Concise Synthesis of Vesnarinone and Its Analogues by Using Pd-Catalyzed C-N Bond-Forming Reactions

Article abstract of DOI:10.1002/ejoc.201403054

An efficient and concise synthesis of vesnarinone and its analogues from readily available starting materials and by using catalytic C-N bond-forming reactions is reported. In this protocol, a homogeneous Pd-catalyzed Buchwald-Hartwig amination and a supported Pd nanoparticles catalyzed aminocarbonylation were utilized as the two key reactions to prepare vesnarinone in an overall yield of 73 %. Sixteen analogues were also synthesized in up to 89 % overall yield. An efficient and concise synthesis of vesnarinone was achieved in three steps by using palladium-catalyzed C-N bond-forming reactions, which included the Buchwald-Hartwig amination and an aminocarbonylation reaction. High overall yields were obtained by using this strategy for the preparation of several vesnarinone analogues.

Full text of DOI:10.1002/ejoc.201403054

FULL PAPER
DOI: 10.1002/ejoc.201403054
Concise Synthesis of Vesnarinone and Its Analogues by Using Pd-Catalyzed
C–N Bond-Forming Reactions
Yi Yang See,[a,b] Tuan Thanh Dang,[a] Anqi Chen,[a] and Abdul Majeed Seayad*[a]
Keywords: Total synthesis / Homogeneous catalysis / Heterogeneous catalysis / Cross-coupling / Amination / Palladium
An efficient and concise synthesis of vesnarinone and its
analogues from readily available starting materials and by
using catalytic C–N bond-forming reactions is reported. In
this protocol, a homogeneous Pd-catalyzed Buchwald–Hart-
wig amination and a supported Pd nanoparticles catalyzed
aminocarbonylation were utilized as the two key reactions
to prepare vesnarinone in an overall yield of 73%. Sixteen
analogues were also synthesized in up to 89% overall yield.
catalytic aminocarbonylation could be employed to create
one of the C–N bonds (i.e., the amide C–N bond) and
Introduction
Vesnarinone (1a) was initially developed by the Otsuka achieve a more efficient and environmentally benign route
pharmaceutical company as a positive inotropic drug for to vesnarinone and its analogues. Accordingly, we report
the treatment of congestive heart failure.[1] Biological stud- herein a concise, three-step synthesis of vesnarinone and
ies show that vesnarinone also possesses valuable antican- its analogues by utilizing palladium-catalyzed C–N bond-
cer[2] and anti-inflammatory[3] activities. The first synthesis forming cross-coupling reactions,[7] such as an aminocarb-
of vesnarinone, along with its pharmacological evaluations, onylation[8] and a Buchwald–Hartwig amination,[9] as the
was reported by Tominaga and co-workers to take place in key steps.
six stoichiometric steps and in 23% overall yield.[4] In this
synthesis, hazardous reagents such as metal hydrides, con-
centrated mineral acids, alkyl halides, and acid chlorides
were used, which made the synthesis unattractive from a
Results and Discussion
green and sustainable perspective. Although there were sub-
sequent improvements to the route,[5] the length of it and Scheme 1) highlights the strategy of the catalytic coupling
the nature of chemistry were not significantly changed. of three readily available components, that is, 4-bromovera-
The retrosynthetic analysis of vesnarinone (see
In light of our recent work on sustainable amide synthe- trole (2a), N-protected piperazine (3), and bromoquinol-
ses based on supported palladium nanoparticles catalyzed inone 4a, by using catalytic aminocarbonylation and Buch-
aminocarbonylations of aryl halides,[6] we envisioned that a wald–Hartwig amination reactions. This strategy, which in-
Scheme 1. Retrosynthetic analysis of vesnarinone.
[a] Organic Chemistry, Institute of Chemical and Engineering
volves two catalytic C–N cross-coupling reactions should
be more efficient than the previous approach, in which the
central piperazine ring was constructed through a nitration,
reduction, and cyclization by using nucleophilic substitu-
tion reactions.[4] With a suitably monoprotected piperazine
3, two approaches could be explored for the C–N cross-
coupling reactions at the two nitrogen atoms, that is, by
Sciences,
8 Biomedical Grove, #07-01 Neuros, 138665 Singapore
E-mail: abdul_seayad@ices.a-star.edu.sg
http://www.ices.a-star.edu.sg
[b] Department of Chemistry, The Scripps Research Institute,
10550 North Torrey Pines Road, La Jolla, California 92037,
USA
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201403054.
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Y. Y. See, T. T. Dang, A. Chen, A. M. Seayad
FULL PAPER
using the two aryl bromide fragments 2a and 4a in an ami- Disappointingly, this reaction did not yield the expected
nocarbonylation[8] and a Buchwald–Hartwig amination re- vesnarinone product even after significant efforts to screen
action,[9] respectively, in two different sequences.
the reaction conditions. The debrominated quinolinone was
In the first approach, an aminocarbonylation followed isolated as the only side product with the remaining uncon-
by a Buchwald–Hartwig amination was investigated (see verted amide 5b recovered.
Scheme 2). The aminocarbonylation of monoprotected N-
Because cyclic amide bromoquinolinone 4a failed to un-
Boc-piperazine (3a, Boc = tert-butoxycarbonyl) with com- dergo the C–N coupling reaction with the N-amide pro-
mercially available 2a by using our recently developed recy- tected piperazine 5b under the reported conditions, the sec-
clable Pd nanoparticles (NP) supported on ZIF-8 [PdNP/ ond approach, that is, a Buchwald–Hartwig coupling fol-
ZIF-8 (zeolitic imidazolate framework 8)][6a] as a catalyst in lowed by an aminocarbonylation reaction sequence was ex-
the presence of DPEPhos {bis[2-(diphenylphosphino)- amined. The investigation began with 4-bromoacetanilide
phenyl] ether} as a ligand proceeded smoothly to provide (4b), which would not only serve as a readily available
the desired amide 5a in 90% isolated yield. The reaction model compound to establish the coupling conditions but
required only 0.25 mol-% of Pd loading at 120 °C and also enable access to acetamide analogues of vesnarinone,
10 bar of carbon monoxide, despite the lower reactivity of which would be useful for structure–activity relationship
the aryl bromide. The removal of the Boc protecting group studies. When N-Boc-piperazine (3a) was employed in the
by using trifluoroacetic acid (TFA) in dichloromethane[10] Buchwald–Hartwig coupling reaction, no product was
provided amide 5b in nearly quantitative yield. In the sec- formed, but 67% of the debrominated product of 4b was
ond step, the coupling of amide 5b with commercially avail- isolated from the reaction (see Scheme 3). When N-benzyl-
able bromoquinolinone 4a was examined by using a C–N piperazine (3b) was used as the coupling partner in the pres-
coupling protocol reported by Buchwald and co-workers.[11] ence of Pd2(dba)3 and the DavePhos ligand with LiNTMS2
Scheme 2. Synthetic strategy for vesnarinone by using an aminocarbonylation and amination sequence [DCM = dichloromethane, dba
=
dibenzylideneacetone, DavePhos
=
2-dicyclohexylphosphino-2Ј-(dimethylamino)biphenyl, LiNTMS2
=
lithium bis(tri-
methylsilyl)amide, THF = tetrahydrofuran].
