Reactions of 5-aryloxazolidines with CH-acidic compounds

Article abstract of DOI:10.1016/j.tetlet.2019.05.031

5-Aryloxazolidines react with active methylene compounds in the presence of catalytic magnesium ethoxide to give methylene-linked 1,3-dicarbonyl compounds, while the similar reaction with 2-oxindoles results in 3-methyl derivatives.

Full text of DOI:10.1016/j.tetlet.2019.05.031

Accepted Manuscript
Reactions of 5-aryloxazolidines with CH-acidic compounds
Anastasia A. Smorodina, Evgeny M. Buev, Vladimir S. Moshkin, Vyacheslav
Y. Sosnovskikh
PII:
S0040-4039(19)30476-9
https://doi.org/10.1016/j.tetlet.2019.05.031
TETL 50803
DOI:
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
15 April 2019
16 May 2019
17 May 2019
Please cite this article as: Smorodina, A.A., Buev, E.M., Moshkin, V.S., Sosnovskikh, V.Y., Reactions of 5-
aryloxazolidines with CH-acidic compounds, Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet.
2
019.05.031
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Graphical Abstract
Reactions of 5-aryloxazolidines with CH-acidic
compounds
Leave this area blank for abstract info.
Anastasia A. Smorodina, Evgeny M. Buev, Vladimir S. Moshkin*, Vyacheslav Y. Sosnovskikh
O
O
O
N Me
O
Ph
X
R
R
R
Mg(OEt) (10 mol%)
2
X
X
PhMe, 120–200 °C, 1.5 h
39–71% yield
X = CO Et, CO Me, Ph; R = OEt, OMe, Ph
2
2
*
Corresponding author. Tel: +7 3433899597; e-mail: mvslc@mail.ru (V. S. Moshkin).

Tetrahedron Letters
journal homepage: www.elsevier.com
Reactions of 5-aryloxazolidines with CH-acidic compounds
Anastasia A. Smorodina, Evgeny M. Buev, Vladimir S. Moshkin*, Vyacheslav Y. Sosnovskikh
Institute of Natural Sciences and Mathematics, Ural Federal University, 620000 Ekaterinburg, Russian Federation
*
Corresponding author. Tel: +7 3433899597; e-mail: mvslc@mail.ru
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
5-Aryloxazolidines react with active methylene compounds in the presence of catalytic
magnesium ethoxide to give methylene-linked 1,3-dicarbonyl compounds, while the similar
reaction with 2-oxindoles results in 3-methyl derivatives.
2
018 Elsevier Ltd. All rights reserved.
Available online
Keywords:
Oxazolidines
Formaldehyde
Methylenation
1
,5-Dicarbonyl compounds
1
The oxazolidine ring is widely used in organic chemistry, and
the formed iminium cation participates in a Mannich reaction.
Mannich base 10 eliminates dimethylamine and the intermediate
alkene 11 reacts with a second azomethine ylide derived from 7.
despite the simplicity of this heterocyclic system it possesses
versatile reactivity. In particular, the general reactivity of 5-
aryloxazolidines 1 is their ring-opening via nucleophilic attack at
the C-2 position, located between two electron-deficient atoms
Me
(
N and O), resulting in aminoalcohol 2 formation (Scheme 1).2
HO
Ar
N R
HO HN R
An intramolecular version of this ring-opening which leads to
3
tetrahydroisoquinolin-4-oles is also known in the literature. The
Ar
4
3
hydrolysis of oxazolidine 1 under acidic conditions or by treating
with nucleophiles such as hydrazine or hydroxylamine eliminates
an aminoacetal methylene group to form biogenic
arylethanolamines 3. Oxazolidines can be reduced at the C-2
position to give tertiary amines 4. There are more complicated
reaction sequences, such as ring-opening with indole at the
aminoacetal methylene group and subsequent intramolecular
indole attack at the C-5 position in acidic media for the synthesis
of γ-carbolines 5. The attack at C-5 occurs due to C–O cleavage
with the formation of an intermediate carbocation which is
stabilized by an aryl moiety. Sato and co-workers published a
4
5
R
Nu
2
1
O
3
HO
Ar
N
N R
Ar
5
4
2
6
1
7
rare example of oxazolidine ring expansion to give morpholines.
Ryan and co-workers carried out an unusual recyclization of
oxazolidines to form diazepines. It is known that the oxazolidine
R
N
8
ring can undergo cycloreversion to form stabilized azomethine
9
ylides. Recently, we have found that the cycloreversion of
N
R
6
strained spiro-oxazolidines leads to the formation of highly
N
H
Ar
1
0
reactive nonstabilized azomethine ylides 6. On the other hand, a
convenient and straightforward method for the synthesis of a
wide range of oxazolidines is the cycloaddition reaction of
5
1
d
nonstabilized azomethine ylides with carbonyl compounds.
Scheme 1. Selected examples of aryloxazolidine reactivity.
Previously, we found that the reaction of spiro[anthracene-
oxazolidine] 7 with active methylene compounds 8 occurs via a
domino process and results in pyrrolidine 9 formation (Scheme
This reaction is based on the cycloreversion of
spirooxazolidine 7 which gives an intermediate azomethine ylide.
The latter reacts as a base with active methylene compound 8 and
From another point of view, we were interested in the further
investigation of this process. In particular, how would the
reaction proceed if 3-methyl-5-phenyloxazolidine (12) was used
instead of spiro-oxazolidine 7? Taking into account the fact that
oxazolidine 12 does not readily undergo cycloreversion
1
1
2
).

