Hydroxysulfonylation of Quinones with Aryl(alkyl)sulfonyl Hydrazides for the Synthesis of 1,4-Dihydroxy-2-aryl(alkyl)sulfonylbenzenes

Article abstract of DOI:10.1002/ejoc.201701199

β-Ketoacyl-ACP-synthase III (FabH) plays an important role in bacterial fatty-acid biosynthesis as an important condensing enzyme. 1,4-Dihydroxy-2-tosylnaphthalene and its analogues are potent inhibitors of FabH. Traditional methods for the synthesis of these compounds still suffer from some drawbacks. In this work, an efficient copper-catalyzed method for the hydroxysulfonylation of quinones with aryl(alkyl)sulfonyl hydrazides was developed for the direct synthesis of 1,4-dihydroxy-2-phenylsufonylbenzenes. A series of biologically useful FabH inhibitors were obtained in good yields under argon. Both aryl and alkyl substituents were well tolerated in the reaction.

Full text of DOI:10.1002/ejoc.201701199

A Journal of
Accepted Article
Title: Hydroxysulfonylation of Quinones with Aryl(Alkyl)sulfonyl
Hydrazides for the Synthesis of 1,4-Dihydroxy-2-
aryl(alkyl)sulfonylbenzenes
Authors: Lianghua Zou, Pinggui Li, Yanchun Li, Tao Zhu, and Zhimeng
Wu
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201701199
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10.1002/ejoc.201701199
European Journal of Organic Chemistry
COMMUNICATION
Hydroxysulfonylation of Quinones with Aryl(Alkyl)sulfonyl
Hydrazides for the Synthesis of 1,4-Dihydroxy-2-
aryl(alkyl)sulfonylbenzenes
Ping-Gui Li,[c]# Yan-Chun Li,[a]# Tao Zhu,[a] Liang-Hua Zou,*[a],[b] and Zhimeng Wu*[a]
of FabH inhibitors have been developed. In 2004, Yadav and
coworkers described a method for the synthesis of such compounds
through addition of arylsulfinic acids to p-quinones using ionic
liquids as media (Scheme 2, eq 1).[7] Besides, sulfinic salts were
also employed for such transformations by Reynolds[4] and Bruce[8]
group (Scheme 2, eq 2). Very recently, Wang and coworkers
reported a Pd-catalyzed system through two step reactions staring
from quinones and aryl sulfonyl chlorides (Scheme 2, eq 3).[9]
However, narrow substrate scope still remains a big challenge for
these methods, which may limit their application in medicinal
chemistry. For example, normally only arylsulfonyl groups were
employed in the reaction system.[7], [9] Based on our previous work
on the sulfenylation of indoles with arylsulfonyl chlorides,[10]
herein, we report a copper-catalyzed strategy for the synthesis of
Abstract: -Ketoacyl-ACP-synthase III (FabH) plays an important
role in bacterial fatty acid biosynthesis as an important condensing
enzyme. 1,4-Dihydroxy-2-tosylnaphthalene and its analogs are
potent inhibitors of FabH. The traditional methods for the synthesis
of these compounds still remain some drawbacks. In this work, an
efficient copper-catalyzed hydroxysulfonylation of quinones with
aryl(alky)sulfonyl hydrazides has been developed for the direct
synthesis of 1,4-dihydroxy-2-phenylsufonyl benzenes. A series of
biologically useful FabH inhibitors were obtained in good yields
under argon atmosphere. Both aryl and alkyl substituents were well
tolerated in the reaction.
