Regio- and stereochemistry of Na-mediated reductive cleavage of alkyl aryl ethers

Article abstract of DOI:10.1016/j.tetasy.2014.10.015

We have investigated the regio-and stereochemistry of the reductive dealkoxylation of alkyl aryl ethers. Chiral non-racemic secondary alcohols were converted into the corresponding m-terphenyl or 2-biphenyl ethers either via inversion of configuration under Mitsunobu reaction conditions or with retention of configuration under S_NAr conditions. The successive cleavage of the aromatic C-O bond occurred in the presence of a stoichiometric amount of Na metal in dry tetrahydrofuran at rt with retention of configuration, thus highlighting that the overall inversion or retention of configuration for the whole two-step procedure is dictated by the stereochemistry of the first synthetic step.

Full text of DOI:10.1016/j.tetasy.2014.10.015

Tetrahedron: Asymmetry 25 (2014) 1550–1554
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Regio- and stereochemistry of Na-mediated reductive cleavage
of alkyl aryl ethers
a
a
a
a,
a
Ugo Azzena a, , Massimo Carraro , Claudia Meloni , Irene Murgia , Luisa Pisano , Mario Pittalis ,
⇑
⇑
Renzo Luisi b, Biagia Musio b, Leonardo Degennaro b
a Dipartimento di Chimica e Farmacia, Università degli Studi di Sassari, via Vienna 2, 07100 Sassari, Italy
b Dipartimento di Farmacia—Scienze del Farmaco, Università degli Studi di Bari—A. Moro, Via E. Orabona 4, 70125 Bari, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 5 October 2014
Accepted 23 October 2014
We have investigated the regio- and stereochemistry of the reductive dealkoxylation of alkyl aryl ethers.
Chiral non-racemic secondary alcohols were converted into the corresponding m-terphenyl or 2-biphenyl
ethers either via inversion of configuration under Mitsunobu reaction conditions or with retention of
configuration under SNAr conditions. The successive cleavage of the aromatic CAO bond occurred in
the presence of a stoichiometric amount of Na metal in dry tetrahydrofuran at rt with retention of
configuration, thus highlighting that the overall inversion or retention of configuration for the whole
two-step procedure is dictated by the stereochemistry of the first synthetic step.
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
ence alcohols due to interest in their biological properties.
Although it is reasonable to assume that the synthesis of aryl alkyl
The reductive cleavage of aromatic carbonAoxygen bonds of
alkyl aryl ethers (dealkoxylation) is a topic of great interest in
organic chemistry.1 Within this field, we have recently reported
on the protection of functionalized and non-functionalized
alcohols as 2,6-dimethoxy- and 2,6-diphenylphenyl (m-terphenyl,
m-TPh) ethers.2 Such ethers are easily accessible via an ultrasound
stimulated Mitsunobu reaction.3 Despite the well known stability
of these ethers under a variety of reaction conditions (e.g., towards
basic and organometallic reagents as well as towards acidic
hydrolysis),2 we have developed a particularly mild, transition
metal free, removal of such protection. Indeed, the aromatic
portion was easily removed with high regioselectivity under single
electron transfer (SET) reaction conditions, using Na metal as a par-
ticularly inexpensive and easily available reducing agent leading,
after aqueous work-up, to the formation of low impact waste. This
procedure, successfully run at rt, allowed the transformation of
sensitive functional groups, such as the carbonyl moiety shown
in the example reported in Scheme 1.
ethers under Mitsunobu conditions occurs with inversion of
configuration,7 there is no report concerning the stereochemistry
of the cleavage of the aromatic carbonAoxygen bonds under SET
reaction conditions. Indeed, such a reaction occurs with the forma-
tion of radical intermediates,8 so that racemization at a secondary
stereocenter cannot be a priori ruled out, also in view of the
relatively low dissociation energy of CAH bonds at the a-position
of an ether oxygen.9
2. Results and discussion
With the aim of demonstrating the regioselectivity of the
deprotection step, aryl ethers 1a–i were prepared via reaction of
the appropriate phenol with the required alkyl alcohol according
to the ultrasound promoted Mitsunobu reaction.2,3 A drawback of
the previously reported procedure relies on the intrinsic difficulties
in separating the desired apolar ethers from residual Ph3P, thus
requiring extensive chromatographic purification of the reaction
products. As an improvement, we found it particularly effective
to submit the crude mixtures to an oxidative washing with 15%
aq H2O2.10 This modified protocol led us to recover aryl ethers
1a–i in satisfactory to good yields (Scheme 2) and high purity
(P95%) by filtering the reaction mixtures through silica gel.
