Dual use of propargylamine building blocks in the construction of polyheterocyclic scaffolds

Article abstract of DOI:10.1016/j.tetlet.2020.151970

The cyclization reactions of 2-(N-propargyl)imidazole-2-yl)indoles (synthesized via the hydroamination reaction between N-propargyl indole-2-carboxamides and propargylamine) have been investigated under Lewis acid- and base-promoted conditions. The polyhe

Full text of DOI:10.1016/j.tetlet.2020.151970

Tetrahedron Letters xxx (xxxx) xxx
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Dual use of propargylamine building blocks in the construction of
polyheterocyclic scaffolds
Anna Bakholdina a, Alexei Lukin a, Olga Bakulina b, Natalia Guranova b, Mikhail Krasavin b,c,
⇑
a Lomonosov Institute of Fine Chemical Technologies, MIREA – Russian Technological University, Moscow 119571, Russian Federation
b Saint Petersburg State University, Saint Petersburg 199034, Russian Federation
c Immanuel Kant Baltic Federal University, Kaliningrad 236016, Russian Federation
a r t i c l e i n f o
a b s t r a c t
Article history:
The cyclization reactions of 2-(N-propargyl)imidazole-2-yl)indoles (synthesized via the hydroamination
reaction between N-propargyl indole-2-carboxamides and propargylamine) have been investigated
under Lewis acid- and base-promoted conditions. The polyheterocyclic compounds thus obtained were
shown to possess promising photophysical properties.
Received 29 March 2020
Revised 17 April 2020
Accepted 21 April 2020
Available online xxxx
Ó 2020 Elsevier Ltd. All rights reserved.
Keywords:
Hydroamination-cyclization
Zinc triflate
Cesium carbonate
Propargyl group cyclization
Polyheterocycles
Blue emitters
Ring-forming reactions involving positions 1 and 3 of the indole
nucleus and a propargylamino motif attached at position 2 via var-
ious linkers is a common method of building polycyclic heteroaro-
matic scaffolds. Recent noteworthy examples of utilizing this
strategy include the Au(III)- and Pt(II)-catalyzed cyclizations of
propargylic indole-2-carboxamides reported by Padwa [1] and Bel-
tion N-1 or C-3, depending on the reaction conditions. We rea-
soned that compounds 1 could be obtained via the Zn(OTf)2-
catalyzed hydroamination-cyclization sequence described by Bel-
ler and co-workers [6] as well as Krasavin and co-workers [7]. If
applied to readily available N-propargyl indole-2-carboxamides 2
and propargylamine, this approach would deliver the expected
starting materials 1 for further cyclizations. The possibility of
cyclization at position C-3 was preliminarily indicated by the
recent report by Nagarajan and co-workers [8] of cyclizations
involving position 3 of N-substituted indole and a propargyl group
attached to position 2 via various heterocycles. However, similar
cyclization at position N-1 has not been investigated. Both of these
divergent cyclizations would deliver tetracyclic aromatic imidazo
[10,20:1,2]pyrido[3,4-b]indole (3) and imidazo[20,10:3,4]pyrazino
[1,2-a]indole (4) scaffolds (Fig. 1) which are known for their anal-
ogy to anticancer kinase inhibitors [9] as well as their valuable
photophysical properties [10], respectively.
Unfortunately, the yields of N-propargyl imidazoles 1a–d from
the respective N-propargyl indole-2-carboxamides 2a–d proved
disappointingly low, under modified literature conditions employ-
ing 20 mol% Zn(OTf)2 [7b]. Lowering the amount of the catalyst to
5 mol% (as described by Beller and co-workers [6]) led to no pro-
duct formation while raising it to 50 mol% [7a] did not improve
the yield (Scheme 1). Notably, attempts to carry out the same
transformations with N1-methylated versions of 2 did not result
ler [2], respectively. Interestingly,
a similar cyclization was
achieved by Watkins and co-workers upon heating in the presence
of weakly basic sodium bicarbonate [3]. Cyclizations onto N-1 of an
indole core are also typically achieved under base-promoted condi-
tions. The use of a rather strong base is considered necessary as the
propargylamide moiety needs initially to be converted into the
respective C-reactive allene amide. This approach is illustrated by
the DBU-promoted cyclization reported by Llauger [4] and post-
condensational modification of indole- and propargyl-containing
products of the Ugi reaction achieved by Shafiee and co-workers
upon brief treatment with t-BuOK [5]. We became interested in
exploring the possibility of employing 2-(imidazol-2-yl)indoles 1
as a template for complexity-generating cyclizations at either posi-
⇑
Corresponding author at: Laboratory of Chemical Pharmacology, Institute of
Chemistry, Saint Petersburg State University, 26 Universitetskii Prospect, Peterhof
198504, Russian Federation.
E-mail address: m.krasavin@spbu.ru (M. Krasavin).
URL: http://krasavin-group.org (M. Krasavin).
https://doi.org/10.1016/j.tetlet.2020.151970
0040-4039/Ó 2020 Elsevier Ltd. All rights reserved.
Please cite this article as: A. Bakholdina, A. Lukin, O. Bakulina et al., Dual use of propargylamine building blocks in the construction of polyheterocyclic
scaffolds, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2020.151970

