Preparation of Functionalized α,β-Unsaturated Sulfonamides via Olefin Cross-Metathesis

Article abstract of DOI:10.1021/acs.orglett.0c01471

The synthesis of functionalized α,β-unsaturated sulfonamides by means of cross-metathesis of vinyl sulfonamides and olefins has been developed. The reaction proceeds smoothly in the presence of Hoveyda-Grubbs catalyst and its nitro analogue, providing a w

Full text of DOI:10.1021/acs.orglett.0c01471

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Letter
Preparation of Functionalized α,β-Unsaturated Sulfonamides via
Olefin Cross-Metathesis
§
§
Łukasz Wozniak, Adam A. Rajkiewicz, Louis Monsigny, Anna Kajetanowicz,* and Karol Grela*
́
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ABSTRACT: The synthesis of functionalized α,β-unsaturated
sulfonamides by means of cross-metathesis of vinyl sulfonamides
and olefins has been developed. The reaction proceeds smoothly in
the presence of Hoveyda−Grubbs catalyst and its nitro analogue,
providing a wide range of substituted products. The usefulness of
this methodology has been proven in the preparation of new
derivatives of biologically active ingredients, moxifloxacin and
naratriptan.
unctionalized α,β-unsaturated compounds are highly
useful substrates in organic synthesis. Because of their
inherent advantages, such as mild reaction conditions and
availability of the olefinic substrates, the catalytic olefin cross-
metathesis (CM) reaction appears to be potentially a very
Table 1. Optimizations of the CM Reaction of Sulfonamide
3a and Alkene 2a
F
useful method for synthesis of these building blocks (Scheme
1
1
). However, it should be noted that not all functionalities at
a
the reacting C−C double bond (functional groups, FG, in
entry
solvent
DCM
DCM
catalyst
GC conversion (%)
1
Scheme 1) are easily tolerated in CM. For example, while
1
2
3
4
5
6
1a
1b
1c
1c
1c
1d
76
92
89
81
87
57
acrylic acid esters and amides or α,β-unsaturated aldehydes
and ketones are usually well tolerated, acrylonitrile got
DCM
2
reputation of a rather problematic substrate. The same is
toluene
diethyl ether
DCM
true for vinyl phosphine oxides which require extensive
3
optimization to react in CM.
Similarly, a number of challenges were noted in the cross-
a
Tetradecane was used as an internal standard.
metathesis reaction of α,β-unsaturated partners containing
4
sulfur at various oxidation states. In contrast to allyl sulfides
the propagating Ru species into stable Fisher carbenes during
the reaction course. While this problem can be at least
partially overcome by using higher loading of the catalyst and
(
type I olefins), vinyl sulfides (type III olefins) are much less
reactive, which is generally assumed with their ability to arrest
5
microwave irradiation, vinyl sulfides are not easy partners in
Ru-catalyzed CM.
Scheme 1. Synthesis of Functionalized α,β-Unsaturated
Compounds by Cross-Metathesis
6
a
Another important building blocks are sulfone- and
sulfoxide-containing alkenes. Vinyl sulfoxides were reported
7
as completely inert in the CM reaction with olefins, and
according to our knowledge, only one example of a partially
4
successful allylsulfoxide CM was reported. The latter was,
however, not seamless, and despite the high catalyst loading
and forcing conditions used only 31% of the product was
Received: April 28, 2020
a
Selected Ru catalysts used in this transformation.
©
XXXX American Chemical Society
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Table 2. Cross-Metathesis between Sulfonamide 3a and
Alkenes 2a−i
Table 3. Cross-Metathesis between Sulfonamides 3b,c and
Alkenes 2a-b,d
Scheme 2. Cross-Metathesis between Vinyl Sulfonamide 3a
and Moxifloxacin Derivative 2j
a
Reaction performed in the presence of 10 mol % of Ti(OiPr) ; the
4
dimer of 2f was obtained with 62% yield.
to synthetically useful products, and herein, we present a
detailed report on this transformation.
formed in this transformation. In contrary, allyl sulfones very
easily undergo cross-metathesis reactions even in the presence
of the first generation Grubbs catalyst under mild conditions.
Vinyl sulfonamides 3a−c, needed as CM partners, were
conveniently obtained in the reaction between 2-chloroetha-
nesulfonyl chloride and the corresponding amine in the
8
The analogous CM reaction of vinyl sulfones is far more
demanding and requires the use of a second-generation
16
presence of Et N (see the SI).
