Formylation of electron-rich aromatic rings mediated by dichloromethyl methyl ether and TiCl4: Scope and limitations

Article abstract of DOI:10.3390/molecules20045409

Here the aromatic formylation mediated by TiCl₄ and dichloromethyl methyl ether previously described by our group has been explored for a wide range of aromatic rings, including phenols, methoxy- and methylbenzenes, as an excellent way to produce aromatic aldehydes. Here we determine that the regioselectivity of this process is highly promoted by the coordination between the atoms present in the aromatic moiety and those in the metal core.

Full text of DOI:10.3390/molecules20045409

Molecules 2015, 20, 5409-5422; doi:10.3390/molecules20045409
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Formylation of Electron-Rich Aromatic Rings Mediated by
Dichloromethyl Methyl Ether and TiCl4: Scope and Limitations
Iván Ramos-Tomillero 1,2, Marta Paradís-Bas 1,2, Ibério de Pinho Ribeiro Moreira 3,4
,
Josep María Bofill 2,4, Ernesto Nicolás 2,5,* and Fernando Albericio 1,2,6,7,8,
*
1
Institute for Research in Biomedicine (IRB Barcelona), Barcelona 08028, Spain;
E-Mails: ivan.ramos@irbbarcelona.org (I.R.-T.); marta.paradis@irbbarcelona.org (M.P.-B.)
Deparment of Organic Chemistry, University of Barcelona, Barcelona 08028, Spain;
E-Mail: jmbofill@ub.edu
2
3
4
Department of Physical Chemistry, University of Barcelona, Barcelona 08028, Spain;
E-Mail: i.moreira@ub.edu
Institut de Química Teòrica i Computacional (IQTCUB), University of Barcelona,
Barcelona 08028, Spain
5
6
7
8
Institut de Biomedicina (IBUB), University of Barcelona, Barcelona 08028, Spain
CIBER-BBN, Barcelona 08028, Spain
School of Chemistry, University of KwaZulu-Natal, Durban 4000, South Africa
School of Chemistry, Yachay Tech, Yachay City of Knowledge, Urcuqui 100119, Ecuador
* Authors to whom correspondence should be addressed; E-Mails: enicolas@ub.edu (E.N.);
albericio@irbbarcelona.org or falbericio@yachaytech.edu.ec (F.A.); Tel.: +34-93-403-7088 (F.A.).
Academic Editor: Jean Jacques Vanden Eynde
Received: 27 January 2015 / Accepted: 12 March 2015 / Published: 26 March 2015
Abstract: Here the aromatic formylation mediated by TiCl4 and dichloromethyl methyl ether
previously described by our group has been explored for a wide range of aromatic rings,
including phenols, methoxy- and methylbenzenes, as an excellent way to produce aromatic
aldehydes. Here we determine that the regioselectivity of this process is highly promoted
by the coordination between the atoms present in the aromatic moiety and those in the
metal core.
Keywords: formylation; TiCl4; aromatic rings; aldehydes; dichloromethyl methyl ether

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1. Introduction
The high reactivity of aldehydes makes them a key functional group in organic chemistry. This
group is widespread in Nature, and its use in the synthesis of natural products is noteworthy.
Furthermore, as efficient electrophiles, aldehydes can undergo further transformations to be converted
into an extensive range of functional groups, such as hydroxyls, carboxylic acids, double bonds, and
alkanes, among others [1]. As a result of this feature, aldehydes are widely used as active
pharmaceutical ingredients and also commonly found in food and cosmetics [2]. Thus the synthesis
and manipulation of this kind of compound is a continuous focus of research. In this regard, there is
increased interest in the development of mild and efficient methods for the introduction of the
aldehyde moiety into organic structures [3–11]. Traditionally, these methods involve the oxidation of
alcohols, the selective reduction of esters, the reductive ozonolysis of alkenes, and so on [12–14].
During recent years, our group has channeled much research effort into developing new strategies
for solid-phase peptide synthesis (SPPS) [15–19]. Special attention has been devoted to the
development of protecting groups and linkers, which are the cornerstones of SPPS. Most of these are
based on the benzyl (Bzl) moiety. To make this moiety more acid-labile and therefore more user
friendly, we and other groups have developed linkers [20] and protecting groups [19,21] based on
electron-rich aromatic compounds. The relatively higher acid lability of these groups when compared
with the naked benzyl group is due to the stability of the carbocation formed in the removal
process [22]. In this regard, electron-rich aromatic aldehydes, which can be easily transformed into
hydroxymethyl- or aminomethyl benzyl-type moieties, are key intermediates for the development of
new protecting groups and/or linkers. There is currently a wide range of choice of approaches
regarding the introduction of a formyl group into aromatic rings [3,6]; however, the organic chemist
continues to face the challenge of formylation through C-C bond formation [23], which is the most
convenient approach for the case of aromatic aldehydes. One of the most widely used procedures is the
well-known Vilsmeier-Haack reaction [24], whereby, in the presence of N,N-dimethylformamide
(DMF) and phosphorous oxychloride, the activated aromatic compound furnishes the corresponding
aromatic aldehyde. Additionally, the procedures described by Duff [25] or Casiraghi-Skattebøl [26] are
typically used for phenolic formylation.
We have reported the successful ortho-formylation of electron-rich phenols mediated by
dichloromethyl methyl ether and titanium (IV) tetrachloride [27], as well as a description of the
reaction mechanisms in phenolic compounds [28]. This methodology was based on the outstanding
procedure pioneered by Gross [29] and Cresp [30] that affords aromatic aldehydes (Scheme 1).
Herein we report an extensive study of this formylation procedure, where the dichloromethyl
methyl ether (Cl2CHOMe) acts as a formylating agent for pre-activated aromatic rings in the presence
of titanium tetrachloride.
Scheme 1. Titanium-mediated formylation reaction.

