A Concise Synthesis of Asymmetrically 4,5-Disubstituted 9,9-Dimethyl-9H-xanthenes

Abstract

A concise synthesis of asymmetrically 4,5-disubstituted 9,9-dimethyl-9H-xanthenes was developed. The monolithiation of 4,5-dibromo-9H-xanthene, subsequent zincation, and the Negishi coupling with diverse electrophiles afforded the corresponding 4-aryl- or 4-vinyl-9H-xanthenes in good yields and with high selectivity. The second substitution reactions were performed under mild reaction conditions, thus providing a convenient synthetic route to functionalized molecules based on the 9H-xanthene skeleton.

9,9-Dimethyl-9H-xanthene (9,9-DMX) has a rigid architecture (Figure [1]); the two substituents at the 4- and 5-positions are located in parallel to each other with a fixed distance. Therefore, 9,9-DMX can be used as a backbone of the functionalized molecules with the active sites at the 4- and 5-positions of 9,9-DMX, as exemplified by Xantphos,[1] a bidentate phosphine ligand with a large bite angle. Several asymmetrically 4,5-disubstituted 9,9-DMXs (R¹ ≠ R²) have been reported as functionalized materials and catalysts as shown in Figure [2].[2]

4,5-Dibromo-9,9-DMX is the common intermediate of the asymmetrically 4,5-disubstituted 9,9-DMXs, which were often further substituted by di-tert-butyl groups at the 2- and 7-positions.[3] The modification of only one bromine atom was implemented by the halogen–lithium exchange with alkyllithium reagents followed by nucleophilic reactions.[2] The exception is the synthesis of a chemosensor dye,[4] in which the Mizoroki–Heck reaction of 4,5-dibromo-9,9-DMX with a vinylarene afforded the monoadduct, albeit with low selectivity (mono/di = 4:1). To the best of our knowledge, the selective monoarylation of 4,5-dibromo-9,9-DMXs by coupling reactions has not been reported. In this paper, we report a concise synthesis of asymmetrically 4,5-disubstituted 9,9-DMXs using the selective coupling reactions.

First, the transition-metal-catalyzed cross-coupling reaction of 1 with arylboronic acid was attempted (Scheme [1]). Because monoarylated product 2 may be less reactive than starting material 1 due to steric hindrance, a selective monocoupling reaction may be possible. Therefore, the reaction of equimolar amounts of 1 and arylboronic acid was carried out in the presence of Pd(PPh₃)₄ as the catalyst. However, a mixture of monoarylated product 2 and di­arylated product 3 was obtained in a nonselective manner (2/3 = 2:1 to 1:1). A change in the solvent, base, or the transition metal catalyst did not improve the selectivity of the reaction.[5] To our surprise, even when two equivalents of 1 to arylboronic acid were used, the selectivity did not improve; a considerable amount of 3 was still obtained. This is probably because the π-electrons of the newly substituted aryl group of 2 may coordinate to the palladium catalyst and promote its oxidative addition to the second C–Br bond, resulting in more amounts of diarylated product 3 than that expected only because of the steric factor (Scheme [2]).

Finding that the C–Br bonds of 1 and 2 have similar susceptibility to oxidative addition by palladium, another strategy was considered, in which 1 would be subjected to halogen–metal exchange resulting in monometalation, followed by treatment with a haloarene. Under the optimized reaction conditions, the organozinc species prepared by the treatment of 1 with t-BuLi (1.2 equiv) followed by ZnCl₂ (1.4 equiv) underwent the Negishi cross-coupling reaction[6] with methyl 4-iodobenzoate (1.4 equiv) in the presence of the palladium catalyst (10 mol%) to afford monoarylated product 2a in 68% yield (Table [1], entry 1). Diarylated product 3 was obtained in <5% yield. The selectivity in the lithiation was determined to be 5:86:9 (1/Li-1/Li₂-1) by the treatment of the lithiated xanthenes with MeOH. With the suitable reaction conditions for the selective monoarylation of 1, the substrate scope of this reaction was investigated (Table [1]). Diverse aryl iodides participated in the Negishi coupling resulting in moderate to good yields, regardless of the electronic nature of the substituents on aryl iodides (entries 2–6). The xanthenes with a formyl group could be synthesized efficiently (entries 7 and 8). The basic nitrogen atom did not affect the cross-coupling reaction (entry 9). Both aryl and vinyl iodides underwent coupling with 1 under the standard reaction conditions; vinyl-9H-xanthene 2j was obtained in a reasonable yield (52%, entry 10). The intermediate organozinc species derived from 1 could be trapped using an acid chloride without catalyst, affording monoacylated product 2k (entry 11).

