Lateral lithiation of N,N′-diaryl ureas

Article abstract of DOI:10.1016/j.tetlet.2006.07.134

Aromatic ureas bearing N-(2-alkylaryl) groups may be laterally lithiated by treatment with sec-butyllithium. Quenching with a range of electrophiles yields functionalised aryl ureas in excellent yield. Lateral lithiation is favoured when the urea nitrogen

Full text of DOI:10.1016/j.tetlet.2006.07.134

Tetrahedron Letters 47 (2006) 6945–6946
Lateral lithiation of N,N0-diaryl ureas
*
´ ´
Jonathan Clayden and Jeremy Dufour
School of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL, United Kingdom
Received 28 June 2006; revised 24 July 2006; accepted 25 July 2006
Abstract—Aromatic ureas bearing N-(2-alkylaryl) groups may be laterally lithiated by treatment with sec-butyllithium. Quenching
with a range of electrophiles yields functionalised aryl ureas in excellent yield. Lateral lithiation is favoured when the urea nitrogen
adjacent to the aromatic ring in question is alkylated, and when competitive lithiations of such a ring are possible, lateral lithiation is
more favourable than the alternative ortholithiation.
Ó 2006 Elsevier Ltd. All rights reserved.
Directed metallation has become the most powerful way
of functionalising aromatic systems regioselectively.1,2
Despite their importance in medicinal chemistry, the
directed metallation of ureas has received little atten-
tion,3,4 even though ureas share with some of the most
powerful metallation directing groups, features such as
an electron-rich carbonyl group and electron-deficient
nitrogen atoms. We recently reported that N,N-diaryl-
ureas 1 may be ortholithiated regioselectively when
one (and only one) of the two nitrogen atoms is alkyl-
ated (Scheme 1).3
position (Scheme 2).3 This promising result suggested
that lateral lithiation might be a useful, and previously
unknown, way of elaborating ureas, and we set out to
investigate the generality of this reaction and to assess
regioselectivity in substrates containing both ortho and
lateral lithiation sites.5
Importantly, although 3 undergoes lateral lithiation in
preference to ortholithiation, the competition between
the two reactivities is also subject to the influence of
the site of N-alkylation: it is clear for example that
ortholithiation of mono-N-alkylated ureas 1 exhibits a
strong preference for functionalisation of the ring carry-
ing the alkylated nitrogen atom.3 We investigated a po-
tential reversal of this bias by lithiating a urea 5 carrying
benzylic methyl group on the ring adjacent to the unsub-
stituted nitrogen atom (Scheme 3). In this case, a slower
reaction (significant amounts of starting material
remained at ꢀ78 °C) gave a mixture of regioisomeric
Urea 3 has no available ortho protons on one ring, and
yet it still undergoes lithiation, at a lateral (benzylic)2
O
O
R2
1.
R2
s
-BuLi x 2,
N
N
N
N
THF, –78 ºC
H
H
E
R1
R1
2. E+
1
2
O
O
1. s-BuLi x 2,
Scheme 1. Ortholithiation of ureas.
N
N
H
N
N
THF, –42 ºC
H
E
2. E+
5
6 26% (E+ = Me3SiCl)
O
O
1. s-BuLi x 2,
THF, –78 ºC
45% (E+ = Me2C=O)
+
N
N
H
N
N
H
t
-Bu
t
-Bu
O
O
2. MeI
3
4 64%
O
N
N
N
H
E
Scheme 2. Lateral lithiation of ureas.
8 10% (E+ = Me2C=O)
7 8% (E+ = Me3SiCl)
*
Corresponding author. Fax: +44 161 275 4939; e-mail addresses:
clayden@man.ac.uk; j.p.clayden@manchester.ac.uk
Scheme 3. ortho versus lateral lithiation.
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.07.134

