1,2-Aryl Migration Induced by Amide C?N Bond-Formation: Reaction of Alkyl Aryl Ketones with Primary Amines Towards α,α-Diaryl β,γ-Unsaturated γ-Lactams

Article abstract of DOI:10.1002/anie.202014900

Rearrangement reactions incorporated into cascade reactions play an important role in rapidly increasing molecular complexity from readily available starting materials. Reported here is a Cu-catalyzed cascade reaction of α-(hetero)aryl-substituted alkyl (hetero)aryl ketones with primary amines that incorporates an unusual 1,2-aryl migration induced by amide C?N bond formation to produce a class of structurally novel α,α-diaryl β,γ-unsaturated γ-lactams in generally good-to-excellent yields. This cascade reaction has a broad substrate scope with respect to primary amines, allows a wide spectrum of (hetero)aryl groups to smoothly undergo 1,2-migration, and tolerates electronically diverse α-substituents on the (hetero)aryl ring of the ketones. Mechanistically, this 1,2-aryl migration may stem from the intramolecular amide C?N bond formation which induces nucleophilic migration of the aryl group from the acyl carbon center to the electrophilic carbon center that is conjugated with the resulting iminium moiety.

Full text of DOI:10.1002/anie.202014900

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How to cite: Angew. Chem. Int. Ed. 2021, 60, 8425–8430
International Edition: doi.org/10.1002/anie.202014900
doi.org/10.1002/ange.202014900
Heterocycles
German Edition:
À
1,2-Aryl Migration Induced by Amide C N Bond-Formation: Reaction
of Alkyl Aryl Ketones with Primary Amines Towards a,a-Diaryl b,g-
Unsaturated g-Lactams
Rong Hu, Yigao Tao, Xiaofeng Zhang, and Weiping Su*
Abstract: Rearrangement reactions incorporated into cascade
reactions play an important role in rapidly increasing molec-
ular complexity from readily available starting materials.
Reported here is a Cu-catalyzed cascade reaction of a-
(hetero)aryl-substituted alkyl (hetero)aryl ketones with pri-
mary amines that incorporates an unusual 1,2-aryl migration
very recently, diverse types of metal-catalyzed methods for
efficient dehydrogenative desaturation of saturated sub-
strates have been established, which provided a broader
platform for discovering and developing dehydrogenative
desaturation-triggered cascade reactions.[8] Owing to the
versatile reactivity of unsaturated compounds as synthetic
intermediates, dehydrogenative desaturation reactions have
a great potential to couple a variety of reactions of
unsaturated compounds, affording various cascade processes.
In light of such a potential reaction diversity, these dehydro-
genative desaturation-triggered cascade reactions promis-
ingly complement the regular metal-catalyzed direct C(sp3)-H
À
induced by amide C N bond formation to produce a class of
structurally novel a,a-diaryl b,g-unsaturated g-lactams in
generally good-to-excellent yields. This cascade reaction has
a broad substrate scope with respect to primary amines, allows
a wide spectrum of (hetero)aryl groups to smoothly undergo
1,2-migration, and tolerates electronically diverse a-substitu-
ents on the (hetero)aryl ring of the ketones. Mechanistically,
this 1,2-aryl migration may stem from the intramolecular
functionalization reactions[9] by generating the formal C H
À
functionalization products that are not easy to access by way
of other approaches. To date, the vast majority of the
established dehydrogenative desaturation-triggered cascade
reactions of carbonyl compounds have focused on the b-
functionalization reactions, and the examples of the dehy-
drogenative desaturation-triggered cascade towards the
À
amide C N bond formation which induces nucleophilic
migration of the aryl group from the acyl carbon center to
the electrophilic carbon center that is conjugated with the
resulting iminium moiety.
