Gold-catalyzed synthesis of α-fluoro acetals and α-fluoro ketones from alkynes

Article abstract of DOI:10.1002/adsc.201000559

A new method to synthesize α-fluoro acetals and α-fluoro ketones is presented here. In the presence of alcohols and Selectfluor, catalytic amounts of gold selectively transformed alkynes into the corresponding fluorinated acetals or ketones depending on the reaction conditions. This protocol has been applied to both terminal and internal alkynes showing a high degree of chemo- and regioselectivity. The reaction mechanism seems to proceed via two co-existing pathways, since at least partially, the formation of the C(sp³)-F bond in the final products occurs at the metal center.

Full text of DOI:10.1002/adsc.201000559

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DOI: 10.1002/adsc.201000559
Gold-Catalyzed Synthesis of a-Fluoro Acetals and a-Fluoro
Ketones from Alkynes
Teresa de Haroa and Cristina Nevadoa,*
a
Organic Chemistry Institute, University of Zꢀrich, Winterthurerstrasse 190, CH-8057, Zꢀrich, Switzerland
Fax : (+41)-44-635-6812; phone: (+41)-44-635-3945; e-mail: nevado@oci.uzh.ch
Received: July 15, 2010; Published online: October 26, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000559.
Abstract: A new method to synthesize a-fluoro ace-
tals and a-fluoro ketones is presented here. In the
presence of alcohols and Selectfluor, catalytic
amounts of gold selectively transformed alkynes
into the corresponding fluorinated acetals or ke-
tones depending on the reaction conditions. This
protocol has been applied to both terminal and in-
ternal alkynes showing a high degree of chemo- and
regioselectivity. The reaction mechanism seems to
proceed via two co-existing pathways, since at least
cellent way to obtain aldehydes, ketones or their cor-
responding acetals depending on whether the reaction
occurs in a Markownikoff or anti-Markownikoff
manner (Scheme 1).[5] Hg(II) was the first metal used
to promote the hydration of alkynes in an industrially
relevant process for the synthesis of acetaldehyde and
crotonaldehyde.[6,7] Soon it became clear that mercury
had to be replaced, not only because of its toxicity
but also due to its rapid reduction to catalytically in-
active Hg(0) species under the reaction conditions.
3
À
partially, the formation of the C
N
Other metals such as Ag(I), Cu(I), Tl
Ru(III), Rh(III) and Os(II) were explored, although
the reactions proved to be more limited in scope.[8] In
contrast, Pt(II),[9] Au(I) and Au(III)[10] have showed a
ACHTUNGTREN(NUNG III), Pd(II),
final products occurs at the metal center.
N
ACHTUNGTRENNUNG
Keywords: alkynes; catalysis; fluorination; gold; hy-
ACHTUNGTRENNUNG
dration
much better profile in terms of scope, selectivity and
catalytic activity. Noticeably, the most active catalysts
reported so far are those based on gold,[10c,d,11] which,
due to the strong relativistic effects governing its co-
ordination behaviour, is able to activate unsaturated
Metal complexes of alkynes are important intermedi- moieties in an unparalleled mild and efficient
ates in many transformations such as 1,n-enyne cycli- manner.
zation, polymerization and metathesis reactions.[1] Ac-
Our ongoing program is focused on the develop-
cording to the classical Dewar–Chatt–Duncanson ment of novel methodologies for the construction of
model,[2] the bonding between the metal and the molecular complexity triggered by the p-activation
alkyne can be described as a combination of a s- and ability of gold species.[12] We have recently developed
a p-interaction (by overlap of the p-system of the an efficient method to synthesize a-fluoroenones
acetylene with dsp orbitals of the metal and from based on a tandem gold-catalyzed process starting
filled d-orbitals of the metal into p*-orbital of acety- from easily available propargyl acetates.[13] The effi-
À
lene, respectively). Late transition metals, such as Hg, cient formation of C F bonds represents a major in-
Cu, Pd, Pt, Au, etc., show a more important s-contri-
bution to the bond with almost no back-donation,
thus diminishing the electron density on the alkyne
and increasing its susceptibility to a nucleophilic
attack.[3] Such a reactivity mode has been thoroughly
exploited over the past century. Alkynes, as an abun-
dant hydrocarbon source, have been reported to un-
dergo the addition of C, N, S and O nucleophiles
upon p-activation with transition metals.[4] The nucle-
ophilic addition of water or alcohols to alkynes has at-
tracted enormous attention since it represents an ex- Scheme 1. Metal-catalyzed hydration of alkynes.
