Sulfenylation of β-Diketones Using C- H Functionalization Strategy

Article abstract of DOI:10.1021/acs.orglett.5b01221

Sulfenylation of β-diketones is challenging as β-diketones undergo deacylation after sulfenylation in the reaction medium. The sulfenylation of β-diketones without deacylation under metal-free conditions at ambient temperature via a cross dehydrogenative coupling (CDC) strategy is reported. The resultant products can be further manipulated to form α,α-disubstituted β-diketones and pyrazoles.

Full text of DOI:10.1021/acs.orglett.5b01221

Letter
pubs.acs.org/OrgLett
Sulfenylation of β‑Diketones Using C−H Functionalization Strategy
Begur Vasanthkumar Varun, Karthik Gadde, and Kandikere Ramaiah Prabhu*
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, Karnataka, India
S
* Supporting Information
ABSTRACT: Sulfenylation of β-diketones is challenging as β-diketones undergo deacylation after sulfenylation in the reaction
medium. The sulfenylation of β-diketones without deacylation under metal-free conditions at ambient temperature via a cross
dehydrogenative coupling (CDC) strategy is reported. The resultant products can be further manipulated to form α,α-
disubstituted β-diketones and pyrazoles.
Generally, further attempts to synthesize such compounds by
cleavage of the disulfide linkage or its equivalent have resulted in
deacylation of the product (Scheme 1, eq 2).10,11 Moreover,
these methods require a prefunctionalization thereby adding
extra steps in the synthetic protocol. Recently, Bolm and co-
workers reported a deacylative thiolation of β-diketones, using
copper catalysts, and described that the deacylation is due to an
attack by an unknown nucleophile, probably the residual water,
on the carbonyl carbon.11 Thus, the sulfenylation of β-diketones,
without any deacylation, remains a challenge and such a loss of
one acyl group limits the further manipulation of the product
along with the loss of a potential chiral center. In continuation of
our work in the formation of the C−S bond utilizing benzazoles
(benzoxazole-2-thione and benzothiazole-2-thione) as a thiol
equivalent, we envisaged the coupling of the benzazole with the
β-diketone using K2S2O8 to obtain α-sulfenylated β-diketones.
To the best of our knowledge, the synthesis of α-sulfenylated β-
diketones using a CDC reaction is unprecedented.
rganosulfur compounds are abundant in nature, and they
Oplay a prominent role in the efficient functioning of the
living system.1 Many of the well-known antibiotics such as
penicillin, amoxicillin, etc. contain sulfur atoms.2 Therefore, the
discovery and development of new C−S bond forming reactions
is of prime importance for organic chemists.3 Many pharmaceuti-
cally valuable heterocyclic molecules such as pyrazoles,4 oxazoles
and diazepines,5 etc. utilize β-diketones as essential building
blocks. The active methylene/methine group in this class of
molecules can be used as a nucleophile for a variety of
substitution and addition reactions.6 Further, α-substituted
unsymmetrical β-diketones are useful precursors for generating
new quaternary chiral centers.7 In particularly, thioether of active
methylene compounds are known to inhibit the prevulcanization
of rubber.8
Traditionally, the sulfenylation of active methylene com-
pounds is achieved by direct substitution of a leaving group
(Scheme 1, eq 1).9
The optimization studies were initiated using 5-methyl
benzoxazole-2-thione (1a, 1 equiv) and acetylacetone (2a, 1.5
equiv) in the presence of K2S2O8 and TfOH in CH3CN at room
temperature. Our first reaction yielded 72% of 3a (entry 1, Table
1). Upon increasing the amount of 2a to 2 equiv, the product was
isolated in 87% yield. Further screening was carried out using
Scheme 1. Development of the Reaction
other Bronsted acids such as TFA, MSA, PTSA, and HClO
̈
4
(70% in water) (entries 3−6). Among these acids, aq. HClO4 was
found to be the best alternative for TfOH. Using 5 equiv of aq.
