Facile Access to Multiaryl-1H-pyrrol-2(3H)-ones by Copper/TEMPO-Mediated Cascade Annulation of Diarylethanones with Primary Amines and Mechanistic Insight

Article abstract of DOI:10.1002/ejoc.201601178

A straightforward approach to an array of multiaryl-1H-pyrrol-2(3H)-ones featuring an α-diarylated all-carbon quaternary center was developed by using diarylethanones and primary amines as the raw materials. A complete mechanism involving a CuO/TEMPO-mediated multistep cascade process with an inherent delicate balance of substituent electronic effect is proposed. Moreover, this class of multiaryl β,γ-unsaturated γ-lactams demonstrates an intriguing aggregation-induced emission effect valuable for potential application in developing luminescent materials.

Full text of DOI:10.1002/ejoc.201601178

A Journal of
Accepted Article
Title: Facile Access to Multi-Aryl 1H-Pyrrol-2(3H)-ones via Copper-TEMPO Media-
ted Cascade Annulation of Diarylethanones with Primary Amines and Mecha-
nistic Insights
Authors: Xing Wang; Chen-Yang Zhang; Hai-Yang Tu; Aidong Zhang
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201601178
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COMMUNICATION
Facile Access to Multi-Aryl 1H-Pyrrol-2(3H)-ones via Copper-
TEMPO Mediated Cascade Annulation of Diarylethanones with
Primary Amines and Mechanistic Insights
Xing Wang,[a] Chen-Yang Zhang,[a] Hai-Yang Tu,*[a] and Ai-Dong Zhang*[a]
Abstract: A straightforward approach to an array of multi-aryl 1H-
pyrrol-2(3H)-ones featuring an α-diarylated all-carbon quaternary
center has been developed using diarylethanones and primary
amines as the raw materials. A complete mechanism involving a
CuO-TEMPO mediated multi-step cascade process with an inherent
delicate balance of substituent electronic effect is depicted.
Moreover, this class of multi-aryl β,γ-unsaturated γ-lactams
demonstrates an intriguing aggregation-induced emission effect
valuable for potential application in developing luminescent materials.
pyrrol-2(3H)-ones would feature an α-diarylated all-carbon
quaternary center, and the construction using easily accessible
diarylethanones has not been explored so far. Herein, we report
this straightforward approach and the mechanistic insights.
Moreover, inspired by the unique structure, we also investigated
their intriguing aggregation-induced emission (AIE) property.
Introduction
1H-Pyrrol-2(3H)-ones, a type of β,γ-unsaturated γ-lactams,
represent an important class of N-heterocycles and are found as
key structural motifs in many valuable biologically active
molecules, or as crucial intermediates in natural products
synthesis.[1] However, the approaches for synthsis of these
scaffolds with polysubstitution have been scarcely reported to
date,[2] which mainly take use of intramolecular cyclization or
intermolecular annulation with prefunctionalized precursors. For
example, Wang et al reported an elegant method for the
synthesis of enantiopure functionalized 1H-pyrrol-2(3H)-ones via
the intramolecular nucleophilic addition of tertiary enamide to
carbonyl group (Scheme 1a);[2b] You and co-worker recently
disclosed an copper-catalyzed intermolecular annulation of
prefunctionalized α-amino acid esters with β-enamino esters to
Scheme 1. Methods for constructing polysubstituted 1H-pyrrol-2(3H)-ones.
Results and Discussion
Initially, we evaluated feasibility of the approach by reacting
diphenylethanone (1a) with toluidine (2a) in the presence of CuO
catalyst, TEMPO (2,2,6,6-tetramethylpiperidine-1-oxyl) and
Cs2CO3 in DMF under an air atmosphere at 150 °C (Tables S1-
S8 and discussion, Supporting Information). The desired product
3,3,4,5-tetraphenyl-1-(p-tolyl)-1H-pyrrol-2(3H)-one (3a) was
indeed obtained in 38% yield (Table S1, entry 1), and its
structure confirmed by single-crystal X-ray diffraction.[6]
Encouraged by this result, various variables such as reaction
atmosphere, catalysts, bases and solvents, etc., were
systematically examined to improve the reaction efficiency.
Finally, the optimal conditions were determined and 3a was
obtained in 83% yield (Scheme 2).
