Systematic Variation of Ligand and Cation Parameters Enables Site-Selective C-C and C-N Cross-Coupling of Multiply Chlorinated Arenes through Substrate-Ligand Electrostatic Interactions

Article abstract of DOI:10.1021/jacs.0c11056

Use of attractive noncovalent interactions between ligand and substrate is an emerging strategy for controlling positional selectivity. A key question relates to whether fine control on molecules with multiple, closely spaced reactive positions is achievable using typically less directional electrostatic interactions. Herein, we apply a 10-piece "toolkit"comprising of two closely related sulfonated phosphine ligands and five bases, each possessing varying cation size, to the challenge of site-selective cross-coupling of multiply chlorinated arenes. The fine tuning provided by these ligand/base combinations is effective for Suzuki-Miyaura coupling and Buchwald-Hartwig coupling on a range of isomeric dichlorinated and trichlorinated arenes, substrates that would produce intractable mixtures when typical ligands are used. This study develops a practical solution for site-selective cross-coupling to generate complex, highly substituted arenes.

Full text of DOI:10.1021/jacs.0c11056

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Systematic Variation of Ligand and Cation Parameters Enables Site-
Selective C−C and C−N Cross-Coupling of Multiply Chlorinated
Arenes through Substrate−Ligand Electrostatic Interactions
William A. Golding,† Hendrik L. Schmitt,† and Robert J. Phipps*
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ABSTRACT: Use of attractive noncovalent interactions between
ligand and substrate is an emerging strategy for controlling positional
selectivity. A key question relates to whether fine control on
molecules with multiple, closely spaced reactive positions is
achievable using typically less directional electrostatic interactions.
Herein, we apply a 10-piece “toolkit” comprising of two closely
related sulfonated phosphine ligands and five bases, each possessing
varying cation size, to the challenge of site-selective cross-coupling of
multiply chlorinated arenes. The fine tuning provided by these
ligand/base combinations is effective for Suzuki−Miyaura coupling and Buchwald−Hartwig coupling on a range of isomeric
dichlorinated and trichlorinated arenes, substrates that would produce intractable mixtures when typical ligands are used. This study
develops a practical solution for site-selective cross-coupling to generate complex, highly substituted arenes.
respective halogens must be regioselectively incorporated and
the synthesis of which can be challenging. There are
remarkably few ways to tackle the inherent challenge of site-
selective coupling of arenes that have the same chloride located
at two or more positions.7 In notable work, Manabe and co-
workers developed an elegant catalyst-controlled strategy,
although this requires strong organometallic bases and is
restricted to Kumada and Sonogashira couplings, two of the
lesser used cross-coupling reactions.8 This paucity of methods
is regrettable considering the much greater ease of accessing
multiply chlorinated arenes when compared with differentially
di- or trihalogenated arenes. This ease of access is reflected in a
simple comparison of commercial availability between these
types of compounds in the context of benzylamines that are
relevant to this study (Figure 1a).
Catalyst designs which incorporate attractive, noncovalent
interactions between ligand and substrate are rapidly gaining
traction as powerful approaches for influencing site selectivity
in transition metal catalysis.9 While hydrogen-bonding
interactions have been the focus of most studies, electrostatic
interactions remain underexplored.10,11 A likely reason is
concern related to the low directionality of electrostatic
interactions, particularly when an application demands precise
INTRODUCTION
■
Established guidelines relating to chemoselectivity enable
synthetic chemists to reliably predict which functional group
in a molecule is likely to undergo reaction in a given context.1
The challenge of site-selectivity presents itself in molecules
which possess two or more instances of the same functional
group. Sometimes electronic or steric factors may dispose one
to be more reactive than others, but in many cases, mixtures of
isomers as well as overreaction typically preclude practically
useful procedures.2 Consequently, synthetic chemists will
intuitively incorporate numerous extra synthetic steps into a
planned route to avoid a site-selectivity challenge which could
risk derailment. The uncalculated cost, both economically and
environmentally, resulting from the paucity of methods for
carrying out common chemical transformations in a site-
selective manner is likely to be large indeed. One of the most
widely utilized reaction classes in contemporary synthetic
chemistry is cross-coupling.3 Cross-coupling reactions of
arenes should be of particular value if able to be carried out
in a site-selective manner because aryl halides, chlorides in
particular, are remarkably inert to many other reaction types
and can be retained during many synthetic steps. Strong
electronic biases mean that cross-coupling selectivity trends in
heteroarenes have been well documented.4 In recent years,
much progress, particularly from Schoenebeck and co-work-
ers,5 has been made in the development of catalysts that are
able to carry out highly chemoselective cross-coupling of
arenes that possess several different (pseudo)halides.6
However, in these cases, differentially di- or tri(pseudo)-
halogenated arene precursors are required, in which the
Received: October 20, 2020
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Figure 1. Site-selective cross-coupling of multiply chlorinated arenes guided by ligand−substrate electrostatic interactions. (A) Greater accessibility
of multiply chlorinated arenes versus differentially halogenated variants. Prices in GBP from Fluorochem as of Oct 2020. (B) Our previous work on
site-selective cross-coupling of 3,4-dichloroarenes using sSPhos. (C) Outline of the design plan for a fully tunable system, based on an electrostatic
interaction, to control site selectivity in oxidative addition of palladium. (D) This study.
