Rapid and efficient microwave-assisted synthesis of N-carbamoyl-L-amino acids

Article abstract of DOI:10.1080/00397910701317068

A rapid and efficient method for the synthesis of N-carbamoyl-L-amino acids is reported. The procedure, involving the reaction between urea and α-amino acids sodium salts, was performed under microwave conditions using an unmodified domestic microwave oven. A careful study of the operative conditions indicated proline (1d) as the less reactive substrate and phenylglycine (1e) as the more reactive one among all the α-amino acids tested. Substitution of urea with potassium cyanate produced a low conversion into the corresponding N-carbamoyl derivative, and a possible explanation of this result is reported. Copyright Taylor & Francis Group, LLC.

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Rapid and Efficient Microwave‐Assisted
Synthesis of N‐Carbamoyl‐L‐amino Acids
a
a
a
Giancarlo Verardo , Paola Geatti & Paolo Strazzolini
a
Department of Chemical Sciences and Technologies, University of Udine,
Udine, Italy
Published online: 30 Jun 2007.
To cite this article: Giancarlo Verardo , Paola Geatti & Paolo Strazzolini (2007) Rapid and Efficient
Microwave‐Assisted Synthesis of N‐Carbamoyl‐L‐amino Acids, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 37:11, 1833-1844, DOI:
10.1080/00397910701317068
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Synthetic Communications , 37: 1833–1844, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701317068
Rapid and Efficient Microwave-Assisted
Synthesis of N-Carbamoyl-L-amino Acids
Giancarlo Verardo, Paola Geatti, and Paolo Strazzolini
Department of Chemical Sciences and Technologies, University of
Udine, Udine, Italy
Abstract: A rapid and efficient method for the synthesis of N-carbamoyl-L-amino acids
is reported. The procedure, involving the reaction between urea and a-amino acids
sodium salts, was performed under microwave conditions using an unmodified
domestic microwave oven. A careful study of the operative conditions indicated
proline (1d) as the less reactive substrate and phenylglycine (1e) as the more
reactive one among all the a-amino acids tested. Substitution of urea with potassium
cyanate produced a low conversion into the corresponding N-carbamoyl derivative,
and a possible explanation of this result is reported.
Keywords: amino acids, N-carbamoyl derivatives, microwave, potassium cyanate, urea
N-Carbamoyl-L-amino acids are important derivatives involved in antimicro-
[
bial therapy, used as such or in the role of side chains for different synthetic
1]
[
antibacterial agents, as well as in the prevention of hyperammonemia;
2]
[3]
[4]
moreover, they are useful intermediates in heterocyclic
[
and peptide
5]
chemistry.
Among all the reported procedures thus far, the most common source of
these derivatives appears to be the enzymatic hydrolysis of 5-substituted
[
6]
hydantoins. Because of the specificity of the enzyme, in connection with
the spontaneous racemization of the hydantoins observed under the reaction
conditions (pH . 8), this method allows for conversion of the racemic
starting materials into the enantiomerically pure N-carbamoyl D- or L-amino
Received October 19, 2006
Address correspondence to Giancarlo Verardo, Dipartimento di Scienze e Tecno-
logie Chimiche, Universit a` degli Studi di Udine, Via del Cotonificio 108, 33100
Udine, Italy. E-mail: giancarlo.verardo@uniud.it
1
833

