Silver‐Catalyzed Stereoselective Aminosulfonylation of Alkynes

Abstract A silver‐catalyzed intermolecular aminosulfonylation of terminal alkynes with sodium sulfinates and TMSN3 is reported. This three‐component reaction proceeds through sequential hydroazidation of the terminal alkyne and addition of a sulfonyl radical to the resultant vinyl azide. The method enables the stereoselective synthesis of a wide range of β‐sulfonyl enamines without electron‐withdrawing groups on the nitrogen atom. These enamines are found to be suitable for a variety of further transformations.

Alkynes are one of the most common and versatile functional groups in organic synthesis,and catalytic methods that enable their efficient transformation into other useful functionalities are therefore highly appealing in both academic research and industrial applications. [1] Direct difunctionalization reactions of alkynes,c apable of affording tri-and tetrasubstituted alkenes,h ave attracted much attention in recent years. [2] Among these,r adical-based 1,2-difunctionalizations of alkynes offer astraightforward means to construct functionalized alkenes by reaction with both carbon- [3] and heteroatom-centered radicals [4] with excellent step-and atomeconomy. [5] Mechanistically,ac ommon reaction pathway is observed involving initiation of the reaction by radical addition to the alkyne to generate av inyl radical intermediate,w hich is then coupled with another component to form the alkene product ( Figure 1a). However,s uch vinyl radical species are highly reactive and readily undergo hydrofunctionalization by H-atom abstraction, [6] which is as ignificant challenge in developing radical-based alkyne difunctionalization reactions.M oreover,a liphatic alkynes are generally unreactive in these processes,which is most likely due to the lack of a p-conjugation stabilizing effects of intermediate alkyl-substituted vinyl radicals compared to aryl-substituted analogues. [7] Consequently,c onceptually distinct approaches are in high demand. In the last years,t he nitrogenation of alkynes with trimethylsilylazide (TMSN 3 )has attracted much attention, where carbon-carbon triple bond cleavage leads to av ariety of nitrogen-containing molecules. [8] Building from our recent efforts on the activation of alkynes by silver catalysis, [9] we herein report an ew strategy to effect radicalbased difunctionalization of terminal alkynes through an unprecedented hydroazidation/ radical addition cascade (Figure 1b). Thek ey point for this successful transformation is that we discovered amild and efficient approach to generate sulfonyl radical from sodium sulfinate,t hus avoiding the initial competitive radical addition to alkynes. [6] To the best of our knowledge,t his is the first example of intermolecular alkyne aminosulfonylation, [10] resulting in stereoselective synthesis of b-sulfonyl N-unprotected enamines,w hich are useful synthetic intermediates whose applications are currently limited by al ack of practical synthetic methods for their preparation. [11] Moreover,only one report regarding the synthesis of N-unprotected enamines by alkyne difunctionalization has been reported. [12] Initial optimization of the reaction was performed using alkyne 1a,T MSN 3 ,a nd sodium p-toluenesulfinate 2a,w ith variation of reaction parameters including metal catalyst, solvent, and temperature (Table 1). Silver salts proved highly effective in promoting the hydroazidation/ sulfonation cascade;A g 2 CO 3 ,A g 3 PO 4 ,a nd AgF all gave the aminosulfonylated product 3a in high yields,w ith Ag 3 PO 4 delivering an optimum yield of 85 %(entries 1-3). In contrast, other metal catalysts such as Pd(OAc) 2 ,C uI, and Mn(OAc) 3 were ineffective,w hich is presumably due to their inability to catalyze the hydroazidation reaction (entries 4-6). Water was found to be an essential additive,a sap oor yield (30 %) was obtained in its absence (entry 7);t he use of less than two equivalents of TMSN 3 also resulted in ad ecrease in product yield. Thereaction solvent also proved important, with DCE and 1,4-dioxane giving only trace amounts of the desired product using Ag 3 PO 4 as catalyst (entries 8and 9), compared to polar aprotic solvents such as NMP (65 %, entry 10) and [*] Y. Ning DMSO.F inally,i ncreasing or reducing the reaction temperature led to ad ecrease in product yield (entries 11 and 12). Thes cope of the reaction with respect to the alkyne proved broad, with aw ide range of aryl-and heteroarylfunctionalized terminal alkynes being suitable for this silvercatalyzed cascade reaction, affording the corresponding bsulfonyl enamines in good to excellent yields (Scheme 1). For instance,avariety of para-substituted phenylacetylenes 1a-1j underwent smooth reaction with TMSN 3 and 2a to give the products 3a-3j in 69-87 %y ields.P leasingly,c ommon functional groups such as alkoxy,a lkyl, aryl, halogen, cyano, trifluoromethyl, aldehyde,a nd ester were all well-tolerated, with X-ray diffraction analysis of 3c confirming the (Z)configuration of the alkene.S imilarly, ortho-, meta-, and 3,4disubstituted phenylacetylenes gave the desired enamine products 3k-3p in high yields (79-83 %). Heteroaryl acetylenes including 2-and 3-pyridyl, 2-and 3-thienyl, as well as ferrocenyl acetylene were also evaluated, and the corresponding products 3s-3w were obtained with high efficiency. Amore elaborate estrone-derived terminal alkyne could also be successfully transformed into the corresponding b-sulfonyl enamine 3x (79 %), underlining the robust nature of the method.
Following this success with aryl-substituted alkynes,w e turned our attention to the reactivity of aliphatic alkynes, where it is notable that alkyl-substituted b-sulfonyl enamines have not been prepared by other methods.I nt he event, we were delighted to find that reactions of alkyl-substituted terminal alkynes generally proceeded with equal efficiencyto aryl alkynes,affording anumber of functionalized b-sulfonyl enamines 4 in high yields.Apart from simple alkyl acetylenes (4a-4d,6 9-81 %), cyclopropyl, hydroxyl, and phthalimide substituents were all tolerated, giving the functionalized sulfonyl enamines 4e-4h (59-82 %). Further,e nyne systems such as 1-cyclohexenyl and styryl acetylenes also participated efficiently in this three-component reaction, giving the 1,3butadienes 4i and 4j in reasonable yields.The presence of an internal alkyne did not affect the formation of b-sulfonyl enamine 4k(79 %), illustrating the exquisite chemoselectivity between internal and terminal alkynes.A ll of these heteroaryl-and alkyl-substituted b-sulfonyl enamines in Scheme 1 are novel compounds that could prove useful as intermediates in organic and medicinal chemistry research.
We next set out to evaluate the reaction scope with respect to the sulfinate component in reactions with 4-phenyl phenylacetylene 1y (Table 2). Whether electron-rich or electron-deficient, aryl sulfinates afforded the corresponding b-sulfonyl enamines in high yields (5a-5c,7 5-82 %). Alkyl sulfinate salts also proved suitable reaction partners,g iving products 5d-5fwith similar efficiency.
To gain insight into the reaction mechanism, the reaction of 4-ethynyltoluene 1b was monitored by 1 HNMR spectroscopy under standard reaction conditions in [D 6 ]DMSO (Figure 2a). By comparison with authentic samples,signal A at 4.1 ppm was assigned as the acetylenic proton of 1b.After 40 min, this signal had almost completely disappeared, and new doublets at 4.97 and 5.61 ppm were assigned as the olefinic hydrogens of vinyl azide VA,w hich reached am aximum intensity after 20 min. Thes inglet at 5.07 ppm was assigned as the olefinic hydrogen of product 3b,w hich

