2019 Volume 67 Issue 6 Pages 587-593
Formylations of fluorine-containing aromatic compounds with dichloromethyl alkyl ethers have been investigated. Dichloromethyl propyl ether and dichloromethyl butyl ether have been applied for the formylation of fluorine-containing anisoles to give the corresponding aldehydes in good yields. Application of these ethers is preferable to that of methyl ether, which is prepared from volatile methyl formate. Reaction of fluorine-containing phenols with these dichloromethyl alkyl ethers did not give salicylaldehyde derivatives, leading instead to corresponding aryl formates in high yields. A plausible mechanism is discussed.
2-Methoxy-5-(trifluoromethoxy)benzaldehyde (4a) is a key reagent for the preparation of several pharmaceutical intermediates. It has been variously prepared, by reactions of dichloromethyl methyl ether (2a) with TiCl4,1–3) hexamethyltetramine with acid,4,5) and t-butyllithium with N,N-dimethylformamide (DMF).6) Although direct formylation of aromatic compounds suggests application of a Vilsmeier–Haack reagent,7–9) there is seemingly no literature precedence for the preparation of 4a from 4-(trifluoromethoxy)anisole (3a). Indeed, attempted reaction of 3a with the Vilsmeier–Haack reagent prepared from DMF and POCl3 in CH2Cl2 did not proceed at all in our hands (Chart 1). Although fluorine-containing aromatics have recently flourished as pharmaceutical and agrochemical intermediates, the Vilsmeier–Haack reagent is, unfortunately, almost useless in their formylation.10) On the other hand, formylations of aromatic compounds with dichloromethyl alkyl ethers (2) mediated by Lewis acids have emerged as a powerful tool for the assembly of benzaldehyde motifs. Thus far, these formylations have heavily relied on 2a as an electrophilic reagent.11) To the best of our knowledge, however, formylation with 2a has found no industrial application.12) We assume that the reason for this may be the difficulty associated with large-scale handling of very volatile and inflammable methyl formate and the use of toxic PCl5, which are the reagents for the preparation of 2a.13) The focus of our research has been to devise operationally secure formylations of fluorine-containing aromatics with dichloromethyl alkyl ethers having long carbon chains and hence higher boiling points, which are more easily applicable in large-scale syntheses. Although they are putative alternatives to 2a, dichloromethyl propyl ether (2c) and dichloromethyl butyl ether (2d) do not always react in the same way. Indeed, whereas reaction of fluorobenzene with 2a gives a mixture of 2- and 4-fluorobenzaldehydes in good yield, no reaction occurs with 2c or 2d.14)
We have recently developed an alternative efficient and general preparation method for dichloromethyl alkyl ethers (2), whereby alkyl formates (1) react with oxalyl chloride in the presence of a catalytic amount of N-methylformanilide (NMF)15) (Chart 2). The scope and limitations of formylations of several aromatic substrates with 2a–d were reported in a subsequent publication.14)
In continuation of our previous work, we have now examined the synthesis of fluorine-containing benzaldehydes by the direct formylation of the corresponding aromatics with 2. Formylations of three types of substrates have been tested: 1) aryl fluorides bearing an electron-donating group, 2) phenols bearing fluoro-substituents, and 3) fluorobenzenes without other substituents.
Formylations of fluorine-containing anisole derivatives 3a–d with 2 mediated by Lewis acids were examined. As shown in Chart 3 and Table 1, dichloromethyl propyl ether (2c) and dichloromethyl butyl ether (2d) proved to be useful reagents besides 2a. FeCl3, AlCl3 and TiCl4 were all effective, though some substrate-dependence was evident. In the case of 4-fluorotoluene (3e), 2a was found to be a powerful reagent mediated by AlCl3, but dichloromethyl ethyl ether (2b) was ineffective. Formylations of various fluorine-containing aromatics are generally possible on a large scale with 2c and 2d, with safe handling.
