Reductive lithiation of 1,3-dimethyl-2-arylimidazolidines

Article abstract of DOI:10.1016/j.tet.2005.01.093

Naphthalene catalyzed lithiation of 1,3-dimethyl-2-phenylimidazolidine led to cleavage of the benzylic carbon-nitrogen bond, with formation of an intermediate dianion. Under similar conditions, 1,3-dimethyl-2-(4-chlorophenyl) imidazolidine underwent regioselective cleavage of the aromatic carbon-chlorine bond, leading to a 4-formylphenyllithium equivalent, whilst 1,3-dimethyl-2-(4- methoxymethylphenyl)imidazolidine underwent regioselective cleavage of the benzylic carbon-oxygen bond, leading to a 4-formylbenzyllithium equivalent.

Full text of DOI:10.1016/j.tet.2005.01.093

Tetrahedron 61 (2005) 3177–3182
Reductive lithiation of 1,3-dimethyl-2-arylimidazolidines
*
Ugo Azzena, Giovanna Dettori, Luisa Pisano and Immacolata Siotto
`
Dipartimento di Chimica, Universita di Sassari, via Vienna 2, I-07100 Sassari, Italy
Received 23 September 2004; revised 6 December 2004; accepted 21 January 2005
Abstract—Naphthalene catalyzed lithiation of 1,3-dimethyl-2-phenylimidazolidine led to cleavage of the benzylic carbon–nitrogen bond,
with formation of an intermediate dianion. Under similar conditions, 1,3-dimethyl-2-(4-chlorophenyl)imidazolidine underwent
regioselective cleavage of the aromatic carbon–chlorine bond, leading to a 4-formylphenyllithium equivalent, whilst 1,3-dimethyl-2-(4-
methoxymethylphenyl)imidazolidine underwent regioselective cleavage of the benzylic carbon–oxygen bond, leading to a 4-formylbenzyl-
lithium equivalent.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
Furthermore, looking for protective groups suitable to
generate stable solutions of organolithium derivatives
bearing masked carbonyl groups,11 we investigated the
reductive lithiation of 1,3-dimethyl-2-(4-chlorophenyl)-
imidazolidine, 1b, and 1,3-dimethyl-2-(4-methoxymethyl)-
imidazolidine, 1c, and wish to report on the generation of
4-formylphenyllithium and 4-formylbenzyllithium
synthetic equivalents (Scheme 1).
The arene-mediated reductive lithiation of 2-aryl-substi-
tuted heterocycles is a highly effective reaction leading,
through regioselective cleavage of benzylic carbon–hetero-
atom bonds, to the generation of a wide array of
functionalized organolithium derivatives. Interesting
results on this topic include, inter alia, the reductive
cleavage of 4-aryl-1,3-dioxanes,1 2-aryl-1,3-oxazolidines,2
benzannelated cyclic ethers3,4 and amines,3 phthalans,5,6
thiophthalan,7 N-isopropyl-2-phenylpyrrolidine and
N-phenylisoindoline,8 and styrene oxide.9,10
2. Results and discussion
2.1. Synthesis of starting materials
We investigated an extension of this procedure to 1,3-
dimethyl-2-arylimidazolidines, and wish to report here that,
notwithstanding the known relative stability of benzylic
carbon–nitrogen bond to reductive metalation,2,3,8 1,3-
dimethyl-2-phenylimidazolidine, 1a, undergoes reductive
lithiation under particularly mild reaction conditions.
1,3-Dimethyl-2-arylimidazolidines 1a–c were synthesize0d
by refluxing the corresponding aldehyde with N,N -
dimethylethylenediamine in dry toluene, in the presence
of a catalytic amount of p-toluenesulfonic acid. Reductive
metalations were carried out in dry tetrahydrofuran (THF)
Scheme 1. Reductive lithiation of 2-aryl-substituted-1,3-dimethylimidazolidines 1a–c.
Keywords: Aromatic aldehydes; Lithiation; Protective groups; Reduction.
* Corresponding author. Tel.: C39 079229549; fax: C39 079229559; e-mail: ugo@uniss.it
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.01.093

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U. Azzena et al. / Tetrahedron 61 (2005) 3177–3182
under Ar, with an excess of Li metal and in the presence of a
catalytic amount of naphthalene (C10H8).
2.2. Reductive metalation of 1,3-dimethyl-2-phenyl-
imidazolidine, 1a
Reductive cleavage of imidazolidine 1a with 6 equiv of Li,
in the presence of a catalytic amount of C10H8 (10 mol%), at
K20 8C, afforded, after hydrolysis with water, N-benzyl-
N,N0-dimethylethylenediamine, 2aa, as the only reaction
product, in variable yields, depending upon the reaction
time (Scheme 2, Table 1, entries 1 and 2). Diamine 2aa is a
Scheme 2. Reductive lithiation and reaction with electrophiles of 1,3-
dimethyl-2-phenylimidazolidine, 1a.
