The Journal of Organic Chemistry
Note
and using toluene (3 mL) as solvent. 1H NMR (300 MHz, CDCl3): δ
7.74 (d, J = 8.0 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 3,71−3.64 (m, 1H),
3.10 (dd, J = 18.2, 5.3 Hz, 1H), 2.56 (dd, J = 18.2, 6.4 Hz, 1H), 2.43
(s, 3H), 2.16 (s, 3H), 1.85−1.72 (m, 1H), 1.55−1.38 (m, 1H), 1.31−
1.12 (m, 4H), 0.80 (t, J = 6.9 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ
204.1, 144.8, 134.7, 129.8, 128.8, 59.5, 41.3, 30.2, 28.6, 28.5, 22.4, 21.6,
13.7. IR (neat): 1720, 1297, 1142 cm−1. MS (70 eV) m/z: 183 (1),
150 (9), 139 (12), 127 (62), 119 (8), 109 (26), 91 (29), 83 (7), 65
(13), 55 (14), 43 (100). HRMS: calcd for [C15H23O3S]+:283.1368 [M
+ H]+, found 283.1379.
did not observe in any case the formation of any sulfa-Michael
addition product. This is an indication of the participation of
the hydrazone itself in the sulfur-transfer step of the catalytic
cycle rather than as a simple source of sulfinate anion. Further
efforts are ongoing in our laboratories in order to unveil the
exact role played by these hydrazone reagents as nucleophilic
sulfonyl transfer reagents. Finally, it should also be pointed out
that several attempts have also been carried out in order to
render this transformation enantioselective but all experiments
carried out up to date using either chiral tertiary amines
(cinchona alkaloids) as catalysts or under PTC conditions
(cinchonidinium salts) have furnished racemic materials. Along
the same line, attempts to apply the iminium activation
approach to the reaction with α,β-unsaturated aldehydes using
O-TMS diphenylprolinol as catalyst have also resulted into the
formation of racemic products under all conditions tested.
In conclusion, we have demonstrated that N-tosylhydrazones
can be used as sulfur-centered pro-nucleophiles for performing
sulfa-Michael reactions with α,β-unsaturated ketones and
aldehydes, providing a straightforward synthesis of γ-keto-
and γ-hydroxy sulfones. Overall, the operational simplicity of
the method together with the high chemical yields obtained
make this methodology a strategy of choice for the direct
synthesis of sulfonyl compounds.
5-Methyl-4-(p-toluenesulfonyl)-2-hexanone (3d). Following the
general procedure, 1h (55 mg, 0.20 mmol) was isolated by FC
(hexanes/EtOAc gradient from 9:1 to 7:3) in 68% yield as a colorless
oil starting from (Z)-ethyl 2-(2-tosylhydrazono)acetate 1a (81 mg,
0.30 mmol), 5-methyl-3-hexen-2-one 2d (53 μL, 0.30 mmol), and
1
DBU (2 mg, 0.015 mmol) and using toluene (3 mL) as solvent. H
NMR (300 MHz, CDCl3): δ 7.74 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.4
Hz, 2H), 3.76 (ddd, J = 7.0, 4.1, 1.9 Hz, 1H), 3.08 (dd, J = 18.5, 7.0
Hz, 1H), 2.54 (dd, J = 18.5, 4.1 Hz, 1H), 2.44 (s, 3H), 2.34 (m, 1H),
2.15 (s, 3H), 1.03 (d, J = 6.9 Hz, 3H), 0.88 (d, J = 6.9 Hz, 3H).13C
NMR (75 MHz, CDCl3): δ 204.3, 144.7, 135.7, 129.8, 128.5, 64.0,
36.7, 30.1, 26.7, 21.6, 17.5. IR (neat): 1719, 1300, 1145 cm−1. MS (70
eV) m/z: 183 (M+ − C5H10O, 2), 150 (6), 139 (10), 119 (7), 113
(77), 91 (27), 65 (13), 55 (6), 43 (100). HRMS: calcd for
[C14H21O3S]+ 269.1211 [M + H]+, found 269.1215.
