Palladium-Catalysed Aminosulfonylation of Aryl-, Alkenyl ... · ! 2! Experimental General...

! 1!

Palladium-Catalysed Aminosulfonylation of Aryl-, Alkenyl- and Heteroaryl

Halides: Scope of the Three-Component Synthesis of N-

Aminosulfonamides

Edward J. Emmett,a Charlotte S. Richards-Taylor,a Bao Nguyen,a Alfonso

Garcia-Rubia,a Barry R. Hayterb and Michael C. Willisa,*

a Department of Chemistry, University of Oxford, Chemistry Research

Laboratory, Mansfield Road, Oxford, OX1 3TA. Fax: 44 1865 285002; E-mail:

[email protected]

b Oncology Innovative Medicines, AstraZeneca, Alderley Park, Macclesfield,

Cheshire, SK10 4TG, UK.

Electronic Supporting Information

Electronic Supplementary Material (ESI) for Organic & Biomolecular ChemistryThis journal is © The Royal Society of Chemistry 2012

! 2!

Experimental

General considerations

Chemicals were purchased from Sigma Aldrich, Alfa Aesar, TCI UK or Acros and used without further purification with the exception of DABCO which was sublimed (50 oC, 1 mbar) prior to use. Anhydrous (where stated), HPLC grade solvents were purchased from Sigma Aldrich, Fisher Scientific or Rathburn and used directly without further purification with the exception of 1,4-dioxane which was distilled from calcium hydride onto 4 Å molecular sieves which had been activated by heating under vacuum (0.1 mbar) at >200 oC for 12 hrs. ‘Petrol’ refers to the fraction of light petroleum ether boiling in the range 40-60 oC. Cesium carbonate was dried prior to use in a vacuum drying pistol (120 oC, 10 mbar) for 18 hrs.

Reactions were performed with continuous magnetic stirring, under an atmosphere of nitrogen, unless otherwise stated, using standard Schlenk techniques and all glassware was dried in an oven (>200 oC, overnight) and allowed to cool under a flow of nitrogen (passed through a Drierite® filled tube) prior to use. Flash column chromatography was performed using Apollo scientific silica gel 60 (particle size 0.040-0.063 nm) with the indicated eluents. Thin Layer Chromatography (TLC) analysis was carried out on Merck Kieselgel 60 PF254 pre-coated aluminium backed sheets and visualised either by UV fluorescence (254 nm) and/or by staining with potassium permanganate (KMnO4).

NMR spectra were recorded at ambient temperature on either Brüker DPX200 (200 MHz), DPX400 (400 MHz) or AVC500 (500 MHz) spectrometers. Chemical shifts (δ) are reported in parts per million (ppm) and referenced relative to the residual solvent peak(s) (as specified). Coupling constants (J) are given in Hertz (Hz) and rounded to the nearest 0.1 Hz. Assignments were made on the basis of chemical shifts, coupling constants, COSY, HSQC and comparison with spectra of related compounds. Signal multiplicities are denoted as: s, singlet; d, doublet; t, triplet; q, quartet; quin., quintet; m, multiplet; br., broad; app., apparent.

Melting points were measured using a Leica Gallen III hot-stage microscope. Low resolution mass spectra were recorded on a Fisons Platform spectrometer (ESI). High resolution mass spectra were measured by the internal service at the University of Oxford using a Bruker Daltronics microTOF spectrometer. m/z ratio values are reported in Daltons; high resolution values are calculated to four decimal places from the molecular formula, all found within a tolerance of 5 ppm. Infrared spectra were determined neat using a Bruker Tensor 27 FT spectrometer with an internal range of 600-4000 cm-1.

Data for compounds not included below can be found in our earlier Communicaiton.1


! 3!

N-Aminosulfonamides

General procedure for the formation of N-morpholinosulfonamides using 4-

aminomorpholine-sulfur dioxide complex, 8, exemplified by the preparation of

4!methyl!N-morpholinobenzenesulfonamide, 4a

A glass reaction tube was charged with 4%iodotoluene (50 mg, 0.23 mmol),

4%aminomorpholine%sulfur dioxide complex 8 (57 mg, 0.34 mmol),

1,4%diazabicyclo[2.2.2]octane (DABCO) (28 mg, 0.25 mmol), palladium(II) acetate (5 mg, 23

µmol) and tri%tert-butylphosphonium tetrafluoroborate (13 mg, 46 µmol) and sealed under N2.

1,4%Dioxane (1.6 mL) was added and the tube heated at 70 °C with stirring for 16 hrs. After

cooling, the reaction mixture was filtered through Celite. The Celite pad was washed

sequentially with CH2Cl2 (10 mL) and Et2O (5 mL) and the combined organic extracts

concentrated in vacuo. Purification by flash column chromatography (50–100% Et2O in

petrol) afforded the N-aminosulfonamide 4a as colourless crystals (54 mg, 92%). Data for all

compounds made by this method is either previously reported in our communication1 or

reported below, made by the DABSO method.

General procedure (A) for the formation of N-aminosulfonamides using DABCO·(SO2)2

complex, 1 (0.6 equivalents), and DABCO (0.5 equivalents), exemplified by the

preparation of 4-methyl-N-morpholinobenzenesulfonamide, 4a

A glass reaction tube was charged with 4!iodotoluene (50 mg, 0.23 mmol),

4!aminomorpholine (33 µl, 0.34 mmol), DABCO·(SO2)2 complex 1 (33 mg, 0.14 mmol),

1,4!diazabicyclo[2.2.2]octane (13 mg, 0.11 mmol), palladium(II) acetate (5 mg, 23 µmol) and

tri!tert-butylphosphonium tetrafluoroborate (13 mg, 46 µmol) and sealed under N2.

1,4!Dioxane (1.6 mL) was added and the tube heated at 70 °C for 16 hrs. After cooling, the

reaction mixture was filtered through Celite. The Celite pad was washed sequentially with

CH2Cl2 (10 mL) and Et2O (5 mL) and the combined organic extracts concentrated in vacuo.

Purification by flash column chromatography (50–100% Et2O in petrol) afforded the N-

Me

SNHN

OO O


! 4!

aminosulfonamide 4a as colourless crystals (54 mg, 92%). Data previously reported in

communication.1

General procedure (B) for the formation of N-aminosulfonamides using DABCO·(SO2)2

complex, 1 (1.1 equivalents), exemplified by the preparation of 2-methoxy-N-

morpholinobenzenesulfonamide (Table 2, Entry 7)

A glass reaction tube was charged with 2!iodoanisole (50 mg, 0.21 mmol),

4!aminomorpholine (31 µl, 0.32 mmol), DABCO·(SO2)2 complex 1 (57 mg, 0.24 mmol),

palladium(II) acetate (5 mg, 21 µmol) and tri!tert-butylphosphonium tetrafluoroborate (12

mg, 42 µmol) and sealed under N2. 1,4!Dioxane (1.6 mL) was added and the tube heated at

70 °C for 16 hrs. After cooling, the reaction mixture was filtered through Celite. The Celite

pad was washed sequentially with CH2Cl2 (10 mL) and Et2O (5 mL) and the combined

organic extracts concentrated in vacuo. Purification by flash column chromatography (50–

100% Et2O in petrol) afforded the N-aminosulfonamide as colourless crystals (44 mg, 76%).

Data previously reported in communication.1

4-Amino-N-morpholinobenzenesulfonamide (Table 2, Entry 9)

The general procedure A was followed with the use of 4-iodoaniline (50 mg, 0.23 mmol).

Flash column chromatography (100% Et2O) afforded the N-aminosulfonamide as colourless

crystals (52 mg, 88%); mp 159-160 oC (CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 7.73 (2H, d,

J 8.6, Ar-H), 6.69 (2H, d, J 8.6, Ar-H), 5.17 (1H, s, NH), 4.16 (2H, br. s, NH2), 3.62 (4H, t, J

4.6, (NCH2CH2O)2), 2.63 (4H, t, J 4.6, (NCH2CH2O)2); 13C NMR (125 MHz, CDCl3) δ

150.8, 130.3, 126.6, 113.8, 66.7, 56.8; IR υmax (neat)/cm-1 3478, 3374, 3148, 1632, 1594,

1501, 1314 (SO2), 1143 (SO2), 1099; LRMS (ESI) m/z 280 (35%, [M+Na]+), 537 (100%,

[2M+Na]+); HRMS (ESI) found m/z 280.0718 [M+Na]+, C21H22N2O3SNa requires m/z

280.0726.

SNHN

OO O

OMe

H2N

SNHN

OO O


! 5!