Table 1. Reductive metalation of imidazolidine 1a and reaction with electrophilesa
Entry
Li equiv
T (8C)
t (h)
EX (equiv)
Product, EZ
Yield (%)b
1
2
3
4
5
6
7
8
9
6
6
6
6
12
12
12
12
12
K20
K20
K20
K20
K30
K30
K30
K30
K30
2.5
8.0
8.0
8.0
12.0
12.0
12.0
12.0
12.0
H2O
H2O
H2O
D2O
2aa, H
2aa, H
2aa, H
2ab, D
2ab, D
2ac, n-Bu
2ad, i-Pr
2ae, [(CH3)2CH]2COH
2af, (CH3)3CCHOHf
44c,d
O95c
85e
86c
91c
65
52
52
56
D2O
n-BuBr (1.1)
i-PrBr (1.1)
[(CH3)2CH]2CO (1.5)
(CH3)3CCHO (1.5)
a All reactions were run with 2.5 mmol of starting material, in the presence of a catalytic amount of C10H8 (10 mol%), unless otherwise indicated.
b Isolated yield, unless otherwise indicated.
c As determined by 1H NMR spectroscopy.
d 56% starting material was detected.
e 40 mmol of starting material were employed.
f
As a 77:23 mixture of diastereoisomers.
key intermediate in the synthesis (via alkylation or
acylation, followed by hydrogenolysis) of selectively
N-functionalized-N,N0-dimethylethylenediamines, a class
of potentially biologically active compounds.12 Therefore,
we find it interesting to scale up its preparation: lithiation of
40 mmol of imidazolidine 1a, afforded 34 mmol (85%
isolated yield) of diamine 2aa (Table 1, entry 3).
Under the conditions described in Table 1, entry 2 (6 equiv
of Li, 10 mol% of C10H8, K20 8C, 8 h), intermediate
formation of a functionalized benzylic organolithium
derivative was evidenced, by quenching the reduction
mixture with D2O (Table 1, entry 4). A somewhat better
Scheme 3. Reductive lithiation and reaction with electrophiles of 1,3-
result was obtained performing the reaction at K30 8C, in
dimethyl-2-(4-chlorophenyl)imidazolidine, 1b.
the presence of 12 equiv of Li, during 12 h (Table 1, entry
5). This intermediate was successfully trapped with several
Table 2. Reductive metalation of imidazolidine 1b and reaction with electrophilesa
Entry
EX (T 8C)b
Product, EZ
Yield (%)c
1
2
3
4
5
6
7
8
H2O (K40)
D2O (K40)
n-BuBr (K80)
(CH3)3CCHO (K40)
PhCHO (K40)
[(CH3)2CH]2CO (K80)
HCOOCH3 (K80)
HCOOCH3 (K80)f
1a, H
2ba, D
1a, H
O95d
O90d
d,e
—
3bb, (CH3)3CCHOH
3bc, PhCHOH
3bd, [(CH3)2CH]2COH
3be, CHO
72
76
64
65
54
3bf, ArCHOHg
a All reactions were run at K40 8C, during 3 h, in the presence of 6 equiv of Li and a catalytic amount of C10H8 (5 mol%).
b Temperature of addition of the electrophile (2 equiv, unless otherwise indicated).
c Isolated yield, unless otherwise indicated.
d As determined by 1H NMR spectroscopy.
e O95% 1a was detected.
The electrophile (0.45 equiv) was added at K80 8C, then the mixture was allowed to reach K25 8C within 4 h, before aqueous work up.
f
g ArZ4-(CHO)C6H4.

U. Azzena et al. / Tetrahedron 61 (2005) 3177–3182
3179
electrophiles, including primary and secondary alkyl
halides, as well as enolizable and non-enolizable carbonyl
derivatives, affording diamines 2ac–2af in satisfactory
yields (Table 1, entries 6–9).
The resulting products were not isolated, but directly
submitted to acidic work up (2 N H2SO4/THFZ1:1, rt,
1 h), to give the corresponding substituted benzaldehydes
3bb–3bd, in satisfactory isolated yields (Table 2, entries
4–6).
2.3. Reductive metalation of 1,3-dimethyl-2-(4-chloro-
phenyl)imidazolidine, 1b
Results obtained quenching the reduction mixture with
HCOOCH3, followed by acidic work up, are strongly
dependent upon quenching conditions. Indeed, quenching
with 2 equiv of the electrophile led to formation of
terephthalaldehyde, 3be, as the main reaction product
(Table 2, entry 7), whilst quenching with 0.45 equiv of the
electrophile led to alcohol 3bf, in 54% isolated yield
(Table 2, entry 8).
