Catalytic Hydration of Alkynes and Its Application in ......4 Mechanisms of Catalytic Alkyne...

REVIEW 1121

Catalytic Hydration of Alkynes and Its Application in SynthesisCatalytic Hydration of AlkynesLukas Hintermann,* Aurélie LabonneInstitut für Organische Chemie, RWTH Aachen, Landoltweg 1, 52074 Aachen, GermanyFax +49(241)8092391; E-mail: [email protected] 31 January 2007; revised 14 February 2007

SYNTHESIS 2007, No. 8, pp 1121–1150xx.xx.2007Advanced online publication: 23.03.2007DOI: 10.1055/s-2007-966002; Art ID: E17407SS© Georg Thieme Verlag Stuttgart · New York

Abstract: The catalytic addition of water to alkynes (hydration)generates valuable carbonyl compounds from unsaturated hydro-carbon precursors. Traditional mercury(II) catalysts hydrate termi-nal alkynes with Markovnikov selectivity to methyl ketones. Muchresearch has been devoted to finding catalysts based on less toxicmetals, the most promising being gold(I), gold(III), platinum(II),and palladium(II). Catalytic anti-Markovnikov hydration of termi-nal alkynes to aldehydes has been realized in an efficient mannerwith ruthenium(II) complex catalysts. The present review articlelists known hydration catalysts and discusses applications of cata-lytic hydration to different classes of substrates, with an emphasison functional group tolerance and regioselectivity.

1 Introduction2 Timeline3 Alkyne Hydration Catalysts3.1 Brønsted Acid and Base Catalysts3.2 Mercury Catalysts3.3 Non-Mercurial Catalysts for Alkyne Hydration3.4 Anti-Markovnikov Hydration of Terminal Alkynes3.5 Enzymatic Hydration of Alkynes4 Mechanisms of Catalytic Alkyne Hydration4.1 Brønsted Acid Catalyzed Hydration4.2 Mercury-Catalyzed Hydration4.3 Other-Metal-Catalyzed Markovnikov Hydrations4.4 Mechanism of Ruthenium-Catalyzed Anti-Markovnikov

Hydration5 Substrate Spectrum and Selectivity of Catalytic Alkyne

Hydration5.1 Markovnikov Hydration Catalysis5.2 Anti-Markovnikov Hydration Catalysts6 Reactions Related to Catalytic Alkyne Hydration7 Conclusions and Outlook

Key words: alkynes, catalysis, hydration, ketones, aldehydes

1 Introduction

The addition of water to alkynes is a synthetic method forgenerating carbonyl compounds. The transformation isclassified as a dihydro, oxo-biaddition, but may usually bedivided into a hydro-hydroxylation of a triple bond, fol-lowed by tautomerization of the intermediary alkenol.1

The hydration of terminal alkynes gives either a methylketone (Markovnikov addition) or an aldehyde (anti-Markovnikov addition; Scheme 1a), whereas non-sym-metrical internal alkynes can give two regioisomeric ke-tones (Scheme 1b).

Unlike many other syntheses of carbonyl compounds, thehydration of alkynes is an atom-economical2 additionwithout energy-intensive redox chemistry. The reaction isexergonic, though: hydration of acetylene (g) to acetalde-hyde (g) is characterized by DrG = –105.8 kJ/mol andDrH = –111.2 kJ/mol,3 and hydrations of higher alkynesare slightly more exergonic; for example, propyne (g) →acetone (g): DrH = –118 kJ/mol and 1-butyne (g) → 2-bu-tanone (g): DrH = –117 kJ/mol.3 This reaction opens adoor between alkyne chemistry and carbonyl chemistry,and thus its potential for use in organic synthesis is enor-mous, provided the transformation can be carried out se-lectively under mild conditions.

The chemical union of apolar hydrocarbons with water isagainst their ‘affinities’: reaction half-lifes of >20 000years have been estimated for the uncatalyzed hydrationof alkyl alkynes in acetone at 70 °C (see section 3.4.1)!For this reason, a hydration catalyst is required, the role ofwhich is to polarize the alkyne unit to facilitate attack ofwater. Since Kucherov’s observation in 1881 that mercu-ry(II) salts catalyze the hydration of alkynes under mildconditions (see section 3.2), the reaction has seen manyapplications in synthesis. The toxicity of mercury com-pounds and the problems associated with their handlingand disposal make the Kucherov reaction unsuitable formodern, sustainable organic synthesis or any large-scaleapplication. A steady development of alternative alkynehydration catalysts has taken place over the past 30 years,nurtured by the desire to replace mercury(II) by less toxicand more active metal catalysts (see section 3.3).

Another focus of research emerges from the recent fasci-nating discovery of anti-Markovnikov hydration of termi-nal alkynes to give aldehydes (Scheme 1a). The firstcatalyst was found in 1998, and the methodology has al-ready seen an impressive development (see section 3.4).The current article reviews most of the literature on cata-lytic methodology and selected examples of synthetic ap-plications of catalytic alkyne hydration. By presenting (a)recent developments in non-mercury-based catalyticmethodology together with (b) established synthetic ap-plications, we hope to encourage use of the former to-wards improving the latter. Indirect methods of hydrationusing nucleophilic additives (e.g., hydroamination/hydrolysis) are only included in the application section,where their use is typical for certain substrates. Redoxprocedures for formal alkyne hydration, such as hydrobo-ration–oxidation sequences,4 are not covered. Alkyne hy-dration has a long history, and it was not possible to coverall the literature; related books and articles may be con-

1122 L. Hintermann, A. Labonne REVIEW

Synthesis 2007, No. 8, 1121–1150 © Thieme Stuttgart · New York

sulted for additional information. The synthesis ofaldehydes5 and ketones6 from alkynes has been reviewed,as have regioselective catalytic additions of heteronucleo-philes to alkynes (and alkenes)7 and the activation of O–Hbonds by transition metals.8 Older reviews on the hydra-tion of acetylenic compounds from 1963 in French9 and ofthe Kucherov reaction from 1952 in Russian10 exist. Infor-mation on alkyne hydration is also found in referenceworks on alkyne chemistry.11–15 Finally, we note that theterm hydrolysis is sometimes incorrectly applied to the ti-tle reaction; since lysis implies the cleavage of a bond,whereas hydration denotes addition of water, the latter isthe correct description of the title reaction.

Scheme 1 General scheme of alkyne hydration.

2 Timeline

Berthelot discovered acetylene in 1860 and described itshydration in sulfuric acid to give a product initially be-lieved to be vinyl alcohol,16 but later identified as a mix-ture of acetaldehyde and crotonaldehyde.17 Meanwhile,propyne (allylene gas) had been hydrated to acetone bymeans of sulfuric acid and water.18 The concept of alkynehydration was thus known when Kucherov (M. G.Kucherov, 1850–1911; M. Kutscheroff in German translit-eration) described the mercury salt catalyzed hydration ofalkynes in 1881.19 The reaction is one of the earliest exam-ples of homogeneous metal-complex catalysis.20 Startingfrom 1916, acetic acid was produced in Germany on an in-dustrial scale from acetylene via hydration to acetalde-hyde followed by manganese-catalyzed air-oxidation.21

Acetylene was initially prepared from water and calciumcarbide, but already in the 1940s, thermal cracking ofmethane started to supersede the energy-intensive carbideprocess as source for acetylene.22 Based on the hydrationof acetylene, a variety of industrial chemicals have beenproduced on large scale over many years (Scheme 2).

Catalytic hydration of higher alkynes had rarely been usedin synthetic research, and procedures for hydration of ter-minal alkynes in organic media were not published until1938.24 Partly as a consequence of ‘Reppe chemistry’,25

many alkynes became readily available from 1940 on-wards, and research on alkyne chemistry was flourishing,

Lukas Hintermann (left) was bornin 1972 in Switzerland. After study-ing chemistry at the ETH Zurich, hepursued PhD studies with Prof. Anto-nio Togni, ETH Zurich, developingan asymmetric catalytic fluorinationreaction. From 2001–2002, he stayed

at the Tokyo Institute of Technologyas a JSPS fellow, working on naturalproduct synthesis with Prof. KeisukeSuzuki. In 2003, he started indepen-dent research projects at the RWTHAachen, Germany, supported by anEmmy Noether Programm of the

Deutsche Forschungsgemeinschaft(German science foundation). His re-search interests center around devel-oping catalytic heterofunctional-ization reactions and applying themin new strategies for sustainable or-ganic synthesis.

Aurélie Labonne (right) was born inParis, France, in 1979. She studiedbiochemistry and chemistry at theUniversity Pierre et Marie Curie ofParis VI, obtaining a MSc degree in

2003 in the field of enantioselectivesynthesis with Prof. Lavielle. Since2004, she has been a PhD student atthe RWTH-Aachen in the team of Dr.L. Hintermann, where she is working

on the synthesis of new aza-aryl-phosphane ligands and their applica-tion in ruthenium-catalyzed anti-Markovnikov hydration of terminalalkynes.

Biographical Sketches

R R'

O

RR' R

R'

O

H H H H

H2O

a)

RH2O

R

O

R

O

Markovnikovproduct

anti-Markovnikovproduct

b)

REVIEW Catalytic Hydration of Alkynes 1123


including studies on the hydration of higher alkynes,which continued into the late 1960s. Up until the 1970s,acetylene remained a primary cheap organic raw material,but ethene and propene have now surpassed it in impor-tance; still, acetylene is used in the production of vinyl de-rivatives, acrylates and acetylenic chemicals.22 After theintroduction of the Wacker process (ethene + O2 → acet-aldehyde) and acetic acid syntheses based on carbonyla-tion of methanol, industrial acetylene hydration becameobsolete.26 Pollution by toxic mercurial waste had alwaysbeen an inherent problem of the process, as illustrated bythe shocking case of Minamata disease: many people inthe city of Minamata (Japan) died or suffered from intox-ication by methylmercury compounds, because the fishthey ate had accumulated the poison from untreatedwaste-waters of an acetaldehyde-producing factory.27 Thesearch for new and more efficient processes for alkyne hy-dration, based on metals other than mercury, has contin-ued over the years, as documented in section 3.3. Appliedalkyne chemistry has experienced a recent revival with theadvent of catalytic cross-coupling methodology and itsapplication in synthetic, materials and supramolecularchemistry.28 In 1998, catalytic anti-Markovnikov hydra-tion of terminal alkynes to aldehydes was discovered (seesection 3.4), and in 2002, highly active gold(I) catalystsfor Markovnikov hydration of alkynes were described(see section 3.3.5); clearly, research on alkyne hydrationis making steady and growing progress.

3 Alkyne Hydration Catalysts

This section describes catalysts that have been reported tohydrate alkynes, together with reaction conditions and, forthe more thoroughly investigated systems, generalized in-formation on substrate range in tabular form.

3.1 Brønsted Acid and Base Catalysts

Acetylene and terminal alkynes have been hydrated toMarkovnikov products in pure water at elevated tempera-tures (200–350 °C; see Table 1).29–31 Microwave irradia-tion is the procedure of choice in recent reports.30,31

Electron-rich aryl-alkynes react readily, aliphatic sub-

strates with more difficulty. Addition of gold(III) bromideaccelerates the reaction, presumably by acid catalysis.31

Even in pure water, the hydrations are probably catalyzedby H3O

+, and the addition of protic acids certainly increas-es reaction velocity. Alkynes are hydrated to ketones indilute sulfuric acid at 280 °C.32 The hydration of activatedp-donor-(het)aryl-substituted alkynes is readily mediatedby p-toluenesulfonic acid (p-TsOH) in alcohols at reflux33

or with microwave heating.34 Activated hetaryl-alkynesare also hydrated by stoichiometric sodium sulfide–hydrochloric acid aq in methanol35 (see section 5.1.12 forapplications in hetaryl systems). Truly catalytic amountsof trifluoromethanesulfonic acid (TfOH) or trifluoro-methanesulfonimide (Tf2NH) hydrate alkynes in hot di-oxane,36 and acidic ion-exchange resins mediate thereaction in water at reflux (p-MeOC6H4C≡CH)37a or 60–70 °C (PhC≡CR).37b Many other procedures use stoichio-metric or excess amounts of acid: p-acceptor-alkynes arehydrated by dissolution in cold, concentrated sulfuric ac-id, followed by dilution with water.38 A mixture of phos-phoric acid and boron trifluoride hydrates alkynes inbenzene–acetonitrile (1 h; 60–70 °C; 54–73%).39 Activat-ed aryl- or hetaryl-alkynes react in trifluoroacetic acidcontaining a little water at room temperature40 (section5.1.12). Many alkynes are hydrated in refluxing formicacid;41 notably, formic acid catalyzes its own addition tothe alkyne, and the intermediary enol formate undergoesdecarbonylation (Scheme 3).41b,42 With less activatedalkynes, Ru3(CO)12 is added as a catalyst for the additionof carboxylic acids to alkynes in order to facilitate the re-action.41b

Scheme 3 Alkyne hydration mediated by formic acid.42

Aryl alkynes are hydrated in dilute acid at room tempera-ture under irradiation with ultraviolet light (photohydra-tion; l = 254 nm), because the excited states are morestrongly basic than the ground state, which facilitates vi-nyl cation formation.43 Alkynes have been hydrated overphosphoric acid on solid support at 150–350 °C in the va-por phase.44 There is extensive literature on hydrationover solid metal oxides or phosphates in connection withmercury-free production of acetaldehyde; mixed cadmi-um phosphomolybdates are the most active cata-lysts.9,11,13,45 Such catalysts are probably bestcharacterized as solid acids.45a Catalyst deactivation is of-ten a problem.46 Base-catalysed hydrations of alkynes areless common, since carbonyl compounds are not stableunder the reaction conditions. p-Acceptor-substitutedalkynes react by conjugate addition of hydroxide ion to

Scheme 2 Base-chemicals from acetylene, around 1950.23

O

OH

O

OAc

O

O

OEt

OOH O

CO2R

O

OHOMe

OH

OAc

OO

H2O

Hg(II)

CO2Me

OMe

CO2Me

HCO2H

100 °C, 1 h

CO2Me

OMe

CO2Me

O91%



give stable enolates of b-keto-compounds; stoichiometricamounts of base are required for full conversions.47 Thebase-catalyzed addition of alcohols to alkynes results invinyl ethers or acetals, which can be hydrolysed in a sep-arate step.25f

Scheme 4 p-Acceptor-alkyne hydration via a dioxolane acetal.48

p-Acceptor alkynes can be hydrated via base-catalyzedaddition of ethylene glycol to a dioxolane, followed bytransacetalization in acetone (Scheme 4).48

The most common way of hydrating p-acceptor alkynes,including propiolic acid amides, esters and nitriles, is theMoureu method, which proceeds by stoichiometric conju-gate addition of primary or secondary amines followed byan acid-mediated hydrolysis.49–51 For application exam-ples, see section 5.1.9.

