A de novo synthetic method to the access of N-substituted benzazepines

Article abstract of DOI:10.1016/j.jfluchem.2020.109466

A novel, convenient procedure has been described for the construction of fluorine-containing benzazepines. The synthetic protocol starting from readily available dihydronaphthalene regioisomers is based on oxidative ring olefin bond cleavage followed by r

Full text of DOI:10.1016/j.jfluchem.2020.109466

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A de novo synthetic method to the access of N-substituted benzazepines
´
Lamiaa Ouchakour, Melinda Nonn, Matthias D’hooghe, Lorand Kiss
PII:
S0022-1139(20)30017-8
DOI:
https://doi.org/10.1016/j.jfluchem.2020.109466
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10 December 2019
17 January 2020
19 January 2020
Please cite this article as: Ouchakour L, Nonn M, D’hooghe M, Kiss L, A de novo synthetic
method to the access of N-substituted benzazepines, Journal of Fluorine Chemistry (2020),
doi: https://doi.org/10.1016/j.jfluchem.2020.109466
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A de novo synthetic method to the access of N-substituted benzazepines
Lamiaa Ouchakour a,b, Melinda Nonn a,b,d, Matthias D’hooghe c, Loránd Kissa,b*
kiss.lorand@pharm.u-szeged.hu
aInstitute of Pharmaceutical Chemistry, University of Szeged, H-6720 Szeged, Eötvös u. 6,
Hungary
bInterdisciplinary Excellence Centre, Institute of Pharmaceutical Chemistry, University of
Szeged, H-6720 Szeged, Eötvös u. 6, Hungary
cDepartment of Green Organic Chemistry and Technology, Faculty of Bioscience
Engineering, Ghent University, Coupure Links 653, B-9000 Ghent, Belgium
dMTA-SZTE Stereochemistry Research Group, Hungarian Academy of Sciences, H-6720
Szeged, Eötvös u. 6, Hungary
Graphical abstract:
Highlights
 A novel access route was developed for the synthesis of benzazepine derivatives
1

 The protocol was based on the oxidative ring cleavage of dihydronaphthalenes
followed by reductive cyclization with primary amines
 The synthetic protocol was extended for the preparation of fluorine-containing analogs
 Various fluorine-containing primary amines were used in the synthesis
 The applicability of the method was illustrated by the synthesis of 13 different
scaffolds
Abstract: A novel, convenient procedure has been described for the construction of fluorine-
containing benzazepines. The synthetic protocol starting from readily available
dihydronaphthalene regioisomers is based on oxidative ring olefin bond cleavage followed by
ring closure of the diformyl intermediates in the presence of some fluorine-containing primary
amines across double reductive amination. The applicability of the developed synthetic
method was demonstrated by the synthesis of 13 benzazepine compounds isolated in 22–35%
overall yields.
Keywords: benzazepine, fluorine, reductive amination, ring expansion, azaheterocycle, ring
closing
Introduction
Functionalized azepanes constitute important components of several biologically
relevant natural and non-natural products with interesting pharmaceutical properties. Some
representatives of this class of azaheterocycles are known as antiviral agents, glycosidase
inhibitors, anticancer agents or antidiabetics [1-5]. Therefore, in view of their medicinal
relevance, an increasing number of synthetic methods have been described in recent years for
the construction of highly substituted azepane derivatives [6-10]. Fluorine chemistry has
become a rapidly expanding research area during the last 10–15 years. Because of the high
impact of organofluorine molecules in drug research (approximately 25% of the drugs
2

introduced in the market contain at least one fluorine atom) and agrochemistry, the synthesis
of fluorinated organic scaffolds has been recognized to be a hot topic in synthetic organic
chemistry over the past decades [11-13]. This high interest is based on the general
understanding that the presence of fluorine atom(s) can influence biological property,
metabolic stability, acid–base character, and lipophilicity [14-20]. Functionalized azepanes
are important frameworks in small drug molecular design. Accordingly, the incorporation of F
atom(s) in these seven-membered azaheterocycles has generated increasing interest in
pharmaceutical research.
Benzo-fused azepines (benzazepines) including their functionalized derivatives form a
relevant subclass in the area of azaheterocyclic compounds. Many representatives of these
compounds, some of them found in various commercial drugs, are known to possess
important biological properties. The structures of some representative drugs with a
benzazepine core are presented on Figure 1.
Figure 1. Structures of some bioactive benzazepine derivatives.
For example, Lorcaserin (1) [21] is a drug used in the treatment of obesity, Ivabradine
(2) [15] and Zatebradine (3) [22] are cardioprotective drugs (hyperpolarization-activated
cyclic nucleotide-gated (HCN) channel blocker), Benazepril (4) [23] is known as angiotensin-
converting enzyme (ACE) inhibitor, Fedovapagon (5) [23] possesses antidiuretic properties,
while Fenoldopam (Corlopam) (6) [24] is a D1-like receptor agonist (Figure 1).
3

