A new approach for the synthesis of N-sulfonyl hydantoins

Article abstract of DOI:10.1016/j.tetlet.2014.04.110

Two methods are described for the synthesis of a new series of hydantoins using the same reagents. The best process is based on the addition of N-aryloxy(alkoxy)sulfonyl isocyanates to an equimolar mixture of bromoamides and triethylamine dissolved in anhydrous acetone. This reaction is violent and provides the urea salts in situ which are transformed into the corresponding substituted hydantoins.

Full text of DOI:10.1016/j.tetlet.2014.04.110

Accepted Manuscript
A new approach for the synthesis of N-sulfonyl hydantoins
Hamdi Rmedi, Ahmed Baklouti
PII:
S0040-4039(14)00747-3
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.04.110
TETL 44572
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
26 December 2013
9 April 2014
30 April 2014
Please cite this article as: Rmedi, H., Baklouti, A., A new approach for the synthesis of N-sulfonyl hydantoins,
Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.04.110
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A new approach for the synthesis of N-sulfonyl hydantoins
Hamdi Rmedia ∗, Ahmed Bakloutib
a Faculty of Sciences of Bizerte, Jarzouna 7021, Tunisia.
b Faculty of Sciences of Tunis, Laboratory of Structural Organic Chemistry, University of Tunis-El Manar, 1092 Tunis,
Tunisia.
Abstract: Two methods are described for the synthesis of a new series of hydantoins using the same reagents. The best process is
based on the addition of N-aryloxy(alkoxy)sulfonyl isocyanates to an equimolar mixture of bromoamides and triethylamine
dissolved in anhydrous acetone. This reaction is violent and provides the urea salts in situ which are transformed into the
corresponding substituted hydantoins.
Keywords: Sulfonyl isocyanates, α-bromoacetamides, N-sulfonyl hydantoins, Aryloxy and alkoxysulfonyl imidazolidine-2,4-diones.
Hydantoins constitute a class of biologically interesting compounds1 and are widely used due to their anti-
arrythmic,2 anticonvulsant,3 anticancer,4 antidiabetic5 and anti-inflammatory6 properties. They are also good precursors
to non-natural amino acids, which can play a significant role as metabotropic ligands.7-9 Therefore, several studies on
the important biological and pharmaceutical properties of these heterocycles as potential drugs, e.g., phenytoin,
nilutamide and azimilide10 have been described. It is believed that most of the biologically active hydantoins are
unsubstituted and act as Zn-binding groups through the acidic N, with the additional NH forming a hydrogen bond
with the carbonyl group of the backbone residue Ala186 in MMP13 (Collagenase 3).11
The synthesis of hydantoins is often realized using the Bucherer-Bergs reaction starting from readily available
aldehydes and ketones.12-14 In some cases, they are obtained by solid phase microwave techniques through reaction of
isocyanates on resins charged with amino acids.15
In this work, we report the synthesis of a new series of 1,3-disubstituted hydantoins using two different methods
based on a selective combination of isocyanates, amines and bromoacetyl bromide. The reactions gave N-sulfonyl urea
intermediates that, in the presence of a base, afford the corresponding hydantoins.
Our initial investigation on the synthesis of hydantoins was realized through N-sulfonylureas obtained from 2,4,6-
trimethyl phenoxysulfonyl isocyanate 1a and primary amines such as propylamine, cyclopentylamine or benzylamine.
The condensation of these substrates in equimolar amounts was immediate and gave the N-sulfonylureas 2a-c in
almost quantitative yields. The latter reacted with one equivalent of bromoacetyl bromide, in the presence of an excess
of pyridine or triethylamine in refluxing acetone, to afford hydantoins 4a-c (Scheme 1) in low yields (Table 1).
The mechanism of this reaction seems to be selective and should proceed through acylation of the alkylated
nitrogen of ureas 2a-c followed by intramolecular ring closure to yield hydantoins 4a-c exclusively. The absence of
hydantoins 4a'-c' could be interpreted by the weak nucleophilicity of the sulfonylated nitrogen due to the electron-
withdrawing effect of the sulfonyl group, in disagreement with literature results on the reactivity of N-sulfonyl ureas.16,
17
Due to the low yields obtained from the above reaction (Scheme 1), we investigated another method using the same
reagents, but starting from α-bromoacetamides.18 These amides in the presence of triethylamine reacted easily with N-
sulfonyl isocyanates 1a-c to provide the corresponding urea salts 3a-i. On heating in refluxing acetone, these
intermediates (Scheme 2) underwent intramolecular cyclization to give N-sulfonyl hydantoins 4a-i in good yields
(Table 2).
It should be noted that if triethylamine was added after the formation of ureas 3a-i [route (b) vs. route (a) in Scheme
3], the products 4a-i were formed, but with much lower yields and after prolonged reaction times. It seems therefore
∗
Corresponding author. Tel.: +216 52 231 659; fax: +216 71 550 168; e-mail: hamdiram@yahoo.fr
1

