Base-Catalyzed Cascade Reaction of ortho-(Propargylamino)aryl Ketones with N-, O-, or S-Based Nucleophiles for the Synthesis of 3-Functionalized Quinoline Scaffolds

Article abstract of DOI:10.1002/adsc.201800120

A metal-free and base-catalyzed cascade reaction of ortho-(propargylamino)aryl ketones with primary alcohols, secondary amines, including various N-heterocycles, and thiols through 1,4-benzoxazepine intermediates was developed, providing a series of synth

Full text of DOI:10.1002/adsc.201800120

Title: Base-Catalyzed Cascade Reaction of ortho-(Propargylamino)aryl
Ketones with N-, O-, or S-Based Nucleophiles for the Synthesis
of 3-Functionalized Quinoline Scaffolds
Authors: Min Shi, Liu-Zhu Yu, and Hao-Zhao Wei
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201800120
Link to VoR: http://dx.doi.org/10.1002/adsc.201800120

10.1002/adsc.201800120
Advanced Synthesis & Catalysis
.
Full Paper
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Base-Catalyzed Cascade Reaction of ortho-(Propargylamino)aryl
Ketones with N-, O-, or S-Based Nucleophiles for the Synthesis of 3-
Functionalized Quinoline Scaffolds
Liu-Zhu Yu,a Hao-Zhao Wei,b Min Shi*a,b,c
a
State Key Laboratory of Organometallic Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of
Organic Chemistry, University of Chinese Academy of Science, Chinese Academy of Sciences, 345 Lingling Road,
Shanghai 200032 China.
b
Key Laboratory for Advanced Materials and Institute of Fine Chemicals, School of Chemistry & Molecular Engineering,
East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237 China.
c State Key Laboratory and Institute of Elemento-organic Chemistry, Nankai University, Tianjin 300071, P. R. China.
Fax: (+86)-21-6416-6128; e-mail: mshi@mail.sioc.ac.cn
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
monocyclic 1,4-oxazepine, which is not very stable but difficult to
be obtained owing to antiaromatic character, is often emerged as a
reactive species for the construction of molecular complexity.[7]
Abstract:
A metal-free and base-catalyzed cascade
reaction of ortho-(propargylamino)aryl ketones with
primary alcohols, secondary amines, including various N-
heterocycles, and thiols through 1,4-benzoxazepine
intermediates was developed, providing a series of
synthetically and medically valuable 3-functionalized
quinoline derivatives. The reaction process was easily
manipulable and environmentally benign, producing 1.0
equiv of water as the sole byproduct. Furthermore,
bimolecular reactions for the synthesis of products
containing two quinoline units were also succesful by
utilizing this newly developed protocol.
Keywords: metal-free; ortho-(propargylamino)aryl ketones;
1,4-benzoxazepine; 3-functionalized quinolines; bimolecular
reactions.
Figure 1. Representative examples of bioactive 3-substituted
quinolines.
Recently, N-propargylic β-enaminones, readily accessible
synthetic intermediates, have attracted much attention[8] and
could be employed as precursors of 1,4-oxazepines.[9] For
example, in 2015, Cui’s group has described a base-promoted
Quinoline scaffolds are probably the most ubiquitous
heterocycles that widely exist in natural products,[1] medicinal
agents,[2] as well as important intermediates for asymmetric
synthesis.[3] Especially, 3-functionalized quinolines display a
range of biological activities and are exploited as synthetic
intermediates in the preparation of drugs and functional materials
(Figure 1).[4] Classical methods for quinoline synthesis mainly
include some name reactions, such as Skraup, Doebner−Von
Miller, Friedländer, and Povarov reactions.[5,6] However, these
approaches mostly suffer from the requirement of
prefunctionalized substrates and expensive transition metals.
Therefore, the development of metal-free and environmentally
friendly methods for quinoline synthesis is of great significance
and highly pursued in synthetic chemistry and pharmaceutical
chemistry.
N-pyridylation
of
heteroarenes
via
1,4-oxazepine
intermediates from N-propargyl enaminones with N-based
nucleophiles to deliver 2,3-disubstituted pyridines.[9a] They
also found that N-based nucleophiles could be in situ
generated from N-propargyl enaminones and trapped by 1,4-
oxazepines.[9b] In 2017, they also reported alcohols and thiols
were also adopted as nucleophiles, thereby providing similar
products via consecutive 6π-electrocyclization and walk
rearrangement processes (Scheme 1a).[9c] Moreover, Cui and
Zhang’s groups simultaneously reported terminal carbon of N-
propargyl enaminones could also be used as nucleophiles to
trap extern aryl aldehydes or N-sulfonyl imines, providing
pyridine-fused heterocycles.[9c,d] Encouraged by above
achievements, we wondered whether 1,4-benzoxazepine[10]
could also be used as reactive intermediate to induce new
The development of cascade reactions for the synthesis of
synthetically valuable frameworks from easily available substrates
is strongly demanded in organic chemistry. Fully unsaturated
1
