Imides: Forgotten players in the Ugi reaction. One-pot multicomponent synthesis of quinazolinones

Article abstract of DOI:10.1039/c1cc12067k

Up to now, the synthesis of quinazolinones has required lengthy synthetic procedures. Here, we describe an innovative one-pot multicomponent reaction leading to highly substituted quinazolinones. We believe that this novel transformation may open the door

Full text of DOI:10.1039/c1cc12067k

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Imides: forgotten players in the Ugi reaction. One-pot multicomponent
synthesis of quinazolinonesw
Riccardo Mossetti, Tracey Pirali, Desiree Saggiorato and Gian Cesare Tron*
Received 11th April 2011, Accepted 28th April 2011
DOI: 10.1039/c1cc12067k
Up to now, the synthesis of quinazolinones has required lengthy
synthetic procedures. Here, we describe an innovative one-
pot multicomponent reaction leading to highly substituted
quinazolinones. We believe that this novel transformation may
open the door for the generation of new and pharmacologically
active quinazolinones, but, most important of all, the resurrection of
the imide-Ugi scaffold paves the way for the synthesis of novel
molecular architectures
oblivion, and its potential has been lying dormant ever since.8
We reasoned that the presence of the reactive imide group could
provide a new twist to the classical Ugi reaction, going beyond the
generation of two un-reactive amide bonds and expanding the
potential of the reaction. By leveraging on this concept, a further
in situ reaction could, in fact, be envisaged, increasing the
complexity of the final products by post-Ugi transformations.
We describe here the implementation of these concepts9 into
novel-generation Ugi reactions to access to different heterocyclic
molecular scaffolds.
Multicomponent reactions have the potential to build complex
molecular scaffolds in a more straightforward way compared to
classical two component chemistry. The past decades have
therefore witnessed a growing interest for the discovery of novel
reactions of this type.1,2 Within multicomponent reactions, the
four-component Ugi reaction3 holds a special ‘‘cream of the crop’’
status, because of its generality, versatility, experimental
simplicity, and atom economy. Furthermore, the possibility to
modulate and/or delete one or more components has further
expanded the range of the molecular architectures available
from this reaction.4 The deviation from the classical Mumm
rearrangement induced by a primary-to-secondary amine swap
is a cogent example.5 Within this context, we were intrigued by an
early report by Ugi himself, where the imide 4 was obtained by
reaction of the carboxylic acid 1, the isocyanide 2 and the
pre-formed enamine 3.6 The isocyanide nitrogen atom is
responsible for the critical 1,3(O–N) acyl transfer of the transient
imidate (Scheme 1).7
To investigate the potential of this reaction, we first evaluated
the possibility of forming the enamine in situ rather than
pre-forming it. In the event, we were pleased to observe formation
of imides 9 by simply combining equimolar amounts of an
isocyanide, a secondary amine 6, a carboxylic acid 7 and an
aldehyde 8 in the presence of 4 A molecular sieves at room
temperature. Scheme 2 exemplifies the reaction with an acid
bearing a substituent useful for the pre-condensation chemistry.
Despite the presence of an apolar solvent, no trace of the
Passerini adduct could be detected, while the amine did not
interfere by trapping the imino-anhydride intermediate.10 The
use of other apolar solvents and different reaction conditions
gave a decreased yield (see ESIw). Imide 9 was then used as a
substrate for the intramolecular aza-Wittig reaction11 and,
after adding 1 eq. of triphenylphosphine and heating at reflux
in toluene for 1 h, the corresponding quinazolinone (10) could
be isolated in 80% yield (Scheme 3).
The reaction offers remarkable mechanistic hints for further
development, but, after this seminal contribution, went into
Scheme 2 Imide formation via a four component reaction.
Scheme 1 The three component reaction of an imide described by Ugi.
Dipartimento di Scienze Chimiche, Alimentari,
`
Farmaceutiche e Farmacologiche, Universita del Piemonte Orientale,
Via Bovio 6, 28100 Novara, Italy. E-mail: tron@pharm.unipmn.it
w Electronic supplementary information (ESI) available: Experimental
details, proton and carbon NMR spectra. See DOI: 10.1039/c1cc12067k
Scheme 3 Imide–quinazolinone conversion via an intramolecular
aza-Wittig reaction.
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6966 Chem. Commun., 2011, 47, 6966–6968
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Fig. 1 Building blocks.
In a further advancement, we discovered that the imide
primary adduct did not need isolation, and that, after
monitoring the formation of the imide adduct, and a change
of solvent from dichloromethane to toluene,12 the reaction
could be telescoped toward the formation of quinazolinone
derivatives by simple addition of triphenylphosphine.
