Palladium-catalyzed intermolecular fluoroesterification of styrenes: Exploration and mechanistic insight

Article abstract of DOI:10.1039/c3sc50690h

A novel palladium-catalyzed intermolecular oxidative fluoroesterification of vinylarenes has been developed using NFSI, one of the mildest electrophilic fluorinating reagents. The reaction presents an efficient synthetic pathway to afford a series of α-monofluoromethylbenzyl carboxylates in good to excellent yields. Rather than following an electrophilic fluorination pathway, the reaction is initiated through oxidation of Pd(0) to a Pd(ii) fluoride complex by NFSI, followed by fluoropalladation of a styrene to generate an α-monofluoromethylbenzyl-Pd intermediate. Generally, reductive elimination of benzyl-Pd^II complexes is favored with relatively strong oxy-nucleophiles to afford C-O bonds. This reaction, however, exhibited the opposite reactivity: strong acids with weak nucleophilicity, such as CF ₃CO₂H and CCl₃CO₂H, were prone to afford the fluoroesterification product, while weak acids with strong nucleophilicity, such as HOAc and BzOH, did not deliver the C-O bond product. Further mechanistic studies determined that Csp³-Pd(O₂CR), a key intermediate, was generated through ionic ligand exchange between benzyl-Pd(NZ₂) and CF₃CO₂H, and the final C-O bond was possibly formed through reductive elimination of a high-valent Csp ³-Pd(O₂CR) complex via an S_N2-type nucleophilic attack pathway.

Full text of DOI:10.1039/c3sc50690h

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Palladium-catalyzed intermolecular fluoroesterification
of styrenes: exploration and mechanistic insight†
Cite this: DOI: 10.1039/c3sc50690h
a
a
b
b
a
*
Haihui Peng, Zheliang Yuan, Hao-yang Wang, Yin-long Guo and Guosheng Liu
A novel palladium-catalyzed intermolecular oxidative fluoroesterification of vinylarenes has been
developed using NFSI, one of the mildest electrophilic fluorinating reagents. The reaction presents an
efficient synthetic pathway to afford a series of a-monofluoromethylbenzyl carboxylates in good to
excellent yields. Rather than following an electrophilic fluorination pathway, the reaction is initiated
through oxidation of Pd(0) to a Pd(II) fluoride complex by NFSI, followed by fluoropalladation of a
styrene to generate an a-monofluoromethylbenzyl–Pd intermediate. Generally, reductive elimination of
benzyl–PdII complexes is favored with relatively strong oxy-nucleophiles to afford C–O bonds. This
reaction, however, exhibited the opposite reactivity: strong acids with weak nucleophilicity, such as
CF3CO2H and CCl3CO2H, were prone to afford the fluoroesterification product, while weak acids with
strong nucleophilicity, such as HOAc and BzOH, did not deliver the C–O bond product. Further
mechanistic studies determined that Csp3–Pd(O2CR), a key intermediate, was generated through ionic
ligand exchange between benzyl–Pd(NZ2) and CF3CO2H, and the final C–O bond was possibly formed
through reductive elimination of a high-valent Csp3–Pd(O2CR) complex via an SN2-type nucleophilic
attack pathway.
Received 13th March 2013
Accepted 20th May 2013
DOI: 10.1039/c3sc50690h
www.rsc.org/chemicalscience
(Scheme 1a).7 Thus, exploration of alternative approaches
employing NFSI or even milder electrophilic uorinating
Introduction
Monouorinated analogues of biologically active compounds
are considered as potential drugs because the mono-
uoromethyl group can sterically mimic the methyl or hydroxy-
methyl group with considerably altered bioactivity and
bioavailability.1,2 Thus, efforts towards the efficient synthesis of
those compounds have attracted much attention.3 For instance,
electrophilic uorination of alkenes can be used to synthesize
the corresponding monouoro-alcohols,4 an important moiety
in biological active compounds.5 However, such uorooxyge-
nation reactions are oen restricted to electron-rich alkenes
and required strong electrophilic uorinating reagents,6 such
as CsSO4F,6a,b AcOF,6c XeF2,6d TfN2F,6e and substituted N-uoro-
pyridinium salts.6f–h These limitations, narrow substrate scope,
poor selectivity and poor functional group compatibility, can be
usually overcome by employing a mild uorinating reagent.
Unfortunately, readily available N-uoro-benzenesulfonimide
(NFSI), one of mildest electrophilic uorinating reagents, is
inert toward uorination of alkenes due to its low reactivity
reagents for uorooxygenation are in urgent need.
