Preparation and application of odorless 1,3-propanedithiol reagents

Article abstract of DOI:10.1248/cpb.54.141

2-Dodecyl-1,3-propanedithiol (2a) was prepared without a malodorous procedure as an odorless reagent that was usable in place of 1,3-propanedithiol (1) in organic reactions, e.g., in the reduction of azides and protection of carbonyl groups. The 1,3-dithioacetals obtained in the latter reaction were effectively reduced to methylene with Raney nickel and reconverted to the original carbonyl compounds by hydrolysis with N-bromosuccinimide in aqueous 2-butanone. In addition, the anion of 1,3-dithiane prepared from 2a and formaldehyde could be utilized as a synthetic equivalent of an anionic carbonyl carbon.

Full text of DOI:10.1248/cpb.54.141

January 2006
Notes
Chem. Pharm. Bull. 54(1) 141—146 (2006)
141
Preparation and Application of Odorless 1,3-Propanedithiol Reagents
*
Manabu MATOBA, Tetsuya KAJIMOTO, Kiyoharu NISHIDE, and Manabu NODE
Department of Pharmaceutical Manufacturing Chemistry, 21st Century COE Program, Kyoto Pharmaceutical University;
1 Shichono-cho, Misasagi, Yamashina-ku, Kyoto 607–8414, Japan.
Received September 2, 2005; accepted October 3, 2005
2-Dodecyl-1,3-propanedithiol (2a) was prepared without a malodorous procedure as an odorless reagent
that was usable in place of 1,3-propanedithiol (1) in organic reactions, e.g., in the reduction of azides and protec-
tion of carbonyl groups. The 1,3-dithioacetals obtained in the latter reaction were effectively reduced to methyl-
ene with Raney nickel and reconverted to the original carbonyl compounds by hydrolysis with N-bromosuccin-
imide in aqueous 2-butanone. In addition, the anion of 1,3-dithiane prepared from 2a and formaldehyde could be
utilized as a synthetic equivalent of an anionic carbonyl carbon.
Key words 2-dodecyl-1,3-propanedithiol; odorless 1,3-propanedithiol; dithioacetal; odorless 1,3-dithiane
We have reported the preparation and application of odor- thioacetate12,13) but by modifying Shon et al.’s method14) to
less organosulfur reagents that can be used in place of avoid generating malodorous odors during the reaction. The
ethanethiol, benzenethiol, phenylmethanethiol, and dimethyl reaction of dodecyl bromide and diethyl malonate in the
sulfide in organic synthesis.1—5) The strategy for reducing presence of sodium ethoxide giving diethyl 2-dodecyl-
malodorousness is based on the increase in their molecular malonate (3a) was followed by reduction with lithium alu-
weights to raise boiling points and suppress volatilities. For minum hydride to afford 2-dodecyl-1,3-propanediol (4a).
example, dodecanethiol is completely odorless although de- Thus the 1,3-diols (4a) were derived to give mesylate (5a),
canethiol still smells faintly and ethanethiol, as is well which was treated with thiourea and successively hydrolyzed
known, creates a stench.
with sodium hydroxide. The obtained substance must be re-
1,3-Propanedithiol (1) as well as the other organosulfuric duced once with sodium borohydride to afford 2a in pure
reagents mentioned above is an indispensable chemical espe- form due to the formation of disulfides (6a) by air oxidation
cially in the protection of carbonyl groups, reduction of car- during hydrolysis. 2-Decyl-1,3-propanedithiol (2b) was pre-
bonyl groups to methylene via dithioacetal, and reduction pared in the same way from 3b via 4b, and 5b (Chart 1). As
of azides. Polymer-supported 1,3-dithiol6—8) and ketene expected, 2a that was reported to form chelates with Au or
dithioacetal derivatives9—11) were already reported to be 99mTc was not malodorous,14,15) while 2b smelled faintly.
odorless 1,3-dithiols, although the preparation of these Next, the reactivity of 2a in several organic reactions was
reagents still requires odorous chemicals such as carbon compared with that of 1.
disulfide and thioacetate. We here report a useful procedure
In general, reactions with 1,3-propanedithiol (1) proceed
in which neither odorous reagents nor a malodorous work-up much faster than those with alkane thiols in the reaction re-
are required to prepare odorless 1,3-propanedithiol and 1,3- quiring two equivalents of mercapto groups, since intramole-
dithiane derivatives with a long alkyl chain at the C-2 posi- cular nucleophilic attack by the second mercapto group of 1
tion, and their reactivity in several organic reactions as a part causes less decrease in the activated entropy in the transition
of our study on odorless organosulfuric reagents.
state than the corresponding intermolecular reactions. This
could explain why the reduction of azides or dithioacetaliza-
tion of carbonyl groups proceed more quickly when using 1
Results and Discussion
In spite of being a known compound, 2-dodecyl-1,3- than when using alkane thiols. Thus diphenylmethyl azide
propanedithiol (2a) was not prepared by the method reported (7)16) and p-bromophenyl azide (8) were respectively reduced
in the literature accompanied by the generation of with 2a to amines (9, 10) initially. The reaction proceeded in
Chart 1. Synthesis of 2-Alkyl-1,3-propanedithiols
∗ To whom correspondence should be addressed. e-mail: node@mb.kyoto-phu.ac.jp
© 2006 Pharmaceutical Society of Japan

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Vol. 54, No. 1
iodide,18,19) phenyl iodine(III)bis(trifluoroacetate),20) and
Dess–Martin periodate21) did not give good results (Table 3).
