Synthesis of α-Fluoroketones by Insertion of HF into a Gold Carbene

Article abstract of DOI:10.1002/anie.201603914

Reported is an efficient synthesis of α-fluoroketones by insertion of hydrogen fluoride (HF) into the gold carbene intermediate, generated from a cationic gold catalyzed addition of N-oxides to alkynes. This method results in excellent chemical yields for a wide range of alkyne substrates and demonstrates good functional-group tolerance.

Full text of DOI:10.1002/anie.201603914

Angewandte
Communications
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International Edition: DOI: 10.1002/anie.201603914
German Edition: DOI: 10.1002/ange.201603914
Carbenes
Synthesis of a-Fluoroketones by Insertion of HF into a Gold Carbene
Xiaojun Zeng, Shiwen Liu, Zhenyu Shi, Guangchang Liu, and Bo Xu*
Abstract: Reported is an efficient synthesis of a-fluoroketones
by insertion of hydrogen fluoride (HF) into the gold carbene
intermediate, generated from a cationic gold catalyzed addition
of N-oxides to alkynes. This method results in excellent
chemical yields for a wide range of alkyne substrates and
demonstrates good functional-group tolerance.
F
luorine substitution is a proven and successful strategy in
pharmaceuticals, agrochemicals, and materials research.[1]
However, introducing fluorine into organic molecules has
been a long-standing challenge for organic chemists.[1j] In
recent years, more and more attention has been paid to
transition metal catalyzed fluorinations.[2] But fluorine is not
a transition metal friendly element, and well-defined tran-
À
sition metal catalyzed C F bond-formation processes with
broad scope are surprisingly rare (Scheme 1).[2b] One impor-
tant process is reductive elimination from either R-PdII-F
(Scheme 1a)[3] or R-PdIV-F (Scheme 1b).[4] Another C F
À
bonding-forming mechanism is the attack of a nucleophilic
fluorine source to an allyl palladium complex (Tsuji–Trost-
type reaction; Scheme 1c).[5] C F bond formation can also be
À
achieved through addition of HF to alkynes activated by
cationic metals (e.g. Au, Ag; Scheme 1d).[6] This process has
been used in gold-catalyzed hydrofluorination of alkynes by
the group of Sadighi[7] as well as ourseleves.[8] In addition,
other mechanisms like silver-based reductive elimination,[9]
fluorodemetalation,[10] fluoropalladium,[11] and aminofluori-
nation[12] have been proposed, although these mechanisms are
not well defined.
À
Scheme 1. Common C F bond-formation mechanisms in transition-
metal catalysis. BrettPhos=2-(dicyclohexylphosphino)-3,6-dimethoxy-
2’,4’,6’-triisopropyl-1,1’-biphenyl, dba=dibenzylideneacetone,
DMPU=1,3-dimethy1-2-oxohexahydropyri midine.
À
Transition metal mediated C F bond formations are
almost always much more difficult than their nonfluorine
carbene intermediate has not been used in transition metal
catalyzed fluorinations.
counterparts (e.g. C C, C O bond formations).[13] In general,
they have narrower scope and often need special ligands/
reagents and harsh reaction conditions, such as strong
oxidants and high temperature. Because of limitations of
existing C F bond-forming pathways, it is highly desirable to
find a new, efficient, and broadly applicable C F bond-
forming strategy. Our strategy for transition metal catalyzed
fluorination moves away from these processes, and employs
another elementary process, that is, insertion HF into metal
carbene intermediates (Scheme 1e). Although fluorination of
carbene precursors, like diazo compounds, has been
reported,[14] as far as we know, HF insertion into a metal
Our proof of concept application was difunctionalization
of alkynes to give a-fluoroketones (Scheme 1e). The method
we used to generate the gold carbene[15] is the gold-catalyzed
alkyne oxidation by N-oxides, a protocol developed by the
groups of Zhang[16] and others.[17] N-oxide is a mild oxidant, so
this fluorination protocol is expected to have good functional-
group tolerance.
a-Fluoroketones are important building blocks and motifs
in medicinal chemistry.[18] One straightforward method for the
synthesis of a-fluoroketones is electrophilic fluorination of
the corresponding ketones or nucleophilic fluorine displace-
ment of a-haloketones,[1j] but this method has an inherent
regioselectivity problem. The groups of Nevado[19] and
Gouverneur,[20] as well as ours[21] have developed the synthesis
of a-fluoroketones by gold-catalyzed fluorinations of alkynes.
Yang and co-workers have reported a synthesis of a-
fluoroketones through oxidation of aromatic alkenes by
a radical mechanism.[22] All these methods are based on the
electrophilic fluorination reagent Selectfluor, which is
a strong oxidant, especially when used with transition-metal
catalysts. As a result, these methods have limited scope as
À
À
À
À
[*] X. Zeng, S. Liu, Z. Shi, G. Liu, Dr. B. Xu
College of Chemistry, Chemical Engineering and Biotechnology
Donghua University
2999 North Renmin Lu, Shanghai 201620 (China)
E-mail: bo.xu@dhu.edu.cn
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201603914.
