Palladium-Catalyzed Fluorination of Cyclic Vinyl Triflates: Effect of TESCF3as an Additive

Article abstract of DOI:10.1002/anie.201608927

A method for the palladium-catalyzed fluorination of cyclic vinyl triflates has been developed. As with several previous palladium-catalyzed fluorination reactions using fluoride salts, controlling the regioselectivity presented a challenge in developing a practical synthetic procedure. The addition of triethyl(trifluoromethyl)silane (TESCF₃) was found to effectively address this problem and resulted in drastically improved regioselectivities in this palladium-catalyzed fluorination reaction. This discovery, along with the use of a new biarylphosphine ligand, allowed for the development of an efficient and highly regioselective protocol for the fluorination of vinyl triflates. This method is compatible with a range of sensitive functional groups and provides access to five-, six-, and seven-membered cyclic vinyl fluorides.

Full text of DOI:10.1002/anie.201608927

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International Edition: DOI: 10.1002/anie.201608927
German Edition: DOI: 10.1002/ange.201608927
Fluorination
Palladium-Catalyzed Fluorination of Cyclic Vinyl Triflates: Effect of
TESCF3 as an Additive
Yuxuan Ye, Takashi Takada, and Stephen L. Buchwald*
Abstract: A method for the palladium-catalyzed fluorination
of cyclic vinyl triflates has been developed. As with several
previous palladium-catalyzed fluorination reactions using
fluoride salts, controlling the regioselectivity presented a chal-
lenge in developing a practical synthetic procedure. The
addition of triethyl(trifluoromethyl)silane (TESCF3) was
found to effectively address this problem and resulted in
drastically improved regioselectivities in this palladium-cata-
lyzed fluorination reaction. This discovery, along with the use
of a new biarylphosphine ligand, allowed for the development
of an efficient and highly regioselective protocol for the
fluorination of vinyl triflates. This method is compatible with
a range of sensitive functional groups and provides access to
five-, six-, and seven-membered cyclic vinyl fluorides.
enhanced stability towards hydrolysis compared to amides.
Moreover, in contrast to amides, which often exist as
equilibrating s-cis and s-trans rotamers, fluoroalkenes are
configurationally stable. As a result, they have been inves-
tigated as amide bioisosteres with improved lipophilicity and
metabolic stability in pharmaceutical applications and as tools
for probing the conformational properties of biologically
active amides.[4] In addition to these applications, fluoroal-
kenes also serve as versatile starting materials for a variety of
transformations, including the Diels–Alder reaction,[5a] cyclo-
propanation,[5b,c] and epoxidation,[5d] allowing for the con-
struction of other classes of fluorine-containing molecules.
Despite considerable potential, fluoroalkenes are underutil-
ized due to challenges in their synthesis. Current approaches
for their preparation generally require multistep functional
group manipulations or the use of harsh reaction conditions,
which limit the functional group compatibility of these
techniques.[6–11] The development of a mild and general
method for fluoroalkene synthesis would therefore be
highly desirable. Due to the challenge of preparing suitable
precursors, cyclic fluoroalkenes are particularly difficult to
access using existing methods, and new methods that provide
access to these compounds would be especially useful.
