Cleavage of benzyl ethers by triphenylphosphine hydrobromide

Article abstract of DOI:10.1016/j.tetlet.2010.09.065

Triphenylphosphine hydrobromide was found to cleave the benzyl ethers derived from 1°, 2° alkyl, and aryl alcohols to the corresponding alcohols and benzyltriphenylphosphonium bromide in good yields. Alkene and allyl phosphonium salts were produced from the benzyl ethers with 3° alkyl and allyl groups, respectively. These results indicate that the formation of the product is determined by the relative stability of the carbocationic intermediate. The anhydrous, stoichiometric amount of PPh₃·HBr offers a new and effective method for the deprotection of benzyl ethers.

Full text of DOI:10.1016/j.tetlet.2010.09.065

Tetrahedron Letters 51 (2010) 6143–6145
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Tetrahedron Letters
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Cleavage of benzyl ethers by triphenylphosphine hydrobromide
⇑
Mani Ramanathan, Duen-Ren Hou
Department of Chemistry, National Central University, 300 Jhong-Da Rd. Jhong-Li, Taoyuan, Taiwan
a r t i c l e i n f o
a b s t r a c t
Article history:
Triphenylphosphine hydrobromide was found to cleave the benzyl ethers derived from 1°, 2° alkyl, and
aryl alcohols to the corresponding alcohols and benzyltriphenylphosphonium bromide in good yields.
Alkene and allyl phosphonium salts were produced from the benzyl ethers with 3° alkyl and allyl groups,
respectively. These results indicate that the formation of the product is determined by the relative stabil-
ity of the carbocationic intermediate. The anhydrous, stoichiometric amount of PPh3ꢀHBr offers a new and
effective method for the deprotection of benzyl ethers.
Received 9 August 2010
Revised 13 September 2010
Accepted 17 September 2010
Available online 22 September 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Protecting hydroxyl groups as benzyl ethers (Bn–OR) have been
widely applied in multi-step organic synthesis. Benzyl ether is ro-
bust, relatively low cost in preparation, and orthogonal to other
protective groups, making benzyl ether and its derivatives, such
as p-methoxybenzyl ether (PMB–OR), among the most used pro-
tective groups.1 Conventionally, the removal of the benzyl group
is achieved by hydrogenolysis2 (H2, Pd/C, or Raney Nickel), reduc-
tive or oxidative cleavage (Na/ammonia and 2,3-dichloro-5,6-dicy-
ano-1,4-benzoquinone, etc);3–5 however, these methods might be
incompatible with unsaturated substrates and reduction/oxidation
sensitive functional groups. Brønsted acid and Lewis acid based
cleavage provides alternative deprotection methods when such
concerns are involved. For example, trifluoromethanesulfonic acid,
trifluoroacetic acid, iodotrimethylsilane, and boron trichloride
have been developed along this direction.6,7 Recently, debenzyla-
tion with the combination of chlorosulfonyl isocyanate–sodium
hydroxide was reported.8 Although ethers are known to hydrolyze
in hydrobromic acid or anhydrous hydrogen bromide,9 only a few
examples using HBr to cleave benzyl ethers have been re-
ported,10,11 probably due to the strongly acidic or aqueous reaction
conditions being incompatible with other functional groups. Here-
in, we would like to report the deprotection of benzyl ethers using
triphenylphosphine hydrobromide (PPh3ꢀHBr). In contrast to the
volatile and flammable boron/silicon based Lewis acids, or incon-
venient HBr, the salt PPh3ꢀHBr is a stable, white powder (mp
196 °C),12 which makes it easy to apply with a correct quantity. In-
deed, PPh3ꢀHBr has been used as the source of anhydrous hydrogen
bromide,13 an alternative of sulfonic acids,14 and the precursor of
phosphorus ylides.15 We found that PPh3ꢀHBr could also be used
in the deprotection of benzyl ethers (Eq. 1) and would like to report
this finding herein.
