Intercepting the Gold-Catalysed Meyer-Schuster Rearrangement by Controlled Protodemetallation: A Regioselective Hydration of Propargylic Alcohols

Article abstract of DOI:10.1002/adsc.201600101

The regioselective gold-catalysed hydration of propargylic alcohols to β-hydroxy ketones can be achieved by diverting the gold-catalysed Meyer-Schuster rearrangement through the addition of a protic additive with a pK_a of 7-9 such as p-nitrophe

Full text of DOI:10.1002/adsc.201600101

UPDATES
DOI: 10.1002/adsc.201600101
Intercepting the Gold-Catalysed Meyer–Schuster Rearrangement
by Controlled Protodemetallation: A Regioselective Hydration of
Propargylic Alcohols
Matthew N. Pennell,a Michael P. Kyle,b Samantha M. Gibson,a Louise Male,b
Peter G. Turner,c Richard S. Grainger,b,* and Tom D. Shepparda,*
a
Department of Chemistry, University College London, Christopher Ingold Laboratories, 20 Gordon Street, London,
WC1H 0AJ, U.K.
E-mail: tom.sheppard@ucl.ac.uk
School of Chemistry, University of Birmingham, Edgbaston, Birmingham B15 2TT, U.K.
b
Fax: (+44)-(0)121-414-4403; phone: (+44)-(0)121-414-4465; e-mail: r.s.grainger@bham.ac.uk
GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Herts, SG1 2NY, U.K.
c
Received: January 22, 2016; Revised: March 18, 2016; Published online: April 27, 2016
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201600101.
ꢀ 2016 The author. Published by Wiley-VCH Verlag GmbH &Co. KGaA. This is an open access article under
the terms of the Creative Commons Attribution Licence, which permits use, distribution and reproduction in
any medium provided the original work is properly cited.
Abstract: The regioselective gold-catalysed hydra-
tion of propargylic alcohols to b-hydroxy ketones
can be achieved by diverting the gold-catalysed
Meyer–Schuster rearrangement through the addi-
tion of a protic additive with a pKa of 7–9 such as
p-nitrophenol, boric acid or a boronic acid. This
provides an interesting alternative to an aldol reac-
tion when combined with the straightforward addi-
tion of an alkyne to an aldehyde or ketone. The
gold-catalysed reaction of an electron-deficient,
sterically hindered propargylic alcohol with a boron-
ic acid led to the formation of an unusually stable
cyclic boron enolate.
trolled protodemetallation to divert the gold-cata-
lysed Meyer–Schuster rearrangement to give access to
b-hydroxy ketones and related derivatives.
In 2010, we reported that the gold-catalysed cyclisa-
tion of o-alkynlbenzeneboronic acids could be used as
an extremely mild method to generate boron enolates
2 (Scheme 1, A).[7] In an attempt to extend this
chemistry, we envisaged that propargylic alcohols 3
would react with boronic acids to give half esters 4,
which could undergo cyclisation to the corresponding
boron enolate 5. In the event, these reactions led
almost exclusively to the formation of Meyer–Schus-
ter products 6. We observed, however, that a protic
additive such as an alcohol or boronic acid served to
accelerate the gold-catalysed Meyer–Schuster rear-
rangement of propargylic alcohols 3 to enones 6 in
Keywords: aldol reaction; alkynes; boronic acids;
enolates; gold
a
non-polar organic solvent such as toluene
(Scheme 1, B and C).[3] During the course of our
study, we found that in the presence of a catalytic
quantity of boronic acid the b-hydroxy ketone 7a was
Propargylic alcohols are versatile compounds which observed as a significant by-product in reactions of
can be used in a wide variety of gold-catalysed trans- some secondary propargylic alcohols (Scheme 2).
formations.[1] The gold-catalysed Meyer–Schuster re- When methanol was used as the additive with the
arrangement of propargylic alcohols is a well-estab- same substrates, the sole product was the enone 6a,
lished method for the efficient preparation of a wide and the formation of 7a was completely suppressed.
variety of enones.[2,3] It is also possible to intercept
We envisaged that a regioselective hydration of
the Meyer–Schuster rearrangement with a variety of a propargylic alcohol to a ketone (Scheme 1, D)
electrophiles to give access to a-haloenones,[4] a-aryl- could provide an interesting alternative to a traditional
enones,[5] or a,a-diiodo-b-hydroxy ketones.[6] In this aldol reaction between a ketone and an aldehyde.
update, we describe our studies on the use of con- This would circumvent the requirement to use low
Adv. Synth. Catal. 2016, 358, 1519 – 1525 ꢀ 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1519

UPDATES
Matthew N. Pennell et al.