Under the optimized conditions, the scope and limitations of
the reaction were examined, and the results are summarized in
Scheme 2. Notably, a wide range of aromatic and aliphatic
primary amines could be employed in this transformation and
delivered 1H-pyrrol-2(3H)-ones in moderate to good yields. The
steric hindrance of substituents on the aromatic amines had little
influence on the yield, for example, o- and m-methylanilines
gave the desired products 3c and 3d with slightly decreased
yields. However, the electronic nature of the substituents
strongly impacted the yield as exemplified by the reaction of 4-
trifluoromethylaniline with diphenylethanone, in which no desired
product (3j) was observed. Interestingly, functional groups such
as Cl, Br, and vinyl on aniline ring were tolerant and the reaction
gave the correspondingly 1H-pyrrol-2(3H)-ones in synthetically
useful yields (3l, 3m, 3q). These functional groups would
synthesize
3-amino-1,3-dihydro-2H-pyrrol-2-ones
(Scheme
1b).[2c] These 1H-pyrrol-2(3H)-ones feature an α-quaternary
center and a β,γ-unconjugated double bond and are hardly
accessible by other methods, since the unconjugated double
bond is generally more prone to shift to a conjugated one.[3] In
this context, developing facile approaches to these structurally
unique 1H-pyrrol-2(3H)-ones using simpler raw materials and/or
routes would be highly valuable and challenging.
Diarylethanones, on the other hand, have been widely used as
building blocks for synthesis of various mutil-aryl heterocycles.[4]
Recently, the copper-catalyzed oxidative coupling of
diarylethanones to give multi-aryl 1,4-diketones for synthesis of
multi-aryl pyrroles[4b] has drawn our attention. To continue our
efforts in exploiting diarylethanones for divergent synthesis,[5] we
envisioned that the oxidative coupling products 1,4-diketones
might be captured with amines to afford 1H-pyrrol-2(3H)-ones
with a single operation (Scheme 1c) through a variant of the
classic Paal-Knorr pyrrole synthesis since dehydration is unlikely
to occur due to the absence of neighboring hydrogen. These 1H-
[a]
X. Wang, C.-Y. Zhang, Prof. Dr. H.-Y. Tu, Prof. Dr. A.-D. Zhang
Key Laboratory of Pesticide & Chemical Biology of Ministry of
Education, College of Chemistry, Central China Normal University
152 Luoyu Road, Wuhan, Hubei 430079 (China)
E-mail: adzhang@mail.ccnu.edu.cn; haiytu@mail.ccnu.edu.cn
http://chem.ccnu.edu.cn/info/1057/1159.htm
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European Journal of Organic Chemistry
10.1002/ejoc.201601178
COMMUNICATION
provide good handles for further functionalization, making multi-
aryl 1H-pyrrol-2(3H)-ones useful in preparation of functional
materials through catalyzed coupling reactions, styrene
epoxidation, or vinylic polymerization. Polycyclic aromatic
amines such as 1- and 2-aminonaphthalenes, and 2-
aminoanthracene were able to successfully transform into the
desired products 3n, 3o, and 3p, respectively, in reasonable
1,4-butanedione (5a) in 7% yield [Eq.(4)], implying that 5a may
be another key intermediate. The low yield of 5a means the
radical oxidative homocoupling unlikely to occur because of the
existence of TEMPO. Next, if 5a was subjected to the reaction
without adding 2a, 4a was isolated in 81% yield [Eq.(5)],
suggesting 5a is one precursor of 4a. Finally, 5a was able to
convert to 3a in 72% yield by reacting with 2a [Eq.(6)]. Therefore,
4a and 5a are two possible key intermediates.
yields.
Heterocycle-containing
3-aminopyridine and
4-
morpholinoaniline were also suitable substrates, affording the
corresponding products 3r and 3s in 63% and 72% yields. In
addition, benzylamine and aliphatic primary amines such as
cyclohexylamine and n-octyl amine furnished 3t, 3u, 3v in 55%,
37% and 84% yields, respectively. Furthermore, N-unsubstituted
1H-pyrrol-2(3H)-one 3w was also obtained in 74% yield when
NH4OAc was used as the ammonia source. N-Unsubstituted γ-
lactams are important skeletons in bioactive natural products
and drugs,[7] and can be further functionalized through acylation
and arylation.[8] Importantly, a scale-up synthesis of 3a was
demonstrated in 65% yield (1.12g, Scheme S2).
Scheme 3. Control reactions under the standard conditions and the inner
relationship network in mechanistic insights.
