Tert-Butyl Sulfoxide as a Starting Point for the Synthesis of Sulfinyl Containing Compounds

Article abstract of DOI:10.1021/acs.orglett.5b02743

Sulfoxides bearing a tert-butyl group can be activated using N-bromosuccinimide (NBS) under acidic conditions and then subsequently treated with a variety of nitrogen, carbon, or oxygen nucleophiles to afford a wide range of the corresponding sulfinic acid amides, new sulfoxides, and sulfinic acid esters.

Full text of DOI:10.1021/acs.orglett.5b02743

Letter
pubs.acs.org/OrgLett
tert-Butyl Sulfoxide as a Starting Point for the Synthesis of Sulfinyl
Containing Compounds
Juhong Wei and Zhihua Sun*
College of Chemistry and Chemical Engineering, Shanghai University of Engineering Science, 333 Longteng Road, Shanghai 201620,
China
S
* Supporting Information
ABSTRACT: Sulfoxides bearing a tert-butyl group can be activated
using N-bromosuccinimide (NBS) under acidic conditions and then
subsequently treated with a variety of nitrogen, carbon, or oxygen
nucleophiles to afford a wide range of the corresponding sulfinic acid
amides, new sulfoxides, and sulfinic acid esters.
used in a radical promoted cyclization reaction involving direct
he sulfinyl group is present in a large number of organic
Tcompounds that are important for applications in homolytic substitution at the sulfur center;8 and aryl sulfinic
chemical, biological, and material sciences.1,2 Synthetic
acids have been used in water to prepare indole-3-yl sulfoxides
(through a sulfinyl cation).9 Here, we report our study of using
methods for the introduction of the sulfinyl group vary. For
a sulfoxide-bearing tert-butyl group as a versatile sulfinyl
source.10 Through direct activation by NBS under acidic
conditions (Scheme 1) and subsequent reaction with N-, C-, or
O-based nucleophiles, new sulfinyl-containing compounds can
be efficiently obtained.
the synthesis of sulfinic acid esters and amides, sulfinyl halides
or thioesters are common starting materials.3 For sulfoxides,
oxidation of a thioether is widely used.4,5 In recent years, new
methodologies for the introduction of a sulfinyl group have
emerged with the goal of widening the reaction scope, using
mild conditions, and improving overall synthetic efficiency.6
For example, as shown in Scheme 1, certain aryl alkyl sulfoxides
can be transformed to new diaryl sulfoxides by transition metal
catalysis;7 alkyl or aryl sulfinic acid esters or amides have been
We first used the model reaction shown in Table 1 for the
synthesis of 2a to identify the optimal conditions for activation
Table 1. Exploration of Optimal Conditions for Activation of
a
tert-Butyl Sulfinyl Group
Scheme 1. Recent New Protocols for Synthetizing
Compounds Containing a Sulfinyl Group
c
reagent ratio
(1a/NBS/Acid/amine)
yield 2a
b
entry
acid
solvent
(%)
1
2
AcOH
AcOH
AcOH
PhCO2H
TsOH
TFA
DCM
DCM
DCM
DCM
DCM
DCM
1.0/0.1/1.2/1.1
1.0/1.0/1.2/1.1
1.0/2.0/1.2/1.1
1.0/2.0/1.2/1.1
1.0/2.0/1.2/1.1
1.0/2.0/1.2/1.1
1.0/2.0/1.2/1.1
1.0/2.0/1.2/1.1
1.0/2.0/1.2/1.1
1.0/2.0/1.2/1.1
trace
50
3
92
4
79
5
20
6
50
7
AcOH
AcOH
AcOH
AcOH
toluene
THF
15
8
0
9
CH3CN
DMF
trace
40
10
a
Reaction conditions: 1a (0.5 mmol), NBS, acid, and solvent (2 mL)
were stirred at room temperature for 10 min under a nitrogen
atmosphere. Then PhNH2 (0.55 mmol) was added. The mixture was
stirred at room temperature for another 10 min under a nitrogen
b
c
atmosphere. Purified solvent. Isolated yield.
