From simple Ugi adducts to indanes and δ-amidomalonates: New manganese(III)-induced radical cascades

Article abstract of DOI:10.1021/ol701678d

A complete change of the traditional Ugi adducts framework has been obtained using new radical cascades as Ugi post-condensation reactions. Indanes and δ-amidomalonates were thus obtained in a one-pot procedure from aromatic aldehydes under a sequence inv

Full text of DOI:10.1021/ol701678d

ORGANIC
LETTERS
2007
Vol. 9, No. 21
4171-4173
From Simple Ugi Adducts to Indanes
and -Amidomalonates: New
Manganese(III)-Induced Radical
Cascades
δ
Laurent El Kaim,* Laurence Grimaud, and Emilie Vieu*
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
Received July 16, 2007
ABSTRACT
A complete change of the traditional Ugi adducts framework has been obtained using new radical cascades as Ugi post-condensation reactions.
Indanes and -amidomalonates were thus obtained in a one-pot procedure from aromatic aldehydes under a sequence involving Ugi addition
followed by treatment of the adducts with Mn(III) and malonate or -ketoester. The radical step probably involves an intramolecular aryl
δ
â
transfer followed by an oxidative cleavage and final cyclization to indanes.
Since the pioneering work of Ugi, the use of isocyanides
has been strongly associated with the multicomponent
formation of peptide derivatives.1 Most recent efforts on this
reaction have focused on the extension of molecular diversity
by the use of post-condensation reactions.2 Cycloadditions,3
cyclocondensations,4 or organometallic couplings5 with
properly functionalized Ugi adducts have thus been thor-
oughly reported giving, in particular, access to many different
cyclic scaffolds. Notwithstanding all these reports, the
structural diversity reached by all these processes is often
limited by the peptide nature of the adducts which is partially
retained in the final compounds. Our contention was that
radical cascades could further increase the potential of Ugi
four-component reactions and give scaffolds of high diversity
with structures contrasting with the traditional Ugi peptide
backbone. The success encountered by the tin free radical
procedure6 coupled with the very few reports on the use of
radical couplings on Ugi adducts7 encouraged us further in
this direction.
(1) For recent reviews, see: (a) Banfi, L.; Riva, R. Org. React. 2005,
65, 1-140. (b) Zhu, J. Eur. J. Org. Chem. 2003, 1133-1144. (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.
(2) Marcaccini, S.; Torroba, T. In Multicomponent Reactions; Zhu, J.,
Bienayme, H., Eds.; Wiley-VCH: Weinheim, Germany, 2005; Chapter 2,
pp 33-75.
(3) (a) Lu, K.; Luo, T.; Xiang, Z.; You, Z.; Fathi, R.; Chen, J.; Yang, Z.
J. Comb. Chem. 2005, 7, 958-967. (b) Paulvannan, K. J. Org. Chem. 2004,
69, 1207-1214. (c) Akritopoulou-Zanze, I.; Gracias, V.; Moore, J. D.;
Djuric, S.W. Tetrahedron Lett. 2004, 45, 3421-3423. See also ref 2.
(4) (a) Marcaccini, S.; Miliciani, M.; Pepino, R. Tetrahedron Lett. 2005,
46, 711-713. (b) Nixey, T.; Tempest, P.; Hulme, C. Tetrahedron Lett. 2002,
43, 1637-1639. See also ref 2.
(5) (a) Xiang, Z.; Luo, T.; Lu, K.; Cui, J.; Shi, X.; Fathi, R.; Chen, J.;
Yang, Z. Org. Lett. 2004, 6, 3155-3158. (b) Krelaus, R.; Westermamann,
B. Tetrahedron Lett. 2004, 45, 5987-5990. (c) Kazmaeir, U.; Hebach, C.;
Watzke, A.; Maier, S.; Mues, H.; Huch, V. Org. Biomol. Chem. 2005, 3,
136-145. See also ref 2.
10.1021/ol701678d CCC: $37.00
© 2007 American Chemical Society
Published on Web 09/13/2007

