Tandem oxidative radical brominative addition of activated alkynes and spirocyclization: switchable synthesis of 3-bromocoumarins and 3-bromo spiro-[4,5] trienone

Abstract

A K₂S₂O₈-mediated tandem radical brominative addition of alkynoates, oxidative spiro-cyclization, and 1,2-migration of esters is reported for the synthesis of 3-bromocoumarins with high efficiency. The prepared 3-bromocoumarins are successfully converted into 3-alkynyl and 3-phosphite coumarins under mild conditions. The synthesis of a specific bromo-incorporated spiro-[4,5]trienyl-2,8-dione is achieved under the same conditions when N-methyl-N,3-diphenylpropiolate is used as the substrate.

---

As a privileged scaffold, the coumarin core is ubiquitous in many bioactive natural products and pharmaceuticals.¹ Understandably, particular emphasis has been put on the development of methodologies for its synthesis, with an aim to develop facile and efficient protocols to provide coumarin and coumarin-based compound libraries.² The Pechmann condensation, recognized as one of the most attractive approaches, represents an elegant method to construct the coumarin core.³ Additionally, transitional metal catalysis (especially palladium catalysis) provides an alternative route to various coumarins.⁴ Despite these achievements, it is still highly desirable to develop novel synthetic methodologies for the preparation of coumarin derivatives, due to the demands of chemical genetic research and the process of coumarin-based drug discovery.

The bromo group is a very important synthon in the field of organic synthesis since it can be elaborated into other versatile building blocks through known nucleophilic substitution and transitional metal-catalyzed coupling reactions. In this respect, tremendous efforts have been made to introduce bromo groups into structures of interest.⁵ The bromination of alkynes attracts ever-growing interest from chemists. Particularly, numerous heterocyclic compounds have been synthesised via electrophilic bromination of alkynes combined with sequential cyclization. However, the selective formation of exo-dig-cyclization products and endo-dig-cyclization products is still challenging (Scheme 1a).⁶ With the development of palladium chemistry, bromopalladation has also been employed to incorporate bromo groups into alkynes to provide bromo-elaborated architectures. In these transformations, the bromo group is generally introduced into the product via a selective exo-dig-cyclization (Scheme 1b) and a trans-bromovinylpalladium species is involved as a key intermediate.⁷

Scheme 1 Reaction design for the synthesis of 3-bromocoumarins via a radical process.

Guided by the above results and considering the versatility of the bromo group in organic synthesis, in this paper we exploit the addition of bromo radicals to alkynes. Combined with cyclization, we envisioned that a radical brominative addition of alkynes may selectively give rise to endo-dig-cyclization products (Scheme 1c). Considering the importance of coumarin derivatives, we turned our attention to alkynoate-based transformations for the synthesis of 3-bromocoumarins, an important synthon for the construction of antimicrobial inhibitors, fluorescent dyes, and mercury detection sensors.⁸ Traditional methods towards 3-bromocoumarins have been focused on the electrophilic bromination of the prepared coumarins.⁹ These known protocols often use liquid bromine as a bromo source (also including in situ generated liquid bromine from oxidation of HBr/Et₄NBr by oxone/Dess–Martin reagent).^9a–c In the method reported herein, we employed tetra-n-butyl ammonium bromide (TBAB) as the bromo source. We assumed that TBAB would be oxidized by K₂S₂O₈ into a bromo radical, and importantly the generated bromo radical did not undergo homocoupling to liquid bromine. According to our previous findings,¹⁰ we hypothesized that the bromo radical would add to the triple bond of the alkynoate, followed by oxidative spiro-cyclization and 1,2-migration of the ester group to provide 3-bromocoumarin. In this planned transformation, the bromo-incorporated spiro-bicycle cation A was proposed as a critical intermediate (Scheme 1c).

In our preliminary trials, we were pleased to find that the model reaction of tolyl alkynoate 1a with TBAB 2a gave the desired product in 42% yield in the presence of 2.0 equiv. K₂S₂O₈ in 1,2-dichloroethane/H₂O (v/v 1 : 1) at 60 °C (Table 1, entry 1). As expected, structure identification by NMR, HRMS, and X-ray diffraction suggested that the desired 3-bromo-7-methylcoumarin 3a had been synthesised.¹⁴ The 3-bromo-6-methylcoumarin 3a′, which should be observed according to the results reported by Wu and Wang,¹¹ was not detected in this reaction. From this result, it seemed that our proposed pathway involving a radical bromination, oxidative spiro-cyclization and 1,2-ester migration was reliable. Comparing the product 3a with 3a′, the methyl group in the coumarin core migrated from the C6 position to the C7 position due to the 1,2-migration of the ester group (Scheme 2). This protocol represents a safe and efficient alternative to traditional methods for the synthesis of 3-bromocoumarins.

