Photochemically-mediated nickel-catalyzed synthesis of N-(hetero)aryl sulfamides

Abstract

A general method for the N-arylation of sulfamides with aryl bromides is described. The protocol leverages a dual-catalytic system, with [Ir(ppy)₂(dtbbpy)]PF₆ as a photosensitizer, NiBr₂•glyme as a precatalyst, and DBU as a base, and proceeds at room temperature under visible light irradiation. Using these tactics, aryl boronic esters and aryl chlorides can be carried through the reaction untouched. The developed reactions efficiently engage simple bromoarenes and primary sulfamides in between 66% and quantitative yields. For more challenging substrates, such as secondary sulfamides, reaction efficiency is documented. Thereby, these methods complement known Buchwald-Hartwig coupling methods for N-arylation of sulfamides.

Graphical Abstract

INTRODUCTION

N-Aryl sulfamides are critical components of active pharmaceutical¹ and agrochemical² agents (Figure 1).^{3, 4} In drug discovery, sulfamides can be valuable analogues of sulfamate, sulfonamide, urea, carbamate, and amide functional groups.^1a In reactions, N,N’-disubstituted sulfamides are useful as chiral auxiliaries,⁵ as organocatalysts,⁶ as reagents to promote dehydration,⁷ as precursors to sterically encumbered carbon–carbon bonds⁸ and as directing groups for C–H functionalization processes.⁹ Despite the potential of this valuable functional group, sulfamides may be underutilized due to limitations in practical methods for their preparation.^{10, 11, 12}

Figure 1.

N-heteroaryl sulfamides are important FDA-approved drugs and therapeutic targets

To date, approaches to prepare N-(hetero)aryl sulfamides rely on N–S bond-forming reactions that involve the nucleophilic addition of amines to SO₂ sources (not depicted),^{12, 13} or on C–N bond-forming strategies (Scheme 1). These direct methods for C–N bond formation have been primarily limited to nucleophilic substitution reactions (Scheme 1A), copper-mediated Chan-Lam coupling processes that transform sulfamoyl azides (Scheme 1B),¹⁴ and Buchwald-Hartwig amination conditions that are palladium-mediated (Scheme 1C).^{15, 16, 17} Herein disclosed is the first photochemically-mediated, nickel-catalyzed method to access N-(hetero)aryl sulfamides.

Scheme 1.

Recent advances allow for diverse and complementary strategies for the synthesis of N-(hetero)aryl sulfamides

These investigations are inspired by a pioneering disclosure by Buchwald, MacMillan, and co-workers, who together have developed a light-driven dual nickel- and iridium-catalyzed amination reaction¹⁸ that has sparked an ongoing revolution in nickel-mediated C–N bond forming technologies (Scheme 2).^{19, 20, 21, 22} These approaches have been developed in parallel with recent innovations in copper-mediated reactions,²³ and complement palladium-mediated protocols in terms of the range of nucleophilic coupling partners engaged and breadth of arenes tolerated.^{18, 20} Accordingly, we anticipated that the developed photo-driven, nickel-catalyzed processes would afford an efficient, robust, and complementary strategy to access valuable N-(hetero)aryl sulfamides. ²⁴

Scheme 2.

This research extends the development of light-driven dual catalytic C–N bond-forming technologies, first pioneered by Buchwald, MacMillan, and co-workers¹⁸

Results and Discussion

We²⁰ and others^.19c have observed that, relative to electron-deficient arylbromides, electron-rich arylbromides can be more challenging electrophiles when employing nickel-mediated cross-coupling technologies. Accordingly, we optimized the reactions of sulfamide 1a with electron-deficient 4-(trifluoromethyl)bromobenzene and electron-rich 4-(tert-butyl)bromobenzene concurrently (Table 1).

Table 1.

Optimization informs distinct conditions for electron-deficient and electron-rich aryl bromides^a

entry	R	X	[Ni] (mol %)	ligand	solvent	unreacted 1a (%)b	yield (%)b
1	CF3	Br	5	–	MeCN	0	>98c
2	CF3	I	5	–	MeCN	10	79
3	CF3	Cl	5	–	MeCN	39	43
4	tBu	Br	5	–	MeCN	30	32
5	tBu	Br	10	–	MeCN	22	33
6	tBu	Br	10	dtbbpy	MeCN	12	47
7	tBu	Br	10	dtbbpy	EtOH	7	89c
8	tBu	Br	10	dtbbpy	9:1 MeCN: EtOH	5	90
9	tBu	Br	10	dtbbpy	EtOH with H2O (100 equiv)	72	6
10	tBu	Br	10	dtbbpy	MeOH	27	76
11	tBu	Br	10	dtbbpy	iPrOAc	50	7
12	tBu	Br	10	dtbbpy	CH2Cl2	38	0
13	tBu	Br	10	dtbbpy	DMSO	27	32
14	tBu	Br	10	dtbbpy	acetone	46	35
15	tBu	Br	10	dtbbpy	2-methyl tetrahydrofuran	26	23
16	CF3	Br	5	–	EtOH	18	70
17	CF3	Br	5	–	MeOH	12	81c
18	tBu	I	10	dtbbpy	EtOH	6	81
19	tBu	Cl	10	dtbbpy	EtOH	60	7

^aGeneral reaction conditions: sulfamide 1a (1.0 equiv), aryl halide 2 (1.5 equiv), NiBr₂•glyme, [Ir(ppy)₂(dtbbpy)]PF₆ (1 mol %), DBU (3.0 equiv), and ligand (4 mol %) in indicated solvent (0.25 M) with stirring and irradiation between two 34 W blue Kessil lamps for 24 h.

^bYields determined by ¹H NMR using an internal standard of 2,3,5,6–tetrachloronitrobenzene.

^cIsolated yield.

Relying on previously established conditions for the arylation of sulfamate esters,²⁰ in the presence of light, [Ir(ppy)₂(dtbbpy)]PF₆ as a photosensitizer, NiBr₂•glyme as a precatalyst, and DBU as a base, sulfamide 1a reacts with 4-(trifluoromethyl)bromobenzene to afford N-aryl sulfamide 3a in quantitative yield (Table 1, entry 1). This synthetic protocol can transform aryl chloride and iodide electrophiles, albeit in diminished yields (entries 2–3). Unsurprisingly, sulfamide 1a reacts with 4-(tert-butyl)bromobenzene inefficiently (entries 4–5). Consistent with previous observations,^{19c, 20} higher turnover numbers can be achieved when 4,4’-di-tert-butyl-2,2’-dipyridyl (dtbbpy) is employed as a ligand for nickel (entry 6).

To our surprise, the efficiency of this reaction improves substantially when it is run in absolute ethanol, or with ethanol as a co-solvent (entries 7–8). Importantly, the solvent and the aryl bromide do not engage in undesirable C–O coupling processes, as the predicted products of these processes are not detected. Unfortunately, the reaction efficiency drops in the presence of 100 equiv of water (entry 9).²⁵ When we assessed a single solvent from each of seven solubility clusters,²⁶ the reaction was less efficient in these other solvents (entries 10–15). The advantages of ethanol were isolated to reactions engaging this more electron-rich aryl bromide, and did not translate to the reaction of 4-(trifluoromethyl)bromobenzene (entries 16–17). This synthetic protocol can be used to transform aryl iodide electrophiles but does not transform electron-rich aryl chlorides in synthetically useful efficiencies (entries 18–19). Control experiments confirm that nickel, base, and light are critical to the success of the cross-coupling reaction (see supporting information for details).

The design for photocatalyst evaluation was inspired by MacMillan and co-workers’ approach to gathering preliminary data to interrogate their hypothesis about the mechanism of their sulfonamidation reaction. MacMillan and co-workers correlate photocatalyst efficiency with catalyst oxidation potentials and triplet state energies (E_T). They use these correlations to interrogate their hypothesis that their light-driven dual catalytic C–N sulfonamidation reaction productively engages the excited state photocatalyst not to drive electron transfer, but rather to transfer energy to a reaction intermediate. ^19c If an excited state photocatalyst mediates a reaction based on energy transfer, efficient photocatalysts would be expected to have triplet state energies that cluster around a narrow range of values. Indeed, this phenomena has been reported in light-driven dual catalytic C–N bond-forming reactions with sulfonamides,^19c and sulfamate esters.²⁰

Fortunately, many photosensitizers drive the developed sulfamide arylation reactions (Tables 2 and S8). The optimized reaction conditions rely on [Ir(ppy)₂(dtbbpy)]PF₆ as a photosensitizer (Table 1; Table 2, entries 3, 11). More generally, to date, the most efficient reactions rely on photoexcitable metal complexes with triplet state energies (E_T) in the range of 46.2–49.2 kcal/mol (Table 2, entries 3–5, 11–13), which would be expected for reactions mediated by energy transfer from an excited state photocatalyst to a reaction intermediate. Importantly, these N-arylation reactions are more efficient in the presence of a photochemical mediator, suggesting that light-harvesting by the photocatalyst is important to the efficiency of the developed reaction protocols (Table 2, entries 8, 16). Nevertheless, in ethanol absent photocatalyst, the product yield is not insignificant (entry 16). Under these conditions, any product that forms may be generated through a mechanism that involves direct excitation of an intermediate nickel species by light, as this process can drive nickel-mediated C–N bond-forming reactions,²² and direct photochemical excitation of a nickel complex cannot be ruled out as a contributing to product formation in ethanol. While these data are suggestive of processes that rely on energy transfer from an excited state photocatalysts, these data are not conclusive.

Table 2.

