Non-phosgene route to unsymmetrical ureas from N-Cbz-α-amino acid amides

Article abstract of DOI:10.1016/j.tetlet.2013.07.141

A convenient method toward the synthesis of α-amino acid-derived unsymmetrical ureas 2 is described herein. This route involves an interesting rearrangement of amides of N-Cbz-α-amino acids 1, which presumably entails the intermediacy of hydantoins that is followed by hydrolysis to afford unsymmetrical ureas 2 in quantitative yields and high purity.

Full text of DOI:10.1016/j.tetlet.2013.07.141

Tetrahedron Letters 54 (2013) 5467–5469
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Non-phosgene route to unsymmetrical ureas from N-Cbz-a-amino
acid amides
Ebrahim H. Ghazvini Zadeh a,b, , Nader E. Abo-Dya a,c, Ania C. Sotuyo a, Ion Ghiviriga a, C. Dennis Hall a
⇑
a Center for Heterocyclic Compounds, University of Florida, Department of Chemistry, Gainesville, FL 32611-7200, USA
b University of Central Florida, Department of Chemistry, Orlando, FL 32816-1356, USA
c Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt
a r t i c l e i n f o
a b s t r a c t
Article history:
A convenient method toward the synthesis of
herein. This route involves an interesting rearrangement of amides of N-Cbz-
sumably entails the intermediacy of hydantoins that is followed by hydrolysis to afford unsymmetrical
ureas 2 in quantitative yields and high purity.
a
-amino acid-derived unsymmetrical ureas 2 is described
-amino acids 1, which pre-
Received 14 July 2013
Revised 22 July 2013
Accepted 25 July 2013
Available online 2 August 2013
a
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Urea synthesis
Rearrangement
Non-phosgene
a-Amino acid amides
Introduction
tates the conversion of carbamic acids into intermediates that are
susceptible to condensation with other amines in order to afford
Ureas are widely used as antioxidants,1 intermediates in dyes,2
and corrosion inhibitors3 as well as in many biologically active
compounds,4 agrochemicals,5 and polymers.6 The classical litera-
ture methods devised for the preparation of urea-containing com-
pounds employ hazardous reagents such as phosgene gas or
isocyanates7 whose production and storage impose serious toxico-
logical and environmental issues. Thus, continuous efforts are
made to design ‘safer’ methods for the preparation of urea deriva-
tives.8 Toward that goal, new protocols involving reagents such as
S,S-dimethylthiocarbonate,9 N,N0-carbonyldiimidazole,10 1,10-car-
bonylbisbenzotriazole,11 and carbamoyl azides12 are implemented,
yet often demand longer reaction times, tedious preparations of
phosgene-based reagents, and the isolation of the reactive inter-
mediates (Scheme 1).
Milder catalytic processes that exploit simple and cheap raw
materials such as CO and CO2 have surfaced recently.13 These in-
volve carbonylation of primary amines using organometallic com-
plexes, which are often present in stoichiometric ratio and hence
lead to the generation of large amounts of inorganic wastes
(Scheme 1).14 The formation of ureas through the intermediacy
of carbamic acids usually demands high pressures of CO2
(10 MPa) at elevated temperatures (ꢀ200 °C) to generate the reac-
tive isocyanate intermediates.15 The use of carbodiimides facili-
the desired urea derivatives (Scheme 1).16 This route is of little
practical interest since it requires multistep preparation and the
use of stoichiometric amounts of relatively expensive and mois-
ture-sensitive reagents. More conveniently, carbamate esters,
which can be prepared from amines or amino acids and CO2 using
O
(a)
O
1. RR'NH
2. RR'NH
R
R
N
R'
N
X
X
R'
R, R'= alkyl, cycloalkyl, aryl, allyl
O
X = Cl, OR, SMe, Im, Bt
(b)
CO
or
2 RNH2
R
R'
R
R
R'
R'
Mn+
N
R
N
R
+
CO2
M = W, Se, Pd, Ru, ...
(c)
(d)
O
O
RN
2. R'NH2
C NR
1.
+
+
RNH2
CO2
CO2
N
H
N
H
1. base
2. R'Cl
R1NH2
N
H
O
⇑
Corresponding author. Tel.: +1 352 281 9408.
E-mail address: ehg02@ufl.edu (E.H. Ghazvini Zadeh).
Scheme 1. Various routes to substituted ureas and carbamates.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.07.141

