Dibutylphosphate (DBP) mediated synthesis of cyclic N,N′- disubstituted urea derivatives from amino esters: A comparative study

Article abstract of DOI:10.1016/j.tetlet.2012.08.083

The N,N′-disubstituted urea derivatives such as amino acid hydantoins and dihydrouracil derivatives were prepared starting from natural and unnatural amino acid esters using dibutylphosphate (DBP). During the attempted synthesis of N-heterocycles with larger than six-membered rings containing the N,N′-disubstituted urea functionalities, three unexpected products namely squamolone, N-methyl pyrrolidine-2-one, and diketopiperazine were isolated.

Full text of DOI:10.1016/j.tetlet.2012.08.083

Tetrahedron Letters 53 (2012) 5996–5999
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Tetrahedron Letters
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Dibutylphosphate (DBP) mediated synthesis of cyclic N,N0-disubstituted
urea derivatives from amino esters: a comparative study
Sumit K. Agrawal a, Manisha Sathe a, A. K. Halve b, M. P. Kaushik a,
⇑
a Process Technology Development Division, Defence R&D Establishment, Jhansi Road, Gwalior 474 002, MP, India
b Department of Chemistry, Jiwaji University, Gwalior, MP, India
a r t i c l e i n f o
a b s t r a c t
The N,N0-disubstituted urea derivatives such as amino acid hydantoins and dihydrouracil derivatives
were prepared starting from natural and unnatural amino acid esters using dibutylphosphate (DBP).
During the attempted synthesis of N-heterocycles with larger than six-membered rings containing the
N,N0-disubstituted urea functionalities, three unexpected products namely squamolone, N-methyl pyrrol-
idine-2-one, and diketopiperazine were isolated.
Article history:
Received 26 June 2012
Revised 20 August 2012
Accepted 21 August 2012
Available online 30 August 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Dibutylphosphate
N,N0-Disubstituted urea
Hydantoin
Dihydrouracil
The N,N0-disubstituted urea functionality has recently attracted
much attention as an ubiquitous moiety incorporated into the
compounds with numerous biological activities and therapeutic
applications,1 such as anticonvulsant,2 antiarrhythmic,3 antibacte-
rial,4 antitumor,5 antidiabetic,6 and antiepileptic activity.7 Hydan-
the synthesis of amino acid hydantoins 4a–g starting from amino
acid methyl ester hydrochlorides 1a–g in good to excellent yield.
The methodology was further extended to the synthesis of six-
membered N-heterocycles containing the N,N0-urea linkage like
dihydrouracil 9 and N-methyl dihydrouracil 17. In an attempt to
toins,
dihydrouracil,
quinazoline-2,4-(1H,3H)-dione,
and
pyrido[2,3-d] pyrimidine-2,4-(1H,3H)-dione derivatives are the
classes of N-heterocycles containing N,N0-disubstituted urea link-
ages (Fig. 1).
O
O
O
R
O
N
NH
NH
NH
Cyclic compounds containing the N,N0-urea linkage have great
importance in synthetic organic and medicinal chemistry; conse-
quently, various synthetic methods have been developed over
time. Conventional synthetic methods involve the reaction of urea
with different natural and un-natural amino acids.8 General access
to 5-mono- and 5,5-disubstituted hydantoins was provided earlier
by Read1a,9 synthesis and by Bucherer–Bergs10 synthetic methods,
respectively. Apart from the above mentioned methods, hydantoin
derivatives can also be synthesized by a variety of other meth-
ods.9c,11 However, these methods suffer from various drawbacks,
such as substitution invariability, low yields, expensive substrates,
and harsh reaction conditions. In order to overcome these bottle-
necks, we recently reported dibutylphosphate (DBP) mediated syn-
thesis of diversely substituted hydantoins.11k Encouraged by its
simplicity and diverse applicability, we applied this protocol to
the synthesis of various N,N0-disubstituted urea derivatives. In con-
tinuation of our work on bioactive molecules,12 herein we report
R
O
N
H
O
N
H
O
N
H
N
N
H
O
Amino acid
Dihydrouracil
derivative
quinazoline-2,4 pyrido[2,3-d]pyrimidine-
hydantoins
(1H,3H)-dione 2,4(1H,3H)-dione
Figure 1. N-Heterocycles containing N,N0-disubstituted urea linkage.
