Synthesis of functionalized oxazolones by a sequence of Cu(ll)- And Au(l)-catalyzed transformations

Article abstract of DOI:10.1021/ol703077g

A study concerning a two-step sequence leading to the formation of diversely 1,5-disubstituted oxazolones is described. The mild conditions employed allow the efficient and rapid synthesis of a variety of such compounds via an initial Cu(II)-catalyzed coupling of a bromoalkyne with a secondary tert-butyloxycarbamate followed by a Au(l)-catalyzed cycloisomerization of the N-alkynyl tert-butyloxycarbamates thus obtained.

Full text of DOI:10.1021/ol703077g

ORGANIC
LETTERS
2008
Vol. 10, No. 5
925-928
Synthesis of Functionalized Oxazolones
by a Sequence of Cu(II)- and
Au(I)-Catalyzed Transformations
Florin M. Istrate, Andrea K. Buzas, Igor Dias Jurberg, Yann Odabachian, and
Fabien Gagosz*
Laboratoire de Synthe`se Organique, UMR 7652 CNRS/Ecole Polytechnique,
Ecole Polytechnique, 91128 Palaiseau, France
gagosz@dcso.polytechnique.fr
Received December 21, 2007
ABSTRACT
A study concerning a two-step sequence leading to the formation of diversely 1,5-disubstituted oxazolones is described. The mild conditions
employed allow the efficient and rapid synthesis of a variety of such compounds via an initial Cu(II)-catalyzed coupling of a bromoalkyne with
a secondary tert-butyloxycarbamate followed by a Au(I)-catalyzed cycloisomerization of the N-alkynyl tert-butyloxycarbamates thus obtained.
Oxazolones and their derivatives are attractive building
blocks in organic synthesis. They have been sucessfully
employed in a range of transformations mostly as an alkene
unit in intramolecular Pauson-Khand reactions,1 [4 + 2]
cycloadditions,2 palladium-catalyzed coupling reactions,3
radical additions or cyclizations,4 and in hydrogenation
reactions for the synthesis of functionalized oxazolidinones.5
The oxazolone motif is also found in a variety of synthetic
substances exhibiting a wide range of pharmacological
activities.6 Surprisingly, there are only a few methods to
synthesize polysubstituted oxazolones. Most use 1,2-ami-
noketone derivatives as starting materials and involve either
high temperature,7 strong basic8 or acidic conditions,9 or the
use of toxic carbonylating reagents10 which are not always
compatible with the substitution pattern of the substrates.
Gold(I) complexes have emerged as efficient and mild
catalysts11 for the synthesis of various oxygen-containing
(6) (a) Nam, N.-H.; Kim, Y.; You, Y.-J.; Hong, D.-H.; Kim, H.-M.; Ahn,
B.-Z. Bioorg. Med. Chem. Lett. 2001, 11, 3073-3076. (b) Kudo, N.;
Taniguchi, M.; Furuta, S.; Sato, K.; Endo, T.; Honma, T. J. Agric. Food
Chem. 1998, 46, 5305-5312. (c) Puig, C.; Crespo, M. I.; Godessart, N.;
Feixas, J.; Ibarzo, J.; Jimenez, J.-M.; Soca, L.; Cardelus, I.; Heredia, A.;
Miraplex, M.; Puig, J. J. Med. Chem. 2000, 43, 214-223. (d) Pereira, E.
R.; Sancelme, M.; Voldoire, A.; Prudhomme, M. Bioorg. Med. Chem. Lett.
1997, 7, 2503-2506.
(7) Krieg, B.; Lautenschlaeger, H. Justus Liebigs Ann. Chem. 1976, 788-
792.
(8) Lenz, G. R.; Costanza, C. J. Org. Chem. 1988, 53, 1176-1183.
(9) Aichaoui, H.; Poupaert, J. H.; Lesieur, D.; Henichart, J.-P. Tetrahe-
dron 1991, 47, 6649-6654.
(1) (a) Nomura, I.; Mukai, C. J. Org. Chem. 2004, 69, 1803-1812. (b)
Nomura, I.; Mukai, C. Org. Lett. 2002, 4, 4301-4304.
(2) (a) D’Andrea, S. V.; Freeman, J. P.; Szmuszkovicz, J. J. Org. Chem.
