CC BY ND NC 4.0 · SynOpen 2018; 02(02): 0105-0113
DOI: 10.1055/s-0036-1591977
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Copyright with the author

One-pot Synthesis of 2-Substituted 4H-Chromeno[3,4-d]oxazol-4-ones from 4-Hydroxy-3-nitrocoumarin and Acids in the Presence of Triphenylphosphine and Phosphorus Pentoxide under Microwave Irradiation

T. D. Balalas
Laboratory of Organic Chemistry, Department of Chemistry, Aristotle University of Thessaloniki, University Campus, Thessaloniki 54124, Greece   Email: klitinas@chem.auth.gr
,
G. Stratidis
Laboratory of Organic Chemistry, Department of Chemistry, Aristotle University of Thessaloniki, University Campus, Thessaloniki 54124, Greece   Email: klitinas@chem.auth.gr
,
D. Papatheodorou
Laboratory of Organic Chemistry, Department of Chemistry, Aristotle University of Thessaloniki, University Campus, Thessaloniki 54124, Greece   Email: klitinas@chem.auth.gr
,
E.-E. Vlachou
Laboratory of Organic Chemistry, Department of Chemistry, Aristotle University of Thessaloniki, University Campus, Thessaloniki 54124, Greece   Email: klitinas@chem.auth.gr
,
C. Gabriel
Center for Research of the Structure of Matter, Magnetic Resonance Laboratory, Department of Chemical Engineering, Aristotle University of Thessaloniki, University Campus, Thessaloniki 54124, Greece
,
D. J. Hadjipavlou-Litina
Department of Pharmaceutical Chemistry, School of Pharmacy, Aristotle University of Thessaloniki, Thessaloniki 54124, Greece
,
K. E. Litinas*
Laboratory of Organic Chemistry, Department of Chemistry, Aristotle University of Thessaloniki, University Campus, Thessaloniki 54124, Greece   Email: klitinas@chem.auth.gr
› Author Affiliations
Further Information

Publication History

Received: 31 January 2018

Accepted after revision: 13 March 2018

Publication Date:
17 April 2018 (online)

 

Abstract

2-Substituted 4H-chromeno[3,4-d]oxazol-4-ones are prepared from 4-hydroxy-3-nitrocoumarin and acids by one-pot reaction in the presence of PPh3 and P2O5 under microwave irradiation or by one-pot two-step reactions in the presence of Pd/C and hydrogen and then P2O5 under microwave irradiation. The fused oxazolocoumarins were also synthesized from 3-amido-4-hydroxycoumarins and P2O5 under microwave irradiation. The 3-amido-4-hydroxycoumarins are obtained almost quantitatively from 4-hydroxy-3-nitrocoumarin, acids and PPh3 under microwave irradiation, or in the presence of Pd/C and H2 on heating. Preliminary biological tests indicate significant inhibition of soybean lipoxygenase and antilipid peroxidation for both oxazolocoumarins and o-hydroxyamidocoumarins.


#

Coumarins are a class of compounds that are widely distributed in natural products and in synthetic biologically active derivatives[1] with interesting biological properties, such as anticoagulant, antibiotic, anti-inflammatory, anti-HIV, and anticancer activity. Fused coumarins are also biologically active agents. In particular, fused oxazolocoumarins have been examined for antibacterial,[2] anti-inflammatory,[2] [3] antimicrobial,[4] and photosensitizing[5] activities and as agonists/antagonists[6] of benzodiazepine receptors. Recently, such derivatives have been used as photolabile protecting groups, forming conjugates with active compounds as prodrugs, for the photorelease and controlled delivery of the active molecules.[7] 3-Acylamino-4-hydroxycoumarins and 3-amino-4-hydroxycoumarin, the usual precursors of oxazolocoumarins, also exhibit significant biological activities. They have been studied for their influence on the binding affinity and selectivity against adenosine receptors (Ars),[8] as anticoagulants,[9] as potent inhibitors of heat-shock protein 90 (hsp90),[10] for antibacterial and antifungal activities,[11] as well as for antitumor activity.[12]

Among the many reported methods for the synthesis of benzoxazoles and oxazoles, there are usually two approaches. One is the condensation of o-aminophenols[13] with aldehydes, orthoesters, acids, acid derivatives, alcohols or β-diketones catalyzed by metal derivatives. The other is the intramolecular cyclization of o-hydroxyamides,[14] or the metal-catalyzed cyclization of o-haloamides,[15] enamides,[16] and amides.[17] Benzoxazoles have also been prepared by a one-pot multistep procedure, from o-nitrophenols with alcohols in the presence of Au nanoparticles/TiO2,[18] Cu-Pd nanoparticles/γ-Al2O3,[19] with orthoesters and In as catalyst,[20] or with acetic anhydride and hydrogenation over Ni.[21]

Several methodologies are available for the synthesis of fused oxazolocoumarins. These have been prepared by condensation of o-aminohydroxycoumarins with aldehydes,[2] [4] [6] [12] [22] acids[6,22] or anhydrides,[2,12] or by condensation of o-amidohydroxycoumarins with anhydrides,[23] POCl3,[24] or P2O5.[25] 2-Methyl-4H-[l]benzopyrano[3,4-d]oxazol-4-one has also been formed by Beckmann rearrangement of the oxime of 3-acetyl-4-hydroxycoumarin,[26] by the reduction of 4-hydroxy-3-nitrosocoumarin in acetic anhydride in the presence of Pd/C,[26] or by heating 3-diazo-2,4-chromene­dione in CH3CN in the presence of Rh2(OAc)4 as catalyst.[27] Heating a mixture of 6-hydroxy-4-methyl-5-nitrocoumarin acetate with iron powder, CH3COONa, and (CH3CO)2O in CH3COOH leads to the corresponding oxazolocoumarin.[28] The formation of oxazolocoumarins has likewise been reported by the anodic oxidation[29] of 7-hydroxycoumarin in a solution of MeCN and LiClO4 and by condensation of 7-methoxyimino­-4-methylchromen-2,8-dione with methyl­arenes, or arylacetic esters.[30] Very recently, we have synthesized oxazolocoumarins by one-pot tandem reactions of o-hydroxynitrocoumarins with benzyl alcohol in toluene under catalysis with gold nanoparticles supported on TiO2, by FeCl3 or by silver nanoparticles supported on TiO2.[31]

Zoom Image
Scheme 1 Reagents and conditions: (i) 2 (2 mL, 0.5 M), PPh3 (3) (2.5 equiv), P2O5 (4 equiv), MW irradiation, 130 °C or 140 °C, 1.5 h (not for 4a); (ii)2 (2 mL, 0.5 M), 5 mole % Pd/C (10%), H2 1 atm, r.t., 1–3 h then P2O5 (4 equiv), MW irradiation, 130 °C, 1 h; (iii) 2 (1.5 equiv), PPh3 (3) (2.5 equiv), MW, 110–140 °C, 0.5–1 h; (iv) 2 (10 equiv), Pd/C 10% (0.05 equiv), H2 1 atm, 110–140 °C, 12 h; (v) P2O5 (6 equiv), toluene (10 mL), MW irradiation, 140 °C, 1 h.

Triphenylphosphine (PPh3) is a versatile reagent for the reduction of a range of substrates including azides[32] (Staudinger reaction), disulfides,[33] sulfonyl chloride,[34] peroxides,[35] ozonides,[36] nitro compounds (for the Cadogan type reductive cyclization),[37] nitroso compounds,[38] and N-oxides­.[39] In a continuation of our studies on fused oxazolocoumarin derivatives,[1d] [30] [31] we would like to present, herein, the use of PPh3 for the one-pot synthesis of fused oxazolocoumarins from o-hydroxynitrocoumarin in the presence of acid and phosphorus pentoxide. The PPh3 is utilized for the first time to our knowledge for the synthesis of oxazoles. The reactions studied and the products obtained are depicted in Scheme [1].

