Access to Difluoromethylated Arenes by Pd-Catalyzed Reaction of Arylboronic Acids with Bromodifluoroacetate

Article abstract of DOI:10.1021/acs.orglett.5b03206

An unprecedented example of Pd-catalyzed difluoromethylation of aryl boronic acids with bromodifluoroacetate is described. The reaction proceeds under mild reaction conditions with hydroquinone and Fe(acac)₃ as additives. Preliminary mechanistic studies reveal that a difluorocarbene pathway is involved in the reaction, which is unusual compared to the most traditional approaches. This reaction has advantages of high efficiency and excellent functional group compatibility, even toward bromide and hydroxy group, thus providing a useful protocol for drug discovery and development.

Full text of DOI:10.1021/acs.orglett.5b03206

Letter
pubs.acs.org/OrgLett
Access to Difluoromethylated Arenes by Pd-Catalyzed Reaction of
Arylboronic Acids with Bromodifluoroacetate
Zhang Feng, Qiao-Qiao Min, and Xingang Zhang*
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling
Road, Shanghai 200032, China
S
* Supporting Information
ABSTRACT: An unprecedented example of Pd-catalyzed difluor-
omethylation of aryl boronic acids with bromodifluoroacetate is
described. The reaction proceeds under mild reaction conditions
with hydroquinone and Fe(acac)3 as additives. Preliminary
mechanistic studies reveal that a difluorocarbene pathway is involved
in the reaction, which is unusual compared to the most traditional
approaches. This reaction has advantages of high efficiency and
excellent functional group compatibility, even toward bromide and hydroxy group, thus providing a useful protocol for drug
discovery and development.
he demand for discovery of new bioactive compounds and
advanced functional materials has triggered considerable
pathway is involved in the reaction, which is unusual compared to
the traditional reactions.
T
efforts in the introduction of fluorinated functional groups into
organic molecules.1 It has become an intensive topic of
organosynthetic chemistry. Among the organofluorinated
compounds, difluoromethylated arenes constitute a type of
distinct compound because of the unique properties of the
difluoromethyl group (CF2H)2 and important applications of
difluoromethylated arenes in pharmaceuticals and agrochem-
icals.3 To date, however, compared to trifluoromethylation of
arenes,4 strategies for the introduction of CF2H into an aromatic
ring remain limited and have been less explored.5 Although
CF2H can be prepared through deoxyfluorination of aldehydes
with SF4 or dialkylaminosulfur trifluorides (i.e., DAST or
DeoxoFluor),6 these reactions suffer from important functional
group incompatibility and the need for expensive and/or toxic
fluorinated reagents.
We began our studies on the basis of the hypothesis that if an
active species I could be generated in situ by the reaction of ethyl
bromodifluoroacetate 2 with a nucleophile Nu-H (i.e., hydro-
quinone) the formation of difluoromethylated arenes would be
possible through the catalytic cycle illustrated in Scheme 1.
Scheme 1. Hypothesis for Pd-Catalyzed Difluoromethylation
of Arylboronic Acids with Bromodifluoroacetate
Recently, some new strategies for the use of difluoroalkylated
reagents as fluorine sources to access such a fluorinated structural
motif have been developed.7−10 Despite the importance of these
methods, the development of new strategies and efficient
methods to access difluoromethylated arenes remains a require-
ment for drug discovery and development. We envisioned that
the transition-metal-catalyzed difluoromethylation of aryl metals
with electrophilic difluoromethylated reagents, such as difluor-
oalkyl halides, would be an attractive alternative. To date,
however, such a transformation is a longstanding challenge and
has not been reported because some difluoromethyl transition-
metal complexes are unstable.11 To the best of our knowledge,
the palladium complex [HCF2Pd(Ln)X] (X = halides) has not
been documented thus far. As part of a systematic study on the
transition-metal-catalyzed direct introduction of fluorinated
functional groups into organic molecules,12 we herein disclose
an unprecedented example of Pd-catalyzed difluoromethylation
of arylboronic acids with low-cost ethyl bromodifluoroacetate.13
Preliminary mechanistic studies reveal that a difluorocarbene
We envisioned that once the intermediate I was formed, the
oxidative addition of the C−Br bond to Pd(0)Ln would produce
the palladium complex II, which would subsequently deliver an
active palladium complex III via transmetalation. The key step to
realize the hypothesized reaction is to generate the key
intermediate [ArPd(Ln)CF2H] IV. We considered that with
the aid of an oxidant, if the −CONu group (Nu = OPh-p-OH) of
the complex III could be removed through a redox pathway to
release CO and benzoquinone, the formation of IV would be
possible; as a result, the reductive elimination of IV would give
Received: November 6, 2015
© XXXX American Chemical Society
A
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Letter
the difluoromethylated arenes and regenerate Pd(0)Ln simulta-
neously.