Scheme 3. C–N coupling reaction and deprotection step.
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Concise Synthesis of Vesnarinone and Its Analogues
as the base, up to 80% of amination product 6b was ob- in an H-Cube flow hydrogenation system by using the Pd/
tained.[11] These conditions were successfully applied to the C catalyst at 10 bar of hydrogen at 70 °C under a recircu-
amination of bromoquinolinone 4a to provide the desired lation mode for 16 h to give 7a and 7b in quantitative yields.
coupling product 6a in 91% isolated yield.
Piperazines 7a and 7b, which were prepared by using these
The debenzylation of arylated piperazines 6a and 6b was procedures, were then subjected to the next aminocarb-
initially examined by using the Sam and Spicer pro- onylation step without further purification.
cedure[12] with ammonium formate and the Pd/C catalyst,
The aminocarbonylation of 4-bromoveratrole (2a) with
but there were difficulties with this reaction. Although com- acyclic piperazine derivative 7b by using the heterogeneous
plete conversion was achieved, the deprotected products PdNP/ZIF-8 catalyst[6a] in toluene at 130 °C and 10 bar of
were contaminated with unidentified polar impurities that CO for 12 h readily gave the desired amide product in 76%
were inseparable from the polar N-aryl piperazines 7a and isolated yield. Unfortunately, cyclic piperazine 7a failed to
7b. After screening a number of debenzylation condi- yield the corresponding product (i.e., vesnarinone) under
tions,[10] quantitative yields of 7a and 7b were obtained by the optimized aminocarbonylation conditions. We recog-
using the Pd/C catalyst (10 mol-% of Pd) under 10 bar of nized that the reactivity difference between the cyclic and
hydrogen in methanol at 70 °C for 4 h, which resulted in no acyclic derivatives could be a result of the low solubility of
detectable impurities. Alternatively, the debenzylation of the piperazine 7a in toluene. Accordingly, a number of solvents
arylated piperazines 6a and 6b could be readily carried out including N,N-dimethylformamide (DMF), diglyme, and di-
Scheme 4. Completion of vesnarinone (1a) synthesis by employing aminocarbonylation reaction.
Table 1. Synthesis of vesnarinone analogues.
[a] Reagents and conditions: ArBr (0.7 mmol, 1.4 equiv.), 7a (or 7b) (0.5 mmol), K2CO3 (1.0 mmol, 2 equiv.), CO (10 bar), PdNP/ZIF-8
(1 wt.-%, 24.0 mg, 0.25 mol-% Pd), DPEPhos (5.4 mg, 1.0 mol-%), dioxane (8.0 mL). [b] Reagents and conditions: ArI (0.7 mmol,
1.4 equiv.), 7a (or 7b) (0.5 mmol), K2CO3 (1.0 mmol, 2 equiv.), CO (10 bar), PdNP/ZIF-8 (1 wt.-%, 24.0 mg, 0.25 mol-% Pd), dioxane
(8.0 mL).
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Y. Y. See, T. T. Dang, A. Chen, A. M. Seayad
FULL PAPER
oxane were screened, and dioxane was found to be the most leaching heterogeneous PdNP/ZIF-8 catalyst in the amino-
suitable solvent to provide vesnarinone (1a) in 80% isolated carbonylation step is beneficial because of the stringent reg-
yield (see Scheme 4).
ulations with regard to metal residues in active pharma-
With the optimized aminocarbonylation conditions in ceutical ingredients (API).
hand, a series of vesnarinone analogues that contained
either the quinolinone or a p-acetamidophenyl motif were
synthesized by carrying out the aminocarbonylations of 7a
Experimental Section
General Methods: Commercially available reagents were used as re-
and 7b with a variety of functionalized aryl bromides and
iodides (see Table 1). As we reported earlier with the prepa-
rations of 6a and 6b, a phosphine ligand such as DPEPhos
and the PdNP/ZIF-8 catalyst are needed for the aminocarb-
onylation of aryl bromides. However, the aminocarb-
onylation of the more reactive aryl iodides do not require
the use of a ligand. Good to excellent isolated yields were
obtained for methoxy-substituted (i.e., 1b, 1m, and 1n),
cyclic ethers (i.e., 1c and 1o), and fluoro-substituted (i.e., 1d
ceived without further purification. Technical-grade solvents were
used for chromatographic purifications. Reactions were monitored
by thin layer chromatography with Merck Silica Gel 60 F254 plates.
Chromatographic purifications of the products were performed on
silica gel. The 1H and 13C NMR spectroscopic data were measured
in the given solvent with a Bruker Avance 400 (400 MHz for 1H
NMR, 101 MHz for 13C NMR). Chemical shifts (δ) are reported
in parts per million (ppm) relative to tetramethylsilane (TMS) for
the 1H and 13C NMR spectroscopic data and also calibrated
and 1p) products from the corresponding aryl bromides and against the residual solvent peak. The multiplicity of the signals
are reported by using the abbreviations s (singlet), d (doublet), t
(triplet), q (quartet), m (multiplet), and br. (broad) signal or a com-
bination of them. Coupling constants (J) are reported in Hertz.
HRMS data were measured with a Thermo Finnigan MAT95XP
model instrument, and ESI-TOF mass spectrometry was employed.
A 25 mL Parr (Hastelloy-C) reactor (5500) with a 4848 controller,
which had the capacity for temperature control as well as monitor-
ing pressure and rpm, was used for performing the aminocarb-
onylation reaction.
iodides. Electron-withdrawing substituents such as those
contained in ester 1e, nitrile 1f, and trifluoromethyl-substi-
tuted 1g were well tolerated, and the corresponding amide
products were obtained in up to 98% yield. In addition, the
analogues that contained N-heteroaromatic (i.e, 1h–1j) and
4-(methylthio)phenyl (i.e., 1l) groups were also conveniently
obtained in up to 93% yield by employing the PdNP/ZIF-8-
catalyzed aminocarbonylation, and these reactions occurred
without any deactivation to the catalyst.