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10.1002/adsc.201800120
Advanced Synthesis & Catalysis
cascade reactions. Herein, we report a metal-free and base-
catalyzed cascade reaction of ortho-(propargylamino)aryl
ketones with N-, O-, or S-based nucleophiles to construct
various monosubstituted quinoline scaffolds without walk
rearrangement process (Scheme 1b).
led to a deleterious effect on the reaction efficiency and the
reaction became sluggish (Table 1, entry 8). Solvent effect
was also examined, and we found that the solvent strongly
influenced the reaction outcomes. It was identified that only
strongly polar solvents such as dimethyl sulfoxide (DMSO)
and N,N-dimethylformamide (DMF) could catalyze the
reaction smoothly, whereas MeCN and 1,2-dichloroethane
(DCE) had no reaction efficiency probably due to the lower
solubility of inorganic base (Table 1, entries 9-11). Moreover,
no desired product was obtained when no base was added
(Table 1, entry 12).
Table 2. Reaction Scope: synthesis of 3-functionalized
quinolines from ortho-(propargylamino)aryl ketones and
alcoholsa,b
Scheme 1. 1,4-oxazepine vs 1,4-benzoxazepine intermediates for
synthesis of N-heterocycles.
Table 1. Optimization of the reaction conditions for the
synthesis of 3aaa,b
With the optimized reaction conditions in hands, we began
to survey the reaction scope of this reaction and the results
are shown in Table 2. Various primary alkyl alcohols were
tolerable, providing the corresponding products 3aa-3ad in
good yields ranging from 61% to 85%. As for benzyl
alcohols, both electron-deficient and electron-rich ones were
compatible, furnishing alkoxymethyl-substituted quinolines
3ae-3aj in good yields ranging from 60% to 86%, and the
former seemed to show better reaction activity. Moreover,
heterocyclic benzyl alcohols were also suitable substrates,
With this working hypothesis in mind, we commenced our
studies
by
employing
phenyl(2-(prop-2-yn-1-
ylamino)phenyl)methanone 1a with methanol 2a to simply
optimize the reaction conditions. In the presence of the
equivalent amount of NaOH (2.0 or 1.0 eq.), we were able to
obtain 3-(methoxymethyl)quinoline 3aa in 80% and 79%
yields, respectively (Table 1, entries 1-2). Surprisingly, the
reaction still performed well to give the corresponding
product 3aa in 85% yield when the catalytic amount of
NaOH was applied (Table 1, entry 3). Then, the influence of
base was investigated, and we found that only inorganic
bases including KOH, Cs2CO3, K2CO3, and Na2CO3 could
catalyze the reaction and NaOH gave the best reaction
outcome (Table 1, entries 4-7). However, organic base Et3N
and the desired products 3ak-3am were obtained without the
erosion of the heterocyclic subunits under the standard
reaction conditions. Then the scope of R1 was examined as
follows: when R1 was aryl group, the reactions proceeded
smoothly to give the desired products 3be-3ge in good yields
ranging from 60% to 86%. However, electron-rich
substituents gave higher yield than electron-poor ones, which
is opposite to the electronic effect of alcohols. Heterocyclic
groups including thienyl and furyl were also examined,
affording the corresponding products 3he and 3ia in 57% and
73% yields, respectively. Disappointingly, the reaction
2
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10.1002/adsc.201800120
Advanced Synthesis & Catalysis
became sluggish when R1 was substituted by alkyl groups or
hydrogen atom. This cascade reaction also proceeded
smoothly when the phenyl ring of aniline moiety was
substituted by OMe or Cl group, affording products 3je and
3ke in 73% and 61% yields, respectively, indicating the
electrocyclization process was not affected by substituents.
Finally, both phenyl rings substituted substrate 1l was also
amenable, delivering product 3la in 70% yield. It should be
noted that secondary and tertiary alcohols presented poor
reaction activity. The structure of 3ce has been also
confirmed by single crystal X-ray analysis, and its ORTEP
drawing is shown in Table 2.[11] When the nucleophile was
turned to thiol 4a, a mixture of desired product of 5aa and
byproduct 6a was formed in 32% and 54% yields,
respectively in the presence of the equivalent amount of base
(Scheme 2).
Scheme 2. Further investigation of thiol.
Furthermore, we explored the reaction scope of N-based
nucleophiles in Table 3. We firstly screened the optimized
reaction conditions as follows: 1 and 7 in a molar ratio of 1:1.2 in
o
the presence of 20 mol% Cs2CO3 in DMF at 80 C under argon
atmosphere. Various N-heterocycles including pyrrole, indol, 1H-
pyrrolo[2,3-b]pyridine, pyrazole, imidazole, and carbazole were
tolerable for the synthesis of 8ea-8ag in good yields ranging from
71% to 92%. Scalable synthesis was also achieved, providing 1.55
grams of 8ab in 93% yield from 5.0 mmol scale of 1a and 7b.
Notably, substituted anilines were also suitable substrates in this
reaction if using KOH as the catalyst at room temperature,
delivering products 8ah-8aj in moderate yields ranging from 66%
