Unusually facile palladium catalysed oxidation of imidazolidines and oxazolidines

Article abstract of DOI:10.1039/b010089g

An unusually facile palladium catalysed oxidation of imidazolidines is described, affording in good yield, the monoamide of the corresponding diamine or the corresponding imidazolines. Oxazolidines derived from ephedrine react similarly.

Full text of DOI:10.1039/b010089g

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Unusually facile palladium catalysed oxidation of imidazolidines
and oxazolidines
Alexandre Alexakis,*a Isabelle Aujard,b Julien Pytkowicz,b Sylvain Rolandb and
Pierre Mangeney*b
1
a Department of Organic Chemistry, University of Geneva, 30 quai Ernest Ansermet, Genève 4,
CH-1211 Switzerland. Tel. ϩ41 22 702 65 22; Fax (int.) ϩ41 22 328 73 96;
E-mail: alexandre.alexakis@chiorg.unige.ch
b Laboratoire de Chimie des Organoéléments, UMR 7611, Université Pierre et Marie Curie,
4 place Jussieu, 75252 Paris Cedex 05 France
Received (in Cambridge, UK) 11th December 2000, Accepted 3rd April 2001
First published as an Advance Article on the web 18th April 2001
Table 1 Catalysts (5%) used for the oxidation of 2 to 3
An unusually facile palladium catalysed oxidation of
imidazolidines is described, affording in good yield, the
monoamide of the corresponding diamine or the
corresponding imidazolines. Oxazolidines derived from
ephedrine react similarly.
Entry
Catalyst (5%)
Conditionsa
Conversion (%)
1
2
3
4
5
6
7
8
Pd(OH)2
Pd(PPh3)4
10% Pd/C
Raney Ni
Pt/C
RuCl3
Rh/C
i-PrOH, H2, 20 ЊC, 6 h
MeOH, 20 ЊC, 30 min
MeOH, 20 ЊC, 5 h
MeOH, 60 ЊC, 6 h
MeOH, 20 ЊC, 5 h
MeOH, 65 ЊC, 24 h
MeOH, 20 ЊC, 15 h
MeOH, 20 ЊC, 15 h
85
100
100
47
100
20
In the course of our studies to find a method for the isomeris-
ation of meso C2 symmetrical diamines into their (ϩ),(Ϫ)
isomers,1 we thought that the formation of an imidazolidine
ring (an aminal) would help in this process. Indeed, in such a
ring, the driving force would be the transformation of the cis
relationship of the two substituents into a trans one (Scheme 1).
65
50
RhCl(PPh3)3
a Allowed solvents: MeOH, EtOH, i-PrOH, PhCH3 ϩ 10% MeOH. Not
allowed solvents: THF, CH2Cl2, PhCH3, benzene, cyclohexane, EtSH,
i-Pr2NH, H2O.
atmosphere. The reaction also occurs in open air, but a
cleaner product is obtained under inert atmosphere (N2 or Ar).
Obviously, overoxidation products may be formed with oxygen.
Solvents other than i-PrOH or MeOH were tried. No reaction
at all was noticed in aprotic solvents such as cyclohexane,
DCM, THF and toluene, or protic solvents such as ethanethiol
or dimethylamine. In contrast, alcohols, such as methanol,
ethanol, propan-2-ol, or even n-decanol may be used. Toluene
containing MeOH is also possible, but no reaction occurred
with water.
Scheme 1
A possible route for such an epimerisation, could be to take
advantage of the benzylic position and to use a transition
metal, the most obvious being palladium. When aminal 2 was
treated with 10% Pd(OH)2, in i-PrOH, under a hydrogen
atmosphere, a rapid reaction took place, and, within 6 h at
room temperature, all of the starting material disappeared in
favor of a new very polar compound. This new compound was
the monoformamide 3 of the starting diamine 1 (Scheme 2).
By analogy to Grigg and Heaney,5b we tentatively hypothesise
that a palladium catalysed dehydrogenation occurs, leading
to the imidazolinium 4. This step is followed by addition of
methanol to form a 2-alkoxy-1,3-imidazolidine 5. In the case of
these meso aminals, intermediates 4 and 5 were not observed
since they are probably easily hydrolysed, even by moisture,
to the monoamide 3 (Scheme 3).6 That a dehydrogenation is
involved, was checked by measuring the volume of gas
evolution, and also by running a experiment with the aminal
Scheme 2
Moreover, no isomerisation took place in this process, as was
checked by hydrolysing amide 3.
This net oxidation process of aminals has been achieved by
electrochemical2 or biogenetic3 means, and more generally,
by chemical oxidation.4 In particular, palladium oxidation of
amines has been described, but a high temperature (200 ЊC) is
usually required.5 This oxidation is also catalysed by other
metals (see Table 1). However, the most practical and efficient
was Pd/C (entry 3) which allows, by simple filtration and
evaporation of the solvent, the easy obtention of the product.
Of course there is no need to run the reaction under a hydrogen
Scheme 3
DOI: 10.1039/b010089g
J. Chem. Soc., Perkin Trans. 1, 2001, 949–951
This journal is © The Royal Society of Chemistry 2001
949

