M -Terphenyl Ethers, a new hydroxy protecting group cleavable under reductive single electron transfer reaction conditions

Article abstract of DOI:10.1055/s-0030-1259997

m-Terphenyl ethers and, to a lesser extent, 2,6-dimethoxyphenyl ethers, were tested as protected hydroxy derivatives under a variety of reaction conditions. These ethers underwent regioselective cleavage of the aromatic C(1)-O bond under reductive SET reaction conditions using alkali metals in tetrahydrofuran at room temperature. This deprotective procedure was efficiently realized in the presence of several other functional groups, including an acetal, a phenyl alkyl ether, an unprotected alcohol, and carbon-carbon double and triple bonds. Furthermore, m-terphenyl ethers proved stable under different reaction conditions, including acidic hydrolysis and formation and/or employment of different organometallic reagents. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0030-1259997

PAPER
1575
m-Terphenyl Ethers, a New Hydroxy Protecting Group Cleavable under
Reductive Single Electron Transfer Reaction Conditions
m
-Terphenyl Ether
g
s,
a
Ne
w
H
y
o
droxy Protecting G
A
roup zzena,* Sarah Mocci, Luisa Pisano*
Department of Chemistry, University of Sassari, via Vienna 2, 07100 Sassari, Italy
Fax +39(79)229559; E-mail: ugo@uniss.it; luisa@uniss.it
Received 26 January 2011; revised 7 March 2011
G
G
Abstract: m-Terphenyl ethers and, to a lesser extent, 2,6-dimeth-
oxyphenyl ethers, were tested as protected hydroxy derivatives under
a variety of reaction conditions. These ethers underwent regioselec-
tive cleavage of the aromatic C(1)–O bond under reductive SET re-
OH
O
G
R
n
R(CH2)nX, NaI
K2CO3, DMF
G
action conditions using alkali metals in tetrahydrofuran at room
temperature. This deprotective procedure was efficiently realized in
1a,b, 2a,b
Scheme 1 Synthesis of ethers 1a,b, 2a,b; X = Br for 1a and 2a, or
Cl for 1b and 2b; 1a, G = Ph, n = 3, R = Ph, 60%; 1b, G = Ph, n = 4,
R = CH(OCH2)2, 77%; 2a, G = OMe, n = 3, R = Ph, 70%; 2b,
G = OMe, n = 4, R = CH(OCH2)2, 85%
the presence of several other functional groups, including an acetal,
a phenyl alkyl ether, an unprotected alcohol, and carbon–carbon dou-
ble and triple bonds. Furthermore, m-terphenyl ethers proved stable
under different reaction conditions, including acidic hydrolysis and
formation and/or employment of different organometallic reagents.
Ph
Ph
Key words: alcohols, electron transfer, protecting groups, reduc-
tion, sodium
OH
Ph
O
R
n
R(CH2)nOH
DIAD, Ph3P, THF
r.t., sonication
Ph
1c–g
The effective protection of hydroxy groups plays a central
role in many multistep reaction sequences, and there is a
need to develop new and efficient protecting groups
which can be selectively removed under mild reaction
conditions without affecting other functionalities.1,2 Such
an efficiency can be achieved by the reduction of suitable
compounds under single electron transfer (SET) reaction
conditions from alkali metals or aromatic radical anions in
ethereal solvents, as already demonstrated, e.g., by the re-
ductive cleavage of allyl,3 benzyl,3,4 and trityl5 ethers.
Scheme 2 Synthesis of ethers 1c–g; 1c, n = 9, R = Me, 73%; 1d,
n = 0, R = octan-2-yl, 65%; 1e, n = 2, R = pent-1-ynyl, 72%; 1f,
n = 3, R = OPh, 75%; 1g, n = 6, R = Cl, 80%
We next investigated the reductive cleavage of these
ethers under SET reaction conditions (Scheme 3), focus-
ing at first our attention on the reactivity of m-TPh ethers
1a and 1b and m-DMPh ethers 2a and 2b, whose reactions
with different alkali metals were investigated in some de-
tail.
Despite their well-known inertness and high reductive po-
tential, the aromatic C–O bond of aryl alkyl ethers can be
cleaved by electron transfer from alkali metals in aprotic
solvents. In the course of our extensive studies on the
mechanism6,7 and synthetic usefulness6,8 of this reaction,
we reported that 2,6-dimethoxyphenyl (m-DMPh)9 or 2,6-
diphenylphenyl (m-terphenyl, m-TPh)10 methyl ethers un-
dergo a highly regioselective demethoxylation at the C1-
position, in almost quantitative yields.