The same synthetic protocol was applied to the reaction of the
chiral non-racemic alcohol (R)-2, with 2-hydroxybiphenyl or
2,6-diphenylphenol, affording the highly enantioenriched ethers
(S)-1f and (S)-1h, respectively. Under similar conditions, the
In continuation of our research programme aimed at developing
Na metal mediated organic reactions,4 we extended our investiga-
tion to biphenyl and naphthyl alkyl ethers. Furthermore, we inves-
tigated the stereochemical behaviour under the aforementioned
protection/deprotection reaction sequence using chiral non-race-
mic aryl ethers obtained from 2-octanol5 and 3-octanol,6 as refer-
⇑
Corresponding authors. Tel.: +39 079229549 (U.A.), +39 079229548 (L.P.).
E-mail addresses: ugo@uniss.it (U. Azzena), luisa@uniss.it (L. Pisano).
http://dx.doi.org/10.1016/j.tetasy.2014.10.015
0957-4166/Ó 2014 Elsevier Ltd. All rights reserved.

U. Azzena et al. / Tetrahedron: Asymmetry 25 (2014) 1550–1554
1551
1. DIAD, Ph3P,
THF, rt,
Ar-OH
O
Ph
Ph
-1f h
(S)
,
O
Ar
5
Mitsunobu
conditions
sonication
O
HO
OH
Ph
HO
O
5
O
+
4
er> 95:5
4
2. 1M HCl
THF
Ph
-2
(R)
Ar-F
O
Ar
(R)-1f
5
er> 95:5
SNAr
Ph
1. Ph3MeP+I-
n-BuLi
Ph
HO
+
CH2
2. Na, THF
4
O
O
O
Ph
5
5
5
Scheme 1. m-Terphenyl ethers as hydroxyl protecting groups.2
Ph
Ph
Ph
-1f
(S)-1f, 70%
(R) , 41%
(S)-1h, 80%
Mitsunobu
O
HO
( )n
( )n
R1
conditions
R1
Ar
Ar-OH
+
Mitsunobu
conditions
R
R
HO
O
Ar-OH
4
Ar
4
+
-3
(S)
(R)-1g,i
O
O
O
er> 95:5
er> 95:5
5
5
9
R
Ph
Ph
O
O
1c, 80%
1b, 60%
1a, 73%
4
4
Ph
Ph
O
O
Ph
O
(R)-1g, 83%
(R)-1i, 80%
5
9
Ph
Ph
1e
Ph
, 70%
Scheme 3. Synthesized chiral non-racemic ethers.
-1f
)
(
1d
, 88%
, 85%
Ph
Ph
O
O
O
4
4
5
C-O bonds amenable
of reductive cleavage
Ph
Ph
Ph
HO
H
( )n
path a
R1
R1
+ Ar-H
-1i
(
)
, 80%
-1g
)
(
)-1h, 80%
(
, 83%
dealkoxylation
R
R
O
Na
( )n
R1
Ar
Scheme 2. Synthesized achiral and racemic ethers 1a–1i.
R
( )n
path b
+ Ar-OH
dealkylation
reaction of chiral non-racemic alcohol (S)-3 with 2-hydroxybiphe-
nyl or 2,6-diphenylphenol afforded ethers (R)-1g and (R)-1i,
respectively, (Scheme 3). The absolute configurations were
assigned to the aforementioned ethers on the assumption that
the Mitsunobu reaction proceeded with an inversion of configura-
tion at the stereocenter.7 To confirm this hypothesis, ether (R)-1f
was synthesized under SNAr conditions (Scheme 3), that is, with
retention of configuration, by the reaction of sodium (R)-2-octano-
late with 2-fluorobiphenyl in NMP.11 The enantiomeric ratios of
aryl ethers (R)-1f, (S)-1f, (R)-1g, (S)-1h and (R)-1i, (>95:5) were
determined by a comparison of chiral HPLC analysis of the optically
active compounds with that of the corresponding racemic samples.
