Pummerer rearrangement using bis(p-nitrophenyl) phosphorazidate as an azidation reagent: A novel synthesis of azidomethyl sulfides

Article abstract of DOI:10.1016/j.tetlet.2017.08.065

A novel method for the synthesis of azidomethyl sulfides by Pummerer rearrangement using bis(p-nitrophenyl) phosphorazidate (p-NO₂DPPA) as an azidation reagent was developed. Various methyl sulfoxides were converted into the corresponding azidomethyl sulfides. Importantly, this reaction enables the preparation of azidomethyl sulfides without the use of toxic or explosive azide sources.

Full text of DOI:10.1016/j.tetlet.2017.08.065

Accepted Manuscript
Pummerer Rearrangement using Bis(p-nitrophenyl) Phosphorazidate as an Azi-
dation Reagent: A Novel Synthesis of Azidomethyl Sulfides
Kotaro Ishihara, Takayuki Shioiri, Masato Matsugi
PII:
S0040-4039(17)31086-9
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.08.065
TETL 49255
Reference:
Tetrahedron Letters
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25 August 2017
28 August 2017
Please cite this article as: Ishihara, K., Shioiri, T., Matsugi, M., Pummerer Rearrangement using Bis(p-nitrophenyl)
Phosphorazidate as an Azidation Reagent: A Novel Synthesis of Azidomethyl Sulfides, Tetrahedron Letters (2017),
doi: http://dx.doi.org/10.1016/j.tetlet.2017.08.065
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Tetrahedron Letters
jo u r n a l h o m e p a g e : w w w . e ls e v i e r . c o m
Pummerer Rearrangement using Bis(p-nitrophenyl) Phosphorazidate as an Azidation
Reagent: A Novel Synthesis of Azidomethyl Sulfides
Kotaro Ishihara, Takayuki Shioiri, and Masato Matsugi
Faculty of Agriculture, Meijo University, 1-501 Shiogamaguchi, Tempaku, Nagoya 468-8502, Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A novel method for the synthesis of azidomethyl sulfides by Pummerer rearrangement using
bis(p-nitrophenyl) phosphorazidate (p-NO2DPPA) as an azidation reagent was developed.
Various methyl sulfoxides were converted into the corresponding azidomethyl sulfides.
Importantly, this reaction enables the preparation of azidomethyl sulfides without the use of
toxic or explosive azide sources.
Available online
.
Keywords:
2014 Elsevier Ltd. All rights reserved.
Pummerer Rearrangement
Sulfoxide
Bis(p-nitrophenyl) phosphorazidate
Azidation
α-Azido sulfide
The Pummerer rearrangement, whereby sulfoxides react with
electrophiles to give α-substituted sulfides, has been widely
studied since it was first reported in 1909.1 Different substituted
groups can be introduced at the α-position of the sulfide by
employing different nucleophiles.2 However, although a broad
range of Pummerer rearrangement reactions are known, only two
reactions have been reported in which the azide ion is employed
as the nucleophile.3
The azidation reagent bis(p-nitrophenyl)phosphorazidate (p-
NO2DPPA)9 is less explosive than other currently employed
azidation regents owing to its stabilization by the conjugated
phosphorus atom. Thus, we reasoned that the use of p-NO2DPPA
as the azide ion source in the Pummerer rearrangement would be
an attractive strategy. We also hypothesized that p-NO2DPPA
would also act as an electrophile for the activation of the
sulfoxide moiety.
The azide group is an extremely useful functional group as it
can be converted into a wide range of substituents. In particular,
Huisgen cycloaddition, which affords triazoles from azides and
alkynes, has been extensively used in click chemistry to prepare
functional substances.4 Recently, triazoles derived from α-azido
sulfides have been attracting increasing attention owing to their
application as bioactive compounds such as histone deacetylase
inhibitors,5 ricin toxin A inhibitors,6 and quorum sensing
modulators (QSM).7
Herein, we report the use of p-NO2DPPA as both the
electrophile and azide source in the Pummerer rearrangement for
the synthesis of α-azido sulfides. This method enables the
preparation of α-azido sulfides without the use of toxic or
explosive azide sources via a facile synthetic procedure.
First, we investigated whether azidation via Pummerer-type
reactions with p-NO2DPPA is feasible using methyl phenyl
sulfoxide as a model substrate. The reaction conditions were
explored by varying different reaction parameters, including
reagent equivalents, reaction time, and the base and solvent
employed (Table 1).
The general strategy for the synthesis of α-azido sulfides is
the use of substitution reactions between α-halo sulfides and
azidating agents.8 However, these reactions can be problematic
owing to the use of toxic or explosive azide sources.
Consequently, safer and more user-friendly methods for the
synthesis of α-azido sulfides would be of enormous benefit to
organic chemistry.
In the absence of base or at room temperature, the reaction
does not proceed in toluene, even in the presence of two
equivalents of p-NO2DPPA (Table 1, entries 1–2). Conversely,
the desired -azido sulfide is obtained in 41% yield in the
presence of two equivalents of 1,4-diazabicyclo[2.2.2]octane
(DABCO) at reflux (Table 1, entry 3). However, under these
———
 Corresponding author. Tel.: +81-52-832-1151; fax: +81-52-835-7450; e-mail: matsugi@meijo-u.ac.jp

