A direct and mild formylation method for substituted benzenes utilizing dichloromethyl methyl ether-silver trifluoromethanesulfonate

Article abstract of DOI:10.1021/jo400056k

A silver trifluoromethanesulfonate (AgOTf)-promoted direct and mild formylation of benzenes has been developed. The reaction utilizing dichloromethyl methyl ether (Cl₂CHOMe) and AgOTf powerfully formylated various substituted benzenes under temperature conditions as low as -78 C without losing the protecting groups on the phenolic hydroxyl group.

Full text of DOI:10.1021/jo400056k

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Note
A Direct and Mild Formylation Method for Substituted Benzenes
Utilizing Dichloromethyl Methyl Ether–Silver Trifluoromethanesulfonate
Kosuke Ohsawa, Masahito Yoshida, and Takayuki Doi
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo400056k • Publication Date (Web): 11 Mar 2013
Downloaded from http://pubs.acs.org on March 17, 2013
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A Direct and Mild Formylation Method for Substituted Benzenes
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Utilizing Dichloromethyl Methyl Ether–Silver Trifluoromethanesulfonate
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Kosuke Ohsawa, Masahito Yoshida and Takayuki Doi*
Graduate School of Pharmaceutical Sciences, Tohoku University
6-3 Aza-Aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan
E-mail address: doi_taka@mail.pharm.tohoku.ac.jp
Table of Contents Graphic
X
AgOTf (3 equiv)
Cl2CHOMe (3 equiv)
X
O
R1
R1
X = OBn, OMe, OAllyl, OAc, OTs
OH, Me, i-Pr, t-Bu
R1 = Alkyl, Alkoxyl, Halogen
Moderate to good yield
without losing any protecting groups
Abstract: A silver trifluoromethanesulfonate (AgOTf)–promoted direct and mild formylation of benzenes has
been developed. The reaction utilizing dichloromethyl methyl ether (Cl2CHOMe) and AgOTf powerfully
formylated various substituted benzenes under temperature conditions such as low as –78 °C without losing the
protecting groups on the phenolic hydroxyl group.
Many formylation reactions of aromatic compounds have been reported over the last decades.1 Reimer and
Tiemann first reported the direct formylation reaction of benzenes known as the Reimer–Tiemann reaction, which
utilized dichlorocarbene generated from chloroform under strongly basic conditions. This formylation reaction has
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been applied to the synthesis of vanillin on an industrial scale.2 Similar to the Reimer–Tiemann reaction, a
Friedel–Crafts electrophilic aromatic substitution, such as Gatterman reaction, is useful to introduce a formyl group
onto a benzene ring.3 In particular, the Vilsmeier–Haack reaction has been widely utilized in current organic
syntheses because of facile in situ preparation of the reactive species generated from POCl3 and DMF.4 Related
concise reaction conditions, such as the Duff reaction, have been found.5 A reaction utilizing dichloromethyl methyl
ether (Cl2CHOMe) as a formylating reagent for benzenes6 is also well known and has been applied to the natural
product syntheses.7 Dichloromethyl methyl ether can act as formyl chloride equivalents for the formylation, and the
active species can be readily generated in situ in the presence of a Friedel–Crafts catalyst such as strong Lewis
acids, i.e., TiCl4, SnCl4 and AlCl3. The formylations via electrophilic aromatic substitution of phenol derivatives 2
are facile and efficient methods to obtain the corresponding benzaldehyde derivatives 1. However, partial removal
of the protecting group of the phenols 2 was often observed because formylation proceeds under harsh conditions
such as highly acidic conditions (Figure 1).8 Therefore, a formylation method for alkoxybenzenes without losing
the protecting groups would be an attractive and useful method in organic syntheses. Herein, we report the direct
formylation method for alkyl- or alkoxybenzenes utilizing the highly reactive formylating reagent,
Cl2CHOMe–silver trifluoromethanesulfonate (AgOTf).
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OR
Formylation via
Electrophilic Substitution
OR
O
OH
O
R1
R1
R1
1
3
2
(Desired)
(Undesired)
Figure 1 Problematic Formylation in Protected Salicylaldehyde
The formylation of p-benzyloxytoluene 2a was initially investigated (Table 1). The formylations of 2a by
treatment with phosphorus oxychloride4 in DMF at 80 °C or N-methylformanilide (NMFA) at 100 °C did not
proceed and the substrate was completely recovered (entries 1 and 2). The reaction with hexamethylenetetramine
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(HMTA)5 in TFA gave the undesired phenol 4a. The benzyloxy group at the ortho-position of the formyl group in
1a was easily deprotected under acidic conditions,9 and a capture of the benzyl cation in Friedel–Crafts fashion
concomitantly occurred to provide the undesired phenol 4a (entry 3).10 Although it has been reported that
Cl2CHOMe is a highly reactive formylating reagent,6 the reaction with Cl2CHOMe–TiCl4 gave a complex mixture
because of strong Lewis acid (entry 4). While the formylation with milder Lewis acids SnCl4 and AlCl3 provided an
inseparable mixture of the desired 1a and the debenzylated product 3a (entries 5 and 6), the reaction of 2a utilizing
AgOTf smoothly proceeded at –78 °C to afford the desired 1a in 76% yield without formation of the debenzylated
product 3a (entry 7). On the other hand, other Ag-salts such as AgClO4, AgNTf2, AgCl and AgI did not promote the
desired formylation of 2a (entries 8–11); therefore, it should be noted that AgOTf specifically promoted the
formylation of p-benzyloxytoluene 2a without losing a benzyl group.
