Synthesis of new azapolycyclic scaffolds via the domino aminolysis of dicyclopentadiene diepoxide in water

Article abstract of DOI:10.1016/j.tetlet.2020.152097

A convenient method is reported for the multigram scale synthesis of compounds containing the novel octahydro-1H-2,5-epimino-4,7-methanoindene azapolycyclic system in good yields. This method involves the domino aminolysis of readily available dicyclopentadiene diepoxide in water at 165 °C. 2D NMR and XRD spectra of the products were studied in detail.

Full text of DOI:10.1016/j.tetlet.2020.152097

Journal Pre-proofs
Synthesis of new azapolycyclic scaffolds via the domino aminolysis of dicy‐
clopentadiene diepoxide in water
Vitalii A. Palchykov, Rita G. Gaponova, Iryna V. Omelchenko, Liliya I.
Kasyan
PII:
S0040-4039(20)30548-7
DOI:
Reference:
https://doi.org/10.1016/j.tetlet.2020.152097
TETL 152097
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
20 April 2020
22 May 2020
28 May 2020
Please cite this article as: Palchykov, V.A., Gaponova, R.G., Omelchenko, I.V., Kasyan, L.I., Synthesis of new
azapolycyclic scaffolds via the domino aminolysis of dicyclopentadiene diepoxide in water, Tetrahedron Letters
(2020), doi: https://doi.org/10.1016/j.tetlet.2020.152097
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Synthesis of new azapolycyclic scaffolds via the domino
aminolysis of dicyclopentadiene diepoxide in water
Vitalii A. Palchykova,b*, Rita G. Gaponovaa, Iryna V. Omelchenkoc
and Liliya I. Kasyana†
aResearch Institute of Chemistry and Geology, Oles Honchar Dnipro National University, 72 Gagarina
Ave., Dnipro 49010, Ukraine
bDepartment of Chemistry and Biochemistry, University of Texas at Dallas, 800 West Campbell Road,
Richardson, TX 75080, United States
cSSI «Institute for Single Crystals», National Academy of Sciences of Ukraine, 60 Nauky Ave.,
Kharkiv 61001, Ukraine
*Corresponding author e-mail: vitalii.palchykov@utdallas.edu. Tel. +38 066 3007157.
† Deceased
Keywords: 2-Azabicyclo[3.3.1]nonane (morphan), Amino alcohols, Piperidine, Cage-like compounds
Abstract
A convenient method is reported for the multigram scale synthesis of compounds containing the novel
octahydro-1H-2,5-epimino-4,7-methanoindene azapolycyclic system in good yields. This method
o
involves the domino aminolysis of readily available dicyclopentadiene diepoxide in water at 165 C.
2D NMR and XRD spectra of the products were studied in detail.
Graphical abstract
Highlights
First reported synthesis of the octahydro-1H-2,5-epimino-4,7-methanoindene azapolycyclic system
Operationally simple method using water as the solvent
2D NMR and XRD spectra of the products were studied in detail

Introduction
Compounds with unusual three-dimensional structures have frequently attracted the attention of
chemists as possible synthetic targets because the shape of chemical structures in drug discovery is a
crucial component for evoking molecular recognition events with biological targets [1]. Medicinal
chemists typically exploit novel conformationally restricted 3D-shaped building blocks with a high
fraction of C(sp3)-hybridized carbons (Fsp3) [2]. Natural products often contain enhanced three-
dimensionality in their structures reflecting the necessary interactions with their biological partners. As
many drugs are derived from natural products, creating natural cage-like cores may offer an increased
chance of finding bioactive compounds. Moreover, azaheterocyclic cage compounds have received
attention from both synthetic and mechanistic considerations for comparing the reactivity pattern of
carbon cage compounds with their heteroatom analogs. It is not surprising, therefore, that medicinal
chemists are increasingly searching for novel, unique, 3D-shaped, and conformationally restricted
building blocks [3].
As part of our drug discovery program, we are interested in developing practical synthetic
pathways that allow quick access to alkaloid-like chemical scaffolds that can be used to produce a
library of drug-like compounds for bioscreening. Herein, we report the synthesis of the octahydro-1H-
2,5-epimino-4,7-methanoindene azapolycyclic system 1. A literature survey of substructures derived
from this scaffold emphasizes its unique place among many well-documented bi- and tricyclic
analogues (Fig. 1). It is also worth mentioning that core 1 includes the pharmacophore 2-
azabicyclononane (2-ABN, Morphan) fragment as a subunit. This fragment is found in more than 300
natural compounds of high biological importance including two of the best-known alkaloids, morphine
and strychnine [4]. In addition, a number of similar polycyclic cage structures have already been used
as lipophilic scaffolds for neuroactive drugs and antiviral agents [5].

