Organocatalyst-controlled site-selective arene C–H functionalization

Article abstract of DOI:10.1038/s41557-021-00750-x

Over the past three decades, organocatalysis has emerged as a powerful catalysis platform and has gradually been incorporated into the routine synthetic toolbox to obtain chiral molecules. However, its application in the site- and enantioselective functionalization of inactive aryl C–H bonds remains in its infancy. Here, we present an organocatalyst-controlled para-selective arene C–H functionalization strategy that addresses this issue, which remains an enduring challenge in arene functionalization chemistry. By emulating enzyme catalysis, the chiral phosphoric acid catalyst offers an ideal chiral environment for stereoinduction, and the projecting substituents give control of chemo- and site-selectivity. Various types of nucleophile are compatible with this method, affording more than 100 para-selective adducts with stereodefined carbon centres or axes in viable molecular contexts. This protocol is expected to provide a general strategy for para-selective functionalization of arene C–H bonds in a controlled manner. [Figure not available: see fulltext.]

Full text of DOI:10.1038/s41557-021-00750-x

Articles
https://doi.org/10.1038/s41557-021-00750-x
Organocatalyst-controlled site-selective arene
C–H functionalization
2,4
3
1
1
Jian-Hui Mao1,4, Yong-Bin Wangꢀ ꢀ1,4 , Limin Yang , Shao-Hua Xiang , Quan-Hao Wu , Yuan Cui ,
ꢀ✉
1
1
3
1
ꢀ✉
Qian Lu , Jie Lv , Shaoyu Li and Bin Tanꢀ ꢀ
Over the past three decades, organocatalysis has emerged as a powerful catalysis platform and has gradually been incorporated
into the routine synthetic toolbox to obtain chiral molecules. However, its application in the site- and enantioselective function-
alization of inactive aryl C–H bonds remains in its infancy. Here, we present an organocatalyst-controlled para-selective arene
C–H functionalization strategy that addresses this issue, which remains an enduring challenge in arene functionalization chem-
istry. By emulating enzyme catalysis, the chiral phosphoric acid catalyst offers an ideal chiral environment for stereoinduction,
and the projecting substituents give control of chemo- and site-selectivity. Various types of nucleophile are compatible with
this method, affording more than 100 para-selective adducts with stereodefined carbon centres or axes in viable molecular
contexts. This protocol is expected to provide a general strategy for para-selective functionalization of arene C–H bonds in a
controlled manner.
irect site- and enantioselective arene C–H functionaliza- the introduction of a sterically hindered co-catalyst or ligand23–27
tion streamlines methods for acquiring multi-substituted (Fig. 1b). However, these systems are tied to metal catalysis, and
D
chiral arene structures1–3. Among the latent reactive sites asymmetric variants remain under-represented.
on a substituted benzene ring, functionalization of the most distal
para-C–H bond appears particularly challenging due to its rela- a powerful catalysis platform that is gradually being incorporated
tive remoteness from the directing handle. By virtue of the innate into the routine synthetic toolbox to obtain chiral molecules30–34
Over the last three decades, organocatalysis28,29 has emerged as
.
substituent orientation effect enforced by electron-donating arene However, organocatalytic site- and enantioselective functional-
substituents, such transformations could be enabled by SEAr-type ization of inactive aryl C–H bonds remains in its infancy, largely
reactions4,5 and C–H substitution via a radical path6–8. However, due to the scarcity of organocatalysts with activating potency that
rival ortho-C–H bond functionalization presents in most scenarios. compares favourably to metal catalysts, as well as the high energy
A chelation-assisted C–H activation strategy could override the barrier encountered during the dearomatization process. The
inherent electronic bias by regulating site-selectivity through coor- capability of finely tuned organocatalysts carrying an enzyme-like
dination with the metal centre; however, only limited examples of chiral microenvironment to foster stereoinduction in challenging
D-shaped assemblies—formed by the substrate, directing group asymmetric reactions, as well as the tunability of the chiral control
and transition metal—are currently available9–17, so strategies for region35–40, prompted our postulation of an organocatalytic reaction
ideal para-selective reactions remain to be developed (Fig. 1a). mode to realize long-range enantiocontrolled functionalization of
Accordingly, a robust protocol for functionalizing the arene C–H the para-C–H bond of arene. Our previous findings41 showed that
bond with competent para control is still a challenging issue in interaction between a chiral phosphoric acid (CPA)42–45 and an azo
conventional arene chemistry. More importantly, the harsh reac- group directs activation towards the adjacent carbon centre on the
tion conditions needed to overcome the high dearomatization bar- naphthalene ring under mild conditions. By analogy to enzymatic
rier and/or to provoke inert C–H bond activation/insertion could catalysis19, where the site-selectivity of a reaction is modulated by
hinder achieving the desired site- and enantiocontrol. On a related the spatial position of residues at the active site, we envisioned
note, a more efficient catalyst-controlled strategy is realized in achieving asymmetric functionalization of arene para-C–H bonds
nature by enzymatic catalysis, which accomplishes the site-selective by methodical modulation of the activation channel in the CPA
functionalization of an electronically unbiased C–H bond18. Varying catalyst, as well as tactical introduction of the azo functionality
the enzyme cavity by mutation of amino-acid residues at the active on substrates as an association point (Fig. 1c). Contrary to classic
pockets of toluene monooxygenase leads to modular and regiospe- electrophilic aromatic substitution (SEAr) reactions4, this nucleo-
cific oxidation19. The intriguing correlation between the configu- philic aromatic substitution (SNAr) protocol enables a fundamental
rational structure of the enzyme and site-selectivity incentivized shift to utilize nucleophilic reactants, thus broadening the sub-
the work of Davies et al. showing enantioselective differentiation strate choices and avoiding the latent side reactions that otherwise
of the pervasive non-activated sp3 C–H bonds without direct- beleaguer SEAr reactions because of the substituent orientation
ing groups, but via subtly modified spatial arrangement of chiral effect. Concurrently, a nucleophilic addition onto a single benzene
dirhodium catalysts20–22. The catalyst-controlled strategy was also ring exerts more drastic aromaticity disruption compared to the
efficiently used to selectively functionalize the para-C–H bond by naphthalene system, and thus necessitates a more ideal reactivity
1Shenzhen Grubbs Institute and Department of Chemistry, Guangdong Provincial Key Laboratory of Catalysis, Southern University of Science and
Technology, Shenzhen, China. 2College of Materials, Chemistry and Chemical Engineering, Hangzhou Normal University, Hangzhou, China. 3Academy for
Advanced Interdisciplinary Studies, Southern University of Science and Technology, Shenzhen, China. 4These authors contributed equally: Jian-Hui Mao,
✉
Yong-Bin Wang, Limin Yang. e-mail: wangyb@sustech.edu.cn; tanb@sustech.edu.cn
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a
Ile100
b
SEAr reaction
Radical substitution
Chelation-assisted C–H activation
Gly103
Phe176
His137
X
Distal C–H bond
Template
R
H
FeA
R
O
H
Fe IV
X
H
H
H
X
Glu231
FeB
R
H
Ala107
S
M
ortho vs para
Glu197
His234
Phe180
Competitive process
Radical cations
CYP119-1 with substance
H
T3Mo with substance
R
c
Favoured sites
Tunable
chiral
H
space
N
R
N
R
N
N
Nu
CPA
H
M
Nu
Direct arylation
Steric arm =
Remote site
Defined dirhodium catalyst
co-catalyst or ligand
Fig. 1 | Selective functionalization of C–H bonds and our design blueprint. a, Substituent-directed para-selective C–H functionalization, including
classic electrophilic aromatic substitution (SEAr) reactions, radical substitution and a chelation-assisted C–H activation strategy. b, Catalyst-controlled
site-selective C–H functionalization in enzyme and metal catalysis. Enzymes adjust the site-selectivity of C–H activation reactions by changing the
spatial configuration of the active pocket. Metal catalysis can also achieve site-selective C–H activation by adjusting the spatial structure of the ligands.
