PAPER
Sulforaphane and Related Isothiocyanates
3995
mL), dried (Na2SO4), concentrated in vacuo, and purified by flash
column chromatography (50–100% EtOAc–hexane) to give a yel-
low oil; yield: 137 mg (83%). The NMR spectra of the product were
identical to those of the product obtained by the one-pot procedure
described above.
A soln of the crude 4-[(tert-butoxycarbonyl)amino]butyl methane-
sulfonate (~22 g, ~80 mmol) in anhyd DMF (40 mL) was added
dropwise to a stirred mixture of NaSMe (8.4 g, 120 mmol, 1.5
equiv) in anhyd DMF (80 mL) at 0 °C within 12 min to give a thick
yellow suspension. The mixture was stirred for 10 min, the ice-bath
was removed, and stirring was continued for an additional 1 h to
give a gray–yellow suspension. The mixture was chilled in an ice
bath and H2O (200 mL) was then added. The mixture was extracted
with Et2O (4 × 150 mL) and the combined extracts were washed
with H2O (100 mL) and brine (100 mL) then dried (Na2SO4). The
crude product was purified by flash column chromatography (10–
20% EtOAc–hexane) to give a light-yellow oil: yield: 15.7 g (~90%
yield based on 10).
4-Isothiocyanatobutyl Mesylate (7)
MsCl (0.38 mL, 4.8 mmol, 1.2 equiv) was added dropwise to an ice-
cold stirred soln of alcohol 6 (520 mg, 5 mmol) and Et3N (0.83 mL,
6 mmol, 1.5 equiv) in anhyd CH2Cl2 (20 mL). The mixture was
stirred at 0 °C for 40 min, allowed to warm to r.t., and stirred for an
additional 1 h to give an almost colorless soln. The reaction was
then quenched by adding H2O (30 mL). The CH2Cl2 layer was sep-
arated and the aqueous layer was extracted with CH2Cl2 (2 × 30
mL). The combined organic phases were washed with brine (30
mL), dried (Na2SO4), and concentrated in vacuo. The crude product
was purified by flash column chromatography (50% EtOAc–hex-
ane) to give a colorless oil; yield: 770 mg (73%).
1H NMR (500 MHz, CDCl3): d = 1.39 (s, 9 H), 1.54 (m, 4 H), 2.04
(s, 3 H), 2.46 (t, J = 7.2 Hz, 2 H), 3.08 (m, 2 H).
13C NMR (125 MHz, CDCl3): d = 15.65, 26.48, 28.60, 29.40, 34.04,
40.32, 79.24, 156.18.
1H NMR (500 MHz, CDCl3): d = 1.85 (m, 4 H), 3.02 (s, 3 H), 3.59
(t, J = 6.0 Hz, 2 H), 4.26 (t, J = 6.0 Hz, 2 H).
13C NMR (125 MHz, CDCl3): d = 26.42, 26.56, 37.72, 44.71, 68.89,
130.00.
MS: m/z = 220 [M + 1], 242 [M + Na].
4-(Methylsulfanyl)butan-1-amine Hydrochloride (12)
A 4 M soln of HCl in dioxane (51 mL, 204 mmol, 3 equiv) was add-
ed to a soln of carbamate 11 (14.9 g, 68 mmol) in anhyd CH2Cl2
(150 mL), and the soln was stirred at r.t. for 2 h. The resulting light-
yellow soln was evaporated to dryness in a rotary evaporator and
then kept under a high vacuum for 1 h to give an off-white solid;
yield: 10.6 g (99%; 97% purity by LC-MS). The product was used
in the next step without further purification.
1H NMR (500 MHz, CD3OD): d = 1.68–1.82 (m, 4 H), 2.08 (s, 3 H),
2.54 (t, J = 6.9 Hz, 2 H), 2.95 (t, J = 6.5 Hz, 2 H).
13C NMR (125 MHz, CD3OD): d = 14.10, 25.71, 26.37, 33.11,
39.29.
Methyl Pyrrolidine-1-carbodithioate (8)
A soln of mesylates 7 (314 mg, 1.5 mmol) in anhyd DMF (4 mL)
was cooled to 0 °C in an ice bath, NaSMe (105 mg, 1.5 mmol) was
added in one portion, and the mixture was stirred at 0 °C for 1 h. The
resulting light yellow soln was treated with H2O (25 mL) and ex-
tracted with CH2Cl2 (3 × 30 mL). The combined CH2Cl2 extracts
were washed with H2O (30 mL) and brine (30 mL) then dried (an-
hyd Na2SO4) and concentrated in vacuo. The crude product was pu-
rified by flash column chromatography (10% EtOAc–hexane) to
give a white solid; yield: 170 mg (70%).