3.2 Mercury Catalysts

The mercury(II) salt catalyzed hydration of alkynes is theclassic method that continues to be in use because of its re-liability. In 1881, Kucherov found that mercury(II) saltsmediate the hydration of acetylene to acetaldehyde, and ofhigher terminal alkynes to ketones.19a,52 Even though thequantity of mercury salt was not specified, its catalytic na-ture was recognized and compared to that of an en-zyme.19b Various mercury(II) salts are catalytically activein aqueous or organic/aqueous solution: mercury(II) bro-mide,19a mercury(II) chloride, mercury(II) sulfate (alsofrom HgO and aq H2SO4),

19b,24 mercury(II) acetate,52 ormercury(II) perchlorate in perchloric acid.53 Other reagentcombinations include mercury(II) acetate and p-toluene-sulfonic acid in methanol,54 mercury(II) acetate in aceticacid,21 mercury(II) acetate and acetic acid in methanol,55

and mercury(II) trifluoromethanesulfonate and tetrameth-ylurea (TMU) in acetonitrile–dichloromethane–water(see Table 2).56 The most popular catalyst is an acidic so-lution of mercury(II) sulfate, often obtained by dissolutionof mercury(II) oxide in aqueous sulfuric acid, that is dilut-ed in organic solvents such as alcohols, acetone, acetic ac-id,24 formic acid, tetrahydrofuran, dioxane, acetonitrile, ordichloromethane and chloroform (in mixtures with othersolvents); for typical applications, see section 5. Severalpractical procedures have been published.57,58

Mercury(II) oxide (HgO) exists in both yellow and red va-riety, but the materials differ only in particle size, and bothcan be used. The addition of iron(III) sulfate prolongs cat-alyst lifetime through reoxidation of mercury(0) to activemercury(II).26 As already noted in the development oftechnical hydrations of acetylene, the presence of excessacid (H2SO4, H3PO4, sulfonic acids, AcOH, etc.) acceler-ates the reaction.21 If a strongly acidic reaction medium isnot desirable, pyridinium p-toluenesulfonate (PPTS) maybe used,59 or the acid is simply omitted,60 or stoichiomet-ric methods are applied (see below).

The counterion of the mercury salt is important for reac-tion kinetics; non-nucleophilic counterions give faster re-actions, but their solutions tend to be less stable towardsprecipitation of elemental mercury. An important catalystin this respect is that developed by Hennion and Nieuw-land,61 which is prepared by dissolution of mercury(II) ox-ide in methanol by addition of boron trifluoride–diethyletherate.61a,b Even better results are obtained by additionof cocatalytic trichloroacetic acid (0.3 equiv relative toHgO).61c,d These preparations may contain fluoroboratecounterions.61a The Hennion–Nieuwland catalyst medi-ates the addition of alcohols (and carboxylic acids) to tri-ple bonds, but an acidic workup of the acetals

O

NMe2

O

OO

OOTBS

H

HO OH

THF, K2CO3

r.t., 2 h

oxalic acid,

H2O–Me2CO

60 °C

O

NMe2

O

OO

O OH

H

O

O

O

OOTBS

Table 1 Brønsted Acids and Bases for Alkyne Hydration

Catalyst/reagent

Amount (mol%)

Conditions Substratesa Lit.

H2O H2O200–350 °C0.5–3 h

RC≡CHRC≡CR

29–31

H2SO4 H2O280 °C1 h

RC≡CH 32

p-TsOH 20 ROH–H2O 80–170 °C6–144 h

ArC≡CHHetarC≡CHRC≡CR

33,34

HOTf 10–20 dioxane, H2O100 °C50 h

RC≡CHRC≡CR

36

HCO2H 100 100 °C0.5–10 h

RC≡CHRC≡CR

41

CF3CO2H >100 H2Or.t. to 60 °C

HetarC≡CH b

ArC≡CH b40

Na2S–HCl >100 H2O, MeOHr.t.

HetarC≡CH b

ArC≡CH b ArC≡CR b

35

R2NH 100 1. THF–EtOHheating2. H+, H2O

RC≡CZ c 49–51

a Note for all tables: AlkC≡CH = alkyl alkynes; ArC≡CH = aryl alkynes; HetarC≡CH = hetaryl alkynes; RC≡CH includes aryl and alkyl; RC≡CR = internal alkynes (aryl and alkyl).b Only p-donor-activated aryls.c Z = p-acceptor group.



(dioxolanes) resulting from methanol (or ethylene glycol)addition gives ketones.62

Another kind of non-nucleophilic counterion is providedby ion-exchange resins as solid supports for mercury(II).63

Sulfonated polystyrene resins or the perfluoroalkylsulfon-ic acid based Nafion polymer63b are suitable.63 The simplehandling and work-up (by filtration) are advantageous. Toconclude on the use of mercury catalysts, both theKucherov (HgO/H2SO4, etc.) and Hennion–Nieuwlandcatalysts are powerful tools that have seen many applica-tions over the years, with minor variations. Little im-provement of the basic methodology has occurred exceptfor the introduction by Nishizawa and co-workers ofHg(OTf)2·2TMU in acetonitrile–dichloromethane as anefficient catalyst at room temperature.56 For mercury(II)in general, catalyst loadings from 0.1 mol% to excess(≥250 mol%) have been reported, but the range of 2–10mol% is more usual. Reaction temperatures range from–20 °C64 or, more typically, room temperature, to refluxtemperature of the organic solvent. Reaction times varyfrom minutes to a day. Little information about systematicattempts to optimize catalyst loading or other reaction pa-rameters is available.

The hydration of alkynes has also been carried out withstoichiometric amounts of mercury reagents. Possible rea-sons for doing so are: milder reaction conditions, shorterreaction times, higher yields, or the convenience ofweighing out larger quantities of catalyst in the case ofsmall-scale reactions. The stoichiometric use of N-mercu-ry amides in boiling aqueous ethanol assures neutral reac-tion conditions with acid-sensitive substrates. Bothmercury acetamide [Hg(NHAc)2]

65 and mercury tosyl-amide [Hg(HNTs)2]

66 salts have been used. Similarly, amixture of mercury(II) chloride and aniline hydrates triplebonds via hydroamination/hydrolysis.67 Phenylmercurichydroxide has been proposed as a stoichiometric reagent

for hydration of aliphatic, nonconjugated terminalalkynes.68

3.2.1 Industrial Synthesis of Acetaldehyde26

In the industrial production of acetaldehyde, acetylene gasis introduced into an aqueous solution containing mercu-ry(II) sulfate and sulfuric acid at 90–95 °C. An excessflow of acetylene removes acetaldehyde as it is formedand thereby reduces secondary reactions (aldol condensa-tions, oxidation), which lead to precipitation of metallicmercury. The addition of iron(III) sulfate prolongs thelifetime of the catalyst solution, since it oxidizes mercu-ry(0) to the active mercury(II) catalyst. Different processschemes exist; however, the industrial production of acet-aldehyde by this method has been discontinued in mostcountries.26

3.3 Non-Mercurial Catalysts for Alkyne Hydration

The section is organized as a walk through the periodicsystem to highlight catalytic activity of metals and non-metals in a hopefully comprehensive way.

3.3.1 Groups 1 through 7 and Lanthanides

There are very few alkyne hydration catalysts in the firstthird of the periodic system of elements from the left. Asingle report on cerium(IV) sulfate catalyzed alkyne hy-dration has appeared.69 A versatile methodology has beendeveloped with zero-valent Mo(CO)5(L) (L = Et3N, sol-vent) for mediating cyclizations of alkynols,70 but no re-lated hydration chemistry has been described.

Analogous reactions are known with tungsten hexacarbo-nyl, which acts as a catalyst when activated by UV irradi-

Table 2 Mercury Catalysts for Alkyne Hydration

Catalyst Amount (mol%) Conditions Substrates Lit

HgO–H2SO4 0.5–250 H2Or.t.–100 °C

RC≡CHRC≡CR

19b,57

HgO–H2SO4 0.7 ROH (Me2CO; HOAc)–H2O60–80 °C4 h

RC≡CHRC≡CR

24

Hg(OTf)2–2TMUb 1–5 MeCN–CH2Cl2–H2Or.t.6–48 h

RC≡CH 56

Hg(II)–IERa – HOAc(EtOH)–H2Or.t. to 100 °C

AlkC≡CHRC≡CR

63

HgO–BF3 1–4 Cl3CCO2HMeOH/ROHc

r.t. to 60 °C

RC≡CHRC≡CR

61

a IER = ion-exchange resin. b TMU = tetramethylurea. c Generates acetals, which are hydrolyzed on acidic workup.



ation and heating (Scheme 5).71 The combination of[W(CO)5(THF)] and o-ethynylacetophenone with watergave 1,2-diacetylbenzene via neighboring group attack tocomplexed alkyne and hydrolysis.72 In a model studyaimed at reproducing enzymatic alkyne hydration activityof tungsten–iron–sulfur enzymes (section 3.5), the tung-sten(IV) complex (Et4N)2[W(O)(mnt)2] (mnt = maleo-nitrile dithiolate) was identified as a catalyst for hydrationof acetylene to acetaldehyde (nine turnovers in four hoursat ambient temperature) which was isolated as the dinitro-phenyl hydrazone.73

Scheme 5 Anti-Markovnikov hydroalkoxylation catalyzed by atungsten complex.71a

3.3.2 Group 8: Iron, Ruthenium and Osmium

There are no iron catalysts for alkyne hydration, but thestoichiometric hydration of phenylacetylene to acetophe-none is mediated by the combined action of iron(III) chlo-ride/water.74 a-Chlorostyrene was an intermediate in thereaction, which appears to be a Brønsted acid mediatedaddition of water and hydrochloric acid to the alkyne.Acetophenone was also generated from phenyl acetylenewith iron(III) chloride and either acetic acid or camphor-sulfonic acid.75

Ruthenium is one of the prominent elements in researchon alkyne hydration chemistry. In 1961, hydration of sim-ple acetylenes and phenyl propiolic acid in solutions ofruthenium(III) chloride in hydrochloric acid (5 M) wasobserved.76 Since the catalytically less efficient complex[RuIICl4(CO)(H2O)]2– and eventually inactive[RuIICl4(CO)2]

2– were formed, catalysis stopped aftersome time, and the deactivation was faster for higheralkynes.76b No synthetic applications have been reported.The complex salt K[RuIIICl(EDTA-H)]·2H2O was foundto hydrate acetylene in neutral aqueous solution at80 °C,77 and ruthenium(III)-loaded Nafion ion-exchangeresin hydrates 3-methylbut-1-yn-3-ol to the hydroxyke-tone.78 In spite of such precedence and the rich organome-tallic alkyne activation chemistry of ruthenium(II), abroadly applicable hydration catalyst has not been foundover the years. A mechanistic study by Bianchini and co-workers shed light on possible reasons for catalyst deacti-vation:79 whereas ruthenium(II) readily forms vinylidenecomplexes that add water to give ruthenium–acyl species,the latter decompose to inactive carbonyl complexes withrelease of alkane rather than aldehyde (Scheme 6).

Scheme 6 Bianchini mechanism for alkyne splitting by water.79

In the course of studies on anti-Markovnikov hydration(section 3.4), [RuCl2(h6-C6H6)(PPh3)] was identified as acatalyst (10 turnovers) for terminal alkyne hydration withpredominant Markovnikov selectivity (≥8:1).80 Relatedcomplexes [RuCl2(h6-arene)(PR3)] or [RuCl(h6-arene)-(PR3)2]Cl with variations in the arene and phosphaneligands also catalyze the hydration of phenyl acety-lene.81,82

Complexes [RuCl(P–P)(arene)]Cl (P–P = diphosphane or2 Bu3P) show catalytic activity for aryl alkyne hydrationafter pre-treatment with two equivalents of silver hexa-fluoroantimonate(IV).83 The in situ generated species hy-drate aryl alkynes (electron-rich substrates react faster) atroom temperature, but alkyl acetylenes do not react; alarge excess of water stops the catalysis.83 The complex[Ru(h5-indenyl)Cl(h4-COD)] hydrates terminal alkyneswith Markovnikov selectivity (Table 3).84

Osmium catalysts for alkyne hydration are not known.The complex [Os(NH3)5(h2-MeC≡CMe)](OTf)2 adds anequivalent of water to give an h2-enol species. Whereasthis stoichiometric transformation is notable for mecha-nistic reasons, no catalytic turnover has been achieved.85

OOHW(CO)6 (10 mol%)

DABCO

PhMe

hν, 60 °C

OO

OO

72%

Table 3 Ruthenium Catalysts for Markovnikov Alkyne Hydration

Catalyst Amount (mol%)

Conditions Substrates Lit

RuCl3–HCl (aq) – [Ru] = 0.1 M5 M HCl50–80 °C

HC≡CHRC≡CH

76

[RuCl2(PR3)(arene)]

2.5–5 i-PrOH–H2O80–100 °C24–48 h

AlkC≡CHArC≡CH

80–82

[RuCl(P–P)]Cl–2 AgSbF6

5 Me2CO–H2Or.t., 10–36 h

ArC≡CH 83

[(Ind)RuCl(COD)]a

5 i-PrOH–H2O90–100 °C 12–48 h

AlkC≡CHArC≡CH

84

a Ind = indenyl; COD = h4-1,5-cyclooctadiene.

