Site- and stereoselective synthesis of bridgehead tetrahydropyrrolo[2,3-c]pyridines from ketoximes and acetylene gas in two synthetic operations

Article abstract of DOI:10.1016/j.tetlet.2019.151533

3H-Pyrroles, synthesized in one-pot from ketoximes and acetylene gas in a KOH/DMSO system, undergo [4 + 2] cyclodimerization in the presence of t-BuOH (closed vessel, autogenic pressure, 140 °C, 8 h) to site- and stereoselectively afford partially hydroge

Full text of DOI:10.1016/j.tetlet.2019.151533

Journal Pre-proofs
Site- and Stereoselective Synthesis of Bridgehead Tetrahydropyrrolo[2,3-c]pyr-
idines From Ketoximes and Acetylene Gas in Two Synthetic Operations
Dmitrii A. Shabalin, Igor' A. Ushakov, Anton V. Kuzmin, Alexander V.
Vashchenko, Elena Yu. Schmidt, Boris A. Trofimov
PII:
S0040-4039(19)31332-2
DOI:
https://doi.org/10.1016/j.tetlet.2019.151533
TETL 151533
Reference:
Tetrahedron Letters
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Revised Date:
Accepted Date:
18 October 2019
11 December 2019
15 December 2019
Please cite this article as: Shabalin, D.A., Ushakov, I.A., Kuzmin, A.V., Vashchenko, A.V., Yu. Schmidt, E.,
Trofimov, B.A., Site- and Stereoselective Synthesis of Bridgehead Tetrahydropyrrolo[2,3-c]pyridines From
Ketoximes and Acetylene Gas in Two Synthetic Operations, Tetrahedron Letters (2019), doi: https://doi.org/
10.1016/j.tetlet.2019.151533
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Site- and Stereoselective Synthesis of Bridgehead Tetrahydropyrrolo[2,3-
c]pyridines From Ketoximes and Acetylene Gas in Two Synthetic Operations
Dmitrii A. Shabalin,a Igor’ A. Ushakov,a Anton V. Kuzmin,a,b Alexander V. Vashchenko,a Elena
Yu. Schmidt,a Boris A. Trofimova,*
a
A. E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch of the Russian Academy of
Sciences, 1 Favorsky St, 664033 Irkutsk, Russia
b
Limnological Institute, Siberian Branch of the Russian Academy of Sciences, 3 Ulan-
Batorskaya St, 664033 Irkutsk, Russia
Corresponding Author: e-mail: boris_trofimov@irioch.irk.ru; tel.: +7 395 242 1411; fax: +7 395
241 9346
Abstract: 3H-Pyrroles, synthesized in one-pot from ketoximes and acetylene gas in a
KOH/DMSO system, undergo [4+2] cyclodimerization in the presence of t-BuOH (closed vessel,
autogenic pressure, 140 °C, 8 h) to site- and stereoselectively afford partially hydrogenated
bridgehead pyrrolo[2,3-c]pyridines in 15-60% yield. An essential feature of this synthesis is the
activating effect of t-BuOH which is attributed to reversible H-bonding of the 3H-pyrroles.
R2 R3
R3
R2
t-BuOH (200 mol %)
R2
R3
R1
140 oC, 8 h
N
N
R1
N
R1
R1 = Ph, p-Tol, 2,5-Me2C6H3, 2-furyl;
R2 = R3 = Me or R2-R3 = (CH2)5
6 examples
15-60%
Keywords: acetylene, 3H-pyrrole, pyrrolopyridine, H-bonding, Diels-Alder dimerization
The fused pyrrolopyridine core, formed from pyrroles and pyridines, represents an
important synthetic platform for medicinal chemistry. This core is found in various natural
products (e.g. vallesamidine, phalarine, strictamine) and as a structural motif in antibacterial and
anticancer agents [1], inhibitors of matrix metalloproteinase [2], orexin receptor antagonists [3],
and therapeutics for the treatment of central nervous system disorders [4] (Scheme 1). Therefore,
the development of expedient approaches to this bicyclic scaffold is an urgent synthetic task [5].
1

