Hydrothiolation catalysts

Abstract The use of A-heterocyclic carbene (NHC) complexes as homogeneous catalysts in addition reactions across carbon-carbon double and triple bonds and carbon-heteroatom double bonds is described. The discussion is focused on the description of the catalytic systems, their current mechanistic understanding and occasionally the relevant organometallic chemistry. The reaction types covered include hydrogenation, transfer hydrogenation, hydrosilylation, hydroboration and diboration, hydroamination, hydrothiolation, hydration, hydroarylation, allylic substitution, addition, chloroesterification and chloroacylation. 

The thiolato complex 97 that was postulated as the active catalytic species in the reaction was prepared from 96 and the thiol in the presence of NEtj. Certain analogues of 97 (NHC = Mes, SIMes, IPr, SIPr R = Ph) have also been independently synthesised, isolated and fully characterised. A plausible mechanism for the hydrothiolation involves insertion of the alkyne into the Ni-SR bond forming the (non-isolable) p-thioalkenyl complex, from which the product can be released via alkanolysis of the Ni-C bond by the thiol and regeneration of the active catalyst 97 [84]. 

Fig. 2.17 Nickel and copper complexes as catalysts for the hydrothiolation of alkynes and activated alkenes...

This reaction exemplified that the regiochemistry of RS and H introduced by car-bonylahve addition differed from that of those by simple hydrothiolation. In the Rh-catalyzed hydrothiolation, the ArS group added to the terminal carbon and H to the internal carbon (Eq. 7.12). On the other hand, in the Rh-catalyzed thioformylation, RS was placed at internal carbon and formyl at the terminal carbon in spite of using the same catalyst precursor, [RhCljPPhsjs], which was also active for the thioformylation shown in Eq. (7.17). In 1997, the Pt-catalyzed hydrothiocarboxylation using RSH, alkyne and CO was reported to furnish 24 (Eq. 7.18), which showed the same regiochemistry as the Ni-catalyzed reaction shown in Eq. (7.1) [28]. 

When the reaction of 1,1-dimethyl allene with o-BrC6H4SH was carried out in the presence of Pd(OAc)2/dppf/i-Pr2HN/CO in benzene, hydrothiolation of the allene took place (Eq. 7.26) [37]. However, the regiochemistry of the adduct 36 was different from that obtained by the Pd(OAc)2-catalyzed hydrothiolation of mono-substituted allenes (cf. Eq. 7.24), showing that the regiochemistry of the hydrothiolation of allenes can be controlled by the reaction conditions even when the same metal(Pd) catalyst is used. 

In some cases, aUc5me hydrothiolation can be achieved in the absence of transition metal catalysts. Examples include the use of indium halides, selenium halides and salts, bases and p-cyclodextrin [215-226]. In particular, Cesium bases yield exclusively the anti-Markovnikov product and fi equently give high regioselectivity for the Z-linear olefin, which is complementary to transition metal catalysis. While these approaches as yet lack the generality of the transition metal-catalyzed systems, the ability to achieve hydrothiolation without the need for a metal catalyst is attractive. Undoubtedly, this area of research will continue to yield promising results. 

Thiols can be added to alkenes under radical, acidic and basic conditions, as well as by use of main group metal catalysts. In particular, Dunach demonstrated high yields of inter- and intramolecular In(III)-catalyzed hydrothiolation [249]. Both aliphatic and aromatic thiols react efficiently, as do sterically hindered olefins. Functional group compatibility remains to be demonstrated. In addition, these approaches lack selectivity, functional group compatibility and generality. 

Building from Krause s study with allenes,it was discovered that Au(l) catalysts can effect intermolecular hydrothiolation of unactivated olefins (32) [12]. 2-Mer-captoethanol reacts exclusively with sulfur, demonstrating chemoselectivity and functional group compatibility. As with the other systems, both aliphatic and aromatic thiols work well. 

Equation 32 Hydrothiolation of unactivated alkenes with Au(I) catalysts [12]... 

The mechanism of the catalytic hydrothiolation and hydroselenation reactions differs from the bis-thiolation and bis-selenation reactions at the product formation stage. For the Z—H bond addition to alkynes the last stage of the catalytic cycle is protonolysis or C—H reductive elimination. It was found that, independently of the catalyst precursor (either Pd or Pd derivatives), the same catalytically active species [Pd(ZR)2] were formed (Scheme 3.81) [147, 148]. 

In a simpler NiCl2/Et3N catalytic system, high selectivity and good yields in the hydrothiolation reaction were achieved in the presence of a radical trap, which suppressed the side-reaction [149]. For the activated alkynes with R= Ph and COOMe significant amounts of anti-Markovnikov products were obtained. Regioselectivity of the reaction depended on the alkyne RZH ratio and much better yields were achieved using Ni(acac)2 as a catalyst precursor [151]. 

