The Journal of Organic Chemistry
Note
As reported,14 the reaction of C−H acidic compounds with
sulfur chlorides can lead to thiolation or chlorination at carbon.
It is also known15 that (chloroacetyl)arenes react with sulfur to
yield α-oxodithiocarboxylic acids 8. The formation of carbon
disulfide as a C1-byproduct indicates that α-oxodithiocarboxylic
acids 8 could indeed be intermediates of the present reaction.
Because chloride is a poor nucleophile and almost no
chlorine-mediated C−C bond cleaving reactions are known, an
intramolecular transfer of chloride to the carbonyl C atom
seems likely. The precursor of the acyl chloride could be an S-
chloro α-oxodithiocarboxylate 9, or compounds such as
ArCOC(=S)(S)nCl, but this remains to be proven.
Scheme 5. Optimized Conversion of Methyl Ketones into
Acyl Chlorides with S2Cl2/SO2Cl2
Table 1. Yields of Crude and Isolated Acyl Chlorides 3
Obtained with S2Cl2 Alone or with S2Cl2/SO2Cl2
Sulfuryl chloride appears to facilitate the formation of acyl
chlorides (Scheme 5). This may be caused by further activation
of the S-chloro α-oxodithiocarboxylate 9, by chlorination for
instance, to yield compounds such as 10. Thioketones, for
instance, undergo facile chlorination to yield α-chlorosulfenyl
chlorides.16
S2Cl2 and
a
b
S2Cl2 alone
SO2Cl2
If the mechanism in Scheme 6 is correct, sulfuryl chloride
should be replacable by chlorine, which would reduce the
amount of waste generated by this process and its overall costs
even further. For laboratory preparations, however, sulfuryl
chloride is easier to dose and handle than chlorine.
equiv
S2Cl2
ArAc
Ar
crude
82%
crude isolated
2a
phenyl
4.0
4.0
3.5
3.5
3.5
3.0
4.0
3.5
3.0
87%
90%
90%
90%
91%
86%
77%
65%
80%
c
2b 2-thienyl
2c 4-biphenylyl
2d 4-nitrophenyl
86%
c
d
83% (68%)
83%
83%
71%
69%
63%
47%
e
2e
2f
2-naphthyl
82%
EXPERIMENTAL SECTION
■
4-methoxyphenyl
3,4-dimethoxyphenyl
91%
Chemical shifts (δ) in NMR spectra are reported in ppm relative to
Me4Si (δ = 0.00 ppm). All reagents and starting materials were
commercially available and used without further purification. Reactions
on a 1−2 mmol scale were performed by mixing all reagents and
starting materials at once, followed by heating. Addition of an internal
standard (iBu3PO4), dilution with CDCl3, filtration, and analysis by 1H
NMR gave an estimate of the yield and purity of the acyl chlorides
(Table 1). Larger scale reactions had to be conducted in a dosage-
controlled manner to prevent thermal runaway. In the present case,
the most convenient procedure was to add 1/10th to 1/5th of a
solution of the starting ketone and the catalyst (pyridine or 3-picoline)
in a minimal amount of chlorobenzene to sulfur monochloride and
heat the mixture until HCl evolution started. The remainder of the
ketone solution was then added at room temperature to the cooled
reaction mixture at such a rate that the reaction remained controllable.
Addition funnels tended to get clogged because the evolving HCl
caused pyridine hydrochloride to precipitate from the ketone solution.
All products were known, commerically available compounds and
identified by comparison of their 1H and 13C spectra with the reported
spectra. Because the typical impurities (S8, S6, Cl3CSCl, S2Cl2) were
difficult to detect and quantify, the purity of the products was
determined by 1H NMR weight % determination with an internal
standard (triisobutyl phosphate).
2g
79%
2h 2-furyl
2i 5-chloro-2-thienyl
44%
68%
a
The ketone was mixed with S2Cl2 and pyridine (0.15 equiv) and
b
stirred first at 75 °C for 2.5 h and then at 137 °C for 19 h. The
ketone, pyridine (0.15 equiv), chlorobenzene, and S2Cl2 (2.0 equiv)
were stirred at 20 °C for 2−6 h. Then, SO2Cl2 (1.5 equiv) was added,
and the mixture was stirred at 20 °C for 0.5 h and then at 132 °C for
c
15−20 h. The purity of the distilled products (20 cm Vigreux column,
d
e
100 mmol scale) was 70−80%. Isolated yield in parentheses. S2Cl2
(1.5 equiv) and SO2Cl2 (2.0 equiv) were used.
When the amount of product was determined by 1H NMR of
the reaction mixture with an internal standard, yields were
generally 80−90%, and no starting material or intermediates
could be detected. Purification of the acyl chlorides was best
accomplished by evaporation of the solvent, dilution of the
residue with hexane, decantation, and crystallization at low
temperature or careful distillation. Complete removal of sulfur
and sulfur chlorides, however, proved difficult. Most solvents
suitable for recrystallizing acyl chlorides also dissolve sulfur and
its chlorides, and a single recrystallization was rarely enough to
obtain products with >90% purities.
When applying the conditions of Scheme 5 to 4-nitro-
acetophenone 2d, partial (<5%) reduction of the nitro group
occurred. This could be prevented by using 1.5 equiv of S2Cl2
and 2.0 equiv of SO2Cl2.
Because of their high reactivity, acyl chlorides are usually not
purified but rather are used as crude products directly after their
preparation. After evaporation of chlorobenzene and sulfur
monochloride, the main nonvolatile byproduct of the current
preparation is sulfur, which should not interfere in most
reactions of acyl chlorides.
Typical Procedure for the Synthesis of Acyl Chlorides 3
from Methyl Ketones 2 with Sulfur Monochloride Alone: 4-
Phenylbenzoyl Chloride. To sulfur monochloride (4.80 mL, 60.0
mmol) at room temperature were added 4-phenylacetophenone (716
mg, 3.31 mmol) and pyridine (0.081 mL, 1.00 mmol), and the mixture
was heated to 80−90 °C for approximately 10 min, when strong HCl
formation set in. The mixture was cooled to room temperature with a
water bath, and the remainder of 4-phenylacetophenone (total: 3.85 g,
19.6 mmol) and pyridine (total: 0.32 mL, 4.0 mmol) was added in
three portions within 20 min. The mixture became increasingly viscous
and difficult to stir. After 1 h at room temperature, the mixture was
heated to 140 °C (oil bath temperature) and stirred at this
temperature for 16 h. The mixture was allowed to cool, and the
product was extracted two times by adding hexane (50 mL), heating to
reflux, and decanting. The combined hexane phases were kept at −30
°C for 3 h and decanted, and the solid was recrystallized once more
from hexane (150 mL). 4-Phenylbenzoyl chloride (3.06 g, 95% pure,
yield: 68%) was obtained as yellow needles.
Although no detailed mechanistic studies of this new reaction
have been performed, various results from the literature and my
own observations point toward a mechanism as sketched in
Scheme 6.
C
J. Org. Chem. XXXX, XXX, XXX−XXX