Table 1 Monofunctionalization of 4,5-Dibromo-2,7-di-tert-butyl-9,9-dimethyl-9H-xanthene^a

Entry	Electrophile	Product	Yield (%)b
1		2a	68
2		2b	73
3		2c	52
4		2d	57
5		2e	54
6		2f	58
7		2g	50
8		2h	70
9		2i	69
10		2j	52
11c		2k	34

^a See the experimental section for details.

^b Isolated yield.

^c Pd(dba)₂ and Ph₃P were not added.

To demonstrate the utility of the developed method for the synthesis of asymmetrically 4,5-disubstituted 9,9-DMXs, several functionalizations of product 2a were conducted (Scheme [3]).[7] The olefination of 2a resulted in high yields by either Migita–Kosugi–Stille coupling[8] (step b) or Mizoroki–Heck reaction[9] (step c). The Suzuki–Miyaura coupling[10] of 2a introduced the second aryl substituent into the 9H-xanthene backbone (step d). The Miyaura boration[11] of 2a proceeded smoothly to afford borylated 9H-xanthene 7 in a high yield (step e). Pinacol borate 7 served as the intermediate for further transformations to synthesize diverse asymmetrically 4,5-disubstituted 9,9-DMXs. The Suzuki–Miyaura coupling of 7 with an aryl iodide afforded the corresponding 4,5-diaryl-9,9-DMX 6b (step f). The oxidation of 7 with sodium perborate introduced a hydroxyl group on the 9H-xanthene scaffold (step g). The installation of the trifluoromethyl group on the 9H-xanthene scaffold could be achieved by reacting 7 with the CuCF₃ reagent (step h).[12] The hydrolysis of 7 [13] followed by the rhodium-catalyzed 1,4-conjugate addition[14] to cyclohex-2-en-1-one afforded alkylated product 10 (step i). Thus, diverse asymmetrically 4,5-disubstituted 9,9-DMXs could be synthesized using this method.

In conclusion, we have developed a concise synthesis of asymmetrically 4,5-disubstituted 9,9-DMXs. The selective metal–halogen exchange of 4,5-dibromo-9,9-DMX afforded a monolithiated species, which was transmetalated to zinc organometallics and coupled with diverse reagents affording the corresponding monofunctionalized 9H-xanthenes. The 9H-xanthenes were then transformed to the corresponding asymmetrically 4,5-disubstituted 9,9-DMXs, which are potentially useful functionalized molecules.

All reactions were carried out in well-cleaned and oven-dried glassware under magnetic stirring. The operations were performed under an atmosphere of dry argon using Schlenk and vacuum techniques. All the starting materials were obtained from commercial sources or synthesized following standard procedures. Melting points were measured using a Yanaco MP-500D instrument and are not corrected. IR spectra were recorded as films on a Thermo Scientific Nicolet iS5 FT-IR­ spectrophotometer in ATR mode. ¹H and ¹³C NMR spectra were recorded using JEOL JNM-LA 400 and Bruker Avance 500 instruments using Me₄Si (δ = 0 ppm) and CDCl₃ (δ = 77.0 ppm) as the internal standard, respectively. Standard abbreviations are used to report NMR spectra. Due to the machine feature, inevitable noises were observed at 96 and 74 ppm in ¹³C NMR spectra taken by the JEOL JNM-LA 400 spectrometer. Mass spectra were measured using a JEOL JMS-T100LP mass spectrometer. Elemental analyses were carried out using a Yanako CHN Corder MT-5 instrument. Preparative column chromatography was carried out using Fuji Silysia BW-4:10MH silica gel or YMC_GEL Silica (6 nm, I-40-63 μm). TLC was carried out using Merck 25 TLC aluminum sheets, silica gel 60 F₂₅₄. 4,5-Dibromo-2,7-di-tert-butyl-9,9-DMX (1) was synthesized according to the reported method.[3]

