Catalytic Hydroalkoxylation

Lee and coworkers went on to show that the concept of alkenylidene formation and functionalization by a single catalyst can be applied to other transformations. Under conditions similar to those reported by Trost and coworkers for vmylidene-mediated catalytic intramolecular hydroalkoxylation (see Section 9.2.3), alcohol 111 was transformed into a mixture of enol ethers with moderate selectivity for three-component coupling (Equation 9.9). 

Mechanistic hypotheses play an important role in developing new catalytic and selective heterofunctionalizations of alkenes. Two basic reaction cycles for metal-catalyzed hydroalkoxylation (and hydration, for R = H) of alkenes can be postulated (Scheme 2). One pathway leads to Markovnikov products via activation of the nucleophile, oxy-metallation, and protonolysis (hydro-de-metallation) (Scheme 2a). Alternatively to the inner sphere syn-oxymetallation depicted in Scheme 2a, external anti-attack of the nucleophUe to coordinated olefin is plausible. The oxidation state of the metal remains constant in this cycle. The alternative hydrometallation pathway (Scheme 2b) proceeds via oxidative addition of the H-OR bond, hydrometallation of the olefin, and reductive elimination to the anti-Markovnikov addition product [3,4]. 

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]. 

Copper The catalytic activity of copper(II) triflate for cyclizations of alkenols or intermolecular additions of alcohols and carboxylic acids to norbomene has been reported [62, 63]. In dioxane at 80°C, high conversions were achieved at prolonged reaction times, and those were superior to those obtained with Lewis acids such as Yb(OTf)3, though the latter also displayed catalytic activity [62]. In a control experiment with triflic acid (10 mol%) only little product (29%) resulted with low stereoselectivity. However, it is now clear that this control experiment was flawed, as too much triflic acid and overly long reaction times had been applied. The previously mentioned study by Carpentier and coworkers on copper triflate catalyzed hydroaUcoxylations has established that Cu(OTf)2 decomposes to CuOTf and triflic acid when heated in organic solvents [50]. Triflic acid is catalytically active in hydroaUcoxylation at levels down to 0.1 mol%, if a polymerization inhibitor is present to prevent consumption of the olefinic substrate. Indeed, Cu (OTf)2 is an excellent reagent for releasing small amounts of triflic acid in this case, because the coreleased CuOTf acts as polymerization inhibitor for the acrylic substrate (Scheme 12) [50]. Other metal triflates like Sc(OTf)3 or Yb(OTf)3 displayed catalytic activity at the 1 mol% level in the reaction of Scheme 12. Additional experiments were presented to support the conclusion that triflic acid is the actual catalyst in this and other Lewis acid catalyzed hydroalkoxylations [50]. 

For alkynes (and in part, allenes), synthetically useful protocols for Markovnikov and anti-Markovnikov selective hydrations, hydroalkoxylations (mainly intramolecular), and hydrocarboxylations are available and find increasing applications in organic synthesis. In the past decade, the research focus on cationic gold(l) complexes has led to new additions to the catalysis toolbox. It can be predicted that a further refining of such tools for alkyne functionalization with respect to catalytic activity and functional group tolerance will take place. 

The corresponding reaction of but-3-yn-l-ols or pent-4-yn-l-ols with primary or secondary alcohols in the presence of catalytic amounts of Ph3PAuBF4 and p-TsOH afforded tetrahydrofuranyl ethers (Scheme 4-76). This tandem 5-endo-cycloisomerization/hydroalkoxylation proceeds via 2,3-dihydrofurans, which then undergo an intermolecular Bronsted acid-catalyzed addition of the external alcohol. The transformation is not restricted to internal alkynols but can be applied to terminal acetylenes as well. Application of the method to the s thesis of bicyclic heterocycles with a P-lactam structure was reported recently.Under the same conditions, epoxyalkynes undergo a sequence of epoxide opening, 6-exo-cycloisomerization, and nucleophilic addition to afford tetrahydropyranyl ethers. In a closely related transformation, cyclic acetals were obtained from alk-2-ynoates bearing a hydroxy group in 6- or 7-position by treatment with AuCU and MeOH. ... 

