A novel three-component reaction toward dihydrooxazolopyridines

Article abstract of DOI:10.1021/ol802515v

Isocyano dihydropyridones accessible via a recently reported multicomponent reaction react with aldehydes and amines to afford dihydrooxazolopyridines in high yield. The scope and limitations of this novel multicomponent reaction were investigated. The ef

Full text of DOI:10.1021/ol802515v

ORGANIC
LETTERS
2009
Vol. 11, No. 1
125-128
A Novel Three-Component Reaction
toward Dihydrooxazolopyridines
Rachel Scheffelaar,† Monica Paravidino,† Daan Muilwijk,† Martin Lutz,‡ Anthony
L. Spek,‡ Frans J. J. de Kanter,† Romano V. A. Orru,*,† and Eelco Ruijter†
Department of Chemistry and Pharmaceutical Sciences, Vrije UniVersiteit Amsterdam,
De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands, and BijVoet Center for
Biomolecular Research, Crystal and Structural Chemistry, Utrecht UniVersity,
Padualaan 8, 3584 CH Utrecht, The Netherlands
orru@few.Vu.nl
Received October 30, 2008
ABSTRACT
Isocyano dihydropyridones accessible via a recently reported multicomponent reaction react with aldehydes and amines to afford
dihydrooxazolopyridines in high yield. The scope and limitations of this novel multicomponent reaction were investigated. The efficient
combination of two highly variable multicomponent reactions allows the construction of a very broad range of dihydrooxazolopyridines, an
unexplored class of bicyclic compounds. The implications of the observed reactivity profile for the mechanism of this multicomponent reaction
are discussed.
Multicomponent reactions (MCRs) have gained considerable
popularity in the synthetic community. They provide efficient
access to complex molecules from readily available starting
materials.1 They also form an ideal platform for rapid
generation of both complexity and diversity in a collection
of compounds with predefined functionality, e.g., ligands for
catalysis or bioactive compounds. This may be achieved by
combining MCRs with other common organic reactions or
even with additional yet different MCRs, thus allowing
coverage of large portions of chemical space. Moreover,
MCRs are ideal synthetic tools to generate multiple molecular
scaffolds from the same starting materials or intermediates
and are therefore considered to be most effective to increase
structural or skeletal diversity. Within the concept of
diversity-oriented synthesis (DOS), this generation of scaffold
diversity is one of the major hurdles to overcome.2
We have contributed to this area by the rational design of
modular reaction sequences based on a common intermediate,
a 1-azadiene derived from a one-pot reaction of phosphonates,
nitriles, and aldehydes (Figure 1).3-7 This versatile inter-
mediate can be trapped in situ by a fourth component to
afford various heterocyclic scaffolds (1-5, Figure 1).4,5
Relevant to this communication is the application of this
(2) (a) Schreiber, S. L. Science 2000, 287, 1964. (b) Burke, M. D.;
Schreiber, S. L. Angew. Chem., Int. Ed. 2004, 43, 46. (c) Tan, D. S. Nat.
Chem. Biol. 2005, 1, 74. (d) Spandl, R. J.; Bender, A.; Spring, D. R. Org.
Biomol. Chem. 2008, 6, 1149. (e) Nielsen, T. E.; Schreiber, S. L. Angew.
Chem., Int. Ed. 2008, 47, 48.
(3) Groenendaal, B.; Ruijter, E.; Orru, R. V. A. Chem. Commun. 2008,
5474
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(4) (a) Vugts, D. J.; Jansen, H.; Schmitz, R. F.; de Kanter, F. J. J.; Orru,
R. V. A. Chem. Commun. 2003, 2594. (b) Vugts, D. J.; Koningstein, M. M.;
Schmitz, R. F.; de Kanter, F. J. J.; Groen, M. B.; Orru, R. V. A. Chem.
