Pd-Catalyzed Selective Synthesis of Cyclic Sulfonamides and Sulfinamides Using K2S2O5 as a Sulfur Dioxide Surrogate

Article abstract of DOI:10.1021/acs.orglett.7b00402

A variety of cyclic sulfonamides and sulfinamides could be selectively synthesized under Pd catalysis using haloarenes bearing amino groups and a sulfur dioxide (SO₂) surrogate. The amount of base was key in determining the selectivity. Mechanistic studies revealed that sulfinamides were initially formed via an unprecedented formal insertion of sulfur monoxide and were oxidized to sulfonamides in the presence of an iodide ion and DMSO.

Full text of DOI:10.1021/acs.orglett.7b00402

Letter
pubs.acs.org/OrgLett
Pd-Catalyzed Selective Synthesis of Cyclic Sulfonamides and
Sulfinamides Using K2S2O5 as a Sulfur Dioxide Surrogate
Hideyuki Konishi, Hiromichi Tanaka, and Kei Manabe*
School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan
S
* Supporting Information
ABSTRACT: A variety of cyclic sulfonamides and sulfinamides
could be selectively synthesized under Pd catalysis using haloarenes
bearing amino groups and a sulfur dioxide (SO2) surrogate. The
amount of base was key in determining the selectivity. Mechanistic
studies revealed that sulfinamides were initially formed via an
unprecedented formal insertion of sulfur monoxide and were
oxidized to sulfonamides in the presence of an iodide ion and
DMSO.
ulfonamides and sulfinamides are important classes of
organic halides use hydrazines as amine sources, resulting in the
Sorganosulfur compounds in medicinal and synthetic synthesis of only N-aminosulfonamides.10,11,12d,e,g,i,k,n,s To
chemistry.1 Both sulfonamides and sulfinamides can be
obtain sulfonamides from simple amines, multistep procedures
via the corresponding sulfonyl halides are required.12j,l,m,o,r,t,13
Moreover, only a few examples have disclosed the catalytic
synthesis of sulfinamides using thiols or disulfides.14 A one-step
catalytic method from organic halides and amines has not been
reported to date.
employed as amide isosteres in peptidomimetics.2 Since sulfa
drugs were discovered as antibacterial agents,3 sulfonamides have
been applied in the development of many types of drugs such as
antimicrobials, diuretics, and anti-retrovirals.1a On the other
hand, because of the characteristic chiral sulfur atom,
sulfinamides are also used in synthetic chemistry as chiral
auxiliaries4 and chiral ligands.5
During our investigation on practical synthetic methods using
toxic gas surrogates,15 the lack of direct synthetic methods for
sulfonamides from organic halides, a SO2 surrogate, and amines
piqued our interest. We recently reported that a variety of cyclic
carbonyl compounds could be synthesized from haloarenes
bearing nucleophilic groups via Pd-catalyzed external-CO-free
carbonylation.16 Likewise, if the introduction of a sulfonyl group
were achieved under Pd catalysis, the formation of sulfonamides
would proceed via an entropically favored intramolecular
nucleophilic cyclization to afford a benzo-fused cyclic sulfona-
mide (sultam), which is present in many biologically interesting
molecules.17 Herein, we report the direct synthesis of cyclic
sulfonamides using a Pd catalyst, a SO2 surrogate, and various
haloarenes with amino groups (Scheme 1). Furthermore, we
describe the selective synthesis of cyclic sulfinamides where the
SO2 surrogate is used as a formal sulfur monoxide (SO) source to
introduce a sulfinyl group.18
Initial trials to synthesize cyclic sulfonamides were conducted
using compound 1a and K2S2O5 (2) (Scheme 2). 1,4-Dioxane
and tetra-n-butylammonium bromide (TBAB) were previously
reported to be effective for the synthesis of N-amino-
sulfonamides.11 However, desired sulfonamide 3a was not
obtained under these conditions. When 1,4-dioxane was replaced
with DMSO, 3a was obtained in 21% yield. Surprisingly, in DMF,
sulfinamide 4a was obtained instead of sulfonamide 3a, albeit in a
Sulfonamides are generally synthesized by the condensation of
sulfonyl chlorides and amines.6 Sulfinamides can also be
synthesized by the condensation of sulfinyl chlorides, by
multistep procedures starting from disulfides or sulfinates7 or
by the reaction of sulfonyl chlorides and amines in the presence
of reductants.8 However, the corrosive, easily hydrolyzable
nature of sulfonyl and sulfinyl chlorides makes their handling
troublesome. Formation of these chlorides often requires highly
hazardous chlorine or strong chlorinating agents,9 which restricts
the synthetic utility. Considering the disadvantages of the
aforementioned synthetic procedures, an alternative method to
access sulfonamides and sulfinamides is highly desired.
