Rearrangement strategy for the synthesis of 2-aminoanilines

Article abstract of DOI:10.1021/ol100196a

(Figure Presented) Treatment of N-aryl hydroxylamines with trichloroacetonitrile in the presence of imidazole provides a simple and effective method for the preparation of synthetically versatile 2-aminoanilines. Reactions proceed in DMF at 40°C, providing the products In up to 86% isolated yield.

Full text of DOI:10.1021/ol100196a

ORGANIC
LETTERS
2010
Vol. 12, No. 7
1492-1495
Rearrangement Strategy for the
Synthesis of 2-Aminoanilines
Achim Porzelle,† Michael D. Woodrow,‡ and Nicholas C. O. Tomkinson*,†
School of Chemistry, Main Building, Cardiff UniVersity, Park Place,
Cardiff, CF10 3AT, U.K., and ImmunoInflammation Centre of Excellence for Drug
DiscoVery, GlaxoSmithKline Medicines Research Centre, SteVenage,
Hertfordshire, SG1 2NY, U.K.
tomkinsonnc@cardiff.ac.uk
Received January 26, 2010
ABSTRACT
Treatment of N-aryl hydroxylamines with trichloroacetonitrile in the presence of imidazole provides a simple and effective method for the
preparation of synthetically versatile 2-aminoanilines. Reactions proceed in DMF at 40 °C, providing the products in up to 86% isolated yield.
The 2-aminoaniline scaffold has exceptional industrial
significance and is embedded in the structure of a number
of important pharmaceuticals. For example, Nexium, Zyprexa,
and Alphagan P (Figure 1), which contain this group, had
combined worldwide sales in excess of $6.5 billion in 2008.1
Due to the fact that the structure serves as a precursor to a
number of pharmacophores including benzimidazoles,2 1,5-
benzodiazepines,3 quinoxalines,4 benzotriazoles,5 and ben-
zimidazolones,6 among others, simple methods for the
selective introduction of this group have great synthetic
potential.
† Cardiff University.
‡ GlaxoSmithKline, Stevenage.
(1) Drug Top. 2009, 6, 7. For a chemical summary of this information
see http://www.chem.cornell.edu/jn96/outreach.html.
(2) (a) Bhattacharya, S.; Chaudhuti, P. Curr. Med. Chem. 2008, 15, 1762.
Figure 1. The 2-aminoaniline scaffold in important pharmaceuticals.
(b) Chassaing, C.; Berger, M.; Heckeroth, A.; Ilg, T.; Jaeger, M.; Cern, C.;
Schmid, K.; Uphoff, M. J. Med. Chem. 2008, 51, 1111. (c) Lyaskovskyy,
V. V.; Voitenko, Z. V.; Kovtunenko, V. A. Chem. Heterocycl. Compd. 2007,
43, 253. (d) Spasov, A. A.; Yozhitsa, I. N.; Bugaeva, L. I.; Anisimova,
Methods for the selective amination of monosubstituted
aromatics are scarce, which severely restricts the potential
of the 2-aminoaniline core in drug discovery programs with
V. A. Pharm. Chem. J. 1999, 33, 232.
(3) (a) Zhao, H.-Y.; Liu, G. J. Comb. Chem. 2007, 9, 1164. (b) Horton,
D. A.; Bourne, G. T.; Smythe, M. L. Chem. ReV. 2003, 103, 893. (c) Herpin,
T. F.; Van Kirk, K. G.; Salvino, J. M.; Yu, S. T.; Labaudinie`re, R. F.
J. Comb. Chem. 2000, 2, 513.
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2006, 6, 1179. (b) Sato, N. Sci. Synth. 2004, 16, 751.
(6) (a) Kamal, A.; Reddy, K. L.; Devaiah, V.; Shankaraiah, N.; Rao,
M. V. Mini ReV. Med. Chem. 2006, 6, 71. (b) Smith, D. M. In Chemistry
of Heterocyclic Compounds; Preston, P. N., Ed.; Wiley-Interscience:
Chichester, 1981; Vol. 40, p 331.
(5) Craig, P. N. In ComprehensiVe Medicinal Chemistry; Drayton, C. J.,
Ed.; Pergamon Press: New York, 1991; Vol. 8.
10.1021/ol100196a  2010 American Chemical Society
Published on Web 03/03/2010

