Direct metalation of methoxymethyl arylmethyl ethers: A tin-free approach to the generation of α-alkoxyalkoxy-substituted aryllithiums

Article abstract of DOI:10.1016/j.jorganchem.2009.07.007

The generation of a series of α-methoxymethoxy-substituted arylmethyllithiums was achieved by direct metalation of the corresponding arylmethyl methoxymethyl ethers. While the effect of substituents at the benzylic position is straightforward, substituent

Full text of DOI:10.1016/j.jorganchem.2009.07.007

Journal of Organometallic Chemistry 694 (2009) 3619–3625
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Journal of Organometallic Chemistry
journal homepage: www.elsevier.com/locate/jorganchem
Direct metalation of methoxymethyl arylmethyl ethers: A tin-free approach
to the generation of a-alkoxyalkoxy-substituted aryllithiums
*
Ugo Azzena , Luisa Pisano, Sarah Mocci
Dipartimento di Chimica, Università di Sassari, via Vienna 2, I-07100 Sassari, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
The generation of a series of a-methoxymethoxy-substituted arylmethyllithiums was achieved by direct
Received 18 May 2009
Received in revised form 2 July 2009
Accepted 6 July 2009
metalation of the corresponding arylmethyl methoxymethyl ethers. While the effect of substituents at
the benzylic position is straightforward, substituents located on the aromatic ring promote the set up
of a competition between lateral and aromatic metalation, strongly affected by the position and relative
ortho directing properties of the new substituent. The proposed methodology allows a simple approach to
the generation of a wide array of functionalized organolithium reagents.
Available online 9 July 2009
Keywords:
Lithiation
Ó 2009 Elsevier B.V. All rights reserved.
Regioselectivity
Funtionalized organolithiums
Acetals
Protecting groups
1. Introduction
to shorten the reaction sequence, and to avoid the manipulation
of toxic organotin reagents, we undertook an investigation aimed
Directed ortho (DoM) and benzylic metalation of aromatic com-
pounds are widely employed synthetic procedures allowing the
regioselective generation of funtionalized organometals, although,
with appropriate substrates, competition between the two reaction
pathways could lead to the formation of isomeric reaction products
[1,2].
to establish the reactivity of a series of arylmethyl methoxymethyl
[18] ethers, 1a–l, under metalation reaction conditions (Scheme 2).
2. Results and discussion
2.1. Synthesis of methoxymethyl ethers
From this point of view, acetals of arylmethyl alcohols are usu-
ally considered as weak ortho directing metalation groups (DMGs)
[3]. Indeed, benzyl methoxymethyl or 1-ethoxyethyl ethers substi-
tuted at C3 with a methoxy group [4,5], or with a fluorine [6], un-
dergo regioselective metalation at C2 under various reaction
conditions.
Arylmethyl methoxymethyl ethers were synthesized by the
reaction of the corresponding arylmethyl alcohol with CH3OCH2Cl
according to known procedures, either under basic (1a and 1c–l,
NaH, THF) [19] or acidic (1b, Na–Y zeolite, CH2Cl2) [20] reaction
conditions.
Despite the known possibility to generate
a-methoxy-substi-
tuted benzyllithiums by the metalation of arylmethyl methyl
ethers [7,8], only a single example concerns the application of this
procedure to the generation of an O-alkoxyalkyl-substituted ben-
zyllithium [9].
Indeed, the most widely employed procedure for the generation
of these organometals involves condensation of lithium tributylst-
annane with an aromatic aldehyde, followed by protection of the
2.2. Metalation of benzyl methoxymethyl ether, 1a
Metalation reactions were carried out under dry Ar in the pres-
ence of an excess (2 equiv) of sec-BuLi. Metalation of benzyl
methoxymethyl ether, 1a, taken as a model compound, was inves-
tigated in some detail; the results are reported in Table 1 (Scheme
2). Reaction of 1a with sec-BuLi in THF at À80 °C, followed by
quenching with D2O, showed a not quantitative formation of the
desired intermediate organometal within 3 h (Table 1, entry 1). A
somewhat better result was obtained running the reaction at
À40 °C under otherwise identical reaction conditions (Table 1, en-
try 2), and similar results were obtained employing n-BuLi as a
base (not reported in Table 1). These results underline the thermal
stability of organolithium 2a, in contrast with the recent hypothe-
resulting
a-tributylstannyl-substituted benzyl alcohol, and final
tin–lithium exchange (Scheme 1) [9–17].
Planning to develop an alternative approach to the generation
of this interesting class of functionalized organometallic reagents,
* Corresponding author. Tel.: +39 079229549; fax: +39 079229559.
E-mail address: ugo@uniss.it (U. Azzena).
0022-328X/$ - see front matter Ó 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2009.07.007

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U. Azzena et al. / Journal of Organometallic Chemistry 694 (2009) 3619–3625
Scheme 1. Generation of alkoxyalkoxyl-substituted benzyllithiums, according to
Ref. [9–15].
Scheme 3. Deprotection of methoxymethyl benzyl ethers.
Accordingly, chloroether 4ad was hydrolyzed by reacting it
with 1 N HCl in MeOH during 3 h at r.t., and the resulting chloroal-
cohol 6 was reacted with NaH in dry THF to afford the correspond-
ing tetrahyropyran 7 in 59% overall yield. Under similar hydrolytic
conditions, acetal 4ae afforded the monoprotected diol 8, and
hydroxyether 4ag was hydrolyzed to the corresponding diol, 9.
Scheme 2. Metalation of arylmethyl methoxymethyl ethers, and reaction with
electrophiles. 1a–5a: G = R = H; 1b–5b: G = 4-OCON(CH3)2, R = H; 1c–5c: G = 4-F,
R = H; 1d–5d: G = 3-F, R = H; 1e–5e: G = 4-OCH3, R = H; 1f–5f: G = 4-OCH(CH3)2,
R = H; 1g–5g: G = 3-OCH3, R = H; 1h–5h: G = 4-Cl, R = H; 1i–5i: G = 4-CH3, R = H; 1j–
5j: G = H, R = C6H5; 1k–5k, G = H, R = CH3; 1l–5l, G = 4-OCH3, R = CH3; EX, E, see text
and tables.
2.3. Metalation of Arylmethyl Methoxymethyl Ethers, 1b–l
Table 1
To obtain more information on the ability of the O-methoxy-
methyl substituent to direct a-metalation, we extended our study
to the metalation of several arylmethyl methoxymethyl ethers
bearing an additional substituent, located either on the benzylic
carbon or on the aromatic ring including, in the last series, groups
known for their ability to direct the metalation reaction at their
ortho position (DMGs) [1–3].
