Cis-specific hydrofluorination of alkenylarenes under palladium catalysis through an ionic pathway

Article abstract of DOI:10.1002/anie.201310056

This paper describes the hydrofluorination of alkenes through sequential H^- and F⁺ addition under palladium catalysis. The reaction is cis specific, thus providing access to benzylic fluorides. The mechanism of this reaction involves an ionic pathway and is distinct from known hydrofluorinations involving radical intermediates. The first catalytic enantioselective hydrofluorination is also disclosed. See attached PdF: A series of benzylic fluorides was prepared by hydrofluorination which proceeds through a Pd^II/IV catalytic manifold. The method is mechanistically distinct from previously reported radical hydrofluorination, and is characterized by its clean regioselectivity and unique cis stereospecificity. The first example of enantioselective net HF addition onto 2-vinylnaphthalene is also disclosed.

Full text of DOI:10.1002/anie.201310056

Angewandte
Chemie
DOI: 10.1002/anie.201310056
Homogeneous Catalysis
cis-Specific Hydrofluorination of Alkenylarenes under Palladium
Catalysis through an Ionic Pathway**
Enrico Emer, Lukas Pfeifer, John M. Brown, and Vꢀronique Gouverneur*
Dedicated to Professor Pier Giorgio Cozzi on the occasion of his 50th birthday
Abstract: This paper describes the hydrofluorination of
alkenes through sequential HÀ and F+ addition under palla-
dium catalysis. The reaction is cis specific, thus providing
access to benzylic fluorides. The mechanism of this reaction
involves an ionic pathway and is distinct from known hydro-
fluorinations involving radical intermediates. The first catalytic
enantioselective hydrofluorination is also disclosed.
Catalytic hydrofunctionalization has become a topic of
considerable interest as these reactions allow feedstock
olefins to be transformed, regio- and stereoselectively, into
high-value compounds. In this context, the hydrofluorination
of alkenes has remained a challenging transformation. The
addition of HF/pyridine or HF/SbF5 across alkenes,[1] and free
radical hydrofluorinations[2] have been studied. The harsh
reaction conditions offer narrow substrate scope and restrict
control over product selectivity. These limitations have
encouraged us to develop metal-catalyzed hydrofluorinations
that avoid such drawbacks. The importance of benzylic
fluorides in agrochemical and medicinal chemistry provided
a focus.[3] As a result the first successful catalytic method for
the regiocontrolled addition of HF to styrenes, a reaction
which involves electrophilic fluorination of an h3-palladium
benzyl compound, arises from the work described herein.
There are three examples of related metal-mediated
reactions in the literature. Barker and Boger disclosed
a powerful FeIII/NaBH4-mediated free radical hydrofluorina-
tion for unactivated alkenes using Selectfluor as the fluorine-
atom donor.[4] This regioselective reaction is functional-group
tolerant, but is not diastereospecific, an observation consis-
tent with the free radical mechanism (Scheme 1a). Shigehisa,
Hiroya, and co-workers reported a catalytic procedure which
enhances this approach, and is general for mono- and a,a’-
disubstituted alkenes. Hydrofluorination is achieved with N-
Scheme 1. Hydrofluorination of alkynes and alkenes.
hepta-1,6-diene, cyclization occurred, and is consistent with
the intermediacy of a 5-hexenyl radical (Scheme 1b). Sadighi
and co-workers[7] reported a unique trans hydrofluorination
of internal alkynes catalyzed by electrophilic (NHC)gold(I)
complexes, a reaction which was further developed by Miller
and co-workers,[8] and it is regio- and stereoselective, but is
not applicable to alkenes (Scheme 1c).
