Gold(I)-catalyzed alkoxyhalogenation of β-hydroxy-α,α- difluoroynones

Article abstract of DOI:10.1002/anie.200802162

(Chemical Equation Presented) Gold standard: AuCl was found to be the only suitable catalyst for the 6-endo-dig ring closure of hydroxylated difluorinated ynones (see scheme), a class of substrates that displays low reactivity owing to the presence of the

Full text of DOI:10.1002/anie.200802162

Angewandte
Chemie
DOI: 10.1002/anie.200802162
Homogeneous Catalysis
Gold(I)-Catalyzed Alkoxyhalogenation of b-Hydroxy-a,a-
Difluoroynones**
Marie Schuler, Franck Silva, Carla Bobbio, Arnaud Tessier, and VØronique Gouverneur*
Dedicated to Professor LØon Ghosez
The presence of fluorine substituents can significantly impact
the physicochemical properties of organic compounds.[1]
Novel methods for the preparation of fluorinated molecules
À
based on fluorinated building blocks or C F bond forming
reactions are therefore in great demand. New approaches to
dihydro- or tetrahydropyranones featuring two or more
fluorine substituents are valuable,as these compounds may
be manipulated to enable,among other things,the synthesis
Scheme 1. Gold(I)-catalyzed alkoxyhalogenation (and -protonation) of
ynones.
of fluorinated carbohydrate analogues.[2] The number of
synthetic routes to difluorinated dihydropyranones remains
limited,a notable exception being the hetero-Diels–Alder
reaction of difluorinated Danishefsky dienes.[2a] Although
gold catalysis has brought forth spectacular achievements,[3]
the usefulness of gold complexes has not been explored with
reactions involving fluorinated starting materials or to
Initial investigations focused on validating the ring closure
in the absence of an additional electrophile. This study was
aimed at comparing the efficiency of gold catalysts with
alternative catalytic systems.[7] For substrate 1a (Table 1)
À
promote C F bond forming reactions. A rare example of
gold-catalyzed fluorination is the trans-hydrofluorination of
alkynes catalyzed by N-heterocyclic carbene gold(I) com-
plexes.[4] This process relies on the use of a gold catalyst with a
nucleophilic source of fluorine. The ability of gold catalysts to
activate alkynes towards nucleophilic addition led us to
hypothesize that di- and trifluorinated dihydropyranones may
be accessible from b-hydroxy-a,a-difluoroynones,the key
Table 1: 6-Endo-dig cyclizations of ynone 1a.
Entry Catalyst
Loading [mol%] Conditions
Yield [%]
[a]
event being
a gold-catalyzed 6-endo-dig ring closure
1
2
3
4
5
6
7
[(MeCN)2PdCl2]
10
8
–
100
100
50
5
CH2Cl2, 18 h
–
(Scheme 1). A gold-catalyzed 6-endo-dig cyclization also
offers the possibility to capture the gold intermediate with
electrophiles other than H+.[5,6] We were particularly
intrigued by the prospect of developing a cyclization–
halogenation sequence including a process that features an
unprecedented oxidative fluorination of a transient vinylgold
species. Herein,we report that gold(I)-catalyzed alkoxyhalo-
genations of b-hydroxy-a,a-difluoroynones are feasible,
including a cyclization–fluorination cascade,a reaction com-
bining for the first time a gold catalyst with an electrophilic
source of fluorine.
[(MeCN)4Pd](BF4)2
amberlyst-15
NaH
HCl
TfOH
CH2Cl2, 18 h 15
[b]
[a]
CH2Cl2, 18 h
CH2Cl2, 5 h
CH3CN, 40 h
CH2Cl2, 29 h
CH2Cl2, 18 h
CH2Cl2, 18 h
THF, 18 h
–
–
–
–
–
–
–
[c]
[a]
[c]
[a]
[a]
[a]
PtCl2
8
InCl3
5
9
AgNO3
5
10
11
12
13
AgSbF6
AuCl3
AuCl
5
5
5
5
CH2Cl2, 18 h 25
CH2Cl2, 18 h 79
CH2Cl2, 18 h 93
CH2Cl2, 18 h 90
[Au(PPh3)OTf]
[a] Starting material recovered. [b] 2 wt equiv. [c] Decomposition. OTf=
CF3SO3, Bn=benzyl.
[*] Dr. M. Schuler, Dr. F. Silva, Dr. C. Bobbio, Dr. A. Tessier,
Dr. V. Gouverneur
University of Oxford, Chemistry Research Laboratory
12 Mansfield Road, OX1 3TA Oxford (UK)
Fax: (+44)1865-275-644
featuring the key gem-difluoro motif,the ring closure did not
proceed (or was not efficient) under basic or acidic conditions
or using catalytic systems other than gold catalysts. The poor
reactivity of this substrate is likely the result of the
deactivating effect of the gem-difluoro group that reduces
the nucleophilicity of the proximal hydroxy group. The
desired 6-endo-dig ring closure took place efficiently in the
presence of 5 mol% AuCl in CH2Cl2. No product resulting
E-mail: veronique.gouverneur@chem.ox.ac.uk
[**] This work was supported the European Community (MRTN-CT-
2003-505020, MEIF-CT-2006-039270 and MEIF-CT-2006-040558)
and the EPSRC (GR/S79268/02). We thank G. Giuffredi and A.
