MICROREVIEW
DOI: 10.1002/ejoc.200((will be filled in by the editorial staff))
Coinage metal catalysts for the addition of O–H to C=C bonds
Elena M. Barreiro,[a] Luis A. Adrio,[b] King Kuok (Mimi) Hii[a] and John B. Brazier*[a]
Keywords: ((Copper / Silver / Gold / Alkenes / Allenes))
The direct addition of O–H bonds to C=C bonds is a very attractive
way of synthesising alcohols, ethers and esters due to the inherent
atom- and step-economy of the process. This micro-review focuses
on the development of group 11 metal catalysts in mediating these
transformations.
Brønsted acid catalysis has been shown to play a role in some of
these processes and this is highlighted where appropriate. The
utility of these methods in organic synthesis is addressed
through selected examples.
____________
[a]
[b]
Department of Chemistry, Imperial College London, South
Kensington, London SW7 2AZ, U.K.
Fax: +44-(0)20-75945904
E-mail: j.brazier@imperial.ac.uk
Laboratorio de Compuestos Organometálicos y Catálisis,
Departamento de Química Orgánica e Inorgánica, Universidad de
Oviedo, Julián Clavería 8, E-33006 Oviedo, Spain.
The shortcomings of these methods demonstrate the need for a
new approach: the direct/formal addition of O–H to C=C bonds,
with control of chemo-, regio- and stereo-selectivities under mild
reaction conditions.
1. Introduction
Traditionally, there are three general ways of converting alkenes
into alcohols. The first route requires protonation of the C=C bond
to form a carbocation intermediate, which is then attacked by water
to give an alcohol (Scheme 1, eq. 1). Selective formation of the
thermodynamically-preferred
carbocation
results
in
the
Markovnikov addition product. The process is not widely adopted
in organic synthesis as harsh reaction conditions (strong acids and
high temperatures) often lead to competitive side-reactions, such as
rearrangement of the carbocation intermediate. More
problematically, the process can be thermodynamically
unfavourable (the reverse reaction being elimination), particularly
for intermolecular reactions involving stabilised oxygen
nucleophiles.
Oxymercuration followed by reduction of the resulting carbon–
metal bond provides a milder route to the same Markovnikov
addition products (Scheme 1, eq. 2). The method avoids formation
of carbocation intermediates and hence obviates the possibility of
rearrangement side-products.[1] Nevetherless, the high toxicity of
the stoichiometrically produced mercury waste and the drive
towards environmentally benign industrial processes make this an
unattractive method for the addition of O–H to C=C bonds.
The third route involves hydroboration of the C=C bond
followed by oxidative cleavage of the trialkylborane intermediate,
to provide the alcohol under mild reaction conditions (Scheme 1,
eq. 3). In this case, good selectivity for the anti-Markovnikov
hydration product is observed, as the formation of the less
sterically hindered borane is kinetically favoured. The process is
widely adopted in organic chemistry, and asymmetric variants have
been developed using either chiral boranes[2] or chiral transition
metal catalysts.[3] Unfortunately, the process suffers from poor
atom-economy, generating a stoichiometric amount of borate waste
and the oxidative workup is not compatible with fragile functional
groups.
Scheme 1. Tradition routes for the addition of O–H to C=C bonds.
In this regard, catalytic hydrofunctionalisation of C=C bonds can
offer considerable step and atom-economy for these processes.[4]
The field has flourished in recent years due to a growing interest in
developing more sustainable chemical processes. While there are
many recent reviews on hydroamination reactions (N–H
addition),[5] less attention has been given to the corresponding
addition of O–H to C=C bonds.[6] In this micro-review, we
highlight the contribution of group 11 metal catalysts in this area;
specifically, the 1,2-addition of O–H (alcohols, phenols or acids) to
three types of C=C bonds: unactivated alkenes, conjugated alkenes
and allenes. O–H addition to electron-deficient olefins such as
acrylate (oxa-Michael reaction) is excluded, as these reactions are
more generally catalysed by Lewis acids.[7] The involvement of
Brønsted acid catalysis in certain reactions is also discussed.[8]
2. Addition to unactivated alkenes
2.1 Intermolecular additions
In 2005, He reported the first examples of gold(I)-mediated
addition of phenols and carboxylic acids to simple olefins, under
relatively mild conditions (Scheme 2).[9] Across a range of alkenes,
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the selectivity was for the Markovnikov products. In the case of
homoallylarenes and 1-hexene, side-products were observed,
formed from isomerisation of the C=C bond prior to reaction with
the nucleophile. Four equivalents of olefin were used in all cases,
although much of this could be recovered at the end of the reaction.
A year later, the same group showed that 5 mol-% triflic acid could
catalyse many of the same transformations, although milder
conditions are required to prevent decomposition.[10]
A few years later, a very similar catalytic system was reported
by Tokunaga and co-workers,[11] for the direct hydroalkoxylation
of unactivated alkenes by HOCH2CH2X (where X = halogen or
alkoxy groups). In this case, the replacement of PPh3 in the
previous system with the electron-deficient P(C6F5)3 was found to
enhance the reaction. Notably, the addition to 1-octene was found
to be reversible under the reaction conditions, while alkanols such
as ethanol were unreactive.
of low concentrations of triflic acid in the reaction mixture has not
been ruled out. Conversely, where -halo alcohols were found to
be superior substrates for addition to alkenes may also be attributed
to Bronsted acid catalysis, made feasible by Au- or Ag-mediated
elimination of HCl which, in the presence of AgOTf (co-catalyst),
to form triflic acid.
