A one-pot three-component synthesis of β-nitro-a-amino acids and their W-alkyl derivatives

Article abstract of DOI:10.1039/a906223h

A water-based condensation of glyoxylic acid, nitroalkanes and amines is described, offering a straightforward synthesis of β-nitro-a-amino acids and their AT-alky! derivatives. The Royal Society of Chemistry 1999.

Full text of DOI:10.1039/a906223h

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A one-pot three-component synthesis of ꢀ-nitro-ꢁ-amino acids and
their N-alkyl derivatives
Phillip A. Coghlan and Christopher J. Easton*
Research School of Chemistry, Australian National University, Canberra, ACT 0200, Australia.
E-mail: easton@rsc.anu.edu.au
Received (in Cambridge, UK) 2nd August 1999, Accepted 9th August 1999
A water-based condensation of glyoxylic acid, nitroalkanes
and amines is described, offering straightforward
Table 1 Condensation of glyoxylic acid, nitroalkanes and amines in
basic aqueous solution at room temperature
a
synthesis of ꢀ-nitro-ꢁ-amino acids and their N-alkyl
derivatives.
Amine
(equivalents)
Yield
(%)
Nitroalkane
t/h
Product
Multi-component reactions offer a number of advantages over
other methods since they afford rapid syntheses of often com-
plex compounds from relatively simple building blocks, fre-
NH
(10)
1
50
38
54
3
1
quently in one pot. Syntheses via multi-component couplings,
2
such as the Strecker and Ugi reactions, provide access to a wide
variety of amino acids. However, the initial products are gener-
ally protected amino acids and the methods require the use of
undesirable or exotic reagents such as cyanide or alkylboronic
acids.
NH (10)
1
2
3
3
β-Nitro amino acids have been studied as enzyme inhibitors
and as precursors in the synthesis of other classes of α-amino
4,5
acids, such as β-amino and α,β-dehydro amino acids. Some
time ago we reported the multi-step synthesis of β-nitro amino
acid derivatives through reaction of N-acyl-2-bromoglycine
MeNH (5)
2
4,5
ester derivatives with the anions of nitroalkanes. We now
report a new procedure for the preparation of β-nitro amino
acids and their N-alkyl derivatives, via a three-component con-
densation of glyoxylic acid, nitroalkanes and amines, in water
MeNH (5)
1
57
41
2
[eqn. (1)]. This offers straightforward access to amino acids,
BnNH (1)
20
2
BnNO2
BnNH (1)
2
42
2
some of which are not available using methods previously
reported.
The method involves separate addition of an aqueous
ammonia solution, or an amine, and aqueous glyoxylic acid to a
solution of a nitroalkane and potassium hydroxide in water,
with stirring at room temperature, followed by acidification
with aqueous hydrochloric acid to pH 2–4. Table 1 shows the
generality of the method in the range of β-nitro amino acids
and their N-alkyl derivatives prepared from four different nitro-
alkanes and three different amine components. The free amino
acids 1 and 2 were obtained after a short work-up whilst prod-
ucts 3–6 containing N-alkyl groups precipitated from the reac-
tion mixtures upon acidification and were isolated by filtration.
Significantly, no chromatography was necessary, with analytic-
ally pure products being obtained directly from the reaction
mixtures for products 3 and 4, after re-crystallization for 2, 5
and 6, and after a short work-up and purification for 1. Prod-
ucts 4 and 5 were isolated as ca. 1:6 and 1:2 diastereomeric
mixtures, respectively, whilst 6 was isolated as a single diaster-
eomer. Of particular significance are the N-alkyl derivatives 3–6
which are not attainable using the previously reported multi-
4,5
step methodology.
The mechanism of the three-component condensation pre-6
sumably involves the in situ formation of imine intermediates
(from glyoxylic acid and ammonia and the amines) followed by
7
Mannich-type addition of the alkyl nitronates. Grieco and co-
8
workers have shown that a similar imine undergoes a Diels–
Alder cycloaddition when methylamine, glyoxylic acid and
cyclopentadiene are mixed in aqueous media. Confirmation
that imines are intermediates in the present three-compon-
ent condensation was obtained by exploiting the chemistry of
9
Santaballa and co-workers. They showed that under basic
aqueous conditions N-chloroglycine decomposes via the corre-
sponding imine. In the present work, treatment of glycine in
base with sodium hypochlorite, to produce N-chloroglycine,
in the presence of 2-nitropropane afforded β-nitrovaline 1.
J. Chem. Soc., Perkin Trans. 1, 1999, 2659–2660
This journal is © The Royal Society of Chemistry 1999
2659