We investigated suitable conditions for the one-pot transformation of 4-hydroxy-3-nitrocoumarin[40] (1) to the fused oxazolocoumarins 4 by using formic acid (2a) and acetic acid (2b) as representative reactants. At first, the reactions of 1 with 2a and 2b was performed in the presence of tin(II) chloride under microwave conditions by analogy with the reported one-pot transformation of o-nitroanilines to benzimidazoles.[41] In contrast to expectations, only the amides 6a and 6b [23b] were isolated, with a significant amount (40%) of the starting material being recovered (Table [1], entries 1 and 2). Next, we tried PPh3 as the reducing agent in the presence of P2O5 (Method A) as condensation agent for the one-pot synthesis of oxazolocoumarins 4. The reaction of 1 with 2b under MW irradiation resulted in formation of oxazolocoumarin 4b [26] in excellent yield (89%) (entry 3), better than all the former methods.[23] [26] [27] The yield of this reaction remained almost unchanged (88%) on repeating the reaction at larger scale (10 fold). Another one-pot, but two step, reaction was also tested between 1 and 2b in the presence of Pd/C and H2 as reducing agent and subsequent addition of P2O5 (Method B) under MW conditions and longer reaction time and this approach gave 4b in similar yield (entry 4). It must be mentioned that formic acid was not investigated because it reacts violently with strong acids.[42] Method A was used mainly in the following efforts as more convenient procedure.

The reaction of o-hydroxynitrocoumarin 1 with propionic acid (2c) with both Methods A and B (140 °C) resulted in the 2-ethyl substituted oxazolocoumarin 4c [23a] in excellent yields (Table [1], entries 5 and 6). The 3-propyl and 2-butyl­ substituted oxazolocoumarins 4d and 4e isolated also by both Methods A and B from the reactions of starting compound 1 with butyric (2d) and pentanoic (2e) acids, respectively, with the latter required higher temperature and longer reaction time (entries 7–10).

The one-pot reactions of 1 with the acids 2fi by Method A also led to the corresponding oxazolocoumarin derivatives 4fi in 89–91% yield, with the more steric hindered compounds requiring 2.5 h (Table [1], entries 11–15). The above oxazolocoumarins 4di are new compounds.

Table 1 One-Pot Synthesis of 2-Substituted 4H-Chromeno[3,4-d]oxazol-4-ones 4bj from 4-Hydroxy-3-nitrocoumarin (1) and Acids 2aj

Entry

Acid RCOOH 2aj (R)

Conditions

Temp. (°C)

Time (h)

Product
(yield, %)a

1

2a (H)b

SnCl2·2H2O, MW

100

45 min

6a (48),
1 (40)

2

2b (CH3)

SnCl2·2H2O, MW

120

2.5

6b (42),
1 (40)

3

2b (CH3)

PPh3 (3), P2O5, MW (Method A)

130

1.5

4b (89)

4

2b (CH3)

Pd/C, H2, then P2O5, MW (Method B)

r.t. then 130

1 then 1

4b (87)

5

2c (CH2CH3)

Method A

130

1.5

4c (89)

6

2c (CH2CH3)

Method B

r.t. then 140

1 then 1

4c (86)

7

2d (CH2CH2CH3)

Method A

140

1.5

4d (89)

8

2d (CH2CH2CH3)

Method B

r.t. then 140

2 then 1.5

4d (84)

9

2e (CH2CH2CH2CH3)

Method A

140

1.5

4e (89)

10

2e (CH2CH2CH2CH3)

Method B

150

3 then 1.5

4e (85)

11

2f [CH2(CH2)5CH3]

Method A

140

1.5

4f (90)

13

2g (i-Pr)

Method A

140

1.5

4g (89)

14

2h (i-Bu)

Method A

140

1.5

4h (90)

15

2i (t-Bu)

Method A

140

2.5

4i (91)

16

2j (CH2OCH3)

Method A

140

1.5

4j (7)

17

2j (CH2OCH3)

Method B

r.t. then 130

1 then 1

4j (7)

a Isolated yield.

b Formic acid not tested with P2O5 because they react violently under CO production.[42]

In the case of the reaction of o-hydroxynitrocoumarin 1 with methoxyacetic acid (2j) by both Methods A and B, the expected new oxazolocoumarin 4j was obtained in only 7% yield (Table [1], entries 16 and 17) after chromatographic separation of the tar reaction mixture. During the microwave irradiation, a rapid increase in the pressure of the reaction vessel was observed in the first seconds of both procedures (18–20 bar for temperature >45 °C). The complication of methoxyacetic acid (2j) could be attributed to the possibility of Friedel–Crafts reaction products and decarboxylative formation of diarylmethanes during the treatment of this acid with arenes in the presence of P2O5.[43]

We examined, in parallel, the reactions of 4-hydroxy-3-nitrocoumarin (1) with the acids 2aj in the absence of P2O5 (Scheme [1]). The reaction of 1 with formic acid (2a) with PPh3 (3), as reducing agent, under microwave irradiation (Method C) led to 3-formamido-4-hydroxycoumarin (6a) in almost quantitative yield (Table [2], entry 1). 3-Amino-4-hydroxycoumarin (5), the reduction product, was also isolated in trace amounts after separation by column chromatography. This kind of reaction was performed for the first time to our knowledge.

Some 3-amido-4-hydroxycoumarins had been prepared by the reaction of 1 with anhydrides under Raney-nickel reduction­.[23a] We tested the Pd/C and hydrogen for the reaction of 1 with formic acid (2a) under heating (Method D) at 100 °C for 12 h and the formamidocoumarin 6a was formed in excellent yield (Table [2], entry 2).

The reactions of 1 with the acetic acid (2b) or propionic acid (2c) under Method C and MW conditions at 130 °C for 1 h resulted in the formation of the known acetamidocoumarin 6b [44] or propionamidocoumarin 6c,[23a] respectively (Table [2], entries 3 and 5). The same products were also obtained in excellent yields by Method D and heating at 120 °C for 12 h (entries 4 and 6). The analogous reactions of 1 with butanoic acid (2d) or pentanoic acid (2e) at higher temperature under both Methods C and D led to the known coumarin derivatives 6d [44] or 6e [44] (entries 7–10). The new 4-hydroxy-3-octanamidocoumarin (6f) was isolated from the reaction of 1 with octanoic acid (2f) by both Methods C and D (entries 11 and 12). The known amidocoumarin derivative 6g was obtained from the reaction of 1 with 2-methylpropanoic acid (2g) under either microwave irradiation (Method C) or thermal heating (Method D) (entries 13 and 14).

The more steric hindered acids 3-methylbutanoic acid (2h) and 2,2-dimethylpropanoic acid (2i) reacted with 1 at higher temperature and longer reaction time under Method C to give the new amidocoumarins 2h and 2i (Table [2], entries 15 and 17). The same derivatives were also obtained at higher temperature by using Method D (entries 16 and 18). Product 6i formed in lower yield, but was isolated in reasonable amount from 3-amino-4-hydroxycoumarin (5) (entries 17 and 18). In the case of methoxyacetic acid, the new 4-hydroxy-3-methoxyacetamidocoumarin (6j) was obtained at lower temperature and with less irradiation time by Method C or at lower temperature by Method D (entries 19 and 20).

The condensation of 3-amido-4-hydroxycoumarins 6 was then tested for the formation of oxazolocoumarins 4. The 3-acetamido-4-hydroxycoumarin (6b), as representative reactant, failed to react with POCl3 in refluxing CHCl3, as expected for the analogous benzoxazole synthesis.[14b] This led to 4b in refluxing acetic anhydride[23b] for 10 min, quantitatively (99%). Oxazolocoumarin 4b was also obtained quantitatively from a toluene solution of 6b in the presence of P2O5 [25] under reflux for 6 h or microwave irradiation at 140 °C for 1 h. An effort to get oxazolocoumarin 4a by refluxing a solution of 3-formamido-4-hydroxycoumarin (6a) in acetic anhydride for 10 min led to only 15% 4a along with 80% 4b. So, the condensation of 3-amido-4-hydroxycoumarins­ 6ai was performed in the presence of P2O5 in toluene under MW conditions at 140 °C for 1 h, quantitatively (99%) (Method E; Scheme [1]).