Application of the reductive lithiation procedure to
imidazolidine 1b allowed regioselective cleavage of the
carbon–chlorine bond. Indeed, reduction of 1b at K40 8C
during 3 h, with 6 equiv of Li metal and in the presence of
5 mol% of C10H8, afforded quantitatively imidazolidine 1a
(Scheme 3, Table 2, entry 1). Quenching the reduction
mixture with D2O evidenced formation of an intermediate
organolithium (Table 2, entry 2). However, quenching the
reduction mixture with n-BuBr at K40 8C (not reported in
Table 2) or at K80 8C (Table 2, entry 3), led to exclusive
recovery of imidazolidine 1a.
Relatively similar results were obtained employing
ClCOOCH3 as an electrophile [Eq. 1; ArZ4-(CHO)C6H4].
To rationalize the last result, we suggest that the
organometal acts as a base towards the alkyl halide,
promoting a b-elimination reaction. Support for this
hypothesis was provided as follows: quenching the
reduction mixture with n-BuBr, followed by D2O work up
of the resulting mixture, led to recovery of unlabelled 1a, in
almost quantitative yield.
(1)
Direct quenching at K80 8C, with 1.1 equiv of the
electrophile led, after acidic work up, to a mixture of
ketone 3bh and alcohol 3bi almost in a 4:6 ratio (25 and
30% isolated yield, respectively), together with trace
amounts of ester 3bg. However, addition of the reduction
mixture to 2 equiv of the electrophile, afforded a reaction
mixture containing 3bg/3bh/3bi in a 41:14:45 ratio. From
this mixture, ester 3bg was recovered in 32% isolated yield.
More satisfactory results were obtained quenching the
intermediate organolithium with aldehydes and a ketone.
2.4. Reductive metalation of 1,3-dimethyl-2-(4-methoxy-
methylphenyl)-imidazolidine, 1c
As reported above, reductive lithiation of imidazolidine 1b
did not allow the introduction of an alkyl chain upon the
aromatic ring (see above). To overcome this limitation, and
taking into account the lower basicity of benzylic
organometals as compared to aromatic ones,13 we investi-
gated the reductive lithiation of 1,3-dimethyl-2-(4-methoxy-
methylphenyl)imidazolidine, 1c, as an approach to the
Scheme 4. Reductive lithiation and reaction with electrophiles of 1,3-
dimethyl-2-(4-methoxymethylphenyl)imidazolidine, 1c.
generation of
a 4-formylbenzyl-lithium equivalent
(Scheme 4, Table 3).14,15
Table 3. Reductive metalation of imidazolidine 1c and reaction with electrophilesa
Entry
Li equiv
T (8C)
t (h)
EX (equiv)
Product, EZ
Yield (%)b
1
2
3
4
5
6
7
8
6c
K40
K40
K50
K80
K50
K50
K50
K50
4.5
4.5
6.0
12.0
6.0
6.0
6.0
6.0
H2O
D2O
D2O
D2O
2ca, H
2ca, H
2cb, D
2cb, D
2cb, D
3cc, n-Bu
3cd, (CH2)4Arg
3ce, (CH2)7OTHP
O95
–
d
6c
20
20
30
30
30
30
67
70e
86
D2O
n-BuBr (1.2)
Br(CH2)3Br (0.45)
Br(CH2)7OTHPh (1.2)
71f
70f
45f
a All reactions were run in the presence of a catalytic amount of C10H8 (10 mol%), unless otherwise indicated.
b As determined by 1H NMR spectroscopy, unless otherwise indicated.
c In the presence of 5 mol% of C10H8.
d No deuterium incorporation was detected.
e 32% of 1c was also detected.
Isolated yield.
f
g ArZ4-(CHO)C6H4.
h THPZtetrahydropyranyl.

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U. Azzena et al. / Tetrahedron 61 (2005) 3177–3182
We obtained regioselective, and quantitative, reductive
dealkoxylation of imidazolidine 1c within 4.5 h, under
conditions otherwise identical to those reported for
imidazolidine 1b (Table 3, entry 1); no evidence for the
formation of products of carbon–nitrogen bond cleavage
was obtained. However, D2O quenching of the reduction
mixture, did not show the intermediate formation of any
stable organometal (Table 3, entry 2). Whilst investigating
the effect of the relative amount of the metal and catalyst, as
well as of reaction temperature, on the formation of an
intermediate carbanion, (Table 3, entries 3 and 4), we found
that reduction of imidazolidine 1c with 30 equiv of the
metal, 10 mol% of C10H8, at K50 8C during 6 h, followed
by D2O quenching, led to complete conversion of starting
material, and recovery of 1,3-dimethyl-2-(4-deuteromethyl-
phenyl)imidazolidine, 2cb, with 86% isotopic purity
(Table 3, entry 5).
