Palladium-Catalyzed Suzuki–Miyaura Cross-Coupling of Secondary α-(Trifluoromethyl)benzyl Tosylates

Article abstract of DOI:10.1002/anie.201706631

A palladium-catalyzed C(sp³)?C(sp²) Suzuki–Miyaura cross-coupling of aryl boronic acids and α-(trifluoromethyl)benzyl tosylates is reported. A readily available, air-stable palladium catalyst was employed to access a wide range of functionalized 1,1-diaryl-2,2,2-trifluoroethanes. Enantioenriched α-(trifluoromethyl)benzyl tosylates were found to undergo cross-coupling to give the corresponding enantioenriched cross-coupled products with an overall inversion in configuration. The crucial role of the CF₃ group in promoting this transformation is demonstrated by comparison with non-fluorinated derivatives.

Full text of DOI:10.1002/anie.201706631

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Accepted Article
Title: Palladium Catalyzed Suzuki-Miyaura Cross-Coupling of
Secondary α-(Trifluoromethyl)benzyl Tosylates
Authors: Marta Brambilla and Matthew Tredwell
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201706631
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Palladium Catalyzed Suzuki-Miyaura Cross-Coupling of
Secondary α-(Trifluoromethyl)benzyl Tosylates
Marta Brambilla and Matthew Tredwell*
Abstract:
A
palladium catalyzed C(sp3)-C(sp2) Suzuki-Miyaura
1,1-diaryl motif is ubiquitous in drug targets and agrochemical
structures.[13] While these compounds can be synthesised via
Friedel-Crafts type reactions, which are often high yielding,
these approaches require electron-rich arenes, may suffer from
regioisomeric mixtures and lack of an asymmetric variant.[14]
Molander et al were able to demonstrate an improved substrate
scope, relative to these methods, with a dual photoredox/nickel
catalysis cross-coupling technique, employing a chiral catalyst
gave up to 80:20 e.r for a single substrate, notably this level of
stereoselectivity was not general for other substrates
reported.[15] To address the limitations in accessing 1,1-diaryl-
2,2,2-trifluoroethanes, especially in enantioenriched form, the
cross-coupling of aryl boronic acids and α-(trifluoromethyl)benzyl
tosylates is reported. The reaction uses a readily available, air-stable
palladium catalyst to access a wide range of functionalized 1,1-
diaryl-2,2,2-trifluoroethanes.
Enantioenriched
α-
(trifluoromethyl)benzyl tosylates were found to undergo cross-
coupling to give the corresponding enantioenriched cross-coupled
products with an overall inversion in configuration. The crucial role of
the CF3 group in promoting this transformation is demonstrated by
comparison with non-fluorinated derivatives.
Fluorine incorporation into organic molecules is
a well-
development of
a
Suzuki-Miyaura cross-coupling of α-
recognized strategy to beneficially modify the properties of
agrochemical and pharmaceutical compounds and remains a
major driving force for the development of new methodologies.[1]
In this context the ability to generate stereogenic centers
containing a trifluoromethyl group, in a selective fashion, is an
important goal.[2] The majority of existing methods are based
around the addition of the Ruppert-Prakash reagent to
aldehydes and imines.[3] An alternative approach has been the
desymmetrisation of prochiral trifluoromethylated building
blocks,[4] an advantage of this method being that the
construction of Csp3-CF3 bond, which is often a non-trivial
(trifluoromethyl)carbinol derivatives with aryl boronic acids was
undertaken.
undertaking, can be avoided. When employing
a
trifluoromethylated building block it is necessary to consider how
the CF3 group impacts the reactivity of the functional group
undergoing transformation, and whether this altered reactivity
can be productively harnessed. Herein, we report the first
stereoselective synthesis of 1,1-diaryl-2,2,2-trifluoroethanes, via
a Suzuki-Miyaura cross-coupling of α-(trifluoromethyl)benzyl
tosylates, with the activating effect of the CF3 group being critical.
Cross-coupling reactions have been developed that employ
secondary alkyl-halides and -pseudohalides as electrophiles
with a variety of transition metals.[5] The greatest breath of scope
and utility is arguably demonstrated by nickel catalysts,[6] with
both stereospecific[7] and stereoconvergent variants known.[8]
Palladium catalyzed cross-coupling reactions with secondary
Figure 1. Synthesis of 1,1-diaryl-2,2,2-trifluoroethanes.
