C O M M U N I C A T I O N S
Table 2. Examples of Oxidative One-Carbon Homologationa
pseudooxazolone 12e (R1 ) R2 ) Ph) was synthesized from readily
available mandelic acid and phenylglycine.13 Simply mixing 12e
and 3a in toluene in the presence of triethylamine produced 5e in
90% yield. This control experiment revealed that pseudooxazolone
could well be the intermediate of the present homologation
procedure.
In summary, we have developed a novel method for oxidative
homologation of aldehyde to amide. The reaction is realized under
very mild conditions using readily accessible reagents. While
multicomponent reaction (MCR) is gaining popularity for creating
the structural complexity and diversity,14 we demonstrated herein
that research on MCR can also lead to the discovery of new funda-
mental transformations. In the present case, R-p-methoxyphenyl-
R-isocyano acetic acid served as donor of the CONH2 function to
aldehyde, while the dimethylamine acted only as a shuttle molecule
to initiate/terminate the sequence and to mediate the internal redox
process of one of the three-component adducts. Further studies on
the scope and limitations of this new reaction are underway.
a All reactions were run in toluene at room temperature in the presence
of the hydrochloride salt of dimethylamine and potassium salt of R-p-
methoxy-R-isocyano acetic acid (1c). b Yields refer to the mass isolated
after silica gel chromatography. c Isolated as a mixture of two diastereomers.
Acknowledgment. Financial support from CNRS and a doctoral
fellowship from AstraZeneca to D.B. are gratefully acknowledged.
Supporting Information Available: Experimental procedures and
product characterization for all compounds synthesized. This material
Scheme 2. From Aldehyde to Amide, a Mechanistic Hypothesis
References
(1) For reviews, see: (a) Martin, S. F. Synthesis 1979, 633-665. (b) Stowell,
J. C. Chem. ReV. 1984, 84, 409-435.
(2) For recent examples, see: (a) Katritzky, A. R.; Zhang, S.; Hussein, A. H.
M.; Fang, Y. J. Org. Chem. 2001, 66, 5606-5612. (b) Badham, N. F.;
Medelson, W. L.; Allen, A.; Diederich, A. M.; Eggleston, D. S.; Filan, J.
J.; Freyer, A. J.; Killmer, L. B.; Kowalski, C. J.; Liu, L.; Novack, V. J.;
Vogt, F. G.; Webb, K. S.; Yang, J. J. Org. Chem. 2002, 67, 5440-5443.
(c) Nicolaou, K. C.; Vassilikogiannakis, G.; Kranich, R.; Baran, P. S.;
Zhong, Y.-L.; Natarajan, S. Org. Lett. 2000, 2, 1895-1898. (d) Schummer,
D.; Ho¨fle, G. Tetrahedron 1995, 51, 11219-11222. (e) Satoh, T.; Kubota,
K. Tetrahedron Lett. 2000, 41, 2121-2124. (f) Arroyo-Gomez, Y.;
Rodriguez-Amo, J. F.; Santos-Garcia, M.; Sanz-Tejedor, M. A. Tetra-
hedron: Asymmetry 2000, 11, 789-796. (g) Alcaraz, L.; Cridland, A.;
Kinchin, E. Org. Lett. 2001, 3, 4051-4053.
(3) For recent studies, see: (a) Aller, E.; Molina, P.; Lorenzo, A. Synlett 2000,
4, 526-528. (b) Winum, J.-Y.; Kamal, M.; Leydet, A.; Roque, J.-P;
Montero, J.-L. Tetrahedron Lett. 1996, 37, 1781-1782. (c) Maruoka, K.;
Concepcion, A. B.; Yamamoto, H. J. Org. Chem. 1994, 59, 4725-4726.
(d) Loeschorn, C. A.; Nakajima, M.; McCloskey, P. J.; Anselme, J.-P. J.
Org. Chem. 1983, 48, 4407-4410. (e) Angle, S. R.; Neitzel, M. L. J.
Org. Chem. 2000, 65, 6458-6461.