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. 4-Methoxymethylbenzaldehyde
was synthesized as described in Ref. 18. 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 with SiMe4 as internal standard. CDCl3 for
recording spectra of imidazolidine-derivatives was stored
over K2CO3 in the refrigerator. Deuterium incorporation
was calculated by monitoring the 1H NMR spectra of crude
reaction mixtures, and comparing the integration of the
signal corresponding to protons in the arylmethyl (2ab, 2cb)
or aryl (2ba) position with that of known signals. 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 of the
According to our expectations, quenching of the reduction
mixture with n-BuBr, with Br(CH2)3Br and with a protected
bromoalcohol, followed by acidic work up (see above),
afforded benzaldehydes 3cc, 3cd, and 3ce, respectively, in
satisfactory isolated yields. Interestingly, in the last
example, acidic work up allowed selective removal of the
aldehyde protecting group in the presence of a tetrahydro-
pyranyl ether.
`
Dipartimento di Chimica, Universita di Sassari.
4.2. Preparation of imidazolidines 1a–c. General
procedure
A solution of the appropriate benzaldehyde (0.15 mol), N,N0-
dimethylethylenediamine (0.17 mol, 14.54 g, 17.6 mL) and
p-toluenesulfonic acid (150 mg, 0.8 mmol) in 100 mL of
dry toluene, was distilled with fractionation under dry N2,
until the azeotrope toluene-H2O was distilled away. The
mixture was chilled at 0 8C and triethylamine (5 mL,
36 mmol) was added at once. The mixture was stirred at rt
for 5 min, washed with saturated NaHCO3 (2!20 mL),
H2O (2!20 mL), dried (K2CO3), and evaporated.
3. Conclusions
C10H8-catalyzed reductive lithiation of imidazolidine 1a
represents an extension of our approach to the generation of
a-amino-substituted benzyllithium derivatives via a reduc-
tive metalation procedure,2,16,17 Interestingly, this cleavage
reaction occurs under particularly mild conditions. Indeed,
reductive lithiation of similar carbon–nitrogen bonds, for
example, of N-isopropyl-2-phenylpirrolidine or N-phenyl-
isoindoline, occurs at room temperature,8 and it is worth
noting that less than 10% of the literature concerning the
reductive metalation of heterocycles refers to carbon–
nitrogen bond cleavages.10
Crude products were purified by distillation. Imidazolidines
1a (24.7 g, 0.14 mol, 93%)19 and 1b (27.4 g, 0.13 mol,
87%)20 were characterized by comparison with literature
data. Imidazolidine 1c was characterized as follows.
4.2.1. 2-(4-Methoxymethylphenyl)-1,3-dimethylimidazo-
lidine, 1c. 23.5 g, 0.11 mol, 73%. Colourless oil, bp 116–
119 8C/1 mmHg. (Found: C, 70.95; H, 9.30; N, 12.56;
C13H20N2O requires C, 70.87; H, 9.15; N, 12.72); dH 2.17
(6H, s, 2!CH3), 2.52–2.59 (2H, m, CH–CH), 3.25 (1H, s,
CH-Ar), 3.37–3.45 (2H, m, CH–CH), 3.40 (3H, s, CH3O),
4.46 (2H, s, CH2–O), 7.29–7.36 (2H, m, 2!ArH), 7.39–
7.45 (2H, m, 2!ArH); dC 39.4, 53.3, 58.1, 74.5, 92.1, 127.6,
128.9, 138.4, 139.3.
Nevertheless, the imidazolidine moiety can be employed as
an efficient carbonyl protecting group in the reductive
lithiation of suitably functionalized benzaldehydes. Indeed,
lithiation of chlorine-substituted imidazolidine 1b
allowed regioselective cleavage of carbon–chlorine bond;
interestingly, this procedure represents the first report
concerning the generation of a stable solution of a synthetic
equivalent of 4-formylphenyllithium, under the above
reported reaction conditions.11 Moreover, reductive
metalation of methoxymethyl-substituted imidazolidine 1c
allowed the generation of a stable solution of a 4-formyl-
benzyllithium analogue, whose reactivity was shown to be
complementary to that of the parent 4-formylphenyllithium
equivalent.
4.3. Reductive cleavage of imidazolidines 1a–c, and
reaction with electrophiles. General procedure
Li wire (6–12 equiv) was placed under Ar in a 50 mL two-
necked flask equipped with reflux condenser and magnetic
stirrer, and suspended in THF (7 mL). A catalytic amount of
C10H8 (5–10 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
(Tables 1–3) and a solution of the appropriate imidazolidine
(2.5 mmol), dissolved in 3 mL of dry THF, was added
dropwise. The mixture was stirred for the reported time
(Tables 1–3), and a solution of the appropriate electrophile
4. Experimental
4.1. General
Boiling and melting points are uncorrected; the air bath

U. Azzena et al. / Tetrahedron 61 (2005) 3177–3182
3181
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.