4-Aryl-5-bromo-2,7-di-tert-butyl-9,9-dimethyl-9H-xanthenes 2a–i and 4-Bromo-2,7-di-tert-butyl-9,9-dimethyl-5-[(1E)-oct-1-en-1-yl]-9H-xanthene (2j); General Procedure

A THF solution of t-BuLi (0.25 M, 0.25 mmol) was added to a stirred solution of 4,5-dibromo-2,7-di-tert-butyl-9,9-DMX (1; 100 mg, 0.21 mmol) in THF (3 mL) over 30 min using a syringe pump at –78 °C. The stirring was continued for 1 h at –78 °C. Then, a THF solution of ZnCl₂ (1 M, 0.29 mL, 0.29 mmol) was added to the solution, and the resulting mixture was warmed to r.t. The stirring was continued for 30 min at r.t., and then Pd(dba)₂ (12 mg, 0.021 mmol), Ph₃P (11 mg, 0.042 mmol) and the appropriate aryl iodide or trans-1-iodooct-1-ene (0.29 mmol) were added to the solution in this order. The mixture was stirred for 24 h at r.t. The reaction was quenched by adding sat. aq NH₄Cl (5 mL), and the mixture was extracted with CH₂Cl₂ (3 × 10 mL). The combined organic layers were dried (MgSO₄), and the residue obtained after evaporation was purified by chromatography on silica gel (EtOAc–hexane) to afford the product.

4-Bromo-2,7-di-tert-butyl-5-[4-(methoxycarbonyl)phenyl]-9,9-dimethyl-9H-xanthene (2a)

Yield: 74.9 mg (68%); white solid; mp 174.9–176.1 °C; R_f = 0.50 (hexane­–EtOAc, 10:1).

IR (neat, ATR): 2962, 2903, 2867, 1719, 1612, 1568, 1477, 1445, 1417, 1398 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.14 (d, J = 8.4 Hz, 2 H), 7.81 (d, J = 8.4 Hz, 2 H), 7.46 (d, J = 2.4 Hz, 1 H), 7.42 (d, J = 2.0 Hz, 1 H), 7.36 (d, J = 2.4 Hz, 1 H), 7.31 (d, J = 2.4 Hz, 1 H), 3.97 (s, 3 H), 1.68 (s, 6 H), 1.37 (s, 9 H), 1.31 (s, 9 H).

¹³C NMR (125 MHz, CDCl₃): δ = 167.3, 146.9, 146.1, 145.2, 142.8, 131.2, 130.3, 130.0, 129.1, 128.6, 128.4, 128.1, 126.1, 122.5, 121.6, 115.6, 110.1, 52.1, 35.3, 34.6, 34.6, 32.1, 31.5, 31.4

HRMS (ESI): m/z [M + Na]⁺ calcd for C₃₁H₃₅BrO₃ + Na: 557.1667; found: 557.1651.

Anal. Calcd for C₃₁H₃₅BrO₃: C, 69.53; H, 6.59. Found: C, 69.90; H, 6.64.

4-Bromo-2,7-di-tert-butyl-9,9-dimethyl-5-phenyl-9H-xanthene (2b)

Yield: 70 mg (73%); white solid; mp 151.5–153.8 °C; R_f = 0.30 (hexane­).

