Hydrothiolation

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. 

Hydrothiolations (addition of H-SR across the CC multiple bond) of alkynes, electron-deficient aUcenes and electron-deficient vinyl arenes have been catalysed by NHC complexes of Ni and Cu, respectively [Scheme 2.17a-c],... 

Scheme 2.17 Product formation in the hydrothiolation of alkynes and alkenes...

The hydrothiolation of terminal alkyl alkynes with 96 (Fig. 2.17) proceeds with good degree of regio- and chemo-selectivity, especially with thiophenol and p-methoxy-thiophenol as substrates. Isomerisation to the internal alkenyl thiolates accounts for less than 9% of the thiolated products under the reaction conditions. In addition, further hydrothiolation of the vinyl thioether product is not observed. Typical conversions of 70-85% at 1 mol% loading at 80°C within 5 h are observed. Arylthiols substituted with electron-withdrawing groups afford lower conversions. 

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]. 

The hydrothiolation of electron-deficient alkenes [X = CN, C(=0)(0Me)] and p-nitro-styrene was catalysed by the Cu complexes 98 and 99. The reactions with phenyl- or benzyl-thiol proceed with high conversions (>90%, rt, 5 mol%). 

Scheme 7-1 A proposed reaction path of Pd(OAc)2-catalyzed hydrothiolation of alkyne...

Although the path (a) has been verified by a stoichiometric reaction [23], the details of exact reaction mechanism remain unsettled. Triggered by this publication [and the Pd-catalyzed doublethiolation of alkynes described in Eq. (7.7) in Section 7-3], a number of transition metal-catalyzed additions of S-X or Se-X bonds to C-C unsaturated organic compounds started to be published. In 1994, BackvaU et al. applied the Pd(OAc)2-catalyzed hydrothiolation to conjugated enynes and obtained 17,... 

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 platinum-catalyzed hydrothiolation was performed for acetylenic alcohols, intramolecular cyclization took place to afford a-methylene lactone 25 in up to 67% yield (Eq. 7.19) [30]. 

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. 

Hydrothiolation of Allenes The first example of a gold-catalyzed carbon-sulfur bond formation was published by Kraus et al. who synthesized 2,5-dihydrothiophenes by allenyl thiocarbinols [38]. The best results were obtained with AuCI in CH2C12, providing an impressive diastereoselectivity. In the same study, other coin-metal precatalysts were tested but only gold afforded the cydization product. 

For sulfur nucleophiles, the intramolecular gold-catalyzed hydrothiolation of allenes was described in 2006. a-Thio-allenes led to the formation of 2,5-dihydrothiophenes in moderate to good yields and with complete stereoselectivity. ... 

The intermolecular addition of carbamates to 1,3-dienes (equation 147) under mild conditions has been described as well. The hydrothiolation of 1,3-dienes has also been reported. " Other related conjugate additions can be performed over methylenecyclopropanes (equation 148) with sulfonamides and the resulting product cyclizes by a second hydroamination of an olefin, finally yielding cyclic sulfonamides. This behavior is reproduced in a similar reaction for the ring opening of vinylcyclopropanes with sulfonamides. One more example in this group of reactions is the synthesis of dUiydrobenzofurans from aryl-allyl ethers. ... 

Synthesis, structure, and hydrothiolation activity of rhodium pyrazolylborate complexes Rt>R N—N pph, / / 3 Rh y/ / Xpph N—N PPh3 3... 

These inherent difficulties have elicited considerable attention, which has led to the emergence of synthetically viable protocols. The first catalytic alkyne hydrothiolation was reported by Ogawa in 1992 [151]. A number of late transition metal salts were found to be effective. In particular, Pd(OAc)2 demonstrated excellent selectivity for the branched olefin. High yields were obtained even with stericaUy demanding substrates and potentially reactive functional groups (19). 

Equation 19 Observed regioselectivity in the Pd (OAc)2 catalyzed alkyne hydrothiolation [151]... 

Since this initial report, significant advances have been made with Ni [121, 152-159], Pd [160-189], Pt [187, 190-201], Rh [202-212] and Ir [204, 211]. In general, group 10 metals generate the branched isomer and proceed by syn-insertion of the alkyne into an M-S bond, followed by protonolysis of the resulting M-C bond, although this is dependent on the reaction conditions. Eor example, under photolytic conditions, certain Pt complexes react through a trans-insertion mechanism [192, 200]. Likewise, Pd-catalyzed reactions of thiols with 1-alkynyl-phosphines proceeds by anfi-hydrothiolation (20) [213]. 

Scheme 4 Complexity generated through hydrothiolation carhonylation cascades [160, 165]...

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. 

Interception of reactive intermediates provides access to an even broader range of products. For example, insertion of CO leads to conjugated lactones and thioe-sters (Scheme 4). A wide variety of sulfur derivatives can be used in these processes producing an array of interesting synthetic intermediates. These organosulfur compounds can be free thiol [164, 167-170, 175, 190, 193, 197, 202, 204], disulfide [160, 165, 183, 207], thiocyanate [179, 182, 186], thioborate [161], thiostannane [196], sulfenamide [180], and thioester [187, 189, 191, 194, 195]. Palladium catalyzed thiocarbonylation, and the development of multicomponent reactions centering on hydrothiolation with free thiols and disulfides has been reviewed extensively [19, 20, 23-26, 167, 227-231]. 

The products of standard hydrothiolation processes are capable of further undergoing subsequent transformations, such as Pt-catalyzed Heck reactions with appropriately tethered alkyne acceptors (23) [235]. Furthermore, Beletskaya demonstrated that following the organometallic intermediates formed in addition of disulfides to terminal alkynes may be intercepted these were found to undergo further carbon-carbon bond formation in the presence of a suitable ligand and excess alkyne (24) [158],... 

A number of similar transformations of allenes have been reported. As with alkyne hydrothiolation, the key to the utility of this process is the ability to control regio-and stereoselectivity. A few key recent discoveries are highlighted below. For related reactions, see the following references [165, 168, 197, 236-243]. 

Equation 27 Pd(PPh3)4 allene hydrothiolation carbonylation sequence [183]... 

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. 

Transition metal catalysis has the potential to alleviate these shortcomings. Nevertheless, while catalytic alkene hydrothiolation has been achieved, the number of reports is stUl hmited [250-254],... 

---