Deacylation-aided C–H alkylative annulation through C–C cleavage of unstrained ketones

Article abstract of DOI:10.1038/s41929-021-00661-7

Arene- and heteroarene-fused rings are pervasive in biologically active molecules. Direct annulation between a C–H bond on the aromatic core and a tethered alkyl moiety provides a straightforward approach to access these scaffolds; however, such a strategy is often hampered by the need of special reactive groups and/or less compatible cyclization conditions. It would be synthetically appealing if a common native functional group can be used as a handle to enable a general C–H annulation with diverse aromatic rings. Here, we show a deacylative annulation strategy for preparing a large variety of aromatic-fused rings from linear simple ketone precursors. The reaction starts with homolytic cleavage of the ketone α C–C bond via a pre-aromatic intermediate, followed by a radical-mediated dehydrogenative cyclization. Using widely available ketones as the robust radical precursors, this deconstructive approach allows streamlined assembly of complex polycyclic structures with broad functional group tolerance. [Figure not available: see fulltext.]

Full text of DOI:10.1038/s41929-021-00661-7

Articles
https://doi.org/10.1038/s41929-021-00661-7
Deacylation-aided C–H alkylative annulation
through C–C cleavage of unstrained ketones
1
ꢀ✉
Xukai Zhouꢀ ꢀ1, Yan Xuꢀ ꢀ1,2 and Guangbin Dongꢀ ꢀ
ꢀ✉
Arene- and heteroarene-fused rings are pervasive in biologically active molecules. Direct annulation between a C–H bond on
the aromatic core and a tethered alkyl moiety provides a straightforward approach to access these scaffolds; however, such a
strategy is often hampered by the need of special reactive groups and/or less compatible cyclization conditions. It would be
synthetically appealing if a common native functional group can be used as a handle to enable a general C–H annulation with
diverse aromatic rings. Here, we show a deacylative annulation strategy for preparing a large variety of aromatic-fused rings
from linear simple ketone precursors. The reaction starts with homolytic cleavage of the ketone α C–C bond via a pre-aromatic
intermediate, followed by a radical-mediated dehydrogenative cyclization. Using widely available ketones as the robust radical
precursors, this deconstructive approach allows streamlined assembly of complex polycyclic structures with broad functional
group tolerance.
renes and heteroarene-fused rings are commonly found in substrates (Fig. 1c). Herein, we report a deacylation-aided C–H
structures of drugs, natural products and other bioactive alkylative annulation of a wide array of arenes and heteroarenes, in
A
compounds (Fig. 1a)1–4. Among many possible synthetic which better step-economy and FG compatibility are realized using
approaches, thedirectintramolecularC–Halkylationofthearomatic unstrained ketones as robust and native radical precursors under
core from a linear precursor, namely C–H alkylative annulation, reductant/oxidant-free and near pH-neutral conditions.
provides a straightforward approach to access these fused scaf-
folds, as prefunctionalization of arenes could be avoided (Fig. 1b)5–8
.
Results
However, a long-standing challenge of this strategy arises from Initial considerations. Homolytic cleavage of ketone α-C–C bonds
limited choices of reactive moieties at the alkyl terminus, regard- has been achieved through the Norrish–Young reaction under
less of whether this is through either a polar- or radical-addition ultraviolet light irradiation47; alternatively, it can be elegantly real-
pathway9–20. The typical alkylative annulation relies on the use of ized by converting ketones into the corresponding oxime esters48–54
/
special or very reactive coupling partners, such as alkyl halides9–13
,
activated ethers55–58 or tertiary alcohols followed by β-scission59–61
.
