Modular bismacycles for the selective C–H arylation of phenols and naphthols

Article abstract of DOI:10.1038/s41557-020-0425-4

Given the important role played by 2-hydroxybiaryls in organic, medicinal and materials chemistry, concise methods for the synthesis of this common motif are extremely valuable. In seeking to extend the lexicon of synthetic chemists in this regard, we have developed an expedient and general strategy for the ortho-arylation of phenols and naphthols using readily available boronic acids. Our methodology relies on in situ generation of a uniquely reactive Bi(v) arylating agent from a bench-stable Bi(iii) precursor via telescoped B–to–Bi transmetallation and oxidation. By exploiting reactivity that is orthogonal to conventional metal-catalysed manifolds, diverse aryl and heteroaryl partners can be rapidly coupled to phenols and naphthols under mild conditions. Following arylation, high-yielding recovery of the Bi(iii) precursor allows for its efficient re-use in subsequent reactions. Mechanistic interrogation of each key step of the methodology informs its practical application and provides fundamental insight into the underexploited reactivity of organobismuth compounds.

Full text of DOI:10.1038/s41557-020-0425-4

Articles
https://doi.org/10.1038/s41557-020-0425-4
Modular bismacycles for the selective C–H
arylation of phenols and naphthols
Mark Jurrat1,2, Lorenzo Maggiꢀ ꢀ1,2, William Lewisꢀ ꢀ2,3 and Liam T. Ballꢀ ꢀ1,2
ꢀ✉
Given the important role played by 2-hydroxybiaryls in organic, medicinal and materials chemistry, concise methods for the
synthesis of this common motif are extremely valuable. In seeking to extend the lexicon of synthetic chemists in this regard,
we have developed an expedient and general strategy for the ortho-arylation of phenols and naphthols using readily available
boronic acids. Our methodology relies on in situ generation of a uniquely reactive Bi(v) arylating agent from a bench-stable
Bi(iii) precursor via telescoped B–to–Bi transmetallation and oxidation. By exploiting reactivity that is orthogonal to conven-
tional metal-catalysed manifolds, diverse aryl and heteroaryl partners can be rapidly coupled to phenols and naphthols under
mild conditions. Following arylation, high-yielding recovery of the Bi(iii) precursor allows for its efficient re-use in subsequent
reactions. Mechanistic interrogation of each key step of the methodology informs its practical application and provides funda-
mental insight into the underexploited reactivity of organobismuth compounds.
he 2-hydroxybiaryl motif forms the core of numerous biologi- cross-coupling and C–H arylation strategies rely on activation of a
cally and synthetically important molecules (Fig. 1a). This carbon–halogen bond, resulting in chemoselectivity issues for poly-
T
includes more than 4,000 natural products, many of which halogenated substrate combinations. Thus, there is still an unmet
possess antimalarial, anti(retro)viral or cytotoxic properties1–4
.
need for expedient, user-friendly ortho-arylation methods that can
The frequency with which 2-hydroxybiaryls occur in functional be applied directly to unmodified hydroxyarenes. Here we report
molecules reflects the well-defined steric profile that results from the development of modular arylbismuth(v) reagents as a general
the rigid biaryl axis (a feature that has been exploited routinely in solution to this challenge.
1,1′-bi-2-naphthol-derived asymmetric catalysts5,6) and the hydro-
Pioneered by Barton and co-workers in the 1980s, Bi(v)-
gen-bonding abilities that are conferred by the phenolic hydroxyl mediated oxidative arylation of phenols and naphthols does not
group. Phenols constitute the most common type of hydroxyl in require prefunctionalization of the substrate (Fig. 1b)27–30. This
synthetic drugs,7 and the combined rigidity and hydrogen-bonding methodology benefits further from the low cost of bismuth and its
properties of the 2-hydroxybiaryl moiety have been implicated in salts, as well as the high stability and low toxicity of triarylbismuth
the bioactivity of both natural8 and synthetic9 therapeutics. Phenolic reagents (for example, LD50(BiPh3)=180gkg–1 (ref. 31). However,
hydroxyls are better hydrogen-bond donors and poorer hydrogen- despite these appealing attributes, the synthetic potential of both
bond acceptors than aliphatic alcohols, and the donicity of this Bi(v) and Bi(iii)32 reagents for C–H arylation has been largely over-
function can be modulated both by substitution of the phenolic ring looked. This is due to several major challenges that limit its current
itself10, and also by through-space interactions with the flanking practicality (Fig. 1b), including:
aromatic ring11. The ability of chemists to access diverse 2-hydroxy-
a. the poor availability of arylbismuth reagents, which necessitates
biaryls therefore enables precise modulation of the properties and
their multistep synthesis;
ultimately the function of this important motif.
b. the ofen unpredictable, substrate-controlled chemoselectivity
Given the broad significance of 2-hydroxybiaryls, methods
between Cortho- versus O-arylation;
for their preparation are highly valued and have been the subject
c. the waste associated with transfer of just one of the three aryl
of much research effort. The most widely used strategies involve
groups available in Ar3BiX2; and
metal-catalysed arylation of a hydroxyarene-derived substrate via
d. the lack of systematic studies of reaction scope or mechanism,
either cross-coupling12 or C–H functionalization13–20; however,
which impedes extrapolation of the methodology to untested
although extremely powerful, the atom and step economies of these
substrate combinations.