spatial control. Yet many common functional groups can act as
participants in attractive electrostatic interactions and if these
can be harnessed present exciting but untapped opportunities
for exploitation in control of site-selective catalysis.
group on the lower ring of the dialkylbiaryl phosphine scaffold.
It is well established that the palladium metal typically resides
over this lower ring, and we anticipated that whether the
sulfonate is at the 3′ or 4′ position will have a small but
significant effect on the crucial distance between the sulfonate
and the palladium metal center (Figure 1c, middle row).14
sSPhos and sXPhos are both commercially available, and while
sulfonation occurs at the 3′ position of SPhos, on XPhos an
ipso-sulfonation occurs, substituting the iPr group at the 4′
position.12 This regiodivergence between the two scaffolds
conveniently provides two closely related ligands between
which the site of sulfonation on the lower aryl ring is varied in
the desired manner. At the outset of this study, we envisaged
that a ligand/base “toolkit” comprising both sSPhos and
sXPhos together with bases containing the five most common
alkali metal cations could be readily screened against a given
substrate and the optimum combination leading to site-
selectivity be quickly identified. This would tackle the question
of whether fine control of position selectivity is viable using
electrostatic interactions as well as provide a much needed
approach to site-selective coupling of di- and trichloroarenes
using the most commonly used protocols of Suzuki−Miyaura
coupling and Buchwald−Hartwig amination (Figure 1d).
In an initial proof-of-concept study with this goal in mind,
we recently disclosed that sSPhos, a sulfonated version of the
common ligand SPhos, originally developed by Anderson and
Buchwald for performing cross-couplings in water,12 could be
repurposed as a bifunctional ligand for controlling site-selective
cross-coupling.13 This was demonstrated on 3,4-dichlorinated
arene substrates that contained suitable functionality with
which to interact with the catalyst sulfonate group. We
hypothesized that the interaction was electrostatic in nature
and involved the alkali metal cation of the deprotonated
substrate sitting between it and the anionic sulfonate group of
the ligand (Figure 1b). High levels of site-selectivity for cross-
coupling at the chlorine located at the meta position were
observed, while SPhos resulted in no selectivity. While that
study provided proof-of-concept for ligand-directed cross-
coupling at distal positions, we only explored the 3,4-
dichloroarene motif in combination with sSPhos (depicted),
and it was unclear whether the success in this limited context
would translate to other substitution patterns or higher orders
of halogenation, factors which would be crucial for this
approach to be applied in a generally applicable and
synthetically useful manner.