Recently, Willis and co-workers elegantly demonstrated the
Pd-catalyzed synthesis of N-aminosulfonamides from iodoarenes
using hydrazines and DABSO, a complex of sulfur dioxide (SO2)
and 1,4-diazabicyclo[2.2.2]octane, as a SO2 surrogate.10 There-
after, the use of potassium metabisulfite (K2S2O5) as a SO2
surrogate was reported in the synthesis of N-aminosulfonamides
from organic halides.11 Because these methods avoid the use of
sulfonyl chlorides or toxic SO2 gas, they have accelerated the
development of synthetic methods for the introduction of
sulfonyl moieties using SO2 surrogates.12
While the Pd-catalyzed, one-step synthesis of sulfonamides
from organic halides with amines and SO2 surrogates is
operationally simple and has good functional group compati-
bility, most reported methods for sulfonamide synthesis from
Received: February 8, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00402
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Letter
Scheme 1. Synthesis of Cyclic Sulfonamides and Sulfinamides
Using SO2 Surrogates
Scheme 2. Formation of Sulfonamide 3a and Sulfinamide 4a:
Initial Studies
Figure 1. Substrate scope. Isolated yields of products (%) are described
as “sulfonamide 3/sulfinamide 4 in method A, sulfonamide 3/
sulfinamide 4 in method B”. aMethod A (for synthesis of sulfonamide
3a−o): Pd(OAc)2 (10 mol %), (t-Bu)3P·HBF4 (20 mol %), 2 (2.0
equiv), Bu3N (1.0 equiv). Method B (for synthesis of sulfinamide 4a−
o): Pd(OAc)2 (10 mol %), PCy3 (20 mol %), 2 (1.5 equiv), Bu3N (2.0
equiv). b1.0 mmol scale. c120 °C. dComplex mixture.
a
Bu3N (1.0 equiv) was used instead of TBAB.
low yield. This unexpected change in products encouraged us to
develop a selective method for the synthesis of either
sulfonamides or sulfinamides. Notably, when 1.0 equiv of tri-n-
butylamine (Bu3N) was used instead of TBAB to trap in situ
generated hydrogen iodide, the yield of 3a was improved to 59%.
Next, the effect of the amount of Bu3N was examined (Table
1). Surprisingly, sulfonamide 3a was obtained when 1.0 equiv or
sulfinamides 4a−o, respectively. In general, both products were
obtained in moderate to good yields with almost complete
selectivity, with the exception of N-phenyl substrate 1e. Bulky
substituents on the N atom such as t-Bu (1d) did not interfere
with the reaction. Regardless of the substituents on the benzene
ring, the desired products were selectively obtained using either
method, although 1j bearing a nitro group did not tolerate the
reaction conditions. While 1n containing a pyridine moiety failed
to produce sulfonamide 3n due to the formation of byproducts,
sulfinamide 4n could be obtained by method B. The reactions to
afford ring-expanded sulfonamide 3o and sulfinamide 4o also
proceeded, although the yields were low.
Table 1. Effect of the Amount of Bu3N
To gain insight into the reaction mechanism, the reaction was
monitored in detail. When the conditions for the synthesis of
sulfonamide 3a (Table 1, entry 5) were applied, sulfinamide 4a
was formed during the initial stages of the reaction (Figure 2, X =
entry
X (equiv)
yield of 3a (%)
yield of 4a (%)
1
2
3
4
0
25
33
20
48
59
0
0
0
0.10
0.50
1.0
1.0
1.5
2.0
3.0
2.0
0
0
a
5
0
6
7
8
39
54
48
75
0
0
b
9
0
a
b
K2S2O5 (2.0 equiv) was used. PCy3 (20 mol %) was used instead of
(t-Bu)3P·HBF4.
less Bu3N was used, and sulfinamide 4a was obtained when 1.5
equiv or more Bu3N was utilized. Since the selective formation of
3a or 4a was feasible, we further optimized the conditions (for
details, see Tables S1−S4 in Supporting Information (SI)) and
finally found the best conditions for sulfonamide 3a (entry 5)
and for sulfinamide 4a (entry 9).
