Selective synthesis of n-acylnortropane derivatives in palladium-catalysed aminocarbonylation

Article abstract of DOI:10.3390/molecules26061813

The aminocarbonylation of various alkenyl and (hetero)aryl iodides was carried out using tropane-based amines of biological importance, such as 8-azabicyclo[3.2.1]octan-3-one (nortropinone) and 3α-hydroxy-8-azabicyclo[3.2.1]octane (nortropine) as N-nucleophile. Using iodoalkenes, the two nucleophiles were selectively converted to the corresponding amide in the presence of Pd(OAc)₂ /2 PPh₃ catalysts. In the presence of several iodo(hetero)arenes, the application of the bidentate Xantphos was necessary to produce the target compounds selectively. The new carboxamides of varied structure, formed in palladium-catalyzed aminocarbonylation reactions, were isolated and fully characterized. In this way, a novel synthetic method has been developed for the producing of N-acylnortropane derivatives of biological importance.

Full text of DOI:10.3390/molecules26061813

molecules
Article
Selective Synthesis of N-Acylnortropane Derivatives in
Palladium-Catalysed Aminocarbonylation
László Kollár 1,2,3, Ádám Erdélyi 1, Haroon Rasheed 1 and Attila Takács 1,2,
*
1
Department of Inorganic Chemistry, Faculty of Sciences, University of Pécs, Ifjúság útja 6, H-7624 Pécs,
Hungary; kollar@gamma.ttk.pte.hu (L.K.); erdelyi.adam99@gmail.com (Á.E.);
privateharoon@gmail.com (H.R.)
János Szentágothai Research Centre, University of Pécs, Ifjúság útja 20, H-7624 Pécs, Hungary
MTA-PTE Research Group for Selective Chemical Syntheses, Ifjúság útja 6, H-7624 Pécs, Hungary
Correspondence: takacsattila@gamma.ttk.pte.hu; Tel.: +36-72-503-600
2
3
*
Abstract: The aminocarbonylation of various alkenyl and (hetero)aryl iodides was carried out using
tropane-based amines of biological importance, such as 8-azabicyclo[3.2.1]octan-3-one (nortropinone)
and 3α-hydroxy-8-azabicyclo[3.2.1]octane (nortropine) as N-nucleophile. Using iodoalkenes, the two
nucleophiles were selectively converted to the corresponding amide in the presence of Pd(OAc)2/2
PPh3 catalysts. In the presence of several iodo(hetero)arenes, the application of the bidentate
Xantphos was necessary to produce the target compounds selectively. The new carboxamides
of varied structure, formed in palladium-catalyzed aminocarbonylation reactions, were isolated and
fully characterized. In this way, a novel synthetic method has been developed for the producing of
N-acylnortropane derivatives of biological importance.
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
Keywords: aminocarbonylation; N-acylnortropanes; carbon monoxide; palladium
Citation: Kollár, L.; Erdélyi, Á.;
Rasheed, H.; Takács, A. Selective
Synthesis of N-Acylnortropane
Derivatives in Palladium-Catalysed
Aminocarbonylation. Molecules 2021,
26, 1813. https://doi.org/10.3390/
molecules26061813
1. Introduction
Amide functionality can be found in numerous pharmaceutically, biologically active
and agrochemical molecules [1–3], and its formation has been deeply studied [4,5]. There
are several ways of introducing acyl functionality into simple model compounds or skele-
tons of practical importance. The application of conventional acylating agents is well
Academic Editors: Julien Petrignet,
Mauro Pineschi and Rafael Chinchilla
known and is referenced in reviews [
boxy compounds are widely used acylating agents producing the desired amide derivative
in the presence of amines. Acyl azides [ ], anhydrides [ 11], as well as esters [12 13] can
6], handbooks, and even textbooks [7]. Activated car-
Received: 18 February 2021
Accepted: 18 March 2021
Published: 23 March 2021
8
9–
,
be successfully used in the formation of amide bond. The most efficient and widely-used
method among the conventional amide synthesis is the reaction with acyl chlorides and
amines [14
to be noted that acyl chlorides have significant limitations (e.g., hydrolysis, racemization,
cleavage of protecting groups) [ ]. Due to the importance of amides, several novel methods
–18]. Despite of the widespread use of acyl chlorides in amide synthesis, it has
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iations.
6
have also been developed for their synthesis [19–22].
The palladium-catalyzed aminocarbonylation is also an effective and widespread
synthetic method for producing amides. Since the discovery of the aminocarbonylation
by Heck et al. (“Heck-carbonylation”) [23–25], the use of a primary or secondary amine,
carbon monoxide, and aryl/alkenyl halides (or their synthetic surrogates, aryl triflates,
and alkenyl triflates) in the presence of palladium catalysts leads to carboxamides in great
Copyright:
© 2021 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
variety [26
palladium-catalyzed aminocarbonylation as a key reaction, were recently synthesized in
our laboratory [38 45]. Just to illustrate the most recent developments, the functionalization
–37]. Several α,β-unsaturated carboxamides and aryl carboxamides, using
–
of aromatic N-heterocycles in aminocarbonylation should be mentioned [46–49].
When the hundreds of examples of aminocarbonylation reactions are surveyed, we
might conclude that great variety of aryl/alkenyl halides/triflates were investigated as
Molecules 2021, 26, 1813. https://doi.org/10.3390/molecules26061813
https://www.mdpi.com/journal/molecules

Molecules 2021, 26, 1813
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substrates in the presence of simple primary or as secondary amines as N-nucleophiles.
However, a relatively small number of investigations are focused on the “opposite” reaction,
i.e., applying amines of practical (for instance, pharmaceutical) importance and palladium-
acyl intermediates formed in situ from relatively simple aryl or alkenyl halide by oxidative
addition followed by carbon monoxide insertion. The palladium(II)-acyl species can be
considered as highly reactive acylating agents [50–52].
Considering the fact that the palladium-catalyzed aminocarbonylation reactions have
been widely applied to build-up amide functionality in several bioactive compounds and
natural products, this method has been chosen to produce novel N-acylnortropane deriva-
tives in our research. The high selectivity, the mild reaction conditions, and the tolerance
of wide range of functional groups make also more applicable the palladium-catalyzed
aminocarbonylation for the synthesis of our target compounds than the conventional
acylating methods.
The tropane-based derivatives have great importance in chemistry, which have been
indicated by their wide-ranging use. The synthesis of N-substituted nortropinones via
reactivity umpolung of tropinone has been carried out by Willand et al. [53]. The role
of twist-boat conformers in hydride reduction of tropinone has been investigated com-
putationally and compared with experiments [54]. The diastereoselective acetylation of
6,7-dihydroxytropinones has been investigated in enzyme-catalyzed reaction [55]. Recently,
a tropine-based ionic liquid was used for the resolution of racemic amino acids [56].
The functionalization of the tropane skeleton can be carried out efficiently in homo-
geneous catalytic reactions. The nonaflation–Heck reaction protocol was used for the
synthesis of 1,3-tropadiene [57]. The palladium-catalyzed alkoxycarbonylation of the enol-
triflate obtained from tropinone afforded the three epimers of diester in the presence of
ethylene glycol [58]. The vinylboronate derivative obtained from tropinone underwent
Suzuki–Miyaura coupling with aryl bromides resulting in aryl substituted nortopanes [59].
3-Iodo-2-tropene was transformed to the corresponding 3-carboxamides and 3-esters in
palladium-catalyzed amino- and alkoxycarbonylation, respectively [60]. A tropane-ring
heterocyclic compound, scopolamine was synthesized in rhodium-catalyzed [4 + 3] cy-
cloaddition reaction [61].
To the best of our knowledge, only just a few aromatic or
α,β-unsaturated N-acyl
nortropane derivatives can be found in the literature [62 63], and the using of nortropinone
,
and nortropine as nucleophiles in aminocarbonylation has not been mentioned. It has to
also be noted that the tropane-based derivatives have enormous biological relevance [64].
As a part of our long-standing interest in the investigation of the fine details of aminocar-
bonylation, we decided to investigate of use of tropane-derived nucleophiles in aminocar-
bonylation.
In this paper, the selective synthesis of N-acylnortropane derivatives, possessing a
variety of N-acyl moieties will be described.
2. Results
2.1. Aminocarbonylation of Iodoalkenes (
Azabicyclo[3.2.1]octan-3-one (nortropinone) (
tane (nortropine) ( ) as N-nucleophiles were applied for the aminocarbonylation of iodoalke
nes (such as 1-iodocyclohexene ( ), 4-tert-butyl-1-iodocyclohexene ( ), trans-1-iodo-1-octene
), 17-iodoandrost-16-ene ( ), and 2-iodobornene ( )) in the presence of palladium catalysts
(Scheme 1). Based on the prior knowledge of our research group [65 66], a low-ligated,
1–
5
) in the Presence of Tropane-Based Nucleophiles (
a, b)
a
) and 3 -hydroxy-8-azabicyclo[3.2.1]oc
α
b
1
2
(3
4
5
,
highly active Pd(0) catalyst, prepared in situ from Pd(OAc)2 and PPh3, was used. The
reduction of Pd(II) to catalytically active, highly unsaturated Pd(0) species took place on
the influence of the phosphine while it is oxidized to phosphine oxide [67–69].

