Hydroalkoxylation reactions

A large number of examples of the intramolecular hydroalkoxylation reaction of alkynes bearing pendant alcohols have been reported. In the reactions of enynols, the cyclization process has typically been accompanied by isomerization of the resulting enol ethers to give rise to furan or pyran products. These processes have been achieved using Pd(ll),294-297 Ru(n),298,299 Au(i),300 Au(m)286,300,301 Ir(i)302 Ir(m) 303 and Ag(i) 304 catalysts. Some examples are shown in Equations (83)-(87). 

Aside from alcohols, other oxygen nucleophiles have also participated in hydroalkoxylation reactions with alkynes. The most common of these are 1,3-dicarbonyl compounds, whose enol oxygens are readily available to add to alkynes. Cyclization reactions of this type have been carried out under Pd(0) catalysis with various aryl or vinyl iodides or triflates, often in the presence of CO, affording the corresponding furan derivatives (Equation (95)).337-340 A similar approach employing cyclic 1,3-diketones has also been reported to prepare THFs and dihydropyrans under Pd, Pt, or W catalysis.341 Simple l-alkyn-5-ones have also been isomerized to furans under the influence of Hg(OTf)2.342... 

Alkoxides that arise from simple carbonyl additions have also functioned as excellent in situ nucleophiles for intramolecular hydroalkoxylation reactions. Garbinols derived from the addition of allyltin reagents have proved to be potent nucleophiles in reactions of this type (Equation (99)),349 and this approach has also been used for the combined addition-cyclization of alkynals under Pd(n)350 or Cu(i)351 catalysis, and alkynones under Pd(n) catalysis.352... 

The three component aminoallylation reaction of the activated olefins 4 was also reported by us (Scheme 7) [39]. The palladium catalyzed reaction between phthalimid 10, olefins 4 and allyl chloride 11 proceeded well in the presence of CS2CO3 to give the corresponding aminoallylation products 12 in high yields. Likewise, cyanoallylation of activated olefins was also reported (Scheme 8) [40]. In both cases only aryl substituded and f-bulyl substituded olefins are proved good substrates. The mechanism of these reactions is presumably similar to that of hydroalkoxylation reaction (see Scheme 5). 

The bis(hydroalkoxylation) reaction of butynone 11 with ethanediol and 5% DMAP gives the valuable synthetic intermediate 12 in 81% yield <05CC227> and a range of ring-fused... 

Ruthenium In one of the earliest examples of a transition metal-catalyzed hydroalkoxylation reaction from 1998, the cyclization of 2-allylphenols to benzo-dihydrofurans was catalyzed by a cocktail of ruthenium chloride, silver- and copper triflates, and a phosphane ligand (Scheme 8a) [44]. A control experiment implied that triflic acid alone was ineffective as catalyst, but this experiment is at variance with a later report where 2-allylphenol was cyclized using only 5 mol% of triflic acid as catalyst (CH2CI2, 40°C, 3 h) [45]. 

Tin Coulombel and coworkers have used tin(IV) triflate as catalyst in the hydroalkoxylation of unsaturated alcohols (Scheme 9a) [51]. The substrate reactivity decreases along the order trisubstituted olefins 1,1-disubstituted olefins > 1,3-disubstituted > monosubstituted olefin. Incidentally, this is a typical reactivity profile for most Lewis acid catalysts discussed in this section. The catalyst loading could be reduced down to 0.1% in favorable cases and in the absence of a solvent. As trifiic acid alone (5%) also catalyzed the reaction in Scheme 9 efficiently, and because Sn(OTf)4 is readily hydrolyzed, a control experiment with cocatalytic amounts (5% each) of Sn(OTf)4 and 2,6-lutidine as proton quencher was performed, in which catalytic activity was retained. We do not believe that this experiment is sufficient proof of tin catalysis, as Sn(OTf)4 may release more than a single equivalent of triflic acid upon hydrolysis. In any case, the selectivity profile of the tin-catalyzed reaction matches that of the trifiic acid-induced hydroalkoxylation reactions studied earlier in the same research group [45]. 

