Reductive lithiation of alkoxy-substituted benzyl methyl ethers and connection with cross-coupling reactions

Article abstract of DOI:10.1016/j.tet.2003.11.085

2-and 4-Ethoxymethoxybenzyl methyl ethers were employied as useful starting materials for the synthesis of 1,2- or 1,4-dicarbo-substituted benzenes. The proposed reaction sequence involves connection between the reductive lithiation of benzyl alkyl ethers and the metal-catalyzed cross-coupling reaction of aromatic triflates.

Full text of DOI:10.1016/j.tet.2003.11.085

Tetrahedron 60 (2004) 1617–1623
Reductive lithiation of alkoxy-substituted benzyl methyl ethers
and connection with cross-coupling reactions
*
Ugo Azzena, Giovanna Dettori, Roberta Pireddu and Luisa Pisano
`
Dipartimento di Chimica, Universita di Sassari, via Vienna 2, I-07100 Sassari, Italy
Received 26 September 2003; revised 3 November 2003; accepted 28 November 2003
Abstract—2-and 4-Ethoxymethoxybenzyl methyl ethers were employied as useful starting materials for the synthesis of 1,2- or 1,4-dicarbo-
substituted benzenes. The proposed reaction sequence involves connection between the reductive lithiation of benzyl alkyl ethers and the
metal-catalyzed cross-coupling reaction of aromatic triflates.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
lithiation of acetals of 2- and 4-hydroxy-substituted benzyl
ethers, planning to complete the reaction sequence through
successive hydrolysis of the acetal group and transformation
of the resulting phenols into the corresponding triflates,
followed by metal-catalyzed cross-coupling reaction of the
last compounds (Scheme 1).
The arene-catalyzed reductive lithiation of benzyl alkyl
ethers is a highly regioselective reaction finding application
in the generation of a wide array of benzyllithium
organometals.1–5 Interestingly, the presence of strong
electron donor substituents on the aromatic ring does not
affect the efficiency of this procedure.1,4 Indeed, this
reaction shows unique features in the generation of stable
solutions of methoxy-substituted benzyllithium derivatives
both in terms of regioselectivity and mildness of reaction
conditions.6–8
2. Results and discussion
2.1. Synthesis of starting materials
The stability of acetal-type phenolic protecting groups, like
the methoxymethyl (MOM), towards reduction with alkali
metals, has been seldom investigated. We already reported15
that this type of protecting groups are stable towards
reduction with Na metal in aprotic solvents, whilst it was
previously reported that, under similar conditions, phenolic
acetals cleave with relatively ease, e.g. more easily than the
corresponding methyl ethers.16 In the present work, we
investigated the stability, under arene-catalyzed lithiation
conditions, of the ethoxymethyl (EOM) group. This
protecting group shows distinct advantages over the above
mentioned MOM group. Indeed, phenolic ethoxymethyl
With the aim to expand the synthetic utility of this reaction,
and following our interest in the development of highly
regioselective strategies for the synthesis of polysubstituted
aromatic compounds, we developed a synthetic protocol
leading to the synthesis of dicarbo-substituted benzenes by a
reaction sequence connecting our reductive lithiation
procedure to well known and versatile reactions, i.e.
metal-catalyzed cross-coupling reactions of aromatic tri-
flates.9–14
To achieve this result, we investigated the reductive
Scheme 1. (i) Reductive lithiation and reaction with an electrophile; (ii) acidic hydrolysis and reaction with (Tf)2O; (iii) metal catalyzed cross-coupling
reaction.
Keywords: Ethers; Reduction; Lithiation; Cross-coupling.
*
Corresponding author. Tel.: þ39079229549; fax: þ39079229559; e-mail address: ugo@uniss.it
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.11.085

1618
U. Azzena et al. / Tetrahedron 60 (2004) 1617–1623
ethers can be easily synthesized reacting phenolates with
chloromethyl ethyl ether, which is a cheaper, and much less
toxic reagent, than the corresponding chloromethyl methyl
ether.
2.2. Reductive metalation reactions
Reductive metalations of ethers 1 and 2 were carried out
under Ar with an excess of Li wire in the presence of a
catalytic amount of naphthalene in tetrahydrofuran (THF);
the results are reported in Table 1 (Scheme 3).
Accordingly, deprotonation of easily available 2- and
4-hydroxybenzyl methyl ether17 with NaH in dry THF,
followed by reaction with chloromethyl ethyl ether, afforded
2- and 4-ethoxymethoxybenzyl methyl ether, 1 and 2,
respectively, in good isolated yields (Scheme 2).
Reaction of a 0.15 M THF solution of ether 1 with 5 equiv.
of Li metal in the presence of a catalytic amount of
naphthalene (10 mol%) at 0 8C during 1.2 h, furnished a
deep red reaction mixture which, upon aqueous work-up,
afforded 1-ethoxymethoxy-2-methylbenzene, 3, in quanti-
tative yield. It is worth noting that we did not observe
formation of products of cleavage of the acetal-protecting
group, thus showing the stability of the EOM group under
reductive electron transfer conditions (Table 1, entry 1).
Under these conditions, quantitative formation of an
intermediate benzyllithium derivative was evidenced as
quenching the reduction mixtures with D2O (Table 1,
entry 2). Similar results were obtained employing di-tert-
butylbiphenyl (DBB), instead of naphthalene, as an
homogeneous electron transfer carrier (not reported in the
Table).
Scheme 2. Synthesis of ethoxymethyl ethers of 2-and 4-hydroxybenzyl
methyl ether. EOM¼CH3CH2OCH2.
Trapping of this intermediate with acetone or benzaldehyde
afforded the corresponding 2-substituted homobenzylic
alcohols,18 4 and 5, in satisfactory isolated yields (Table
1, entries 3 and 4).