xanthates14,15 phenyl selenides16, allyl sulfones17, redox-active In our ongoing efforts to develop new C–C activation methods, we
,
esters18,19 and so on; it is generally not a trivial task to introduce recently reported an iridium-catalysed cleavage of the α-C–C bonds
these high-energy functional groups (FGs) with tolerating FGs that of unstrained common ketones using aromatization as the driving
exist in the molecule21,22. In addition, carrying out multi-step opera- force (Fig. 2)62. The reaction involves the formation of a pre-aromatic
tions with these sensitive FGs could also be difficult, which hin- intermediate (A) between the ketone substrate and two activat-
ders implementation of convergent synthetic approaches. Hence, ing reagents (hydrazine and 1,3-diene), which then undergoes the
from the viewpoint of synthetic efficiency, it would be attractive Ir(III)-mediated C–C cleavage driven by pyrazole formation to gen-
to employ common, stable, native FGs as a handle for C–H alkyla- erate a carbon-centred radical and an odd-electron metal-hydride
tive annulation, as this should minimize FG manipulations or the species (B). The radical–metal recombination can be facile, as shown
usage of protecting groups. Recently, successes on mild radical previously, leading to the deacylation products via C–H reductive
annulations have been achieved with unactivated olefins through elimination. However, we hypothesize that, in the presence of an
metal-hydride hydrogen atom transfer23,24 or with carboxylic acids adjacent arene or heteroarene, the transient carbon-centred radical
through oxidative decarboxylation25–29. Tolerance of FGs that are could be trapped intramolecularly; the resulting delocalized radical
sensitive to atom-transfer processes or oxidants in complex settings intermediate (C) could then lose a hydrogen and restore aromaticity
can be a concern. Additionally, primary radicals are hard to gener- to afford the fused bicyclic product.
ate via the metal-hydride hydrogen atom transfer pathway30,31
.
Complementary to the prior arts in the C–H alkylative annula- Reaction discovery and optimization. To test this hypothesis,
tion, a deacylation-aided C–H annulation could serve as a promis- 5-(anthracenyl)pentan-2-one (1), prepared in one step from the
ing alternative strategy for preparing aromatic-fused rings. Ketone corresponding aryl bromide and homoallyl alcohol, was selected
is among one of the most versatile FGs in organic synthesis: they as a model substrate. 4-Methyl-2-pyridylhydrazine (D1) and
can be readily prepared from various other FGs and are derivable 1,3-butadiene were employed as the activating reagents to allow
at the α or β positions32,33. If site-selective C–C cleavage of alkyl in situ formation of the pre-aromatic intermediate. On optimization,
ketones can be realized to generate an active alkyl terminus33–42
,
we were delighted to observe the formation of the desired annula-
such as a carbon-centred radical43–46, for cyclization, a two-phase tion product (2) in 62% yield using [Ir(cod)2]BArF (where cod is
annulation strategy could be imagined from simple arene and alkyl 1,5-cyclooctadiene and BArF is tetrakis[3,5-bis(trifluoromethyl)
1Department of Chemistry, University of Chicago, Chicago, IL, USA. 2The Arnold and Mabel Beckman Laboratory of Chemical Synthesis, Division of
✉
Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA, USA. e-mail: yanxu@caltech.edu; gbdong@uchicago.edu
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a
c
CN
Two-phase annulation
O
HO
For example,
X
MeN
NH
O
R
O
Ar
Ar
OMe
Ar
N
N
MeN
N
N
O
N
NMe2
HO
O
O
OH
Me
OH
Reactive site
Coelonin
(anti-inflammation)
Ro 31-0432
(PKC inhibitor)
CYP11B2
inhibitor
Xanthine analogue
b
R
R
[A]
C–H alkylative annulation
Ar
X
Ar
X
Rapid construction of
linear precursors
Phase I
H
e.g. SEAr or radical cyclization
(ketones as versatile
synthetic handles)
X = C, N
Ar
Annulation usingspecial or
activated FGs as alkylation reagents
Annulation usingcommon, native FGs as alkylation reagents
Previous
Previous
This work
O
[A] =
O
S
R
SeR
X
[A] =
[A] =
Cyclization without
O
FG manuipulation
S
S
(ketones as native
radical precursors)
O
OH
Ketone as robust, native
alkylative annulation reagents
O
Phase II
O
O
N
O
O
Readily available
Readily available
Reductant/oxidant free
1° radical readily accessible
Ar
Reductive/oxidative condition
1° radical hard to access from olefin
Need additional steps to introduce
hard to enable convergent synthesis
Fig. 1 | alkylative annulation of aromatic C(sp2)–H bonds. a, Arene- and heteroarene-fused rings are commonly found in bioactive compounds.