Monney for performing selected experiments, and A. L. Thompson
of the Oxford Chemical Crystallography Service for X-ray studies.
Supporting information for this article is available on the WWW
underhttp://dx.doi.org/10.1002/anie.200802162.
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Table 3: Gold(I)-catalyzed alkoxyiodination and alkoxybromination.
from a 5-exo-dig ring closure or other side products were
detectable in the crude reaction mixtures (Table 1).
We investigated the scope and limitations of this reaction
using the difluorinated ynones 1b–i as starting materials
(Table 2).[8,9] The cyclization was performed with 5 mol%
Table 2: Gold-catalyzed cyclization of b-hydroxyynones 1b–k.
Entry
Ynone
Conditions
Product
Yield 3, 4, or 5 [%][a]
1
2
3
4
5
6
7
8
1a
1b
1d
1e
1 f
1b
1d
1d
A
A
A
A
A
B
B
C
3a
3b
3d
3e
3 f
4b
4d
5d
65
76
92
65
68
82
70
0[b]
Entry
Ynone
R1
R2
R3
Yield 2 [%][a]
1
2
3
4
5
6
7
8
9
10
1b
1c
1d
1e
Ph
Ph
Ph
Ph
Ph
nPrF
SiMe3
Me
H
Ph
Et
F
F
F
F
90
F
F
F
H
H
92
94
92
94
4-CF3C6H4
4-MeOC6H4
cyclohexyl
cyclohexyl
BnOCH2
BnOCH2
BnOCH2
PhCH2CH2
p-NO2C6H4
[a] Yields of isolated products. [b] 32% 2d and 37% 1d. NIS=N-
iodosuccinimide, NBS=N-bromosuccinimide, NCS=N-chlorosuccin-
imide.
1 f
1g
1h
1i
1j
(R)-1k
<5[b]
83[c]
75[d]
89
65[e]
site of functionalization through cross-coupling reactions is
available.[9,11]
[a] Yields of isolated products. [b] Decomposition. [c] Reaction in MeCN.
[d] Reaction carried out with 10 mol% AuCl3. [e] ee=74% for 1k and 2k.
The alkoxybromination[6e] and alkoxychlorination[6f,g]
were attempted using N-bromosuccinimide (NBS) and N-
chlorosuccinimide (NCS). The gold(I)-catalyzed alkoxybro-
AuCl in CH2Cl2 at room temperature. Numerous structural
variations were tolerated for the difluorinated ynones,both
on the alkyne and on the group flanking the alcohol. The aldol
product 1g with the silyl-protected alkyne was the only ynone
that failed to cyclize (entry 6,Table 2). The unfluorinated
ynones 1j–k were successfully cyclized under gold(I) catalysis
with yields of isolated product reaching 89% (entries 9 and
10,Table 2). For the enantioenriched b-hydroxyynone (R)-
1k,the product ( R)-2k was formed with no erosion of
enantiomeric excess.
We next investigated the possibility of coupling the 6-
endo-dig cyclization with an iodination of the presumed
vinylgold intermediate (Table 3). Literature precedent indi-
cates that electrophilic iodinating reagents can capture in situ
generated organogold species.[6] The difluoroiodopyranones
were successfully formed when treating the b-hydroxyynones
with 1.2 equivalents of N-iodosuccinimide (NIS) in the
presence of 5 mol% AuCl. The yields ranged from 65 to
92% (entries 1–5,Table 3). The structure of 3b was con-
firmed by X-ray analysis.[9] Crude reaction mixtures showed
no trace of dihydropyranones resulting from a competing
protodeauration. As unfluorinated dihydropyranones are
known to undergo iodination upon treatment with iodine
and pyridine,[10] we performed control experiments to probe
the reactivity of the protodeaurated difluorinated dihydro-
pyranone 2b in the presence of NIS but in the absence of gold
catalyst.[9] Under these conditions, 2b did not react,a result in
line with the deactivating effect of the gem-difluoro group. An
additional control experiment revealed that ynone 1d
remained unchanged upon treatment with NIS in the absence
of gold catalyst. Therefore,the iodination event likely
involves the capture of an in situ generated vinylgold
intermediate. When vinyl iodides are formed,an additional
mination delivered the brominated pyranones 4b and 4d in 82
[9,12]
and 70% yield,respectively.
Control experiments similar
to those conducted with NIS suggested that the bromination
event involved a vinylgold species.[9] The alkoxychlorination
of 1d was unsuccessful; the protodeaurated dihydropyranone
2d was formed as the sole product in 32% yield.
The scarce information available on transition-metal-
À
catalyzed methods for C F bond construction prompted us to
investigate the feasibility of a cascade alkoxylation–fluorina-
tion.[13] This study raised several important questions such as
the compatibility of the gold catalyst with electrophilic
fluorinating reagents as well as the ability of the vinylgold
intermediate to undergo oxidative fluorination. This reaction
was attempted with ynone 1b to determine the optimal
combination of solvent,catalyst,and fluorinating reagent for
the alkoxyfluorination (Table 4).