Furthermore, the organometallic intermediate was success-
fully trapped with primary or secondary alkyl halides,
affording the corresponding 2-alkylated ethoxymethoxy-
benzenes 6–8 in good yields (Table 1, entries 5–7); these
compounds were not isolated, but directly hydrolysed to the
corresponding phenols (see below).
Similar results were obtained in the reductive lithiation of
ether 2: reduction of a 0.15 M solution of this substrate with
5 equiv. of Li metal and a 10 mol% of naphtahlene was
accomplished within 2.0 h at 210 8C, affording 1-ethoxy-
methoxy-4-methylbenzene, 9, in quantitative yield (Table 1,
entry 8). It is worth noting that reductive cleavage of ether 2
at 0 8C, under otherwise identical reaction conditions,
afforded minor amounts (5–10%) of unindefied by
products. Intermediate formation of an organolithium
reagent was evidenced by quenching the reduction mixture
with D2O (Table 1, entry 9), and this reactive intermediate
was efficiently trapped with benzaldehyde, decylbromide,
and 2-bromopropane, to afford the corresponding 4-substi-
tuted ethoxymethoxybenzenes 10–12 in good yields
(Table 1, entries 10–12); ether 12 was not isolated, but
directly hydrolysed to the corresponding phenol (see below).
Scheme 3. Reductive lithiation and reaction with electrophiles of ethers
1 and 2. 3, 9: E¼H or D; 4: E¼(CH3)2COH; 5, 10: E¼PhCHOH; 6:
E¼n-C4H9; 7: E¼n-C12H25; 8, 12: E¼(CH3)2CH; 11, E¼n-C10H21
.
Table 1. Reductive lithiation of ethers 1 and 2, and reaction with
electrophilesa
Entry Compoud T (8C) t (h)
EX
Product, E¼
Yield
(%)b
1
2
3
4
5
6
7
8
1
1
1
1
1
1
1
2
2
2
2
2
0
0
0
0
0
0
0
1.2
1.2
1.2
1.2
1.2
1.2
1.2
H2O
D2O
(CH3)2COd 4, (CH3)2COH
3, H
3d, D
.95c
.95c
56
PhCHO
5, PhCHOH
6, n-BuBr
n-C12H25Br 7, n-C12H25
67
n-BuBr
61e
68e
56e
.95c
92c
70
i-PrBr
H2O
D2O
8, i-Pr
9, H
9d, D
10, PhCHOH
210 2.0
210 2.0
210 2.0
210 2.0
210 2.0
2.3. Synthesis of triflates
9
10
11
12
PhCHO
n-C10H21Br 11, n-C10H21
i-PrBr 12, i-Pr
85
72e
Mild acidic hydrolysis of compounds 6–8 and 11–12
(0.6 M HCl in MeOH, rt) allowed the removal of the
protecting group, and the corresponding phenols 13–17
were obtained in almost quantitative yield. According to a
known procedure,14 reaction of phenols 13–17 with
trifluoromethanesulfonic anhydride in pyridine afforded
triflates 18 (69%), 19 (76%), 20 (70%), 21 (76%),
respectively, in good isolated yields (Scheme 4).
a
All reactions were run in the presence of 5 equiv. of Li metal and a
catalytic amount of naphthalene (10 mol%).
Isolated yield, unless otherwise indicated.
As determined by H NMR spectroscopy.
The electrophile was added at 280 8C.
b
c
d
e
1
Yield determined on the corresponding phenol, after acidic hydrolysis of
the acetal moiety.

U. Azzena et al. / Tetrahedron 60 (2004) 1617–1623
1619
Scheme 4. Synthesis of phenols 13–17, and triflates 18–21. 6, 13: E¼n-C4H9; 7, 14, 18: E¼n-C12H25; 8, 12, 15, 17, 19, 21: E¼CH(CH3)2; 11, 16, 20:
E¼n-C10H21
.
Table 2. Cross-coupling reactions
Entry
Compound
Catalyst (mol%)
RM
Solvent
DMF
THF/NMP
DME
DMF
T (8C)
t (h)
Product [yield (%)]a
1
2
3
4
18
19
20
21
PdCl2(PPh3)2 (5)b
Fe(acac)3 (10)
PhCCH
90
20
85
90
16
16
5
22, 70
23, 54
24, 75
25, 79
C6H13MgBr
PhB(OH)2
PhCCH
Pd(PPh3)4 (5)b
PdCl2(PPh3)2 (5)b
16
a
Isolated yield.
The catalyst was added in two portions (see Section 4).
b
3. Conclusions
Our results clearly show that reductive metalation of benzyl
alkyl ethers is a particularly mild and practical approach to
the generation of stable solutions of alkoxy-substituted
benzyllithium derivatives. The observed stability of the
EOM group under reductive electron transfer conditions,
allowed to develop a synthetic protocol connecting our
reductive metalation procedure with metal-catalyzed cross-
coupling reactions, thus leading to the regioselective
synthesis of 1,2- and 1,4-dicarbo-substituted aromatics,
with satisfactory overall yields.
Scheme 5. Cross-coupling reactions. 18: E¼n-C12H25
; 19, 21:
E¼CH(CH3)2; 20: E¼n-C10H21; 22: E¼n-C12H25, R¼PhCC, 70%; 23:
E¼CH(CH3)2, R¼n-C6H13, 54%; 24: E¼n-C10H21, R¼Ph, 75%; 25:
E¼CH(CH3)2; R¼PhCC, 79%.
4. Experimental
4.1. General
2.4. Cross-coupling reactions
To test the flexibility of the proposed methodology, triflates
18–21 were allowed to react with different coupling
reagents in the presence of a Pd or a Fe catalyst. Reaction
conditions and yields are reported in Table 2 (Scheme 5).