c, Organocatalyst-controlled para-selective and enantioselective arene C–H functionalization. High site-selective and enantioselective arene C–H
functionalization is achieved through organocatalysed nucleophilic aromatic substitution (SNAr) of azobenzenes.
channel to counterbalance the high activation energy via an of acetonitrile over other tested solvents. Performing the titled
enhanced substrate–catalyst interaction. We further posited pro- transformation at higher reaction molarity and with prolonged
jecting substituents onto the CPA backbone to hinder the approach duration finally afforded 3a-C-para in 92% yield (optimal condi-
of reactants and suppress C-functionalization of the ortho-carbon tions; Fig. 2a, entry 15). Notably, outstanding enantioinduction was
and N-functionalization at the azo entity, making available the consistently imposed by most CPAs bearing sufficiently bulky sub-
para-C–H bond for activation. Judicious selection of other react- stituents, regardless of the other reaction parameters. This substan-
ing partners that can facilely approach and form effectual binding tiated the decisive role of the unique interactions between CPA and
with the active site of CPA is equally instrumental. Ultimately, pre- the oxazolone nucleophile in this catalysis protocol.
cise enantiocontrol at the distant para position calls for extraordi-
narily effective chiral recognition of substrates by the CPA catalyst. Substrate scope. With establishment of the optimal reaction condi-
Guided by these propositions, we have realized a robust organocata- tions, we set out to evaluate the substrate generality of azobenzene
lytic system to give exquisite control of site- and stereoselectivity in derivative 1, as outlined in Table 1. Absolute enantiocontrol was
para-C–H bond functionalization of azobenzene compounds with similarly observed for azobenzene with an ethyl ester group (in place
diversified C-nucleophiles.
of the methyl ester) to provide para-selective product 3b in 84%
yield. Installing ortho-substituents relative to the azo handle, such
as methyl, methoxy and methylthio groups and halides, had a neg-
results and discussion
Reaction development. Because a confined reactivity pocket may ligible influence on the reaction outcomes, regardless of electronic
be inaccessible for sterically demanding nucleophiles, and small property (3c–3h). Other isomers of disubstituted azobenzenes with
nucleophilic reactants could endanger selectivity control, we chose meta substitution gave chiral molecules 3j–3l in relatively lower
elaborated oxazolone nucleophiles possessing synthetic potential as yields, except the methyl congener (3i). Interestingly, extremely
cyclic precursors of amino acids to verify our hypothesis. As shown high efficiency was restored with the addition of a C2 substituent
in Fig. 2a, the initial trial began by treating azobenzene 1a with (3m–3o). The moderate yields obtained for 3,5-disubstitued azo
oxazolone 2a and a catalytic amount of achiral Brønsted acid C1 substrates could indicate the presence of an undesired steric effect
in CH2Cl2 at room temperature. The 12-h reaction yielded a prod- during nucleophilic addition (3q and 3r). A subsequent probe of
uct mixture composed of the ortho-C–H functionalization product the oxazolones scope afforded an array of highly enantioenriched
(3a-C-ortho) as the major component and azo-functionalization amino-acid precursors (3s–3ae) in yields ranging from 69 to 98%
adduct 3a-N in 16% yield, without any targeted 3a-C-para and e.e. values exceeding 99%, demonstrating the compatibility of
(Fig. 2a, entry 1). This was in line with a dominating ortho-C–H oxazolone substrates with the current catalytic system. Other than
bond activation when the steric shielding impact from the catalyst the benzyl-type substituents, cyclohexyl and isopropyl groups con-
is not there to obstruct the native reaction sites. We next surveyed a taining oxazolones were also well suited, with the beneficial effect of
collection of CPAs bearing varied axially chiral backbones and began C2 substitution in this transformation evident. Subsequently, oxin-
to observe trace formation of 3a-C-para (6% yield, 50% e.e.) when dole 4a, a similar prochiral C-nucleophile, was treated under stan-
C4 with a 3,5-dimethylphenyl group at both the 3- and 3′-positions dard conditions with the chosen substrate, 2-methoxy-substituted
of the 1,1′-bi-2,2′-naphthol (BINOL) scaffold was used (Fig. 2a, azobenzene 1d. The high yield of para-selective adduct 5a (95%)
entry 4). In line with our hypothesis, product distributions with and virtually vanishing enantioinduction (2% e.e.) when using the
respect to site selection were found to be dependent on the steric bulk same catalyst C10 suggested a sustained CPA–azo group association
of the core backbones in the CPAs surveyed (Fig. 2a, entries 2–11), bypassing reactions on the nitrogen and ortho-carbon centres, but
as displayed in the bar chart in Fig. 2b. When a 1,1′-spirobiindane- a reduced enantio-discrimination due to the specificity of the chiral
7,7′-diol (SPINOL)-derived C10 was included, 3a-C-para was the cavity. As shown in Table 2, changing to C12, embracing the same
major product, with 66% yield and extraordinary enantiopurity SPINOL scaffold, notably enhanced the enantioselectivity to 95% in
(Fig. 2a, entry 10). Subsequent examination revealed a superiority CCl4, without erosion of efficiency. Oxindoles 4 with a broad range
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a
H
O
O
O
Tol
N
CO2Me
O
Tol
N
1
N
2
O
Bn
O
H
O
Tol
N
CO2Me
N
Cat. (5 mol%)
Conditions
N
Bn
Bn
H
+
+
+
O
N
N
CO2Me
N
CO2Me
N
N
H
N
Bn
3
H
1a
2a
3a-N
3a-C-ortho
Tol
3a-C-para
e.e. (%)b
b
Catalyst
Isolated yield (%)
C1
C2
Entrya
1
Cat.
