Ring-selective functionalization of N,N′-diarylureas by regioselective N-alkylation and directed ortho metalation

Article abstract of DOI:10.1021/ol0508025

(Chemical Equation Presented) Unsymmetrical N,N′-diarylureas may be alkylated regioselectively at the more sterically congested nitrogen atom. The resulting mono-N-alkylated ureas undergo directed metalation (ortholithiation) with sec-BuLi to yield, on el

Full text of DOI:10.1021/ol0508025

ORGANIC
LETTERS
2005
Vol. 7, No. 15
3147-3150
Ring-Selective Functionalization of
N,N -Diarylureas by Regioselective
′
N-Alkylation and Directed Ortho
Metalation
Jonathan Clayden,* Hazel Turner, Mark Pickworth, and Thomas Adler
School of Chemistry, UniVersity of Manchester,
Oxford Road, Manchester M13 9PL, UK
j.p.clayden@man.ac.uk
Received April 13, 2005
ABSTRACT
Unsymmetrical N,N′-diarylureas may be alkylated regioselectively at the more sterically congested nitrogen atom. The resulting mono-N-
alkylated ureas undergo directed metalation (ortholithiation) with sec-BuLi to yield, on electrophilic quench, products functionalized regioselectively
at the ring bearing the alkylated nitrogen atom.
The conformation of N,N′-diarylureas 1 has been of interest
for some time because of the tendency, with certain substitu-
tion patterns, for the two urea N-CO bonds to adopt a
conformation placing the aryl rings cis,1 allowing them to
engage in π-π interactions. As part of a research program
investigating the possibility of conformational control in
amide-like systems,2 we are interested in developing reliable
routes to unsymmetrical N,N′-diarylureas.3 Many N +
O-containing functional groups, particularly secondary and
tertiary amides 2,4 oxazolines 3,5 tertiary O-aryl carbamates
4,6 and anilides 5,7 are powerful directors of ortholithiation.8
In contrast, the synthetic potential of ortholithiation in ureas
has remained largely unexplored.9
(1) (a) Lepore, G.; Migdal, S.; Blagdon, D. E.; Goodman, M. J. Org.
Chem. 1973, 38, 2590. (b) Lepore, U.; Castronuovo Lepore, G.; Ganis, P.;
Germain, G.; Goodman, M. J. Org. Chem. 1976, 41, 2134. (c) Yamaguchi,
K.; Matsumura, G.; Kagechika, H.; Azumaya, I.; Ito, Y.; Itai, A.; Shudo,
K. J. Am. Chem. Soc. 1991, 113, 5474. (d) Tanatani, A.; Kagechika, H.;
Azumaya, I.; Fukutomi, R.; Ito, Y.; Yamaguchi, K.; Shudo, K. Tetrahedron
Lett. 1997, 38, 4425. (e) Kurth, T. L.; Lewis, F. D.; Hattan, C. M.; Reiter,
R. C.; Stevenson, C. D. J. Am. Chem. Soc. 2003, 125, 1460. (f) Lewis, F.
D.; Kurth, T. L.; Hattan, C. M.; Reiter, R. C.; Stevenson, C. D. Org. Lett.
2004, 6, 1605.
Figure 1. N,N′-Diarylureas and N + O-based metalation-directing
groups.
(2) For recent papers, see: Clayden, J.; Lund, A.; Vallverdu´, L.; Helliwell,
M. Nature (London) 2004, 431, 966 and references therein.
(3) Batey, R. A.; Santhakumar, V.; Yoshina-Ishii, C.; Taylor, S. D.
Tetrahedron Lett. 1998, 39, 6267.
N,N′-Diarylureas are readily available by addition of
anilines to isocyanates, and our first attempts at ortholithia-
10.1021/ol0508025 CCC: $30.25
© 2005 American Chemical Society
Published on Web 06/29/2005