Boiling and melting points are uncorrected; the air bath
temperature on bulb-to-bulb distillation are given as boiling
points. Starting materials were of the highest commercial
quality and were purified by distillation or recrystallization
immediately prior to use. D2O was 99.8% isotopic purity.
THF was distilled from Na/K alloy under N2 immediately
prior to use. 1H NMR spectra were recorded at 300 MHz and
13C NMR spectra were recorded at 75 MHz in CDCl3
(unless otherwise indicated) with SiMe4 as internal
standard. CDCl3 for recording spectra of EOM-derivatives
was stored over K2CO3 in the refrigerator. Deuterium
Good yields were obtained in cross-coupling reactions
involving Pd-catalysed coupling reaction of triflates 18 and
21 with phenylacetylene,19 as well as of triflate 20 with
phenyl boronic acid20 according to known procedures
(Table 2, entries 1, 3 and 4, respectively); as a variation,
however, we found that adding the catalyst to the reaction
mixtures in two successive portions (see Section 4),
significantly improved the yields of these reactions.
1
incorporation was calculated by monitoring the H NMR
spectra of crude reaction mixtures, and comparing the
integration of the signal corresponding to protons in the
arylmethyl position with that of known signals. Resonances
of the CHD protons are usually shifted 0.02–0.04 ppm (d)
upfield relative to the resonances of the corresponding CH2
protons; the resonances of the arylmethyl CHD carbons
Furthermore, a satisfactory yield was obtained coupling
triflate 19 with C6H13MgBr in the presence of 10 mol%
of Fe(acac)3 in THF/NMP (Table 2, entry 2), under reac-
tion conditions recently described by Fu¨rstner and
co-workers.9

1620
U. Azzena et al. / Tetrahedron 60 (2004) 1617–1623
appear as triplet (J¼18–20 Hz) shifted 0.3–0.5 ppm (d)
upfield relatively to the corresponding arylmethyl CH2
carbons. IR spectra were recorded on pure samples.
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). Elemental
analyses were performed by the microanalytical laboratory
(1.2 equiv.) in THF (2 mL) was slowly added. After stirring
for 30 min, the mixture was quenched by slow dropwise
addition of H2O (10 mL, caution), the cold bath removed,
and the resulting mixture extracted with Et2O (3£10 mL).
The organic phase was washed with brine (10 mL), dried
(K2CO3) and the solvent evaporated.
`
of the Dipartimento di Chimica, Universita di Sassari.
D2O quenching was performed by slow dropwise addition
of 1 mL of the electrophile, followed by aqueous work-up as
described above.
4.2. Preparation of ethers 1 and 2. General procedure
NaH (1.96 g of a 60% dispersion in mineral oil, 49 mmol)
was placed under dry N2 in a 100 mL two-necked flask
equipped with reflux condenser and magnetic stirrer,
washed with dry THF (3£10 mL), and suspended in dry
THF (30 mL). The mixture was chilled to 0 8C and a
solution of the appropriate methyl benzyl ether (5.7 g,
41 mmol) dissolved in THF (15 mL) was added dropwise.
The resulting mixture was stirred for 4 h at rt. To this
reaction mixture, chilled to 0 8C, a solution of CH3CH2
OCH2Cl (4.6 g, 4.5 mL, 49 mmol), dissolved in 10 mL of
THF, was slowly added. After stirring overnight at rt, the
mixture was quenched by slow dropwise addition of H2O
(20 mL), and the resulting mixture was extracted with Et2O
(3£20 mL). The organic phase was washed brine (10 mL),
dried (K2CO3) and evaporated. Crude products were
purified by distillation, and were characterized as follows.
Compounds 6–8 and 12 were not characterized but directly
hydrolysed to the corresponding phenols. Other products
were characterized as follows.
4.3.1. 1-Ethoxymethoxy-2-methylbenzene, 3. Purified
by flash-chromatography (petroleum ether/AcOEt/Et3N¼
7:3:1), colourless oil; Rf¼0.75 (petroleum ether/AcOEt/
Et3N¼7:3:1); bp 55 8C/1 mm Hg (lit.21 bp 86–87 8C/
8 mm Hg); dH122 (3H, t, J¼6.9 Hz, CH3), 2.23 (3H, s,
ArCH3), 3.72 (2H, q, J¼6.9 Hz, CH2), 5.24 (2H, s, CH2),
6.90 (1H, td, J¼7.5, 1.5 Hz, ArH), 7.03–7.12 (1H, m, ArH),
7.12–7.16 (2H, m, 2£ArH); dC 15.1, 16.3, 64.1, 93.2, 113.9,
121.4, 126.8, 130.7, 157.9.
4.3.2. 1-(2-Ethoxymethoxyphenyl)-2-methylpropan-2-ol,
4. Purified by flash-chromatography (CH2Cl2/AcOEt/
Et3N¼9.8:0.2:0.1), colourless oil. (Found: C, 69.43; H,
9.12; C13H20O3 requires C, 69.60; H, 9.00); Rf¼0.30
(CH2Cl2/AcOEt/Et3N¼9.8:0.2:0.1); bp 105 8C/1 mm Hg;
nmax 3420 cm21; dH 1.23 (6H, s, 2£CH3), 1.23 (3H, t, J¼
7.2 Hz, CH3), 2.39 (1H, bs, OH), 2.87 (2H, s, ArCH2), 3.72
(2H, q, J¼7.2 Hz, CH2), 5.25 (2H, s, OCH2O), 6.93–6.99
(1H, m, ArH), 7.13–7.23 (3H, m, 3£ArH); dC 15.1, 29.4,
43.7, 64.5, 71.6, 93.5, 114.3, 121.6, 127.1, 127.9, 132.5,
155.8.