À
T
he rearrangement reactions featuring group-migration
remote C H functionalization of carbonyl compounds have
constitute an indispensable part of classic organic chemistry,[1]
and is still of considerable interest to chemists[2–4] due to their
importance in both fundamental chemistry and synthesis
application. To rapidly construct structurally complex mole-
cules starting from readily available reactants, the rearrange-
ment reactions are often incorporated into the cascade
reactions, as exemplified by a variety of elegant studies.[2a,b,4]
Recently, the cascade reactions initiated by dehydrogenative
desaturation have appeared as a promising tool for syntheses
of functionalized products in an atom- and step-economical
fashion from the simple saturated compounds.[5–7] Notably,
been extremely scarce.[7c,10] Our recent investigations on the
metal-catalyzed dehydrogenative desaturation-triggered cas-
cade reactions of ketones have uncovered that a,b-desatura-
3
[11]
À
tion of ketone leads to the activation of g-Csp H bond.
Inspired by these discoveries, we explored the dehydrogen-
ative desaturation-triggered cascade reactions towards the
remote Csp3-H functionalization, diversifying the dehydro-
genative desaturation-triggered cascade reactions.
Herein, we report a copper-catalyzed dehydrogenative
desaturation-triggered cascade reaction of a-(hetero)aryl-
substituted alkyl (hetero)aryl ketones with primary amines
that goes through a formal ketone g-Csp3-H amination and an
À
unusual amide C N bond formation-induced 1,2-aryl migra-
[*] R. Hu, Y. Tao, X. Zhang, Prof. W. Su
tion to generate structurally novel a,a-diaryl b,g-unsaturated
g-lactams in good-to-excellent yields. The 1,2-aryl migration
process present in our dehydrogenative cascade reaction
likely originates from intramolecular nucleophilic addition of
imine nitrogen to carbonyl carbon to generate the a,b-
unsaturated iminium intermediate that induces 1,2-aryl
migration from acyl carbon to ketone a-carbon [Scheme 1c,
Eq. (1)]. Interestingly, our previous work demonstrated that
the dehydrogenation-triggered cascade reaction of a-aryl-
substituted alkyl aryl ketones with secondary amines pro-
duced 2-amino furan,[10] reflecting the dependence of chemo-
selectivity on the substrate identity [Scheme 1c, Eq. (2)]. This
1,2-aryl migration is distinct from the classic amide-formation
1,2-migration reactions, that is, the Schmidt reaction (Sche-
me 1a)[12a] and the Beckmann rearrangement (Scheme 1b) in
State Key Laboratory of Structural Chemistry, Center for Excellence in
Molecular Synthesis, Fujian Institute of Research on the Structure of
Matter, Chinese Academy of Sciences
Yangqiao West Road 155, Fuzhou, Fujian 350002 (China)
E-mail: wpsu@fjirsm.ac.cn
R. Hu, Y. Tao, Prof. W. Su
University of Chinese Academy of Sciences
Beijing 100049 (P. R. China)
and
School of Physical Science and Technology, ShanghaiTech University
100 Haike Road, Shanghai 201210 (China)
R. Hu, Y. Tao
Shanghai Advanced Research Institute
Chinese Academy of Sciences (China)
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.202014900.
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Table 1: Discovery and development of dehydrogenative desaturation-
triggered cascade reaction.[a]
Entry
L
Additives (mol%)
–
Solvent
Yield [%][b]
1
2
3
4
5
6
7
8
L1
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
CH3CN
PhMe/CH3CN (1:1)
PhMe/CH3CN (1:1)
PhMe/CH3CN (1:1)
PhMe/CH3CN (1:1)
PhMe/CH3CN (1:1)
39
44
41
55
37
41
31
44
66
70
83
64
61
L1 TsOH (10)
L1 TsOH (20)
L1
L1
L1
L1
L1
L1
L1
L2
L3
L4
CsOAc (20)
NaOAc (20)
KOAc (20)
Cs2CO3 (20)
CsOAc (20)
CsOAc (20)
CsOH·H2O (20)
CsOH·H2O (20)
CsOH·H2O (20)
CsOH·H2O (20)
9
10
11
12
13
Scheme 1. Amide-forming 1,2-migration reaction of ketone.