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OBn
OBn O
OH
O
OH O
Bn
Conditions
2a
1a
3a
4a
Reagent
(equiv)
Product
Ratio of
Entry
1
Solvent
DMF
Temp (°C) Time
(Yield %)b)
1a:3aa)
POCl3 (5)
POCl3 (5)
80
12 h
-
-
-
-
No reaction
No reaction
4a (28)
2
3
4
5
6
7
8
9
NMFA
TFA
100
reflux
–78
–78
–78
–78
–78
–78
rt
24 h
1 h
HMTA (1.1)
Cl2CHOMe (3)–TiCl4 (3)
Cl2CHOMe (3)–SnCl4 (3)
Cl2CHOMe (3)–AlCl3 (3)
Cl2CHOMe (3)–AgOTf (3)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
10 min
Complex mixture
1a, 3ac)
10 min 4:1
10 min 1.8:1
10 min > 95:5
1a, 3ac)
1a (76)
Cl2CHOMe (3)–AgClO4 (3) CH2Cl2
Cl2CHOMe (3)–AgNTf2 (3) CH2Cl2
1 h
-
-
-
-
Complex mixture
Complex mixture
No reaction
No reaction
15 min
1 h
10 Cl2CHOMe (3)–AgCl (3)
CH2Cl2
CH2Cl2
11 Cl2CHOMe (3)–AgI (3)
rt
1 h
a) The ratio of 1a and 3a was determined by crude 1H NMR.
b) Isolated yield. c) Inseparable mixture of 1a and 3a.
Table 1. Investigation of the reaction conditions for formylation of 2a
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Under optimal reaction conditions, the scope of the substrate in AgOTf-promoted formylation of substituted
benzenes 2 was investigated, and the results are summarized in Table 2. The substrates, p-allyloxy- and p-methoxy
toluenes 2b and 2c, were smoothly converted into the corresponding aldehydes 1b and 1c without losing the
ethereal protecting groups (entries 1 and 2). On the other hand, acetoxy- and tosyloxytoluenes 2d and 2e were not
formylated because of the electron-withdrawing protecting group on the phenols (entries 3 and 4). The formylation
of anisole 2f was complete within 5 min at –78 °C, and the product 1f was concurrently obtained with the
regioisomer 1f’ in the ratio of 1:1.5 (entry 5). The formylation of 1,3-dimethoxybenzene 2g was also smoothly
performed at –78 °C to provide 1g in 58% yield (entry 6). In contrast to the formylation of 2g,
1,3,5-trimethoxybenzene 2h was intact at –78 °C but was consumed at 0 °C leading to 1h in 65% yield and double
formylated 1h’ (4%) (entry 7). The anisole derivatives containing electron-withdrawing groups 2i–k were smoothly
consumed at –78 °C to regioselectively provide aldehydes 1i–k in moderate yields (entries 8–10). Among the
3,5-dimethyl phenol derivatives, methyl ether 2l smoothly underwent formylation at –78 °C leading to the desired
1l (51%) and its regioisomer 1l’ (18%) (entry 11). The formylation of phenol 2m at 0 °C provided the desired 1m
(40%) and 1m’ (15%), although the alkylation of the phenolic hydroxyl group in 2m was initially faster than the
formylation of the benzene ring at –78 °C; therefore, a higher temperature would be required to provide the desired
1m via a rearrangement of the formyl equivalent onto the benzene ring (entry 12). The formylation of acetate 2n
was also investigated. The substrate 2n was completely consumed at 0 °C; however, an inseparable mixture of 1n
and its regioisomer 1n’ was obtained in a ratio of 1.2:1 (entry 13).11 Penta-substituted benzene 2o was smoothly
formylated to provide the desired 1o in 70% yield without performing demethylation of the methyl ethers (entry 14).
In AgOTf-promoted formylation of alkylbenezene derivatives, the electron-rich 1,3,5-trialkylbenzenes 2p and 2q
were readily formylated at –78 °C to give 1p and 1q in moderate yields, respectively (entries 15 and 16). The
formylation of the substrate 2r, however, did not proceed because of steric hindrance from the t-Bu groups (entry
17). Pentamethylbenzene 2s, known as a radical scavenger, smoothly reacted at –78 °C to give 1s in 77% yield
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(entry 18). The formylation of the mono-bromobenzene derivative 2t proceeded at 0 °C to afford 1t and its
regioisomer 1t’ in a ratio of 3:1 (entry 19). Due to the electron-withdrawing effect of a bromine atom, the
electrophilic substitution of dibromo substituted 2u hardly proceeded, thereby a trace amount of 1u and 1u’ was
provided (entry 20). The polycyclic aromatic compound such as 2v was also tolerated in this condition and the
corresponding formylated product 1v was provided in good yield (entry 21). In addition, the reaction conditions we
developed powerfully formylated the electron-deficient heteroaromatics 2w, 3-formyl indole derivative 1w was
obtained in moderate yield (entry 22).12
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AgOTf (3 equiv)
Cl2CHOMe (3 equiv)
X
X
O
5
6
7
8
CH2Cl2
Conditions
R1
R1
1
2
Product
(Yield %)a)
Product
(Yield %)a)
Entry
Substrate
AllylO
Conditions
Entry
12
Substrate
HO
Conditions
9
AllylO
O
HO
HO
O
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–78 °C
10 min
0 °C
30 min
1
O
2b
1b (76)
2m
1m (40)
1m' (15)
MeO
MeO
O
AcO
AcO
O
AcO
–78 °C
10 min
0 °C
30 min
2
13b)
O
2n
1n
2c
1c (69)
AcO
1n'
AcO
O
O
O
O
O
z
O
–78 °C
10 min
;0 °C
MeO
0 °C
12 h
MeO
MeO
3
4
14
15
MeO
OMe
25 min
2o
1o (70)
2d
1d (0)
TsO
O
TsO
–78 °C
20 min
0 °C
12 h
2p
1p (69)
iPr
2e
1e (0)
iPr
O
MeO
MeO
MeO
MeO
–78 °C
10 min
–78 °C
20 min
16
5
iPr
iPr
iPr
iPr
1q (72)
2q
2f
1f (28)
O
1f' (43)
tBu
tBu
O
MeO
O
0 °C
12 h
–78 °C
5 min
6
17
18
tBu
tBu
tBu
tBu
O
MeO
MeO
MeO
2g
MeO
1g (58)
2r
1r (0)
MeO
O
MeO
O
–78 °C
10 min
0 °C
15 min
7
MeO
OMe
MeO
OMe
OMe
2h
1h (65)
O
2s
1s (77)
1h' (4)
Br
Br
Br
O
MeO
MeO
O
0 °C
10 min
–78 °C
10 min
19
8
Br
2i
Br
1i (61)
O
1t' (19)
2t
1t (62)
O
MeO
MeO
O
rt
1.5 h
–78 °C
10 min
20
9
Br
Br
Br
Br
Br
Br
I
2j
I
O
2u
1u (3)
1j (51)
1u' (2)
MeO
MeO
O
MeO
–78 °C
10 min
;0 °C
MeO
–78 °C
10 min
;0 °C
10
11
21
22
20 min
10 min
COOMe
2k
COOMe
O
1k (66)
2v
1v (83)
MeO
O
MeO
MeO
O
–78 °C
10 min
;0 °C
–78 °C
10 min
N
N
30 min
Ts
Ts
O
2l
1l (51)
2w
1w (66)
1l' (18)
a) Isolated yield.
b) Inseparable mixture of 1n and 1n' was obtained in 49% yield after column chromatography. The ratio of 1n and 1n' was determined to be 1.2:1 by 1H NMR.