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In our screening, phenylacetylene (1a) was used as
a benchmark substrate. The results on the optimiza-
tion of the reaction conditions have been summarized
in Table 1.
The reaction of 1a in the presence of commercially
available Ph3PAuCl (5 mol%) and Selectfluor
(2 equiv.) in refluxing MeOH for 24 h afforded only
Scheme 2. Hydrofluorination of alkynes.
terest in organic chemistry due to the rather unique starting material (Table 1, entry 1). When a cationic
properties of fluorinated compounds compared to complex such as Ph3PAuNTf2 was used, fluoro-
À
their corresponding C H counterparts: hydrophobici- dimethyl acetal 2a could be isolated in 78% yield
ty, solubility, metabolic stability, etc.[14] Gold com- after only 2 h together with 8% of a-fluoro ketone 3a
plexes have only now started to arise as a potential (Table 1, entry 2). Ketone 3a was the only product ob-
source of catalytic fluorinations, as shown independ- tained when the reaction was run overnight (Table 1,
ently by the groups of Sadighi and Governeur.[15]
entry 3).[21] The reaction in the presence of anhydrous
Here we report a novel and highly efficient method methanol slightly improved the yield in 2a, although
to selectively synthesize a-fluoro acetals or a-fluoro 3a could still be detected in the reaction mixture
ketones from alkynes using Ph3PAuNTf2 as catalyst (Table 1, entry 4).[22] The reaction was also performed
and Selectfluor through an alkoxylation/hydration– at room temperature for 24 h. In this case, a lower
fluorination protocol using alcohols as solvent yield for 2a was obtained due to the competitive for-
(Scheme 2).
mation of acetophenone (Table 1, entry 5). The con-
a-Fluoro ketones are important building blocks in centration seemed not to have a pronounced effect on
organic chemistry and are considered compounds of the reaction outcome, as reflected by entry 6. Finally,
intrinsic biological interest.[16] The synthesis is usually in an attempt to reduce the acidity of the media, the
derived from the corresponding ketones, which are reaction was performed in the presence of 1 equiva-
activated via a metal enolate anion, enol ether, enam- lent of NaHCO3. Under these conditions, in contrast
ine or imine prior to electrophilic fluorination.[17] Few to the previous examples, homocoupling of 1a was ob-
direct fluorinations of ketones have been reported served (Table 2, entry 7).[23] Noticeably, 2a and 3a
mainly using NFTh Accufluor.[18] The use of Select- were always obtained as single regioisomers, with the
fluor as stoichiometric fluorinating agent of ketones addition taking place at the more substituted carbon
has been reported although the substrate scope is lim- atom of the triple bond (Markownikoff).
ited and low selectivities are observed.[19] To the best
For the sake of simplicity, we decided to use the
of our knowledge, the selective formation of a-fluoro conditions from Table 1, entry 6, to explore the reac-
acetals or, alternatively, a-fluoro ketones from al- tion scope with other alkynes and alcohols (Table 2).
kynes presented here is rather unexplored.[20]
p-Methoxyphenyl-substituted alkyne 1b reacted effi-
Table 1. Optimization of the reaction conditions.
Entry
Catalyst (5 mol%)
Modifications[a]
Yield[b] [%] of (2a)
Yield[c] [%] of (3a)
1
2
3
4
5
6
7
Ph3AuCl
24 h
–
17 h
–
78
–
82
55[e]
78
–
8
Ph3AuNTf2
Ph3AuNTf2
Ph3AuNTf2
Ph3AuNTf2
Ph3AuNTf2
Ph3AuNTf2
quant.[d]
MeOH (anhydr.)
258C, 24 h
0.1M
6
–
8
[f]
[f]
NaHCO3 (1 equiv.)
–
–
[a]
Unless otherwise stated the reactions were run at 708C for 2 h (0.02M) and quenched with one drop of Et3N before evap-
oration of the solvent.
Isolated yield after column chromatography in SiO2 neutralized with Et3N (2%).
Isolated yield after column chromatography in SiO2.
Reaction was directly rotavaped.
[b]
[c]
[d]
[e]
[f]
Acetophenone was formed in the reaction.
Homocoupling of 1a was obtained (Ref.[23]).
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Gold-Catalyzed Synthesis of a-Fluoro Acetals and a-Fluoro Ketones from Alkynes
Table 2. Reaction scope.