G
G
O
G
R
1. M, THF
2. H2O
n
HO
R
+
n
G
3a–f
1a–f, 2a,b
Scheme 3 Reductive deprotection of ethers 1a–f and 2a,b; G = Ph,
OMe; M = Na, K, or Li; n and R, see Schemes 1 and 2
To improve this procedure to develop new hydroxy pro-
tecting groups, it was necessary to investigate the reactiv- When a solution of ether 1a (or 1b) was reacted with an
ity towards alkali metals of several functionalized and excess (1:2.2 molar ratio) of sodium metal in dry tetrahy-
nonfunctionalized m-TPh and m-DMPh alkyl ethers. This drofuran, we observed complete disappearance of the
goal was realized, converting the appropriate phenol into starting material after few hours at room temperature;
the desired ethers by reacting them either with alkyl ha- quenching of this mixture with water, followed by usual
lides via the Williamson synthesis (Scheme 1) or alcohols workup, gave a mixture of the corresponding alcohol 3a
via the ultrasound stimulated Mitsunobu reaction11 (or 3b) and 1,3-diphenylbenzene (m-terphenyl) in a 1:1
1
(Scheme 2). The corresponding protected alcohols 1 and molar ratio, as determined by H NMR spectroscopic
2 were recovered in satisfactory to good yields.
analysis of the crude mixture. Similar results were ob-
tained in the reaction of 1a with potassium metal (Table 1,
entries 1–3).
SYNTHESIS 2011, No. 10, pp 1575–1580
x
x.
x
x
.
2
0
1
1
Advanced online publication: 08.04.2011
DOI: 10.1055/s-0030-1259997; Art ID: Z15111SS
© Georg Thieme Verlag Stuttgart · New York
Relatively different results were obtained in the reductive
cleavage of the corresponding m-DMPh ethers 2a and 2b.

1576
U. Azzena et al.
PAPER
Table 1 Reductive Cleavage of Ethers 1a–f and 2a,ba
Entry
Substrate
M (equiv)
Time (h)
Product
Yieldb (%)
1
2
Na (2.2)
K (3.0)
6
24
>95
>95
HO
Ph
3
O
Ph
3
1a
3a
m-TPh
O
O
3
1b
2a
Na (2.2)
6
3b
3a
>95
O
HO
HO
O
O
m-TPh
4
4
4
5
6
Na (2.2)
Li (3.0)
K (3.0)
18
24
24
9
84
94
O
O
Ph
Ph
m-DMPh
3
3
O
O
7
8
Na (2.2)
K (3.0)
24
24
12
>95
2b
1c
1d
3b
3c
3d
HO
HO
O
O
m-DMPh
4
4
9
O
9
Na (2.2)
Na (2.2)
6
6
>95
78c
m-TPh
m-TPh
m-TPh
9
10
HO
HO
O
5
5
O
11
12
1e
1f
Na (2.2)
Na (2.2)
6
6
3e
3f
73c
C3H7
C3H7
2
2
HO
OPh
O
OPh
>95
m-TPh
3
3
a All reactions were performed in THF at r.t.; m-TPh = 2,6-diphenylphenyl; m-DMPh = 2,6-dimethoxyphenyl.
b As determined by 1H NMR analysis of crude reaction mixtures, unless otherwise indicated.
c Isolated yield.
Indeed, reduction of these substrates with sodium metal with deuterium oxide did not provide evidence for the for-
led to the recovery of the starting material as the main re- mation of intermediate aromatic organometals in the re-
action product even after a prolonged reaction time (en- ductive cleavage of ethers 1a,b and 2a,b. Due to the
tries 4 and 7), whilst good results were obtained known stability of these organometals,9,10 and considering
employing lithium (as a dispersion) or potassium as re- that the mechanism of the cleavage reactions implies the
ducing agents (entries 5, 6, and 8). As a possible explana- intermediate formation of aromatic radicals,6,7 this finding
tion, it can be considered that the nature of the alkali metal suggests that some components of the reaction medium
affects the ease of the cleavage step in different ways. In- behave as hydrogen atom donors towards these reactive
deed, the more negative its reduction potential12 the easier intermediates, thus preventing their further reduction to
the formation of an intermediate radical anion, i.e., of the the corresponding carbanions.
intermediate that is usually considered to undergo break-
ing of the scissile bond. Furthermore, it is known that in-
teractions between cation and radical anions within an
ionic pair could affect the electronic distribution of the re-
The easier reducibility of the m-TPh ether compared to the
corresponding m-DMPh ether was further demonstrated
by the outcome of the reduction of a mixture of ethers 1a
and 2a with sodium metal in a 1:1:2.2 molar ratio; indeed,
aqueous work up of this mixture led to the recovery of
equimolar quantities of 3-phenylpropan-1-ol (3a), m-ter-
active intermediate, thus affecting the ease of the cleavage
step.6,7,10
Independent of the reducing agent, it is worth noting that phenyl, and unreacted 2a (Scheme 4).
aromatic ethers 1b and 2b underwent clean dealkoxyla-
tion without affecting the acetal moiety (entries 3 and 8).