Table 2 Synthesis of 3-Amido-4-hydroxycoumarins 6aj from 4-Hydroxy-3-nitrocoumarin (1) and Acids 2aj

Entry

Acid RCOOH 2aj (R)

Conditions

Temp. (°C)

Time (h)

Product (yield, %)

1

2a (H)

PPh3 (3), MW (Method C)

110

30 min

6a (98), 5 (trace)

2

2a (H)

Pd/C, H2, heating (Method D)

100

12

6a (96), 5 (trace)

3

2b (CH3)

Method C

130

1

6b (94), 5 (trace)

4

2b (CH3)

Method D

120

12

6b (94), 5 (trace)

5

2c (CH2CH3)

Method C

130

1

6c (96), 5 (trace)

6

2c (CH2CH3)

Method D

120

12

6c (94), 5 (trace)

7

2d (CH2CH2CH3)

Method C

140

1

6d (94), 5 (trace)

8

2d (CH2CH2CH3)

Method D

130

12

6d (91), 5 (trace)

9

2e (CH2CH2CH2CH3)

Method C

140

1

6e (93), 5 (trace)

10

2e (CH2CH2CH2CH3)

Method D

140

12

6e (91), 5 (trace)

11

2f [CH2(CH2)5CH3]

Method C

140

1.5

6f (89), 5 (trace)

12

2f [CH2(CH2)5CH3]

Method D

140

12

6f (85), 5 (trace)

13

2g (i-Pr)

Method C

130

1.5

6g (95), 5 (trace)

14

2g (i-Pr)

Method D

130

12

6g (92), 5 (trace)

15

2h (i-Bu)

Method C

140

1.5

6h (95), 5 (trace)

16

2h (i-Bu)

Method D

140

12

6h (92), 5 (trace)

17

2i (t-Bu)

Method C

140

1.5

6i (25), 5 (67)

18

2i (t-Bu)

Method D

140

12

6i (39), 5 (56)

19

2j (CH2OCH3)

Method C

130

45 min

6j (95), 5 (trace)

20

2j (CH2OCH3)

Method D

120

12

6j (93), 5 (trace)

As revealed from the above procedures, for the mechanism of one-pot oxazolocoumarin formation, the reactions of 4-hydroxy-3-nitrocoumarin (1) with the acids 2 proceed through reduction of the nitro group to the amino group and formation of 3-amino-4-hydroxycoumarin (5). Acylation of the latter to amido-derivatives 6, followed by condensation–cyclization in the presence of P2O5, resulted to oxazolocoumarins 4.

Preliminary biological experiments were then performed in vitro. The compounds were tested as inhibitors of soybean lipoxygenase,[45] which is an enzyme that is implicated in arachidonic acid cascade and inflammation and constitutes an attractive biological target for drug design (Table [3]). The tests showed that compounds 4d and 4e (IC50 = 30 and 32 μM) (entries 4 and 5) are the most active within the set, whereas compound 6d is inactive under the reported experimental conditions (entry 14) and 6c presents very low activity (48% at 100 μM) (entry 13). Considering the anti-lipid peroxidation behavior of the compounds, as tested by the 2,2′-azobis(2-amidinopropane) dihydrochloride (AAPH) protocol,[45] we found that all derivatives 4 and 6 showed significant inhibition of lipid peroxidation (anti-LP) (42–100%). In our studies, AAPH was used as a free radical initiator to follow oxidative changes of linoleic acid to conjugated diene hydroperoxide. Our results indicated that LOX inhibition is accompanied and correlated with anti-lipid peroxidation. Judging overall the structural characteristics, the derivatives of series 4 are more potent than the molecules of series 6. The main difference within the two sets is the presence of the condensed heterocyclic ring in positions 3 and 4 of the coumarin ring. Thus, the combination of the coumarin with the heterocyclic moiety offers anti-LOX and anti-lipid peroxidation activities.

Table 3Inhibition (%) of Lipid Peroxidation (AAPH%): in vitro Inhibition of Soybean Lipoxygenase (%LOX) /(IC50 μM)

Entry

Compounds

Anti-LP%
@ 100 μM (±SD)a

IC50 μM or %LOX Inh.
@ 100 μM (±SD)a

1

4a

53±0.7

74±1.4

2

4b

100±3

53.5±0.4

3

4c

74±1.1

74±1.1

4

4d

95±1.8

30±1

5

4e

95±0.8

32.5±0.6

6

4f

100±2

75±2.3

7

4g

95±0.6

49±1

8

4h

100±1.2

56±1.7

9

4i

56±1.7 μM

60±1.4

10

4j

57±0.6

70±1

11

6a

83±1.8

61.5±0.7

12

6b

79±2

64±1.3

13

6c

100±3.1

48±1%

14

6d

54±0.5

NAb

15

6e

100±2.8

59±0.9

16

6f

67±0.5

62±1.2

17

6g

79±1.3

70±0.3

18

6h

45±0.4

45±0.9

19

6i

79±1.1

62±1.1

20

6j

67±0.8

53±1

21

NDGA

93%/0.55 μM (±0.1)

22

Trolox

88±1

a Values are means ±SD of three or four different determinations.

b NA: no activity under the reported experimental conditions.

In conclusion, 2-substituted [3,4]-fused oxazolocoumarins were synthesized in excellent yields from 4-hydroxy-3-nitrocoumarin and acids through the one-pot reaction, for the first time, in the presence of PPh3 and P2O5 under micro­wave irradiation or through one-pot, two-step reaction under reduction in Pd/C and hydrogen and then microwave irradiation in the presence of P2O5. The fused oxazolocoumarins were also obtained quantitatively from the 3-amido-4-hydroxycoumarins and P2O5 in microwaves. The 3-amido-4-hydroxycoumarins were prepared from 4-hydroxy­-3-nitrocoumarin, acids and PPh3 under microwave conditions. The compounds present interesting antioxidant and inhibitory activity of lipoxygenase; especially, derivatives 4d and 4e could be used as lead compounds for the design­ of agents with biological interest.

All the chemicals were procured from either Sigma–Aldrich Co. or Merck & Co., Inc. Melting points were determined with a Kofler hot-stage apparatus and are uncorrected. IR spectra were obtained with a Perkin–Elmer 1310 spectrophotometer as KBr pellets. NMR spectra were recorded with an Agilent 500/54 (DD2) (500 MHz and 125 MHz for 1H and 13C respectively) using CDCl3 as solvent and TMS as an internal standard. J values are reported in Hz. Mass spectra were determined with a LCMS-2010 EV Instrument (Shimadzu) under electrospray ionization (ESI) conditions. HRMS (ESI-MS) were recorded with a ThermoFisher Scientific model LTQ Orbitrap Discovery MS. Silica gel No. 60, Merck A.G. was used for column chromatography. The MW experiment was performed in a scientific focused microwave reactor (Biotage Initiator 2.0) in a 2 mL tube or in a 20 mL tube for the larger scale reaction. 4-Hydroxy-3-nitrocoumarin were prepared according to a reported procedure.[40]


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2-Methyl-4H-chromeno[3,4-d]oxazol-4-one (4b); Typical Procedures

Method A: 4-Hydroxy-3-nitrocoumarin (1; 0.1035 g, 0.5 mmol), acetic acid (2b; 1 mL, 0.5 M), PPh3 (3; 0.328 g, 1.25 mmol) and P2O5 (0.284 g, 2 mmol) were added to a flask for the MW oven. The mixture was irradiated at 130 °C (ca. 2 bar, ca. 48 W) for 1.5 h. After cooling, the liquid mixture was poured in a separation funnel. The remaining solid in the reaction flask was treated alternately with EtOAc (10 × 2 mL) and saturated solution Na2CO3 (10 × 2 mL) and poured in the funnel. The separated organic layer was washed with saturated solution Na2CO3 (2 × 10 mL) and water (10 mL). The aqueous layers were extracted with CH2Cl2 (3 × 20 mL). The combined organic layers were dried over anhydrous Na2SO4 and separated by column chromatography [silica gel; hexane/EtOAc, 3:1] to afford compound 4b (90 mg, 89%).

When the same reaction was performed in larger scale by using 1 (1.035 g, 5 mmol), 2b (10 mL), 3 (3.28 g, 12.5 mmol) and P2O5 (2.84 g, 20 mmol) under irradiation at 130 °C (ca. 4 bar, ca. 45 W) for 1.5 h, the compound 4b (0.884 g, 88%) was isolated, as described above.