Gold is not the only group 11 metal catalyst reported for
intermolecular hydroalkoxylation reactions. The first example of
copper-catalysed intermolecular hydroalkoxylation reaction was
demonstrated by Hii et al.[13] In the presence of copper(II) triflate, a
wide range of aromatic and aliphatic alcohols and acids adds to
norbornene with good yields, except sterically hindered secondary
and tertiary alcohols (Scheme 3). It was noted that similar additions
to styrene, cyclic and acyclic 1,3-dienes and limonene were
unsuccessful under these conditions.
Subsequently, the system was studied in greater detail by
Carpentier and co-workers, in the hydroalkoxylation of
dicyclopentadiene and norbornene with 2-hydroxyethyl
methacrylate.[14] In this work, the authors concluded that triflic acid
is the active catalyst, generated from reduction of Cu(OTf)2 by the
olefin reagent. However, copper also acts as an olefinpolymerization retardant, improving the selectivity and yield of the
reaction. Independently, Hartwig et al. have shown that such
reactions can be catalysed by triflic acid alone, but a high
concentration of triflic acid can cause competitive decomposition
of the product.[15] From these studies, it may be inferred that the
Brønsted acid is similarly involved in the reactions catalysed by
gold and silver (Scheme 2), at least for reactions involving strained
alkenes, such as norbornene.
Scheme 2. Au-catalysed addition of phenols and acids to simple olefins.
It was generally believed that these reactions proceed by the
direct activation of the C=C bond by -coordination to Au.
Theoretical calculations on the possible reaction mechanisms for
the addition of phenols to olefins using gold(I)-phosphine catalysts
were performed by Ujaque et al.,[12] where the most favourable
pathway for catalysis by gold was found to occur in a concerted
fashion (nucleophile attack and proton transfer in one single step)
assisted by a proton-transfer agent (phenol, triflate, or water)
present in the solution. The most intriguing outcome from this
work was the finding that the reaction barrier for the gold catalysed
process was in fact higher than that for triflic acid by 3 kcal/mol.
Scheme 3. Cu-catalysed O-H addition to strained alkenes.
2.2 Intramolecular reactions
Reviewing these contributions together suggests that triflic acid
may indeed play a role in the alkoxylation of alkenes in the
presence of gold(I) complexes. Although He has shown that
5 mol-% triflic acid will result in (product?) decomposition at the
temperatures usually employed for metal catalysis,[10] the presence
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Scheme 4. Cyclisation of -alkenols or alkenoic acids.
Cyclisation of -alkenols and alkenoic acids to form 5- and/or
6-membered O-heterocycles is kinetically and thermodynamically
favourable. For a given substrate, the reaction could potentially
give rise to endo- or exo-products (Scheme 4); the latter is
generally the predominant product. These reactions can be
promoted by very strong Brønsted acids (e.g. TfOH) in a polar
solvent at elevated temperature (100 ºC),[16] thus the involvement
of H+ in reactions that employ a metal catalyst cannot be entirely
ruled out, particularly when the metal salt is formed from a strong
acid.
AgOTf was the first group 11 metal catalyst reported to catalyse
the intramolecular addition of carboxylic acids (X = O) and
alcohols (X = H2, R2) to C=C bonds.[17] In refluxing DCE, a wide
range of substrates underwent excellent conversions to furnish
great selectivity for the Markovnikov product. Notably, the
addition of certain phosphine ligands, such as PPh3, proved to be
detrimental to the process. Furthermore, other silver salts of weaker
conjugate acids (trifluoroacetate, benzoate, tosylate and nitrate)
were found to be catalytically inactive. The authors proposed a
mechanism whereby the C=C bond is activated by formation of a
-complex with Ag, and suggested that involvement of Brønsted
acid catalysis is unlikely in this case. Among the evidence
presented is the cyclisation of a TIPS-protected substrate catalysed
by AgOTf. The same substrate decomposes in the presence of
5 mol-% of triflic acid. No other control experiments with the acid
were carried out and more recent work has demonstrated that triflic
acid can be formed quantitatively under these reaction
conditions.[8]
Building on their earlier work, Hii et al. employed Cu(OTf)2 as a
catalyst for the intramolecular cyclisation of a number of
-alkenoic acids and alkenols[18] In striking similarity to the silvercatalysed system, a wide range of substrates can be accommodated,
and the reactions proceeded under identical conditions in high
yields and with excellent selectivity for the Markovnikov product.
More revealingly, the authors also found that the use of 10% TfOH
as catalyst is equally effective in a number of the cyclisation
reactions, even for the TIPS-protected substrate that was previously
reported to be unstable under these reaction conditions. Thus, it
was concluded that H+ is likely to be the only active catalyst
species in these systems.