4.2.1. 1-Ethoxymethoxy-2-methoxymethylbenzene, 1.
6.2 g, 32 mmol, 77%. Colourless oil, bp 125–128 8C/
1 mm Hg. (Found: C, 67.12; H, 8.47; C11H16O3 requires
C, 67.31; H, 8.23); dH (CD3OD) 1.23 (3H, t, J¼7.2 Hz,
CH3), 3.42 (3H, s, OCH3), 3.76 (2H, q, J¼7.2 Hz, OCH2),
4.53 (2H, s, ArCH2), 5.29 (2H, s, OCH2O), 7.01 (1H, td,
J¼7.5, 1.2 Hz, ArH), 7.16 (1H, dd, J¼7.5, 1.2 Hz, ArH),
7.27 (1H, td, J¼7.5, 1.5 Hz, ArH), 7.37 (1H, dd, J¼7.5,
1.5 Hz, ArH); dC (DMSO) 6.0, 48.9, 55.8, 61.1, 84.8, 105.7,
113.0, 118.7, 120.4, 120.9, 147.1.
4.3.3. 2-(2-Ethoxymethoxyphenyl)-1-phenylethanol, 5.
Purified by flash-chromatography (CH2Cl2/AcOEt/Et3N¼
9:1:0.1), colourless oil. (Found: C, 74.76; H, 7.63;
C17H20O3 requires C, 74.97; H, 7.40); Rf¼0.73 (CH2Cl2/
4.2.2. 1-Ethoxymethoxy-4-methoxymethylbenzene, 2.
6.8 g, 35 mmol, 85%. Colourless oil, bp 110–113 8C/
1 mm Hg. (Found: C, 67.09; H, 8.50; C11H16O3 requires
C, 67.31; H, 8.23); dH121(3H, t, J¼7.2 Hz, CH3), 3.36
(3H, s, OCH3), 3.72 (2H, q, J¼7.2 Hz, OCH2), 4.39 (2H, s,
ArCH2), 5.22 (2H, s, OCH2O), 6.98–7.05 (2H, m, 2£ArH),
7.23–7.28 (2H, m, 2£ArH); dC 14.7, 53.3, 60.1, 77.7, 97.8,
114.1, 128.6, 129.5, 161.3.
AcOEt/Et3N¼9:1:0.1); bp 160 8C/1 mm Hg; nmax 3410 cm21
;
dH 1.26 (3H, t, J¼6.9 Hz, CH3), 2.43 (1H, bs, OH), 3.01
(1H, dd, J¼13.7, 8.4 Hz, ArCH), 3.14 (1H, dd, J¼13.7,
4.2 Hz, ArCH), 3.75 (2H, q, J¼6.9 Hz, CH2), 4.98 (1H, dd,
J¼8.4, 4.2 Hz, ArCHO), 5.24 (1H, d, J¼6.9 Hz, OCHO),
5.27 (1H, d, J¼6.9 Hz, OCHO), 6.94 (1H, td, J¼7.5, 1.5 Hz,
ArH), 7.09–7.16 (2H, m, 2£ArH), 7.19–7.40 (6H, m,
6£ArH); dC 15.1, 41.0, 64.4, 74.3, 93.3, 114.1, 121.7, 125.7,
127.2, 127.3, 128.0, 128.2, 131.5, 144.4, 155.6.
4.3. Reductive cleavage of ethers 1 and 2, and reaction
with electrophiles. General procedure
150 mg of Li wire (22 mg atom, 10 equiv.) was placed
under Ar in a 50 mL two-necked flask equipped with reflux
condenser and magnetic stirrer, and suspended in THF
(5 mL). A catalytic amount of naphthalene (28 mg,
0.22 mmol, 10 mol%) was added to the suspended metal,
each metal piece was cut into 2–3 smaller pieces with a
spatula, and the mixture stirred until a dark green colour
appeared. The mixture was chilled to the reported
temperature (Table 1) and a solution of the appropriate
ether (0.43 g, 2.2 mmol), dissolved in 5 mL of dry THF, was
added dropwise. The mixture was stirred for the reported
time (Table 1), and a solution of the appropriate electrophile
4.3.4. 1-Ethoxymethoxy-4-methylbenzene, 9. Purified by
flash-chromatography (petroleum ether/AcOEt/Et3N¼
8:2:1), colourless oil; Rf¼0.69 (petroleum ether/AcOEt/
Et3N¼8:2:1); bp 70 8C/1 mm Hg (lit.22 bp 78 8C/
4.5 mm Hg); dH121(3H, t, J¼6.8 Hz, CH3), 2.29 (3H, s,
ArCH3), 3.72 (2H, q, J¼6.8 Hz, CH2), 5.18 (2H, s, OCH2O),
6.92–6.96 (2H, m, 2£ArH), 7.06–7.10 (2H, m, 2£ArH).
4.3.5. 2-(4-Ethoxymethoxyphenyl)-1-phenylethanol, 10.
Purified by flash-chromatography (petroleum ether/CH2Cl2/
Et3N¼8:2:0.1), colourless oil. (Found: C, 74.81; H, 7.68;
C17H20O3 requires C, 74.97; H, 7.40); Rf¼0.68 (petroleum

U. Azzena et al. / Tetrahedron 60 (2004) 1617–1623
1621
ether/CH2Cl2/Et3N¼8:2:0.1); nmax 3450 cm21; dH 1.23
(3H, t, J¼6.8 Hz, CH3), 2.03 (1H, bs, OH), 2.92 (1H, dd,
J¼13.6, 8.4 Hz, ArCH), 2.99 (1H, dd, J¼13.6, 4.8 Hz,
ArCH), 3.73 (2H, q, J¼6.8 Hz, CH2), 4.82–4.89 (1H, m,
CHO), 5.20 (2H, s, OCH2O), 6.96–7.01 (2H, m, 2xArH),
7.09–7.14 (2H, m, 2£ArH), 7.26–7.36 (5H, m, 5£ArH); dC
15.1, 45.2, 64.1, 75.3, 93.2, 116.3, 125.9, 127.5, 128.4,
130.4, 131.2, 143.8, 156.2.
