Scope and limitations of the dual-gold-catalysed hydrophenoxylation of alkynes

Article abstract of DOI:10.3762/bjoc.12.19

Due to the synthetic advantages presented by the dual-gold-catalysed hydrophenoxylation of alkynes, a thorough study of this reaction was carried out in order to fully define the scope and limitations of the methodology. The protocol tolerates a wide range of functional groups, such as nitriles, ketones, esters, aldehydes, ketals, naphthyls, allyls or polyphenols, in a milder and more efficient manner than the previously reported methodologies. We have also identified that while we are able to use highly steric hindered phenols, small changes on the steric bulk of the alkynes have a dramatic effect on the reactivity. More importantly, we have observed that the use of substrates that facilitate the formation of diaurated species such as gem-diaurated or s,pdigold-acetylide species, hinder the catalytic activity. Moreover, we have identified that the use of directing groups in unsymmetrical alkynes can help to achieve high regioselectivity in the hydrophenoxylation.

Full text of DOI:10.3762/bjoc.12.19

Scope and limitations of the dual-gold-catalysed
hydrophenoxylation of alkynes
Adrián Gómez-Suárez1, Yoshihiro Oonishi1,2, Anthony R. Martin1,3
and Steven P. Nolan*4,5
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2016, 12, 172–178.
1EaStCHEM School of Chemistry, University of St. Andrews, North
Haugh, St. Andrews, Fife, KY16 9ST, U.K, 2Faculty of Pharmaceutical
Sciences, Hokkaido University, Sapporo 060-0812, Japan, 3Institut de
Chimie de Nice, UMR 7272, Université de Nice Sophia Antipolis,
CNRS, Parc Valrose, 06108 Nice cedex 2, France, 4Chemistry
Department, College of Science, King Saud University, P.O. Box
2455, Riyadh 11451, Saudi Arabia and 5Universiteit Gent,
Department of Inorganic and Physical Chemistry, Krijgslaan 281, S-3,
B-9000 Ghent, Belgium
doi:10.3762/bjoc.12.19
Received: 08 December 2015
Accepted: 14 January 2016
Published: 01 February 2016
This article is part of the Thematic Series "N-Heterocyclic carbenes".
Associate Editor: K. Itami
Email:
© 2016 Gómez-Suárez et al; licensee Beilstein-Institut.
License and terms: see end of document.
Steven P. Nolan* - stevenpnolan@gmail.com
* Corresponding author
Keywords:
cooperative catalysis; gold catalysis; hydrophenoxylation;
N-heterocyclic carbene; vinyl ethers
Abstract
Due to the synthetic advantages presented by the dual-gold-catalysed hydrophenoxylation of alkynes, a thorough study of this reac-
tion was carried out in order to fully define the scope and limitations of the methodology. The protocol tolerates a wide range of
functional groups, such as nitriles, ketones, esters, aldehydes, ketals, naphthyls, allyls or polyphenols, in a milder and more effi-
cient manner than the previously reported methodologies. We have also identified that while we are able to use highly steric
hindered phenols, small changes on the steric bulk of the alkynes have a dramatic effect on the reactivity. More importantly, we
have observed that the use of substrates that facilitate the formation of diaurated species such as gem-diaurated or σ,π-
digold–acetylide species, hinder the catalytic activity. Moreover, we have identified that the use of directing groups in unsymmetri-
cal alkynes can help to achieve high regioselectivity in the hydrophenoxylation.
Introduction
During the last 30 years, N-heterocyclic carbenes (NHCs) have steric and electronic properties [2-6], NHCs are nowadays used
evolved from mere curiosities to one of the most powerful tools in a myriad of chemical processes, for example as catalysts in
within the synthetic chemist’s arsenal [1]. Due to their unique organocatalysed reactions [7-9], or as ligands in transition metal
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Beilstein J. Org. Chem. 2016, 12, 172–178.