Method B: 4-Hydroxy-3-nitrocoumarin (1; 0.1035 g, 0.5 mmol), acetic acid (2b; 1 mL, 0.5 M) and Pd/C 10% (26 mg, 0.025 mmol) were added to a flask for a MW oven under 1 atm of hydrogen. The mixture was stirred at r.t. for 1 h until 1 was consumed as indicated by TLC. The hydrogen was removed, P2O5 (0.284 g, 2 mmol) was added and the flask was irradiated in the MW oven at 130 °C (ca. 2 bar, ca. 48 W) for 1 h. After cooling, EtOAc (15 mL) was added and the solid was filtered and washed with EtOAc (15 mL). The filtrate was washed with saturated solution Na2CO3 (2 × 10 mL) and water (10 mL), dried over anhydrous Na2SO4 and separated by column chromatography [silica gel, hexane/EtOAc, 3:1] to afford 4b (87 mg, 87%).

Method E: 3-Acetamido-4-hydroxycoumarin (6b; 0.11 g, 0.5 mmol), P2O5 (0.426 g, 3 mmol) and toluene (5 mL) were added to a flask for a MW oven. The mixture was irradiated at 140 °C (ca. 2 bar, ca. 53 W) for 1 h. After cooling, the toluene solution was removed. The remaining solid was diluted with water (20 mL) and extracted with CH2Cl2 (5 × 10 mL). The organic layer was combined with the toluene solution, dried over anhydrous Na2SO4, filtered and evaporated to give 4b (0.1 g, 99%).


#

Synthesis of 4b from 6b and Acetic Anhydride

3-Acetamido-4-hydroxycoumarin (6b; 0.11 g, 0.5 mmol) and acetic anhydride (1 mL) were heated at reflux for 10 min. EtOAc (20 mL) was added and the mixture was washed with water (3 × 10 mL). The organic layer was dried over anhydrous Na2SO4, filtered and evaporated to give 4b (0.1 g, 99%).


#

Compound 4b

White solid; m.p. 198–200 °C (toluene/hexane) (lit.[26] 196–197 °C).

IR (KBr): 3086, 2928, 2856, 1747, 1641, 1599, 1585 cm–1.

1H NMR (CDCl3, 500 MHz): δ = 7.80 (d, J = 7.9 Hz, 1 H), 7.57 (t, J = 7.9 Hz, 1 H), 7.48 (d, J = 8.4 Hz, 1 H), 7.38 (t, J = 7.6 Hz, 1 H), 2.70 (s, 3 H).

13C NMR (CDCl3, 126 MHz): δ = 163.7, 156.0, 155.7, 153.0, 131.6, 124.95, 124.9, 121.4, 117.8, 111.7, 14.4.

MS (ESI): m/z = 202 [M + H]+, 224 [M + Na]+.


#

4H-Chromeno[3,4-d]oxazol-4-one (4a)

Yield (Method E): 93 mg (99%); white solid; m.p. 196–198 °C (toluene/hexane).


#

Synthesis of 4a from 6a and Acetic Anhydride

3-Formamido-4-hydroxycoumarin (6a; 0.1025 g, 0.5 mmol) and acetic anhydride (1 mL) were heated at reflux for 10 min, EtOAc (20 mL) was added and the mixture was washed with water (3 × 10 mL). The organic layer was dried over anhydrous Na2SO4, filtered, evaporated and separated by column chromatography [silica gel; hexane/EtOAc, 3:1] to give 4a (14 mg, 15%) followed by 4b (80 mg, 80%).

IR (KBr): 3134, 1752, 1630, 1599, 1510 cm–1.

1H NMR (CDCl3, 500 MHz): δ = 8.15 (s, 1 H), 7.87 (dd, J 1= 7.8, J 2 = 1.1 Hz, 1 H), 7.64–7.60 (m, 1 H), 7.51 (d, J = 8.5 Hz, 1 H), 7.42 (t, J = 7.8 Hz, 1 H).

13C NMR (CDCl3, 126 MHz): δ = 155.9, 155.6, 153.2, 152.0, 132.3, 125.1, 124.3, 121.8, 117.8, 111.5.

MS (ESI): m/z = 188 [M + H]+, 210 [M + Na]+.

HRMS (ESI-MS): m/z [M + H]+ calcd C10H6NO3: for 188.0342; found: 188.0343.


#

2-Ethyl-4H-chromeno[3,4-d]oxazol-4-one (4c)

Yield (Method A): 96 mg (89%); (Method B): 92 mg (86%); (Method E): 0.106 g (99%); white solid; m.p. 151–153 °C (toluene/hexane) (lit.[23a] 147 °C).

IR (KBr): 3058, 2995, 2879, 1754, 1640, 1599, 1584 cm–1.

1H NMR (CDCl3, 500 MHz): δ = 7.81 (d, J = 7.9 Hz, 1 H), 7.57 (t, J = 7.9 Hz, 1 H), 7.47 (d, J = 8.4 Hz, 1 H), 7.38 (t, J = 7.6 Hz, 1 H), 3.02 (q, J = 7.6 Hz, 2 H), 1.48 (t, J = 7.6 Hz, 3 H).

13C NMR (CDCl3, 126 MHz): δ = 168.1, 156.2, 155.5, 153.0, 131.5, 124.9, 124.8, 121.4, 117.8, 111.7, 22.1, 11.0.

MS (ESI): m/z = 216 [M + H]+, 238 [M + Na]+.


#

2-Propyl-4H-chromeno[3,4-d]oxazol-4-one (4d)

Yield (Method A, 140 °C): 0.101 g, 89%; (Method B, 2 h then 1.5 h): 96 mg (84%); (Method E, 150 °C): 0.113 g (99%); white solid; m.p. 119–121 °C (toluene/hexane).

IR (KBr): 3080, 2963, 2929, 2924, 2871, 1753, 1641, 1600, 1584 cm–1.

1H NMR (CDCl3, 500 MHz): δ = 7.81 (d, J = 7.8 Hz, 1 H), 7.57 (t, J = 7.8 Hz, 1 H), 7.48 (d, J = 8.4 Hz, 1 H), 7.38 (t, J = 7.5 Hz, 1 H), 2.96 (t, J = 7.5 Hz, 2 H), 1.98–1.91 (m, 2 H), 1.07 (t, J = 7.4 Hz, 3 H).

13C NMR (CDCl3, 126 MHz): δ = 167.2, 156.1, 155.4, 152.8, 131.5, 124.9, 124.7, 121.4, 117.6, 111.6, 30.2, 20.3, 13.7.

MS (ESI): m/z = 230 [M + H]+, 252 [M + Na]+.

HRMS (ESI-MS): m/z [M + H]+ calcd for C13H12NO3: 230.0812; found: 230.0812.


#

2-Butyl-4H-chromeno[3,4-d]oxazol-4-one (4e)

Yield (Method A, 140 °C): 0.108 g (89%); (Method B, 3 h then 1.5 h): 0.103 g (85%); (Method E, 150 °C): 0.120 g (99%); white solid; m.p. 113–114 °C (toluene/hexane).

IR (KBr): 3085, 2952, 2930, 2870, 1750, 1642, 1600, 1583, 1500 cm–1.

1H NMR (CDCl3, 500 MHz): δ = 7.80 (d, J = 7.8 Hz, 1 H), 7.56 (t, J = 7.8 Hz, 1 H), 7.46 (d, J = 8.4 Hz, 1 H), 7.38 (t, J = 7.6 Hz, 1 H), 2.98 (t, J = 7.6 Hz, 2 H), 1.91–1.86 (m, 2 H), 1.49–1.44 (m, 2 H), 0.97 (t, J = 7.4 Hz, 3 H).

13C NMR (CDCl3, 126 MHz): δ = 167.4, 156.2, 155.4, 152.9, 131.5, 124.9, 124.8, 121.4, 117.7, 111.7, 28.8, 28.1, 22.3, 13.7.

MS (ESI): m/z = 244 [M + H]+, 266 [M + Na]+.

HRMS (ESI-MS): m/z [M + Na]+ calcd for C14H13NNaO3: 266.0793; found: 266.0767.


