Org. Synth. 2005, 81, 244
DOI: 10.15227/orgsyn.081.0244
PHENYLSULFENYLATION OF NONACTIVATED δ-CARBON ATOM BY PHOTOLYSIS OF ALKYL BENZENESULFENATES: PREPARATION OF 2-PHENYLTHIO-5-HEPTANOL
[Heptane, 2-phenylthio-5-hydroxy]
Submitted by Goran Petrovic, Radomir N. Saicic, and Zivorad Cekovic
1.
Checked by Fangzheng Li and Marvin J. Miller.
1. Procedure
A. 3-Heptyl benzenesulfenate. A 1-L, three-necked, round-bottomed flask equipped with a 50-mL pressure-equalizing addition funnel fitted with an argon inlet, an internal thermometer, a drying tube, and a magnetic stir bar is charged with 10.0 g (86.1 mmol) of 3-heptanol (Note 1), 420 mL of anhydrous methylene chloride (Note 2), and 30 mL (22 g, 215 mmol) of freshly distilled triethylamine (Note 3). The flask is flushed with argon and the solution is cooled in a acetone/dry ice bath to an internal temperature of −72°C. Benzenesulfenyl chloride (10.93 mL, 13.7 g, 94.73 mmol) (Note 4) is added over 20 min to the efficiently stirred solution. The reaction mixture is stirred at −72°C for 45 min and then protected from light (Note 5) and allowed to warm to room temperature. The resulting mixture is diluted with 200 mL of methylene chloride and then washed successively with 200 mL of deionized water, 200 mL of 1.5M hydrochloric acid, 200 mL of deionized water, 200 mL of saturated aqueous sodium hydrogen carbonate solution, and 200 mL of deionized water. The organic solution is dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure from a flask wrapped with aluminum foil. The residual oil is purified by vacuum distillation (bp 131-132°C, 3 mm) to give 17.2 g (89% yield) of the title compound 1 as a green-yellow oil (Notes 6, 7, 8).
B. 2-Phenylthio-5-heptanol. A photochemical reactor consisting of a tubular pyrex flask, a magnetic stirbar, a water-cooled high pressure mercury lamp, and an argon inlet tube (Note 9) is charged with 12.3 g (54.8 mmol) of 3-heptyl benzenesulfenate, 1.6 g (2.8 mmol) of hexabutylditin (Note 10), and 220 mL of benzene (Note 11). The solution is purged with argon for 10 min to remove oxygen and then irradiated for 1 hr with water cooling (Note 12). The solvent is then removed under reduced pressure to afford a pale yellow oil which is purified by dry flash chromatography on silica gel (Note 13). The fractions containing the desired product are combined and concentrated by rotary evaporation under reduced pressure to afford 6.5 g (53%) of 2-phenylthio-5-heptanol as a colorless oil (Note 14).
2. Notes
1.
3-Heptanol was purchased from Fluka Chemika and distilled (
bp 155°C) before use. The checkers purchased
3-heptanol from Aldrich Chemical Company and used it without purification.
2.
Methylene chloride was distilled from
phosphorus pentoxide and stored over activated molecular sieves (4Å).
3.
Triethylamine was purchased from the Merck & Company, Inc. and distilled from
calcium hydride. The checkers used
triethylamine purchased from Aldrich Chemical Company.4.
Benzenesulfenyl chloride was prepared from the reaction of
thiophenol with
sulfuryl chloride in the presence of
triethylamine in petroleum ether (
bp 35-50°C) according to the procedure of Barrett, A. G. M.; Dhanak, D.; Graboski, G. G.; Taylor, S. J.
Org. Synth. Coll. Vol. VIII,
1993, 550. This reagent was stored under
argon in a refrigerator and protected from light, under which conditions it can be stored for one month without significant change (G. Zelcans,
Encyclopedia of Reagents for Organic Synthesis, Ed. L. A. Paquette, Wiley, New York, 1995, Vol. 1, p. 272).
