Hydrofluorination of alkynes catalysed by gold bifluorides

Article abstract of DOI:10.1002/cctc.201402891

We report the synthesis of nine new N-heterocyclic carbene gold bifluoride complexes starting from the corresponding N-heterocyclic carbene gold hydroxides. A new methodology to access N,N′-bis(2,6-diisopropylphenyl)imidazol-2-ylidene gold(I) fluoride starting from N,N′-bis(2,6-diisopropylphenyl)imidazol-2-ylidene gold(I) hydroxide and readily available potassium bifluoride is also reported. These gold bifluorides were shown to be efficient catalysts in the hydrofluorination of symmetrical and unsymmetrical alkynes, thus affording fluorinated stilbene analogues and fluorovinyl thioethers in good to excellent yields with high stereo- and regioselectivity. The method is exploited further to access a fluorinated combretastatin analogue selectively in two steps starting from commercially available reagents.

Full text of DOI:10.1002/cctc.201402891

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DOI: 10.1002/cctc.201402891
Hydrofluorination of Alkynes Catalysed by Gold
Bifluorides
Fady Nahra, Scott R. Patrick, Davide Bello, Marcel Brill, Alan Obled, David B. Cordes,
Alexandra M. Z. Slawin, David O’Hagan, and Steven P. Nolan*[a]
We report the synthesis of nine new N-heterocyclic carbene
gold bifluoride complexes starting from the corresponding N-
heterocyclic carbene gold hydroxides. A new methodology to
access N,N’-bis(2,6-diisopropylphenyl)imidazol-2-ylidene gold(I)
fluoride starting from N,N’-bis(2,6-diisopropylphenyl)imidazol-2-
ylidene gold(I) hydroxide and readily available potassium bi-
fluoride is also reported. These gold bifluorides were shown to
be efficient catalysts in the hydrofluorination of symmetrical
and unsymmetrical alkynes, thus affording fluorinated stilbene
analogues and fluorovinyl thioethers in good to excellent
yields with high stereo- and regioselectivity. The method is ex-
ploited further to access a fluorinated combretastatin analogue
selectively in two steps starting from commercially available re-
agents.
bifluoride complexes compared to their fluoride analogues, we
became intrigued by the possibility of applying this methodol-
ogy to NHC gold(I) complexes. Even though late transition
metal bifluoride complexes have been known for over three
decades,[11–15] the use of late transition metal bifluorides is still
underdeveloped. Most reported complexes are phosphine or
amine-based with only two examples bearing a NHC by Riant,
Leyssens and co-workers[11] (Cu) and more recently by Whittle-
sey and co-workers (Rh).[15] We now report on the synthesis of
new NHC gold(I) bifluoride complexes and their subsequent
role in enabling the hydrofluorination of a range of alkynes.
Strategies consisting of late transition metal tert-butoxide
complexes and triethylamine trihydrofluoride (NEt3·3HF)
proved unreliable when applied to NHC gold(I) complexes, due
mainly to the poor stability of the [Au(NHC)(OtBu)] complexes.
Previously, we have reported on the synthesis of [Au(IPr)(OH)]
(1).[16] We proposed that 1 could be a viable alternative to gold
tert-butoxide complexes, thus permitting access to a wide vari-
ety of gold bifluoride complexes. Preliminary results proved
encouraging, affording exclusively the cationic [{Au(IPr)-
(NEt3)}(HF2)] complex (2a, Scheme 1). Notably, during our initial
optimisations, the gold fluoride complex 3 was always ob-
served but its formation was suppressed subsequently by con-
trolling the amount and dilution of NEt3·3HF.
Fluorinated organic compounds are highly important in the
pharmaceutical and agrochemical industries.[1] Incorporating
a fluorinated group into drug-like compounds or biologically
active molecules can improve many of their properties, includ-
ing solubility, bioavailability, and metabolic stability.[2] The
number of reports describing such chemistry has increased
drastically over the last few years, giving rise to numerous pro-
cedures[3–9] catalysed mainly by Cu,[3] Pd,[4] Ir,[5] Ag,[6] Rh[7] and
Mn[8] complexes.
