Highly regioselective gold-catalyzed formal hydration of propargylic: Gem -difluorides

Article abstract of DOI:10.1039/c7ob02406a

Herein, we report a highly regioselective gold-catalyzed formal hydration of propargylic gem-difluorides. Not only does this transformation provide access to versatile fluorinated building blocks that were difficult or hardly possible to access beforehand, but it also represents a rare case of a highly regioselective gold-catalyzed hydroalkoxylation of internal alkynes and puts forward the utility of the difluoromethylene unit as a directing group in catalysis.

Full text of DOI:10.1039/c7ob02406a

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Highly regioselective gold-catalyzed formal
hydration of propargylic gem-difluorides†
Cite this: DOI: 10.1039/c7ob02406a
Jean-Denys Hamel, Tatsuru Hayashi, Mélissa Cloutier, Paul R. Savoie,
Olivier Thibeault, Meggan Beaudoin and Jean-François Paquin
*
Herein, we report a highly regioselective gold-catalyzed formal hydration of propargylic gem-difluorides.
Not only does this transformation provide access to versatile fluorinated building blocks that were difficult
or hardly possible to access beforehand, but it also represents a rare case of a highly regioselective gold-
catalyzed hydroalkoxylation of internal alkynes and puts forward the utility of the difluoromethylene unit
as a directing group in catalysis.
Received 26th September 2017,
Accepted 7th November 2017
DOI: 10.1039/c7ob02406a
rsc.li/obc
Parallel to this, owing to the distinctive properties of the
fluorine atom,11 organofluorine compounds have found wide
Introduction
Gold catalysts1 attracted a lot of attention in the past years for applications in various fields including medicinal chemistry,
their propensity to selectively activate alkynes2 over other func- agrochemistry and material sciences.12–14 As such, the develop-
tionalities towards nucleophilic attack under mild reaction ment of synthetic methods involving organofluorine com-
conditions, and relativistic effects would be at the root of this pounds has been a stimulating research topic over the past
preference for the activation of alkynes. Au(I) and Au(III) years.15 In that context and given the aforementioned impact
species both display such reactivity, and as such have been of electron-withdrawing substituents onto the regioselectivity
used in conjunction with a broad selection of O-, N- and of the gold-catalyzed addition of O-based nucleophiles to
C-based nucleophiles, for example. However, regarding inter- alkynes, we set out to exploit the strong electrowithdrawing
molecular hydration and hydroalkoxylation reactions, caveats character of fluorine atoms to direct such a reaction. We
should be raised regarding the regioselectivity of the trans- hypothesized that the difluoromethylene unit intrinsic to pro-
formation. Indeed, while the Markovnikov product (i.e., the pargylic gem-difluorides16 would impose a significant-enough
ketone) is typically obtained upon performing the reaction on electronic bias to result in high regioselectivity,17 thus favoring
terminal alkynes (Scheme 1a), the use of internal alkynes gen- the formation of 3,3-difluoroketones in presence of a suitable
erally leads to the formation of regioisomeric products nucleophile.
(Scheme 1b).3,4 This can be completely or partially solved
using neighboring nucleophile as directing group difluoroketones appears really attractive as it would circumvent
It is noteworthy that this new synthetic route to access 3,3-
a
a
(Scheme 1c).5 Alternatively, the electronic nature of the substi- issues associated with the deoxofluorination reaction. Indeed,
tuents on the alkyne has also been shown to play a role in the the deoxofluorination of aldehydes or ketones is a classical
regioselectivity in the Au-catalyzed hydrophenoxylation6 or approach for the preparation of gem-difluoro compounds, and
hydroalkoxylation7 of 1,2-diarylalkynes, in the Au(I)-catalyzed this transformation can be performed using various reagents
hydration of propargylic alcohols8 and in a Au(I)-catalyzed including sulfur tetrafluoride,18 (diethylamino)sulfur trifluor-
tandem intermolecular hydroalkoxylation/Claisen rearrange- ide (DAST) or derivatives,19 Deoxofluor,20 XtalFluor21 and
ment of 1-aryl-2-alkylalkynes.9 In these cases, nucleophilic Fluolead22 (Scheme 1e). However, while this reaction can be
attack was found to occur preferentially at the carbon distal to applied to a wide range of substrates, its use with 1,3-diketones
the electrowithdrawing fragment (Scheme 1d). In a few is known to be challenging (Scheme 1f). In the best cases, the
instances, ynamides and alkynyl ethers were also found to desired 3,3-difluoroketone is obtained in low yield, while the
react regioselectively with O-nucleophiles.10
presence of multiple side products, including tetrafluorinated
products, fluoroalkenes, difluoroalkenes, as well as others, is
generally observed.23 The only exception is when a biased
system (where one of the carbonyl groups is electronically de-
activated in the form of an ester or an amide) is used,24
although this may also be further complicated by the ketone/
enol tautomerization leading to fluoroalkene derivatives.25
CCVC, PROTEO, Département de chimie, 1045 avenue de la Médecine, Université
Laval, Québec, Québec, Canada G1V 0A6.
