Fe-catalyzed Fukuyama-type indole synthesis triggered by hydrogen atom transfer

Article abstract of DOI:10.1039/d1sc03058b

Fe, Co, and Mn hydride-initiated radical olefin additions have enjoyed great success in modern synthesis, yet the extension of other hydrogen radicalophiles instead of olefins remains largely elusive. Herein, we report an efficient Fe-catalyzed intramolec

Full text of DOI:10.1039/d1sc03058b

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Fe-catalyzed Fukuyama-type indole synthesis
triggered by hydrogen atom transfer†
Cite this: Chem. Sci., 2021, 12, 10501
*
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have been paid for by the Royal Society
of Chemistry
Tianze Zhang, Min Yu and Hanmin Huang
Fe, Co, and Mn hydride-initiated radical olefin additions have enjoyed great success in modern synthesis, yet
the extension of other hydrogen radicalophiles instead of olefins remains largely elusive. Herein, we report
an efficient Fe-catalyzed intramolecular isonitrile–olefin coupling reaction delivering 3-substituted indoles,
in which isonitrile was firstly applied as the hydrogen atom acceptor in the radical generation step by MHAT.
The protocol features low catalyst loading, mild reaction conditions, and excellent functional group
tolerance.
Received 5th June 2021
Accepted 5th July 2021
DOI: 10.1039/d1sc03058b
rsc.li/chemical-science
hydrofunctionalization, however, the variant process of trans-
ferring hydrogen atoms to other unsaturated groups remains
Introduction
largely elusive (Scheme 1A). For instance, it is logically reason-
able to assume that the isonitrile group could abstract
a hydrogen atom from Fe hydride species to form a carbon-
centered imidoyl radical, which may further undergo undis-
covered radical addition or cyclization reactions. In this context,
we envisioned that enlarging the tool-box of the MHAT strategy
to include these different hydrogen radicalophiles would open
up a new development orientation for metal hydride chemistry.
Isonitriles, as classical radical acceptors, have been widely
utilized in a number of imaginative radical cascade reactions
for the construction of diverse nitrogen-containing
Metal hydride species have been a longstanding topic of study
in organometallic chemistry. Since the 1960s, noble metal-
hydrides have been substantially explored in catalytic homo-
geneous hydrogenation.1 With the increasing demand for
sustainable chemical processes, researchers were prompted to
develop reactions catalyzed by earth-abundant metal hydrides.2
A landmark in this continuously growing eld was the radical
generation initiated by Fe, Co, and Mn hydrides through a metal
catalyzed hydrogen atom transfer (MHAT) process, which was
rst discovered in Drago–Mukaiyama hydrofunctionalization of
olens.3 In this process, the in situ generated metal-hydride is
prone to homolysis due to its low bond dissociation enthalpy
(BDE), producing a hydrogen radical which further undergoes
radical addition to olens.4 Based on this scenario, a toolkit of
catalytic methods has been established, such as Carreira's Co/
salen catalysts,5 Boger's Fe/NaBH4 system,6 and Shenvi's dual
catalytic platform.7 Remarkably, Baran's Fe(acac)3/phenylsilane
system has proved to be a useful methodology for both inter-
and intramolecular reductive olen coupling,8 as well as
a general protocol for construction of polycyclic frameworks.9
By means of this catalysis system, a variety of SOMOphiles were
further introduced as radical traps, achieving diverse olen
hydrofunctionalization such as hydroamination, hydrogena-
tion, and the Minisci reaction.10
While the literature pertaining to the MHAT process is
replete with creative advances, we recognized a gap existing in
the current research: tremendous efforts have been devoted to
the development of extensive SOMOphiles for olen
Hefei National Laboratory for Physical Sciences at the Microscale, Department of
Chemistry, Center for Excellence in Molecular Synthesis of CAS, University of
Science and Technology of China, Hefei, 230026, P. R. China. E-mail: hanmin@ustc.
edu.cn
Scheme 1 (A) Fe–H initiated radical addition via the MHAT process. (B)
This work: Fe-catalyzed indole synthesis through radical isonitrile–
olefin coupling.