3
9
catalyst. Nevertheless, under optimized conditions the desired
First, a model cross-metathesis between N,N-diethylethene-
sulfonamide (3a) and tert-butyl(hex-5-en-1-yloxy)-
dimethylsilane (2a) was carried out in order to find the
optimal reaction conditions (Table 1). The CM reaction was
performed in the presence of 2.5 mol % of selected second-
generation ruthenium catalysts, with tetradecane as an internal
standard. As the result, we found that Hoveyda−Grubbs-type
catalysts 1b and 1c give the best yields and DCM is the solvent
of choice. In all cases, the expected product 4a was formed
exclusively as (E)-isomer. Importantly, as olefin 2a is a Type I
CM products can be obtained in high yield and with complete
7
(
E)-selectivity. In addition, the reactivity of divinyl sulfone
10
was investigated, and the selective formation of monosub-
stituted derivatives exclusively as (E)-isomer was observed.
Therefore, this transformation found applications in total
synthesis, providing easy access to variously functionalized α,β-
unsaturated sulfone building blocks. Importantly, the CM
reaction of vinyl sulfones has become useful also in a medicinal
chemistry context, as this function can increase the biological
11
12
5
activity of a drug.
CM partner in Grubbs classification, in order to avoid a
It is striking that despite so many functional groups (Scheme
) having already been tested in CM, the applicability of vinyl
concomitant formation of the undesired homodimer (TBSO-
(CH ) CH = CH(CH ) OTBS), 2 equiv of vinyl sulfonamide
3a was used. The self-CM of 3a was not observed during the
1
2
4
2 4
sulfonamides as partners in this transformation is barely
1
3
known (although there are single examples of use in RCM -
process, which renders this substrate as a type III CM partner
14
17
ring-closing metathesis), and only one report describing CM
(not undergoing “homodimerization”).
15
of allyl sulfonamides is available.
With the optimized conditions in hand, the scope of the CM
reaction between sulfonamide 3a and selected alkenes was
examined. A wide range of CM partners underwent these
On the basis of our previous investigations, we assumed that
vinyl sulfonamides can act as suitable partners in CM, leading
B
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Scheme 3. Synthesis of Naratriptan Analogue 4s and Structures of Selected Marketed Triptan Drugs
reactions leading to diversely substituted sulfonamide deriva-
tives, as shown in Table 2. For example, when simple terminal
olefins (2a−d) were reacted with 3a in the presence of
Hoveyda−Grubbs-type catalyst, the desired products 4a−d
were obtained in good or very good yields (entries 1−4). The
situation was slightly different when the styrene derivative 2e
was used (entry 5). Under standard conditions (2.5 mol % of
result, we were pleased to see that with help of catalyst 1b (5
mol %) the corresponding heavily functionalized product 4p
was obtained in a good yield of 60% as the exclusive (E)-
isomer.
Another example of a polyfunctional molecule of pharma-
ceutical interest is naratriptan, one of the potent triptan drugs
marketed by GlaxoSmithKline used for the treatment of acute
19
1
b, 5 h) the only product was a stilbene, resulting from self-
CM of styrene 2e. However, increasing the catalyst loading to
mol % and extending the reaction time to 22 h allowed the
migraine attacks and severe headaches. This drug can be
produced by Heck cross-coupling between vinyl sulfonamide
and the appropriate brominated indole and subsequent
5
20
hydrogenation of the product. In an alternative approach
envisioned by us, the cross-metathesis reaction between 5-
vinyl-1H-indole derivative and vinyl sulfonamide may be
considered (Scheme 3). Indeed, when indole 2l was subjected
to CM with N,N-diethylethenesulfonamide (3a) in the
presence of 5 mol % of the nitro analogue of Hoveyda−
Grubbs catalyst 1c, the precursor 4s of the naratriptan
analogue was obtained with a satisfactory yield of 52%.
isolation of sulfonamide 4e in a satisfactory yield of 62%.
Sulfonamide 3a also worked with ketone 2f and sterically
demanding allylmalonate derivative 2g, although in these cases
lower yields were obtained, 30 and 32%, respectively, even with
increased catalysts loading (entries 7 and 8). As mentioned
before, sulfoxides are considered as very demanding partners in
CM, and achieving the expected sulfoxide-containing product
4
requires forcing conditions. Thus, we were pleased to find that
In summary, we have developed a simple but effective
methodology leading to functionalized α,β-unsaturated sulfo-
namides by means of olefin cross-metathesis utilizing a wide
range of alkene partners. The title CM reactions can be simply
carried out in the presence of commercially available Hoveyda-
Grubbs-type catalysts 1b and 1c and the expected products
were formed in moderate to good yields exclusively as (E)-
isomers. Notably, a range of functionality is tolerated within
this reaction, including not only carbonyl functions, esters, and
sulfoxides, but also carboxylic acids and basic nitrogen groups.