Scheme 2. Pd-Catalyzed Difluoromethylation of Arylboronic
Acids 1 with Bromodifluoroacetate 2
a
Accordingly, our initial studies focused on the Pd-catalyzed
cross-coupling of bromodifluoroacetate 2 with arylboronic acid
1a in the presence of hydroquinone14 and a variety of oxidants
(for details, see Tables S1−S8 in the Supporting Information).
After extensive efforts, we found that an optimal yield of 3 (85%
upon isolation) could be obtained with utilization of
PdCl2(PPh3)2 (5 mol %), Xantphos (7.5 mol %), hydroquinone
(2.0 equiv), Fe(acac)3 (3.5 mol %), and styrene (20 mol %) in
dioxane at 80 °C (eq 1). Styrene is used because of its beneficial
effect on the reaction efficiency. We reasoned that this is
probably because styrene can coordinate with iron species and
improve the reactivity of the iron complexes.15,16 Any absence of
other reaction factors, such as hydroquinone, Fe(acac)3, and
styrene, all led to no or lower yields of 3 (see Table S8 in the
Supporting Information). No product 3 was observed without
the palladium or Xantphos, thus demonstrating that the Pd/
Xantphos do play an essential role to promote the reaction.
A wide range of arylboronic acids could be difluoromethylated
with 2 through this method (Scheme 2). Many versatile
functional groups, including base or nucleophile-sensitive
moieties, such as formyl, alkoxycarbonyl, enolizable ketone,
cyano, siyl, thioether, and amine, were tolerated quite well (18−
25, 30, 31, and 36). Most remarkably, chloride, bromide, and free
hydroxy group containing aryl boronic acids are also suitable
substrates (28, 29, and 32). This is in sharp contrast to previous
results,7,9,10c in which aryl halides and/or free proton-containing
substrates were incompatible with their reaction conditions.
Furthermore, heteroaromatic rings, such as dibenzo[b,d]furan
and -thiophene, and carbazole-derived boronic acids all under-
went difluoromethylation smoothly (33−35). However, pyr-
idine-containing boronic acids were not suitable substrates.
Additionally, the difluoromethylated arene 3 could also be
synthesized on a 1 g scale with good yield (68%).
The utility of this method can also be demonstrated by late-
stage difluoromethylation of different bioactive molecules (37−
40). As shown in Scheme 2, good yields were obtained when the
flavanone and estrone derived arylboronic acids were employed
(37 and 40). The difluoromethylation of tyrosine-derived
arylboronic acid also proceeded smoothly with 61% yield (38).
The most significant example is the direct difluoromethylation of
Zetia, a drug famous for the treatment of high blood cholesterol,
without protecting the free hydroxy group (39), thus providing
an useful tool for the medicinal chemistry.
a
Reaction conditions (unless otherwise specified): 1 (0.3 mmol), 2
(2.0 equiv), K2CO3 (4.0 equiv), dioxane (2.5 mL) for 24 h. All
b
reported yields are isolated yields. Determined by 19F NMR using
c
fluorobenzene as an internal standard. 1 (0.6 mmol) and dioxane (3.0
mL). Reaction carried out on a gram scale.
d
Scheme 3. Cross-Coupling of 1a with 2 or V
To probe the reaction mechanism illustrated in Scheme 1, we
conducted a kinetic study of the reaction of 1a with 2 (Scheme
3a), and the yield of 3 was plotted against time (Figure 1b, black
line). It was found that a new species BrCF2CO2K (V) instead of
4-hydroxylphenyl difluoroacetate (BrCF2O2Ph-pOH, I) was
generated at the beginning of the reaction and the production
of 3 at initial stage required formation of a large amount of V
(Figure 1a, black line), thus indicating the critical role of V in
promotion of the reaction. This finding was further confirmed by
the kinetic study of the reaction of V with arylboronic acid 1a
under standard reaction conditions, in which a similar kinetic
profile was also observed (Scheme 3b, Figure 1b, red line).