NaHCO3 (aq.),
diethyl
CNBr
ether,
(1.0
R
R
equiv), 0 oC, 2 h,
NC
HCl.H2N COOMe
N
H
COOMe
2a-g
1a-g
2c,
DBP
DBP
R
(2 equiv),
(2 equiv),
O
HN
O
2
O
Toluene
Toluene
H2N
N
H
COOMe
NH
4
110 oC,
110 oC, 2 h
0.5 h
3, 82%
⇑
Corresponding author. Tel.: +91 751 2343972; fax: +91 751 2340042.
E-mail address: mpkaushik@rediffmail.com (M.P. Kaushik).
Scheme 1. Synthesis of amino acid hydantoins.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.08.083

S. K. Agrawal et al. / Tetrahedron Letters 53 (2012) 5996–5999
5997
synthesize larger rings containing N,N0-urea linkages like 1,3-dia-
NaHCO3 (aq.),
diethyl ether,
CNBr (1.0 equiv),
0 oC, 2 h,
zepane-2,4-dione 10 (seven-membered), 1-methyl-1,3-diaze-
pane-2,4-dione 18 (seven-membered), and cyclic dipeptide 28
(eight-membered), we ended up with 2-oxopyrrolidine-1-
carboxamide or squamolone 12 (five-membered), N-methyl
pyrrolidine-2-one 20 (five-membered), and diketopiperazine 27
(six-membered) as unexpected products, respectively.
O
H
N
O
NC
O
HCl.H2N
n
O
n
7, n = 2, 65%
5, n = 2
8, n = 3, 58%
6, n = 3
The initial synthetic studies are summarized in Scheme 1. Stan-
dardization of the reaction conditions was performed on phenylal-
anine hydantoin (4c). The synthesis of 4c was achieved starting
O
DBP
(2 equiv),
HN
N
7
Toluene
from (L)-phenylalanine methyl ester hydrochloride (1c). On treat-
oC, 5 h
O
110
9, 68%
ing 1c with cyanogen bromide (caution: cyanogen bromide is toxic;
reaction should be carried out in a fume hood) in diethyl ether: NaH-
CO3 (aq) at 0 °C for 2 h,11k,13 N-cyano phenylalanine methyl ester
2c was isolated in good yield. Uncyclized disubstituted urea deriv-
ative 3 was obtained when 2c was refluxed with DBP in toluene for
30 min. However, extended refluxing for 2 h gave the desired prod-
uct, that is, phenylalanine hydantoin 4c. With the optimized reac-
tion conditions in hand, we synthesized seven amino acid
hydantoins 4a–g starting from amino acid methyl ester hydrochlo-
rides 1a–g (Table 1) in good to excellent yields.11b The mechanism
for the formation of 4 from 2 proceeds by nucleophilic attack of the
hydroxyl group of DBP on the electrophilic cyanamide group, as
earlier described.11k
In order to explore the applicability of this procedure, we ex-
tended this methodology for the synthesis of six-membered N-
heterocycles containing the N,N0-urea linkage, that is, dihydrouracil
9. Conventionally, 9 is synthesized by the reaction of b-alanine
with KNCO,14 although the major limitation with this procedure
lies in the synthesis of N-substituted dihydrouracil. In the present
studies, b-alanine methyl ester hydrochloride 5 was converted into
methyl 3-cyanamidopropanoate 7 by the reaction of cyanogen bro-
mide in biphasic solution for 1 h and the crude 7 was refluxed with
DBP in toluene for 5 h to give analytically pure dihydrouracil 9
(Scheme 2).
H
N
DBP
DBP
O
(2 equiv),
(2 equiv),
O
N
8
NH
Toluene
Toluene
O
NH2
oC, 5 h
110
oC, 5 h
110
O
12, 71%
10
Scheme 2. Synthesis of dihydrouracil and squamolone.
DBP
O
O
H
N
(2 equiv.),
Toluene
H
N
-CH3OH
O
N
O
NC
O
O
O
NH2
12
110 o
8
NH2 11
C, 5 h
O
NH
O
N
H
10
Figure 2. Plausible mechanism for the formation of squamolone.
