Org. Synth. 2002, 79, 43
DOI: 10.15227/orgsyn.079.0043
PREPARATION OF n-BUTYL 4-CHLOROPHENYL SULFIDE
Submitted by J. Christopher McWilliams
1
, Fred J. Fleitz, Nan Zheng, and Joseph D. Armstrong III.
Checked by Scott E. Denmark and Ramzi F. Sweis.
1. Procedure
A.
4-Chlorophenyl trifluoromethanesulfonate
.
A 250-mL, three-necked flask equipped with a Teflon-coated
thermocouple, nitrogen bubbler, and septum
is charged with a Teflon-coated magnetic stir bar,
4-chlorophenol (13.2 g, 102.5
mmol), and
methylene chloride
(125 mL) at room temperature (Note 1).
Pyridine
(9.1 mL, 112.5 mmol) is added to the solution
via syringe, and the reaction mixture is cooled to −10°C with an ice/methanol
cooling bath
(Note 2).
Triflic
anhydride (18.7 mL, 111.3 mmol)
is added dropwise to the reaction mixture via syringe at a rate such that the temperature
remains below −2°C (Note 3). Upon completion of the addition,
the reaction mixture is stirred for 1 hr at −10°C, then allowed to warm to room
temperature. When the reaction is complete, water (75 mL) is added to the mixture
and the resulting two-phase mixture is stirred for 15 min (Note 4).
In a 500-mL separatory funnel, the layers are separated and
the organic (lower) layer is washed sequentially with 0.2
N hydrochloric acid (HCl), water, and brine
(75 mL each). The final organic layer is concentrated
to a yellow oil via rotary evaporation. The yellow oil is diluted with
25
mL of 5%
ethyl acetate in hexanes
and filtered through a bed of silica gel (63 g charged to a 150-mL filter
funnel and prewetted with
5%
ethyl acetate in hexanes, Note 5). The silica gel is washed with
5%
ethyl acetate in hexanes until the desired triflate
is no longer detected in the filtrate (250 mL). The filtrate is concentrated via rotary
evaporation to give the desired triflate as a clear, colorless liquid (25.7 g, 96%
yield)(Note 6).
B.
n-Butyl 4-chlorophenyl
sulfide
. A 1-L,
single-necked, pear-shaped flask, equipped with a Teflon-coated
magnetic stir bar and septum, is charged with
4-chlorophenyl
trifluoromethanesulfonate (17.6 g, 67.5 mmol),
palladium acetate [Pd(OAc)2,
(0.9 g, 4.1 mmol)], and
toluene
(425 mL), (Note 7). A nitrogen
source is introduced through a 12-in., 16-gauge needle, which
is punctured through the septum and submerged into the mixture. A second 16-gauge
needle leading to a bubbler is punctured through the septum. The mixture
is stirred while vigorously purging with nitrogen for 15 min
(Note 8). The septum is opened briefly to introduce [(R)-Tol-BINAP, (3.1 g, 4.5 mmol, Note
9)], and the mixture is stirred
for 15 min with continuous purging with nitrogen, yielding a
homogenous orange solution.
A 2-L, three-necked, round-bottomed flask is equipped with
a mechanical stirrer, reflux condenser
leading to a nitrogen inlet and a septum. A Teflon-coated thermocouple
is introduced into the flask through the septum. The septum is removed and the flask
is charged with
toluene (515
mL). A second nitrogen source is introduced
into the solution through a 12-in., 16-gauge needle, and the
solution is vigorously purged with nitrogen for 5 min. To this
mixture is immediately added via syringe 0.6 M sodium
bis(trimethylsilyl)amide
in
toluene
(157.5 mL, 94.5 mmol, Note 10). While the solution is stirred vigorously,
1-butanethiol
(10.1 mL, 94.5 mmol) is added over the
course of 3 min (Note 11). A gel-like solid forms and the internal
temperature increases from 21°C to 28°C.
The solution containing the
palladium
catalyst and
4-chlorophenyl trifluoromethanesulfonate
in
toluene
is transferred
via a cannula to the mixture containing
sodium
1-butanethiolate
(Note 12). The mixture
is heated to 100°C and stirred at this temperature for 12 hr (Note 13).
The mixture is cooled to ambient temperature and transferred to a 2-L extraction
funnel. The organic phase is washed with 2 N
sodium hydroxide (125 mL), 2 N hydrochloric acid (100 mL)
and an aqueous saturated solution of
sodium chloride
(50 mL). The organic phase is dried over
sodium
sulfate
and concentrated on a rotary evaporator,
yielding a heterogeneous mixture. The mixture is triturated with hexanes
(150 mL) and stored at 0°C overnight (Note 14).