Received: September 21, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02743
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
of the tert-butyl sulfinyl group. Our study involved changing the
reagent ratio, choice of acid, and solvent. As summarized in
Table 1, 2 equiv of NBS were found to be necessary for
complete activation to occur to achieve a high reaction yield
(entry 3 vs entries 1 and 2). With regard to the acids used,
weaker acids such as acetic acid or benzoic acid were better
than stronger acids such as TFA or TsOH in promoting the
reaction (entries 3 and 4 vs entries 5 and 6). Among the
solvents tested, DCM seemed to be the best while THF, DMF,
toluene, or acetonitrile all produced much worse yields (entry 3
vs entries 7, 8, 9, and 10). In addition to the data shown in
Table 1, we also compared reaction outcomes using isopropyl
or ethyl sulfinyl benzene instead of tert-butyl sulfinyl benzene;
neither produced the desired products. A longer activation time
(such as 60 min for step 1) was also tested and gave a slightly
lower yield of 2a (80%) when compared to the 20 min
procedure (Table 1, entry 3).
desired final products 2. Electron-withdrawing or -donating
groups on the starting materials do not significantly impact the
final yields, although sterically bulky substitutions on the amine
nucleophile lower the yield (2g). It is interesting to note that,
for 2k and 2l, which started from di-tert-butyl sulfoxide, the
standard procedure using AcOH did not afford the desired
products. Instead, the corresponding acetamides were obtained.
It seems that during the activation step, a mixed anhydride is
formed between the sulfinyl and the acetyl groups, and the
subsequent reaction does not occur at the sulfur center. In
order to change the reactivity of the mixed anhydride to allow
reaction at the sulfur center, we used TFA to replace AcOH in
the standard protocol and successfully obtained 2k and 2l in
very good yields.
The reactions with carbon nucleophiles are shown in Scheme
3. Again, very good yields of all the final products 3 were
a
Scheme 3. Reactions with Carbon Nucleophiles
Therefore, a 10 min activation time with 2 equiv of NBS in
DCM in the presence of AcOH seemed to be the optimal
conditions for activation of the tert-butyl sulfinyl group. With
these conditions identified, we then investigated scope of the
transformation using nitrogen, carbon, or oxygen-based
nucleophiles.
We first studied the reactions with different nitrogen
nucleophiles. Because amines are incompatible with NBS
activation of tert-butyl sulfinyl group under acidic conditions, all
reactions were carried out in two steps, and the results are
summarized in Scheme 2.
The examples in Scheme 2 covered aryl and alkyl starting
sulfoxides as well as aryl and alkyl amine nucleophiles for the
second step. All produced good to excellent yields of the
a
Scheme 2. Reactions with Nitrogen Nucleophiles
a
Reaction conditions: 1 (0.5 mmol), NBS (1.0 mmol), AcOH (0.6
mmol), and DCM (2 mL) were stirred at room temperature for 10
min under a nitrogen atmosphere. Then the nucleophile (0.55 mmol)
was added. The mixture was stirred at room temperature for another
b
10 min under a nitrogen atmosphere. For 3a, TFA was used in step 1
c
instead of AcOH. The nucleophiles for 3a−3c are Grignard reagents.
d
The nucleophile for 3d is alkyne sodium salt.
obtained. The examples covered both aryl and alkyl starting
sulfoxides, with di-tert-butyl sulfoxide requiring the use of TFA
to afford the final product (3a). It is very encouraging that sp3,
sp2, or sp1 hybridized carbon nucleophiles (in the form of
Grignard reagents or alkyne sodium salts) can all be used
successfully (3a−3d). In addition, indoles as a carbon
nucleophile source can also be conveniently employed without
protection of the indole nitrogen (products 3e−3n) and with
either electron-withdrawing or -donating substituents.
a
Reaction conditions: 1 (0.5 mmol), NBS (1.0 mmol), AcOH (0.6
mmol), and DCM (2 mL) were stirred at room temperature for 10
min under a nitrogen atmosphere. Then amine (0.55 mmol) was
added. The mixture was stirred at room temperature for another 10
Scheme 4 summarizes the reaction outcomes using oxygen
nucleophiles. The first three examples used simple alcohols as
the nucleophile, and all of those gave satisfactory results (4a−
b
min. For 2k and 2l, TFA was used in step 1 instead of AcOH.
