Direct synthesis of N-substituted, functionalized aspartic acids using alkali maleates and amines

Article abstract of DOI:10.1016/j.tetlet.2005.02.159

A practical and general one-pot synthesis of mono-N-substituted, functionalized aspartic acids has been developed. The N-substituted aspartic acids are formed directly from alkali maleates and primary amines in hot DMSO. Products from several different primary amines can be prepared chemoselectively in moderate to good yields.

Full text of DOI:10.1016/j.tetlet.2005.02.159

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 2751–2755
Direct synthesis of N-substituted, functionalized aspartic
acids using alkali maleates and amines
Peter S. Piispanen and Petri M. Pihko*
Helsinki University of Technology, Laboratory of Organic Chemistry, PO Box 6100, FIN-02015 TKK, Finland
Received 19 November 2004; revised 15 February 2005; accepted 25 February 2005
Abstract—A practical and general one-pot synthesis of mono-N-substituted, functionalized aspartic acids has been developed. The
N-substituted aspartic acids are formed directly from alkali maleates and primary amines in hot DMSO. Products from several
different primary amines can be prepared chemoselectively in moderate to good yields.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
R'
O
transition metal
activation
R'
O
RNH2
RNH2
RNH2
+
+
+
R
The synthesis of amino acids is of great importance.
Non-proteinogenic a-amino acids are important in bio-
logical, medicinal and synthetic chemical applications.1–7
Furthermore, b-amino acids8 and their derivatives are
common in a large number of natural products, anti-
biotics9 and chiral auxiliaries.10
N
H
takes place
readily
OH
OH
R
N
H
O
O
?
The direct addition of amines to unactivated alkenes is
very difficult to accomplish, and such addition reactions
always have to proceed via activation of the amine or the
alkene.11–13 Although the direct amination of a,b-unsat-
urated carboxylic acids can readily be effected,14 amina-
tion of unsaturated di-carboxylic acids, such as maleic
and fumaric acid, is most successfully performed by the
aspartase enzyme class.15 No man-made catalyst for this
transformation has been discovered, and no general one-
step method for the synthesis of N-substituted function-
alized aspartic acids has been reported (see Scheme 1).
OH
OH
OH
OH
R
only isolated
cases
N
H
O
O
fumaric or maleic acid
Aspartic acids
Scheme 1. Typical methods for amination of alkenes.
reported one-step synthetic approaches proceed either
via activation of the double bond by use of stoichiome-
tric amounts of lanthanides21,22 or via maleate salts in
aqueous media. In nearly all cases, these methods are
limited to functionalized amines capable of chelation to
the lanthanide ion (i.e., hydroxyl- or carboxyl-containing
amines23–25). The only reported example of an uncata-
lyzed addition reaction is the production of N-methyl
aspartic acid in ethanol.26 Scattered examples of the
addition of amines to monohydrogen maleate in aqueous
solution have been reported, including the addition of
benzylamine18,27,28 and long, straight-chain alkyl
amines.29 However, no general method for the Michael
addition of a wide array of primary amines is available.
Known multi-step, indirect methods for this transform-
ation proceed via activating protecting groups. These
include derivatization of the acid as its mono-16 or di-
ester17 or monoamide.18–20 While the Michael addition
to these protected compounds proceeds smoothly, two
additional synthetic steps are required to install and
remove the activating/protecting groups. Previously
Keywords: Aspartic acid derivatives; Conjugate addition; Chemoselec-
tivity; Lithium, sodium.
*
In this communication, we present a novel and facile
one-step method for the preparation of a number of
Corresponding author. Tel.: +358 9 451 2536; fax: +358 9 451
2538; e-mail: petri.pihko@tkk.fi
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.02.159

2752
P. S. Piispanen, P. M. Pihko / Tetrahedron Letters 46 (2005) 2751–2755
works well for the chemoselective preparation of a
O
O
O
RNH2
potentially large number of previously inaccessible N-
alkyl/aryl aspartic acids in one synthetic step, followed
by simple purification.
