Palladium-catalyzed domino carbopalladation/5-exo-allylic amination of α-amino allenamides: An efficient entry to enantiopure imidazolidinones

Article abstract of DOI:10.1021/ol900171g

Allenamides of α-amino acids were converted into enantiopure 2-vinylimidazolidin-4-ones by a carbopalladation/exo-cyclization process. The products were obtained in 2.5:1-5.5:1 dr, with 94-99% ee. The palladium-catalyzed carbonylative cyclization of the s

Full text of DOI:10.1021/ol900171g

ORGANIC
LETTERS
2009
Vol. 11, No. 7
1563-1566
Palladium-Catalyzed Domino
Carbopalladation/5-exo-Allylic Amination
of r-Amino Allenamides: An Efficient
Entry to Enantiopure Imidazolidinones
Egle M. Beccalli,† Gianluigi Broggini,‡,* Francesca Clerici,† Simona Galli,‡
Claire Kammerer,§ Micol Rigamonti,‡ and Silvia Sottocornola‡
Istituto di Chimica Organica “A. Marchesini”, Facolta` di Farmacia, UniVersita` di
Milano, Via Venezian 21, 20133 Milano, Italy, Dipartimento di Scienze Chimiche e
Ambientali, UniVersita` dell’Insubria, Via Valleggio 11, 22100 Como, Italy, and UPMC
UniV Paris 06, UMR CNRS 7201 Institut Parisien de Chimie Mole´culaire, FR2769,
case 183, F-75005 Paris, France
gianluigi.broggini@uninsubria.it
Received January 27, 2009
ABSTRACT
Allenamides of r-amino acids were converted into enantiopure 2-vinylimidazolidin-4-ones by a carbopalladation/exo-cyclization process. The
products were obtained in 2.5:1-5.5:1 dr, with 94-99% ee. The palladium-catalyzed carbonylative cyclization of the same substrates afforded
enone structures. Starting from properly substituted allenamides, an intramolecular carbopalladation followed by intramolecular amination
gave rise to tricyclic fused-ring imidazolidinones.
Heteroannulation processes involving an allenyl functional
group and transition metal catalysis have been extensively
studied in the past years.1 Among the most employed
transition metals, palladium has played a relevant role when
used in both 0 and II oxidation states throughout C-C, C-N,
and C-O bond formations.2,3 A variety of nitrogen-contain-
ing heterocyclic products having an outside (Scheme 1, path
Scheme 1
. General Procedure for Nitrogen-Containing
Heterocycles Having an Outside or Inside Double Bond
† Universita` di Milano.
‡ Universita` dell’Insubria.
§ UPMC Paris.
(1) (a) Zimmer, R.; Dinesh, C. U.; Nandanan, E.; Khan, F. A. Chem.
ReV. 2000, 100, 3067. (b) Bates, R. W.; Satcharoen, V. Chem. Soc. ReV.
2002, 31, 12. (c) Widenhoefer, R. A.; Han, X. Eur. J. Org. Chem. 2006,
4555. (d) Peng, L.; Zhang, X.; Ma, M.; Wang, J. Angew. Chem., Int. Ed.
2007, 46, 1905. (e) Watanabe, T.; Oishi, S.; Fujii, N.; Ohno, H. Org. Lett.
2007, 9, 4821. (f) Morita, N.; Krause, N. Org. Lett. 2004, 6, 4121. (g) Morita,
N.; Krause, N. Eur. J. Org. Chem. 2006, 4634. (h) Yoneda, E.; Kaneko,
T.; Zhang, S.-W.; Onitsuka, K.; Takahashi, S. Org. Lett. 2000, 2, 441.
10.1021/ol900171g CCC: $40.75
Published on Web 03/04/2009
2009 American Chemical Society