that the base has a significant effect not only on the ring closure, but also on the condensation step. This could be
explained by the poor reactivity of amides towards isocyanates 1a-c as compared to amines.
In conclusion, we have developed a convenient one-pot method for the synthesis of a new class of hydantoins
obtained from N-sulfonyl isocyanates and α-bromoamides. This synthetic route can be extended to a diverse set of
hydantoins substituted with different groups at the N1, N3 and C5 positions through the use of other α-bromoamides.
The simplicity of this method in terms of reactivity and reagent choice makes it an interesting alternative to access
such heterocycles.
General procedure for the preparation of hydantoins 4a-c (method A)
To a solution of isocyanate19 1a (10 mmol) in anhydrous Et2O or THF at 0 °C under a nitrogen atmosphere, was
added dropwise a primary amine (10 mmol). The reaction was spontaneous and led to the formation of a white
precipitate corresponding to N-sulfonyl urea 2a-c, which was filtered and washed with cold Et2O (20 mL). The
products were dissolved in acetone and treated with bromoacetyl bromide (10 mmol) and an excess of base such as
pyridine or Et3N (25 mmol) and then refluxed in the same solvent for 6 h. The precipitate that formed was filtered and
the residue evaporated in vacuo. The crude hydantoins 4a-c were purified by column chromatography on silica using
(EtOAc / petroleum ether, 1:3) to give white solids.
General procedure for the preparation of hydantoins 4a-i (method B)
To a solution of an equimolar mixture of α-bromoacetamide (10 mmol) and Et3N (10 mmol) in anhydrous acetone
(20 mL) at 0 °C under a nitrogen atmosphere, was slowly added isocyanate 1a-c (10 mmol) dissolved in the same
solvent. The mixture was refluxed for 3 h. The white precipitate that formed was filtered and the solvent was removed
in vacuo. The crude product was then purified by flash column chromatography on silica gel (EtOAc / petroleum ether,
1:3) to provide the pure hydantoins 4a-i.
1
4a: white solid; yield 90%; mp= 106 °C; IR (ν, cm-1): 1813, 1740 (C=O), 1331, 1152 (SO2); H NMR (300 MHz,
CDCl3): δ 6.91 (s, 2H arom), 4.38 (s, 2H), 3.59 (t, 2H, J =7.5 Hz), 2.40 (s, 6H), 2.32 (s, 3H), 1.73 (m, 2H), 0.99 (t, 3H,
J =7.4 Hz); 13C NMR (75 MHz, CDCl3): δ 11.1, 16.8, 20.7, 21.0, 41.4, 50.7, 130.3, 131.2, 137.5, 145.3, 151.4, 166.3;
HRMS [M+H]+: C15H21N2O5S requires 341.1171, found 341.1173.
1
4b: white solid; yield 87%; mp= 122 °C; IR (ν, cm-1): 1822, 1740 (C=O), 1330, 1165 (SO2); H NMR (300 MHz,
CDCl3): δ 6.89 (s, 2H arom), 4.50 (m, 1H), 4.31 (s, 2H), 2.39 (s, 6H), 2.27 (s, 3H), 1.94 (m, 4H), 1.61 (m, 4H); 13C
NMR (75 MHz, CDCl3): δ 16.8, 20.7, 24.8, 28.8, 50.4, 52.8, 130.3, 131.1, 137.4, 145.3, 151.1, 166.3; HRMS [M+H]+:
C17H23N2O5S requires 367.1327, found 367.1327.
1
4c: white solid; yield 80%; mp= 126 °C; IR (ν, cm-1): 1813, 1732 (C=O), 1348, 1160 (SO2); H NMR (300 MHz,
CDCl3): δ 7.28 (m, 5H arom), 6.77 (s, 2H arom), 4.61 (s, 2H), 4.19 (s, 2H), 2.17 (s, 6H), 2.12 (s, 3H); 13C NMR (75
MHz, CDCl3): δ 16.1, 19.6, 42.3, 49.8, 127.2, 128.3, 129.1, 130.5, 133.5, 134.8, 136.4, 144.3, 150.2, 164.9; HRMS
[M+H]+: C19H21N2O5S requires 389.1171, found 389.1172.
1
4d: white solid; yield 92%; mp= 60 °C; IR (ν, cm-1): 1817, 1748 (C=O), 1367, 1171 (SO2); H NMR (300 MHz,
CDCl3): δ 7.13 (m, 4H arom), 4.16 (s, 2H), 3.42 (t, 2H, J = 7.5 Hz), 1.64 (m, 2H), 0.88 (t, 3H, J = 7.5 Hz); 13C NMR
(75 MHz, CDCl3): δ 11.1, 20.9, 41.4, 50.9, 116.9, 123.4, 145.1, 151.5, 161.5, 166.3; HRMS [M+H]+: C12H14FN2O5S
requires 317.0607, found 317.0610.
1
4e: white solid; yield 89%; mp= 63 °C; IR (ν, cm-1): 1810, 1740 (C=O), 1400, 1164 (SO2); H NMR (300 MHz,
CDCl3): δ 7.18 (m, 4H arom), 4.37 (m, 1H), 4.18 (s, 2H), 1.99 (m, 4H), 1.77 (m, 4H); 13C NMR (75 MHz, CDCl3): δ
25.0, 28.9, 50.6, 52.9, 116.8, 123.4, 145.2, 151.3, 161.3, 166.3; HRMS [M+H]+: C14H16FN2O5S requires 343.0763,
found 343.0762.
1
4f: white solid; yield 81%; mp= 59 °C; IR (ν, cm-1): 1813, 1728 (C=O), 1380, 1168 (SO2); H NMR (300 MHz,
CDCl3): δ 7.18 (m, 4H arom), 7.09 (m, 5H arom), 4.64 (s, 2H), 4.12 (s, 2H); 13C NMR (75 MHz, CDCl3): δ 43.4, 51.2,
116.7, 123.5, 127.2, 128.3, 129.1, 134.8, 144.9, 151.4, 161.2, 165.9, HRMS [M+H]+: C16H14FN2O5S requires
365.0607, found 365.0607.
1
4g: white solid; yield 86% mp= 92 °C; IR (ν, cm-1): 1809, 1732 (C=O), 1374, 1180 (SO2); H NMR (300 MHz,
CDCl3): δ 5.08 (s, 2H), 4.41 (s, 2H), 3.54 (t, 2H, J = 7.4 Hz), 1.69 (m, 2H), 1.01 (t, 3H, J = 7.3 Hz); 13C NMR (75
2

