Role of quaternaryammonium permanganates in the synthesis of substituted guanidines - A comparative study

Article abstract of DOI:10.1016/S0040-4039(00)01956-0

Quaternaryammonium permanganate transforms 1,3-diarylthioureas in the presence of an amine to the respective trisubstituted guanidines in excellent yields.

Full text of DOI:10.1016/S0040-4039(00)01956-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 343–346
Role of quaternaryammonium permanganates in the synthesis of
substituted guanidines—a comparative study
Natarajan Srinivasan† and Krishnamurthy Ramadas*
Centre for Agrochemical Research, SPIC Science Foundation, 110 Mount Road, Chennai 600 032, India
Received 4 September 2000; revised 25 September 2000; accepted 2 November 2000
Abstract—Quaternaryammonium permanganate transforms 1,3-diarylthioureas in the presence of an amine to the respective
trisubstituted guanidines in excellent yields. © 2000 Elsevier Science Ltd. All rights reserved.
On account of their immense pharmaceutical and agro-
chemical activities1 guanidines dominate our recent re-
search efforts. As substituted guanidine is an
established NMDA receptor antagonist2 with anti-
acetylcholinesterase activity, it has a special significance
for our synthetic interest. We have already emphasized
the usefulness of thiourea as an ideal substrate for the
preparation of unsymmetrical guanidines of industrial
importance.3 Desulfurization of thioureas utilizing
metal oxides is one of the classical methods.4 Synthetic
schemes using phosgene,5 cyanamide and cyanogen
bromide2,6 are less attractive due to the toxicity of the
reagents employed. Guanidines prepared through the
intermediacy of carbodiimides7 are not interesting due
to factors such as a tedious preparation procedure and
poor stability of the carbodiimides. Reaction of S-
methylated thioureas with amines leading to the
guanidines seems to be less applicable owing to the
formation of obnoxious and toxic mercaptans as side
products.8 Synthesis of guanidines from the sulfonic
acid obtained by oxidation of unsubstituted thiourea
using H2O2 has already been reported,9 and the above
method was based on the synthesis by Maryanoff et
al.10 for the preparation of disubstituted guanidines
from monosubstituted thioureas. Surprisingly, diaryl
thioureas behave differently with hydrogen peroxide to
yield thiadiazolidines instead of the expected sulfonic
acid, as reported by Kulkarni et al.11
Consequently, we have investigated a different proce-
dure for the oxidation of diaryl thioureas under milder
conditions. Potassium permanganate is known to oxi-
dize many sulfur-containing compounds like thiols, sul-
foxides and disulfides.12 Many aliphatic thiols12 and
certain cyclic thioureas13 have been oxidized to sulfonic
acid derivatives. A potassium permanganate/acetic acid
system oxidizes 2-alkylthio benzothiazole to the sul-
fonic acid.14
Although KMnO4 in aqueous solution is a commonly
used oxidant in preparative organic synthesis,15 it can-
not be used advantageously for organic substrates
which are poorly soluble in water. The major disadvan-
tage is due to the thermodynamic instability with re-
spect to water.16
4MnO4− +2H2O“4MnO2+3O2+4OH−
Therefore, KMnO4 is usually used in excess and the
yields are often low, probably due to over-oxidation of
the product.15 Our efforts in oxidizing 1,3-disubstituted
thioureas with alkaline and aqueous KMnO4 along
with an amine in presence of a phase-transfer catalyst
also failed to give the desired product.
This observation led us to examine the use of quater-
naryammonium permanganates in non-aqueous media.
Organic permanganates have been widely exploited in
synthetic organic chemistry and these include bis-
pyridyl silver permanganate,17 bis(2,2%-bipyridyl)copper-
(II) permanganate18 which are known to oxidize alco-
hols and oximes to carbonyl compounds, aromatic
amines to azo compounds and benzylamine to ben-
zaldehyde. Reich et al. reported cis-hydroxylation of
olefins by triphenylmethylphosphonium permanga-
nate.19 Permanganates derived from various quater-
Keywords: benzyltriethylammonium permanganate; thiourea; oxida-
tion; guanidine.
* Corresponding author. Present address: Vice President (R&D),
Chemfab Alkalis Limited, Kalapet, Pondicherry, Union Territory,
Pin: 605 014, India. Tel.: 0413-655116; fax: 0413-655125; e-mail:
chemfab alkalis@vsnl.com
–
† Present address: Department of Chemistry, Faculty of Science and
Technology, New University Lisbon, 2825-114 Caparica, Portugal.
E-mail: srinivasan@dq.fct.unl.pt
0040-4039/01/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01956-0

