Site-Selective Cross-Coupling of Remote Chlorides Enabled by Electrostatically Directed Palladium Catalysis

Article abstract of DOI:10.1021/jacs.8b08686

Control of site-selectivity in chemical reactions that occur remote from existing functionality remains a major challenge in synthetic chemistry. We describe a strategy that enables three of the most commonly used cross-coupling processes to occur with high site-selectivity on dichloroarenes that bear acidic functional groups. We have achieved this by repurposing an established sulfonylated phosphine ligand to exploit its inherent bifunctionality. Mechanistic studies suggest that the sulfonate group engages in attractive electrostatic interactions with the cation associated with the deprotonated substrate, guiding cross-coupling to the chloride at the arene meta position. This counterintuitive combination of anionic ligand and anionic substrate demonstrates an alternative design principle when considering the application of noncovalent interactions to direct catalysis.

Full text of DOI:10.1021/jacs.8b08686

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Communication
Site-Selective Cross-Coupling of Remote Chlorides
Enabled by Electrostatically-Directed Palladium Catalysis
William A Golding, Robert Pearce-Higgins, and Robert J Phipps
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 08 Oct 2018
Downloaded from http://pubs.acs.org on October 8, 2018
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Site‐Selective Cross‐Coupling of Remote Chlorides Enabled by Elec‐
trostatically‐Directed Palladium Catalysis
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William A. Golding, Robert Pearce‐Higgins and Robert J. Phipps*
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, United Kingdom.
Supporting Information Placeholder
identical halogens is typically more straightforward than
regioselectively accessing variants bearing non‐identical hal‐
ogens. Thus development of catalyst‐controlled methods to
differentiate identical, remote halogens could rapidly add
value and complexity to readily available building blocks. We
hypothesized that this challenge might be met using bifunc‐
tional phosphine ligands that bear a remote functional group
able to interact with the substrate though a non‐covalent
ABSTRACT: Control of site‐selectivity in chemical reactions
that occur remote from existing functionality remains a ma‐
jor challenge in synthetic chemistry. We describe a strategy
that enables three of the most commonly used cross‐
coupling processes to occur with high site‐selectivity on di‐
chloroarenes which bear acidic functional groups. We have
achieved this by repurposing an established sulfonylated
phosphine ligand to exploit its inherent bifunctionality.
Mechanistic studies suggest that the sulfonate group engages
in attractive electrostatic interactions with the associated
cation of deprotonated substrate, guiding cross‐coupling to
the chloride at the arene meta‐position. This counterintuitive
combination of anionic ligand and anionic substrate demon‐
strates an alternative design principle when considering ap‐
plying non‐covalent interactions to direct catalysis.
interaction.11,12 With the proper scaffold,
a
pseudo‐
intramolecular transition state could realize site‐selective
oxidative addition through either hydrogen bonding or elec‐
trostatic interactions (Fig 1, g or h). A variety of sulfonylated
phosphine ligands are known, for the purposes of carrying
out catalysis in water13 and we envisaged these may be repur‐
posed to exploit their inherent bifunctionality. In particular,
electrostatic interactions have been under‐explored as direct‐
ing elements for site‐selective catalysis.14,15 We recently
demonstrated that an anionic sulfonate‐bearing bipyridine
ligand can direct C‐H borylation through electrostatic inter‐
actions with a cationic substrate.16 The pairing together of
Transition metal‐catalyzed cross coupling has become a
key tool in the synthetic chemist’s arsenal.1 A key feature is
its predictability with regard to which functional group un‐
dergoes reaction. In simple cases, with only a single (pseu‐
do)halide and a single organometallic, the outcome is cer‐
tain. In more complex substrates bearing multiple halides,
particularly heteroarenes, it can be less obvious.2 For stand‐
ard arenes, C‐X Bond dissociation energy is the strongest
indicator of reactivity towards oxidative addition, in some
cases allowing iterative cross coupling of substrates bearing
several different halides (Figure 1, a).3,4,5 An often more chal‐
lenging scenario involves arenes bearing the same halide at
multiple sites. For specific substitution patterns it may be
possible to differentiate them according to steric (b) and/or
electronic (c) considerations, as typically the least hindered
and most electron deficient C‐X bonds will be most
reactive.3b, 6 In some cases, it has been possible to invert in‐
trinsic selectivity by employing a directing group to interact
with either the palladium catalyst (d)7 or a bifunctional lig‐
and for palladium which complexes with a magnesium salt of
the substrate after deprotonation of both with strong base
(e).8 However, these strategies have only resulted in coupling
proximal to the directing group, at the ortho position.
