Parallel syntheses of eight-membered ring sultams via two cascade reactions in water

Article abstract of DOI:10.1021/co400116p

From vinyl sulfonamides as precursors to vinyl sulfonamide epoxides, two cascade reaction protocols were developed to synthesize eight-membered ring sultams in water. These protocols employ intermolecular Michael addition by NaOH or NaHS in water, followed by rapid proton transfer and intramolecular 8-endo-tet epoxide ring-opening to give medium-size sultams selectively in one-pot. Novel core structures and high synthetic efficiency make these cascade reactions highly suitable for sultam library production. Both reactions proceeded well and afforded the respective sultams in good yields under environmentally friendly conditions.

Full text of DOI:10.1021/co400116p

Technology Note
pubs.acs.org/acscombsci
Parallel Syntheses of Eight-Membered Ring Sultams via Two Cascade
Reactions in Water
Tao Ji,† Yanjie Wang,† Min Wang,† Ben Niu,† Ping Xie,‡ Charles U. Pittman, Jr.,§ and Aihua Zhou*,†
†Pharmacy School, Jiangsu University, Xuefu Road 301, Zhenjiang City, Jiangsu, 212013, China
‡Scientific Information Research Institute, Jiangsu University (Library), Xuefu Road 301, Zhenjiang, Jiangsu, 212013, China
§Department of Chemistry, Mississippi State University, Mississippi State, Mississippi 39762, United States, United States
S
* Supporting Information
ABSTRACT: From vinyl sulfonamides as precursors to vinyl
sulfonamide epoxides, two cascade reaction protocols were
developed to synthesize eight-membered ring sultams in water.
These protocols employ intermolecular Michael addition by NaOH
or NaHS in water, followed by rapid proton transfer and
intramolecular 8-endo-tet epoxide ring-opening to give medium-
size sultams selectively in one-pot. Novel core structures and high
synthetic efficiency make these cascade reactions highly suitable for
sultam library production. Both reactions proceeded well and afforded the respective sultams in good yields under
environmentally friendly conditions.
KEYWORDS: Michael addition, sultam, sulfonamide, parallel synthesis, eight-membered ring compound
ulfonamides are known to possess broad-spectrum
bioactivity.1 these compounds have gradually become
inorganic NaOH and NaHS can be easily dissolved in it.
Sulfonamides are also slightly soluble in water. Here NaOH and
NaHS were used as nucleophiles for initiating these two
reaction sequences, both of which proceeded well under
environmentally friendly conditions.
S
favorite compounds for drug discovery. Until now, some
powerful synthetic methods for the generation of sultam
derivatives have been developed. These routes include several
transition metal-catalyzed reactions that afforded sultams,2
Friedel−Craft reactions,3 ring-closing metathesis (RCM),4
cyclizations of aminosulfonyl chlorides,5 [3 + 2] cyclo-
additions,6 both Diels−Alder7 and Heck reactions,8 and both
intramolecular oxa-Michael and Baylis−Hillman reactions.9
However, most sultam cyclization reactions above have been
carried out in toxic organic solvents and complex procedures
are needed to make compound libraries. Until now, no
explorations of using water as a solvent for sultam synthesis
has appeared, let alone the use of efficient cascade reactions to
synthesize medium-sized ring sultams. Using water as a reaction
solvent not only avoids toxic organic solvents and a tiresome
solvent recovery but also prevents environmental pollution.
Water is a polar and universal solvent suitable for reactions
employing inorganic salt reactants, making water a reaction
solvent of choice for most people.
Vinyl sulfonamide is an important type of precursor for
making sultams. It embodies a potent Michael acceptor with an
electron-deficient double bond, which can be used for many
different Michael-addition reactions.18 Vinyl sulfonamides were
prepared by reacting 2-chloroethanesulfonyl chloride with
primary amines in DCM containing triethylamine (Scheme
1). These reactions with a variety of amines afforded a series of
vinyl sulfonamides 1a−h in good yields. Alkylation of the
resultant sulfonamides with allyl bromide in CH3CN in the
presence of K2CO3 at 95 °C afforded a series of secondary vinyl
sulfonamides 2a−h (Scheme 1), also in high yields.19
Compounds 2a−h have two carbon−carbon double bonds of
different reactivity. One is electron-rich, and other is electron-
poor. Thus, selective epoxidations of the electron-rich double
bond of vinyl sulfonamides 2a−h with m-CPBA were carried
out and the expected vinyl sulfonamide epoxides 3a−h were
obtained in good yields.20
Linear sulfonamides have been well studied,10 but their cyclic
analogs, sultams, are far less explored in the respect of synthetic
methods and biological activities.11 Figure 1 presents several
sulfonamide derivatives which display various potent biological
With both a potent Michael acceptor and an epoxide
function present in the molecule, several cyclization reactions
to generate sultams can be envisioned. Here, two cascade
reactions were designed, one using NaOH and the other using
NaHS as the triggering nucleophile. NaOH and NaHS can
activities. These include a H4 receptor inverse agonist,12
a
carbonic anhydrase inhibitor,13 a cannabinoid-1 receptor
(CB1R) inverse agonist for the treatment of obesity,14 an
MMP inhibitor,15 an HIV-1 protease inhibitor,16 or an
antagonist for the EP1 receptor.17 Here, we’ve developed two
efficient cascade ring-forming sultam synthesis reactions which
were carried out in water. Water is a polar, protic solvent,
Received: September 13, 2013
Revised: October 30, 2013
Published: November 1, 2013
© 2013 American Chemical Society
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ACS Combinatorial Science
Technology Note
Figure 1. Representative biologically active sulfonamides and sultams.
Scheme 1. Selective Epoxidations of Vinyl Sulfonamides
Scheme 3. Representative Example Using NaOH as a
Nucleophile
easily provide OH− and SH− ions in water. Both of which are
good nucleophiles, which participate in Michael addition