More information on the proposed deprotective method-
ology were obtained by extending it to the reductive
Furthermore, at variance with that observed with the cor- cleavage of m-TPh ethers 1c–f (Table 1, entries 9–12); the
responding methyl ethers and once again independent of new results, whilst affording more evidence of the regio-
the reducing agent, quenching of the reaction mixtures selectivity of the cleavage reaction, show that this depro-
Ph
OMe
Ph
O
Ph
O
Ph
HO
Ph
1. Na, THF
2. H2O
3
3
2a
+
+
+
3
Ph
OMe
Ph
3a
1a
2a
Scheme 4 Selectivity in the reductive cleavage of ethers 1a and 2a
Synthesis 2011, No. 10, 1575–1580 © Thieme Stuttgart · New York

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m-Terphenyl Ethers, a New Hydroxy Protecting Group
1577
tective procedure can be performed without affecting
other functionalities, including an internal carbon–carbon
triple bond (entry 11) and an alkyl phenyl ether (entry 12).
Ph
O
Ph
CH2Cl2
r.t., 3 h
H2O
no reaction
+ CF3COOH
3
Ph
The effectiveness of the m-TPh ether as a hydroxy pro-
tecting group was further tested through the reaction se-
quences depicted in Schemes 5 and 6. Accordingly, this
protection proved stable during the formation of a
Grignard reagent by the reaction of a chloride with acti-
vated Mg (1g → 4 Scheme 5), as well as during the acidic
hydrolysis of an acetal moiety and a Wittig reaction (1b
→ 5 → 6, Scheme 6). Furthermore, reductive cleavage of
m-TPh ethers 4 and 6 was selectively obtained without af-
fecting either an unprotected alcohol (4 → 3g, Scheme 5)
or a carbon–carbon double bond (6 → 3h, Scheme 6).
1a
Ph
Ph
Ph
Me
CH2Cl2
r.t., 30 min
H2O
+ CF3COOH
Ph
O
Ph
OH
+ MeOH
Ph
7
Scheme 7 Relative stabilities towards acidic hydrolysis of ethers 1a
and 7
The regioselective deprotection of these ethers was suc-
cessfully realized under reductive SET reaction condi-
tions from alkali metals in tetrahydrofuran at room
temperature, even in the presence of a variety of function-
al groups. Finally, it is worth noting that the reductive
cleavage of m-TPh ethers was realized in the presence of
a slight excess of sodium metal, a particularly inexpensive
and easy-to-handle reagent.
Ph
Ph
O
O
Cl
OH
1. Mg, Br(CH2)2Br, Et2O
6
6
2. acetone
3. H3O+
Ph
Ph
4, 71%
1g
Ph
Starting materials were of the highest commercial quality and were
purified by distillation or recrystallization immediately prior to use.
Compound 7 was synthesized using the literature procedure.13 THF
was distilled from Na/K alloy under N2 immediately prior to use.
All reactions were run under a dry argon atmosphere. 1H (300 MHz)
and 13C NMR spectra (75 MHz) were recorded in CDCl3 (unless
otherwise indicated) with TMS as internal standard on a Varian
VXR 300 spectrometer. IR spectra were recorded on a FT-IR Jasco
680 P. Flash chromatography was performed on Merck silica gel 60
(40–63 mm), and TLC analyses on Macherey-Nagel silica gel pre-
coated plastic sheets (0.20 mm); petroleum ether = PE. Elemental
analyses were performed by the microanalytical laboratory of the
Dipartimento di Chimica, Università di Sassari.
Na, THF
HO
4
+
OH
3g, 70%
6
Ph
Scheme 5 Synthesis of 7-methyloctane-1,7-diol (3g)
Ph
Ph
O
Ph3MeP+I–
n-BuLi
O
O
O
O
1 M HCl
THF
4
4
THF
Ph
Ph
1b
5, 86%
Ph
Ph
Synthesis of Ethers 1a,b and 2a,b; General Procedure
The appropriate phenol (12.0 mmol) and alkyl halide (10.0 mmol),
NaI (1.58 g, 10.6 mmol), and K2CO3 (1.99 g, 14.4 mmol), were
placed in a 250-mL two-necked flask equipped with reflux condens-
er and magnetic stirrer, and suspended in anhyd DMF (70 mL); the
mixture was stirred at reflux temperature for 48 h. After cooling to
r.t., the mixture was filtered and the solvent evaporated in vacuo.
The residue was diluted with H2O (30 mL) and extracted with Et2O
(3 × 30 mL). The combined organic phases were washed with brine
(30 mL) and dried (K2CO3), and the solvent was evaporated. Crude
reaction products were purified by flash chromatography.