Metalation of benzyl methoxymethyl ether, 1a, and reaction with electrophiles.a
T (°C)
EX
Product, E
Yield (%)b
1
2
3
4
À80
À40
À40c
À10c
0c
D2O
D2O
D2O
D2O
4aa, D
4aa, D
4aa, D
4aa, D
81
88
d
–
–
d
e
5
D2O
4aa, D
–
Metalation reactions were run as described in the above para-
graph, followed by quenching with an electrophilic reagent, aque-
ous work up, and 1H NMR analyses of crude mixtures to determine
the distribution of reaction products (benzylic versus ring hydro-
gen abstraction). Selected results, as reported in Table 2, show that
the prevalence of one of these reaction pathways depends on the
nature and the relative position of the new substituent; a (minor)
effect of reaction temperature was also observed in few instances
(Table 2, entries 2, 5 and 7 versus entries 3, 6 and 8).
Metalation of carbamate 1b followed by quenching with TMSCl,
afforded the corresponding 1,2,4-trisubstituted benzene 5bb, with
no evidences for the formation of an intermediate arylmethyllithi-
um derivative (Table 2, entry 1). Clearly, the strong ortho-directing
properties of the carboxyamido group overwhelm the ability of the
methoxymethyl ether to direct benzylic metalation.
At variance with this result, lithiation of para-substituted fluo-
ride 1c (Table 2, entries 2–4) afforded mixtures of ortho-fluoro-
and benzylic-metalated organometals [21], and similar results
were obtained with the corresponding meta-isomer 1d (Table 2,
entries 5 and 6). Interestingly, aromatic metalation of fluoride 1d
regioselectively afforded the corresponding 2,6-disubstituted orga-
nolithium, thus highlighting the already known ortho-directing
properties of the acetal moiety [4–6].
More complex results were obtained with the alkoxy-
substituted acetals 1e–g. Indeed, while metalation of the 4-meth-
oxy-substituted derivative 1e afforded a mixture of ortho-meth-
oxy- and benzylic-metalated regioisomers (Table 2, entries 7 and
8), steric hindrance at the aromatic oxygen promoted the highly
regioselective benzylic deprotonation of the corresponding 4-iso-
propoxy derivative 1f (Table 2, entry 9). Furthermore, the meta-
methoxy-substituted acetal 1g underwent exclusive benzylic
hydrogen–metal exchange (Table 2, entry 10). The last example
shows a major solvent effect on the regioselectivity of metalation
6
7
8
9
10
11
À40
À40
À40
À40
À40
À40
n-BuBr
i-PrI
Cl(CH2)4Cl
PhCH2O(CH2)3Cl
(CH3)2CO
(CH2)5CO
4ab, n-Bu
4ac, i-Pr
4ad, (CH2)4Cl
4ae, PhCH2O(CH2)3
4af, (CH3)2COH
4ag, (CH2)5COH
74f
80f
76f
63f
40f
56f
a
All metalations were run in THF, in the presence of 2 equiv of sec-BuLi during
3 h, unless otherwise indicated; 1.1 equiv of the EX was added at À80 °C.
As determined by 1H NMR spectroscopy of crude reaction mixtures, unless
b
otherwise indicated.
c
Reaction run in hexane.
Starting material was quantitatively recovered.
Extended decomposition.
Yield calculated on the isolated product.
d
e
f
sis of an easy Wittig rearrangement of similar organometals [6]. Fi-
nally, it is worth noting that, besides several attempts (Table 1, en-
tries 3–5), we were unable to generate stable solutions of the same
organometal in hexane.
To evaluate the reactivity of organometal 2a, and in agreement
with the above reported results, additional metalations were run at
À40 °C, in dry THF, employing sec-BuLi as a base; the resulting
mixtures were quenched by slow dropwise addition of a THF solu-
tion of an electrophile. Satisfactory results were obtained employ-
ing either alkyl halides (Table 1, entries 6–9) or ketones (Table 1,
entries 10 and 11) as electrophilic reagents. Careful inspection of
1H NMR of crude reaction mixtures showed that metalation reac-
tions occurred regioselectively at the benzylic position of the start-
ing material, with no evidences of substitution on the aromatic
ring.
To check the versatility of the proposed methodology, few reac-
tion products were submitted to acidic hydrolysis to remove the
MOM-protecting group (Scheme 3).

U. Azzena et al. / Journal of Organometallic Chemistry 694 (2009) 3619–3625
3621
Table 2
Metalation of arylmethyl methoxymethyl ethers, 1b–l, and reaction with electrophiles.a
Entry
Substrate, G, R
EX
E
Product distribution (%)b
4
5
1
2
3
4
5
6
7
8
1b, 4-OCONEt2, H
1c, 4-F, H
1c, 4-F, H
1c, 4-F, H
1d, 3-F, H
(CH3)3SiCl
(CH3)3SiCl
(CH3)3SiCl
(CH3)3CCHO
(CH3)3SiCl
(CH3)3SiCl
(CH3)3SiCl
(CH3)3SiCl
(CH3)3SiCl
(CH3)3SiCl
D2O
(CH3)3SiCl
D2O
(CH3)3SiCl
D2O
n-BuBr
D2O
(CH3)3Si
(CH3)3Si
(CH3)3Si
(CH3)3CCHOH
(CH3)3Si
(CH3)3Si
(CH3)3Si
(CH3)3Si
(CH3)3Si
(CH3)3Si
D
(CH3)3Si
D
(CH3)3Si
D
n-Bu
D
4ba, –
5ba, >90 (85)c
5ca, 73 (54)c
5ca, 88 (65)c,d
5cb, 71 (52)c
5da, 55 (41)c
5da, 31d
5ea, 46 (27)c
5ea, 57d
5ba, –
5ga, –
5ha, –
5hb, –
4ca, 27 (20)c
4ca, 12d
4cb, 29 (23)c,e
4da, 45 (33)c
4da, 69d
1d, 3-F, H
1e, 4-OCH3, H
1e, 4-OCH3, H
1f, 4-OCH(CH3)2, H
1g, 3-OCH3, H
1h, 4-Cl, H
4ea, 54 (32)c
4ea, 43d
9
4fa, >90 (86)
4ga, >90 (82)c
4ha, >90
10
11
12
13
14
15
16
17
18
1h, 4-Cl, H
4hb, >90 (78)c
4ia, >90
1i, 4-CH3, H
1i, 4-CH3, H
1j, H, C6H5
1j, H, C6H5
1k, H, CH3
5ia, –
5ib, –
5ja, –
5jb, –
4ib, >90 (81)c
4ja, >90
4jb, >90 (78)c
4ka, 34
5ka, –
1l, 4-OCH3, CH3
(CH3)3SiCl
(CH3)3Si
4lb, –
5lb, >90 (84)c
a
All metalations were run in THF at À40 °C, in the presence of 2 equiv of sec-BuLi, during 3 h, unless otherwise indicated; 1.1 equiv of the EX was added at À80 °C.
As determined by 1H NMR spectroscopy of crude reaction mixtures, unless otherwise indicated.