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2. Results and Discussion
Aiming to explore the range of applications of formylation by CHCl2OMe and TiCl4 in aromatic
rings, we tested the reaction with three benzene-like activated rings. These substrates are structurally
based on phenols, methoxy- and methylbenzenes (Scheme 2).
OH
OH
OMe
TiCl4, Cl2CHOMe
DCM, 0ºC
OMe
CHO
CHO
Me
Me
R
R
R
R
CHO
R
R
Scheme 2. Formylated scaffolds examined in the present study.
The general formylation procedure was carried out using the corresponding aromatic ring (1 eq.)
mixed with TiCl4 (2.2 eq.) in dry dichloromethane (DCM) for 1 h under Ar at 0 °C. CHCl2OMe
(1.1 eq.) was immediately added to the solution and stirred for 45 min, after which the reaction was
quenched with a saturated aqueous solution of NH4Cl to furnish a mixture of regioisomers, giving
satisfactory results in terms of regioselectivity, purity of the reaction crude products, and yields. This
result contrasts with other common procedures that render less regioselectivity and more complex
reaction crude products [24,25].
Table 1. Formylation of phenols, methoxy- and methylbenzenes.
Main Product
Formylation
Conversion [a] %, [%]
Regioisomeric
Ratio [b] [mp: : ]
Entry
Reactant
Aldehyde
Yield (%)
Phenols
[c]
1
2
3
4
5
68 [22]
94 [6]
97
▬
[2.8:1]
[3:1.6:1]
[3.7:1.3:1]
[5:1]
40 [d]
44 [d]
65
98 [2]
80 [11]
63
[30:1]
6
64 [25]
56
▬

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Table 1. Cont.
Main Product
Aldehyde Yield (%)
Methoxybenzenes
Formylation
Conversion [a] %, [%]
Regioisomeric
Ratio[b] [mp: : ]
Entry
Reactant
7
>99
97 [d]
[1.1:1]
8
9
>99
62 [38]
>99
61
44
15
[3:1]
▬
10
[3.5:1]
Methylbenzenes
11
12
13
14
89 {4}
>99
70 [d]
62 [d]
97
[3.2:1]
[32:1]
▬
95% {3%}
97
96
▬
[a]
Notes: The % corresponds to the chromatographic peak area in the reaction crude determined by HPLC:
total % of formylated products, [%] remaining starting material and {%} dimerization by-product. [b] mp:
:
indicates the ratio for the formylation of the main product and the other regioisomers. [c] Degradation during
the purification. [d] The final products were isolated as mixture of regioisomers.
Table 1 provides a summary of the reactions. Some reactions furnish only one main product, as a
result of the symmetry of the starting materials (entries 6, 9, 13 and 14). Meanwhile, non-symmetric
starting reagents yielded distinct regioisomers.
2.1. Phenols
Regarding the formation of phenolic aldehydes (entries 1–6), the formylation takes place preferably
in the ortho position with respect to the hydroxyl group (entries 1–5). This common behaviour is due
to coordination between the metal atom and the oxygen of the OH, as previously studied by our
group [27] and others [30]. After taking into account the role of the metal coordination, the steric
hindrance caused by substituents also plays a significant role in formylation. Thus the formyl group
was introduced in the less hindered position in each studied compound (entries 2, 3, 8, 10, 11 and 12).