respect to novelty and diversity. An isolated report by
Blechert showed that N-aryl hydroxylamines (e.g., 1) can
be converted to the ortho-functionalized derivative 2 by
deprotonation with sodium hydride followed by treatment
with imidoyl chlorides (Scheme 1).7 Although the examples
in this report were limited, it is surprising this potentially
useful rearrangement has not been exploited.8 Reasoning the
synthetic applicability of this approach could be significantly
enhanced by removing the air-sensitive nature of both
reactant and reagent we set out to develop this rearrangement
further. Within this paper we describe a simple and effective
method for the conversion of N-aryl hydroxylamines to
differentially protected 1,2-diaminobenzenes in a controlled
and efficient manner.
Table 1. Variation of N-Protecting Groupa
entry
substrate
R1
R2
product
% yieldb
1
2
3
4
5
6
3
4
5
6
7
8
OMe
OMe
OBn
OBn
OtBu
OtBu
H
Me
H
Me
H
Me
9
70
80
62
76
73
83
10
11
12
13
14
a All reactions performed in duplicate at 0.5 M concentration of
hydroxylamine, tichloroacetonitrile (4 equiv), imidazole (1.05 equiv), DMF;
40 °C, 6 h. b Isolated yield.
Scheme 1. Blechert Synthesis of 2-Aminoanilines
Each of these groups worked with equal efficiency (62-83%)
with the N-aryl hydroxylamines examined.
Assessment of functional group tolerance and regiochemi-
cal course of the rearrangement is outlined in Table 2. In
the development of this chemistry, we were concerned with
incorporation of useful synthetic handles within the sub-
strates. Chlorides (entry 1; 59%), bromides (entry 2; 45%),
and protected phenols (entries 3 and 4; 82% and 79%,
The N-aryl hydroxylamines used within this study were
prepared from either nitroarenes9 or aryl halides10 by known
methods, were amenable to scale-up, and had good functional
group tolerance. The considerable number of commercially
available nitroarenes and aryl halides suggest the technology
described will allow for the synthesis of a wide variety of
2-aminoanilines.
Scheme 2. Transformations of Products
As a starting point we examined the reaction of hydroxy-
lamine 3 (R1 ) OMe; R2 ) H) with trichloroacetonitrile
varying base, solvent, and temperature. Optimized conditions
involved reaction of hydroxylamine 3 with trichloroaceto-
nitrile (4 equiv) in the presence of imidazole (1.05 equiv) in
DMF at 40 °C for 6 h, which gave 2-aminoaniline 9 in a
pleasing 70% isolated yield (Table 1, entry 1). This represents
an operationally simple method for the preparation of
differentially protected 2-aminoanilines that proceeds under
mild reaction conditions without the need for rigorous
exclusion of moisture and air.
In order to determine some of the scope of this transfor-
mation, we investigated the effect of changing the nitrogen
protecting group on the substrate (Table 1). Three common
carbamate protecting groups were examined (Boc, Cbz, and
methoxycarbonyl) due to their widespread use in synthesis.
(7) Ho¨felmeier, R.; Blechert, S. Angew. Chem., Int. Ed. Engl. 1982, 21,
370.
(8) For a related rearrangement using cyanogen bromide leading directly
to imidazolones, see: Almeida, P. S.; Lobo, A. M.; Prabhakar, S.
Heterocycles 1989, 28, 653.
(9) Porzelle, A.; Woodrow, M. D.; Tomkinson, N. C. O. Synlett 2009,
798.
(10) (a) Porzelle, A.; Woodrow, M. D.; Tomkinson, N. C. O. Org. Lett.
2009, 11, 233. (b) Jones, K. L.; Porzelle, A.; Hall, A.; Woodrow, M. D.;
Tomkinson, N. C. O. Org. Lett. 2008, 10, 797.
Org. Lett., Vol. 12, No. 7, 2010
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Table 2. Scope of Rearrangementa
a All reactions performed in duplicate at 0.5 M concentration of hydroxylamine, tichloroacetonitrile (4 equiv), imidazole (1.05 equiv), DMF, 40 °C, 6 h.
d
b Isolated yield. c Reaction performed at room temperature. Conversion based on H NMR spectroscopy of crude reaction mixture in CDCl3.
1
respectively) were tolerated on the aromatic ring. Unprotected
carbonyl groups were not effective substrates under the
optimized conditions (entry 5; ∼15%); however, this could
be circumvented by protection as the acetal (entry 6; 68%;
entry 10; 66%). Introduction of the versatile alkyne func-
tionality was possible (entry 7; 66%), and common hetero-
cycles such as thiazole were also tolerated (entry 8; 67%).
We also examined regiochemical aspects of the rearrange-
ment process (entries 9-14). With larger substituents in the
3-position of the aromatic ring the rearrangement proceeded
regioselectively (entries 9-11). Introduction of smaller
groups reduced this selectivity such that with a 3-methyl-
substituted N-aryl hydroxylamine the ratio of products fell
to around 1:1 (entry 12). 2-Substitution of the substrates was
also well tolerated, providing the expected products in good
yield (entries 14-16; 62-86%).
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Org. Lett., Vol. 12, No. 7, 2010