O
Na, THF
HO
4
+
4
Ph
Ph
3h, 81%
6, 76%
Scheme 6 Synthesis of hex-5-en-1-ol (3h)
Finally, we found it interesting to investigate further the
inertness of m-TPh ethers towards protic acids (see
Scheme 6); indeed, it is well known that several hydroxy
protecting groups that undergo cleavage under SET con-
ditions, e.g., trityl ethers,1,2 are equally well cleaved under
acidic conditions. To highlight this point, m-TPh ether 1a
(1.5 mmol) was added at room temperature to a 2.5 M so-
lution of trifluoroacetic acid in dichloromethane (10 mL);
after stirring for three hours, usual workup led to the quan-
titative recovery of the starting material. As a comparison,
triphenylmethyl methyl ether (7) taken as a model for tri-
tylated alcohols, was quantitatively cleaved within 30
minutes under similar conditions (Scheme 7).
2,6-Diphenylphenyl 3-Phenylpropyl Ether (1a)
Colorless oil; yield: 2.64 g (60%); Rf = 0.48 (PE–EtOAc, 8:2).
IR (neat): 3025, 2994 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.42–1.45 (m, 2 H, CH2), 2.24 (t,
J = 7.5 Hz, 2 H, ArCH2), 3.24 (t, J = 6.3 Hz, 2 H, OCH2), 6.82 (d,
J = 7.5 Hz, 2 H, ArH), 7.12–7.48 (m, 12 H, ArH), 7.61–7.64 (m, 4
H, ArH).
13C NMR (75 MHz, CDCl3): d = 31.3, 31.9, 72.5, 124.1, 125.5,
127.1, 128.1, 128.2, 129.0, 129.6, 130.2, 136.1, 138.8, 141.9, 154.1.
Anal. Calcd for C27H24O: C, 88.97; H, 6.64. Found: C, 88.74; H,
6.81.
In conclusion, we have shown that m-TPh alkyl ether can
be considered as a new class of hydroxy protecting group,
stable under a variety of reaction conditions, including the
employment of acidic, basic, and nucleophilic reagents.
2-[4-(2,6-Diphenylphenoxy)butyl]-1,3-dioxolane (1b)
Colorless oil; yield: 3.51 g (77%); Rf = 0.57 (PE–EtOAc–Et3N,
8:2:0.2).
Synthesis 2011, No. 10, 1575–1580 © Thieme Stuttgart · New York

1578
U. Azzena et al.
PAPER
IR (neat): 1218, 1142 cm–1.
IR (neat): 2929, 1218 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.98–1.38 (m, 6 H, CH2), 3.21 (t,
J = 6.3 Hz, 2 H, CH2), 3.72–3.95 (m, 4 H, CH2), 4.62 (t, J = 4.8 Hz,
1 H, CH), 7.19–7.46 (m, 9 H, ArH), 7.58–7.64 (m, 4 H, ArH).
13C NMR (75 MHz, CDCl3): d = 20.2, 29.5, 33.2, 64.6, 72.7, 104.3,
124.0, 126.9, 127.9, 129.4, 130.1, 136.0, 138.7, 153.9.
1H NMR (300 MHz, CDCl3): d = 0.52 (d, J = 6.3 Hz, 3 H, CH3),
0.70–1.30 (m, 13 H, CH2, CH3), 3.35 (quint, J = 6.3 Hz, 1 H, CH),
7.21 (dd, J = 8.1, 6.6 Hz, 1 H, ArH), 7.27–7.44 (m, 8 H, ArH), 7.58–
7.64 (m, 4 H, ArH).
13C NMR (75 MHz, CDCl3): d = 14.0, 18.7, 22.5, 24.8, 29.1, 31.6,
35.9, 78.6, 123.7, 126.8, 127.9, 129.8, 130.1, 136.9, 139.6, 152.6.
Anal. Calcd for C25H26O3: C, 80.18; H, 7.00. Found: C, 79.92; H,
7.15.
Anal. Calcd for C26H30O: C, 87.10; H, 8.43. Found: C, 86.95; H,
8.61.
2,6-Dimethoxyphenyl 3-Phenylpropyl Ether (2a)
Colorless oil; yield: 3.49 g (70%); Rf = 0.47 (PE–EtOAc, 8:2).
2,6-Diphenylphenyl Hept-3-ynyl Ether (1e)
Colorless oil; yield: 1.99 g (72%); Rf = 0.63 (PE–EtOAc, 9.5:0.5).
IR (neat): 2348, 1222 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.84 (t, J = 7.2 Hz, 3 H, CH3),
1.37 (sext, J = 7.2 Hz, 2 H, CH2), 1.90–2.00 (m, 4 H, CH2), 3.28 (t,
J = 7.5 Hz, 2 H, CH2), 7.22 (dd, J = 8.4, 6.3 Hz, 1 H, ArH), 7.27–
7.44 (m, 8 H, ArH), 7.56–7.64 (m, 4 H, ArH).