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2.2. Methoxybenzenes
In the case of the methoxy group (entries 7–10), Hamilton and co-workers demonstrated that TiCl4
are able to coordinate with several ethers [31], but it showed a weaker coordination effect in
comparison with the hydroxyl one. Hence, the steric hindrance had a considerable effect on the
formylated position. Thus for entry 7, the para substitution was favored, taking into account the
presence of two ortho positions. The result in entry 7 reinforces the regioselectivity shown in entry 1.
A special case of discussion is entry 10 vs. 7. In the first case, where the ortho and para positions were
flanked by two substituents, the ortho one was favored. This observation indicates that both
coordination and steric effects play a key role in the regioselectivity of formylation.
2.3. Methylbenzenes
Concerning methylbenzene derivatives (entries 11–14), when formylation took place in the absence
of oxygen atoms, coordination with the metal atom was not possible and therefore the less hindered
isomer was favored. In this case, it is believed that the reaction mechanism occurs through the
formation of an activated complex involving a π-interaction between the transition metal and the
aromatic ring, as Calderazzo and co-workers proposed [32]. Indeed, another interesting point was the
observed dimerization of two aromatic rings, affording diphenylmethanol compounds, as the proposed
mechanism indicates (Scheme 3).
Scheme 3. Proposed dimerization side-reaction mechanisms.
Accordingly, the chloride intermediate or the plausible oxocarbenium species [23] may undergo
nucleophilic attack by an unreactive aromatic ring. This process provided the condensed diphenyl
methoxy ether compound, which, with the acidolytic cleavage mediated by aqueous NH4Cl and the
HCl obtained from the hydrolysis of TiCl4 (TiCl4 + 2 H2O → TiO2 + 4 HCl) [33,34], furnished the
diphenylmethanol derivative in small quantities.
In general, most of the reactions tested showed high formylation conversions ranging from 64% to
more than 99%. Accordingly, the titanium tetrachloride and Cl2CHOMe combination can be
considered an effective formylating reagent.

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3. Experimental Section
3.1. General Information
The commercially available products were used as received without further purification. Glass
equipment was oven-dried, and DCM was dried using 4-Å molecular sieves under argon and protected
from the light. All the reactions were carried out under argon. IR spectra were recorded on a Nicolet
510 FT-IR spectrometer equipped with an ATR Smart Orbit adaptor and are reported as frequency of
absorption (cm−1). NMR spectra were recorded on a Varian Mercury-400 (1H/400 MHz and
1
13C/100 MHz). H data is reported as follows: chemical shift (δ ppm), [integration, multiplicity
(s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet), and coupling constant (J in Hz)]. Data
for 13C-NMR are reported in terms of chemical shift. NMR spectra are referenced by tetramethylsilane
(TMS). Melting points were measured with a Nikon Eclipse polarized microscope (MOP), which
contains a Linkam THMS E600 thermal tray and a CI 93 temperature programmer. The HPLC
reversed-phase column Xbridge C18 (75 × 4.6 mm, 3.5 μm) 4.6 × 3 × 150 mm, 5 µm was from Waters
(Dublin, Ireland). Analytical HPLC (HPLC A and B) was carried out on using HPLC A: a Waters
instrument comprising two solvent-delivery pumps (Waters 1525), an automatic injector (Waters 717
auto sampler), diode array wavelength detector (Waters 2487), and linear gradients of MeCN
(+0.036% TFA) into H2O (+0.045% TFA) at 1 mL/min; or using HPLC B: a Shimadzu system
comprising two solvent-delivery pumps (LC-20AD), an automatic injector (SIL-10ADvp), a variable
wavelength detector (SPD-20A; 220 nm) and linear gradients of MeCN (+0.036% TFA) into H2O
(+0.045% TFA) at 1 mL/min, which are specified in each case. The average in the chromatograms was
determined by the area integration of the chromatographic peaks at λ = 220 nm. The thin-layer
chromatography plates (TLC) used was purchased from Merck (TLC Silica gel 60 F254, silica-plated
aluminium sheets). Column chromatography was performed on wet packed silica (Merck Silica gel 60,
0.2 mm). The automatic purification was performed by CombiFlash® Rf Teledyne ISCO with a Waters
detector 2487 Dual λ Absorbance using pre-packed Redisep Rf Gold C18 (20–40 μm, 100 Å) from
Teledyne Technology Company.
3.2. General Formylation Procedure
The appropriate benzene derivative (3.2–10.6 mmol) was dissolved in dry DCM (10–20 mL),
purged with Ar, and cooled with an ice bath to 0 °C. Next, TiCl4 (2.2 eq.) was added dropwise. The
reaction mixture was stirred for 1 h. Afterwards, dichloromethyl methyl ether (1.1 eq.) was added, and
the mixture was left to react for a further 45 min. As a reaction quencher, a saturated solution of NH4Cl
(25 mL) was added. The mixture was then left for 2 h. The organic layer was separated and washed
with 0.1 N HCl solution (3 × 50 mL) and brine (3 × 50 mL). The organic layer was dried over MgSO4
and filtered, and the solvent was evaporated under vacuum to furnish the desired aldehydes (Figure 1).
The purified products were homogeneous by HPLC and were characterized and purified by using
various physical techniques.

