Transition-Metal-Free Intermolecular α-CH Amination of Ethers at Room Temperature Supporting

72 Pages·2014·4.83 MB·English

by  Group Hu

Transition-Metal-Free Intermolecular α-C-H Amination of Ethers at Room
Temperature

Ivan Buslov and Xile Hu*

Laboratory of Inorganic Synthesis and Catalysis
Institute of Chemical Sciences and Engineering
Ecole Polytechnique Fédérale de Lausanne (EPFL)
ISIC-LSCI, BCH 3305, Lausanne 1015 (Switzerland)
E-mail: [email protected]

Supporting information

Content Page
1. Chemicals and Reagents
2. Physical methods S2
3. General procedures for the entries reported in Table 1
4. The procedures for the preparation of starting materials S3
5. General procedures for the intermolecular α-C-H amination of ethers S4
6.Mechanistic studies S5
7. Detailed descriptions of the products S7
8. References S21
9. NMR spectra S22

S1
Experimental Section

1. Chemicals and Reagents

All manipulations were carried out under an inert N (g) atmosphere using standard Schlenk
2
or glovebox techniques. Solvents were purified using a two-column solid-state purification
system (Innovative Technology, NJ, USA) and transferred to the glove box without exposure
to air. Deuterated solvents were purchased from Cambridge Isotope Laboratories, Inc., and
were degassed and stored over activated 3 Å molecular sieves. THF-d was purchased from
8
ARMAR AG, and was degassed and stored over activated 3 Å molecular sieves. Unless
otherwise noted, all other reagents and starting materials were purchased from commercial
sources and used without further purification. Liquid compounds were degassed by standard
freeze-pump-thaw procedures prior to use. Tetrahydropyran and 2-methyltetrahydrofuran
were distilled from stabilizers before use. Dry 1,2-dimethoxyethane was purchased from
Aldrich and used without purification. Diphenyl iodonium hexafluorophosphate and triflate
were purchased from ABCR and Aldrich correspondently. 2,2-Dimethylpent-4-en-1-amine
was synthesized according to literature procedure.1 Other amines were purchased from
commercial sources. Sulfonamides2, amides and trifluoroacetyl amides3 were prepared from
corresponding amines by standard methods. 3-(4-methoxybenzyl)-5-methylpyrimidine-
2,4(1H,3H)-dione4 and di-tert-butyl 5-fluoro-2,4-dioxopyrimidine-1,3(2H,4H)-dicarboxylate5
were prepared according to known procedures.

2. Physical methods

The 1H and 13C NMR spectra were recorded at 293 K or 373 K on Bruker Avance 400
spectrometers. 1H NMR chemical shifts were referenced to residual solvent as determined
relative to Me Si (δ = 0 ppm). The 13C{1H} chemical shifts were reported in ppm relative to
4
the carbon resonance of CDCl (77.16 ppm), DMSO-d (39.52 ppm), CD Cl (53.84 ppm) or
3 6 2 2
CD CN (118.26 ppm). GC measurement was conducted on a Perkin-Elmer Clarus 400 GC
3
with a FID detector. HRESI-MS measurements were conducted at the EPFL ISIC Mass
Spectrometry Service with a Micro Mass QTOF Elemental analyses were performed on a
Carlo Erba EA 1110 CHN instrument at EPFL.