Based on these control reactions, a complete mechanism can
be outlined in Scheme 4 using the model reaction of 1a with 2a
as example. First, 1a undergoes enolization to give a copper
enolate intermediate, which partakes in oxidative enolate
homocoupling[9] to yield 5a. Following the conversion of 5a to a
radical intermediate via a single electron transfer (SET)
process,[10] the key intermediate 4a is generated with TEMPO
mediated oxidative dehydrogenation.[11] Next, 4a is attacked
nucleophilically by 2a to afford an imine intermediate, which
takes part in 5-exo-trig cyclization to give a cyclic iminium
intermediate. Finally, the iminium intermediate undergoes the
Wagner-Meerwein 1,2-shift[12] of phenyl group leading to
formation of 3a. Interestingly, as shown in Scheme 4, the whole
mechanism can be arranged in two symmetric hemicyclic parts
and the key intermediate 4a locates at the intersectional point.
Before the point, Cu(II) participates in the enolate homocoupling
and the one-electron oxidation, following with the TEMPO
mediated oxidative dehydrogenation and the internal
regeneration of Cu(II).[13] It is worthy of mention that 2.0 equiv of
Scheme 2. Substrate scope. Reaction conditions: 1a (1.0 mmol), 2a (1.2
mmol), CuO (5 mol-%), TEMPO (2.0 equiv) and Cs2CO3 (2.5 equiv) in DMF (8
mL) at 150 °C under an argon atmosphere for 12~24 h. Yields are based on
isolated products. [a] 3.0 Equiv of TEMPO was used. [b] NH4OAc was used.
It is interesting that there is no direct correlation in structure
between the reactants and the products, and this attracted us to
gain insight into the underlying mechanism using control
reactions as shown in Scheme 3 [Eqs.(1~6)]. It was first noted
that two major new spots appeared on the TLC plate after the
reaction of 1a with 2a for 12 h, and gradually disappeared over
time to produce the desired product 3a. The two spots were
isolated and characterized to be compound 4a in E/Z isomers by
single crystal X-ray diffraction [Eq.(1)].[6] Without adding 2a, the
reaction stopped at the stage of formation of 4a, which was
obtained in 58% yield [Eq.(2)] and able to react with 1.7 equiv of
2a to give 3a in 91% yield [Eq.(3)], indicating that 4a is a key
intermediate. On the other hand, without adding Cs2CO3, 1a
underwent oxidative homocoupling to give 1,2,3,4-tetraphenyl-
Scheme 4. Proposed mechanism for the cascade annulation.
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European Journal of Organic Chemistry
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COMMUNICATION
TEMPO is needed in this hemicycle as expected and
demonstrated in the conditions optimization. After the
intersectional point, the most worthwhile to note is the Wagner-
Meerwein 1,2-shift of phenyl group to form an on-ring α-
diarylated all-carbon quaternary center, which is otherwise
inaccessible.[14]
After the successful one-pot one-step synthesis of multi-aryl
1H-pyrrol-2(3H)-ones and the mechanism insights, we intended
to explore further the substrate scope of diphenylethanones. It
has proven to be a great challenge that whatever substituents,
electron-rich or electron-poor, are present on the phenyl ring, the
diphenylethanones could not be converted to the desired 1H-
pyrrol-2(3H)-ones. Closely inspecting the reaction products
found that diphenylethanones bearing an electron-rich
substituent (e.g., 4-OCH3, 1b) gave the non-cyclized (E/Z)-
1,2,3,4-tetra(4-methoxyphenyl)-2-butene-1,4-dione (4b). By
intensity order of 3y<3k<3b<3v<3a<3o (Figure 1a and
Supporting Information Figures S7-S13). Taking 3o as an
example, it displayed a fluorescence emission onset at the water
fraction of 70%, following a sharp increase till the maximum
intensity reached at the water fraction of 90% (Figure 1b). There
are several mechanisms proposed for the AIE effect and the
most typical one is the restriction of intramolecular rotation (RIR)
upon formation of nanoaggregates in poor mixed solvent.[19] As
shown in Figures 1c-d, 3a presents a clearly propeller-like
conformation preventing π-π stacking from the peripheral phenyl
groups; but there exist multiple intra- and intermolecular C-H···π
interactions, as revealed by X-ray analysis. The massive C-
H···π interactions help restrict the rotation of phenyl groups and
lead to blocking the nonradiative relaxation pathways and
opening the radiative processes.[19b]
contrast,
diphenylethanones
bearing
an
electron-poor
substituent (e.g., 4-F, 1c) yielded no desired product either but a
complicated mixture. Furthermore, if 4b was used to react with
2a, no desired product but 98% of 4b was recovered [Scheme
S1, Eqs.(1-3)]. Interestingly, 1,2,3,4-tetra(4-fluorophenyl)butane-
1,4-dione (5b),[4e] an analogue of intermediate 5a, could react
with 2a and delivered the desired product 3y in 63% yield [Eq.