Successful synthesis of 9 by this methodology motivated us to
synthesize 1,3-diazepane-2,4-dione 10, a seven-membered cyclic
compound containing the N,N0-urea linkage. Methyl 4-aminobut-
anoate hydrochloride 6 was cyanated to give methyl 4-cyanamido-
butanoate 8, and was used crude for the cyclization step. Refluxing
8 with DBP in toluene for 5 h resulted in the formation of 12 in-
stead of the anticipated product 1015 as shown in Scheme 2 and
Figure 2. From this result it was apparent that if the nucleophilic
attack by NH in compound 8 or 11 cannot be prevented, then the
synthesis of 10 or N-heterocycles having larger rings containing
the N,N0-urea linkage may not be possible. Therefore, an alternate
route was attempted for the preparation of larger rings containing
the N,N0-urea linkage.
iii-iv
O
O
i-ii
NC
O
H2N
.HCl
N
N
n
n
n
Boc O
O
O
15, n = 2, 62%
16, n = 3, 56%
5, n = 2
13, n = 2, 73%
6, n = 3
14, n = 3, 65%
O
N
v
NC
N
O
O
N
H
O
15
17, 79%
NH2
v
NC
O
O
N
O
O
N
O
O
N
O
16
19, 48%
20, 39%
v
N
The reaction conditions were first standardized on compound
17, that is, N-methyl dihydrouracil. In this method, the free amine
group of 5 was protected with di-tert-butyl dicarbonate (Boc-
anhydride) in dioxane: NaHCO3 (aq) at 0 °C warming to rt for
N
O
H
18
Scheme 3. Synthesis of N-methyl dihydrouracil and N-methyl pyrrolidine-2-one.
Reagents and conditions. (i) Boc2O (1.1 equiv), dioxane: NaHCO3(aq), 0 °C, rt, 5 h, (ii)
CH3I (5 equiv), DMF, NaH (2.5 equiv), 0 °C to rt, over night, (iii) TFA:DCM, 0 °C, 2 h,
(iv) diethyl ether: NaHCO3 (aq), CNBr (1 equiv), 0 °C, 2 h, (v) DBP (2 equiv), toluene,
110 °C, 5 h.
Table 1
Results for synthesized amino acid hydantoins
Entry
Product
R
Time (h)
Yieldb (%)
5 h,16 followed by N-methylation using methyl iodide and sodium
hydride in DMF.17 The resulting methyl-3-(tert-butoxycarbonyl
(methyl)amino) propanoate 13, was deprotected using TFA:DCM16
and was immediately cyanated with cyanogen bromide to give
methyl 3-(N-methylcyanamido) propanoate 15. The resulting cya-
nated ester was then refluxed with DBP in toluene for 5 h to give
17 in good yield (Scheme 3). We then applied the same
protocol of Boc protection, N-methylation, Boc deprotection, and
1
2
3
4
5
6
7
4a
4b
4c
4d
4e
4f
H
CH3
CH2Ph
CH(CH3)2
CH(CH3)CH2CH3
CH2CH(CH3)2
CH2CO2CH3
1.5a
2a
2
75
79
73
85
82
77
74
2a
1.5
2
4g
2a
a
Reaction was carried out without solvent.
Isolated yield.
b

5998
S. K. Agrawal et al. / Tetrahedron Letters 53 (2012) 5996–5999
O
R1
O
H
N
O
O
R2
H
N
-CH3OH
O
H2N
N
O
N
H2N
N
H
O
N
OH
20
R1
N
O
H
O
R2
H
H3C
N
O
O
20 a
H
O C NH
O
N
H
O
O
20 b
19
25 I
24
Methoxy ion
Figure 3. Plausible mechanism for the formation of N-methylpyrrolidine-2-one.
H
H
R2
OH
O
N
R2
O
O
N
R1
N
H
25
R1
HN
O
R1
N
25 II
NH
h
2
-
R2
O
1
N
O C NH
,
R2
H
v
i
O
O
R1
R2
O
H
N
20 b
i-iii
COOMe
O
26
NC
O
N
H
i
v
,
BocHN
COOH H2N
R1
O
1
Figure 4. Plausible mechanism for the formation of diketopiperazines.
0
22
21
23
1
2
i
v
5 h
h
,
,
H
N
v
1
i
O
R2
O
0
-
1
which resulted in uncyclized urea ester derivatives 24a–d. On ex-
tended refluxing hours, diketopiperazines (DKPZ) 25a–d were
formed instead of carboxamide group containing DKPZ 25 I
(Scheme 4 and Table 2). From the above experiments it became
apparent that the construction of seven-membered (10 and 18)
and even eight-membered (26) ring structures containing the
N,N0-urea linkage from 8, 16, and 23 is not feasible by this method.