OH
O
OH
OH
R
M
DMSO, 125 °C
thenpH 2.8
N
H
O
Monoalkali maleate 1
Aspartic acids 2-7
In all reactions, only trace amounts of amides were
formed. Thus, the carbonyl groups of monolithium
maleate are sufficiently protected towards nucleophiles
to only allow for a Michael-like addition to the double
bond of the maleate. The conjugate addition reaction
proceeds most effectively with monoalkali maleates.
Isomerization to fumarate takes place rapidly especially
with disodium maleate.32 However, with n-hexylamine,
the rate of the Michael addition was sufficiently rapid
to allow even dilithium maleate to give a good yield of
the product.
Scheme 2. General reaction scheme.
alkyl as well as functionalized N-substituted aspartic
acids from inexpensive maleic anhydride and amines
via the simple monolithium salt of maleic acid (Scheme
2).
Our initial experiments in aqueous media gave mixed re-
sults, with only benzylamine giving fair reaction rates.30
We discovered, however that the Michael addition of
primary amines to monolithium maleate takes place
smoothly in hot DMSO (125 ꢁC). Other organic solvents
gave poorer yields of the desired product and gave more
by-products such as fumarate and aminolyzed solvent.31
Regarding the mechanism of the reaction, we can only
suggest that the reactive species is a charged and perhaps
structurally distorted maleic acid alkali salt. Complexes
of maleate with other metal ions are known to possess a
distorted maleate structure.33 Such a distortion might
activate the maleate towards addition and/or isomeriz-
ation. The reaction appears to be sensitive to steric
effects, with straight-chain alkyl amines generally afford-
ing the highest yields.
Both monolithium and monosodium salts readily affor-
ded the products in good yields (Table 1). However,
increasing the size of the alkali metal cation also in-
creased the rates of side reactions such as isomerization
and polymerization. Reactions with potassium salts
always gave increased amounts of decomposition and
side reactions.
Typically, the only observed side reaction that takes
place in the reactions reported is the isomerization of
maleate to fumarate. Although the conditions are rela-
tively harsh, they are justified in view of the difficulty
of the reaction. Importantly, non-polar, lipophilic
amines of low water solubility, such as n-octylamine,
also afford the aspartic acid product under our non-
aqueous conditions. Non-dry or recycled solvents can
readily be used. The reaction gives access to racemic
material at a very low cost and the procedure is a useful
alternative in cases where direct synthesis of the amino
acid is required.
Simple primary alkylamines readily underwent the reac-
tion, as did benzylamine, albeit much more slowly.
Remarkably, 2-aminoethanol also gave a clean reaction
with no O-alkylation observed (entry 6). However, poor
conversions were observed with aromatic amines as well
as more hindered amino alcohols (see footnote a, Table
1).
The reaction works only with the maleate salt, but not
with uncharged maleic acid. Under the same reaction
conditions maleic acid also isomerizes to unreactive
fumaric acid. The reaction proceeds best in highly polar
solvents, but water, or even amines with several hydr-
oxyl groups, inhibit the reaction and reduce the product
yield. Use of a large excess of maleate also reduces the
rate of reaction. Gradual addition of maleate to a solu-
tion of the amine increased the yield considerably.
Despite these limitations, the method described here
In summary, we have developed an efficient, general
protocol for the addition of both unfunctionalized and
functionalized primary amines to monoalkali maleates.
The reaction affords various N-substituted aspartic
acids, including some previously unreported hydropho-
bic compounds, in moderate to high yields and uses a
very simple purification method and inexpensive starting
materials. No metal catalysts are required.
Table 1. Synthesis of N-substituted aspartic acidsa produced via Scheme 2
Entry Product
R
Yield (%); Method A (M = Li)b Yield (%); Method B (M = Li)c Yield (%); Method A (M = Na)
1
2
3
4
5
6
2
3
4
5
6
7
n-Hexyl
n-Octyl
59d
—
30
—
19
35
85
54
36
62
62
76
85
65
39
—
—
—
Cyclohexyl
Cyclohexanemethyl
Benzyl
2-Hydroxyethyl
a The following amines were also tested with Method A: 3-methylbutylamine (28% conversion); L-tert-leucinol (24% conversion); p-anisidine
(11% conversion); L-phenylalaninol (23% conversion).
b Method A: all reactants were added together in the beginning.
c Method B: the monoalkali maleate was added in three portions over the course of the reaction.
d The dilithium salt and the monopotassium maleates afforded 2 in 77% and 53% yields, respectively.

