Acetic anhydride to the rescue: Facile access to privileged 1,2,3,4-tetrahydropyrazino[1,2-a]indole core via the Castagnoli-Cushman reaction

Article abstract of DOI:10.1016/j.tetlet.2018.08.049

Indole-fused cyclic anhydrides earlier deemed unreactive in the Castagnoli-Cushman reaction with imines have been rendered valid participant in this process. The new reaction format involves the use of respective indole-based dicarboxylic acids and in sit

Full text of DOI:10.1016/j.tetlet.2018.08.049

Tetrahedron Letters xxx (2018) xxx–xxx
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Acetic anhydride to the rescue: Facile access to privileged 1,2,3,
4-tetrahydropyrazino[1,2-a]indole core via the Castagnoli-Cushman
reaction
⇑
Maria Chizhova, Olesya Khoroshilova, Dmitry Dar’in, Mikhail Krasavin
Saint Petersburg State University, Saint Petersburg 199034, Russian Federation
a r t i c l e i n f o
a b s t r a c t
Article history:
Indole-fused cyclic anhydrides earlier deemed unreactive in the Castagnoli-Cushman reaction with imi-
nes have been rendered valid participant in this process. The new reaction format involves the use of
respective indole-based dicarboxylic acids and in situ cyclodehydration of the latter by acetic anhydride.
This finding validates a fundamentally new approach to synthesizing compounds based on the privileged
1,2,3,4-tetrahydropyrazino[1,2-a]indole core characterized by hitherto undescribed substitution pattern.
Ó 2018 Elsevier Ltd. All rights reserved.
Received 27 July 2018
Revised 22 August 2018
Accepted 25 August 2018
Available online xxxx
Keywords:
Castagnoli-Cushman reaction
Dicarboxylic acids
In situ cyclodehydration
Acetic anhydride
trans-Diastereoselectivity
Vicinal coupling constants
If a particular heterocyclic motif is frequently employed as a
core scaffold in synthetic bioactive compounds, it is regarded as
privileged [1] from drug design prospective. Hence, various syn-
thetic methods to access such a heterocyclic system flexibly and
conveniently from readily available precursors become particularly
valuable. Recently, our attention was drawn to one such ring sys-
tem, namely, 1,2,3,4-tetrahydropyrazino[1,2-a]indole which is
prominently featured in synthetic compounds displaying diverse
biological activities. These are eloquently exemplified by the small
[9]), are lacking in the literature. Recently, we established a one-
step pathway to polysubstituted azole-fused piperazines via the
Castagnoli-Cushman reaction [10–11] of a new type of cyclic anhy-
drides with imines [12]. This reaction successfully applied to pyra-
zole-containing cyclic anhydrides 8 (to give, after esterification,
bicycles 9) and should, in principle, be applicable to their indole
counterpart 10a which would offer a remarkably streamlined entry
into 1,2,3,4-tetrahydropyrazino[1,2-a]indoles 11. Unfortunately,
involving anhydride 10a in the Castagnoli-Cushman reaction failed
as the latter delivered only an undiscernible mixture of products
(Scheme 1). This was an unfortunate outcome as compounds 11
molecules endowed with such activities as analgesic (r1 receptor
modulator 1) [2], antiviral (‘indole-flutimide’ 2) [3], antiprolifera-
tive (3) [4] or acting as neurogenesis modulators (4) [5], phospho-
represent
a rare substitution pattern around the privileged
diesterase inhibitors (5) [6], indoleamine-2,3-dioxygenase
inhibitors (longamide B analog 6) [7] and non-covalent proteasome
inhibitors (‘indolo-phakellin’ 7) [8] (Fig. 1).
A brief survey of strategies typically employed to access the tri-
cyclic core in question revealed that those normally rely on a step-
wise grafting of the piperazine cycle onto the existing indole core
while more convergent methods, particularly those involving mul-
ticomponent chemistry (except for an example of post-condensa-
tional modification of indole-containing Ugi reaction products
1
1,2,3,4-tetrahydropyrazino[1,2-a]indole core, as evidenced by the
SciFinder substructure search results summarized in Fig. 2.
Concomitantly with this work, we discovered that the recently
described [13] variant of the Castagnoli-Cushman reaction (which
involves the use of dicarboxylic acids as starting materials and
in situ generation of the respective cyclic anhydride) can be the
only workable format for the reaction when the cyclic anhydride
employed as a starting material fails to react in the desired fashion
[14]. Curious to see if the same approach would make the Castag-
noli-Cushman reaction toward 11 more productive, we attempted
to apply the in situ cyclodehydration protocol (involving the use of
acetic anhydride as the dehydrating agent) to dicarboxylic acids
12a–c synthesized as shown in Scheme 2. Herein, we describe
our findings in this regard.
