In Situ Generated TEMPO Oxoammonium Salt Mediated Tandem Cyclization of β-Oxoamides with Amine Hydrochlorides for the Synthesis of Pyrrolin-4-ones

Article abstract of DOI:10.1021/acs.joc.7b00686

A novel in situ generated TEMPO oxoammonium salt mediated one-pot tandem reaction has been developed for the straightforward construction of pyrrolin-4-ones from readily available β-oxoamides with amine hydrochlorides. The reaction tolerates various functional groups and represents a reliable method for the synthesis of highly substituted pyrrolin-4-ones in good yields under mild conditions. Detailed mechanistic studies disclosed that TEMPO oxoammonium salt generated in situ was crucial for the transformation involving the formation of enaminone precursors in situ by condensation of the β-oxoamides with amines, followed by sequential oxidative coupling with β-oxoamides, intramolecular cyclization, and 1,2-alkyl migration steps.

Full text of DOI:10.1021/acs.joc.7b00686

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Article
In Situ Generated TEMPO Oxoammonium Salt-Mediated Tandem Cyclization of
#-Oxoamides with Amine Hydrochlorides for the Synthesis of Pyrrolin-4-ones
Xuna Zhao, Tong-Xin Liu, Nana Ma, and Guisheng Zhang
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 18 May 2017
Downloaded from http://pubs.acs.org on May 19, 2017
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In Situ Generated TEMPO Oxoammonium SaltꢀMediated
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Tandem
Cyclization
of
βꢀOxoamides
with
Amine
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Hydrochlorides for the Synthesis of Pyrrolinꢀ4ꢀones
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Xuna Zhao, TongꢀXin Liu, Nana Ma, Guisheng Zhang*
Collaborative Innovation Center of Henan Province for Green Manufacturing of Fine
Chemicals, Key Laboratory of Green Chemical Media and Reactions, Ministry of
Education, School of Chemistry and Chemical Engineering, Henan Normal
University, Xinxiang, Henan 453007, P. R. China
E-mail: zgs6668@yahoo.com
ABSTRACT
_____________________________________________________________________
A novel in situ generated TEMPO oxoammonium saltꢀmediated oneꢀpot tandem
reaction has been developed for the straightforward construction of pyrrolinꢀ4ꢀones
from readily available βꢀoxoamides with amine hydrochlorides. The reaction tolerates
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various functional groups and represents a reliable method for the synthesis of highly
substituted pyrrolinꢀ4ꢀones in good yields under mild conditions. Detailed
mechanistic studies disclosed that TEMPO oxoammonium salt generated in situ was
crucial for the transformation involving the formation of enaminone precursors in situ
by condensation of the βꢀoxoamides with amines, followed by sequential oxidative
coupling with βꢀoxoamides, intramolecular cyclization, and 1, 2ꢀalkyl migration steps.
_____________________________________________________________________
INTRODUCTION
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Pyrrolinꢀ4ꢀones are prevalent in many pharmaceuticals, biologically active natural
products and materials.1ꢀ3 Compounds belonging to this class have consequently
received remarkable attentions as privileged Nꢀheterocycle building blocks,4 with
particular emphasis on the development of potential drugs with interesting biological
activities, such as anticancer, antithrombotic and antimalarial agents.5 Various
synthetic methods have been developed for the construction of pyrrolinꢀ4ꢀone
scaffolds, including the transitionꢀmetalꢀcatalyzed/mediated cycloisomerization of
1ꢀamino ynones and the dimerization of enaminones or αꢀdiazoꢀβꢀoxoamides.6,7 Dong,
Guan and other groups recently reported three novel approaches to a series of
substituted pyrrolinꢀ4ꢀones using αꢀdiazoꢀβꢀoxoamides and enaminones as starting
materials.7 The substrates required for these reactions usually need
preꢀfunctionalization from βꢀoxoamides. In addition, for the methods using
enaminones as reaction substrates7aꢀc, half of enaminones were hydrolyzed to the
initial βꢀoxoamides to couple with the rest enaminone precursors in these reaction
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processes, and these methods suffered from the limitation of some unstable
enaminone substrates. In this paper, we report a straightforward method for the direct
construction of pyrrolinꢀ4ꢀones from readily available βꢀoxoamides and amine
hydrochlorides by a simple and ecoꢀfriendly oneꢀstep reaction. The enaminone
precursors were generated in situ in the transformation avoiding the preꢀpreparation
and hydrolysis of the enaminone steps, and overcoming the limitations described
above.
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βꢀOxoamides and their derivatives have been widely used as readily available
starting materials and reagents to synthesize a wide variety of biologically active
heterocyclic compounds.8 We recently reported the synthesis of 4ꢀpyridones via the
selfꢀcondensation of βꢀoxoamides, as well as the construction of a series of
4ꢀolefinated dihydropyridines from βꢀoxoamides with pyridinium ylides.8b,9 Given
that the approaches of Dong and Guan involved the hydrolysis of half of the
enaminone reactants to the corresponding βꢀoxoamides,7a,b we supposed that the direct
reaction of βꢀoxoamides with amines would allow for the oneꢀpot construction of
pyrrolinꢀ4ꢀones. This strategy would therefore provide a straightforward method for
the synthesis of pyrrolinꢀ4ꢀones from readily available βꢀoxoamides and amines.
The development of metalꢀfree oxidative coupling reactions has attracted
considerable interest from synthetic chemists, and reactions of this type have become
attractive alternatives to conventional techniques for the direct construction of
nitrogenꢀcontaining heterocycles. During the last two decades, stable nitroxyl radicals
such as 2,2,6,6ꢀtetramethylpiperidineꢀNꢀoxyl (TEMPO) have emerged as clean, mild
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oxidants that can be used to construct C–N bonds via the oxidation of in
situꢀgenerated imines without the need for a transitionꢀmetal catalyst.10 With this in
mind, we investigated the use of TEMPO as an oxidant to evaluate our
aforementioned supposition.