reactions easily, and theoretically can also react with an
epoxide. NaOH and NaHS reacted with vinyl sulfonamide
epoxides very slowly in water at room temperature. However,
when the temperature increased to 90 °C, these reactions
became much faster. TLC analysis demonstrated both reactions
afforded a single major product after overnight.
Scheme 2. Three Possible Reaction Routes Using NaOH or NaHS
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Table 1. Cascade Reactions of Vinyl Sulfonamide Epoxides with NaOH in Water
There are three possible reaction routes (Scheme 2). In
Route A, NaOH or NaHS attacks epoxide ring from the less
hindered side first, which then could be followed by
intramolecular 7-endo-trig oxa-Michael addition to give the
seven-membered ring sultams 4/5. In route B, NaOH, or
NaHS undergo intermolecular Michael-addition first, followed
by 7-exo-tet epoxide ring-opening to give seven-membered ring
sultams 6/7. Finally, in route C, NaOH or NaHS again first
initiate intermolecular Michael-addition, which is followed by 8-
endo-tet epoxide ring-opening to produce eight-membered ring
sultams 8/9.21 Each of these three cascade routes afford
different reaction products.
sulfonamide epoxide 3c with NaOH was used as a
representative example (Scheme 3). After the reaction, 8c
was obtained in 77.8% yield. Then 8c was reacted with TBSCl
in the presence of DMAP and triethylamine to give compound
1
11. The H NMR of compound 11 exactly matched those of
eight-membered ring compound 11′ which was synthesized by
us previously from 10.11 This proved that the cascade reactions
triggered by NaOH in hot water afforded eight-membered ring
sultam (Route C). The aqueous OH− ion underwent Michael-
addition first. Then the resulting alkoxy ion intermediate
attacked the epoxide ring at the least substituted end opening
the epoxide while closing system to the eight-membered ring
sultam 8c (Route C).
The reaction of vinyl sulfonamide epoxide with NaOH
conducted in hot 90 °C water only afforded one major product,
so it was easy to isolate the product and verify its structure.
Here the major product 8c from the reaction of vinyl
Seven different vinyl sulfonamide epoxides were reacted with
NaOH in hot water, affording eight-membered ring sultams
8a−g, as presented in the Table 1. When the more nucleophilic
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Table 2. Cascade Reactions of Vinyl Sulfonamide Epoxide with NaHS in Water
out because the reaction product’s IR spectra did not exhibit
any S−H absorption at 2400−2600 cm−1.22 This ruled out the
presence of the -SH function in the final product, which means
the HS− ion did not attack epoxide ring from the less hindered
side first. Instead, this nucleophile first induced intermolecular
Michael-addition and then the resultant thiol ion intermediate
attacked epoxide ring via the 8-endo-tet process to give the
eight-membered ring sultams 9b−h (Route C). Table 2
summarizes the reactions of seven vinyl sulfonamide epoxides
with NaSH in hot water. All reactions produced eight-
membered ring sultams 9b−h in yields of 63−77%.
Scheme 4. Synthesis of Reaction Precursor for Making Nine-
Membered Ring Sultam
To further investigate a modified protocol to possibly make
nine-membered ring sultams, benzylamine was reacted with 2-
chloroethylsulfonyl chloride and vinyl sulfonamide 2g was
obtained in a good yield. However, alkylation of 2g by 4-
bromide-1-butene in acetonitrile solvent in the presence of
HS− was used as the nucleophile to react with the vinyl
sulfonamide epoxide, one major product was again readily
generated in hot water based on TLC analysis. Scheme 2
illustrates the three possible reaction routes. Route A was ruled
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Molecular Modeling Studies of TIBO-Like Cyclic Sulfones as Non-
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K2CO3 at 95 °C afforded only a very small amount of 12. The
majority of 2g still remained unreacted after 48 h, even when
2−3 equivalent excesses of 4-bromide-1-butene were used.
Instead, 4-bromide-1-butene was converted into butadiene
instead of reacting with sulfonamide 2g. Another base, NaH,
was also tried, but the yield was also low so not further tests
were made to produce nine-membered ring sultams in water
were conducted.
Compared to what is known about cyclic sultam syntheses,
the advantages of these two cascade protocols are their high
synthetic efficiency, novel core structures, and the use of water
as a reaction solvent. Both reactions are suitable for synthetic
Auto-Robot application. Within a short reaction time, a series
of novel medium-sized ring core structures can be produced in
good yields, and they are good scaffolds for sultam libraries.
In conclusion, we have discovered two cascade reactions
which were triggered by NaOH or NaHS in hot water to
synthesize eight-membered ring sultams in one pot. This is the
first report of using water as a convenient and environmentally
friendly solvent for sultam parallel synthesis. Both cascade
reactions followed the same reaction route, in which an initial
intermolecular Michael addition reaction was followed by
proton transfer and then an 8-endo-tet intramolecular epoxide
ring-opening which then closed the eight-membered sultam
ring. Both reaction sequences afforded the respective sultams in
moderate to good yields under mild conditions. These resultant
novel sultams can be directly used as scaffolds for large sultam
libraries.
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ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental details and spectral characterization for all
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: ahz@ujs.edu.cn.
■
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T.J., Y.W., M.W., and B.N. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This investigation was generously supported by funds (Item
Num.: 1281290006) provided by Jiangsu University.
■
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