3. General procedures for the entries reported in Table 1
Entries 1-10, 18-20
Sodium hydride (60% dispersion in mineral oil, 10 mg, 0.25 mmol, entries 1-7) or
corresponding base (0.25 mmol, entries 8-10) was added to a stirred solution of N-
benzylmethanesulfonamide (46 mg, 0.25 mmol) in 1 mL of dry tetrahydrofuran at room
temperature under nitrogen. After stirring for 1 hour an oxidant (0.3 mmol) was added slowly
and the reaction mixture was left stirred for 10 hours. In entry 5 no oxidant was added;
instead a balloon with O was connected to reaction vessel. After the indicated time, the
2
reaction mixture was analyzed by GCMS using 30 μL of dodecane as an internal standard.
Entries 11-17
Sodium hydride (60% dispersion in mineral oil, 10 mg, 0.25 mmol) was added to a stirred
solution of N-benzylmethanesulfonamide (46 mg, 0.25 mmol) and dry tetrahydrofuran (0.18
g, 2.5 mmol) in 1 mL of the corresponding solvent at room temperature under nitrogen. After
stirring for 1 hour Ph IPF (128 mg, 0.3 mmol) was added and the reaction mixture was left
2 6
stirred for 10 hours.
S2
4. The procedures for the preparation of starting materials
General procedure for the preparation of sulfonamides (1a-1m)
To a stirred solution of primary amine (20 mmol) and pyridine (2.37 g, 30 mmol) in CH Cl
2 2
(50 mL) at 0° C a corresponding sulfonyl chloride (20 mmol) was slowly added. The reaction
mixture was slowly warmed to room temperature and stirred for 12 hours, then the reaction
was quenched with water (30 mL), extracted with CH Cl (2x50 mL) and washed with water.
2 2
The organic phase was dried over anhydrous Na SO The solvent was evaporated to afford
2 4.
the product. If needed, crude product was purified by silica gel flash chromatography using
mixture of ethylacetate/hexane as an eluent.

General procedure for the preparation of N-acetamides (2a-2d, 2i-2o)
20 mmol of the corresponding amine was dissolved in 50 mL of CH Cl followed by the
2 2
addition of triethylamine (3.03 g, 30 mmol) and dropwise addition of acetyl chloride (1.72 g,
22 mmol) at 0° C. After stirring for 10 hours at room temperature 30 mL of water was added
to the reaction solution. The organic phase was separated and aqueous layer was extracted
two times with 50 mL of chloroform, and the resulting organic layer was concentrated after
drying with anhydrous Na SO to obtain the product. If needed, crude product was purified
2 4
by silica gel flash chromatography using mixture of ethylacetate/hexane as an eluent.

General procedure for the preparation of N-trifluoroacetamides (2e-2h)
20 mmol of the corresponding amine and pyridine (2.37 g, 30 mmol) were dissolved in 50
mL of dry CH Cl . Trifluoracetic anhydride (22 mmol 4.62 g) in 20 mL of CH Cl was added
2 2 2 2
slowly at 0ºC. The reaction was stirred overnight at room temperature, quenched with water,
extracted twice with CH Cl and washed with water. The organic layers were dried with
2 2
Na SO , and the solvent was evaporated. The residue was purified by silica gel flash
2 4
chromatography using mixture of hexane/ethyl acetate as an eluent.

Tert-butyl 5-fluoro-2,6-dioxo-3,6-dihydropyrimidine-1(2H)-carboxylate (9b)

5-Fluorouracil (3.9 g, 30.0 mmol), di-tert-butyl dicarbonate (26.2 g, 120 mmol), pyridine (5
mL), DMAP (100 mg, 0.8 mmol) and MeCN (50 mL) were stirred together for 12 h at room
temperature. The reaction mixture was concentrated in vacuo, and the residue was partitioned
between CH Cl (100 mL) and water (100 mL). The organic layer was separated, and the
2 2
aqueous phase was extracted twice with CH Cl (2×50 mL). The combined organic layers
2 2
were dried over MgSO and filtered, and the solvent was removed by evaporation in vacuo.
4
The residue was purified by recrystallization from Hexane-EtOAc (10:1) to afford 6.70 g
(68%) of di-tert-butyl 5-fluoro-2,4-dioxopyrimidine-1,3(2H,4H)-dicarboxylate (9b’).
S3
Purified 9b’ (330 mg, 1 mmol) was dissolved under argon in 2 mL of dry THF. A 1 M
solution of Bu NF (1.5 mL, 1.5 mmol) in THF was then added and the reaction mixture was
4
refluxed for 8 h. After cooling to room temperature, water (20 mL) was added. After
extraction with AcOEt (2×20 mL), the organic layers were washed with brine (10 mL), dried
with Na SO , filtered and the solvent was removed under reduced pressure. The crude
2 4
product was purified by gradient silica gel chromatography (hexane/AcOEt 10:1 to 1:1) to
afford N3-Boc-5-fluorouracil as white powder 87 mg (38%).