In order to assess the regioselectivity of the carbonAoxygen
bond cleavage as a function of the aromatic protecting moiety, a
set of reactions was carried out with ethers 1a–e and a stoichiom-
etric amount of Na metal as the reducing agent. The reductive
cleavage of alkyl aryl ethers by electron transfer from alkali metals
most likely occurs via fragmentation of the corresponding radical
anion intermediates, giving rise to competitive cleavage pathways
leading to dealkoxylation (by aromatic CAO bond cleavage, path a
in Scheme 4) or dealkylation (by aliphatic CAO bond cleavage, path
b in Scheme 4).8,12 Selected results, as reported in Table 1, show
that among the systems investigated, only 2-biphenyl (2-BiPh)
alkyl ethers 1d and 1e underwent the desired dealkoxylation reac-
tion with high regioselectivities (Table 1, entries 4 and 5). Indeed,
both 1- and 2-naphthyl alkyl ethers 1a and 1b afforded mixtures of
reaction products (Table 1, entries 1 and 2), whilst moderate
regioselectivity was observed in the reductive cleavage of the 4-
biphenyl derivative 1c (Table 1, entry 3).
Scheme 4. Reductive cleavage pathways.
Table 1
Reduction of ethers 1a–e with Na metala
Entry
Ether
Ar
t (h)
Product distributionb (%)
Ar-Hc
Ar-OHd
1
1a
5
35
65
2
3
1b
1c
5
42
75
58
15
10e
Ph
4
5
1d
1e
22
5
>95
>95
—
—
Ph
Ph
a
All reactions were carried out with a substrate/Na molar ratio of 1.0:2.2, in THF
under dry Ar at rt.
As determined by 1H NMR analysis of crude reaction mixtures.
Comparable amounts of the corresponding alcohol were recovered.
No attempt was carried out to evidence the formation of the corresponding
b
c
d
alkane.
e
15% of the starting material was also recovered.

1552
U. Azzena et al. / Tetrahedron: Asymmetry 25 (2014) 1550–1554
In agreement with literature data, these results show that even
1) Na
in the presence of identical alkyl chains (compare 1c with 1d,
Table 1, entry 3 vs entry 4), minor modifications of the structure
of the aromatic moiety of the starting material strongly affect the
regioselectivity of the deprotection step, likely due to the signifi-
cant differences in the distribution of electron density within inter-
mediate aromatic radical anions.8,12
THF, rt
O
O
(R)-2
O
O
-1f
(R)
E
E
Ar
Ar
5
5
5
or
Ar-H
Ar-H
+
2) EX
-4
(R)
er> 95:5
er> 95:5
-1f,h
1) Na
THF, rt
-2
(S)
(S)
5
or
-4
+
Taking into account these, as well as our previous results,2 we
evaluated the stereochemical outcome of chiral secondary alcohols
under the whole protection/deprotection sequence, by submitting
to the reductive procedure the highly enantioenriched alkyl aryl
ethers (R)-1f, (S)-1f, (R)-1g, (S)-1h and (R)-1i (Scheme 5 and
Table 2).
The reduction mixtures were quenched either with H2O or with
PhCOCl. Quenching with H2O followed by chromatographic purifi-
cation of the reaction mixtures led to the recovery of highly enan-
tioenriched and inverted alcohols (R)-2, (S)-2 and (R)-3 (Table 2,
entries 1, 3, 5, 7 and 9) while quenching with PhCOCl led to the cor-
responding chiral benzoic esters (R)-4, (S)-4 or (R)-5 (Table 2,
entries 2, 4, 6, 8 and 10) (Scheme 5).
2) EX
(S)
1) Na
THF, rt
O
O
E
Ar
4
4
+
Ar-H
2) EX
-1g,i
(R)
er> 95:5
-3
-5
(R) or (R)
er> 95:5
Scheme 5. Reductive cleavage of chiral non-racemic ethers.