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most of substrates are either simple unfunctionalized alkynes
or alkenes.
We used the fluorination of the alkyne 1a as our model
reaction to study the HF insertion protocol (Table 1). We used
a faster reaction, and we could even reduce the gold catalyst
loading to 0.5 mol%, although longer reaction time was
needed (entry 15). It should be noted this reaction is not
sensitive to moisture and oxygen as the reactions can be
conducted at ambient atmosphere without any precautions.
With the optimized reaction conditions in hand, we
explored the scope and functional-group tolerance of our
HF insertion protocol (Table 2). First we evaluated aromatic
terminal alkynes (3a–u). Phenyl acetylene and alkyl-group-
substituted phenyl acetylenes all gave excellent yields of a-
fluoroketones (3a–c). Electron-rich phenol and phenol ether
groups were also well tolerated (3d–g), and this kind of
functional-group tolerance is not possible when strong
oxidants like Selectfluor are used.[25] Electron-withdrawing
functional-groups (ketone, ester, and acetonitrile) on the aryl
group of the alkynes all gave excellent yields (3h–j). Nonbasic
amine groups (TsNH, TsMeN) are also well tolerated (3k,l).
Halogen-substituted (F, Cl, Br) phenyl acetylenes all gave
excellent yields of the products 3. In general, substitution
patterns (ortho, meta, para) and the presence of either
electron-donating or electron-withdrawing groups on the
aromatic ring of alkynes have little influence on the efficiency
of the reactions.
Table 1: Development of reaction conditions.[a]
Entry
[Au]
Activator
2
HF Reagent
Yield
[%][b]
1
2
3
4
5
6
7
8
PPh3AuCl
PPh3AuCl
PPh3AuCl
PPh3AuCl
AgOTf
AgNTf2
AgSbF6
NaBARF
AgOTs
AgNTf2
AgNTf2
AgNTf2
AgNTf2
AgNTf2
AgNTf2
AgNTf2
AgNTf2
AgNTf2
–
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
2a
2a
Pyridine-HF
Pyridine-HF
Pyridine-HF
Pyridine-HF
Pyridine-HF
Pyridine-HF
Pyridine-HF
Pyridine-HF
Pyridine-HF
Pyridine-HF
Pyridine-HF
Pyridine-HF
Pyridine-HF
Et3N-HF
trace
70%
trace
trace
trace
44
54
77
89
85
PPh3AuCl
(RO)3PAuClc
tBuXPhosAuCl
XPhos
We also tested alkynes containing fused aromatics and
heteroaromatics (naphthalene, thiophene, benzothiophene,
indole, benzofuran), and they all gave excellent results
(Table 2, 3q–u). It should be noted that these heteroaromatics
are highly electron rich and can be easily oxidized, but they all
tolerated our reaction conditions. An alkenyl-substituted
alkyne (enyne) also worked well, and the highly functional-
ized fluoroketone 3v was obtained in good yield.
9
JohnPhos-AuCl
SPhos-Au-Cl
Dppf(AuCl)2
JohnPhos-AuCl
JohnPhos-AuCl
JohnPhos-AuCl
JohnPhos-Au-NTf2
(0.5% loading)
10
11
12
13
14
15
trace
n.r.
n.r.
n.r.
Pyridine-HF
90[d]
We then moved our focus to reactions of aliphatic alkynes.
Simple unfunctionalized aliphatic alkynes worked very well
(Table 2, 3w–y). And various common functional groups
(allyl, ether, ester, halogen, tosylate, mesylate, amide) are
well tolerated (3z-ah), and in all cases excellent yields of the
products 3 were obtained. Finally, we explored the feasibility
of our method in synthesis of complex target molecules. We
were glad to find that a structurally complex and highly
biologically important glycoside, an estrone derivative, and
a cholesterol derivative were suitable substrates and excellent
product yields (3ai–ak) were obtained.
In general, our method did not work for internal alkynes
(sluggish reaction). Because of the lower reactivity of internal
alkynes, the generation of a gold carbene is very slow.[16a–e] For
alkynes with strong nucleophilic groups present (e.g. prop-
argyl alcohol), our method did not give a clean transforma-
tion, and it could be due to the nucleophilic groups competing
with the N-oxide in the addition to the alkyne.
