Simple and quick preparation of α-thiocyanate ketones in hydroalcoholic media. Access to 5-aryl-2-imino-1,3-oxathiolanes

Article abstract of DOI:10.1039/b900137a

A simple preparation on gram-scale of thiocyanate derivatives via nucleophilic substitution of halogenated compounds with SCN salts at high substrate concentrations in a few minutes and excellent yields was successfully accomplished in hydroalcoholic media. The obtained compounds were employed for the efficient synthesis of valuable 5-aryl-2-imino-1,3-oxathiolane derivatives (a one-pot approach is also presented).

Full text of DOI:10.1039/b900137a

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Simple and quick preparation of a-thiocyanate ketones in hydroalcoholic
media. Access to 5-aryl-2-imino-1,3-oxathiolanes†‡
Fabricio R. Bisogno, An´ıbal Cuetos, Iva´n Lavandera and Vicente Gotor*
Received 6th January 2009, Accepted 17th February 2009
First published as an Advance Article on the web 26th February 2009
DOI: 10.1039/b900137a
A simple preparation on gram-scale of thiocyanate deriva-
tives via nucleophilic substitution of halogenated com-
pounds with SCN salts at high substrate concentrations in
a few minutes and excellent yields was successfully accom-
plished in hydroalcoholic media. The obtained compounds
were employed for the efficient synthesis of valuable 5-aryl-
2-imino-1,3-oxathiolane derivatives (a one-pot approach is
also presented).
is in contrast with the optimum conditions to synthesise these
compounds since the isomerisation thiocyanate-isothiocyanate
can occur in solution at temperatures above 50 ◦C and/or
acidic conditions.10,16,22 For these reasons, the development of
new procedures for the easy and rapid synthesis of thiocyanate
derivatives in high yields is required.
Herein we report our efforts in the preparation of versatile
thiocyanate compounds in aqueous mixtures at high substrate
concentrations and further conversion into the interesting
heterocyclic 2-imino-1,3-oxathiolane system employing mild
reaction conditions and cheap reagents.
In a first set of experiments, we carried out the reactions using
a-bromoacetophenone (1a) as the model substrate at a very high
substrate concentration and room temperature (Table 1). MeCN
and MeOH were chosen as solvents for the first approach since
they could solubilise the SCN salt (entries 1 and 2). The reactions
took place homogeneously and were accomplished very quickly
but a tedious and inconvenient work-up was necessary: evapo-
ration of the water-miscible solvent at low temperature to avoid
the isomerisation of the thiocyanate group, redisolution of the
crude reaction in a suitable solvent (for instance, CH2Cl2), wash
with water several times to eliminate the remaining salts, and
reevaporation of the organic solvent at low temperature. Bearing
this in mind, we speculated that whether the reaction took place
heterogeneously in an aqueous mixture and the desired product
would precipitate, a simpler and more effective work-up could
be applied. In this way, when a MeOH/H2O 1 : 1 (v/v) mixture
was employed (entry 3), a solid was quickly formed, then filtered
off and washed with water, obtaining to our delight an excellent
In the last few years, sustainable processes are highly demanded
in the chemical industry.1 The “process efficiency” concept is not
only related to a high chemical yield, but also to the minimised
use of large amounts of harmful organic solvents and production
of chemical waste.2 The choice of an appropriate solvent is not
a simple issue.3–5 From an environmental point of view, aqueous
solvents are often an attractive option.6,7 Consequently a number
of organic processes are designed to be carried out either in pure
water or in aqueous mixtures.8,9
Thiocyanate compounds have attracted great attention as
interesting intermediates due to its easy transformation into
highly valuable molecules applied to both organosulfur and het-
