Microwave-assisted cyclization under mildly basic conditions: Synthesis of 6 h -benzo [c] chromen-6-ones and their 7,8,9,10-tetrahydro analogues

Article abstract of DOI:10.1021/acs.joc.8b00048

Aryl 2-bromobenzoates and aryl 2-bromocyclohex-1-enecarboxylates are cyclized by microwave irradiation in dimethylformamide in the presence of K₂CO₃ to give the corresponding 6H-benzo[c]chromen-6-ones and their 7,8,9,10-tetrahydro analogues, respectively, in 50-72% yields. Aryl 3-bromoacrylates are also converted into 2H-chromen-2-ones under the employed conditions.

Full text of DOI:10.1021/acs.joc.8b00048

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Microwave-Assisted Cyclization under Mildly Basic Conditions: Synthesis
of 6H-Benzo[c]chromen-6-ones and Their 7,8,9,10-Tetrahydro-Analogs
Pham Duy Quang Dao, Son Long Ho, Ho-Jin Lim, and Chan Sik Cho
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00048 • Publication Date (Web): 22 Mar 2018
Downloaded from http://pubs.acs.org on March 22, 2018
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Microwave-Assisted Cyclization under Mildly Basic Conditions: Synthesis of 6H-
Benzo[c]chromen-6-ones and Their 7,8,9,10-Tetrahydro-Analogs
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Pham Duy Quang Dao,† Son Long Ho,† Ho-Jin Lim,‡ and Chan Sik Cho*,†
†Department of Applied Chemistry, Kyungpook National University, 80 Daehakro, Bukgu, Daegu
41566, Republic of Korea
‡Department of Environmental Engineering, Kyungpook National University, 80 Daehakro, Bukgu,
Daegu 41566, Republic of Korea
KEYWORDS: Cyclization, Heterocycles, Lactones, 6H-Benzo[c]chromen-6-ones, Radical
ABSTRACT: Aryl 2-bromobenzoates and aryl 2-bromocyclohex-1-enecarboxylates are cyclized by
microwave irradiation in dimethylformamide in the presence of K2CO3 to give the corresponding 6H-
benzo[c]chromen-6-ones and their 7,8,9,10-tetrahydro-analogs, respectively, in 50-72% yields. Aryl 3-
bromoacrylates are also converted into 2H-chromen-2-ones under the employed conditions.
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It is known that many naturally occurring 6H-benzo[c]chromen-6-ones exhibit diverse biological
activities.1,2 Thus, many synthetic methods have been developed and documented for such 6H-
benzo[c]chromen-6-ones due to limited quantities in natural sources.1 It is reported that such a scaffold
can be synthesized by copper(I) thiophene carboxylate (CuTC)-mediated lactonization of 2'-
halobiphenyl-2-carboxylic acids and Lewis acid-mediated lactonization of 2’-methoxybiphenyl-2-
carboxylic acids and methyl 2’-methoxybiphenyl-2-carboxylates (Scheme 1, route a).3,4 Deng et al. also
demonstrated palladium/copper-catalyzed decarboxylative coupling and cyclization of 2-nitrobenzoic
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acids with methyl 2-halobenzoates leading to 6H-benzo[c]chromen-6-ones (Scheme 1, route b).5 A
similar reaction is also exemplified by the palladium-catalyzed Suzuki-Miyaura cross-coupling of 2-
halobenzaldehydes and methyl 2-halobenzoates with 2-hydroxyarylboronic acids followed by
lactonization (Scheme 1, route c).6 Several groups also have shown that 2-arylbenzoic acids can be
converted into 6H-benzo[c]chromen-6-ones by carboxyl-directed C-H activation/C-O cyclization in the
presence of catalysts such as Pd, Cu, Ag, and iodine reagents as well as photocatalyst 9-mesityl-10-
methylacridinium perchlorate combined with (NH4)2S2O8 (Scheme 1, route d).7 Ray and co-workers
reported that 2-arylbenzaldehydes undergo aryl C-H oxidative lactonization in the presence of CuCl as
catalyst and tert-butyl hydroperoxide (TBHP) as oxidant to afford 6H-benzo[c]chromen-6-ones
(Scheme 1, route e).8 Such a similar lactonization through C-H activation was also shown by
palladium- and ruthenium-catalyzed carbonylation and cyclization (carbonylative cyclization) of 2-
arylphenols leading to 6H-benzo[c]chromen-6-ones (Scheme 1, route f).9 Palladium-catalyzed direct
oxidative coupling and annulation of benzoic acids with phenols was also reported to construct 6H-
benzo[c]chromen-6-ones (Scheme 1, route g).10 A classical Baeyer-Villiger oxidation of 9-fluorenone
also gives 6H-benzo[c]chromen-6-one (Scheme 1, route h).11 In connection with this reports, it is also
reported that 6H-benzo[c]chromen-6-ones can be synthesized by palladium-catalyzed intramolecular
biaryl coupling of aryl 2-halobenzoates (Scheme 1, route i).12 Besides the above mentioned synthetic
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methods, multicomponent and multistep protocols to construct such scaffold also have been
developed.13 These precedents, even though showing their individual advantages, have some drawbacks
such as requiring an expensive consumable transition metals to synthesize startings and products,
contamination of residual metals in startings and products, tedious procedures and using hazardous
carbon monoxide gas. During the course of our continuing studies directed toward developing novel
and efficient synthetic methods for heterocycles,14 this report describes transition metal free
microwave-assisted lactonization of aryl 2-bromobenzoates in the presence of a weak base leading to
6H-benzo[c]chromen-6-ones.