(4) (a) Kowalski, C. J.; Reddy, R. E. J. Org. Chem. 1992, 57, 7194-7208.
(b) Gray, D.; Concellon, C.; Gallagher, T. J. Org. Chem. 2004, 69, 4849-
4851.
racemization. When 2o was subjected to the same reaction
conditions, two separable diastereomers 6o were produced most
probably via a sequence of â-elimination and intramolecular
Michael addition process (entry 14). Cyclic ketone can be homolo-
gated (entries 3 and 4), but aliphatic ketone failed to participate in
the reaction (entry 6).
A plausible mechanism for the formation of the compound 5 is
shown in Scheme 2. The condensation of the ammonium ion 3a
with aldehyde 2 would give the iminium 8 that would be trapped
by nucleophilic addition of isonitrile to provide the putative
isonitrilium intermediate 9. Intramolecular addition of carbonyl
oxygen would lead to oxazolone 10, which would be in equilibrium
with 5-hydroxyoxazole 11. Depending on the nature of the
substituent R1, the subsequent reaction diverged. In the case of an
alkyl group, the oxazolone 10 may exist predominantly over
5-hydroxyoxazole 11. Nucleophilic attack of amine would then
provide the dipeptide 4. However, when R1 is an aryl group, the
equilibrium between 10 and 11 should shift toward the latter species
due to the increased acidity of the proton R to the carbonyl function
and additional stabilization offered by the conjugation with the
aromatic ring. The 1,6-elimination of the ammonium ion assisted
by the 5-hydroxy group from 11 would lead to the pseudooxazolone
12. This process was apparently favored over reprotonation, which
is anyway degenerative since the oxazolone 10 would tautomerize
back to the resonance-stabilized hydroxyoxazole 11. Ring opening
of pseudooxazolone 12 by dimethylamine would afford the N-acyl
imino amide 5.12 To validate this mechanistic proposal, authentic
(5) Barton, D. H. R.; Chern, C.-Y.; Jaszberenyi, J. S. Tetrahedron Lett. 1992,
33, 5013-5016.
(6) Via dibromoalkene, see: (a) Huh, D. H.; Jeong, J. S.; Lee, H. B.; Ryu,
H.; Kim, Y. G. Tetrahedron 2002, 58, 9925-9932. (b) Shen, W.; Kunzer,
A. Org. Lett. 2002, 4, 1315-1317.
(7) Bonne, D.; Dekhane, M.; Zhu, J. Org. Lett. 2004, 6, 4771-4774.
(8) For an earlier example, see: Bossio, R.; Marcaccini, S.; Paoli, P.; Pepino,
R. Synthesis 1994, 672-674.
(9) (a) Do¨mling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168-3210.
(b) Zhu, J. Eur. J. Org. Chem. 2003, 1133-1144.
(10) Compound 1c is synthesized in four steps from commercially available
and inexpensive 4-hydroxy phenylglycine. Racemic aryl glycine is
synthesized by Strecker reaction from the corresponding aromatic alde-
hyde.
(11) Prepared by saponification of the corresponding ester with a stoichiometric
amount of LiOH, KOH, and CsOH and used without purification.
(12) The crude reaction mixture of 1c, 3a, and 2a, after quenching with water,
was subjected to GC/MS analysis. Besides 5a (82%), pseudooxazolone
12a (6%) and dipeptide 4a (R1 ) 4-MeO-phenyl, R2 ) C6H13, R3 ) R4
) Me, 9%) have been detected. However, the dipeptidic acid resulting
from the ring opening of oxazolone 10 by water was not observed (for
details, see Supporting Information). Pseudooxazolone 12a and dipeptide
4a have also been isolated from the reaction mixture by preparative TLC.
(13) Breitholle, E. G.; Stammer, C. H. J. Org. Chem. 1974, 39, 1311-1312.
(14) Multicomponent Reaction; Zhu, J., Bienayme´, H., Eds.; Wiley-VCH:
Weinheim, Germany, 2005.
JA0511220
9
J. AM. CHEM. SOC. VOL. 127, NO. 19, 2005 6927