[a] Reaction conditions: 1a (1.5 equiv), 2a (0.4 mmol), Cu(OAc)2
(10 mol%), L (10 mol%), TEMPO (3 equiv), additive, solvent, N2, 1208C
for 48 h. [b] Yields of isolated products.
which groups migrate from a carbon to a nucleophilic nitro-
gen.[12b]
When investigating the Cu-catalyzed dehydrogenative
desaturation-triggered g-amination reaction of a-phenyl-sub-
stituted 1-phenyl-1-butanone (1a) with 4-phenylbutan-2-
amine (2a), we observed that this reaction produced a,a-
diaryl b,g-unsaturated g-lactam via an unexpected 1,2-aryl
migration (Table 1, entry 1). The structure of a,a-diaryl b,g-
unsaturated g-lactam was unambiguously established by
single crystal X-ray diffraction and NMR spectroscopy
technologies (see below).[13] In spite of the fact that g-lactams
have been widely studied due to the prevalence of g-lactam
moiety in bioactive molecules,[14] the product observed in the
reaction of 1a with 2a, namely, a,a-diaryl b,g-unsaturated g-
lactam, is very scarce presumably because such a complex
molecule is not easy to construct. Our interest in the novelty
of both the product structure and this 1,2-aryl migration
prompted us to conduct optimization studies of this Cu-
catalyzed cascade reaction (Table 1). The initial reaction of
2a (0.4 mmol) with 1.5 equiv of 1a was conducted in toluene
(2 mL) at 1208C for 48 hours in the presence of 3 equiv of
TEMPO as an oxidant using 10 mol% Cu(OAc)2 as a catalyst
and 10 mol% 2,2’-bipyridine as a ligand, which produced a,a-
diaryl b,g-unsaturated g-lactam 3a in 39% yield (entry 1).
10 mol% TsOH was added to the reaction system to protect
primary amine from oxidation, giving slightly improved yield
(44% yield) (entry 2). However, increasing loading of TsOH
to 20 mol% reduced the reaction yield (entry 3) probably
because strong acid TsOH impeded the nucleophilic attack of
primary amine. In contrast, using 20 mol% CsOAc as base
additive improved the yield of 3a (entry 4), implicating that
base additive might promote oxidative dehydrogenation of 1a
by accepting protonation released from 1a other base
additives such as NaOAc, KOAc and Cs2CO3 (entries 5–7)
were found to be inferior to CsOAc. Then, we investigated the
effects of solvents on the reaction outcomes. Although
acetonitrile gave the lower yield than toluene (entry 8 vs.
entry 4), a mixed solvent of toluene and acetonitrile (the
volume ratio of 1: 1) was better than either of two solvents
(entry 9 vs. entry 8 or entry 4). Using this mixed solvent,
replacement of CsOAc with more basic CsOH·H2O
(20 mol%) could improve the reaction yield (entry 10).
After identifying suitable solvent and base additive, ligand
effect was checked for the model reaction (entries 11–13),
which disclosed that more electron-rich 4,4’-dimethoxy-2,2’-
bipyridine was able to increase the yield of 3a to 83%
(entry 11).
With the optimized reaction conditions (Table 1, entry 11)
in hand, we firstly explored the scope of primary amines for
this dehydrogenative desaturation-triggered cascade reaction.
As shown in Scheme 2, a broad spectrum of alkyl amines
smoothly underwent the reaction to produce the correspond-
ing a,a-diaryl b,g-unsaturated g-lactams in good-to-excellent
yields (3a–3r). This reaction was not sensitive to the steric
bulkiness of alkyl substituents of amines. Various bulky
substituents such as tertiary butyl group adjacent to amino
group (3i) and other tertiary alkyl groups linked to amino
group (3k–3n) were well tolerated. Meanwhile, less bulky
alkyl amines, such as straight-chain alkyl amines (3a–3e) and
alicyclic amines (3o–3r) also worked well for this reaction.
