6
24
T. Rosenau et al.
LETTER
Table 1. Deoxygenation of Amine Oxides with PFA
Scheme 2
The fact that no deoxygenation of amine oxides occurs
with the non-acylating mixtures of formic acid and pivalic
a
5
mmol of starting material was used, product purity determined by acid, or sodium formate and pivalic acid, is a strong indi-
b
c
GC. See (15) for experimental procedure. 0.1 mol of starting mate- cation of the O-formylated amine oxide 5 being the actual
rial. d Purity and yield determined additionally by capillary electro-
reagent for the subsequent reduction step. The assumption
e
phoresis (CE). Isolated by extraction into water, n. d. by GC.
of a concerted two-electron reaction mechanism is sup-
ported by the observations that no by-products indicative
of homolytic pathways are found, and that the release of
Pivaloyl formic anhydride (2) is a rather labile reagent
that is difficult to dose exactly as it always contains at
least traces of pivalic acid, formic acid, and the symmetric
CO is occurring synchronously with the addition of the
2
amine oxide to the PFA solution.
anhydrides. However, it is prepared in situ from pivaloyl Perhaps the biggest advantage of the procedure in terms of
chloride (1) and dry, pulverized sodium formate in chlo- general applicability is the fact that pure amines are ob-
roform. In that way, a controlled dosage became possible. tained without the need to laboriously separate by-prod-
To ensure that complete formation of PFA has occurred ucts or purify the product. The addition of anhydrous
before the addition of the amine oxide, it is recommended potassium carbonate converts pivalic and formic acid into
to employ reaction times of 30 min or longer.
their solid potassium salts, and NaCl, the by-product of
the in situ-generation of PFA, is a solid as well. Thus, all
other products of the deoxygenation reaction are easily
separable by filtration, and the remaining amine solution
can be used for manipulations without further purification
steps. Simple evaporation of the solvent yields a pure
product.
The deoxygenation of the amine oxides 3 by PFA is an
exothermic reaction that proceeds smoothly at 0 °C. No
reaction between PFA (2) and the product amine 4 was
observed at this temperature. However, higher tempera-
tures (rt) or the lack of cooling during the reaction, appar-
ently favor the formation of amines generated in
Polonowski- type side-reactions with subsequent formyl- In summary, we have introduced an improved approach
ation over the desired O-acylation of the amine oxide, N- towards the deoxygenation of tertiary and heteroaromatic
formylmorpholine being the major by-product.
amine oxides. Being admittedly only one of many other
similar methods, the procedure presented is attractive for
the ease of preparation and work-up, and the exclusive use
of simple chemicals.
The first step of the deoxygenation reaction is the nucleo-
philic attack of the negatively-charged oxygen in 3 at the
carbonyl group of the mixed anhydride producing an N-
oxyformylammonium cation 5. Strong steric hindrance
prevents a reaction at the pivaloyl carbonyl group ac-
counting for the highly regioselective attack at the formyl
group. This is the advantage over the other mixed formic
anhydrides, which deoxygenate amine oxides if the ”prop-
er” carbonyl reacts, but can also provoke Polonowski-type
reactions if the ”wrong” carbonyl group is involved. The
O-formylated amine oxide 5 immediately undergoes an
intramolecular redox reaction, in which the formic ester is
oxidized to carbon dioxide while the amine oxide is re-
duced to corresponding amine. The N-O bond is cleaved
during this decarboxylative fragmentation. In Scheme 2,
the course of the reaction is shown for N-methylmorpho-
line-N-oxide as an example.
Acknowledgement
We are grateful to Prof. C. L. Chen, North Carolina State Universi-
ty, Raleigh, USA, for helpful discussions and inspiring advice. The
authors would like to dedicate this work to Prof. J. S. Gratzl,
th
Raleigh, USA on the occasion of his 70 birthday.
References and Notes
(
1) a) Albini, A. Heterocycles 1992, 34, 1973. b) Albini, A.;
Pietra, S. Heterocyclic N-Oxides; CRC: Boca Raton, 1991.
(2) Several synthetically useful manipulations, such as
Meisenheimer and Cope rearrangements, start from amine
oxides. See for instance: a) Meisenheimer, J. Ber. Dtsch.
Chem. Ges. 1919, 52, 1667. b) Johnstone, R.A.W. In
Mechanism of Molecular Migration; Thyagarajan, B.S., Ed.;
Interscience: New York, 1969; Vol.2, p. 249. c) Cope, A.C.;
Trumbull, E.R. Org. React. 1960, 11, 317.
Synlett 1999, No. 5, 623–625 ISSN 0936-5214 © Thieme Stuttgart · New York