MHz, CDCl3): δ 11.1, 21.0, 41.5, 50.5, 81.3, 92.7, 152.4, 166.2; HRMS [M+H]+: C8H12Cl3N2O5S requires 352.9532,
found 352.9534.
1
4h: white solid; yield 78%; mp= 68 °C; IR (ν, cm-1): 1810, 1728 (C=O), 1364, 1166 (SO2); H NMR (300 MHz,
CDCl3): δ 5.02 (s, 2H), 4.7 (m, 1H), 4.39 (s, 2H), 1.93 (m, 4H), 1.72 (m, 4H); 13C NMR (75 MHz, CDCl3): δ 24.9,
28.8, 50.1, 52.9, 81.2, 92.8, 152.1, 166.9; HRMS [M+H]+: C10H14Cl3N2O5S requires 378.9688, found 378.9691.
1
4i: white solid; yield 75%; mp= 136 °C; IR (ν, cm-1): 1810, 1736 (C=O), 1352, 1168 (SO2); H NMR (300 MHz,
CDCl3): δ 7.39 (m, 5H arom), 5.02 (s, 2H), 4.71 (s, 2H), 4.40 (s, 2H); 13C NMR (75 MHz, CDCl3): δ 43.4, 50.6, 81.2,
92.6, 128.7, 128.9, 129.1, 134.2, 152.1, 165.8; HRMS [M+H]+: C12H12Cl3N2O5S requires 400.9532, found 400.9532.
Acknowledgements
The authors are grateful to the Tunisian Ministry of Higher Education and Scientific Research for financial support
(LR99ES14) of this research, and to Dr M. A. Sanhoury, MRSC of the Department of Chemistry, Faculty of Sciences
of Tunis for helpful discussions and technical assistance.
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3