Table 4: Optimization of the gold(I)-catalyzed alkoxyfluorination of 1b.
Entry F+ Reagent (equiv) Conditions
1b:6b:2b[a]
1
2
NFSI (2.5)
NFSI (1.5)
CH2Cl2, RT, 18 h
CH2Cl2, reflux, 24 h
MeCN, RT, 6 d
MeCN, RT, 55 h
MeCN, RT, 48 h
73:0:27
93:0:7
68:0:32
0:40:60
0:45:55
3[b]
4
pyridinium (2)[c]
selectfluor(1.5)
selectfluor(2.5)
selectfluor(2.5)
5
6
CH 2Cl2, NaHCO3, RT, 66 h 100:0:0
[a] Ratios determined by 19F NMR spectroscopy of crude material.
[b] AuCl 10 mol%. [c] N-fluoro-2,3,6-trimethylpyridinium tetrafluorobo-
rate. NFSI=N-fluorobenzenesulfonimide.
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The best results were obtained upon treatment of 1b with
5 mol% AuCl in the presence of 2.5 equivalents selectfluor in
MeCN. Analysis of the crude reaction mixture by 19F NMR
spectroscopy revealed the formation of two products,the
trifluorinated dihydropyranone 6b and the protodeaurated
difluorinated dihydropyranone 2b in a ratio of 2:3. Attempts
to eradicate the protodeauration by starting from O-silylated
b-hydroxyynones,adding coreagents such as various bases,or
modulating the stoichiometry of the fluorinating reagent were
unsuccessful.[9]
Investigations into the scope and limitations of this
gold(I)-catalyzed cyclization–fluorination were carried out,
probing the reactivity of both difluorinated and unfluorinated
b-hydroxyynones (Table 5). The difluorinated ynones deliv-
ered the trifluorodihydropyranones along with difluorinated
(entries 1–5,Table 5). The ratios of these two products were
in the range of approximately 1:1 to 2:3,as determined by
19F NMR spectroscopy of crude material. Since the starting
material was completely consumed,the low yields of isolated
fluorodeaurated pyranones 6 may be due to the instability of
these products upon isolation. The structures of 6b and 6e
were unambiguously characterized by X-ray analysis.[9] Upon
treatment with 2.5 equivalents selectfluor in the presence of
5 mol% AuCl,the unfluorinated ynones 1j,l,m delivered two
products identified as the difluorinated tetrahydropyranones
7j,l,m and the ring-opened monofluorinated ketones 8j,l,m
(entries 6–8,Table 5). The best yields for the ring closure of
these unfluorinated b-hydroxyynones were obtained when
the reactions were performed in MeCN/water.
Several control experiments were conducted to gain
insight into the mechanism of these gold(I)-catalyzed alkoxy-
fluorinations. No reaction occurred when the difluorinated
ynone 1b was treated with selectfluor in the absence of gold
catalyst. We found that the reaction of the difluorinated
dihydropyranone 2b and selectfluor with or without AuCl
delivered unreacted starting material with no trace of 6b
detectable by 19F NMR spectroscopy. The gem-difluoro group
in 2b therefore strongly deactivates the alkoxyenone group
towards electrophilic fluorination. These control experiments
suggest that 2b is not a plausible intermediate of the reaction
pathway leading to 6b,reinforcing the hypothesis that the
transient vinylgold species 9b undergoes fluorination
(Scheme 2). This reaction constitutes the first example of
oxidative fluorination of an organogold intermediate,possi-
pyranones resulting from
a competing protodeauration
Table 5: Gold(I)-catalyzed alkoxyfluorination of b-hydroxyynones.
Entry Ynone
Products
Yield [%]
20/33
À
bly by electrophilic attack of selectfluor on the Au C bond.
1[a]
2[a]
3[a]
4[a]
5[a]
6[b]
7[b]
8[b]
1b
1d
1e
1 f
However,the exact mechanistic pathway leading to trifluori-
nated pyranones will require further investigation.
The control experiments carried out on the unfluorinated
hydroxyynones were less conclusive,as the ring-closed
dihydropyranones underwent double fluorination when
treated with selectfluor in the absence of gold catalyst.[9] For
26/33
20/15
27/37
24/43
59/39
50/13
41/32
1h
1j
1l
1m
[a] AuCl 5–10 mol%, selectfluor2.5 equiv, MeCN, RT, 72–96 h; [b] AuCl
5 mol% selectfluor2.5 equiv, MeCN/H 2O 1:1, RT, 18 h.
Scheme 2. Proposed mechanism for the catalytic formation of 6b.
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Communications
[5] For examples of capture of vinylgold intermediates with allyl or
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preparation of 5-iodo,5-bromo- and 5-fluoro-33, ’-difluorodi-
hydropyranones from b-hydroxy-a,a-difluoroynones. The
gold-catalyzed 6-endo-dig cyclization of these substrates is
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Keywords: cyclization · fluorine · gold · homogeneous catalysis ·
ynones
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