New benzotriazole and benzimidazole scaffolds from Ugi-Smiles couplings of isocyanides

Article abstract of DOI:10.1021/ol8029438

When allylamine is used as the amino input in Ugi-Smiles couplings of o-nitrophenols, the resulting adducts can be deallylated by a palladiumcatalyzed process leading to a formal Ugi-Smiles coupling with ammonia. This new sequence, combined with hydrogeno

Full text of DOI:10.1021/ol8029438

ORGANIC
LETTERS
2009
Vol. 11, No. 4
995-997
New Benzotriazole and Benzimidazole
Scaffolds from Ugi-Smiles Couplings
of Isocyanides
Didier Coffinier, Laurent El Kaim,* and Laurence Grimaud*
Laboratoire Chimie et proce´de´s, Ecole Nationale Supe´rieure de Techniques AVance´es,
32 Bd Victor, 75739 Paris Cedex 15, France
laurent.elkaim@ensta.fr, laurence.grimaud@ensta.fr
Received December 22, 2008
ABSTRACT
When allylamine is used as the amino input in Ugi-Smiles couplings of o-nitrophenols, the resulting adducts can be deallylated by a palladium-
catalyzed process leading to a formal Ugi-Smiles coupling with ammonia. This new sequence, combined with hydrogenolysis of the nitro
group, offers an interesting multicomponent entry to benzotriazole and benzimidazole scaffolds.
Since the pioneering work of Ugi, the use of isocyanides
has been strongly associated with the multicomponent
formation of peptide derivatives.1 While carboxylic acids are
the most popular acidic components, Ugi demonstrated very
early that these couplings could be extended to different
acidic partners. We recently disclosed the use of electron-
deficient phenols as acidic partners in Ugi-type reactions
(Scheme 1).2 Starting from o-nitrophenol, the hydrogenolysis
of the Ugi adduct affords an interesting approach to the
synthesis of benzofused heterocycles as shown by the
preparation of quinoxaline derivatives (Scheme 1).3 However,
the substitution of primary amines by ammonia4 in such a
sequence could afford a much wider access to o-phenylene-
diamine-related heterocycles.
Scheme 1
.
Ugi-Smiles Coupling Followed by Azepine
Formation
(1) For recent reviews, see: (a) Banfi, L.; Riva, R. Org. React. 2005,
65, 1–140. (b) Zhu, J. Eur. J. Org. Chem. 2003, 113, 3–1144. (c) Ugi, I.;
Werner, B.; Do¨mling, A. Molecules 2003, 8, 53–66. (d) Hulme, C.; Gore,
V. Curr. Med. Chem. 2003, 10, 51–80. (e) Bienayme´, H.; Hulme, C.; Oddon,
G.; Schmitt, P. Chem.sEur. J. 2000, 6, 3321–3329. (f) Do¨mling, A.; Ugi,
I. Angew. Chem., Int. Ed. 2000, 39, 3168–3210. (g) Do¨mling, A. Chem.
ReV. 2006, 106, 17–89.
As previously reported for the Ugi reaction, the poor results
obtained with ammonia (probably due to the formation of side
products)5 have led chemists to choose “convertible primary
amines” such as nitrobenzylamine6 that can be deprotected after
Ugi reaction. In our case, we believed that the electron-
(2) (a) El Kaim, L.; Grimaud, L.; Oble, J. Angew. Chem., Int. Ed. 2005,
44, 7165–7169. El Kaim, L.; Gizolme, M.; Grimaud, L.; Oble, J. J. Org.
Chem. 2007, 72, 4169–4180.
(3) Oble, J.; El Ka¨ım, L.; Gizzi, M.; Grimaud, L. Heterocycles 2007,
73, 503–517.
(5) Pick, R.; Bauer, M.; Kazmaier, U.; Hebach, C. Synlett 2005, 757–
760.
(4) Kazmaier, U.; Hebach, C. Synlett 2003, 1591–1594.
(6) Sung, K. S.; Chen, F. L.; Huang, P. C. Synlett 2006, 2667–2669.
