Metal-Free C-H [5 + 1] Carbonylation of 2-Alkenyl/Pyrrolylanilines Using Dioxazolones as Carbonylating Reagents

Article abstract of DOI:10.1021/acs.orglett.1c01147

A novel metal-free C-H [5 + 1] carbonylative annulation of 2-alkenyl/pyrrolylanilines with dioxazolones has been established for the assembly of the privileged quinolinones and pyrrolyl-fused quinoxalinones. Entirely differing from the existing reports, the dioxazolones herein behave with an innovative chemistry and first emerge as carbonylating reagents to participate in annulation reactions. Moreover, this process features exceedingly simple operation (only solvent) and tolerates both vinyl and aryl substrates. Comprehensive mechanistic studies indicate that the formed isocyanate intermediate plays a crucial role in enabling the carbonylation annulation.

Full text of DOI:10.1021/acs.orglett.1c01147

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Letter
Metal-Free C−H [5 + 1] Carbonylation of 2‑Alkenyl/Pyrrolylanilines
Using Dioxazolones as Carbonylating Reagents
Jiang Nan,* Pu Chen, Xue Gong, Yan Hu, Qiong Ma, Bo Wang, and Yangmin Ma
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ABSTRACT: A novel metal-free C−H [5 + 1] carbonylative annulation of 2-alkenyl/pyrrolylanilines with dioxazolones has been
established for the assembly of the privileged quinolinones and pyrrolyl-fused quinoxalinones. Entirely differing from the existing
reports, the dioxazolones herein behave with an innovative chemistry and first emerge as carbonylating reagents to participate in
annulation reactions. Moreover, this process features exceedingly simple operation (only solvent) and tolerates both vinyl and aryl
substrates. Comprehensive mechanistic studies indicate that the formed isocyanate intermediate plays a crucial role in enabling the
carbonylation annulation.
he carbonylation process comprises one of the most
Tfundamental and promising tactics for building up the
privileged carbonyl-containing organic molecules and deriva-
tives, which has greatly benefited both academia and industry
application.1 Meanwhile, CO gas as the most direct C1 source
in organic syntheses has been extensively exploited for over a
half century, especially with respect to the transition-metal
catalyzed version, and has gained remarkable achievements,2
even benefiting the total synthesis of a myriad of natural
products.3 Notwithstanding its robustness, this conversion still
encounters several non-negligible restraints such as a difficult
system (toxicity, flammability, and high pressure)4 as well as
aspects affecting reaction efficacy (poison metal catalyst).5
Again, in recent years, seeking new carbonylating agent
candidates in lieu of gaseous CO has been gaining increasing
focus in the organic community.6 The current CO surrogates
predominantly encompass the matured M(CO)n and CO2
reagents as well as the evolving (CH2O)n, CHCl3, TFBen,
COCl2, HCO2R, CH3NO2, and so forth (Scheme 1A),7 each
of which is practically applied as CO alternatives through the
specific reaction fashion. Nonetheless, consistent with the
model of CO gas transformation, inevitably capitalizing on the
transition metals combined with external oxidants appears
imperative in the majority of these cases. Thus, exploring more
CO substitutions and new carbonylation tactics will continue
to be highly demanded.
environmental friendliness by generating only CO2 and H2O
as chemical wastes, typically applies to homogeneous catalysis
systems as quite a “smart” nitrene transfer agent. In this arena,
Chang,9 Li,10 Bolm,11 and others12 have had numerous
successes associated with implementing a plethora of intriguing
amidating reactions (Scheme 1B, left). As a dramatic
comparison, the other chemical properties of dioxazolones
are scarcely documented, and only two studies described that
the dioxazolones were capable of coupling with amines to
access ureas without metal catalysts,13 which selectively formed
a challenging N−C(O) bond by means of the Curtius-type
rearrangement (Scheme 1B, right). Inspired by these seminal
works, we speculate whether the further intramolecular
transformation could take place to construct complicated and
value-added cyclic carbonyl molecules by installing an
appropriate nucleophilic unit on the urea species.
