(Scheme 1). Herein, we wish to report the first three-component
reaction of allenoates, isocyanides, and carboxylic acids to
synthesize highly substituted acryl imide derivatives.
A Novel Three-Component Reaction of
Allenoates, Isocyanides, and Carboxylic Acids:
Facile Synthesis of Highly Substituted Acryl
Imide Derivatives
Initially, the reaction of 4-methylpenta-2,3-dienoate 1a with
p-tolyl isocyanide 2a and benzoic acid 3a was conducted in
CH2Cl2 at room temperature for 48 h, which underwent a smooth
1:1:1 addition reaction (Table 1). However, the desired product
3-(benzoyl-p-tolylaminocarbonyl)-4-methylpent-3-enoic acid eth-
yl ester 4a was isolated only in 43% yield (entry 1, Table 1).
Subsequent optimization studies indicated that MeCN was a
better solvent, and the yield of product 4a was greatly increased
to 86% at 65 °C (entry 3). Our further investigations proved
that DMF, THF, and toluene did not work well (entries 5-8).
With the optimized conditions in hand, we investigated the
scope of this reaction. The results indicated that the reaction
proceeded smoothly to give the corresponding highly substituted
acryl imides 4 in good to excellent yields (Table 2).
Xian Huang*,†,‡ and Feng Sha†
Department of Chemistry, Zhejiang UniVersity (Xixi Campus),
Hangzhou 310028, People’s Republic of China, and State Key
Laboratory of Organometallic Chemistry, Shanghai Institute of
Organic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, People’s Republic of China
ReceiVed NoVember 3, 2007
As indicated in Table 2, the allenoates could be mono-, di-,
or trisubstituents, and the isocyanides or the carboxylic acids
could be alkyl or aryl substituted. In addition, it was interesting
to observe that when R1 was different from R2, the reaction
gave the E-isomer as the major product in good yield (entries
13 and 14). When R1 ) Ph, R2 ) R3 ) H, the NMR analysis
of crude product indicated that the reaction furnished E-4o as
a sole product (entry 14).
Furthermore, when 1-substituted allenoate was employed, the
reaction gave the expected product 4m in 24% yield together
with 51% yield of the CdC bond rearranged product 5 (Scheme
2). The formation of compound 5 was probably due to the
rearrangement of 4m under acidic conditions. This was further
proved by the fact that when H2O was employed instead of
PhCO2H, the reaction furnished the unrearrangement product
6 as a single product under similar conditions.
A novel synthesis of highly substituted acryl imide deriva-
tives by the three-component reaction of allenoates, isocya-
nides, and carboxylic acids was reported, and the intramo-
lecular cyclization reaction of allenoic acids with isocyanides
was also described.
Multicomponent reactions provide a powerful tool for the
synthesis of diverse and complex compounds because of their
atom economy, simple experimental procedures, and high bond
forming efficiency.1 Isocyanide-based multicomponent reactions
(IMCRs) play important roles in this realm due to their diversity
of bond-forming processes, functional group tolerance, and high
levels of chemo-, regio-, and stereoselectivity.2 Although IMCRs
involving electron-deficient acetylenic compounds and active
hydrogen compounds have been investigated,3-5 allene-attended
reactions of this kind have not been reported yet.
On the basis of the well-established chemistry of isocyanides,8
it is reasonable to assume that the nucleophilic addition of
isocyanides 2 to allenoates 1 forms the zwitterionic intermediate
7, which could be trapped with carboxylic acids 3 to produce
the imidoyl carboxylate 8. Subsequently, an acyl group shift
from oxygen to nitrogen occurs to produce the final product 4
(Scheme 3).9
According to the above three-component reaction, we con-
ceived that allenoic acids, which combine the reactive sites of
Considering the great synthetic potentials of allenes which
arise from their axial chirality, substituent loading capability,6
and the higher reactivity of the electron-deficient allenes
compared to the corresponding alkynes,7 we proposed that the
adduct between electron-deficient allenes and isocyanides might
provide a convenient zwitterionic nitrilium intermediate species
which would be trapped with E+, leading to useful products
(6) For reviews and accounts, see: (a)Yamamoto, Y.; Radhakrishnan,
U. Chem. Soc. ReV. 1999, 28, 199. (b) Ma, S. Acc. Chem. Res. 2003, 36,
701. (c) Larock, R. C. J. Organomet. Chem. 1999, 576, 111. (d) Grigg, R.;
Sridharan, V. J. Organomet. Chem. 1999, 576, 65. (e) Zimmer, R.; Dinesh,
C. U.; Nandanan, E.; Khan, F. A. Chem. ReV. 2000, 100, 3067. (f) Hashmi,
A. S. K. Angew. Chem. 2000, 112, 3737; Angew. Chem., Int. Ed. 2000, 39,
3590. (g) Ma, S.; Li, L. Synlett 2001, 1206. (h) Reissing, H. U.; Schade,
W.; Amombo, M. O.; Pulz, R.; Hausherr, A. Pure Appl. Chem. 2002, 175.
(i) Ma, S. Carbopalladation of Allenes. In Handbook of Organopalladium
Chemistry for Organic Synthesis; Negishi, E., Ed.; Wiley-Interscience:
NewYork, 2002; p 1491.
(7) (a) Schuster, H. F.; Coppola, G. M. Allenes in Organic Synthesis;
John Wiley & Sons: New York, 1988. (b) The Chemistry of Ketenes,
Allenes, and Related Compounds; Patai, S., Ed.; John Wiley & Sons: New
York, 1980; Part 1. (c) Landor, S. R. The Chemistry of Allenes; Academic
Press: New York, 1982; Vols. 13. (d) Krause, N.; Hashmi, A. S. K. Modern
Allene Chemistry; Wiley-VCH: Weinheim, Germany, 2004; Vol. 12.
(8) (a) Ugi, I. Isonitrile Chemistry; Academic: London, 1971. (b) Ugi,
I. Angew. Chem., Int. Ed. 1982, 21, 810. (c) Do¨mling, A.; Ugi, I. Angew.
Chem., Int. Ed.2000, 39, 3169. (d) Nair, V.; Vinod, A. U.; Nair, J. S.;
Sreekanth, A. R.; Rath, N. P. Tetrahedron Lett. 2000, 41, 6675. (e)
Marcaccini, S.; Torroba, T. Org. Prep. Proc. Int. 1993, 25, 141.
† Zhejiang University.
‡ Chinese Academy of Sciences.
(1) Tietze, L. F. Chem. ReV. 1996, 96, 115.
(2) Do¨mling, A. Chem. ReV. 2006, 106, 17.
(3) Yavari, I.; Anary-Abbasinejad, M.; Alizadeh, A.; Hossaini, Z.
Tetrahedron 2003, 59, 1289.
(4) Yavari, I.; Alizadeh, A.; Anary-Abbasinejad, M.; Bijanzadeh, H. R.
Tetrahedron 2003, 59, 6083.
(5) (a) Yavari, I.; Esmaili, A. A.; Asghari, S.; Bijanzadeh, H. R. J. Chem.
Res. Synop. 1999, 368. (b) Yavari, I.; Hazeri, N.; Maghsoodlou, M. T.;
Zabarjad-Shiraz, N. Monatsh. Chem. 2001, 132, 683. (c) Alizadeh, A.;
Rostamnia, S.; Hu, M. L. Synlett 2006, 10, 1592.
10.1021/jo702382h CCC: $40.75 © 2008 American Chemical Society
Published on Web 01/10/2008
J. Org. Chem. 2008, 73, 1173-1175
1173