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Table 2 Oxidation of meso aminals, according to Scheme 4
Entry
R1
R2
R3
Conditionsa
Product
Yieldb (%)
1
2
3
4
5
6
Ph
Ph
Ph
Ph
Ph
Cy
Me
Me
Me
Me
i-Pr
Me
H
i-Pr
Ph
-CH᎐CH–CH3
H
H
20 ЊC, 5 h
20 ЊC, 8 h
60 ЊC, 18 h
20 ЊC, 8 h
20 ЊC, 6 h
20 ЊC, 5 h
3a
3b
3c
3d
3e
3f
89
83
70
70c
73
84
᎐
a 3 Å Molecular sieves were usually added. b Isolated by SiO2 column chromatography. c The saturated compound was obtained (R3 = Pr).
of crotonaldehyde, whereupon saturation of the double bond
was observed (entry 4, Table 2).
In addition several other imidazolidines derived from meso
diamines were treated under the above conditions. The results
are summarised in Table 2 (Scheme 4).
Scheme 4
Scheme 6
We also examined the case of the aminal 2Ј, obtained from
formamide was obtained in 75% isolated yield. Interestingly,
when the same reaction was performed in an aprotic solvent,
such as cyclohexane, a reaction occurred giving the formamide
with cleavage of the benzylic C–O bond, in 72% isolated yield
(Scheme 7).
the (ϩ),(Ϫ) diamine 1Ј. The oxidation does not occur at all
at room temperature, but only after heating at 65 ЊC for 9 h.
In this aminal, the preferred conformation allows only one
nitrogen lone pair to be anti to the C–H bond (Scheme 5),
Scheme 7
In summary, we have disclosed an interesting palladium
catalysed oxidation of aminals,8 which may find several
synthetic applications, due to its mild conditions and efficiency.
We are studying the extension of this reaction to other cyclic
or acyclic aminals, as well as its potential in asymmetric
synthesis.
Scheme 5
whereas the all-cis aminal, seen above, allows the lone pairs of
both nitrogens to adopt such a conformation. In this reaction,
the imidazolinium 4Ј seems more stable than its meso analogue
4 since it could be observed in the crude reaction mixture. The
use of sodium hydroxide is then necessary, in addition to
methanol and water, to have a complete hydrolysis into 3Ј.
We also observed the same palladium mediated oxidation
reaction on the (ϩ),(Ϫ) aminal 6.7 Indeed, in the hydrogenolysis
of the chiral benzylic groups, we obtained very cleanly the
imidazoline 8 instead of the expected imidazolidine 9. As
above, this reaction probably proceeds through the imidazo-
linium 7 which is neither sensitive to addition of EtOH nor
to hydrolysis by moisture in contrast to the intermediate 4Ј.
This hydrogenolysis/oxidation process occurred in one step in
refluxing EtOH, using ammonium formate and palladium
hydroxide as the catalyst. Nevertheless, the imidazolidine 9
could be obtained as the single product by performing the
reaction at 50 ЊC with the same reagents. The palladium
oxidation of 9 is then quantitative using Pd/C in refluxing
ethanol without a hydrogen donor (Scheme 6).
Notes and references
1 A. Alexakis, I. Aujard and P. Mangeney, Synlett, 1998, 873; A.
Alexakis, I. Aujard and P. Mangeney, Synlett, 1998, 875.
2 T. Shono, Y. Matsumara, J. Hayashi, M. Usui, S.-I. Yamane and
K. Inoue, Acta Chem. Scand., Ser. B, 1983, 37, 491.
3 E. Brode and L. Jaenicke, Liebigs Ann. Chem., 1959, 120.
4 (a) E. Rabe and H.-W. Wanzlick, Liebigs Ann. Chem., 1973, 40;
(b) E. Rabe and H.-W. Wanzlick, Liebigs Ann. Chem., 1975, 195;
(c) S. M. Hecht, B. L. Adams and J. W. Kozarich, J. Org. Chem., 1976,
41, 2302; (d) Y.-L. Lin, R.-L. Huang, C.-M. Chang and Y.-H. Kuo,
J. Nat. Prod., 1997, 60, 982; (e) For a review on aminals, see:
L. Duhamel, in The Chemistry of amino, nitroso and nitro compounds
and their derivatives, ed. F. S. Patai, J. Wiley, Chichester, 1982, pp.
849–907.
5 (a) S. I. Murahashi and T. J. Watanabe, J. Am. Chem. Soc., 1979, 101,
7429; (b) S. I. Murahashi, Angew Chem., Int. Ed. Engl., 1995, 34,
2443; (c) R. Grigg and F. Heaney, J. Chem. Soc., Perkin Trans. 1,
1989, 198.
6 R. F. Abdulla and R. S. Brinkmeyer, Tetrahedron, 1979, 35, 1675.
7 S. Roland, P. Mangeney and A. Alexakis, Synthesis, 1999, 228. The
Finally, we extended this reaction to oxazolidines. Thus,
when the oxazolidine 10, formed with ephedrine and formalde-
hyde, was treated under the standard conditions, the expected
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J. Chem. Soc., Perkin Trans. 1, 2001, 949–951