PPh3·HBr
+ BnPPh3·Br
R
OH
(1.1 equiv.)
R
O Bn
ð1Þ
(1)
R = alkyl, aryl
CH3CN, Δ
The reactions of various benzyl alkyl or aryl ethers with
PPh3ꢀHBr were carried out in refluxing acetonitrile (Table 1).16
The insoluble by-product, benzyltriphenylphosphonium bromide,
could be removed by simple filtration and the deprotected alcohols
were harvested after the removal of the solvent. Later, we short-
ened the reaction time to 30 min by elevating the reaction temper-
ature to 100 °C under a microwave-assisted heating condition. This
protocol also removed p-methoxybenzyl (PMB) group (entry 2). In-
deed, we found that the PMB ether is more susceptible to PPh3ꢀHBr
than the benzyl ether and the selective deprotection was achieved
(entry 3). All the primary, secondary, and aryl alcohol-derived ben-
zyl ethers were deprotected successfully (entries 4–11). Internal
olefin and alkynyl groups remained intact under the reaction con-
dition (entries 4 and 6) but partial hydrobromination was observed
for the terminal olefin (entry 5). Although 1-admantanol (22) was
produced from the ether 21 (entry 12), the tertiary alcohol-derived
benzyl ether 23 gave the elimination product 24 (entry 13). Allyl
and cinnamyl ethers, 25 and 27 gave only the corresponding
phosphonium bromides 26 and 28, rather than the allyl and cin-
namyl alcohols (entries 14 and 15). These results are consistent
with the triphenylphosphine attaching to the ether substituents
(R–O–Bn) with the more carbocationic character (Scheme 1). The
formation of tertiary or allyl alcohols was not observed because
the corresponding carbocations have better or parallel stability
compared to the benzyl group.18,19
The anhydrous condition and stoichiometric amount of HBr
offer some advantages that hydrobromic acid and gaseous HBr can-
not provide. For example, debenzylations were achieved in the
presence of the ester, amide, and 1,3-dioxolane functional groups
(entries 16, 18–19). The oxidation/reduction sensitive functional
groups, such as alkene, alkyne, and nitro are compatible with
⇑
Corresponding author. Tel.: +886 3 4279442; fax: +886 3 4227664.
E-mail address: drhou@ncu.edu.tw (D.-R. Hou).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.09.065

6144
M. Ramanathan, D.-R. Hou / Tetrahedron Letters 51 (2010) 6143–6145
Table 1
Cleavage of benzylethers with PPh3ꢀHBr
Entry
1
Reactant
Product
Conditiona
Yieldb (%)
A
B
77
54
MeO
(CH2)2OBn
MeO
MeO
(CH2)2OH
1a
2
A
B
88
76
MeO
(CH2)2OPMB
(CH2)2OH
2
1b
2
PMBO
OBn
HO
OBn
3
4
A
A
63
88
4
3
H3CH2C
(CH2)3OBn
H3CH2C
(CH2)3OH
6
5
A
B
45(26)c
63(8)c
(CH2)8OBn
(CH2)8OH
7
5
6
8
n-C6H13
CH2OBn
n
-C6H13
CH2OH
10
A
A
62
87
9
OBn
11
OH
12
7
8
9
OBn
(CH2)2CHCH3
OH
(CH2)2CHCH3
A
A
93
88
14
13
OBn
15
OH
16
OBn
OH
10
11
12
A
A
A
94
66
83
18
17
OBn
OH
20
19
OBn
21
OH
22
OBn
C(CH3)2
(CH2)2C(CH3)2
24
13
A
89
23
CH2OBn
CH2PPh3Br
14d
15d
16
A
A
A
A
91
93
97
61
n
-C3H7
25
26
n-C3H7
OBn
PPh3Br
27
OBn
28
H3CO2C
O2N
H3CO2C
OH
29
30
OBn
O2N
OH
17
18
32
31
O
BzHN
OH
OBn
N
A
B
67
84
34
H
33
O
O
O
OBn
OH
19
A
57e
O
36
35
20d
A
B
72
66
BnHN
BnHN
OBn
37
OH
38
a
b
c
Condition A: microwave heating, 100 °C for 30 min in a sealed tube; condition B: reflux for 12 h.15
Isolated yield.