Procedure for the Preparation of PdNP/ZIF-8 Catalyst: As de-
scribed in the reported procedure,[6a] potassium tetrachloropallad-
ate(II) (17.3 mg, 0.053 mmol) was first dissolved in deionized water
(40 mL) to give a yellow solution, to which ZIF-8 (500 mg) was
added. The resulting mixture was stirred vigorously at room tem-
perature for 30 min until a suspension fully formed. This rapidly
stirred murky orange suspension was added with 1 wt.-% of
aqueous polyvinyl alcohol (PVA, 2.0 mL, 99% hydrolyzed) in one
portion. An aqueous solution of hydrazine (1.0 mL in 30 mL water,
excess amount) was then added to this mixture slowly and dropwise
over 1 h. The resulting dark suspension was filtered through a
fritted funnel (fine porosity). The filter cake was washed success-
ively with water (2ϫ 10 mL), methanol (1ϫ 10 mL), and diethyl
ether (1ϫ 10 mL) and then was dried under vacuum at 90 °C for
24 h. Pd/ZIF-8 was obtained as a grey powder (495 mg) and was
stored without any strict inert conditions.
Notably, when p-bromoiodobenzene was used as a sub-
strate and the reaction was carried out without a phosphine
ligand, the monoaminocarbonylated product 1k, which
contained the bromo group, was obtained in 69% yield.
The presence of the bromo substituent would allow for fur-
ther functionalizations through various coupling reactions
and, thus, provide access to diverse and more complex
vesnarinone analogues for biological and structure–activity
relationship studies.
Similar to our previous observations,[6a] we found that
the PdNP/ZIF-8 catalyst is highly stable under the present
aminocarbonylation conditions. In addition, the catalyst is
recyclable and offers very low palladium leaching
(Ͻ3 ppm), which is very important for the recovery of the
catalyst and to ensure that the palladium residue is within
the allowed limits for pharmaceutical products.[13]
General Procedures and Characterization of Compounds
tert-Butyl 4-(3,4-Dimethoxybenzoyl)piperazine-1-carboxylate (5a):
4-Bromoveratrole (1.085 g, 5.0 mmol), tert-butyl piperazine-1-carb-
oxylate (1.395 g, 7.5 mmol, 1.5 equiv.), 1 wt.-% Pd/ZIF-8 (100 mg,
0.19 mol-% of Pd), DPEphos (27 mg, 0.05 mmol, 1.0 mol-%), and
anhydrous potassium carbonate (1.035 g, 7.5 mmol, 1.5 equiv.)
were added to a Parr reactor followed by dry toluene (12.0 mL)
Conclusions
In summary, we have developed an efficient catalytic
route for the synthesis of vesnarinone (73% overall yield) under air. The reactor was then quickly purged with dry N2 (3ϫ)
and then CO (3ϫ). The CO pressure was then adjusted to 6 bar,
and the reaction was conducted at 120 °C for 12 h. Upon comple-
tion of the reaction, the reactor was cooled to room temperature
and purged with N2 (3ϫ). The solvent was removed in vacuo, and
the residue was dry loaded onto a silica column (ethyl acetate/
petroleum ether, 1:1) to give compound 5a (1.575 g, 90%) as a
and its analogues (up to 89% overall yield) by using a
homogeneous palladium-catalyzed Buchwald–Hartwig
amination and a heterogeneous Pd nanoparticles catalyzed
aminocarbonylation reaction as the key steps. This concise
route not only provides convenient access to valuable com-
pounds for the exploration of new therapeutic applications
but also demonstrates the potential use of catalytic C–N
cross-coupling reactions in the synthesis of pharmaceuti-
cally relevant compounds that have amide and amine func-
white solid. IR (film): ν = 1685.6, 1621.8, 1515.3, 1424.5, 1246.6,
˜
1176.8, 822.2 cm–1. 1H NMR (400 MHz, CDCl3): δ = 6.97 (m, 2
H), 6.85 (d, J = 8.1 Hz, 1 H), 3.89 (s, 3 H), 3.88 (s, 3 H), 3.58 (s,
4 H), 3.45 (s, 4 H), 1.45 (s, 9 H) ppm. 13C NMR (101 MHz,
tionalities.[14] In addition, the use of the stable and low- CDCl3): δ = 170.6, 154.7, 150.6, 149.2, 127.8, 120.2, 111.1, 110.7,
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Concise Synthesis of Vesnarinone and Its Analogues
80.4, 56.1, 43.8, 28.5 ppm. HRMS (ESI-TOF): calcd. for
C18H27N2O5 [M + H]+ 351.1920; found 351.1916.
combined organic layers were dried with anhydrous magnesium
sulfate and filtered, and the solvent was removed in vacuo. The
yellow residue was purified on a silica column (ethyl acetate) to give
the target product 6a (3.768 g, 91%) as a yellow solid. IR (film):
1-(3,4-Dimethoxybenzoyl)piperazine (5b): tert-Butyl 4-(3,4-dimeth-
oxybenzoyl)piperazine-1-carboxylate (350 mg, 1.0 mmol) was dis-
solved in DCM (20 mL), and the resulting solution was cooled in
an ice bath. Trifluoroacetic acid (2.0 mL, excess amount) was
added dropwise, and the reaction mixture was warmed to room
temperature as it was stirred overnight. The solvent was then re-
moved in vacuo, and the resulting residue was diluted with satu-
rated sodium hydrogen carbonate (20 mL). After adjusting the the
aqueous phase to pH Ͼ 10, the mixture was extracted with ethyl
acetate until there was no product remaining in the aqueous phase
as determined by TLC and UV visualization. The combined or-
ganic extracts were dried with anhydrous magnesium sulfate and
filtered. The solvent was removed to give a residue, which was dry
loaded onto a silica column (ethyl acetate/petroleum ether, 1:1) to
give compound 5b (249.6 mg, quantitative yield) as a foamy pale
ν = 1669.0, 1509.1, 1388.3, 1236.6, 958.9, 738.9 cm–1. 1H NMR
˜
(400 MHz, CDCl3): δ = 8.93 (s, 1 H), 7.32–7.39 (m, 5 H), 6.75 (m,
3 H), 3.61 (s, 2 H), 3.20–3.11 (m, 1 H), 2.93 (dd, J = 8.5, 6.5 Hz,
2 H), 2.71–2.56 (m, 1 H) ppm. 13C NMR (101 MHz, CDCl3): δ =
171.7, 147.7, 137.9, 130.5, 129.3, 128.4, 127.3, 124.6, 116.5, 116.2,
115.6, 63.1, 53.2, 50.0, 30.9, 26.0 ppm. HRMS (ESI-TOF): calcd.
for C20H24N3O [M + H]+ 322.1919; found 322.1921.