chromatography (AcOEt/Et3NZ7:3); colourless oil, which
solidifies upon standing, mp 95–96 8C. (Found C, 73.87; H,
11.19; N, 9.36; C18H32N2O requires C, 73.92; H, 11.03; N,
9.58); Rf 0.54 (AcOEt/Et3NZ7:3); nmax 3308 cmK1 (nujol);
dH 0.68 (3H, d, JZ7.2 Hz, CH3), 0.95 (3H, d, JZ7.2 Hz,
CH3), 1.13 (3H, d, JZ6.9 Hz, CH3), 1.16 (3H, d, JZ6.9 Hz,
CH3), 1.84–1.99 (2H, m, 2!CH), 2.31 (3H, s, CH3N), 2.44
(3H, s, CH3N), 2.46–2.74 (3H, m, 3!CH), 2.82–2.96 (1H,
m, CH), 3.70 (1H, s, CH), 7.20–7.38 (3H, m, 3!ArH),
7.48–7.53 (2H, m, 2!ArH); dC 18.6, 18.8, 20.2, 34.2, 34.7,
36.8, 41.1, 50.2, 54.8, 70.8, 81.6, 126.5, 127.3, 131.4, 136.6.
D2O quenching was performed by slow dropwise addition
of 1 mL of the electrophile, dissolved in 1 mL of dry THF,
followed by aqueous work up as described above.
Derivatives 2bb–2bi and 2cb–2ce were directly hydrolyzed
to the corresponding benzaldehydes 3bb–3bi and 3cb–3ce,
respectively, by acidic hydrolysis (THF/2 N H2SO4Z1:1,
10 mL, 1 h, rt).
4.3.5. 1-[Methyl-(2-methylaminoethyl)amino]-1-phenyl-
3,3-dimethylbutan-2-ol, 2af. First diastereoisomer: puri-
fied by flash-chromatography (CH2Cl2/Et3NZ9:1); colour-
less oil. (Found C, 72.62; H, 10.85; N, 10.43; C16H28N2O
requires C, 72.68; H, 10.67; N, 10.59); Rf 0.43 (CH2Cl2/
Et3NZ9:1); nmax 3316 cmK1 (neat); dH 0.74 (9H, s, 3!
CH3), 2.13 (3H, s, CH3N), 2.20–2.60 (4H, br m, CH2, NH,
OH), 2.46 (3H, s, CH3N), 2.64–2.79 (2H, m, CH2), 3.56
(1H, d, JZ9.9 Hz, CH), 3.78 (1H, d, JZ9.9 Hz, CH), 7.15–
7.18 (2H, m, 2!ArH), 7.27–7.36 (3H, m, 3!ArH); dC 26.9,
34.8, 36.6, 37.4, 49.3, 53.1, 68.9, 74.3, 127.5, 127.8, 129.9,
135.4; second diastereoisomer: purified by flash-chroma-
tography (CH2Cl2/Et3NZ9:1); colourless oil. Rf 0.31
(CH2Cl2/Et3NZ9:1); dH 0.82 (9H, s, 3!CH3), 2.16 (3H,
s, CH3N), 2.40 (3H, s, CH3N), 2.46–2.54 (4H, br m, CH2,
NH, OH), 2.59–2.70 (2H, m, CH2), 3.47 (1H, d, JZ4.8 Hz,
CH), 3.84 (1H, d, JZ4.8 Hz, CH), 7.20–7.37 (5H, m, 5!
ArH); dC 26.7, 34.8, 36.5, 39.4, 49.4, 54.0, 71.0, 77.7, 127.4,
127.8, 130.5, 137.2.
Compound 2aa21 was purified by distillation and charac-
terized by comparison with literature data. Other products
were purified by flash chromatography (AcOEt/petroleum
ether or AcOEt/petroleum ether/Et3N). Compounds 3bh,22
2ca,20 and 3cc,23 were characterized by comparison with
literature data. Compounds 3be and 3bg were characterized
by comparison with commercially available samples. Other
products were characterized as following.
4.3.1. N-(Phenyl)deuteromethyl-N,N0-dimethylethylene-
diamine, 2ab. Purified by flash-chromatography (AcOEt/
petroleum ether/Et3NZ7:1:3); colourless oil. (Found C,
73.56; H, 10.84; N, 15.59; C11H17DN2 requires C, 73.69; H,
10.68; N 15.63); Rf 0.41 (AcOEt/petroleum ether/Et3NZ
7:1:3); nmax 3326 cmK1 (neat); dH 1.68 (1H, br s, NH), 2.18
(3H, s, CH3), 2.41 (3H, s, CH3), 2.53 (2H, t, JZ5.7 Hz,
CH2N), 2.68 (2H, t, JZ5.7 Hz, CH2N), 3.46 (1H, br s,
CHD), 7.22–7.32 (5H, m, 5!ArH); dC 36.5, 42.1, 49.3,
56.7, 62.3 (t, JZ20 Hz), 126.9, 128.2, 128.9, 139.1.
