Use of methyllithium in metal/halogen exchange; a mild and efficient method for the synthesis of ortho substituted toluenes

Article abstract of DOI:10.1081/SCC-100104832

Methyllithium, in the presence of excess methyl iodide, can be used to convert suitably substituted aromatic bromides to the corresponding toluenes under mild conditions and in high yield.

Full text of DOI:10.1081/SCC-100104832

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
USE OF METHYLLITHIUM IN METAL/HALOGEN
EXCHANGE; A MILD AND EFFICIENT METHOD
FOR THE SYNTHESIS OF ORTHO SUBSTITUTED
TOLUENES
Ian P. Andrews , John Kitteringham & Martyn Voyle
To cite this article: Ian P. Andrews , John Kitteringham & Martyn Voyle (2001) USE OF
METHYLLITHIUM IN METAL/HALOGEN EXCHANGE; A MILD AND EFFICIENT METHOD FOR THE
SYNTHESIS OF ORTHO SUBSTITUTED TOLUENES, Synthetic Communications, 31:15, 2323-2327,
DOI: 10.1081/SCC-100104832
To link to this article: http://dx.doi.org/10.1081/SCC-100104832
Published online: 09 Nov 2006.
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SYNTHETIC COMMUNICATIONS, 31(15), 2323–2327 (2001)
USE OF METHYLLITHIUM IN
METAL/HALOGEN EXCHANGE; A MILD
AND EFFICIENT METHOD FOR
THE SYNTHESIS OF ORTHO
SUBSTITUTED TOLUENES
Ian P. Andrews, John Kitteringham,* and Martyn Voyle
Synthetic Chemistry Department, SmithKline Beecham
Pharmaceuticals, New Frontiers Science Park,
Third Avenue, Harlow, Essex, CM19 5AW
ABSTRACT
Methyllithium, in the presence of excess methyl iodide, can be
used to convert suitably substituted aromatic bromides to the
corresponding toluenes under mild conditions and in high
yield.
The metal/halogen exchange reaction between an alkyllithium and an
aryl bromide or iodide has been used extensively since it was first reported by
1
Gilman and Wittig over 50 years ago. The reagent most commonly used
,2
for this interconversion is n-butyllithium, presumably because it is readily
3
available and is also usually highly effective. However, the formation of n-
butyl bromide or iodide as a by-product when this reagent is used can give
rise to impurities either through alkylation or proton quench
*
Corresponding author.
2
323
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

ORDER
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2
324
ANDREWS, KITTERINGHAM, AND VOYLE
4
via dehydrohalogenation) of the newly formed aryllithium. In large scale
,5
(
reactions where addition times are often longer these side reactions can cause
significant problems by lowering the yield or compromising the purity of the
product. These undesirable side reactions can be avoided by, for example,
6
using two equivalents of tert-butyllithium as the exchange reagent.
In the early reports of the metal/halogen exchange reaction methyl-
lithium was described as the least effective of all the alkyllithiums investi-
gated and it was therefore believed to have little synthetic utility in this
7
,8
reaction. Consequently there are very few literature examples of the use
,10
9
of methyllithium for this interconversion.
Included in the small number
that are known are examples where the methyl bromide by-product reacted
with the newly formed aryllithium to produce the corresponding methyl
1
1,12
compound.
We have found that if methyllithium is reacted with aryl bromides
bearing a suitable ortho substituent it is very effective in the metal/halogen
1
3
exchange reaction (Scheme 1). If the desired product is the corresponding
methyl compound excellent yields can be obtained if additional methyl
iodide is used. Furthermore, by having the methyl iodide present ‘‘in-situ’’
with the aryl bromide before the methyllithium is added, the impurity
formed by proton quench of the aryllithium intermediate can be reduced
to an almost negligible level. This methodology has been used for the syn-
thesis of multi-kilo quantities of the methylindoline 2 (R ¼ Me).
Scheme 1.
In contrast, it was found that 1-benzyl-5-bromoindoline 3 failed to
undergo metal/halogen exchange under the same reaction conditions
(
Scheme 2).
To gain a further understanding of these results we investigated this
reaction with a series of aryl bromides. The results shown in Table 1 confirm