Additionally, the 19F NMR and GC−MS analysis of the reaction
showed no I was formed during the reaction process. Thus, these
results imply that the hypothesized mechanism illustrated in
Scheme 1 is less likely.
To rule out the possibility that the formation of
difluoromethylated arenes arises from the decarboxylation of
difluoroacetylated arene, the reaction of compound 4 or 4′ with
hydroquinone under standard reaction conditions was con-
ducted (eq 2). However, no difluoromethylated arene 3 was
observed during the reaction, thus clearly indicating that an
intriguing mechanism is involved in the reaction.
B
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Scheme 5. Mechanistic Studies
Figure 1. (a) Yield (black line) or recovery of V (red line) and (b) yield
of 3 with BrCF2CO2Et (black line) or BrCF2CO2K (red line) as a
starting material.
To further understand the role of hydroquinone, several
experiments were performed (Scheme 4). It was found that when
oxidants (Scheme 5c), we envisioned that probably only the PdII
species was involved for the formation of difluoromethylated
arenes. This was further confirmed by the X-ray photoelectron
spectroscopy (XPS) analysis of the reaction, in which only PdII
was found (Scheme S9 and Figure S4, Supporting Information).
What is more, when we used a catalytic amount of palladium
complex [PhPd(Xantphos)I] VI (20 mol %) as a catalyst,
compound 3 (47% yield) was indeed generated (Scheme 5d).
However, it is worthy to note that no difluoromethylbenzene was
generated during the reaction process, even when 50 mol % of VI
was used (for details, see Scheme S7b , Supporting Information).
Thus, these results clearly indicate that the aryl group of the
difluoromethylated arene does not derive from [ArPd-
(Xantphos)X]. In the meantime, a difluorocarbon elongated
tetrafluoroethylated 3a was produced in 20% yield (Scheme 5d).
These findings confirm that a difluorocarbene species is involved
in the reaction, as it has been demonstrated that an elongated
difluorocarbon can be produced by the insertion of a
difluorocarbene into fluoroalkylmetal species.19
Scheme 4. Roles of Hydroquinone for the Reaction
bromodifluoroacetate 2 was treated with K2CO3 (2.0 equiv) in
the presence of hydroquinone, 55% yield of V (determined by
19F NMR) was formed after the reaction was stirred for only 45
min (Scheme 4a). However, the absence of hydroquinone led to
no V (Scheme 4a), while prolonging the reaction time to 5 h
could afford V in 24% yield (determined by 19F NMR, Scheme
4b). Thus, these results clearly demonstrate that the hydro-
quinone has a beneficial effect on the formation of V, but it is not
essential. On the contrary, the hydroquinone plays an essential
role for the generation of difluoromethylated arenes, as no
product 3 was observed in the absence of hydroquinone (Scheme
4c). In addition, the comparison of reaction of 1a with 2 or V in
the presence of hydroquinone with or without Fe(acac)3
(Schemes S4 and S5 and Figures S2 and S3 in the Supporting
Information) reveals that the iron species is not essential for the
reaction, but it can facilitate the transformation of V into final
product 3.
Therefore, on the basis of above results, the hypothesized
mechanism illustrated in Scheme 1 can be ruled out, and a
plausible mechanism through a the PdII-involved difluorocarbene
pathway is proposed (Scheme 6). The reaction was initiated by
Scheme 6. Proposed Reaction Mechanism
It has been demonstrated that BrCF2CO2K can serve as a
precursor of difluorocarbene.17 This inspired us to surmise that a
difluorocarbene may be generated in situ from V and a palladium
catalytic cycle via a difluorocarbene pathway may be involved in
the reaction. To identify whether a difluorocarbene is involved in
the reaction, a difluorocarbene scavenger pyridine-2-thiol18 was
added to the reaction by using V as a coupling partner (Scheme
5a). It was found that the difluoromethylthiopyridine 41 instead
of 3 was produced, thus indicating that a difluorocarbene is
involved in the reaction.