5. General procedures for the intermolecular α-C-H amination of ethers
General procedure for the synthesis of N-(tetrahydrofuran-2-yl)sulfonamides (3a-3n)
To a suspension of sodium hydride (60% dispersion in mineral oil, 20 mg, 0.5 mmol) in 1 mL
of dry THF a sulfonamide (0.5 mmol) in 1 mL of THF was added at room temperature under
nitrogen. After stirring for 1 hour at room temperature Ph IPF (256 mg, 0.6 mmol) was
2 6
added and the reaction mixture was left stirred for 6 hours. The solvent was removed under
reduced pressure and resulting solid was subjected to column chromatography (silica gel) to
afford the product. For the new compounds, their 1H and 13C data were reported together with
high resolution mass spectrometric data or elemental analysis.

General procedure for the synthesis of N-(tetrahydrofuran-2-yl)amides (5a-5o)
To a suspension of sodium hydride (60% dispersion in mineral oil, 20 mg, 0.5 mmol) in 1 mL
of dry THF an amide (0.5 mmol) in 1 mL of THF was added at room temperature under
nitrogen. After stirring for 3 hours at room temperature Ph IPF (319 mg, 0.75 mmol) in 1
2 6
mL of THF was added and the reaction mixture was left stirred for 6 hours. The solvent was
removed under reduced pressure and resulting solid was subjected to the column
chromatography (silica gel) to afford the product. For the new compounds, their 1H and 13C
data were reported together with high resolution mass spectrometric data or elemental
analysis.

General procedure for the synthesis of phthalimide derivatives (5p, 8b, 8d)
To a suspension of potassium phthalimide (92.5 mg, 0.5 mmol) in 2 mL of corresponding
alkyl ether Ph IPF (256 mg, 0.6 mmol) was added and reaction mixture stirred at 40˚C or
2 6
60˚C overnight under nitrogen. The solvent was removed under reduced pressure and
resulting solid was subjected to the column chromatography (silica gel) to afford the product.

General procedure for the α-C-H bond amination with N-heterocyclic amines (7a-7d)
To a suspension of sodium hydride (60% dispersion in mineral oil, 20 mg, 0.5 mmol) in 1 mL
of dry THF an amine (0.5 mmol) in 1 mL of THF was added at room temperature under
nitrogen. After stirring for 1 hour at room temperature Ph IPF (319 mg, 0.75 mmol) was
2 6
added and the reaction mixture was left stirred for 6 hours. The solvent was removed under
reduced pressure and resulting solid was subjected to column chromatography (silica gel) to
afford the product. For the new compounds, their 1H and 13C data were reported together with
high resolution mass spectrometric data or elemental analysis.

General procedure for the α-C-H bond amination of various alkyl ethers (8a-8h)
S4
To a suspension of sodium hydride (60% dispersion in mineral oil, 20 mg, 0.5 mmol) in 3 mL
of dry alkyl ether an amide or sulfonamide (0.5 mmol) was added at room temperature under
nitrogen. After stirring for 3 hours at room temperature Ph IPF (319 mg, 0.75 mmol) was
2 6
added and the reaction mixture was left stirred for 6 hours. The solvent was removed under
reduced pressure and resulting solid was subjected to the column chromatography (silica gel)
to afford the product. For the new compounds, their 1H and 13C data were reported together
with high resolution mass spectrometric data or elemental analysis.

General procedure for the synthesis of nucleoside analogues (10a-10d)
To a suspension of sodium hydride (60% dispersion in mineral oil, 20 mg, 0.5 mmol) in 1 mL
of dry alkyl ether and N3-protected nucleobase (0.5 mmol) was added at room temperature
under nitrogen. After stirring for 3 hours at room temperature Ph IPF (362 mg, 0.85 mmol)
2 6
in 2 mL of ether was added and the reaction mixture was left stirred for 6 hours. The solvent
was removed under reduced pressure and resulting solid was subjected to the column
chromatography (silica gel) to afford the product. For the new compounds, their 1H and 13C
data were reported together with high resolution mass spectrometric data or elemental
analysis.

6. Mechanistic studies
Reaction in the presence of TEMPO
Sodium hydride (60% dispersion in mineral oil, 20 mg, 0.5 mmol) was added to a stirred
solution of N-benzylmethanesulfonamide (93 mg, 0.5 mmol) in 1 mL of dry tetrahydrofuran
at room temperature under nitrogen. After stirring for 1 hour TEMPO (7.8 mg, 0.05mmol)
and Ph IPF (256 mg, 0.6 mmol) was added, and the reaction mixture was left stirred for 6
2 6
hours. After the indicated time the reaction mixture was analyzed by GCMS using 30 μL of
dodecane as an internal standard. 3a was not detected.