Krause has reported the gold-catalyzed intramolecular endo-hydroalkoxylation of (3-hydroxyallenes to form dihydropyrans [103]. For example, treatment of a 70 30 diastereomeric mixture of (3-hydroxyallene 61 with a catalytic 1 1 mixture of AuCl and pyridine in dichloromethane led to isolation of dihydropyran 62 in 84% yield as a 70 30 mixture of diastereomers (Eq. (12.32)). This transformation was also catalyzed effectively by a 1 1 mixture of (PPh3)AuCl and AgBp4 in toluene. (3-Hydroxyallenes that possessed substitution at the internal allenyl carbon atom also underwent gold-catalyzed cycloisomerization with selective transfer of chirality from the allenyl... 

In 2006, Widenhoefer reported an effective gold(I)-catalyzed protocol for the exo-hydroalkoxylation of y- and 6-hydroxy allenes to form 2-vinyl tetrahydrofurans and 2-vinyl tetrahydropyrans, respectively [104]. For example, treatment of 1-phenyl-5,6-heptadienol with a catalytic 1 1 mixture of [P(f-Bu)20-biphenyl]AuCl and AgOTs in toluene at room temperature led to isolation of 2-phenyl-6-vinyltetrahydropyran in 96% yield as a 7.2 1 mixture of diastereomers (Eq. (12.33)). This gold(I)-catalyzed hydroalkoxylation protocol tolerated substitution at the terminal allenyl carbon atoms and along the alkyl chain that tethered the hydroxy group to the allenyl moiety and was also effective for the S-exo hydroalkoxylation of y-hydroxy allenes. Alcaide and Almendros have shown that gold(III) also catalyzes the S-exo hydroalkoxylation of y-allenyl alcohols in modest yields (Eq. (12.34)) [105]. 

In early 2007, Widenhoefer and Zhang reported the gold(I)-catalyzed intramolecular enantioselective hydroalkoxylation of y- and 6-hydroxyallenes [106]. For example, reaction of 2,2-diphenyl-4,5-hexadienol with a catalytic 1 2 mixture of [(S)-63]Au2Cl2 [(S)-63 = (S)-DTBM-MeObiphep] and AgOTs at 20 °C in toluene for 18h led to isolation of 4,4-diphenyl-2-vinyltetrahydrofuran in 67% yield with 93% ee (Eq. (12.35)). This protocol was also effective for the enantioselective 6-e%o-hydro-alkoxylation of 6-hydroxyallenes to form tetrahydropyrans. Gold(I)-catalyzed cycli-zation of y-hydroxyallenes that possessed an axially chiral 1,3-disubstituted allenyl moiety occurred with high enantioselectivity/low diastereoselectivity in a catalyst-... 

Toste and coworkers have developed effective gold(I)-catalyzed protocols for the intramolecular enantioselective hydroalkoxylation of y- and 8-hydroxy allenes employing chiral, enantiomerically pure silver salts [107]. For example, treatment of y-hydroxy allene 66 with a catalytic 1 2 mixture of the achiral bis(gold) complex (dppm)Au2Cl2 [dppm = bis(diphenylphosphino)methane] and chiral silver phos-phonate Ag-(J )-67 in benzene at room temperature led to isolation of 2-alkenyl tetrahydrofuran 68 in 90% yield with 97% ee (Eq. (12.36)). A combination of chiral bis(gold) complex with a chiral silver salt proved effective for terminally unsubstituted allenyl alcohols. For example, reaction of 5,6-heptadienol catalyzed by a mixture of [(S,S)-DIPAMP]Au2Cl2 [DIPAMP = l,2-ethanediylbis[(2-methoxyphenyl) phenylphosphine] and Ag-(J )-67 gave 2-vinyltetrahydropyran 69 in 96% yield with 92% ee (Eq. (12.37)). 

Nishina and Yamamoto have also reported the gold(I)allenes with alcohols [109]. As an example, treatment of a neat mixture of p-tolyl allene and isopropanol with a catalytic 1 1 mixture of (PPh3)AuCl and AgOTf at 30 °C led to isolation of isopropyl )-3-(4-tolyl)-2-propenyl ether in 98% yield (Eq. (12.39)). The protocol was most effective for monosubstituted and 1,3-disubstituted allenes and gave no transfer of chirality for the hydroalkoxylation of 1-phenyl-l,2-butadiene. Horino has reported the gold(I)-catalyzed intermolecular addition of alcohols to the allenyl moiety of 4-vinylidene-2-oxazolidinones [110]. 