IR (neat): 1595, 1253 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.09–2.12 (m, 2 H, CH2), 2.85 (t,
J = 8.1 Hz, 2 H, ArCH2), 3.84 (s, 6 H, CH3), 4.02 (t, J = 6.3 Hz, 2
H, CH2O), 6.58 (d, J = 8.1 Hz, 2 H, ArH), 6.99 (t, J = 8.1 Hz, 1 H,
ArH), 7.18–7.35 (m, 5 H, ArH).
13C NMR (75 MHz, CDCl3): d = 31.7, 32.1, 55.9, 72.4, 105.1,
123.3, 125.5, 128.1, 128.4, 137.2, 142.1, 153.6.
13C NMR (75 MHz, CDCl3): d = 13.4, 19.9, 20.6, 22.2, 71.0, 75.8,
81.1, 124.4, 127.1, 128.0, 129.4, 130.2, 136.0, 138.5, 153.4.
Anal. Calcd for C17H20O3: C, 74.97; H, 7.40. Found: C, 74.83; H,
7.58.
Anal. Calcd for C25H24O: C, 88.20; H, 7.11. Found: C, 88.03; H,
7.23.
2-[4-(2,6-Dimethoxyphenoxy)butyl]-1,3-dioxolane (2b)
Colorless oil; yield: 4.35 g (85%); Rf = 0.25 (PE–EtOAc–Et3N,
8:2:0.2).
2,6-Diphenylphenyl 3-Phenoxypropyl Ether (1f)
Colorless oil; yield: 1.70 g (75%); Rf = 0.73 (PE–EtOAc, 9.5:0.5).
IR (neat): 1595, 1253, 1111 cm–1.
IR (neat): 2955, 1245 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.53–1.88 (m, 6 H, CH2), 3.82–
3.99 (m, 12 H, CH2), 4.88 (t, J = 4.8 Hz, 1 H, CH), 6.57 (d, J = 8.4
Hz, 2 H, ArH), 6.98 (t, J = 8.4 Hz, 1 H, ArH).
13C NMR (75 MHz, CDCl3): d = 20.2, 29.7, 33.4, 55.8, 64.2, 72.8,
104.4, 105.0, 123.2, 137.1, 153.5.
1H NMR (300 MHz, CDCl3): d = 1.62 (quint, J = 6 Hz, 2 H, CH2),
3.37 (t, J = 5.7 Hz, 2 H, CH2), 3.53 (t, J = 6.6 Hz, 2 H, CH2), 6.62–
6.70 (m, 2 H, ArH), 6.87–6.95 (m, 1 H, ArH), 7.20–7.42 (m, 11 H,
ArH), 7.56–7.62 (m, 4 H, ArH).
13C NMR (75 MHz, CDCl3): d = 29.6, 64.3, 69.5, 114.3, 120.3,
124.3, 127.1, 128.1, 129.1, 129.4, 130.2, 136.1, 138.7, 153.7, 158.7.
Anal. Calcd for C15H22O5: C, 63.81; H, 7.85. Found: C, 63.65; H,
8.04.
Anal. Calcd for C27H24O2: C, 85.23; H, 6.36. Found: C, 85.15; H,
6.47.
Synthesis of Ethers 1c–g; General Procedure
2,6-Diphenylphenol (2.0 g, 8.1 mmol), the appropriate alcohol (8.1
mmol), and Ph3P (2.25 g, 8.6 mmol) were dissolved in anhyd THF
(8 mL) in a 50-mL two-necked flask equipped with reflux condens-
er, dropping funnel. The mixture was stirred and sonicated (Bran-
sonic® 2200, 47 KHz) to obtain dissolution of the solid materials.
While sonicating, DIAD (1.59 mL, 8.1 mmol) was added dropwise
to the mixture over the course of 2 min, and sonication was contin-
ued for 30 min. The mixture was treated with cold hexane (ca. 20
mL) to remove the majority of the Ph3PO byproduct. The hexane
mixture was filtered and the precipitate was washed with cold hex-
ane (5 × 10 mL), the organic phases were collected and the solvent
evaporated. Crude reaction products were purified by flash chroma-
tography.
6-Chlorohexyl 2,6-Diphenylphenyl Ether (1g)
Colorless oil; yield: 5.64 g (80%); Rf = 0.63 (PE–EtOAc, 9.5:0.5).
