Oxidative decarboxylative synthesis of 2-H-imidazolines from glyoxylic acid and 1,2-diamines

Article abstract of DOI:10.1039/b807810f

A novel method to prepare 2-H-imidazolines from glyoxylic acid monohydrate and 1,2-diamines is described; the key reaction of this method is the oxidative decarboxylation of the 2-carboxy imidazolidines by NBS. The Royal Society of Chemistry.

Full text of DOI:10.1039/b807810f

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Oxidative decarboxylative synthesis of 2-H-imidazolines from
glyoxylic acid and 1,2-diaminesw
Kenichi Murai, Maiko Morishita, Ryo Nakatani, Hiromichi Fujioka* and
Yasuyuki Kita*
Received (in Cambridge, UK) 8th May 2008, Accepted 27th June 2008
First published as an Advance Article on the web 4th August 2008
DOI: 10.1039/b807810f
A novel method to prepare 2-H-imidazolines from glyoxylic acid
monohydrate and 1,2-diamines is described; the key reaction of
this method is the oxidative decarboxylation of the 2-carboxy
imidazolidines by NBS.
We recently reported the efficient synthesis of 2-substituted
imidazolines.1 The method involves the condensation of alde-
hydes and 1,2-diamines without any catalyst. The reaction
mixtures are then oxidized by N-bromosuccinimide (NBS) to
Scheme 1
afford the imidazolines in a one-pot operation. This is the first
method to prepare imidazolines from aldehydes and 1,2-dia-
mines and has several advantages. Thus the reaction proceeds
under mild conditions at low reaction temperature (0 1C–rt)
using an almost neutral reagent (NBS). Furthermore, functions
such as esters and nitriles can be tolerated, whereas such
functions are used for constructing imidazoline rings in pre-
vious methods.2 The utility of this reaction was also demon-
strated by our recent total synthesis of spongotine A having the
imidazoline-ketone moiety.3 On the other hand, this method
had not been applied to the synthesis of the 2-H-imidazolines.
2-H-Imidazolines are pharmacologically important skeletons.4
The condensation of 1,2-diamines and an appropriate reagent
provides the straightforward and convenient syntheses of 2-H-
imidazolines, and several useful methods using 1,2-diamines
have been reported. For example, under elevated temperature
conditions, condensations with triethyl orthoformate in the
presence of a catalytic amount of the acid,5 tert-butyl cyanide
using a silver cyanide catalyst,6 and dimethylformamide di-
methyl acetal7 were reported. On the contrary, at room tem-
perature, condensations with formamidine4c or formimidate4d
reagents are known. In this paper, we describe a novel approach
for the synthesis of 2-H-imidazolines by oxidative decarboxyla-
tion from glyoxylic acid and 1,2-diamines.
It is well known that a-amino acids generate imines by
oxidative decarboxylation (Scheme 1, (1)).8 We considered
that the 2-carboxy imidazolidines, similar to a-amino acids,
could provide the 2-H-imidazolines if their oxidative cleavage
could occur (Scheme 1, (2)). Glyoxylic acid bearing a car-
boxylic acid group at the a position of aldehyde was selected
as the coupling partner of the 1,2-diamines.
The results of the reaction with glyoxylic acid monohydrate
and diamine 1a are shown in Table 1. As expected, the
condensation of glyoxylic acid monohydrate with diamine 1a
followed by oxidative cleavage by NBS very smoothly pro-
ceeded to produce 2-H-imidazoline 2a in 88% yield in CH2Cl2 at
room temperature (Table 1, entry 2). MeOH was revealed to be
a better solvent and gave an excellent result (98% yield), because
of the good solubility of glyoxalic acid in this solvent (Table 1,
entry 3). On the other hand, other oxidants such as NaOCl,8i
NaIO4,8j and H5IO6,8k that are generally used for cleavage of
a-amino acids, were not effective (Table 1, entries 4–6).
Table 1 Optimization
For the synthesis of the 2-H-imidazolines, we initially
examined the reaction using formaldehyde. To our delight,
the condensation with (Æ)-1,2-diphenylethylenediamine 1a
followed by oxidation with NBS in CH2Cl2 gave compound
2a in 79% yield. As the yield was not very efficient, we tried to
search for a more effective reaction.