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The synthetic utility of both multi-component and aqueous
δ (CD OD–DCl, 300 MHz) 5.15 (1H, ddd, J 2, 6 and 8.5 Hz,
H 3
1,10
reactions is generally well recognized
and is now further
CHNO ), 4.62 (1H, d, J 2 Hz, CHCO ), 2.86 (3H, s, NCH ),
2
2
3
demonstrated by the synthesis of β-nitro amino acids and their
N-alkyl derivatives on a multi-gram scale. The nitro group is a
versatile functional group in synthetic organic chemistry as
exemplified by the Henry, Michael and Nef reactions. There-
fore a wide range of other amino acids should also be accessible
using this methodology.
2.40 (1H, ddq, J 8.5, 14.5 and 7.5 Hz, CHHCH ), 2.10 (1H,
3
ddq, J 6, 14.5 and 7.5 Hz, CHHCH ), 1.12 (3H, t, J 7.5 Hz,
3
CH CH ); δ (CD OD–DCl, 75.5 MHz) 167.1, 87.6, 62.8, 33.9,
2
3
C
3
11
25.3, 11.0; separate resonances were detected for the minor
isomer at δ (CD OD–DCl, 300 MHz) 2.88 (3H, s, NCH ), 1.10
H
3
3
(3H, t, J 7 Hz, CH CH ); δ (CD OD–DCl, 75.5 MHz) 167.4,
2
3
C
3
8
7.8,62.6,34.1,25.4,11.1.ForN-benzyl-2-amino-3-nitropentan-
oic acid 5: ca. 1:2 mixture of diastereomers, mp 129–131 ЊC; the
Experimental
major diastereomer had δ (CD OD–DCl, 300 MHz) 7.40–7.62
H
3
Synthesis of the ꢀ-nitro amino acids 1 and 2
(5H, m, br, Ar), 5.29 (1H, ddd, J 2.5, 6 and 8.5 Hz, CHNO ),
2
4
.63 (1H, d, J 2.5 Hz, CHCO ), 4.43 (2H, s, PhCH ), 2.36 (1H,
2
2
For the synthesis of β-nitrovaline 1, ammonia (25% in water, 75
ml, 1.1 mol) and glyoxylic acid (25% in water, 17 ml, 0.057 mol)
were added to a solution of 2-nitropropane (9.8 g, 0.11 mol)
and KOH (7.4 g, 0.13 mol) in water (140 ml). After stirring at
room temperature for 1 h, the mixture was carefully adjusted to
ddq, J 8.5, 14.5 and 7.5 Hz, CHHCH ), 2.11 (1H, ddq, J 6,
3
1
4.5 and 7.5 Hz, CHHCH ), 1.03 (3H, t, J 7.5 Hz, CH );
3
3
δ (CD OD–DCl, 75.5 MHz) 167.1, 132–130, 88.0, 61.2, 60.3,
C
3
2
5.5, 11.2; separate resonances were detected for the minor
diastereomer at δ (CD OD–DCl, 300 MHz) 5.20 (1H, ddd, J 4,
5
ddq, J 9, 15 and 7.5 Hz, CHHCH ), 2.11 (1H, ddq, J 5, 15 and
H
3
pH 1 with conc. 2 M HCl, washed with CHCl (2 × 50 ml) and
3
and 9 Hz, CHNO ), 4.51 (1H, d, J 4 Hz, CHCO ), 2.36 (1H,
2 2
freeze dried. The solid residue was suspended in dry EtOH, the
suspension was filtered and the filtrate was concentrated under
3
7
.5 Hz, CHHCH ), 0.89 (3H, t, J 7.5 Hz, CH ); δ (CD OD–
3
3
C
3
reduced pressure. Et O was added and the resulting insoluble
2
DCl, 75.5 MHz) 167.4, 87.3, 61.0, 60.0, 24.0, 11.1. For
N-benzyl-3-nitrophenylalanine 6: mp 123–125 ЊC; δ (CD OD–
DCl, 300 MHz) 7.38–7.51 (10H, m, br, 2 × Ar), 6.56 (1H, d, J 5
Hz, CHNO ), 5.03 (1H, d, J 5 Hz, CHCO ), 4.45 (1H, d, J 13
Hz, PhCHH), 4.37 (1H, d, J 13 Hz, PhCHH); δ
salts were removed by filtration. To the filtrate was added anil-
ine (5 ml) and the mixture was allowed to stand at room
temperature for 30 min. The solid was collected by filtration
H
3
2
2