5.
Alkyl benzenesulfenates are sensitive to light and their preparation should be carried out in a darkened hood.
6.
The crude product is sufficiently pure for use in the next step. The submitters preferred to perform the distillation at a lower pressure (89°C, 0.3 mm) in order to minimize decomposition and obtained the product in
91% yield. The checkers obtained the product in
84-89% yield in several runs.
7.
The preparation of alkyl benzenesulfenates is accompanied by the formation of products of higher oxidation states of
sulfur. These products have higher boiling points and are separated by careful distillation of the product under reduced pressure.
8.
The product exhibits the following spectroscopic properties: IR (KBr) cm
−1: 3061, 2960, 2934, 2874, 2000-1600, 1583, 1477, 1464, 1439, 1113, 1069, 1024, 943, 916, 893, 811, 737, 690;
1H NMR
pdf (300 MHz, CDCl
3) δ: 0.88 (t, J = 7.5 Hz, 6H), 1.24-1.31 (m, 4H), 1.56-1.70 (m, 4H), 3.52 (q, J = 5.7 Hz, 1H), 7.16-7.52 (m, 5H);
13C NMR (75 MHz, CDCl
3) δ: 9.5, 14.1, 22.9, 26.9, 27.5, 33.5, 89.3, 125.3, 128.9, 141.8.
9.
The reaction apparatus used by the submitters for irradiation on a 12-g scale was 18 cm high and 6 cm in diameter and had a 55/50 joint at the top for an immersion well. The apparatus is fitted with an argon inlet tube and
water-cooled condenser which is connected to a
mineral oil bubbler. The light source was a 125W high pressure
Hanovia mercury lamp. The checkers used a tubular pyrex flask 15 cm high and 7.5 cm in diameter. The light source was a 450W high pressure
ACE mercury lamp (7825-34 lamp) with filter to provide 250 nm light.
10.
Hexabutylditin was purchased from Aldrich Chemical Company, Inc. and used without purification.
11.
Anhydrous
benzene was purchased from Aldrich Chemical Company and used without purification.
12.
The course of the reaction was followed by TLC (silica gel 60 A, 2.5 × 7.5 cm plates, elution with
95:5 ethyl acetate/hexane, visualization with
50% sulfuric acid followed by heating) by monitoring the disappearance of benzenesulfenate starting material
1.
13.
A chromatography column of 4.5-cm diameter was charged with 250 g of silica gel (ICN Silica 10/18 60 A). The viscous oily crude product is dissolved in
10 mL of methylene chloride, 10 g of silica gel is added, and the solvent is evaporated. The resulting dry powder is applied on the top of the column which is then successively eluted with
petroleum ether,
95:5 petroleum ether/acetone, and
90:10 petroleum ether/acetone.
14.
The submitters obtained the product in
61% yield; the checkers isolated the purified product in
53-56% yield in several runs. The product exhibits the following spectroscopic properties: IR (KBr) cm
−1: 3400, 3074, 2961, 2930, 2874, 2000-1600, 1584, 1480, 1458, 1439, 1376, 1303, 1263, 1178, 1092, 1068, 1025, 1000, 971, 923, 746, 692;
1H NMR
pdf (300 MHz, CDCl
3) δ: 0.92 (t, J = 7.5 Hz, 3H), 1.27 (d, J = 6.9 Hz, 3H), 1.40-1.80 (m, 6H), 3.22 (m, 1H), 3.48 (m, 1H), 7.18-7.29 (m, 3H), 7.37-7.40 (m, 2H);
13C NMR (75 MHz, CDCl
3) δ: 9.9, 21.5, 21.5, 30.4, 30.4, 32.9, 33.1, 34.3, 34.5, 43.7, 43.8, 73.2, 73.3, 126.9, 128.9, 132.3, 135.7.
