Catalytic activation of unstrained C(aryl)–C(aryl) bonds in 2,2′-biphenols

Article abstract of DOI:10.1038/s41557-018-0157-x

Transition metal catalysis has emerged as an important means for C–C activation that allows mild and selective transformations. However, the current scope of C–C bonds that can be activated is primarily restricted to either highly strained systems or more polarized C–C bonds. In contrast, the catalytic activation of non-polar and unstrained C–C moieties remains an unmet challenge. Here we report a general approach for the catalytic activation of the unstrained C(aryl)–C(aryl) bonds in 2,2′-biphenols. The key is to utilize the phenol moiety as a handle to install phosphinites as a recyclable directing group. Using hydrogen gas as the reductant, monophenols are obtained with a low catalyst loading and high functional group tolerance. This approach is also applied to the synthesis of 2,3,4-trisubstituted phenols. A further mechanistic study suggests that the C–C activation step is mediated by a rhodium(i) monohydride species. Finally, a preliminary study on breaking the inert biphenolic moieties in lignin models is illustrated.

Full text of DOI:10.1038/s41557-018-0157-x

Articles
https://doi.org/10.1038/s41557-018-0157-x
Catalytic activation of unstrained C(aryl)–C(aryl)
bonds in 2,2′-biphenols
JunZhu, JianchunWang and GuangbinDongꢀ ꢀ*
Transition metal catalysis has emerged as an important means for C–C activation that allows mild and selective transforma-
tions. However, the current scope of C–C bonds that can be activated is primarily restricted to either highly strained systems
or more polarized C–C bonds. In contrast, the catalytic activation of non-polar and unstrained C–C moieties remains an unmet
challenge. Here we report a general approach for the catalytic activation of the unstrained C(aryl)–C(aryl) bonds in 2,2′-biphe-
nols. The key is to utilize the phenol moiety as a handle to install phosphinites as a recyclable directing group. Using hydrogen
gas as the reductant, monophenols are obtained with a low catalyst loading and high functional group tolerance. This approach
is also applied to the synthesis of 2,3,4-trisubstituted phenols. A further mechanistic study suggests that the C–C activation
step is mediated by a rhodium(i) monohydride species. Finally, a preliminary study on breaking the inert biphenolic moieties in
lignin models is illustrated.
arbon skeletons exist ubiquitously in commodity chemicals, Here we report a general approach for the catalytic activation of the
pharmaceuticals, agrochemicals, synthetic polymers, fuels unstrained C(aryl)−C(aryl) bonds in 2,2′-biphenols through utiliz-
C
and biomasses. To date, carbon–carbon bond (C−C) cleav- ing the phenol moieties as a handle to install recyclable directing
age reactions have found important applications in strategic synthe- groups (RDGs)15, which then guide the transition metal insertion
ses of complex organic molecules1 and the cracking of petroleum into the aryl−aryl bond (Fig. 1c).
chemicals2. Among various approaches to break a C−C bond,
transition metal catalysis has emerged as an important means3–10 Result and discussion
to allow mild and selective transformations. However, the current To this end, phosphinites were chosen as the RDGs16,17 as they can be
scope of C−C bonds that can be activated is primarily restricted to conveniently installed to and removed (and, in principle, recycled)
either highly strained systems3,8,10, in which strain release provides from phenols (Fig. 1c). Through carefully tuning the electronic and
thermodynamic driving forces, or more polarized C−C bonds6,9, steric properties of the phosphinite RDGs, a directed oxidative addi-
such as carbon−cyanide and carbon−carbonyl bonds, in which the tion of the C(aryl)−C(aryl) bond with a low valent transition metal7,
electrophilic moiety serves as a handle for the initial reactivity. In forexample,Rh(i),couldbeimaginedtogiveaspiro-rhodacycleinter-
contrast, the catalytic activation of non-polar and unstrained C−C mediate, which provides monophenol products on hydrogenolysis
moieties remains an unmet challenge.
