A practical and convenient Blanc-type chloromethylation catalyzed by zinc chloride under solvent-free conditions

Article abstract of DOI:10.1080/00397911.2019.1571209

Chloromethylation of various aromatic hydrocarbons and substituted phenolic derivatives with dimethoxymethane and chlorosulfonic acid was carried out in the presence of 10 mol% of ZnCl₂ in a mild and efficient manner under solvent-free conditions. In addition, 2,6-dimethyltyrosine was synthesized in high yield via this protocol.

Full text of DOI:10.1080/00397911.2019.1571209

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
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A practical and convenient Blanc-type
chloromethylation catalyzed by zinc chloride
under solvent-free conditions
Jian Tang, Hongtao Liu, Kailun He & Xingxian Zhang
To cite this article: Jian Tang, Hongtao Liu, Kailun He & Xingxian Zhang (2019): A practical and
convenient Blanc-type chloromethylation catalyzed by zinc chloride under solvent-free conditions,
Synthetic Communications, DOI: 10.1080/00397911.2019.1571209
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https://doi.org/10.1080/00397911.2019.1571209
A practical and convenient Blanc-type chloromethylation
catalyzed by zinc chloride under solvent-free conditions
Jian Tang, Hongtao Liu, Kailun He, and Xingxian Zhang
College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, Zhejiang, P. R. China
ABSTRACT
ARTICLE HISTORY
Received 5 November 2018
Chloromethylation of various aromatic hydrocarbons and substituted
phenolic derivatives with dimethoxymethane and chlorosulfonic acid
was carried out in the presence of 10 mol% of ZnCl2 in a mild and
efficient manner under solvent-free conditions. In addition, 2,6-dime-
thyltyrosine was synthesized in high yield via this protocol.
KEYWORDS
Aromatic compounds;
chloromethylation;
chlorosulfonic acid;
zinc chloride
GRAPHICAL ABSTRACT
Introduction
Chloromethyl substituted aromatic compounds are promising key intermediates for a
variety of fine or special chemicals, polymers, and pharmaceuticals. The chloromethyla-
tion of aromatic compounds has been well documented,[1–8] including the chloromethy-
lation of aromatic hydrocarbons with hydrochloric acid and trioxane or
paraformaldehyde in the absence of a catalyst.[6–8] However, the reaction is very slow
and insufficient for practical chemical processes. Later Lewis acids such as zinc chloride,
stannic chloride, aluminum chloride, and boron trifluoride have been employed as cata-
lysts for the reaction.[9–11] These catalysts, in general, suffer from the inherent problems
of corrosiveness, high susceptibility to water, environmental hazards, waste control after
the reaction, etc.[12–14] Zinc chloride is one of the most effective catalysts. However,
normally a stoichiometric amount of zinc chloride is required, making the workup pro-
cedure tedious. Recently, rare-earth metal triflates were reported as active catalysts for
this reaction, but these catalysts are expensive and not suitable to be used in indus-
try.[15,16] The use of ionic liquids[17–21] and surfactant micelles[22,23] as catalysts for the
chloromethylation of aromatic hydrocarbons were also reported. However, these ionic
liquids are inevitably associated with one or more disadvantages, such as high cost or
difficulty of synthesis. Therefore, it is important to replace these highly corrosive,
CONTACT Xingxian Zhang
zhangxx@zjut.edu.cn
College of Pharmaceutical Sciences, Zhejiang University of
Technology, Hangzhou, Zhejiang, 310032, P. R. China.
Supplemental data for this article is available online at on the publisher’s website.
ß 2019 Taylor & Francis Group, LLC