Reaction efficiency is maximized when photocatalyst triplet state energies are within the range of 46.2–49.2 kcal/mol

entry	R	Photocatalyst	E1/2 (Pc*/Pc−) (V vs SCE)	ET (kcal/ mol)	1a (%)b	3 (%)b
1a	CF3	4b	+1.21d	60.4d	78	14
2 a	CF3	4c	+0.97e	60.1e	78	12
3 a	CF3	4a	+0.66f	49.2e	< 5	92
4 a	CF3	4d	+0.58 g	47.7g	9	85
5 a	CF3	4e	+0.61 g	46.3g	9	81
6 a	CF3	4f	+0.74g	39.2g	57	33
7 a	CF3	4g	+1.37h	46.5h	59	32
8 a	CF3	none	–	–	77	< 5
9 b	tBu	4b	+1.21d	60.4d	78	12
10 b	tBu	4c	+0.97e	60.1e	62	26
11 b	tBu	4a	+0.66f	49.2e	21	78
12 b	tBu	4d	+0.58 g	47.7g	21	73
13 b	tBu	4e	+0.61 g	46.3g	22	71
14 b	tBu	4f	+0.74g	39.2g	68	15
15 b	tBu	4g	+1.37h	46.5h	30	61
16 b	tBu	none	–	–	78	13

^aGeneral conditions: sulfamide 1a (1.0 equiv, 0.2 mmol scale), 4-bromobenzotrifluoride (1.5 equiv), photocatalyst (1 mol %), NiBr₂•glyme (5 mol %), and DBU (3.0 equiv) in MeCN (0.25 M) with stirring between two 34W blue Kessil lamps for 24 h.

^bGeneral conditions: sulfamide 1a (1.0 equiv, 0.2 mmol scale), bromo-4-(tert-butyl)benzene (1.5 equiv), photocatalyst (1 mol %), NiBr₂•glyme (10 mol %), DBU (3.0 equiv), and dtbbpy (4 mol %) in EtOH (0.25 M) with stirring between two 34W blue Kessil lamps for 24 h.

^cYields and unreacted starting material determined by ¹H NMR using an internal standard of 2,3,5,6–tetrachloronitrobenzene.

^dE_T in (kcal/mol), E_1/2 (V vs SCE) in MeCN²⁷

^eE_T in (kcal/mol), E_1/2 (V vs SCE) in MeCN ²⁸

^fE_1/2 (V vs SCE) in MeCN²⁹

^gE_T in (kcal/mol), E_1/2 (V vs SCE) in MeCN.^19c

^hE_T in (kcal/mol), E_1/2 (V vs SCE) in MeCN³⁰

Indeed, only recently, Miyake and co-workers have disclosed the first studies to provide unambiguous evidence that a light-driven dual catalytic C–N bond-forming reaction proceeds not based on electron transfer to the excited state photocatalyst, but instead based on energy transfer from an excited state photocatalyst.^19f Miyake, Thordarson, and co-workers’ investigations rely on the ability to isolate intermediate nickel amine complexes, and study them spectroscopically. A thorough and rigorous analysis of the mechanism(s) of the developed reactions is beyond the scope of this manuscript.

The developed dual catalyzed processes offer complementary reactivity profiles to those available through palladium-mediated Buchwald-Hartwig reactions. We have employed the ligand-free protocol to recapitulate palladium-mediated C–N bond-forming reactions to access arylated 3c and 3d.^16a The developed nickel-mediated transformations furnish these products with increased yields relative to those documented using a known palladium-mediated protocol,^16a suggesting that this nickel-mediated approach is worthy of concurrent investigation in the course of synthetic campaigns. Given our interest in functionalized pyridines,³¹ we were pleased to find that bromopyridines were effective arylating agents using the disclosed protocol. Furthermore, this dual catalytic reaction manifold can transform aryl bromides, without engaging either C(sp²)–B (3e) and C(sp²)–Cl (3f-g) bonds to afford products with useful synthetic handles for further functionalization.

The ligand-free protocol arylates N,N-disubstituted sulfamides in synthetically useful yields, to access products that incorporate N-morpholino groups (i.e. 3a–3g), N,N-dimethylated sulfamides (i.e 3h–3i), and N-carbonyl-N-alkylated sulfamides (i.e. 3j). In this arylation reaction, such N-carbonyl-N-alkylated sulfamides are appropriate surrogates for N-monosubstituted sulfamides, which do not react cleanly under the developed reaction conditions.³² Notably, this protocol does not productively transform a secondary sulfamide substrate unless a modified procedure is used that employs less base (c.f. 3i). This change in protocol may partially mitigate base-catalyzed decomposition of sulfamide substrate, a competitive process that has been reported in some reactions that engage electron-rich, tri-substituted sulfamides.^{10, 33}

In general, electron-deficient aryl bromides N-arylate sulfamides in good to excellent yields (Scheme 3, 3c–3h, 3j). By contrast, in acetonitrile, some electron-rich aryl bromides can be incorporated into the product with limited efficiency (c.f. Table 1, entry 4). Indeed, 3-bromo thiophene reacts with a primary sulfamide to furnish sulfamide 3k in limited yield. Nevertheless, this reaction suggests that this protocol overcomes the common tendency of nickel catalysts to engage in C–S bond activation³⁶ or to be deactivated upon reaction with sulfur.

Scheme 3.

Photochemically-mediated nickel-catalyzed conditions engage a variety of electron-deficient aryl bromides and sulfamides

^a General conditions: sulfamide 1 (1.0 equiv), (hetero)aryl bromide (1.5 equiv), [Ir(ppy)₂(dtbbpy)]PF₆ (1 mol %), NiBr₂•glyme (5 mol %), and DBU (3.0 equiv unless otherwise specified) in MeCN (0.25 M) with stirring between two 34W blue Kessil lamps for 24–48 h. ^b Isolated yield through a palladium-mediated cross-coupling reaction.^16ac Isolated yield when prepared from subjecting morpholinyl sulfamoyl chloride³⁴ following literature conditions.^35d DBU (0.5 equiv).

Fortunately, with the use of EtOH as a solvent and inclusion of a ligand, the protocol can transform a similar range of sulfamide substrates and allows the efficient cross-coupling of electronically-varied (hetero)aryl bromides (Scheme 4). Specifically, para- and meta-substituted N-aryl sulfamides 3l and 3m were synthesized with similar or improved yields relative to those reportedly isolated upon reaction of morpholinyl sulfamyl chloride with anilines. As anticipated, under these conditions, aryl bromides can react, without engaging either C(sp²)–B and C(sp²)–Cl bonds, to afford products 3e and 3n with useful synthetic handles for further functionalization. Furthermore, these conditions can be used to install heteroaryl groups including a pyrimidine (3o). Unfortunately, the installation of more conjugated benzothiazole, tert-butyl indole-1-carboxylate, quinoline, and 2-methylnaphthalene moieties has proven less efficient (c.f. 3p–3t). By comparison, while 13% yield of the quinoline analogue 3r can be isolated under the developed nickel/iridium-mediated conditions, its preparation has proven more efficient by way of nucleophilic substitution on sulfur(VI), which proceed in 57% yield.^13b

Scheme 4.

Photochemically-mediated nickel-catalyzed reactions proceed in ethanol

^a General conditions: sulfamide 1 (1.0 equiv), (hetero)aryl bromide (1.5 equiv), [Ir(ppy)₂(dtbbpy)]PF₆ (1 mol %), NiBr₂•glyme (10 mol %), dtbbpy (4 mol %) and DBU (3.0 equiv) in EtOH (0.25 M) with stirring between two 34 W blue Kessil lamps for 24–96 h. ^b Isolated yield when prepared from N,N-dichlorosulfamide.^37c Isolated yield when prepared from sulfamic acid.^13b

In EtOH, some variations in sulfamide substitution are well tolerated. The reaction engages N,N-disubstituted sulfamides in synthetically useful yields, with examples producing N-morpholino 3e, 3l–3q, N-carbonyl-N-alkylated 3u, and N,N-dimethylated 3v sulfamides. In this arylation reaction, N-carbonyl-N-alkylated sulfamides, like 3u, are appropriate surrogates for more sterically accessible sulfamides, such as 3r and 3t, which cannot be efficiently derived directly from N-monosubstituted sulfamides. Notably, N-monosubstituted sulfamides can be forced to engage in monoarylation reactions when larger aryl bromide electrophiles are employed, albeit in low efficiency. Further, this protocol does not provide efficient access to a tetrasubstituted sulfamide 3w. Ultimately, these protocols are most effective when using primary N,N-disubstituted sulfamides as substrates.

Conclusion

We have developed a new catalytic method for sulfamide N-(hetero)arylation. This protocol offers several attributes, as it proceeds under mild conditions, and employs a variety of readily available substrates and reagents that complements the range that may be used under palladium-mediated Buchwald-Hartwig reaction conditions. The developed photo-driven nickel-mediated tactics can be employed with (hetero)aryl bromide, iodide, and chloride electrophiles. Fortunately, owing to the higher reaction efficiency with (hetero)aryl bromides, aryl boronic esters and aryl chlorides can be carried through the reaction untouched, so these useful synthetic handles can be retained for further synthetic manipulation. Owing to these attributes, this method extends chemists’ ability to use a sulfamide in the most versatile step a medicinal chemistry campaign, the “production step.”³⁸ Moreover, it broadens the synthetic access to N-(hetero)aryl sulfamides, which are of increasing pharmacological interest.

Experimental

General Considerations.

