Iodine-catalyzed sulfenylation of pyrazolones using dimethyl sulfoxide as an oxidant

Article abstract of DOI:10.1039/c7ob00561j

An iodine catalyzed sulfenylation of pyrazolones with a diverse range of heterocyclic thiols, heterocyclic thiones and disulfides has been described using dimethyl sulfoxide as an oxidant, which is an inexpensive, readily available and green oxidant. The present methodology exhibits a wide range of substrate scope and targeted products were obtained in good to excellent yields under metal-free conditions in a short duration. This methodology provides a simple process for the formation of C-S bonds through the thioetherification of pyrazolones.

Full text of DOI:10.1039/c7ob00561j

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DOI: 10.1039/C7OB00561J
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ARTICLE
Iodine-Catalyzed Sulfenylation of Pyrazolones Using Dimethyl
Sulfoxide as an Oxidant
Received 00th January 20xx,
Accepted 00th January 20xx
Yogesh Siddaraju and Kandikere Ramaiah Prabhu*
DOI: 10.1039/x0xx00000x
An iodine catalyzed sulfenylation of pyrazalones with a diverse range of heterocyclic thiols, heterocyclic thiones and
disulfides has been described using dimethyl sulfoxide as an oxidant, which is an inexpensive, readily available and green
oxidant. The present methodology exhibits a wide range of substrate scope and targeted products were obtained in good
to excellent yields under metal-free conditions in short duration. This methodology provides a simple process for the
formation of C–S bonds through the thioetherification of pyrazalones.
www.rsc.org/
Scheme 1. Approach for Sulfenylation of Pyrazolones
Known methods
Introduction
R1
R1
N
Pyrazoles are an important class of heterocyclic moieties
that can be found in a wide range of compounds including
natural products and medicinally active compounds (Fig 1).1 In
light of their applications in the medicinal field, a considerable
effort has been directed towards the construction of pyrazole
derivatives.2 In recent years, synthesis of pyrazole thioether
derivatives is gaining much attention owing to their application
as antioxidants3 and herbicidal agents.4 As a result, the
development of mild and efficient methods for the formation
of C-S bonds has gained significant attention. In this direction,
the traditional methods of C-S bond forming reactions require
prefunctionalized precursors employing (i) nucleophilic
S
I
-5 mol
%)
2 (1
TsOH
Ar
Ar
N
ArSO2NNH2
-
1
Zhao ad Lu work
Ref 6
(0.5
equiv)
N
N
O
O
HO
120 °C
i-PrOH,
R2
R1
R2
R1
S
Purohit work
N
N
ArSH
mol
Pd(NHC)Cl2 (5
%)
7
Ref
N
N
HO
K2CO
R2
3 (1.5 equiv)
R2
100 °C
DMF,
R1
R1
S
Ar
Wei and
work
Wang
Ref 8
N
N
ArSH
NaOH
(1.2 equiv)
N
N
O
HO
CH
3CN,
60 °C
R2
R2
R1
N
R1
S
TBAI
HBr
Ar
Ar
(2 equiv)
(2 equiv)
Lin ad Yan work
Ref 9
substitution
reaction
of
sodium
thiolate
with
N
ArSO2Cl
ArSO2Cl
bromopyrazolones,3,5 (ii) the cyclization reaction of methyl 3-
oxo-2-(phenylthio)butanoate with phenylhydrazine,3,5 and (iii)
N
N
O
HO
PEG400, 100 °C
R2
R2
R1
R1
S
PPh
3 (2 equiv)
Zhao ad Lu work
Ref 10
N
N
Figure 1. Pharmaceutically active pyrazoline derivatives
KI
mol
%)
(20
N
N
O
HO
O
80 °C
1,4 Dioxane,
R2
R2
NC
N
O
HN
N
N
Current method and
R1
challenges
N
Het
or
SH
S
N
N
R1
N
R1
N
S
S
Het
R
R-SS-R
I2 DMSO
Het
N
O2S
N
N
N
N
,
OH
HO
I2 DMSO
O
,
I
R2
R2
R2
80 ° 1-3 h
C,
80
1-2 h
°C,
II
PNU-32945
Sildenafil
reverse
HIV-1
inhibitor
F
S
S
transcriptase
S