b, Different alkylation approaches used in the alkylative annulation of aromatic C–H bonds. c, A two-phase annulation strategy using ketones as both a
versatile synthetic handle and a native radical precursor. Ar, arene or heteroarene; PKC, protein kinase C; SE, electrophilic aromatic substitution.
O
This work
H
R
R
Deacylation
Unactivated ketone
Deacylative annulation
(and other transformation)
Activating
reagents
Rearomatization and
catalyst regeneration?
-[Ir]I
A
N
Pre-aromatic
intermediate
N
H
R
H
[Ir]II
C
Previously
established
N
N
[Ir]I
Intramolecular trapping
before radical–metal
recombination?
R = Ar
B
H
[Ir]II
R
Fig. 2 | Reaction design. A working mechanistic hypothesis of deacylative C–H annulation through aromatization-driven C–C cleavage.
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Table 1 | Optimal condition and control experiments
Side-products:
Py′-NHNH2 (D1)
0.66 mol% TsOH, 1,4-dioxane, then
10 mol% [Ir(cod)2]BArF
H
H
Py′
N
N
+
P
P
H
Et
10 mol%
(L1)
O
1,3-butadiene
1
2
3
4
5
3 Å MS, 160 °C
Deacylation
Deacylative crotylation
Variation from the
standard condition
Selectivity
2:(3 + 4)
Entry
Total yield (%)
Ph
PPh2
PPh2
1
2
None
68
trace
trace
15
10:1
N/A
Ph2P
PPh2
PPh2
PPh2
O
PPh2
PPh2
PPh2
[Ir(cod)2]BF4 instead of [Ir(cod)2]BArF
[Ir(cod)2]Cl instead of [Ir(cod)2]BArF
L2, 47%
(3.8:1)
L3, 44%
(2.1:1)
L4, 22%
(2.1:1)
L5, 0%
L6, trace
3
N/A
OMe
OMe
CO2Me
OMe
4
3.2:1
2.1:1
2.3:1
Without 3Å MS
5
2-MeTHF instead of 1,4-dioxane
57
OMe
Ph2P
PPh2
Ph2P
PPh2
Ph2P
PPh2
Ph2P
PPh2
6
DME instead of 1,4-dioxane
36
L7, 61%
(5.3:1)
L8, 51%
(2.4:1)
L9, 65%
(4:1)
L10, 57%
(3.7:1)
7a
L2-L10 instead of L1
See right
The reactions were conducted with 1 (0.05ꢀmmol), 4-methyl-2-pyridylhydrazine (0.052ꢀmmol) and 1,3-butadiene (0.54ꢀmmol). The total yield and selectivity were determined by 1H NMR analysis of the
crude products using 1,1,2,2-tetrachloroethane as an internal standard. aThe reaction was conducted using different ligands (l2–l10) instead of l1 and a preformed hydrazone as the substrate. For detailed
experimental procedures, see Supplementary Methods. Et, ethyl; Py’, 4-methyl-2-pyridyl.