We attempted to use 5-dodecyl-1,3-dithiane (19), which
can be easily prepared from 2a and paraformaldehyde in the
presence of p-toluenesulfonic acid in refluxed benzene, as a
precursor of a carbonyl anion equivalent. First, the proton at
the C-2 position of 19 was abstracted with n-butyllithium to
afford the odorless 1,3-dithiane anion. The reaction of the
anion with n-dodecyl iodide gave trans-2,5-didodecyl-1,3-
dithiane (20) in excellent yield.22) Deprotonation of 2-substi-
tuted 5-dodecyl-1,3-dithianes (21, 22) and successive alkyla-
tion with n-dodecyl iodide yielded trans-2,5-didodecyl-1,3-
dithiane derivatives (23, 24), of which the yield was depen-
dent on the bulkiness of the substituent at the C-2 position
(Table 4). The trans-configuration of 20, 23, and 24 was af-
fected by the thermodynamically favorable orientation of the
equatorial anion stabilized by the gauche effect,23) formation
excellent yields accompanied by a mixture of 2a and 6a,
which was reusable after the reduction with sodium borohy-
dride (Chart 2).
Next, 1,3-dithiol (2a) was applied in the reduction of the
carbonyl group in ketones to the methylene group via
dithioacetals. The formation of dithioacetals (11—13) from
carbonyl compounds (14—16) proceeded in excellent yields
using the conventional method (Table 1), and the reduction
of 11—13 with Raney nickel gave satisfactory results (Table
2). The dithioacetals (11—13) were obtained as a mixture of
cis- and trans-isomers, of which the ratio was dependent on
the structures of ketones. Among them, only compound 12
could be separated on HPLC .
Moreover, hydrolysis of dithioacetals (17, 18) with N-bro-
mosuccinimide (NBS)17) in aqueous 2-butanone gave the
original ketones in good yields, while hydrolysis with methyl
of a lithium complex,24) and nc→s* interaction,25) and other
s-c
factors reported in the literature.26—28)
In conclusion, 2-dodecyl-1,3-propanedithiol (2a), a useful
odorless substitute for 1,3-propanedithiol (1) in organic reac-
tions, was prepared without using a malodorous procedure
via a synthetic route using thiourea as the sulfur source. It
was possible to utilize 5-dodecyl-1,3-dithiane (19) prepared
from 2a and formaldehyde as an odorless dithiane substitute,
e.g., abstraction of the proton at C-2 with n-butyllithium or s-
butyllithium provided a useful synthetic equivalent of anionic
carbonyl carbon. It is noteworthy that there are no malodor-
ous procedures either in the preparation of 2a and 19 or dur-
Chart 2. Reduction of Azides into Amines with 2a
Table 1. Dithioacetalization of Carbonyl Compounds with 2a
Entry
Ketones
2a (eq)
1.2
Time (h)
Product
11
Yield (%)
Diastereomer ratioa)
1
2
3
22
24
24
99
89
98
3 : 1
4 : 1
1.2
12
b)
1.2
13
—
a) The ratio was determined by 1H-NMR on the basis of the integral value of the signals assigned to the protons at C-4 and C-6 on the dithiane rings. b) The ratio could not
be determined.
Table 2. Reduction of Dithioacetals (11—13) with Raney Nickel
Table 3. Hydrolysis of Dithioacetals (17, 18) with NBS
Entry
Dithioacetals
Product
Yield (%)
Entry
1
2
3
1
2
C12H25–CHO
87
98
Dithioacetals
Yield (%)
78
93
91

January 2006
143
Table 4. Substitution of Odorless Dithiane (19) and Its Derivatives
Entry
1
Substrate
Base
Conditions
Product
Yield (%)
95
n-BuLi
ꢁ20 °C to r.t. 14 h
2
3
n-BuLi
s-BuLi
0 °C to r.t. 10 h
73
96
ꢁ20 °C to r.t. 28 h
trans : cisꢀ7 : 3
The stereochemistry of 20, 21, 23, 24 was supported by 1H–1H COSY and NOESY spectra.
(100 MHz, CDCl3) d: 14.3, 22.9, 27.4, 27.9, 29.5, 29.7, 29.82, 29.84, 29.85,
29.86, 30.1, 32.1, 42.2, 67.1. IR (CHCl3) cmꢁ1: 3628, 3447, 3034, 3018,
3009, 2928, 2855, 1468, 1423, 1379, 1352, 1238, 1267, 1198, 1022, 960.
ing the work-up of the reactions mentioned above.
Experimental
General Infrared (IR) spectra were recorded on a Shimadzu FTIR-8300 HR-MS m/z: 245.2480 [Calcd for C15H33O2 (Mꢂ+1): 245.2476]. MS (CI)
diffraction-grating infrared spectrophotometer and 1H-NMR spectra were m/z: 245 (Mꢂ+1), 227, 208, 196, 168, 153, 139, 125. Anal. Calcd for
obtained on a JEOL JNM-AL300, Varian XL-300, or Varian Unity INOVA-
400 spectrometer with tetramethylsilane as an internal standard. 13C-NMR
C15H32O2: C, 73.71; H, 13.20. Found: C, 73.95, H, 13.22.
2-Dodecyl-1,3-propanediol Dimethanesulfonate (5a) Methanesul-
spectra were obtained on a Varian Unity INOVA-400 spectrometer with fonyl chloride (38.8 g, 339 mmol) and triethylamine (34.3 g, 339 mmol) were
CDCl3 as an internal standard. Mass spectra (MS) were determined on a
added to a suspension of 2-dodecyl-1,3-propanediol (4a) (37.7 g, 154 mmol)
JEOL JMS-SX 102A QQ or a JEOL JMS-GC-mate mass spectrometer. in ethyl acetate (650 ml) at 0 °C, and the mixture was stirred for 24 h. After
Wako gel C-200 (silica gel) (100—200 mesh, Wako) was used for open col-
umn chromatography. Flash column chromatography was performed using
Silica Gel 60N (Kanto Chemical Co., Inc.) as a solid support in the immo-
the reaction, the reaction mixture was washed with water, dried over sodium
sulfate, and evaporated. The residue was purified by recrystallization from
ethyl acetate to afford 2-dodecyl-1,3-propanediol dimethanesulfonate (5a)
bile phase. Kieselgel 60 F-254 plates (Merck) were used for thin-layer chro- (51.8 g, 84%). Colorless needles (ethyl acetate): mp 63—64 °C. 1H-NMR
matography (TLC). Preparative TLC (PTLC) was conducted with Kieselgel (400 MHz, CDCl3) d: 0.88 (3H, t, Jꢀ7.2 Hz), 1.48—1.18 (22H, m), 2.23—
60 F-254 plates (0.25 mm, Merck) or Silica gel 60 F-254 plates (0.5 mm,
Merck). Unless purification with silica gel gave a sufficiently pure com-
pound, the compounds were further treated with recycling HPLC (JAI LC-
908) on a GPC column (JAIGEL 1H and 2H). When possible, diastere-
omeric mixtures were also separated with recycling HPLC (JAI LC-908) on
a silica gel column (Kusano Si-10) after the purification mentioned above.
