Reinvestigation of the reaction between aromatic aldehydes, 3-phenyl-5-isoxazolone and sarcosine: Stabilized azomethine ylides as a synthetic equivalent of the methylaminomethyl anion

Article abstract of DOI:10.1016/j.tetlet.2020.151770

The reaction of aromatic aldehydes, 3-phenyl-5-isoxazolone and sarcosine proceeds smoothly at reflux in methanol to give (Z)-4-arylidene-3-phenylisoxazol-5(4H)-ones, whereas the addition of isatin to the reaction mixture changes the result, providing oxim

Full text of DOI:10.1016/j.tetlet.2020.151770

Journal Pre-proofs
Reinvestigation of the reaction between aromatic aldehydes, 3-phenyl-5-iso‐
xazolone and sarcosine: stabilized azomethine ylides as a synthetic equivalent
of the methylaminomethyl anion
Vladimir S. Moshkin, Konstantin V. Martynov, Vyacheslav Y. Sosnovskikh
PII:
S0040-4039(20)30202-1
DOI:
Reference:
https://doi.org/10.1016/j.tetlet.2020.151770
TETL 151770
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
17 January 2020
18 February 2020
20 February 2020
Please cite this article as: Moshkin, V.S., Martynov, K.V., Sosnovskikh, V.Y., Reinvestigation of the reaction
between aromatic aldehydes, 3-phenyl-5-isoxazolone and sarcosine: stabilized azomethine ylides as a synthetic
equivalent of the methylaminomethyl anion, Tetrahedron Letters (2020), doi: https://doi.org/10.1016/j.tetlet.
2020.151770
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Graphical Abstract
Reinvestigation of the reaction between aromatic
aldehydes, 3-phenyl-5-isoxazolone and sarcosine:
Leave this area blank for abstract info.
stabilized azomethine ylides as
a
synthetic
equivalent of the methylaminomethyl anion
Vladimir S. Moshkin*, Konstantin V. Martynov, Vyacheslav Y. Sosnovskikh
O
Ph
O
O
Ar
N
N
OH
CO2H
NHMe
CHO
H
+
O
+
R
MeOH, , 5.5 h
O
N
N
Ph
Me
R = H, 4-Me, 4-F, 4-Cl, 4-Br, 4-CF3, 4-NO2, 3-NO2,
4-MeO, 3-MeO, 2-EtO, 3,4-(MeO)2, 3,4-(CH=CH–CH=CH)
13 examples
38–72% yield
* Corresponding author. Tel: +7 3433899597; e-mail: mvslc@mail.ru (V. S. Moshkin).

Tetrahedron Letters
journal homepage: www.elsevier.com
Reinvestigation of the reaction between aromatic aldehydes, 3-phenyl-5-
isoxazolone and sarcosine: stabilized azomethine ylides as a synthetic equivalent
of the methylaminomethyl anion
Vladimir S. Moshkin*, Konstantin V. Martynov, 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
The reaction of aromatic aldehydes, 3-phenyl-5-isoxazolone and sarcosine proceeds smoothly at
reflux in methanol to give (Z)-4-arylidene-3-phenylisoxazol-5(4H)-ones, whereas the addition of
isatin to the reaction mixture changes the result, providing oximes of 4-aryl-3-benzoyl-1-
methylpyrrolidin-2-ones in 38–72% yield.
Available online
2020 Elsevier Ltd. All rights reserved.
Keywords:
Stabilized azomethine ylides
3-Phenyl-5-isoxazolone
4-Aryl-2-pyrrolidones
Sarcosine
Azomethine ylides are one of the most widely used 1,3-dipoles in organic chemistry.1 Their major application is the [3+2]-
cycloaddition with electron-deficient dipolarophiles leading to functionalized pyrrolidines and oxazolidines.2 At the same time, the
chemistry of azomethine ylides is not limited to the classical [3+2]-cycloaddition. In recent years, there have been many examples of
the use of azomethine ylides to obtain unusual pyrrolidines,3 functionalized piperidines,4 open-chain alkylamines,5 and other
azaheterocycles.6 In particular, our group is developing the application of nonstabilized azomethine ylides as synthetic equivalents of an
alkylaminomethyl anion.7
In 2012, we discovered the direct methylaminomethylation of electron-deficient alkenes with sarcosine (1) in the presence of
cyclohexanone.8 In this reaction, coumarins 2 or diethyl benzylidenemalonate provided 4-aryl-2-pyrrolidones 3 via the intermediate
formation of nonstabilized azomethine ylide A (Scheme 1). Our attention was attracted by a paper published by Lakshmi and Perumal
in 2013, in which aromatic aldehydes 4, 3-phenylisoxazolone 5 and sarcosine (1) gave related arylpyrrolidones 6 under reflux in
methanol (Scheme 2).9 This reaction seemed to be an unprecedented example of the introduction of a methylaminomethyl anion to the
intermediate 4-arylideneisoxazolones 7 in a protic solvent. It was unclear if this reaction was related to our synthesis of pyrrolidones 3
proceeding via azomethine ylide formation. A hypothetical azomethine ylide could arise only from the starting aromatic aldehyde and
sarcosine. However, to the best of our knowledge, such nonstabilized ylides would be protonated by methanol rather than reacting with
7.3b,6f On the other hand, the authors proposed a non-ylide mechanism, which included the nucleophilic opening of isoxazole ring 7 by
sarcosine. The resulting amido acid B was decarboxylated, followed by Michael addition of the formed anion at the conjugated double
bond (Scheme 2).
O
EWG
O
EWG
O
CO2H
HO
+
DIPEA, PhMe
NHMe
O
N
, 36 h
2
1
via
Me
Me
EWG = PO(OEt)2,
CO2Et, COPh
3
N
A
ref. 8
Scheme 1. Domino reaction leading to 4-arylpyrrolidones 3.