It
was
proposed
that
a
secondary
alkyl-
halide/pseudohalide would be electronically activated by the
presence of a α-CF3 group to promote oxidative addition to a
Pd(0) species.[16,17,18] The intermediate Pd(II) species could be
readily functionalized to give a range of products bearing a
stereogenic trifluoromethylated center.[19]
Preliminary studies began by examining the reactivity of 1-
[1,1’-biphenyl]-4-yl-2,2,2-trifluoroethanol derivatives whereby the
tosylate 1a was found to be the most suitable and was used for
further validation and optimization studies.[20] The use of XPhos-
Pd-G2 precatalyst, developed by Buchwald,[21] was found to
completely prevent undesired β-fluoride elimination, giving the
product in >95% yield, as determined by 19F NMR.[20] These
optimized conditions were applied to a range of secondary α-
(trifluoromethyl)benzyl tosylates 1a-l (Scheme 1a). Electron-
neutral and –poor arenes were all suitable substrates for this
transformation. Substrate 1k, derived from piperonal underwent
hydrolysis to the corresponding alcohol under the reactions
electrophiles are comparatively far less well developed,[9]
a
consequence of the relatively slow rate of oxidative addition and
the undesired competing β-hydride elimination.[10] In particular
examples of palladium catalyzed Suzuki-Miyaura cross-
couplings of secondary electrophiles are rare.[11,12]
1,1-Diaryl-2,2,2-trifluoroethanes are attractive targets as the
[a]
Dr. M. Brambilla, Dr. M. Tredwell
Max-Planck-Institut für Kohlenforschung
Kaiser-Wilhelm-Platz 1
45470 Mülheim an der Ruhr, Germany
E-mail: tredwell@kofo.mpg.de
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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Scheme 1. Substrate scope of Suzuki-Miyaura cross-croupling with α-
(trifluoromethyl)benzyl tosylates; [a] 19F NMR yield [b] 5 mol% Pd cat, Cs2CO3,
1,4-dioxane, 90 °C 12 hrs; [c] isolated yield starting from precursor 1l, 1-(3-
bromophenyl)-2,2,2-trifluoroethyl tosylate; [d] 1 equiv of arylboronic acid.
conditions. By removing water from the reaction and changing
the base to Cs2CO3, under these conditions substrate 1k gave
the desired cross-coupled product 2k in 86% isolated yield.
Protected nitrogen 2j and ester functionalities 2i were well
tolerated in addition a quinoline derivative 2g. Substituents at
the meta- and para-positions were not problematic, although
substituents in the ortho-position were detrimental, with 2d being
isolated in only 36% isolated yield. The additional steric
hindrance present in 1e resulted in either recovery of starting
material, or hydrolysis to the corresponding alcohol, dependent
on the reaction conditions employed. Substrate 2l resulted from
1-(3-bromophenyl)-2,2,2-trifluoroethyl tosylate indicating that
under these optimized conditions aryl bromides undergo
competitive cross-coupling with the phenylboronic acid.
The scope with regard to the arylboronic acid component
was investigated (Scheme 1b). Several heterocyclic boronic
acids gave the desired 1,1-diaryl-2,2,2-trifluoroethanes with
yields ranging between 60 – 93% 2m, 2v, 2w. Both electron-rich
and electron-poor boronic acids were successful in the
transformation, with substitution tolerated in the ortho-, meta-
and para-positions. Ketone, nitro and nitrogen functional groups
had no detrimental effect on the reaction. To facilitate
purification of 2n, the reaction was performed using only 1
equivalent of 2-methylphenylboronic acid, under these
conditions 2n was obtained in 64% yield.
To evaluate the stereoselectivity of this transformation
()1a (e.r > 99 : 1) was prepared by a Corey-Bakshi-Shibata
(CBS) reduction of the corresponding trifluoromethylated ketone
followed by tosylation. Under the optimized conditions described
in Scheme 1, the enantiospecificity of the reaction was poor with
several of the boronic acids tested, resulting in extensive
optimization of the reaction conditions in order to produce
products in good enantiomeric purity.[20] Key was the use of
catalytic sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate
(NaBAr’F), which Lloyd-Jones and co-workers have previously
reported as a means to lower catalyst loadings and optimize
enantioselectivity in Tsuji-Trost allylations.[22] Subjecting
enantioenriched substrates 1b,c,g (e.r > 99 : 1) to Pd(dba)2 (1.5
mol%), XPhos (3 mol%), NaBAr’F (6 mol%) and phenyl boronic
acid (3 equiv) in 1,4-dioxane at 90 °C for 12 hours, gave the
desired products in moderate to good yield and typically high e.r
(Scheme 2a). Substrate 1f required 20 mol% NaBAr’F for the
reaction to go to completion. For substrate ()-1a (e.r > 99 : 1)
with 20 mol% NaBAr’F, the loading of the Pd(dba)2 and XPhos
could be decreased to 0.2 mol% and 0.4 mol% respectively to
give 2a in 92% yield and e.r 96 : 4. Using a higher catalyst
loading, Pd(dba)2 (1.5 mol%) and XPhos (3 mol%), 2a was
obtained in 90% yield but in an e.r 86 : 14, suggestive that the
loss in stereochemical integrity may be due to isomerization of
the initially formed Pd(II) intermediate by a Pd0 species.[7c][23] The
propensity of 1k towards hydrolysis required the implementation
of a modified catalyst system (XPhos-Pd-G2, 5 mol %), however,
under these conditions 2k was isolated in >95% yield and 95 : 5
e.r. Disappointingly substrate 1j gave only 51% yield and a low
e.r 74 : 26.
