Tuning Reactivity in Pd-catalysed C(sp3)-H Arylations via Directing Group Modifications and Solvent Selection

Article abstract of DOI:10.1002/adsc.202000726

The palladium-catalysed sp³ C?H arylation of a selection of saturated amine scaffolds was investigated using substituted picolinamide directing groups. On the bornylamine scaffold, highly selective monoarylation takes place using unsubstituted picolinamide or 3-methylpicolinamide, whereas a double C?H arylation occurs with other substituents present, becoming a significant product with 3-trifluoromethylpicolinamide. DFT calculations were used to help rationalise the effect of directing groups on the C?H palladation steps which were found experimentally to be irreversible. The substituted picolinamide directing groups were also examined on acyclic amine scaffolds and in many cases increased yields and selectivity could be obtained using methylpicolinamides. For a selection of other amine scaffolds, the yield of C?H arylation could be improved significantly using 3-methylpicolinamide as the directing group and/or 3-methylpentan-3-ol as the solvent. (Figure presented.).

Full text of DOI:10.1002/adsc.202000726

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Title: Tuning Reactivity in Pd-catalysed C(sp3)-H Arylations via
Directing Group Modifications and Solvent Selection
Authors: Charlotte Coomber, Michael Porter, Abil Aliev, Peter Smith,
and Tom Sheppard
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.202000726
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Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.202((will be filled in by the editorial staff))
Tuning Reactivity in Pd-catalysed C(sp3)-H Arylations via
Directing Group Modifications and Solvent Selection
Charlotte E. Coombera, Michael J. Portera, Abil E. Alieva, Peter D. Smithb and Tom D.
Shepparda*
a
aDepartment of Chemistry, Christopher Ingold Laboratories, University College London, 20 Gordon Street, London
WC1H 0AJ, U.K. tom.sheppard@ucl.ac.uk
Early Chemical Development, Pharmaceutical Sciences, R&D, AstraZeneca, Macclesfield, U.K.
b
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. The palladium-catalysed sp3 C-H arylation of a The substituted picolinamide directing groups were also
selection of saturated amine scaffolds was investigated using examined on acyclic amine scaffolds and in many cases
substituted picolinamide directing groups. On the increased yields and selectivity could be obtained using
bornylamine scaffold, highly selective monoarylation takes methylpicolinamides. For a selection of other amine
place
using
unsubstituted
picolinamide
or
3- scaffolds, the yield of C-H arylation could be improved
methylpicolinamide, whereas a double C-H arylation occurs significantly using 3-methylpicolinamide as the directing
with other substituents present, becoming a significant group and/or 3-methylpentan-3-ol as the solvent
product
with
3-trifluoromethylpicolinamide.
DFT
calculations were used to help rationalise the effect of
directing groups on the C-H palladation steps which were
found experimentally to be irreversible.
Keywords: Palladium, C-H Activation, Density Functional
Calculations, Regioselectivity, Arylation
membered palladacycle, though transannular
functionalisation reactions have been observed in
some cases.[5d]
Introduction
Palladium-mediated C-H functionalisation reactions
provide
a
powerful approach for selective
transformation of individual C-H bonds on sp3-rich
scaffolds.[1] Given the increasing importance of these
compounds in medicinal chemistry,[2] the ability to
selectively introduce novel functionality at particular
locations in the molecular framework could provide a
highly useful tool in drug development. Building
upon pioneering work on the use of stoichiometric
quantities of palladium(II) salts to mediate selective
reactions of C-H bonds in sp3-rich scaffolds,[3]
catalytic reactions employing a directing group to
coordinate to the palladium(II) catalyst to control the
site of reaction have proved to be especially
effective.[4-5] In most cases, the directing group
incorporates one or more heteroatoms which can act
as ligands for the palladium and deliver it to an
adjacent C-H bond. Nitrogen-rich scaffolds are of
particular importance in a wide range of chemistry-
related fields, so nitrogen-linked directing groups
have been the focus of considerable attention.[5] In
2005 Daugulis introduced the 8-aminoquinoline and
picolinamide directing groups,[5a] and since then a
number of nitrogen-linked directing groups for C-H
activation have been reported (Figure 1).[5] Typically,
these directing groups deliver the palladium catalyst
to a nearby C-H bond via the formation of a 5- or 6-
Figure 1. Amide-linked directing groups employed in Pd-
catalysed C-H functionalisation reactions of sp3-rich
scaffolds.[5a-5e]
Two major drawbacks of many of these reactions
are the requirement for excess silver salt in the C-H
activation reaction, as well as difficulty in removing
the directing group from the product molecule to
recover a free amine for use in further synthetic
manipulation. In recent work we have shown that
1
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Table 1. C-H arylation of the bornylamine scaffold using
selective monoarylation of bicyclic amine scaffolds
can be achieved efficiently under silver-free
conditions using the 2-picolinamide directing
group.[6] The picolinamide group can readily be
removed under mild reductive conditions using
Zn/HCl.[7] We envisaged (Fig. 2) that by
manipulating the electronic and steric properties of
the picolinamide directing group, it should be
possible to enhance the efficiency and selectivity of
Pd-catalysed C-H functionalisation reactions, as well
as potentially enabling C-H functionalisation at
different reaction sites within a molecule.
different picolinamide directing groups
Directing Group
Yield[a] Ratio of 2:3[b]
91%
>98:2
1a
97%
>98:2
1b
97%
99%
88:12
89:11
1c
1d
99%
73%
52:48
1e
1f
Figure 2. Proposed use of functionalised picolinamides for