IR (neat): 1388, 1203 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.86–1.26 (m, 6 H, CH2), 1.55
(quint, J = 7.8 Hz, 2 H, CH2), 3.19 (t, J = 6.3 Hz, 2 H, CH2), 3.38 (t,
J = 6.9 Hz, 2 H, CH2), 7.23 (dd, J = 8.4, 6.6 Hz, 1 H, ArH), 7.31–
7.47 (m, 8 H, ArH), 7.58–7.64 (m, 4 H, ArH).
13C NMR (75 MHz, CDCl3): d = 25.0, 26.2, 29.5, 32.3, 44.8, 72.7,
124.0, 126.9, 127.9, 129.4, 130.1, 136.0, 138.8, 154.0.
Anal. Calcd for C24H25ClO: C, 78.99; H, 6.91. Found: C, 78.76; H,
7.02.
8-(2,6-Diphenylphenoxy)-2-methyloctan-2-ol (4)
Decyl 2,6-Diphenylphenyl Ether (1c)
Mg turnings (0.40 g, 16.4 mmol) were suspended in a minimal
amount of anhyd Et2O in a 50-mL two-necked flask equipped with
reflux condenser, dropping funnel, and magnetic stirrer. Halide 1g
(2 g, 5.5 mmol) and 1,2-dibromoethane (1.03 g, 5.5 mmol) were dis-
solved in anhyd Et2O (11 mL), and this soln was dropwise added to
the Mg, causing the suspension to reflux. After a further reflux for
1 h, the mixture was cooled to r.t. A soln of acetone (0.48 g, 8.3
mmol) in anhyd Et2O (11 mL) was added dropwise, and the result-
ing mixture was refluxed for 2 h. After cooling to r.t. the mixture
was hydrolyzed with sat. NH4Cl and extracted with Et2O (3 × 15
mL). The combined organic phases were washed with brine (15
mL) and dried (Na2SO4), and the solvent was evaporated. The crude
product was purified by flash chromatography to give a colorless
oil; yield: 1.50 g (71%); Rf = 0.36 (PE–EtOAc, 8:2).
Colorless oil; yield: 2.93 g (73%); Rf = 0.78 (PE–EtOAc, 8:2).
IR (neat): 2925, 1218 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.86–1.28 (m, 19 H, CH2, CH3),
3.18 (t, J = 6.3 Hz, 2 H, OCH2), 7.22 (dd, J = 8.4, 6.9 Hz, 1 H, ArH),
7.28–7.46 (m, 8 H, ArH), 7.58–7.66 (m, 4 H, ArH).
13C NMR (75 MHz, CDCl3): d = 14.1, 22.7, 25.7, 29.1, 29.3, 29.4,
29.5, 29.7, 31.9, 73.1, 124.0, 127.0, 127.9, 129.5, 130.2, 136.1,
138.8, 154.2.
Anal. Calcd for C28H34O: C, 87.00; H, 8.87. Found: C, 86.83; H,
8.97.
2,6-Diphenylphenyl Octan-2-yl Ether (1d)
Colorless oil; yield: 0.95 g (65%); Rf = 0.73 (PE–EtOAc, 9.5:0.5).
Synthesis 2011, No. 10, 1575–1580 © Thieme Stuttgart · New York

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m-Terphenyl Ethers, a New Hydroxy Protecting Group
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IR (neat): 3359, 1216 cm–1.
(30% dispersion in mineral oil) was washed with THF (3 × 10 mL)
and suspended in THF; freshly cut K metal was vigorously stirred
in THF at a temperature above its melting point and then cooled to
r.t. without stirring; freshly cut Na metal was used as such. To these
suspensions, was added at once the appropriate substrate (3 mmol)
dissolved in THF (5 mL); the mixture was then stirred at r.t. under
argon for 24 h. The mixture was cooled to 0 °C and quenched by
slow, dropwise addition of H2O (10 mL) (CAUTION!). After stir-
ring at r.t. for 1 h, the mixture was extracted with Et2O (3 × 30 mL);
the combined organic layers were dried (Na2SO4), and the solvent
was evaporated. Crude reaction mixtures were analyzed by 1H
NMR spectroscopy, and reaction products were purified by flash
chromatography. The 1H and 13C NMR and IR spectral data of com-
pounds 3a,14 3c,15 3d,16 3e,16 and 3f17 were identical with those of
commercially available samples.
1H NMR (400 MHz, CDCl3): d = 0.88–0.97 (m, 4 H, CH2), 1.08–
1.20 (m, 10 H, CH2, CH3), 1.25–1.35 (m, 2 H, CH2), 3.18 (t, J = 6.4
Hz, 2 H, OCH2), 7.23 (dd, J = 8.4, 7.2 Hz, 1 H, ArH), 7.32–7.37 (m,
4 H, ArH), 7.40–7.45 (m, 4 H, ArH), 7.60– 7.62 (m, 4 H, 4 ArH).
13C NMR (100 MHz, CDCl3): d = 24.08, 25.6, 29.1, 29.53, 29.6,
43.7, 70.93, 73.0, 124.0, 126.9, 127.9, 129.5, 130.2, 136.1, 138.8,
154.1.