10.1021/ol8029438 CCC: $40.75
Published on Web 01/26/2009
2009 American Chemical Society

withdrawing effect of the N-nitrophenyl group offered interest-
ing opportunities for various primary amines to act as suitable
ammonia equivalents. After several deceiving attempts with
benzylamines, allylamine was selected owing to its well-known
facile deallylation. These deprotections are usually performed
under palladium catalysis, the allyl residue being trapped either
by the solvent or by an additional nucleophile in the medium.7
A Pd/C-sulfonic acid system7b was selected as it combines the
interest of activating the amine while destructing remaining
traces of isocyanide.8 Thus, after completion of the Ugi-Smiles
step, the mixture was treated with 1 equiv of p-toluenesulfonic
acid (PTSA) followed by addition of palladium on carbon (10%
Pd/C). After additional heating for 1 day, the expected secondary
anilines were isolated in fair to good yields (entries 1-9, Table
1).
scaffolds, adducts obtained after the Ugi-Smiles/deallylation
sequence were quantitatively reduced to o-phenylenediamine
through catalytic hydrogenation under flow conditions. The
products were not isolated but directly converted to benzo-
triazoles under treatment with sodium nitrite and acetic acid
(Table 2). Besides their potential biological activities,12 these
new R-benzotriazolyl amides may find interesting applica-
tions in the synthesis of pyridones.13
Alternatively, two different benzimidazole14 families have
been prepared from these o-phenylenediamines either under
treatment with CS2 or by adding aldehydes under oxidative
conditions (Table 3). For the preparation of mercaptobenz-
imidazoles (entries 1 and 2, Table 3), several procedures are
available according to the sulfur reagent. Carbon disulfide
was preferred over thiocarbonyldiimidazole15 or thiophos-
gene.16 Additions with this reagent are usually performed
either in hot DMF17 or in refluxing ethanol in the presence
Table 1. Ugi-Smiles Formation of Secondary Anilines
(7) (a) Garro-Helion, F.; Merzouk, A.; Guibe´, F. J. Org. Chem. 1993,
58, 6109–6113. (b) Liu, Q.; Marchington, A. P.; Boden, N.; Rayner, C. M.
J. Chem. Soc., Perkin Trans. 1 1997, 511–518. (c) Honda, M.; Morita, H.;
Nagakura, I. J. Org. Chem. 1997, 62, 8932–8936. (d) Karpf, M.; Trussardi,
R. J. Org. Chem. 2001, 66, 2044–2051. (e) Ohmura, N; Nakamura, A.;
Hamasaki, A.; Tokunaga, M. Eur. J. Org. Chem. 2008, 5042–5045.
(8) Remaining isocyanide might inhibit the palladium catalytical cycle.
For such an effect in a one-pot synthesis of indole, see: El Kaim, L.; Gizzi,
M.; Grimaud, L. Org. lett. 2008, 10, 3417–3419.
(9) (a) Fan; W.-Q.; Katritzky, A. R. In ComprehensiVe Heterocyclic
Chemistry; Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon
Press: Oxford, 1996; Vol. 4, pp 101-126. (b) Gillespie, H. B.; Spano, F.;
Graff, S. J. Org. Chem. 1960, 25, 942–944. (c) Plater, M. J.; Greig, I.;
Helfrich, M. H.; Ralston, S. H. J. Chem. Soc., Perkin Trans. 1 2001, 20,
2553–2559. (d) Sasmal, P. K.; Sridhar, S.; Iqbal, J. Tetrahedron Lett. 2006,
47, 8661–8665.
(10) (a) Grimmett, M. R. Imidazoles and their Benzo Derivatives. In
ComprehensiVe Heterocyclic Chemistry; Katritzky, A. R., Rees, C. W., Eds.;
Pergamon: Oxford, 1984; Vol. 5, pp 457-487. (b) Tumelty, D.; Cao, K.;
Holmes, C. P. Org. Lett. 2001, 1, 83–86 (O2-RCHO). (c) Hioki, H.;
Matsushita, K.; Kubo, M.; Kodama, M. J. Comb. Chem. 2006, 8, 462–463
(O2-RCHO). (d) Raju, B.; Nguyen, N.; Holland, G. W. J. Comb. Chem.