inhibitor of 5 cGMP
SH
N
phosphodiesterase
SH
N
SH
SH
S
Het
Het
HN
HN
S
O
H
HN
S
F
N
or
=
N
N
N
N
N
N
N
NH2
O
N
N
N
N
F
III
IV
the reaction of pyrazolones with unstable sulphenyl chlorides.5
Recently, a variety of reports have appeared in the literature
on sulfenylation of pyrazolones using sulfonyl hydrazide,
aromatic thiols, and aryl sulfonyl chloride.6-10 The Zhao and Lu
group reported sulfenylation of pyrazalones using sulphonyl
hydrazide, which are odourless and stable solids.6 Whereas,
Cl
inhibitor of
dipeptidyl peptidase
antidepressant zometapine
a Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012,
Karnataka, India. E-mail: prabhu@orgchem.iisc.ernet.in
† Electronic Supplementary Information (ESI) available: For experimental
procedures, spectral data and spectra. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
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ARTICLE
Journal Name
the groups of Purohit , Wei and Wang independently reported reaction also proceeded well either under an argon or oxygen
View Article Online
DOI: 10.1039/C7OB00561J
sulfenylations of pyrazolones using cross dehydrogenative coupling balloon (entries 12 and 13, Table 1). However, the reaction did
(CDC) strategy (Scheme 1).7,8 Purohit and coworker reported a not proceed in the absence of iodine or DMSO (entries 14 and
palladium N-heterocyclic carbene catalysed CDC reaction of 15, Table 1). With these screening studies, further
thiophenol derivatives with various pyrazalones,7 whereas Wei and investigation was continued using 1a (1 equiv), 2a (1.1 equiv)
Wang developed an efficient CDC method for
a similar and iodine 20 mol % in DMSO (1 mL) at 80 °C (entry 5, Table 1).
transformation using NaOH under metal-free conditions.8 Lin and
Yan group reported a method for sulfenylation using aryl
sulfonyl chlorides employing PEG400 as a green solvent.9 Zhao
and Lu reported another method for sulfenylation using
arylsulfonyl chlorides.10 Even though sulfenylation of
pyrazalones have been studied extensively, sulfenylation of
heterocyclic thiols, thiones and aliphatic thiols using C–H
functionalization strategy have drawn lesser attention and
remain as an unaddressed problem.6-10 Heterocyclic thiols and
thiones serve as precursors for a variety of biologically active
compounds. Development of efficient C–H functionalization
strategies using heterocyclic thiols and thiones are well sought
after as they have high potential of providing results that are
useful in academia and industry.11 Unlike thiophenol
derivatives, most of the heterocyclic thiols and thiones are not
smelling and are stable compounds. Therefore, heterocyclic
thiols and thiones can be directly used for CDC reactions.12 In
recent years, iodine promoted C–H functionalization reactions
are emerging as one of the hot areas due to the low toxicity
and easy availability of iodine, and the environmental benign
reaction conditions enabled by iodine.13 Similarly, reactions
involving DMSO as an oxidant have attracted organic chemists
as DMSO is less toxic and green oxidant.14 In this context,
research on sulfenylation of pyrazalone through C–H
functionalization strategy using iodine and DMSO
combinations provides an efficient, useful, and green strategy.
In continuation of our effort on metal-free reactions,14f-h, 15
herein we report a convenient and efficient approach for the
sulfenylation of pyrazolone using heterocyclic thiols, thiones
and disulfides.