Yield calculated on the isolated product.
b
c
d
e
Metalation run at À80 °C, during 6 h.
A diastereoisomeric mixture (75:25) was obtained.
reactions; indeed, it was reported that metalation of acetal 1g, run
in hexane, occurred exclusively at C2 [5].
chlorine, alkoxy (depending upon the relative position and/or ste-
ric hindrance) and alkyl groups. From this point of view, it is worth
Finally, with substituents endowed with poor or no directing
metalation properties, i.e., aryl chloride 1h and toluene derivative
1i, respectively, we observed clean benzylic metalation (Table 2,
entries 11–14). It is however worth noting that chloride 1h was
metalated at À80 °C; indeed, reactions run at À40 °C led to the for-
mation of complex reaction mixtures (not reported in Table 2),
thus suggesting competitive metalation ortho to the clorine atom,
followed by LiCl elimination and aryne formation [22].
noting that THF appears as the solvent of choice to promote a-lith-
iation of our acetals, as also evidenced by a comparison with liter-
ature reports concerning similar reactions run in hydrocarbon
solvents [4,5]. On the other side, the strong acidifying effect of fluo-
rine competes well with the methoxymethoxy group, leading to
the formation of mixtures of regioisomers, easily separated by sim-
ple column chromatography.
The effect of
methoxymethyl ethers is straightforward. Indeed, we obtained
quantitative -metalation of benzydrylic derivative 1j under stan-
dard conditions, and the corresponding intermediate organolith-
ium was efficiently trapped with electrophilic reagents (Table 2,
entries 15 and 16).
a-substitution on the a-lithiation of arylmethyl
3. Experimental
a
3.1. General
All air sensitive reactions were carried out under dry Ar. 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 on a Varian VXR 300 spectrom-
eter. Deuterium incorporation was calculated by monitoring the 1H
NMR spectra of crude reaction mixtures, and comparing the inte-
gration of the signal corresponding to protons in the arylmethyl
position with that of known signals. Resonances of arylmethyl
CHD protons appear as unresolved broad triplets shifted 0.02–
0.05 ppm (d) upfield relatively to the corresponding arylmethyl
CH2 protons; the resonances of the arylmethyl CHD carbons appear
as triplets (J = 19–21 Hz) shifted 0.3–0.4 ppm (d) upfield relatively
to the corresponding arylmethyl CH2 carbons. IR spectra were re-
corded on a FT-IR Jacso 480 P. Flash chromatography was per-
On the other side, under similar conditions, lithiation of (1-
methoxymethoxy)ethylbenzene, 1k, led to extensive decomposi-
tion of the starting material (not reported in Table 2), while only
a minor amount of deuterium incorporation was evidenced when
the metalation reaction, run at À80 °C, was quenched with D2O
(Table 2, entry 17). We were unable to improve this result on run-
ning a similar reaction in the presence of 2 equiv of TMEDA (not re-
ported in Table 2). According to these findings, reaction of sec-BuLi
with 1-methoxy-4-(1-methoxymethoxy)ethylbenzene, 1l, run at
À40 °C, led to regioselective deprotonation at C2 (Table 2, entry
18).
formed on Merck silica gel 60 (40–63 lm), and TLC analyses on
2.4. Concluding remarks
Macherey-Nagel silica gel pre-coated plastic sheets (0.20 mm). Ele-
mental analyses were performed by the microanalytical laboratory
of the Dipartimento di Chimica, Università di Sassari.
In conclusion, we have shown that direct
methyl methoxymethyl ethers is a feasible reaction allowing the
generation of a wide array of -methoxymethoxy-substituted aryl-
a-metalation of aryl-
a
methyl organolithiums, thus avoiding manipulation of tin deriva-
tives. Although in the presence of a strong DMG, i.e., an O-
carbamate, the MOM group acts as an effective protective group
of the alcoholic moiety, this acetal is able to promote the formation
of arylmethyl organolithiums in the presence of substituents en-
dowed with moderate to low ortho-directing properties, including
3.2. Starting materials
Acetals 1a [19], 1b [20] and 1c–k [19] were synthesized accord-
ing to general procedures, and purified either by fractional distilla-
tion or flash chromatography. Typical yields range from 70% to
85%. Acetals 1a [19], 1c [6,19], 1d [6], 1j [23], and 1k [24], were

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U. Azzena et al. / Journal of Organometallic Chemistry 694 (2009) 3619–3625
characterized according to the literature. Other products were
purified and characterized as follows.
d = 23.5, 55.2, 55.2, 73.1, 93.8, 113.7, 127.6, 135.2, 159.0. Anal.
Calcd. for C11H16O3: C, 67.32; H, 8.22. Found: C, 67.14; H, 8.39%.
3.2.1. 4-Methoxymethoxymethylphenyl ester of N,N-diethylcarbamic
acid (1b)
3.3. General procedure for lithiation methoxymethyl arylmethyl ethers,
and reaction with electrophiles
Oil, purified by flash chromatography (CH2Cl2/EtOAc/
Et3N = 7:3:0.5; Rf: 0.80). Bp 126/1 (°C/Torr). IR (neat): 1716 cmÀ1
(CO). 1H NMR (300 MHz, CDCl3): d = 1.16–1.28 (m, 6H, 2 Â CH3),
3.35–3.47 (m, 4H, 2 Â CH2N), 3.41 (s, 3H, OCH3), 4.58 (s, 2H,
ArCH2), 4.69 (s, 2H, OCH2O), 7.08–7.14 (m, 2H, 2 Â ArH), 7.31–
7.37 (m, 2H, 2 Â ArH). 13C NMR (75 MHz, CDCl3): d = 13.3, 14.2,
41.8, 42.1, 55.2, 68.4, 95.4, 121.6, 128.6, 134.5, 150.9, 154.1. Anal.
Calcd. for C14H21NO4: C, 62.90; H, 7.92; N, 5.24. Found: C, 62.78;
H, 8.06; N, 5.36%.
To a cooled (see tables) solution of the appropriate acetal
(3.0 mmol) in 10 mL of dry THF, sec-butyllithium (6.0 mmol;
3.8 mL of a 1.6 M solution in cyclohexane) was added dropwise
with stirring. Stirring was continued for 3–6 h (see tables) and then
the appropriate electrophile (1.1 equiv), dissolved in 5 mL of THF
was added to the reaction mixture chilled at À80 °C. After the addi-
tion, the reaction mixture was allowed to warm to r.t. overnight,
then quenched by dropwise addition of 20 mL of H2O. The resulting
mixture was extracted with Et2O (3 Â 40 mL), washed with brine
(20 mL), and the organic phase dried (K2CO3) and evaporated.
Crude products were purified and characterized as follows.