2
A. Bakholdina et al. / Tetrahedron Letters xxx (xxxx) xxx
Fig. 1. Examples of cyclization of a propargylamino moiety onto C-3 or N-1 of the indole core and the chemodivergent strategy investigated in this work.
Scheme 1. Synthesis of N-propargyl imidazoles 1a–d.
Scheme 2. Zn(OTf)2-catalyzed cyclizations of substrates 1a–d.
in the formation of the imidazole product. Nonetheless, this
approach provided a rapid entry into NH-indoles 1a–d which we
intended to engage in regiodivergent cyclizations involving the
propargyl moiety and either C-3 or N-1 of the indole core.
substitution pattern with the most electron-rich substrate 1d
affording no product (Scheme 2).
For the cyclization involving the propargyl substituent and the
N-1 atom of the indole nucleus, presumably proceeding via the cor-
responding allene, various base promoters (employed in equimolar
amount or two-fold excess) were screened against substrate 1a. As
is evident from the data provided in Table 1, the range of inorganic
as well as organic bases capable of driving the reaction forward is
rather wide. While the reaction was faster at elevated temperature,
the product purity was better for reactions conducted over 7 h at
ambient temperature. Overall, the use of Cs2CO3 (2 equiv.) at room
temperature (Table 1, Entry 1) was deemed optimal. These condi-
tions were then applied to substrates 1a–d (Scheme 3). To our
delight, the desired cyclization products 4 formed in each case;
Screening of Lewis acid catalysts for the cyclization at C-3 using
1a as a model substrate, identified Zn(OTf)2 (50 mol%) as the opti-
mum catalyst which gave 99% yield of the respective cyclized pro-
duct (3a). Among the examined catalysts (including Gd(OTf)3, Cu
(OTf)2, AuPPh3Cl, AuPPh3Cl/AgOTf, AgOTf, PtCl2, PtCl2/AgOTf, K2-
PtCl6, Pd(OAc)2, TfOH, CuI, CuBr, Ce2(SO4)3, Yb(OTf)3, Zn(OAc)2, Sc
(OTf)2) screened at 10 mol% in compatible solvents and at temper-
atures varying from ambient to reflux, only Cu(OTf)2 and Gd(OTf)3
also gave the desired product 3a in 10% and 70% yield, respectively.
With Zn(OTf)2 as a catalyst, the cyclizations were extended to sub-
strates 1b–d; however, the reaction was rather sensitive to the
Please cite this article as: A. Bakholdina, A. Lukin, O. Bakulina et al., Dual use of propargylamine building blocks in the construction of polyheterocyclic
scaffolds, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2020.151970