RESULTS AND DISCUSSION
■
We commenced our study by examining the three other
nonsymmetrical dichlorinated isomers of N-triflated benzyl-
amine: 2,3-, 2,4-, and 2,5-dichloro (Figure 2, 1−3). For each
isomer, the whole ligand/base toolkit was evaluatedsSPhos
and sXPhos in combination with each of the carbonate bases of
the first five group 1 metals. For the purpose of establishing a
reliable measure of site-selectivity, a limiting amount of
boronic acid (0.5 equiv) was used to avoid formation of
We used our mechanistic hypothesis to identify two key
factors that we anticipated, if systematically varied, could
feasibly impact site-selectivity for any given substrate. The first
factor was the size of the alkali metal cation, arising from the
exogenous base used, and modulation of which should impact
the positioning between the ligated palladium metal center and
any particular carbon−halogen bond on the substrate (Figure
1c, top row). The second was the positioning of the sulfonate
B
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proximal chlorine, at the 2-position, was again favored, but in
contrast, sSPhos performed relatively poorly, even with the
larger metal cations. It was solidly outperformed by sXPhos,
which gave 7:1 selectivity for coupling at Cl2 when used in
combination with Rb2CO3 in a clear standout combination
(entry 9). A similar trend was observed with sXPhos as in the
Cl2 vs Cl3 competition: once the cation became too large (Cs),
the selectivity decreased (entry 10). In the Cl2 vs Cl5
competition of 3, sXPhos showed a weak preference for the
Cl2-coupled product (Chart 3, Figure 2). However, sSPhos
together with Rb2CO3 gave 7:1 selectivity, this time for the
more remote chlorine at C5. To complete this systematic study,
we finally returned to the Cl3 vs Cl4 competition from our
initial report, where both chlorines are at remote positions in
substrate 4 (Chart 4, Figure 2). In this case, sSPhos was far
superior, showing the highest levels of selectivity (>20:1) with
every cation larger than sodium. sXPhos showed a similar
trend as it had with other substrates (Charts 1 and 2, Figure 2)
but peaked at a much lower level than sSPhos (6:1).
Having applied the toolkit in a screening capacity to identify
the optimal ligand/base combinations for each dichlorinated
isomer of the N-triflated benzylamine, we next evaluated the
reaction on a preparative scale under practically relevant
conditions with the dichloroarene as the limiting reagent. We
were initially concerned that dicoupling may be problematic,
but this was not the caseonly small amounts were typically
observed, allowing isolation of good to excellent yields of the
desired monocoupled products (Scheme 1). The low levels of
overcoupling are again an indicator of a high degree of catalyst
control in the process. The isomeric ratios observed in the
crude reaction mixtures were often higher than the values in
Charts 1−3, Figure 2, and we attribute this to formation of
small amounts of dicoupled product, wherein the minor isomer
is apparently being consumed preferentially in some cases,
enhancing the observed selectivity. Advantageously, upon
isolation, the isomeric ratio was further improved in some
cases (isolated ratio quoted in parentheses). All three
dichlorinated isomers were coupled each with two different
aryl boronic acids and a heteroaryl boronic acid, demonstrating
the practical utility of this procedure following identification of
the optimal ligand/base combination from the initial screen.
The few cases where selectivity did appear to vary between
boronic acids most likely reflects differences in the amount of
dicoupled product being formed in those particular cases due
to differing conversion.
We next sought to explore Buchwald−Hartwig coupling
given the importance of this disconnection for C−N bond
formation.15 On the assumption that oxidative addition of Pd
to the C−Cl bond is irreversible and selectivity determining,
we initially attempted to use the same ligand/base combina-
tions that had been optimal for each substrate in the Suzuki−
Miyaura couplings. From our previous experience in
transitioning from Suzuki to Buchwald−Hartwig couplings
we were aware that to obtain reactivity we would need to use
higher reaction temperatures (60−110 °C) and accordingly
change solvent (THF to 1,4-dioxane), factors which could
affect the finely tuned ligand/base combinations. Gratifyingly,
the original optimal combination of sSPhos with Rb2CO3 was
still highly effective for the 2,5-dichloro substrate 3, and we
proceeded to couple three electronically distinct anilines with
very good site selectivity for coupling at the meta position
(Scheme 2, top row). Usefully, the minor isomer was able to
be removed during purification, giving isomerically pure
Figure 2. Systematic evaluation of ligand/base combinations with all
four dichlorinated isomers of N-triflated benzylamine. Ratios and
conversions determined by 1H NMR analysis with reference to
internal standard.
dicoupled product, which could mask the true site-selectivity of
the combination under assessment.