and washed with 1:1 EtOH–Et O to give β-nitrovaline 1 (4.66
2
4
C
(CD
5.5 MHz) 166.9, 131.9, 131.8, 131.0, 131.0, 130.5, 130.2, 130.1,
29.7, 88.3, 61.3, 52.8. All new compounds were fully
3
OD–DCl,
g, 50%) as a white solid; mp 143–144 ЊC (lit. 145–147 ЊC);
7
1
δ (D O, 300 MHz) 4.23 (1H, s, CH), 1.68 (3H, s, CH ), 1.63
H
2
3
(
3H, s, CH ). Compound 2 was obtained using a similar pro-
3
characterized.
cedure, except that in this case concentrating the reaction mix-
ture under reduced pressure and acidifying with 2 M HCl to
approximately pH 4.5 resulted in the product precipitating from
solution. It was isolated by filtration as a white solid and
References
1
I. Ugi, J. Prakt. Chem., 1997, 339, 499.
washed with 1:5 H O–EtOH; mp 128–129.5 ЊC; δ (D O, 300
2
H
2
2 G. Dyker, Angew. Chem., Int. Ed. Engl., 1997, 36, 1700.
3 T. A. Alston, D. J. T. Porter and H. J. Bright, Acc. Chem. Res., 1983,
16, 418.
MHz) 4.14 (1H, s, CHCO ), 2.57–2.69 (1H, m), 2.25–2.37 (1H,
2
m), 2.00–2.15 (2H, m), 1.60–1.85 (4H, m); δ (D O, 75.5 MHz)
C
2
4
5
V. A. Burgess and C. J. Easton, Aust. J. Chem., 1988, 41, 1063.
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72.9, 101.5, 63.1, 40.4, 39.1, 26.9, 26.6.
5
4
1, 7809; P. A. Coghlan and C. J. Easton, Tetrahedron Lett., 1999,
Synthesis of the N-alkyl ꢀ-nitro amino acids 3–6
0, 4745.
6
7
8
A. J. Hoefnagel, H. van Bekkum and J. A. Peters, J. Org. Chem.,
992, 57, 3916.
M. Arend, B. Westermann and N. Risch, Angew. Chem., Int. Ed.,
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P. A. Grieco, S. D. Larsen and W. F. Fobare, Tetrahedron Lett., 1986,
27, 1975.
The procedure employed for the synthesis of the N-alkyl amino
acids 3–6 is illustrated by the synthesis of N-methyl-3-
nitrovaline 3. To a solution of 2-nitropropane (0.98 g, 0.011
mol) and KOH (0.74 g, 0.013 mol) in water (15 ml) was added
methylamine (33% in EtOH, 5.0 ml, 0.055 mol) and glyoxylic
acid (50% in water, 1.6 ml, 0.011 mol). After stirring at room
temperature for 2 h the mixture was carefully adjusted to pH 3
with 2 M HCl and the resultant precipitate was collected by
filtration to give N-methyl-3-nitrovaline 3 (1.06 g, 54%) as a
1
1
9 For example, see: X. L. Armesto, M. Canle L., M. V. García and
J. A. Santaballa, Chem. Soc. Rev., 1998, 27, 453.
0 P. A. Grieco, Organic Synthesis in Water, Blackie Academic &
Professional Press, London, 1998; A. Lubineau, J. Augé and
Y. Queneau, Synthesis, 1994, 741.
1
white solid; mp 146–147 ЊC; δ (d -DMSO, 300 MHz) 3.61 (1H,
H
6
11 H. H. Baer and L. Urbas, in The Chemistry of the Nitro and Nitroso
Groups. Part 2, ed. H. Feuer, Interscience Publishers, New York,
1970, p. 75.
s, CHCO ), 2.31 (3H, s, NCH ), 1.55 (3H, s, CH ), 1.51 (3H, s,
2
3
3
CH ); δ (D O, 75.5 MHz) 170.8, 90.8, 71.2, 36.6, 27.9, 24.3. For
3
C
2
N-methyl-2-amino-3-nitropentanoic acid 4: ca. 1:6 mixture of
diastereomers, mp 159–160 ЊC; the major diastereomer had
Communication 9/06223H
2
660
J. Chem. Soc., Perkin Trans. 1, 1999, 2659–2660