Hydroalkoxylation allenes

Intermolecular hydroalkoxylation of 1,1- and 1,3-di-substituted, tri-substituted and tetra-substituted allenes with a range of primary and secondary alcohols, methanol, phenol and propionic acid was catalysed by the system [AuCl(IPr)]/ AgOTf (1 1, 5 mol% each component) at room temperature in toluene, giving excellent conversions to the allylic ethers. Hydroalkoxylation of monosubstituted or trisubstituted allenes led to the selective addition of the alcohol to the less hindered allene terminus and the formation of allylic ethers. A plausible mechanism involves the reaction of the in situ formed cationic (IPr)Au" with the substituted allene to form the tt-allenyl complex 105, which after nucleophilic attack of the alcohol gives the o-alkenyl complex 106, which, in turn, is converted to the product by protonolysis and concomitant regeneration of the cationic active species (IPr)-Au" (Scheme 2.18) [86]. 

Hydroalkoxylation of Allenes In the year 2000, during their investigation of transition metal catalyzed reactions of allenyl ketones [29], Hashmi et al. discovered that gold(III) salts were able to lead the cydoisomerization and dimerization of these substrates (Equation 8.2) with a considerable improvement related to other assays with Ag (I) or Pd (II) catalysts [18]. 

At the beginning of 2007, Zhang and Widenhoefer published a very interesting study of the enantioselective hydroalkoxylation of allenes using certain dinuclear chlorodiarylphosphino complexes and AgOTs as cocatalyst [35]. 

The transition metal-catalyzed addition of alcohols to unsaturated systems has not been widely investigated. Reports on addition of alcohols to 1,3-diene [24] or allene [25] have appeared but have very limited scope. We recently reported the palladium/benzoic acid-catalyzed inter- and intramolecular addition of alcohols to alkynes in which various acyclic and cyclic allylic ethers are produced [26], The Pd-catalyzed addition of alcohols to alkylidenecyclopropanes proceeds smoothly providing a powerful tool for synthesis of allylic ethers [27a]. An intramolecular version of the hydroalkoxylation has been demonstrated in which the phenol-tethered alkylidenecyclopropanes undergo facile cyclization to give exomethylene products [27b],... 

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. 

Phenyl-1-propyne (55) underwent facile formal intermolecular hydroamination, affording the allylic amine 56 in high yield at 0 "C in the presence of AcOH or benzoic acid. In this reaction, at first, Pd-catalyzed isomerization of 55 to pheny-lallene (57) occurs by addition-elimination of H-Pd-OAc to internal alkyne 55, and then the allene 57 is converted to jr-allylpalladium intermediate 58 by hydropal-ladation. The final step is a well-known amination to produce the allylic amine 56. As an intramolecular version, 2-(2-phenylpropenyl)pyrrole (60) was obtained from l-phenyl-7-amino-l-hexyne 59 [16,16a]. Similarly Pd/benzoic acid-catalyzed hydroalkoxylation of 55 with (—)-menthol (61) afforded the allylic ether 62 [17]. 

Gold-catalyzed intermolecular hydroalkoxylations of allenes have received much less attention than their intramolecular counterpart. Nishina and Yamamoto performed the addition of primary or secondary alcohols using 5 mol% each of PhsPAuCl and AgOTf without any solvent and obtained the allylic ethers resulting from attack of the alcohol at the less substituted allenic terminus with moderate to high yield. The best results were obtained for aryl-substituted allenes. Unfortunately, enantiomerically enriched allenes provided only racemic addition products under these conditions. In the presence of a gold(I) catalyst and iV-iodosuccinimide, 2-iodoallylic ethers were obtained in a regioselective and stereoselective manner. 

Representative procedure for the gold-catalyzed intermolecular hydroalkoxylation of allenes. I-((E)-3-Isopropoxyprop-l-enyl)-4-methylbenzen ... 

For example, the bimetallic Au catalyst 36 was shown to catalyse the intramolecular hydroalkoxylation of allene alcohols with exceptional enantios-electivity (>93% ee) (Scheme 15c). 

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]. 

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)). 

Zhang and Widenhoefer have reported a highly regio- anddiastereo-selective method for the intermolecular hydroalkoxylation of aUenes with alcohols [108]. As an example, reaction of 1-phenyl-l,2-butadiene with 2-phenyl-l-ethanol catalyzed by a 1.1 mixture of (IPr)AuCl [IPr = l,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene] and AgOTf in toluene at room temperature led to isolation of ( )-(3-phenethoxy-l-butenyl)benzene in 96% yield as a single regio- and stereo-isomer (Eq. (12.38)). The protocol was effective for primary and secondary alcohols and for monosubstituted, 1,1- and 1,3-disubstituted, trisubstituted, and tetrasubstituted allenes. Transfer of moiety to the newly formed tetrahedral stereocenter in the y o oxy ation of axially chiral 1,3-disubstituted allenes ranged from 0 to 81%, epen ing on the nature of the allene and the concentration of the alcohol. 

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]. 

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. 

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. 

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... 

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]. 

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. 

The hydroalkoxylation of alkynes has recently attracted some marked interest. Several groups have developed alkyne alkoxylation/Claisen rearrangement tandem processes using allylic alcohols as nucleophiles and NHC-Au complexes as the catalysts. The group of Nolan developed, in 2013, the hydrophenoxylation of alkynes by using a cooperative NHC-Au catalysis pro-cess. The hydroalkoxylation of allenes could also be performed. This reaction was shown to proceed in a regioselective manner with the alcohol being introduced on the least hindered terminal carbon of the allene. ... 

The iron hydride complex FeH(CO)(NO)(Ph3P)2 has been reported to catalyse selective hydrosilylation of internal alkynes Ar C=CAr with PhSiHj. The corresponding intermediate (Z)-vinylsilanes Ar CH=C(SiH2Ph)Ar thus generated then produce trans-Ar CH=CHAr. With PhMeSi(H)CH=CH2 as the reagent, di-Ar CH=CHAr were obtained. Mechanistic details of this stereodivergent method have been diseussed. Tetrahydropyrans and piperidines (218) were obtained by the Fe -catalysed intramolecular hydroalkoxylation and hydroamination of allenes (217). ... 

Mechanistic investigation of the Au -catalysed SiO)"-exo-trig hydroalkoxylation of allene (240) revealed a rapid and reversible C-0 bond formation to generate (241), followed by the turnover-limiting protodeauration producing the vinyl tetrahydrofuran (242). This pathway competes with catalyst aggregation and formation of an off-cycle bis(gold) vinyl complex (243). ... 

Zhang Z, Widenhoefa RA (2008) Regio- and stereoselective synthesis of alkyl ally lie ethers via gold(I)-catalyzed intermolecular hydroalkoxylation of allenes with alcohols. Org Lett 10 2079-2081... 

Nishina N, Yamamoto Y (2008) Gold-catalyzed intermolecular hydroalkoxylation of allenes difference in mechanism between hydroalkoxylation and hydroamination. Tetrahedron Lett 49 4908 911... 

Scheme 17 Proposed mechanism for Rh(I) catalyzed hydroalkoxylation of allenes...

Cui D-M, Yu K-R, Zhang, C (2009) Regio- and stereoselective Au(l)-catalyzed intermole-cular hydroalkoxylation of aryl allenes. Synlett 1103-1106... 

Scheme 36 Intermolecular hydroalkoxylation of allenes catalyzed by gold(l)...

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