Scheme 2 Synthetic applications of 3-bromocourmarins. Isolated yield based on alkynoates.

Table 1 Initial studies for the metal-free based reaction of alkynoate 1a with TBAB 2b ^a

Entry	Solvent	Oxidant	Temp. (°C)	Yield^b (%)
a Reaction conditions: alkynoates 1a (0.2 mmol), tetra-n-butyl amonium bromide (TBAB) 2b (1.0 equiv.), K2S2O8 (2.0 equiv.), overnight. b Isolated yield based on alkynoates 1a. c In the presence of 2.0 equiv. TBAB. d 2.5 equiv. TBAB was added. e 2.0 equiv. TEMPO was added as an additive. f The starting material disappeared and many byproducts were observed.
1	DCE/H2O (v/v = 1 : 1)	K2S2O8(2.0 equiv.)	60	42
2	MeCN/H2O (v/v = 1 : 1)	K2S2O8(2.0 equiv.)	60	27
3	DCE	K2S2O8(2.0 equiv.)	60	NR
4	H2O	K2S2O8(2.0 equiv.)	60	11
5	MeOH/H2O (v/v = 1 : 1)	K2S2O8(2.0 equiv.)	60	Messy^f
6	DCE/H2O (v/v = 1 : 2)	K2S2O8(2.0 equiv.)	60	36
7	DCE/H2O (v/v = 2 : 1)	K2S2O8(2.0 equiv.)	60	28
8	DCE/H2O (v/v = 1 : 1)	K2S2O8(3.0equiv.)	60	41
9	DCE/H2O (v/v = 1 : 1)	K2S2O8(1.5 equiv.)	60	42
10	DCE/H2O (v/v = 1 : 1)	(NH4)2S2O8(1.5 equiv.)	60	37
11	DCE/H2O (v/v = 1 : 1)	K2S2O8(1.5 equiv.)	80	52
12	DCE/H2O (v/v = 1 : 1)	K2S2O8(1.5 equiv.)	90	58
13	DCE/H2O (v/v = 1 : 1)	K2S2O8(1.5 equiv.)	100	60
14	DCE/H 2 O (v/v = 1 : 1)	K 2 S 2 O 8 (1.5 equiv.)	90	72
15^d	DCE/H2O (v/v = 1 : 1)	K2S2O8(1.5 equiv.)	90	75
16^e	DCE/H2O (v/v = 1 : 1)	K2S2O8(1.5 equiv.)	90	NR

---

Encouraged by these results, we optimized the reaction conditions. Relevant factors including oxidant, solvent, temperature etc. were evaluated. The results are illustrated in Table 1. From the solvent screening, it seemed that a co-solvent was critical in the reaction, and a mixture of DCE and water (v/v = 1 : 1) was the best choice (entry 1, Table 1). This is probably because water can improve the solubility of the oxidant K₂S₂O₈. The use of a co-solvent probably stabilizes the bromo radical, thus lowering the tendency towards the formation of liquid bromine via homocoupling. The use of DCE or H₂O only did not improve the reaction (entries 3 and 4, Table 1). The reactions using other mixtures such as MeOH/H₂O or MeCN/H₂O did not give better yields (entries 2 and 5, Table 1). Changing the DCE/H₂O ratio did not improve the efficiency of the reaction (entries 6 and 7, Table 1). Increasing the oxidant loading did not have significant impact on the yield (entry 8, Table 1). An identical result was observed when the loading of oxidant K₂S₂O₈ was decreased to 1.5 equiv. (entry 9, Table 1). Other oxidants such as (NH₄)₂S₂O₈ and TBHP were also explored, and no improvements were detected (entry 10, Table 1). From the results of the temperature screening, the temperature affected the yields significantly. When the reaction was run at 80 °C, the yield improved to 52% (entry 11, Table 1). Further increase of the temperature to 90 °C gave a better yield (58%, entry 12, Table 1). However, when the reaction was carried out at 100 °C, the yield of the reaction did not change significantly (entry 12, Table 1). The loading of TBAB was critical for the reaction efficiency. By altering the amount of TBAB from 1.0 equivalent to 2.0 equivalents, the reaction efficiency improved greatly, leading to the desired product 3a in 72% yield (entry 14, Table 1). A comparable yield was achieved when the loading of TBAB was increased to 2.5 equiv. (entry 15, Table 1). In order to understand the mechanism of the reaction, 2.0 equivalents of TEMPO were added (entry 16, Table 1). The negative result indicated that the transformation probably followed a radical pathway.

