Phosphino-Triazole Ligands for Palladium-Catalyzed Cross-Coupling

Article abstract of DOI:10.1021/acs.organomet.8b00539

Twelve 1,5-disubtituted and fourteen 5-substituted 1,2,3-triazole derivatives bearing diaryl or dialkyl phosphines at the 5-position were synthesized and used as ligands for palladium-catalyzed Suzuki-Miyaura cross-coupling reactions. Bulky substrates wer

Full text of DOI:10.1021/acs.organomet.8b00539

Article
pubs.acs.org/Organometallics
Cite This: Organometallics XXXX, XXX, XXX−XXX
Phosphino-Triazole Ligands for Palladium-Catalyzed Cross-Coupling
Yiming Zhao,† Huy van Nguyen,† Louise Male,‡ Philip Craven,† Benjamin R. Buckley,§
and John S. Fossey*,†
†School of Chemistry and ‡X-ray Crystallography Facility, School of Chemistry, University of Birmingham, Edgbaston, Birmingham,
West Midlands B15 2TT, United Kingdom
§Department of Chemistry, Loughborough University, Loughborough, Leicestershire LE11 3TU, United Kingdom
S
* Supporting Information
ABSTRACT: Twelve 1,5-disubtituted and fourteen 5-sub-
stituted 1,2,3-triazole derivatives bearing diaryl or dialkyl
phosphines at the 5-position were synthesized and used as
ligands for palladium-catalyzed Suzuki−Miyaura cross-cou-
pling reactions. Bulky substrates were tested, and lead-like
product formation was demonstrated. The online tool
SambVca2.0 was used to assess steric parameters of ligands
and preliminary buried volume determination using XRD-
obtained data in a small number of cases proved to be
informative. Two modeling approaches were compared for the
determination of the buried volume of ligands where XRD
data was not available. An approach with imposed steric
restrictions was found to be superior in leading to buried
volume determinations that closely correlate with observed reaction conversions. The online tool LLAMA was used to
determine lead-likeness of potential Suzuki−Miyaura cross-coupling products, from which 10 of the most lead-like were
successfully synthesized. Thus, confirming these readily accessible triazole-containing phosphines as highly suitable ligands for
reaction screening and optimization in drug discovery campaigns.
are not always employed as innocent bystander linkage motifs.
Triazoles of this type have been used as analogues of peptide
linkages (Figure 1, 2),16 such peptidomimetics are physiolog-
ically stable, and their modular synthesis allows access to a
broad range of biologically relevant applications.17,18 The
utility of further synthetic transformations has been probed,
particularly in the derivatization at the 5-position (Figure 1,
3).19,20
INTRODUCTION
■
Click chemistry, as defined by Sharpless and co-workers,1−4
has transformed the face, and accessibility to the nonspecialist
of molecular linking strategies. Among click approaches, the
highly regioselective copper-catalyzed, Huisgen cycloaddition
reaction to form 1,4-triazoles (Figure 1, 1) by Meldal and
Copper-catalyzed triazole formation has been exploited in a
wide range of scenarios21 and has been the subject of various
mechanistic studies,22−26 leading to the proposal of a binuclear
transition state involving two copper atoms. 1,2,3-Triazole
derivatives have been employed as nitrogen-coordinating
ligands,27 e.g. in N,N′-,28−34 N,S-,29 N,Se-29 and cyclo-
metalated35−37 bidentate coordination complexes. Further-
more, tris-triazoles, such as TBTA (Figure 2, 4) and its
analogues, have been used as ligands for reactions including
the CuAAC by both Fokin38 and Zhu39 and their co-workers,
demonstrating exceptional ligand-mediated reaction acceler-
ation.
Figure 1. Upper: copper-catalyzed azide−alkyne cycloaddition
(CuAAC). Lower: examples of 1,2,3-triazole-containing structures.
Sharpless,4,5 has grown in popularity and has been employed in
increasingly varied applications over the intervening years.6
The copper-catalyzed azide−alkyne cycloaddition (CuAAC) is
ubiquitous,5,7−9 and often referred to as “the click reaction”,
and the product 1,2,3-triazoles, bearing 1,4-substition patterns,
with reliable fidelity and yields being synonymous with click
chemistry (Figure 1, 1).8,10−15 However, the resulting triazoles
Alkylation of a 1,2,3-triazole derivative, to furnish a 1,3,4-
trisubstituted triazolium salt, is the first step in the synthesis of
a newer class of N-heterocyclic carbene (NHC) reported in
Received: July 30, 2018
© XXXX American Chemical Society
A
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Figure 2. Examples of triazole-containing or -derived ligands.
2008 by Albrecht and co-workers40 and later extended by Lee
and Crowley41−43 as ligands for gold and by Grubbs and
Bertrand as ligands for ruthenium-mediated catalysis (Figure 2,
5).44 The ready access to a range of ligand scaffolds through
the CuAAC has led the triazole−NHC platform to continue to
gain in popularity.45−49 These reports demonstrate the 1,2,3-
triazole unit is a legitimate candidate for further exploitation as
a key component in ligand design and catalyst development.50
The co-authors of this report have investigated triazoles as
chemosensors51−53 and as products of asymmetric syn-
thesis.54−58 Furthermore, an interest in boronic acid derivatives
as chemosensors,59−64 including the use of cross-coupling
reactions as a means of sensing,65 means the co-authors of this
report are familiar with boronic acids and esters.66 As such, a
desire to bring together these streams of research under one
umbrella has led to the research reported in this manuscript.
Herein, the development of bulky and highly active triazole-
containing phosphine ligands for palladium-catalyzed Suzuki−
Miyaura cross-coupling reactions is explored (Scheme 1).
Figure 3. Representative examples of bulky phosphine ligands
including: upper: S-Phos (7) and X-Phos (8); middle left:
heteroaromatic phosphine derivative (9); middle right and lower
row: Phosphino-ferrocene derivatives displaying planar chirality.
access to highly active palladium-ligand conjugates for cross-
coupling some of the least active substrates.