and hydrolysis. Hence, we commenced our study with bisphosphi-
Although breaking hydrocarbon C−C chains has been carried nite 2a as the model substrate, which can be easily synthesized via
out on multimillion tonne scales in the petrochemical industry, that phosphinylation of 2,2′-biphenol 1a (Table 1). After examining a
is, the cracking processes2, the related reaction for to activate non- range of metal precatalysts, additives and phosphorous groups, the
polar unstrained C−C bonds with homogeneous catalysis is rare. To C(aryl)−C(aryl) bond cleavage was successfully achieved using a
the best of our knowledge, the only example of such a transforma- low loading (0.5mol%) of [Rh(C2H4)2Cl]2 with diisopropylphos-
tion was reported by Milstein and co-workers11,12 in which the scis- phinite as the RDG under a 50psi (345kPa) H2 atmosphere. The
sion of an aryl−alkyl bond was achieved in a pincer-type substrate monophenol product (3a) was isolated in 77% yield on workup
driven by forming a two-five-membered-fused rhodacycle (Fig. 1a). on silica gel (Table 1, entry 1). A series of control experiments was
However, despite the prevalence of biaryl compounds, the activa- subsequently conducted to understand the role of each reactant.
tion of unstrained aryl−aryl bonds remains an elusive transforma- Unsurprisingly, in the absence of [Rh(C2H4)2Cl]2 or H2, no desired
tion13 with a threefold challenge. First, unlike the ketones commonly product was obtained (Table 1, entries 2 and 3). When using diphe-
used as substrates in C−C activation,6,9 the non-polar aryl−aryl nylphosphinite as the RDG, only a trace amount of 3a was observed
moiety lacks an electrophilic centre to interact with electron-rich (Table 1, entry 4). We reasoned that the less-electron-rich Ph2P
transition metals. Second, overlap between the biaryl C−C σ bond moiety might impede the oxidative addition of the aryl−aryl bond
and transition metal d orbitals becomes more difficult due to the to Rh; in contrast, the electron-rich dicyclohexylphosphinite RDG
preferred twisted conformation of biaryls (for 2,2′-disubstituted gave a comparable yield (Table 1, entry 5). Reducing the H2 pres-
biphenyl, the twist angel is close to 90°)14, which hinders the forma- sure to 30psi (207kPa) still offered a 69% yield of the monophe-
tion of the initial σ complex (Fig. 1b). Third, the bond-dissociation nol 3a (Table 1, entry 6) and increasing the H2 pressure marginally
energy of an aryl−aryl bond (often >110kcalmol–1) is significantly improved the yield (entry 7). Note that the turnover number (TON)
higher than that of typical C−C bonds (for example, the bond-dis- of Rh can reach 298 using 0.13mol% RhH(PPh3)4 as the precatalyst
sociation energy of an acyl–alkyl bond is ~82kcalmol–1). Thus, one (Table 1, entry 8). When the reaction was run at a lower temperature
key factor to enable catalytic aryl−aryl bond activation is to con- or with toluene as the solvent, the yield slightly decreased (Table 1,
trol the conformation of the biaryl structure and bring low-valent entries 9 and 10). Finally, other group 9 metals, such as Ir and Co,
transition metals in close proximity to the targeted C−C σ bond. gave no desired product (Table 1, entries 11 and 12).
Department of Chemistry, University of Chicago, Chicago, IL, USA. *e-mail: gbdong@uchicago.edu
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a
Me
PR2
Me
Me
PR2
[Rh]
PR2
Me
Me
PR2
H
Table 1 | selected optimization of reaction conditions
[Rh]
H2
Me
OMe
Me
Me
R = i-Pr
Me
OMe
OH
[Rh(C2H4)2Cl]2 (0.5 mol%)
Me
PR2
PR2
OX
OX
H2 (50 psi), 150 °C
6 mL 1,4-dioxane
b
H
"Standard" conditions
TM
TM
Me
OMe
3a
versus
CH3
X = H, 1a
X = PR2, 2a
Up to 298 TON
Et3N, Cl-PR2
X
X
X
c
Entrya
Yield (%)b
Entrya
Yield (%)b
Changes
Changes
150 psi H2
R
R
1
as above
no [Rh]
77
nd
7
79
39
R
R
R
O
P
P
+
C–C
H2, H
8c,d
9c
0.13 mol% RhH(PPh3)4
OH
OH
O
O
2
3
P
Rh
P
activation
+ P
– P
OH
50 psi Ar instead of H2
R = Ph instead of iPr
R = Cy instead of iPr
30 psi H2
nd
trace
58
130 °C
70
71
O
R
R
10c
toluene as solvent
[Ir(COD)Cl]2 (2.5 mol%)
4
5
6
11c
nd
nd
e.g. 5–5 lignin
linkage
Recyclable
12c
69
Co2(CO)8 (2.5 mol%)
aAll the reactions were run on a 0.3ꢀmmol scale. nd, not detected. bIsolated yields. c150ꢀpsi
Fig. 1 | Catalytic activation of non-polar unstrained C−C bonds.
