Palladium-catalyzed allylic fluorination

Article abstract of DOI:10.1002/anie.201007307

Mild and rapid: The title reaction is presented and its applicability to ¹⁸F radiolabeling is demonstrated (see scheme; TBAF=tetra-n- butylammonium fluoride, THF=tetrahydrofuran, dba=dibenzylideneacetone). The use of p-nitrobenzoate as the leaving group is significant to the success of this catalytic organometallic fluorination process. A range of allylic fluorides were synthesized by this method. Copyright

Full text of DOI:10.1002/anie.201007307

DOI: 10.1002/anie.201007307
Catalytic Fluorination
Palladium-Catalyzed Allylic Fluorination**
Charlotte Hollingworth, Amaruka Hazari, Matthew N. Hopkinson, Matthew Tredwell,
Elena Benedetto, Mickael Huiban, Antony D. Gee, John M. Brown,* and
Vꢀronique Gouverneur*
Transition metal catalyzed allylic substitution is a powerful
method for carbon–carbon and carbon–heteroatom bond
formation and plays a pivotal role in modern organic syn-
thesis.[1] These reactions encompass a wide variety of hetero-
atoms (N, O, S, Si, P) as nucleophiles. A transition metal
catalyzed allylic fluorination would unveil new synthetic
approaches towards highly valuable fluorinated compounds
such as fine pharmaceuticals or 18F-labeled radiotracers for
positron emission tomography (PET). The conceptual diffi-
culties in developing such a reaction are, however, numerous
and have been well documented. Togni and co-workers
concluded that this process is thermodynamically unfavor-
able, as a result of unsuccessful attempts to trap cationic h3-
(1,3-diphenylallyl)palladium diphosphine complexes with
fluoride ions.[2] The use of the fluoride ion as the nucleophilic
component presents a series of challenges, including the
potential reversibility of the reaction.[3] Solvation can dra-
matically decrease the reactivity of the fluoride ion and in its
desolvated form it becomes a strong Brønsted base favoring
elimination instead of substitution.[4] The low intrinsic
nucleophilicity of the fluoride ion is demonstrated by its
frequent use as an additive to modulate catalytic reactivity or
product distribution.[5]
be a superior leaving group to acetate, but inferior to methyl
carbonate (Scheme 1). Based on this recent discovery, and by
applying the principle of microscopic reversibility, we consid-
Scheme 1. a) The palladium-catalyzed allyl fluoride alkylation[6] and
b) the palladium-catalyzed allyl fluoride formation. Bz=benzoyl.
ered that the catalytic allylic substitution by fluoride ions
would be achieved by a judicious choice of the allylic leaving
group, the fluoride source, and the ligand. The catalytic
In previous work, we demonstrated that allyl fluorides are
reactive under Tsuji–Trost allylic alkylation conditions, and
that the reaction deviates from the expected stereochemical
course, with much higher levels of inversion being observed
than with the standard carboxylate or carbonate leaving
groups.[6] Critically, a reactivity order was established by
internal competition, in which fluoride was demonstrated to
[7,8]
À
formation of Csp3 F bonds is uncommon,
which is in
À
F
contrast with the intense output of catalytic routes to Csp2
bonds.[9]
Initial investigations focused on the palladium-catalyzed
fluorination of simple allylic carbonates derived from 1- or 2-
arylprop-2-en-1-ols. The results derived from 2-(4-(tert-
butyl)phenyl)allyl methyl carbonate (1a) are shown in
Table 1. This model substrate was selected for the conceptual