With the optimized conditions in hand (2.0 equiv. TBAB, 2.0 equiv. K₂S₂O₈, in DCE/H₂O (v/v 1 : 1) at 90 °C), we examined the scope of the reaction. The results are presented in Table 2. From the results shown in Table 2, various R¹ substituents were suitable for the reaction. The corresponding products 3a–3j were delivered in 63–78% yields. For example, the reactions using bromo, iodo, and acetyl-bearing alkynoates 1g–1i gave the corresponding products 3g–3i in good yields. The scope of the substituents R² was also explored. From the results, it seems that aryl groups were more favorable for the formation of 3-bromocoumarins. For example, the reaction of phenyl 3-phenylpropiolate provided 3-bromo-4-phenylcoumarin 3j in 80% yield, while the reaction of phenyl 3-cyclopropylpropiolate produced 3-bromo-4-cyclopropylcoumarin 3k in 42% yield. The electronic effect of aryl R² groups did not affect the yields significantly. The reactions using substrates with methyl, fluoro, chloro, and methoxyl substitutents offered similar yields, providing the corresponding products 3l–3o in good yields. To our surprise, under the standard conditions the reactions using tetra-n-butylammonium fluoride (TBAF), tetra-n-butylammonium chloride (TBAC) and tetra-n-butylammonium iodide (TBAI) as halo sources did not give the desired halogenated coumarins.

Table 2 Synthesis of substituted 3-bromocoumarins via a metal free based spiro-cyclization of alkynoates and TBAB^a

a Isolated yield based on alkynoates 1.

---

As mentioned above, the bromo group is a versatile building block. Structural elaboration was thus performed. From the results presented in Scheme 2, alkynyl groups and phosphite groups were successfully installed onto the coumarin core through transition-metal-catalyzed coupling reactions in good yields.

In order to expand the application of this radical process, the reaction of N-methyl-N-3-diphenylpropiolamide 1p and TBAB was also carried out. To our surprise, a distinctive spiro [4,5]trienyl-2,8-dione 6 was observed in reasonable yields (Scheme 3). Water from the solvent was incorporated into spiro-[4,5]trienyl-2,8-dione 6.

Scheme 3 Metal-free based spiro-cyclization of N-methyl-N,3-diphenylpropiolamide 1p and TBAB. Isolated yield based on alkynoates 1.

In light of the above results (especially, the result from entry 16, Table 1), a radical process involving the brominative addition of alkynes, oxidative spiro-cyclization¹² and 1,2-ester migration was proposed to account for the formation of 3-bromocoumarins. As illustrated in Scheme 4, a bromo radical was obtained from the treatment of TBAB with K₂S₂O₈.¹³ The generated bromo radical selectively adds to the α-carbon of propiolate to produce intermediate A. A sequential spiro-cyclization offered intermediate B, which was oxidized to a key intermediate C. 1,2-Ester migration of the intermediate C gave a coumarin cation D. Re-aromatization of the intermediate D provided the desired coumarins 3. The formation of [4,5]trienyl-2,8-dione 6 did not undergo amide migration but cation isomerization of intermediate C, where key intermediate E was formed. Subsequently, intermediate E was trapped by the water from the solvent to give F, which was oxidized to the desired [4,5]trienyl-2,8-dione 6. However, the selective formation of intermediates D and E from the same intermediate C remains to be explained. Related studies are underway in our laboratory.

Scheme 4 A possible mechanism involving tandem oxidative radical spiro cyclization and carbon cation rearrangement.

In conclusion, we have developed a metal-free and liquid bromine-free protocol for the synthesis of 3-bromocoumarins. In these reactions, tetra-n-butyl ammonium bromide was employed as bromo radical source in the presence of K₂S₂O₈. A preliminary exploration of the mechanism showed that a radical process consisting of a radical brominative addition of alkynoates, oxidative spiro-cyclization and 1,2-migration of esters was involved. Under the same conditions, the reaction of N-methyl-N-3-diphenylpropiolamide 1p and TBAB gave 3-bromo-1-methyl-4-phenyl-1-azaspiro[4.5]deca-3,6,9-triene-2,8-dione 6. More importantly, the prepared 3-bromocoumarins were useful synthons, which were converted into alkynyl, phosphite, aryl and arylamino-substituted coumarins. Applications of this radical process to the synthesis of other heterocycles are ongoing in our laboratory, and the results will be reported in due course.