Molecules 2021, 26, 1813
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Scheme 1. Aminocarbonylation of tropane-based nucleophiles (
a
,
b
) in the presence of iodoalkenes
(1–5) using Pd(OAc)2 +2 PPh3 in situ catalysts.
The investigation of aminocarbonylation of nortropane-based nucleophiles was started
with iodoalkenes ( ), as shown on Scheme 1 and in Table 1. Nortropinone ( ) was reacted
with 1-iodocyclohexene ( ) under atmospheric CO pressure. The target compound was
1–
5
a
1
observed just in traces by GC (entry 1) in short reaction time. Surprisingly, just 42%
conversion was observed after 24 h (entry 2), and the complete conversion was not reached
still after 48 h stirring (entry 3). Using elevated carbon monoxide pressure (40 bar), the
substrate 1 was completely transformed to the corresponding carboxamide (1a) after 24 h
(entry 5). It has to be noted, that double carbon monoxide insertion was not observed
under these conditions. It can be stated, based on this experiment and our previous
results, that the aminocarbonylation reactions of iodoalkenes do not provide the 2-keto-
carboxamide type products [70
time (entries 6 and 7) was necessary to reach the complete conversion than in the case of
and (entries 8 and 10). The N-acyl-nortropinone derivatives (1a 5a), synthesized in the
aminocarbonylation reactions, were isolated in good yields (77–86%).
The aminocarbonylation of nortropine (b) was also carried out in the presence of the
above mentioned substrates ( ). While the complete conversion of 17-iodoandrost-16-ene
) to the corresponding carboxamide (4b) required 6 h (entry 15), the other substrates (
5) were fully converted in 1 h (entries 11–13, 16).
Considering the behavior of the two nortropane-based nucleophiles, used in the re-
actions, decreased reactivity was observed in the case of nortropinone ( ): the starting
substrates ( ) were completely converted into the target carboxamides in substantially
,71]. In the presence of substrates 2 and 3, shorter reaction
4
5
–
1–5
(4
1–3,
a
1–5
longer reaction times (4–24 h). This phenomenon can be explained by the different confor-
mation of the two nucleophiles. We believe that the different reactivity of the two secondary
amines is due to steric factors. That is, the close to perfect chair conformation of nortropine
is highly distorted when an sp2 carbon (that is, keto functionality) is introduced into the
ring. This distortion could result in different reactivities both in the amine activation step
toward the formation of the Pd-amide intermediate, and also in the product-forming step,
where the acyl–amide–palladium(II) complex undergoes reductive elimination.

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Table 1. Aminocarbonylation of nortropane-based nucleophiles (
(1–5) using Pd(OAc)2 +2 PPh3 in situ catalyst a.
a,
b) in the presence of iodoalkenes
b
R. Time
[h]
Isolated
Conv.
[18]
Entry
Substrate
Amine
Yield c [18]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
1-iodocyclohexene (1)
1-iodocyclohexene (1)
1-iodocyclohexene (1)
1-iodocyclohexene (1) d
1-iodocyclohexene (1) d
4-tert-butyl-1-iodocyclohexene (
trans-1-iodo-1-octene (3)
17-iodoandrost-16-ene (4)
2-iodobornene (5)
a
a
a
a
a
a
a
a
a
a
b
b
b
b
b
b
4
24
48
4
24
4
4
24
4
24
1
1
1
1
3
42
88
70
100
100
100
100
75
100
100
100
100
80
n.i.
n.i.
n.i.
n.i.
80 (1a)
86 (2a)
81 (3a)
80 (4a)
n.i.
77 (5a)
89 (1b)
79 (2b)
65 (3b)
n.i.
2
)
)
2-iodobornene (5)
1-iodocyclohexene (1)
4-tert-butyl-1-iodocyclohexene (
trans-1-iodo-1-octene (3)
17-iodoandrost-16-ene (4)
17-iodoandrost-16-ene (4)
2-iodobornene (5)
2
6
1
100
100
55 (4b)
63 (5b)
a
Reaction conditions: 0.5 mmol substrate (1–5), 0.55 mmol of nucleophile (a, b), 0.025 mmol of Pd(OAc)2, 0.05
mmol of PPh3, 0.5 mL of Et3N, 10 mL of DMF, 50 ◦C, 1 bar of CO. The reaction was purged with Argon and then
replaced by carbon monoxide. Determined by GC-MS. c Yields of the isolated target compound (based on the
b
d
substrates (1–5)); n.i. = not isolated. The reaction was carried out at 40 bar carbon monoxide pressure.
2.2. Aminocarbonylation of Iodoarenes (6–10) in the Presence of Tropane-Based Nucleophiles (a, b)
After completing the reactions with the above mentioned iodoalkene substrates, we
turned our attention to the investigation of aminocarbonylation of iodoarene compounds
in the presence of nortropinone (a) and nortropine (b).
2.2.1. Optimization Study with Iodobenzene (6)
The aminocarbonylation of iodobenzene (6) was carried out in the presence of nortropin
one ( ) and nortropine ( ) under different reaction conditions to find to optimal parameters
a
b
for the further investigations (Scheme 2). Pd(OAc)2 was used as the catalyst precursor, and
the influence of ligand, CO pressure, and temperature on the reactivity and selectivity was
investigated.
Scheme 2. Aminocarbonylation of iodobenzene (6) in the presence of nortropinone (a).

Molecules 2021, 26, 1813
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Performing the reactions in the presence of PPh3 at 1 bar of CO, it can be seen, that the
◦
conversion was very low both at 50 and 70 C (Figure 1). Using elevated carbon monoxide
pressure (40 bar), 55% conversion was detected after 24 h. Under high pressure conditions,
the corresponding 2-keto-carboxamide (6a’) was also formed due to the second carbon
monoxide insertion. The ratio of amide (6a): ketoamide (6a’) type products was 56:44.
Figure 1. Conversion of
6 in the presence of a as a function of reaction conditions used during their
aminocarbonylation in DMF after 24 h.
Based on our previous results [72], the PPh3 was changed to the bidentate Xantphos
to reach complete conversion in sort reaction time. Surprisingly, under atmospheric
conditions, only 60 % conversion was observed after 24 h in a selective reaction towards the
corresponding carboxamide (6a). Higher conversion (73%) was detected under elevated
CO pressure (40 bar) and the ratio of 6a
70 C, the target carboxamide (6a) was synthesized selectively after 6 h under atmospheric
:
6a’ was 39:61. Increasing the temperature to
◦
conditions (Figure 1).
The optimization study was also performed in the reaction on iodobenzene (6) with
nortropine (b) under aminocarbonylation conditions (Scheme 3).
Scheme 3. Aminocarbonylation of iodobenzene (6) in the presence of nortropine (b).
Performing the reactions in the presence of PPh3 both under atmospheric and 40 bar
CO pressure, after 24 h, the conversion was just 80% and 76%, respectively. After 24 h
stirring, the ratio of the amide (6b):ketoamide (6b’) type products was 66:34 under atmo-
spheric CO pressure, while the chemoselectivity was shifted toward 6b’ at 40 bar (73%).
Changing the PPh3 to the bidentate Xantphos, as we expected, the iodobenzene was com-
◦
pletely converted after 2 h at 50 C, producing the target carboxamide (6b) selectively