In this paper, in line with our ongoing interest in
heterocyclic chemistry,14 we communicate a novel [5 + 1]
cycloaddition example of 2-alkenyl/pyrrolylanilines with
dioxazolones (Scheme 1C), thus resulting in a broad collection
of ubiquitous quinolinone and pyrrolyl-fused quinoxalinone
derivatives frequently found in pharmaceutical chemistry
(Scheme 1D).15 Most strikingly, the dioxazolone herein
Received: April 5, 2021
Published: April 15, 2021
Alternatively, the chemical reactivity of dioxazolone has
more recently increasingly captured substantial attention,8
largely due to its phenomenal reaction performance in
constructing new C−N bonds. This blooming reagent,
featuring concise preparation, easy handling, as well as
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© 2021 American Chemical Society
Org. Lett. 2021, 23, 3761−3766
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MeCN, toluene, DCE, and DMF were all feasible to perform
this titled [5 + 1] conversion, the toluene solvent was
identified as the better choice and delivered the anticipated
product 3a in 73% yield (entry 6). Further adjusting the
temperature to higher or lower level proved to be ineffective
for higher productivity (entries 9 and 10). In the end, it was
found that the ratio of reaction substrates could affect the
reaction performance (entries 11 and 12), improving the yield
of 3a to 73% when modifying the ratio of 1a:2a to 1:1.2 (entry
12). In addition, the air atmosphere resulted in a diminished
outcome (entry 13).
Scheme 1. Carbonylation Reaction and Dioxazolone
Chemistry
To further harness this modest synthetic methodology at
this stage, we proceeded to optimize transformation efficiency
by tuning the C3-substituent of carbonylation agent 2a. A
sequence of differentially substituted dioxazolones was
prepared, including electronically or sterically diverse aromatic
(2b−k) and aliphatic (2l) reagents, to react with substrate 1a
for executing this [5 + 1] annulation according to the
aforementioned reaction conditions (Scheme 2). All of these
a
Scheme 2. Optimization of the Dioxazolones
behaves with a new chemistry and represents a CO surrogate
to participate in cyclization transformation for the first time via
simultaneously constructing C−C(O) and N−C(O)bonds.
Initially, the reaction was optimized by employing 2-(1-
phenylvinyl)aniline 1a to react with phenyl-ligated dioxazolone
2a as a potential carbonyl source. Some representative
experiments are summarized in Table 1. A comprehensive
screening of reaction solvents was first conducted (entries 1−
8). Although cases such as HFIP, EtOH, TFE, 1,4-dioxane,
a
Isolated yield of 3a (reacting 0.2 mmol 1a with 0.24 mmol 2).
a
Table 1. Optimization of the Reaction Conditions
cases took place properly to furnish the target 3a in 54−85%
yields, and the electronic effect on the reaction productivity
appeared inconspicuous, in which adapting 2d as the
carbonylation reagent presented a comparatively preferential
reaction performance (85% isolated yield).
b
Having established the optimal conditions, the generality
and scope of this novel [5 + 1] reaction was next investigated.
As depicted in Scheme 3, with substrate 2d as the
carbonylating reagent, a broad range of 2-alkenylanilines
(1a−w) participated quite well in this protocol, constructing
the corresponding products (3a−w) in moderate to good
yields. First, with regard to the alkenyl segment, it
accommodated diversified organic functionalities such as
substituted phenyl with distinct electron traits (3b−d),
naphthyl (3e), thienyl (3f), methyl (3g), ethyl (3h), phenyl-
methyl (3i), and even fused-cyclohexyl (3j) groups, rapidly
assembling the respective quinolinone derivatives in 70−87%
yields. Subsequently, studies on decorating the phenylamine
ring were also performed. Satisfyingly, a large number of
functional groups was able to be introduced and capable of
resulting in the titled [5 + 1] carbonylation issue smoothly,
encompassing electron-donating groups such as methyl (3k),
methoxyl (3l), thiomethyl (3m), methylenedioxyl (3u), and
entry
solvent
HFIP
EtOH
2a (mmol)
T (°C)
yield (%)
1
2
3
4
5
6
7
8
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.3
0.24
0.24
120
120
120
120
120
120
120
120
110
130
120
120
120
65
30
68
49
67
73
66
38
64
69
68
73
55
TFE
1,4-dioxane
MeCN
toluene
DCE
DMF
9
toluene
toluene
toluene
toluene
toluene
10
11
12
c
13
a
Reaction conditions: 1a (0.2 mmol) and 2a in solvent (1.5 mL) were
stirred for 15 h under Ar atmosphere. Isolated yield. Air instead of
Ar.