Moisture-sensitive reactions were performed using flame-dried glassware under an atmosphere of dry nitrogen (N₂). Air- and water-sensitive manipulations, where noted, were performed in an MBraun MB200 glove box held under an atmosphere of nitrogen gas (working pressure 2–6 mbar). Flame-dried equipment was stored in a 130 °C oven before use and either allowed to cool in a cabinet desiccator or assembled hot and allowed to cool under an inert atmosphere. Air- and moisture-sensitive liquids and solutions were transferred via plastic or glass syringe or by stainless steel cannula. Chromatographic purification of products was accomplished by flash column chromatography using Silicycle Silica flash F60 (particle size 40–63 μm, 230–400 mesh).³⁹ Thin layer chromatography was performed on EMD Millipore silica gel 60 F254 glass-backed plates (layer thickness 250 μm, particle size 10–12 μm, impregnated with a fluorescent indicator). Visualization of the developed chromatogram was accomplished by fluorescence quenching under shortwave UV light and/or by staining with p-anisaldehyde, ninhydrin, or KMnO₄ stains followed by heating. Room temperature is 22–23 °C. NMR spectra were obtained at 20–23 °C on Varian iNOVA spectrometers operating at 400 or 500 MHz for ¹H NMR, 126 MHz for ¹³C NMR, and 376 or 470 MHz for ¹⁹F NMR, and are reported as chemical shifts (δ) in parts per million (ppm). Spectra were referenced internally according to residual solvent signals (¹H: CDCl₃, 7.26 ppm; CD₂Cl₂, 5.32 ppm; CD₃CN, 1.94 ppm; DMSO-d₆, 2.50 ppm; Acetone-d₆, 2.05 ppm. ¹³C: CDCl₃, 77.2 ppm; CD₃CN, 118.3 ppm; DMSO-d₆, 39.5 ppm; Acetone-d₆, 206.3 ppm). Data for NMR spectra use the following abbreviations to describe multiplicity: s, singlet; br s, broad singlet; d, doublet; t, triplet; dd, doublet of doublets; td, triplet of doublets; tt, triplet of triplets; app t, apparent triplet; app dd, apparent doublet of doublets; app td, apparent triplet of doublets; m, multiplet. Coupling constant (J) are reported in units of Hertz (Hz). IR spectra were obtained on a Nicolet iS50 FT-IR system. Peaks are reported in cm^–1 with indicated relative intensities: s (strong, 0–33% T); m (medium, 34–66% T); w (weak, 67–95% T); and br (broad). High resolution mass spectra (HRMS, m/z) were recorded on an Agilent LCMS-TOF-DART spectrometer using electrospray ionization (ESI, Duke University Department of Chemistry Instrumentation Center). Ultraviolet/visible/near-infrared (UV-Vis-NIR) spectra were obtained on an Agilent Cary 5000 UV−vis−NIR spectrophotometer. Lamps were allowed to warm up for a minimum of 30 minutes prior to background or spectral data being collected. All visual representations of data collected were produced in Microsoft Excel under the Duke University Microsoft Office 365 license. Blue Kessil H150 LED Grow Light LED: 30W High Luminous DEX 2100 LED, emission wavelength range: ca. 400–500 nm, dimensions: 4.49” length × 2.48” diameter, power supply: 100–240V AC (Input), 24V DC (Output) S4, power usage: 36W (40W max), http://www.kessil.com/horticulture/H150.php

Preparation of sulfamides via the (tert-butyl)carbamate sulfamoylation of amines:

General Procedure A.

Sulfamides were prepared according to modified literature procedures.⁴⁰ A flame-dried round bottom flask equipped with a stir bar was evacuated and filled with nitrogen. The flask was then charged with chlorosulfonyl isocyanate (CSI, 1.5 equiv) in diethyl ether (1M) and placed in an ice bath. To this flask was added dropwise neat tert-butanol (1.49 equiv). Following this addition, the flask was removed to from the ice bath and allowed to warm to room temperature with continued stirring for 1 hour. At 1 hour of reaction time, the solution was diluted with hexanes (100% initial volume of diethyl ether) and concentrated under reduced pressure, without heating, to yield a powdery, white solid. This solid was then dissolved in acetonitrile (1M), flask was evacuated and filled with nitrogen. A separate flame-dried round bottom flask was charged with the amine substrate (1.0 equiv), triethylamine (1.5 equiv), and acetonitrile (1M). Both flasks were then placed in an ice bath and the solution containing the amine substrate was added dropwise by cannula transfer to the solution of sulfamoyl chloride over the course of 10–60 minutes. Transfer of the amine solution was made quantitative with additional acetonitrile (5–10% of initial volume). The reaction mixture was allowed to continue stirring as the ice bath warmed to room temperature. Upon completion of the reaction, as determined by TLC analysis, the reaction was quenched by the addition of saturated aqueous NaCl (ca. 10 mL/mmol of amine substrate). The mixture was transferred to a separatory funnel, and the aqueous layer was extracted with portions of ethyl acetate (three times ca. 10 mL/mmol of amine substrate). The organic phase was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to less than 10% initial volume. The resulting concentrate was diluted in dichloromethane (4M), to which, trifluoroacetic acid (0.66M) was carefully (!) added portion-wise over 30–60 minutes. Gas evolution was observed upon addition of the acid and care was taken to avoid foaming or overheated from rapid addition. The reaction was allowed to continue stirring at room temperature until completion of the reaction, as determined by TLC analysis. The reaction was concentrated under reduced pressure onto silica gel and purified by silica gel flash chromatography using conditions indicated below to isolate pure sulfamide products. The preparation and characterization of sulfamides 1b⁴¹ and 1e⁴² have been previously published.

Preparation of sulfamides via the sulfamoylation of amines:

General Procedure B.

Sulfamides were prepared according to modified literature procedures.⁴³ A flame-dried round bottom flask equipped with a stir bar was evacuated and filled with nitrogen. The flask was then charged with chlorosulfonyl isocyanate (CSI, 1.5 equiv) and placed in an ice bath. To this flask was added dropwise neat formic acid (1.5 equiv). During addition, vigorous gas evolution was observed, and the solution solidified as a white solid. Stirring continued for 5 minutes at 0 °C. Next, the solid was dissolved in acetonitrile (1M). The flask was removed from the ice bath and allowed to warm to room temperature, where it stirred for 12–18 hours. A separate flame-dried round bottom flask equipped with a stir bar was charged with amine substrate (1.0 equiv), triethylamine (1.5 equiv), and acetonitrile (1M). Both flasks were then placed in an ice bath and the solution containing amine substrate was added dropwise by cannula transfer to the solution of sulfamoyl chloride over the course of 10–60 minutes. Transfer of the amine solution was made quantitative with additional acetonitrile (5–10% of initial volume). The reaction mixture was allowed to continue stirring, as the ice bath warmed to room temperature. Upon completion of the reaction, as determined by TLC analysis, the reaction was quenched by the addition of saturated aqueous NaCl (ca. 10 mL/mmol of amine substrate). The mixture was transferred to a separatory funnel, and the aqueous layer was extracted with portions of ethyl acetate (three times ca. 10 mL/mmol of amine substrate). The organic phase was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resultant residue was purified by silica gel flash chromatography using the conditions indicated below to isolate pure sulfamide products. The characterization of sulfamide 1d has been previously published.⁴⁴

Morpholine-4-sulfamide (1a).

Prepared from morpholine (3.99 g, 45.0 mmol, 1.0 equiv) following general procedure A. The product was obtained as a white, amorphous solid (5.444 g, 72% yield) after silica gel column chromatography using hexanes:EtOAc (gradient elution, 4:1 to 1:4). The obtained spectrum matched that reported in the literature.^{3b 1}H NMR (400 MHz, DMSO-d₆) δ 6.83 (s, 2H), 3.65 (t, J = 4.7 Hz, 4H), 2.91 (t, J = 4.7 Hz, 4H) ppm. ¹³C{¹H} NMR (126 MHz, acetone-d₆) δ 66.7 (s), 47.3 (s) ppm. IR (neat) ν 3299 (br), 3177 (br), 3079 (br), 2994 (w), 2929 (w), 2870 (w), 1564 (w), 1472 (w), 1462 (w), 1348 (s), 1330 (m), 1299 (m), 1264 (m), 1219 (w), 1145 (m), 1109 (s), 1071 (s), 1022 (w), 933 (s), 905 (m), 849 (m), 753 (s), 628 (m), 534 (s), 429 (m) cm⁻¹. TLC R_f = 0.18 in 1:1 hexanes:EtOAc.

N,N-(dimethyl) sulfamide (1b)

Prepared from N,N-(dimethyl) sulfamoyl chloride (1.1 mL, 10 mmol, 1.0 equiv) and 30% aqueous ammonium hydroxide (5 mL) according to known literature procedures.⁴⁵ The product was obtained as a white, amorphous solid (0.443 g, 37% yield) after extraction by acetone. ¹H NMR (400 MHz, acetone-d₆) δ 5.93 (br, 2H), 2.69 (s, 6H). TLC R_f = 0.23 in 1:1 hexanes:EtOAc The obtained spectrum matched that reported in the literature.⁴⁵

tert-butyl pentyl(sulfamoyl)carbamate (1c).

Prepared from tert-butylpentyl carbamate⁴⁶ (1.87 g, 10 mmol, 1.0 equiv) following general procedure B. The product was obtained as a white, amorphous solid (0.386 g, 15% yield) after silica gel column chromatography using acetone:hexanes (gradient elution, 1:19 to acetone:hexanes). ¹H NMR (500 MHz, CDCl₃) δ 5.33 (br, 2H), 3.66 (t, J = 7.6 Hz, 2H), 1.68 – 1.62 (m, 2H), 1.53 (s, 9H), 1.35 – 1.25 (m, 4H), 0.90 (t, J = 7.2 Hz, 3H) ppm. ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 152.6, 82.3, 47.8, 29.4, 28.9, 28.2, 22.4, 14.1 ppm. IR (neat) ν 3354 (br), 3269 (br), 3120 (w), 2972 (w), 2941 (w), 2859 (w), 1694 (s), 1566 (w), 1456 (w), 1367 (s), 1345 (m), 1330 (m), 1309 (m), 1293 (m), 1284 (m), 1247 (m), 1216 (w), 1186 (m), 1168 (m), 1140 (br), 1031 (w), 1011 (w), 979 (w), 913 (m), 845 (m), 786 (m), 771 (m), 720 (s), 638 (s), 584 (m), 566 (s), 532 (s), 468 (m), 420 (w), 403 (w) cm⁻¹. TLC R_f = 0.56 in 4:1 hexanes:EtOAc. HRMS (ESI) m/z: [M+Na]⁺ Calcd for C₁₀H₂₂N₂O₄S•Na⁺: 289.1193; Found 289.1197.

n-Pentyl sulfamide (1d)

Prepared from n-pentyl amine (0.701 g, 10 mmol, 1.0 equiv) following general procedure B. The product was obtained as a white, amorphous solid (0.398 g, 31% yield) after silica gel column chromatography using hexanes:EtOAc (gradient elution, 9:1 to 1:1). ¹H NMR (400 MHz, CDCl₃) δ 4.48 (br s, 2H), 4.23 (br s, 1H), 3.13 (q, J = 6.8 Hz, 2H), 1.60 – 1.56 (m, 2 H), 1.32 – 1.36 (m, 4H), 0.91 (t, J = 6.9 Hz, 3H). TLC R_f = 0.35 in 1:1 hexanes:EtOAc. The obtained spectrum matched that reported in the literature.⁴⁷

