Efficient suzuki and stille reactions for regioselective strategies of incorporation of the 1,3-oxazole heterocycle: Mild desulfonylation for the synthesis of C-4 and C-5 monosubstituted oxazoles

Article abstract of DOI:10.1055/s-0029-1220128

Suzuki and Stille cross-coupling reactions are surveyed for site-selective C-4 and C-5 elaboration of 2-(phenylsulfonyl)-1,3-oxazole derivatives. Conditions for mild reductive desulfonylations provide for direct incorporation of the intact oxazole heteroc

Full text of DOI:10.1055/s-0029-1220128

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Synlett. Author manuscript; available in PMC 2011 July 1.
Published in final edited form as:
Synlett. 2010 July 1; 2010(11): 1641–1646. doi:10.1055/s-0029-1220128.
Efficient Suzuki and Stille Reactions for Regioselective Strategies
of Incorporation of the 1,3-Oxazole Heterocycle. Mild
Desulfonylation for the Synthesis of C-4 and C-5 Monosubstituted
Oxazoles
*
David R. Williams and Liangfeng Fu
Department of Chemistry, Indiana University, 800 East Kirkwood Avenue, Bloomington, IN
47405-7102, USA
Abstract
Suzuki and Stille cross-coupling reactions are surveyed for site-selective C-4 and C-5 elaboration of
2-(phenylsulfonyl)-1,3-oxazole derivatives. Conditions for mild reductive desulfonylations provide
for direct incorporation of the intact oxazole heterocycle through bonding at C-4 and C-5.
Keywords
cross-coupling reactions; arylation; alkenylation; reductive desulfonylation
1
Oxazoles represent an important class of five-membered heterocycles. In recent years, this
heterocyclic system has frequently been identified as a significant structural feature, embedded
2
within the architecture of complex natural products. Several interesting antibiotics
prominently display 1,3-oxazoles as a result of cyclodehydration of serine or threonine residues
3
in the course of biosynthesis. Not surprisingly, a number of cyclodehydration strategies,
beginning with acyclic amides, have been developed to provide for the de novo preparation of
4
substituted 1,3-oxazoles. These pathways for oxazole synthesis have limitations, which are
often based on the reactivity and the availability of the starting amide precursors. As a result,
there is a need for generally applicable techniques, which permit regioselective incorporation
of the intact oxazole heterocycle. Our studies have documented a synthetic design utilizing 2-
(phenylsulfonyl)-1,3-oxazole (1) for site specific arylations, alkenylations, and alkylations of
the heterocyclic ring leading to the production of 2,4- and 2,5-disubstituted oxazoles 2 as well
as 4- and 5-monosubstituted-1,3-oxazoles 3 (Scheme 1).
Several laboratories have described examples of cross-coupling processes of arylation and
5
alkenylation at C-2 of the oxazole nucleus, and Stille reactions of 2-phenyl-1,3-oxazole have
6
led to C-4 and C-5 arylation reactions. Recently, Stambuli and coworkers have described the
selective C-5 deprotonation of 2-methylthio-1,3-oxazole with tert-butyllithium affording
7
access to 2,5-disubstituted oxazoles. These efforts have advanced the previous studies of
8
Shafer and Molinski, as well as a previous report by Marino and Nguyen disclosing the
9
regioselective allylation of 2-(n-butylthio)-1,3-oxazole.
Fax +1(812)8558300; williamd@indiana.edu.
Supporting Information for this article is available online at http://www.thieme-connect.com/ejournals/toc/synlett.

