Bismuth trichloride–mediated cleavage of phenolic methoxymethyl ethers

Article abstract of DOI:10.1080/00397911.2016.1158270

A simple and efficient method for removal of phenolic methoxymethyl ethers in the presence of 30?mol% of bismuth trichloride in acetonitrile/water is described. Notable features of the cleavage protocol entail use of an ecofriendly bismuth reagent, ease of handling, low cost, operational simplicity, and good functional group compatibility. A number of structurally varied phenolic methoxymethyl ethers were cleaved in good to excellent yields.

Full text of DOI:10.1080/00397911.2016.1158270

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Bismuth Trichloride Mediated Cleavage of Phenolic
Methoxymethyl Ethers
Oghale Obaro-Best, Jack Reed, Alya A.F.D. Norfadilah, Ryan Monahan &
Rajesh Sunasee
To cite this article: Oghale Obaro-Best, Jack Reed, Alya A.F.D. Norfadilah, Ryan Monahan &
Rajesh Sunasee (2016): Bismuth Trichloride Mediated Cleavage of Phenolic Methoxymethyl
Ethers, Synthetic Communications, DOI: 10.1080/00397911.2016.1158270
To link to this article: http://dx.doi.org/10.1080/00397911.2016.1158270
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Date: 16 March 2016, At: 12:17

Bismuth Trichloride Mediated Cleavage of Phenolic Methoxymethyl Ethers
Oghale Obaro-Best, Jack Reed, Alya A.F.D. Norfadilah, Ryan Monahan, Rajesh Sunasee
1Department of Chemistry, State University of New York at Plattsburgh, Plattsburgh,
New York, USA
Corresponding author, ,. E-mail: rajesh.sunasee@plattsburgh.edu
Abstract
A simple and efficient method for removal of phenolic methoxymethyl ethers in the
presence of 30 mol% of bismuth trichloride in acetonitrile/water is described. Notable
features of the cleavage protocol entail use of an eco-friendly bismuth reagent, ease of
handling, low cost, operationally simple and good functional group compatibility. A
number of structurally varied phenolic methoxymethyl ethers were cleaved in good to
excellent yields.
KEYWORDS: Bismuth trichloride, eco-friendly, cleavage, phenolic MOM ethers
1. INTRODUCTION
Protection and deprotection of functional groups in multi-step organic syntheses remain
crucial for the success of complex natural product syntheses, although the concept of
free-protecting group syntheses has recently emerged.[1] The methoxymethyl (MOM)
ether group is a well-known acid-labile protecting group for alcohols and phenols due to
1

its ease of installation and high stability in strongly basic condition as well as under
cleavage conditions of other commonly used protecting groups. [2] A number of methods
are available for demethoxymethylation of alcohols and phenols including the use of
Brønsted acids,[3] Lewis acids, [4] or solid catalysts [5] among others. [6] While each of
these cleavage conditions has its own attributes, synthetic application of these methods
has been hampered due to the high reactivity, use of expensive stoichiometric reagents
and tedious work-up procedures. As such, there is still scope to develop mild cleavage
protocol of MOM groups, in particular, using inexpensive and eco-friendly reagents for
use in syntheses of multifunctional compounds.
During the course of the synthesis of an acetylenic hydroquinonic antimicrobial agent,
culpin, an unexpected loss of phenolic bis-MOM ethers was observed in the presence of
stoichiometric amount of bismuth trichloride (Scheme 1). [7] Inspired by this observation,
we decided to optimize the conditions for phenolic MOM deprotection using BiCl3 as an
inexpensive, easily handled, and eco-friendly reagent. Although a number of methods are
available for alkyl MOM deprotection, there are very few reports in literature that
surveyed in detail the cleavage of substituted phenolic MOM ethers. [4l, 5c] Furthermore,
Bi(III) compounds with remarkable non-toxic and environmentally benign properties
have been well utilized for a wide variety of synthetic transformations [8] and in medicinal
chemistry. [9] The recent expanding activity of bismuth compounds as green Lewis acid
catalysts in organic synthesis is an emerging field. Of the known bismuth salts, bismuth
trifluoromethanesulphonate has gained significant attention for many organic
transformations. It is worth mentioning here that bismuth trifluoromethanesulphonate has
2