Figure 1. Site‐selective cross‐coupling of dihaloarenes
Arguably the greatest challenge in this area, which remains
largely unaddressed, is that of how to achieve remote site‐
selective coupling on arenes with minimal steric or electronic
bias (f).9,10 Access to polyhalogenated arenes bearing multiple
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oppositely charged components in an ‘ion‐pairing’ strategy, is
sXPhos was inferior (entry 4). Variation of the N‐group on
the amine revealed that while trifluoroacetyl and Boc gave
poor selectivity (entries 5 and 6), Tosyl increased to 7.5:1 and
p‐Nosyl to >20:1, albeit with moderate conversion (entries 7
and 8). Continuing the electronic trend, triflate provided
excellent selectivity and now with excellent conversion (en‐
try 9). A small amount of water as co‐solvent increased con‐
version without reducing site‐selectivity (entry 10) and Pd
loading could be reduced to 2 mol% (entry 11). Reducing the
boronic acid to 1.2 eq. gave less di‐coupled byproduct 4 (en‐
try 12). A control experiment on this substrate using SPhos
demonstrated that in the absence of the sulfonate group on
the ligand there is essentially no selectivity (entry 13). Under
these optimized conditions, sXPhos gave 7:1 m:p, inferior to
sSPhos (entry 14), whilst XPhos was non‐selective (entry 15).
Analysis as the reaction progressed revealed that site‐
selectivity remained constant over time.21
an intuitive way to invoke attractive electrostatic interactions
but this combination may not always be practical. In this
work we present a distinct mechanistic concept for utilizing
electrostatic interactions in which an anionic substrate and
anionic catalyst are able to be united through putative inter‐
action with a bridging alkali metal cation (Fig 1, i).
An important criterion at the outset was to develop a pro‐
tocol that would be effective on aryl chlorides, given their
greater availability than the corresponding bromides or io‐
dides.17 Accordingly, we sought to use derivatives of the dial‐
kylbiaryl phosphine ligand family pioneered by Buchwald,18
in which the lower aryl ring offers several positions for func‐
tionality. In 2005, Anderson and Buchwald reported sodium
salts of sulfonylated SPhos and XPhos, sSPhos and sXPhos,
for cross‐coupling of aryl chlorides in water, which have
since been used widely and are commercially available.19,20 To
probe their ability to act as bifunctional ligands, we evaluat‐
ed sSPhos and sXPhos in the Suzuki coupling of N‐Acetyl‐
3,4‐dichlorobenzylamine (1a) alongside standard SPhos and
XPhos (Table 1), initially to probe whether a hydrogen bond‐
ing interaction may result in site‐selectivity (Figure 1,g). As
expected, SPhos and XPhos gave equal coupling at the meta
and para chlorides (entries 1 and 2). In contrast, sSPhos gave
an encouraging 3.8:1 ratio, favoring Clm (entry 3) whilst
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Given the striking increase in selectivity as the N‐
protecting groups became more electron‐withdrawing, we
considered whether the potassium phosphate base may be
deprotonating 1f to form a potassium salt. Indeed, stirring 1f
in d8‐THF with K3PO4 showed complete deprotonation by
1H‐NMR within 30 mins at room temperature, whilst no such
changed was observed for 1a. This suggests that the superior
site‐selectivity observed with the N‐Tf group may be best
rationalized by invoking an electrostatic interaction of the
potassium salt of 1f with the sulfonate group of the ligand
(Figure 1,h). We sought to test this hypothesis by addition of
an appropriately sized crown ether, which should disrupt
this putative interaction by sequestration of the potassium
cation.12, 22 Accordingly, in the presence of 18‐crown‐6, site‐
selectivity was completely eroded, but as the crown ether
became too small to complex K+, selectivity was restored,
providing support for the importance of the uncomplexed
potassium cation (Scheme 1, entries 1‐4). Systematic variation
of the cation size suggested that it should be of a minimum
ionic radius in order to achieve high selectivity (entries 5‐8).
Table 1. Evaluation of ligand/substrate parametersa
Scheme 1. Effect of crown ethers and cationic radius
Entry
R
Ligand
% Yield
2:3
%
Conv.