4-Phenyl-4-(p-toluenesulfonyl)-2-butanone (3e).12 Following the
general procedure, 1a (55 mg, 0.18 mmol) was isolated by FC
(hexanes/EtOAc gradient from 9:1 to 7:3) in 61% yield as a white
solid starting from (Z)-ethyl 2-(2-tosylhydrazono)acetate 1a (81 mg,
0.30 mmol), 4-phenyl-3-buten-2-one 2e (44 mg, 0.30 mmol), and
EXPERIMENTAL SECTION
■
General Procedure for the Preparation of γ-Ketosulfones
3a−j. To a solution of (Z)-ethyl 2-(2-tosylhydrazono)acetate 1a (0.30
mmol) in toluene (3 mL) at room temperature were added DBU
(0.015 mmol) and the corresponding α,β-unsaturated ketone 2a−j
(0.30 mmol), and the mixture was stirred for 3 days. Afterward, the
solvent was removed under reduced pressure and reaction crude was
purified by flash column chromatography to afford β-tosylated ketones
3a−j.
1
DBU (2 mg, 0.015 mmol) and using toluene (3 mL) as solvent. H
NMR (300 MHz, CDCl3): δ 7.43−7.07 (m, 9H), 4.70 (dd, J = 9.1, 4.3
Hz, 1H), 3.58 (dd, J = 17.8, 4.3 Hz, 1H), 3.25 (dd, J = 17.8, 9.1 Hz,
1H), 2.37 (s, 3H), 2.15 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 203.4,
144.8, 133.9, 132.6, 129.7, 129.4, 129.0, 128.8, 128.5, 66.2, 41.6, 30.5,
21.6. IR (neat): 1719, 1303, 1144 cm−1. MS (70 eV) m/z: 147 (32),
131 (17), 123 (11), 104 (23), 91 (19) 77 (13), 65 (9), 43 (100).
HRMS: calcd for [C10H11O]+ 147.0810 [M − C7H7O2S]+, found
147.0791. Mp (hexanes/EtOAc): 149−150 °C.
4-(p-Toluenesulfonyl)-2-pentanone (3a). Following the general
procedure, 3a (60 mg, 0.25 mmol) was isolated by FC (hexanes/
EtOAc gradient from 9:1 to 7:3) in 83% yield as a white solid starting
from (Z)-ethyl 2-(2-tosylhydrazono)acetate 1a (81 mg, 0.30 mmol), 3-
penten-2-one 2a (45 μL, 0.30 mmol), and DBU (2 mg, 0.015 mmol)
and using toluene (3 mL) as solvent. 1H NMR (300 MHz, CDCl3): δ
7.73 (d, J = 8.1 Hz, 2H), 7.33 (d, J = 8.1 Hz, 2H), 3.71−3.52 (m, 1H),
3.16 (dd, J = 18.0, 3.4 Hz, 1H), 2.55 (dd, J = 18.0, 9.4 Hz, 1H), 2.42
(s, 3H), 2.15 (s, 3H), 1.20 (d, J = 6.8 Hz, 3H). 13C NMR (75 MHz,
CDCl3): δ 204.1, 144.9, 134.0, 129.9, 128.9, 55.5, 42.5, 30.4, 21.6, 14.2.
IR (neat): 1715, 1286, 1140 cm−1. MS (70 eV) m/z: 240 (M+, 1), 198
(8), 156 (10), 139 (9), 119 (21), 91 (36), 85 (25), 65 (20), 43 (100).
HRMS: calcd for [C12H17O3S]+ 241.0898 [M + H]+, found 241.0891.
Mp (hexanes/EtOAc): 79−80 °C.
4-(p-Toluenesulfonyl)-2-heptanone (3b). Following the general
procedure, 1g (64 mg, 0.24 mmol) was isolated by FC (hexanes/
EtOAc gradient from 9:1 to 7:3) in 79% yield as a colorless oil starting
from (Z)-ethyl 2-(2-tosylhydrazono)acetate 1a (81 mg, 0.30 mmol), 3-
hepten-2-one 2b (40 μL, 0.30 mmol), and DBU (2 mg, 0.015 mmol)
and using toluene (3 mL) as solvent. 1H NMR (300 MHz, CDCl3): δ
7.74 (d, J = 8.4 Hz, 2H), 7.34 (d, J = 8.4 Hz, 2H), 3.78−3.65 (m, 1H,
CH), 3.10 (dd, J = 18.2, 5.2 Hz, 1H), 2.55 (dd, J = 18.2, 6.5 Hz, 1H),
2.43 (s, 3H), 2.15 (s, 3H), 1.82−1.69 (m, 1H), 1.52−1.10 (m, 3H),
0.82 (t, J = 7.3 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 204.1, 144.8,
134.7, 129.9, 128.8, 59.4, 41.4, 30.9, 30.2, 21.6, 19.9, 13.8. IR (neat):
1718, 1287, 1143 cm−1. MS (70 eV) m/z: 183 (1), 150 (8), 139 (11),
119 (10), 113 (71), 91 (30), 65 (14), 55 (13), 43 (100). HRMS: calcd
for [C14H21O3S]+ 269.1211 [M + H]+, found 269.1208.