Diethyl 2-Dodecylmalonate (3a) Sodium ethoxide (19.1 g, 281 mmol)
in ethanol (120 ml) was added to a solution of diethyl malonate (48.2 g,
301 mmol) and n-dodecyl bromide (50.0 g, 201 mmol) in THF (200 ml) at
2.09 (1H, m), 3.05 (6H, s), 4.20 (2H, d, B part of AB, JABꢀ10.1 Hz,
Jꢀ6.8 Hz), 4.29 (2H, d, A part of AB, JABꢀ10.1 Hz, Jꢀ4.4 Hz). 13C-NMR
(100 MHz, CDCl3) d: 14.1, 22.7, 26.6, 27.0, 29.32, 29.37, 29.49, 29.52,
29.58, 29.61, 29.63, 31.9, 37.3, 38.2, 68.2. IR (CHCl3) cmꢁ1: 3036, 2928,
2855, 1468, 1362, 1344, 1265, 1231, 1209, 1176. HR-MS m/z: 400.1954
[Calcd for C17H36O6S2 (Mꢂ): 400.1953]. MS (CI) m/z: 400 (Mꢂ), 304, 208,
193, 180, 166, 152. Anal. Calcd for C17H36O6S2: C, 50.97; H, 9.06. Found:
C, 50.86, H, 8.88.
2-Dodecyl-1,3-propanedithiol (2a) Thiourea (24.5 g, 322 mmol) was
0 °C and refluxed for 4 h. After the reaction, the reaction mixture was neu- added to a suspension of 2-dodecyl-1,3-propanediol dimethanesulfonate
tralized with HCl 1 M, condensed in vacuo, and extracted with ethyl acetate.
(5a) (51.6 g, 129 mmol) in 2-propanol (589 ml), and the mixture was re-
The organic layer was successively washed with an aqueous solution of fluxed for 24 h. After the reaction mixture was cooled to room temperature,
sodium thiosulfate and brine, dried over sodium sulfate, and evaporated. The
residue was purified by distillation to afford 3a (60.4 g, 92%). Colorless oil:
bp. 160 °C (3.5 mmHg). 1H-NMR (400 MHz, CDCl3) d: 0.88 (3H, t,
a 10% aqueous solution of sodium hydroxide (124 ml) was added, and the
mixture was refluxed for another 24 h. The reaction was quenched by adding
hydrochloric acid 1 M until the pH value reached 1. The mixture was ex-
Jꢀ7 Hz), 1.27 (6H, t, Jꢀ7.2 Hz), 1.34—1.20 (20H, m), 1.88 (2H, q, tracted with ethyl acetate, and the organic layer was washed with brine, dried
Jꢀ7.2 Hz), 3.31 (1H, t, Jꢀ7.6 Hz), 4.20 (4H, q, Jꢀ7.2 Hz). 13C-NMR over sodium sulfate, and evaporated. The residue was purified on silica gel
(100 MHz, CDCl3) d: 14.06, 14.09, 22.66, 27.30, 28.72, 29.19, 29.30, 29.32, column chromatography (n-hexane) to afford a mixture of 2-dodecyl-1,3-
29.5, 29.6, 29.61, 29.63, 31.2, 52.1, 61.2, 169.9. IR (CHCl3) cmꢁ1: 2928, propanedithiol (2a) and 4-dodecyl-1,2-dithiorane (6a) (31.5 g). To a solution
2855, 1724, 1466, 1371, 1300, 1238, 1178, 1030. HR-MS m/z: 328.2613 of the mixture in THF and methanol (1 : 1, 380 ml), NaBH4 (5.21 g,
[Calcd for C19H36O4 (Mꢂ): 328.2614]. MS (70 eV) m/z: 328 (Mꢂ) 283, 173, 138 mmol) was added at 0 °C, and the mixture was stirred for 2 h. After the
160, 133.
2-Dodecyl-1,3-propanediol (4a)
malonate (4a) (59.0 g, 180 mmol) in THF (150 ml) was added to a suspen-
sion of LiAlH4 (15.0 g, 395 mmol) in THF (100 ml) at 0 °C, and the mixture
was stirred for 1.5 h at room temperature. After the reaction, water (15 ml),
reaction, the reaction mixture was acidified to pH 1 with hydrochloric acid
6 M and extracted with n-hexane. The organic layer was washed with brine,
dried over sodium sulfate, and evaporated. The residue was purified on silica
gel column chromatography (n-hexane) to afford 2-dodecyl-1,3-
propanedithol (2a) (31.0 g, 87%). Colorless oil: 1H-NMR (400 MHz, CDCl3)
A
solution of 2-diethyl dodecyl-
15% aqueous solution of sodium hydroxide (30 ml), and water (15 ml) were d: 0.88 (3H, t, Jꢀ6.4 Hz), 1.20 (2H, t, Jꢀ8.0 Hz), 1.35—1.18 (20H, m),
successively added to the reaction mixture, which was filtered through Hyflo 1.39 (2H, q, Jꢀ7 Hz), 1.73—1.63 (1H, m), 2.76—2.59 (4H, m). 13C-NMR
Super-Cel. The filtrate was condensed in vacuo, and the residue was purified
(100 MHz, CDCl3) d: 14.1, 22.7, 26.7, 26.9, 29.3, 29.54, 29.60, 29.63,
by recrystallization from ethyl acetate to afford 2-dodecyl-1,3-propanediol 29.66, 29.71, 31.4, 31.9, 42.6. IR (CHCl3) cmꢁ1: 3030, 3020, 3009, 2928,
(4a) (37.7 g, 86%). Colorless needles (ethyl acetate): mp 67—68 °C. 1H-
NMR (400 MHz, CDCl3) d: 0.88 (3H, t, Jꢀ6.8 Hz), 1.39—1.19 (22H, m),
2855, 1466, 1425, 1377, 1342, 1279, 1227, 1207. HR-MS m/z: 276.1943
[Calcd for C15H32S2 (Mꢂ): 276.1945]. MS (70 eV) m/z: 278 (Mꢂꢂ2), 276
1.83—1.72 (1H, m), 2.13 (2H, s), 3.66 (2H, d, B part of AB, JABꢀ10.5 Hz, (Mꢂ), 274.
