Metal-Free Synthesis of 3-Arylquinolin-2-ones from Acrylic Amides via a Highly Regioselective 1,2-Aryl Migration: An Experimental and Computational Study

Article abstract of DOI:10.1021/acs.joc.6b00345

Combined experimental and theoretical investigations into the phenyliodine bis(trifluoroacetate) (PIFA)-mediated reaction of N-arylcinnamamide to produce 3-arylquinolin-2-one derivatives have been conducted. High regioselectivity during the aryl migration process was observed in 3,3-disubstituted acrylamides. Density functional theory calculation was conducted in an attempt to understand the mechanism and the origin of the regioselectivity. On the basis of both the experimental and the theoretical results, a mechanism involving an oxidative annulation, followed by an aryl migration, has been proposed. The annulation is the regioselectivity determining step.

Full text of DOI:10.1021/acs.joc.6b00345

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Article
Metal-free Synthesis of 3-Arylquinolin-2-ones from Acrylic Amides via a Highly
Regioselective1,2-Aryl Migration: An Experimental and Computational Study
Le Liu, Tonghuan Zhang, Yun-Fang Yang, Daisy Zhang-
Negrerie, Xinhao Zhang, Yunfei Du, Yun-Dong Wu, and Kang Zhao
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b00345 • Publication Date (Web): 28 Apr 2016
Downloaded from http://pubs.acs.org on May 3, 2016
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Metalꢀfree Synthesis of 3ꢀArylquinolinꢀ2ꢀones from Acrylic Amides
via a Highly Regioselective1,2ꢀAryl Migration: An Experimental and
Computational Study
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Le Liu,†,ǁ Tonghuan Zhang,‡,ǁYunꢀFang Yang,‡Daisy ZhangꢀNegrerie,† Xinhao
Zhang,‡ Yunfei Du,*,† YunꢀDong Wu,*,‡ and Kang Zhao*,†
†Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical
Science and Technology, Tianjin University, Tianjin 300072, China
‡Lab of Computational Chemistry and Drug Design, Key Laboratory of Chemical Genomics,
Peking University Shenzhen Graduate School, Shenzhen 518055, China
duyunfeier@tju.edu.cn; wuyd@pkusz.edu.cn; kangzhao@tju.edu.cn
ABSTRACT: Combined experimental and theoretical investigations into the
phenyliodine bis(trifluoroacetate) (PIFA)ꢀmediated reaction of Nꢀarylcinnamamide to
produce 3ꢀarylquinolinꢀ2ꢀone derivatives have been conducted. High regioselectivity
during the aryl migration process was observed in 3,3ꢀdisubstituted acrylamides.
Density functional theory (DFT) was conducted in an attempt to understand the
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mechanism and the origin of the regioselectivity. Based on both the experimental and
theoretical results, a mechanism involving an oxidative annulation followed by an aryl
migration has been proposed. The annulation is the regioselectivity determining step.
Introduction
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CꢀH functionalization, having emerged over the past few decades, represents an
attractive area of great significance for its capacity to directly enhance molecular
complexity.1 Numerous elegant works have been reported in recent decades on the
construction of heterocyclic compounds via CꢀH functionalization.2 The frameworks
of quinolinꢀ2ꢀone compounds, especially those bearing 3ꢀaryl groups, are frequently
found in many natural products and pharmaceutically active molecules, examples of
which are shown in Figure 1.3 Compounds with the 3ꢀarylquinolinꢀ2ꢀone subunit
have been used as anticancer,4a antiplatelet,4b and antihypertensive agents.4c Moreover,
they are also valuable building blocks for the synthesis of many natural alkaloids.5
Therefore, many efforts for the synthesis and functionalization of this class of
molecules have been made. Aside from the classic baseꢀcatalyzed Friedlӓnder
reaction5 and the acidꢀcatalyzed Knorr synthesis,6 several alternative approaches have
been disclosed for accessing quinolinꢀ2ꢀone skeletons based on CꢀH activation
including metalꢀcatalyzed intraꢀ7a or intermolecular7b carbocyclization of internal
alkynes, Pdꢀcatalyzed amidation of oꢀcarbonylꢀsubstituted aryl halides7c and tandem
decarboxylative radical addition/cyclization of Nꢀarylcinnamaides with aliphatic
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carboxylic acids.7dRecently, Jiao and coꢀworkers reported a synthesis of
quinolinꢀ2ꢀones involving an efficient Rhꢀcatalyzed carbonylation and annulation of
Figure 1. Representative biological or natural compounds bearing
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3ꢀarylquinolinꢀ2ꢀone framework
Cl
Cl
Cl
H
N
O
O
Cl
N
O
MeO
N
N
N
O
O
N
O
Et
Benzosumuline
α 4 integrin inhibitory
Farnesyl protein transfer inhibitor
simple COꢀcontaining anilines and alkynes through NꢀH and CꢀH bond activation.7e
In addition, Dong and coꢀworkers reported an Rhꢀcatalyzed [5+2ꢀ1] transformation
between isatins and alkynes to synthesize 2ꢀquinolinone derivatives, proposed to
proceed through an exclusive CꢀC activation, decarbonylation and alkyne insertion
process.7f All the aforementioned methods have merit in the preparation of the
corresponding quinolinꢀ2ꢀones, but the majority of these methods suffer one or more
limitations such as harsh reaction conditions, involvement of transition metals, and
limited substrate scope. Compared with the intensively investigated transitionꢀmetal
catalyzed processes, metalꢀfree methods are less explored.8 Therefore, the
development of alternative mild and metalꢀfree procedures involving CꢀH
functionalization for the construction of quinolinones remains of great significance.