(1,035ꢀkPa) H2. d1.2ꢀmmol of 2a were used and the gas chromatography yield was obtained.
a, Milstein’s seminal work on cleavage of the C(aryl)−C(alkyl) bond in a
pincer ligand. b, Challenge for biaryl substrates: unlike activation of the
C(aryl)−C(alkyl) bond, the twisted conformation of biaryls hinders the
formation of the initial σ complex. c, Strategy for the catalytic activation of
unstrained C(aryl)−C(aryl) bonds of 2,2′-biphenols: the phenol moieties
are used as the handle. P, phosphinite directing groups.
precatalyst can first react with H2 to give a Rh(i) monohydride spe-
cies, which is more electron rich than the corresponding Rh(i)−Cl
complex and can serve as the real catalyst in this reaction (path
B). In this pathway, the Rh(i)−H first undergoes oxidative addition
Toinvestigatethegeneralityandrobustnessofthecatalyticsystem, with the aryl−aryl bond to give a Rh(iii) intermediate, followed by
the substrate scope was then explored (Table 2). The biphenol com- C−H reductive elimination to give one monomer and a Rh(i)–aryl
pounds with substituents at the 5,5′-positions were tested first; it is species. The following oxidative addition of H2 converts the Rh(i)−
encouragingthat5,5′-substituentswithdifferentlengthsandbranch- aryl species back to the Rh−H catalyst and also produces another
ing properties all provided the desired monophenols in good yields. equivalent of the monomer. Thus, path B only involves Rh(I) and
Substrates with bulky alkyl groups (2i and 2j) required more forc- Rh(iii) intermediates.
ing conditions (2.5mol% [Rh(C2H4)2Cl]2 and 100psi (690kPa) H2),
To differentiate the two pathways, the following experi-
probably to promote the rotation of the sterically hindered aryl− ments were conducted. First, treatment of the substrate derived
aryl bond, which is critical for forming the key C−C σ-complex from Ph2PCl with [Rh(C2H4)2Cl]2 provided a Rh(i) complex that
intermediate. Besides having methoxyl groups at the 3,3′-positions, contained chloride bridges (Fig. 2b); however, heating a similar
i
the corresponding alkyl- or aryl-substituted substrates (2r–2t or 2w, complex prepared from Pr2PCl in the absence of H2 only gave a
respectively) also provided the desired products in high efficiency. trace amount of the C−C activation product. The density functional
For comparison, the 3,3′-unsubstituted (2u) or bromosubstituted theory (DFT) calculation (Supplementary Section 14) shows that
substrates (2v) showed a very low reactivity, probably caused by direct oxidative addition of the aryl−aryl bond to the Rh(i)−Cl
competing ortho-C−H (refs 16,17) or C−Br bond activation, respec- species (path A) can be reversible and endothermic; in addition,
tively. Although substitution at the 6,6′-positions inhibited the reac- the subsequent H2 oxidative addition to give the Rh(v) intermedi-
tivity under the current conditions, probably due to the increased ate requires a high energy barrier of 34.2kcalmol–1. Alternatively,
steric hindrance around the aryl−aryl bond, the 4,4′-substituted in path B, the reaction of Rh(i)−Cl with H2 should generate one
biphenols (2af and 2ag) are highly competent substrates. Moreover, equivalent of HCl (ref. 20). It is known that HCl rapidly consumes
a number of functional groups were found compatible, including phosphinites through P−O bond cleavage (vide infra and Fig. 3d),
electron-richarenes(2x),furan(2aa),thiophenes(2ab),amides(2o), and is thus detrimental to the reaction. Indeed, when a higher
sulfonamides (2p), nitriles (2q and 2s), silyl ethers (2m), esters (2n [Rh(C2H4)2Cl]2 loading was used, the yield of the C−C cleavage
and 2t), aryl fluorides (2ac), chlorides (2ad) and bromides (2ae and product was dramatically reduced, whereas adding bases under
2ag). Note that, although sulfur moieties often poison heteroge- these conditions can restore the good yields (Fig. 2c). These obser-
neous catalysts, in this homogeneous system the sulfur-containing vations suggest that HCl was formed in this reaction. The role of
substrates (2w and 2x) still show a good reactivity.