compared to oxazolidine 7,10 we hypothesized that the product
may be different.
malonate 13a proceeds better in the presence of a base. As it
turned out, heating of the reagents with sodium hydride in DMF
at 90 °C joined two molecules of diethyl malonate 13a by a
methylene group to form product 15a, while only traces of 14a
was observed (Table 1, entry 2). In view of these results, it
seemed difficult to stop the reaction at the formation of amino
alcohol 14a, therefore we began to develop conditions for the
synthesis of 15a. The low conversion of diethyl malonate 13a
could be explained by the nature of the oxazolidine ring, which
possesses an ability to undergo ring-opening under acidic
conditions with nucleophiles or in the reaction with aryl
R
N
O
EWG
EWG
N
R
9
7
O
7
2
b
magnesium bromides.
Taking into account the above
EWG
R = Me, Bn
information, basic reaction conditions are not sufficient for the
investigated reaction and the presence of Lewis or Brønsted acids
is required for the oxazolidine ring-opening. Thus, heating
EWG
8
2
diethyl malonate 13a (3 mmol) at reflux with Mg(OEt) (3 mmol)
and excess oxazolidine 12 (2 mmol, 1.3 equiv.) in acetonitrile for
3 h led to the methylenation product 15a which was isolated from
the starting material by flash column chromatography in 59%
yield (NMR ratio 13a : 15a was 1 : 4, Table 1, entry 3). We also
examined the reaction at a lower temperature (reflux in THF),
which gave product 15a in 52% yield (Table 1, entry 4). The
EWG
EWG
EWG
EWG
R N
Me
10
11
2
reaction also proceeds at reflux in Et O (NMR ratio 13a : 15a
Scheme 2. Reaction of spiroanthraceneoxazolidine 7 with active methylene
was 2.3 : 1, Table 1, entry 5). At the same time, heating the
reagents at reflux in dry toluene for 3 h almost completely
converted malonate 13a to tetraethyl ester 15a (Table 1, entry 7).
Also it was found that magnesium ethoxide acts as a catalyst and
decreasing the amount did not affect the yield. Thus, most
suitable conditions for this reaction were heating the reagents at
compounds.
As a model experiment we carried out the reaction of
oxazolidine 12 with diethyl malonate 13a using the previously
developed conditions for the reaction between malonate 13а
and oxazolidine 7: heating in a microwave reactor at 210 °C for
1
1
4
5
min
(Table
1,
entry
1).
However,
reflux in dry toluene for 1.5 h with 10 mol% of Mg(OEt)
2
(Table
di(ethoxycarbonyl)pyrrolidine 9 was not formed and the reaction
gave a complicated mixture with only traces of oxazolidine ring-
opening product 14a. Presumably, the reaction of diethyl
1
,
entry 8). As the result, tetraethyl propane-1,1,3,3-
tetracarboxylate 15a was isolated in 71% yield.
Table 1. Optimization of the reaction conditions.
EtO C
2
CO2Et
OH Me CO Et
2
CO Et
2
O
base