O
O
R'
acetone / N2 / 0 °C
NH2
1. Pyridine
ROSO2 NCO
ROSO2
R'
ROSO2
R'
N
N
N
H
N
H
2. BrCH2COBr
1a
2a-c
O
4a'-c'
1. Pyridine
BrCH2COBr
Me
2.
R =
Me
O
Me
O
N
ROSO2
R'
ROSO2
N
N
N
Br
O
R'
O
4a-c
3a-c
Scheme 1. Synthesis of hydantoins 4a-c from N-sulfonylureas and bromoacetyl bromide.
Et3NH+
O
O
R'
O
- Et3NH+,Br-
Br-CH2-CONHR' / Et3N
N
ROSO2
N
ROSO2 NCO
1a-c
ROSO2
N
acetone / N2 /0 °C
60 °C
N
Br
O
3a-i
R'
4a-i
Scheme 2. Synthesis of hydantoins 4a-i from N-sulfonylisocyanates and α-bromoacetamides.
O
H
R'
..
N
Et3N /acetone/ 60 °C
route (a)
N
O2SOR
N
C
O
O2SOR
N
+
R'
Br
O
O
1a-c
4a-
Et3N /60 °
..
Br
H
N
acetone / N2 /0 °C
route (b)
O2SOR
N
O
R'
3a-i
Scheme 3. Mechanism of the addition of α-bromoacetamides to N-sulfonylisocyanates 1a-c.
4

Table 1. N-Sulfonylhydantoins 4a-c produced via Scheme 1.
Product
R'
Time (h)
Yield (%)
4a
4b
4c
propyl
5
6
6
40
36
29
cyclopentyl
benzyl
Table 2. N-Sulfonylhydantoins 4a-i produced in a one-pot manner via Scheme 2.
Product
R
R'
Time (h)
Yield (%)
4a
4b
4c
4d
4e
4f
2,4,6-trimethylphenyl
2,4,6-trimethylphenyl
2,4,6-trimethylphenyl
4-fluorophenyl
propyl
2.5
2.5
3
90
87
80
92
89
81
86
78
75
cyclopentyl
benzyl
propyl
2.5
3
4-fluorophenyl
cyclopentyl
benzyl
4-fluorophenyl
3
4g
4h
4i
2,2,2-trichloroethyl
2,2,2-trichloroethyl
2,2,2-trichloroethyl
propyl
3
cyclopentyl
benzyl
3
3
5

Graphical Abstract
A new approach for the synthesis of N-
sulfonyl hydantoins
Hamdi Rmedia, ∗, Ahmed Bakloutib
O
O
O
O
R'
O
O
S
Et3N
O
N
R
S
R'
Br
+
N
O
NCO
N
H
acetone / N2
R
O
+
O
O
O
O
Br
Br
R' NH2
R
S
R'
N
H
O
N
H
Et2O / N2 / 0 °C
base / acetone / 60 °C
6