Oxidative Cascade Reaction of N-Aryl-3-alkylideneazetidines and Carboxylic Acids: Access to Fused Pyridines

Article abstract of DOI:10.1021/acs.orglett.8b01427

A versatile silver-promoted oxidative cascade reaction of N-aryl-3-alkylideneazetidines with carboxylic acids is reported, providing a very efficient pathway to functionalized fused pyridines. This method allows introduction of fused pyridine ring systems

Full text of DOI:10.1021/acs.orglett.8b01427

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Oxidative Cascade Reaction of N‑Aryl-3-alkylideneazetidines and
Carboxylic Acids: Access to Fused Pyridines
Wangshui Cai,†,⊥ Shuang Wang,†,⊥ Hitesh B. Jalani,‡ Junxian Wu,† Hongjian Lu,*,†
and Guigen Li†,§
†Institute of Chemistry & BioMedical Sciences, Jiangsu Key Laboratory of Advanced Organic Materials, School of Chemistry and
Chemical Engineering, Nanjing University, Nanjing 210023, China
‡Department of Chemistry and Chemical Biology, Northeastern University, 360 Huntington Avenue, Boston, Massachusetts 02115,
United States
§Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, Texas 79409-1061, United States
S
* Supporting Information
ABSTRACT: A versatile silver-promoted oxidative cascade reaction of N-
aryl-3-alkylideneazetidines with carboxylic acids is reported, providing a
very efficient pathway to functionalized fused pyridines. This method allows
introduction of fused pyridine ring systems to heterocycles, drugs, and
natural products. A mechanistic study revealed that silver salt is essential for
the chemo- and regioselective ring expansion, sequential oxidative
nucleophilic additions, and oxidative aromatization. This approach
represents the first example of the strained N-heterocycles undergoing a cascade reaction with a π bond and a nucleophile
together.
he ring opening and rearrangement of small strained N-
selectivity is controlled proficiently by fine-tuning of suitable
strained N-heterocycle, nucleophiles, and oxidant then the
process could provide an efficient cascade strategy7 to
construct complex molecules in one step.
T
heterocycles provide powerful strategies for the synthesis
of useful N-containing compounds.1,2 The most important and
widely used transformations of these rings are intra- or
intermolecular nucleophilic addition to form linear or cyclic
amines3 and cycloaddition with a π bond to form heterocycles4
(Scheme 1, eq 1). Regardless of many reports for the reaction
The carbon−carbon double bond in small strained N-
heterocycles can coordinate with transition metals and can
participate in stabilizing any cations, anions, or radicals that are
formed, which helps this type of compound to exhibit adequate
reactivity toward various transformations.8 Among these, 3-
alkylideneazetidine is known for easy isolation9 and can be
stored for several months without decomposition; thus it
should be suitable for synthetic transformation. However, its
considerably lower ring opening propensity10 can be a
challenge in synthetic chemistry.11 Herein, we report a silver-
promoted cascade reaction of N-heteroaryl-3-alkylideneazeti-
dines and carboxylic acids (Scheme 1, eq 2). This reaction
involves (I) intramolecular ring expansion involving a
neighboring phenyl ring followed by (II) intermolecular
oxidative nucleophilic addition of carboxylate and finally
(III) oxidative aromatization, providing a new strategy to
useful functionalized fused pyridines including quinoline, an
important scaffold found widely in many natural products and
pharmaceuticals.12 Other competitive pathways also exist with
different chemo- and regioselectivity (Scheme 1, eq 2).
We began our investigation of the chemoselectivity by
examining the reaction of 1a with a neighboring N-phenyl
group as a 2π component and acetic acid as a nucleophile.