13a
N Me
+
N
Ph
CO Et
2
CO2Et
Ph
CO Et
2
EtO C
14a
2
15a
1
2
13a
Me
Me
other examined oxazolidines:
N
N
O
O
O
16
7a
Oxazolidine
mmol)
NMR ratio 13a : 15aa
(isolated yield 15a (%))
Entry
13a (mmol)
Solvent
Temperature
Time (h)
Base (mmol)
b
(
1
2 (2)
2 (2)
2 (2)
2 (2)
2 (2)
3
3
3
3
3
3
3
3
3
3
o-xylene
MW, 210 °C
90 °C
0.75
2
–
–c
1
2
3
4
5
6
7
8
9
1
1
1
1
DMF
NaH (4.2)
4 : 1
CH
THF
Et
3
CN
reflux
3
Mg(OEt)
Mg(OEt)
Mg(OEt)
Mg(OEt)
Mg(OEt)
2
2
2
2
2
(3.0)
(3.0)
(3.0)
(3.0)
(3.0)
(0.3)
(0.3)
(0.3)
1 : 4 (59)
1 : 3 (52)
2.3 : 1
reflux
3
2
O
reflux
2.5
3
1
2 (1.5)
PhMe
PhMe
PhMe
PhMe
PhMe
reflux
1 : 4
1
2 (2)
2 (2)
6 (2)
a (2)
reflux
3
1 : 19 (70)
1 : 19 (71)
1 : 1
1
reflux
reflux
1.5
1.5
1.5
Mg(OEt)
2
1
7
Mg(OEt)
2
reflux
Mg(OEt)
2
3 : 1c
1
0
a
In crude product. b Yield of product 15a was calculated based on malonate 13a. c Complex mixture of products with traces of 14a and 15a.

We also examined aryloxazolidines 7a and 16 in this reaction.
'-Methylspiro[fluorene-9,5'-oxazolidine] (16) reacted in the
same way as 5-phenyloxazolidine 12 and product 15a was
obtained as a mixture with diethyl malonate 13a in a 1 : 1 ratio
mol%) in a microwave reactor at 200 °C for 30 min resulted in a
mixture of the methylenation product 15c and the starting ketone
13c (NMR ratio 13c : 15c was 45 : 55). Increasing the reaction
time to 1.5 h gave 1,2,4,5-tetraphenylpentane-1,5-dione (15c) as
a mixture of diastereomers (NMR ratio 1 : 1) in 55% yield after
column chromatography. The reaction of ethyl benzoylacetate
13d proceeded under the optimised conditions for diethyl
malonate (Table 1, entry 8) and gave diethyl 2,4-
dibenzoylglutarate 15d as a mixture of diastereomers (NMR ratio
0.56 : 0.44) in 60% yield. It should be noted that 1,5-dicarbonyl
compounds are widely used building-blocks for the synthesis of
3
(
according to the NMR data, Table 1, entry 9). A special point of
interest was to identify the difference in the reactivity of
spiroanthraceneoxazolidine 7 in the presence of magnesium
ethoxide. Under the optimised conditions (Table 1, entry 8) the
reaction of N-methyloxazolidine 7a with diethyl malonate
resulted in the formation of methylenation product 15a in low
yield (Table 1, entry 10). It should be pointed that no traces of
pyrrolidine 9 were found in the crude mixture.
1
2
various heterocycles.
EWG
EWG
Table 2. Starting materials and products of the methylenation reaction.
O
EWG
X
X
N Me
O
+
EWG
N
Me
Ph
X
X
X
EWG
X
Ph
1
2
13
15
Mg(OEt)2
PhMe, 
EWG
13
5a
-EtOH Mg(OEt)2
1
MeO C
2
EWG
EtOMgO
Ph
CO Me
CO2Me
CO2Me
2
N
Me
X
CO Me
2
A
B
MeO C
2
13b
15b (39%)
EtOMgO
Ph
Me
H
O
EWG
X
N
Ph
Ph
Ph
Ph
O
C
EWG
Ph
3c
-Mg(OEt)2 EtOH
Ph
1
O
X
13
OH
EWG
X
5c (55%)b
H
1
+
N
Me
Ph
dr = 1 : 1
D
E
O
Scheme 3. Proposed reaction mechanism.
Ph
Ph
Ph
CO Et
2
O
A proposed mechanism for the formation of 1,5-dicarbonyl
compounds 15 is shown in Scheme 3. This pathway is based on
the ring-opening of oxazolidine ring 12 by magnesium ethoxide
and the formation of iminium cation A. The latter reacts with
deprotonated methylene active compound B to form Mannich
adduct C. Intermediate C then eliminates ethanolamine D under
heating and forms terminal alkene E which reacts with a second
molecule of active methylene compound 13. As a result Michael
adduct 15 is formed. Clearly, this domino-sequence is due to the
unusual properties of magnesium ethoxide, which is able to act as
a Brønsted base as well as a Lewis acid.
CO Et
CO Et
2
2
1
3d
O
1
5d (60%)
dr = 1.3 : 1
a
Reagents and conditions: 12 (2 mmol), 13 (3 mmol), Mg(OEt)
2
(0.3 mmol),
Reagents and
(0.3 mmol), dry PhMe,
b
dry PhMe, reflux, 1.5 h. Isolated yield are specified.
conditions: 12 (2 mmol), 13c (3 mmol), Mg(OEt)
00 °С, MW, 1.5 h.
2
2
We then investigated the reaction using N-substituted
oxindoles 17 (Scheme 4). Unexpectedly, no methylenation
products were observed (heating in PhMe, MW, 210 °C, 1.5 h, 10
mol% Mg(OEt) ) and 3-methyloxindoles 18a and 18b were
2
isolated in 23% and 26% yield, respectively. In fact, the formed
methylene oxindole was reduced during the reaction.
With optimized conditions in hand, we expanded the reaction
of 5-phenyloxazolidine 12 to other active methylene compounds.
As expected, dimethyl malonate (13b) gave the methylenation
product 15b in 39% yield. At the same time, the reaction of
desoxybenzoin 13с at reflux in toluene was not successful and
starting materials were recovered. Therefore, we performed the
reaction under alternative conditions. Thus, heating ketone 13с
and oxazolidine 12 with catalytic magnesium ethoxide (10