a) or inside double bond (Scheme 1, path b) were obtained
by intramolecular nucleophilic attack of the nitrogen atom
to a π-allylic palladium complex generated by carbopalla-
dation of the allene starting from organic halides4or hyper-
valent iodinonium salts.5
propargylamine 2, followed by t-BuOK promoted isomer-
ization of the resulting propargylamides 3 (Scheme 2). The
Following our continuing interest in the development of
new protocols toward nitrogen-containing heterocycles via
intramolecular Pd-catalyzed reactions,6 we turned our atten-
tion to the heterocyclization of substrates bearing an allene
moiety and a nitrogen nucleophile. In particular, our studies
were aimed at obtaining 2-vinylimidazolidin-4-ones from
R-amino acid derived R-amino allenamides via a palladium-
catalyzed domino carbopalladation/5-exo-allylic amination
process. It should be noted that this type of procedure has
never been reported on substrates wherein an amide group
tethers the reacting function.
Scheme 2. Preparation of Allenamides 4
Because imidazolidine derivatives show interesting bio-
logical activities7 and are used successfully as organocata-
lysts,8 the discovery of new pathways for their enantiopure
synthesis represents a valuable goal. Moreover, the presence
of the vinylic substituent makes them important building
blocks suitable for further functionalization, increasing their
interest as organocatalysts.
exposure time of 3 to the base is crucial and must not exceed
1 min, so as to prevent the base-promoted cyclization path.9
The reaction conditions tested in the preliminary cycliza-
tion experiments gave straightforwardly satisfactory yields
of the desired imidazole products. In fact, use of Pd(PPh3)4
(0.02 equiv), PhI (1.2 equiv), and K2CO3 (4 equiv) in DMF
as solvent gave the products 5a-e and 6a-e in 2.5:1-5.5:1
diastereoisomeric ratio through an exo-cyclization of the
π-allyl intermediate A (Scheme 3).
Amino allenamides 4 were obtained in near quantitative
yields by reaction of L-R-amino acids 1 and the N-methyl-
(2) Pd(0)-promoted heterocyclization reactions: (a) Hamaguchi, A.;
Kosaka, S.; Ohno, H.; Fujii, N.; Tanaka, T. Chem. Eur. J. 2007, 13, 1692.
(b) Ma, S.; Zhao, S. J. Am. Chem. Soc. 1999, 121, 7943. (c) Karstens,
W. F. J.; Klomp, D.; Rutjes, F. P. J. T.; Hiemstra, H. Tetrahedron 2001,
57, 5123.
(3) Pd(II)-promoted heterocyclization reactions: (a) Beccalli, E. M.;
Broggini, G.; Martinelli, M.; Sottocornola, S. Chem. ReV. 2007, 107, 5318.
(b) Yu, F.; Lian, X.; Ma, S. Org. Lett. 2007, 9, 1703.
Scheme 3. Heterocyclization Reaction of Allenamides 4 by
Intermolecular Carbopalladation-Intramolecular Amination
(4) (a) Cheng, X.; Ma, S. Angew. Chem., Int. Ed. 2008, 47, 4581. (b)
Ma, S.; Yu, F.; Li, J.; Gao, W. Chem. Eur. J. 2007, 13, 247. (c) Yang, Q.;
Jiang, X.; Ma, S. Chem. Eur. J. 2007, 13, 9310. (d) Rutjes, F. P. J. T.;
Tjen, K. C. M. F.; Wolf, L. B.; Karstens, W. F. J.; Schoemaker, H. E.;
Hiemstra, H. Org. Lett. 1999, 1, 717. (e) Karstens, W. F. J.; Rutjes,
F. P. J. T.; Hiemstra, H. Tetrahedron Lett. 1997, 38, 6275. (f) Davies, I. W.;
Scopes, D. I. C.; Gallagher, T. Synlett 1993, 85. (g) Anzai, M.; Toda, A.;
Ohno, H.; Takemoto, Y.; Fujii, N.; Ibuka, T. Tetrahedron Lett. 1999, 40,
7393. (h) Ohno, H.; Anzai, M.; Toda, A.; Ohishi, S.; Fujii, N.; Tanaka, T.;
Takemoto, Y.; Ibuka, T. J. Org. Chem. 2001, 66, 4904. (i) Grigg, R.;
Sansano, J. M.; Santhakumar, V.; Sridharan, V.; Thangavelanthum, R.;
Thornton-Pett, M.; Wilson, D. Tetrahedron 1997, 53, 11803.
(5) (a) Kang, S.-K.; Baik, T.-G.; Kulak, A. N. Synlett 1999, 324. (b)
Kang, S.-K.; Baik, T.-G.; Hur, Y. Tetrahedron 1999, 55, 6863.
(6) (a) Abbiati, G.; Beccalli, E. M.; Broggini, G.; Zoni, C. J. Org. Chem.
2003, 68, 7625. (b) Beccalli, E. M.; Broggini, G.; Paladino, G.; Penoni,
A.; Zoni, C. J. Org. Chem. 2004, 69, 5627. (c) Beccalli, E. M.; Broggini,
G.; Paladino, G.; Zoni, C. Tetrahedron 2005, 61, 61. (d) Beccalli, E. M.;
Broggini, G.; Martinelli, M.; Paladino, G. Tetrahedron 2005, 61, 1077. (e)
Beccalli, E. M.; Broggini, G.; Martinelli, M.; Paladino, G.; Rossi, E.
Synthesis 2006, 2404. (f) Beccalli, E. M.; Broggini, G.; Martinelli, M.;
Masciocchi, N.; Sottocornola, S. Org. Lett. 2006, 8, 4521. (g) Abbiati, G.;
Beccalli, E. M.; Broggini, G.; Martinelli, M.; Paladino, G. Synlett 2006,
73. (h) Beccalli, E. M.; Borsini, E.; Broggini, G.; Rigamonti, M.;
Sottocornola, S. Synlett 2008, 1053. (i) Beccalli, E. M.; Borsini, E.; Broggini,
G.; Palmisano, G.; Sottocornola, S. J. Org. Chem. 2008, 73, 4746. (j) Basolo,
L.; Beccalli, E. M.; Borsini, E.; Broggini, G.; Pellegrino, S. Tetrahedron
2008, 64, 8182.
(7) (a) Vale, N.; Collins, M. S.; Gut, J.; Ferraz, R.; Rosenthal, P. J.;
Cushion, M. T.; Moreira, R.; Gomes, P. Bioorg. Med. Chem. Lett. 2008,
18, 485. (b) Araujo, M. J.; Bom, J.; Capela, R.; Casimiro, C.; Chambel, P.;
Gomes, P.; Iley, J.; Lopes, F.; Morais, J.; Moreira, R.; De Oliveira, E.; Do
Rosario, V.; Vale, N. J. Med. Chem. 2005, 48, 888. (c) Elrod, D. B.; Worley,
S. D. Ind. Eng. Chem. Res. 1999, 38, 4144.
Change of the catalyst (palladium acetate), the base (Et3N,
Cs2CO3, t-BuOK), or the solvent (acetonitrile, DMSO)
(8) (a) Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2000, 122, 4243. (b) Jen, W. S.; Wiener, J. J. M.; MacMillan, D. W. C.
J. Am. Chem. Soc. 2000, 122, 9874. (c) Quellet, S. J.; Tuttle, J. B.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 32.
(9) Broggini, G.; Galli, S.; Rigamonti, M.; Sottocornola, S.; Zecchi, G.
Tetrahedron Lett. 2009, 50, 1447.
1564
Org. Lett., Vol. 11, No. 7, 2009