Table 2. Scope and Limitation of the Formylation Utilizing Cl2CHOMe–AgOTf
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This proposed formylation would proceed via the reaction pathway illustrated in Figure 2. Activation of
Cl2CHOMe by AgOTf may initially occur, leading to a highly active species 5. Nucleophilic addition of benzenes
to 5 preferentially at the ortho-position of an electron-rich substituent, such as OR, in a Friedel–Crafts fashion,
followed by hydrolysis would provide the corresponding aldehyde 1. Although highly acidic
trifluoromethanesulfonic acid is generated under the reaction conditions, the protecting groups of phenols would be
tolerant under a low reaction temperature.
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OR
OR
O
AgOTf
R1
Cl
OTf
OMe
OTf
Cl
Cl
OMe
OMe
Cl
R1
5
1
Figure 2. Plausible Reaction Mechanism of the AgOTf-promoted formylation
In conclusion, we have demonstrated the formylation of substituted benzenes under mild conditions.
A
formylating species generated from Cl2CHOMe–AgOTf is highly reactive, and the formylation of benzenes
smoothly proceeded at low temperature (–78–0 °C) to provide the corresponding aldehydes in moderate yields. The
protecting groups of phenol such as benzyl, allyl and methyl ether are tolerant under such reaction conditions;
therefore, the reaction should be useful in the synthesis of highly functionalized aromatic compounds.
Experimental Section
General Techniques: Chemicals and solvents were all purchased from commercial supplies and used without
further purification. All reactions in solution-phase were monitored by thin-layer chromatography carried out on
glass-packed silica gel plates (60F-254) with UV light, and visualized by p-anisaldehyde H2SO4-ethanol solution
or phosphomolybdic acid ethanol solution. Flash column chromatography was carried out with silica gel (40-100
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µm) with the indicated solvent system. H NMR spectra (400 MHz) and 13C NMR spectra (100 MHz) were
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recorded in the indicated solvent. Chemical shifts (δ) are reported in units parts per million (ppm) relative to the
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signal for internal tetramethylsilane (0.00 ppm for H) for solutions in chloroform-d. NMR spectral data are
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reported as follows: chloroform-d (77.0 ppm for 13C), methanol-d3 (3.30 ppm for H), dimethyl sulfoxide-d4
(2.49 ppm for 1H and 39.5 ppm for 13C) when internal standard is not indicated. Multiplicities are reported by the
following abbreviations: s (singlet), d (doublet), t (triplet), m (multiplet), dd (double doublet), dt (double triplet),
dq (double quartet), ddd (double double doublet), ddt (double double triplet), J (coupling constants in Hertz).
High-resolution mass spectra were measured on TOF-MS with EI probe. Infrared spectra are reported in reciprocal
centimeters (cm-1). Melting points were measured on a melting point apparatus and are not corrected.
1-Benzyloxy-4-methylbenzene (2a)13: To a solution of 4-methylphenol (541 mg, 5.00 mmol) in DMF (10 mL) was
added K2CO3 (2.07 g, 15.0 mmol, 3.0 equiv) and benzyl bromide (891 µL, 7.50 mmol, 1.5 equiv) at room
temperature under an argon atmosphere. After being stirred at room temperature for 5.5 h, the reaction mixture was
filtered through a pad of Celite®. The filtrate was diluted with EtOAc and acidified with 3 M HCl. The organic
layer was separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were
washed with brine twice, saturated aq NaHCO3 and brine, dried with MgSO4 and filtered. The filtrate was
concentrated in vacuo, and the resulting residue was purified by flash column chromatography on silica gel (eluted
with hexane/EtOAc = 20:1) to afford benzyl ether 2a (906 mg, 4.57 mmol, 91%) as a white solid. Melting point
37–38 °C [lit. 41–42 °C]14; H NMR (400 MHz, CDCl3) δ 7.31-7.44 (5H, m), 7.08 (2H, d, J = 8.4 Hz), 6.88 (2H,
1
d, J = 8.4 Hz), 5.04 (2H, s), 2.29 (3H, s); 13C NMR (100 MHz, CDCl3) δ 156.7, 137.3, 130.1, 129.9, 128.5, 127.8,
127.4, 115.8, 114.7, 70.0, 20.5; IR (Neat) 3031, 2922, 1615, 1585, 1511, 1455, 1239, 1026, 734, 696 cm−1;
HREIMS calcd for C14H14O 198.1045, found 198.1036.
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1-Allyloxy-4-methylbenzene (2b)15: To a solution of 4-methylphenol (541 mg, 5.00 mmol) in DMF (10 mL) was
added K2CO3 (2.07 g, 15.0 mmol, 3.0 equiv) and allyl bromide (648 µL, 7.50 mmol, 1.5 equiv) at room temperature
under an argon atmosphere. After being stirred at room temperature for 3.5 h, the reaction mixture was filtered
through a pad of Celite®. The filtrate was diluted with EtOAc and acidified with 3 M HCl. The organic layer was
separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with
brine twice, saturated aq NaHCO3 and brine, dried with MgSO4 and filtered. The filtrate was concentrated in vacuo,
and the resulting residue was purified by flash column chromatography on silica gel (eluted with hexane/EtOAc =
20:1) to afford allyl ether 2b (622 mg, 4.20 mmol, 84%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.07 (2H,
d, J = 8.8 Hz), 6.82 (2H, d, J = 8.8 Hz), 6.01 (1H, ddt, J = 17.2, 10.2, 5.2 Hz), 5.40 (1H, dq, J = 17.2, 1.4 Hz), 5.27
(1H, dq, J = 10.2, 1.4 Hz), 4.51 (2H, dt, J = 5.2, 1.4 Hz), 2.28 (3H, s); 13C NMR (100 MHz, CDCl3) δ 156.4, 133.5,
129.84, 129.77, 117.2, 114.5, 68.7, 20.3; IR (Neat) 3029, 2922, 1613, 1585, 1510, 1291, 1241, 1029, 818cm−1;
HREIMS calcd for C10H12O 148.0888, found 148.0887.
