A facile synthesis of N-carbamoylamino acids

Article abstract of DOI:10.1055/s-2008-1078017

N-Carbamoylamino acids were obtained through the alkylation of monosubstituted parabanic acids followed by hydrolysis of the intermediate products. This new methodology furnishes structurally and functionally diverse N-carbamoylamino acids in high preparative yields and excellent purity. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1078017

LETTER
2279
A Facile Synthesis of N-Carbamoylamino Acids
Synthesis of
N
-
Car
n
bamoylamin
d
o
A
cids rey V. Bogolubsky,a Sergey V. Ryabukhin,*a,b Gennadiy G. Pakhomov,a Eugeniy N. Ostapchuk,a
Alexander N. Shivanyuk,a,b Andrey A. Tolmachevb
a
Enamine Ltd., 23 A. Matrosova st., 01103 Kyiv, Ukraine
Fax +380(44)5373253; E-mail: Ryabukhin@mail.enamine.net
National Taras Shevchenko University, 62 Volodymyrska st., 01033 Kyiv-33, Ukraine
b
Received 17 May 2008
The model reaction of methylparabanic acid 1a with me-
thylchloroacetate 2a resulted in N-methyl-N¢-carb-
methoxymethyl parabanic acid (3a), which was hy-
drolyzed (NaOH, H2O–dioxane, sonication) to give urea
4a in nearly quantitative yield (Scheme 1).
Abstract: N-Carbamoylamino acids were obtained through the
alkylation of monosubstituted parabanic acids followed by hydro-
lysis of the intermediate products. This new methodology furnishes
structurally and functionally diverse N-carbamoylamino acids in
high preparative yields and excellent purity.
Key words: monosubstituted parabanic acids, N-carbamoylamino
acids, ureas, hydrolysis, alkylation
Monosubstituted parabanic acids 1a–g were quantitative-
ly converted into disubstituted derivatives 3a–q in the re-
action with alkylating agents 2a–g (16 h, 20 °C, DMF, or
dioxane)15 in the presence of diisopropylethylamine as a
base.
Peptide-like N-carbamoylamino acids were widely used
as starting materials for the synthesis of various pharma-
cologically active compounds such as HIV protease,1 cys-
teine protease2 and glutamate carboxypeptidase3 in-
hibitors, rennin inhibitors,4 and selective antagonists for
the endothelin receptors.5
The two procedures described above were carried out in
one pot as follows. The equimolar solution of compounds
1a–g, 2a–g, and DIPEA in DMF or dioxane was sonicated
for 16 hours at 20 °C to accomplish the synthesis of the
corresponding compounds 3a–q. The addition of aqueous
NaOH to the reaction mixture followed by sonication (8 h
at 60 °C) and neutralization resulted in N-carbamoylami-
no acids 4a–q (Scheme 2). Most of compounds were ob-
tained in 95+% purity through precipitation with water,
filtering off, washing with methanol and drying. The com-
pounds that could not be precipitated with water were ex-
tracted by CH2Cl2.16 This procedure was successfully
applied for the synthesis of hundred-gram-scale samples
of ureas 4.17
N-Carbamoylamino acids are usually prepared through
stepwise transformation of various amino acid esters to
imidazole carbonates using 1,1-carbonyldiimidazole;1,5b,6
to N-carbophenoxy derivatives using phenyl chlorofor-
mate;7 or to isocyanato esters using triphosgene,3,8 diphos-
gene,4,5c phosgene,9 or acid azides10 followed by reaction
with amines, and then de-esterification. Alternatively, this
ureas can be obtained from amino acid esters and different
isocyanates through condensation and hydrolysis.11 Since
the multistep synthetic procedures are not useful for syn-
thesis of diverse combinatorial libraries the elaboration of
one-pot procedures using O-silylated amino acids and
triphosgene,12 or solid-phase technique,13 were devel-
oped. These methods utilize limited number of amino ac-
ids as starting materials. This greatly narrows the scope
and creates serious limitations for the use in combinatorial
chemistry and drug discovery.
