A very practical and selective method for PMB protection of alcohols

Article abstract of DOI:10.1016/j.tetlet.2012.06.084

A very simple, practical and efficient one-step heterogeneous protocol for the PMB protection of alcohols using Amberlyst-15 has been developed. The stability and hazard issues regarding PMBCl and PMBBr are totally avoided by directly using anisyl alcohol for the protection. Alcohols are protected in very good yields. The selective mono-PMB protection of diols as well as di-PMB protection of diols was achieved in good yields, along with the demonstration of recyclability of the catalyst.

Full text of DOI:10.1016/j.tetlet.2012.06.084

Tetrahedron Letters 53 (2012) 4683–4686
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Tetrahedron Letters
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A very practical and selective method for PMB protection of alcohols
⇑
Subhash P. Chavan , Kishor R. Harale
Division of Organic Chemistry, CSIR-NCL, National Chemical Laboratory, Pune 411008, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A very simple, practical and efficient one-step heterogeneous protocol for the PMB protection of alcohols
using Amberlyst-15 has been developed. The stability and hazard issues regarding PMBCl and PMBBr are
totally avoided by directly using anisyl alcohol for the protection. Alcohols are protected in very good
yields. The selective mono-PMB protection of diols as well as di-PMB protection of diols was achieved
in good yields, along with the demonstration of recyclability of the catalyst.
Received 16 March 2012
Revised 14 June 2012
Accepted 16 June 2012
Available online 21 June 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
4-Methoxybenzyl protection
Mono-PMB protection
Di-PMB protection
4-Methoxybenzyl alcohol
Amberlyst-15
Most of the complex natural product syntheses include a pro-
tection–deprotection strategy,1 in case of handling of more than
one functional groups. The main role of protecting groups is to
selectively mask one functional group in order to perform transfor-
mation on the other non-compatible groups.2 The ease of selective
protection as well as deprotection is of paramount importance and
is reflected in the synthetic feasibility as well as overall yield of the
molecule.3
acetamidates7c and p-methoxybenzyl azide7d depending upon the
degree of mildness required.7e Amongst the two available methods
for PMB protection using anisyl alcohols, both involve the use of
8
expensive Yb(OTf)3 catalyst and the other zeolite, which requires
extended time of action.9
To avoid drawbacks in the synthesis and handling of PMBCl or
PMBBr, it is highly desirable to look for an alternate protocol for
PMB protection. Current protocol described herein totally avoids
these issues by using stable, easy to handle p-anisyl alcohol
(PMBOH), directly for protection. We surmised that PMBOH would
be highly desirable as it is readily available, easy to synthesize, safe
to store and handle. It was our premise that under acidic condi-
tions PMBOH would easily form a good electrophile which could
be trapped by nucleophile. This communication details our efforts
in this regard.
We have developed a highly practical and very simple method
for PMB protection (Scheme 1). Alcohols can be protected directly
using anisyl alcohol in the presence of acidic resin viz. Amberlyst-
15. Just heating of alcohol and anisyl alcohol in a low boiling
solvent in the presence of heterogeneous acid catalyst provides
excellent yield of the corresponding protected alcohol. A notewor-
thy feature of this protocol is the high regioselectivity observed in
mono-PMB protection of diols. Our method is logically based on
the formation of benzylic cation by protonation of anisyl alcohol
(Scheme 2). The resultant benzylic cation is additionally stabilized
by p-OMe group by mesomeric donation. This cation can be
trapped by alcohol leading to PMB protection.
Hydroxy group is one of the most common functional groups.
Over the years, a number of protecting groups for hydroxy moiety
have been developed.4 The most important one of them is 4-
methoxybenzyl (PMB) group.5 The PMB group has an additional
advantage over the benzyl group due to its ease of deprotection
under mild conditions in the presence of other functional groups
like alkenes, benzyl ethers, carboxybenzyl (CBZ) groups, methoxy
methyl (MOM), methoxyethoxymethyl ether (MEM), tetrahydro-
pyranyl (THP) tert-butyldimethylsilyl (TBDMS) ethers etc.6
Since hydroxy compounds are the important starting materials,
easy and selective protection of the hydroxy functionality with
PMB is highly desirable. The most commonly employed methods
for PMB protection of alcohols involve usage of p-methoxybenzyl
chloride (PMBCl) or p-methoxybenzyl bromide (PMBBr) in the
presence of strong base like NaH. The main problem associated
with this method is handling and storage of PMBCl and PMBBr
which are very prone to decomposition. Additionally, this protocol
requires anhydrous conditions and use of hazardous bases like
NaH, n-BuLi etc. The other p-methoxybenzylation methods involve
use of methoxybenzyl iodides,7a trichloroacetamidates,7b trifuloro-
The different acid catalysts were screened for the PMB protec-
tion of cis-butene diol in a constant time period of 4 h in DCM at
room temperature. The PMB protection of cis-2-butene-1,4-diol
was carried out using Bronsted acids like HCl, H2SO4, HClO4 and
⇑
Corresponding author. Tel.: +91 020 25902289; fax: +91 020 25902629.