1,4-dihydroxy-2-phenylsufonylbenzenes
using
arylsulfonyl
Introduction
hydrazides as reagents (Scheme 2, eq 4).[11]
-Ketoacyl-ACP-synthase III (FabH) is an important condensing
enzyme in bacterial fatty acid biosynthesis and also a part of the
dissociated fatty acid synthase (FAS).[1] The enzyme widely exists
in Plasmodium falciparum and Mycobacterium tuberculosis and
acts as a target for developing promising new antibacterial,
antiparasitic, and antimycobacterial agents.[2] 1,4-Dihydroxy-2-
tosylnaphthalene (Scheme 1, A) and its analogs are potent
inhibitors of FabH.[3] In 2008, Reynolds group reported that the
sulfonyl group and 1,4-dihydroxynaphthalene motif were crucial
building blocks for the activity against FabH enzymes
(Scheme 1).[4]
O
OH
R3
R2
R3
SO2Ar
[bmim]BF4
r.t.
+
+
Ar-SO2H
RSO2Na
eq 1
R1
R2
R1
O
OH
OH
O
O
R1
R2
R1
R2
SO2R
TFA, DCM, H2O
eq 2
OH
O
O
R
O
S
O
Pd(OAc)2, K2CO3
DCE, 90 o
+
S
Cl
O
O
C
R
O
O
O
Me
Me
OH
O
S
OH
R
O
S
OH
O
NaBH4, MeOH
r.t., 1 h
S
eq 3
O
O
OH
OH
A
OH
This work:
O
B
Anti-ecFabH, Ic50 (nM): 13.6
Anti-mtFabH, Ic50 (nM): 0.61
OH
OH
O
S
Cu(OAc)2 H2O (0.1 equiv.)
Mn(OAc)3
Anti-pfFabH, Ic50 (nM): 31.4
R'
O
2H2O (0.1 equiv.)
toluene, 100 o
eq 4
+
R'
S
NHNH2
O
Scheme 1. Bioactive FabH inhibitors.
C
O
R' = Aryl or alkyl groups
O
The traditional procedure for the synthesis of 1,4-dihydroxy-2-
phenylsufonylbenzenes involves the nucleophilic addition of
arylsulfinic acids to quinones catalyzed by an acid or a base.[5] By
varying pH value, the reaction was further investigated using
various solvents.[6] Recently, some novel methods for the synthesis
Scheme 2. Represented procedures for the synthesis of 1,4-dihydroxy-
2-phenylsufonylbenzenes.
Results and Discussion
[a]
The Key Laboratory of Carbohydrate Chemistry and Biotechnology,
Ministry of Education, School of Biotechnology, Jiangnan University
Lihu Avenue 1800, Wuxi 214122 (P.R. China)
E-mail: zoulianghua@jiangnan.edu.cn; zwu@jiangnan.edu.cn
School of Pharmaceutical Science, Jiangnan University, Lihu
Avenue 1800, Wuxi 214122 (P.R. China)
The initial screening and optimization of the reaction conditions
was conducted with 1,4-naphthalenedione (1a) and p-
toluenesulfonyl hydrazide (2a) as model substrates (Table 1).
Using 1a and 2a in a 1:2 ratio (on a 0.25 mmol scale),
Cu(OAc)2·H2O (0.2 equiv.) as catalyst, Mn(OAc)3·2H2O
(0.2 equiv.) as additive in toluene, product 3a was obtained in
48% yield after 4 h at 80 oC under air atmosphere (Table 1,
entry 1). Next, various solvents were screened for their influence
on the reaction behaviour. Other solvents such as CH3CN, DMSO,
[b]
[c]
Peter Grünberg Institute (PGI-8), Forschungszentrum Jülich GmbH,
Jülich 52425, Germany
# These authors contributed equally to this work.
Supporting information for this article is available on the WWW
under https://www.eurjoc.com.ꢀ
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10.1002/ejoc.201701199
European Journal of Organic Chemistry
COMMUNICATION
Table 1. Screened reaction conditions.a
entry 11). At last, a simple quinone was also investigated, affording
product 3l in 50% yield (Table 2, entry 12).