erocyclic chemistry. These compounds possess a broad range of
bioactivities and applications as anticancer agents, insecticides,
antiasthmatic drugs, DNA topoisomerase inhibitors, etc.10–13
Several routes to prepare alkyl thiocyanate derivatives have
been reported including the oxidative thiocyanation of silyl enol
ethers with hypervalent iodine-lead(II) thiocyanate reagents10
and SN2 reactions using task-specific ionic liquids containing
SCN as a counterion11,12 or in organic solvents employing
KSCN14,15 or TMSNCS.16 Also the a-thiocyanation of ketones
Table 1 Optimisation of the model reactiona
17
18
using I2 or FeCl3 with NH4SCN or the transformation of
thiols employing a Ph3P/Br2/NH4SCN mixture19 or alkenes
with CAN/NH4SCN20 have been shown. Finally, the forma-
tion of b-hydroxy thiocyanates via oxirane ring-opening with
NH4SCN has been described.21 In most cases, several reagents,
organic solvents and high temperatures were employed, and
therefore purification by chromatography was necessary. This
Entry
Solvent
Time/min
SCN source
Yield (%)b
1
2
3
4
5
6
7
8
9
MeCN
MeOH
MeOH/H2O 1 : 1 10
MeOH 25
MeOH/H2O 1 : 1 20
4
4
NH4SCN
NH4SCN
NH4SCN
KSCN
95
90
94
87
68
93
96
96
96
Departamento de Qu´ımica Orga´nica e Inorga´nica, Instituto Universitario
de Biotecnolog´ıa de Asturias, University of Oviedo, 33006, Oviedo,
Spain. E-mail: vgs@fq.uniovi.es; Fax: +34 985 103448; Tel: +34 985
103448
KSCN
EtOH
3
8
3
3
NH4SCN
NH4SCN
NH4SCN
NH4SCN
EtOH/H2O 1 : 1
† Electronic supplementary information (ESI) available: General exper-
imental procedures as well as compound characterisation of 1c, 2c, 4c,
5c, and 6c. See DOI: 10.1039/b900137a
iPrOH
iPrOH/H2O 1 : 1
‡ Compounds 1b,10,18 2b,13,29 4b,20,29 5b,29 6b,30,31 7b,16,32 8b33 and 9b34
have previously been described and their physical properties were in
agreement with those reported.
a Substrate concentration: 1.25 M. For reaction conditions, see ESI†.
b Isolated yields.
452 | Green Chem., 2009, 11, 452–454
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Table 2 SN2 reaction with different types of alkyl halides (2a–9a)a
Entrya
Substrate
Product
Time
T/◦C
Solvent
Yield (%b conv.)c
1
2
3
4
5
6
7
8e
2a
3a
4a
5a
6a
7a
8a
9a
2b
1b
4b
5b
6b
7b
8b
9b
4 min
24 h
27 h
27 h
25 h
5 h
rt
rt
rt
rt
rt
rt
50
50
iPrOH/H2O 1 : 1
iPrOH/H2O 1 : 1
iPrOH/H2O 1 : 1
iPrOH/H2O 1 : 1
iPrOH/H2O 1 : 1
iPrOH
97
82
96
95
94
16d (65)
95
3.3 h
3 h
EtOH
iPrOH/H2O 1 : 1
30d (88)
a Substrate concentration: 1.25 M. For reaction conditions, see ESI†. b Isolated yields. c Conversions calculated by 1H-NMR. d After flash
chromatography on silica gel. e Substrate concentration: 0.26 M.
yield of the pure desired product 1b. Regarding to the SCN
source, the ammonium salt provided shorter reaction times as
compared with the potassium one (entries 4 and 5), and therefore
was chosen for the subsequent experiments. We extended this
procedure to other alcohols such as EtOH and 2-propanol,
these reactions were either homogeneous (entries 6 and 8) or
heterogeneous (entries 7 and 9). For the homogenous one, we
modified the work-up of the reactions. Once the process was
complete, water (five-fold volume) was added to the crude,
precipitating the final compound with very high yields. As can
be noticed, water/organic solvent combinations also afforded
excellent yields in a very short time.
mixture of products was obtained. For bromides 8a and 9a, no
conversions were detected even after long reaction time when
reactions were performed at room temp◦erature, but good to
excellent conversions were reached at 50 C. To synthesise 8b,
ethanol was employed as solvent to avoid the transesterification
reaction. The final product appeared as a second phase which
could easily be separated as the pure derivative. When flash
chromatography was used to isolate the final compounds 7b and
9b (entries 6 and 8), yields substantially dropped emphasising
the relevance of avoiding this separation technique.