Handling and Disposal of Hazardous Chemicals
The procedures in this article are intended for use only by persons with prior training in experimental organic chemistry. All hazardous materials should be handled using the standard procedures for work with chemicals described in references such as "Prudent Practices in the Laboratory" (The National Academies Press, Washington, D.C., 2011 www.nap.edu). All chemical waste should be disposed of in accordance with local regulations. For general guidelines for the management of chemical waste, see Chapter 8 of Prudent Practices.
These procedures must be conducted at one's own risk. Organic Syntheses, Inc., its Editors, and its Board of Directors do not warrant or guarantee the safety of individuals using these procedures and hereby disclaim any liability for any injuries or damages claimed to have resulted from or related in any way to the procedures herein.
3. Discussion
The introduction of various functional groups onto a remote nonactivated
carbon atom is of great synthetic importance.
2 The regioselective functionalization of a nonactivated δ-carbon atom involves a free radical 1,5-hydrogen transfer from δ-carbon atom to
oxygen or
nitrogen centered radicals.
3 Transposition of a radical center from
oxygen or
nitrogen to the remote
carbon atom offers possibilities for introduction of different functional groups onto the nonactivated
carbon atom or for formation of a new
carbon-carbon bond. Diversity of this type of reaction offers possibilities for introduction of different
oxygen,
2 nitrogen,
4 halogen,
5 and
sulfur6 functional groups as well as an olefinic bond
7 onto the δ-carbon atom. The present procedure is based on the original results
6 of the author and co-workers.
Formation of δ-phenylthio alcohols from alkyl benzenesulfenates
3 formally represents a simple interchange of the positions of δ-hydrogen and phenylthio group. The sequence of radical reactions is initiated by tributyltin radical and is based on its thiophilic addition to the sulfur of an alkyl benzenesulfenate.
6 The formed alkoxyl radical
4 upon intramolecular 1,5-hydrogen migration gives the δ-carbon radical
5. In the absence of any other reactive species the carbon radical undergoes homolytic substitution at the
sulfur atom in the alkyl benzenesulfenate
3 to give the δ-phenylthio alcohol
6 and to generate the alkoxyl radical
4 as a transfer radical which continues the chain (see Scheme 1).
δ-Phenylsulfenylation is also conceivable in a tin-free variant; however, when alkyl benzenesulfenates were irradiated in the absence of
hexabutylditin, the reaction proceeded at a lower rate and gave 10-15% lower yields of δ-phenylthio alcohols.
6This method for introduction of the thioether functional group tolerates the presence of a broad range of functional groups, such as alkene, ester, carbonyl, and cyano groups.
Introduction of the phenylthio group onto the δ-carbon atom of alcohols can have valuable synthetic applications. δ-Phenylthio alcohols can be oxidized to the corresponding δ-sulfoxides and sulfones (with their versatile reactivities) or they can be deprotonated by strong base converting the δ-carbon atom to a nucleophilic species. Conversion of δ-phenylthio alcohols to the corresponding δ-carbonyl compounds can be achieved via halogenation followed by subsequent hydrolysis. In this way an inversion of the reactivity of the δ-carbon atom may be accomplished and it can react as an electron acceptor.
The procedure of phenylsulfenylation of δ-carbon atom was applied to a variety of other substrates as summarized in Table 1.
Appendix
Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)
2-Phenylthio-5-heptanol:
3-Heptanol, 6-(phenylthio); (198778-75-5)
3-Heptyl benzenesulfenate:
Benzenesulfenic acid, 1-ethylpentyl ester; (198778-69-7)
3-Heptanol; (589-82-2)
Triethylamine:
Ethanamine, N,N-diethyl-; (121-44-8)
Benzenesulfenyl chloride; (931-59-9)
Hexabutylditin:
Distannane, hexabutyl; (813-19-4)
Thiophenol:
Benzenethiol; (108-98-5)
Sulfuryl chloride; (7791-25-5)
Petroleum ether: Ligroine; (8032-32-4)
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