Selective synthesis of seven- and eight-membered ring sultams via two tandem reaction protocols from one starting material

Article abstract of DOI:10.1021/ol301535j

From one starting material, two tandem reaction protocols to synthesize seven- and eight-membered ring sultams were developed. One protocol employs intermolecular epoxide ring-opening by NaN₃, followed by an intramolecular 7-endo-trig oxa-Michael addition reaction. The second protocol applies to intermolecular aza-Michael addition of a primary amine, followed by 8-endo-tet intramolecular epoxide ring-opening of the resultant amine intermediate. Both protocols afforded the respective sultams in good yields under mild reaction conditions.

Full text of DOI:10.1021/ol301535j

ORGANIC
LETTERS
2012
Vol. 14, No. 14
3700–3703
Selective Synthesis of Seven- and Eight-
Membered Ring Sultams via Two Tandem
Reaction Protocols from One Starting
Material
Min Wang,† Yanjie Wang,† Xueyong Qi,† Guohua Xia,† Kun Tong,† Jinchang Tu,†
Charles U. Pittman Jr.,‡ and Aihua Zhou*,†
Pharmacy School, Jiangsu University, Xuefu Road 301, Zhenjiang City, Jiangsu 212013,
China, and Mississippi State University, Mississippi State, Mississippi 39762,
United States
ahz@ujs.edn.cn
Received June 4, 2012
ABSTRACT
From one starting material, two tandem reaction protocols to synthesize seven- and eight-membered ring sultams were developed. One protocol
employs intermolecular epoxide ring-opening by NaN3, followed by an intramolecular 7-endo-trig oxa-Michael addition reaction. The second
protocol applies to intermolecular aza-Michael addition of a primary amine, followed by 8-endo-tet intramolecular epoxide ring-opening of the
resultant amine intermediate. Both protocols afforded the respective sultams in good yields under mild reaction conditions.
The growing demand for quick syntheses of small
molecules for high-throughput screening has provided
many opportunities and challenges for medicinal chemists.
This is especially true for small molecules with privileged
functional groups such as sulfonamides.1 This category of
compounds were well investigated before, but their analo-
gues, the cyclic sulfonamide compounds (also called
sultams), have been much less studied. Recently, sultams
have attracted more attention because of their varieties of
biological activities. Figure 1 shows six sultam derivatives
that display different biological activities. These include an
HIV integrase inhibitor,2 a carbonic anhydrase inhibitor,3
a cannabinoid-1 receptor (CB1R) inverse agonist for the
treatment of obesity,4 an MMP inhibitor,5 an HIV-1
protease inhibitor,6 and an inhibitor of both falcipain-2
and Plasmodium falciparum W-2.7
Some powerful synthetic methods for the generation of
sultam derivatives have been developed. These methods
include several transition metal-catalyzed reactions that
† Jiangsu University.
‡ Mississippi State University.
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r
10.1021/ol301535j
Published on Web 07/02/2012
2012 American Chemical Society

Table 1. Tandem Reactions Initiated by an Epoxide Ring
Opening Using NaN3, Followed by 7-endo-trig Intramolecular
Oxa-Michael Addition
Figure 1. Biologically active sultams.
afforded sultams,8 Friedel-Craft reactions,9 Ring-Closing
Metathesis (RCM),10 cyclizations of aminosulfonyl
chlorides,11 [3 þ 2] cycloadditions,12 both DielsꢀAlder13
and Heck reactions,14 and intramolecular oxa-Michael
and BaylisꢀHillman reactions.15 All of these reactions
afforded sultams in a few step with good yields.
Scheme 1. Selective Epoxidation of Vinyl Sulfonamides
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In this paper, two tandem reactions are reported that use
the same vinyl sulfonamide epoxide starting material
ꢁ
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Overman, L. E. J. Am. Chem. Soc. 1999, 121, 700–709. (b) Greig, I. R.;
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Kataeva, O.; Metz, P. Adv. Synth. Catal. 2005, 347, 754–758.
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Org. Lett., Vol. 14, No. 14, 2012
3701

