Sulfamides direct radical-mediated chlorination of aliphatic C–H bonds†

Given the prevalence of aliphatic amines in bioactive small molecules, amine derivatives are opportune as directing groups. Herein, sulfamides serve as amine surrogates to guide intermolecular chlorine-transfer at γ-C(sp3) centers. This unusual position-selectivity arises because accessed sulfamidyl radical intermediates engage preferentially in otherwise rare 1,6-hydrogen-atom transfer (HAT) processes through seven-membered transition states. The site-selectivity of C–H abstraction can be modulated by adjusting the steric and electronic properties of the sulfamide nitrogen substituents, an ability that has not been demonstrated with other substrate classes. The disclosed reaction relies on a light-initiated radical chain-propagation mechanism to oxidize C(sp3)–H bonds efficiently.

Inspired by a procedure reported by Alexanian and coworkers, 6 a flame-dried round bottom flask was charged with g-valerolactone (2.2 mL, 20.0 mmol, 1.0 equiv) and hydrogen bromide solution (32% in acetic acid, 5 mL, 27 mmol, 1.4 equiv). The flask was fitted with a reflux condenser with rubber septum and nitrogen inlet and heated in an oil bath set at 75 °C for 4 h. After this time, the flask was removed from the heat and allowed to cool to room temperature. Once cooled, freshly distilled methanol (8.0 mL, 2.5 M) was added and the reaction was stirred at 22 °C for 16 h. After 16 h, the reaction was partially concentrated under reduced pressure (to remove methanol) and taken up in EtOAc (10 mL). The mixture was then transferred to a separatory funnel, rinsing the flask with EtOAc to achieve quantitative transfer. The organic phase was washed three times with saturated aqueous NaHCO3 (3 x 25 mL) and once with brine (25 mL). The organic phase was dried with MgSO4, filtered, and concentrated under reduced pressure. The crude bromoester was used in the next step without further purification.
The crude bromoester was taken up in anhydrous DMF (13 mL) and LiCl (1.67 g, 39.3 mmol, 2.0 equiv) was added in a single portion. The flask was fitted with a Vigreux column with rubber septum and nitrogen inlet and heated in an oil bath set at 90 °C for 18 h. After 18 h, the reaction flask was removed from the heat and allowed to cool to room temperature. Once cool, the reaction was diluted with Et2O (30 mL) and 1 M HCl (30 mL). The biphasic mixture was transferred to a separatory funnel, rinsing the flask with Et2O to achieve quantitative transfer. The aqueous phase was removed and the organic phase was washed twice more with 1 M HCl (2 x 30 mL) and once with brine (30 mL). The organic phase was dried with MgSO4, filtered, and concentrated under reduced pressure. The crude chloroester was used in the next step without purification.
The crude chloroester was added dropwise to a suspension of lithium aluminum hydride (797 mg, 21.0 mmol, 1.1 equiv) in Et2O (45 mL, 2.3 M) that had been cooled at 0 °C in an ice water bath. The reaction was left to stir at 0 °C for 30 minutes and then heated to reflux overnight. After refluxing overnight, the flask was again cooled to 0 °C, and the reaction was carefully quenched by sequential dropwise addition of H2O (0.8 mL), 15% aqueous NaOH (0.8 mL), and H2O (0.8 mL). The resulting suspension was filtered by vacuum filtration through a pad of celite in a glass fritted funnel. The filtrate was concentrated under reduced pressure and then purified by silica gel flash chromatography by dry loading the sample and eluting with hexanes:EtOAc (Gradient: 100% hexanes ® 9:1 hexanes/EtOAc) to yield the desired product as a colorless oil (390 mg, 14% yield over 3 steps).
After refluxing overnight, the reaction was removed from the heat and allowed to cool to room temperature and then further cooled at 0 °C in an ice/water bath. The reaction was then carefully quenched by careful, sequential addition of deionized H2O (1 mL/g LiAlH4), 15% w/v aq. NaOH (1 mL/g LiAlH4), and deionized H2O (1 mL/g LiAlH4). The quenched reaction was left stirring at 0 °C for ca. 30 minutes to ensure complete quenching of remaining LiAlH4. Once fully quenched, the reaction was filtered through a pad of celite in a glass-fritted funnel by vacuum filtration eluting with Et2O (ca. ½ reaction volume). The filtrate was then concentrated under reduced pressure. The concentrated crude material was generally pure without need for further purification.
The characterization data for this compound were in agreement with previously published information.
After stirring overnight, the reaction was diluted with deionized H2O (0.2 M) and the biphasic mixture was transferred to a separatory funnel. The organic phase was removed and the aqueous was extracted twice more with CH2Cl2 (2 x 0.2 M). The combined organic layers were dried with MgSO4, filtered, and concentrated under reduced pressure. The product was obtained as a  13