A plausible mechanism for the formation of DKPZ 25 is depicted
in Figure 4. The mechanism proceeds by the nucleophilic attack of
nitrogen on the electrophilic carbonyl to form intermediate 25 I.
Intermediate 25 I, on internal rearrangement, forms the more sta-
ble DKPZ 25 via another intermediate 25 II19 and eliminates isocy-
anic acid 20b, which can easily be removed by precipitating the
product with petroleum ether. All the synthesized compounds
were characterized by FT-IR, 1H NMR, 13C NMR, and ESI-MS. The
purity of the compounds was checked by HPLC analysis.
2
O
R1
O
h
R1
N
H
H
N
H
N
H2N
N
H
R2
O
25
O
R2
R
R
1 = CH(CH3)CH2CH3,
R1
N
24,
2 = CH2Ph, 65%
O
NH2
25 I
Scheme 4. Synthesis of diketopiperazines. Reagents and conditions. (i) CDI
(1 equiv), THF, 0 °C to rt, overnight, (ii) TFA:DCM, 0 °C to rt, 2 h, (iii) diethyl ether:
NaHCO3 (aq), CNBr (1.0 equiv), 0 °C, 2 h, (iv) DBP (2 equiv), toluene, 110 °C, 5 h or
11–12 h.
Table 2
Results for synthesized diketopiperazines
Entry
Product
R1
R2
Time (h)
Yielda (%)
We have described a comparative study on DBP mediated syn-
thesis of N-heterocycles containing the N,N0-urea linkage of five- to
eight-membered ring systems. Various types of N-heterocycles
containing N,N0-urea linkages like amino acid hydantoins, dihydro-
uracil, N-methyl dihydrouracil, and their derivatives can be synthe-
sized by applying the presented methodology. We anticipate that
the methodology can also be useful for the synthesis of two fused
six-membered rings containing the N,N0-urea linkage like quinazo-
1
2
3
4
25a
25b
25c
25d
Ile
Ile
Phe
Phe
Phe
Val
Ala
Leu
11
12
12
12
58
62
60
56
a
Isolated yield.
N-cyanation for the synthesis of seven-membered ring 18, that is,
1-methyl-1,3-diazepane-2,4-dione. The resulting methyl
4-(N-methyl-cyanamido) butanoate 16 was when refluxed with
DBP in toluene for 5 h to give a mixture of uncyclized urea ester,
that is, methyl 4-(N-methylureido) butanoate 19 and a five-mem-
bered cyclic compound, that is, N-methylpyrrolidin-2-one 20 as an
unexpected product instead of giving the desired compound 18
(Scheme 3).
A plausible mechanism for the formation of 20 instead of 18 is
depicted in Figure 3. The reaction proceeds via the formation of
unstable cyclic quaternary amine 20a along with the loss of a
methoxy anion. The methoxy anion abstracts a proton from the
amide nitrogen and in situ forms an unexpected five-membered
ring, that is, N-methylpyrrolidine-2-one 20 and isocyanic acid
20b. The formation of two unexpected five-membered rings, that
is, 12 and 20 prompted us to expand this protocol to dipeptides.
All dipeptides were synthesized in solution phase by using ami-
no acids, that is, 21 (N-protected), 22 (C-protected), and carbonyl-
diimidazole (CDI) as coupling reagent.18 The Boc group was
deprotected16 to give a TFA salt of the dipeptide, followed by the
reaction with cyanogen bromide to give N-cyanated dipeptide es-
ters 23a–d. The overall yield of the crude product 23a–d was rea-
sonably good, that is, 55–65%. Without further purification
compounds 23a–d were refluxed with DBP in toluene for 5–8 h,
line-2,4-(1H,3H)-dione,
pyrido[2,3-d]pyrimidine-2,4-(1H,3H)-
dione, and their derivatives.
Acknowledgments
We thank Director, DRDE, Gwalior for his keen interest and
encouragement. We also thank Mr. A. K. Srivastava and Mr. Ajay
Pratap for recording MS and NMR spectra, respectively. S.K.A. is
thankful to DRDO, New Delhi, for financial support.
Supplementary data
Supplementary data (Details experimental procedure and char-
acterization data of all compounds and copies of 1H NMR, 13C NMR
spectra and HPLC chromatograms are given in supplementary
material.) associated with this article can be found, in the online
version, at http://dx.doi.org/10.1016/j.tetlet.2012.08.083.
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