Table 2. Tandem Reactions Initiated by an R2-NH2 Intermo-
lecular Aza-Michael Addition Followed by an 8-endo-tet In-
tramolecular Ring-Opening of an Epoxide
Scheme 2. Possible Tandem Reaction Routes
to make both seven- and eight-membered ring sultams.
This vinyl sulfonamide epoxide was produced in three
effective steps presented in Scheme 1.15
The synthesis started by reacting a primary amine with
2-chloroethanesulfonyl chloride in DCM solvent in the
presence of triethylamine to generate an R,β-unsaturated
sulfonamide 1. Alkylation of 1 with allyl bromide in the
presence of K2CO3 afforded product 2 with an electron-
poor and an electron-rich double bond.10,15 The latter was
selectively epoxidized by m-CPBA to give vinyl sulfona-
mide epoxides 3 (see Scheme 1) in good yield under mild
conditions (totally eight different amines were used).
A tandem intermolecular ring-opening reaction of the
epoxide followed by intramolecular oxa-Michael reaction
to the electron-deficient double bond was planned and
developed. NaN3 was used as a nucleophile for this reac-
tion first. Experiments proved that NaN3 was not a good
nucleophile for intermolecular aza-Michael addition reac-
tion of vinyl sulfonamide in water. However a facile
intermolecular epoxide ring-opening reaction by NaN3
occurred in water solution (pH around 9). Furthermore,
thisreactiondid not stopatthe epoxide ring-opening stage,
but the neucleophilic oxygen anion intermediate that
resulted from epoxide ring-opening by NaN3 initiated an
intramolecular 7-endotrig oxa-Michael reaction. This tan-
dem sequence afforded seven-membered ring sultams
4aꢀh in good yields under mild conditions (see Table 1).
Besides NaN3, several other nucleophiles can also be
used for epoxide ring-opening of vinyl sulfonamide ep-
oxides 3aꢀh. Primary amines were among the top choices
for this tandem reaction. Interestingly, when the reaction
was initiated by a primary amine, it did not follow the
NaN3-initiated route shown in Table 1. Instead, the pri-
mary amine became the nucleophile in an initial Michael-
addition to the vinyl sulfonamide epoxides first, followed
by subsequent 8-endo-tet intramolecular epoxide ring-
opening reaction to give eight-membered-ring sultams
5aꢀh in good yields within 5 h. Theoretically, there are
three possible tandem reaction routes (see Scheme 2).
Route A was ruled out by 1H NMR spectra of products.
Further experiments also proved that primary amines
underwent aza-Michael addition faster than epoxide
ring-opening reaction. In order to make sure the sturcture
of the tandem reaction product was 5 (Scheme 2, Table 2),
the reaction product was oxidized by PCC, PDC, and
Jones agent, respectively, and no aldehyde or acid was
isolated. Only keto sultam 8 was obtained as a major
product. Because of steric factors, the resultant secondary
amine from the Michael addition attacked the epoxide
ring only at the least substituted (CH2) end, so no
3702
Org. Lett., Vol. 14, No. 14, 2012

seven-membered ring sultams were found in the reaction
products. The results are shown in Table 2.
these two reactions can be conveniently combined into one
synthetic route to produce skeletally diverse scaffolds from
a single starting material in excellent yields. In addition, the
method is highly amenable to library generation and
current efforts are engaged in this direction.
In summary, two tandem reaction protocols to synthe-
size seven- and eight-membered ring sultams from one
starting material were developed. One protocol employed
intermolecular epoxide ring-opening of R,β-unsaturated
sulfonamide epoxides by NaN3 followed by intramolec-
ular 7-endo-trig oxa-Michael addition reaction to give
seven-membered ring sultams exclusively. The second
protocol applies an amine nucleophile to the same starting
material to induce intermolecular aza-Michael addition
reaction, followedbyan8-endo-tetintramolecular selective
epoxide ring-opening of the resultant amine intermediate.
Eight-membered ring sultams were mainly formed. Ovreall,
Acknowledgment. This investigation was generously
supported by funds provided by Jiangsu University.
Supporting Information Available. Experimental de-
tails and spectral characterization for all compounds.
This material is available free of charge via the Internet
at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 14, 2012
3703