Further exploration of the higher activity of the Ni complexes compared to Pd analogs led to the discovery of a novel nano-sized catalytic system with superior performance for hydrothiolation and hydroselenation reactions of alkynes [ 152,153]. Furthermore, it was found that with a simple catalyst precursor - Ni(acac)2 - the reaction was carried out with excellent yields and excellent selectivity, even at room temperature. Both terminal and internal alkynes were successfully involved in the addition reaction. This catalytic system was tolerant to various functional groups in alkynes and was easily scaleable for the synthesis of 1-50 g of product (Scheme 3.85) [152, 153]. The proposed mechanism of the catalytic reaction involved (i) catalyst self organization with nano-sized particles formation, (ii) alkyne insertion into the Ni—Z bond and (iii) protonolysis with RZH (Scheme 3.86). 

Though tremendous success has been achieved with the development of Cu(I)-mediated Huisgen 1,3-dipolar cycloaddition reaction of azides and acetylenes as a robust and ef cient synthetic tool, it has several limitations which inclnde the need for a metal catalyst, an inability to photochemi-cally control the reaction or to conduct the reaction in the absence of solvent. In comparison, the century-old addition of thiols to alkene (the hydrothiolation of a C=C bond), which is currently called thiol-ene coupling (TEC), has many of the attributes of chck chemistry without, however, some of the aforesaid disadvantages of the CuAAC reaction. 

Hydrothiolation of Conjugated C-C Double Bonds. This reaction reported by He was best catalyzed by Ph3PAuBF4 in most cases and showed excellent regioselectivity. Complex 1 was shown in one case as an effective catalyst (eq 17). 

Usually, sulfur compounds are obstacles to catalysis due to catalyst poisoning. In spite of this, Gunnoe and coworkers reported the hydrothiolation of a range of substrates. Hydrothiolation occurred with mono-, di-, and trisubstituted electron-deficient alkenes and styrenes. Anti-Markovnikov regioselectivity was observed in all cases, with [Cu(SR)(IMes)] as the most efficient catalyst The transformation of benzenethiol with cyclohexenone reached full conversion in 5 min with IMes, whereas 8 h were required with the IPr complex. The less steri-cally hindered NHC is more active (IMes > IPr > SIPr) in this transformation. SIPr remained the least efficient which was mainly due to the low solubility of the complex. 

Hydrothiolation of unsaturated compounds is an atom economical process, especially the formation of C—S bonds, which are present in many biologically active molecules [146]. Moreover, vinyl sulfides are very convenient synthetic intermediates in organic reactions. Despite the existence of several active catalysts, the stereo- and regioselective controk remain a challenge [147]. Castarle-nas and coworkers reported the selective hydrothiolation of alkynes catalyzed by NHC-based rhodium complexes 62 and 63 (Scheme 10.6) imder mild reaction conditions [147]. A regioselective switch from linear to branched vinyl sulfides was observed when mononuclear compound 62 was used. The authors proposed... 

The palladium-catalyzed hydrothiolation of terminal alkynes has been achieved using a metallocycle catalyst that was generated through the treatment of palladium acetate with phosphinic acids (Scheme 5.53) [79], Using this catalyst system, benzenethiol was added to 1-octyne in moderate yield with high selectivity for the Markovnikov-isomer. While only a single hydrothiolation example was reported, this chemistry provides the foundation for the design of additional palladium-catalyzed reactions. 

The introduction of sulfur moieties to unsaturated hydrocarbon compounds is an important synthetic strategy in the preparation of bioactive compounds. In particular, the use of alkynes enables the facile synthesis of alkenyl sulfides that are stereochemically as well as regiochemically defined structures. Given the important role of catalysts in the stereospecific addition of sulfur-containing reagents to alkynes, the following four sections are devoted to hydrothiolation, bisthiolation, carbothiolation, and related reactions. 

The regiochemical outcomes, thus, are strong indicatives for the reaction pathways the formation of linear alkenyl sulfides via a radical-mediated reaction pathway and the branched alkenyl sulfides via an insertion of alkyne into an M S bond. An interesting complementary selectivity between Tp Ph(PPh3)2 and Wilkinson s catalysts has been observed in the hydrothiolation of alkyl thiols, where a migratory Rh-H insertion pathway 17 was proposed (Scheme 46.4). 

