Sequential copper-catalyzed vinylation/ cyclization: An efficient synthesis of functionalized oxazoles

Article abstract of DOI:10.1021/ol7024718

A modular and practical synthesis of highly substituted oxazoles has been developed. The transformation consists of a sequential copper-catalyzed amidation of vinyl halides followed by cyclization promoted by iodine. A wide variety of functionalized oxazo

Full text of DOI:10.1021/ol7024718

ORGANIC
LETTERS
2007
Vol. 9, No. 26
5521-5524
Sequential Copper-Catalyzed Vinylation/
Cyclization: An Efficient Synthesis of
Functionalized Oxazoles
Rube´n Mart´ın, Ana Cuenca, and Stephen L. Buchwald*
Department of Chemistry, Massachusetts Instituteof Technology,
Cambridge, Massachusetts 02139
sbuchwal@mit.edu
Received October 10, 2007
ABSTRACT
A modular and practical synthesis of highly substituted oxazoles has been developed. The transformation consists of a sequential copper-
catalyzed amidation of vinyl halides followed by cyclization promoted by iodine. A wide variety of functionalized oxazoles and polyazoles can
be obtained in a selective manner from simple and easily accessible precursors.
The ubiquity of oxazoles in a wide variety of natural
products1 and their pivotal role as synthetic intermediates
has attracted the attention of both industrial and academic
communities for decades.2 This interest arises from the fact
that a significant number of complex molecules, such as
Hennoxazoles, Diazonamide A, Micrococcin P1, Telomesta-
tin, or Leucamide A, display significant biological activity
as cytotoxic, antifungal, antibacterial, antitumor, and antiviral
agents (Figure 1).3 The discovery of their important phar-
macological properties stimulated substantial interest in the
chemistry and synthesis of these important heterocycles.
Figure 1. Linked polyazoles in natural products.
Classical procedures for their preparation include, among
others,4 the Cornforth protocol,5 decomposition of R-diazo-
carbonyl compounds in nitriles,6 pyrolysis of N-acylisox-
azolones,7 oxidations of oxazolines,8 or Robinson-Gabriel-
type reactions.9,10
In recent years, novel strategies based on metal-catalyzed
reactions11 have overcome most of the disadvantages of the
classic synthetic protocols, as harsh conditions are generally
(1) For recent reviews: (a) Jin, Z. Nat. Prod. Rep. 2006, 23, 464. (b)
Yeh, V. S. C. Tetrahedron 2004, 60, 11995.
(2) (a) Palmer, D. C.; Taylor, E. C. Oxazoles: Synthesis, Reactions and
Spectroscopy, Parts A & B, Chemistry of Heterocyclic Compounds;
JohnWiley & Sons: New York, 2004; Vol 60. (b) Maryanoff, C. A. In
Heterocyclic Compounds; Turchi, I. J., Ed.; Wiley & Sons: New York,
1986; Vol. 45, Chapter 5.
(3) For a review on the occurrence of linked polyazoles in natural
products, see: Riego, E.; Hernandez, D.; Albericio, F.; Alvarez, M. Synthesis
2005, 1907.
(4) For selected methods for the preparation of oxazoles, see: (a) Herrera,
A.; Mart´ınez-Alvarez, R.; Ramiro, P.; Molero, D.; Almy, J. J. Org. Chem.
2006, 71, 3026. (b) Morwick, T.; Hrapchak, M.; De Turi, M.; Campbell,
S. Org. Lett. 2002, 4, 2665. (c) Sisko, J.; Kassick, A. J.; Mellinger, M.;
Filan, J. J.; Allen, A.; Olsen, M. A. J. Org. Chem. 2000, 65, 1516.
(5) (a)Yokohama, M.; Menjo, Y.; Watanabe, M.; Togo, H. Synthesis
1994, 1467. (b) Cornforth, J. W.; Cornforth, R. H. J. Chem. Soc. 1947, 96.
(6) Doyle, M. P.; Buhro, W. E.; Davidson, J. G.; Elliot, R. C.; Hoekstra,
J. W.; Oppenhuizen, M. J. Org. Chem. 1980, 45, 3657.
10.1021/ol7024718 CCC: $37.00
© 2007 American Chemical Society
Published on Web 11/17/2007