1
834
G. Verardo, P. Geatti, and P. Strazzolini
acids. However, the process requires long reaction times (from 10 to 40 h) and
the availability of a suitable enzyme. In this context, of particular synthetic
value is the reaction of a-amino acids with sodium or potassium
[
2e,2g,2h,4c,7]
cyanate.
The protocol is very simple, but the reaction efficiency
is significantly dependent either on pH or temperature (10 h at 40–508C and
[
7b]
a pH range of 7–8; 70 h at 508C and pH 9.4).
attention has been paid so far to the strightforward reaction of a-amino
On the other hand, little
[
8]
acids with urea, most likely because of the lower yields obtained when
compared with the two previously cited methods, the high reaction temperatures
(
100–1708C), and the long reaction times (from 4 to 10 h) required.
Recently, microwave (MW) irradiation to effect organic reactions
has been widely used by organic chemists, and remarkable reduction in
reaction times, clean conditions, and better yields have been reported in
[
9]
MW-induced reactions.
Taking into account these reports, as well as our interest in amino acid
[
10]
derivatives,
a-amino acids and urea to give the corresponding N-carbamoyl derivatives
3). The simple and convenient synthesis of 3 here reported involves the
we describe herein the MW-enhanced reaction between
(
reaction of the sodium salt of the appropriate a-amino acid 1 with urea (1.7
equivalents) in water (Scheme 1, Table 1), carried out in an unmodified
domestic microwave oven at 1000 W in a beaker of fairly large size (50 mL
using 0.5–1.0 g of 1). An additional beaker (500 mL) filled with water was
placed close to the first one to serve as a heat sink, providing a finer control
on the amount of MW energy input transmitted to the system. After few
minutes, the reaction mixture was cooled to 08C, and 1.0 equivalent of 6 M
HCl was added to precipitate 3, which was finally washed with water to
eliminate excess urea and NaCl.
The amount of water employed as the solvent in the reaction has to be as
2
1
.
small as possible (0.3 mL mmol 1), because its only role is to dissolve and
homogenize the salt 1, obtained from the neutralization of the a-amino acid
with 1 equivalent of sodium hydroxide, and urea. Indeed, after 1 min of
irradiation at 1000 W, the water was completely distilled off, and the
reaction proceeded in the melt state. Moreover, when the reaction of 1b
with urea was carried out (MW, 1000 W) in a more diluted system
2
1
.
1.0 mL mmol 1), after 10 min, the observed conversion proved to be
(
incomplete, and the C NMR spectrum of the intact reaction mixture after
1
3
Scheme 1.

N-Carbamoyl-L-amino Acid Synthesis
Table 1. Identity of compounds 1–3
1835
Compounds 1–3
R
a
b
c
d
e
f
CH3
(CH
(CH
3
)
)
2
CH
3
CHCH
2 2
Proline
C H
6
6
5
5
C
H
CH
2
g
h
i
CH
1H-indole-3-CH2
4-HO-C CH
HOOCCH CH
3 2 2
SCH CH
6
H
4
2
j
2
2
dilution with D O showed the presence of a mixture of 2b and starting 1b in a
2
ratio 3:1. Therefore, to solubilize tyrosine (1i) and keep the amount of water as
low as possible, 2 equivalents of sodium hydroxide were used; as a conse-
quence, at the end of the reaction, 2 equivalents of 6 M HCl were necessary
to precipitate 3i.
To optimize the reaction time required to achieve a complete conversion
of 1 into 2, the intact reaction mixture was monitored at regular times (2 min)
1
by C NMR spectroscopy after dilution with D O. This study evidenced that
3
2
the reaction was complete within 4 min, with the exception of proline (1d),
which required 7 min. Phenylglycine (1e) proved to be the more reactive
substrate, giving a complete conversion into 2e after 2 min.
Because N-carbamoyl-L-glutamic acid (3j) proved to be very soluble in
water, excess urea was eliminated by washing the N-carbamoyl-L-glutamic
acid disodium salt (2j) obtained after the MW irradiation with MeOH,
followed by treatment with concentrated HCl, giving the corresponding acid
3
NaCl. When the procedure was repeated with L-aspartic acid (1k),
j, which was finally filtered and washed with little water to eliminate
1
L-glutamine (1l), and L-lysine (1m), the C NMR analysis of the intact
3
reaction mixture after dilution with D O showed the complete conversion
2
into the corresponding N-carbamoyl derivatives 2k–l, but unfortunately in
these three instances we were unable to obtain pure 3k–m because of the
unexpected high solubility in water and also MeOH of the corresponding
sodium salts (2k–m).
Finally, we have attempted to extend the method of MW irradiation to the
preparation of 3 using potassium cyanate instead of urea, but with poor results.
In fact, all of the tested amino acids 1 showed a low conversion into 2
(20–30%, using the conditions described previously, 1000 W, 4 min), as
evidenced by C NMR analysis of the intact reaction mixture after dilution
1
3
with D O. On the other hand, better results (50% conversion into 2 after
2