Comparison of rate constants of the reactions of acetanilide (4d) with THF and THF-d
8
Four stock solutions were prepared: 405 mg of acetanilide and 102 mg of dodecane in 6.0
mL of THF (Solution A); 1.50 g of Ph IPF in 5.0 mL of THF (Solution B); 405 mg of
2 6
acetanilide and 102 mg of dodecane in 6.0 mL of THF-d (Solution C); 1.50 g of Ph IPF in
8 2 6
5.0 mL of THF-d (Solution D). To 1.0 mL of Solution A 20 mg of sodium hydride (60%
8
dispersion in mineral oil) was added and the mixture was stirred for 30 minutes. Then 1.0 mL
of Solution B was added at once at room temperature (23,5 ˚C). The aliquotes of the reaction
mixture were quenched with ethanol and analyzed by GC (calibration was performed using
dodecane as an internal standard). The procedure was repeated with Solutions C and D. The
ratio between both reaction rate constants was determined to be 4.60.
S5
7
y = 0,40053x + 0,08652
6
R2 = 0,9963
5
2
^
0
1 4
*
]lo
m
m 3
[ ,d
le
iy 2
1
0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
time, [min]

Figure S1. The rate of the reaction of acetanilide (4d) in THF
7
y = 0.08711x + 1,6717
R2 = 0,9308
6
5
2
^
0
1
*
]lo 4
m
m
[ ,d
le 3
iy
2
1
0 10 20 30 40 50 60 70
time, [min]

Figure S2. The rate of the reaction of acetanilide (4d) in THF-d
8

S6
7. Detailed descriptions of the products

N-benzyl-N-(tetrahydrofuran-2-yl)methanesulfonamide (3a)
Isolated by gradient elution from the column with hexane-EtOAc (9:1 to 4:1) in 73% yield as
a colorless oil.
1H NMR (400 MHz, CDCl ): 7.42 (d, J = 7.5 Hz, 2H), 7.37-7.34 (m, 2H), 7.30-7.26 (m, 1H),
3
5.72 -5.69 (m, 1H), 4.57 (d, J = 16.7 Hz, 1H), 4.27 (d, J = 16.7 Hz, 1H), 4.07-4.01 (m, 1H),
3.84-3.79 (m, 1H), 2.97 (s, 3H), 2.08-1.81 (m, 3H), 1.75-1.69 (m, 1H).
13C NMR (101 MHz, CDCl ): 138.3, 128.7, 127.5, 127.1, 88.8, 68.4, 46.6, 39.6, 29.6, 24.8.
3
HRESI-MS: calculated for (C H NO S, M+H), 256.1007; found, 256.1000.
12 17 3

N-cyclohexyl-N-(tetrahydrofuran-2-yl)methanesulfonamide (3b)
Isolated by gradient elution from the column with hexane-EtOAc (20:1 to 9:1) 76% yield as a
colorless oil.
1H NMR (400 MHz, CDCl ): 5.34 (m, 1H), 4.05-3.99 (m, 1H), 3.77-3.73 (m, 1H), 3.38-3.31
3
(m, 1H), 2.98 (s, 3H), 2.19-2.02 (m, 3H), 1.92-1.60 (m, 8H), 1.34-1.08 (m, 3H).
13C NMR (101 MHz, CDCl ): 88.7, 68.1, 57.5, 43.4, 34.2, 31.4, 31.0, 26.6, 25.3.
3
HRESI-MS: calculated for (C H NO S, M+Na), 270.1140; found, 270.1143.
11 21 3

N-(tert-butyl)-N-(tetrahydrofuran-2-yl)methanesulfonamide (3c)
Isolated by gradient elution from the column with hexane-EtOAc (19:1 to 9:1) in 39% yield
as a white solid.
1H NMR (400 MHz, CD Cl ): 5.33-5.29 (m, 1H), 4.08-4.03 (m, 1H), 3.74-3.69 (m, 1H), 2.99
2 2
(s, 3H), 2.51-2.44 (m, 1H), 2.12-1.99 (m, 2H), 1.88-1.79 (m, 1H), 1.43 (s, 9H).
13C NMR (101 MHz, CD Cl ): 90.6, 68.5, 59.7, 45.7, 32.9, 30.8, 25.8.
2 2
HRESI-MS: calculated for (C H NO S, M+Na), 244.0983; found, 244.0984.
9 19 3
Elemental analysis: Anal. Calcd for C H NO S: C, 48.84; H, 8.65; N 6.33. Found: C,
9 19 3
48.88; H, 8.35; N 6.15.