1,4-Disubstituted-1,2,3-triazoles have been used in the
assembly of phosphorus-containing species that have the
potential to be employed as ligands. Ready access to libraries of
products using CuAAC reactions has permitted the develop-
ment of phosphines connected to triazoles with sp3 linkages to
Scheme 1. Outline of a General Palladium-Catalyzed
Suzuki−Miyaura Formation of Biaryl 6
the 1-N and 4-C positions. Examples include those reported by
95
̈
Dubrovnia, Borner and co-workers (Figure 4, 13), Gandel-
man and co-workers who prepared PCP′ pincer complexes
from bis-phosphinotriazoles (Figure 4, 14),96 and Kann and
Palladium-catalyzed cross-coupling reactions are well-stud-
ied and offer ready access to an extensive range of (bi)aryl
motifs (Scheme 1, 6).67−76 The suite of palladium-catalyzed
cross-coupling chemistry available for the construction of
biologically relevant products has transformed the field of
medicinal chemistry, yet cross-coupling between sterically
hindered and lead-like building blocks, particularly with aryl
chlorides, remains challenging.77
Developments in palladium-catalyzed chemistry have been
heavily influenced by ligand design and optimization. Among
the superior ligands for palladium-catalyzed cross-coupling
reactions are bulky alkyl phosphines,78−82 and bulky ortho-
substituted aryl-alkyl phosphines,83,84 such as S-Phos (Figure 3,
7)85 and X-Phos (Figure 3, 8).86 Metallocyclic precatalysts
have been developed which delivered greater stability, more
facile manipulation and enhanced reaction outcomes.87−89
Phosphines appended to one or more five-membered, all sp2
rings have been shown to offer advantages in some cases. The
pyrrole-appended phosphines of Beller and co-workers (Figure
3, 9)90,91 have proven to be useful ligands in cross-coupling
catalysis that furnishes drug-like products. Furthermore, the
bulky, electron-rich, ferrocene-appended phosphines of
Richards (Figure 3, 10),92 Johannsen (Figure 3, 11),93 Fu
(Figure 3, 12),94 and their respective co-workers provide
Figure 4. Phosphorus-containing 1,2,3-triazole derivatives.
B
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co-workers who used a borane-protected P-chiral azide to
deliver protected P-chiral triazole-containing phosphines
(Figure 4, 15).97 Since proximal stoichiometric phosphine
can arrest the CuAAC through coordinative saturation of
substoichiometic copper catalyst or unwanted Staudinger-type
reactions between phosphine and azide derivative, alternative
approaches are required to deliver P-appended triazoles. Zhang
and co-workers reported on the use of alkynyl Grignard
reagents for the synthesis of a phosphine series where
phosphorus is attached directly to a 1,2,3-triazole ring at the
4-position (Figure 4, 16).98−101 As part of an impressive,
rigorous, and detailed study, Balakrishna and co-workers
prepared not only expected aryl phosphine triazole derivative
17a (Figure 4) through lithium-halogen exchange and
subsequent reaction with diphenylphosphorus chloride on
the corresponding bromide under kinetic control but also
thermodynamically favored 5-phosphino triazole 18a (Figure
4) from the same aryl bromide starting material under different
conditions.102 Fukuzawa and co-workers also employed
deprotonation of the 5-position of a 1,2,3-triazole to facilitate
installation of 5-phosphino functionality in their ferroncenyl
bisphosphino ligand synthesis (Figure 4, 19).103 Glover et
al.104 and Austeri et al.105 also utilized deprotonation of the
triazole 5-position to create planar chiral cyclophane-
containing analogues of 18a. In order to successfully synthesize
a bis-5-phosphino-triazole bidentate ligand, Manoury, Virieux,
and co-workers employed an ethynyl phosphine oxide in their
homocoupled dimer synthesis, which after treatment with
trichlorosilane resulted in 20 (Figure 4).106 A structurally
related 5−18 hybrid system was also recently reported by Cao
et al., who showed the formation of bimetallic complexes of
NHC−phosphine mixed systems.107
Scheme 2. Reaction of 1,2,3-Triazoles 21a−d with n-
Butyllithium Followed by Treatment with Diphenyl
Phosphorous Chloride Led Primarily to Formation of
Phosphino-Triazole 18a
Bulky, or sterically hindered, phosphorus-containing ligands
have also found application outside of the palladium catalysis
arena; steric parameters appear to be important in a variety of
gold-mediated transformations.108−110 Steric and electronic
parameters of phosphine ligands have been a subject of study
for more than 40 years.111 More recent contributions have
built upon Tolman’s concept of cone angle as a descriptor of
the steric bulk a ligand imparts about a metal, resulting in a
parameter known as buried volume (%VBur) coming to the
fore.112 Cavallo and co-workers have developed a free web-
based tool for the calculation of %VBur, named SambVca.113
This parametrization of ligands, using both spectroscopic
measurements and calculated properties (using principle
component analysis for example), has facilitated exceptional
ligand design and optimization across a range of catalyzed
reactions.114−116
While a range of ligand-based solutions for cross-coupling
reactions exist, a platform to rapidly deliver alternatives and
explore chemical space around novel catalyst constructs, such
as through CuAAC, offers approaches and complementary
tools to the field. Furthermore, cross-coupling catalysis
manifolds that provide access to increasingly three-dimensional
products,117 and those directly delivering products with lead-
or drug-like properties118 without need of protecting group
removal or further derivatization are desired and less-well
explored.77
Figure 5. Representation of the crystal structures of isomeric 17a
(left) and 18a (right), ellipsoids drawn at the 50% probability level
(Ortep3 for Windows and PovRay). For 17a the structure contains
two crystallographically independent molecules with only one shown
for clarity. For 18a the phenyl-appended 1-nitrogen and 4-carbon
atoms of the triazole unit are disordered such that the triazole ring
occupies two opposing orientations, related by a 180° rotation of the
triazole ring about the phosphorus-triazole bond. The refined
percentage occupancy ratio of the two positions are 59.7 (15) and
40.3 (15); one arbitrary molecule depicted and hydrogen atoms
removed for clarity.
protection of the phosphine (as a phosphine oxide for
example)106 is possible, the initial approach chosen in this
program was to probe the potential for triazole-mediated
directed ortho-lithiation or halogen-lithium exchange, and
subsequent reaction with diphenyl phosphorus chloride, as
possible routes to phosphino-triazoles 17a−c. Accordingly,
1,4-diphenyl-1,2,3-triazole (21a) was selected as a model
substrate to test if ortho-lithiation could deliver the required
intermediate to give the desired product 17a. As such, 21a was
reacted at −78 °C with n-butyllithium, followed by addition of
the phosphorus chloride reagent, before being allowed to warm
to room temperature, and being allowed to stir for a period of
RESULTS AND DISCUSSION
■
In order to overcome the general incompatibility of
phosphines with the CuAAC reaction, an approach other
than direct phosphine incorporation is required. While
C
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Scheme 3. Previously Reported Kinetic (Upper) and
Thermodynamic (Lower) Lithiation and Subsequent
Phosphorous Addition to Brominated Triazole 22a
Affording P-Aryl and P-Triazole Derivatives, Respectively
Table 1. Ligand Screening: 1,4-Disubstituted 1,2,3-Triazole-
Containing Phosphine Ligand Mediate, Palladium-
Catalyzed, Formation of 27
a
a
b
entry
R1
R2
R3
ligand
conversion [%]
1
2
3
4
5
6
7
8
17a
18a
18b
18c
18d
18e
18f
18g
18h
18i
29
47
62
75
86
69
83
92
90
84
92
91
99
Ph
Ph
Ph
Cy
Ph
Ph
Ph
Cy
Ph
Ph
Ph
Cy
H
H
H
H
Ph
i-Pr
Cy
Ph
Ph
Ph
Ph
Ph
Ph
Cy
Ph
Ph
a
Ref 102.