Scheme 3. Investigation of the effect of additive acidity on
the ratio of 7a:6a.
Table 1. The effect of different additives on the gold-cata-
lysed reaction of propargylic alcohol 3a.
Entry Additive
pKa (H2O) Conv.[a] Ratio of 7a:6a[b]
1
2
3
4
5
6
7
8
none
–
64%
100% 6a only
59% 1:1
100% 2:3
1:1.1
MeOH
CF3CH2OH
PhOH
15.7
12.5
10.0
9.2
B(OH)3
87%
99%
2:3
1:2
[c]
PMPB(OH)2 8–9
PNPOH[d]
C6F5OH
C6Cl5OH
AcOH
7.1
5.5
4.7
4.7
0.3
100% 3:1
61%
93%
68%
1:2
1:1
2:3
9
10
11
Scheme 1. Gold-catalysed addition of boronic acids to al-
kynes[7] and the gold-catalysed Meyer–Schuster rearrange-
ment in the presence of protic additives.[3]
CF3CO2H
100% 1:3
[a]
Conversion of 3a to 7a/6a as measured by crude
1H NMR.
[b]
[c]
[d]
1
Determined from the crude H NMR.
PMP=4-MeOC6H4.
PNP=4-O2NC6H4.
7a as the major product (Scheme 3 and Table 1). In
the absence of an additive, almost equal quantities of
the b-hydroxy ketone 7a and the enone 6a were ob-
tained (entry 1). Interestingly, the outcome of the re-
action appeared to correlate reasonably well with the
pKa of the protic additive used (entries 2–11). As the
acidity of the additive increased (Table 1, entries 2–7),
increasing amounts of the direct hydration product 7a
Scheme 2. Gold-catalysed Meyer–Schuster rearrangement of
propargylic alcohol 3a in the presence of protic additives.
temperatures and stoichiometric reagents to achieve were observed, with this compound being the major
regioselective enolisation of the ketone, prior to addi- reaction product when 4-nitrophenol (PNPOH) was
tion of the aldehyde. Whilst isolated examples of used. However, as the acidity of the additive was in-
gold- or mercury-catalysed hydration reactions of creased further (entries 8–11), the product ratio re-
propargylic alcohols have been described,[8,9] these re- versed with enone 6a once again becoming the major
ports largely involve terminal alkynes[8] or the forma- product. This suggests that there is an optimum ꢁpKa
tion of b-hydroxy ketones as by-products.[9] To the windowꢂ in which the formation of 7a is favoured.
best of our knowledge, the gold-catalysed regioselec- With this information in hand, we went on to examine
tive hydration of propargylic alcohols containing an these conditions for the regioselective hydration of
internal alkyne has not been described.[10,11]
We hypothesised that through suitable selection of (Scheme 4).
a
selection of different propargylic alcohols
a protic additive, the Meyer–Schuster pathway could
Pleasingly, under these conditions the b-hydroxy
be diverted either to give b-hydroxy ketone 7 directly ketone 7a was obtained in 65% isolated yield, with
(Scheme 1, path 1), or to generate the boron enolate the remaining balance of the material being the corre-
5 which could yield 7 via hydrolysis (path 2). We sponding enone 6a. The hydration reaction proceeded
therefore set out to investigate in more detail the with very high regioselectivity and no trace of the iso-
effect of the choice of protic additive on the product meric a-hydroxy ketone was observed.[11] Aryl ke-
distribution of the reaction, with the aim of identify- tones 7b–7e, including a heterocyclic example 7b,
ing conditions which would give the b-hydroxy ketone were obtained in variable yields, depending upon the
1520
asc.wiley-vch.de
ꢀ 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2016, 358, 1519 – 1525

UPDATES
Intercepting the Gold-Catalysed Meyer–Schuster Rearrangement
gylic alcohols such as 3k, derived from pinacolone,
failed to give any b-hydroxy ketone with the enone
6k being observed as the sole product (Scheme 5).
