Regioselective lithiation of aryl benzyl ethers

Article abstract of DOI:10.1016/j.tetlet.2005.02.006

The lithiation of a series of aryl benzyl ethers containing -F and -OMe groups has been studied. It was found that the presence of one or two fluorine atoms in the meta position relative to the oxygen atom prevents the lithiation at the benzyl carbon atom. 3-(3′,5′-Dimethoxybenzyloxy)fluorobenzene was lithiated and next reacted with DMF to give 2-(3′,5′- dimethoxybenzyloxy)-6-fluorobenzaldehyde. A three-step procedure was applied to remove three hydrogen atoms from 1,3-difluoro-5-(3′,5′- dimethoxybenzyloxy)benzene and replace them with methyl groups by reactions of the lithiated compounds with MeI.

Full text of DOI:10.1016/j.tetlet.2005.02.006

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 1963–1965
Regioselective lithiation of aryl benzyl ethers
*
´
Jan Chodakowski, Tomasz Klis and Janusz Serwatowski
Faculty of Chemistry, Warsaw University of Technology, Noakowskiego 3, 00-664 Warsaw, Poland
Received 5 January 2005; revised 27 January 2005; accepted 1 February 2005
Abstract—The lithiation of a series of aryl benzyl ethers containing –F and –OMe groups has been studied. It was found that the
presence of one or two fluorine atoms in the meta position relative to the oxygen atom prevents the lithiation at the benzyl carbon
atom. 3-(30,50-Dimethoxybenzyloxy)fluorobenzene was lithiated and next reacted with DMF to give 2-(30,50-dimethoxybenzyloxy)-
6-fluorobenzaldehyde. A three-step procedure was applied to remove three hydrogen atoms from 1,3-difluoro-5-(30,50-dimethoxy-
benzyloxy)benzene and replace them with methyl groups by reactions of the lithiated compounds with MeI.
Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
ABE molecules contain benzylic protons which are also
a to oxygen. Generally the metallation of protons a to
oxygen is unfavourable because of antibonding interac-
tions between the oxygen lone pairs with the C–Li bond.
However, the inductive effect of the oxygen atom and
the phenyl ring can overcome this effect making lith-
iation of these compounds easier. Lithiation at the
benzylic position can also be accelerated by ortho sub-
stituents working in conjunction. Napolitano et al. stud-
ied the influence of alkoxyalkyl substituents on the
regioselective lithiation of a benzene ring and found that
the concomitant presence an alkoxyalkyl group and an
alkoxy group in a meta relationship generally permits
easy lithiation by deprotonation at C-2.14
The regiospecific introduction of lithium into an aro-
matic ring a process known as Ôortho lithiationÕ is well
documented.1–5 However, the ortho lithiation of aryl
benzyl ethers (ABEs) has not been previously studied.
An ABE contains two types of centre which can be met-
allated: the aromatic rings and the benzylic position.
Metallation of either center is of great synthetic poten-
tial.6–9
Two generally accepted factors influence the regioselec-
tivity: (1) the inductive effect of a substituent on the phen-
yl ring which increases the acidity of the ortho hydrogen
and, (2) complexation of the metallating agent by a lone
pair of electron.10 The mechanism suggested for this
process involves complex formation between a BuLi
dimer and an alkoxy group. The metallation of 4-fluoro-
anisole illustrates this difference well.11 With butyl-
lithium alone, deprotonation of the 2-position ortho
to the –OMe group occurs, because the lithium atom
interacts with the lone electron pair of the oxygen. Addi-
tion of pentamethyldiethylenetriamine (PMDTA), how-
ever, coordinatively saturates the butyllithium so the
most acidic proton, ortho to the fluorine, is removed.
The lithiation of both fluorobenzene and anisole by
butyllithium is efficient, but the reaction itself is very
slow.12,13
In this work we have studied the lithiation of ABEs pos-
sessing –F and –OMe substituents (Scheme 1). The reac-
tion of 1 with butyllithium is very slow at ꢀ60 °C and
gives 1a (after trapping with MeI).