4-Me
Scheme 4. CuAAC Reaction to Form 1,4-Disubstituted
1,2,3-Triazole Derivatives 21a−i
4-OMe
2,6-OMe
2,6-OMe
2-Ph
2-Ph
2-Napth
9
10
11
12
13
18j
18k
18l
e
e
2-Napth
a
Reaction conditions: 2-bromo-m-xylene (0.4 mmol), o-tolylboronic
acid (0.6 mmol), potassium phosphate (1.2 mmol), Pd2(dba)3 (0.5
b
mol %), ligand (2 mol %), toluene (3 mL), 10 h, 90 °C. Conversion
1
determined by inspection of the corresponding H NMR spectra of
crude reaction isolates. See the Supporting Information for details.
e
Meaning derived from naphthyl azide.
Scheme 5. Deprotonation and Subsequent Reaction with
Phosphorous Chloride Reagent Protocol for Delivery of
18a−l
Figure 6. Electrostatic potential charges as determined by Gevorgyan
and co-workers,19 indicates rationale for selective C-5 deprotonation.
Scheme 6. Trimethylsilylacetylene (23c) and Aryl Azides
(24a−i) React under Desilylative CuAAC Reaction
Conditions to Deliver 1-Substituted 1,2,3-Triazoles (28a−i)
time. Over numerous attempts only the unanticipated product
18a was isolated from such reactions, Scheme 2. This indicates
that deprotonation of the 5-position of the triazole is facile,
resulting in formation of the observed major product. In order
to mitigate against the formation of unanticipated triazole-
phosphine 18a, brominated triazole derivatives 22a−c were
employed under a similar protocol, with varying amounts of n-
butyllithium. In all cases, the same 5-phosphino-triazole
product, 18a, was obtained, shown in Scheme 2. In the case
of 22a, it was possible to isolate small quantities of the desired
D
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Scheme 7. Deprotonation of 1-Aryl 1,2,3-Triazole
Derivatices and Subsequent Reaction with Phosphorous
Chloride Reagent Protocol for Delivery of 29a−n
Table 2. Ligand Screening: 1-Substituted 1,2,3-Triazole-
Containing Phosphine Ligand Mediated, Palladium-
Catalyzed, Reaction of Arylbromide 25 in the Formation of
27
ab
,
entry
R1
R2
Ph
Cy
Ph
Ph
Ph
i-Pr
Cy
t-Bu
Ph
Ph
Ph
ligand
29a
29b
29c
29d
29e
29f
29g
29h
29i
29j
29k
29l
29m
29n
S-Phos (7)
X-Phos (8)
conversion [%]
1
2
3
4
5
6
7
8
H
H
20
98
54
28
90
99
99
98
82
29
83
51
99
99
98
99
4-Me
4-OMe
2,6-OMe
2,6-OMe
2,6-OMe
2,6-OMe
2-Ph
9
c
10
11
12
13
14
15
16
C4H4
4-CF3
3,5-OMe
2,6-i-Pr
2,6-i-Pr
Ph
Cy
t-Bu
a
Reaction conditions: 2-bromo-m-xylene (0.4 mmol), o-tolylboronic
acid (0.6 mmol), potassium phosphate (1.2 mmol), Pd2(dba)3 (0.5
mol %), ligand (2.0 mol %), toluene (3 mL), 10 h, 90 °C.
b
Conversion determined by inspection of the corresponding 1H NMR
spectra of crude reaction isolates. See the Supporting Information for
c
details. Derived from 2-naphthyl azide.
Table 3. Ligand Screening: 1-Substituted 1,2,3-Triazole-
Containing Phosphine Ligand Mediated, Palladium-
Catalyzed, Reaction of Arylbromide 30 in Formation of 32
Figure 7. Representation of the crystal structure of 29g, ellipsoids
drawn at the 50% probability level (Ortep3 for Windows and
PovRay), hydrogen atoms omitted for clarity.
product 17a. X-ray crystal structures of both 17a and 18a were
determined as shown in Figure 5.
In fact these observations should not have been at all
unanticipated.102,104 The aforementioned report of Balakrishna
and co-workers had previously probed the reaction of 17a in
more detail than us under analogous conditions102 and
determined a “kinetic” and “thermodynamic” relationship
between lithium-halogen exchange alone, versus lithium-
halogen exchange followed by lithium (triazole-) proton
exchange leading to products 17a and 18a respectively,
Scheme 3.
Attempts to block the triazole 5-H position, using the
deuterium masking approach deployed by Richards and co-
workers in the preparation of ferrocene derivatives,119 did not
dramatically modify reaction outcomes in our hands. Variously
deuterated products were always obtained from attempted
lithiation-mediated access to products under routine con-
ditions.
ab
,
entry
ligand
29g
29g
29h
29m
29n
S-Phos (7)
X-Phos (8)
conversion [%]
1
2
3
4
5
6
7
99
84
47
60
13
87
50
c
a
Reaction conditions: 2-bromomesitylene (0.5 mmol), 2,6-xylylbor-
onic acid (1.0 mmol), potassium phosphate (2 mmol), Pd2(dba)3 (2.0
mol %), ligand (8.0 mol %), toluene (3 mL), 18 h, reflux.
Determined by GC analysis with n-dodecane as internal standard.
b
Since the scope of 18a-like ligands had not been investigated
beyond the three triazole backbones reported by Glover et
c
Pd2(dba)3 (0.5 mol %), ligand (2 mol %).
E
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Table 5. Ligand Screening: 1-Substituted 1,2,3-Triazole-
Containing Phosphine Ligand Mediate, Palladium-
Catalyzed, Reaction of Arylchloride 37 in Formation of 32
ab
,
entry
ligand
29g
29m
S-Phos (7)
X-Phos (8)
conversion [%]
1
2
3
4
49
37
55
5
a
Reaction conditions: 2-chloro-m-xylene (0.5 mmol), 2,4,6-trimethyl-
phenylboronic acid (1.0 mmol), potassium phosphate (2 mmol),
Pd2(dba)3 (2.0 mol %), ligand (8.0 mol %), toluene (3 mL), 18 h,
reflux. Determined by GC analysis with n-dodecane as internal
Figure 8. Ligands compared in Table 3 and Table 4.
b
standard.
Table 4. Ligand Screening: 1-Substituted 1,2,3-Triazole-
Containing Phosphine Ligand-Mediated, Palladium-
Catalyzed, Reaction of Arylchloride 37 in the Formation of
27
Scheme 8. Percentage Homo-Coupled Product 36 under
Described Reaction Conditions Using 50% Excess Boronic
Acid 34
a b
,
entry
ligand
29g
29g
29h
29m
29n
S-Phos (7)
X-Phos (8)
conversion [%]
isolated yield [%]
1
2
3
4
5
6
7
99
99
99
99
70
33
99
93
92
82
92
c
25
90
of 2-bromo-m-xylene (25) and ortho-tolylboronic acid (26)
under standard conditions (1 mol % palladium, 2 mol % ligand,
three equivalents of base, 10 h, toluene, 90 °C, see the
Supporting Information) was compared. The catalyzed
formation of compound 27 represents a challenging but
achievable cross-coupling: While an aryl bromide is employed
in the reaction, the product (a triply ortho-substituted biaryl) is
sterically congested about the formed bond. Diphenyl aryl
phosphine 17a and 5-phosphino triazoles 18a−l were
employed as ligands in the benchmark reaction (Table 1).
