Tosyl cyanide as a C-sulfinylating agent: 3-sulfinylation of 4-hydroxycoumarins and related heterocycles

Article abstract of DOI:10.1039/c3ra45987j

Treatment of 4-hydroxycoumarins and related heterocycles with TsCN under mild basic reaction conditions produces the corresponding 3-sulfinylated products in high yields. Sulfinyl transfer is proposed to occur from sulfinyl cyanate 1, generated in situ by base-catalysed rearrangement of TsCN.

Full text of DOI:10.1039/c3ra45987j

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Tosyl cyanide as a C-sulfinylating agent: 3-sulfinylation
of 4-hydroxycoumarins and related heterocycles†
Cite this: RSC Adv., 2013, 3, 25719
*
Ramulu Akula and Hasim Ibrahim
Received 21st October 2013
Accepted 29th October 2013
DOI: 10.1039/c3ra45987j
www.rsc.org/advances
Treatment of 4-hydroxycoumarins and related heterocycles with
We report in this communication on the discovery of a novel
TsCN under mild basic reaction conditions produces the corre- C-sulnylation reaction with TsCN using 4-hydroxycoumarins
sponding 3-sulfinylated products in high yields. Sulfinyl transfer is and related heterocyclic structures as substrates, leading to 3-p-
proposed to occur from sulfinyl cyanate 1, generated in situ by base- toluenesulnylated products in a single operation.
catalysed rearrangement of TsCN.
As part of our programme on the introduction of C-1
building blocks,7 we recently reported a mild, efficient and
general electrophilic a-cyanation of activated methylene
compounds using commercially available TsCN as the CN+
equivalent.8 In an attempt to access medicinally relevant 3-
cyano-4-hydroxycoumarins by direct electrophilic cyanation,9
we treated 4-hydroxycoumarin with TsCN and K2CO3 in a 1 : 1
mixture of THF/H2O under our original cyanation conditions,8
and did not observe any cyanation products. Instead, we
obtained aer 24 hours an unexpected product which was
identied as the 3-p-toluenesulnylated 4-hydroxycoumarin in
30% yield (Table 1, entry 1).
This functionalisation was deemed worth pursing as the
p-toluenesulnyl substituent is a useful functional group
handle in aromatic systems,10 in addition of being an efficient
stereo-directing group,11 and a “traceless” resolving agent.12
Thus, we set out to identify reaction conditions that delivered
the C-sulnylated product in an improved yield (Table 1).
Due to the poor solubility of 4-hydroxycoumarin in THF/H2O
mixture, we reasoned that conducting the reaction at 60 ꢀC
might improve the solubility and obtained the product in a
higher conversion of 60% (Table 1, entry 2). A literature survey
for a polar solvent suitable for reactions with 4-hydrox-
ycoumarin revealed the 1,4-dioxane/MeNO2 mixture as a
possible choice.13 Thus, TLC monitoring of the reaction in this
solvent mixture indicated aer 2 hours the consumption of the
starting material and, to our delight, the desired sulnylated
product was isolated in an excellent yield of 96% aer chro-
matography (Table 1, entry 3). A control experiment without
K2CO3 at 60 ꢀC conrmed that the presence of base is a
prerequisite for reaction progress (entry 4). Subsequently, a
straightforward work-up procedure was developed in which the
pure product was obtained in good yield aer precipitation
(Table 1, entry 5), and this work-up procedure was adopted for
Functional group transfer from p-toluenesulfonyl cyanide
(TsCN) occurs mostly by two distinct modes of reactivity. The
rst is cyano group transfer to a variety of heteroatom and
carbon nucleophiles, as well as to carbon-centered radicals.1
The second mode involves p-toluenesulfonyl group transfer, for
instance in the formation of allyl sulfones from allyl alcohols.2 A
case involving both of these modes is the free radical addition of
TsCN across unsaturated hydrocarbons.3
Less studied is p-toluenesulnyl transfer from TsCN. Barton
and co-workers were the rst to describe such a transformation
in a study aimed at the attempted preparation of imidates from
the reaction of alcohols with TsCN, where they observed the
formation of the O-p-toluenesulnylated products instead.4
Sulnyl transfer from TsCN was also proposed to occur with
oximes giving rise to in situ generated oxime O-sulnates that
subsequently rearranged to the N-sulfonylimine derivatives.5
These reactions represent base-catalysed sulnyl transfer from
TsCN to oxygen nucleophiles. To the best of our knowledge,
there has been only one report detailing p-toluenesulnyl
transfer from TsCN to a carbon centre. In this case, activation of
TsCN with titanium(IV) chloride was proposed to generate a
p-toluenesulnyl electrophile equivalent which upon reaction
with alkenes gave hydrolytically unstable b-chlorosulfoxides.6
Centre for Synthesis and Chemical Biology, School of Chemistry and Chemical Biology,
University College Dublin, Beleld, Dublin 4, Ireland. E-mail: hasim.ibrahim@ucd.ie;
Fax: +353 1 7161178; Tel: +353 1 7162978
† Electronic supplementary information (ESI) available: Experimental procedures,
copies of 1H and 13C NMR spectra, as well as the crystal structure for the product
of Table 2, entry 2. CCDC 938546. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c3ra45987j
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Table 1 p-Toluenesulfinylation of 4-hydroxycoumarin with TsCNa
Entry
Base (equiv.)