Aryl groups adjacent to amino group were also compatible
(3g–3j), as exemplified by 1-(1’-naphthalenyl)ethylamine
(3j). Amino esters were suitable substrates for this cascade
reaction (3d, 3l, 3p), which provided an opportunity to
further investigate the bioactivity of such a structurally novel
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of this cascade reaction. Ortho-methyl anilines (3al–3am)
gave slightly lower yields than para-methyl aniline (3x), once
again demonstrating that this cascade reaction was compat-
ible with steric hindrance in primary amine substrates.
Differing from other anilines, 4-vinylaniline gave a low yield
for the target product due to formation of several unknown
side-products (3an). Notably, this cascade reaction could be
carried out on gram-scale as demonstrated by the reaction
producing 3e, though such a gram-scale reaction gave a lower
yield (62%) than that occurring under standard conditions
(92%). Unfortunately, the reaction was not compatible with
linear alkyl primary amines due to the oxidation of such
amines by TEMPO.
Next, we investigated the scope and limitation of a-
substituted alkyl aryl ketones. Initially, the scope of migrating
a-phenyl-substituted alkyl aryl ketones with 1-ethyl propyl-
amine. As shown in Scheme 3, phenyl groups bearing various
substituents including electron-withdrawing fluoro (4a),
chloro (4b), bromo (4c–4d), ester (4e, 4 f), trifluoromethyl
(4g), acetyl (4h) groups, electron neutral tert-butyl group (4i)
and electron-donating methoxy group (4k) all underwent 1,2-
migration to produce the target product in excellent yields. Of
these products, 4e was structurally characterized by single
crystal X-ray diffraction analysis, validating that 1,2-migration
of para-ester phenyl group occurred. Tolerance of the acetyl
group on migrating phenyl ring (4h) indicated that reaction
selectively occurred on longer propyl chain. Bulky aryl groups
(4l, 4m) and heteroaryl groups including pyridyl groups (4n–
4o) also underwent 1,2-migration smoothly. The effect of a-
substituents on the reaction outcomes was also evaluated. 2’-
naphathalenyl a-substituent (4p) gave rise to higher yield
than sterically more demanding 1’-naphathalenyl a-substitu-
ent (4q), implicating that steric hindrance from a-substituent
was unfavorable to the reaction. A series of aryl a-substitu-
ents with varying electronic properties allowed the reaction to
occur (4r–4z). The trend for a-substituent to have an effect
on the reaction is that relative electron-deficient aryl sub-
stituent is beneficial to the reaction, as disclosed by the
comparison of 4’-methyl phenyl substituent (4v) with elec-
tron-deficient phenyl substituents (4s, 4y) as well as the
difference in yield between 4k and 4ab. In line with this trend,
electron-deficient 4-pyridyl a-substituent gave an excellent
yield (4z). Using chiral amine as coupling partner did not give
diastereoselective product (4ae), likely due to the high
reaction temperature. When the (hetero)aryl substituents on
the a-positions of aryl alkyl ketones were replaced with alkyl
groups (1af) or other functional groups such as acyl group
(1ah), the reaction of a-substituted alkyl aryl ketone with
primary amine gave only a trace of a,b-unsaturated ketone
instead of the targeted lactam product even at higher
temperatures. Dialkyl ketone, for example, 1ag, did not
work for this reaction either.