4.3.6. 1,3-Dimethyl-2-(4-deuterophenyl)imidazolidine,
2ba. Purified by flash-chromatography (AcOEt/petroleum
ether/Et3NZ7:3:1); colourless oil. (Found C, 74.32; H,
9.81; N, 15.65; C11H15DN2 requires C, 74.53; H, 9.67; N
15.80); Rf 0.53 (AcOEt/petroleum ether/Et3NZ7:3:1); dH
2.18 (6H, s, 2!CH3), 2.53–2.59 (2H, CH–CH), 3.25 (1H, s,
CH), 3.38–3.44 (2H, m, CH–CH), 7.32–7.38 (2H, m, 2!
ArH), 7.42–7.47 (2H, m, 2!ArH); dC 39.5, 53.3, 92.5,
128.1, 128.2 (t, JZ18 Hz), 128.8, 139.8.
4.3.2. 1-[Methyl-(2-methylaminoethyl)amino]-1-phenyl-
pentane, 2ac. Purified by flash-chromatography (AcOEt/
petroleum ether/Et3NZ7:1:3); colourless oil. (Found C,
76.69; H, 11.27; N, 11.90; C15H26N2 requires C, 76.87; H,
11.18; N 11.95); Rf 0.46 (AcOEt/petroleum ether/Et3NZ
7:1:3); nmax 3320 cmK1 (neat); dH 0.84 (3H, t, JZ7.5 Hz,
CH3), 1.02–1.38 (5H, m, 2!CH2, NH), 1.68–1.94 (2H, m,
CH2), 2.14 (3H, s, CH3N), 2.41 (3H, s, CH3N), 2.48–2.68
(4H, m, 2!CH2N), 3.43 (1H, dd, JZ8.7, 5.7 Hz, CHPh),
7.17–7.35 (5H, m, 5!ArH); dC 14.0, 22.7, 29.0, 31.9, 36.3,
37.8, 49.1, 53.0, 68.9, 126.8, 127.8, 128.7, 139.9.
4.3.7. 4-(1-Hydroxy-2,2-dimethylpropyl)benzaldehyde,
3bb. Purified by flash-chromatography (AcOEt/petroleum
etherZ3:7); thick colourless oil. (Found C, 74.82; H, 8.47;
C12H16O2 requires C, 74.97; H, 8.39); Rf 0.43 (AcOEt/
petroleum etherZ3:7); nmax 1707 cmK1 (nujol); dH 0.94 (9H,
s, 3!CH3), 2.07 (1H, br s, OH), 4.48 (1H, s, CH), 7.46–7.54
(2H, m, 2!ArH), 7.80–7.88 (2H, m, 2!ArH), 10.00 (1H, s,
CHO); dC 25.8, 35.8, 81.9, 128.3, 129.0, 135.6, 149.1, 192.0.
4.3.3. 1-[Methyl-(2-methylaminoethyl)amino]-1-phenyl-
2-methylpropane, 2ad. Purified by flash-chromatography
(AcOEt/petroleum ether/Et3NZ7:1:3); colourless oil.
(Found C, 76.26; H, 11.04; N, 12.63; C14H24N2 requires
C, 76.31; H, 10.98; N, 12.71); Rf 0.42 (AcOEt/petroleum
ether/Et3NZ7:1:31); nmax 3324 cmK1(neat); dH 0.61 (3H, d,
JZ6.6 Hz, CH3), 0.99 (3H, d, JZ6.6 Hz, CH3), 2.00 (3H, s,
CH3N), 2.10–2.34 (4H, m, 2!CH, CH(Me)2, NH), 2.38
(3H, s, CH3N), 2.51–2.58 (2H, m, 2!CH), 2.96 (1H, d, JZ
10.2 Hz, CHPh), 7.01–7.08 (2H, m, 2!ArH), 7.13–7.27
(3H, m, 3!ArH); dC 20.2, 20.7, 28.4, 36.4, 36.6, 49.0, 53.2,
75.5, 126.7, 127.6, 129.2, 137.2.
4.3.8. 4-Formylbenzhydrol, 3bc. Purified by flash-
chromatography (AcOEt/petroleum ether/Et3NZ4:6:1);
colourless oil. (Found C, 79.01; H, 5.87; C14H12O2 requires
C, 79.22; H, 5.70); Rf 0.45 (AcOEt/petroleum ether/Et3NZ
4:6:1); nmax 3424, 1697 cmK1 (neat); dH 2.60 (1H, br s, OH),
5.86 (1H, s, CH), 7.25–7.35 (5H, m, 5!ArH), 7.52–7.58
(2H, m, 2!ArH), 7.80–7.86 (2H, m, 2!ArH), 9.94 (1H, s,
CHO); dC 75.8, 126.7, 126.9, 128.0, 128.7, 129.9, 135.5,
143.1, 150.5, 192.0.