R

[Ru]

H2O

[Ru]–

OH

R

H

[Ru]–

O

R

H H

[Ru]–

CO[Ru]

R

CO

H3C R

HH

+

H1,2-shift

– H+

H+

[Ru] = (PNP)RuCl2 or [η5-CpRu(PPh3)2]+

[Ru]

R

H



3.3.3 Group 9: Cobalt, Rhodium, Iridium

Catalytic activity has not been reported for cobalt, but theheavier elements have a well-documented alkyne additionchemistry. The catalytic hydration of acetylene in anaqueous acidic solution of rhodium(III) chloride wasfound to be three times faster than that of ruthenium(III)chloride (vide supra), but deactivation was also a problemfor the rhodium system.86 Catalysts composed of rhodi-um(III) chloride and quarternary ammonium salts (seeTable 4) provide Markovnikov products from terminalalkynes and regiosomeric mixtures from internal alkynes,both in low yields.87 Kinetic parameters for this catalystsystem were recorded; [RhCl4(H2O)2]

– was also immobi-lized on an ion-exchange resin88 and the resulting materialhad some activity in the hydration of aromatic terminalalkynes.88 The catalytic activity of iridium(III) chloride incombination with a quarternary ammonium salt was notedin passing.87 A water-soluble iridium(I) complex[IrCl(TPPTS)2(CO)] [TPPTS = (m-NaOSO2C6H4)3P] cat-alyzes the hydration of terminal alkynes and of acetylene(900 turnovers), whereas internal alkynes did not react.89

Notably, water was much less efficient as solvent than or-ganic media containing 10% of water; presumably, com-petitive coordination of substrates and water at the metalcenter plays a role. Methanol was also added to alkynes,giving acetals, but at a lower rate.89 The precursor com-plex [Ir(COD)2]BF4, in combination with triisopropylphosphite and zirconium(IV) chloride or other chloride-containing Lewis acids, hydrates alkynes at low catalystloadings.90 With some changes, namely triethyl phosphiteas coligand and aluminum trichloride as Lewis acid, thiscatalyst also generated acetals by addition of methanol orhigher alcohols to terminal alkynes.90 The iridium(III)complex [Ir(Me)(OTf)(CO)(H2O)(PPh3)2]OTf catalyzesacetalizations of terminal alkynes by several a,w-diols;the cyclic acetals are hydrolyzed separately to methyl ke-

tones, whereas direct catalytic hydration was not possi-ble.91 The interaction of the iridium(III) aqua complex[Cp*Ir(III)(bpy)(H2O)]2+ (Cp* = h5-pentamethylcyclo-pentadiene) with phenylacetylene was investigated inaqueous solution at 70 °C.92 Either metal–acyl or metal–2-oxoalkyl (ketonyl) species were formed, depending onthe pH of the medium, but only three turnovers to ace-tophenone were observed at 80 °C and pH 1.92

3.3.4 Group 10: Nickel, Palladium, Platinum

As with the previous groups, the first-row element ofgroup 10, nickel, does not catalyze alkyne hydration,whereas the second- and third-row elements do. A speciesgenerated from cis-dichlorobis(dimethylphenylphos-phine)palladium(II) [Pd(PhPMe2)2Cl2] and silver tetraflu-oroborate catalyzes the addition of water to dimethylacetylene dicarboxylate in refluxing acetone.93 Extensivestudies by Utimoto and co-workers on the use of palladi-um(II) chloride (or solvates like [PdCl2(MeCN)2]) as cat-alysts for cycloisomerizations of alkynols or alkynylketones to oxygen heterocycles also resulted in protocolsfor hydration of the same substrates (Table 5).94 Internalalkynes bearing two alcoholic groups in suitable distancegive spiro-acetals instead (Scheme 7).94,95

Scheme 7 Palladium(II)-catalyzed cycloisomerization of alkynediols.94

The palladium(II) chloride catalyst is highly specific forhydrations assisted by anchimeric assistance (neighboringgroup participation), and simple alkylacetylenes do not

Table 4 Rhodium and Iridium Catalysts for Alkyne Hydration

Catalyst Amount (mol%) Conditions Substrates (yields) Lit.

RhCl3 – [Rh] = 0.0125 MHCl aq (3 M)50–65 °C

HC≡CHPhC≡CCO2H

86

RhCl3–NR4Cl 20 NR4Cl (0.3)THF–H2Or.t.–80 °C, 3–25 h

AlkC≡CHArC≡CH(20%)

87

IrCl3–NR4Cl 20 NR4Cl (0.3)104 °C, 230 h

RC≡CR' (20–40%)

87

IrCl(CO)(PR3)2a 33 MeOH–H2O

25 °C, 4–24 hPhC≡CHHC≡CH(>90%)

89

[Ir(COD)2]BF4b 1 P(Oi-Pr)3 (0.02)

ZrCl4 (0.1)n-BuOH–H2O70 °C, 15 h

AlkC≡CHArC≡CH (70–80%)

90

a PR3 = P(m-NaOSO2C6H4)3. b COD = h4-1,5-cyclooctadiene.

OH

HO

Me PdCl2(PhCN)2

(1 mol%)O

O

frontalin

60%THF, r.t., 24 h



usually undergo hydration. Ultrasound irradiation hasbeen recommended, but seems not to be mandatory.96,97

Modified conditions use tetra-n-butylammonium chlorideas phase-transfer catalyst in a two-phase dichlo-romethane/aqueous hydrochloric acid system.98 Amongother palladium(II) compounds, the complex tetraamine-palladium(II) chloride [Pd(NH3)4Cl2], in the presence ofiron(III) sulfate and sulfuric acid, hydrates acetylene,99

and a Nafion/palladium(II) resin hydrates a propargylicalcohol.78

In a study concerning the preparation of alkyne–plati-num(II) complexes, hydrations of alkynes in ethanolicsodium tetrachloroplatinate(II) hydrate (Na2PtCl4·4H2O)solution were mentioned in passing.100 Jennings and co-workers established that Zeise’s dimer [{PtCl2(C2H4)}2],or simply platinum(II) chloride and other platinum ha-lides, are catalysts for the hydration of terminal an internalalkynes at rather low catalyst loading.101,102 The regiose-lectivity of the catalyst for hydration of internal alkyneswas compared to mercury catalysis (see sections 5.1.7 and9).103 The platinum(II) catalysts hydrate selectively in thepresence of a large excess of alcohol, but upon addition ofco-catalytic non-nucleophilic base (Na2SO4, MgSO4, 2,6-di-tert-butylpyridine) alcohols also add to give acetals di-rectly.104 No added base was necessary for the cyclizationof alkynols to acetals or spiro-acetals with Zeise’sdimer.95

Platinum(IV) chloride catalyzes the hydration ofalkynones in aqueous tetrahydrofuran or under phase-transfer conditions,105 but a superior catalyst is generatedin situ from platinum(IV) chloride and carbon monoxide(14 bar), followed by reaction under carbon monoxide(1.4 bar).106 Reactions are performed in either homoge-neous tetrahydrofuran solution or a two-phase systemwith a quaternary ammonium chloride (Table 5).106 Highyields (>90%) were initially reported for alkyl, aryl andinternal alkynes, but problems with reproducibility werelater mentioned and considerably lower yields wereachieved.106b The active species is presumably[PtH(CO)Cl(L)] (L = CO, H2O, THF), which is in equilib-

rium with green-colored clusters [Pt3(CO)3(m2-CO)3)]n2–

(n = 5,6) and hydrochloric acid.106 The water-solublecomplex cis-(TPPTS)2PtCl2 catalyzes regioselective hy-drations of both pent-4-yn-1-ol and pent-3-yn-1-ol to thecommon product 5-hydroxy-2-pentanone, as expectedfrom a mechanism with anchimeric group assistance.107

A sulfonated version of the chelating ligand DPPE(1,2-bis-diphenylphosphinoethane), DPPETS ({m-NaO3SC6H4}2PCH2CH2P{m-C6H4SO3Na}2), is also cata-lytically active in the same model reactions,108 but hydra-tions of other alkynes were not reported.

3.3.5 Group 11: Copper, Silver, Gold

Vartanyan and co-workers developed a catalyst composedof copper(I) chloride (28–34%), ammonium chloride (14–18%), mineral acids (e.g., HCl, 1–3%) and a sulfide addi-tive, either inorganic (hydrogen sulfide, sodium sulfide, orheavy metal sulfides; 0.4–3%) or organic (1-octanethiol,mercaptobenzoic acid, thioglycol) for the catalytic hydra-tion of acetylene at 80–85 °C (see Table 6).109 The hydra-tion of propyne with this catalyst led to mixtures ofMarkovnikov and anti-Markovnikov products in ratios(acetone/propanal) from 10.5 down to 1.6 with increasingamounts of copper(I) sulfide as additive (Scheme 8).110

Scheme 8 Copper-catalyzed hydration in presence of sulfide addi-tives.110

Organic thiol additives had similar effects,111 and theirsteric size affected the regioselectivity of the reaction.112

The generation of aldehydes was explained by the inter-mediacy of a vinyl sulfide and its hydrolysis. Copper(I)chloride clusters were proposed to be the active catalystsin the presence of thiol additives.113 These and other114

copper catalysts have been investigated as replacements

Table 5 Palladium and Platinum Catalysts for Alkyne Hydration

Catalyst Amount (mol%) Conditions Substrates (Yields) Lit.

PdCl2

or PdCl2(RCN)2

1–5 MeCN–H2Or.t. to 80 °C, 0.5–40 hultrasounda

AlkC≡CHb

RC≡CRb

94–98

Pt2Cl4(C2H4)2 or PtCl2 0.7 THF–H2O70 °C, 24 h

AlkC≡CHRC≡CR

101–103

PtCl4/CO 2 CO (1.4 bar) (i) H2O–THF/glyme 80–108 °C or (ii) NR4Cl (0.04)C2H2Cl4; 110 °C(i) and (ii): 1.5–9 h

AlkC≡CH (46%)ArC≡CH (74%)RC≡CR (80%)

106

a Optional. b Anchimeric assistance required.

OO+

H2O, 80 °Cvariable ratio

CuCl, NH4Cl

HCl, Cu2S



for mercury catalysts in industrial-scale hydration of acet-ylene or propyne. The kinetics of copper(I)-catalyzed hy-dration of acetylene has been determined in the course ofa study on the dimerization of acetylene to vinylacetylene,where hydration is a side-reaction.115 Furthermore, cop-per(II) trifluoromethanesulfonate and copper(II) tetra-fluoroborate are catalysts for the hydration of 2-methylbut-3-yn-2-ol (10 mol%).78 A copper(II)-ex-changed Nafion resin hydrates several alkynes ratherslowly.78 Non-coordinating counterions are important forthe catalytic action; for example, copper(II) acetate is notactive in the hydration of simple alkynes,54,78 though itmediates the hydration of N-propargylamides with anchi-meric assistance (Scheme 9).116

Scheme 9 Copper-catalyzed hydration with anchimeric assis-tance.116

Silver has a high affinity for alkynes, and cationic sourcesof the metal (AgOTf, AgPF6) can activate alkynes to-wards attack of oxygen nucleophiles, mostly in cycliza-tion reactions.117 Hydration is realized in the case ofanchimeric assistance; silver nitrate is a catalyst for thehydration of N-propargylamides (compare withScheme 9) with intermediacy of an oxazoline.116 Intermo-lecular reactions are less common for non-activatedalkynes. The hydration of 2-methylbut-3-yn-2-ol was cat-alyzed by silver trifluoromethanesulfonate with difficul-ty,78 but this salt catalyzes the addition of alcohols to p-acceptor alkynes more readily.118

The catalytic hydration of alkynes with a gold catalyst(HAuCl4) was observed in 1976.119 Later, a syntheticallyuseful protocol appeared for alkyne hydration with sodi-um tetrachloroaurate(III) (NaAuCl4) as catalyst under al-most neutral conditions (pH 5).96,120 Terminal and internalalkynes are hydrated in excellent yields, but propargylicalcohols do not react.120 In anhydrous methanol, dimethyl-acetals are formed. The failure of K[Au(CN)2] to act as acatalyst was taken as evidence for a gold(III) rather than agold(I) species as the active catalyst,120 but the cyanidecomplex is probably not a good model for the kind ofgold(I) species that forms under reaction conditions. Thequestion of gold(III) versus gold(I) has become morestringent in light of recent success with gold(I) catalysts(see below). Sodium tetrachloroaurate(III) catalyzes theMeyer–Schuster reaction of internal propargyl ethers toa,b-unsaturated ketones, whereas a terminal propargylether gave the regular hydration product.121 A variety ofgold(III) organometallic compounds, containing Au–C6F5

or Au–Mes (Mes = 2,4,6-trimethylphenyl) units and chlo-ro ligands are catalyst precursors for the hydration of phe-nylacetylene and hept-1-yne under neutral or acidic(HOTf, H2SO4) conditions.122 The best results were ob-tained with mononuclear complexes bearing electro-negative ligands such as NBu4[Au(C6F5)2Cl2] orPR4[Au(Arl)Cl3], whose activity was similar to that of so-dium tetrachloroaurate(III). Higher turnover numberswere achieved in acidic media. Complexes of gold(III)chloride with neutral donors (triphenylphosphine, tetrahy-drothiophene) were either poor catalysts or inactive.122

In 1998, Teles and co-workers at BASF reported that cat-ionic gold(I) complexes of the type [L–Au+] (where L is aphosphane, arsane or phosphite) are highly active cata-lysts for additions of alcohols to alkynes in the presenceof an acid co-catalyst (such as MeSO3H) (Scheme 10).123

N

OCu(OAc)2

(10 mol%)

MeOH, H2O

O

N

O

66%

Table 6 Copper and Gold Catalysts for Alkyne Hydration

Catalyst Amount (mol%) Conditions Substrates (Yields) Lit.

