Modulating the reactivity of α-isocyanoacetates: Multicomponent synthesis of 5-methoxyoxazoles and furopyrrolones

Article abstract of DOI:10.1002/anie.200605005

A simple approach to complexity: The reactivity pattern of α-isocyanoacetates can be tuned by modulating the acidity of the α C-H bond(s) against the nucleophilicity of the conjugate base. The unique reactivity of the α-(p-nitrophenyl)-α-isocyanoacetate 1 was exploited in a three-component synthesis of 5-methoxyoxazoles 2 and four-component synthesis of furopyrrolones 3. R¹,R²,R ³ = alkyl, aryl, benzyl; R⁴ = aryl. (Chemical Equation Presented).

Full text of DOI:10.1002/anie.200605005

Angewandte
Chemie
DOI: 10.1002/anie.200605005
Synthetic Methods
Modulating the Reactivity of a-Isocyanoacetates: Multicomponent
Synthesis of 5-Methoxyoxazoles and Furopyrrolones**
Damien Bonne, Mouloud Dekhane, and Jieping Zhu*
The chemistry of methyl a-isocyanoacetate (1) was inves-
tigated thoroughly in the 1970s, mainly by the research groups
of Schöllkopf and Matsumoto.[1,4] One particularly powerful
transformation is the reaction of metalated 1 with polar
multiple bonds to afford heterocycles.[2] By taking advantage
of the higher acidity of the a-phenyl-a-isocyanoacetate 2,
Orru and co-workers recently developed an elegant three-
component synthesis of imidazolines 5 without the need for
premetalation (Scheme 1).[3] The reaction was initiated by the
nucleophilic addition of the a carbanion derived from 2 to an
iminium ion generated in situ from 3 and 4, which was
followed by cyclization and protonation. The presence of the
phenyl group is essential for this one-pot process: The
reaction with a-isocyanoacetate 1 under otherwise identical
conditions provided the corresponding imidazoline in low
yield.[4] The phenyl group was thought to render the a CH
position acidic enough to be deprotonated by a weak base. In
general, the exploitation of the nucleophilicity of the a carbon
atom and the electrophilicity of the divalent carbon atom of
carbon atom of the isocyanide was exploited only for trapping
a proton.
In connection with our ongoing project aimed at the
development of novel multicomponent reactions[5,6] with
functionalized isocyanides as
a
key component,[7–9] we
became interested in the reactivity profile of hitherto
unknown methyl a-(p-nitrophenyl)-a-isocyanoacetate (6).
The nitro group is strategically incorporated into the phenyl
À
ring to render the a C H bond even more acidic, so that it can
be deprotonated by weaker bases. Whereas the ready
formation of the carbanion is the key consideration in the
development of the three-component reaction described by
Orru and co-workers, we expected that the carbanion derived
from 6 would display decreased nucleophilicity, as it is highly
stabilized. Consequently, its reaction with a polar double
bond, such as that of an imine, would be initiated by the
nucleophilicity of the divalent carbon atom of the isocyanide
and lead to different heterocycles.[10,11] We report herein the
development of a three-component synthesis of 5-methoxy-
oxazoles 7 and a four-component synthesis of furopyrrolones
8 on the basis of the unique reactivity of methyl a-(p-
nitrophenyl)-a-isocyanoacetate (6; Scheme 2).
À
À
the isocyanide for the effective construction of C C and C N
bonds characterized the known chemistry of a-isocyanoace-
tates.[1–4] In all these transformations, the ester functionality
served only as an activator without participating in the bond-
forming process, and the nucleophilicity of the divalent
Compound 6 was synthesized readily by a nucleophilic
substitution reaction (SNAr) between the commercially
available a-isocyanoacetate 1 and 4-fluoronitrobenzene (10)
under basic conditions that we developed previously for the
monoalkylation of 1 (Scheme 3).[12] Detailed NMR spectro-
scopic studies indicated that 6 exists as the ester and not in the
enol form in common organic solvents. To evaluate the
chemical reactivity of 6, we next examined its three-compo-
nent reaction with morpholine (3a) and cyclohexanal (4a).
Gratifyingly, when a solution of 3a, 4a, and 6 in toluene was
simply stirred at room temperature for 4 h, the corresponding
5-methoxyoxazole 7a was obtained in 92% yield.[13] The same
Scheme 1. Three-component synthesis of imidazolines described by
Orruand co-workers.
