Iron-catalyzed stereoselective haloamidation of amide-tethered alkynes

Article abstract of DOI:10.1039/d1cc00870f

In this work, by usingN-methoxybenzamides as efficient acyl nitrene precursors, an iron-catalyzed formalcis-haloamidation of alkyne is reported. Without assistance of additives, the reaction worked well in the presence of 50 mol% FeCl₃or FeBr₃, leading to a series of chloro/bromo-containing isoindolin-5-ones with high efficiency and wide reaction scope. In the reaction, the iron-facilitated haloamidation proceeds through a halo anion-participating concerted [3+2] cyclization to release the final products. The key intermediate ferric acyl nitreneAis generatedin situfrom a formal removal of MeOH.

Full text of DOI:10.1039/d1cc00870f

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Iron-catalyzed stereoselective haloamidation of
amide-tethered alkynes†
Cite this: Chem. Commun., 2021,
57, 4259
a
b
Jin-Biao Liu,
Miaofeng Ren,b Xiaojing Laib and Guanyinsheng Qiu
*
Received 16th February 2021,
Accepted 25th March 2021
DOI: 10.1039/d1cc00870f
rsc.li/chemcomm
In this work, by using N-methoxybenzamides as efficient acyl functionalization of the resulting copper nitrene with
nitrene precursors, an iron-catalyzed formal cis-haloamidation of alkynes.4a By adopting dioxazoles as acyl nitrene precursors,
alkyne is reported. Without assistance of additives, the reaction in 2019 De Bruin and co-workers found that ketenimine and
worked well in the presence of 50 mol% FeCl3 or FeBr3, leading to a ynamide species could be prepared via a copper-catalyzed
series of chloro/bromo-containing isoindolin-5-ones with high acyl nitrene transfer into intramolecular C–C triple bonds
efficiency and wide reaction scope. In the reaction, the iron-facilitated (Scheme 1a).5a In the reaction, the formation of ketenimines
haloamidation proceeds through a halo anion-participating concerted or ynamides was ascribed to the insertion of the resulting
[3+2] cyclization to release the final products. The key intermediate ferric copper acyl nitrene into the copper acetylide Cu–C bond.
acyl nitrene A is generated in situ from a formal removal of MeOH.
Distinctively, the dioxazole-derived nitrene transfer into
intramolecular alkynes under iridium catalysis, developed
Regarded as a highly reactive species, the nitrene intermediate by Chang and co-workers, proceeds through a chloro anion-
has long attracted the attention of synthetic chemists.1 This is participating concerted [3+2] cyclization mechanism
most likely because, via a nitrene transfer reaction, nitrogen- (Scheme 1b).5b
containing building blocks can be incorporated into target
The use of amides or carbamates as acyl nitrene precursors is
products for the construction of structurally complex motifs. attracting the interest of chemists, and an array of publications
To date, a series of well-recognized nitrene precursors, which
predominantly include azides, sulfonamides, and iminoiodi-
nanes, etc., enable nitrene transfer reactions for C–N bond
formation through typical C–H bond insertion and aziridination.
In addition to well-established C–H insertion and aziridinations,2
nitrene/alkyne metalation has attracted significant attention.
A rhodium-catalyzed nitrene/alkynes metalation was initially inves-
tigated by the Blakey, Panek, Xu, and Shi groups.3 The resulting
rhodium nitrene could be trapped by an intramolecular/intermole-
cular allylic ester,3a,b alkene/arene,3c,d intramolecular cyclopropane,3e
and even by water.3f It is noteworthy that this elegant methodology
employs sulfonamides as precursors and the use of a stoichiometric
amount of hypervalent iodide is thus required. Notably, enantio-
selective reactions have also been demonstrated.3g Employing open-
shell catalysis enabled by iminoiodinanes,4a,c Perez and co-workers
´
recently realized
a Cu-catalyzed intermolecular radical
a School of Metallurgical and Chemical Engineering, Jiangxi University of Science
and Technology, Ganzhou 341000, China
b College of Biological, Chemical Sciences and Engineering, Jiaxing University,
Jiaxing 314001, Zhejiang, China. E-mail: qiuguanyinsheng@mail.zjxu.edu.cn
† Electronic supplementary information (ESI) available. CCDC 1992175. For ESI
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
d1cc00870f
Scheme 1 Reaction design for iron-catalyzed acyl nitrene addition into
alkynes.
