Exploiting the divergent reactivity of α-isocyanoacetate: Multicomponent synthesis of 5-alkoxyoxazoles and related heterocycles

Article abstract of DOI:10.1002/chem.201002098

A novel multicomponent synthesis of 5-alkoxyoxazoles, based on a new reactivity profile of α-isocyanoacetates, is described. Thus, simply heating a solution of amine, aldehyde, and α-(EWG-phenyl)-α- isocyanoacetate or α-(4-pyridyl)-α-isocyanoacetate (EWG=

Full text of DOI:10.1002/chem.201002098

DOI: 10.1002/chem.201002098
Exploiting the Divergent Reactivity of a-Isocyanoacetate: Multicomponent
Synthesis of 5-Alkoxyoxazoles and Related Heterocycles
Claudia Lalli,[a] Marinus J. Bouma,[a] Damien Bonne,[a, b] Gꢀraldine Masson,*[a] and
Jieping Zhu*[a]
Abstract:
A
novel multicomponent
the 5-alkoxyoxazoles with various a,b-
unsaturated acyl chlorides led to the
formation of epoxytetrahydropyrrolo-
acylation/Diels–Alder cycloaddition se-
quence. Subsequent fragmentation
under basic conditions provided 6,7-di-
synthesis of 5-alkoxyoxazoles, based on
a new reactivity profile of a-isocyanoa-
cetates, is described. Thus, simply heat-
ing a solution of amine, aldehyde, and
a-(EWG-phenyl)-a-isocyanoacetate or
A
hydro-5H-pyrroloACTHNGUTER[NNUG 3,4-b]pyridin-5-ones.
A four-component synthesis of the pyr-
idin-5-one compounds, without isola-
tion of the 5-alkoxyoxazole, was subse-
quently developed.
Keywords: Diels–Alder reaction ·
isocyanoacetates · multicomponent
reactions · oxygen heterocycles ·
sustainable chemistry
a-(4-pyridyl)-a-isocyanoACTHNUTRGNEaNUG cetate
(EWG=electron-withdrawing group)
in toluene provided 5-alkoxyoxazoles
in good to excellent yields. Reaction of
Introduction
2) atom economic:[2] most MCRs involve addition rather
than substitution reactions. Indeed, addition reactions
are susceptible to the generation of new reactive func-
tionalities, essential for the multicomponent domino pro-
cess, whereas substitution reactions consume functional
groups.
Multicomponent reactions (MCRs) are processes in which
three or more reactants are combined in a single chemical
operation to produce a compound that incorporates substan-
tial portions of all starting materials.[1] They are, by defini-
tion, sustainable chemistry and inherently have the follow-
ing characteristics:
3) step efficient and cost effective: they create at least two
chemical bonds in one operation.[3]
4) convergent and efficient in generating molecular com-
plexity and diversity.
1) chemo- and regioselective: a prerequisite for a successful
MCR because at least three reactive functional groups
are involved and must react in an ordered and selective
fashion.
5) cost effective: MCRs significantly reduce waste produc-
tion by minimizing the number of costly end-of-pipe
treatments by decreasing the number of synthetic steps.
6) operationally simple: most MCRs are performed under
mild reaction conditions and, in some cases, proceed
spontaneously in the absence of external reagents.
[a] Dr. C. Lalli, M. J. Bouma, Dr. D. Bonne, Dr. G. Masson, Dr. J. Zhu
Centre de Recherche de Gif
Institut de Chimie des Substances Naturelles CNRS
Avenue de la Terrasse, 91198 Gif-sur-Yvette Cedex (France)
Fax : (+33)1-6907-7247
By virtue of its inherent convergence, high productivity, ex-
ploratory, and complexity-generating power,[4] the MCR is
recognized as one of the most promising approaches in
target-oriented[5] and diversity-oriented synthesis[6] and is
undoubtedly a well-suited tool for lead compound discovery
and optimization in medicinal chemistry.[7] The development
of novel MCRs is an enthralling and intellectually challeng-
ing task; one has to consider, not only the reactivity match
of the starting materials, but also the reactivity of the inter-
mediate functions generated in situ. It is fair to say that a
E-mail: masson@icsn.cnrs-gif.fr
zhu@icsn.cnrs-gif.fr
[b] Dr. D. Bonne
Aix-Marseille Universitꢀ
Institut des Sciences Molꢀculaires de Marseille
iSm2 CNRS UMR 6263, Centre Saint Jꢀrꢁme
service 531-13397 Marseille Cedex 20 (France)
Supporting information for this article is available on the WWW
1
under http://dx.doi.org/10.1002/chem201002098. It contains H and
13C NMR spectra for compounds 8a–f, 10a–v, 11a–o, and 12a–c.