1
Integration of the methylene signals in the H NMR
(400 MHz) spectrum of the reaction mixture confirmed
that 22% of 1 remained unreacted. The use of other met-
allating reagents (BuLi/t-BuOK or BuLi/PMDTA) gave
1
1a (80%, calculated from the H NMR spectrum) and
traces of 1b. Ether 2 was also metallated at the benzylic
position using BuLi in THF to give 2a after trapping
with DMF. However when the reaction was carried
out in the presence of PMDTA, a mixture of 2a–d was
formed. Integration of the aldehyde proton signals in
1
the H NMR spectrum revealed that 2a was the main
product (50%). This non-selective outcome results from
an increase in metallating power of BuLi in the presence
Keywords: Aryl benzyl ether; Lithiation; Butyllithium.
*
Corresponding author. Fax: +48 226282741; e-mail: serwat@
ch.pw.edu.pl
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.02.006

1964
J. Chodakowski et al. / Tetrahedron Letters 46 (2005) 1963–1965
R10
R6
R5
R4
R3
O
R4
R3
O
R9
i, ii
R6
R1
R1
R7
R8
R5
R 2
R 2
1. (1) R2=-OMe
2. (1)
(1a) R2=-OMe, R6=-Me (78%)
(1a) (80%)
(1b) R1=-Me, R2=-OMe (5%)
3. (2), R2=-OMe, R5=-F
4. (2)
(2a) R2=-OMe, R6=-CHO, R8=F (75%)
(2a) (50%)
(2b) R1=-CHO, R2=-OMe, R8=F (8%)
(2c) R2=-OMe, R8=F, R9=-CHO (20%)
(2d) R2=-OMe, R7=-CHO, R8=F, (20%)
(3a) R1=-CHO, R2=-F, R8,10=-OMe (95%)
5. (3) R2=-F, R5,6=-OMe
6. (4) R2,4=-F, R5,6=-OMe
7. (5)
(5)
(6) R2,4=-F, R1,3=-Me, R8,10=-OMe (85%)
(7)
2,4=-F, R1,3,5=-Me, R8,10=-OMe (68%)
n = H unless otherwise stated
R
2,4=-F, R3=-Me, R8,10=-OMe (90%)
8. (6)
R
R
Scheme 1. Reagents and conditions: (1) (i) n-BuLi/THF, ꢀ60 °C, (ii) MeI, H+/H2O; (2) (i) n-BuLi/THF/PMDTA, ꢀ60 °C, (ii) MeI, H+/H2O;
(3) (i) n-BuLi/THF, ꢀ60 °C, (ii) DMF, H+/H2O; (4) (i) n-BuLi/THF/PMDTA, ꢀ60 °C, (ii) DMF, H+/H2O; (5) (i) n-BuLi/THF, ꢀ60 °C, (ii) DMF,
H+/H2O; (6)–(8) (i) n-BuLi/THF, ꢀ60 °C, (ii) MeI, H+/H2O.
of PMDTA and thus some deprotonation ortho to fluo-
rine is possible. Metallation of 3 with BuLi occurred eas-
ily and selectively to give 3a after addition of DMF.
Only the hydrogen between the fluorine and the oxygen
was removed. This hydrogen is the most acidic and addi-
tionally, complexation of the BuLi by the lone electron
pair of oxygen is possible. We did not observe any met-
allation of the carbon atom between two –OMe groups.
This would require a higher temperature to occur effi-
ciently. The metallation of 4 is especially interesting be-
cause of the presence of three very reactive centres, one
between two fluorine atoms and two between fluorine
and oxygen atoms. We expected that BuLi would re-
move the proton between fluorine and oxygen, however,
4 was metallated exclusively between the two fluorine
atoms, then reacted with MeI to give 5. Our explanation
is that the lithiation of 4 is kinetically controlled and
that the most acidic hydrogen is removed. Complexation
of the lithium by oxygen must be slower in this case than
the deprotonation. When 5 reacted with BuLi and the
intermediate was trapped with MeI, 6 was isolated. This,
in turn, was also easily metallated by BuLi and then re-
acted with MeI to give 7.