The catalytic method was extended to a series of different unsaturated alcohols in order to investigate the scope of the reaction. More specifically, only substrates leading upon protonation to the formation of tertiary carbocations turned out to be suitable substrates for the reaction. In all cases, the synthesis of a wide range of differently substituted tetrahydropyran and oxepane derivatives was achieved under mild experimental conditions within up to 6 days, with only 10 mol% of the supramolecular capsule as catalyst, while in the presence of the ammonium competitive guest the reactions were sluggish. For all substrates, the hydroalkoxylation always showed the formation of the cyclic product corresponding to the Markovnikov addition to the unsaturated double bond. 

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. 

Fig. 4.13 Depiction of the two nanoparticle synthesis techniques used and the initial reactivity results for electrophilic catalysis, (a) In the top scheme, Pt ions are loaded onto a PAMAM den-drimer and reduced to form a dendrimer-encapsulated NP. Sonication deposits the NPs on the mesoporous silica, SBA-15, to generate the NP catalysts. In the bottom scheme, polyvinylpyrrolidone (PVP) encapsulates the NP. Deposition on SBA-15 follows to produce the catalyst. In both cases, the NPs are synthesized before loading onto SBA-15. (b) Hydroalkoxylation of 1 with Pt NPs. To obtain electrophilic activity from the Pt NPs, treatment with the mild oxidant PhlClj is required. Pt4o/G40H/SBA-15 NPs must be further reduced under H atmosphere at 100 °C for 24 h before reaction. This treatment generates catalytically active NPs that activate the jc-bond in 1, resulting in hydroalkoxylation to benzofuran 2. Yields were determined by comparing peaks in NMR against an internal standard. Reprinted with permission from ref. [100]. Copyright 2009 Nature Publishing Group...

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. 

The same catalytic system also performed well in the hydroalkoxylation of allenes where the C-O bond was formed at the least hindered terminal carbon of the allene. This report was later the subject of a DFT study by Maseras and Patton. Interestingly, it was found that the addition of the alcohol likely occurred, in fact, at the most hindered carbon and was followed by a second hydroalkoxylation of the allylic ether and subsequent elimination, the whole process accounting for the observed regioselectivity. This second addition could nevertheless be impeded through appropriate choice of reaction conditions (i.e. DMF as solvent at 0°C with 10 equivalents of the alcohol), leading to the formation of the most substituted ether. 

Differently to silicon or germanium, tin triflate was even considered as a Lewis superacid, and investigated in multiple catalytic reactions. Hydroalkoxylation of nonactivated disubstituted or trisubstituted double bonds (Equation (8.7)) was reported to proceed in alcoholic solvents at moderate temperatures in the presence of tin(IV) triflate, without the need of hgands, additives, or cocatalysts [23]. Very important, it is also the control of the selectivity by these catalysts. In this particular reaction, the Markovnikov-type adducts were formed with regiose-lectivities of 84-100%. 

Activity of a (CH3)3PAu cation as a catalyst of intramolecular hydroalkoxylation of allenes became eight times higher upon its encapsulation within the cavity of the Ga4Lg coordination capsule 575. This allowed performing these reactions in water up to 67 catalytic turnovers by the caged catalyst have been observed in [34]. 

An efficient total synthesis of bruguierol A was accomplished from commercially available (S)-epichlorydrin (Scheme 18.57) [47]. The key step is a catalytic tandem intramolecular hydroalkoxylation/hydroarylation reaction to construct a 2,3-benzofused 8-oxobicyclo[3.2.1]octane system. Bruguierol A belongs to a family of compounds termed bruguierol A to C, isolated from the stem of the Bruguiera gym-morrhiza tree. 

Adrio and Hii reported that an air- and moisture-stable Cu(OXf)2-bipy catalyzes the addition of phenols to 1,3-dienes under aerobic conditions in a tandem hydroalkoxylation-rearrangement-hydroalkylation sequence, furnishing benzopyrans in moderate to good yields, and can be recycled without any loss in catalytic activity [189] (Scheme 8.114). 

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]. 

Bartolome C, Garcia-Cuadrado D, Ramiro Z, Espinet P. Synthesis and catalytic activity of gold chiral nitrogen acycHc carbenes and gold hydrogen bonded heterocyclic carbenes in cyclopropanation of vinyl arenes and in intramolecular hydroalkoxylation of allenes. Inorg Chem. 2010 49 9758-9764. 

---