Molecules 2021, 26, 1813
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(Figure 2). It has to be also mentioned, comparing the reactions of both nortropine-based
nucleophile, that the nortropinone (
under same reaction conditions.
b) showed higher reactivity than the nortropinone
Figure 2. Conversion of
6 in the presence of b as a function of carbon monoxide pressure and the
ligand used during the aminocarbonylation in DMF in 24 h stirring.
2.2.2. Extending the Scope of Iodoarene Substrates
According to the results of the paragraph in Section 2.1, it can be seen that the Xantphos
could be a good choice to produce selectively N-acyl-nortropane derivatives selectively
under mild aminocarbonylation conditions in the presence of other iodo-heteroaromatic
substrates. In this way, 2-iodopyridine (
5-iodoindole (10) were reacted with nortropinone (
bonylation conditions in the presence of Pd(OAc)2/Xantphos catalysts (Scheme 4, Table 2)
7
), 3-iodopyridine (
8
), 2-iodothiophene (
9), and
a
) and nortropine (
b) under aminocar-
.
Scheme 4. Aminocarbonylation of iodo-heteroaromatic substrates (
nortropane-based nucleophiles (a, b).
7–10) in the presence of

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Table 2. Aminocarbonylation of nortropane-based nucleophiles (
a,
b
) in the presence of iodo-
heteroaromatics (7–10) using Pd(OAc)2 + Xantphos in situ catalyst a.
R. Time
[h]
Temp
[ C]
Conv.
[18]
Isolated
Entry
Substrate
Amine
◦
b
Yield c [18]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
2-Iodopyridine (7)
3-Iodopyridine (8)
3-Iodopyridine (8)
2-Iodothiophene (9)
2-Iodothiophene (9)
5-Iodoindole (10)
5-Iodoindole (10)
5-Iodoindole (10)
2-Iodopyridine (7)
3-Iodopyridine (8)
2-Iodothiophene (9)
2-Iodothiophene (9)
5-Iodoindole (10)
5-Iodoindole (10)
a
a
a
a
a
a
a
a
b
b
b
b
b
b
6
6 d
24
6 d
24
6 d
24 d
48
2
70
70
70
70
70
70
70
70
50
50
50
50
50
50
100
66
100
82
100
47
68
90 (7a)
n.i.
82 (8a)
n.i.
82 (9a)
n.i.
n.i.
68 (10a)
73 (7b)
62 (8b)
n.i.
92 (9b)
n.i.
86
100
100
85
100
90
2
2 d
6
2 d
4
100
51 (10b)
a
Reaction conditions: 0.5 mmol substrate (7–10), 0.55 mmol of nucleophile (a, b), 0.025 mmol of Pd(OAc)2,
0.025 mmol of Xantphos, 0.5 mL of Et3N, 10 mL of DMF, 1 bar of CO. The reaction was purged with argon and
b
then replaced by carbon monoxide. Determined by GC–MS. c Yields of the isolated target compound (based on
d
the substrates (7–10)); n.i. = not isolated. Sample was taken and analyzed by GC.
Nitrogen-containing iodo-heteroarene substrates (
the correspondig carboxamides (7a 8a 7b 8b) after 2–6 h reaction time (entries 1, 2, 9, 10).
The difference between the reactivity of nortropinone ( ) and nortropine ( ) can easily be
seen in the reactions with 2-iodothiophene ( ) and 5-iodoinole (10). While in the presence
of , the reaction was complete with substrates and 10 in short reaction time (entries 12,
14); using nucleophile , the reaction was conspicuously slower (24–48 h) (entries 5, 7, 8).
7, 8) were converted completely into
,
,
,
a
b
9
b
9
a
The N-acylnortropane derivatives synthesized in the reactions with substrates
isolated in good to high yield (except 10b).
7–10 were
3. Materials and Methods
3.1. General Procedures
1H and 13C NMR spectra were recorded in CDCl3 or DMSO-d6 on a Bruker Avance III
500 spectrometer (Bruker BioSpin Corp., Karlsruhe, Germany) at 500 and 125.7 MHz, re-
spectively (See Supplementary Materials). Chemical shifts δ are reported in ppm relative to
CDCl3 (7.26 and 77.00 ppm for 1H and 13C, respectively) or DMSO-d6 (2.50 and 39.50 ppm
for 1H and 13C, respectively). Elemental analyses were measured on a 1108 Carlo Erba
apparatus (Carlo Erba Reagents SAS, Val de Reuil, France). The FT-IR spectra were taken in
KBr pellets using a Nicolet IMPACT 400 spectrometer (Thermo Fisher Scientific, Waltham,
MA, USA) applying a DTGS detector in the region of 400–4000 cm−1; the resolution was
4 cm−1. The amount of the samples was ca. 0.5 mg. Samples of the catalytic reactions were
analysed with Chrom-Card Trace GC-Focus GC gas-chromatograph (Thermo Fisher Scien-
tific, Waltham, MA, USA) fitted with a capillary column coated with OV-1 (injector temp.
250 ◦C; oven: starting temp. 50 ◦C (hold-time 1 min), heating rate 15 ◦C min−1, final temp.
320 ◦C (hold-time 11 min); detector temp. 280 ◦C; carrier gas: helium (rate: 1 mL min−1
Mass spectrometry data have been obtained using a GC–MS system consisting of a Perkin
)).

Molecules 2021, 26, 1813
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Elmer AutoSystem XL gas-chromatograph (PerkinElmer Life and Analytical Sciences, Shel-
ton, CT, USA). Melting points were measured with a Büchi apparatus (Büchi Labortechnik
AG, Flawil, Switzerland). TLC plates (silica gel on TLC Al foils with fluorescence indicator
254 nm) were purchased from Sigma-Aldrich (St. Louis, MO, USA). The eluents used in
thin-layer chromatography are specified below.
The Pd(OAc)2, the ligands (PPh3 and Xantphos), and the solvents were used without
further purification. trans-1-Iodo-1-octene (
10) were purchased from Sigma-Aldrich and were used without any further purification.
The amine nucleophiles (nortropinone ( ) and nortropine ( )) were purchased from TCI
Chemicals and were used without further purification. 1-Iodocyclohexene ( ) [73], 4-tert-
butyl-1-iodocyclohexene ( ) [73], 17-iodoandrost-16-ene ( ) [74], and 2-iodobornene (
were synthesized by the modified Barton-procedure [75 76]. The compound 6a is known,
3) and iodo-(hetero)aromatic substrates (6–
a
b
1
2
4
5)
,
and the characterization data were in accordance with the literature. The 6b compound
1
is also described, but its melting point is known only. H and 13C NMR data for these
compounds are provided here for the sake of completeness.
3.2. Aminocarbonylation of Nortropane Derivatives (
a, b) in the Presence of Iodoalkenes (1–5) and
Iodoarenes (6–10) under Atmospheric Carbon Monoxide Pressure
In a typical experiment Pd(OAc)2 (5.6 mg, 0.025 mmol), triphenylphosphine (13.1 mg,
0.05 mmol) or Xantphos (14.5 mg, 0.025 mmol), iodoalkene ( ) or iodo-(hetero)arene
11) substrates (0.5 mmol), tropane-based nucleophiles (nortopinone ( ), nortropine ( ))
1–5
(6–
a
b
(0.55 mmol), and triethylamine (0.5 mL) were dissolved in DMF (10 mL) under argon in a
100 mL three-necked flask equipped with reflux condenser connected to a balloon filled with
argon. The atmosphere was changed to carbon monoxide. The reaction was conducted for
the given reaction time upon stirring at 50 or 70 ◦C and analyzed by GC and GC–MS. The
cooled reaction mixture was then concentrated and evaporated to dryness under reduced
pressure. The residue was dissolved in chloroform (20 mL) and washed twice with water
(20 mL). The organic phase was dried over Na2SO4, filtered and evaporated under reduced
pressure to a solid material. All compounds were subjected to column chromatography
(Silicagel 60 (Sigma), 0.063–0.200 mm), CHCl3/MeOH or CHCl3/EtOAc eluent mixtures
(the exact ratios are specified in Characterization (Section 3.4) for each compound).
3.3. Aminocarbonylation of Nortropane Derivatives (
a, b) in the Presence of Iodoalkenes (1–5) and
Iodoarenes (6–11) under High Carbon Monoxide Pressure
In a typical experiment Pd(OAc)2, triphenylphosphine or Xantphos, iodoalkene (
1–5)
or iodo-(hetero)arene ( 11) and tropane-based nucleophile ( ) and triethylamine were
6–
a, b
used in the same amount as above and were dissolved in 10 mL of DMF under argon in a
100 mL autoclave. The atmosphere was changed to carbon monoxide, and the autoclave
was pressurized to the given pressure with carbon monoxide (caution: high pressure
carbon monoxide should only be used with adequate ventilation (hood) using CO sensors
as well). The reaction was conducted for the given reaction time upon stirring at 50 ◦C.
After the given reaction time, the reaction mixture was cooled to room temperature, and
the autoclave was carefully depressurized in a well-ventilated hood. The product mixture
was analyzed by GC and GC–MS. The work-up of the reaction mixture was identical to
that discussed for the atmospheric experiments.
3.4. Characterization of the Products
(1R,5S)-8-(Cyclohex-1-enecarbonyl)-8-azabicyclo[3.2.1]octan-3-one (1a), yield: 94 mg (80%);
colourless oil; [Anal. Calcd. for C14H19NO2: C, 72.07; H, 8.21; N, 6.0. Found: C, 71.87;
1
H, 8.16; N, 6.10]; Rf (30 % EtOAc, 70 % CHCl3) 0.5; H NMR (500 MHz, CDCl3): 5.99
(1 H, s, C=CH), 4.69 (2 H, br s, N-CH), 2.62 (2 H, br s, CH-CHaHb), 2.37 (2 H, d, 16 Hz,
C(O)-CHaHb), 2.27–2.18 (2 H, m, cyclohex. CH2), 2.14–2.07 (2 H, br s, CH- CHaHb), 2.06–2.00
(2 H, m, cyclohex. CH2), 1.73–1.64 (4 H, m, overlapping of cyclohex. CH2 and C(O)-CHaHb),
1.63–1.57 (2 H, m cyclohex. CH2); 13C NMR (125 MHz, CDCl3): 207.7, 170.2, 134.5, 129.4,
54.8 (br s, 2 C), 49.4 (br s, 2 C), 28.9 (br s, 2 C), 25.8, 24.7, 22.0, 21.6. MS m/z (rel. int.): 233