E-mail address: sp.chavan@ncl.res.in (S.P. Chavan).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.06.084

4684
S. P. Chavan, K. R. Harale / Tetrahedron Letters 53 (2012) 4683–4686
1.1 eq. Anisyl
alcohol
DCM as a solvent. One of the main advantages of this method is
simplicity of the work-up which involves just filtration of reaction
mixture to provide products with fairly good purity.
(a)
(b)
R
OH
R
OPMB
OPMB
Amberlyst-15
DCM
In this study, cis-2-butene-1,4-diol was reacted with p-anisyl
alcohol in the presence of Amberlyst-15 in toluene at room tem-
perature for 4.5 h when a mono-PMB protected product was ob-
tained in a 63% yield (Table 2). In order to study the role of
solvent on the outcome of this reaction we performed the protec-
tion of alcohols in solvents of varying polarity whose results are
summarized in Table 2. Reaction in dichloromethane (DCM) com-
pleted in 4 h with 85% yield, proved to be the good solvent for pro-
tection. Reaction in tetrahydrofuran (THF) took 5 h for the
completion with 78% yield. However use of the polar solvents like
acetonitrile (ACN), dimethyl formamide (DMF) and acetone took
longer times for the completion of reaction and were found to be
less effective.
A wide variety of alcohols were subjected to PMB protection
using anisyl alcohol (1.1 equiv), resin as a catalyst (10% w/w) and
DCM as a solvent under reflux conditions to furnish the corre-
sponding PMB protected alcohols in excellent yields (Table 3).10
The primary and secondary alcohols gave excellent yield of protec-
tion (entry 1–5) in a short period of time whereas tert-alcohol (en-
try 6) gave moderate yield. However, acetic acid (entry 7) did not
show any product formation under standard protection conditions.
The (Z)-4-hydroxybut-2-en-1-yl acetate, containing base sensitive
acetate group, gave excellent yield of the corresponding ether (en-
try 8). In case of mono-TBS protected cis-2-butene-1,4-diol as a
starting material, PMB protection was observed, with simulta-
neous deprotection of TBS group (entry 10).
1.1 eq. Anisyl
alcohol
HO
HO
OH
n
n
Amberlyst-15
DCM
n = 1,2,3,....10
2.2 eq. Anisyl
alcohol
(c)
HO
PMBO
OH
OPMB
n
n
Amberlyst-15
DCM
n = 1,2,3,....10
Scheme 1. (a) PMB protection of alcohols, (b) Selective mono-PMB protection of
diols and (c) Di-PMB protection of diols.
HO
+
CH2
H+
OMe
OMe
R
OMe
+
In order to establish the reusability and recyclability of the re-
sin, the used resin in reaction was recovered and reused. It was
found that the resin can be used up to 3 cycles without any appre-
ciable loss in activity (Table 4).
OH
R
OPMB
Having established the generality and efficiency of this catalytic
protocol for protection of alcohols, we turned our attention to
selective protection of diols. Gratifyingly, the selective mono-
PMB protection of diols was also achieved in good yields (Table
5). A variety of diols on treatment with 1.1 equiv anisyl alcohol
in the presence of resin (10% w/w) in DCM as a solvent under reflux
conditions provided excellent yields of mono-PMB protected
diols.13
The saturated diols (Table 5, entry 2–5) furnished mono pro-
tected PMB ether in good yields. The diol with tertiary hydroxyl
groups (entry 6) was also protected successfully in fairly good
yield. The di-protected compound was observed in minor amount
(18%) in case of but-2-yne-1,4-diol (entry 8).
Scheme 2. Proposed mechanism for PMB protection.
PTSA in DCM as the solvent which gave good to excellent yields of
PMB protected alcohol (Table 1).
Since the employed conditions were very harsh, other milder
conditions involving Lewis acid BF3ÁOEt2 and acidic resin Amber-
lyst-15 were explored. It was observed that the acidic resin Amber-
lyst-15 (entry 6) proved to be an excellent choice of all the acids
tried. However, further reduction of time period from 4 to 3 h for
completion of the reaction was observed under reflux conditions.