P. S. Piispanen, P. M. Pihko / Tetrahedron Letters 46 (2005) 2751–2755
2753
2. General procedure for the preparation of N-alkyl/aryl
aspartic acids
tional crops were obtained by concentration of the
mother liquor.
Method A: To a mixture of maleic anhydride (1.00 g;
10.20 mmol; 200 mol %) in DMSO (15 mL) was added
the alkali metal hydroxide (e.g., LiOH · H2O: 0.490 g;
11.67 mmol; 228 mol %), and the mixture was heated
to 50 ꢁC with stirring for 20 min to allow the alkali male-
ate to form. The temperature was then raised to 125 ꢁC.
The reaction flask was left open for 10 min to allow water
to evaporate. The amine (5.10 mmol, 100 mol %) was
then added dropwise to the now wine-red mixture. The
mixture was stirred and heated at 125 ꢁC for up to 72 h
and was then worked up as described below.
3.1. N-Hexyl aspartic acid (2)
Yield: 59% (Method A), 85% (Method B or Method A/
Na); colourless crystals; mp 167.9–168.8 ꢁC (from water/
ethanol), lit.16 mp 168 ꢁC; IR (KBr) 3424, 2960, 2932,
2860, 1711, 1643, 1592, 1405, 767, 738 cmÀ1; H NMR
1
(400 MHz, D2O) d 3.96 (dd, 1H, J = 5, 7 Hz), 3.11 (t,
2H, J = 6 Hz), 3.04 (dd, 1H, J = 5, 18 Hz), 2.98 (dd,
1H, J = 7, 18 Hz), 1.71 (qn, 2H, J = 8 Hz), 1.30–1.40
(m, 6H), 0.87 (t, 3H, J = 7 Hz); 13C NMR (400 MHz,
D2O) d 13.1, 21.6, 25.2, 25.3, 30.3, 33.8, 47.1, 57.7,
172.1, 174.0 (neutral compound); 13C NMR
(400 MHz, D2O) d 13.9, 22.4, 25.9, 26.3, 31.0, 36.4,
47.3, 60.1, 174.3, 178.1 (monolithium salt).
Method B is otherwise identical to Method A with the
exception that equimolar amounts of monolithium
maleate (prepared as in Method A from 10.20 mmol
of maleic anhydride and 11.67 mmol LiOH · H2O) and
amine (10.20 mmol) were initially used. Two further por-
tions of monolithium maleate were added as a suspen-
sion in DMSO (prepared as in Method A from maleic
anhydride (5.10 mmol), LiOH · H2O 5.84 mmol and
DMSO (6 mL)) after 24 h and 48 h. The mixture was
allowed to react for a further 48–72 h after the last maleate
addition, and was then worked up as described below.
3.2. N-Octyl aspartic acid (3)
Yield: 54% (Method B); 65% (Method A/Na); white
crystals; mp 159.7–160.8 ꢁC (from water/ethanol); IR
(KBr) 3430, 2925, 2860, 1643, 720 cmÀ1 1H NMR
;
(400 MHz, D2O) d 3.96 (dd, 1H, J = 5, 6 Hz), 3.12
(m, 2H), 3.03 (dd, 1H, J = 5, 18 Hz), 2.97 (dd, 1H,
J = 6, 18 Hz); 1.73 (qn, 2H, J = 7 Hz), 1.41–1.28
(m, 10H), 0.87 (t, 3H, J = 7 Hz); 13C NMR (400 MHz,
D2O) d 174.3, 172.2, 57.8, 47.1, 34.0, 30.9, 28.1, 28.0,
25.6, 25.4, 21.9, 13.3 (neutral compound); 13C NMR
(400 MHz, D2O) d 178.1, 174.1, 60.0, 47.3, 36.2, 31.7,
28.8 (2C), 26.3 (2C), 22.6, 14.1 (monolithium salt);
HRMS (ESIÀ) calcd for C12H22NO4 (MÀH):
244.1549, found: 244.1537.