Me
H
H
MeO2C
N
H
N
N
Me
H
N
H
N
H
HO2C
N
OH
Et
(-)-Vallesamidine
(+)-Strictamine
-
anticancer agent
Scheme 1. Representative examples of fused pyrrolopyridines
Looking for such approaches we have analyzed a number of possible reaction sequences,
which could provide a short atom-, step- and reactor-economic access (in context of the PASE
paradigm [6]) towards functionalized pyrrolopyridines. A clue to the solving this problem might
be the recent report on the alkaloid longeracemine [7], which demonstrated a potential
application of 3H-pyrroles as a springboard to construct complex molecular architectures.
Indeed, these compounds can be used as 1,3-diene components in [4+2] cycloadditions. This
assumption happens to be in line with our current interest in 3H-pyrrole chemistry. These
nonaromatic, energy rich pyrrole isomers were synthesized by us in a one-pot procedure from
ketoximes and acetylene gas in a KOH/DMSO system (Scheme 2) [8].
R2
R3
R2
R1
R1
R3
KOH/DMSO
+
HC CH
70-90 oC, 5 min - 4 h
N
N
OH
8-38%
R1 = Ph, 4-MeC6H4, 2,5-Me2C6H3, 2-furyl, 2-thienyl;
R2 = R3 = Me or R2-R3 = (CH2)5
Scheme 2. Synthesis of 3H-pyrroles from ketoximes and acetylene gas in the KOH/DMSO
system.
It seemed probable that this reaction could initiate a two-step construction of
pyrrolopyridines, provided the appropriate conditions for their auto [4+2] cycloaddition could be
developed. A hope for the success of such a synthetic scheme followed from our previous
observation that certain 3H-pyrroles upon long-term storage (9.5 months) were transformed into
the diverse tetrahydropyrrolopyridine structure [9]. Such a short-cut to the above partially
hydrated heterocyclic systems meets the interests of modern medicinal chemistry which today
focuses on the study of semi-aromatic molecules. This trend is now gaining strength [10]
because sp3 carbon centers render the molecules potentially chiral, 3D-structured, and more
soluble which improves the odds for drug discovery.
2

In this communication, we describe our efforts to substantiate this two-step approach
towards pyrrolopyridines. Below it is shown that our initial assumptions were accurate.
However, our first attempts to realize this auto-Diels-Alder condensation failed, as illustrated by
the experiments at dimerising 2-phenyl-3,3-dimethyl-3H-pyrrole 1a (Table 1).
Table 1. Attempted cyclodimerization of 2-phenyl-3,3-dimethyl-3H-pyrrole 1a to 3,3,8,8-
tetramethyl-2,7-diphenyl-3a,4,7,7a-tetrahydro-3H-4,7-methanopyrrolo[2,3-c]pyridine 2a.
Me Me
Me
Me
M
conditions
N
Ph
N
Ph
N
P
1a
2a
Entry T (°C) t (h)
Ratio of 1a:2aa
95:5
93:7
1
2
3
4
100
120
140
150
160
110
202
6
6
6
6
6
82
2-15
86:14
60:40b
35:65b
45:55b
5
6c
7d
b
-
a According to 1H NMR spectroscopy of the crude reaction.
b Significant tar formation was observed.
c In toluene.
d In NMP.
Neither temperature nor time variation were effective. At 100 °C for 6 h, only trace
amounts of the desired dimer 2a were detected (Entry 1). Further increase of the reaction
temperature to 160 °C facilitated the dimerization, but was accompanied by significant tar
formation (Table 1, Entries 2-5). A similar extent of the dimerization of 3H-pyrrole 1a together
with tar formation took place, when it was heated at reflux in toluene (110 °C, 82 h), while reflux
in N-methylpyrrolidone (202 °C, 2-15 h) gave no product 2a (the starting pyrrole 1a was
consumed entirely) and the same strong resinification occurred.
This reluctance of 3H-pyrrole 1a towards cyclodimerization is probably due to the fact
that both 1,3-diene and dienophile components are of the same electron-rich nature, hence they
lack the mutual electron orbital affinity. This inference is in line with publications [11] regarding
the successful Diels-Alder condensation of 3H-pyrroles with selected electron-deficient
dienophiles, including an intramolecular version of the cyclization of 3H-pyrroles having
unsaturated alkenyl side chains at position 3, albeit under harsh conditions (245 °C, 65 h) [12].
Also, the inverse-electron-demand Diels-Alder condensation of electron-deficient pentachloro-
3H-pyrrole with electron-rich dienophiles was successful [13]. Therefore, we employed acidic
3