N-(2,2-dimethylpent-4-en-1-yl)-N-(tetrahydrofuran-2-yl)methanesulfonamide (3d)
Isolated by gradient elution from the column with hexane-EtOAc (6:1 to 4:1) in 78 % yield as
colorless oil.
S7
1H NMR (400 MHz, CDCl ): 5.88-5.78 (m, 1H), 5.32-5.03 (m, 3H), 4.11-4.06 (m, 1H), 3.81-
3
3.76 (m, 1H), 3.24 (d, J = 14.7 Hz, 1H), 2.98 (s, 3H), 2.91 (d, J = 14.7 Hz, 1H), 2.54-2.45 (m,
1H), 2.22-2.10 (m, 2H), 2.03 (m, 2H), 1.89-1.82 (m, 1H), 0.95 (s, 3H), 0.94 (s, 3H).
13C NMR (101 MHz, CDCl ): 134.8, 117.8, 94.7, 77.2, 68.6, 59.6, 45.4, 40.8, 35.5, 31.7,
3
25.737, 25.3, 25.1.
HRESI-MS: calculated for (C H NO S, M+H), 262.1477; found 262.1472.
12 23 3

N-allyl-N-(tetrahydrofuran-2-yl)methanesulfonamide (3e)
Eluated from the column with hexane-EtOAc (9:1) in 77% yield as a colorless oil
1H NMR (400 MHz, CDCl ): 5.97-5.87 (m, 1H), 5.63-5.60 (m, 1H), 5.28 (dd, J =17.2, 1.4
3
Hz, 1H), 5.16 (dd, J= 10.2, 1.4 Hz, 1H), 3.99-3.93 (m, 1H), 3.82-3.78 (m, 3H), 2.93 (s, 3H),
2.13-2.05 (m, 1H), 1.98-1.85 (m, 3H).
13C NMR (101 MHz, CDCl ): 135.5, 117.1, 88.7, 68.2, 45.4, 39.7, 29.4, 25.0.
3
HRESI-MS: calculated for (C H NO S, M+Na), 228.0670; found, 228.0668.
8 15 3

N-(1-phenylethyl)-N-(tetrahydrofuran-2-yl)methanesulfonamide
Isolated by gradient elution from the column with hexane-EtOAc (20:1 to 9:1) in 75 % yield
as white solid. Diastereomeric ratio is 2:3 (3f:3g).
N-(1-phenylethyl)-N-(tetrahydrofuran-2-yl)methanesulfonamide (d.r- 2:3) major
product (3f)
1H NMR (400 MHz, CD Cl ): 7.55 (d, J = 7.6 Hz, 2H), 7.38-7.27 (m, 3H), 5.48 (m, 1H),
2 2
4.89 (q, J = 7.24 Hz, 1H), 4.11-4.06 (m, 1H), 3.80-3.75 (m, 1H), 2.45 (s, 3H), 2.12-2.02 (m,
3H), 1.96-1.88 (m, 1H), 1.73 (d, J = 7.2 Hz, 3H).
13C NMR (101 MHz, CD Cl ): 140.1, 129.00, 128.5, 128.00, 89.3, 67.9, 54.6, 42.4, 30.8,
2 2
25.5, 21.1.
HRESI-MS: calculated for (C H NO S, M+Na), 292.0983; found, 292.0981.
13 19 3

N-(1-phenylethyl)-N-(tetrahydrofuran-2-yl)methanesulfonamide (d.r- 2:3) minor
product (3g)
Contains 15% of major isomer.
1H NMR (400 MHz, CD Cl ): 7.41-7.24 (m, 5H), 5.06-5.02 (m, 2H), 4.03-3.98 (m, 1H),
2 2
3.71-3.66 (m, 1H), 3.04 (s, 3H), 2.28-2.22 (m, 1H), 2.02-1.97 (m, 1H), 1.77-1.72 (m, 5H).
13C NMR (101 MHz, CD Cl ): 142.2, 128.7, 127.5, 127.4, 89.3, 68.5, 55.6, 53.8, 43.8, 31.34,
2 2
25.5, 17.9.
Elemental analysis: Anal. Calcd for C H NO S: C, 57.97; H, 7.11; N 5.20. Found: C,
13 19 3
57.64; H, 7.20; N 4.88.