2
J. TANG ET AL.
Scheme 1. Chloromethylation of aromatic compounds.
Table 1. Optimization of reaction conditions for Lewis acid-catalyzed chloromethylation reaction
under solvent-free conditionsa.
Entry
Lewis acid
Amounts of catalyst (mol%)b
Time (h)
Yields (%)c
1
2
3
4
5
6
7
8
None
AlCl3
CaCl2
SnCl4
LiCl
None
50
50
50
50
50
50
15
10
5
7.0
5.0
20.0
2.0
20.0
2.0
2.5
2.0
2.0
12.0
12.0
2.0
30
25
26
35
34
50
60
86
88
68
56
68
66
55
36
FeCl3
TiCl4
ZnCl2
ZnCl2
ZnCl2
ZnCl2
Zn(OAc)2
ZnO
9
10
11
12
13
14
15
1
10
10
10
10
2.0
2.0
2.5
Zn(OTf)2
ZnSO4
aThe reaction was carried out by the mixture of chlorosulfonic acid (31 mmol), dimethoxymethane (31 mmol) and O-car-
bethoxy-3,5-dimethylphenol (26 mmol) in the presence of Lewis acid at 5–10 ꢀC under solvent-free condition.
bRelative to the amount of O-carbethoxy-3,5-dimethylphenol.
cIsolated yield by silica gel flash chromatography.
hazards and polluting acid catalysts with eco-conscious catalysts which are active under
mild conditions.
Herein, we wish to report an efficient and convenient method for the chloromethyla-
tion of aromatic compounds with dimethoxymethane as a formaldehyde precursor and
chlorosulfonic acid catalyzed by ZnCl2 under solvent-free conditions (Scheme 1).
Results and discussion
Initially, we chose O-carbethoxy-3,5-dimethylphenol 6 as the model substrate for sur-
veying the reaction parameters. The results are shown in Table 1. The reaction was car-
ried out sluggishly without a catalyst under the solvent-free condition and the yield was
only 30% (Table 1, entry 1). By screening various Lewis acid catalysts we have found
that low yields were given using 50 mol% of AlCl3, CaCl2, SnCl4, LiCl as promoters,
respectively (Table 1, entries 2–5). FeCl3 and TiCl4 could give moderate yields (Table 1,
entries 6–7). Gratifyingly, the chloromethylation of O-carbethoxy-3,5-dimethylphenol
was proceeded effectively in a short time catalyzed by 10 mol% of ZnCl2 and gave
exclusively O-carbethoxy-3,5-dimethyl-4-chloromethylphenol product in 88% yields
(Table 1, entry 9).