6946
J. Clayden, J. Dufour / Tetrahedron Letters 47 (2006) 6945–6946
Table 2. Lithiation of 12
O
O
Entry SM E+
Yield Yield Yield Remaining
1.
s-BuLi x 2,
N
N
N
N
H
THF, –78 ºC
H
13
14
15
12
E
1
2
3
4
5
6
7
12a Me2C@O
81
62
0
0
0
0
0
9
21
11
83b
81
0
0
4
5
39
0
15
14
60
40
36
0
2. E+
10
Me3SiCl
12b Me2C@O
Me2C@Oa
Me3SiCl
12c PhCHO
Me3SiCl
9
O
Me3Si
Me3Si
N
N
H
—
—
0
0
11
a
ꢀ42 °C.
b From Ref. 3.
Scheme 4. Efficient lateral lithiation.
Table 1. Lateral lithiation of 9
tuted urea 12c, and significant quantities of a-lithiated7
products 15 are observed (Table 2). a-Lithiation is well
known in amides, the products being dipole stabilised
carbanions.8
Entry E+
E
Yield 10
Remaining 9
1
2
3
4
5
6
7
8
Me2C@O
PhCHO
MeCHO
(CH2)5C@O
Me(C@O)Ph Me(COH)Ph 92
PhCH@NMe PhNMeCH
PhCH@NPh PhNPhCH
Me2COH
PhCHOH
MeCHOH
91
89
89
6
10
3
9
7
—
—
3
In conclusion, lateral lithiation of benzylic sites adjacent
to urea functions is a favourable reaction pathway and
may be of use for the functionalisation of aromatic ureas.
(CH2)5COH 88
89
97
Me3SiCl
Me3Si
7 + 47 11
Acknowledgments
products (6 arises from lateral lithiation, while 7 and 8
arise from ortholithiation, 8 forming spontaneously un-
der the conditions of the reaction) with no useful syn-
thetic outcome. Like ortholithiation,3 lateral lithiation
favours functionalisation of the less electron-rich ring
adjacent to the alkylated nitrogen atom.
We thank the EU Erasmus programme and the Pro-
gramme de Mobilite´ Internationale de la Re´gion Langue-
doc-Roussillon for support.
References and notes
When the sites of possible ortho and lateral lithiation lie
in the same, favoured ring, a broad preference for lateral
lithiation is observed. Thus treatment of 9 with sec-butyl-
lithium and a range of electrophiles (Scheme 4) gave the
excellent yields of laterally lithiated products 10 indi-
cated in Table 1. No sign of products arising from alter-
native lithiations was observed, although the product of
silylation (entry 9) was susceptible to further lithiation
to form doubly silylated 11.6
1. Clayden, J. In Chemistry of Organolithium Compounds;
Rappoport, Z., Marek, I., Eds.; Wiley: Chichester, 2004; pp
495–592; Clayden, J. Organolithiums: Selectivity for Syn-
thesis; Pergamon: Oxford, 2002: pp 28–72; Snieckus, V.
Chem. Rev. 1990, 90, 879; Gschwend, H. W.; Rodriguez, H.
R. Org. React. 1979, 26, 1.
2. Clayden, J. In Chemistry of Organolithium Compounds;
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597–618; Clayden, J. Organolithiums: Selectivity for Syn-
thesis; Pergamon: Oxford, 2002: pp 73–83; Clark, R. D.;
Jahangir, A. Org. React. 1995, 47, 1.
Secondary benzylic sites are less acidic than primary
benzylic sites,5 but lateral lithiation of an ethyl group
is still favoured over ortholithiation: lithiation and
quench of 12a give good yields of products 13 (Scheme
5 and Table 2). Interestingly, while we would not expect
the 2-isopropyl substituted compound 12b to undergo
lateral lithiation, it is surprising that it undergoes ortho-
lithiation much less efficiently than the 2-t-butyl substi-
3. Clayden, J.; Turner, H.; Pickworth, M.; Adler, T. Org. Lett.
2005, 7, 3147.
4. Cram, D. J.; Dicker, I. B.; Lauer, M.; Knoibler, C. B.;
Trueblood, K. N. J. Am. Chem. Soc. 1984, 1984, 7150;
Smith, K.; El-Hiti, G. A.; Hawes, A. C. Synlett 1999, 945;
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Joule, J. A. Can. J. Chem. 2004, 82, 1649.
5. For a comparable study of ortho vs. lateral lithiation in
aromatic amides, see: Court, J. J.; Hlasta, D. J. Tetrahedron
Lett. 1996, 37, 1335; See also Clayden, J.; Pink, J. H.;
Westlund, N.; Wilson, F. X. Tetrahedron Lett. 1998, 39,
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R.; Kirmani, B. A.; Linton, D. J.; Schooler, P.; Wheatley,
A. E. H. Angew. Chem., Int. Ed. 2004, 43, 2135.
O
1. s-BuLi x 2,
THF, –78 ºC
12a (R1 = R2 = H)
12b (R1 = H, R2 = Me)
12c (R1 = R2 = Me)
R1 R2
N
NHPh
2. E+
6. It is well known that metallation by sec-BuLi can take place
in the presence of Me3SiCl, see: Seyferth, D.; Cheng, Y. M.;
Traficante, D. D. J. Organomet. Chem. 1972, 46, 9; Mills,
R. J.; Horvath, R. F.; Sibi, M. P.; Snieckus, V. Tetrahedron
Lett. 1985, 26, 1145.
O
O
E
O
R1 R2
R1 R2
R1 R2
N
N
NHPh
N
NHPh
NHPh
+
+
E
E
7. Clayden, J. Organolithiums: Selectivity for Synthesis; Perg-
amon: Oxford, 2002; pp 10–26.
13
14
15
8. Beak, P.; Reitz, D. B. Chem. Rev. 1978, 78, 275.
Scheme 5. More substituted benzylic sites.