been communicated for removal of MOM groups in THF/water (1:1, v/v) [4j] but with a
limited phenolic substrate scope. It is also a masked source of one of the strongest acids,
triflic acid in aqueous medium. Surprisingly, it was also reported that bismuth
trifluoromethanesulphonate and microencapsulated bismuth trifluoromethanesulphonate
could catalyze methoxymethylation reaction of alcohols, and carboxylic acids with
dimethoxymethane. [10] In this work, we explore the use of BiCl3 as a mild, inexpensive
[11] and eco-friendly reagent for cleavage of a variety of substituted phenolic MOM
ethers.
2. RESULTS AND DISCUSSION
Our investigation began with the simple phenolic MOM substrate 1a (1 mmol) as test
case compound, which was treated with BiCl3 (10 mol%) in acetonitrile/water (5:0.1 v/v)
and stirred at room temperature (Table 1, entry 1). The reaction progress was monitored
by TLC, which indicated presence of unreacted starting material after overnight stirring
with the desired phenolic product 1b isolated in 50% yield. In an attempt to decrease the
reaction time and increase the yield, a series of experiments were conducted by varying
the amount of BiCl3 and temperature. The results of the optimization studies are
summarized in Table 1. An increase in the amount of BiCl3 (10-30 mol%) used while
stirring the reaction at room temperature resulted into a decrease in reaction time with an
enhancement in the isolated yield of the desired product 1b (Table 1, entries 1-3).
Excellent yield of the deprotected phenol was obtained when the temperature was
elevated to 50 oC using 30 mol% BiCl3 (Table 1, entry 4). No significant change in yield
was observed when the amount of BiCl3 was increased above 30 mol%.
3

The effect of different solvents such as DCM, MeOH, THF and acetone on the bismuth
trichloride-mediated deprotection of 1a was also evaluated. While the deprotection
proceeded well in THF/H2O and MeOH/H2O, acetonitrile was found to be the best
solvent based on reaction time and yield. The binary solvent system (MeCN/H2O, 5:0.1
v/v) was required for a rapid deprotection of the MOM ethers. The use of neat organic
solvent afforded lower yield of the deprotected product. At this stage we suspected that
HCl generated from BiCl3 in presence of water might be responsible for the hydrolysis of
MOM ethers. Thus, as a control experiment, we attempted to mimic the hydrolysis of
MOM ether (1a) in the presence of HCl (same amount that would be generated by 30
mol% BiCl3) but deprotection proceeded in lower yield. Further experiments are required
to understand the mechanistic aspects and the exact role of water in the BiCl3-mediated
deprotection of phenolic MOM ethers. The optimized reaction conditions were applied to
the cleavage of various substituted MOM protected phenolic ethers as depicted in Table
2.
A wide range of structurally varied phenolic MOM ethers possessing both electron-
donating or withdrawing groups on the aromatic ring, underwent easy cleavage to afford
the corresponding phenols in good to excellent yields (Table 2, entries 1-16). All the
phenolic products obtained were characterized by FT-IR, 1HNMR, 13CNMR and
compared with authentic samples. Alkyl and alkenyl substituted phenolic MOM ethers
(Table 2, entries 3-5) responded well under the cleavage conditions. The present BiCl3
mediated cleavage protocol displays good chemoselectivity, with deprotection of the
4

