Microwave-assisted synthesis of N,N-bis(phosphinoylmethyl)amines and N,N,N-tris(phosphinoylmethyl)amines bearing different substituents on the phosphorus atoms

Article abstract of DOI:10.3762/bjoc.15.40

A family of N,N-bis(phosphinoylmethyl)amines bearing different substituents on the phosphorus atoms was synthesized by the microwave-assisted and catalyst-free Kabachnik–Fields reaction of (aminomethyl)phosphine oxides with paraformaldehyde and diphenylphosphine oxide. The three-component condensation of N,N-bis(phosphinoylmethyl)amine, paraformaldehyde and a secondary phosphine oxide affording N,N,N-tris(phosphinoylmethyl)amine derivatives was also elaborated. This method is a novel approach for the synthesis of the target products.

Full text of DOI:10.3762/bjoc.15.40

Microwave-assisted synthesis of N,N-bis(phosphinoyl-
methyl)amines and N,N,N-tris(phosphinoylmethyl)amines
bearing different substituents on the phosphorus atoms
Erika Bálint*, Anna Tripolszky, László Hegedűs and György Keglevich
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2019, 15, 469–473.
Department of Organic Chemistry and Technology, Budapest
University of Technology and Economics, 1521 Budapest, Hungary
doi:10.3762/bjoc.15.40
Received: 03 December 2018
Accepted: 30 January 2019
Published: 15 February 2019
Email:
Erika Bálint* - ebalint@mail.bme.hu
* Corresponding author
This article is part of the thematic issue "Multicomponent reactions III".
Guest Editor: T. J. J. Müller
Keywords:
(aminomethyl)phosphine oxides; Kabachnik–Fields reaction; ligand;
microwave; N,N-bis(phosphinoylmethyl)amines;
N,N,N-tris(phosphinoylmethyl)amines
© 2019 Bálint et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
A family of N,N-bis(phosphinoylmethyl)amines bearing different substituents on the phosphorus atoms was synthesized by the
microwave-assisted and catalyst-free Kabachnik–Fields reaction of (aminomethyl)phosphine oxides with paraformaldehyde and
diphenylphosphine oxide. The three-component condensation of N,N-bis(phosphinoylmethyl)amine, paraformaldehyde and a
secondary phosphine oxide affording N,N,N-tris(phosphinoylmethyl)amine derivatives was also elaborated. This method is a novel
approach for the synthesis of the target products.
Introduction
α-Aminophosphine oxides are of considerable importance as α-aminophosphine oxides. (Phenylaminomethyl)dibenzylphos-
potential precursors of α-aminophosphine ligands [1]. phine oxide was prepared by the three-component reaction of
α-Aminophosphines play an important role in the synthesis of aniline, paraformaldehyde and dibenzylphosphine oxide [7], as
P(III)-transition metal complexes [2], which are often applied well as by the reaction of (hydroxymethyl)dibenzylphosphine
catalysts in homogeneous catalytic reactions [2-4]. In addition, oxide and aniline [8]. The condensation of butylamine, para-
a few Pt, Ru and Au complexes incorporating phosphine ligands formaldehyde and di(p-tolyl)phosphine oxide to afford (butyl-
show significant anticancer activity [5,6].
aminomethyl)di(p-tolyl)phosphine oxide was also described [9].
A microwave (MW)-assisted, catalyst-free method was elabo-
One of the most common synthetic routes to α-aminophosphine rated by us for the synthesis of several (aminomethyl)phos-
oxides is the Kabachnik–Fields (phospha-Mannich) reaction, phine oxides [10,11].
where an amine, an oxo compound (aldehyde or ketone) and a
secondary phosphine oxide react in a condensation reaction [1]. As regards α-aminophosphine oxides with different P-substitu-
However, only a few papers deal with the synthesis of ents, only two different types were reported. Olszewski and
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Beilstein J. Org. Chem. 2019, 15, 469–473.
co-workers synthesized chiral thiazole-substituted aminophos- N,N-bis(phosphinoylmethyl)amine and N,N,N-tris(phosphinoyl-
phine oxides 2 through the Pudovik reaction of alkylphenyl- methyl)amine derivatives bearing different substituents on the
phosphine oxides and the corresponding aldimine derivatives of phosphorus atoms.
thiazole 1 (Scheme 1) [12].
Results and Discussion
Synthesis of N,N-bis(phosphinoyl-
Cherkasov and his group applied the Kabachnik–Fields reac-
tion to synthesize a P-chiral aminophosphine oxide with a
methyl)alkylamines containing different
2-pyridyl substituent 3 (Scheme 2) [13].
substituents on the phosphorus atoms
Bis(aminophosphine oxide) derivatives were also prepared by First, the (aminomethyl)phosphine oxide starting materials 5–7
the double Kabachnik–Fields reaction using primary amines were synthesized following our previous protocol [11]. Thus,
[11,14,15], amino acids [16,17] or aminoethanol [14] as the the MW-assisted Kabachnik–Fields reaction of primary amines
amine component.