phenyl]borate) and L1 as an effective catalyst–ligand combination albeit in lower efficiency due to competing hydrogen termination
in 1,4-dioxane (Table 1, entry 1). A very small amount of TsOH and crotylation. Moreover, a double annulation (16) proved to be
(0.66mol%, where Ts is p-toluenesulfonyl) was used together with feasible, directly affording a symmetrical tetracycle from a simple
molecular sieves to ensure complete condensation between the biaryl precursor. On the other hand, various FGs, such as Weinreb
hydrazine and the ketone substrate (entry 4). The counter anion amides (10), esters (6), nitriles (11) and aryl halides (17, 21 and
of the Ir catalysts appears to play a pivotal role in determining the 22), can all be tolerated in this transformation. It is worth noting
reactivity (entries 2 and 3). While the site selectivity of the C–C that the carbon skeletons of many substrates were forged through
cleavage was high (>15:1), major side-products came from other either 1,4-additions with methyl vinyl ketone or migrative oxidative
competing deacylative transformations, such as hydrogen termi- Heck reactions with enols; the resulting ketones were directly sub-
nation and crotylation, which are expected to be influenced by the jected to the annulation process, further highlighting the efficiency
solvent and choice of ligands. For example, much lower cyclization of the two-phase approach. Further, heteroarenes such as indoles
selectivity was achieved in 2-methyl tetrahydrofuran (2-MeTHF) (31), quinolines (41), dibenzofurans (37), benzothiophenes (38),
or 1,2-dimethoxyethane (DME) despite a comparable total yield imidazoles (39) and quinazolinones (35 and 36) can also be incorpo-
(entries 5 and 6). A study of the ligand effect further suggested rated, providing pharmaceutically interesting fused-ring skeletons
that large bite-angle bisphosphines (L5) or monophosphines (L6) that are non-trivial to prepare otherwise64. Interestingly, when the
were not effective, whereas bidentate ligands with small bite angles cyclization took place on thiophenes or isoquinolinones, a dearo-
(L1–L3, L7–L10, ref. 63) generally worked better, with L1 giving mative annulation pathway competed with the re-aromatization
both the optimal yield and selectivity (entry 7).
process, showing the potential to access partially saturated hetero-
cycles (42′–44′)65,66
.
Substratescope.Withtheoptimalconditionsinhand,thescopeofthe
substrates was next explored (Table 2). A wide variety of single- and Mechanistic considerations. While the detailed mechanism of the
multi-arenes, including benzene, naphthalene (26), phenanthrene deacylative annulation reaction remains to be uncovered, a pro-
(27), anthracene (28) and even pyrene (30), can effectively undergo posed reaction pathway is depicted in Fig. 3a. Based on our pre-
the desired alkylative annulation. Both electron-rich and deficient vious experimental and computational mechanistic studies of the
aromatic substrates are competent during the cyclization process. deacylative functionalization62, this reaction may be initiated from
In all cases, the formation of six-membered rings was strongly hydrazone formation between the ketone and hydrazine D1, fol-
favoured9,14–18, and the possible five-membered ring side-product lowed by an Ir-catalysed [3+2] cycloaddition with 1,3-diene and
(for example, in the case of 14) was essentially negligible. When alkene migration to form the pre-aromatic intermediate (Int 2).
the formation of six-membered rings was not realizable, five- and Subsequently, a directed N–H oxidative addition with the Ir(I) cata-
seven-membered rings (24, 25 and 35) can still be constructed, lyst could take place to give an Ir(III)-hydride intermediate (Int 3),
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Table 2 | scope of the substrates
O
0.66 mol% TsOH, 1,4-dioxane
Ar
Py'-NHNH2
Ar
then
(D1)
10 mol% [Ir(cod)2]BArF, 10 mol% L1
3 Å MS, 160 oC
H
Ketone
Activating reagents
Activating reagents
Simple arene
O
MeO2C
F
Ph
MeO
N
Me
6: 62% yield
7: 61% yield
8: 56% yield
9: 58% yield
10: 60% yield
N
Ph
Ph
OMe
F
11: 52% yield
12: 52% yield
13: 50% yield
14: 50% yield
15: 43% yield
F
Cl
O
F
Ph
MeO
F
Ph
F
Cl
F
16: 44% yielda
17: 52% yield
18: 55% yield
19: 48% yieldb
20: 43% yield
F
Br
I
7
5
CO2Et
EtO2C
a
21: 52% yield
Multi-arene
22: 32% yield
24: 21% yield
25: 32% yield
23: 42% yield
major
26: 70% yield, 4:1
27: 64% yield
28: 52% yield
29: 50% yield
30: 36% yield
Heteroarene
N
N
O
MeO2C
N
n
N
N
N
F
35: n = 1, 48% yield
36: n = 2, 53% yield
N
31: 57% yield
32: 50% yield
33: 49% yield
34: 60% yield
Me
N
MeO
S
N
N
N
O
O
MeO
O
39: 52% yieldb
41: 42% yield
37: 44% yield
40: 47% yield
38: 49% yield
H
H
S
S
+
+
+
N
N
S
S
H
O
O
42 + 42': 65% yield, 1:1
43 + 43': 61% yield, 1:2.6
44 + 44': 60% yield, 1:3.3
The reactions were conducted on a 0.05ꢀmmol scale. The reported isolated yields of the desired products were based on an average of two runs. aKetone condensation with D1 (2 equiv.) at 90ꢀ°C for 15ꢀh.