Hypervalent iodine reagents, featuring readily availability, low toxicity and
environmental benign properties, have fascinated chemists for a couple of decades.
Consequently, a handful of efficient organic transformations mediated by hypervalent
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iodine reagents have been reported.9 As a continuation of our work on hypervalent
chemistry,10 we extended our research on the metalꢀfree approach to construct the
3ꢀarylquinolinone skeleton from the readily available Nꢀarylcinnamamides by
focusing on the intriguing stereoselectivity and the mechanistic studies. Some initial
results concerning the construction of core skeleton have been reported in an early
Communication.11 In this paper, we present the evidence for a mechanism consisting
of an exclusive I(III)ꢀmediated oxidative C(sp2)–C(sp2) bond formation, followed by a
1,2ꢀaryl migration12 with extremely high regioselectivity supported by both
experimental observations and theoretical investigations of the transition state
structures and reaction coordinate energy profiles.
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Results and Discussion
NꢀArylacrylamide derivatives, which have been well studied and used as useful
substrates for the construction of heterocyclic framework through oxidative C–C bond
formation,13 were selected as model substrates. To our delight, the reaction of 1.0
equivalent of 1a with 1.5 equivalent of PIFA in the presence of 1.0 equivalent of
BF3·Et2O
in
DCE
afforded
20%
yield
of
a
sixꢀmembered
Nꢀmethylꢀ3ꢀphenylquinolinꢀ2(1H)ꢀone 2a (Table 1, entry 1). The reaction appeared to
involve an unprecedented oxidative C–C bond formation and a 1,2ꢀaryl migration.
Further studies were subsequently carried out to formulate the optimal conditions for
the transformation. As shown in Table 1, the substrate turned to be inert to treatment
with the oxidant PIFA in the absence of Lewis acid (BF3·Et2O) (Table 1, entry 2).
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Solventꢀscreening tests of THF, CH3CN, MeOH, TFE and DMF showed that none of
them is more effective than DCE for the desired reaction (Table 1, entries 2ꢀ8). An
increased yield was observed when the additive was switched to TFA. The desired
product was isolated in a much improved yield of 43% (Table 1, entry 9). When
Table 1. Optimization for the synthesis of quinolinones mediated by I(III)a
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oxidant
(equiv)
additive
(equiv)
entry
solvent
time (h) yield(%)b
.
1
2
DCE
DCE
PIFA (1.5)
PIFA (1.5)
PIFA (1.5)
PIFA (1.5)
PIFA (1.5)
PIFA (1.5)
PIFA (1.5)
PIFA (1.5)
PIFA (1.5)
PIFA (1.5)
PIFA (1.5)
PIFA (1.5)
PIFA (1.5)
PIFA (1.5)
PIFA (1.5)
PIFA (1.0)
PIFA (2.0)
PIDA (2.0)
PhIO (2.0)
IBX (2.0)
BF3 Et2O (1)
12
24
12
10
12
24
12
24
24
12
6
20
NR
trace
15
_
.
3
THF
BF3 Et2O (1)
.
4
5
EA
BF3 Et2O (1)
BF3 Et2O (1)
.
CH3CN
MeOH
CF3CH2OH
DMF
DCE
17
.
6
BF3 Et2O (1)
NR
20
NR
43
.
7
8
BF3 Et2O (1)
BF3 Et2O (1)
.
9
TFA (5)
.
10
11
12
13c
14d
15e
16d, f
17d
18d
19d
20d
DCE
BF3 Et2O (1)/ TFA (5)
60
.
DCE
DCE
BF3 Et2O (1)/ TFA (10)
BF3 Et2O (1)/ TFA (20)
68
.
6
67
.
DCE
DCE
BF3 Et2O (1)/ TFA (10)
BF3 Et2O (1)/ TFA (10)
6
72
.
6
88
.
DCE
BF3 Et2O (1)/ TFA (10)
6
85
.
DCE
BF3 Et2O (1)/ TFA (10)
24
8
70
.
DCE
DCE
BF3 Et2O (1)/ TFA (10)
BF3 Et2O (1)/ TFA (10)
85
.
6
65
.
DCE
DCE
BF3 Et2O (1)/ TFA (10)
BF3 Et2O (1)/ TFA (10)
12
12
ND
ND
.
aAll the reaction were carried out at rt with 1a (0.4 mmol) at the concentration of 0.1M. bIsolated
yield.c The concentration of 1a was reduced to 0.05 M. dThe concentration of 1awas 0.025 M.
eThe concentration of 1a was 0.01 M. fBased on 80% conversion of 1a. NR = no reaction. ND =
no desired product.
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BF3·Et2O and TFA were combined and used as coꢀadditive, the yield was improved to
60% (Table 1, entry 10). With an increased dosage of TFA, the yield continued to
improve to 68% and the reaction time was dramatically shortened to 6 h (Table 1,
entry 11). However, further increase of the dosage beyond 10 equivalents provided no
further improvement in the yield (Table 1, entry 12). Concentration screeningwith the
starting substrate indicated that dilution favors the reaction, with the most ideal
concentration identified to be 0.025 M (Table 1. entries 12ꢀ15). Evaluation of the most
appropriate amount of the oxidant found the optimal amount of PIFA to be 1.5
equivalents (Table 1, entries 16ꢀ17). Applications of other hypervalent iodine reagents
including PIDA, PhIO and IBX resulted in a decreased yield or no desired product.
Combining all the testing results, the optimized conditions are determined to be: 0.025
M of reactant, 1.5 equivalent of PIFA as oxidant and a combination of 1 equivalent of
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.
BF3 Et2O and 10 equivalents of TFA as coꢀadditives in DCE as solvent (Table 1, entry
14).
