Reactivity of spiroanthraceneoxazolidines with cyclopropanes: An approach to the oxindole alkaloid scaffold

Article abstract of DOI:10.1016/j.tetlet.2018.08.001

The reaction of N-methylspiro[anthracene-oxazolidine] with spiro[cyclopropane-3,3′-indolin]-2-ones in the presence of MgI₂ formed the corresponding spiro[pyrrolidine-3,3′-indolin]-2-ones in 42–65% yields. The use of N-benzylspiro[anthracene-oxazolidine] in this reaction led to the formation of a mixture of the corresponding N-methyl- and N-benzylpyrrolidines.

Full text of DOI:10.1016/j.tetlet.2018.08.001

Accepted Manuscript
Reactivity of spiroanthraceneoxazolidines with cyclopropanes: an approach to
the oxindole alkaloid scaffold
Evgeny M. Buev, Vladimir S. Moshkin, Vyacheslav Y. Sosnovskikh
PII:
S0040-4039(18)30970-5
https://doi.org/10.1016/j.tetlet.2018.08.001
TETL 50176
DOI:
Reference:
Tetrahedron Letters
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20 July 2018
1 August 2018
Please cite this article as: Buev, E.M., Moshkin, V.S., Sosnovskikh, V.Y., Reactivity of spiroanthraceneoxazolidines
with cyclopropanes: an approach to the oxindole alkaloid scaffold, Tetrahedron Letters (2018), doi: https://doi.org/
10.1016/j.tetlet.2018.08.001
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Graphical Abstract
Reactivity of spiroanthraceneoxazolidines
with cyclopropanes: an approach to the
oxindole alkaloid scaffold
Leave this area blank for abstract info.
Evgeny M. Buev, Vladimir S. Moshkin*, Vyacheslav Y. Sosnovskikh
* Corresponding author. Tel: +7 3432616824; fax: +7 3432615978.
E-mail address: mvslc@mail.ru (V. S. Moshkin).

Tetrahedron Letters
Reactivity of spiroanthraceneoxazolidines with cyclopropanes: an approach to
the oxindole alkaloid scaffold
Evgeny M. Buev, Vladimir S. Moshkin*, Vyacheslav Y. Sosnovskikh
Institute of Natural Sciences and Mathematics, Ural Federal University, 620000 Ekaterinburg, Russian Federation
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The reaction of N-methylspiro[anthracene-oxazolidine] with spiro[cyclopropane-3,3'-indolin]-2-
ones in the presence of MgI2 formed the corresponding spiro[pyrrolidine-3,3'-indolin]-2-ones in
42–65% yields. The use of N-benzylspiro[anthracene-oxazolidine] in this reaction led to the
formation of a mixture of the corresponding N-methyl- and N-benzylpyrrolidines.
Available online
2018 Elsevier Ltd. All rights reserved.
Keywords:
Domino reaction
Spiroanthraceneoxazolidines
Pyrrolidines
Oxindole alkaloids
Horsfiline
Coerulescine
The pyrrolidine core is one of the most important building
blocks in organic synthesis and is a popular fragment in
medicinal chemistry.1 In particular, compounds which are spiro-
fused at the 3-position of the indolin-2-one pyrrolidine ring
constitute the basis for naturally occurring oxindole alkaloids.2
The oxindole motif is present in the core of numerous
biologically active compounds such as coerulescine and
horsfiline (Fig. 1). The latter were isolated from the Malaysian
medicinal plant Horsfieldia superba and have attracted
significant attention as analgesic medicinal compounds.3
such an approach has been effectively applied to the chemistry of
donor-acceptor cyclopropanes, whose structure promotes an
easier ring-opening of the cyclopropane ring.5 In particular,
previously we reported that the reaction of D-A cyclopropanes6
with spiro[anthracene-oxazolidine] resulted in diethyl 5-
arylpyrrolidine-3,3-dicarboxylates.7
Thus,
the
spiroanthraceneoxazolidine system8 unexpectedly appeared to be
a synthetic equivalent of N-methylmethanimine. Herein, we
report the reactivity of spiro[anthracene-oxazolidines] and its
application in the synthesis of a valuable natural oxindole
scaffold.
Figure 1. Examples of naturally occurring alkaloids containing an oxindole
framework.
Straightforward approaches for the synthesis of the oxindole
framework based on a formal [3+2]-cycloaddition of imines to
cyclopropanes were reported by the Carreira, Grant and Watson
groups (Scheme 1).4 These works are based on the high strain
energy of the cyclopropane ring which allows its facile ring-
opening with formation of an iodide-enolate. The latter possesses
a dipolar nature and successfully forms the pyrrolidine ring after
reaction with imines or 1,3,5-triazinanes. It should be noted that
_______________
* Corresponding author at: Institute of Natural Sciences and Mathematics, Ural
Federal University, 620000 Ekaterinburg, Russian Federation.
e-mail address: mvslc@mail.ru (V. S. Moshkin).
Scheme 1. Selected reactions of cyclopropanes.