The absolute configuration and enantiomeric purity of chiral
alcohols were ascertained by the measurement of the sign of their
specific rotation, and the enantiomeric ratios of the recovered
esters were determined by chiral HPLC analysis. Taken as a whole,
these results clearly show that the alkali metal mediated reductive
cleavage of these ethers proceeds with complete retention of
configuration at the stereocenter, due to the highly regioselective
fragmentation of the aryl carbonAoxygen bond. Accordingly, the
resulting overall retention (Table 2, entries 1 and 2) or inversion
(Table 2, entries 3–10) of configuration for the whole two-step pro-
cedure is dictated by the stereochemistry of the procedure
employed in the synthesis of ethereal derivatives 1 (Mitsunobu
vs SNAr see above).
Table 2
Reductive cleavage of chiral ethers (R)-1f, (S)-1f, (R)-1g, (S)-1h and (R)-1ia
Entry
1
Ether
Ar
EX
Productb (yield %)
er
(R)-1f
H2O
(R)-2 (86)
>95:5c
Ph
Ph
Ph
Ph
Ph
Ph
2
3
4
5
6
(R)-1f
(S)-1f
(S)-1f
(R)-1g
(R)-1g
PhCOCld
H2O
(R)-4 (86)
(S)-2 (68)
(S)-4 (75)
(R)-3 (82)
(R)-5 (70)
>95:5e
>95:5c
>95:5e
>95:5c
>95:5f
PhCOCld
H2O
3. Conclusion
Our results support the finding that the appropriate choice of the
aromatic moiety is a key step to synthesize alkyl aryl ethers that
undergo the cleavage of the aromatic carbonAoxygen bond under
SET reaction conditions with high regioselectivity.8,12 2-Biphenyl
and m-terphenyl alkyl ethers underwent the cleavage reaction
under particularly mild conditions, that is, in THF at room temper-
ature and employing a slight excess of Na metal as a reducing agent.
Furthermore we have demonstrated that such a reaction could
be carried out on non-racemic secondary alkyl aryl ethers, such
as 1f–i, without affecting the stereochemistry at the stereogenic
centre. Taking advantage of the possibility to transform chiral sec-
ondary alcohols into the corresponding aryl ethers either with
inversion or retention of configuration, we have found new
synthetic applications of the described protection/deprotection
reaction sequence, such as the possibility to realize a two-step
inversion of configuration of chiral secondary alcohols, as
described above. From this point of view, it is worth noting that
most similar protection/deprotection sequences of non-racemic
alcohols involve the intermediate formation of esters13 whilst to
the best of our knowledge, no report deals with the use of aryl
ethers as protecting groups, despite their well known inertness
under a variety of reaction conditions.14
PhCOCld
Ph
Ph
Ph
Ph
7
(S)-1h
(S)-1h
(R)-1i
(R)-1i
H2O
(S)-2 (82)
(S)-4 (74)
(R)-3 (70)
(R)-5 (68)
>95:5c
>95:5e
>95:5c
>95:5f
Ph
Ph
Ph
Ph
8
PhCOCld
9
H2O
10
PhCOCld
a
All reactions were carried out with a substrate/Na molar ratio of 1.0:2.2, in THF
under dry Ar at rt.
b
As determined by 1H-NMR analysis of crude reaction mixtures; comparable
4. Experimental
4.1. General
amounts of the corresponding aromatic hydrocarbon were also detected.
c
As determined by specific rotation measurements.
Quenching with PhCOCl was performed by adding 1.2 equiv of the electrophile
d
to the reduction mixture chilled at 0 °C.
e
As determined by specific rotation measurements and chiral HPLC analysis of
Starting materials were of the highest commercial quality and
were purified by distillation or recrystallization immediately prior
the crude reaction mixtures.
f
As determined by chiral HPLC analyses of the crude reaction mixtures.

U. Azzena et al. / Tetrahedron: Asymmetry 25 (2014) 1550–1554
1553
to use. (R)-(À)-2-Octanol and (S)-(+)-2-octanol were 99% purity
and 98% ee, and (S)-(+)-3-octanol was 97% purity. Na metal
(chunks) was 99% purity. THF was distilled from Na/K alloy under
N2 immediately prior to use. Enantiomeric excess was measured by
HPLC analyses at 25 °C on a LuxTM Cellulose-1 column for ethers 1
and ester 4, and on a Daicel CHIRALCELÒ OD-H column for ester 5.