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3
To examine the anion effect, a variety of zinc salts such as Zn(OAc)2, ZnO,
Zn(OTf)2, and ZnSO4 were compared under similar conditions, respectively. Moderate
yields were given in the presence of Zn(OAc)2 and ZnO (Table 1, entries 12 and 13).
Zn(OTf)2 and ZnSO4 were less effective in terms of substrate conversion (Table 1,
entries 14 and 15).
With these optimal conditions in hand, we further explored the scope and limitation
of this simple process by reaction of electronically, sterically and functionally diverse
aromatic compounds under the optimized conditions (Table 2). The reaction proceeded
smoothly under solvent-free conditions and provided mono-chloromethyl substituted
aromatic compounds in moderate to good yields, which was attributed to the deactivat-
ing effect of a ꢁ CH2Cl group. The aromatic compounds such as ethylbenzene, cumene,
and tert-butylbenzene gave mono-chloromethylated products in better yields (Table 2,
entries 3-5) than that of benzene, phenyl benzene (Table 2, entries 1 and 2), which are
attributed to the electron-donating effect of the alkyl group. In addition, we have found
that the chloromethylation of 3,5-dimethyl phenol failed due to its coordination of
hydroxyl group with ZnCl2. When the hydroxyl group of 3,5-dimethyl phenol was pro-
tected by ethyl chloroformate, the chloromethylation could be carried out smoothly and
provided the desired products in good yield (Table 2, entry 6). The chloromethylation
of various substituted O-carbethoxy phenol was also carried out smoothly in a short
time and afforded good yields, respectively (Table 2, entries 7–10). The chloromethyla-
tion of O-carbethoxy phenol bearing electron-withdrawing group (i.e. –Cl, –NO2) on
benzene ring was inert under the parallel condition. The chloromethylation of O-carbe-
thoxy-1-naphthol exclusively provided O-carbethoxy- 8-chloromethyl-1-naphthol 11a at
5–10 ꢀC (Table 2, entry 11). As well, the chloromethylation of 1-chloronaphthalene
afforded 8-chloromethylated product 12a (Tablꢀe 2, entry 12), while no reaction was
observed in the case of chlorobenzene at 5–10 C. The chloromethylation of O-carbe-
thoxy-6-bromo-2-naphthol 13 exclusively afforded the desired 5-chloromethyl product
ꢀ
in moderate yield at 40 C (Table 2, entry 13). It is worthy to be noted that no double
chloromethylation products are observed by this protocol. In addition, to our surprise,
no chloromethylation of styrene was observed on the benzene ring under this catalysis
system, which was replaced by addition of double bond and afforded 1-phenyl-1-
chloro-3-methoxypropane 15 (Table 2, entry 14).
A plausible mechanism for this catalysis is shown as Scheme 2. Firstly, treatment of
dimethoxymethane with chlorosulfonic acid in situ produces methyl chloromethyl ether,
followed by excretion of methanol and SO3. Then, methyl chloromethyl ether reacts
with ZnCl2 to yield chloromethyl cation (ClCH2þ) and methoxylated zinc chloride
anion ([CH3OZnCl2]-). Electrophilic addition occurred by a subsequent attack of the
[ClCH2]þ on the benzene ring of the aromatic compounds to give chloromethylated
aromatic carbonium ion, which very rapidly gave the desired products via aromatiza-
tion. Finally, methoxylated zinc chloride anion ([CH3OZnCl2]-) was protonated to pro-
duce methanol and led to the regeneration of ZnCl2. In this process, the catalyst ZnCl2
plays a vital role in the activation of methyl chloromethyl ether to form chloromethyl
cation and methoxylated zinc chloride anion ([CH3OZnCl2]). As a control experiment,
the chloromethylation of benzene using CH3OCH2Cl as chloromethylation reagent[10]
was furnished in the presence of ZnCl2 under solvent-free conditions in 65% yield.

4
J. TANG ET AL.
Table 2. Chloromethylation of aromatic compounds cat-
alyzed by ZnCl2 under solvent-free conditionsa.
Entry
Substrate
t (h)
4.0
Product
Yield (%)b
1
2
67
66
4.0.
3
4
5
6
3.0
1.0
1.0
2.0
77
75
76
88
7
8
9
2.0
2.0
2.0
84
87
85
10
11
12
2.0
4.0
5.0
82
82
65
13c
14
2.0
2.0
68
90
a
Reaction conditions: The reaction mixture of aromatic compounds (26
mmol), chlorosulfonic acid (31 mmol) and dimethoxymethane (31 mmol)
was carried out in the presence of 10 mol% of ZnCl2.
b
c
Isolated yield by silica gel flash chromatography.
The reaction was carried out at 40 ꢀC.

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5
Scheme 2. Plausible mechanism of chloromethylation catalyzed by ZnCl2.
Scheme 3. Synthesis of dimethyltyrosine.
To demonstrate the applicability of this protocol we employed it for the synthesis of
2,6-dimethltyrosine (Scheme 3), which is the key intermediate of d-opioid receptor
antagonist H-Dmt-Tic-OH[24]. The condensation of chloromethylated compound 6a
with diethyl 2-acetamidomalonate in the presence of sodium methoxide afforded
dimethyl acetamido-(2,6-dimethyl-4-hydroxybenzyl) malonate 16 in 90% yield, which
was subjected to decarboxylation in concentrated hydrochloric acid under reflux to give
the desired product 2,6-dimethyltyrosine.
Conclusion
In conclusion, an efficient and practical chloromethylation protocol with ZnCl2 as a
catalyst in combination with chlorosulfonic acid and dimethoxymethane has been devel-
oped, which is capable of converting aromatic compounds into the corresponding

