Gold‐Catalyzed Cycloisomerization of Sulfur Ylides to Dihydrobenzothiepines

Abstract The metal‐promoted nucleophilic addition of sulfur ylides to π‐systems is a well‐established reactivity. However, the driving force of such transformations, elimination of a sulfide moiety, entails stoichiometric byproducts making them unfavorable in terms of atom economy. In this work, a new take on sulfur ylide chemistry is reported, an atom‐economical gold(I)‐catalyzed synthesis of dihydrobenzo[b]thiepines. The reaction proceeds under mild conditions at room temperature.

Recently,our group has reported that gold-catalyzed electrophilic activation of alkenes allows the construction of highly functionalized cyclopropane scaffolds. [25][26][27][28][29][30] Prior to that, we [31] and others [32] have demonstrated the synthesis of multisubstituted furan cores throughg old-catalyzed activation of alkynes in the presence of sulfonium ylides, either in intra-or intermolecular fashion. Interestingly,t he majority of these and related transition metal-catalyzed reactions of sulfur ylides mostly employ variations on substituents tethered to the ylidic carbon.O nt he other hand, only minor variations on the sulfur substitution have been reported, [25,30] probably due to the fact that most of those transformationse ventually result in elimination of the sulfur tether during the reaction, thus, leading to stoichiometric sulfide byproducts (cf. Scheme 1a,i i-iv).
[a] C. Knittl-Frank,I.S aridakis,T .Stephens, Dr.R.Gomes, Dr.J. Neuhaus by ap rior study of our group (Scheme 1a iv). [31] To our surprise, the obtained spectroscopic data for the major product were not in agreement with our hypothesis. Thorough analysis revealed that dihydrobenzo[b]thiepine 2a was formed as a major product in lieu of the anticipatedf uran (Scheme 1b). This serendipitously discovered reactivity prompted us to investigate the scope of this atom-economical transformation, especially since the benzothiepine scaffold is ak nown pharmacophore. [34] Herein, we report on ag old-catalyzed cycloisomerization of S-homopropargyl sulfonium ylides to functionalized dihydrobenzo[b]thiepines. [35] Whilst minute amounts (5 %) of the furan product could be detected in initial setups, the addition of silver triflate and employmento fabinary solvents ystem (isopropanol/water 4:1 v/ v)s uppressed it entirely and was optimal for the dihydrobenzo[b]thiepine formation (see SI for details). Hence, 2a (along with its isomer 2a')w as isolated in 77 %y ield. [36] To investigate the scope of our reaction, we first screened variations in the northern 1,3-dicarbonyl substituent. We found that electron-neutral, -rich, and -poor aromaticsw ere all well tolerated ( Figure 1, 2a-c). Interestingly,t he p-NO 2 substituted sulfonium ylide 1c required higher temperature (50 8C) than the rest of the substrates to reach full conversion. This might be ascribed to the decreased nucleophilicity of the ylidic carbon,d ue to better delocalization of its formal negative charge.M oreover,t he aliphatic b-keto esters 1d and 1e delivered the benzothiepine in satisfying yields, too.
We then devised ac ompetition experiment by subjecting the sulfonium ylides 1f and 1g,b earing ap ropargyl and an allyl ester-substituted ylidic C-atom to our reaction conditions, respectively.I np reviouslyr eported gold(I)-catalyzed processes, propargyl-a nd allyl-tetheredd iphenylsulfonium ylides were readilyt ransformed into the corresponding furans [31] and cyclopropanes, [29] respectively.F ollowing this reactivity, 1f would react to the corresponding furan 2f'' through an initial 5-exodig attack of the ylidic carbon onto the gold(I)-activated triple bond followedb ya5-endo-trig cyclization along with sulfide release( Scheme 2a). [31] Likewise, 1g would form cyclopropane 2g'' after an initial 5-exo-trig attack of the ylidic C-atomo nto the gold(I)-activated double bond with as ubsequent3 -exo-tet cyclization concomitantw ith sulfide release (Scheme 2b). [29] In contrastt ot hose reports, the presence of the S-homopropargyl group completely shut down this pathway in both cases examined. Thus, under our reaction conditions we observed complete selectivitytowards the formationofdihydrobenzo[b]thiepines,t hrough an initial attack of the ylidic carbon onto the gold(I)-activatedS -homopropargyl triple bond (cf. also Scheme 3). Hence, the reactiono f1f and 1g yielded 2f/2f' and 2g with the propargyl and allyl moiety remaining intact, respectively.
Furthermore, the acetylacetoned erivative 1h afforded the corresponding benzo[b]thiepine in moderate yield. It is noteworthy that 2h resided solely in its enol form (in chloroform), whilst the rest of the synthesized dihydrobenzo[b]thiepines 2 were present in both tautomeric forms.
Finally,w es urveyed the functionality tolerance on the southernd omain of the sulfonium ylides. Hence, different para-a nd ortho-substituted S-aryl moieties weree xamined, and gratifyingly deliveredt he desired benzothiepines 2i-l in modest-to-good yields.
From am echanistic point of view,w ee nvisaged that the reaction starts with activation of the alkyne by p-coordination to the gold catalyst, [37] as shown in intermediate A (Scheme 3). An intramolecular 5-exo-dig attack of the ylidic carbon to the internal alkyne C-atom leads to ag old-vinyl complex B, [38] which undergoes ac harge-accelerateds ulfonium [3,3]-sigmatropic rearrangement [24, 35c, 39] to furnish the seven-membered thiepine ring C.F inally,r earomatization and protodeauration [40] deliver the dihydrobenzo[b]thiepines 2,c ompleting the catalytic cycle.
In conclusion, aA u I -catalyzed synthesis of dihydrobenzo[b]thiepines was developed. The mild conditions of the cycloisomerization and the simple accessibility of the sulfonium ylide startingm aterials are distinctive characteristics of this process. Interestingly,t his process appears to supersede the previously reported Au I -catalyzedi ntramolecularf uran and cyclopropane syntheses. The retention of the sulfur atom onto the final product after the reactionisanu nusualtrait of metal-catalyzed transformationso fs ulfonium ylides and enables the development of atom-economical synthetic transformations.