approaches are impacted by the need to prefunctionalize the sub-
strate. Cross-coupling, for example, typically requires challenging
In this communication we present a convenient and general
ortho-selective halogenation or borylation of the hydroxyarene13, protocol for the Bi(v)-mediated arylation of phenols and naphthols
whereas C–H functionalization demands installation and sub- that addresses each of the challenges outlined above. Arylation
sequent removal of Lewis-basic directing groups. Pioneering is achieved in a single telescoped operation that does not require
approaches that entirely avoid additional directing groups21–23
—
exclusion of either air or moisture. All of the reagents employed are
or that allow the in situ installation and removal of co-catalytic commercially available and the bismuth-containing co-product can
directing groups21,24–26—represent an almost ideal solution to the be efficiently recovered and recycled. By exploiting reactivity that
problems of step and atom efficiencies, but suffer from practical is orthogonal to conventional metal-catalysed manifolds, diverse
limitations such as moderate scope and poor selectivity. In addi- aryl and heteroaryl partners can be rapidly coupled to phenols and
tion to the potential issues surrounding the step count, the extant naphthols under mild conditions. Supporting mechanistic studies
1GSK Carbon Neutral Laboratories for Sustainable Chemistry, University of Nottingham, Nottingham, UK. 2School of Chemistry, University of Nottingham,
3
✉
University Park, Nottingham, UK. School of Chemistry, The University of Sydney, Sydney, Australia. e-mail: liam.ball@nottingham.ac.uk
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Articles
a
CO2H
OH
MeO
OH
HO
O
O
F
OH
N
OH
P
NMe2
B
F
N
N
OH
N
N
O
N
H
N
H
N
Cl
iPr
O
OMe
Ar
Alkaloids
e.g. ancistrolikokine J
(cytotoxic)
Lignans
e.g. piperitylmagnolol
Pharmaceuticals
e.g. eltrombopag
(aplastic anemia)
Agrochemicals
e.g. pyridafol
(herbicide)
Reagents for synthesis
e.g. Monophos ligand
Materials
e.g. boroquinols
(antibacterial, cyctotoxic)
(tonne-scale hydrogenation)
(large Stokes-shift dye)
b
MgX
Ar
OH
Ar
R
X
Bi
Bi
Ar
Ar
O
[O]
X
Ar
Ar
Ar
BiCl3
+
+
Bi
X
Ar
R
Ar
Ar
Ar
OH
Base
R
Bi and valuable
Ar wasted
Multistep synthesis of arylating agent via reactive organometallic reagents
Poor and unpredictable chemoselectivity
c
[M]
OH
Ar
Ar
R
Bi
Bi
Bi
X
[O]
Y
X
+
Ar
OH
Bi
X
Ar
R
Bench-stable
universal precursor
Chemoselectivity
conferred by [Bi]
Recoverable [Bi]
No Ar wasted
One-pot synthesis and application of arylating agent
Fig. 1 | Occurrence and Bi(v)-mediated synthesis of 2-hydroxybiaryls. a, The 2-hydroxybiaryl motif is ubiquitous to societally important molecules,
including biologically active natural and unnatural compounds, fine chemicals for synthesis and functional materials. Continued exploration of this
privileged region of chemical space will benefit from efficient methods for synthesis of the key biaryl linkage. b, Barton’s Bi(v) arylating agents offer unique
reactivity, but the state of the art is marred by limited practicality, poor selectivity and unacceptable atom and step economies. c, The design strategy
for this work. We propose that the challenges associated with Bi(v)-mediated arylation will be solved through the in situ formation and application of
bismacyclic arylating agents, thereby providing a general and practical platform for the ortho-selective arylation of hydroxyarenes. Ar, aryl or heteroaryl; X
and Y, (pseudo)halogen; [O], oxidant; r, aryl, alkyl or heteroatomic substituent; [M], metal.
render the methodology predictable and provide new fundamental and pseudohalides based on this scaffold (1-X) were prepared sim-
insights into the reactivity of organobismuth compounds.
ply by changing the Brønsted acid employed in protodebismutha-
tion of a common arylbismacycle(iii) intermediate (Supplementary
Section 4). By telescoping the bismacycle construction and pro-
results and discussion
Strategic blueprint. As outlined in Fig. 1c, our strategy was based todebismuthation steps (Fig. 2), bismacycle tosylate 1-OTs was
on tethering two aryl rings of a homoleptic triarylbismuthane to synthesized and isolated without chromatographic purification in
form a bismacycle. The resulting diaryl scaffold would function as excellent yield on a decagram scale (11g of 1-OTs, 93% yield over
an inert spectator, enabling selective transfer of an exocyclic aryl both steps). Unusually for a diarylbismuth (pseudo)halide, 1-OTs
group to and from the bismuth centre33–35. As a consequence, the effi- is stable towards both hydrolysis (at neutral pH) and aryl ligand
ciency with respect to the valuable aryl moiety would be improved, redistribution reactions. The compound can be handled and stored
and the reactivity and selectivity of the arylating agent could be without exclusion of air, water or light, and shows no sign of decom-
tuned by modification of the bismacyclic scaffold. We envisaged position following storage for two years under ambient laboratory
that in situ preparation of diverse bismacycle(v) arylating agents conditions. Inspection of its solid-state structure reveals a short
could be achieved from a universal bismacycle(iii) halide precursor transannular contact between the bismuth centre and one oxygen
via a modular, one-pot transmetallation/oxidation sequence. This of the sulfone (Bi⋯O=2.556(5)Å), which is probably responsible
telescoped process would avoid the need for multistep synthesis of for this uncharacteristic stability34,38,39. Bismacycle tosylate 1-OTs is
each new bismacyclic reagent, which—in combination with a stable commercially available through Key Organics (catalogue number
bismacycle(iii) precursor that is readily available on scale—would NS-00138).