Molecules 2021, 26, 1813
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(26, [M]+), 205 (6), 176 (7), 148 (3), 124 (19), 109 (100), 81 (67), 53 (27). IR (KBr,
1716 (CO), 1655 (C=C), 1628 (Amide I.), 1413.
ν
(cm−1)):
(1R,5S)-8-(4-(tert-Butyl)cyclohex-1-enecarbonyl)-8-azabicyclo[3.2.1]octan-3-one (2a)◦(diastere-
omers can be distinguished), yield: 125 mg (86%); white solid, m.p. 123–124 C, [Anal.
Calcd. for C18H27NO2: C, 74.70; H, 9.40; N, 4.80. Found: C, 74.97; H, 9.44; N, 4.93]; Rf (10 %
EtOAc, 90 % CHCl3) 0.66; 1H NMR (500 MHz, CDCl3): 7.11–7.07/6.08–6.02 (1 H, m, C=CH),
4.78 (2 H, br s, N-CH), 2.68 (2 H, br s, CH-CHaHb), 2.51 (1 H, m, CH-C(CH3)3), 2.42 (2 H, d,
16Hz, C(O)-CHaHb), 2.32–2.20 (2 H, m, cyclohex. CH2), 2.13–2.06 (2 H, br s, CH-CHaHb),
1.98–1.87 (2 H, m, cyclohex. CH2), 1.80–1.68 (2 H, m, C(O)-CHaHb), 1.41–1.23 (2 H, m,
cyclohex. CH2), 0.89 (9 H, s, C(CH3)3); 13C NMR (125 MHz, CDCl3): 207.7, 170.9/170.1,
140.9/134.3, 129.9/129.8, 55.3 (br s, 2 C), 49.5 (br s, 2 C), 43.5/43.2, 32.2/32.1, 28.7 (br s, 2 C),
27.7/27.5, 27.1, 26.6/26.5, 23.6/23.5. MS m/z (rel. int.): 289 (52, [M]+), 274 (10), 261 (6), 232
(24), 204 (8), 165 (100), 124 (40), 81 (39), 57 (53). IR (KBr,
1618 (Amide I.), 1410.
ν
(cm−1)): 1714 (CO), 1663 (C=C),
(1R,5S)-8-((E)-Non-2-enoyl)-8-azabicyclo[3.2.1]octan-3-one (3a), yield: 107 mg (81%); colour-
less oil, [Anal. Calcd. for C16H25NO2: C, 72.97; H, 9.57; N, 5.32. Found: C, 72.76; H, 9.44;
N, 5.48]; Rf (10 % EtOAc, 90 % CHCl3) 0.66; 1H NMR (500 MHz, CDCl3): 7.03 (1H, dt, J
15.0 Hz, 7.0 Hz, =CH), 6.23 (1 H, dt, J 15.0 Hz, 1.4 Hz, =CH), 4.97 (1 H, br s, N-CH), 4.60 (1
H, br s, N-CH), 2.85–2.75 (1 H, m, CH-CHaHb), 2.60–2.51 (1 H, m, CH-CHaHb), 2.49–2.36
(2 H, m, C(O)-CHaHb), 2.28–2.14 (3 H, m, overlapping of CH-CHaHb and =CH-CH2), 2.09
(1 H, br s, CH-CHaHb), 1.87–1.77 (1 H, m, C(O)-CHaHb), 1.75–1.65 (1H, m, C(O)-CHaHb),
1.52–1.42 (2 H, m, CH2CH3), 1.38–1.21 (6 H, br m, 3 × CH2), 0.89 (3 H, t, 7.2 Hz, CH2CH3);
13C NMR (125 MHz, CDCl3): 207.5, 163.7, 148.1, 119.9, 53.6, 51.4, 50.01, 48.8, 32.5, 31.6, 29.9,
28.9, 28.3, 27.8, 22.5, 14.0. MS m/z (rel. int.): 263 (9, [M]+), 235 (1), 206 (10), 178 (7), 150 (11),
124 (73), 81 (15), 55 (100). IR (KBr,
ν
(cm−1)): 1718 (CO), 1660 (C=C.), 1619 (Amide I.), 1425.
(1R,5S)-8-((10S,13S)-10,13-dimethyl-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetradecahydro-1H-cyclopen
ta[a]phenanthrene-17-carbonyl)-8-azabicyclo[3.2.1]octan-3-one (4a), yield: 163 mg (80%); pale
◦
white solid, m.p. 186–187 C, [Anal. Calcd. for C27H39NO2: C, 79.17; H, 9.60; N, 3.42.
Found: C, 79.13; H, 9.82; N, 3.45]; Rf (20 % EtOAc, 80 % CHCl3) 0.5; 1H NMR (500 MHz,
CDCl3): 6.00 (1 H, s, =CH), 5.09/4.89 (1 H, br s, N-CH2), 4.62/3.56 (1 H, br s, N-CH2), 2.69
(2 H, br s, CH-CHaHb), 2.43 (2 H, d, 16.1 Hz, C(O)-CHaHb), 2.33–2.22 (1 H, m, steroid-
CH), 2.15–2.05 (2 H, br s, CH-CHaHb), 2.01–1.92 (1 H, m, steroid-CH), 1.84–0.75 (22 H,
C(O)-CHaHb and 22 steroidal skeleton H), 1.11 (3 H, s, CH3), 0.85 (3 H, s, CH3); 13C NMR
(125 MHz, CDCl3): 207.8, 166.3, 149.7, 132.3, 56.8, 55.3, 54.9, 49.8, 48.6, 47.3, 38.5, 36.5, 34.8,
33.9, 32.2, 32.1, 29.6, 29.0, 28.9, 26.8, 22.1, 20.6, 16.8, 12.2. MS m/z (rel. int.): 409 (100, [M]+),
394 (95), 366 (8), 285 (46), 206 (4), 161 (8), 105 (14), 67 (29). IR (KBr,
1635 (C=C), 1599 (Amide I.), 1420.
ν
(cm−1)): 1731 (CO),
(1R,5S)-8-((1S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-ene-2-carbonyl)-8-azabicyclo[3.2.1]octan-3-
one (5a), yield: 111mg (77%); grey solid, m.p. 126–127 ◦C, [Anal. Calcd. for C18H25NO2: C,
75.22; H, 8.77; N, 4.87. Found: C, 74.61; H, 9.02; N, 5.10]; Rf (20 % EtOAc, 80 % CHCl3) 0.5;
1H NMR (500 MHz, CDCl3): 6.22 (1 H, s, =CH), 5.11/4.85 (1 H, br s, N-CH2), 4.78/3.56 (1 H,
br s, N-CH2), 2.76 (2 H, br s, CH-CHaHb), 2.51 (1 H, dd, 4.0 Hz, 3.6 Hz, 4-CH), 2.46 (2 H, br
s, C(O)-CHaHb), 2.08 (2 H, br s, CH-CHaHb), 2.02–1.92 (1 H, m, 5-CHcCHd), 1.78 (2 H, br s,
C(O)-CHaHb), 1.66 (1 H, ddd, 12.1 Hz, 8.7 Hz, 3.7 Hz, 6-CHcCHd), 1.48 (1 H, ddd, 12.1 Hz,
8.9 Hz, 3.8 Hz, 6-CHcCHd), 1.17 (3 H, s, 9-CH3), 1.09 (1 H, ddd, 12.1 Hz, 8.8 Hz, 3.6 Hz,
5-CHcCHd), 0.89 (3 H, s, 10-CH3), 0.86 (3 H, s, 8-CH3); 13C NMR (125 MHz, CDCl3): 207.7,
166.6/, 165.3, 143.9, 136.9/136.6, 55.6, 54.5/51.1, 52.6, 50.2/49.1, 31.7, 30.1/29.6, 28.3/28.0,
25.2, 19.5, 19.1, 11.2. MS m/z (rel. int.): 287 (97, [M]+), 272 (47), 258 (25), 230 (8), 202 (6),
163 (100), 135 (91), 91 (75), 67 (37). IR (KBr,
ν
(cm−1)): 1721 (CO), 1620 (C=C), 1578 (Amide