The mobile phase used for the analysis consisted of different mix-
tures of hexaneAiPrOH. The wavelength for detection was adjusted
to 230 nm. 1H NMR spectra were recorded at 300 MHz and 13C
NMR spectra were recorded at 75 MHz in CDCl3 on a Varian VXR
300 spectrometer using TMS as a reference. IR spectra were
recorded on a FTIR Jacso 680 P. TLC analyses were performed on
Macherey-Nagel silica gel pre-coated plastic sheets (0.20 mm).
31.9, 68.3, 112.4, 120.7, 126.6, 127.7, 128.4, 129.6, 130.8, 138.6,
156.0.
4.2.5. 2-Biphenyl 3-phenylpropyl ether 1e
Purified by flash chromatography, light yellow oil, [Found: C,
87.28; H, 7.16. C21H20O requires C, 87.46; H, 6.99]; Rf = 0.80 (petro-
leum ether/EtOAc = 8:2); IR (liquid film) m ;
: 1261, 1236 cmÀ1 1H
NMR (300 MHz, CDCl3): d = 1.94–2.09 (m, 2H, CH2), 2.70 (t,
J = 7.8 Hz, 2H, CH2Ph), 3.96 (t, J = 6.3 Hz, 2H, OCH2), 6.94 (d,
J = 8.1 Hz, 1H, ArH), 7.03 (td, J = 1.2, 6.9 Hz, 1H, ArH), 7.09–7.22
(m, 3H, 3Â ArH), 7.26–7.46 (m, 7H, 7Â ArH), 7.58 (dt, J = 1.2,
7.2 Hz, 2H, 2Â ArH); 13C NMR (75 MHz, CDCl3): d = 30.9, 32.1,
67.2, 112.4, 120.8, 125.8, 126.7, 127.8, 128.3, 128.4, 128.5, 129.6,
130.8, 130.9, 138.6, 141.5, 155.8.
4.2. Synthesis of ethers
4.2.6. 2-Biphenyl 2-octyl ether 1f
Purified by flash chromatography, light yellow oil, [Found: C,
84.89; H, 9.46. C20H26O requires 85.06; H, 9.28]; Rf = 0.70 (petro-
Ethers 1a–1e, rac-1f, (S)-1f, rac-1g, (R)-1g, rac-1h, (S)-1h, rac-1i,
and (R)-1i were synthesized according to an already described
ultrasound stimulated Mitsunobu reaction procedure.2,3 Ether
(R)-1f was synthesized according to a known procedure by the
reaction of (R)-2-octanol with NaH and 2-fluorobiphenyl in
NMP.11 All reaction products were purified by flash chromatogra-
phy and characterized as reported below.
leum ether/EtOAc = 9.5:0.5); IR (liquid film) m ;
: 1261, 1232 cmÀ1
1H NMR (300 MHz, CDCl3): d = 0.86 (t, J = 6.9 Hz, 3H, CH3), 1.08–
1.72 (m, 13H, 1Â CH3 + 5Â CH2), 4.30 (q, J = 6 Hz, 1H, CHO),
6.94–7.04 (m, 2H, 2Â ArH), 7.24–7.42 (m, 5H, 5Â ArH), 7.50–7.57
(m, 2H, 2Â ArH); 13C NMR (75 MHz, CDCl3): d = 14.1, 19.5,
22.5, 25.3, 29.2, 31.7, 36.3, 74.5, 114.7, 120.7, 126.5, 127.6, 128.3,
25 = À45.9 (c 1.1, EtOH);
4.2.1. 2-Octyl 1-naphthyl ether 1a15
129.6, 131.0 132.0, 139.0, 155.1; (R)-1f: [
a
]
D
(S)-1f: [
a]
25 = +46.6 (c 1.0, EtOH).