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Scheme 1. Various Synthetic Methods for 6H-Benzo[c]chromen-6-ones
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Treatment of phenyl 2-bromobenzoate (1a) in dimethylformamide at 120 C for 0.5 h in the
presence of K2CO3 (5 equiv) under microwave irradiation (100 W of initial power) afforded 6H-
benzo[c]chromen-6-one (2a) in 19% yield with incomplete conversion of 1a (Table 1, entry 1). The
yield of 2a increases on prolonging the reaction time up to 2 h, however, the starting 1a still remained
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(Table 1, entries 2-4). Higher reaction temperature did not affect the yield of 2a (Table 1, entry 5).
Performing the reaction under the increased amount of K2CO3 up to 10 equiv. to 1a resulted in a
considerably increased yield of 2a along with complete conversion of 1a (Table 1, entries 6 and 7).15 It
is unclear why such a large excess of base is needed for the effective formation of 2a. Here again,
lower yield along with incomplete conversion of 1a was observed under shorter reaction time (Table 1,
entry 8). The reaction also proceeded with other bases such as K3PO4 and Cs2CO3, but the yields of 2a
were generally lower than that obtained in the presence of K2CO3 (Table 1, entries 9 and 10). However,
the reaction did not proceed at all in the presence of NaOtBu or in the absence of base, and the starting
1a was recovered almost completely (Table 1, entries 11 and 12).16 Treatment of 1a under usual heating
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method (screw-capped vial, 120 C for 24 h) afforded 2a in only 15% yield (Table 1, entry 13). It is
known that transition metal-free cross-coupling of aryl iodides with arenes was accelerated by the
addition of a diamine ligand.17 However, treatment of phenyl 2-iodobenzoate under the employed
conditions afforded 2a in similar yields irrespective of the addition of N,N’-dimethylethylenediamine
(DMEDA) (Table 1, entries 14 and 15).
Table 1. Optimization of Conditions for the Reaction of 1aa
entry
base (mmol)
temp. (oC) time (h)
yieldb (%)
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K2CO3 (1.5)
K2CO3 (1.5)
K2CO3 (1.5)
K2CO3 (1.5)
K2CO3 (1.5)
K2CO3 (2.1)
K2CO3 (3)
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0.5
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K2CO3 (3)
K3PO4 (3)
Cs2CO3 (3)
NaOtBu (3)
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120
0.5
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K2CO3 (3)
K2CO3 (3)
K2CO3 (3)
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aReaction conditions: 1a (0.3 mmol), DMF (3 mL), under
microwave irradiation (100 W of initial power) and N2, unless
b
c
otherwise stated. Isolated yield. Under usual heating (screw-capped
vial). dPhenyl 2-iodobenzoate was used in place of 1a. eN,N’-
dimethylethylenediamine (0.06 mmol) was further added.
Various aryl 2-bromobenzoates 1a-k were subjected to the reaction under the optimized reaction
conditions in order to investigate the scope of the reaction, and several representative results are
summarized in Table 2. Performing the reaction with aryl 2-bromobenzoates 1b-g having electron-
donating and withdrawing substituents on O-attached aryl groups afforded the corresponding 6H-
benzo[c]chromen-6-ones 2b-g in 51-68% yields without identifiable byproducts by ester hydrolysis.18
The product yield was not significantly affected by the position of the substituent, whereas the
electronic nature of that had a somewhat relevance to the product yield. Lower reaction rates and yields
were observed with 1c and 1f having electron-donating methoxy group. With meta-substituted aryl 2-
bromobenzoate 1h, the corresponding product was obtained as regioisomers (2h and 2h’) in similar
yield, favoring the cyclization of less sterically hindered position.19 The cyclization of benzo-fused and
methoxy-substituted phenyl 2-bromobenzoates (1i and 1j) also proceeded to give the corresponding
6H-benzo[c]chromen-6-ones (2i and 2j) in similar yields. Treatment of phenyl 2-bromopyridine-3-
carboxylate (1k) under the employed conditions also afforded 5H-chromeno[4,3-b]pyridin-5-one (2k)
in 60% yield. The present protocol can be extended to the reaction with aryl 2-bromocyclohex-1-
enecarboxylates 1l-t (Table 2). Similar treatment of phenyl 2-bromocyclohex-1-enecarboxylate (1l)
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under the same conditions afforded 7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one (2l) in 72% yield.
Phenyl 2-bromocyclohex-1-enecarboxylates (1m and 1n) having methyl- and phenyl-substituents on
cyclohexene ring were also cyclized to give the corresponding 7,8,9,10-tetrahydro-6H-
benzo[c]chromen-6-ones (2m and 2n) in similar yields, irrespective of such substituents. Aryl 2-
bromocyclohex-1-enecarboxylates 1o-q having methyl- and chloro-substituents on aryl groups also
afforded the corresponding 7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-ones 2o-q in 65-69% yields. As
is the case for the reaction with 1h, the cyclization of m-tolyl 2-bromocyclohex-1-enecarboxylate (1r)
proceeded with similar regioselective pattern.19 For testing the effect of the position of bromide and
carbophenoxy groups on benzo-fused phenyl 2-bromocyclohex-1-enecarboxylates, 1s and 1t were
employed. Even though the cyclization took place irrespective of the position, in the reaction with 1s,
2i was formed by dehydrogenation of 11,12-dihydronaphtho[1,2-c]chromen-5-one initially formed by
the cyclization of 1s under the employed conditions.20 Dehydrogenation of the starting 1s prior to
cyclization also could not be excluded. Such a similar dehydrogenation was observed by our recent
reports on copper-catalyzed coupling and cyclization reactions.14a,21 It is known that 7,8,9,10-
tetrahydro-6H-benzo[c]chromen-6-ones, analogs of 6H-benzo[c]chromen-6-ones, exhibit biological
activities such as cholinesterase inhibitors, atypical antipsychotics, and steroid sulfatase inhibitors.22
Similar treatment of phenyl 3-bromoacrylates (1u and 1v) under the employed conditions also afforded
2H-chromen-2-ones (2t and 2u), however, the product yield was lower than that when previously
described aryl 2-bromobenzoates and aryl 2-bromocyclohex-1-enecarboxylates were used. A variety of
synthetic methods and a fascinating array of pharmacological properties for 2H-chromen-2-one
(coumarin)-containing compounds are well-documented.23 The reaction with benzyl 2-bromobenzoate
under the employed conditions did not proceed at all toward cyclization and the starting was recovered
almost completely (96%).
