Optional ortho and lateral lithiations of 4,4-dimethyl-2-(o-tolyl)oxazolines

Article abstract of DOI:10.1016/S0040-4039(02)02318-3

4,4-Dimethyl-2-(o-tolyl)oxazolines 1 undergo normal lateral lithiation at the benzylic position by treatment with sec-BuLi in diethyl ether at -78°C. In contrast, metalation of 1 with sec-BuLi/TMEDA in diethyl ether at the same temperature leads to ortho-

Full text of DOI:10.1016/S0040-4039(02)02318-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 9069–9072
Optional ortho and lateral lithiations of
4,4-dimethyl-2-(o-tolyl)oxazolines
Naruki Tahara, Tsutomu Fukuda and Masatomo Iwao*
Department of Applied Chemistry, Faculty of Engineering, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan
Received 5 September 2002; revised 9 October 2002; accepted 11 October 2002
Abstract—4,4-Dimethyl-2-(o-tolyl)oxazolines 1 undergo normal lateral lithiation at the benzylic position by treatment with
sec-BuLi in diethyl ether at −78°C. In contrast, metalation of 1 with sec-BuLi/TMEDA in diethyl ether at the same temperature
leads to ortho-lithiation at the 6%-position. Rationalization for the unusual ortho-lithiation of 1 is proposed. © 2002 Elsevier
Science Ltd. All rights reserved.
Directed lithiation has been recognized as an excellent
method for the synthesis of regiospecifically substituted
aromatic compounds.1 The lithiation of benzene deriva-
tives occurs selectively at the ortho-position to a direct-
ing group (ortho-lithiation). However, if a methyl group
exists at the ortho-position to the directing group,
deprotonation proceeds at the adjacent-benzylic posi-
tion preferentially due to intrinsic high acidity of the
benzylic protons (lateral lithiation).2 The lateral lithia-
tion is especially facile for o-toluic acid and derivatives,
such as esters, amides, nitriles, and 2-oxazolines.2 This
may be rationalized by the additional stabilization of
the benzylic anion by its extended delocalization to the
carbonyl (or its equivalent) moiety. The lateral lithia-
tion of 4,4-dimethyl-2-(o-tolyl)oxazoline (1a) has been
reported by Gschwend and Hamden.3 We have reinves-
tigated this reaction and discovered very unusual ortho-
lithiation of 1a (Scheme 1).4 Herein, we report this
interesting finding.
The regioselectivity of the lithiation of 1a was estimated
by methylation of the lithio species followed by capil-
lary column GC analysis. Thus, a solution of 1a (1
mmol) in an appropriate solvent (5 mL) was treated
with sec-BuLi (1.2 mmol) at −78°C for 1 h and the
resulting lithio species were reacted with MeI (3.6
mmol) at −78°C for 3 h. Yields of the recovered 1a, the
lateral methylation product 2, and the ortho-methyla-
tion product 3 are shown in Table 1. The lithiation
proceeded smoothly in diethyl ether or THF, but it was
sluggish in hexane. However, all reactions were highly
lateral-selective (entries 1–3). In contrast, when the
lithiation was carried out in the presence of TMEDA
(1.5 equiv.) in hexane or diethyl ether, the reaction
underwent ortho-selectively (entries 4 and 5). The
remarkable effect of TMEDA was not observed in
THF (entry 6). This is apparently due to the strong
coordinating ability of THF which overrides the chelat-
ing effect of TMEDA.5 The ortho-selectivity was
Scheme 1.
* Corresponding author. Fax: +81-95-843-7313; e-mail: iwao@net.nagasaki-u.ac.jp
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02318-3