Similarly, aryl-substituted propargylic alcohols 3l–3n
yielded only the corresponding enones 6l–6n, regard-
less of whether the aryl group was unsubstituted, elec-
tron-rich or electron-deficient.
Scheme 5. Attempted hydration of tertiary propargylic alco-
hol 3k and aryl-substituted propargylic alcohols 3l–3n.
The formation of b-hydroxy ketones 7 by regiose-
lective hydration of propargylic alcohols offers an in-
triguing alternative to the aldol reaction of a ketone
and an aldehyde. In order to further demonstrate the
potential of this approach, we subjected enantioen-
riched propargylic alcohol 3o, prepared using Carrei-
raꢂs asymmetric addition method,[12] to the hydration
reaction. Pleasingly, the corresponding b-hydroxy
Scheme 4. Scope of the regioselective hydration reaction.
Isolated yields shown; the ratio of 7:6, measured by crude
1H NMR, is shown in parentheses.
electronics of the aromatic ring. Whilst the hydration ketone 7o was obtained in 65% yield with complete
reactions to generate electron-rich ketones 7b and 7c retention of enantiopurity (Scheme 6).
proved to be particularly effective, phenyl ketone 7d
and electron-deficient aryl ketone 7e were obtained
in lower yields. In the latter case, the enone 6e was
the major product from the reaction and in contrast
to all the other reactions studied, small quantities of
the isomeric a-hydroxy ketone were isolated. Pleas-
ingly, an enone could also be obtained effectively
through regioselective hydration of a conjugated
enyne (7f). Hydration of propargylic alcohols 3g and
3h, to give aryl b-hydroxy ketone 7g and branched
Scheme 6. Regioselective hydration of an enantioenriched
propargylic alcohol.
alkyl ketone 7h, respectively, also proceeded smooth-
In most of the hydration reactions, the formation of
ly. Initial attempts to achieve regioselective hydration the desired b-hydroxy ketone (7a–7h, 7o) was accom-
of the fluorinated tertiary propargylic alcohols 3i and panied by the formation of smaller quantities of the
3j were unsuccessful under the standard conditions as Meyer–Schuster rearrangement product (6a–6h, 6o).
no reaction was observed. Higher conversions were Interestingly, under the hydration reaction conditions,
seen upon heating the reaction mixture, but complex the conversion of the starting material 3 into both
mixtures of products were observed with PNPOH as products 6 and 7 was considerably slower than the
the additive. However, by using boric acid, the fluori- Meyer–Schuster rearrangement to give enone 6 in the
nated ketones 7i and 7j were obtained in excellent presence of methanol as an additive.[13] This suggests
yields from the direct hydration reaction, and in these that the PNPOH additive is able to suppress the
cases no traces of the Meyer–Schuster rearrangement Meyer–Schuster rearrangement pathway that operates
products 6i/6j were observed. Other tertiary propar- in the presence of MeOH. The formation of the
Adv. Synth. Catal. 2016, 358, 1519 – 1525
ꢀ 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1521

UPDATES
Matthew N. Pennell et al.
enone by-product in these hydration reactions ap-
pears to be strongly influenced by the electronic envi-
ronment around the alcohol group. Substrates con-
taining strongly electron-withdrawing substituents
close to the alcohol (e.g., CF3) did not readily form
the enone at all, whereas propargylic alcohols which
contained groups able to stabilise a positive charge at
the alcohol carbon (tertiary propargylic alcohols, aryl-
substituted secondary propargylic alcohols) tended to
form exclusively the enone 6. We therefore hypothes-
ised that under these conditions, enone formation
must proceed via a mechanism that involves an inter-
mediate with substantial cationic character at the al-
cohol carbon. Coupled with the fact that the regiose-
lective hydration reactions in Scheme 4 were general-
ly much slower than the direct Meyer–Schuster rear-
Scheme 8. Proposed mechanistic pathways leading to 6 and
7.