The use of 17a as ligand (Table 1, entry 1) resulted in 29%
conversion to product 27. The 5-phosphino isomer of 17a,
18a, also gave less than 50% conversion to desired product 27
in the same reaction (Table 1, entry 2). As may be expected,
switching the diphenylphosphine part of 18a to dialkylphos-
phine groups di-iso-propyl (18b) and dicyclohexyl (18c)
improved the reaction outcomes, resulting in 62 and 75%
conversion, respectively (Table 1, entries 3 and 4). Changing
the alkyne-derived part of the triazole from phenyl (18a) to
cyclohexyl (18d) gave a marked improvement delivering
product 27 in 86% conversion (Table 1, entry 2 versus 5).
a
Reaction conditions: 2-chloro-m-xylene (1.0 mmol), o-tolyboronic
acid (1.5 mmol), potassium phosphate (3.0 mmol), Pd2(dba)3 (0.5
mol %), ligand (2.0 mol %), toluene (3 mL), 10 h, 90 °C.
b
Determined by GC analysis with n-dodecane as internal standard.
c
Pd2(dba)3 (0.25 mol %), ligand (1.0 mol %).
al.104 and Choubey et al.,102 we chose to focus attention on
triazole 5-H lithiation to deliver a range of potential ligands for
cross-coupling catalysis. To this end, alkynes 23a and 23b
reacted smoothly with azides 24a−f to furnish 1,5-
disubstituted 1,2,3-triazoles 21a−i in acceptable to good
yields, shown in Scheme 4.
Applying the aforementioned triazole lithiation and
subsequent quench with dicyclohexyl-, di-iso-propyl-, or
diphenyl- phosphorus chloride reagent protocol to isolated
21a−i triazole set, with the express expectation of generating 5-
phosphino triazole derivatives, delivered 12 targeted phosphi-
no-triazoles 18a−l in acceptable to good yields (Scheme 5).
In order to benchmark the catalytic capability of ligands in
this report, the palladium-catalyzed Suzuki−Miyaura reaction
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Figure 9. Virtual Suzuki−Miyaura catalysis products generated and analyzed in the LLAMA web tool. Left: A log P versus molecular mass, Lipinski
and lead-like space indicated. Right: PMI plot, rod, disc, sphere axis. (See the Supporting Information for data tables.)
While good results were obtained in the Suzuki−Miyaura
cross-coupling reactions with 18-derived catalysts the more
effective ligands (generally larger) suffered somewhat from
poor solubility. Thus, ligand modifications that retained
activity but allowed for more ready synthesis and manipulation
at larger scale were sought. From briefly surveying the results
in Table 1 it was concluded that changes in the R1 (alkyne-
derived) part (e.g., entry 8 versus entry 9) were less influential
on the reaction outcome than changes in the R2 (azide-
derived) part (e.g., entry 5 versus entry 13). Reasoning that
smaller ligands may benefit from enhanced solubility and
tractability, a strategy to retain the N-substituents (azide-
derived parts) while minimizing the alkyne-derived parts was
chosen for further elaboration. Gevorgyan and co-workers have
already reported that 1,5-disubstituted 1,2,3-triazoles may be
accessed by selective reaction at the 5-position of 1-substituted
triazoles (Figure 6 shows the electrostatic potentials of the
triazole-carbons they determined), and coupled with the
synthetic strategies reported by Oki et al.103 for chiral
bisphosphine synthesis, this led to the conclusion that 1-
substitutued triazoles may be readily converted to a library of
1-substituted, 5-phosphino 1,2,3-triazoles
this orientation about a central five-membered ring describes a
relatively wide binding pocket for metals with potential for
arene-metal interactions alongside primary phosphorus−metal
ligation.
Ligands 29a−n were tested in the aforementioned bench-
mark Suzuki−Miyaura cross-coupling reaction of 25 with 26
catalyzed by a palladium−phosphine complex, to produce
biaryl 27 (Table 2, entries 1−14). Under the same conditions,
commercially sourced ligands, S-Phos (7) and X-Phos (8)
were also used for comparison (Table 2, entries 15 and 16,
respectively). Diphenyl-phosphino triazole derived ligands
failed to deliver product 27 in good yields, under the
conditions employed the best conversion for this ligand class
was only 54% (ligand 29c, Table 2, entry 3), whereas dialkyl-
phosphino triazoles gave universally excellent conversion, equal
to the commercially sourced S- and X-Phos in performance,
under these conditions.
While pleased to have created ligands offering good
performance in a benchmark reaction, the reaction itself did
not offer enough diversity of outcomes to evaluate dialkyl-
phosphino ligand performances against each other nor against
readily available commercial ligands 7 and 8. Next, a more
sterically demanding test-reaction was chosen to evaluate the
ligands further. The formation of biaryl C−C bonds where the
formed bond is flanked by four ortho-substituents presents a
particularly challenging yet attractive transformation, not in the
least due to the apparent three-dimensional nature of the cross-
coupled products.117 The reaction of bromide 30 with boronic
acid 31 was selected as one such reaction to probe catalyst
effectiveness (Table 3). Conversion to product 32 may be
monitored by gas chromatographic analysis, facilitating ready
comparison of reactions performed in parallel. Having given
quantitative conversions to product 27 (Table 2, entries 7, 8,
13, and 14), and being both relatively easy to synthesize and
available in sufficient quantities, ligands 29g, 29h, 29m, and
29n were selected for further investigation. These ligands are
triazole-analogues of leading phenylene ligands 7 and 8; thus,
in order to probe any specific advantages of triazole-core
ligands they were compared directly against S-Phos and X-
Phos phenylene ligands. (For retained and compared ligands,
see Figure 8.)
Following the optimized protocol of Oki et al.103 deployed
in the synthesis of more complex constructs, a range of 1-
substituted triazoles were synthesized. Specifically, trimethylsi-
lylacetylene (23c) and aryl azides (24a−i) were exposed to
CuAAC reaction conditions (Scheme 6) that led to effective
triazole formation and desilylation in one pot. Acceptable to
good yields of 1-substituted triazoles 28a−i were isolated after
24 h room temperature reactions.
Triazoles 28a−i reacted smoothly under the deprotonation
and phosphorus chloride reagent quench reaction conditions
described earlier. Deprotonation at −78 °C, by treatment with
n-butyllithium, followed by addition of dicyclohexyl-, di-iso-
propyl-, di-tert-butyl- or diphenyl-phosphorus chloride at the
same temperature (Scheme 7) resulted in formation of the
desired triazole-containing phosphines 29a−n in acceptable to
good yields. The X-ray crystal structure of 29g was determined
(Figure 7); the orientation of the molecule (in the solid state)
is such that the lone pair of the phosphine is oriented to the
same direction as the 1-aryl substituent of the triazole. In turn,
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(Table 3, entry 2), and under these conditions, a conversion of
84% to 32 was achieved.