spiroanthraceneoxazolidine 2a did not lead to the formation of
product 3a, and the crude mixture was contaminated with
oxazolidine 2 (Entry 3). At this stage, it was clear that the
reaction of spiro-oxazolidine 2 requires higher temperatures than
the reactions of imines and 1,3,5-triazinanes. For this reason, we
chose higher boiling 1,4-dioxane and after variation of the
reaction temperature and equivalents of MgI2 (Entries 4, 7) we
found optimal conditions for this process: heating the reagents in
1,4-dioxane with MgI2 (0.5 equiv.) in a microwave reactor at 190
C for 1 h (Entry 10). At the same time, attempts to use other
solvents or Lewis acids did not improve the yield (Entries 5, 6, 8,
9).
Scheme 2. Synthesis of spiro-pyrrolidine 3a.
Table 1. Optimisation of the reaction conditions.a
Lewis acid
(equiv.)
Yield 3a
Entry
Conditions
Solvent
(%)b
Table 2. Synthesis of spiro[pyrrolidine-3,3'-indolin]-2-ones 3a–e.
2a (1.7 equiv.),
c
1
2
MgBr2·Et2O
o-xylene
o-xylene
–
reflux, 4 h
(1.0)
2a (2.25 equiv.),
MW, 210 C, 2 h
MgBr2·Et2O
25d
(1.0)
2a (1.1 equiv.),
MgI2
(0.1)
recovered
3
THF
MW, 120 C, 30
2a
min
2a (1.3 equiv.),
MgI2
(0.2)
29d
27d
4
5
1,4-dioxane
DMF
MW, 170 C, 1 h
2a (1.45 equiv.),
MW, 210 C, 1 h
MgI2
(0.2)
2a (1.2 equiv.),
BBr3
(1.0)
c
6
THF
–
MW, 150 C, 15
min
2a (1.2 equiv.),
MgI2
(1.1)
40d
30d
27
7
8
1,4-dioxane
THF
MW, 170 C, 1 h
2a (1.3 equiv.),
MgBr2
(0.2)
MW, 170 C, 1 h
Further efforts were directed toward an extension of the
starting substrates. For this purpose, we synthesized a number of
cyclopropanes 1 from commercially available isatin. The first
stage was alkylation of isatin with an alkyl halide in the presence
of K2CO3 in DMF, the second, Wolff–Kishner reduction of N-
substituted isatin at reflux in hydrazine-hydrate (65% water
solution). The third stage was the ethylenation of oxindoles by
treatment with 1,2-dibromoethane and NaH in DMF (see ESI for
details). With the optimized conditions for ring expansion in
hand, we synthesized a number of oxindole pyrrolidines 3b–f via
the reaction of N-substituted spiro[cyclopropane-oxindoles] 1
with spiro[anthracene-oxazolidine] 2a in 42–65% yield (Table 2).
Remarkably, the desired spiro[pyrrolidine-3,3'-oxindoles] 3 could
be easily purified from the side products by conversion into water
soluble hydrochlorides. Subsequent extraction of the non-basic
admixtures using PhMe and basification with NaHCO3 resulted
in pure pyrrolidines 3. Thus, the proposed approach appears to be
an attractive method due to its simple implementation.
2a (1.2 equiv.),
MgBr2
(1.1)
9
1,4-dioxane
1,4-dioxane
MW, 170 C, 1 h
2a (1.45 equiv.),
MW, 190 C, 1 h
MgI2
(0.5)
10
58
a Reactions were performed on a 0.8 mmol scale.
b Isolated yields of product 3a based on cyclopropane 1a.
c Complex mixture of products.
d NMR yield: product was contaminated by the starting oxazolidine.
We commenced our study with optimization of the reaction
conditions using the model reaction of N-benzyloxindole
cyclopropane 1a with spiroanthraceneoxazolidine 2a (Scheme 2).
Unfortunately, it was discovered that the previously developed
conditions for the reactions of D-A cyclopropanes (o-xylene,
MgBr2·Et2O, reflux, 3.5 h)7 were not appropriate (Table 1, entry
1). The same experiment at higher temperature (210 C) in a
microwave reactor led to the desired N-benzylcoerulescine (3) in
low yield with an admixture of starting oxazolidine 2 (Entry 2).
As mentioned above, Carreira and co-workers reported the
successful reaction of oxindole cyclopropane with 1,3,5-
trimethyl-1,3,5-triazinane catalyzed by MgI2 in THF at 125 C.4b
Nevertheless, we found that under the same conditions
Interestingly,
the
reaction
of
N-
benzylspiroanthraceneoxazolidine 2b led to an unexpected result.
Thus, heating 2b with 1-methylspiro[cyclopropane-indolinone]
(1, R = Me) using the previously developed conditions resulted in
the formation of
a
mixture of N-benzyl- and N-
methyl[pyrrolidine-oxindoles] 4a and 3b in a 1.7 : 1 ratio
according to the NMR data. Subsequent chromatographic
purification allowed the isolation of N-benzylpyrrolidine 4a and
N-methylpyrrolidine 3b in 35% and 20% yields, respectively.