rangements reported previously, this suggests that the protodeauration of the likely vinylgold intermediate
formation of the by-product 6 may take place via 8, generated by gold-catalysed addition of water or
elimination of water from the desired b-hydroxy the protic additive[16] across the alkyne (Scheme 8). If
ketone product 7. Resubmission of a purified sample ROH is sufficiently acidic, rapid protodemetallation
of hydroxy ketone 7a to the reaction conditions to give intermediate 9 takes place, followed by tauto-
(Scheme 7a) led to approximately 30% conversion merisation or hydrolysis to provide b-hydroxy ketone
into the corresponding enone 6a, suggesting that, in 7. This then undergoes slow acid-catalysed elimina-
the presence of PNPOH as the additive, the majority tion of water (either via an enol-assisted elimination
of the enone by-product observed is formed via an of water under general acid catalysis 10, or via an E1
acid-catalysed elimination of water from 7a. This is mechanism depending on the substrate structure). If
also consistent with the observation that additives ROH is not sufficiently acidic (MeOH), then inter-
that were more acidic than PNPOH led to increased mediate 8 can evolve via proton transfer and then
formation of enone 6a (Table 1). Resubmission of al- elimination of water, accompanied by cleavage of the
cohol 7a to the Meyer–Schuster rearrangement condi- carbon-gold bond, to give allene 12, which undergoes
tions[3] (1 equiv. of MeOH as the additive, Scheme 7b) tautomerisation or hydrolysis to provide 6. Again, the
did not lead to any elimination of water to give enone elimination step (11 to 12) must involve a transition
6a.
state with considerably positive charge build up at the
We believe that the protic additive[14] plays multiple propargylic alcohol carbon, as enone formation was
roles in the reaction: (i) inhibition of the ꢁnormalꢂ entirely suppressed in the case of strongly electron-
Meyer–Schuster pathway which gives the enone 6; (ii) deficient propargylic alcohols (3i and 3j) The hypoth-
promotion of an alternative pathway leading directly esis that intermediate 8 should undergo protodemetal-
to the b-hydroxy ketone 7; (iii) Brønsted acid catalyst lation with PNPOH is further supported by the fact
for the conversion of 7 into 6 via elimination of that phenols (but not alcohols) have been shown to
water; and (iv) solubilisation of water in the non- be capable of protonating an sp2 aryl-gold bond.[17] It
polar organic solvent.[15] We propose that the most should also be noted that the propargylic alcohol 3
important role of the acidic additive is to promote (and indeed the b-hydroxy ketone 7) can also act as
a nucleophile and/or proton source in the mechanism.
An alternative mechanism may operate in the case
of boronic (or boric) acid additives. We have previ-
ously proposed cyclic enol boronates 5 as common in-
termediates in the formation of the enone 6 and b-hy-
droxy ketone 7 (Scheme 1). Enol boronates of the
general structure 5 have rarely been reported and
structural data are limited.[18] Remarkably, however,
we were recently able to isolate an unusually stable
example in the course of our studies directed towards
a total synthesis of phyllaemblic acid and related nat-
ural products.[19] Reaction of sterically hindered elec-
tron-deficient propargylic alcohol 3p with phenylbor-
onic acid in the presence of a gold catalyst led to the
Scheme 7. Resubmission of alcohol 7a to the reaction condi-
tions.
formation of boron enolate 5p, with no evidence of
1522
asc.wiley-vch.de
ꢀ 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2016, 358, 1519 – 1525

UPDATES
Intercepting the Gold-Catalysed Meyer–Schuster Rearrangement
part of a complex mixture directly from propargyl al-
cohol 3p, by reaction with a gold catalyst using
MeOH as the protic additive. Attempted reactions of
5p with various nucleophiles (NaOH/H2O2) or elec-
trophiles (mCPBA, NBS, butyraldehyde) in an at-
tempt to either promote breakdown to the enone (6p)
or b-hydroxy ketone (7p), or to use 5p productively
for new carbon-carbon or carbon-heteroatom bond
formation were unsuccessful, leading to degradation
or trace amounts of 7p only.
The unusual reactivity of propargylic alcohol 3p is
consistent with the observations made during our
study of the direct hydration reactions of other sub-
strates (Scheme 4, 3i–3j), in that the presence of the
Scheme 9. Formation of an unusually stable boron enolate
5p via gold-catalysed reaction of a hindered propargylic al- two carbon-oxygen bonds adjacent to the propargylic
cohol 3p with phenylboronic acid.