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Table 2. Scope of Cyclization Reactiona
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aReaction conditions: 1 (0.3 mmol), K2CO3 (3 mmol), DMF (3 mL),
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120 C, 2 h, under microwave irradiation (100 W initial power) and
N2.
Based on several similar precedents,24 the reaction pathway seems to proceed via an initial K2CO3-
induced generation of an aryl radical 3 from para-substituted 1 by single-electron transfer prior to
homolytic aromatic substitution (Scheme 2). Intermediate radical 3 triggers preferential 6-exo/endo-trig
radical cyclization to produce a cyclohexadienyl radical 4, which is deprotonated by K2CO3 to form an
anionic radical 5. This is followed by transfer of an electron to the starting to give product 6 along with
radical 3 and KBr (Scheme 2, route a). An alternative initial 5-exo-trig ipso cyclization to form a
spirocyclohexadienyl radical 7 followed by a concerted ring expansion and subsequent deprotonation
and radical chain transfer produces an isomer 10 (Scheme 2, route b). However, no isomer 10 was
detected from the reaction with para-substituted 1. The reaction pathways for ortho- and meta-
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substituted 1, consistent with the products formed, are also shown in Scheme 2. Intermediate radicals A
and B initially formed by such single-electron transfer are also preferentially cyclized in 6-exo/endo-
trig fashion to give the corresponding products. We confirmed in a separate experiment that the
reaction of 1a under the condition of the entry 7 of Table 1 with further addition of radical scavenger,
2,6-di-tert-butyl-4-methylphenol, TEMPO or galvinoxyl (equimolar amount to 1a) caused the
cyclization to slow down (5-9% yield of 2a). These results indicate that the present reaction seems to
proceed via radical pathway.
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Scheme 2. Reaction Pathway
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In conclusion, it has been shown that aryl 2-bromobenzoates, aryl 2-bromocyclohex-1-
enecarboxylates and phenyl 3-bromoacrylates trigger lactonization under microwave irradiation in the
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presence of potassium carbonate to form the corresponding 6H-benzo[c]chromen-6-ones and their
7,8,9,10-tetrahydro-analogs and 2H-chromen-2-ones, respectively. The present reaction provides an
environmentally benign synthetic method for such scaffolds from readily available starting compounds
compared with known protocols. Further divergent synthetic application for heterocycles using such
metal-free microwave-assisted cyclization is currently under investigation.
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EXPERIMENTAL SECTION
General Information. 1H and 13C NMR spectra were recorded at 500 and 125 MHz, respectively,
in CDCl3. Melting points were determined on a microscopic melting point apparatus. High-resolution
mass data were recorded using electronic ionization (HRMS-EI, magnetic sector-electric sector double
focusing mass analyzer) at the Korea Basic Science Center, Daegu, Korea. All microwave reactions
(CEM, Discover LabMate) were carried out in sealed tube (5 mL) and maintenance of the reaction
temperature was monitored by an external infrared sensor. The isolation of pure products was carried
out via thin-layer (a glass plate coated with Kieselgel 60 GF254, Merck) chromatography. All starting
esters were prepared by one-pot initial conversion of the corresponding carboxylic acids to acid
chlorides using thionyl chloride followed by treatment with phenols.12e All other reagents were
purchased from commercial sources and used without further purification.
General Procedure for the Synthesis of 2. A 5 mL microwave reaction tube was charged with 1
(0.3 mmol) with K2CO3 (0.415 g, 3.0 mmol), and DMF (3 mL). After the tube was flushed with N2 and
o
capped, the reaction mixture was heated to 120 C for 2 h by microwave irradiation at 100 W initial
power. The mixture was then cooled to room temperature and filtered through a short silica gel column
(ethyl acetate) to remove inorganic components. Removal of the solvent left a crude mixture, which
was separated by TLC (hexane/ethyl acetate = 10/1) to give 2. All products were characterized
spectroscopically as shown below.
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6H-Benzo[c]chromen-6-one (2a).7d Rf = 0.42. White solid (38 mg, 64%). mp 93-94 C. H NMR
(500 MHz, CDCl3) δ 7.32-7.37 (m, 2H), 7.46-7.50 (m, 1H), 7.57-7.60 (m, 1H), 7.81-7.84 (m, 1H), 8.06
(dd, J = 8.0 and 1.5 Hz, 1H), 8.12 (d, J = 8.1 Hz, 1H), 8.39-8.41 (m, 1H); 13C NMR (125 MHz, CDCl3)
δ 117.8, 118.0, 121.3, 121.7, 122.8, 124.5, 128.9, 130.4, 130.6, 134.7, 134.8, 151.3, 161.2.
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2-Methyl-6H-benzo[c]chromen-6-one (2b).5,25 Rf = 0.40. White solid (36 mg, 57%). mp 121-123
oC. H NMR (500 MHz, CDCl3) δ 2.45 (s, 3H), 7.22-7.27 (m, 2H), 7.54-7.57 (m, 1H), 7.78-7.84 (m,
1
2H), 8.08 (d, J = 8.1 Hz, 1H), 8.38 (dd, J = 8.0 and 1.0 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 21.1,
117.5, 117.6, 121.3, 121.6, 122.7, 128.7, 130.5, 131.3, 134.1, 134.7, 134.8, 149.3, 161.3.