9.41); Rf¼0.28 (petroleum ether/AcOEt¼9.5:0.5); nmax
3380 cm21; dH 0.92 (6H, d, J¼6.8 Hz, 2£CH3), 1.26 (1H,
bs, OH), 1.92 (1H, n, J¼6.8 Hz, CH), 2.47 (2H, d, J¼
6.8 Hz, CH2), 6.74–6.76 (1H, dd, J¼8.0, 1.2 Hz, ArH), 6.85
(1H, td, J¼7.6, 1.2 Hz, ArH), 7.05–7.09 (2H, m, ArH).
4.4.4. 4-Undecylphenol, 16. Purified by flash-chromatog-
raphy (petroleum ether/AcOEt/AcOH¼9:1:0.2), colourless
oil which solidifies upon standing, mp 52–54 8C (lit.23 mp
56.5–57 8C); Rf¼0.34 (petroleum ether/AcOEt/AcOH¼
9:1:0.2); nmax 3350 cm21; dH 0.89 (3H, J¼6.8 Hz, CH3),
1.22–1.34 (16H, m, 8£CH2), 1.53–1.62 (2H, m, CH2), 2.53
(2H, t, J¼8.0 Hz, ArCH2), 4.48 (1H, bs, OH), 6.72–6.78
(2H, m, 2£ArH), 7.02–7.07 (2H, m, 2£ArH); dC 14.1, 22.7,
29.2, 29.3, 29.5, 29.6, 29.6, 29.7, 31.7, 31.9, 35.0, 115.0,
129.4, 135.2, 153.3.
4.3.6. 1-Ethoxymethoxy-4-undecylbenzene, 11. Purified
by flash-chromatography (petroleum ether/Et3N¼10:0.1),
colourless oil. (Found: C, 78.12; H, 11.46; C20H34O2
requires C, 78.36; H, 11.20); Rf¼0.27 (petroleum ether/
Et3N¼10:0.1); dH 0.89 (3H, t, J¼6.6 Hz, CH3), 1.23 (3H, t,
J¼7.2 Hz, CH3), 1.24–1.36 (16H, m, 8£CH2), 1.52–1.64
(2H, m, CH2), 2.55 (2H, t, J¼8.1 Hz, ArCH2), 3.74 (2H, q,
J¼7.2 Hz, CH2O), 5.20 (2H, s, OCH2O), 6.94–6.99 (2H, m,
2£ArH), 7.06–7.13 (2H, m, 2£ArH); dC 14.1, 15.1, 22.7,
29.3, 29.3, 29.5, 29.6, 29.6, 29.7, 31.7, 31.9, 35.1, 64.1,
93.3, 116.1, 129.2, 136.3, 155.4.
4.4.5. 4-(2-Methyl)propylphenol, 17. Purified by flash-
chromatography (petroleum ether/AcOEt¼9:1), colourless
oil, which solidifies upon standing; bp 70–75 8C/1 mm Hg
(lit.25 bp 131 8C/20 mm Hg) Rf¼0.28 (petroleum ether/
AcOEt¼9:1); nmax 3420 cm21; dH 0.87 (6H, d, J¼7.2 Hz,
2£CH3), 1.25 (1H, bs, OH), 1.79 (1H, n, J¼7.2 Hz, CH),
2.39 (2H, d, J¼7.2 Hz, ArCH2), 6.72–6.77 (2H, m,
2£ArH), 6.98–7.24 (2H, m, 2£ArH).
4.4. Acidic hydrolysis of acetals 6–8 and 11–12. General
procedure
The appropriate acetal (2–5 mmol) was added under Ar to a
stirred 0.6 M solution of HCl in MeOH [obtained by adding
AcCl (1 mL) to MeOH (20 mL)] chilled to 0 8C. The
mixture was stirred at rt for 2–3 h, until complete
disappearence of the starting material, as determined by
TLC. The mixture was diluted with H2O (20 mL), and the
MeOH evaporated under reduced pressure. The resulting
mixture was extracted with Et2O (4£20 mL), and the
organic phase dried (CaCl2) and evaporated. Crude products
were purified by flash chromatography and characterized as
follows.
4.5. Synthesis of trifluoromethanesulfonates 18–21.
General procedure
These compounds were synthesized according to a general
procedure described in Ref. 14. Crude products were
purified by flash chromatography and characterized as
follows.
4.5.1. 2-Trydecylphenyl trifluoromethanesulfonate, 18.
Purified by flash-chromatography (petroleum ether), colour-
less oil, bp .150 8C/1 mm Hg. (Found: C, 58.57; H, 7.93;
C20H31F3O3S requires C, 58.79; H, 7.66); Rf¼0.48 (petro-
leum ether); dH 0.90 (3H, t, J¼6.6 Hz, CH3), 1.21–1.39
(20H, m, 10£CH2), 1.58–1.65 (2H, m, CH2), 2.71 (2H, t,
J¼8.1 Hz, ArCH2), 7.23–7.36 (4H, m, 4£ArH); dC 14.1,
22.7, 29.3, 29.5, 29.6, 29.6, 29.7, 29.9, 30.0, 31.9, 118.6
(q, J¼318 Hz), 121.2, 127.6, 128.2, 131.2, 135.5, 148.0.