5468
E. H. Ghazvini Zadeh et al. / Tetrahedron Letters 54 (2013) 5467–5469
Table 1
Preparation of N-Cbz-
2 starting from N-Cbz-
R1
O
R1
O
a-amino acid amides 1a and the corresponding urea derivatives
O
a or b
O
a
-amino acids 3
R2HN
N
H
BnO
N
H
NHR2
Entry
1
R
R1
R2
% Yield
2
% Yield
OR
1
1
2
3
4
5
6
7
a
b
c
d
e
f
Cbz
Cbz
Cbz
Cbz
Cbz
Cbz
Cbz
Bn
4-APAa
pPDb
89
87
90
89
89
82
95
a
b
c
d
e
f
99
99
99
99
—
2
CH2-2-indole
CH(CH3)2
Bn-4-(OBn)
CH2CH2SCH3
H
4-APAa
4-APAa
4-APAa
4-APAa
pATc
Scheme 2. Basic rearrangement of N-Cbz-a-amino acid amides 1 into ureas 2.
Reagents and conditions: (a) NaOHaq, 15 °C, 5 min; (b) MeOK, anhydrous MeOH,
15 °C, 5 min.
0
99
g
Bn
g
hindered guanidine bases, may represent simple intermediates for
the synthesis of ureas (Scheme 1).17 However, the condensation of
a
b
c
4-APA is abbr. for 2-(4-amino-1H-pyrazol-1-yl)acetic acid.
pPD is abbr. for p-phenylenediamine.
pAT is abbr. for p-toluidine.
amines with carbamates of
a-amino acids has not been well ex-
plored. In fact, most reported amino acid-based ureas are prepared
following the classical methods which make use of phosgene gas,
isocyanates, or phosgene substitutes.18 This necessitates the use
4 of the pyrazole and the carbonyl on the other NH demonstrated
that the hydrolysis product of 1 is structure 2a (Fig. 1). This was
further supported by the HRMS spectrum which indicated a peak
of [M+H]ꢁ 333.1185.
of
a-amino acid esters that prevent the formation of the corre-
sponding N-carboxyanhydrides that are obtained from the cycliza-
tion of the intermediate isocyanates. This results in an additional
step in order to hydrolyze the ester moiety and may lead to lower
overall yields.
The synthesis of ureas through the hydrolysis of substituted
hydantoins has been achieved using metal hydroxides.18,21 In addi-
tion, unsubstituted hydantoins can be converted into N-car-
In order to limit the use of phosgene gas or its substitutes for
bamoylamino acids using D
-hydantoinase at pH 10.5.22 Therefore,
the preparation of
a convenient synthesis of unsymmetrical ureas 2 by rearrangement
of N-Cbz- -amino acid amides 1a–g (Scheme 2). Compounds 1a–g
were prepared from commercially available N-Cbz- -amino acids
via their Bt derivatives 4 by reaction with arylamines
a-amino acid derived ureas, we now introduce
we suggest that following the hydrolysis of the ester group, the
amidic nitrogen is deprotonated, resulting in a resonance-stabi-
lized anion that displaces the benzyloxy group leading to the for-
mation of a hydantoin intermediate, which undergoes base-
catalyzed hydrolysis to afford 2 (Scheme 4).
a
a
3
5
(Scheme 3).
Insight into the mechanism and therefore the versatility of this
transformation were obtained by the reaction of N1,N4-bis-(Z-
Trp)benzene-1,4-diamine 1b with potassium methoxide in anhy-
drous methanol. Remarkably, 1H and 13C NMR spectra indicated
that both amide groups rearranged into the corresponding urea
through hydrolysis of the hydantoin ring intermediate with meth-
oxide ion. This led to the formation of methyl ester derivative 2b.
This suggests that anhydrous alcoholic solvents can be used to af-
ford the corresponding esters when intended. In addition, more
controlled conditions (use of hindered base) can afford various
Results and discussion
In an effort to design new protein-binding molecules as poten-
tial inhibitors of b-amyloid deposition that is associated with neu-
rodegenerative disease,19 we became interested in the preparation
of novel amino acid conjugates of ethyl 2-(4-amino-1H-pyrazol-1-
yl)acetate 1a, 1c–f (Scheme 3, Table 1). Compound 1 were pre-
pared on a basis similar to that of 3-aminopyrazoles that can slow
or block Ab aggregation by binding through the corresponding do-
nor–acceptor–donor H-bonding pattern to sites at the surface of
peptide dimers, which can effectively block further aggregation.
Interestingly, one study shows that the arylacetic acid NSAIDs, ibu-
profen, indomethacin, and sulindac sulfide, may preferentially in-
hibit b-amyloid deposition; this prompted us to prepare the
corresponding carboxylic acids of 1.20 Therefore, 1a was treated
with aq NaOH then quenched with dilute HCl (2 N). 1H NMR spec-
trum of the pure product showed, in addition to the absence of the
peaks corresponding to the ethyl group, an unexpected loss of the
benzyl component of the carbobenzyloxy (Cbz) group. A cross-
peak in the gHMBC spectrum between the NH proton at position
conjugates of
a-amino acid-derived ureas by adding the desired
nucleophile into the reaction mixture.
In order to investigate the scope of this transformation, 1b and
1d,e (Table 1, entries 2, 4, and 5) were treated with aq NaOH. While
7.27
128.6
7.19
7.19
128.7
126.9
2.89
7.27
303.1
N
3.04
130.3
37.8
4.81
O
4.38
53.2
155.0
N
54N.4
N
HO
195.7
120.9
7.63
123.1
174.1
OH
O 170.2
H
87.5
6.35
H
O
87.6
8.56
2a
Figure 1. Chemical shifts of 2a deduced from 1H 13C and 1H 15N gHMBC
experiments.
N
O
R1
O
R1
N
N
BtH, SOCl2
THF, rt, 2 h
OH
RO
N
H
RO
N
H
O
O
3
4
O
N
O
R1
OR
"H+"
R2NH2
CH2Cl2, rt, 1 h
N
HN
R1
R2
5
BnO
R2
N
H
R2
2
- BnOH
O
O
O
R1
NHR2
N
N
CO2Et
=
RO
N
H
O
4-APA
AT
p
1
pPD
Scheme 3. Synthesis of amides 1 starting from
a-amino acids 3.
Scheme 4. Postulated reaction mechanism for the formation of 2.

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5469
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Conclusions
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benefit of using carbamates that are prepared from CO2 in an
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This work was supported by the Kenan Foundation (University
of Florida) and the King Abdulaziz University (Kingdom of Saudi
Arabia). We thank Professor Alan R. Katritzky and Mr. Akash K. Ba-
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Supplementary data
Supplementary data (copies of 1H, 13C NMR spectra for com-
pounds 1a–g, and 2a–d and 2g, 1H 13C and 1H 15N gHMBC spectra
for compounds for 2a and 2c,d) associated with this article can be
found, in the online version, at http://dx.doi.org/10.1016/
j.tetlet.2013.07.141.
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