alcohol is likely to prevent enone formation via desta-
bilisation of the cationic transition state for the elimi-
nation of water from intermediate 11, hydroxy ketone
further conversion to the enone 6p or b-hydroxy 7 (Scheme 8), or indeed the boron enolate 5p. Thus,
ketone 7p under the reaction conditions (Scheme 9). when the propargylic alcohol carbon bears electron-
The structure of 5p was confirmed by single crystal withdrawing substituents, the Meyer–Schuster rear-
X-ray crystallography (Figure 1).[20] The solid state rangement pathway becomes too high in energy, and
structure clearly shows the planarity of the boron protodemetallation of intermediate 8 becomes the
atom and how the two bulky TBS groups may shield only available pathway (Scheme 8), regardless of the
both the boron atom towards nucleophilic attack and protic additive present. With these substrates, the
the enol double bond towards electrophilic attack. propargylic alcohol itself is also likely to be more
Boron enolate 5p was exceptionally stable, being re- acidic than a typical alcohol, and therefore may also
covered unchanged after heating for 2 h at 2008C in be able to promote protodemetallation of the vinyl-
toluene in a microwave reactor. Treatment of 5p with gold intermediate 8.
TsOH in toluene[19a] at room temperature gave
In conclusion, we have shown that the gold-cata-
a modest 48% yield of the corresponding b-hydroxy lysed Meyer–Schuster rearrangement of propargylic
ketone 7p, which was also obtained in low yield as alcohols to enones can be diverted to give b-hydroxy
ketone products by the addition of protic additives to
the reaction mixture. In combination with the
straightforward addition of a terminal alkyne to a car-
bonyl compound, this offers an interesting alternative
to the aldol reaction. Furthermore, we have prepared
an unusually stable cyclic boron enolate 5p through
gold-catalysed reaction of a hindered electron-defi-
cient propargylic alcohol with a boronic acid. The iso-
lation of 5p supports our earlier hypothesis[3b] that
cyclic boron enolates 5 are intermediates in the gold-
catalysed reactions of propargylic alcohols using bor-
onic acid additives.
Experimental Section
Please see the Supporting Information for full details of the
experimental procedures, together with 1H and 13C NMR
spectra and crystallographic data for enolate 5p.[20]
General Procedure A: Preparation of Propargylic
Alcohols
Figure 1. Crystal structure of molecule 1 of 5p with ellip-
soids drawn at the 50% probability level. The structure con-
tains two crystallographically-independent molecules of
which only one is shown.
n-Butyllithium (1.6M in hexanes, 1.2 equiv.) was added
dropwise to a stirred solution of alkyne (1 equiv.) in dry
THF (1 mLmmolÀ1) at À788C under an argon atmosphere.
Adv. Synth. Catal. 2016, 358, 1519 – 1525
ꢀ 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1523

UPDATES
Matthew N. Pennell et al.
After 30 min aldehyde (1 equiv.) was added and the result-
ing solution was allowed to warm to room temperature and
stirred overnight. The reaction was quenched with saturated
aqueous NaHCO3 and the organic phase extracted with di-
ethyl ether. The combined organic extracts were washed
with brine, dried (MgSO4) and concentrated under vacuum.
The residue was purified by column chromatography to give
the propargylic alcohol.
G. B. Dudley, Org. Lett. 2006, 8, 4027; g) S. S. Lopez,
D. A. Engel, G. B. Dudley, Synlett 2007, 949.
[3] a) M. N. Pennell, P. G. Turner, T. D. Sheppard, Chem.
Eur. J. 2012, 18, 4748; b) M. N. Pennell, M. G. Unthank,
P. Turner, T. D. Sheppard, J. Org. Chem. 2011, 76, 1479.
[4] a) L. Ye, L. Zhang, Org. Lett. 2009, 11, 3646; b) T.
de Haro, C. Nevado, Chem. Commun. 2011, 47, 248;
c) M. Yu, G. Zhang, L. Zhang, Org. Lett. 2007, 9, 2147;
d) M. Yu, G. Zhang, L. Zhang, Tetrahedron 2009, 65,
1846.
Dec-5-yne-4-ol (3a):[3] yield: 75%; IR (film): nmax =3331,
2958, 2933, 2873, 2231 cmÀ1 1H NMR (600 MHz, CDCl3):
;
d=0.89 (3H, t, J=7.2 Hz), 0.91 (3H, t, J=7.3 Hz), 1.43
(4H, m), 1.64 (4H, m), 1.93 (1H, br s), 2.20 (2H, td, J=7.2,
1.9 Hz), 4.35 (1H, m); 13C NMR (150 MHz, CDCl3): d=
13.7, 13.9, 18.5, 18.6, 22.0, 30.9, 40.4, 62.6, 81.4, 85.6.