The composition and structure of compounds 4 was estab-
lished by molecular elemental analysis, LC-MS, and
NMR spectroscopy (Table 1).
In summary, an efficient one-pot methodology has been
elaborated for preparative synthesis of N-carbamoylami-
no acids from monosubstituted parabanic acids. In con-
trast to known procedures our method does not employ
the amino acids. The developed procedure can be applied
both for generating diverse combinatorial libraries of
druglike compounds 4 and for large-scale synthesis of the
dis-symmetrically substituted ureas that can be used as
Herein we report a facile one-pot, high-yield procedure
for the synthesis of N-carbamoylamino acids through con-
secutive N-alkylation and hydrolysis of monosubstituted
parabanic acids.14
O
O
O
O
Cl
COOMe
i
2a
H
H
COOMe
N
N
COOH
NH
N
N
N
Me
Me
Me
O
O
O
1a
3a
4a
Scheme 1 Reagents and conditions: (i) NaOH–H2O–dioxane, 8 h, 60 °C, ultrasound.
SYNLETT 2008, No. 15, pp 2279–2282
1
5
.0
9
.2
0
0
8
Advanced online publication: 31.07.2008
DOI: 10.1055/s-2008-1078017; Art ID: G18008ST
© Georg Thieme Verlag Stuttgart · New York

2280
A. V. Bogolubsky et al.
LETTER
Table 1 Structures, Yields, Melting Points, and LC-MS Data of
Compounds 418,19 (continued)
building blocks in medicinal chemistry and peptidomi-
metics.
4
Structurea
Yield
(%)b
Mp
[M – 1]d
Table 1 Structures, Yields, Melting Points, and LC-MS Data of
Compounds 418,19
(°C)c
COOH
4
Structurea
Yield
(%)b
Mp
[M – 1]d
(°C)c
H
N
H
4o
4p
78
71
221
193
249
N
H
N
H
N
O
COOH
4a
71
76
84
91
139
238
175
130
131
H
H
N
N
COOH
O
O
157
COOH
O
H
N
H
N
4b
4c
4d
207
207
283
COOH
H
N
H
N
4q
74
190
251
H
H
O
N
N
COOH
O
Ph
Ph
O
a Satisfactory microanalysis obtained C 0.33; H 0.45; N 0.25.
b Yields refer to pure isolated product. According to HPLC MS data
all the synthesized compounds have purity >95%.
COOH
COOH
H
N
H
N
c Melting points were measured with a Buchi melting-points appara-
tus and are uncorrected.
O
d The LC-MS spectra were recorded using chromatography/mass
spectrometric system that consists of high-performance liquid chro-
matograph ‘Agilent 1100 Series’ equipped with diode matrix and
mass-selective detector ‘Agilent LC/MSD SL’.
H
N
H
N
4e
89
125
283
Ph
Ph
Ph
O
O
O
H
N
H
N
COOH
COOH
4f
88
88
75
165
130
113
221
235
283
Acknowledgment
The authors acknowledge V. V. Polovinko (Enamine Ltd.) for spec-
tral measurements.
H
N
H
N
4g
4h
References and Notes
H
N
H
N
COOH
(1) Zhang, X.; Rodrigues, J.; Evans, L.; Hinkle, B.; Ballantyne,
L.; Pefia, M. J. Org. Chem. 1997, 62, 6420.
(2) Palmer, J. T.; Rasnick, D.; Klaus, J. L.; Bromme, D. J. Med.
Chem. 1995, 38, 3193.
(3) (a) Kozikowski, A. P.; Nan, F.; Conti, P.; Zhang, J.;
Ramadan, E.; Bzdega, T.; Wroblewska, B.; Neale, J. H.;
Pshenichkin, S.; Wroblewski, J. T. J. Med. Chem. 2001, 44,
298. (b) Kozikowski, A. P.; Zhang, J.; Nan, F.; Petukhov, P.