Experimental section

Alkynoates 1 (0.2 mmol), TBAB 2 (2.0 equiv.), and K₂S₂O₈ (1.5 equiv.) were added into the test tube, and then the solvent mixture DCE/H₂O (1 : 1 v/v, 2 mL) was added. The mixture was stirred at 90 °C overnight. After completion of the reaction as indicated by TLC, the mixture was filtrated, and the filtrate was extracted with EtOAc, and dried by anhydrous Na₂SO₄. Evaporation of the solvent followed by purification on silica gel provided the products 3 and 6.

Coumarin 3a (0.2 mmol), ethynyltrimethylsilane (1.5 equiv.), CuI (2.5 mol%) and Pd(PPh)₃Cl₂ (5 mol%) were added into the test tube, and then Et₃N was added. The mixture was stirred at 55 °C for 24 h. After completion of reaction as indicated by TLC, evaporation of the solvent followed by purification on silica gel provided the product 4.

Coumarin 3a (0.2 mmol), diethyl phosphonate (2.0 equiv.) and Pd(PPh)₄ (10 mol%) were added into a thick-walled pressure bottle, and then Et₃N was added. The mixture was stirred at 90 °C for 24 h. After completion of the reaction as indicated by TLC, evaporation of the solvent followed by purification on silica gel provided the product 5.

3-Bromo-7-methyl-4-phenyl-2H-chromen-2-one 3a (78%, 49.0 mg):

¹H NMR (400 MHz, CDCl₃) δ 7.61–7.50 (m, 3H), 7.30 (d, J = 7.6, 2H), 7.21 (s, 1H), 7.04–6.94 (m, 2H), 2.44 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 157.53, 154.61, 152.47, 143.44, 135.36, 129.22, 128.74, 128.03, 127.26, 125.86, 117.92, 116.86, 111.19, 21.61; HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₆H₁₁BrNaO₂⁺: 336.9840; found: 336.9835.

3-Bromo-7-tert-butyl-4-phenyl-2H-chromen-2-one 3b (75%, 53.4 mg)

¹H NMR (400 MHz, CDCl₃) δ 7.57–7.51 (m, 3H), 7.42–7.41 (m, 1H), 7.32–7.20 (m, 3H), 7.01 (d, J = 8.5 Hz, 1H), 1.34 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ 157.65, 156.71, 154.49, 152.50, 135.40, 129.23, 128.74, 128.06, 127.11, 122.21, 117.86, 113.54, 111.43, 35.24, 30.92; HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₉H₁₇BrNaO₂⁺: 379.0310; found: 379.0340.

7-Benzyl-3-bromo-4-phenyl-2H-chromen-2-one 3c (73%, 56.9 mg)

¹H NMR (400 MHz, CDCl₃) δ 7.59–7.54 (m, 3H), 7.34–7.24 (m, 6H), 7.20 (d, J = 7.0 Hz, 2H), 7.05–7.02 (m, 2H), 4.06 (s, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 157.41, 154.50, 152.56, 146.52, 139.21, 135.28, 129.25, 128.86, 128.74, 128.70, 128.00, 127.55, 126.61, 125.46, 118.43, 116.77, 111.59, 41.70; HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₂H₁₅BrNaO₂⁺: 413.0153; found: 413.0148.

3-Bromo-7-methoxy-4-phenyl-2H-chromen-2-one 3d (63%, 41.6 mg)

¹H NMR (400 MHz, CDCl₃) δ 7.59–7.49 (m, 3H), 7.33–7.25 (m, 2H), 6.97 (d, J = 8.9 Hz, 1H), 6.92–6.88 (m, 1H), 6.79–6.71 (m, 1H), 3.88 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 162.89, 157.73, 154.74, 154.18, 135.48, 129.22, 128.74, 128.61, 128.05, 113.94, 112.82, 108.72, 100.59, 55.84; HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₆H₁₁BrNaO₃⁺: 352.9789; found: 352.9796.