In particular, the Pd Si02 yolk-shell nanocatalyst activated by PhICl2 showed high reactivity and superior stability to the other Pd-based catalysts for hydroalkoxylation reactions even at 25 °C (14CC14938). 

Synthesis of saturated heterocycles via metal-catalyzed formal cycloaddition reactions that generate a C—N or C—O bond 13THC(32)225. Synthesis of saturated heterocycles via metal-catalyzed alkene carboami-nation, carboalkoxylation diamination, aminoalkoxylation, dialkoxyla-tion hydroamination or hydroalkoxylation reactions 13THC(32)1, 13THC(32)39, 13THC(32)109. 

Scheme 15 (a) Au(I) catalysed intermolecular hydroalkoxylation reaction, (b) attempted isolation of geminal-digold complexes from Au(I) bimetallic complexes during the hydroalkoxylation of alkynols, and (c) enantioselective synthesis of O-heterocycles using the chiral bimetallic Au(I) complex (36)... 

Several Au-ADC catalysts have been examined in intramolecular hydroamina-tion and hydroalkoxylation reactions of allenes, although no advantages over established systems were uncovered [27c,29a]. Notably, Hong and coworkers showed that highly bulky Au -ADC complex 32 and a comparably hindered acyclic aminooxycarbene complex provide catalytic activities comparable to those attained with equivalently bulky NHC-based catalyst 33 in a fairly challenging intramolecular alkene hydroamination reaction [15b,32]. By contrast, less bulky Au-ADC catalysts were ineffective. 

Hydroalkoxylation reactions refer to the addition of an alcohol over an insaturation. This highly atom economical process is potentially a straightforward and clean access to ethers, and the reaction is successfully applied at the industrial level for the production of MTBE (methyl terf-butyl ether) and ETBE (ethyl tert-butyl ether) from isobutylene and methanol or ethanol. If this transformation is well known with activated olefins (reaction referred to a Michael addition), a real challenge is the synthesis of ethers from unactivated olefins. Veiy few reactions involving carbohydrates or polyols have been reported to date and most of them involve isobutylene as this substituted olefin is prompt to generate stabilized carbenium ion under acidic conditions. Dimerization reactions of the alcohol or isobutylene are the main side reactions that have to be avoided in order to reach high selectivities into the desired ethers. ... 

Scheme 23 Synthesis of glycerol ethers from an hydroalkoxylation reaction.

Scheme 25 Synthesis of isosorbide ethers from a hydroalkoxylation reaction.

Recently, Pt DENs were used as an electrophilic catalyst in an intramolecular addition of phenols to alkynes (intramolecular hydroalkoxylation), as shown in Fig. 4.13b [100], The Pt DENs were supported on a mesoporous silica material known as SBA-15 (Fig. 4.13a). Since the as-synthesized SBA-15 consists of micrometer-sized particles, the supported Pt DENs can be easily separated from the reaction solution by centrifugation. This reaction has only been catalyzed by homogeneous catalysts (e.g., PtCy before this report. The use of the supported Pt DENs to catalyze this reaction was the first demonstration that a heterogeneous catalyst could also catalyze this conversion. It was also found that adding an oxidation agent, PhICF, would dramatically increase the benzofuran yield from 10 to 98 %, as shown in Fig. 4.13b. The authors proposed that PhICl2 could render the surface of the Pt nanoparticles more electrophilic, which is required for the Pt DENs to be active for the hydroalkoxylation reaction. 

The authors also designed and performed extensive experiments, such as three-phase and catalyst filtration tests, to prove the heterogeneous nature of the SBA-15 supported Pt DENs in the intramolecular hydroalkoxylation reaction. No leaching of the active catalytic species was detected in these tests. PVP-capped Pt nanoparticles were also tested for use in this reaction, but they could not be recycled. 

Pd DENs also catalyzed the same intramolecular hydroalkoxylation reaction [101]. SBA-15 supported Pd DENs achieved 95 % yield of benzofuran in 15 h at 20 °C, while PdBr2 and PdCla only achieved 10 % yield under the same conditions. Even at 100 °C, PdCl2 only gave 25 % yield of benzofuran after 15 h. After proving that there is no leaching of Pd during the reaction, the SBA-15 supported Pd DENs were applied in a continuous flow reactor. It was found that the presence of 5 tnM... 