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Tetrahedron
conditions, the extended reaction time leads to decomposition
Therefore, we limited the substrate scope to methyl sulfoxides
and expanded the reaction to the broad range of methyl
sulfoxides shown in Table 3. Both aromatic and aliphatic
sulfoxides afford the desired products, i.e., the azidation
selectively occurs on the methyl group alone (Table 3, entries 11
and 13–18). Aromatic sulfoxide containing an electron-donating
group afford improved yield, while aromatic sulfoxides
containing an electron-withdrawing group afford decreased
yields (Table 3, entries 3–7). Using aromatic sulfoxides with
electron-withdrawing groups, the corresponding sulfides are
obtained in significant amounts (Table 3, entries 4, 5 and 7).3a
Furthermore, heteroaromatic sulfoxides give lower yields than
their aromatic counterparts (Table 3, entries 9–10). However,
sulfoxides adjacent to benzyl or ester groups do not afford the
desired products (Table 3, entries 6, 11, 12, and 17), and
sulfoxides in proximity to tertiary carbon atoms are also not
converted owing to the instability of the substrates (Table 3,
entries 19–20).
of the product, decreasing the yield (Table 1, entries 4–6). The
yield is improved by increasing the quantities of p-NO2DPPA
and DABCO employed, whereas the use of an excess of DABCO
over p-NO2DPPA lowers the yield (Table 1, entries 7–9). The
reaction proceeds smoothly using 2.5 equivalents of p-NO2DPPA
and DABCO to give the product in 79% yield in 2 h (Table 1,
entry 10). Each corresponding sulfide was obtained in all cases.
Moreover, a considerable amount of the starting material (methyl
phenyl sulfoxide) remained, except for the optimum condition
(Table 1, entry 10).
Table 1. Optimization of the reaction conditions.
Table 2. Scope of the Pummerer-type azidation.
Next, we demonstrated the application of azidomethyl sulfides
to the synthesis of bioactive compounds. As shown in Scheme 1,
the synthesized azidomethyl phenyl sulfide was reacted with
alkynes in the presence of CuI as a catalyst to give a histone
deacetylase inhibitor (NCC–149)5 and a QSM7 in high yields.
Therefore, our strategy for the synthesis of azidomethyl sulfides
provides safer synthetic routes to various functional substances.
Although the desired product is obtained in satisfactory yield
under the above conditions, we attempted to further optimize the
reaction conditions by investigating different bases. However, no
improvement over the use of DABCO is observed (Table 1,
entries 11–18).
The effect of different solvents was also examined, and it was
found that the use solvents other than toluene lowers the yield
(Table 1, entries 19–25). The use of DPPA10 affords the desired
product in moderate yield, but a large excess of reagents is
required owing to the low reactivity of DPPA compared to that of
p-NO2DPPA (Table 1, entries 26–30). When the reaction was
performed under same conditions, the use of DPPA decreased the
yield compared with p-NO2DPPA (Table 1, entries 10 vs. 26).
Encouraged by these results, the substrate scope was
investigated using various sulfoxides, as shown in Table 2.
However, sulfoxides with substituent groups other than the
methyl group do not afford the corresponding α-azido sulfides in
high yields. This may be due to the reactions being suppressed by
steric hindrance at the reaction center. In addition, sulfoxides
adjacent to the active methylene groups give the disulfide as a
byproduct. These results indicate that this reaction is significantly
affected by steric hindrance.
Scheme 1. Derivation of azidomethyl phenyl sulfide to
bioactive compounds.

Table 3. Synthesis of various azidomethylsulfides.
elimination of the phosphonate group in the sulfonium
intermediate proceeds via an E1CB process. The advantages of
this method are the use of less toxic and explosive azide sources
and the simplicity of the synthetic procedure.
A plausible reaction mechanism for this reaction is shown in
Scheme 2. As discussed above, we believe that the reaction
proceeds via a Pummerer-type rearrangement.3b The oxygen atom
of the sulfoxide attacks p-NO2DPPA to generate a sulfonium
intermediate and releases the azide ion. Subsequently, the
sulfonium intermediate undergoes elimination to produce the
thionium ion, which is subject to nucleophilic addition of the
azide ion to give the desired α-azido sulfide.
General procedure
p-NO2DPPA (91.3 mg, 0.25 mmol) and DABCO (28.0 mg,
0.25 mmol) were added to a solution of the sulfoxide (0.10
mmol) in toluene (0.35 mL). After stirring for 2 h at reflux, the
mixture was diluted with AcOEt/n-hexane (1:5) (30 mL). Then,
the mixture was washed with saturated aqueous NaHCO3 (25
mL) and brine (25 mL), and dried over Na2SO4. Concentration of
the solvent in vacuo followed by purification of the residue on a
silica gel column (AcOEt:n-Hexane 1:5–0:1) gave the desired α-
azido sulfide.
In conclusion, we have developed a novel method for the
synthesis of azidomethyl sulfides via the Pummerer
rearrangement using p-NO2DPPA as the azidation reagent.
Various methyl sulfoxides were easily converted into the
corresponding azidomethyl sulfides. The azidation selectively
occurs on the methyl group when hydrogen atom abstraction is
possible from two places. This observation suggests that the
Acknowledgments
This work was supported by JSPS Grant-in-Aid for Scientific
Research (C), 26450145, and Professor Y. Uozumi’s JST-
ACCEL program (JPMJAC1401).
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://xxxxx.
Scheme 2. Plausible reaction mechanism.

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Tetrahedron
7. Stacy, D. M.; Le Quement, S. T.; Hansen, C. L.; Clausen, J. W.; Tolker-
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Highlights
・ Various azidomethyl sulfides were prepared via Pummerer rearrangement using p-NO2DPPA.
・ Methyl sulfoxides were easily converted into the corresponding azidomethyl sulfides.
・ Azidosulfides could be prepared without the use of toxic or explosive azide sources.
・ Bioactive compounds were prepared using the synthesized azidomethyl sulfide.

4
Tetrahedron
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Pummerer Rearrangement using
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Bis(p-nitrophenyl) Phosphorazidate as an
Azidation Reagent: A Novel Synthesis of Azidomethyl Sulfides
Kotaro Ishihara, Takayuki Shioiri, and Masato Matsugi *