Direct formylation of fluorine-containing aromatics with dichloromethyl alkyl ethers

Article abstract of DOI:10.1248/cpb.c19-00176

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.

Full text of DOI:10.1248/cpb.c19-00176

Chemical and Pharmaceutical Bulletin Advance Publication by J-STAGE
DOI:10.1248/cpb.c19-00176
Advance Publication
April 3, 2019
Chem. Pharm. Bull.
(Regular Article)
Direct formylation of fluorine-containing aromatics with
dichloromethyl alkyl ethers
Takuya Warashina, Daisuke Matsuura, and Yoshikazu Kimura*
R&D, Iharanikkei Chemical Industry Co. Ltd. Kambara, Shimizu-ku, Shizuoka 421-3203,
Japan
* Correspondence e-mail: kimura.yoshikazu@iharanikkei.co.jp
Ⓒ 2019 The Pharmaceutical Society of Japan

Summary
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.
Keywords
dichloromethyl alkyl ethers, fluorobenzaldehydes, aryl formates, fluoroanisoles, fluorophenols, Lewis
acids
Chemical and Pharmaceutical Bulletin Advance Publication

Introduction
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)
Chart 1. Formylations of fluorine-containing aromatics
Chemical and Pharmaceutical Bulletin Advance Publication

Chart 2. Recent improved preparations for dichloromethyl alkyl ethers
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) (Chart 2).15) The scope and
limitations of formylations of several aromatic substrates with 2a–2d 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.
Results and Discussion
Formylation of methoxy- or methyl-substituted fluorobenzenes
Chart 3. Examples for formylation of fluorine-containing aromatics
Chemical and Pharmaceutical Bulletin Advance Publication

Table 1. Formylations of methoxy- and methyl-substituted fluorobenzene derivativesa
Substrate
2 (eq)
Lewis acid (eq) b
Fe (1.2)
Fe (1.2)
Ti (1.5)
Product (GC yield, %) [isolated yield, %]
4a ( 97) [73]
3a
2a (1.5)
2c (1.5)
2c (1.5)
2d (1.3)
2d (1.3)
2c (1.3)
2c (1.3)
2c (1.3)
2d (1.4)
2d (1.3)
2a (1.5)
2a (1.5)
2b (1.5)
4a (100) [93]
4a (75) [-]
3b
3c
3d
Fe (1.3)
Ti (1.3)
4b (100) [86]
4b ( 90) [89]
Al (1.3)
Fe (1.3)
Fe (1.3)
Fe (1.3)
Ti (1.3)
4c (79) [-]
4c (100) [93]
4d/5d = 79/21 (96)
4d/5d = 78/22 (98) [98]
4d/5d = 76/24 (93) [-]
4e/5e = 77/23 (94) [57]
4e/5e = 78/22 (34) [-]
4e/5e = 77/23 (39) [-]
3e
Al (1.2)
Ti (1.2)
Al (1.2)
a Reaction conditions: see Experimental
b Fe = FeCl3, Ti = TiCl4, Al = AlCl3
Formylations of fluorine-containing anisole derivatives 3a–3d 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.
Formylations of fluorinated and non-fluorinated phenol derivatives.
Chemical and Pharmaceutical Bulletin Advance Publication

Table 2. Formylations of phenol derivatives with dichloromethyl alkyl ethers (2)a
Yield of products, GC % (isolated %)
6
2
LA
appendix
Reference
7
8
6
a: R = H
a
c
Ti
Fe
Al
Ti
Ti
Al
Al
Fe
Al
Ti
Al
Al
Al
Fe
Ti
Fe
Ti
Ti
Ti
Ti
Ti
Ti
Fe
Al
Fe
Ti
Ti
quant
68
-
this work
this work
this work
Ref [16]
-
messy
d
a
a
a
c
90(60)
-
10
22
6
68(decomp)
-
o/p = 2.8/1
b: R = 4-F
93
96
this work
this work
this work
this work
this work
Ref [19]
this work
this work
this work
this work
this work
quant
c
messy
d
a
a
b
c
88(86)
39
1
10
50
9
c: R =3,5-F2
91
quant
89
-
-
c
25
1
-
74
-
messy
messy
d: R = 4-Cl
a
a
b
a
a
a
d
d
d
b
b
a
a
>99
76
-
97
e: R = 3,5-Me2
trace
90
84
5
2
o/p = 92/8 this work
o/p = 82/18 Ref [18]
98 (65)
44
o/p = 5/1
Ref [16]
Ref [18]
this work
2
4
92
5
2
0
0
6
o/p = 8/2
94
o/p = 77/23
f: R = 4-OMe
90
62
0
0
messy
g: R = 3-Me
94
Ref [16]
Ref [16]
h: R = 3-OMe
97
aReaction conditions: see Experimental
bo/p refers to the position of the formyl group with respect to the hydroxyl group
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
Chemical and Pharmaceutical Bulletin Advance Publication

the presence of TiCl4.19)
We examined the reactions of various fluorinated and non-fluorinated phenol derivatives
with dichloromethyl alkyl ethers 2a–2d, 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).
Chart 4. Overview of formylations of phenols according to substituent types
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.
Chemical and Pharmaceutical Bulletin Advance Publication

Literature
This work
1H NMR
Mass
8.28 (lit. [20])
m/z 140 (M+, 19%), 112 (100%)
9.849 (lit. [22])
m/z 140 (M+, 100 %)
(lit. [22])
(lit. [21])
1H NMR
Mass
8.25
m/z 140 (M+, 12%), 112 (100%)
Chart 5. Structures assigned on the basis of NMR and Mass spectral data
Chart 6. Plausible reaction mechanism for the formylation of phenol derivatives
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.
Chemical and Pharmaceutical Bulletin Advance Publication