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RESULTS AND DISCUSSION
We initially selected acetoacetanilide 1a and aniline hydrochloride 2a as model
substrates to screen the reaction conditions (Table 1). Pleasingly, the reaction of 1a
with 2a in DMF in the presence of 2 equiv of TEMPO at 120 °C afforded
pyrrolinꢀ4ꢀone 3aa in 54% yield (Table 1, entry 1). Lowering the temperature to 50 °C
led to obvious improvements in the yield, although further reducing the temperature
to 30 °C resulted in no reaction (Table 1, entries 2–4). A variety of different solvents
were also evaluated, including CH3CN, toluene, THF, EtOH, DMSO, CH2Cl2 and
DMF, and the results revealed that DMF gave the highest yield of 3aa when the
reaction was conducted at 50 °C with 2 equiv of TEMPO in DMF (Table 1, entries
5–10). Diminishing the solvent volume from 10 to 5 mL, the yield of 3aa was
improved to 82% (entry 11). Increasing the TEMPO loading from 2 to 3 equiv did not
led to any obvious change in the yield (Table 1, entry 12). In contrast, decreasing the
TEMPO loading from 2 to 1 equiv led to a considerable decrease in the yield from 82
to 53%, accompanying with the 40% recovery of the starting material (Table 1, entry
13). We also found that the aniline hydrochloride loading as well as the TEMPO
loading have certain effect on the reaction (Table 1, entries 14 and 15). Furthermore,
the reaction failed when it was conducted in the absence of TEMPO (Table 1, entry
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16). Several other oxidants, including O2, PhI(OAc)2, tertꢀbutyl hydroperoxide (TBHP)
and oxone were also evaluated but found to be ineffective with none of the desired
product being formed (Table 1, entries 17–20). For comparison, we also tested aniline
instead of aniline hydrochloride, but this reaction also failed to afford any of the
desired products, even after 5 h (Table 1, entry 21). Notably, the addition of aqueous
hydrochloric acid to a reaction system containing aniline instead of aniline
hydrochloride gave the desired product 3aa in 80% yield (Table 1, entry 22).
Table 1. Optimization of the Reaction Conditionsa
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entry
oxidant
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
solvent (mL)
DMF (10)
DMF (10)
DMF (10)
DMF (10 )
CH3CN (10)
Toluene (10)
THF (10)
T (oC)
120
80
yield (%)b
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73
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30
N.R.
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32
50
trace
38
EtOH (10)
DMSO (10)
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trace
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TEMPO
CH2Cl2 (10)
DMF (5)
DMF (5)
DMF (5)
DMF (5)
DMF (5)
DMF (5)
DMF (5)
DMF (5)
DMF (5)
DMF (5)
DMF (5)
DMF (5)
50
32
82
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO

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50
50
12c
13d
14e
15f
16
80
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53
77
83
N.R.
N.R.
trace
trace
trace
N.R.
80
17
O2
18
PhI(OAc)2
TBHP
19
20
Oxone
21g
22h
TEMPO
TEMPO
a Reaction conditions: 1a (0.5 mmol), oxidant (1 mmol), aniline hydrochloride (0.5
mmol), 5h. b Isolated yield. c TEMPO (1.5 mmol). TEMPO (0.5 mmol). aniline
d
e
f
g
hydrochloride (0.4 mmol). aniline hydrochloride (0.6 mmol). Aniline was used
instead of aniline hydrochloride. h 1 equiv. of aniline and aqueous hydrochloric acid
were added into the reaction solution instead of aniline hydrochloride.
With the optimized conditions in hand (Table 1, entry 11), we proceeded to explore
the substrate scope of this TEMPOꢀmediated tandem reaction. Initially, we examined
the effect of the R1 substituent attached to the βꢀoxoamide substrate. Various aromatic
groups with electronꢀwithdrawing and electronꢀdonating substituents at various
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positions were well tolerated, giving the corresponding pyrrolinꢀ4ꢀones in 71 to 82%
yields (Table 2, 3aa−3ka). It is noteworthy that Nꢀbenzyl and Nꢀtertꢀbutyl substituted
acetoacetamides also reacted smoothly with 2a to give the corresponding products 3la
and 3ma in 54% and 61% yield, respectively.
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Next, we evaluated a series of amines 2 bearing different substituents at R2 (Table 2,
3ab−3hk). Aromatic amines bearing electronꢀwithdrawing and electronꢀdonating
substituents at various positions of the phenyl ring reacted with 1a to afford the
corresponding pyrrolinꢀ4ꢀones 3ab−3ag in satisfactory yields. Notably, amines
bearing an electronꢀdonating substituent gave higher yields than those bearing an
electronꢀwithdrawing group (e.g., 3ab, 3ac vs 3af; 3ad vs 3ag). The scope of this
reaction also extended to propynylamine hydrochloride (2h), which reacted well with
1a under the optimized conditions to produce 3ah in 63% yield. Similarly, the
aliphatic and benzyl amines propylamine (2j) and benzylamine (2i) also underwent
this cyclization reaction to afford the corresponding Nꢀfunctionalized pyrrolinꢀ4ꢀones
3aj and 3ai in 72 and 70% yields, respectively. It is noteworthy that these reactions
were carried out at an elevated temperature of 120 °C for 3 h. Ammonium chloride
(NH4Cl) was also investigated as an amine source to construct Nꢀunsubstituted
pyrrolinꢀ4ꢀones. This amine worked in a similar manner to aliphatic amines, in that it
required a higher temperature of 120 °C to produce pyrrolinꢀ4ꢀones 3ak, 3bk and 3hk
in good yields of 64%, 68% and 61%, respectively (Table 2). The structure of 3ak
was further confirmed by the Xꢀray singleꢀcrystal analysis.11
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Table 2. TEMPOꢀPromoted Cyclization of βꢀOxoamides with Amine
Hydrochloridesa,b
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a Reaction conditions: βꢀketoamides (0.5 mmol), amine hydrochlorides (0.5 mmol),
b
c
TEMPO (1 mmol) in DMF (5 mL) at 50 oC for 5ꢀ7 h. Isolated yield. The reactions
carried out at 120 oC for 3 h.