resulted in less clean crude reaction mixtures with the same
degree of diastereoselectivity. The heterocyclization process
occurred also with PhBr as the arylating agent, although in
lower yields.
Scheme 4
.
Pd-Catalyzed Carbonylative Cyclization of
Allenamides 4
The X-ray crystal structure analysis10 of the minor product
6e (Figure 1) revealed a trans relationship between the
Figure 1. ORTEP drawing of compound 6e at 30% probability
level.
hydrogens in the stereogenic positions and indirectly proved
a cis disposition for its diastereoisomer 5e. Analogy of the
1H NMR spectra of compounds 5e and 6e with those of 5a-d
and 6a-d, respectively, allowed the assignment of their
absolute configuration. The constant presence of two rota-
6:1 ratio, making possible the isolation the cis-product 8.
To optimize this procedure, the reaction was carried out
under CO pressure (20 atm), but no improvements in
diastereoisomeric ratio or time of the reaction were observed.
Finally, R-amino allenamides bearing a juxtaposed internal
o-iodoaryl function were tested as precursors, so as to access
imidazoisoquinolinones via a doubly intramolecular version
of the above domino sequence. It should be noted that the
intramolecular carbopalladation of allenes followed by an
intramolecular amination is still a rare procedure.12
1
mers in the H and 13C NMR spectra of the trans diastere-
oisomers 6a-e exclusively is the most peculiar feature
allowing differentiation of the two diastereoisomers.
HPLC comparison (Chiralcel ODH column) of a sample
of 5b with that of a racemic sample obtained starting from
(()-valine proved an enantiomeric purity better than 99.0%.
The same analytical procedure on compound 5e revealed ee
) 94%.
The carbopalladation/amination process was then extended
to carbonylative conditions with the aim of obtaining 2-enoyl
imidazolidinones. To the best of our knowledge, only one
example of a Pd-catalyzed three-component carbonylation/
N-heterocyclization of allenes with aryl iodide under CO
pressure has been reported in the literature.11
Thus, treatment of R-amino acids 1a-c with amine 9
afforded the propargylamides 10a-c, which were isomerized
to allenes 11a-c in high yields (Scheme 5). Subsequent
carbopalladation/amination of the latter using Pd(PPh3)4 as
Accordingly, running the reaction under CO at atmospheric
pressure gave the enoyl imidazolidinones 7a-e. Such a result
indicated that the initially generated PhPd(II)I complex
inserted carbon monoxide prior to undergoing carbopalla-
dation, to give the new π-allyl complex B. Again, intramo-
lecular allylic amination gave the final products (Scheme 4).
The trans-configuration of 7a-e was assigned by comparing
their NMR spectra with those of compounds 6a-e and is
probably due to the bulky effect of CO group in intermediate
B. Only the heterocyclization of the isopropyl-substituted
substrate 4b took place, giving two diastereoisomers in a
(10) Crystal data for species 6e: orthorhombic, space group P212121, a
) 6.001(3) Å, b ) 18.387(5) Å, c ) 19.338(6) Å, V ) 2134(1) Å3, Z ) 4,
F(000) ) 808, F ) 1.178 g cm-3, µ(Mo KR) ) 0.078 mm-1. R(F) and
wR(F2) for I > 2σ(I) ) 0.061 and 0.105. CCDC number CCDC 717937.
Figure 2
. Catalytic cycle of intramolecular carbopalladation/
intramolecular amination of allenamides 11.
Org. Lett., Vol. 11, No. 7, 2009
1565