N-[4-(Piperazin-1-yl)phenyl]acetamide (7b):[15] N-[4-(4-Benzyl-
piperazin-1-yl)phenyl]acetamide (3.09 g, 10 mmol), 10 wt.-% palla-
dium on carbon (1.64 g, 10% Pd), and methanol (10 mL) were
added to a Parr reactor. The reactor was purged with dry N2 (3ϫ)
and then H2 (3ϫ). The H2 pressure was adjusted to approximately
10 bar, and the reaction was carried out at 70 °C for 4 h. Upon
completion of the reaction, the reactor was cooled to room tem-
perature, and the mixture was filtered through a plug of Celite. The
resulting filtrate was evaporated in vacuo to dryness to give product
yellow solid. IR (film): ν = 1678.4, 1515.9, 1440.8, 1207.0, 1134.9,
˜
802.2, 724.7 cm–1. 1H NMR (400 MHz, [D6]DMSO): δ = 7.02–6.95
(m, 3 H), 3.78 (s, 3 H), 3.77 (s, 3 H), 3.41 (br. s, 4 H), 2.69 (br. s,
4 H) ppm. 13C NMR (101 MHz, [D6]DMSO): δ = 45.6, 55.6, 111.0,
111.2, 119.8, 128.2, 148.4, 149.7, 168.9 ppm. HRMS (ESI-TOF):
calcd. for C13H19N2O3 [M + H]+ 251.1396; found 251.1395.
7b (2.08 g, 95%) as a pale yellow solid. IR (film): ν = 1662.8,
˜
1603.8, 1543.7, 1514.7, 1254.3, 904.5, 823.9 cm–1. 1H NMR
(400 MHz, CD3OD): δ = 7.40 (d, J = 9.0 Hz, 2 H), 6.93 (d, J =
9.0 Hz, 2 H), 3.31 (m, 4 H), 3.09 (m, 4 H), 2.98 (m, 4 H), 2.09 (s,
3 H) ppm. 13C NMR (101 MHz, CD3OD): δ = 171.3, 149.9, 132.6,
122.5, 117.9, 51.5, 46.5, 23.6 ppm. HRMS (ESI-TOF): calcd. for
C12H18N3O [M + H]+ 220.1444; found 220.1449.
N-[4-(4-Benzylpiperazin-1-yl)phenyl]acetamide (6b):[15] 4-Bromo-
acetanilide (3.17 g, 14.8 mmol), tris(dibenzylideneacetone)dipalla-
dium (135.6 mg, 0.1 mmol, 2.0 mol-% Pd), and DavePhos (140 mg,
0.24 mmol, 2.4 mol-%), were added to a Schlenk tube, which was
evacuated and refilled with argon (3ϫ). N-Benzylpiperazine
(3.13 mL, 17.8 mmol, 1.2 equiv.) was then added by syringe fol-
lowed by LiNTMS2 (1.06 m in THF, 32.5 mL, 32.6 mmol,
2.2 equiv.). The resulting red-brown solution was heated to 65 °C,
and the reaction was carried out for 24 h. After cooling to room
temperature, the reaction mixture was quenched by the addition of
aqueous HCl (2 n, 20 mL) and then stirred at room temperature
for 5 min. The resulting mixture was then basified by the addition
of aqueous saturated sodium hydrogen carbonate solution (20 mL)
and then extracted with ethyl acetate (4ϫ 50 mL). The combined
organic layers were dried with anhydrous magnesium sulfate and
filtered, and the solvent was removed in vacuo. The yellow residue
was purified on a silica column (ethyl acetate) to give the target
6-(Piperazin-1-yl)-3,4-dihydro-1H-quinolin-2-one (7a):[4a] 6-(4-Benz-
ylpiperazin-1-yl)-3,4-dihydro-1H-quinolin-2-one (3.21 g, 10 mmol),
10 wt.-% palladium on carbon (1.64 g, 10% Pd), and methanol
(10 mL) were added to a Parr reactor. The reactor was purged with
dry N2 (3ϫ) and then H2 (3ϫ). The H2 pressure was then adjusted
to 10 bar, and the reaction mixture heated to 70 °C for 4 h. The
reactor was cooled to room temperature, and the resulting mixture
was filtered through a plug of Celite. The filtrate was evaporated
in vacuo to dryness to give a residue, which was purified by column
chromatography on silica gel (EtOAc/MeOH, 1:1) to give product
7a (2.19 g, 95%) as a pale yellow solid. IR (film): ν = 1668.6,
˜
1508.8, 1375.4, 1234.5, 949.0, 850.2, 824.4, 666.3 cm–1. 1H NMR
(400 MHz, CD3OD): δ = 7.7 (s, 1 H), 7.07–6.17 (m, 3 H), 3.17–
2.98 (m, 8 H), 2.92 (dd, J = 8.5, 6.5 Hz, 4 H), 2.60 (dd, J = 8.5,
6.5 Hz, 1 H), 1.78 (s, 1 H) ppm. 13C NMR (101 MHz, CD3OD): δ
= 171.5, 148.3, 130.5, 124.7, 116.6, 116.1, 115.7, 51.4, 46.3, 31.0,
26.1 ppm. HRMS (ESI-TOF): calcd. for C13H18N3O [M + H]+
232.1450; found 232.1450.
product 6b (3.66 g, 80%) as a yellow solid. IR (film): ν = 1654.3,
˜
1515.6, 1224.2, 825.3, 749.8, 694.9 cm–1. 1H NMR (400 MHz,
CDCl3): δ = 7.46–7.13 (m, 7 H), 7.05 (s, 1 H), 6.87 (d, J = 9.0 Hz,
2 H), 3.58 (s, 2 H), 3.37–2.97 (m, 4 H), 2.84–2.40 (m, 4 H), 2.14 (s,
3 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 168.2, 148.6, 137.9,
130.4, 129.4, 128.4, 127.3, 121.6, 116.8, 63.2, 53.2, 49.7, 24.5 ppm.
HRMS (ESI-TOF): calcd. for C19H24N3O [M + H]+ 310.1919;
found 310.1920.
Alternative Debenzylation Procedure: Debenzylation was also
carried out in an H-Cube hydrogenation reactor (from Thales
NanoTM) using a 10 wt.-% Pd/C Catcart column. First, the H-Cube
reactor was purged with MeOH for 20 min at a rate of 1.0 mL/
min. A solution of 6a (200 mg, 0.62 mmol) in MeOH (200 mL) was
passed through the system (1.0 mL/min) by using full H2 mode (ca.
10 bar) at 70 °C. The reaction mixture was set at circulation mode
overnight and monitored by TLC. The final reaction mixture was
collected, and the solvent was removed under vacuum to give a
residue, which was purified on a short silica gel column to give the
product (143.8 mg, quantitative yield).