Palladium-catalyzed intra/inter-molecular difunctionaliza-
tion of olens represents one of the best strategies to introduce
two functional groups into double bond simultaneously.8 In
addition, electrophilic uorinating reagents have been reported
as oxidants to carry out Pd-catalyzed organic transformations.9
Therefore, we envisioned that applying a palladium catalyst
might be a good strategy to achieve the uorooxygenation of
aState Key Laboratory of Organometallics Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai, 200032,
China. E-mail: gliu@mail.sioc.ac.cn; Fax: +86-21-64166128; Tel: +86-21-54925346
bShanghai Mass Spectrometry Center, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 345 Lingling Road, 200032, Shanghai, China
† Electronic supplementary information (ESI) available: Full experimental
procedures and spectroscopic characterization data are provided. See DOI:
10.1039/c3sc50690h
Scheme 1 Fluoroesterification of styrene.
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Table 1 Ligand screeninga
alkenes.10 As part of our efforts to develop novel uorination
reactions,10e,11 we disclosed a Pd-catalyzed intermolecular uo-
roamination of styrene using NFSI as uorine source.12 In this
reaction, NFSI served as a good reagent to oxidize Pd(0) to a
palladium uoride complex, and subsequent uoropalladation
of styrene was proposed as the key step to generate the a-
monouoromethyl benzyl–Pd intermediate. Based on this
discovery, we speculated that if the benzyl–Pd intermediate was
attacked by a carboxylic acid,13 efficient uoroesterication of
alkenes could be expected (Scheme 1b).
Generally, reductive elimination of benzyl–PdII complexes is
favoured with relatively strong oxy-nucleophiles to afford C–O
bonds.14 Herein, we reported
a Pd-catalyzed uoroester-
ication of styrenes, in which carboxylic acids with weak
nucleophilicity but strong acidity, such as CF3CO2H and
CCl3CO2H, are prone to afford the C–O bond formation
product. In contrast, weak acids with strong nucleophilicity,
such as HOAc and BzOH, still form C–N bonds, rather than
C–O bonds. Further mechanistic studies support that the nal
C–O bond is derived from the reductive elimination of a high-
valent Csp3–Pd(O2CR) complex.
a
All reactions were run at 0.2 mmol scale. 19F NMR yield of 3a (2a) with
CF3C6H5 as internal standard. b PdCl2 (5 mol%) as catalyst. c 5.0 equiv.
TFAH. d 15% pyridine.
best results (3a, 45% yield), combined with a small amount of
uoroamination product 2a (10%). In contrast, pyridine was
ineffective. Pd catalyst screening results showed that both Pd(II)
and Pd(0) were good catalysts for this transformation,15 and
PdCl2 exhibited the best reactivity to give 3a in 82% yield.
Increasing the amount of triuoroacetic acid (5 equiv.)
improved the yield of uoroesterication (91% yield).
Under the optimized reaction conditions, the substrate
scope of the reaction was investigated, and the results are
compiled in Table 2. The reaction of 1a afforded the desired
product 3a in 91% yield. Due to easy hydrolysis of product 3a
on a silica gel column,16 the desired product 3a could be
directly transformed to the corresponding alcohol 5a in 87%
yield by addition of pyridine and methanol in one pot. In
addition, substrates bearing an alkyl-, aryl-, ester- or halogen-
substituted benzene ring were suitable to give corresponding
products 3b–3j (or 5b–5j) in good to excellent yields (entries
2–10). In contrast, the reactions of electron-decient styrenes
1k and 1l afforded products in slightly lower yields (entries
11–12). Similarly, the reaction of a-methylstyrene 1m
smoothly proceeded to give desired product 5m in 84% yield.
Gratifyingly, internal alkenes, such as 1n–1r, proved to be
good substrates, giving products 5n–5r with excellent regio-
selectivity but poor diastereoselectivity (entries 14–20).
Results and discussion
To test the above hypothesis, the reaction of 1a was initially
investigated by screening a series of carboxylic acids with
different pKa values under the previous reaction conditions
(eqn (1)). We were pleased to nd that uoroesterication
product 3a or 4a was obtained when CF3CO2H or CCl3CO2H
was used as the additive. Although the yield of the desired
product was low, the uoroamination process was completely
inhibited. It is noteworthy that the above two acids have much
lower pKa values and weaker nucleophilicity than (PhSO2)2NH.
