Methoxymethylation of alcohols, phenols, and avermectin aglycones using MOM-2-pyridylsulfide

Article abstract of DOI:10.1021/jo9822582

Methoxymethyl-2-pyridylsulfide (MOM-ON) is an effective methoxymethylating reagent when used in conjunction with AgOTf, NaOAc, and THF. A wide range of MOM ethers are produced from corresponding phenols and alcohols, including tertiary and allylic alcohols, in good yields and under mild, neutral conditions. This method is also effective for the methoxymethylation of avermectin aglycones.

Full text of DOI:10.1021/jo9822582

2446
J . Org. Chem. 1999, 64, 2446-2449
Meth oxym eth yla tion of Alcoh ols, P h en ols, a n d Aver m ectin
Aglycon es Usin g MOM-2-p yr id ylsu lfid e
Benjamin F. Marcune,* Sandor Karady, Ulf-H. Dolling, and Thomas J . Novak
Department of Process Research, Merck Research Laboratories, Merck & Co., P.O. Box 2000,
Rahway, New J ersey 07065
Received November 13, 1998
Methoxymethyl-2-pyridylsulfide (MOM-ON) is an effective methoxymethylating reagent when used
in conjunction with AgOTf, NaOAc, and THF. A wide range of MOM ethers are produced from
corresponding phenols and alcohols, including tertiary and allylic alcohols, in good yields and under
mild, neutral conditions. This method is also effective for the methoxymethylation of avermectin
aglycones.
In tr od u ction
allylic, and benzylic alcohols, are not suitable for meth-
oxymethylation under these conditions. Therefore, these
methods have not been proven to have general applica-
tions. When applying these conditions to avermectin
aglycone 1l (Table 1), rapid desilylation followed by slow
indiscriminate methoxymethylation ensued.
The methoxymethyl moiety (MOM) is a frequently used
protecting group for alcohols, phenols, and carboxylic
acids.1-3 We became interested in methoxymethylations
during the preparation of antiparasitic ivermectin de-
rivative 2l.4
Herein, we report a new method for the methoxy-
methylation of avermectin aglycones, alcohols, and phe-
nols under very mild and neutral conditions. Inspired by
work showing that thioglycosides are effective glycosyl
donors in the presence of thiophilic silver salts,12 we
prepared and tested a variety of MOM-thiol reagents. We
now present MOM-2-pyridylsulfide (5), MOM-ON, as an
efficient methoxymethylating reagent of alcohols and
phenols, including acid-sensitive allylic and tertiary
alcohols.
MOM derivatives are usually prepared by alkylation
with an excess of chloromethyl methyl ether.2 Because
of the potent carcinogenic properties of chloromethyl
methyl ether,5 the task of finding alternate methods for
the preparation of MOM ethers was undertaken.
The ideal reagent would have no alkylating activity
until it is activated by a suitable Lewis acid (eq 1). This
Resu lts a n d Discu ssion
Our search for an effective MOM-thiol reagent began
with commercially available MOM-phenyl sulfide (3).
Reaction of 3 with alcohol 1b and a Lewis acid such as
TMSOTf, Cu(OTf)2, BF3‚Et2O, Sn(OTf)2, or AgOTf in
methylene chloride resulted in the production of 4 with
only a trace or poor yield of the desired product 2b (eq
2). Nucleophilic attack by thioether 3 or the thiol
principle has been extensively explored in transacetal-
ization reactions of dimethoxymethane with alcohols,
utilizing various catalysts such as P2O5,6 p-toluene-
sulfonic acid,7 Nafion-H,8 iodotrimethylsilane,9 molybde-
num(VI) acetylacetonate,10 and BF3.11 Though these
methods have their advantages over using chloromethyl
methyl ether, the strong acid catalysts limit their use.
Complex, acid-sensitive molecules, such as avermectin
aglycones, and easily ionizable alcohols, such as tertiary,
(1) Greene, T. W. Protective Groups in Organic Chemistry; Wiley-
Interscience: New York, 1981; p 10.
(2) McComie, J . F. W. Advances in Organic Chemistry; Wiley-
Interscience: New York, 1963; p 232 and references therein.
(3) Fieser, L. F.; Fieser, M. Reagents for Organic Synthesis; J ohn
Wiley & Sons: New York, 1967; Vol. 1, p 132.
(4) Mrozik, H.; Linn, B. O. U. S. Patent 4,587,247, May 6, 1986.
(5) Occupational Safety and Health Administration, U.S. Depart-
ment of Labor, Federal Register 39 (20); U.S. Government Printing
Office: Washington, DC, 1974.
(6) Fuji, K.; Nakano, S.; Fujita, E. Synthesis 1975, 276-277.
(7) Yardley, J . P.; Fletcher, H. Synthesis 1976, 244.
(8) Olah, G. A.; Husain, A.; Gupta, B. G. B.; Narang, S. C. Synthesis
1981, 471-472.
analogue of 3 on the metal-oxygen complex of 3 is a
likely mechanism. This result alerted us to the need for
a reagent with a more sulfur-selective coordinating
capability and reduced thio nucleophilicity, thereby
eliminating the competing reaction with itself. With this
in mind, reagents 5-14 were prepared from the corre-
(9) Olah, G. A.; Husain, A.; Narang, S. C. Synthesis 1983, 896-
897.
(10) Kantam, M. L.; Santhi, P. L. Synlett. 1993, 429-430. Although
this method employs mildly acidic conditions, in our hands it failed to
yield any desired product when attempting to methoxymethylate 1l.
(11) Danheiser, R. L.; Romines, K. R.; Koyama, H.; Gee, S. K.;
J ohnson, C. R.; Medich, J . R. Org. Synth. 1992, 71, 133-139.
(12) Toshima, K.; Tatsuta, K. Chem. Rev. 1993, 93, 1503-1531.
10.1021/jo9822582 CCC: $18.00 © 1999 American Chemical Society
Published on Web 03/17/1999