Supporting Information for Sulfamides Direct Radical-Mediated Chlorination
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General Procedure G: Preparation of N-Chlorosulfamides with Trichloroisocyanuric acid
A flame-dried round bottom flask equipped with stir bar was charged with sulfamide (1.0 equiv) and trichloroisocyanuric acid (TCICA, 1.2 equiv). The flask was evacuated and backfilled with N2. Anhydrous CH2Cl2 (0.2 M) was then added via syringe. The suspension was stirred at 21 ºC until complete consumption of the starting material as evidenced by TLC.
The suspension was quenched by addition of H2O (~0.2 M) and the biphasic mixture was transferred to a separatory funnel rinsing the flask with CH2Cl2 (ca. 5 mL) to ensure quantitative transfer. The organic phase was separated and the aqueous phase was extracted with CH2Cl2 (2 x ca. 5 mL/mmol sulfamide). The combined organic extracts were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude reaction mixtures were then purified by flash column chromatography on silica gel or florisil eluting with a hexanes/EtOAc solvent system as noted below.

General Procedure H: Preparation of N-Chlorosulfamides with tert-butyl hypochlorite
A flame-dried round bottom flask equipped with stir bar was charged with sulfamide (1.0 equiv). The flask was evacuated and backfilled with N2. Anhydrous CH2Cl2 (0.2 M) was then added via syringe. To the stirring solution was added neat tert-butyl hypochlorite ( t BuOCl, equiv indicated below) in portions via syringe until complete consumption of the starting material as evidenced by TLC.
Upon complete consumption of the starting material as indicated by TLC, all volatiles were removed under reduced pressure to afford the pure compound or crude mixtures to be purified as indicated below.

General Procedure I: Chlorine Transfer from N-chlorosulfamides.
A flame-dried vial equipped with a stir bar was charged with sulfamide (1.0 equiv, 0.2 mmol). The vial was transferred to a nitrogen-filled glovebox where it was charged with anhydrous benzene (PhH, 0.04 M). The vial was sealed with a Teflon lined screw cap and removed from the glovebox. The vial was placed on a stir plate in the center of a Southern New England Ultraviolet Co. RPR-100 Photochemical Reactor barrel and irradiated with 16 ultraviolet lamps until consumption of the starting material as indicated by TLC or 1 H NMR analysis of a smaller scale reaction set up simultaneously.
Upon consumption of starting material as evidenced by TLC or 1 H NMR, the solution was concentrated under reduced pressure and the crude material was purified as noted below.
The product was obtained following purification in 94% yield (72 mg) after irradiating for 3 h in i PrOAc (2.0 mL, 0.1 M) in front of two 26W CFL bulbs (1600 lumens).
The product was obtained following purification in 95% yield (81 mg) after irradiating for 2 h in i PrOAc (2.0 mL, 0.1 M) in front of two 26W CFL bulbs (1600 lumens).
In order to determine the ratio of g-chlorinated:d-chlorinated isomers, duplicate reactions of chlorosulfamide 1j (11 mg, 0.03 mmol) were subjected to general procedure I. After irradiating for 15 minutes, each sample was concentrated under reduced pressure and 1,2,4,5-tetrachloro-3nitrobenzene (1.0 equiv) was added as an internal standard. 1