Angewandte Chemie
Communications appeared after about 20 min, and was almost the sole reaction component by 180 min. This result clearly suggests initial rapid alkyne hydroazidation, followed by slower addition of sulfonyl radical to the vinyl azide generated in situ, and also illustrates the clean conversion of the terminal alkyne to the b-sulfonyl enamine.F urther information on the radical addition step was obtained by submission of vinyl azide (VA)t ov arious reaction conditions (Figure 2b), which revealed ad ual role of TMSN 3 :i nt he absence of TMSN 3 , no reaction took place,whereas in the presence of 1.5 equivalents,p roduct 3b was afforded in high yield (85 %) after ashort reaction time (40 min). This implies that TMSN 3 plays ac ritical role in generation of the sulfonyl radical. That this second step indeed involves ar adical intermediate was supported by the formation of only at race amount of 3b in the presence of TEMPO. On the basis of above experimental results,apossible mechanism is illustrated in Scheme 2. Initially,A gN 3 is generated by anion exchange of TMSN 3 with Ag 3 PO 4 . [13] Its subsequent addition to the terminal alkyne 1a produces vinylsilver intermediate A' '. [8a] Meanwhile,T olSO 2 TMS (A)is generated from sulfinate salt 2a (possibly promoted by Ag I ).
Such intermediates are known to be somewhat unstable, [14] and could be oxidized by Ag I to give ar adical cation B, [15] which could then release sulfonyl radical C and atrimethylsilyl cation. [9g] Thel atter is captured by water to produce trimethylsilanol with release of ap roton, which could affect protodemetalation of intermediate A' ' to give the observed vinyl azide (VA). This in turn is readily attacked by the sulfonyl free radical C,l eading to carbon-centered radical D, [16] which rapidly converts to iminyl radical E with release of N 2 .F ollowing sequential reduction and protonation, an imine intermediate (G)i sf ormed. Product 3b is obtained by tautomerization of this imine. [17] Stereochemistry of the product should be ascribed to the intramolecular hydrogenbonding effect. Note that the screening of av ariety of potential radical precursors,s uch as Tognisr eagent, diphenylphosphine oxide,and potassium 2-oxo-2-phenylacetate, [18] were not successful in the desired aminofunctionalization of terminal alkynes,and therefore demonstrated the generation of sulfonyl radical under above mild conditions appears to play ac rucial role in controlling the reaction sequence. [9b,19] Finally,agram scale reaction of phenylacetylene 1c, TMSN 3 and sodium p-toluenesulfinate 2a was tested;delightfully,this reaction could be performed on 20 mmol scale and proceeded smoothly to give product 3c with only am odest decrease in yield (3.11 g, 57 %; Scheme 3). Next, further synthetic manipulations were conducted to explore its reactivity.A sr eported by Jiang, [11] b-ketosulfone 6 could be prepared by treatment of 3c with silica gel (95 %), while 2Hazirine 7 was obtained in 65 %y ield through hypervalent iodine-induced oxidative cyclization. [20] Unexpectedly,d ihydropyrrole 8 was obtained under Bao and GuansK 2 S 2 O 8mediated oxidative cyclization conditions,instead of apyrrole as observed with analogous b-keto or b-ester enamines. [21] Similarly,anew reaction pattern was discovered on treatment of 3c with NBS,w hich afforded polybrominated imine 9 in 72 %y ield. N-brominated imines have rarely been reported. [22] In summary,aconvenient and functional-group-tolerant silver-catalyzed three-component reaction of terminal alkynes,T MSN 3 ,a nd sodium sulfinates has been developed, which shows broad substrate scope with respect to both the  alkyne and sulfinate.T he reaction proceeds through an unprecedented sequence of alkyne hydroazidation, and radical addition of as ulfonyl radical to the in situ generated vinyl azide.T his strategy represents an appealing means to achieve alkyne aminofunctionalization under mild reaction conditions;e xtension to other radical species is under way, and will be reported in due course.