4-(4-Chlorophenyl)-4-(p-toluenesulfonyl)-2-butanone (3f). Fol-
lowing the general procedure, 1b (53 mg, 0.16 mmol) was isolated
by FC (hexanes/EtOAc gradient from 9:1 to 7:3) in 53% yield as a
white solid starting from (Z)-ethyl 2-(2-tosylhydrazono)acetate 1a (81
mg, 0.30 mmol), 4-(4-chlorophenyl)-3-buten-2-one 2f (56 mg, 0.30
mmol), and DBU (2 mg, 0.015 mmol) and using toluene (3 mL) as
1
solvent. H NMR (300 MHz, CDCl3): δ 7.40 (d, J = 8.3 Hz, 2H),
7.23−7.16 (m, 4H), 7.06 (d, J = 8.5 Hz, 2H), 4.66 (dd, J = 9.3, 4.1 Hz,
1H), 3.57 (dd, J = 17.9, 4.1 Hz, 1H), 3.21 (dd, J = 17.9, 9.3 Hz, 1H),
2.39 (s, 3H), 2.15 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 203.0,
145.0, 140.9, 134.8, 131.2, 130.4, 129.6, 129.0, 128.7, 65.4, 41.6, 30.4,
21.7. IR (neat): 1713, 1310, 1142 cm−1. MS (70 eV) m/z: 181 (26),
165 (27), 150 (6), 138 (16), 119 (6), 102 (12), 91 (18) 75 (7), 65
(8), 43 (100). HRMS: calcd for [C10H10OCl]+ 181.0420 [M −
C7H7O2S]+, found 181.0403. Mp (hexanes/EtOAc): 141−142 °C.
4-(4-Methylphenyl)-4-(p-toluenesulfonyl)-2-butanone (3g). Fol-
lowing the general procedure, 1c (46 mg, 0.14 mmol) was isolated by
FC (hexanes/EtOAc gradient from 9:1 to 7:3) in 48% yield as a white
solid starting from (Z)-ethyl 2-(2-tosylhydrazono)acetate 1a (162 mg,
0.60 mmol), 4-(4-methylphenyl)-3-buten-2-one 2g (50 mg, 0.30
mmol), and DBU (2 mg, 0.015 mmol) and using toluene (3 mL) as
solvent. 1H NMR (300 MHz, CDCl3): δ 7.40 (d, J = 8.4 Hz, 2H), 7.17
(d, J = 8.4 Hz, 2H), 7.03 (d, J = 8.8 Hz, 2H), 6.99 (d, J = 8.8 Hz, 2H),
4.67 (dd, J = 9.2, 4.4 Hz, 1H), 3.54 (dd, J = 17.7, 4.4 Hz, 1H), 3.23
(dd, J = 17.7, 9.2 Hz, 1H), 2.39 (s, 3H), 2.29 (s, 3H), 2.14 (s, 3H). 13C
NMR (75 MHz, CDCl3): δ 203.4, 144.7, 138.8, 134.0, 129.5, 129.4,
129.2, 129.1, 65.9, 41.7, 30.5, 21.6, 21.2. IR (neat): 1721, 1284, 1141
cm−1. MS (70 eV) m/z: 161 (70), 145 (57), 115 (29), 91 (34) 77 (4),
65 (12), 43 (100). HRMS: calcd for [C11H13O]+ 161.0966 [M −
C7H7O2S]+, found 161.0946. Mp (hexanes/EtOAc): 93−94 °C.
4-(p-Toluenesulfonyl)-2-octanone (3c). Following the general
procedure, 1f (70 mg, 0.25 mmol) was isolated by FC (hexanes/
EtOAc gradient from 9:1 to 7:3) in 82% yield as a colorless oil starting
from (Z)-ethyl 2-(2-tosylhydrazono)acetate 1a (81 mg, 0.30 mmol), 3-
octen-2-one 2c (45 μL, 0.30 mmol), and DBU (2 mg, 0.015 mmol)
C
dx.doi.org/10.1021/jo402518q | J. Org. Chem. XXXX, XXX, XXX−XXX