Jꢀ7.5 Hz), 3.83 (2H, d, A part of AB, JABꢀ10.5 Hz, Jꢀ3.8 Hz). 13C-NMR
Diphenylmethyl Azide (7)16) Sodium azide (109.7 mg 1.69 mmol) was

144
Vol. 54, No. 1
added to a solution of benzhydryl chloride (114.0 mg, 0.562 mmol) in DMF
(1 ml), and the reaction mixture was stirred for 4 h at room temperature.
After the reaction, the reaction mixture was poured into ice water and ex-
tracted with diethyl ether. The organic layer was successively washed with
water and brine, dried over magnesium sulfate, and evaporated. The residue
was purified on silica gel column chromatography (n-hexane) to afford
diphenylmethyl azide (7) (28.0 mg, 24%).
Jꢀ6.4 Hz), 2.86 (2H, dd, A part of AB, JABꢀ14.6 Hz, Jꢀ11.6 Hz), 3.81 (3H,
s), 6.75 (1H, dd, Jꢀ8.4, 2.8 Hz, aromatic), 6.96 (1H, d, Jꢀ8.4 Hz, aromatic),
7.54 (1H, d, Jꢀ2.4 Hz, aromatic). 13C-NMR (100 MHz, CDCl3) d: 14.1,
20.3, 22.7, 26.4, 29.2, 29.3, 29.53, 29.59, 29.63, 29.65, 29.67, 31.9, 33.6,
35.9, 36.0, 36.7, 52.4, 55.4, 113.8, 115.2, 128.0, 129.8, 129.9, 157.8. IR
(CHCl3) cmꢁ1: 2928, 2855, 1609, 1501, 1466, 1317, 1238. HR-MS m/z:
434.2676 [Calcd for C26H42OS2 (Mꢂ): 434.2677]. MS (70 eV) m/z: 434
(Mꢂ), 401, 273, 192, 159, 144.
Colorless oil: 1H-NMR (400 MHz, CDCl3) d: 5.71 (1H, s) 7.43—7.25
(10H, m). 13C-NMR (100 MHz, CDCl3) d: 68.5, 126.5, 127.4, 128.0, 128.5,
128.7. IR (CHCl3) cmꢁ1: 3034, 2102, 1603, 1495, 1454. HR-MS m/z:
209.0955 [Calcd for C13H11N3 (Mꢂ): 209.0953]. MS (70 eV) m/z: 209 (Mꢂ),
180, 167, 152.
1
Minor Isomer: Colorless oil, H-NMR (400 MHz, CDCl3) d: 0.88 (3H, t,
Jꢀ6.4 Hz), 1.18—1.42 (20H, m), 1.86—1.78 (1H, m), 1.88—2.00 (4H, m),
2.57—2.58 (2H, m), 2.58 (2H, dd, B part of AB, JABꢀ14.2 Hz, Jꢀ2.8 Hz),
2.73 (2H, t, Jꢀ6.4 Hz), 3.37 (2H, dd, A part of AB, JABꢀ14.2 Hz,
Jꢀ2.8 Hz), 3.82 (3H, s), 6.75 (1H, dd, Jꢀ8.4, 2.8 Hz, aromatic), 6.96 (1H, d,
Jꢀ8.4 Hz, aromatic), 7.59 (1H, d, Jꢀ2.8 Hz, aromatic). 13C-NMR
(100 MHz, CDCl3) d: 14.1, 20.2, 22.7, 27.2, 28.1, 29.2, 29.36, 29.66, 29.7,
29.9, 31.9, 32.6, 36.0, 52.4, 55.3, 114.3, 114.8, 129.6, 129.8, 139.4, 157.8.
IR (CHCl3) cmꢁ1: 3686, 2928, 2855, 1609, 1499, 1466, 1317, 1238. HR-MS
m/z: 434.2676 [Calcd for C26H42OS2 (Mꢂ): 434.2677]. MS (70 eV) m/z: 434
(Mꢂ), 401, 273, 192, 159.
1-Azido-4-bromobenzene (8) A solution of 4-bromoaniline (166.1 mg,
0.966 mmol) in hydrochloric acid 6 M (1.0 ml) was added to an aqueous solu-
tion (1.2 ml) of sodium nitrite (100 mg, 1.45 mmol) at 0 °C and the mixture
was stirred for 1 h. Then, an aqueous solution (2 ml) of sodium azide
(251.1 mg, 3.86 mmol) and diethyl ether (4 ml) was added to the solution,
and the reaction mixture was stirred for another 2 h at room temperature.