reagents to reduce the basicity of the imine moiety, although in equilibrium both electron-
deficient (H-bonded) and electron-rich (free) 3H-pyrroles are present. The selective results of
these experiments are shown in Table 2.
Only tert-butanol demonstrated satisfactory activity (Entry 8), while other protogenic
additives did not display any positive effect (Entries 11-14). Both trifluoroacetic acid and
aluminium chloride as strong Brønsted and Lewis acids (Entries 15-17) led to decomposition of
the starting 3H-pyrrole 1a. Thus, the mild activating effect of t-BuOH has been established.
After a thorough study of this process, including variation in additive loading, reaction time and
temperature (Entries 2-10), the following optimised conditions for the dimerization of 3H-
pyrrole 1a were found: t-BuOH (200 mol%), heating (closed vessel, autogenic pressure of ca. 3-
3.5 atm [14]) at 140 °C, 8 h (Table 2, Entry 8), which provided the desired dimer 2a in 60%
isolated yield.
Table 2. Effect of additives on the dimerization of 3H-pyrrole 1a.
Entry Additive (mol%) T (°C) t (h) Ratio of 1a:2aa
1
2
3
4
5
6
7
8
n-BuOH (100)
t-BuOH (100)
t-BuOH (200)
t-BuOH (300)
t-BuOH (200)
t-BuOH (200)
t-BuOH (200)
t-BuOH (200)
t-BuOH (200)
t-BuOH (200)
100
100
100
100
100
80
120
140
140
140
6
8
8
8
16
8
8
8
4
12
8
8
8
8
8
8
8
13:47b
68:32
55:45
73:27
55:45 (46%)c
88:12
43:57 (51%)c
35:65 (60%)c
38:62
9
10
11
12
13
14
15
16
17
38:62d
89:11
93:7
90:10
CF3CH2OH (100) 100
PhOH (100)
H2O (100)
AcOH (100)
TFA (10)
AlCl3 (10)
AlCl3 (100)
100
100
100
100
100
100
90:10
indefinabled
95:5
indefinabled
a According to 1H NMR spectroscopy of the crude reaction.
b Product of nucleophilic addition (40%) was observed.
c Isolated yields are given in parentheses.
d Significant tar formation was observed.
These reaction conditions were then applied to a series of diverse 3H-pyrroles 1b-f (Table
3). Although in all cases only the target dimers 2 and starting 3H-pyrroles 1 were observed in the
1
reaction mixture (according to H NMR spectroscopy), the other mode of starting material
conversion was tar formation.
4

Table 3. Dimerization of 3H-pyrroles 1a-f.
R2 R3
R3
R2
R2
R3
t-BuOH (200 mol%)
R1
140 oC, 8 h
N
N
R1
N
R1
1
2
Entry
1
3H-Pyrrole 1
Cyclodimer 2
Yield (%)
60
Me Me
Me
Me
Me
Me
N
Ph
N
Ph
N
Ph
1a
2a
2
3
51
49
N
Ph
N
Ph
N
Ph
1b
2b
Me Me
Me
Me
N
Me
Me
N
N
Me
Me
Me
1c
2c
N
4
49
N
N
Me
Me
Me
1d
2d
Me Me
Me
Me
N
Me
Me
Me
Me
N
a
5
6
–
Me
N
Me
Me
Me
1e
2e
Me Me
Me
Me
Me
N
Me
N
N
O
O
O
1f
2f
22
a
1
According to H NMR spectroscopy of the crude reaction both with and without t-BuOH, the
ratio of 1e:2e was ca. 85:15.
5

In the cyclodimerization studied, the asymmetry of the dienes and dienophiles might
result in the formation of a number of site- and stereoisomeric dimers. Pleasingly, the
transformation of 3H-pyrroles 1 to dimers 2 turned out to be a regio- and endo-diastereoselective
process that was unambiguously proved by the X-ray diffraction of dimer 2a (Fig. 1), as well as
13
15
1H, C and N NMR spectroscopy (2D COSY, NOESY, HMBC, HSQC techniques were also
employed).
Figure 1. ORTEP diagram of dimer 2a as determined by X-ray analysis.
The activating effect of t-BuOH is likely associated with reversible H-bonding between
the highly basic imine nitrogen of 3H-pyrroles and t-BuOH. Consequently, in the reaction
mixture both H-bonded, i.e. electron-deficient 3H-pyrroles and their non-bonded counterparts are
present. The adverse influence of further increasing the t-BuOH content (Table 2, entry 4)
possibly originated from augmentation of the H-bonded form concentration. Likewise, the higher
acidity additives (Table 2, Entries 11-14) strongly diminish the concentration of the non-bonded
form.
This mechanistic rationalization is in line with the substituent effect observed in the
dimerization (Table 3). The lowest yield (15%) in the case of 3,3-dimethyl-2-(2,5-
dimethylphenyl)-3H-pyrrole 1e is predictable when accounting for the fact that nitrogen atom H-
bonding is sterically restricted by the ortho-methyl group of the substituent. The decreased yields
in cases of 2-furyl (22%, Entry 6) and p-tolyl-3H-pyrroles (49%, Entries 3 and 4) result from
their donor nature that reduces the acceptor effect caused by H-bonding. The MO analysis of
both 3H-pyrrole 1a and its H-bonded by t-BuOH form did not show significant differences in the
HOMO and LUMO energies and their localizations (see ESI for details). Nevertheless, the
activating effect of t-BuOH, as attributed to its possible coordination with the transition state,
decreases the activation energy from 16.1 to 10.9 kcal/mol for non-catalytic and t-BuOH-
catalyzed transformations, respectively (wB97XD level for both, Fig. 2).
6