Scheme 2. The scope of primary amines for dehydrogenative desatura-
tion-triggered cascade reaction. [a] The yields are the yields of the
isolated products. The migrating groups are marked in red. [b] The
reaction was carried out in 4 mmol scale of 2e.
lactam products since they are readily converted into the
corresponding acids by hydrolysis of ester groups. Besides
alkyl amines, anilines with diverse functional groups on their
phenyl rings participated in reaction, affording lactam
products in good yields (3s–3an). Both electron-withdrawing
groups such as halo substituents (3t–3v, 3ag–3ai), ester (3w)
and trifluoromethyl (3ad), and electron-donating groups such
as alkoxy (3z, 3ac, 3ak, 3am) and alkylthio (3aa–3ab) were
all tolerated, indicating the good functional group tolerance
To understand this dehydrogenative desaturation-trig-
gered cascade reaction, study of reaction mechanism was
performed. In the crossover experiment (Scheme 4a), no
crossover product was produced, which illustrated that 1,2-
aryl migration is an intramolecular process. When the model
reaction was carried out at lower temperature (1008C), the
reaction did not proceed to completion, giving the target
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Scheme 4. Studies of the mechanism for the Cu-catalyzed cascade
reaction.
(20% yield) (Scheme 4b). Moreover, g-keto enal was
observed to readily react with primary amine even at 808C
to generate a,a-diaryl b,g-unsaturated g-lactam via 1,2-aryl
migration regardless of the presence or absence of Cu catalyst
(Scheme 4c). This result indicates that a Cu catalyst may not
be responsible for 1,2-aryl migration event, which is sup-
ported by the fact that a chiral pyridine oxazoline ligand gave
no diastereoselectivity in the reaction of 2-(3-bromophenyl)-
1-(4-(tert-butyl)phenyl)butan-1-one with chiral (S)-1-cylo-
hexylethan-1-amine, similar to the reaction outcome with
nonchiral bipyridine ligand. Our previous work confirmed
À
that g-keto enal resulted from oxygenation of g-C H of
Scheme 3. The scope and limitations with respect to the a-substituted
alkyl (hetero)aryl ketones for the dehydrogenative desaturation-trig-
gered cascade reaction. [a] The yields are those of the isolated
products. The migrating groups are marked in red.
enone.[10] These experiments shed light on the possible
intermediate products in the cascade reaction of a-aryl-
substituted alkyl aryl ketone with primary amine. In light of
these results, a plausible reaction pathway is proposed for this
cascade reaction (Scheme 4d). The cascade process begins
with Cu-catalyzed a,b-dehydrogenation desaturation of alkyl
aryl ketone with TEMPO as oxidant to form enone. The a,b-
product 3a in a moderate yield with concomitant formation of
a considerable amount of enone that derived from the
dehydrogenation of alkyl aryl ketone 1a, which implicated
that enone was a possible intermediate product. In the
absence of primary amine, treatment of a-phenyl-substituted
phenyl propyl ketone with 3 equiv of TEMPO at 1008C
allowed for isolation of enone (25% yield) and g-keto enal
=
À
C C double bond formation activates the g-C H bond of
enone towards oxygenation, so that enone is subsequently
converted into g-keto enal via oxygenation reaction at g-
carbon. The amine-aldehyde condensation between the
resultant g-keto enal with primary amine generates a b-
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benzoyl-substituted a,b-unsaturated imine species. Upon
o)aryl-substituted alkyl (hetero)aryl ketones with primary
À
formation of this imine species, the intramolecular nucleo-
philic addition of nitrogen to carbonyl carbon takes place to
generate a zwitterionic intermediate that induces 1,2-migra-
tion of aryl group from the carbonyl carbon atom to the
electrophilic carbon atom that is conjugated with iminium, to
construct a,a-diaryl b,g-unsaturated g-lactam as a final prod-
uct. Alternatively, the intramolecular nucleophilic addition of
nitrogen to carbonyl and the 1,2-aryl migration may simulta-
neously occur in a concerted reaction. Analyzing product
distribution in the uncomplete cascade reaction that was
carried out at relatively low temperature, did not show any
detectable amount of g-keto enal. Non-observable g-keto
enal in the cascade process implied that oxygenation of enone
to g-keto enal was the rate-determining process in the cascade
reaction towards g-lactam product, which is consistent with
the above-mentioned observation that the reaction of g-keto
enal with primary amine (Scheme 4c) took place at lower
temperature than the whole cascade reaction. Moreover, the
proposed reaction pathway may rationalize our other obser-
vations on this cascade reaction, including the beneficial
effect of base additive and the higher reactivity of ketone
substrates bearing electron-deficient aryl a-substituents. In
this context, base additive should promote a,b-dehydrogen-
ation desaturation of ketone substrates and g-oxygenation of
enone to g-keto enal by assisting formation of enolate CuII
species and dienolate CuII species,[15] respectively. The elec-
tron-deficient aryl a-substituents of ketone substrates may
not only assist in amine-aldehyde condensation of g-keto enal
intermediate with primary amine, and promote 1,2-aryl
nucleophilic migration by enhancing electrophilicity of
migration terminus, but also accelerate g-oxygenation of
enone to g-keto enal by facilitating g-deprotonation of enone
to form dienolate CuII species.