| Substrate | 2 (eq) | Lewis acid (eq)b) | Product (GC yield, %) [isolated yield, %] |
|---|---|---|---|
| 3a | 2a (1.5) | Fe (1.2) | 4a (97) [73] |
| 2c (1.5) | Fe (1.2) | 4a (100) [93] | |
| 2c (1.5) | Ti (1.5) | 4a (75) [—] | |
| 3b | 2d (1.3) | Fe (1.3) | 4b (100) [86] |
| 2d (1.3) | Ti (1.3) | 4b (90) [89] | |
| 3c | 2c (1.3) | Al (1.3) | 4c (79) [—] |
| 2c (1.3) | Fe (1.3) | 4c (100) [93] | |
| 3d | 2c (1.3) | Fe (1.3) | 4d/5d = 79/21 (96) |
| 2d (1.4) | Fe (1.3) | 4d/5d = 78/22 (98) [98] | |
| 2d (1.3) | Ti (1.3) | 4d/5d = 76/24 (93) [—] | |
| 3e | 2a (1.5) | Al (1.2) | 4e/5e = 77/23 (94) [57] |
| 2a (1.5) | Ti (1.2) | 4e/5e = 78/22 (34) [—] | |
| 2b (1.5) | Al (1.2) | 4e/5e = 77/23 (39) [—] |
a) Reaction conditions: see Experimental. b) Fe = FeCl3, Ti = TiCl4, Al = AlCl3.
Formylation of phenol derivatives with 2a has been reported to give benzaldehyde derivatives, mainly salicylaldehyde (8).16–18) Only a dissertation by Bouvier describes generation of the O-formyl derivative in 39% yield by treating 4-fluorophenol (6b) with 2a in the presence of TiCl4.19)
We examined the reactions of various fluorinated and non-fluorinated phenol derivatives with dichloromethyl alkyl ethers 2a–d, mediated by Lewis acids. The results are summarized in Table 2, besides those reported previously. To be summarized the results, phenols having electron-donating groups (Me, OMe) at the meta-position, underwent nuclear formylation to give 8, whereas electron-deficient phenols, including unsubstituted phenol, gave aryl formate derivatives (7) in high yields. In the case of 6f, phenol bearing para-methoxy group, O-formylation (7f) was exclusively observed, to the contrast that 6h bearing meta-methoxy group gave salicylaldehyde derivative 8h. When the ortho-position with respect to the OH group is activated (electron-rich carbon) by an electron-donating group R in 6, salicylaldehyde derivatives 8 are produced, as described previously.16–18) However, with a less-activated or non-activated carbon atom in the ortho-position with respect to the OH group, alkyl formate derivatives 7 are formed exclusively (Chart 4).
 | |||||||
|---|---|---|---|---|---|---|---|
| 6 | 2 | LA | Yield of products, GC % (isolated %) | Appendix | Reference | ||
| 7 | 8 | 6 | |||||
| a: R = H | a | Ti | Quant | — | This work | ||
| c | Fe | 68 | — | Messy | This work | ||
| d | Al | 90 (60) | — | 10 | This work | ||
| a | Ti | 68 (decomp) | 22 | o/p = 2.8/1 | ref. 16 | ||
| b: R = 4-F | a | Ti | 93 | — | 6 | This work | |
| a | Al | 96 | This work | ||||
| c | Al | Quant | This work | ||||
| c | Fe | Messy | This work | ||||
| d | Al | 88 (86) | 1 | 10 | This work | ||
| a | Ti | 39 | 50 | ref. 19 | |||
| c: R = 3,5-F2 | a | Al | 91 | 9 | This work | ||
| b | Al | Quant | — | This work | |||
| c | Al | 89 | — | This work | |||
| c | Fe | 25 | 1 | 74 | Messy | This work | |
| d: R = 4-Cl | a | Ti | >99 | — | — | This work | |
| a | Fe | 76 | — | Messy | This work | ||
| b | Ti | 97 | This work | ||||
| e: R = 3,5-Me2 | a | Ti | Trace | 90 | 5 | o/p = 92/8 | This work |
| a | Ti | 84 | o/p = 82/18 | ref. 18 | |||
| a | Ti | 98 (65) | 2 | o/p = 5/1 | ref. 16 | ||
| d | Ti | 44 | ref. 18 | ||||
| d | Ti | 2 | 92 | 5 | o/p = 8/2 | This work | |
| d | Fe | 4 | 94 | 2 | o/p = 77/23 | This work | |
| f: R = 4-OMe | b | Al | 90 | 0 | 0 | This work | |
| b | Fe | 62 | 0 | 0 | Messy | This work | |
| g: R = 3-Me | a | Ti | 94 | 6 | ref. 16 | ||
| h: R = 3-OMe | a | Ti | 97 | ref. 16 | |||
a) Reaction conditions: see Experimental. b) o/p refers to the position of the formyl group with respect to the hydroxyl group.