A.; Grajkowska, E.; Wroblewski, J. T.; Yamamoto, T.;
Bzdega, T.; Wroblewska, B.; Neale, J. H. J. Med. Chem.
2004, 47, 1729.
Ph
O
O
Ph
H
N
H
N
COOH
4i
4j
87
91
194
196
273
193
O
Ph
Ph
H
H
N
N
COOH
O
COOH
(4) Yamada, Y.; Ando, K.; Ikemoto, Y.; Tada, H.; Shirakawa,
E.; Inagaki, E.; Shibata, S.; Nakamura, I.; Hayashi, Y.;
Ikegami, K.; Uchida, I. Chem. Pharm. Bull. 1997, 45, 1631.
(5) (a) von Geldern, T. W.; Hutchins, C.; Kester, J. A.; Wu-
Wong, J. R.; Chiou, W.; Dixon, D. B.; Opgenorth, T. J.
J. Med. Chem. 1996, 39, 957. (b) Fukami, T.; Yamakawa,
T.; Niiyama, K.; Kojima, H.; Amano, Y.; Kanda, F.; Ozaki,
S.; Fukuroda, T.; Ihara, M.; Yano, M.; Ishikawa, K. J. Med.
Chem. 1996, 39, 2313. (c) He, J. X.; Cody, W. L.; Doherty,
A. M. J. Org. Chem. 1995, 60, 8262.
H
N
H
N
4k
94
148
269
Ph
Ph
O
O
H
N
H
N
COOH
4l
91
88
172
205
221
259
H
N
H
N
COOH
COOH
4m
O
Ph
(6) Batey, R. A.; Santhakumar, V.; Yoshina-Ishii, C.; Taylor,
S. D. Tetrahedron Lett. 1998, 39, 6267.
(7) Buntain, I. G.; Suckling, C. J.; Wood, H. C. S. J. Chem. Soc.,
O
Perkin Trans. 1 2002, 3175.
(8) Majer, P.; Randad, R. S. J. Org. Chem. 1994, 59, 1937.
H
H
4n
74
224
221
N
N
O
Synlett 2008, No. 15, 2279–2282 © Thieme Stuttgart · New York

LETTER
Synthesis of N-Carbamoylamino Acids
2281
Scheme 2 Reagents and conditions: (i) DIPEA, dioxane (or DMF), ultrasound, 20 °C, 16 h; (ii) NaOH–H2O, dioxane, ultrasound, 60 °C, 8 h.
(9) (a) Nowick, J. S.; Powell, N. A.; Nguyen, T. M.; Noronha,
G. J. Org. Chem. 1992, 57, 7364. (b) Nowick, J. S.;
Holmes, D. L.; Noronha, G.; Smith, E. M.; Nguyen, T. M.;
Huang, S.-J. J. Org. Chem. 1996, 61, 3929.
(10) (a) Patil, B. S.; Vasanthakumar, G.-R.; Sureshbabu, V. V.
J. Org. Chem. 2003, 68, 7274. (b) Sureshbabu, V. V.; Patil,
B. S.; Venkataramanarao, R. J. Org. Chem. 2006, 71, 7697.
(c) Sureshbabu, V. V.; Sudarshan, N. S.; Krishna, G. C.
Protein Pept. Lett. 2006, 13, 493.
(d, 3JHH = 7.8 Hz, 2 H), 12.75 (br s, 1 H).
Compound 4c (500 MHz): d = 3.69 (d, 3JHH = 5.9 Hz, 2 H),
4.19 (d, 3JHH = 5.9 Hz, 2 H), 6.16 (t, 3JHH = 5.9 Hz, 1 H), 6.62
(t, 3JHH = 5.9 Hz, 1 H), 7.27 (m, 5 H).