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4-Methylphenyl acetate (2d)16: To a solution of 4-methylphenol (300 mg, 2.77 mmol) in dry CH2Cl2 (5.0 mL) was
added triethylamine (965 µL, 6.93 mmol, 2.5 equiv), acetic anhydride (315 µL, 3.33 mmol, 1.2 equiv) and DMAP
(16.9 mg, 0.139 mmol, 0.05 equiv) at room temperature under an argon atmosphere. After being stirred at room
temperature for 12 h, the reaction mixture was quenched with 3 M HCl. The organic layer was separated and the
aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with saturated aq
NaHCO3 and brine, dried with MgSO4 and filtered. The filtrate was concentrated in vacuo, and the resulting residue
was purified by flash column chromatography on silica gel (eluted with hexane/EtOAc = 9:1) to afford acetate 2d
(382 mg, 2.54 mmol, 92%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.17 (2H, d, J = 8.4 Hz), 6.96 (2H, d, J
= 8.4 Hz), 2.34 (3H, s), 2.28 (3H, s); 13C NMR (100 MHz, CDCl3) δ 169.5, 148.5, 135.3, 129.8, 121.2, 20.9, 20.7;
IR (Neat) 3035, 2925, 1760, 1506, 1369, 1217, 1197, 1166, 909 cm−1; HREIMS calcd for C9H10O2 150.0681, found
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150.0684.
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4-Methylphenyl tosylate (2e)17: To a solution of 4-methylphenol (300 mg, 2.77 mmol) in dry CH2Cl2 (5.0 mL) was
added triethylamine (965 µL, 6. 93 mmol, 2.5 equiv), p-toluenesulfonyl chloride (635 mg, 3.33 mmol, 1.2 equiv)
and DMAP (16.9 mg, 0.139 mmol, 0.05 equiv) at room temperature under an argon atmosphere. After being stirred
at room temperature for 12 h, the reaction mixture was quenched with 3 M HCl. The organic layer was separated
and the aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with saturated
aq NaHCO3 and brine, dried with MgSO4 and filtered. The filtrate was concentrated in vacuo, and the resulting
residue was purified by flash column chromatography on silica gel (eluted with hexane/EtOAc = 9:1) to afford
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tosylate 2e (629 mg, 2.40 mmol, 87%) as a white solid. Melting point 68-69 °C [lit. 68-69 °C]18; H NMR (400
MHz, CDCl3) δ 7.70 (2H, d, J = 8.6 Hz), 7.30 (2H, d, J = 8.6 Hz), 7.06 (2H, d, J = 8.6 Hz), 6.85 (2H, d, J = 8.5 Hz),
2.44 (3H, s), 2.30 (3H, s); 13C NMR (100 MHz, CDCl3) δ 147.5, 145.2, 136.7, 132.5, 130.0, 129.7, 128.5, 122.0,
21.7, 20.8; IR (Neat) 3041, 1597, 1376, 1198, 1175, 1158, 829, 654 cm−1; HREIMS calcd for C14H14O3S 262.0664,
found 262.0664.
3,5-Dimethylphenyl acetate (2n)19: To a solution of 3,5-dimethylphenol (1.00 g, 8.19 mmol) in dry CH2Cl2 (10 mL)
was added triethylamine (3.41 mL, 24.6 mmol, 3.0 equiv), acetic anhydride (1.08 mL, 11.5 mmol, 1.4 equiv) and
DMAP (20.0 mg, 0.164 mmol, 0.02 equiv) at room temperature under an argon atmosphere. After being stirred at
room temperature for 2 h, the reaction mixture was quenched with 3 M HCl. The organic layer was separated and
the aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with saturated aq
NaHCO3 and brine, dried with MgSO4 and filtered. The filtrate was concentrated in vacuo, and the resulting residue
was purified by flash column chromatography on silica gel (eluted with hexane/EtOAc = 9:1) to afford acetate 2n
(1.30 g, 7.92 mmol, 97%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 6.86 (1H, s), 6.70 (2H, s), 2.31 (3H, s),
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Methyl 2,4-dimethoxy-3,6-dimethylbenzoate (2o): To a solution of methyl 2,4-dihydroxy-3,6-dimethylbenzoate20
(1.00 g, 5.10 mmol) in DMF (10 mL) was added K2CO3 (5.64 g, 40.8 mmol, 8.0 equiv) and methyl iodide (925 µL,
20.4 mmol, 4.0 equiv) at room temperature under an argon atmosphere. After being stirred at 50 °C for 9 h, the
reaction mixture was filtered through a pad of Celite®. The filtrate was diluted with EtOAc and acidified with 3 M
HCl. The organic layer was separated and the aqueous layer was extracted twice with EtOAc. The combined
organic layers were washed with brine twice, saturated aq NaHCO3 and brine, dried with MgSO4 and filtered. The
filtrate was concentrated in vacuo, and the resulting residue was purified by flash column chromatography on silica
gel (eluted with hexane/EtOAc = 9:1) to afford methyl ether 2o (1.12 g, 5.01 mmol, 98%) as a colorless oil. 2o: 1H
NMR (400 MHz, CDCl3) δ 6.46 (1H, S), 3.90 (3H, s), 3.82 (3H, s), 3.75 (3H, s), 2.30 (3H, s), 2.10 (3H, s); 13C
NMR (100 MHz, CDCl3) δ 168.8, 159.2, 156.5, 134.5, 120.6, 117.0, 107.6, 61.6, 55.4, 51.8, 19.6, 8.5; IR (Neat)
2949, 1733, 1605, 1579, 1464, 1322, 1277, 1154, 1121 cm−1; HREIMS calcd for C12H16O4 224.1049, found
224.1052.