We also surveyed the reaction of acetylacetone 1n and ethyl acetoacetate 1o under
the standard condition. In the case of the acetylacetone substrate (Scheme 1), we
obtained the deacylation product 4na in 63% yield, which was formed by the
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deacylation of the desired 2,5ꢀdiacetyl pyrrolinꢀ4ꢀone product.7a In contrast, the
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reaction of ethyl acetoacetate 1o resulted in the formation of a complex mixture.
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Scheme 1. Reactions of Acetylacetone with Aniline Hydrochloride.
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To develop a deeper understanding of the reaction mechanism, we conducted a
series of control experiments, and the results are shown in Scheme 2. First, no
reaction occurred when enaminone A, which was generated by the reaction of
acetoacetanilide 1a with aniline 1b,12 was treated with 2.0 equiv of TEMPO in DMF
at 50 °C (eq. 1). In contrast, enaminone A reacted smoothly to give 3aa in 63% yield
in the presence of 2 equiv. aqueous hydrochloric acid (eq. 2). We also examined the
reaction of A with 1a under the same condition, which resulted in the formation of the
desired product 3aa in 67% yield (eq. 3). The results of these screening and control
experiments confirmed that hydrochloric acid played a critical role in the formation of
the pyrrolinꢀ4ꢀone products. Further experiments proved the current reaction could
not occur only in the presence of acid, which was different with the previous reported
acid promoted dimerization of alkyl substituted βꢀoxoamides.7c The environmentally
friendly oxidant TEMPO therefore promoted the in situ formation of the key
enaminone intermediate10a,13 and the subsequent oxidative coupling reaction. However,
the reaction of A with 1a in the absence of hydrochloric acid did not work (eq. 4),
indicating that the acid played other roles in addition to helping the formation of
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intermediate A. TEMPO is a too weak oxidant to oxidize intermediate A and then to
couple with 1a. In the reported most of nitroxidesꢀmediated organic transformations,
the active oxidant is not a nitroxide but its oxidized form, the corresponding
oxoammonium salt.14 The reactive TEMPO oxoammonium salt can be readily
generated in the presence of acid.15 Perhaps it might be precisely that TEMPO
oxoammonium salt instead of TEMPO to mediate the reaction of A with 1a. Next, we
employed the Bobbittꢀsalt as an oxidant to verify this hypothesis. As expected, the
product 3aa could be obtained in 42% yield by the treatment of the reaction of A with
1a using 1 equiv. of Bobbittꢀsalt (eq. 5). Similarly, the reaction of 1a with 2a provided
3aa in 39% yield (eq. 6). In contrast, the reaction of 1a with aniline instead of aniline
hydrochloride 2a in the presence of 1 equiv of Bobbittꢀsalt afforded trace amount of
3aa (eq. 7), indicting that enaminone A is a key intermediate and the acid is also
responsible for the effective generation of enaminone A. Thus, the dual roles of the
acid are clearly revealed in this unique transformation including the help for effective
generation of enaminone A and the real oxidant TEMPO oxoammonium salt. In
addition, compared to the current reaction system, the Bobbittꢀsalt gave a poor yield,
which might be attributed to the consumption of raw materials resulting from its
strong oxidation capacity.
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Scheme 2. Control Experiments.
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In order to further corroborate the reaction mechanism, the redox potentials of the
corresponding reactions were determined by cyclic voltammetry in DMF with use of
glassy carbon working electrode (See Supporting Information, Figure S2).16 The
enaminone intermidiate A oxidation occurs at potentials about +0.56 V vs Ag/AgCl in
DMF, while TEMPO oxoammonium salt and TEMPO shows their oxidation
potentials at near +0.61 V and −1.88 V vs Ag/AgCl in DMF, respectively. Meanwhile,
we also carried out theoretical study, and the calculation results are consistent with the
experiment data (See Supporting Information, Table S3). All above these results
further indicates that TEMPOꢀoxoammonium salt rather than TEMPO
plays a critical role in this transformation. Finally, we also examined the redox
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potentials of the current reaction, and they were almost consistent with the above
results.
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On the basis of the former investigations, and several other reports from the
literature,7a,7b,17 we have proposed plausible mechanism for the synthesis of
multiꢀsubstituted pyrrolinꢀ4ꢀones, which was shown in Scheme 3. Consideration of
the structural characteristics of this transformation suggested that this reaction
involved an oxidative coupling reaction to give a pyrrole core, which was
accompanied by a semipinacol rearrangement.18 This process therefore represents an
area of chemical research that has been investigated in detail over the past two
decades. According to this rearrangement process, the pyrrolinꢀ4ꢀone products would
be produced by sequential 1, 2ꢀmethyl migration and vicinal carbonyl group
generation steps. At the begin, according to the literature,7a,b we speculated that a
singleꢀelectronꢀtransfer (SET) oxidation of the anilinium radical cation B to generated
nitrenium ion B’, then the nucleophilic attack of the enol C to B’ produced the
intermediate E (path a). However, the calculated oxidation potential of the SET step
from B to B’ at 2.035 V vs Ag/AgCl in DMF (See Supporting Information, Table S3),
indicating that this step could not occur under the current condition. Therefore, the
reaction probably proceeds through pathway b. Firstly, the condensation of
βꢀoxoamide 1a with amine 2a would produce the enaminone intermediate A.
Subsequent singleꢀelectronꢀtransfer (SET) reactions with TEMPOꢀoxoammonium salt
generated in situ gave the anilinium radical cation B. the aminyl radical B would react
with the enol C to produce the adduct radical D. And then, the SET oxidation of
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radical D formed the intermediate E. Next, intramolecular cyclization of E led to
intermediate F. Tautomerization followed by two steps of SET oxidations (from F to I)
then generated 3Hꢀpyrrolꢀ1ꢀium intermediate I. Finally, the semipinacol
rearrangement of I would give the desired product 3aa. With regard to the
acetylacetone substrate, the deacylation reaction of 3 would readily occur to afford the
corresponding pyrrolinꢀ4ꢀone of type 4 (Scheme 1).