344
N. Srini6asan, K. Ramadas / Tetrahedron Letters 42 (2001) 343–346
naryammonium salts play a role in several transforma-
tions, such as the oxidation of CꢀC double bonds.20
Sargent et al. first isolated tetrabutylammonium per-
manganate as a stable solid and exploited it for the
oxidation of aldehydes to carboxylic acids.16 Chemose-
lective oxidation of hydrocarbons to alcohols, ethers to
esters and cyclic acetals to hydroxyalkyl carboxylates
have been reported using benzyltriethylammonium per-
manganate.21 Stereospecific trans-dichlorination of
olefins was achieved by benzyltriethylammonium per-
manganate with oxalyl chloride.22 A series of imines
were oxidized to nitrones with permanganates under
phase-transfer conditions.23 Cetyltrimethylammonium
permanganate has been found to oxidize benzyl alco-
hols to the corresponding aldehyde or ketone.24 The use
of quaternaryammonium permanganates for the
present transformation has no precedent in the
literature.
in the case of monosubstituted thioureas.10 Use of
quaternaryammonium permanganate on dialkylth-
ioureas did not bear fruitful results. A comparative
study was made using benzyltriethylammonium per-
manganate (BTEAP), cetyltrimethylammonium per-
manganate (CTMAP) and tetrabutylammonium
permanganate (TBAP) on several thioureas and amines
(see Tables 1 and 2).
From the data generated in Table 1, it is clear that
benzyltriethylammonium permanganate is better than
the other two. CTMAP furnished poor results and the
product isolation was rendered difficult due to the
formation of a lather during the aqueous work-up. We
found that CTMAP is more moisture sensitive and
decomposes to a dark brown solid even when storaging
for a short time unlike BTEAP or TBAP. Our observa-
tions and the results gathered conclude BTEAP to be
the reagent of choice. BTEAP can be advantageously
used over the other two oxidants since it is stable,21
shock-resistant and decomposes above 100°C. This
makes the reagent convenient to handle unlike copper
and silver bis-pyridyl permanganates, which suffer from
low stability and are thermally explosive.17
1. Use of quaternaryammonium permanganate—a
comparative study
Quaternaryammonium permanganates were prepared21
in a pure, dry state for the onward reaction with
thioureas in the presence of an amine nucleophile,
which rapidly furnished the guanidines in appreciable
yields.
In summary, this one-pot synthetic scheme can be
exploited for the rapid synthesis of any 1,3-diaryl-2-
alkylguanidine in a high yield under mild and simple
experimental conditions free from any toxic and obnox-
ious by-products.
There was no progress in the reaction when the
thiourea and oxidant were allowed to react whereas a
notable change was found in the presence of an amine.
This prompted us to study the effect of the reagent in
the absence of an amine nucleophile but in the presence
of a tertiary amine such as triethylamine. Thin-layer
chromatography was used to indicate the exclusive
consumption of thiourea and formation of a product
which might be the oxidized thiourea (sulfinic or sul-
fonic acid, Scheme 1).
2. Typical procedure for the synthesis of substituted
guanidines using benzyltriethylammonium permanganate
(BTEAP)
1,3-Diarylthiourea in THF (10 mmol, 20 ml) and amine
(20 mmol) were stirred at 5–10°C before the portion-
wise addition of BTEAP (10 mmol, 3.2 g) over 15 min.
The reaction mixture was then stirred for a further 15
min. Work-up involved filtration and washing the
residue with THF (2×3 ml). The filtrate, together with
the combined washings, was evaporated to leave a
dense liquid that, upon dilution with water, furnished
the guanidine as a solid. In certain cases where the
guanidine was not a clear solid was subjected to column
chromatography using an ether–hexane (1:1) system as
the eluent. The above experimental conditions were
adopted for other quaternaryammonium perman-
ganates.
Unfortunately, the product formed rapidly decomposed
to a dark brown complex mixture. This is in agreement
with an observation in the previous report25 stating that
oxides of thiourea (sulfinic or sulfonic acid) are un-
stable in basic media. Thus, it is believed that the
thiocarbamide reacts with quaternaryammonium per-
manganate to yield the oxidized thiourea (not charac-
terized), which reacts rapidly with the amine present to
form the guanidine (Scheme 1). This is preferred since
the sulfonyl group is reported to be displaced about 15
times faster than the corresponding S-alkylated species
Scheme 1.