Table 1. Regioselective Alkylation of Unsymmetrical Ureas
entry
starting material
X
Y
Z
product 7
yield of 7 (%)
R
product
yield of 11 (%)
yield of 12 (%)
1
2
3
4
5
6
7
8
9
6a
6b
6c
6d
6e
6f
F
Cl
Br
I
Me
Et
i-Pr
t-Bu
t-Bu
t-Bu
t-Bu
H
H
H
H
H
H
H
H
H
7a
7b
7c
7d
7e
7f
83
71
70
81
86
94
65
90
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Me
Bn
Me
Me
11a
11b
11c
11d
11e
11f
11g
11h
11i
11j, 12j
12k
56
42
39
42
44
33
60
86
58
65
0
0
0
0
0
0
0
0
0
0
H
H
H
H
H
H
H
H
H
Me
6g
6h
7g
7h
H
Me
Me
10
11
6ea
6h
7j
7k
54
55
12
75
a From o-toluidine and 14.
tion were made using the simple urea 7h obtained by addition
of phenyl isocyanate to 2-tert-butylaniline 6h. However,
treatment with up to 3.5 equiv of s-BuLi in THF at -78 °C
gave no discernible ring lithiation products (by electrophilic
quench with benzaldehyde). Double alkylation of 7h with
an excess of methyl iodide gave the fully substituted urea 9.
Treatment with s-BuLi gave an anion, which deuteration (to
give 10)10 showed was not an ortholithiated but an R-lithiated
compound, namely, the dipole-stabilized carbanion11 formed
by preferential lithiation at one of the methyl groups.
aggregate formation offered by the electron-rich heteroatom,
anionic directing groups frequently perform better than their
neutral analogues in metalation reactions.12 We hoped
therefore that ortholithiation of the monoanions of some
N-alkyl N,N′-diarylureas 11 or 12 arising from monoalkyl-
ation of a series of unsymmetrical ureas 7 would be more
successful.
Scheme 2. Regioselective N-Alkylation of Unsymmetrical
Ureas
Scheme 1. Attempted Lithiation of Simple Ureas
Perhaps counterintuitively, but probably owing to greater
stability to nucleophilic attack, along with the assistance to
The ureas were made by addition of some 2-substituted
anilines 6 to phenyl isocyanate, 2-methylphenyl isocyanate
or 2,6-dimethylphenyl isocyanate. Alkylation of the products
7 with a single equivalent of methyl iodide or of benzyl
bromide (Scheme 2 and Table 1) resulted in regioselective
monoalkylation in all cases but one, with the nitrogen
carrying the more heavily substituted ring being reliably
alkylated preferentially (with the possible exception of 11a,
whose regiochemistry we were unable to establish unequivo-
cally13). Thus, alkylation of 7b-h gave 11 only, with no
trace of 12, while alkylation of 7k gave only 12. With the
unsymmetrically 2,2′-dialkylated urea 7j, a mixture of 11
(4) (a) Snieckus, V. Chem. ReV. 1990, 90, 879. (b) Beak, P.; Brown, R.
A. J. Org. Chem. 1977, 42, 1823. (c) Beak, P.; Brown, R. A. J. Org. Chem.
1982, 47, 34. (d) Beak, P.; Snieckus, V. Acc. Chem. Res. 1982, 15, 306.
(5) Reuman, M.; Meyers, A. I. Tetrahedron 1985, 51, 837.
(6) Sibi, M. P.; Snieckus, V. J. Org. Chem. 1983, 48, 1935 and ref 4a.
(7) Fu¨hrer, W.; Gschwend, H. W. J. Org. Chem. 1979, 44, 1133
(8) For reviews, see: (a) Clayden, J. Organolithiums: SelectiVity for
Synthesis; Pergamon: Oxford, 2002; Chapter 2, p 28. (b) Clayden, J. In
The Chemistry of Organolithium Compounds; Rapoport Z., Marek, I., Ed.;
Wiley: New York, 2004; 495.
(9) See, however: (a) Cram, D. J.; Dicker, I. B.; Lauer, M.; Knobler, C.
B.; Trueblood, K. N. J. Am. Chem. Soc. 1984, 106, 7150. (b) Smith, K.;
El-Hiti, G. A.; Shukla, A. P. J. Chem. Soc., Perkin Trans. 1 1999, 2305.
(c) Smith, K.; El-Hiti, G. A.; Hawes, A. C. Synlett 1999, 945. (d) Meigh,
J.-P.; Alvarez, M.; Joule, J. A. J. Chem. Soc., Perkin Trans. 1 2001, 2012.
3148
Org. Lett., Vol. 7, No. 15, 2005