IR (neat, ATR): 2962, 2866, 1602, 1568, 1475, 1456, 1434, 1403, 1362, 1325 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.73 (dd, J = 8.0, 1.6 Hz, 2 H), 7.48–7.44 (m, 2 H), 7.42–7.40 (m, 2 H), 7.38–7.36 (m, 1 H), 7.35 (d, J = 2.4 Hz, 1 H), 7.31 (d, J = 2.4 Hz, 1 H), 1.68 (s, 6 H), 1.37 (s, 9 H), 1.31 (s, 9 H).

¹³C NMR (100 MHz, CDCl₃): δ = 146.7, 145.9, 145.6, 145.3, 138.0, 131.4, 130.3, 129.8, 129.3, 128.3, 127.9, 127.1, 126.3, 121.7, 121.6, 110.2, 35.3, 34.5, 34.5, 32.0, 31.5, 31.3.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₉H₃₃BrO + Na: 499.1613; found: 499.1607.

Anal. Calcd for C₂₉H₃₃BrO: C, 72.95; H, 6.97. Found: C, 72.69; H, 6.98.

4-Bromo-2,7-di-tert-butyl-5-(4-methoxyphenyl)-9,9-dimethyl-9H-xanthene (2c)

Yield: 54.7 mg (52%); white solid; mp 150.3–152.2 °C; R_f = 0.50 (hexane­–benzene, 2:1).

IR (neat, ATR): 2961, 1609, 1514, 1464, 1440, 1422, 1400, 1361 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.68 (d, J = 8.0 Hz, 2 H), 7.41 (d, J = 2.0 Hz, 1 H), 7.38 (d, J = 2.8 Hz, 1 H), 7.35 (d, J = 2.4 Hz, 1 H), 7.29 (d, J = 2.0 Hz, 1 H), 7.02 (d, J = 8.8 Hz, 2 H), 3.88 (s, 3 H), 1.67 (s, 6 H), 1.36 (s, 9 H), 1.31 (s, 9 H).

¹³C NMR (100 MHz, CDCl₃): δ = 158.8, 146.7, 145.9, 145.6, 145.3, 131.4, 131.4, 130.4, 129.7, 128.9, 128.3, 126.1, 121.6, 121.3, 113.3, 110.1, 55.3, 35.3, 34.5, 32.0, 31.5, 31.3.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₃₀H₃₅BrO₂ + Na: 529.1718; found: 529.1714.

Anal. Calcd for C₃₀H₃₅BrO₂: C, 71.00; H, 6.95. Found: C, 70.79; H, 7.00.

4-Bromo-2,7-di-tert-butyl-9,9-dimethyl-5-(4-nitrophenyl)-9H-xanthene (2d)

Yield: 62.3 mg (57%); yellow solid; mp 236.3–237.9 °C; R_f = 0.20 (hexane­–benzene, 10:1).

IR (neat, ATR): 2961, 2902, 2864, 1597, 1515, 1442, 1394, 1344, 1264, 1244 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.33 (d, J = 6.8 Hz, 2 H), 7.90 (d, J = 8.8 Hz, 2 H), 7.51 (d, J = 2.4 Hz, 1 H), 7.43 (d, J = 2.0 Hz, 1 H), 7.37 (d, J = 2.4 Hz, 1 H), 7.30 (d, J = 2.0 Hz, 1 H), 1.69 (s, 6 H), 1.38 (s, 9 H), 1.31 (s, 9 H).

¹³C NMR (100 MHz, CDCl₃): δ = 147.2, 146.9, 146.4, 145.3, 145.1, 145.0, 131.2, 131.1, 130.3, 128.5, 126.9, 126.0, 123.4, 123.2, 121.8, 110.1, 35.3, 34.6, 34.5, 32.1, 31.4, 31.3.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₉H₃₂BrNO₃ + Na: 544.1463; found: 544.1450.

Anal. Calcd for C₂₉H₃₂BrNO₃: C, 66.67; H, 6.17; N, 2.68. Found: C, 66.58; H, 6.24; N, 2.59.