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FULL PAPER
MCR was rarely devised with the aim of exploring new
chemical reactivity of an individual functional group.
Rather, the process is designed on the basis of well-known
bimolecular reactions. It is, therefore, reasonable to assume
that one can devise novel MCRs on rational grounds.[8,9]
Indeed, a proper combination of suitably functionalized sub-
strates that could react with each other in a highly ordered
and productive fashion (substrate-design approach)[10] would
result a novel MCR.
activity profile relative to 1 (Scheme 1b).[15] Thus, reaction
of 6 with 4 and 5 was initiated by nucleophilic addition of
the divalent isocyanide carbon atom to the in situ generated
imine. This led to the 5-aminooxazole (7), after internal
trapping of the nitrilium intermediate by the amide oxygen,
in excellent yield. The design of 6 was based on the follow-
ing considerations: first, the pKa(aCH) of the amide is 3–5
units higher than that of the ester (Scheme 2). Therefore,
The chemistry of a-isocyanoacetate (1) was thoroughly in-
vestigated in the 1970s, mainly by the groups of Schçll-
kopf[11,12] and Matsumoto.[13] One particularly powerful
transformation is the reaction of metallated 1 with polar
multiple bonds to afford heterocycles. By taking advantage
of the higher acidity of a-phenyl-a-isocyanoacetate (2),
Orru and co-workers described an elegant three-component
synthesis of imidazolines (3) without the need for pre-metal-
lation (Scheme 1a).[14] The reaction was initiated by nucleo-
Scheme 2. Effect of a-CH acidity on nucleophilicity.
the a-methylene proton of the amide should be less prone
to deprotonation, which consequently avoids the a-carban-
ion chemistry characteristic to acetate 1. The fact that the
amide function is less electron withdrawing than the ester
function should also render the isonitrile carbon atom slight-
ly more nucleophilic. Second, the higher Lewis basicity of
the amide oxygen relative to the ester counterpart should
kinetically favor the ring-forming process. Because oxazole
formation is irreversible the increased reaction rate of this
step should provide the overall driving force to the desired
sequence.
As a continuation of this ongoing project, we became in-
terested in the reactivity profile of a-isocyanoacetates with
an electron-withdrawing group (EWG) at the a position (8)
(Scheme 2). As stated above, the key to the design of 6 was
the reduced acidity of the a-CH, such that it would not be
deprotonated under mild basic conditions.[16] The principle
that guided us in the design of 8 is completely different.
Indeed, it was our intention to design an a-isocyanoacetate
with increased a-CH acidity by incorporation of an EWG or
a heteroatom (X=N, for example) into the aromatic ring of
compound 2. The a-CH of the resultant a-substituted ana-
logue 8 would be much more acidic than that of 2, which
Scheme 1. Differing reactivity of a) a-phenyl-isocyanoacetates (2) and
b) a-isocyanoacetamides (6).
philic addition of the a-carbanion to the imine, which was
generated in situ from an amine 4 and an aldehyde 5, fol-
lowed by cyclization and protonation. The presence of the
phenyl group is essential for this one-pot process because
the reaction with 1, under otherwise identical conditions,
provided the equivalent imidazoline in low yield. In general,
exploitation of the nucleophilicity of the a carbon and the
electrophilicity of the divalent carbon of isocyanide for the
À
À
effective construction of the C C and C N bonds character-
izes the known chemistry of 1. In all of these transforma-
tions, the ester function served only as an activator, with no
participation in the bond-forming process, and the nucleo-
philicity of the divalent carbon of the isocyanide has been
exploited only for trapping a proton.