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Figure 1. Obtained compounds.
3.3. Phenols
3.3.1. Entry 1
Reaction of phenol (1.0 g, 10.63 mmol), TiCl4 (2.6 mL, 26.71 mmol), dichloromethyl methyl ether
(1.0 mL, 11.02 mmol) and DCM (20 mL) gave a purple oil. The products decomposed during SiO2
purification and only aldehyde 2 could be isolated (10 mg, 0.75%). HPLC detected 18%, 22% and
50% of 4-hydroxyaldehyde (2), the starting material, and 2-hydroxybenzaldehyde (1) respectively.
2-Hydroxybenzaldehyde (1): HPLC (H2O/MeCN from 95:5 to 0:100 over 8 min): tR = 4.9 min.
4-Hydroxybenzaldehyde (2): Appearance: White solid. HPLC (H2O/MeCN from 95:5 to 0:100 over
8 min): tR = 3.6 min. 1H-NMR (C3D6O) δ 9.86 (1H, s), 9.38 (1H, s), 7.83–7.77 (2H, m), 7.03–6.99 (2H,
m) ppm. 13C-NMR (C3D6O) δ 191.0, 163.9, 132.8, 130.5, 116.7 ppm.
3.3.2. Entry 2
Reaction of 3-methylphenol (336 μL, 3.21 mmol), TiCl4 (780 μL, 7.11 mmol), dichloromethyl methyl
ether (320 μL, 3.54 mmol) and DCM (10 mL) afforded a pink solid. The mixture of the regioisomers
was chromatographed on SiO2 (hexane/AcOEt, 9:1) to yield 4-hydroxy-2-methylbenzaldehyde (5)
(69.8 mg, 16%) and a mixture of inseparable products, 2-hydroxy-6-methylbenzaldehyde (3) and
1
2-hydroxy-4-methylbenzaldehyde (4) in a 1:3.6 ratio, as determined by H-NMR (175.8 mg of the
1
mixture was obtained, 40% yield of the formylation reaction). HPLC and H-NMR detected a small