6-(4-Benzylpiperazin-1-yl)-3,4-dihydro-1H-quinolin-2-one (6a):[4a] 6-
Bromo-3,4-dihydro-1H-quinolin-2-one (2.911 g, 12.9 mmol), tris-
(dibenzylideneacetone)dipalladium (119 mg, 0.1 mmol, 2.0 mol-%
Pd), and DavePhos (122 mg, 0.24 mmol, 2.4 mol-%) were added to
a Schlenk tube, which was evacuated and refilled with Ar (3ϫ). N-
benzylpiperazine (2.75 mL, 15.5 mmol, 1.2 equiv.) was then added
by syringe followed by LNTMS2 (1.06 m in THF, 28.5 mL,
28.5 mmol, 2.2 equiv.). The red-brown solution was then heated to
65 °C, and the reaction was carried out for 24 h. After cooling to
room temperature, the reaction mixture was quenched by the ad-
dition of aqueous HCl (2 n, 20 mL) and then stirred at room tem-
perature for 5 min. The resulting mixture was then basified by the
addition of aqueous saturated sodium hydrogen carbonate solution
(20 mL) and then extracted with ethyl acetate (4ϫ 50 mL). The
General Procedure for the Aminocarbonylation of Piperazines and
Aryl Bromide: Piperazine (0.5 mmol), anhydrous potassium carb-
onate (138 mg, 1.0 mmol, 2.0 equiv.), DPEPhos (5.4 mg,
0.01 mmol, 2.0 mol-%), 1 wt.-% Pd/ZIF-8 (24.0 mg, 0.45 mol-% of
Pd), and the aryl bromide (0.7 mmol, 1.4 equiv.) were added to a
Parr reactor followed by the addition of dry dioxane (6.5 mL). The
Eur. J. Org. Chem. 2014, 7405–7412
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7409

Y. Y. See, T. T. Dang, A. Chen, A. M. Seayad
FULL PAPER
reactor was then closed and purged with dry N2 (3ϫ) and then CO
(3ϫ). The CO pressure was then adjusted to 10 bar, and the reac-
tion was carried out at 120 °C for 18 h. Upon completion of the
reaction, the reactor was cooled to room temperature and then
purged with N2 (3ϫ). The solvent was removed under vacuum to
give a residue, which was loaded onto a silica gel column (ethyl
acetate or 5% MeOH in DCM) to give the pure product.
6.77 (m, 1 H), 6.69 (d, J = 8.4 Hz, 1 H), 3.79 (s, 4 H), 3.14 (t, J =
5.1 Hz, 4 H), 2.94 (dd, J = 8.5, 6.5 Hz, 2 H), 2.65–2.57 (m, 2
H) ppm. 13C NMR (101 MHz, CDCl3): δ = 171.7, 168.21 (d, J =
1.8 Hz), 151.4 (dd, J = 250, 10 Hz), 150.3 (dd, J = 250, 10 Hz),
146.9, 132.4 (t, J = 4.7 Hz), 131.7, 124.8, 123.9 (dd, J = 6.7,
3.9 Hz), 117.7 (d, J = 17.7 Hz), 117.5, 117.1 (d, J = 18.4 Hz), 116.6,
116.4, 50.8, 47.7, 42.6, 30.8, 25.9 ppm. HRMS (ESI-TOF): calcd.
for C20H19F2N3O2 [M + H]+ 372.1524; found 372.1520.
General Procedure for the Aminocarbonylation of Piperazines and
Aryl Iodide: Piperazine (0.5 mmol), anhydrous potassium carb-
onate (138 mg, 1.0 mmol, 2.0 equiv.), 1 wt.-% Pd/ZIF-8 (24.0 mg,
0.45 mol-% of Pd), and the aryl iodide (0.7 mmol, 1.4 equiv.) were
added to a Parr reactor followed by the addition of dry dioxane
(6.5 mL). The reactor was then closed and purged with dry N2 (3ϫ)
and then CO (3ϫ). The CO pressure was then adjusted to 10 bar,
and the reaction was conducted at 120 °C for 18 h. Upon comple-
tion of the reaction, the reactor was cooled to room temperature
and purged with N2 (3ϫ). The solvent was removed under vacuum
to give a residue, which was was loaded onto a silica gel column
(ethyl acetate or 5% MeOH in DCM) to give the product.
Methyl 4-[4-(2-Oxo-1,2,3,4-tetrahydroquinolin-6-yl)piperazine-1-
carbonyl]benzoate (1e): Following the general procedure and start-
ing from 6-(piperazin-1-yl)-3,4-dihydro-1H-quinolin-2-one
(0.5 mmol) and methyl 4-bromobenzoate (0.7 mmol) afforded com-
pound 1e (194.5 mg, 99%) as a white solid. IR (film): ν = 1725.8,
˜
1673.9, 1620.3, 1509.6, 1440.9, 1276.3, 1246.1, 835.6, 764.7, 749.9,
1
732.7 cm–1. H NMR (400 MHz, CDCl3, 60 °C): δ = 8.53 (br. s, 1
H), 8.11 (tt, J = 3.4, 1.5 Hz, 2 H), 7.64 (dq, J = 7.9, 1.8 Hz, 1 H),
7.56–7.47 (m, 1 H), 6.81–6.71 (m, 2 H), 3.93–3.48 (br. s, 4 H), 3.13
(br. s, 4 H), 2.91 (dd, J = 8.6, 6.4 Hz, 2 H), 2.61 (dd, J = 8.6,
6.4 Hz, 2 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 171.5, 169.5,
166.4, 136.0, 131.7, 131.1, 130.7, 129.0, 128.3, 124.9, 117.6, 116.6,
116.3, 52.5, 50.9, 47.8, 42.3, 30.8, 26.0 ppm. HRMS (ESI-TOF):
calcd. for C22H23N3O4 [M + H]+ 394.1761; found 394.1757.
Vesnarinone (1a):[4a] Following the general procedure and starting
from 6-(piperazin-1-yl)-3,4-dihydro-1H-quinolin-2-one (0.5 mmol)
and 4-bromoveratrole (0.7 mmol) afforded compound 1a
1
(158.0 mg, 80%) as a white solid. H NMR (400 MHz, CDCl3): δ
4-[4-(2-Oxo-1,2,3,4-tetrahydroquinolin-6-yl)piperazine-1-carbonyl]-
benzonitrile (1f): Following the general procedure and starting from
6-(piperazin-1-yl)-3,4-dihydro-1H-quinolin-2-one (0.5 mmol) and
4-bromobenzonitrile (0.7 mmol) afforded compound 1f (171.7 mg,
= 8.86 (s, 1 H), 7.06–6.94 (m, 2 H), 6.92–6.65 (m, 1 H), 3.89 (s, 3
H), 3.88 (s, 3 H), 3.84–3.74 (m, 4 H), 3.12 (br. s, 2 H), 2.91 (dd, J
= 8.2, 6.8 Hz, 1 H), 2.59 (m, 1 H) ppm. 13C NMR (101 MHz,
CDCl3): δ = 171.6, 170.4, 150.7, 149.2, 146.9, 131.7, 127.8, 124.8,
120.4, 117.5, 116.6, 116.3, 111.2, 110.7, 56.14, 56.11, 51.0, 30.8,
25.9 ppm.