bKetone condensation with D1 at 60ꢀ°C for 18ꢀh. For detailed experimental procedures, see Supplementary Methods.
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a
Et
Et
Py’
H
Py′
Py′
N
N
N
N
Int 3
N
[Ir]III
H
N
[Ir]I
H
N–H insertion
Ar
Ar
Ar
Int 2
Pre-aromatic
Int 1
Aromatization-driven
homolytic
C–C cleavage
1,3-Butadiene
[3 + 2] Cycloaddition
Et
Py’
[Ir]II
[Ir]I
N
N
Py’-NHNH2
Hydrazone formation
H
Int 4
Int 5
Radical
cyclization
O
Re-aromatization
and extrusion of
an ‘H2’ equivalent
Ar
Ar
H
Int 6
‘H–H’
b
O
6
O
6
O
6
D
O
Consistent with radical cyclization
inconsistent with metal-mediated C–H activation
F
O
2
2
2
F
F
H
45
46
47
C2 product : C6 product = 1:1
C2 product : C6 product = 1:1
C2 product : C6 product = 1:1
c
Ar with weak aromaticity
Ar with stronger aromaticity
S
H
–2 × [H]
O
S
42
Re-aromatization product
Ar
=
X
Int 7
H
S
N
R
[Ir]II
(or other H source)
S
H
N
H
42′
Re-aromatization product only
Competing dearomative annulation
Fig. 3 | Preliminary mechanistic consideration. a, A proposed reaction pathway. b, A radical-based cyclization was suggested by the lack of steric
influence and intramolecular kinetic isotope effect. c, Dearomative annulation was observed with heteroarenes having relatively weak aromaticity.
which then undergoes aromatization-driven homolytic C–C cleav- be ruled out. Nevertheless, the potential involvement of the Ir(II)
age to form a pyrazole-coordinated Ir(II) hydride (Int 4) and an hydride species could be supported by the formation of these
alkyl radical (Int 5). While facile radical–metal recombination was partially aromatic products (42′–44′) from thiophenes or iso-
observed in the previous study, the alkyl radical is intercepted by quinolinones. For example, due to the relatively weak aromaticity
a tethered arene in the current system. In line with the proposed in thiophene, the radical-cyclization intermediate (Int 7) suffers
pathway, the site selectivity of the cyclization appears to be less sen- from a slow re-aromatization process; an alternative pathway that
sitive to the steric environment on the arene (for example, in 45 involves coupling with the Ir(II) hydride intermediate to form a
and 46), which argues against a metal-mediated C–H activation C–H bond can compete or even dominate (Fig. 3c). In contrast, no
pathway (Fig. 3b). In addition, no intramolecular kinetic isotope partial aromatic products were observed for arenes or heteroarenes
effect was observed in substrate 47, which is also consistent with with high aromaticity. Note that, at this stage, an Ir-triggered radical
a radical-cyclization mechanism. While it is not completely clear chain mechanism cannot be fully excluded.