1
836
G. Verardo, P. Geatti, and P. Strazzolini
2
5 min) have been obtained using 750 W and more water (5 mL mmol 1),
1
.
1
pointing out that the reaction with potassium cyanate occurred in solution and
indicating that when water was completely distilled off (5–7 min), the process
did not proceed to completion in the solid residue. In this context, we observed
that it is difficult to standardize the correct amount of water to be used, being
correlated to the type and amount of the substrate 1 as well as to the size of the
reaction vessel employed.
The results obtained accompanied by some relevant properties of 3 are
reported in Table 2. Data pertinent to the synthesized N-carbamoyl-L-amino
acids 3 are collected in Table 3.
In conclusion, we describe here a fast, simple, and cheap MW-induced
protocol for the preparation of N-carbamoyl-L-amino acids, which is useful
as an alternative to the currently available procedures.
EXPERIMENTAL
Materials
All the reactions were carried out in an unmodified domestic Bauknecht
MCID 1125 microwave oven at 1000 W placed in a hood. All chemicals
were commercial grade (Aldrich, Fluka) and were used without further puri-
fication. Direct inlet mass spectra (DI-MS) have been obtained with a Fisons
TRIO 2000 gas chromatograph–mass spectrometer, working in the positive
ion electron impact mode (70 eV; 120–2008C), and were recorded in the
range 35–450 u. IR spectra were obtained with a Bruker Vector 22
Table 2. Yields and some properties of N-carbamoyl-L-amino acids 3
a
b
[
20]
Product
Yield (%)
Mp (8C) [Lit.]
[a]
D
(c, MeOH)
[
[
[
4c]
4c]
7b]
3
3
3
3
3
3
3
3
3
3
a
b
c
d
e
f
75
90
92
78
92
94
80
90
82
65
177 [178–179]
200 [200–201]
217 [216–218]
203
þ4.0 (1.0)
þ18.0 (1.0)
26.0 (0.5)
253.8 (0.7)
[
[
4c]
4c]
194 [195–196]
193 [192–193]
186
þ140.0 (1.0)
þ33.3 (1.0)
þ2.3 (1.0)
þ18.3 (1.0)
25.4 (1.3)
þ4.2 (2.0)
g
h
i
198
218 dec [218]
[8f]
151 [150]
c
[
8f]
j
a
Satisfactory microanalyses obtained: C + 0.12, H + 0.12, N + 0.14.
Yields refer to pure isolated products.
Solvent: 0.25 M NaOH.
b
c

Table 3. Spectroscopic data of N-carbamoyl-L-amino acids 3
2
1
)
1
13
Product
IR (KBr) (cm
H NMR d, J (Hz)
C NMR d
MS m/z (%)
þ
3
a
3650–3000, 1680, 1635,
1.19 (d, 3H, J ¼ 7.1, CH
3
),
18.5, 48.3,
158.6, 176.5
132 (M , 1), 79 (8), 87 (55), 44 (100),
43 (17), 42 (17)
a
ꢀ
1
1
5
572, 1453, 1408, 1305,
190, 1065, 1010, 598,
63
3.90–4.20 (m, 1H, CH), 5.63
(br s, 2H, NH ), 6.34 (br d, 1H,
2
J ¼ 6.8, NH), 12.40 (br s, 1H,
a
COOH)
0.85 [app t, 6 H, J ¼ 6.7,
þ
3
b
3454, 3300, 1685, 1635,
17.6, 19.1, 30.2,
57.4, 158.7,
160 (M , 1), 143 (1), 142 (1), 118 (13),
1
1
560, 1309, 1286, 1176,
164, 1012, 721
CH(CH ) ], 1.85–2.10 [m, 1
3
115 (100), 101 (21), 100 (81), 74
(28), 72 (56), 57 (29), 56 (23), 55
(33), 44 (33), 43 (20), 41 (16)
2
a
H, CH(CH
J ¼ 8.1, 5.1, CH), 5.49 (br s,
H, NH ), 6.23 (br d, 1 H,
3
)
2
ꢀ
], 3.99 (dd, 1 H,
174.0
2
2
J ¼ 8.1, NH), 12.40 (br s, 1 H,
a
COOH)
0.85 and 0.88 [2 d, 6 H, J ¼ 5.4,
þ
3c
3460, 3355, 3305, 2958,
21.6, 22.8, 24.3,
41.1, 50.9,
174 (M , 1), 121 (2), 129 (100), 118
2
1
925, 1685, 1635, 1574,
320, 1262, 1173, 716
CH(CH
H, CH ), 1.50–1.80 (m, 1 H,
3
)
2
], 1.30–1.50 (m, 2
(30), 100 (46), 86 (86), 74 (37), 57
(20), 44 (84), 43 (57), 42 (17), 41
(25)
a
2
158.6, 175.2
CH(CH ) ], 3.90–4.18 (m, 1
2
3
ꢀ
H, CH), 5.58 (br s, 2 h, NH ),
2
6
1
.25 (br d, 1 H, J ¼ 8.3, NH),
a
2.30 (br s, 1 H, COOH)
(continued)