4-(4-Acetylphenyl)-5-bromo-2,7-di-tert-butyl-9,9-dimethyl-9H-xanthene (2e)

Yield: 59.2 mg (54%); white solid; mp 187.4–189.8 °C; R_f = 0.35 (hexane­–EtOAc, 10:1).

IR (neat, ATR): 2960, 2865, 1681, 1605, 1478, 1440, 1395, 1361, 1261, 1243 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.07 (d, J = 8.4 Hz, 2 H), 7.85 (d, J = 8.8 Hz, 2 H), 7.47 (d, J = 2.8 Hz, 1 H), 7.42 (d, J = 2.0 Hz, 1 H), 7.36 (d, J = 2.4 Hz, 1 H), 7.31 (d, J = 2.4 Hz, 1 H), 2.67 (s, 3 H), 1.69 (s, 6 H), 1.38 (s, 9 H), 1.31 (s, 9 H).

¹³C NMR (100 MHz, CDCl₃): δ = 198.3, 147.0, 146.2, 145.3, 145.3, 143.1, 137.9, 135.6, 131.2, 130.5, 130.1, 129.8, 128.4, 128.0, 126.1, 122.7, 121.7, 107.8, 35.3, 34.5, 34.5, 32.1, 31.4, 31.3.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₃₁H₃₅BrO₂ + Na: 541.1718; found: 541.1753.

Anal. Calcd for C₃₁H₃₅BrO₂: C, 71.67; H, 6.79. Found: C, 71.60; H, 6.89.

4-Bromo-2,7-di-tert-butyl-5-(4-cyanophenyl)-9,9-dimethyl-9H-xanthene (2f)

Yield: 60.3 mg (58%); white solid; mp 204.3–206.5 °C; R_f = 0.80 (benzene).

IR (neat, ATR): 2959, 2229, 1607, 1567, 1441, 1394, 1362, 1264, 1247 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.84 (d, J = 8.0 Hz, 2 H), 7.76 (d, J = 8.4 Hz, 2 H), 7.48 (d, J = 2.4 Hz, 1 H), 7.42 (d, J = 2.0 Hz, 1 H), 7.36 (d, J = 2.4 Hz, 1 H), 7.26 (d, J = 2.0 Hz, 1 H), 1.68 (s, 6 H), 1.37 (s, 9 H), 1.31 (s, 9 H).

¹³C NMR (100 MHz, CDCl₃): δ = 206.4, 147.2, 146.4, 145.2, 145.1, 142.9, 131.7, 131.2, 131.0, 130.2, 128.5, 127.4, 125.9, 123.1, 121.7, 110.6, 110.1, 35.3, 34.5, 34.5, 32.1, 31.4, 31.3.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₃₀H₃₂BrNO + Na: 524.1565; found: 524.1538.

4-Bromo-2,7-di-tert-butyl-5-(4-formylphenyl)-9,9-dimethyl-9H-xanthene (2g)

Yield: 51.6 mg (50%); white solid; mp 197.4–199.1 °C; R_f = 0.45 (hexane­–EtOAc, 10:1).

IR (neat, ATR): 2958, 1695, 1605, 1564, 1466, 1443, 1423, 1404, 1391, 1362 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 10.10 (s, 1 H), 7.99 (d, J = 8.0 Hz, 2 H), 7.91 (d, J = 8.0 Hz, 2 H), 7.48 (d, J = 2.4 Hz, 1 H), 7.42 (d, J = 2.0 Hz, 1 H), 7.36 (d, J = 2.0 Hz, 1 H), 7.31 (d, J = 2.4 Hz, 1 H), 1.69 (s, 6 H), 1.38 (s, 9 H), 1.31 (s, 9 H).

¹³C NMR (100 MHz, CDCl₃): δ = 192.5, 147.1, 146.3, 145.3, 145.2, 144.6, 135.0, 131.2, 131.0, 130.2, 129.4, 128.4, 127.9, 126.1, 122.9, 121.7, 35.3, 34.6, 34.5, 32.1, 32.1, 31.4, 31.3.