Under the optimal reaction conditions, the scope and generality of this method were
explored. The results, summarized in Table 2, show that substrates bearing benzyl
(1b), isopropyl (1c) and cyclopropylmethyl (1d) substituents on the nitrogen atom
were all transformed to the desired cyclized/migrated products in good to excellent
yields (Table 2, entries 2–4). However, for the cinnamamide that bears no substitution
on the nitrogen atom, the reaction resulted in a complex mixture, without any trace of
the desired product (Table 2, entry 5). On a side note, we did find that debenzylation
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of 2b with NBS in the presence of AIBN under reflux in chlorobenzene proceeded
smoothly to give the NH product 2e in 83% yield.11
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As for the R2 group, both electronꢀdonating and electronꢀwithdrawing groups at the
paraꢀposition were well tolerated (Table 2, entries 6–8), albeit the electronꢀrich amide
1g was converted to 2g in a slightly lower yield. In the case of substrates bearing
either a F or a CF3 group at the metaꢀposition (Table 2, entries 9–10), cyclization
occurred preferentially at the less hindered position with two separable regioisomeric
3ꢀarylquinolinꢀ2ꢀone products 2i/2i'and 2j/2j' formed in each case. orthoꢀSubstituted
Table 2. Synthesis of 3ꢀarylquinolinꢀ2ꢀone via PIFAꢀmediated CꢀC bond formation
and 1,2ꢀaryl migration
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substrate 1
entrya
2
time (h) yield(%)b
R1
H
R2
Me
Bn
R3
Ph
1
2
6
6
88
75
90
71
0
55
48
87
50c
77d
78
44
63e
34
41
1a
1b
1c
1d
1e
1f
2a
2b
H
Ph
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4
H
H
iꢀPr
cPrMe
H
Ph
Ph
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7
2c
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2e
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H
Ph
Ph
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6
4ꢀMe
4ꢀMeO
4ꢀBr
3ꢀF
3ꢀCF3
2ꢀCl
2ꢀCO2Me
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
2f
7
Ph
5
1g
1h
1i
2g
8
Ph
7
2h
9
Ph
Ph
8
6
2i/ 2i'
2j/ 2j'
2k
10
11
12
13
14
15
1j
Ph
Ph
7
7
1k
1l
2l
4ꢀMeOꢀPh
4ꢀBrꢀPh
2ꢀClꢀPh
10
12
12
1m
1n
1o
2m
2n
H
H
2o
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H
H
H
Me
Me
Me
2ꢀBrꢀPh
2ꢀthienyl
Me
12
6
44
30
0
1q
1r
1s
2q
2r
2s
12
7
8
aAll reactions were carried out with 1a (0.4 mmol) and PIFA (1.5 equiv) in DCE (16 mL) unless
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b
c
otherwise stated. Isolated yield. The ratio of 2i (7ꢀF) and 2i
'
(5ꢀF) is 1.2:1. dThe ratio of 2j
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(7ꢀCF3) and 2j
'
(5ꢀCF3) is 1.3:1. eTFA was used as the solvent. cPrMe = cyclopropylmethyl.
substrates were also compatible with the methods as demonstrated by the formation of
2k and 2l (Table 2, entries 11–12). Further investigation was focused on the
substituent effect of the acrylic motif of R3. Entries 13ꢀ16 show that reactants
containing substituted aryl R3 groups, regardless of the electronic nature of the
substituent, all delivered the corresponding 3ꢀarylꢀquinolinones in acceptable yields,
though lower in comparison with the unsubstituted counterpart 1a. It should be
mentioned that 2q is a key intermediate in the construction of naturally occurring
cryptotackieine 1 and cryptosanguinolentine 2.4e In addition, we found that the
method could be potentially applied to heterocyclic R3 groups, as illustrated by the
transformation of the 2ꢀthienyl substituted acylic amide, although the yield was a
modest 30%. Attempts to extend the method to alkyl substituted acrylamides was
found to be unsuccessful, as the reaction of NꢀmethylꢀNꢀphenylbutꢀ2ꢀenamide 1s
turned out to be sluggish with no cyclized product detected (Table 2, entry 18).
In order to gain more insights into the reaction, we designed and synthesized a
series of 3,3ꢀdisubstituted acrylamides with varying properties in the size of the steric
hindrance, electronic effects, and configurations. The results are listed in Table 3.
Reactions occurred for the 3,3ꢀdiarylacrylamides bearing two identical substituents
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(3a–c) in an identical pattern, all affording the desired product 4a–c in moderate to
good yields (Table 3, entries 1ꢀ3). Among the three substrates, 3c, bearing the
electronꢀdonating paraꢀmethoxy substituent, gave the highest yield. In the case of 3d,
where one of the phenyl groups in 3a was replaced by a less bulky methyl group, the
reaction afforded only the phenylꢀmigrated product in 86% yield, with no detection of
the methyl migrated product (Table 3, entry 4). For substrates 3eꢀh which contained
two aromatic rings of different electron densities in the acrylic moiety, only one single
product (4eꢀh) with specifically the aryl group in the trans position having migrated
was formed (Table 3, entries 5ꢀ8).
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Table 3. Further investigation on the PIFAꢀmediated CꢀC bond formation and 1,2ꢀaryl
migration reactiona
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aAll reactions were carried out with 3 (0.4 mmol) and PIFA (1.5 equiv) in DCE (16 mL). bIsolated
yield. cThe ratio of 3i and 3i
' '
is 1.0:0.80, determined by 1H NMR analysis. dThe ratio of 4i and 4i
is 1.0:0.8 by 1H NMR analysis.