Table 3. Continued
Product IR (KBr) (cm
3420, 3341, 3230, 1688,
2
1
)
1
13
H NMR d, J (Hz)
C NMR d
MS m/z (%)
ꢀ
þ
3d
1.65–2.30 [m, 4 H, CH(CH
3.10–3.50 (m, 2 H, NCH
2
)
2
],
24.1, 29.3, 46.0,
58.5, 157.5,
174.4
158 (M , 2), 140 (1), 129 (1), 114 (47),
113 (36), 86 (34), 70 (100), 63 (19),
44 (21), 43 (46), 42 (15), 41 (24)
1
1
658, 1545, 1458, 1313,
300, 1077
2
),
a
4.16 (dd, 1 H, J ¼ 8.2, 2.9,
ꢀ
2
CH), 5.85 (br s, 2 H, NH ),
a
1
4.74 (s, 1 H, CH), 6.95–7.25
0.57 (br s, 1 H, COOH)
ꢀ
þ
3
e
f
3461, 3356, 3316, 1687,
62.6, 129.5,
130.4, 131.5,
142.0, 162.9,
194 (M , 1), 176 (25), 151 (13), 150
b
1
1
630, 1550, 1308, 1270,
147, 725, 695
(m, 5 H, Harom
)
(9), 149 (23), 133 (8), 106 (100),
105 (39), 104 (67), 79 (32), 78 (12),
77 (32), 51 (12), 44 (9)
b
180.1
37.8, 54.0,
þ
3
3600–3000, 1695, 1635,
2.87 and 3.03 (AB of ABX, 2 H,
J ¼ 13.8, 7.9, 5.3, CH
208 (M , 1), 191 (2), 190 (3), 148 (27),
147 (12), 120 (18), 91 (100), 74
(23), 65 (12), 44 (21), 43 (13)
1
7
560, 1302, 1258, 1160,
13, 693
2
),
126.3, 128.1,
129.3, 137.7a,
158.4, 174.1
ꢀ
4.25–4.45 (m, 1 H, CH), 5.66
(
br s, 2 H, NH ), 6.27 (br d, 1
2
H, J ¼ 8.2, NH), 7.10–7.35
m, 5 H, Haarom), 11.45 (br s, 1
H, COOH)
1.65–2.10 (m, 2 H, CHCH
2.03 (s, 3 H, CH ), 2.46 (t, 2 H,
), 4.00–4.25
(
ꢀ
þ
3g
3600–3000, 1687, 1630,
2
),
14.6, 29.6, 31.8,
51.6, 158.5,
192 (M , 8), 175 (11), 174 (13), 129
1
1
560, 1307, 1293, 1195,
000, 728, 603, 478
3
(15), 118 (63), 113 (24), 100 (100),
88 (20), 75 (36), 61 (67), 56 (49), 44
(32), 43 (14)
a
J ¼ 7.6, SCH
2
174.2
ꢀ
(
m, 1 H, CH), 5.61 (br s, 2 H,
NH
1
2
), 6.39 (br d, 1 H, J ¼ 8.2),
a
1.32 (br s, 1 H, COOH)

þ
3h
3600–2700, 1700, 1647,
3.03 and 3.15 (AB of ABX, 2 H,
J ¼ 14.6, 6.7, 5.1, CH
28.1, 53.6,
247 (M , 1), 130 (100), 103 (6), 102
(4), 77 (9), 44 (5), 43 (3)
1
1
5
573, 1540, 1455, 1340,
250, 1217, 1060, 748,
45, 510
2
),
109.9, 111.6,
118.6, 118.7,
121.2, 123.9,
127.7, 136.4a,
158.9, 174.7
ꢀ
4.30–4.50 (m, 1 H, CH), 5.64
(br s, 2 H, NH ), 6.21 (br d, 1
2
H, J ¼ 7.9, NH), 6.90–7.22
(
m, 3 H, Harom), 7.35 (app d, 1
H, J ¼ 7.6, Harom), 7.54 (app
d, 1 H, J ¼ 7.3, Harom), 10.88
(
br s, 1 H, NHarom), 12.5 (br s,
a
1
H, COOH
2.54 and 2.72 (AB of ABX, 2 H,
J ¼ 13.7, 7.3, 5.4, CH ), 3.28
(dd, 1 H, J ¼ 7.3, 5.4, CH),
.45 (app d, 2 H, J ¼ 8.3,
arom), 6.86 (app d, 2 H,
þ
3
3
i
3650–2200, 1607, 1590,
42.9, 60.6,
121.7, 126.8,
224 (M , 1), 206 (1), 181 (4), 136 (3),
135 (2), 120 (2), 107 (100), 91 (6),
77 (12), 44 (10), 43 (10)
1
1
515, 1452, 1364, 1331,
243, 838, 795, 650, 572
2
ꢀ
133.7, 167.6,
186.0
b
6
H
b
J ¼ 8.3, Harom
)
1.77–2.24 (m, 2 H, CHCH ),
ꢀ
þ
j
3650–2500, 1711, 1667,
31.6, 36.9, 58.4,
163.8, 183.3,
190 (M , 1), 154 (78), 129 (5), 127
2
1
1
635, 1560, 1407, 1341,
230, 1170, 524
2.36 (app t, 2 H, J ¼ 7.8,
(11), 126 (26), 112 (48), 99 (23), 84
(100), 73 (17), 56 (29), 44 (59), 43
(15), 42 (19), 41 (26)
c
CH COOH), 3.97–4.11 (m, 1
H, CH)
2
ꢀ
185.3
c
a
Solvent: DMSO-d6.
b
Solvent: D
2
O-NaOH.
c
Solvent: D
2
O.