4!Cyano!N!morpholinobenzenesulfonamide (Table 2, Entry 11)

The general procedure B was followed with the use of 4-iodobenzonitrile (50 mg, 0.22

mmol). Flash column chromatography (50–100% Et2O in petrol) afforded the N-

aminosulfonamide as colourless crystals (25 mg, 43%); mp 185%186 °C (CH2Cl2); 1H NMR

(400 MHz, DMSO-d6) δ 9.24 (1H, s, NH), 8.08 (2H, d, J 8.4, Ar-H), 8.01 (2H, d, J 8.4, Ar-

H), 3.45 (4H, t, J 4.4, (NCH2CH2O)2), 2.50 – 2.47 (4H, m, (NCH2CH2O)2); 13C NMR (100

MHz, DMSO-d6) δ 142.9, 132.6, 128.7, 117.2, 116.9, 66.5, 56.9; IR υmax (neat)/cm-1 3194,

2960, 2923, 2853, 2233 (CN), 1459, 1338 (SO2), 1264, 1165 (SO2), 1110, 1090; LRMS (ESI)

m/z 266 (100%, [M-H]-); HRMS (ESI) found m/z 266.0610 [M%H]%, C11H12N3O3S requires

266.0605.

Methyl 2-(N-morpholinosulfamoyl)benzoate (Table 2, Entry 13)

The general procedure B was followed with the use of 2-iodomethylbenzoate (50 mg, 0.19

mmol). Flash column chromatography (25–50% EtOAc in petrol) afforded the N-

aminosulfonamide as a yellow oil (20 mg, 39%). 1H NMR (500 MHz, CDCl3) δ 8.22 – 8.20

(1H, m, Ar-H), 7.78 – 7.76 (1H, m, Ar-H), 7.69 – 7.66 (2H, m, Ar-H), 6.77 (1H, s, NH), 3.99

(3H, s, Me), 3.58 (4H, t, J 4.5, (NCH2CH2O)2), 2.68 (4H, t, J 4.5, (NCH2CH2O)2); 13C NMR

(125 MHz, CDCl3) δ 168.3, 137.7, 132.8, 131.6, 131.2, 131.1, 130.1, 66.5, 56.4, 53.5; IR υmax

(neat)/cm-1 3240, 2961, 2855, 1723 (CO), 1436, 1340 (SO2), 1297, 1263, 1171 (SO2), 1112,

1061; LRMS (ESI) m/z 323 (90%, [M+Na]+), 623 (100%, [2M+Na]+); HRMS (ESI) found

m/z 323.0678 [M+Na]+, C12H16N2O5SNa requires m/z 323.0672.

N-Morpholinobenzenesulfonamide (Table 2, Entry 15)

The general procedure B was followed with the use of iodobenzene (50 mg, 0.25 mmol).

Flash column chromatography (50–100% Et2O in hexane) afforded the N-aminosulfonamide

as colourless crystals (46 mg, 77%); mp 121-122 oC (CH2Cl2); 1H NMR (400 MHz, CDCl3) δ

NC

SNHN

O O O

SHNN

OO OOMeO

SNH

O ON

O


! 6!

8.00 – 7.97 (2H, m, Ar-H), 7.64 – 7.60 (1H, m, Ar-H), 7.56 – 7.52 (2H, m, Ar-H), 5.43 (1H,

s, NH), 3.61 (4H, t, J 4.5, (NCH2CH2O)2), 2.62 (4H, t, J 4.5, (NCH2CH2O)2); 13C NMR (125

MHz, CDCl3) δ 138.6, 133.2, 128.8, 128.1, 66.6, 56.8; IR υmax (neat)/cm-1 3213, 2963, 2858,

1448, 1362, 1327 (SO2), 1264, 1164 (SO2), 1110; LRMS (ESI) m/z 265 (60%, [M+Na]+), 507

(100%, [2M+Na]+); HRMS (ESI) found m/z 265.0618 [M+Na]+, C10H14N2O3SNa requires

m/z 265.0617.

4!Chloro!N!morpholinobenzenesulfonamide (Table 2, Entry 17)

The general procedure B was followed with the use of 1-chloro-4-iodobenzene (50 mg, 0.21


aminosulfonamide XX as colourless crystals (49 mg, 84%); mp 174-175 °C (CH2Cl2); 1H

NMR (400 MHz, CDCl3) δ 7.92 (2H, d, J 8.6, Ar-H), 7.51 (2H, d, J 8.6, Ar-H), 5.58 (1H, s,

NH), 3.62 (4H, t, J 4.6, (NCH2CH2O)2), 2.65 (4H, t, J 4.6, (NCH2CH2O)2); 13C NMR (100

MHz, CDCl3) δ 139.8, 137.1, 129.6, 129.2, 66.6, 56.8; IR υmax (neat)/cm-1 3190, 2975, 2856,

1336 (SO2), 1164 (SO2), 1111; LRMS (ESI) m/z 277, 279 (20%, 10%, [M+H]+), 299, 301

(70%, 40%, [M+Na]+), 331 (30%, [M+Na+MeOH]+), 577 (100%, [2M+Na]+); HRMS (ESI)

found m/z 299.0228, 301.0198 [M+Na]+, C10H13ClN2O3SNa requires m/z 299.0228,

301.0198.

4!Bromo!N!morpholinobenzenesulfonamide (Table 2, Entry 18)

The general procedure B was followed with the use of 1-bromo-4-iodobenzene (65 mg, 0.23


aminosulfonamide as colourless crystals (57 mg, 77%); mp 170-171 °C (CH2Cl2); 1H NMR

(400 MHz, CDCl3) δ 7.84 (2H, d, J 8.6, Ar-H), 7.67 (2H, d, J 8.6, Ar-H), 5.60 (1H, s, NH),

3.63 (4H, t, J 4.6, (NCH2CH2O)2), 2.65 (4H, t, J 4.6, (NCH2CH2O)2); 13C NMR (100 MHz,

CDCl3) δ 137.6, 132.2, 129.7, 128.3, 66.6, 56.8; IR υmax (neat)/cm-1 3195, 2970, 2858, 1338

(SO2), 1165 (SO2), 1112; LRMS (ESI) m/z 321, 323 (20%, [M+H]+), 342, 344 (45%,

[M+Na]+), 663, 665, 667 (80%, 100%, 90%, [2M+Na]+); HRMS (ESI) found m/z 342.9729,

344.9706 [M+Na]+, C10H13BrN2O3SNa requires m/z 342.9722, 344.9702.

Br

SNHN

OO O

Cl

SNHN

OO O


! 7!

N',N',4-Trimethylbenzenesulfonohydrazide (Table 3, Entry 4)

The general procedure A was followed with the use of 1,1-dimethylhydrazine (21 mg, 0.34


aminosulfonamide as colourless crystals (32 mg, 65%); mp 76-77 oC (CH2Cl2); 1H NMR (400

MHz, CDCl3) δ 7.84 (2H, d, J 8.1, Ar-H), 7.32 (2H, d, J 8.1, Ar-H), 5.14 (1H, br. s, NH),

2.45 (3H, s, Ar-Me), 2.40 (6H, s, NMe2); 13C NMR (100 MHz, CDCl3) δ 143.8, 135.8, 129.5,

128.2, 48.5, 21.6; IR υmax (neat)/cm-1 3258, 2919, 1596, 1458, 1394, 1325 (SO2), 1156 (SO2),

1092, 1036; LRMS (ESI) m/z 237 (70%, [M+Na]+), 269 (30%, [M+Na+MeOH]+), 451

(100%, [2M+Na]+); HRMS (ESI) found m/z 237.0670 [M+Na]+, C9H14N2O2SNa requires m/z

237.0668.

N'-Benzyl-N',4-dimethylbenzenesulfonohydrazide (Table 3, Entry 5)

The general procedure A was followed with the use of 1-benzyl-1-methylhydrazine (47 mg,

0.34 mmol). Flash column chromatography (11:8:1 petrol:Et2O:Et3N) afforded the N-

aminosulfonamide as yellow crystals (53 mg, 80%); mp 84-85 oC (CH2Cl2); 1H NMR (400

MHz, CDCl3) δ 7.83 (2H, d, J 8.2, Ar-H), 7.29 – 7.25 (5H, m, Ar-H), 7.16 – 7.14 (2H, m, Ar-

H), 5.51 (1H, s, NH), 3.71 (2H, s, NCH2Ph), 2.43 (3H, s, Ar-Me), 2.32 (3H, s, NHNMe); 13C

NMR (100 MHz, CDCl3) δ 143.7, 135.7, 135.2, 129.6, 129.4, 128.3, 128.2, 127.7, 64.5, 44.8,

21.6; IR υmax (neat)/cm-1 3236, 1597, 1493, 1452, 1399, 1328 (SO2), 1162 (SO2), 1091;

LRMS (ESI) m/z 291 (20%, [M+H]+), 313 (80%, [M+Na]+), 603 (100%, [2M+Na]+); HRMS

(ESI) found m/z 313.0972 [M+Na]+, C15H18N2O2SNa requires m/z 313.0981.