[*] Dr. D. Bonne, Dr. J. Zhu
Institut de Chimie des Substances Naturelles
CNRS, 91198 Gif-sur-Yvette Cedex, France,
http://www.icsn.cnrs-gif.fr/article.php3?id_article=122
Fax: (+33)1-6907-7247
E-mail: zhu@icsn.cnrs-gif.fr
Dr. M. Dekhane
AstraZeneca, Mereside, Alderley Park
Macclesfield, Cheshire, SK10 4TG (UK)
[**] Financial support from the CNRS and a doctoral fellowship from
AstraZeneca to D.B. are gratefully acknowledged.
Supporting information for this article, including experimental
procedures, product characterization, and 1H NMR spectra of 6, 7,
and 8, is available on the WWW under http://www.angewandte.org
or from the author.
Scheme 2. Multicomponent synthesis of 5-methoxyoxazoles 7 and
furopyrrolones 8.
Angew. Chem. Int. Ed. 2007, 46, 2485 –2488
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2485

Communications
Scheme 3. Synthesis of methyl a-(p-nitrophenyl)-a-isocyanoacetate (6).
Scheme 5. Synthesis and three-component reaction of the potassium
enolate 14: a) KOH, THF/H2O; b) Me2NH·HCl, c-C6H11CHO, toluene.
reaction proceeded smoothly in MeOH to afford 7a in 90%
yield. That this reaction occurred in toluene in the absence of
any additive is intriguing, as nonpolar aprotic solvents are
known to favor the alternative Passerini-type reaction.[14] The
colorless solution of the aldehyde and the amine turned deep
red instantaneously upon the addition of the yellowish
solution of 6. A possible reaction scenario is shown in
Scheme 4: Condensation of the aldehyde with the amine
affords the iminium ion 11. The hydroxide counterion then
serves as a base to abstract the a hydrogen atom of 6 to
furnish the enolate 12. The addition of the isocyanide to the
iminium ion provides the nitrilium intermediate 13, which
undergoes cyclization to afford the 5-methoxyoxazole.[15] In
this reaction, the carbene-like reactivity of the divalent
The scope of this reaction was examined by using eight
amines and seven aldehydes as starting materials (see the
Supporting Information). Some representative 5-methoxy-
oxazoles synthesized are listed in Scheme 6. In most cases, the
reaction was performed with an approximately equimolar
amount of the three components and was complete within 4 h
in toluene at room temperature. Aliphatic aldehydes, includ-
ing formaldehyde, linear aldehydes, and a-branched alde-
hydes, were found to be good substrates, as were aromatic
aldehydes. Both aliphatic and aromatic amines participated in
the reaction; cyclic secondary amines generally afforded the
oxazole product in higher yield than primary amines.
Although the corresponding oxazole was formed in excellent
yield with dimethylamine, more hindered acyclic secondary
amines, such as dibenzylamine, failed to provide the three-
component adduct. When dibenzylamine was used, the
addition of the isocyanide to the aldehyde occurred to
afford 2-(1-hydroxyalkyl) 5-methoxyoxazoles in excellent
yield.[16] Most probably, dibenzylamine serves only as a base
to deprotonate 6, and the ammonium enolate thus formed
undergoes a Passerini type of reaction. This observation is
also in line with the mechanistic proposal shown in Scheme 4
and might highlight the importance of the ion-pair inter-
mediate 12 in the multicomponent process. When 3a and 6
were treated with ketones, such as 4-phenylcyclohexanone,
the corresponding 2-(hydroxyalkyl) 5-methoxyoxazoles were
obtained.
À
carbon atom is exploited fully for the formation of one C C
À
bond and one C O bond, whereas the ester functionality
serves as an internal nucleophile to trap the incipient nitrilium
intermediate. Thus, the reactivity profile of 6 is completely
different from that of 2, and more like that of a-isocyanoa-
cetamide.[7]
À
The high acidity of the a C H bond of the isocyanide 6
was clear from the following control experiment: The treat-
ment of 6 with aqueous potassium hydroxide led to exclusive
formation of the enolate 14 instead of the potassium salt of
the carboxylic acid. It is noteworthy that the enolate is formed
and stable under aqueous conditions. The treatment of 14
with the hydrochloride salt of dimethylamine and cyclo-
hexanal afforded the corresponding oxazole 7b in 55% yield
over two steps (Scheme 5). These experimental results
provided indirect evidence that the reaction of 6 with 3a
and 4a might indeed proceed via the enolate intermediate 12.