3.2.2. 1-Methoxy-4-methoxymethoxymethylbenzene (1e)
Oil, purified by flash chromatography (petroleum ether/EtOAc/
Et3N = 8:2:0.5; Rf: 0.52). 1H NMR (300 MHz, CDCl3): d = 3.41 (s,
3H, CH3O), 3.81 (s, 3H, CH3OAr), 4.53 (s, 2H, ArCH2), 4.69 (s, 2H,
OCH2O), 6.86–6.92 (m, 2H, 2 Â ArH), 7.26–7.31 (m, 2H, 2 Â ArH).
13C NMR (75 MHz, CDCl3): d = 55.2, 68.8, 71.6, 95.4, 113.8, 129.5,
129.9, 159.2. Anal. Calcd. for C10H14O3: C, 65.91; H, 7.74. Found:
C, 65.76; H, 7.94%.
3.3.1. 1-Methoxymethoxy-1-phenylpentane (4ab)
Oil, purified by flash chromatography (hexane/EtOAc = 9:1; Rf:
0.53). Bp 95/1 (°C/Torr). 1H NMR (300 MHz, CDCl3): d = 0.88 (t,
J = 7.2 Hz, t, 3H, CH3), 1.20–1.48 (m, 4H, 2 Â CH2), 1.58–1.74 (m,
1H, CH), 1.78–1.92 (m, 1H, CH), 3.37 (s, 3H, CH3O), 4.52 (s, 2H,
OCH2O), 4.55 (dd, J = 7.8, 6.0 Hz, 1 H CHPh), 7.23–7.37 (m, 5H,
5 Â PhH). 13C NMR (75 MHz, CDCl3): d = 14.0, 22.6, 28.1, 37.7,
55.5, 78.0, 94.0, 126.9, 127.5, 128.3, 142.3. Anal. Calcd. for
C13H20O2: C, 74.96; H, 9.68. Found: C, 74.75; H, 9.83%.
3.2.3. 1-Isopropoxy-4-methoxymethoxymethylbenzene (1f)
Oil, purified flash chromatography (petroleum ether/EtOAc/
Et3N = 7:3:1; Rf: 0.79). 1H NMR (300 MHz, CDCl3): d = 1.33 (d, 6H,
J = 6.0 Hz, 2 Â CH3), 3.41 (s, 3H, OCH3), 4.52 (s, 2H, ArCH2), 4.55
(hept, J = 6.0 Hz, CH), 4.69 (s, 2H, OCH2O), 6.84–6.90 (m, 2H,
2 Â ArH), 7.24–7.30 (m, 2H, 2 Â ArH). 13C NMR (75 MHz, CDCl3):
d = 22.0, 55.2, 68.8, 69.8, 95.4, 115.8, 129.6, 129.6, 157.5. Anal.
Calcd. for C12H18O3: C, 68.54; H, 8.63. Found: C, 68.37; H, 8.81%.
3.3.2. 1-Methoxymethoxy-1-phenyl-2-methylpropane (4ac)
Oil, purified by flash chromatography (petroleum ether/
Et3N = 9:1; Rf: 0.35). 1H NMR (300 MHz, CDCl3): d = 0.75 (d,
J = 6.9 Hz, 3H, CH3), 1.04 (d, J = 6.9 Hz, 3H, CH3), 1.90–2.03 (m,
1H, CH), 3.37 (s, 3H, CH3), 4.22 (d, J = 7.5 Hz, 1H, PhCH), 4.50 (s,
2H, OCH2O), 7.23–7.33 (m, 5H, 5 Â PhH). 13C NMR (75 MHz,
CDCl3): d = 19.0, 19.1, 34.6, 55.5, 83.5, 94.2, 127.4, 127.6, 128.0,
140.9. Anal. Calcd. for C12H18O2: C, 74.19; H, 9.34. Found: C,
73.91; H, 9.52.
3.2.4. 1-Methoxy-3-methoxymethoxymethylbenzene, (1g)
Oil, purified by flash chromatography (petroleum ether/EtOAc/
Et3N = 9:1:0.5; Rf: 0.43). 1H NMR (300 MHz, CDCl3): d = 3.42 (s,
3H, CH3O), 3.82 (s, 3H, CH3OAr), 4.58 (s, 2H, ArCH2), 4.72 (s, 2H,
OCH2O), 6.81–6.86 (m, 1H, ArH), 6.90–6.96 (m, 2H, 2 Â ArH),
7.23–7.29 (m, 1H, ArH). 13C NMR (75 MHz, CDCl3): d = 55.1, 55.3,
68.9, 95.6, 113.1, 113.3, 120.0, 129.4, 139.4, 159.7. Anal. Calcd.
For C10H14O3: C, 65.91; H, 7.74. Found: C, 66.10; H, 7.84%.
3.3.3. 1-Methoxymethoxy-1-phenyl-5-chloropentane (4ad)
Oil, purified by flash chromatography (hexane/EtOAc = 9:1; Rf:
056;). Bp 160/1 (°C/Torr). 1H NMR (300 MHz, CDCl3): d = 1.37–
1.96 (m, 6H, 3 Â CH2), 3.37 (s, 3H, CH3O), 3.52 (t, J = 6.6 Hz, 2H,
CH2Cl), 4.52 (s, 2H, OCH2O), 4.57 (dd, J = 7.8, 5.1 Hz, 1H, CHPh),
7.24–7.38 (m, 5H, 5 Â PhH). 13C NMR (75 MHz, CDCl3): d = 23.3,
32.5, 37.2, 44.9, 55.6, 77.7, 94.1, 126.8, 127.7, 128.3, 141.9. Anal.
Calcd. For C13H19ClO2: C, 64.32; H, 7.89. Found: C, 64.21; H, 7.96.
3.2.5. 1-Chloro-4-methoxymethoxymethylbenzene (1h)
Oil, purified by flash chromatography (petroleum ether/
EtOAc = 9:1; Rf: 0.52). 1H NMR (300 MHz, CDCl3): d = 3.41 (s, 3H,
OCH3), 4.56 (s, 2H, ArCH2), 4.70 (s, 2H, OCH2O), 7.27–7.35 (m,
4H, 4 Â ArH). 13C NMR (75 MHz, CDCl3): d = 55.3, 68.3, 95.6,
128.5, 129.1, 133.4, 136.3. Anal. Calcd. for C9H11ClO2: C, 57.92; H,
5.94. Found: C, 57.78; H, 6.11%.
3.3.4. 4-Methoxymethoxy-4-phenylbutyl benzyl ether (4ae)
Oil, purified by flash chromatography (hexane/EtOAc = 9.5:0.5;
Rf: 0.53;). 1H NMR (300 MHz, CDCl3): d = 1.52–1.98 (m, 4H,
2 Â CH2), 3.35 (s, 3H, CH3O), 3.44–3.51 (m, 2H, CH2O), 4.48 (s,
2H, CH2Ph), 4.52 (s, 2H, OCH2O), 4.57 (dd, J = 7.8, 5.1 Hz, 1H, CHPh),
7.23–7.37 (m, 10H, 10 Â PhH). 13C NMR (75 MHz, CDCl3): d = 26.3,
34.6, 55.6, 70.1, 72.9, 77.8, 94.0, 126.9, 127.5, 127.6, 127.6, 128.3,
138.5, 142.0. Anal. Calcd. for C19H24O3: C, 75.97; H, 8.05. Found:
C, 75.84; H, 8.26%.