2-Methoxy-6H-benzo[c]chromen-6-one (2c).5 Rf = 0.27. White solid (35 mg, 51%). mp 118-120 oC.
1H NMR (500 MHz, CDCl3) δ 3.90 (s, 3H), 7.03 (dd, J = 9.0 and 2.9 Hz, 1H), 7.27 (d, J = 9.0 Hz, 1H),
7.45 (d, J = 2.9 Hz, 1H), 7.55-7.59 (m, 1H), 7.79-7.82 (m, 1H), 8.03 (d, J = 8.1 Hz, 1H), 8.38 (dd, J =
13
8.0 and 1.0 Hz, 1H); C NMR (125 MHz, CDCl3) δ 55.8, 106.3, 117.1, 118.5, 118.6, 121.3, 121.7,
128.9, 130.6, 134.6, 134.7, 145.6, 156.3, 161.3.
2-Chloro-6H-benzo[c]chromen-6-one (2d).5 Rf = 0.45. White solid (47 mg, 68%). mp 180-181 oC.
1H NMR (500 MHz, CDCl3) δ 7.31 (d, J = 8.8 Hz, 1H), 7.43 (dd, J = 8.8 Hz and 2.4 Hz, 1H), 7.62-7.65
(m, 1H), 8.01 (d, J = 2.4 Hz, 1H), 8.06 (d, J = 8.1 Hz, 1H), 8.41 (dd, J = 8.0 and 1.0 Hz, 1H); 13C NMR
(125 MHz, CDCl3) δ 119.2, 119.4, 121.3, 121.8, 122.6, 129.6, 130.1, 130.4, 130.8, 133.6, 135.1, 149.7,
160.6.
4-Methyl-6H-benzo[c]chromen-6-one (2e).5 Rf = 0.48. White solid (38 mg, 61%). mp 120-122 oC.
1H NMR (500 MHz, CDCl3) δ 2.49 (s, 3H), 7.22 (t, J = 7.7 Hz, 1H), 7.31-7.33 (m, 1H), 7.55-7.58 (m,
1H), 7.79-7.82 (m, 1H), 7.88-7.90 (m, 1H), 8.10 (d, J = 8.1 Hz, 1H), 8.39-8.41 (m, 1H); 13C NMR (125
MHz, CDCl3) δ 16.0, 117.7, 120.4, 121.1, 121.9, 124.0, 127.0, 128.6, 130.5, 131.8, 134.7, 135.1, 149.6,
161.2.
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4-Methoxy-6H-benzo[c]chromen-6-one (2f). Rf = 0.30. White solid (37 mg, 54%). mp 134-136 oC.
1H NMR (500 MHz, CDCl3) δ 3.99 (s, 3H), 7.05 (dd, J = 8.1 and 1.2 Hz, 1H), 7.26-7.29 (m, 1H), 7.58-
7.61 (m, 1H), 7.65 (dd, J = 8.2 and 1.1 Hz, 1H), 7.81-7.85 (m, 1H), 8.12 (d, J = 8.1 Hz, 1H), 8.42-8.44
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(m, 1H); C NMR (125 MHz, CDCl3) δ 56.3, 112.2, 114.2, 118.8, 121.3, 122.2, 124.2, 129.0, 130.6,
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134.8, 135.0, 141.1, 148.1, 160.6. HRMS (EI) calcd for C14H10O3 (M+) 226.0630, found 226.0627.
4-Chloro-6H-benzo[c]chromen-6-one (2g). Rf = 0.35. White solid (45 mg, 65%). mp 144-146 oC.
1H NMR (500 MHz, CDCl3) δ 7.28 (t, J = 8.0 Hz, 1H), 7.55 (dd, J = 7.9 and 1.4 Hz, 1H), 7.61-7.64 (m,
1H), 7.84-7.87 (m, 1H), 7.97 (dd, J = 8.1 and 1.3 Hz, 1H), 8.12 (d, J = 8.1 Hz, 1H), 8.42 (dd, J = 8.0
and 1.0 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 119.6, 121.1, 121.2, 122.0, 122.7, 124.5, 129.5, 130.7,
130.9, 134.2, 135.1, 147.1, 160.0. HRMS (EI) calcd for C13H7ClO2 (M+) 230.0135, found 230.0132.
3-Methyl-6H-benzo[c]chromen-6-one (2h).7a Rf = 0.43. White solid (21 mg, 33%). mp 124-125 oC.
1H NMR (500 MHz, CDCl3) δ 2.46 (s, 3H), 7.16-7.18 (m, 1H), 7.19 (s, 1H), 7.56-7.58 (m, 1H), 7.80-
7.82 (m, 1H), 7.95 (d, J = 8.1 Hz, 1H), 8.10 (d, J = 8.1 Hz, 1H), 8.40 (dd, J = 7.9 and 1.0 Hz, 1H); 13C
NMR (125 MHz, CDCl3) δ 21.5, 115.5, 117.9, 120.9, 121.5, 122.5, 125.7, 128.4, 130.6, 134.8, 135.0,
141.3, 151.3, 161.5.
1-Methyl-6H-benzo[c]chromen-6-one (2h’).7e Rf = 0.43. White solid (17 mg, 26%). mp 176-178
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oC. H NMR (500 MHz, CDCl3) δ 2.91 (s, 3H), 7.18-7.19 (m, 1H), 7.28-7.30 (m, 1H), 7.35-7.39 (m,
1H), 7.59-7.63 (m, 1H), 7.83-7.86 (m, 1H), 8.41 (d, J = 8.4 Hz, 1H), 8.51 (dd, J = 7.9 and 1.4 Hz, 1H);
13C NMR (125 MHz, CDCl3) δ 25.6, 116.3, 117.6, 122.2, 126.2, 128.1, 128.9, 129.3, 130.9, 134.3,
136.1, 136.2, 152.3, 161.3.