Despite the fact that a relatively large number of functionalized azepanes, fluorine-
containing azepines, and various benzazepines with biological properties are known, there are
only a very limited number of examples of fluorine-containing bioactive benzazepines
available in the literature. The structure of several representatives of this group of bioactive
products is collected in Figure 2 (structures 7–12) [25-27].
Figure 2. Several fluorine-containing benzazepines with biological activities.
Considering the potential biological importance of fluorine-containing benzazepines on the
one hand and the limited number of literature reports on these scaffolds on the other hand, the
development of new synthetic strategies towards these structures represents a relevant
challenge in synthetic organic chemistry. Within that framework, the main objective of this
research involved the preparation of different types of fluorine-containing benzazepines via a
convenient new approach.
Results and Discussion
The synthetic concept towards the construction of benzazepine scaffolds was based on
our earlier findings regarding the synthesis of functionalized, saturated azaheterocyclic
substances. This protocol involved the oxidative cleavage of the ring olefin bond of
substituted cycloalkenes, followed by ring closing of the diformyl intermediates mediated by
double reductive amination with various primary amines [28-30].
Our synthetic strategy for the creation of the benzazepine ring system started with the
dihydroxylation of the ring C–C double bond of 1,2-dihydronaphthalene (1) with OsO4 (2
mol%)/NMO in acetone at room temperature, which provided the corresponding cis-diol
4

derivative (±)-2 [31]. Vicinal diol (±)-2 was next subjected to oxidative C–C ring cleavage
with NaIO4 in a THF/H2O solvent system giving an unstable diformyl intermediate (I-1),
which was then used further without isolation. It is well known that fluorine atoms
incorporated into the structure of an organic scaffold, especially in the skeleton of an
azaheterocycles, will significantly affect basic characteristics. Therefore, we intended to carry
out the construction of the benzazepine skeleton by ring closing of dialdehyde intermediate I-
1 using various fluorine-containing primary amines. First we selected trifluoroethylamine as
the amine component.
Scheme 1. Synthesis of benzazepine 3 containing a trifluoromethyl group.
Thus, dialdehyde I-1 resulting from the ring opening of diol (±)-2 was submitted to
double reductive amination with 2,2,2-trifluoroethylamine hydrochloride in the presence of
NaHCO3 and reducing agent in CH2Cl2 at room temperature. After investigating various
reducing agents such as NaBH4, NaBH(OAc)3 and NaBH3CN, while the first two provided
the desired product in low yields (12% and 18%), the reaction in the presence of the latter
reagent, after 3 h, yielded the corresponding trifluoromethyl-containing benzazepine 3 in
moderate yield (55%, two steps) (Scheme 1) confirming the feasibility of the proposed
synthetic strategy.
In continuation, we extended the protocol described above towards the preparation of
other benzazepines derivatives. Thus, diol (±)-2 was submitted to NaIO4-mediated ring
opening followed by subsequent treatment of diformyl intermediate I-1 with four different
fluorine-containing primary amines: 2-fluoroethylamine, 2,2-difluoroethylamine, 3,3,3-
5

trifluoropropylamine, and 1,1,1-trifluoropropan-2-amine. The reductive amination with the
involvement of cyclization provided the corresponding fluorine-containing benzazepines 4–7
(Table 1).
fluorine-
product
yield (two steps);
compound number
containing amine
45%, (4)
26%, (5)
25%, (6)
43%, (7)
55%, (8)
47%, (9)
Table 1. Synthesized benzazepane derivatives 4–9 from diol (±)-2.
Obviously, this procedure could be applied for the access of non-fluorinated
derivatives as well. When benzylamine or (R)-methylbenzylamine its methyl-substituted
counterpart was reacted, the corresponding benzazepines 8 and 9 could be isolated in
moderate yields (two steps, 47% and 55%) (Table 1).
6

Next, we intended to further extend the synthetic methodology and increase the
number of benzazepine derivatives by targeting structural isomers. Accordingly, 1,4-
dihydronaphthalene (10) a regioisomer of 1 was subjected to the same oxidative ring opening.
First compound 10 under OsO4-mediated dihydroxylation conditions yielded the
corresponding diol (±)-11,8 which subsequently underwent ring opening upon treatment with
NaIO4 to furnish diformyl intermediate I-2 (Scheme 2).
Scheme 2. Synthesis of benzazepine 12 containing a trifluoromethyl group.
fluorine-
product
yield (two steps);
compound number
containing amine
25%, (13)
26%, (14)
36%, (15)
30%, (16)
7