#

2-Heptyl-4H-chromeno[3,4-d]oxazol-4-one (4f)

Yield (Method A, 140 °C): 0.116 g (90%); (Method E, 150 °C): 0.140 g (98%); white solid; m.p. 99–101 °C (toluene/hexane).

IR (KBr): 3084, 2955, 2921, 2849, 1748, 1640, 1582, 1558, 1499 cm–1.

1H NMR (CDCl3, 500 MHz): δ = 7.81 (d, J = 7.8 Hz, 1 H), 7.55–7.60 (m, 1 H), 7.48 (d, J = 8.4 Hz, 1 H), 7.39 (t, J = 7.6 Hz, 1 H), 2.98 (t, J = 7.6 Hz, 2 H), 1.94–1.85 (m, 2 H), 1.45–1.40 (m, 2 H), 1.39–1.34 (m, 2 H), 1.32–1.26 (m, 4 H), 0.88 (t, J = 6.8 Hz, 3 H).

13C NMR (CDCl3, 126 MHz): δ = 167.4, 156.2, 155.5, 153.0, 131.5, 124.9, 124.8, 121.5, 117.8, 111.8, 31.7, 29.1, 28.9, 28.5, 26.9, 22.7, 14.2.

MS (ESI): m/z = 286 [M + H]+, 308 [M + Na]+.

HRMS (ESI-MS): m/z [M + H]+ calcd for C17H20NO3: 286.1443; found: 286.1439.


#

2-Isopropyl-4H-chromeno[3,4-d]oxazol-4-one (4g)

Yield: (Method A, 140 °C): 0.102 g (89%); (Method E, 150 °C): 0.113 g (99%); white solid; m.p. 125–126 °C (toluene/hexane).

IR (KBr): 3064, 2981, 2946, 2910, 2879, 1753, 1637, 1598, 1575 cm–1.

1H NMR (CDCl3, 500 MHz): δ = 7.83 (d, J = 7.8 Hz, 1 H), 7.57 (t, J = 7.8 Hz, 1 H), 7.47 (d, J = 8.4 Hz, 1 H), 7.39 (t, J = 7.6 Hz, 1 H), 3.35–3.26 (m, 1 H), 1.49 (d, J = 7.0 Hz, 6 H).

13C NMR (CDCl3, 126 MHz): δ = 171.4, 156.3, 155.4, 153.0, 131.5, 124.9, 124.7, 121.5, 117.7, 111.8, 29.0, 20.4.

MS (ESI): m/z = 230 [M + H]+, 252 [M + Na]+.

HRMS (ESI-MS): m/z [M + H]+ calcd for C13H12NO3: 230.0812; found: 230.0811.


#

2-Isobutyl-4H-chromeno[3,4-d]oxazol-4-one (4h)

Yield: (Method A, 140 °C): 0.109 g (90%); (Method E, 150 °C): 0.12 g (99%); white solid; m.p. 117–119 °C (toluene/hexane).

IR (KBr): 3086, 2936, 2961, 2898, 2876, 1753, 1640, 1601, 1579 cm–1.

1H NMR (CDCl3, 500 MHz): δ = 7.81 (d, J = 7.7 Hz, 1 H), 7.59–7.55 (m, 1 H), 7.47 (d, J = 8.4 Hz, 1 H), 7.38 (t, J = 7.6 Hz, 1 H), 2.86 (d, J = 7.1 Hz, 2 H), 2.36–2.28 (m, 1 H), 1.06 (d, J = 6.7 Hz, 6 H).

13C NMR (CDCl3, 126 MHz): δ = 166.7, 156.2, 155.5, 152.9, 131.5, 124.9, 124.8, 121.5, 117.7, 111.8, 37.3, 27.6, 22.5.

MS (ESI): m/z = 244 [M + H]+, 266 [M + Na]+.

HRMS (ESI-MS): m/z [M + H]+ calcd for C14H14NO3: 244.0968; found: 244.0972.


#

2-(tert-Butyl)-4H-chromeno[3,4-d]oxazol-4-one (4i)

Yield: (Method A, 140 °C): 0.111 g (91%); (Method E, 150 °C): 0.12 g (99%); white solid; m.p. 218–219 °C (toluene/hexane).

IR (KBr): 3083, 2970, 2939, 2876, 1755, 1638, 1601, 1574 cm–1.

1H NMR (CDCl3, 500 MHz): δ = 7.84 (d, J = 7.8 Hz, 1 H), 7.57 (t, J = 7.8 Hz, 1 H), 7.47 (d, J = 8.4 Hz, 1 H), 7.39 (t, J = 7.6 Hz, 1 H), 1.52 (s, 9 H).

13C NMR (CDCl3, 126 MHz): δ = 173.7, 156.4, 155.4, 153.0, 131.5, 124.8, 124.6, 121.5, 117.7, 111.8, 34.7, 28.6.

MS (ESI): m/z = 244 [M + H]+, 266 [M + Na]+.

HRMS (ESI-MS): m/z [M + H]+ calcd for C14H14NO3: 244.0968; found: 244.0963.


#

2-(Methoxymethyl)-4H-chromeno[3,4-d]oxazol-4-one (4j)

Yield: (Method A, 140 °C): 9 mg (7%); (Method B): 9 mg (7%); (Method E): 0.114 g (99%); white solid; m.p. 142–144 °C (toluene/hexane).

IR (KBr): 3088, 2937, 2907, 2829, 1748, 1641, 1596, 1500 cm–1.

1H NMR (CDCl3, 500 MHz): δ = 7.87 (d, J = 7.9 Hz, 1 H). 7.61 (t, J = 7.9 Hz, 1 H), 7.50 (d, J = 8.4 Hz, 1 H), 7.41 (t, J = 7.6 Hz, 1 H), 4.74 (s, 2 H), 3.53 (s, 3 H).

13C NMR (CDCl3, 126 MHz): δ = 162.5, 156.3, 155.9, 153.2, 132.2, 125.1, 124.7, 121.8, 117.9, 111.5, 66.4, 59.4.

MS (ESI): m/z = 232 [M + H]+, 254 [M + Na]+.

HRMS (ESI-MS): m/z [M + Na]+ calcd for C12H9NNaO4: 254.0424; found: 254.0420.


#

N-(4-Hydroxy-2-oxo-2H-chromen-3-yl)formamide (6a); Typical Procedures

Method C: 4-Hydroxy-3-nitrocoumarin (1; 0.207 g, 1 mmol), formic acid (2a; 0.114 mL, 0.138 g, 3 mmol), and PPh3 (3; 0.656 g, 2.5 mmol) were added to a flask for a MW oven. The mixture was irradiated at 100 °C (ca. 1 bar, ca. 44 W) for 30 min. After cooling, CH2Cl2 (10 mL) was added and the solution was evaporated and the mixture was separated by column chromatography (silica gel, hexane/EtOAc, 2:1 to1:10) to give compound 6a (0.2 g, 98%) followed by 3-amino-3-hydroxycoumarin 5 (2 mg, 2%).

Method D: A mixture of 4-hydroxy-3-nitrocoumarin (1; 0.207 g, 1 mmol), formic acid (2a; 0.38 mL, 0.46 g, 10 mmol) and Pd/C 10% (51 mg, 0.05 mmol) was heated in an oil bath at 100 °C under 1 atm hydrogen and stirring for 12 h. The hydrogen was removed, EtOAc (5 mL) was added to the hot mixture (without further heating) and the mixture was filtered. The solid was washed with hot EtOAc (8 × 5 mL) and the solution was evaporated and purified by column chromatography (silica gel; hexane/EtOAc, 1:1) to afford 6a (0.197 g, 96%) followed by derivative 5 (2 mg, 2%).


#

Compound 6a

White solid; m.p. 233–234 °C (chloroform).

IR (KBr): 3299, 3239, 3046, 2955, 2858, 1675, 1629, 1601, 1545 cm–1.

1H NMR (CDCl3, 500 MHz): δ = 12.62 (brs, 1 H). 9.95 (brs, 1 H), 8.17 (d, J = 1.9 Hz, 1 H), 7.89 (dd, J 1 = 7.8, J 2 = 1.0 Hz, 1 H), 7.65 (t, J = 7.8 Hz, 1 H), 7.43–7.38 (m, 2 H).