(7)]. This two-pot two-step procedure looks like the classic Paal-
Knorr pyrrole synthesis[15] in reaction substrate although 1H-
pyrrol-2(3H)-ones instead of pyrroles were obtained in our case.
The above exploration manifests a delicate balance of the
substituent electronic effect of diphenylethaones in the
transformation, and any deviation would result in terminating the
cascade process. This balance may originate from twofold: 1) an
electron-rich substituent disfavors the imine formation of
diphenylethanone with 2a, thus the reaction proceeds well along
the first hemicycle of the mechanism to form 4b; but the next
imine formation of 4b with 2a is impeded at the beginning of the
second hemicycle; 2) an electron-poor substituent favors the
imine formation of diphenylethanone with 2a, which inactivates
the enolate oxidative homocoupling at the beginning of the first
hemicycle, leading to neither expected intermediates nor desired
product. Thus the transformation of diphenylethanones with
electron-poor substituent must occur via a two-pot two-step
procedure where 2a is added in the second pot.
Figure 1. a) Relative fluorescence peak intensities in THF/water for selected
compounds. b) Fluorescence spectra of 3o in THF/water (inset: digital image
of 3o fluorescence excited at 365 nm in THF and the mixed solvent of 90%
H2O). Concentration: 8×10-5 mol/L; excitation: 310 nm. c) Conformation of 3a
in crystal with intramolecular C−H···π interactions and the dihedral angles
indicated. d) Unit cell of 3a crystal and intermolecular C−H···π interactions.
Conclusions
In summary, we have developed an unprecedented one-pot
one-step strategy to achieve the rapid construction of multi-aryl
1H-pyrrol-2(3H)-ones featuring an α-diarylated all-carbon
quaternary center from easily accessible diarylethanones and
primary amines. A plausible mechanism was proposed that
One of the most attractive features of these 1H-pyrrol-2(3H)-
ones is the highly arylated structure resembling the multi-aryl
five-membered heterocyles, such as hexaphenylsilole[16] and
pentaphenylpyrrole[17], that have the intriguing aggregation-
induced emission (AIE) effect as firstly introduced by Tang’s
group.[18] We examined the fluorescence behavior of selected
representative compounds including 3a, 3b, 3k, 3o, 3v and 3y in
solutions with different THF/water ratio, and found that all these
compounds showed the typical AIE effect with the fluorescence
involves
comprising
a
copper-TEMPO mediated cascade process
oxidative enolate homocoupling, oxidative
dehydrogenation, heterocyclization, and Wagner-Meerwein 1,2-
shift of phenyl group. The delicate balance of the substituent
electronic effect from diphenylethanones makes the cascade a
great challenge; and in this situation, an alternative two-pot two-
step procedure was provided. Moreover, these compounds as
new AIEgens showed interesting aggregation-induced emission.
The present developed atom- and step-economic approach to
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Acknowledgements
This work was supported by the National Natural Science
Foundation of China (NSFC) (Project Nos. 21172087, 21172088
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Keywords: annulation • aggregation-induced emission •
dehydrogenation • homocoupling • γ-lactam
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European Journal of Organic Chemistry
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COMMUNICATION
Layout 2:
COMMUNICATION
Cascade Annulation
Xing Wang, Chen-Yang Zhang, Hai-
Yang Tu,* and Ai-Dong Zhang*
Page No. – Page No.
Facile Access to Multi-Aryl 1H-Pyrrol-
Long way in short path: An unprecedented copper-TEMPO mediated cascade
process comprising oxidative enolate homocoupling, oxidative dehydrogenation,
heterocyclization, and Wagner-Meerwein 1,2-phenyl shift has been revealed in the
rapid access to mutil-aryl 1H-pyrrol-2(3H)-ones, a class of structurally unique and
highly phenylated β,γ-unsaturated γ-lactams that have intriguing AIE effect.
2(3H)-ones
via
Copper-TEMPO
Mediated Cascade Annulation of
Diarylethanones with Primary Amines
and Mechanistic Insights
[*]
X. Wang, C.-Y. Zhang, Prof. Dr. H.-Y. Tu, Prof. Dr. A.-D. Zha
Key Laboratory of Pesticide & Chemical Biology of Ministry o
Education, College of Chemistry, Central China Normal Univ
152 Luoyu Road, Wuhan, Hubei 430079 (China)
E-mail: adzhang@mail.ccnu.edu.cn
haiytu@mail.ccnu.edu.cn
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