1990, 55, 4356-4358. (b) Hashimoto, N.; Ishizuka, T.; Kunieda, T.
Tetrahedron Lett. 1994, 35, 721-724.
(3) Choshi, T.; Fujimoto, H.; Sugino, E.; Hibino, S. Heterocycles 1996,
43, 1847-1854.
(4) (a) Yuasa, Y.; Ando, J.; Shibuya, S. J. Chem. Soc., Perkin Trans. 1
1996, 465-474. (b) Butora, G.; Hudlicky, T.; Fearnley, S. P.; Gum, A. G.;
Stabile, M. R.; Abboud, K. Tetrahedron Lett. 1996, 37, 8155-8158. (c)
Hoshimoto, S.; Matsunaga, H.; Wada, M.; Kunieda, T. Chem. Pharm. Bull.
2002, 50, 435-438.
(5) (a) Shono, T.; Matsumura, Y.; Kanazawa, T. Tetrahedron Lett. 1983,
24, 4577-4580. (b) Yonezawa, Y.; Shin, C.; Ohtsu, A.; Yoshimura, J. Chem.
Lett. 1982, 1171-1172.
(10) For selected examples, see: With phosgene (a) Hamad, M. O.;
Kiptoo, P. K.; Stinchcomb, A. L.; Crooks, P. Bioorg. Med. Chem. 2006,
14, 7051-7061. With triphosgene (b) Makino, K.; Okamoto, N.; Hara, O.;
Hamada, Y. Tetrahedron: Asymmetry 2001, 12, 1757-1762.
(11) For recent reviews on gold catalysis, see: (a) Gorin, D. J.; Toste,
F. D. Nature 2007, 46, 395-403. (b) Fu¨rstner, A.; Davies, P. W. Angew.
Chem., Int. Ed. 2007, 46, 2-42. (c) Hashmi, S. A.; Huchings, G. J. Angew.
Chem., Int. Ed. 2006, 45, 7896-7936.
10.1021/ol703077g CCC: $40.75
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Published on Web 02/02/2008

heterocycles12 by intramolecular addition of an oxygenated
nucleophile onto an alkyne or an allene. In this respect,
special attention has been paid to the tert-butyloxycarbonyl
moiety which was used as the nucleophilic partner in the
gold-catalyzed formation of butenolides,13a dioxanones,13b,c
dioxolanones,13d,e and oxazolidinones.13f
Following our ongoing efforts in developing new gold-
catalyzed transformations,14 we now report that diversely
functionalized oxazolones could be efficiently synthesized
by a gold(I) isomerization of N-alkynyl tert-butyloxycar-
bamates.
Ph3PAuNTf2 (Scheme 1, eq 2).16 Even if this procedure
proved to be efficient (65-93% yield) and led to the desired
products under mild conditions (0 °C or rt), we believed that
our sequence could present a major advantage. Given the
restricted access to functionalized iodonium salt 5 and its
inefficient coupling with 3 (27-51%), it appeared to us that
the Cu(II)-catalyzed coupling of 1 with 2 might advanta-
geously broaden the scope of the transformation.17
We first investigated the Cu(II)-catalyzed step leading to
the formation of the N-alkynyl tert-butyloxycarbamate 3.
Although numerous examples of direct copper-catalyzed
cross-coupling of an alkynyl bromide with a carbamate, a
sulfonamide, or an amide are described in the literature,15
only one example of such a reaction was previously reported
using a tert-butyloxycarbamate such as 2 as the reactant, and
the yield was very low (12%).15a
Scheme 1. Synthetic Approach to Functionalized Oxazolones
In spite of the poor yield, attributed by the authors to steric
hindrance,15a we decided to study this cross-coupling between
a series of functionalized bromoalkynes 1a-g and tert-
butyloxycarbamates 2a-i (Figure 1).
Our synthetic approach, depicted in Scheme 1 (eq 1), relies
on a two-step sequence. The initial Cu(II)-catalyzed coupling
of a bromoalkyne 1 with a tert-butyloxycarbamate 2,15 would
lead to the formation of an N-alkynyl tert-butyloxycarbamate
3. A subsequent 5-endo gold-catalyzed isomerization of 3
would furnish the desired oxazolone 4 (Scheme 1, eq 1).