The a-fluoroketones 3 are versatile building blocks in
synthesis (Scheme 2). It can be simply reduced by NaBH4 to
give the fluorohydrin 4 in quantitative yield.[26] 3 can also react
with aldehyde to give the aldol condensation product 5
(fluorinated a,b-unsaturated ketone).[27] Reaction of 3 with
a Michael acceptor gives the 1,4-addition product 6 via an
enamine intermediate.[28] And reductive amination of 3 gives
the b-fluoroamine 7 in good yield.[29]
[a] Reaction conditions: 1a (0.2 mmol), N-oxide 2 (0.28 mmol), pyridine-
HF (1.3 mmol HF, 6.5 equiv), ligand-AuCl (5 mol%), and activator
(5 mol%) were stirred in DCM (1 mL) at RT in a sealed polypropylene
tube for 1.5 h. [b] Determined by GC-MS analysis. [c] R=2,4-di-tBuC6H3.
[d] Reaction time 24 h. DCM=dichloromethane, Dppf=1,1’-bis(diphe-
nylphosphanyl)ferrocene, JohnPhos=2-dicyclohexylphosphinobiphenyl,
SPhos=2-dicyclohexylphosphino-2’,6’-dimethoxybiphenyl, XPhos=2-
dicyclohexylphosphino-2’,4’,6’-triisopropylbiphenyl, Tf=trifluorometha-
nesulfonyl.
8-methylquinoline N-oxide (2a) as our oxidant and pyridine-
HF as our fluorine source. First, screening of silver activators
indicated AgNTf2 was the best choice (entries 1–5). Then we
investigated the ligand effects (entries 6–11).[23] In general,
gold catalysts derived from Buchwald-type ligands gave good
results, and among them the JohnPhos-based gold catalyst
gave the best chemical yield (entry 9). It was interesting to see
that the bidentate-ligand-based (Dppf) gold catalyst only
gave trace product (entry 11). Other N-oxides such as
pyridine N-oxide (2b) and dichloropyridine N-oxide (2c)
could not mediate this reaction (entries 12 and 13). We also
tested another HF-based fluorination reagent Et3N-HF, but
no reaction took place (entry 14). The low reactivity of the
Et3N-HF system may be due to high basicity of Et3N.[8]
Previously, we found that excess amounts of silver activators
are harmful to gold-catalyzed reactions, and preformed
cationic gold catalysts usually have the best efficiency.[24]
Indeed, the preformed gold catalyst JohnPhos-Au-NTf2 gave
Our proposed mechanism is shown in Scheme 3. Our
preferred mechanism is the carbene pathway, the key step of
2
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Table 2: Scope for the synthesis of a-fluoroketones 3.[a]
[a] Reaction conditions: alkyne 1 (0.2 mmol), N-oxide 2a (0.28 mmol), pyridine-HF (1.3 mmol), and JohnPhosAuNTf2 (5 mol%) in DCM (1 mL) at RT.
1
All yields are those of the isolated products unless otherwise stated. [b] Determined by GC-MS analysis. [c] Determined by H NMR spectroscopy.
Ts =4-toluenesulfonyl.
Scheme 3. Proposed mechanism.
which is the insertion of HF into the gold carbene inter-
mediate A (Scheme 3a). Zhang and co-workers recently
reported that an alkyne could react with N-oxide to give the
pyridinium enolate salt B in the presence of stoichiometric
Scheme 2. Synthetic applications of the a-fluoroketones 3.
amount of HNTf2. B could react with a nucleophile by a SN2’
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pathway,[30] and serves as an alternative pathway for the
formation of fluoroketones (Scheme 3b). We think this
pathway is unlikely. First, the generation of B needs
a strong acid (HNTf2)[30] and pyridine-HF is only weakly
acidic, and we did not detect formation of B during the course
of the reaction. Second, the reactivity of B is relatively low,[30]
and in our fluorination protocol, many reactions could
complete at room temperature in less than 5 minutes. This
high reactivity can only be explained by the intermediacy of
the highly reactive A.
In summary, our new synthesis of a-fluoroketones by
insertion of HF into a gold carbene intermediate is a practical
efficient method. Most functional groups can be tolerated and
the reactions can be conducted at ambient atmosphere
without any precautions. Because only a mild oxidant, N-
oxide, is used, compared to literature methods, it has high
functional-group tolerance. Other fluorination systems based
on the insertion of HF into gold carbenes are currently being
investigated in our laboratory and will be communicated in
due course.
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Acknowledgements
We are grateful to the National Science Foundation of China
(NSFC-21472018) and China Recruitment Program of Global
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b) T. de Haro, C. Nevado, Adv. Synth. Catal. 2010, 352, 2767 –
2772.
Received: April 22, 2016
Revised: June 12, 2016
Published online: && &&, &&&&
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Carbenes
X. Zeng, S. Liu, Z. Shi, G. Liu,
B. Xu*
&&&& — &&&&
Synthesis of a-Fluoroketones by Insertion
of HF into a Gold Carbene
An HF insert: Insertion of hydrogen
fluoride (HF) into a metal carbene is
a new approach in transition metal
catalyzed fluorination and provides an
efficient synthesis of a-fluoroketones.
This method gives excellent chemical
yields for wide range of alkyne substrates.
6
www.angewandte.org
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
These are not the final page numbers!