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Scheme 3. Plausible Mechanism.
O
O
O
O
OH
O
H
Me
N
OH
NHPh
Me
N
OH
NHPh
PhHN
Me
NHPh
PhHN
Me
SET
NHPh
1a
C
+
Ph
O
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PhNH2
Ph
HCl
D
-H
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path b
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Me
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NHPh
N
O
Ph
Ph
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SET
path a
NH
O
NH
O
NH
O
N
Ph
O
SET
NHPh
NHPh
NHPh
F
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B'
A
-
H
O
O
PhHN
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O
Me
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Me
OH
OH
PhHN
Me
NHPh
PhHN
Me
H
SET
SET
NHPh
NHPh
3aa
Me
N
N
N
-
H
Ph
O
Ph
O
Ph
O
I
H
G
It would be very valuable to realize the crossꢀcoupling reaction of different
βꢀoxoamides to form the pyrrolinꢀ4ꢀones bearing different amide groups, which will
largely enrich the library of polysubstituted pyrrolinꢀ4ꢀones. For this purpose, as
preliminary investigations, the reactions of two βꢀoxoamides (1b and 1h) with
enaminone A preꢀprepared from βꢀoxoamide 1a were conducted in the presence of 2
equiv of fuming HNO3 acid to produce the crossꢀcyclization products 3Ab and 3Ah in
satisfactory yields (Scheme 4). When aqueous hydrochloric acid was used, the
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reactions gave relatively lower yields of the products 3Ab and 3Ah, and some
byproducts (3aa and 3ba, or 3ha). The water mainly coming from aqueous
hydrochloric acid resulted in the hydrolysis of A, thereby generating the byproducts.
Scheme 4. CrossꢀCyclization Reactions of Enaminone with βꢀOxoamides.
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CONCLUSION
In conclusion, a practical and reliable method has been developed for the
straightforward synthesis of highly substituted pyrrolinꢀ4ꢀones from readily available
βꢀoxoamides and amine hydrochlorides in good yields under mild conditions. This
tandem reaction is very simple, and features good atom and step economy, as well as
a broad substrate scope. In situ generated TEMPO oxoammonium salt is crucial for
the success of this transformation, and a plausible reaction mechanism has been
proposed for the tandem formation of substituted pyrrolinꢀ4ꢀones. More importantly,
the crossꢀcyclization products can also be prepared by the reactions of the enaminone
intermediate with other different βꢀoxoamides mediated by TEMPO with the
assistant of acid. Further work towards evaluating the reactions of other 1, 3ꢀdione
systems, such as acetoacetate and acetylacetone, is currently underway in our
laboratory.
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EXPERIMENTAL SECTION
General Information. All chemicals, reagents, and solvents were purchased from
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commercial sources and used without further treatment. H NMR and C {1H}NMR
spectra were recorded on a 400 MHz or 600 MHz NMR spectrometer. Data are
represented as follows: chemical shift, integration, multiplicity (s = singlet, d =
doublet, dd = double doublet, t = triplet, q = quartet, m = multiplet), coupling
constants in Hertz (Hz). Chemical shifts are reported in δ units, parts per million (ppm)
relative to the residual chloroform (1H 7.26 ppm and 13C 77.16 ppm) in the deuterated
solvent. All of the new compounds were analyzed for HRMS on an ESIꢀQTOF mass
spectrometer using electrospray ionization in positive ion mode. Melting points were
measured on a melting point apparatus equipped with a thermometer and were
uncorrected. All reactions were monitored by TLC with GF254 silica gel preꢀcoated
plates. Flash chromatography was carried out on SiO2 (silica gel 200−300 mesh).
Typical Procedure for Synthesis of Pyrrolinꢀ4ꢀones 3aa−3ah: To a round bottom
flask (50 mL) were added a stir bar, βꢀoxoamides (0.5 mmol), amine hydrochlorides
(0.5 mmol), TEMPO (1 mmol) and DMF (5 mL). The flask was heated up to 50 °C
and the resulting reaction mixture was stirred for 5−7 h. When the reaction was
completed (detected by TLC), the mixture was cooled to room temperature and then
diluted with AcOEt, washed with water and a saturated NaCl (aq) solution, and dried
over anhydrous Na2SO4. After filtration, the filtrate was concentrated in vacuo. The
residue was purified by flash column chromatography on silica gel using petroleum
ether and CH2Cl2 (V/V = 1:6 ) as the eluent to 3aa−3ah.
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Typical Procedure for Synthesis of Pyrrolinꢀ4ꢀones 3ai−3hk: To a round bottom
flask (50 mL) were added a stir bar, βꢀoxoamides (0.5 mmol), amine hydrochlorides
(0.5 mmol), TEMPO (1 mmol) and DMF (5 mL). The flask was heated up to 120 °C
and the resulting reaction mixture was stirred for 3 h. When the reaction was
completed (detected by TLC), the mixture was cooled to room temperature and then
diluted with AcOEt, washed with water and a saturated NaCl(aq) solution, and dried
over anhydrous Na2SO4. After filtration, the filtrate was concentrated in vacuo. The
residue was purified by flash column chromatography on silica gel using petroleum
ether and CH2Cl2 (V/V = 1:6) as the eluent to give 3ai−3hk.
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Typical Procedure for Synthesis of Pyrrolinꢀ4ꢀones 3Ab and 3Ah: To a round
bottom flask (50 mL) loaded with a stir bar, βꢀoxoamides (0.5 mmol), TEMPO (0.5
mmol), HCl or fuming HNO3 (0.5 mmol) in DMF (dry, 5 mL), an enaminone solution
(0.25 mmol was dissolved in the 3 mL dry DMF) was slowly and dropwisely added
with a syringe for 4 h at 50 °C. And then, the resulting reaction mixture was stirred for
1 h. When the reaction was completed (detected by TLC), the mixture was cooled to
room temperature and then diluted with AcOEt, washed with water and a saturated
NaCl (aq) solution, and dried over anhydrous Na2SO4. After filtration, the filtrate was
concentrated in vacuo. The residue was purified by flash column chromatography on
silica gel using petroleum ether and CH2Cl2 (V/V = 1:6) as the eluent to give 3Ab and
3Ah.