Solvent
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
3a-N
3a-C-para
3a-C-para
–
3a-C-orthoc
C3
C1
16
27
15
15
13
19
13
19
8
0
0
49
64
54
36
19
9
C4
2
(rac)-C2
(R)-C3
(R)-C4
(R)-C5
(R)-C6
(R)-C7
(S)-C8
–
3a-C-para
3a-C-ortho
3a-N
C5
C6
3
Trace
6
67
C7
4
50
C8
C9
5
7
92
C10
dC10
6
3
>99
91
Yield (%)
100
7
2
24
22
12
8
0
20
40
60
80
c
R
(rac)-C2, R = H
(R)-C3, R = C6H5
8
11
19
66
54
33
51
78
92
99
O
O
O
O
O
(R)-C4, R = 3,5-Me2C6H3
(R)-C5, R = 3,5-tBu2C6H3
(R)-C6, R = 9-anthryl
9
(S)-C9
>99
>99
–99
>99
>99
>99
>99
P
P
O
OH
OH
10
11
12
13
14
15d
(S)-C10
(R)-C11
(S)-C10
(S)-C10
(S)-C10
(S)-C10
7
(R)-C7, R = 9-phenanthryl
C1
R
15
35
7
4
Me
4
R
R
(S)-C8, R = 1-naphthyl
(S)-C9, R = 3,5-(CF3)2C6H3
(S)-C10, R = 3,5-Ph2C6H3
DCE
9
O
O
O
O
P
P
O
OH
O
OH
CH3CN
CH3CN
5
5
(R)-C11, R = 3,5-Ph2C6H3
R
R
Trace
Trace
H
Me
H
N
d
NH2
N
CO2Me
O
N
Bn
MeO2C
Tol
H
Bn
O
Bn
1) MeOH, MeONa
BzCl, TEA, CH2Cl2
99%
NH
O
2) H2, Raney Ni
two steps:
86%
MeO2C
N
CCDC
NH
O
1992068
3a (0.92 g)
Tol
O
Tol
90%, >99% e.e.
13 (>99% e.e.)
14 (>99% e.e.)
NH2
H
NH2
e
N
CO2Me
H
N
S
N
EtO2C
H
EtO2C
H2, Raney Ni
94%
1) p-NsCl, pyridine
EtO2C
O
OMe
O
O
OMe
OMe
2) SnCl2, MeOH
two steps:
57%
O
CCDC
O
N
N
1992069
N
5b (1.10 g)
Me
Me
95%, 97% e.e.
15 (97% e.e.)
16 (97% e.e.)
Me
Me
H
f
MeO
NH2
MeO
N
CO2Me
H
N
S
N
MeO
H
H2, Raney Ni
99%
TsCl, pyridine
94%
O
O
Me
CCDC
Me
N
N
Me
H
Me
Me
8a (1.21 g)
99%, 96% e.e.
1992073
H
N
Me
H
17 (94% e.e.)
18 (94% e.e.)
MeO2C
S
g
H
N
CO2Me
NH2
MeO2C
SO2Cl
N
N
H2, Raney Ni
TEA, CH2Cl2
S
+
O
O
S
N
OMe
N
H
OMe
N
OMe
H
H
10a
19
20
GSK0660, 77%
Fig. 2 | Condition optimization and transformations. a, Summary of the reaction outcomes for all generated products and selectivities. aReaction
carried out with 1a (0.10ꢀmmol), 2a (0.12ꢀmmol) and catalyst (5ꢀmol%) in 2.0ꢀml of solvent at r.t. for 12ꢀh, unless noted otherwise. bThe e.e. values were
determined by HPLC analysis using a chiral stationary phase. cContains other compounds derived from 3a-C-ortho. d0.5ꢀml of CH3CN was used and the
reaction proceeded for 36ꢀh. b, Site selectivity for the examined CPAs. c, CPA structures. d, Transformation of 3a to amino-acid derivatives. The absolute
configuration of 3a was derived from the X-ray diffraction analysis of 14. e, Derivatization of compound 5b. The absolute configuration of 5b was derived
from the X-ray diffraction analysis of 16. f, Derivatization of compound 8a. The absolute configuration of 8a was derived from the X-ray diffraction analysis
of 18. g, Two-step synthesis of bioactive GSK0660 from amination products 10a.
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Table 1 | Organocatalysed arene C–H functionalization with oxazolones under condition a
Me
H
N
CO2R1
R
Ar
N
R
CO2R1
H
N
C10 (5 mol%)
O
O
O
O
N
P
R2
+
N
O
R2
OH
CH3CN, r.t.
N
O
O
Ar
C10
Tol
1
2
3
Ar = 3,5-Ph2C6H3
Tol
CO2Me
Me
CO2Me
H
N
H
H
N
H
H
Ph
O
N
e
CO2M
CO2Me
N
CO2Et
N
N
N
N
N
N
H
H
H
H
H
N
Nu
Me
OMe
SMe
O
Nu
Nu
Nu
Nu
Nu
Nu
Nu
Nu
Nu
Tol
3a, 92%, >99% e.e.
3b, 84%, >99% e.e.
3c, 98%, >99% e.e.
3d, 93%, >99% e.e.
3e, 95%, >99% e.e.
H
H
H
H
H
H
N
CO2Me
N
CO2Me
N
CO2Me
N
CO2Me
N
CO2Et
N
CO2Et
N
N
N
N
N
N
H
H
H
H
H
H
Cl
Br
I
Nu
Nu
Nu
Me
SMe
Cl
3f, 97%, >99% e.e.