Ph
Ph
Ar
N
CO2H
N
OH
ArCHO
+
+
O
MeOH, 
40 min
ref. 9
O
NHMe
1
N
4
O
5
Me
6
Ph
Ph
N
N
CO2H
OH
O
O
Ar
O
NHMe
NMe
Ar
O
1
7
O
H
B
Scheme 2. Domino reaction leading to 4-arylpyrrolidones 6.
Table 1. Optimisation of the reaction conditions.
Cl
O
Ph
CHO
Ph
O
Ph
N
N
OH
N
O
CO2H
H
8
N
O
+
+
MeOH, 
MeOH, 
O
NHMe
1
Cl
N
O
5.5 h
5.5 h
O
5
Cl
Me
4a
7a
6a
Isoxazolone 5
(equiv.)
Sarcosine (1)
(equiv.)
Isatin 8
(equiv.)
Entry
Solvent
Time
Yield 7a (%)
Yield 6a (%)
1
2
3
4
5
6
7
8
9
1.00
1.35
1.00
1.15
1.15
1.15
1.35
1.15
1.35
1.00
1.70
1.00
1.50
1.50
1.50
1.70
1.50
2.10
0
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
EtOH
40 min
5.5 h
40 min
5.5 h
5.5 h
5.5 h
5.5 h
3.5 h
3.5 h
61
64
trace
0
0
0
0
0.25
0.25
0.50
0.10
0.25
0.50
0.50
47a
72
68
42
54
55
65
0
0
0
0
EtOH
0
a The product was contaminated by the intermediate arylideneisoxazolidinone 7a.
We were unable to find examples of such facile decarboxylation of amido acids in the literature. On the contrary, their
photodecarboxylation is more expected.10 From any point of view, the reaction described by Lakshmi and Perumal represented a unique
and unobvious transformation. However, when we tried to repeat the reaction using a mixture of p-chlorobenzaldehyde 4a, 3-
phenylisoxazolone 5 and sarcosine (1) the reaction did not lead to pyrrolidone 6a, but to the arylidene derivative 7a in 61% yield (Entry
1, Table 1). The use of excess isoxazolone (1.35 equiv.), sarcosine (1.70 equiv.) and an increased time (5.5 h) did not change the result
(Entry 2).
At the same time, it is well-known that stabilized azomethine ylides can react in methanol. Among them, an ylide derived from
sarcosine and isatin (8) is one of the most widely utilized. Bearing in mind that Lakshmi and Perumal were extensively applying isatin
in their other work at the time,11 we hypothesized that trace amounts of isatin may have been present in the reaction mixture. To our
delight, the addition of 0.25 equivalents of isatin changed the result, and, indeed, the major product was pyrrolidone 6a contaminated by
arylideneisoxazolidinone 7a (Entry 3). Prolonging the time (5.5 h) and utilising excess isoxazole 5 (1.15 equiv.) and the amino acid
(1.50 equiv.) increased the yield to 72% and gave pure 4-arylpyrrolidone 6a (Entry 4). Neither an increase (Entry 5) nor a decrease
(Entry 6) in the amount of isatin improved the yield. The application of a larger quantity of isoxazole 5 and sarcosine also did not lead
to a better result (Entries 7 and 8). We also found that the reaction proceeded in 95% ethanol to give pyrrolidone 6a in 55–65% yield
(Entries 8 and 9).
We successfully carried out this reaction on a wide range of aromatic aldehydes containing both electron-donating and electron-
withdrawing substituents. The position of a substituent in the starting aldehyde did not affect the reaction. On the other hand, in the case
of highly electron-rich 2,4-dimethoxybenzaldehyde the intermediate, and less reactive, arylidene derivative 7 was isolated. (Table 2).
Products containing Me, Cl, Br, or NO2 groups at the para position of the benzene ring crystallized directly from the reaction mixture.
At the same time, compounds containing an unsubstituted phenyl ring, p-F, m-NO2 or alkoxy groups did not crystallize from methanol
and were isolated by the extraction of an aqueous-methanolic mixture with dichloromethane followed by crystallization from CH2Cl2–
C6H14.
Table 2. Products obtained and their yields.