Indeed, while this work was in progress, Hashmi and co-
workers validated this approach and reported that 3 could
actually be isomerized into oxazoles 4, using 5 mol % of
Figure 1. Bromoalkynes and tert-butyloxycarbamates used in the
Cu(II)-catalyzed cross-coupling reaction.
(12) For selected examples, see: Furans (a) Hashmi, A. S. K.; Schwarz,
L.; Choi, J.-H.; Frost, T. M. Angew. Chem., Int. Ed. 2000, 39, 2285-2289.
(b) Yao, T.; Zhang, X.; Larock, R. C. J. Org. Chem. Soc. 2005, 70, 7679-
7685. (c) Hashmi, A. S. K.; Sinha, P. AdV. Synth. Catal. 2004, 346, 432-
438. (d) Liu, Y.; Song, F.; Song, Z.; Liu, M.; Yan, B. Org. Lett. 2005, 7,
5409-5412. (e) Istrate, F.; Gagosz, F. J. Org. Chem. 2007, 73, 730-733.
Oxazoles and oxazolines (f) Hashmi, A. S. K.; Rudolph, M.; Shymura, S.;
Visus, J.; Frey, W. Eur. J. Org. Chem. 2006, 4905-4909. (g) Hashmi, A.
S. K.; Weyrauch, J. P.; Frey, W.; Bats, J. W. Org. Lett. 2004, 6, 4391-
4394. (h) Milton, M. D.; Inada, Y.; Nishibayashi, Y.; Uemura, S. Chem.
Commun. 2004, 2712-2713. (i) Kang, J. E.; Kim, H.-B.; Lee, J.-W.; Shin,
S. Org. Lett. 2006, 8, 3537-3540. Lactones and furanones (j) Genin, E.;
Toullec, P. Y.; Antoniotti, S.; Brancour, C.; Geneˆt, J.-P.; Michelet, V. J.
Am. Chem. Soc. 2006, 128, 3112-3113. (k) Liu, Y.; Liu, M.; Guo, S.; Tu,
H.; Zhou, Y.; Gao, H. Org. Lett. 2006, 8, 3445-3448.
(13) (a) Kang, J. E.; Lee, E.-S.; Park, S.-I.; Shin, S. Tetrahedron Lett.
2005, 46, 7431-7433. (b) Shin, S. Bull. Korean Chem. Soc. 2005, 26,
1925-1926. (c) Kang, J;-E.; Shin, S. Synlett 2006, 717-720. (d) Buzas,
A.; Gagosz, F. Org. Lett. 2006, 8, 515-518. (e) Lim, C.; Kang, J.-E.; Lee,
J.-E.; Shin, S. Org. Lett. 2007, 9, 3539-3542. (f) Buzas, A.; Gagosz, F.
Synlett 2006, 2727-2730. (g) Robles-Machin, R.; Adrio, J.; Carretero, J.
C. J. Org. Chem. 2006, 71, 5023-5026. (h) Lee, E.-S.; Yeom H.-S., Hwang
J.-H., Shin S. Eur. J. Org. Chem. 2007, 3503-3507.
Using slightly modified reaction conditions15a (20 mol %
of CuSO4·5H2O and 40 mol % of 1,10-phenanthroline as the
ligand with K3PO4 as the base in toluene at 80 °C), we were
delighted to see that the cross-coupling was generally much
more efficient than previously reported (Table 1). A wide
range of N-alkynyl tert-butyloxycarbamates 3a-v containing
various functionalities were thus synthesized in yields ranging
(15) For leading references dealing with the Cu(II)-catalyzed coupling
of bromoalkynes with carbamates, see: (a) Zhang, X.; Zhang, Y.; Huang,
J.; Hsung, R. P.; Kurtz, K. C. M.; Oppenheimer, J.; Petersen, M. E.;
Sagamanove, I. K.; Shen, L.; Tracey, M. R. J. Org. Chem. 2006, 71, 4170-
4177. (b) Zhang, Y.; Hsung, R. P.; Tracey, M. R.; Kurtz, K. C. M.; Vera,
E. L. Org. Lett. 2004, 6, 1151-1154. (c) Frederick, M. O.; Mulder, J. A.;
Tracey, M. R.; Hsung, R. P.; Huang, J.; Kurtz, K. C. M.; Shen, L.; Douglas,
C. J. J. Am. Chem. Soc 2003, 125, 2368-2369. (d) Dunetz, J. R.; Danheiser,
R. L. Org. Lett. 2003, 5, 4011-4014.
(16) Hashmi, A. S. K.; Salathe´, R.; Frey, W. Synlett 2007, 1763-1766.