One shortcoming of this three-component reaction is that
it provides only two points of diversity. To further illustrate
the utility of methyl a-(p-nitrophenyl)-a-isocyanoacetate (6)
in the development of novel multicomponent reactions for
heterocycle synthesis, the chemical transformation of the
products 7 was next investigated by taking advantage of the
functionalities of the 5-methoxyoxazoles. As 5-methoxy-
oxazole is known to be an active diene that readily undergoes
Diels–Alder reactions with a range of dienophiles,[17] our
initial experiments focused on the intermolecular cycloaddi-
tion between 7a and dimethyl acetylenedicarboxylate
(DMAD). However, no cycloadduct was produced under
thermal conditions, and decomposition occurred instead
under forcing conditions. On the other hand, when a solution
in toluene of the oxazole 7i and 3-phenylprop-2-ynoyl
chloride (9a) was heated at reflux, the furopyrrolone 8a
was obtained in 81% yield. The formation of 8a can be
explained by a three-step domino sequence (Scheme 7):
Acylation of the secondary amine 7i with the acyl chloride
9a affords the tertiary amide 15, which undergoes an intra-
molecular Diels–Alder cycloaddition to furnish the oxa-
Scheme 4. Three-component synthesis of the 5-methoxyoxazole 7a.
2486 www.angewandte.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2007, 46, 2485 –2488

Angewandte
Chemie
Scheme 7. Synthesis of the furopyrrolone 8a by a domino process.
Scheme 6. Structures of 5-methoxyoxazoles synthesized.
bridged polyheterocycle 16. A retro-Diels–Alder reaction of
16 then affords the observed product 8a together with 4-
nitrophenylcyanide, which was also isolated from the reaction
mixture.
Both the three-component synthesis of the oxazole and
the subsequent domino process are performed in toluene and
are therefore potentially compatible. We therefore attempted
a four-component synthesis of the furopyrrolone. Thus, when
a solution in toluene of n-butylamine, n-hexanal, and 6 was
stirred for 4 h, after which time the acyl chloride 9a and
triethylamine (Et3N) were added, and the resulting mixture
was heated at reflux for 10 min, the corresponding furopyr-
rolone 8a was obtained in 51% overall yield. This four-
component reaction turned out to be quite general. Some
representative furopyrrolones synthesized are shown in
Scheme 8. Both electron-withdrawing groups and electron-
donating groups are tolerated in the aromatic ring of 3-aryl
prop-2-ynoyl chlorides 9. The presence of a substituent ortho
to the triple bond did not interrupt the reaction sequence. In
Scheme 8. One-pot four-component synthesis of furopyrrolone.
hindered rotation about the biaryl axis. Although the yield
À
À
is moderate, we emphasize that two C N bonds, one C O
À
=
bond, one C C bond, and two C C double bonds are created
in this experimentally simple process. Furthermore, the
reaction allowed the introduction of three points of diversity
and should therefore be highly useful for the synthesis of
libraries of medicinally important heterocycles of this type.
Since the 4-nitrophenyl substituent of the isocyanide 6 is not
incorporated in the structure of the final product, the
invariability of this substrate is not a major concern in this
novel four-component reaction.[18]
In conclusion, by carefully considering the acidity of the
1
À
the case of 8c and 8d, the H NMR spectra indicated the
presence of two diastereomers, which exist because of
a C H bond(s) versus the nucleophilicity of the conjugate
base, we have uncovered a new reactivity pattern of the well-
Angew. Chem. Int. Ed. 2007, 46, 2485 –2488
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 2487

Communications
[4] For an alternative reaction pathway, see: M. Suzuki, K.-I.
Nunami, T. Moriya, K. Matsumoto, N. Yoneda, J. Org. Chem.
1978, 43, 4933 – 4935.
known a-isocyanoacetates. These studies highlighted the
concept of a substrate-design approach to the development
of novel multicomponent reactions.[5e] Indeed, by simply
incorporating a nitro group into the phenyl ring of 2, we
obtained an isocyanoacetate, 6, which displayed a completely
different reactivity profile to that of 2 as a result of the
[5] For recent reviews, see: a) C. Hulme, V. Gore, Curr. Med. Chem.
2003, 10, 51 – 80; b) R. V. A. Orru, M. De Greef, Synthesis 2003,
1471 – 1499; c) A. Jacobi von Wangelin, H. Neumann, D.
Gördes, S. Klaus, D. Strübing, M. Beller, Chem. Eur. J. 2003, 9,
4286 – 4294; d) V. Nair, C. Rajesh, A. U. Vinod, S. Bindu, A. R.
Sreekanth, J. S. Mathen, L. Balagopal, Acc. Chem. Res. 2003, 36,
899 – 907; e) J. Zhu, Eur. J. Org. Chem. 2003, 1133 – 1144; f) G.