3g, 98%, >99% e.e.
3h, 94%, >99% e.e.
3i, 91%, >99% e.e.
3j, 70%, >99% e.e.
3k, 59%, >99% e.e.
OMe
H
H
H
H
H
H
N
CO2Me
N
CO2Me
N
CO2Me
N
CO2Me
MeO
Nu
N
CO2Me
N
CO2Me
N
N
N
N
N
N
H
H
H
H
H
H
OMe
Cl
Me
Nu
Nu
Nu
Nu
Br
OMe
3m, 97%, >99% e.e.
OMe
3n, 99%, >99% e.e.
OMe
3o, 99%, >99% e.e.
OMe
3q, 42%, >99% e.e.
OMe
3p, 69%, 96% e.e.
3l, 50%, >99% e.e.
H
H
H
3y, R = 4-MeC6H4CH2, 98%, >99% e.e.
3z, R = 4-CNC6H4CH2, 88%, >99% e.e.
3aa, R = 4-PhC6H4CH2, 91%, >99% e.e.
3ab, R = 1-NaphthylCH2, 93%, >99% e.e.
3ac, R = CyclohexylCH2, 87%, >99% e.e.
3ad, R = Cyclohexyl, 75%, >99% e.e.
3ae, R = Isopropyl, 86%, >99% e.e.
F
N
CO2Me
N
CO2Me
N
CO2Me
3s, R = 4-MeC6H4, 82%, >99% e.e.
3t, R = 4-FC6H4, 85%, >99% e.e.
3u, R = 4-CNC6H4, 70%, >99% e.e.
3v, R = 4-PhC6H4, 93%, >99% e.e.
3w, R = 1-Naphthyl, 81%, >99% e.e.
3x, R = Cyclohexyl, 69%, >99% e.e.
N
N
N
R
H
H
H
R
O
OMe
O
Nu
N
N
OMe
3r, 65%, >99% e.e.
O
O
Tol
Tol
Condition A: all reactions were carried out with 1 (0.10ꢀmmol), 2 (0.12ꢀmmol), C10 (5ꢀmol%) and CH3CN (0.5ꢀml) at room temperature for 36ꢀh. The e.e. values were determined using HPLC analysis.
Table 2 | Organocatalysed arene C–H functionalization with oxindoles under condition B
Br
H
N
CO2Me
CO2R1
O
Ar
N
R1O2C
H
N
CO2Me
C12 (5 mol%)
O
N
O
O
R2
P
+
R
R
OH
R2
O
CCl4, r.t.
N
Ar
N
Me
C12
1
4
5
Me
Ar = 9-phenanthryl
Br
H
H
H
H
H
N
N
H
N
CO2Me
N
CO2Me
N
CO2Me
N
CO2Me
CO2Me
N
N
H
N
N
H
H
H
MeO2C
EtO2C
EtO2C
MeO2C
EtO2C
OMe
SMe
Me
Me
OMe
O
O
O
O
O
N
N
N
N
Me
N
5a, 95%, 96% e.e.
5b, 94%, 98% e.e.
5c, 99%, 98% e.e.
5d, 87%, 95% e.e.
5e, 86%, 97% e.e.
Me
Me
Me
Me
H
H
N
N
H
H
H
N
CO2Me
CO2Me
N
CO2Me
N
CO2Me
N
N
N
H
EtO2C
Br
H
H
EtO2C
EtO2C
EtO2C
OMe
F
OMe
O
OMe
OMe
O
O
O
N
N
N
Me
N
Cl
Br
Me
5f, 91%, 96% e.e.
5g, 94%, 97% e.e.
5h, 94%, 96% e.e.
5i, 95%, 97% e.e.
Me
Me
Condition B: all reactions were carried out with 1 (0.10ꢀmmol), 4 (0.12ꢀmmol), C12 (5ꢀmol%) and CCl4 (2.0ꢀml) at room temperature for 12–36ꢀh. The e.e. values were determined using HPLC analysis.
of substituents and substituent patterns were tested to give the cor- rable size to the substantiated nucleophiles were first considered.
responding products 5 carrying a quaternary carbon stereocentre, Experimental results for the reaction between indole 6a and azo-
in excellent yields and enantioselectivities (5a–5i).
benzene 1a with respect to representative CPAs are summarized in
The established strategy for asymmetric access to two classes of Supplementary Table S2. Similarly, achiral C1 and (rac)-C2 without
quaternary carbon stereocentres with excellent para- and enanti- 3,3′-substituents on the BINOL skeleton delivered a trace amount of
oselectivities stimulated our exploration of aromatic C-nucleophiles the desired para-addition heterobiaryl 7a in this system on account
to synthesize biaryl structures. Indole derivatives 6 of compa- of competitive addition onto the azo group. Similar results were
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Table 3 | Organocatalysed arene C–H functionalization with indoles under conditions C and D
Me
Me
R1
H
Ar
N
CO2Me
Conditions
C or D
Ar
R2
N
R1
H
N
CO2Me
O
R2
O
O
O
O
O
N
P
+
P
OH
OH
N
H
Ar
N
H
Ar
C14
(rac)-C10
1
6
7 / 8
Me
Me
Ar = 3,5-Ph2C6H3
Ar = 3,4,5-(MeO)3Ph
Achiral products: Condition C
HO
H
H
N
H
N
N
H
H
HO
HO
HO
HO
N
CO2Me
CO2Me
CO2Me
N
CO2Me
N
N
N
H
H
H
Me
OMe
SMe
N
N
H
N
H
N
H
7a, 71%
7b, 98%
7c, 79%
7d, 91%
Me
H
Me
Me
Me
Me
Me
H
H
H
H
HO
HO
HO
N
CO2Me
N
CO2Me
N
CO2Me
N
CO2Me
N
N
N
N
H
H
H
H
Cl
Me
Br
OMe
OMe
N
N
H
N
H
N
H
Me
H
Me
Me
7e, 95%
7f, 86%
7g, 86%
7h, 98%
H
H
H
H
N
CO2Me
N
CO2Me
N
CO2Me
MeO
N
CO2Me
N
N
N
N
H
H
H
H
Me
N
OMe
Me
SMe
OMe
N
H
N
H
N
H
Me
H
Me
Me
7i, 74%
7j, 89%
7k, 95%
7l, 97%
Cl
H
H
H
H
Br
N
CO2Me
N
CO2Me
N
CO2Me
N
CO2Me
N
N
N
N
H
H
H
H
OMe
N
OMe
OMe
OMe
OMe
OMe
OMe
N
H
N
H
N
H
Me
H
Me
Me
Me
Ph
Me
7m, 97%
7n, 94%
7o, 98%
7p, 89%
H
H
H
H
Me
MeO
N
CO2Me
N
CO2Me
N
CO2Me
N
CO2Me
N
N
N
N
H
H
H
H
OMe
N
N
H
N
H
N
H
Me
H
tBu
7q, 94%
7r, 97%
7s, 98%
7t, 97%
Axially chiral products: Condition D
H
H
H
H
MeO
N
CO2Me
MeO
N
CO2Et
MeO
N
CO2iBu
MeO
N
CO2Bn
N
N
N
N
H
H
H
H
Me
Me
Me
Me
N
N
N
N
H
Me
Me
Me
Me
Me
Me
Me
Me
H
H
H
8a, 99%, 96% e.e.