Entry
Alkyne
Conditions[a]
R1
R2
Products, Ratio, (Yields [%])[b]
1
2
3
4
5
6
7
8
1b
1b
1c
1d
1d
1d
1e
1e
1f
A
B
A
A
B
C
A
B
A
A
B
p-MeO-C6H4
p-MeO-C6H4
n-C6H13
Ph
Ph
Ph
p-Et-C6H4
p-Et-C6H4
p-Br-C6H4
Ph
H
H
H
Ph
Ph
Ph
p-Et-C6H4
p-Et-C6H4
p-Br-C6H4
n-C6H13
n-C6H13
2b, (71)[c]
3b, (93)
2c/2c-1,[24] 1:2, (78)
2d, (92)
3d, (80)[25]
4d, (84)[c]
2e, (73)[c]
3e, (68)
9
10
11
2f, (85)[d]
1g
1g
2g/2g’, 10:1,(72)
3g/3g’, 10:1,(80)
Ph
12
1h
A
D
Ph
Ph
2h, (86)
13
1h
3h, (99)
[a]
Conditions A: as entry 6 in Table 1. Conditions B: same as conditions A but the reaction mixture was stirred for 17 h
before solvent evaporation. Conditions C: same as conditions A, but with i-PrOH as solvent. Conditions D: same as con-
ditions A, but the crude mixture was treated with a THF/H2O/TFA mixture (3:1:3) for 1 h.
Isolated yield.
Ketones 3b, 3d and 3e could be isolated from the reaction mixtures in 5, 8 and 7% yield respectively.
10% catalyst.
[b]
[c]
[d]
ciently to give a-fluoro acetal 2b in 71% yield attack at the Ca to the aromatic ring (Table 2, en-
(Table 2, entry 1), whereas the corresponding ketone tries 10 and 11).
3b could be obtained in 93% yield upon prolonged re-
1,6-Enyne 1h was also subjected to the standard re-
action times (Table 2, entry 2). As previously ob- action conditions. In this case, the double bond is a
served for 1a, the reaction is completely regioselec- mere spectator and only the triple bond reacts to give
tive. However, a terminal alkyne with an alkyl sub- acetal 2h, thus highlighting the regio- and chemose-
stituent (1c) afforded a 1:2 mixture of regioisomeric lectivity of the reaction driven by the gold coordina-
acetals 2c and 2c-1[24] in 78% yield (Table 2, entry 3). tion to the alkyne moiety (Table 2, entry 12). To
Internal alkynes were also suitable substrates for this obtain ketone 3h, a one-step procedure was devised
transformation. First, symmetric substrates with aro- using a mixture of THF/H2O/TFA to hydrolyze the
matic substituents such as 1d, 1e and 1f were tested acetal (Table 2, entry 13). Finally, dimethyl acetylene-
affording the corresponding acetals 2d, 2e and 2f in dicarboxylate (1i) was exposed to the reaction condi-
good to excellent yields (Table 2, entries 4, 7, 9). Sub- tions A and B from Table 2. In contrast to all previ-
strates 1d and 1e could also be cleanly transformed ous results, the reaction afforded enol 5i in 84% yield
into their corresponding ketones (3d and 3e) under as a 3:1 Z:E mixture of isomers (Scheme 3).[26]
the appropiate conditions (Table 2, entries 5 and 8).[25]
We also decided to explore the reactivity of N-con-
Other alcohols such as isopropyl alcohol, could be taining nucleophiles.[27] Thus, amide 6 was reacted in
employed as solvent affording diisopropyl acetal 4d in the presence of Ph3PAuSbF6 as catalyst in a mixture
excellent yield from 1d (Table 2, entry 6). In contrast,
phenol or ethylene glycol afforded only unreacted
starting material. Asymmetrically disubstituted al-
kynes were also successfully transformed in a highly
regioselective manner. Thus, 1g was transformed into
a regioisomeric mixture of acetals (2g and 2g’) or ke-
tones (3g and 3g’) in a 10:1 ratio in favour of the Scheme 3. Reaction of 1i.
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To this end, acetophenone was subjected to the stan-
dard reaction conditions. After 2 h, the reaction mix-
ture showed starting material, and only trace amounts
1
of 2a and 3a could be detected by H NMR, ruling
out this mechanistic hypothesis [Scheme 5, Eq. (1)].