13C NMR (CDCl3, 126 MHz): δ = 162.2, 159.7, 155.8, 150.9, 132.2, 124.5, 123.7, 116.2, 116.15, 102.8.

MS (ESI): m/z = 204 [M – H] {MS (GC-MS) lit.[46]}.


#

Compound 5

White solid; m.p. 220–222 °C (ethanol) (lit.[47] 220–222 °C).


#

N-(4-Hydroxy-2-oxo-2H-chromen-3-yl)acetamide (6b)

Yield (Method C, 130 °C, 1 h): 0.205 g (94%); (Method D, 120 °C): 0.205 g (94%); white solid; m.p. 230–231 °C (chloroform/hexane) [lit.[44] 228–230 °C].

IR (KBr): 3288, 3059, 2938, 2867, 1687, 1628, 1600, 1572 cm–1.

1H NMR (CDCl3, 500 MHz): δ = 12.31 (brs, 1 H). 9.48 (brs, 1 H), 7.88 (d, J = 7.7 Hz, 1 H), 7.64 (d, J = 7.7, 1 H), 7.42–7.36 (m, 2 H), 2.11 (s, 3 H).

13C NMR (CDCl3, 126 MHz): δ = 171.1, 160.1, 157.1, 151.1, 132.1, 124.4, 123.6, 116.3, 116.1, 103.6, 22.7.

MS (ESI): m/z = 218 [M – H].


#

N-(4-Hydroxy-2-oxo-2H-chromen-3-yl)propionamide (6c)

Yield (Method C, 130 °C, 1 h): 0.222 g (96%); (Method D, 120 °C): 0.218 g (94%); white solid; m.p. 150–152 °C (hexane) (lit.[44] 154–155 °C).

IR (KBr): 3287, 3231, 3063, 2975, 2940, 2878, 1692, 1636, 1604, 1573 cm–1.

1H NMR (CDCl3, 500 MHz): δ = 13.62 (brs, 1 H). 8.18 (brs, 1 H), 7.98 (d, J = 7.9 Hz, 1 H), 7.56–7.51 (m, 1 H), 7.36–7.30 (m, 2 H), 2.56 (q, J = 7.6 Hz, 2 H), 1.30 (t, J = 7.6 Hz, 3 H).

13C NMR (CDCl3, 126 MHz): δ = 175.3, 161.1, 152.8, 150.6, 131.8, 124.8, 124.5, 117.2, 116.3, 104.7, 30.0, 9.9.

MS (ESI): m/z = 232 [M – H].


#

N-(4-Hydroxy-2-oxo-2H-chromen-3-yl)butyramide (6d)

Yield (Method C, 140 °C, 1 h): 0.231 g (94%); (Method D, 130 °C): 0.224 g (91%); white solid; m.p. 169–171 °C (hexane) (lit.[44] 173–174 °C).

IR (KBr): 3281, 3217, 3054, 2961, 2934, 2874, 1690, 1634, 1606, 1571 cm–1.

1H NMR (CDCl3, 500 MHz): δ = 13.65 (brs, 1 H). 8.15 (brs, 1 H), 7.98 (d, J = 7.9 Hz, 1 H), 7.56–7.52 (m, 1 H), 7.36–7.31 (m, 2 H), 2.50 (q, J = 7.5 Hz, 2 H), 1.83–1.76 (m, 2 H), 1.04 (t, J = 7.4 Hz, 3 H).

13C NMR (CDCl3, 126 MHz): δ = 174.6, 161.1, 152.9, 150.6, 131.8, 124.8, 124.5, 117.2, 116.3, 104.8, 38.7, 19.3, 13.7.

MS (ESI): m/z = 246 [M – H].


#

N-(4-Hydroxy-2-oxo-2H-chromen-3-yl)pentanamide (6e)

Yield (Method C, 140 °C, 1 h): 0.243 g (93%); (Method D, 140 °C): 0.237 g (91%); white solid; m.p. 139–141 °C (hexane) (lit.[44] 132.5–133.5 °C).

IR (KBr): 3279, 3209, 3071, 3039, 2951, 2930, 2868, 1693, 1623, 1602, 1570, 1549 cm–1.

1H NMR (CDCl3, 500 MHz): δ = 13.65 (brs, 1 H), 8.16 (brs, 1 H), 7.98 (dd, J 1 = 7.9, J 2=1.1 Hz, 1 H), 7.56–7.51 (m, 1 H), 7.36–7.30 (m, 2 H), 2.52 (q, J = 7.6 Hz, 2 H), 1.77–1.71 (m, 2 H), 1.47–1.40 (m, 2 H), 0.97 (t, J = 7.4 Hz, 3 H).

13C NMR (CDCl3, 126 MHz): δ = 174.8, 161.1, 152.9, 150.6, 131.8, 124.8, 124.5, 117.2, 116.3, 104.8, 36.6, 27.9, 22.4, 13.8.

MS (ESI): m/z = 260 [M – H].


#

N-(4-Hydroxy-2-oxo-2H-chromen-3-yl)octanamide (6f)

Yield (Method C, 140 °C, 1.5 h): 0.27 g (89%); (Method D, 140 °C): 0.279 g (85%); white solid; m.p. 122–123 °C (hexane).

IR (KBr): 3281, 3217, 3040, 2952, 2929, 2854, 2868, 1693, 1623, 1603, 1571 cm–1.

1H NMR (CDCl3, 500 MHz): δ = 13.65 (brs, 1 H). 8.18 (brs, 1 H), 7.97 (d, J = 7.9, 1 H), 7.53 (t, J = 7.8 Hz, 1 H), 7.36–7.29 (m, 2 H), 2.51 (q, J = 7.6 Hz, 2 H), 1.77–1.72 (m, 2 H), 1.41–1.26 (m, 8 H), 0.88 (t, J = 6.8 Hz, 3 H).

13C NMR (CDCl3, 126 MHz): δ = 174.8, 161.1, 152.8, 150.6, 131.8, 124.8, 124.5, 117.2, 116.3, 104.8, 36.8, 31.7, 29.1, 29.0, 25.8, 22.7, 14.2.

MS (ESI): m/z = 302 [M – H].

HRMS (ESI-MS): m/z [M + H]+ calcd for C17H22NO4: 304.1549; found: 304.1547.


#

N-(4-Hydroxy-2-oxo-2H-chromen-3-yl)isobutyramide (6g)

Yield (Method C, 130 °C, 1.5 h): 0.233 g (95%); (Method D, 130 °C): 0.226 g (92%); white solid; m.p. 140–141 °C (hexane) (lit.[11] 164–166 °C).

IR (KBr): 3297, 3060, 3966, 2934, 2879, 1679, 1635, 1606, 1572, 1537 cm–1.

1H NMR (CDCl3, 500 MHz): δ = 13.74 (brs, 1 H). 8.22 (brs, 1 H), 7.97 (d, J = 7.9 Hz, 1 H), 7.52 (t, J = 7.8 Hz, 1 H), 7.35–7.29 (m, 2 H), 2.78–2.72 (m, 1 H), 1.30 (d, J = 6.9 Hz, 6 H).

13C NMR (CDCl3, 126 MHz): δ = 178.5, 161.1, 152.8, 150.6, 131.7, 124.8, 124.5, 117.2, 116.3, 104.7, 36.1, 19.7.

MS (ESI): m/z = 246 [M – H].


#

N-(4-Hydroxy-2-oxo-2H-chromen-3-yl)-3-methylbutanamide (6h)

Yield (Method C, 140 °C, ca. 57 W, 1.5 h): 0.239 g (95%); (Method D, 140 °C): 0.232 g (92%); white solid; m.p. 154–155 °C (hexane).

IR (KBr): 3293, 3055, 2964, 2953, 2872, 1682, 1635, 1603, 1571, 1537 cm–1.

1H NMR (CDCl3, 500 MHz): δ = 13.64 (brs, 1 H), 8.19 (brs, 1 H), 7.97 (d, J= 7.9 Hz, 1 H), 7.55–7.50 (m, 1 H), 7.35–7.29 (m, 2 H), 2.39 (d, J = 7.2 Hz, 2 H), 2.27–2.16 (m, 1 H), 1.04 (t, J = 6.6 Hz, 3 H).