3. Purification of N-alkyl/aryl aspartic acids
The reaction mixture was allowed to cool to rt. Acetone
(Method A: 40–80 mL; Method B: 80–160 mL; higher
amounts were used with more polar products) was
added to the reaction mixture. The solution was cooled
to +4 ꢁC for 1–2 h and the precipitated crude product
was filtered off and washed with further acetone (10–
15 mL) and Et2O (10 mL) to afford a crude mixture con-
sisting of the product and alkali fumarate. With lipo-
philic compounds such as 3 and 6, higher yields could
be obtained as follows: 10 M NaOH (1.0 mL, 10 mmol,
100 mol %) was added to the reaction mixture at 50 ꢁC
and the mixture was heated to 120 ꢁC for 10 min to
allow all the water to evaporate. The reaction mixture
was then worked up exactly as above.
3.3. N-Cyclohexyl aspartic acid (4)
Yield: 30% (Method A), 36% (Method B), 39% (Method
A/Na); white crystalline powder; mp 216.3–217.4 ꢁC
(from water/ethanol), lit.16 mp 216 ꢁC; IR (KBr) 3424,
2927, 2856, 1637, 1598, 1411, 726 cmÀ1 1H NMR
;
(400 MHz, D2O) d 3.92 (dd, 1H, J = 4, 9 Hz), 3.14
(m, 1H), 2.79 (dd, 1H, J = 4, 17 Hz), 2.63 (dd, 1H,
J = 9, 17 Hz), 2.07 (m, 2H), 1.80 (m, 2H), 1.64 (m,
1H), 1.18–1.51 (m, 5H) (neutral compound); 13C
NMR (400 MHz, D2O) d 177.3, 173.6, 57.1, 56.9, 36.0,
29.6, 28.8, 24.4, 23.74, 23.67; 13C NMR (400 MHz,
D2O) d 23.7, 23.8, 24.4, 28.5, 29.5, 36.0, 56.8, 57.0,
173.7, 177.4 (monolithium salt).
Analytically pure N-substituted aspartic acids were iso-
lated as follows. The salt mixture was dissolved in
H2O (2–5 mL); if necessary the solution was heated to
60 ꢁC. The pH of the solution was adjusted to 2.77 by
the addition of 4 M HCl. The solution was cooled to
+4 ꢁC for 1–2 h. The precipitated fumaric acid was fil-
tered off and the solution was concentrated to a volume
of 2 mL. Ethanol (8 mL) was added dropwise to the
mother liquor and the resulting solution was cooled to
+4 ꢁC to allow crystals of the pure product to form.
The crystals of the neutral product were isolated by fil-
tration and dried in vacuo. The recrystallization proce-
dure was repeated three more times, adding further
ethanol (8–20 mL each time) to obtain additional crops
of the pure product.
3.4. N-(Cyclohexanemethyl) aspartic acid (5)
Yield: 62% (Method B); white crystalline powder; mp
209.8–210.8 ꢁC (from water/ethanol); lit.34 mp 194–
195 ꢁC; IR (KBr) 3424, 2924, 2856, 1648, 1595, 1411,
1
738 cmÀ1; H NMR (400 MHz, D2O) d 3.76 (dd, 1H,
J = 4, 9 Hz), 2.97 (dd, 1H, J = 6, 12 Hz), 2.87 (dd, 1H,
J = 7, 12 Hz), 2.79 (dd, 1H, J = 4, 18 Hz), 2.65 (dd,
1H, J = 9, 18 Hz), 1.75 (m, 5H), 1.65 (m, 1H,), 1.13–
1.32 (m, 3H), 1.03 (m, 2H); 13C NMR (400 MHz,
D2O) d 24.9, 24.9, 25.5, 29.6, 29.7, 34.6, 35.1, 52.4,
59.7, 173.1, 177.5 (neutral compound); 13C NMR
(400 MHz, D2O) d 25.9, 26.0, 26.5, 30.9, 31.0, 36.5,
39.2, 53.9, 61.4, 175.3, 179.5 (monolithium salt); HRMS
Very lipophilic compounds such as 3 and 6 were prefer-
entially recrystallized from 5:1 water/ethanol and addi-

2754
P. S. Piispanen, P. M. Pihko / Tetrahedron Letters 46 (2005) 2751–2755
also: (b) Bartoli, G.; Cimarelli, C.; Marcantoni, E.;
Palmieri, G.; Petrini, M. J. Org. Chem. 1994, 59, 5328–
5335.