Within the context of a substrate-design approach for the
development of novel MCRs, we have demonstrated that by
switching the ester function of 1 to an amide, the resulting
a-isocyanoacetamide (6) displayed a completely different re-
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881

G. Masson, J. Zhu et al.
would consequently lead to facile deprotonation, even
under very mild basic conditions. Logically, we could expect
that the highly stabilized enolate 9 would display much-re-
duced nucleophilicity relative to that derived from 2. Conse-
quently, it was hypothesized that the reaction of 8 with a
polar double bond, such as an imine, would be initiated by
the nucleophilicity of the divalent isonitrile carbon atom
rather than the a-carbon atom of the isocyanoacetate. In
other words, the a-(EWG-phenyl)-a-isocyanoacetates (8)
would display isocyanoacetamide-type reactivity rather than
that of the parent, a-isocyanoacetate (1). Herein, we report
in detail the development and application of this concept
through a three-component synthesis of 5-alkoxyoxazoles
10.[17] We also document a four-component synthesis of
Scheme 4. One-pot synthesis of a-(EWG-phenyl)- and a-(4-pyridyl)-iso-
cyanoacetates 8.
epoxytetrahydropyrrolo
subsequent fragmentation to 6,7-dihydro-5H-pyrrolo
b]pyridin-5-ones (12) (Scheme 3).
G
in essentially quantitative yield. On the other hand, treat-
ment of 8a under identical conditions led to the exclusive
formation of enolate 14, instead of the carboxylic acid
(Scheme 5). These results clearly indicated 1) the high acidi-
ty of the a-CH of 8a, such that deprotonation of 8a took
place in preference to nucleophilic attack of the hydroxide
onto the carbonyl group, and 2) the stability, hence, the low
reactivity of the enolate of 8a, which persisted even in aque-
ous conditions.
AHCTUNGTRENNUNG
Scheme 3. Multicomponent
epoxytetrahydropyrrolo[3,4-b]pyridin-5-ones (11) and 6,7-dihydro-5H-
pyrrolo[3,4-b]pyridin-5-ones (12).
synthesis
of
5-alkoxyoxazoles
(10),
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
Results and Discussion
Preparation of 8: In our preliminary work,[17] methyl a-(p-
nitrophenyl)-a-isocyanoacetate (8a) was synthesized by nu-
cleophilic aromatic substitution reaction (SNAr) between
commercially available methyl-a-isocyanoacetate (1a) and
4-fluoro-nitrobenzene (13a) in acetonitrile in the presence
of CsOH.[18] However, application of the same conditions to
ethyl-a-isocyanoacetate and 4-fluoropyridine failed to pro-
Scheme 5. Differing reactivity of a-isocyanoacetates 2 and 8a under sapo-
nification conditions.
Three-component synthesis of 10 from 8: Oxazoles are an
important class of heterocycles, widely found in nature and
medicinally relevant compounds.[20] They also constitute a
useful platform for the construction of more complex heter-
ocyclic scaffolds.[21] In addition to classical synthetic meth-
ods,[20] many new strategies have been developed for the
construction of oxazoles.[22] In line with our structure–reac-
tivity analysis, detailed above, we assumed that the nucleo-
philicity of the divalent isonitrile carbon atom in 8 should
be higher than that of the a-carbon atom. Therefore, the re-
action between 8 and an imine should afford a new access
to 5-alkoxyoxazoles 10, in parallel to the chemistry of a-iso-
cyanoacetamides 6. To evaluate the chemical reactivity of 8,
the reaction of 8a with morpholine (4a) and cyclohexane-
carbaldehyde (5a) was initially examined. When the reac-
duce ethyl-a-(pyridinyl)-a-isocyanoacetate (8c). After
a
survey of the reaction parameters—various solvents
(DMSO, DMF, MeCN, THF) and bases (Cs2CO3, K2CO3,
Na2CO3, NaH)—the best conditions found consisted of per-
forming the SNAr reaction in DMSO in the presence of
cesium carbonate at room temperature. Under these condi-
tions, reaction of 1 (R=Et) and 4-fluoropyridine afforded
8c in 72% yield. These conditions were general and the a-
(EWG-phenyl)-a-isocyanoacetates synthesized by this
method are summarized in Scheme 4.[19]
The higher acidity of the a-CH of 8a relative to that of 2
was evidenced by the following control experiments: Hy-
drolysis of 2, under classic saponification conditions (K2CO3,
MeOH/H2O), afforded the carboxylic acid potassium salt 13
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Multicomponent Synthesis of 5-Alkoxyoxazoles
FULL PAPER
Scheme 7. Three-component reaction with potassium enolate 14.
Scheme 6. Three-component synthesis of 5-alkoxyoxazole 10a.
tion was carried out in toluene at room temperature, 5-me-
thoxyoxazole 10a was isolated in 92% yield (Scheme 6).