Aryl formates are known to be susceptible to decomposition upon slightly pH changes, and therefore it is difficult to isolate them in pure form by distillation or column chromatography. GC-MS analyses of the reaction mixtures showed that they consisted of almost pure 7, and the products were isolated by rapid bulb-to-bulb distillation. Nevertheless, small amounts of the starting phenol derivatives were still present. Compounds 7 and 8, however, can clearly be distinguished by their mass and NMR spectra (Chart 5). This work constitutes the first systematic study of O-formylation of fluorine-containing phenols with dichloromethyl alkyl ethers.
Further explanation is given in Chart 6. Complex [I] or [I′] of a phenol with AlCl3 is first formed (generation of gases is observed). When the ortho-position of a phenol derivative is cooperatively activated by two electron-donating groups, the intermediate [II] or [III] undergoes intramolecular Friedel–Crafts reaction to afford salicylaldehyde derivatives 8. On the other hand, substrates whose ortho-position was activated only by one substituent will be attacked by oxygen to give the intermediate [IV′] through [III′], which then undergoes hydrolysis to give the formate derivative 7.
Formylation of fluorobenzene with 2a in the presence of FeCl3 has been reported in a U.S. patent, but no information on the yield or selectivity or on the applicability of Lewis acids other than FeCl3 was provided.23) In our previous paper, fluorobenzaldehyde derivatives were revealed to be accessible in good yields from fluorobenzene with 2a in the presence of FeCl3 and TiCl4. AlCl3 gave fluorobenzaldehydes accompanied by diphenylmethane derivatives. 2b–d, having long carbon chains, were found to be ineffective for the synthesis of fluorobenzaldehydes.14) We have now examined the formylation of difluorobenzene derivatives, and our results were summarized in Table 3.
 | ||||
|---|---|---|---|---|
| 9 | 2 | LA | 10 (o/p) | Isolated yield (%) |
| R = H | a | Al | 37 (16/84)b) | 22 |
| a | Ti | 80 (10/90) | 63 | |
| a | Fe | 90 (15/85) | 66 | |
| b | Fe | No reaction | ||
| R = 2-F | a | Al | 40 (3/97)c) | 12 |
| a | Ti | Trace | — | |
| a | Fe | No reaction | ||
| b | Fe | No reaction | ||
| R = 3-F | a | Al | 73c) | 33 |
| R = 4-F | a | Al | No reaction | |
a) Reaction conditions: see Experimental. b) Diphenylmethane derivatives are formed as by-products (GC-MS). c) Diphenylmethane and triphenylmethane derivatives are formed as by-products (GC-MS).
Reaction of 1,2-difluorobenzene or 1,3-difluorobenzene with 2a in the presence of AlCl3 gave the corresponding aldehydes in yields of 40 and 73%, respectively, with high regioselectivity, accompanied by higher-boiling-point products, suggested to be the diphenyl-methane and triphenyl-methane derivatives by GC-MS. Attempted reaction of 1,4-difluorobenzene with 2a did not afford any aldehyde, and all the starting material was fully recovered. Likewise formylation did not proceed with 1,2-, 1,3-, or 1,4-difluorobenzenes in the presence of the other Lewis acids FeCl3 and TiCl4. It could thus be concluded that 2c and 2d having long carbon chains are not useful for formylations of fluorobenzene and difluorobenzenes.
We have introduced a new protocol for the formylation of fluorine-containing aromatic rings. Dichloromethyl propyl ether and dichloromethyl butyl ether are very attractive candidates for formylations of fluorine-containing aromatics bearing methoxy or methyl groups. Fluorine-containing phenols afforded O-formylation products with these reagents in very high yields. The present method is straightforward and should find wide application in organic synthesis.