(ESI+) calcd for C11H20NO4 (M+H): 230.1392, found:
230.1398.
9. Hashiguchi, S.; Kawada, A.; Natsugari, H. J. Chem. Soc.,
Perkin Trans. 1 1991, 2435–2444.
3.5. N-Benzyl aspartic acid (6)
10. Senanayake, C. H.; Fang, K.; Grover, P.; Bakale, R. P.;
Vandenbassche, C. P.; Wald, S. A. Tetrahedron Lett. 1999,
40, 819–822.
Yield: 19% (Method A); Yield: 62% (Method B); white
crystals; mp 193.7–194.6 ꢁC (from water/ethanol); lit.18
mp 195 ꢁC; IR (KBr) 3430, 3070, 2992, 2932, 2860,
11. Roundhill, D. M. Chem. Rev. 1992, 92, 1–27.
12. Muller, T. M.; Beller, M. Chem. Rev. 1998, 98, 675–703.
1721, 1633, 1578, 1409 cmÀ1 1H NMR (400 MHz,
;
¨
D2O) d 7.18 (m, 5H), 4.05 (d, 1H, J = 13 Hz), 3.99
(d, 1H, J = 13 Hz), 3.65 (dd, 1H, J = 5, 7 Hz), 2.69
(dd, 1H, J = 5, 18 Hz), 2.64 (dd, 1H, J = 7, 18 Hz); 13C
NMR (400 MHz, D2O) d 174.0, 171.9, 134.2, 130.4,
129.9, 129.7, 129.3 (2C), 57.1, 50.5, 34.1 (neutral com-
pound); 13C NMR (400 MHz, D2O) d 177.3, 173.1,
135.3, 131.0, 129.7, 129.6, 129.3, 120.9, 58.7, 49.9, 35.6
(monolithium salt).
13. Johannsen, M.; Jørgensen, K. A. Chem. Rev. 1998, 98,
1689–1708.
14. For examples, see: (a) Wabnitz, T.; Spencer, J. B. Org.
Lett. 2003, 5, 2141–2144; (b) Zilkha, A.; Rivlin, J. J. Org.
Chem. 1958, 23, 96–98.
15. For a review on aspartases, see: Viola, R. E. Adv.
Enzymol. Relat. Areas Mol. Biol. 2000, 74, 295–341.
16. Zilkha, A.; Bachi, M. D. J. Org. Chem. 1959, 24, 1096–
1098, See also Ref. 34.
17. Pfau, M. Bull. Soc. Chim. Fr. 1967, 4, 1117–1125.
18. Frankel, M.; Liwschitz, Y.; Amiel, Y. J. Am. Chem. Soc.
1953, 75, 330–332.
3.6. N-(2-Hydroxyethyl) aspartic acid (7)
19. Liwschitz, A.; Singerman, A. J. Chem. Soc. C 1966, 1200–
1202.
20. Gorelov, I. P.; Samsonov, A. P.; NikolÕskii, V. M.; Babich,
V. A.; Svetogorov, Yu. E.; Smirnova, T. I.; Malakhaev, E.
D.; Kozlov, Yu. M.; Kapustnikov, A. I. J. Gen. Chem.
USSR (Engl. Transl.) 1979, 49, 573.