Addition of lithium bromide (1 equiv) provided 10a in
lower yield due to undesired ring-chain tautomerization of
isocyanide 8a, which led to the 2-unsubstituted oxazole.[23]
The same reaction proceeded smoothly in MeOH to afford
10a in 90% yield. The reaction performed in DMSO pro-
duced compound 10a but with a much-reduced yield.[24] Nei-
ther imidazoline[14] nor amidine,[13] as a result of the compet-
itive aldol- and Mannich-type condensations, were observed.
A plausible reaction scenario that accounts for the forma-
tion of 10a is shown in Scheme 6. Thus, condensation of the
aldehyde 5a with the amine 4a would afford the iminium
ion 15a. The hydroxide counterion would then serve as a
base to abstract the hydrogen atom of 8a to furnish the eno-
late 16a. The addition of isocyanide to the iminium ion pro-
vided the nitrilium intermediate 17a, which underwent cycli-
zation to afford the 5-methoxyoxazole 10a. In this reaction,
the carbene-like reactivity of the divalent carbon atom was
Scheme 8. Structures of amines and aldehydes used in the three-compo-
nent reaction.
of these three-component reactions were performed with
approximately equimolar quantities of the components and
reached completion between 4 and 16 h in toluene at RT or
608C (see the Supporting Information). Both linear (5c–g)
and a-branched (5a, b) aldehydes were found to be good
substrates, as well as an aromatic aldehyde (5h) and cinna-
maldehyde (5i). A wide range of aliphatic amines, including
primary (4d, f, g) and cyclic secondary amines (4a, c, e),
were suitable partners and afforded the respective 5-alkoxy-
oxazoles 10 in moderate to high yields (Scheme 9). In the
case of 2-(3,4-dimethoxyphenyl)ethanamine (4 f), the com-
petitive Pictet–Spengler reaction to form the tetrahydroiso-
quinoline was not observed, which indicated that the inter-
molecular addition of isocyanide to the in situ generated
iminium was faster than the alternative intramolecular Frie-
del–Crafts type reaction. N-Methylaniline (4h) also partici-
pated in the reaction to afford 5-alkoxyoxazole 10n in mod-
erate yield. Isocyanoacetates 8a–f all displayed similar reac-
tivity to afford the 5-alkoxyoxazoles 10. The structure of the
three-component adducts derived from a-(4-cyanophenyl)-
a-isocyanoacetate (8e) and a-(2-nitrophenyl)-a-isocyano-
acetate (8 f) are not shown in Scheme 9, since they were di-
rectly engaged in the subsequent four-component reactions
(see below).
À
exploited fully for the formation of one C C bond and one
À
C O bond, whereas the ester functionality served as an in-
ternal nucleophile to trap the incipient nitrilium intermedi-
ate. The reactivity profile of 8a is, therefore, completely dif-
ferent to that of isocyanoacetates 1 and 2. Rather, it resem-
bles that of a-isocyanoacetamide 6.
That the enolate 14 could indeed be the reactive inter-
mediate of this reaction was evidenced by the following con-
trol experiment: Treatment of a solution of 8a in methanol
with aqueous potassium hydroxide afforded, after evapora-
tion of the volatile compounds, the potassium enolate 14.
Reaction of crude 14 with the hydrochloride salt of dime-
thylamine (4b) and aldehyde 5a provided oxazole 10b in
55% yield over two steps (Scheme 7).
The scope of this reaction was next examined by variation
of the structure of the three components: a-isocyanoacetate
8 (Scheme 4), amine 4, and aldehyde 5 (Scheme 8). Repre-
sentative synthesized examples are shown in Scheme 9. All
Although reaction of dimethylamine (4b) with 8a afford-
ed oxazole 10i in excellent yield, more-hindered acyclic sec-
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883

G. Masson, J. Zhu et al.
Scheme 9. 5-Alkoxyoxazoles 10 synthesized by the three-component reaction.
ondary amines, such as dibenzyl amine or dibutylamine,
failed to provide the three-component adducts. In these last
cases, addition of isocyanide to the aldehyde occurred to
afford 2-hydroxyalkyl-5-methoxyoxazoles 18 in excellent
yield (Scheme 10a).[25] Most probably, the dibenzyl amine
served only as a base and led to the formation of the ammo-
nium enolate of 8, which underwent Passerini-type reaction
with the aldehyde.[26] When a ketone, such as 4-phenylcyclo-
hexanone (19), was submitted to react with 4a and 8a, the
Passerini-type reaction occurred once again and led to 2-hy-
droxyalkyl-5-methoxyoxazole 18c. It is interesting to note
that these constituted the very first examples of a Passerini
reaction that proceeds under basic conditions. The Passerini
reaction normally occurs only in the presence of a carboxyl-
ic acid reaction partner or in the presence of Lewis acid/
Bronsted acid catalysts.[27] One possible explanation for our
observation was that the secondary amine served as a base
to form an enolate and ammonium salt, which could subse-
quently activate the aldehyde function toward nucleophilic
attack. This hypothesis was also in line with the mechanistic
proposal shown in Scheme 6.