E-mail: jean-francois.paquin@chm.ulaval.ca
†Electronic supplementary information (ESI) available: Experimental procedures
and characterizations. See DOI: 10.1039/c7ob02406a
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Scheme 1 Background for this study: (a–d) current status including regioselectivity issues in terms of Au-catalyzed addition of O-based nucleo-
philes to alkynes, (e–f) challenges associated with the installation of a difluoromethylene unit via a deoxofluorination reaction and (g) this work.
In that context and given the potential utility of 3,3-difluoro- selective Au-catalyzed hydroalkoxylation of internal alkynes.
ketones and their derivatives as versatile fluorinated building Under the reaction conditions, 4 would partially convert to
blocks or as bioactive compounds,26 an alternative and more ketone 2a and acetal 3 through classical acid-catalyzed proces-
efficient approach for their synthesis is highly sought after.
ses.4d,28,29 Upon an acidic treatment after the reaction (3 N
Taking all this into account, we now wish to describe HCl/CH2Cl2 (1 : 1), 21 °C, 3 h), both 3 and 4 would convert to
herein the development of a highly regioselective Au-catalyzed 2a, which was isolated in 82% yield as the single regioisomer.
formal hydration of propargylic gem-difluorides (Scheme 1g). When the reaction was repeated on 1 mmol scale, a 77% yield
Notably, our report documents a rare occurence of a highly of 2a was obtained, proving the applicability of the present
regioselective Au-catalyzed hydroalkoxylation of internal methodology on a larger scale.
alkynes3 and puts forward the utility of the difluoromethylene
To compare this unprecedented effect of fluorine substi-
unit as a directing group. The current methodology also pro- tution on the reactivity and regioselectivity, the reaction was
vides access to fluorinated compounds that were difficult or performed on related non-fluorinated substrates (Scheme 3).
hardly possible to access beforehand.
First, 1-phenyl-1-butyne (5) was reacted under our optimized
conditions (cf. Scheme 2). An 82% conversion was observed
and NMR analysis of the crude mixture indicated that both
regioisomers 6 (produced by an attack at C1) and 7 (produced
by an attack at C2) were formed in 41% and 30% NMR yields,
Results
While preliminary studies focused on the Au-catalyzed respectively. In this case, without the strong electronic bias
hydration of propargylic difluoride 1a, the corresponding 3,3- brought about by the two fluorine atoms, a modest selectivity
difluoroketone (2a) was never observed (results not shown). We is observed, where attack at the more electrophilic carbon is
next explored the hydroalkoxylation of 1a using MeOH, a predominant. This result highlights the critical role played by
slightly better nucleophile for such transformation,27 and after the difluoromethylene unit in directing the addition at the C1
some experiments (cf. Table S1†), optimized conditions were carbon, while, at the same time, increasing the reactivity of the
found (Scheme 2). Essentially, using a cationic gold complex alkyne towards addition. Surprisingly, using 3,3-dichloro-1-
derived from Ph3PAuCl, generated in situ by the addition of phenyl-1-propyne (8), almost no reaction was observed (ca. 1%
5 mol% of AgOTf in a THF/MeOH (9 : 1) mixture provided full conversion) even though related fluorinated substrates
conversion. Analysis of the crude mixture indicated a mixture behaved normally (vide infra), suggesting that the strong elec-
of related products all originating from a regioselective attack tron-withdrawing ability of the fluorine atoms of the difluoro-
of methanol at C1, and no products arising from attack at C2 methylene unit is not the only factor at play and that a steric
were detected, thus representing a rare case of a highly regio- component may also be present. To probe this, 3,3-dimethyl-1-
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ably slows down the reaction. Overall, these results demon-
strate that the difluoromethylene unit offers a unique combi-
nation of a strong electron-withdrawing effect combined with
a small steric impact, both of which seem essential for this
transformation.