HRMS (DART): m/z [M + H]⁺ calcd for C₃₀H₃₄BrO₂: 505.1742; found: 505.1739.

4-Bromo-2,7-di-tert-butyl-5-(5-formylfuran-2-yl)-9,9-dimethyl-9H-xanthene (2h)

Yield: 73.2 mg (70%); orange solid; mp 162.3–164.0 °C; R_f = 0.35 (hexane­–EtOAc, 10:1).

IR (neat, ATR): 2961, 1674, 1569, 1511, 1445, 1407, 1363, 1268, 1239, 1220 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 9.71 (s, 1 H), 8.02 (d, J = 4.0 Hz, 1 H), 7.96 (d, J = 2.4 Hz, 1 H), 7.50 (d, J = 2.8 Hz, 1 H), 7.48 (d, J = 2.4 Hz, 1 H), 7.43 (d, J = 4.0 Hz, 1 H), 7.40 (d, J = 2.4 Hz, 1 H), 1.68 (s, 6 H), 1.39 (s, 9 H), 1.33 (s, 9 H).

¹³C NMR (100 MHz, CDCl₃): δ = 177.5, 155.7, 151.2, 147.5, 146.3, 145.5, 145.1, 131.2, 130.0, 128.8, 124.2, 122.8, 122.1, 116.9, 114.2, 109.6, 35.0, 34.6, 34.5, 32.5, 31.4, 31.3.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₈H₃₁BrO₃ + Na: 517.1354; found: 517.1370.

Anal. Calcd for C₂₈H₃₁BrO₃: C, 67.88; H, 6.31. Found: C, 67.59; H, 6.35.

4-Bromo-2,7-di-tert-butyl-9,9-dimethyl-5-(pyridin-2-yl)-9H-xanthene (2i)

Yield: 68.6 mg (69%); white solid; mp 172.2–173.7 °C; R_f = 0.30 (hexane­–EtOAc, 10:1).

IR (neat, ATR): 2960, 2867, 1588, 1566, 1467, 1441, 1434, 1405, 1363, 1288 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.75 (d, J = 10.4 Hz, 1 H), 8.15 (d, J = 8.0 Hz, 1 H), 7.77 (td, J = 8.0, 2.0 Hz, 1 H), 7.73 (d, J = 2.4 Hz, 1 H), 7.48 (d, J = 2.8 Hz, 1 H), 7.42 (d, J = 2.4 Hz, 1 H), 7.37 (d, J = 2.0 Hz, 1 H), 7.27–7.24 (m, 1 H), 1.68 (s, 6 H), 1.39 (s, 9 H), 1.32 (s, 9 H).

¹³C NMR (100 MHz, CDCl₃): δ = 155.6, 149.4, 146.9, 146.1, 145.7, 145.3, 135.5, 131.4, 129.8, 128.4, 127.8, 126.6, 126.4, 123.3, 121.9, 121.8, 110.0, 35.2, 34.6, 34.5, 32.2, 31.5, 31.3.

HRMS (DART): m/z [M + H]⁺ calcd for C₂₈H₃₃BrNO: 478.1746; found: 478.1714.

4-Bromo-2,7-di-tert-butyl-9,9-dimethyl-5-[(1E)-oct-1-en-1-yl]-9H-xanthene (2j)

Yield: 37.0 mg (52%); colorless liquid; R_f = 0.70 (hexane–EtOAc, 100:1).