Scheme 9. Microwave-Heated Synthesis (1 h) of 10 Lead-
like Compounds by Suzuki−Miyaura Cross-Coupling
Reactions Using 2 mol % Palladium and 4 mol % Ligand
29g
To further probe the utility of 1-aryl 5-phosphino 1,2,3-
triazoles as ligands in Suzuki−Miyaura catalysis the synthesis of
compound 27 from aryl chloride 37 and boronic acid 26 was
investigated (shown in Table 4) deploying the same ligand set
as in Table 3. The reaction conditions mirrored those used
earlier for cross-coupling with bromide analogue 25 in Table 2,
but in order to ensure good reaction conversions the reaction
temperature was increased slightly (toluene at reflux).
Under the reaction conditions employed (Table 4), catalysts
derived from triazole-containing ligands 29g, 29h, and 29m
delivered compound 27 in quantitative yield (Table 4, entries
1, 3, and 4, respectively). Using 29g as ligand at a lower
catalyst loading of 0.5 mol % of palladium proportionally,
quantitative conversion to 27 (isolated yield 92%) was
achieved. In this comparison, the use of S-Phos (7) as ligand
gave 33% conversion (Table 4, entry 6), and the use of X-Phos
(8) as ligand gave quantitative conversion (Table 4, entry 7) to
compound 27.
Next, a demanding palladium-catalyzed reaction between 2-
chloro-meta-xylene (37) and 2,4,6-trimethylphenylboronic acid
(38) leading to product 32 was attempted. Two triazole
ligand-based catalyst systems were compared against catalyst
systems derived from S-Phos (7) and X-Phos (8); see Table 5.
Under the conditions employed, the four catalyst systems
compared produced only moderate yields. That is not to say
that these reactions could not be optimized further, but the
side-by-side comparison revealed S-Phos (7) to be slightly
better than triazole-containing phosphine 29g (55 versus 49%
conversion; Table 5, entry 4 versus entry 1, respectively).
Slightly lower conversions were obtained when 29m or X-Phos
were used as ligands (Table 5 entries 2 and 4 respectively).
One potential problem with Suzuki−Miyaura catalyzed
reactions, particularly evident when using less reactive aryl
chlorides in cross-coupling, is homocoupling of the boronic
acid containing reaction partner.120 In order to test our routine
reaction protocols and our four selected triazole ligands (29g,
29h, 29m, and 29n) for their propensity to lead to undesired
homocoupled product, the following reaction was probed. Aryl
chloride 33 was reacted with 1.5 equiv of phenyl boronic acid
34. Catalyst loading was 2 mol % palladium and 4 mol %
ligand. The reactions were conducted in toluene at 90 °C with
3 equiv of potassium phosphate as base; see Scheme 8. Set up
like this, we can judge a reaction to be successful, i.e., not
suffering from an adventitious homocoupling side reaction
leading to product composition, if conversion of aryl chloride
33 is high (near 100%) and the amount of formed byproduct
36 is low. Choosing 1.5 equiv of boronic acid gives a chance
for the formation of 36, thus evidencing the cross- versus
homo-coupling potential of the ligands in the chosen Suzuki−
Miyaura reaction under the conditions described.
In order to ensure good reaction conversions, the catalyst
loading, temperature, and reaction time were all increased in
comparison to the earlier Suzuki−Miyaura reactions. The
standard conditions employed in the comparisons of Table 3
(entries 1 and 3−7) were 4 mol % palladium and 8 mol %
ligand in toluene at reflux for 16 h. Under these conditions,
cyclohexyl-substituted triazole-containing ligands 29g and 29m
gave higher conversions to 32 than did their tert-butyl-
substituted analogues 29h and 29n (Table 3, entries 1 and 4
(99 and 60%) versus entries 3 and 5 (47 and 13%),
respectively). In this comparison, the use of S-Phos (7) as
ligand gave 87% conversion (Table 3, entry 6) and the use of
X-Phos (8) as ligand gave 50% conversion (Table 3, entry 7)
to compound 32 (under these conditions). Since ligand 29g
gave the best conversion (under the conditions employed),
catalyst loading was reduced to 1 mol % palladium (in the form
of 0.5 mol % Pd2(dba)3) alongside 2 mol % 29g as ligand
All four of the tested ligands (Scheme 8, 29g, 29h, 29m, and
29n) gave good conversion to product 35 (ligands 29h and
29n leading to complete consumption of stating aryl chloride
33). In this case the apparently most bulky ligand, 29n,
performed best giving just 6% (mol/mol) homocoupled
product (36); the other three ligands gave rise to only slightly
elevated amounts of homocoupled side product (10−12%
(mol/mol)). Thus, demonstrating that under the conditions
employed, reaction protocols used throughout this study do
not suffer appreciably from loss of halide-containing starting
materials through unwanted homocoupling.
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Figure 10. Left: Mw vs A log P. Right: PMI analysis of products synthesized in Scheme 9.
Figure 12. Representation of the crystal structure of 43, ellipsoids are
drawn at the 50% probability level (Ortep3 for Windows and
PovRay). The structure contains two molecules of dichloromethane
per palladium complex (omitted for clarity).
Figure 11. Representation of the crystal structure of 42, ellipsoids are
drawn at the 50% probability level (Ortep3 for Windows and
PovRay). The structure contains a palladium complex, which is
located on an inversion center and two molecules of dichloromethane
per complex. Only half of the complex and one dichloromethane
molecule are unique. Pd···P bond lengths 2.322(9) Å. 2,6-Bismethoxy
aryl-centroid···Pd 3.843(2) Å. Symmetry code used to generate
equivalent atoms: 1 − x, −y, −z.
Lead-like Compounds. While the results discussed thus
far have exemplified the effectiveness of ligands 29g and 29m
to catalyze sterically demanding cross-coupling reactions, the
ability to catalyze the cross-coupling of functionalities relevant
to medicinal chemistry, to give lead- and drug-like products
remains a critical need in the agrochemical and pharmaceutical
sectors.77 To this end, a range of bis-aromatic products,
containing motifs of the type that are commonly encountered
in medicinal chemistry,121−123 were identified, and their
synthesis embarked upon. The products of virtual Suzuki−
Miyaura cross-couplings of 48 aromatic halides (iodides,
bromides, or chlorides) and 44 aromatic boronic acids (or
esters) from (i) a collection held within the lead research
group; (ii) those curated within the University of Birmingham
Figure 13. Steric map of phosphine-palladium complex: Derived from
crystal structure of free ligand 29g with a P−Pd distance of 2.280 Å
applied, resulting in a 47.0%Vbur
.
