One-step synthesis of sulfonamides from N-tosylhydrazones

Article abstract of DOI:10.1021/acs.orglett.5b03545

The first described reaction between N-tosylhydrazone and SO₂ is reported to provide alkyl sulfonamides in the presence of various amines. In this procedurally simple method, hydrazones of both unsaturated aldehydes and ketones proceed in moder

Full text of DOI:10.1021/acs.orglett.5b03545

Letter
pubs.acs.org/OrgLett
One-Step Synthesis of Sulfonamides from N‑Tosylhydrazones
Andy S. Tsai,* John M. Curto, Benjamin N. Rocke, Anne-Marie R. Dechert-Schmitt,
Gajendrasingh K. Ingle, and Vincent Mascitti
Pfizer Worldwide Medicinal Chemistry, Eastern Point Road, Groton, Connecticut 06340, United States
S
* Supporting Information
ABSTRACT: The first described reaction between N-tosylhydrazone and SO2 is reported to provide alkyl sulfonamides in the
presence of various amines. In this procedurally simple method, hydrazones of both unsaturated aldehydes and ketones proceed
in moderate to excellent yields. Primary and secondary aliphatic amines are accommodated in this reaction, which provides a
novel route to sulfonamides.
Scheme 1. Summary of One Pot Sulfonamide Syntheses
ulfonamides have become important structural elements in
Sdrug design since the development of sulfa antibiotics in
the 1930s.1 Although the traditional synthesis of sulfonamides
from sulfonyl chlorides and amines is straightforward, obtaining
the necessary sulfonyl chloride can be cumbersome. Classical
methods toward sulfonyl chlorides typically require the
oxidation and/or chlorination of less commonly encountered
sulfides/thiols/sulfonates or harsh electrophilic aromatic
substitution with SO3.2 Recently, various groups have reported
more streamlined syntheses of aryl sulfonamides through a one-
pot combination of an organic fragment, sulfur source, and
amine.3 The organic fragments have ranged from boronic acids
(Buchwald, Pfizer/Toste, and Willis),4a−c to anilines (Malet-
Sanz),4d aryl halides (Pfizer),4e and aryl Grignards (Willis and
Barrett)4f−h (Scheme 1).4 These advances have provided
medicinal chemists increased flexibility for the introduction of
sulfonamides.
While previous one-pot reactions have focused on aryl
sulfonamides, we sought a method to access alkyl variants.5
With this goal in mind, we were particularly attracted to
decades-old reports that showed alkyl diazo species react with
SO2 to purportedly generate sulfenes which undergo further
reaction with amines to yield sulfonamides.6 While a topic of
mechanistic study, these reports were not further explored for
their synthetic value, likely due to the fact that diazo
compounds are difficult to obtain and exhibit explosive
potential. We sought to elaborate this chemistry through in
situ generation of diazo compounds from N-tosylhydrazones
which are stable and straightforward to obtain in one step from
aldehydes/ketones.7 Thus, we endeavored to develop a
conversion of N-tosylhydrazones to sulfonamides through
reaction with sulfur dioxide and an amine.8 To our knowledge,
such a transformation would be the first report of a reaction
between N-tosylhydrazones and sulfur dioxide.
It was found that heating DABSO (a 1,4-diazabicyclo[2.2.2]
octane bis(sulfur dioxide) adduct),9 a convenient, commercially
available, solid source of SO2, with 1a and piperidine in DMSO
Received: December 14, 2015
© XXXX American Chemical Society
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DOI: 10.1021/acs.orglett.5b03545
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a
(dimethyl sulfoxide) at 100 °C in a sealed tube afforded direct
formation of sulfonamide 2a in 80% yield (Table 1, entry 1).
Scheme 2. Substrate Scope in Amine
Table 1. Deviation from Optimal Conditions
a
entry
variation from standard conditions
yield
1
none
80%
61%
36%
35%
0%
2
DMF solvent
3
toluene solvent
4
MeCN solvent
5
DCE solvent
6
dioxane solvent
40%
49%
73%
39%
50%
60%
7
1.2 equiv of piperidine
DABCO (2 equiv)
LiOtBu (2 equiv)
Cs2CO3 (2 equiv)
SO2 (1 equiv) instead of DABSO
open to atmosphere
8
9
10
11
12
b
26%
a
Yields are for products isolated after chromatography.
a
NMR yields based on 2,6-dimethoxytoluene as internal standard.
Reaction was connected to a mineral oil bubbler.
b
a
Scheme 3. Substrate Scope in Hydrazone
DMF, dioxane, acetonitrile, and toluene provided products in
lower yields whereas a reaction in dichloroethane provided no
sulfonamide product (entries 2−6). The use of 2 equiv of
piperidine provided a higher yield than 1.2 equiv (entry 7). As
SO2 is consumed during the reaction, DABSO generates
DABCO (1,4- diazabicyclo[2.2.2] octane). Thus, the effect of
excess DABCO was explored and a minimal reduction in yield
was found (entry 8). Interestingly, this reaction does not
require the addition of an inorganic base such as LiOtBu or
Cs2CO3 which is typically used to initiate the decomposition of
the N-tosylhydrazone to the diazo species.7 The addition of
such bases actually lead to a decrease in yield (entries 9−10).
Use of SO2 instead of DABSO also provides the sulfonamide
product albeit in a slightly lower yield (entry 11). Finally, all
reported reactions were carried out in a sealed container to
prevent loss of SO2 gas from DABSO. Heating the reaction
while open to the atmosphere provided significantly diminished
yields (entry 12).
The substrate scope was next explored using different amines
(Scheme 2). While cyclic secondary amines such as piperidine