9-Bromodecanol.
d
e
2.1 equiv of PPh3ꢀHBr were used.
Basic, aqueous work-up was applied; Ref. 17.

M. Ramanathan, D.-R. Hou / Tetrahedron Letters 51 (2010) 6143–6145
6145
3. Reductive cleavage: (a) Alonso, E.; Ramón, D. J.; Yus, M. Tetrahedron 1997, 53,
14355; (b) Liu, H.-J.; Yip, J.; Shia, K. S. Tetrahedron Lett. 1997, 38, 2252;
(c) Schön, I. Chem. Rev. 1984, 84, 287.
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2524; (b) Baek, S.; Jo, H.; Kim, H.; Kim, S.; Kim, D. Org. Lett. 2005, 7, 75.
5. Other debenzylation: Hwu, J. R.; Wong, F.-F.; Huang, J.-J.; Tsay, S.-C. J. Org.
Chem. 1997, 62, 4097.
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1974, 107; (b) Fletcher, S.; Gunning, P. T. Tetrahedron Lett. 2008, 49,
4817.
R
O
Bn
PPh3·HBr
Br
+
PPh3
R
O
H
CH2
R
O
H
CH2
R O CH2
H
7. (a) Petchmanee, T.; Ploypradith, P.; Ruchirawat, S. J. Org. Chem. 2006, 71, 2892;
(b) Sharma, G. V. M.; Reddy, C. G.; Krishna, P. R. J. Org. Chem. 2003, 68, 4574;
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R = 3° alkyl,
allyl
R = 1º, 2º alkyl,
aryl
8. (a) Kim, J. D.; Han, G.; Zee, O. P.; Jung, Y. H. Tetrahedron Lett. 2003, 44, 733;
(b) Rizzi, E.; Dallavalle, S.; Merlini, L.; Beretta, G. L.; Pratesib, G.; Zunino, F.
Bioorg. Med. Chem. Lett. 2005, 15, 4313.
R
OH + BnPPh3·Br
RPPh3·Br
or elimination
Scheme 1. Proposed debenzylation mechanism by PPh3ꢀHBr.
9. (a) Bhatt, M. V.; Kulkarni, S. U. Synthesis 1983, 249; (b) Tiecco, M. Synthesis
1988, 749.
10. (a) Evans, D. A.; Scheerer, J. R. Angew. Chem., Int. Ed. 2005, 44, 6038; (b) Xiong,
Z.; Gao, D. A.; Cogan, D. A.; Goldberg, D. R.; Hao, M.-H.; Moss, N.; Pack, E.;
Pargellis, C.; Skow, D.; Trieselmann, T.; Werneburg, B.; White, A. Bioorg. Med.
Chem. Lett. 2008, 18, 1994; (c) Hajela, S. P.; Johnson, A. R.; Xu, J.; Sunderland, C.
J.; Cohen, S. M.; Caulder, D. L.; Raymond, K. N. Inorg. Chem. 2001, 40, 3208;
(d) Kim, M.; Mao, Q.; Davidson, B. L.; Wiemer, D. F. J. Med. Chem. 2003, 46,
1603; (e) Leighton, P.; Sanders, J. K. M. J. Chem. Soc., Perkin Trans. I 1987, 2385;
(f) Messeri, T.; Pentassuglia, G.; Di Fabio, R. Tetrahedron Lett. 2001, 42, 3227.