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N. Tahara et al. / Tetrahedron Letters 43 (2002) 9069–9072
Table 1. Lithiation–methylation of 4,4-dimethyl-2-(o-tolyl)oxazoline (1a)
Entry
Additive (equiv.)
Solvent
1a (%)a
2 (%)a
3 (%)a
2:3
1
2
3
4
5
6
7
8
None
None
None
Hexane
Et2O
THF
Hexane
Et2O
THF
Et2O
Et2O
Et2O
Et2O
Et2O
65.4
2.1
1.9
7.4
81.1
90.7
13.9
14.8
94.6
9.9
8.9
8.1
6.3
82.1
0
0.7
4.2
50.1
68.3
4.7
67.2
66.4
63.6
1.3
–
116:1
21.6:1
1:3.6
1:4.6
20.1:1
1:6.8
1:7.5
1:7.9
4.8:1
74.6:1
TMEDA (1.5)
TMEDA (1.5)
TMEDA (1.5)
TMEDA (3.0)
TMEDA (5.0)
TMEDA (10.0)
PMDTA (1.5)
Sparteine (1.5)
26.9
11.3
0.9
15.0
17.9
23.5
90.0
15.3
9
10
11
1.1
a Yield was determined by capillary column GC analysis using naphthalene as an internal standard.
improved in accord with increasing amount of
TMEDA (entries 5, 7–9). A synthetically useful level of
selectivity (ortho versus lateral=7.9:1) was achieved by
using 10 equiv. of TMEDA (entry 9).6 The ortho-direct-
ing effect induced by an external ligand is specific for
TMEDA. Other nitrogen ligands, such as N,N,N%,
N¦,N¦-pentamethyldiethylenetriamine (PMDTA) and
spartein, did not exert the ortho-directing effect (entries
10 and 11).
p-chloro derivative 1c, the ortho-selectivity was excel-
lent (entry 6).
Next, we examined the effects of the methyl group at
the oxazoline 4-position using mono- and non-methyl-
ated substrates 1d and 1e (entries 7–10). The lateral
selectivity of the lithiation of these substrates in the
absence of TMEDA was excellent to give 3,4-dihy-
droisocoumarin 4a exclusively (entries 7 and 8). On the
other hand, the ortho-selectivity in the presence of
TMEDA decreased considerably (entries 9 and 10).
Thus, two methyl groups at the oxazoline 4-position are
essential to lead the high ortho-selectivity. Based on
these critical results, we offer a tentative rationalization
for the unusual ortho-lithiation of 1 (Fig. 1). Both ortho
and lateral lithiations may start with initial coordina-
tion of the oxazoline nitrogen to the lithium of sec-
BuLi/TMEDA.11 A molecular model of the complex of
sec-BuLi/TMEDA/4,4-dimethyl-2-(o-tolyl)oxazoline indi-
cates there is serious steric repulsion between the
methyl groups of TMEDA and the methyl groups on
the oxazoline ring in a plausible transition state of the
lateral lithiation, where the s orbital of LiꢀC bond
interacts with the s* orbital of the benzylic CꢀH
bond.12 Such steric interactions, however, are not
remarkable in the transition state of the ortho-lithia-
tion. We presume, therefore, the unusual ortho-lithia-
tion proceeds much faster than the normal lateral
lithiation under these kinetically controlled conditions.
Following these preliminary experiments, we tested the
adaptability of these reagent-controlled optional
regioselective lithiations7 to different 2-aryloxazolines
1a–e. Each oxazoline was lithiated with sec-BuLi in
diethyl ether in the absence or presence of TMEDA.
The lithio species was reacted with p-anisaldehyde and
the crude product was treated with trifluoroacetic acid
(TFA) in aqueous THF at room temperature overnight
to give a mixture of 3,4-dihydroisocoumarin 4 and
7-methylphthalide 5.8 These compounds were readily
separated by column chromatography and the isolated
yields are shown in Table 2.
First, we checked the effects of the substituent (p-OMe
or p-Cl) on the benzene ring (entries 1–6). In the
absence of TMEDA, the oxazolines 1a,b afforded 3,4-
dihydroisocoumarins 4a,b almost exclusively to show
excellent lateral selectivity in the lithiation step (entries
1 and 2). The selectivity, however, decreased when
p-chloro derivative 1c was used (entry 3). This can be
accounted for by an inductively electron-withdrawing
effect of chlorine,9 which increases the acidity of the
ring protons rather than the lateral protons. In the
presence of TMEDA, the lithiation of 1a–c proceeded
ortho-selectively to give 7-methylphthalides 5a–c as the
major products (entries 4–6).10 Especially in the case of
In conclusion, we have discovered unprecedented ortho-
lithiation of 4,4-dimethyl-2-(o-tolyl)oxazolines 1.
Optional ortho and lateral lithiations of 1 may open the
way to the synthesis of polysubstituted aromatic com-
pounds, which are not readily available by known
procedures.

N. Tahara et al. / Tetrahedron Letters 43 (2002) 9069–9072
Table 2. Regioselective lithiation of oxazolines 1a–e
9071
Entry
Substrate
Additive (equiv.)
4 (%)a
5 (%)a
1
2
3
4
5
6
7
8
9
1a
1b
1c
1a
1b
1c
1d
1e
1d
1e
None
None
None
TMEDA (10)
TMEDA (10)
TMEDA (10)
None
None
TMEDA (10)
TMEDA (10)
84
93
64
10
5
2
2
15
75
75
80
0
0
34
34
1
74
79
42
26
10
a Isolated yield after column chromatography.
Figure 1.

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N. Tahara et al. / Tetrahedron Letters 43 (2002) 9069–9072
8. (a) Fu, P. P.; Unruh, L. E.; Miller, D. W.; Huang, L. W.;
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the lateral position was 12% (1H NMR analysis). A
similar experiment without TMEDA resulted in 102%
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the ortho-position.
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