† Electronic supplementary information (ESI) available. See DOI:
10.1039/d1sc03058b
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heterocycles.11 Among them, the Fukuyama indole synthesis sterically bulky iron catalyst Fe(dpm)3 was found to be able to
encompassing radical isonitrile insertion followed by an intra- signicantly improve the yield to 75%, which might result from
molecular radical cyclization has proved to be efficient for the high stability and decreased decomposition of the catalyst
accessing indole skeletons (Scheme 1B).12 Despite its efficiency, (Table 1, entries 2 and 3). A higher yield could be obtained even
the radical generation step oen requires an initiator and if the loading of Fe(dpm)3 was reduced to 5% equivalent (Table
stoichiometric amounts of toxic Bu3SnH, making the approach 1, entry 4). Further screening disclosed that other metal acety-
neither environment-friendly nor broad-functional group lacetonates such as Co(dpm)2 and Mn(dpm)3 could also be
compatible. Although there have been some attempts to over- employed in this system with declined yields (Table 1, entries 5
come these limitations,13 the vast majority lay exclusively on the and 6). No reaction occurred without metal catalysts, excluding
construction of 2,3-disubstituted indoles, prompting us to the process of direct hydrogen atom transfer from hydrosilane
explore the idea of merging this radical cyclization with the Fe (Table 1, entry 7).14
hydride catalytic system to create a novel platform to 3-mono-
With Fe(dpm)3 set as the optimal catalyst, other reaction
substituted indole derivatives. To this end, we herein report an parameters were further screened to maximize the efficiency of
Fe-catalyzed intramolecular isonitrile–olen coupling reaction this reaction. The evaluation with various solvents revealed that
with the MHAT process as the radical initiation step, which the reaction did not proceed at all in aprotic solvents such as
provides a convenient and rapid approach to 3-substituted THF or DCE, while it worked well in alcohol solvents. In
indole motifs.
branched alcohols, such as i-PrOH and t-BuOH, the reaction
proceeded smoothly, and i-PrOH proved to be the ideal solvent
(Table 1, entries 8–10). Notably, the use of DCE as a co-solvent
gave a comparable result, which could benet some insoluble
substrates (Table 1, entry 11). Finally, various hydrosilanes were
investigated as the reductant, among which the use of Et3SiH
and (EtO)3SiH was found to give poor yields (Table 1, entries 12
and 13), whereas inexpensive DEMS ((EtO)2MeSiH) was
compatible, providing the desired product in 81% yield.
Results and discussion
To test our hypothesis, we initiated the investigation with the
reaction by using ethyl o-isonitrile cinnamate (1aa) as the
standard substrate. We rst examined the reaction conditions
previously described by Baran and coworkers for olen reduc-
tive coupling,8b which was carried out in i-PrOH at 60 C with
ꢀ
30 mol% of Fe(acac)3 and PhSiH3 as the hydrogen source. To
our delight, we successfully obtained the desired product in
25% yield (Table 1, entry 1). When other metal acetylacetonates
were then evaluated under these experimental conditions, the
With the established optimum reaction conditions in hand,
we then evaluated the substrate generality of this Fe hydride
initiated isonitrile–olen coupling reaction (Table 2). First, the
inuence of various substituents on the alkene-moiety was
Table 1 Optimization of reaction conditionsa
Table 2 Substrate scope with respect to the alkenea
Entry
Catalyst
Solvent
Reductant
Yield (%)
1b
2b
3b
4
Fe(acac)3
Fe(dibm)3
Fe(dpm)3
Fe(dpm)3
Co(dpm)3
Mn(dpm)3
—
Fe(dpm)3
Fe(dpm)3
Fe(dpm)3
Fe(dpm)3
Fe(dpm)3
Fe(dpm)3
Fe(dpm)3
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
EtOH
t-BuOH
DCE
i-PrOH/DCE
i-PrOH
i-PrOH
i-PrOH
PhSiH3
PhSiH3
PhSiH3
PhSiH3
PhSiH3
PhSiH3
PhSiH3
PhSiH3
PhSiH3
PhSiH3
PhSiH3
Et3SiH
(EtO)3SiH
DEMS
25
59
75
82
21
46
NR
56
77
NR
82 (81)c
12
28
81
5b
6b
7b
8
9
10
11
12
13
14d
a
Reaction conditions: 1aa (0.2 mmol), catalyst (5 mol%), hydrosilane
(0.4 mmol), solvent (1.2 mL), 35 ꢀC, 2 h. Yield determined by GC
b
a
using n-hexadecane as the internal standard. Used 30 mol% catalyst.
Reaction conditions: 1 (0.5 mmol), Fe(dpm)3 (5 mol%), PhSiH3 (1.0
c
d
Isolated yield. Reaction at 60 ꢀC for 5 h. acac ¼ acetylacetone, mmol), i-PrOH/DCE (2.0 mL + 1.0 mL), 35 ꢀC, 2 h. Isolated yield.
b
dibm ¼ diisobutyrylmethane, dpm ¼ dipivaloylmethane.
Reaction for 12 h.