F
luorine-substituted olefins constitute a valuable class of
compounds of interest for medicinal chemistry and chemical
biology (Figure 1).[1,2] The alkenyl fluoride group resembles
an amide linkage in terms of both steric demand and charge
distribution,[3] but fluoroalkenes exhibit substantially
In this context, the palladium-catalyzed coupling of cyclic
vinyl triflates with simple metal fluoride salts represents
a particularly attractive strategy to access fluoroalkenes. In
2009, we reported a palladium(II)-catalyzed fluorination of
aryl triflates using a bulky biaryl monophosphine ligand (t-
BuBrettPhos).[12a] Since then, more effective catalysts based
on AdBrettPhos and HGPhos were developed and the
fluorination of aryl bromides was achieved.[12b,c] However,
the generation of regioisomeric side products in these
reactions remained an unsolved problem.[12d] Recently,
a new fluorinated biaryl phosphine ligand (AlPhos) was
developed to improve the rate and regioselectivity in the
fluorination of aryl triflates and bromides.[12e] However, as
described below, direct application of these new ligands and
reaction conditions to cyclic vinyl triflate substrates afforded
the corresponding vinyl fluoride products in low yield and as
mixtures of regioisomers. Herein, we report the development
of a highly regioselective palladium(II)-catalyzed reaction for
the fluorination of cyclic vinyl triflates. High regioselectivity
was realized through the development of a new biaryl
phosphine ligand (L8) and the serendipitous discovery of
triethyl(trifluoromethyl)silane (TESCF3) as an additive.
We commenced our study using 4-phenylcyclohexenyl
triflate (1a) as the model substrate (Table 1). Preliminary
ligand evaluation showed that catalysts based on t-BuBrett-
Phos (L1), AdBrettPhos (L2), HGPhos (L3), or AlPhos (L4),
which were effective ligands for the fluorination of aryl
Figure 1. Representative fluoroalkenes as peptidomimetics.
[*] Y. Ye, Prof. Dr. T. Takada, Prof. Dr. S. L. Buchwald
Department of Chemistry, Room 18-490
Massachusetts Institute of Technology
Cambridge, MA 02139 (USA)
E-mail: sbuchwal@mit.edu
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201608927.
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Table 1: Reaction optimization studies.
Scheme 1. Fluorinated side products generated in the palladium-cata-
lyzed trifluoromethylation reaction.
Entry
Ligand
Additive
2a [%]
3a [%]
2a/3a
1
2
3
4
5
6
7
8
9
10
11
12
13[b]
14[b]
L1
L2
L3
L4
L5
L6
L7
L8
L8
L8
L8
L6
L8
L8
–
–
–
–
–
–
–
–
23
18
11
19
27
37
23
37
68
73
47
57
74
7
21
18
13
19
20
19
20
21
2
1.0
10
5.0
0.4
4
1.1:1
1.0:1
0.8:1
1.0:1
1.4:1
1.9:1
1.2:1
1.8:1
34:1
73:1
4.7:1
11:1
>99:1
1.8:1
results in the absence of the trifluoromethyl silane additive,
the yield and regioselectivity obtained with L8 were consid-
erably higher when TESCF3 (30 mol%) was added (entries 6,
8, 10 and 12). Finally, performing the reaction in 2-MeTHF at
908C with L8 as the supporting ligand, along with a sub-
stoichiometric amount of TESCF3 afforded the desired
product 2a in 74% yield with excellent regioselectivity
(> 99:1) (entry 13). In addition to this significant improve-
ment in regioselectivity, the addition of the TESCF3 additive
also allowed the reaction to be conducted at a lower temper-
ature (entry 13 vs. entry 14).
TMSCF3
TESCF3
TIPSCF3
TESCF3
TESCF3
–
We subsequently examined the substrate scope using
these optimized reaction conditions, and found this protocol
to be applicable to the fluorination of a variety of 1,2-
disubstituted cyclic vinyl triflates (Table 2). In addition, the
fluorination of 1,2,2-trisubstituted vinyl triflates, for which
regioisomer formation is not an issue,[12d] was possible with L3
as the ligand and CsF as the fluoride source. TESCF3 was not
required for these processes. Interestingly, our new ligand
(L8) developed for vinyl triflate 1a, did not perform well for
1,2,2-trisubstituted vinyl triflates, which likely stems from its
sterically encumbered nature.
[a] Reactions were run at 0.1 mmol scale. Yields were determined by
19F NMR analysis of the crude reaction mixture using 1-fluoronaphtha-
lene as an internal standard. [b] 2-MeTHF, 908C.
