Synthesis of arylsulfonyl-quinones and arylsulfonyl-1,4-diols as FabH inhibitors: Pd-catalyzed direct C-sulfone formation by CS coupling of quinones with arylsulfonyl chloride

Article abstract of DOI:10.1016/j.tetlet.2014.08.023

The Pd-catalyzed direct C-sulfone formation by C-S coupling of quinones with arylsulfonyl chloride has been developed. This methodology provides an effective, convenient method for the synthesis of arylsulfonyl-quinones and arylsulfonyl-1,4-diols, which a

Full text of DOI:10.1016/j.tetlet.2014.08.023

Tetrahedron Letters 55 (2014) 5443–5446
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Synthesis of arylsulfonyl-quinones and arylsulfonyl-1,4-diols as FabH
inhibitors: Pd-catalyzed direct C-sulfone formation by CAS coupling
of quinones with arylsulfonyl chloride
⇑
⇑
Bingyang Ge, Dawei Wang , Weifu Dong, Piming Ma, Yongliang Li, Yuqiang Ding
The Key Laboratory of Food Colloids and Biotechnology, Ministry of Education, School of Chemical and Material Engineering, Jiangnan University, Wuxi 214122, Jiangsu Province, China
a r t i c l e i n f o
a b s t r a c t
Article history:
The Pd-catalyzed direct C-sulfone formation by CAS coupling of quinones with arylsulfonyl chloride has
been developed. This methodology provides an effective, convenient method for the synthesis of aryl-
sulfonyl-quinones and arylsulfonyl-1,4-diols, which are potent inhibitors of FabH.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 8 May 2014
Revised 22 July 2014
Accepted 8 August 2014
Available online 14 August 2014
Keywords:
C-sulfone
Coupling
Quinones
Sulfonyl-1,4-diols
FabH inhibitors
2-Tosylnaphthalene-1,4-diol (A) is considered to be a potent
inhibitor of b-Ketoacyl-ACP-synthase III (FabH),1 which is a key con-
densing enzyme in bacterial fatty acid biosynthesis and a part of
the dissociated fatty acid synthase (FAS).2 In 2008, Reynolds and
co-workers conducted research study in regard to the biological
evaluation of several analogs of 2-tosylnaphthalene-1,4-diol and
2-tosylbenzene-1,4-diol (B, C, D, etc.).3 They found that the sulfo-
nyl group and naphthalene-1,4 diol/quinones were required for
activity against all enzymes (Scheme 1). One important discovery
is that 2-tosylnaphthaquinone (B) was observed to have quite good
activity against Mycobacterium tuberculosis FabH (mtFabH).
OH
OH
O
O
O
S
O
O
S
O
A
B
Anti-ecFabH, Ic50 (nM): 13.6
Anti-mtFabH, Ic50 (nM): 0.61
Anti-mtFabH, Ic50 (nM): 1.99
OH
OH
O
S
O
S
O
C
D
OH
O
OH
During the past twenty years, transition metal catalyzed car-
bonAheteroatom bond formation has been useful as a means to
construct organic molecules by cross coupling from CAX or direct
CAH activation reactions.4 For the CAH activation reactions, qui-
nones and naphthoquinones are important oxidants.5 However, it
is easy for scientists to ignore some quinones and naphthoquinone
derivatives, which are practical intermediates for many drugs,
medicines, and insecticides and can be synthesized by transition
metal catalyzed couplings of quinones with boron reagents,6
indoles,7 anilines,8 and others.9 For example, tosylquinone, as a
potent inhibitor of FabH mentioned in the previous paragraph,
Anti-pfFabH, Ic50 (nM): 31.4
Anti-ecFabH, Ic50 (nM): 9.7
Scheme 1. Several FabH inhibitors.
was synthesized by two-step reactions from two main methods
(Scheme 2).10 Although there have been attempts with one step,
reactions usually need harsh terms or strongly acidic conditions.11
Based on our research on the synthesis of metal complexes and
their photophysical properties and catalytic reactivity,12 herein,
we report Pd-catalyzed direct C-sulfone formation by CAS coupling
of quinones with sulfonyl chloride, which could be easily con-
verted to sulfonyl-1,4-diols.
⇑
Corresponding authors. Tel./fax: +86 510 85917763.
E-mail addresses: wangdw@jiangnan.edu.cn (D. Wang), yding@jiangnan.edu.cn
Initially, simple quinone and TsCl were selected as model sub-
strates in order to check the proposed concept. The reaction was
(Y. Ding).
http://dx.doi.org/10.1016/j.tetlet.2014.08.023
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