greatly enhance the practicality of the methodology.
Development and scope of a one-pot arylation procedure. Having
Synthesis of a universal Bi(iii) precursor. We first had to identify identified bismacycle tosylate 1-OTs as an easily accessible uni-
an appropriate bismacyclic scaffold to deliver our proposed meth- versal precursor, we turned our attention to development of the
odology. Initial assessments indicated that the sulfone-bridged bis- transmetallation process required to install an exocyclic aryl group
macycle previously reported by Suzuki34,36,37 (Fig. 2) was uniquely at the Bi(iii) centre. Conventionally, transmetallation of an aryl
competent in model transmetallation, oxidation and C–H arylation group to Bi(iii) is achieved using reactive organometallic reagents
reactions (Supplementary Section 2). A library of bismacycle halides (ArLi, ArMgX or ArZnX)29, which require careful handling and
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BiBr3
Ar3Bi
O
O
[ArBiBr2]
O
S
Bi
F
O
S
Bi OTs
TsOH
Li
Li
O
O
nBuLi
S
Ph2SO2
1-OTs 93%
Fig. 2 | synthesis of a universal bismacycle(iii) precursor. Decagram quantities of bismacycle tosylate 1-OTs can be prepared via a telescoped,
chromatography-free route that starts from readily available starting materials. 1-OTs is stable to ambient laboratory conditions, presumably due to
intramolecular Osulfone–Bi coordination (see X-ray diffraction structure; thermal ellipsoids are shown at 50% probability, hydrogen atoms are omitted for
clarity), and is commercially available through Key Organics (catalogue number NS-00138). Ar, 4-FC6h4; Ts, tosyl.
have restricted functional group compatibility. Such methods were to the substrate. The co-product of this one-pot procedure was
deemed antithetical to our objective of developing a practical and identified spectroscopically as bismacycle meta-chlorobenzoate
general one-pot procedure for the arylation of phenols and naph- 1-OmCB (Fig. 3a), the bismacyclic component of which can be
thols, which demands that transmetallation occurs from a conve- recovered in excellent yield as the corresponding acetate (1-OAc)
nient aryl donor under mild conditions. We therefore envisaged simply by column chromatography with acetic acid as the co-elu-
using a boron-based aryl donor, given the ease of handling and ent. This material undergoes near-quantitative transmetallation
ready commercial availability of many arylboronic acids and esters. under our standard conditions, allowing for effective recovery
However, although B–to–Bi transmetallation is well precedented and recycling of the bismacyclic scaffold. Together this represents
for Bi(v) (refs. 40–44), this process is limited to just two examples a facile process that proceeds from a readily available, universal
45
for Bi(iii): aryl transfer from tetraarylborates to Bi(OAc)3 (ref.
)
precursor, is convenient to execute (no inert atmosphere/anhy-
and from arylboronic acids to monoarylbismuth(iii) oxides46. After drous conditions) and achieves economy with respect to both the
investigation of different arylboron reagents and reaction variables aryl group being transferred (1.1 equiv. arylboronic acid relative to
(Supplementary Section 3), we identified robust conditions for 1-OTs) and the bismacycle itself (high-yielding recovery and recy-
transmetallation from boronic acids to 1-OTs (Table 1). Notably, cling via 1-OAc).
excellent conversions were achieved with just 1.1 equivalents of the
The resulting one-pot process exhibits excellent scope with
arylboronic acid. The presence of added water and base, the choice respect to the aryl group being installed on the substrate (Fig.
of solvent and the identity of the (pseudo)halide associated with the 3b), with electron-donating (3–7), -withdrawing (9–15), sterically
bismacyclic precursor were found to be critical to the success of the demanding (16 and 17) and synthetically useful substituents (6, 7,
transmetallation (Supplementary Section 3).