4.3.4. 2,4-Dimethyl-3-[methyl-(2-methylaminoethyl)-
amino]phenylmethylpentan-3-ol, 2ae. Purified by flash-
4.3.9. 2,4-Dimethyl-3-(4-formylphenyl)pentan-3-ol, 3bd.
Purified by flash-chromatography (AcOEt/petroleum ether/

3182
U. Azzena et al. / Tetrahedron 61 (2005) 3177–3182
Et3NZ2:9:1); white solid, mp 103–105 8C (Et2O). (Found
C, 76.12; H, 9.31; C14H20O2 requires C, 76.33; H, 9.15); Rf
0.48 (AcOEt/petroleum ether/Et3NZ2:9:1); nmax 3465,
1692 cmK1 (nujol); dH 0.78 (6H, d, JZ6.6 Hz, 2!CH3),
0.85 (6H, d, JZ6.6 Hz, 2!CH3), 1.62 (1H, br s, OH), 2.33
(2H, ept, JZ6.6 Hz, 2!CH), 7.56–7.62 (2H, m, 2!ArH),
7.81–7.88 (2H, m, 2!ArH), 10.02 (1H, s, CHO); dC 16.4,
17.4, 34.1, 81.3, 127.4, 128.8, 134.7, 150.5, 192.1.
References and notes
1. Arrica, M. A.; Azzena, U.; Pilo, L.; Piras, E. Tetrahedron Lett.
2002, 43, 5137–5139.
2. Azzena, U.; Pilo, L.; Piras, E. Tetrahedron 2000, 56,
3775–3780.
3. Azzena, U.; Demartis, S.; Pilo, L.; Piras, E. Tetrahedron 2000,
56, 8375–8382.
4. Foubelo, F.; Moreno, B.; Yus, M. Tetrahedron 2004, 60,
4655–4662.
4.3.10. 4,40-Diformylbenzhydrol, 3bf. Purified by flash-
chromatography (AcOEt/petroleum ether/Et3NZ7:4:1);
white solid, mp 98–100 8C (triturated form petroleum
ether). (Found C, 74.86; H, 5.15; C15H12O3 requires C,
74.99; H, 5.03); Rf 0.50 (AcOEt/petroleum ether/Et3NZ
7:4:1); nmax 1674 cmK1 (nujol); dH 2.82 (1H, br s, OH), 5.97
(1H, s, CH), 7.52–7.60 (4H, m, 4!ArH), 7.82–7.90 (4H, m,
4!ArH), 9.98 (2H, s, 2!CHO); dC 75.4, 127.0, 130.1,
136.0, 149.5, 191.7.
5. Almena, J.; Foubelo, F.; Yus, M. Tetrahedron 1995, 51,
3351–3364.
6. Azzena, U.; Demartis, S.; Melloni, G. J. Org. Chem. 1996, 61,
4913–4919.
7. Almena, J.; Foubelo, F.; Yus, M. J. Org. Chem. 1996, 61,
1859–1862.
8. Almena, J.; Foubelo, F.; Yus, M. Tetrahedron 1996, 52,
8545–8564.
4.3.11. 4,40,400-Triformyltrityl alcohol, 3bi. Purified by
flash-chromatography (AcOEt/petroleum etherZ4:6); thick
colourless oil. (Found C, 76.59; H, 4.81; C22H16O4 requires
C, 76.73; H, 4.68); Rf 0.22 (AcOEt/petroleum etherZ4:6);
nmax 3461, 1682 cmK1 (neat); dH 3.41 (1H, br s, OH), 7.38–
7.46 (6H, m, 6!ArH), 7.74–7.84 (6H, m, 6!ArH), 9.92
(3H, s, 3!CHO); dC 81.7, 128.4, 129.7, 135.8, 151.5, 191.6.
9. Bartmann, E. Angew. Chem., Int. Ed. Engl. 1986, 25, 653–654.
10. For recent reviews on the reductive lithiation of oxygen-,
nitrogen- and sulfur-containing heterocycles, see: Yus, M.
Pure Appl. Chem. 2003, 75, 1453–1475. Yus, M.; Foubelo, F.
Targets Heterocycl. Syst. 2002, 6, 136–171.
11. Reductive lithiation, and reaction with electrophiles under
Barbier conditions, of chlorine-substituted 2-aryl-1,3-dioxo-
´
lanes, was already investigated: Huerta, F. F.; Gomez, C.; Yus,
M. Tetrahedron 1999, 55, 4043–4050.
´
12. See for example (a) Bolos, J.; Gubert, S.; Anglada, L.; Planas,
4.3.12. 1,3-Dimethyl-2-(4-deuteromethylphenyl)imi-
dazolidine, 2cb. Purified by flash-chromatography
(AcOEt/petroleum ether/Et3NZ7:3:1); colourless oil; Rf
0.55 (AcOEt/petroleum ether/Et3NZ7:3:1); dH 2.17 (6H, s,
2!CH3N), 2.33 (2H, t, JZ2.1 Hz, CH2D), 2.51–2.57 (2H,
m, CH–CH), 3.21 (1H, s, CHAr), 3.36–3.43 (2H, m, CH–
CH), 7.14–7.19 (2H, m, 2!ArH), 7.29–7.34 (2H, m, 2!