In a separate study by Ito et al., a direct comparison between
Cu(OTf)2 and AgOTf catalysts was performed, for the
intramolecular hydroalkoxylation
of phenol derivatives
(Scheme 5).[19] Among the many different metal salts screened for
the reaction, Cu and Ag complexes of triflate and perchlorates have
comparable catalytic activity. In this case, cooperative HOTf and
metal catalysis was proposed; the reaction was thought to initiate
by -coordination of the C=C bond to Cu(II). The same reaction
can also be catalysed using a PPh3AuCl/AgOTf catalyst mixture
with Au(I) proving a superior catalyst to Au(III).[20]
Scheme 5. Intramolecular hydroalkoxylation
catalysed by Cu and Ag triflates.
of
phenol
derivatives
A heterogeneous Au:PVP catalyst was reported to effect the
cyclisation of -alkenols under aerobic conditions at 50 ºC.[21] The
atom-economy of the reaction is eroded by the need to employ 2
equivalents of DBU. Nevertheless, this is an interesting example
where catalytic turnover was achieved under basic conditions.
Scheme 6. Au:PVP-catalysed hydroalkoxylation of γ-alkenols.
3. O-H addition to conjugated C=C bonds (styrenes
and dienes)
3.1 Intermolecular additions
The hydroalkoxylation of conjugated C=C bonds is underrepresented in the literature. Few examples exist, perhaps hinting at
difficulties with this class of substrate. Polymerisation of the
starting alkenes may pose a significant problem and difficulties
controlling regiochemistry can be expected with 1,3-dienes.
The Markovnikov addition of alcohols and phenols to alkenes,
has been reported to be mediated by a combination of
Au(III)-Cu(II) catalysts at 120 ºC (Scheme 7).[22] It was proposed
that Au(III) acts as a Lewis acid active site, while CuCl2 slows
down its deactivation. However, it should be noted that the
hydroalkoxylation of styrene derivatives can also be catalysed by
Brønsted acids alone, under similar reaction conditions. Using a
heterogeneous cation (H+)-exchange resin (Amberlyst 15)
Verevkin and Heintz studied the thermodynamic parameters of the
reaction between 70 ºC and 160 ºC, for styrene derivatives with
both linear[23] and branched[24] alcohols. Thus, it is particularly
important that the presence of a Brønsted acid catalysis component
be considered for substrates such as styrenes.
Scheme 7. Addition of alcohols and phenols to alkene over gold and acid
catalysts.
4. O–H addition to allenes (1,2-dienes)
The intramolecular addition of O–H to allenes provides the
strongest case for metal-mediated processes, where regioselectivity can raise interesting challenges. The following
discussion will start with silver, where the greatest number of
examples exists, followed by gold and copper. Intermolecular
hydroalkoxylation reactions of allenes have been recently reviewed
by Munoz.[25] Given that no new reports have been made since then,
only intramolecular reactions will be discussed in this review.
4.1 Silver-catalysed processes
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Silver catalysts have a long established record in cyclisation of
alcohol bearing allenes. An important landmark was set in 1979,
when Olsson and Claesson successfully converted - and
-allenols into dihydrofurans and dihydropyrans, respectively, by
treating them with a catalytic amount of silver tetrafluoroborate or
silver nitrate (Scheme 8).[26] It was found that different reaction
conditions are required, depending on the nature of the substrate.
The cyclisation of -monoalkyl or -dialkyl substituted
-allenols proceeded cleanly with approx. 3 mol-% of silver
tetrafluoroborate in chloroform (Scheme 8, eq. 1). When
unsubstituted allenes (R4=R5=H, eq. 1) were used, these
conditions gave only low yields. In these cases, a higher catalyst
loading (approx. 10 mol-% AgNO3) in a water-dioxane or wateracetone mixture in the presence of calcium carbonate was required.
Likewise, allenols did not react as readily as substituted
allenols and these more active conditions were needed for the
synthesis of 5,6-dihydropyrans (eq. 2, Scheme 8). In both cases, the
regioselectivity of the reaction favours the exclusive formation of
the endo-product, i.e. the C–O bond is forged at the terminal
position of the allene.
in this manner. Notably, the reaction favoured the formation of the
cis diastereomer.
Scheme 10. Gallagher’s synthesis of cis-(6-methyltetrahydropyran-2yl)acetic acid, a minor component of civet.
Two years later, Wang et al. treated trimethylsilyl-substituted
-allenols with stoichiometric silver nitrate, which afforded the
corresponding 3-(trimethylsilyl)-2,5-dihydrofurans (Scheme 11).[29]
Where tertiary alcohols were used as the nucleophile, a competitive
process generating an -unsaturated ketone was observed,
presumably via the formation of a tertiary carbocation, which
benefits from additional stabilisation from the trimethylsilyl group,
followed by attack of water at the central carbon of the allene.
Scheme 8. Ag-catalysed cyclisation of - and -allenols discovered by
Olsson and Claesson.