All melting points were determined with a Buchi melting point apparatus (model B-545) and are uncorrected. IR spectra were acquired with a Shimadzu IRAffinity-1 Fourier transform infrared spectrophotometer. 1H-NMR spectra were recorded with a JEOL, JNM-AL300 spectrometer in CDCl3 using tetramethylsilane (TMS) as a reference. GC-mass spectra were recorded with a Shimadzu GCMS-QP2010 SE using a DB-5 column (0.32 mm i.d. × 30 m, df = 0.50 µm) using an InertCap1 column (0.25 mm i.d. × 60 m, df = 0.4 µm).
Unless stated otherwise, all reagents and chemicals were obtained commercially and used without further purification. AlCl3 was pulverized to be powder in mortar, and used. CH2Cl2 was dried over molecular sieves 4A.
General Procedure for the Formylation of Fluorine-Containing AromaticsLewis acid (1.0–1.5 eq) (powdered AlCl3, powdered FeCl3, 1 or 2 M solution of TiCl4 in CH2Cl2) was added portionwise to a stirred 1 M solution of the aromatic compound in dry CH2Cl2, and then 2a–f (1.2–1.5 eq) was added dropwise at 0°C over a period of 2–10 min. The mixture was stirred for several hours at room temperature. Following complete conversion of starting material, as confirmed by GC analysis, the mixture was quenched with H2O and extracted with CH2Cl2 or EtOAc. The combined organic layers were successively washed with satd. aq. NaHCO3 and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by distillation or column chromatography on silica-gel, if necessary.
Formylation of Fluorine-Containing AnisolesFormylation of 1-Methoxy-4-(trifluoromethoxy)benzene (3a)2c (0.76 g, 5.33 mmol) was added to a mixture of 3a (0.68 g, 3.52 mmol) and FeCl3 (0.68 g, 4.22 mmol) in CH2Cl2 (3.5 mL) over a period of 10 min with cooling in an ice bath. The mixture was stirred at room temperature for 2 h, and then poured into EtOAc–H2O. The aqueous layer was extracted with EtOAc, and the combined organic layers were washed with aq. NaHCO3, dried over Na2SO4, and concentrated in vacuo to afford 2-methoxy-5-(trifluoromethoxy)benzaldehyde (4a) in quantitative yield. The crude product was purified by bulb–to–bulb distillation (135–140°C, 5 torr) to afford 0.72 g (93% yield) of pure 4a as an oil. 1H-NMR (300 MHz, CDCl3) δ: 3.96 (s, 3H), 7.04 (s, 1H), 7.42 (dd, J = 6.3, 3.0 Hz, 1H), 7.68 (d, J = 3.0 Hz, 1H) 10.43 (s, 1H). 13C-NMR (75 MHz, CDCl3) δ: 188.30, 160.13, 158.17, 142.58, 128.52, 125.21, 120.58, 112.99, 56.00. GC-MS: m/z (relative intensity) = 221 (10%), 220 (M+, 100%), 219 (28%), 203 (27%), 202 (27%), 189 (10%), 188 (11%), 174 (28%), 160 (27%), 135 (19%). The 1H-NMR spectrum matched that previously reported.2)