10, 12, 13) all being well tolerated. Although the propensity of poly-
The scope of B–to–Bi transmetallation is extensive under our fluorophenylboronic acids towards protodeboronation48 renders
optimal conditions (Table 1), with electronically (2a–2l) and steri- them challenging partners in conventional cross-coupling48,56,57
,
cally (2m–2p) diverse aryl and heteroaryl (2t–2aa) boronic acids these moieties can be installed conveniently using our Bi(v)-
reacting in excellent spectroscopic yield. Although protodebis- mediated arylation methodology (14 and 15), allowing facile access
muthation renders isolation challenging for more electron-rich aryl to product motifs that are prized in materials chemistry research58.
moieties (for example, 2t and 2w), this is irrelevant in the proposed Notably, the bismacyclic framework improves reactivity relative to
one-pot procedure where isolation of intermediates is neither nec- conventional Bi(v) reagents: following transmetallation and oxida-
essary nor desirable. Notably, polyfluorophenyl moieties are trans- tion, arylation of 2-naphthol is complete in seconds at room tem-
ferred smoothly and afford stable, isolable arylbismacycles (2q–2s), perature without the need for additional base. This high reactivity
despite the susceptibility of the corresponding boronic acids to pro- stands in contrast to Barton’s triarylbismuth(v) reagents, which
todeboronation47,48. The mildness of the transmetallation protocol is arylate 2-naphthol over several hours in the presence of guanidine
reflected in the diversity of compatible functionality, much of which or hydride bases. For example, whereas a mesityl group is trans-
is not tolerated by conventional organometallic routes to arylbis- ferred to 2-naphthol rapidly at room temperature by our method
muthanes. Previous attempts to circumvent these incompatibilities (17, 89%), only 61% yield is obtained after 27h at 50°C using tri-
have led to low yields of triarylbismuthanes containing, for example, mesitylbismuth dichloride59.
aryliodides (21% yield via an aryldiazonium salt)49 and aryl esters
Installation of several heteroarenes, including those with basic
(26% yield over four steps)50, both of which can be installed quan- nitrogen and an unprotected indole, can be achieved in good yield
titatively in a single step by our method (2h, 2i). Similarly, triaryl- (18–20). However, very electron-rich heteroaryl groups are not
bismuthanes that contain thienyl, furanyl, pyrrolyl or unprotected well tolerated due to the sensitivity of the intermediate aryl bisma-
indolyl groups that are accessible in only moderate yields (28–53%) cycle 2 to protodebismuthation and the inherent instability of the
via conventional organometallic routes51–55 can now also be pre- corresponding Bi(v) species (for example, 2-furyl gives 0% yield,
pared in excellent yield (2t–2z, >99% yield).
Supplementary Table 2). Despite this limitation, the synthesis of
With conditions for transmetallation in hand, we next addressed 18–20 represents important first examples of heteroaryl Bi(v) spe-
the oxidation and arylation steps of our proposed methodology. We cies being used directly as arylating agents.
found that oxidation of aryl bismacycles 2 with meta-chloroper-
Electronically diverse naphthols are arylated in excellent yield
benzoic acid (mCPBA) is rapid and that the in situ generated Bi(v) with complete regio- and (Cortho-versus-O) chemoselectivity (Fig.
species are efficient arylating agents without the addition of base. 3c, 21–25). The methodology is equally applicable to heterocyclic
Conveniently, commercial mCPBA can be used without prior puri- naphthol analogues (27–30), a class of substrates that has not been
fication, and the transmetallation (Table 1), oxidation and arylation explored previously in either Bi(v)-mediated arylation or C–H
procedurescanbeperformedasasingletelescopedoperation(Fig.3a). functionalization. Synthetically useful functionality such as bro-
Arylation is typically complete within seconds at room tempera- mides, iodides and boronic esters (13, 22–24) are also compatible
ture, occurs with exclusive transfer of the exocyclic aryl moiety with the reaction, further illustrating its complementarity to both
and exhibits perfect Cortho-versus-O chemoselectivity with respect conventional cross-coupling and C–H functionalization strategies.
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Table 1 | Transmetallation to universal bismacyclic precursor 1-OTs from aryl- and heteroarylboronic acids
B(OH)2
O
S
O
O S
Ar
Bi OTs
Bi
Ar
O
(1.1 equiv.), K2CO3 (1.2 equiv.)
PhMe/water (99:1), 60 °C, 2 h
1-OTs
2
R = NMe2
2a
2b
2c
2d
2e
2f
>99% (X-ray)
>99% (X-ray)
>99% (X-ray)
>99%
2g
2h
2i
2ja
2ka
>99% (X-ray)
>99% (X-ray)
R = Cl
Br
O
S
O
S
OMe
Me
Vinyl
H
I
Bi
R
O
Bi
O
OAc >99% (X-ray)
CF3 >99% (X-ray)
>99% (X-ray)
>99%
CN
>99% (X-ray)
X-ray of 2e
2l >99%
F
CF3O
Me
Me
Me
F
O
O
O
S
O
S
O
S
Bi
Bi
Bi
Bi
Me
Bi
O
S
O
S
O
O
O
F
2pb >99%
2qb 80%
2m >99%
2n >99%
2o >99%
(X-ray)
F
F
F
F
O
O
O
O
O
Bi
Bi
F
Bi
Bi
Bi
O
O
S
O
S
O
S
O
S
O
S
S
S
2tc >99%
2u >99%
2v >99%
2rb >99%
2sb 91%
(X-ray)
(X-ray)
NH
Me
O
S
O
S
O
S
O
S
O
S
O
N
Bi
Bi
Bi
Bi
Bi
OMe
O
O
O
O
O
O
N
N
Boc
Me
2wc >99%
2x >99%
2y >99%
2z >99%
2aa >99%
Conversions were determined by 1h NMr spectroscopic analysis before characterization of isolated pure material. a The reaction time was 6 h. b The reaction time was 14 h. c Characterized without isolation.