The scope of the reaction was expanded three years later by
Audin et al., who prepared 2-alkenyl tetrahydropyrans by
cyclisation of -allenols using silver nitrate as a quantitative
reagent (Scheme 9).[27] Unsubstituted -allenol cyclised in a
straightforward manner, but more complex allenes required harsher
conditions. In the case of substrates bearing two substituents at the
allene terminus, only moderate yields (35–40%) were obtained
even with 6 equivalents of the silver salt.
Scheme 11.
-allenols.
Ag-catalysed
cyclisation
of
trimethylsilyl-substituted
The stereochemical course of the reaction was consequently
examined by Marshall et al., who found that the cyclisation of the
enantioenriched -allenols occur stereospecifically to furnish
distinctive diastereoisomers (Scheme 12).[30]
Scheme 9. Cyclisation of -allenols.
Scheme 12. Stereospecific cyclisation of enantioenriched -allenols.
The method was subsequently employed by Gallagher for the
synthesis of cis-(6-methyltetrahydropyran-2-yl)acetic acid (1), by
the cyclisation of a secondary allenol (Scheme 10).[28] The
remaining alkene in the cyclised product allowed further
elaboration, demonstrating a distinct advantage of cyclising allenes
The regioselectivity of the reaction was also examined by Chilot
et al., with the cyclisation of allenyl diols.[31] For terminal allenes,
the reaction favoured the formation of bicyclic acetals, resulting
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from a nucleophilic attack on the central sp-hybridised carbon
(Scheme 13, eq.s 1 and 2). However, the presence of a terminal
methyl switched the selectivity towards the formation of a
dihydropyran (Scheme 13, eq. 3).
Scheme 15. Regioselective cyclisation of tertiary -allenols.
The importance of steric effects was reinforced in work
described by Krause and Poonoth, in their attempts to synthesise
bis(2,5-dihydrofurans) from bis(-allenols) (Scheme 16).[34] The
treatment of bis-allenols bearing two isopropyl groups with 0.25
equiv. of silver nitrate under ambient conditions induced a rapid
cyclisation to afford the corresponding 2-allenyl-substituted 2,5dihydrofurans with excellent yields and axis-to-centre chirality
transfer. However, a second cyclisation to the corresponding
bis(2,5-dihydrofurans) was not possible. This was attributed to
steric hindrance caused by two adjacent isopropyl groups, which
prevent the coordination of Ag(I) to the double bond. Indeed, the
bis-cyclization of ethyl- or benzyl-substituted bis-allenes afforded
the corresponding bis(2,5-dihydrofurans) with good yields, albeit
with longer reaction times and higher catalyst loading. As expected,
attempts to extend the cycloisomerization to substrates bearing
very bulky substituents R2 (tBu, Ph) were met with failure, even at
higher temperatures or under microwave irradiation.
Scheme 13. Cyclisation of allenyl diols.
The regioselectivity of the process was further examined by the
Marshall group, with the cyclization of allene diols containing
primary and secondary hydroxyl groups.[32] In all the cases
examined, reaction proceeded with complete preservation of
stereochemistry, and the cyclization of the secondary alcohol was
found to be most favourable (Scheme 14). This was attributed to
the preferential complexation of Ag+ at the less congested end of
the allenyl  system.
Scheme 16. Attempted synthesis of bis(2, 5-dihydrofurans).
Scheme 14. Regioselective cyclisation of secondary -allenols.
A more extensive study was performed by Aurrecoechea and
Solay, with the cyclisation of 2,5-pentadiene-1,5-diols containing
different combinations of tertiary and primary or secondary
hydroxyl groups (Scheme 15).[33] As was observed before,
cyclization takes place through the more hindered hydroxyl group.
When both of the allene termini are equally substituted,
complexation at the less congested site is the dominant factor
controlling selectivity. Syn- and anti-substituted precursors gave
opposite stereoselectivities, confirming that these reactions proceed
via well-defined transition states.
In 2009, a regio-divergent cyclisation of -allenols was reported
by the research group of Hii.[35] While the exclusive formation of
the 5-exo-trig product was obtained using silver catalysts, triflic
acid induced a 6-endo-trig cyclisation, which was accompanied by
electrophilic cyclisation to afford a tricyclic product
(Scheme 17).[36]
Scheme 17. Regio-divergent cyclisation of -allenols.
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DFT calculation of the transition state of the silver-catalysed
process predicted that the replacement of silver triflate with silver
trifluoroacetate would have a significant acceleration effect – a
hypothesis which was subsequently verified experimentally.[35]
Based on these observations, the first silver-catalysed
enantioselective hydroalkoxylation of allenols was developed.[37]
Notable enantioselectivity was obtained by using the
oxophosphorus(V) phosphinate and phosphate complexes of silver
(Scheme 18).
Scheme 20. Silver-mediated allenol cyclisation of complex molecules.
Scheme 18.
reactions.
Enantioselective
Ag-catalysed
hydro(acyl)alkoxylation
Independently, Hong and co-workers reported a kinetic
resolution of -allenols, by using a chiral silver-phosphate salt at
(Scheme 19).[38] Although the process is quite slow, the method
proved to be quite general, as 22 examples of -allenols (both alkyl
and aryl substituted) were successfully resolved.