IR (neat, ATR): 2957, 2924, 2855, 1479, 1442, 1362, 1270, 1250, 1208, 1197, 1112, 969, 872, 815 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.45 (d, J = 2.4 Hz, 1 H), 7.39 (d, J = 2.4 Hz, 1 H), 7.34 (d, J = 2.4 Hz, 1 H), 7.27 (d, J = 2.8 Hz, 1 H), 7.05 (d, J = 15.6 Hz, 1 H), 6.41 (dt, J = 16.4, 6.8 Hz, 1 H), 2.31 (q, J = 7.2 Hz, 2 H), 1.61 (s, 6 H), 1.54–1.50 (m, 8 H), 1.34 (s, 9 H), 1.32 (s, 9 H), 0.92–0.89 (m, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 146.7, 145.7, 145.6, 145.4, 132.5, 131.7, 129.7, 128.1, 125.4, 124.2, 121.6, 121.2, 120.8, 110.3, 35.3, 34.5, 34.5, 33.5, 31.8, 31.6, 31.5, 31.4, 29.2, 28.9, 22.6, 14.1.

HRMS (DART): m/z [M + H]⁺ calcd for C₃₁H₄₄BrO: 511.2576; found: 511.2531.

Anal. Calcd for C₃₁H₄₃BrO: C, 72.78; H, 8.47. Found: C, 72.96; H, 8.76.

Methyl (5-Bromo-2,7-di-tert-butyl-9,9-dimethyl-9H-xanthen-4-yl)oxoacetate (2k)

A THF solution of t-BuLi (0.25 M, 0.25 mmol) was added to a stirred solution of 1 (100 mg, 0.21 mmol) in THF (3 mL) over 30 min using a syringe pump at –78 °C. The stirring was continued for 1 h at –78 °C. Then, a THF solution of ZnCl₂ (1 M, 0.29 mL, 0.29 mmol) was added to the solution, and the mixture was warmed to r.t. The stirring was continued for 30 min at r.t., and then methyl chlorooxoacetate (36 mg, 0.29 mmol) was added to the solution. The mixture was stirred for 24 h at r.t. The reaction was quenched by adding H₂O (5 mL), and the mixture was extracted with CH₂Cl₂ (3 × 10 mL). The combined organic layers were dried (MgSO₄), and the residue obtained after evaporation was purified by chromatography on silica gel (EtOAc–hexane); yield: 34.6 mg (34%); white solid; mp 208.0–210.0 °C; R_f = 0.50 (hexane–EtOAc, 10:1).

IR (neat, ATR): 2961, 1756, 1740, 1680, 1602, 1568, 1446, 1403, 1363, 1323 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 7.65 (d, J = 2.0 Hz, 1 H), 7.60 (d, J = 2.0 Hz, 1 H), 7.45 (d, J = 2.0 Hz, 1 H), 7.35 (d, J = 2.0 Hz, 1 H), 3.99 (s, 3 H), 1.66 (s, 6 H), 1.35 (s, 9 H), 1.32 (s, 9 H).

¹³C NMR (125 MHz, CDCl₃): δ = 187.0, 162.8, 147.7, 147.6, 146.3, 144.1, 130.6, 129.9, 128.8, 128.5, 126.1, 123.3, 122.0, 109.7, 53.2, 34.9, 34.7, 34.6, 32.6, 31.3, 31.3.

HRMS (DART): m/z [M + H]⁺ calcd for C₂₆H₃₂BrO₄: 487.1484; found: 487.1474.

Acknowledgment

Financial support from a Grant-in-Aid for Scientific Research on Innovative Areas ‘Advanced Molecular Transformations by Organocatalysts’ from MEXT, Japan, The UBE Foundation, The Japan Prize Foundation, and Chugai Pharmaceutical Co., Ltd. Award in Synthetic Organic Chemistry, Japan is appreciated.