General procedure for the formylation of the benzenes 2 utilizing Cl2CHOMe–AgOTf
To a suspension of substrate 2 (1.00 mmol) and AgOTf (3.00 mmol, 3.0 equiv) in dry CH2Cl2 (1.5 mL/mmol)
was added a solution of Cl2CHOMe (3.00 mmol, 3.0 equiv) in dry CH2Cl2 (0.5 mL/mmol) at –78 °C under an argon
atomosphere. After being stirred at the optimal temperature (see, Table 2), the reaction mixture was quenched with
saturated aqueous NaHCO3. After being stirred at room temperature for 30 min, the reaction mixture was filtered
through a pad of Celite®. The organic layer was separated and the aqueous layer was extracted twice with EtOAc.
The combined organic layers were washed with brine, dried with MgSO4 and filtered. The filtrate was concentrated
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in vacuo and the resulting residue was purified by flash column chromatography on silica gel (eluted with
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hexane/EtOAc = 50/1 ~ 1/4) to afford the desired benzaldehyde derivative 1.
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2-Benzyloxy-4-methylbenzaldehyde (1a)21: Yield 76% (172 mg, 0.760 mmol), a white solid (m.p. 56-57 °C, [lit.
58.5-59 °C]22); Rf 0.52 (hexane/EtOAc = 4:1); 1H NMR (400 MHz, CDCl3) δ 10.5 (1H, s), 7.65 (1H, d, J = 2.0 Hz),
7.31-7.44 (6H, m), 6.94 (1H, d, J = 8.4 Hz), 5.15 (2H, s), 2.30 (3H, s); 13C NMR (100 MHz, CDCl3) δ 189.8, 159.1,
136.5, 136.2, 130.4, 128.6, 128.4, 128.2, 127.2, 124.8, 113.0, 70.5, 20.2; IR (Neat) 3033, 2923, 2861, 1685, 1612,
1583, 1500, 1286, 1246, 1220, 1160, 1025, 725, 696 cm−1; HREIMS calcd for C15H14O2 226.0994, found 226.0978.
2-Allyloxy-4-methylbenzaldehyde (1b)23: Yield 69% (122 mg, 0.691 mmol), a yellowish oil; Rf 0.53
(hexane/EtOAc = 4:1); 1H NMR (400 MHz, CDCl3) δ 10.5 (1H, s), 7.64 (1H, d, J = 2.4 Hz), 7.33 (1H, dd, J = 8.2,
2.4 Hz), 6.88 (1H, d, J = 8.2 Hz), 6.07 (1H, ddt, J = 17.2, 10.6, 5.0 Hz), 5.44 (1H, dq, J = 17.2, 1.4 Hz), 5.33 (1H,
dq, J = 10.6, 1.4 Hz), 4.63 (1H, dt, J = 5.0, 1.4 Hz), 2.31 (3H, s); 13C NMR (100 MHz, CDCl3) δ 189.8, 159.0,
136.4, 132.5, 130.2, 128.3, 124.7, 117.8, 112.8, 69.2, 20.2; IR (Neat) 2860, 1685, 1612, 1496, 1284, 1247, 1224,
1161, 995 cm−1; HREIMS calcd for C11H12O2 176.0837, found 176.0823.
2-Methoxy-4-methylbenzaldehyde (1c)24: Yield 60% (89.4 mg, 0.595 mmol), a yellowish oil; Rf 0.53
(hexane/EtOAc = 4:1); 1H NMR (400 MHz, CDCl3) δ 10.4 (1H, s), 7.63 (1H, d, J = 2.4 Hz), 7.36 (1H, dd, J = 8.4,
2.4 Hz), 6.89 (1H, d, J = 8.4 Hz), 3.91 (3H, s), 2.32 (3H, s); 13C NMR (100 MHz, CDCl3) δ 189.9, 159.9, 136.5,
129.9, 128.4, 124.4, 111.5, 55.6, 20.1; IR (Neat) 2946, 2863, 1680, 1611, 1583, 1497, 1394, 1285, 1254, 1157,
1029 cm−1; HREIMS calcd for C9H10O2 150.0681, found 150.0670.
2-Methoxybenzaldehyde (1f)25: Yield 28% (38.6 mg, 0.284 mmol), an orange oil; Rf 0.27 (hexane/EtOAc = 9:1); 1H
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NMR (400 MHz, CDCl3) δ 10.5 (1H, s), 7.83 (1H, dd, J = 7.6, 1.6 Hz), 7.56 (1H, ddd, J = 8.4, 7.6, 1.6 Hz), 7.03
(1H, t, J = 7.6 Hz), 6.89 (1H, d, J = 8.4 Hz), 3.93 (3H, s); 13C NMR (100 MHz, CDCl3) δ 189.8, 161.8, 135.9, 128.5,
124.8, 120.6, 111.6, 55.6; IR (Neat) 2945, 2845, 1688, 1600, 1484, 1287, 1246, 758 cm−1; HREIMS calcd for
C8H8O2 136.0524, found 136.0518.
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4-Methoxybenzaldehyde (1f’)26: Yield 43% (59.1 mg, 0.434 mmol), a yellowish oil; Rf 0.19 (hexane/EtOAc = 9:1);
1H NMR (400 MHz, CDCl3) δ 9.89 (1H, s), 7.85 (2H, d, J = 8.8 Hz), 7.01 (2H, d, J = 8.8 Hz), 3.90 (3H, s); 13C
NMR (100 MHz, CDCl3) δ 190.8, 164.5, 131.9, 129.9, 114.2, 55.5; IR (Neat) 2841, 1684, 1600, 1577, 1511, 1260,
1160, 834 cm−1; HREIMS calcd for C8H8O2 136.0524, found 136.0518.
2,4-Dimethoxybenzaldehyde (1g)27: Yield 58% (96.4 mg, 0.580 mmol), a white solid (m.p. 66-67 °C, [lit.