Molecules 2015, 20
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amount of the starting material (5.6%). 4-Hydroxy-2-methylbenzaldehyde (5): Appearance: White
solid. Mp = 106–108 °C. TLC: Rf = 0.1 (hexane/AcOEt, 9:1). HPLC (H2O/MeCN from 95:5 to 0:100
1
over 8 min): tR = 4.1 min. H-NMR (C3D6O) δ 10.1 (1H, s), 9.21 (1H, s), 7.71 (1H, d, J = 8.4 Hz),
13
6.86–6.81 (1H, m), 6.78–6.74 (1H, m), 2.58 (4H, s) ppm. C-NMR (C3D6O) δ 191.3, 162.9, 144.0,
͂
135.7, 128.3, 119.1, 114.1, 19.7 ppm. IR (ATR, Smart orbit): v = 3118.7, 1657.5, 1556.0, 1307.4
(෤max) cm−1.
3.3.3. Entry 3
Reaction of 3-methoxyphenol (352 μL, 3.21 mmol), TiCl4 (780 μL, 7.11 mmol), dichloromethyl methyl
ether (320 μL, 3.54 mmol) and DCM (10 mL) gave an orange solid. The mixture of regioisomers was
chromatographed on SiO2 (hexane/AcOEt, 8:2) to yield 4-hydroxy-2-methoxy- benzaldehyde (8)
(81.1 mg, 17%) and a mixture of inseparable products: 6-hydroxy-2-methoxy- benzaldehyde (6) and
1
2-hydroxy-4-methoxybenzaldehyde (7) in a 1:3.2 ratio determined by H-NMR (212.7 mg of the
mixture was obtained, 44% yield of the formylation reaction). 4-Hydroxy-2-methoxybenzaldehyde (8):
Appearance: White solid. Mp = 155–157 °C. TLC: Rf = 0.1 (hexane/AcOEt, 8:2). HPLC (H2O/MeCN
from 95:5 to 0:100 over 8 min): tR = 4.4 min. 1H-NMR (C3D6O) δ 10.2 (1H, s), 9.35 (1H, s), 7.64 (1H,
d, J = 8.5 Hz), 6.57 (1H, d, J = 2.1 Hz), 6.53 (1H, ddd, J = 8.5, 2.1, 0.6 Hz), 3.91 (3H, s) ppm.
13C-NMR (C3D6O) δ 186.4, 164.7, 164.1, 129.7, 118.1, 108.2, 98.8, 55.2 ppm. IR (ATR, Smart orbit):
v = 3137.8, 1654.3, 1634.6, 1569.3 (෤max) cm−1.
͂
3.3.4. Entry 4
Reaction of 3,5-dimethylphenol (395.8 mg, 3.24 mmol), TiCl4 (790 μL, 7.21 mmol), dichloromethyl
methyl ether (330 μL, 3.65 mmol) and DCM (10 mL) gave an orange solid which was
chromatographed on SiO2 (hexane/AcOEt, 9:1) to yield 2-hydroxy-4,6-dimethylbenzaldehyde (9)
(318.2 mg, 65%) and 4-hydroxy-2,6-dimethylbenzaldehyde (10) (61.7 mg, 13%). The ratio of the
products 9:10 was 5:1 and the global yield 78%. 2-Hydroxy-4,6-dimethylbenzaldehyde (9):
Appearance: Pale yellow solid. Mp = 48–50 °C. TLC: Rf = 0.77 (hexane/AcOEt, 8:2). HPLC
(H2O/MeCN from 95:5 to 0:100 over 8 min): tR = 5.1 min. 1H-NMR (CDCl3) δ 11.9 (1H, m), 10.2 (1H, m),
6.62 (1H, s), 6.53 (1H, m), 2.55 (3H, s), 2.30 (3H, s) ppm. 13C-NMR (100 MHz, CDCl3) δ 194.7, 163.6,
͂
149.4, 142.0, 123.3, 116.7, 116.3, 77.5, 77.2, 76.8, 22.3, 18.1 ppm. IR (ATR, Smart orbit): v = 2879.8,
1640.8, 1625.6 (vmax), 1567.2 cm−1. 4-Hydroxy-2,6-dimethylbenzaldehyde (10): Appearance: White
͂
solid. Mp = 195–197 °C. TLC: Rf = 0.23 (hexane/AcOEt, 8:2). HPLC (H2O/MeCN from 95:5 to 0:100
over 8 min): tR = 6.9 min. 1H-NMR (C3D6O) δ 10.4 (1H, s), 6.60 (2H, s), 2.54–2.53 (6H, m). 13C-NMR
͂
(C3D6O) δ 206.1, 191.7, 145.3, 126.2, 117.2, 21.0 ppm. IR (ATR, Smart orbit): v = 3138.5, 1649.9,
1602.3, 1555.7, 1313.9, 1151.3 (v max) cm−1.
͂
3.3.5. Entry 5
Reaction of 3,5-dimethoxyphenol (502.8 mg, 3.26 mmol), TiCl4 (790 μL, 7.21 mmol),
dichloromethyl methyl ether (330 μL, 3.65 mmol) and DCM (10 mL) afforded an orange solid, which
was chromatographed on SiO2 (hexane/AcOEt, 9:1) to yield 6-hydroxy-2,4-dimethoxybenzaldehyde