2. General procedure for lithiation and reaction with
electrophiles
To a cooled (ꢀ68 °C) solution of the ABE in 100 mL of
THF, butyllithium (1.1 equiv) as a 10 M solution in hex-
ane was added dropwise with stirring while maintaining
the temperature below ꢀ60 °C. The stirring was contin-
ued for 1 h and then the appropriate electrophile (DMF,
MeI) was added maintaining the temperature below
ꢀ60 °C. After the addition, the cooling bath was re-
moved and the reaction mixture was allowed to warm
to ꢀ40°C. Water (100 mL) and 3 M sulfuric acid
(20 mL) were added to make the mixture slightly acidic.
The resulting solution was extracted twice using 50 mL
portions of diethyl ether and the extracts were evapo-
rated under reduced pressure. The solid obtained was
washed with hexane and recrystallised from hexane.
2.1. 2-(30,50-Dimethoxybenzyloxy)-6-fluorobenzaldehyde,
3a
2-(30,50-Dimethoxybenzyloxy)-6-fluorobenzaldehyde, 3a
obtained from 3-(30,50-dimethoxybenzyloxy)fluorobenz-
ene (8.64 g, 0.033 mol), BuLi (3.5 mL, 0.035 mol) and
DMF (2.55 g, 0.035 mol), (9 g, yield 95%). Analysis:
1H NMR (400 MHz, CDCl3) d 10.52 (d, J = 1.2 Hz,
1H), 7.45 (m, J = 6.4 Hz, 1H), 6.80 (d, J = 8.4 Hz,
1H), 6.74 (m, J = 8.4 Hz, 1H), 6.59 (d, J = 2.4 Hz,
2H), 6.43 (t, J = 2.4 Hz, 1H), 5.14 (s, 2H), 3.81 (s,
6H). Anal. Calcd for C16H15FO4: C, 66.20; H, 5.21.
Found: C, 66.01; H, 5.19.
We conclude that a molecule of an ABE can be selec-
tively lithiated on the phenyl ring when it contains a
fluorine atom meta to the oxygen, or two fluorine atoms
in a meta orientation. The regioselectivity of the reac-
tion depends on the acidity of the hydrogen atoms.
When two fluorine atoms and an oxygen are mutually
in a meta relationship, as in 4, the hydrogen atom be-
tween the two fluorine atoms is removed first. When
there is no fluorine or the fluorine and oxygen atoms
are not in a meta relationship, the benzylic position is
lithiated selectively, but the yield of the reaction is
low. It is worth mentioning that we did not observe a
[1,2]-Wittig rearrangement at ꢀ60 °C for all the studied
reactions.15 However, we did find that this process
occured with 1 at ꢀ10 °C.
2.2. 2,6-Difluoro-4-(30,50-dimethoxybenzyloxy)toluene, 5
2,6-Difluoro-4-(30,50-dimethoxybenzyloxy)toluene, 5 ob-
tained from 1,3-difluoro-5-(30,50-dimethoxybenzyloxy)-
benzene (9.40 g, 0.033 mol), BuLi (3.5 mL, 0.035 mol)
and MeI, (4.97 g, 0.035 mol), (8.73 g, yield 90%).
Analysis: 1H NMR (400 MHz, CDCl3) d 6.54 (d,

J. Chodakowski et al. / Tetrahedron Letters 46 (2005) 1963–1965
1965
J = 2.4 Hz, 2H), 6.46 (d, J = 8.8 Hz, 2H), 6.41 (t,
J = 2.4 Hz, 1H), 4.92 (s, 2H), 3.78 (s, 6H), 2.09
(t, J = 1.6 Hz, 3H). Anal. Calcd for C16H16F2O3: C,
65.30; H, 5.48. Found: C, 65.18; H, 5.51.