how the re-aromatization occurs from Int 6 at this stage, a plau-
sible pathway may involve H-atom abstraction or radical trapping Synthetic utility. Further study was carried out to show the util-
by the Ir(II) hydride intermediate. The resulting Ir(III) dihydride ity of the deacylative annulation strategy in streamlined two-phase
could eventually regenerate the Ir(I) catalyst, for example using a syntheses of aromatic-fused rings (Fig. 4). For example, the bicy-
sacrificial 1,3-diene as the H2 acceptor. For instance, when a heavier clic dicarboxylate 49, the key intermediate towards synthesis of
1.3-diene, myrcene, was used in place of 1,3-butadiene, partially anticonvulsant-active 50, was readily prepared in two steps through
reduced myrcene with a molecular mass increased by 2Da was 1,4-addition (phase I) followed by deacylative annulation (phase
observed. On the other hand, the oxidation of Int 6 into a carboca- II); for comparison, the conventional synthesis required a five-step
tion intermediate by the Ir(II), followed by deprotonation, cannot sequence (Fig. 4a)67. In another study, xanthine analogue 54
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a
b
CO2Me
Me
N
Me
N
Previous: three steps
(23% yield,R = H)
O
O
NH2
NH
N
Previous: five steps (12% yield)
MeO
N
OMe
CO2Me
+
MeN
MeN
OMe
O
O
O
O
53
O
O
HN
NH
R
48
52
54 and 55
49
O
Electrophilic
site
Or protected
Electrophilic
site
50
ketones
O
57 and 58
Me
Me
N
Anticonvulsant
O
O
N
O
N
N
N
O
O
X
MeN
MeN
R
N
Deacylative
annulation
Deacylative
annulation
1,4-addition
H
Traceless precursor
of carbon radical
O
O
MeO2C CO2Me
R
59 and 60
56
Traceless precursor
of carbon radical
51
SN 2 reaction
Theophylline
(US$0.2 per gram, Aldrich)
This route: 2 steps
(50% yield, R = H, 54; 46% yield, R = CH2Bn, 55)
This route: two steps (43% yield)
c
O
R
H
O
57,70–74
δ
N
N
N
R
X
X
X
X
H
R
H
Deacylative
annulation
(Or protected ketones)
O
O
N
O
N
N
O
R
H
H
SN
2
N
N
R
N
H
61–69
75–83
84–92
O
O
O
MeO
O
OMe
O
O
N
O
N
N
N
N
N
N
N
MeO
O
N
OMe
O
CF3
CF3
O
Oct
CF3
84
87
88
86
58%, two steps
85
36%, two steps
48%, two steps
41%, two steps
40%, two steps
O
H
H
N
N
O
N
N
H
O
H
N
N
N
O
O
O
H
H
Ph
Bn
Oct
50%, d.r. = 1:1, two steps
89
90
91
43%, d.r. = 1:1, two steps
92
47%, two steps
57%, two steps
Fig. 4 | synthetic applications of the deacylative C–H annulation. a, Synthesis of bicyclic dicarboxylate 49 was achieved in two steps, which required five
steps previously. b, Improved synthesis of xanthine analogue 54 with a shortened route and doubled overall yield. c, Examples of using the two-phase
annulation strategy for the late-stage construction of complex N-heteroarene polycyclic compounds. For detailed experimental procedures, see
Supplementary Methods. d.r., diastereomeric ratio; SN2, bimolecular nucleophilic substitution.
was previously made through a three-step sequence, while our structures despite the complexity of the substrates. Given the ubiq-
approach only needs a two-step operation with doubled overall uity of N-heterocycle moieties in pharmaceuticals, this approach
yield (Fig. 4b)68. Encouraged by these results, the two-phase annu- may find use in medicinal chemistry.