The results presented are consistent with the reaction
proceeding via addition of the hydroxylamine oxygen to
trichloroacetonitrile followed by [3,3] sigmatropic rearrange-
ment. We have no direct evidence to support this proposal,
and further investigation would be necessary in order to
determine the precise mechanistic course of the transforma-
tion.
Finally, some of the potential products from this trans-
formation are outlined in Scheme 2. Direct access to the
benzimidazolidinone pharmacophore (e.g., 15) is easily
achieved by prolonged solvolysis (NaOH, MeOH, 40 °C,
4 h) with Boc, Cbz, and methoxy carbamate protecting
groups (70-81%). The benzimidazoles 18 (78%) and 19
(84%) can be prepared directly from the rearranged products
16 and 17 under acidic reaction conditions. The trichlorom-
ethyl benzimidazole scaffold resulting from this reaction has
been used extensively as a versatile synthetic intermediate.11
Additionally, the less common trichloroacetyl protecting
group can be selectively removed in the presence of Cbz
(20; 72%), Boc (21; 69%), and methoxy (22; 55%) carbam-
ates by treatment with an excess of sodium borohydride at
room temperature.12
In summary, we have developed an effective method for
preparation of the 2-aminoaniline scaffold, a privileged
pharmacophore. Substrates for these transformations are
easily accessed from aryl halides or nitroarenes, and func-
tional group tolerance on both the nitrogen and aromatic
substituents suggests the methodology will provide a robust
and practical method with which to address this important
chemical challenge. The methodology has distinct advantages
over literature precedent due to operational simplicity; the
reaction proceeds without purification of solvent or reagents
and does not require the rigorous exclusion of either moisture
or air.
Acknowledgment. The authors thank the EPSRC and
GlaxoSmithKline for financial support and the Mass Spec-
trometry Service, Swansea, for high-resolution spectra.
Supporting Information Available: Analytical data,
experimental procedures, and NMR spectra. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL100196A
(11) Grimmett, M. R. Sci. Synth. 2002, 12, 529.
(12) Weygand, F.; Frauendorfer, E. Chem. Ber. 1970, 103, 2437.
Org. Lett., Vol. 12, No. 7, 2010
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