Functionalised tetrahydrofuran rings are a common motif in
marine natural products, particularly in the highly oxygenated
framework of polyketide macrolides. The high stereoselectivity
and total chiral transfer exhibited in silver-promoted allenol
cyclisations make them an important synthetic tool in tackling this
class of molecule. This was frequently exploited by the group of
Fürstner, notably en route to amphidinolides X and Y,[41] and more
recently leiodolide B,[42] a natural product produced by sponges
from the genus leiodermatium (Scheme 21).
Scheme 19. Kinetic resolution of -allenols using a chiral silver salt.
Silver-mediated cyclisation of allenols has been employed
successfully in the synthesis of complex molecules containing
dihydrofurans. VanBrunt and Standaert reported a 7-step synthesis
of (+)-furanomycin, using, as one of the key steps, the Ag+
mediated cyclization of an -allenol to construct the core trans2,5-dihydrofuran (Scheme 20).[39] Alcaide and Almendos later
employed a similar method to prepare enantiopure spirocyclic
-lactams from the corresponding allenols (Scheme 20).[40]
Scheme 21. Silver mediated allenol cyclisation in natural product synthesis
4.2 Gold-catalysed processes
The first gold(III)-catalysed intramolecular hydroalkoxylation of
functionalised α-allenols to the corresponding 2,5-dihydrofurans
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was reported by Krause in 2001.[43] Analogous with the silvercatalysed process, the reaction occurs with complete axis-to-centre
chirality transfer (Scheme 22). It was noted that although the
reactions also proceed well using an acid catalyst, such as
Amberlyst 15, the use of the gold catalyst allow for greater
tolerance of acid-labile functional groups, and also offered better
reaction rates compared with the corresponding reaction catalysed
by AgNO3 in acetone/water. Alternatively, the gold catalyst can be
supported in ionic liquids: the best system proved to be AuBr3 in
[BMIM][PF6], which can be applied to various alkyl- or arylsubstituted α-allenols.[44] HAuCl4 may be employed as a catalyst in
water, where its stability was found to be greatly improved by the
presence of lithium chloride.[45]
Scheme 24. Gold-catalysed synthesis of 2,5-dihydrofuran 4 and structures
of (−)-isocyclocapitelline and (−)-isochrysotricine.
Formation of larger O-heterocycles can also be achieved.
Cyclisation of a -allenol derived from D-glyceraldehyde occurred
in the presence of AuCl3 to furnish tetrahydrooxepines through a
regioselective 7-endo-trig process (Scheme 25).[51]
Scheme 22. 5-endo Au-catalysed intramolecular hydroalkoxylation of
allenes.
Alcaide and Almendros reported a study on chemo-divergent
cyclisation reactions. When allene and alkene groups are present in
the same substrate, the use of AuCl3 was found to lead exclusively
to the formation of dihydrofuran through selective activation of the
allene (Scheme 23).[46] Although the same chemoselectivity was
also afforded by AgNO3, it was necessary to use stoichiometric
quantities of silver salt and heating was required.
Scheme 25. Au(III)-catalyzed hydroalkoxylation reaction of γ-allenols with
7-endo-trig regioselectivity.
Recently, reports have appeared detailing efforts to use
supramolecular complexes[52] to encapsulate the gold catalyst or
directly as ligands.[53] Such methods are still at an early stage of
development and have not yet been widely adopted but, so far,
results in this area appear promising.
4.3 Gold-silver bimetallic systems
Scheme 23. Chemoselective cyclisation of an -allenol in the presence of
an alkene.
Hashmi reported evidence for the presence of catalytically active
Au(I) species formed in situ from AuCl3.[47] The importance of this
process in the wider field of gold catalysed hydroalkoxylations has
not been determined and may even be reaction specific, but it
raises important questions about the mechanism of the reaction.
The advent of homogeneous gold catalysis has opened up
versatile access to various 5- and 6-membered heterocycles,[48] and
has become a valuable tool for the stereoselective construction of
complex natural products.[49] Krause took advantage of the highly
efficient chirality transfer offered by these reactions in the first
enantioselective total syntheses of β-carboline alkaloids
(−) isochrysotricine and (−)-isocyclocapitelline (Scheme 24).[50]
Cyclisation of the α-allenol 3 required only 0.05 mol-% AuCl3 to
produce the highly-functionalised dihydrofuran 4 in 97% yield,
after only 10 minutes at room temperature. This afforded a
turnover number as high as 1900 on a 2 g scale, placing the
reaction amongst the most efficient transformations in
homogeneous gold catalysis.
In some cases, the addition of a silver co-catalyst is found to
enhance the gold-catalysed process quite significantly. For
example, a number of 3-carboxylate-2,5-dihydrofurans can be
synthesised from the cyclisation of functionalised -allenols in
good to excellent yields in an hour at ambient conditions, using a
gold(I)-phosphine complex in combination with AgOTf as a
co-catalyst (Scheme 26).[54] In the absence of the silver salt, the
reaction only afforded 15% of the product in 15 hours.
Scheme 26. 5-endo allenol cyclisation catalysed by Au(I).