For another gold-catalyzed transformation of alkynylamides, see: Couty,
S.; Meyer, C. Cossy, J. Angew. Chem., Int. Ed. 2006, 45, 6726-6730.
(17) The reaction reported by Hashmi and coworkers (ref 16) was limited
to the use of substrates 3 bearing a hydrogen or a silyl group on the akyne
and another electron-withdrawing group (Boc, Ts, Piv) on the nitrogen atom.
(14) (a) Istrate, F., Gagosz, F. Org. Lett. 2007, 9, 16, 3181. (b) Buzas,
A.; Istrate, F.; Gagosz, F. Angew. Chem., Int. Ed. 2007, 46, 1141-1144.
(c) Buzas, A.; Gagosz, F. J. Am. Chem. Soc 2006, 128, 12614-12615. (d)
Buzas, A.; Istrate, F.; Gagosz, F. Org. Lett. 2007, 9, 985-988. (e) Buzas,
A.; Istrate, F.; Gagosz, F. Org. Lett. 2006, 8, 1957-1959.
926
Org. Lett., Vol. 10, No. 5, 2008

Table 1. Cu(II)-Catalyzed Formation of N-Alkynyl
tert-Butyloxycarbamatesa
Table 2. Optimization of the Catalytic Systema
temp.
(°C)
convrsn. yield
entry
catalyst
time
(%)b
(%)
1
2
3
4
5
PPh3AuNTf2
20
20
40
20
40
7 h
63
85
100
100
100
28c
52d
40d
69d
74c
entry
1
2
time (h)
product
yield (%)b
(pCF3Ph)3PAuNTf2
72 h
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
1c
1d
1d
1d
1e
1e
1e
1e
1f
2a
2b
2c
2d
2e
2g
2h
2i
2a
2a
2g
2a
2c
2h
2a
2f
40
16
18
16
48
48
36
48
38
52
48
67
67
67
65
48
72
62
45
62
48
48
3a
3b
3c
3d
3e
3f
3g
3h
3i
80
65
68
48
22
62
70
23
24
75
69
72
80
50
55
49
49
48
88
72
74
65
(pCF3Ph)3PAuNTf2
2.5 h
4.5 h
30 min
-
-
[Ph3P-Au-(NCCH3)]+SbF6
[Ph3P-Au-(NCCH3)]+SbF6
a Reaction conditions: 0.5 M substrate in CH2Cl2. b Estimated by 1H
NMR. c Isolated yield. d Estimated by 1H NMR on the crude reaction
mixture.
The reaction proved to be quite general, and various
3j
3k
3l
N-alkynyl tert-butyloxycarbamate 3a-v reacted using 1 mol
-
% of [Ph3P-Au-(NCCH3)]+SbF6 as the catalyst to furnish
the corresponding oxazolones 4a-v in generally good yields
(38-94%) (Table 3). The time required to reach completion
3m
3n
3o
3p
3q
3r
3s
3t
2g
2h
2a
2g
2a
2f
Table 3. Au(I)-Catalyzed Formation of Oxazolonesa
1f
1g
1g
3u
3v
a
Reaction conditions: 1 (1 equiv), 2 (1.2 equiv), CuSO4·5H2O (0.2
equiv), 1,10-phenanthroline (0.4 equiv), K3PO4 (2.4 equiv) in toluene (0.33
M based on 1) at 80 °C. Isolated yield.
b
from 22% to 88%.18 To the best of our knowledge, this
procedure represents the first general entry into synthesizing
such compounds.
Having in hands an efficient procedure for the formation
of 3, we next focused our attention on the second step of
the sequence, using carbamate 3j as a model substrate (Table
2). While Ph3PAuNTf219 proved to be efficient in the proce-
dure reported by Hashmi and co-workers,16 poor results were
obtained in our case with 1 mol % of this catalyst (entry 1).
