Microwave-Assisted Cyclization under Mildly Basic Conditions

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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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The Journal of Organic Chemistry

Microwave-Assisted Cyclization under Mildly Basic Conditions: Synthesis of 6HBenzo[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*,† †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 6Hbenzo[c]chromen-6-ones and their 7,8,9,10-tetrahydro-analogs, respectively, in 50-72% yields. Aryl 3bromoacrylates 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 6Hbenzo[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-2carboxylic 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 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 2halobenzaldehydes 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-10methylacridinium 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 2arylphenols 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 6Hbenzo[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 2


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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. Scheme 1. Various Synthetic Methods for 6H-Benzo[c]chromen-6-ones

Treatment of phenyl 2-bromobenzoate (1a) in dimethylformamide at 120 oC for 0.5 h in the presence of K2CO3 (5 equiv) under microwave irradiation (100 W of initial power) afforded 6Hbenzo[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 3



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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 method (screw-capped vial, 120 oC 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 1a a

entry

base (mmol)

temp. (oC)

time (h)

yieldb (%)

1

K2CO3 (1.5)

120

0.5

19

2

K2CO3 (1.5)

120

1

26

3

K2CO3 (1.5)

120

2

45

4

K2CO3 (1.5)

120

3

46

5

K2CO3 (1.5)

150

2

45

6

K2CO3 (2.1)

120

2

52

7

K2CO3 (3)

120

2

64 4


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8

K2CO3 (3)

120

0.5

39

9

K3PO4 (3)

120

2

28

10

Cs2CO3 (3)

120

2

31

t

11

NaO Bu (3)

120

2

0

12

-

120

2

0

13c

K2CO3 (3)

120

24

15

d

K2CO3 (3)

120

2

63

K2CO3 (3)

120

2

57

14

15d,e a

Reaction conditions: 1a (0.3 mmol), DMF (3 mL), under

microwave irradiation (100 W of initial power) and N 2, unless otherwise stated. bIsolated yield. cUnder 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 electrondonating and withdrawing substituents on O-attached aryl groups afforded the corresponding 6Hbenzo[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 2bromobenzoate 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-3carboxylate (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-1enecarboxylates 1l-t (Table 2). Similar treatment of phenyl 2-bromocyclohex-1-enecarboxylate (1l) 5



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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 2bromocyclohex-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 7,8,9,10tetrahydro-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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a

Reaction conditions: 1 (0.3 mmol), K2CO3 (3 mmol), DMF (3 mL),

120 oC, 2 h, under microwave irradiation (100 W initial power) and N 2.

Based on several similar precedents,24 the reaction pathway seems to proceed via an initial K2CO3induced 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 meta8


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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/endotrig 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

In conclusion, it has been shown that aryl 2-bromobenzoates, aryl 2-bromocyclohex-1enecarboxylates and phenyl 3-bromoacrylates trigger lactonization under microwave irradiation in the 10


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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. 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 capped, the reaction mixture was heated to 120 oC 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. 11



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6H-Benzo[c]chromen-6-one (2a).7d Rf = 0.42. White solid (38 mg, 64%). mp 93-94 oC. 1H 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. 2-Methyl-6H-benzo[c]chromen-6-one (2b).5,25 Rf = 0.40. White solid (36 mg, 57%). mp 121-123 C. 1H 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,

o

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. 1

H 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 = 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,

13

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. 1

H 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. 1

H 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. 12


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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. 1

H 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 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 56.3, 112.2, 114.2, 118.8, 121.3, 122.2, 124.2, 129.0, 130.6, 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. 1

H 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. 1

H 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 C. 1H 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,

o

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); C 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,

13

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 oC (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, 13



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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, 127.2, 127.3, 128.7, 129.6, 130.8, 132.1, 133.3, 136.5, 136.7, 151.7, 160.4. 8-Methoxy-6H-benzo[c]chromen-6-one (2j).5 Rf = 0.37. White solid (47 mg, 70%). mp 152-153 C. 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

o

Hz, 1H), 7.99 (dd, J = 7.9 and 1.5 Hz, 1H), 8.04 (d, J = 8.9 Hz, 1H); 13C 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. 1

H 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 117-119 oC. 1H 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, 1H);

13

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, 67%). mp 104-106 oC. 1H 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), 7.267.29 (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); C 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,

13

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 14


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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, 3H), 7.25-7.28 (m, 3H), 7.40-7.43 (m, 1H), 7.52 (dd, J = 7.9 and 1.3 Hz, 1H).

13

C NMR (125 MHz,

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, 146.8, 152.2, 161.6. HRMS (EI) calcd for C19H16O2 (M+) 276.1150, found 276.1151. 2-Methyl-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one (2o).27 Rf = 0.33. White solid (42 mg, 65%). mp 136-138 oC. 1H NMR (500 MHz, CDCl3) δ 1.70-1.81 (m, 4H), 2.33 (s, 3H), 2.49-2.52 (m, 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); 13C 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 (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);

13

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, 69%). mp 107-108 oC. 1H 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, 32%). mp 109-110 oC. 1H NMR (500 MHz, CDCl3) δ 1.78-1.89 (m, 4H), 2.43 (s, 3H), 2.57-2.60 (m, 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); 13C 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, 15



Page 16 of 21

152.1, 162.1. 1-Methyl-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one (2r’). Rf = 0.37. White solid (17 mg, 26%). mp 164-166 oC. 1H 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. 7,8-Dihydro-6H-naphtho[2,1-c]chromen-6-one (2s).28 Rf = 0.47. Viscous oil (45 mg, 61%). 1H 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, 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);

13

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), 7.237.25 (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. 1

H 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

16


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Supporting Information The Supporting Information is available free of charge on the ACS Publications website. Copies of 1H and

13

C NMR spectra of all products, COSY and NOESY NMR spectra of 2b and ICP-

AES data of K2CO3 (PDF). AUTHOR INFORMATION Corresponding Author * E-mail: [email protected] (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)

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The reaction with 1 mmol scale of 1a under the condition of entry 7 in Table 1 afforded 2a in similar yield (60%).

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ICP-AES analysis of commercial K2CO3 indicated no significant amount of transition metals, see the Supporting Information. 19



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COSY and NOESY NMR spectra for 2b are shown in the Supporting Information.

(19)

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.

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Microwave-Assisted Cyclization under Mildly Basic Conditions

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