The same result was obtained in the reactions of N-ethyl and N-
propyl substituted spiro[cyclopropane-3,3'-oxindoles] 1 (Table
3).
Table 3. Reaction of N-benzylspiroanthraceneoxazolidine 2b with
spiro[cyclopropane-3,3'-indolinones].a
Scheme 3. Proposed mechanism.
a Isolated yields of chromatographically purified products.
Scheme 4. Dealkylation of an N-benzyl-N-methylammonium quaternary salt.
The reaction of spiroanthraceneoxazolidines
2
with
spiro[cyclopropane-3,3'-indolinones] 1 differs significantly from
the known reactions of cyclopropanes with imines and
triazinanes.5 Presumably, oxazolidine 2b initially underwent
cycloreversion to form nonstabilised azomethine ylide A. Then
ylide А was protonated by trace water in the reaction mixture and
reacted with enolate C. Subsequent intramolecular cyclization of
intermediate D leads to quaternary ammonium base E (Scheme
3). The latter possesses a benzyl moiety and, presumably,
competition between dealkylation of the Me and Bn groups takes
place. As the result, the mixture of pyrrolidines 3 and 4 forms
Such a hypothesis is consistent with the recently discovered
dealkylation of quaternary ammonium salts due to the fact that
dealkylation of N-benzyl-N-methylammonium salts was not
selective.9 To examine this assumption we obtained quaternary
salt 5 from methylpyrrolidine 3b and benzylchloride (Scheme 4).
Heating this salt in DMF at 190 C for 30 min resulted in the
formation of a mixture of 4a and 3b in a 2 : 1 ratio (according to
the NMR data). This finding is in agreement with the reaction of
1-methylspiro[cyclopropane-indolinone] (1, R = Me) and spiro-
oxazolidine 2b.
when
the
starting
compound
is
N-
benzylspiroanthraceneoxazolidine 2b. N-Methylspiro[anthracene-
9,5'-oxazolidine] 2a reacts through the same pathway, however
the process results in the single product 3.
We also carried out the same reaction with D-A cyclopropane
6 and obtained a similar result (Scheme 5). However, N-
methylpyrrolidine 7 predominated over N-benzyl compound 8
(molar ratio 7 : 8 = 3 : 1 according to the NMR data).