TsCN (equiv.)
Solvent
Time (h)
Conv.b (%)
Yield (%)
1
K2CO3 (1.5)
K2CO3 (1.5)
K2CO3 (1.5)
—
K2CO3 (1.5)
K2CO3 (1.2)
K2CO3 (1.2)
Et3N (1.2)
1.5
1.5
1.5
1.5
1.5
1.2
1.2
1.2
THF/H2O (9 : 1)
THF/H2O (9 : 1)
24
24
2
24
2
2
2
2
40
60
$98
—
$98
$98
$98
$98
30c
nd
96c
—
85e
84e
90e
90c
2d
3
1,4-dioxane/MeNO2 (1 : 1)
1,4-dioxane/MeNO2 (1 : 1)
1,4-dioxane/MeNO2 (1 : 1)
1,4-dioxane/MeNO2 (1 : 1)
1,4-dioxane
4d
5
6
7
8
1,4-dioxane
a
Reaction conditions: 4-hydroxycoumarin (1.0 mmol), solvent (5 mL), rt. b Determined by 1H NMR spectroscopy of the crude material. c Isolated yield
aer column chromatography. Reaction conducted at 60 ꢀC. e Isolated yield aer precipitation.
d
most subsequent reactions. Further optimisation revealed that
Subjecting 4-hydroxy-6-methyl-2-pyrone to the reaction
1.2 equivalents in both K2CO3 and TsCN were equally effective conditions of Table 1, entries 6 or 7 gave no conversion to the
(Table 1, entry 6), and that in spite of the limited solubility of sulnylated product due to the poor solubility of the pyrone in
4-hydroxycoumarin in 1,4-dioxane alone, a complete conversion 1,4-dioxane/MeNO2 or 1,4-dioxane. We were happy to nd that
was observed with the product being isolated in 90% yield replacing MeNO2 in the former with DMSO allowed the reaction
(Table 1, entry 7). Amine bases such as Et3N also promoted this to proceed at room temperature in 2 hours with the product
transformation, however, chromatography was required for being isolated in 83% yield aer chromatography (Table 2, entry
purication (entry 8).
4). However, 2.2 equivalents of TsCN were needed for complete
We proceeded to study the substrate scope of our sulnyla- conversion, presumably due to the incompatibility of TsCN with
tion reaction employing initially conditions from Table 1, entry DMSO. Switching to a mixture of 1,4-dioxane/DMF (1 : 1) as the
7. These proved suitable for the 6-methyl and 6-chloro solvent allowed us to reduce the TsCN amount to 1.5 equiva-
substituted 4-hydroxycoumarins affording the corresponding lents with the 3-sulnylated product obtained in a comparable
3-sulnylated products in excellent yields (Table 2, entries 2 and yield (Table 2, entry 5). The 1,4-dioxane/DMF solvent system was
3). Crystals suitable for X-ray analysis were obtained from DCM/ adopted for all subsequent reactions.
pentane for the former, which showed an expected intra-
molecular OH/OS hydrogen bond.14
The sulnylation of N-analogues was attempted next and,
gratifyingly, gave the 3-sulnylated products in high yields.
Table 2 p-Toluenesulfinylation of 4-hydroxy heterocycles with TsCNa
Entry
TsCN (equiv.)