Table 1. Optimization studiesa
SH
N
N
S
N
I
N
2 (mol %)
80 °C
N
N
N
N
N
N
O
DMSO,
N
HO
N
1a
2a
3a
(1 equiv)
(1.1 equiv)
catalyst
or
additive (mol %)
I2 (20)
I2 (20)
I2 (20)
oxidant
(equiv)
time
(h)
isolated
entry
solvent
yield (%) b
1
2
3
4
DMSO (3)
DMSO (3)
DMSO (3)
DMSO (3)
none
none
ACN
EtOAc
1.5
12
2
83
48
82
81
90
77
nd
90 c
82d
82
90
88e
89f
nd
nd
I2 (20)
I2 (20)
toluene
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
none
2
5
1.5
2
6
7
8
55% aq. HI (20)
55% aq. HBr (20)
I2 (20)
none
none
none
12
1.5
1.5
2.5
1
9
I2 (20)
none
10
11
12
13
14
15
I2 (10)
I2 (30)
I2 (20)
I2 (20)
none
I2 (20)
none
none
none
none
none
none
2
1
12
12
aReaction conditions: 1a (0.6 mmol), 2a (0.66 mmol), catalyst (0.12 mmol) in 1
mL of solvent at 80 °C. bIsolated yield. c1 Equiv of 1a and 1.5 equiv of 2a. d1.5
Equiv of 1a and 1 equiv of 2a. eReaction under argon atmosphere. fReaction
under oxygen atmosphere. nd = not detected.
Under the optimized reaction conditions, the sulfenylation
of a variety of pyrazolone derivatives were explored (Scheme
2). In general, the reactions were clean and furnished the
Results and Discussion
The exploration for the optimization of the reaction sulfenylated products in excellent yields (Scheme 2). The
conditions began with 1-phenyl-1H-tetrazole-5-thiol (1a) and reactions of pyrazolones 2b
-e proceeded smoothly affording
5-methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one (2a) as model the products 3b
-
e
in 81-97% yield. The influence of tert-butyl
substrates and performing the reaction with 20 mol % of and amine functional groups at C-5 position of pyrazolone was
iodine and 3 equiv of DMSO as oxidant. To our delight, in this examined. From these reactions, it was found that reactivity
reaction the sulfenylated product 3a was obtained in 83% yield was unaffected with sterically hindered tert-butyl group or
(entry 1, Table 1). The solvent screening studies revealed that amino functional groups, and the reactions yielded the
solvents such as acetonitrile, ethyl acetate and toluene with corresponding sulfenylated products 3f and 3g in 94 and 78%
DMSO (3 equiv) as an oxidant resulted in the formation of yields, respectively. Furthermore, it was interesting to note
product 3a in 48, 82, and 81%, respectively (entries 2-4, Table that in the reaction of 5-amino-2-phenyl-2,4-dihydro-3H-
1, also see the ESI Table 1 for more details). Use of DMSO as a pyrazol-3-one, the basic amine functional group survived
solvent (1 mL) furnished 3a in excellent yield (90%, entry 5, under highly acidic reaction conditions and the corresponding
Table 1). Further screening was performed using DMSO as a sulfenylated product was obtained in good yield (Scheme 2).
solvent (entries 6-14, Table 1). Using aq. HI (55% in water, 20 Further, 2-methyl-5-propyl-2,4-dihydro-3H-pyrazol-3-one and
mol %) instead of iodine, the desired product 3a was obtained 5-methyl-2,4-dihydro-3H-pyrazol-3-one failed to undergo the
in 77% (entry 6), whereas aq. HBr (55% in water, 20 mol %) did sulfenylation reaction under the standard conditions (3h and
not afford the expected product (entry 7, Table 1). Increasing 3i, Scheme 2). Our attempts for isolation of nitrile and nitro
or decreasing the equivalent of 1a, or 2a or iodine, was not substituted pyrazolone derivatives such as 4-(3-methyl-5-oxo-
helpful in enhancing the yield of 3a (entries 8-11, Table 1). The 4, 5-dihydro-1H-pyrazol-1-yl)benzonitrile and 5-methyl-2-(4-
2 | J. Name., 2012, 00, 1-3
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nitrophenyl)-2,4-dihydro-3H-pyrazol-3-one with 1a afforded butyl)-2-phenyl-2,4-dihydro-3H-pyrazol-3-one wViitehw ArtivclaerOionluines
DOI: 10.1039/C7OB00561J
insoluble compounds in DMSO (for structures see ESI Table heterocyclic thiols and heterocyclic thiones. Thus, 5-(tert-
11).
butyl)-2-phenyl-2,4-dihydro-3H-pyrazol-3-one was successfully
coupled with heterocyclic thiols such as 1-methyl-1H-tetrazole-
5-thiol, pyridine-2-thiol and pyrimidine-2-thiol and the
Scheme 2. Substrate Scope for the reaction of heterocyclic thiols
with pyrazolesa,b
corresponding sulfenylated products 4e-4g were obtained in
N
N
good to excellent yields. It was noticed that addition of
pyridine as an additive (100 mol %) results in lowering the
yield of 3a to 36% from 90% (see ESI Table 5 for more details).