A plausible mechanistic rationale for the one-pot generation of
10 can be summarized in the following way. After the in situ
formation of the iminium ion, this latter is intercepted by the
isocyanide to give the nitrilium ion, which is attacked by the
carboxylate. The imidate undergoes the acyl transfer thanks to the
isocyanide nitrogen atom to give the imide 9. The addition of
PPh3 gives the iminophosphorane via a Staudinger reaction,13
which, under heating, reacts with the carbonyl group of the imide
in an aza-Wittig reaction to form the quinazolinone 10.
Fig. 2 Synthesized quinazolinones.
In order to demonstrate the generality and versatility of this
novel strategy, different isocyanides, aldehydes, secondary
amines, and carboxylic acids were used (Fig. 1).
Scheme 4 Synthesis of 45 using formaldehyde as carbonyl input.
As it can be seen in Fig. 2, the reaction showed to be really
robust and versatile suffering from neither steric nor electronic
effects, giving the desired quinazolinones (28–39) with yields
between 81–45%. In particular, aliphatic and aromatic alde-
hydes, these latter requiring higher reaction time for the
generation of the imide intermediates compared with the
aliphatic ones (1 day versus 3 days) were prone to generate
the iminium ion. Experiments showed that ketones are not
able to generate the corresponding iminium ion with the same
reaction conditions. Azido carboxylic acids did not suffer from
the presence of electron-withdrawing or releasing groups and
these building blocks can be easily prepared via a diazotation–
azidation protocol starting from the commercially available
anthranilic acid derivatives. Alicyclic and linear secondary
amines are also suitable for this type of reaction.
Scheme 5 Formation of the Passerini educt by using tert-butyl
isocyanide.
for not favouring the Mumm rearrangement of the imidate
intermediate (Scheme 5).
The replacement of the two un-reactive amide bonds with a
reactive imide bond can provide a host of new opportunities to
explore uncharted territories of chemical diversity as exemplified
by the preparation of so far unreported 2,3-diaminoindoles
and fully substituted pyrimidinone constructs.
The use of formaldehyde appeared to be problematic but,
using 40 as a surrogate of the corresponding iminium ion
between morpholine and formaldehyde, the quinazolinone 45
could be obtained in 30% yield (Scheme 4).
In brief, just using 2-azidobenzaldehyde (47), phenylacetic
acid (48), pentylisocyanide (5) and N-methyl benzylamine (6),
the imide intermediate 49 obtained in 75% yield was reacted
under an aza-Wittig protocol to give the 2,3-diamino indole
derivative 50 in 70% yield (Scheme 6).
Regarding the isocyanides, primary and secondary aliphatic
isonitriles as well as aromatic isonitriles reacted efficiently,
while using tert-butyl isocyanide the Passerini educt 46 was
isolated in 70% yield. Steric hindrance could be responsible
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Thus, reaction between benzylisocyanide (9), isobutyralde-
hyde (54), 2-azido-4-chloro benzoic acid (25) and the N-Boc
protected N-benzylpropane-1,3-diamine (55) afforded the
quinazolinone (56) in 40% yield. Selective hydrogenolysis of
the N-benzylamine over the N-benzylamide was achieved in
90% yield. Finally, acylation and Boc-deprotection yielded the
target molecule (58) (Scheme 8).
Scheme 6 Formation of the 2,3-diaminoindole derivative 50.
In conclusion, we have demonstrated the potential
of the imide-Ugi products to generate diversity that goes
substantially beyond the classic a-acylamidoamide constructs
typical of the canonical reaction.
Notes and references
1 (a) Multicomponent reactions, ed. J. Zhu and H. Bienayme,
Wiley-VCH, Weinheim, 2005, and references therein; (b) Synthesis of
heterocycles via multicomponent reactions I and II, ed. R. V. A. Orru
and E. Ruijeter, Springer GmbH, Berlin, 2010, and references
therein.
2 For reviews see: (a) A. Domling, Chem. Rev., 2006, 106, 17;
¨
(b) I. Akritopoulou-Zanze and S. W. Djuric, Heterocycles, 2007,
73, 125; (c) J. Zhu, Eur. J. Org. Chem., 2003, 1133;
(d) J. D. Sunderhaus and S. F. Martin, Chem.–Eur. J., 2009, 15,
1300; D. M. D’Souza and T. J. J. Muller, Chem. Soc. Rev., 2007,
¨
36, 1095; (e) B. B. Toure and D. G. Hall, Chem. Rev., 2009, 109,
Scheme 7 Formation of pyrimidinone 53.
4439.