ArH); dC 21.2 (t, JZ21 Hz), 39.5, 53.3, 92.3, 128.7, 128.9,
136.7, 138.1.
´ ´
J. M.; Burgarolas, C.; Castello, J. M.; Sacristan, A.; Ortiz, J. A.
J. Med. Chem. 1996, 39, 2962–2970. (b) Manoury, P. M.;
`
Binet, J. L.; Dumas, A. P.; Lefevre-Borg, F.; Cavero, I. J. Med.
Chem. 1986, 29, 19–25.
13. Schlosser, M. Organoalkali reagents. In Organometallics in
Synthesis, A Manual; Schlosser, M., Ed.; Wiley: New York,
1994; pp 1–166; particularly pages 18–22.
14. Azzena, U.; Carta, S.; Melloni, G.; Sechi, A. Tetrahedron
1997, 53, 16205–16212.
4.3.13. 4-[5-(4-Formylphenyl)pentyl]benzaldehyde, 3cd.
Purified by flash chromatography (AcOEt/petroleum
etherZ2.5:7.5); white solid, mp 75 8C (AcOEt/petroleum
ether); (Found C, 81.31; H, 7.25; C19H20O2 requires C,
81.40; H, 7.19); Rf 0.44 (AcOEt/petroleum etherZ2.5:7.5);
nmax 1687 cm-1 (nujol); dH 1.34–1.46 (2H, m, CH2), 1.69
(4H, quint, JZ7.8 Hz, 2!CH2), 2.69 (4H, t, JZ7.8 Hz,
ArCH2), 7.30–7.36 (4H, m, 4!ArH), 7.77–7.83 (4H, m,
4!ArH), 9.97 (2H, s, CHO); dC 28.8, 30.8, 36.0, 129.0,
129.9, 134.5, 150.0, 191.9.
15. Azzena, U.; Dettori, G.; Idini, M. V.; Pisano, L.; Sechi, G.
Appl. Organometal. Chem. 2003, 17, 851–855.
16. Azzena, U. J. Chem. Soc., Perkin Trans. 1 2002, 360–365.
17. Azzena, U.; Pisano, L.; Pittalis, M. Heterocycles 2004, 63,
401–409.
18. Wang, W.; Li, T.; Attardo, G. J. Org. Chem. 1997, 62,
6598–6602.
19. Lambert, J. B.; Wang, G.-T.; Huseland, D. E.; Takiff, L. C.
J. Org. Chem. 1987, 52, 68–71.
20. Fife, T. H.; Hutchins, J. E. C. J. Am. Chem. Soc. 1976, 98,
2536–2543.
4.3.14. 4-[8-(Tetrahydropyran-2-yloxy)octyl]benzalde-
hyde, 3ce. Purified by flash chromatography (AcOEt/
petroleum etherZ1.5:8.5); colourless oil; (Found C,
75.25; H, 9.68; C20H30O3 requires C, 75.43; H, 9.50); Rf
0.34 (AcOEt/petroleum etherZ1.5:8.5); nmax (neat)
1703 cmK1; dH 1.22–1.92 (18H, m, 9!CH2), 2.68 (2H, t,
JZ7.5 Hz, CH2Ar), 3.38 (1H, dt, JZ9.3, 6.6 Hz, CHO),
3.46–3.55 (1H, m, CHO), 3.73 (1H, dt, JZ9.3, 6.9 Hz,
CHO), 3.82–3.92 (1H, m, CHO), 4.53–4.60 (1H, m,
OCHO), 7.31–7.36 (2H, m, 2!ArH), 7.76–7.82 (2H, m,
2!ArH), 9.97 (1H, s, ArCHO); dC 19.7, 25.5, 26.2, 29.1,
29.3, 29.7, 30.7, 30.8, 31.0, 36.2, 62.3, 67.6, 98.9, 129.0,
129.8, 134.4, 150.4, 192.0.
21. Salerno, A.; Ceriani, V.; Perillo, I. A. J. Heterocycl. Chem.
1992, 29, 1725–1733.
22. Denholm, A. A.; George, M. H.; Hailes, H. C.; Tiffin, P. J.;
Widdowson, D. A. J. Chem. Soc., Perkin Trans. 1 1995,
541–547.
23. Koide, Y.; Hasegawa, T.; Takahashi, A.; Endo, A.; Mochizuki,
N.; Nakagawa, M.; Nishida, A. J. Med. Chem. 2002, 45,
4629–4638.