21. Aksela, R.; Renvall, I.; Paren, A. PCT Int. Appl. WO
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22. Bartoli, G.; Bosco, M.; Marcantoni, E.; Petrini, M.;
Sambri, L.; Torregiani, E. J. Org. Chem. 2001, 66, 9052–
9055.
Yield: 35% (Method A), 76% (Method B); off-white
crystals; mp > 280 ꢁC dec (from water/ethanol; phase
transition occurs at 230–235 ꢁC); lit.35 mp 231–233 ꢁC;
IR (KBr) 3420, 3244, 2997, 2930, 2878, 1642, 1413,
1
719 cmÀ1; H NMR (400 MHz, D2O) d 3.88 (m, 2H),
3.86 (m, 1H), 3.29 (m, 1H), 3.19 (m, 1H), 2.84
(dd, 1H, J = 4, 18 Hz), 2.71 (dd, 1H, J = 9, 18 Hz); 13C
NMR (400 MHz, D2O) d 35.3, 48.2, 56.8, 59.4, 173.0,
177.3 (neutral compound); 13C NMR (400 MHz, D2O)
d 36.2, 48.5, 57.5, 59.9, 174.2, 178.0 (monolithium salt).
23. Hoffmann, U.; Jacobi, B. U.S. Patent, 1935, 2.017.537.
Chem. Abstr. 1935, 29, 60908.
24. van Westrenen, J.; van Haveren, J.; Alblas, F. J.;
Hoefnagel, M. A.; Peters, J. A.; van Bekkum, H. Recl.
Trav. Chim. Pays-Bas 1990, 109, 474–478.
Acknowledgements
Financial support from Kemira Ltd is gratefully
acknowledged. We thank Drs. Jari Koivisto and Juho
Helaja (both at HUT) for NMR assistance.
´
´
25. Maderova, J.; Pavelcık, F.; Marek, J. Acta Crystallogr.,
Sect. E: Struct. Rep. Online 2002, E58, 469–470.
26. Madsen, D.; Pattison, P. Acta Crystallogr., Sect. C: Cryst.
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27. Reppe, W.; Ufer, H. German Patent DE 697802, 1940.
Chem. Abstr. 1941, 35, 40245.
Supplementary data
´
´
28. Arsenijevic, L.; Arsenijevic, V.; Damanski, A. F. C.R.
Acad. Sc. Fr. 1963, 265, 4039–4040.
Copies of H and 13C NMR spectra of all products are
1
29. Additions of long, straight-chain alkylamines have been
reported in the patent literature. For an example, see:
Yamamoto, A.; Kobayashi, Y.; Mori, Y. Japanese Patent,
2000, 2000.136.172. Chem. Abstr. 2000, 132, 336131.
30. Similar observations have been made earlier by Liwschitz
and Irsay (quoted by Zilcha and Bachi, see Footnote 5 in
Ref. 16). They note that ‘‘. . . reaction of other amines with
maleic acid either in aqueous solution or otherwise did not
give the required N-alkyl-aspartic acid but led to the
formation of amine salts of maleic acid or to unidentified
products.’’
31. The solvents screened included DMF, tetrabutylurea,
tetramethylurea, tri-n-butylphosphate, N-methylpyrrol-
idone and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimid-
inone (DMPU).
32. Isomerization of a 0.1 M solution of maleic acid into
fumaric acid was attempted at 125 ꢁC in DMSO for 72 h.
Less than 1% isomerization could be detected during this
included. Supplementary data associated with this arti-
cle can be found, in the online version, at doi:10.1016/
j.tetlet.2005.02.159.
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A
control experiment with added NaBr
(200 mol %) gave identical results. A mixture of maleic
acid (3 mmol), n-hexylamine (1 mmol) and NaBr (6 mmol)
in DMSO did not give any reaction even at +125 ꢁC except
for the slow formation of n-hexylmaleamide.

P. S. Piispanen, P. M. Pihko / Tetrahedron Letters 46 (2005) 2751–2755
2755
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ˇ
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