To gain a better understanding of the origin of the high
regioselectivity observed for the addition of methanol to 1a, we
performed DFT calculations (BP86/def2-TZVP)30 on intermedi-
ate π-complex 14 where the actual PPh3 ligand was replaced
with PMe3.31 Interestingly, a highly unsymmetrical π-complex
is calculated. Indeed, while the C2–Au bond is 2.16 Å, the C1–
Au bond is 2.45 Å (Scheme 4).32 In comparison, Au–C bond
distances in a H3PAu/acetylene complex have been calculated
to be 2.25 Å,30 while a fully-relativistic calculation of the
AuCl3–propyne complex yielded Au–C distances of 2.162 and
2.197 Å.33
The profound difference in the calculated Au–C distances
can be explained by the computed Mulliken charges and the
structure of the HOMO for the π-complex 14. The computed
charges for the gold atom, C1, and C2 are +0.47, +0.06, and
−0.21; favorable interactions between oppositely-charged Au
and C2 result in a shorter Au–C2 distance from electrostatic
attraction, while unfavorable interactions between similarly-
charged Au and C1 would yield a greater Au–C distance from
electrostatic repulsion. In the HOMO orbital density of
π-complex 14, there is a small contribution from Au, consistent
with data reported previously.33 Between the alkyne carbon
atoms, however, the largest coefficients are found on C2, while
there is little contribution from C1. By contrast, the LUMO
density is much greater at C1, and there is some interaction
Scheme 2 Optimized conditions using gem-difluoride 1a. a NMR yield
estimated by 19F NMR analysis of the crude mixture after an aqueous
work-up (sat. aq. NaHCO3) using 2-fluoro-4-nitrotoluene as the internal
standard. b Isolated yield of 2a.
Scheme 3 Effect of fluorine atom replacement. Yields were deter-
mined by 1H NMR analysis of the crude mixture using 1,4-dimethoxy-
benzene as the internal standard.
phenyl-1-butyne (11) was submitted to the optimized reaction
conditions and a very low conversion was observed with both
isomers 12 and 13 detected in the crude mixture (4% and <1%
respectively). This suggests that the steric effect of the substitu-
Scheme 4 Calculated structure for intermediate 14. Distances are
ent at C2 is important and that a bulky substituent consider- reported in Å.
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between C1 and the ipso carbon of the adjacent phenyl ring, and 2e were isolated in 72% and 61% yields, respectively. In
which would also preclude C1–Au interactions. both cases, a slight heating (40 °C) along with a prolonged
Other calculations had us find a 6.1 kcal mol−1 energy reaction time was required for complete conversion. We attri-
difference between attack on C1 vs. attack on C2 (see ESI†). bute this lower reactivity to a steric effect caused by the pres-
Together, the Mulliken charge, orbital density, and energy ence of a secondary carbon at the R2 position. For substrates
data explain why addition of methanol at C1 is preferred over bearing R1/R2 = alkyl/alkyl, high yields were obtained for the
C2, and supports our initial hypothesis that the difluoro- formation of 3,3-difluoroketones 2f and 2g (84–89%), those
methylene unit would impose a significant electronic bias.