Eur. J. 2006, 12, 7178. (c) Groenendaal, B.; Vugts, D. J.; Schmitz, R. F.;
de Kanter, F. J. J.; Ruijter, E.; Groen, M. B.; Orru, R. V. A. J. Org. Chem.
2008, 73, 719. (d) Groenendaal, B.; Ruijter, E.; de Kanter, F. J. J.; Lutz,
M.; Spek, A. L.; Orru, R. V. A. Org. Biomol. Chem. 2008, 6, 3158. (f)
Glasnov, T. N.; Vugts, D. J.; Koningstein, M. M.; Desai, B.; Fabian,
† Vrije Universiteit Amsterdam.
‡ Utrecht University.
(1) (a) Orru, R. V. A.; de Greef, M. Synthesis 2003, 1471. (b) Zhu,
J. P. Eur. J. Org. Chem. 2003, 7, 1133. (c) Multicomponent Reactions;
Zhu, J., Bienayme´, H., Eds.; Wiley-VCH: Weinheim, 2005. (d) Ramo´n,
D. J.; Yus, M. Angew. Chem., Int. Ed. 2005, 44, 1602. (e) Do¨mling, A.
Chem. ReV. 2006, 106, 17.
W. M. F.; Orru, R. V. A.; Kappe, C. O. QSAR Comb. Sci. 2006, 25, 509
(5) Paravidino, M.; Bon, R. S.; Scheffelaar, R.; Vugts, D. J.; Znabet,
A.; Schmitz, R. F.; de Kanter, F. J. J.; Lutz, M.; Spek, A. L.; Groen, M. B.;
.
Orru, R. V. A. Org. Lett. 2006, 23, 5369
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10.1021/ol802515v CCC: $40.75
Published on Web 12/03/2008
2009 American Chemical Society

strategy to arrive at 3,4-dihydropyridin-2-ones (DHP-2-ones,
1).5
Scheme 1. Initial Results of Isonitrile-Based MCRs Using 1
Figure 1. Scaffold diversity from our 1-azadiene based MCRs.
In this case, the normally rather reactive isocyanide
group1,6 is retained in the DHP-2-one MCR products. This
allows the combination with a second complexity-generating
reaction, as we demonstrated by the (one-pot) combination
of this four-component reaction (4CR) with the well-known
Passerini 3CR leading to a 6CR for conformationally
constrained depsipeptides.7 To further explore the synthetic
potential of this concept, we turned our attention to the
combination of our 4CR for isocyano DHP-2-ones 1 with
another isonitrile-based MCR, the Ugi 4CR.1a,e,8 First, the
Ugi reaction of 1a, paraformaldehyde, benzylamine, and
propionic acid was studied. Indeed, Ugi product 6 was
obtained, albeit in moderate yield (29%), together with
iminoimidazolidine 7a (61%, Scheme 1) and unreacted 1a
(10%).9 We then studied the combination of 1b with
isobutyraldehyde, benzylamine, and propionic acid. This did
not afford the expected Ugi product nor the corresponding
iminoimidazolidine. Instead, a product was isolated that
clearly did not incorporate the propionic acid. Thorough
spectroscopic analysis led to dihydrooxazolopyridine (DHOP)
8b (Scheme 1, 43%) as the most plausible structure, which
is the result of the condensation between 1b and the imine
derived from the aldehyde and amine components. It should
be noted that N-alkylated derivatives of 1 were successfully
combined with aldehydes, amines, and carboxylic acids to
afford a diverse set of Ugi products.9a X-ray crystal structure
determination of 8k (Table 1, entry 11) confirmed the
unprecedented heterobicyclic DHOP structure10 (Figure 2)
as the product of this new 3CR.