After the reaction, water was added to the reaction mixture, which was ex-
tracted with diethyl ether. The organic layer was washed with a saturated
aqueous solution of sodium bicarbonate, dried over magnesium sulfate, and
evaporated. The residue was purified on silica gel column chromatography
(5S)-4,5-Dihydrotestosterone Cyclic 2-Dodecyl-1,3-propanediyl Di-
thioacetal (13) (5S)-4,5-Dihydrotestosterone (16) (90.5 mg, 0.312 mmol)
and boron trifluoride diethylether complex (17.7 mg, 0.125 mmol) were
added to a solution of 2a (103.4 mg, 0.374 mmol) in toluene at 0 °C, and the
reaction mixture was stirred at room temperature. After the reaction, a satu-
rated aqueous solution of sodium bicarbonate was added to the reaction mix-
ture, which was extracted with ethyl acetate. The organic layer was washed
with brine, dried over sodium sulfate, and evaporated. The residue was puri-
fied on silica gel column chromatography (n-hexane : ethyl acetateꢀ20 : 1
and then 2 : 1) to afford (5S)-4,5-dihydrotestosterone cyclic 2-dodecyl-1,3-
propanediyl dithioacetal (13) (167.0 mg, 98%). Amorphous powder: a mix-
ture of cis- and trans-isomers; 1H-NMR (400 MHz, CDCl3) d: 0.719 (3H, s),
0.881 (3H, t, Jꢀ6.4 Hz), 0.97 (3H, s), 0.95—1.12 (1H, m), 1.15—1.92
(42H, m), 1.95—2.26 (3H, m), 2.46—2.80 (4H, m), 3.63 (1H, t, Jꢀ8.4Hz).
13C-NMR (100 MHz, CDCl3) d: 11.1, 14.1, 20.5, 22.7, 23.3, 23.5, 25.8,
26.48, 26.51, 29.33, 29.52, 29.58, 29.62, 29.64, 30.6, 31.3, 31.7, 31.9, 32.8,
35.4, 35.5, 35.7, 35.9, 36.8, 38.4, 39.0, 40.2, 43.0, 50.9, 51.0, 81.9. IR
(CHCl3) cmꢁ1: 3609, 3454, 2928, 2855, 1603, 1468, 1447, 1412, 1379,
1358, 1342, 1312, 1269, 1236, 1205, 1198, 1171, 1157, 1136, 1119, 1094,
1069, 1051, 1032, 1009. HR-MS m/z: 548.4091 [Calcd for C34H60OS2 (Mꢂ):
548.4085]. MS (70 eV), m/z 548 (Mꢂ), 515, 313, 291, 274, 255, 239, 213,
201, 173.
1
(n-hexane) to afford 1-azido-4-bromobenzene (8) (133 mg, 69%). H-NMR
(200 MHz, DMSO-d6) d: 7.14—7.04 (2H, m), 7.63—7.54 (2H, m). 13C-
NMR (50 MHz, DMSO-d6) d: 117.1, 121.4, 132.8, 139.0. IR (CHCl3) cmꢁ1
:
3032, 3022, 2124, 2093, 1883, 1655, 1585, 1482, 1294, 1273, 1128, 1072,
1011. HR-MS m/z: 196.9586 [Calcd for C6H4BrN3 (Mꢂ): 196.9588]. MS
(70 eV) m/z: 199 (Mꢂꢂ2), 197 (Mꢂ), 171, 169.
1,1-Diphenylmethyl Amine (9) 2-Dodecyl-1,3-propanedithiol (2a)
(142.7 mg, 0.516 mmol) was added to a solution of diphenylmethyl azide (7)
(18.0 mg, 0.0860 mmol), triethylamine (52.2 mg, 0.516 mmol), and trioctyl-
methylammonium chloride (1 drop) in methanol (1.5 ml) and stirred. 1,1-
Diphenylmethylamine (9) (15.4 mg, 98%) was finally obtained, and distilla-
tion of the residue gave a mixture of 2a and 6a (138.3 mg, 97% recovery).
4-Bromoaniline (10) 2-Dodecyl-1,3-propanedithiol (2a) (393.3 mg,
1.422 mmol) was added to a solution of 1-azido-4-bromobenzene (8)
(47.0 mg, 0.237 mmol) and triethylamine (143.8 mg, 1.422 mmol) in
methanol (2 ml) and stirred. 4-Bromoaniline (10) (38.6 mg, 95%) was finally
obtained, and distillation of the residue gave a mixture of 2a and 6a
(373.7 mg, 95% recovery).
2-Cyclohexyl-5-dodecyl-2-phenyl-1,3-dithiane
(11) Cyclohexyl
phenyl ketone (14) (79.9 mg, 0.424 mmol) and boron trifluoride diethylether
complex (24.0 mg, 0.170 mmol) were added to a solution of 2a (140.8 mg,
0.509 mmol) in toluene at 0 °C, and the reaction mixture was stirred at room
temperature. After the reaction, saturated aqueous solution of sodium bicar-
bonate was added to the reaction mixture, which was extracted with ethyl ac-
etate. The organic layer was washed with brine, dried over sodium sulfate,
and evaporated. The residue was purified on silica gel column chromatogra-
phy (n-hexane) to afford 2-cyclohexyl-5-dodecyl-2-phenyl-1,3-dithiane (11)
Reduction of 2-Cyclohexyl-5-dodecyl-2-phenyl-1,3-dithiane (11)
A
suspension of Raney nickel (W-2) (6.0 ml) was added to 2-cyclohexyl-5-do-
decyl-2-phenyl-1,3-dithiane (11) (147.9 mg, 0.312 mmol), and the mixture
was stirred at room temperature for 15 h. After the reaction, the mixture was
filtered through celite, and the filtrate was condensed in vacuo. The residue
was purified on silica gel preparative TLC (n-hexane) to afford benzylcyclo-
1