From 10 to 11: The synthesis of strained polycyclic oxa-
bridged heterocycles is a fascinating research field because
Scheme 10. 2-Hydroxyalkyl-5-methoxyoxazoles 18 from the three-compo-
nent reaction.
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Multicomponent Synthesis of 5-Alkoxyoxazoles
FULL PAPER
of their unusual geometries and chemical properties.[28] Cy-
cloaddition reactions are certainly one of the most efficient
means for the construction of this type of heterocycle. On
the basis of our previous work on 5-aminooxazoles[29] and
taking advantage of the polyfunctionality of 10, a sequence
of N-acylation and Kondratꢃevaꢃs Diels–Alder reaction[30]
was sought to further elaborate the structure of the oxa-
zole.[31] Dissolving 5-alkoxyoxazole 10t, (E)-a,b-unsaturated
acyl chloride 20a and triethylamine in toluene at 08C and
heating the mixture to reflux for 20 min, afforded the oxa-
bridged tricyclic compound 11a in 75% yield as a mixture
of two diastereomers (Scheme 11). Toluene was the solvent
of choice; the same reaction performed in other solvents
(THF, MeCN, and dioxane) produced only a low yield of
the desired oxa-bridged heterocycle.
Scheme 12. Four-component synthesis of polyheterocycle 11a.
8d in toluene was stirred at RT for 4 h. After being cooled
to 08C, the acyl chloride 20a and Et3N were added. The re-
sulting mixture was heated to reflux for 20 min. The usual
workup procedure afforded the four-component adduct 11a
in 72% yield (Scheme 12). In this transformation, five chem-
ical bonds were created and three heterocyclic rings and five
chiral asymmetric centers were formed. Furthermore, it was
found that the one-step process gives a better yield (72%)
than the two-step protocol (45% overall yield), which indi-
cates that the formation of 10 is, in fact, a much cleaner re-
action than the isolated yield may suggest. Partial degrada-
tion of the oxazole 10 during chromatographic purification
(SiO2) may account for the phenomenon.
With these optimized conditions, the scope of this four-
component reaction was investigated. As shown in
Scheme 13, the reaction is applicable to a variety of alde-
hydes, amines, a-isocyanoacetates, and a,b-unsaturated acyl
chlorides. The diastereoselectivity of the reaction appears to
be highly dependent on the structure of the aldehyde used.
Generally, high diastereoselectivities were observed when
5a was used as a substrate. Surprisingly, when (Z)-ethyl-4-
chloro-4-oxobut-2-enoate (20b) was used, the same diaste-
reomer as that derived from (E)-ethyl-4-chloro-4-oxobut-2-
enoate (20c) was obtained. We assumed that, in the pres-
ence of triethylamine, an epimerization of the initial cyclo-
adduct 11-cis occurred via the enolate intermediate 23 to
afford the thermodynamically more stable product 11-trans
(Scheme 14). Alternatively, a stepwise Michael addition/
aldol sequence could also explain the formation of 11-trans
from 20b.
Scheme 11. Synthesis of epo 11a by intramolecular Diels–Alder reaction.
The coupling constants between Ha and Hb were almost
identical in both diastereomers (JACTHNUTRGNE(UNG Ha,Hb)=4.5 Hz), which
indicated the trans relationship between these two protons
in both compounds.[32] Because Ha has to be endo oriented
for the inherent ring strain imposed by the connecting
bridge, the observed coupling constant indicated an exo po-
sition of Hb, hence, an endo position of the ethyl ester
group. It is interesting to note that five stereocenters were
created in this three-component reaction, therefore, sixteen
pairs of diastereomers would theoretically be expected.
However, only two of them were isolated, in a 13:1 diaste-
reomeric ratio (d.r.); a result of a face-selective Diels–Alder
process, which was in turn governed by the stereochemistry
of the carbon atom bearing the cyclohexyl unit (Cc,
Scheme 11). A concerted lactam-exo-ester-endo mode of cy-
cloaddition could explain the observed high diastereoselec-
tivity.