The identity of the arylboronic acid was found to have a
large influence on the reaction and required additional
optimization. For these optimization studies substrate ()-1a was
selected as a model tosylate as it does not contain an extended
π-system and so may lead to conditions that are generally
applicable to a wide range of substrates. Extended π-systems
(eg naphthyl) are required in many related transformations due
to their favorable reactivity profile, but limit substrate scope.[7] It
was found to be necessary to increase the loading of NaBAr’F to
20 mol% in order to maintain high yields, and the addition of
water to the system was also critical in some cases for the
reaction to proceed.[20] Isolated yields were typically high and e.r
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up to > 99 : 1 could be obtained in the case of 4-[tert-
butoxycarbonyl)amino]benzene boronic acid (Scheme 2b). It
was not possible to decrease the Pd loading below 0.75 mol%
without significant detriment to the yield, and where possible this
often had little or no effect on the e.r.[20] In order to rule out
racemization under the basic reaction conditions a sample of 2s
(e.r 74 : 26) was re-subjected to the reaction conditions and was
recovered in an identical e.r 74 : 26, indicating that was not the
cause of the low e.r for this substrate.
The stereospecificity of this transformation was studied
using the enantioenriched α-(trifluoromethyl)benzyl tosylate 1k
with 4-(N-Boc-amino)phenylboronic acid. These coupling
partners were selected by virtue of the fact that the alcohol
precursor of tosylate 1k and H3PO4 salt of 2y produced suitable
crystals for determination of their absolute configuration by X-ray
crystallography.[20] In agreement with previous studies, an
overall inversion of configuration was observed (Scheme
3a).[11,24]
Scheme 3. a) Stereochemical outcome of Suzuki-Miyaura cross-coupling; b)
Activating effect of fluorine substitution; [a] relative product distribution
determined by 1H NMR of crude reaction.
The influence of the perfluoroalkyl group on the reactivity
of secondary tosylates towards oxidative addition with palladium
was investigated by examining the reactivity of substrates 4a-6a.
The difluorinated precursor 4a gave the diaryl product 4b in 39%
conversion, however the major product observed was the alkene
4c a result of fluoride elimination. No alkene resulting from β-
1
hydride elimination could be detected in either H or 19F NMR.
Substrate 5a resulted in a complex mixture of products, the
predominant product resulting from hydrolysis. No cross-coupled
product could be observed by 1H or 19F NMR. It was not possible
to prepare a pure sample of 1-([1,1’-biphenyl]-4-yl)ethyl tosylate
due to its propensity to dimerise[25] as a consequence we
examined the reactivity of the analogous bromine derivative 6a.
When subjecting 6a to reaction conditions only the
corresponding alkene was formed. These results demonstrate
the role of the CF3 in promoting the Suzuki-Miyaura coupling by
decreasing the barrier to oxidative addition.
In summary, reported is a stereoselective C(sp3)-C(sp2)
Suzuki-Miyaura coupling for the synthesis of unsymmetrical 1,1-
diaryl-2,2,2-trifluoroethanes.The transformation uses air stable,
readily available Pd catalysts, arylboronic acids and tolerates a
Scheme 2. Stereoselective synthesis with α-(trifluoromethyl)benzyl tosylates
(e.r = 99 : 1); [a] 0.2 mol% Pd, 0.4 mol% XPhos; [b] 20 mol% NaBAr’F; [c] 0.75
mol% Pd cat, 1.5 mol% XPhos; [d] 5 mol% XPhos-Pd-G2; [e] 5 mol% XPhos-
Pd-G2, K3PO4, dioxane/H2O, 90 °C; [f] 3 mol% Pd, 6 mol% XPhos.
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stereoselective synthesis of 1,1-diaryl-2,2,2-trifluoroethanes.
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Marta Brambilla and Matthew Tredwell*
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Palladium Catalyzed Suzuki-Miyaura
Cross-Coupling of Secondary α-
(Trifluoromethyl)benzyl Tosylates
Text for Table of Contents
A stereoselective synthesis of 1,1-diaryl-2,2,2-trifluoroethanes via a palladium catalyzed cross-coupling of secondary α-
(trifluoromethyl)benzyl tosylates with (hetero)aryl boronic acids is described. More than twenty examples for this
transformation are reported employing readily available Pd cataylsts. The stereospecificity of the cross-coupling was shown to
occur with predominant inversion of configuration.
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