5444
B. Ge et al. / Tetrahedron Letters 55 (2014) 5443–5446
Table 2
O
O
O
O
Substrate expansion of quinonesa
Previous work
[O]
ArSH
O
S
O
O
O
O
SAr
Ar
Ar
O
Pd(OAc)2, K2CO3
DCE, 90 o
O
O
S
O
Cl
O
S
O
+
O
O
R
C
O
R
O
SO2X2
or X2
1
2
3
O
S
O
X
Entry
1
Substrate
Product
Yieldb (%)
X = Ci, Br I
O
O
O
O
S
O
Cl
O
O
O
This work
O
O
O
S
O
89 (3a)
Pd
O
S
O
S
Cl
Ar
C-Sulfone forming
One step, directly
Ar
H
O
O
O
O
O
S
O
Cl
Scheme 2. C-sulfone forming reaction from quinones and naphthoquinones.
O
S
O
2
3
71 (3b)
82 (3c)
O
O
carried out in dichloromethane at room temperature. It was found
that the desired product was separated at only 10%, but it implied
that the direct C-sulfone formation of quinones with sulfonyl chlo-
ride would be feasible. Next, the screening of reaction conditions
was conducted in order to obtain a better yield. Results are sum-
marized in Table 1. Generally, the reaction has great dependence
on solvent and base. When potassium carbonate was used as the
base in DCE (1,2-dichloroethane), 89% yield of the target product
was separated (Table 1, entry 12). We also screened other palla-
dium catalysts in this reaction, the results showed that Pd(OAc)2
is the best catalyst. Blank testing showed that the reaction could
not happen without Pd catalyst (Table 1, entry 16).
Having established the optimal conditions: Pd(OAc)2 (5%),
K2CO3 as the base in DCE, we explored the reaction scope of the
Pd-catalyzed direct C-sulfone coupling of quinones with sulfonyl
chloride and the results are shown in Table 2. In general, all the
substrates reacted smoothly to give the corresponding quinone
derivatives. Moderate to excellent yields were obtained regardless
of the steric hindrance of substituent groups in most cases.
O
S
O
MeO
Cl
Cl
OMe
O
S
O
O
O
O
S
O
S
O
O
4
5
6
7
91 (3d)
81 (3e)
83 (3f)
74 (3g)c
O
O
OCH3
OCH3
OMe
O
S
O
Cl
O
S
O
MeO
O
O
O
S
O
n-Pr
n-Pr
Cl
Cl
O
S
O
O
O
O
O
O
S
O
OMe
MeO
F3C
O
S
O
Table 1
Screening of reaction conditionsa
O
O
O
O
CF3
S
Cl
Pd(OAc)2, Base
Solvent
+
TsCl
O
S
O
O
S
O
O
8
9
<5 (3h)
<5 (3i)
O
O
O
3a
O
S
O
1a
2a
O2N
Cl
NO2
Yieldb (%)
O
S
Entry
Catalyst
Base
Solvent
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
NaHCO3
KOH
tBuOK
Cs2CO3
K2CO3
K2CO3
K2CO3
CH2Cl2
Toluene
Benzene
DMF
THF
Dioxane
DCE
DCE
DCE
DCE
DCE
DCE
10
<5
<5
21
18
14
47
41
27
34
44
89
41
23
37
<5
O
O
a
Conditions:
1
(0.5 mmol, 1.0 equiv),
2
(1.5 equiv), Pd(OAc)2 (5%), base
(1.5 equiv), 2 mL DCE, 24 h, reflux.
b
Isolated yields based on 1.
c
2,6-Dimethyl-quinone was used as substrate.
Next, the Pd-catalyzed C-sulfone formation of naphthoquinone
substrates with sulfonyl chloride was explored under the optimized
reaction conditions. A series of reactions could be successfully
converted to afford corresponding naphthoquinone derivatives. As
illustrated in Table 3, full conversions and high yields were
achieved with different substituent groups. For the substrates
bearing the alkyl chain, the yield was slightly affected. In the case
of substrates with a strong electron withdrawing group, this meth-
odology produced a disappointing result.
DCE
DCE
DCE
DCE
Pd(PPh3)4
Pd2(dba)3
—
K2CO3
K2CO3
a
Conditions: 1a (0.5 mmol, 1.0 equiv), 2a (1.5 equiv), Pd (5 mol %), base
(1.5 equiv), 2 mL solvent, 24 h, reflux.
b
Isolated yields based on 1a.