Entry Aldehyde
Oxidant
NBS
Solvent Yield (%)
1
2
3
4
5
6
7
HCHO aq.
CH2Cl2 79
CH2Cl2 88
HCOCO2HÁH2O NBS
HCOCO2HÁH2O NBS
HCOCO2HÁH2O NaOCl
HCOCO2HÁH2O NaIO4
HCOCO2HÁH2O H5IO6
MeOH 98
MeOH N.D.a
MeOH N.D.a
MeOH 44
Graduate School of Pharmaceutical Sciences, Osaka University, 1-6
Yamada-oka, Suita, Osaka 565-0871, Japan.
E-mail: fujioka@phs.osaka-u.ac.jp; kita@phs.osaka-u.ac.jp;
Fax: +81 6 6879 8229; Tel: +81 6 6879 8226
HCOCO2HÁH2O NBS + galvinoxyl MeOH 93
(1.1 eq.)
a
w Electronic supplementary information (ESI) available: Experimental
details and NMR spectra. See DOI: 10.1039/b807810f
N. D. = Not detected on TLC.
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Table 2 Generality
Yield
(%)
Entry
1
Diamine
Product
98
2
3
4
Scheme 2
95
83
Although it is known that some oxidative cleavages of a-
amino acids proceed via a radical mechanism,8c,d,9 the reaction
that developed is not a radical reaction, considering the fact
that the addition of galvinoxyl, which is a radical scavenger,
had little influence on this reaction (Table 1, entry 7). There-
fore, as shown in Scheme 2, the reaction proceeds through a
sequence involving the formation of aminal i, the bromination
of the nitrogen atom, and simultaneous elimination of bro-
mine and CO2 from intermediate ii to give 2-H-imidazoline.
It can be assumed that the carboxylic acid of the glyoxylic
acid monohydrate plays two important roles in this reaction.
First, it increases the reactivity of the aldehyde and makes the
formation of the aminal much easier. Secondly, at the oxida-
tion stage, the decarboxylation is a good assistant for the
elimination of the bromine. Therefore glyoxylic acid mono-
hydrate effectively produced the 2-H-imidazoline when com-
pared with formaldehyde. Additionally, the carboxylic acid
moiety of glyoxylic acid is essential in this reaction, because
condensation of the diamine 1a with ethyl glyoxylate, which
has an ester moiety instead of a carboxylic acid formed the
6-membered pyrazinone ring (Scheme 3).10
73
5
6
91
61
Promotion of Science and by Grant-in-Aid for Scientific
Research on Priority Areas (17035047) from the Ministry of
Education, Culture, Sports, Science, and Technology, Japan.
K.M. thanks the Japan Society for the Promotion of Science
(JSPS) for a Research Fellowship for Young Scientists.
The generality of this reaction is shown in Table 2. N-
substituted diamines 1b and 1c afforded the corresponding
2-H-imidazolines 2b and 2c in good yields (Table 2, entries 2,
3). The 2-H-imidazolines 2d and 2e, which have a bulky iso-
propyl or cyclohexyl substitution on the nitrogen atom, were also
obtained in high yields (Table 2, entries 4, 5). Furthermore, the
diamine 1f bearing a quaternary carbon can be applicable
(Table 2, entry 6).
Notes and references
1 (a) H. Fujioka, K. Murai, Y. Ohba, A. Hiramatsu and Y. Kita,
Tetrahedron Lett., 2005, 46, 2197–2199; (b) H. Fujioka, K. Murai,
O. Kubo, Y. Ohba and Y. Kita, Tetrahedron, 2007, 63, 638–643;
After our report, several groups reported methods to prepare
imidazolines from aldehydes by using other oxidants. See: (c) P.
Gogoi and D. Konwar, Tetrahedron Lett., 2006, 47, 79–82; (d) M.
Ishihara and H. Togo, Synlett, 2006, 227–230; (e) S. Sayama,
Synlett, 2006, 1479–1484.
2 For the example, see: (a) R. J. Ferm and J. L. Riebsomer, Chem.
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3 K. Murai, M. Morishita, R. Nakatani, O. Kubo, H. Fujioka and
Y. Kita, J. Org. Chem., 2007, 72, 8947–8949.
In summary, we have developed a novel method to prepare
2-H-imidazolines from various 1,2-diamines and glyoxylic acid
monohydrate. The mild and smooth oxidative decarboxylation
of the 2-carboxy imidazolidines is characteristic of this reaction.
We believe that this method is useful and will become an
alternative method for the synthesis of the 2-H-imidazolines.
This work was financially supported by Grant-in-Aid for
Scientific Research (A) and Grant-in-Aid for Scientific Re-
search for Exploratory Research from Japan Society for the
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Scheme 3
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