3-Bromo-7-fluoro-4-phenyl-2H-chromen-2-one 3e (65%, 41.2 mg)

¹H NMR (400 MHz, CDCl₃) δ 7.61–7.55 (m, 3H), 7.31–7.29 (m, 2H), 7.15–7.07 (m, 2H), 6.96–6.91 (m, 1H);¹³C NMR (100 MHz, CDCl₃) δ 164.38 (d, ¹J_CF = 255.3 Hz), 154.14, 153.46 (d, ³J_CF = 12.9 Hz), 135.07, 129.51, 129.43, 129.33, 128.94, 127.97, 117.10, 112.81 (d, ²J_CF = 22.6 Hz), 111.39, 104.33 (d, ²J_CF = 25.8 Hz); HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₅H₈BrFNaO₂⁺: 340.9589; found: 340.9584.

3-Bromo-7-chloro-4-phenyl-2H-chromen-2-one 3f (71%, 47.4 mg)

¹H NMR (400 MHz, CDCl₃) δ 7.63–7.52 (m, 3H), 7.43–7.40 (m, 1H), 7.33–7.26 (m, 2H), 7.20–7.14 (m, 1H), 7.02 (d, J = 8.6 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 156.71, 153.97, 152.58, 137.95, 134.85, 129.55, 128.97, 128.46, 127.97, 125.28, 118.95, 117.03, 112.54; HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₅H₈BrClNaO₂⁺: 356.9294; found: 356.9288.

3,7-Dibromo-4-phenyl-2H-chromen-2-one 3g (68%, 51.4 mg)

¹H NMR (400 MHz, CDCl₃) δ 7.60–7.53 (m, 4H), 7.32–7.27 (m, 3H), 6.94 (d, J = 8.6 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 154.06, 152.56, 134.85, 129.59, 129.01, 128.57, 128.16, 128.01, 125.97, 120.04, 119.36, 112.81; HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₅H₈Br₂NaO₂⁺: 400.8789; found: 400.8781.

3-Bromo-7-iodo-4-phenyl-2H-chromen-2-one 3h (68%, 57.9 mg)

¹H NMR (400 MHz, CDCl₃) δ 7.79–7.75 (m, 1H), 7.60–7.55 (m, 3H), 7.51 (d, J = 8.4, 1H), 7.30–7.28 (m, 2H), 6.78 (d, J = 8.4 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 156.46, 154.08, 152.11, 134.70, 133.93, 129.52, 128.94, 128.45, 127.95, 125.79, 119.79, 113.00, 97.51; HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₅H₈BrINaO₂⁺: 448.8650; found: 448.8645.

7-Acetyl-3-bromo-4-phenyl-2H-chromen-2-one (3i) (69%, 47.2 mg)

¹H NMR (400 MHz, CDCl₃) δ 7.94–7.92 (m, 1H), 7.76–7.73 (m, 1H), 7.63–7.56 (m, 3H), 7.32–7.29 (m, 2H), 7.19 (d, J = 8.3 Hz, 1H), 2.65 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 196.22, 156.79, 153.71, 152.22, 139.31, 134.74, 129.62, 129.01, 127.97, 123.87, 123.48, 116.65, 115.2, 109.92, 26.77; HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₇H₁₁BrNaO₃⁺: 364.9789; found: 364.9782.

3-Bromo-4-phenyl-2H-chromen-2-one (3j) (80%, 48.0 mg)

¹H NMR (400 MHz, CDCl₃) δ 7.60–7.55 (m, 4H), 7.42 (d, J = 8.3 Hz, 1H), 7.34–7.30 (m, 2H), 7.23–7.18 (m, 1H), 7.09 (d, J = 8.0 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 157.29, 154.59, 152.41, 135.22, 132.00, 129.31, 128.81, 128.03, 127.57, 124.67, 120.28, 116.76, 112.57; HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₅H₉BrNaO₂⁺: 322.9684; found: 322.9691.

3-Bromo-4-cyclopropyl-2H-chromen-2-one (3k) (42%, 22.2 mg)

¹H NMR (400 MHz, CDCl₃) δ 8.14 (d, J = 8.3 Hz, 1H), 7.60–7.51 (m, 1H), 7.39–7.29 (m, 2H), 1.99–1.85 (m, 1H), 1.43–1.32 (m, 2H), 0.95–0.87 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 157.42, 153.51, 151.91, 131.59, 125.54, 124.42, 120.64, 116.89, 115.53, 14.43, 9.39; HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₂H₉BrNaO₂⁺: 286.9684; found: 286.9678.