Williams and Fu
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In 1997, we reported the site-selective (C-4) deprotonation of 1-[2′-(trimethylsilyl)
ethoxymethyl]-2-(phenylsulfonyl)-imidazole (4), and subsequent reactions with a variety of
10
electrophiles (Scheme 2). As illustrated with the formation of 6, mild removal of SEM
protection and reductive desulfonation with 2% Na(Hg) provided a scheme for imidazole
incorporation.
Our studies also examined the analogous (C-5) ring metalation of 2-(phenylsulfonyl)-1,3-
oxazole and alkylations of this reactive carbanion. Subsequent reactions for displacement of
the 2-(phenylsulfonyl) group have established a general route to 2,5-disubstituted-1,3-
11
oxazoles. Prior literature reveals relatively little information regarding useful methods for
C-4 and C-5 halogenation of oxazoles.12 However, the well-behaved carbanion from 7
(Scheme 3, R = SO Ph, X = Li) facilitates convenient halogenation and stannylation reactions
2
11
yielding 9 and 10, respectively. Furthermore, we have shown that 5-bromo-2-
(phenylthio)-1,3-oxazole (8) undergoes a facile base-induced isomerization, characterized as
13
a halogen dance rearrangement to provide access to the 4-bromo-1,3-oxazole 11 (85%). In
this letter, we have described a survey of Suzuki and Stille cross-coupling reactions, which
demonstrate the utility of these derivatives for a convenient general preparation of 2,5- and
2,4-disubstituted oxazoles. In addition, we have documented the use of sodium hydrosulfite
for reductive desulfonylations to yield C-4 and C-5 monosubstituted-1,3-oxazoles.
A compilation of our results for Suzuki cross-coupling arylation reactions is summarized in
Table 1. These reactions have evaluated the effective use of the C-5 iodide 9 and C-4 bromide
11 with a series of commercially available arylboronic acids. High yields of the expected
products are uniformly obtained using 10 mol% Pd(PPh ) at 70 °C to 80 °C in a mixture of
3 4
THF and toluene containing aqueous Na CO or K CO (2:2:1 by volume).
2
3
2
3
The effective coupling of iodide 9 or bromide 11 with boronic acids suggested its use as a
cross-coupling partner in Stille reactions. Indeed, this expection is confirmed by the Stille
reactions of 9 and 11 with tri-n-butylvinylstannane (1.2 equiv) under standard conditions to
afford oxazoles 20 and 21 in 85% and 74% yields, respectively (Table 2). Likewise, Stille
coupling also proceeded uneventfully to afford the trisubstituted alkene 22.
To survey the utility of Stille cross-coupling reactions of the readily available 5-(tri-n-
butylstannyl)oxazole 10 (from Scheme 3), we employed a variety of aryl, alkenyl and allyl
halides. The results of this study are summarized in Table 3. In this regard, the Stille reaction
leading to the C-5 linked bisoxazole 24 (entry 3) is particularly noteworthy, and entry 4
documents the facile formation of the conjugated trisubstituted alkene 25 in excellent yield.
Entry 6 indicates that π-allyl Stille reactions of stannane 10 will produce regioisomeric
products. However, prenylation predominantly leads to bond formation at the less hindered
allylic position giving 27 as the major isomer (ratio 7:1).
Finally, our studies have found conditions for the mild reductive desulfonylation of 2-
(phenylsulfonyl)-1,3-oxazoles using aqueous sodium hydrosulfite. A survey of reactions in
Table 4 demonstrates the effective replacement of the C-2 sulfonyl substituent with hydrogen.
Reactions are conducted with excess sodium hydrosulfite (5 equiv) in aqueous N-
methylpyrrolidone (1:1 by volume) in the presence of sodium bicarbonate at 80 °C. These
reductions were complete within three hours and have consistently provided good yields of the
desired 4- and 5-monosubstituted-1,3-oxazoles. Common O-protecting ethers (PMB and THP)
are stable under the reaction conditions, whereas the labile N-Boc protection of the indoles
31 and 34 is cleaved via hydrolysis.
In summary, our studies of ring metalation of the oxazole nucleus have provided convenient
access to C-4 and C-5 halogenation and C-5 stannylation for use in cross-coupling reactions.
A survey of Suzuki and Stille processes for arylation and alkenylation demonstrates broad
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Williams and Fu
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versatility of these oxazole derivatives as coupling partners, and illustrates a general strategy
for the regioselective preparation of 2,4- and 2,5-disubstituted-1,3-oxazoles. These findings
provide for the incorporation of the intact oxazole heterocycle through bonding at C-4 or C-5
by using the phenylsulfonyl moiety as a blocking unit of the reactive C-2 position. Mild
conditions for reductive desulfonylation have been described. Applications for natural product
synthesis will be reported in due course.
Supplementary Material
Refer to Web version on PubMed Central for supplementary material.