Figure 2. Displacement ellipsoid plot of 8k. Drawn at 50%
probability level. The compound is crystallized as a racemate in
the centrosymmetric space group P1.
can therefore be considered as promising alternatives for the
oxazolopyridines. The novelty and interesting products of
this MCR spurred us to find optimal conditions and
investigate the scope of the reaction. The absence of the
carboxylic acid apparently excludes several side reactions,
since the yield of 8b increased considerably when 1b was
treated with only isobutyraldehyde and benzylamine in
MeOH at room temperature (cf. Scheme 1 and entry 2, Table
1). Formation of 8b proceeded more efficiently in the polar
protic solvent MeOH (73%) than in aprotic THF (49%) or
less polar CH2Cl2 (29%). The 3CR performs optimally when
Oxazolopyridines display anti-inflammatory,11 antibacte-
rial,12 antipyretic, and analgesic properties.13 Although not
aromatic, the DHOPs are fairly flat bicyclic ring systems
with R2 and R3 substituents in a trans-pseudodiaxial orien-
tation (as is evident from the crystal structure of 8k) and
(10) The dihydrooxazolopyridine (DHOP) scaffold has not been reported
previously and there are only limited reports of the synthesis of iminoox-
azolines: (a) Middleton, W. J.; Krespan, C. G. J. Org. Chem. 1968, 33,
3625. (b) Jackson, B.; Gakis, N.; Ma¨rky, M.; Hanse, H.-J.; von Philipsborn,
W.; Schmid, H. HelV. Chim. Acta 1972, 55, 916. (c) Gru¨tzmacher, H.;
Roesky, H. W. Chem. Ber. 1986, 119, 2127. (d) Koksch, B.; Mutze, K.;
Osipov, S. N.; Golubev, A. S.; Burger, K. Tetrahedron Lett. 2000, 41, 3825.
(e) Donati, D.; Fusi, S.; Ponticelli, F Eur. J. Org. Chem. 2002, 4211. (f)
Wehner, V.; Stilz, H.-U.; Osipov, S. N.; Golubev, A. S.; Sieler, J.; Burger,
K. Tetrahedron 2004, 60, 4295. (g) Shevchenko, I.; Rogalyov, A.;
Rozhenko, A. B.; Ro¨schenthaler, G.-V. Eur. J. Inorg. Chem. 2007, 254,
and ref 14.
(6) (a) Bon, R. S.; Van Vliet, B.; Sprenkels, N. E.; Schmitz, R. F.; de
Kanter, F. J. J.; Stevens, C. V.; Swart, M.; Bickelhaupt, F. M.; Groen, M. B.;
Orru, R. V. A. J. Org. Chem. 2005, 70, 3542. (b) Elders, N.; Schmitz,
R. F.; de Kanter, F. J. J.; Ruijter, E.; Groen, M. B.; Orru, R. V. A. J. Org.
Chem. 2007, 72, 6135. (c) Elders, N.; de Kanter, F. J. J.; Ruijter, E.; Groen,
M. B.; Orru, R. V. A. Chem. Eur. J. 2008, 14, 4961.
(7) Paravidino, M.; Scheffelaar, R.; Schmitz, R. F.; de Kanter, F. J. J.;
Groen, M. B.; Ruijter, E.; Orru, R. V. A. J. Org. Chem. 2007, 72, 10239.
(8) (a) Ugi, I. Angew. Chem. 1962, 74, 9; Angew. Chem., Int. Ed. 1962,
1, 8. (b) Marcaccini, S.; Torroba, T. Nat. Protoc. 2007, 2, 632
.
(9) (a) Scheffelaar, R.; Klein Nijenhuis, R. A.; Paravidino, M.; Lutz,
M.; Spek, A. L.; Ehlers, A. W.; de Kanter, F. J. J.; Groen, M. B.; Ruijter,
E.; Orru, R. V. A. J. Org. Chem. Manuscript accepted. (b) Similar
iminoimidazolidines and R-amino amidines were previously isolated in our
study towards ꢀ-turn mimics; see ref 9a.
(11) Clark, R. L.; Pessolano, A. A.; Witzel, B.; Lanza, T.; Shen, T. Y.