lation strategy was further applied to the late-stage construction
of complex N-heteroarene-based polycyclic compounds (Fig. 4c)19. Conclusions. In summary, we have disclosed a distinct C–H
This process requires consecutive and orthogonal N–H and C–H alkylative annulation strategy for preparing diverse arene- and
alkylations in the presence of multiple FGs including olefins, heteroarene-fused scaffolds. This strategy capitalized on the use
nitriles, electron-rich arenes and reactive carbonyls, which is dif- of simple unstrained ketones as an unusual but native annulation
ficult to achieve under strongly Lewis acidic, oxidative or reductive reagent; through the Ir-catalysed aromatization-driven C–C cleav-
conditions. Here, using δ-halo ketones as the linchpin, hetero- age, a deacylation process generates a reactive alkyl radical that
cycles, for example, indoles, imidazoles and quinazolinones, could undergoes subsequent C–H annulation with the tethered arene
all undergo the desired annulation to afford various fused-ring in good efficiency. Owing to the wide availability of the ketone
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18. Sherwood, T. C. et al. Decarboxylative intramolecular arene alkylation using
N-(acyloxy)phthalimides, an organic photocatalyst, and visible light.
J. Org. Chem. 84, 8360–8379 (2019).
moiety and reductant/oxidant/strong acid-free reaction conditions,
this deacylative annulation approach exhibits high FG tolerance and
provides streamlined access to complex fused-ring systems. The
general approach of generating alkyl radicals from ketones could
19. Saget, T. & König, B. Photocatalytic synthesis of polycyclic indolones.
Chem. Eur. J. 26, 7004–7007 (2020).
have broad implications and further applications beyond this work. 20. Clare, D., Dobson, B. C., Inglesby, P. A. & Aïssa, C. Chemospecifc
cyclizations of α-carbonyl sulfoxonium ylides on aryls and heteroaryls.
Methods
Angew. Chem. Int. Ed. 58, 16198–16202 (2019).
General procedure for the deacylation-aided C–H alkylative annulation. For
a 0.05-mmol scale reaction, a 1,4-dioxane (1ml) solution of the ketone substrate
(0.05mmol, 1.0 equiv.), D1 (6.4mg, 0.052mmol, 1.04 equiv.) and p-TsOH·H2O
(stock solution in 1,4-dioxane; 0.05M, 6.6μl, 0.0066 equiv.) was heated at 90°C
for 5h under N2 atmosphere in an 8-ml vial. Afer cooling to room temperature,
the vial was charged with [Ir(cod)2]BArF (6.4mg, 0.005mmol, 0.1 equiv.) and
L1 (2.0mg, 0.005mmol, 0.1 equiv.) under air atmosphere, transferred into a
glove box and further charged with a 3-Å molecular sieve (predried, 100mg) and
1,3-butadiene (20wt% in toluene, 180μl, about 10.8 equiv.). Te vial was sealed
and heated at 160°C while stirring for 72h. Afer cooling to room temperature,
the reaction mixture was fltered through a short plug of Celite, concentrated and
purifed by fash column chromatography over silica to provide the product.
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Data availability
Details about materials and methods, experimental procedures and
characterization data are available in the Supplementary Information. Additional
data are available from the corresponding authors upon request.
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Received: 13 December 2020; Accepted: 1 July 2021;
Published: xx xx xxxx
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acknowledgements
This work was supported by NIGMS (grant no. 2R01GM109054). X.Z. thanks the
International Talent Training Project of Dalian Institute of Chemical Physics for
financial support. Umicore AG & Co KG is acknowledged for a donation of Ir salts.
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additional information
Supplementary information The online version contains supplementary material
available at https://doi.org/10.1038/s41929-021-00661-7.
Correspondence and requests for materials should be addressed to Y.X. or G.D.
Peer review information Nature Catalysis thanks Laurent Chabaud, Zhiwei Zuo and the
other, anonymous, reviewer(s) for their contribution to the peer review of this work.
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