Scheme 1. Reactions of Small Strained N-Heterocycles
of the strained N-heterocycles with one nucleophile or a single
π bond,5 there are no reports on the cascade reaction of
strained N-heterocycles with a π bond and a nucleophile
together. This could be the result of the chemoselectivity issues
governed in strained N-heterocycles due to the competition
between a π bond and a nucleophile and the oxidative
conditions required in the secondary addition step,6 which
makes the reaction system more complicated. If this preferred
Received: May 5, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01427
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Selected results of different reaction conditions are summar-
ized in Table 1A (for details, see Table S1). As expected,
cation intermediate formed under these conditions could be
stabilized by the neighboring phenyl group. Use of CF3COOH
furnished a 3b and 4b mixture in 81% yield with a 3b/4b ratio
of 40:60 (Table 1, entry 15). When less acidic 4-nitrobenzoic
acid was used, 3b was obtained in 57% isolated yield in high
regio- and chemoselectivity (Table 1, entry 16). When the
reaction was performed with AcOH, the ratio of 2b/3b/4b was
94:3:3, and interesting product 2b was isolated in 72% yield
(Table 1, entry 17). The yield is slightly decreased (62%)
when the reaction is performed on a large scale (Table 1, entry
18).
a
Table 1. Optimization of the Reaction Conditions
We explored the substrate scope with respect to the N-aryl
part of azetidine (Table 2). An N-aryl group with ortho
Table 2. Scope of Azetidine 1 and Carboxylic Acid
a
b
1
Yield was calculated based on crude H NMR spectra. Heating in
c
d
e
microwave reactor. Isolated yield. AcOH (13 μL). Without AcOH.
f
g
h
i
1.5 equiv of AgOAc. 0.5 equiv of AgOAc. 20 μL of CF3COOH. 10
j
equiv of acid was used. 2 mmol scale of 1b.
reaction in the absence of Lewis acid furnished exclusively the
ring-opening product (2a′) as a result of intermolecular
nucleophilic addition (Table 1, entry 1). When a silver salt
such as AgSbF6 with Lewis acidity was used, the quinoline
heterocycle (2a) was formed in 30% yield along with 2a′
(Table 1, entry 2). This result indicated that the silver salt not
only suppressed inherent intermolecular nucleophilic addition
of acetate but also promoted oxidation, inducing aromaticity.
Upon screening different additives, AgOAc or Cu(OAc)2 was
found to increase the yield of 2a with good selectivity (Table 1,
entries 2−7). Using Lewis acid BF3·Et2O, Sc(OTf)3, Zn-
(OTf)2, AlCl3, or InCl3, oxidant 3-chloroperbenzoic acid (m-
CPBA), tert-butyl hydroperoxide (THBP), or K2S2O8 as the
additive, a very small amount of 2a could be observed (Table
S1). Finally, we carried out the reaction in a microwave reactor
using AgOAc as both a Lewis acid and an oxidizing reagent,
providing 2a in 77% isolated yield with a good chemo-
selectivity ratio (2a/2a′) of 89:11 (Table 1, entry 8). Reducing
AcOH or AgOAc diminished the product formation (Table 1,
entries 9−12). Next, the regio- and chemoselectivity were
studied by using 3-benzylidene-1-phenylazetidine (1b) as a
reaction partner with different acids (Table 1B). No major
products were formed when CF3SO3H was used (Table 1,
entry 13). Use of MeSO3H afforded the quinoline (4b) as a
major product (Table 1, entry 14), perhaps because the allylic
a
Standard conditions: 1 (0.1 mmol), RCOOH (0.1 mL), AgOAc
(0.25 mmol), DCE (0.5 mL), microwave at 110 °C for 2 h, isolated
yield. 95 °C. Using CF3COOH (10 equiv) instead of AcOH.
b
c
substituents such as methyl, methyl carboxylate, and hydroxyl
led to the corresponding quinolines 2b−d. An N-phenyl group
without any substituents could be tolerated (2e). p-Phenyl or
p-methoxy N-aryl groups worked well (2f, 79%; 2g, 63%).