hexane (45.2 mg, 78%), which was identified by the comparison of the H-
NMR spectrum with the data reported in the literature.29)
1
(188 mg, 99%). Colorless oil: a mixture of cis- and trans-isomers. H-NMR
Reduction of Spiro[5-dodecyl-1,3-dithiane-2,1ꢀ(2H)-7ꢀ-methoxy-3ꢀ,4ꢀ-
dihydronaphtalene] (12) A suspension of Raney nickel (W-2) (6.0 ml)
was added to spiro[5-dodecyl-1,3-dithiane-2,1ꢃ(2H)-7ꢃ-methoxy-3ꢃ,4ꢃ-dihy-
dronaphtalene] (12) (102.0 mg, 0.235 mmol), and the mixture was stirred at
room temperature for 16 h. After the reaction, the mixture was filtered
through celite, and the filtrate was condensed in vacuo. The residue was pu-
rified on silica gel column chromatography (n-hexane : ethyl acetateꢀ80 : 1
and then ethyl acetate) to afford 7-methoxy-3,4-dihydronaphtalene (35.6 mg,
93%), which was identified by the comparison of the 1H-NMR spectrum
with the data reported in the literature.30)
Reduction of (5S)-4,5-Dihydrotestosterone Cyclic 2-Dodecyl-1,3-
propanediyl Dithioacetal (13) A suspension of Raney nickel (W-2)
(6.0 ml) was added to (5S)-4,5-dihydrotestosterone cyclic 2-dodecyl-1,3-
propanediyl dithioacetal (13) (56.0 mg, 0.102 mmol), and the mixture was
stirred at room temperature for 11 h. After the reaction, the mixture was fil-
tered through celite, and the filtrate was condensed in vacuo. The residue
was purified on silica gel column chromatography (n-hexane and then
CHCl3 : MeOHꢀ10 : 1) to afford (5S)-3-deoxy-4,5-dihydrotestosterone
(25.6 mg, 91%), which was identified by the comparison of the 1H-NMR
spectrum with the data reported in the literature.31)
(400 MHz, CDCl3) d: 1.34—0.84 (31H, m), 1.74—1.62 (2H, m), 1.90—1.76
(2H, m), 2.06—1.92 (2H, m), 2.62—2.54 (1.6H, m), 2.31—2.22 (1.6 H, m),
2.51—2.45 (0.4H, m), 2.81—2.77 (0.4H, m), 7.27—7.25 (1H, m), 7.39—
7.35 (2H, m), 7.93—7.90 (2H, m). 13C-NMR (100 MHz, CDCl3) d: 14.1,
22.7, 26.2, 26.3, 26.6, 27.9, 28.2, 29.3, 29.4, 29.5, 29.6, 32.2, 32.9, 33.2,
36.3, 36.4, 50.2, 64.8, 126.5, 127.8, 128.0, 130.3. IR (CHCl3) cmꢁ1: 2928,
2855, 1600, 1215, 1204. HR-MS m/z: 446.3048 [Calcd for C28H46S2 (Mꢂ):
446.3041]. MS (70 eV) m/z: 446 (Mꢂ), 363, 273, 204, 171.
Spiro[5-dodecyl-1,3-dithiane-2,1ꢀ(2H)-7ꢀ-methoxy-3ꢀ,4ꢀ-dihydronaph-
talene] (12) 7-Methoxy-1-tetralone (15) (117.2 mg, 0.666 mmol) and
boron trifluoride diethylether complex (37.8 mg, 0.226 mmol) were added to
a solution of 2a (220.7 mg, 0.798 mmol) in toluene at 0 °C, and the reaction
mixture was stirred at room temperature. After the reaction, a saturated
aqueous solution of sodium bicarbonate was added to the reaction mixture,
which was extracted with ethyl acetate. The organic layer was washed with
brine, dried over sodium sulfate, and evaporated. The residue was purified
on silica gel column chromatography (n-hexane : ethyl acetateꢀ40 : 1) to af-
ford spiro[5-dodecyl-1,3-dithiane-2,1ꢃ(2H)-7ꢃ-methoxy-3ꢃ,4ꢃ-dihydronaph-
talene] (12) (256.7 mg, 89%). Further separation of the diastereoisomers was
achieved with HPLC equipped with Kusano Si-10 (n-hexane : ethyl
acetateꢀ20 : 1).
Hydrolysis of 2,5-Didodecyl-1,3-dithiane (17) A solution of 2,5-dido-
decyl-1,3-dithiane (17) (200 mg, 0.409 mmol) in 2-butanone (80 ml) was
added to an aqueous 97% 2-butanone (20 ml) solution of NBS (582.8 mg,
3.27 mmol) at 0 °C, and the reaction mixture was stirred for 20 min at room
temperature. After the reaction, a saturated aqueous solution of sodium
1
Major Isomer: Colorless oil, H-NMR (400 MHz, CDCl3) d: 0.88 (3H, t,
Jꢀ7.2 Hz), 1.20—1.52 (22H, m), 1.90—2.25 (3H, m), 2.60—2.58 (2H, m),
2.65 (2H, dd, B part of AB, JABꢀ14.6 Hz, Jꢀ3.2 Hz), 2.74 (2H, t,

January 2006
145
bisulfite (40 ml) was added to the reaction mixture, and the mixture was
stirred another 20 min. The reaction mixture was extracted with chloroform,
H, 11.86.
2-Phenyl-5-dodecyl-1,3-dithiane (22) Benzaldehyde (20.0 mg, 0.188
and the aqueous layer was extracted with n-hexane after the pH value was mmol) and BF3·Et2O (10.7 mg, 0.075 mmol) were added to a solution of 2a
adjusted to 11. The organic layer was washed with brine, dried over sodium (62.5 mg, 0.226 mmol) in toluene (1.0 ml), and the mixture was stirred at
sulfate, and evaporated to afford tridecanal (75.6 mg, 87%).