Following our initial study on the reactivity of xanthate-
tethered Ugi adducts,7 we turned our attention to the use of
manganese acetate. The most interesting features of Mn(III)-
based radical chemistry are the ability to easily form radicals
from â-dicarbonyl compounds coupled with efficient intra-
and intermolecular additions due to slow oxidation of
electron-deficient radicals.8 These properties have allowed
the disclosure of efficient radical cascades by selecting the
appropriate combination of allyl and aryl residues in the
starting material.9
Table 1. Indane Formation
When equimolar amounts of 2,3-dimethoxybenzaldehyde,
allylamine, tert-butylisocyanide, and acetic acid were added
in MeOH, the Ugi adduct 1a was formed in quantitative
yield. Evaporation of the solvent, followed by treatment with
diethylmalonate and manganese acetate in refluxing acetic
acid, affords substituted indane 3a (Scheme 1). This one-
Scheme 1. Indane Formation from Aromatic Aldehydes
a Ugi reaction was performed with equimolar amount of reagents in molar
methanol and left overnight at room temperature. The oxidation step was
performed in acetic acid (90 °C, 0.3 M) with 4 equiv of malonate or ketoester
and 4.5 equiv of manganese acetate; the reaction was stopped after
decoloration of the medium (3-6 h). b Obtained as a 1:1.2 mixture of
diastereomers. c Six equivalents of manganese was used instead of 4.5.
d Obtained as a 1:1.5 mixture of diastereomers. e Overall isolated yield after
purification of intermediate Ugi adduct.
pot Ugi/Mn(III) oxidation sequence probably represents one
of the most efficient formations of complex cyclopentanes
from aldehyde derivatives.10
Various aldehydes (1a-1e) behaved similarly forming
amidoindanes (3a-3f) in good to moderate yields (Table
1). As most of these Ugi adducts were formed in quantitative
yields, the given yields basically represent the efficiency of
the radical cascade.
In terms of diversity, the loss of the isocyanide part in the
first step of the sequence is counterbalanced by the addition
of the malonyl moiety in the second step, allowing the
disclosure of a new four-component indane formation.
Indeed, the malonyl group can be efficiently replaced by
other activated methylene derivatives: ethylacetoacetate
behaves similarly in this reaction, giving the new indanes
3b and 3e as a mixture of diastereomers with low diaste-
reoselectivity (entries 2 and 5). Other amide derivatives may
be formed as well by the proper choice of the starting
carboxylic acid. With phenylacetic acid (entry 6), the Ugi
adduct formation was not however quantitative (60%); the
intermediate was best purified before the oxidation final step
to give 3f in a 69% isolated yield.
(6) For some recent papers on tin free radical reactions, see: (a) Kim,
S.; Lim, C. J. Angew. Chem., Int. Ed. 2002, 41, 3265-3267. (b) Gagosz,
F.; Zard, S. Z. Org. Lett. 2002, 4, 4345-4348. (c) Boivin, J.; Jrad, R.;
Juge, S.; Nguyen, V. T. Org. Lett. 2003, 5, 1645-1648. (d) Schaffner, A.-
P.; Renaud, P. Angew. Chem., Int. Ed. 2003, 42, 2658-2660. (e) Studer,
A. Chem. Soc. ReV. 2004, 33, 267-273.
(7) El Kaim, L.; Grimaud, L.; Miranda, L. D.; Vieu, E. Tetrahedron
Lett. 2006, 47, 8259-8261.
(8) For reviews on manganese(III) acetate reactions, see: (a) Snider, B.
B. Chem. ReV. 1996, 96, 339-364. (b) Melikyan, G. G. In Organic
Reactions; Paquette, L., Ed.; John Wiley: New York, 1997; Vol. 49, Chapter
3, p 427. For recent examples of Mn(III)-based radical reactions, see: (c)
Yang, D.; Ye, X. Y.; Xu, M.; Pang, K. W.; Cheung, K. K. J. Am. Chem.
Soc. 2000, 122, 1658-1663. (d) Zhang, Z.; Wang, G. W.; Miao, C. B.;
Dong, Y. W.; Shen, Y. B. Chem. Commun. 2004, 1832-1833. (e) Chen,
Z. X.; Wang, G. W. J. Org. Chem. 2005, 70, 2380-2383. (f) Fu, W.-J.;
Huang, X. J. Organomet. Chem. 2007, 692, 740-745. (g) Tanyeli, C.
Ozdemirhan, D. Tetrahedron 2005, 61, 8212-8217.
The reaction sequence seems to need an ortho substituent
on the aromatic aldehyde: though p-chlorobenzaldehyde
(10) For radical cyclization to indane, see: (a) Ly, T.; Quiclet-Sire, B.;
Sortais, B.; Zard, S. Z. Tetrahedron Lett. 1999, 40, 2533-2536. (b) Kurono,
N.; Honda, E.; Komatsu, F.; Orito, K.; Tokuda, M. Tetrahedron 2004, 60,
1791-1801. (c) Bailey, W. F.; Mealy, M. J.; Wiberg, K. B. Org. Lett. 2002,
4, 791-794. (d) Kunding, E. P.; Ratni, H.; Crousse, B.; Bernardinelli, G.
J. Org. Chem. 2001, 66, 1852-1860.
(9) For some radical cascades induced by manganese, see: (a) Snider,
B. B.; Kiselgof, J. Y.; Foxman, B. M. J. Org. Chem. 1998, 63, 7945-
7952. (b) Dombroski, M. A.; Kates, S. A.; Snider, B. B. J. Am. Chem. Soc.
1990, 112, 2759-2767.
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Org. Lett., Vol. 9, No. 21, 2007