8b, 99%, 95% e.e.
8c, 81%, 93% e.e.
8d, 97%, 93% e.e.
H
H
F
Me
H
H
MeO
N
CO2Me
HO
MeO
N
CO2Me
MeO
MeO
N
CO2Me
MeO
N
CO2Me
N
N
N
N
H
H
H
H
Me
8h, 99%, 95% e.e.
Me
N
H
Me
Me
N
N
H
N
H
H
8e, 99%, 90% e.e.
8f, 98%, 92% e.e.
8g, 99%, 95% e.e.
H
H
N
MeO
N
CO2Me
H
N
Br
MeO
CO2Me
MeO
CO2Me
N
N
H
N
H
H
Me
tBu
N
Me
Me
N
H
N
iPr
Me
H
H
8i, 98%, 93% e.e.
8j, 95%, 98% e.e.
8k, 92%, 99% e.e.
Condition C: all reactions were carried out with 1 (0.20ꢀmmol), 6 (0.24ꢀmmol), (rac)-C10 (5ꢀmol%) and CH2Cl2 (2.0ꢀml) at room temperature for 0.5–120ꢀh. Condition D: all reactions were carried out with 1
(0.20ꢀmmol), 6 (0.24ꢀmmol), C14 (2ꢀmol%) and CH2Cl2 (2.0ꢀml) at −40ꢀ°C for 6–120ꢀh. The e.e. values were determined using HPLC analysis.
obtained for C7 and C8, which could not provide a suitable cavity π–π interaction with the reactant, gave rise to lower efficiency (for
to position the substrates in a favourable fashion. Pleasingly, both details see Supplementary Table 2). Unfruitful investigations of
racemic and enantiopure C10, with verified and well-organized spa- other reaction parameters to improve the reaction outcome further
tial configuration, boosted the para-selective functionalization effi- demonstrated the unique correlation between site-selectivity and
ciency to 71% yield in 24h, whereas C13, which provided a stronger the three-dimensional structure of the catalyst.
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Table 4 | arene para-activation using anilines under condition e
Me
R
N
CO2Me
N
CO2Me
N
O
O
(rac)-C10 (1 mol%)
N
P
NH2
+
O
OH
CH2Cl2/MeOH, r.t., 6 d
N
OMe
OMe
H
R
(rac)-C10
R = 3,5-Ph2C6H3
1d (0.44 mmol)
9a (0.20 mmol)
10a, 79%
Me
F
N
CO2Me
Cl
N
CO2Me
N
CO2Me
N
CO2Me
N
N
N
N
N
H
OMe
N
OMe
N
O2N
N
OMe
Cl
N
OMe
H
H
H
10b, 83%
10c, 69%
10d, 87%
10e, 69%
10i, 73%
N
CO2Me
N
CO2Me
N
CO2Me
CO2Me
N
N
N
N
N
OMe
N
OMe
Br
N
H
OMe
MeO2C
N
H
OMe
H
H
OMe
Br
10f, 69%
10g, 78%
10h, 73%
CO2Me
CO2Me
CO2Me
N
CO2Me
N
N
CO2Me
N
N
CO2Me
N
CO2Me
N
N
N
OMe
MeO2C
N
H
OMe
MeO2C
N
SMe
MeO2C
N
Me
H
H
10j, 90%
10k, 86%
10l, 94%
10m, 64%
Condition E: all reactions were carried out with 1 (0.20–0.44ꢀmmol), 9 (0.10–0.20ꢀmmol), (rac)-C10 (1–5ꢀmol%) and MeOH/CH2Cl2 (0.25–2.0ꢀml) at room temperature for 24–240ꢀh. The e.e. values were
determined using HPLC analysis.
The generality of the indole-aryl structures was exploited by the and azobenzene 6c with impressive site-selectivity (10a). Notably,
current para-selective C–H functionalization strategy. As shown in the conventionally formed hydrazine was unstable in this trans-
Table 3, a wide range of azobenzenes 1 were surveyed, and notice- formation due to its low oxidation potential and spontaneously
ably improved transformation yields were demonstrated on sub- converted to azo by the oxidation of azobenzene41,46. Thus, excess
strates bearing one or two substituents on the aromatic ring (7b–7t). azobenzene was added to completely oxidize the hydrazine for
This reaction was also amendable to halogen-atom-containing sub- this class of substrates to simplify the reaction system. In contrast
strates and formed the desired heterobiaryls with remarkable effi- to other tested nucleophiles, a longer reaction duration was essen-
ciencies (7e and 7g). The installation of a strong electron-donating tial for better conversion due to the potential catalyst deactivation
group at the meta position of azobenzene exhibited a commendable induced by basic anilines (Table 4). Electron-poor ester groups
positive effect reflected in high product yields (7j–7o). Negative on the 3,5-positions of aniline could allay this adverse effect, giv-
results were obtained when using the indoles without substitu- ing satisfactory reaction efficiencies (10j–10l). Indoline, repre-
ents at the 2-position as substrates (for details see Supplementary senting a secondary amine substrate, was incorporated in 10m in
Fig. 6), indicating that the 2-substituents play a critical role in the a synthetically useful yield. This arene C–H amination protocol
transformation. It should be noted that substitution patterns on provided to be an effective complementary method to conven-
2-substituted indoles exerted a negligible influence on the reaction tional transition-metal catalytic variants, which often proceed
outcomes (7p–7t). Moreover, the excellent yield of product 7l with under harsh conditions. Subsequently, 2-mercaptopyridine 11a
di-meta-substituted azobenzene suggested the implementation of was chosen and verified as a competent S-nucleophile to assemble
an atroposelective variant with the current protocol.