Synthesis of 12 by fragmentation of 11: Impelled by an inter-
est in the general and rapid construction of polyheterocyclic
scaffolds with a high degree of diversity, we were interested
in studying the ring-opening reaction of 11. Its fragmenta-
Both the three-component synthesis of the 5-alkoxyoxa-
zoles 10 and the subsequent domino process were per-
formed in toluene, so a one-pot four-component synthesis of
the oxa-bridged heterocycles 11 was next sought
(Scheme 12). Thus, a solution of benzylamine (4d), 5a, and
tion could give access to pyrroloACTHUGNETRNNU[G 3,4-b]pyridin-5-ones 12,
found in many pharmacologically active substances of syn-
thetic origin. We selected 11c as the model substrate to ex-
plore the reaction conditions. The fragmentation of cycload-
ducts derived from 5-alkoxyoxazoles 10 was generally per-
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885

G. Masson, J. Zhu et al.
Scheme 14. Epimerization of cycloadduct 11-cis.
Scheme 15. Base-mediated fragmentation of 11c and representative
structures of 12.
possible reaction sequence to account for the formation of
12 is given in Scheme 16. The deprotonation of the acidic
proton in 11 (Ha) under basic conditions would trigger frag-
mentation and ejection of ethanol to afford ketone 24; sub-
sequent tautomerization would provide compound 12.
Scheme 13. Epoxytetrahydropyrrolo
by the four-component reaction.
ACHTUNGTRENN[UNG 3,4-b]pyridin-5-ones 11 synthesized
formed under acidic conditions,[30a,31,33] however, we found
that 11c was recovered from the reaction mixture under a
variety of acidic conditions (AcOH, toluene, RT to reflux
temperature; trifluoroacetic acid, CH2Cl2, RT). Interestingly,
by heating a solution of 11c in methanol to reflux in the
presence of KOH, fragmentation occurred to provide dihy-
Scheme 16. Mechanistic proposal for the formation of 12.
The conditions for the four-component synthesis of oxa-
bridged tricycle 11 and the subsequent fragmentation to 12
seemed to be compatible, so we examined a one-pot synthe-
sis of 12. Thus, upon completion of the four-component re-
dropyrrolopyridinone 12a in 83% yield (Scheme 15).[34]
A
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Multicomponent Synthesis of 5-Alkoxyoxazoles
FULL PAPER
(broad), and m (multiplet). HRMS data were measured on a MALDI-
TOF spectrometer (Voyage-De STR, perspective Biosystems). Infrared
spectra were recorded on an IR spectrometer (Perkin Elmer BX FT-IR),
and absorption frequencies were reported in reciprocal centimeters
(cmÀ1). Known compounds were characterized by comparison of the 1H
and 13C NMR spectra and melting point to those reported in the litera-
ture.
action of 4d, 5h, 8e, and 20c a solution of potassium hy-
droxide in methanol was added and the mixture was heated
to reflux. This protocol directly afforded 12c in 40% yield
(Scheme 17).
General procedure for the synthesis of 8: Cs2CO3 (1.5 mmol) was added
to a solution of methyl isocyanoacetate (1.0 mmol) in dry DMSO (0.2m)
and the mixture was stirred for 10 min at RT under an argon atmosphere.
1-Fluoro-4-nitrobenzene was added and stirring was continued for 16 h at
RT. The reaction was quenched by the addition of water and the aqueous
phase was extracted with EtOAc. The combined organic extracts were
washed with brine, dried over Na2SO4, filtered, and concentrated in
vacuo. The crude product was purified by flash column chromatography
on silica gel (heptanes/EtOAc 2:1) to give 8a as yellow solid (63%).
1H NMR (300 MHz, CDCl3): d=3.85 (s, 3H), 5.53 (s, 1H), 7.72 (d, J=
5.1 Hz, 2H), 8.32 ppm (d, J=5.1 Hz, 2H); 13C NMR (75 MHz, CDCl3):
d=53.4 (CH), 54.3 (CH3), 124.4 (2ꢄCH), 127.8 (2ꢄCH), 137.9 (C), 148.7
(C), 163.6 (C), 164.8 ppm (C); IR (neat): n˜ =2957, 2149, 1753, 1523, 1347,
1212 cmÀ1; MS (ES+): m/z: 221 [M+H]+.