Meta-substituted N-aryl groups were tolerated well (2h,i), and
a mixture of two regioisomers for 1i was obtained (p-2i and o-
2i). Reaction of 9-aminophenanthrene provided a polycyclic
ring containing a fused pyridine 2j, thus showcasing the fusion
of a heterocycle within aromatic compounds. The method not
only can access aryl-fused pyridines, but it is also able to
B
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provide pyridines by employing enamines. For example, the
reaction of (E)-2-phenylethen-1-amine achieved desired
product 2k in moderate yield. Heteroaryl-fused pyridines
2l,m can be obtained with high regioselectivity by use of an
azetidine-containing pyridine and benzothiazole. The thiazo-
loquinoline 2m is the key fragment of kuanoniamines D and E,
which are structurally unique, highly cytotoxic alkaloids
obtained from marine sources.13
Scheme 2. Plausible Mechanisms under Different Reaction
Conditions
Next, we explored the substrate scope with respect to the
vinyl part of the azetidine. Various styrene derivatives, such as
4-bromo-, 4-fluoro-, 4-nitro-, and 2-bromostyrene participated
well, providing desired products in good yields (2n−r). The
structure of 2q was identified by X-ray diffraction analysis
(CCDC: 1823285). Alkyl substituents in the terminal position
of vinyl group, such as ethyl, isopropyl, and cyclopropyl were
all compatible (2s−u). The alkene without any substituent in
the terminal position furnished 2a in 77% yield. When the
reaction of 1a was performed in the presence of trifluoroacetic
acid, the nonfunctionalized quinoline 3a was formed.
Substrates with an electron-withdrawing group in the terminal
position of the vinyl group provided the quinolines without the
acetoxy group (2v,w), possibly due to the difficulty of
completing an oxidative nucleophilic addition in the α-position
of a carboxylate or nitrile group.6
Then, we investigated the general nature of the carboxylic
acids. Alkyl carboxylic acids, such as propionic acid, butyric
acid, and chloroacetic acid, were tolerated well (2x, 53%; 2y,
50%; 2z, 61%), but pivalic acid failed to facilitate formation of
the desired product, possibly due to the steric hindrance of the
tert-butyl group. Since an acetyloxy group can be easily
transformed to other functional groups, acetic acid was used as
a reactant in most cases.
In order to gain a better understanding the mechanism,
several experiments were carried out, as described in the
Supporting Information (Scheme S1, eqs 1−7). Treatment of
byproduct 3,8-dimethylquinoline 3a under the standard
conditions failed to produce 2a (Scheme S1, eq 1), indicating
the acetoxylation step occurs prior to oxidative aromatization.
When the byproduct 2a′ was reacted under the standard
conditions, no 2a was produced (Scheme S1, eq 2). This
suggested that the ring expansion with the π bond of phenyl
ring is the first step in the cascade sequence. When the
substrate 1a with two deuteriums in the terminal position of
the olefin D2-1a was conducted in absence of silver acetate,
only 2a′ with two deuteriums in the terminal position of the
olefin (D2-2a′) was formed (Scheme S1, eq 3). The results
suggest that inherent intermolecular nucleophilic addition of
acetic acid proceeded through an SN2 mechanism. Several
competitive experiments suggested the increase of the
nucleophilicity of N-aryl group (2e, 23% vs 2g, 29%), the
presence of phenyl group instead of p-nitrophenyl (2b, 21% vs
2p, 13%), ethyl (2b, 25% vs 2s, 11%), or carboxylate group
(2e, 21% vs 2v, 7%) in the terminal position of the olefin have
a positive influence (Scheme S1, eqs 4−7).
Plausible reaction mechanisms are described in Scheme 2.
When the reaction was performed in the absence of silver salt,
acetic acid lead to protonation of nitrogen to give the
azetidinium ion intermediate A,14 which is attacked by acetate
ion to furnish linear ring opened product 2a′. In the case of a
stronger acid such as trifluoroacetic acid (pKa ∼ −0.25), the
conjugate base is a very weak nucleophile and fails to attack the
azetidinium ion and consequently, the allylic carbocation B is
formed which undergoes cationic 6-endotet type ring closure
sequence followed by oxidative aromatization, leading to
isomers 3b and 4b. When the reaction was performed under
less acidic conditions (acetic acid (pKa ∼ 4.76), 4-nitrobenzoic
acid (pKa ∼ 3.44)), azetidine 1 with silver acetate forms a silver
complex C and then selective intramolecular ring expansion
with π bond of phenyl group by suppressing inherent
intermolecular nucleophilic addition of acid gives D. Due to
the weak nuclephilic ability of 4-nitrobenzoic acid, diaryl-
methane 3b could be obtained with high selectivity after direct
oxidative aromatization. When acetic acid was used, a
subsequent oxidative nucleophilic addition reaction of D by
acetate ion15 followed by oxidative aromatization with the aid
of silver acetate forms the desired product 2b in high
selectivity.