4-Methylpentyl tert-butylsulfamate (S13a)
To a flame-dried round bottom flask equipped with magnetic stir bar and fitted with a rubber septum and nitrogen inlet was added hexanes (50 mL, 0.6 M). The reaction flask was then cooled at 0 °C in an ice water bath. Tert-butanol (4.3 mL, 30 mmol, 1.5 equiv) and chlorosulfonyl isocyanate (3.9 mL, 45 mmol, 1.5 equiv) were then sequentially added dropwise via syringe. Upon complete addition, the ice water bath was removed and replaced with an oil bath. The oil bath was heated to 45 °C and the reaction was stirred for 3 h. After 3 h, the reaction was removed from heat and allowed to cool to room temperature. The suspension was then concentrated under reduced pressure to remove all volatile materials. The crude material was then taken up in anhydrous benzene (50 mL, 0.60 M) and tetra-butylammonium bromide (TBAB, 0.97 g, 3.0 mmol, 0.1 equiv), 4-methylpentanol (3.06 g, 30 mmol, 1.0 equiv), and sodium carbonate (9.54 g, 90 mmol, 3.0 equiv) were added sequentially. Following addition, the reaction was left to stir at 22 °C for 18 h.
After 18 h, the reaction was quenched by dropwise addition of 1 M HCl until the aqueous phase reached a pH = 1.0. The biphasic solution was then transferred to a separatory funnel rinsing the flask with EtOAc (~50 mL) to achieve quantitative transfer. The organic phase was separated and the aqueous phase was extracted twice more with EtOAc (2 x 50 mL). The combined organic layers were washed once with brine (~50 mL), dried with MgSO4, filtered, and concentrated under reduced pressure. The product was obtained as a colorless oil (3.06 g, 43% yield) following silica gel column chromatography (9:1 hexanes:EtOAc). 1

S53
(1.25 mL) that had been freshly removed from the glovebox was then added to the cooled solution dropwise via syringe. The reaction was allowed to stir at 0 °C in an ice water bath for 15 minutes. A solution of sulfamic acid salt (2.1 g, 7.5 mmol, 1.5 equiv) in CH2Cl2 (4.0 mL) was added to the activated Ph3PO via cannula transfer. The flask was rinsed with additional CH2Cl2 (1 mL) to achieve quantitative transfer. The resulting pale yellow solution was stirred for 15 minutes at 0 °C. During this time, a clean, flame-dried round bottom flask equipped with stir bar was fitted with a rubber septum and subsequently evacuated and backfilled with N2. This process was repeated two more times. The flask was then charged with Et3N (2.1 mL, 15.0 mmol, 3.0 equiv) and CH2Cl2 (20 mL) and the mixture was cooled at -78 °C in an i PrOH/dry ice bath. The activated sulfamic acid salt solution was transferred dropwise to the Et3N solution via cannula (during which time an intense red color developed), rinsing the flask with additional CH2Cl2 (5 mL) to achieve quantitative transfer. The resultant solution was stirred at -78 °C for 15 minutes. 4-Methylpentanol (511 mg, 5.0 mmol, 1.0 equiv) was then added as a solution in CH2Cl2 (5 mL) to the Et3N solution via canula. The alcohol-containing flask was rinsed with additional CH2Cl2 (1 mL) to achieve quantitative transfer. Without removing the cooling bath, the reaction was then stirred for 18 h, during which time no additional dry ice was added and the mixture warmed to room temperature.
After 18 h, the reaction was diluted with 1 M HCl (~20 mL) and H2O (~30 mL). The biphasic mixture was transferred to a separatory funnel, rinsing the flask with CH2Cl2 to achieve quantitative transfer. The organic phase was separated and the aqueous phase was extracted twice more with CH2Cl2 (2 x ~40 mL). The combined organic phases were dried with MgSO4, filtered, and concentrated under reduced pressure. The product was obtained as a white powder (958 mg, 73% yield) following silica gel column chromatography (8:1 hexanes:EtOAc).

