A concise synthesis of N-(trideuteromethyl)morpholine-N-oxide monohydrate

Article abstract of DOI:10.1055/s-1999-2963

An efficient synthesis of N-(trideuteromethyl)morpholine N-oxide monohydrate (3) is described. The procedure applies the tocopheryl protecting group, and makes use of sodium percarbonate as the oxidant and water donor, thus avoiding both the troublesome direct alkylation of morpholine and the unsuitable oxidation by aqueous hydrogen peroxide. Overall yields of purified material range above 90%.

Full text of DOI:10.1055/s-1999-2963

1972
LETTER
A Concise Synthesis of N-(Trideuteromethyl)morpholine-N-oxide
Monohydrate
Thomas Rosenau, Antje Potthast, Paul Kosma*
Christian-Doppler-Laboratory, University of Agricultural Sciences - Vienna, Muthgasse 18, A - 1190 Vienna, Austria
Fax:+43 1 36006 6059; E-mail: pkosma@edv2.boku.ac.at
Received 23 August 1999
parently tend to decompose the NMMO already formed to
unknown products. Second, with aqueous hydrogen per-
oxide as the oxidant,5 the monohydrate of NMMO can
only be obtained after removal of the excess of oxidant,
Abstract: An efficient synthesis of N-(trideuteromethyl)morpho-
line-N-oxide monohydrate (3) is described. The procedure applies
the tocopheryl protecting group, and makes use of sodium percar-
bonate as the oxidant and water donor, thus avoiding both the trou-
blesome direct alkylation of morpholine and the unsuitable concentration of the mixture to give the 2.5 hydrate, fur-
oxidation by aqueous hydrogen peroxide. Overall yields of purified
material range above 90%.
ther azeotropic removal of water to obtain the monohy-
drate, distillative removal of the water carrier, and, finally,
Key words: N-methylmorpholine-N-oxide, amine oxides, sodium
percarbonate, Toc protecting group
successive recrystallization to increase the purity of the
product.6 This protocol, besides being rather lengthy and
tedious, is hard to apply in lab scale synthesis of smaller
amounts and can only be done at significant yield penalty.
N-Methylmorpholine-N-oxide (NMMO) is a very com-
mon reagent that is widely used in organic synthesis as an
oxidant in transition metal catalyzed reactions.1 It is also
used on a large scale as a bulk solvent for cellulose in in-
dustrial fibre processing,2 e.g., in the Lyocell process. Af-
ter observations of autocatalytic decomposition reactions3
and thermal runaway processes4 with NMMO, the com-
pound has recently induced new research activities. Inves-
tigations on the mechanisms of those reactions made the
lab scale synthesis of N-(trideuteromethyl)-morpholine-
N-oxide monohydrate (3, NMMO-D3*H2O) necessary.
Consequently, another approach was chosen which was
supposed to meet two requirements: the synthesis should
be able to provide N-(trideuteromethyl)morpholine (2)
free of morpholine and ammonium salts to ensure a clean
oxidation, and the oxidation step should proceed in non-
aqueous media. We therefore used the reaction sequence
shown in Scheme 2.
The simple route of trideuteromethylation of morpholine
(1) by CD3I followed by oxidation of N-(trideuterometh-
yl)morpholine (2) with aqueous hydrogen peroxide as
shown in Scheme 1 seemed to offer convenient access to
3 at a first glance, but was proven to be unfeasible after ex-
perimental testing.
Scheme 2
Scheme 1
The synthesis applied the Toc protecting group (Toc = 5a-
α-tocopheryl = [6-hydroxy-2,7,8-trimethyl-2-(4,8,12-tri-
methyltridecyl)-chroman-5-yl]methyl) that was attached
to morpholine by its reaction with Toc-Br (5a-bromo-α-
tocopherol, 4).7 The free Toc-protected amine 5 was liber-
First, separation of sufficiently pure 2 from the alkylation
mixture is rather difficult since already trace amounts of
impurities interfere with the subsequent oxidation, and ap-
Synlett 1999, No. 12, 1972–1974 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
A Concise Synthesis of N-(Trideuteromethyl)morpholine-N-oxide Monohydrate
1973
ated from the ammonium salt by addition of solid K2CO3,
and subsequently quaternized by trideuteromethyl iodide
in the presence of K2CO3 according to a modified Claisen
etherification method. The Toc group ensures selective
monoalkylation at the nitrogen, and a small excess of
alkylating agent guarantees complete conversion of 1. The
resulting quaternary ammonium salt 6 was not isolated,
but immediately treated with sodium percarbonate
(Na2CO3*1.5H2O2), a solid, easily dosable addition com-
pound of sodium carbonate and hydrogen peroxide which
has not yet been reported as an oxidant for the production
of amine oxides in non-aqueous media.8 In the present
case, this reagent allowed to accomplish three synthetic
steps at once: removal of the protecting group (at about
50 °C), oxygenation of 2, and formation of the monohy-
drate 3. As the H2O2 consumed in the oxidation is directly
converted into H2O, no more water is produced than need-
ed for the stoichiometric formation of the monohydrate of
N-(trideuteromethyl)morpholine-N-oxide.
Acknowledgement
