Efficient Organocatalytic α-Sulfenylation of Substituted Piperazine-2,5-diones

Abstract

Organocatalytic α-sulfenylation of substituted piperazine-2,5-diones is reported through the use of cinchona alkaloids as Lewis bases and electrophilic sulfur transfer reagents. 1-Phenylsulfanyl[1,2,4]triazole, a novel sulfur transfer reagent, gave excellent product yields with a number of substituted piperazine-2,5-diones under mild conditions. Catalyst loading, stoichiometry of sulfur electrophile, temperature and solvent were optimized to achieve high product yields.

Organocatalytic α-sulfenylation of carbonyl compounds is of considerable synthetic utility because it produces synthetic intermediates useful in a variety of organic transformations.¹ To date, the majority of reported organocatalytic sulfenylations utilized aldehydes,² ketones,³ lactones, lactams and β-dicarbonyl compounds⁴ as substrates. Despite their simplicity and low catalyst costs such transformations, to our knowledge, have not been reported for β-amido esters or diketopiperazines. In this communication, we report the first organocatalytic α-sulfenylation of substituted piperazine-2,5-diones.

Direct α-sulfenylation of substituted β-amido esters and diketopiperazines could facilitate synthesis of epidithiodiketopiperazines (ETPs) – an intriguing class of biologically active natural products.⁵ ETPs are cytotoxic and immunomodulatory constituents produced by the filamentous fungi Chaetomium and Pithomyces sp. They contain one or two polysulfide-bridged piperazine-2,5-dione fragments and display a broad spectrum of biological activity. Recent studies have shown that two members of this diverse family, chaetocin⁶ and chetomin⁷ (Figure 1), suppress neovascularization in solid tumors⁸ by disrupting the expression of VEGF gene mediated by hypoxia-inducible factor 1α (HIF-1α).⁹ All reported methods for the preparation of ETPs require multistep sequences for the introduction of sulfur.^10–13 Direct, catalytic procedure for α-sulfenylation of piperazine-2,5-diones could prove valuable in the development of a concise synthetic route to ETPs.

Figure 1.

Epidithiodiketopiperazine fungal metabolites.

Organocatalytic transformation of piperazine-2,5-dione ring system is more challenging as compared to aldehydes, ketones and esters due to its lower reactivity toward electrophilic sulfur reagents and greater steric bulk. Hence, the preliminary goal was to investigate the reactivity of the substituted piperazine-2,5-diones under typical conditions of organocatalytic α-sulfenylation with cinchona alkaloids as catalysts. Initially, 1-benzylsulfanyl[1,2,4]triazole (2a)^2,4 was used as the electrophilic sulfenylating reagent in attempts to convert substrates 1a–1e to products 3 (Table 1). This reagent is known to give products in high yields with the variety of aldehydes, ketones and β-ketoesters.⁴ However, with substituted piperazine-2,5-dione 1a, only low yields of the product 3a were obtained. Therefore, our goal was to improve the efficiency of this reaction by varying the amount of sulfenylating reagent 2a and changing the type of catalyst 4a–4d (Figure 2).

Table 1.

Organocatalytic α-sulfenylation of 1a–1e with 1-benzylsulfanyl[1,2,4]triazole 2a and Lewis bases 4a–4d.

substrate	solvent	temp., °C	time, hr	catalyst	eq. of 2a	yield,a %
1a	CH2Cl2	rt	120	4a	5.0	46
1a	Toluene	rt	120	4a	5.0	44
1a	CH2Cl2	rt	120	4d	10.0	55
1b	CH2Cl2	rt	48	4d	2.0	93
1b	Toluene	rt	24	4c	2.0	95
1b	Toluene	−10	24	4c	1.5	90
1b	Toluene	−78	24	4c	1.5	20
1b	Toluene	−10	24	4a	2.0	94
1b	Toluene	−10	24	4b	2.0	91
1cb	Toluene	rt	72	4a	2.6	10
1cb	Toluene	−10	72	4a	2.6	10
1db	Toluene	rt	72	4a	2.6	10
1e	Toluene	rt	72	4a	2.6	c

^aYield of purified product after chromatographic separation.

^b3b was obtained as the product.

^cNo product was formed, as observed by ¹H NMR.

Figure 2.

Cinchona alkaloids used as catalysts.

In order to obtain higher yields, the loading of the sulfenylating reagent 2a was increased (Table 1). Despite using an excess of 2a, the product 3a was still obtained in low yields. Using precursor 1b without substituent at the N-4 position resulted in significantly improved yields. Compounds 1c and 1d gave product 3b in low yields, along with the removal of the substituents at the N-4 position. Such a removal could be the result of an attack of the formed in the trace amounts thiolate anion on acetyl or benzoyl groups of 1c–1d. The small quantities of the newly formed 1b could then be sulfenylated by 2a, producing compound 3b. No product formation could be observed with substrate 1e. It is believed that the low reactivity of the N-4 substituted piperazine-2,5-diones is attributable to the steric clash between the approaching sulfenylating reagent and the substrate, because only the compound lacking N-4 substituent, 1b, gave high yields with 2a. This limits the scope of 2a as an electrophile in sulfenylation of substituted piperazine-2,5-diones.

In an attempt to improve the substrate scope, we also synthesized 1-(p-methoxybenzyl)sulfanyl[1,2,4]triazole and 1-(p-nitrobenzyl)sulfanyl[1,2,4]triazole. These reagents, prepared in a manner similar to 2a, were found to be too unstable for practical application.