Ac, acetyl; Boc, tert-butoxycarbonyl.
Although 1-naphthol is a poor substrate for established Bi(v) nols such as 4-nitro- or 4-cyanophenol are not arylated under our
reagents (48% with BiPh5)28 and metal-catalysed C–H functional- standard conditions and can also be recovered unchanged from the
ization (38–43% with 5mol% rhodium at T≥100°C)24–26, it is ary- reaction mixture.
lated efficiently using our protocol (26, 86%). The contrast between
Arylation of meta-substituted phenols has not been adequately
our results and those of Barton et al.28 are especially striking and explored in either the extant bismuth60,64 or C–H functionaliza-
again highlight the enhanced reactivity conferred by Suzuki’s sul- tion24–26 literature, but typically occurs with low regioselectivity.
fone-bridged bismacycle scaffold34.
Competing 2,6-diarylation precludes the construction of meaning-
A similar reactivity enhancement is observed for phenols (Fig. ful structure–selectivity relationships from the few examples that do
3d, 31–42), which are arylated rapidly at room temperature by exist. Given that non-symmetrically (meta) substituted phenols also
the bismacyclic system but require extended reaction times and react to form regioisomeric mixtures under our conditions (35–40),
elevated temperatures with Barton’s Bi(v) reagents (for example, we sought to understand the factors that govern this selectivity in
Ph3BiCl2: 48h in refluxing THF with a guanidine base)60. In addi- greater detail.
tion to benefitting reactivity, the use of a bismacycle also improves
For the arylation of 3-fluorophenol—where the 2- and 6- posi-
the chemoselectivity of phenol arylation: where Barton and co- tions are electronically different65,66 but sterically similar67—moder-
workers observe competing Cortho- and O-arylation, we observe ate selectivity (2.6:1, 35:35ʹ) is observed for the more electron-rich
exclusive Cortho-arylation. Our methodology therefore provides not 6-position. Further investigation revealed that this regioselectivity
only an improvement on extant Bi(v)-mediated arylation meth- was not appreciably impacted by variation of the reaction tem-
ods, but also a useful complement to the copper-catalysed, oxy- perature (Supplementary Fig. 9) or the electronic properties of the
gen-selective phenol arylation reported by Chan, Evans and Lam aryl moiety being transferred (reaction constant (ρ)=0.23; Fig. 3d,
using boronic acids61,62, or by Gagnon using Bi(iii) reagents63. inset Hammett plot). Where the 2- and 6-positions are differenti-
By contrast, the occurrence of 2,6-diarylation60 is not apprecia- ated sterically rather than electronically, moderate regioselectivity
bly influenced by the use of a bismacycle, but can be largely sup- is again observed (3.4:1; 36:36ʹ). The apparent preference for ary-
pressed by using a higher relative stoichiometry of the phenol lation of the more electron-rich, less sterically encumbered site is
(Supplementary Fig. 8).
borne out in the arylation of other non-symmetrically substituted
The scope of phenols extends from moderately electron-defi- phenols (37–40) and gives an excellent linear correlation against a
cient to very electron-rich substrates under these modified con- hybrid descriptor derived from Verloop’s Sterimol B5 parameters67,
ditions (31–34). The excess phenol remains unreacted and can be experimentally derived σpara (ref. 65) and computed σortho (ref. 66) val-
recovered in excellent yield (for example, in the synthesis of 45, ues (Supplementary Fig. 11 and Supplementary Table 3), where σ is
excess estrone is isolated in 97% yield). Very electron-deficient phe- the substituent constant.
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a
B(OH)2
OH
O
O
S
O
S
Ar
Ar
R
O
S
Bi OTs
O
Bi
O
Bi OmCB
Ar
(1.1 equiv.), K2CO3 (1.2 equiv.)
(n equiv.)