Compound 4d (400 MHz): d = 4.26 (d, 3JHH = 6.0 Hz, 2 H),
4.32 (d, 3JHH = 6.0 Hz, 2 H), 5.55 (m, 2 H), 7.35 (m, 1 H),
7.51 (m, 4 H), 7.61 (m, 2 H), 7.85 (m, 2 H).
Compound 4e (400 MHz): d = 4.22 (d, 3JHH = 6.0 Hz, 2 H),
4.28 (d, 3JHH = 6.0 Hz, 2 H), 6.69 (t, 3JHH = 6.0 Hz, 1 H), 6.74
(t, 3JHH = 6.0 Hz, 1 H), 7.18–7.31 (m, 5 H), 7.40 (t, 3JHH = 7.5
Hz, 1 H), 7.46 (d, 3JHH = 7.5 Hz, 1 H), 7.78 (d, 3JHH = 7.5 Hz,
1 H), 7.86 (s, 1 H).
(11) Sedlak, M.; Keder, R.; Hanusek, J.; Ruzicka, A.
J. Heterocycl. Chem. 2005, 42, 899.
(12) Weiberth, F. J. Tetrahedron Lett. 1999, 40, 2895.
(13) Chong, P. Y.; Petillo, P. A. Tetrahedron Lett. 1999, 40,
4501.
(14) A diverse set of monosubstituted parabanic acids was
obtained by the cyclization of monosubstituted ureas. With
oxalyl chloride, see: (a) Biltz, H.; Topp, E. Ber. Dtsch.
Chem. Ges. 1913, 46, 1387. With diethyl oxalate see:
(b) Liao, Z.-K.; Kohn, H. J. Org. Chem. 1984, 25, 4745.
(15) The selection of the solvent based only on the solubility of
starting compounds.
Compound 4f (500 MHz): d = 1.22 (d, 3JHH = 7.4 Hz, 3 H),
4.09 (quin, 3JHH = 7.4 Hz, 1 H), 4.18 (d, 3JHH = 5.6 Hz, 2 H),
6.28 (d, 3JHH = 7.4 Hz, 1 H), 6.54 (t, 3JHH = 5.6 Hz, 1 H), 7.28
(m, 5 H).
Compound 4g (400 MHz): d = 0.85 (t, 3JHH = 7.3 Hz, 3 H),
1.55–1.59 (m, 1 H), 1.65–1.70 (m, 1 H), 4.06 (q, 3JHH = 5.6
Hz, 1 H), 4.19 (m, 2 H), 6.23 (d, 3JHH = 8.2 Hz, 1 H), 6.50 (t,
3JHH = 5.6 Hz, 1 H), 7.22 (m, 3 H), 7.25 (m, 2 H).
Compound 4h (500 MHz): d = 4.20 (m, 2 H), 5.18 (d,
3JHH = 7.3 Hz, 1 H), 6.67 (t, 3JHH = 5.6 Hz, 1 H), 6.82 (d,
3JHH = 7.7 Hz, 1 H), 7.23 (m, 3 H), 7.28 (m, 4 H), 7.35 (m, 3
H).
(16) General Procedure
Monosubstituted parabanic acid 1a–g (2 mmol) and
alkylating agent 2a–g (2 mmol) were placed in a 15 mL tube
and dissolved in 3–4 mL of DMF (or dioxane in the case of
4a,p). Diisopropylethylamine (0.35 mL, 2 mmol) was added
to the solution. The tube was thoroughly sealed and allowed
to stand at 20 °C in ultrasonic bath (BRANSON 2510E-MT)
for 16 h. After that, the reaction mixture was diluted by 8–10
mL of 10% aq solution of NaOH and sonicated at 60 °C for
8 h. After the neutralization by HCl, the precipitate formed
was filtered and washed with i-PrOH (2 mL). Targeted N-
carbamoylamino acids 4c–m were obtained as a white
powders. In the case of water-soluble compounds 4a,b,n–q
the extraction by CH2Cl2 was used.