The mixture is filtered through a sintered-glass funnel, washing
with hexanes. The filtrate is concentrated on
a rotary evaporator, and the concentrate is transferred to
a 35-mL, pear-shaped flask equipped with a Teflon-coated
magnetic stir bar, a 12-cm Vigreux column and a short-path
distillation apparatus. The oil is distilled at reduced pressure (0.3
mm), discarding the fractions that boil at 55-91°C (Note 15).
The fraction boiling at 92°C is collected, to yield
n-butyl
4-chlorophenyl sulfide
as a colorless oil (11.2 g, 83%
yield) (Notes 16 and 17).
2. Notes
1.
An atmosphere of
nitrogen is maintained throughout
the course of the reaction.
4-Chlorophenol
and dichloromethane were purchased from Aldrich Chemical
Company, Inc.
, and used without further purification.
2.
Unless otherwise noted, all temperatures refer to internal temperatures
measured with Teflon-coated thermocouples.
Pyridine
was purchased from Aldrich Chemical Company, Inc.
,
and used without further purification.
3.
Triflic anhydride
was purchased from Aldrich Chemical Company, Inc.
,
and used without further purification.
4.
The course of the reaction was followed by TLC (
95:5
ethyl acetate/hexanes,
Silica
Gel 60 F254, 2.5 × 7.5 cm, 250 μ thickness, UV visualization at 254 nm),
monitoring for the disappearance of
4-chlorophenol
:
TLC: R
f
(4-chlorophenol) = 0.09, R
f
(4-chlorophenyl
trifluoromethanesulfonate) = 0.56.
5.
Silica Gel 60 (230-400 mesh) was purchased
from EM Science
.
6.
The physical properties are as follows:
1H NMR (400 MHz, CDCl
3) δ:
7.24 (m, 2 H, J = 9.0, 3.4, 2.2), 7.44 (m, 2 H, J = 8.9, 3.4, 2.1)
;
13C NMR (100
MHz, CDCl
3) δ: 118.7 (q, J = 316.8), 122.6,
130.2, 134.2, 147.8, ppm; IR (neat) cm
−1: 1208,
1139, 880
. Anal. Calcd for C
7H
4ClF
3O
3S:
C, 32.26; H, 1.55. Found: C, 32.25; H, 1.65.
7.
Pd(OAc)2 was purchased from
Strem Chemical Co.
and
toluene
was purchased from EM Science
.
8.
Most of the solids dissolve within 15 min.
9.
(R)-Tol-BINAP [(R)-(+)-2,2'-bis(di-p-tolylphosphino)-1,1'-binaphthyl]
was purchased from Strem Chemical Co.
, and used without
further purification.
10.
The
0.6 M solution of sodium
bis(trimethylsilyl)amide in toluene was purchased
from Aldrich Chemical Company, Inc.
, and used as received.
11.
1-Butanethiol
was purchased from Aldrich Chemical Company, Inc., and stored
over 4Å molecular sieves
. An excess of thiol is employed
because of the formation of the disulfide as a competing side reaction.
12.
The color of the mixture becomes bronze.
13.
The submitters followed the course of the reaction by HPLC, monitoring
for the disappearance of
4-chlorophenyl trifluoromethanesulfonate
.
HPLC conditions were as follows: 0.46 × 7.5 cm Eclipse-XDB column, gradient elution
(10:80 → 85:15 acetonitrile/10 mM pH 6.3 phosphate buffer over 8.5 min, flow
rate = 1.5 mL/min, detection = 210 nm). R
T
(4-chlorophenyl trifluoromethanesulfonate)
= 6.25 min, R
T
(n-butyl 4-chlorophenyl sulfide) =
7.10 min.
14.
Triturating the mixture with
hexanes
and storing overnight at 0°C induces the precipitation of solid
(R)-Tol-BINAP,
which is then removed by filtration.
15.
Distillation is required to remove the primary side-product,
di-n-butyl disulfide
. Purification
by silica gel chromatography gave inferior results because of similar retention times
of the two compounds. The initial distillate fractions are turbid, indicating the
presence of
di-n-butyl disulfide
.
The absence of turbidity in the higher boiling fraction indicates distillate that
is predominantly the desired
n-butyl 4-chlorophenyl
sulfide
, containing only small amounts of
n-butyl
disulfide
.
16.
The isolated oil contains
0.5
mol%
n-butyl disulfide
. Additional
n-butyl 4-chlorophenyl sulfide
remains
in the distilling flask, but is not recovered. The physical properties are as follows:
1H NMR (500 MHz,
CDCl
3) δ: 0.94 (t, 3 H, J = 7.3), 1.43-1.48 (m,
2 H), 1.59-1.65 (m, 2 H), 2.90 (t, 2 H, J = 14.6),
7.27 (br s, 4 H)
;
13C NMR (126 MHz, CDCl
3) δ: 13.6,
21.9, 31.1, 33.5, 128.9, 130.2,
131.6, 135.6
; IR
(neat) cm
−1: 1096, 810
. Anal.