Formylation of 4-Fluoroanisole (3b)2d (2.12 g, 13.5 mmol) was added to a mixture of 3b (1.27 g, 10.1 mmol) and FeCl3 (2.10 g, 12.9 mmol) in CH2Cl2 (5 mL) over a period of 2 min with cooling in an ice bath. The mixture was stirred at room temperature for 0.5 h, and then poured into EtOAc–H2O. 5-Fluoro-2-methoxybenzaldehyde (4b) was obtained in quantitative yield (1.54 g). GC-MS: m/z = 154 (M+, 65%), 153 (21%), 137 (28%), 136 (34%), 108 (49%), 95 (67%), 83 (100%). A portion of the product was purified by bulb-to-bulb distillation (150°C, 1 torr) and was recovered in 86% yield as a colorless liquid. 1H-NMR (300 MHz, CDCl3) δ: 3.92 (s, 3H), 6.96 (dd, J = 8.7, 3.6 Hz, 1H), 7.23–7.29 (m, 1H), 7.49 (dd, J = 8.4, 3.0 Hz, 1H), 10.41 (d, J = 3.0 Hz, 1H). 13C-NMR (75 MHz, CDCl3) δ: 188.63, 158.38, 156.64 (d, J = 217.7 Hz), 125.35 (d, J = 5.5 Hz), 122.39 (d, J = 23.4 Hz), 113.89 (d, J = 23.4 Hz), 113.12 (d, J = 7.4 Hz), 56.09. The NMR spectroscopic data matched those previously reported.24)
Formylation of 2-Fluoroanisole (3c)2c (1.95 g, 13.6 mmol) was added to a mixture of 3c (1.30 g, 10.3 mmol) and FeCl3 (2.31 g, 12.9 mmol) in CH2Cl2 (5 mL) over a period of 2 min with cooling in an ice bath. The mixture was stirred at room temperature for 0.5 h. Similar work-up as above gave 3-fluoro-4-methoxybenzaldehyde (4c) in quantitative yield (1.58 g). The crude product was purified by bulb-to-bulb distillation (170°C, 1 Torr) to afford 1.46 g (93%) of pure 4c as a white solid (lit. mp 30–31°C).25) GC-MS: m/z = 154 (M+, 81%), 153 (100%), 125 (28%), 110 (26%), 95 (42%), 83 (55%). 1H-NMR (300 MHz, CDCl3) δ: 3.98 (d, J = 4.5 Hz, 3H), 7.09 (t, J = 8.1 Hz, 1H), 7.61 (dd, J = 11.1, 2.1 Hz, 1H), 7.65 (dd, J = 8.4, 2.1 Hz, 1H), 9.86 (d, J = 2.1 Hz, 1H). 13C-NMR (75 MHz, CDCl3) δ: 189.83 (d, J = 1.88 Hz), 152.99 (d, J = 10.5 Hz), 152.00 (d, J = 247.88 Hz), 129.93 (d, J = 4.88 Hz), 128.17 (d, J = 2.48 Hz), 115.40 (d, J = 18.53 Hz), 112.59 (d, J = 1.28 Hz), 56.27. The NMR spectroscopic data matched with those of ref. 22.
Formylation of 3,5-Difluoroanisole (3d)2d (760.0 mg, 4.84 mmol) was added to a mixture of 3d (504.9 mg, 3.51 mmol) and FeCl3 (744.2 mg, 4.59 mmol) in CH2Cl2 (3.5 mL) over a period of 2 min with cooling in an ice bath. The mixture was stirred at room temperature for 2 h, and then poured into EtOAc–H2O. Similar work-up as above afforded 590.0 mg (98% yield) of a white solid. GC-MS analysis of this solid showed that it consisted of no the starting 3d and a mixture of formylated products (two isomers, 78 : 22), which could not be separated by column chromatography on silica-gel (EtOAc–hexane 1 : 9–1 : 4).
2,4-Difluoro-6-methoxybenzaldehyde 4d (major isomer): GC-MS: m/z = 172 (M+, 86%), 171 (75%), 157 (21%), 156 (30%), 155 (61%), 154 (59%), 128 (67%), 112 (100%). 1H-NMR (300 MHz, CDCl3) δ: 3.92 (s, 3H), 6.54–6.50 (m, 2H), 10.33 (s,1H). 13C-NMR (75 MHz, CDCl3) δ: 185.71 (d, J = 2.5 Hz), 166.94 (dd, J = 254.6, 16.7 Hz), 164.48 (ddd, J = 260.0, 9.6, 3.6 Hz), 163.53 (dd, J = 13.0, 8.0 Hz), 98.62 (dd, J = 25.3, 1.9 Hz), 97.24 (t, J = 25.3 Hz), 95.9 (dd, J = 25.3, 3.7 Hz). 2,6-Difluoro-4-methoxybenzaldehyde 5d (minor isomer): GC-MS: m/z = 172 (M+, 58%), 171 (100%), 156 (4%), 128 (17%). 1H-NMR (300 MHz, CDCl3) δ: 3.88 (s, 3H), 6.49–6.48 (m, 2H), 10.20 (s, 1H). 1H-NMR spectra were consistent with that of ref. 26.