1
840
G. Verardo, P. Geatti, and P. Strazzolini
spectrophotometer, using the KBr technique, and recorded in the range 4000–
2
00 cm . H and C NMR spectra were recorded on a Bruker AC-F 200
1
1
13
4
spectrometer at 200 and 50 MHz, respectively, using D O or D O-NaOH at
2
2
room temperature or DMSO-d at 408C as solvents. NMR peak locations
6
1
are reported as d values from TMS. Some H multiplets are characterized
by the term app (apparent): this refers only to their appearance and may be
an oversimplification. Optical rotations were determined at 208C (concen-
tration in g/100 mL) using a Atago (Japan) Polax-D polarimeter. Elemental
analyses were performed with a Carlo Erba Mod. 1106 elemental analyser.
Melting points were determined with an automatic Mettler (Mod. FP61)
melting-point apparatus and are uncorrected.
General Procedure
N-Carbamoyl-L-amino Acids 3
The selected a-amino acid (6.0 mmol) was added into a 50-mL beaker con-
taining a stirred solution of NaOH (0.24 g, 6.0 mmol) in water (1.8 mL).
When a clear solution was obtained, urea (0.62 g, 10.30 mmol) was added,
and the reaction mixture was made homogeneous by well admixing with
the help of a glass rod. The reaction vessel was covered with a watch glass
and placed into an unmodified domestic microwave oven, together with a
500-mL beaker containing water (300–400 mL), and irradiated for 4 min
[
7 min with proline (1d)] at 1000 W. The reaction mixture was then cooled
at 08C, and 6 M HCl (1.0 mL, 6.0 mmol) was added while stirring. The
obtained solid was filtered and washed with water (3 ꢁ 2.0 mL) to
eliminate excess urea and NaCl, yielding the N-carbamoyl amino acids
3a–h in a spectroscopically pure form.
To solubilize L-tyrosine (1i), 2 equivalents of NaOH was used, and
therefore at the end of the reaction, 2 equivalents of 6 M HCl was added to
give the corresponding N-carbamoyl derivative 3i, after washing with water.
N-Carbamoyl-L-glutamic Acid (3j)
L-Glutamic acid (1j, 0.88 g, 6.0 mmol) was added into a 50-mL beaker con-
taining a stirred solution of NaOH (0.48 g, 12.0 mmol) in water (1.8 mL).
When a clear solution was obtained, urea (0.62 g, 10.30 mmol) was added,
and the reaction mixture was made homogeneous by well admixing with
the help of a glass rod. The reaction vessel was covered with a watch glass
and placed into an unmodified domestic microwave oven, together with a
5
1
00-mL beaker containing water (300–400 mL), and irradiated for 4 min at
000 W. The reaction mixture was then cooled at 08C, and the residue was tri-
turated in MeOH and thoroughly washed with the same solvent (3 ꢁ 1.5 mL)
to eliminate excess urea. N-Carbamoyl-L-glutamic acid disodium salt (2j) was

N-Carbamoyl-L-amino Acid Synthesis
1841
treated with concd. HCl (1.0 mL, 12.0 mmol), and the solid was finally
washed with water (2 ꢁ 1.0 mL) to eliminate formed NaCl, yielding 3j in a
spectroscopically pure form.
ACKNOWLEDGMENT
Financial support was obtained from Ministero dell’ Istruzione dell’ Univer-
sit a` e della Ricera (MIUR) Fondo Universitario per la Ricera Dipartimentale
(
FURD) 2004–2005 to G. V.). The authors are grateful to P. Martinuzzi for
13
1
recording H and C NMR spectra and P. Padovani for expert instrumental
maintenance.
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