General Procedure for Electrochemical Measurement. The electrochemical
experiments were conducted in a threeꢀelectrode glass cell, controlled by a CH
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Instruments 600D potentiostat using a glassy carbon working electrode. A Pt mesh
counter electrode and solid Ag/AgCl electrode were used as a counter and reference
electrode, respectively. Redox potentials were measured at 50 oC in DMF solution of
tetrabutylammonium tetrafluoroborate (TBAF). The scan rate was 0.1 V/s.
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3aa7: 87.1 mg, 82%; Yellow solid; mp 198−200 °C. 1H NMR (400 MHz, CDCl3) δ
10.15 (s, 1H), 8.89 (s, 1H), 7.66−7.61 (m, 2H), 7.56−7.51 (m, 2H), 7.51−7.46 (m, 3H),
7.43−7.38 (m, 2H), 7.36−7.28 (m, 4H), 7.16−7.05 (m, 2H), 2.58 (s, 3H), 1.76 (s, 3H).
HRMS (ESI) m/z calcd for C26H24N3O3 [M + H]+ 426.1812, found 426.1817.
3ba7d: 97 mg, 80%; White solid; mp 156−158 °C. 1H NMR (600 MHz, CDCl3) δ
10.00 (s, 1H), 8.72 (s, 1H), 7.53 (d, J = 8.4 Hz, 2H), 7.49−7.45 (m, 3H), 7.44−7.36 (m,
4H), 6.85 (d, J = 7.8 Hz, 4H), 3.79 (s, 3H), 3.78 (s, 3H), 2.57 (s, 3H), 1.73 (s, 3H).
HRMS (ESI) m/z calcd for C28H28N3O5 [M + H]+ 486.2023, found 486.2031.
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3ca: 92.5 mg, 76%; Yellow solid; mp 162−164 °C. H NMR (600 MHz, CDCl3) δ
10.14 (s, 1H), 8.80 (s, 1H), 7.51−7.46 (m, 3H), 7.44−7.39 (m, 2H), 7.38 (s, 1H),
7.24−7.17 (m, 3H), 7.15 (d, J =7.8 Hz, 1H), 7.06 (d, J = 7.8 Hz, 1H), 6.69 (dd, J = 7.8,
1.8 Hz, 1H), 6.64 (dd, J = 7.8, 1.8 Hz, 1H), 3.81 (s, 3H), 3.80 (s, 3H), 2.58 (s, 3H),
1.75 (s, 3H). 13C {1H}NMR (150 MHz, CDCl3) δ 195.4, 182.7, 163.3, 161.6, 160.2,
160.2, 139.8, 138.2, 135.8, 129.8, 129.8, 129.7, 129.6, 112.5, 112.4, 110.8, 109.9,
106.0, 105.4, 103.7, 76.8, 55.4, 55.3, 22.3, 16.6. HRMS (ESI) m/z calcd for
C28H27N3O5Na [M + Na]+ 508.1843, found 508.1836.
3da7d: 88.3 mg, 73%; White solid; mp 175−177 °C. 1H NMR (600 MHz, CDCl3) δ
10.56 (s, 1H), 9.00 (s, 1H), 8.52 (d, J = 7.8 Hz, 1H), 8.22 (dd, J = 8.4, 1.2 Hz, 1H),
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7.50−7.39 (m, 3H), 7.40 (dd, J = 7.8, 1.8 Hz, 2H), 7.07 (td, J = 7.8, 1.2 Hz, 1H), 7.02
(td, J = 7.8, 1.2 Hz, 1H), 6.98−6.87 (m, 4H), 3.97 (s, 3H), 3.91 (s, 3H), 2.65 (s, 3H),
1.75 (s, 3H). HRMS (ESI) m/z calcd for C28H28N3O5 [M + H]+ 486.2023, found
486.2016.
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3ea7d: 87.6 mg, 77%; White solid; mp 178−180 °C. 1H NMR (400 MHz, CDCl3) δ
10.09 (s, 1H), 8.81 (s, 1H), 7.51 (d, J = 8.4 Hz, 2H), 7.48−7.44 (m, 3H), 7.43−7.35 (m,
4H), 7.11 (t, J = 8.0Hz, 4H), 2.57 (s, 3H), 2.32 (s, 3H), 2.31 (s, 3H), 1.73 (s, 3H).
HRMS (ESI) m/z calcd for C28H27N3O3Na [M + Na]+ 476.1945, found 476.1938.
3fa7a, 7d: 81.9 mg, 72%; White solid; mp 166−168 °C. 1H NMR (600 MHz, CDCl3)
δ 10.07 (s, 1H), 8.89 (s, 1H), 8.22 (d, J = 7.8 Hz, 1H), 7.80 (d, J = 7.8 Hz, 1H),
7.55−7.45 (m, 5H), 7.24−7.15 (m, 4H), 7.07 (t, J = 7.2 Hz, 1H), 7.02 (t, J = 7.2 Hz,
1H), 2.60 (s, 3H), 2.41 (s, 3H), 2.32 (s, 3H), 1.83 (s, 3H). HRMS (ESI) m/z calcd for
C28H28N3O3 [M + H]+ 454.2125, found 454.2132.
3ga7d: 85.2 mg, 71%; Yellow solid; mp 183−185 °C. 1H NMR (600 MHz, CDCl3) δ
9.99 (s, 1H), 8.75 (s, 1H), 8.06 (d, J = 7.8 Hz, 1H), 7.61 (d, J = 7.8 Hz, 1H),
7.52−7.43 (m, 5H), 7.05−6.96 (m, 4H), 2.59 (s, 3H), 2.37 (s, 3H), 2.30 (s, 3H), 2.27(s,
3H), 2.25 (s, 3H), 1.80 (s, 3H). HRMS (ESI) m/z calcd for C30H32N3O3 [M + H]+
482.2438, found 482.2444.