phenolic MOM ethers in good to excellent yields in the presence of several other
functional groups on the aromatic ring. For instance, benzylic (Table 2, entry 8) and alkyl
ethers (Table 2, entries 5-7, 12), nitrile (Table 2, entry 9), aldehyde (Table 2, entries 11,
12), and ester (Table 2, entries 13, 14) were unaffected. Bis-phenolic MOM ethers (14a)
were smoothly cleaved under the optimized conditions in good yield (Table 2, entry 14).
Monodeprotection was first observed in 3h of reaction as monitored by TLC with
complete cleavage after 6 h to afford 14b in 82 % yield. The naphthalene MOM ether
(16a) took longer reaction time (8h) for deprotection, but gratifyingly, when 16a was
treated with 1 equiv. of BiCl3, deprotection was achieved in 3h in 80 % yield of 16b.
In the past few decades, BINOL derivatives have emerged as efficient chiral ligands and
auxiliaries for asymmetric synthesis.[12] Our BiCl3-mediated cleavage conditions
converted the bis-MOM ether of (R)-BINOL (17a) to the corresponding (R)-BINOL
(17b) in very good yield (Scheme 2) whereby the free phenolic groups can further be
exploited for derivatization of the phenyl rings.
3. CONCLUSION
In conclusion, we have described a convenient and operationally simple cleavage
protocol of several substituted phenolic methoxymethyl ethers using a less expensive
eco-friendly reagent, BiCl3. The MOM deprotection proceeded in good to excellent
yields and the method is amenable to groups such as benzyl, nitrile, ester, aldehyde and
chiral BINOL molecule. The method should have widespread applications in the
5

syntheses of complex and multi-functional organic molecules possessing phenolic MOM-
protected fragments.
4. EXPERIMENTAL
4.1 General Information
Commercial grade reagents and solvents were used as received without further
purification. 1HNMR and 13CNMR spectra were recorded in deuterated chloroform
(CDCl3) on an Agilent/Varian VNMRS 400 MHz instrument. Chemical shifts (δ) are
referenced to the residual proton in the NMR solvent (CDCl3, 7.26 ppm). Data are
reported as follows: chemical shift, multiplicity, coupling constants (J) reported in Hertz
(Hz) and integration and the following abbreviations are used: s = singlet, d = doublet, t =
triplet, q = quartet, dd = doublet of doublets, br = broad, m = multiplet. IR spectra were
recorded on a Thermo/Nicolet 6700 FT-IR Spectrometer and only the more significant
peaks are reported. Reactions were monitored by thin layer chromatography (TLC) on
glass-backed plates coated with a 0.2 mm thickness of silica gel 60 F254; chromatograms
were visualized by UV radiation (254 nm) or by staining with KMnO4. Flash column
chromatography was performed on 300–400 mesh silica gel using mixtures of ethyl
acetate and hexane as the eluent system.
4.2 General Experimental Procedure For MOM Protection
MOMCl (1.5 mmol) was added to a stirred solution of the phenolic substrate (1 mmol) in
CH2Cl2 (15 mL) at 0 oC. DIPEA (2 mmol) was slowly added to the reaction mixture. The
ice-bath was removed and the mixture was stirred at room temperature for 1-12 h
6

(depending on the type of phenol used). Distilled water (15 mL) was added in the
reaction mixture and the organic phase was separated, washed with 0.5 M of HCl,
distilled water, 1M of NaOH, and brine. The organic phase was dried using anhydrous
sodium sulphate, filtered and concentrated. Flash column chromatography of the residue
over silica gel (hexane: EtOAc mixture) gave the desired MOM protected phenol. (Note:
In some cases, the crude MOM protected phenols were pure (as indicated by 1HNMR and
TLC) and were used directly for the next step without further purification).
4.3 General Experimental Procedure For Bicl3 Mediated MOM Deprotection
BiCl3 (30 mol%) was added to a stirred solution of MOM protected phenol (1 mmol) in
MeCN/H2O (5 mL/0.1 mL; 5:0.1 v/v) and the mixture was stirred at 50 oC until reaction
was complete (TLC control). The mixture was filtered over a pad of celite using CH2Cl2
(10 mL), the resulting filtrate was dried over anhydrous sodium sulphate, filtered and
concentrated under reduced pressure. Flash column chromatography of the residue over
silica gel (hexane:EtOAc mixture) afforded the desired pure phenol (76-95%). All
phenolic products were analyzed by IR and NMR spectroscopy and by comparison with
authentic samples.
4.4 Spectral Data For Selected Compounds
4.4.1 Following the general procedure for MOM protection, 4-allyl-2-methoxy-1-
(methoxymethoxy)benzene (5a) was as obtained as an oil in 75 % yield. FTIR (CDCl3)
2980, 1513, 1452, 1432, 1266 cm-1; 1H NMR (400 MHz, CDCl3) δ 3.32 (d, J=6.7 Hz,
2H), 3.49 (s, 3H), 3.85 (s, 3H), 5.04-5.09 (m, 2H), 5.18 (s, 2H), 5.88-5.99 (m, 1H), 6.68-
7

