Smiles cascades toward heterocyclic scaffolds

Article abstract of DOI:10.1021/ol1028817

Two different Smiles rearrangements can be combined to afford a multicomponent formation of isoquinolinones and isoindolinones from nitro methyl salicylate. After a Ugi-Smiles four-component coupling, the base-triggered cyclization of the resulting adduct

Full text of DOI:10.1021/ol1028817

ORGANIC
LETTERS
2011
Vol. 13, No. 3
534-536
Smiles Cascades toward Heterocyclic
Scaffolds
Laurent El Kaim,*,† Laurence Grimaud,*,† Xavier F. Le Goff,‡ and Aure´lie Schiltz†
Laboratoire Chimie et Proce´de´s, Ecole Nationale Supe´rieure de Techniques AVance´es,
32 Bd Victor, 75739 Paris Cedex 15, France, and Laboratoire He´te´roe´le´ments et
Coordination, Ecole Polytechnique, CNRS, Route de Saclay,
F-91128 Palaiseau Cedex, France
laurent.elkaim@ensta-paristech.fr; laurence.grimaud@ensta-paristech.fr
Received November 29, 2010
ABSTRACT
Two different Smiles rearrangements can be combined to afford a multicomponent formation of isoquinolinones and isoindolinones from nitro
methyl salicylate. After a Ugi-Smiles four-component coupling, the base-triggered cyclization of the resulting adduct is followed by a ring
contraction via a Truce-Smiles rearrangement.
The Smiles rearrangements consist of an intramolecular
migration of aromatic rings between two nucleophilic cen-
Scheme 1. Envisioned Smiles Cascades
ters.1 The presence of electron-withdrawing groups on the
aromatic ring ensures the efficiency of the interaction with
the nucleophiles, which are most often based on heteroatoms
such as N, O, or S. However, in the Truce-Smiles rear-
rangement, a nucleophilic carbon is involved, leading to new
carbon-carbon bond formation.2
A few years ago, we reported a four-component Ugi-type
coupling with electron-deficient phenols (Scheme 1).3 The
† Ecole Nationale Supe´rieure de Techniques Avance´es.
‡ Ecole Polytechnique, CNRS.
(1) (a) Levy, A. A.; Rains, H. C.; Smiles, S. J. Chem. Soc 1931, 3264.
For reviews see: (b) Bunnet, J. F.; Zaller, R. E. Chem. ReV. 1951, 49, 273–
308. (c) Truce, W. E.; Kreider, E. M.; Brand, W. W. Org. React. (N. Y.)
1970, 18, 99–215. (d) Plesniak, K.; Zarecki, A.; Wicha, J. Top. Curr. Chem.
2007, 275, 163–250.
reaction features as the key step of an efficient Smiles
rearrangement controlled by the conversion from an imidate
to an amide conversion. Since this report, we have contem-
plated using these Ugi-Smiles adducts in further Truce-
Smiles reactions (Scheme 1).
Beside the attraction of performing a cascade of Smiles
rearrangements, we felt that the synthetic strategy of creating
an intermediate N-aryl compound to form the final C-aryl
(2) (a) Truce, W. E.; Ray, W. J., Jr.; Norman, O. L.; Eickemeyer, D. B.
J. Am. Chem. Soc. 1958, 80, 3625–3629. For a review, see: (b) Snape,
T. J. Chem. Soc. ReV. 2008, 37, 2452–2458.
(3) (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.
10.1021/ol1028817  2011 American Chemical Society
Published on Web 12/22/2010