2
3
18
32
10
22
20
11
4
17
10
5
1
Ac (1a)
Ac
SPhos
XPhos
sSPhos
sXPhos
19
1.1:1
1.3:1
65
100
54
70
73
2
3
41
Ac
38
42
39
17
3.8:1
1.8:1
1.9:1
1.5:1
4
Ac
6
5
TFA (1b) sSPhos
Boc (1c) sSPhos
14
8
6
34
We next evaluated the scope with regard to the boronic
acid component, for which excellent site‐selectivity was re‐
tained (>20:1 in all cases, Scheme 2). This included electron‐
deficient (2f, 5b) and electron‐rich (5c, 5e, 5g) aromatics.
Versatile functional groups are tolerated, including a methyl
ketone (5d) and a free aniline (5e). Notably, several groups
that could potentially engage in hydrogen bonding interac‐
tions with the catalyst (eg. phenol 5c and acetamide 5f) are
tolerated well, suggesting that the presumed electrostatic
mode of catalyst direction has orthogonality with potential
hydrogen bonding interactions. Furthermore, a boronic acid
bearing a chloride could be coupled selectivity with little
evidence of further coupling of the product (5h), demon‐
strating the high level of catalyst control over which site un‐
7
Ts (1d)
sSPhos
48
48
78
63
60
6
4
7.5:1
>20:1
>20:1
>20:1
>20:1
>20:1
1.6:1
7:1
53
8
pNs (1e) sSPhos
2
<1
9
50
91
9
Tf (1f)
Tf
sSPhos
sSPhos
sSPhos
<1
<1
<1
<1
19
9
10b
11 b,c
12 b,c,d
13 b,c,d
14 b,c,d
15 b,c,d
31
31
11
100
100
100
75
Tf
Tf
sSPhos 88 (82)
Tf
SPhos
sXPhos
XPhos
30
67
40
30
10
22
Tf
91
Tf
33
1.2:1
88
1
a Yields determined by H‐NMR with internal standard ex‐
cept in parentheses (isolated) b Solvent used: 19:1 THF:H2O. c
2 mol% Pd(OAc)2 and 4 mol% ligand used. d 1.2 Equivalents
boronic acid used.
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dergoes oxidative addition. Heterocyclic boronic acids in‐
cluding pyridine (5i), pyrimidine (5j), thiophene (5k) and
pyrrole (5l) also gave excellent site‐selectivity. For the latter
three substrates, commercially available precatalyst sSPhos‐
PdG2 was required, due to the sensitivity of the boronic ac‐
ids.23,24 Longer chain lengths did not result in reduction of
site‐selectivity, despite their greater flexibility (5m, 5n). We
evaluated whether Sonogashira coupling, to form sp2‐sp C‐C
bonds, would be compatible with our ligand‐directed ap‐
proach. This worked well under copper‐free conditions giv‐
ing excellent selectivity for coupling at the meta‐chloride.25
Several alkynes were evaluated: TIPS‐acetylene (5o), two
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arylacetylenes (5p, 5q), and
acetylene (5r).
a cyclohexanol‐substituted
Scheme 2. Scope of Site‐Selective Suzuki‐Miyaura and
Sonogashira couplingsa
For Suzuki coupling we also examined several substrates
that bear chlorides on different aromatic rings, comparing
any intrinsic selectivity (SPhos) with directed‐selectivity
(sSPhos) (Scheme 4). In all cases, the directing effect of the
ligand had a large impact on the intrinsic selectivity, pulling
it dramatically towards the meta‐chloride. Intrinsic selectivi‐
ty was either reversed (7a, 7b) and or went from non‐
selective to highly selective (7c, 7d). These results highlight
the potential for this method in the late stage functionaliza‐
tion of more complex molecules that bear multiple chlorides.
NHTf
2 mol% Pd(OAc)2
B(OH)2
n
4 mol% sSPhos
5
or
+
R
3 eq. K3PO4
19:1 THF:H2O
R
Clm
Clp
1
40 oC or 70 oC, 16h
NHTf
NHTf
NHTf
NHTf
5h
5g
OH
R
R
Cl
Cl
Cl
Cl
OMe
5d, R=COCH3, >20:1, 84%
5e, R=NH2, >20:1, 64%
5f, R=NHAc, >20:1, 73%
Cl
5b, R=CF3, >20:1, 92%
5c, R=OH, >20:1, 75%
>20:1, 82%
>20:1, 70%
NHTf
Scheme 4. Competition substrates bearing chlorides
on different rings
NHTf
NHTf
NHTf
5l
5j
5k
5i
Boc
N
N
S
Cl
Cl
Cl
Cl
N
OMe
N
OMe
CHO
>20:1, 80%b
>20:1, 73%b
>20:1, 85%b
>20:1, 88%
NHTf
NHTf
NHTf
NHTf
n
5o
5r
OH
Cl
Cl
TIPS
Cl
The chemistry works very effectively on gram‐scale and we
demonstrate several synthetic manipulations of the products
involving removal of the triflate group (Scheme 5).27
Cl
>20:1, 57%
CO2Et
R
2f, n=1, >20:1, 88%
5m, n=2, >20:1, 70%
5n, n=3, >20:1, 65%
>20:1, 47%
5p, R=CO2Et, >20:1, 60%
5q, R=OMe, >20:1, 62%
a Yields shown are isolated. Ratios of coupling at Clm:Clp were
determined by 1H‐NMR. b sSPhosPdG2 (2 mol%) was used.