the bases is proposed to be twofold: first, they could promote the
Next, both experimental and computational studies were car- formation of the Rh monohydride species via reacting with the HCl
ried out to probe the reaction pathway, with the key question as generated from [Rh(C2H4)2Cl]2 (ref. 20); second, they could also pro-
to how the C(aryl)−C(aryl) bond is cleaved during this reaction. tect the phosphinite substrate from P−O bond cleavage. In addition,
Based on previous organometallic studies on C−C activation11,18,19
,
the reaction of bisphosphinite 2c with Rh(PPh3)4H led to a puta-
two pathways are possible. Path A involves a direct oxidative addi- tive Rh−hydride species, which on heating directly afforded a good
tion of the aryl−aryl bond to the Rh(i)−Cl species to generate a yield of the monomer product in the absence of any chloride or H2
diaryl−Rh(iii) intermediate; a further oxidative addition of H2 (Fig. 2d). This result strongly supports the Rh−hydride-mediated
and subsequent two C−H reductive elimination (a formal σ-bond C−C bond activation pathway (path B). Moreover, consistent with
metathesis) result in two monomer products (Fig. 2a). Thus, the experiments, the DFT calculation shows that path B is more
path A involves a Rh(v) intermediate. Alternatively, the Rh(i)−Cl energetically favourable than path A, and the turnover-limiting step
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Table 2 | substrate scope for the reductive C−C cleavage of 2,2′-biphenols
4
5
3
2
iPr
iPr
iPr
iPr
R
[Rh(C2H4)2Cl]2 (0.5 mol%)
6
O
O
P
P
R
H
2 (50 psi), 150 °C
1,4-dioxane
OH
6'
5'
2'
3'
R
Silica gel work up
4'
3
2
Me
Me
OMe
OH
Et
OMe
OH
n-Pr
OMe
OH
n-Bu
OMe
OH
n-C5H11
OMe
OH
iPr
OMe
OH
OMe
Me
Me
OH
3a, 77%
3b, 80%
3c, 75%
3d, 69%
3e, 76%
3f, 72%
3g, 66%
Me
Me Me
Me Me
Me
OMe Me
OH
OMe t-Bu
OMe
OH
OMe
OH
OMe
OMe
TBSO
OH
OH
OH
3i, 77%a
3j, 77%a
3h, 79%
3k, 70%
3l, 71%
3m, 84%
O
O
Ts
N
n-Pr
OMe
n-Pr
OMe
OH
OMe
OMe
OH
Me
CN
O
N
n-Pr
NC
n-Pr
OH
OH
OH
OH
3o, 62%b
3p, 56%b
3q, 73%b
3n, 70%
3r, 76%
3s, 70%
O
H
Me
Br
Ar
Ar
Me
Me
Me
OH
Ph
Me
OH
OEt
OH
3t, 65%b
OH
OH
OH
3w, 70%b
OH
3u, trace
3v, 0%
3x, 66%b
3y 77%
3z, 85%
Ar = 4-SCH3–C6H4–
Me
Me
Me
OH
Me
OH
F
Me
OH
Cl
Me
Br
Me
OH
Me
OH
Br
Me
OH
O
S
OH
3aa, 79%b
3ab, 78%
3ac, 55%a
3ad, 77%
3ae, 75%
3af, 82%
3ag, 85%
2 (0.3ꢀmmol) and [Rh] (0.0015ꢀmmol). All the reactions were worked up on silica gel. All the yields are isolated yields. a2.5ꢀmol% [Rh], 100ꢀpsi H2. b0.2ꢀmmol 2. Ar, 4-SCH3–C6H4–. TBS, tert-butyldimethylsilyl.