Balme, E. Bossharth, N. Monteiro, Eur. J. Org. Chem. 2003,
4101 – 4111; g) C. Simon, T. Constantieux, J. Rodriguez, Eur. J.
Org. Chem. 2004, 4957 – 4980; h) P. Tempest, Curr. Opin. Drug
Discovery Dev. 2005, 8, 776 – 788; i) A. Dömling, Chem. Rev.
2006, 106, 17 – 89.
À
increased acidity of the a C H bond and hence the decreased
nucleophilicity of the resulting carbanion. We have demon-
strated previously that the exchange of the ester group of an
isocyanoacetate for an amide group also modulates the
reactivity of these compounds, in this case by decreasing the
À
acidity of the a C H bond(s). The multicomponent reactions
reported herein should find applications in a number of fields
in view of the synthetic and medicinal importance of 5-
methoxyoxazoles[19] and furopyrrolones.[20]
[6] For a monograph, see: Multicomponent Reactions (Eds.: J. Zhu,
H. BienaymØ), Wiley-VCH, Weinheim, 2005.
[7] For a-isocyanoacetamide, see: a) X. Sun, P. Janvier, G. Zhao, H.
BienaymØ, J. Zhu, Org. Lett. 2001, 3, 877 – 880; b) P. Janvier, X.
Sun, H. BienaymØ, J. Zhu, J. Am. Chem. Soc. 2002, 124, 2560 –
2567; c) P. Janvier, M. Bois-Choussy, H. BienaymØ, J. Zhu,
Angew. Chem. 2003, 115, 835 – 838; Angew. Chem. Int. Ed. 2003,
42, 811 – 814.
[8] For ortho-isocyanobenzamide, see: D. Bonne, M. Dekhane, J.
Zhu, Org. Lett. 2005, 7, 5285 – 5288.
[9] For a-isocyanoacetic acid, see: a) D. Bonne, M. Dekhane, J. Zhu,
Org. Lett. 2004, 6, 4771 – 4774; b) D. Bonne, M. Dekhane, J. Zhu,
J. Am. Chem. Soc. 2005, 127, 6926 – 6927.
Experimental Section
Typical procedure: Heptanal (25 mL, 0.18 mmol, 1.2 equiv) was added
to a solution of n-butylamine (20 mL, 0.20 mmol, 1.3 equiv) in toluene
(1 mL), and the mixture was stirred for 10 min at room temperature.
The isocyanide 6 (33 mg, 0.15 mmol, 1.0 equiv) was then added, and
stirring was continued for 4 h at room temperature. The reaction
mixture was then cooled to 08C, and triethylamine (100 mL,
0.75 mmol, 5.0 equiv) was added, followed by a solution of 3-
phenylpropioloyl chloride (49 mg, 0.30 mmol, 2.0 equiv) in toluene
(0.7 mL). The reaction mixture was warmed to room temperature and
was then heated at reflux for 10 min. The solvent was removed in
vacuo, and the crude product was purified by preparative TLC (SiO2,
30% ethyl acetate in heptane) to afford 8a (28.5 mg, 51%) as a
colorless oil.
[10] A. Dömling, I. Ugi, Angew. Chem. 2000, 112, 3300 – 3344;
Angew. Chem. Int. Ed. 2000, 39, 3168 – 3210.
[11] For recent innovative development of Ugi-type reactions, see:
a) L. El Kaïm, L. Grimaud, J. Oble, Angew. Chem. 2005, 117,
8175 – 8178; Angew. Chem. Int. Ed. 2005, 44, 7961 – 7964; b) L.
El Kaïm, M. Gizolme, L. Grimaud, J. Oble, Org. Lett. 2006, 8,
4019 – 4021; c) G. B. Giovenzana, G. C. Tron, S. D. Paola, I. G.
Menegotto, T. Pirali, Angew. Chem. 2006, 118, 1117 – 1120;
Angew. Chem. Int. Ed. 2006, 45, 1099 – 1102.
Received: December 11, 2006
Published online: February 26, 2007
[12] a) C. Housseman, J. Zhu, Synlett 2006, 1777 – 1779; b) R.
Beugelmans, A. Bigot, J. Zhu, Tetrahedron Lett. 1994, 35,
5649 – 5652.
[13] For examples of Ugi-type reactions in toluene in the absence of
additives, see: a) A. Fayol, J. Zhu, Org. Lett. 2005, 7, 239 – 242;
b) R. Gµmez-Montaæo, E. Gonzµlez-Zamora, P. Potier, J. Zhu,
Tetrahedron 2002, 58, 6351 – 6358.