The optimized conditions for selective PMB protection of cis-2-bu-
tene-1,4-diol involved the use of 1.1 equiv of anisyl alcohol and
catalytic amounts of resin (10% w/w) under reflux conditions in
Having established conditions for selective protection of diols,
we undertook the bis-protection of diols. The di-PMB protection
Table 1
Optimization for mono-PMB protection of cis-2-butene-1,4-diol using different acid
catalysts
Table 2
PMB protection of cis-2-butene-1,4-diol in the presence of Amberlyst-15 under
acid catalyst,
(Table-1)
various conditions
Amberlyst-15
HO
OH
HO
OPMB
1.1 eq. anisyl
alcohol, DCM,
room temp.
HO
OPMB
HO
OH
1.1 eq. anisyl
alcohol,solvent,
room temp.
Entrya
Acid (catalytic)
Time (h)
Yieldb (%)
Entrya
Solvent
Time (h)
Yieldb (%)
1
2
3
4
5
6
Conc. HCl
Conc. H2SO4
HClO4
4
4
4
4
4
4
79
55c
51c
80
70
85
1
2
3
4
5
6
Toluene
DCM
4.5
4
5
6
14
8
63
85
78
67
52
56
PTSA
BF3ÁOEt2
THF
CH3CN
DMF
Amberlyst-15
Acetone
a
All reactions were carried out in DCM at room temperature using 10% w/v or w/
w acid catalyst.
a
All reactions were carried out using alcohol (1 equiv), anisyl alcohol (1.1 equiv)
b
Isolated yields. Unreacted alcohol was fully recovered.
Formation of 4-methoxy benzyl ether was observed.
and 10% w/w of Amberlyst-15 catalyst at room temperature.
c
b
Isolated yields. Unreacted alcohol was fully recovered.

S. P. Chavan, K. R. Harale / Tetrahedron Letters 53 (2012) 4683–4686
4685
Table 3
Table 6
PMB protection of alcohols
Di-PMB protection of diols
Entry
18a,11
Producta
Time (h)
2.5
Yieldd (%)
Entry
Producta
Time (h)
Yieldc (%)
OPMB
119
2b
8
75
70
Quantitative
H3C
PMBO
PMBO
OPMB
OPMB
28a
3
2
96
95
OPMB
OPMB
9.5
2.5
3
7
92
PMBO
OPMB
47e
1.5
3
96
90
OPMB
OPMB
a
Corresponding diol as a starting material (1 equiv), anisyl alcohol (2.2 equiv)
and acid catalyst (10% w/w) in DCM under reflux conditions.
58a
b
3 equiv of anisyl alcohol used.
Isolated yields.
c
OPMB
OPMB
614
3
73
The cis-2-butene-1,4-diol on treatment with anisyl alcohol
(2.2 equiv) in DCM using catalytic amount of resin (10% w/w)
provided 75% of di-PMB protected compound (entry 1). Similarly,
butane diol and but-2-yne-1,4-diol gave very good yields (entry
2 & 3) of corresponding di-protected compounds.
In conclusion, we have developed a very simple, mild, useful
and efficient method for PMB protection of alcohols under hetero-
geneous conditions in excellent yields. The ease of performing the
reactions under heterogeneous conditions makes the work-up
operationally extremely simple involving mere filtration to get
the corresponding ether.
We feel our method should find a widespread usage amongst
organic chemists. The unprecedented method for mono-PMB pro-
tection of diols in very high yields and simplicity has been devel-
oped. Di-PMB protection of diols has been carried out in good
yields.
7b
No reaction
O
AcO
OPMB
OPMB
8
5
92
88
68
912
10c
1.5
3.5
HO
OPMB
a
Corresponding alcohol as a starting material (1 equiv), anisyl alcohol (1.1 equiv)
and Amberlyst-15 10% w/w in DCM under reflux conditions.
b
Entry 7, the corresponding acid was subjected to protection.
Entry 10, starting material was the mono-TBS cis-2-butene-1,4-diol.
Isolated yields.
c
d
Table 4
Recycling of the catalyst
p-Anisyl alcohol
OH
OPMB
Amberlyst-15
(10% w/w)
Acknowledgments
K.R.H. thanks CSIR, New Delhi, India for financial support and
Dr. H. B. Borate & Dr. U. R. Kalkote for their help.