for path B is calculated to be the C−C cleavage step with a barrier aspect and the C6 position would be more reactive from the elec-
of 28.1kcalmol–1 (Supplementary Section 14). To further support tronic viewpoint. Thus, it is difficult to access 2,3,4-trisubstituted
path B, we hypothesized that, if the C−C bond can be activated by phenols through a direct functionalization at the C3 position of
a Rh−H species, by analogy it could also be activated by a Rh−aryl/ substrate 5. To address this challenge, we hypothesized that, using
alkyl species. Treatment of the substrate–Rh(i)Cl adduct with PhLi the corresponding 2,2′-dimer (via a one-step preparation from
in pentane led to transmetallation and the precipitation of the LiCl the monomer) as the substrate, the desired C3 selectivity could be
salt, and on heating the putative Rh−Ph species in 1,4-dioxane, as realized as the biaryl moiety should effectively block both the C5
expected, provided the desired biaryl product (4c). This observa- and C6 positions; subsequent C−C cleavage using this hydroge-
tion demonstrates that the oxidative addition of a strong aryl−aryl nolysis method should provide 2,3,4-trisusbtituted phenols. To test
bond to Rh(i)−Ph species is feasible, which should open the door to this hypothesis, substrate 5a, prepared in one step from the com-
develop new C−C forming reactions via aryl−aryl bond activation. mercially available 4-bromo-2-methylanisole, was employed as
Altogether, the results from the mechanistic study support C−C the substrate, and C−H halogenation was attempted as halogen
activation through path B.
substituents could be conveniently converted into various other
The synthetic utility of this method was first explored in the FGs. As expected, the direct subjection of substrate 5a to the
synthesis of 2,3,4-trisubstituted phenols. Given that electrophilic Rh-catalysed C−H bromination conditions23 followed by deprotec-
substitution of phenols is generally para and ortho selective, func- tion only led to the 2,4,5-substituted phenol (7a). However, using
tionalization at the phenol meta position is often realized via direct- substrate 6a prepared via a gold-catalysed dimerization of 5a24, fol-
ing group (DG)-based approaches21,22. If phenol substrate 5 with a lowed by the sequence of a Rh-catalysed C−H halogenation, depro-
DG at the C4 position is used (Fig. 3a), the less bulky C5 position tection and the key aryl−aryl cleavage, the desired 2,3,4-substituted
would be much more reactive than the C3 position from the steric phenols were obtained with good efficiency. Further, the Br or I
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a
R1
R1
R1
R2
R2
R2
R2
H
R1
H2
R2
O
P
H
O
P
R2
O
O
O
P
Rh
P
Rh
P
P
Rh
P
Cl
P
H
Rh
Rh
H
O
Cl
R2
O
P
H
R2
P
O
R2
R2
O
O
R2
R2
R1
28.1 kcal mol–1
R1
H2
R1
R1
OMe
OMe
34.2 kcal mol–1
Path B
Path A
R1
P
P
P
H
Cl
O
O
H2
R2
P
R2
R1
Rh
Rh
R2
H
O
O
R1
O
2
2
R1
P
R2
R2
O
P
R2
HCl
P
R2
R1
OMe
OMe
O
O
P
H
Rh
R1
R1
P
Cl
Rh
R2
R2
P
O
H
H
R2
H
O
O
P
O
P
R1
R2
R1
H
Rh
H
Rh
R2
R1
R2
P
R1
P
H
O
O
Rh(V)
P
P
Cl
H
H
O
O
O
O
R2
P
R2
R2
R2
P
R1
R1
R1
R1
b
Me
OMe
Me
OMe
R2
MeO
R2
Me
Me
i. [Rh(C2H4)2Cl]2 (50 mol%)
1,4-dioxane, 150 °C, 24 h
R
R
[Rh(C2H4)2Cl]2
(50 mol%)
Me
OMe
P
P
Cl
Cl
O
O
P
R
R
O
O
O
Rh
Rh
P
O
P
P
OH
ii. 4 M HCl in 1,4-dioxane
R = iPr
THF, r.t.