For the reaction containing an inseparable mixture of E and Z geometric isomers 3i
and 3i', a mixture of two regioisomeric products 4i and 4i' was formed, in a ratio
practically identical to that of 3i and 3i' (Table 3, entry 9). The results of these
examples revealed the regiospecific nature of the reaction mechanism, dominated by
the position of the aryl group irrelevant to the electronic effect of the groups.
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The newly discovered regiospecific nature of the reaction led us to reconsider the
previously proposed mechanism.11 We show it again here in Scheme 1, path a. In this
mechanistic pathway, the carbonyl oxygen was proposed to attack the
electronꢀdeficient hypervalent iodine(III) reagent, and the 1,2ꢀaryl migration occurred
on the tetrahedral C3 in intermediate III. Obviously such a pathway cannot account
for the regiospecific character observed in this research.
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Scheme 1. Proposed Mechanistic Pathways for the Transformation
Herein, we propose a different pathway (Scheme 1, path b) in which the alkenyl
double bond initiates the nucleophilic attack on the hypervalent iodine(III) reagent.
Regioselectivity is controlled through a preferred, unhindered side during the
aromatic electrophilic substitution reaction in forming II', as well as an intramolecular
SN2ꢀtype of reaction of III' during the aryl migration. Xꢀray crystallography structure
of 3g supports the proposition, as the molecule is shown to be nonplanar, having the
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alkenyl moiety twisted out of the plane to form an almost Tꢀshape arrangement likely
to benefit from the extra stability brought by π−π stacking interactions.
The new mechanism (path b) also explains the experimental observation of
electronꢀrich aryl groups favoring the reaction (Table 3, 3aꢀc), as intermediate I' is a
benzylic carbocation connected to aryl group, while there is no such intermediate in
the mechanism described in path a.
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Figure 2. Freeꢀenergy profile (kcal/mol) of the formation of 3ꢀarylquinolinꢀ2ꢀone in
in DCE as solvent calculated at M06/6ꢀ311++G (d,p).
In order to acquire more mechanistic details at atomic level, DFT calculations were
carried out on a representative substrate 3g, as well as all the transition states and
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intermediates along the reaction pathway. The optimized geometry of 3g adopts the
conformation consistent with its Xꢀray crystal structure, in which Ph1 blocks one side
of the double bond. The reaction initiated with the addition of the electronꢀdeficient
hypervalent iodine(III) complex to the carbonyl oxygen of the amide moiety in
substrate affords 3ꢀazatriene intermediate A, concomitant with release of one
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ꢀ
trifluoroacetate anion (CF3CO2 ). Notably, boron trifluoride (BF3) also participates in
this reaction as an important additive to stabilize the leaving group, the
ꢀ
trifluoroacetate anion (CF3CO2 ) in the form of [CF3CO2ꢀꢀBF3]ꢀ anion. Intermediate A
isomerizes to two enantiomeric intermediates B or B
the carbonyl oxygen to the αꢀposition of the substrate. As the iodonium group in B
has the advantage of a more spacious environment than that in B , it was computed to
be 6.1 kcal/mol lower in free energy than B . The transition states TSꢀBC and TSꢀBC
for the ring closure step from B and B respectively, were calculated to have a
noticeable free energy difference of 5.8 kcal/mol. The optimized transitionꢀstate
structures TSꢀBC and TSꢀBC are illustrated in Figure 2. In TSꢀBC where the
ʹ via iodonium migration from
ʹ
ʹ
ʹ
ʹ
ʹ
iodonium group is anti- to the CꢀC bond being formed, the late transition state occurs
with the CꢀC distance being 1.91 Å. With the bulky iodonium group in close
proximity to the forming CꢀC bond, the CαꢀCβ bond in TSꢀBC
ʹ was twisted, while the
newly formed CꢀC bond remains apart with a distance of 2.11Å. The weaker
interaction in TSꢀBC
ʹ
accounts for its instability.
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Consequently, intermediate C, resulting from TSꢀBC, in which the iodonium
located trans to Ph2, was predicted to be the predominant intermediate along the
pathway. From C, reductive elimination of iodonium(III) releases PhI giving D, in
which trifluoroacetate is installed trans to the ꢀPh2. Attempts to locate the transition
state for reductive elimination were not successful. Given the significant driving force
for the formation of D, the process may be barrierless. The ꢀPh2 at Cβ in D could
undergo 1,2ꢀarylꢀmigration with the expulsion of CF3CO2ꢀ anion via TSꢀDE.
Coordination of Lewis acid, boron trifluoride (BF3), to the trifluoroacetate anion
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(CF3CO2ꢀ) is expected to promote the dissociation of the leaving group. TSꢀDE
an activation barrier of 23.7 kcal/mol, was indeed found to be more favorable than
TSꢀDE. The transition state TSꢀDE is a typical transition state structure in an
ʹ, with
ʹ
intramoleular SN2 reaction, which accounts for the stereospecific nature of the
reaction. Alternatively, the 1,2ꢀmigration of the synꢀaryl group with the dissociation of
the [CF3CO2ꢀꢀBF3]ꢀ anion at the same side, was also considered. The synꢀattack
transition structure TSꢀDEꢀ1′ was found to be 11.0 kcal/mol higher in energy than
TSꢀDE′. Therefore, the synꢀaryl migration was excluded. The step from D to E is
exergonic due to the resonance stability in E. For this reason, the aryl group is
indispensible as we have observed in our experiments (Table 1, entry 18). Additional
calculations were carried out for the free energy barrier for the methyl migration, via
TSꢀDEꢀmethyl, and this was computed to be 42.5 kcal/mol, a prohibitively high
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value (see SI for calculation details). Facile deprotonation of E yields the final
product 3ꢀphenylquinolinꢀ2ꢀone (4g).