Scaffold Diversification Resource;124 and (iii) drawn from a
boronic acid collection via the GSK Free Building Blocks
resource; were enumerated and analyzed by the online
resource LLAMA (Figure 9).118
The open-access web tool LLAMA allows the user to
conduct virtual reactions and analyze the virtual product library
for molecular properties such as molecular weight, A log P, and
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Figure 14. (i) Chemical structure of part of the crystallographically determined complex 42, with a 2.323(2) Å Pd−P distance (from the crystal
structure) used in the calculation of buried volume, 36.2%Vbur. (ii) Chemical structure of the bond-length-modified, crystal-structure-informed
palladium complex of ligand 29e in complex 42 (2.280 Å Pd−P distance was used in the buried volume calculation), 36.9%Vbur
.
the library of virtual Suzuki−Miyaura cross-coupled products.
A PMI plot describes the 3D shape of the lowest energy
conformation of a compound on a triangular plot. The upper
left corner represents rod-like compounds, the bottom corner
represents disc-like compounds, and the upper right corner
represents spherical compounds. This analysis shows that the
majority of the virtual library resides close to the rod−disc axis,
representing flat compounds.
From the 1661 virtual compounds constructed within the
LLAMA tool, 14 possible products that accessed preferable
lead-like chemical space and were selected for testing 29g-
mediated Suzuki−Miyaura cross-coupling reactions, as in
Scheme 9. In this case, the screening conditions involved
microwave heating in a sealed-tube at 100 °C in acetonitrile for
just 1 h. The possible products include challenging
heteroatom-containing and/or ortho substituents, representing
both a set of possible products displaying favorable character-
istics for drug discovery and a robust challenge for road-testing
our best new ligand, 29g.
Figure 15. Protocol for obtaining structures for comparison of steric
parameters via an unrestricted (right) and a dihedral angles restricted
model (left). In both cases, a phosphine oxide model was minimized
using Spartan’16 and the PO later replaced with a P−Pd bond of
2.280 Å. The structures thus obtained were then analyzed by the
SambVca2.0 free web tool to determine the %Vbur and to create a
steric map.
Pleasingly, most of the reactions attempted gave greater than
50% isolated yield of these challenging cross-coupled products
(41a−j); however, 2-bromo-1-methyl-1H-imidazole 39g and
(3,5-dimethylisoxazol-4-yl)boronic acid 40g failed to deliver
detectable amounts of desired cross-coupled products in four
test scenarios under the conditions employed.
To determine the utility of the products created in this
analysis, they were analyzed using the LLAMA web tool to
determine their suitability as lead-like compounds (Figure 10).
Figure 10 (left), shows how products 41a−j explore the drug-
like space, with all products lying within the Lipinski space
(Mw < 500, A log P < 5) and a significant proportion lying
within the lead-like space (40% of the synthesized com-
3D character. Figure 9 left shows the full virtual library of 1661
compounds created from the virtual Suzuki−Miyaura cross-
coupling of the boronic acids and aryl halides described above.
It shows that while the majority of these virtual products fall
within Lipinkski space (Mw < 500, A log P < 5) only ∼20% lie
within lead-like space as defined by Churcher et al. (200 < Mw
< 350, A log P < 3). This fact is illustrated by the lead-likeness
penalty scores of these compounds, which have an average of
3.47. This penalty scoring system was developed by the
creators of LLAMA to visualize how far away from ideal lead-
likeness a compound may be and incorporates all determined
molecular properties into one score. Figure 9 (right side)
shows the PMI analysis of the same 1661 virtual compounds in
Figure 16. (i) Chemical structure and computationally determined steric map and buried volume, structures derived in silico and calculated with
restricted dihedral angles as describe in Figure 15 (left), 44.2%Vbur. (ii) Chemical structure and computationally determined steric map and buried
volume of structures derived in silico and calculated without any dihedral restrictions as describe in Figure 15 (right), 47.3%Vbur
.
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Figure 17. SambVca2.0 derived %Vbur and steric maps for the: (a) left side: (i) 29g; (ii) 29h; (iii) 29n; (iv) 29m; (v) 7 S-Phos; (vi) 8 X-Phos,
derived palladium complexes of structures derived in silico and calculated with restricted dihedral angles as describe in Figure 15 (left); (b) right
side: (i) 29g; (ii) 29h; (iii) 29n; (iv) 29m; (v) 7 S-Phos; (vi) 8 X-Phos, derived palladium complexes of structures derived in silico and calculated
without any dihedral restrictions as describe in Figure 15 (right).
pounds). This illustrates the potential for this catalyst system
to access both drug- and lead-like chemical space. Figure 10
(right) shows a PMI analysis of products 41a to j, this analysis
demonstrates a capability of this catalyst system to access
nonflat Suzuki−Miyaura cross-coupled products.
These 10 compounds are now under evaluation for biological
activity across a range of targets.125
Palladium Complexes. During the course of this study
numerous attempts to grow crystals of palladium-phosphine
complexes suitable for single crystal X-ray diffraction were
made. Thus far, two attempts to generate X-ray quality crystals
of palladium phosphine complexes have been achieved, using
ligands 29e and 29h with palladium(II) chloride.
These analyzes show that these compounds can be described
as high-quality starting points for drug discovery programs.
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Table 6. Calculated (Spartan v16 and SambVca2.0) Steric Properties of 29e, 29g, 29h, 29m, 29n, S-Phos 7, and X-Phos 8
Vbur calcd [%]
Vbur calcd [%]
Ar centroid−Pd distance [Å]
Ar centroid−Pd distance [Å]
entry
ligand
29e
29g
29h
29m
29n
7 (S-Phos)
8 (X-Phos)
(restricted)
(unrestricted)
(restricted)
(unrestricted)
a
a
1
2
3
4
5
6
7
44.2 (36.2)
45.5 (46.9)
47.3
49.6
50.1
48.0
53.3
55.4
3.363 (3.843(2))
3.403 (3.457)
4.176
3.745
3.580
3.901
3.794
3.253
b
b
47.8
47.1
47.5
50.8 (49.7)
53.3 (53.1)
3.558
3.639
3.647
3.127
3.309
c
c
53.2
3.481
a
b
c
Measured from the unadjusted XRD structure of 42. Using free ligand 29g XRD and applying Pd−P bond length 2.280 Å. Refers to ligand/
metal 1:1 complex P-M distance 2.8 A (M = Au).112,129
about a trans-dichloride palladium(II) metal center. Since
ligand 29h functions as expected in the aforementioned
catalyzed reactions, it is suggested that a more crystalline and
readily formed (kinetic) complex is formed under the
crystallization conditions employed. However, that this stable
complex is formed reminds us of another potentially important
feature of the triazole-core ligands, namely, a rear-side ancillary
coordination point. It is conceivable that the ancillary nitrogen
may offer some advantages in some catalyzed reaction, such as
aggregation suppression for example. Suffice it to say, the
sterically encumbered phosphine face of ligand 29h, as
evidenced by the isolation of 43, bodes well for understanding
differing catalysis modes of action on steric rationales as well as
opportunities for divergence from phenylene core ligands.
