A hitherto undescribed addition of the lithium salt of dimethyl methylphosphonate to N-substituted phthalimides

Article abstract of DOI:10.1016/j.tetlet.2016.03.045

The hitherto unknown addition of the lithium salt of dimethyl methylphosphonate 6 to the N-substituted phthalimides 7 is described. This reaction allows the synthesis of new systems in which the phosphono group is connected to the heterocyclic skeleton of an isoindolinone at the 3-position by one methylene group.

Full text of DOI:10.1016/j.tetlet.2016.03.045

Accepted Manuscript
A hitherto undescribed addition of the lithium salt of dimethyl methylphosph-
onate to N-substituted phthalimides
Piotr M. Zagórski, Andrzej Jó źwiak, Mieczysław W. Płotka, Dariusz Cal
PII:
S0040-4039(16)30267-2
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.03.045
TETL 47433
Reference:
Tetrahedron Letters
To appear in:
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Revised Date:
Accepted Date:
8 February 2016
9 March 2016
14 March 2016
Please cite this article as: Zagórski, P.M., Jó źwiak, A., Płotka, M.W., Cal, D., A hitherto undescribed addition of
the lithium salt of dimethyl methylphosphonate to N-substituted phthalimides, Tetrahedron Letters (2016), doi:
http://dx.doi.org/10.1016/j.tetlet.2016.03.045
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A hitherto undescribed addition of the lithium salt of
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dimethyl methylphosphonate to N-substituted phthalimides.
Piotr M. Zagórski,a* Andrzej Jóźwiak,a Mieczysław W. Płotka,a Dariusz Calb

1
Tetrahedron Letters
journal homepage: www.elsevier.com
A hitherto undescribed addition of the lithium salt of dimethyl methylphosphonate to
N-substituted phthalimides.
Piotr M. Zagórski,a* Andrzej Jóźwiak,a Mieczysław W. Płotka,a Dariusz Calb
a University of Łódź, Department of Organic Chemistry, Tamka 12, 91-403 Łódź, Poland
b University of Łódź, Department of Organic and Applied Chemistry, Tamka 12, 91-403 Łódź, Poland
Corresponding author. Tel. +48 42 635-63-12; fax: +48 42 678 65 83
E-mail address: zagorek@op.pl (P. M. Zagórski)
ABSTRACT
ARTICLE INFO
Article history:
Received
Received in revised form
Accepted
The hitherto unknown addition of the lithium salt of dimethyl methylphosphonate 6 to the N-substituted phthalimides
7 is described. This reaction allows the synthesis of new systems in which the phosphono group is connected to the
heterocyclic skeleton of an isoindolinone at the 3-position by one methylene group.
2009 Elsevier Ltd. All rights reserved.
Available online
Keywords:
Nucleophilic addition
Lithiation
Phosphorylation
Heterocycles
1. Introduction
the preparation of new systems in which the heterocyclic ring is
connected to the phosphonic moiety by one methylene group
Molecules containing the isoindolinone ring system have a
variety of biological activities and are part of the structure of
many natural products. For example, alkaloids such as
Lennoxamine (1)1, Nuevamine2 and Magallanesine3 have been
isolated from Berberidaceae plants, which have been used in the
past as anti-inflammatory and antirheumatic agents. It has also
been shown that the presence of a phosphonyl group can
influence the biological function of aza-heterocyclic systems. For
example, proline derivatives 2 and 3 play an important role in
biochemical processes: compound 2 has antifungal, antibacterial
and herbicidal activity, while compound 3 is used as an antibiotic
against the bacteria Pseudomonas aeruginosa and Proteus
vulgaris.4-5
(structure C). Such systems have the potential to show biological
activity that can be of use in medicine.
Figure 2
2. Results and discussion
Alkylation of the lithium derivative 5 (resulting from lithiation
at the 3-position of isoindolinone 4), using diethyl
bromomethylphosphonate is potentially an easy way to access
compounds in which the phosphono moiety is separated from the
isoindolinone skeleton by one methylene group (structure C).
Unfortunately, using this procedure, we did not isolate the
desired products; only the starting material 4 and products that
did not contain the isoindolinone skeleton, which were not
further investigated, were formed (Scheme 1). The reaction was
probably unsuccessful since the bromomethylphoshonate protons
are much more acidic than the phthalimide protons, resulting in
the phthalimide anion deprotonating the phosphonate and starting
material isolation.
Figure 1
Phosphono derivatives of isoindolinones A, B and C can be
considered as belonging to two pre-specified classes of
compounds. Substances having such a structure in which the
phosphono group is linked directly to the heterocyclic ring
(structure A) or via two or three methylene groups (structure B)
have already been reported in the literature.6-17 The aim of our
study was to develop a method of synthesis which would enable