Formylation of 4-Fluorotoluene (3e)2a (502.0 mg, 4.36 mmol) was added to a mixture of 3e (383.5 mg, 3.48 mmol) and AlCl3 (560.4 mg, 4.21 mmol) in CH2Cl2 (3.5 mL) over a period of 5 min with cooling in an ice bath. The mixture was stirred at room temperature for 2 h. Standard work-up gave the formylation product (586.0 mg).The crude product was purified by bulb-to-bulb distillation (150°C, 5 Torr) afforded 275.3 mg (57%) of an inseparable isomer mixture (85 : 15) as a colorless liquid. Major product: 2-fluoro-5-methylbenzaldehyde (4e); 1H-NMR (300 MHz, CDCl3) δ: 2.37 (s, 3H), 7.06 (dd, J = 10.2, 8.4 Hz, 1H), 7.37–7.43 (m, 1H), 7.66 (dd, J = 6.3, 2.1 Hz, 1H), 10.34 (s, 1H). GC-MS: m/z = 138 (M+, 74%), 137 (91%), 109 (100%), 83 (51%). Minor product: 5-fluoro-2-methylbenzaldehyde (5e); 1H-NMR (300 MHz, CDCl3) δ: 2.64 (s, 1H), 7.18 (dd, J = 8.7, 2.7 Hz, 1H), 7.23–7.25 (m, 1H), 7.50 (dd, J = 8.7, 2.7 Hz, 1H), 10.26 (d, J = 1.8 Hz, 1H). GC-MS: m/z = 138 (M+, 53%), 137 (44%), 109 (100%), 83 (35%). The NMR spectroscopic data matched with those of ref. 22.
Formylation of PhenolsThe requisite phenol derivative was added to a 1.0 M suspension or solution of a Lewis acid (1.2–1.5 eq) in CH2Cl2. After the evolution of gas had ceased, 2a–d (1.2–1.5 eq) was slowly added to the mixture with cooling in an ice-bath. The mixture was stirred at room temperature for 1 h. It was then poured into EtOAc–H2O, and the resulting mixture was extracted with EtOAc. The combined organic layers were washed with saturated aq. NaHCO3 and aqueous NaCl, and dried over Na2SO4. The organic phase was concentrated in vacuo and analyzed by GC-MS, which indicated an almost pure product. Purification by rapid bulb–to–bulb distillation gave a colorless product, but some aryl formate derivatives were partially decomposed to the original phenols.
Formylation of Phenol (6a)Phenyl formate (7a) was prepared by reaction of phenol 6a (0.49 g, 5.2 mmol), 2d (1.0 g, 6.4 mmol), and AlCl3 (0.88 g, 6.6 mmol) in CH2Cl2 (5 mL). It was recovered in almost quantitative yield as an essentially pure product. A portion of this sample was purified by bulb-to-bulb distillation, affording 60% isolated yield. GC-MS analysis of the distilled sample showed that it consisted of 90% 7a accompanied by 10% of 6a as a result of decomposition during the distillation. GC-MS analysis of 7a showed m/z = 122 (M+, 19%), 94 (100%), 66 (46%), 65 (34%). To confirm the structure, 7a was prepared in 97% yield according to ref. 20 and its mass spectrum was identical to that of the above formylation product.
