Org. Synth. 1999, 76, 271
DOI: 10.15227/orgsyn.076.0271
2-CHLOROPHENYL PHOSPHORODICHLORIDOTHIOATE
[
Phosphorodichloroidothioic acid, O-(2-chlorophenyl)ester
]
Submitted by Vasulinga T. Ravikumar and Bruce Ross
1
.
Checked by Adam R. Renslo and Rick L. Danheiser.
1. Procedure
A 2-L, three-necked, round-bottomed flask equipped with a 250-mL addition funnel, glass stoppers, and a magnetic stirring bar is charged with
thiophosphoryl chloride (271 g, 1.60 mol)
(Note 1),
tetrabutylammonium bromide (3.2 g; 0.01 mol)
(Note 1), and
400 mL of dichloromethane
(Note 2), and the resulting solution is cooled in an ice bath at 0-5°C.
2-Chlorophenol (51.4 g, 0.400 mol)
(Note 1) is added to a magnetically stirred solution of
sodium hydroxide (25%, 350 mL, (Note 1)) in a 500-mL Erlenmeyer flask cooled in an ice bath at 0-5°C, and the resulting solution is transferred to the addition funnel and added slowly over a period of 30 min to the reaction mixture. The resulting two-phase mixture is stirred for 8 hr while the bath is allowed to warm to room temperature, and the aqueous layer is then separated and extracted with
100 mL of dichloromethane
. The combined organic layers are washed with
100 mL of brine
, dried over
magnesium sulfate
, and filtered. The dichloromethane is removed by rotary evaporation, and the residue is distilled under reduced pressure through a short-path still head (Note 3) to give 93.2-98.4 g (89-94%) of
2-chlorophenyl phosphorodichloridothioate
as a colorless oil (Note 4).
2. Notes
1.
Reagent grade
2-chlorophenol, sodium hydroxide, thiophosphoryl chloride, and tetrabutylammonium bromide were purchased from Aldrich Chemical Company, Inc.
, and used without purification.
2.
HPLC-grade
dichloromethane was purchased from Mallinckrodt Inc.
and used without further purification.
3.
Two traps cooled in liquid
nitrogen are connected between the distillation apparatus and the vacuum pump to trap excess
thiophosphoryl chloride.
4.
2-Chlorophenyl phosphorodichloridothioate has the following properties: bp
90-93°C (0.2 mm); IR (neat) cm
−1: 3160, 1580, 1475, 1450, 1260, 1210, 1060, 1040, 940, 780, 760, 720
;
1H NMR (CDCl
3, 300 MHz) δ: 7.22-7.34 (m, 2 H), 7.43-7.51 (m, 2 H)
;
13C NMR (CDCl
3, 75 MHz) δ: 122.5, 122.6, 126.7, 126.8, 127.7, 127.8, 127.91, 127.95, 131.09, 131.12, 146.7, 146.9
;
31P NMR (CDCl
3, 202 MHz) δ: 54.4
. Anal. Calcd for C
6H
4Cl
3OPS: C, 27.56; H, 1.54. Found: C, 27.57; H, 1.42.
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
Deoxyribonucleotides, deoxyribonucleotide phosphorothioates, modified DNA, and analogs have wide applications in molecular biology, antisense applications, antigene therapy, etc. Three methods are available for the synthesis of oligonucleoside phosphorothioates:
phosphoramidite, H-phosphonate, and phosphotriester approaches. Different protecting groups, most of which are base labile, have been used for the
phosphoramidite approach. In the H-phosphonate approach, no protecting group is involved. In the phosphotriester approach, aryl groups are used as O-protecting groups, and deprotection occurs via a nucleophilic attack on the phosphorus center with the aryloxy group being the leaving group. Because of their base labile nature, most of the groups used in the
phosphoramidite approach are not suitable for the synthesis of aryl phosphorodichloridothioates, which are used as the starting material in the phospho triester approach. The previously reported
2,3 routes for the synthesis of aryl phosphorodichloridothioates involve drastic conditions such as refluxing or the use of liquid
sulfur dioxide, and are not amenable to very large scale synthesis. A much simpler alternative method involving phase transfer reaction is described here.
Phase transfer catalysis
4 is a valuable tool in organic synthesis. The process is exemplified by the convenient synthesis of
2-chlorophenyl phosphorodichloridothioate. Using this phase transfer reaction, a number of dichloridothioates of substituted phenyl, benzyl, thiophenyl, and thiobenzyl alcohols are accessible. The
phosphorodichloridothioate reacts with various coupling reagents to form activated species that are useful in the synthesis of oligonucleotide phosphorothioates via the phosphotriester approach as illustrated below.
5,6
The procedure shown here describes the preparation of a fully protected phosphorothioate triester dimer. The dimer can then be coupled subsequently in a similar way to form elongated oligomers.
Appendix
Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)
2-Chlorophenyl phosphorodichloridothioate:
Phosphorodichlorodiothioic acid, O-(2-chlorophenyl)ester (10); (68591-34-4)
Thiophosphoryl chloride: HIGHLY TOXIC (8,9); (3982-91-0)
Tetrabutylammonium bromide (8);
1-Butanaminium, N,N,N-tributyl-, bromide (9); (1643-19-2)
2-Chlorophenol:
Phenol, o-chloro- (8);
Phenol, 2-chloro- (9): (95-57-8)
Sodium hydroxide (8,9); (1310-73-2)
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