The reaction was extended to various N,N’-bis(2,6-diisopro-
pylphenyl)imidazol-2-ylidene (IPr)-based NHCs, whereby six
new bifluoride complexes (2a–f) were isolated in good yields
The pioneering work of Sadighi, Gray and co-workers on the
Au-catalysed hydrofluorination of alkynes revealed a new path-
way for the easy formation of
CÀF bonds and, subsequently,
the immense potential of N-het-
erocyclic carbene (NHC) gold(I)
complexes in this field.[10]
Following reports by Riant,
Leyssens and co-workers[11] and
more recently by Huang, Weng
and co-workers[12] on the high
Scheme 1. Initial synthetic route to complex 2a.
stability and reactivity of copper
and characterised fully (Scheme 2). Furthermore, the reaction
was effectively scaled to 1 g for the IPr-bearing complex 2a.
In an attempt to exchange the triethylamine moiety for
other ligands, we found that the former could be substituted
by pyridine by two methods (Scheme 3): reacting [Au(NHC)OH]
either with diluted pyridine hydrofluoride (Py·HF; method A) or
NEt3·3HF in the presence of 1 equivalent of pyridine (meth-
od B) readily afforded the desired [{Au(NHC)(Py)}(HF2)] com-
plexes 4a,b. Method B was particularly interesting as it allowed
[a] Dr. F. Nahra, S. R. Patrick, Dr. D. Bello, Dr. M. Brill, A. Obled, Dr. D. B. Cordes,
Prof. Dr. A. M. Z. Slawin, Prof. Dr. D. O’Hagan, Prof. Dr. S. P. Nolan
EaStCHEM School of Chemistry
University of St Andrews
St Andrews, KY16 9ST (UK)
E-mail: snolan@st-andrews.ac.uk
Homepage: http://chemistry.st-and.ac.uk/staff/spn/group/SP_Nolan/
Home.html
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/cctc.201402891.
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In an attempt to selectively form the gold mono-
fluoride species, 1 and NEt3·3HF (0.33 equiv) were re-
acted in benzene[10] and a mixture of mono- and bi-
fluoride complexes were obtained in a 70:30 ratio.
However, when the [Au(IPr)(OtAm)][16] (6; Am=amyl)
complex was reacted under the same conditions,
only the gold monofluoride was observed.[19] There-
fore, we reasoned that these two species might be in
equilibrium and the presence of H2O as a by-product
(from the gold hydroxide reaction) was sufficient to
shift the equilibrium towards the bifluoride. This phe-
nomenon could be especially important for catalytic
fluorination or fluorination and ring-opening process-
es, in which catalysts, particularly metal fluorides, are
exposed to an excess of a HF source.[3a,5b,7,10a]
To examine the persistence of the bifluoride
moiety in the presence of a base, [{Au(IPr)(NEt3)}(HF2)]
(2a) was reacted with a stoichiometric amount of
KOtBu. Full conversion to the
Scheme 2. Synthesis of [{Au(NHC)(NEt3)}(HF2)] complexes 2a–f.
corresponding monofluoride (3)
was observed within 4 h. More-
over,
addition
of
diluted
NEt3·3HF (NEt3·2HF) to 3 rapidly
regenerated the metal bifluoride
(2a).[20] Hence, these two species
were found to be inherently
linked (Scheme 4) and in the
presence of an excess of
NEt3·3HF or residual H2O,
a metal fluoride or hydroxide
would more than likely have de-
livered the metal bifluoride
in situ. This might have implica-
tions for the future design and
development of transition metal-
catalysed fluorination methodol-
ogies.
Scheme 3. Synthesis of [{Au(NHC)(L)}(HF2)] complexes and X-ray crystal structure of 4a. All hydrogen atoms are
omitted for clarity (see the Supporting Information for the disorder found for the HF2À anion).
We next reasoned that if KOR
was able to deprotonate the
gold bifluoride species, the re-
for other ligands to be used. This strategy was exploited fur-
ther by using Se(IPr) as ligand,[17] thus affording the desired
cationic complex 5 in good yield. To the best of our knowl-
edge, complex 5 constitutes the first example of a Se-based bi-
fluoride.
All gold bifluorides were air and moisture-stable in the solid
state, and may be considered an anhydrous source of fluoride.
More importantly, these species were also highly stable in solu-
tion if stored in plastic vials. The 19F NMR signal of these bi-
fluorides showed a broad singlet at approximately À170 ppm,
characteristic of a symmetric FHFÀ anion.[11] The acidic proton
À
of the HF2 moiety for complexes 2a–d was observed in
CD2Cl2, whereas the remaining bifluorides only revealed this
proton in CD3CN.[18a] In all cases, the proton resonated be-
tween 13.2 and 13.7 ppm, which is consistent with the struc-
ture of these complexes.[11a] Single crystals of 4a and 5 were
grown and X-ray analysis confirmed their structure (see the
Supporting Information).[18b]
Scheme 4. Gold fluoride versus gold bifluoride species.