As pyridine thiol and pyramidine thiols contains basic nitrogen
group, we believe that the strong acid HI (which is formed in
the reaction) was quenched by pyridine or pyramidine. As a
result, stoichiometric amount of iodine is necessary for these
reactions. Similarly, heterocyclic thiones such as
benzo[d]thiazole-2(3H)-thione and 4-methylthiazole-2(3H)-
thione successfully participated in CDC reaction affording 4h
and 4i, respectively, in good yields (81 and 80%, respectively).
Benzo[d]oxazole-2(3H)-thione found to be less reactive under
the reaction conditions and afforded 4j in moderate yield
(54%, Scheme 3).
SH
N
S
N
O
N
I
mol
N
2 (20
80
%)
1.5 h
°C,
N
+
HO
N
DMSO,
N
R2
R1
N
N
R2
R1
N
1a
2a
3
(0.6 mmol)
(0.66 mmol)
N
N
N
N
N
N
N
S
N
S
N
N
S
N
N
HO
HO
HO
N
N
N
N
N
N
3a 90%
,
3b 93%
3c 97%
,
,
N
N
N
N
N
N
N
S
N
N
N
N
N
HO
HO
S
HO
S
Scheme 3. Substrate Scope for the reaction of heterocyclic thiols
and thiones with pyrazolesa,b
N
N
N
N
N
N
Cl
Br
R1
R1
3d 81%
,
3e 85%
,
3f 94%
,
S
Het
Het
Het
N
I
-100 mol
SH
S
2 (20
DMSO,
%)
80 °C
N
N
N
O
+
or
HO
N
N
N
N
N
N
N
N
N
N
N
N
1
2
4
(0.6 mmol)
S
(0.66 mmol)
HO
S
HO
S
HO
S
N
N
S
S
NH2
N
N
HN
N
N
N
N
N
N
N
N
S
N
N
N
N
N
3h ND
,
3i ND
,
, 78%
HO
HO
3g
HO
aReaction conditions: 1a (0.6 mmol), 2a (0.66 mmol), catalyst (0.12 mmol),
DMSO (1 mL) at 80 °C, 1.5 h. b Isolated yield. ND= Not detected
88%
4a,
80%c
82%c
4c,
4b,
N
After exploring the reactivity of various pyrazolone
derivatives with 1-phenyl-1H-tetrazole-5-thiol (1a), further
exploration has been continued using a variety of heterocyclic
thiols and thiones (Scheme 3). These reactions led to smooth
sulfenylation. The reaction of 2a with heterocyclic thiol such as
1-methyl-1H-tetrazole-5-thiol furnished the corresponding
sulfenylated product 4a in good yield (88%). Similarly,
pyridine-2-thiol underwent sulfenylation with 2a to form 4b in
good yield (80%). However, this reaction required
stoichiometric amount of iodine (see ESI Table 6 for more
details). The scope of the sulfenylation reaction was further
extended to the heterocyclic thiones such as benzo[d]thiazole-
S
N
S
S
N
N
S
N
N
N
N
N
N
HO
N
N
HO
4e,
HO
78%c
88%
S
82%c
4f,
4d,
N
N
N
S
S
N
N
N
N
S
S
N
N
N
HO
HO
HO
60%c
81%c
80%c
4i,
4h,
4g,
2(3H)-thione
derivatives.
Thus,
the
reaction
of
benzo[d]thiazole-2(3H)-thione under optimal reaction
conditions afforded the expected sulfenylated product 4c in
low yield (28 %) (see the ESI Table 7 for more details).