validation because it does not allow for competitive elimi-
[*] C. Hollingworth, Dr. A. Hazari, M. N. Hopkinson, Dr. M. Tredwell,
E. Benedetto, Dr. J. M. Brown, Prof. V. Gouverneur
Chemistry Research Laboratory, University of Oxford
12 Mansfield Road, Oxford OX1 3TA (UK)
Fax: (+44)1865-275-644
1
nation and the desired allylic fluoride 2 has distinctive H
NMR (d = 5.27 ppm, dd, J = 47 Hz, 6 Hz, CH2 in CDCl3) and
19F NMR spectra (d = À212.7 ppm, td, J = 47 Hz, 3 Hz) that
permit easy tracking. The choice of carbonate as the leaving
group was driven by its established superior reactivity
compared with fluoride in the Tsuji–Trost alkylation; a
E-mail: john.brown@chem.ox.ac.uk
veronique.gouverneur@chem.ox.ac.uk
Dr. M. Huiban
GSK Clinical Imaging Centre, Hammersmith Hospital
London W12 0NN (UK)
À
crucial requirement to overcome the competing C F dis-
placement.[6] Early screening experiments that employed CsF
in THF with 5 mol% [Pd(dba)2] and 15 mol% PPh3 revealed
the presence of the desired product 2 in a trace amount
(entry 1). When TBAF rather than CsF was used, the
complete consumption of the starting material led disappoint-
ingly to the allylic alcohol 3 as the main product (entry 2). It is
well known that tetra-alkylammonium fluorides are notori-
ously difficult to maintain in their dehydrated state owing to
Prof. A. D. Gee
Division of Imaging Sciences and Bioengineering
King’s College London, London, SE1 7EH (UK)
[**] We thank Dr. S. Fletcher for very helpful discussions. This research
was financially supported by the EPSRC (C.H., A.H., M.T.), GSK
(M.H.), the CRUK (M.T.), the European Union FP7-ITN-238434
(E.B.), and the Leverhulme Trust (J.M.B.).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201007307.
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Communications
Table 1: Palladium-catalyzed allylic fluorination of 1a.
zoate is rarely used as a leaving group in palladium
catalysis.[12] Pleasingly, we found that fluorination of 1e with
2.5 equivalents of TBAF·(tBuOH)4 in the presence of
5 mol% of [Pd(dba)2] and 15 mol% PPh3 for one hour at
room temperature, led to the isolation of the allylic fluoride 2
in quantitative yield (entry 5). A control experiment con-
firmed that the presence of the catalyst is essential for the
fluorination to proceed (entry 6). This further optimization
study indicated that among the esters investigated, the
substrate releasing the stronger carboxylic acid is not the
one that leads to successful fluorination (pKa (H2O) = À0.25
Entry Catalyst
Ligand Fluoride 1a/2/3[a]
Yield 2
Source
[%][b]
1
2
3
4
5
6
7
[Pd(dba)2]
[Pd(dba)2]
[Pd(dba)2]
[Pd(OAc)2]
[Pd(PPh3)4]
[Pd(C3H5)(PPh3)2]+[d]
–
PPh3
PPh3
PPh3
PPh3
–
CsF
TBAF
4[c]
1:0.02:0.4
0:1:12
1:4:4
1:3:5
1:5:2
–
–
30
–
–
4[c]
4[c]
for
CF3COOH,
4.20
for
PhCOOH,
3.44
for
–
–
4[c]
1:2:5
1:0:0
–
–
pNO2C6H4COOH, and 3.18 for HF).
4[c]
The identification of a leaving group leading exclusively to
the formation of the desired allylic fluoride 2 enabled us to
examine the scope of this new allylic fluorination protocol.
Our results are summarized in Table 3. Various 2-substituted
propenyl fluorides (19–21), which are structurally related to 2,
were obtained in high yields (> 80%; entries 1–4). The
reaction to form the parent compound 22 is comparably
efficient, but the volatility of this product attenuates the yield
of isolated product (entry 5). The reaction is not limited to 2-
propenyl esters (5–8). Under these reaction conditions,
cinnamyl fluoride (23) was isolated in high yield (entry 6).