4.4.1. 2-Pentylphenol, 13. Purified by flash-chroma-
tography (petroleum ether/AcOEt/AcOH¼9:1:0.2), colour-
less oil. (Found: C, 80.27; H, 10.06; C11H16O requires C,
80.42; H, 9.82); Rf¼0.34 (petroleum ether/AcOEt/AcOH¼
9:1:0.2); nmax 3410 cm21; dH 0.89 (3H, t, J¼6.9 Hz, CH3),
1.24–1.44 (4H, m, 2£CH2), 1.56–1.70 (2H, m, CH2), 2.59
(2H, t, J¼8.1 Hz, ArCH2), 4.67 (bs, 1H, OH), 6.75 (1H, dd,
J¼7.8, 1.2 Hz, ArH), 6.86 (1H, td, J¼7.5, 1.2 Hz, ArH),
7.04–7.15 (2H, m, 2£ArH); dC 14.0, 22.5, 29.4, 29.8, 31.7,
115.1, 120.7, 126.9, 128.5, 130.1, 153.3.
4.5.2. 2-(2-Methylpropyl)phenyl trifluoromethanesulfo-
nate, 19. Purified by flash-chromatography (petroleum
ether), colourless oil, bp 80–85 8C/1 mm Hg. (Found: C,
46.61; H, 4.91; C11H13F3O3S requires C, 46.80; H, 4.65);
Rf¼0.48 (petroleum ether); dH 0.92 (6H, d, J¼6.6 Hz,
2£CH3), 1.93 (1H, n, J¼6.6 Hz, CH), 2.58 (2H, d, J¼
6.6 Hz, ArCH2), 7.21–7.32 (4H, m, 4£ArH); dC 22.3, 29.1,
39.3, 119.0 (q, J¼318 Hz), 121.2, 127.7, 128.0, 132.1,
134.3, 148.3.
4.4.2. 2-Tridecylphenol, 14. Purified by flash-chroma-
tography (petroleum ether/AcOEt/AcOH¼9:1:0.2), colour-
less oil, which solidifies upon standing; Rf¼0.41 (petroleum
ether/AcOEt/AcOH¼9:1:0.2); mp 43–46 8C (lit.23 42.5–
43 8C); nmax 3380 cm21; dH 0.87 (3H, t, J¼6.9 Hz, CH3),
1.18–1.40 (20H, m, 10£CH2), 1.60 (2H, quint, J¼7.5 Hz,
CH2), 2.59 (2H, t, J¼7.5 Hz, ArCH2), 4.67 (1H, bs, OH),
6.75 (1H, dd, J¼8.1, 0.9 Hz, ArH), 6.86 (1H, td, J¼7.2,
0.9 Hz, ArH), 7.02–7.14 (2H, m, 2£ArH); dC 14.1, 22.7,
29.4, 29.6, 29.6, 29.7, 29.8, 29.9, 31.9, 115.1, 120.7, 127.0,
128.5, 130.1, 153.3.
4.5.3. 4-Undecylphenyl trifluoromethanesulfonate, 20.
Purified by flash-chromatography (petroleum ether), colour-
less oil, bp 125–130 8C/1 mm Hg. (Found: C, 56.64; H,
7.32; C18H27F3O3S requires C, 56.81; H, 7.17); Rf¼0.48
(petroleum ether); dH 0.90 (3H, t, J¼6.6 Hz, CH3), 1.21–
1.39 (16H, m, 8£CH2), 1.58–1.65 (2H, m, CH2), 2.71 (2H,
t, J¼8.1 Hz, ArCH2), 7.23–7.36 (4H, m, 4£ArH); dC 14.1,
22.7, 29.2, 29.3, 29.4, 29.5, 29.6, 29.6, 31.3, 31.9, 35.3,
116.8 (q, J¼318 Hz), 120.9, 130.0, 143.5, 147.6.
4.4.3. 2-(2-Methyl)propylphenol, 15. Purified by flash-
chromatography (petroleum ether/AcOEt¼9.5:0.5), colour-
less oil, bp 45–50 8C/1 mm Hg (lit.24 bp 57 8C/10 mm Hg).
(Found: C, 80.12; H, 9.76; C10H14O requires C, 79.94; H,

1622
U. Azzena et al. / Tetrahedron 60 (2004) 1617–1623
4.5.4. 4-(2-Methylpropyl)phenyl trifluoromethanesulfo-
nate, 21. Purified by flash-chromatography (petroleum
ether), colourless oil, bp 85–90 8C/1 mm Hg. (Found: C,
46.67; H, 4.73; C11H13F3O3S requires C, 46.80; H, 4.65);
Rf¼0.37 (petroleum ether); dH 0.90 (6H, d, J¼6.4 Hz,
2£CH3), 1.85 (1H, n, J¼6.4 Hz, CH), 2.49 (2H, d,
J¼6.4 Hz, ArCH2), 7.14–7.23 (4H, m, 4£ArH); dC 22.2,
30.2, 44.6, 118.7 (q, J¼318 Hz), 120.8, 130.7, 142.3, 147.7;
although this triflate was already described,26 its character-
ization was not reported.