N,N,N’-(trimethyl) sulfamide (1e)

Prepared from N,N-(dimethyl) sulfamoyl chloride (0.8 mL, 7.5 mmol, 1.0 equiv) and methylamine 2.0 M in THF (7.5 mL, 15.0 mmol, 2.0 equiv) according to known literature procedures.⁴⁸ The product was obtained as a clear, yellow oil (1.036 g, ≥98% yield) after silica gel column chromatography using hexanes:acetone (gradient elution, 4:1 to 1:1). ¹H NMR (500 MHz, CDCl₃) δ 4.41 (br s, 1H), 2.80 (s, 6H), 2.71 (d, J = 5.3 Hz, 3H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 38.1, 29.8. IR (neat) ν 3306 (br), 2924 (w), 1635 (w), 1458 (w), 1415 (w), 1313 (m), 1261 (w), 1185 (w), 1142 (m), 1076 (m), 1051 (m), 952 (m), 834 (m), 697 (m), 590 (m), 511 (m), 426 (m), 406 (m) cm⁻¹. TLC R_f = 0.12 in 3:1 hexanes:acetone HRMS (ESI) m/z: [M+H]⁺ Calcd for C₃H₁₁N₂O₂S⁺: 139.0536; Found 139.0535.

Photochemically driven, nickel-catalyzed N-(hetero)arylation of sulfamides (for electron-deficient and electron-neutral (hetero)aryl bromides):

General Procedure C.

A 10 mL microwave tube (CG-4920–01) equipped with a stir bar was charged with [Ir(ppy)₂dtbbpy]PF₆ (4.7 mg, 0.005 mmol, 0.01 equiv), sulfamide (0.5 mmol, 1.0 equiv), and if solid, (hetero)aryl bromide (0.75 mmol, 1.5 equiv). The vial was then transferred into a nitrogen-filled glovebox where it was charged with nickel (II) bromide glyme (NiBr₂•glyme, 7.7 mg, 0.025 mmol, 0.05 equiv), and partially solubilized upon syringe addition of anhydrous acetonitrile (2 mL). The mixture turned bright green-blue. The microwave tube was sealed with a crimp cap containing a Teflon lined septum and removed from the glovebox. If liquid, the (hetero)aryl bromide (0.75 mmol, 1.5 equiv) was added by syringe to the mixture, followed by DBU (1.5 mmol, 3.0 equiv). Upon addition, the mixture turned dark yellow. The reaction mixture was placed in front of two 34W blue LED lamps, approximately 5–10 cm away from each light source. The reaction mixtures were then stirred at ~1000 rpm with cooling via air circulation for at least 24 hours (temperatures were found to stay below 30 °C). The reaction mixtures were then removed from irradiation and the caps were removed. The reaction mixtures were diluted with ethyl acetate (ca. 25 mL) and transferred to a separatory funnel. The mixture was washed with 1M aqueous hydrochloric acid (ca. 25 mL). The aqueous phase was then extracted with additional ethyl acetate (ca. 2 × 10 mL). The combined organic phases were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was then purified by silica gel flash chromatography eluting with the indicated solvent system. Deviations from the general procedure are noted below.

Photochemically driven, nickel-catalyzed N-(hetero)arylation of sulfamides with dtbbpy in ethanol:

General Procedure D.

A 10 mL microwave tube (CG-4920–01) equipped with a stir bar was charged with [Ir(ppy)₂dtbbpy]PF₆ (4.7 mg, 0.005 mmol, 0.01 equiv), sulfamide (0.5 mmol, 1.0 equiv), dtbbpy (5.4 mg, 0.02 mmol, 0.04 equiv), and if solid, (hetero)aryl bromide (0.75 mmol, 1.5 equiv). The vial was then transferred into a nitrogen-filled glovebox where it was charged with nickel (II) bromide glyme (NiBr₂•glyme, 15.6 mg, 0.05 mmol, 0.1 equiv). The microwave tube was sealed with a crimp cap containing a Teflon lined septum and removed from the glovebox. The microwave tube was charged with ethanol (200 proof abs., 2.0 mL) by syringe. If liquid, the (hetero)aryl bromide (0.75 mmol, 1.5 equiv) by syringe to the solution, followed by DBU (1.5 mmol, 3.0 equiv). Upon addition, the solution turned dark yellow in color. The reaction mixture was placed in front of two 34W blue LED lamps, approximately 5–10 cm away from each light source. The reaction solution was then stirred at ~1000 rpm with cooling via air circulation for 24 hours (temperatures were found to stay below 30 °C). The reaction solution was then removed from irradiation and the cap was removed. The reaction solution was diluted with ethyl acetate (ca. 25 mL) and transferred to a separatory funnel. The organic phase was washed with 1M aqueous hydrochloric acid (ca. 25 mL). The aqueous phase was then extracted with additional ethyl acetate (ca. 2 × 10 mL). The combined organic phases were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was then purified by silica gel flash chromatography eluting with the indicated solvent system. Deviations from the general procedure are noted below.

N-(4-(trifluoromethyl)phenyl)morpholine-4-sulfamide (3a).

Prepared from 1a (0.5 mmol, 1.0 equiv) and 4-bromobenzotrifluoride (0.75 mmol, 1.5 equiv) following general procedure C. The product was obtained as a yellow solid (155 mg, ≥98% yield) after silica gel column chromatography using hexanes:EtOAc (gradient elution, 9:1 to 1:1). ¹H NMR (500 MHz, CDCl₃) δ 7.58 (d, J = 8.6 Hz, 2H), 7.26 (d, J = 8.6 Hz, 2H), 7.06 (s, 1H), 3.68 (t, J = 4.7 Hz, 4H), 3.28 (t, J = 4.7 Hz, 4H) ppm. ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 140.4 (s), 124.4 (q, J = 271.6 Hz), 126.8 (q, J = 3.7 Hz), 126.3 (q, J = 32.5 Hz), 118.9 (s), 66.2 (s), 46.5 (s) ppm. ¹⁹F NMR (376 MHz, CDCl₃) δ −62.20 (s) ppm. IR (neat) ν 3279 (br), 2863 (w), 1617 (w), 1521 (w), 1456 (w), 1404 (w), 1321 (s), 1298 (m), 1263 (m), 1237 (w), 1153 (s), 1107 (s), 1067 (s), 1015 (m), 939 (w), 837 (m), 734 (m), 659 (m), 637 (m), 621 (m), 593 (m), 571 (m), 524 (m), 507 (m), 469 (m) cm⁻¹. TLC R_f = 0.58 in 1:1 hexanes:EtOAc. HRMS (ESI) m/z: [M+H]⁺ Calcd for C₁₁H₁₄F₃N₂O₃S⁺: 311.0672; Found 311.0676.

N-(4-(tert-butyl)phenyl)morpholine-4-sulfamide (3b).

Prepared from 1a (0.5 mmol, 1.0 equiv) and bromo-4-(tert-butyl)benzene (0.75 mmol, 1.5 equiv) following general procedure D. The product was obtained as a white solid (133 mg, 89% yield) after silica gel column chromatography using hexanes:EtOAc (gradient elution, 9:1 to 1:1). Prepared from 1a (1.0 mmol, 1.0 equiv) and bromo-4-(tert-butyl)benzene (1.5 mmol, 1.5 equiv) following general procedure D, using double the amount of all reagents. The product was obtained as a white solid (243.7 mg, 82% yield) after silica gel column chromatography hexanes:EtOAc (gradient elution 3:2 to 1:4). ¹H NMR (400 MHz, CDCl₃) δ 7.33 (d, J = 8.5 Hz, 2H), 7.13 (d, J = 8.5 Hz, 2H), 6.8 (s, 1H), 3.66 (t, J = 4.8 Hz, 4H), 3.25 (t, J = 4.8 Hz, 4H), 1.30 (s, 9H) ppm. ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 148.3, 134.3, 126.4, 120.7, 66.3, 46.5, 34.5, 31.5 ppm. IR (neat) ν 3183 (w), 2963 (w), 2917 (w), 2861 (w), 1613 (w), 1512 (m), 1447 (m), 1400 (w), 1364 (m), 1349 (m), 1332 (w), 1331 (w), 1262 (m), 1239 (w), 1193 (w), 1156 (s), 1127 (m), 1106 (m), 1077 (m), 1068 (m), 1017 (m), 947 (m), 911 (m), 852 (m), 843 (m), 837 (m), 819 (m), 737 (m), 712 (m), 638 (w), 614 (m), 588 (s), 548 (m), 522 (s), 467 (m), 425 (w), 410 (w) cm⁻¹. TLC R_f = 0.66 in 1:1 hexanes:EtOAc. HRMS (ESI) m/z: [M+H]⁺ Calcd for C₁₄H₂₃N₂O₃S⁺: 299.1424; Found 299.1431.

N-(4-cyanophenyl)morpholine-4-sulfamide (3c).

Prepared from 1a (0.5 mmol, 1.0 equiv) and 4-bromobenzonitrile (0.75 mmol, 1.5 equiv) following general procedure C. The product was obtained as a white solid (121 mg, 92% yield) after silica gel column chromatography using hexanes:EtOAc (gradient elution, 9:1 to 6:4). The obtained spectrum matched that reported in the literature.^{16a 1}H NMR (400 MHz, DMSO-d₆) δ 10.70 (br s, 1H), 7.77 (dd, J = 1.3 Hz, 9.0, 2H), 7.31 (dd, J = 1.3 Hz, 8.9, 2H), 3.55 – 3.48 (m, 4H), 3.10 – 3.05 (m, 4H) ppm. ¹³C{¹H} NMR (126 MHz, DMSO-d₆) δ 143.0, 133.6, 118.9, 118.2, 104.7, 65.3, 45.9 ppm. IR (neat) ν 3124 (w), 3061 (w), 2934 (w), 2218 (w), 1603 (w), 1507 (m), 1497 (w), 1454 (w), 1415 (w), 1364 (m), 1338 (w), 1304 (w), 1265 (m), 1240 (w), 1219 (w), 1174 (w), 1159 (m), 1127 (w), 1104 (m), 1071 (m), 943 (m), 931 (w), 904 (m), 849 (m), 837 (m), 818 (m), 803 (w), 726 (m), 642 (m), 619 (w), 581 (m), 544 (m), 526 (m), 502 (m), 425 (w) cm⁻¹. TLC R_f = 0.33 in 1:1 hexanes:EtOAc. HRMS (ESI) m/z: [M+H]⁺ C₁₁H₁₄N₃O₃⁺: 268.0750; Found 268.0753.