Methoxymethylation Using MOM-2-pyridylsulfide
J . Org. Chem., Vol. 64, No. 7, 1999 2447
Ta ble 1
a
LC response factors of the alcohols and their corresponding MOM ethers are essentially identical. Therefore, the LC assay yields of
the MOM ethers were calculated using the pure alcohols as standards.
sponding commercially available thiols, dimethoxy-
methane, and BF3‚Et2O.
With the exception of 9 and 14, which exhibited no
reaction, the thioamidate heterocycles 5-8 and 10-12
and thioether 13, in combination with AgOTf and THF,
all produced 2b with yields in excess of 40%. Thioacetal
byproducts analogous to 4 were not detected. Because
MOM-ON (5) gave the highest yields, it was selected for

2448 J . Org. Chem., Vol. 64, No. 7, 1999
Marcune et al.
Sch em e 1
alcohols and phenols. Tertiary alcohols, though slower
to react than primary and secondary alcohols, still
produced high yields. With only a slight increase of
reagents needed, allylic and benzylic alcohols also gave
good yields. Even the highly ionizable and hindered trityl
alcohol (1g) was methoxymethylated in modest yield.
Phenol gave an exceptionally high yield when 4.0 equiv
of MOM-ON was used. Finally, the method was tested
on the avermectin aglycones, which are prone to acid-
catalyzed rearrangements.13 Good yields of MOM-ethers
2l and 2m were produced with no desilylation or rear-
rangement products detected. In contrast, the Lewis acid
catalyzed reactions of 1l with dimethoxymethane pro-
duced mainly desilylation products.
Relative rates of reaction were tested by mixing
equimolar amounts of two given alcohols, 1 equiv of each,
with 0.5 equiv of MOM-ON. The results showed very little
difference between primary, secondary, and tertiary
alcohols. However, phenols reacted much slower than
alcohols.
The experimental procedure is quite simple. A solution
of AgOTf in THF is added very quickly to a solution of
the alcohol, NaOAc, and 5, resulting in the immediate
precipitation of the silver salts. After a few minutes, brine
solution and toluene are added to complete the precipita-
tion, and the solids are removed by filtration. The basic
byproducts are removed by acidic extractions. After
solvent removal, MOM ethers are left with little to no
byproducts detectable by NMR.
further development. Reaction of this reagent with 1b
resulted in a 5:95 ratio of 1b to 2b, with a yield of only
53%. The major byproduct was identified as acetal 16.
We hypothesized that production of 16 was caused by an
indiscriminate complexation of 5 allowing either the
methoxy moiety or the sulfide moiety to be the leaving
group. In the case of the former, intermediate 15 would
form, leading to 16 (Scheme 1). Alternatively, 16 could
form from the reaction of 1b with product 2b. To facilitate
formation of the sulfur-silver complex, we tested various
additives (Ag2O, acetic acid, silver acetate, and sodium
acetate), of which the acetates were shown to produce
dramatic improvement of yield with minimal formation
of 16.
With our model secondary alcohol 1b, optimal results
were obtained when 1.8 equiv of 5, 1.6 equiv of AgOTf,
and 1.2 equiv of NaOAc in THF were used. Numerous
solvents were tested, with THF giving the highest yields.
Excess 5 was required because of a rearrangement of
5 to 17 which competed with the main pathway. Isomer
17 and the analogous 9, both N-methoxymethylated, are
completely nonreactive in this reaction. Reacting 5 with
AgOTf and NaOAc in THF (eq 3) directly generated
Rapid addition of the silver triflate solution is impera-
tive. Slow addition results in incomplete transformations.
The excess reagents required for optimal yield with
various alcohols and phenols are shown in Table 1. As a
rule, the ratio of 5 to AgOTf should remain 1.1:1.
isomer 17. Upon standing neat at ambient temperature
for a few weeks, 17 reverted to a mixture of 5 and 17 in
a ratio of 80:20. Likewise, 5 under similar conditions
converted to a mixture of 5 and 17 in a ratio of 70:30. To
verify this apparent thermodynamic equilibrium, 5 and
17 were each subjected to 100 °C temperatures for 48 h.
As expected, each sample resulted in the same mixture
of 5 and 17 in a ratio of 65:35.
Con clu sion
MOM-ON is an effective reagent for the methoxy-
methylation of a wide range of alcohols and phenols. The
(13) Mrozik, H.; Eskola, R. L.; Arison, B. H.; Fisher, M. H.; Albers-
Schonberg, G. J . Org. Chem. 1982, 47, 489-492.
(14) Goff, D. A.; Harris, R. N., III; Bottaro, J . C.; Bedford, C. D. J .
Org. Chem. 1986, 51, 4711-4714.
As shown in Table 1, MOM-ON produced high yields
of methoxymethyl ethers when used with a variety of