ORDER
REPRINTS
METHYLLITHIUM
2325
that a suitable ortho substituent is required to enable metal/halogen
exchange to occur when methyllithium is used. Presumably the same factors
that facilitate the complementary technique of ortho directed lithiation
1
4,15
(
also first reported by Gilman and Wittig) are in operation here.
Thus
Scheme 2.
Table 1. The Reaction of Aryl Bromides with
Methyllithium in the Presence of Methyl Iodide

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2
326
ANDREWS, KITTERINGHAM, AND VOYLE
heteroatoms that can co-ordinate with the attacking allkyllithium species
are particularly effective.
The results shown with the trifluoromethyl substituent indicate that
inductively electron withdrawing substituents will facilitate the metal halo-
gen exchange and can also have an albeit diminished influence on the meta
and even para positions.
In summary, we have developed a mild and efficient process for the
preparation of toluenes bearing a suitable ortho substituent from the corres-
ponding bromo compound.
TYPICAL EXPERIMENTAL PROCEDURE
1
8
Methyllithium (3 M solution in diethoxymethane, 1.2 eq) was added
dropwise to a stirred mixture of aryl bromide (1 g) and methyl iodide (2 eq)
ꢀ
in tert-butyl methyl ether (10 ml) at 5–10 C under nitrogen. The reaction
mixture was stirred at ambient over 18 hours before aqueous quench. The
aqueous mixture was extracted into TBME (10 ml), the organics were dried
over sodium sulphate and the volatiles were removed under vacuum to leave
1
9
product.
1
-Benzyl-5-methyl-6-trifluoromethylindoline 2
To a solution of 1-benzyl-5-bromo-6-trifluoromethylindoline 1 (10 g,
8 mmol) and methyl iodide (7.95 g, 56 mmol) in TMBE (100 ml) stirred at 0–
2
1
ꢀ
0 C under N was added dropwise methyllithium (3 M solution in diethox-
2
ꢀ
ymethane, 11.2 ml, 33.6 mmol). The reaction mixture was stirred at 0–10 C
for 1 hour before addition of water (50 ml). The aqueous phase was discarded
and the TBME solution of crude product washed with water (50 ml) before
drying over sodium sulphate. Solvent was removed under vacuum to leave an
1
oil that crystallised on standing to give 2, (7.9 g, 97% yield). H-NMR
(
400 MHz, CDCl ) d: 7.30 (m,5H); 6.99 (s,1H); 6.70 (s,1H) 4.24 (s,2H);
3
1
3
3
.32 (m,2H); 2.95 (m,2H); 2.35 (m,3H); C-NMR (100 MHz, CDCl ) d
3
:
5
151.2; 138.6; 134.5; 129.3; 128.8; 128.3; 128.2; 127; 126.5; 124.1; 103.0;
þ
þ
3.7; 31.2; 28.3; 21.9; MS (APCI) m/z: 292 ([MþH] ); 200 ([C H F N] ).
1
0
9 3
REFERENCES
1
2
3
. Gilman, H.; Langham, W.; Jacoby, A.L. J. Am. Chem. Soc. 1939, 61, 106.
. Wittig, G.; Fuhrman, G. Chem. Ber. 1940, 73, 1197.
. Jones, R.G.; Gilman, H. Org. React. (N.Y.) 1951, 6, 339.

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METHYLLITHIUM
2327
4. Wakefield, B.J. The Chemistry of Organolithium Compounds, Pergamon
Press: New York, 1974.
5. Eastham, J.F.; Gibson, G.W. J. Org. Chem. 1963, 28, 280.
6. Seebach, D.; Neumann, H. Chem. Ber. 1974, 107, 847.
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1
1
1
0. Huddle, P.A.; Perold, G.W. J. Chem. Soc., Perkin Trans. 1 1980, 2617.
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1
4. Gilman, H.; Jacoby, A.L. J. Org. Chem. 1938, 3, 108.
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6. All starting materials were commercially available with the exception
of the N,N-dimethyl compound, prepared according to the method of
2
0
Giumanini et al. from the corresponding dibromoaniline.
7. Refers to isolated yields in which the balance is made up of starting
1
1
1
2
material, unless otherwise stated.
8. A non-pyrophoric solution supplied by Chemetall GMBH,
Langelsheim, Germany.
1
9. All compounds were characterised by mass spectrometry, Hand
13
C
nmr.
0. Giumanini, A.G.; Chiavari, G.; Musiani, M.M.; Rossi, P. Synthesis
980, 743.
1
Received in the UK January 27, 2000

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