diaryl thioether 12a in commendable yield and selectivity (para/
Accordingly, the assembly of enantioenriched aryl-indole atropi- others>20/1) with catalyst (rac)-C10 in CH2Cl2 or acetonitrile
somers was launched by exposing 3,5-disubstituted azobenzene 1v (Table 5). It should be pointed out that on switching the catalyst to
to 2-methylindole 6b under the developed standard conditions. The C1, the reaction efficiency for 12a was compromised pronouncedly
targeted atropisomer 8a was produced in near quantitative yield as a result of the dominant formation of by-products. With 11a as a
(97%) but modest atroposelectivity (52% e.e.) with (S)-C10, while model nucleophile, a wide array of azobenzenes worked well for this
(rac)-C10 forged racemic 8a in a similar excellent yield. Subtle reaction to generate aryl-thiolated compounds 12b–12q in moder-
modification of the SPINOL framework in the CPA structure pre- ate to excellent yields (Table 5). In contrast to the earlier reactions,
sented C14 as the optimal facilitator. As shown in Table 3, a range of halide substituent(s) on azobenzene could hamper the product yield
azobenzenes and indoles were investigated for this atroposelective and site-selectivity (12d–12e, 12h–12i and 12p–12q). Meanwhile,
transformation to deliver the respective axially chiral adducts with 2-mercaptobenzoxazole (11b), 2-mercaptobenzothiazole (11c and
outstanding enantiocontrol (8a–8k). In particular, this reaction 11d) as well as 1,3,4-thiadiazole-2-thiol (11e) complied well with
exhibited good tolerance to the electron-withdrawing ester moiety this chemistry to provide 12n–12w in high para selectivities and
on azobenzene partners, axial rotation restriction groups, as well as yields. Additionally, control experiments (Supplementary Fig. 7)
the C5 substituent on indole substrates.
revealed that the sp2-N in the S-nucleophiles plays a critical role in
The attested capability of CPA in activating the para position the control of para selectivity and reactivity.
of azobenzene offered opportunities to expand on the diversity of
nucleophiles. Beyond C-nucleophiles, aniline 9a could be engaged Transformation of chiral products. To test the scalability and prac-
as the N-nucleophile to realize N-arylation (Table 4). With catalyst ticality of the developed protocol, a gram-scale synthesis of com-
(rac)-C10, the desirable C–N bond was forged between aniline 9a pound 3a was implemented with the standard set of conditions.
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Table 5 | arene para-activation using arylthiols under condition F
Me
3,5-Ph2C6H3
H
N
CO2Me
N
CO2Me
(rac)-C10 (5 mol%)
O
N
O
O
N
SH
P
+
H
OH
CH3CN, r.t., 1 d
N
N
S
3,5-Ph2C6H3
(rac)-C10
1a (0.10 mmol)
11a (0.12 mmol)
12a, 95%
Me
Br
H
H
H
N
H
N
CO2Et
N
CO2tBu
Cl
CO2Me
CO2Me
N
CO2Me
CO2Et
CO2Me
N
N
H
N
H
N
H
H
N
S
N
S
N
S
N
S
12b, 93%
12c, 88%
12d, 66%
12e, 56%
H
H
H
N
H
N
Me
S
N
CO2Me
MeS
S
N
CO2Me
N
N
H
N
H
N
H
H
N
N
N
N
S
S
Cl
12h, 71%
N
S
Br
12f, 97%
12j, 93%
OMe
12g, 97%
12i, 71%
H
N
H
N
H
CO2Me
N
CO2Me
N
H
N
H
N
H
N
S
R
N
N
S
Me
OMe
OMe
R = Me, 12l, 86%
12j CCDC 1992074
12k, 99%
R = OMe, 12m, 96%
H
N
H
H
N
N
H
H
CO2Me
MeO
N
CO2Me
MeO
S
CO2Me
MeO
N
CO2Me
N
H
N
N
H
H
S
Cl
N
S
N
N
S
OMe
12o, 92%
F
Cl
12q, 62%
12n, 82%
12r, 94%
12t, 96%
12p, 65%
H
H
N
N
CO2Me
CO2Me
N
N
N
N
H
H
O
S
S
S
S
12r
12s
CCDC 1992075
12s, 97%
12v, 78%
CCDC 1992076
H
N
H
H
N
H
Me
S
CO2Me
MeS
N
CO2Me
Br
CO2Me
Cl
N
N
CO2Me
N
N
H
N
N
N
N
H
N
H
H
S
S
S
N
S
S
S
12u, 98%
12w, 74%
Cl
Cl
Cl
H
N
CO2Me
H
H
H
N
N
N
CO2Me
Me
N
CO2Me
Cl
CO2Me
N
H
N
N
N
N
N
N
H
H
H
S
S
S
S
S
S
S
S
12x, 99%
12y, 97%
12z, 95%
12aa, 99%
Condition F: all reactions were carried out with 1 (0.10ꢀmmol), 11 (0.12–0.14ꢀmmol), (rac)-C10 (5ꢀmol%) and CH3CN (0.50–2.0ꢀml) at room temperature for 12–96ꢀh. The e.e. values were determined using
HPLC analysis.
As displayed in Fig. 2d, the synthesis efficiency and enantiocon- (loss of 2% e.e.). Tosylation then gave compound 18, and the abso-
trol observed for the small-scale reaction were perfectly preserved. lute configuration for this class of atropisomerically enriched prod-
The ring-opening reaction of adduct 3a with sodium methoxide ucts (CCDC 1992073) was determined by X-ray diffraction analysis
and subsequent hydrogenation with Raney nickel gave the chiral of the representative derivative 18 (Fig. 2f). Finally, a bioactive mol-
amino-acid derivative 13 in 86% yield, without any loss of stereo- ecule GSK0660 was synthesized from the amination product 10a
chemical integrity. Facile benzoylation of 13 generated compound in two steps with 77% overall yield, further illustrating the utility of
14 in near quantitative yield, for which the absolute configuration this strategy (Fig. 2g).