The gold(I)-catalysed 6-endo cycloisomerization of -allenols to
functionalized dihydropyrans can also be achieved using the
bimetallic system (Scheme 27, eq. 1).[55] In this case, the formation
of the 5-exo isomer was not detected. Interestingly, the yield was
little affected by the solvent and the presence of silver salts, and
reactivity could be increased by the use of gold(I) chloride with a
co-catalyst such as pyridine or 2,2'-bipyridine. Chirality transfer
was examined further with diastereomerically pure β-allenols
Submitted to the European Journal of Organic Chemistry
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(Scheme 27, eq. 2), which afforded diastereomerically pure
products in moderate yields. The formation of a dihydrofuran side
product (5) was observed when PG = Ac, which resulted from
migration of the protecting group from the secondary to the
primary alcohol.
5-membered heterocycles, using gold(I)-triflimide (AuNTf2)
complexes of H-KITPHOS, o-MeO-KITPHOS, as well as
cyclohexyl-JohnPhos and DavePhos, with excellent TON´s of up to
1980 (Scheme 29, eq. 2).[57]
Scheme 27. 6-endo Au-catalysed intramolecular hydroalkoxylation of
allenes.
The proposed mechanistic model is shown in Scheme 28. In the
first step, coordination of the gold catalyst to the terminal double
bond of the allene (6) gives rise to the formation of intermediate 7
which, upon nucleophilic attack of the oxygen, is transformed into
σ-gold complex 8. Protodemetalation of the latter provides
heterocyclic product 9 and releases the gold catalyst back into the
catalytic cycle.
Scheme 29. Au(I)-phosphine catalysed cyclisation of - and -allenols and
-allenoic acid with exo-trig selectivity.
A mechanism for the 5-exo-trig cyclisation was proposed by
Gagné and Widenhoefer, based on mechanistic studies performed
on the cyclisation of 2,2-diphenyl-4,5-hexadien-1-ol (10) to
2-vinyltetrahydrofuran (11), largely by using NMR spectroscopy
(Scheme 30).[58] A stoichiometric mixture of the acyclic substrate,
[(L)AuCl] (where L = JohnPhos), AgOTs and Et3N in toluene
generated a stable mono(gold) vinyl complex 13, which was
isolated and fully characterised. The addition of an equivalent of
[(L)AuCl] to 13 generated a thermally unstable bis(gold) vinyl
complex 14. After examining the reactivity of these two gold
complexes with an acid, it was proposed that the formation of
complex 13 is rapid and reversible under catalytic conditions, with
complex 14 as an off-cycle catalyst reservoir (Scheme 30). These
observations have important implications regarding stereochemical
control of these reactions.
Scheme 28. Mechanism for the intramolecular hydroalkoxylation of
β-allenes proposed by Krause.
Similarly, the first gold-catalysed cyclisation of - and δ-allenols
was reported by Widenhoefer et al.,[56] using a 1:1 mixture of
[(JohnPhos)AuCl] [JohnPhos = P(tBu)2(o-biphenyl)] and AgOTs in
toluene,
to
afford
exo-cyclised
tetrahydrofurans
and
tetrahydropyrans, respectively, with good to excellent results
(Scheme 29, eq. 1). Regioselectivity in the cyclisation of -allenols
using a Au(I) catalyst showed a strong dependence on the choice of
counterion in the silver salt: while silver triflate gave very poor
selectivity, forming a mixture of tetrahydrofuran and dihydropyran
products, silver tosylate was much more selective, producing only
traces of the 6-membered ring. Similarly, Hashmi reported the
cyclization of a γ-allenol and an allenoic acid to the corresponding
Submitted to the European Journal of Organic Chemistry
8
Enantioselectivity can be further improved by combining a chiral
ligand on the gold complex (DIPAMP) with chiral counterions in
the silver salts. This combination creates a highly selective system
capable of good enantio-induction, even for the most challenging
substrates, such as unsubstituted -allenol (Scheme 32).
Scheme 32. Hydroxylation using chiral gold complex and counterion.
Scheme 30. Proposed mechanism for the gold-catalyzed conversion of
-allenol to tetrahydrofuran.
What is perhaps more exciting is the attainment of asymmetric
catalysis using the Au-Ag bimetallic system. The first highly
enantioselective hydroalkoxylation reactions were reported by
Wildenhoefer et al., using chiral diphosphine complexes of gold
[Au2(P–P)Cl2] (P–P = 2,2’-bis(diarylphosphino)-biphenyl).[59]
Employing AgOTs as a co-catalyst at low temperature (–20 °C)
and increased dilution, excellent enantioselectivity of up to 99% e.e.
can be obtained for the cyclisation of axially-chiral -allenols with
good tolerance for dialkyl or diaryl substitution along the alkyl
chain. This system was also effective for the cyclization of both
achiral and chiral δ-allenols to form substituted tetrahydropyrans.
Attempts to use chiral NAC ligands in this fashion have also been
made, but only low levels of stereocontrol were obtained.[60]
The use of chiral anions to direct the stereochemical outcome of
reactions has seen significant growth in recent years.[61] Toste and
co-workers devised a different strategy to induce chirality for the
intramolecular hydroalkoxylation of allenols (Scheme 31).[62] In
this system, a dinuclear gold complex of an achiral diphosphine
ligand bis(diphenylphosphinomethane) (dppm) was used in
combination with a chiral silver phosphate salt 15, providing the
desired product in an exceptional 97% ee. The generality of the
method was demonstrated with a variety of allenol substrates, with
substituents well tolerated at several positions, including the allene
terminus and also the α- and β-positions of the alcohol.