N. Srini6asan, K. Ramadas / Tetrahedron Letters 42 (2001) 343–346
Table 1. Synthesis of guanidines using quaternaryammonium permanganate
345
No.
R
R1
R2
Yielda (%)
TBAP
BTEAP
CTMAP
1
2
3
4
5
6
7
8
Phenyl
Phenyl
Phenyl
Phenyl
Phenyl
o-Tolyl
Phenyl
Phenyl
Phenyl
c-C6H11
Ethyl
H
Benzyl
n-Butyl
H
c-C6H11
i-Propyl
-(CH2)2O(CH2)2-
-(CH2)2O(CH2)2-
H
Ethyl
H
H
H
H
c-C6H11
i-Propyl
–
–
92
95
90
87
86
82
82
78
89
95
80
82
75
75
70
72
60
65
72
70
70
63
60
65
56
55
50
50
55
61
9b
10b
2,6-Diethylphenyl
a Isolated yield.
b New compounds.30
Table 2. Melting points (uncorrected) of substituted guanidines (°C)
No.
1
2
3
4
5
6
7
8
9
10
Obs.
Lit.
145–147
14326
75–78
150–152
220–221
124–127
173–175
88–89
48–50
138–140
–
142–144
–
76–7827
148–15028
222–22429
127–12929
175–17628
86–8727
49–5026
Acknowledgements
H2O2 in presence or absence of sodium molybdate and
yielded thiadiazolidines.
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We thank the analytical division of the SPIC Science
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6.80; N, 14.93. Found: C, 72.13; H, 7.01; N, 14.75. 10. IR
(cm−1), 3325(s), 3251(s), 2930(m), 2335(m), 1563(s),
1485(s), 1231(s), 685(m), 525(m). 1H NMR (l ppm,
CDCl3, 400 MHz): 7.3–6.9 (7H, 6×Ar and 1×NH, m),
3.8–3.6 (4H, -O(CH2)2, t, J=4.68 Hz), 3.5–3.4 (4H,
-N(CH2)2, t, J=4.7 Hz), 3.1–2.9 (12H, 4CH3, m), 1.6–
2.0 (8H, 4CH2, m). 13C NMR (l ppm, CDCl3, 100 MHz):
150.7, 144.7, 139.5, 135.5, 126.6, 67.6, 47.8, 25.1, 14.2.
MS: 394 (M++1), 393 (M+), 363, 306, 291, 248, 158.
Analysis: calcd for C25H35N3O: C, 76.29; H, 8.90; N,
10.73. Found: C, 76.25; H, 9.03; N, 10.58.
30. Spectral data of new compounds 9 and 10
9. IR (cm−1): 3348(s), 3174(s), 2358(m), 1321(s), 12121(s),
700(m), 656(m), 502(m). 1H NMR (l ppm, CDCl3, 400
MHz): 7.3–6.8 (10H, Ar, m), 3.6 (4H, -O(CH2)2, t,
J=4.72 Hz), 3.3 (4H, -N(CH2)2, t, J=4.72 Hz). 13C
NMR (l ppm, CDCl3, 100 MHz):10 150.5, 129.3, 127.2,
122.3, 65.5, 46.9. MS (m/e): 282 (M++1), 281 (M+), 189,
145, 93, 77. Analysis: calcd for C17H19N3O: C, 72.56; H,
.