amines that incorporates an unusual amide C N bond
formation-induced 1,2-aryl migration of alkyl aryl ketones
as a key element. As a result of the unique 1,2-aryl migration
mode, this Cu-catalyzed cascade reaction afforded a class of
structurally novel products, that is, a,a-diaryl b,g-unsaturated
g-lactams, demonstrating the competence of dehydrogenative
desaturation-triggered cascade reaction to rapid construct
complex molecular frameworks from readily available start-
ing materials. The optimized reaction conditions allowed
a broad range of primary amines including anilines to
participate in the reaction, enabled a wide spectrum of
(hetero)aryl groups to undergo 1,2-migration, and tolerated
a variety of (hetero)aryl a-substituents of ketone substrates.
In general, good-to-excellent yields were achieved for this
cascade reaction. Besides, the established reaction conditions
enabled this cascade reaction to be conducted on gram-scale,
further highlighting the applicability of this synthetic method.
Mechanistic investigation uncovered that this cascade reac-
tion likely involved amine-aldehyde condensation of g-keto
enal intermediate with primary amine to form a b-benzoyl-
substituted a,b-unsaturated imine species that underwent
intramolecular nucleophilic addition of imine nitrogen to
carbonyl carbon and subsequent 1,2-aryl migration to deliver
the final product. The ongoing work in our group is to develop
the method for achieving stereoselective version of this
cascade reaction by means of the strategy to conduct the
cascade reaction in separated steps with the identified chiral
catalyst for 1,2-aryl migration reaction, and to expand the
substrate scope of this cascade reaction beyond ketones since
the advance has recently achieved in the development of
catalytic methods for dehydrogenation desaturation of other
carbonyls.
Recognizing the pathway of this Cu-catalyzed cascade
reaction, we conducted this cascade reaction in the manner of
separated steps to expand the substrate scope. As shown in
Scheme 5, the primary amines that is sensitive to oxidative
conditions, such as isoleucine and mexiletine hydrochloride,
smoothly reacted with g-keto enal that was isolated from
oxidative dehydrogenation of corresponding ketone, giving
the expected a,a-diaryl b,g-unsaturated g-lactam products in
good yields.
Acknowledgements
This work was supported by the National Key Research and
Development Program of China (2018YFA0704502),
National Natural Science Foundation of China Grant
(21931011), the Key Research Program of Frontier Sciences
of the Chinese Academy of Sciences (QYZDJ-SSW-
SLH024), and the Strategic Priority Research Program of
the Chinese Academy of Science (XDB20000000).
In summary, we have developed a Cu-catalyzed dehydro-
genative desaturation-triggered cascade reaction of a-(heter-
Conflict of interest
The authors declare no conflict of interest.
Keywords: copper · heterocycles · ketones · lactams ·
synthetic methods
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Manuscript received: November 12, 2020
Revised manuscript received: December 18, 2020
Accepted manuscript online: January 11, 2021
Version of record online: March 5, 2021
8430 www.angewandte.org
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