provided the highest yield, useful yields were obtained with
isopropyl, tert-butyl, diethyl, and benzyl amine (2a−2d).
Versatile functional handles such as alkene, alkyne, and
hydroxyl groups were also tolerated, allowing for potential
subsequent diversification (2f−2h). Aryl amines provided only
trace products under these conditions (2i). Bulky secondary
amines such as dibenzyl and diisopropylamine furnished no
product (not shown).
a
b
Yields are for products isolated after chromatography. Reaction was
performed in dioxane.
Various N-tosylhydrazones of aromatic aldehydes and
ketones are accommodated (Scheme 3, 2j−2k), though
sterically congested hydrazones such as that derived from
isobutyrophenone provided significantly lower yields (2l).
Electronically diverse aryl hydrazones provided the sulfonamide
products in moderate to good yields (2n−2r, 2u). Of note, it
was empirically discovered that electron-deficient substrates
provided higher yields in dioxane instead of DMSO.10 This
method tolerated aryl chlorides, bromides, and ortho
substitution (2s, 2t, 2v). Diaryl hydrazones (2m), thiazoles
(2w), and pyridines (2x) were all accommodated. Good yields
were obtained for the reaction of α,β-unsaturated hydrazones
providing homovinyl sulfonamide, 2y, which could be leveraged
for consequent reactions. Yields were significantly decreased for
the hydrazones of alkyl aldehydes (2z) and completely
repressed for dialkyl ketones (2aa). In these low yielding
reactions, the starting hydrazone was largely consumed and
B
DOI: 10.1021/acs.orglett.5b03545
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Letter
significant amounts of tosyl piperidine were obtained. No
elimination or carbene dimerization products were observed.
However, the bulk of the mass balance is unaccounted for.
Furthermore, in substrates bearing the ester moiety (i.e., 2o,
2q), no amidation products were observed, suggesting that the
amine may be sequestered during the reaction. Finally, a two-
step, one-pot conversion of acetophenone to sulfonamide 2a
was demonstrated to provide the product in comparable yields
to that found in Scheme 2 (Scheme 4).
Several plausible nonradical mechanisms might be consid-
ered for the reported reaction (Scheme 7). Path A is based on
Scheme 7. Possible Mechanisms
Scheme 4. One-Pot Conversion of Ketones to Sulfonamide
Additionally, alternate sources of SO2 were viable for this
reaction. Use of commonly available potassium metabisulfite
and tetrabutylammonium bromide in place of DABSO
provided sulfonamide 2a in good yield (Scheme 5).4e
Scheme 5. Potassium Metabisulfite as Sulfur Source
previous reports from reactions of SO2 with nucleophilic diazo
species.6 In this pathway, the diazo species generated from the
amine-initiated decomposition of the N-tosylhydrazone7 acts as
a nucleophile in a reaction with SO2, forming intermediate 3.
Loss of N2 gas then yields a sulfene (4) which reacts with
piperidine to generate 2a. Alternatively in path B, the diazo
intermediate may act as a base and be protonated to generate 5.
Displacement with a nucleophilic amine−SO2 complex would
also provide 2a.12 Finally in path C, SO2 may undergo an ene
reaction with the N-tosylhydrazone to generate intermediate 6
which could decompose to sulfene 4. Similar ene reactivity with
SO2 has been reported previously with alkenes.5 Other
mechanistic possibilities include formation of a free carbene
which could react with SO2 to generate sulfene 4 directly. This
may be less likely, as no carbene side products (i.e., alkenes)
were observed in the couplings. Further investigation is
ongoing to elucidate the mechanism.
To elucidate the mechanism, reactions were first carried out
to probe for radical intermediates which have been reported for
amine−SO2 adducts.11 Addition of TEMPO had little effect on
yield, and no TEMPO adducts were observed (Scheme 6).
Scheme 6. Mechanistic Studies To Probe Existence of
Radical Intermediates
In conclusion, the first reported reaction between N-
tosylhydrazones, SO2, and amines is shown to generate
sulfonamides. Unsaturated hydrazones provide moderate to
excellent yields, and the mild reaction conditions accommodate
a variety of useful functional groups. Of note, this reaction
neither requires nor benefits from the addition of commonly
used transition metals such as Pd, Cu, or Rh,10 and it adds to a
growing list of metal-free coupling reactions with N-tosyl-
hydrazones. Ultimately, this method affords a new route to
sulfonamides from readily available ketones and aldehydes.
a
b
NMR yields based on 2,6 dimethoxytoluene as internal standard. No
c
TEMPO adducts observed. Yield obtained after chromatography.
ASSOCIATED CONTENT
■
S
* Supporting Information
Addition of BHT (butylated hydroxytoluene) as a radical
inhibitor did not suppress the reaction. Finally, use of phenyl
cylcopropyl ketone provided the expected sulfonamide product
(2ab) without ring opening of the cyclopropyl group.
Combined, these observations suggest that radical processes
are not operative during this transformation.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b03545.
Experimental procedures and characterization data
(PDF)
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AUTHOR INFORMATION
Corresponding Author
■
*E-mail: andy.tsai@pfizer.com.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Andrei Shavnya and Roger Ruggeri of Pfizer
Worldwide Medicinal Chemistry, Groton CT, for valuable
discussions.
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