was determined by X-ray diffraction analysis (CCDC 1992068) as
R and the configurations of other products were assigned by anal- Mechanistic studies. Kinetic studies showed a distinct linear
ogy. Similarly, 1.1g of 5b was assembled from 1d and 4b in excel- relationship between the initial reaction rates and catalyst con-
lent yield and enantiopurity. Cleavage of the N–N bond by Raney centrations, hinting that the reaction was first order with respect
nickel under H2 atmosphere gave the free amine-containing struc- to the catalyst (Fig. 3b,c). These results, combined with the linear
ture 15 in 94% yield. The absolute configuration of the sulfonylated relationship between the enantiopurities of the product and the
congener 16 was established by X-ray diffraction analysis (CCDC catalyst, indicated that only one CPA molecule participates in the
1992069) as R; compounds 5 as well as precursor 15 were desig- rate- and enantio-determining step47,48. To provide experimental
nated analogously (Fig. 2e). Conserved reactivity and selectivity evidence, we designed and synthesized deuterium-labelled azo-
were correspondingly achieved in scaled-up atroposelective forma- benzene 1a-d1 and 1a-d5 for isotopic labelling studies. We also
tion of axially chiral compounds, as exemplified by heterobiaryl 8a. investigated the products and reaction rates of the para-selective
Hydrogenation of 8a reliably gave product 17 in quantitative yield C–H functionalization of 1a, 1a-d1 and 1a-d5 separately. Under
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a
b
N
R
Tol
O
N
1.20
1.00
0.80
0.60
0.40
0.20
0
H
O
H
O
O
H
Bn
N
O
O
y = 0.0754x
2 = 0.9978
N
P
R
N
N
R
O
OH
Bn
I
Tol
Addition
Aromatization
Pathway A
H
N
R
O
N
R
O
Tol
N
N
Bn
O
H
CPA
+
N
O
0
5.0
10.0
cat (mmol ml−1
15.0
20.0
Bn
N
1
2a
3
C
)
c
Tol
120
H
N
Addition
O
O
N
R
O
O
1.0443
Pathway B
100
80
60
40
20
0
y = 0.8095x
P
Bn
N
Aromatization
Tol
R
2 = 0.9998
O
H
O
H
N
N
R
R
N
N
H
Bn
H
H
Bn
Bn
N
N
[3,3]
[3,3]
N
R
O
N
H
N
O
O
O
II
III
I
O
O
0
20
40
60
80
100
120
Tol
Tol
Tol
Cat. e.e. (%)
O
d
N
HN
O
CO2Me
CO2Me
Bn
H
N
Bn
ΔG (kcal mol−1
)
N
O
O
Bn
N
20.9
H
O
N
H
H
O
P
TSN
N
O
Tol
H
O
P
15.7
O
O
H
Tol
O
P
O
O
TS1
H
O
Tol
O
TS1
*
O
*
O
*
TSp
O
TS3
12.5
O
1a
TS3
10.8
9.9
Bn
IN1
O
TSo
N
H
6.0
O
H
5.4
Tol
TSp
O
P
O
*
IN2
O
IN1
MeO2C
Bn
N
0.0
O
N
–0.4
3a
IN0
–1.9
O
Bn
N
H
O
O
N
IN3
C10
H
Tol
N
O
CO2Me
O
Bn
N
O
P
O
*
O
P
H
H
N
O
O
H
Tol
CO2Me
O
O
O
O
*
IN2
N
Bn
H
H
N
O
IN0
O
P
Tol
H
N
O
O
O
Tol
O
H
IN3
*
–14.4
O
P
O
*
IN4
IN4
O
Fig. 3 | Proposed reaction pathways and mechanistic studies. a, Pathway A: direct nucleophilic addition on the para site of azobenzene. Pathway B:
nucleophilic addition on the azo group, followed by two-fold [3,3]-sigmatropic rearrangement. b, Kinetic study, showing that the transformation for 3a
shows a distinct linear relationship between the initial reaction rate (vinitial) and catalyst concentration (Ccat). Corresponding data can be found on pages 6–8
of the Supplementary Information. c, Graph of the enantiopurity correlation between product and catalyst, showing a linear relationship. Corresponding
data can be found on page 8 of the Supplementary Information. d, Calculated free-energy profile for the formation of 3a. Energies are given in kcalꢀmol−1.
ΔG, Gibbs free energy change; TS, transition state.
standard conditions, 1a-d1 smoothly afforded product 3a in 93% these experimental results were not able to definitively determine
yield and >99% e.e., while 3a-d4 was generated from 1a-d5 in the transition states and reaction mechanism of the para-selective
90% yield and >99% e.e. Kinetic analysis of these labelling experi- arene C–H functionalization. A mechanistic delineation of the
ments showed that the kinetic isotope effect of 1a/1a-d1 was 1.07 aforementioned transformations was put forward as depicted in
and that of 1a/1a-d5 was 0.907, indicating that C–H bond cleavage Fig. 3a, guided by experimental observations. The control experi-
is not the rate-determining step of the catalytic cycle (for details, ments showed that products 3a-N could not be converted to desired
see pages 8 and 9 in the Supplementary Information). However, product 3a-C-para under standard conditions. These observations
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ruled out pathway B49,50, which commences from nucleophilic addi-
tion on the azo group, followed by two-fold [3,3]-sigmatropic rear-
rangement51. To investigate the origins of site selectivities during
C–H functionalization, density functional theory calculations were
conducted on the reaction between 1a and 2a with C10 as catalyst.
In the calculated free-energy profile for the reaction (Fig. 3d), the
CPA C10 and oxazolone 2a form a relatively stable reactant complex
IN0, with the imine entity acting as proton acceptor in the hydrogen
bonding with the catalyst. With the CPA operating as a bifunctional
catalyst and proton shuttle, the reaction is initiated by the deproton-
ation of oxazolone 2a to form munchnone-type intermediate IN1.
An additional hydrogen bond formed between azobenzene 1a and
the bifunctional Brønsted acid catalyst results in a relatively stable
intermediate IN2. An ensuing nucleophilic attack of the deprot-
onated oxazolone on different positions of the activated azo arene
species will lead to regioisomeric products, including 3a-C-para,
3a-C-ortho and 3a-N. The transition state TSp for re-face addition
of the deprotonated oxazolone to the para carbon of the phenyl ring
on the activated azo arene species is energetically most favoured,
with a reaction barrier of only 6.0kcalmol−1, and thus leads to the
major product 3a-C-para (for details, see pages 13 and 14 in the
Supplementary Information).