General procedure for the three-component synthesis of 10: A solution
of amine 4a (1.0 mmol) and aldehyde 5a (1.0 mmol) in dry toluene
(1.0 mL) was stirred at RT for 10 min. a-Isocyanoacetate 8c (1.0 mmol)
was added and the reaction mixture was stirred at RT. After the disap-
pearance of a-isocyanoacetate (monitored by TLC), the solvent was
evaporated. The crude product was purified by flash chromatography on
silica gel (EtOAc) to give oxazole 10u as yellow oil (81%). 1H NMR
(300 MHz, CDCl3): d=0.86–0.97 (m, 2H), 1.14–1.37 (m, 4H), 1.42 (t, J=
6.9 Hz, 3H), 1.63–1.93 (m, 4H), 2.01–2.05 (m, 1H), 2.36–2.55 (m, 4H),
3.25 (d, J=10.5 Hz, 1H), 3.58–3.78 (m, 4H), 4.34 (q, J=6.9 Hz, 2H), 7.62
(d, J=6.0 Hz, 2H), 8.48 ppm (d, J=6.0 Hz, 2H); 13C NMR (75 MHz,
CDCl3): d=15.1 (CH3), 25.9 (CH2), 26.6 (CH2), 30.2 (2ꢄCH2), 30.5
(CH2), 36.6 (CH), 49.9 (2ꢄCH2N), 67.3 (2ꢄCH2O), 68.5 (CHN), 69.4
(OCH2), 111.7 (C), 119.1 (2ꢄCH), 139.5 (C), 149.4 (2ꢄCH), 153.4 (C),
155.7 ppm (C); IR (neat): n˜ =2922, 2849, 1631, 1602, 1114, 1028, 1005,
829 cmÀ1; MS (ES+): m/z: 372 [M+H]+.
Scheme 17. One-pot synthesis of 12c.
Conclusion
We have developed a three-component synthesis of 2,4,5-tri-
substituted oxazoles 10 and a four-component synthesis of
epoxytetrahydropyrrolo
ACHTUNGTRENN[UNG 3,4-b]pyridin-5-ones 11 and 6,7-di-
hydro-5H-pyrrolo[3,4-b]pyridin-5-ones 12. We have demon-
ACHTUNGTRENNUNG
strated that a-(EWG-phenyl)-a-isocyanoacetates 8 and a-
(4-pyridyl)-a-isocyanoacetate (8c) displayed completely dif-
ferent reactivity profiles than a-isocyanoacetate (1) and a-
phenyl-a-isocyanoacetate (2). Key to our design is the care-
ful consideration of the CH acidity versus the nucleophilici-
ty of the conjugate base. The strategic incorporation of an
EWG group or a heteroatom in the phenyl ring of a-isocya-
noacetate 2 increased the acidity of the a-CH, which conse-
quently reduced the nucleophilicity of the conjugated carb-
anion. Overall, this subtle structural modification dramati-
cally changed the chemical reactivity of a-(EWG-phenyl)-a-
isocyanoacetates 8 to resemble that of isocyanoacetamide 6
more than the parent isocyanoacetates 1 and 2. We believe
that the substrate design is a fruitful approach in the devel-
opment of novel MCRs.[35]
Four-component synthesis of 11: Aldehyde 5a (1.0 mmol) was added to a
solution of amine 4e (1.0 mmol) in dry toluene (1 mL). After stirring at
RT for 10 min, a-isocyanoacetate 8d (1.0 mmol) was added and the reac-
tion mixture was stirred at RT until the disappearance of a-isocyanoace-
tate was detected by TLC. The reaction mixture was cooled to 08C and
diluted with toluene (1.0 mL). Et3N (5.0 mmol) was added, followed by
acyl chloride 20a (2.2 mmol). The reaction mixture was warmed to RT
and then heated to reflux for 20 min. The crude material was purified by
column chromatography on silica gel (heptanes/EtOAc 1:2) to give het-
erocycle 11a as yellow solid (68%). 1H NMR (300 MHz, CDCl3): d=
1.04 (t, J=7.2 Hz, 3H), 1.29–1.32 (m, 2H), 1.35 (t, J=7.2 Hz, 3H), 1.74–
1.98 (m, 8H), 2.02–2.04 (m, 1H), 3.28 (d, J=4.2 Hz, 1H), 3.55 (d, J=
4.2 Hz, 1H), 3.63 (d, J=3.6 Hz, 1H), 3.72–3.77 (m, 1H), 3.92–3.96 (m,
2H), 3.95 (s, 3H), 3.97–4.04 (m, 1H), 4.19 (d, J=15.3 Hz, 1H), 5.10 (d,
J=15.3 Hz, 1H), 7.27–7.34 (m, 5H), 8.07 ppm (brs, 4H); 13C NMR