Table 2. The reaction scope of quinones with sulfonyl hydrazides.a
Entry Product, Yield
Entry
Product, Yield
Cl
Me
OH
O
S
OH
O
1
7
S
O
O
3a, 82%
OMe
3g, 66%
OH
OH
I
OH
O
OH
OH
S
O
O
S
2
3
8
9
3b
, 81%
O
3h, 75%
OH
OH
tBu
CN
O
S
OH
O
O
S
O
3c, 65%
OH
3i, 30%
OH
OH
O
S
O
NO2
OH
O
a
4
10
Reaction conditions: 1,4-naphthalenedione (1a) (0.25 mmol), p-
S
3d
, 81%
O
toluenesulfonyl hydrazide (2a) (0.5 mmol), Cu(OAc)2·H2O (0.2 equiv.),
OH
o
3j, 86%
Mn(OAc)3·2H2O (0.2 equiv.), toluene (4 mL), 100 C, air atmosphere,
b
4 h. In the absence of Mn(OAc)3·2H2O. c Argon atmosphere. d Using
OH
OH
OH
O
S
0.1 equiv. of Cu(OAc)2·H2O and 0.1 equiv. of Mn(OAc)3·2H2O.
OH
OH
O
S
O
5
6
11
12
O
DMF and dioxane gave lower yields (Table 1, entries 2-5). In the
absence of Cu(OAc)2·H2O or Mn(OAc)3·2H2O, the yield was
dropped to 36% and 31% yields, respectively (Table 1, entries 6
and 7). Under argon atmosphere instead of air, the yield was
increased to 60% (Table 1, entry 8). Decreasing the loading of
Cu(OAc)2·H2O and Mn(OAc)3·2H2O to 0.1 equivalents led to a
better yield of 82% when the reaction was performed at 100 oC
(Table 1, entry 9). The yield was dropped to 30% yield when a
catalyst and an additive were both omitted in the reaction (Table 1,
entry 10). Different copper salts such as CuI, Cu2O and CuCN
were screened in the reaction, albeit gave lower yields (Table 1,
entries 11-13).
3k, 61%
3e, 30%
F
Me
OH
OH
OH
O
S
O
S
O
3f, 65%
O
3l, 50%
OH
a Reaction conditions: 1,4-naphthalenedione (1a) (0.25 mmol), sulfonyl
hydrazides (2b-l) (0.5 mmol), Cu(OAc)2·H2O (0.1 equiv.),
Mn(OAc)3·2H2O (0.1 equiv.), toluene (4 mL), 100 oC, argon
atmosphere, 4 h.
With the optimized reaction conditions in hand (see entry 9 of
Table 1), the scope of reaction was investigated with a broad range
of substrates with electron-rich or -deficient substituents at the 4-
position of arylsulfonyl hydrazides (Table 2). At first, electron-rich
substituents -OMe and -tBu were tested in the reaction, providing
the corresponding products 3b-c in 81% and 65% yields,
respectively (Table 2, entries 2 and 3). For the substrate without a
substituent at the aromatic group, product 3d was obtained in 81%
yield (Table 2, entry 4). The yield was dropped to 30% when a
bulky biphenyl group was substituted for the sulfonyl hydrazide
(Table 2, entry 5). Furthermore, some substrates with various
electron-poor substituents were tried under the optimized reaction
conditions. For example, substituents such as -F, -Cl and -I
afforded the corresponding products in good yields (Table 2,
entries 6-8). An attempt to use nitrile group led to a low yield of
30% (Table 2, entry 9). To our delight, however, the reaction
worked very well with a nitro group (Table 2, entry 10). It is
noteworthy that alkylsulfonyl hydrazide could also be employed in
the reaction system, providing product 3k in good yield (Table 2,
In order to examine whether substituents in ortho-position would
hamper the outcome of the reaction, compounds 4a and 4b were
chosen to react under the optimized reaction conditions (Scheme 3).
Interestingly, for the substrate 4a, the C-Cl bond was cleaved to
provide the same product 3a (35% yield) as for substrate 1a. When
the substrate 4b was applied to the procedure, an unexpected
product 5 was obtained in an acceptable yield of 30%. The
structure of
5 was unambiguously determined by X-ray
crystallography (Scheme 3).[12]
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Scheme 5. Gram scale synthesis of 3a.