Acknowledgments
We acknowledge the support of Indiana University and partial support of the National Institute of Health (GM 042897).
We acknowledge the assistance of Fese Mokube (Indiana University) for the preparation of vinyl stannane in Entry
3, Table 2.
References and Notes
1. Taylor, EC.; Wipf, P. Oxazoles: Synthesis, Reactions, And Spectrometry. John Wiley & Sons;
Hoboken: 2003.
2. For examples, see: (a) Ichiba T, Yoshida WY, Scheuer PJ, Higa T, Gravalos DG. J Am Chem Soc
1991;113:3173. (b) Shin-ya K, Wierzba K, Matsuo K, Ohtani T, Yamada Y, Furihata K, Hayakawa
Y, Seto H. J Am Chem Soc 2001;123:1262. [PubMed: 11456694] (c) Searle PA, Molinski TF. J Am
Chem Soc 1995;117:8126. (d) Rosener JA, Scheuer PJ. J Am Chem Soc 1986;108:846. (e) Dalisay
DS, Rogers EW, Edison AS, Molinski TF. J Nat Prod 2009;72:732. [PubMed: 19254038] (f) Li J,
Burgett AWG, Esser L, Amezcua C, Harran PG. Angew Chem Int Ed 2001;40:4770. (g) Irschik H,
Jansen R, Gerth K. J Antibiot 1995;48:31. [PubMed: 7868386]
3. For examples, see: (a) Kanoh K, Matsuo Y, Adachi K, Imagawa H, Nishizawa M, Shizuri Y. J Antibiot
2005;58:289. [PubMed: 15981418] (b) Perez LJ, Faulkner DJ. J Nat Prod 2003;66:247. [PubMed:
12608858] (c) Kohno J, Kameda N, Nisho M, Kinumaki A, Komatsubara S. J Antibiot 1996;49:1063.
[PubMed: 8968404]
4. Phillips AJ, Uto Y, Wipf P, Reno MJ, Williams DR. Org Lett 2000;2:1165. [PubMed: 10804580] (b)
For the initial application of this methodology in the synthesis of hennoxazole A, see: Williams DR,
Brooks DA, Berliner MA. J Am Chem Soc 1999;121:1303. (c) Wipf P, Rahman LT, Rector SR. J Org
Chem 1998;63:7132. [PubMed: 11672349] (d) Wipf P, Miller CP. J Org Chem 1993;58:3604.
5. (a) Besselièvre F, Piguel S, Mahuteau-Betzer F, Grierson DS. Org Lett 2008;10:4029. [PubMed:
18720988] (b) Flegeau EF, Popkin ME, Greaney MF. Org Lett 2008;10:2717. [PubMed: 18540631]
(c) Hodgetts KJ, Kershaw MT. Org Lett 2002;4:2905. [PubMed: 12182585] (d) Smith AB III, Minbiole
KP, Freeze S. Synlett 2001:1739.
6. Hämmerle J, Spina M, Schnürch M, Mihovilovic MD, Stanetty P. Synthesis 2008:3099.
7. Lee K, Counceller CM, Stambuli JP. Org Lett 2009;11:1457. [PubMed: 19239243]
8. Shafer CM, Molinski TF. J Org Chem 1998;65:551. [PubMed: 11672044]
9. Marino JP, Nguyn HN. Tetrahedron Lett 2003;44:7395.
10. Phillips JG, Fadnis L, Williams DR. Tetrahedron Lett 1997;38:7835.
11. Williams DR, Fu L. Org Lett 2010;12:808. [PubMed: 20085311]
12. (a) For the initial report of the halogen dance isomerization of 5-bromo-2-phenyl-1,3-oxazole:
Stanetty P, Spina M, Mihovilovic MD. Synlett 2005:1433. (b) Iso Y, Shindo H, Hamana H.
Tetrahedron 2000;56:5353. (c) Kashima C, Arao H. Synthesis 1998:873.
13. Williams DR, Fu L. Synlett 2010:591.
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Scheme 1.
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Scheme 2.
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Scheme 3.
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Table 1
Suzuki arylations of 5-iodo (9) or 4-bromo-2-(phenylsulfonyl)-1,3-oxazole (11)
Entry Boronic acid
a
b
Product
Yield (%)
1
12 91
2
3
13 96
14 92
4
15 94
5
16 96
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Entry Boronic acid
a
b
Product
Yield (%)
6
17 96
7
18 89
8
19 87
a
Reaction conditions: Under N atmosphere, Pd(PPh ) (10 mol%) was added into a degassed mixture of sulfone 9 (1.0 equiv) and aryl boronic acid
3 4
2
(2.0 equiv) in THF, toluene and 2M aqueous Na CO /K CO (2:2:1 by volume) (0.04 M concentration), and the reaction was heated to 70-80 °C;
2
3
2
3
b
Yields are provided for purified products following flash silica gel chromatography.
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Table 3
Stille cross-coupling reactions of oxazole 10
Entry Halide
a
b
Product
Yield (%)
1
23 96
2
3
13 98
24 71
4
25 92
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Entry Halide
a
b
Product
Yield (%)
5
26 94
6
27
28
c
86
a
Reaction conditions: Under N atmosphere, Pd(PPh ) (10 mol%) was added into a degassed mixture containing sulfone 10 and organic halide (1.2
3 4
2
equiv) in the presence of CuCl (5 equiv) and LiCl (6 equiv) in DMSO (0.05 M concentration), and reactions were heated to 60-80 °C;
b
Yields are provided for purified products following flash silica gel chromatography;
c
Ratio for 27 and 28 is 7:1.
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Table 4
Reductive desulfonylation with sodium hydrosulfite
Entry Sulfone
a
b
Product
Yield (%)
1
29 89
2
30 92
3
4
31 89
32 93
5
6
33 97
34 91
7
35 94
a
Reaction conditions: Sulfone (1.0 equiv) was added into a mixture of N-methylpyrrolidone and water (1:1 by volume) (0.05 M concentration)
containing sodium bicarbonate (10 equiv) and sodium hydrosulfite (5 equiv) at room temperature;
b
Yields are provided for purified products following flash silica gel chromatography.
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