3.2.6. 4-Methoxymethoxymethyltoluene, (1i)
Oil, purified by flash chromatography (petroleum ether/
EtOAc = 9:1; Rf: 0.34). 1H NMR (300 MHz, CDCl3): d = 2.35 (s, 3H,
CH3Ar), 3.41 (s, 3H, CH3O), 4.56 (s, 2H, ArCH2), 4.70 (s, 2H, OCH2O),
7.14–7.19 (m, 2H, 2 Â ArH), 7.23–7.27 (m, 2H, 2 Â ArH). 13C NMR
(75 MHz, CDCl3): d = 21.0, 55.2, 68.9, 95.4, 127.9, 129.0, 134.7,
137.3. Anal. Calcd. for C10H14O2: C, 72.26; H, 8.49. Found: C,
72.13; H, 8.56%.
3.3.5. 1-Methoxymethoxy-1-phenyl-2-methylpropan-2-ol (4af)
Oil, purified by flash chromatography (petroleum ether/EtOAc/
Et3N = 8:2:0.5); Rf: 0.40. IR (neat): 3463 cmÀ1 (OH). 1H NMR
(300 MHz, CDCl3): d = 1.12 (s, 3H, CH3), 1.23 (s, 3H, CH3), 3.40 (s,
3H, CH3O), 4.45 (s, 1H, PhCH), 4.55 (d, J = 6.6 Hz, 1H, OCHO), 4.60
(d, J = 6.6 Hz, 1H, OCHO), 7.28–7.35 (m, 5H, 5 Â PhH). 13C NMR
(75 MHz, CDCl3): d = 24.8, 26.3, 56.0, 7.1.6, 84.7, 94.7, 127.9,
127.9, 128.5, 137.9. Anal. Calcd. for C12H18O3: C, 68.54; H, 8.63.
Found: C, 68.38; H, 8.81%.
3.2.7. 1-Methoxy-4-(1-methoxymethoxyethyl)benzene (1l)
Oil, purified by distillation or flash chromatography (petroleum
ether/EtOAc/Et3N = 8:2:0.5; Rf: 0.52. 1H NMR (300 MHz, CDCl3):
d = 1.46 (d, J = 6.6 Hz, 3H, CH3CH), 3.37 (s, 3H, CH3OCH2), 3.81 (s,
3H, CH3OAr), 4.52 (d, J = 6.6 Hz, 1H, OCHO), 4.55 (d, J = 6.6, Hz,
1H, OCHO), 4.71 (q, J = 6.6 Hz, 1H, ArCH), 6.85–6.91 (m, 2H,
2 Â ArH), 7.22–7.29 (m, 2H, 2 Â ArH). 13C NMR (75 MHz, CDCl3):

U. Azzena et al. / Journal of Organometallic Chemistry 694 (2009) 3619–3625
3623
3.3.6. 1-(Methoxymethoxyphenyl)methylcyclohexanol (4ag)
3.3.11. 1-(2-Fluoro-5-methoxymethoxymethyl)phenyl-2,2-
dimethylpropan-1-ol (5cb)
Oil, purified by flash chromatography (petroleum ether/EtOAc/
Et3N = 8:2:0.5; Rf: 0.56). IR (neat): 3481 cmÀ1 (OH). 1H NMR
(300 MHz, CDCl3): d = 1.10–2.05 (m, 11H, 5 Â CH2 + OH), 3.39 (s,
3H, CH3O), 4.43 (s, 1H, PhCH), 4.52 (d, J = 6.6 Hz, 1H, OCHO), 4.56
(d, J = 6.6 Hz, 1H, OCHO), 7.30–7.35 (m, 5H, 5 Â PhH). 13C NMR
(75 MHz, CDCl3): d = 21.3, 21.5, 25.8, 33.0, 34.5, 55.9, 73.1, 84.0,
94.4, 127.8, 127.8, 128.8, 137.5. Anal. Calcd. for C15H22O3: C,
71.97; H, 8.86. Found: C, 72.18; H, 8.64%.
Oil, purified by flash chromatography (petroleum ether/EtOAc/
Et3N, 8:2:0.5; Rf: 0.37). IR (neat): 3465 cmÀ1 (OH). 1H NMR
(300 MHz, CDCl3): d = 0.95 (d, 9H, J = 1.2 Hz, 3 Â CH3Si), 3.41 (s,
3H, CH3O), 4.56 (s, 2H, ArCH2), 4.70 (s, 2H, OCH2O), 4.80 (d, 1H,
J = 4.2 Hz, CHO), 6.90 (dd, J = 8.4, 1.8 Hz, 1H, ArH), 7.21–7.28 (m,
1H, ArH), 7.43 (dd, J = 4.8, 2.1 Hz, 1H, ArH). 13C NMR (CDCl3, d/
ppm): 25.5, 36.2, 55.3, 68.7, 74.5, 95.6, 114.8 (d, J = 23 Hz), 128.3
(d, J = 9 Hz), 128.8 (d, J = 5 Hz), 129.3 (d, J = 14 Hz), 133.1 (d,
J = 3 Hz), 159.5 (d, J = 244 Hz). Anal. Calcd. for C14H21FO3: C,
65.60; H, 8.26. Found: C, 65.48; H, 8.39%.
3.3.7. 2-Trimethylsilyl-4-methoxymethoxymethylphenyl ester of N,N-
diethylcarbamic acid (5ba)
Oil, purified by flash chromatography (CH2Cl2/EtOAc/
Et3N = 7:3:1; Rf: 0.56). IR (neat): 1718 cmÀ1 (CO). 1H NMR
(300 MHz, CDCl3): d = 0.28 (s, 9H, 3 Â CH3Si), 1.16–1.28 (m, 6H,
2 Â CH3), 3.35–3.52 (m, 4H, 2 Â CH2N), 3.42 (s, 3H, OCH3), 4.57
(s, 2H, ArCH2), 4.71 (s, 2H, OCH2O), 7.01–7.05 (m, 1H, 1 Â ArH),
7.24–7.38 (m, 1H, 1 Â ArH), 7.40–7.42 (m, 1H, 1 Â ArH). 13C NMR
(75 MHz, CDCl3): d = À1.0, 13.2, 14.1, 41.5, 41.8, 55.3, 68.7, 95.5,
122.2, 130.1, 131.5, 133.9, 134.4, 154.3, 155.9. Anal. Calcd. for
C17H29NO4Si: C, 60.14; H, 8.61; N, 4.13. Found: C, 59.87; H, 8.79;
N, 4.02%.