69-71 °C]28); Rf 0.09 (hexane/EtOAc = 9:1); 1H NMR (400 MHz, CDCl3) δ 10.3 (1H, s), 7.82 (1H, d, J = 8.4 Hz),
6.56 (1H, d, J = 8.4 Hz), 6.45 (1H, s), 3.91 (3H, s), 3.88 (3H, s); 13C NMR (100 MHz, CDCl3) δ 188.3, 166.2, 163.6,
130.8, 119.1, 105.7, 97.9, 55.61, 55.59; IR (Neat) 2977, 2863, 2781, 1673, 1600, 1580, 1456, 1335, 1285, 1268,
1216, 1028, 829 cm−1; HREIMS calcd for C9H10O3 166.0630, found 166.0616.
2,4,6-Trimethoxybenzaldehyde (1h)29: Yield 65% (127 mg, 0.647 mmol), a white solid (m.p. 132-133 °C, [lit.
115-116 °C]29); Rf 0.18 (hexane/EtOAc = 9:1); 1H NMR (400 MHz, CDCl3) δ 10.4 (1H, s), 6.08 (2H, s), 3.89 (6H,
s), 3.88 (3H, s); 13C NMR (100 MHz, CDCl3) δ 187.7, 166.2, 164.1, 108.8, 90.2, 56.0, 55.5; IR (Neat) 2975, 2881,
2843, 2796, 1671, 1606, 1578, 1475, 1334, 1230, 1217, 1129, 809 cm−1; HREIMS calcd for C10H12O4 196.0736,
found 196.0729.
2,4-Diformyl-1,3,5-trimethoxybenzene (1h’)30: Yield 4% (7.9 mg, 0.0352 mmol), a white solid (m.p. 169-170 °C,
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[lit. 70 °C]29); Rf 0.30 (hexane/EtOAc = 1:4); 1H NMR (400 MHz, CDCl3) δ 10.3 (1H, s), 6.28 (1H, s), 4.01 (6H, s),
3.96 (3H, s); 13C NMR (100 MHz, CDCl3) δ 187.1, 167.9, 167.2, 112.7, 90.9, 64.9, 56.3; IR (Neat) 2953, 2859,
1679, 1589, 1559, 1236, 1149, 1106 cm−1; HREIMS calcd for C11H12O5 224.0685, found 224.0674.
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5-Bromo-2-methoxybenzaldehyde (1i)31: Yield 61% (132 mg, 0.612 mmol), a white solid (m.p. 116-117 °C, [lit.
116-119 °C]31); Rf 0.30 (hexane/EtOAc = 1:4); 1H NMR (400 MHz, CDCl3) δ 10.4 (1H, s), 7.93 (1H, d, J = 2.6 Hz),
7.64 (1H, dd, J = 8.8, 2.6 Hz), 6.90 (1H, d, J = 8.8 Hz), 3.93 (3H, s); 13C NMR (100 MHz, CDCl3) δ 188.3, 160.7,
138.3, 131.0, 126.1, 113.7, 113.5, 56.0; IR (Neat) 3103, 2967, 2844, 1674, 1590, 1477, 1389, 1266, 1243, 1178,
1019, 823, 756 cm−1; HREIMS calcd for C8H7BrO2 213.9629, found 213.9597.
5-Iodo-2-methoxybenzaldehyde (1j)32: Yield 51% (133 mg, 0.506 mmol), a white solid (m.p. 144-145 °C, [lit.
142-143 °C]32); Rf 0.32 (hexane/EtOAc = 9:1); 1H NMR (400 MHz, CDCl3) δ 10.3 (1H, s), 8.10 (1H, d, J = 2.4 Hz),
7.81 (1H, dd, J = 8.8, 2.4 Hz), 6.79 (1H, d, J = 8.8 Hz), 3.92 (3H, s); 13C NMR (100 MHz, CDCl3) δ 188.2, 161.4,
144.1, 137.0, 126.5, 114.1, 83.0, 55.8; IR (Neat) 2963, 1671, 1584, 1472, 1389, 1268, 1244, 1176, 1020, 819 cm−1;
HREIMS calcd for C8H7IO2 261.9491, found 261.9498.
Methyl 3-formyl-4-methoxybenzoate (1k): Yield 66% (128 mg, 0.657 mmol), a white solid (m.p. 101-102 °C); Rf
0.17 (hexane/EtOAc = 4:1); 1H NMR (400 MHz, CDCl3) δ 10.5 (1H, s), 8.51 (1H, d, J = 2.2 Hz), 8.25 (1H, dd, J =
9.0, 2.2 Hz), 7.05 (1H, d, J = 9.0 Hz), 4.01 (3H, s), 3.91 (3H, s); 13C NMR (100 MHz, CDCl3) δ 188.8, 165.9, 164.7,
137.1, 130.6, 124.4, 122.9, 111.5, 56.0, 52.1; IR (Neat) 2952, 1714, 1685, 1606, 1267, 1125, 761 cm−1; HREIMS
calcd for C10H10O4 194.0579, found 194.0572.
4,6-Dimethyl-2-methoxybenzaldehyde (1l): Yield 51% (84.0 mg, 0.512 mmol), a white solid (m.p. 48-49 °C); Rf
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0.30 (hexane/EtOAc = 9:1); H NMR (400 MHz, CDCl3) δ 10.6 (1H, s), 6.64 (1H, s), 6.63 (1H, s), 3.88 (3H, s),
2.55 (3H, s), 2.35 (3H, s); 13C NMR (100 MHz, CDCl3) δ 191.7, 163.3, 145.6, 142.0, 125.0, 121.0, 109.7, 55.7,
22.1, 21.4; IR (Neat) 2965, 2926, 1678, 1599, 1319, 1148 cm−1; HREIMS calcd for C10H12O2 164.0837, found
164.0829.
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2,6-Dimethyl-4-methoxybenzaldehyde (1l’)33: Yield 18% (28.8 mg, 0.175 mmol) a white solid (m.p. 42-43 °C, [lit.
40-41 °C]34); Rf 0.26 (hexane/EtOAc = 9:1); 1H NMR (400 MHz, CDCl3) δ 10.5 (1H, s), 6.59 (2H, s), 3.84 (3H, s),
2.61 (6H, s); 13C NMR (100 MHz, CDCl3) δ 191.6, 162.7, 144.5, 125.9, 114.8, 55.2, 21.0; IR (Neat) 2961, 2923,
1678, 1609, 1462, 1304, 1202, 1097, 832 cm−1; HREIMS calcd for C10H12O2 164.0837, found 164.0824.
