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

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.

Oxazoles represent an important class of five-membered heterocycles.¹ In recent years, this heterocyclic system has frequently been identified as a significant structural feature, embedded within the architecture of complex natural products.² Several interesting antibiotics prominently display 1,3-oxazoles as a result of cyclodehydration of serine or threonine residues in the course of biosynthesis.³ Not surprisingly, a number of cyclodehydration strategies, beginning with acyclic amides, have been developed to provide for the de novo preparation of substituted 1,3-oxazoles.⁴ 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).

Scheme 1.

Several laboratories have described examples of cross-coupling processes of arylation and alkenylation at C-2 of the oxazole nucleus,⁵ and Stille reactions of 2-phenyl-1,3-oxazole have led to C-4 and C-5 arylation reactions.⁶ Recently, Stambuli and coworkers have described the selective C-5 deprotonation of 2-methylthio-1,3-oxazole with tert-butyllithium affording access to 2,5-disubstituted oxazoles.⁷ These efforts have advanced the previous studies of Shafer and Molinski,⁸ as well as a previous report by Marino and Nguyen disclosing the regioselective allylation of 2-(n-butylthio)-1,3-oxazole.⁹

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 electrophiles (Scheme 2).¹⁰ 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.

Scheme 2.

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-oxazoles.¹¹ 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 = SO₂Ph, X = Li) facilitates convenient halogenation and stannylation reactions yielding 9 and 10, respectively.¹¹ Furthermore, we have shown that 5-bromo-2-(phenylthio)-1,3-oxazole (8) undergoes a facile base-induced isomerization, characterized as a halogen dance rearrangement to provide access to the 4-bromo-1,3-oxazole 11 (85%).¹³ 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.

Scheme 3.

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(PPh₃)₄ at 70 °C to 80 °C in a mixture of THF and toluene containing aqueous Na₂CO₃ or K₂CO₃ (2:2:1 by volume).

Table 1.

Suzuki arylations of 5-iodo (9) or 4-bromo-2-(phenylsulfonyl)-1,3-oxazole (11)

Entry	Boronic acid	Producta		Yield (%)b
1			12	91
2			13	96
3			14	92
4			15	94
5			16	96
6			17	96
7			18	89
8			19	87

^aReaction conditions: Under N₂ atmosphere, Pd(PPh₃)₄ (10 mol%) was added into a degassed mixture of sulfone 9 (1.0 equiv) and aryl boronic acid (2.0 equiv) in THF, toluene and 2M aqueous Na₂CO₃/K₂CO₃ (2:2:1 by volume) (0.04 M concentration), and the reaction was heated to 70-80 °C;

^bYields are provided for purified products following flash silica gel chromatography.

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.

Table 2.

Stille reaction of oxazoles 9 and 11

Entry	Oxazole	Stannane	Producta		Yield (%)b
1				20	85
2				21	74
3				22	70

^aReaction conditions: Under N₂ atmosphere, Pd(PPh₃)₄ (10 mol%) was added into a degassed mixture containing sulfone 10 (1.0 equiv) and organic halide (1.2 equiv) in the presence of CuCl (5 equiv) and LiCl (6 equiv) in DMSO (0.05 M concentration), and reactions were heated to 80-90 °C;

^bYields are provided for purified products following flash silica gel chromatography.

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).

Table 3.

Stille cross-coupling reactions of oxazole 10

Entry	Halide	Producta		Yield (%)b
1			23	96
2			13	98
3			24	71
4			25	92
5			26	94
6			27	86c
			28

^aReaction conditions: Under N₂ atmosphere, Pd(PPh₃)₄ (10 mol%) was added into a degassed mixture containing sulfone 10 and organic halide (1.2 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;

^bYields are provided for purified products following flash silica gel chromatography;

^cRatio for 27 and 28 is 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.

Table 4.

Reductive desulfonylation with sodium hydrosulfite

Entry	Sulfone	Producta		Yield (%)b
1			29	89
2			30	92
3			31	89
4			32	93
5			33	97
6			34	91
7			35	94

^aReaction 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;

^bYields are provided for purified products following flash silica gel chromatography.

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 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.