This work was financially supported by the Russian Science
Foundation (Grant 17-73-20070).
References and notes
1. (a) Plunkett AO. Nat Prod Rep. 1994;11:581;
(b) Döndas HA, de Gracia Retamosa M, Sansano JM. Synthesis.
2017;49:2819;
(c) Obst U, Betschmann P, Lemer C, Seiler P, Diederich F, Gramlich V,
Weber L, Banner DW, Schönholzer P. Helv Chim Acta. 2000;83:855;
(d) Pandey G, Dey D, Tiwari SK. Tetrahedron Lett. 2017;58:699;
(e) Kawasaki M, Shinada T, Hamada M, Ohfune Y. Org Lett.
2005;7:4165;
(f) Hanessian S, Bayrakdarian M, Luo X.
2002;124:4716;
J Am Chem Soc.
(g) Scott JD, Williams RM. Chem Rev. 2002;102:1669;
(h) Dubuffet T, Muller O, Simonet SS, Descombes J-J, Laubie M,
Verbeuren TJ, Lavielle G. Bioorg Med Chem Lett. 1996;6:349;
(i) Ivanov KL, Villemson EV, Budynina EM, Ivanova OA, Trushkov IV,
Melnikov MY. Chem Eur J. 2015;21:4975.
Scheme 5. Reaction of D-A cyclopropane 6 with spiro-oxazolidine 2b.
It is interesting to note that we recently reported the synthesis
of oxindole scaffold 3 from spiroanthraceneoxazolidines 2 by
another method.8b The reaction of spiro-oxazolidine 2a (2.3
equiv.) with 1-benzylindolinone 9 occurred as a domino-process:
Mannich reaction – elimination of dimethylamine – [3+2]-
cycloaddition, and led to the formation of N-benzylcoerulescine
3a in 73% yield (Scheme 6). The reaction of N-
2. (a) Bindra JS. In The Alkaloids. In: Manske RHF, ed, Vol. 14. New
York: Academic Press; 1973:84;
(b) Marti C, Carreira EM. Eur J Org Chem. 2003;2209;
(c) Akaev AA, Villemson EV, Vorobyeva NS, Majouga AG, Budynina
EM, Melnikov MY. J Org Chem. 2017;82:5689;
(d) Sebahar PR, Williams RM. J Am Chem Soc. 2000;122:5666;
(e) Santos MMM. Tetrahedron. 2014;70:9735.
3. (a) Jossang A, Jossang P, Hadi HA, Sévenet T, Bodo B. J Org Chem.
1991;56:6527;
benzylspiro[cyclopropane-3,3'-indolin]-2-one
1a
described
t , Weber M, Borschberg H-J. Tetrahedron:
Asymmetry. 1994;5:1979;
(c) Hsieh J-C, Cheng A-Y, Fu J-H, Kang T-W. Org Biomol Chem.
2012;10:6404;
(d) Le Goff R, Lawson AM, Daïch A, Comesse S. Org Biomol Chem.
2013;11:1818;
herein resulted in the same product 3a in 58% yield. In the first
case a nonstabilized azomethine ylide derived from oxazolidine
2a additionally acted as a synthetic equivalent of formaldehyde,
in the second, as the synthetic equivalent of N-
methylmethanimine.
(e) Palmisano G, Annunziata R, Papeo G, Sisti M. Tetrahedron:
Asymmetry. 1996;7:1.
4. (a) Alper PB, Meyers C, Lerchner A, Siegel DR, Carreira EM. Angew
Chem Int Ed. 1999;38:3186;
(b) Fischer C, Meyers C, Carreira EM. Helv Chim Acta. 2000;83:1175;
(c) Helan V, Mills A, Drewry D, Grant D. J Org Chem. 2010;75:6693;
(d) Seath CP, Fyfe JWB, Molloy JJ, Watson AJB. Synthesis.
2017;49:891.
5. (a) Parsons AT, Smith AG, Neel AJ, Johnson JS. J Am Chem Soc.
2010;132:9688;
(b) Garve LKB, Kreft A, Jones PG, Werz DB.
2017;82:9235;
J Org Chem.
(c) Kang Y-B, Tang Y, Sun X-L. Org Biomol Chem. 2006;4:299;
(d) Chu Z-Y, Li N, Liang D, Li Z-H, Zheng Y-S, Liu J-K. Tetrahedron
Lett. 2018;59:715.
6. (a) Schneider TF, Kaschel J, Werz DB. Angew Chem Int Ed.
2014;53:5504;
(b) Tomilov YV, Menchikov LG, Novikov RA, Ivanova OA, Trushkov
IV. Russ Chem Rev. 2018;87:201;
(c) Melnikov MY, Budynina EM, Ivanova OA, Trushkov IV. Mendeleev
Commun. 2011;21:293;
(d) Nanteuil F, Simone F, Frei R, Benfatti F, Serrano E, Waser J. Chem
Commun. 2014;50:10912;
Scheme 6. Synthetic potential of spiroanthraceneoxazolidine system.
(e) Grover HK, Emmett MR, Kerr MA. Org Biomol Chem. 2015;13:655.
7. Buev EM, Moshkin VS, Sosnovskikh VY. Tetrahedron Lett.
2016;57:3731.
In summary, a new method is reported for the synthesis of the
spiro[pyrrolidine-3,3'-oxindole]
system
using
8. (a) Buev EM, Moshkin VS, Sosnovskikh VY. Org Lett. 2016;18:1764;
spiroanthraceneoxazolidines 2 as an unusual synthetic equivalent
of an imine. These spiro-oxazolidines 2, despite their simple
structure, possess wide synthetic capabilities for the construction
of various azaheterocycles. Their further application for the
synthesis of natural and potentially bioactive compounds is
underway in our laboratory and will be reported in due course.
(b) Buev EM, Moshkin VS, Sosnovskikh VY.
2017;82:12827.
J Org Chem.
9. Buev EM, Smorodina AA, Stepanov MA, Moshkin VS, Sosnovskikh
VY. Tetrahedron Lett. 2018;59:1638.
Supplementary data
Acknowledgments
Supplementary data associated with this article can be found
in the online version.

Spiroanthraceneoxazolidines for the synthesis of natural spiro[pyrrolidine-3,3'-oxindole] core.
A new plausible mechanism of the reaction spiroanthraceneoxazolidines with cyclopropanes.
Spiroanthraceneoxazolidines as an unusual synthetic equivalents of imines and triazinanes.