Molecules 2015, 20
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(11) (339.0 mg, 63%). 6-Hydroxy-2,4-dimethoxybenzaldehyde (11): Appearance: Pale orange solid.
Mp = 70–72 °C. TLC: Rf = 0.28 (hexane/AcOEt, 8:2). HPLC B (H2O/MeCN from 95:5 to 0:100 over
1
11 min): tR = 8.3 min. H-NMR (CDCl3) δ 12.5 (1H, s), 10.1 (1H, s), 6.01 (1H, d, J = 2.2 Hz), 5.91
13
(1H, d, J = 2.2 Hz), 3.85 (3H, s), 3.83 (3H, s) ppm. C-NMR (CDCl3) δ 191.8, 168.1, 166.4, 163.5,
106.0, 92.9, 90.6, 55.7, 55.7 ppm. IR (ATR, Smart orbit): v = 1642.3, 1619.4, 600.7 (vmax) cm−1.
͂
͂
3.3.6. Entry 6
Reaction of 3,4,5-trimethoxyphenol (579.6 mg, 3.15 mmol), TiCl4 (760 μL, 6.93 mmol), dichloro-
methyl methyl ether (320 μL, 3.54 mmol) and DCM (10 mL) provided a pale orange solid, which was
chromatographed on SiO2 (DCM/hexane, 9:1) to yield 6-hydroxy-2,3,4-trimethoxybenzaldehyde (12)
(372.0 mg, 56%). The HPLC analysis of the isolated mixture reveals 25% of starting material.
6-Hydroxy-2,3,4-trimethoxybenzaldehyde (12): Appearance: Pale yellow solid. Mp = 63–65 °C. TLC:
Rf = 0.52 (DCM/hexane, 9:1). HPLC B (H2O/MeCN from 95:5 to 0:100 over 11 min): tR = 8.1 min.
1H-NMR (CDCl3) δ 12.1 (1H, s), 10.1 (1H, s), 6.19 (1H, s), 4.04 (3H, s), 3.90 (3H, s), 3.79 (3H, s)
ppm. 13C-NMR (CDCl3) δ 192.8, 162.2, 161.3, 155.6, 134.0, 108.5, 95.4, 62.2, 61.4, 56.4 ppm. IR
(ATR, Smart orbit): v = 2945.4, 2850.4, 1638.5, 1623.2 (vmax) cm−1.
͂
͂
3.4. Methoxybenzenes
3.4.1. Entry 7
Reaction of anisole (352 μL, 3.21 mmol), TiCl4 (780 μL, 7.11 mmol), dichloromethyl methyl ether
(320 μL, 3.54 mmol) and DCM (10 mL) were used to obtain a pale rosy oil that contained the two
products. The mixture were not possible to isolate by SiO2 and ratio of 1:1.1 was determined by 1H-NMR
for 2-methoxybenzaldehyde (13) and 4-methoxybenzaldehyde (14) respectively (424.4 mg, 97%
global yield). 2-Methoxybenzaldehyde and 4-methoxybenzaldehyde (13 and 14): TLC: Rf = 0.43–0.37
(DCM/hexane, 1:1). HPLC (H2O/MeCN from 95:5 to 0:100 over 8 min): tR (13) = 6.0 min,
tR (14) = 6.3 min. 1H-NMR and 13C-NMR see SI.
3.4.2. Entry 8
Reaction of 1,3-dimethoxybenzene (420 μL, 3.21 mmol), TiCl4 (780 μL, 7.11 mmol),
dichloro-methyl methyl ether (320 μL, 3.54 mmol) and DCM (10 mL) gave a grey solid, which was
purified on SiO2 (DCM) to yield 2,6-dimethoxybenzaldehyde (15) (97.4 mg, 18%) and
2,4-dimethoxybenzaldehyde (16) (323.9 mg, 61%). The ratio of regioisomers 16:15 was 3:1 and the
global yield 79%. 2,6-Dimethoxybenzaldehyde (15): Appearance: Pale yellow solid. Mp = 94–97 °C.
1
TLC: Rf = 0.21 (DCM). HPLC (H2O/MeCN from 95:5 to 0:100 over 8 min): tR = 4.9 min. H-NMR
(CDCl3) δ 10.5 (1H, s), 7.45 (1H, t, J = 8.5 Hz), 6.58 (2H, d, J = 8.5 Hz), 3.90 (6H, s) ppm. 13C-NMR
͂
(CDCl3) δ 189.6, 162.4, 136.0, 114.5, 104.0, 56.2 ppm. IR (ATR, Smart orbit): v = 2844.9, 2796.7,
1671.7, 1589.9, 1576.0, 1109.6 (vmax) cm−1. 2,4-Dimethoxybenzaldehyde (16): Appearance: White
͂
solid. Mp = 68–70 °C. TLC: Rf = 0.51 (DCM). HPLC (H2O/MeCN from 95:5 to 0:100 over 8 min):
1
tR = 5.7 min. H-NMR (CDCl3) δ 10.3 (1H, d, J = 0.7 Hz), 7.80 (1H, d, J = 8.7 Hz), 6.54 (1H, ddd,
13
J = 8.7, 2.2, 0.7 Hz), 6.44 (1H, d, J = 2.2 Hz), 3.90 (3H, s), 3.87 (3H, s) ppm. C-NMR (CDCl3) δ

