The use of aqueous potassium dichloroiodate for the synthesis of ureas

Article abstract of DOI:10.1016/j.tetlet.2012.12.045

We report a straightforward and efficient reaction protocol for the syntheses of substituted ureas via treatment of thioureas with aqueous potassium dichloroiodate (KICl₂). By tuning the reaction condition, thioureas bearing activated N-aryl substituents may undergo either selective oxidation or sequential oxidation and iodination, forming iodoaryl ureas in the latter case.

Full text of DOI:10.1016/j.tetlet.2012.12.045

Tetrahedron Letters 54 (2013) 936–940
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Tetrahedron Letters
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The use of aqueous potassium dichloroiodate for the synthesis of ureas
Gil Mendes Viana a, Lúcia Cruz de Sequeira Aguiar a, , Jonas de Araújo Ferrão a,
⇑
Alessandro Bolis Costa Simas b, Marcela Guariento Vasconcelos b
a Universidade Federal do Rio de Janeiro, Instituto de Química, CT, Bloco A, Cidade Universitária, Rio de Janeiro, RJ 21941-909, Brazil
b Universidade Federal do Rio de Janeiro, NPPN, CCS, Bloco H, Cidade Universitária, Rio de Janeiro, RJ 21941-902, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
We report a straightforward and efficient reaction protocol for the syntheses of substituted ureas via
treatment of thioureas with aqueous potassium dichloroiodate (KICl2). By tuning the reaction condition,
thioureas bearing activated N-aryl substituents may undergo either selective oxidation or sequential oxi-
dation and iodination, forming iodoaryl ureas in the latter case.
Received 12 November 2012
Revised 3 December 2012
Accepted 5 December 2012
Available online 21 December 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Ureas
Potassium dichloroiodate
Oxidation
Halogenation
Mild and efficient methods for the synthesis of ureas have at-
tracted a widespread interest over the years due to their diverse
biological activities. Substituted ureas have been shown to have a
potent inhibiting effect on HIV-1 protease enzyme,1 as well as anti-
cancer,2 anticonvulsive and sedative-hypnotic activities.3 Exten-
sive application as agrochemicals, resin precursors and synthetic
intermediates4 has also been reported. In continuation to our re-
search efforts devoted to the development of practical and eco-
nomical organic processes,5 herein we report an efficient and
facile method for the synthesis of symmetrical and unsymmetrical
ureas, bearing aryl and alkyl groups, by means of clean oxidation of
the corresponding thioureas. By our approach, based upon the use
of potassium dichloroiodate (KICl2),6 N-aryl thioureas may also un-
dergo sequential oxidation and aryl group iodination in situ
(Scheme 1). One-pot syntheses, which may involve multi-step pro-
cedures or multiple reactions in the same pot, are methodologies of
choice in contemporary organic synthesis, providing, in many
cases, the target compounds in high overall yields with low cost.
A number of reports in the literature deal with the oxidation of
thioureas. Depending on the oxidizing agent, reaction conditions
and the substitution pattern of thioureas, a variety of products
may be formed, such as ureas and disulfides. Oxidative cyclization
or degradation may also occur.7
ide in alkali, peroxide–hypochloride–bicarbonate (H2O2/NaOCl/
HCO3ꢀ), potassium monopersulfate (KHSO5) in phosphate buffer,
Fe (V or VI), cetyltrimethyl–ammonium dichromate (CTADC), etc.
Reagents such as lead tetraacetate,8 manganese dioxide,9 manga-
nese (III) acetate10 and tetrabutylammonium periodate11 have also
been employed. To the best of our knowledge, the reaction of thio-
ureas with aqueous KICl2 has not been previously explored.
KICl26 is a mild oxidizing agent, convenient for iodochlorination
of multiple bonds12 and as an iodinating agent for (heterocyclic)
aromatic compounds.13 Recently, the use of related reagents, such
as
benzyl-triethylammonium14/benzyl-trimethylammonium
dichloroiodate15 and tetramethylammonium dichloroiodate16 has
been employed in aromatic iodination, but none of these studies
have investigated the use of substrates functionalized with ure-
ido/thioureido substituents.
The aqueous solution of KICl2 (ꢁ2 N) can be easily prepared in
the laboratory, as described by Larsen and co-workers,6a and it is
stable at room temperature without any appreciable concentration
loss for a considerably long period.
S
O
Mishra and co-workers7 have recently reviewed the oxidation
reactions of thiourea and substituted thioureas by different re-
agents such as bromine water (Br2/H2O), bromate (BrO3ꢀ), perox-
KICl2 aq. R2
R2
N
H
NHR1
N
H
NHR1
(R1= alkyl, Ar and R2= alkyl)
(R1= alkyl, Ar, I-Ar)
⇑
Corresponding author. Tel.: +55 021 2562 7140; fax: +55 021 2562 7001.
E-mail address: luciasequeira@yahoo.com.br (L.C. de Sequeira Aguiar).
Scheme 1. Oxidation of thioureas with KICl2 aq.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.12.045