58%, (17)
Table 2. Synthesized benzazepane derivatives 13–17 diol (±)-11.
Similar to Scheme 1, dialdehyde I-2 was used in the forthcoming step without
isolation. Thus on treatment with 2,2,2-trifluoroethylamine in the presence of NaBH3CN,
double reductive amination afforded by cyclization the desired benzazepine derivative 12
containing the trifluoromethyl group. This product is a regioisomer of 3 (45%, two steps)
(Scheme 2).
Finally, diformyl intermediate I-2 derived from diol 11 was treated with the
fluorinated primary amines 2-fluoroethylamine, 2,2-difluoroethylamine, 3,3,3-
trifluoropropylamine, 1,1,1-trifluoropropan-2-amine and benzylamine under reductive
condition, in the presence of NaBH3CN, to deliver the corresponding opposite regioisomers
13–17 in moderate yield (Scheme 2).
Conclusions
In this paper we described a novel route for the construction of 2-benzazepine and 3-
benzazepine ring systems starting from dihydronaphthalene regioisomers, providing a
convenient access to both tetrahydrobenzo[c]azepine and tetrahydrobenzo[d]azepine
regioisomers. The key steps of the synthetic procedure are (i) oxidative olefin bond cleavage
of dihydronaphthalenes followed by (ii) cyclization resulting in a formal ring expansion under
reductive amination with various primary amines. In view of the importance of organofluorine
scaffolds, we applied fluorinated amines for the ring-closing step, which yielded various
fluorine-containing benzazepines. Further extensions of the described procedure regarding the
access of functionalized benzazepines are currently being studied in our laboratory.
Experimental
General procedure for dihydroxylation of dihydronaphthalene
To a solution of 1,2-dihydronaphthalene or 1,4-dihydronaphthalene (2 mmol) in acetone (30
mL) was added NMO (1.5 equiv) at 0 °C with stirring, followed by addition of a solution of
2% OsO4 in t-butyl alcohol (0.3 mL). Next the resulting mixture was stirred for 3 h at room
temperature. After termination of the reaction (monitored by TLC) 10 mL of saturated
8

aqueous Na2SO3 solution was added and the reaction mixture was extracted with CH2Cl2 (3 ×
20 mL). The combined organic layers were dried over Na2SO4, filtered, and evaporated under
reduced pressure. The crude product was purified by means of column chromatography on
silica gel (n-hexane/EtOAc or n-hexane/acetone).
General procedure for the synthesis of fluorine-containing benzazepine derivative by
oxidative ring cleavage followed by ring closure by reductive amination
To a stirred solution of dihydroxylated tetrahydronaphthalene (2 mmol) NaIO4 (1.5 equiv)
was added in THF/H2O (25 mL/2 mL). After stirring for 30 min at 20 °C under Ar
atmosphere, H2O was added (40 mL). The mixture was then extracted with CH2Cl2 (3 × 20
mL) and the combined organic layers were dried over Na2SO4. The resulting solution
containing the dialdehyde derivative concentrated to half of its volume was used without
purification for the next reaction.
To the solution of the dialdehyde was added fluorine-containing amine hydrochloride (1
equiv) and NaHCO3 (2 equiv) or benzylamine or methylbenzylamine (1 equiv, without
NaHCO3). Then the mixture was stirred at 20 °C for 10 min and, after adding NaBH3CN (1
equiv) and AcOH (2 drops), stirring was continued for another 3 h at 20 °C. The reaction
mixture was diluted with H2O (20 mL) and extracted with CH2Cl2 (3 × 20 mL). The
combined organic layers were dried over Na2SO4 and concentrated under reduced pressure.
The residue was purified by column chromatography on silica gel (n-hexane/EtOAc or n-
hexane/acetone).
Characterization and 1H NMR and 13C NMR spectra of the synthetized compounds are
available in the Supporting Information
Conflict of interest
The authors declare no conflict of interest.
Acknowledgments
We are grateful to the Hungarian Research Foundation (NKFIH No. K 119282) for
financial support. The financial support of the GINOP-2.3.2-15-2016-00038 project is also
9

acknowledged. This research was supported by the EU-funded Hungarian grant EFOP-3.6.1-
16-2016-00008. Ministry of Human Capacities, Hungary grant 20391-3/2018/FEKUSTRAT
is also acknowledged.
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