CuCl NH4Cl, H2S or RSH, HCl, H2O80 °C

HC≡CHMeC≡CHa

109–113

NaAuCl4 2 MeOH–H2O70 °C, 1–5 h

RC≡CHRC≡CR

90%)

120

AuMe(PPh3) 0.1–1 H2SO4 (0.5)MeOH–H2O70 °C, 2 h

RC≡CHRC≡CR(50–99%)

125,126

AuX(PPh3) 0.1–0.5 BF3·OEt2 (0.05)MeOH–H2OX = OCOC2F5 or p-TsO 45 °C

AlkC≡CHRC≡CR

127

[Au(C6F5)2 Cl2]–, etc. 2–4.5 (H2SO4)

b

MeOH–H2O70 °C, 1.5 h

PhC≡CH AlkC≡CH(90–98%)

122

a Generates propanal and propanone in variable ratios. b Optional.



Scheme 10 Highly active gold(I) acetalization catalysts reported byTeles et al.123

These catalysts were generated from (a) [AuX(PPh3)](X = Cl, CF3CO2, MeSO3, NO3) and boron trifluoride, orfrom (b) [AuCl(PPh3)] and AgY (Y = non-nucleophiliccounterion), or from (c) [AuMe(PPh3)] by protonolysis ofthe gold–carbon bond with a strong acid that provides anon-nucleophilic counterion (H2SO4, HBF4, MeSO3H).Reactions take place under mild conditions (20–50 °C)with a TOF of up to 5400 h–1.123 Prior to this report, goldwas intuitively considered by many chemists to be insuf-ficiently reactive for applications in catalysis.123,124 Exten-sion of this catalyst system to alkyne hydration wasachieved simply by choice of aqueous methanol as thesolvent and a range of simple alkynes as substrates.125

Terminal aliphatic and aromatic alkynes react in good toexcellent yields at low catalyst loadings. Tertiary propar-gyl alcohols require catalyst loadings of 1 mol% and givemixtures of ketoalcohols and rearranged a,b-unsaturatedaldehydes (Meyer–Schuster reaction). Either the additivetriphenyl phosphite or the use of an atmosphere of carbonmonoxide resulted in improved catalyst stability and ac-tivity (TOF up to 15600 h–1 at 70 °C, 0.005 mol% of[Au]). A practical laboratory procedure for the hydrationof terminal alkynes with a gold catalyst has been pub-lished (Scheme 11).126

Scheme 11 Laboratory-scale alkyne hydration with gold(I) cata-lysts.126

The complexes [Au(PPh3)(RCO2)] or [Au(PPh3)(RSO3)]have been proposed as catalyst precursors for hydrationof terminal and internal alkynes in combination withboron trifluoride–diethyl etherate.127 Of these,[(Ph3P)Au(C2F5CO2)] was the most active compound in-vestigated (TOF up to 3900 h–1 for hydration of hex-3-ynein MeOH at 70 °C), and is even reusable.127 Cationic com-plexes of gold(I) incorporating heterocyclic imidazol-ylidene carbene ligands also hydrate hex-3-yne,128 and the

catalytic hydration of phenylacetylene by a porphyrincomplex [Au(TPP)Cl] (TPP = tetraphenylporphine) wasnoted.129

3.3.6 Other Elements: Zinc, Cadmium, Tellurium, Thallium

Considering the success of mercury(II) catalysts in alkynehydration, studies of both zinc and cadmium salts wereobvious pursuits. Kucherov had reported, as early as1909, that aqueous solutions of zinc salts and cadmiumsalts mediate the hydration of 3-methylbut-1-yne withinthree hours at 150 °C, and that acetylene reacted sluggish-ly.52 In a more recent patent, the reaction with acetylene iscarried out under a pressure of 22 atmospheres at 140 °C(four hours) in solutions of zinc sulfate.130

With regard to tellurium: in a somewhat isolated report, p-methoxytellurinic acid anhydride was shown to hydrateterminal alkynes selectively, in the presence of internalalkynes, in refluxing acetic acid (Scheme 12).131

Scheme 12 Methoxytellurinic acid as selective hydration cata-lyst.131

Thallium(III) salts, such as the chloride, acetate and sul-fate, catalyze the hydration of phenylacetylene in hot ace-tic acid.132,133 The reaction is relatively slow and more ofacademic interest, if one considers the toxicity of thalliumcompounds.

3.4 Anti-Markovnikov Hydration of Terminal Alkynes

Markovnikov selectivity had long been taken for grantedin catalytic alkyne hydration. In 1986, Dixneuf and co-workers demonstrated that certain donor-stabilized ruthe-nium(II) complexes were able to catalyze anti-Markovni-kov additions of carbamates to terminal alkynes,134,135 asa consequence of a reaction mechanism that proceeds byan alkyne–vinylidene tautomerization pathway.136 Thischemistry was successfully extended to ligand-controlledregioselective additions of carboxylic acids and other nu-cleophiles,7 but anti-Markovnikov hydration of terminalalkynes could not have been considered a straightforwardextension of the reaction principle. As mentioned in sec-tion 3.3.2, a mechanistic study had implied that hydrationof alkynes by the vinylidene pathway would stop at thestage of ruthenium(II)–carbonyl complexes with poison-ing of the catalyst (see Scheme 6).79 It took more than 100years from Kucherov’s demonstration of metal-catalyzed

R RR

OMeMeOR

MeOH

20–50 °C

(Ph3P)Au+, H+

RR'OH R

OR'R'O

R = Me, H, Ph

R' = Me, Et, i-Pr, allyl

R = Ph, Et

TON up to 100000,

TOF up to 5400 h–1

(Ph3P)Au+, H+

AuMe(PPh3) (0.2 mol%)

O O

70 °C, 2 h

86%H2SO4 (0.5 equiv)

MeOH, H2O

TON 860

TOF 430 h–1

O

20 h

85%

HOAc, 120 °C

[Te] cat. (10 mol%)

[Te] cat: RTe

OTe

R

O O

R = p-C6H4OMe



Markovnikov-selective alkyne hydration to the discoveryof a predominant137 anti-Markovnikov hydration reaction(Scheme 13). In the meantime, the best synthetic solutionfor anti-Markovnikov hydration of terminal alkynes was ahydroboration–oxidation sequence.4

Scheme 13 General scheme of anti-Markovnikov hydration.

3.4.1 Ruthenium-Catalyzed Anti-Markovnikov Hydration

In 1998, Tokunaga and Wakatsuki described the first anti-Markovnikov hydration catalyzed by ruthenium(II) com-plexes, which yielded aldehydes from terminalalkynes.80,138 The reactions were carried out in the pres-ence of 10 mol% of [RuCl2(C6H6){PPh2(C6F5)}] and 30mol% of additional ligand PPh2(C6F5) (Figure 1, A) inaqueous isopropanol from 65–100 °C. Alkyl alkynes givealdehydes with selectivities (aldehyde/ketone) from 9:1 to67:1, but phenylacetylene hardly reacts (< 2% conversion,selectivity 1:1). The water-soluble ligand P(m-C6H4SO3Na)3 gave similar results.80 NMR spectroscopyindicated release of the arene ligand under the reactionconditions, therefore the catalyst is presumably of theform [RuCl2(PAr3)n].

80 In a further advance, Wakatsukiand co-workers found a remarkable increase in reactionrate and selectivity with complexes [CpRu(PR3)2]X ascatalysts (Cp = h5-cyclopentadienyl; R = aryl, alkyl,bridging alkyl; X = Cl, nonnucleophilic counterion).139,140

These hydrations are best carried out with 2–10 mol% of[CpRuCl(dppm)] (dppm = bis(diphenylphosphino)meth-ane; Figure 1, B) in isopropanol–water (3:1) at 100 °C andgive the aldehydes in good to excellent yields after 12hours. Ketones were no longer detected as side-products.The substrate scope included phenylacetylene and thebulky tert-butylacetylene (81% and 90% yield, respec-tively). Besides dppm, the best ligands (PR3)2 were dppe,PMe3, PMePh2, PMe2Ph and dppb.141 In an accompanyingpatent, complexes [CpRu(L2)]X with incorporated chelat-ing nitrogen ligands (L2) were shown to be active in thehydration of oct-1-yne;140 from among those tested, 2,2¢-bipyridine (52% conversion), phenanthroline (49% con-version), and PyBOX-i-Pr142 (94% conversion) were themost successful.140 The cationic complexes [Cp-Ru(L2)(solvent)]PF6, with either phosphane or nitrogenligands, were no more active than the corresponding neu-tral chloro complexes.140

In 2001, Grotjahn and co-workers reported on the applica-tion of the principle of cooperative catalysis by the metalcenter and functional groups in the ligand sphere to anti-Markovnikov hydration.143 A [CpRu(PR3)2]

+ fragmentwhich incorporated a sterically demanding phosphinoim-idazole ligand was synthesized and shown by X-ray crys-tallography to be an aquo complex with two hydrogenbonds from coordinated water to the nitrogen lone-pairs of

the imidazolyl-phosphane ligands (Figure 1, C). The cat-alytic hydration of hex-1-yne with complex C (2 mol%,acetone, 5 equiv H2O, 70 °C) went to 92% conversion af-ter 21 hours. The regioselectivity for aldehydes was usu-ally ≥100:1.143 While the X-ray crystal structure of theaquo complex amply demonstrates the principle of coop-erative binding of a water molecule, the catalytic activityof C appeared not so much different from B (1 mol%,100 °C, 12 h, 95% yield), to imply that a different mech-anism via cooperative catalysis was operating. However,this view changed when a direct kinetic comparison in ace-tone at 70 °C showed that catalyst C is 90 times more ac-tive than B.144 Furthermore, the Grotjahn group presented,in 2004, the complex [CpRu(Ph2P-Py-t-Bu)2(MeCN)]PF6

(Figure 1, D; S = MeCN) as an astonishingly active cata-lyst for anti-Markovnikov hydration of terminal alkyneswhich surpasses the activity of B by a factor of 1000, andoperates even at room temperature (1-nonyne; 5 mol% D,48 h, 99% conversion).144 This enormous rate differenceis not readily explained on the basis of simple steric andelectronic ligand variations and is a strong argument forthe occurrence of cooperative catalysis. Based on extrap-olated kinetic data, the uncatalyzed hydration of non-1-yne in acetone with five equivalents of water at 70 °C wasestimated to posess a reaction half-life of >20 000 years,and the anti-Markovnikov hydration a half-life of>600 000 years.144

Catalyst D therefore accelerates the hydration by a factorof >2.4 × 1011 and changes regioselectivity by a factor of300 000. These numerical values are comparable to theperformance of enzymes.144

Breit and Chevallier investigated the self-assembly of bi-dentate ligands through hydrogen-bonding association ofmonodentate subunits to the CpRu fragment.145 On mix-ing the catalyst precursor [CpRu(MeCN)3]PF6 with 1:1combinations of one of three phosphinoisoquinolones andone of three phosphinoaminopyridines (nine pairs), com-plex E emerged as most active and selective catalyst foranti-Markovnikonv hydration of terminal alkynes. Typi-cal reaction conditions are: 2–10 mol% of E, aqueous ac-etone, 120 °C (sealed tube), 26–96 hours, 65–91% yield.The regioselectivity was often higher than 99:1, though afew substrates capable of anchimeric assistance producedsome ketone (maximum 13%). The hydration of a steroi-dal tertiary propargyl alcohol proceeded without elimina-tion to an aldol (10 mol% E, 70 °C, 124 hours, 61% yield;see substrates in Figure 2).145

With the aim of applying anti-Markovnikov hydration inorganic synthesis, we were working towards developingalternative CpRu-based catalysts when the seminal work,by the Grotjahn group, on bifunctional catalysis with cat-alyst D appeared.144 The problem of catalytic activitycould be considered as solved for the time-being, but theavailability of the catalyst in large amounts was problem-atic since the required phosphinopyridine ligand (F2,R = t-Bu) is synthesized in six steps and low overallyield.146,147 Additionally, the catalyst precursor [Cp-Ru(MeCN)3]PF6 is air-sensitive and quite expensive. We

Rcatalyst

solvent+ H2O R

O



found that an in situ catalyst F, composed of the air-stablecomplex [CpRu(h6-C10H8)]PF6 (F1)148 (C10H8 = naph-thalene) with two equivalents of a 6-aryl-2-diphenylphos-phinopyridine ligand (F2; R = aryl) gave highly activecatalysts for anti-Markovnikov hydration of terminalalkynes.149 The in situ catalysts were formed from F1 andF2 by ligand exchange in hot acetonitrile solution, fol-lowed by evaporation. ESI-MS spectrometry and NMRspectroscopy confirm that complexes [Cp-Ru(F2)2(MeCN)]PF6, analogous to Grotjahn’s catalyst D,are formed.149 Hydrations are then carried out in acetone(1–5 mol% [Ru], 45–65 °C, 1–20 h, 69–99% yield). Thesize of R in ligands F2 was crucial in that the activity ofcatalyst F increased in the series Ph < Mes < t-Bu < 2,4,6-(i-Pr)3C6H2 < 2,4,6-Ph3C6H2. The most active catalystswere faster than D by a factor of up to four at 60 °C. Thein situ catalyst with F2 (R = t-Bu) was almost as active asthe pure complex D.149 The experimental procedure forapplying catalyst F was further simplified when it wasnoted that ligand exchange with F1 also takes place underthe reaction conditions.150 Catalytic reactions are nowsimply performed by mixing substrate, F1 (2–3 mol%),and F2 (4–6 mol%) in acetone containing five equivalentsof water, and heating to 70 °C overnight. In addition tophosphinopyridine ligands F2, a range of aza-arylphos-phanes F3 (X = N, CH; R, R¢ = aryl, alkyl) have been syn-thesized and found to give very active in situ catalystswhen combined with F1.150

In addition to the above-described CpRu-based systems,complex [(Ind)RuCl(PPh3)2] (G) has been reported to cat-alyze alkyne hydration.151 Under standard conditions [i-PrOH–H2O (4:1), 90 °C, 48 h], alkynes gave mixtures ofaldehyde and ketone in ratios of 3:1 to 4:1, but in an aque-ous solution of sodium dodecyl sulfate (or related ten-sides), aldehydes were formed with higher selectivity at60 °C (8:1 to 80:1). Unprotected propargyl alcohols areclaimed to give aldols, but neither isolated yields nor char-acterization data for these rather unstable compoundshave been given, thus one hopes for a continuation ofthese studies.151 The hydration of secondary propargyl al-cohols with CpRuCl(PMe3)2 as catalyst gave a clean

Meyer–Schuster rearrangement to the a,b-unsaturated al-dehydes (5 mol% [Ru], i-PrOH–H2O, 100 °C, 12 h).152

The generation of a,b-unsaturated aldehydes from propar-gyl alcohols is not necessarily indicative of an anti-Markovnikov hydration, since those products are easilyformed by a propargylic rearrangement (Meyer–Schusterreaction; see section 5.1.3). Even when b-hydroxycarbon-yl compounds are isolated from a catalytic hydration,153

they might result from an oxa-Michael addition to initiallyformed a,b-unsaturated aldehydes.