+
OH
mCPBA (1.5 equiv.), r.t., 10 min
PhMe/H2O (99:1), 60 °C, 2 h
R
1-OTs
2
1-OmCB
1-OAc 91%
AcOH elution
4-FC6H4B(OH)2, K2CO3, 60 °C, 2 h: 96%
b
c
F
F
R
R = NMe2
OMe
76%
95%
95%
8
9
10
11a
12a
R = H
89%
3
4
5
6
7
F
96% (X-ray)
90%
22 R = Br
86%
94%
Me
Cl
23c
24
I
MeO
OH
OH
OH
NHBoc 93%
Vinyl 89%
CF3
CN
96%
Bpin 74%
91%
R
21 92%
F
F
F
Br
F
F
F
F
OH
OH
OH
OH
OH
OH
OH
CO2Me
N
13 87%
14b 65%
15b 81%
16 93%
25 85%
26 86%
27 84%
Me
OMe
F
F
F
H
N
S
N
Me
Me
OH
OH
OH
OH
N
OH
OH
OH
N
S
Me
N
Boc
17b 89%
18 62%
19 59%
20 86%
28 93%
29 74%
30 90%
d
0.2
F
F
F
F
X
r = 0.23
Br
CF3
σX
F
OH
OH
F
OH
MeO
OH
OH
H
Me
–1.0
0.5
OMe
*
Br
F
OMe
F
NMe2
35d (X = F) 60%
(r.r. = 2.6:1)
r.r.X
r.r.H
31 59%
32 69%
33 58%
34 77%
log10
0.3
F
F
F
F
F
F
NHBoc
OH
OH
OH
OH
OH
OH
Br
OH
Ph
Me
Cl
Cl
*
*
*
*
*
iPr
Me
OMe
Br
OMe
37d 57%
(r.r. = 2.4:1)
39d 67%
(r.r. = 0.6:1)
40d 82%
(r.r. = 3.3:1)
36 72%
(r.r. = 3.4:1)
38 69%
(r.r. > 20:1)
41 55%
42 68%
Fig. 3 | One-pot, Bi(v)-mediated arylation of phenols and naphthols. a, Starting from bismacycle tosylate 1-OTs, B–to–Bi transmetallation, oxidation
and arylation can be performed as a single telescoped operation without exclusion of air or moisture, and the bismacyclic scaffold can be recovered
in a high yield as acetate 1-OAc. b, The scope with respect to aryl- and heteroarylboronic acids (nꢀ=ꢀ0.9). c, The scope with respect to naphthol-like
substrates (nꢀ=ꢀ0.9). d, The scope with respect to phenol substrates (nꢀ=ꢀ3.0) and a hammett plot (inset) that quantifies the effect of the boronic acid on
regioselectivity. The formation of 35–40 was accompanied by minor regioisomers (35ʹ–40ʹ) that arise from arylation at the positions denoted with an
asterisk. regisomeric ratios (r.r.) were determined by 19F NMr spectroscopic analysis before purification; where regioisomer separation was not possible,
the composition was confirmed by comparison to authentic samples of single regioisomers prepared via alternative methods. aThe transmetallation time
was 6ꢀh. bThe transmetallation time was 14ꢀh. cArylation was performed in the presence of 1 equiv. mCBA. dYields refer to mixtures of regioisomers. mCB,
meta-chlorobenzoyl; Boc, tert-butoxycarbonyl; Bpin, pinacolatoboron.
The utility of our methodology is showcased in the concise syn- directed C–H arylations which favour functionalization of the
thesis of leukotriene B4 receptor agonist 43 (ref. 68,69) and cannabi- 2-position17,71–74. Both 2- and 4-arylated estrones exhibit biological
noid mimetic 44 (ref. 70), and in the late-stage arylation of estrone activity75, so the ability to access both regioisomers in a single opera-
45 and a naproxen derivative 46 (Fig. 4). The preference of Bi(v) tion is of potential utility in discovery projects.
for arylation of estrone at the 4-position is apparently unique in
The complementarity of our bismuth-mediated arylation to con-
the literature, and provides a direct complement to metal-catalysed ventional cross-coupling was exploited in the concise synthesis of
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F
F
F
Me
Me
OH
Pd(PPh3)4
ArB(OH)2
OH
OH
OH
OH
H
H
OH
Me Me
NC
K2CO3
100 °C
R1
R2
*
MeO2C
Et
H
Me
Me
Br
MeO2C
O
Me
R1
H
R2
Me
O
43 61%
44 58%
45 65%
(r.r. = 8:1)
46 85%
From naproxen
47 97%
93%
94%
Estrogen agonist
48
OH
H
Leukotriene B4
receptor agonist
Cannabinoid
mimetic
-HSD1 inhibitor
β
49 OH
From estrone
Fig. 4 | Bi(v)-mediated arylation enables concise synthesis and diversification of biologically active compounds without substrate prefunctionalization.
As demonstrated by the preparation of 48 and 49 via intermediate 47, the orthogonality that exists between Bi(v)-mediated arylation and conventional
cross-coupling can be exploited in the design of new, modular synthetic strategies. Bi(v)-mediated arylation was performed as per Fig. 3a, with the
following substrate stoichiometries: nꢀ=ꢀ3.0 (43 and 44), 5.0 (45) or 0.9 (46 and 47). Formation of 45 was accompanied by a minor regioisomer (45ʹ)
that arises from arylation at the position denoted with an asterisk. The regisomeric ratio (r.r.) was determined by 19F NMr spectroscopic analysis before
purification. Detailed conditions for the synthesis of 48 and 49 from 47 are provided in the Supplementary Section 6.
estrogen receptor agonist 48 (ref. 76) and β-HSD1 inhibitor 49 (ref. 77) at bismuth in the solid state (Fig. 5c), as has been observed previ-
(Fig. 4). Although 48 and 49 were previously prepared in seven ously in a related bis(μ-oxo)-bridged Bi(v) dimer83. Each bismuth
steps (which included four separate cross-coupling and three non- centre supports a diphenylsulfone scaffold that spans an equatorial
productive halogenation/deprotection operations), our methodol- and apical position, and distinct equatorial and apical Bi–Ooxo bonds
ogy delivers both compounds in >90% yield in just three total steps (2.03Å versus 2.20Å, respectively). Titration of this dimer with
via common intermediate 47.