Purified by flash chromatography, pale yellow oil; Rf = 0.70
D
(petroleum ether/EtOAc = 9.5:0.5). IR (liquid film) m: 3052, 2929,
4.2.7. 2-Biphenyl 3-octyl ether 1g
1267 cmÀ1; 1H NMR (300 MHz, CDCl3): d = 0.79–0.90 (m, 3H, CH3),
1.19–1.95 (m, 13H, 5Â CH2, CH3), 4.57 (sex, J = 6 Hz, 1H, CH), 6.81
(dd, J = 0.3, 6.9 Hz, 1H, ArH), 7.31–7.52 (m, 4H, 4Â ArH), 7.73–7.82
(m, 1H, ArH), 8.24–8.34 (m, 1H, ArH); 13C NMR (75 MHz, CDCl3):
d = 14.1, 19.7, 22.6, 25.6, 29.4, 31.8, 36.6, 74.0, 105.9, 119.7, 122.4,
124.9, 125.9, 126.2, 126.5, 127.4, 134.8, 153.9.
Purified by flash chromatography, light yellow oil, [Found: C,
84.81; H, 9.52. C20H26O requires 85.06; H, 9.28]; Rf = 0.73 (petro-
leum ether/EtOAc = 8:2); IR (liquid film) m ;
: 1259, 1230 cmÀ1 1H
NMR (300 MHz, CDCl3): d = 0.85 (t, J = 7.5 Hz, 6H, 2Â CH3), 1.12–
1.66 (m, 10H, 5Â CH2), 4.16 (pent, J = 5.7 Hz, 1H, CH), 6.92–7.04
(m, 2H, 2Â ArH), 7.26–7.42 (m, 5H, 5Â ArH), 7.50–7.58 (m, 2H,
2Â ArH); 13C NMR (75 MHz, CDCl3): d = 9.4, 14.0, 22.5, 24.8, 26.1,
31.9, 32.8, 79.4, 114.2, 120.5, 126.5, 127.6, 128.3, 129.6, 131.0,
4.2.2. 2-Octyl 2-naphthyl ether 1b15
Purified by flash chromatography, pale yellow oil; Rf = 0.89
132.0, 139.0, 155.4; (R)-1g: [
a]
25 = À26.0 (c 1.2, EtOH).
D
(petroleum ether/EtOAc = 7:3). IR (liquid film)
m:
3058,
2929, 1214 cmÀ1 1H NMR (300 MHz, CDCl3): d = 0.80–0.91 (m,
;
4.2.8. 2,6-Diphenylphenyl 2-octyl ether 1h2
3H, CH3), 1.26–1.80 (m, 13H, 5Â CH2, CH3), 4.51 (sex, 1H, J = 6 Hz,
CH), 7.10–7.15 (m, 2H, 2Â ArH), 7.32 (t, J = 6.6 Hz, 1H, ArH), 7.41
(t, J = 6.9 Hz, 1H, ArH), 7.66–7.78 (m, 3H, 3Â ArH); 13C NMR
(75 MHz, CDCl3): d = 14.1, 19.6, 22.6, 25.5, 29.3, 31.8, 36.5, 73.8,
108.3, 119.8, 123.4, 126.2, 126.6, 127.6, 128.8, 129.4, 134.7, 156.1.
Purified by flash chromatography, light yellow oil [Found: C,
86.95; H, 8.61. C26H30O requires C, 87.10; H, 8.43]; Rf = 0.63 (petro-
leum ether/EtOAc = 9.5:0.5); IR (liquid film) m ;
: 2348, 1222 cmÀ1
1H NMR (300 MHz, CDCl3 d = 0.52 (d, J = 6.3 Hz, 3H, CH3), 0.70–
1.30 (m, 13H, 5Â CH2, CH3), 3.35 (quint, J = 6.3 Hz, 1H, CH), 7.21
(dd, J = 8.1, 6.6 Hz, 1H, ArH), 7.27–7.44 (m, 8H, 8Â ArH), 7.58–
7.64 (m, 4H, 4Â 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,
4.2.3. 4-Biphenyl decyl ether 1c
Purified by flash chromatography, white powder (mp 67–70 °C),
[Found: C, 84.94; H, 9.89. C22H30O requires C, 85.11; H, 9.74];
136.9, 139.6, 152.6; (S)-1h: [
a
]
D
25 = À10.2 (c 1.0, EtOH).
