Synthesis of N-substituted sulfamate esters from sulfamic acid salts by activation with triphenylphosphine ditriflate

Abstract

A general approach to access sulfamate esters through preparation of sulfamic acid salts, subsequent activation with triphenylphosphonium ditriflate, and nucleophilic trapping is disclosed. The method proceeds in modest to excellent yields to incorporate nucleophiles derived from aliphatic alcohols and phenols. This approach can be employed to furnish differentially substituted sulfamides.

Graphical abstract

The sulfamate ester functional group has found broad utility, including use as nitrogen sources for amination and aziridination reactions,¹ as electrophiles in cross-coupling reactions,² and as an alcohol-masking moiety to modulate the bioactivity and bioavailability of pharmacologically relevant compounds (Scheme 1).³ One classical approach to access sulfamate esters relies on the use of sulfuryl chloride to furnish sulfamoyl or sulfonyl chloride intermediates. These procedures are inefficient or ineffective when the involved nucleophiles are sterically hindered, or electron deficient (Scheme 2, eq 3).^{4, 5} Although several alternative methods have been reported to access sulfamate esters (eqs 4–6),^{6, 7, 8} there are no operationally straightforward, efficient, general methods to prepare acyclic O-alkyl sulfamate esters incorporating primary or secondary alkyl substituents on the nitrogen. To identify a protocol that would provide access to these types of sulfamate esters with varied electronic and steric properties, we anticipated that initial sulfamation⁹ of an amine with a sulfur trioxide complex would furnish a sulfamic acid salt. We hypothesized that use of sulfamic acid salts would allow us to investigate an array of esterification strategies to install the sulfamate ester S–O bond. Based on this approach, described herein is a broadly effective protocol to prepare sulfamate esters (Scheme 3).

Scheme 1. Utility of sulfamate esters.

Scheme 2. Methods to prepare sulfamate esters.

Scheme 3. Disclosed strategy.

As anticipated, reaction of amines with sulfur trioxide sources provided facile access to diverse sulfamic acid salts (Table 1). Initially, treatment of 2,2,2-trifluoroethylamine with sulfur trioxide pyridine complex and triethylamine in acetonitrile furnished sulfamic acid salt 2a in quantitative yield as an oil without need for purification. Solid trimethylammonium salt 2b could be prepared through the reaction of 2,2,2-trifluoroethylamine with sulfur trioxide trimethylamine complex, and then recrystalized to purity. While the analogous sodium salt could be prepared from chlorosulfonic acid, incorporation of the ammonium cation simplified isolation and offered a better solubility profile in subsequent reactions. Using this strategy, sulfamic acid salts have been prepared efficiently from anilines, primary and secondary amines, enantioenriched amines, and amines with pendant heteroaromatic functionality.

Table 1. Preparation of sulfamic acid salts^a.

^aGeneral reaction conditions: 1.0 equiv amine 1, 1.0 equiv sulfur trioxide pyridine complex (SO₃•pyr),0.33 M acetonitrile, 1.5 equiv Et₃N, 30 min, 0 → 22 °C.

^b1 equiv SO₃•NMe₃in place of SO₃•pyr and Et₃N.

^c>90% purity.

These readily accessible salts enabled us to interrogate a variety of tactics for esterification of 2,2,2-trifluoroethyl sulfamic acid salt 2a with n-pentanol (3a) to install a sulfamate ester S–O bond.While sulfamoyl chlorides have been used for efficient access of unsubstituted sulfamate esters,^{1, 2} activation by in situ generation of a sulfamoyl chloride furnished, at best, modest yields of N-(2,2,2-trifluoroethyl)sulfamate ester 4a (Table 2, entries 1–5). Anticipating that the reaction might be driven forward by formation of a strong phosphorous–oxygen double bond, DIAD and PPh₃ were used to activate the salt, and furnish desired sulfamate ester 4a in moderate yield (entry 6). As an extension to this approach, the Hendrickson reagent¹⁰ furnished desired sulfamate ester 4a in slightly increased yield (entry 7). Under the optimal conditions, 1.5 equivalents of triethylammonium sulfamate 2a were activated by addition to a solution of triphenylphosphine ditriflate, which was generated in situ from 1.5 equivalents of Tf₂O and 1.65 equivalents of Ph₃PO (entry 10). Subsequent treatment with 3 equivalents of triethylamine and 1 equivalent of n-pentanol (3a) at −78 °C furnished sulfamate ester 4a in 95% isolated yield. Trimethylammonium sulfamate salt 2b reacted with similar efficiency under the optimal conditions (entry 11).