For the 2,3-dichloro substrate 1, we observed that using the
larger alkali metal cations, good selectivity for cross-coupling at
the most proximal chlorine, at the 2-position, could be
obtained (Chart 1, Figure 2). While this was true for both
sSPhos (red line) and sXPhos (blue line), the former gave the
highest ratio at 10:1 Cl2:Cl3 when Cs2CO3, possessing the
largest cation, was used (entry 5). Importantly, control
experiments with both SPhos (green line) and XPhos (yellow
line) gave no selectivity with any base, demonstrating that
there is no intrinsic selectivity bias and that the sulfonate group
of the phosphine is playing a crucial role. We next examined an
ortho versus para competition in the form of the 2,4-
dichlorinated isomer 2 (Chart 2, Figure 2). Here, the most
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Scheme 1. Preparative Reactions Using Three Boronic Acid
Partners in Suzuki Couplings with Isomeric Dichloro
Substrates 1−3
Scheme 2. Variation of the Aniline Partner in Buchwald−
Hartwig Couplings with Dichloro Substrates 1−3
a
a
1
Bold ratios were determined from the crude H NMR. Yields given
are isolated, and the isomeric ratio in parentheses is that of the
isolated material.
product in all cases. The crude isomeric ratio is denoted first,
with the isolated ratio in parentheses. Disappointingly, low
conversion was observed using the original ligand/base
combinations identified for both the 2,3-dichloro (1, sSPhos
and Cs2CO3) and the 2,4-dichloro (2, sXPhos and Rb2CO3)
substrates, and further optimization was required. The
complete ligand/base toolkit was screened afresh against the
2,3-isomer 1, but in all cases, very low product formation was
observed (<10% in all cases, see SI for full details). We
discovered that switching the conjugate anion of the base to
phosphate was crucial for promoting reactivity with this
substrate and that K3PO4 gave acceptable conversion, allowing
a moderate yield of the C2-coupled isomer to be isolated, with
good site-selectivity (1d). It is important to note here that the
moderate yields are due to incomplete conversion rather than
formation of any other isomers. Two other anilines were
demonstrated as effective partners in addition (Scheme 2,
middle row). Application of the complete toolkit to the 2,4-
dichloro isomer 2 revealed that switching both ligand to
sSPhos and base to Cs2CO3 gave uniquely high conversion as
well as 6:1 selectivity for coupling at Cl2 (Chart 5, Scheme 2).
This effect was found to be consistent across all three anilines
tested, and indeed, the ortho-coupled isomer could be isolated
in >20:1 isomeric purity in all cases in good yields (Scheme 2,
lower row).
Having used our ligand/base toolkit to achieve site-selective
cross-couplings on dichlorinated isomers of benzylamine, we
next turned to the challenge of trichlorinated arenes to explore
whether catalyst control could be maintained in these
extremely challenging systems. Trichlorinated benzylamines
bearing three nonsymmetrical substation patterns (2,3,4 (5),
2,4,5 (6), and 2,3,5 (7)) were examined in their N-triflated
form (Scheme 3). In these coupling reactions there are seven
possible products: three mono products which could all
undergo further coupling to afford an additional three
regioisomers of dicoupled product and finally the tricoupled
product. Standard cross-coupling conditions would be
expected to result in complex, intractable mixtures. Impor-
tantly, these isomerically pure, trichlorinated arenes are readily
accessible in a few steps from cheap, commercially available
compounds at low cost (see SI for details).
We first attempted to draw analogy with the most closely
related dichlorinated substrates in the hope that these would
guide us to well-performing combinations for the trichlorinated
compounds. In the case of the 2,3,4-trichlorinated substrate 5,
we used sXPhos and Rb2CO3, which had been optimal for the
2,4-dichlorinated substrate, and were happy to see that this
gave a 4:1 ratio of the desired coupling at Cl2 with respect to
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of Cl5:others in which others comprised at least four
compounds. Finally, we examined the 2,3,5-trichlorinated
isomer 7 (Scheme 3, lower row). This was a very challenging
substrate which required us to examine the full toolkit of
ligands and bases (Chart 6, Scheme 3). This survey revealed
that sSPhos with the larger metal cations gave the best
outcomes, resulting in a 2.3:1 ratio of Cl5:others using K2CO3.