S8
N-phenyl-N-(tetrahydrofuran-2-yl)methanesulfonamide (3h)
Eluated from the column with CH Cl in 59 % yield as a white solid.
2 2
1H NMR (400 MHz, CDCl ): 7.46-7.44 (m, 2H), 7.42-7.27 (m, 3H), 6.03-6.00 (dd, J = 7.1,
3
6.0 Hz, 1H), 3.92-3.87 (m, 1H), 3.78-3.72 (m, 1H), 3.07 (s, 3H), 2.13-2.04 (m, 1H), 1.77-1.59
(m, 2H), 1.46-1.36 (m, 1H).
13C NMR (101 MHz, CDCl ): 136.2, 131.4, 129.3, 129.1, 89.5, 68.4, 39.8, 29.7, 24.8.
3
HRESI-MS: calculated for (C H NO S, M+H), 242.0851; found, 242.0853.
11 15 3

N-hexyl-4-methyl-N-(tetrahydrofuran-2-yl)benzenesulfonamide (3i)
Eluated from the column with hexane-EtOAc (9:1) in 67% yield as a colorless oil.
1H NMR (400 MHz, CDCl ): 7.78 (d, J = 8.3 Hz, 2H), 7.28 (d, J = 8.1, 2H), 5.80-5.76 (m,
3
1H), 3.91-3.85 (m, 1H), 3.76-3.71 (m, 1H), 3.02-2.88 (m, 2H), 2.41 (s, 3H), 2.17-2.11 (m,
1H), 1.95-1.76 (m, 4H), 1.61-1.50 (m, 1H), 1.32-1.19 (m, 6H), 0.88 (t, J = 6,7 Hz, 3H).
13C NMR (101 MHz, CDCl ): 143.2, 137.2, 129.5, 127.8, 88.8, 68.1, 43.4, 31.5, 31.5, 30.3,
3
26.9, 25.0, 22.7, 21.6, 14.1.
HRESI-MS: calculated for (C H NO S, M+Na), 348.1609; found, 348.1610.
17 27 3

N-cyclohexyl-4-methyl-N-(tetrahydrofuran-2-yl)benzenesulfonamide (3j)
Eluated from the column with hexane-EtOAc (9:1) in 43% yield as a colorless oil.
1H NMR (400 MHz, CDCl ): 7.81 (d, J = 8.3 Hz, 2H), 7.25 (d, J = 8.6 Hz, 2H), 5.44-5.30
3
(m, 1H), 4.11-4.06 (m, 1H), 3.80-3.76 (m, 1H), 3.30-3.26 (m, 1H), 2.40 (s, 3H), 2.35-2.29
(m, 1H), 2.15-2.07 (m, 2H), 1.95-1.43 (m, 8H), 1.26-0.99 (m, 3H).
13C NMR (101 MHz, CDCl ): 142.8, 140.0, 129.4, 127.4, 88.8, 68.1, 57.7, 33.8, 31.4, 26.7,
3
25.5, 25.4, 21.6.
HRESI-MS: calculated for (C H NO S, M+H), 324.1633; found, 324.1639.
17 25 3