2002, 4, 320–328. (e) Bahrami, K.; Khodaei, M. M.; Naali, F. J. Org. Chem.
2008, 73, 6835–6837. (f) Salehi, P.; Dabiri, M.; Zolfigol, M. A.; Otokeshb,
S.; Baghbanzadeh, M. Tetrahedron Lett. 2006, 47, 2557–2560.
(11) For some biologically relevant benzimidazoles and benzotriazoles,
see: (a) Salluja, S.; Zou, R.; Drach, J. C.; Townsend, L. B. J. Med. Chem.
1996, 39, 881–891. (b) Craigo, W. A.; LeSueur, B. W.; Skibo, E. B. J. Med.
Chem. 1999, 42, 3324–3333. (c) Zhao, Z. S.; Arnaiz, D. O.; Griedel, B.;
Sakata, S.; Dallas, J. L.; Whitlow, M.; Trinh, L.; Post, J.; Liang, A.;
Morrissey, M. M.; Shaw, K. J. Bioorg. Med. Chem. Lett. 2000, 10, 963–
966. (d) Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. ReV. 2003,
103, 893–930. (e) Kopanska, K.; Najda, A.; Zebrowska, J.; Chomicz, L.;
Piekarczyk, J.; Myjak, P.; Bretner, M. Bioorg. Med. Chem. 2004, 12, 2617–
2624. (f) He, F. Q.; Liu, X. H.; Wang, B. L.; Li, Z. M. J. Chem. Res. 2006,
809–811. (g) Caliendo, G.; Greco, G.; Grieco, P.; Novellino, E.; Perissutti,
E.; Santagada, V.; Barbarulo, D.; Esposito, E.; De Blasi, A. Eur. J. Med.
Chem. 1996, 31, 207–213.
(12) Sparatore, F.; Rotonda, M. I.; Caliendo, G.; Novellino, E.; Silipo,
C.; Vittoria, A. Farmaco 1988, 43, 29–48.
(13) For a one-step pyridone formation from R,ꢀ-unsaturated ketones
and R-benzotriazolylamides, see: Katritzky, A. R.; Belyakov, S. A.;
Sorochinsky, A. E.; Henderson, S. A.; Chen, J. J. Org. Chem. 1997, 62,
6210–6214.
a Ugi-Smiles reaction (2 mmol scale, 1 M in methanol) was performed
with equimolar amount of reagents and left for 1 day at 60 °C. PTSA (1
equiv) in methanol (2 mL) was then added before addition of 10% Pd/C
(10 mol %). The resulting mixture was heated at 60 °C for 24 h before
workup. b The Ugi-Smiles step required a 10 day heating for completion.
(14) Such substituted benzimidazoles can also be produced by the UDC
sequence described by Tempes, Hulme, and co-workers (Tempest, P.; Ma,
V.; Thomas, S.; Hua, Z.; Kelly, M. G.; Hulme, C. Tetrahedron Lett. 2001,
42, 4959–4962. ). Formally, similar products could also be formed by a
U-3CR of phenylenediamine and condensation or by using o-nitroaniline
and subsequent reductive cyclization.
(15) Dannhardt, G.; Kohl, B. Arch. Pharm. 2000, 333, 123–129.
(16) Charles, E. S.; Rao, K. V. B.; Sharma, S. Pharmazie 1982, 37,
413–415.
o-Phenylenediamine derivatives are important starting
materials for the preparation of various benzofused hetero-
cycles such as benzotriazoles9or benzimidazoles.10 These two
families have been the focus of many synthetic efforts due
to their potential in medicinal chemistry.11 To reach such
(17) Ellsworth, E. L.; Domagala, J.; Vara Prasad, J. V. N.; Hagen, S.;
Ferguson, D.; Holler, T.; Hupe, D.; Graham, N.; Nouhan, C.; Tummino,
P. J.; Zeikus, G.; Lunney, E. A. Bioorg. Med. Chem. Lett. 1999, 9, 2019–
2024.