J. Med. Chem. 1978, 21, 1158.
(12) Suzuki, N. Chem. Pharm. Bull. 1980, 761.
(13) Shen, T. Y.; Clark, R. L.; Pessolano, A. A.; Witzel, B. E.; Lanza,
T., U.S. Patent 4,038,396, 1977.
126
Org. Lett., Vol. 11, No. 1, 2009

Table 1. Scope Study of the New 3CR towards Dihydrooxazolopyridines (DHOPs)a
entry
DHP-one
R1
R2
R3
Ph
Ph
Ph
R4
R5
R6
R7
DHOP
yield (%)
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1e
1e
1e
1f
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
iPr
iPr
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
PMP
PCP
iPr
iPr
iPr
tBu
iPr
H
H
H
H
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
Bn
Bn
Bn
Bn
Bn
Bn
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
8a
8b
8c
8d
8e
8f
8g
8h
8i
8j
8k
8l
8m
8n
8o
8p
8q
8r
81
73
76
89
77
77
77
77
cyclohexen-1-yl
Ph
Ph
Ph
Ph
Ph
PMP
PMP
Ph
Ph
Ph
PCP
Ph
Ph
PCP
PCP
PCP
PCP
PCP
PCP
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
cyclohexyl
iPr
nBu
Ph
iPr
iPr
iPr
iPr
Me
Ph
Ph
H
9
Bn
Ph
100
75
10
11
12
13
14
15
16
17
18
1f
1a
1a
1a
1c
1a
1a
1c
1c
PNB
Bn
89
34b (62)c
Bn
d
e
f
g
nBu
Bn
H
tBu
iPr
Ph
-(CH2)2-O-(CH2)2-
-(CH2)2-O-(CH2)2-
45h (62)i
83
Ph
a Generally, the reactions were carried out in a homogeneous methanolic solution of 1 (0.06-0.68 M), aldehyde, and amine in a 1:1.1:1.1 ratio; 1:1
mixtures of diastereomers are isolated (except for 8l). b 45% of 1a was recovered. c Yield based on recovered 1a. d Formation of 7b (14%) was accompanied
by at least four other unidentified products. e 79% of 1c was recovered. f 44% of 7a was isolated. g 39% of 7c together with 55% of 1a was isolated. h 27%
of 1c was recovered. i Yield based on recovered 1c. PMP ) p-methoxyphenyl, PNP ) p-nitrophenyl, PCP ) p-chlorophenyl, PNB ) p-nitrobenzyl.
the inputs are homogeneously mixed in MeOH at room
temperature with a slight excess of the amine and aldehyde
relative to the DHP-2-one. Under these optimized conditions
the scope of the 3CR for DHOPs 8 was further explored
(Table 1). Six DHP-2-ones 1a-1f were successfully com-
bined with various aldehydes and amines to afford a series
of DHOPs 8 in good to excellent yield (entries 1-12, 17,
and 18). Stereochemical induction was not observed and
typically inseparable ∼1:1 mixtures of diastereoisomers were
isolated. In general, the 3CR reaches full conversion in 1-5
days, but additional aldehyde and amine may be added to
accelerate the reaction. A wide range of different aliphatic
and aromatic primary amines were tolerated in the 3CR
(entries 1-11) and the corresponding DHOPs 8a-8k were
obtained efficiently. The use of secondary amines is also
allowed, even combined with very hindered aldehydes
(entries 17 and 18). The choice of the carbonyl compound
is more crucial. The use of aliphatic aldehydes generally
results in efficient DHOP formation (entries 1-11). Even
the use of acetone in combination with 1a and benzylamine
(entry 12) afforded the corresponding DHOP 8l. The
increased steric constraints may account for the somewhat
lower yields in this case. Benzaldehyde and paraform-
aldehyde (entries 13-16) are less efficient inputs in this 3CR.