N-(2-cyanophenyl)morpholine-4-sulfamide (3d).

Prepared from 1a (0.5 mmol, 1.0 equiv) and 2-bromobenzonitrile (0.75 mmol, 1.5 equiv) following general procedure C. The product was obtained as a white solid (95 mg, 71% yield) after silica gel column chromatography using hexanes:EtOAc (gradient elution, 9:1 to 6:4). ¹H NMR (400 MHz, CDCl₃) δ 7.73 (d, J = 8.1 Hz, 1H), 7.66 – 7.55 (m, 2H), 7.23 (t, J = 7.8, 1H), 6.88 (s, 1H), 3.68 (m, 4H), 3.28 (m, 4H) ppm. ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 140.2, 134.4, 133.0, 124.9, 121.4 116.2, 103.8, 66.1, 46.6 ppm. IR (neat) ν 3145 (br), 2966 (w), 2921 (w), 2856 (w), 2233 (w), 2098 (w), 1598 (w), 1496 (w), 1455 (w), 1424 (w), 1392 (w), 1359 (m), 1343 (w), 1332 (w), 1297 (w), 1262 (m), 1236 (w), 1217 (w), 1162 (m), 1122 (w), 1099 (m), 1073 (m), 1064 (m), 1019 (w), 942 (m), 908 (m), 878 (w), 841 (m), 771 (m), 753 (m), 741 (m), 716 (br), 668 (w), 639 (w), 622 (w), 579 (m), 563 (m), 556 (m), 550 (m), 524 (m), 502 (m), 473 (m), 454 (w), 425 (w) cm⁻¹. TLC R_f = 0.44 in 1:1 hexanes:EtOAc. HRMS (ESI) m/z: [M+H]⁺ Calcd for C₁₁H₁₄N₃O₃⁺: 268.0756; Found 268.0753.

N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholine-4-sulfamide (3e).

Prepared from 1a (0.5 mmol, 1.0 equiv) and 2-(4-bromophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane⁴⁹ (0.75 mmol, 1.5 equiv) following general procedure C or D. The product was obtained as a colorless solid after silica gel column chromatography using hexanes:acetone (gradient elution, 4:1 to 1:4). The compound was prepared in 75% yield (136 mg) according to general procedure C for 72 h. The compound was prepared in 86% yield (156 mg) according to general procedure D for 72 h. ¹H NMR (400 MHz, CDCl₃) δ 7.75 (d, J = 8.2 Hz, 2H), 7.16 (d, J = 8.2 Hz, 2H), 7.06 (s, 1H), 3.66 – 3.52 (m, 4H), 3.31 – 3.17 (m, 4H), 1.33 (s, 12H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 139.7, 136.3, 118.8, 84.0, 66.2, 46.5, 25.0. IR (neat) ν 3266 (br), 2977 (w), 2923 (w), 2861 (w), 1607 (m), 1453 (w), 1391 (m), 1357 (s), 1297 (m), 1262 (m), 1215 (w), 1140 (s), 1114 (m), 1091 (m), 1073 (m), 1019 (w), 941 (m), 857 (m), 828 (m), 735 (m), 719 (m), 673 (m), 656 (m), 634 (w), 622 (w), 571 (s), 522 (m), 468 (s), 450 (s), 415 (s) cm^–1. TLC R_f = 0.5 in 4:1 hexanes:EtOAc. HRMS (ESI) m/z: [M+H]⁺ Calcd for C₁₆H₂₆¹⁰BN₂O₅S⁺: 368.1691; Found 368.1692. [M+H]⁺ Calcd for C₁₆H₂₆¹¹BN₂O₅S⁺: 369.1655; Found 369.1666.

N-(3-chlorophenyl)morpholine-4-sulfamide (3f).

Prepared from 1a (0.5 mmol, 1.0 equiv) and 1-bromo-3-chlorobenzene (0.75 mmol, 1.5 equiv) following general procedure C. The product was obtained as a yellow solid (113 mg, 82% yield) after silica gel column chromatography using hexanes:EtOAc (gradient elution, 9:1 to 1:1). ¹H NMR (400 MHz, CDCl₃) δ 7.25 (dd, J = 7.9, 8.0 Hz, 1H), 7.21 (s, 1H), 7.12 (d, J = 7.9 Hz, 1H), 7.06 (d, J = 8.0 Hz, 1H), 6.91 (br s, 1H), 3.67 (t, J = 4.7 Hz, 4H), 3.27 (t, J = 4.6 Hz, 4H) ppm. ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 138.4, 135.3, 130.6, 125.0, 120.1, 118.1, 66.2, 46.5 ppm. IR (neat) ν 3278 (br), 2977 (w), 2861 (w), 1595 (w), 1509 (w), 1477 (w), 1453 (w), 1399 (w), 1341 (m), 1298 (w), 1261 (m), 1216 (w), 1154 (s), 1113 (m), 1074 (m), 1026 (w), 998 (w), 935 (s), 850 (w), 778 (w), 733 (s), 703 (m), 680 (m), 621 (m), 592 (w), 562 (m), 522 (s), 477 (w), 445 (w), 420 (w) cm⁻¹. TLC R_f = 0.53 in 1:1 hexanes:EtOAc. HRMS (ESI) m/z: [M+H]⁺ Calcd for C₁₀H₁₄ClN₂O₃S⁺: 277.0408; Found 277.0416.

N-(6-chloropyridin-2-yl)morpholine-4-sulfamide (3g).

Prepared from 1a (0.5 mmol, 1.0 equiv) and (0.75 mmol, 1.5 equiv). The product was obtained as an off-white after silica gel column chromatography using hexanes:EtOAc (gradient elution, 1:0 to 4:1). The compound was prepared in 78% yield (108 mg) according to general procedure C (24 h). The compound was prepared in 11% yield (8 mg) according to general procedure D (24 h), and byproduct S1 was obtained in 8% yield (12 mg). ¹H NMR (400 MHz, CDCl₃) δ 7.61 (dd, J = 8.0, 7.8 Hz, 1H), 7.15 (d, J = 8.1 Hz, 1H), 7.04 (d, J = 7.8 Hz, 1H), 3.77 – 3.59 (m, 4H), 3.41 – 3.16 (m, 4H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 150.9, 150.0, 141.0, 119.5, 109.9, 66.3, 46.6. IR (neat) ν 3156 (w), 2917 (w), 2861 (w), 1723 (w), 1569 (w), 1464 (w), 1447 (w), 1395 (w), 1345 (w), 1287 (w), 1259 (w), 1163 (w), 1151 (m), 1124 (w), 1104 (m), 1065 (m), 1018 (w), 987 (w), 942 (m), 925 (w), 967 (w), 835 (w), 789 (m), 732 (w), 709 (w), 693 (m), 643 (w), 602 (w), 561 (m), 430 (w), 414 (w) cm⁻¹. TLC R_f = 0.58 in 4:1 hexanes:EtOAc. HRMS (ESI) m/z: [M+H]⁺ Calcd for C₉H₁₃ClN₃O₃S⁺ 278.0361; Found 278.0364.

Characterization data for byproduct S1: N-(6-(ethoxy)pyridine-2-yl)morpholine-4-sulfamide. ¹H NMR (400 MHz, CDCl₃) δ 7.54 (t, J = 8.0 Hz, 1H), 6.81 (d, J = 7.8 Hz, 1H), 6.45 (d, J = 8.1 Hz, 1H), 4.25 (q, J = 7.0 Hz, 2H), 3.77 – 3.54 (m, 4H), 3.40 – 3.17 (m, 4H), 1.37 (t, J = 7.1 Hz, 3H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 163.3, 148.8, 140.9, 105.9, 103.7, 66.3, 62.2, 46.6, 14.7. IR (neat) ν 3257 (w), 2978 (w), 2860 (w), 1599 (m), 1579 (s), 1440 (s), 1388 (m), 1329 (m), 1299 (m), 1260 (m), 1247 (m), 1224 (w), 1150 (s), 1111 (s), 1072 (m), 1042 (m), 1014 (m), 942 (m), 790 (m), 725 (m), 623 (m), 569 (2), 524 (w) cm⁻¹. TLC R_f = 0.61 in 4:1 hexanes:EtOAc. HRMS (ESI) m/z: [M+H]⁺ Calcd for C₁₁H₁₈N₃O₄S⁺ 288.1013; Found 288.1013.

N-(4-(trifluoromethyl)phenyl)-N’,N’-dimethyl sulfamide (3h).