Use of resina
Time (h)
Yield (%)
1st run
2nd run
3rd run
2
2.5
3
96
92
87
Supplementary data
a
Reactions were carried out in refluxing DCM. Amberlyst-15 was recovered by
Supplementary data (experimental procedures and analytical
data and copies of NMR spectra for all new compounds) associated
with this article can be found, in the online version, at http://
dx.doi.org/10.1016/j.tetlet.2012.06.084.
filtration from first reaction and used for 2nd run, again recovered and used for 3rd
run.
Table 5
References and notes
Selective mono-PMB protection of diols
Entry
114
Producta
Time (h)
3
Yieldb (%)
85
1. (a) Wuts, P. G. M.; Greene, T. W. Protective Groups in Organic Synthesis, fourth
ed.; Wiley and Sons: New York, 2006; (b) Kocienski, P. J. Protecting Groups, third
ed.; Thieme: Stuttgart, 2005.
2. (a) Schelhaas, M.; Waldmann, H. Angew. Chem. Int. Ed. 1996, 35, 2056; (b)
Sartori, G.; Ballini, R.; Bigi, F.; Bosica, G.; Maggi, R.; Righi, P. Chem. Rev. 2003,
104, 199.
3. (a) Inoue, M.; Uehara, H.; Maruyama, M.; Hirama, M. Org. Lett. 2002, 4, 4551;
(b) Hoffmann, R. W. Synthesis 2006, 3531.
4. Wuts, P. G. M.; Greene, T. W. Protective Groups in Organic Synthesis, fourth ed.;
Wiley and Sons: New York, 2006. p. 16–299.
HO
OPMB
OPMB
215
316
415
515
3.5
4
78
75
83
79
HO
HO
OPMB
OPMB
4.5
4
HO
HO
HO
OPMB
OPMB
5. Wuts, P. G. M.; Greene, T. W. Protective Groups in Organic Synthesis, 4th ed.;
Wiley and Sons: New York, 2006. p. 120–135.
6
4
63
6. (a) Brewer, S. E.; Vickery, T. P.; Bachert, D. C.; Brands, K. M. J.; Emerson, K. M.;
Goodyear, A.; Kumke, K. J.; Lam, T.; Scott, J. P. Org. Process Res. Dev. 2005, 9,
1009; (b) Luzzio, F. A.; Chen, J. J. Org. Chem. 2008, 73, 5621. and references cited
therein.
7. (a) Mootoo, D. R.; Fraser-Reid, B. Tetrahedron 1990, 46, 185; (b) Nakajima, N.;
Horita, K.; Abe, R.; Yonemitsu, O. Tetrahedron Lett. 1988, 29, 4139; (c) Nakajima,
N.; Saito, M.; Ubukata, M. Tetrahedron Lett. 1998, 39, 5565; (d) Kamaike, K.;
Tsuchiya, H.; Imai, K.; Takaku, H. Tetrahedron 1986, 42, 4701; (e) Kotturi, S. R.;
Tan, J. S.; Lear, M. J. Tetrahedron Lett. 2009, 50, 5267.
HO
OPMB
717
818
2.5
3.5
70
65
10
HO
OPMB
a
Corresponding diol as a starting material (1 equiv), anisyl alcohol (1.1 equiv)
and Amberlyst-15 (10% w/w) in DCM under reflux conditions.
b
8. (a) Sharma, G. V. M.; Mahalingam, A. K. J. Org. Chem. 1999, 64, 8943; (b) Shah, S.
T. A.; Singh, S.; Guiry, P. J. J. Org. Chem. 2009, 74, 2179.
Isolated yields.
9. Sharma, G. V. M.; Punna, S.; Ratnamala, A.; Kumari, V. D.; Subrahmanyam, M.
Org. Prep. Proced. Int. 2004, 36, 581.
10. General procedure for PMB protection of alcohols: 1-(Ethoxymethyl)-4-
methoxybenzene (Table 3, entry 2): A mixture of ethanol (200 mg, 4.3 mmol),
p-anisyl alcohol (660 mg, 4.8 mmol) and catalytic amount (10% w/w, 20 mg) of
of diols was carried out in good yields (Table 6) wherein the same
method of protection as in mono-PMB protection was employed
except the use of 2.2 equiv of anisyl alcohol.20

4686
S. P. Chavan, K. R. Harale / Tetrahedron Letters 53 (2012) 4683–4686
Amberlyst-15 resin in anhydrous CH2Cl2 (10 mL) was refluxed. After 2 h, the
(50 MHz, CDCl3+CCl4) d = 159.2, 132.4, 129.8, 129.4, 128.0, 113.8, 72.0, 65.2,
58.4, 55.1. ESIMS (m/z): 231 (M+Na)+.