19
The use of the more electrophilic (pCF3Ph)3PAuNTf2
improved the conversion, but the yield of the desired
oxazolone 4j remained modest (40-52%, entries 2-3).
Finally, the cationic [Ph3P-Au-(NCCH3)]+SbF6- 20 complex,
developed by Echavarren and co-workers, proved to be the
catalyst of choice (entries 4-5). Under optimal conditions
(1 mol % of [Ph3P-Au-(NCCH3)]+SbF6- in dichloromethane
at 40 °C), oxazolone 4j could be isolated in 74% yield. In
the light of these preliminary results, experimental conditions
as mentioned in entry 5 were retained for the study of the
scope of this transformation.21
(18) The poor yields obtained in the case of 3e and 3h may be attributed
to a greater steric hindrance around the nitrogen center.
(19) Mezailles, N.; Ricard, L.; Gagosz, F. Org. Lett. 2005, 7, 4133-
4136.
(20) Nieto-Oberhuber, C.; Lo´pez, S.; Mun˜oz, M. P.; Jime´nez-Nu´n˜ez, E.;
Echavarren, A. M. Chem. Eur. J. 2006, 11, 5916-5923.
a Reaction conditions: 3 (1 equiv), [(Ph3P)Au(NCMe)]SbF6 (0.01 equiv)
in refluxing CH2Cl2 (0.5 M). b Isolated yield. c Yield determined by 1H
NMR on the crude reaction mixture using 1,3,5-trimethoxybenzene as an
internal standard.
Org. Lett., Vol. 10, No. 5, 2008
927

was in most cases shorter than 2 h. Various substituted aryl,
benzyl, or acetyl groups were tolerated on the nitrogen atom.
The experimental conditions were also compatible with a
variety of commonly used functionnal groups such as a
propargylic acetate (3o-r), a silyl ether (3s,t), or an alkene
(3l-n and 3u,v). Substrates possessing a benzyl group on
the nitrogen atom (3k, 3q, and 3t) furnished the desired
products in moderate yields (38-50%),22 but surprisingly,
these proved to be instable and could not be isolated.
In the cases where the formation of the oxazolone was
rapid enough (substrates 3a-d), we attempted to run the
reaction using 5 mol % of AgNTf2 as the catalyst (eq 3).
We were delighted to see that the corresponding oxazolones
4a-d could be obtained in excellent yields (88-96%). These
conditions were, however, not general. Substrate 3o led, for
instance, to a poor 36% yield of oxazolone 4o (eq 4).
Scheme 2. Proposed Mechanism
vinyl-gold species 7, which is subsequently protonated to
finally furnish oxazolone 4.
In summary, we have developed an efficient two-step
sequence for the synthesis of oxazolones from readily
available bromoalkynes and tert-butyloxycarbamates. The
Cu(II)-catalyzed cross-coupling reaction proved to be a
general and efficient method for the preparation of various
N-alkynyl tert-butyloxycarbamates. These were converted
under mild conditions into a range of diversely substituted
oxazolones by using a low loading of a gold(I) catalyst.
Further studies related to the gold-catalyzed isomerization
of other N-alkynyl carbamates are underway and will be
reported in due course.
To account for these observations, a mechanism for the
formation of the oxazolones is proposed in Scheme 2. Gold-
(I) activation of the triple bond in N-alkynyl tert-butyloxy-
carbamate 3 promotes the formation of the stabilized cationic
species 6. Fragmentation of the C-O bond of the tert-
butyloxy group in 6 then leads to the formation of the neutral
Acknowledgment. We thank Prof. S. Z. Zard (CNRS/
Ecole Polytechnique) for helpful discussions and Rhodia
Chimie Fine for a gift of HNTf2.
Supporting Information Available: Experimental pro-
cedures and spectral data for new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
(21) Brønsted acid (HNTf2) did not promote the reaction and led to
extensive decomposition of the substrate. Silver salts (AgNTf2, AgSbF6)
did promote the reaction (53%, 64%) but their efficiency proved limited to
a few substrates (see eqs 1 and 2).
(22) The yield was determined by 1H NMR on the crude reaction mixture.
OL703077G
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Org. Lett., Vol. 10, No. 5, 2008