the general direction of the reaction of 5-aryloxazolidines with
active methylene compounds is the methylenation of 1,3-
dicarbonyl compounds and the methylation of oxindoles.
O
Me
N Me
Ph
O
O
N
Mg(OEt) PhMe
N
2
,
2
10 C, 1.5 h
Acknowledgments
R
R
17
18a
(23%)
R = Me
This work was financially supported by the Russian Science
Foundation (Grant 17-73-20070).
R = Ph 18b (26%)
Scheme 4. Reaction of oxindoles 17 with 3-methyl-5-phenyloxazolidine.
Appendix A. Supplementary data
Supplementary data for this article (analytical data and
experimental procedures for compounds 15a–d, 18a,b and 9a)
can be found online at https://doi.org/
Another point of interest was the reaction of tetraethyl
propanetetracarboxylate 15a with a source of an azomethine
1
1
ylide. According to the previous results, the formation of bis-
Mannich adduct 19 might be expected. However, heating
References and notes
methylene-linked
bis-malonate
15a
with
excess
spiroanthraceneoxazolidine 7a at 210 °C in a microwave reactor
1
1
1.
(a) G.P. Rizzi, J. Org. Chem. 35 (1970) 2069;
for 15 min resulted in the formation of pyrrolidine 9a in 55%
yield (Scheme 5). Apparently, compound 15 was unstable at high
temperature in the presence of a base and retro-Michael addition
gave diethyl methylene malonate G, which reacted with N-
methylazomethine ylide H to give [3+2]-cycloaddition product
(
(
(
b) H. Heaney, G. Papageorgiou, R.F. Wilkins, Tetrahedron 53
1997) 14381;
c) J.H. Ryan, N.Spiccia, L.S.-M. Wong, A.B. Holmes, Aust. J.
Chem. 60 (2007) 898;
(d) A.G. Meyer, J.H. Ryan, Molecules 21 (2016) 935.
(a) R.A. Fairhurst, H. Heaney, G. Papageorgiou, R.F. Wilkins, S. C.
Eyley, Tetrahedron Lett. 30 (1989) 1433;
2
.
9
a, and CH-acidic diethyl malonate F. The latter reacted with a
second molecule of azomethine ylide H to form Mannich adduct
I which eliminated dimethylamine to give methylene derivative
G.
(b) V.S. Moshkin, V.Y. Sosnovskikh, Tetrahedron Lett. 54 (2013)
2
699;
(
(
c) V.S. Moshkin, V.Y. Sosnovskikh, Mendeleev Commun. 25
2015) 440.
EtO C
2
Me N
3.
4.
(a) P. Lienard, J.-C. Quirion, H.-P. Husson, Tetrahedron 49 (1993)
3995;
2
CO Et
2
CO Et
2
7a
(b) V.S. Moshkin, V.Y. Sosnovskikh, Tetrahedron Lett. 54 (2013)
CO Et
2
2
455.
CO Et
2
CO Et
2
(a) M. Madesclaire, J. Couquelet, F. Leal, V.P. Zaitsev, S.K.
Sharipova, Chem. Heterocycl. Compd. 38 (2002) 71;
CO Et
EtO C
2
2
Me N
2
(b) V. Banphavichit, W. Bhanthumnavin, T. Vilaivan, Tetrahedron
1
5a
19
63 (2007) 8727;
(
(
(
c) J. Danielsson, L. Toom, P. Somfai, Eur. J. Org. Chem. 2011
2011) 607;
d) V.S. Moshkin, V.Y. Sosnovskikh, Tetrahedron Lett. 54 (2013)
7
a (1.8 equiv.)