and 12 was observed, the major product being alkylated at
the nitrogen closer to the tert-butyl group. The regiochemistry
of the products 11b-g was assigned on the basis that their
CHAHBPh groups display diastereotopic signals (due to slow
rotation about an Ar-N axis14) and confirmed for 11g by
X-ray crystal structure (Figure 2), for 11h by comparison
with an authentic sample of the alternative regioisomer (see
Scheme 3), and for 12j and 12k by NOE studies. Presumably,
Scheme 4. Lithiation of Unsymmetrically Methylated Ureas
11h with 2.5 equiv of sec-BuLi in THF at -78 °C and
allowing the mixture of dilithiourea 15 and electrophile to
warm to -40 °C before aqueous quench of excess base.
Other bases (n-BuLi, t-BuLi, sec-BuLi in the presence of
TMEDA) generally gave lower yields. A range of electro-
philes reacted with 15, as shown in Table 2, providing ureas
16a-g. In every case, regioselectivity was complete, with
the newly introduced electrophile occupying the 6-position
on the 2-alkylated ring, the left-hand ring of 16.15 No
lithiation was observed on the right-hand phenyl ring.
Figure 2. X-ray crystal structure of 11g.
Table 2. Regioselective Ortholithiation
the twist in the Ar-N bond imposed by the steric require-
ments of a substituent in the ortho position prevents
delocalization of the anion 13 into the more hindered ring,
increasing electron density and reactivity at the nearer
nitrogen atom, despite its more crowded environment.
The alternative N-alkylated regioisomer 12h was available
simply by addition of N-methylaniline to isocyanate 14
(Scheme 3). Regioisomers 11h and 12h were clearly different
by NMR.
entry
E+
E
product 16 yield of 16 (%)
1
2
3
4
5
6
7
MeI
Me
16a
16b
16c
16d
16e
16f
65
80
93
95
81
66
83a
BrCH2CH2Br Br
I2
I
Me2S2
SMe
Me3SiCl
Me2NCHO
PhCHO
SiMe3
CHO
CH(OH)Ph
16g
a Product formed as a separable mixture of two diastereoisomeric
atropisomers.
Scheme 3. Alternative Regioisomer
Two structural features differentiate the two rings: the ring
tert-butyl substituent and the N-methyl group, and we wanted
to know which was governing this remarkable regioselec-
tivity. We therefore made the two isomeric ureas 17a and
17b and lithiated them under our optimized conditions,
quenching with trimethylsilyl chloride to determine regio-
With the regioselectively alkylated ureas 11 in hand, we
proceeded to study their ortholithiation. Optimum conditions
were established by treating 11h with at least 2 equiv of
organolithium base and quenching with an electrophile
(Scheme 4 and Table 2) to yield the functionalized ureas
16. We found that the best yields resulted from lithiating
(14) An Ar-N axis rotating slow enough to indicate chirality on the
NMR time scale is possible only if the nitrogen is fully substituted and the
Ar group is unsymmetrically functionalized (Adler, T.; Bonjoch, J.; Clayden,
J.; Font-Bardia, M.; Pickworth, M.; Solans, X.; Sole´, D.; Vallverdu´, L. Org.
Biomol. Chem., in press. These conditions are not met in compounds 12,
which cannot show chirality on the NMR time scale.
(15) Regioselectivity was assigned by analysis of coupling patterns in
the aromatic region of the 1H NMR spectra of 16, and for 16g by NOE
indicating proximity of NMe and PhCH. Alcohol 16g was isolated as two
separable diastereoisomers: a future publication will report our observations
on atropisomerism in related N,N′-diarylureas.
(10) Monodeuteration was indicated by a 1/6 decrease in the intergral
of the NMe peaks of the 1H NMR spectrum, but the regioselectivity remains
unassigned.
(11) Beak, P.; Reitz, D. B. Chem. ReV. 1978, 78, 275.
(12) See ref 8 for a discussion.
(16) Remainder is starting material. Urea 19 exists as an inseparable
mixture of diastereoisomeric conformers. Compare ref 15.
(13) No diastereotopic signals were seen for 11a (see ref 14), but we
cannot be sure whether this is due to fast Ar-N rotation resulting from the
small size of the fluoro substituent or because electronegative F induces a
reversal of reactivity in the two monoanion tautomers 13.
(17) (a) Clark, R. D.; Jahangir, A. Org. React. 1995, 47, 1. (b) Clayden,
J. Organolithiums: SelectiVity for Synthesis; Pergamon: Oxford, 2002;
Chapter 2.4, p 73. Lateral lithiation of ureas was, to our knowledge,
previously unknown.
Org. Lett., Vol. 7, No. 15, 2005
3149