5H-Naphtho[1,2-c]chromen-5-one (2i).6b Rf = 0.40. White solid (49 mg, 67%). mp 188-189 C
o
(lit.--- mp 191 oC). 1H NMR (500 MHz, CDCl3) δ 7.35-7.39 (m, 1H), 7.41-7.43 (m, 1H), 7.51-7.55 (m,
1H), 7.61-7.65 (m, 1H), 7.75-7.78 (m, 1H), 7.90-7.92 (m, 1H), 8.15-8.18 (m, 2H), 8.22 (d, J = 8.8 Hz,
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1H), 9.80 (d, J = 8.3 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 115.2, 117.2, 118.2, 118.8, 123.5, 124.3,
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127.2, 127.3, 128.7, 129.6, 130.8, 132.1, 133.3, 136.5, 136.7, 151.7, 160.4.
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8-Methoxy-6H-benzo[c]chromen-6-one (2j).5 Rf = 0.37. White solid (47 mg, 70%). mp 152-153
oC. 1H NMR (500 MHz, CDCl3) δ 3.94 (s, 3H), 7.31-7.37 (m, 2H), 7.39-7.45 (m, 2H), 7.82 (d, J = 2.8
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Hz, 1H), 7.99 (dd, J = 7.9 and 1.5 Hz, 1H), 8.04 (d, J = 8.9 Hz, 1H); C NMR (125 MHz, CDCl3) δ
55.8, 111.2, 117.6, 118.2, 122.2, 122.5, 123.4, 124.3, 124.6, 128.2, 129.3, 150.5, 160.1, 161.3.
5H-Chromeno[4,3-b]pyridin-5-one (2k).6a,26 Rf = 0.38. White solid (45 mg, 60%). mp 165-166 oC.
1H NMR (500 MHz, CDCl3) δ 7.25-7.29 (m, 1H), 7.36-7.39 (m, 2H), 7.51-7.54 (m, 1H), 7.73 (dd, J =
7.7 and 2.0 Hz, 1H), 7.96 (d, J = 8.1 Hz, 1H), 8.43-8.44 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 118.6,
118.8, 122.0, 122.5, 123.5, 125.3, 129.7, 131.2, 131.3, 135.6, 152.1, 161.9.
7,8,9,10-Tetrahydro-6H-benzo[c]chromen-6-one (2l).7d Rf = 0.37. White solid (44 mg, 72%). mp
o
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117-119 C. H NMR (500 MHz, CDCl3) δ 1.79-1.90 (m, 4H), 2.58-2.61 (m, 2H), 2.78-2.80 (m, 2H),
7.25-7.29 (m, 1H), 7.31 (dd, J = 8.3 and 0.9 Hz, 1H), 7.44-7.47 (m, 1H), 7.56 (dd, J = 7.9 and 1.3 Hz,
13
1H); C NMR (125 MHz, CDCl3) δ 21.4, 21.6, 24.1, 25.2, 116.7, 120.2, 123.1, 123.8, 124.0, 130.2,
147.0, 152.0, 161.7.
8-Methyl-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one (2m). Rf = 0.47. White solid (43 mg,
o
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67%). mp 104-106 C. H NMR (500 MHz, CDCl3) δ 1.12 (d, J = 6.6 Hz, 3H), 1.39-1.47 (m, 1H),
1.78-1.88 (m, 1H), 1.98-2.03 (m, 1H), 2.07-2.14 (m, 1H), 2.70-2.84 (m, 2H), 2.93-2.97 (m, 1H), 7.26-
7.29 (m, 1H), 7.32 (dd, J = 8.2 and 1.0 Hz, 1H), 7.44-7.48 (m, 1H), 7.57 (dd, J = 8.0 and 1.4 Hz, 1H);
13C NMR (125 MHz, CDCl3) δ 21.3, 25.3, 27.9, 29.4, 32.3, 116.8, 120.1, 123.3, 123.4, 124.0, 130.3,
146.7, 152.0, 161.8. HRMS (EI) calcd for C14H14O2 (M+) 214.0994, found 214.0996.
8-Phenyl-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one (2n). Rf = 0.38. White solid (52 mg,
62%). mp 122-123 oC. 1H NMR (500 MHz, CDCl3) δ 1.84-1.93 (m, 1H), 2.17-2.23 (m, 1H), 2.52-2.59
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(m, 1H), 2.77-2.83 (m, 1H), 2.85-2.90 (m, 1H), 2.92-3.02 (m, 2H), 7.16-7.19 (m, 1H), 7.20-7.24 (m,
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3H), 7.25-7.28 (m, 3H), 7.40-7.43 (m, 1H), 7.52 (dd, J = 7.9 and 1.3 Hz, 1H). C NMR (125 MHz,
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CDCl3) δ 25.9, 28.6, 31.7, 39.2, 117.0, 120.1, 123.4, 123.5, 124.2, 126.7, 126.9, 128.7, 130.6, 145.1,
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146.8, 152.2, 161.6. HRMS (EI) calcd for C19H16O2 (M+) 276.1150, found 276.1151.
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2-Methyl-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one (2o).27 Rf = 0.33. White solid (42 mg,
o
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65%). mp 136-138 C. H NMR (500 MHz, CDCl3) δ 1.70-1.81 (m, 4H), 2.33 (s, 3H), 2.49-2.52 (m,
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2H), 2.68-2.71 (m, 2H), 7.11 (d, J = 8.4 Hz, 1H), 7.17 (dd, J = 8.4 and 1.6 Hz, 1H), 7.26 (s, 1H); C
NMR (125 MHz, CDCl3) δ 21.1, 21.4, 21.6, 24.1, 25.2, 116.4, 119.9, 123.1, 123.6, 131.2, 133.5, 146.9,
150.1, 162.0.