With the aim of demonstrating the applicability of this class of
compounds we envisaged the possibility of synthesising several
2-imino-1,3-oxathiolane derivatives starting from a-thiocyanate
ketones 1b–6b. There are only a few reports concerning the
synthesis of this valuable motif, either by [4 + 1] cycload-
dition reactions employing harsh conditions (100 ◦C, sealed
tube) in argon atmosphere23 or by Cu(I)-catalysed coupling of
o-iodophenols and aryl isothiocyanates under nitrogen atmo-
sphere at 80 ◦C.24 The 2-imino-1,3-oxathiolane core is present in
compounds with potential bioactivities.23,25 With this in mind,
we designed a strategy whereby simple reduction of the carbonyl
moiety plus further addition of a suitable base and/or adjuvant
such as a crown ether or phase transfer catalyst,21 it would be
possible to obtain the desired heterocycle. Thus, the standard
reduction of 1b with NaBH4 in MeOH was assayed (Table 3,
entry 1). After three min, we were pleased to find out that
the formed product was not the expected hydroxy thiocyanate
intermediate but the 2-imino-1,3-oxathiolane derivative 1c. This
finding may be rationalised by considering the high pH (~9, see
ESI†) due to the presence of hydride and methoxide species
which deprotonate the OH group of the hydroxy thiocyanate
intermediate. Those deprotonated species could act as suitable
Due to the simplicity of the reaction conditions and the
i
excellent yields obtained when using the mixture PrOH/H2O,
we tested it as a medium with different alkyl halides 2a–9a
(Table 2). From the results obtained, several interesting features
can be highlighted. An important reactivity difference was
noticed depending on the halide (compare Table 1, entry 9 with
Table 2, entries 1–5) since the reaction with a-bromo ketones
1a–2a took a few minutes while several hours for a-chloro
derivatives 3a–6a although excellent yields were also obtained.
This fact can be explained due to the better ability of Br over Cl as
leaving group. Such a big difference makes this method suitable
to chemoselectively substitute bromide rather than chloride by
careful control of the SCN equivalents and the reaction time.
It is important to remark that these reactions were performed
on gram-scale, showing the robustness of this methodology. On
the other hand, it was noteworthy the different reactivity of
activated substrates such a-carbonyl or benzylic halides (2a–7a,
entries 1–6) in contrast to the non-activated ones (8a–9a, entries
7 and 8). In the case of compound 7a, the solvent used was
iPrOH due to the fact that in the aqueous solution a complex
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Table 3 Preparation of 5-aryl-2-imino-1,3-oxathiolanes 1c-6ca
inexpensive reagents (NH4SCN, NaBH4) producing a minimal
amount of waste with high atom economy.
Acknowledgements
F. R. B. is supported by the Programme Alban, the European
Union Program of High Level Scholarships for Latin America
(scholarship no. E07D402519AR). I. L. thanks Principado
de Asturias for personal funding (Clar´ın Program). Financial
support from the Spanish Ministerio de Ciencia e Innovacio´n
(MICINN, Project CTQ2007–61126/PPQ) is gratefully ac-
knowledged.
Entry
Substrate
Product
Time/min
Yield (%)b
1
2
3
4
5
1b
2b
4b
5b
6b
1c
2c
4c
5c
6c
3
3
3
3
3
95
71
84
90
95
Notes and references
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In order to corroborate the proposed reaction pathway, we
followed the formation of the desired heterocycle 1c through
1H-NMR. Thus, the a-thiocyanate ketone 1b was dissolved in
d4-MeOH and the corresponding amount of NaBH4 was added
in the NMR tube, but unfortunately we were not able to detect
any intermediate since the reaction proceeded extremely fast.
We employed instead a mixture of d8-THF : d4-MeOH 90 :
10% v/v to decelerate the process, thus detecting the hydroxy
thiocyanate derivative. These results are in agreement with the
accepted mechanism for the epoxide–thiirane conversion.21,26–28
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the subsequent reduction/cyclisation process occurred under
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oxathiolane 1c on gram-scale was carried out as depicted in
Scheme 1. We were satisfied to find out that this process smoothly
proceeded, furnishing the desired product in 88% overall yield
in a few minutes.
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Scheme 1 One-pot synthesis of 2-imino-5-phenyl-1,3-oxathiolane from
a-bromoacetophenone.
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with excellent yields, at high substrate concentrations and very
short reaction times has been developed. On the other hand,
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was possible to efficiently access the promising 2-imino-1,3-
oxathiolane core using readily available starting materials and
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454 | Green Chem., 2009, 11, 452–454
This journal is
The Royal Society of Chemistry 2009
©