selectively, though in very low yield, the alcohol 19 on
quenching with benzaldehyde, again indicating lithiation of
the ring bearing the methylated nitrogen.16 Finally, ortholithi-
ation of 12k, in which the ring bearing the methylated
nitrogen has no ortho protons, was attempted: instead of
ortholithiation of the other ring, lateral (benzylic) lithiation17
gave 20 after quenching with methyl iodide. The results
presented in Scheme 5 confirm that the presence of an
N-alkyl group alone is sufficient to direct the regioselectivity
of ortholithiation.
Scheme 5. Origin of the Regioselectivity
Ortholithiation results from a combination of two factors,
the “complex-induced proximity effect”18 offered by electron-
rich centers, which delivers the organolithium to nearby C-H
bonds, and the acidification of ortho hydrogen atoms (and
consequent stabilization of the anion) resulting from inductive
electron withdrawal by electronegative atoms.19 In the
generalized intermediate 21, the lithiourea directing group
contains an anionic oxygen atom placed equidistant from
both rings, which might equally well direct lithiation of
either. However, we propose that delocalization of charge
through only the unsubstituted nitrogen atom deactivates the
adjacent, leading to preferential lithiation adjacent ring to
the N-alkyl group.
Acknowledgment. We are grateful to the EPSRC, Pfizer,
Organon and the EU (Erasmus Program) for support, to
Dr. Lyn Jones (Pfizer) and Dr, Elizabeth Moir (Organon)
for helpful discussions, and to Dr. Madeleine Helliwell for
determining the X-ray crystal structure of 11g.
selectivity (Scheme 5). Lithiation took place exclusively on
the ring bearing the methylated nitrogen to give 18a and
18b, respectively. Moreover, lithiation of 12h gave, regio-
Supporting Information Available: Experimental pro-
cedures and data for all new compounds; X-ray crystal-
lographic data for 11g (CIF). This material is available free
of charge via the Internet at http://pubs.acs.org.
(18) (a) Beak, P.; Meyers, A. I. Acc. Chem. Res. 1986, 19, 356.
(b) Whisler, M. C.; MacNeil, S.; Snieckus, V.; Beak, P. Angew. Chem.,
Int. Ed. 2004, 43, 2206.
(19) Gschwend, H. W.; Rodriguez, H. R. Org. React. 1979, 26, 1.
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