However, addition of HOAc or p-nitrobenzoic acid, which has
higher pKa values and better nucleophilicity, still afforded the
uoroamination product 2a rather than uoroesterication
product. Upon further increasing the acidity, addition of
methanesulfonic acid completely inhibited uorination of 1a.
In comparison, triuoroacetate salts, such as CF3CO2Na,
CF3CO2Ag and CF3CO2Cs, did not afford any uorination
products.
Based on above results, the substrate scope of styrenes was
further explored (Table 3). We found that more sterically
hindered styrenes such as 1s, and electron-decient styrenes
with halide (X ¼ Cl, Br) atoms at the b-position, such as 1t or
1u, were compatible under these reaction conditions and
yielded the desired products in moderate to good yields. 3-
vinylquinoline substrate 1v was also good for this trans-
formation, giving product 5v in 65% yield. The substrate 1w
with a triazole group provided corresponding product 5w
in 55% yield. In addition, styrenes with more functional
groups, such as aldehyde, acid, and nitrile groups, reacted
Encouraged by the above interesting uoroesterication
results, further ligand effects were investigated. As shown in
Table 1, bidentate nitrogen ligands were crucial to the success
of the uoroesterication. Electron-decient ligand L2 gave the
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Table 2 Pd-catalyzed fluoroesterification of styrenesa
Entry
Substrate
3
Yieldb
5
Yieldc
1
2
1a
1b
3a
3b
91%
89%
5a
5b
87%
83%
R ¼ p-Me
3
4
5
6
7
8
9
10
11
12
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
o-Me
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
79%
80%
83%
73%
91%
82%
83%
80%
57%
53%
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
71%
75%
80%
p-tBu
p-(p-F)C6H4
p-CH2Cl
p-F
p-Cl
p-Br
p-OAc
p-COOMe
p-CF3
d
—
85%
80%
81%
80%
50%
43%
13
1m
3m
3n
88%
5m
5n
84%
14
E-1n
R ¼ Me
91% (1.4 : 1)
81% (1.3 : 1)
15
16
17
18
Z-1n
E-1o
E-1p
Z-1p
97% (1 : 2.4)
73% (2 : 1)
91% (1.3 : 1)
65% (1 : 1.5)
87% (1 : 2.3)
70% (2 : 1)
90% (1.3 : 1)
55% (1 : 1.5)
R ¼ Et
R ¼ Ph
3o
3p
5o
5p
19
1q
3q
3r
81% (1.4 : 1)
5q
5r
71% (1.3 : 1)
20
1r
81% (2 : 1)
71% (2 : 1)
a
Reactions were conducted at 0.3 mmol scale. b 19F NMR Yield with CF3Ph as internal standard. c Isolated yield based on the substrate 1 (the data in
parentheses is the value of diastereoselectivity). d Complex result.
smoothly to afford the corresponding products in good
yields. Finally, styrene 1aa bearing a steroid motif proved to
be a good substrate to give product 5aa.17 Estrone derivative
1ab also afforded the corresponding ester product 3ab,
which is physiologically active and could be utilized in
medicine.18
Furthermore, substrate 1ac, frequently employed as a
The reaction was also explored using CCl3CO2H, since the
trichloroacetate ester products were stable enough to be
handled via silica gel chromatography. As shown in Table 4, a
variety of substrates proved suitable to afford trichloroacetate
ester products 4 in moderate to good yields.
Due to the important biological activities of a-methylbenzyl
thioacetates in medicinal chemistry, such as the compound
illustrated below as a p38-a protein kinase inhibitor,22 we
speculated that introducing uorine into methyl group
might provide an opportunity to modulate its biological
activity.
radical “clock” was subjected to the standard uoroester-
ication conditions.19 The reaction afforded the desired
product 5ac in moderate yield, which rules out the possibility
of a radical pathway (eqn (2)).20 Furthermore, product 3ac
could not be obtained through the reaction of 1ac with strong
F+ reagents (eqn (2)), in which ring-opening of cyclopropane
occurred to give complex results. This observation indicates
that the electrophilic uorination pathway is less likely.21
Finally, unactivated olens, such as 1-octene and allylbenzene,
were found to be ineffective in this uoroesterication
reaction.
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Table 3 Pd-catalyzed fluoroesterification of styrenesa,b
a
Reactions were conducted at 0.2 mmol scale. b Isolated yield (the data
c
in parentheses is the value of diastereoselectivity). 80% conversion.
d
e
The ester product was hydrolysed with aq. NaHCO3. With Pd(dba)2
(5 mol%) as catalyst.