Figure 1. Representative bi- and tricyclic substructures based on the octahydro-1H-2,5-epimino-4,7-
methanoindene azapolycyclic system 1 and the total number of references (red numbers in brackets)
according to the SciFinder database (April, 2020).
Results and Discussion
The chemistry of exo-epoxynorbornanes 2 has attracted considerable attention from our group as
convenient and inexpensive starting compounds for the preparation of cage-like azaheterocycles [6]
(Scheme 1A). While searching for a convenient method for the synthesis of new azaheterocycles, we
turned our attention to previous work [7a-d] where diepoxides were used for the synthesis of 2-
azaadamantanes 3, 9-azabicyclo[3.3.1]- and [4.2.1]nonanes 4a,b, 5 and 2,6-diazaadamantane 6
(Scheme 1B). Inspired by these results we developed a simple protocol for the synthesis of octahydro-
1H-2,5-epimino-4,7-methanoindene derivatives by the domino aminolysis of dicyclopentadiene exo-
diepoxide 7 [7e-g] (Scheme 1C).

Scheme 1. A) Diversity of cage-like azaheterocycles obtained in our laboratory starting from exo-
epoxynorbornanes 2. B) Diepoxides in the synthesis of cage-like azaheterocycles 3–6. С) This work.
To optimize the aminolysis of dicyclopentadiene diepoxide 7, several amines were evaluated and
the results are summarized in Table 1. Our experiments showed that the optimal solvent is water and
the reaction temperature needs to be in the range of 160–165 °C (sealed steel reactor). Heating of
diepoxide 7 with concentrated aqueous ammonia under microwave irradiation at 100 °C did not lead to
the formation of aminolysis products and starting material 7 was recovered quantitatively (Table 1,
entry 1). The aminolysis of 7 with benzylamine under various conditions demonstrated the key role of
the solvent (water) in the course of this reaction. There is considerable evidence in the literature that
the aminolysis of epoxides effectively occurs in aqueous medium [8]. Thus the use of
dimethylformamide (DMF), acetonitrile, benzylamine (as solvent) and 2-propanol led to lower
conversions of 7 compared to water (Table 1, entries 3, 4, 6–12). Under solvent free conditions the
aminolysis of 7 did not occur (Table 1, entry 5). In our experiments aniline was the least reactive
amine, and no aminolysis products were isolated in this case (Table 1, entry 13).
Table 1. Screening of the reaction conditions.
Entry
Reaction conditions
Molar ratio
time
Conversion of the
Temp. (°C)

7 : amine
(h)
4
starting epoxide 7
(%, NMR data)
Microwave irradiation (800W),
H2O
1
1 : 480 (NH3)
100
0
2
3
Sealed steel reactor, H2O
Reflux, DMF
1 : 27 (NH3)
1 : 2 (BnNH2)
165
153
48
60
90
0
LiClO4 (1 equiv.), reflux, dry
MeCN
4
1 : 2 (BnNH2)
85
70
0
5
6
7
8
9
10
11
12
13
Sealed steel reactor, solvent free
Reflux, excess benzylamine
Sealed steel reactor, i-PrOH
Sealed steel reactor, i-PrOH
Sealed steel reactor, i-PrOH
Sealed steel reactor, i-PrOH
Sealed steel reactor, H2O
Sealed steel reactor, H2O
Sealed steel reactor, i-PrOH
1 : 2 (BnNH2)
1 : 15 (BnNH2)
1 : 2 (BnNH2)
1 : 2 (BnNH2)
1 : 2 (BnNH2)
1 : 2 (BnNH2)
1 : 1.2 (BnNH2)
1 : 2 (BnNH2)
1 : 1 (PhNH2)
160
185
160
160
160
165
165
165
150
70
64
75
200
240
336
70
200
60
0
25
30
50
60
80
90
95
0
The reaction of diepoxide 7 with ammonia was found to be non-regioselective, thus competing
pathways a and b led to the formation of all plausible products of aminolysis 8, 9a,b in different
quantities. Clearly the attack via pathway a was more sterically hindered, resulting in a low yield of
the product 8 (up to 6%). Path b has two non-equivalent sites for intramolecular aminolysis of the exo-
epoxynorbornane fragment – pathways c and d. These pathways led to a 1.6:1.0 mixture of isomers 9a
and 9b in 72% total yield (Scheme 2).
Scheme 2. Aminolysis of dicyclopentadiene diepoxide 7 with ammonia.
Thus, we consider the aminolysis of dicyclopentadiene diepoxide 7 as a two-step domino
process, where the first (slow) step is chemo-, stereo- and, in the case of ammonia, non-regioselective
amine attack (paths a, b, Scheme 2) on the epoxycyclopentane moiety of 7. The intermediates of this
step are the corresponding epoxyaminoalcohols 10a,b, which were not isolated in any of the reactions.
A characteristic feature of intermediates 10a,b is the placement of the amino group in the endo-
position of the norbornane fragment, which makes the second (faster) step a non-regioselective attack
of the amino group on the carbon atoms of the epoxynorbornane fragment. The reaction of diopexide 7
with a 1.2-fold excess of benzylamine predictably led to the formation of regioisomeric aminodiols
11a,b in a ratio of 1.7:1.0. The synthesis of compounds 9a,b was also achieved by reductive
debenzylation of aminodiols 11a,b over a palladium or nickel catalyst in 90–93% yield. Despite the