fluorotrimethylpyridinium
tetrafluoroborate
and
In considering routes for catalytic hydrofluorination of
olefins, we envisaged a palladium-catalyzed reaction for
which the fluorine and hydrogen atoms stemmed from
separate sources. This criteria led us to consider alkene
hydropalladation with subsequent oxidative interception of
the resulting organopalladium(II) species with an electro-
philic fluorine source. Precedent suggests that the ensuing
PdIVF intermediate would readily undergo reductive elimi-
nation.[9] This important class of substrates is not amenable to
hydrofluorination using known protocols.[4,5] The hydropalla-
dation of styrenes is known to lead to h3-benzyl complexes
responsive to benzylic functionalization, but not to fluorina-
tion.[10] Ultimately, our successful route uses an excess of
Selectfluor, which acts both as an electrophilic fluorinating
(Me2SiH)2O under cobalt catalysis.[5,6] By using a substituted
[*] Dr. E. Emer, L. Pfeifer, Dr. J. M. Brown, Prof. V. Gouverneur
Chemistry Research Laboratory, University of Oxford
Mansfield Road, Oxford, OX1 3TA (UK)
E-mail: veronique.gouverneur@chem.ox.ac.uk
[**] We thank the European Union (PIEF-GA-2011-300774 to E.E. and
FP7-PEOPLE-2012-ITN-RADIOMI-316882 to L.P.) for generous
funding, and Dr. A. Thompson (Chemical Crystallography Service,
University of Oxford). V.G. holds a Royal Society Wolfson Research
Merit Award.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201310056.
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agent and an oxidant at different stages in the catalytic cycle
(Scheme 1d).
entry 9). 4-Ethyl-1,1’-biphenyl (3a) was formed at room
temperature along with traces of the benzylic alcohol 4a
(Table 1, entry 14). Pleasingly, the ratio of iPr3SiH could be
reduced to 1.5 equivalents with a beneficial effect on product
formation (Table 1, entry 10). The conversion of 1a into 2a
remained low with 1.5 equivalents of Selectfluor but was
improved with an excess of N-F reagent (Table 1, entries 11
and 12). At this point, Et3SiH was found to be better suited
than iPr3SiH (Table 1, entry 13). Amongst the palladium
catalysts tested (Table 1, entries 15–17), [Pd(PPh3)4] was
superior, thus allowing full conversion of 1a into 2a. Pd-
(OAc)2, [PdCl2(MeCN)2], and [Pd(dba)2] all led to 2a along
with 3a. Benzylic chlorination was detectable (3%) with
[PdCl2(MeCN)2] but acetoxylation was not observed with
Pd(OAc)2. In the absence of a catalyst or of Et3SiH, 1a was
recovered along with trace amounts of 4a (Table 1, entries 18
and 19). During the course of this study a vicinal fluoroamide,
resulting from Ritter-type functionalization, was not typically
detected.[12] Under the optimized reaction conditions the
palladium-catalyzed reaction of 1a with 3 equivalents of
Selectfluor and 1.5 equivalents of Et3SiH in MeCN (0.025m)
at 08C afforded 2a in 69% yield as a single regioisomer
(Table 1, entry 13).
In our initial experiments,[11] we focused on the reactivity
of 4-vinylbiphenyl (1a) and examined a range of palladium
catalysts combined with various fluorine and hydride sources
(Table 1). Selectfluor emerged as the most suitable fluorina-
tion reagent when used in the presence of iPr3SiH and
10 mol% of [Pd(PPh3)4] in acetonitrile at 08C (Table 1,
entry 1). Selectfluor bis(triflate) was as efficient as Selectfluor
bis(tetrafluoroborate) (Table 1, entry 2). N-Fluorobenzene-
sulfonimide, N-fluoropentachloropyridinium triflate, and
XeF2 were less effective fluorine sources as these reagents
led preferentially to the reduced product 4-ethyl-1,1’-biphenyl
(3a; Table 1, entries 3–5). The formation of 3a was also
observed when iPr3SiH was replaced with PhSiH3 or with
NaBH4 (Table 1, entries 6 and 7). Bu3SnH gave mainly
starting material with only trace amounts of 2a (Table 1,
entry 8). These results indicate that product formation is
favored with the most reactive hydride source.[12] The reaction
concentration and temperature were important parameters,
with hydrofluorination best performed at 08C and lower
substrate concentration (0.025m instead of 0.05m; Table 1,
The substrate scope proved quite general, with various
vinylarenes and disubstituted alkenylarenes participating
effectively in the hydrofluorination reaction (Scheme 2). All
the reactions of terminal as well as 1,1- and 1,2-disubstituted
alkenylfluorides are regiospecific for benzyl fluoride forma-
tion. The electronic nature of the aryl motif is important with
electron-neutral or electron-withdrawing groups leading to
isolated benzylic fluorides with the highest yields (up to
99%). The method tolerates a wide range of functional
groups including ether, amide, ester, sulfonamide, fluoro,
bromo, alkyl, and trifluoromethyl groups. The method
permits the installation of a fluorine substituent at a quater-
nary benzylic position as illustrated by the successful synthesis
of 2p (65%). However, the homologous but-1-en-2-ylben-
zene gives approximately 10% yield.[11,14] The method gave
access to 2u and 2v, two compounds that possess three
Table 1: Hydrofluorination of 1a.[a]
Entry
[Pd][b]
F
H
Source
Conv.