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• 5 The different reaction conditions were as follows: catalyst: Pd(PPh₃)₄, Pd(dppf)Cl₂, Pd(PPh₃)₂Cl₂, Pd/C, NiCl₂(dppp); base: CsF, Cs₂CO₃, K₂CO₃, K₃PO₄; solvent: DME, DMF with or without H ₂ O, toluene, THF, Et₂O; temp: 40–100 °C.
• 6 King AO, Okukado N, Negishi E. J. Chem. Soc., Chem. Commun. 1977; 683
• 7 Compound 2a bearing a methyl ester group was selected as the substrate for the purpose of demonstrating that the transformations shown in Scheme 1 can be applied to the substrates bearing electrophilic substituents. Lithiation and subsequent derivatizations such as alkylation and phosphorylation would be possible if the substrates have no functional groups that would react with the alkyllithium reagent in the bromine–lithium exchange reaction.
• 8a Kosugi M, Sasazawa K, Shimizu Y, Migita T. Chem. Lett. 1977; 301
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• 2c Liu S.-Y, Nocera DG. J. Am. Chem. Soc. 2005; 127: 5278
  CrossrefSearch in Google Scholar
• 2d Schwalbe M, Metzinger R, Teets TS, Nocera DG. Chem. Eur. J. 2012; 18: 15449
  CrossrefSearch in Google Scholar
• 3 4,5-Dibromo-2,7-di-tert-butyl-9,9-DMX (1) was prepared from 9H-xanthen-9-one in three steps: Nowick JS, Ballester P, Ebmeyer F, Rebek JJr. J. Am. Chem. Soc. 1990; 112: 8902
  CrossrefSearch in Google Scholar
• 4 Reinert S, Mohr GJ. Chem. Commun. 2008; 2272
• 5 The different reaction conditions were as follows: catalyst: Pd(PPh₃)₄, Pd(dppf)Cl₂, Pd(PPh₃)₂Cl₂, Pd/C, NiCl₂(dppp); base: CsF, Cs₂CO₃, K₂CO₃, K₃PO₄; solvent: DME, DMF with or without H ₂ O, toluene, THF, Et₂O; temp: 40–100 °C.
• 6 King AO, Okukado N, Negishi E. J. Chem. Soc., Chem. Commun. 1977; 683
• 7 Compound 2a bearing a methyl ester group was selected as the substrate for the purpose of demonstrating that the transformations shown in Scheme 1 can be applied to the substrates bearing electrophilic substituents. Lithiation and subsequent derivatizations such as alkylation and phosphorylation would be possible if the substrates have no functional groups that would react with the alkyllithium reagent in the bromine–lithium exchange reaction.
• 8a Kosugi M, Sasazawa K, Shimizu Y, Migita T. Chem. Lett. 1977; 301
• 8b Milstein D, Stille JK. J. Am. Chem. Soc. 1978; 100: 3636
  Search in Google Scholar
• 8c Littke AF, Schwarz L, Fu GC. J. Am. Chem. Soc. 2002; 124: 6343
  CrossrefPubMedSearch in Google Scholar
• 9a Mizoroki T, Mori K, Ozaki A. Bull. Chem. Soc. Jpn. 1971; 44: 581
  Search in Google Scholar
• 9b Heck RF, Nolley JP. Jr. J. Org. Chem. 1972; 37: 2320
  Search in Google Scholar
• 10 Miyaura N, Suzuki A. J. Chem. Soc., Chem. Commun. 1979; 866
• 11 Ishiyama T, Murata M, Miyaura N. J. Org. Chem. 1995; 60: 7508
  CrossrefSearch in Google Scholar
• 12a Oishi M, Kondo H, Amii H. Chem. Commun. 2009; 1909
• 12b Morimoto H, Tsubogo T, Litvinas ND, Hartwig JF. Angew. Chem. Int. Ed. 2011; 50: 3793
  CrossrefPubMedSearch in Google Scholar
• 13 Larsen MA, Hartwig JF. J. Am. Chem. Soc. 2014; 136: 4287
  CrossrefPubMedSearch in Google Scholar
• 14a Sakai M, Hayashi H, Miyaura N. Organometallics 1997; 16: 4229
  CrossrefSearch in Google Scholar
• 14b Grugel H, Albrecht F, Minuth T, Boysen MM. K. Org. Lett. 2012; 14: 3780
  CrossrefSearch in Google Scholar

• Supplementary Material