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3ha7d: 92.5 mg, 75%; Yellow solid; mp 151−153 °C. H NMR (400 MHz, CDCl3)
δ 10.16 (s, 1H), 8.96 (s, 1H), 7.58 (d, J = 8.8 Hz, 2H), 7.54−7.47 (m, 5H), 7.42−7.37
(m, 2H), 7.32−7.24 (m, 4H), 2.57 (s, 3H), 1.76 (s, 3H). HRMS (ESI) m/z calcd for
C26H21Cl2N3O3Na [M + Na]+ 516.0852, found 516.0861.
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3ia: 91.0 mg, 74%; Yellow solid; mp 169−171 °C. H NMR (600 MHz, CDCl3) δ
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10.13 (s, 1H), 8.93 (s, 1H), 7.82 (s, 1H), 7.66 (s, 1H), 7.56−7.50 (m, 3H), 7.48−7.40
(m, 3H), 7.36 (d, J = 8.4 Hz, 1H), 7.26−7.20 (m, 3H), 7.11 (d, J = 7.8 Hz, 1H), 7.05 (d,
J = 7.8, 1H), 2.58 (s, 3H), 1.78 (s, 3H). HRMS (ESI) m/z calcd for C26H21Cl2N3O3Na
[M + Na]+ 516.0852, found 516.0850.
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3ja7d: 87.6 mg, 71%; Yellow solid; mp 158−160 °C. 1H NMR (600 MHz, CDCl3) δ
10.57 (s, 1H), 9.22 (s, 1H), 8.51 (d, J = 8.4 Hz, 1H), 8.19 (d, J = 8.4 Hz, 1H),
7.54−7.49 (m, 3H), 7.46−7.42 (m, 2H), 7.39 (t, J = 7.8 Hz, 3H), 7.26−7.21 (m, 2H),
7.07 (t, J = 7.8, 1H), 7.00 (t, J = 7.8, 1H), 2.62 (s, 3H), 1.82 (s, 3H). HRMS (ESI) m/z
calcd for C26H22Cl2N3O3 [M + H]+ 494.1033, found 494.1038.
3ka: 109.8 mg, 77%; Yellow solid; mp 151−153 °C. 1H NMR (600 MHz, CDCl3) δ
10.31 (s, 1H), 9.09 (s, 1H), 8.03−7.96 (m, 4H), 7.71 (d, J = 7.8 Hz, 2H), 7.61 (d, J =
9.0 Hz, 2H), 7.50 (t, J = 2.4 Hz, 3H), 7.43 (d, J = 3.0 Hz, 2H), 4.38−4.32 (m, 4H),
2.57 (s, 3H), 1.79 (s, 3H), 1.38 (q, J = 6.6 Hz, 6H). 13C {1H}NMR (151 MHz, CDCl3)
δ 195.2, 183.2, 166.4, 166.0, 163.5, 161.6, 142.8, 141.1, 135.6, 130.8, 130.8, 129.9,
129.9, 129.7, 126.7, 125.2, 119.4, 119.1, 103.5, 76.8, 61.0, 60.8, 22.7, 16.6, 14.5, 14.4.
HRMS (ESI) m/z calcd for C32H31N3O7Na [M + Na]+ 592.2054, found 592.2054.
3la: 61.5 mg, 54%; Yellow solid; mp 202−204 °C. 1H NMR (400 MHz, CDCl3) δ
8.51 (t, J = 5.6 Hz, 1H), 7.46−7.38 (m, 3H), 7.32 (d, J = 4.4 Hz, 4H), 7.30−7.23 (m,
6H), 7.23−7.17 (m, 3H), 4.55 (dd, J = 14.8, 6.0 Hz, 1H), 4.47 (dd, J = 14.8, 6.0 Hz,
1H), 4.42−4.33 (m, 2H), 2.49 (s, 3H), 1.59 (s, 3H). 13C {1H}NMR (100 MHz,
CDCl3) δ 195.6, 181.8, 165.6, 163.8, 139.1, 137.7, 135.9, 129.6, 129.6, 129.4, 128.8,
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128.6, 127.7, 127.7, 127.6, 127.2, 103.3, 76.6, 43.8, 42.5, 21.4, 16.3. HRMS (ESI)
m/z calcd for C28H28N3O3 [M + H]+ 454.2125, found 454.2125.
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3ma: 58.9 mg, 61%; Yellow solid; mp 175−177 °C. 1H NMR (600 MHz, CDCl3) δ
8.05 (s, 1H), 7.48−7.41 (m, 3H), 7.30 (d, J = 7.2 Hz, 2H), 6.43 (s, 1H), 2.49 (s, 3H),
1.53 (s, 3H), 1.43 (s, 9H), 1.32 (s, 9H). 13C {1H}NMR (150 MHz, CDCl3) δ 196.1,
181.4, 164.7, 163.4, 136.4, 129.9, 129.5, 129.3, 104.3, 76.7, 51.8, 50.6, 29.3, 28.6,
22.1, 16.4. HRMS (ESI) m/z calcd for C22H31N3O3Na [M + Na]+ 408.2258, found
408.2257.
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3ab7d: 87.5 mg, 77%; Yellow solid; mp 179−181 °C. 1H NMR (600 MHz, CDCl3) δ
10.13 (s, 1H), 8.86 (s, 1H), 7.65 (d, J = 7.8 Hz, 2H), 7.52 (d, J = 8.4 Hz, 2H),
7.38−7.29 (m, 6H), 7.13 (t, J = 7.2 Hz, 1H), 7.07 (t, J = 7.2 Hz, 1H), 6.97 (d, J = 9.0
Hz, 2H), 3.86 (s, 3H), 2.57 (s, 3H), 1.75 (s, 3H). HRMS (ESI) m/z calcd for
C27H25N3O4Na [M + Na]+ 478.1737, found 478.1745.