controlling reactivity on Pd-catalysed C-H activation.
73:27 [c]
Results and Discussion
We elected to study three different scaffolds which
each contain two chemically distinct C-H bonds
capable of undergoing C-H activation to yield a 5-
membered palladacycle (Fig. 2). A wide range of
picolinic acids are available commercially and we
selected seven examples bearing both electron-
donating (Me, MeO) and electron-withdrawing (CF3)
substituents at a variety of positions around the ring,
alongside the unsubstituted picolinic acid as a
benchmark.
75%
79%
79:21
88:12
1g
1h
In the case of the bornylamine scaffold, despite the
proximity of the methyl C-H bond to the directing
group, we had not observed C-H activation taking
place at that site during our original study with an
unsubstituted picolinamide directing group.[6]
Interestingly, in our evaluation of the substituted
picolinic acid directing groups, it rapidly became
apparent that the substituent on the directing group
exerts a significant effect on the reactivity of the
methyl group (Table 1). As reported previously, the
unsubstituted picolinamide 1a gives an excellent
yield of monoarylated product 2a under our
optimised reaction conditions, with no trace of
methyl C-H activation. The 3-methylpicolinamide 1b
also gives the monoarylated product 2b with
complete selectivity and with the highest yield.
Conditions: 5 mol% Pd(OAc)2, 4 equiv. CsOAc, 10 mol%
CuBr2, 4 equiv. 4-iodoanisole, tert-amyl alcohol (tAmOH)
1 M, 140 °C, 24 h. [a]Combined isolated yield of a mixture
of mono and diarylated products; [b]Ratio of 2:3 was
determined from the crude 1H NMR spectrum;.
[c]Diarylated product 3f was isolated in 17% yield.
Interestingly, upon changing the position of the
methyl substituent to the 4 or 5 positions on the
pyridine ring (1c/1d), a novel diarylated compound
(3c/3d) was observed as a minor product, perhaps
suggesting that the conformational or electronic
effects of the substituent are able to facilitate C-H
activation on the methyl group, although the C-H
activation still evidently occurs preferentially at the
CH2 in both substrates.[8] Introduction of an electron
2
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withdrawing CF3 group at the 3-position (1e)
increased the quantity of diarylated product formed,
giving almost equal amounts of monoarylated
product 2e and diarylated product 3e. The 5-CF3
derivative 1f gave the lowest overall conversion, with
a mixture of monoarylated 2f and diarylated 3f
products being generated. The 4- and 5-
methoxypicolinamides 1g and 1h gave similar overall
yields of product, with small quantities of diarylated
product in both cases.[9] As a general rule, high
overall yields were obtained with all of the
picolinamides bearing the moderately electron-
On changing the coupling partner from an aryl
iodide to an aryl bromide,[11] the formation of the
diarylated product was no longer observed (Scheme
2). Electron withdrawing directing groups gave lower
overall yields of the arylated products (2e and 2f) and
higher yields were seen with the unsubstituted
picolinamide and substrates bearing electron donating
groups (2a-2c and 2h). This monoarylation reaction
almost certainly provides a better reflection of the
inherent reactivity of each directing group in terms of
facilitating the catalytic cycle. The improved
efficency of the reaction with 3-methylpicolinamide
perhaps reflects conformational effects on the
palladium complexation/decomplexation steps which
enable better catalytic turnover. More generally,
electron-donating substituents on the picolinamide
are clearly preferable to electron-withdrawing
substituents in terms of reaction efficiency.
donating
methyl
group,
with
the
3-
methylpicolinamide giving the highest yield of
monoarylated product 2b with no observable
formation of the corresponding diarylated compound
3b. The 3-trifluoromethylpicolinamide 1e provided
the largest quantity of diarylated product 3e as well as
giving a high overall product yield.
Control experiments (Scheme 1) demonstrated that
the C-H insertion step for the initial methylene
arylation reaction was not reversible as no deuterium
exchange was observed at the methylene unit to give
d1-1a upon heating 1a in the presence of Pd(OAc)2
and CsOAc in deuterated tert-butanol.[10]
Furthermore, the palladated complex 1a-Pd
(L=CD3CN) generated from 1a and Pd(OAc)2/CsOAc
in acetonitrile[6] did not undergo deuteration upon
treatment with either deuterated tert-butanol or
deuterated acetic acid. In addition we observed that
the monoarylated product 2e was not converted into
the diarylated product 3e upon resubmission to the
reaction conditions. This suggests that the selectivity
in the Pd-catalysed C-H arylation is under kinetic
control, and hence determined by the energy barriers
of the C-H insertion steps. The diarylation product
must be formed via two sequential C-H arylation
processes without dissociation of the palladium
catalyst, as dissociation of the palladium from the
monoarylated product 2e seems to be irreversible.
Scheme 2. Reactions of bornylamine scaffold with 4-
bromoanisole. Conditions: 5 mol% Pd(OAc)2, 4 equiv.
CsOAc, 10 mol% CuBr2, 4 equiv. 4-bromoanisole, tAmOH
1 M, 140 °C, 24 h; isolated yields shown.
Again, the 3-methylpicolinamide 1b gave the
highest yield of monoarylated product. Subsequent
results (vide infra, Scheme 5) suggested that bromide
ions could suppress C-H activation processes, so this
is probably the reason why no arylation of the methyl
group is observed in these reactions.
To gain further insight into the regioselectivity of
the arylation processes, we undertook computational
studies of the various possible C-H activation steps.
Density functional theory (DFT) calculations were
carried out with the M06 functional,[12] using the 6-
31+G(d) basis set for C, H, N, O and F atoms and the
LANL2DZ basis set for Pd. All optimised structures
were confirmed by the presence of zero or one
Scheme 1. Control experiments.
3
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