General Procedure J. Preparation of N-chlorosulfamate esters (9).
Following a literature procedure, 6b a round bottom flask equipped with magnetic stir bar was charged with trichloroisocyanuric acid (TCICA, 1.2 equiv) and the flask was evacuated and backfilled with N2. Anhydrous CH2Cl2 (0.2 M) was then added to create a suspension. Sulfamate ester S13 (1.0 equiv) was then added to the suspension via syringe (if oil) or in a single portion Upon complete consumption of starting material as judged by TLC, the reaction was diluted with H2O (~0.2 M) and the biphasic suspension was transferred to a separatory funnel. The reaction flask was rinsed with CH2Cl2 (5 mL) to ensure quantitative transfer. The organic phase was separated and the aqueous phase was extracted twice more with CH2Cl2. The combined organic phases were dried with MgSO4, filtered, and concentrated under reduced pressure. The crude reaction mixtures were then purified by flash column chromatography on silica gel by loading samples as a solid and eluting with a hexanes:EtOAc solvent system as noted below.

4-Methylpentyl (2,2,2-trifluoroethyl)chlorosulfamate ester (9b).
Prepared from sulfamate ester S13b (479 mg, 1.8 mmol) and TCICA (508 mg, 2.2 mmol) following general procedure J. The product was obtained as a colorless oil (489 mg, 90% yield) after silica gel flash column chromatography using hexanes:EtOAc (20:1). 1  The reactions were performed as described for previously reported sulfamate ester guided chlorination processes. 6b In a flame-dried microwave vial equipped with magnetic stir bar and sealed with a crimp cap, N-chlorosulfamate ester 7 (0.2 mmol, 1.0 equiv) was dissolved in anhydrous PhH (3.0 mL, 0.07 M) under an inert atmosphere. The vial was then placed in between two Kessil lamps (ca. 5 cm away from each light source) and irradiated for 15 minutes. After 15 minutes, the vial was removed from the light, and the reaction was analyzed by TLC. If starting material remained, the reaction was irradiated between two Kessil lamps in 15 minute increments until all starting material had been consumed as judged by TLC.
Upon consumption of starting material as judged by TLC, the reaction solution was transferred to a flask rinsing the microwave vial with CH2Cl2 (ca. 3 mL) to make transfer quantitative. Volatiles were removed under reduced pressure and the crude material was purified by flash column chromatography on silica gel or Florisil by loading the samples as liquids in column eluent and eluting with a hexanes:EtOAc solvent system as noted below.

X. Sulfamide cleavage to access 3-chloroalkylamines.
A clean microwave vial equipped with a stir bar was charged with sulfamide (1 equiv) and DMAP (1.5 equiv) and sealed with an aluminum seal cap. The vial was evacuated and backfilled with N2 and the process was repeated two more times. 1,4-dioxane (0.13 M) and H2O (2 equiv) were then added via syringe and the resulting solution was heated in an oil bath at 80 ºC overnight.
After stirring overnight, the suspension was allowed to cool to 21 ºC and then concentrated under reduced pressure. The crude mixture was then purified by silica gel flash chromatography as indicated below.
The light intensity was measured to determine the photon flux of the fluorimeter. 20 All solutions were stored in the dark and used the same day as prepared. Manipulations were performed in the dark and care was taken such that samples were protected from ambient light. A buffered 1,10-phenanthroline solution was prepared by dissolving phenanthroline (50 mg, 0.277 mmol) and sodium acetate (11.25 g) in 0.5 M H2SO4 and diluting to 50 mL total volume with 0.5 M H2SO4 in a 50 mL volumetric flask.
Determination of background Fe 2+ concentration.
2.00 mL of the ferrioxalate solution was added to a quartz cuvette. Next 0.35 mL of the phenanthroline solution was added and the mixture was stored in the dark for 1 h. The UV-vis spectrum was subsequently obtained and the absorbance value recorded at 510 nm. The process was repeated 2 additional times for 3 total trials. Determination of photon flux.
2.00 mL of the ferrioxalate solution was added to a quartz cuvette. The cuvette was immediately irradiated with ultraviolet light (313 nm ± 5 nm) in a fluorimeter for 90 seconds. The cuvette was then removed from the fluorimeter and 0.35 mL of the phenanthroline solution was added to the ferrioxalate solution. The resulting solution was stored in the dark for 1 h and the UV-vis spectrum was obtained. The absorbance value at 510 nm was recorded and the process was repeated 2 additional times for 3 total trials. Calculations.
The amount of Fe 2+ formed after irradiation was calculated according to the Beer-Lambert law:

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where V is the volume of the sample analyzed (2.35 mL), DA is the difference in average absorbances (between the irradiated and unirradiated ferrioxalate solutions) at 510 nm, l is the path length of the cuvette, and e is the molar absorptivity at 510 nm. The photon flux was calculated using the following equation: where f is the quantum yield of the ferrioxalate actinometer at 313 nm, 21  In a nitrogen-filled glovebox, a quartz cuvette was charged with sulfamide 1h (42.7 mg, 0.10 mmol, 1 equiv) and PhH (2.5 mL, 0.04 M). The cuvette was fitted with a Teflon cap and sealed with parafilm. The vial was then placed in a fluorimeter and irradiated with ultraviolet light (313 nm ± 5 nm) for 60 minutes. After 60 minutes, the vial was removed from the fluorimeter and the reaction mixture was transferred to a scintillation vial and concentrated under reduced pressure. The residue was purified as detailed above to provide the desired product (25.7 mg, 60% yield, 0.064 mmol). A duplicate experiment afforded 24.0 mg of the desired product (56% yield). The quantum yield was calculated as an average of the two runs.
The minimum quantum yield (f) was calculated using the following equation: Where t is the reaction time and f is the fraction of light absorbed by sulfamide 1h.

UV-Vis Spectrum of 4h
Supporting Information for Sulfamides Direct Radical-Mediated Chlorination S66

XIV. S-N bond lengths in related sulfamides
1.6875 (10) 1.6147 (11) 24 GaussView 25 was used to generate input geometries and visualize output. Geometry minimizations and frequency calculations for 1,6-and 1,7-HAT pathways were initially performed using the uB3LYP 26 functional and the 6-31+G(d,p) basis set 27 with inspiration from related calculations by Leonori and co-workers. 28 The calculations were performed using the polarizable continuum model (PCM) to account for solvation effects in benzene and an ultrafine (99,590) integration grid to limit errors associated with low-frequency vibrational modes. 29 . These calculations were performed without any corrections for quantum tunneling. Quasi-Harmonic Approximation [d] Supporting Information for Sulfamides Direct Radical-Mediated Chlorination S69 calculated Gibbs free energies using the functional/basis set combination reported at the top of each column. [c] Corrected using the quasi-RRHO approximation of Grimme. 30 [d] Corrected using the quasi-harmonic approximation of Cramer and Truhlar. 31 The computed energies of the transition states were found to be highly dependent upon the molecule's orientation, 29 which we expect leads, at least in part, to the discrepancies in both qualitative and quantitative trends between the experimental and calculated values. These discrepancies appear to be most drastic for sulfamide substrates where there is a significant difference in BDE of the hydrogen atoms being engaged by the associated 1,6-and 1,7-HAT processes (entries 6-8). The observed trends hold even when quasi-harmonic corrections have been applied. 30,31 These corrections should limit error associated with contributions with the sensitive entropic component of small vibrational frequencies.