4. Zhou, Z. & Parr, R. G. Activation hardness: new index for describing the
orientation of electrophilic aromatic substitution. J. Am. Chem. Soc. 112,
5720–5724 (1990).
5. Dey, A., Maity, S. & Maiti, D. Reaching the south: metal-catalyzed
transformation of the aromatic para-position. Chem. Commun. 52,
12398–12414 (2016).
6. Romero, N. A., Margrey, K. A., Tay, N. E. & Nicewicz, D. A. Site-selective
arene C–H amination via photoredox catalysis. Science 349,
1326–1330 (2015).
7. Boursalian, G. B., Ham, W. S., Mazzotti, A. R. & Ritter, T.
Charge-transfer-directed radical substitution enables para-selective C–H
functionalization. Nat. Chem. 8, 810–815 (2016).
8. Berger, F. et al. Site-selective and versatile aromatic C−H functionalization by
thianthrenation. Nature 567, 223–228 (2019).
9. Bag, S. et al. Remote para-C–H functionalization of arenes by a
D-shaped biphenyl template-based assembly. J. Am. Chem. Soc. 137,
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10. Maji, A. et al. Experimental and computational exploration of para-selective
silylation with a hydrogen-bonded template. Angew. Chem. Int. Ed. 56,
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11. Patra, T. et al. Palladium-catalyzed directed para C−H functionalization of
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12. Hoque, M. E., Bisht, R., Haldar, C. & Chattopadhyay, B. Noncovalent
interactions in Ir-catalyzed C–H activation: L-shaped ligand for
para-selective borylation of aromatic esters. J. Am. Chem. Soc. 139,
7745–7748 (2017).
13. Maji, A. et al. H-bonded reusable template assisted para-selective ketonisation
using sof electrophilic vinyl ethers. Nat. Commun. 9, 3582 (2018).
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Conclusion
Although organocatalysis has emerged as a powerful chemical tool
for various synthetic transformations, application to direct arene
activation has not been trivial, especially when chemo-, site- and
enantioselectivities are also primary considerations. We have show-
cased a highly efficient arene activation tactic in which diversified
nucleophiles can be engaged to afford a wide range of para-selective
functionalization products. This chemistry capitalizes on the suc-
cessful merger of CPA and azobenzene derivatives, in which the
CPA facilitates hydrogen-bond-associated catalytic generation
of an active intermediate, where the association could supple-
ment the CPA to mediate arene activation. At the same time, the
well-organized chiral cavity of CPA enables enantio-discrimination
when control of central or axial chirality is viable. The optical
purities of all chiral products were maintained with high fidel-
ity on conversion to the respective derivatives and, notably, enan-
tiopure amino-acid derivatives could be synthesized facilely. It is
expected that this distinctive use of CPA catalysis to coordinate
the reactivity of active species for controllable aromatic ring acti-
vation may be of broad interest to practitioners pursuing selec-
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Online content
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ing summaries, source data, extended data, supplementary infor-
mation, acknowledgements, peer review information; details of
author contributions and competing interests; and statements of
data and code availability are available at https://doi.org/10.1038/
s41557-021-00750-x.
Received: 21 September 2020; Accepted: 8 June 2021;
Published: xx xx xxxx
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Methods
acknowledgements
Method A. To a solution of 2 (0.12mmol) and C10 (4.0mg, 0.005mmol)
in CH3CN (0.5ml), 1 (0.10mmol) was added. Afer stirring for 36h
at room temperature, the mixture was directly purifed by fash column
chromatography on silica gel (eluted with PE/DCM/EtOAc) to give
enantiopure product 3.
We are grateful for financial support from the National Natural Science Foundation of
China (grants 21825105 to B.T. and 21801121 to Y.-B.W.), Guangdong Provincial Key
Laboratory of Catalysis (grant 2020B121201002 to B.T.), Guangdong Innovative Program
(grant 2019BT02Y335 to B.T.), Shenzhen Special Funds (grants JCYJ20180305123508258
to S.-H.X. and JCYJ20180302174106405 to Y.-B.W.), Shenzhen Nobel Prize Scientists
Laboratory Project and SUSTech Special Fund for the Construction of High-Level
Universities (grant G02216402, B.T.). We dedicate this paper to the 100th Anniversary of
Xiamen University.
Method B. To a solution of oxindole 4 (0.12mmol) and C12 (3.4mg,
0.005mmol) in CCl4 (2.0ml), 1 (0.10mmol) was added. After stirring for
12h at room temperature, the mixture was directly purified by flash
column chromatography on silica gel (eluted with PE/DCM/EtOAc) to give
pure product 5.
author contributions
B.T. conceived and directed the project. J.-H.M. and Y.-B.W. designed and performed
experiments. L.Y. performed the density functional theory calculations and mechanism
analysis. S.-H.X., S.L., Q.-H.W., Y.C., Q.L. and J.L. helped with the collection of some new
compounds and data analysis. B.T., S.-H.X., Y.-B.W., S.L. and L.Y. wrote the manuscript
with input from all other authors. All authors discussed the results and commented on
the manuscript.
Method C. To a solution of 1 (0.2mmol), (rac)-C10 (8.0mg, 0.010mmol)
in DCM (2.0ml), indole 6 (0.24mmol) was added at room temperature.
The reaction was stirred until compound 1 was completely consumed
(detected by thin layer chromatography). If a side product from the oxidization
of product was detected, Hantzsch ester (0.10mmol) should be added into the
reaction and stirred for another 6h. The resulting solution was directly purified by
flash column chromatography on silica gel (eluted with PE/EtOAc) to
give pure product 7.
Competing interests
The authors declare no competing interests.
additional information
Data availability
Supplementary information The online version contains supplementary material
available at https://doi.org/10.1038/s41557-021-00750-x.
The X-ray crystallographic coordinates for the products reported in this Article
have been deposited at the Cambridge Crystallographic Data Centre (CCDC),
under deposition nos. CCDC 1992074 (12j), CCDC 1992075 (12r), CCDC
1992076 (12s), CCDC 1992068 (14), 1992069 (16) and 1992073 (18). Copies of the
data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/.
Experimental procedures and characterization of new compounds are available in
the Supplementary Information.
Correspondence and requests for materials should be addressed to Y.-B.W. or B.T.
Peer review information Nature Chemistry thanks Debabrata Maiti and the other,
anonymous, reviewer(s) for their contribution to the peer review of this work.
Reprints and permissions information is available at www.nature.com/reprints.
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