R = Ph
R2
R2
3a
Me
OMe
Me
OMe
MeO
Trace by GC-MS
[Rh(2al)Cl)]2
X-ray obtained
c
d
n-Pr
OMe
OH
Rh(PPh3)4H (100 mol%)
Me
OMe
iPr
Me
OMe
OH
1,4-dioxane
150 °C
3c
iPr
[Rh(C2H4)2Cl]2 (20 mol%)
O
O
P
P
iPr
58% NMR yield
based on [Rh]
H
2 (50 psi), 1,4-dioxane
iPr
150 °C, 24 h
3a
2c
Me
OMe
n-Pr
OMe
36%-50% yield
2a
n-Pr
OMe
iPr
[Rh(C2H4)2Cl]2
With NaH (100 mol%)
With KOtBu (50 mol%)
73% yield
70% yield
50 mol%
iPr
OH
150 °C
1,4-dioxane
P
O
O
then PhLi
pentane
[Rh]
Ph
P
iPr
From Table 1, [Rh] (0.5 mol%)
77% yield
4c
iPr
OMe
HCl is probably generated in this reaction.
LiCl
n-Pr
17%
Unoptimized
Fig. 2 | exploratory mechanistic study. a, Two proposed mechanistic pathways for the C−C activation step. Path A starts with a Rh−Cl species and
involves a formal Rh(v) intermediate; path B involves a Rh−H-mediated oxidative addition of the aryl−aryl bond. Supplementary Section 14 gives the
computed activation energies from the DFT study. b, Stoichiometric Rh−Cl-mediated transformations in the absence of H2 afforded a trace amount of
product after heating, and the chlorine-bridged dirhodium complex could be obtained at room temperature. c, A higher [Rh] loading led to significantly
reduced yields and adding bases restored the yields. d, Stoichiometric reactions with Rh−H and Rh−Ph species. Stoichiometric Rh(PPh3)4H afforded
product 3c in a moderate yield in the absence of H2. PhLi could be used to transfer a phenyl group to the aryl−aryl bond. These results support path B. r.t.,
room temperature.
moiety was easily transformed into a number of other common FGs of dimerization as a ‘traceless’ protecting tool to deliver unusual site
via cross couplings, such as aryls (8a and 8b), alkynyl (8d), vinyl selectivity, which is enabled by this new C−C activation method.
(8e), allyl (8f) and hetero-aryls (8g and 8h) groups. The amide
Also, the C−C activation protocol is scalable. On a gram scale,
DG could also be converted into other FGs, such as an amine (8c). an 83% yield was obtained using 1 mol% [Rh(C2H4)2Cl]2 under
Therefore, the key to the success of this synthetic strategy is the use 100 psi H2 (Fig. 3b). Furthermore, a one-pot procedure was also
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a
O
O
O
Me
Me
Me
FG
(1)
(2)
N
C−H
N
N
DG
R2
DG
R2
functionalization
88%
90%
Br
OH
OMe
Br
OMe
X
5a
One step from
OR1
5b
7a
Less
bulky
OH
2,4,5-Substituted phenol
More
electron rich
commerically available
anisole (95% yield)
2,3,4-Substituted phenol
5
(3)
60%
Versatile FGs
O
X
This
method
O
Dimerization
Me
Me
N
N
(1)
O
X
N
N
This
method
X = Br, 66%
X = I, 70%
Me
OH
OH
OH
N
OMe
OMe
FG
(2)
R2
DG
R2
DG
DG
X = Br, 93%
X = I, 94%
C−H
functionalization
Me
2,3,4-Substituted phenol
Me
OR1
OR1
OR1
OR1
Also
blocked
O
X
O
6a
X = Br (3ah), 66%
X = I (3ai), 69%
X = Br (1ah)
X = I (1ai)
Condition (1): [RhCp*Cl2]2, NXS, AgSbF6, PivOH, 1,2-dichloroethane, 70 °C
Condition (2): BBr3, CH2Cl2, –78 °C to r.t.
R2
DG
R2
FG
Condition (3): AuCl3, PhI(OAc)2, AcOH, 60 °C
Examples:
OMe
O
O
O
O
Ph
Ph
Y
O
O
O
O
O
O
Me
Me
Me
OH
Me
OH
Me
OH
Me
Me
N
N
N
N
N
N
N
OH
OH
OH
O
H
From X = Br
From X = Br
8b, 85%
From 8b
8c, 80%
From X = I
From X = Br
From X = Br
From X = I
8a, 81%
8d, 81%
8e, 79%
8f, 61%
8g, Y = O, 80%
8h, Y = S, 82%
c
b
n-Pr
OMe
Me
Me
OMe
[Rh(C2H4)2Cl]2 (1.0 mol%)
(17.4 mg)
NaH, iPr2PCl
1,4-dioxane, rt then
OMe
OH
Me
OMe
OPiPr2
OPiPr2
OH
OH
[Rh(C2H4)2Cl]2 (0.5 mol%)
H2 (50 psi), 150 °C
H2 (100 psi), 150 °C, 1,4-dioxane
OH
n-Pr
OMe
OMe
2c
3c
1a
One pot!