Anal. Calcd for C27H32O2: C, 83.46; H, 8.30. Found: C, 83.31; H,
8.42.
5-(2,6-Diphenylphenoxy)pentanal (5)
In a two-necked flask equipped with reflux condenser and magnetic
stirrer, acetal 1b (0.50 g, 1.33 mmol) was dissolved in 1 M HCl and
THF (1:1, 10 mL) and stirred overnight at reflux temperature. After
cooling to r.t., the mixture was neutralized with 1 M NaOH, diluted
with H2O (10 mL), and extracted with Et2O (3 × 10 mL). The com-
bined organic phase were dried (K2CO3), and the solvent was evap-
orated. The crude reaction product was purified by flash
chromatography to give a colorless oil; yield: 0.38 g (86%);
Rf = 0.65 (PE–CH2Cl2–Et3N, 8:2:0.2).
4-(1,3-Dioxolan-2-yl)butan-1-ol (3b)
Colorless oil; yield: 0.280 g (73%); Rf = 0.34 (EtOAc–Et3N,
10:0.4).
IR (neat): 3415, 1141 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.42–1.78 (m, 6 H, CH2), 3.56–
3.71 (m, 2 H, CH2OH), 3.80–4.03 (m, 4 H, CH2), 4.86 (t, J = 4.8 Hz,
1 H, CH).
IR (neat): 3056, 1724, 1218 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.17 (quintd, J = 6.0, 2.1 Hz, 2 H,
CH2), 1.28 (quintd, J = 6.9, 2.1 Hz, 2 H, CH2), 1.96 (td, J = 6.9, 2.1
Hz, 2 H, CH2), 3.19 (t, J = 5.7 Hz, 2 H, CH2O), 7.23 (dd, J = 8.4, 6.6
Hz, 1 H, ArH), 7.30–7.45 (m, 8 H, ArH), 7.57–7.64 (m, 4 H, ArH),
9.50 (t, J = 1.8 Hz, 1 H, CHO).
13C NMR (75 MHz, CDCl3): d = 18.2, 28.9. 42.8, 71.9, 124.2,
127.0, 128.0, 129.5, 130.2, 136.0, 138.7, 153.8, 202.5.
13C NMR (75 MHz, CDCl3): d = 20.1, 32.3, 33.3, 62.3, 64.7, 104.3.
Anal. Calcd for C7H14O3: C, 57.51; H, 9.65. Found: C, 55.56; H,
9.72.
7-Methyloctane-1,7-diol (3g)
Colorless oil; yield: 0.179 g (70%); Rf = 0.36 (PE–EtOAc, 8:2).
IR (neat): 3345, 1191 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.20 (s, 6 H, CH3), 1.26–1.65 (m,
10 H, CH2), 3.64 (t, J = 6.4 Hz, 2 H, CH2OH).
Anal. Calcd for C23H22O2: C, 83.60; H, 6.71. Found: C, 83.49; H,
6.83.
2,6-Diphenylphenyl Hex-5-enyl Ether (6)
13C NMR (75 MHz, CDCl3): d = 24.1, 25.6, 29.0, 29.8, 32.5, 43.7,
MePh3P+I– (2.26 g, 4.8 mmol) was suspended in THF (30 mL) in a
two-necked flask equipped with reflux condenser, dropping funnel,
and magnetic stirrer. To this mixture, cooled to 0 °C, 1.6 M BuLi in
hexane (3.3 mL, 5.28 mmol) was added dropwise. The resulting
mixture was stirred at this temperature for 30 min after which time
a soln of aldehyde 5 (0.8 g, 2.4 mmol) dissolved in THF (12 mL)
was added dropwise, and stirring was continued for 2 h. The mix-
ture was quenched by dropwise addition of cold sat. NH4Cl soln,
and the phases were separated. The aqueous phase was extracted
with EtOAc (3 × 20 mL), the combined organic phases were dried
(Na2SO4), and the solvent was evaporated. The crude product was
purified by flash chromatography to give a colorless oil; yield: 0.60
g (76%); Rf = 0.73 (PE–EtOAc, 9:1).
62.5, 70.9.
Anal. Calcd for C9H20O2: C, 67.45; H, 12.58. Found: C, 67.30; H,
12.66.
Acknowledgment
Financial support from the Università di Sassari (Fondo di Ateneo
per la Ricerca) is gratefully acknowledged.
References
(1) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis; John Wiley & Sons: New York, 2007.
(2) Kocienski, P. Protecting Groups; Georg Thieme Verlag:
Stuttgart, 2003.
(3) Alonso, E.; Ramón, D. J.; Yus, M. Tetrahedron 1997, 53,
14355.