Figure 2. Energy diagram [wB97XD/6-311+G(d,p)] for non-catalytic (dashed line) and catalytic
(solid line, hydrogen atoms are omitted for clarity) 1a→2a transformation.
Another question to be answered is the electronic characterization of the studied
cyclization. According to the quantum-chemical calculations, activation of the dimerization by
only one molecule of t-BuOH is equal to 13.1 kcal/mol. Notably, the difference in energy of the
two transition states in which t-BuOH coordinates with the diene or dienophile component is ca.
0.01 kcal/mol and therefore cannot be an unambiguous parameter for the electronic nature
assignment. Nevertheless, since for the successful implementation of the inverse-electron-
demand Diels-Alder reaction it is necessary to activate 3H-pyrrole as the diene component
significantly (e.g. by introducing five chlorine atoms [13]) one may conclude that the described
dimerization represents a formal Diels-Alder condensation between electron-rich dienes and
electron-deficient dienophiles, i.e. a normal electron-demand case.
In conclusion, we have developed a two-reaction strategy to provide site- and
stereoselective access, starting from simple and readily available materials (ketoximes, acetylene
gas, KOH, DMSO, t-BuOH), to novel pharmaceutically prospective structures of a higher
molecular complexity, 3H-4,7-methanopyrrolo[2,3-c]pyridines. The strategy comprises of the
reaction of ketoximes with acetylene gas in the KOH/DMSO system to afford non-aromatic
pyrrole congeners, 3H-pyrroles, which then undergo [4+2] cyclodimerization under the action of
excess t-BuOH. The activating effect of the latter on this cyclodimerization is due to the
reversible H-bonding of 3H-pyrroles leading to partially protonated species, which act as
electron-deficient dienophiles relative to the remaining non-bonded electron-rich partners. The
7

synthesized isomerically pure bridgehead tetrahydropyrrolo[2,3-c]pyridines represent potentially
rewarding compounds for medicinal chemistry.
Acknowledgements
This work was supported by a grant of Russian Science Foundation (Project No. 18-73-
00010). The spectral data were obtained with the equipment of the Baikal Analytical Center for
collective use SB RAS. ESI-HRMS-TOF Spectra were recorded using the equipment of Shared
Research Facilities for Physical and Chemical Ultramicroanalysis, Limnological Institute, SB
RAS.
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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:
9

Site- and Stereoselective Synthesis of Bridgehead Tetrahydropyrrolo[2,3-
c]pyridines From Ketoximes and Acetylene Gas in Two Synthetic Operations
Dmitrii A. Shabalin,a Igor’ A. Ushakov,a Anton V. Kuzmin,a,b Alexander V. Vashchenko,a Elena
Yu. Schmidt,a Boris A. Trofimova,*
a
A. E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch of the Russian Academy of
Sciences, 1 Favorsky St, 664033 Irkutsk, Russia
b
Limnological Institute, Siberian Branch of the Russian Academy of Sciences, 3 Ulan-
Batorskaya St, 664033 Irkutsk, Russia
R2 R3
R3
R2
t-BuOH (200 mol %)
R2
R3
R1
140 oC, 8 h
N
N
R1
N
R1
R1 = Ph, p-Tol, 2,5-Me2C6H3, 2-furyl;
R2 = R3 = Me or R2-R3 = (CH2)5
6 examples
15-60%
Highlights:
An efficient two-reaction strategy approach to tetrahydropyrrolo[2,3-c]pyridines.
Available starting materials are used.
The tetrahydropyrrolo[2,3-c]pyridines were obtained site- and stereoselectively in good yields.
The first example of organocatalytic [4ꢀ+ꢀ2]-cyclodimerization of 3H-pyrroles.
Structural elucidation using NMR and single crystal X-ray studies.
10

11