[%][d]
Yield [%][d]
2a 3a
Source[c]
1
2
3
4
5
6
7
8
I
I
I
I
I
I
I
I
I
I
I
I
I
I
A
B
C
iPr3SiH
iPr3SiH
iPr3SiH
iPr3SiH
iPr3SiH
PhSiH3
NaBH4
Bu3SnH
iPr3SiH
iPr3SiH[g]
iPr3SiH[g]
iPr3SiH[g]
Et3SiH[g]
Et3SiH[g]
Et3SiH[g]
Et3SiH[g]
Et3SiH[g]
Et3SiH[g]
–
>95
>95
25
>95
72
>95
>95
9
>95
>95
37
>95
>95
>95
>95
>95
92
30
0
0
34
11
0
16
0
18
<5
35
41
22
54
69
48
27
38
31
0
12
23
28
31
48
0
0
0
0
0
D
E[e]
A
A
A
A
A
9[f]
10[f]
11[f]
12[f]
13[f]
14[f,j]
15[f]
16[f]
17[f]
18[f]
19[f]
benzylic positions, and are not accessible by direct benzylic
[9]
À
A[h]
A[i]
A[i]
A[i]
A[i]
A[i]
A[i]
A[i]
A[i]
C H activation/fluorination or by applying the iron(III)-
mediated or cobalt-catalyzed hydrofluorinations previously
reported.[4,5] Pleasingly, (E)- and (Z)-2-benzylidene-3-meth-
ylbutan-1-ol (1x) gave anti-2x and syn-2x, respectively, in
good yields and with a d.r value of greater than 20:1. This
result implies that the hydrofluorination is cis specific.[15]
A proposed catalytic cycle that explains the need for
excess Selectfluor in the hydrofluorination reaction is pre-
sented in Scheme 3. Initial oxidation of the precatalyst gives
the electrophilic PdII species Awhich activates the silane, thus
giving access to the PdII hydride species B, which in turn
effects reversible syn hydropalladation to the alkenylarene to
afford the h3-benzyl complex C. Electrophilic fluorination of
C with Selectfluor affords the PdIVF dication D (or its h3-
complex). Reductive elimination then forms generic product
E, and regenerates A.
0
15
10
12
16
0
II
III
IV
–
I
10
<5
0
0
[a] Reaction conditions: 1a (18 mg), MeCN (2 mL), fluorine source
(2.0 equiv), hydride source (2.0 equiv), 08C, 2 h. [b] I=[Pd(PPh3)4],
II=Pd(OAc)2, III=PdCl2(MeCN)2, IV=[Pd(dba)2]. [c] A=Selectfluor
bis(tetrafluoroborate) [(1-chloromethyl-4-fluoro-1,4-diazoniabicyclo-
[2.2.2]octane bis(tetrafluoroborate), B=Selectfluor bis(triflate), C=N-
fluorobenzenesulfonimide (NFSI), D=N-fluoropentachloropyridinium
1
triflate, E=XeF2. [d] Determined by H NMR spectroscopy by peak
integration using 1-fluoro-3-nitrobenzene as an internal reference.
[e] Reaction performed in CH2Cl2 (2 mL). [f] 4 mL of solvent. [g] 1.5 equiv
of iPr3SiH (or with 1.5 equiv of Et3SiH). [h] 1.5 equiv of Selectfluor
bis(tetrafluoroborate). [i] 3 equiv of Selectfluor bis(tetrafluoroborate).
[j] Reaction performed at RT.