⇑
Corresponding author at: Laboratory of Chemical Pharmacology, Institute of
Chemistry, Saint Petersburg State University, 26 Universitetskyi prospekt, Peterhof
198504, Russian Federation.
E-mail address: m.krasavin@spbu.ru (M. Krasavin).
https://doi.org/10.1016/j.tetlet.2018.08.049
0040-4039/Ó 2018 Elsevier Ltd. All rights reserved.
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M. Chizhova et al. / Tetrahedron Letters xxx (2018) xxx–xxx
Fig. 1. Examples of bioactive compounds 1–7 containing the 1,2,3,4-tetrahydropyrazino[1,2-a]indole scaffold (highlighted).
The initial experiments involved the use of the earlier devel-
oped protocol, i. e. heating a solution of an imine and dicarboxylic
acid 12a in chlorobenzene at 150 °C in presence of an equimolar
amount of acetic anhydride. To our delight, in this conditions, the
desired product 11a was detected in the reaction mixture by 1H
NMR analysis. However, a significant amount of decarboxylated
product (such as 13, structure shown in Scheme 3) was also
detected. Lowering the reaction temperature to 130 °C significantly
suppressed the formation of the decarboxylation product. Thus,
these conditions were extended to the preparation of 1,2,3,4-
tetrahydropyrazino[1,2-a]indoles 11a–i (Table 1).
With the exception of compounds 11c and 11d, the reaction
gave predominantly trans-configured products in low to moderate
yields. The scope of the reaction appears to be limited to imines
derived from aromatic aldehydes (R3 = Ar) while the amine portion
of the imine can be either aromatic or aliphatic. The high reaction
temperature required for the reaction to proceed is indicative of
the diminished reactivity of the intermediate cyclic anhydrides
10 (presumably formed in a low concentration via cyclodehydra-
tion by Ac2O). This is in line with our previous observation of rel-
atively low reactivity of pyrazole-including anhydrides 8 (vide
supra). Irrespective of the reactivity of 10a–c, the formation of tri-
cyclic products 11 appears to be consistent with the reaction pro-
ceeding along the pathway of i. cyclodehydration of dicarboxylic
acid 12, ii. Mannich-type addition of the enolized anhydride 10
to protonated imine, iii. intramolecular aminolysis of the anhy-
dride to give the observed product (isolated herein after esterifica-
tion). The pivotal role, for the success of the reaction, of in situ
cyclodehydration of 12a–c (as opposed to employing anhydrides
10a–c as reagents) is probably due to the low concentration of
10a–c being maintained in this case during the course of the reac-
tion. This may lead to the preferred interaction of 10a–c with the
imine component rather than the formation of the complex pro-
duct mixture as discussed above (Scheme 3). Unfortunately,
attempting to maintain concentration of 10a–c low intentionally
by a slow addition protocol did not produce compounds 11 either.
So, it does appear that using acetic anhydride remains the only
workable reaction format.
Scheme 1. Recently described successful (8 ? 9) and failed (10a ? 11) Castagnoli-
Cushman reaction of azole-based cyclic anhydrides [12].
Fig. 2. Specific substitutions around the 1,2,3,4-tetrahydropyrazino[1,2-a]indole
scaffold. Analyzed by SciFinder substructure search (hits with literature references
only).
Interestingly, introduction of electron-withdrawing cyano
group in position 3 of the indole ring (12b) did not significantly
influence the outcome of the reaction while nitro group in position
5 of indole ring (12c) led to the noticeably higher yield of the reac-
tion (cf. 11h–i). The reasons for the observed difference remain to
be elucidated.
In addition to the routine characterization data (1H and 13C
NMR as well as high-resolution mass-spectrometry) which allow
establishing the identity of the target compounds, we confirmed
the connectivity and relative stereochemistry of selected Castag-
noli-Cushman adducts containing the privileged 1,2,3,4-tetrahy-
dropyrazino[1,2-a]indole scaffold with hitherto undescribed
substitution pattern by single-crystal X-ray crystallography
Scheme 2. Synthesis of dicarboxylic acids 12a–c employed in this study. Reagents
and conditions: i. BrCH2CO2Me, K2CO3, MeCN, reflux, 18 h; ii. NaOH, aqÁTHF, r. t.,
18 h; iii. POCl3, DMF, 0 °C to 60 °C; iv. NH2OH∙HCl, pyridine, EtOH, reflux, 15 h; v.
MsCl, pyridine, 1,4-dioxane, reflux, 5 h; vi. BrCH2CO2Me, NaH, DMF,80 °C, 3 h; vii.
CH3COCO2Et, AcOH, MeOH, r. t., 3 h; viii. polyphosphoric acid, o-xylene, 110 °C,
18 h.