3.3.12. (3-Fluorophenyl)methoxymethoxymethyltrimethylsilane (4da)
Oil, purified by flash chromatography (petroleum ether/EtOAc/
Et3N = 9.7:0.3:0.2; Rf: 0.49. 1H NMR (300 MHz, CDCl3): d = 0.02 (s,
9H, 3 Â CH3Si), 3.38 (s, 3H, CH3O), 4.48 (s, 1H, CHAr), 4.53 (d,
J = 6.3 Hz, 1H, OCHO), 4.56 (d, J = 6.3 Hz, 1H, OCHO), 6.81–6.92
(m, 3H, 3 Â ArH), 7.18–7.27 (m, 1H, ArH). 13C NMR (75 MHz,
CDCl3): d = À4.0, 55.5, 72.5, 95.2, 112.5 (d, J = 3 Hz), 112.8 (d,
J = 3 Hz), 121.6 (d, J = 3 Hz), 129.4 (d, J = 8 Hz) 144.0 (d, J = 7 Hz),
163.0 (d, J = 243 Hz). Anal. Calcd. for C12H19FO2Si: C, 59.47; H,
7.90. Found: C, 59.38; H, 7.96%.
3.3.13. (2-Trimethylsilyl-3-methoxymethoxymethylfluorobenzene
(5da)
3.3.8. (4-Fluorophenyl)methoxymethoxymethyltrimethylsilane (4ca)
Oil, purified by flash chromatography (petroleum ether/
EtOAc = 9:1; Rf: 0.54). 1H NMR (300 MHz, CDCl3): d = À0.01 (s,
9H, 3 Â CH3Si), 3.36 (s, 3H, CH3O), 4.44 (s, 1H, ArCH), 4.50 (d,
J = 6.3 Hz, 1H, OCHO), 4.53 (d, J = 6.3 Hz, 1H, OCHO), 6.92–7.01
(m, 2H, 2 Â ArH), 7.06–7.13 (m, 2H, 2 Â ArH). 13C NMR (75 MHz,
CDCl3): d = À4.0, 55.5, 72.1, 94.9, 114.9 (d, J = 21 Hz), 127.5 (d,
J = 8 Hz), 136.4 (d, J = 3 Hz), 161.3 (d, J = 242 Hz). Anal. Calcd. for
C12H19FO2Si: C, 59.47; H, 7.90. Found: C, 59.24; H, 8.12%.
Oil, purified by flash chromatography (petroleum ether/EtOAc/
Et3N = 9.7:0.3:0.2; Rf: 0.39). 1H NMR (300 MHz, CDCl3): d = 0.39
(d, J = 2.1 Hz, 9H, 3 Â CH3Si), 3.40 (s, 3H, CH3O), 4.63 (s, 2H, ArCH2),
4.68 (s, 2H, OCH2O), 6.89–6.95 (m, 1H, ArH), 7.22 (dd, 1H, J = 7.5,
0.3 Hz, ArH), 7.32 (td, 1H, J = 7.8, 6.0 Hz, ArH). 13C NMR (75 MHz,
CDCl3): d = 1.4 (d, J = 4 Hz), 55.5, 68.7 (d, J = 2 Hz), 95.5, 114.4 (d,
J = 28 Hz), 124.7 (d, J = 2 Hz), 124.8 (d, J = 27 Hz), 130.8 (d,
J = 10 Hz), 145.0 (d, J = 10 Hz), 169.2 (d, J = 239 Hz). Anal. Calcd.
for C12H19FO2Si: C, 59.47; H, 7.90. Found: C, 59.63; H, 7.95%.
3.3.9. 2-Trimethylsilyl-4-methoxymethoxymethylfluorobenzene (5ca)
Oil, purified by flash chromatography (petroleum ether/
EtOAc = 9:1; Rf: 0.43). 1H NMR (300 MHz, CDCl3): d = 0.31 (d,
J = 0.6 Hz, 9H, CH3Si), 3.42 (s, 3H, CH3O), 4.55 (s, 2H, ArCH2), 4.70
(s, 2H, OCH2O), 6.93–7.01 (m, 1H, ArH), 7.30–7.38 (m, 2H, 2 Â ArH).
13C NMR (75 MHz, CDCl3): d = À1.12, 55.3, 68.8, 95.7, 114.6 (d,
J = 26 Hz), 126.2 (d, J = 31 Hz), 131.1 (d, J = 9, Hz), 133.1 (d,
J = 3 Hz), 134.8 (d, J = 10 Hz), 167.0 (d, J = 239 Hz). Anal. Calcd. for
C12H19FO2Si: C, 59.47; H, 7.90. Found: C, 59.21; H, 8.18%.
3.3.14. (4-Methoxyphenyl)methoxymethoxymethyltrimethylsilane
(4ea)
Oil, purified by flash chromatography (petroleum ether/EtOAc/
Et3N = 9:1:0.5; Rf: 0.42). 1H NMR (300 MHz, CDCl3): d = 0.00 (s,
9H, 3 Â CH3Si), 3.37 (s, 3H, CH3O), 3.79 (s, 3H, CH3OAr), 4.41 (s,
1H, ArCH), 4.50 (d, 1H, J = 6.6 Hz, OCHO), 4.55 (d, 1H, J = 6.6 Hz,
OCHO), 6.81–6.87 (m, 2H, 2 Â ArH), 7.04–7.10 (m, 2H, 2 Â ArH).
13C NMR (75 MHz, CDCl3): d = À3.9, 55.1, 55.3, 72.1, 94.6, 113.5,
127.4, 132.6, 157.9. Anal. Calcd. for C13H22O3Si: C, 61.38; H, 8.72.
Found: C, 61.13; H, 8.92%.
3.3.10. 1-(4-Fluorophenyl)-2-hydroxy-3,3-dimethylbutyl
methoxymethyl ether (4cb)
3.3.15. 2-Trimethylsilyl-4-methoxymethoxymethylanisole (5ea)
Oil, purified by flash chromatography (petroleum ether/EtOAc/
Et3N = 9:1:0.5; Rf: 0.28). 1H NMR (300 MHz, CDCl3): d = 0.26 (s,
9H, 3 Â CH3Si), 3.42 (s, 3H, CH3O), 3.80 (s, 3H, CH3OAr), 4.52 (s,
2H, ArCH2), 4.70 (s, 2H, OCH2O), 6.70–6.85 (m, 1 H, ArH), 7.30–
7.34 (m, 2H, 2 Â ArH). 13C NMR (75 MHz, CDCl3): d = À1.0, 55.1,
55.3, 69.1, 95.5, 109.4, 128.1, 129.3, 130.9, 135.2, 164.1. Anal.
Calcd. for C13H22O3Si: C, 61.38; H, 8.72. Found: C, 61.17; H, 8.89%.
