Development of p-phenylbenzyl as a new protecting group: Protection and deprotection of alcohols

Article abstract of DOI:10.1016/S0040-4039(01)01058-9

p-Phenylbenzyl is developed as a new 'PMB' like protecting group. p-Phenylbenzyl (PPB) ethers were prepared from alcohols with PPBBr-NaH or p-phenylbenzyl trichloroacetimidate-TfOH and subjected to oxidative deprotection using DDQ or DDQ (10 mol%)-3 equiv. Mn(OAc)₃.

Full text of DOI:10.1016/S0040-4039(01)01058-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 5571–5573
Development of p-phenylbenzyl as a new protecting group:
protection and deprotection of alcohols†
G. V. M. Sharma* and Rakesh
D-211, Discovery Laboratory, Organic Chemistry Division III, Indian Institute of Chemical Technology,
Hyderabad 500 007, India
Received 27 April 2001; accepted 14 June 2001
Abstract—p-Phenylbenzyl is developed as a new ‘PMB’ like protecting group. p-Phenylbenzyl (PPB) ethers were prepared from
alcohols with PPBBr–NaH or p-phenylbenzyl trichloroacetimidate–TfOH and subjected to oxidative deprotection using DDQ or
DDQ (10 mol%)–3 equiv. Mn(OAc)3. © 2001 Elsevier Science Ltd. All rights reserved.
A wide range of blocking groups1,2 are currently avail-
able for different functional groups, but very few of
them find wide application. Identifying the correct pro-
tecting group is often decisive for the successful synthe-
sis of a complex natural product. For a protecting
group to find wide application in organic synthesis, it
must fulfil certain criteria, such as being introduced and
cleaved under mild conditions in high yield without
affecting acid or base sensitive functionalities that are
present in the molecule. Protecting groups such as
benzyl, trityl,3 diphenylmethyl,4 p-methoxybenzyl5 play
a prominent role in multistep synthesis, especially in
carbohydrate chemistry. In carbohydrate chemistry, a
regularly encountered problem is the discriminative lib-
eration of a specific protecting group in the presence of
several others of comparable reactivity. Even though
the p-methoxybenzyl6 (PMB) group is a very versatile
oxidation-labile7 benzyl group, which can be removed
oxidatively with DDQ, it is sensitive to acid-catalysed
hydrolysis. To circumvent such a problem, development
of a new ‘PMB like’ benzyl protecting group which can
be introduced easily and deblocked oxidatively, is war-
ranted. In continuation of our efforts3–5,8–10 in the area
of protection and deprotection in organic synthesis,
herein, for the first time, we report our results on the
development of p-phenylbenzyl (PPB) as a new group
for the protection of alcohols and its removal under
oxidative conditions (Eq. (1)).
The requisite p-phenylbenzyl bromide 1 was prepared
in two steps. Accordingly, commercially available alde-
hyde 2 (Scheme 1) on reduction with NaBH4/MeOH
furnished 3 (98%), which on reaction with PBr3 in
diethyl ether gave 1 in 75% yield.
Initially alcohol 4 was treated with 1 in the presence of
NaH in THF to afford the aryl ether 4a (63%) success-
fully (Table 1). Similarly alcohols 5–8 gave the corre-
sponding ethers 5a–8a in good yields. The alcoholic
function in sugar derivative 9 underwent protection to
Br
, NaH, THF or
Ph
NH
(1)
, TfOH, CH2Cl2
CCl3
O
OR
Ph
------- equation 1
ROH
Ph
DDQ, CH2Cl2:H2O or
DDQ, Mn(OAc)3, CH2Cl2
Keywords: p-phenylbenzyl bromide; p-phenylbenzyl (PPB) ethers; p-phenylbenzyl trichloroacetimidate.
* Corresponding author. E-mail: esmvee@iict.ap.nic.in
†
IICT Communication No. 4787.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01058-9

5572
G. V. M. Sharma, Rakesh / Tetrahedron Letters 42 (2001) 5571–5573
CHO
Br
OH
OR
c
a
b
Ph
Ph
Ph
Ph
4a R = n-C8H17
1
2
3
Scheme 1. Reagents and conditions: (a) NaBH4, MeOH, rt, 1 h; (b) PBr3, dry (C2H5)2O, 0°C to rt, 1 h; (c) ROH, NaH, THF, 0°C
to rt, 24 h.
give 9a in 68% yield. Likewise, the secondary alcoholic
functions in ‘diacetone glucose’ 10 and menthol 11 gave
the ethers 10a (64%) and 11a (74%), respectively. All
the ethers thus prepared showed characteristic signals
for the PPB group at the expected chemical shifts.
Having developed ‘PPB’ as an efficient benzylic protect-
ing group for alcohols in both acidic and basic condi-
tions, removal of the PPB group was investigated to
obtain the alcohols. It was envisaged, under oxidative
conditions, that the p-phenyl group in PPB would
facilitate the formation of a benzylic carbocation.
Accordingly, when 4a was subjected to reaction with
DDQ in CH2Cl2–H2O (19:1) at room temperature for 3
h, alcohol 4 was obtained in 72% yield (Table 2).
Since base sensitive groups are unstable under the
above reaction conditions for the protection of alco-
hols, the trichloroacetimidate 3a was envisaged as the
best alternative. Accordingly, 3 (Scheme 2) was treated
with NaH and CCl3CN11 to give 3a, which on further
reaction with 12 in the presence of a catalytic quantity
of triflic acid afforded 12a in 58% yield.
Similarly, the other PPB ethers 5a–12a were subjected
to deprotection under the above reaction conditions to
afford the respective alcohols (66–86%) in 1–5 h. In the
Table 1. Preparation of p-phenylbenzyl ethers
Starting Material
(CH2)5
Product
Time (h)
24
Yield (%)
63
S.No.
1.
(CH2)5
OH
OPPB
OPPB
4
4a
THPO
THPO
2.
71
65
24
24
OH
OH
5
5a
6a
OPPB
3.
6
BnO
BnO
OH
12
15
4.
5.
75
65
OPPB
7
7a
8a
Ph
Ph
Ph
Ph
O
O
OH
OPPB
8
OPPB
OH
O
O
O
O
68
24
O
O
6.
O
O
O
O
9
9a
O
O
O
O
O
O
7.
8.
O
O
15
26
64
O
PPBO
O
HO
10a
10
74
OPPB
OH
11a
11
AcO
AcO
9.
OH
12
58
OPPB
12
12a