4,6-Dimethyl-2-hydroxy-benzaldehyde (1m)35: Yield 40% (60.1 mg, 0.402 mmol), a white solid (m.p. 49-50 °C, [lit.
49 °C]6); Rf: 0.43 (hexane/EtOAc = 4:1); H NMR (400 MHz, CDCl3) δ 12.0 (1H, s), 10.2 (1H, s), 6.63 (1H, s),
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6.54 (1H, s), 2.56 (3H, s), 2.31 (3H, s); 13C NMR (100 MHz, CDCl3) δ 194.5, 163.4, 149.2, 141.8, 123.1, 116.5,
116.1, 22.1, 17.9; IR (Neat) 3412, 2928, 2884, 1641, 1572, 1443, 1311, 1238, 1193, 1038, 804, 757 cm−1; HREIMS
calcd for C9H10O2 150.0681, found 150.0668.
2,6-Dimethyl-4-hydroxybenzaldehyde (1m’)36: Yield 15% (22.6 mg, 0.150 mmol), a white solid (m.p. 194-195 °C,
[lit. 190-191 °C]37); Rf 0.21 (hexane/EtOAc = 4:1); H NMR (400 MHz, DMSO-d6) δ 10.3 (1H, s), 6.52 (2H, s),
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3.34 (6H, s); 13C NMR (100 MHz, DMSO-d6) δ 191.4, 161.4, 144.1, 124.3, 116.3, 20.5; IR (Neat) 3132, 2961,
2931, 1652, 1603, 1560, 1315, 1272, 1157, 641 cm−1; HREIMS calcd for C9H10O2 150.0681, found 150.0689.
2-Acetoxy-4,6-dimethylbenzylaldehyde (1n) and 4-Acetoxy-2,6-dimethylbenzaldehyde (1n’): Yield 49%
(determined by 1H NMR, 1n:1n’ = 1.2:1) 1n11): a colorless oil, Rf 0.20 (hexane/EtOAc = 9:1); 1H NMR (400 MHz,
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CDCl3) δ 189.3, 169.5, 152.7, 145.7, 142.3, 130.4, 123.6, 121.7, 21.6, 20.8, 20.2; IR (Neat) 2926, 1773, 1691, 1618,
1369, 1202, 1140, 1050 cm−1; HREIMS calcd for C11H12O3 192.0786, found 192.0782; 1n’11): a colorless oil, Rf
0.20 (hexane/EtOAc = 9:1); 1H NMR (400 MHz, CDCl3) δ 10.6 (1H, s), 6.85 (2H, s), 2.61 (6H, s), 2.31 (3H, s); 13C
NMR (100 MHz, CDCl3) δ 192.2, 168.9, 153.5, 143.5, 130.2, 122.6, 21.1, 20.7; IR (Neat) 2927, 1771, 1683, 1596,
1199, 1134 cm−1; HREIMS calcd for C11H12O3 192.0786, found 192.0768.
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Methyl 4,6-dimethoxy-2,5-dimethyl-3-formylbenzoate (1o)38: Yield 70% (177 mg, 0.703 mmol), a yellowish oil; Rf
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2.47 (3H, s), 2.23 (3H, s); 13C NMR (100 MHz, CDCl3) δ 191.5, 168.1, 165.1, 160.3, 137.1, 127.2, 124.2, 123.1,
63.1, 61.7, 52.4, 17.2, 8.9; IR (Neat) 2950, 1735, 1685, 1570, 1310, 1206, 1106 cm−1; HREIMS calcd for C13H16O5
252.0998, found 252.0991.
2,4,6-Trimethylbenzaldehyde (1p)39: Yield 69% (102.3 mg, 0.690 mmol), a yellowish oil; Rf 0.35 (hexane/EtOAc
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= 9:1); H NMR (400 MHz, CDCl3) δ 10.6 (1H, s), 6.89 (2H, s), 2.57 (6H, s), 2.31 (3H, s); 13C NMR (100 MHz,
CDCl3) δ 192.9, 143.8, 141.4, 130.5, 129.9, 21.4, 20.4; IR (Neat) 2963, 2922, 2863, 1683, 1609, 1436, 1208, 1148,
852, 782 cm−1; HREIMS calcd for C10H12O 148.0888, found 148.0873.
2,4,6-Triisopropylbenzaldehyde (1q)40: Yield 72% (168.0 mg, 0.723 mmol), a yellowish oil; Rf 0.53
(hexane/EtOAc = 9:1); 1H NMR (400 MHz, CDCl3) δ 10.7 (1H, s), 7.11 (2H, s), 3.60 (2H, septet, J = 6.8 Hz), 3.60
(1H, septet, J = 6.8 Hz), 1.274 (6H, d, J = 6.8 Hz), 1.266 (3H, d, J = 6.8 Hz); 13C NMR (100 MHz, CDCl3) δ 195.0,
153.6, 150.4, 121.6, 34.7, 28.7, 24.2, 23.7; IR (Neat) 2964, 1691, 1604, 1459, 878 cm−1; HREIMS calcd for
C16H24O 232.1827, found 232.1823.
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Pentamethylbenzaldehyde (1s): Yield 77% (136 mg, 0.773 mmol), a white solid (m.p. 150-151 °C, [lit.
143-148.5 °C]41); Rf 0.41 (hexane/EtOAc = 9:1); 1H NMR (400 MHz, CDCl3) δ 10.6 (1H, s), 2.42 (6H, s), 2.29 (3H,
s), 2.24 (6H, s); 13C NMR (100 MHz, CDCl3) δ 196.5, 140.0, 134.5, 133.6, 133.0, 17.6, 16.1; IR (Neat) 2921, 2868,
1688, 1566, 1287, 755 cm−1; HREIMS calcd for C12H16O 176.1201, found 176.1181.
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2-Bromo-4,6-dimethylbenzaldehyde (1t): Yield 62% (133 mg, 0.621 mmol), a white solid (m.p. 39-40 °C); Rf 0.40
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(hexane/EtOAc = 9:1); H NMR (400 MHz, CDCl3) δ 10.5 (1H, s), 7.35 (1H, s), 7.01 (1H, s), 2.56 (3H, s), 2.35
(3H, s); 13C NMR (100 MHz, CDCl3) δ 194.2, 144.9, 142.6, 132.3, 132.2, 129.1, 128.7, 21.24, 21.16; IR (Neat)
2970, 2927, 2858, 2761, 1691, 1601, 1376, 1131, 848 cm−1; HREIMS calcd for C9H9BrO 211.9837, found
211.9822.