This mechanism is supported by the various experiments
described in Scheme 4. The hydrofluorination of 1b with
Et3SiD leads to (2-2H)-2b and confirms that this reagent
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Scheme 4. Regio- and stereochemical probes. Reaction conditions:
1) [Pd(PPh3)4] (10 mol%), Selectfluor (3.0 equiv) Et3SiD (1.5 equiv),
CH3CN, 08C, 2 h. 2) PCC/alumina, benzene, RT, 12 h.
serves as the hydrogen atom source. The formation of the
labeled alkene (2-2H)-1b (< 1%) and dideutero product (2,2-
2H2)-2b indicates that the hydropalladation event is reversible
during the course of the reaction (Scheme 4a). The product is
not deuterated when the reaction is performed in CD3CN,
hence the solvent is not serving as a hydrogen donor. The
substrate (E)-1s provided the single deuterated product
syn-(2-2H)-2s[16] with no detectable anti-(2-2H)-2s upon
deuterofluorination, thus implying that the addition of
deuterium and fluorine across the double bond is syn ster-
eospecific (Scheme 4b). For stereochemical assignment, the
stilbenes (E)- and (Z)-1y were subjected to hydrofluorination
using Et3SiD because both syn- and anti-(2-2H)-2y could be
prepared through independent synthesis.[11,17] (Z)-Stilbene led
to 21% of anti-(2-2H)-2y along with trace amounts of syn-(2-
2H)-2y and the fluoroamide 5y, resulting from Ritter-type
functionalization (Scheme 4c). Conversely, (E)-1y led to
a complex mixture of products, out of which syn-(2-2H)-2y
was detectable in trace amounts (2%) in addition to
significant amounts of the syn- and anti-5y (18%). The
synthesis of syn-(3-2H)-2z provided additional evidence for
cis-stereospecific hydrofluorination (Scheme 4d). Both syn-
(3-2H)-2z and anti-(3-2H)-2z are known compounds.[18] Sub-
jecting the allylic alcohol (E)-1z to deuterofluorination, by
using our standard reaction conditions, with subsequent
oxidation led exclusively to syn-(3-2H)-2z, formed as
a single stereoisomer.[11] The stereochemical course of hydro-
Scheme 2. Hydrofluorination of alkenylarenes (1a–x). Regioselectivity
>20:1. Phth=phtalimido. iPr=isopropyl. [a] Yield determined by
19F NMR spectroscopy with 1-fluoro-3-nitrobenzene as an internal
reference. [b] Single-crystal diffraction data are available for 2k.[11,13]
[c] anti-2x was prepared from (E)-2-benzylidene-3-methylbutan-1-ol
(1x). [d] The reaction time is 15 h. [e] syn-2x was prepared from (Z)-
1x.
fluorination under palladium catalysis is consistent with the
3
studies of Gagnꢀ and co-workers[19] who reported C(sp ) F
À
bond formation with XeF2 proceeding with retention of
stereochemistry from putative PtIVF intermediates, and the
work of Gary and Sanford[20] reporting on the first example of
3
IV
a C(sp ) F bond formation from a Pd center.[20]
À
Additional experiments were carried out with isolated h3-
benzyl complexes (Scheme 5). We could not isolate either C
or D (Scheme 3), or its h3-analogue, but found that the h3-
benzyl complex C1[21] ligated with dppp (1,3-bis(diphenyl-
phosphino)propane) led to 2a in 50% yield upon treatment
with Selectfluor in MeCN at room temperature (Scheme 5a).
Scheme 3. Suggested catalytic cycle for hydrofluorination. Et3SiF is
formed upon hydrofluorination.[11]
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fluorination performed under palladium catalysis as de-
scribed here is regioselective and characterized by the
unique cis specificity. The methodology is best suited for
alkenylarenes which can be transformed in a range of
functionalized benzyl fluorides. The formation of (S)-2-(1-
fluoroethyl)naphthalene (2w) from C2, used either as starting
material or as catalyst, demonstrates the feasibility of
enantioselective net HF addition to alkenes. We believe that
the underlying principles, whereby HF addition is effected
through sequential HÀ and F+ additions under palladium
catalysis, are novel and may be applied to other catalytic
reactions.