The ‘chiral anion’ strategy was subsequently extended to the
enantioselective hydroalkoxylation of N-linked hydroxylamines, to
form vinyl isoxazolidines (n = 1) and oxazines (n = 2) (Table 1).[63]
Cyclic and linear alkyl substitutions at the allene terminus were
well tolerated, and corresponding vinyl-isoxazolidines can be
obtained in good yield and with high enantiomeric excess.
Formation of the 6-membered heterocycle proved to be more
challenging, but the combination of a chiral ligand and chiral silver
salt helped overcome this; match and mismatch of chirality was
observed in this instance (entries 5 vs 6).
Table 1. Hydroxylamine hydroalkoxylation scope.
Entry
n
R1; R2[b]
Conditions[a]
Yield[%][b]
ee[%][c]
1
1
Me; H
A
98
98
2
1
-(CH2)5-; H
A
75
99
3
1
Me; Me
A
99[d]
40/97
4
2
Me; H
A[e]
66
50
5
2
Me; H
B
94
87
6
2
Me; H
C
36
45
[a] Reaction Conditions: A = [(dppm)(AuCl)2] (3 mol-%), (S)-15 (6 mol-%),
18 h; B = [(S,S)-DIPAMP(AuCl)2] (3 mol-%), (S)-15 (6 mol-%), 18 h; C =
[(S,S)-DIPAMP(AuCl)2] (3 mol-%), (R)-15 (6 mol-%), 18 h. [b] Isolated
yield after column chromatography. [c] Determined by HPLC. [d] 5:1 d.r.
[e] 60 h.
Scheme 31. Asymmetric hydroalkoxylation of allenes using chiral
counteranions.
Submitted to the European Journal of Organic Chemistry
9
Scheme 34. Cu-catalysed cyclisation of -allenols
5. Conclusions
Scheme 33. Asymmetric catalytic hydroalkoxylation with monocationic
dinuclear gold complex.
The synergistic effect between enantiopure [Au2(BIPHEP)Cl2]
complexes and chiral phosphate anions was examined by Mikami
and co-workers (Scheme 33).[64] In this work, the dinuclear gold
complex generated from a 2:1 ratio of Au:Ag affords higher
catalytic activity and enantioselectivity than the dicationic gold
complex (generated from equivalent amounts of Au:Ag). It was
thus suggested that the active catalyst is a monocationic di(gold)
complex, although the precise involvement of the metal centres in
catalysis was not clear.
The role of chiral counterions in gold-catalysed asymmetric
intramolecular hydroalkoxylation reactions of allenes was
examined by Nguyen et al. using extended X-ray absorption fine
spectroscopy (EXAFS).[65] Experimental data suggested the
existence of a strong non-dynamic bond between the oxygen of the
phosphate and the gold cation in solution, suggesting that the
phosphate may stay coordinated to the gold cation during the
catalytic cycle. While it is not possible to rule out phosphateassisted proton-transfer as the stereochemical determining step, it
was suggested that direct bonding between the chiral phosphate
counterion and the metal catalyst should be given due
consideration in these reactions.
4.4 Copper catalysis
Compared with silver and gold, there are very few reports of the
successful employment of copper salts for the intramolecular
hydroalkoxylation of allenes. A recent example is the report of a
selective conversion of functionalized α-allenols into the
corresponding 2,5 dihydrofurans in good to excellent yields using
5 mol-% of copper(II) chloride as the catalyst (Scheme 34).[66] It is
worth comparing this to the previously described Au/Ag system
(Scheme 26), which affords much milder reaction conditions
The use of coinage metal catalysts in hydroalkoxylation
reactions has received a great deal of attention over the last decade.
Addition of alcohols and carboxylic acids to alkenes has been
demonstrated to have synthetic utility for both intermolecular and
intramolecular reactions. One area of caution has become evident
as the field developed: it is clear that in some processes Brønsted
acid catalysis can play a significant role. This has been shown for
Cu(OTf)2 and AgOTf, where TfOH is generated in the reaction, but
cannot be ruled out for other metals. The metal may still have a
role to play in these reactions since the results obtained using of
metal triflate catalysts can differ from those obtained when triflic
acid is used directly. One possible role of the metal is to act as a
reservoir controlling the concentration of triflic acid present.
The role of Brønsted acid catalysis is particularly notable for
simple unactivated alkenes and is reflected in the absence of
asymmetric hydroalkoxylation methods for these substrates. Future
success will rely on negating the efficient background reaction
promoted by triflic acid. It is thus very important for the
development of the field to ensure that suitable control experiments
are carried out and reported. Concurrently, the selectivity of these
additions is overwhelmingly for the Markovnikov products as is
the case for Brønsted acid catalysed reactions. There is little in the
current literature to suggest that this inherent selectivity can be
overturned.