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aminal 6 can also be obtained by the modified following procedure:
To a solution of crude diamine (1 mmol) in Et2O or CH2Cl2 (10 ml),
were added a solution of formaldehyde (37% aq, 5 mmol), MgSO4
(0.5 g) and acetic acid (one drop). The mixture was stirred at 20 ЊC
for 6 h, filtered and concentrated. The crude was recrystallised in
acetonitrile to give 50–60% of the expected aminal as colourless
crystals.
8 Typical Procedures: Oxidation of aminals, 2 and 2Ј: To a suspension
of 10% Pd/C (0.053 g, 0. 05 mmol) and molecular sieves 3 Å (0.5 g),
under argon, in MeOH (10 ml), was added the imidazolidine
(1 mmol). The suspension was stirred for the time and the temper-
ature stated in Table 2. After completion of the reaction, the Pd/C
was filtered off through Celite, the solvents were evaporated and the
crude product was purified by silica gel chromatography (Et2O–
MeOH, 50 : 50). Oxidation of aminal, 6: To a solution of imidazolid-
ine (1 mmol) in EtOH (20 ml), were added Pd(OH)2/C (0.1 mmol)
and ammonium formate (10 mmol). The mixture was refluxed for 6 h,
filtered and concentrated. To the residue were added Et2O (15 ml) and
K2CO3 (0.5 g) and the suspension was stirred for 1 h, filtered and
1
concentrated to give the imidazoline 8 as a white solid. H NMR:
δH (CDCl3) 0.86 (s, 18H), 3.27 (s, 2H), 4.8 (s, 1H), 7.05 (s, 1H). 13C
NMR: δC 24.5, 33.2, 69.1, 150.7.
J. Chem. Soc., Perkin Trans. 1, 2001, 949–951
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