This result indicated that the conditions of allylic fluorination
are sufficiently mild to prevent decomposition of 23, which is
known to be unstable upon standing at room temperature.[13]
The branched regioisomer 3-fluoro-3-phenylpropene that
arises from fluorination at the benzylic position, and is
easily differentiated by 19F NMR spectroscopy, was not
detected. This result contrasts with the fluorination of
cinnamyl alcohol carried out using diethylaminosulfur tri-
[a] Ratio determined on crude reaction mixture by using 1H NMR
spectroscopy. [b] Yield of the isolated product. [c] 4 is TBAF·(tBuOH)4.
[d] Used as BF4À salt. dba=dibenzylideneacetone, TBAF=tetra-n-butyl-
ammonium fluoride, THF=tetrahydrofuran.
their very high hygroscopicity. We therefore turned to tetra-n-
butylammonium tetra(tert-butyl alcohol)-coordinated fluo-
ride [TBAF·(tBuOH)4; 4]; a reagent that possesses low
hygroscopicity and is reported to display good nucleophilicity
and low basicity (entries 3–7).[10] A substantial improvement
was observed when using this anhydrous crystalline reagent.
Under the most favorable reaction conditions, the allylic
fluoride 2 was isolated in a 30% yield, in addition to the
undesired allylic alcohol 3 (entry 3). Importantly, control
reactions that were run in the absence of a palladium catalyst
did not result in formation of the fluoride 2 (entry 7).
At this stage the viability of catalytic allylic fluorination
had been demonstrated. Under the chosen reaction condi-
tions, persistent competition from side reactions in which
allyloxy-type compounds were formed, was unavoidable. To
assess the extent to which the methylcarbonate leaving group
is responsible for these undesired processes,[11] alternative
reactive leaving groups were investigated (Table 2). The
acetate 1b and trifluoroacetate 1c were subjected to the
reaction conditions, but only the starting material or the
allylic alcohol were observed by 1H NMR spectroscopy
(entries 2 and 3). With benzoate 1d, allylic fluoride 2 was
formed in low conversion (entry 4). We then turned to 2-(4-
(tert-butyl)phenyl)allyl 4-nitrobenzoate (1e); p-nitroben-
fluoride (DAST);
a reaction that gives a mixture of
regioisomers, with the branched product being formed pre-
dominantly (linear/branched 1:1.75).[14] The procedure was
successful for several other linear allyl p-nitrobenzoates (10–
15), although the yields were generally lower (entries 7–12).
For the formation of the electron-rich allyl fluorides 24 and
25, the reaction was efficient and rapid, but the products were
sensitive to the work-up conditions (entries 7 and 8).[15]
Formation of 4-bromocinnamyl fluoride (26) and more
particularly the 4-trifluoromethyl analogue 27 were slower,
and in the latter case required heating to 408C (entries 9 and
10, respectively). The sterically hindered mesityl ester 14 also
required heating to 408C (entry 11); palladium coupling
chemistry has not previously been observed in a 2,6-disub-
stituted arylallyl ester.[16] Formation of the 4-chloromethyl
derivative 29 indicates that the incorporation of a sensitive
and easily manipulated functional group is feasible under
these mild reaction conditions (entry 12). As anticipated, an
attempt to form the allyl fluoride from ester 30 (Scheme 2)
was not possible under our standard reaction conditions.[2]
Substrate 31 was reactive, and in this case a mixture of
stereoisomers of 32 was formed together with traces of the
benzylic regioisomer (21% yield determined by 19F NMR
spectroscopy). One limitation of the current protocol is a
propensity for the competing elimination to give diene
products, when possible. For example, reactant 33 gives
approximately 5% of the desired allyl fluoride, as well as the
Table 2: Palladium-catalyzed allylic fluorination of 1a–e.