bond held tremendous appeal, since to create directly such
a carbon-aryl bond intermolecularly would be far more
difficult. We recently reported various deprotonations of the
CH peptidic position of Ugi-Smiles adducts leading to
carbon-carbon bond formations.4 Using these anions in
Truce-Smiles reactions was rather challenging, as this
project would imply a 3-exo-trig cyclization, whereas most
Smiles rearrangements feature 5-exo-cyclizations.5
Table 1. Optimization of the Reaction Conditions
entry
base(equiv)
solvent
temperature(time) yield
The Ugi-Smiles adduct 1a obtained from propyl amine,
isovaleraldehyde, 4-chlorobenzylisocyanide, and 2-nitrophe-
nol failed to give any Truce-Smiles rearranged products
under a set of basic conditions. In the search for more
electrophilic aromatic rings, we next examined the behavior
of adducts 1b-1d derived from 2,4-dinitrophenol, methyl
4-hydroxy-3-nitro-benzoate, and methyl 4-nitro-salicylate, the
latter being of further interest due to potential cyclizations
onto the ester moiety. Though different basic conditions
failed to give any reaction with adducts 1b and 1c, an
interesting transformation was observed when salicylate
derivative 1d was treated under microwave irradiation in
triethylamine as solvent. Indeed, the formation of isoquino-
linone 2d in a moderate 35% isolated yield revealed a
quaternarized peptidic position with the carbon directly linked
to the aromatic core, which could be explained by a
Truce-Smiles rearrangement (Scheme 2).
1
2
3
4
5
6
7
8
t-BuOK (1.2) THF
80 °C (3 d)
100 °C (4 d)
100 °C (3 d)
80 °C (3 d)
80 °C (3 d)
80 °C (2 d)
60 °C (1 d)
60 °C (1 d)
nra
nr
43%
nr
NaH (1.2)
NaH (5)
DMF
DMF
DBU (1.2)
DBU (1.2)
MeCN
1,2-DCE
nr
DBU/1,2-DCE (1:1)
53%
65%
77%
DBU (5)
DBU (5)
THF
CF3CH2OH
a nr: no reaction.
Scheme 3. Behavior of 1d in Protic Solvents
Scheme 2. First Truce-Smiles Rearrangement
The structure of byproduct 3d was confirmed by an X-ray
analysis (Scheme 3).6 Though 3d might result from a direct
Truce-Smiles rearrangement followed by a cyclization, a
time/ratio dependence is more in favor of a formation of 3d
through rearrangement of isoquinolinone 2d. This last
observation led us to propose a set of two conditions for the
formation of either isoquinolinone 2 or isoindolinone 3
according to the solvent used in the reaction. Thus, various
Ugi-Smiles adducts were treated with an excess of DBU
in THF and 2,2,2-trifluoroethanol at 60 °C to form the
corresponding isoquinolinones 2 and isoindolinones 3 as
listed in Table 2.
Encouraged by this first result, different sets of conditions
were next investigated to optimize such a reaction as
displayed in Table 1.
The best conditions were obtained when using a large
excess of base, at least 5 equiv of DBU (Table 1, entries
6-8) or NaH (Table 1, entry 3), in a polar solvent such as
THF (Table 1, entry 7) or DMF (Table 1, entry 3) or a polar
protic solvent such as CF3CH2OH (Table 1, entries 8).
However, when using DBU in 2,2,2-trifluoroethanol, the
desired isoquinolinone 2d was isolated along with 20% of
the isoindolinone 3d (Scheme 3).
The results depicted above indicate a strong influence of
the bulkiness of the isocyanide and aldehyde on the fate of
the reaction. When cyclohexyl and tert-butyl isocyanides
(6) The crystallographic data can be obtained free of charge under the
reference CCDC 801186 at the Cambridge Crystallographic Data Centre
(www.ccdc.cam.ac.uk/data_request_cif).
(7) A related Truce-Smiles rearrangement was already observed in a
Ugi cyclic adduct (Dai, W.-M. Book of Abstracts, IV International
Conference on Multi-component Reactions and Related Chemistry
(MCR2009), Ekaterinburg, Russia, 24-28 May 2009, p 14).
(4) (a) El Kaim, L.; Gamez-Montan˜o, R.; Grimaud, L.; Ibarra-Rivera,
T. Chem. Commun. 2008, 1350–1352. (b) El Kaim, L.; Grimaud, L.;
Wagschal, S. J. Org. Chem. 2010, 75, 5343–5346.
(5) (a) For a possible Smiles rearrangement of N-aryl sulfonamide
involving a three-membered spiro intermediate, see: Muller, P.; Phuong,
N.-T. M. HelV. Chim. Acta 1979, 62, 494–496.
Org. Lett., Vol. 13, No. 3, 2011
535

Table 2. Scope of the Cyclization-Truce-Smiles Cascades
Scheme 4. Plausible Mechanism
(Table 2, entries 1-2). For the reactant 1e, the cyclization
to an intermediate benzodiazepinedione is either impossible
or disturbed by the steric hindrance of the tert-butyl group.
The results obtained from cyclohexyl isocyanide adduct 1f
further confirm this cyclization path. In this case, most
surprisingly, the intermediate benzodiazepinedione 4f failed
to undergo the Truce-Smiles rearrangement, suggesting a
strong dependence on the conformation of the cyclic
intermediates. Final conversion of 2d into 3d may be
explained by an intramolecular addition of the amino residue
onto the imide with subsequent release of an amido group.
In conclusion, we have reported a new isocyanide-based
multicomponent sequence toward isoquinolinones and isoin-
dolinones. The strategy implies a series of Smiles rearrange-
ments allowing the formation of scaffolds, which are unusual
in IMCR-based synthesis. The interest of the sequence is
further enhanced by the Truce-Smiles rearrangement in-
volved. Indeed, its mechanism involves [3,6]-spiro species
which is unprecedented in the literature.7 Mechanistic
calculations are currently being studied to gain more insight
into this transformation.
a Isolated yield for the synthesis of 1. b Isolated yields for 2 using DBU
(5 equiv) in THF at 60 °C. c Isolated yields for 3 using DBU (10 equiv) in
CF3CH2OH at 60 °C.
were used, the corresponding isoquinolinones and isoindoli-
nones could not be obtained (Table 2, entries 1-2). In the
case of aldehydes, these cyclizations could not be observed
with an aromatic susbstituent probably due to the higher
stability of the peptidyl enolate.
With all these results in hand, the obtention of 2d may be
understood by a sequence of events involving a cyclization
of the amide onto the ester moiety, followed by a
Truce-Smiles rearrangement (Scheme 4). The timing of this
sequence is confirmed by the lack of reactivity of 1e and 1f
Acknowledgment. We wish to thank the De´le´gation
Ge´ne´rale de l’Armement and the ENSTA for financial
support and Charlotte Mocquard (ENSTA) for her fruitful
help.
Supporting Information Available: Experimental pro-
cedures and spectral data for new compounds are detailed.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL1028817
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Org. Lett., Vol. 13, No. 3, 2011