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verse procedure using gold hydroxide species and
KHF2 could be possible, thus affording the desired
gold fluoride complexes. Gratifyingly, [Au(IPr)OH]
complex (1a) was able to deprotonate inexpensive
and readily available KHF2 and deliver the desired
[Au(IPr)F] (3) in 81% yield (Scheme 4).
The newly prepared gold bifluoride complexes
were then tested in the catalytic hydrofluorination of
alkynes as convenient and air-stable alternatives to
the previously described gold catalysts.[10,21] The ini-
tial optimisation reactions were performed by using
diphenylacetylene (7a) as a model substrate. After an
extensive optimisation, complexes bearing bulkier li-
gands IPr* (2e) and IPr*Tol (2 f) proved most effective
(see the Supporting Information). The use of a Py or
Se moiety instead of NEt3 gave poorer results, which
could be explained by their stronger coordination to
the gold centre. The final optimal conditions com-
prised the use of complexes 2e or 2 f in CH2Cl2 at
Scheme 6. Hydrofluorination of unsymmetrical alkynes. Reaction conditions: alkynes 9a–
f (0.5 mmol), 2 f (2 mol%), NEt3·3HF (1.5 mmol, 3 equiv), NH4BF4 (0.75 mmol, 1.5 equiv) in
CH2Cl2 (0.7m) at RT.
508C in a sealed plastic vial. The use of the NEt3·3HF (3 equiv)/
NH4BF4 (1.5 equiv) system allowed for lower catalyst loadings
and shorter reaction times (see the Supporting Information,
Tables 1–4).
strates also introduced a regioselectivity challenge, thus four
different products could be obtained. Early test reactions
showed that only the Z isomers were obtained. However, ele-
vated temperatures eroded the regioselectivity and traces of
the minor Z isomer were observed by 19F NMR. Therefore, the
reactions were performed at room temperature and the lower
reactivity was offset by increasing the reaction time to 5 days.
This procedure allowed expedient access to compounds that
were otherwise extremely difficult to generate. Catalyst 6 f was
also employed, as preliminary reactions had shown it to lead
to improved selectivities. The method differentiated quite se-
lectively between alkyl and aryl groups (10a–b) and only one
isomer was obtained, even if the alkyl group was a benzyl
moiety (10e). More interestingly, substrates 9c and 9d allowed
for the 1,4-addition of fluoride
The optimised conditions were then applied to various sym-
metrical alkynes (Scheme 5). Generally, excellent isolated yields
were obtained for 8a–i with a wide range of substitution pat-
terns. The reaction conditions tolerated bulky groups and elec-
tron-withdrawing and donating groups in meta and para posi-
tions. However, the use of ortho-substituted alkynes led to no
reactivity, presumably for steric reasons. Notably, in each case
only the Z isomer was afforded, with no E isomer observed.
The use of unsymmetrical alkynes was then examined
(Scheme 6). In addition to stereoselectivity issues, these sub-
and the desired products were
obtained with high selectivity.
The formation of enone 10c was
the only reaction without com-
plete regioselectivity, but the se-
lectivity was still high (especially
for this class of substrates) and
the major product could be iso-
lated straightforwardly. Finally,
9 f also afforded the desired
product 10 f in high yield and
selectivity. To the best of our
knowledge, this last example
constitutes the first of this class
of substrates to be catalytically
hydrofluorinated in an efficient
and selective manner.[22]
To fully exploit this strategy,
we applied these reaction condi-
tions to a highly functionalised
unsymmetrical alkyne. Alkyne 9g
was synthesised by using a modi-
fied literature procedure[23] and
Scheme 5. Hydrofluorination of symmetrical alkynes. Reaction conditions: alkynes 7a–i (0.5 mmol), 2e (2 mol%),
NEt3·3HF (1.5 mmol, 3 equiv), NH4BF4 (0.75 mmol, 1.5 equiv) in CH2Cl2 (0.7m) at 508C. [a] t=48 h; [b] 4 mol% of
2e used.