Ph
O
Ar
N
CO2H
8 (0.25 equiv.)
OH
O
ArCHO +
+
MeOH, ,
5.5 h
O
N
5
NHMe
1
N
4
Ph
Me
6
Aryl groups and yields of pyrrolidones 6:
Me
F
Br
6b
6c
6d
6e
(69%)
(47%)
(39%)
(50%)
NO2
F3C
O2N
MeO
6f
6g
6h
6i
(55%)
(40%)
OMe
(38%)
(62%)
OMe
OEt
MeO
6j
6k
6l
6m
(42%)
(64%)
(56%)
(54%)
1
The H NMR data of product 6m matched that previously reported.9 Its relative stereoconfiguration was determined using X-ray
analysis.9
Considering a possible mechanism for the formation of pyrrolidones 6, we undertook an experiment in which the starting
isoxazolone 5 and benzaldehyde 4a were replaced by 4-(4-chlorobenzylidene)isoxazolone 7a. As a result, the reaction proceeded
smoothly to give the final pyrrolidone 6a in 62% yield. In view of this, it can be assumed that 4-arylideneisoxazolone 7 is formed at the
first
stage
of
the
domino-sequence
as
a
result
of
the
Knoevenagel
condensation
of
the
O
H
N
O
ArCHO
O
4
N
Me
N
H
8
+
-H2O
-CO2
C
Ph
+
Ph
N
O
-H2O
N
CO2H
Ar
O
O
7
NHMe
5
Transition state
O
1
Michael addition
[3+2]-Cycloaddition
Ph
O
Me
N
O
HN
O
H
N
N
N
Ph
N
O
Ar
Me
O
Ar
O
D
H2O
F
8
-
Ph
Ar
Ar
N
Ph
OH
Me HN
O
N
N
O
O
Me
6
E
Scheme 3. Plausible reaction mechanism.