avoided and readily available starting materials are utilized.
Although considerable efforts have been made, the develop-
ment of a milder and general route to access these nitrogen-
containing heterocycles in the presence of other sensitive
functional groups would be highly desirable. In this context,
Cu-catalyzed transformations provide a promising alternative,
mainly due to their high efficiency, mild reaction conditions,
and low cost.12,13
(Scheme 2).14a With no need for further optimization, 2a was
prepared in 94% yield. According to the general route
Scheme 2. Synthesis of Oxazoles through a Stepwise or a
Sequential Protocol
Recently, our research group has disclosed several se-
quential and cascade one-pot procedures for the synthesis
of nitrogen-containing heterocycles based on Cu-catalyzed
C-N bond-forming reactions.14 Herein, we report our studies
on the development of a general protocol for the synthesis
of highly substituted oxazoles by a sequential Cu-catalyzed
amidation of vinyl halides15 followed by intramolecular
cyclization promoted by iodine (Scheme 1).
Scheme 1. Synthesis of Oxazoles through a Sequential
Cu-Catalyzed Vinylation/Cyclization
depicted in Scheme 1, we next focused on the cyclization
of substrate 2a promoted by iodine, leading to intermediate
type I (Scheme 1). Although some electrophilic iodine
sources were also examined (ICl, NIS, and IPy2‚BF4), the
best results were obtained when using I2 in THF at 80 °C.16,17
In contrast, the use of I2 in THF at room temperature resulted
in a lower conversion of 2a. The choice of the base played
a crucial role; the use of 2 equiv of K2CO3 was found to be
optimal, whereas reactions with Cs2CO3, K3PO4, NaOtBu,
NaH, or NEt3 were much slower or produced only decom-
position products.18 All attempts to isolate an intermediate
of type I (Scheme 1) were unsuccessful. Instead, addition
of DBU to the reaction mixture promoted the formation of
3a in good overall yield. It is noteworthy that under these
reaction conditions 4a was not detected by 1H NMR
spectroscopy of the crude reaction mixture. Subsequent acidic
treatment was necessary to achieve isomerization, and
oxazole 4a was obtained in near quantitative yield. More
importantly, oxazole 4a could also be obtained from readily
available vinyl halide 1a without purification of the corre-
sponding intermediates, in an overall yield similar to that
achieved in the stepwise process.19
We started our work by examining the conversion of vinyl
bromide 1a to 2a following the conditions we originally
developed for the Cu-catalyzed amidation of vinyl bromides
(7) Prager, R. H.; Smith, J. A.; Weber, B.; Williams, C. M. J. Chem.
Soc., Perkin Trans. 1 1997, 2665.
(8) For some selected examples, see: (a) Williams, D. R.; Lowder, P.
D.; Gu, Y.-G.; Brooks, D. A. Tetrahedron Lett. 1997, 38, 331. (b) Meyers,
A. I.;Tavares, F. X. J. Org. Chem. 1996, 61, 8207.
(9) (a) Keni, M.; Tepe, J. J. J. Org. Chem. 2005, 70, 4211. (b) Pulici,