Rf = 0.73 (petroleum ether/EtOAc = 8:2); IR (nujol)
m: 1288, 1270,
1257 cmÀ1 1H NMR (300 MHz, CDCl3): d = 0.90 (t, J = 7.2 Hz, 3H,
;
4.2.9. 2,6-Diphenylphenyl 3-octyl ether 1i
CH3), 1.20–1.50 (m, 14H, 7Â CH2), 1.81 (quint, J = 8.1 Hz, 2H, CH2),
4.00 (t, J = 6.6 Hz, 2H, OCH2), 6.94–7.10 (m, 2H, 2Â ArH), 7.30 (tt,
J = 1.2, 7.2 Hz, 1H, ArH), 7.38–7.46 (m, 2H, 2Â ArH), 7.50–7.60 (m,
4H, 4Â ArH); 13C NMR (75 MHz, CDCl3): d = 14.1, 22.7, 26.1, 29.3,
29.3, 29.4, 29.6, 31.9, 68.1, 114.8, 126.6, 126.7, 128.1, 128.7,
133.5, 140.9, 158.7.
Purified by flash chromatography, light yellow oil, [Found: C,
86.87; H, 8.79. C26H30O requires C, 87.10; H, 8.43]; Rf = 0.86 (petro-
leum ether/EtOAc = 8:2); IR (liquid film) m ;
: 3056, 2931, 1216 cmÀ1
1H NMR (300 MHz, CDCl3): d = 0.37 (t, J = 7.5 Hz, 3H, CH3), 0.70–
1.15 (m, 13H, 5Â CH2, CH3), 3.24 (quint, J = 5.1 Hz, 1H, CH), 7.19
(dd, J = 1.5, 6.9 Hz, 1H, ArH), 7.28–7.36 (m, 4H, 4Â ArH), 7.37–
7.45 (m, 4H, 4Â ArH), 7.56–7.63 (m, 4H, 4Â ArH); 13C NMR
(75 MHz, CDCl3): d = 8.7, 14.0, 22.5, 24.2, 24.9, 31.7, 31.8, 82.8,
123.4, 126.8, 127.9, 129.8, 130.1, 136.8, 139.7, 152.7; (R)-1i:
4.2.4. 2-Biphenyl decyl ether 1d
Purified by flash chromatography, pale yellow oil, [Found: C,
84.90; H, 9.81. C22H30O requires C, 85.11; H, 9.74]; Rf = 0.73
[a]
25 = +13.0 (c 1.2, EtOH).
D
(petroleum ether/EtOAc = 8:2); IR (liquid film)
m
:
1261,
1234 cmÀ1 1H NMR (300 MHz, CDCl3): d = 0.88 (t, J = 7.2 Hz, 3H,
;
4.3. Reductive cleavage reactions
CH3), 1.15–1.45 (m, 14H, 7Â CH2), 1.71 (quint, J = 8.1 Hz, 2H,
CH2), 3.95 (t, J = 6.6 Hz, 2H, OCH2), 6.95–7.05 (m, 2H, 2Â ArH),
7.24–7.43 (m, 5H, 5Â ArH), 7.52–7.58 (m, 2H, 2Â ArH); 13C NMR
(75 MHz, CDCl3): d = 14.1, 22.7, 26.0, 29.1, 29.2, 29.3, 29.5, 29.6,
4.3.1. General procedure
A suspension of freshly cut Na metal (76 mg, 3.3 mg atom) in
dry THF (10 mL) was prepared under dry Ar in a two-necked flask

1554
U. Azzena et al. / Tetrahedron: Asymmetry 25 (2014) 1550–1554
equipped with a reflux condenser and magnetic stirrer, and chilled
at 0 °C. To this suspension was added dropwise a solution of the
appropriate substrate (1.5 mmol) dissolved in THF (5 mL). The
mixture was stirred vigorously at rt for several hours (Table 1)
until the disappearance of the starting material (TLC). The mixture
was cooled at 0 °C and quenched by the dropwise addition of H2O
(10 mL) (CAUTION!). After stirring at rt for 1 h, the mixture was
extracted with Et2O (4 Â 10 mL), the organic layers were com-
bined, washed with brine (10 mL) and dried (Na2SO4). Quenching
with PhCOCl was performed by adding the electrophile (0.21 mL,
1.8 mmol, 1.2 equiv) to the reduction mixture chilled at 0 °C, fol-
lowed by stirring at the same temperature during 1 h, quenching
with H2O (5 mL) and worked-up as described above. Reaction
products were purified by flash chromatography and characterized
as follows.
the Consortium CINMPIS and by the National Project FIRB—Futuro
in Ricerca (code: RBFR083M5N).