Methoxymethylation Using MOM-2-pyridylsulfide
J . Org. Chem., Vol. 64, No. 7, 1999 2449
(4-Met h oxym et h oxy-b u t yl)-b en zen e (2a ): 1H NMR
(CDCl3) δ 1.70 (m, 4H), 2.67 (t, J ) 7.2 Hz, 2H), 3.37 (s, 3H),
3.56 (t, J ) 6.3 Hz, 2H), 4.63 (s, 2H), 7.24 (m, 5H); 13C NMR
(CDCl3) δ 28.14, 29.40, 35.72, 55.11, 67.59, 96.41, 125.74,
128.30, 128.43, and 142.40; MS (APCI) m/e 194.
(3,3-Meth oxym eth oxy-m eth yl-bu tyl)-ben zen e (2c): 1H
NMR (CDCl3) δ 1.31 (s, 6H), 1.83 (m, 2H) 2.69 (m, 2H) 3.42 (s,
3H), 4.77 (s, 2H), 7.24 (m, 5H); 13C NMR (CDCl3) δ 12.21, 30.44,
43.90, 55.21, 75.99, 91.06, 125.67, 128.49, and 142.78; MS
(APCI) m/e 208.
Dip h en yl-m et h oxym et h oxym et h a n e (2f): 1H NMR
(CDCl3) δ 3.45 (s, 3H), 4.74 (s, 2H), 5.80 (s, 1H), 7.37 (m, 10H);
13CNMR (CDCl3) δ 55.68, 78.75, 94.04, 127.29, 127.55, 128.45,
and 141.83; MS (APCI) m/e 228.
Tr ip h en yl-m eth oxym eth oxym eth a n e (2g): 1H NMR
(CDCl3) δ 3.31 (s, 3H), 4.63 (s, 2H), 7.28 (m, 3H), 7.45 (dd,
2H); 13C NMR (CDCl3) δ 56.06, 92.53, 86.65, 127.11, 127.80,
128.59, and 144.41; MS (APCI) m/e 304.
conditions are extremely mild, resulting in very quick and
clean reactions. We have shown this method to be broadly
applicable. Even highly ionizable and nonnucleophilic
compounds such as triphenylmethanol and p-nitrophenol
react to some extent.
Exp er im en ta l Section
1H and 13C NMR were run at 250 MHz. HPLC was carried
out with a Zorbax SB phenyl column (4.6 mm × 15 cm). MS
data was obtained by a Finnigan TSQ 7000 instrument with
an atmosphere pressure ionization interface. Ionization was
accomplished with atmosphere pressure chemical ionization.
Alcohols and phenols 1a -k and thiols used to produce reagents
5-14 were purchased from Aldrich Chemical Co.
MOM-ON (5). To a 0 °C solution of 2-mercaptopyridine
(24.7 g, 222 mmol) in dimethoxymethane (100 mL) under N2
was added BF3‚Et2O (34.7 g, 245 mmol). The mixture was
allowed to warm to room temperature and was stirred for 4
h. In an open flask, 100 mL of saturated NaHCO3 was added
slowly, followed by extraction with CH2Cl2 (1 × 100 mL, 1 ×
50 mL). The combined organic layers were washed with brine
and dried with anhydrous Na2SO4. The solvent was removed
in vacuo, and the residue was purified by vacuum distillation
(66 °C at 0.28 mmHg) yielding 26 g of 5 (75% yield) as a clear
yellow oil. Quick, low-pressure distillation is necessary because
of rearrangement of 5 to 17 at elevated temperatures. 1H NMR
(CDCl3) δ 3.29 (s, 3H), 5.22 (s, 2H), 6.91 (m, 1H), 7.17 (d, J )
8.7 Hz, 1H), 7.40 (m, 1H), 8.35 (m, 1H); 13C NMR (CDCl3) δ