B. Ge et al. / Tetrahedron Letters 55 (2014) 5443–5446
5445
Table 3
ArSO2Cl
Substrate expansion of naphthoquinonesa
O
Pd(0)
O
A
O
oxidation
Pd(OAc)2
K2CO3
O
S
O
addition
SO2Ar
β -H elimination
O
S
O
Cl
+
DCE
O
R
90 oC
R
O
O
2
5
4
ArSO2Pd(II)Cl
B
O
Entry
1
Substrate
Product
Yieldb (%)
Pd(II)
O
O
O
S
O
O
Cl
SO2Ar
O
S
O
84 (5a)
carbopalladation
O
C
O
O
O
S
Scheme 4. The proposed possible mechanism.
Cl
O
S
O
O
2
3
4
63 (5b)
78 (5c)
52 (5d)
O
O
elimination, intermediate C released the coupling product to com-
plete the catalytic cycle.
O
S
O
OMe
MeO
Cl
O
S
O
In conclusion, the direct CAS coupling of quinones and naph-
thoquinones with arylsulfonyl chloride by Pd-catalyzed CAH bond
activation was developed with high yields for the first time. This
methodology provides an effective, convenient method for the syn-
thesis of arylsulfonyl-quinones and arylsulfonyl-1,4-diols. Further
investigation to expand different substrate experiments and
clearly understand this transformation is under way.
O
O
O
S
O
Cl
O
S
O
O
O
OMe
O
S
OCH3
Acknowledgments
Cl
O
S
O
5
6
81 (5e)
73 (5f)
O
MeO
We gratefully acknowledge the financial support of this work by
the National Natural Science Foundation of China (No. 21371080),
the Natural Science Foundation of Jiangsu Province of China
(BK20130125), 333 Talent Project of Jiangsu Province of China
(BRA2012165), and MOE & SAFEA for the 111 Project (B13025).
O
O
OCH3
n-Pr
O
S
O
n-Pr
Cl
O
S
O
O
a
Conditions: 4 (0.5 mmol, 1.0 equiv), 2 (1.5 equiv), Pd(OAc)2 (5 mol %), K2CO3
Supplementary data
(1.5 equiv), 2 mL DCE, 24 h.
b
Isolated yields based on 4.
Supplementary data (detailed experimental procedures, IR, 1H
NMR, and 13C NMR for 3a–3f, 5a–5f, and 6a–6c) associated with
this article can be found, in the online version, at http://
dx.doi.org/10.1016/j.tetlet.2014.08.023. These data include MOL
files and InChiKeys of the most important compounds described
in this article.
Additionally, naphthoquinone and quinone derivatives were
very easily converted to corresponding sulfonyl-1,4-diols. The
reaction was carried out under conditions of sodium borohydride
in methanol, and thereby high yields of sulfonyl-1,4-diols were
separated (Scheme 3).
Finally, a possible reaction mechanism for the reaction was pro-
posed (Scheme 4). Initially, the oxidation addition of Pd with sulfo-
nyl chloride was conducted, forming species B and followed with
carbopalladation, whereby intermediate C was formed. After b-H
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: 94% yield
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