Me

SNHNMe

MeO O

Me

SNHNMe

O O


! 8!

N',N'-Dibenzyl-4-methylbenzenesulfonohydrazide (Table 3, Entry 6)

The general procedure A was followed with the use of 4-iodotoluene (350 mg, 1.61 mmol),

1,1-dibenzylhydrazine (511 mg, 2.41 mmol), DABCO-(SO2)2 complex (231 mg, 0.96 mmol),

DABCO (90 mg, 0.80 mmol), palladium(II) acetate (36 mg, 0.16 mmol), tri%tert-

butylphosphonium tetrafluoroborate (93 mg, 0.32 mmol) and 1,4-dioxane (11 mL). Flash

column chromatography (13:6:1 petrol:Et2O:Et3N) afforded the N-aminosulfonamide XX as

pale yellow crystals (499 mg, 85%); mp 123-124 oC (CH2Cl2); 1H NMR (400 MHz, CDCl3) δ

7.72 (2H, d, J 8.3, Ar-H), 7.28 – 7.26 (6H, m, Ar-H), 7.19 – 7.16 (6H, m, Ar-H), 5.53 (1H, s,

NH), 3.73 (4H, s, N(CH2Ph)2), 2.41 (3H, s, Me); 13C NMR (100 MHz, CDCl3) δ 143.6,

135.4, 134.9, 129.8, 129.4, 128.4, 128.2, 127.6, 59.7, 21.6; IR υmax (neat)/cm-1 3203, 1738,

1598, 1427, 1325 (SO2), 1157 (SO2), 1091; LRMS (ESI) m/z 367 (80%, [M+H]+), 389 (60%,

[M+Na]+), 755 (100%, [2M+Na]+); HRMS (ESI) found m/z 389.1280 [M+Na]+,

C21H22N2O2SNa requires m/z 389.1294.

(E)-N-Morpholino-4-phenylbut-1-ene-1-sulfonamide (Table 4, Entry 1)

The general procedure B was followed with the use of (E)-(4-iodobut-3-enyl)benzene2 (50

mg, 0.19 mmol). Flash column chromatography (25–75% Et2O in petrol) afforded the N-


(400 MHz, CDCl3) δ 7.33 – 7.27 (2H, m, Ar-H), 7.24 – 7.17 (3H, m, Ar-H), 6.92 (1H, dt, J

15.2, 6.7, CH2CHCH), 6.26 (1H, dt, J 15.2, 1.5, CH2CHCH), 5.13 (1H, br. s, NH), 3.67 (4H,

t, J 4.6, (NCH2CH2O)2), 2.84 (2H, t, J 7.4, CCH2CH2CH), 2.72 (4H, t, J 4.6, (NCH2CH2O)2),

2.67 – 2.59 (2H, m, CCH2CH2CH); 13C NMR (100 MHz, CDCl3) δ 146.7, 139.9, 128.6,

128.3, 127.2, 126.4, 66.6, 57.2, 33.7, 32.6; IR υmax (neat)/cm-1 3210, 3060, 2960, 2856, 2284,

1960, 1714, 1632, 1496, 1361 (SO2), 1278, 1149 (SO2), 1072, 1011; LRMS (ESI) m/z 297

(20%, [M+H]+), 319 (80%, [M+Na]+), 615 (100%, [2M+Na]+), 911 (10%, [3M+Na]+);

HRMS (ESI) found m/z 319.1091 [M+Na]+, C14H20N2O3SNa requires m/z 319.1087.

Me

SNHN

O O

SNHN

OO O


! 9!

(E)-N-Morpholino-2-phenylethenesulfonamide (Table 4, Entry 3)

The general procedure B was followed with the use of (E)-(2-iodovinyl)benzene3 (50 mg,

0.22 mmol). Flash column chromatography (25–75% Et2O in petrol) afforded the N-

aminosulfonamide as colourless crystals (31 mg, 53%); mp 159-161 oC (CH2Cl2); 1H NMR

(400 MHz, CDCl3) δ 7.62 (1H, d, J 15.5, CHCHSO2), 7.56 – 7.40 (5H, m, Ar-H), 6.81 (1H,

d, J 15.5, CHCHSO2), 5.31 (1H, br. s, NH), 3.73 (4H, t, J 4.6, (NCH2CH2O)2), 2.88 (4H, t, J

4.6, (NCH2CH2O)2); 13C NMR (100 MHz, CDCl3) δ 143.7, 132.5, 131.1, 129.2, 128.3, 123.5,

66.6, 57.4; IR υmax (neat)/cm-1 3175, 2851, 1457, 1370, 1327 (SO2), 1263, 1137 (SO2), 1108;

LRMS (ESI) m/z 269 (15%, [M+H]+), 291 (55%, [M+Na]+), 323 (15%, [M+Na+MeOH]+),

559 (100%, [2M+Na]+), 827 (20%, [3M+Na]+); HRMS (ESI) found m/z 291.0772 [M+Na]+,


(Z)-N-Morpholino-2-phenylethenesulfonamide (Table 4, Entry 4)

The general procedure B was followed with the use of (Z)-(2-iodovinyl)benzene3 (>20:1,

Z:E) (50 mg, 0.22 mmol). Flash column chromatography (25–75% Et2O in petrol) afforded

an inseparable mixture (3.5:1, Z:E) of Z N-aminosulfonamide and E N-aminosulfonamide as a

yellow oil (30 mg, 51%); 1H NMR (400 MHz, CDCl3) δ 7.77 – 7.72 (2H, m, Ar-H, Z), 7.62

(0.3H, d, J 15.5, CHCHSO2, E), 7.54 – 7.33 (4.5H, m, Ar-H, Z and E), 7.09 (1H, d, J 12.2,

CHCHSO2, Z), 6.81 (0.3H, d, J 15.5, CHCHSO2, E), 6.48 (1H, d, J 12.2, CHCHSO2, Z), 5.51

(0.3H, s, NH, E), 5.48 (1H, s, NH, Z), 3.75 – 3.65 (5.2H, m, (NCH2CH2O)2, Z and E), 2.87

(1.2H, t, J 4.6, (NCH2CH2O)2, E), 2.78 (4H, t, J 4.5, (NCH2CH2O)2, Z); 13C NMR (100 MHz,

CDCl3) δ 143.7 (E), 141.3 (Z), 132.5 (E), 131.1 (E), 130.4 (Z), 130.1 (Z), 129.2 (E), 128.3 (E

and Z) (2H), 126.9 (Z), 123.5 (E and Z) (2H), 66.6 (E), 66.5 (Z), 57.4 (E), 57.1 (Z); LRMS

(ESI) m/z 269 (15%, [M+H]+), 291 (55%, [M+Na]+), 323 (15%, [M+Na+MeOH]+), 559

(100%, [2M+Na]+), 827 (20%, [3M+Na]+); HRMS (ESI) found m/z 291.0772 [M+Na]+,


SNHN

OO O

SNHN

OOO


! 10!