3ac7d: 87.6 mg, 80%; Yellow solid; mp 170−172 °C. 1H NMR (600 MHz, CDCl3) δ
10.12 (s, 1H), 8.82 (s, 1H), 7.65 (d, J = 7.8 Hz, 2H), 7.52 (d, J = 7.2 Hz, 2H),
7.34−7.27 (m, 8H), 7.13 (t, J = 7.2 Hz, 1H), 7.08 (t, J = 7.2 Hz, 1H), 2.58 (s, 3H),
2.42 (s, 3H), 1.77 (s, 3H). HRMS (ESI) m/z calcd for C27H26N3O3 [M + H]+ 440.1969,
found 440.1973.
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3ad7d: 76.1 mg, 69%; Yellow solid; mp 178−180 °C. H NMR (600 MHz, CDCl3)
δ 10.12 (s, 1H), 8.78 (s, 1H), 7.65 (d, J = 8.4 Hz, 2H), 7.52 (d, J = 7.2 Hz, 2H),
7.39−7.28 (m, 6H), 7.25−7.18 (m, 2H), 7.13 (t, J = 7.2 Hz, 1H), 7.07 (t, J = 7.8 Hz,
1H), 2.59 (s, 3H), 2.42 (s, 3H), 1.77 (s, 3H). HRMS (ESI) m/z calcd for C27H26N3O3
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[M + H]+ 440.1969, found 440.1977.
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3ae7d: 54.7 mg, 50%; Yellow solid; mp 183−185 °C. 1H NMR (600 MHz, CDCl3) δ
10.12 (s, 1H), 8.41 (s, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.64 (d, J = 7.8 Hz, 2H), 7.54 (d,
J = 7.8 Hz, 2H), 7.40−7.29 (m, 7H), 7.15 (t, J = 7.2 Hz, 1H), 7.07 (t, J = 7.2 Hz, 1H),
2.56 (s, 3H), 2.16 (s, 3H), 1.65 (s, 3H). HRMS (ESI) m/z calcd for C27H26N3O3 [M +
H]+ 440.1969, found 440.1965.
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3af7d: 74.5 mg, 65%; Yellow solid; mp 189−192 °C. 1H NMR (600 MHz, CDCl3) δ
10.05 (s, 1H), 8.89 (s, 1H), 7.65 (d, J = 7.8 Hz 2H), 7.53−7.46 (m, 4H), 7.41 (d, J =
7.8 Hz, 2H), 7.36−7.30 (m, 4H), 7.14 (t, J = 7.8 Hz, 1H), 7.08 (t, J = 7.2 Hz, 1H),
2.59 (s, 3H), 1.77 (s, 3H). HRMS (ESI) m/z calcd for C26H22ClN3O3Na [M + Na]+
482.1242, found 482.1248.
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3ag: 55.2 mg, 48%; Yellow solid; mp 166−168 °C. H NMR (600 MHz, CDCl3) δ
10.06 (s, 1H), 8.87 (s, 1H), 7.65 (d, J = 7.8 Hz, 2H), 7.54−7.48 (m, 4H), 7.44 (t, J =
7.8 Hz, 1H), 7.38−7.30 (m, 5H), 7.14 (t, J = 7.8 Hz, 1H), 7.09 (t, J = 7.8 Hz, 1H),
2.61 (s, 3H), 1.78 (s, 3H). 13C {1H}NMR (150 MHz, CDCl3) δ 195.4, 182.6, 163.3,
161.3, 138.5, 137.1, 136.9, 135.1, 130.4, 130.3, 130.0, 129.1, 128.9, 128.6, 125.1,
123.7, 120.3, 120.2, 104.0, 76.6, 22.8, 16.6. HRMS (ESI) m/z calcd for
C26H22ClN3O3Na [M +Na]+ 482.1242, found 482.1256.
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3ah7d: 61.3 mg, 63%; Yellow solid; mp: 156−158 °C. H NMR (600 MHz, CDCl3)
δ 10.01 (s, 1H), 9.27 (s, 1H), 7.63 (d, J = 8.4 Hz, 2H), 7.54 (d, J = 8.4 Hz, 2H),
7.37−7.28 (m, 4H), 7.15 (t, J = 7.8 Hz, 1H), 7.07 (t, J = 7.2 Hz, 1H), 5.04 (d, J = 18.6
Hz, 1H), 4.60 (d, J = 18.6 Hz, 1H), 2.97 (s, 3H), 2.41 (s, 1H), 1.89 (s, 3H). HRMS
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(ESI) m/z calcd for C23H22N3O3 [M + H]+ 388.1656, found 388.1662.
3ai7a, 7b: 76.8 mg, 70%; white solid; mp 167−168 ºC. 1H NMR (600 MHz, CDCl3) δ
10.11 (s, 1H), 9.20 (s, 1H), 7.65 (d, J = 7.8 Hz, 2H), 7.54 (d, J = 7.8 Hz, 2H),
7.40−7.29 (m, 7H), 7.21− 7.12 (m, 3H), 7.07 (t, J = 7.2 Hz, 1H), 5.39−5.24 (m, 2H),
2.75 (s, 3H), 1.72 (s, 3H). HRMS (ESI) m/z calcd for C27H26N3O3 [M + H]+ 440.1969,
found 440.1976.