B
DOI: 10.1021/acs.orglett.5b02743
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 4. Reactions with Oxygen Nucleophiles
Scheme 5. Proposed Reaction Mechanism
a
Reaction conditions: 1 (0.5 mmol), NBS (1.0 mmol), AcOH (0.6
mmol), and DCM (2 mL) were stirred at room temperature for 10
min under a nitrogen atmosphere. Then alcohol (0.55 mmol) was
added. The mixture was stirred at room temperature for another 10
required to achieve high reaction yields. We did attempt to use
molecular bromine directly for the reaction to replace NBS, and
only <10% of the final product was obtained. This indicated
that although bromine is not a good reagent as NBS for
activation of sulfoxides bearing a tert-butyl group, its presence
as a byproduct during NBS activation is not detrimental to the
desired reaction pathway. The formation of bromine during the
reaction also raises two potential issues: (1) for products
containing alkene or alkyne groups (such as 2e), will bromine
form adducts to the product and lower the yields11 and (2) will
bromine further oxidize the sulfur atom in the products? In
order to answer these two questions, we performed studies by
incubating reaction product 2e with bromine under conditions
that represent reaction mixtures. We found no significant
oxidation of sulfur, but 10−15% of bromine adduct could be
found. This indicates that reaction conditions could be further
improved for alkene or alkyne starting materials.
In summary, we have shown that sulfoxides bearing a tert-
butyl group can be conveniently and efficiently activated under
acidic conditions using NBS. The resulting activated sulfinyl
group, in the form of a mixed anhydride, can be smoothly
transformed to new sulfoxides or sulfinic acid amides or esters
with an appropriate nucleophile. The reaction protocol can be
applied to a wide variety of substrates. Given the feasibility of
synthesizing, isolating, and storing sulfoxides, our procedure
shows the great advantage and potential of using tert-butyl
sulfoxides to replace labile sulfinyl halides or thioesters in the
synthesis of sulfinyl-containing compounds.
b
min under a nitrogen atmosphere. Reaction conditions: 1 (0.5
mmol), NBS (1.0 mmol), AcOH (0.6 mmol), and DCM (2 mL) were
stirred at room temperature for 10 min under a nitrogen atmosphere.
4c). Because alcohols are compatible to the activation of the
tert-butyl sulfinyl group under acidic conditions, we turned our
attention to intramolecular cyclization reactions using un-
protected alcohols in a one-step procedure. As shown in
Scheme 2, all seven examples (some of those were performed
with chiral starting materials; see 4d−4i) form either five- or
six-membered rings and gave very good isolated yields (71−
87%).
Based on the reaction outcomes and the amount of NBS
used to achieve optimal yields, we propose the following
reaction mechanism for activation of sulfoxides bearing a tert-
butyl group (Scheme 5).
Charged starting sulfoxide first attacks one NBS via its sulfur
center to generate a positively charged sulfur intermediate. The
latter converts into a sulfinyl bromide through the loss of a
stable tert-butyl cation which in turn produces gaseous
isobutene and one proton. We did observe gas formation
during the activation step. tert-Butyl cation formation is the
driving force of the activation, as sulfoxides with an isopropyl or
ethyl group did not produce desirable outcomes. Subsequently,
the sulfinyl bromide reacts with AcOH to form a mixed
anhydride which can be further transformed though reaction
with a proper nucleophile. The idea of mixed anhydride
formation was supported by the isolation of phenyl acetamide
from the reaction using di-tert-butyl sulfoxide as starting
material in the presence of AcOH.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b02743.
The resulting bromide during the formation of the mixed
anhydride can react with a second NBS to form bromine, as
evidenced by the heavy brown color observed during the first
step of the reaction. This explains why 2 equiv of NBS were
Procedures and characterization data for all new
compounds (PDF)
C
DOI: 10.1021/acs.orglett.5b02743
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(11) Yu, W. Z.; Chen, F.; Cheng, Y. A.; Yeung, Y. Y. J. Org. Chem.
2015, 80, 2815.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: sungaris@gmail.com.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank Dr. Erkang Fan at the University of
Washington for helpful discussions and are grateful for financial
support from Shanghai Municipal Education Commission (No.
14ZZ159), and the Program for the Special Appointment
(Eastern Scholar) at Shanghai Institutions of Higher Education.
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DOI: 10.1021/acs.orglett.5b02743
Org. Lett. XXXX, XXX, XXX−XXX