A practical synthesis of chloromethyl esters from acid chlorides and trioxane or paraformaldehyde promoted by zirconium tetrachloride

Article abstract of DOI:10.1016/S0040-4039(02)01396-5

A practical synthesis of chloromethyl esters from acid chlorides and trioxane or paraformaldehyde using zirconium tetrachloride as the Lewis acid has been demonstrated. The new procedure is highly chemoselective and applies to a variety of acid chlorides.

Full text of DOI:10.1016/S0040-4039(02)01396-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 6317–6318
A practical synthesis of chloromethyl esters from acid chlorides
and trioxane or paraformaldehyde promoted by zirconium
tetrachloride
Boguslaw Mudryk,a,* Shanthi Rajaramanb and Nachimuthu Soundararajana
aProcess Research and Development, Bristol-Myers Squibb Pharmaceutical Research Institute, One Squibb Drive, PO Box 191,
New Brunswick, NJ 08903, USA
bDepartment of Chemistry, Rutgers University, 610 Taylor Road, Piscataway, NJ 08854, USA
Received 5 June 2002; revised 8 July 2002; accepted 10 July 2002
Abstract—A practical synthesis of chloromethyl esters from acid chlorides and trioxane or paraformaldehyde using zirconium
tetrachloride as the Lewis acid has been demonstrated. The new procedure is highly chemoselective and applies to a variety of acid
chlorides. © 2002 Elsevier Science Ltd. All rights reserved.
Chloromethyl esters represent an important class of
intermediates in the synthesis of prodrugs1 in which the
methylene bridge links the lipophilic and hydrophilic
parts of a molecule. The need for a practical and
scalable synthesis of the linker 1 arose during the
process development of an antifungal drug candidate.
cinogenic alkylating agents. Our initial attempts
(Scheme 1) to improve the reported procedure4
involved replacing paraformaldehyde with the easier to
handle trioxane and the use of tin tetrachloride instead
of zinc chloride as the Lewis acid.5 Although those
changes resulted in higher yields of 1 and improved the
reaction scale-up feasibility, the formation of the meth-
ylene-bridged ‘dimer’ 2 in ꢀ20% yield was observed on
a larger scale as a secondary reaction pathway, result-
ing in laborious work-up and tedious purification of the
product. In addition, the presence of tin salts in the
waste streams raised safety concerns.
Cl
O
O
Cl
1
After screening a series of Lewis acids, we were
delighted to find that the use of zirconium tetrachloride
instead of tin tetrachloride virtually completely sup-
pressed the formation of dimer 2. The only by-product
under these reaction conditions was the corresponding
carboxylic acid, which could be removed easily by an
aqueous sodium carbonate wash during work up. The
Examination of the literature on the preparation of
chloromethyl esters identified two main protocols: (1)
alkylation of carboxylates with chlorobromomethane2
or chloromethyl chlorosulfonate3 and, (2) condensation
of aldehydes with acid chlorides in the presence of a
Lewis acid.4 The latter procedure was selected for evalu-
ation as it did not involve the use of potentially car-
O
O
O
O
SnCl4, trioxane
Cl
O
Cl
O
O
+
CH2Cl2
1, 50-60%
Cl
Cl
2, ~20 %
Cl
Cl
Scheme 1.
Keywords: chloromethyl ester; acid chloride; trioxane; paraformaldehyde; zirconium tetrachloride.
* Corresponding author. Tel.: (732) 519-1620; e-mail: mudrykb@bms.com
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01396-5