Entry
1a–e
R
1/2/3[a]
Yield 2
[%][b]
1
2
3
4
1a
1b
1c
1d
1e
1e
OMe
Me
CF3
Ph
p-NO2C6H4
p-NO2C6H4
1:4:4
30
–
–
–
>95
–
100:0:0
0:0:100
80:20:0
0:100:0
100:0:0
5
6[c]
[a] Ratio determined by 1H NMR spectroscopy. [b] Yields of the isolated
product. [c] Reaction run in the absence of palladium catalyst.
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Table 3: Fluorination of 2- and 3-substituted propenyl esters.[a]
rination to proceed, and the prospect to include
transition-metal-based chemistry in the portfolio of
Entry Ester (R=COC6H4pNO2)
Allyl Fluoride
Yield [%][b]
radiosynthetic transformations available for 18F C bond
À
construction, prompted us to study the 18F-fluorination
of a representative allylic precursor. This investigation
started with the preparation of the no-carrier-added
reagent [18F]TBAF.[20] A solution of [18F]TBAF in
anhydrous acetonitrile was added to a large excess of
cinnamyl methyl carbonate 34 (Scheme 3), [Pd(dba)2],
and triphenylphosphine in anhydrous acetonitrile. The
mixture was stirred at room temperature for either 5 or
30 minutes. After quenching with water, radio-HPLC
analysis of the reaction mixture indicated the formation
of [18F]-labeled cinnamyl fluoride ([18F]23; Scheme 3a),
the identity of which was confirmed by coelution with
the “cold” reference compound (Scheme 3b). The
decay-corrected radiochemical yield (RCY) was 9–
42% (n = 12) for reactions quenched after 5 minutes.
No significant improvement was observed after
30 minutes (RCY= 10–51%, n = 5). Control experi-
ments in the absence of [Pd(dba)2] did not lead to the
formation of [18F]23 at room temperature or upon
heating at 1108C for 20 minutes; a result indicating that
the transition metal is essential for 18F-fluorination to
proceed. The p-nitrobenzoate group of 9 was success-
fully displaced with [18F]TBAF in the presence of
[Pd(dba)2] but this process was much less efficient
with a RCY not exceeding 7%. This result indicates that
because of the constraints imposed by 18F-fluorination,
tailored optimization is required. This new labeling
protocol was compared with conventional direct SN2
18F-fluorination.[21] We examined the reactivity of cin-
namyl chloride and cinnamyl bromide with [18F]TBAF.
After 5 minutes at room temperature, cinnamyl chloride
remained intact; cinnamyl bromide was successfully
fluorinated leading to [18F]23 with a RCY not exceeding
1
1e
5
2
>95
2
3
4
5
19
20
21
22
95
85
84
66
6
7
8
6
9
23 >95
7[c]
8
10
11
12
24
25
26
27
39
46
53
35
9
10[d]
11[d]
12
13
14
15
28
29
65
60
[a] Reaction conditions: 4 (2.5 equiv), [Pd(dba)2] (5 mol%), PPh3 (15 mol%),
THF, RT, 1 h. [b] Yield of the isolated product. [c] Reaction run for 1 h at RT and
20 min at 408C. [d] Reaction run at 408C for 4 h; 27 is unstable.
Scheme 2. Fluorination of 30, 31, and 33.[25]
diene that is formed by formal loss of p-nitrobenzoic acid and
the unreacted starting material.[17]
The reactivity of the substrate in allylic fluorination is very
responsive to carbocation stabilizing substituents in the
substrate at the 1- and 2-positions of the allyl moiety. This
observation militates in favor of the involvement of an h3-
allylpalladium cation in the catalytic cycle, and places
emphasis on factors that facilitate its formation, rather than
the subsequent trapping with a fluoride ion.[18]
At this stage, we were poised to investigate whether this
new reaction would proceed with [18F]fluoride because PET
can only benefit from the availability of a wider range of
radiosynthetic methods for 18F labeling.[19] The very mild
conditions required for the palladium-catalyzed allylic fluo-
Scheme 3. Palladium-mediated 18F C bond formation. a) Ordinate
À
HPLC-radioactivity of [18F]-23. b) Ordinate HPLC-UV (254nm) spectrum
of 23. n=number of experiments conducted.