A. Bakholdina et al. / Tetrahedron Letters xxx (xxxx) xxx
3
propargyl 2,20-bis-indolyl derivatives, we became interested in
introducing aryl substituents at the terminus of the propargyl
group in 1a. Surprisingly, the standard Sonogashira coupling pro-
tocol failed to give the expected derivatives 6. Therefore, we
resorted to preparing 3-arylprop-2-yn-1-ylamines 5a–d from
Boc-protected propargylamine as described in the literature
[11]. The use of these 3-arylpropargylamines in the Beller imida-
zole synthesis under catalysis by Zn(OTf)2 (20 mol%) led directly
to the double cyclization products 7a–c. In the case of propargy-
lamine bearing the electron-poor 4-nitrophenyl group (5d), the
second cyclization did not proceed, even under forcing conditions,
and the respective imidazole product 6d was isolated in low yield
(Scheme 4).
It should be noted that positioning the (N-propargyl)imidazole-
2-yl moiety at C-2 of the indole appears crucial for the success of
subsequent Zn(OTf)2-catalyzed cyclization. Indeed, imidazoles
9a–b prepared from propargylic indole-3- (8a) and indole-4-car-
boxmides (8b), respectively, did not undergo subsequent cycliza-
tion (Scheme 5).
Considering the propensity of polycyclic heteroaromatic sys-
tems such as imidazo[20,10:3,4]pyrazino[1,2-a]indole (4) to display
useful photophysical properties, we recorded emission and absorp-
tion spectra for selected compounds in the 3, 4 and 7 series. All of
the compounds were found to be phosphors and showed blue
emission with maxima at 350–400 nm under excitation at 305–
355 nm in DMSO solutions at concentrations of 50 mM (Fig. 2a).
All compounds exhibited complex absorption spectra with maxima
in the UV region at 270–320 nm (Fig. 2b). Each series of com-
pounds (3, 4 or 7) showed its own characteristic absorption and
emission pattern (Figs. S1 and S2). More detailed information on
the absorption and emission characteristics of compounds investi-
gated is provided in the Supplementary data.
Table 1
Optimization of the base-promoted cyclization of 1a.
Entry
Base (equiv.)
Solvent
T (°C)
Yield 4a (%)
1
2
3
4
5
6
7
8
Cs2CO3 (2.0)
Cs2CO3 (1.0)
Cs2CO3 (2.0)
KOH (2.0)
KOH (2.0)
t-BuOK (1.0)
TBAF (1.0)
K2CO3 (2.0)
NaHCO3 (2.0)
DBU (1.0)
DMSO
DMSO
DMSO
DMSO
DMSO
THF
22a
22a
120b
22a
120b
22a
22a
22a
22a
22a
22a
120a
76
66
74c
70
68
70
70
63
30
10
0
THF
DMSO
DMSO
CH2Cl2
CHCl3
DMF
9
10
11
12
TEA (1.0)
None
0
a
b
c
Reaction time – 7 h.
Reaction time – 1 h.
The product was contaminated with an unknown impurity.
In summary, we have investigated the cyclization reactions of
2-(N-propargyl)imidazole-2-yl)indoles (synthesized via a previ-
ously described hydroamination-cyclization protocol from readily
available indole-2-(propargyl)carboxamides) at the C-3 and N-1
atom of the indole nucleus under the influence of a Lewis acid
(Zn(OTf)2) and base (Cs2CO3) promoter, respectively. Although
the reaction was found to be rather sensitive to the indole substi-
tution pattern, it provided a rapid access to two distinct polyhete-
rocyclic cores. Interestingly, the attempted preparation of
terminally arylated propargyl derivatives from N-propargyl
indole-2-carboxamide led directly to the corresponding tetracyclic
products.
Scheme 3. CsCO3-promoted cyclizations of substrates 1a–d.
however, for substrates bearing substituents at position 5 the yield
was markedly lower.
Finally, capitalizing on the prior work of Nagaraja and co-
workers [8] who described similar cyclizations of N-(3-aryl)
Scheme 4. Preparation of 1-arylproparylamines 5a–d and their use in the hydroamination-cyclization sequence with 2a (acompound 6d was isolated in 11% yield).
Please cite this article as: A. Bakholdina, A. Lukin, O. Bakulina et al., Dual use of propargylamine building blocks in the construction of polyheterocyclic
scaffolds, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2020.151970