In these cases, iminoimidazolidines 7a-7c were isolated in
14-44%. As reported previously, these are possibly formed
via the R-amino amidines 10 (Scheme 2, pathway A).9b Imine
formation is a reversible process, making formation of 7 (via
10) feasible. However, neither application of a drying agent
(molecular sieves), nor substitution of MeOH by trifluoro-
ethanol as solvent, nor heating the mixture to reflux proved
beneficial for DHOP formation. A second reasonable path-
way for the formation of 7 is the condensation of a second
imine to intermediate 9 and subsequent cyclization of 11
(Scheme 2, Pathway B).
Scheme 2. Formation of Iminoimidazolidine Side Products
The 3CR toward DHOPs 8 may be rationalized by the
two pathways depicted in Scheme 3A. Pathway I involves
Org. Lett., Vol. 11, No. 1, 2009
127

Scheme 3.
(A) Possible Pathways for the 3CR in MeOH towards DHOPs 8 and (B) Iminooxazolines Reported by Zhu et al.14
initial attack of the isonitrile carbon in 1 to the imine 12
forming dipolar intermediate 9, followed by attack of the
nucleophilic amide oxygen atom and proton transfer. In
pathway II, the resonance structure 1′ initiates formation of
the DHOP bicyclic core 13. Subsequent proton transfer to
the imine 12 and attack of the oxazolide nucleophile 14 to
the resulting iminium ion 15 accounts for formation of 8.
Formation of iminoimidazolidines 7 presumably involves
intermediate 9, which supports pathway I. Subsequent
cyclization of 9 to give 8 should be fast and irreversible, at
least faster than attack of a carboxylate since no Ugi product
was observed when a carboxylic acid is present. Recently,
Zhu et al. rationalized a 3CR of R-isocyanoacetamides,
aldehydes, and amines to afford 5-iminooxazolines 17,14 by
a mechanism similar to pathway I (Scheme 3B).
Other observations are in favor of pathway II. For example
the use of paraformaldehyde in the Ugi reaction resulted in
a slow formation of 6 and 7a (96 h, Scheme 1), while the
same reaction with the N-alkylated analog resulted in much
faster (22 h) quantitative formation of the Ugi product.9 This
may indicate that the isonitrile moiety is less accessible,
caused by an equilibium of 1 and 13/14 in MeOH. Although
efforts to trap intermediate 14 by stirring 1 in MeOH in the
absence of imine did not result in the isolation of 2H-DHOP,
Zhu et al. observed a similar conversion of their R-iso-
cyanoacetamide 16 to 2H-2-oxazoline 18 in MeOH (Scheme
3B).14 Finally, DHOP formation was never observed in
Passerini reactions of 1.7 Most likely the charged DHOP
intermediate 13 is not formed in the less polar DCM.
Moreover, aldehydes are much poorer electrophiles than
iminium ions, making attack of 14 less favorable.
The experimental support is not conclusive in favor of one
specific pathway (I or II). Moreover, none of the presented
pathways can explain why DHOPs 8 are not formed with
benzaldehyde and formaldehyde as the carbonyl inputs. More
detailed mechanistic studies will be required.
In summary, combination of our 1-azadiene based 4CR
for DHP-2-ones and the Ugi 4CR led to the serendipitous
discovery of a novel three-component condensation afford-
ing dihydrooxazolopyridines (DHOPs) in high yield. This
interesting new scaffold has high potential for drug discovery,
which will be further investigated in the future.
Acknowledgment. We thank the Dutch Science Founda-
tion (NWO, VICI grant) for financial support. Dr. H. Peeters
(University of Amsterdam, The Netherlands) is kindly
acknowledged for HRMS measurements. M.L. and A.L.S.
were financially supported by NWO-CW.
Supporting Information Available: Detailed experimen-
tal methods and complete characterization data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(14) Pirali, T.; Tron, G. C.; Masson, G.; Zhu, J. Org. Lett. 2007, 9,
5275.
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