3 (a) I. Ugi, R. Meyr and C. Steinbruckner, Angew. Chem., 1959, 71,
¨
386; (b) A. Domling and I. Ugi, Angew. Chem., Int. Ed., 2000, 39,
¨
3168.
4 (a) B. Ganem, Acc. Chem. Res., 2009, 42, 463; (b) L. El Kaim and
L. Grimaud, Tetrahedron, 2009, 65, 2153.
5 (a) G. B. Giovenzana, G. C. Tron, S. Di Paola, I. Menegotto and
T. Pirali, Angew. Chem., Int. Ed., 2006, 45, 1099; (b) R. Mossetti,
T. Pirali and G. C. Tron, J. Org. Chem., 2009, 74, 4890; (c) X. Ye,
C. Xie, Y. Pan, L. Han and T. Xie, Org. Lett., 2010, 12,
4240–4243.
6 I. Ugi and C. Steinbruckner, Chem. Ber., 1961, 94, 2802.
¨
7 O. Mumm, Ber. Dtsch. Chem. Ges., 1910, 43, 886.
8 To the best of our knowledge, we could not find reports of other
synthesized imides through the methods described by Ugi in ref. 6.
9 S. Eguchi and H. Takeuchi, J. Chem. Soc., Chem. Commun., 1989,
602.
10 J. W. McFarland, J. Org. Chem., 1963, 28, 2179.
11 For general reviews on aza-Wittig reaction and its potentiality in
organic synthesis see: (a) F. Palacios, C. Alonso, D. Aparicio,
G. Rubiales and J. M. de los Santos, Tetrahedron, 2007, 63, 523;
(b) P. M. Fresneda and P. Molina, Synlett, 2004, 1. For the
synthesis of quinazolinones via an intramolecular aza-Wittig reac-
tion see: (c) H. Takeuchi and S. Eguchi, Tetrahedron Lett., 1989,
30, 3313.
Scheme 8 Total synthesis of racemic ispinesib.
It is important to stress that not only an aza-Wittig protocol
can be used during the post-modification step of the imide, as
exemplified by the generation of a fully substituted pyrimidinone
(54). Indeed, reaction among Boc-protected amino aldehyde (51),
an isocyanide (5), a carboxylic acid (48) and a secondary amine
(6) gave the imide 52 in 70% yield with a diastereoisomeric ratio
of 6 : 1. Removal of the Boc group leads to the formation of the
pyrimidinone 53 in 90% yield (Scheme 7).
12 When the reaction was performed in dichloromethane the yield
dropped to 60%.
13 H. Staudinge, Helv. Chim. Acta, 1919, 2, 635.
14 S. B. Mhaske and N. P. Argade, Tetrahedron, 2006, 62, 9787.
15 See for example: (a) J. F. Liu, Curr. Org. Synth., 2007, 4, 223;
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J. Med. Chem., 2001, 44, 1710; (c) V. Bavetsias, L. A. Skelton,
F. Yafai, F. Mitchell, S. C. Wilson, B. Allan and A. L. Jackman,
J. Med. Chem., 2002, 45, 3692; (d) J. F. Liu, C. J. Wilson, P. Ye,
K. Sprague, K. Sargent, Y. Si, G. Beletsky, D. Yohannes and
S. C. Ng, Bioorg. Med. Chem. Lett., 2006, 16, 686; (e) J. Liu, Z. Fu,
A. R. Li, M. Johnson, L. Zhu, A. Marcus, J. Danao, T. Sullivan,
G. Tonn, T. Collins and J. Medina, Bioorg. Med. Chem. Lett.,
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16 D. J. Connolly, D. Cusack, T. P. O’Sullivan and P. J. Guiry,
Tetrahedron, 2005, 61, 10153.
17 (a) G. Bergnes, E. Ha, G. Yiannikouros, K. A. Jr Welday,
P. Kalaritis and B. E. Yonce, WO 03070701, 2003;
(b) L. A. Sorbera, J. Bolos, N. Serradell and M. Bayes, Drugs
´
Quinazolinones are an important class of heterocycles.
More than 150 natural products containing the quinazolinone
core have been reported14 and, over the years, both natural
quinazolinones and their synthetic analogues have demon-
strated to possess a vast array of biological activities.15 Several
synthetic routes for their synthesis have also been reported but
all of them require a multistep synthetic approach.16 The
synthetic power of this transformation can be exemplified by
an abridged (four steps only) synthesis of the mitotic spindle
kinesin inhibitor ispinesib, previously obtained in an 8-step
sequence in racemic form.17
Future, 2006, 31, 778; (c) M. McCoy, Chem. Eng. News, 2010,
88, 16.
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6968 Chem. Commun., 2011, 47, 6966–6968
This journal is The Royal Society of Chemistry 2011