Oil, purified by flash chromatography (petroleum ether/EtOAc/
Et3 N = 8:2:0.5; Rf: 0.24). IR (neat): 3484 cmÀ1 (OH). Major Diaste-
roisomer: 1H NMR (300 MHz, CDCl3): d = 0.91 (s, 9H, 3 Â CH3C),
2.86 (1H, d, J = 6.0 Hz, OH), 3.36 (s, 3H, OCH3), 3.36 (1H, d, J = 6.0,
4.5 Hz, CHOH), 4.49 (1H, d, J = 6.6 Hz, OCHO), 4.54 (1H, d,
J = 6.6 Hz, OCHO), 4.67 (1H, d, J = 4.5 Hz, ArCH), 6.99–7.08 (m, 2H,
2 Â ArH), 7.30–7.36 (m, 2, 2 Â ArH); 13C NMR (75 MHz, CDCl3):
d = 26.5, 34.8, 56.4, 76.5, 81.8, 94.0, 115.3 (d, J = 21 Hz), 129.4 (d,
J = 8 Hz), 136.3 (d, J = 3 Hz), 162.4 (d, J = 245 Hz). Minor diastereo-
isomer: 1H NMR (300 MHz, CDCl3): d = 0.87 (s, 9H, ÂCH3C), 1.9 (1H,
d, J = 3.6 Hz, OH), 3.34 (s, 3H, OCH3), 3.65 (1H, dd, J = 4.5, 3.6 Hz,
CHOH), 4.44 (1H, d, J = 6.6 Hz, OCHO), 4.49 (1H, d, J = 6.6 Hz,
OCHO), 4.63 (1H, d, J = 4.5 Hz, ArCH), 6.99–7.08 (m, 2H, 2 Â ArH),
7.38–7.44 (m, 2H, 2 Â ArH). 13C NMR (75 MHz, CDCl3): d = 26.5,
34.3, 55.9, 77.7, 81.1, 93.7, 115.1 (d, J = 21 Hz), 130.8 (d, J = 8 Hz),
134.5 (d, J = 3 Hz), 162.4 (d, J = 245 Hz). Anal. Calcd. for
C14H21FO3: C, 65.60; H, 8.26. Found: C, 65.76; H, 8.01%.
3.3.16. (4-Isoproxyphenyl)methoxymethoxymethyltrimethylsilane
(4fa)
Oil, purified by flash chromatography (CH2Cl2/EtOAc/
Et3N = 7:3:1; Rf: 0.56). 1H NMR (300 MHz, CDCl3): d = 0.00 (s, 9H,
3 Â CH3Si), 1.32 (d, 6H, J = 6.0 Hz, 2 Â CH3), 3.37 (s, 3H, CH3O),
4.39 (s, 2H, OCH2O), 4.49 (d, J = 6.3, Hz, 1H, OCHO), 4.51 (hept,
J = 6.0 Hz, 1H, ArCH), 4.56 (d, J = 6.3, Hz, 1H, OCHO), 6.79–6.83
(m, 2H, 2 Â ArH), 7.01–7.07 (m, 2H, 2 Â ArH). 13C NMR (75 MHz,
CDCl3): d = À3.9, 22.1, 55.4, 69.8, 72.2, 94.6, 115.5, 127.4, 132.4,

3624
U. Azzena et al. / Journal of Organometallic Chemistry 694 (2009) 3619–3625
156.2. Anal. Calcd. for C15H26O3Si: C, 63.78; H, 9.28. Found: C,
63.68; H, 9.41%.
127.3, 127.6, 127.7, 128.3, 128.4, 138.1, 144.8. Anal. Calcd. for
17H20O2: C, 79.65; H, 7.86. Found: C, 79.49; H, 8.04%.
C
3.3.17. (3-Methoxyphenyl)methoxymethoxymethyltrimethylsilane
(4ga)
3.4.2. (Hydroxyphenylmethyl) cyclohexanol (9)
Oil, purified by flash chromatography (petroleum ether/EtOAc/
Et3N = 8:2:0.5; Rf: 0.26). IR (nujol): 3346 cmÀ1 (OH). 1H NMR
(300 MHz, CDCl3): d = 1.19–1.64 (m, 11H, 5 Â CH2+OH), 2.48 (d,
1H, J = 4.2 Hz, OH), 4.48 (d, 1H, J = 4.2 Hz, CH), 7.30–7.38 (m, 5H,
5 Â PhH); 13C NMR (75 MHz, CDCl3): d = 21.3, 21.5, 25.7, 32.1,
34.2, 73.7, 80.7, 127.6, 127.9, 140.4. Anal. Calcd. for C13H18O2: C,
75.69; H, 8.80. Found: C, 75.78; H, 8.98%.
Oil, purified by flash chromatography (petroleum ether/EtOAc/
Et3N = 9:1:0.5; Rf: 0.38). 1H NMR (300 MHz, CDCl3): d = 0.01 (s,
9H, 3 Â CH3Si), 3.38 (s, 3H, CH3), 3.79 (s, 3H, CH3OAr), 4.46 (s,
1H, ArCH), 4.53 (d, J = 6.3, Hz, 1H, OCHO), 4.58 (d, J = 6.3, Hz, 1H,
OCHO), 6.68–6.75 (m, 3H, 3 Â ArH), 7.15–7.22 (m, 1H, ArH). 13C
NMR (75 MHz, CDCl3): d = À3.9, 55.0, 55.5, 72.8, 95.1, 111.2,
111.5, 118.7, 129.0, 142.6, 159.5. Anal. Calcd. for C13H22O3Si: C,
61.38; H, 8.72. Found: C, 61.25; H, 8.95%.
3.4.3. Synthesis of 2-phenyltetrahydro-2H-pyran (7)
Acetal 4ad (1.10 g, 4.5 mmol), hydrolyzed according to the gen-
eral procedure described above, afforded 0.8 g (4.0 mmol, 89%) of
crude 1-phenyl-5-chloropentan-1-ol, 6. The crude material was
dissolved in dry THF (5 mL) and dropwise added to a suspension
of NaH (0.12 g, 5.04 mmol) in dry THF (5 mL), chilled at 0 °C. The
reaction mixture was stirred overnight at r.t., then quenched by
slow dropwise addition of H2O (10 mL). The resulting mixture
was extracted with Et2O (3 Â 10 mL), washed with brine (10 mL),
and the organic phase dried (Na2SO4) and evaporated. The reaction
product was purified by flash chromatography (petroleum ether/
EtOAc = 9:1, Rf: 0.61); yield: 0.43 g (2.7 mmol, 59% from 4ad); col-
orless oil; compound 7 was characterized by comparison with lit-
erature data [26].
3.3.18. (4-Chlorophenyl)methoxymethoxymethyltrimethylsilane (4hb)
Oil, purified by flash chromatography (petroleum ether/EtOAc/
Et3N = 9:1:0.5; Rf: 0.60). 1H NMR (300 MHz, CDCl3): d = 0.00 (s,
9H, 3 Â CH3Si), 3.36 (s, 3H, CH3O), 4.45 (s, 1H, ArCH), 4.52 (s, 2H,
OCH2O), 7.05–7.10 (m, 2H, 2 Â ArH), 7.23–7.28 (m, 2H, 2 Â ArH).