meta-chlorobenzoic acid (mCBA) allowed sequential spectroscopic
Having investigated their scope, we sought to better understand identification of Bi(v) hydroxy benzoate 51 and Bi(v) dibenzoate 52
the transmetallation, oxidation and arylation processes. We envis- (Fig. 5d). Bi(v) hydroxy benzoate 51 can also be obtained directly as
aged that an appreciation of the fundamental processes would a single species by oxidation of aryl bismacycle 2f with one equiva-
not only provide new fundamental insight, but would also help to lent of purified mCPBA. For mCBA:Bi ratios of between ~1.3 and
explain observations and ultimately guide application and future 2, Bi(v) hydroxy benzoate 51 and Bi(v) dibenzoate 52 equilibrate
development of our methodology.
at a rate commensurate with the NMR timescale. This results in a
single broadened feature in the 19F NMR spectrum, consistent with
Mechanistic observations pertaining to transmetallation. that observed when aryl bismacycle 2f is oxidized with commercial
Transmetallation from electron-neutral or -rich boronic acids to (impure) mCPBA.
bismacycle tosylate 1-OTs reaches completion in less than 2h with-
Bismuth(v) species 50–52 exhibit very distinct reactivity towards
out observable intermediates (Table 1). In contrast, cyano- and tri- phenol (Fig. 5b). Bis(μ-oxo)-bridged dimer 50 does not arylate phe-
fluoromethyl-substituted phenylboronic acids require ~6h to reach nol, but instead undergoes unproductive reduction to 2f in under
completion; in these cases, an ill-defined mixture of species accu- 1min. By contrast, Bi(v) hydroxy benzoate 51 reacts with 1 equiva-
mulates prior to formation of aryl bismacycle 2j or 2k. The mix- lent of phenol to afford the expected Cortho-arylation products quan-
ture of intermediates could be recreated by subjecting bismacycle titatively within seconds. Finally, in the presence of excess mCBA,
tosylate 1-OTs to the transmetallation conditions in the absence Bi(v) dibenzoate 52 shows no reactivity towards phenol over 48h.
of boronic acid (Fig. 5a). This allowed isolation of μ-oxo-bridged On the basis of these studies, Bi(v) hydroxy benzoate 51 is identi-
dimer 12O, which was found to equilibrate with the corresponding fied as the kinetically competent arylating reagent.
monomeric bismuth hydroxide 1-OH in the presence of trace water.
The dichotomous behaviour of bismacycles 50–52 highlights the
Analogous behaviour has been reported for related bismuth(iii) major reactivity consequences of seemingly minor changes to the
hydroxides and oxides78,79. Reaction of isolated dimer 12O with Bi(v) ligand sphere. Although the fundamental origins of these dif-
4-fluorophenylboronic acid in the absence of base afforded aryl bis- ferences are not yet known, we propose that the unique reactivity of
macycle 2f quantitatively in under 1min at room temperature. The Bi(v) hydroxy benzoate 51 reflects the ability of the basic hydrox-
higher rate of transmetallation to 12O (<1min, r.t.) versus 1-OTs ide moiety to facilitate formation of key Bi(v) phenoxy benzoate
(~1h with base, 60°C) indicates that 1-OH/12O are kinetically intermediate 54 (Fig. 5e) without added base. Similar phenoxide
competent intermediates. The accumulation of these Bi–oxo intermediates have been widely proposed in the group transfer
species for electron-deficient boronic acids suggests a substrate- chemistry of bismuth and other main-group elements84 and are well
dependent change in rate-determining step for the overall trans- documented in copper-mediated phenol ortho-oxygenation85,86
.
metallation process. The potential involvement of a Bi–O–B Furthermore, Bi(v) phenoxides have been isolated and character-
pre-transmetallation intermediate (Fig. 5a, inset) is analogous to ized for electron-poor phenols and have been shown to undergo
the Pd–oxo transmetallation pathway in Suzuki–Miyaura cross- ligand coupling upon heating87.
coupling80–82, and has been implicated in Si–to–Bi52 and B–to–Bi46
transmetallation.
The divergent chemoselectivity exhibited by bismacycles 50 and
51 has parallels in other systems that are based on bismuth(v)60,
iodine(iii)88,89 and lead(iv)90,91, each of which engage phenols
Mechanistic observations pertaining to oxidation and arylation. in either oxidation or aryl transfer processes as a function of the
Oxidation of aryl bismacycle 2f with commercial mCPBA of ~75% ligands at the metal centre13. Although the basicity of the ligands
purity furnishes an equilibrating mixture of stable Bi(v) species, the associated with Bi(v) clearly differentiates 50 and 51, the dimeric
composition of which could not be elucidated directly. However, nature of the former may also contribute to the observed chemose-
treatment of the mixture with base allowed for the isolation of lectivity differences. By contrast, the lack of reactivity observed in
bis(μ-oxo)-bridged dimer 50 (Fig. 5b). Characterization by single- the presence of excess mCBA presumably reflects the absence of an
crystal diffraction reveals a distorted trigonal bipyramidal geometry appropriate base, either at the metal centre of Bi(v) dibenzoate 52
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a
B(OH)2
(1.1 equiv.), K2CO3 (1.2 equiv.)