G. M. Viana et al. / Tetrahedron Letters 54 (2013) 936–940
937
Further experiments were carried out to expand the scope of
the methodology. Trisubstituted thioureas (4j–k, 5j–k) as well as
other 1,3-dialkyl (4a–c) and 1-alkyl-3-aryl (4e–i, 5a–b) disubsti-
tuted thioureas led to good/high yields of the expected products,
according to the chosen protocol (method A or B). However, as a
limitation of this methodology, the oxidation of 1,3-diaryl-thio-
ureas (ex. 5e, entry 25) led to mixtures of iodinated products even
when method A was applied. We have also performed studies with
the mono-substituted thioureas 4d and 5d, under both conditions
(method A or B). The phenyl thiourea 5d underwent efficient
one-pot oxidation and iodination to urea 12, via protocol B (85%,
entry 24). Conversely, the reactions of 4d via method A or B and
the reaction of 5d via method A led to a mixture of unidentified
products.
S
N
H
NHR
N=C=S
BITC (1)
or
R
NH2/R2NH
4
3
or
S
N=C=S
N
NHR
PITC (2)
H
5
Scheme 2. Synthesis of thioureas from BITC or PITC.
The oxidation/iodination of thioureas was successfully scaled-
up to afford 2–4 mmol of N-phenyl-N0-butylurea (7a, 85%) and N-
(p-iodophenyl)-N0-butylurea (8, 83%).
Initially, several alkyl and aryl thioureas 4 and 5 were prepared
by the reaction of their corresponding amines and benzylisothiocy-
anate (1:BITC) or phenylisothiocyanate (2:PITC), according to the
literature (Scheme 2).5,17
In summary, we have developed a simple procedure for the syn-
thesis of a variety of alkyl, aryl and iodinated aryl ureas. Most prod-
ucts were obtained in excellent yields, not requiring purification.
Contrary to the present study, most previous works focused on
the reactions of thiourea itself or N-aryl thioureas. In a number
of cases, the developed procedures intended the degradation
(desulfurization) of such compounds for detoxification purposes.7
Finally, besides allowing two sequential in situ transformations
with quite a broad scope, gratifyingly, the present protocol has
the advantage of being metal-free.
The reactions of thioureas 4 or 5 with excess of KICl2 (10 equiv)
were run at rt (method A) or under reflux (method B). We observed
that both aryl and alkyl thioureas led to their respective ureas 6 or
7, in high yields, when the reaction was maintained at rt, for
30 min (Scheme 3; Table 1—entries 1–3, 5–15). The reactions were
complete in all cases. IR and 13C NMR data confirmed the formation
of ureas. On the other hand, when aryl thioureas 4e, 4g, 5a–b and
5d were treated by the same reagent, under reflux for 1.5 h (meth-
od B), the formed ureas could be further iodinated in situ to afford
ureas 8–12 (Table 1). 13C NMR data clearly confirmed the iodine
atom introduction (dC–I = 83–85 ppm contrasting with the original
dC–H = 121–122 ppm).
It is important to note that the benzyl group in 1,3-dialkyl-thio-
ureas 4a and 4b was not iodinated when their reactions were
maintained at reflux for longer periods of time (5 h) (Table 1, en-
tries 16 and 17). We have also investigated the possibility of poly-
iodinated products. However, when 1-alkyl-3-phenyl-thiourea 5b
was maintained under reflux for a longer period (7 h), the same
monoiodinated urea 9 was still obtained (Table 1, entry 19—Bc).
The presence of an activated aryl group, as in thiourea 4h, led to
a mixture of iodinated products when the reaction was realized
under method B (Table 1, entry 23).15c On the other hand, when
the same thiourea was subjected to method A, pure non-iodinated
urea 6h was obtained in good yield (Table 1, entry 8).
General methods
Commercially reagents were used without further purification.
1H and 13C NMR spectra were recorded on a Bruker Avance
200 MHz spectrometer using DMSO-d6 as solvent. Standard Bruker
software was used throughout. Chemical shifts are given in ppm (d
scale) and coupling constants (J) are given in hertz. The IR spectra
were obtained on a Nicolet Magna-IR 760 spectrometer. High-res-
olution mass spectra (HRMS) were obtained on a Bruker microTOF
II mass spectrometer using ESI.
Experimental procedures
General method A: To a solution of thiourea 4 or 5 (0.4 mmol)
in 4 ml of acetonitrile was added 2 ml (10 equiv) of an aqueous
solution of potassium dichloroiodate (KICl2: ꢁ2 N).6b The mixture
was stirred at room temperature for 30 min. Then the reaction
was quenched with saturated aqueous NaHSO3 (10 ml). The pre-
cipitated product was filtered, not needing further purification.
When the product did not precipitate, the aqueous mixture was
extracted with dichloromethane, dried over anhydrous Na2SO4,
These protocols proceed with high selectivity, showing the
importance of electronic effects upon these reactions using this
technique. Most of the produced ureas were insoluble after addi-
tion of saturated aqueous NaHSO3 solution, during the work up.
Therefore, they were easily isolated by a simple vacuum filtration,
without the need of purification.
Method A
S
O
O
KICl2 aq./CH3CN
N
H
NHR1
N
H
NHR1
or
N
H
NHR1
rt; 30 min.
or
4a-k
6a-c / 6e-k
7a-b / 7j-k
or
S
O
Method B
a: R1= Bu
g: R1= Ph-2-CH3
I-Aryl
KICl2 aq./CH3CN
b: R1= iPr
h: R1= Ph-4-OCH3
i: R1= Ph-3-COCH3
j: R1= morpholinyl
k: R1= di-iPr
N
NHR1
N
H
NHR
8-12
c: R1= Bn
H
d: R1= H
reflux; 1.5 h
5a-e and 5j-k
e: R1= Ph
f : R1= Ph-4-NO2
Scheme 3. Synthesis of ureas with the use of aqueous potassium dichloroiodate.