3.4.2 Substrate Range and Applications of Anti-Markovnikov Hydration

Aliphatic terminal alkynes are hydrated by all catalysts inFigure 1. Slow reactions occur with bulky substrates, as isevident with tert-butylacetylene.80,143 Hydration of aro-matic alkynes generally proceeds more slowly and is notsatisfactory with some catalysts (A, C), though good re-sults at the 1–2 mol% level are obtained with catalysts Dand F. Nitrophenylacetylene is a problematic substrate.144

The activity of anti-Markovnikov hydration catalysts ap-pears to be limited to terminal alkynes, since hydration ofan internal alkyne has not been reported.

The functional group tolerance is broad (Figure 2). Typi-cal oxygen functionality like ketones, esters or malonatesare compatible. As a result of the mild reaction conditionswith catalysts D and F, even TBS ethers or THP acetalsare tolerated in a substrate.143,144,149 A nitrile group mayslow down catalysis by competitive binding,139,144 but b-ketoesters, potential ligands for ruthenium(II), are readilyhydrated.149 An application of considerable synthetic rel-evance would be the hydration of propargyl alcohols to al-dols,144,151 but propargyl alcohols are often found toundergo Meyer–Schuster rearrangements with anti-Markovnikov hydration catalysts.144,152

In spite of specific examples,145,151 the problem of aldolsynthesis via anti-Markovnikov hydration cannot yet beconsidered solved for the most interesting substrates,namely enantiopure secondary propargyl alcohols. The

Figure 1 Catalysts and ligands for anti-Markovnikov hydration.

Ru

PPh2

ClPh2P

+

N

N

PPh2 Me

N

N

Ph2PMe Ru

OHH

OTf–

Ru+

PF6–

N N

PPh2

N

Ph2P

O H

COt-Bu

HRu+

PF6–

RuC6F5

P

PCl

F5C6

Ph

PhPh

Ph

XX

N PPh2R

R'

N(S)

Ph2P

N

PPh2

t-Bu t-But-Bu t-Bu

A B C D

RuPh3P

PPh3

Cl

ERu+

N PPh2R

Cl+ 3

PF6–

isoquinolone

aminopyridine

F

G

F1 F2

precursor complex + 2 equiv ligand

+ 2

F3



hydration of TBS- or THP-protected propargyl alcoholshas been realized for propargyl aclohol itself143,144 and theresulting O-protected derivatives are very useful for syn-thetic applications. Basic nitrogen functional groups (suchas tertiary amines) are not tolerated, but amides,145

imides,145 and sulfonamides144,154 can be hydrated. Wehave recently hydrated secondary prop-2-yn-1-yl-N-tosyl-amides with catalysts F and obtained b-amidoaldehydeswithout elimination (Scheme 14a).155

Scheme 14 (a) Synthesis of b-amidoaldehydes by anti-Markovni-kov hydration. F2 = 6-(2,4,6-triphenylphenyl)-2-diphenylphosphino-pyridine.155 (b) Sequential iterative synthesis of oligo-1,4-diols; F2with R = tert-amyl was used as principal ligand for catalyst F.154

The reactions were also performed under conditions ofmicrowave irradiation and gave the products in very shortreaction time. We have studied the application of anti-Markovnikov hydration in multistep syntheses and havedeveloped an iterative sequential strategy for the synthesisof oligo-1,4-diols by (a) addition of allenylzinc bromideto an aldehyde, (b) O-protection of the resulting homopro-pargylic alcohol, and (c) anti-Markovnikov hydration togive an elongated aldehyde (Scheme 14b). Starting frombenzaldehyde, up to four iterative cycles of propargyla-tion and hydration led to a hexadecynoic acid derivative,which is intended to be a substrate for natural-product-likemacrolactone synthesis.154

3.5 Enzymatic Hydration of Alkynes

Enzymes that catalyze the hydration of alkynes are hydro-lyases (EC 4.2.1) (alternatively: hydrases, hydratases). Anacetylene hydratase has been isolated from Pelobacteracetylenicus which feeds anaerobically on acetylene asthe sole carbon source.156 The enzyme is a tungsten iron–sulfur protein requiring a strongly reducing environ-ment,156,157 but the reaction mechanism is presently un-known.158 A model tungsten complex that imitates thecatalytic activity of the enzyme has been prepared (seesection 3.3.1). An enzyme for hydration–decarboxylationof acetylene dicarboxylic acid to pyruvic acid has beendescribed,159 as has a hydrase that converts acetylene-monocarboxylic acid into malonic acid semialdehyde.160

The regioselectivity of water addition with these sub-strates corresponds to that of a nucelophilic additionmechanism. Enzymes for the hydration of propiolic sub-strates need not be highly specific. The preparatively use-ful hydration of 2-alkynoic esters of coenzyme A to 3-ketoacyl-CoA derivatives is mediated by crotonase,161

which normally catalyzes the addition of water to enoyl-CoA, i.e. an alkenoyl substrate. Crotonase also hydratesthe nonconjugated alkyne 3-octynoyl-CoA,162 presum-ably via isomerization to a 2,3-allenoyl intermediate. Achloroacrylic acid dehalogenase adds water to several ac-tivated alkynoyl substrates.163

Figure 2 Selected substrates (substructures) for anti-Markovnikov hydration catalysis (see also Figure 1 and Scheme 13).

Rn

N

O OTsHN

R

OH

B,D–G B,D,E

D ?

B–E

C,D

SiMe3

D [–SiMe3]B,C

R

O

O

B,E,F

n

O

E,F

N

O

E

OH

MeO

H HE

RO2C

CO2R

RO2C

O

R

OTBS

TBSO

C

F FF

NHTs

R

F

R

A–G

n

OAc

Ph

OAc

OH

Ph

1. F (3 mol%) Me2CO, H2O 70 °C, 12 h

2.

OAc

TBSO

Ph

OTBS

OTBS

OH

CO2Me

OAc

OTBS

Ph

OTBS

OTBS

b)

a)

R

NHTs

BrZn

1. hydration

2. LiC≡CCO2Me

R

NHTs O

Me2CO, H2O

[CpRu(F2)2]PF6

10 mol% [Ru], 55 °C, 15–24 h; 83–91%

3–10 mol% [Ru], 90–115 °C, 5–30 min; 73–94%

regular:

microwave:

THF, 0 °C, 15 min82%

74%



4 Mechanisms of Catalytic Alkyne Hydration

4.1 Brønsted Acid Catalyzed Hydration

Acid-catalyzed hydration proceeds by protonation of thecarbon–carbon triple bond, followed by fast addition ofwater to generate an enol.164–166 The strong kinetic depen-dence on the cation-stabilizing ability of alkyl or aryl sub-stituents connected to the triple bond, together with akinetic isotope effect (H2SO4/D2SO4) of ~2 is taken as in-dication of rate-determining protonation of the alkyne togenerate a vinyl cation.165,166 Under conditions of photo-excitation, alkynes hydrate more readily, because the ex-cited state is of higher basicity than the ground state.43 Thereaction then proceeds in dilute acid, and the enol interme-diate could be observed spectroscopically.43a

4.2 Mercury-Catalyzed Hydration

The current picture of the mechanism of the Kucherov re-action is relatively simple, but several aspects are notknown in detail.12,53–55,164,167,168

Scheme 15 Mechanism of the Kucherov reaction.

At least a single free coordination site on the mercury cat-ion is needed in order to form a short-lived p-complexwith the substrate (Scheme 15, I). The Markovnikov se-lectivity observed in most alkyne hydrations is explainedby steric and electronic arguments; the better stabilizationof a partial positive charge at the internal alkyne carbon(larger s-donor effect of R vs H), as well as the steric re-pulsion between metal ion and alkyl group R, favor an at-tack at the inner alkyne carbon atom.7 Water then attacksthe triple bond to form, presumably, a b-hydroxyethynyl–mercury species (II). Judging from related acetoxy mer-curations, where organomercurial addition products canbe isolated, the addition step is often anti stereoselective,though syn adducts have sometimes been obtained.168 Inthe case of hydration, compounds II have neither beenisolated nor characterized spectroscopically. An acid-mediated hydrodemercuration takes place (II → IV, may-be via III), and this step might be rate-determining, basedon measured deuterium isotope effects of 5 (reaction inD2O with D2SO4, Hg2SO4).

169 Curiously, a-mercuriatedcarbonyl compounds (Scheme 15, III), which are well

characterized and for which X-ray crystal structure deter-minations exist,170 have been little considered in mecha-nistic discussions. It is assumed that the reaction productis initially released as an enol (IV), before tautomerizingto the final product, though enols have not been directlyobserved.

4.3 Other-Metal-Catalyzed Markovnikov Hydrations

The mechanistic scheme for hydration of alkynes withother metal catalysts is superficially similar to that withmercury (Scheme 15), with subtle differences due to therelative stabilities of the catalytic intermediates. Transi-tion-metal ions with a partially filled d-electron shell formstable p-complexes with alkynes; the attack of water to thecoordinated substrate then becomes rate-determining, andthere is neither acceleration by acids nor a primary deute-rium kinetic isotope effect.87,101 On the other hand, d10

ions such as gold(I) or copper(I) are combined with acidadditives (section 3.3.5). Note, however, that data on ki-netics and kinetic isotope effects are not available formost catalyst systems. The stereochemistry of water addi-tion (syn vs anti) with metal catalysts is not known; someresearchers have discussed the necessity of an additionalcoordination site for water in the context of a proposed in-nersphere (syn) addition mechanism.96,77 For the gold(I)-catalyzed addition of methanol to alkynes, a syn-additionmode involving activation of both methanol and thealkyne by LAu+ has been proposed (Scheme 16).123

Scheme 16 Mechanism proposed for gold(I)-catalyzed alcoholaddition.123

Whether this picture is transferable to gold(I)-catalyzedhydrations is unclear. The addition of water to alkynes isoften selective, even in the presence of excess of alcoholor carboxylic acid, thus there might be a specific additionmechanism for water.103 On the other hand, hydration cat-alysts often add alcohols to alkynes in the absence of wa-ter, sometimes after slight modification of reactionconditions.

A theoretical study on transition-metal-catalyzed alkynehydration has investigated pathways of the Rh-catalyzedalkyne hydraton along the lines of the above discussion.171

R H

Hg2+

R H

Hg2+

H2O

HO

R Hg+

H

HO

R

H

H

O

R Hg+

HH

I

II

III

IV

H+

H+

O

R

AuMe3P CH3

O

H

CH3H

AuMe3POCH3

HH

H3C

Ph3P Au

OMe

H Me

H

Ph3P Au

Me

MeOH

OMe

Me

Me

H

+

+

+

+



In summary, the mechanism of metal-catalyzed alkyneMarkovnikov hydration can be rationalized in a simplescheme (see Scheme 15), though details of the mechanis-tic pathway are not properly understood.

4.4 Mechanism of Ruthenium-Catalyzed Anti-Markovnikov Hydration

Anti-Markovnikov products cannot be obtained along asimple electrophilic activation pathway as discussedabove, so these products must emerge by a competing andfundamentally different mechanism. In analogy to themechanism for alkyne splitting by water (Scheme 6), afirst mechanistic proposal for anti-Markovnikov hydra-tion of alkynes assumed addition of water to a vinylideneintermediate, generating a metal–acyl species, whichwould undergo protonolysis of a carbon–metal bond to re-lease aldehyde (Scheme 17).80

Scheme 17 Initial mechanistic proposal for anti-Markovnikov hy-dration.

This mechanism satisfactorily explained the generation ofaldehydes, but it failed to correctly predict the result ofdeuterium marker experiments, which revealed that theterminal alkyne hydrogen remains connected to C-1 of theproduct aldehyde (Scheme 18).172

Scheme 18 Crucial deuterium incorporation experiments.172

Wakatsuki and co-workers therefore proposed a newmechanism, where external attack of an alkyne p-complexby H+ leads to a vinyl–ruthenium(IV) species, which isstabilized by a 1,2-shift of hydrogen (deuterium) to themetal (Scheme 19). Addition of OH– to the vinylideneruthenium(IV) complex and tautomerization leads to aruthenium(IV) hydrido-acyl complex that reductivelyeliminates aldehyde.172

The new mechanism is consistent with the deuteriummarker experiments and has been backed up by DFT cal-

culations.172 Several questions remain to be answered,though: Why is an external protonation taking place in analmost neutral reaction medium, under conditions wherethe p-alkyne–vinylidene equilibirum is apparently wellestablished? Likewise, it is notable that the hydrido ruthe-nium(IV) species does not exchange protons [by loss ofH+ to give a ruthenium(II) species] with the solvent, end-ing up in the ‘conventional’ catalytic cycle (Schemes 17and 6) that leads to decarbonylation. The recent introduc-tion of bifunctional catalysts by Grotjahn and co-workerswith their spectacularly accelerated reactionkinetics143,144,173 provides an important test-case for mech-anistic postulates, since any mechanistic scheme shouldalso be capable of explaining the accelerations induced bythe phosphinopyridine ligands. Grotjahn notes that py-ridylphosphanes with large substituents R in position C-6are required for anti-Markovnikov hydration catalysis(Figure 3a), whereas small R groups block the catalyst bya P,N,P coordination mode (Figure 3b), and the simplepyridylphosphine (R = H) undergoes irreversible additionto ruthenium-coordinated alkyne.173

Figure 3 Role of the 6-R group in pyridylphosphane ligands.