Figure 2. Reaction profile. Yields were determined by isolation of each
compound in separate experiments.
We also evaluated other SO2 surrogates (for details, see Table
S5 in SI). Na2S2O5 and DABSO afforded sulfonamide 3a and
sulfinamide 4a, albeit in yields (up to 45% for 3a and up to 43%
for 4a) lower than that of K2S2O5. The formation of the products
with all SO2 sources suggests that SO2 was generated in situ and
used to produce 3a and 4a.
The selective synthesis of sulfonamides or sulfinamides was
tested with various substrates (Figure 1). Method A and method
B were applied for the synthesis of sulfonamides 3a−o and
1.0). Sulfonamide 3a was not formed during the accumulation of
4a. After 6 h, the amount of 4a decreased, and sulfonamide 3a
formed simultaneously. On the other hand, when the conditions
for the synthesis of sulfinamide 4a (Table 1, entry 7) were
applied, 4a was generated at a rate similar to that of the
sulfonamide synthesis, with no decrease in the yield of 4a (Figure
2, X = 2.0). These results suggest that sulfonamide 3a was formed
B
DOI: 10.1021/acs.orglett.7b00402
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Letter
via sulfinamide 4a and that excess Bu3N suppressed the
formation of sulfonamide 3a.
To confirm the formation of 3a from 4a, the direct conversion
of 4a to 3a was tested. The formation of 4a was not observed
when the conditions for synthesis of 3a were applied (Scheme 3,
be converted into sulfonamides when 1.0 equiv or less of base
was used. Iodide and DMSO played important roles in the
formation of sulfonamides from sulfinamides. Although the
mechanism behind the formation of sulfinamides requires further
investigation, this synthetic method represents an unprece-
dented approach to the direct introduction of sulfinyl groups into
haloarenes using a SO2 surrogate and will be a powerful tool for
the synthesis of cyclic sulfonamides and sulfinamides.
Scheme 3. Mechanistic Studies for the Formation of 3a from
4a and Reaction of Bromoarene 5
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b00402.
Detailed optimization studies, experimental procedures,
and physical and spectral data of newly obtained products
(PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail manabe@u-shizuoka-ken.ac.jp.
ORCID
Kei Manabe: 0000-0002-9759-1526
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
eq 1). Since an iodide ion must be generated during the reaction
of 1a to 3a, potassium iodide (KI) was added as an iodide source
for the conversion of 4a to 3a. As expected, 3a was obtained in
64% yield (Scheme 3, eq 2). Furthermore, when the reaction was
carried out in DMF, 4a was not obtained (Scheme 3, eq 2),
suggesting that DMSO served as an oxygen source.19 In fact, the
scent of dimethyl sulfide was noticed upon quenching the
reaction. We assumed that molecular iodine (I2) might be
generated in the course of the reaction,20 and that I2 would work
as an oxidant. To confirm this hypothesis, sulfinamide 4a and I2
were mixed in DMSO at 100 °C, giving sulfonamide 3a in a high
yield (Scheme 3, eq 3). Furthermore, conversion of 4a to 3a
failed when the reaction was performed in DMF (Scheme 3, eq
3), corroborating DMSO as an oxygen source. These
mechanistic studies revealed that sulfonamide 3a was obtained
via the formation of sulfinamide 4a, and that the conversion from
4a to 3a requires an iodide source and DMSO as an oxygen
source. Larger amounts (1.5 equiv or more) of Bu3N may quench
I2 that forms in situ, thus suppressing the formation of 3a. Finally,
we tested bromoarene 5 as the substrate and found that KI
determined the selectivity between 3a and 4a (Scheme 3, eq 4).
Notably, 4a was selectively obtained even in the presence of 1.0
equiv of Bu3N without KI (the conditions for synthesis of 3a
from iodoarenes). With KI, 3a was obtained, albeit in lower yield
(Scheme 3, eq 4). This result also supports the involvement of
iodide ion in the formation of 3a. The reaction mechanism
behind the formation of sulfinamide 4a, including the possibility
of the generation of unstable SO in the reaction system, is under
investigation.21
■
We gratefully acknowledge financial support from JSPS
KAKENHI (15H04634, 15K18834, and 16K15101), Takeda
Science Foundation, and grant for the Platform Project for
Supporting in Drug Discovery and Life Science Research
(Platform for Drug Discovery, Informatics, and Structural Life
Science) from the Ministry of Education, Culture, Sports,
Science and Technology (MEXT), and Japan Agency for
Medical Research and Development (AMED).
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