In the absence of gold, the reaction afforded only
starting material [Scheme 5, Eq. (2)].[10] a-Fluoro
ketone 3a was also screened, but the corresponding
dimethyl acetal 2a could not be detected in the reac-
Scheme 4. Amino-hydroxyfluorination of alkynes.
of acetonitrile/water. This transformation afforded tion mixture [Scheme 5, Eq. (3)]. These results con-
amino alcohol 7 as a single reaction product in 80% firm the hypothesis that ketones (fluorinated or not)
yield (Scheme 4). In the absence of gold, only starting are not the productive intermediates for the synthesis
material 6 was recovered.
of the corresponding acetals in these transformations.
A different mechanistic scenario was then devised
To gain some insight into the reaction mechanism,
several experiments were designed. First, we evaluat- as shown in Scheme 6. First, upon gold activation of
ed whether the formation of a-fluorodimethyl acetals the alkyne (I) a first molecule of alcohol attacks the
(2) proceeded via acetalization/fluorination of the cor- triple bond forming an enol ether intermediate (III)
2
[10b,c]
À
responding methyl ketones generated in situ through upon protonolysis of the CACTHNUGTRNEUNG(sp ) Au bond in II.
a standard gold-catalyzed hydration of the alkyne.[10] The involvement of enol ethers in gold-catalyzed
alkoxylation/hydration of alkynes has ample prece-
dents.[10c,11,26] Selectfluor could then activate the in situ
3
À
produced enol ether (III) to form the C
(sp ) F bond
with concomitant attack of a second molecule of
methanol (IV) to give a-fluorodimethyl acetals (V).
Upon hydrolysis of the acetals in the slightly acidic
media of the reaction the corresponding ketones
would be obtained (Scheme 6, broken arrows).[28]
To test this hypothesis, enol ether 8 was prepared
as previously reported by Nolan and co-workers using
IPrAuSbF6 (2 mol%) as catalyst.[11] When 8 was react-
ed in the presence of Ph3PAuNTf2 (5 mol%), and two
equivalents of Selectfluor in MeOH at 708C, 2d was
cleanly obtained. In the absence of gold, 2d was also
Scheme 5. Mechanistic probes.
Scheme 6. Mechanistic proposal.
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Gold-Catalyzed Synthesis of a-Fluoro Acetals and a-Fluoro Ketones from Alkynes
MeOH (0.1M). The reaction mixture was stirred for 2 h at
708C and monitored by TLC. Upon consumption of the
starting material, 1 drop of triethylamine was added and the
mixture was filtered over a short pad of Celite. The solvent
was evaporated under reduced pressure and the residue was
purified by silica gel flash column chromatography (pen-
tane/diethyl ether) to afford the a-fluoro acetals 2.
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3
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(sp ) F bond
À
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3
À
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Teresa de Haro and Cristina Nevado
COMMUNICATIONS
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[28] The reaction of 2a under the reaction conditions shown
in entry 6 of Table 1, afforded 3a quantitatively.
[29] In contrast, the reaction of 1i shown in Scheme 3
stopped at enol ether 5i likely due to the electron-with-
drawing nature of the ester functions, even after pro-
longed reaction times.
[30] For substrate 1c, the formation of regioisomeric fluori-
nated product 2c-1 can be explained by the formation
of a more thermodynamically favoured trisubstituted
enol ether along the reaction pathway, which seems to
indicate that the fluorination reaction is slower for ter-
minal alkynes with alkylic substituents than for those
with aromatic ones (1a, b).
[31] Neither 8 nor 9 could be detected in the reaction mix-
tures of 1d and 6 to give 2d and 7, respectively.
[22] The presence of adventitious water in the reaction mix-
ture could also explain the formation of ketone 3a in
small amounts. Nevertheless, when the reaction was
run in anhydrous methanol 3a was still detected. We
favour the hypothesis of the Brønsted acidity of trifli-
mide to justify the hydrolysis of the acetals to the cor-
responding ketones.
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[33] An intermediate similar to VIII has been already pro-
posed to undergo gold displacement in the presence of
a suitable nucleophile (ref.[32d]). MeOH could displace
the AuACTHNURGTNE(NUG III) in our reaction, thus explaining the forma-
tion of compound 3d-1 (ref.[25]). A control experiment
was performed to confirm that 3d-1 was not obtained
from 3d upon prolonged stirring under the standard re-
action conditions.
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Adv. Synth. Catal. 2010, 352, 2767 – 2772