 Hz, J2 = 1.9 Hz, 2
H, H6′,6′′′′), 7.58 (br s, 2 H, H2′,2′′′′), 7.31 (d, J = 8.8 Hz, 1 H, H8′′), 7.16–6.92
(m, 5 H, H5′,4′′,5′′,7′′,5′′′′), 5.26 (m, 1 H, H3), 5.18 (m, 1 H, H3′′′), 4.83 (br s, 2
H, H1,5), 4.35 (br s, 2 H, H1′′′,5′′′), 3.91 (s, 6 H, H7′,8′), 3.89 (s, 6 H, H7′′′′,8′′′′),
3.69 (s, 3 H, H9′′), 2.80 (br s, 2 H, H2,4), 2.44–2.22 (m, 6 H, H2,4,6,7),
1.87–1.76 (m, 8 H, H2′′,4′′,6′′,7′′).
H
6,7).
13C NMR (75 MHz, CDCl3):  = 165.74 (C8), 153.13 (C4′), 148.88 (C3′),
146.30 (C1′′), 129.72 (C3′′,5′′), 123.42 (C6′), 123.36 (C1′), 117.25 (C4′′),
115.07 (C2′′,6′′), 112.08 (C2′), 110.53 (C5′), 68.96 (C3), 56.17(C7′), 56.07
(C8′), 52.94 (C1,5), 31.53 (C2,4), 28.33 (C6,7).
13C NMR (75 MHz, acetone-d6):  = 165.87 (C8,8′′′), 154.46 (C2′′), 150.05
(C4′,4′′′′), 138.16 (C3′,3′′′′), 136.66 (C6′′), 134.57 (C1′′), 130.92 (C4′′a), 130.35
(C8′′a), 124.13 (C1′,1′′′′), 124.00 (C6 ′,6′′′′), 115.60 (C2′,2′′′′), 114.72 (C7′′),
112.98 (C5′,5′′′′), 111.90 (C4′′,5′′), 69.27 (C3,3′′′’), 56.24 (C7′,8′), 56.12
(C7′′′′,8′′′′), 55.00 (C1,5,1′′′,5′′′), 34.68 (C2,4,2′′′,4′′′), 32.26 (C9′′), 28.27 (C6,7,6′′′,7′′′).
MS: m/z = 368.1870 ([M + H]+).
8-(1-Methyl-1H-indol-5-yl)-8-azabicyclo[3.2.1]octan-3-yl 3,4-Di-
methoxybenzoate (5m)
Yield: 70% (0.70 mmol); white solid; mp 188–189 °C; Rf = 0.31 (cyclo-
hexane/EtOAc 7:3).
MS: m/z = 738.3414 ([M + H]+).
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–J

I
M. Hassine et al.
Paper
Synthesis
Protocol for Cell Culture and Proliferation Assay
References
Cancer cell lines were obtained from the American type Culture Col-
lection (Rockville, MD, USA) and were cultured according to the sup-
plier’s instructions. Briefly, HCT116 cells were grown in RPMI 1640
containing 10% FCS and 1% glutamine. All cell lines were maintained
at 37 °C in a humidified atmosphere containing 5% CO2. Cell viability
was assessed using Promega CellTiter-Blue TM reagent according to
the manufacturer’s instructions. Cells were seeded in 96-well plates
(5 × 103 cells/well) containing 50 L growth medium. After 24 h of
culture, the cells were supplemented with 50 L of the tested com-
pound dissolved in DMSO (less than 0.1% in each preparation). After
72 h of incubation, 20 L of resazurin was added for 2 h before record-
ing fluorescence (ex = 560 nm, em = 590 nm) using a Victor microti-
ter plate fluorimeter (PerkinElmer, USA). The IC50 corresponds to the
concentration of the tested compound that caused a decrease of 50%
in fluorescence of drug treated cells compared with untreated cells.
Experiments were performed in triplicate.
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Authors acknowledge support of this project by CNRS, University Par-
is Sud, and by La Ligue Nationale Contre le Cancer throughout an
Equipe Labellisée 2014 grant. The authors are grateful to the Ministry
of Higher Education and Scientific Research of Tunisia for financial
support. Our laboratory (BioCIS UMR 8076) is a member of the labo-
ratory of excellence LERMIT supported by a grant from ANR (ANR-10-
LABX-33).
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Acknowledgment
The authors are grateful to Prof. Fethia Harzallah-Skhiri, High Insti-
tute of Biotechnology of Monastir, Tunisia, for botanical identification
of the plant material.
Cambridge
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Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1690238.
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© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–J