(E)-N-Morpholino-2-phenylprop-1-ene-1-sulfonamide (Table 4, Entry 6)

The general procedure B was followed with the use of (E)-(1-iodoprop-1-en-2-yl)benzene3

(50 mg, 0.20 mmol). Flash column chromatography (25–75% Et2O in petrol) afforded the N-


(400 MHz, CDCl3) δ 7.46 – 7.40 (5H, m, Ar-H), 6.54 (1H, d, J 1.2, CH), 5.43 (1H, s, NH),

3.75 (4H, t, J 4.5, (NCH2CH2O)2), 2.89 (4H, t, J 4.5, (NCH2CH2O)2), 2.59 (3H, d, J 1.2, Me); 13C NMR (100 MHz, CDCl3) δ 154.0, 140.3, 129.8, 128.8, 126.3, 124.1, 66.7, 57.3, 17.9; IR

υmax (neat)/cm-1 3226, 2830, 1608, 1309 (SO2), 1263, 1140 (SO2), 1106; LRMS (ESI) m/z

283 (10%, [M+H]+), 305 (15%, [M+Na]+), 587 (100%, [2M+Na]+), 869 (30%, [3M+Na]+);


(Z)-N-Morpholinooct-4-ene-4-sulfonamide (Table 4, Entry 7)

The general procedure B was followed with the use of (Z)-4-iodooct-4-ene4 (50 mg, 0.21



(400 MHz, CDCl3) δ 6.78 (1H, t, J 7.6, CH), 5.09 (1H, br. s, NH), 3.70 (4H, t, J 4.5,

(NCH2CH2O)2), 2.81 (4H, t, J 4.5(NCH2CH2O)2), 2.34 (2H, app. t, J 8.0, CHCCH2), 2.21

(2H, app. q, J 7.4, CH2CHCCH2), 1.67 – 1.46 (4H, m, 2 x CH2), 1.00 – 0.94 (6H, m, 2 x Me); 13C NMR (100 MHz, CDCl3) δ 144.2, 137.7, 66.7, 57.3, 30.5, 29.0, 22.8, 21.8, 14.1, 13.8; IR

υmax (neat)/cm-1 3205, 2957, 2872, 1455, 1323 (SO2), 1279, 1170, 1138 (SO2), 1108, 1074;

LRMS (ESI) m/z 277 (25%, [M+H]+), 299 (85%, [M+Na]+), 331 (20%, [M+Na+MeOH]+),

575 (100%, [2M+Na]+), 851 (15%, [3M+Na]+); HRMS (ESI) found m/z 299.1400 [M+Na]+,


MeSNHN

OO O


! 11!

N-Morpholinocyclohex-1-ene-1-sulfonamide (Table 4, Entry 8)

The general procedure B was followed with the use of 1-iodocyclohex-1-ene3 (50 mg, 0.24



(400 MHz, CDCl3) δ 6.98 – 6.94 (1H, m, CH), 5.13 (1H, br. s, NH), 3.72 (4H, t, J 4.6,

(NCH2CH2O)2), 2.82 (4H, t, J 4.6, (NCH2CH2O)2), 2.40 – 2.34 (2H, m, CH2), 2.32 – 2.25

(2H, m, CH2), 1.76 – 1.69 (2H, m, CH2), 1.67 – 1.60 (2H, m, CH2); 13C NMR (100 MHz,

CDCl3) δ 140.2, 136.5, 66.6, 57.3, 25.5, 23.7, 22.1, 20.9; IR υmax (neat)/cm-1 3196, 1438,

1319 (SO2), 1263, 1143 (SO2), 1108, 1052; LRMS (ESI) m/z 247 (10%, [M+H]+), 269 (85%,

[M+Na]+), 301 (25%, [M+Na+MeOH]+), 515 (100%, [2M+Na]+), 761 (10%, [3M+Na]+);


N-Morpholinocyclohept-1-ene-1-sulfonamide (Table 4, Entry 9)

The general procedure B was followed with the use of 1-iodocyclohept-1-ene2 (50 mg, 0.23



(400 MHz, CDCl3) δ 7.16 (1H, t, J 6.5, CH), 5.09 (1H, br. s, NH), 3.73 (4H, t, J 4.6,

(NCH2CH2O)2), 2.84 (4H, t, J 4.6, (NCH2CH2O)2), 2.58 – 2.54 (2H, m, CH2), 2.40 – 2.34

(2H, m, CH2), 1.83 – 1.77 (2H, m, CH2), 1.66 – 1.56 (4H, m, 2 x CH2); 13C NMR (100 MHz,

CDCl3) δ 144.8, 141.3, 66.6, 57.6, 31.4, 28.6, 28.0, 26.5, 25.5; IR υmax (neat)/cm-1 3168,

2919, 2849, 1645, 1455, 1299 (SO2), 1157, 1140 (SO2), 1114; LRMS (ESI) m/z 261 (15%,

[M+H]+), 283 (45%, [M+Na]+), 543 (100%, [2M+Na]+), 803 (25%, [3M+Na]+); HRMS (ESI)

found m/z 283.1088 [M+Na]+, C11H20N2O3SNa requires m/z 283.1087.

SNHN

OO O

S NH

N

O

OO


! 12!

3-Methyl-N-morpholinobut-2-ene-2-sulfonamide (Table 4, Entry 10)

The general procedure B was followed with the use of 2-iodo-3-methylbut-2-ene5 (50 mg,

0.26 mmol). Flash column chromatography (25–75% Et2O in petrol) afforded the N-

aminosulfonamide as colourless crystals (43 mg, 72%); mp 132-133 oC (CH2Cl2); 1H NMR

(400 MHz, CDCl3) δ 5.26 (1H, br. s, NH), 3.71 (4H, t, J 4.6, (NCH2CH2O)2), 2.81 (4H, t, J

4.6, (NCH2CH2O)2), 2.25 (3H, app. d, J 2.7, MeCSO2), 2.07 (3H, app. t, J 1.0, MeCCSO2),

1.92 (3H, app. d, J 0.8, MeCCSO2); 13C NMR (100 MHz, CDCl3) δ 147.4, 128.8, 66.8, 57.0,

24.3, 22.8, 16.6; IR υmax (neat)/cm-1 3174, 2960, 2920, 2863, 1653, 1457, 1319 (SO2), 1260,

1151 (SO2), 1106; LRMS (ESI) m/z 235 (5%, [M+H]+), 257 (80%, [M+Na]+), 289 (30%,

[M+Na+MeOH]+), 491 (100%, [2M+Na]+), ; HRMS (ESI) found m/z 257.0932 [M+Na]+,


N-(Morpholin-4-yl)-1-benzothiophene-3-sulfonamide (Table 5, Entry 2)

The general procedure B was followed with the use of 3-iodo-1-benzothiophene5 (62 mg,

0.24 mmol). Flash chromatography (25—100% Et2O in petrol) afforded the N-

aminosulfonamide as a white solid (53 mg, 73%); mp 142-144 °C (CH2Cl2); 1H NMR (400

MHz, CDCl3) δ 8.38 (1H, s, C=CHS), 8.37-8.32 (1H, m, Ar-H), 7.95-7.88 (1H, m, Ar-H),

7.57-7.44 (2H, m, 2 × Ar-H), 5.68 (1H, s, NH), 3.55 (4H, app t, J 4.5, N(CH2CH2)2O), 2.60

(4H, app t, J 4.5, N(CH2CH2)2O); 13C NMR (100 MHz, CDCl3) δ 140.1, 136.2, 133.8, 132.3,

125.8, 125.7, 123.8, 122.9, 66.5, 56.9; IR νmax (neat)/cm-1 3242, 2963, 2857, 2361, 1336

(SO2), 1158 (SO2); LRMS (ESI+) m/z 619 (100%, [2M + Na]+) 321 (69%, [M + Na]+);

HRMS (ESI+) found m/z 321.0335 [M + Na]+, C12H14N2NaO3S2+ requires m/z 321.0344.

tert-Butyl 3-(morpholin-4-ylsulfamoyl)-1H-pyrrole-1-carboxylate (Table 5, Entry 3)

The general procedure B was followed with the use of tert-butyl 3-iodo-pyrrole-1-

carboxylate6 (70 mg, 0.24 mmol). Flash chromatography (25—100% Et2O in petrol) afforded

Me

SMe

Me

NHN

O

OO

NO

NH

SO O

S

NO

NH

SO O

BocN


! 13!

the N-aminosulfonamide as a white solid (16 mg, 20%); mp 130-132 ºC (CH2Cl2); 1H NMR

(400 MHz, CDCl3) δ 7.84-7.81 (1H, m, C=CHN), 7.30-7.28 (1H, m, CH=CHN), 6.55 (1H,

dd, J 3.5, 2.0, CH=CHN), 5.47 (1H, s, NH), 3.68 (4H, app t, J 4.5, N(CH2CH2)2O), 2.75 (4H,

app t, J 4.5, N(CH2CH2)2O), 1.63 (9H, s, Me); 13C NMR (100 MHz, CDCl3) δ 147.5, 125.3,

124.2, 121.5, 110.5, 86.0, 66.6, 57.0, 27.9; IR νmax (neat)/cm-1 3227, 2979, 2925, 2857, 1755

(CO), 1334 (SO2), 1154 (SO2); LRMS (ESI+) m/z 686 (100%, [2M + Na]+); HRMS (ESI+)

found m/z 354.1094 [M + Na] +, C13H21N3NaO5S+ requires m/z 354.1095.

tert-Butyl 3-(morpholin-4-ylsulfamoyl)-1H-indole-1-carboxylate (Table 5, Entry 4)