Prepared from 1b (0.5 mmol, 1.0 equiv) and 4-bromobenzotrifluoride (0.75 mmol, 1.5 equiv) following general procedure C. The product was obtained as a pale yellow solid (133 mg, ≥98% yield) after silica gel column chromatography using hexanes:acetone (single eluent, 1:1). ¹H NMR (400 MHz, CDCl₃) δ 9.14 (s, 1H), 7.66 (d, J = 8.4 Hz, 2H), 7.48 (d, J = 8.4 Hz, 2H), 2.83 (s, 6H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 143.9, 127.6 (q, J = 4.2 Hz), 125.8 (q, J = 270.7 Hz), 125.4 (q, J = 31.8 Hz), 119.6, 38.6. ¹⁹F NMR (376 MHz, CDCl₃) δ −62.45. IR (neat) ν 3244 (br), 3107 (w), 2962 (br), 2923 (br), 2854 (br), 1694 (w), 1617 (w), 1603 (w), 1590 (w), 1544 (w), 1522 (w), 1467 (m), 1403 (w), 1390 (w), 1369 (w), 1360 (w), 1321 (m), 1298 (m), 1259 (m), 1191 (w), 1141 (s), 1111 (s) 1067 (m), 1016 (m), 954 (m), 922 (m), 856 (m), 836 (m),803 (m), 779 (w), 771 (w), 755 (w), 711 (s), 645 (m), 628 (m), 594 (s), 573 (m), 560 (m), 528 (m), 509 (m), 499 (m), 490 (m), 465 (m), 452 (w), 433 (w), 413 (m), 401 (m) cm⁻¹. TLC R_f = 0.66 in 1:1 hexanes:EtOAc. HRMS (ESI) m/z: [M+H]⁺ Calcd for C₉H₁₂F₃N₂O₂S⁺: 269.0566; Found 269.0572.

N-(4-(trifluoromethyl)phenyl)-N,N’,N’-trimethyl sulfamide (3i).

Prepared from 1e (0.5 mmol, 1.0 equiv) and 4-bromobenzotrifluoride (0.75 mmol, 1.5 equiv) following a general procedure C, using a reduced quantity of DBU (0.25 mmol, 0.5 equiv). The product was obtained as a bright yellow solid (32 mg, 23% yield) after silica gel column chromatography using hexanes:EtOAc (single eluent, 4:1). Starting material 1e was recovered as a yellow oil (48 mg, 70% recovery). Without a reduction in the quantity of DBU, a trace amount of product was observed by TLC, but was not isolable; the starting material 1e, recovered as a yellow oil (12 mg, 17% recovery), was the only isolable constituent. ¹H NMR (400 MHz, CDCl₃) δ 7.62 (d, J = 8.4 Hz, 2H), 7.51 (d, J = 8.4 Hz, 2H), 3.31 (s, 3H), 2.82 (s, 6H) ppm. ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 146.0, 128.4 (q, J = 32.7 Hz), 126.4 (q, J = 3.6 Hz), 125.3, 124.0 (q, J = 272.1 Hz), 39.1, 38.4 ppm. ¹⁹F NMR (376 MHz, CDCl₃) δ −62.43 ppm. IR (neat) ν 3307 (br), 2959 (w), 2922 (w), 2852 (w), 1629 (w), 1458 (w), 1415 (w), 1316 (m), 1260 (w), 1185 (w), 1144 (m), 1078 (m), 1053 (m), 953 (m), 835 (m), 699 (m), 579 (w), 513 (m), 428 (w), 403 (w) cm⁻¹.TLC R_f = 0.61 in 1:1 hexanes:acetone. HRMS (ESI) m/z: [M+H]⁺ Calcd for C₁₀H₁₄F₃N₂O₂S⁺: 283.0723; Found 283.0723.

tert-butyl pentyl(N-(4-(trifluoromethyl)phenyl)sulfamoyl)carbamate (3j).

Prepared from 1c (0.5 mmol, 1.0 equiv) and 4-bromobenzotrifluoride (0.75 mmol, 1.5 equiv) following general procedure C. The product was obtained as an off-white solid (164 mg, 80% yield) after silica gel column chromatography using hexanes:acetone (gradient elution, 4:1 to 1:4). ¹H NMR (400 MHz, acetone-d₆) δ 9.25 (s, 1H), 7.75 (d, J = 8.6 Hz, 2H), 7.50 (d, J = 8.6 Hz, 2H), 3.60 (t, J = 7.4 Hz, 2H), 1.46 (s, 9H), 1.39 (m, 2H), 1.22 (m, 2H), 1.14 (m, 2H), 0.83 (t, J = 7.3 Hz, 3H). ¹³C{¹H} NMR (126 MHz, acetone-d₆) δ 152.1, 141.8, 127.5 (q, J = 3.9 Hz), 127.4 (q, J = 32.9 Hz), 124.4 (q, J = 270.7 Hz), 122.4, 84.5, 49.3, 30.0, 29.4, 28.2, 23.0, 14.3. ¹⁹F NMR (376 MHz, acetone-d₆) δ −62.46. IR (neat) ν 3244 (br), 3108 (br), 3041 (br), 2959 (w), 2918 (br), 2852 (w), 2788 (br), 1890 (w), 1616 (w), 1602 (w), 1589 (w), 1544 (m), 1520 (m), 1467 (m), 1451 (m), 1389 (m), 1370 (m), 1360 (m), 1324 (s), 1297 (m), 1288 (m), 1258 (m), 1232 (m), 1191 (m), 1175 (m), 1160 (m), 1141 (s), 1111 (s), 1067 (s), 1018 (m), 987 (w), 953 (m), 930 (m), 921 (m), 859 (m), 833 (m), 803 (m), 779 (m), 771 (m), 713 (s), 686 (m), 644 (s), 627 (m), 595 (s), 570 (m), 560 (m), 528 (m), 508 (m), 498 (m), 490 (m), 470 (m), 464 (m), 452 (m), 433 (m), 417 (m), 401 (m) cm⁻¹. TLC R_f = 0.56 in 4:1 hexanes:EtOAc. HRMS (ESI) m/z: [M+Na]⁺ Calcd for C₁₇H₂₅F₃N₂O₄S•Na⁺: 433.1379; Found 433.1382.

N-(thiophen-3-yl)morpholine-4-sulfamide (3k).

Prepared from 1a (0.5 mmol, 1.0 equiv) and 3-bromothiophene (0.75 mmol, 1.5 equiv) in ethanol according to general procedure C. The product was obtained as a purple oil (46 mg, 37% yield) after silica gel column chromatography using hexanes:acetone (gradient elution, 4:1 to 1:4). 1a was recovered (36 mg, 43% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.33 – 7.25 (m, 1H), 7.03 (s, 1H), 6.97 (d, J = 5.1 Hz, 1H), 6.39 (s, 1H), 3.68 – 3.49 (m, 4H), 3.28 – 3.10 (m, 4H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 134.7, 126.1, 123.1, 113.6, 66.4, 46.6. IR (neat) ν 3279 (w), 2922 (w), 1562 (w), 1446 (w), 1350 (m), 1264 (w), 1171 (s), 1108 (w), 1005 (m), 914 (s), 783 (m), 585 (w), 550 (s) cm^–1. TLC R_f = 0.35 in 4:1 hexanes:EtOAc. HRMS (ESI) m/z: [M+H]⁺ Calcd for C₈H₁₂N₂O₃S₂⁺: 249.0362; Found 249.0361.

N-(3-methoxyphenyl)morpholine-4-sulfamide (3l).

Prepared from 1a (0.5 mmol, 1.0 equiv) and 3-bromoanisole (0.75 mmol, 1.5 equiv) following general procedure D. The product was obtained as a white solid (95 mg, 70% yield) after silica gel column chromatography using hexanes:EtOAc (gradient elution, 9:2 to 1:1). ¹H NMR (500 MHz, CDCl₃) δ 7.21 (dd, J = 7.8, 8.1 Hz, 1H), 7.02 (br s, 1H), 6.70 (s, 1H), 6.76 (d, J = 7.8 Hz, 1H), 6.68 (d, J = 8.1 Hz, 1H), 3.79 (s, 1H), 3.65 (t, J = 4.5 Hz, 4H), 3.25 (t, J = 4.5 Hz, 4H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 160.6, 138.3, 130.3, 112.5, 110.2, 106.4, 66.3, 55.5, 46.5. IR (neat) ν 3202 (br), 2969 (w), 2922 (w), 2857 (w), 1609 (w), 1591 (w), 1507 (w), 1482 (w), 1452 (w), 1410 (w), 1347 (m), 1332 (w), 1300 (w), 1281 (m), 1262 (m), 1216 (w), 1195 (w), 1178 (w), 1168 (w), 1145 (m), 1126 (w), 1106 (m), 1075 (m), 1067 (m), 1053 (m), 998 (w), 944 (m), 930 (m), 868 (w), 854 (m), 841 (m), 768 (m), 716 (m), 685 (m), 642 (w), 617 (w), 574 (m), 549 (m), 524 (m), 456 (w) cm⁻¹. TLC R_f = 0.41 in 1:1 hexanes:EtOAc. HRMS (ESI) m/z: [M+H]⁺ Calcd for C₁₁H₁₆N₂O₄S+H⁺: 273.0904; Found 273.0909.

N-(4-methoxyphenyl)morpholine-4-sulfonamide (3m).

Prepared from 1a (0.5 mmol, 1.0 equiv) and 4-bromoanisole (0.75 mmol, 1.5 equiv) following general procedure D. The product was obtained as an yellow solid (88 mg, 66% yield) after silica gel column chromatography using hexanes:EtOAc (gradient elution, 10:0 to 1:1). ¹H NMR (400 MHz, CDCl₃) δ 7.18 (d, J = 8.8 Hz, 2H), 6.86 (d, J = 8.9 Hz, 2H), 6.43 (br s, 1H), 3.80 (s, 3H), 3.66 – 3.64 (m, 4H), 3.22 – 3.20 (m, 4H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 157.8, 129.3, 124.7, 114.6, 66.2, 55.5, 46.5. IR (neat) ν 3281 (br), 3015 (w), 2978 (w), 2914 (w), 2859 (w), 1609 (w), 1507 (m), 1469 (w), 1451 (m), 1400 (w), 1343 (m), 1332 (m), 1303 (w), 1292 (w), 1260 (m), 1246 (m), 1214 (m), 1184 (m), 1157 (m), 1109 (m), 1074 (m), 1069 (m), 1027 (m), 934 (m), 927 (m), 912 (m), 856 (w) 850 (m), 819 (m), 768 (w), 732 (m), 629 (m), 592 (m), 545 (m), 518 (m), 478 (m), 450 (m), 424 (w), 410 (w) cm⁻¹. TLC R_f = 0.41 in 1:1 hexanes:EtOAc. HRMS (ESI) m/z: [M+H]⁺ Calcd for C₁₁H₁₇N₂O₄S⁺: 273.0904; Found 273.0909.

