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N-oxide 3c was observed in 31P NMR spectra (see ESI‡) but could not be isolated.
Unsubstituted pyridine N-oxide did not form phosphobetaines.
structures and charges similar to the oxyonium species 5.
Indeed, simple adaptation of the procedure for the preparation
of compounds of type 107 by replacing pyridines by N-oxides led
unambiguously to the formation of the expected betaines 5
(reactions in DCM or pyridine, 31P NMR analysis). Unfortunately,
these were accompanied by a number of other products, and the
yields did not exceed 50%, indicating incompatibility of N-oxides
with the other reactants. However, pyridinium betaines 10a and
10b can be generated quantitatively in situ,7 and when N-oxides
3a/3b were added to such reaction mixtures, we were satised to
observe signals of betaines 5a/5b, respectively, as practically sole
products. In these experiments, pyridinium betaine 10a reacted
with the N-oxides very rapidly, while the more stable 4-(N,N-
dimethylamino)pyridinium derivative 10b required 15–30 min,
and the progress of the reaction could be monitored with 31P
NMR. Also phenyl phosphorochloridate 11 (prepared in situ by
partial hydrolysis of commercial phenyl phosphorodichloridate)
yielded betaines 5 in reaction with N-oxides, conrming the
general character of this approach.
k It is worth noting that the sequence 70 / 9 / 5 in route B1 is in line with the
mechanism postulated by Stec et al. for oxidation of phosphines and phosphite
triesters with N-oxides.3 In contrast, an intramolecular: P–OBt / O]P–Bt rear-
rangement postulated by Sekine et al. for oxidation of phosphoramidite diesters
with hydroxybenzotriazole (HOBt)15 cannot operate for quaternary nitrogen atoms
in the oxyonium intermediates formed from H-phosphonates and N-oxides.
1 (a) Y. Mizuno and T. Endo, J. Org. Chem., 1978, 43, 747; (b)
V.
A.
Emov,
O.
G.
Chakhmakhcheva
and
Y. A. Ovchinnikov, Nucleic Acids Res., 1985, 13, 3651; (c)
V. A. Emov, O. G. Chakhmakhcheva and S. V. Reverdatto,
Nucleophilic Catalysis in the Oligonucleotide Synthesis, in
Biophosphates and Their Analogues – Synthesis, Structure,
Metabilism and Activity, ed. K. S. Bruzik and W. J. Stec,
Elsevier Science Publishers B.V.: Amsterdam, 1987, pp. 23–
36; (d) V. A. Emov, N. S. Molchanova and
O. G. Chakhmakhcheva, Nucleosides, Nucleotides Nucleic
Acids, 2007, 26, 1087; (e) H. Almer, T. Szabo and
J. Stawinski, Chem. Commun., 2004, 290; (f) J. I. Murray,
R. Woscholski and A. C. Spivey, Chem. Commun., 2014, 50,
13608; (g) J. I. Murray, R. Woscholski and A. C. Spivey,
Synlett, 2015, 26, 985.
Conclusions
Concluding, neither of the H-phosphonates studied was
oxidized directly by N-oxides, indicating that the last species are
much poorer oxidants for H-phosphonate esters than e.g.
iodine, CCl4, or S8. However, DPP 1a and other H-phosphonate
diesters bearing an aryl ligand were found to react promptly
with aliphatic and aromatic N-oxides with formation of a new
type of compounds, oxyonium-type phosphobetaines 5. A
plausible mechanism involves substitution of one phenoxy
group with an N-oxide, addition of a second molecule of the N-
oxide, and oxidative collapse of the tbp intermediate. Despite
this rather complex mechanism, the products were formed with
surprisingly high yields, oen >90%. An alternative route to the
same betaines is a reaction of N-oxides with active derivatives of
phosphate monoesters. It is worth noting that according to
preliminary experiments, the obtained betaines reacted readily
with amines and some other nucleophilic reagents. This fact,
together with clean formation of betaines 5, their easy isolation
(if necessary) and appreciable stability during storage, make
them potentially valuable intermediates in synthetic applica-
tions. Studies on this topic are in progress in this laboratory and
will be reported in due course.
´
2 M. Sobkowski, J. Stawinski and A. Kraszewski, New J. Chem.,
2009, 33, 164.
3 W. J. Stec, A. Okruszek and J. Michalski, Bull. Pol. Acad. Sci.,
Chem., 1973, 21, 445.
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5 M. Sobkowski, J. Stawinski, A. Sobkowska and A. Kraszewski,
J. Chem. Soc., Perkin Trans. 1, 1994, 1803.
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A. Kraszewski, J. Stawinski and D. Shugar, J. Org. Chem.,
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Acknowledgements
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2571.
Financial support from the National Science Centre of Poland
(Project No. DEC-2011/03/B/ST5/03102) and the Polish Ministry
of Science and Higher Education (the KNOW program) is greatly
appreciated.
Notes and references
§ The second product was MPP (2a), probably due to a rapid N-oxide-catalyzed
hydrolysis of DPP by residual water (Fig. S3–S8‡).
15 (a) T. Wada, Y. Sato, F. Honda, S. Kawahara and M. Sekine, J.
Am. Chem. Soc., 1997, 119, 12710; (b) A. Ohkubo, Y. Ezawa,
K. Seio and M. Sekine, J. Am. Chem. Soc., 2004, 126, 10884.
{ Only the most reactive aromatic N-oxides (3a and 3d) formed phosphobetaines
(5a and 5d, respectively) efficiently. Compound 5c derived from 4-methylpyridine
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