[5] a) G. Zhang, Y. Peng, L. Cui, L. Zhang, Angew. Chem.
2009, 121, 3158; Angew. Chem. Int. Ed. 2009, 48, 3112;
b) B. S. L. Collins, M. G. Suero, M. J. Gaunt, Angew.
Chem. 2013, 125, 5911; Angew. Chem. Int. Ed. 2013, 52,
5799.
[6] J. M. D’Oyley, A. E. Aliev, T. D. Sheppard, Angew.
Chem. 2014, 126, 10923; Angew. Chem. Int. Ed. 2014,
53, 10747.
[7] C. Kçrner, P. Starkov, T. D. Sheppard, J. Am. Chem.
Soc. 2010, 132, 5968.
General Procedure B: Preparation of b-Hydroxy
Ketones using p-Nitrophenol as Additive
[Ph3PAuNTf2]2PhMe (2 mol%) was added to a solution of
propargylic alcohol (1 equiv.) and 4-nitrophenol (1 equiv.)
dissolved/suspended in toluene (10 mLgÀ1; sonication was
used to dissolve the 4-nitrophenol as much as possible) and
the solution stirred magnetically at room temperature until
the starting material had disappeared by TLC (24–48 h).
The reaction was quenched with aqueous NH4Cl and the or-
ganic phase extracted with Et2O. The combined organic
phases were washed with brine, dried (MgSO4), concentrat-
ed under vacuum, and the crude product was purified by
column chromatography to give the b-hydroxy ketone.
[8] For regioselective hydration of terminal propargylic al-
cohols to methyl ketones, see: a) C. Palomo, A. Gon-
zµlez, J. M. García, C. Landa, M. Oiarbide, S. Rodrí-
guez, A. Linden, Angew. Chem. 1998, 110, 190; Angew.
Chem. Int. Ed. 1998, 37, 180; b) R. C. Gupta, P. A. Har-
land, R. J. Stoodley, J. Chem. Soc. Chem. Commun.
1983, 754; c) see also ref. [3a].
[9] For reports of the formation of b-hydroxy ketone by-
products during the study of other Au-catalysed reac-
tions of propargylic alcohols, see: a) J.-H. An, H. Yun,
S. Shin, S. Shin, Adv. Synth. Catal. 2014, 356, 3749;
b) B. Alcaide, P. Almendros, M. T. Quirós, Chem. Eur.
J. 2014, 20, 3384.
[10] For indirect hydration of propargylic alcohols via hy-
drosilylation or hydroboration followed by oxidation,
see: a) B. M. Trost, Z. T. Ball, T. Jçge, Angew. Chem.
2003, 115, 3537; Angew. Chem. Int. Ed. 2003, 42, 3415;
b) B. M. Trost, Z. T. Ball, K. M. Laemmerhold, J. Am.
Chem. Soc. 2005, 127, 10028; c) J. K. Park, B. A. On-
drusek, D. T. McQuade, Org. Lett. 2012, 14, 4790.
[11] For Ag-catalysed hydration of propargylic alcohols to
a-hydroxy ketones, see: H. He, C. Qi, X. Hu, Y.
Guana, H. Jianga, Green Chem. 2014, 16, 3729.
[12] D. Boyall, D. E. Frantz, E. M. Carreira, Org. Lett. 2002,
4, 2605.
[13] The regioselective hydration of alcohol 3a was carried
out in C6D6 and followed by 1H NMR. Rapid initial for-
mation of a small amount of enone 6a was observed (<
5%), followed by slow formation of 7a and further 6a
over the course of 48 h.
7-Hydroxydecan-5-one (7a):[21] yield: 65%; IR (film):
1
nmax =3429, 2958, 2932, 2873, 1704 cmÀ1; H NMR (600 MHz,
CDCl3): d=0.90 (3H, t, J=7.4 HZ), 0.92 (3H, t, J=7.2 Hz),
1.25–1.59 (8H, m), 2.42 (2H, t, J=7.4 Hz), 2.49 (1H, dd, J=
17.6, 8.4 Hz), 2.59 (1H, dd, J=17.6, 2.7 Hz), 4.02–4.06 (1H,
m); 13C NMR (150 MHz, CDCl3): d=13.9, 14.1, 18.7, 22.3,
25.8, 38.6, 43.5, 49.0, 67.4, 212.7.