1H NMR (500 MHz, CDCl3): d = 1.96 (m, 2 H), 2.02 (m, 2 H), 2.60
(s, 3 H), 3.60 (t, J = 6.9 Hz, 2 H), 3.89 (t, J = 6.9 Hz, 2 H).
13C NMR (125 MHz, CDCl3): d = 19.64, 24.56, 26.30, 50.72, 55.20,
194.02.
MS (ESI): m/z = 120 [M + 1].
1-Isothiocyanato-4-(methylsulfanyl)butane (9)
Method A: A soln of PhOC(S)Cl (3.4 g, 20 mmol) in anhyd CH2Cl2
(20 mL) was added dropwise to an ice-cold stirred soln of amine 12
(3.1 g, 20 mmol) and Et3N (8.4 mL, 60 mmol) in anhyd CH2Cl2 (140
mL). The mixture was stirred at 0 °C for 1 h, the ice bath was re-
moved, and the mixture was stirred at r.t. overnight (11 h). The re-
action was quenched by adding H2O (150 mL) and the mixture was
extracted with CH2Cl2 (2 × 60 mL). The combined organic phase
was washed with brine (80 mL), dried (Na2SO4), and concentrated
in vacuo. The crude product was purified by flash column chroma-
tography (10% EtOAc–hexane) to give a light-yellow oil; yield: 2.5
g (77%; 98% purity by HPLC).
1H NMR (500 MHz, CDCl3): d = 1.65–1.80 (m, 4 H), 2.04 (s, 3 H),
2.48 (t, J = 7.2 Hz, 2 H), 3.51 (t, J = 6.6 Hz, 2 H).
13C NMR (125 MHz, CDCl3): d = 15.63, 26.05, 29.06, 33.49, 44.97,
130.51.
MS (ESI): m/z = 162 [M + 1].
tert-Butyl (4-Hydroxybutyl)carbamate (10)
(Boc)2O (12.4 g, 56.7 mmol, 1.05 equiv) was added to a stirred soln
of hydroxy amine 2 (4.8 g, 54 mmol) in THF (80 mL) at r.t, and the
mixture was stirred at r.t. for 1 h. The soln was concentrated to dry-
ness, and the oily residue was purified by flash column chromatog-
raphy (40–60% EtOAc–hexane) to give a colorless oil that
solidified to a white solid on standing; yield: 10.1 g (98%).
1H NMR (500 MHz, CDCl3): d = 1.37 (s, 9 H), 1.50 (m, 4 H), 3.05
(m, 2 H), 3.56 (m, 2 H).
13C NMR (125 MHz, CDCl3): d = 26.71, 28.59, 29.87, 40.48, 62.23,
79.30, 156.47.
Method B: Et3N (13.1 mL, 95 mmol, 3.5 equiv) was added to a soln
of amine 12 (4.2 g, 27 mmol) in anhyd THF (60 mL) and the mix-
ture was cooled to 0 °C in an ice bath. A soln of CS2 (2.06 g, 27
mmol) in anhyd THF (10 mL) was added dropwise over 10 min to
give a gray suspension. When the addition was complete, the ice
bath was removed and the mixture was stirred at r.t. for 80 min. The
resulting gray suspension was cooled to 0 °C and MsCl (2.3 mL,
29.7 mmol, 1.1 equiv) was added in one portion. The ice bath was
removed and the mixture was stirred at r.t. for 30 min. The resulting
yellow suspension was diluted with Et2O (200 mL), washed succes-
sively with 1 M aq HCl (2 × 50 mL), H2O (50 mL), and brine (50
mL), and then dried (anhyd Na2SO4). The solvent was concentrated
in vacuo and the crude product was purified by flash column chro-
matography (10% EtOAc–hexane) to give a light-yellow oil; yield:
MS (ESI): m/z = 190 [M + 1], 212 [M + Na].
tert-Butyl [4-(Methylsulfanyl)butyl]carbamate (11)
MsCl (7.47 mL, 96 mmol, 1.2 equiv) was added dropwise over 5
min to an ice-cold stirred soln of carbamate 10 (15.2 g, 80 mmol)
and Et3N (16.7 mL, 120 mmol, 1.5 equiv) in anhyd CH2Cl2 (240
mL). The mixture was stirred at 0 °C for 30 min then allowed to
warm to r.t. with stirring for 1 h to give a yellow suspension. The
suspension was filtered off and the filter cake was rinsed with
CH2Cl2 (50 mL). The combined filtrate was washed with H2O (100
mL) and brine (100 mL), dried (Na2SO4), and concentrated to give
4-[(tert-butoxycarbonyl)amino]butyl methanesulfonate (~22 g) as a
colorless oil that was used in the next step without further purifica-
tion.
Synthesis 2011, No. 24, 3991–3996 © Thieme Stuttgart · New York