Photochemically-Mediated, Nickel-Catalyzed Synthesis of N-(Hetero)aryl Sulfamate Esters

Abstract

A general method is described for the coupling of (hetero)aryl bromides with O-alkyl sulfamate esters. The protocol relies on catalytic amounts of nickel and photoexcitable iridium complexes and proceeds under visible light at ambient temperature. This technology engages a broad range of simple and complex O-alkyl sulfamate ester substrates under mild conditions. Furthermore, it is possible to avoid undesirable N-alkylation, which was found to plague palladium-based protocols for N-arylation of O-alkyl sulfamate esters. These investigations represent the first use of sulfamate esters as nucleophiles in transition metal-catalyzed C–N coupling processes.

Graphical abstract

Nitrogen-containing small molecules, including arylamines, are valuable given their importance as bioactive agents.¹ While a variety of methods exist to access many N-alkyl, N-aryl, N-acyl, and N-sulfonyl aniline derivatives, examples of N-aryl sulfamate esters remain limited, as user-friendly and efficient preparations of N-aryl sulfamate esters have only recently emerged (Scheme 1).² Unfortunately, these strategies engage multistep reaction sequences and use highly reactive reagents, which may detract from their utility. Furthermore, using these approaches, preparations of sulfamate esters featuring Lewis basic N-heteroaromatic substituents are exceedingly rare, despite the importance of heteroaryl motifs in medicinally-relevant small molecules.³ Given these limitations, a transition metal-catalyzed protocol capable of coupling easily prepared primary sulfamate esters with widely available (hetero)aryl halide electrophiles would expand the accessibility of elusive N-(hetero)aryl sulfamate esters.⁴

Scheme 1.

Access to N-(Hetero)aryl Sulfamate Esters Remains Limited Despite Recent Strategic Innovations

Transition metal-catalyzed C(sp²)–N bond-forming reactions have revolutionized access to arylamines, and are among the most practiced synthetic manipulations in both academic and industrial settings.⁵ The majority of transformations developed to convert (hetero)aryl halide substrates to valuable aniline derivatives feature palladium-based catalysts.⁶ In addition to traditional aliphatic amines, advances in the Buchwald-Hartwig reaction have enabled the efficient coupling of a variety of less nucleophilic substrates, including amides, carbamates, sulfonamides, and sulfamides.⁷ While sulfamate esters are employed as electrophilic components in a variety of transition metal-mediated cross-coupling manifolds, ⁸ sulfamate esters have not been described as viable nucleophiles within these transformations. Owing to their low nucleophilicity, even examples of their use as substrates in S_NAr reactions is rare.^2g

Given that similarly nucleophilic sulfonamide and sulfamide substrates have been previously disclosed as effective components in palladium-catalyzed C(sp²)–N coupling reactions,⁷ we questioned whether sulfamate esters would serve as effective nucleophiles under palladium-mediated Buchwald-Hartwig amination conditions. Unfortunately, using these established protocols, the N-arylation of pentyl sulfamate (1a) was found to proceed in poor yield (Scheme 2). Furthermore, N-alkylated byproducts 3a and 3b were observed to form via a competitive decomposition pathway, indicating a potential barrier to the elucidation of an efficient palladium-catalyzed protocol.

Scheme 2.

When Applied to Sulfamate Esters, Palladium-Catalyzed N-Arylation Protocols Generate Undesired Byproducts

As compared to palladium-mediated C(sp²)–N bond forming methods, fewer technologies rely on nickel catalysis.⁹ Such transformations often requires a challenging reductive elimination step from Ni(II)–amido complexes, which can demonstrate increased thermal stability.¹⁰ Recently, photochemically-driven, nickel-catalyzed strategies have emerged as an approach to facilitate C(sp²)–N bond formation under mild conditions at ambient temperatures.¹¹ We hypothesized that the mild conditions offered by photochemically-driven nickel catalysis might bypass the deleterious sulfamate ester N-alkylation processes observed when palladium catalysts were employed (Scheme 2). Despite the remarkable potential offered by this dual catalytic approach, the range of nitrogen-based nucleophiles has been limited to those previously known to efficiently engage in palladium-catalyzed processes. To date, only amines, sulfonamides, amides and carbamates, which are substrates tolerated in analogous palladium-mediated processes, have been employed in these light-enabled, nickel-catalyzed reactions.¹¹

Herein disclosed is the first general N-(hetero)arylation reaction featuring sulfamate esters as nucleophilic components, and provides broad access to O-alkyl sulfamate esters bearing both N-aryl and N-heteroaryl substituents. This protocol employs readily available substrates and reagents, and proceeds under mild conditions. This process highlights the chemically distinct reactivity afforded by the dual catalyzed reaction manifold, and provides access to N-(hetero)aryl sulfamate esters, which have traditionally been underexplored, presumably owing to their challenging preparation.