95%) as a pale yellow solid. IR (film): ν = 1667.6, 1636.3, 1507.9,
˜
1434.7, 1388.8, 1235.4, 1018.3, 848.2, 762.8 cm–1 1H NMR
.
(400 MHz, CDCl3, 60 °C): δ = 8.17 (br. s, 1 H), 7.78–7.71 (m, 2
H), 7.57–7.50 (m, 2 H), 6.84–6.74 (m, 2 H), 6.71 (d, J = 8.4 Hz, 1
H), 3.25–4.12 (br. m, 4 H), 3.13 (br. m, 4 H), 2.92 (dd, J = 8.5,
6.5 Hz, 2 H), 2.71–2.40 (m, 1 H) ppm. 13C NMR (101 MHz,
CDCl3): δ = 171.6, 168.4, 147.0, 140.1, 132.6, 131.6, 127.9, 124.8,
118.1, 117.5, 116.6, 116.3, 113.9, 50.8, 47.7, 42.5, 30.8, 26.0 ppm.
HRMS (ESI-TOF): calcd. for C21H21N4O2 [M + H]+ 361.1659;
found 361.1660.
6-[4-(4-Methoxybenzoyl)piperazin-1-yl]-3,4-dihydroquinolin-2(1H)-
one (1b): Following the general procedure and starting from 6-
(piperazin-1-yl)-3,4-dihydro-1H-quinolin-2-one (0.5 mmol) and 1-
bromo-4-methoxybenzene (0.7 mmol) afforded compound 1b
(65.8 mg, 36 %) as a white solid. IR (film): ν = 1660.9, 1514.3,
˜
1233.8, 1225.9, 1136.8, 816.5, 731.9, 695.5 cm–1 1H NMR
.
(400 MHz, CDCl3): δ = 7.42 (d, J = 8.5 Hz, 2 H), 6.93 (d, J =
8.7 Hz, 2 H), 6.81 (m, 2 H), 6.72 (m, 1 H), 3.84 (s, 3 H), 3.82 (br.
s, 4 H), 3.14 (br. s, 4 H), 2.93 (dd, J = 8.5, 6.5 Hz, 1 H), 2.61 (dd,
J = 8.5, 6.5 Hz, 1 H) ppm. 13C NMR (101 MHz, CDCl3): δ =
171.4, 170.6, 161.1, 147.0, 131.7, 129.4, 127.7, 124.9, 117.6, 116.6,
116.2, 114.0, 55.5, 51.3, 30.8, 29.8, 26.0 ppm. HRMS (ESI-TOF):
calcd. for C21H24N3O3 [M]+ 366.1818; found 366.1803.
6-{4-[4-(Trifluoromethyl)benzoyl]piperazin-1-yl}-3,4-dihydroquin-
olin-2(1H)-one (1g): Following the general procedure and starting
from 6-(piperazin-1-yl)-3,4-dihydro-1H-quinolin-2-one and 1-
bromo-3-(trifluoromethyl)benzene afforded compound 1g
(185.2 mg, 92 %) as a pale yellow solid. IR (film): ν = 1670.1,
˜
1637.7, 1509.3, 1423.9, 1331.9, 1239.1, 1165.7, 1113.5, 811.2 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.47 (br. s, 1 H), 7.74–7.68 (m,
2 H), 7.66–7.54 (m, 2 H), 6.79 (br. m, 2 H), 6.74 (d, J = 8.3 Hz, 1
H), 3.77 (br. m, 4 H), 3.26–3.04 (m, 4 H), 2.93 (dd, J = 8.5, 6.6 Hz,
1 H), 2.61 (dd, J = 8.5, 6.5 Hz, 1 H) ppm. 13C NMR (101 MHz,
CDCl3): δ = 171.3, 168.8, 146.3, 136.3, 131.2 (q, J = 33 Hz), 130.4,
129.2, 126.7 (q, J = 3 Hz), 124.8, 124.1 (q, J = 4 Hz), 123.6 (q, J
= 271 Hz), 117.6, 116.6, 116.1, 50.8, 47.7, 42.1, 30.7, 25.8 ppm.
HRMS (ESI-TOF): calcd. for C21H21F3N3O2 [M + H]+ 404.1586;
found 404.1588.
6-[4-(2,3-Dihydro-1,4-benzodioxine-6-carbonyl)piperazin-1-yl]-
1,2,3,4-tetrahydroquinolin-2-one (1c): Following the general pro-
cedure and starting from 6-(piperazin-1-yl)-3,4-dihydro-1H-quin-
olin-2-one (0.5 mmol) and 6-iodo-2,3-dihydro-1,4-benzodioxine
(0.7 mmol) afforded compound 1c (177.0 mg, 90%) as a white so-
lid. IR (film): ν = 1671.9, 1628.8, 1508.5, 1436.9, 1286.6, 1066.8,
˜
1
889.9, 730.5 cm–1. H NMR (400 MHz, CDCl3): δ = 8.21 (br. s, 1
H), 7.02–6.66 (m, 6 H), 4.27 (s, 4 H), 3.79 (br. s, 4 H), 3.12 (br. s,
4 H), 2.93 (dd, J = 8.5, 6.5 Hz, 1 H), 2.69–2.49 (m, 1 H) ppm. 13C
NMR (101 MHz, CDCl3): δ = 171.3, 170.1, 145.3, 143.6, 128.7,
124.9, 120.9, 118.0, 117.5, 116.83, 117.0, 116.6, 116.2, 64.6, 64.5,
51.0, 30.8, 26.0 ppm. HRMS (ESI-TOF): calcd. for C22H24N3O4
[M + H]+ 394.1761; found 394.1759.
6-(4-Nicotinoylpiperazin-1-yl)-3,4-dihydroquinolin-2(1H)-one (1h):
Following the general procedure and starting from 6-(piperazin-1-
yl)-3,4-dihydro-1H-quinolin-2-one (0.5 mmol) and 3-bromopyr-
idine (0.7 mmol) afforded compound 1h (147.8 mg, 88%) as a pale
6-[4-(3,4-Difluorobenzoyl)piperazin-1-yl]-3,4-dihydro-1H-quinolin-2-
one (1d): Following the general procedure and starting from 6-
yellow solid. IR (film): ν = 1673.9, 1636.2, 1512.7, 1440.8, 1239.5,
˜
1012.2, 708.2 cm–1. 1H NMR (400 MHz, CDCl3): δ = 8.70 (m, 2
(piperazin-1-yl)-3,4-dihydro-1H-quinolin-2-one (0.5 mmol) and 4- H), 8.48 (br. s, 1 H), 7.80 (dt, J = 7.8, 1.9 Hz, 1 H), 7.46–7.32 (m,
bromo-1,2-difluorobenzene (0.7 mmol) afforded compound 1d
(135.8 mg, 73%) as a white solid. IR (film): ν = 1669.9, 1649.5,
1 H), 6.89–6.59 (m, 3 H), 4.21–3.25 (br. m, 4 H), 3.12 (m, 4 H),
2.93 (dd, J = 8.5, 6.5 Hz, 1 H), 2.61 (dd, J = 8.5, 6.6 Hz, 1 H) ppm.