6.72 (m, 2H), 7.05 (d, J=7.9 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 40.1, 56.1, 56.4,
96.2, 112.9, 116.3, 117.3, 121.3, 135.2, 138.3, 145.6, 150.5 ppm; spectra data was
consistent with previous literature report. [13]
4.4.2 Following the general procedure for BiCl3 mediated MOM deprotection, eugenol
(5b) was obtained as an oil in 89 % yield. FTIR (CDCl3) 3515, 2976, 1613, 1511, 1464,
1432, 1264 cm-1; 1H NMR (400 MHz, CDCl3) δ 3.30 (d, J=6.8 Hz, 2H), 3.86 (s, 3H),
5.03-5.08 (m, 2H), 5.46 (s, 1H), 5.91-6.00 (m, 1H), 6.68-6.70 (m, 2H), 6.82 (d, J=8.4 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 40.1, 56.2, 111.7, 114.9, 116.1, 121.8, 132.6, 138.6,
144.7, 147.3 ppm; spectra data was consistent by comparison with authentic sample.
4.4.3 Following the general procedure for MOM protection, methyl 2-
(methoxymethoxy)benzoate (13a) was obtained in 77 % yield. FTIR (CDCl3) 2954, 1713,
1489, 1238 cm-1; 1H NMR (400 MHz, CDCl3) δ 3.49 (s, 3H), 3.88 (s, 3H), 5.23 (s, 2H),
5.24 (s, 2H), 7.00-7.05 (m, 1H), 7.18 (d, J=8.4 Hz, 1H), 7.40-7.45 (m, 1H), 7.76 (dd, J =
2.0, 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 51.9, 56.3, 95.1, 116.4, 121.4, 121.6,
131.3, 133.2, 156.6, 166.6; spectra data was consistent with previous literature report. [14]
4.4.4 Following the general procedure for BiCl3 mediated MOM deprotection, methyl 2-
hydroxybenzoate (13b) was obtained as an oil in 88 % yield. FTIR (CDCl3) 3330, 2954,
1690, 1288 cm-1; 1H NMR (400 MHz, CDCl3) δ 3.92 (s, 3H), 5.21 (s, 1H), 6.84-6.88 (m,
1H), 6.96 (dd, J=1.2, 8.4 Hz, 1H), 7.41-7.45 (m, 1H), 7.81 (dd, J=2.0, 8.4 Hz, 1H); 13C
8

NMR (100 MHz, CDCl3) δ 52.2 112.3, 117.5, 119.1, 129.9, 135.6, 161.6, 170.5; spectra
data was consistent by comparison with authentic sample.
ACKNOWLEDGEMENTS
We thank the Department of Chemistry, SUNY Plattsburgh for financial support, J. Jones
for NMR measurements, S. Blair, B. Rosenthals, M. McNaught and N. Danyashah for
assistance for preparing phenolic MOM ethers 2a, 4a, 8a, 16a respectively.
SUPPLEMENTARY INFORMATION
Supplementary data (full experimental procedures and characterization data) associated
with this article can be found via the ‘‘Supplementary Content’’ section of this article’s
webpage.
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Table 1. Optimization conditions for BiCl3-mediated deprotection of phenolic MOM
ether
13

Table 2. Cleavage of phenolic MOM ethers (BiCl3 (30 mol%) in MeCN-H2O (5:0.1 v/v)
at 50oC)
14

15

Scheme 1. BiCl3-mediated loss of bis-MOM phenolic ethers during the synthesis of
culpin
16

Scheme 2. BiCl3-mediated cleavage of bis-MOM BINOL ether derivative
17