We are grateful to Dr. A. Hofinger and Dr. M. Puchberger, Univer-
sity of Agricultural Sciences Vienna, Austria, for recording the
NMR spectra, and to Dr. H. Sanford, North Carolina State Univer-
sity at Raleigh, USA, for carrying out the MS measurements. The
authors would also like to thank Doz. Dr. Sixta, Lenzing AG, Aus-
tria, for helpful discussions.
References and Notes
(1) For a review on the application of amine oxides in synthesis
see: Albini, A. Synthesis 1993, 263. Albini, A.; Pietra, S.
Heterocyclic N-Oxides; CRC: Boca Raton, 1991. For
oxidations in combination with transition metal catalysts, such
as OsO4: Schröder, M. Chem. Rev. 1980, 80, 187. Jacobsen,
E.N.; Markò, I.; Mungall, W.S.; Schröder, G.; Sharpless, K.B.
J. Am. Chem. Soc. 1988, 110, 1968.
(2) a) Chanzy, H. J. Polym. Sci. Polymer Phys. Ed. 1980, 1137. b)
Taeger, E.; Michels, C.; Nechtawal, A. Papier 1991, 12, 784.
(3) Rosenau, T.; Potthast, A.; Kosma, P.; Chen, C.L.; Gratzl, J.S.
J. Org. Chem. 1999, 64, 2166.
(4) Buijtenhuis, F.A.; Abbas, M.; Witteveen, A.J. Papier 1986,
The Toc protecting group can be cleaved at slightly ele-
vated temperatures above 50 °C as in the present case, or
by treatment with a base or a mild oxidant. The protecting
group is released as the spiro-dimer of α-tocopherol (7)7
which is highly soluble in n-hexane, whereas product 3
and the remaining inorganic auxiliary agents (K2CO3,
Na2CO3, excess of Na2CO3*1.5H2O2) are completely in-
soluble. The product is then separated from these salts by
washing with boiling, dry acetone. Since acetone is the
most suitable solvent for recrystallization of 3, the
product9 precipitates from the filtrate in long, white nee-
dles upon slow cooling.10 The overall yield of the se-
quence is excellent, taking into account that it actually
consists of six individual reaction steps. The two addition-
al operations, introduction and removal of the protecting
group, are more than compensated by the high overall
yields obtained (Table 1).
40, 615.
(5) Representative procedures for the preparation of amine oxides
by oxidation of tertiary amines with aqueous hydrogen
peroxide of different concentrations: Hoh, G.L.H.; Barlow,
D.O.; Chadwick, A.F.; Lake, D.B.; Sheeran, S.R. J. Am. Oil
Chem. Soc. 1963, 9, 268. Huisgen, R.; Bayerlein, F.;
Heydkamp, W. Chem. Ber. 1959, 92, 3223; besides vast patent
literature.
(6) Preparation of anhydrous or lower-hydrate amine-oxides from
aqueous solutions or higher hydrates: Köster, R; Morita, Y.
Liebigs Ann. Chem. 1967, 704, 70. Sonderquist, J.A.;
Anderson, C.L. Tetrahedron Lett. 1986, 27, 3961.
(7) For the preparation of Toc-Br see: Rosenau, T.; Habicher,
W.D. Tetrahedron 1995, 51, 7919. Protection of amines with
Toc-Br and removal of the protecting group: Rosenau, T.;
Chen, C.L.; Habicher, W.D. J. Org. Chem. 1995, 60, 8120.
(8) Other forms of “solid hydrogen peroxide”, such as sodium
persulphate, sodium perborate or urea-H2O2 adduct, have not
been tested.
(9) The melting point is also a good indicator of the water content,
cf.: m.p. = 74-76 °C: Eastman Kodak Co., Patent GB
1144048, 1966; Chem. Abstr. 1969, 70, 106537r.
m.p. = 75 °C: Krafft, M.E.; Cheung, Y.Y.; Wright, C.; Cali,
R. J. Org. Chem. 1996, 61, 3912.
(10) Experimental procedure: The synthesis had been optimized by
means of non-deuterated CH3I, and was then repeated with
CD3I. Morpholine (0.464 g, 5.33 mmol) was dissolved in 10
mL of dichloromethane / n-hexane (v/v = 1:1) (CAUTION! n-
hexane is known to have neurotoxic effects!) and cooled to
-10 °C in an inert atmosphere. A precooled solution of 5a-
bromo-α-tocopherol (3.060 g, 6 mmol) in dichloromethane /
n-hexane (v/v = 1:1, 10 mL) was added dropwise, and the
solution was stirred for additional 30 min. After addition of
anhydrous K2CO3 (2.210 g; 16 mmol) the mixture was stirred
for 15 min at –10 °C and then warmed to room temperature
over 30 min under stirring. A solution of CD3I (0.850 g, 5.86
mmol) (CAUTION! Methyl iodide is toxic and possibly
carcinogenic!) in 20 mL of dry acetonitrile was added
dropwise at room temperature. The solution was further
agitated for about 3 h. Powdered sodium percarbonate (2.510
g; 16 mmol) (CAUTION! The substance may be explosive
when mixed with easily oxidizable materials!) was added at
once, and the reaction temperature was raised to 50 °C while
the CH2Cl2 was slowly distilling off. A condenser was placed
on the vessel, and the mixture was held at 50 °C for 1 h under
further intensive stirring. After cooling to 0 °C by means of an
In summary, we have developed a straightforward high-
yield preparation of N-(trideuteromethyl)morpholine-N-
oxide monohydrate. The synthesis employs sodium per-
carbonate that is both the oxidant and the source of stoi-
chiometric amounts of water. The procedure is a conve-
nient one-pot approach with easy work-up which may find
general application in the synthesis of N-methylamine-N-
oxides.
Synlett 1999, No. 12, 1972–1974 ISSN 0936-5214 © Thieme Stuttgart · New York