Molecules 2015, 20
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͂
188.5, 166.3, 163.8, 130.9, 119.2, 105.9, 98.1, 55.8, 55.7 ppm. IR (ATR, Smart orbit): v = 2855.6,
2779.3, 1663.6, 1596.3, 1578.4, 826.5 (vmax) cm−1.
͂
3.4.3. Entry 9
Reaction of 1,3,5-trimethoxybenzene (533.5 mg, 3.17 mmol), TiCl4 (760 μL, 6.93 mmol),
dichloromethyl methyl ether (320 μL, 3.54 mmol) and DCM(10 mL), afforded a purple solid, which
was purified on SiO2 (DCM/hexane, 9:1) to yield 2,4,6-trimethoxybenzaldehyde (17) (275.0 mg,
44%). 2,4,6-Trimethoxybenzaldehyde (17): Appearance: Orange solid. Mp = 118–121 °C. TLC:
Rf = 0.37 (DCM/hexane, 9:1). HPLC B (H2O/MeCN from 95:5 to 0:100 over 11 min): tR = 7.0 min.
13
1H-NMR (CDCl3) δ 10.4 (1H, s), 6.07 (2H, s), 3.88 (6H, s), 3.87 (3H, s) ppm. C-NMR (CDCl3) δ
͂
187.9, 166.3, 164.2, 109.0, 90.4, 56.1, 55.6 ppm. IR (ATR, Smart orbit): v = 2843.2, 2796.0, 1661.3,
1596.1, 1574.3, 806.6 (vmax) cm−1.
͂
3.4.4. Entry 10
Reaction of 3,5-dimethylanisole (453 μL, 3.21 mmol), TiCl4 (780 μL, 7.11 mmol), dichloromethyl
methyl ether (320 μL, 3.54 mmol) and DCM (10 mL), gave a violet oily solid, which was purified by
reverse-phase liquid chromatography (Semipreparative HPLC: Xbridge Prep BEH 130 C18, 5 μm
OBDTM 19 × 100 mm column, gradient H2O/MeCN from 55:45 to 50:50 over 30 min) to yield a 3.5:1
ratio of 2-methoxy-4,6-dimethylbenzaldehyde (18) (77.4 mg, 14.7%) and 4-methoxy-2,6-
dimethylbenzaldehyde (19) (22.1 mg, 4.2%) respectively. 2-Methoxy-4,6-dimethylbenzaldehyde (18):
Appearance: Yellow solid. Mp = 48–50 °C. TLC: Rf = 0.50 (DCM). HPLC (H2O/MeCN from 95:5 to
0:100 over 8 min): tR = 5.6 min. 1H-NMR (CDCl3) δ 10.6 (1H, s), 6.63 (1H, s), 6.62 (1H, s), 3.88 (3H,
s), 2.54 (3H, s), 2.35 (3H, s) ppm. 13C-NMR (CDCl3) δ 191.9, 163.5, 145.8, 142.2, 125.2, 121.1, 109.9,
−1
͂
55.9, 22.3, 21.6 ppm. IR (ATR, Smart orbit): v = 2965.3, 2926.5, 1671.3, 1598.5, 1319.1, 1146.5 cm .
4-Methoxy-2,6-dimethylbenzaldehyde (19): Appearance: White solid. Mp = 49–50 °C. TLC: Rf = 0.24
(DCM). HPLC (H2O/MeCN from 95:5 to 0:100 over 8 min): tR = 4.7 min. 1H-NMR (CDCl3) 10.5 (1H,
13
s), 6.59 (2H, s), 3.84 (3H, s), 2.61 (6H, s) ppm. C-NMR (CDCl3) 191.8, 162.9, 144.6, 126.2, 115.0,
͂
55.4, 21.3 ppm. IR (ATR, Smart orbit):v = 2960.2, 2921.5, 1678.8, 1610.3, 1465.1, 1299.4, 1205.1,
1097.2, 836.8 (vmax) cm−1.
͂
3.5. Methylbenzenes
3.5.1. Entry 11
Reaction of o-xylene (386 μL, 3.20 mmol), TiCl4 (780 μL, 7.11 mmol), dichloromethyl methyl ether
(320 μL, 3.54 mmol) and DCM (10 mL), afforded a green oil, which was purified on SiO2
(hexane/AcOEt, 8:2). During the purification, partial decomposition was observed. Both regioisomers
were isolated as a 3.2:1 mixture of 3,4-dimethylbenzaldehyde (21) and 2,3-dimethylbenzaldehyde (20)
1
respectively, determined by the H-NMR of the isolated mixture (see SI). TLC: Rf = 0.48–0.53
(hexane/AcOEt, 8:2). HPLC (H2O/MeCN from 95:5 to 0:100 over 8 min): tR = 6.7 min.