13C NMR (CDCl3, 126 MHz): δ = 174.2, 161.1, 153.0, 150.6, 131.8, 124.8, 124.5, 117.2, 116.3, 104.8, 45.8, 26.7, 22.4.

MS (ESI): m/z = 260 [M – H].

HRMS (ESI-MS): m/z [M + H]+ calcd for C14H16NO4: 262.1074; found: 262.1072.


#

N-(4-Hydroxy-2-oxo-2H-chromen-3-yl)pivalamide (6i)

Yield (Method C, 140 °C, 1.5 h, ca. 57 W): 65 mg (25%); (Method D, 140 °C): 0.101 g (39%); white solid; m.p. 149–151 °C (hexane).

IR (KBr): 3370, 3065, 2969, 2874, 1687, 1637, 1607, 1533 cm–1.

1H NMR (CDCl3, 500 MHz): δ = 13.87 (brs, 1 H). 8.41 (brs, 1 H), 7.98 (dd, J 1 = 7.9, J 2=1.0 Hz, 1 H), 7.55–7.51 (m, 1 H), 7.36–7.31 (m, 2 H), 1.37 (s, 9 H).

13C NMR (CDCl3, 126 MHz): δ = 180.2, 161.3, 152.8, 150.6, 131.7, 124.8, 124.5, 117.3, 116.3, 104.7, 39.8, 27.7.

MS (ESI): m/z = 260 [M – H].

HRMS (ESI-MS): m/z [M + H]+ calcd for C14H16NO4: 262.1074; found: 262.1075.


#

N-(4-Hydroxy-2-oxo-2H-chromen-3-yl)-2-methoxyacetamide (6j)

Yield (Method C, 130 °C, 45 min): 0.236 g (95%); (Method D, 120 °C): 0.231 g (93%); white solid; m.p. 165–166 °C (hexane).

IR (KBr): 3312, 3020, 2971, 2945, 2907, 2840, 1701, 1645, 1605, 1542 cm–1.

1H NMR (CDCl3, 500 MHz): δ = 13.38 (brs, 1 H). 9.15 (brs, 1 H), 7.98 (d, J= 7.9 Hz, 1 H), 7.55 (t, J = 7.8 Hz, 1 H), 7.36–7.31 (m, 2 H), 4.11 (s, 2 H), 3.56 (s, 3 H).

13C NMR (CDCl3, 126 MHz): δ = 170.6, 160.7, 153.0, 150.8, 131.9, 124.8, 124.5, 117.1, 116.4, 104.2, 71.1, 59.7.

MS (ESI): m/z = 248 [M – H].

HRMS (ESI-MS): m/z [M + H]+ calcd for C12H12NO5: 250.0710; found: 250.0711.


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#

Supporting Information

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  • 12 Nofal ZM. El-Zahar MI. Abd El-Karim SS. Molecules 2000; 5: 99
    • 13a Sharma H. Singh N. Jang DO. Green Chem. 2014; 16: 4922
    • 13b Mohammadpoor-Baltork I. Khosropour AR. Hojati SF. Monatsh. Chem. 2007; 138: 663
    • 13c Yamamoto K. Watanabe H. Chem. Lett. 1982; 11: 1225
    • 13d Maleki B. Baghayeri M. Vahdat SM. Mohhamadzadeh A. Akhoondi S. RSC Adv. 2015; 5: 46545
    • 13e Khalafi-Nezhad A. Panahi F. ACS Catal. 2014; 4: 1686
    • 13f Mayo MS. Yu X. Zhou X. Feng X. Yamamoto Y. Bao M. J. Org. Chem. 2014; 79: 6310
    • 14a Rambabu D. Murthi PR. K. Dulla b. Rao MV. B. Pal M. Synth. Commun. 2013; 43: 3083
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  • 17 Ueda S. Nagasawa H. J. Org. Chem. 2009; 74: 4272
  • 18 Tang L. Guo X. Yang Y. Zha Z. Wang Z. Chem. Commun. 2014; 6145
  • 19 Feng F. Ye J. Cheng Z. Xu X. Zhang Q. Ma L. Lu C. Li X. RSC Adv. 2016; 6: 72750
  • 20 Lee JJ. Kim J. Jun JM. Lee BM. Kim BH. Tetrahedron 2009; 65: 8821
  • 21 Ryuzaburo N. Watanabe H. Kuwata S. Yokoyama S. Yakugaku Zasshi 1959; 79: 1378; Chem. Abstr. 1960, 10936
  • 22 Reddy S. J. Indian Chem. Soc. 1981; 58: 599
    • 23a Dallacker F. Kratzer P. Lipp M. Justus Liebigs Ann. Chem. 1961; 643: 97
    • 23b Stammer CH. J. Org. Chem. 1960; 25: 460
    • 23c Hinman JW. Caron EL. Hoeksema H. J. Am. Chem. Soc. 1957; 79: 3789
  • 24 Gammon DW. Hunter R. Wilson SA. Tetrahedron 2005; 61: 10683
  • 25 Saikachi H. Ichikawa M. Chem. Pharm. Bull. 1966; 14: 1162
  • 26 Chantegrel B. Nadi AI. Gelin S. J. Org. Chem. 1984; 49: 4424
  • 27 Lee YR. Suk JY. Kim BS. Tetrahedron Lett. 1999; 40: 6603
  • 28 Kaufman KD. McBride DW. Eaton DC. J. Org. Chem. 1965; 30: 4344
  • 29 Abdelghani S. Abd El-Aal A. Shehab W. El-Mobayed M. Synthesis 2003; 1373
  • 30 Bezergiannidou-Balouctsi C. Litinas KE. Malamidou-Xenikaki E. Nicolaides DN. Mentzafos D. Terzis A. Tetrahedron 1993; 49: 9127
  • 31 Vlachou E.-EN. Armatas GS. Litinas KE. J. Heterocycl. Chem. 2017; 54: 2447
    • 32a Staudinger H. Meyer J. Helv. Chim. Acta 1919; 2: 635
    • 32b Pal B. Jaisankar P. Giri VS. Synth. Commun. 2004; 34: 1317
  • 33 Humphrey RE. McGrary AL. Webb RM. Talanta 1965; 12: 727
  • 34 Bellale EV. Chaudhari MK. Akamanchi KG. Synthesis 2009; 3211
  • 35 Erden I. Gartner C. Azimi MS. Org. Lett. 2009; 11: 3986
  • 36 Carles J. Fliszar S. Can. J. Chem. 1969; 47: 1113
    • 37a Mustafa AH. Malakar CC. Ajaar N. Merisor E. Conrad J. Beifuss U. Synlett 2013; 24: 1573
    • 37b Creencia EC. Kosaka M. Muramatsu T. Kobayashi M. Oizuka T. Horaguchi T. J. Heterocycl. Chem. 2009; 46: 1309
    • 37c Sanz R. Escribano J. Pedrosa MR. Aguado R. Arnaiz FJ. Adv. Synth. Catal. 2007; 349: 713
    • 37d Freeman AW. Urvoy M. Criswell ME. J. Org. Chem. 2005; 70: 5014
    • 37e Scott PH. Smith CP. Kober E. Churchill JW. Tetrahedron Lett. 1970; 1153
    • 37f Cadogan JI. G. Cameron-Wood M. Mackie RK. Searle RJ. G. J. Chem. Soc. 1965; 4831
  • 38 Odum RA. Brenner M. J. Am. Chem. Soc. 1966; 88: 2074
  • 39 Kaneko C. Yamamori M. Yamamoto A. Hayashi R. Tetrahedron Lett. 1978; 31: 2799
  • 40 Iaroshenko VO. Mkrtchyan S. Gevorgyan A. Vilches-Herrera M. Sevenard DV. Villinger A. Ghochikyan TV. Saghiyan A. Sosnovskikh VY. Lange P. Tetrahedron 2012; 68: 2532
  • 41 VanVliet DS. Gillespie P. Scicinski JJ. Tetrahedron Lett. 2005; 46: 6741
  • 42 http://www.inchem.org/documents/icsc/icsc/eics0485.htm.
  • 43 Kameda A. Nishimori H. Omura S. Koike M. Hino T. Jobashi T. Maeyama K. Yonezawa N. Nippon Kagaku Kaishi 2002; 211
  • 44 Reppel L. Schmollak W. Arch. Pharm. 1964; 297: 45
  • 45 Balalas T. Abdul-Sada A. Hadjipavlou-Litina DJ. Litinas KE. Synthesis 2017; 49: 2575
  • 46 https://pubchem.ncbi.nlm.nih.gov/compound/54738232#section.
  • 47 Wang Z.-M. Xie S.-S. Li X.-M. Wu J.-J. Wang X.-B. Kong L.-Y. RSC Adv. 2015; 5: 70395