Compound 4i (500 MHz): d = 4.21 (d, 3JHH = 5.3 Hz, 2 H),
4.26 (d, 3JHH = 4.6 Hz, 2 H), 6.33 (br t, 1 H), 6.50 (br q, 2 H),
7.11 (t, 3JHH = 1.9 Hz, 1 H), 7.23 (m, 3 H), 7.29 (m, 2 H).
Compound 4j (500 MHz): d = 3.47 (d, 3JHH = 5.9 Hz, 2 H),
6.51 (t, 3JHH = 5.9 Hz, 1 H), 6.82 (t, 3JHH = 6.5 Hz, 1 H), 7.17
(t, 3JHH = 7.8 Hz, 2 H), 7.41 (d, 3JHH = 7.8 Hz, 2 H), 9.28 (s,
1 H).
Compound 4k (400 MHz): d = 4.38 (m, 2 H), 6.51 (m, 1 H),
6.84 (m, 1 H), 7.38 (m, 4 H), 7.91 (m, 2 H), 7.91 (m, 2 H),
8.33 (m, 1 H).
Compound 4l (500 MHz): d = 0.88 (t, 3JHH = 7.3 Hz, 3 H),
1.53 (m, 1 H), 1.55 (m, 1 H), 4.13 (m, 1 H), 6.47 (d,
3JHH = 7.9 Hz, 1 H), 6.90 (t, 3JHH = 6.5 Hz, 1 H), 7.22 (t,
3JHH = 7.8 Hz, 2 H), 7.36 (d, 3JHH = 7.8 Hz, 2 H), 8.70 (s, 1
H).
(17) Compounds 4a,b,f,g,i were obtained in hundred-gram scale
by the general procedure.
(18) 1H NMR Data
1H NMR (400 MHz and 500 MHz) were recorded on a
Varian Mercury-400 and Bruker Avance DRX 500
spectrometers with TMS as an internal standard in DMSO-
d6 as a solvent.
Compound 4m (500 MHz): d = 4.31 (br d, 2 H), 6.23 (s, 1
H), 6.65 (s, 1 H), 6.82 (t, 3JHH = 6.5 Hz, 1 H), 7.18 (t,
3JHH = 7.8 Hz, 2 H), 7.54 (d, 3JHH = 7.8 Hz, 2 H), 8.68 (s, 1
H), 10.01 (s, 1 H).
Compound 4a (500 MHz): d = 2.79 (s, 3 H), 3.86 (s, 2 H),
8.02 (s, 1 H), 11.82 (br s, 2 H).
Compound 4n (500 MHz): d = 0.98 (t, 3JHH = 7.1 Hz, 3 H),
3.01 (m, 2 H), 4.23 (d, 3JHH = 6.0 Hz, 2 H), 5.93 (t, 3JHH = 5.2
Hz, 1 H), 6.38 (t, 3JHH = 6.0 Hz, 1 H), 7.33 (d, 3JHH = 7.8 Hz,
2 H), 7.86 (d, 3JHH = 7.8 Hz, 2 H), 12.75 (br s, 1 H).
Compound 4b (500 MHz): d = 2.55 (d, 3JHH = 4.4 Hz, 3 H),
4.24 (d, 3JHH = 6.0 Hz, 2 H), 5.85 (q, 3JHH = 4.4 Hz, 1 H),
6.46 (t, 3JHH = 6.0 Hz, 1 H), 7.32 (d, 3JHH = 7.8 Hz, 2 H), 7.86
Synlett 2008, No. 15, 2279–2282 © Thieme Stuttgart · New York

2282
A. V. Bogolubsky et al.
LETTER
128.7, 127.8, 131.7, 131.9, 141.4, 142.0, 158.8, 168.0.
Compound 4f: d = 18.8, 43.2, 48.7, 127.01, 127.5, 128.7,
141.2, 158.1, 175.6.