Table 4 Pd-catalyzed fluoroesterification of styrenesa,b
Mechanism
As proposed above, the nucleophilic attack on the benzyl–
PdII complex by CF3CO2H is responsible for the benzyl C–O
bond formation. However, a pioneering study by Yamamoto
demonstrated that reductive elimination of the benzyl–
PdII(O2CCF3) complex via a Pd(II/0) cycle is more difficult
than that of the benzyl–PdII(OAc) complex.23 To elucidate
the mechanism, benzyl–Pd complex
8 was employed to
examine the C–O bond formation (Scheme 2). We found that
treatment of complex 8 with either (PhSO2)2NH or CF3CO2H
afforded the corresponding palladium complex 9 or 10 in
good yield. Complex 10 was also obtained from 9 in 82%
yield, however, 9 was transformed from 10 in low yield.
This ionic ligand exchange is possibly triggered due to
the higher acidity of CF3CO2H than that of (PhSO2)2NH or
HOAc. Furthermore, complexes 8–10 were too stable to
allow the formation of the corresponding C–O and C–N
bonds, even with the assistance of PPh3, bipyridine and
ligand L2. The results indicate that C–O bond formation is
unlikely to follow the reductive elimination pathway via
Pd(0/II) cycle.
a
b
Reactions were conducted with 0.3 mmol scale. Isolated yield (the
c
data in parentheses is the value of diastereoselectivity). E-(b-methyl)
styrene as substrate. d Z-(b-methyl)styrene as substrate.
Thus, the direct thiolation of product 4 was further investi-
In contrast, the reductive elimination process did occur in
gated. Treatment of 4f with thioacetic acid (AcSH) afforded the presence of NFSI. For instance, reductive elimination
substituted product 6 in 95% yield (eqn (3)). Benzylthioether 7 products 11 and 12 were selectively yielded from complexes 9
was also obtained from 4f with related thiophenol in 90% yield (47% yield) and 10 (39% yield), respectively. Product 11 could
(eqn (4)). Therefore, the sequential uoroesterication of alkenes also be directly obtained from complex 8 in 23% yield without
and thiolation provided a versatile way to build up a library of observation of the C–O bond product. In addition, product 12
benzyl thioacetates containing a monouoromethyl group.
could be selectively obtained from complex 9 when treated
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Pd(0) by NFSI to give Pd(II) uoride complex I, and subse-
quent uoropalladation of styrene yields intermediate II.27,28
Then, two possible scenarios are presented to address the
transformation from complex II to product 3. The rst
pathway involves ligand exchange between II and CF3CO2H
to give intermediate III, and then subsequent oxidation
of III by NFSI generates the high-valent Pd intermediate IV,
which undergoes SN2-type reductive elimination to form
the C–O bond (path a). For the second pathway, the trans-
formation from Pd complex II to IV is via an alternative
sequential process of oxidation of Pd(II) species II, and
ligand exchange between V and CF3CO2H (path b). It is
difficult to differentiate the above two pathways at
present.29
To gain insight into the mechanism, time course experi-
ments were conducted. As displayed in Fig. 1A, a noticeable
induction period was found in the reaction with PdCl2 as
the catalyst. In contrast, reactions with Pd(PPh3)4 and
Pd(dba)2 showed a monotonic decrease in styrene concen-
tration, and the lack of an induction period enabled us
to obtain much of our kinetic data via initial-rates
methods.
Further kinetic studies were performed using 1g as
the substrate and Pd(PPh3)4 as catalyst. The reaction rate
exhibited a saturation dependence on the concentration of
1g, and rst-order dependence on the concentration of the
palladium catalyst and NFSI.30 It is interesting that the rate
Scheme 2 Reductive elimination processes from Pd(II) complexes.
with equal equivalents of NFSI and CF3CO2H. The above
observations suggested that the C–O bond should be derived
from a high-valent Pd complex, such as a Pd(IV) or Pd(III)
intermediate.24
Interestingly, the order of reductive elimination of high-
valent C–Pd(Nu) complexes is opposite to the nucleophilicity of
ꢀ
Nu: CF3CO2 > (PhSO2)2Nꢀ > CH3CO2ꢀ. Due to easier disasso-
ciation of CF3CO2ꢀ, reductive elimination of the palladium
complex possibly involves a dissociative SN2 nucleophilic attack
pathway (Scheme 3, bottom), which is consistent with the DFT
of 3g formation presented
a saturation dependence on
the concentration of CF3CO2H, but the overall rate of
formation of 2g and 3g was independent on the concen-
tration of CF3CO2H (Fig. 1B). This observation is consistent
with both paths a and b. In the case of low [CF3CO2H],
the formation of a mixture of products 2g and 3g should
calculations on the C–N bond formation from Pd(IV) interme-
25,26
~
diate reported by Muniz.