˜
1508.4, 1420.7, 1294.1, 1193.1, 832.4, 751.1 cm–1 1H NMR 13C NMR (101 MHz, CDCl3): δ = 171.4, 167.9, 151.1, 148.1, 146.9,
.
(400 MHz, CDCl3): δ = 7.71 (s, 1 H), 7.34–7.16 (m, 3 H), 6.87– 135.3, 131.7, 131.6, 124.9, 123.7, 117.6, 116.6, 116.3, 50.8, 47.7,
7410
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 7405–7412

Concise Synthesis of Vesnarinone and Its Analogues
42.3, 30.8, 26.0 ppm. HRMS (ESI-TOF): calcd. for C19H21N4O2
[M + H]+ 337.1659; found 337.1659.
(s, 3 H), 3.91 (s, 3 H), 3.81 (br. s, 4 H), 3.16 (br. s, 4 H), 2.13 (s, 3
H) ppm. 13C NMR (101 MHz, CDCl3): δ = 170.5, 168.4, 150.8,
149.3, 127.8, 121.6, 120.4, 117.9, 111.2, 110.8, 56.2, 56.1, 50.9,
24.5 ppm. HRMS (ESI-TOF): calcd. for C21H26N3O4 [M + H]+
384.1918; found 394.1902.
6-[4-(6-Methoxynicotinoyl)piperazin-1-yl]-3,4-dihydroquinolin-
2(1H)-one (1i): Following the general procedure and starting from
6-(piperazin-1-yl)-3,4-dihydro-1H-quinolin-2-one (0.5 mmol) and
5-bromo-2-methoxypyridine (0.7 mmol) afforded compound 1i
N-{4-[4-(3,4,5-Trimethoxybenzoyl)piperazin-1-yl]phenyl}acetamide
(1n): Following the general procedure and starting from N-[4-(pip-
erazin-1-yl)phenyl]acetamide (0.5 mmol) and 5-iodo-1,2,3-tri-
methoxybenzene (0.7 mmol) afforded compound 1n (136.3 mg,
(159.2 mg, 87%) as a white solid. IR (film): ν = 1667.6, 1616.8,
˜
1600.6, 1500.3, 1427.5, 1373.3, 1293.6, 1238.8, 1021.3, 848.9 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.85 (br. s, 1 H), 8.29 (dd, J =
2.5, 0.8 Hz, 1 H), 7.69 (dd, J = 8.6, 2.4 Hz, 1 H), 6.91–6.58 (m, 4
H), 3.96 (s, 3 H), 3.78 (dd, J = 5.8, 3.6 Hz, 4 H), 3.12 (m, 4 H),
2.92 (dd, J = 8.5, 6.5 Hz, 1 H), 2.71–2.51 (m, 1 H) ppm. 13C NMR
(101 MHz, CDCl3): δ = 171.7, 168.4, 165.1, 146.9, 146.5, 138.4,
131.7, 124.8, 124.4, 117.5, 116.6, 116.3, 111.1, 53.9, 50.9, 30.8,
26.0 ppm. HRMS (ESI-TOF): calcd. for C20H23N4O3 [M + H]+
367.1765; found 367.1759.
66%) as a pale yellow solid. IR (film): ν = 1655.4, 1614.8, 1518.3,
˜
1
1434.9, 1269.6, 1145.3, 816.2 cm–1. H NMR (400 MHz, CDCl3):
δ = 7, 80 (br. s, 1 H), 7.39 (d, J = 9.0 Hz, 1 H), 6.89 (d, J = 9.0 Hz,
1 H), 6.653 (s, 2 H), 3.85 (s, 3 H), 3.84 (s, 6 H), 3.79–3.68 (m, 4
H), 3.13 (m, 4 H), 2.09 (s, 3 H) ppm. 13C NMR (101 MHz, CDCl3):
δ = 170.3, 168.6, 153.5, 147.1, 139.5, 132.1, 130.8, 121.6, 117.6,
104.6, 61.0, 56.4, 50.6, 24.3 ppm. HRMS (ESI-TOF): calcd. for
C22H28N3O5 [M + H]+ 414.2029; found 414.2023.
6-[4-(Pyrimidine-5-carbonyl)piperazin-1-yl]-3,4-dihydroquinolin-
2(1H)-one (1j): Following the general procedure and starting from
6-(piperazin-1-yl)-3,4-dihydro-1H-quinolin-2-one (0.5 mmol) and
5-bromopyrimidine (0.7 mmol) afforded compound 1j (146.6 mg,
N-{4-[4-(2,3-Dihydro-1,4-benzodioxine-6-carbonyl)piperazin-1-
yl]phenyl}acetamide (1o): Following the general procedure and
starting from N-[4-(piperazin-1-yl)phenyl]acetamide (0.5 mmol)
and 6-iodo-2,3-dihydro-1,4-benzodioxine (0.7 mmol) afforded com-
87%) as a white solid. IR (film): ν = 1672.9, 1636.8, 1509.3, 1403.5,
˜
1
1293.6, 1240.8, 847.1, 629.7 cm–1. H NMR (400 MHz, CDCl3): δ
pound 1o (177.7 mg, 93%) as a white solid. IR (film): ν = 1655.2,
˜
1625.8, 1604.1, 1509.1, 1431.7, 1294.6, 1065.9, 824.9 cm–1. 1H
NMR (400 MHz, CDCl3): δ = 7.77 (br. s, 1 H), 7.39 (d, J = 8.7 Hz,
1 H), 6.99–6.83 (m, 5 H), 4.26 (m, 4 H), 3.77 (br. s, 4 H), 3.11 (br.
s, 4 H), 2.10 (s, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 170.1,
168.6, 147.1, 145.3, 143.5, 132.2, 128.5, 121.6, 120.9, 117.7, 117.4,
116.9, 64.6, 64.4, 50.6, 24.3 ppm. HRMS (ESI-TOF): calcd. for
C21H24N3O4 [M + H]+ 382.1767; found 382.1778.
= 9.30 (s, 1 H), 8.85 (s, 2 H), 8.03 (s, 1 H), 6.85 (m, 2 H), 6.72 (d,
J = 8.4 Hz, 1 H), 4.26–3.48 (br. m, 4 H), 3.17 (br. s, 4 H), 2.94 (dd, J
= 8.6, 6.4 Hz, 2 H), 2.66–2.57 (m, 2 H) ppm. 13C NMR (101 MHz,
CDCl3): δ = 171.1, 165.3, 159.7, 155.7, 131.8, 129.6, 125.0, 117.8,
116.8, 116.2, 50.9, 30.8, 26.0 ppm. HRMS (ESI-TOF): calcd. for
C18H20N5O2 [M + H]+ 338.1612; found 338.1607.