3-Bromo-4-p-tolyl-2H-chromen-2-one (3l) (67%, 42.1 mg)

¹H NMR (400 MHz, CDCl₃) δ 7.59–7.55 (m, 1H), 7.42–7.37 (m, 3H), 7.22–7.18 (m, 3H), 7.13 (d, J = 8.0 Hz, 1H), 2.48 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 157.35, 154.76, 152.38, 139.39, 132.24, 131.92, 129.45, 127.99, 127.66, 124.60, 120.38, 116.71, 112.51, 21.40; HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₆H₁₁BrNaO₂⁺: 336.9840; found: 336.9835.

3-Bromo-4-(4-fluorophenyl)-2H-chromen-2-one (3m) (64%, 40.7 mg)

¹H NMR (400 MHz, CDCl₃) δ 7.61–7.51 (m, 1H), 7.43 (d, J = 8.3 Hz, 1H), 7.35–7.20 (m, 5H), 7.09 (d, J = 8.0 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 163.10 (d, ¹J_CF = 250.0 Hz), 153.65, 152.44, 132.16, 131.11, 130.28, 130.20, 127.35, 124.78, 120.23, 116.92, 116.15 (d,²J_CF = 21.9 Hz), 113.10; m/z [M + Na]⁺ calcd for C₁₅H₈BrFNaO₂⁺: 340.9589; found: 340.9582.

3-Bromo-4-(4-chlorophenyl)-2H-chromen-2-one (3n) (71%, 53.7 mg)

¹H NMR (400 MHz, CDCl₃) δ 7.60–7.55 (m, 3H), 7.42 (d, J = 8.3 Hz, 1H), 7.28–7.25 (m, 2H), 7.24–7.19 (m, 1H), 7.07 (d, J = 8.0 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 157.07, 153.43, 152.44, 135.59, 133.54, 132.22, 129.62, 129.27, 127.27, 124.82, 120.00, 116.94, 112.91; HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₅H₈BrClNaO₂⁺: 356.9294; found: 356.9288.

3-Bromo-4-(2-methoxyphenyl)-2H-chromen-2-one (3o) (76%, 50.2 mg)

¹H NMR (400 MHz, CDCl₃) δ 7.57–7.51 (m, 2H), 7.40 (d, J = 8.3 Hz, 1H), 7.21–7.14 (m, 3H), 7.10 (d, J = 8.4 Hz, 1H), 7.05 (d, J = 8.0 Hz, 1H), 3.78 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 157.46, 155.79, 152.74, 152.33, 131.69, 131.00, 129.20, 127.20, 124.56, 124.11, 120.86, 120.22, 116.64, 113.57, 111.48, 55.65; HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₆H₁₁BrNaO₃⁺: 352.9789; found: 352.9786.

7-Methyl-4-phenyl-3-((trimethylsilyl)ethynyl)-2H-chromen-2-one (4) (82%, 54.4 mg)

¹H NMR (400 MHz, CDCl₃) δ 7.52–7.50 (m, 3H), 7.42–7.39 (m, 2H), 7.18 (s, 1H), 7.12 (d, J = 8.2 Hz, 1H), 7.01 (d, J = 7.5 Hz, 1H), 2.45 (s, 3H), 0.04 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ 159.68, 157.87, 152.92, 143.70, 134.30, 129.12, 128.77, 128.24, 128.04, 127.34, 125.66, 117.06, 109.66, 104.68, 98.30, 21.63, −0.56; HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₁H₂₀NaO₂Si⁺: 355.1130; found: 355.1125.

Diethyl 7-methyl-2-oxo-4-phenyl-2H-chromen-3-ylphosphonate (5) (76%, 64.1 mg)

¹H NMR (400 MHz, CDCl₃) δ 7.44–7.43 (m, 3H), 7.26–7.25 (m, 2H), 7.10 (s, 1H), 6.92–6.84 (m, 2H), 4.08–3.96 (m, 2H), 3.81–3.89 (m, 2H), 2.39 (s, 3H), 1.07 (m, 6H); ¹³C NMR (100 MHz, CDCl₃) δ 162.32 (d, J = 6.6 Hz), 159.02 (d, J = 16.3 Hz), 153.76, 145.21, 135.01 (d, J = 4.8 Hz), 128.62, 128.58, 127.91, 127.77, 125.40, 117.49 (d, J = 14.2 Hz), 116.57, 115.02 (d, J = 201.0 Hz), 62.40 (d, J = 6.0 Hz), 21.50, 15.89 (d, J = 6.3 Hz); ³¹P NMR (162 MHz, CDCl₃) δ 11.06; HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₀H₂₁NaO₅P⁺: 395.1024; found: 395.1019.