Formylation of unsubstituted aromatic fluorides
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–2d, 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.
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.
Chemical and Pharmaceutical Bulletin Advance Publication

Table 3. Formylations of fluorobenzene derivativesa
9
2
LA
10 (o/p)
Isolated yield (%)
R = H
a
a
a
b
a
a
a
b
a
a
Al
Ti
Fe
Fe
Al
Ti
Fe
Fe
Al
Al
37 (16/84)b
80 (10/90)
90 (15/85)
No reaction
40 (3/97)c
trace
22
63
66
R = 2-F
12
-
No reaction
No reaction
73c
R = 3-F
R = 4-F
33
-
No reaction
aReaction conditions: see Experimental
bDiphenylmethane derivatives are formed as by-products (GC-MS).
cDiphenylmethane and triphenylmethane derivatives are formed as by-products (GC-MS).
Conclusions
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.
Experimental
General
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. 1NMR 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
ID × 30 m, df = 0.50µm) using an InertCap1 column (0.25 mm ID × 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.
Chemical and Pharmaceutical Bulletin Advance Publication

General procedure for the formylation of fluorine–containing aromatics
Lewis acid (1.0–1.5 equiv.) (powdered AlCl3, powdered FeCl3, 1 or 2M solution of TiCl4 in
CH2Cl2) was added portionwise to a stirred 1M solution of the aromatic compound in dry
CH2Cl2, and then 2a–2f (1.2–1.5 equiv.) was added dropwise at 0 ºC 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 anisoles
Formylation 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):  3.96 (s, 3H), 7.04 (s, 1H), 7.42 (dd, J = 6.3,
13
3.0 Hz, 1H), 7.68 (d, J = 3.0 Hz, 1H) 10.43 (s, 1H). C NMR (75 MHz, CDCl3):  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
1
(11%), 174 (28%), 160 (27%), 135 (19%). The H 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
1
recovered in 86% yield as a colorless liquid. H NMR (300 MHz, CDCl3):  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):  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),
Chemical and Pharmaceutical Bulletin Advance Publication

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. m.p. 30-31). 25) GC-MS: m/z = 154 (M+, 81%), 153 (100%), 125 (28%), 110
(26%), 95 (42%), 83 (55%). 1H NMR (300 MHz, CDCl3): 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): 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
1
(75%), 157 (21%), 156 (30%), 155 (61%), 154 (59%), 128 (67%), 112 (100%). H NMR
(300 MHz, CDCl3): 3.92 (s, 3H), 6.54–6.50 (m, 2H), 10.33 (s,1H). 13C NMR (75 MHz,
CDCl3):  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):
1
GC-MS: m/z = 172 (M+, 58%), 171 (100%), 156 (4%), 128 (17%). H NMR (300 MHz,
CDCl3): 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
Chemical and Pharmaceutical Bulletin Advance Publication

(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
1
liquid. Major product: 2-fluoro-5-methylbenzaldehyde (4e); H NMR (300 MHz, CDCl3):
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): 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 phenols
The requisite phenol derivative was added to a 1.0 M suspension or solution of a Lewis
acid (1.2–1.5 equiv.) in CH2Cl2. After the evolution of gas had ceased, 2a–2d (1.2–1.5 equiv.)
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
Chemical and Pharmaceutical Bulletin Advance Publication

1
(43%). H NMR (300 MHz, CDCl3): 7.04–7.13 (m, 4H), 8.27 (s, 1H) [0.3% of
13
benzaldehyde proton (9.83)was observed]. C NMR (75 MHz, CDCl3): 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): 6.73–6.78 (m, 3H), 8.25 (s, 1H). 13C NMR (75 MHz, CDCl3):
 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 (1M 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 (1M
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 × 30mL), and the
combined organic layers were successively washed with satd. aq. NaHCO3 and brine, dried
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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):  3.80 (s, 3H) 6.90
13
(d, J = 9.0 Hz, 2H), 7.05 (d, J = 9.0 Hz, 2H), 8.28 (s, 1H). C NMR (75 MHz, CDCl3): 
159.67, 157.46, 143.19, 121.79, 114.48, 55.39. The spectroscopic data matched those
reported previously.21)
Formylation of fluorobenzene derivative.
Formylation of fluorobenzene with 2a catalyzed by TiCl4, FeCl3, or AlCl3
The procedures have been described in detail ref. 14.
Formylation of 1,2-difluorobenzene
2a (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):  7.34–7.38 (m, 1H), 7.69–7.76 (m, 2H), 9.94 (d, J = 2.1 Hz,
13
1H) [0.2% of 1,2-difluorobenzaldehyde ( = 10.36) was also present]. C NMR (75 MHz,
CDCl3): 189.44, 154.35(dd, J = Hz(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-difluorobenzene
2a (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%),
1
113 (76%). H NMR (300 MHz, CDCl3 ): 6.92 (ddd, J = 10.8, 8.7, 2.4 Hz, 1H), 6.98 7.04
13
(m, 1H), 7.94 (dt, J = 8.4, 6.3 Hz, 1H), 10.29 (s, 1H), C NMR (75 MHz, CDCl3): 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).
Chemical and Pharmaceutical Bulletin Advance Publication

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%).
Acknowledgment
We are grateful to Dr. Tetsuya Sengoku (Shizuoka University) for NMR analysis and
valuable discussion.
Conflict of Interest The authors declare no conflict of interest.
Supplementary Materials The online version of this article contains supplementary
materials.
Chemical and Pharmaceutical Bulletin Advance Publication

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