HClO4 resulted in a comparatively less yield (79%, entry 6), but
on using 7 equiv that yield was found to be 94% (entry 7).12
Further, upon decreasing the amount of K2S2O8 to 2.5 equiv, the
yield of the product 3a remains same (entry 8). However, a
further decrease in the amount of K2S2O8 reduces the yield of 3a
to 88% (entry 9). The use of other oxidants such as Na2S2O8,
(NH4)2S2O8, Oxone, DDQ, and aq. TBHP (70%) led to a
Received: April 26, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01221
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Organic Letters
Letter
a
a b
,
Table 1. Screening Studies for Optimization
Scheme 2. Substrate Scope
bcd
, ,
oxidant
(equiv)
acid
(equiv)
yield
entry
oxidant
K2S2O8
Brønsted acid
(%)
e
1
3.0
3.0
3.0
3.0
3.0
3.0
3.0
2.5
2.0
2.5
2.5
2.5
2.5
2.5
2.5
2.5
CF3SO3H
5.0
5.0
5.0
5.0
5.0
5.0
7.0
7.0
7.0
7.0
7.0
7.0
7.0
7.0
7.0
7.0
72
2
K2S2O8
CF3 SO3H
87
nr
3
K2S2O8
CF3COOH
4
K2S2O8
MeSO3H
52
nr
5
K2S2O8
PTSA·H2O
6
K2S2O8
HClO4 (70%)
HClO4 (70%)
HClO4 (70%)
HClO4 (70%)
HClO4 (70%)
HClO4 (70%)
HClO4 (70%)
HClO4 (70%)
HClO4 (70%)
HClO4 (70%)
HClO4 (70%)
79
94
94
88
76
27
59
23
32
nd
nd
7
K2S2O8
8
K2S2O8
9
K2S2O8
10
11
12
13
14
15
16
Na2S2O8
(NH4)2S2O8
Oxone
TBHP (70%)
DDQ
m-CPBA
H2O2 (50%)
a
Reaction conditions: 1a (0.5 mmol), 2a (1.0 mmol), oxidant,
b
c
Brønsted acid, CH3CN (3 mL), rt, 2 h. Isolated yields. nr = no
reaction. nd = not detected. 1.5 equiv of 2a was used.
d
e
decrease in the yield of desired product 3a (entries 10−14).
Using m-CPBA and aq. H2O2 (50%) under the optimized
conditions did not lead to any detection of the required products.
With the optimized reaction conditions in hand, the scope of
the method was explored (Scheme 2). Acetyl acetone (2a) was
treated with a variety of benzazole-2-thione derivatives to furnish
the corresponding sulfenylated products (Scheme 2). As
tabulated, the alkyl and aryl substituted benzoxazole-2-thiones
furnished the desired products 3b, 3c, and 3d in excellent yields
(92%, 77%, and 81% respectively).
Similarly, the halogen substituted benzoxazole-2-thiones
provided the products 3e, 3f, 3g, and 3h in good to excellent
yields (88%, 82%, 73%, and 71% respectively). The unsub-
stituted benzoxazole-2-thione (1i) and benzothiazole-2-thione
(1j) also furnished the corresponding products 3i and 3j in good
yields (77% and 78% respectively). Likewise, the naphthyl ring
fused oxazole-2-thione 1k furnished the desired product 3k in
81% yield. Further, sulfenylation reaction was found to afford the
corresponding products, even in the presence of interfering
functional groups, thus demonstrating the chemoselectivity of
the reaction. Ketone, ester, and carboxylic acid moieties were well
tolerated to yield the products in excellent yields (3l, 3m, and
3n).
Moreover, various β-diketones consisting of the alkyl, aryl, and
hetero aryl group were subjected to undergo the reaction under
the optimal conditions. 3,5-Heptanedione (2b) reacted well with
benzazole-2-thione derivatives such as 1a, 1f, and 1j affording the
products 3o, 3p, and 3q in good to moderate yield (89%, 85%,
and 64%, respectively). Similarly, the unsymmetrical β-diketone
such as benzoylacetone (2c) reacted well with 1a and 1j
respectively to provide the products 3r and 3s in good yields
(84% and 75%). Further, the para-methyl and para-methoxy
substituted benzoyl acetone 2d and 2e reacted well with 1a under
the optimized reaction conditions to afford the products 3t and
3u in moderate NMR yields (89% and 81%, respectively).13
a
Reaction conditions: 1 (0.5 mmol), 2 (1 mmol), K2S2O8 (1.25
mmol), HClO4 (70%, 3.5 mmol), CH3CN (3 mL), at room
b
c
temperature, 2 h. Isolated yield. 1H NMR yield (determined by
d
using terephthalaldehyde as internal standard). Reaction time = 12 h.
Similarly, the para-bromo substituted benzoylacetone (2f) also
provided the corresponding product in good yields (3v, 62%).
The β-diketone containing a heterocyclic moiety such as 1-
(thiophen-2-yl)butane-1,3-dione (2g) underwent a smooth
reaction with 1a and furnished the product 3v (70%). However,
the reaction of 1a with an α-substituted β-diketone, 3-
benzylpentane-2,4-dione (2h), furnished the sulfenylated
diketone 3x in only 11% NMR yield (due to steric reasons).
On the other hand, benzylation of the presulfenylated product
(3a) was found to be successful (see Scheme 5). The scope of
this coupling reaction has been explored by subjecting 4-
methyloxazole-2(3H)-thione (1o) under the optimal reaction
conditions which furnished the expected coupled product 3y in
71% yield.14Also, under the optimal conditions thiophenol (1p)
in a reaction with 2a furnished the product 3z in low yield (17%).
However, 6-nitrobenzo[d]oxazole-2(3H)-thione (1q) did not
furnish the expected product but afforded the oxygen substituted
product 6-nitrobenzo[d]oxazol-2(3H)-one (3aa) in moderate
yield (57%).