1-Acetyl-3-bromo-4-phenyl-1-azaspiro[4.5]deca-3,6,9-triene-2,8-dione (6) (42%, 30.4 mg)

¹H NMR (400 MHz, CDCl₃) δ 7.48–7.35 (m, 3H), 7.23–7.17 (m, 2H), 6.56 (d, J = 10.1 Hz, 2H), 6.40 (d, J = 10.6 Hz, 2H), 2.64 (s, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 183.69, 168.50, 164.41, 156.22, 142.81, 132.49, 130.53, 128.57, 128.11, 119.15, 68.49, 25.59; HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₇H₁₃BrNO₃⁺: 358.0079; found: 358.0072.

Acknowledgements

Financial support from the National Natural Science Foundation of China (no. 21502069) and the Natural Science Foundation of Zhejiang Province (No. LQ15B020006) is gratefully acknowledged.

Notes and references

1. For selected examples, see: (a) B. Naser-Hijazi, B. Stolze and K. Zanker, Second Proceedings of the International Society of Coumarin Investigators, Springer, Berlin, 1994; (b) L. Santana, E. Uriarte, F. Roleira, N. Milhazes and F. Borges, Curr. Med. Chem., 2004, 11, 3239; (c) F. Borges, F. Roleira, N. Milhazes, L. Santana and E. Uriarte, Curr. Med. Chem., 2005, 12, 887; (d) B. M. Trost and F. Tost, J. Am. Chem. Soc., 1996, 118, 6305; (e) X. Peng, G. Damu and C. Zhou, Curr. Pharm. Des., 2013, 19, 3884.
2. For selected reviews of the synthesis of coumarins, see: (a) R. Vekariya and H. Patel, Synth. Commun., 2014, 44, 2756; (b) S. Trenor, A. Shulty, B. Love and T. Long, Chem. Rev., 2004, 104, 3059; (c) S. Sethna and N. Shah, Chem. Rev., 1945, 36, 1.
3. S. Sethna and R. Phadke, Organomet. React., 1953, 7, 1.
4. For selected examples see: (a) B.-M. Trost and F.-D. Toste, J. Am. Chem. Soc., 1996, 118, 6305; (b) J. Ferguson, F. Zeng and H. Alper, Org. Lett., 2012, 14, 5602; (c) M. Amézquita-Valencia and H. Alper, Org. Lett., 2014, 16, 5827.
5. For selected reviews, see: (a) P. S. Skell and J. G. Traynham, Acc. Chem. Res., 1984, 15, 160; (b) M. F. Ruass, Acc. Chem. Res., 1990, 23, 87; (c) C. J. Easton and C. A. Hutton, Synlett, 1998, 457.
6. For selected reviews, see: (a) R. S. Brown, Acc. Chem. Res., 1997, 30, 131; (b) N. Suryakiran, Synlett, 2008, 1267; (c) S.-H. Yang, Synlett, 2009, 1351; (d) G. Qiu, Y. Kuang and J. Wu, Adv. Synth. Catal., 2014, 356, 3483.
7. For selected examples, see: (a) G. Zhu and Z. Zhang, J. Org. Chem., 2005, 70, 3339; (b) X.-C. Huang, F. Wang, Y. Liang and J.-H. Li, Org. Lett., 2009, 11, 1139; (c) X. Lu, Handbook of Organopalladium Chemistry for Organic Synthesis, John Wiley & Sons, Inc, 2002, vol. 2, p. 2267; (d) X. Lu, Z. Wang and A. Lei, Current Trends In Organic Synthesis, Proceedings of the international Conference on Organic Synthesis, 12th, Venezia, June 28–July 2, 1998, 275.
8. For selected examples, see: (a) S. S. Soman and T. H. Thaker, Med. Chem. Res., 2013, 22, 4223; (b) T. H. V. Huynh, B. Abrahamsen, K. K. Madsen, A. Franquesa-Gonzalez, A. A. Jensen and L. Bunch, Bioorg. Med. Chem., 2012, 20, 6831; (c) L. Meimetis, J. Carlson, R. Giedt, R. Kohler and R. Weissleder, Angew. Chem., Int. Ed., 2014, 53, 7531; (d) M.-S. Schiedel, C. A. Briehn and P. Bauerle, Angew. Chem., Int. Ed., 2001, 40, 4677; (e) L. Zhang, T. Meng, R. Fan and J. Wu, J. Org. Chem., 2007, 72, 7279.