Molecules 2021, 26, 1813
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I.), 1427.
(1R,5S)-8-Benzoyl-8-azabicyclo-[3.2.1]octan-3-one (6a), yield: 93 mg (81%); off white solid,
m.p. 108–109 ◦C, [Anal. Calcd. for C14H15NO2: C, 73.34; H, 6.59; N, 6.11. Found: C, 72.82;
H, 6.45; N, 6.16]; Rf (30 % EtOAc, 70 % CHCl3) 0.52; 1H NMR (500 MHz, CDCl3): 7.56–7.52
(2 H, m, Ar-H), 7.51–7.41 (3 H, m, Ar-H), 5.07 (1 H, br s, N-CH), 4.41 (1 H, br s, N-CH), 2.95
(1 H, br s, CH), 2.47 (2 H, br s, CH2), 2.34 (1 H, br s, CH), 2.17 (2 H, br s, CH2), 1.77 (2 H, d,
8.2 Hz, CH2); 13C NMR (125 MHz, CDCl3): 207.5, 168.9, 135.5, 130.6, 128.7 (2 C), 127.1 (2 C),
56.0, 51.5, 49.7, 48.8, 29.6, 28.1. MS m/z (rel. int.): 229 (14, [M]+), 200 (4), 172 (7), 124 (33),
105 (100), 77 (49), 51 (13). IR (KBr,
ν
(cm−1)): 1719 (CO), 1643 (C=C), 1621 (Amide I.), 1422.
1-((1R,5S)-3-oxo-8-azabicyclo[3.2.1]octan-8-yl)-2-phenylethane-1,2-dione (6a’), yield: 57 mg
(44%); off white viscous material, [Anal. Calcd. for C15H15NO3: C, 70.02; H, 5.88; N, 5.44.];
1
Rf (20 % EtOAc, 80 % CHCl3) 0.57; H NMR (500 MHz, CDCl3): 8.05 (2 H, dd, 8.4 Hz,
1.2 Hz, Hortho(Ph)), 7.69 (1 H, t, 7.4 Hz, Hpara(Ph)), 7.55 (2 H, t, 7.6 Hz, Hmeta(Ph)), 5.16–5.08
(1 H, m, N-CH), 4.36–4.28 (1 H, m, N-CH), 2.93–2.85 (2 H, m, 2
×
CH), 2.54 (1 H, d, 16.4 Hz,
CH), 2.42 (1 H, d, 16.4 Hz, CH), 2.26–2.08 (2 H, br m, 2
×
CH), 1.87–1.79 (2 H, m, 2 CH);
×
13C NMR (125 MHz, CDCl3): 206.4, 190.7, 162.3, 135.0, 132.9, 129.9 (2 C), 129.1 (2 C), 54.4,
51.2, 49.9, 49.1, 29.7, 27.9. MS m/z (rel. int.): 257 (8, [M]+), 152 (13), 124 (1), 105 (100), 77
(38), 67 (20), 51 (13). IR (KBr,
I.), 1452.
ν
(cm−1)): 1751 and 1718 (CO), 1653 (C=C), 1628 (Amide
(1R,5S)-8-Picolinoyl-8-azabicyclo-[3.2.1]octan-3-one (7a), yield: 103 mg (90%); beige solid, m.p.
98–99 ◦C, [Anal. Calcd. for C13H14N2O2: C, 67.81; H, 6.13; N, 12.17. Found: C, 67.38; H,
6.13; N, 12.30]; Rf (3 % MeOH, 97 % CHCl3) 0.48; 1H NMR (500 MHz, CDCl3): 8.61 (1 H,
ddd, 4.8 Hz, 1.7 Hz, 0.9 Hz, Py-H), 7.95 (1 H, ddd, 7.8 Hz, 1.7 Hz, 1.0 Hz, Py-H), 7.85 (1 H, td,
7.8 Hz, 1.7 Hz, Py-H), 7.41 (1 H, ddd, 7.8 Hz, 4.8 Hz, 1.2 Hz, Py-H), 5.24–5.13 (2 H, m, N-CH),
3.08 (1 H, dd, 16.1 Hz, 4.5 Hz, CH), 2.90 (1 H, dd, 16.1 Hz, 4.4 Hz, CH), 2.46 (2 H, q, 16.1 Hz,
CH2), 2.24–2.10 (2 H, m, CH2), 1.89–1.73 (2 H, m, CH2); 13C NMR (125 MHz, CDCl3):
208.3, 164.3, 153.5, 148.1, 137.1, 125.3, 124.5, 55.2, 52.2, 50.3, 49.1, 30.0, 27.5. MS m/z (rel.
int.): 230 (37, [M]+), 202 (8), 174 (8), 161 (13), 133 (4), 124 (16), 106 (36), 93 (19), 78 (100), 51
(22). IR (KBr,
ν
(cm−1)): 1718 (CO), 1629 (Amide I.), 1617 (C=C), 1586, 1472, 1448, 1420, 1411.
(1R,5S)-8-Nicotinoyl-8-azabicyclo-[3.2.1]octan-3-one (8a), yield: 94 mg (82%); yellowish oil,
[Anal. Calcd. for C13H14N2O2: C, 67.81; H, 6.13; N, 12.17. Found: C, 67.52; H, 6.09; N,
12.30]; Rf (6 % MeOH, 94 % CHCl3) 0.45; 1H NMR (500 MHz, CDCl3): 8.78 (1 H, dd, 2.2 Hz,
0.7 Hz, Py-H), 8.69 (1 H, dd, 4.9 Hz, 1.8 Hz, Py-H), 7.87 (1 H, dt, 7.9 Hz, 1.9 Hz, Py-H), 7.38
(1 H, ddd, 7.9 Hz, 4.9 Hz, 0.8 Hz, Py-H), 5.05 (1 H, br s, N-CH), 4.36 (1 H, br s, N-CH), 2.90
(1 H, br s, CH), 2.64–2.26 (3 H, br m 3
×
CH), 2.21–2.09 (2 H, m, CH2), 1.77 (2 H, d, 8.4 Hz,
CH2); 13C NMR (125 MHz, CDCl3): 206.6, 166.2, 151.6, 148.0, 135.1, 131.3, 123.6, 56.1, 51.6,
49.6, 48.8, 29.7, 28.0. MS m/z (rel. int.): 230 (13, [M]+), 201 (3), 173 (15), 147 (2), 124 (51),
106 (100), 78 (64), 51 (28). IR (KBr,
1436, 1411.
ν
(cm−1)): 1717 (CO), 1651 (C=C), 1631 (Amide I.), 1589,
(1R,5S)-8-(Thiophene-2-carbonyl)-8-azabicyclo[3.2.1]octan-3-one (9a), yield: 96 mg (82%); beige
solid, m.p. 71–72 ◦C, [Anal. Calcd. for C12H13NO2S: C, 61.25; H, 5.57; N, 5.95. Found: C,
61.04; H, 5.51; N, 6.09]; Rf (20 % EtOAc, 80 % CHCl3) 0.40; 1H NMR (500 MHz, CDCl3): 7.53–
7.49 (2 H, m, overlapping of two thiophenyl-H), 7.09 (1 H, dd, 5.1 Hz, 3.9 Hz, thiophenyl-H),
4.99 (2 H, br s, N-CH), 2.80 (2 H, d, 16.1 Hz, CH2), 2.45 (2 H, d, 16.1 Hz, CH2), 2.22–2.11 (2
H, m CH2), 1.82–1.75 (2 H, m, CH2); 13C NMR (125 MHz, CDCl3): 207.2, 161.4, 137.2, 129.8,
129.5, 54.0 (2 C), 49.3 (2 C), 28.8 (2 C). MS m/z (rel. int.): 235 (11, [M]+), 207 (1), 178 (5), 124
(28), 111 (100), 97 (2), 83 (9), 68 (3), 54 (3). IR (KBr,
(Amide I.), 1522, 1432, 1406.
ν
(cm−1)): 1717 (CO), 1652 (C=C), 1606