Scheme 5. Gram‐scale reaction and manipulations
Given the importance of C‐N bond‐formation, we next in‐
vestigated whether Buchwald‐Hartwig amination would be
feasible. Gratifyingly, aniline could be selectively coupled
with 1f and after optimization we found that the novel ligand
s(tBuSPhos), the P‐(tBu)2 version of sSPhos, gave superior
reactivity (Scheme 3).26 A range of electron rich (6a, 6b) and
poor (6c, 6e, 6f) anilines participated as well as several aro‐
matic heterocyclic amines (6d and 6g). As previously, control
experiments with standard SPhos gave very low selectivity.21
If our mechanistic hypothesis regarding the origin of selec‐
tivity is correct (Figure 1h), we reasoned that arenes bearing
Brønsted acidic groups other than triflamide may also partic‐
ipate effectively as they would readily form potassium salts
under the reaction conditions. Not only would this broaden
the scope of the process, but also provide a further test of the
Scheme 3. Site‐selective Buchwald‐Hartwig coupling
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proposed mechanism. Accordingly, we evaluated 3,4‐
ASSOCIATED CONTENT
Supporting Information
dichlorophenylacetic acid in Suzuki‐Miyaura coupling using
sSPhos and were happy to observe that, in line with our hy‐
pothesis, >20:1 site‐selectivity for the meta chloride was again
achieved (Scheme 6a, 11a), whilst SPhos gave none.21 Con‐
versely, sSPhos gave poor selectivity with the corresponding
methyl ester of the carboxylic acid.21 High selectivity was
maintained with the longer chain of a hydrocinnamic acid
(11b), and Sonogashira couplings were also compatible with
both (11c, 11d). Interestingly, 3,4‐dichlorobenzoic acid un‐
dergoes preferential coupling at the para‐Cl using standard
SPhos, due to electronic effects (Scheme 6b, 11e). In con‐
trast, sSPhos completely switches site‐selectivity to the me‐
ta‐Cl (11f). Further validating the mechanistic hypothesis,
sodium sulfonate 12, derived from the corresponding benzyl
chloride, also underwent site‐selective coupling (Scheme 6c).
The product could be converted directly to sulfonamide 13, a
group used extensively in medicinal chemistry, or alterna‐
tively transformed directly back to a benzyl chloride.21
The Supporting Information is available free of charge on the
ACS Publications website. Experimental procedures, addi‐
tional reaction optimization, and characterization data (pdf).
AUTHOR INFORMATION
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Corresponding Author
*rjp71@cam.ac.uk
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
We are grateful to AstraZeneca for PhD studentships
through the AZ‐Cambridge PhD program (W.A.G. and R.P.),
the Royal Society for a University Research Fellowship
(R.J.P.), the EPSRC (EP/N005422/1) and the ERC (StG
757381). We thank the EPSRC UK National Mass Spectrome‐
try Facility at Swansea University as well as Professors Steven
V. Ley and Matthew J. Gaunt for support and useful discus‐
sion and Iain Cumming and Thomas McGuire (AstraZeneca).
We are also very grateful to Professor Stephen L. Buchwald
for useful discussion at the outset of this project.
Scheme 6. Coupling of carboxylic acids and benzyl‐
sulfonatesa
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In conclusion, we have demonstrated that a commercially
available sulfonylated phosphine ligand, in which the sul‐
fonate group is conventionally used to engender water solu‐
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range of site‐selective cross couplings at remote positions.
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interaction between the alkali metal cation of a deprotonated
substrate and the anionic sulfonate group of the ligand. This
counterintuitive combination of anionic ligand and anionic
substrate demonstrates an alternative design principle when
considering applying non‐covalent interactions to direct
catalysis. The process effectively controls site‐selectivity in
three of the most widely used cross‐coupling processes (Su‐
zuki‐Miyaura, Sonogashira and Buchwald‐Hartwig)28 and has
been demonstrated on substrates bearing three different
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