2-Chloro-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one (2p). Rf = 0.38. White solid (48 mg,
69%). mp 132-134 oC. 1H NMR (500 MHz, CDCl3) δ 1.80-1.91 (m, 4H), 2.59-2.61 (m, 2H), 2.74-2.76
13
(m, 2H), 7.26 (d, J = 8.1 Hz, 1H), 7.41 (dd, J = 8.8 and 2.3 Hz, 1H), 7.53 (d, J = 2.3 Hz, 1H); C
NMR (125 MHz, CDCl3) δ 21.2, 21.4, 24.2, 25.1, 118.1, 121.4, 122.9, 125.1, 129.5, 130.2, 146.0,
150.4, 161.2. HRMS (EI) calcd for C13H11ClO2 (M+) 234.0448, found 234.0445.
4-Methyl-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one (2q). Rf = 0.42. White solid (45 mg,
o
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69%). mp 107-108 C. H NMR (500 MHz, CDCl3) δ 1.73-1.82 (m, 4H), 2.38 (s, 3H), 2.51-2.54 (m,
2H), 2.70-2.73 (m, 2H), 7.09 (t, J = 7.7 Hz, 1H), 7.23 (d, J = 7.3 Hz, 1H), 7.33 (d, J = 7.9 Hz, 1H); 13C
NMR (125 MHz, CDCl3) δ 15.7, 21.5, 21.6, 24.1, 25.3, 119.9, 120.8, 123.4, 123.5, 126.0, 131.6, 147.3,
150.4, 161.9. HRMS (EI) calcd for C14H14O2 (M+) 214.0994, found 214.0994.
3-Methyl-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one (2r).27 Rf = 0.37. White solid (21 mg,
o
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32%). mp 109-110 C. H NMR (500 MHz, CDCl3) δ 1.78-1.89 (m, 4H), 2.43 (s, 3H), 2.57-2.60 (m,
13
2H), 2.76-2.79 (m, 2H), 7.08 (dd, J = 8.1 and 1.0 Hz, 1H), 7.12 (s, 1H), 7.44 (d, J = 8.1 Hz, 1H); C
NMR (125 MHz, CDCl3) δ 21.4, 21.5, 21.7, 24.0, 25.2, 116.9, 117.8, 122.6, 122.9, 125.1, 141.1, 147.1,
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1-Methyl-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one (2r’). Rf = 0.37. White solid (17 mg,
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9
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26%). mp 164-166 C. H NMR (500 MHz, CDCl3) δ 1.77-1.82 (m, 4H), 2.61-2.63 (m, 2H), 2.72 (s,
3H), 2.99-3.02 (m, 2H), 7.03 (dd, J = 7.5 and 0.6 Hz, 1H), 7.17 (dd, J = 8.2 and 0.8 Hz, 1H), 7.26-7.30
(m, 1H); 13C NMR (125 MHz, CDCl3) δ 20.9, 22.5, 25.0, 25.2, 30.9, 115.7, 120.1, 124.0, 128.6, 129.4,
135.8, 149.7, 153.0, 161.4. HRMS (EI) calcd for C14H14O2 (M+) 214.0994, found 214.0996.
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7,8-Dihydro-6H-naphtho[2,1-c]chromen-6-one (2s).28 Rf = 0.47. Viscous oil (45 mg, 61%). H
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NMR (500 MHz, CDCl3) δ 2.75-2.78 (m, 2H), 2.82-2.85 (m, 2H), 7.28-7.32 (m, 1H), 7.36-7.43 (m,
13
4H), 7.50-7.53 (m, 1H), 7.83 (d, J = 7.7 Hz, 1H), 8.04 (dd, J = 8.1 and 1.4 Hz, 1H); C NMR (125
MHz, CDCl3) δ 22.2, 28.1, 117.5, 117.6, 123.9, 124.2, 126.3, 126.4, 128.0, 128.5, 130.1, 130.3, 130.5,
140.1, 144.4, 153.4, 161.7.
3-Methyl-4-phenyl-2H-chromen-2-one (2t). Rf = 0.52. White solid (35 mg, 50%). mp 96-98 oC. 1H
NMR (500 MHz, CDCl3) δ 2.00 (s, 3H), 7.01 (dd, J = 8.0 and 1.5 Hz, 1H), 7.12-7.15 (m, 1H), 7.23-
7.25 (m, 2H), 7.37 (dd, J = 8.3 and 1.1 Hz, 1H), 7.44-7.51 (m, 2H), 7.52-7.55 (m, 2H); 13C NMR (125
MHz, CDCl3) δ 14.7, 116.6, 120.7, 122.9, 124.0, 127.0, 128.4, 128.7, 128.9, 130.5, 134.9, 150.6, 152.5,
162.4. HRMS (EI) calcd for C16H12O2 (M+) 236.0837, found 236.0835.
3,4-Diphenyl-2H-chromen-2-one (2u). Rf = 0.50. Pale yellow solid (48 mg, 54%). mp 218-220 oC.
1H NMR (500 MHz, CDCl3) δ 7.12-7.14 (m, 4H), 7.17-7.19 (m, 3H), 7.20-7.24 (m, 2H), 7.29-7.32 (m,
3H), 7.43-7.45 (m, 1H), 7.52-7.55 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 116.8, 120.6, 124.2, 127.0,
127.7, 127.78, 127.83, 128.3, 128.4, 129.4, 130.6, 131.5, 133.9, 134.5, 151.6, 153.3, 161.3. HRMS (EI)
calcd for C21H14O2 (M+) 298.0994, found 298.0992.