aromatic aldehyde and isoxazolone under sarcosine catalysis (Scheme 3). Simultaneously, sarcosine (1) and isatin (8) generate
stabilized azomethine-ylide C, which participates in Michael addition with its more accessible terminal carbon at the conjugated bond
of the arylidene derivative 7 to provide zwitterion D. The latter undergoes hydrolysis to form secondary amine E followed by a
recyclization yielding the final pyrrolidone 6. The possibility of the classical [3+2]-cycloaddition of ylide C with the electron-deficient
alkene 7 cannot be ruled out. In this case, the subsequent cleavage of a strained C–C bond between the electron-withdrawing groups in
adduct F and the formation of the same intermediate D can take place. Rare examples of pyrrolidine ring-opening in cycloadducts are
known in the literature.12 It should be noted that our attempt to obtain adduct F at room temperature was unsuccessful. Only pyrrolidone
6a was isolated in 45% yield after stirring equimolar amounts of isatin, sarcosine, 4-chlorobenzaldehyde and isoxazolone in methanol
for 5 days. It was also impossible to obtain adduct F from arylideneisoxazolone 7a, sarcosine (1) and isatin (8) at reflux in a mixture
PhMe–DMF with a Dean-Stark trap to remove the water formed which, presumably, hydrolyzes intermediate D. This reaction led to a
difficult to purify mixture of at least of seven compounds and traces of pyrrolidone 6a.
We were also interested in whether compounds other than isatin would be able to initiate the methylaminomethylation of
arylideneisoxazolones 7 by sarcosine. We screened a number of carbonyl compounds and found that N-methylisatin and
acenaphthoquinone also promoted this reaction (Scheme 4). At the same time, ninhydrin, benzil, ethyl phenylglyoxylate and phenyl
trifluoromethyl ketone proved fruitless.
O
O
O
O
O
O
N
N
H
Me
63%
6a
72%
41%
yield of
:
Scheme 4. Promoters of the reaction.
Finally, we examined the reaction with alkenes, whose [3+2]-cycloaddition with ylide C was previously not documented in the
literature. We examined widely available diethyl benzylidenemalonate, 3-ethoxycarbonylcoumarin, and a mixture of Meldrum’s acid
with 4-chlorobenzaldehyde (4a), but these reactions did not give the corresponding pyrrolidones. Although Lakshmi and Perumal9 have
reported that proline reacts in a similar manner to sarcosine, we could not reproduce these reactions. As a result, complex mixtures of
compounds were formed from which we were unable to isolate or detect the corresponding pyrrolizidinones.
Notably, the obtained pyrrolidones 6a–m contain phenethylamine and 4-aryl-2-pyrrolidone moieties, which are known to possess
valuable biological activities.13 Related pharmaceuticals, showing anxiolytic and nootropic effects, are Phenylpiracetam (Phenotropil)13b
and the open-chain amino acid Phenibut.13a
In summary, we found that sarcosine can indeed be used to introduce a methylaminomethyl moiety into the 4-arylideneisoxazolone
structure to form the 4-aryl-2-pyrrolidone framework. This domino-sequence proceeds only in the presence of dicarbonyl compounds
such as isatin, N-methylisatin or acenaphthoquinone. The most likely intermediates of this reaction are stabilized azomethine ylides,
which makes it an unprecedented case of using these ylides as synthetic equivalents of the methylaminomethyl anion in a protic
medium. Further investigation of these reactions is currently underway in our laboratory and will be reported in due course.
Acknowledgments
This work was financially supported by the Russian Science Foundation (Grant 17-73-20070). We also thank Evgeny Buev and
Sergey Usachev for their comments on the article.
References and notes
1. (a) O. Tsuge, S. Kanemasa, Adv. Heterocycl. Chem. 45 (1989) 231;
(b) L.M. Harwood, R.J. Vickers, in: Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry Toward Heterocycles and Natural Products,
Chemistry of Heterocyclic Compounds, Vol. 59 (Eds.: A. Padwa and W.H. Pearson), Wiley: Chichester, 2002, p. 169;
(c) H.A. Döndas, M. de Gracia Retamosa, J.M. Sansano, Synthesis 49 (2017) 2819.
2. (a) R. Grigg, S. Thianpatanagul, J. Chem. Soc., Chem. Commun. (1984) 180;
(b) C. Nájera, J.M. Sansano, Curr. Org. Chem. 7 (2003) 1105;
(c) I. Coldham, R. Hufton, Chem. Rev. 105 (2005) 2765;
(d) G. Pandey, P. Banerjee, S.R. Gadre, Chem. Rev. 106 (2006) 4484;
(e) A.G. Meyer, J.H. Ryan, Molecules 21 (2016) 935.
3. (a) D. Yang, D. Zhao, L. Mao, L. Wang, R. Wang, J. Org. Chem. 76 (2011) 6426;
(b) D. Das, M.T. Richers, L. Ma, D. Seidel, Org. Lett. 13 (2011) 6584.
4. (a) S. Samala, G. Singh, R. Kumar, R.S. Ampapathi, B. Kundu, Angew. Chem. Int. Ed. 54 (2015) 9564;
(b) S. Verma, P.K. Mishra, M. Kumar, S. Sur, A.K. Verma, J. Org. Chem. 83 (2018) 6650;
(c) A. Paul, N.R. Thimmegowda, T.G. Cruz, D. Seidel, Org. Lett. 20 (2018) 602.
5. (a) M. Rudas, I. Fejes, M. Nyerges, Á. Szöllõsy, L. Tõke, P.W. Groundwater, J. Chem. Soc., Perkin Trans. 1 (1999) 1167;
(b) J.H. Ryan, N. Spiccia, L.S.-M. Wong, A.B. Holmes, Aust. J. Chem. 60 (2007) 898;
(c) E.M. Buev, V.S. Moshkin, V.Y. Sosnovskikh, J. Org. Chem. 82 (2017) 12827.
6. (a) T.M.V.D. Pinho e Melo, Eur. J. Org. Chem. (2006) 2873;
(b) M. Nyerges, J. Tóth, P.W. Groundwater, Synlett (2008) 1269;
(c) C. Zhang, C.K. De, R. Mal, D. Seidel, J. Am. Chem. Soc. 130 (2008) 416;
(d) L. Zheng, F. Yang, Q. Dang, X. Bai, Org. Lett. 10 (2008) 889;
(e) 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 (2011) 486;
(f) D. Seidel, Acc. Chem. Res. 48 (2015) 317.
7. (a) V.S. Moshkin, V.Y. Sosnovskikh, Tetrahedron Lett. 54 (2013) 5869;
(b) V.S. Moshkin, E.M. Buev, V.Y. Sosnovskikh, Tetrahedron Lett. 56 (2015) 5278;
(c) E.M. Buev, V.S. Moshkin, V.Y. Sosnovskikh, Tetrahedron Lett. 56 (2015) 6590.
8. V.S. Moshkin, V.Y. Sosnovskikh, G.-V. Röschenthaler, Tetrahedron Lett. 53 (2012) 3568.
9. N.V. Lakshmi, P.T. Perumal, Tetrahedron Lett. 54 (2013) 1817.