In a preliminary account on the mechanism of bifunction-al hydration catalysis, Grotjahn suggests that the nitrogenlone-pairs of the pendant pyridyl units serve as generalacid (NH+ form) and base catalysts for the initial alkyneprotonation that leads to the ruthenium(IV)–vinyl speciesin the Wakatsuki mechanism (Scheme 19).173 Unrelatedresearch on catalytic H/D exchange with [CpRu(phosphi-

R

[Ru]

H

R

H

[Ru]H2O

R

H

[Ru]–

OH

R

H

O

H

H

R

H

[Ru]

OH

R

H[Ru]

OH

H

or

H+

– H+

H+

R H

R D

catalytic anti-Markovnikov

hydration

D2O

H2O

RD

O

RH

O

D D

H H

Scheme 19 New mechanistic proposal for anti-Markovnikov hy-dration, which explains the results of deuterium marker studies.172

RD

[RuII]H+

D

[RuIV] R

H

1,2-shift

[RuIV]

D H

R

OH-[RuIV]

DH

R

HO

[RuIV]

O

R

H H

D

D

O

R

H H

+

+

N

R

Ph2P Ru

N

R

Ph2PRu

(S) N

R

PPh2 N

R

PPh2

+ +

small Rlarge R

a) b)



nopyridine)2]+ fragments also hints at a specific role of the

pyridine lone-pairs in activating weakly acidic sub-strates.174 In any case, the riddle of the mechanism of anti-Markovnikov hydration is not yet solved, but fascinatingresults can be expected in the near future!

5 Substrate Spectrum and Selectivity of Catalytic Alkyne Hydration

In this section, applications of alkyne hydration catalyststowards classes of substrates are discussed systematically.The number of application examples in the literature isvery large and only a small selection could be included.Alkynes bearing heteroatoms directly at the alkynyl car-bon have a special reactivity of their own and will not beconsidered in the present review.

5.1 Markovnikov Hydration Catalysis

The discussion of the substrate scope and selectivity isbased on a large part on results that have been obtainedwith mercury(II) catalysts, because these have been usedmost often in the past. Other catalysts with a basicMarkovnikov selectivity will often perform similarly. Ingeneral, hydration of terminal alkynes is compatible witha wide range of functional groups, as is summarized in thefollowing sections.

5.1.1 Terminal Alkynes Bearing Carbon Functionality

Non-functionalized terminal alkynes are hydrated to me-thyl ketones, the exception being acetylene which givesacetaldehyde. The regioselectivity is rather high and alde-hydes are hardly ever reported as side-products. Of the cy-cloalkyl alkynes, ethynyl cyclopropanes have beenhydrated without rearrangement in many cases(Scheme 20),175 but partial or full ring opening occurred inothers.176 Hydration via acetalization using the Hennion–Nieuwland catalyst and ethylene glycol, followed by hy-drolysis of the intermediary dioxolane, was successful.62c

Ethynyl cyclobutanes can also be hydrated.177

Scheme 20 Hydration of ethynyl cyclopropanes.175

The presence of a non-conjugated alkene unit is tolerated,and hydration is selective over oxy-mercuration of alk-enes (Scheme 21).178,179

In the case of conjugated enynes, an a,b-unsaturatedmethyl ketone is formed, which can undergo in situ addi-tion of water or alcohols. These reactions have been ap-plied in industry: vinyl acetylene yields methyl vinylketone180 and 3-methylbut-3-en-1-yne yields methyl iso-

propenyl ketone (Scheme 22a).181 In the presence of waterand alcohols, vinyl acetylene reacts to produce a range of4-alkoxybutan-2-ones (Scheme 22b),182 whereas wateralone adds to give aldol derivatives.183

Scheme 22 (a) Vinyl ketones from vinylacetylenes.181 (b) Aldol de-rivatives from hydration of vinyl acetylene.182

The conversion of conjugated enynes into a,b-unsaturatedketones is synthetically valuable and has been applied toadvanced synthetic intermediates (Scheme 23).184,185

Scheme 23 Alkenyne hydration on advanced intermediates: (a)from the total synthesis of dysidiolide;184 (b) from the total synthesisof tetrodotoxine.185

These reactions are, in principle, also mediated by acidsalone (e.g., formic acid), but in connection with the Rupperearrangement, where the enyne is initially formed byacid-mediated elimination from a propargyl alcohol (sec-tion 5.1.3). Nonconjugated a,w-dialkynes are hydrated todiketones,186,187 see Scheme 11 for catalysis by gold(I).The hydration of a terminal alkyne in the presence of aninternal alkyne was performed selectively with mercu-ry(II) oxide–boron trifluoride–methanol, in cases where amercury(II) sulfate catalyst gave mixtures of diketones.188

Tellurinic acid anhydride acts as a selective hydration cat-alyst for terminal, in the presence of internal, alkynes(Scheme 12).131 For the concomitant hydration of termi-

Cl Cl OCl ClMeOH, 80 °C, 2 h

61%

HgO (2.3 mol%)

H2SO4

Scheme 21 Alkyne hydration in presence of alkenes.179

OH

OH O

HgO, H2SO4

Me2CO, H2O

60 °C, 12 min 81%

O

O

OR

a)

b)

H2O, HOAc

75–85 °C, 3.5 h

HgSO4, H2SO4

80 °C, 12 h

Hg(OAc)2

91% (33% conv.)

60–90%

ROH, H2O

O

OBz

O

OR

OTBS

OiPrO OMe

OHO

OBz

H

OOR

R = TBDPS

HgO (cat.)

H2SO4

MeOH 82%

b)

MeO Me

OBnHg(OAc)2

AcOH 75%

OBn

a)



nal and internal alkynes, see section 5.1.8. The selectivehydration of the terminal alkyne unit in a conjugated di-or tri-alkyne has only been described in a few examples(Scheme 24).189,190 Diacetylene (butadiyne) is hydrated tobutan-2,3-dione (diacetyl) by means of the Hennion–Nieuwland catalyst, via a dioxolane.191

Scheme 24 The selective hydration of a terminal alkyne in a conju-gated dialkyne or trialkyne is difficult to control.189

5.1.3 Terminal Alkynes Bearing Oxygen Functionality

The hydration of propargyl alcohols (available by acetyl-ide addition to carbonyls) is one of the most popular ap-plications of alkyne hydration of all, because it gives a-hydroxyketones in a straightforward manner. Analysis ofthe sequence carbonyl → propargyl alcohol → hydroxy-carbonyl reveals that the acetylide anion is an acyl anionequivalent (Scheme 25).192

Scheme 25 The acetylide anion as an acyl anion equivalent.

Propargyl alcohol gives hydroxy acetone and but-1-yn-3-ol acetoin (3-hydroxybutanone).25e The reaction is appli-cable to enantiopure secondary propargylic alcohols(Scheme 26)193,194 including C-silylated derivatives,which are deprotected in situ.195 On the other hand, the hy-dration of propargyl alcohols is often accompanied by twoacid-mediated propargylic rearrangements, namely theMeyer–Schuster and the Ruppe rearrangements196 whichconcern changes in the oxygen-substitution pattern, butnot the carbon skeleton (Scheme 27).

The acid-mediated generation of a propargyl cation (I) isfollowed by either addition of water to give an allenol (I→ II) that tautomerizes to the Meyer–Schuster product,an a,b-unsaturated aldehyde (from terminal alkynes). Al-ternatively, if I eliminates to vinyl alkyne III, reprotona-tion can lead to alkylidene-allyl cation IV, to which theaddition of water results in an a,b-unsaturated ketone, theRuppe product.

Scheme 27 The Ruppe and Meyer–Schuster rearrangements.

Both products might principally result from one substrate,but in practice, Meyer–Schuster products are obtained ei-ther from propargyl cations (I) that cannot undergo elim-ination for lack of b-hydrogens, or by use of specific metalcatalysts.197 Otherwise, Ruppe products are formed underusual, acidic conditions.

The Ruppe and Meyer–Schuster rearrangements can in-deed interfere with the hydration of propargyl alcohols, asis seen with gold(I) catalysts (section 3.3.5).120,121,125

However, the experience with mercury(II) catalysts is thateven sensitive substrates are hydrated with high yields(Scheme 28a).198 The hydration product of ethynylatedcamphor is a useful chiral auxiliary for acetate aldol reac-tions (Scheme 28b) with high diastereomeric excess-es.58,199

Literature reports on ring-expansions of ethynylatedsteroids200 imply that rearrangements might interfere withcertain tertiary substrates. In such cases, stoichiometricamounts of mercury (sulfon)amide complexes are recom-mended to bring about the reaction without rearrangement(Scheme 29).65,66

HO

OH

HO

OH O

11%HgSO4 H2SO4

H2O, MeOH, 16 h

O

R2

R1

O

HO

R2R1

H2O

cat.HO

O

R2R1

acyl anion equivalent

Scheme 26 Synthesis of enantioenriched a-hydroxyketones: (a)Ref.193 (b) Ref.194 (c) Ref.195

OH

TBSO

OH

TBSO

O

O

OBn

MeBnO

OHOBnO

OBn

MeBnO

OH

O

OBn

TMS

OH

n-Bu O

OH

n-Bu

a)

b)

c)

HgO

H2SO4

EtOH

HgO

H2SO4

H2O, Me2CO

1 h, r.t., 90%

HgSO4

H2SO4, H2O

THF, 94%

HOH+

H2O

OHO

H+

H+

OHO

Meyer–Schuster

product

Ruppe product

I

II

III

IV

– H+



Scheme 29 (a) Rearrangement of ethynylated steroids on attemptedhydration.200 (b) Stoichiometric hydration without rearrangement.66a

The hydration of propargylic alcohols (or esters) is alsothe standard method for setting up the a-hydroxy-acetyl-cyclohexane fragment in syntheses of tetracycline naturalproducts (Scheme 30).201,202,203

Scheme 30 Alkyne hydration in tetracycline synthesis.201

Since a-hydroxyketone synthesis is a major application ofmercury-catalyzed hydration in synthesis, it would be de-sirable to have less toxic alternative catalysts for this reac-tion. A range of metal salts has been tested in thehydration of 2-methylbut-3-yn-2-ol, but satisfactory re-sults were only obtained with copper(II) trifluoro-methanesulfonate or copper(II)/Nafion, and the reactiontimes were very long (>70 h).78 As mentioned above,gold(I) catalysts give Meyer–Schuster side-productswhereas sodium tetrachloroaurate(III) was unreactive to-wards propargyl alcohols.97

Homopropargyl alcohols have been hydrated to aldol de-rivatives,204 and the reaction is suitable for enantioen-riched compounds (Scheme 31). 1-Alkyn-5-ols can behydrated via hydroalkoxylation with silver carbonate andhydrolysis of the intermediary heterocycle.117 Remote al-cohols do not interfere with hydration.56 Propargyl ethersalso hydrate well (Scheme 32),205–207 and the reaction hasoften been used to prepare acetonyl ethers from propargylethers, like methoxy acetone25e or higher derivatives.206

Scheme 31 Synthesis of enantioenriched aldols by hydration.204

Scheme 32 Acetonyl ethers from catalytic hydration of propargylethers. (a) Ref.205 (b) Ref.207 (c) Ref.206

Homopropargyl ethers bearing a stereogenic center givealdol derivatives on hydration (Scheme 33).59 The exam-ple features the use of weakly acidic conditions. The cat-alyst combination chloro(triphenylphosphine)gold(I)[AuCl(PPh3)]/silver hexafluoroantimonate(IV) in wetdichloromethane, or simply sodium tetrachloroaurate(III),also hydrate the triple bond of homopropargyl ethers, butat the same time induce reversible b-elimination.208

Scheme 28 (a) Sensitive propargyl alcohols can be hydrated with-out rearrangements.198 (b) Hydration of a camphor-derived propargylalcohol gives a useful chiral auxiliary.58,199

Ph

OH

Ph

OH

O89%

HgO, H2SO4

THF, 80 °C, 2 h

OH

O

OH

OH

O

1) LDA

2) MeCHO

OH

O OH

70% (dr = 96:4)

HgO, H2SO4

Me2CO, H2O

60 °C, 1.75 h90%

(a)

(b)

OH OOAc

OH

H

OH O

H

HgO

BF3·OEt2

1. Hg(NHTs)2

2. H2S

a)

b)

HOAc

O

O

OH

OH

OH

O

O

OH

OH

OH

O

OMe OMe

HgOH2SO4

70 °C4 h 40%

Cy

OH

Cy

OH OHgSO4, H2SO4

THF, H2O86–88%

OMe

O

OMe

OBn

(CH2)3OBn

Me

O

OBn

(CH2)3OBn

Me

ArO ArO

O1) HgO, BF3·OEt2MeOH, CCl3CO2H

a)

b)

c)

HgO, H2SO4

50%

MeOH

60 °C

2) HCl (aq), Me2CO

heat, 2 h

HgCl2

Scheme 33 Hydration of an a-propargyl tetrahydropyran.59 PPTS =pyridinium p-toluenesulfonate.