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    • 13a Sharma H. Singh N. Jang DO. Green Chem. 2014; 16: 4922
    • 13b Mohammadpoor-Baltork I. Khosropour AR. Hojati SF. Monatsh. Chem. 2007; 138: 663
    • 13c Yamamoto K. Watanabe H. Chem. Lett. 1982; 11: 1225
    • 13d Maleki B. Baghayeri M. Vahdat SM. Mohhamadzadeh A. Akhoondi S. RSC Adv. 2015; 5: 46545
    • 13e Khalafi-Nezhad A. Panahi F. ACS Catal. 2014; 4: 1686
    • 13f Mayo MS. Yu X. Zhou X. Feng X. Yamamoto Y. Bao M. J. Org. Chem. 2014; 79: 6310
    • 14a Rambabu D. Murthi PR. K. Dulla b. Rao MV. B. Pal M. Synth. Commun. 2013; 43: 3083
    • 14b Li K.-L. Du Z.-B. Guo C.-C. Chen Q.-Y. J. Org. Chem. 2009; 74: 3286
    • 14c Doeller W. Ber. Dtsch. Chem. Ges. B. 1939; 72: 2148
    • 14d Phillips MA. J. Chem. Soc. 1930; 2685
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    • 15b Saha P. Ramana T. Purkait N. Ali MA. Paul r. Punniyamurthy T. J. Org. Chem. 2009; 74: 8719
    • 15c Evindar G. Batey RA. J. Org. Chem. 2006; 71: 1802
    • 15d Altenhoff G. Glorius F. Adv. Synth. Catal. 2004; 346: 1661
  • 16 Cheung CW. Buchwald SL. J. Org. Chem. 2012; 77: 7526
  • 17 Ueda S. Nagasawa H. J. Org. Chem. 2009; 74: 4272
  • 18 Tang L. Guo X. Yang Y. Zha Z. Wang Z. Chem. Commun. 2014; 6145
  • 19 Feng F. Ye J. Cheng Z. Xu X. Zhang Q. Ma L. Lu C. Li X. RSC Adv. 2016; 6: 72750
  • 20 Lee JJ. Kim J. Jun JM. Lee BM. Kim BH. Tetrahedron 2009; 65: 8821
  • 21 Ryuzaburo N. Watanabe H. Kuwata S. Yokoyama S. Yakugaku Zasshi 1959; 79: 1378; Chem. Abstr. 1960, 10936
  • 22 Reddy S. J. Indian Chem. Soc. 1981; 58: 599
    • 23a Dallacker F. Kratzer P. Lipp M. Justus Liebigs Ann. Chem. 1961; 643: 97
    • 23b Stammer CH. J. Org. Chem. 1960; 25: 460
    • 23c Hinman JW. Caron EL. Hoeksema H. J. Am. Chem. Soc. 1957; 79: 3789
  • 24 Gammon DW. Hunter R. Wilson SA. Tetrahedron 2005; 61: 10683
  • 25 Saikachi H. Ichikawa M. Chem. Pharm. Bull. 1966; 14: 1162
  • 26 Chantegrel B. Nadi AI. Gelin S. J. Org. Chem. 1984; 49: 4424
  • 27 Lee YR. Suk JY. Kim BS. Tetrahedron Lett. 1999; 40: 6603
  • 28 Kaufman KD. McBride DW. Eaton DC. J. Org. Chem. 1965; 30: 4344
  • 29 Abdelghani S. Abd El-Aal A. Shehab W. El-Mobayed M. Synthesis 2003; 1373
  • 30 Bezergiannidou-Balouctsi C. Litinas KE. Malamidou-Xenikaki E. Nicolaides DN. Mentzafos D. Terzis A. Tetrahedron 1993; 49: 9127
  • 31 Vlachou E.-EN. Armatas GS. Litinas KE. J. Heterocycl. Chem. 2017; 54: 2447
    • 32a Staudinger H. Meyer J. Helv. Chim. Acta 1919; 2: 635
    • 32b Pal B. Jaisankar P. Giri VS. Synth. Commun. 2004; 34: 1317
  • 33 Humphrey RE. McGrary AL. Webb RM. Talanta 1965; 12: 727
  • 34 Bellale EV. Chaudhari MK. Akamanchi KG. Synthesis 2009; 3211
  • 35 Erden I. Gartner C. Azimi MS. Org. Lett. 2009; 11: 3986
  • 36 Carles J. Fliszar S. Can. J. Chem. 1969; 47: 1113
    • 37a Mustafa AH. Malakar CC. Ajaar N. Merisor E. Conrad J. Beifuss U. Synlett 2013; 24: 1573
    • 37b Creencia EC. Kosaka M. Muramatsu T. Kobayashi M. Oizuka T. Horaguchi T. J. Heterocycl. Chem. 2009; 46: 1309
    • 37c Sanz R. Escribano J. Pedrosa MR. Aguado R. Arnaiz FJ. Adv. Synth. Catal. 2007; 349: 713
    • 37d Freeman AW. Urvoy M. Criswell ME. J. Org. Chem. 2005; 70: 5014
    • 37e Scott PH. Smith CP. Kober E. Churchill JW. Tetrahedron Lett. 1970; 1153
    • 37f Cadogan JI. G. Cameron-Wood M. Mackie RK. Searle RJ. G. J. Chem. Soc. 1965; 4831
  • 38 Odum RA. Brenner M. J. Am. Chem. Soc. 1966; 88: 2074
  • 39 Kaneko C. Yamamori M. Yamamoto A. Hayashi R. Tetrahedron Lett. 1978; 31: 2799
  • 40 Iaroshenko VO. Mkrtchyan S. Gevorgyan A. Vilches-Herrera M. Sevenard DV. Villinger A. Ghochikyan TV. Saghiyan A. Sosnovskikh VY. Lange P. Tetrahedron 2012; 68: 2532
  • 41 VanVliet DS. Gillespie P. Scicinski JJ. Tetrahedron Lett. 2005; 46: 6741
  • 42 http://www.inchem.org/documents/icsc/icsc/eics0485.htm.
  • 43 Kameda A. Nishimori H. Omura S. Koike M. Hino T. Jobashi T. Maeyama K. Yonezawa N. Nippon Kagaku Kaishi 2002; 211
  • 44 Reppel L. Schmollak W. Arch. Pharm. 1964; 297: 45
  • 45 Balalas T. Abdul-Sada A. Hadjipavlou-Litina DJ. Litinas KE. Synthesis 2017; 49: 2575
  • 46 https://pubchem.ncbi.nlm.nih.gov/compound/54738232#section.
  • 47 Wang Z.-M. Xie S.-S. Li X.-M. Wu J.-J. Wang X.-B. Kong L.-Y. RSC Adv. 2015; 5: 70395

Zoom Image
Scheme 1 Reagents and conditions: (i) 2 (2 mL, 0.5 M), PPh3 (3) (2.5 equiv), P2O5 (4 equiv), MW irradiation, 130 °C or 140 °C, 1.5 h (not for 4a); (ii)2 (2 mL, 0.5 M), 5 mole % Pd/C (10%), H2 1 atm, r.t., 1–3 h then P2O5 (4 equiv), MW irradiation, 130 °C, 1 h; (iii) 2 (1.5 equiv), PPh3 (3) (2.5 equiv), MW, 110–140 °C, 0.5–1 h; (iv) 2 (10 equiv), Pd/C 10% (0.05 equiv), H2 1 atm, 110–140 °C, 12 h; (v) P2O5 (6 equiv), toluene (10 mL), MW irradiation, 140 °C, 1 h.