9. For selected examples, see: (a) K.-M. Kim and I.-H. Park, Synthesis, 2004, 2641; (b) G. V. Ramanarayanan, V. G. Shukla and K. G. Akamanchi, Synlett, 2002, 2059; (c) M. A. Kumar, C. N. Rohitha, S. J. Kulkarni and N. Narender, Synthesis, 2010, 1629; (d) C.-G. Cho, J.-S. Park, I.-H. Jung and H. Lee, Tetrahedron Lett., 2001, 42, 1065; (e) R. M. Kelkar, U. K. Joshi and M. V. Paradkar, Synthesis, 1986, 214.
10. (a) T. Liu, Q. Ding, Q. Zong and G. Qiu, Org. Chem. Front., 2015, 2, 670; (b) T. Liu, Q. Ding, G. Qiu and J. Wu, Tetrahedron, 2016, 72, 279.
11. (a) W. Yang, S. Yang, P. Li and L. Wang, Chem. Commun., 2015, 51, 7520; (b) W. Fu, M. Zhu, G. Zou, C. Xu, Z. Wang and B. Ji, J. Org. Chem., 2015, 80, 4766; (c) K. Yan, D. Yang, W. Wei, F. Wang, Y. Shuai, Q. Li and H. Wang, J. Org. Chem., 2015, 80, 1550; (d) W. Wei, J. Wen, D. Yang, M. Guo, Y. Wang, J. You and H. Wang, Chem. Commun., 2015, 51, 768; (e) Y. Li, Y. Lu, G. Qiu and Q. Ding, Org. Lett., 2014, 16, 4240; (f) X. Mi, C. Wang, M. Huang, J. Zhang, Y. Wu and Y. Wu, Org. Lett., 2014, 16, 3356.
12. For selected examples of electrophilic spiro-cyclizations of alkynoates, see: (a) T. Okitsu, D. Nakazawa, A. Kobayashi, M. Mizohata, Y. In, T. Ishida and A. Wada, Synlett, 2010, 203; (b) X. Zhang and R. C. Larock, J. Am. Chem. Soc., 2005, 127, 12230; (c) T. Dohi, D. Kato, R. Hyodo, D. Yamashita, M. Shirao and Y. Kita, Angew. Chem., Int. Ed., 2011, 50, 3784; (d) B.-X. Tang, D.-J. Tang, S. Tang, Q.-F. Yu, Y.-H. Zhang, Y. Liang, P. Zhong and J.-H. Li, Org. Lett., 2008, 10, 1063; (e) B.-C. Tang, Y.-H. Zhang, R.-J. Song, D.-J. Tang, G.-B. Deng, Z.-Q. Wang, Y.-X. Xie, Y.-Z. Xia and J.-H. Li, J. Org. Chem., 2012, 77, 2837; (f) B.-X. Tang, Q. Yin, R.-Y. Tang and J.-H. Li, J. Org. Chem., 2008, 73, 9008; (g) J. Wen, W. Wei, S. Xue, D. Yang, Y. Lou, C. Gao and H. Wang, J. Org. Chem., 2015, 80, 4966; (h) Y. Chen, X. Liu, M. Lee, C. Huang, I. Inoyatov, Z. Chen, A. C. Perl and W. H. Hersh, Chem. – Eur. J., 2013, 19, 9795; (i) L.-J. Wang, A.-Q. Wang, Y. Xia, X.-X. Wu, X.-Y. Liu and Y.-M. Liang, Chem. Commun., 2014, 50, 13998; (j) W.-T. Wei, R.-J. Song, X.-H. Ouyang, Y. Li, H.-B. Li and J.-H. Li, Org. Chem. Front., 2014, 1, 484; (k) H. Cui, W. Wei, D. Yang, J. Zhang, Z. Xu, J. Wen and H. Wang, RSC Adv., 2015, 5, 84657.
13. (a) K. Moriyama, Y. Nakamura and H. Togo, Org. Lett., 2014, 16, 3812; (b) U. Dutta, A. Deb, D. Lupton and D. Maiti, Chem. Commun., 2015, 51, 17744.
14. CCDC 1439381 contains the supplementary crystallographic data for this paper.

---

Footnote

† Electronic supplementary information (ESI) available: Experimental procedure, characterization data, ¹H and ¹³C NMR spectra of compounds 3. CCDC 1439381 (compound 3a). For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6qo00041j

---