O

OTIPS

OPMB

O

O

OTIPS

OPMB

Hg(OAc)2, PPTS

THF, H2O

45 °C, 1.5 h

86%



The epoxide of an ethynyl oxirane209 and also peroxidegroups210 are tolerated in alkyne hydration. Aldehydes canbe present in the starting material.56,211 Several acetalgroups, including the tetrahydropyranyl (THP)60 protect-ing group, survive hydration reactions. Ketones are obvi-ously not problematic. If the less active palladium(II)catalysts are used, the presence of a ketone (or an alcohol)is even required, because the reaction proceeds via anchi-meric assistance (Scheme 34)96 The hydration of a-prop-argyl ketones is part of a cyclopentenone annulationsequence (ketone → a-propargylketone → 1,4-diketone→ cyclopentenone) that has found much use in synthesis(Scheme 34b).212,62a,213

Scheme 34 1,4-Diketone synthesis via anchimerically assisted hy-dration with palladium(II) catalysts. (a) Ref.96 (b) Ref.212a

Non-enolizable b-diketones64 or b-keto esters ormalonates214 bearing an a-propargyl substituent are readi-ly hydrated; the Hennion–Nieuwland acetalization cata-lyst has been used.62a Unprotected carboxylic acids arealso hydrated,64,215 as are carboxylic acid esters. A five-membered-ring lactone was hydrated to give either of twoepimeric products, depending on the reaction conditions(Scheme 35).216

Scheme 35 Stereoselective hydration of a lactone.216

With regard to conjugated alkynones and propiolates, pro-piolyl compounds without substitution at the alkyne unitare hydrated with Markovnikov selectivity (Scheme 36),217

implying that the p-acceptor influence is overridden bythe carbon–hydrogen versus carbon–carbon bond dona-tion argument; the outcome is different with internalalkyne substrates (section 5.1.9).

Scheme 36 Hydration of unsubstituted propiolyl derivatives.217b

5.1.4 Terminal Alkynes Bearing Nitrogen Functionality

N-Heterocyclic ethynyl compounds218 are hydrated toregular acetyl products, even with strongly p-acceptingheterocycles that otherwise readily undergo base-cata-lyzed conjugate addition of methanol in the inverted sense(Scheme 37a).218a A sequence of Sonogashira couplingwith trimethylsilylacetylene followed by catalytic hydra-tion is therefore a general method for acetylating hetero-cycles.218 Amines have been hydrated in acidic media(Scheme 37b),219,220 and propargylamines give a-amino-ketones.219,221

Scheme 37 Hydration of nitrogen bases: (a) ethynylquinoline;218a

(b) hydration of a tertiary amine in mineral acid solution.220

Propargylamides react readily because of anchimeric as-sistance of the amide group. They have been hydratedwithout a catalyst in water at 150 °C,222 in dilute sulfuricacid at 60 °C (Scheme 38a)223 or by a range of metal cat-alysts.116 Nitriles are tolerated by the mercury(II) oxide–sulfuric acid reagent,224 as are nitro groups,225 an-thraquinone imines,226 and diazo ketoesters.60 Hantzschesters were hydrated without catalyst decomposition byreduction.227

Scheme 38 Hydration of N-functionalized substrates: (a) amides;223

(b) Hantzsch esters (Ar = 2,3-dichlorophenyl).227

O O OPdCl2(MeCN)2

H2O, MeCN

r.t., 24 99%

a)

b)

O

OMe

1. HgO, H2SO4

MeOH, H2O

60 °C, 1 h, quant.

89%

O

MeO 2. t-AmONa, PhH

O OMe

n-Bu

O

O

Me

n-BuOHgO (1 equiv)

H2SO4 (0.04 equiv)

r.t., 1 h, 94%

O

O

Me

n-BuOHgO (1 equiv)

H2SO4 ( 3 equiv)

r.t. 48 h, 85%

DBU

r.t., 98%

HgSO4, H2SO4

EtOH, 80 °C, 6 h

O O

O

55%

NOEt

OEt

N

OEt

O

OEt

N N

O

HgSO4, H2SO4

Me2CO

60 °C, 2 h 75%

HgSO4, H2SO4

H2O, 85–90 °C

6 h 89%

a)

b)

ClNH

O

ClNH

O

O

H2SO4 (aq)

60 °C

a)

b)

dioxane

H2O

60 °C, 2 h88%

HgSO4

H2SO4

NH

CO2Me

EtO2C

Ar

ONH

CO2Me

EtO2C

OO

Ar



5.1.5 Terminal Alkynes Bearing Sulfur Functionality

Propargyl thioethers are hydrated under the usual condi-tions with mercury catalysts.228 The hydration of tertiarypropargyl alcohols in acetic acid in the presence of a thiolleads to a-alkylthioketones (Scheme 39).229 Hydrationshave also been performed in the presence of sulfoxides230

and sulfones (using the Hennion–Nieuwland catalyst).231

Scheme 39 Hydration of sulfur-containing substrates. (a) Ref.228 (b)Ref.229

5.1.6 Terminal Alkynes Bearing Halogen and Other Functionality

The hydration of trifluoropropyne is notable because ke-tone-to-aldehyde ratios of 2:1232a or 85:15232b have beenobserved, as a result of the inductive effect of the trifluo-romethyl group. Other alkyl halogenides give regular re-sults.233 1-Bromo- and 1-iodoalkynes are hydrated to a-haloketones.234

5.1.7 Hydration of Non-Functionalized Internal Alkynes

A certain lack of regioselectivity is characteristic in thehydration of internal alkynes without specific functional-ity. The problem is absent with symmetrical internalalkynes, such as 4-octyne125 or cycloalkynes235

(Scheme 40).

Scheme 40 Hydration of symmetrical alkynes. (a) Ref.125 (b) Ref.235

The regioselectivity of hydration of non-symmetrical di-alkyl alkynes with an aqueous mercury(II) catalyst hasbeen investigated,236 and complementary information forplatinum(II) catalysts is available.103 From these results(Figure 4), it appears that the oxygen of water usually

adds to the acetylene carbon which bears the morebranched alkyl group, which is in line with steric and elec-tronic effects (section 4), though exceptions (such as i-Prvs Me) exist, and medium- and ligand-effects are also im-portant. In any case, high regioselectivity is typically notachieved. The upcoming sections present many exampleswhere regioselectivity is achieved by virtue of functional-ity within the substrate.

Figure 4 Regioselectivity of hydration of internal alkynes; arrowsand numbers indicate percentage of attack of OH at the respective car-bon. Data for Hg in aqueous solution: Ref.236; for Hg in other solvents,and for Pt in THF: Refs.101–103 ‘Zeise’ = Zeise’s dimer.

5.1.8 Internal Alkynes Bearing Carbon Functionality

A bicyclic alkynyl cyclopropane was hydrated regioselec-tively, as a result of the cation-stabilizing property of thecyclopropyl group (Scheme 41a).237 Nonconjugated al-kenynes are sometimes hydrated with high regioselectivi-ty, perhaps owing to pre-coordination of the metal catalyst(Scheme 41b).238

Scheme 41 Regioselective hydration of internal alkynes induced bycarbon functionality. (a) Ref.237 (b) Ref.238

Nonconjugated di- and tri-alkynes are hydrated with highregioselectivity in a cascade reaction (Scheme 42) thatleads to 1,4-diketones and 1,4,7-triketones.239 An initialMarkovnikov hydration of the terminal alkyne is followedby carbonyl-group-directed regioselective internal hydra-tions (see below).

PhS

OH

PhS

OH

O

THF, H2O

80 °C, 1 h62%

OH SBn

O

BnSH

Hg(OAc)2 (4 mol%)

a)

b)

AcOH, H2SO4

Hg(OAc)2

p-TsOH

63%

C3H7 C3H7

AuMe(PPh3)H2SO4

MeOH, H2O70 °C, 5 h

C3H7C3H7

O

92%

55

OHgSO4, H2SO4

dioxane, H2O

a)

b)

58% (Hg) 56% (Hg)

54% (Hg)

65% (Hg)

69% (Hg; MeOH)

58% (Hg; Me2CO)Zeise: 71%

PtCl2: 64%

PtBr2: 74%

PtI2: 78%

(in THF)

62–65% (Pt)

Zeise: 76%

PtCl2: 65%

PtBr2: 78%

PtI2: 61%

50% (Hg; MeOH)

(in THF)

Hg (MeOH)

50:50

or:

or:

or:

O

HgSO4 (aq)

H3PO4

quant.

CHCl3, MeOH

r.t., 24 h

a)

OHgSO4

H2O, EtOH

b)



Scheme 42 Regioselective cascade hydrations of internal al-kynes.239

Conjugated internal dialkynes are hydrated by concentrat-ed sulfuric acid.240 An a,b-unsaturated ketone is initiallyformed at low temperatures and further hydrated to a 1,3-diketone (Scheme 43).240 A mercury catalyst directlyleads to a mixture of 1,3-diketone with a little 1,4-dike-tone. Higher (tri- and tetra-) alkynes react sluggishly.240

The regioselectivity of the acid-catalyzed route is due toresonance stabilization of the conjugated carbocation, fol-lowed by a 1,4-addition.

Scheme 43 Hydration of an internal diyne.240

Terminal alka-1,3-diynes are doubly hydrated to alka-2,4-diones; the reaction is initiated by regioselective hydra-tion of the terminal alkyne unit.190 Butadiyne–ketone ad-ducts undergo the Ruppe rearrangement in formic acid,followed by an acid-catalyzed conjugate hydration to a2,4-dione (Scheme 44). The mercury(II)-catalyzed hydra-tion leads to a furanone instead.241 The acid-mediatedreaction sequence was used in the synthesis of a di-noflagellate metabolite (Scheme 44, inset).241

Scheme 44 Buta-1,3-diyne–carbonyl adducts give unsaturateddiones by Ruppe rearrangement and conjugate hydration.241

The hydration of internal mono- and di-alkenyl alkyneshas been studied intensively by Nazarov and co-workers,and later, by others.242–244 A single alkenyl group directsthe attack of OH to the alkyne carbon to which it is at-tached. In doubly alkenyl-substituted alkynes, OH adds tothe carbon which bears the higher substituted alkenylgroup (Scheme 45a,b).242 The resulting alkenyl ketonescan further add water or alcohols from the reaction medi-um (Scheme 45b).242,243 By acid-catalyzed elimination,such adducts have been converted into bis-a,b-unsaturat-ed ketones, and in the course of such studies, a new reac-tion was discovered: the Nazarov cyclization of dialkenylketones to cyclopentenones (Scheme 45c)!243,244

Scheme 45 Hydration of alkenyl alkynes, and secondary reactions.(a) Ref.242a (b) Ref.242b (c) Ref.243

5.1.9 Internal Alkynes Bearing Oxygen Functionality

Alcohols exert a profound influence on the regioselectiv-ity of hydration of internal alkynes by electronic andneighboring group effects; oxygen heterocycles can be in-termediates, and the reaction is best carried out usingUtimoto’s palladium(II) catalyst, which does not catalyzethe direct hydration of triple bonds.94 Both alk-3-yn-1-olsand alk-4-yn-1-ols selectively give 4-ketoalcohols by in-termediacy of dihydrofurans and derived hemiacetals,whereas 5-alkynols give 5-ketoalcohols by intermediacyof dihydropyrans (Scheme 46).94

Scheme 46 Regioselective hydration of alkynols.94

O

O

O

O

O

Hg(II)

H2O

Hg(II)

H2O

a)

b)

1. H2SO4

–20 °C, 45 min O

2. H2O

45%

OO

Hg(II)

O

O

H+(0:100)

(20:80)

OH HCO2H

74%

O O

O

OHg(II)

40%

O O

HO

O

OMe O

O

a)

b)

c)

60 °C

HgSO4, H2SO4

HgSO4, H2SO4

HgSO4

MeOH

MeOH, H2O

R

OH

R

OH

R

OH

ROH

O

R OH

O

ROH

O

as above

as above

PdCl2

H2O, MeCN



The reaction has found several applications,94,95,98,245 as inthe synthesis of a peach moth sex pheromone(Scheme 47).245

4-Arylbut-3-yn-1-ols can be prepared by the Sonogashiracoupling of aryl bromides with but-3-yn-1-ol and a palla-dium catalyst; work-up of the reaction mixture with aque-ous hydrochloric acid in air is accompanied by hydrationof the triple bond, presumably by the catalytic action ofpalladium(II) chloride.95,246 An important family of sub-strates are the but-2-yne-1,4-diols, available from doubleaddition of acetylene to carbonyl compounds.25d The par-ent but-2-yne-1,4-diol is catalytically rearranged to hy-droxymethyl vinyl ketone (Scheme 48),25e which is eitherdistilled from the reaction solution, or hydrated further tobutan-2-one-1,4-diol.25e,247 In the presence of alcohols, 4-alkoxy-1-hydroxybutan-2-ones are formed.25e,248,249 Cat-ionic gold(I) also catalyzes the latter reaction efficiently(5500 turnovers).123b A technical synthesis of histaminewas developed based on but-2-yne-1,4-diol hydration(Scheme 48).25e

Scheme 48 Products from hydrative rearrangements of but-2-yne-1,4-diol.25e,248,249

With substituted but-2-yne-1,4-diols, the reaction takes adifferent course and releases alkylated furan-3-ones(Scheme 49).25e,250–253 Strictly speaking, the overall reac-tion is not a hydration, but a (cyclo)isomerization. Un-symmetrical diols give mixtures of regioisomers, but ifone alcohol is primary and the other tertiary, high regiose-lectivity can be achieved (Scheme 49b).252

The regioselective hydration of internal alkynes bearingethers or thioethers was investigated with a platinum(II)catalyst [Zeise’s dimer, {PtCl2(C2H4)}2] (Figure 5).103 Re-mote ether groups affect regioselectivity by precoordina-tion of the catalyst, placing the metal center ‘closer’ to onealkyne carbon. The results are in line with a higher coor-dinating power of a methyl ether over an ethyl ether, or ofa thioethyl ether over an ethyl ether donor. The s-acceptoreffect of the alkoxy group may play an important role inpropargyl ethers.103

Figure 5 Regioselectivity of hydration with Zeise’s dimer as cata-lyst. Arrows and numbers indicate site and extent of attack by OH.103