(butyl-, cyclohexyl- or benzylamine), paraformaldehyde and
di(p-tolyl)- or dibenzylphosphine oxide was carried out in
To the best of our knowledge, only one example can be found acetonitrile at 100 °C for 1 h affording the products with excel-
for a bis(α-aminophosphine oxide) containing different P-func- lent yields (Scheme 4).
tions that was prepared by the condensation of (octylamino-
methyl)dihexylphosphine oxide, paraformaldehyde and di(p- Then, (aminomethyl)diphenylphosphine oxide (9) was pre-
tolyl)phosphine oxide in the presence of p-toluenesulfonic acid pared through debenzylation of (benzylaminomethyl)di-
in boiling acetonitrile (Scheme 3) [12].
phenylphosphine oxide (8, Scheme 5). The reduction was
carried out in the presence of a 10% palladium on carbon cata-
Furthermore, tris(α-aminophosphine oxide) derivatives have not lyst (Selcat Q), in methanol, at 75 °C for 3 h, and the (amino-
been described in the literature up to now. In this paper, we methyl)diphenylphosphine oxide (9) was obtained in a yield of
report the efficient, catalyst-free and MW-assisted synthesis of 47% after column chromatography.
Scheme 1: Synthesis of chiral thiazole-substituted aminophosphine oxides.
Scheme 2: Synthesis of a P-chiral aminophosphine oxide containing a 2-pyridyl moiety.
Scheme 3: Condensation of (octylaminomethyl)dihexylphosphine oxide with paraformaldehyde and di(p-tolyl)phosphine oxide.
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Beilstein J. Org. Chem. 2019, 15, 469–473.
Scheme 4: Synthesis of (aminomethyl)phosphine oxides 5–7.
come the heterogeneity of the reaction mixture. After an irradia-
tion of 1 h at 100 °C, the mixed N,N-bis(phosphinoyl-
methyl)amines 10a,b, 11a,b and 12a,b were obtained in yields
of 92–97% and their structures were confirmed by 31P, 13C and
1H NMR, as well as HRMS measurements. Due to the two dif-
ferently substituted phosphorous nuclei in the molecules, two
signals were observed in the 31P NMR spectra.
Scheme 5: Synthesis of (aminomethyl)diphenylphosphine oxide (9).
The valuable intermediate 9 was then utilized in the synthesis of
N,N-bis(phosphinoylmethyl)amines 13a–c (Scheme 7). The
In the next step, (aminomethyl)phosphine oxides 5–7 were con- condensation of (aminomethyl)diphenylphosphine oxide (9),
verted to bis(phosphinoylmethyl)amine derivatives bearing dif- paraformaldehyde and various secondary phosphine oxides,
ferent substituents at the phosphorous atoms (Y2P=O) by such as diphenyl, di(p-tolyl) or dibenzylphosphine oxide, at
reacting them with one equivalent of paraformaldehyde and 100 °C for 40 min led to the corresponding N,N-bis(phosphi-
diphenylphosphine oxide under MW conditions (Scheme 6). noylmethyl)amines containing identical (13a) or different
The three-component condensations were performed in the substituents on the phosphorus atoms (13b and 13c) in excel-
absence of any catalyst in acetonitrile as the solvent to over- lent yields (95–97%).
Scheme 6: Synthesis of N,N-bis(phosphinoylmethyl)amines 10a,b, 11a,b and 12a,b bearing different substituents at the phosphorus atoms (Y2P=O).
Scheme 7: Synthesis of N,N-bis(phosphinoylmethyl)amines 13a–c.
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Beilstein J. Org. Chem. 2019, 15, 469–473.
Scheme 8: Synthesis of N,N,N-tris(phosphinoylmethyl)amines 14–17.
Synthesis of N,N,N-
tris(phosphinoylmethyl)amines
and in part (E. B.) by the János Bolyai Research Scholarship of
the Hungarian Academy of Sciences (BO/00278/17/7) and by
Finally, N,N-bis(phosphinoylmethyl)amines 13a and 13b were the ÚNKP-18-4-BME-131 New National Excellence Program
reacted further with paraformaldehyde and a secondary phos- of the Ministry of Human Capacities. The authors thank for
phine oxide (diphenyl-, di(p-tolyl)- or dibenzylphosphine oxide) Zoltán Márta to the HRMS measurements.
to afford the N,N,N-tris(phosphinoylmethyl)amine derivatives
ORCID® iDs
Erika Bálint - https://orcid.org/0000-0002-5107-7089
bearing identical (14) and different Y2P=O groups (15–17)
(Scheme 8). The condensations were performed as mentioned
Anna Tripolszky - https://orcid.org/0000-0002-3223-7315
above. The introduction of a third phosphinoylmethyl moiety
László Hegedűs - https://orcid.org/0000-0002-7980-0443
into the bis-derivatives containing an NH unit (13a and 13b) re-
György Keglevich - https://orcid.org/0000-0002-5366-472X
quired a longer reaction time (2 h) at 100 °C. In these cases, the
conversion was 70–95%, and the corresponding N,N,N-
References
1. Goud, E. V.; Sivaramakrishna, A.; Vijayakrishna, K. Top. Curr. Chem.
tris(phosphinoylmethyl)amine derivatives 14–17 were isolated
in yields of 27–77%. However, applying a higher temperature
2017, 375, 10. doi:10.1007/s41061-016-0090-7
and/or longer reaction time, lead to decomposition.