However, the yield of 4c has increased to 82% by using iodine
in stoichiometric amount. Similarly, benzo[d]thiazole-2(3H)-
thione derivatives such as 4-methylthiazole-2(3H)-thione
afforded the product 4d in good yield (78% Scheme 3). The
scope of the reaction was further extended for the
sulfenylation of sterically hindered pyrazolone such as 5-(tert-
N
S
N
O
N
HO
54%c
4j,
aReaction conditions: 1a (0.6 mmol), 2a (0.66 mmol), catalyst (0.12 mmol) in 1
mL of DMSO at 80 °C, 1.5 h. bIsolated yield. c1 equiv of iodine used, 80 °C for 1 h
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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ARTICLE
Next to demonstrate the generality of this methodology,
Journal Name
Scheme 4. Substrate Scope for the reaction of disulfides with
View Article Online
pyrazolesa,b
DOI: 10.1039/C7OB00561J
the sulfenylation reaction with thiophenol was investigated.
However, this reaction furnished the sulfenylated product 5a
in poor yield (26%) (see the ESI Table 10 for more details). This
problem was circumvented by using disulfides instead of thiols
(Scheme 4). Thus the disulfides with either electron-donating
or electron withdrawing groups on phenyl ring reacted well
furnishing the corresponding sulfenylated products 5a, 5b and
5c in 92, 94, and 79% yields, respectively. The reaction
proceeded well with dibenzyl disulfide to form 5d in good yield
(73%) showing the robustness of this methodology. It is
noteworthy that it is difficult to achieve the sulfenylation using
dibenzyl disulfide under previous reported methods.6-10
R2
R2
S
R1
N
N
R1
I
mol
%)
N
2 (20
S
N
O
HO
S
R1
DMSO
80
2-3 h
°C,
R3
R3
1
2
5
(0.6 mmol)
(1.32 mmol)
NO2
S
S
S
S
N
N
N
N
N
N
HO
HO
N
N
HO
HO
Further,
sulfenylation with diphenyl sulfide affording the corresponding
sulfenylated products 5e 5h in excellent yields (82-95%,
respectively) Alkyl-substituted pyrazolone such as 2-(tert-
butyl)-2,4-dihydro-3H-pyrazol-3-one afforded 5i in 83% yield.
The pyrazolones without a substituent at C5 position such as 2-
phenyl-2,4-dihydro-3H-pyrazol-3-one failed to undergoes
sulfenylation. Our attempts for sulfenylation of 1,2-
diethyldisulfane and 1,2-di-tert-butyldisulfane with pyrazalone
were unsuccessful (Scheme 4). To achieve the synthesis of 1-
a variety of pyrazalone derivatives underwent
5a
5b
5c
5d
, 73%
, 92%
, 94%
, 79%
-
S
S
S
.
N
S
N
N
N
N
N
HO
HO
N
HO
N
HO
Br
Cl
5e
5h
, 86%
S
, 82%
, 95%
S
5f, 82%
5g
S
S
R
alkyl-3-methyl-1H-pyrazol-5(4H)-one,
the
benylated
N
N
N
N
N
N
N
HO
HO
pyrazolone derivative was synthesized, which was
susuccessfully sulfenylated under optimal reaction conditions
to obtain the product 5m in 81% yield. Our attempts to
deprotect the benzylic group from 5m were unsuccessful.