N-isopropyl-4-methyl-N-(tetrahydrofuran-2-yl)benzenesulfonamide (3k)
Isolated by gradient elution from the column with hexane-EtOAc (9:1 to 4:1) in 63 % yield as
a colorless oil.
1H NMR (400 MHz, CDCl ): 7.72 (d, J = 8.3 Hz, 2H), 7.17 (d, J = 8.1 Hz, 2H), 5.30 (t, J =
3
7.0 Hz, 1H), 4.02-3.96 (m, 1H), 3.72-3.63 (m, 2H), 2.31 (s, 3H), 2.28-2.22 (m, 1H), 2.08-2.01
(m, 2H), 1.85-1.77 (m, 1H), 1.19 (d, J = 6.8 Hz, 3H), 1.00 (d, J = 6.8 Hz, 3H).
S9
13C NMR (101 MHz, CDCl ): 142.8, 139.7, 129.4, 127.5, 88.3, 68.0, 49.1, 31.3, 25.4, 23.4,
3
21.6, 21.0.
HRESI-MS: calculated for (C H NO S, M+H), 284.1320; found 284.1316.
14 21 3

N-allyl-4-methyl-N-(tetrahydrofuran-2-yl)benzenesulfonamide (3l)
Eluated from the column with hexane-EtOAc (3:1) in 73 % yield as a colorless oil.
1H NMR (400 MHz, CDCl ): 7.78 (d, J = 8.2 Hz, 2H), 7.28 (d, J = 8.2 Hz, 2H), 5.93-5.84
3
(m, 2H), 5.23 (dd, J = 17.2, 1.2 Hz, 1H), 5.10 (dd, J = 10.0, 1.2 Hz, 1H), 3.90-3.84 (m, 1H),
3.76-3.67 (m, 3H), 2.42 (s, 3H), 2.16-2.08 (m, 1H), 2.00-1.85 (m, 3H).
13C NMR (101 MHz, CDCl ): 143.3, 137.1, 136.0, 129.5, 127.8, 116.4, 88.8, 68.3, 45.2,
3
30.0, 25.0, 21.6.
HRESI-MS: calculated for (C H NO S, M+H), 282.1164; found, 282.1166.
14 19 3

N-(2,2-dimethylpent-4-en-1-yl)-4-methyl-N-(tetrahydrofuran-2-yl)benzenesulfonamide
(3m)
Isolated by gradient elution from the column with hexane-EtOAc (9:1 to 6:1) in 62% yield as
a colorless oil.
1H NMR (400 MHz, CDCl ): 7.77 (d, J = 8.2 Hz, 2H), 7.28 (d, J = 8.2 Hz, 2H), 5.89-5.78
3
(m, 1H), 5.27-5.24 (m, 1H), 5.08-5.02 (m, 2H), 4.00-3.95 (m, 1H), 3.71-3.67 (m, 1H), 3.27
(d, J = 15.2 Hz, 1H), 2.83 (d, J = 15.2 Hz, 1H), 2.42 (s, 3H), 2.36-2.27 (m, 1H), 2.14-2.06 (m,
1H), 1.90-1.81 (m, 1H), 0.99 (s, 6H).
13C NMR (101 MHz, CDCl ): 143.1, 138.4, 135.1, 129.3, 127.90 117.7, 93.1, 68.0, 57.7,
3
45.9, 35.2, 31.3, 26.2, 25.8, 25.0, 21.6.
HRESI-MS: calculated for (C H NO S, M+Na), 360.1609; found, 360.1611
18 27 3

N-benzyl-4-methyl-N-(tetrahydrofuran-2-yl)benzenesulfonamide (3n)
Isolated by gradient elution from the column with hexane-EtOAc (9:1 to 4:1) in 61% yield as
a white solid.
1H NMR (400 MHz, CDCl ): 7.81 (d, J = 8.2 Hz, 2H), 7.43 (d, J = 7.5 Hz, 2H), 7.35-7.27
3
(m, 5 H), 5.95-5.92 (m , 1H), 4.44 (d, J = 17.0 Hz, 1H), 4.15 (d, J = 17.0 Hz, 1H), 3.91-3.86
(m, 1H), 3.78-3.73 (m, 1H), 2.44 (s, 3H), 2.03-1.97 (m, 1H), 1.95-1.64 (m, 3H).
13C NMR (101 MHz, CDCl ): 143.4, 138.5, 136.9, 129.5, 128.5, 127.8, 127.2, 127.1, 88.9,
3
68.5, 46.0, 30.2, 24.8, 21.6.
HRESI-MS: calculated for (C H NO S, M+H), 332.1320; found, 332.1311
18 21 3

N-(2,2-dimethylpent-4-en-1-yl)-N-(tetrahydrofuran-2-yl)acetamide (5a)
S10