Among the reactions discussed here, the utility of group 11 metal
catalysts for the hydroalkoxylation of allenes is most varied and
has the most synthetic applications. The regiochemical challenges
which they pose have attracted much attention and a fair degree of
success. The dominant catalyst in activating allenes has proved to
be AgNO3, with a great many examples to be found in the literature.
Unfortunately, in many cases, this is required in stoichiometric or
super-stoichiometric amounts, limiting the attractiveness of this
method. Perhaps the greatest success in this area has been the
advent of chiral Au(I) catalysts in conjunction with chiral silver
salts. Highly active catalysts of this type have been demonstrated
and are already finding synthetic utility. The greatest challenge in
this area is perhaps the synthesis of the allene starting materials.
Unlike alkenes, relatively few are commercially available, limiting
the wide-spread adoption of the transformation. The successes in
the hydroalkoxylation of allenes have not readily transferred to the
simple unactivated alkenes highlighting chemical differences in the
nature of the two classes of C=C bonds.
Challenges also remain in understanding the exact role of the
components in what is often a complex catalyst mixture,
particularly the involvement of H+ in the catalytic cycle. Progress
is being made in trying to understand the exact mechanistic role
and implications of counterions and solvents in these reactions, but
some questions remain unanswered. What is certain is that the use
of group 11 metals to promote the addition of O–H to C=C bonds
is no longer just a matter of academic curiosity. The field has
Submitted to the European Journal of Organic Chemistry
10
matured to the point where these reactions can be usefully applied
to the synthesis of complex organic molecules.
Dr. Elena M. Barreiro received her BSc and MSc degrees from the University of Santiago de Compostela (Spain) and
completed her PhD under the supervision of Prof. José Sordo Rodríguez (2007) working on silver and gold complexes
with potential biological activity. She was awarded pre-doctoral and doctoral fellowships from the Galician
Government, a FPI grant from the Spanish Ministry of Education and Science and undertook a short stay in the group
of Prof. Claire Carmalt at University College London (2004). She conducted post-doctoral research in the group of
Prof. Agustín Sánchez at the University of Santiago (2007–2009) before joining the group of Dr. Mimi Hii at Imperial
College London (2010–2011), working on the development of new catalysts for organic reactions. To date, she is
co-author of over 18 original research publications and has presented work at several national and international
conferences.
Dr. Luis Angel Adrio studied Chemistry at the University of Santiago (Spain) and received his PhD degree in 2006
under the supervision of Prof. José Manuel Vila Abad and Prof. Mª Teresa Pereira Lorenzo. Soon after, he joined the
group of Dr. Mimi Hii at the Imperial College (United Kingdom), as a postdoctoral researcher, where he developed
catalytic systems able to promote C–C and C–O bond formation. In January 2012, he moved to the University of
Oviedo (Spain) where he works, in collaboration with Prof. José Gimeno, on the development of new environmentally
benign catalytic systems, based on ruthenium complexes. He is co-author of 26 publications including 3 reviews and
two book chapters.
Dr. Mimi Hii graduated with a BSc degree from the University of Leeds, followed by a PhD degree for research
performed under the supervision of Prof. Bernard L. Shaw, FRS. This was followed by postdoctoral work at Oxford
University (with Dr John M. Brown, FRS), where she was awarded a Keeley Junior Research Fellowship by Wadham
College. The award of a Ramsay Memorial Fellowship, co-sponsored by ICI Strategic Funding, enabled her to initiate
independent research at Leeds before appointment to a lectureship at King's College London. She later moved to a
Senior Lectureship at Imperial College, where she was promoted to a Readership in Catalysis in 2009.
Dr. John Brazier received his MSci in Natural Sciences and his PhD from the University of Cambridge. He undertook
post-doctoral research with Nicholas Tomkinson at Cardiff University, studying mechanistic organocatalysis, and at
The University of Edinburgh (with Scott Cockroft) working on - stacking interaction., He moved to Imperial College
London in 2011 where he is a Research Associate in the Department of Chemistry working in the group of Dr. Mimi Hii.
His research interests are mainly in homogeneous catalysis and in particular the role which solvents play in reactions.
Acknowledgments
JBB is supported by an EPSRC grant (“Elucidate and Separate”,
EP/G070172/1). We are grateful to Fundación Barrié de la Maza and Xunta
Galicia (Angeles Alvariño program) for the award of postdoctoral
fellowships to EMB and LAA, respectively.
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13
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Received: ((will be filled in by the editorial staff))
Published online: ((will be filled in by the editorial staff))
Entry for the Table of Contents
Layout 1:
((Key Topic))
The direct addition of O–H bonds to
C=C bonds is an attractive way to
synthesise alcohols, ethers and esters.
This micro-review addresses the use of
group 11 metals in promoting these
transformations. The involvement of
Brønsted acid catalysis in some of these
reactions is highlighted.
Elena M. Barreiro, Luis A. Adrio,
King Kuok (Mimi) Hii and John B.
Brazier* …….. Page No. – Page No.
Coinage metal catalysts for the addition
of O–H to C=C bonds
Keywords: Copper / Silver / Gold /
Alkenes / Allenes
Submitted to the European Journal of Organic Chemistry
14