Scheme 1. Synthetic Routes to N-Acyl Vinylogous Carbamic
base
amide
(equiv) (%)b
yield
4
(%)c
entry
Cu source
CuTC
CuI
Cu(CH3CN)4PF6 Cs2CO3(2.0)
Cu(CH3CN)4PF6 Rb2CO3(2.0)
Cu(CH3CN)4PF6 K2CO3(2.0)
Cu(CH3CN)4PF6 Rb2CO3(3.0)
(equiv)
1
2
3
4
5
6
Cs2CO3(2.0)
Cs2CO3(2.0)
1.5
1.5
1.5
1.5
1.5
3.0
33
36
38
33
13
45
0
0
0
15
83
10
7
ing esters, Pd (II)-catalyzed coupling of lactams and
a
Reaction conditions: 10 mol % Cu source, 20 mol % ligand 9a, 1.0
8
alkenes, and elimination of thioacetals and phenylselenides
to prepare the N-acyl vinylogous urea side chain of paly-
toxin. In the latter methodology, Z-isomers were generally
b
equiv of vinyl iodide 4. HPLC yields using benzophenone as internal
standard. c Recovered 4 based on same HPLC analysis.
9
observed as the major, thermodynamic products. An over-
view of our current approach is depicted in Scheme 1. We
have developed two routes to N-acyl vinylogous ureas using
Cu(I)-catalyzed amidation. In route A, amidation of (E)-allyl-
â-iodoacrylate 4 affords N-acyl vinylogous carbamate 5.
Pd(0)-catalyzed deallylation11 of 5 should afford N-acyl
vinylogous carbamic (â-amidoacrylic) acid 6, a substructure
found in CJ-15,801. Amide coupling of 6 and amines
provides N-acyl vinylogous ureas 7. In route B, direct
amidation of 3-iodo-N-alkyl-2-propenamides 8 affords 7,
which may also form the corresponding Z-isomers under
thermodynamic control.9
slightly improved yield (entry 3). In contrast to copper
sources, different bases showed significant effects on reaction
yields (entries 3-5). The weaker base K
low conversion (entry 5). Although the highest yield (38%)
was obtained using Cs CO , severe decomposition of product
a and competitive dimerization of 4 were observed in
control experiments. Rb CO afforded optimal results em-
2 3
CO afforded very
1
0
2
3
12b
5
2
3
ploying an excess of amide (entry 6) and was used for further
amidation experiments. A variety of ligands, including
13c,16
3
,4,7,8-tetramethyl-1,10-phenanthroline 9b,
1,4-diaza-
1
,3-butadienes (DAB) 9c, bis(arylimino)acenaphthenes (Ar-
17
BIAN) 9d, and 2,2′-bipyridine 9e, were next evaluated to
further improve the yield of 5a (Figure 2). In this case,
Initial investigation of the cross-coupling of (E)-allyl-â-
iodo acrylate 4 and benzamide (Table 1) with copper(I)
thiophene-2-carboxylate (CuTC)1 as the catalyst and Cs
2
2
-
CO
3
as base afforded the desired product 5a in trace amounts.
13
However, addition of 1,10-phenanthroline 9a as ligand
improved the yield of 5a to 33% (entry 1). CuI and Cu-
14
15
(CH
3
CN)
4
PF
6
were also examined as Cu(I) sources, in
CN) PF afforded a
which case it was found that Cu(CH
3
4
6
(6) For representative publications on Cu(I)-catalyzed amide arylation,
see: (a) Klapars, A.; Antilla, J. C.; Huang, X., Buchwald, S. L. J. Am.
Chem. Soc. 2001, 123, 7727. (b) Klapars, A.; Huang, X., Buchwald, S. L.
J. Am. Chem. Soc. 2002, 124, 7421.
(
7) (a) Buckler, R. T.; Hartzler, H. E. J. Med. Chem. 1975, 18, 509. (b)
Boger, D. L.; Wysocki, R. J., Jr. J. Org. Chem. 1989, 54, 714.
8) Hosokawa, T.; Takano, M.; Kuroki, Y.; Murahashi, S. I. Tetrahedron
Lett. 1992, 33, 6643.
(
9) Suh, E. M.; Kishi, Y. J. Am. Chem. Soc. 1994, 116, 11205.
allyl alcohol: Boden, E. P.; Keck, G. E. J. Org. Chem. 1985, 50, 2394.
For preparation of the (Z)-isomer, see: (b) Ma, S.; Lu, X.; Li, Z. J. Org.
Chem. 1992, 57, 709.
Figure 2. Evaluation of 1,10-phenanthroline and diimine ligands.
Yields are based on HPLC analysis using benzophenone as internal
standard.
(
11) For a review, see: Guib e´ , F. Tetrahedron 1998, 54, 2967.
(12) (a) Allred, G. D.; Liebeskind, L. S. J. Am. Chem. Soc. 1996, 118,
2
2
748. (b) Zhang, S.; Zhang, D.; Liebeskind, L. S. J. Org. Chem. 1997, 62,
312.
(13) For use of 1,10-phenanthroline in Cu(I)-catalyzed C-N bond
formation, see: (a) Kiyomori, A.; Marcoux, J. F.; Buchwald, S. L.
Tetrahedron Lett. 1999, 40, 2657. (b) Wolter, M.; Klapars, A.; Buchwald,
S. L. Org. Lett. 2001, 3, 3803. (c) Kelkar, A. A.; Patil, N. M.; Chaudhari,
R. V. Tetrahedron Lett. 2002, 43, 7143.
phenanthroline ligand 9b showed noticeable improvement
over the parent 9a and was employed for subsequent
experiments.
18
(14) Diamine ligands including N,N′-dimethylethylenediamine (refs 5c,
6
4
) proved to be less effective than 1,10-phenanthroline for the transformation
f 5a.
(16) Nordmann, G.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 4978.
(17) For use of Ar-BIAN ligands in copper-catalyzed aziridination and
cyclopropanation, see: Llewellyn, D. B.; Adamson, D.; Arndtsen, B. A.
Org. Lett. 2000, 2, 4165.
(15) (a) Kubas, G. J. Inorg. Synth. 1979, 19, 90. (b) For use of Cu(CH3-
CN)4PF6 in C-O bond formation reactions, see: Kalinin, A.; Bower, J. F.;
Riebel, P.; Snieckus, V. J. Org. Chem. 1999, 64, 2986.
28
Org. Lett., Vol. 6, No. 1, 2004