6-[4-(4-Bromobenzoyl)piperazin-1-yl]-3,4-dihydro-1H-quinolin-2-one
(1k): Following the general procedure and starting from 6-(piper-
azin-1-yl)-3,4-dihydro-1H-quinolin-2-one (0.5 mmol) and 1-bromo-
4-iodobenzene (0.7 mmol) afforded compound 1k (142.2 mg, 69%)
N-{4-[4-(3,4-Difluorobenzoyl)piperazin-1-yl]phenyl}acetamide (1p):
Following the general procedure and starting from N-[4-(piperazin-
1-yl)phenyl]acetamide and 4-bromo-1,2-difluorobenzene afforded
as a white solid. IR (film): ν = 1666.6, 1641.5, 1507.9, 1434.2,
˜
compound 1p (154.4 mg, 86%) as a white solid. IR (film): ν =
˜
1
1234.1, 1009.9, 862.0 cm–1. H NMR (400 MHz, CDCl3): δ = 8.29
1659.7, 1630.7, 1604.3, 1517.3, 1442.9, 1314.8, 1296.6, 1022.6,
(s, 1 H), 7.58 (d, J = 8.6 Hz, 2 H), 7.33 (d, J = 8.5 Hz, 2 H), 6.87
(m, 2 H), 6.74 (d, J = 8.5 Hz, 1 H), 3.82 (m, 4 H), 3.14 (br. m, 4
H), 2.94 (dd, J = 8.6, 6.5 Hz, 2 H), 2.61 (dd, J = 8.5, 6.6 Hz, 2
H) ppm. 13C NMR (101 MHz, CDCl3): δ = 171.3, 169.5, 134.3,
132.0, 129.0, 125.0, 124.5, 118.0, 116.9, 116.3, 31.3, 30.8, 26.0 ppm.
HRMS (ESI-TOF): calcd. for C20H21BrN3O2 [M + H]+ 414.0812;
found 414.0804.
1
825.4, 748.4 cm–1. H NMR (400 MHz, CDCl3): δ = 7.43 (d, J =
8.5 Hz, 1 H), 7.39–7.15 (m, 4 H), 6.95 (br. m, 2 H), 3.81 (br. s, 4 H),
3.17 (br. s, 4 H), 2.15 (s, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ
= 168.4, 168.3 (d, J = 1.8 Hz), 151.6 (dd, J = 250, 10 Hz), 150.5
(dd, J = 250, 10 Hz), 146.8, 132.3 (t, J = 4.7 Hz), 124.0 (dd, J =
6.7, 4.0 Hz), 121.6, 118.1, 117.9, 117.8, (d, J = 18.4 Hz), 117.2 (d,
J = 18.5 Hz), 50.9, 24.5 ppm. HRMS (ESI-TOF): calcd. for
C19H20F2N3O2 [M + H]+ 360.1518; found 360.1512.
6-{4-[4-(Methylthio)benzoyl]piperazin-1-yl}-3,4-dihydroquinolin-
2(1H)-one (1l): Following the general procedure and starting from
6-(piperazin-1-yl)-3,4-dihydro-1H-quinolin-2-one (0.5 mmol) and 4
(4-bromophenyl)(methyl)sulfane (0.7 mmol) afforded compound 1l
Supporting Information (see footnote on the first page of this arti-
1
cle): H and 13C NMR spectra for all compounds.
(177.2 mg, 93 %) as a pale yellow solid. IR (film): ν = 1668.9,
˜
1625.7, 1508.4, 1427.0, 1235.6, 1191.5, 829.1 cm–1 1H NMR
.
Acknowledgments
(400 MHz, CDCl3): δ = 8.6 (br. s, 1 H), 7.39 (d, J = 8.3 Hz, 1 H),
7.29 (d, J = 7.1 Hz, 1 H), 7.29 (m, 2 H), 6.77 (d, J = 8.3 Hz, 1 H),
3.83 (s, 4 H), 2.95 (dd, J = 8.5, 6.6 Hz, 2 H), 2.63 (dd, J = 8.5,
6.5 Hz, 1 H), 2.51 (s, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ
= 171.5, 170.2, 141.7, 131.7, 130.4, 128.0, 125.96, 126.0, 125.1,
124.9, 117.7, 116.7, 116.3, 51.1, 47.1, 42.1, 30.8, 25.9, 15.4 ppm.
HRMS (ESI-TOF): calcd. for C21H23SN3O2 [M + H]+ 382.1584;
found 382.1580.
This work was funded by the GSK (GlaxoSmithKline)–EDB
(Economic Development Board) Singapore Partnership for Green
and Sustainable Manufacturing (GSM) and the Institute of Chemi-
cal and Engineering Sciences (ICES), Agency for Science, Technol-
ogy, and Research (A*STAR), Singapore.
[1] a) E. Cavusoglu, W. H. Frishman, M. Klapholz, J. Card. Fail.
1995, 1, 249; b) A. M. Feldman, M. R. Bristow, W. W. Parm-
Ley, P. E. Carson, C. J. Pepine, E. M. Gilberg, J. E. Strobeck,
G. H. Hendrix, E. R. Powers, R. P. Bain, B. G. White, N. Engl.
J. Med. 1993, 329, 149; c) J. N. Cohn, S. O. Goldstein, B. H.
Greenberg, B. H. Lorell, R. C. Bourge, B. E. Jaski, S. O.
Gottlied, F. McGrew, D. L. DeMets, B. G. White, N. Engl. J.
Med. 1998, 339, 1810; d) A. Matsumori, T. Shioi, T. Yamada,
N-{4-[4-(3,4-Dimethoxybenzoyl)piperazin-1-yl]phenyl}acetamide
(1m): Following the general procedure and starting from N-[4-(pip-
erazin-1-yl)phenyl]acetamide and 4-bromoveratrole afforded com-
pound 1m (149.4 mg, 76%) as a white solid. IR (film): ν = 1655.0,
˜
1613.4, 1517.6, 1427.2, 1268.6, 1144.9, 1015.1, 816.4, 770.1 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.41 (d, J = 8.5 Hz, 2 H), 7.05–
6.97 (m, 2 H), 6.97–6.90 (m, 1 H), 6.88 (d, J = 8.8 Hz, 1 H), 3.92
Eur. J. Org. Chem. 2014, 7405–7412
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7411

Y. Y. See, T. T. Dang, A. Chen, A. M. Seayad
FULL PAPER
S. Matsui, S. Sasayama, Circulation 1994, 89, 955; e) K. Ka-
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Received: August 7, 2014
Published Online: October 14, 2014
C. L. Allen, J. M. J. Williams, Chem. Soc. Rev. 2011, 40, 3405;
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