G. V. M. Sharma, Rakesh / Tetrahedron Letters 42 (2001) 5571–5573
5573
NH
CCl3
OR
OH
O
a
b
Ph
Ph
Ph
12a
3
3a
Scheme 2. Reagents and conditions: (a) CCl3CN, NaH, dry (C2H5)2O, rt, 1 h; (b) ROH, TfOH, CH2Cl2, rt, 4 h.
Table 2. Oxidative removal of the p-phenylbenzyl protec-
worthy of note. Thus, the PPB group due to its stability
towards acids and oxidative deblocking could find wide
use, particularly in carbohydrate chemistry.
tion
S. No.
1
Starting
material
Product
Time (h)
Yield (%)
Spectral data for selected compounds: 1H NMR (200
MHz, CDCl3, TMS): 4a: l 0.9 (t, 3H, J=6.8 Hz, CH3),
1.30 (br. s, 10H), 1.60 (t, 2H, J=6.8 Hz), 3.45 (t, 2H,
J=6.8 Hz, OCH2), 4.50 (s, 2H, OCH2Ar), 7.20–7.42
(m, 5H, ArH), 7.44–7.60 (m, 4H, ArH); EIMS: m/z 296
(M+, 17.0%), 236 (5.2%), 167 (100%), 77 (20.3%), 42
(55.4%); 5a: l 1.40–1.95 (m, 10H), 3.30–3.58 (m, 4H),
3.65–3.90 (m, 2H), 4.45–4.60 (m, 3H), 7.22–7.45 (m,
5H, ArH), 7.48–7.60 (m, 4H, ArH); EIMS: m/z 255
(M+−THP, 13.7%), 167 (61.7%), 85 (59.2%), 42 (100%);
11a: l 0.75 (d, 2H, J=5.0 Hz), 0.82–1.05 (m, 10H),
1.22–1.45 (m, 2H), 1.60–1.75 (m, 2H), 2.18–2.42 (m,
2H), 3.10–3.25 (m, 1H), 4.55 (dd, 2H, OCH2Ar), 7.30–
7.48 (m, 5H, ArH), 7.50–7.60 (m, 4H, ArH); [h]D=
−77.72 (c 1.15, CHCl3); EIMS: m/z 322 (M+, 7.5%), 167
(100%), 123 (13.2%), 81 (29.3%), 42 (99.5%).
4a
4
4a
5
3.0
17.0
2.5
5.0
1.0
12.0
2.0
4.5
5.0
2.0
72
69
74
74
70
63
68
82
66
86
66
2
3
4
5a
6a
7a
6
7
7a
8
5
6
7
8
9
8a
9a
10a
11a
12a
9
10
11
12
2.5
a DDQ (10 mol%)–3 equiv. Mn(OAc)3 was used.
case of 7a and 8a, the PPB group was selectively
removed in the presence of both benzyl as well as
diphenylmethyl groups, thus making it a very useful
benzylic protecting group. All the alcohols were charac-
References
1
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Very recently, our group has reported the regeneration
12
of DDQ using Mn(OAc)3 as a reoxidant. Since DDQ
is expensive to use in a stoichiometric quantity and the
by-product quinol can create problems; in the present
study, the ether 4a was treated with DDQ (10 mol%)
and 3 equiv. Mn(OAc)3 to give the alcohol 4 (69%),
albeit in a longer duration of time (17 h). A similar
result was observed for the ether 7a.
To evaluate the stability of the PPB group to acid
hydrolysis, ether 4a was subjected to reaction with 60%
aq. AcOH at 60°C and with CF3COOH in CH2Cl2 at
room temperature, independently, for several hours.
However, no trace of hydrolysis was observed by TLC
analysis and the starting ether was recovered
unchanged.
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Ilangovan, A.; Radhakrishna, P. Synlett 1999, 1200–
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10326.
Thus, the present study discloses the development of
the p-phenylbenzyl (PPB) group as an efficient protect-
ing group, that can be introduced under both basic and
acidic reaction conditions. Similarly, a facile removal
using DDQ or cat. DDQ–Mn(OAc)3, even in the pres-
ence of other benzylic groups, makes it a potentially
very useful protecting group. Finally, unlike the PMB
group, the stability of the PPB group towards acids is
.