F
O
O
O S
Bi OTs
Bi
F
O
S
F
PhMe/water (99:1), 60 °C, 1 h
>99%
B(OH)n
O
S
1-OTs
2f
Bi
O
O
K2CO3
PhMe/water
r.t., 30 min
4-FC6H4B(OH)2
r.t., <1 min
>99%
O
S
O
S
Bi
O
O
Bi OH
O
– H2O
Bi
O
Plausible
pre-transmetallation
intermediate
+ H2O
S
O
12O
1-OH
b
O
1) mCPBA
O
F
S
F
PhMe, 30 min
2) DBU, 30 min
O
S
O
O
O
O
Bi
Bi
F
O
S
S
mCBA
F
mCBA
F
O
O
Bi
Bi
PhOH
Bi
OH
OmCB
OmCB
OmCB
51
52
S
2f
O
OmCB:
F
O
PhOH (1 equiv.)
k > 40 M–1s–1
OH
PhOH
O
Cl
R'
50
O
(X-ray)
41 (R' = H)
53 (R' = C6H4F)
c
d
1
50
51
52
0.75
0.5
0.25
0
[mCBA]
0
0.5
1
1.5
2
[Bi]tot
e
f
F
F
O
S
O
S
5 equiv. d0-PhOH
5 equiv. d5-PhOH
Bi
F
O
mCPBA, PhOH
Bi
F
O
PhMe, r.t.
OH
mCPBA, PhMe, r.t.
kH/kD = 1.03 0.10
OH
2f
D0/D4
41
2f
mCPBA
41/d4-41
RDS
k = 1.6 M–1s–1
g
D
F
OH
O
O
S
O
S
O
O
S
F
F
PhOH
– H2O
Bi
F
O
H
Bi
Bi
mCPBA, PhMe, r.t.
OH
OH
OPh
OmCB
OmCB
54
Proposed intermediate
2f
H/D
kH/kD
= 0.83
51
41/
d1-41
Fig. 5 | Preliminary mechanistic investigations. a, Bi(iii)–oxo species generated by basic hydrolysis of 1-OTs are kinetically competent intermediates
en route to aryl bismacycles 2. The rate-determining step (rDS) for very electron-deficient arylboronic acids changes from hydrolysis to B–to–Bi
transmetallation. By analogy to the Suzuki–Miyaura cross-coupling, an oxo-bridged Bi–O–B species is proposed as a plausible, fleeting pre-transmetallation
intermediate. b, Bi(v) species 51 and 52 can be accessed via oxidation of 2f with commercial mCPBA, or titration of isolable bis-µ-oxo dimer 50 with
mCBA. Only hydroxy benzoate 51 engages in productive arylation of phenol. DBU, 1,8-diazabicyclo(5.4.0)undec-7-ene. c, Different orientations of the
single crystal X-ray diffraction structure of 50 are shown (thermal ellipsoids shown at 50% probability; all hydrogen atoms and a molecule of acetonitrile
are omitted for clarity). d, Titration of bis-µ-oxo dimer 50 with mCBA affords Bi(v) species 51 and 52, confirming their formation by direct oxidation of
2f. e, Oxidation of 2f with mCPBA is slower than the subsequent arylation of phenol by the resulting Bi(v) species, precluding direct kinetic interrogation
of the arylation process. f, No appreciable KIE is observed in the intermolecular competition between d0- and d5-PhOh in Bi(v)-mediated arylation. g,
An α-SKIE (α-secondary kinetic isotope effect) of 0.83 is observed for the Bi(v)-mediated arylation of 2-d1-phenol. The apical/equatorial distribution of
substituents in 50–52 and 47 in solution is unknown. All yields were determined by 19F NMr spectroscopy against an internal standard.
or in solution. The different reactivity of Bi(v) hydroxy benzoates
Competitive kinetic isotope effect (KIE) studies provide valu-
and dibenzoates is reproduced in simple triaryl bismuth systems able insight into the key product-forming processes that follow
(Supplementary Figs. 14 and 15).
Bi(iii)→Bi(v)oxidation(Fig.5f,g).TheabsenceofanobservableKIE
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Data availability
Competing interests
Crystallographic data for the structures reported in this Article have been deposited at the
Cambridge Crystallographic Data Centre under deposition numbers 1904059 (1-OTs),
1904060 (2a), 1904061 (2b), 1904062 (2c), 1904063 (2e), 1904064 (2g), 1904065 (2h),
1904066 (2i), 1904069 (2j), 1904067 (2k), 1904068 (2m), 1904070 (2u), 1904071 (2v),
1904072 (9) and 1904073 (50). Copies of the data can be obtained free of charge at www.
ccdc.cam.ac.uk/data_request/cif. The authors declare that all other data supporting the
findings of this study are available within the paper and its Supplementary information.
Bismacycle 1-OTs has been made commercially available via Key Organics.
The sales revenue that is returned to the University of Nottingham covers the
costs of commercialization; the authors do not receive profit from any of the sales
that are made.
acknowledgements
additional information
This work was supported by The University of Nottingham.
Supplementary information is available for this paper at https://doi.org/10.1038/
s41557-020-0425-4.
author contributions
M.J. and L.T.B. conceived this work. M.J. and L.M. performed the experiments and
analysed the data. W.L. acquired and solved X-ray diffraction data. L.T.B. wrote the
manuscript with input from M.J. and L.M.
Correspondence and requests for materials should be addressed to L.T.B.
Reprints and permissions information is available at www.nature.com/reprints.
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