Describing Phosphines. There is a growing body of
literature discussing the importance of various parameters
including steric effects116 of bulky phosphines83,84,126 relating
to suitability and efficacy in catalysis (primarily as ligands for
metals in metal mediated catalysis).108,115,127 While the
Tolman cone angle has been an effective descriptor of ligand
bulkiness for many years,111 it has been complimented more
recently by Nolan’s percentage buried volume parameter (%
Figure 18. Conversion to 27 (see Table 2) versus computed burried
volume (%) as determined by the protocol discussed in Figure 15.
V
bur).112 The %Vbur of ligands can be calculated using the
The combination of 29e and trans-Pd(CH3CN)2Cl2 in
dichloromethane at room temperature led to the formation of
material that was precipitated by addition of pentane and the
residue thus obtained was recrystallized from dichloromethane
and hexane. A representation of the single crystal XRD
structure of the palladium complex (42) thus obtained is
depicted in Figure 11. A 2:1 ligand/metal square planar trans
dichloride palladium(II) complex 42 was identified. Complex
42 may offer insight into the structural features of 29 series
complexes as catalysts. The five-membered 1,5-disubstituted
1,2,3-triazole core presents the triazole 2,6-bismethoxy aryl
fragment oriented toward the metal with an aryl-centroid···Pd
distance of 3.843(2) Å, in this solid-state structure. The
triazole phosphine ligand offers a distinct geometric difference
to phenylene core ligands (c.f., S-Phos and X-Phos, Figure 3),
being more akin to other five-membered ring core ligands (c.f.,
9 and 10, Figure 3), generating a slightly wider metal-binding
pocket while still offering a stabilizing shield about the metal
center.
The combination of 29h and trans-Pd(CH3CN)2Cl2 in
dichloromethane at room temperature led to the formation of
material that was precepted by addition of pentane and
recrystallized from dichloromethane and hexane. A representa-
tion of the single crystal XRD structure of the palladium
complex (43) thus obtained is depicted in Figure 12. To our
surprise, the XRD crystal structure shows 29h functioning as a
3-N-coordinating ligand, with two such ligations are present
SambVca (2.0) free web tool from Cavallo and co-work-
ers;113,128 so we set about determining some steric parameters
of our phosphines using this tool.
First, the crystal structure of the free ligand 29g was
investigated, as follows: The PDB file corresponding to the
XRD crystal structure of ligand 29g was edited in Spartan’16
Parallel Suite (Wave function Inc.) by changing the valence of
phosphorus to four and adding a palladium atom with a
standard bond length of 2.280 Å to generate a metal-
coordinated model. The PBD file thus generated was not
minimized or edited further, i.e., the atoms of the ligand
remained in their crystallographically determined free-ligand
position, and uploaded for analysis to the SambVca2.0 web
tool for analysis. The added palladium atom was set as the
center and then deleted; a summary of this analysis is shown in
Figure 13. A steric map generated from this analysis is shown
and a 47.0%Vbur was calculated, using otherwise default
SambVca settings.
Following this analysis, the only palladium phosphine
complex thus far successfully analyzed by single crystal X-ray
diffraction studies (42) was investigated in a similar manner.
Compound 42 is a square planar palladium(II) complex of
ligand 29e and as such does not necessarily represent the
catalytically relevant species, the determined %Vbur of 36.2%
(Figure 14i) may not be the best comparator across a number
of ligand structures, so three other forms of the complex were
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generated and compared. In order to find an appropriate
comparison to fairly evaluate relative steric parameters of
ligands 29e and 29g. The ligand portion of the crystal structure
of 42 was edited in Spartan’16 Parallel Suite, the Pd−P bond
length adjusted to 2.280 Å, and the SambVca-determined %
than the 2.280 Å P−Pd distances imposed throughout). It is
interesting and confounded our expectations that the
unrestricted geometry-minimized structures give a higher
buried volume than the restricted dihedral angle structures
(Figure 17 column a versus column b). Among the two data
treatments, there is broad agreement with and relative
similarity to each other. While the geometry-unrestricted
structures of triazole ligands bear a striking resemblance (by
rudimentary visual inspection) to any XRD-derived structures,
the buried volume determinations of previously reported S-
and X-Phos (by the PO minimization proxy discussed
earlier) complexes more closely match the geometry-restricted
models we employed (Table 6, entries 6 and 7).
Vbur of 36.9% (Figure 14ii) was essentially the same as that for
the slightly longer, crystallographically determined, Pd−P bond
length in the earlier analysis. Since a model to allow for
comparison of ligands where crystallographically determined
data is not available was ultimately sought two further analyses
were conducted.
Sigman and co-workers have previously used phosphine
oxides as computational models for structural minimization
proxies of ligand−metal complexes,115 so it was reasoned that
computational minimization of in silico generated phosphine
oxides may be a sensible starting point to allow for comparison
among some of the ligands in this report. Two approaches
were compared for optimizing and computationally determin-
ing the %Vbur of ligand 29e (summarized in Figure 15) using
Spartan’16 Parallel Suite. In one case a phosphine oxide
structure with no geometric restrictions was used (Figure 15,
right); in the second case, the dihedral geometries of atoms 1−
6 were restricted presenting the ligand’s ancillary aryl group
directly and orthogonally aligned to the coordination vector of
the phosphine (the P−O bond in this minimization), as shown
in (Figure 15, left). Through comparison of the geometry
unrestricted and geometry restricted protocols, with the
structurally determined geometry (as shown in Figure 13) a
protocol for analysis across the ligands of this report might be
reasonably determined. In both cases the same minimization
and optimization cascade was adopted; the structures used for
computationally determined %Vbur calculations were obtained
as follows. First, molecular mechanics (MMFF) conformer
distribution (1000 max conformers) and subsequent molecular
mechanics equilibrium geometries were ranked, and the 20
lowest energy conformers were retained for DFT investigation.
The 20 retained conformers’ equilibrium geometries were used
as starting points for ground-state, gas phase equilibrium
geometry determination (B3LYP 6-31G*). The lowest energy
structure thus obtained was then edited to replace the oxygen
(of the phosphine oxide) with a palladium atom and a standard
P−Pd bond length of 2.280 Å was applied (Figure 15, center).
The procedure outlined in Figure 15 was first applied to
ligand 29e, and buried volumes of 44.2 and 47.3% were
determined for the restricted and unrestricted geometries,
respectively (Figure 16) and compared to the buried volume
determined crystallographically. While this protocol gives
slightly higher values, the restricted geometry model is more
closely aligned to the XRD-derived model than the
unrestricted one. With this information alone, it is difficult to
ascertain if any one model provides a superior approach for
assessing ligands where solid state data is not available.
Furthermore, it should be remembered that the 42-derived %
Vbur numbers are from solid-state structures and might not
offer the best cross-ligand comparison. As such, the most active
ligands of our study were examined using both protocols
shown below (Figure 17).