Calcd for C
10H
13ClS: C, 59.84; H, 6.53. Found: C, 59.62; H,
6.76.
17.
The checkers employed
rac-BINAP purchased
from Strem Chemical Company
and used it in place of
(R)-Tol-BINAP.
2 The same procedure
was followed, except that
3 equiv of lithium chloride
was added to the complete reaction mixture immediately prior to heating to 100°C.
The reaction was run on one-half the scale used for
(R)-Tol-BINAP
and the product was obtained as before after two distillations (
5.07 g,
75%
yield). Anal. Calcd for C
10H
13ClS: C, 59.84; H, 6.53. Found:
C, 59.85; H, 6.75. The initial dissolution of
rac-BINAP
is not complete because of the lower solubility of this ligand compared with
(R)-Tol-BINAP.
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
This procedure describes the preparation of
n-butyl
4-chlorophenyl sulfide
starting from
4-chlorophenol
.
The intermediate
4-chlorophenyl trifluoromethanesulfonate
highlights the chemoselectivity of this procedure, which overwhelmingly favors coupling
at the carbon bearing the triflate functionality. As a consequence, the product contains
a handle for additional functionalization by any one of the newly developed methods
for coupling nucleophiles to aryl chlorides.
3 This
procedure also highlights a modification of the originally described protocol, in
which
sodium tert-butoxide
had been employed as the base.
2 Since the submitters'
initial disclosure, they have discovered that the use of
sodium
bis(trimethylsilyl)amide
decreases the amount of
phenol
by-product formed during the course of the reaction. In head-to-head experiments with
sodium tert-butoxide
versus
bis(trimethylsilyl)amide
,
greater amounts of
phenol
were observed with the former base. This recent development allows the use of higher
reaction temperatures and shorter reaction times if desired. The same yield of
n-butyl 4-chlorophenyl sulfide
was
obtained when the reaction was conducted at 80°C, but a longer reaction time was required.
Furthermore, the commercially available solutions of
bis(trimethylsilyl)amide
in
toluene
can be used directly,
obviating the usual difficulties encountered with handling hygroscopic solids.
The preparations of aryl sulfides typically employ aryl halides as starting materials.
4
The procedure described here makes use of the ubiquitous class of commercially available
phenolic compounds in the form of aryl triflates, which expands the range of readily
accessible aryl sulfides. Prior to this disclosure, the use of aryl triflates in a
palladium-catalyzed process for the formation of aryl alkyl sulfides
was unprecedented.
5 This procedure appears
to be general with regard to electronically neutral or electron-deficient aryl triflates
(Table 1). The yields in Table I correspond to the initially disclosed procedure employing
sodium tert-butoxide
as the base. Lower yields were obtained with the 4-nitro-substituted triflate, and
in the case of the electronically enriched substrate containing a 4-methoxy group.
Table 1
Appendix
Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)
4-Chlorophenyl trifluoromethanesulfonate:
Methanesulfonic
acid, trifluoro-, p-chlorophenyl ester (8);
Methanesulfonic acid,
trifluoro-, 4-chlorophenyl ester (9); (29540-84-9)
4-Chlorophenol: TOXIC:
Phenol, p-chloro-
(8);
Phenol, 4-chloro- (9); (106-48-9)
Pyridine (8, 9); (110-86-1)
Triflic anhydride:
Methanesulfonic acid,
trifluoro-, anhydride (8, 9); (358-23-6)
Palladium acetate:
Acetic acid, palladium(2+)
salt (8, 9); (3375-31-3)
(R)-(+)-2,2'-Bis(di-p-tolylphosphino)-1,1'-binaphthyl:
STREM CHEMICALS: (R)-Tol-BINAP:
Phosphine, [1,1'-binaphthalene]-2,2'-diylbis[bis(4-methylphenyl)-,
(R)- (11); (99646-28-3)
Sodium bis(trimethylsilyl)amide:
Disilazane,
1,1,1,3,3,3-hexamethyl-, sodium salt (8);
Silanamine, 1,1,1-trimethyl-N-(trimethylsilyl)-,
sodium salt (9); (1070-89-9)
1-Butanethiol (8, 9); (109-79-5)
rac-2,2'-Bis(diphenylphosphino)-1,1'-binaphthyl:
rac-BINAP:
Phosphine, [1,1'-binaphthalene]-2,2'-diylbis[diphenyl]-
(11); (98327-87-8)
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