11. Cohen, N.; Weber, G.; Banner, B. L.; Lopresti, R. J.; Schaer, B.; Focella, A.;
Zenchoff, G. B.; Chiu, A.-M.; Todaro, L.; O’Donnel1, M.; Welton, A. F.; Brown, D.;
Garippa, R.; Crowley, H.; Morgan, D. W. J. Med. Chem. 1989, 32, 1842.
12. Meier, M. S.. In Encyclopedia of Reagents for Organic Synthesis; Paquette, L. A.,
Ed.; John Wiley & Sons: New York, 1995; Vol. 8, p 5392.
PPh3ꢀHBr (entries 4, 6, and 17, respectively). Benzyl amine is unaf-
fected during the removal of the benzyl ether (entry 20).
In summary, it was found that triphenylphosphine hydrobro-
mide is a new and effective reagent for the deprotection of benzyl
ethers. The studies of the reaction scope indicate that the forma-
tion of product is determined by the relative stability of the
carbocationic intermediate.
Acknowledgments
13. Hercouet, A.; Le Corre, M. Synthesis 1988, 157.
14. Bolitt, V.; Mioskowski, C.; Shin, D. S.; Falck, J. R. Tetrahedron Lett. 1988, 29,
4583.
15. McCullough, K. J. Tetrahedron Lett. 1982, 23, 2223.
This research was supported by the National Science Council
(NSC 98-2113-M-008-001-MY3), Taiwan, ROC. The authors are
grateful to Ms. Ping-Yu Lin at the Institute of Chemistry, Academia
Sinica and Valuable Instrument Center in National Central Univer-
sity for obtaining mass analysis.
16. Standard procedure for debenzylation, condition A: A solution of a benzyl
ether (0.5 mmol), triphenylphosphine hydrobromide (0.55 mmol) in dry
acetonitrile (0.5 mL) was placed in a vial (10 mL, for microwave reaction).
The vial was capped and heated to 100 °C for 30 min in a microwave oven
(CEM Discover). After cooling to room temperature, the suspension was diluted
with EtOAc (10 mL), and filtered to remove the benzyltriphenylphosphonium
bromide salt. The organic layer was concentrated under reduced pressure to
give the desired product. The crude product could be further purified by flash
column chromatography.
Supplementary data
Supplementary data (experimental procedures including the
syntheses, 1H NMR and 13C NMR spectra for all the new com-
pounds) associated with this article can be found, in the online ver-
sion, at doi:10.1016/j.tetlet.2010.09.065.
Condition B: A solution of an alkyl benzyl ether or aryl benzyl ether (0.5 mmol)
in dry acetonitrile (1 mL) was added with triphenylphosphine hydrobromide
(0.55 mmol). The reaction mixture was heated to reflux for 12 h. The work-up
procedure was the same as the microwave-assisted condition.
17. The work-up procedure for compound 36: After cooling to rt, the reaction
mixture, starting from 0.45 mmol of 35 was added with ammonium hydroxide
(30%, 1 mL), and extracted with diethyl ether (10 mL ꢁ 2). The organic layers
were combined, dried over Na2SO4, filtered, and concentrated. The crude
product was further purified by flash column chromatography (20%, EA/
hexanes) to give 36 (34 mg, 0.26 mmol, 57%).
References and notes
1. (a) Wuts, P. G. M.; Greene, T. W. In Protective Groups in Organic Synthesis, 4th
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Trans. 1 2001, 2109, and references cited therein.
18. Smith, M. B.; March, J. In March’s Advanced Organic Chemistry; Wiley-
Interscience: New York, 2007; p 244.
19. This deprotection is another example of ‘push–pull’ mechanism: (a) Fuji, K.;
Ichikawa, K.; Node, M.; Fujita, E. J. Org. Chem. 1979, 44, 1661; (b) Kiso, Y.;
Ukawa, K.; Nakamura, S.; Ito, K.; Akita, T. Chem. Pharm. Bull. Jpn. 1980, 28, 673;
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W. F.; Merrifield, R. B. J. Am. Chem. Soc. 1986, 108, 5242. A reviewer’s comment
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