The general procedure B was followed with the use of tert-butyl 3-iodo-1H-indole-1-

carboxylate7 (92 mg, 0.24 mmol). Flash chromatography (25—100% Et2O in petrol) afforded

the N-aminosulfonamide as a white solid (44 mg, 48%); mp 149-153 °C (CH2Cl2); 1H NMR

(400 MHz, CDCl3) δ 8.24 (1H, s, C=CHN) overlapping 8.23 (1H, app d, J 9.5, Ar-H), 8.02-

7.95 (1H, m, Ar-H), 7.48-7.35 (2H, m, 2 × Ar-H), 5.71 (1H, s, NH), 3.60 (4H, app t, J 4.5,

N(CH2CH2)2O), 2.69 (4H, app t, J 4.5, N(CH2CH2)2O), 1.70 (9H, s, Me); 13C NMR (100

MHz, CDCl3) δ 148.5, 135.5, 131.3, 126.0, 125.1, 124.2, 120.7, 118.7, 115.5, 85.8, 66.5,

57.0, 28.1; IR νmax (neat)/cm-1 3161, 2976, 2957, 2360, 1748 (CO), 1341 (SO2), 1146 (SO2);

LRMS (ESI+) m/z 785 (100%, [2M + Na]+), 404 (48%, [M + Na]+), 382 (18%, [M + H]+);

HRMS (ESI+) found m/z 404.1244 [M + Na]+, C17H23N3NaO5S+ requires m/z 404.1251.

tert-Butyl 5-iodo-1H-indole-1-carboxylate

Di-tert-butyldicarbonate (1.55 g, 7.11 mmol), NEt3 (2.7 mL, 19.4 mmol) and

4-dimethylaminopyridine (79 mg, 0.65 mmol) were added to a solution of 5-iodoindole (1.57

g, 6.46 mmol) in CH2Cl2 (30 mL). The reaction mixture was stirred at rt for 1 h and then

washed twice with sodium metabisulphite (5% aq solution), dried over MgSO4, filtered and

concentrated in vacuo. Flash chromatography (5% ethyl acetate in petrol) afforded the titled

iodide as a light orange solid (1.41 g, 63%); mp 45-46 °C (CH2Cl2); 1H NMR (400 MHz,

CDCl3) δ 7.93 (1H, d, J 8.5, ArH) overlapping 7.90 (1H, d, J 2.0, ArH), 7.59 (1H, dd, J 8.5,

NO

NH

SO O

BocN

BocN

I


! 14!

2.0, ArH) overlapping 7.56 (1H, d, J 3.5, CH=CHN), 6.49 (1H, d, J 3.5, CH=CHN), 1.68

(9H, s, 3 × Me); 13C NMR (100 MHz, CDCl3) δ 149.4, 134.5, 132.9, 132.6, 129.7, 126.7,

117.0, 106.2, 86.7, 84.1, 28.2; IR νmax (neat)/cm-1 3115, 2979, 2933, 1731 (CO); m/z (FI+)

C13H14INO2+ ([M]+) requires 343.0096; found 343.0092.

tert-Butyl 5-(morpholin-4-ylsulfamoyl)-1H-indole-1-carboxylate (Table 5, Entry 5)

The general procedure B was followed with the use of tert-butyl 5-iodo-1H-indole-1-

carboxylate (82 mg, 0.24 mmol). Flash chromatography (25—100% Et2O in petrol) afforded

the N-aminosulfonamide as an off-white solid (75 mg, 81%); mp 167-170 °C (CH2Cl2); 1H

NMR (400 MHz, CDCl3) δ 8.30 (1H, app d, J 9.0, Ar-H), 8.23 (1H, app d, J 1.5, Ar-H), 7.90

(1H, app dd, J 9.0, 1.5, Ar-H), 7.72 (1H, d, J 3.5, CH=CHN), 6.69 (1H, d, J 3.5, CH=CHN),

5.56 (1H, s, NH), 3.58 (4H, app t, J 4.5, N(CH2CH2)2O), 2.61 (4H, app t, J 4.5,

N(CH2CH2)2O), 1.69 (9H, s, Me); 13C NMR (100 MHz, CDCl3) δ 149.1, 137.5, 132.6, 130.2,

128.1, 123.6, 122.0, 115.4, 107.5, 84.8, 66.6, 56.7, 28.1; IR νmax (neat)/cm-1 3211, 2977,

2858, 1740 (CO), 1335 (SO2), 1156 (SO2); LRMS (ESI‾) m/z 380 (100%, [M – H]‾); HRMS

(ESI+) found m/z 404.1245 [M + Na]+, C17H23N3NaO5S+ requires m/z 404.1251.

1H-indole-5-sulfonamide, N-4-morpholinyl (Table 5, Entry 6)

The general procedure B was followed with the use of 5-iodo-1H-indole (58 mg, 0.24 mmol).

Flash chromatography (25—100% Et2O in petrol) afforded the N-aminosulfonamide as a

white solid (50 mg, 74%); mp 143-145 °C (CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 8.48 (1H,

br. s, N(indole)H), 8.33 (1H, app br. d, J 1.0, Ar-H), 7.79 (1H, app dd, J 8.5, 1.0, Ar-H), 7.49

(1H, app d, J 8.5, Ar-H), 7.37 (1H, app t, J 3.0, CH=CHN), 6.71 (1H, app dt, J 3.0, 1.0,

CH=CHN), 5.25 (1H, br. s, NH), 3.59 (4H, app t, J 4.5, N(CH2CH2)2O), 2.59 (4H, app t, J

4.5, N(CH2CH2)2O); 13C NMR (100 MHz, CDCl3) δ 138.0, 129.3, 127.3, 126.7, 122.4, 121.2,

111.5, 104.0, 66.6, 56.7; IR νmax (neat)/cm-1 3356, 3224, 2858, 1326 (SO2), 1151 (SO2);

LRMS (ESI‾) m/z 280 (100%, [M – H]‾); HRMS (ESI+) found m/z 304.0725 [M + Na]+,

C12H15N3NaO3S+ requires m/z 304.0726.

NNH

SO O O

NBoc

NNH

SO O O

NH


! 15!

N-(Morpholin-4-yl)dibenzo[b,d]furan-2-sulfonamide (Table 5, Entry 7)

The general procedure B was followed with the use of 3-iododibenzofuran (71 mg, 0.24

mmol). Flash chromatography (25—100% Et2O in petrol) afforded the N-aminosulfonamide

as a white solid (71 mg, 89%); mp 197-199 °C (decomp.) (CH2Cl2); 1H NMR (400 MHz,

CDCl3) δ 8.63 (1H, app d, J 2.0, Ar-H), 8.10 (1H, app dd, J 8.5, 2.0, Ar-H), 8.05-8.00 (1H,

m, Ar-H), 7.69 (1H, app d, J 8.5, Ar-H), 7.67-7.62 (1H, m, Ar-H), 7.57 (1H, app td, J 7.5,

1.5, Ar-H), 7.44 (1H, app t, J 7.5, Ar-H), 5.50 (1H, s, NH), 3.60 (4H, app t, J 4.5,

N(CH2CH2)2O), 2.65 (4H, app t, J 4.5, N(CH2CH2)2O); 13C NMR (100 MHz, CDCl3) δ

158.4, 157.0, 133.1, 128.6, 127.2, 124.8, 123.8, 123.1, 121.7, 121.2, 112.10, 112.08, 66.6,

56.8; IR νmax (neat)/cm-1 3196, 2962, 2917, 2859, 1324 (SO2), 1159 (SO2); LRMS (ESI+) m/z

687 (100%, [2M + Na]+), 355 (77%, [M + Na]+); HRMS (ESI+) found m/z 355.0707 [M +

Na]+, C16H16N2NaO4S+ requires m/z 355.0723.

N-(Morpholin-4-yl)dibenzo[b,d]thiophene-4-sulfonamide (Table 5, Entry 8)

The general procedure B was followed with the use of 4-iododibenzothiophene (74 mg, 0.24

mmol). Flash chromatography (25—100% Et2O in petrol) afforded the N-aminosulfonamide

XX as a white solid (77 mg, 92%); mp 169-172 °C (CH2Cl2); 1H NMR (400 MHz, CDCl3) δ

8.40 (1H, app dd, J 8.0, 1.0, Ar-H), 8.23-8.19 (1H, m, Ar-H), 8.17 (1H, app dd, J 7.5, 1.0, Ar-

H), 7.95-7.91 (1H, m, Ar-H), 7.64 (1H, app t, J 7.5, Ar-H), 7.60-7.51 (2H, m, Ar-H), 5.70

(1H, s, NH), 3.51 (4H, app t, J 4.5, N(CH2CH2)2O), 2.54 (4H, app t, J 4.5, N(CH2CH2)2O); 13C NMR (125 MHz, CDCl3) δ 140.1, 137.6(4), 137.6(0), 134.0, 132.3, 128.7, 127.9, 126.0,

125.0, 124.3, 122.7, 121.8, 66.5, 56.7; IR νmax (neat)/cm-1 3218, 2964, 2922, 2858, 1335

(SO2), 1142 (SO2); LRMS (ESI‾) m/z 347 (100%, [M – H]‾); HRMS (ESI+) found m/z

371.0490 [M + Na]+, C16H16N2NaO3S2+ requires m/z 371.0495.