Compound 4o (500 MHz): d = 0.81 (d, 3JHH = 6.6 Hz, 6 H),
1.59 (m, 1 H), 2.50 (t, 3JHH = 6.1 Hz, 2 H), 4.25 (d, 3JHH = 5.9
Hz, 2 H), 6.01 (t, 3JHH = 6.1 Hz, 1 H), 6.35 (t, 3JHH = 5.9 Hz,
1 H), 7.32 (d, 3JHH = 7.8 Hz, 2 H), 7.87 (d, 3JHH = 7.8 Hz, 2
H), 12.75 (br s, 1 H).
Compound 4g: d = 10.3, 25.7, 43.3, 54.1, 127.1, 127.5,
128.7, 141.2, 158.2, 174.9.
Compound 4p (500 MHz): d = 0.32 (m, 2 H), 0.54 (m, 2 H),
2.38 (s, 1 H), 3.66 (d, 3JHH = 7.5 Hz, 2 H), 6.12 (s, 1 H), 6.41
(s, 1 H), 12.50 (br s, 1 H).
Compound 4h: d = 43.3, 57.6, 127.03, 127.4, 127.5, 127.9,
128.7, 128.8, 139.5, 141.1, 157.8, 173.2.
Compound 4i: d = 37.2, 43.5, 108.9, 119.1, 127.1, 127.5,
128.7, 141.2, 144.2, 158.2, 158.8, 159.8.
Compound 4j: d = 44.6, 117.9, 120.9, 128.9, 141.7, 155.7,
173.1.
Compound 4k: d = 42.5, 127.1, 128.4, 129.5, 131.1, 141.2,
153.8, 156.9, 157.7, 166.6.
Compound 4l: d = 10.3, 25.5, 53.8, 117.9, 121.5, 129.1,
140.9, 155.5, 174.6.
Compound 4q (500 MHz): d = 3.14 (q, 3JHH = 5.5 Hz, 2 H),
3.18 (s, 3 H), 3.30 (t, 3JHH = 5.5 Hz, 2 H), 4.24 (d, 3JHH = 5.9
Hz, 2 H), 6.02 (t, 3JHH = 5.5 Hz, 1 H), 6.46 (t, 3JHH = 5.9 Hz,
1 H), 7.31 (d, 3JHH = 7.8 Hz, 2 H), 7.86 (d, 3JHH = 7.8 Hz, 2
H), 12.75 (br s, 1 H).
(19) 13C NMR Data
13C NMR (125 MHz) were recorded on a Bruker Avance
DRX 500 spectrometer with TMS as an internal standard in
DMSO-d6 as a solvent.
Compound 4m: d = 36.3, 108.2, 112.9, 118.2, 120.9, 128.8,
141.9, 151.7, 153.9, 155.9, 163.7.
Compound 4a: d = 24.4, 46.5, 161.8, 172.6.
Compound 4b: d = 26.9, 43.2, 127.4, 129.5, 129.8, 146.8,
159.1, 167.7.
Compound 4c: d = 42.1, 43.4, 127.0, 127.5, 128.7, 141.2,
158.5, 172.9.
Compound 4d: d = 42.2, 42.5, 128.1, 128.2, 128.3, 128.9,
129.8, 135.9, 141.3, 154.8, 157.9, 166.4.
Compound 4e: d = 43.1, 43.4, 126.9, 127.4, 127.9, 128.2,
Compound 4n: d = 16.2, 34.7, 43.2, 127.4, 129.6, 129.8,
146.9, 158.5, 167.7.
Compound 4o: d = 20.5, 29.1, 43.2, 47.4, 127.4, 129.6,
129.8, 146.9, 158.6, 167.6.
Compound 4p: d = 6.9, 22.8, 42.04, 159.2, 172.9.
Compound 4q: d = 43.2, 58.3, 58.4, 72.1, 127.4, 129.6,
129.8, 146.8, 158.8, 167.7.
Synlett 2008, No. 15, 2279–2282 © Thieme Stuttgart · New York

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