3a
2.53 g, 4.5 mmol
1.24 g, 83%
50%
d
n-Pr
n-Pr
OMe
n-Pr
n-Pr
OMe
RhH(PPh3)4
(2.0 mol%)
Quantitative
conversion
n-Pr
OMe
OH
n-Pr
OMe
Et3N
OPiPr2
OPiPr2
OH
OH
81% overall yield from 1c
iPr2PCl
H2 (100 psi)
Dry HCl
OPiPr2
150 °C, 1,4-dioxane
3c
3c′
OMe
OMe
+
1c
2c
iPr2PCl
(70% recycled after distillation)
4.5 g
Fig. 3 | Catalytic reductive cleavage of C(aryl)−C(aryl) bonds in 2,2′-biphenols. a, Synthesis of 2,3,4-trisubstituted phenols. This method could be
useful to prepare 2,3,4-trisubstituted phenols from substrate 5a. In contrast, the direct C−H activation approach only gives the 2,4,5-substituted product.
Supplementary Section 4 gives the experimental details. b, The reaction is scalable and can be run on a gram scale with a good yield. c, The reaction can be
run in one pot directly from 2,2′-biphenols. d, The RDG moiety can be recycled. Simple treatment of the reaction mixture after C−C activation with dry HCl
regenerates iPr2PCl with a quantitative conversion. The lower isolated yield of iPr2PCl is mainly caused by its volatility during the handling and purification.
Cp*, pentamethylcyclopentadienyl. NXS represents either NBS (N-bromosuccinimide) or NIS (N-iodosuccinimide).
established to allow the in situ RDG installation and subsequence in a good yield, and the regenerated iPr2PCl reagent can be recov-
hydrogenolysis, in which free 2,2′-biphenols can be directly ered by distillation.
employed as the substrate (Fig. 3c). Lastly, although using a catalytic
Given that the 2,2′-biphenol moiety is often found in lignin
RDG remains challenging at this stage, the diisopropylphosphino extracted from softwood25, the use of the C(aryl)−C(aryl) activation
RDG moiety could, nevertheless, be recycled (Fig. 3d). After the method was also investigated in a model study to cleave the biaryl
C−C activation, the diisopropylphosphino moiety was found to linkages in lignin, that is the ‘5–5’ and ‘dibenzodioxocin’ moieties
remain bound to the monophenol product; simple treatment of the (Fig. 4a). Converting lignin into valued-added products is attrac-
reaction mixture with dry HCl led to a quantitative protonation of tive from both economic and environmental viewpoints. Although
the monophenol phosphinite 3c′ to give the free phenol product 3c breakthroughs have been obtained lately on cleaving the polar
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a
OAr
HO
HO
HO
O
O
O
O
O
HO
5-5
OH
Spirodienone
HO
OH
O
O
O
OH
O
O
O
OH
HO
O
OH
O
O
OH
O
OH
O
OH
β-β
HO
O
HO
O
O
O
O
β−O-4
OH
O
O
O
O
β-1
O
OH
O
Dibenzodioxocin
O
OH
OH
HO
Dibenzodioxocin
HO
OH
OH
O
OH
HO
O
O
O
O
O
O
O
HO
O
HO
b
c
n-Pr
n-Pr
n-Pr
n-Pr
n-Pr
OMe
Pd/C or Ru/C
n-Pr
OMe
OH
This
method
MeO
OMe
Ru/C
O
O
MeO
OMe
OH
OH
1,4-dioxane
p-cymene
200 °C
OH
OH
400 psi H2
MeOH, 250 °C
1c
70%
OH
3c
"5–5" model
n-Pr
OMe
9
H2-free
Pd/C (20 mol%), 72%
Ru/C (20 mol%), 66%
HO
OMe
ca. 40.6 mg 1c
in a crude mixture
Wet spruce
sawdust
conditions
Dibenzodioxocin
model
81%
Ru/C (20 mol%)
H2, CH3OH, 200 °C
Fig. 4 | model study for the cleavage of aryl−aryl bonds in lignin dimers. a, Representative structure of softwood lignin that highlights the 5–5 and
dibenzodioxocin units, which are arguably the most difficult linkers to be cleaved; in contrast, cleavage of the β-O-4 linkage has been widely studied.
