One-pot synthesis of functionalized β-amino sulfides/β-amino selenides via ring opening of cyclic sulfamidates

Abstract

A number of functionalized β-amino and γ-amino sulfides and selenides have been synthesized involving a one-pot process of ring opening of cyclic sulfamidates with ‘in situ’ generated thiolate and selenoate species from diaryl disulfides and diphenyl diselenide using rongalite. A mild and efficient method has been developed for the synthesis of cysteines from serine.

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Introduction

Compounds containing sulfur/selenium and nitrogen have generated profound interest due to their applications in drug design,^1,2 organo catalysis,^3–9 and medicine^10–12 etc. Among these compounds, β-amino sulfides have recently received much attention. For example, some of these compounds serve as potent inhibitors of various toxins like tetanus toxin,¹³ and botulinum neurotoxin type B.¹⁴ On the other hand, organoselenium chemistry plays a pivotal role in the synthesis of a large number of biologically active compounds and they are important in therapeutics.¹⁵ Recent advances in the synthesis of organoselenium compounds have been propelled by the interesting reactivities¹⁶ and their potential pharmaceutical significance.¹⁷ Moreover, β-amino sulfides/selenides are used as excellent chiral ligands in asymmetric catalysis and hetero bidentate N,S-ligands have proved to be very effective in enantioselective palladium-catalyzed allylic substitution reactions.^4–9 In general the synthesis of β-amino sulfides/selenides has been achieved using the ring opening of aziridines,^18–20 and nucleophilic substitution of amino alcohols derived tosylates by thiolate/in situ generated selenoate anion.^21,22 From our laboratory, we have earlier reported the synthesis of the β-amino sulfides/selenides by ring opening of aziridines by chalocgenide anions generated in situ from dichalcogenides mediated by rongalite (1, sodium hydroxymethanesulfinate).¹⁹

However the regioselectivity of ring opening in the case of highly substituted aziridines is a serious problem. The size of substituents R₁ and R₂ and the nature of protecting group R₃ on nitrogen atom dictate the course of the reaction (Fig. 1). To overcome these problems, we decided to study the reactivity of cyclic sulfamidates with organic disulfides in the presence of rongalite 1.

Fig. 1 Reactivity of aziridines vs. cyclic sulfamidates.

Cyclic sulfamidates are considered as synthetically versatile electrophiles that can be synthesized from readily available (and enantiomerically pure) 1,2- and 1,3-amino alcohols or 1,3-diols.²³ Ring opening reactions of cyclic sulfamidates A with nucleophiles can give N-sulfate intermediate B, which on further hydrolysis with either protic or Lewis acidic conditions results in the formation of the final product C (Scheme 1).²⁴ However, the ring opening of cyclic sulfamidates with sulfur nucleophiles has not been explored in detail.²⁵

Scheme 1 Nucleophilic ring opening of sulfamidates.

We have already reported the synthesis of β-amino disulfides/diselenides from aziridines²⁶ and sulfamidates^27,28 using benzyltriethylammonium tetrathiomolybdate [BnEt₃N]₂MoS₄ as a sulfur transfer reagent.

Herein, we wish to report the synthesis of β-amino sulfides/selenides via ring opening of cyclic sulfamidates using diaryl dichalcogenides in the presence of rongalite 1 (Scheme 2).

Scheme 2 General scheme for the synthesis of β-amino sulfides/selenides.

Results and discussion

Reaction of sulfamidate 2a with diaryl disulfides 3 in the presence of rongalite 1

Initially, the sulfamidate 2a (ref. 28) derived from (S)-2-amino butanol 2a was taken as a model substrate for screening (Scheme 3).

Scheme 3 Reaction of sulfamidate 2a with diphenyl disulfide 3a in the presence of 1.