(4) Liu, H.-J.; Yip, J.; Shia, K.-S. Tetrahedron Lett. 1997, 38,
2253.
(5) Yus, M.; Behloul, C.; Guijarro, D. Synthesis 2003, 2179.
(6) Azzena, U. Trends Org. Chem. 1997, 6, 55; and references
therein.
IR (neat): 1639, 1218, 995, 910 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.98–1.07 (m, 2 H, CH2), 1.13–
1.20 (m, 2 H, CH2), 1.69 (qt, J = 7.2, 0.8 Hz, 2 H, CH2), 3.19 (t,
J = 6 Hz, 2 H, OCH2), 4.75–4.78 (m, 2 H, CH2), 5.59 (ddt, J = 16.4,
10.4, 6.8 Hz, 1 H, CH), 7.22 (dd, J = 8.0, 6.8 Hz, 1 H, ArH), 7.30–
7.37 (m, 4 H, ArH), 7.39–7.45 (m, 4 H, ArH), 7.59–7.66 (m, 4 H,
ArH).
13C NMR (100 MHz, CDCl3): d = 24.8, 29.1, 33.1, 72.8, 114.1,
124.1, 127.0, 127.9, 129.5, 130.1, 136.1, 138.6, 138.8, 154.1.
(7) See, for example: (a) Pisano, L.; Farriol, M.; Asensio, X.;
Gallardo, I.; Gonzàlez-Lafont, A.; Lluch, J.-M.; Marquet, J.
J. Am. Chem. Soc. 2002, 124, 4708. (b) Azzena, U.;
Casado, F.; Fois, P.; Gallardo, I.; Pisano, L.; Marquet, J.;
Melloni, G. J. Chem. Soc., Perkin Trans. 2 1996, 2563.
(c) Azzena, U.; Denurra, T.; Melloni, G.; Fenude, E.; Rassu,
G. J. Org. Chem. 1992, 57, 1444.
Anal. Calcd for C24H24O: C, 87.76; H, 7.37. Found: C, 87.55; H,
7.41.
Reductive Cleavage of Compounds 1, 2, 4, and 6 with Alkali
Metals; General Procedure
Suspensions of alkali metals (6 mg atom, 2 equiv) in anhyd THF (25
mL) were prepared under argon in a two-necked flask equipped
with reflux condenser and magnetic stirrer as follows: Li metal
Synthesis 2011, No. 10, 1575–1580 © Thieme Stuttgart · New York

1580
U. Azzena et al.
PAPER
(12) For a comparison of the electrode potentials of the alkali
(8) See, for example: (a) Azzena, U.; Dettori, G.; Mascia, I.;
Pisano, L.; Pittalis, M. Tetrahedron 2007, 63, 11998.
(b) Azzena, U.; Dettori, G.; Idini, M. V.; Pisano, L.; Sechi,
G. Tetrahedron 2003, 59, 7961. (c) Azzena, U.; Melloni,
G.; Pisano, L. J. Chem. Soc., Perkin Trans. 1 1995, 261.
(d) Azzena, U.; Melloni, G.; Piroddi, A. M.; Azara, E.;
Contini, S.; Fenude, E. J. Org. Chem. 1992, 57, 3101; and
references therein.
metals, see: Hwu, J. R.; Wein, Y. S.; Leu, Y.-J. J. Org.
Chem. 1996, 61, 1493.
(13) Stoochnoff, B. A.; Benoiton, N. L. Tetrahedron Lett. 1973,
14, 21.
(14) Hanada, S.; Yuasa, A.; Kuroiwa, H.; Motoyama, Y.;
Nagashima, H. Eur. J. Org. Chem. 2010, 1021.
(15) Fuller, J. C.; Stangeland, E. L.; Jackson, T. C.; Singaram, B.
Tetrahedron Lett. 1994, 35, 1515.
(16) Bothwell, J. M.; Angeles, V. V.; Carolan, J. P.; Olson, M. E.;
Mohan, R. S. Tetrahedron Lett. 2010, 51, 1056.
(17) Murphy, J. A.; Schoenebeck, F.; Findlay, N. J.; Thomson, D.
W.; Zhou, S. Z.; Garnier, J. J. Am. Chem. Soc. 2009, 131,
6475.
(9) Azzena, U.; Denurra, T.; Melloni, G.; Piroddi, A. M. J. Org.
Chem. 1990, 55, 5386.
(10) Casado, F.; Pisano, L.; Farriol, M.; Gallardo, I.; Marquet, J.;
Melloni, G. J. Org. Chem. 2000, 65, 322.
(11) Lepore, S. D.; He, Y. J. Org. Chem. 2003, 68, 8261.
Synthesis 2011, No. 10, 1575–1580 © Thieme Stuttgart · New York