4-Bromo-2,6-dimethylbenzaldehyde (1t’)42: Yield 19% (39 mg, 0.186 mmol), a white solid (m.p. 66-67 °C); Rf 0.36
(hexane/EtOAc = 9:1); 1H NMR (400 MHz, CDCl3) δ 10.6 (1H, s), 7.27 (2H, s), 2.59 (6H, s); 13C NMR (100 MHz,
CDCl3) δ 192.5, 143.0, 132.5, 131.1, 127.7, 20.3; IR (Neat) 2964, 2925, 1690, 1577, 1417, 1256, 852 cm−1;
HREIMS calcd for C9H9BrO 211.9837, found 211.9824.
2,4-Dibromo-6-methylbenzaldehyde (1u): Yield 3% (7.7 mg, 0.0277 mmol), a white solid (m.p. 58-59 °C); Rf 0.41
(hexane/EtOAc = 9:1); 1H NMR (400 MHz, CDCl3) δ 10.5 (1H, s), 7.70 (1H, d, J = 1.6 Hz), 7.39 (1H, d, J = 1.6
Hz), 2.57 (3H, s); 13C NMR (100 MHz, CDCl3) δ 193.6, 144.0, 134.4, 134.1, 130.5, 128.7, 127.7, 21.1; IR (Neat)
2927, 2869, 1699, 1573, 1537, 1379, 1170, 892, 856, 791 cm−1; HREIMS calcd for C8H6Br2O 275.8785, found
275.8776.
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2,6-Dibromo-4-methylbenzaldehyde (1u’)43: Yield 2% (5.1 mg, 0.0184 mmol), a white solid (m.p. 100-101 °C [lit.
95-97 °C]43); Rf 0.37 (hexane/EtOAc = 9:1); 1H NMR (400 MHz, CDCl3) δ 10.2 (1H, s), 7.48 (2H, s), 2.37 (3H, s);
13C NMR (100 MHz, CDCl3) δ 190.9, 145.6, 134.4, 129.6, 125.1, 20.9; IR (Neat) 2924, 2865, 2761, 1706, 1587,
1058, 858, 733 cm−1; HREIMS calcd for C8H6Br2O 275.8785, found 275.8795.
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4-Methoxynaphtalene-1-carbaldehyde (1v)44: Yield: 77% (143 mg, 0.766 mmol), a yellowish oil; Rf: 0.16
(hexane/EtOAc = 9:1); 1H NMR (400 MHz, CDCl3) δ 10.2 (1H, s), 9.31 (1H, d, J = 8.4 Hz), 8.34 (1H, d, J = 8.7
Hz), 7.93 (1H, d, J = 8.0 Hz), 7.70 (1H, ddd, J = 8.4, 7.0, 1.2 Hz), 7.58 (1H, ddd, J = 8.7, 7.0, 1.2 Hz), 6.93 (1H, d,
J = 8.0 Hz), 4.11 (3H, s); 13C NMR (100 MHz, CDCl3) δ 192.2, 160.7, 139.6, 131.8, 129.4, 126.3, 125.4, 124.9,
124.8, 122.3, 102.8, 55.9; IR (Neat) 2940, 2846, 1677, 1619, 1513, 1429, 1251, 1220, 1092, 1059, 765 cm−1;
HREIMS calcd for C12H10O2 186.0681, found 186.0669.
1-[(4-Methylphenyl)sulfonyl]-1H-indole-3-carbaldehyde (1w)45: Yield: 66% (198 mg, 0.661 mmol), a yellowish
solid (m.p. 146-147 °C, [lit. 147-149 °C]); Rf 0.15 (hexane/EtOAc = 4:1); 1H NMR (400 MHz, CDCl3) δ 10.1 (1H,
s), 8.26 (1H, d, J = 7.8 Hz), 8.23 (1H, s), 7.95 (1H, dd, J = 7.8, 1.1 Hz), 7.86 (2H, d, J = 8.4 Hz), 7.41 (1H, dt, J =
7.8, 1.3 Hz), 7.36 (1H, dt, J = 7.8, 1.1 Hz), 7.30 (2H, d, J = 8.4 Hz), 2.38 (3H, s); 13C NMR (100 MHz, CDCl3) δ
185.3, 146.1, 136.2, 135.2, 134.4, 130.3, 127.2, 126.3, 125.0, 122.6, 122.4, 113.2, 21.6; IR (Neat) 3127, 2824, 1679,
1596, 1541, 1379, 1177, 1100, 970, 748, 661 cm−1; HREIMS calcd for C16H12NO3S 299.0616, found 299.0615.
3-Benzyl-2-hydroxy-5-methylbenzaldehyde (4a): Yield 28% (63 mg, 0.28 mmol), a yellowish powder (melting
point 74-75 °C); Rf 0.42 (hexane/EtOAc = 9:1); 1H NMR (400 MHz, CD3OD) δ 9.86 (1H, s), 7.13-7.28 (5H, m),
7.24 (2H, s), 3.95 (2H, s), 2.27 (3H, s); 13C NMR (100 MHz, CDCl3) δ 196.6, 157.4, 140.1, 138.6, 131.6, 129.6,
128.9, 128.8, 128.4, 126.1, 120.1, 34.7, 20.3; IR (Neat) 3026, 2923, 2851, 1651, 1603, 1452, 1260, 696 cm−1;
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HREIMS calcd for C15H14O2 226.0994, found 226.1005.
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Acknowledgement
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This work was supported by Platform for Drug Discovery, Informatics and Structural Life Science from the
Ministry of Education, Culture, Sports, Science and Technology, Japan. We also thank to CAMPUS Asia Support
for the Formation of a Core Center under the MEXT for financial support (K.O.).
Supporting Information
1
Copies of H and 13C NMR spectra for 1a–1w, 2o and 4a. This material is available free of charge via the
Internet at http://pubs.acs.org.
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