1-Cyclohexenyl triflates with substituents at the 4- (2a and
2c), 3- (2e), or 2- (2b) position were all excellent substrates
(Table 2, n = 1). Benzofused (2 f) and oxygen-containing six-
membered cyclic triflates (2g) were compatible as well.
Moreover, the method could be used to access fluorinated
analogues of biologically active terpene and steroid deriva-
tives (2h, 2i, and 2j). In the case of 1j, isomerization of the
terminal double bond to the more thermodynamically stable
internal position occurs under these reaction conditions.
In general, the fluorination of 1-cyclopentenyl triflates
was more difficult, presumably due to the higher energy
eletrophiles,[12a–c] provided low yields of the desired vinyl
fluoride 2a and a substantial amount of the undesired
regioisomer 3a (close to 1:1 ratio, entry 1–4). Replacing the
6-methoxyl group of the ligand with a methyl substituent (L5
and L6) led to improved yields, indicating that ligand rigidity
may be important in this transformation (entry 5, 6).[13] After
further evaluation of ligands possessing a trimethylmethoxy-
substituted top ring (L7 and L8),[14] a novel biarylphosphine
ligand L8 was found to provide 2a in moderate combined
yield (58%) though still with poor regioselectivity (1.8:1;
entry 7, 8).
À
barrier for C F reductive elimination from the respective
palladium(II) complex (Table 1, n = 0).[16] Thus, vinyl triflate
1k without additional substitution on the double bond
provided the desired cyclopentenyl fluoride in low yield.
However, substrates possessing an additional substituent at
the 2-position reacted efficiently to provide the corresponding
cyclic vinyl fluorides in good to excellent yield (2l, 2m, and
2n).
During our investigation of the palladium-catalyzed
trifluoromethylation of vinyl sulfonates,[15b] we made the
serendipitous discovery that the corresponding vinyl fluoride
was formed as a side product with relatively high regioselec-
tivity (6.3:1, Scheme 1). We hypothesized that the presence of
Although 1-cycloheptenyl triflate 1o was fully consumed
under these conditions, the fluorinated product was not
obtained (Table 1, n = 2). GC/MS analysis of the crude
reaction mixture indicated the formation of the correspond-
ing alkyne or allene product, implying that the vinyl triflate
starting material decomposed through b-hydrogen elimina-
tion. Consistent with this hypothesis, seven-membered cyclic
vinyl triflates without b-hydrogen atoms were fluorinated in
good yields (2p, 2q, and 2r).
À
trifluoromethylsilanes, which were used as CF3 sources in
trifluoromethylation reactions, might be responsible for the
improved regioselectivity of the fluorination process. Indeed,
the use of TMSCF3, TESCF3 or TIPSCF3 as substoichiometric
additives (30 mol%) drastically improved the regioselectivity
(34:1, 73:1, and 4.7:1, respectively) (Table 1, entry 9–11).
Although catalyst based on L6 and L8 gave comparable
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Table 2: Palladium-catalyzed fluorination of cyclic vinyl triflates.
Table 3: Palladium-catalyzed fluorination of acyclic vinyl triflates.
[a] Yields of isolated products are reported as an average of two runs on
a 1.0 mmol scale. [b] 1108C.
the challenges often encountered during the separation of
fluorinated products from side-products with similar physical
properties. Thus, careful analysis of the crude reaction
mixture in this fluorination protocol was performed. Gen-
erally speaking, the corresponding reduction product was
formed in less than 0.5% in all cases while the corresponding
vinyl chloride was formed in 2.5–0.5%. Although the entries
in Table 2 could all be purified to > 99.5% purity by column
chromatography, conditions that would avoid the formation
of the vinyl chloride side product would significantly simplify
purification of the desired vinyl fluoride.
Towards this goal, the use of precatalysts of the form [(1,5-
cyclooctadiene)(LPd)2] that activate with minimal generation
of reactive or other undesired byproducts were investigated.