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Conclusion
In conclusion, we have developed a novel metalꢀfree protocol for the preparation of
the quinolinꢀ2ꢀone framework from readily available
Nꢀarylcinnamic amides. This
hypervalent iodine reagentꢀmediated reaction involves a cascade sequence of
oxidative annulation and a highly regioselective 1,2ꢀaryl migration process. A
mechanism was proposed which accounts for the high regioselectivity observed
experimentally and is supported by the computational results. Further investigations
on the scope and application of this method are currently on going in our laboratory.
Experimental Section
1. General Information
All reactions were carried out at room temperature and stirred magnetically. 1H and
13C NMR spectra were recorded on a 400 MHz, or 600 MHz spectrometer at 25 C.
o
Chemical shifts values are given in ppm and referred as the internal standard to TMS:
0.00 ppm. The peak patterns are indicated as follows: s, singlet; d, doublet; t, triplet;
q, quartet; qui, quintet; m, multiplet and dd, doublet of doublets. The coupling
constants J, are reported in Hertz (Hz). High resolution mass spectrometry (HRMS)
was obtained on a QꢀTOF micro spectrometer. Melting points were determined with a
national MicroMelting point apparatus without corrections. Organic solutions were
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concentrated by rotary evaporation below 40 °C in vacuum. TLC plates were
visualized by exposure to ultraviolet light. Reagents and solvents were purchased as
reagent grade and were used without further purification. All reactions were
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performed in standard glassware, heated at 70 C for 3 h before use. Flash column
chromatography was performed over silica gel 200ꢀ300 m and the eluent was a
mixture of ethyl acetate (EA) and petroleum ether (PE).
2. Preparation of Substrates 1 and 311
To a suspension of the acid (1.0 equiv) in DCM (0.3 M) was added a catalytic
amount of DMF (0.1 mL/mmol acid). At ambient temperature, oxalylchloride (1.5
equiv) was added dropwise over a period of 0.5 h, forming a homogenous solution.
The resulting solution was kept at room temperature for 3 h. Then, the solvent was
removed under reduced pressure. The residue was dissolved in dry DCM and slowly
added dropwise to a solution of the appropriate aniline derivative (1.0 equiv) and Et3N
(2.5 equiv) in DCM (0.25 M). The reaction mixture was maintained at ambient
temperature and monitored by TLC. Upon completion, the mixture was extracted with
CH2Cl2 (3× 50 mL) and the combined organic phase was washed with aq saturated
NH4Cl (1 × 80 mL) and saturated brine (1 × 80 mL), then dried over
Na2SO4.Evaporation of the solvent under reduced pressure and purification of the
crude residue by flash column chromatography on silica gel (EA/PE) afforded the
desired amides.
Compounds 1aꢀs and 3aꢀc have been reported in our previous work.11 The new
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compounds thus obtained were characterized as follows:
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(
E NꢀMethylꢀN,3ꢀdiphenylbutꢀ2ꢀenamide (3d) Following the general procedure,
)ꢀ
3d was purified by silica gel chromatography (15% EA/PE) to give a yellow oil, 355
mg, yield: 55%. 1H NMR (600 MHz, CDCl3) δ 7.36 (t,
= 8.0 Hz, 2H), 7.26 (t, J =
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J
7.5 Hz, 1H), 7.24 – 7.11 (m, 7H), 5.96 (s, 1H), 3.37 (s, 3H), 2.50 (s, 3H). 13C NMR
(150 MHz, CDCl3) δ 167.3, 148.8, 144.1, 142.7, 129.4, 128.3, 128.2, 127.3, 126.9,
126.1, 119.8, 37.0, 18.0. HRMS (ESI) m/z calcd for C17H18NO [M + H+] 252.1388,
found 252.1385.
(E)ꢀ3ꢀ(4ꢀChlorophenyl)ꢀ3ꢀ(4ꢀmethoxyphenyl)ꢀNꢀmethylꢀNꢀphenylacrylamide (3e)
Following the general procedure, 3e was purified by silica gel chromatography (15%
EA/PE) to give a pale oil, 353 mg, yield: 33%.1H NMR (600 MHz, CDCl3) δ 7.33 –
7.27 (m, 4H), 7.21 (t,
J
= 7.4 Hz, 1H), 7.04 (d,
J = 7.3 Hz, 2H), 6.98 (d, J = 7.5 Hz,
2H), 6.93 (d, = 7.6 Hz, 2H), 6.74 (d,
J
J
= 8.2 Hz, 2H), 6.11 (s, 1H), 3.76 (s, 3H), 3.24
(s, 3H).13C NMR (150 MHz, CDCl3) δ 167.1, 160.1, 148.1, 143.6, 137.9, 133.9,
133.5, 130.9, 129.4, 129.1, 128.1, 127.0, 126.6, 119.7, 113.6, 55.3, 36.8. HRMS (ESI)
m/z calcd for C23H2135ClNO2 [M + H+] 378.1261, found 378.1263.