4.6.3. 4-Undecylbiphenyl, 24. The reaction was run
according to a general procedure described in Ref. 19,
starting with 0.396 g (1.04 mmol) of 20 and 0.254 g
(2.1 mmol) of phenylboronic acid in 25 mL of DME, in
the presence of 5 mL of 2 M aqueous Na2CO3, 0.132 g
(3.1 mmol) of LiCl, and 60 mg (0.05 mmol) of Pd(PPh3)4, at
85 8C for 5 h. However, as a variation to the literature
procedure, the catalyst was divided in two portions, and the
second one was added to the reaction mixtures after 2 h
stirring at the reported temperature. The reaction was
worked-up as described in the literature, and the crude
product was recrystallized from EtOH, to afford 0.240 g
(0.78 mmol, 75%) of 24, mp 45–47 8C. (Found: C, 89.21;
H, 10.68; C23H32 requires C, 89.53; H, 10.47); dH 0.88 (3H,
t, J¼6.8 Hz, CH3), 1.24–1.42 (16H, m, 8£CH2), 1.64 (2H,
quint, J¼7.6 Hz), 2.64 (2H, t, J¼7.6 Hz, ArCH2), 7.22–
7.27 (2H, m, 2£ArH), 7.31 (1H, td, J¼7.2, 1.6 Hz, ArH),
7.37–7.44 (2H, m, 2£ArH), 7.49–7.53 (2H, m, 2£ArH),
7.56–7.60 (2H, m, 2£ArH); dC 14.1, 22.7, 29.4, 29.4, 29.5,
29.6, 29.7, 29.7, 31.5, 31.9, 35.6, 126.9, 127.0, 128.7, 128.8,
138.5, 141.2, 142.1.
4.6. Cross-coupling reactions
4.6.1. 1-Phenylethynyl-2-tridecylbenzene, 22. The reac-
tion was run according to a general procedure described in
Ref. 18, starting with 0.16 g (0.38 mmol) of 18 and 58 mg
(0.57 mmol) of phenyl acetylene in 1.2 mL of dry DMF, in
the presence of 0.25 mL (1.7 mmol) of Et3N and 13 mg
(0.019 mmol) of PdCl2(PPh)3, at 90 8C for 16 h. However,
as a variation to the literature procedure, the catalyst was
divided in two portions, and the second one was added to the
reaction mixtures after 2 h stirring at the reported tempera-
ture. The reaction was worked-up as described in the
literature, and the crude product purified by flash chroma-
tography (petroleum ether), to afford 97 mg (0.27 mmol,
70%) of 22, as a colourless oil. (Found: C, 90.08; H, 10.36;
C27H36 requires C, 89.92; H, 10.08); Rf¼0.54 (petroleum
ether); dH 0.90 (3H, t, J¼6.9 Hz, CH3), 1.18–1.42 (20H,
m, 10£CH2), 1.62–1.76 (2H, m, CH2), 2.86 (2H, t, J¼
7.8 Hz, ArCH2), 7.15–7.26 (3H, m, 3£ArH), 7.30–7.40
(3H, m, 3£ArH), 7.47–7.55 (3H, m, 3£ArH); dC 14.1,
22.7, 29.4, 29.6, 29.6, 29.7, 29.7, 30.8, 31.9, 34.8, 88.4,
92.7, 122.5, 123.6, 125.6, 128.1, 128.3, 128.8, 131.4, 132.1,
145.1.
4.6.4. 1-Phenylethynyl-4-(20-methyl)propylbenzene, 25.
The reaction was run according to a general procedure
described in Ref. 18, starting with 0.217 g (0.77 mmol) of
21 and 0.118 g (1.16 mmol) of phenyl acetylene in 2.5 mL
of dry DMF, in the presence of 0.50 mL (3.5 mmol) of Et3N
and 27 mg (0.038 mmol) of PdCl2(PPh)3, at 90 8C for 16 h.
However, as a variation to the literature procedure, the
catalyst was divided in two portions, and the second one
was added to the reaction mixtures after 2 h stirring at
the reported temperature. The reaction was worked-up as
described in the literature, and the crude product purified by
flash chromatography (petroleum ether), to afford 0.142 g
(0.61 mmol, 79%) of 25, as a colourless oil. (Found: C,
91.97; H, 7.89; C18H18 requires C, 92.24; H, 7.76); Rf¼0.43
(petroleum ether); dH 0.90 (6H, d, J¼6.8 Hz, 2£CH3), 1.86
(1H, n, J¼6.8 Hz, CH), 2.47 (2H, d, J¼6.8 Hz, CH2), 7.10–
7.14 (2H, m, 2£ArH), 7.30–7.36 (3H, m, 3£ArH), 7.42–
7.46 (2H, m, 2£ArH), 7.50–7.55 (2H, m, 2£ArH); dC 22.3,
30.2, 45.3, 88.8, 89.6, 120.4, 123.5, 128.0, 128.3, 129.1,
131.4, 131.5, 142.2.
4.6.2. 1-Hexyl-2-(20-methyl)propylbenzene, 23. The
described procedure is a variation of a general one described
in Ref. 9. A carefully dried two-necked flask is charged
under Ar with 0.20 g (0.71 mmol) of 19, 12 mg
(0.035 mmol) of Fe(acac)3, 5 mL of THF and 0.4 mL of
NMP. The red reaction mixture was chilled to 0 8C and
0.43 mL (0.86 mmol) of a 2 M solution of C6H13MgBr in
Et2O were added dropwise, causing an immediate change
from red to dark brown. The reaction was allowed to warm
to rt under vigorous stirring, whilst monitored by tlc. After
3 h stirring, 12 mg (0.035 mmol) of Fe(acac)3 and 0.43 mL
(0.86 mmol) of a 2 M solution of C6H13MgBr in Et2O were
successively added, and the resulting mixture was stirred
overnight at rt. The mixture was diluted with Et2O (10 mL),
chilled to 0 8C and quenched by dropwise addition of 1 M
HCl (10 mL). The resulting mixture was extracted with
Et2O (3£10 mL), and the collected organic phases were
washed with H2O (20 mL), dried (CaCl2) and the solvent
evaporated. The residue was purified by flash chromato-
graphy (petroleum ether), to afford 84 mg (0.38 mmol,
54%) of 23, as a colourless oil. (Found: C, 87.67; H, 12.31;
C16H26 requires C, 87.98; H, 12.02); Rf¼0.78 (petroleum
ether); dH 0.89 (3H, t, J¼6.0 Hz), 0.92 (6H, d, J¼7.2 Hz,
2£CH3), 1.20–1.42 (6H, m, 3£CH2), 1.52–1.60 (2H, m,
CH2), 1.84 (1H, n, J¼7.2 Hz, CH), 2.48 (2H, d, J¼7.2 Hz,
ArCH2), 2.56–2.61 (2H, m, ArCH2), 7.08–7.16 (4H, m,
4£ArH); dC 14.1, 22.6, 29.5, 29.7, 29.8, 31.3, 31.8, 32.7,
41.9, 125.3, 125.7, 129.0, 130.1, 139.2, 141.0.