Hydroamination of 7i-bonds is one of the most straightforward methods for the construction of C N bonds and, as such, has attracted a lot of attention. NHC- Au catalysts, in line with results obtained in hydration and hydroalkoxylation reactions (vide supra), proved highly efficient in this field and the inter-and intramolecular hydroamination of various alkenes," allenes," and alkynes" were reported with a number of NHC- Au complexes. Among these reports, Widenhoefer published an elegant bis-hydroamination of allenes, leading... 

All these results seemed to indicate that this reaction was ideal for the con-stmction of the (—)-berkelic acid skeleton. However, a serious problem was still unresolved at this point how to constmct the additional pyran ring contained in the natural product. Nevertheless, our experience on cycloisomerization reactions led us to speculate on the possibility that a unique metal complex could promote the cycloisomerization of alkynol 15 to give the exo-cyclic enol ether 19 and also that the cycloisomerization of an alkynyl-substituted salicylaldehyde 23 would give 25. Thus, activation of the alkyne of 15 should promote a hydroalkoxylation reaction to give the exocyclic enol ether 19. On the other hand, activation of the alkyne in 23 should promote a cascade cyclization process to finally give the 8//-isochromen-8-one derivative 25. The formal [4-F 2]-cycloaddition reaction between intermediates 19 and 25 would result in the formation of the core structure of (—)-berkehc acid 24 in a very simple way (Scheme 7). 

Barluenga J, Fernandez A, Di6guez A, Rodriguez F, Fananas FJ (2009) Gold- or platinum-catalyzed cascade processes of alkynol derivatives involving hydroalkoxylation reactions followed by Prins-type cyclizations. Chem-Eur J 15 11660-11667. doi 10.1002/ chem.200900856... 

As an alternative, iridium complexes show exciting catalytic activities in various organic transformations for C-C bond formation. Iridium complexes have been known to be effective catalysts for hydrogenation [1—5] and hydrogen transfers [6-27], including in enantioselective synthesis [28-47]. The catalytic activity of iridium complexes also covers a wide range for dehydrogenation [48-54], metathesis [55], hydroamination [56-61], hydrosilylation [62], and hydroalkoxylation reactions [63] and has been employed in alkyne-alkyne and alkyne - alkene cyclizations and allylic substitution reactions [64-114]. In addition, Ir-catalyzed asymmetric 1,3-dipolar cycloaddition of a,P-unsaturated nitriles with nitrone was reported [115]. 

Fig. 4 Rh(I)- and Ir(I)-based catalysts that have found use in hydroalkoxylation reactions toward...

The same catalyst was used for the double intramolecular hydroalkoxylation reaction for the synthesis of a series of spiroacetals starting from internal and terminal alkynediols [32] (Scheme 15). 

An efficient and interesting route for the construction of useful building blocks, furanyl and pyranyl derivatives, was developed starting from bis-homopropargylic alcohols. The [lr(cod)Cl]2 dimer complex was used for the first time to promote a tandem cyclization/hydroalkoxylation reaction, with total 5-exo-selectivity [50] (Scheme 30). 

Sigman reported a particular hydrochlorination/hydroalkoxylation reaction catalyzed by Pd(ll) in combination with Cu(ll), starting from styrenes. The first formed hydrochlorinated product in the presence of an alcohol was converted in situ to benzylic ethers [96] (Scheme 47). 

In the case of conjugated diynes, the hydroalkoxylation reaction in the presence of phenol afforded alkoxylated enyne products. Aliphatic alcohols do not add to the diyne system indicating the necessity of an acidic alcohol (phenols, naphthol or 2,2,2-trifluoroethanol). The mechanism supposed the formation of a a-cumulenyl palladium complex intermediate is consistent with the absence of the double addition of phenol to the starting diyne or the second addition of phenol to the resulting enyne [100] (Scheme 50). 

Lee H-Y, Jung Y, Moon H (2009) A facile total synthesis of (—)-Frontalin, (-)-endo-brevicomin and (-)-exo-brevicomin through PtCLi catalyzed hydroalkoxylation reaction. Bull Korean Chem Soc 30 771-772... 

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