N-(6-chloropyridin-3-yl)morpholine-4-sulfamide (3n).

Prepared from 1a (0.5 mmol, 1.0 equiv) and 3-bromo-6-chloropyridine (0.75 mmol, 1.5 equiv). The product was obtained as an off-white solid after silica gel column chromatography using hexanes:EtOAc (gradient elution, 1:0 to 4:1). Prepared in 45% yield (62 mg) according to general procedure C (24 h) and byproduct S2 was obtained in 8% yield. Prepared in 78% yield (108 mg) according to general procedure D (24 h). ¹H NMR (400 MHz, CDCl₃) δ 8.23 (d, J = 2.9 Hz, 1H), 7.61 (dd, J = 8.6, 2.9 Hz, 1H), 7.32 (d, J = 8.6 Hz, 1H), 6.66 (s, 1H), 3.76 – 3.55 (m, 4H), 3.32 – 3.11 (m, 4H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 147.4, 141.7, 133.2, 131.0, 124.8, 66.2, 46.6. IR (neat) ν 3107 (w), 2921 (w), 2860 (w), 1576 (w), 1460 (m), 1376 (w), 1327 (m), 1297 (w), 1262 (m), 1226 (w), 1157 (m), 1111 (m), 1072 (m), 1020 (w), 938 (m), 835 (m), 720 (w), 637 (m), 579 (m), 527 (m), 480 (w), 440 (w), 418 (w) cm⁻¹. TLC R_f = 0.37 in 8:2 hexanes:EtOAc. HRMS (ESI) m/z: [M+H]⁺ Calcd for C₉H₁₃ClN₃O₃S⁺ 278.0361; Found 278.0366.

Characterization data for byproduct S2: N-(5-bromopyridine-2-yl)morpholine-4-sulfamide. ¹H NMR (400 MHz, CDCl₃) δ 8.39 (d, J = 2.0 Hz, 1H), 7.79 (dd, J = 8.7, 2.0 Hz, 2H), 7.24 (s, 1H), 3.86 – 3.57 (m, 4H), 3.39 – 3.19 (m, 4H). ¹³C{¹H} NMR (126 MHz, CDCl₃, −2 × ¹³C_Ar) δ 150.1, 141.5, 113.8, 66.2, 46.5. IR (neat) ν 3101 (w), 3027 (w), 2964 (w), 1577 (w), 1498 (w), 1456 (m), 1377 (m), 1339 (m), 1295 (w), 1281 (w), 1262 (m), 1218 (w), 1153 (m), 1140 (m), 1112 (m), 1074 (m), 1013 (w), 942 (m), 824 (w), 717 (w), 684 (w), 645 (w), 620 (m), 578 (m), 527 (w), 515 (w), 471 (w) cm⁻¹. TLC R_f = 0.49 in 8:2 hexanes:EtOAc. HRMS (ESI) m/z: [M+H]⁺ Calcd for C₉H₁₃BrN₃O₃S⁺ 321.9856; Found 321.9854.

N-(pyrimidin-5-yl)morpholine-4-sulfamide (3o).

Prepared from 1a (0.5 mmol, 1.0 equiv) and 5-bromopyrimidine (0.75 mmol, 1.5 equiv) following general procedure D. The product was obtained white solid (93 mg, 77% yield) after silica gel column chromatography using hexanes:EtOAc (1:4). ¹H NMR (500 MHz, DMSO-d6) δ 10.58 (s, 1H), 8.91 (s, 1H), 8.63 (s, 2H), 3.57 (t, J = 4.6 MHz, 4H), 3.12 (t, J = 4.6 MHz, 4H). ¹³C{¹H} NMR (126 MHz, DMSO-d6)) δ 153.1, 147.2, 134.2, 65.4, 45.9. IR (neat) ν 3114 (br), 3076 (br), 2959 (w), 2924 (br), 2855 (w), 2664 (w), 1575 (br), 1520 (m), 1453 (w), 1438 (m), 1418 (m), 1362 (m), 1325 (m), 1313 (m), 1300 (m), 1282 (m), 1271 (m), 1264 (m), 1216 (w), 1204 (m), 1159 (m), 1146 (m), 1128 (m), 1117 (m), 1106 (m), 1080 (m), 1071 (m), 1043 (m), 935 (br), 923 (m), 902 (m), 848 (m), 720 (m), 711 (s), 655 (m), 632 (s), 619 (m), 567 (s), 524 (s), 466 (m), 426 (w), 414 (m) cm⁻¹. TLC R_f = 0.20 in 1:4 Hexanes/EtOAc. HRMS (ESI) m/z: [M+H]⁺ Calcd for C₈H₁₃N₄O₃S⁺ 245.0703; Found 245.0709.

N-(benzothiazol-2-yl)morpholine-4-sulfamide (3p).

Prepared from 1a (0.5 mmol, 1.0 equiv) and 2-bromobenzothiazole (0.75 mmol, 1,5 equiv) following general procedure D. The product was obtained as a yellow solid (34 mg, 23% yield) after silica gel column chromatography using hexanes:EtOAc (gradient elution, 3:7 to 1:4) with starting material recovered as a white solid (42 mg, 51% recovered starting material). ¹H NMR (400 MHz, CDCl₃) δ 11.28 (s, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.40 (dd, J = 7.9, 7.9 Hz, 2H), 7.26 (t, J = 7.9 Hz, 1H), 3.79 – 3.70 (m, 4H), 3.26 – 3.15 (m, 4H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 169.2, 136.0, 127.7, 124.6, 124.5, 122.1, 113.8, 66.1, 46.7. IR (neat) ν 3108 (br), 3042 (br), 2975 (br), 2913 (w), 2850 (w), 2788 (br), 1712 (w), 1602 (w), 1589 (w) 1544 (s), 1466 (m), 1450 (m), 1392 (w), 1360 (w), 1337 (m), 1327 (m), 1298 (m), 1259 (m), 1214 (w), 1142 (s), 1111 (s), 1064 (s), 1018 (m), 953 (m), 932 (m), 855 (m), 847 (m), 827 (s), 754 (m), 727 (s), 711 (s), 690 (s), 670 (m), 645 (s), 625 (s), 610 (m), 595 (s), 527 (s), 498 (s), 464 (m), 432 (m), 422 (m) cm⁻¹. TLC R_f = 0.13 in 1:1 hexanes:EtOAc. HRMS (ESI) m/z: [M+H]⁺ Calcd for C₁₁H₁₄N₃O₃S₂⁺: 300.0471; Found 300.0476.

tert-butyl 5-(morpholine-4-sulfamoyl)indole-1-carbamate (3q).

Prepared from 1a (0.5 mmol, 1.0 equiv) and 1-boc-5-bromoindole (0.75 mmol, 1.5 equiv) following general procedure D. The product was obtained as a yellow solid (69 mg, 36% yield) after silica gel column chromatography using hexanes:acetone (4:1). 1a was recovered as a white solid (49 mg, 59% recovered yield). ¹H NMR (400 MHz, acetone-d₆) δ 8.71 (br s, 1H), 8.09 (d, J = 8.6 Hz, 1H), 7.67 (d, J = 3.3 Hz, 1H), 7.62 (s, 1H), 7.35 (d, J = 8.6 Hz, 1H), 6.65 (d, J = 3.3 Hz, 1H), 3.55 (t, J = 4.2 Hz, 4H), 3.16 (t, J = 4.2 Hz, 4H), 1.68 (s, 9H). ¹³C{¹H} NMR (126 MHz, acetone-d₆) δ 150.3, 134.6, 133.3, 132.2, 127.9, 119.5, 116.3, 114.4, 108.1, 84.7, 66.9, 47.5, 28.3. IR (neat) ν 3190 (br), 2988 (w), 2930 (w), 2864 (w), 1731 (br), 1616 (w), 1582 (w), 1539 (w), 1454 (m), 1430 (w), 1372 (m), 1348 (m), 1335 (m), 1323 (m), 1286 (m), 1262 (m), 1221 (m), 1162 (m), 1131 (m), 1123 (m), 1104 (m), 1091 (m), 1066 (m), 1030 (m), 963 (m), 932 (m), 904 (m), 871 (m), 844 (m), 810 (m), 777 (m), 764 (m), 745 (m), 732 (m), 715 (m), 663 (m), 622 (m), 598 (m), 578 (m), 554 (m), 522 (m), 507 (m), 481 (m), 458 (m), 428 (m), 411 (m) cm⁻¹. TLC R_f = 0.67 in 1:1 hexanes:EtOAc. HRMS (ESI) m/z: [M+H]⁺ Calcd for C₁₇H₂₄N₃O₅S⁺ 382.1431; Found 382.1436.

N-(quinolin-8-yl)-N’-pentylsulfamide (3r).

Prepared from 1d (0.5 mmol, 1.0 equiv) and 8-bromoquinoline (0.5 mmol, 1.0 equiv) following general procedure D. The product was obtained as an orange solid (18.2 mg, 13% yield) after silica gel column chromatography using hexanes:EtOAc:Acetic Acid (single eluent, 9:1:(1.5%)). ¹H NMR (500 MHz, CDCl₃) δ 8.98 (s, 1H), 8.82 (dd, J = 4.2, 1.7 Hz, 1H), 8.17 (dd, J = 8.3, 1.7 Hz, 1H), 7.80 – 7.69 (m, 1H), 7.53 – 7.51 (m, 2H), 7.48 (dd, J = 8.3, 4.2 Hz, 1H), 4.50 (t, J = 5.4 Hz, 1H), 3.00 (q, J = 7.0 Hz, 2H), 1.38 – 1.32 (m, 2H), 1.09 – 1.05 (m, 4H), 0.70 (t, J = 7.0 Hz, 3H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 148.9, 138.6, 136.4, 134.5, 128.4, 127.1, 122.2, 121.7, 114.4, 43.4, 29.0, 28.7, 22.1, 13.9 ppm. TLC R_f = 0.49 in 1:1 hexanes:EtOAc. The obtained spectrum matched that reported in the literature.^9b

tert-butyl (N-(quinoline-8-yl)sulfamoyl)(pentyl)carbamate (3s).