56.51, 73.48, 120.14, 122.73, 136.36, 149.48, and 157.71; MS
(APCI) m/e 155.
Gen er a l P r oced u r e for th e Meth oxym eth yla tion of
Alcoh ols a n d P h en ols (2a -m ). P r ep a r a tion of (3-m eth -
oxym eth oxy-bu tyl)-ben zen e (2b). To a rapidly stirred solu-
tion of 1b (0.106 g, 0.706 mmol), 5 (0.212 g, 1.37 mmol), and
NaOAc (0.716 g 0.873 mmol) in 6.0 mL of THF under N2 at
room temperature was added all at once a solution of AgOTf
(0.3 g, 1.17 mmol) in THF (5.0 mL). After 5 min, saturated
brine (1.3 mL) and toluene (13 mL) were added. The precipi-
tates were filtered, and the filtrate was washed with 1 N HCl
(3 × 25 mL), saturated NaHCO3 (25 mL), and saturated brine
solution (25 mL). After drying with Na2SO4, the solvent was
removed in vacuo leaving 2b as a yellowish oil with an HPLC
assay yield of 90%: 1H NMR (CDCl3) δ 1.24 (d, J ) 6.2 Hz,
3H), 1.84 (m, 2H), 2.73 (m, 2H), 3.42 (s, 3H), 3.75 (m, 1H),
4.71 (q, J ) 13.3, 6.9 Hz, 2H), 7.26 (m, 5H); 13C NMR (CDCl3)
δ 20.45, 31.96, 38.95, 55.37, 72.91, 95.11, 125.79, 128.39, and
142.28; MS (APCI) m/e 194. The crude products can be further
purified by distillation or silica gel chromatography.
5,6,7,8-Tetr ah ydr o-1-m eth oxym eth oxyn aph th ylen e (2i):
1H NMR (CDCl3) δ 1.78 (m, 4H), 2.73 (m, 4H), 3.49 (s, 3H),
5.21 (s, 2H), 6.77 (d, J ) 7.6 Hz, 1H), 6.87 (d, J ) 7.7 Hz, 1H),
7.05 (t, J ) 8.1 Hz, 1H); 13C NMR (CDCl3) δ 22.82, 23.25, 26.53,
29.67, 55.96, 94.28, 110.45, 122.54, 125.72, 126.65, 138.71, and
154.95.
1-Meth oxy-2-m eth oxym eth oxyben zen e (2j): 1H NMR
(CDCl3) δ 3.48 (s, 3H), 5.20 (s, 2H), 6.88 (m, 3H), 7.13 (d. J )
8.0 Hz, 1H); 13C NMR (CDCl3) δ 55.77, 56.12, 95.45, 111.77,
116.51, 120.86, 122.52, and 149.74; MS (APCI) m/e 168.
N-Meth oxym eth yl-2-m er ca p top yr id in e (17). To a solu-
tion of 5 (0.534 g, 3.44 mmol) in THF (8 mL) under N2 was
added a solution of AgOTf (0.982 g, 3.82 mmol) in THF (7 mL).
After 15 min, the usual work up was applied: 1H NMR (CDCl3)
δ 3.45 (s, 3H), 5.75 (s, 2H), 7.71 (dd, J ) 8.9, 1.0 Hz, 1H), 6.75
(td, J ) 6.8, 1.4 Hz, 1H), 7.22 (ddd, J ) 8.5, 5.3, 1.7 Hz, 1H),
7.86 (dd, J ) 6.8, 1.4 Hz, 1H); 13C NMR (CDCl3) δ 58.23, 84.66,
114.11, 134.93, 136.27, 137.10, and 179.01; MS (APCI) m/e 155.
Ack n ow led gm en t. We gratefully acknowledge Dr.
Guo J ie Ho for insightful discussions and Mr. Bob
Reamer for his assistance with NMR interpretations.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra are available for compounds 2a -c, 2f,g, 2i,j, 5, 16,
and 17. This material is available free of charge via the
Internet at http://pubs.acs.org.
J O9822582