NO

NH

SO O

O

NO

NH

SO O

S


! 16!

N-N Bond Cleavage

General procedure (C) for the formation of unsubstituted sulfonamides from the

corresponding dibenzyl-N-aminosulfonamide, exemplified by the preparation of

tosylamine

A glass reaction tube was charged with recrystallised N',N'-dibenzyl-4-

methylbenzenesulfonohydrazide 4b (293 mg, 0.80 mmol) and Pearlman’s catalyst (Pd(OH)2

on carbon, 20 wt% Pd, ~60% moisture, 140 mg, 0.08 mmol). Acetone (2 mL) was added and

the reaction mixture degassed with N2. The tube was flushed with H2 gas and left stirring

under a balloon of H2 atmosphere for 16 hrs. The reaction flask was purged with N2, the

suspension filtered through Celite and the Celite pad washed with CH2Cl2 (5 mL). The filtrate

was concentrated in vacuo affording tosyl hydrazone 9 (180 mg, 100%) as analytically pure

white crystals; 1H NMR (400 MHz, CDCl3) δ 7.85 (2H, d, J 8.0, Ar-H), 7.31 (2H, d, J 8.0,

Ar-H), 2.43 (3H, s, Ar-Me), 1.94 (3H, s, NCMe), 1.80 (3H, s, NCMe); 13C NMR (100 MHz,

CDCl3) δ 156.2, 144.0, 135.4, 129.5, 128.0, 25.3, 21.6, 16.8; IR υmax (neat)/cm-1 3225, 1655,

1597, 1389, 1330 (SO2), 1158 (SO2), 1086; LRMS (ESI) m/z 227 (65%, [M+H]+), 249 (95%,

[M+Na]+), 281 (40%, [M+Na+MeOH]+), 475 (100%, [2M+Na]+); HRMS (ESI) found m/z

249.0668 [M+Na]+, C10H14N2O2SNa requires m/z 249.0668.

The N-N bond cleavage was carried out in accordance with a similar literature procedure.8

The crude sulfonyl hydrazone (180 mg, 0.80 mmol) was dissolved in acetic acid (5 mL) and

zinc dust (1.31 g, 25 mmol) added under N2. The resulting suspension was stirred at 25 oC for

1 hr. CH2Cl2 (10mL) was added to the reaction mixture, sonicated for 1 min and filtered

through Celite, the zinc residue being washed with further CH2Cl2 (5 mL). The organic

solution was washed with water (10 mL) and brine (10 mL), dried over MgSO4, filtered and

concentrated in vacuo affording analytically pure tosyl amine 10a (114 mg, 83%); 1H NMR

(400 MHz, CDCl3) δ 7.82 (2H, d, J 8.3, Ar-H), 7.31 (2H, d, J 8.3, Ar-H), 4.95 (2H, br. s,

NH2), 2.44 (3H, s, Me); 13C NMR (100 MHz, CDCl3) δ 143.6, 139.0, 129.7, 126.4, 21.5;

LRMS (ESI) m/z 194 (100%, [M+Na]+), 226 (80%, [M+Na+MeOH]+). Data was consistent

with a commercially available sample.


! 17!

N',N'-Dibenzyl-3-methoxybenzenesulfonohydrazide (Scheme 4)

The general procedure B was followed with the use of 3-iodoanisole (350 mg, 1.50 mmol)

and 1,1-dibenzylhydrazine (476 mg, 2.24 mmol). Flash column chromatography (11:8:1

petrol:Et2O:Et3N) afforded the N-aminosulfonamide as a pale yellow oil (450 mg, 79%); 1H

NMR (400 MHz, CDCl3) δ 7.48 (1H, d, J 7.7, Ar-H), 7.34 – 7.25 (8H, m, Ar-H), 7.20 – 7.18

(4H, m, Ar-H), 7.04 (1H, dd, J 8.2, 2.1, Ar-H), 5.59 (1H, s, NH), 3.80 (3H, s, OMe), 3.75

(4H, s, N(CH2Ph)2); 13C NMR (100 MHz, CDCl3) δ 159.5, 139.5, 134.9, 129.7, 129.6, 128.4,

127.7, 120.6, 119.7, 112.4, 59.9, 55.4; IR υmax (neat)/cm-1 1598, 1478, 1315 (SO2), 1240,

1150 (SO2), 1022; LRMS (ESI) m/z 405 (15%, [M+Na]+), 787 (100%, [2M+Na]+); HRMS

(ESI) found m/z 405.1227 [M+Na]+, C21H22N2O3SNa requires m/z 405.1243.

3-Methoxybenzenesulfonamide (10b, Scheme 4)

The general procedure C was followed using re-crystallised N',N'-dibenzyl-3-

methoxybenzenesulfonohydrazide (120 mg, 0.31 mmol) to first afford the hydrazone as a

white solid; 1H NMR (200 MHz, CDCl3) δ 7.57 – 7.38 (3H, m, Ar-H), 7.16 – 7.10 (1H, m,

Ar-H), 3.87 (3H, s, OMe), 1.96 (3H, s, NCMe), 1.80 (3H, s, NCMe); LRMS (ESI) m/z 210

(100%, [M+Na]+). Zinc in acetic acid reduction afforded unsubstituted sulfonamide 10b as

colourless crystals (46 mg, 80%); 1H NMR (400 MHz, DMSO-d6) δ 7.48 (1H, t, J 7.9, Ar-H),

7.41 – 7.35 (4H, m, Ar-H incl. NH2), 7.16 (1H, dd, J 8.2, 2.4, Ar-H), 3.82 (3H, s, OMe); 13C

NMR (100 MHz, DMSO-d6) δ 159.2, 145.4, 130.1, 117.6 (2C), 110.8, 55.5; LRMS (ESI) m/z

186 (100%, [M-H]-). HRMS (ESI) m/z 210.0192 [M+Na]+, C7H9NO3SNa requires 210.0195.

Data consistent with literature.9

OMe

SNH2

O O


! 18!

Sulfur dioxide complexes

4-Aminomorpholine-sulfur dioxide complex, 8

The general procedure as described for DABSO in our communication1 was followed with

the use of distilled 4-aminomorpholine (1.00 mL, 10.4 mmol) affording complex 8 as a white

powder (1.65 g, 96%). Elemental analysis found 29.01% C, 6.15% H, 16.82% N, 19.08% S;

C4H10N2O3S requires 28.91% C, 6.06% H, 16.86% N, 19.29% S; 1H NMR (400 MHz,

MeOD-d4) δ 3.80 (4H, br. s, (NCH2CH2O)2), 2.99 (4H, br. s, (NCH2CH2O)2); 13C NMR (100

MHz, MeOD-d4) δ 66.5, 56.0; IR υmax (neat)/cm-1 2869, 2600 (br.), 2173, 1630, 1595, 1468,

1299 (SO2), 1200, 1104 (SO2). DSC analysis for both this complex and DABSO are attached.

For this complex the first ‘event’ occurs around 95 oC (melting) but for DABSO this occurs

around 220 oC (decomposition).

References

1. B. Nguyen, E. J. Emmett and M. C. Willis, J. Am. Chem. Soc., 2010, 132, 16372. 2. L. L. W. Cheung and A. K. Yudin, Org. Lett., 2009, 11, 1281. 3. J. J. Mousseau, J. A. Bull and A. B. Charette, Angew. Chem. Int. Edit., 2010, 49, 1115. 4. S.-i. Kawaguchi and A. Ogawa, Org. Lett., 2010, 12, 1893. 5. A. Klapars and S. L. Buchwald, J. Am. Chem. Soc., 2002, 124, 14844. 6. J. C. Conrad, J. Kong, B. N. Laforteza and D. W. C. MacMillan, J. Am. Chem. Soc., 2009, 131, 11640. 7. C. l. Mothes, S. Lavielle and P. Karoyan, J. Org. Chem., 2008, 73, 6706. 8. W. Y. Chan and C. Berthelette, Tetrahedron Lett., 2002, 43, 4537. 9. K. L. Lobb, P. A. Hipskind, J. A. Aikins, E. Alvarez, Y.-Y. Cheung, E. L. Considine, A. De Dios, G. L. Durst, R. Ferritto, C. S. Grossman, D. D. Giera, B. A. Hollister, Z. Huang, P. W. Iversen, K. L. Law, T. Li, H.-S. Lin, B. Lopez, J. E. Lopez, L. M. M. Cabrejas, D. J. McCann, V. Molero, J. E. Reilly, M. E. Richett, C. Shih, B. Teicher, J. H. Wikel, W. T. White and M. M. Mader, J. Med. Chem., 2004, 47, 5367.