13C NMR (75 MHz, CDCl3): d = À4.0, 55.5, 72.2, 95.0, 127.3, 128.2,
131.4, 139.5. Anal. Calcd. for C12H19ClO2Si: C, 55.69; H, 7.40. Found:
C, 55.42; H, 7.58%.
3.3.19. (4-Methylphenyl)methoxymethoxymethyltrimethylsilane (4ib)
Oil, purified by flash chromatography (petroleum ether/EtOAc/
Et3N = 9.5:0.5:0.5; Rf: 0.60). 1H NMR (300 MHz, CDCl3): d = 0.00
(s, 9H, 3 Â CH3Si), 2.32 (s, 3H, CH3), 3.38 (s, 3H, CH3O), 4.44 (s,
1H, ArCH), 4.51 (d, J = 6.3, Hz, 1H, OCHO), 4.56 (d, J = 6.3, Hz, 1H,
OCHO), 7.01–7.12 (m, 4H, 4 Â ArH). 13C NMR (75 MHz, CDCl3):
d = À3.9, 21.0, 55.3, 72.6, 94.8, 126.1, 128.8, 135.3, 137.6. Anal.
Calcd. for C13H22O2Si: C, 65.50; H, 9.30. Found: C, 65.36; H, 9.49%.
Acknowledgment
Financial support from the Università di Sassari (Fondo di Ate-
neo) is gratefully acknowledged.
3.3.20. 1,1-Diphenyl-1-methoxymethoxypentane (4jb)
References
Oil, purified by flash chromatography (hexane/EtOAc, 9:1; Rf:
0.61). Bp 120/1 (°C/Torr). 1H NMR (300 MHz, CDCl3): d = 0.84 (t,
J = 7.2 Hz, 3H, CH3), 1.04–1.20 (m, 2H, CH2), 1.21–1.30 (m, 2H,
CH2), 2.29–2.35 (m, 2H, CH2), 3.42 (s, 3H, CH3O), 4.52 (s, 2H,
OCH2O), 7.17–7.23 (m, 2H, 2 Â PhH), 7.24–7.31 (m, 4H, 4 Â PhH),
7.34–7.38 (m, 4H, 4 Â PhH). 13C NMR (75 MHz, CDCl3): d = 14.1,
23.0, 25.5, 37.2, 56.3, 83.1, 92.0, 126.7, 127.0, 127.8, 145.8. Anal.
Calcd. for C19H24O2: C, 80.24; H, 8.51. Found: C, 80.11; H, 8.69%.
[1] J. Clayden, Organolithiums: Selectivity for Synthesis, Pergamon, Amsterdam,
2002. p. 9.
[2] M. Schlosser, in: M. Schlosser (Ed.), Organometallics in Synthesis, Wiley, New
York, 1994, p. 1.
[3] (a) For the relative hierarchy of several DMG’s, see: E. Castagnetti, M.
Schlosser, Chem. Eur. J. 8 (2002) 799–804;
(b) V. Snieckus, Chem. Rev. 90 (1990) 879–933. and references therein.
[4] E. Napolitano, E. Giannone, R. Fiaschi, A. Marsili, J. Org. Chem. 48 (1983) 3653–
3657.
[5] S.J. Coutts, T.W. Wallace, Tetrahedron 50 (1994) 1175–11780.
[6] E. Marzi, A. Spitaleri, F. Mongin, M. Schlosser, Eur. J. Org. Chem. (2002) 2508–
2517.
[7] U. Azzena, L. Pilo, A. Sechi, Tetrahedron 54 (1998) 12389–12398. and
references therein.
[8] Metalation of aryl benzyl ethers was also investigated: J. Chodakowski, T. Klis´,
J. Serwatowski, Tetrahedron Lett. 46 (2005) 1963–1965.
[9] W.C. Still, J. Am. Chem. Soc. 100 (1978) 1481–1487. benzyl 1-ethoxyethyl ether
was metalated with sec-BuLi in THF at À78 °C, and alkylated at the benzylic
position with CH3I; no characterization of diastereoisomeric reaction products
was given.
3.3.21. 2-Trimethylsilyl-4-(1-methoxymethoxy)ethylanisole (5lb)
Oil, purified by flash chromatography (petroleum ether/EtOAc/
Et3N = 8:2:0.5; Rf: 0.59). 1H NMR (300 MHz, CDCl3): d = 0.26 (s,
9H, 3 Â CH3Si), 1.47 (d, J = 6.6 Hz, 3H, CH3Ar), 3.38 (s, 3H, CH3),
3.80 (s, 3H, CH3OAr), 4.55 (s, 1H, OCH2O), 4.71 (q, J = 6.6 Hz, 1H,
CH), 6.78–6.82 (m, 1H, ArH), 7.27–7.33 (m, 2H, 2 Â ArH). 13C
NMR (75 MHz, CDCl3): d = À1.0, 23.5, 55.1, 55.2, 73.4, 93.8, 109.3,
127.9, 128.8, 133.2, 134.5, 163.9. Anal. Calcd. for C14H24O3Si: C
62.64; H, 9.01. Found: C, 62.47; H, 9.14%.
[10] P. Graña, M.R. Paleo, F.J. Sardina, J. Am. Chem. Soc. 124 (2002) 12511–12514.
and references therein.
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3.4. Acidic hydrolysis of methoxymethyl ethers; general procedures
Acidic hydrolysis of acetals was performed according to a gen-
eral procedure described in Ref. [25]. Reaction products 8 and 9
were purified and characterized as follows:
[16] For an alternative route to aryl a-methoxymethyl anions, see: R.J. Linderman,
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[18] (a) Protection of hydroxyl groups as methoxymethyl (MOM) ethers is widely
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3.4.1. 4-Benzyloxy-1-phenylbutan-1-ol (8)
Oil, purified by flash chromatography (petroleum ether/
EtOAc = 8:2; Rf: 0.43). Bp 175/1 (°C/Torr). IR (neat): 3353 cmÀ1
(OH). 1H NMR (300 MHz, CDCl3): d = 1.60–1.90 (m, 4H, 2 Â CH2),
2.47 (1H, br s, OH), 3.51 (t, J = 6.3 Hz, 2H, CH2), 4.51 (s, 2H, CH2Ph),
4.70 (t, J = 6.3 Hz, 1H, CHPh), 7.24–7.35 (m, 10H, 10 Â ArH). 13C
NMR (75 MHz, CDCl3): d = 26.2, 36.5, 70.3, 73.0, 74.1, 125.8,
(b) T.W. Greene, P.G.M. Wuts, Protective Groups in Organic Synthesis, third
ed., Wiley, 1999.

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