and main-group chemistry [10-13]. We have been interested in were well tolerated and the corresponding vinyl ethers were ob-
exploring the use of NHC ligands in transition metal complexes tained in moderate to high yields (50–98%). On the contrary,
for the development of highly active and well-defined catalysts. the use of azide (3ag) or boronic ester (3ah) functionalities did
One of our main interests during the last decade has been to not afford the desired products [29]. The latter case can be ex-
study the use of gold–NHC species as powerful catalysts for the plained due to formation of the corresponding gem-diaurated
construction of valuable organic molecules via the construction aryl species, by reaction of catalyst [{Au(IPr)}2(µ-OH)][BF4]
of C–C or C–O bonds [14-23]. In this regard, we have recently with the boronic ester [30], thus inhibiting the catalytic activity.
reported the use of [{Au(NHC)}2(µ-OH)][BF4] species as dual- The electronic properties of the phenol were also examined. If
activation catalysts for the hydrophenoxylation of alkynes the electron density on the phenol is decreased, its nucleophilic-
[24,25]. This transformation proceeds through the interaction of ity decreases and an increase in catalyst loading is needed in
the gold centres with both the phenol and the alkyne motifs, order to maintain relatively short reaction times (3ai and 3al)
thus generating a synergistic effect that produces unique catalyt- [31]. The steric hindrance on the phenol was studied next. In-
ic activity (Scheme 1) [24,25]. In addition, this reaction is creasing it, with either allyl (3am) or tert-butyl (3an) groups on
highly stereoselective and only the Z-isomer was observed, the ortho-position also required 1 mol % of catalyst, but the
regardless of the substrate used.
reaction proceeded smoothly. Encouraged by these and past
results with highly hindered substrates, we attempted the addi-
This new, dual-catalysed methodology presents several advan- tion of 2,6-di-tert-butylphenol (2ao). Unfortunately, this reac-
tages over previously reported protocols [26,27], such as milder tion did not proceed at all and only starting materials were ob-
reaction conditions or the use of lower catalyst loading. There- served by GC–FID. These results, in combination with our
fore, encouraged by our preliminary studies [24], and the poten- previous studies [24], where para-MeO, -CF3, -NO2, -Cl or -F
tial applications of the vinyl ether derivatives 3 as synthetic substituents were also tolerated, support the robustness of our
building blocks [28], we decided to further explore the scope protocol, as it is highly efficient in the presence of a wide range
and limitations of the dual-gold-catalysed hydrophenoxylation of functional groups.
of alkynes. With this study, we sought to answer the following
questions: what is the functional group tolerance of our trans- Polyphenols as nucleophiles
formation? How do steric and electronic factors affect both Intrigued by the versatility of our protocol, we explored the
reaction partners? Can regioselectivity be achieved for the addi- reaction using polyphenols as substrates (Scheme 3). Interest-
tion of phenols to unsymmetrical alkynes?
ingly, we were able to selectively functionalize one (3ap) or
both (4ap) hydroxy groups of catechol (2p) by using one or two
equiv of 1a, respectively. Unfortunately, for the other
polyphenol derivatives only the difunctionalised products could
Results and Discussion
Functional group tolerance
We commenced our studies by assessing the functional group be observed (4aq–4as). We hypothesize that this difference in
tolerance of the methodology (Scheme 2). With that aim we reactivity may be due to the steric hindrance around the mono-
reacted diphenylacetylene (1a) with several phenols, 2a–o, in functionalised product 3ap, allowing for a significant rate
toluene, using 0.5 mol % of [{Au(IPr)}2(µ-OH)][BF4] (IPr = difference in the reactions of 3ap and 4ap. In other cases, the
1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene) as the cata- greater separation between the hydroxy functional groups likely
lyst. Functional groups such as nitriles (3aa), ketones (3ab), reduces this difference. To put these results in context, the pre-
esters (3ac), aldehydes (3ad), acetals (3ae) and naphthyls (3af) viously reported methodology required 10 mol % of AuCl3 and
Scheme 1: Dual-gold-catalysed hydrophenoxylation of alkynes.
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Beilstein J. Org. Chem. 2016, 12, 172–178.
Scheme 2: Exploring the functional group tolerance. Reaction conditions: 1a (0.50 mmol, 1 equiv), 2a–o (0.55 mmol, 1.1 equiv), [Au] (2.5 µmol,
0.5 mol %), toluene (1 mL), 80 °C. Isolated yields, average of two runs. a[Au] (5 µmol, 1 mol %), 110 °C. bGC analysis showed a complex mixture.