two compounds having the R1 and R2 substituents inverted
After establishing the unique directing ability of the from one another. This illustrates well the versatility of the
difluoromethylene unit, the scope of this transformation was method as this is equivalent to performing the deoxofluorina-
next explored. The results are classified according to the tion of the same 1,3-diketone, but with predictable and perfect
nature of both the R1 and R2 groups and are shown in regioselectivity towards the desired carbonyl moiety. It was
Scheme 5. Hence, substrates bearing aryl/alkyl groups reacted noted that the size of the substituent at R1 had an important
well to provide the desired 3,3-difluoroketones 2a–e in good influence on the yield as a tert-butyl group hindered the reac-
yields (61–84%). Gratifyingly, the preparation of 2a could be tion even under more forcing conditions (7% NMR yield of 2h
performed on a 1 mmol scale without any substantial loss of at 70 °C for 18 h). 3,3-Difluoroketone 2g was also reduced to
yield. The presence of an ester group did not influence the the alcohol 15 in 93% yield under standard conditions. This
regiochemistry of the addition5a and as such, 2c was isolated two-step sequence (from the corresponding propargylic
as the sole regioisomer. Substrates bearing a Cbz-protected difluoride) demonstrates the utility of the products generated
amine or a 1,3-benzodioxole were well tolerated as products 2d as it represents a synthetic equivalent to the selective deoxo-
Scheme 5 Substrate scope of the formal hydration of propargylic gem-difluorides. See ESI† for the detailed experimental procedure. Isolated yield
of 2 after column chromatography. a The reaction was performed on a 1 mmol scale. b The reaction (step i) was performed at 40 °C for 48 h. c The
reaction (step i) was performed at 70 °C for 18 h. d NMR yield estimated by 19F NMR analysis using 2-fluoro-4-nitrotoluene as the internal standard.
e Step ii was stirred for 24 h.
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fluorination of a ketone over an alcohol, an unprecedented more potent precatalyst, and full conversion was achieved
transformation.34 A number of substrates with R1/R2 = aryl/aryl within 18 hours at 50 °C, with formation of the expected 3,3-
were also subjected to the reaction conditions and the pro- difluoroaldehyde 2p in 82% NMR yield (Scheme 6b). As the
ducts 2i–l were isolated in moderate to good yields (49–82%). aldehyde was slightly unstable to purification by column
Surprisingly, the substrate bearing a 3-methoxyphenyl at the chromatography on silica gel, it was reduced to the corres-
R2 position did not react. This result hints that the presence of ponding alcohol 16 prior to isolation, which was finally
an electron-donating group may interfere with the reaction. obtained in 69% yield over two steps.
Further investigations will aim at understanding this phenom-
enon. Substrates of the class alkyl/H or aryl/H both reacted
under the standard conditions to provide the 3,3-difluoro-
ketones 2n and 2o in 78% and 64% yields, respectively.
Conclusions
In conclusion, we have reported a highly regioselective Au-cata-
lyzed formal hydration of propargylic gem-difluorides. This
transformation results in 3,3-difluoroketones, versatile fluori-
nated building-blocks that were difficult or hardly possible to
Interestingly, these compounds pose as synthetic equivalents
to the selective deoxofluorination of an aldehyde over a
ketone. Overall, these results show that the selectivity observed
is independent of the substrate type, hence alkynes bearing
various R1/R2 groups all successfully reacted to provide the
access beforehand, as single regioisomers. As such, this work
represents a rare case of a highly regioselective Au-catalyzed
desired 3,3-difluoroketones as the unique regioisomer.
hydroalkoxylation of internal alkynes. DFT calculations
A substrate with a terminal alkyne was reacted under
suggest that this unusual regioselectivity originates from the
slightly modified reaction conditions, but showed lower reac-
significant electronic bias imposed by the difluoromethylene
tivity (Scheme 6a). Partial conversion was observed even upon
unit. Importantly, the recent development of novel and practi-
increasing catalyst loading, temperature and time (84% conver-
cal methods to access propargylic gem-difluorides36 other than
sion, 46% NMR yield). This might come as a surprise when
the deoxofluorination of ynones should facilitate the use and
only taking steric factors into consideration. However, we attri-
extension of the work presented herein.
bute the lower reactivity of this substrate to the possibility for
the intermediate π-complex to undergo rearrangement to the
vinylidene, which might be an off-cycle resting state.35 Re-
optimization of the system revealed (JohnPhos)AuCl to be a
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
This work was supported by the Natural Sciences and
Engineering Research Council of Canada (NSERC), the FRQNT
Centre in Green Chemistry and Catalysis (CCVC), and the
Université Laval. JDH thanks NSERC for a Vanier Canada
Graduate Scholarship. TH acknowledges Osaka University for a
scholarship for Oversea Research Activities. Elsa Forcellini and
Justine Desroches are thanked for the preparation of com-
pounds 1d and 11, respectively. Computational resources were
provided by Calcul Québec and Compute Canada.
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Scheme 6 Formal hydration of a propargylic gem-difluoride featuring
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