b, Conversion of dibenzodioxocin into 5–5 linkages. c, Conversion of wet spruce sawdust (2.5ꢀgꢀ×ꢀ14 batches) into lignin monomers. Supplementary
Section 12 gives the experimental details.
C−O bonds (for example, the β-O-4 linkage) in lignin26–32, much With a reliable procedure of transforming dibenzodioxocin into
less progress has been achieved for the selective disconnection of 5–5 moieties in hand, we were motivated to examine the possi-
less polar but more robust C−C bonds25,33, which are also com- bility of cleaving biphenolic lignin dimers extracted from natural
monly present in both extracted and industrial lignins34,35. To our wood (Fig. 4c). Treatment of wet sawdust (2.5 g ×14 batches) of
knowledge, selectively breaking the aryl−aryl bonds in 5–5 and/ spruce wood with Ru/C and H2 at 250 °C in MeOH gave 82.9 mg
or dibenzodioxocin structures has not been reported in either of a crude mixture that contained ~40.6mg of the lignin dimer 1c.
i
a real system or a model study. Given that most biaryl moieties Further reaction of the crude mixture with Et3N and Pr2PCl, fol-
in native lignin exist in the form of a dibenzodioxocin struc- lowed by the Rh-catalysed C−C activation, afforded 28.6mg of
tural motif, as suggested by recent studies35, we first explored the pure phenol monomer 3c in 70% yield based on extracted 1c,
the feasibility of converting the dibenzodioxocin linkage to the which corresponded to a 0.08% wt/wt overall yield of the product
5–5 (free phenol) form through a catalytic C−O bond cleav- based on the biomass used. As this process is conducted in a glove
age36. Inspired by the Pd/C-catalysed C−O cleavage method of box, at present it only serves to highlight the potential of aryl−aryl
Hartwig and co-workers30, the dibenzodioxocin model compound bond cleavage in 2,2′-biphenols for lignin valorization.
9 was subjected to the hydrogen-free conditions with a mixture of
1,4-dioxane/p-cymene (1:1) as the solvent (Fig. 4b). Gratifyingly, Conclusion
29
using either Pd/C or Ru/C (ref. ) as the catalyst, the desired 5–5 In summary, the catalytic activation of aryl−aryl bonds into 2,2′
model 1c was provided in good yields. Moreover, an improved -biphenols is enabled by a RDG strategy. The reaction is chemose-
efficiency (81% yield) was obtained when the reaction was run lective and scalable with a low catalyst loading. The preliminary
under a low pressure of H2 in methanol with the Ru/C catalyst. synthetic utility of this biaryl-activation method is described in
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22. Luo, J., Preciado, S. & Larrosa, I. Overriding ortho–para selectivity via a
the realization of an unconventional site selectivity for the syn-
thesis of 2,3,4-trisubstiuted phenols. However, the demonstration
of the use of the methods to break lignin aryl−aryl linkages is still
at the proof-of-concept stage. It is anticipated that the mechanistic
insights obtained from this study should have broad implications
for the discovery of new catalytic methods to activate non-polar and
unstrained C−C bonds in common organic compounds.
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Data availability
Crystallographic data for the structures reported in this article have been deposited at
the Cambridge Crystallographic Data Centre, under deposition nos CCDC 1848268
(2z), 1848266 ([Rh(2al)Cl)]2) and 1848267 (8g). Copies of the data can be obtained
free of charge from www.ccdc.cam.ac.uk/structures/. All other data that supporting
the findings of this study are available within the article and its Supplementary
Information, or from the corresponding author upon reasonable request.
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Received: 19 May 2018; Accepted: 10 September 2018;
Published: xx xx xxxx
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Competing interests
The authors declare no competing interests.
additional information
Supplementary information is available for this paper at https://doi.org/10.1038/
s41557-018-0157-x.
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