Acknowledgements
We thank the Engineering and Physical Sciences Research
Council (EPSRC) and GlaxoSmithKline for providing an or-
ganic synthesis studentship to support MNP (EP/G040680/1),
the Department of Chemistry at University College London
for providing a PhD studentship to SMG, and the EPSRC
and University of Birmingham for providing a PhD student-
ship to MPK.
[14] In principle, only a catalytic amount of the protic addi-
tive is necessary for the reaction. Hydration of propar-
gylic alcohol 3a to give 6a/7a proceeded effectively
with 0.2 or 0.5 equivalents of PNPOH in NMR experi-
ments. However, inconsistent results were obtained
when attempting to carry out preparative scale reac-
tions with catalytic quantities of PNPOH.
[15] Although the hydration reaction requires an equivalent
of water to give complete conversion, addition of fur-
ther water to the reaction mixture was not found to be
beneficial, and adventitious moisture appears to be suf-
ficient for good conversions to be obtained. When a hy-
References
[1] a) E. B. Bauer, Synthesis 2012, 1131; b) Y. Zhu, L. Sun,
P. Lu, Y. Wang, ACS Catal. 2014, 4, 1911.
[2] a) R. S. Ramón, N. Marion, S. P. Nolan, Tetrahedron
2009, 65, 1767; b) M. Egi, Y. Yamaguchi, N. Fujiwara,
S. Akai, Org. Lett. 2008, 10, 1867; c) R. Ramón, S. Gail-
lard, A. M. Z. Slawin, A. Porta, A. DꢁAlfonso, G.
Zanoni, S. P. Nolan, Organometallics 2010, 29, 3665;
d) S. I. Lee, J. Y. Baek, S. H. Sim, Y. K. Chung, Synthe-
sis 2007, 2107; e) D. A. Engel, S. S. Lopez, G. B.
Dudley, Tetrahedron 2008, 64, 6988; f) D. A. Engel,
1524
asc.wiley-vch.de
ꢀ 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2016, 358, 1519 – 1525

UPDATES
Intercepting the Gold-Catalysed Meyer–Schuster Rearrangement
dration reaction of 3a was conducted under ꢁanhydrous
32, 2576; b) Y. Oonishi, A. Gómez-Suµrez, A. R.
Martin, S. P. Nolan, Angew. Chem. 2013, 125, 9949;
Angew. Chem. Int. Ed. 2013, 52, 9767.
conditionsꢂ (pre-drying of PNPOH and PhMe; addition
of dried 4Š molecular sieves to the reaction mixture;
reaction conducted under argon atmosphere), a 5:2
ratio of enone 6a:b-hydroxy ketone 7a was observed in
[17] K. E. Roth, S. A. Blum, Organometallics 2010, 29, 1712.
[18] a) K. Okada, Y. Hosoda, M. Oda, J. Am. Chem. Soc.
1986, 108, 321; b) P. Paetzold, S. Neyses, L. GØret, Z.
Anorg. Allg. Chem. 1995, 621, 732.
1
the H NMR spectrum of the crude product.
[16] In order to investigate whether a gold phenolate spe-
cies could be the active catalyst in this reaction, we
heated a sample of Ph3PAuMe with PNPOH in C6D6.
This led to the disappearance of the methyl signal and
the formation of a new species which did not react with
propargylic alcohol 3a. It should be noted, however,
that no stable gold phenolate complexes with phos-
phine ligands have previously been reported. For exam-
ples of gold phenolate complexes with NHC ligands,
see: a) N. Ibrahim, M. H. Vilhelmsen, M. Pernpointner,
F. Rominger, A. S. K. Hashmi, Organometallics 2013,
[19] T. C. Casey, J. Carlisle, P. Tisselli, L. Male, N. Spencer,
R. S. Grainger, J. Org. Chem. 2010, 75, 7461.
[20] CCDC 1448535 contains the supplementary crystallo-
graphic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
[21] C. Roche, O. Labeeuw, M. Haddad, T. Ayad, J. P.
Genet, V. Ratovelomanana-Vidal, P. Phansavath, Eur.
J. Org. Chem. 2009, 3977.
Adv. Synth. Catal. 2016, 358, 1519 – 1525
ꢀ 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1525