Molecules 2015, 20
5419
3.5.2. Entry 12
Reaction of m-xylene (394 μL, 3.21 mmol), TiCl4 (780 μL (7.11 mmol), dichloromethyl methyl
ether (320 μL, 3.54 mmol) and DCM (10 mL), afforded a yellow oil, which was purified on SiO2
(treated with 1% of NEt3) (hexane/AcOEt, 19:1) to yield a mixture of 2,6-dimethylbenzaldehyde (22)
and 2,4-dimethylbenzaldehyde (23) (267.0 mg, 62%) in a 1:32 ratio, as determined by 1H-NMR of the
isolated mixture. Moreover, bis(2,4-dimethylphenyl)methanol (24) was isolated as a dimerization
by-product (38.0 mg, 9.9%). Mixture of 22 and 23: TLC: Rf = 0.25–0.27 (hexane/AcOEt, 19:1). HPLC
(H2O/MeCN from 95:5 to 0:100 over 8 min): tR = 6.8 min. bis(2,4-Dimethylphenyl)methanol (24):
Appearance: White solid. TLC: Rf = 0.12 (hexane/EtOAc, 19:1). HPLC (H2O/MeCN from 95:5 to
1
0:100 over 8 min): tR = 8.3 min. H-NMR (CDCl3) δ 7.17 (2H, m), 6.99 (4H, m), 6.07 (1H, s), 2.32
13
(6H, s), 2.25 (6H, s) ppm. C-NMR (CDCl3) δ 138.2, 137.2, 135.7, 131.4, 126.8, 126.6, 70.1, 21.1,
19.1 ppm.
3.5.3. Entry 13
Reaction of p-xylene (394 μL, 3.21 mmol), TiCl4 (780 μL, 7.11 mmol), dichloromethyl methyl ether
(320 μL, 3.54 mmol) and DCM (10 mL), gave a rosy oil which was not purified (95% purity). The
dimerization byproduct (3.4% of the peak area) was observed in the chromatographic traces.
2,5-Dimethylbenzaldehyde (25): Appearance: Rosy oil. TLC: Rf = 0.25–0.27 (hexane/EtOAc, 19:1).
HPLC (H2O/MeCN from 95:5 to 0:100 over 8 min): tR = 6.9 min. 1H-NMR (400 MHz, CDCl3) δ 10.23
(1H, s), 7.59 (1H, d, J = 1.2 Hz), 7.28 (1H, dd, J = 7.8, 1.5 Hz), 7.14 (1H, d, J = 7.8 Hz), 2.61 (3H, s),
13
2.37 (3H, s) ppm. C-NMR (100 MHz, CDCl3) δ 192.4, 144.6, 140.7, 132.6, 132.5, 132.0, 127.1, 21.7,
19.6 ppm. IR (ATR, Smart orbit): v = 2923.8, 2722.1, 1690.5 (vmax), 1611.3, 1504.9, 1240.7, 1155.2 cm−1.
͂
͂
3.5.4. Entry 14
Reaction of mesytilene (1000 μL, 7.19 mmol), TiCl4 (1.5 mL, 13.68 mmol), dichloromethyl methyl
ether (720 μL, 7.96 mmol) and DCM (25 mL), gave a colorless oil (1.02 g, 96%), which was not
purified (97% purity). 2,4,6-Trimethylbenzaldehyde (26): Appearance: Colorless oil. TLC: Rf = 0.54
1
(DCM/hexane, 1:1). HPLC (H2O/MeCN from 95:5 to 0:100 over 8 min): tR = 6.0 min. H-NMR
(CDCl3) δ 10.5 (1H, s), 6.87 (2H, s), 2.55 (6H, s), 2.29 (3H, s) ppm. 13C-NMR (CDCl3) δ 192.87,
͂
143.78, 141.43, 130.51, 129.95, 21.43, 20.46 ppm. IR (NaCl): v =2921.4, 2865.3, 2783.1, 1687.1
(vmax), 1608.4 cm−1.
͂
4. Conclusions
In short, the formylation studies presented here demonstrate the potential of aromatic formylation
using TiCl4 and dichloromethyl methyl ether as a straightforward and versatile reaction that affords
a wide range of functionalized aldehydes. Of note, only for phenol derivatives did the oxygen-metal
interaction contribute significantly to determining o-formylation. We consider that this reaction will
allow the development of a new set of protecting groups and linkers for further application in SPPS.

Molecules 2015, 20
5420
Supplementary Materials
Supplementary materials can be accessed at: http://www.mdpi.com/1420-3049/20/04/5409/s1.
Acknowledgments
I.R.T. thanks the Generalitat de Catalunya for a pre-doctoral fellowship. This work was funded in
part by the following: the CICYT (CTQ2012-30930), the Generalitat de Catalunya (2014 SGR 137),
and the Institute for Research in Biomedicine Barcelona (IRB Barcelona) (Spain); the National Research
Foundation and the University of KwaZulu Natal (South Africa); and SENESCYT (Ecuador).
Author Contributions
The manuscript was written through contributions of all authors. All authors have given approval to
the final version of the manuscript. I.R.-T., J.M.B., I.P.R.M., E.N. and F.A. designed the experiments.
I.R.-T. and M.P.-B. performed the experiments and characterized all the compounds. I.R.-T., E.N. and
F.A. wrote the manuscript.
Conflicts of Interest
The authors declare no conflict of interest.
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