From the steric maps of Figure 17, it was noted that the
space between the dark red bulky zone (to the left of the steric
maps arising from the ancillary aryl groups of all ligands)
protrudes in a manner to give more space between the central
axis and red zone. Since space near the coordination site may
be crucial in permitting reaction with bulky substrates, we also
report the distance between the ancillary aryl group’s centroid
and the computed metal center (Table 6) for both the
geometry-restricted and unrestricted ligands of Figure 8 are
also listed in Table 6 (and contrasted against the data
determined for ligand 29e). In Entry 2 the data arising from
analysis of the previously detailed ligand crystal-structure-
determined structures of 29g−complexes are given in
parentheses. Between the restricted and unrestricted models
of ligand−complex analysis, the centroid distance correlates
more closely with the dihedral angle restricted model of a
29g−Pd complex.
It is notable that the PO ligand minimization protocol
adopted gives good structural parameter agreement between
those determined for palladium complexes of ligand 29g both
derived computationally and from a modified XRD structure of
free ligand 29g (Table 6, entry 1). By analyzing 29a−n side-
by-side using the same restricted dihedral angle minimization
protocol (up to 10 conformers analyzed by DFT methods
abbreviating the earlier minimization cascade for newly
analyzed ligands) and plotting the computed %Vbur values
against conversion to 27 (data from Table 2), as shown in
Figure 18, it can be seen that a strong bulkiness versus
conversion trend exists. Essentially any %Vbur value above 46%
leads to quantitative conversion to products, under the
prescribed conditions.
Further analysis of the data obtained for conversion in
reactions catalyzed by 29 ligands is only against smaller data
sets, and significant correlations of variances in conversions do
not lead to any meaningfully comparable correlations.
However, further study of cross-couplings of very bulky aryl
chlorides may be warranted in the future since an intriguing
balance between bulk and centroid distance is suggested (see
the Supporting Information), but across only four data points
surveyed to date, it may be too early to draw conclusion yet.130
A pre-peer-reviewed preprint of this article was deposited and
may be viewed elsewhere.131
CONCLUSIONS
■
Computed structures, percentage buried volumes, and steric
maps of the six ligands of Figure 8, following the protocol
outlined in Figure 15, are shown in Figure 17. The left side
shows the information relating to restricted dihedral angle
restricted complexes and the right side shows the structures
obtained without imposing any geometrical restrictions (other
Two series of 1,2,3-triazole-containing 5-phosphino ligands
were synthesized and tested as ligands in palladium catalyzed
cross-coupling Suzuki−Miyaura reactions of bulky and
heteroatom-containing substrates. The structural parameters
of the 4-H triazole series (29) were determined by a restricted
dihedral angle, phosphine oxide surrogate model, and a strong
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dependence upon bulkiness and catalytic activity were noted.
Furthermore, a link to the space between the metal and the
ancillary aryl group in the computed complexes was noted,
suggesting bulkiness of ligand and space around the metal may
both be implicated in delineating trends in cross-coupling of
the most bulky and challenging substrates. Notably, triazole-
nitrogens’ may not be completely innocent in the coordination
environment created by these ligands, with a nitrogen
coordination complex being characterized by XRD in one
case. The ligands synthesized were benchmarked against
commercially available ligands (X- and S-Phos) and in some
cases the best triazole ligands match or outperformed them
under the employed conditions, in like-for-like tests in
triplicate. The phosphine ligands reported and characterized
in this report represent easy to modify catalytic scaffolds that
could be use in future library generation efforts and we are
looking forward to facilitating access to these compounds and
allowing others to include this type of ligand in their own
catalyst screening campaigns.
analyzing and preparing for publication single crystal XRD
data, writing aspects of the main text and ESI and training
oversight of Y.Z. in aspects of XRD data collection and
analysis; H.v.N. conducted all the experiments of Scheme
offered additional advice and wrote aspects of the ESI; Y.Z. co-
9,
conceived aspects of the project, conducted all ligand synthesis
9
and all-bar the Scheme reactions, wrote aspects of the main
text, drafted a large proportion of the ESI, offered critical
suggestions, under the mentorship of L.M. conducted some of
the XRD data collection and analysis.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
J.S.F., Y.Z., P.C., H.v.N., and L.M. thanks the University of
Birmingham for support. J.S.F. acknowledges the CASE
consortium for networking opportunities.132,133 B.R.B. thanks
Loughborough University and Research Councils UK for a
RCUK Fellowship. J.S.F. thanks the Royal Society for an
Industrial Fellowship and the EPSRC for funding (EP/
J003220/1). Dr. Chi Tsang and Dr. Peter Ashton are thanked
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.organo-
met.8b00539.
■
S
́
for helpful discussions about mass spectrometry. Dr. Cecile S.
Le Duff is thanked for advice on NMR spectroscopy. Helena
Dodd is thanked for providing an initial data analysis and
presentation app for MatLab. J.S.F. and B.R.B. acknowledge
the support of a Wellcome Trust ISSF award within the
University of Birmingham. J.S.F. and H.v.N. are thankful for
the support of the NEURAM H2020 FET Open project
712821. All investigators are grateful for a Royal Society
Research Grant (2012/R1) that underpins this project. The
GSK free building block programme furnished a collection of
boronic acids from which 40a was sourced. The University of
Birmingham Scaffold Diversification Resource is gratefully
acknowledged for providing access to a collection of
compounds from which 39a−f and 40b−f were sourced.
Experimental procedures, spectral data, additional
information, XRD collection parameters and CCDC
deposit numbers (PDF)
Underpinning data of Figure 9 generated by LLAMA
(PDF)
Accession Codes
CCDC 1856208−1856212 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
REFERENCES
■
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AUTHOR INFORMATION
Corresponding Author
*E-mail: j.s.fossey@bham.ac.uk.
■
ORCID
(3) Lewis, W. G.; Green, L. G.; Grynszpan, F.; Radic, Z.; Carlier, P.
R.; Taylor, P.; Finn, M. G.; Sharpless, K. B. Click chemistry in situ:
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Yiming Zhao: 0000-0003-2827-6511
Huy van Nguyen: 0000-0002-3985-1510
Louise Male: 0000-0002-8295-2528
Philip Craven: 0000-0002-7617-132X
Benjamin R. Buckley: 0000-0002-8028-0828
John S. Fossey: 0000-0002-2626-5117
Author Contributions
All authors contributed to the preparation of the manuscript,
specific contributions in addition to this are listed for each
coauthor in alphabetical order: B.R.B. helped direct aspects of
the research, initiated some of the steric parameter analysis and
gave input and critical assessment throughout the progress of
the project; P.C. analyzed molecular property analysis through
use of LLAMA and wrote aspects of the manuscript and ESI
pertaining to this aspect; J.S.F. led and coconceived the
project, providing critical assessment of data, day-to-day
project management and oversight, directed all aspects
throughout, supervised the experimental work and wrote the
majority of the manuscript; L.M. is responsible for collecting,
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