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

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.

Functionalized 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 useful method for synthesis of these building blocks (Scheme 1).¹ However, it should be noted that not all functionalities at the reacting C–C double bond (functional groups, FG, in Scheme 1) are easily tolerated in CM.¹ For example, while acrylic acid esters and amides or α,β-unsaturated aldehydes and ketones are usually well tolerated, acrylonitrile got reputation of a rather problematic substrate.² The same is true for vinyl phosphine oxides which require extensive optimization to react in CM.³

Scheme 1. Synthesis of Functionalized α,β-Unsaturated Compounds by Cross-Metathesis.

Selected Ru catalysts used in this transformation.

Similarly, a number of challenges were noted in the cross-metathesis reaction of α,β-unsaturated partners containing sulfur at various oxidation states.⁴ In contrast to allyl sulfides (type I olefins), vinyl sulfides (type III olefins) are much less reactive, which is generally assumed with their ability to arrest the propagating Ru species into stable Fisher carbenes during the reaction course.⁵ While this problem can be at least partially overcome by using higher loading of the catalyst and microwave irradiation, vinyl sulfides are not easy partners in Ru-catalyzed CM.⁶

Another important building blocks are sulfone- and sulfoxide-containing alkenes. Vinyl sulfoxides were reported as completely inert in the CM reaction with olefins,⁷ and according to our knowledge, only one example of a partially successful allylsulfoxide CM was reported.⁴ The latter was, however, not seamless, and despite the high catalyst loading and forcing conditions used only 31% of the product was 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.⁸ The analogous CM reaction of vinyl sulfones is far more demanding and requires the use of a second-generation catalyst.⁹ Nevertheless, under optimized conditions the desired CM products can be obtained in high yield and with complete (E)-selectivity.⁷ In addition, the reactivity of divinyl sulfone was investigated,¹⁰ and the selective formation of monosubstituted 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.¹¹ Importantly, the CM reaction of vinyl sulfones has become useful also in a medicinal chemistry context, as this function can increase the biological activity of a drug.¹²

It is striking that despite so many functional groups (Scheme 1) having already been tested in CM, the applicability of vinyl sulfonamides as partners in this transformation is barely known¹³ (although there are single examples of use in RCM - ring-closing metathesis),¹⁴ and only one report describing CM of allyl sulfonamides¹⁵ is available.

On the basis of our previous investigations, we assumed that vinyl sulfonamides can act as suitable partners in CM, leading to synthetically useful products, and herein, we present a detailed report on this transformation.

Vinyl sulfonamides 3a–c, needed as CM partners, were conveniently obtained in the reaction between 2-chloroethanesulfonyl chloride and the corresponding amine in the presence of Et₃N (see the SI).¹⁶

First, a model cross-metathesis between N,N-diethylethenesulfonamide (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 partner in Grubbs classification,⁵ in order to avoid a concomitant formation of the undesired homodimer (TBSO(CH₂)₄CH = CH(CH₂)₄OTBS), 2 equiv of vinyl sulfonamide 3a was used. The self-CM of 3a was not observed during the process, which renders this substrate as a type III CM partner (not undergoing “homodimerization”).¹⁷

Table 1. Optimizations of the CM Reaction of Sulfonamide 3a and Alkene 2a.

entry	solvent	catalyst	GC conversiona (%)
1	DCM	1a	76
2	DCM	1b	92
3	DCM	1c	89
4	toluene	1c	81
5	diethyl ether	1c	87
6	DCM	1d	57

^aTetradecane was used as an internal standard.

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 reactions leading to diversely substituted sulfonamide derivatives, 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 1b, 5 h) the only product was a stilbene, resulting from self-CM of styrene 2e. However, increasing the catalyst loading to 5 mol % and extending the reaction time to 22 h allowed the 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 requires forcing conditions.⁴ Thus, we were pleased to find that 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 inactivity of 2i in CM,⁴ 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 is located close to the reacting C–C double bond.¹⁸

Table 2. Cross-Metathesis between Sulfonamide 3a and Alkenes 2a–i.

^aReaction performed in the presence of 10 mol % of Ti(OiPr)₄; the dimer of 2f was obtained with 62% yield.

The scope and limitation study was next extended to other vinyl sulfonamides (Table 3). Morpholine-based sulfonamide 3b exhibited slightly lower reactivity than 3a, although yields 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).

Table 3. Cross-Metathesis between Sulfonamides 3b,c and Alkenes 2a-b,d.

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 (Scheme 2). In order to prevent dimerization of the moxifloxacin derivative 2j (which can be classified as type I olefin), the cross-metathesis partner 3a was used in excess. As a 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.

Scheme 2. Cross-Metathesis between Vinyl Sulfonamide 3a and Moxifloxacin Derivative 2j.

Another example of a polyfunctional molecule of pharmaceutical interest is naratriptan, one of the potent triptan drugs marketed by GlaxoSmithKline used for the treatment of acute migraine attacks and severe headaches.¹⁹ This drug can be produced by Heck cross-coupling between vinyl sulfonamide and the appropriate brominated indole and subsequent hydrogenation of the product.²⁰ 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%.

Scheme 3. Synthesis of Naratriptan Analogue 4s and Structures of Selected Marketed Triptan Drugs.

In summary, we have developed a simple but effective methodology leading to functionalized α,β-unsaturated sulfonamides 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 aliphatic sulfonamides.²¹

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.orglett.0c01471.

• Experimental details and ¹H and ¹³C NMR spectra (PDF)

Author Contributions

^§ Ł.W. and A.A.R. contributed equally.

The authors declare no competing financial interest.