ASSOCIATED CONTENT
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Supporting Information
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The Supporting Information is available free of charge on the ACS Publications website.
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Copies of H and C NMR spectra of all products, COSY and NOESY NMR spectra of 2b and ICP-
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AES data of K2CO3 (PDF).
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AUTHOR INFORMATION
Corresponding Author
* E-mail: cscho@knu.ac.kr (C.S.C.).
ORCID
Pham Duy Quang Dao: 0000-0002-2537-1874
Chan Sik Cho: 0000-0001-6416-174
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This research was supported by the National Strategic Project-Fine Particle of the National Research
Foundation of Korea (NRF) funded by the Ministry of Science and ICT (MSIT), the Ministry of
Environment (ME), and the Ministry of Health and Welfare (MOHW) (2017M3D8A1090658).
REFERENCES
(1)
(a) Garazd, Ya. L.; Garazd, M. M. Chem. Nat. Compd. 2016, 52, 1. (b) Mazimba, O. Turk. J.
Chem. 2016, 40, 1.
(2)
(a) Demuner, A. J.; Barbosa, L. C. A.; Miranda, A. C. M.; Geraldo, G. C.; da Silva, C. M.;
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Giberti, S.; Bertazzini, M.; Forlani, G. J. Nat. Prod. 2013, 76, 2234. (b) Sun, W.; Cama, L. D.;
Birzin, E. T.; Warrier, S.; Locco, L.; Mosley, R.; Hammond, M. L.; Rohrer, S. P. Bioorg. Med.
Chem. Lett. 2006, 16, 1468. (c) Garino, C.; Bihel, F.; Pietrancosta, N.; Laras, Y.; Quéléver, G.;
Woo, I.; Klein, P.; Bain, J.; Boucher, J.-L.; Kraus, J.-L. Bioorg. Med. Chem. Lett. 2005, 15,
135.
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(3)
(4)
(a) Thasana, N.; Worayuthakarn, R.; Kradanrat, P.; Hohn, E.; Young, L.; Ruchirawat, S. J. Org.
Chem. 2007, 72, 9379. (b) Ceylan, S.; Klande, T.; Vogt, C.; Friese, C.; Kirschning, A. Synlett
2010, 2009.
(a) Koch, K.; Podlech, J.; Pfeiffer, E.; Metzler, M. J. Org. Chem. 2005, 70, 3275. (b) Hussain,
I.; Nguyen, V. T. H.; Yawer, M. A.; Dang, T. T.; Fischer, C.; Reinke, H.; Langer, P. J. Org.
Chem. 2007, 72, 6255.
(5)
(6)
Luo, J.; Lu, Y.; Liu, S.; Liu, J.; Deng, G.-J. Adv. Synth. Catal. 2011, 353, 2604.
(a) Vishnumurthy, K.; Makriyannis, A. J. Comb. Chem. 2010, 12, 664. (b) Singha, R.; Roy, S.;
Nandi, S.; Ray, P.; Ray, J. K. Tetrahedron Lett. 2013, 54, 657.
(7)
(a) Dai, J.-J.; Xu, W.-T.; Wu, Y.-D.; Zhang, W.-M.; Gong, Y.; He, X.-P.; Zhang, X.-Q.; Xu, H.-
J. J. Org. Chem. 2015, 80, 911. (b) Wang, X.; Gallardo-Donaire, J.; Martin, R. Angew. Chem.
Int. Ed. 2014, 53, 11084. (c) Wang, Y.; Gulevich, A. V.; Gevorgyan, V. Chem. Eur. J. 2013, 19,
15836. (d) Gallardo-Donaire, J.; Martin, R. J. Am. Chem. Soc. 2013, 135, 9350. (e) Li, Y.;
Ding, Y.-J.; Wang, J.-Y.; Su, Y.-M.; Wang, X.-S. Org. Lett. 2013, 15, 2574. (f) Furuyama, S.;
Togo, H. Synlett 2010, 2325. (g) Togo, H.; Muraki, T.; Yokoyama, M. Tetrahedron Lett. 1995,
36, 7089. (h) Ramirez, N. P.; Bosque, I.; Gonzalez-Gomez, J. C. Org. Lett. 2015, 17, 4550.
(8)
Singha, R.; Dhara, S.; Ghosh, M.; Ray, J. K. RSC Adv. 2015, 5, 8801.
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(9)
(a) He, Y.; Zhang, X.; Fan, X. Chem. Commun. 2014, 50, 14968. (b) Lee, T.-H.; Jayakumar, J.;
Cheng, C.-H.; Chuang, S.-C. Chem. Commun. 2013, 49, 11797. (c) Luo, S.; Luo, F.-X.; Zhang,
X.-S.; Shi, Z.-J. Angew. Chem. Int. Ed. 2013, 52, 10598. (d) Inamoto, K.; Kadokawa, J.;
Kondo, Y. Org. Lett. 2013, 15, 3962.
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(11)
(12)
Wang, Y.; Gu, J.-Y.; Shi, Z.-J. Org. Lett. 2017, 19, 1326.
Mehta, G.; Pandey, P. N. Synthesis 1975, 404.
(a) Sun, C.-L.; Liu, J.; Wang, Y.; Zhou, X.; Li, B.-J.; Shi, Z.-J. Synlett 2011, 883. (b) Taylor, S.