As 1,3-diketones are well-known to exhibit remarkable keto−
enol tautomerism, it is noteworthy to examine the effect of
substituents on ketones on the tautomerism of the products
(Scheme 3). Hence, diketones, 2,2,6,6-tetramethylheptane-3,5-
dione (2i) and 1,3-diphenylpropane-1,3-dione (2j) in a reaction
with 1a under the optimal conditions furnished the products 4a
and 4b (33% and 48%, respectively). Unlike the products that
have been obtained with other diketones (Scheme 2), the
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Scheme 3. Effect of Bulky Group on Keto-enol
Tautomerism
Scheme 6. Mechanist Studies
a b
,
a
Reaction conditions: 1 (0.5 mmol), 2i or 2j (1 mmol), K2S2O8 (1.25
mmol), HClO4 (70%, 3.5 mmol), CH3CN (3 mL) at room
b
temperature, 7 h. Isolated yield.
sulfenylated products 4a and 4b predominantly existed in their
keto form. This observation may be attributed to the steric
hindrance by the bulky substituents such as tert-butyl and phenyl
groups. The steric effect occurs due to the close proximity of the
hydrogen atoms from the phenyl/tert-butyl group to the
benzazole ring when the enol is formed (see the Supporting
Information for relevant spectral data).
To determine the feasibility of sulfenylation in large scale, a
scale up reaction (1 gram, Scheme 4) was performed for 1a and
1j with acetyl acetone to furnish 3a and 3j respectively in 91%
and 82% yields (Scheme 4).
a
Scheme 4. Scaling up Reaction
a
b
Ratio of the products based on 1H NMR conversion. Isolated yields.
a
Isolated yield.
presence of aq. HClO4, the disulfide bond of 1,2-bis(benzo[d]-
thiazol-2-yl)disulfane (1j′) is cleaved to form 3j, 1j, and 7 in a
49:11:9 ratio (1H NMR conversion).3d However, aq HClO4
failed to cleave the disulfide bond of diphenyl disulfide (1p′) and
hence the product 3z was not found, indicating the need for the
protonable nitrogen atom (Scheme 6, eq 1). The acid medium is
essential to alter the thione−thiol equilibrium.
Further, to demonstrate the utility of this reaction, the active
methine carbon of the sulfenylated product, 3a, was used as a
nucleophile with electrophilic reagents such as benzyl bromide
and allyl bromide to yield the corresponding products which
contain quaternary carbons (3x and 5) in excellent yields (78%
and 72%, respectively). Also, 3a was reacted with hydrazine and
phenyl hydrazine to obtain the derivatives of the heterocycle
pyrazoles 6a and 6b, in 93% and 78% yield, respectively (Scheme
5).
Further, the reaction of 1j′ and 2a under standard reaction
conditions give 3j and 8 in the ratio 80:20 (1H NMR
conversion),15 indicating the need for a protonable nitrogen
atom and potassium persulfate (Scheme 6, eq (ii)). Also under
standard reaction conditions, thiophenol and diphenyl disulfide
furnished the product (3z) in very low yields. The reaction
carried out between 1a and 2a in the presence of radical
inhibitors/scavengers such as TEMPO and BHT lowered the
yield of 3a (23% and 42% respectively), indicating a possible
radical mediated pathway (Scheme 6, eq (iii)). Additionally,
K2S2O8 does not have any role in disulfide bond formation under
standard reaction conditions (Scheme 6, eq (iv)). Based on all
these results, a mechanism has been proposed (Scheme 7).16
In conclusion, we have developed a metal-free CDC reaction
for sulfenylation of β-diketones at ambient temperature. The
resultant products do not undergo deacylation, which is the
highlight of this work. Since the reaction has been shown to
generate an asymmetric quaternary carbon center, there is scope
for developing enantioselective methods. Further investigations
in this direction are currently underway in our laboratory.
To understand the reaction mechanism, various control
reactions were carried out (Scheme 6). As expected, in the
Scheme 5. Synthetic Applications
a
b
Reaction conditions: 3a, benzyl bromide (1.5 equiv). Yield based on
c
d
the recovery of starting material. Allyl bromide (5 equiv). NH2NH2·
H2O (80%, 1.5 equiv), rt, 2 h. PhNHNH2 (1.5 equiv), rt, 6 h. Values
e
in the parentheses are isolated yields.
C
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Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ASSOCIATED CONTENT
* Supporting Information
Experimental procedure, characterization data of all the
compounds, spectral data. The Supporting Information is
available free of charge on the ACS Publications website at
DOI: 10.1021/acs.orglett.5b01221.
■
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AUTHOR INFORMATION
Corresponding Author
■
Katebzadeh, K.; Roman, L.; Bergquist, K. E.; Lindstrom, U. M. J. Org.
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*E-mail: prabhu@orgchem.iisc.ernet.in.
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The financial support from IISc, and DST (SERB), New-Delhi is
gratefully acknowledged. Authors thank Dr. A. R. Ramesha (RL
Fine Chem) for useful discussions. B.V.V. thanks CSIR for a
senior fellowship.
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