Formylation of 4-Fluorophenol (6b)4-Fluorophenyl formate (7b) was obtained as an oil in quantitative yield as an almost pure product from the reaction of 6b (0.56 g, 5.0 mmol), 2c (1.0 g, 7.1 mmol), and AlCl3 (0.86 g, 6.4 mmol) in CH2Cl2 (7 mL). GC-MS: m/z = 140 (M+, 10%), 112 (100%), 84 (38%), 83 (43%). 1H-NMR (300 MHz, CDCl3) δ: 7.04–7.13 (m, 4H), 8.27 (s, 1H) [0.3% of benzaldehyde proton (δ 9.83) was observed]. 13C-NMR (75 MHz, CDCl3) δ: 160.43 (d, J = 243.53 Hz), 159.10, 145.54 (d, J = 3.1 Hz), 122.59 (d, J = 8.6 Hz), 116.28 (d, J = 23.4 Hz). The mass and NMR spectra were identical to those described in references.20,21)
Formylation of 3,5-Difluorophenol (6c)2b (0.62 g, 4.8 mmol) was added to a mixture of 6c (0.38 g, 2.9 mmol) and AlCl3 (0.49 g, 3.7 mmol) in CH2Cl2 (3.5 mL). The mixture was stirred for 1 h, and then worked–up as described above. Analysis of the product showed it to be almost pure 3,5-difluorophenyl formate (7c) as an oil. GC-MS: m/z = 158 (M+, 11%), 130 (100%), 102 (69%), 101 (67%). 1H-NMR (300 MHz, CDCl3) δ: 6.73–6.78 (m, 3H), 8.25 (s, 1H). 13C-NMR (75 MHz, CDCl3) δ: 163.00 (dd, J = 247.8, 14.8 Hz), 157.90, 150.87 (t, J = 13.6 Hz), 105.56 (dd, J = 9.8, 9.3 Hz), 102.14 (t, J = 25.3 Hz). Its 1H-NMR spectrum was consistent with that of the product prepared according to ref. 20.
Formylation of 4-Chlorophenol (6d)4-Chlorophenyl formate (7d) was obtained as an oil in almost quantitative yield by stirring a mixture of 2a (0.24 g, 2.09 mmol), 6d (0.13 g, 1.02 mmol), and TiCl4 (1 M solution in CH2Cl2, 3.5 mL) at room temperature for 0.5 h. GC-MS confirmed the product to be 7d. GC-MS: m/z = 158 (M+ + 2, 4%), 156 (M+, 12%) 130 (31%), 128 (100%), 100 (24%), identical to the reported data.21)
Formylation of 3,5-Dimethylphenol (6e)Reaction of 2d (0.49 g, 3.1 mmol) and 6e (0.37 g, 3.0 mmol) in the presence of TiCl4 (1 M in CH2Cl2, 6 mL) at room temperature for 2 h gave 0.41 g (92% yield) of the crude product, which was identified as an 8 : 2 an oily mixture of 2,4-dimethyl-6-hydroxybenzaldehyde (8e) and 2,6-dimethyl-4-hydroxybenzaldehyde (8e′) by GC-MS. The yield and product ratio are similar to those reported previously for a reaction of 2a and TiCl4.16) A small amount (1.4%) of (3,5-dimethylphenyl) formate (7e) was detected by GC-MS. 8e: GC-MS: m/z = 150 (M+, 74%), 149 (100%), 104 (24%), 91 (39%), 77 (50%). 8e′: GC-MS: m/z = 150 (M+, 68%), 149 (100%), 121 (64%), 91 (44%), 77 (56%). 7e: GC-MS: m/z = 150 (M+, 21%), 122 (62%), 121 (29%), 107 (100%), 91 (21%), 77 (38%).
Formylation of 4-Methoxyphenol (6f)2b (1.06 g, 8.3 mmol) was added to a mixture of 6f (0.62 g, 5.0 mmol) and AlCl3 (0.81 g, 6.08 mmol) in CH2Cl2 (5.0 mL). The mixture was stirred for 2 h, and then quenched with H2O (20 mL). The resulting mixture was extracted with EtOAc (2 × 30 mL), and the combined organic layers were successively washed with satd. aq. NaHCO3 and brine, dried over Na2SO4, and concentrated in vacuo. GC-MS analysis of the crude product showed that it consisted of 90% 4-methoxyphenyl formate (7f). Purification by bulb-to-bulb distillation (130°C, 5 torr) gave 401.5 mg (53%) of 7f as a yellow liquid. GC-MS: m/z = 152 (M+, 16%), 124 (60%), 109 (100%), 95 (8%), 81 (50%). 1H-NMR (300 MHz, CDCl3) δ: 3.80 (s, 3H) 6.90 (d, J = 9.0 Hz, 2H), 7.05 (d, J = 9.0 Hz, 2H), 8.28 (s, 1H). 13C-NMR (75 MHz, CDCl3) δ: 159.67, 157.46, 143.19, 121.79, 114.48, 55.39. The spectroscopic data matched those reported previously.21)
Formylation of Fluorobenzene DerivativeFormylation of Fluorobenzene with 2a Catalyzed by TiCl4, FeCl3, or AlCl3The procedures have been described in detail ref. 14.