room temperature. After stirring for 17 h, the mixture was poured into a sat-
urated aqueous solution of sodium bicarbonate and extracted with ethyl ac-
etate. The organic layer was washed with a saturated aqueous solution of
sodium chloride, dried over anhydrous sodium sulfate, and condensed in
vacuo. The residue was purified on preparative TLC on silica gel to afford
22 as a mixture of cis- and trans-isomers. Amorphous powder. 1H-NMR
(400 MHz, CDCl3) d: 0.88 (3H, t, Jꢀ6.8 Hz), 1.20—1.96 (23H, m), 2.70—
2.80 (2H, m), 2.86 (1.4H, dd, Jꢀ14.3, 2.9 Hz), 3.21 (0.6H, dd, Jꢀ13.6,
Hydrolysis of 5-Dodecyl-2,2-diphenyl-1,3-dithiane (18) A solution of
5-dodecyl-2,2-diphenyl-1,3-dithiane (18) (50 mg, 0.113 mmol) in 2-bu-
tanone (20 ml) was added to an aqueous 97% 2-butanone (5 ml) solution of
NBS (161 mg, 0.907 mmol) at 0 °C, and the reaction mixture was stirred for
20 min at room temperature. After the reaction, a saturated aqueous solution
of sodium bisulfite (40 ml) was added to the reaction mixture, and the mix-
ture was stirred another 20 min. The reaction mixture was extracted with
chloroform, and the aqueous layer was extracted with n-hexane after the pH 1.2 Hz), 5.09 (0.3H, s), 5.12 (0.7H, s), 7.25—7.37 (3H, m), 7.45—7.54 (2H,
value was adjusted to 11. The organic layer was washed with brine, dried m). 13C-NMR (CDCl3) d: 14.1, 22.7, 26.9, 28.9, 29.3, 29.52, 29.58, 29.6,
over sodium sulfate, and evaporated. The residue was purified on silica gel
column chromatography (n-hexane : ethyl acetateꢀ20 : 1) to afford ben-
zophenone (20.1 mg, 98%).
29.8, 31.9, 35.7, 36.2, 36.6, 37.7, 51.5, 127.7, 127.9, 128.2, 128.4, 128.6,
128.7. IR (CHCl3) cmꢁ1: 3001, 2986, 2959, 2855, 1497, 1466, 1452. HR-
MS m/z: 364.2250 [Calcd for C22H36S2 (Mꢂ): 364.2258]. MS (70 eV) m/z:
5-Dodecyl-1,3-dithiane (19) Paraformaldehyde (10.97 g) and p-tolue- 364 (Mꢂ), 279, 273, 167, 149.
nesulfonic acid monohydrate (0.695 g, 3.65 mmol) were added to a solution
of 2a (10.1 g, 36.5 mmol) in benzene (82 ml), and the mixture was refluxed
for 2 h. After the reaction, the reaction mixture was filtered. The filtrate was
trans-2,5-Didodecyl-2-propyl-1,3-dithiane (23) n-BuLi (54.0 mg,
0.835 mmol) was added to a solution of trans-2-propyl-5-didodecyl-1,3-
dithiane (21) (138.1 mg, 0.418 mmol) in THF (2 ml) at 0 °C, and the mixture
partitioned between ethyl acetate and water, and the organic layer was suc- was stirred for 1 h. Then n-decyl iodide (495.0 mg, 1.671 mmol) was slowly
cessively washed with saturated aqueous solution of sodium bicarbonate,
water, and brine, dried over sodium sulfate, and evaporated. The residue
added to the reaction mixture. After stirring for 10 h at room temperature, a
saturated aqueous solution of ammonium chloride was added to the mixture,
was purified on silica gel column chromatography (n-hexane : ethyl which was extracted with ethyl acetate. The organic layer was washed with
acetateꢀ10 : 1) to afford 5-dodecyl-1,3-dithiane (19) (10.0 g, 95%). Color-
brine, dried over sodium sulfate, and evaporated. The residue was purified
less needles (n-hexane): mp 41—42 °C. 1H-NMR (400 MHz, CDCl3) d: 0.88 on silica gel column chromatography (n-hexane) to afford trans-didodecyl-
(3H, t, Jꢀ6.8 Hz), 1.16—1.48 (22H, m), 1.81—1.92 (1H, m), 2.54 (2H, dd, 2,5-propyl-1,3-dithiane (23) (151.2 mg, 73%). Colorless needles (n-hexane):
1
B part of ABX, JABꢀ14.5 Hz, Jꢀ9.9 Hz), 2.78 (2H, ddd, A part of ABX, mp 48.0—49.0 °C. H-NMR (400 MHz, CDCl3) d: 0.88 (6H, t, Jꢀ7.2 Hz),
J
ABꢀ14.5 Hz, Jꢀ2.7 Hz, 1.6 Hz), 3.51 (1H, dt, B part of AB, JABꢀ13.9 Hz, 0.95 (3H, t, Jꢀ7.2 Hz), 1.18—1.48 (44H, m), 1.63—1.82 (3H, m), 1.86—
1.6 Hz), 3.90 (1H, d, A part of AB, JABꢀ13.9 Hz). 13C-NMR (100 MHz,
1.98 (2H, m), 2.62 (2H, d, B part of AB, JABꢀ14.3 Hz, Jꢀ9.6 Hz), 2.67 (2H,
CDCl3) d: 14.1, 22.7, 29.26, 29.34, 29.5, 29.58, 29.63, 29.7, 31.7, 31.9, d, A part of AB, JABꢀ14.3 Hz, Jꢀ4 Hz). 13C-NMR (100 MHz, CDCl3) d:
35,3, 35.8, 36.0. IR (CHCl3) cmꢁ1: 2988, 2930, 2855, 2361, 2343, 2332, 14.1, 14.2, 18.0, 22.7, 23.7, 26.5, 29.34, 29.42, 29.54, 29.58, 29.63, 29.66,
1466, 1427, 1410, 1389, 1288, 1236, 1221, 1198, 1186, 1165; HR-MS m/z: 29.9, 31.5, 31.9, 35.2, 35.3, 38.6, 39.6, 53.2. IR (CHCl3) cmꢁ1: 2957, 2932,
288.1946 [Calcd for C16H32S2 (Mꢂ): 288.1945]. MS (70 eV) m/z: 288 (Mꢂ), 2855, 1466, 1411, 1379, 1354, 1303, 1244, 1225, 1205, 1121, 1103. HR-MS
207, 149. Anal. Calcd for C16H32S2: C, 66.60; H, 11.18. Found: C, 66.78; H, m/z: 498.4290 [Calcd for C31H62S2 (Mꢂ): 498.4293]. MS (70 eV) m/z : 498
10.97.
trans-2,5-Didodecyl-1,3-dithiane (20) n-BuLi (35.3 mg, 0.546 mmol)
was added to solution of 5-dodecyl-1,3-dithiane (19) (131.3 mg,
0.456 mmol) in THF (2 ml) at ꢁ20 °C, the mixture was stirred for 1 h, and
then n-dodecyl iodide (161.7 mg, 0.546 mmol) was slowly added to the reac-
tion mixture. After stirring for 14 h at room temperature, a saturated aqueous
solution of ammonium chloride was added to the mixture, which was ex-
(Mꢂ), 455, 329, 273, 255. Anal. Calcd for C31H62S2: C, 74.62; H, 12.52.