9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm

1.56

2.62

2.63

2.64

3.61

3.62

3.63

4.15

5.16

5.17

6.68

6.70

7.27

7.27

7.72

7.74

4.00

4.00

1.79

0.84

1.95

1.86

SNHN

OO O

H2N

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm

56.7

8

66.6

9

76.7

376

.99

77.2

4

113.

81

126.

6313

0.29

150.

83

H2N

SNHN

OO O


9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm

2.47

2.48

2.49

2.50

2.50

3.44

3.45

3.46

8.00

8.02

8.08

8.10

9.24

4.77

4.04

2.06

2.03

1.00

NC

SNHN

OO O

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm

38.8

939

.10

39.3

139

.52

39.7

339

.94

40.1

5

55.8

3

65.8

8

115.

2711

7.76

128.

20

133.

19

143.

54

NC

SNHN

OO O


1.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5 ppm

2.67

2.68

2.69

3.57

3.58

3.59

3.99

6.77

7.27

7.66

7.66

7.67

7.68

7.68

7.76

7.77

7.77

7.77

7.78

8.20

8.20

8.21

8.21

8.22

4.09

4.07

3.00

0.95

2.05

1.00

0.99

OMeO

SHNN

OO O

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm

53.4

856

.42

66.4

7

76.7

477

.00

77.2

5

130.

0713

1.10

131.

2413

1.63

132.

8113

7.75

168.

26

OMeO

SHNN

OO O


190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm

56.7

7

66.6

1

76.7

577

.00

77.2

5

128.

1212

8.84

133.

16

138.

60

SNHN

OO O

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm

2.61

2.62

2.64

3.60

3.61

3.62

5.43

7.27

7.52

7.52

7.54

7.56

7.60

7.60

7.61

7.62

7.62

7.63

7.64

7.64

7.64

7.97

7.98

7.98

8.00

4.00

3.94

0.87

1.82

0.91

1.73

SNHN

OO O


9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm

2.64

2.65

2.66

3.61

3.63

3.64

5.58

7.27

7.50

7.52

7.91

7.93

4.00

3.97

0.91

1.73

1.75

Cl

SNHN

OO O

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm

56.7

4

66.5

9

76.6

877

.00

77.3

2

129.

1612

9.57

137.

0713

9.75

Cl

SNHN

OO O


9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm

2.64

2.65

2.66

3.61

3.63

3.64

5.60

7.27

7.66

7.69

7.83

7.85

4.00

4.02

0.91

1.75

1.77

Br

SNHN

OO O

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm

56.7

5

66.5

9

76.6

977

.01

77.3

3

128.

2912

9.65

132.

16

137.

63

Br

SNHN

OO O


9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm

2.40

2.44

5.26

7.27

7.31

7.33

7.83

7.84

7.85

7.86

6.34

2.99

0.86

2.10

2.00

Me

SNHNMe

MeO O

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm

21.5

8

48.5

1

76.6

977

.01

77.2

177

.32

128.

1712

9.48

135.

75

143.

80

Me

SNHNMe

MeO O


9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm

2.32

2.43

3.71

5.51

7.14

7.14

7.15

7.16

7.25

7.26

7.27

7.27

7.29

7.82

7.84

3.08

3.00

2.00

0.90

1.98

4.96

1.87

Me

SNHNMe

O O

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm

21.5

9

44.8

0

64.4

7

76.7

177

.03

77.3

5

127.

6712

8.26

128.

3212

9.44

129.

6313

5.17

135.

66

143.

74

Me

SNHNMe

O O


190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm

21.5

7

59.7

4

76.6

977

.01

77.3

2

127.

6312

8.19

128.

4012

9.35

129.

7713

4.93

135.

42

143.

56

Me

SNHN

O O

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm

2.41

3.73

5.53

7.16

7.17

7.17

7.18

7.19

7.19

7.26

7.27

7.27

7.27

7.28

7.71

7.73

3.00

4.09

0.94

5.65

6.23

1.89

Me

SNHN

O O


190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm

32.6

233

.66

57.2

2

66.5

7

76.6

977

.01

77.3

3

126.

4012

7.24

128.

2612

8.61

139.

93

146.

67

SNHN

OO O

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm

2.61

2.62

2.64

2.66

2.71

2.72

2.73

2.82

2.84

2.86

3.66

3.67

3.68

5.13

6.24

6.25

6.28

6.28

6.89

6.90

6.92

6.94

6.96

7.18

7.20

7.21

7.23

7.27

7.27

7.28

7.30

7.32

2.13

4.00

2.12

4.10

0.90

0.93

0.92

2.86

1.93

SNHN

OO O


190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm

57.4

2

66.6

0

76.6

877

.00

77.3

2

123.

5012

8.33

129.

1613

1.10

132.

53

143.

75

SNHN

OO O

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm

2.87

2.88

2.89

3.72

3.73

3.74

5.31

6.80

6.84

7.27

7.42

7.43

7.45

7.51

7.52

7.53

7.60

7.64

4.00

4.10

0.90

0.95

2.87

1.99

0.95

SNHN

OO O


1.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5 ppm

2.77

2.78

2.79

2.86

2.87

2.88

3.67

3.68

3.70

3.71

3.72

3.73

5.48

5.51

6.46

6.49

6.80

6.84

7.07

7.10

7.26

7.27

7.34

7.35

7.36

7.38

7.39

7.40

7.41

7.42

7.43

7.44

7.44

7.45

7.45

7.46

7.47

7.47

7.48

7.49

7.51

7.51

7.52

7.52

7.53

7.59

7.63

7.73

7.74

7.74

7.75

7.75

7.76

4.00

1.28

4.30

1.39

0.90

0.29

0.98

0.31

1.12

0.48

4.12

0.80

0.36

1.88

SNHN

O

OO

SNHN

OO O

Major

Minor6.97.07.1 ppm

6.80

6.84

7.07

7.10

0.31

1.12

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm

57.1

057

.41

66.5

266

.60

76.6

977

.01

77.3

3

123.

4912

6.92

128.

2812

8.33

129.

1613

0.10

130.

4013

1.10

132.

5314

1.31

143.

74

SNHN

O

OO

SNHN

OO O

Major

Minor


9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm

2.59

2.89

2.90

3.73

3.75

3.76

5.43

6.54

7.27

7.41

7.42

7.43

7.44

7.45

3.00

4.11

4.33

1.01

0.92

5.17

SMe

NHN

OO O

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm

17.8

7

57.2

6

66.7

2

76.6

977

.01

77.3

3

124.

1112

6.26

128.

8412

9.82

140.

34

154.

00

MeSNHN

OO O


9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm

0.95

0.96

0.96

0.96

0.97

0.98

0.98

0.99

1.50

1.52

1.54

1.55

1.57

1.59

1.61

1.63

1.65

2.18

2.20

2.22

2.24

2.32

2.34

2.36

2.80

2.81

2.82

3.69

3.70

3.71

5.09

6.76

6.78

6.80

7.27

7.27

6.11

4.39

2.06

2.06

4.00

4.07

0.97

0.92

SNHN

O

OO

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm

13.7

714

.14

21.8

122

.83

28.9

530

.48

57.3

4

66.6

7

76.6

977

.00

77.3

2

137.

69

144.

18

SNHN

O

OO


190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm

20.9

422

.07

23.6

725

.55

57.3

3

66.6

4

76.6

977

.01

77.3

3

136.