Based on the above analysis, the mechanism in Scheme 3
was proposed. The reaction is initiated through oxidation of
be delivered from high-valent Pd complexes
V and IV,
which may be generated from the oxidation of both inter-
mediates II and III, respectively, or from the ligand exchange
between complex V and limited CF3CO2H. In the high
[CF3CO2H], either rapid transfer from II to III then oxidation
or rapid transfer from V could generate intermediate IV, and
yield a single product 3g from its reductive elimination
(Scheme 3).
Fig. 1 (A) (left) Time course of reactions of 1g with [Pd]/L2: [styrene] (0.40
M), [CF3CO2H] (2.00 M), [Pd] (0.02 M), [L2] (0.03 M), [NFSI] (1.20 M), dioxane,
30 ꢁC; (B) (right) Dependence of the initial rate on [CF3CO2H]: [styrene]
(0.40 M), [Pd] (0.02 M), [L2] (0.03 M), [NFSI] (1.20 M), [CF3CO2H] (0–3.5 M),
dioxane, 30 ꢁC.
Scheme 3 Proposed mechanism.
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6 For selected examples of electrophilic uorination of
alkenes, see: (a) S. Stavber and M. Zupan, Tetrahedron,
1986, 42, 5035–5043; (b) N. S. Zerov, V. V. Zhdankin,
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Conclusions
We have developed a novel palladium-catalyzed intermolecular
oxidative uoroesterication of vinylarenes. The reaction
affords monouorinated benzyl esters in good yields. The
mechanistic study shows that the key step of C–F bond
formation derives from the uoropalladation process and that
subsequent C–O bond formation comes from a sequential ionic
ligand exchange between the benzyl–Pd(II) intermediate and
CF3CO2H, oxidation by NFSI, then reductive elimination of the
high-valent Pd complex. Further applications of this trans-
formation and asymmetric uoroesterication of styrenes are in
progress.
Acknowledgements
We are grateful for nancial support from the National Basic
Research Program of China (973-2011CB808700), the National
Natural Science Foundation of China (21225210, 21121062, and
20923005), and the Science Technology Commission of the
Shanghai Municipality (11JC1415000).
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15 For optimization of the reaction conditions, see the ESI.†
16 Product 3 can be puried using silica gel purchased from
this
transformation,
both
cis-
and
trans-
uoropalladations were involved, and resulted in poor
diastereoselectivity. A study of uoropalladation stereo-
chemistry has been reported, see ref. 11b.
Sigma Aldrich (Grade 636).
28 In order to investigate the uoropalladation step, substrate
8-vinyl-quinoline was subjected to the reaction conditions.
The reaction was monitored using ESI-MS, and the signals
at m/z 557 and 577 were consistent with the coordinated
Pd complex and a-monouoromethyl benzyl–Pd complex,
respectively. The latter was derived from uoropalladation
of the alkene. For details analysis, see the ESI.†
17 Product 5aa is hard to purify using silica gel column
chromatography, due to an unidentied side product, but
can be puried by HPLC.
18 Substrates 1s–1z, 1aa and 1ab were treated under standard
electrophilic uorination reaction conditions; most
reactions failed to give the corresponding products. For
details, see the ESI.†
19 For a review on radical probes, see: M. Newcomb, in Radicals
in Organic Synthesis, ed. P. Renaud and M. P. Sibi, Wiley-
VCH, Weinheim, Germany, 2001, vol. 1, pp. 317–336.
20 The radical pathway was proposed in uoroesterication of
styrenes by using Tf2NF as electrophilic uorinating
reagent, for details, see ref. 6e.
21 In the electrophilic uorination of styrene, the reaction
afforded a-monouoromethylbenzyl acetate only in the
presence of a mixture of HOAc and CF3CO2H (1 : 1). The
opposite selectivity also suggests that electrophilic
uorination is unlikely to be involved in this transformation.
For details, see the ESI.†
29 Based on the current results, the pathways involving radicals
or carbon cations are less likely, but cannot be completely
ruled out. For the case of a-methylstyrene (1m), however, it
is difficult for the mediated SN2 type substitution to occur
on the tertiary carbon centre. Thus, the detailed pathway
for this substrate is still unknown at the moment.
30 For more kinetic data, see the ESI.†
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Chem. Sci.