4
A. Bakholdina et al. / Tetrahedron Letters xxx (xxxx) xxx
Scheme 5. Attempted positioning of the (N-propargyl)imidazole-2-yl moiety at positions 3 and 4 of the indole nucleus.
Fig. 2. Emission (a) and absorption (b) spectra of selected compounds in the 3, 4 and 7 series measured in DMSO (50 mM).
[5] M. Mahdavi, R. Hasanzadeh-Soureshjan, M. Saeedi, A. Ariafard, R. BabaAhmadi,
Acknowledgement
P.R. Ranjbar, A. Shafiee, RSC Adv. 5 (2015) 101353–101361.
[6] (a) A. Pews-Davtyan, A. Tillack, A.-C. Schmöle, S. Ortinau, M.J. Frech, A. Rolfs,
M. Beller, Org. Biomol. Chem. 8 (2010) 1149–1153;
(b) A. Pews-Davtyan, M. Beller, Org. Biomol. Chem. 9 (2011) 6331–6334.
[7] (a) A. Lukin, A. Bakholdina, A. Kryukova, A. Sapegin, M. Krasavin, Beilstein J.
Org. Chem. 15 (2019) 1061–1064;
This research was supported by the Russian Foundation for
Basic Research (project grant 19-33-90169).
(b) A. Safrygin, E. Krivosheyeva, D. Dar’in, M. Krasavin, Synthesis 50 (2018)
3048–3058.
Appendix A. Supplementary data
[8] S. Ramesh, R. Nagarajan, Synthesis 47 (2015) 3573–3582.
[9] (a) R. J. Andersen, M. Roberge, J. Sanghera, D. Leung, PCT Int. Appl. WO
9947522A1, Chem. Abstr. 131 (1999) 243451.;
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2020.151970.
(b) E. Piers, R. Britton, R.J. Andersen, J. Org. Chem. 65 (2000) 530–535;
(c) J.B. Jaquith, A. Fallis, J. Gillard, PCT Int. Appl. WO 2001087887A2, Chem.
Abstr. 136 (2001) 6198.;
(d) G. Tremblay, A. Kalbakji, M. Filion, PCT Int. Appl. WO 2009127059A1,
Chem. Abstr. 151 (2009) 478570.
References
[1] D.B. England, A. Padwa, Org. Lett. 10 (2008) 3631–3634.
[10] (a) S. Matsumoto, K. Sakamoto, M. Akazome, Heterocycles 91 (2015) 795–814;
(b) G.H. Bae, S. Kim, N.K. Lee, A. Dagar, J.H. Lee, J. Lee, I. Kim, RSC Adv. 10
(2020) 7265–7288.
[2] M. Gruit, A. Pews-Davtyan, M. Beller, Org. Biomol. Chem. 9 (2011) 1148–1159.
[3] D. Uredi, D.R. Motati, E.B. Watkins, Org. Lett. 20 (2018) 6336–6339.
[4] L. Llauger, C. Bergami, O.D. Kinzel, S. Lillini, G. Pescatore, C. Torrisi, P. Jones,
Tetrahedron Lett. 50 (2009) 172–177.
[11] T. Ishida, R. Kobayashi, T. Yamada, Org. Lett. 16 (2014) 2430–2433.
Please cite this article as: A. Bakholdina, A. Lukin, O. Bakulina et al., Dual use of propargylamine building blocks in the construction of polyheterocyclic
scaffolds, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2020.151970