+
(Z)ꢀ3ꢀ(4ꢀChlorophenyl)ꢀ3ꢀ(4ꢀmethoxyphenyl)ꢀNꢀmethylꢀNꢀphenylacrylamide (3f)
Following the general procedure, 3f was purified by silica gel chromatography (10%
EA/PE) to afford awhite solid, 351.0 mg, yield: 31%, m.p. 133ꢀ135 oC. 1H NMR (600
MHz, CDCl3) δ 7.24 (d, J = 7.2 Hz, 2H), 7.18 (d, J = 7.6 Hz, 3H), 6.97 (d, J = 7.8 Hz,
2H), 6.94 (d,
J
= 7.9 Hz, 2H), 6.90 – 6.80 (m, 4H), 6.04 (s, 1H), 3.85 (s, 3H), 3.24 (s,
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3H).13C NMR (150 MHz, CDCl3) δ 167.7, 159.8, 147.0, 143.8, 140.4, 134.3, 131.0,
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131.0, 129.5, 128.9, 128.3, 126.9, 126.5, 121.1, 113.3, 55.3, 36.6. HRMS (ESI) m/z
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calcd for C23H2035ClNNaO2 [M + H+] 400.1080, found 400.1084.
+
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(E)ꢀ3ꢀ(4ꢀChlorophenyl)ꢀNꢀmethylꢀN,3ꢀdiphenylacrylamide (3g) Following the
general procedure, 3g was purified by silica gel chromatography (10% EA/PE) to give
1
a pale yellow solid, 468.5 mg, yield: 45%, m.p. 107–109oC. H NMR (600 MHz,
CDCl3) δ 7.36 – 7.30 (m, 3H), 7.26 – 7.22 (m, 2H), 7.19 (t,
J = 8.0 Hz, 3H), 7.03 (d, J
= 7.0 Hz, 2H), 6.94 (d, = 8.0 Hz, 2H), 6.85 (d, = 7.5 Hz, 2H), 6.14 (s, 1H), 3.22 (s,
J
J
3H). 13C NMR (150 MHz, CDCl3) δ 167.3, 147.2, 143.5, 140.0, 138.6, 134.4, 129.5,
129.4, 128.9, 128.4, 127.9, 126.9, 126.5, 121.9, 36.6 (two carbon peaks overlapped).
HRMS (ESI) m/z calcd for C22H1935ClNO [M + H+] 348.1155, found 348.1153.
(Z)ꢀ3ꢀ(4ꢀChlorophenyl)ꢀNꢀmethylꢀN,3ꢀdiphenylacrylamide (3h) Following the
general procedure, 3h was purified by silica gel chromatography (10% EA/PE) to
give yellow oil, 323.4 mg, yield: 45%. 1H NMR (600 MHz, CDCl3) δ 7.34 – 7.27 (m,
4H), 7.26 – 7.24 (m, 1H), 7.23 – 7.19 (m, 3H), 7.03 (d,
J = 8.0 Hz, 2H), 6.98 (d, J =
7.0 Hz, 2H), 6.94 (d,
J
= 7.5 Hz, 2H), 6.18 (s, 1H), 3.25 (s, 3H). 13C NMR (150 MHz,
CDCl3) δ 167.1, 147.7, 143.5, 141.2, 137.6, 134.1, 131.0, 129.1, 128.6, 128.3, 128.1,
128.0, 127.0, 126.5, 121.8, 36.7. HRMS (ESI) m/z calcd for C22H1935ClNO [M + H+]
348.1155, found 348.1153.
3ꢀ(4ꢀMethoxyphenyl)ꢀNꢀmethylꢀN,3ꢀdiphenylacrylamide (3i) Following the
general procedure, 3i was purified by silica gel chromatography (15% EA/PE) and
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isolated as a mixture of the
E
/Z
isomers, yellow oil, 556.3 mg, yield: 55%,
E/Z ratio is
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1:0.8. H NMR (600 MHz, CDCl3) Major isomer (
E) δ 7.37 – 7.30 (m, 3H, peaks of
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two isomers overlapped), 7.25 – 7.18 (m, 8H, peaks of two isomers overlapped), 7.0 –
6.95 (m, 5H, peaks of two isomers overlapped), 6.93 – 6.87 (m, 4H, peaks of two
isomers overlapped),6.86 – 6.81 (m, 2H ), 6.08 (s, 1H), 3.84 (s, 3H), 3.24 (s, 3H);
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Minor isomer (Z) δ 7.37 – 7.30 (m, 3H, peaks of two isomers overlapped), 7.25 – 7.18
(m, 8H, peaks of two isomers overlapped), 7.10 – 7.04 (m, 2H), 6.93 – 6.87 (m, 4H,
peaks of two isomers overlapped),6.77 – 6.69 (m, 2H ), 6.11 (s, 1H), 3.76 (s, 3H),
3.21 (s, 3H).13C NMR (150 MHz, CDCl3) Major isomer δ167.7, 159.9, 143.8, 139.4,
134.0, 131.1, 129.6, 129.4, 128.9, 128.3, 128.0, 126.7, 126.6, 119.7, 113.6, 55.3, 36.7.
Minor isomer 168.0,159.7,148.7, 148.3,143.7, 131.5,129.2, 128.8, 128.3,128.1, 127.8,
126.7,120.8,113.2, 112.8, 36.6 (one carbon peak missed due to overlapped). HRMS
(ESI) m/z calcd for C23H22NO2 [M + H+] 344.1651, found 344.1649. The ratio of the
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two isomers were was determined by NMR in DMSOꢀd6.
NMR (600 MHz, DMSOꢀd6) Major isomer (
E/Z
ratio is 1.0:0.8. H
E
) δ 7.36 – 7.25 (m, 11H, peaks of two
isomers overlapped), 7.23 – 7.16 (m, 2H, peaks of two isomers overlapped), 7.10 –
7.02 (m, 4H, peaks of two isomers overlapped), 7.01 – 6.80 (m, 10H, peaks of two
isomers overlapped), 6.09 (s, 1H), 3.79 (s, 3H), 3.13 (s, 3H); Minor isomer (Z) δ 7.36
– 7.25 (m, 11H, peaks of two isomers overlapped), 7.23 – 7.16 (m, 2H, peaks of two
isomers overlapped), 7.10 – 7.02 (m, 4H, peaks of two isomers overlapped), 7.01 –
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6.80 (m, 10H, peaks of two isomers overlapped), 6.12 (s, 1H), 3.72 (s, 3H), 3.11 (s,
3H).