In the case of vinyl triflates for which regioisomer formation is
not a concern, the use of the L3-derived precatalysts of this
type in place of L3/[(cinnamyl)PdCl]2 was found to provide
comparable or superior yields without formation of vinyl
chloride (Table 4, 2m and 2p). However, because of the large
size of L8, the corresponding precatalysts based on L8 could
not be prepared. Therefore, for fluorination reactions
employing L8, a modified reaction protocol employing
a “sacrificial” vinyl triflate was developed. We found that
preheating the reaction mixture with cyclohexenyl triflate
(2v) (50 mol%) as the “sacrificial” vinyl triflate for one hour
prior to the addition of the vinyl triflate starting material led
to improved yields (Table 4, 2a, 2 f, 2i). The volatile
fluorination and chlorination products derived from 2v
could be easily removed in vacuo. Using this protocol, the
corresponding vinyl chloride coming from the vinyl triflate
starting material was not detected by GC analysis of the crude
reaction mixtures. Moreover, yields obtained using this
protocol were generally higher than those obtained previ-
ously.
[a] Yields of isolated products are reported as an average of two runs on
a 1.0 mmol scale. [b] Reaction conditions: [(cinnamyl)PdCl]2 (2 mol%),
ligand (5 mol%), CsF (2.0 equiv.), 2-MeTHF, 908C, 12 h. [c] t-BuBrett-
Phos as the ligand. [d] In 1,4-dioxane. [e] In toluene. [f] 1108C. [g] 1308C.
A variety of functional groups were tolerated in this
transformation, including an acetal (2d), a nitrile (2l),
a trifluoromethyl group (2m), an amide (2n), and a nitro
group (2r). Heterocycles, including an indole (2e), a pyrimi-
dine (2q), and a pyridine (2p) were also compatible.
The fluorination of acyclic 1-substituted vinyl triflates 1s
was unsuccessful (Table 3), presumably as a result of com-
petitive b-hydrogen elimination. More highly substituted
vinyl triflates without b-alkenyl hydrogen atoms were suc-
cessfully fluorinated (1t and 1u).
In summary, we have developed a method for palladium-
catalyzed fluorination of vinyl triflates for the synthesis of
cyclic fluoroalkenes. High levels of regiochemical fidelity of
this reaction were achieved by employing a new biarylphos-
phine ligand L8 and TESCF3 as a crucial additive. The
reaction exhibited good functional group tolerance and
proceeded efficiently for five, six and seven-membered vinyl
triflate substrates, as well as a few acyclic substrates. As the
synthesis of cyclic vinyl fluorides using existing methods is
The formation of side-products is an important factor
affecting the synthetic utility of a fluorination reaction due to
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Table 4: Modified fluorination reaction protocol without the generation
of chlorination side products.
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Acknowledgments
We thank the National Institutes of Health (R01GM46059)
for financial support. We thank Dr. Yiming Wang and Dr.
Michael Pirnot for assistance with the preparation of the
manuscript. We also thank Dr. Shiliang Shi and Dr. Aaron
Sather for helpful discussions. We thank Dr. Yong Zhang and
Dr. Jorge Fortanet for preliminary experiments. We thank Dr.
Yang Yang for assistance with this manuscript and for
carrying out preliminary DFT calculations.
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Keywords: cross-coupling · fluorination · fluoroalkenes ·
palladium
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Received: September 12, 2016
Published online: && &&, &&&&
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Communications
Fluorination
Added regioselectivity: A technique for
the palladium-catalyzed fluorination of
cyclic vinyl triflates has been developed.
The reaction exhibited good functional
group tolerance and proceeded efficiently
for five-, six-, and seven-membered vinyl
triflate substrates, as well as a few acyclic
substrates. The addition of triethyl(tri-
fluoromethyl)silane (TESCF3) resulted in
drastically improved regioselectivities in
this method.
Y. Ye, T. Takada,
S. L. Buchwald*
&&&& — &&&&
Palladium-Catalyzed Fluorination of
Cyclic Vinyl Triflates: Effect of TESCF3 as
an Additive
6
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