14. Zheng, T.; Narayan, R. S.; Schomaker, J. M.; Borhan, B. J. Am. Chem. Soc. 2005,
127, 6946.
15. Gaunt, M. J.; Yu, J.; Spencer, J. B. J. Org. Chem. 1998, 63, 4172.
16. Herna‘ndez, D. C.; Lindsay, K. B.; Nielsen, L.; Mittag, T.; Bjerglund, K.; Friis, S.;
Mose, R.; Skrydstrup, T. J. Org. Chem. 2010, 75, 3283.
17. Nuruzzaman, M.; Preston, T. C.; Mittler, S.; Jones, N. D. Synlett 2008, 207.
18. Banfi, L.; Guanti, G.; Basso, A. Eur. J. Org. Chem. 2000, 939.
crude reaction mixture was filtered through a Whatman filter paper and the
residue washed with CH2Cl2, dried (over anhydrous Na2SO4), concentrated in
vacuo and purified using flash chromatography (pet ether: ethyl acetate 95:5)
to provide 690 mg (96%) of pure product as
a
colorless liquid. 1H NMR
(200 MHz, CDCl3+CCl4) d = 7.27–7.23 (m, 2H), 6.88–6.83 (m, 2H), 4.43 (s, 2H),
3.80 (s, 3H), 3.50 (q, J = 6.9 Hz, 2H), 1.23 (t, J = 6.9 Hz, 3H). 13C NMR (50 MHz,
CDCl3+CCl4) d = 158.9, 130.4, 128.9, 113.5, 72.1, 65.1, 54.8, 15.0. ESIMS (m/z):
166 (M+H)+, 189 (M+Na)+.
11. Sun, L.; Guo, Y.; Peng, G.; Li, C. Synthesis 2008, 3487.
12. Shintou, T.; Mukaiyama, T. J. Am. Chem. Soc. 2004, 126, 7359.
13. General procedure for selective mono PMB protection of diols: (Z)-4-((4-
19. Yang, F.; Newsome, J. J.; Curran, D. P. J. Am. Chem. Soc. 2006, 128, 14200.
20. General procedure for di-PMB protection of diols: (Z)-1,4-Bis((4-
methoxybenzyl)oxy)but-2-ene (Table 6, entry 1): A mixture of cis-2-butene-
1,4-diol (500 mg, 5.7 mmol), p-anisyl alcohol (1.73 g, 12.5 mmol) and catalytic
amount (10% w/w, 50 mg) of Amberlyst-15 resin in anhydrous CH2Cl2 (20 mL)
was refluxed. After 8 h, the crude reaction mixture was filtered through a
Whatman filter paper and the residue washed with CH2Cl2, dried (over
anhydrous Na2SO4), concentrated in vacuo and purified using flash
chromatography (pet. ether: ethyl acetate 90:10) to provide 1.4 g (75%) of
pure product as a colorless dense liquid. 1H NMR (200 MHz, CDCl3 + CCl4)
d = 7.29–7.27 (m, 4H), 6.91–6.89 (m, 4H), 5.82–5.78 (m, 2H), 4.46 (s, 4H), 4.07–
4.05 (m, 4H), 3.85 (s, 6H). 13C NMR (50 MHz, CDCl3 + CCl4) d = 159.1, 130.1,
129.4, 129.2, 113.6, 71.7, 65.3, 54.6. ESIMS (m/z): 351 (M+Na).+
Methoxybenzyl)oxy)but-2-en-1-ol (Table 5, entry 1):
A mixture of cis-2-
butene-1,4-diol (200 mg, 2.3 mmol), p-anisyl alcohol (345 mg, 2.5 mmol),
and catalytic amount (10% w/w, 20 mg) of Amberlyst-15 resin in anhydrous
CH2Cl2 (10 mL) was refluxed. After 3 h, the crude reaction mixture was filtered
through a Whatman filter paper and the residue washed with CH2Cl2, dried
(over anhydrous Na2SO4), filtered and concentrated in vacuo and purified using
flash chromatography (pet ether/ethyl acetate 70:30) to provide 401 mg (85%)
of pure product as a colorless dense liquid. 1H NMR (200 MHz, CDCl3 + CCl4)
d = 7.31–7.27 (m, 2H), 6.89–6.84 (m, 2H), 5.66–5.85 (m, 1H), 4.45 (s, 2H), 4.16
(d, J = 6.1 Hz, 2H), 4.06 (d, J = 6 Hz, 2H), 3.80 (s, 3H), 1.80 (br s, 1H). 13C NMR