Molecules 2021, 26, 1813
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(1R,5S)-8-(1H-Indole-5-carbonyl)-8-azabicyclo[3.2.1]octan-3-one (10a), yield: 91 mg (68%); off-
white solid, m.p. 149–150 ◦C, [Anal. Calcd. for C16H16N2O2: C, 71.62; H, 6.01; N, 10.44.
Found: C, 71.45; H, 5.92; N, 10.35]; Rf (99 % EtOAc, 1 % MeOH) 0.59; 1H NMR (500 MHz,
CDCl3): 9.33 (1 H, br s, indole-NH), 7.89 (1 H, s, Ar-H), 7.37 (1 H, dd, 8.3 Hz, 1.5 Hz, Ar-H),
7.33 (1 H, d, 8.4 Hz, Ar-H), 7.23 (1 H, dd, 3.3 Hz, 2.6 Hz, Ar-H), 6.59–6.56 (1 H, m, Ar-H)
5.04 (1 H, br s, N-CH), 4.63 (1 H, br s, N-CH), 2.93 (1 H, br s, CH), 2.67 (1 H, br s, CH), 2.40 (2
H, br s, CH2), 2.26–2.14 (2 H, m CH2), 1.83–1.72 (2 H, m, CH2); 13C NMR (125 MHz, CDCl3):
208.1, 170.9, 137.1, 127.4, 126.7, 126.0, 121.1, 120.4, 111.4, 103.0, 56.2, 51.7, 49.3 (2 C), 28.7 (2
C). MS m/z (rel. int.): 268 (15, [M]+), 239 (1), 144 (100), 124 (4), 116 (27), 89 (10), 62 (3). IR
(KBr, ν (cm−1)): 3318 (NH), 1706 (CO), 1629 (C=C), 1594 (Amide I.), 1431.
Cyclohex-1-en-1-yl((1R,3R,5S)-3-hydroxy-8-azabicyclo[3.2.1]octan-8-yl)methanone (1b), yield:
105 mg (89%); beige solid, m.p. 86–87 ◦C, [Anal. Calcd. for C14H21NO2: C, 71.46; H, 9.00;
N, 5.95. Found: C, 71.31; H, 6.03; N, 9.18]; Rf (8 % MeOH, 92 % CHCl3) 0.38; 1H NMR (500
MHz, CDCl3): 5.84–5.77 (1 H, m, C=CH), 4.58 (1 H, br s, N-CH), 4.16 (1 H, br s, N-CH), 4.08
(1 H, t, 4.8 Hz, CH-OH), 3.09 (1 H, br s, OH), 2.29–1.54 (16 H, skeleton protons of nortropine
and cyclohexen-1-yl ring), 13C NMR (125 MHz, CDCl3): 169.2, 134.9, 127.6, 64.6, 55.5, 50.4,
40.5, 38.7, 28.6, 27.1, 25.9, 24.6, 22.1, 21.6. MS m/z (rel. int.): 235 (39, [M]+), 218 (5), 207
(15), 154 (7), 126 (19), 109 (100), 81 (77), 68 (31), 53 (16). IR (KBr,
ν
(cm−1)): 3426 (OH), 1655
(C=C), 1592 (Amide I.), 1438, 1087 (C-O), 1046 γ(OH).
(4-(tert-butyl)cyclohex-1-en-1-yl)((1R,3R,5S)-3-hydroxy-8-azabicyclo[3.2.1]octan-8-yl)methanone
2b), yield: 115 mg (79%); off-white solid, m.p. 133–134 ◦C, [Anal. Calcd. for C18H29NO2:
(
C, 74.18; H, 10.03; N, 4.81. Found: C, 73.31; H, 10.01; N, 5.16]; Rf (5 % MeOH, 95 % CHCl3)
0.45; 1H NMR (500 MHz, CDCl3): 5.85 (1 H, br s, C=CH), 4.68 (1 H, br s, N-CH), 4.23 (1 H, br
s, N-CH), 4.18 (1 H, br s, CH-OH), 2.89 (1 H, br s, OH), 2.43–1.71 (14 H, skeleton protons of
nortropine and cyclohexen-1-yl ring), 1.34–1.24 (1 H, m, Cy-CH), 1.23–1.13 (1 H, m, Cy-CH),
0.87 (9 H, C(CH3)3), 13C NMR (125 MHz, CDCl3): 169.1, 134.7, 128.1, 64.7, 55.5, 50.3, 43.5,
40.5, 38.7, 32.2, 28.7, 27.7, 27.4, 27.1, 26.5, 23.6. MS m/z (rel. int.): 291 (80, [M]+), 278 (24),
263 (13), 234 (51), 206 (16), 165 (77), 137 (6), 126 (38), 110 (97), 81 (65), 68 (57), 57 (100). IR
(KBr, ν (cm−1)): 3427 (OH), 1661 (C=C), 1584 (Amide I.), 1465, 1093 (C-O), 1047 γ(OH).
(E)-1-((1R,3R,5S)-3-hydroxy-8-azabicyclo[3.2.1]octan-8-yl)non-2-en-1-one (3b), yield: 86 mg
(65%); yellowish oil, [Anal. Calcd. for C16H27NO2: C, 72.41; H, 10.25; N, 5.28. Found: C,
71.58; H, 10.33; N, 5.33]; Rf (5 % MeOH, 95 % CHCl3) 0.51; 1H NMR (500 MHz, CDCl3):
6.91 (1H, dt, J 15.1 Hz, 7.1 Hz, =CH), 6.13 (1 H, dt, J 15.1 Hz, 1.4 Hz, =CH), 4.67 (1 H, br s,
N-CH), 4.29 (1 H, br s, N-CH), 4.12 (1 H, t, 4.8 Hz, CH-OH), 2.52 (1 H, br s, OH), 2.40–1.74
(10 H, protons of nortropine skeleton and CH2 of octene chain), 1.50–1.39 (2 H, m, CH2),
1.37–1.22 (6 H, br m, 3
×
CH2), 0.89 (3 H, t, 6.9 Hz, CH2CH3); 13C NMR (125 MHz, CDCl3):
162.7, 146.3, 120.6, 64.9, 53.9, 51.1, 40.5, 38.6, 32.4, 31.6, 28.9, 28.8, 28.4, 27.0, 22.6, 14.1. MS
m/z (rel. int.): 265 (17, [M]+), 236 (5), 208 (9), 194 (9), 180 (25), 165 (11), 139 (26), 126 (39),
110 (47), 82 (41), 68 (77), 55 (100). IR (KBr,
ν
(cm−1)): 3409 (OH), 1658 (C=C), 1596 (Amide
I.), 1448, 1091 (C-O), 1043 γ(OH).
(((10.S,13S)-10,13-dimethyl-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetradecahydro-1H-cyclopenta[a]phe
nanthren-17-yl)((1R,3S,5S)-3-hydroxy-8-azabicyclo[3.2.1]octan-8-yl)methanone (4b) (1:1 ratio
◦
of diastereomers), yield: 113 mg (55%); white solid, m.p. >260 C [Anal. Calcd. for
C27H41NO2: C, 78.78; H, 10.04; N, 3.40. Found: C, 78.26; H, 9.98; N, 3.50]; Rf (2 % MeOH, 98
% CHCl3) 0.58; 1H NMR (500 MHz, CDCl3): 5.84 (1 H, br s, =CH), 4.79/4.68 (1 H, br s, N-
CH), 4.30/4.24 (1 H, br s, N-CH), 4.19 (1 H, br s, CH-OH), 2.33–0.69 (37 H, skeleton protons
of steroid and nortropine + OH); 13C NMR (125 MHz, CDCl3): 165.3/165.0, 150.2/149.6,
130.5, 65.4, 56.9, 55.7/55.0, 55.4, 50.2/49.8, 48.5/48.4, 47.4, 40.8/40.5, 39.3/38.8, 38.6, 36.5,
34.9/34.3, 33.9, 32.2, 32.0/28.6, 29.1, 29.0, 27.5/27.0, 26.8, 22.2, 20.6, 16.8, 12.2. MS m/z (rel.
int.): 411 (100, [M]+), 396 (82), 368 (4), 326 (2), 285 (20), 246 (4), 207 (12), 161 (5), 126 (10), 93