938
G. M. Viana et al. / Tetrahedron Letters 54 (2013) 936–940
Table 1
Preparation of ureas with KICl2 aq
Entry
1
Thiourea
Method
Producta
Isolated yield (%)
>99
S
S
S
O
O
O
A
N
H
N
H
N
H
N
H
4a
4b
6a
2
3
A
A
N
H
N
H
91
97
N
H
N
H
6b
N
H
N
H
N
H
N
H
4c
6c
S
S
4
5
A or B
Mixture of products
—
N
H
NH2
4d
O
A
89
N
H
N
H
N
H
N
H
4e
6e
NO2
NO2
S
S
O
O
6
7
8
A
A
A
>99
>99
77
4f
N
H
N
H
N
H
N
H
6f
N
H
N
H
N
H
N
H
4g
6g
O
O
S
S
S
O
O
O
N
H
N
H
N
H
N
H
6h
4h
O
9
A
A
A
>99
>99
>99
N
H
N
H
N
H
N
H
O
4i
6i
N
H
N
N
N
H
N
N
10
11
O
O
4j
6j
S
O
N
H
N
H
6k
7a
4k
5a
S
S
S
S
O
O
O
O
12
13
14
15
A
A
A
A
89
95
90
94
N
H
N
H
N
H
N
H
N
H
N
H
N
H
N
H
5b
7b
N
H
N
N
H
N
7j
5j
O
O
N
H
N
S
N
H
N
O
7k
5k
N
H
N
H
N
H
N
H
16
17
Bb
>99
98
4a
6a
S
O
Bb
N
H
N
H
N
H
N
H
4b
6b

G. M. Viana et al. / Tetrahedron Letters 54 (2013) 936–940
939
Table 1 (continued)
Entry
Thiourea
Method
Producta
Isolated yield (%)
I
S
S
O
18
19
20
21
22
B
83
N
H
N
H
N
H
N
H
5a
4e
8
I
I
O
O
O
O
O
B(Bc)
>99 (95c)
N
H
N
H
5b
N
H
N
H
9
S
B
B
B
91
91
73
N
H
N
H
N
H
N
H
10
NO2
NO2
S
S
N
H
N
H
4f
N
H
N
H
6f
I
N
H
N
H
N
H
N
H
4g
11
O
O
S
N
H
N
H
N
H
N
H
23
24
Bd
—
I
4h
Mixture of products
I
I
S
O
5d
12
B
85
—
N
H
NH2
N
H
NH2
I
S
O
N
H
N
H
25
B
N
H
N
H
5e
Mixture of products
a
Products were characterized by physical and spectroscopic methods.
Reflux time: 5 h.
Reflux time: 7 h.
b
c
d
25 equiv of KICl2 aq was used.
filtered and concentrated under reduced pressure to give the
pure product.
Acknowledgments
General method B: The same reaction mixture employed in
method A was heated to reflux for 1.5 h. The same work up
followed.
The authors would like to thank CNPq, CAPES and FAPERJ for the
financial support.
N-Benzyl, N0-butylurea (6a).18a White solid; mp 96–97 °C, (Lit,
98 °C); IR (KBr): 3339, 2954, 2928, 1626, 1594, 1454, 1271,
Supplementary data
696 cmꢀ1 1H NMR (200 MHz, DMSO-d6): d = 7.35–7.20 (m, 5H),
;
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
12.045.
6.24 (br t, 1H), 5.88 (br t, 1H), 4.17 (d, J = 6.1 Hz, 2H), 2.98 (q,
J = 6.1 Hz, 2H), 1.43–1.16 (m, 4H), 0.85 (t, J = 6.8 Hz, 3H); 13C
NMR (50 MHz, DMSO-d6): d = 158.0, 141.0, 128.1, 126.9, 126.4,
42.8, 39.4, 32.1, 19.5, 13.6.
References and notes
N-Phenyl, N0-butylurea (7a).18b Pale yellow solid; mp 122–
124 °C, (Lit, 123 °C); IR (KBr): 3383, 2959, 2932, 2870, 1655,
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;
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6.85 (t, J = 7.1 Hz, 1H), 6.08 (br t, 1H), 3.10–3.01 (m, 2H), 1.49–
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;
(d, J = 8.7 Hz, 2H), 7.22 (d, J = 8.7 Hz, 2H), 6.19 (br t, J = 5.5 Hz,
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