Corma A, Gonzalez-Arellano C, Iglesias M, Sanchez R Efficient synthesis of vinyl and alkyl sulfides via hydrothiolation of alkynes and electron-deficient olefins using soluble and hetereogeneous gold complexes catalysts. Appl. Catal. A 2010 375 49-54. 

Field LD, Messerle BA, Vuong KQ, Turner P. Rhodium(I) and iridium(I) complexes containing bidentate phosphine-imidazolyl donor ligands as catalysts for the hydroamination and hydrothiolation of alkynes. Dalton Trans. 2009 3599-3614. 

Weiss CJ, Marks TJ. Organozirconium complexes as catalysts for Markovnikov-selective intermolecular hydrothiolation of terminal alkynes scope and mechanism. J. Am. Chem. Soc. 2010 132 10533-10546. 

Shoai S, Bichler P, Kang B, Buckley H, Love JA. Catalytic alkyne hydrothiolation with alkanethiols using Wilkinson s catalyst. Organometallics 2007 26 5778-5781. 

C-S bond formation through reaction between aryl halide (Cl, Br, I) and aromatic or aliphatic thiols has been catalysed by a Ni-NHC complex under basic conditions. The reaction is of wide scope and high efficiency. Vinyl sulfides have been synthesized by hydrothiolation of alkynes catalysed by Rh-NHC complexes. Mechanistic investigations have established that the catalysis proceeds via an oxidative addition of the S-H bond to Rh(I) followed by alkyne insertion and reductive elimination. Interestingly, the regioselectivity could be controlled by the nature of the complex (mono or dinuclear precursors), and the use of a strong donor such as the NHC prevents the deactivation of the catalyst. 

Rhodium-NHC complexes [Rh( <-Cl)(IPr)( -olefin)]2 and RhCl(IPr)(py)(t/"-olefin) (IPr= l,3-bis(2,6-diisopropylphenyl)imidazol-2-carbene, py = pyridine, olefin = cyclooctene) have been designed as highly active catalysts for hydrothiolation of alkynes RC=CH with R SH. The dinuclear catalyst was found to promote the formation of the linear product RCH=CHSR, whereas the mononuclear catalyst favoured the branched isomer R(R S)C=CH2- A complex interplay between electronic and steric effects exerted by the carbene (IPr), pyridine, and hydride ligands accounts for the observed regioselectivity. DFT calculations suggested that migratory insertion of the alkyne into the rhodium-thiolate bond is the rate-determining step. ... 

Recently, Tang and coworkers also succeeded in developing the polyhydrothiolation reaction using Diynes (AA-type) with Dithiols (BB-type) (Figure 8.4) [17]. Moreover, the alkyne hydrothiolation reaction proceeded in a linear manner, and no branched isomer was obtained at all. More importantly, they found that both regioselectivity and stereoselectivity of the polyhydrothiolation reaction can be well controlled in the presence of the Rh catalyst (Rh(PPh3)3Cl) [17]. 

Di Giuseppe A, Castarlenas R, Perez-TOTrente JJ, Crucianelli M, Polo V, Sancho R, Lahoz FJ, Oro LA (2012) Ligand-controlled regioselectivity in the hydrothiolation of alkynes by rhodium N-heterocyclic carbene catalysts. J Am Chem Soc 134(19) 8171-8183... 

The hydrothiolation of 1-heptyne with PhSH (2 equiv) was catalyzed by Ni (acac) (2 mol%) at 40°C under solvent-free conditions to produce 9,10, and 11 in 81%, 4%, and 4% yields, respectively (7). In the reaction, the formation of an insoluble dark brown polymer [Ni(SAr)2] was confirmed by elemental analysis [28], and it was verified that the polymer served as the catalyst for the reaction of HC=CC(OH)Me2 with PhSH to give the corresponding Markovnikov-type product in 95% yield. The structure and morphology of the particles of [Ni(SAr)2] were studied by scanning electron microscopy (SEM) [28, 30, 32]. A catalytic cycle for the Ni(acac)-catalyzed hydrothiolation was proposed as shown in Scheme 9 [28,29]. The resulting syn-addition of thiols to alkynes was verified by the reactions employing internal alkynes [28, 29]. A similar mechanism was proposed for the Ni (acac)2-catalyzed hydroselenation [30]. 

Love also reported Tp Rh(PPh3)2-catalyzed hydrothiolation of alkanethiol to alkynes (31) [63-65], in which the regioselectivity was opposite of that obtained with other Rh(I) catalysts mentioned above. In the reaction of arenethiols (ArSH Ar = Ph, p-Tol, p-BrC6H4) with Ar C CH (Ar = Ph, p-MeOCgUr, and o, P-F2C6H3), the selectivity is lowered (1.4 1 to 6 1) [63]. 

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