References
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4.3.2. 2-Octanol 2
1H NMR (300 MHz, CDCl3): d = 0.84–0.88 (m, 3H, CH3), 1.19 (d,
J = 6.3 Hz, 3H, CH3), 1.22–1.51 (m, 11H, 5Â CH2 + OH), 3.75–3.83
(m, 1H, CHO), identical with a commercially available sample;
(S)-2: [
a]
25 = +9.8 (c 1.0, EtOH); (R)-2: [
a
]
D
25 = À9.65 (c 1.0, EtOH).
D
4.3.3. 3-Octanol 3
1H NMR (300 MHz, CDCl3): d = 0.86–0.97 (m, 6H), 1.25–1.56 (m,
11H, 5Â CH2, OH), 3.50–3.53 (m, 1H, CHO), identical with a com-
mercially available sample; (R)-3: [
a
]
D
25 = À12.4 (c 1.0, EtOH).
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4.3.4. Octan-2-yl benzoate 416
Authentic samples of racemic 4, (R)-4 and (S)-4 were prepared
by the reaction of the corresponding commercially available alco-
hol with PhCOCl and Et3N in CH2Cl2; 1H NMR (300 MHz, CDCl3):
d = 0.86–0.90 (m, 3H, CH3), 1.24–1.43 (m, 11H, 1Â CH3, 4Â CH2),
1.54–1.68 (m, 2H, CH2), 5.15 (sex, J = 6.6 Hz, 1H, CHO), 7.41–7.47
(m, 2H, 2Â ArH), 7.55 (tt, J = 7.2, 2.4 Hz, 1H, ArH), 8.02–8.07 (m,
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2H, 2Â ArH); (R)-4:
[
a]
D
25 = À33.1 (c 0.2, CH2Cl2); (S)-4:
[a]
D
25 = +32.9 (c 0.2, CH2Cl2).
4.3.5. Octan-3-yl benzoate 517
Authentic samples of racemic 5 and (S)-5 were prepared by the
reaction of the corresponding commercially available alcohol with
PhCOCl and Et3N in CH2Cl2; 1H NMR (300 MHz, CDCl3): d = 0.84–
0.90 (m, 3H, CH3), 0.95 (t, J = 7.2 Hz, CH3), 1.25–1.4 (m, 6H, 1Â
CH3, 3Â CH2), 1.60–1.78 (m, 4H, 2Â CH2), 5.08 (quint, J = 6.9 Hz,
1H, CHO), 7.41–7.48 (m. 2H, 2Â ArH), 7.56 (tt, J = 7.2, 2.1 Hz, 1H,
14. For recent examples, see (a) Rudzevich, Y.; Rudzevic, V.; Böhmer, V. Chem. Eur.
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Y.; Blascovich, M. A.; Sebti, S. M.; Hamilton, A. D. J. Med. Chem. 2002, 45, 177–
188.
ArH), 8.03–8.09 (m, 2H, 2Â ArH); (R)-5: [
a]
25 = À7.8 (c 0.3, CHCl3);
D
(S)-5: [
a]
25 = +8.0 (c 0.3, CHCl3).
D
15. Hartwig, J. F.; Sevov, C. S. J. Am. Chem. Soc. 2013, 135, 9303–9306.
16. Konrad, T. M.; Leitner, W.; Schmitz, P.; Francio, G. Chem. Eur. J. 2013, 19,
13299–13303.
Acknowledgments
17. Node, M.; Nishide, K.; Shigeta, Y.; Shiraki, H.; Obata, K. J. Am. Chem. Soc. 2000,
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The authors would like to acknowledge Catarina Soares Peixoto
for her contribution. This work was supported by the Regione
Autonoma della Sardegna, L. 07/09/2007 (code CRP-59740), by