Initial investigations to develop this N-(hetero)arylation process employed pentyl sulfamate (1a) as a model substrate, and 4-(trifluoromethyl)bromobenzene as an electrophile (Table 1). Utilizing previously reported conditions,^11d,e 1.5 equiv of sulfamate 1a was treated with 1.0 equiv of bromoarene, photoactive [Ir(ppy)₂(dtbbpy)]PF₆ (1 mol %), NiBr₂•glyme (5 mol %) and tetramethylguanidine (TMG) as a base, and furnished desired N-arylated 2a in 18% yield (entry 1). Importantly, formation of undesired N-alkylated byproducts 3a and 3b was suppressed, as unreacted 1a primarily accounted for the remaining mass balance using this dual catalytic manifold. When three equivalents of DBU were employed, full conversion to desired N-aryl sulfamate 2a was observed (entry 4).¹² Either sulfamate ester or aryl bromide could be used as the limiting substrate (entries 4, 6), which may be an important consideration depending on the relative accessibilities of the requisite starting materials. Equimolar amounts of each substrate could be employed, albeit with a slight decrease in the reaction yield (entry 7).

Table 1.

Optimization of Sulfamate Ester Arylation

entrya	photocatalyst [mol %]	1a [equiv]	aryl halide [equiv]	base [equiv]	yield [%]b
1	[Ir(ppy)2(dtbbpy)]PF6	1.5	1.0	TMG [1.5]	18
2	[Ir(ppy)2(dtbbpy)]PF6	1.5	1.0	DBU [1.5]	67
3	[Ir(ppy)2(dtbbpy)]PF6	1.5	1.0	DBU [2.0]	80
4	[Ir(ppy)2(dtbbpy)]PF6	1.5	1.0	DBU [3.0]	96
5	[Ir(ppy)2(dtbbpy)]PF6	1.0	1.5	DBU [2.0]	72
6	[Ir(ppy)2(dtbbpy)]PF6	1.0	1.5	DBU [3.0]	> 98
7	[Ir(ppy)2(dtbbpy)]PF6	1.0	1.0	DBU [3.0]	84
8	fac-Ir(ppy)3	1.0	1.5	DBU [3.0]	20
9	[Ir(ppy)2(bpy)]PF6	1.0	1.5	DBU [3.0]	> 98
10	[Ir(dF(CF3)ppy)2(dtbbpy)]PF6	1.0	1.5	DBU [3.0]	9
11	[Ru(bpy)3](PF6)2	1.0	1.5	DBU [3.0]	48
12	4-CzIPN	1.0	1.5	DBU [3.0]	70
13	none	1.0	1.5	DBU [3.0]	< 5

^aGeneral reaction conditions: 1.0–1.5 equiv 1a, 1.0–1.5 equiv 4-bromobenzotrifluoride, photocatalyst (1 mol %), NiBr₂•glyme (5 mol %), base (1.0–3.0 equiv), MeCN (0.25 M with respect to limiting reagent), with stirring in front of two 34W blue Kessil lamps for 24 h.

^bIsolated yield.

A variety of photochemical mediators can be used to drive this transformation, yet trends in their efficacy are limited. The yield of this transformation does not improve with increases in the oxidizing power of the excited state iridium complex (entries 6, 8–10; see supporting information for a compilation of experimentally-derived E_1/2^III*/II estimates). To date, the most effective photoexcitable metal complexes have triplet state energies (E_T) in the range of 46.2–49.2 kcal/mol, a trend that could be anticipated for a reaction proceeding through triplet sensitization (entries 6, 9, 11; see supporting information for a compilation of E_T values). Importantly, this N-arylation reaction relies on the presence of a photochemical mediator (entry 13), confirming that the process does not proceed via direct excitation of an intermediate nickel species.¹³

This optimized dual catalytic protocol effectively transforms a variety of ortho-, meta-, and para-substituted electron-neutral and electron-deficient bromobenzene derivatives, including those featuring nitriles, esters, and fluorides, are transformed in good yields (Scheme 3). Furthermore, chloride and boron substituents remain intact over the course of the reaction. These functional groups are important in cross-coupling technologies, and offer the opportunity for further manipulation.