forms an Ugi adduct in quantitative yield, the following
manganese treatment just gives a complex mixture (entry
7); p-methoxybenzaldehyde behaved similarly as well as
pyridine carboxaldehyde 1g (entry 8). The observed frag-
mentation does not seem to be limited to a specific
isocyanide, and a small 7% decrease in yield was just
observed when tert-butylisocyanide was replaced by cyclo-
hexylisocyanide in the Ugi step (entry 1).
increases the diversity of the process and allows further
transformations such as cyclization onto the amine or
aromatic moiety.
All these results are in agreement with a 1,4-radical aryl
migration as the key step of the transformation.13 The
peptidyl radical formed after rearrangement is oxidized and
cleaved in acetic acid to give 4a which cyclizes to 3a under
further oxidation with manganese acetate (Scheme 2).
The main interest of this synthetic sequence lies in the
complete rebuilding of the traditional Ugi adduct’s frame-
work with formation of indanes, a chemical family which
has displayed significant biological activities (anti-HIV,11
antihypertensive,12 or thrombin inhibitor12).
Scheme 2. Proposed Mechanism for Indane Formation
The results obtained with aldehyde 1d gives some clues
into the mechanism involved in this transformation. To obtain
indane 3d, 6 equiv of manganese is needed. With 4.5 equiv
of manganese acetate, the reaction gives the uncyclized
malonate 4a in good yield (Table 2). This latter was
Table 2. Formation of δ-Amidomalonates
starting
aldehyde
time
(h)
entry
R4
4 (%)a
In conclusion, we have shown that the Ugi reaction offers
new entries for the obtention of indanes and δ-amido-
malonate scaffolds by new manganese(III)-induced additions.
Most noteworthy is the complete rebuilding of the traditional
Ugi adduct’s framework. The ability to assemble in a single
step rather complex Ugi-type structures gives chemists
unique opportunities to observe interesting couplings or
cascades that might not settle easily on more simple adducts.
Further work is in progress to explore the radical applications
offered by these Ugi adducts.
1
2
3
4
1d
1a
1c
H
4
4
6
8
4a (83)b
4b (71)
4c (70)
4d (66)c
Me
Me
Me
a The oxidation step was performed in acetic acid (90 °C, 0.3 M) with
3 equiv of malonate and 4.5 equiv of manganese acetate; the reaction was
stopped after decoloration of the medium. b Four equivalents of malonate
was used. c Six equivalents of manganese was used for completion.
Acknowledgment. We thank the De´le´gation Ge´ne´rale
pour l’Armement for financial support.
converted into 3d when subsequently treated with Mn(III).
When a substituted malonate is used, similar uncyclized
products are obtained in good yields (Table 2, entries 2-4).
This new formation of δ-amidomalonates represents in its
own an interesting synthesis as easy malonate alkylation
Supporting Information Available: Experimental pro-
cedures and spectral data for indanes and amidomalonates
formed. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL701678D
(11) Molteni, V.; Rhodes, D.; Rubins, K.; Hansen, M.; Bushman, F. D.;
Siegel, J. S. J. Med. Chem. 2000, 43, 2031-2039.
(12) Hanessian, S.; Ma, J. Tetrahedron Lett. 2001, 42, 8785-8788.
(13) For a review on radical aryl migrations, see: (a) Studer, A.; Bossart,
M. Tetrahedron 2001, 57, 9649-9667. (b) See also: Palframan, M. J.;
Tchabanenko, K.; Robertson, J. Tetrahedron Lett. 2006, 47, 8423-8425.
Org. Lett., Vol. 9, No. 21, 2007
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