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M. Chizhova et al. / Tetrahedron Letters xxx (2018) xxx–xxx
3
Scheme 3. The desired course of the Castagnoli-Cushman reaction of dicarboxylic acids 12a–c, its plausible mechanism and observable side-reactions.
Table 1
Products of the Castagnoli-Cushman reaction of dicarboxylic acids 12a–c with imines.
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M. Chizhova et al. / Tetrahedron Letters xxx (2018) xxx–xxx
A
B
C
D
Fig. 3. X-ray crystal structures of selected compounds prepared in this work: (A) 11c (cis) – CCDC 1856908; (B) 11d (trans) – CCDC 1856911; (C) 11f (trans) – CCDC 1857123;
(D) 11g (trans) – CCDC 1857122.
Centre for Magnetic Resonance, the Center for Chemical Analysis
and Materials Research, and the Centre for X-ray Diffraction
Methods of Saint Petersburg State University Research Park for
obtaining the analytical data.
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at https://doi.org/10.1016/j.tetlet.2018.08.049.
Fig. 4. Vicinal coupling constants as
a criterion for relative stereochemistry
assignment.
References
[1] M.E. Welsch, S.A. Snyder, B.R. Stockwell, Curr. Opin. Chem. Biol. 14 (2010) 347–
361.
[2] Merce-Vidal R, Diaz Fernandez JL, Almansa Rosales C. PCT Int. Appl. WO
2014173901; Chem. Abstr., 2014, 161, 682172.
[3] G. Zoidis, E. Giannakopoulou, A. Stevaert, E. Frakolaki, V. Myrianthopoulos, G.
Fytas, P. Mavromara, E. Mikros, R. Bartenschlager, N. Vassilaki, L. Naesens,
MedChemComm 7 (2016) 447–456.
[4] Y.J. Kim, J.S. Pyo, Y.-S. Jung, J.-H. Kwak, Bioorg. Med. Chem. Lett. 27 (2017) 607–
611.
(Fig. 3). Because we managed to get the crystals of either trans- or
cis-configured tricyclic products in those cases when both isomers
were formed (11c and 11d), it allowed establishing the straightfor-
ward 1H NMR criteria for assigning the relative stereochemistry.
Indeed, in line with previous observations [12], the vicinal coupling
constant (3J) between the methine protons of the piperidone ring is
noticeable smaller (by 2–4 Hz) for the trans-isomer compared to
that in the cis-isomer (Fig. 4).
[5] Jagasia R, Jakob-Roetne R, Wichmann, J. PCT Int. Appl. 2014161801; Chem.
Abstr. 2014, 161, 582298.
In summary, we have described a remarkable case of restoring
the desired reactivity of novel heterocycle-including cyclic anhy-
drides in the Castagnoli-Cushman reaction by applying the
recently developed format of the reaction involving in situ cyclode-
hydration of the respective precursor discarboxylic acids. The latter
protocol allowed preparing compounds based on a privileged
1,2,3,4-tetrahydropyrazino[1,2-a]indole scaffold in one step (fol-
lowed by esterification) from simple precursors in a fundamentally
new fashion.
[6] Chappie TA, Chandrasekaran RY, Helal CJ, et al., PCT Int. Appl. WO
2016203347; Chem. Abstr. 2016, 166, 95443.
[7] Z. Shiokawa, E. Kashiwabara, D. Yoshidome, K. Fukase, S. Inuki, Y. Fujimoto,
ChemMedChem 11 (2016) 2682–2689.
[8] P. Beck, T.A. Lansdell, N.M. Hewlett, J.J. Tepe, M. Groll, Angew. Chem. Int. Ed.
Engl. 54 (2015) 2830–2833.
[9] S. Tsirulnikov, M. Nikulnikov, V. Kysil, A. Ivachtchenko, M. Krasavin,
Tetrahedron Lett. 50 (2009) 5529–5531.
[10] (a) N. Castagnoli, J. Org. Chem. 34 (1969) 3187;
(b) M. Cushman, M. Castagnoli, J. Org. Chem. 38 (1973) 440.
[11] M. Krasavin, D. Dar’in, Tetrahedron Lett. 57 (2016) 1635.
[12] E. Moreau, D. Dar’in, M. Krasavin, Synlett 29 (2018) 890–893.
[13] A. Lepikhina, D. Dar’in, O. Bakulina, E. Chupakhin, M. Krasavin, ACS Comb. Sci.
19 (2017) 702–707.
Acknowledgements
[14] O. Bakulina, M. Chizhova, D. Dar’in, M. Krasavin, Eur. J. Org. Chem. (2018) 362–
371.
This work was supported by the Russian Foundation for Basic
Research (project grant 18-33-00758). We thank the Research
Please cite this article in press as: M. Chizhova et al., Tetrahedron Lett. (2018), https://doi.org/10.1016/j.tetlet.2018.08.049