2. Bálint, E.; Tajti, Á.; Tripolszky, A.; Keglevich, G. Dalton Trans. 2018,
47, 4755–4778. doi:10.1039/c8dt00178b
Conclusion
In summary, we have developed an efficient, catalyst-free and
3. Tsuji, J. Transition Metal Reagents and Catalysts; Wiley: Chichester,
2002. doi:10.1002/0470854766
MW-assisted method for the synthesis of N,N-bis(phosphinoyl-
methyl)amines and N,N,N-tris(phosphinoylmethyl)amines
bearing different substituents on the phosphorus atoms by the
Kabachnik–Fields reaction. This method is a novel approach for
the synthesis of the target products. In all, thirteen new deriva-
tives were isolated in high yields and fully characterized.
4. Beller, M.; Bolm, C. Transition Metals for Organic Synthesis: Building
Blocks and Fine Chemicals; Wiley: Weinheim, 2004.
doi:10.1002/9783527619405
5. Berners-Price, S. J.; Sadler, P. J. Phosphines and metal phosphine
complexes: Relationship of chemistry to anticancer and other biological
activity. Bioinorganic Chemistry. Structure and Bonding; Springer:
Berlin, Heidelberg, Germany, 1988; Vol. 70, pp 27–102.
doi:10.1007/3-540-50130-4_2
6. Nazarov, A. A.; Dyson, P. J. Metal Phosphorus Complexes as
Antitumor Agents. In Phosphorus Compounds; Luca, G.; Peruzzini, M.,
Eds.; Springer: Dordrecht, Netherlands, 2011; Vol. 37, pp 445–461.
doi:10.1007/978-90-481-3817-3_13
Supporting Information
Supporting Information File 1
Experimental procedures, characterization data, details of
the NMR structural determination of all products and
copies of 31P, 1H, and 13C NMR spectra for all compounds
synthesized.
7. Petrov, K. A.; Chauzov, V. A.; Erokhina, T. S.; Chernobrovkina, L. P.
Zh. Obshch. Khim. 1976, 46, 493.
8. Petrov, K. A.; Chauzov, V. A.; Erokhina, T. S.
Khim. Elementoorg. Soedin. 1976, 200.
9. Garifzyanov, A. R.; Vasil'ev, R. I.; Cherkasov, R. A.
Russ. J. Gen. Chem. 2005, 75, 217–224.
[https://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-15-40-S1.pdf]
doi:10.1007/s11176-005-0201-6
10.Keglevich, G.; Szekrényi, A. Lett. Org. Chem. 2008, 5, 616–622.
doi:10.2174/157017808786857598
11.Bálint, E.; Tripolszky, A.; Jablonkai, E.; Karaghiosoff, K.; Czugler, M.;
Mucsi, Z.; Kollár, L.; Pongrácz, P.; Keglevich, G. J. Organomet. Chem.
2016, 801, 111–121. doi:10.1016/j.jorganchem.2015.10.029
Acknowledgements
The above project was supported by the Hungarian Research
Development and Innovation Fund (FK123961 and K119202),
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Beilstein J. Org. Chem. 2019, 15, 469–473.
12.Olszewski, T. K.; Boduszek, B.; Sobek, S.; Kozłowski, H. Tetrahedron
2006, 62, 2183–2189. doi:10.1016/j.tet.2005.12.016
13.Cherkasov, R. A.; Garifzyanov, A. R.; Koshkin, S. A.
Russ. J. Gen. Chem. 2011, 81, 773–774.
doi:10.1134/s107036321104027x
14.Cherkasov, R. A.; Garifzyanov, A. R.; Talan, A. S.; Davletshin, R. R.;
Kurnosova, N. V. Russ. J. Gen. Chem. 2009, 79, 1835–1849.
doi:10.1134/s1070363209090114
15.Bálint, E.; Fazekas, E.; Pongrácz, P.; Kollár, L.; Drahos, L.;
Holczbauer, T.; Czugler, M.; Keglevich, G. J. Organomet. Chem. 2012,
717, 75–82. doi:10.1016/j.jorganchem.2012.07.031
16.Bálint, E.; Fazekas, E.; Kóti, J.; Keglevich, G. Heteroat. Chem. 2015,
26, 106–115. doi:10.1002/hc.21221
17.Zefirov, N. S.; Matveeva, E. D. ARKIVOC 2008, No. i, 1–17.
doi:10.3998/ark.5550190.0009.101
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