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3aj: 70.3 mg, 72%; white solid; mp 191−193 ºC. H NMR (600 MHz, CDCl3) δ
10.10 (s, 1H), 9.22 (s, 1H), 7.62 (d, J = 7.8 Hz, 2H), 7.56−7.50 (m, 2H), 7.36−7.28 (m,
4H), 7.14 (t, J = 7.8 Hz, 1H), 7.05 (t, J = 7.2 Hz, 1H), 3.98 – 3.89 (m, 1H), 3.83−3.75
(m, 1H), 2.84 (s, 3H), 1.90−1.83 (m, 1H), 1.79 (s, 3H), 1.73−1.64 (m, 1H), 1.01 (t, J =
7.2 Hz, 3H). 13C {1H}NMR (150 MHz, CDCl3) δ 194.4, 181.2, 163.9, 161.9, 138.8,
137.1, 129.2, 129.0, 125.0, 123.5, 120.2, 120.2, 102.6, 74.7, 47.4, 23.9, 23.1, 15.2,
11.6. HRMS (ESI) m/z calcd for C23H26N3O3 [M + H]+ 392.1969, found 392.1972.
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3ak7d: 56.1 mg, 64%; Yellow solid; mp: 203−205 °C. H NMR (400 MHz, CDCl3)
δ 9.90 (s, 1H), 9.43 (s, 1H), 8.80 (s, 1H), 7.64 (d, J = 8.0 Hz, 2H), 7.57 (d, J = 7.6 Hz,
2H), 7.40−7.29 (m, 4H), 7.18 (t, J = 7.6 Hz, 1H), 7.08 (t, J = 7.2 Hz, 1H), 2.76 (s, 3H),
1.77 (s, 3H). HRMS (ESI) m/z calcd for C20H20N3O3 [M + H]+ 350.1499, found
350.1507.
3bk: 69.5 mg, 68%; Yellow solid; mp: 194−196 °C. 1H NMR (600 MHz, CDCl3) δ
9.75 (s, 1H), 9.27 (s, 1H), 8.59 (s, 1H), 7.57−7.51 (m, 2H), 7.50−7.43 (m, 2H),
6.92−6.82 (m, 4H), 3.80 (s, 3H), 3.79 (s, 3H), 2.74 (s, 3H), 1.75 (s, 3H). 13C
{1H}NMR (150 MHz, CDCl3) δ 196.4, 181.6, 164.6, 161.5, 157.2, 156.0, 131.8,
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129.8, 122.0, 121.8, 114.4, 114.2, 103.1, 70.3, 55.6, 55.6, 25.2, 17.7. HRMS (ESI) m/z
calcd for C22H24N3O5 [M + H]+ 410.1710, found 410.1725.
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3hk: 63.5 mg, 61%; Yellow solid; mp: 201−203 °C. 1H NMR (600 MHz, CDCl3) δ
9.85 (s, 1H), 9.28 (s, 1H), 7.78 (s, 1H), 7.59 (d, J = 7.8 Hz, 2H), 7.52 (d, J = 7.8 Hz,
2H), 7.33 (d, J = 7.8 Hz, 2H), 7.28 (d, J = 7.8 Hz, 2H), 2.77 (s, 3H), 1.76 (s, 3H). 13C
{1H}NMR (150 MHz, CDCl3) δ 196.1, 181.8, 164.4, 161.3, 137.0, 135.1, 130.5,
129.2, 128.9, 128.5, 121.4, 121.1, 103.0, 70.3, 25.1, 17.7. HRMS (ESI) m/z calcd for
C20H17Cl2N3O3Na [M + Na]+ 440.0539, found 440.0545.
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3Ab: 64.8 mg, 57%; Yellow solid; mp: 176−179 °C. 1H NMR (600 MHz, CDCl3) δ
10.13 (s, 1H), 8.70 (s, 1H), 7.64 (d, J = 7.8 Hz, 2H), 7.49−7.46 (m, 3H), 7.45−7.37 (m,
4H), 7.31 (t, J = 7.8 Hz, 2H), 7.07 (t, J = 7.2 Hz, 1H), 6.85 (d, J = 9.0 Hz, 2H), 3.78 (s,
3H), 2.58 (s, 3H), 1.75 (s, 3H). 13C {1H}NMR (150 MHz, CDCl3) δ 195.6, 182.6,
163.3, 161.7, 156.9, 138.7 135.9, 130.2, 129.9, 129.7, 129.6, 129.0, 123.7, 122.2,
120.2, 114.3, 103.7, 76.8, 55.6, 22.5, 16.6. HRMS (ESI) m/z calcd for C27H26N3O4 [M
+ H]+ 456.1918, found 456.1932.
3Ah: 55.3 mg, 48%; Yellow solid; mp: 185−188 °C. 1H NMR (600 MHz, CDCl3) δ
10.10 (s, 1H), 8.98 (s, 1H), 7.62 (d, J = 8.4 Hz, 2H), 7.54−7.45 (m, 5H), 7.43−7.36 (m,
2H), 7.33−7.27 (m, 4H), 7.08 (t, J = 7.2 Hz, 1H), 2.58 (s, 3H), 1.76 (s, 3H). 13C
{1H}NMR (150 MHz, CDCl3) δ 195.3, 182.9, 163.5, 161.6, 138.5, 135.7, 135.7,
129.9, 129.8, 129.7, 129.6, 129.1, 128.9, 123.7, 121.6, 120.2, 103.7, 76.6, 22.6, 16.6.
HRMS (ESI) m/z calcd for C26H23ClN3O3 [M + H]+ 460.1422, found 460.1413.
4na: 36.2 mg, 63%; White solid; mp: 166−168 °C. 1H NMR (600 MHz, CDCl3) δ
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7.50 (d, J = 5.4 Hz, 3H), 7.27 (d, J = 9.6 Hz, 3H), 3.95 (s, 1H), 2.47 (s, 6H), 1.37 (s,
3H). 13C {1H}NMR (150 MHz, CDCl3) δ 196.7, 194.4, 180.7, 134.2, 129.9, 129.7,
129.1, 107.9, 90.0, 30.1, 22.2, 16.9. HRMS (ESI) m/z calcd for C14H16NO2 [M + H]+
230.1176, found 230.1183.
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications
website. Xꢀray structure of 3ak, cyclic voltammetry of the corresponding reaction,
calculated potentials and cartesian coordinates, and spectra for all compounds.
AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: zgs6668@yahoo.com.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We are grateful for the financial support from the National Natural Science
Foundation of China (21372065, U1604285), the Program for Changjiang Scholars
and Innovative Research Team in University (IRT1061). We gratefully acknowledge
the contribution of the referee who reviewed our revised manuscript, for their help in
discussion of the reaction mechanism.
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