In addition, given the fact that a 48% yield of 3 could be
provided when 1a was treated with 2 in the presence of
Pd(PPh3)4 (5 mol %), hydroquinone and Fe(acac)3 (Scheme
5b), but no 3 was produced in the absence of Fe(acac)3 or other
the reaction of PdII(Ln) with difluorocarbene which was
generated in situ from V (path I). Subsequently, the resulting
palladium(II) difluorocarbene species (VII) was trapped by
arylboronic acid to produce the key intermediate [XPdII(Ln)-
CF2Ar] (VIII). Finally, protonolysis of VIII afforded difluor-
omethylated arenes and regenerate PdII(Ln) simultaneously. In
C
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Letter
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(13) For selected examples employing bromodifluoroacetate as an
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the overall catalytic cycle, the hydroquinone is essential for
promotion of the reaction. However, the exact role of
hydroquinone remains elusive at this stage. As for the role of
Fe(acac)3 in the overall catalytic cycle, one possibility is that a Fe-
based difluorocarbene species20 may be generated in the
reaction, which is being subsequently transferred onto Pd to
produce VII. What is more, taking into account the fact that the
aryl group of difluoromethylated arene does not derive from the
palladium complex [ArPd(Ln)X] (IX), the proposed mechanism
illustrated in path II21 for the current reaction can be excluded.
In conclusion, we have demonstrated an unprecedented
example of Pd-catalyzed difluoromethylation of arylboronic acids
with low-cost ethyl bromodifluoroacetate. The significant
features of this reaction are its high efficiency, broad substrate
scope, and excellent functional group compatibility, even toward
bromide and hydroxyl groups. Applications of the reaction led to
difluoromethylated biologically relevant molecules with high
efficiency, thus providing a useful protocol for drug discovery and
development. Preliminary mechanistic studies reveal that a
palladium catalytic cycle via a difluorocarbene pathway is
involved in the reaction. To the best of our knowledge, this is
the first example of a transition-metal-catalyzed carbon−
difluorocarbon single bond (C−CF2) formation via a difluor-
ocarbene pathway. We believe that it will not only prompt the
research in the field of transition-metal difluorocarbene
chemistry but also be useful for related chemistry.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Informationis also is available free of charge on
the ACS Publications website at DOI: 10.1021/acs.or-
glett.5b03206.
(14) Very recently, a reaction of bromodifluoroacetate with phenols to
prepare difluoromethoxyarene via difluorocarbene pathway was
reported; see: (a) Rafferty, S. W.; Eisner, J. R.; Moore, W. R.;
Schotzinger, R. J.; Hoekstra, W. J. Bioorg. Med. Chem. Lett. 2014, 24,
2444. (b) Stock, N. S.; Chen, A. C.-Y.; Bravo, Y. M.; Jacintho, J. D.; Scott,
J. M.; Stearns, B. A.; Clark, R. C.; Truong, Y. P. WO 2013134562 A1,
2013.
Detailed experimental procedures and characterization
data for new compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
(15) Furstner, A.; Martin, R.; Krause, H.; Seidel, G.; Goddard, R.;
Lehmann, C. W. J. Am. Chem. Soc. 2008, 130, 8773.
*E-mail: xgzhang@mail.sioc.ac.cn.
Notes
(16) An alternative possibility of the role of styrene is that it can
facilitate the reductive elimination by displacing ligands on the
coordination sphere of PdII intermediates.
(17) (a) Wheaton, G. A.; Burton, D. J. J. Fluorine Chem. 1976, 8, 97.
(b) Duan, J. X.; Su, D. B.; Chen, Q.-Y. J. Fluorine Chem. 1993, 61, 279.
(c) Levin, V. V.; Zemtsov, A. A.; Struchkova, M. I.; Dilman, A. D. J.
Fluorine Chem. 2015, 171, 97.
(18) Mehta, V. P.; Greaney, M. F. Org. Lett. 2013, 15, 5036.
(19) Yang, Z.-Y.; Wiemers, D. M.; Burton, D. J. J. Am. Chem. Soc. 1992,
114, 4402.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by the National Basic
Research Program of China (No. 2012CB821600), the National
Natural Science Foundation of China (21425208, 2141002,
21172242 and 21332010), and SIOC.
(20) Crespi, A. M.; Shriver, D. F. Organometallics 1985, 4, 1830.
(21) (a) Bakhmutov, V.; Bozoglian, F.; Gomez, K.; Gonzalez, G.;
Grushin, V. V.; Maacgregor, S. A.; Martin, E.; Miloserdov, F. M.;
Novikov, M. A.; Panetier, J. A.; Romashov, L. V. Organometallics 2012,
31, 1315. (b) Xiao, Q.; Zhang, Y.; Wang, J. Acc. Chem. Res. 2013, 46, 236.
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