Inc., Milwaukee, WI, USA, through donation of chem-
icals and equipment is gratefully acknowledged.
References and notes
2.3. 2,6-Difluoro-4-(30,50-dimethoxybenzyloxy)-3-methyl-
toluene, 6
1. Schlosser, M.; Katsoulos, G.; Takagishi, S. Synlett 1990,
747–748.
2,6-Difluoro-4-(30,50-dimethoxybenzyloxy)-3-methyltolu-
ene, 6 obtained from 5 (5.93 g, 0.020 mol), BuLi (2.5 mL,
0.025 mol) and MeI (3.55 g, 0.025 mol), (4.76 g, yield
2. Takagishi, S.; Schlosser, M. Synlett 1991, 119–
121.
3. Simig, G.; Schlosser, M. Tetrahedron Lett. 1988, 29, 4277–
4280.
4. Oita, K.; Gilman, H. J. Am. Chem. Soc. 1957, 79, 339–
342.
5. Faigl, F.; Schlosser, M. Tetrahedron Lett. 1991, 32, 3369–
3370.
6. Schlosser, M.; Guio, L.; Leroux, F. J. Am. Chem. Soc.
2001, 123, 3822–3823.
7. Clayden, J.; Pink, J. H.; Westlund, N.; Wilson, F. X.
Tetrahedron Lett. 1998, 39, 8377–8380.
8. Ahmed, A.; Clayden, J.; Rowley, M. Chem. Commun.
1998, 297–298.
9. Ahmed, A.; Clayden, J.; Yasin, S. A. Chem. Commun.
1999, 231–232.
10. Bauer, W.; Schleyer, P. v. R. J. Am. Chem. Soc. 1989, 111,
7191–7198.
1
85%). Analysis: H NMR (400 MHz, CDCl3) d 6.56 (d,
J = 2.4 Hz, 2H), 6.42 (t, J = 2.4 Hz, 1H), 6.39 (d, J =
1.6 Hz, 1H), 4.96 (s, 2H), 3.78 (s, 6H), 2.13 (t, J =
7.2 Hz, 3H), 2.10 (t, J = 2.0 Hz, 3H). Anal. Calcd for
C17H18F2O3: C, 66.22; H, 5.88. Found: C, 65.41; H, 5.87.
2.4. 2,6-Difluoro-4-(30,50-dimethoxybenzyloxy)-3,5-di-
methyltoluene, 7
2,6-Difluoro-4-(30,50-dimethoxybenzyloxy)-3,5-dimeth-
yltoluene, 7 obtained from 6 (3.55 g, 0.011 mol), BuLi
(2.5 mL, 0.015 mol) and MeI (2.13 g, 0.015 mol),
(2.4 g, yield 68%). Analysis: 1H NMR (400 MHz,
CDCl3) d 6.61 (d, J = 2.4 Hz, 2H), 6.45 (t, J = 2.4 Hz,
1H), 4.71 (s, 2H), 3.82 (s, 6H), 2.15 (t, J = 2.0 Hz, 6H),
2.14 (t, J = 2.0 Hz, 3H). Anal. Calcd for C18H20F2O3:
C, 67.15, H, 6.24. Found: C, 66.57; H, 6.19.
11. Katsoulos, G.; Takagishi, S.; Schlosser, M. Synlett 1991,
731–732.
12. Gilman, H.; Soddy, T. S. J. Org. Chem. 1957, 22, 1715–
1717.
13. Mallan, J. M.; Rebb, R. L. Chem. Rev. 1969, 69, 693–
755.
14. Napolitano, E.; Giannone, E.; Fiashi, R.; Marsili, A.
J. Org. Chem. 1983, 48, 3653–3657.
15. Garst, J. F.; Smith, C. D. J. Am. Chem. Soc. 1976, 98,
1526–1537.
Acknowledgements
This work was supported by the Warsaw University of
Technology. Support from the Aldrich Chemical Co.,