6
J. TANG ET AL.
chloromethyl substituted aromatic compounds in moderate to good yields under solv-
ent-free conditions. This methodology has some advantages such as simple operation,
mild condition, and easy product purification. We expect this method will find wide
application in organic synthesis and pharmaceutical industry.
Experimental
General procedure for ZnCl2-catalyzed chloromethylation of aromatic compounds: A
three-necked flask was charged with ZnCl2 (2.6 mmol), chlorosulfonic acid (31 mmol),
ꢀ
followed by dropwise addition of dimethoxymethane (31 mmol) at ꢁ10 C. After stir-
ring for 30 minutes, aromatic compound (26 mmol) was slowly added into the reaction
ꢀ
mixture. The resulting mixture continued to be stirred at 5–10 C for several hours.
The reaction was monitored by TLC analysis. After completion, the reaction was
quenched by the addition of water in an ice bath. After extraction with CH2Cl2, the
organic phase was washed with 5% sodium carbonate solution, water and brine, then
evaporated to dryness in vacuo. The residue was purified by flash column chromatog-
raphy on a silica gel to give the desired product.
Dimethyl Acetamido-(2,6-dimethyl-4-hydroxybenzyl)malonate (16)[25]: A three-
necked flask was charged with 500 mL absolute methanol and diethyl 2-acetamidomalo-
nate (98.5 g, 453 mmol), followed by addition of 28% sodium methoxide solution (95.5
g 494.5 mmol). Then 6a (100 g, 412 mmol) was slowly added dropwise. The reaction
mixture was stirred at room temperature for 4 hours. 150 mL of water was added and
ꢀ
then concentrated in vacuo. The reaction residue was filtered and dried at 60 C to give
25
ꢀ
ꢀ
120 g of 16 as white solid. m.p. 155–156 C (lit. 156–157 C); Rf = 0.50 (Petroleum
ether: EtOAc = 1:1); 1 H NMR (500 MHz, DMSO) d 8.33 (s, 1H), 6.38 (s, 2H), 3.57 (s,
6H), 3.49 (s, 2H), 2.09 (s, 6H), 1.89 (s, 3H) ppm. 13C NMR (125 MHz, DMSO) d 169.4,
168.2, 155.3, 139.2, 122.7, 114.8, 66.8, 52.7, 32.3, 22.1, 20.1. ppm.
2,6-Dimethyltyrosine(17)[25]: A mixture of 16 (50.0 g 154.8 mmol) and 200 mL of
conc. HCl was refluxed for 3.5 hours. The reaction mixture was cooled, and the crystal-
line product was collected, washed with cooled water, and dried to give 32.5 g of 2,6-
dimethyltyrosine hydrochloride. The dimethyltyrosine hydrochloride was dissolved in
300 mL of warm water and neutralized to pH 6.5 with saturated aqueous sodium car-
bonate. The reaction mixture was cooled to room temperature. The crystalline amino
acid was collected and washed with acetone to give 24.3 g of 17 as light yellow solid.
[25]
1
ꢀ
ꢀ
m.p. 232–233 C (lit.
230–231 C); Rf = 0.20 (MeOH: EtOAc = 1:1); H NMR (500
MHz, D2O) d 6.45 (s, 2H), 3.93 (t, J = 8.2 Hz, 1H), 3.10 (dd, J = 14.7, 8.5 Hz, 1H), 2.95
(dd, J = 14.7, 7.8 Hz, 1H), 2.08 (s, 6H) ppm. 13C NMR (125 MHz, D2O) d 171.9, 154.3,
139.5, 123.4, 115.1, 52.6, 29.7, 19.2. ppm.
Funding
This work was supported by National Natural Science Foundation of China.
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