Because of their wide compatibility, this transformation can be
successfully used in the synthesis of polyfunctional biologically
active molecules as one of the alternatives in the formation of
sulfoxide−sulfonamide 4h, bearing two sulfur atoms exhibiting
different oxidation states, was produced in 70% isolated yield.
Encouraged by this result, we decided to perform the CM
reaction between 3a and allyl tert-butyl sulfoxide (2i).
Unfortunately, but according to the literature warnings about
4
inactivity of 2i in CM, this reaction was completely ineffective
as even traces of the expected product 4i were not observed.
Such results might suggest that poisoning of the catalyst by
ligation of a sulfoxide function happens mainly when sulfoxide
1
8
is located close to the reacting C−C double bond.
The scope and limitation study was next extended to other
vinyl sulfonamides (Table 3). Morpholine-based sulfonamide
3
b exhibited slightly lower reactivity than 3a, although yields
21
aliphatic sulfonamides.
remained high (entries 1−3). A cross-metathesis reaction of N-
monosubstituted sulfonamide 3c performed under standard
conditions led to the desired products in moderate yields, but
increasing the catalyst loading to 5 mol % in all cases
practically doubled the yield (entries 4−6).
ASSOCIATED CONTENT
sı Supporting Information
■
*
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01471.
Having successfully demonstrated the practicality of the CM
reaction between vinyl sulfonamides and olefins bearing
carbonyl, ester, and sulfoxide groups or halogens, this
methodology was applied to more sophisticated substrates of
potential medicinal interest. To do so, we attempted the CM
reaction between N,N-diethylethenesulfonamide (3a) and a
relative of the fluoroquinolone antibacterial agent moxifloxacin
Experimental details and H and 13C NMR spectra
1
(PDF)
AUTHOR INFORMATION
Corresponding Authors
■
(
Scheme 2). In order to prevent dimerization of the
Anna Kajetanowicz − Institute of Organic Chemistry, Polish
Academy of Sciences, 01-224 Warsaw, Poland; Laboratory of
Organometallic Synthesis, Biological and Chemical Research
moxifloxacin derivative 2j (which can be classified as type I
olefin), the cross-metathesis partner 3a was used in excess. As a
C
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Organic Letters
Centre, Faculty of Chemistry, University of Warsaw, 02-089
Warsaw, Poland; orcid.org/0000-0003-0315-0998;
Email: a.kajetanowicz@uw.edu.pl
Karol Grela − Laboratory of Organometallic Synthesis,
Biological and Chemical Research Centre, Faculty of Chemistry,
University of Warsaw, 02-089 Warsaw, Poland; orcid.org/
pubs.acs.org/OrgLett
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000-0001-9193-3305; Email: karol.grela@gmail.com
Authors
Łukasz Wozn
2
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31−534.
́
iak − Institute of Organic Chemistry, Polish
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Academy of Sciences, 01-224 Warsaw, Poland
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Adam A. Rajkiewicz − Laboratory of Organometallic Synthesis,
Biological and Chemical Research Centre, Faculty of Chemistry,
University of Warsaw, 02-089 Warsaw, Poland
Louis Monsigny − Laboratory of Organometallic Synthesis,
Biological and Chemical Research Centre, Faculty of Chemistry,
University of Warsaw, 02-089 Warsaw, Poland; orcid.org/
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b) Lonchambon, G.; Delacroix, A.; Petit, J.; Lecomte, P. Bull. Soc.
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0
000-0001-9325-1316
(17) As the reactivity of allyl sulfonamides in CM is only little
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01471
explored (cf. ref 15), in order to compare them with vinyl
sulfonamides we conducted a model CM reaction of 3d to find that
unlike the latter (Type III partners) these substrates undergo
homodimerization and so are type I CM partners according to
Grubbs classification.
Author Contributions
§Ł.W. and A.A.R. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
A.K. is grateful to the Homing Plus Programme of the
Foundation for Polish Science cofinanced from the European
Union, Regional Development Fund (HOMING PLUS/2013-
(
18) Due to the ambiguities of sulfoxide-containing alkenes
reactivity in CM (cf. Table 2, entry 9), we applied 2h in
homodimerization and in CM reaction with Type I olefin 2a. In
both cases, good activity was observed, rendering sulfoxide 2h as a
regular Type I partner according to Grubbs classification. On the
contrary, allyl and vinyl sulfoxides are classified as Type IV
7
/6). The study was carried out at the Biological and Chemical
Research Centre, University of Warsaw, established within the
project cofinanced by European Union from the European
Regional Development Fund under the Operational Pro-
gramme Innovative Economy, 2007−2013.
(
nonreactive; ref 4). while homoallyl and higher sulfoxides are
reactive (for more discussion, see the SI).
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