HO
N
HO
=
,
CH2CH3 ND
5k
R
,
c
c
5i
ND
5m
,
63%,
,
,
68%,
(83% )
5j
(81% )
=
5l
R
ND
,
C(CH3)3
,
aReaction conditions: 1a (0.6 mmol), 2a (1.31 mmol), catalyst (0.12 mmol) in 1 mL of
DMSO at 80 °C, 2-3 h. bIsolated yield. c50 mol % of iodine used. ND= Not detected
To get insight into the reaction mechanism, a few control
experiments were performed (Scheme 5). The reaction of 1a
with 2a under the optimal conditions, in the presence of
TEMPO proceeded well suggesting the absence of a radical
intermediacy in the reaction (Scheme 5a). Further to find
whether disulfide is an intermediate, a reaction of 1,2-
di(pyridin-2-yl)disulfane
and
1,2-bis(benzo[d]thiazol-2-
yl)disulfane with 1a was performed. This reaction proceeded
well with catalytic amount of iodine furnishing the sulfenylated
product 4b and 4c in 81 and 84%, respectively (Scheme 5b and
5c), whereas the same reaction with pyridine thiol or
benzo[d]thiazole-2(3H)-thione required stoichiometric amount
of iodine for sulfenylation (4b and 4c, Scheme 3). This
experiment clearly supports that the reaction is proceeding
through disulfide intermediate. 1H NMR experiment for
trapping disulfide intermediate in the reaction of 1-methyl-1H-
tetrazole-5-thiol and 2a was (see the ESI Table 13 and NMR
studies for more details). To confirm the role of DMSO as an
oxidant, a reaction of 1a and 2a was performed
Scheme 5. Control experiments for mechanistic studies
4 | J. Name., 2012, 00, 1-3
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Scheme 6. A tentative mechanism
HS
N
View Article Online
DOI: 10.1039/C7OB00561J
N
N
DMS:I2
or
N
N
S
N
N
(a)
N
N
2
N
N
O
I2
+
DMS
H2O
N
(0.6 mmol)
standard condition
N
N
N
N
SH
)
HO
1a
(
N
S
N
TEMPO
3a, 87%
(1.1 equiv)
N
N
O
S
2a
,
(0.66 mmol)
N
2HI
S
S
S
S
I2
N
N
N
N
N
N
N
N
N
N
N
(II)
N
(b)
(0.3 mmol)
O
HO
N
N
2
N
Iodine
mol
%)
(20
N
N
1.5 80 °C
h,
S
DMSO,
HO
HI
HO
N
I
N
4b 81%
,
2a
,
N
(0.66 mmol)
S
(III)
N
N
N
HO
N
O
N
2
3a
S
N
S
N
S
N
S
S
N
N
N
N
S
N
O
HO
(0.3 mmol)
(c)
Iodine
mol
%)
(20
1.5 80 °C
h,
DMSO,
4c 84%
,
2a
,
(0.66 mmol)
Conclusion
In conclusion, we have developed a sustainable and efficient
strategy for the sulfenylation of pyrazalones under metal-free
reaction conditions using DMSO as an oxidant and iodine as a
catalyst. This strategy is highly practical as most of the
compounds can be isolated in pure form without column
purification. To the best of our knowledge, this is the first
report on sulfenylation of diverse range of heterocyclic thiols
and heterocyclic thiones to pyrazalones derivatives using CDC
reactions.
N
N
Iodine
mol
%)
(100
(d)
O
complete decomposition
complete decomposition
80 °C
DMSO, 1h,
2a
,
(0.6 mmol)
HS
Iodine
mol
%)
(20
N
N
(e)
N
N
1
80 °C
DMSO, h,
1a
,
(0.6 mmol)
using 3 equiv of DMSO in solvents such as ethyl acetate and
toluene. Interestingly, these reactions proceeded well
furnishing the product 3a in 82 and 81% yield, respectively,
and the same reaction failed to form 3a in the absence of
DMSO (entry 3 and 4, Table 1, also see ESI Table 1 for more
details). In the absence of any oxidants, the reaction of 1a with
2a, proceeded well under an argon atmosphere (entry 12,
Table 1). These experiments clearly confirm the role of DMSO
as an oxidant. However, the reaction of thiol 1a or pyrazolone
2a under the reaction conditions led to the complete
decomposition of starting materials (Scheme 5d and 5e).
On the basis of these experimental studies (Schme 5) and
the literature precedence,14 a tentative mechanism has been
proposed in Scheme 6. 1-Phenyl-1H-tetrazole-5-thiol (1a) in
the presence of iodine forms intermediate 1,2-bis(1-phenyl-
1H-tetrazol-5-yl)disulfane (II) and HI as a byproduct. 1,2-bis(1-
Phenyl-1H-tetrazol-5-yl)disulfane (II) reacts with DMS:I2 or I2 to
form intermediate that contains S-I bond (III). Further
nucleophillic displacement of the iodo group by pyrazalone led
to the formation of the product 3a and byproduct HI. Further,
iodine is regenerated by the reaction of HI with DMSO and
cycle continues (Scheme 6).
Acknowledgements
The financial supports from IISc, SERB (NO.SB/S1/OC-56/2013),
New Delhi, CSIR (No. 02(0226)15/EMR-II), New Delhi and RL
Fine Chem are gratefully acknowledged. YS Thanks CSIR for an
SPM fellowship.
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