Prepared from 1c (0.5 mmol, 1.0 equiv) and 8-bromoquinoline (0.75 mmol, 1.5 equiv) following general procedure D. The product was obtained as a yellow solid (30 mg, 15% yield) after silica gel column chromatography using CH₂Cl₂:MeOH (single eluent, 98:2). ¹H NMR (400 MHz, CD₂Cl₂) δ 9.67 (br, 1H), 8.76 (d, J = 4.2 Hz, 1H), 8.23 (d, J = 8.2 Hz, 1H), 7.82 (d, J = 7.5 Hz, 1H), 7.61 (d, J = 8.2 Hz, 1H), 7.56–7.50 (m, 2H), 3.65 (t, J = 7.5 Hz, 2H), 1.49–1.44 (m, 2H), 1.39 (s, 9H), 1.24–1.11 (m, 4H), 0.81 (t, J = 7.2 Hz, 3H) ppm. ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 151.1, 148.8, 138.8, 136.4, 133.7, 128.4, 127.0, 122.8, 122.2, 115.9, 84.5, 49.0, 29.4, 28.7, 27.9, 22.4, 14.0 ppm. IR (neat) ν 3262 (br), 2957 (w), 2930 (w), 2860 (w), 1724 (m), 1624 (w), 15966 (w), 1579 (w), 1505 (m), 1472 (w), 1436 (w), 1416 (m), 1390 (m), 1369 (m), 1341 (w), 1312 (m), 1281 (m), 1257 (m), 1177 (m), 1147 (m), 1087 (m), 1058 (w), 1044 (w), 1028 (w), 1014 (w), 962 (w), 923 (m), 847 (m), 826 (m), 792 (m), 767 (m), 721 (m), 678 (m), 623 (m), 574 (m), 559 (m), 519 (m), 464 (w), 421 (w) cm⁻¹. TLC R_f = 0.74 in 1:1 hexanes/EtOAc. HRMS (ESI) m/z: [M-H]⁻ Calcd for C₁₉H₂₆N₃O₄S⁻ 392.1650; Found 392.1641.

(N-(2-methylnaphth-1-yl))-N’-pentyl sulfamide (3t).

Prepared from 1d (0.5 mmol, 1.0 equiv) and 1-bromo-2-methylnaphthalene (0.75 mmol, 1.5 equiv) following general procedure D. The product was obtained as a yellow solid (28 mg, 18% yield) after silica gel column chromatography using hexanes:acetone (single eluent, 4:1). ¹H NMR (500 MHz, CDCl₃) δ 8.17 (d, J = 8.5 Hz, 1H), 7.81 (d, J = 8.5 Hz, 1H), 7.73 (d, J = 8.5 Hz, 1H) 7.54 (dd, J = 7.5, 7.5 Hz, 1H), 7.45 (dd, J = 7.5, 7.5 Hz, 1H), 7.37 (d, J = 8.5 Hz, 1H), 6.23 (br s, 1H), 4.31 (br s, 1H), 3.11 (q, J = 6.0 Hz, 2H), 2.62 (s, 3H), 1.47 (pentet, J = 6.9 Hz, 2H), 1.21–1.29 (m, 4H), 0.87 (t, J = 7.1 Hz, 3H). ¹³C{¹H} NMR (126 MHz, CDCl₃) δ 135.8, 133.2, 132.1, 129.4, 129.3, 128.4, 128.3, 126.9, 125.6, 122.8, 44.2, 29.7, 28.9, 22.4, 19.4, 14.0. IR (neat) ν 3269 (br), 2949 (w), 2927 (w), 2865 (w), 1600 (w), 1573 (w), 1507 (w), 1483 (w), 1425 (m), 1387 (m), 1366 (m), 1339 (m) 1321 (m), 1235 (w), 1211 (w), 1187 (w), 1159 (m), 1127 (w), 1072 (m), 1030 (w), 975 (w), 964 (w), 927 (m), 845 (w), 810 (m), 781 (m), 745 (w), 729 (w), 711 (w), 662 (w), 624 (w), 602 (m), 566 (w), 527 (w), 517 (w), 496 (w), 450 (w), 435 (w) cm⁻¹. TLC R_f = 0.68 in 1:1 hexanes/acetone. HRMS (ESI) m/z: [M+H]⁺ Calcd for C₁₆H₂₃N₂O₂S⁺ 307.1475; Found 307.1475.

tert-butyl (N-(4-(tert-butyl)phenyl)sulfamoyl)(pentyl)carbamate (3u).

Prepared from 1c (0.5 mmol, 1.0 equiv) and bromo-4-(tert-butyl)benzene (0.75 mmol, 1.0 equiv) following general procedure D. The product was obtained as an off-white solid (167 mg, 85% yield) after silica gel column chromatography using hexanes:EtOAc (9:1). ¹H NMR (500 MHz, acetone-d₆) δ 8.54 (s, 1H), 7.42 (d, J = 8.6 Hz, 2H), 7.22 (d, J = 8.6 Hz, 2H), 3.47 (t, J = 7.4 Hz, 2H), 1.51 (s, 9H), 1.31 (s, 9H), 1.15 (m, J = 7.3 Hz, 4H), 1.05 (m, 2H), 0.80 (t, J = 7.6 Hz, 3H). ¹³C{¹H} NMR (126 MHz, acetone-d₆) δ 152.5, 149.9, 135.1, 126.9, 124.0, 84.1, 48.8, 35.2, 31.8, 29.8, 29.4, 28.3, 23.1, 14.4. IR (neat) ν 3244 (br), 3166 (br), 3106 (br), 3043 (br), 2963 (w), 2923 (br), 2854 (w), 2788 (br), 1697 (m), 1616 (w), 1602 (w), 1589 (w), 1544 (m), 1512 (w), 1462 (m), 1451 (m), 1390 (m), 1369 (m), 1361 (m), 1336 (m), 1327 (m), 1311 (m), 1298 (m), 1287 (m), 1259 (m), 1232 (w), 1217 (w), 1191 (w), 1176 (m), 1141 (s), 1111 (s), 1066 (m), 1018 (m), 987 (w), 921 (m), 856 (m), 837 (m), 796 (m), 771 (m), 720 (s), 693 (m), 645 (s), 628 (m), 593 (s), 574 (m), 542 (m), 528 (m), 510 (m), 498 (m), 465 (m), 453 (m), 433 (m), 420 (m), 411 (m) cm⁻¹. TLC R_f = 0.56 in 4:1 hexanes:EtOAc. HRMS (ESI) m/z: [M+Na]⁺ Calcd for C₂₀H₃₄N₂O₄S•Na⁺: 421.2132; Found 421.2134.

N-(4-(tert-butyl)phenyl)-N’,N’-dimethyl sulfamide (3v).

Prepared from 1b (0.5 mmol, 1.0 equiv) and bromo-4-(tert-butyl)benzene (0.75 mmol, 1.5 equiv) following general procedure D. The product was obtained as a colorless solid (110 mg, 85% yield) after silica gel column chromatography using hexanes:acetone (gradient elution, 4:1 to 1:4). ¹H NMR (400 MHz, acetone-d₆) δ 8.54 (s, 1H), 7.36 (d, J = 8.6 Hz, 2H), 7.26 (d, J = 8.7 Hz, 2H), 2.76 (s, 6H), 1.30 (s, 9H). ¹³C{¹H} NMR (126 MHz, acetone-d₆) δ 147.5, 137.3, 126.8, 120.9, 38.5, 34.9, 31.8. IR (neat) ν 3269 (br), 3034 (w), 2963 (br), 2829 (br), 2904 (w), 2867 (br), 2815 (w), 1691 (w), 1613 (w), 1588 (w), 1515 (m), 1464 (m), 1395 (m), 1367 (m), 1325 (m), 1303 (m), 1287 (m), 1267 (m), 1241 (m), 1192 (w), 1140 (s), 1125 (m), 1066 (w), 1052 (w), 1016 (w), 953 (s), 851 (m), 832 (s), 772 (w), 731 (w), 710 (s) 695 (m), 641 (m), 598 (s), 542 (m), 523 (s), 485 (m), 441 (w), 435 (w), 421 (w) cm⁻¹. TLC R_f = 0.83 in 1:1 hexanes:EtOAc. HRMS (ESI) m/z: [M+H]⁺ Calcd for C₁₂H₂₀N₂O₂S⁺: 257.1318; Found 257.1324.

N-(4-(tert-butyl)phenyl)-N,N’,N’-(trimethyl) sulfamide (3w).

Prepared from 1e (0.5 mmol, 1.0 equiv) and 4-(tert-butyl)bromobenzene (0.75 mmol, 1.5 equiv) following general procedure D. The product was obtained as a colorless solid (8 mg, 6% yield) after silica gel column chromatography using hexanes:acetone (single eluent, 4:1). ¹H NMR (400 MHz, acetone-d₆) δ 7.36 (d, J = 8.9 Hz, 2H), 7.26 (d, J = 8.9 Hz, 2H), 2.81 (s, 3H), 2.77 (s, 6H), 1.30 (s, 9H). ¹³C{¹H} NMR (126 MHz, acetone-d₆) δ 147.4, 137.2, 126.8, 120.8, 38.5, 34.9, 31.8, 30.7. IR (neat) ν 3272 (br), 2961 (w), 2926 (w), 2869 (w), 1614 (w), 1594 (w), 1515 (w), 1457 (w), 1413 (w), 1395 (w), 1364 (w), 1331 (w), 1304 (w), 1268 (w), 1231 (w), 1189 (w), 1148 (m), 1051 (w), 1017 (w), 954 (m), 836 (w), 781 (w), 739 (w), 709 (m), 639 (w), 592(m), 537(m), 525(m), 484(m), 426(m), 418 (m) cm⁻¹. TLC R_f = 0.25 in 3:1 hexanes:acetone. HRMS (ESI) m/z: [M+H]⁺ Calcd for C₁₃H₂₃N₂O₂S⁺ 271.1475; Found 271.1476.