Molecules 2021, 26, 1813
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(12), 68 (10), 55 (8). IR (KBr, ν (cm−1)): 3355 (OH), 1613 (C=C), 1575 (Amide I.), 1435, 1096
(C-O), 1046 γ(OH).
((1R,3S,5S)-3-hydroxy-8-azabicyclo[3.2.1]octan-8-yl)((1S,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-
en-2-yl)methanone (5b) (1:1 ratio of diastereomers), yield: 91 mg (63%); white solid, m.p.
135–136 ◦C [Anal. Calcd. for C18H27NO2: C, 74.70; H, 9.40; N, 4.84. Found: C, 74.26; H,
9.36; N, 4.83]; Rf (5 % MeOH, 95 % CHCl3) 0.48; 1H NMR (500 MHz, CDCl3): 6.01 (1 H, s,
=CH), 4.79/4.60 (1 H, br s, N-CH), 4.42/4.39 (1 H, brs, N-CH), 4.18 (1 H, s, CH-OH), 2.44
(1 H, s, OH), 2.33–1.75 (10 H, br m, CH protons of nortropine and bornene skeleton), 1.62
(1 H, ddd, 12.1 Hz, 8.5 Hz, 3.7 Hz, 6-CHcCHd), 1.46 (1 H, ddd, 12.1 Hz, 8.5 Hz, 3.7 Hz,
6-CHcCHd), 1.13 (3 H, s, 9-CH3), 1.06 (1 H, ddd, 12.1 Hz, 8.5 Hz, 3.7 Hz, 5-CHcCHd), 0.87
(3 H, s, 10-CH3), 0.82 (3 H, s, 8-CH3); 13C NMR (125 MHz, CDCl3): 165.4/164.5, 144.3/144.2,
135.2/135.1, 65.2, 55.7, 55.6/55.5, 54.4, 52.5, 50.5/49.8, 40.9/40.7, 39.2/38.6, 31.7, 29.1/28.7,
27.7/26.7, 25.3, 19.6/19.4, 19.2, 11.2. MS m/z (rel. int.): 289 (100, [M]+), 274 (62), 260 (28),
246 (35), 220 (3), 188 (1), 163 (77), 135 (92), 119 (32), 91 (64), 67 (27), 54 (27). IR (KBr,
ν
(cm−1)): 3425 (OH), 1617 (C=C), 1576 (Amide I.), 1443, 1088 (C-O), 1046 γ(OH).
((1R,3R,5S)-3-hydroxy-8-azabicyclo[3.2.1]octan-8-yl)(phenyl)methanone (6b), yield: 78 mg (68%);
off-white solid, m.p. 126–127 ◦C, [Anal. Calcd. for C14H17NO2: C, 72.70; H, 7.41; N, 6.06.
Found: C, 71.90; H, 7.27; N, 6.17]; Rf (2 % MeOH, 98 % CHCl3) 0.51; 1H NMR (500 MHz,
CDCl3): 7.50–7.37 (5 H, m, Ar-H), 4.80 (1 H, br s, N-CH), 4.18 (1 H, br s, CH-OH), 4.06 (1 H,
br s, N-CH), 2.37–1.71 (9 H, protons of nortropine skeleton); 13C NMR (125 MHz, CDCl3):
167.9, 136.5, 129.9, 128.4 (2 C), 127.0 (2 C), 64.9, 56.0, 51.0, 40.3, 38.7, 28.6, 27.3. MS m/z (rel.
int.): 231 (20, [M]+), 207 (1), 186 (4), 154 (1), 127 (12), 105 (100), 77 (56), 68 (18), 51 (13). IR
(KBr, ν (cm−1)): 3337 (OH), 1607 (C=C), 1596 (Amide I.), 1448, 1084 (C-O), 1041 γ(OH).
1-((1R,3R,5S)-3-hydroxy-8-azabicyclo[3.2.1]octan-8-yl)-2-phenylethane-1,2-dione (6b’), yield: 39
mg (30%); beige solid, m.p. 92–93 ◦C, [Anal. Calcd. for C15H17NO3: C, 69.48; H, 6.61; N,
5.40. Found: C, 69.01; H, 6.50; N, 5.47]; Rf (2 % MeOH, 98 % CHCl3) 0.34; 1H NMR (500
MHz, CDCl3): 7.97 (2 H, dd, 8.5 Hz, 1.2 Hz, Hortho(Ph)), 7.65 (1 H, t, 7.5 Hz, Hpara(Ph)), 7.51
(2 H, t, 7.5 Hz, Hmeta(Ph)), 4.81–4.76 (1 H, m, N-CH), 4.16 (1 H, t, 4.8 Hz, CH-OH), 3.97–3.92
(1 H, m, N-CH), 2.40–1.75 (9 H, skeleton protons of nortropinone); 13C NMR (125 MHz,
CDCl3): 191.4, 161.7, 134.7, 133.1, 129.7 (2 C), 129.0 (2 C), 64.7, 54.6, 50.9, 40.3, 38.9, 28,5,
27.1. MS m/z (rel. int.): 259 (4, [M]+), 154 (85), 136 (11), 126 (1), 105 (63), 93 (100), 78 (63), 67
(38), 51 (20). IR (KBr,
ν
(cm−1)): 3424 (OH), 1681 (CO), 1620 (Amide I.), 1595 (C=C), 1451,
1082 (C-O), 1044 γ(OH), 716, 662.
((1R,3R,5S)-3-hydroxy-8-azabicyclo[3.2.1]octan-8-yl)(pyridin-2-yl)methanone (7b), yield: 85 mg
(73%); beige solid, m.p. 164–165 ◦C, [Anal. Calcd. for C13H16N2O2: C, 67.22; H, 6.94; N,
12.06. Found: C, 66.78; H, 7.14; N, 12.16]; Rf (5 % MeOH, 95 % CHCl3) 0.41; 1H NMR (500
MHz, CDCl3): 8.62 (1 H, d, 4.8 Hz, Py-H), 7.86–7.79 (2 H, m, overlapping of two Py-H), 7.39
(1 H, ddd, 7.1 Hz, 4.8 Hz, 1.8 Hz, Py-H), 4.90 (1 H, brs, N-CH), 4.65 (1 H, brs, N-CH), 4.25 (1
H, t, 4.8 Hz„ CH-OH), 2.42–2.27 (4 H, br m, CH2), 2.11–2.00 (2 H, br m, CH2), 1.91 (1 H, d,
14.6 Hz, CH), 1.87–1.73 (overlapping, 1 H, d, 14.6 Hz, CH and 1H of OH); 13C NMR (125
MHz, CDCl3): 163.9, 154.3, 148.2, 136.9, 124.7, 123.7, 64.9, 55.3, 51.7, 40.5, 38.9, 28.7, 26.7.
MS m/z (rel. int.): 232 (46, [M]+), 216 (13), 187 (2), 160 (17), 126 (63), 106 (36), 78 (100), 66
(18), 51 (20). IR (KBr,
ν
(cm−1)): 3354 (OH), 1599 (Amide I.), 1579 (C=C), 1536, 1479, 1447,
1410, 1089 (C-O), 1038 γ(OH).
((1R,3R,5S)-3-hydroxy-8-azabicyclo[3.2.1]octan-8-yl)(pyridin-3-yl)methanone (8b), yield: 72 mg
(62%); yellowish solid, m.p. 113–114 ◦C, [Anal. Calcd. for C13H16N2O2: C, 67.22; H, 6.94;
N, 12.06. Found: C, 66.83; H, 6.69; N, 12.13]; Rf (5 % MeOH, 95 % CHCl3) 0.32; 1H NMR
(500 MHz, CDCl3): 8.71 (1 H, d, 1.4 Hz, Py-H), 8.67 (1 H, dd, 5.0 Hz, 1.4 Hz, Py-H), 7.82
(1 H, dt, 7.8 Hz, 2.0 Hz, Py-H), 7.38 (1 H, ddd, 7.8 Hz, 4.8 Hz. 0.8 Hz, Py-H), 4.81 (1 H, br