96 h in order to obtain similar yields for 4aq [26]. Moreover, stituents due to synthetic reasons. The use of the ortho-chloro-
only 7% of 4ap could be isolated after 168 h [26].
phenyl derivative 1f afforded the desired vinyl ether 3ft in good
yields, while changing the chlorides for methyl groups resulted
in no reaction, even when using harsher reaction conditions
Electronic and steric effects on the alkyne
Next, we sought to assess how the electron density on the (3gt, Scheme 4). One more highly hindered substrate, 1h, bear-
alkyne affected the reaction. Therefore, both electron-rich (1b, ing a sterically demanding naphthyl group on one side, and a
1e) and electron-poor (1c) alkynes were tested using phenol 2t phenyl on the other was studied. No reaction was observed even
as nucleophile. The desired vinyl ethers, 3bt, 3ct and 3et, were after increasing the catalyst loading and temperature (3ht,
obtained in moderate to good yields (Scheme 4). In order to Scheme 4). Next, we focused our attention on whether the chain
expand the alkyne scope, propargylic ethers were also tested. In length on unsymmetrical alkyl–aryl alkynes, or the electron
this case, 2 equiv of the alkyne were needed to obtain good density on the phenol could affect the regioselectivity of the
yields of the desired product, 3dt. Next, we targeted the steric reaction. The use of 1-phenylbut-1-yne (1i) afforded the desired
hindrance tolerated around the alkyne. With this aim in mind vinyl ethers 3it and 3it' in a 1:0.23 ratio and in good yields.
we decided to use diaryl-substituted alkynes bearing ortho-sub- This selectivity is slightly lower than our previously reported
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Beilstein J. Org. Chem. 2016, 12, 172–178.
Scheme 3: Hydrophenoxylation using polyphenols. Reaction conditions: 1a (1 mmol, 2 equiv), 2p–s (0.50 mmol, 1 equiv), [Au] (2.5 µmol, 0.5 mol %),
toluene (1 mL), 80 °C. Isolated yields, average of two runs. a1 equiv 1a. b[Au] (5 µmol, 1 mol %), 110 °C.
Scheme 4: Hydrophenoxylation of (un)symmetrical alkynes. Reaction conditions: 1b–k (0.50 mmol, 1 equiv), 2t (0.55 mmol, 1.1 equiv), [Au]
(2.5 µmol, 0.5 mol %), toluene (1 mL), 80 °C. Isolated yields, average of two runs. Ratio determined by 1H NMR. a[Au] (5 µmol, 1 mol %), 110 °C.
b1d (1 mmol, 2 equiv), 2t (0.50 mmol, 1 equiv).
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Beilstein J. Org. Chem. 2016, 12, 172–178.
Enhancing regioselectivity using directing
hydrophenoxylation of phenylpropyne (1j, 1:0.18) [24]. We
also studied if the electron density on the phenol could alter the groups
selectivity. Addition of p-methoxyphenol (2u) to 1j afforded a During our preliminary study on the hydrophenoxylation of un-
1:0.22 ratio between the two expected products, 3ju and 3ju'. symmetrical alkynes [24], we observed that the use of alkynes
This selectivity is slightly diminished compared to the addition bearing a 2-pyridinyl moiety afforded only one of the possible
of phenol to 1j (1:0.18), but better than the addition of p-nitro- vinyl ether derivatives (3lt and 3mt, Scheme 5). We hypothe-
phenol (2v, 1:0.35), both reported in our previous study (3jt and sised that this directing effect could be a combination of the
3jv, Scheme 4) [24]. Finally, we tested whether terminal charge polarization on the alkyne and an interaction between
alkynes were tolerated by our methodology. Phenylacetylene the pyridine nitrogen and one of the gold centres. To test our
(1k) was reacted with phenol (2t) under our standard reaction hypothesis, we synthesized an alkyne bearing a 3-pyridinyl (1n)
conditions, 0.5 mol % [{Au(IPr)}2(µ-OH)][BF4] as catalyst, in substituent. In order to reduce the reaction time the catalyst
toluene at 80 °C for 1 h. However, GC–FID analysis of the loading was increased to 3 mol %. Interestingly, the selectivity
reaction mixture revealed only traces of product. A more careful dropped dramatically and a 1:0.43 ratio of products was ob-
study of the crude reaction mixture by 1H NMR spectroscopy, served (3nt, Scheme 5). In order to further test our hypothesis,