C H O o-xylene, 210 °C
14
8
2
MW, 15 min
5
869;
(e) A.V. Pavlushin, V.S. Moshkin, V.Y. Sosnovskikh, Mendeleev
Commun. 27 (2017) 628.
(a) M. Nyerges, I. Fejes, A. Virányi, P.W. Groundwater, L. Töke,
Synthesis (2001) 1479;
CO Et
2
N Me
5.
6.
CO Et
CO Et
CO Et
2
2
2
H
(b) H. Santos, A. Distiller, A.M. D’Souza, Q. Arnoux, J.M. White,
+
A.G. Meyer, J.H. Ryan, Org. Chem. Front. 2 (2015) 705.
V.S. Moshkin, V.Y. Sosnovskikh, Tetrahedron Lett. 55 (2014)
6121.
T. Kitano, N. Shirai, Y. Sato, Chem. Pharm. Bull. 40 (1992) 768.
A.M. D’Souza, N. Spiccia, J. Basutto, P. Jokisz, L.S.-M. Wong,
A.G. Meyer, A.B. Holmes, J.M. White, J.H. Ryan, Org. Lett. 13
N
CO Et
CO Et
2
2
F
G
Me
a (55%)
7
8
.
.
9
-
HNMe2
(
2011) 486.
N Me
9
1
.
F. Felluga, G. Pitacco, C. Visintin, E. Valentin, Helv. Chim. Acta
80 (1997) 1457.
CO Et
2
H
0. E.M. Buev, V.S. Moshkin, V.Y. Sosnovskikh, Org. Lett. 18 (2016)
764.
11. E.M. Buev, V.S. Moshkin, V.Y. Sosnovskikh, J. Org. Chem. 82
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Tetrahedron 42 (1986) 2339;
1
Me N
Me
CO Et
2
(
1
I
4
(
Scheme 5. Reaction of bis-malonate 15a with N-
methylspiroanthraceneoxazolidine 7a.
(
(
(
c) H. Li, Z. He, X. Guo, W. Li, X. Zhao, Z. Li, Org. Lett. 11
2009) 4176;
d) S. Guo, L. Lu, J. Gong, Z. Zhu, F. Xu, Z. Wei, H. Cai, Org.
It can be concluded that depending on the structure of the
oxazolidine and the CH-acidic compound, they can react to form
Mannich bases, substituted pyrrolidines, methylene-linked 1,3-
dicarbonyl compounds or methylated derivatives. In particular,
1
1
Biomol. Chem. 13 (2015) 4426.
5
-Aryloxazolidines as a source of formaldehyde.
Structure of 5-aryloxazolidine determines its reactivity.
Synthesis of 1,5-dicarbonyl compounds from 1,3-dicarbonyl compounds.

Graphical Abstract
Reactions of 5-aryloxazolidines with CH-acidic
compounds
Leave this area blank for abstract info.
Anastasia A. Smorodina, Evgeny M. Buev, Vladimir S. Moshkin*, Vyacheslav Y. Sosnovskikh
O
O
O
N Me
O
Ph
X
R
R
R
Mg(OEt) (10 mol%)
2
X
X
PhMe, 120–200 °C, 1.5 h
39–71% yield
X = CO Et, CO Me, Ph; R = OEt, OMe, Ph
2
2