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3. Preparation of Quinolinones 2 and 4.
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General procedure: To a solution of substrate 1or 3 (0.4 mmol) in DCE (16 mL)
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was slowly added TFA (10 equiv) at 0 C. Then, a solution of PIFA (1.5 equiv) and
.
BF3 Et2O (1.0 equiv) in DCE (2.5 mL) was added dropwise to the mixture with
stirring. The resulting mixture was maintained at room temperature, and the progress
of the reaction was monitored by TLC. Upon completion, the reaction mixture was
poured into cold water (30 mL) and extracted with CH2Cl2 (3 × 30 mL). The
combined organic layer was washed with saturated NaHCO3 (1 × 60 mL) and brine (1
× 60 mL) before being dried over Na2SO4.The solvent was removed under vacuum
and the residue was purified by silica gel chromatography, using a mixture of PE/EA
to afford the desired product 2 or 4.
Compounds 2aꢀr and 4aꢀc have been reported in our previous work.11 The new
compounds thus obtained were characterized as follows:
1,4ꢀDimethylꢀ3ꢀphenylquinolinꢀ2(1
4d was purified by silica gel chromatography (10% EA/PE) to give a yellow solid,
H
)ꢀone (4d)24 Following the general procedure,
o
1
85.7 mg, yield: 86%, m.p. 135ꢀ136 C. H NMR (600 MHz, CDCl3) δ 7.81 (dd,
J =
8.0, 1.0 Hz, 1H), 7.59 (t, = 8.0 Hz, 1H), 7.47 – 7.39 (m, 3H), 7.37 (d, = 7.5 Hz,
J
J
1H), 7.30 – 7.26 (m, 3H), 3.77 (s, 3H), 2.33 (s, 3H). HRMS (ESI) m/z calcd for
C17H16NO+ [M + H+] 250.1232, found 250.1228.
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3ꢀ(4ꢀChlorophenyl)ꢀ4ꢀ(4ꢀmethoxyphenyl)ꢀ1ꢀmethylquinolinꢀ2(1H
)ꢀone(4e)25
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Following the general procedure, 3e was purified by silica gel chromatography (10%
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1
EA/PE) to give a yellow solid, 76.5 mg, yield: 51%, m.p. 194ꢀ195 C. H NMR (600
MHz, CDCl3) δ 7.58 (t, = 7.4 Hz, 1H), 7.44 (d, = 8.4 Hz, 1H), 7.36 (d, = 7.8 Hz,
1H), 7.18 – 7.11 (m, 3H), 7.04 (d, = 8.3 Hz, 2H), 7.00 (d, = 8.5 Hz, 2H), 6.82 (d,
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J
J
J
J
J
J
= 8.5 Hz, 2H), 3.83 (s, 3H), 3.80 (s, 3H). 13C NMR (150 MHz, CDCl3) δ 161.6, 159.0,
147.8, 139.6, 134.7, 132.7, 132.1, 131.1, 130.9, 130.5, 128.6, 128.2, 127.8, 122.0,
121.7, 114.1, 113.6, 55.2, 30.1. HRMS (ESI) m/z calcd for C23H1935ClNO2+ [M + H+]
376.1104, found 376.1101.
4ꢀ(4ꢀChlorophenyl)ꢀ3ꢀ(4ꢀmethoxyphenyl)ꢀ1ꢀmethylquinolinꢀ2(1
H
)ꢀone
(4f)
Following the general procedure, 4f was purified by silica gel chromatography (15%
o
1
EA/PE). to give a pale solid, 94.5 mg, yield: 63%, m.p. 195ꢀ196 C. H NMR (600
MHz, CDCl3) δ 7.60 – 7.55 (m, 1H), 7.45 (d, = 8.4 Hz, 1H), 7.29 – 7.23 (m, 3H),
7.13 (t, = 7.6 Hz, 1H), 7.05 (d, = 8.4 Hz, 2H), 7.03 – 6.99 (m, 2H), 6.73 (d, = 8.7
J
J
J
J
Hz, 2H), 3.84 (s, 3H), 3.75 (s, 3H). 13C NMR (150 MHz, CDCl3) δ 161.9, 158.5,
146.2, 139.5, 135.1, 133.5, 131.9, 131.8, 131.3, 130.3, 128. 1, 128.0, 127.8, 122.0,
121.3, 114.2, 113.2, 55.1, 30.2. HRMS (ESI) m/z calcd for C23H1935ClNO2+ [M + H+]
376.1104, found 376.1103.
3ꢀ(4ꢀChlorophenyl)ꢀ1ꢀmethylꢀ4ꢀphenylquinolinꢀ2(1H
)ꢀone (4g)25 Following the
general procedure, 4g was purified by silica gel chromatography (15% EA/PE) to give
a yellowish solid, 98.0 mg, yield: 71%, m.p. 205–207oC. 1H NMR (600 MHz, CDCl3)
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δ 7.58 (t,
J
= 8.0 Hz, 1H), 7.45 (d,
J
= 8.5 Hz, 1H), 7.32 – 7.27 (m, 4H), 7.15 – 7.11
5
= 7.5, 2.0 Hz, 2H), 7.04 (d, J
= 8.5 Hz, 2H), 3.84 (s, 3H). 13C
6
7
(m, 3H), 7.09 (dd,
J
8
9
NMR (150 MHz, CDCl3) δ 161.6, 148.0, 139.6, 136.1, 134.5, 132.8, 132.1, 130.8,
130.8, 129.8, 128.6, 128.2, 127.8, 127.7, 122.0, 121.4, 114.1, 30.2. HRMS (ESI) m/z
calcd for C22H1735ClNO+ [M + H+] 346.0999, found 346.0995.