References and notes
1. Azzena, U.; Carta, S.; Melloni, G.; Sechi, A. Tetrahedron
1997, 53, 16205–16212.
2. Azzena, U.; Pilo, L.; Piras, E. Tetrahedron 2000, 56,
3775–3780.
3. Arrica, M. A.; Azzena, U.; Pilo, L.; Piras, E. Tetrahedron Lett.
2002, 43, 5137–5139.
4. Azzena, U.; Dettori, G.; Idini, M. V.; Pisano, L.; Sechi, G.
Appl. Organomet. Chem. 2003, 17, 851–855.
5. For recent reviews on the arene-catalyzed reductive lithiation
procedure, see: Najera, C.; Yus, M. Curr. Org. Chem. 2003, 7,
´
867–926. Yus, M. Synlett 2001, 1197–1205. Ramon, D. J.;
Yus, M. Eur. J. Org. Chem. 2000, 225–238. For a recent paper
on the mechanism of this reaction, see: Yus, M.; Herrera, R. P.;
Guijarro, A. Chem. Eur. J. 2002, 8, 2574–2584.
6. Reductive lithiation of methoxy-substituted benzylic chlorides:
Smith, K.; Hou, D. J. Chem. Soc., Perkin Trans. 1 1995,

U. Azzena et al. / Tetrahedron 60 (2004) 1617–1623
1623
´
185–186, and references therein. see also: Gomez, C.; Huerta,
F. F.; Yus, M. Tetrahedron 1998, 54, 1853–1866.
7. Reductive lithiation of alkoxy-substituted trimethylsilyl ethers
18. For a recent synthesis of 2-hydroxy-substituted homobenzylic
alcohols by the reductive lithiation of benzo-1,3-dioxanes, see:
Choudhury, P. K.; Almena, J.; Foubelo, F.; Yus, M.
Tetrahedron 1997, 53, 17373–17382.
´
of benzylic alcohols: Alonso, E.; Ramon, D. J.; Yus, M. J. Org.
Chem. 1997, 62, 417–421, and references therein.
19. Chen, Q.-Y.; Yang, Z.-Y. Tetrahedron Lett. 1986, 27,
1171–1174.
8. Metalation of alkoxy-substitued toluenes: Schlosser, M.;
Maccaroni, P.; Marzi, E. Tetrahedron 1998, 54, 2763–2770.
´
9. Fu¨rstner, A.; Leitner, A.; Mendez, M.; Krause, H. J. Am.
20. Fu, J.-m.; Snieckus, V. Tetrahedron Lett. 1990, 31,
1665–1668.
Chem. Soc. 2002, 124, 13856–13863, and references therein.
10. Beletskaya, I. P.; Cheprakov, A. V. Chem. Rev. 2000, 100,
3009–3066.
21. Mamedov, S.; Alieva, M.; Avanesyan, M. A. Zh. Obshch.
Khim. 1964, 34, 3222–3227. Mamedov, S.; Alieva, M.;
Avanesyan, M. A. Chem. Abs. 1964, 62, 3965f.
22. Hayashi, S.; Furukawa, M.; Fujino, Y.; Ishii, N.; Kamijo, Y.
Chem. Pharm. Bull. 1972, 20, 15–20.
11. Kamikawa, T.; Hayashi, T. Synlett 1997, 163–164.
12. Quesnelle, C. A.; Familloni, O. B.; Snieckus, V. Synlett 1994,
349–350.
23. Itokawa, H.; Totsuka, N.; Nakahara, K.; Maezuru, M.; Takeya,
K.; Kondo, M.; Inamatsu, M.; Morita, H. Chem. Pharm. Bull.
1989, 37, 1619–1621.
13. Ritter, K. Synthesis 1993, 735–762, and references therein.
14. Echavarren, A. M.; Stille, J. K. J. Am. Chem. Soc. 1987, 109,
5478–5486.
24. Selassie, C. D.; Shusterman, A. J.; Kapur, S.; Verma, R. P.;
Zhang, L.; Hansch, C. J. Chem. Soc., Perkin Trans. 2 1999,
2729–2733.
15. Azzena, U.; Melloni, G.; Pisano, L. J. Chem. Soc., Perkin
Trans. 1 1995, 261–266.
16. Birch, A. J. J. Chem. Soc. 1947, 102–105. See also:
Cherkasov, A. N.; Pivnitskii, K. K. Zh. Org. Khim. 1972, 8,
211–212. Cherkasov, A. N.; Pivnitskii, K. K. Chem. Abs.
1972, 77, 101990t.
25. Bowman, R. S.; Stevens, D. R.; Baldwin, W. E. J. Am. Chem.
Soc. 1957, 79, 87–92.
26. Rivera, I.; Colberg, J. C.; Soderquist, J. A. Tetrahedron Lett.
1992, 33, 6919–6922.
17. De Jonge, J.; Bibo, B. H. Recl. Trav. Chim. Pays-Bas 1955, 74,
1448–1452.