With utility in diversity-oriented synthesis approaches in
mind, and aiming to demonstrate possible applications of this
method, we examined the reactions of N-aryl-3-alkylideneaze-
tidine in different scaffolds. Various analogues such as ligands,
heterocycles, steroids, and pharmaceutical substances were
subjected to this cascade reaction, as depicted in Scheme 3.
Scheme 3. Synthetic Applications
Two steps are considered: (i) palladium-catalyzed cross-
coupling reactions between the 3-alkylideneazetidine 5 with
aryl halides or their analogues16 and (ii) the silver-promoted
cascade reaction. Phenanthroline is an important ligand known
for its ability to form useful coordination complexes with
various metals.17 The unsymmetric phenanthroline 7a could be
easily obtained from commercial available 8-bromoquinoline.
The pyridine-fused estrone derivative 7b was produced with
63% yield in two steps. Similarly, the reactions of 6-bromo-1-
tosyl-1H indole and 5 led to the pyrrolo[3,2-h]quinoline 7c, a
core structure of biomedically important compounds.18 This
protocol also has been used in the modification of the
antiallergy drug loratadine, providing its pyridine-fused
C
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Letter
derivative 7d with 73% yield. This late-stage installation of a
fused pyridine functional group is a striking application of this
method.
Postsynthetic functional group transformation is an interest-
ing area of structural modification; therefore, newly synthe-
sized fused pyridines were subjected to various transformations
(Scheme 4). For example, Dess−Martin periodinane oxidation
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: hongjianlu@nju.edu.cn.
ORCID
a
Scheme 4. Derivatization of Functionalized Quinolines
Hitesh B. Jalani: 0000-0002-2442-9798
Hongjian Lu: 0000-0001-7132-3905
Guigen Li: 0000-0002-9312-412X
Author Contributions
⊥W.C. and S.W. contributed equally to this work.
Notes
a
The authors declare no competing financial interest.
See the details of the reaction conditions in the Supporting
Information.
ACKNOWLEDGMENTS
■
We are grateful for financial support by the National Natural
Science Foundation of China (21472085, 21332005, and
21672100).
of 2b provided 3-benzoylquinoline 8a. Acid-induced deacety-
lation of 2b resulted in the quinoline 8b in 94% yield. The
palladium-catalyzed cyclization of 2p was achieved by
activation of the heteroaryl C−H bond, efficiently providing
the acetoxyl-functionalized tetracyclic compound 8c, a
structural unit with a fused quinoline and indene framework
found in a number of pharmaceuticals and bioactive natural
products.19 The nickel-catalyzed Suzuki coupling reaction of
2b with phenylboronic acid furnished the triaryl methane 8d.
The reduction of 2b provided 3-benzylquinoline 3b.
In summary, we have presented a versatile and highly
chemo- and regioselective silver-promoted cascade reaction of
N-heteroaryl-3alkylideneazetidines and carboxylic acids, pro-
viding a general method for the synthesis of acetyloxy-
functionalized fused pyridines. Mechanistic study reveals the
reaction proceeds through intramolecular ring expansion with
the π bond of phenyl ring and subsequent intermolecular
oxidative nucleophilic addition of acetate and oxidative
aromatization under the influence of silver acetate. This
protocol allows useful modification of ligands, drugs, and
natural product analogues with fused pyridine ring systems.
Such compounds are otherwise difficult to produce, and this
shows the general applicability of the present protocol to
generate diverse structural features. We believe this work will
open a new outlook and scientific interest for understanding
and exploiting the strained N-heterocycles through ring-
expansion and nucleophilic substitution cascade strategies.
Investigations toward detailed mechanism and further
synthetic applications of this newly established methodology
are currently underway in our laboratory.
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ASSOCIATED CONTENT
* Supporting Information
TThe Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b01427.
■
S
Experimental details and characterization datas for all
new compounds (PDF)
Accession Codes
CCDC 1823285 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
D
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