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methodology to access gold(I)
fluorides by using inexpensive
and benign potassium bifluoride
has been developed. The gold(I)
fluorides and bifluorides are
shown to be in equilibrium and,
as a function of reaction condi-
tions, these two species can
readily interconvert. The gold(I)
bifluorides have proven to be ef-
ficient catalysts in the hydro-
fluorination of symmetrical and
unsymmetrical alkynes, thus af-
fording fluorinated stilbene ana-
Scheme 7. Synthesis and hydrofluorination of alkyne 9g. Reaction conditions: alkyne 9g (0.5 mmol), 2 f (2 mol%),
NEt3·3HF (1.5 mmol, 3 equiv), NH4BF4 (0.75 mmol, 1.5 equiv) in CH2Cl2 (0.7m) at RT. [a] Corrected isolated yield.[25]
employed to prepare a fluorinated combretastatin analogue
(Scheme 7).[24] Gratifyingly, 40% conversion to the desired
product 10g was observed with high regioselectivity and ste-
reoselectivity (Scheme 7). Only the major regioisomer was iso-
lated in 32% yield,[25] characterised fully and its correct struc-
ture determined (shown in Scheme 7). This non-optimised pro-
cedure is the subject of an on-going investigation in our
group.
logues and fluorovinyl thioethers in good to excellent yields
with high stereo- and regioselectivity. Highly substituted and
functionalised alkynes have been hydrofluorinated. The
method is exploited further to selectively access a fluorinated
combretastatin analogue in two steps starting from commer-
cially available reagents, thus further affirming the usefulness
of the protocol.
We were also interested in the hydrofluorination of alkynyl
sulfides 11 to afford fluorovinyl thioethers 12. The latter are
considered putative biomimetic surrogates for the enol(ate) of
thioesters.[26] Attempts to hydrofluorinate these substrates by
using a range of literature procedures[10a,21a–b] proved unsuc-
cessful and our alternative protocol was subsequently tested
on this substrate class (Scheme 8). Reactions were performed
at room temperature until complete consumption of the start-
Acknowledgements
The ERC (Advanced Investigator Award FUNCAT and PoC award
GOLDCAT), the EPSRC and Syngenta are gratefully acknowledged
for support of this work. Umicore AG is acknowledged for their
generous gift of auric acid. S.P.N. is a Royal Society Wolfson Re-
search Merit Award holder.
Keywords: alkynes · bifluorides · gold · hydrofluorination ·
carbenes
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Chem. Int. Ed. 1999, 38, 3326; Angew. Chem. 1999, 111, 3543; l) B. Trus-
cott, F. Nahra, A. M. Z. Slawin, D. B. Cordes, S. P. Nolan, Chem. Commun.
2014, DOI: 10.1039/C4CC07772E.
[15] N. Bramananthan, M. Carmona, J. P. Lowe, M. F. Mahon, R. C. Poulten,
M. K. Whittlesey, Organometallics 2014, 33, 1986.
[16] F. Nahra, S. R. Patrick, A. Collado, S. P. Nolan, Polyhedron 2014, 84, 59.
[17] For syntheses of Se(NHC) complexes and examples of their coordina-
tion to gold, see: D. J. Nelson, F. Nahra, S. R. Patrick, D. B. Cordes,
A. M. Z. Slawin, S. P. Nolan, Organometallics 2014, 33, 3640.
[18] a) This phenomenon has been observed previously with Cu(NHC) bi-
fluorides with similar structures, see Ref. [11a]for more details; b) for X-
Received: November 6, 2014
ray structures and analyses of 4a (CCDC 1023541) and
5
Published online on && &&, 0000
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemCatChem 0000, 00, 1 – 5
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5
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These are not the final page numbers!

COMMUNICATIONS
F. Nahra, S. R. Patrick, D. Bello, M. Brill,
A. Obled, D. B. Cordes, A. M. Z. Slawin,
D. O’Hagan, S. P. Nolan*
Gold bifluorides: The syntheses of N-
heterocyclic carbene gold bifluoride
complexes are reported. These are
shown to be efficient catalysts in the
hydrofluorination of a wide range of
symmetrical and unsymmetrical alkynes.
The methodology is utilized further to
access a fluorinated combretastatin ana-
logue. R1 =aryl, thioether, R2 =H, Cl,
aryl, alkyl, ketone, ester.
&& – &&
Hydrofluorination of Alkynes
Catalysed by Gold Bifluorides
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemCatChem 0000, 00, 1 – 5
&
6
&
ÞÞ
These are not the final page numbers!