To improve yields, a new sulfenylating reagent 1-phenylsulfanyl[1,2,4]triazole (2b) was tested. This reagent gave excellent product yield with substrate 1a and was chosen for subsequent reaction optimizations. First, we screened the reaction conditions needed to efficiently carry out the αenylation with compound 2b. Catalysts, solvents, temperature as well as amounts of sulfenylating reagent 2b were varied in order to improve yields (Table 2). The most sterically bulky compound 1g was selected because its lower reactivity made it an ideal substrate for screening of sulfenylation conditions.

Table 2.

Optimization of reaction conditions of sulfenylation of 1g with 1-phenylsulfanyl[1,2,4]triazole 2b.

entry	solvent	temp, °C	catalyst	eq. of 2b	yield,a %
1	CH2Cl2	rt	4c	2.0	79
2	Toluene	rt	4a	2.0	60
3	Toluene	rt	4b	2.0	65
4	Toluene	rt	4c	2.0	91
6	Toluene	0	4c	3.0	97
5	PhH/PhMe (3:1)	−10	4c	3.0	96

^aYield of purified product after chromatographic separation.

Gratifyingly, sulfenylating reagent 2b gave considerably higher yields than 2a in all reactions with lower amounts of 2b required for efficient sulfenylation (Table 2). Different catalysts were screened, to find the most suitable candidate. The readily accessible quinine (4c) was found to be superior to catalysts (DHQD)₂PYR (4a) and (DHQD)₂PHAL (4b). This is probably due to the fact that the tertiary amines in both (DHQD)₂PYR (4a) and (DHQD)₂PHAL (4b) are more sterically demanding than quinine. Toluene and benzene/toluene mixture were also found to be superior to dichloromethane for obtaining high yields. The higher stability of 2b as compared to 2a under sulfenylation conditions has facilitated product isolation, because lesser amount of this reagent was required to obtain high yields.

Next, to test the substrate scope, the reactivity of 2b with other substituted piperazine-2,5-diones 1f–1j was studied. Compounds 1a and 1f gave excellent yields with 2b (Table 3). Substrates 1h and 1i with ethyl and benzyl groups at the N-4 position are more sterically demanding than substrates with a methyl group at that position. Compounds 1h and 1i were sulfenylated using 2b in high yields. This shows that 1-phenylsulfanyl[1,2,4]triazole (2b) is able to efficiently sulfenylate piperazine-2,5-dione substrates under different reaction conditions. Compound 1j which has a benzyl subtituent at the N-4 position and a t-butyl ester at the α-position, is the most sterically hindered substrate used in this study. It showed moderate yield with 2b and quinine 4c as the catalyst. When (DHQD)₂PYR 4a and (DHQD)₂PHAL 4b were used, no product formation was observed. Presumably the greater steric bulk of 4a and 4b played a major role in reducing the reaction rate when these catalysts were used with the bulky substrates. Because quinine is the least expensive organocatalyst among all tested cinchona alkaloids, its use in combination with the readily prepared 2b, provides an economical route to α-sulfenylated piperazine-2,5-diones.

Table 3.

Scope of α-sulfenylation of trisubstituted piperazine-2,5-diones with reagent 2b and 10 mol % of cinchona alkaloids 4a–4c.

entry	substrate	R1	R2	R3	solvent	temp, °C	catalyst	eq. of 2b	time, h	product	yield,a %
1	1f	Me	Me	Me	PhH/PhMe (3:1)	−10	4c	3.0	18	3f	99
2	1a	Me	Me	Et	PhH/PhMe (3:1)	−10	4c	3.0	30	3k	99
3	1g	Me	Me	t-Bu	PhH/PhMe (3:1)	−10	4c	3.0	48	3g	96
4	1h	Et	Et	Et	Toluene	rt	4c	3.0	60	3h	77
5	1h	Et	Et	Et	Toluene	rt	4cb	8.0	48	3h	94
6	1i	Bn	Bn	Et	Toluene	rt	4c	3.0	60	3i	75
7	1i	Bn	Bn	Et	Toluene	rt	4cb	8.0	48	3i	95
8	1b	H	Me	Et	Toluene	rt	4c	3.0	16	3l	81
9	1j	Bn	Bn	t-Bu	Toluene	rt	4cb	10.0	72	3j	52
10	1j	Bn	Bn	t-Bu	Toluene	rt	4a	2.0	60	3j	5
11	1j	Bn	Bn	t-Bu	Toluene	rt	4b	2.0	60	3j	5

^aYield of purified product after chromatographic separation.

^b20 mol% catalyst used.

Crystallization of product 3g from ethanol at room temperature provided single crystals suitable for X-ray diffraction analysis.¹⁴ The molecular structure of 3g is shown in Figure 3. The compound 3g has crystallized in the centrosymmetric orthorhombic space group Pbca and the crystal packing shows efficient stacking of the phenyl and diketopiperazine rings in the solid state. It is hypothesized that this stacking may provide additional stabilization in the transition state of the sulfenylation reaction.

Figure 3.

The molecular structure of 3g with anisotropic displacement parameters at 30% probability level.

In summary, direct and efficient organocatalytic α-sulfenylation of substituted piperazine-2,5-diones has been developed. Various substrates, solvents and sulfur transfer reagents have been screened, resulting in high product yields under optimized reaction conditions. This methodology may be of value for future construction of the epidithiodiketopiperazine ring system in a rapid and efficient manner. We continue structural modifications of electrophilic sulfur transfer reagents in order to expand their scope to sterically bulky substrates. Further exploration of the mechanism of organocatalytic α-sulfenylation and development of its enantioselective variant are currently under investigation.