The ring opening of sulfamidate 2a by the thiolate ion formed by the cleavage of diphenyl disulfide 3a by rongalite 1 was studied in different solvents and bases and the results are presented in Table 1. Screening revealed that the reaction gave the best yield when the reaction was performed using K₂CO₃ as a base and DMF as the solvent (Table 1, entry 5).²⁹ It was observed that the product 4a was not formed in the absence of a base (Table 1, entry 1). The mechanism of the reaction as proposed previously^19,30,31 involves the base promoted decomposition of rongalite to form formaldehyde and HSO₂⁻. The HSO₂⁻ transfers a single electron to disulfide 3a to form a thiolate ion in situ which reacts at the C–O bond of 2a in a highly stereospecific manner (S_N2). After the reaction is over, the reaction mixture is acidified, stirred overnight followed by neutralization with aqueous NH₃ to furnish the corresponding β-amino sulfide 4a.

Table 1 Optimization of reaction conditions for the formation of 4a

Entry	Conditions			Yield^b (%)
	Base (1.5 equiv.)	Solvent	Time^a (h)
a Time required for the reaction of sulfamidate 2a with disulfide 3a in the presenceof rongalite 1.b Isolated yields after purification by column chromatography.
1	—	DCM	8	—
2	K2CO3	DCM	3	10
3	K2CO3	CH3CN	3	35
4	K2CO3	THF	3	52
5	K2CO3	DMF	1	86
6	Et3N	DMF	1	78
7	CSCO3	DMF	1	82

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Having optimized the conditions, we next explored the scope and generality of the method with various aryl/alkyl disulfides (Scheme 4).

Scheme 4 Ring opening of (S)-2-amino butanol derived sulfamidate 2a with various disulfides 3.

We have been able to synthesize the corresponding substituted and enantiopure β-amino sulfides 4 by employing the route outlined in Scheme 4 and the results are summarized in Table 2. Irrespective of the nature of the functional group on the phenyl ring of the disulfide, the corresponding β-amino sulfides were obtained regioselectively in good to excellent yields (Table 2, entries 1–9). Heteroaryl disulfide such as 2,2′-dipyridyl disulfide 3k reacted reasonably well with the sulfamidate 2a in the presence of 1 to furnish the corresponding β-amino sulfide 4k in 82% yield (Table 2, entry 10). Additionally, aliphatic disulfide like tetramethylthiuram disulfide 3l also gave the corresponding β-amino sulfide 4l in excellent yield (95%) (Table 2, entry 11). However dibenzyl disulfide 3m failed to react under these conditions (Table 2, entry 12).

Table 2 Synthesis of β-amino sulfides 4 derived from sulfamidate 2a and disulfides 3

Entry	R-S-S-R	Time^a (h)	Product	Yield^b (%)
a Time required for the reaction of sulfamidate 2a with disulfides 3 in the presence of rongalite 1.b Isolated yields after purification by column chromatography.
1		0.75		93
2		1		95
3		1.5		90
4		1.5		93
5		2		87
6		2		85
7		1.5		89
8		1.5		89
9		1.5		85
10		1		82
11		1		95
12		6		No reaction

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Reaction of various sulfamidates 2 with 3a in the presence of 1

We further extended the methodology to various sulfamidates²⁸ (2a–2h) using diphenyl disulfide 3a as the reaction partner. The results are presented in Table 3.

Table 3 Synthesis of β-amino sulfides 4 from various sulfamidates 2a–2h and diphenyl disulfide 3a

Entry	Sulfamidates	Time^a (h)	Product	Yield^b (%)
a Time required for the reaction of sulfamidates 2 with disulfide 3a in the presence of rongalite 1.b Isolated yields after purification by column chromatography.
1		1		93
2		1		95
3		1		94
4		1		92
5		1		82
6		2		80
7		3		82
8		1		84

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The sulfamidates 2b–2e derived from valine, leucine, phenyl alanine and serine gave the desired products 4n–4q respectively in excellent yields (Table 2, entries 2–4). However, substituted sulfamidates such as 2f derived from 2-amino-2-methyl-1-propanol, and 2g derived from (1S, 2R)-1-amino-2,3-dihydro-1H-indan-2-ol reacted slowly (2–3 h) with phenyl thiolate anion generated in situ from diphenyl disulfide 3a and rongalite 1 to furnish the corresponding β-amino sulfides 4r and 4s in good yields (Table 2, entries 6 and 7). This may be due to steric effect of the groups present at the α and β carbon atoms. Protected (Cbz) sulfamidate 2h derived from 2-amino butanol also reacted smoothly to furnish the desired product 4t in 84% yield (Table 2, entry 8). These results suggest that the reaction is general and it overcomes all the problems encountered in the case of aziridines in term of product formation and selectivity.