by oxidative addition of the iodobenzene moiety to a Pd(0)
species is followed by intramolecular carbopalladation of the
central carbon of the allyl group to give the π-allyl complex
D. At this point, the intramolecular nucleophilic attack of
the nitrogen on the inside position of the Pd-complex
generates the imidazolidinone products with concomitant
expulsion of the Pd(0) species, able to restart the catalytic
cycle.
Scheme 5. Heterocyclization Reaction of Allenamides 11 by
Intramolecular Carbopalladation-Intramolecular Amination
In summary, we have developed a new and original
approach to enantiopure imidazolidin-4-ones and imidazoiso-
quinolinones by means of a domino carbopalladation/allylic
amination process, starting from R-amino allenamides of
amino acid derivation. In all three protocols developed, the
vinyl group present in the final products may allow further
improvement of the known organocatalytic properties of such
compounds. Moreover, the results have established the
feasibility of the above heterocyclization process having an
amide group in the tether, without any interference of the
carbonyl oxygen. Work is now in progress to investigate the
ability of the newly obtained imidazolidin-4-ones as building
blocks for more complex structures and as organocatalysts
in reactions involving R,ꢀ-unsaturated aldehydes.
Acknowledgment. The authors thank the Ministero
dell’Universita` e della Ricerca for financial support (Prin
2006-2008) and for the Ph.D. fellowships to S.S. (Progetto
Giovani 2004) and M.R. (Progetto Giovani 2006).
catalyst and K2CO3 as base gave the expected tricyclic
products 12a-c and 13b,c in a 6.5:1 ratio and 51-59%
yields. Comparison of the 1H NMR spectra of these products
with those of 5a-e allowed assignment of a cis configuration
to the former set of major isomers and a trans one to the
minor ones, which could be isolated only in the case of
substrates arising from valine and leucine (13b,c).
Supporting Information Available: Experimental pro-
cedures, characterization data, and copies of 1H and 13C NMR
of new compounds. Crystal data and experimental procedures
for the X-ray structure analysis of 6e. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL900171G
The generation of the 1,5,10,10a-tetrahydro-2H-imidazo[1,2-
b]isoquinolin-3-ones 12 and 13 can be rationalized as
depicted in Figure 2. The initial generation of ArPd(II)I C
(12) (a) Hiroi, K.; Hiratsuka, Y.; Watanabe, K.; Abe, I.; Kato, F.; Hiroi,
M. Synlett 2001, 263. (b) Hiroi, K.; Hiratsuka, Y.; Watanabe, K.; Abe, I.;
Kato, F.; Hiroi, M. Tetrahedron: Asymmetry 2002, 13, 1351. (c) Watanabe,
K.; Hiroi, K. Heterocycles 2003, 59, 453. (d) Inuki, S.; Oishi, S.; Fujii, N.;
Ohno, H. Org. Lett. 2008, 10, 5239.
(11) Kang, S.-K.; Kim, K.-J. Org. Lett. 2001, 3, 511.
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