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4ꢀ(4ꢀChlorophenyl)ꢀ1ꢀmethylꢀ3ꢀphenylquinolinꢀ2(1H)ꢀone (4h) Following the
general procedure,4h was purified by silica gel chromatography (15% EA/PE) to give
a pale yellow solid, 91.1 mg, yield: 66%, mp. 203–205oC.1H NMR (600 MHz,
CDCl3) δ 7.58 (ddd,
J = 8.5, 7.0, 1.5 Hz, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.28 – 7.23
(m, 3H), 7.21 – 7.17 (m, 2H), 7.17 – 7.11 (m, 2H), 7.10 – 7.07 (m, 2H), 7.06 – 7.03
(m, 2H), 3.84 (s, 3H). 13C NMR (150 MHz, CDCl3) δ 161.7, 146.4, 139.6, 135.7,
134.9, 133.6, 132.4, 131.3, 130.5, 130.5, 128.3, 128.2, 127.7, 127.1, 122.0, 121.2,
114.2, 30.2. HRMS (ESI) m/z calcd for C22H1735ClNO+ [M + H+] 346.0999, found
346.0997.
3ꢀ(4ꢀMethoxyphenyl)ꢀ1ꢀmethylꢀ4ꢀphenylquinolinꢀ2(1H
)ꢀone (4i)25 Following the
general procedure, 4i was purified by silica gel chromatography (15% EA/PE) to give
1
a yellow solid, 50.5 mg, yield 37%, m.p. 167–169oC. H NMR (600 MHz, CDCl3) δ
7.58 – 7.52 (m, 1H), 7.43 (d,
J
= 8.5 Hz, 1H), 7.29 – 7.25 (m, 4H), 7.11 (dt,
J = 7.0,
2.0 Hz, 3H), 7.03 (dd, = 8.5, 1.5 Hz, 2H), 6.70 (d,
J
J
= 8.0 Hz, 2H), 3.84 (s, 3H),
3.72 (s, 3H).13C NMR (150 MHz, CDCl3) δ 158.4, 147.5, 139.5, 136.6, 131.9, 130.1,
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129.9, 128.4, 128.3, 128.2, 128.0, 127.5, 127.4, 121.9, 121.6, 114.0, 113.0, 55.1, 30.2.
5
+
HRMS (ESI) m/z calcd for C23H20NO2 [M + H+] 342.1494, found 342.1488.
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4ꢀ(4ꢀMethoxyphenyl)ꢀ1ꢀmethylꢀ3ꢀphenylquinolinꢀ2(1H)ꢀone (4i') Following the
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general procedure, 4i′ was purified by silica gel chromatography (15% EA/PE) to
give a pale solid, 42.3 mg, yield 31%, m.p. 159–161 oC.1H NMR (600 MHz, CDCl3) δ
7.56 (ddd,
J = 8.5, 7.0, 1.5 Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.36 (dd, J = 8.0, 1.5
Hz, 1H), 7.19 – 7.16 (m, 2H), 7.15 – 7.08 (m, 4H), 7.04 – 6.99 (m, 2H), 6.81 – 6.77
(m, 2H), 3.84 (s, 3H), 3.77 (s, 3H).13C NMR (151 MHz, CDCl3) δ 161.9, 158.9,
147.5, 139.6, 136.2, 132.2, 131.2, 130.7, 130.2, 128.6, 128.5, 127.5, 126.8, 121.8,
114.0, 113.5, 55.2, 30.1 (two carbon peaks overlapped). HRMS (ESI) m/z calcd for
+
C23H20NO2 [M + H+] 342.1494, found 342.1490.
Computational details
DFT calculations were performed with the Gaussian09 suite of programs.14
Reactants, transition states (TSs), intermediates, and products were optimized at the
hybrid density functional B3LYP15 level of theory with basis set I (BSI):LANL2DZ16
incorporating a relativistic pseudopotential (effective core potential, ECP)17 for I and
6ꢀ31G(d)18 basis set for the rest of the elements.Single point energy calculations were
then conducted at the M0619 level of theory with basis set II (BSII): StuttgartꢀDresden
basis set (SDD)20 incorporating ECP for I and 6ꢀ311++G(d,p) for other elements.The
SMD solvent model with the parameters for dichloroethane (DCE) were employed to
account for solvent effects.21
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All vibrational frequencies were computed at the B3LYP/BSIto verify the
stationary points and provide the thermal corrections. Intrinsic reaction coordinate
(IRC)22 analyses were performed to confirm that a specific TS connects the two
relevant minima. All energies presented are Gibbs free energies at 298K in DCE in
kcal/mol unless otherwise stated. Geometries were illustrated using CYLVIEW
drawings.23
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Author Information
Author Contributions
ǁ These authors contributed equally to the work.
Notes
The authors declare no competing financial interest.
Acknowledgments
We acknowledge the National Natural Science Foundation of China (#21072148,
#21133002, #21302006), Tianjin Research Program of Application Foundation and
Advanced Technology (#15JCZDJC32900) and the National Basic Research Project
(2014CB932201, 2013CB911501) for financial support.
Supporting Information Available:
Spectral data for all new compounds, Xꢀray structures and data of 3g and 4g and
computational data. The material is available free of charge via the Internet at
http://pubs.acs.org.
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