M.; Quartieri, F.; Felder, E. R. J. Comb. Chem. 2005, 7, 463.
(10) (a) Phillips, A. J.; Uto, Y.; Wipf, P.; Reno, M. J.; Williams, D. R.
Org. Lett. 2000, 2, 1165. (b) Brain, C. T.; Paul, J. M. Synlett 1999, 1642.
(c) Wipf, P.; Miller, C. P. J. Org. Chem. 1993, 58, 3604.
(11) For selected references, see: (a) Kumar, M. P.; Liu, R.-S. J. Org.
Chem. 2006, 71, 4951. (b) Davies, J. R.; Kane, P. D.; Moody, C. J. J. Org.
Chem. 2005, 70, 7305. (c) Black, D. A.; Arndtsen, B. A. Tetrahedron 2005,
61, 11317. (d) Stephen, A.; Hashmi, A. S. K.; Weyrauch, J. P.; Frey, W.;
Bats, J. W. Org. Lett. 2004, 23, 4391. (e) Milton, M. D.; Inada, Y.;
Nishibayashi, Y.; Uemura, S. Chem. Commun. 2004, 23, 2712. (f) Lee, Y.
R.; Yeon, S. H.; Seo, Y.; Kim, B. S. Synthesis 2004, 2787. (g) Arcadi, A.;
Cacchi, S.; Cascia, L.; Fabrizi, G.; Marinelli, F. Org. Lett. 2001, 3, 2501.
(h) Lee, J. C.; Song, I.-G. Tetrahedron Lett. 2000, 41, 5891.
(12) For recent reviews on Cu-catalyzed C-N bond-forming reactions,
see: (a) Beletskaya, I. P.; Cheprakov, A. V. Coord. Chem. ReV. 2004, 248,
2337. (b) Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42,
5400. (c) Kunz, K.; Scholz, U.; Ganzer, D. Synlett 2003, 2428.
(13) For a recent review on the synthesis of heterocycles by Cu-catalyzed
reactions, see: Chemler, S. R.; Fuller, P. H. Chem. Soc. ReV. 2007, 7, 1153.
(14) (a) Jones, C. P.; Anderson, K. W.; Buchwald, S. L. J. Org. Chem.
2007, 72, 7968. (b) Mart´ın, R.; Larsen, C. H.; Cuenca, A.; Buchwald, S. L.
Org. Lett. 2007, 9, 3379. (c) Rodr´ıguez-Rivero, M.; Buchwald, S. L. Org.
Lett. 2007, 9, 973. (d) Mart´ın, R.; Rodr´ıguez-Rivero, M.; Buchwald, S. L.
Angew. Chem., Int. Ed. 2006, 45, 7079.
Encouraged by these results, we sought to examine the
scope and generality of the sequential method (Table 1).
Although vinyl bromides afforded the corresponding ox-
azoles in good overall yields, the best results were ac-
complished by using vinyl iodides as coupling counterparts.
In these cases, the Cu-catalyzed amidation was better
(16) For some selected related cyclizations promoted by iodine, see: (a)
Hu, T.; Liu, K.; Shen, M.; Yuan, X.; Tang, Y.; Li, C. J. Org. Chem. 2007,
72, 8555. (b) Davis, F. A.; Song, M.; Augustine, A. J. Org. Chem. 2006,
71, 2779. (c) Waldo, J. P.; Larock, R. C. Org. Lett. 2005, 7, 5203. (d)
Williams, D. R.; Osterhout, M. H.; Amato, G. S. Heterocycles 2004, 64,
45. (e) Wei, L.-L.; Mulder, J. A.; Xiong, H.; Zificsak, C. A.; Douglas, C.
J.; Hsung, R. P. Tetrahedron 2001, 57, 459.
(17) The screening of the different reaction conditions was analyzed by
(15) (a) Jiang, L.; Job, G. E.; Klapars, A.; Buchwald, S. L. Org. Lett.
2003, 5, 3667. (b) Pan, X.; Cai, Q.; Ma, D. Org. Lett. 2004, 6, 1809. (c)
Shen, R.; Porco, J. A. Org. Lett. 2000, 2, 1333.
1H NMR spectroscopy of the crude reaction mixtures.
(18) The cyclization without base gave low conversions of 1a.
(19) For experimental details, see Supporting Information.
5522
Org. Lett., Vol. 9, No. 26, 2007