b
c
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Scheme 3. Substrate Scope of 2-Alkenylanilines
Scheme 4. Substrate Scope of 2-Pyrrolylanilines
precursors (1a and 4a) in a 2.0 mmol amount were carried out,
respectively, in which the two runs were both able to
accomplish the desired transformation with good yields
(Scheme 5A and B). In addition, the reaction with 2-
pyrrolylaniline 4k was also amenable to perform scale-up
conversion, resulting in 5k with comparable yield and
efficiency (Scheme 5C). To our delight, exposed to the adduct
5k, the late-stage functionalization of estrone ran smoothly to
cyclohexyl (3v) and electron-withdrawing moieties such as
phenyl (3n), fluoro (3o), bromo (3p), trifloromethyloxyl (3q),
nitro (3r), ester (3s), and chloro (3t) groups. Furthermore,
the π-system-expanded 3w could be readily obtained.
Unfortunately, the simplest substrate 1x failed to run in this
protocol.
Inspired by the success of this new carbonylation reagent in
the [5 + 1] annulation reaction, we set out to survey the
feasibility of using this tactic to execute 2-arylaniline derivatives
(Scheme 4). After slightly modifying the reaction parameters
(replacing toluene with TFE as solvent, see details in the
Supporting Information), we observed that the 2-(1H-pyrrol-1-
yl)aniline 4a remained in this carbonylation procedure and
potently generated the pyrrolo[1,2-a]quinoxalin-4(5H)-one
5a, which has generally served as a core skeleton in numerous
bioactive molecules such as the PARP-1 inhibitor (Scheme
1D). By coupling with 2d, various 2-pyrrolylanilines (4b−o)
performed smoothly to provide the anticipated products (5b−
o) in 65−92% yields. A multitude of substituents appended to
the possible sites of the aniline ring were all tolerated properly,
including methoxyl (5b and 5n), bromo (5c and 5i), methyl
(5d, 5e and 5m), tert-butyl (5f), fluoro (5g), chloro (5h and
5l), trifluomethyl (5j), and ester (5k) groups, wherein the
electron-rich compounds expressed relatively preferential
outcomes. In this theme, incorporating dimethyl into the
pyrrolyl portion was allowable. Additionally, replacing pyrrolyl
with imidazo[1,2-a]pyridine was also subjected to this
envisioned [5 + 1] lactamization reaction and led to the
formation of polyheterocycle 5p in 91% yield.
Scheme 5. Gram-Scale Reaction and Synthetic Utilization
Afterward, we embarked on assessing the potential utility of
this established methodology. The larger scale experiments
with the aforementioned two types of representative reaction
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build a new type of complicated ester 6 in 58% yield (Scheme
5D). Moreover, when 5a was treated with POCl3 reagent, the
4-chloropyrrolo[1,2-a]quinoxaline 7 was accessed in 80% yield
(Scheme 5E). Next, the C−Cl bond could be further
functionalized to furnish product 8 by Suzuki−Miyaura
cross-coupling (Scheme 5F).
To gain more insights into the mechanistic rationality,
additional experiments were undertaken. In view of the verified
fact that the dioxazolones could readily decompose into CO2,
we introduced CO2 gas, another typical CO resource, into the
reaction system in the absence or catalytic amount of 2d,
respectively. Both of these cases failed to generate the titled
product smoothly, which unequivocally obviated the involve-
ment of CO2 as the carbonylation source (Scheme 6A). The
which product 3a could be generated properly (Scheme 6D).
This result supported that the urea species were involved in
this cyclization procedure.