Scheme 3. A Wide Range of (Hetero)aryl Bromides are Installed onto Sulfamate Esters^a.

^aGeneral reaction conditions: 1.0 equiv pentyl sulfamate (1a), 1.5 equiv (hetero)aryl bromide, photocatalyst (1 mol %), NiBr₂•glyme (5 mol %), DBU (3.0 equiv), MeCN (0.25 M), with stirring in front of two 34W blue Kessil lamps for 12–72 h. ^bReaction performed with 10 mol % NiBr₂•glyme. ^cReactions performed with NiBr₂•glyme (10 mol %) and dtbbpy (4 mol %). ^dReaction performed in ⁱPrOAc (0.25 M).

Due to the prevalence of heteroaromatic motifs in biologically-relevant small molecules, heteroaryl bromides were also investigated (Scheme 3). Given our interest in functionalized pyridines,¹⁴ we were pleased to find that 2-, 3-, and 4-bromopyridines were all effective arylating agents using the disclosed protocol. Moreover, this procedure transforms a range of other 6-membered heteroaryl bromides, including pyrimidine, quinoline, and azaindole substrates.

Predictably, electron-rich (hetero)arylbromides were more challenging cross-coupling partners. Fortunately, once 4,4’-di(tert-butyl)-2,2’-bipyridine is included in the reaction conditions as a ligand for nickel, the transformation of these substrates becomes more efficient. This observation mirrors that noted during the development of photocatalytically-driven nickel-promoted N-arylation of sulfonamides,^11d and may prove to be a general tactic to enable the use of more challenging aryl electrophiles in photochemically-promoted nickel-catalyzed C–heteroatom coupling reactions. Using this modification, the protocol can effectively engage 4-substituted aryl bromides featuring electron-donating groups (2p–2s), as well as some 5-membered heterocyclic bromides as electrophiles. Of note, a benzothiophene (2t), a thiophene (2u), and a benzothioazole (2v) are effectively installed on sulfamate ester 1a under prolonged reaction times. These substrates overcome the common tendency of sulfur to react with nickel catalysts to deactivate them or to engage in C–S bond activation.¹⁵

This technology efficiently N-arylates complex O-alkyl sulfamate esters derived from primary and secondary alcohols, even those involving oxidatively sensitive functional groups (Scheme 4). Secondary alcohol-derived sulfamate esters based on a steroid (trans-andosterone, 2y), a vasodilator (pentoxifylline, 2z), a triterpene (enoxolone, 2aa) and an analgesic (menthol, 2ab) are efficiently transformed under the standard reaction conditions, as is a primary alcohol-derived sulfamate ester based on a diterpene (dehydroabietic acid, 2ac). The evaluated substrates highlight the compatibility of ketones, α,β-unsaturated ketones, methyl xanthines, esters, and acetals afforded by these mild reaction conditions. This protocol is not an efficient strategy to N-arylate O-aryl sulfamate esters (see supporting information for details).

Scheme 4. Evaluation of Complex Sulfamate Ester Substrates.

^aGeneral reaction conditions: 1.0 equiv sulfamate, 1.5 equiv (hetero)aryl bromide, photocatalyst (1 mol %), NiBr₂•glyme (5 mol %), DBU (3.0 equiv), MeCN (0.25 M), with stirring in front of two 34W blue Kessil lamps for 24–48 h. See Supplementary Information for specific experimental details.

This protocol may prove useful for the evaluation of sulfamate esters during lead optimization. N-aryl sulfamate esters have been assessed during the investigation of analogues of topiramate, an FDA approved anticonvulsant that incorporates a sulfamate ester.¹⁶ Indeed, topiramate undergoes arylation to furnish N-phenyl topiramate (2ad). This approach represents a marked improvement in efficiency over the previously reported route,¹⁴ and makes use of commercially available topiramate as a substrate.

Herein, the N-(hetero)arylation of sulfamate esters has been shown to proceed using a dual photochemically-driven, nickel-catalyzed reaction manifold. This approach marks the first use of sulfamate esters as nucleophiles in a C–N coupling reaction, and avoids potentially competitive and undesired N-alkylation processes. This general technology enables the installation of a diverse range of aryl and heteroaryl substituents onto both simple and complex O-alkyl sulfamate ester substrates, which we expect will facilitate future evaluation of N-(hetero)aryl sulfamate esters. As such, this method compliments synthetic strategies to prepare N-substituted sulfamate esters, and expands the breadth of accessible nitrogen-containing small molecules.