Conclusions
In conclusion, a novel procedure for the direct synthesis of 1,4-
dihydroxy-2-aryl(alkyl)sulfonylbenzenes has been developed. The
reaction might proceed via a free radical process, which is
catalyzed by a copper catalyst in the presence of Mn(OAc)3·2H2O
as an additive. Both aryl and alkyl groups were well tolerated in the
reaction, providing a series of bioactive FabH inhibitors in good
yields.
Scheme 3. Substrate scope with substituents in ortho-position.
As for the mechanism, we speculated that it might be a free
radical process and several control experiments were performed
(Scheme 4). When 2.0 equivalents of radical scavenging reagent
2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) was introduced into
the standard reaction system, a mixture was obtained, containing
little product 3a, which was rather difficult to purify by column
chromatography. It is noteworthy that no product 3a was observed
by TLC when the amounts of TEMPO were increased to 4.0
equivalents. These results indicated that the reaction might proceed
via a free radical process. Initially, a possible radical is generated
from sulfonyl hydrazide with the release of nitrogen. Then,
conjugate addition of the radical to 1,4-benzoquinone afforded the
sulfonylated quinine. Hydrolysis of the intermediate might proceed
to produce the final product.
Experimental Section
General procedure for the synthesis of 1,4-dihydroxy-2-
aryl(alkyl)sulfonylbenzenes (3a as one example): In a schlenk tube
filled with argon,
a mixture of 1,4-naphthoquinone (1a)
(0.25 mmol), p-toluenesulfonyl hydrazide (2a) (0.50 mmol),
Cu(OAc)2·H2O (0.1 equiv.), Mn(OAc)3·2H2O (0.1 equiv.), in
toluene (4.0 mL) was stirred at 100 °C for 4 h. Upon completion,
the mixture was filtered through filtering paper, concentrated and
purified by silica gel column chromatography (ethyl acetate /
petroleum ether: from 1:5 to 1:2, v:v), providing 3a in 82% yield.
Acknowledgements
Scheme 4. Radical experiments.
This work is financially supported by NSF of Jiangsu Province
(BK20150129), a Sponsored Program by Jiangsu Province for the
To test the scalability of the new strategy, a 10 mmol scale
reaction was performed under the optimized reaction conditions
using 10 mmol 1,4-naphthalenedione (1a) and 20 mmol p-
toluenesulfonyl hydrazide (2a) (Scheme 5). Product 3a was
obtained in 80% yield, demonstrating the great potential of the
present method for large scale synthesis in industry.
Cultivation
of
Innovation
and
Pioneering
Doctor
(1016010241151030), the Project for Jiangsu Scientific and
Technological Innovation Team, Fund for Jiangsu Distinguished
Professorship, Program the 111 Project (No. 111-2-06).
Keywords: Copper catalysis • Hydroxysulfonylation • Quinones •
Sulfonyl hydrazides • Radicals
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[12] The structure of 5 was determined by X-ray crystallographic
analysis. CCDC 1517574 (5) contains the supplementary
crystallographic data for this paper. These data can ban
obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
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COMMUNICATION
Hydroxysulfonylation
Ping-Gui Li, Yan-Chun Li, Tao Zhu, Liang-
Hua Zou,* and Zhimeng Wu*
Page No. – Page No.
Hydroxysulfonylation of Quinones with
Aryl(Alkyl)sulfonyl Hydrazides for the
Synthesis
of
1,4-Dihydroxy-2-
aryl(alkyl)sulfonylbenzenes
A copper-catalyzed procedure for the direct synthesis of 1,4-dihydroxy-2-phenylsufonyl
benzenes is presented starting from simple quinones and sulfonyl hydrazides. A series
of biologically useful FabH inhibitors were obtained in good yields. Both aryl and alkyl
substituents were well tolerated in the reaction.
This article is protected by copyright. All rights reserved.