2
Scheme 1
This result forced us to look for other methods to synthesise
structure C. Our retrosynthetic approach leads to the lithiated
synthon of the phosphonomethylene fragment instead of the
lithiated heterocyclic ring. We decided to investigate a method,
which to the best of our knowledge has not yet been described in
the literature, based on the addition of the lithium salt of dimethyl
methylphosphonate 6, obtained from the reaction of dimethyl
Scheme 3
the synthesis of a broad class of isoindolinone derivatives of
potential pharmacological importance.
Acknowledgment
methylphosphonate
with
n-BuLi,18
to
N-substituted
phthalimides.19 N-Methylphthalimide 7a was obtained by the
reaction of the potassium phthalimide 8 with methyl iodide.20 N-
Benzyl, and N-tert-butyl phthalimides 7b-c were obtained by the
reaction of phthalic anhydride 9 with the corresponding primary
amines (Scheme 2).21
The authors thank the University of Lodz for financial
support.
4. References and notes
1.
a) Valencia, E.; Fajardo, V.; Freyer, A. J.; Shamma, M.
Tetrahedron Lett. 1985, 26, 993 b) Comins, D. L.; Schilling, S.;
Zhang, Y. Org. Lett. 2005, 7, 95.
2.
3.
4.
5.
Luzzio, F. A.; Zacherl, D. P. Tetrahedron Lett. 1998, 39, 2285.
Yao, T.; Larock, R. C. J. Org. Chem. 2005, 70, 1432.
Moonen, K.; Laureyn, I.; Stevens, C. Chem. Rev. 2004, 104, 6177.
Kukhar, V. P.; Hudson, H.R. Aminophosphonic and
aminophosphinic acids: chemistry and biological activity, Eds
John Wiley & Sons Chichester, UK, 2000.
6.
7.
8.
9.
Ordonez, M.; Tibhe, G. D.; Zamudio-Medina, A.; Viveros-
Ceballos, J. L. Synthesis 2012, 44, 569.
Reyes-Gonzalez, M. A.; Zamudio-Medina, A, Ordonez, M.
Tetrahedron Lett. 2012, 53, 5756.
Viveros-Ceballos, J. L.; Cativiela, C.; Ordonez, M. Tetrahedron:
Asymmetry 2011, 22, 1479.
Claeys, D. D.; Stevens, C. V.; Roman, B. I.; Van De Caveye, P.;
Waroquier, M.; Van Speybroeck, V. Org. Biomol. Chem. 2010, 8,
3644.
Product
7a
R
Yield (%)
Me
Bn
71
82
55
7b
7c
t-Bu
10. Kachkovskyi, G. O.; Kolodiazhnyi, O. I. Phosphorus Sulfur
Silicon Relat. Elem. 2010, 185, 2441.
Scheme 2. Synthesis of N-substituted phthalimides 7a-c
11. Kachkovskyi, G. O.; Kolodiazhnyi, O. I. Phosphorus Sulfur
Silicon Relat. Elem. 2009, 184, 890.
12. Couture, A.; Deniau, E.; Woisel, P.; Grandclaudon P. Synthesis
1997, 1439.
13. Failla, S.; Finocchiaro, P. Phosphorus Sulfur Silicon Relat. Elem.
1995, 105, 195.
14. Laga, E.; Garcia-Montero, A.; Sayago, F. J.; Soler, T.; Moncho,
S.; Cativiela, C.; Martinez, M.; Urriolabeitia, E. P. Chem. Eur. J.
2013, 19, 17398.
15. Reyes-Gonzalez, M. A.; Zamudio-Medina, A.; Ramirez-
Marroquin, O. A. Monatsh. Chem. 2014, 145, 1001.
16. Muddala, N. P.; Nammalwar, B.; Bunce, R. RCS Adv. 2015, 5,
28389.
Utilization of these phthalimides in the reaction with the
lithium salt of dimethyl methylphosphonate 6 turned out to be a
successful solution. When N-methylphthalimide 7a or N-
benzylphthalimide 7b were used, after hydrolysis of the reaction
mixture, the final unsaturated phosphonates 10a or 10b were
isolated as E/Z diastereomeric mixtures. The E configuration of