R.; Ung, A. T.; Pyne, S. G. Tetrahedron 2007, 63, 10889. (c) Abe, H.; Nishioka, K.; Takeda, S.;
Arai, M.; Takeuchi, Y.; Harayama, T. Tetrahedron Lett. 2005, 46, 3197. (d) Bringmann, G.;
Menche, D. Angew. Chem. Int. Ed. 2001, 40, 1687. (e) Bringmann, G.; Pabst, T.; Henschel, P.;
Kraus, J.; Peters, K.; Peters, E.-M.; Rycroft, D. S.; Connolly, J. D. J. Am. Chem. Soc. 2000,
122, 9127. (f) Harayama, T.; Yasuda, H. Heterocycles 1997, 46, 61.
(13)
(a) Nandaluru, P. R.; Bodwell, G. J. Org. Lett. 2012, 14, 310. (b) Alzaydi, K. M.; Abojabal, N.
S.; Elnagdi, M. H. Tetrahedron Lett. 2016, 57, 3596. (c) Ortiz Villamizar, M. C.; Zubkov, F. I.;
Puerto Galvis, C. E.; Vargas Mendez, L. Y.; Kouznetsov, V. V. Org. Chem. Front. 2017, 4,
1736.
(14)
(15)
(16)
(a) Dao, P. D. Q.; Lee, H. K.; Sohn, H.-S.; Yoon, N. S.; Cho, C. S. ACS Omega 2017, 2, 2953.
(b) Ho, S. L.; Dao, P. D. Q.; Cho, C. S. Synlett 2017, 28, 1811.
The reaction with 1 mmol scale of 1a under the condition of entry 7 in Table 1 afforded 2a in
similar yield (60%).
ICP-AES analysis of commercial K2CO3 indicated no significant amount of transition metals,
see the Supporting Information.
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2
3
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(17)
(a) Shirakawa, E.; Itoh, K.-I.; Higashino, T.; Hayashi, T. J. Am. Chem. Soc. 2010, 132, 15537.
(b) Zhang, L.; Yang, H.; Jiao, L. J. Am. Chem. Soc. 2016, 138, 7151.
5
6
7
8
9
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COSY and NOESY NMR spectra for 2b are shown in the Supporting Information.
The regioisomers were separated by HPLC with an isocratic elution of 80% MeOH in water.
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A reviewer suggested that the deprotonation product would be formed by similar treatment of
1t under stronger basic conditions along with a ligand. However, as is the case for 1a shown in
entry 11 of Table 1, the reaction of 1t under KOtBu and 1,10-phenanthroline (10 mol% to 1t)
as ligand did not proceed at all toward cyclization.
(21)
(22)
(a) Yang, B. W.; Ho, S. L.; Lim, H.-J.; Cho, C. S. J. Organomet. Chem. 2016, 806, 83. (b) Ho,
S. L.; Yoon, I. C.; Cho, C. S.; Choi, H.-J. J. Organomet. Chem. 2015, 791, 13.
(a) Demkowicz, S.; Kozak, W.; Dasko, M.; Mastyk, M.; Gielniewski, B.; Rachon, J. Eur. J.
Med. Chem. 2015, 101, 358. (b) Gulcan, H. O.; Unlu, S.; Esiringu, I, Ercetin, T.; Sahin, Y.; Oz,
D.; Sahin, M. F. Bioorg. Med. Chem. 2014, 22, 5141. (c) Chen, Y.; Lan, Y.; Wang, S.; Zhang,
H.; Xu, X.; Liu, X.; Yu, M.; Liu, B.-F.; Zhang, G. Eur. J. Med. Chem. 2014, 74, 427. (d) Kozak,
W.; Dasko, M.; Mastyk, M.; Pieczykolan, J. S.; Gielniewski, B.; Rachon, J.; Demkowicz, S.
RSC Adv. 2014, 4, 44350.
(23)
(24)
(a) Hu, Y.-Q.; Xu, Z.; Zhang, S.; Wu, X.; Ding, J.-W.; Lv, Z.-S.; Feng, L.-S. Eur. J. Med. Chem.
2017, 136, 122 and references cited therein. (b) Emami, S.; Dadashpour, S. Eur. J. Med. Chem.
2015, 102, 611. (c) Torres, F. C.; Brucker, N.; Andrade, S. F.; Kawano, D. F.; Garcia, S. C.;
von Poser, G. L.; Eifler-Lima, V. L. Curr. Top. Med. Chem. 2014, 14, 2600.
(a) Bhakuni, B. S.; Kumar, A.; Balkrishna, S. J.; Sheikh, J. A.; Konar, S.; Kumar, S. Org. Lett.
2012, 14, 2838. (b) Roman, D. S.; Takahashi, Y.; Charette, A. B. Org. Lett. 2011, 13, 3242. (c)
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1
2
3
4
5
6
7
8
Studer, A.; Curran, D. P. Angew. Chem. Int. Ed. 2011, 50, 5018. (d) Sun, C.-L.; Gu, Y.-F.;
Huang, W.-P.; Shi, Z.-J. Chem. Commun. 2011, 47, 9813. (e) Bajracharya, G. B.; Daugulis, O.
Org. Lett. 2008, 10, 4625.
9
(25)
(26)
(27)
Pal, R. S.; Sharma, R. P.; Bokadia, M. M. J. Ind. Chem. Soc. 1975, 52, 983.
Fritz, E.; Egmont, B.; Hermann, L. Liebigs Ann. Chem. 1983, 2, 165.
10
11
12
13
14
15
16
17
18
19
20
21
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27
28
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47
48
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51
52
53
54
55
56
57
58
59
60
Sawada, K.; Hirai, H.; Golden, P.; Okada, S.; Sawada, Y.; Hashimoto, M.; Tanaka, H. Chem.
Pharm. Bull. 1998, 46, 1683.
(28)
Jianxin, G.; Mary, J. H.; Carl, R. J. Tetrahedron Lett. 2002, 43, 1213.
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