6318
B. Mudryk et al. / Tetrahedron Letters 43 (2002) 6317–6318
a
Table 1.
products in moderate yields (entries 8–10) or produced
complex mixtures (entries 11–13, 15), presumably as a
result of competing Friedel–Crafts processes.
Lewis acid
ArCO2CH2Cl, 1 (ArCO2)2CH2, 2 ArCO2H
SnCl4
TiCl4
ZrCl4
43
62
87
18
2
0.1
26
34
13
In summary, a convenient and practical procedure for
preparation of chloromethyl esters from acid chlorides
and trioxane or paraformaldehyde, promoted by the
easy to handle zirconium tetrachloride, has been devel-
oped. The advantages over alternative methods include
high chemoselectivity, shorter reaction time, straight-
forward processing and simple product isolation.
a Ar=3-ClCH2C6H4-.
Table 2.
Entry
R
Isolated yield of RCO2CH2Cl (%)
1
3-ClCH2-C6H4- 72
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Ph-
75
64
90
98
94
79
66
64
References
2-NO2-C6H4-
4-NO2-C6H4-
4-F-C6H4-
4-Cl-C6H4-
4-Br-C6H4-
3-CH3-C6H4-
4-CH3-C6H4-
3-CH3O-C6H4- 64
2-CH3O-C6H4- Mixture
4-CH3O-C6H4- Mixture
1. For a recent review see: Krise, J. P.; Stella, V. J. Adv. Drug
Delivery Rev. 1996, 19, 287.
2. Ozawa, N.; Yazawa, N. Patent WO 9308152, 1993.
3. (a) Baltzer, B.; Godtfredsen, W. O. J. Antibiot. 1980, 33,
1183; (b) Binderup, E.; Hansen, E. T. Synth. Commun.
1984, 14, 857; (c) Harada, N.; Hongu, N.; Tanaka, M.;
Kawaguchi, T.; Takayuki, H.; Hashiyama, T.; Tsujihara,
K. Synth. Commun. 1994, 24, 767.
2-Furyl-
2-Thienyl-
1-C10H7-
PhCH2-
Mixture
88
Mixture
66
4. Iyer, R. P.; Yu, D.; Ho, N.; Agrawal, S. Synth. Commun.
1995, 25, 2739.
5. Yang, W.; Wang, X.; Bhattacharya, A.; Chau, M. US
Patent 6326509, 2001.
6. A typical procedure is as follows for 3-ClCH2C6H4-
COCH2Cl (Table 2, entry 1): The acid chloride (50 g, 1.0
equiv.) was added to a stirred suspension of zirconium
tetrachloride (55.4 g, 0.9 equiv.) in dichloromethane (500
mL, 10 mL per 1 g acid chloride) at room temperature.
After 15 min, the reaction mixture was cooled to 0°C and
trioxane (8.8 g, 0.37 equiv.) was added as a solution in
dichloromethane (20 mL). The slurry was stirred at 0–
25°C for 1 h (HPLC indicated 92:8 ratio of the product to
the acid by-product) and cooled again to 0°C. Water (250
mL) was added slowly while maintaining the temperature
below 25°C and the biphasic mixture was agitated for 15
min. The organic phase was separated, washed with 1 N
sodium bicarbonate solution (250 mL) to remove the
carboxylic acid, and then washed with water (100 mL).
Dichloromethane was exchanged for heptane (500 mL) by
distillation to a final volume of 300 mL. Ethyl acetate (15
mL) was added to the heptane at 70°C and the product
crystallized upon cooling to room temperature. The
product was filtered, washed with heptane and dried to
give 41.4 g (72%) of 1 as a white solid (mp 42°C), HPLC
purity: 99.8 area%. 1H NMR (300 MHz, CDCl3): l 4.63 (s,
2H), 5.97 (s, 2H), 7.48 (t, J=7.7 Hz, 1H), 7.66 (d, J=7.5
Hz, 1H), 8.05 (d, J=7.9 Hz, 1H), 8.11 (s, 1H). 13C NMR
(75 MHz, CDCl3): l 45.29, 69.31, 129.17, 130.10, 134.03,
138.20, 164.11. IR (KBr, cm−1): 1740, 1281, 1175. MS: 220
[M+H]+, 183 [M−Cl]+, 153 [M−OCH2Cl]+. Anal. calcd for
C9H8O2Cl2: C, 49.34; H, 3.68; Cl, 32.36. Found: C, 49.41;
H, 3.72; Cl, 32.30.
absence of the dimer 2 dramatically simplified the pro-
cessing and product isolation. In addition, substituting
tin tetrachloride with the easier to handle zirconium
tetrachloride improved the process safety.6
Table 1 shows the relative ratios (HPLC area%) of the
chloromethyl ester 1, the methylene bridged dimer 2,
and the carboxylic acid in reaction mixtures when tin,
titanium and zirconium tetrachlorides (1 equiv. each)
were employed.
Using optimized stoichiometric ratios (0.9 equiv. of
ZrCl4, 0.37 equiv. of trioxane or 1.2 equiv. para-
formaldehyde) and reaction conditions (dichloro-
methane, 0–25°C, 1 h) we next examined the scope and
generality of this chloromethylation method. Most aro-
matic and heteroaromatic acid chlorides (Table 2) sub-
jected to the ZrCl4/trioxane (or paraformaldehyde for
entries 4–7) system produced the corresponding
chloromethyl esters in good yield with only trace
amounts of dimeric by-product. The procedure proved
to be particularly effective for benzoyl chlorides bearing
electron withdrawing substituents in the para position
(entries 4–6) and 2-thiophenecarbonyl chloride (entry
14). On the other hand, acid chlorides attached to
electron-rich aromatic and heteroaromatic rings gave