Solvent
Type
X
R
Yieldb (%)
1
2
3
4
5
6
1.2
1.2
1.2
2.2
1.5
1.5
1.5
1.5
1.5
1.5
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane/DMSO (1 : 1)
1,4-dioxane/DMF (1 : 1)
1,4-dioxane/DMF (1 : 1)
1,4-dioxane/DMF (1 : 1)
1,4-dioxane/DMF (1 : 1)
1,4-dioxane/DMF (1 : 1)
1,4-dioxane/DMF (1 : 1)
A
A
A
B
B
A
B
B
B
B
O
O
O
O
H
90
91
92
83c
85c
93
95
70e
84
92
Me
Cl
—
—
H
—
—
—
—
O
NMe
NMe
NMe
NBn
NPh
7
8d
9
10
a
Reaction conditions: 4-hydroxy heterocycle (1.0 mmol), K2CO3 (1.2 mmol), solvent (5 mL). b Isolated yield aer precipitation. c Isolated yield aer
column chromatography. Et3N (1.2 mmol) used as the base. e Conv. determined by 1H NMR spectroscopy of the crude material.
d
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Treating 4-hydroxy-1-methyl-quinolin-2-one with TsCN in 1,4-
dioxane/DMF furnished the 3-sulnylated product in an excel-
lent yield of 93% (Table 2, entry 6). Likewise, high yields were
obtained with N-methyl-, N-benzyl- and N-phenyl-substituted 4-
hydroxy-6-methylpyridin-2-one as substrates (Table 2, entries 7,
9 and 10). The reaction with 4-hydroxy-1,6-dimethylpyridin-2-
one also proceeded, albeit slower, in the presence of 1,2
equivalents of Et3N with 70% conversion observed aer 2 hours
(Table 2, entry 8).
Scheme 2 3-Sulfinylation of 4-hydroxycoumarin with reagent 2.
We conducted preliminary experiments aimed at formu-
lating a possible mechanism for the presented C-sulnylation.
Based on mechanistic studies by Barton in which TsCN was
shown to rearrange to p-toluenesulnyl cyanate (1) in the
presence of DBU or DABCO,4 we reasoned that 1 is formed in
situ under our basic reaction conditions (Scheme 1). To support
this hypothesis, we treated 4-hydroxycoumarin with the bench
stable sulnylating agent 2 (ref. 15) in the presence of Et3N and
were delighted to isolate the C-sulnylated product in 78% yield
aer 6 hours (Scheme 2).16,17
Scheme 3 Proposed mechanism for C-sulfinylation.
These ndings suggest that under the basic reaction condi-
tions, a sulnylating agent is generated in situ from TsCN;
however, how this reagent interacts with the substrate is not
clear at present. We propose two ionic pathways: a direct C–S
bond forming versus a O–S bond forming attack of the enolate
onto 1 (Scheme 3, pathway A vs. B). Pathway B could lead to the
formation of sulnate ester intermediate 3 which we postulate
undergoes a base-catalysed thia-Fries-type rearrangement to the
C-sulnylated product.18
Tentative support for pathway B can be drawn from the fact
that sulfonylation19,20 and acylation21 of 4-hydroxycoumarins and
related heterocycles occur at the 4-hydroxyl group under compa-
rable conditions to those described herein. Moreover, 4-methox-
ycoumarin did not react under our optimised reaction conditions
(Table 1, entry 7) at both room temperature and 60 ꢀC, hinting at a
possible involvement of the hydroxyl group in the sulnylation
step.22
The O-acylation of 4-hydroxycoumarins and subsequent O- to
C-acyl rearrangement in the presence of an amine base and/or
cyanide ion has been documented.21,23 In a mechanistic study on
the formation of 3-acetyl-4-hydroxycoumarin from 4-hydrox-
ycoumarin, acetyl chloride and pyridine, it was demonstrated
that 4-acetoxycoumarin was an isolable intermediate that
subsequently rearranged to product via the reversible formation
of an acetylpyridinium cation.23 A similar mechanism can be
envisaged in our case with Et3N as the base, involving sulny-
lammonium salt 4 formed reversibly from intermediate 3 and
Et3N (eqn (1)). Analogues sulfonylammonium salts are known to
be mild and efficient sulfonylating agents.24
In summary, we have described a novel, efficient and high-
yielding C-sulnylation reaction with TsCN that delivers 3-sul-
nylated 4-hydroxycoumarins and related heterocycles under
mild basic reaction conditions. Sulnyl transfer is proposed to
occur from sulnyl cyanate 1, generated in situ by base-catalysed
rearrangement of TsCN. Efforts towards an asymmetric version
of the presented C-sulnylation are underway and will be
reported in due course.
Acknowledgements
This work was supported by SFI (07/RFP/CHEF394) and the
School of Chemistry and Chemical Biology. We thank Dr Helge
¨
Muller-Bunz for X-ray structure analysis.
Notes and references
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Scheme 1 Base-catalysed rearrangement of TsCN into 1.
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14 CCDC 938546 contains the supplementary crystallographic
data for this paper. See the ESI for more details.†
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25722 | RSC Adv., 2013, 3, 25719–25722
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