10. (a) H. Nakai, Y. Sato, T. Mizoguchi, Y. Kanaoka, Synthesis (1982) 141;
(b) T. Yamada, Y. Ozaki, M. Yamawaki, Y. Sugiura, K. Nishino, T. Morita, Y. Yoshimi, Tetrahedron Lett. 58 (2017) 835.
11. (a) N.V. Lakshmi, P. Thirumurugan, C. Jayakumar, P.T. Perumal, Synlett (2010) 955;
(b) N.V. Lakshmi, Y. Arun, P.T. Perumal, Tetrahedron Lett. 52 (2011) 3437;
(c) N.V. Lakshmi, R. Tamilisai, P.T. Perumal, Tetrahedron Lett. 52 (2011) 5301;
(d) S.E. Kiruthika, N.V. Lakshmi, B.R. Banu, P.T. Perumal, Tetrahedron Lett. 52 (2011) 6508;
(e) N.V. Lakshmi, G.A.S. Josephine, P.T. Perumal, Tetrahedron Lett. 53 (2012) 1282.
12. (a) Y. Zhao, L. Liu, W. Sun, J. Lu, D. McEachern, X. Li, S. Yu, D. Bernard, P. Ochsenbein, V. Ferey, J.-C. Carry, J. R. Deschamps, D. Sun, S. Wang,
J. Am. Chem. Soc. 135 (2013) 7223;
(b) S.A. Usachev, N.V. Popova, V.S. Moshkin, V.Y. Sosnovskikh, Chem. Heterocycl. Compd. 51 (2015) 913;
(c) E.M. Buev, A.A. Smorodina, V.S. Moshkin, V.Y. Sosnovskikh, Tetrahedron Lett. 60 (2019) 649;
(d) I.B. Kutyashev, M.V. Ulitko, A.Y. Barkov, N.S. Zimnitskiy, V.Y. Korotaev, V.Y. Sosnovskikh, New J. Chem. 43 (2019) 18495.
13. (a) I. Lapin, CNS Drug Rev. 7 (2001) 471;
(b) A.G. Malykh, M.R. Sadaie, Drugs 70 (2010) 287.
Supplementary data
Supplementary data associated with this article can be found in the online version.
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:
Graphical Abstract
Reinvestigation of the reaction between aromatic
aldehydes, 3-phenyl-5-isoxazolone and sarcosine:
Leave this area blank for abstract info.
stabilized azomethine ylides as
a
synthetic
equivalent of the methylaminomethyl anion
Vladimir S. Moshkin*, Konstantin V. Martynov, Vyacheslav Y. Sosnovskikh
O
Ph
O
O
Ar
N
N
OH
CO2H
NHMe
CHO
H
+
O
+
R
MeOH, , 5.5 h
O
N
N
Ph
Me
R = H, 4-Me, 4-F, 4-Cl, 4-Br, 4-CF3, 4-NO2, 3-NO2,
4-MeO, 3-MeO, 2-EtO, 3,4-(MeO)2, 3,4-(CH=CH–CH=CH)
13 examples
38–72% yield

Nucleophilic properties of stabilized azomethine ylides
A direct methylaminomethylation promoted by isatin
A rapid access to 4-aryl-2-pyrrolidone framework