rise directly to the corresponding aromatic heterocycle
(entries 3-13); (2) the geometry of the starting vinyl halides
1b-m did not affect the outcome of the sequential metal-
catalyzed vinylation-cyclization, affording oxazoles 2b-m
with similar overall yield;20 (3) selective iodination of the
enamide leading to oxazoles 4 was observed when other
olefinic double bonds or even electron-rich heterocycles were
present (entries 3, 6-8, and 12); (4) although there have
been several reports on the intramolecular haloetherifications
of enamides,21using our protocol, however, no cyclic ether
was detected in the crude reaction mixture leading to 4c
(entry 3).22
Table 1. Scope of the Sequential One-Pot Cu-Catalyzed
Amidation-Iodination Protocola
As the synthesis of mono- or disubstituted oxazoles
afforded complex mixtures or in some instances, decomposi-
tion products, we decided to explore alternative routes for
their synthesis. Given our success on recent cascade Cu-
catalyzed reactions,14b,d we wondered whether it would be
possible to effect a domino Cu-catalyzed C-N/C-O bond-
forming reaction23 employing a 1,2-dihaloalkene substrate
as a means to access disubstituted oxazole (Scheme 3).24
Scheme 3. Synthesis of Disubstituted Oxazoles through a
Domino Cu-Catalyzed C-N/C-O Bond-Forming Reaction
a Reaction conditions: (1) vinyl iodide (X ) I, 1.0 equiv), amide (1.2
equiv), CuI (5 mol %), L (20 mol %), Cs2CO3 (1.5 equiv), THF (0.5 M) at
80 °C; 2) I2 (1.1 equiv), K2CO3 (2 equiv), 3-5 h, and then, DBU (2 equiv).
Cy ) cyclohexyl, Ph ) phenyl, TIPS ) triisopropylsilyl, DBU ) 1,8-
diazabicyclo[5.4.0]undec-7-ene, L ) N,N′-dimethylethylenediamine. b Yields
of the isolated products are the average of two runs. c Starting from vinyl
bromide, using K2CO3 (2 equiv) and toluene (0.5 M) at 100 °C for the
Cu-catalyzed amidation reaction. d ddition of p-TsOH‚H2O (10 mol %) to
the crude reaction mixture in toluene at 100 °C.
As shown in Scheme 3, disubstituted oxazoles bearing silyl
groups, aryl chlorides, or CF3 groups all could be prepared
in quantitative yields from readily available 1,2-dihaloalkene
1n by using essentially our standard protocol. The procedure
allows easy and complete control over the installation of
substitutents around the heterocyclic core, because the C-N
performed using Cs2CO3 and THF as the base and solvent,
respectively.15a With regard to thearyl halide, both electron-
rich and electron-deficient vinyl halides were equally efficient
and could be combined both with aromatic or aliphatic
amides. A variety of functional groups were tolerated in
either substrate, including silyl groups (entry 3), nitriles
(entries 6, 7, and 12), R,â-unsaturated moieties (entry 8),
esters (entries 9-11), aryl halides (entry 10), CF3 groups
(entry 13), and heterocycles(entries 3, 6, 7, and 11-13).
Polyazoles 4l and 4m (entries 12 and 13) could also be
prepared in good yields by using our standard protocol.
(20) Cu-catalyzed amidation of isomerically pure Z-1b and Z-1d gave
rise to mixtures of E- and Z-2b-d (∼4:1), as shown by NMR spectroscopy
of the crude reation mixtures. For similar isomerizations of enamides, see:
(a) Reference 14b. (b) Wallace, D. J.; Klauber, D. J.; Chen, C.-y.; Volante,
R. P. Org. Lett. 2003, 5, 4749.
(21) For some examples on halo-etherification and halo-lactonization of
enamides, see: (a) Rudler, H.; Denise, B.; Xu, Y.; Parlier, A.; Vaissermann,
J. Eur. J. Org. Chem. 2005, 3724. (b) Rudler, H.; Denise, B.; Parlier, A.;
Daranb, J. Chem. Commun. 2002, 9, 940. (c) Mart´ın-Lo´pez, M. J.; Bermejo-
Gonza´lez, F. Tetrahedron 1998, 54, 12379. (d) Williams, R.; Milreis, G.
F. Tetrahedron Lett. 1990, 31, 4297. (e) Shin, C.; Sato, Y.; Yoshimura, J.
Tetrahedron Lett. 1981, 22, 2401.
(22) For a recent intramolecular halo-etherification using silyl ethers,
see: Ko, C.; Hsung, R. P.; Al-Rashid, Z. F.; Feltenberger, T. L.; Yang,
J.-H.; Wei, Y.; Zificsak, C. A. Org. Lett. 2007, 9, 4459.
(23) For related procedures using benzene derivatives, see: (a) Evindar,
G.; Batey, R. A. J. Org. Chem. 2006, 71, 1802. (b) Altenhoff, G.; Glorius,
F. AdV. Synth. Catal. 2004, 346, 1661.
(24) During the preparation of this manuscript, a synthesis of oxazoles
from1,2-dihaloalkene derivatives was published: Schuh, K.; Glorius, F.
Synthesis 2007, 2297.
Some important highlights of this transformation are (1)
addition of p-TsOH‚H2O to induce isomerization to the
oxazole product was not necessary when aromatic or
electron-withdrawing groups were present in position 4 and
5 of the oxazole ring. In this case, treatment with DBU gave
Org. Lett., Vol. 9, No. 26, 2007
5523

bond-forming reaction takes place exclusively at the vinyl
iodide moiety. A limitation of this method, however, is the
lack of a general route for the synthesis of the requisite 1,2-
dihaloalkene substrates.
In summary, a practical and mild new method for the
synthesis of highly functionalized oxazoles and polyazoles
has been developed. The readily availability of the precursors
and the functional group tolerance should make this method
attractive to synthetic chemists. Further investigations into
the application of Cu-catalyzed vinylation processes for the
synthesis of other heterocycles are currently underway in
our laboratory.
Acknowledgment. We thank the National Institutes of
Health (GM58160) for support of this work. R.M and A.C.
thank the Spanish M.E.C for postdoctoral fellowships.
Chemetall is acknowledged for a generous gift of Cs2CO3.
We are also indebted to to Merck, Amgen, and Boehringer-
Ingelheim for unrestricted support.
Supporting Information Available: Experimental pro-
cedures and spectral data for all compounds. This material
isavailable free of charge via the Internet at http://pubs.acs.
org.
OL7024718
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