[14] L. Banfi, R. Riva, Org. React. 2005, 65, 1 – 140.
[15] For recent reviews on the chemistry of oxazoles, see: a) V. S. C.
Yeh, Tetrahedron 2004, 60, 11995 – 12042; b) J. Zhong, Nat.
Prod. Rep. 2005, 22, 186 – 229.
[16] G. Cuny, R. Gµmez-Montaæo, J. Zhu, Tetrahedron 2004, 60,
4879 – 4885.
[17] For reviews on the Diels–Alder reaction of oxazoles with
alkynes, see: a) M. Y. Karpeiskii, V. L. Florentꢀev, Russ. Chem.
Rev. 1969, 38, 540 – 546; b) P. A. Jacobi in Adv. in Heterocyclic
Nat. Prod. Syn., Vol. 2 (Ed.: W. H. Pearson), 1992, pp. 251 – 298;
for examples of the cycloaddition of 5-aminooxazoles with
alkynes, see: c) P. Janvier, H. BienaymØ, J. Zhu, Angew. Chem.
2002, 114, 4467 – 4470; Angew. Chem. Int. Ed. 2002, 41, 4291 –
4294; d) A. Fayol, J. Zhu, Angew. Chem. 2002, 114, 3785 – 3787;
Angew. Chem. Int. Ed. 2002, 41, 3633 – 3635.
Keywords: furopyrrolones · isocyanides ·
multicomponent reactions · oxazoles · Ugi reaction
.
[1] a) D. Hoppe, Angew. Chem. 1974, 86, 878 – 893; Angew. Chem.
Int. Ed. Engl. 1974, 13, 789 – 804; b) U. Schöllkopf, Angew.
Chem. 1977, 89, 351 – 360; Angew. Chem. Int. Ed. Engl. 1977, 16,
339 – 348; c) S. Marcaccini, T. Torroba, Org. Prep. Proced. Int.
1993, 25, 141 – 208.
À
[2] For selected examples of metal-mediated C H activation of a-
isocyanoacetates for the synthesis of heterocycles, see: a) T.
Saegusa, Y. Ito, H. Kinoshita, S. Tomita, J. Org. Chem. 1971, 36,
3316 – 3323; b) H. Takaya, S. Kojima, S. Murahashi, Org. Lett.
2001, 3, 421 – 424; c) Y. Ito, M. Sawamura, T. Hayashi, J. Am.
Chem. Soc. 1986, 108, 6405 – 6406; d) A. Tongi, S. D. Pastor, J.
Org. Chem. 1990, 55, 1649 – 1664; e) T. Hayashi, E. Kishi, V. A.
Soloshonok, Y. Uozumi, Tetrahedron Lett. 1996, 37, 4969 – 4972;
f) Y.-R. Lin, X.-T. Zhou, L.-X. Dai, J. Sun, J. Org. Chem. 1997,
62, 1799 – 1803; g) R. Grigg, M. I. Lansdell, M. Thornton-Pett,
Tetrahedron 1999, 55, 2025 – 2044; h) S. Kamijo, C. Kanazawa, Y.
Yamamoto, J. Am. Chem. Soc. 2005, 127, 9260 – 9266; i) C.
Kanazawa, S. Kamijo, Y. Yamamoto, J. Am. Chem. Soc. 2006,
128, 10662 – 10663.
À
[18] We are exploiting other a-isocyanoacetates that have a C H
bonds with reinforced acidity; see: a) M. Bergemann, R.
Neidlein, Helv. Chim. Acta 1999, 82, 909 – 918; b) S. Müller, R.
Neidlein, Helv. Chim. Acta 2002, 85, 2222 – 2231.
[19] B. H. Lipshutz, Chem. Rev. 1986, 86, 795 – 819, and references
therein.
[3] a) R. S. Bon, C. Hong, M. J. Bouma, R. F. Schmitz, F. J. J.
De Kanter, M. Lutz, A. L. Spek, R. V. A. Orru, Org. Lett.
2003, 5, 3759 – 3762; b) R. S. Bon, B. Van Vliet, N. E. Sprenkels,
R. F. Schmitz, F. J. J. De Kanter, C. V. Stevens, M. Swart, F. M.
Bickelhaupt, M. B. Groen, R. V. A. Orru, J. Org. Chem. 2005, 70,
3542 – 3553.
[20] M. Chapdelaine, WO Patent 2005/100351A1, 2005 [Chem. Abstr.
2005, 143, 422508].
2488 www.angewandte.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2007, 46, 2485 –2488