(75 MHz, CDCl3): d=13.9 (CH3), 15.2 (CH3), 26.3 (CH2), 26.5 (CH2),
26.7 (CH2), 27.6 (CH2), 28.4 (CH2), 38.8 (CH), 45.5 (CH2), 46.2 (CH),
52.3 (CH3), 53.7 (CH), 61.2 (CH2), 63.7 (CH2), 64.1 (CH), 99.7 (C), 113.6
(C), 127.6 (3ꢄCH), 127.9 (2ꢄCH), 128.6 (2ꢄCH), 129.5 (2ꢄCH), 132.5
(C), 134.5 (C), 135.9 (C), 166.4 (C), 168.5 (C), 171.5 (C), 172.0 ppm (C);
Experimental Section
General: All reactions were carried out under an argon atmosphere in
dried glassware. All solvents were dried and distilled by standard proce-
dures. Aldehydes and amines were purchased from commercial suppliers
and were used without further purification. All reactions were monitored
by TLC (aluminum oxide 60 F254, neutral plates) and analyzed under
254 nm UV light. Chromatography was performed with silica gel 60
(0.040–0.063 mm) and visualized by ultraviolet irradiation or KMnO4 so-
lution. Melting points were determined on recrystallized product and are
IR (neat): n˜ =2928, 2854, 1723, 1693, 1272, 1180, 1104, 1018, 699 cmÀ1
MS (ES+): m/z: 597 [M+Na]+.
;
Fragmentation of 11 to 12: KOH (20.0 mmol) was added to a solution of
pyridinone 11c (1.0 mmol) in MeOH (1 mL) and the reaction mixture
was heated to reflux. After completion of the reaction, the mixture was
diluted with saturated aqueous HCl solution and extracted with EtOAc.
The crude material was purified by column chromatography on silica gel
(heptanes/EtOAc 7:3) to give the desired pyrrolopyridinone 12a as
yellow oil (83%). 1H NMR (500 MHz, CDCl3): d=0.54–0.61 (m, 1H),
0.68–0.80 (m, 3H), 0.85–0.92 (m, 1H), 3.72 (d, J=8.9 Hz, 1H), 4.51 (d,
J=15.2 Hz, 1H), 5.37 (d, J=15.2 Hz, 1H), 5.76 (brs, 1H), 7.25–7.34 (m,
1
uncorrected. H and 13C NMR spectra were recorded on 500 (or 300) and
75 MHz spectrometers Bruker, respectively. Chemical shifts (d) are re-
ported in ppm relative to residual CHCl3 (1H: 7.26 ppm, 13C: 77 ppm).
Coupling constants (J) are reported in Hertz (Hz). Peak multiplicity is in-
dicated as follows: s (singlet), d (doublet), t (triplet), q (quartet), br
Chem. Eur. J. 2011, 17, 880 – 889
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www.chemeurj.org
887

G. Masson, J. Zhu et al.
5H), 7.55–7.66 (m, 5H), 8.20–8.27 ppm (m, 4H); 13C NMR (75 MHz,
CDCl3): d=0.8 (CH2), 4.0 (CH2), 12.8 (CH2), 43.8 (CH2), 63.4 (CH),
121.6 (C),127.4 (CH), 127.9 (2ꢄCH), 128.6 (2ꢄCH), 128.9 (C), 129.4 (3ꢄ
CH), 129.8 (2ꢄCH), 129.9 (CH), 130.0 (2ꢄCH), 133.9, (C), 137.2 (C),
142.3 (C), 146.7 (C), 147.6 (C),157.3 (C), 165.5 (C), 170.8 ppm (C); IR
(neat): n˜ =2920, 1674, 1394, 1234, 1106, 1018, 865 cmÀ1; HRMS (ESI):
m/z: calcd for C30H23N3O2Na+: 480.1688 ([M+Na]+); found: 480.1692.
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Acknowledgements
Financial support from the CNRS and ANR are gratefully acknowl-
edged. C.L. and M.B. thank ICSN and ANR for a postdoctoral and doc-
toral fellowship, respectively. D.B. thanks AstraZeneca for a doctoral fel-
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Multicomponent Synthesis of 5-Alkoxyoxazoles
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Received: July 22, 2010
Published online: November 23, 2010
Chem. Eur. J. 2011, 17, 880 – 889
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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