4914

0.18

SNHN

OO O

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm

1.59

1.61

1.63

1.64

1.65

1.65

1.66

1.67

1.70

1.71

1.72

1.72

1.73

1.75

1.76

2.27

2.28

2.29

2.29

2.30

2.31

2.32

2.36

2.37

2.38

2.81

2.83

2.84

3.72

3.73

3.74

5.13

6.96

6.97

6.97

7.27

2.13

2.09

2.11

2.07

4.00

4.11

0.92

0.91

SNHN

OO O


9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm

1.57

1.58

1.59

1.60

1.61

1.62

1.62

1.63

1.64

1.66

1.77

1.79

1.80

1.82

1.83

2.35

2.36

2.38

2.39

2.55

2.56

2.57

2.82

2.83

2.85

3.72

3.73

3.74

5.09

7.14

7.16

7.18

7.27

4.37

2.09

2.09

2.04

4.00

4.14

0.94

0.93

S NH

NOO

O

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm

25.5

326

.45

28.0

528

.61

31.3

5

57.5

6

66.6

3

76.6

977

.00

77.3

2

141.

3114

4.83

S NH

N

O

O O


9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm

1.93

2.07

2.25

2.25

2.25

2.80

2.81

2.82

3.70

3.70

3.71

3.72

5.21

7.27

3.18

3.15

3.13

4.22

4.47

1.00

Me

MeS

MeNHN

O O O

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm

16.5

6

22.7

924

.28

57.0

1

66.8

3

76.6

977

.01

77.3

2

128.

78

147.

41

Me

MeS

MeNHN

OO O


1.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5 ppm

2.59

2.60

2.61

3.54

3.55

3.56

5.68

7.27

7.46

7.48

7.49

7.50

7.51

7.51

7.53

7.55

7.90

7.92

8.33

8.35

8.37

3.97

3.97

1.01

2.14

1.00

1.96

NO

NH

SO O

S

220 200 180 160 140 120 100 80 60 40 20 0 ppm

56.9

2

66.5

1

76.7

177

.03

77.3

4

122.

8512

3.77

125.

6912

5.77

132.

2513

3.82

136.

2114

0.11

N

O

NH

SO O

S


9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm

1.63

2.73

2.75

2.76

3.67

3.68

3.70

5.47

6.55

6.55

6.56

6.56

7.27

7.28

7.28

7.28

7.29

7.81

7.82

7.82

9.00

4.06

4.12

1.02

1.03

1.03

1.00

NO

NH

SO O

NBoc

220 200 180 160 140 120 100 80 60 40 20 0 ppm

27.8

5

56.9

6

66.6

4

76.6

977

.01

77.3

3

85.9

5

110.

53

121.

4612

4.21

125.

31

147.

52

N

O

NH

SO O

NBoc


9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm

1.70

2.68

2.69

2.70

3.58

3.60

3.61

5.71

7.27

7.36

7.36

7.38

7.38

7.40

7.40

7.41

7.42

7.43

7.44

7.45

7.46

7.98

7.98

8.00

8.21

8.23

8.24

9.08

3.99

3.96

1.01

1.01

1.01

1.00

1.88

N

S

Boc

NH

N

O

O

O

220 200 180 160 140 120 100 80 60 40 20 0 ppm

28.0

7

57.0

4

66.5

2

76.7

077

.02

77.3

3

85.8

4

115.

5011

8.67

120.

6512

4.20

125.

1312

5.95

131.

3213

5.48

148.

52

220 200 180 160 140 120 100 80 60 40 20 0 ppm

28.0

7

57.0

4

66.5

2

76.7

077

.02

77.3

3

85.8

4

115.

5011

8.67

120.

6512

4.20

125.

1312

5.95

131.

3213

5.48

148.

52

N

S

Boc

ONH

NO

O


9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm

1.68

6.49

6.50

7.56

7.56

7.57

7.57

7.59

7.60

7.90

7.90

7.92

7.94

8.65

1.01

2.05

2.00

BocN

I

220 200 180 160 140 120 100 80 60 40 20 0 ppm

28.1

7

76.7

377

.05

77.3

784

.11

86.6

7

106.

22

117.

02

126.

6512

9.73

132.

6413

2.85

134.

47

149.

39

BocN

I


9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm

1.69

2.59

2.60

2.62

3.57

3.58

3.59

5.56

6.68

6.69

7.27

7.71

7.72

7.89

7.89

7.91

7.92

8.23

8.23

8.29

8.31

9.08

4.02

4.06

1.03

1.04

0.98

1.03

1.00

0.94

NNH

SO O O

NBoc

220 200 180 160 140 120 100 80 60 40 20 0 ppm

28.1

2

56.7

2

66.6

3

76.7

077

.02

77.3

384

.84

107.

51

115.

38

122.

0212

3.63

128.

0513

0.16

132.

5913

7.48

149.

13

NNH

SO O O

NBoc


9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm

2.58

2.59

2.61

3.57

3.59

3.60

5.25

6.71

6.71

6.71

6.72

7.27

7.36

7.37

7.37

7.49

7.51

7.78

7.78

7.80

8.33

8.48

4.00

3.99

1.03

1.02

1.03

1.01

0.99

0.95

0.97

NH

SHN

NO O O

220 200 180 160 140 120 100 80 60 40 20 0 ppm

56.7

0

66.6

3

103.

96

111.

45

121.

2112

2.44

126.

6712

7.26

129.

31

137.

95

NH

SHN

NO O

O


9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm

2.63

2.65

2.66

3.59

3.60

3.61

5.50

7.27

7.43

7.43

7.45

7.46

7.47

7.55

7.55

7.57

7.57

7.59

7.59

7.64

7.66

7.68

7.71

8.02

8.04

8.09

8.09

8.11

8.11

8.62

8.63

4.06

4.06

1.01

1.06

1.06

1.00

1.00

1.02

1.01

0.96

O

SNH

NO O O

220 200 180 160 140 120 100 80 60 40 20 0 ppm

56.8

0

66.6

3

76.6

977

.01

77.3

3

112.

0811

2.10

121.

1712

1.74

123.

0712

3.75

124.

7912

7.22

128.

6013

3.07

157.

0015

8.40

O

SNH

NO O O


220 200 180 160 140 120 100 80 60 40 20 0 ppm

56.6

7

66.4

9

76.7

476

.99

77.2

4

121.

7912

2.65

124.

3312

4.96

126.

0012

7.86

128.

7013

2.34

134.

0313

7.60

137.

6414

0.05

S

SNH

NO

O

O

1.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5 ppm

2.53

2.54

2.56

3.49

3.51

3.52

5.70

7.27

7.52

7.52

7.54

7.54

7.55

7.55

7.56

7.57

7.57

7.58

7.59

7.62

7.64

7.66

7.92

7.93

7.94

7.94

8.16

8.16

8.18

8.18

8.20

8.21

8.22

8.22

8.22

8.39

8.39

8.41

8.41

4.00

4.02

1.00

2.07

1.05

0.95

2.02

1.00

S

SNH

NO

O

O


9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm

1.80

1.94

2.18

2.43

7.27

7.31

7.33

7.84

7.85

7.85

7.86

7.87

3.00

2.96

3.12

2.02

1.84

Me

SNHN

O OMe

Me

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm

16.8

4

21.5

925

.30

76.6

977

.01

77.3

3

128.

0512

9.52

135.

44

143.

95

156.

19

Me

SNHN

O OMe

Me


9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm3.

753.

80

5.59

7.03

7.03

7.05

7.05

7.18

7.19

7.20

7.26

7.26

7.27

7.28

7.30

7.32

7.34

7.47

7.49

4.00

3.01

0.85

0.95

4.07

7.95

0.99

OMe

SNH

O ON

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm

55.4

4

59.9

1

112.

36

119.

7212

0.55

127.

7112

8.36

129.

6212

9.68

134.

94

139.

48

159.

53

SNHN

OMe

O O


9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm

2.50

3.32

3.33

3.82

7.15

7.15

7.17

7.17

7.35

7.35

7.36

7.38

7.39

7.40

7.41

7.46

7.48

7.50

3.00

0.98

4.01

1.04

OMe

SNH2

O O

220 200 180 160 140 120 100 80 60 40 20 0 ppm

39.0

139

.17

39.3

439

.51

39.6

739

.76

39.8

440

.01

55.5

4

110.

77

117.

62

130.

14

145.

38

159.

24

OMe

SNH2

O O


190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm

48.3

648

.57

48.7

949

.00

49.2

149

.43

49.6

456

.02

66.5

1

ONNH2 SO2

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm

2.99

3.30

3.31

3.31

3.31

3.32

3.80

4.89

3.80

3.98

ONNH2 SO2


DABCO-(SO2)2 DSC

4-Aminomorpholine sulfur dioxide complex DSC


Palladium-Catalysed Aminosulfonylation of Aryl-, Alkenyl ... · ! 2! Experimental General...

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Transcript of Palladium-Catalysed Aminosulfonylation of Aryl-, Alkenyl ... · ! 2! Experimental General...