revealed 8% conversion to the desired vinyl ether 3kt, as well the polarization of the alkyne was next reduced, but the poten-
as 10% of acetophenone, the corresponding hydration product. tial chelating heteroatom was retained. The hydrophenoxyla-
Furthermore, the formation of a new gold species, which was tion of the unsymmetrical propargylic ether 1o afforded, with
characterised as the previously reported σ,π-digold–acetylide complete regioselectivity, the corresponding vinyl ether 3ot
species could also be observed. This diaurated species can be [32]. As expected, when homopropargylic ether 1p was used
formed by reaction of [{Au(IPr)}2(µ-OH)][BF4] with phenyl- diminished selectivity was observed. Thus supporting our
acetylene [30]. As in the case of the formation of a gem-diau- hypothesis that regioselectivity can be obtained by assistance of
rated species when boronic ester 3h was used, it appears that in a directing group, either by polarization of the alkyne or by a
situ formation of highly stable diaurated species, inhibits cata- chelating effect [33].
lytic activity.
Conclusion
These results suggest that while both electron-rich/poor alkynes We have explored an extended range of reactions in order to
are tolerated by our methodology, the tolerated steric hindrance fully define the scope and limitations of the digold-mediated
is very low, in contrast to the results observed for the nucleo- hydrophenoxylation of alkynes. With these additions we have
phile. In addition, in the case of unsymmetrical alkynes, the use performed the gold-catalysed hydroalkoxylation of alkynes on
of electron-rich alkynes appears to favour a better selectivity ca. 50 substrates, thus demonstrating the robustness and synthe-
than their electron-poor counterparts.
tic versatility of the methodology. The protocol tolerates a wide
Scheme 5: Regioselective hydrophenoxylation of unsymmetrical alkynes. Reaction conditions: 1l–p (1 equiv), 2a (1.1 equiv), [Au] (1 mol %), toluene
(1 mL), 110 °C. Isolated yields, average of two runs. Ratio determined by 1H NMR. nd = not detected. a[Au] (3 mol %). b[Au] (0.5 mol %), 1o (2 equiv.)
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aldehydes, acetals, naphthyls or allyls. Furthermore, we have
successfully used polyphenols in a milder and more efficient
manner than the previously reported methodologies. We have
also identified that while we are able to use highly steric
hindered phenols, small changes on the steric bulk of the
alkynes have a dramatic effect on reactivity. More importantly,
we have observed that the use of substrates that facilitate the
formation of diaurated species such as gem-diaurated or σ,π-
digold–acetylide species, hinder the catalytic activity. We have
identified that the use of directing groups in unsymmetrical
alkynes can help achieve regioselectivity in the hydrophenoxy-
lation reaction. With these studies, we have sought to contrib-
ute to a better understanding of the interactions involved in
dual-gold-catalysed reactions, and anticipate that this informa-
tion will help to design more efficient dual-activation protocols.
We are currently studying the use of digold–hydroxide species
in other dual-gold-catalysed reactions and these results will be
published in due course.
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Supporting Information File 1
Experimental procedures and characterisation data for all
the compounds.
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Acknowledgements
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The ERC (Advanced Investigator Award-FUNCAT) and
Syngenta are gratefully acknowledged for support. Umicore AG
is acknowledged for their generous gift of materials. This publi-
cation is based upon work supported by the King Abdullah
University of Science and Technology (KAUST), Office of
Sponsored Research (OSR) under Award No. OSR-2015-CCF-
1974-03. Y.O. thanks the Uehara Memorial Foundation for a
Research Fellowship. We also thank Danila Gasperini for early
synthetic contributions and Dr. David J. Nelson for helpful
discussions.
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