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explored. To our delight, different esters (2aa–2ac), and amido this transformation. For both electron-donating (such as Me–
(2ad), sulfonyl (2ae), and phosphoryl groups (2af) were all and MeO–) and electron-withdrawing (such as F–, Cl–, Br– and
compatible with this reaction and delivered the desired prod- CF3–) substituents on the aromatic rings, the substrates were all
ucts in 62–81% yields. Additionally, the substrate featuring smoothly converted to the corresponding products (2ba–2la) in
a sterically hindered trisubstituted alkene also underwent the good to excellent yields (71–94% yields). Besides, multiple
current reaction smoothly, leading to the desired product 2ag in valuable functional groups such as reducible nitro (2ma),10a
64% yield. Furthermore, substrates bearing the ketone- cyano (2na) and alkoxycarbonyl (2oa, 2pa) groups were all
functionality (2ah–2ai) showed good compatibility to produce tolerated under the mild reaction conditions, showcasing the
the corresponding indole products as well. Encouraged by these strong chemoselectivity of this MHAT approach. It is worth
results, we continued to examine the substrates tethered with mentioning that both the 6-substituted substrates with signi-
less electron-withdrawing groups such as cyano (1aj) and pyr- cant steric effects close to the isonitrile group (1ha, 1pa) can
idyl groups (1ak). The results shown in Table 2 demonstrated undergo the catalytic reaction, delivering the corresponding 7-
that the desired products (2aj and 2ak) could be obtained in substituted indoles (2ha, 2pa) in good yields (84% and 66%
good yields by prolonging the reaction time to 12 hours. Mala- yields, respectively). In particular, with the catalyst loading
thidone (2al) was also achieved albeit with a lower yield under reduced to 1%, the desired product 2ca could be obtained on
standard reaction conditions. Notably, the introduction of a gram-scale in 94% isolated yield, showing the scalability and
electron-withdrawing groups into the alkene was necessary for robustness of this protocol.
getting acceptable yields of products. Only a trace amount of
Aiming to gain insights into the mechanism of this Fe
product (2am) was afforded when using alkene tethered with hydride-initiated isonitrile–olen coupling reaction, we per-
a phenyl group, which might be ascribed to its less propensity to formed some mechanistic experiments. When a radical scav-
undergo single-electron reduction with Fe(II) species.
enger such as TEMPO was added in the standard reaction
We next sought to explore the generality of this methodology conditions, the starting material was fully recovered and the
with respect to substituted-aryl isonitriles. To this end, a variety byproduct 3 was detected, suggesting that the H-radical might
of ethyl o-isonitrile cinnamates were synthesized, and as shown be involved in the present reaction (Scheme 2A). In addition,
in Table 3, the electronic effects had no obvious inuence on almost the same yield could be obtained under oxygen-free
conditions, disclosing that oxygen was not responsible for
reoxidizing the iron catalyst (see the ESI†). The deuterium
Table 3 Substrate scope with respect to the aryl ringa
labeling experiment by using PhSiD3 as the hydrogen source
provided deuterated indole 2aa-1 with over 95% D at the 2-
position, indicating that the hydrogen atom that added across
the isonitrile group originated from PhSiH3 (Scheme 2B).
Another deuterium labeling experiment by using EtOD as
solvent led to 2aa-2 with over 95% deuteration rate, in which the
deuterium atom was incorporated into the position adjacent to
the carbonyl group. This is consistent with a polar protonation
rather than a radical hydrogen atom abstraction from hydro-
silane ending this reaction. It is also worth pointing out that
these reactions provide facile access to deuterium-labeled
a
Reaction conditions: 1 (0.5 mmol), Fe(dpm)3 (5 mol%), PhSiH3 (1.0
mmol), i-PrOH/DCE (2.0 mL + 1.0 mL), 35 ꢀC, 2 h. Isolated yield.
b
Run on a gram-scale with 1 mol% Fe(dpm)3 and 1.5 equiv. PhSiH3.
Reaction for 12 h.
c
Scheme 2 Mechanistic experiments.
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Author contributions
T. Zhang conducted most of the experimental work and wrote
the initial manuscript dra. M. Yu conducted the mechanistic
study experiments. H. Huang conceptualized and directed the
project and nalized the manuscript dra. All authors
contributed to discussions.
Conflicts of interest
The authors declare no conict of interest.
Acknowledgements
This research was supported by the National Natural Science
Foundation of China (21925111 and 21790333).
Fig. 1 Proposed mechanism of the reaction.
Notes and references
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In summary, we have developed a novel and efficient Fe-
catalyzed intramolecular reductive isonitrile–olen coupling
reaction to synthesize indole derivatives, which proceeds
through a Fe–H initiated hydrogen atom transfer process. The
key radical generation step transferring a hydrogen atom to
isonitrile via the MHAT process has not previously been re-
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and moisture make this reaction practical and attractive in
organic synthesis. Not only is this method a complement to
Fukuyama-indole synthesis, but the catalytic patterns open up
a new development orientation for metal-hydride chemistry.
Further studies on the applications of this MHAT-driven iso-
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