fact that amino alcohols 9a,b can be obtained in one step directly from diepoxide 7 and aqueous
ammonia (Scheme 2), in practice, it is more expedient to obtain the multigram amounts of these
compounds by debenzylation of the pure isomers 11a,b. The Bn-derivatives 11a,b (Rf 0.36 (for 11a)
and 0.22 (for 11b) in ethyl acetate) were much better separated by column chromatography due to the
greater difference in Rf сompared with the unsubstituted analogs 9a,b (Rf 0.16 (for 9a) and 0.08 (for
9b) in 2-propanol) (Scheme 3).
Scheme 3. Aminolysis of dicyclopentadiene diepoxide 7 with benzylamine.
The structure of the products 8, 9a,b, 11a,b was studied in detail by 2D NMR techniques and
that of isomers 11a,b was additionally confirmed by X-ray diffraction analysis (Fig. 2, CCDC
1536888 for 11a and 1536889 for 11b). For more information and a detailed study of 2D NMR and
XRD results see the ESI.
Figure 2. Molecular structure of major-isomer 11a (left, see Fig. S3 in ESI) and minor-isomer
11b (right) according to X-ray diffraction data.
Differently functionalized complex building blocks are in high demand in advanced medicinal
chemistry. We hypothesized that the differently oriented hydroxyl groups in aminodiols 11a,b could
be selectively acylated under mild conditions. Thus, we performed the acylation of aminodiol 11b with
acetic acid at reflux according to our previously developed method for protecting hydroxyl groups in
cage-like compounds [9]. A mixture of di- and monoacylated products 12a-c in different ratios was

obtained. According to NMR/LCMS data the reaction was non-regioselective. Prolonged heating in
acetic acid at reflux (36 h) led to diacyl derivative 12a exclusively (Scheme 4).
Scheme 4. Acylation of amino diol 11b.
Next, we studied the reaction of diepoxide 7 with secondary amines. Unfortunately, under all of
the conditions we tested, dibenzylamine did not react with diepoxide 7. The aminolysis was then
carried out with less sterically hindered secondary amines. Interestingly, in the reaction with aqueous
dimethylamine, we also failed to obtain the desired epoxyamino alcohol 13, but the harsh conditions
and long reaction time led to demethylation and the formation of a mixture of regioisomeric amino
alcohols 14a,b in a ratio of 1.4:1.0 (NMR). Further confirmation of the formation of a mixture of N-
monomethyl amino alcohols 14a,b was obtained from the LCMS trace of the reaction mixture after 60
hours. The chromatogram contained two poorly resolved peaks, each corresponding to the same m/z
196.2 (M+H+ of compounds 14a,b) (see ESI, Fig. S4). The chromatographic separation of this mixture
of amino alcohols could not be performed, because they were visualized as a single spot in all of the
examined eluents. The most interesting results were obtained in the reaction with methylbenzylamine.
The LCMS spectrum of the reaction mixture clearly indicated the formation of, in addition to the
mixture of monomethyl derivatives 14a,b, the corresponding intermediate – epoxyamino alcohol 15
with m/z 286.2 [M+H+] (see ESI, Fig. S5) (Scheme 5).
Scheme 5. Aminolysis of dicyclopentadiene diepoxide 7 with secondary amines.
Cage-like polycyclic compounds may interact in a specific way with biological targets. It is
known, for example, that the incorporation of a cage-like structure in biologically active compounds

often increases their biological activity [10]. We believe, the newly synthesized compounds are
promising for biological applications.
Conclusion
We have developed a one-step multigram scale approach to novel octahydro-1H-2,5-epimino-
4,7-methanoindene derivatives from inexpensive and readily available dicyclopentadiene diepoxide.
To the best of our knowledge, this is the first detailed report of the synthesis of such azatetracyclic
cage-like systems. The obtained building blocks can be directly used in drug discovery projects. Given
the simplicity and availability of all starting materials, and the efficient synthesis of the products in
aqueous medium, we believe that this method will find practical applications in both academia and
industry. An investigation of possible ways for the stereoselective functionalization of octahydro-1H-
2,5-epimino-4,7-methanoindene derivatives is ongoing in our laboratory and will be reported in due
course. The chemo-, stereo-, and regiochemical features of the aminolysis of dicyclopentadiene
diepoxide established in this work are crucial in planning further syntheses based on it.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships
that could have appeared to influence the work reported in this paper.
Acknowledgments
This work was financially supported by the grant of the Ministry of Education and Science of Ukraine
(0119U100724).
Appendix A. Supplementary data
Supplementary data (ESI) to this article can be found online at https://doi.org/10.1016
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Declaration of interests
☒ The authors declare that they have no known competing financial interests or personal relationships that
could have appeared to influence the work reported in this paper.
☐The authors declare the following financial interests/personal relationships which may be considered as
potential competing interests:
Highlights
First reported synthesis of the octahydro-1H-2,5-epimino-4,7-methanoindene azapolycyclic system
Operationally simple method using water as the solvent
2D NMR and XRD spectra of the products were studied in detail