the major diastereomer was confirmed by the nuclear Overhauser
effect spectroscopy (NOESY) correlation between the vinylic and
the N-methyl or N-methylene protons. However, attempts to
separate the mixtures of isomers proved unsuccessful. We also
17. Jóźwiak, A.; Zagórski, P. M.; Płotka, M. W.; Cal, D. Tetrahedron
Lett. 2014, 55, 2420.
observed
that
the
addition
of
lithium
dimethyl
18. Edmonds M. K.; Abell A. D. J. Org. Chem. 2001, 66, 3747.
19. A similar reaction using the sodium salt of tetraethyl methylene-
1,1-bisphosphonate and 3-bromopropylphthalimide proceeding
with elimination of the phosphate anion according to the Horner-
Wadsworth-Emmons mechanism was described: Gourves, J. P.;
Couthon, H.; Sturtz, G. Eur. J. Chem. 1999, 3489.
20. Pietka-Ottlik M.; Potaczek P.; Piasecki E.; Mlochowski J.
Molecules 2010, 15, 8214.
21. De Oliveira, K. N.; Costa, P.; Santin, J. R.; Mazzambani, L.;
Buerger, C.; Mora, C.; Nunes, R. J.; De Souza, M. M. Bioorg.
Med. Chem. 2011, 19, 4295.
22. Al-Mousawi, S. M.; El-Apasery, M. A.; Elnagdi, M. H. Molecules
2010, 15, 58.
methylphosphonate 6 to phthalimide 7c followed by hydrolysis
of the reaction mixture resulted in the formation of compound 11.
Thus, it is probable that the steric hindrance caused by the bulky
tert-butyl group forces the formation of the open product 11. As
an example, we have demonstrated the suitability of compound
10a in the synthesis of the phosphonic derivative isoindolinone
of type C in which the phosphono group is separated from the
isoindolinone skeleton by one methylene group. Thus, reduction
of compound 10a with hydrogen in the presence of a palladium
catalyst led to the target compound 12 (Scheme 3).
23. Neves-Filho, R. A. W.; Palm-Forster, M. A. T.; De Oliveira, R. N.
Synthetic Commun. 2013, 43, 1571.
3. Conclusions
24. Bouzobaa, M.; Leclerc, G. Tetrahedron Lett. 1984, 25, 3067.
In summary, we have demonstrated a strategy for the
synthesis of new phosphono-functionalized isoindolinone
systems in which the phosphono group is connected to the
heterocyclic skeleton of an isoindolinone at the 3-position by one
methylene group. The method requires the novel addition of a
lithium salt of dimethyl methylphosphonate to the N-substituted
phthalimides. We plan to further investigate the scope of this
method, along with its diastereoselectivity and applicability to

Captions
Figure 1. Structure of Lennoxamine (1) and bioactive phosphonoprolines 2 and 3.
Figure 2. Structure of phosphono derivatives of isoindolinones A, B (reported in literature) and C
(new).
Scheme 1. Failed attempt to synthesise phosphono-functionalized structure C.
Scheme 2. Synthesis of N-substituted phthalimides 7a-c.
Scheme 3. Addition of lithium salt of 6 to N-substituted phthalimides 7 and reduction of unsaturated
phosphonate 10a to phosphonomethylisoindolinone 12.

3
1) Addition of the lithium salt of dimethyl
methylphosphonate to a phthalimide system
2) Synthesis of the 3-phosphonomethyl
substituted isoindolinone system
3) Catalytic reduction of the 3-oxoisoindolin-
1-ylidene system