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Communications
[7] J. A. Kalow, A. G. Doyle, J. Am. Chem. Soc. 2010, 132, 3268 –
3269.
20% (n = 3). Under forcing conditions (1108C, 20 min), both
cinnamyl chloride and bromide delivered [18F]23 with a RCY
of 40% and 42%, respectively.[22]
[8] Recently, Katcher and Doyle have demonstrated the conversion
of racemic six-membered ring allylic chlorides into enantiomer-
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In conclusion, this paper describes a palladium-catalyzed
À
method for the formation of allylic C F bonds from allyl p-
nitrobenzoate, including “hot” fluoride.[23] This method is
significant, as halides are typically categorized as unsuitable
nucleophiles for transition metal catalyzed allylic substitu-
tion. Ongoing efforts seek to expand the scope of this reaction
to more challenging substrates such as those prone to
elimination and to validate a catalytic asymmetric variant of
this new fluorination reaction. To our knowledge, this work
18
À
demonstrates for the first time that F C bond formation is
feasible using a mild and rapid palladium-based protocol.[24]
The way is paved towards organotransition-metal 18F-radio-
chemistry.
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Experimental Section
General procedure: [Pd(dba)2] (6 mg, 0.01 mmol) and PPh3 (8 mg,
0.03 mmol) were added to a solution of 2-(4-tert-butylphenyl)prop-2-
en-1-yl-4-nitrobenzoate (68 mg, 0.2 mmol) in THF (2 mL). TBAF·-
(tBuOH)4 (279 mg, 0.5 mmol) was then added in one portion. The
reaction was stirred at RT for 1 h. The reaction was quenched by the
addition of NH4Cl(aq). The aqueous layer was extracted with Et2O (2 ꢀ
5 mL), and then the combined organic extracts were washed with
NH4Cl (2 ꢀ 10 mL), H2O (1 ꢀ 5 mL), and dried (Na2SO4). The solvent
was removed in vacuo and the crude reaction mixture was purified by
using silica gel column chromatography with 100% petroleum ether
(b.p. 30–408C) eluent.
Received: November 20, 2010
Published online: February 8, 2011
Keywords: allylic fluorination · fluorides ·
.
homogeneous catalysis · palladium ·
positron emission tomography
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À
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[22] The reaction of cinnamyl chloride, but not cinnamyl bromide,
with TBAF·(tBuOH)4 in THF was modestly accelerated in the
presence of [Pd(dba)2] and PPh3 (from 2%–16% conversion
after 1 h); see the Supporting Information. For examples of allyl
chlorides in allylic alkylation, see: a) ref [8a]; b) M. Matsumoto,
H. Ishikawa, T. Ozawa, Synlett 1996, 366 – 368; c) A. R. Kapdi,
R. J. K. Taylor, I. J. S. Fairlamb, Tetrahedron Lett. 2010, 51,
6378 – 6380.
[25] Note added in proof: Superior results in allylic fluorination have
been obtained with reactant 33 by the use of Pd-Xantphos; for a
chiral analogue of this ligand, see:a) P. Dierkes, S. Ramdeehul,
L. Barloy, A. De Cian, J. Fischer, P. C. J. Kamer, P. W. N. M.
van Leeuwen, J. A. Osborn, Angew. Chem. 1998, 110, 3302 –
3304; Angew. Chem. Int. Ed. 1998, 37, 3116 – 3118; b) J. A.
Gillespie, D. L. Dodds, P. C. J. Kamer, Dalton Trans. 2010, 39,
2751 – 2764.
[23] For silver-promoted 18F-fluorination of benzyl halides, see: C. C.
Caires, S. Guccione, (Leland Stanford Junior University), US
20100152502, 2010; CA 2010:753091.
Angew. Chem. Int. Ed. 2011, 50, 2613 –2617
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
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