Reaction of various sulfamidates 2 with diphenyl diselenide 3n in the presence of 1

To extend the scope of this reaction further, we decided to study the reactivity of different cyclic sulfamidates 2 with diphenyl diselenide 3n in the presence of 1.

The reaction of sulfamidates 2a–2h with diphenyl diselenide 3n in the presence of rongalite 1 (rt, 1–3 h), resulted in the formation of the corresponding β-amino selenides 5a–5h in good to excellent yields (Table 4). The sulfamidates 2a–2e underwent facile ring opening with phenyl selenoate anion derived from diphenyl diselenide 3n regioselectively at C-1 to give the desired products 5a–5e respectively in excellent yields (Table 4, entries 1–5 and 8). Sterically crowded sulfamidates such as 2f, 2g reacted slowly (2–3 h) to give the products 5f and 5g respectively in good yields (Table 4, entries 6–7). The Cbz-protected sulfamidate 2h underwent ring opening smoothly in 1 h give the corresponding β-amino selenide 5h in 83% yield.

Table 4 Synthesis of β-amino selenides from various sulfamidates 2a–2h and diphenyl diselenide 3n in the presence of 1

Entry	Sulfamidates	Time^a (h)	Product	Yield^b (%)
a Time required for the reaction of sulfamidates 2 with diselenide 3n in the presence of rongalite 1.b Isolated yields after purification by column chromatography.
1		1		90
2		1		92
3		1		91
4		1		89
5		1		80
6		2		79
7		3		81
8		1		83

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Reaction of cyclic six membered sulfamidate 2i with diphenyl dichalcogenides (3a and 3n) in the presence of 1

An additional utility of this method was demonstrated in the reaction of six membered cyclic sulfamidate 2i derived from 2,2-dimethylpropane-1,3-diol (Scheme 5). When the sulfamidate 2i was treated with diphenyl disulfide 3a and rongalite 1, the reaction proceeded cleanly (DMF, rt, 1 h) to give the γ-amino sulfide 4u in 85% yield (Scheme 5). In a similar fashion, when the reaction of 2i was performed with diphenyl diselenide 3n and rongalite 1, it underwent facile ring opening to furnish γ-amino selenide 5i in 81% yield (Scheme 5). This result indicates the potential utility of this method for the synthesis of a number of substituted γ-amino sulfides/selenides.

Scheme 5 Reaction of 6-membered cyclic sulfamidate 2i with 3a and 3n.

Conclusions

In this paper, we have reported an efficient, mild and general method for the synthesis of β and γ-amino sulfides/selenides via regioselective ring opening of cyclic sulfamidates with dichalcogenides in the presence of rongalite. The significance of the method is the use of inexpensive reagents and avoiding the use of free chalcogenols. The versatility of this reaction has been demonstrated by preparing a number of β-amino sulfides/selenides having different N-protecting groups.

Acknowledgements

CVR thanks CSIR for a Shyama Prasad Mukherjee (SPM) Senior Research Fellowship, BD thanks the University Grants Commission (UGC), New Delhi for a Dr D. S. Kothari Postdoctoral fellowship, and SCN thanks the Department of Science and Technology (DST) for the award of SERB Distinguished Fellow and the JNCASR, Jakkur for the Hindustan Lever Professorship.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedure, characterization data, ¹H and ¹³C NMR spectra of all the new compounds. See DOI: 10.1039/c4ra06759b

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