Table 2. Optimization of Sulfamate Ester Preparation.

entrya	activating agent	yield (%)b4a
1	PCl5 (2.0 equiv)	41
2	POCl3 (2.0 equiv)	44
3	SOCl2 (2.0 equiv)	<5
4	(COCl)2 (10.0 equiv)	ndc
5	trichlorotriazine (1.0 equiv)	<5
6d	DIAD, PPh3	50
7	Tf2O (1.0 equiv), Ph3PO (2.1 equiv)	56
8e	Tf2O (1.5 equiv), Ph3PO (3.15 equiv)	71
9e	Tf2O (1.5 equiv), Ph3PO (1.65 equiv)	78
10e, f	Tf2O (1.5 equiv), Ph3PO (1.65 equiv)	95
11f, g	Tf2O (1.5 equiv), Ph3PO (1.65 equiv)	94

^aGeneral reaction conditions: 1.0 equiv n-pentanol (3a), 1.0 equiv sulfamate 2a, CH₂Cl₂, 2.0 equiv Et₃N, Tf₂O (1.5 equiv), Ph₃PO (1.65 equiv), 18 h, −78 → 22°C.

^bIsolated yield.

^cNot detected.

^dNo Et₃N.

^e1.5 equiv triethylammonium sulfamate 2a.

^f3.0 equiv Et₃N.

^g1.5 equiv trimethylammonium sulfamate 2b.

Under the optimized conditions, a range of N-substituted salts 2 can be converted to sulfamate esters 4 in modest to excellent yields (Table 3). While aryl and electron-deficient N-alkyl substituents are well-tolerated in the transformation (4a–d), more electron-rich N-alkyl substituents result in modest yields of sulfamate esters 4e–g. Of these, N-tert-butylsulfamate esters can be prepared in similar yield using tert-butanol and chlorosulfonyl isocyanate to generate N-tert-butylsulfamoyl chloride (Scheme 2, eq 4);⁶ however, N-methyl- and N-ethylsulfamate esters cannot be accessed via a similar strategy. In principle, these N-alkyl sulfamates could be prepared in a two-step approach featuring the mono-alkylation of O-pentyl sulfamate (Scheme 2, eq 5).⁷ Neither of these methods would be appropriate to access enantioenriched sulfamate ester 4i, which is generated without any stereochemical erosion using the disclosed approach.

Table 3. N- and O-substitutent variations^a.

^aGeneral reaction conditions: 1.0 equiv alcohol 3 or amine 5, 1.5 equiv sulfamate 2, CH₂Cl₂, 3.0 equiv Et₃N, Tf₂O (1.5 equiv), Ph₃PO (1.65 equiv), 18 h, −78→ 22°C.

^b1.0 equiv sodium pentoxide, 0 → 22°C.Alcohol and Et₃N were omitted.

The optimized protocol is less effective at transforming salts that have been generated from secondary amines or that incorporate heteroaromatic substituents. When triethylammonium N,N-diethyl sulfamate (2h) is employed, diethylsulfamate ester 4h forms in 17% yield (see Supporting Information). Fortunately, this reaction proceeds in 68% yield if sulfamate 2h is treated with 1 equivalent of sodium pentoxide as the nucleophile. Notably, sulfamic acid salts incorporating nitrogen-containing heterocycle substituents are converted to sulfamate esters 4j–k. These products are not detected when utilizing PCl₅ to activate the sulfamic acid salt via sulfamoyl chloride intermediates.

Under the optimized conditions, a variety of alcohols serve as effective nucleophiles to generate sulfamate esters in modest to excellent yields (Table 3, 4l–4w). Primary and secondary aliphatic alcohols, and phenols, including electron-deficient p-hydroxybenzonitrile (3o), are converted to sulfamate esters in high yield. In principle phenol-derived 4p could be generated from an activated sulfonyl imidazolium species (Scheme 2, eq 6).⁸ However, when sulfonyl imidazolium reagents are used for the synthesis of sulfamate esters, the alcohol portion must be installed first and the approach does not tolerate electron rich or neutral aliphatic alcohols. The disclosed reaction tolerates benzyl or silyl ether groups in alcohols 3r and 3s, respectively, and a phthalimide moiety in alcohol 3t, providing potential strategies for site-specific sulfamoylation of polylols and amino alcohols. As expected, these conditions efficiently incorporate more elaborate hydrocarbon scaffolds, such as those of tetrahydrogeraniol and 5α-cholestan-3β-ol, into sulfamate esters 4u–4w.

In addition to alcohols, nitrogen nucleophiles can be incorporated into sulfamides under the reaction conditions to furnish unsymmetrically substituted sulfamides 6a–6c. Sulfamides are valuable components of some bioactive small molecules, with some nonsymmetrically substituted sulfamides demonstrating higher bioactivity than symmetrically substituted analogues. ¹¹ Nevertheless, few methods¹² enable efficient preparation of unsymmetrically substituted sulfamides. Using this approach, differentially substituted sulfamides are accessible from primary, secondary, or tertiary amines, including sterically encumbered tert-butylamine (i.e, 5c→6c).

To conclude, the disclosed method employs inexpensive and readily available sulfur trioxide sources, primary and secondary alkyl amines, and aliphatic or aromatic alcohols to prepare sulfamate esters, many of which are not efficiently accessible through other known methods. Furthermore, the intermediate salts can be employed to generate differentially substituted sulfamides.This new approach provides ready access to a powerful pharmacologically relevant and synthetically versatile motif.