Formylation of 1,2-Difluorobenzene2a (8.6 g, 75 mmol) was added to a mixture of 1,2-difluorobenzene (5.7 g, 50 mmol) and AlCl3 (10.0 g, 75 mmol) in CH2Cl2 (25 mL). Standard work-up gave 2.72 g of a residue. GC-MS analysis of which showed it to consist of the starting material (28%), 3,4-difluorobenzaldehyde (40%), and tris(3,4-difluorophenyl) methane (26%). Bulb-to-bulb distillation (150°C, 20 Torr) afforded 0.85 g of 3,4-difluorobenzaldehyde (12% isolated yield). 1H-NMR (300 MHz, CDCl3) δ: 7.34–7.38 (m, 1H), 7.69–7.76 (m, 2H), 9.94 (d, J = 2.1 Hz, 1H) [0.2% of 1,2-difluorobenzaldehyde (δ = 10.36) was also present]. 13C-NMR (75 MHz, CDCl3) δ: 189.44, 154.35 (dd, J = 243.5, 13.0 Hz), 150.84 (dd, J = 237.3, 13.0 Hz), 133.41 (dd, J = 4.4, 3.7 Hz), 127.23 (dd, J = 6.5, 3.2 Hz), 118.01 (d, J = 17.3 Hz), 117.44 (d, J = 17.3 Hz). GC-MS: m/z = 142 (M+, 74%), 141 (80%), 113 (100%), 63 (56%). The distillation residue (1.34 g) was assigned as a main component of tris(3,4-difluorophenyl) methane.27) GC-MS: m/z = 353 (20%), 352 (M+, 100%), 239 (61%), 238 (39%), 237 (72%), 219 (67%).
Formylation of 1,3-Difluorobenzene2a (8.77 g, 76.2 mmol) was added to a mixture of 1,3-difluorobenzene (5.70 g, 50.0 mmol) and AlCl3 (9.96 g, 74.9 mmol) in CH2Cl2 (50 mL). Similar treatment of the mixture as described above gave 6.67 g of a yellow oil. GC-MS analysis showed that it consisted of the starting 1,3-difluorobenzene (11%) and 2,4-difluorobenzaldehyde (73%), accompanied by diphenyl-methane and triphenyl-methane derivatives and others. The crude product was purified by bulb-to-bulb distillation (80–90°C, 30–35 Torr) to afford 2.35 g of 2,4-difluorobenzaldehyde (33% yield) as an oil. GC-MS: m/z = 142 (M+, 75%), 141 (100%), 113 (76%). 1H-NMR (300 MHz, CDCl3) δ: 6.92 (ddd, J = 10.8, 8.7, 2.4 Hz, 1H), 6.98 7.04 (m, 1H), 7.94 (dt, J = 8.4, 6.3 Hz, 1H), 10.29 (s, 1H), 13C-NMR (75 MHz, CDCl3) δ: 185.60 (d, J = 5.5 Hz), 167.90 (dd, J = 111.9, 12.7 Hz), 164.45 (dd, J = 114.1, 13.0 Hz), 130.65 (dd, J = 11.0, 3.1 Hz), 121.00 (t, J = 4.0 Hz), 112.59 (dd, J = 21.9, 3.4 Hz), 104.71 (t, J = 25.0 Hz). The NMR spectroscopic data matched with those of ref. 28. Bis(2,4-difluorophenyl)chloromethane: GC-MS: m/z = 274 (M+, 1%), 239 (100%), 237 (18%), 219 (47%). Tris(2,4-difluorophenyl)methane: GC-MS: m/z = 353 (17%), 352 (M+, 83%), 351 (6%), 311 (6%), 237 (100%), 239 (88%), 238 (87%), 219 (77%), 114 (18%).
We are grateful to Dr. Tetsuya Sengoku (Shizuoka University) for NMR analysis and valuable discussion.
The authors declare no conflict of interest.
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