1974
T. Rosenau et al.
LETTER
ice bath and addition of n-hexane (100 mL) the mixture was
stirred for 15 min. The solids were removed by filtration and
washed with n-hexane (3 × 10 mL), the combined filtrate and
washings were discarded. The solid remainder was dispersed
in 100 mL of boiling, dry (!) acetone, refluxed for 5 min, and
immediately filtered. The filtrate was concentrated under
vacuum to about 50 mL and left standing at room temperature
or in the fridge for 2 h. The product crystallized upon cooling
of the filtrate in long, colorless needles (m.p. 76 °C) rendering
further purification unnecessary. Concentration of the mother
liquor provided only small amounts (<3%) of less pure
material.
In the following, analytical data are given for the non-
deuterated intermediate 6 and product 3 (cf. Table 1, entry 3)
as well as deuterated 3 (cf. Table 1, entry 1). Intermediate 6:
1H NMR (300 MHz, CDCl3): δ 1.80 (m, 2H, 3CH2), 2.12 (s,
6H, 7aCH3, 8bCH3), 2.29 (s, 3H, N-CH3), 2.42 (t, 4H, N-CH2),
2.60 (t, 2H, 4CH2), 3.72 (t, 2H, O-CH2), resonances of the
isoprenoid side chain are not listed. Product 3: 1H NMR (300
MHz, CDCl3): δ 5.07 (0.5H, s, b), 4.43 (2H, td, O-CH,
J = 11.9 Hz, J = 2.1 Hz), 3.77 (2H, dd, O-CH, J = 12.6 Hz,
J = 3.6 Hz), 3.46 (1.5H, OH), 3.36 (2H, td, N-CH, J = 11.4
Hz, J = 3.6 Hz), 3.26 (3H, s, N-CH3), 3.14 (2H, td, N-CH,
J = 12.0 Hz, J = 1.8 Hz). 13C NMR (CDCl3, APT): δ 61.2 (N-
CH3), 61.8 (N-CH2); 66.1 (O-CH2). m.p. = 75 °C. HR-
MS:117.0785, calcd. for C5H11NO2:117.0790 (∆ = 0.0005
amu). Deuterated product 3: 13C NMR (CDCl3): δ 60.1 (sept,
N-CD3, J = 21.8 Hz), 61.6 (N-CH2); 66.1 (O-CH2).
m.p. = 76 °C (literature values for m.p.: see reference 8). HR-
MS:120.0970, calcd. for C5H8D3NO2:120.0975 (∆ = 0.0005
amu).
Article Identifier:
1437-2096,E;1999,0,12,1972,1974,ftx,en;G21099ST.pdf
Synlett 1999, No. 12, 1972–1974 ISSN 0936-5214 © Thieme Stuttgart · New York