996
Org. Lett., Vol. 11, No. 4, 2009

Table 2. Benzotriazoles from Ugi-Smiles Intermediates
Table 3. Benzimidazoles from Ugi-Smiles Intermediates
starting
aniline
producta
(yield, %)
starting
aniline
product
(yield, %)
entry
R1
R2
R3
entry
R1
R2
R3
X
1
2
3
4
5
2a
2b
2e
2g
2i
H
H
H
H
Et
CH2iPr
CH2iPr
Et
4-ClPh
Me
Cy
tBu
3a (64)
3b (91)
3c (89)
3d (95)
3e (74)
1
2
3
4
5
2a
2f
2a
2c
2c
Cy
tBu Ph
Cy
Cy
Cy
CH2iPr
H
H
H
SH
SH
4a (84)a
4b (40)a
4c (72)b
4d (56)b
4e (52)c
4-ClPhCH2
CH2iPr
4-ClPh
CH2iPr Me CH2-i-Pr
4-NO2Ph
Cy
Cy
Me 4-ClPh
a Typical procedure: 1 mmol of aniline was treated in MeOH with H2
under flow conditions on a Pd/C (10%) cartridge (rt, H2 1 atm, 1 mL/min).
Evaporation of the solvent followed by stepwise addition of acetic acid
and sodium nitrite afforded product after hydrolysis and extraction of the
mixture.
a Typical procedure: Deallylated Ugi-Smiles adduct (1 mmol) was
treated in MeOH with H2 under flow conditions on a Pd/C (10%) cartridge
(rt, 1 atm H2, 1 mL/min). After evaporation of the solvent, the product was
heated under microwave conditions (120 °C, 15 min) with CS2 (3 equiv)
in ethanol (0.3 M). b Deallylated Ugi-Smiles adduct was reduced as in
footnote a followed by heating overnight at 100 °C with an aromatic
aldehyde and catalytic Pd(OAc)2 in DMF under air. c Same procedure as
footnote b except DMF was replaced by pyridine (rt for 3 days).
of sodium or potassium hydroxide.18 We found that the
addition-cyclization step could be much more easily achieved
by simply heating the phenylenediamine under microwave
conditions with an excess of CS2 in ethanol at 120 °C for
15 min. In the case of 2-arylbenzimidazoles (entries 3 and
4, Table 3), the best conversion was obtained with a
palladium-catalyzed oxidation in DMF under air. Indeed, 2a
was converted to 4c in a 72% isolated yield, whereas a lower
50% yield was obtained under heating in nitrotoluene at 160
°C. With aliphatic aldehydes, similar conversion was better
achieved at room temperature with pyridine as solvent (entry
5, Table 3). These preparations of benzimidazoles (4c, 4d,
4e) with three steps involving palladium catalysis illustrate
the power of the latter in heterocyclic synthesis.
last step of the sequence. In the context of lead discovery, it
further demonstrates the utility of multicomponent reactions
for the search of efficient synthetic routes toward privileged
medicinal scaffolds. We are currently extending these
procedures to the use of hydroxypyridines and hydroxypy-
rimidines in place of o-nitrophenol, with the expected
formation of scaffolds of higher biological interest.
Acknowledgment. We thank Dr. J. Sancon (GlaxoSmith-
Kline) for fruitful discussions. D.C. thanks the Centre
National de la Recherche Scientifique as well as Glaxo-
SmithKline for a Ph.D. fellowship.
This study brings forward a new preparation of benzofused
heterocycles with four points of diversity, the allyl moiety
initially lost being replaced by a new component during the
Supporting Information Available: Detailed experimen-
tal procedures and spectral data for deallylated Ugi-Smiles
adducts, benzotriazoles, and benzimidazoles. This material
is available free of charge via the Internet at http://pubs.acs.org.
(18) Devivar, R. V.; Kawashima, E.; Revankar, G. R.; Breitenbach, J. M.;
Kreske, E. D.; Drach, J. C.; Townsend, L. B. J. Med. Chem. 1994, 37,
2942–2949.
OL8029438
Org. Lett., Vol. 11, No. 4, 2009
997