While this substrate arguably represents the limit of the current
system, synthetically useful amounts of the meta-coupled
product could still be obtained whereas standard ligands give
truly intractable mixtures (1:5 Cl5:others with SPhos for 7a).
We then turned our attention to site-selective Buchwald−
Hartwig couplings on the three trichlorinated substrates 5−7.
Because we had found sSPhos to give superior reactivity to
sXPhos in Buchwald−Hartwig couplings on the disubstituted
substrates, we used this ligand in all cases. In addition, the 2,3-
dichloro substitution pattern had required the use of
phosphate base previously, and so this was used for 5 and 7,
which both contain this motif (Scheme 4). Considering the
Scheme 3. Investigation of Site-Selective Suzuki−Miyaura
Coupling with Trichlorinated Arenes 5−7
Scheme 4. Site-Selective Buchwald−Hartwig Couplings on
Trichlorinated Arenes 5, 6, and 7
challenges presented by these substrates, the observed ratios of
major isomer:others of between 3:1 and 7:1 were highly
encouraging. Upon purification, minor isomers could typically
be removed to permit good isolated yields of largely single
isomers to be obtained.
We next explored sequential Suzuki couplings and applied
our ligands to 2,4,5-trichlorinated arene 6, first carrying out a
ligand-directed Cl5-selective coupling using sSPhos/Rb2CO3
for boronic acid A (Figure 3a). We then switched to sXPhos
with the same base to effect a site-selective Suzuki coupling
with boronic acid B at Cl2. Finally, a standard Suzuki coupling
with boronic acid C on the final chlorine (Cl4) gave the
tricoupled product 6f as a single regioisomer. Although in this
case the sequence must be followed in the proper order of meta
then ortho then para, in principle, any combination of coupled
products could be achieved simply by varying the order in
which the boronic acids are used. Given this success, we were
keen to tackle the challenge of the tetrachlorinated isomer 8, in
which all four chlorines are in independent environments. Due
to the complexity of this substrate and anticipating the
potential for deleterious overcoupling, we first screened all 10
ligand/base combinations with limiting boronic acid in order
to find that which gave the highest precision, expressed in
terms of the ratio Cl5:others (Figure 3b, Chart 7). This study
showed sSPhos and Na2CO3 to be optimal, and we proceeded
with this combination in a preparative manner with a slight
excess of boronic acid A for the first step in the sequence,
which enabled isolation of the monocoupled product in 40%
yield with a 5:1 ratio of Cl5:other isomers (Figure 3c). We
believe that there is little precedent for carrying out a cross-
coupling on such a highly halogenated substrate with this level
of selectivity. This was carried forward in a Cl2-selective
“others” (Scheme 3, top row, 5a). In these compounds the
benzylic peaks are highly diagnostic in the H NMR spectra
1
and constitute a reliable indicator of selectivity. To highlight
how challenging this coupling is, a control reaction on this
substrate combination using XPhos instead of sXPhos resulted
in a 1:4 ratio, where “others” comprises five separate peaks,
emphasizing the dramatic effect on site-selectivity that the
sulfonated ligand has. Several different boronic acids were
compatible, and similar selectivities were observed for these
(5b and 5c). We next examined the 2,4,5-trichlorinated isomer
6 and used sSPhos and Rb2CO3, a combination that had been
optimal for Suzuki coupling on the 2,5-dichlorinated
compound. This gave very good selectivity for coupling at
Cl5 (5:1−6:1 Cl5:others) across the three boronic acids tested
(Scheme 3, middle row, 6a−c). Furthermore, in these cases
the minor components could be easily removed by
chromatography, allowing isolation of isomerically pure Cl5-
coupled compound in good yield. For comparison, the control
was run for compound 6a with SPhos, which gave a 1:1.5 ratio
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Figure 3. Sequential Suzuki coupling sequences demonstrated on
trichlorinated arene 6 and tetrachlorinated arene 8.