Molecules 2021, 26, 1813
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s, N-CH), 4.21 (1 H, t, 4.8 Hz, CH-OH), 4.03 (1 H, br s, N-CH), 2.45–1.77 (9 H, protons of
nortropine skeleton and OH); 13C NMR (125 MHz, CDCl3): 165.0, 150.8, 147.8, 135.0, 132.2,
123.5, 64.7, 56.3, 51.3, 40.5, 38.7, 28.7, 27.2. MS m/z (rel. int.): 232 (24, [M]+), 213 (1), 187
(6), 154 (2), 126 (18), 106 (100), 78 (64), 66 (22), 51 (27). IR (KBr,
(Amide I.), 1591 (C=C), 1443 (C-N), 1412, 1088 (C-O), 1046 γ(OH).
ν
(cm−1)): 3422 (OH), 1612
((1R,3R,5S)-3-hydroxy-8-azabicyclo[3.2.1]octan-8-yl)(thiophen-2-yl)methanone (9b), yield: 72
mg (92%); brownish oil, [Anal. Calcd. for C12H15NO2S: C, 60.73; H, 6.37; N, 5.90. Found: C,
59.98; H, 6.33; N, 5.98]; Rf (5 % MeOH, 95 % CHCl3) 0.49; 1H NMR (500 MHz, CDCl3):7.47
(1 H, dd, 5.0 Hz, 1.1 Hz, Ar-H), 7.44 (1 H, dd, 3.7 Hz, 1.1 Hz, Ar-H), 7.08 (1 H, dd, 5.3 Hz,
3.7 Hz, Ar-H), 5.00–4.51 (2 H, overlapping of two br s, N-CH), 4.24 (1 H, t, 4.8 Hz, CH-OH),
2.37–2.28 (2 H, m, CH2), 2.25 (1 H, br s, OH), 2.06–1.99 (2 H, m, CH2), 1.91 (2 H, d, 14.7 Hz,
CH2), 1.69 (2 H, s, CH2); 13C NMR (125 MHz, CDCl3): 160.2, 138.0, 129.0, 128.7, 126.9, 64.7,
55.9, 52.0, 40.2, 36.9, 28.8, 26.7. MS m/z (rel. int.): 237 (17, [M]+), 218 (1), 192 (1), 154 (1), 126
(10), 111 (100), 83 (10), 66 (15), 51 (1). IR (KBr,
ν
(cm−1)): 3424 (OH), 1587 (Amide I.), 1522
(C=C), 1443, 1087 (C-O), 1045 γ(OH).
((1R,3R,5S)-3-hydroxy-8-azabicyclo[3.2.1]octan-8-yl)(1H-indol-5-yl)methanone (10b), yield: 69
mg (51%); white solid, m. p: 92–93 ◦C, [Anal. Calcd. for C16H18N2O2: C, 71.09; H, 6.71;
N, 10.36. Found: C, 70.95; H, 6.58; N, 10.19]; Rf (5 % MeOH, 95 % CHCl3) 0.49; 1H NMR
(500 MHz, DMSO-d6): 11.29 (1 H, br s, NH), 7.67 (1 H, s, Ar-H), 7.44–7.39 (2 H, m, Ar-H),
7.19 (1 H, dd, 8.4 Hz and 1.4 Hz, Ar-H), 6.50 (1 H, s, Ar-H), 4.62 (1 H, d, 2.4 Hz, CH-OH),
4.55 (1 H, br s, N-CH), 4.10 (1 H, br s, N-CH), 2.25 (1 H, br s, OH), 2.30–1.55 (8 H, protons of
nortropine skeleton); 13C NMR (125 MHz, DMSO-d6): 168.9, 137.0, 127.7, 127.4, 126.9, 121.0,
120.0, 111.5, 102.3, 63.6, 56.5, 51.2, 39.2 (overlaping with DMSO-d6), 38.4, 28.7, 27.5. MS
m/z (rel. int.): 270 (19, [M]+), 207 (1), 160 (11), 144 (100), 116 (25), 89 (10), 62 (2). IR (KBr,
ν
(cm−1)): 3414 (OH), 3257 (NH), 1590 (Amide I.), 1571 (C=C), 1440, 1324, 1086 (C-O), 1045
γ(OH).
4. Conclusions
In summary, nortropane-based nucleophiles (nortropinone (a), nortropine (b)) can
be used as N-nucleophiles in palladium-catalyzed aminocarbonylation. In the presence
of simple iodoalkenes, as well as biologically important skeletons possessing iodoalkene
functionality, the target carboxamide derivatives have been produced exclusively by us-
ing Pd(OAc)2/PPh3 catalysts. The iodobenzene has shown lower reactivity than the
iodoalkene substrates using the above-mentioned catalysts. Thus, increasing the carbon
monoxide pressure (40 bar), the chemoselectivity has been shifted toward the correspond-
ing 2-ketocarboxamide formed due to the double CO insertion, but the conversion was
still not complete after 48 h reaction time. Changing the triphenylphosphine to the biden-
tate Xantphos, the target carboxamide has been formed selectively under mild reaction
conditions (1 bar of CO, 50–70 ◦C). Using these optimized reaction conditions, we have
been able to synthesize various N-acylnortropane derivatives in the presence of iodo-
(hetero)arenes in aminocarbonylation reactions. The new carboxamide derivatives were
isolated in moderate to good yields (51–92%), and they were fully characterized.
It can be stated that the palladium-catalyzed aminocarbonylation provides an efficient
tool for the “acylation” of amines possessing biologically important skeletons. It is based
on the good acylating ability of the palladium(II)-acyl species formed during the catalytic
cycle of the aminocarbonylation. In this way, important carboxamides could be synthesized
that cannot be produced by using conventional organic synthetic methods.
Supplementary Materials: 1H and 13C NMR spectra of the products synthesized in this work are
available online.
Author Contributions: Conceptualization, L.K. and A.T.; Data curation, Á.E. and A.T.; Formal
analysis, L.K. and A.T.; Founding acquisition, L.K. and A.T.; Investigation, L.K., Á.E., H.R. and A.T.;

Molecules 2021, 26, 1813
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Methodology, Á.E., H.R. and A.T.; Resources, L.K.; Writing—original draft A.T.; Writing–review and
editing, L.K. and A.T. All authors have read and agreed to the published version of the manuscript.
Funding: This research was financed by the National Research, Development, and Innovation Office
(Grant Number PD-132403) and the GINOP-2.3.2-15-2016-00049 grant.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: The data presented in this study are available in the Supplementary
Materials.
Acknowledgments: The authors thank to G. Mikle for the iodoalkene substrates and V. Takács-Kollár
for the graphs. The project has been supported by the European Union, co-financed by the European
Social Fund Grant no.: EFOP-3.6.1.-16-2016-00004 entitled by Comprehensive Development for
Implementing Smart Specialization Strategies at the University of Pécs. Project no. TKP2020-IKA-08
has been implemented with the support provided from the National Research, Development and
Innovation Fund of Hungary, financed under the 2020-4.1.1-TKP2020 funding scheme.
Conflicts of Interest: The authors declare no conflict of interest.
Sample Availability: Samples of the compounds are not available from the authors.
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