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Table 1 Optimization of the reaction conditionsa
have suggested that N-protecting groups play a pivotal role in the
formation of acyl nitrene intermediates; metal catalysts such as
rhodium and iridium salts have been employed in these reactions.6
Very recently, our group developed an iron-catalyzed acyl nitrene/
alkyne metalation of N-methoxyamides and b-dicarbonyl com-
pounds for the synthesis of pyrrolo[2,1-a]isoindol-5-ones.7 In the
reaction, using iron catalysis, N-methoxyamides serve as efficient
acyl nitrene precursors through a formal removal of MeOH. More-
over, it is interesting that the resulting ferric acyl nitrene should be
in a singlet state, which differs from the previous reports implying
ferric imido radical species.6f,g,8 Considering the low cost of iron
catalysts and their versatility,9 we herein report the further
application of N-methoxylamides10 as acyl nitrene precursors in
iron-catalyzed intramolecular acyl nitrene/alkyne metalation and
chlorination (Scheme 1d). In addition to developing an alternative
pathway for the preparation of various isoindolin-1-ones pre-
products for structural elaboration, we have also provided further
evidence for the formal ferric acyl nitrene-based chloroamidation
(a concerted or stepwise pathway). With the projected idea in
mind, a model reaction of N-methoxybenzamide 1a in the
presence of 0.2 equiv. of FeCl3 was conducted in DCE at 80 1C.
The preliminary result suggested that the above intramolecular
acyl nitrene/alkyne metalation takes place, leading uniquely to a
chloroamidative product (Z)-3-(chloro(phenyl)methylene)isoindolin-
1-one 3a in 33% isolated yield. (E)-3-(chloro(phenyl)methylene)
isoindolin-1-one 3a0, a well-known product derived from 5-exo-dig
chlorocyclization,11 was not observed. Furthermore, it was pleasing
Entry [Fe] (equiv.)
Sol.
Temp. (1C) Yield of 3ab (%)
1
2
3
4
5
6
7
8
FeCl3 (0.2)
FeCl3 (0.4)
FeCl3 (0.5)
FeCl3 (1.0)
FeCl3 (0.5)
FeCl3 (0.5)
FeCl3 (0.5)
FeCl3 (0.5)
FeCl3 (0.5)
FeCl3 (0.5)
FeCl3 (0.2) + KCl (1.5)
DCE
DCE
DCE
DCE
DCE
DCE
DCE
80
80
80
80
60
100
80
33
71
98
91
81
74
79
80
65
74
39
41
43
95
Toluene 80
9
DMF
THF
DCE
80
80
80
80
80
80
10
11
12
13
14c
FeCl3 (0.2) + NH4Cl (1.5) DCE
FeCl3 (0.2) + NaCl (1.5) DCE
FeCl3 (0.5)
DCE
a
Conditions: the reaction of 1a (0.2 mmol) was carried out under air
b
c
atmosphere. Isolated yield based on 1a. 2.0 equiv. of TEMPO was
added.
to find the undesired Curtius rearrangement byproduct was not on reaction efficiency, thus resulting in the need for a relatively
observed.12 The exact structure of product 3a was identified by X-ray high loading of iron salt. Addition of radical scavengers did not
diffraction (CCDC†: 1992175). Additionally, a control experiment have a significant impact on the reaction yield (entry 14,
with 2.0 equiv. of TEMPO gave a similar yield (Scheme 1c), indicat- Table 1), suggesting that the reaction does not involve the
ing the reaction probably proceeds through a non-radical pathway. generation of a ferric imido radical species.8
Assuming that the chloroamidation is a stepwise process, it seems
With the optimized conditions in hand, we investigated the
reasonable that the model reaction should produce a mixture of 3a scope of this reaction. The results are presented in Scheme 2.
and 3a0. The result that the reaction provides only (Z)-product 3a As shown in Scheme 2, the reaction is amenable to an array of
provides some evidence of a concerted chloroamidation mecha- functional groups, and a series of halo-containing isoindolin-1-
nism. It is believed that this ferric acyl nitrene-based chloroamida- ones 3a–3o and 4a–4o were obtained in good to excellent yields.