Figure 4. Application of the toolkit approach to two dichlorinated
substrates bearing different Brønsted acidic functional groups.
coupling using sXPhos and Rb2CO3, which proceeded
smoothly with boronic acid B and allowed the product 8b to
be isolated in a 57% yield as a single isomer. We attempted
selective Suzuki coupling on 8b, but no selectivity between Cl3
and Cl4 was observed: we anticipate that the present ligand
scaffold is not able to reach past an existing ortho substituent.
It is well established that the N-triflyl group in benzylamines
can be readily elaborated to a variety of useful functionalities,
such as N-alkyl amines and aldehydes,13,16 or subjected to
nucleophilic displacement via the ditriflimide.16b,17 Further-
more, we have previously shown that a number of anionic or
Brønsted acidic functional groups are able to act as directing
groups for the putative electrostatic interaction with the
catalyst.13,18 Accordingly, we sought to showcase several
dichlorinated substrates which feature different directing
groups for the electrostatic interaction and demonstrate that
these can also be used together with the “toolkit approach” to
rapidly identify the optimal ligand/base combination for each.
We first selected the commercially available 2,3-dichlorinated
hydrocinnamic acid 9 and evaluated the full ligand/base toolkit
against it in a Suzuki coupling (Figure 4a). This revealed
sSPhos to be the superior ligand, and all cations apart from
lithium gave excellent selectivity for Cl2 (Chart 8, Figure 4).
When translated to a preparative reaction using excess boronic
acid, this allowed compound 9a to be isolated in an excellent
yield, essentially as a single regioisomer. We then targeted 2,4-
dichlorinated sulfamic acid 10, which can be regarded as a
temporarily protected amine and is readily rendered anionic by
treatment with base.19 A full evaluation showed that while
sSPhos gave good outcomes, sXPhos was superior in this case
and gave 15:1 selectivity for Cl2 with the three largest cations.
Translated to preparative conditions, this resulted in isolation
of 10a in good yield and with 17:1 selectivity after acid-
promoted cleavage of the sulfamate and trifluoroacetylation of
the free amine to facilitate isolation.
CONCLUSIONS
■
Taking into account all of the substrates explored, one can
derive a pattern of reactivity with this catalyst system if the
properly fine-tuned ligand/base combination can be identified.
A chloride at the meta position will couple first, so long as
there is no ortho substituent adjacent to it, which would
presumably impede access of the catalyst. Following this, a
chloride at the ortho position is the second favored position.
Chlorides at the para position and those that are meta but
blocked by an ortho substituent are the least reactive with these
sulfonated ligands, presumably as the catalyst is simply unable
to reach. It should be emphasized that control experiments
throughout this study using SPhos and XPhos demonstrate
that the order outlined above is not an intrinsic order of
reactivity toward cross-coupling in general in these substrates.
The sulfonate group on the ligand is crucial to obtaining any
kind of site-selectivity, but this must be fine tuned by
modulation of the sulfonate position and the cation in order
to achieve the optimal site-selectivity. On the basis of our
current understanding, it is not possible to predict de novo
exactly which ligand/base combination will be best, but we
demonstrated that use of a toolkit of two commercially
available ligands and five common bases allows this
combination to be rapidly identified in most cases. We
anticipate that this study will have practical application in
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.0c11056.
■
sı
Experimental procedures and spectral data (PDF)
AUTHOR INFORMATION
Corresponding Author
Robert J. Phipps − Department of Chemistry, University of
Cambridge, Cambridge CB2 1EW, United Kingdom;
orcid.org/0000-0002-7383-5469; Email: rjp71@
cam.ac.uk
■
Authors
William A. Golding − Department of Chemistry, University of
Cambridge, Cambridge CB2 1EW, United Kingdom
Hendrik L. Schmitt − Department of Chemistry, University of
Cambridge, Cambridge CB2 1EW, United Kingdom
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.0c11056
Author Contributions
†W.A.G. and H.L.S. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to AstraZeneca for a Ph.D. studentship through
the AZ-Cambridge PhD program (W.A.G.), the Royal Society
for a University Research Fellowship (R.J.P.), the ERC
(Starting Grant NonCovRegioSiteCat, 757381) and the
EPSRC (EP/N005422/1). Thanks to Iain Cumming (As-
traZeneca) for useful discussion.
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