to 73%. However, aniline failed to provide the corresponding
product, probably because of its lower nucleophilicity.
Interestingly, when the sulfamide 7k was employed, quinoline-3-
carbaldehyde 8ak, which is a valuable synthetic intermediate for
further transformation,[12] was obtained in 75% yield (For the
details, see Scheme S1 in the Supporting Information).
Furthermore, hydrogenated heterocycles including indoline and
tetrahydroquinoline were also compatible, thereby delivering
products 8al-8an in good yields ranging from 55% to 92%.
However, 1-benzazepine 1o failed to give the corresponding
product 8ao. The structures of 8ab and 8ak have been also
confirmed by single crystal X-ray analysis and their ORTEP
drawings are shown in Figure 2.[13]
Figure 2. X-ray crystal structure of products 8ab and 8ak.
To further extend the reaction scope of this newly developed
protocol, a series of bimolecular reactions were conducted. As
shown in Scheme 3, 1,4-phenylenedimethanol 9, (1H-pyrrol-2-
yl)methanol 11 and (1H-indol-3-yl)methanol 13, which contain
two reaction sites, were used to react with 1a; the corresponding
bimolecular products 10, 12 and 14 containing two quinoline units
were obtained in high yields up to 90% (for the details, see
Scheme S2 in the Supporting Information).
Table 3. Reaction Scope: synthesis of 3-functionalized quinolines
from aminesa,b
Scheme 3. Bimolecular reactions.
Based on the above results and previously reported
3
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10.1002/adsc.201800120
Advanced Synthesis & Catalysis
literature,[9] a proposed reaction mechanism is depicted in Scheme
General Procedure for 8: A solution of 1 (0.2 mmol, 1.0 equiv)
and Cs2CO3 (0.04 mmol, 0.02 equiv) and amine 7 (0.24 mmol, 1.2
equiv) in DMF was stirred at 80 C. The reaction was stopped
after 3 h and the mixture was extracted with EtOAc for 3 times.
The organic layer was washed with brine and dried over
anhydrous Na2SO4. After filtration, the filtrate was concentrated
under reduced pressure and the residue was purified by flash
column chromatography on silica gel (eluent: petroleum ether /
ethyl acetate = 4 / 1) to afford the product 8 in good to excellent
yield.
4. In the presence of
a base catalyst, propargyl-allenyl
isomerization followed by enolization of 1a provides an
iminoenolate intermediate I, which may undergo a 7-exo-dig
cyclization to afford a 1,4-benzoxazepine anion II. Then epoxide
anion III was formed via 6π-electrocyclization process, which
was not very stable to undergo expoxide ring-opening with the
assistance of methanol or indol, delivering an allyl alcohol
intermediate IV. Walk rearrangement process reported by Cui’s
group[9a,b,c] dose not take place from the intermediate III, because
dearomatization of phenyl ring is thermodynamically unfavorable
in this case. Meanwhile, methoxyl or indol anion is generated,
which probably assists the construction of the 3-substituted
quinoline scaffold along with the regeneration of a base catalyst.
o
Supporting Information Available
Detailed descriptions of experimental procedures and their
spectroscopic data as well as the crystal structures are presented in
the Supporting Information. CCDC 1588718 (3ce), CCDC
1587921 (8ab), 1811105 (8ak) contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data Center
via www.ccdc.cam.ac.uk/data_request/cif.
Acknowledgements
We are grateful for the financial support from the National Basic
Research Program of China (973)-2015CB856603, the Strategic
Priority Research Program of the Chinese Academy of Sciences,
Grant No. XDB20000000 and sioczz201808, and the National
Natural Science Foundation of China (20472096, 21372241,
21572052, 20672127, 21421091, 21372250, 21121062, 21302203,
and 20732008).
Scheme 4. Proposed reaction mechanism.
References
In summary, we have developed a simple and convenient
access to 3-functionalized quinoline scaffolds through base-
catalyzed cascade reaction of ortho-(propargylamino)aryl ketones
with primary alcohols, secondary amines including various N-
heterocycles and thiols via 1,4-benzoxazepine intermediates. The
reactions exhibit broad substrate scope, good yield and functional
group tolerance. Moreover, bimolecular reactions providing
compounds containing two quinoline units were also available
under the standard reaction conditions. Further extension of the
scope and the potential utilization are currently under
investigation.
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4
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5
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10.1002/adsc.201800120
Advanced Synthesis & Catalysis
Full Paper
Base-Catalyzed Cascade Reaction of ortho-
(Propargylamino)aryl Ketones with N-, O-, or S-
Based Nucleophiles for the Synthesis of 3-
Functionalized Quinoline Scaffolds
Adv. Synth. Catal. Year, Volume, Page – Page
Liu-Zhu Yu, Hao-Zhao Wei, Min Shi*
6
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