Nonconjugated alkynyl aldehydes and ketones are oftenhydrated regioselectively through anchimeric assistance,via heterocyclic intermediates (Scheme 50).94,254 Alkynesthat are separated by two methylene units from a carbonyl(acyl) group give 1,4-diketones on hydration with a mer-cury(II) catalyst, whereas alkynes separated by threemethylene units give 1,5-diketones.254 The former reac-tion, via a kinetically favored five-membered ring inter-mediate, is faster than the latter, and the latter faster thanhydration without anchimeric assistance.254 The protocolhas been applied to a synthesis of cis-jasmone,254b and toother cases (see Scheme 42).213,239

Utimoto and co-workers found that the same type of re-gioselective hydrations are also catalyzed by palladi-um(II) chloride and, with lower selectivity, by sodiumtetrachloroaurate(III).96,97 Cyclohexanones bearing a-alkynylalkyl substituents gave the expected 1,4-ketonesas hydration products, but cyclopentanone derivativesgave 1,5-diketones instead (Scheme 51). Hydrations of

Scheme 47 Synthesis, via hydration, of a peach moth pheromone.245

C10H21

OH

C10H21

LiNH2

O

PdCl2 (3 mol%)

C10H21

HO

O

1) PCC (76%)

2) NaHMDSC7H15PPh3Br

60%

55%65%

H2O,

MeCN

0.5 h

reflux

OC10H21

C6H13

OHHO

HO

O

OH

BnO

O

OH54%

O

OH

BnOH

37-58%

CuSO4, NH3, CH2O

NH

NHO 1) SOCl2

2) NH3

NH

NH2N

HgSO4

H2O

histamine

Scheme 49 Furan-3-ones from hydrative rearrangement of 1,4-al-kylated but-2-yne-1,4-diols. (a) Ref.251 (b) Ref. 252

HO

OH O

O

OH

OH O

ONafion/Hg(II)

62%

up to 90%

HgO/H2SO4

H2O

a)

b)

EtEt

OEt

Et

OEt

Et

OEt

Et

OEt

Et

OMe

Et

SEt

60%

55%

65%

86%

95%

88%

94%



b,g-acetylenic ketones usually lead to furans, unless the a-position of the ketone is blocked by a non-hydrogen sub-stituent.97 Further applications of the palladium(II)-cata-lyzed protocol have been reported.95

Scheme 51 Regioselective hydrations of cycloalkanones bearingexocyclic alkynes.96

Internal alkynes bearing a p-accepting substituent (e.g., acarbonyl group) are always hydrated in the sense of a con-jugate addition to give b-keto compounds, or products de-rived therefrom. The reaction is mediated byconcentrated255 (Scheme 52) or dilute256 sulfuric acid, bytrifluoromethanesulfonic acid,36 and also by a range ofmetal catalysts: mercury(II),257 silver(I),118 gold(III),258

platinum(II) (Scheme 54),103,259 platinum(IV),105,106 andpalladium.260

By far the most common method to hydrate p-acceptoralkynes, including propiolic acid derivatives (amides, es-ters, nitriles), is the Moureu method, which is a stoichio-metric conjugate addition of primary or secondary amines(hydroamination), followed by an acid-mediated hydroly-sis of the intermediary enamine (Scheme 53).49,50,51

This mild method has seen many applications(Scheme 53), also in total synthesis (Scheme 53b,c).Scheme 53c shows a remarkably mild hydration of a p-ac-ceptor aryl-substituted alkyne.51 Related alternative meth-ods to the Moureu procedure include the base-catalyzedaddition of ethylene glycol to p-acceptor alkynes that

leads to hydrolyzable dioxolanes (Scheme 4), or the base-catalyzed conjugate addition of oximes to alkynoates, fol-lowed by a base-mediated elimination; this method doesnot require acidic conditions at any stage.261

5.1.10 Internal Alkynes Bearing Nitrogen and Other Heterofunctionality

Alkynes bearing an amine functionality are hydrated re-gioselectively with the OH group adding to the alkynecarbon that is more remote from the amino group; thismay be due to the strong inductive effect of the ammoni-um group.262 The reaction is very useful for propargyl-amines,262 which can eliminate to vinyl ketones263,264

(Scheme 54a) that serve as Michael acceptors in Robin-son-annulation-type steroid syntheses (Scheme 54b).264

Scheme 50 (a) Regioselective hydration directed by carbonylgroups.254a (b) Synthesis of cis-jasmone by directed hydration.254b

R (CH2)n

OO O

(CH2)n

O

R

M +

n–1

via:

M+ H2O

n = 2, 3

Et

OHgSO4, H2SO4,MeOH

1. hydration

2. NaOH (aq)

O

Et

a)

b)

cis-jasmone

O OO

O

n-Bu

O

n-Bu

O

MeCN, H2O

r.t., 3.5 h

ultrasound 98%

96%

MeCN, H2O

r.t., 10 h

ultrasound

PdCl2(MeCN)2

PdCl2(MeCN)2

Scheme 52 Hydration of internal acceptor alkynes: a) with strongacid;255 b) catalyzed by Pt(II).259

CO2Me

CO2Me

CO2Me

CO2Me

O

O1. H2SO4

–10 °C

78%

MeO2C

OH

R

OO R

OH{PtCl2(C2H4)}2

(2 mol%)

a)

b)

MeOH–H2O

reflux

2. –5 °C, 4 h

3. H2O

Scheme 53 Applications of the Moureu method for hydration of p-acceptor alkynes. (a) Ref.50b (b) Ref.50c (c) Ref.51

Ph

CO2Me

Ph

CO2MeO1. piperidine

PhH, reflux

2. oxalic acid

Et2O, H2O

a)

1. morpholine

THF, reflux

2. HCl (aq)OTBS

MeO

MeO

OO

OMe

CO2Et

Me

Ph

b)

EtO2C

OMe

O

BnO

CO2Me

NO2

O

O

OTBS

OBn

CO2Me

O2N

OO

OTBS

O

1. pyrrolidine

PhH, r.t., 1 h

2. HOAc, H2O

r.t., 4 h 90%

c)

54%

75%



Scheme 54 Catalytic hydration of propargylamines as entryinto vinyl ketone chemistry: (a) preparation of a vinyl ketone;263

(b) Michael addition with an in situ generated vinyl ketone.264

5.1.11 Hydration of Internal Aryl Alkynes

The aryl substituent directs attack of water to the pseudo-benzylic position (the carbon it is bound to) in internalalkynes. Hydration with acid catalysts proceeds with rela-tive ease,41 especially if the arene bears p-donor substitu-ents; hydration is then mediated by p-toluenesulfonic acidin hot ethanol (Scheme 55a),33 formic acid (Scheme 3),42

aqueous trifluoroacetic acid40 or the reagent sodium sul-fide–hydrochloric acid–methanol.35

Scheme 55 Hydration of internal aryl alkynes. (a) Ref.30 (b) Ref. 266

The metal-catalyzed reaction also proceeds with ease forelectronically activated substrates,265 but the electronic in-fluence of an arene is overridden by the directing powerof an anchimeric carbonyl group (Scheme 55b).213,266 If analkyne is substituted by two aryl groups, water adds nextto the more electron-rich group.33,267b

5.1.12 Hydration of Internal Hetaryl Alkynes

A range of donor-substituted hetaryl alkynes undergo re-gioselective hydration to hetaroylketones under mild con-

ditions, for example in aqueous trifluoroacetic acid (TFA;Scheme 56)40 or in p-toluenesulfonic acid–methanol,268

by the reagent sodium sulfide–hydrochloric acid–metha-nol,35 and also under mercury(II) catalysis.269

Scheme 56 Hydration of an indolyl-alkyne in trifluoroacetic acid.40a

On the other hand, electron-poor, strongly p-accepting in-ternal hetaryl-alkynes, such as pyridines and quinolines,display an inverted regioselectivity of hydration.267b,270

The importance of the p-accepting/donating substitutionpattern is illustrated by an example from the isoxazole se-ries (Scheme 57).267

Scheme 57 Variable regioselectivity of hydration due to differentp-donor/p-acceptor substitution patterns.267

5.2 Anti-Markovnikov Hydration Catalysts

The substrate range and applications of anti-Markovnikovhydration catalysis are discussed in section 3.4 along withthe catalysts, for convenience.

6 Reactions Related to Catalytic Alkyne Hydration

Apart from the straightforward catalytic hydration reac-tions, a range of transition-metal-catalyzed hydrative cou-pling reactions of two alkynes with one molecule of water,or of an alkyne, an acceptor alkene and one molecule ofwater, have been described recently (Scheme 58).271–273

The example (a) in Scheme 58 can be analyzed as aMarkovnikov-type hydration, followed by conjugate ad-dition of the intermediary ruthenium enolate to anenone,273a whereas in example (b), a ruthenium–acyl spe-cies derives from an initial anti-Markovnikov addition

Et2NOEt

HgSO4

H2SO4 (aq)

OEt

O

NEt2

O O

Me

80 °C, 1.5 h

a)

b)

OMe 1. HgSO4, H2SO4

H2O, 75 °C, 1 h

2. KOH, MeOH

OO

O

Me

MeO

O

MeO H+

MeO n-Bu80 °C, 60 h

MeO

n-Bu

O

Ph

O Ph

PhPh

O Ph

Ph

O

PdCl2(PhCN)2

60%

b)

a)

81%

MeCN, H2O,

60 °C, 4 h

p-TsOH, EtOH

O

NR2

R3

R1HN

NH

OR

O

NR2

R3

R1HN

NH

OH

O

TFA–H2O

(95:5)

NO

Ph

Bu

HgSO4, H2SO4

Me2CO–H2O NO

Ph

Bu

O

NO

Me

Ph

HgSO4, H2SO4

Me2CO–H2O

NO

Me

Ph

Bu

O Bu

85%

66%



pathway, before it is quenched by an intramolecular con-jugate addition.273c These reactions follow defined donor/acceptor patterns, but in cyclization (b), two alkynes prob-ably react via a ruthenacycle mechanism.273b An intramo-lecular rhodium-catalyzed version, which couples twoterminal alkynes and one water to give an a,b-unsaturatedketone, has also been realized.272 The intramolecular hy-dration/cyclization of ene-1,2-diynes represents a remark-able synthesis of phenols (Scheme 58d).273d These fewexamples of hydrative coupling reactions merely illustratethe potential of such methods for applications in synthe-sis, as a detailed treatment is out of the scope of this re-view article.

7 Conclusions and Outlook

Alkynes can be hydrated catalytically to give synthetical-ly useful carbonyl compounds. The reaction has an enor-mous potential for synthesis, and its importance willprobably grow further in the context of sustainable chem-istry, since catalytic hydrations can generate products in afully atom-economic way from unsaturated hydrocarbonfeedstocks and water.

It cannot be denied that Kucherov’s original catalyst iscurrently still the best developed and most generally ap-plicable for Markovnikov hydration of terminal and inter-nal alkynes, with a remarkable functional group tolerance.There is clearly a need for new, widely available and en-

vironmentally more tolerable catalysts. Research hasshown that many metal and acid catalysts will hydratealkynes under suitable conditions. Already, palladium(II)catalysts are preferred over mercury(II) catalysts forregioselective hydrations of internal alkynes with anchi-meric assistance. Currently, the best-developed non-mer-curial catalysts for Markovnikov-selective alkynehydration are cationic gold(I) species, followed bygold(III) and platinum(II) catalysts. Considering the veryhigh catalytic activity of cationic gold(I) complexes, theyare certainly capable of replacing mercury(II) in many ap-plications; the commercial availability of the catalyst pre-cursor [AuMe(PPh3)] is helpful in that respect.274 A majorproblem in Markovnikov hydration chemistry currently isthe lack of a highly active and selective non-mercurial cat-alyst for the hydration of propargyl alcohols to a-hydroxyketones.

Additional research will be needed to find new principlesfor catalyst- (rather than substrate-) controlled regioselec-tive hydrations of internal alkynes. Additional theoreticaland experimental studies on the mechanism(s) of metal-catalyzed hydration will also be welcome.

Catalytic anti-Markovnikov hydration of terminal alkynesis a new and very promising reaction with many potentialapplications in organic synthesis. Intriguingly, mechanis-tic aspects are not yet fully clarified. Within only a fewyears of the discovery of the reaction, new catalysts withastonishing levels of activity and selectivity have been de-veloped. Studies on the use of anti-Markovnikov hydra-tion in synthesis have just begun. It will be interesting tosee whether metals other than ruthenium(II) can catalyzethe reaction.

Finally, the potential of hydrations, catalyzed or mediatedby water, acids or bases, in the absence of any metal cat-alyst, should be kept in mind. Astonishingly mild reactionconditions have been found for the hydration of suitablyactivated donor or acceptor substrates.

Acknowledgment

We thank the Deutsche Forschungsgemeinschaft (Emmy NoetherProgramm) for support of our work in the field of alkyne hydration,and Prof. Carsten Bolm, RWTH Aachen, for continued support.

References

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http://webbook.nist.gov/chemistry/ (accessed January 2007). Note that phase-changes will affect DrG/DrH.

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Scheme 58 Hydrative couplings of alkynes. (a) Ref.273a (b) Ref.273b

(c) Ref.273c (d) Ref.273d

O

CpRu(COD)Cl (5 mol%)

In(OTf)3 (20 mol%)

NH4PF6 (10 mol%)

81%DMF–H2O,

100 °C, 4 h

(a)

+

(b)

O[Ru3Cl5(dppm)3]PF6

OO

X

(c)

X

O

[CpRu(MeCN)3]PF6 (5 mol%)

H2O, Me2CO, 60 °C, 2 h

70–99%

H2O, dioxane,

120 °C, 12 h 48%

NC

NC

O O

OHH2O, 3-pentanone

100 °C, 24 h

(d)

[Ru(MeCN)2(PPh3)(HBPz3)]PF6

(10 mol%)

77%



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(274) The price of 1 g of AuMe(PPh3) corresponds to that of 1 kg of mercury(II) sulfate!

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