tion may serve as an important supplement for the additive-free For example, the reaction of N-methoxy-4-methyl-2-(phenyl-
synthesis of chloro-containing heteroisoindolin-1-ones5b and bromo- ethynyl)benzamide 1b under the standard conditions provided
containing isoindolin-1-ones.13
the desired products 3b and 4b in 88% and 84% yields, respec-
The above positive result encouraged us to optimize the tively. The reaction of 2-(cyclopropylethynyl)-N-methoxybenzamide
model reaction. To our delight, increasing the loading of FeCl3 proceeded smoothly, leading to the corresponding products 3j in
to 0.5 equiv. drastically improved the reaction efficiency, pro- 92% yield and 4e in 78% yield. From investigations of the
ducing the target product 3a in almost quantitative yield (entry substituent effect on the alkyne, it was found that the substituents
3, Table 1). Other N-nucleophilic or O-nucleophilic chlorocycli- such aryl, alkyl, and heteroaryl groups were all tolerated. Some
zation byproducts were not detected.14 An increase or decrease sensitive functional groups, including cyclohexyl, cyclopropyl and
in reaction temperature did not improve the reaction outcome, thiophene functionalities, were tolerated under the reaction condi-
and inferior yields were obtained when the model reaction was tions, with the formation of the desired products 3h, 3i, 3j, 4e, and
carried out at 100 1C or 60 1C (entries 5 and 6, Table 1). No 4o. It is worth noting that the substrates with complex alkynes were
further improvement for reaction efficiency was observed when efficient reaction partners. For instance, the correspoding products
different solvents were employed (entries 8–10, Table 1). In 3n and 3o were synthesized efficiently when estrone- and
order to reduce the FeCl3 loading, reactions with various chloro cholestrol-derived substrates were used. In particular, the reaction
sources were conducted (entries 11–13, Table 1). To our sur- of N-methoxy-5-(o-tolyl)pent-4-ynamide 1m also worked well, pro-
prise, poorer results were obtained when KCl, NH4Cl, and NaCl viding the desired product 3m in 70% yield when FeCl3 was used.
were used as replacements. These results suggest that the
As mentioned above, it is envisioned that the reaction
additional chloro source does not have a significant impact proceeds through a ferric acyl nitrenoid-based [3+2] cyclization
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Scheme 4 A halo anion-participating [3+2] cyclization mechanism (other
ligand in iron center is omitted).
(Scheme 4). In the reaction, a ferric acyl nitrene species A is
generated via a formal removal of MeOH under iron catalysis.
We reasoned the removal of MeOH involves 1,2-H migration15b
and ligand exchange with FeX3. Subsequentially, the ferric acyl
nitrene intermediate A undergoes a halo anion-participating
concerted [3+2] cyclization, forming an isoindolin-1-one-
containing ferric metallacyle intermediate B. Finally, protona-
tion of the stable metallacyle intermediate B takes place to
regenerate the iron catalyst and deliver the desired products 3
and 4.5b
In conclusion, N-methoxybenzamides have been developed
as efficient acyl nitrene precursors, and an iron-catalyzed for-
mal cis-chloroamidation for the synthesis of isoindol-1-ones
has been reported. The reaction proceeds smoothly with broad
functional group tolerance. Mechanistic studies suggest that
the formal chloroamidation occurs via an iron-catalyzed acyl
nitrene-based chloro anion-participating concerted [3+2] cycli-
zation. Further transformations involving iron-catalyzed acyl
nitrene/alkyne metalations with N-methoxybenzamides are
being investigated in our laboratory, and the results will be
reported in due course.
Financial support from the Natural Science Foundation of
China (21772067,21762018 and 21961014), the Natural Science
Foundation of Jiangxi Province, China (20192BCBL23009 and
20202BABL203005), and The Youth Jinggang Scholars Program
in Jiangxi Province is gratefully acknowledged.
Scheme 2 Reaction scopesa,b
.
pathway. It is well known that nitrenes readily react with
styrene and C–H bonds, and undergo aziridination and
C–H insertion. To support our assumption, aziridination of
N-methoxylbenzamide 5 was carried out under the standard
conditions. To our delight, the aziridinated product 6 was
afforded in 72% yield. Furthermore, treatment of 2-ethyl-N-
methoxybenzamide 7 with 50 mol% FeCl3 under the standard
conditions gave rise to a C–H insertion and sequential oxida-
tion reaction, leading to isoindolin-1-one 8 in moderate yield
(Scheme 3).
Conflicts of interest
There are no conflicts to declare.
In light of the aforementioned results and the previous
findings,7,15
a plausible mechanism has been proposed
Notes and references
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