Found: C, 74.79; H, 12.72.
trans-2,5-Didodecyl-2-phenyl-1,3-dithiane (24) s-BuLi (16.1 mg,
0.249 mmol) was added to a solution of 5-dodecyl-2-phenyl-1,3-dithiane
(22) (75.5 mg, 0.207 mmol) in THF (1.5 ml) at ꢁ20 °C, the mixture was
stirred for 1 h, and then n-dodecyl iodide (161.7 mg, 0.249 mmol) was
slowly added to the reaction mixture. After stirring for 28 h at room temper-
a
tracted with ethyl acetate. The organic layer was washed with brine, dried ature, a saturated aqueous solution of ammonium chloride was added to the
over sodium sulfate, and evaporated. The residue was purified on silica gel
column chromatography (n-hexane) to afford trans-2,5-didodecyl-1,3-dithi-
mixture, which was extracted with ethyl acetate. The organic layer was
washed with brine, dried over sodium sulfate, and evaporated. The residue
ane (20) (210.5 mg, 95%). Colorless needles (n-hexane): mp 73.0—74.0 °C. was purified on silica gel column chromatography (n-hexane) to afford
1H-NMR (400 MHz, CDCl3) d: 0.88 (6H, t, Jꢀ7 Hz), 1.12—1.36 (40H, m),
trans-2,5-didodecyl-2-phenyl-1,3-dithiane (24) (105.6 mg, 96%). Colorless
1.45—1.55 (2H, m), 1.68—1.83 (3H, m), 2.54 (2H, dd, B part of AB, needles (n-hexane): 1H-NMR (400 MHz, CDCl3) d: 0.88 (6H, t, Jꢀ7 Hz),
ABꢀ14.3 Hz, Jꢀ11.2 Hz), 2.76 (2H, dd, A part of AB, JABꢀ14.3 Hz, 1.34—1.08 (42H, m), 1.89—1.92 (1H, m), 1.92—2.00 (2H, m), 2.33 (2H,
Jꢀ2.8 Hz), 4.00 (1H, t, Jꢀ6.8 Hz). 13C-NMR (100 MHz, CDCl3) d: 14.1, dd, B part of AB, JABꢀ14.4 Hz, Jꢀ11.4 Hz), 2.58 (2H, dd, A part of AB,
22.7, 26.4, 26.8, 29.3, 29.6, 31.9, 34.8, 36.4, 36.6, 47.8. IR (CHCl3) cmꢁ1
ABꢀ14.4 Hz, Jꢀ2.9 Hz), 7.28—7.22 (1H, tt, Jꢀ6, 1.2 Hz), 7.40—7.34 (2H,
2922, 2855, 1425, 1377, 1377, 1300. HR-MS m/z: 456.3821 [Calcd for
m), 7.94—7.88 (2H, m). 13C-NMR (100 MHz, CDCl3) d: 14.1, 22.7, 24.0,
C28H56S2 (Mꢂ): 456.3823]. Anal. Calcd for C28H56S2: C, 73.61; H, 12.35. 26.4, 29.2, 29.3, 29.46, 29.48, 29.55, 29.60, 29.63, 31.9, 33.2, 36.0, 36.3,
J
:
J
Found: C, 73.73; H, 12.29.
45.2, 59.2, 126.7, 128.28, 128.33, 128.9, 142.0. IR (CHCl3) cmꢁ1: 3684,
3032, 2926, 2855, 1601, 1466, 1443, 1234, 1200. HR-MS m/z: 532.2434
[Calcd for C34H60S2 (Mꢂ): 532.4136]. MS (70 eV) m/z: 532 (Mꢂ), 363, 289,
274, 257. Anal. Calcd for C34H60S2: C, 76.62; H, 11.35. Found: C, 76.64, H,
11.32.
trans-2-Propyl-5-dodecyl-1,3-dithiane (21) n-BuLi (30.5 mg, 0.472
mmol) was added to a solution of 5-dodecyl-1,3-dithiane (19) (113.5 mg,
0,393 mmol) in THF (2 ml) at ꢁ20 °C, the mixture was stirred for 1 h, and
then n-propyl iodide (80.2 mg, 0.472 mmol) was slowly added to the reaction
mixture. After stirring for 24 h at room temperature, a saturated aqueous so-
lution of ammonium chloride was added to the mixture, which was extracted
Acknowledgments This research was financially supported in part by
with ethyl acetate. The organic layer was washed with brine, dried over the Frontier Research Program and the 21st Century Center of Excellence
sodium sulfate, and evaporated. The residue was purified on silica gel col- Program “Development of Drug Discovery Frontier Integrated from Tradi-
umn chromatography (n-hexane) to afford trans-2-propyl-5-didodecyl-1,3- tion to Proteome” of the Ministry of Education, Culture, Sport and Technol-
dithiane (21) (111.8 mg, 86%). Colorless needles (n-hexane): mp 72—74 °C.
1H-NMR (400 MHz, CDCl3) d: 0.88 (3H, t, Jꢀ7.2 Hz), 0.93 (3H, t,
Jꢀ7.6 Hz), 1.18—1.40 (22H, m), 1.52 (2H, quint, Jꢀ7.5 Hz), 1.73 (2H,
quint. Jꢀ7.9 Hz), 1.70—1.82 (1H, m), 2.54 (2H, dd, A part of AB,
ogy, Japan.
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