Experimental Section
General procedure for catalytic hydrofluorination: [Pd(PPh3)4]
(23.2 mg, 0.02 mmol), Selectfluor (213.0 mg, 0.60 mmol), and Et3SiH
(48 mL, 0.30 mmol) were added to a solution of 4-vinylbiphenyl 1a
(36.0 mg, 0.20 mmol) in dry MeCN (8 mL) in a 10 mL screw-top vial.
The solution was stirred for 2 h at 08C before diluting with water
(4 mL) and extracted with CH2Cl2 (3 ꢁ 6 mL). The combined organic
layers were dried over MgSO4 and evaporated under reduced
pressure. Purification by column chromatography (SiO2, EtOAc/
petroleum ether= 1:15) afforded 2a as a white solid (27.5 mg, 69%
yield).
Scheme 5. Reactivity of the complexes C1 and C2.
Moreover, the enantioenriched naphtylethyl complex C2,
prepared from (R)-T-binap according to the protocol of
Hartwig et al.,[22] afforded (S)-2-(1-fluoroethyl)naphthalene
(2w)[23] in 66% ee at room temperature and 80% ee at À408C
(82% yield) in the presence of XeF2[24] (Scheme 5b). By using
1.2 equivalents of Selectfluor at room temperature, 2w was
formed in 36% yield (19F NMR spectroscopy) and a depleted
ee value of 36%. The sense of enantiocontrol for the major
enantiomer remained S (Scheme 5c). The stereochemical
outcome of fluorination contrasts with the formation of (R)-
N-(1-(naphthalen-2-yl)ethyl)aniline (6; 84% yield, 71% ee)
arising from external attack of the amine on the C2, a reaction
occurring with inversion of configuration (Scheme 5d).[11,25]
These data indicate that the stereochemical outcome for the
Received: November 19, 2013
Revised: January 31, 2014
Published online: March 18, 2014
Keywords: catalysis · fluorine · palladium · regioselectivity ·
.
stereospecificity
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À
the Pd F complex and C F bond-forming reductive elimi-
nation. The cis stereospecificity of this novel palladium-
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cobalt-catalyzed hydrofluorinations which lead to a mixture
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10 mol% of C2, 3.0 equivalents of XeF2, and 1.5 equivalents
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[13] Low-temperature single-crystal diffraction data for 2k were
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solved using SuperFlip, (L. Palatinus, G. Chapuis, J. Appl.
Crystallogr. 2007, 40, 786 – 790) and refined within the CRYS-
TALS suite (P. W. Betteridge, J. R. Carruthers, R. I. Cooper, K.
Prout, D. J. Watkin, J. Appl. Crystallogr. 2003, 36, 1487; R. I.
Cooper, A. L. Thompson, D. J. Watkin, J. Appl. Crystallogr.
2010, 43, 1100 – 1107). See the Supporting Information (CIF) for
more details; CCDC 984222 contains the supplementary crys-
tallographic data for this paper. These data can be obtained free
of charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[23] An authentic sample of (S)-2-(1-fluoroethyl)naphthalene was
prepared by nucleophilic fluorination (SN2) of (R)-1-(naphtha-
lene-2-yl)ethanol using the protocol of Bresciani and OꢃHagan:
S. Bresciani, D. OꢃHagan, Tetrahedron Lett. 2010, 51, 5795 –
5797.
[24] For selected fluorinations of palladium complexes with XeF2,
see: a) A. Kaspi, A. Yahav-Levi, I. Goldberg, A. Vigalok, Inorg.
Chem. 2008, 47, 5 – 8; b) T. Furuya, T. Ritter, J. Am. Chem. Soc.
2008, 130, 10060 – 10061; c) T. Furuya, H. M. Kaiser, T. Ritter,
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[14] But-1-en-2-ylbenzene (1aa) gave 11% of the product 2aa, which
results from hydrofluorination along with a mixture of (E)- and
(Z)-but-2-en-2-ylbenzene (40%). No starting material (1aa) was
recovered.[11]
[25] A. M. Johns, J. W. Tye, J. F. Hartwig, J. Am. Chem. Soc. 2006,
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Angew. Chem. Int. Ed. 2014, 53, 4181 –4185
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