On the basis of these findings, the reaction mechanism was
then put forward (Scheme 6E). The thermal decomposition of
dioxazolones initially takes place to generate isocyanate
accompanied by dislodging the CO2 molecule,13,16 followed
by reacting with 2-alkenylaniline via nucleophilic addition to
access the key intermediate urea 10b. At this stage, two
pathways might be employed, involving a direct cyclization
(path a) or sequential forming isocyanate species/Prins-type
reaction (path b). To further probe the exact reaction path, the
Me-protected 2-alkenylaniline 11 or its corresponding urea 10c
was used to undergo this issue. Notably, the envisioned
quinolinone 12 failed to occur (Scheme 6F), which proved
that the urea species was futile to enable this reaction by one-
step cyclization. Alternatively, to affirm the feasibility with
respect to isocynate, the reaction between substrate 1a with
bis(trichloromethyl) carbonate agent, which is able to in situ
generate the relevant isocyanate smoothly, was carried out and
indeed released quinolione product 3a (Scheme 6G), so the
path b was rational.
Scheme 6. Mechanistic Studies
In summary, we discovered a class of new carbonylating
agents resulting from the dioxazolones, by which the metal-free
[5 + 1] carbonylation of 2-alkenylanilines or 2-pyrrolylanilines
with dioxazolones is accomplished, leading to a variety of
quinolinones (23 examples) and pyrrolyl-fused quinoxalinones
(16 examples) in good yields with excellent functionality
tolerance. This study represents an unprecedented chemistry
reactivity with dioxazolones via simultaneously constructing
new N−C(O) and C(O)−C bonds. Mechanistic investigations
clearly illustrate that the generated double isocyanate species
are pivotal in this carbonylation conversion. Extensive studies
into the scope of the carbonylation reaction generated from
dioxazolones are currently ongoing in our laboratory and will
be presented in due course.
ASSOCIATED CONTENT
* Supporting Information
■
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The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c01147.
Experimental procedures and spectral data (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Jiang Nan − Shaanxi Key Laboratory of Chemical Additives
for Industry, College of Chemistry and Chemical Engineering,
Shaanxi University of Science and Technology, Xi’an 710021,
China; orcid.org/0000-0001-5570-6834;
Email: nanjiang@sust.edu.cn
Authors
Pu Chen − Shaanxi Key Laboratory of Chemical Additives for
Industry, College of Chemistry and Chemical Engineering,
Shaanxi University of Science and Technology, Xi’an 710021,
China
Xue Gong − College of Bioresources Chemical and Materials
Engineering, Shaanxi University of Science and Technology,
Xi’an 710021, China
reaction with 2m still delivered the wanted 3a, but no 4-
phenylquinoline-2(1H)-thione 9 was made (Scheme 6B).
Furthermore, the isotope-labeling experiment with diaxazolone
18O-2a led to the formation of product 18O-3a in 72% yield
(Scheme 6C). These findings provided solid evidence for the
viewpoint that the carbonyl group appended to the product
arose from the C3−O4 fragment. Subsequently, urea
compound 10a was synthesized to execute the reaction, in
Yan Hu − Shaanxi Key Laboratory of Chemical Additives for
Industry, College of Chemistry and Chemical Engineering,
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Dual Light-Driven Palladium Catalyst: Breaking the Barriers in
Carbonylation Reactions. Science 2020, 368, 318.
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Qiong Ma − Shaanxi Key Laboratory of Chemical Additives
for Industry, College of Chemistry and Chemical Engineering,
Shaanxi University of Science and Technology, Xi’an 710021,
China
Bo Wang − Shaanxi Key Laboratory of Chemical Additives for
Industry, College of Chemistry and Chemical Engineering,
Shaanxi University of Science and Technology, Xi’an 710021,
China
Yangmin Ma − Shaanxi Key Laboratory of Chemical
Additives for Industry, College of Chemistry and Chemical
Engineering, Shaanxi University of Science and Technology,
Xi’an 710021, China
Complete contact information is available at:
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by the NSFC (21801159),
the China Postdoctoral Science Foundation (2018M640944),
and the Natural Science Foundation of Shaanxi Province of
China (2019JQ-776, 2020JQ-705).
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