One-Step Conversion of Methyl Ketones to Acyl Chlorides

Article abstract of DOI:10.1021/acs.joc.5b01707

Treatment of aromatic and heteroaromatic methyl ketones with sulfur monochloride and catalytic amounts of pyridine in refluxing chlorobenzene leads to the formation of acyl chlorides. Both electron-rich and electron-poor aryl methyl ketones can be used as starting materials. The resulting C₁-byproduct depends on the precise reaction conditions chosen.

Full text of DOI:10.1021/acs.joc.5b01707

Note
pubs.acs.org/joc
One-Step Conversion of Methyl Ketones to Acyl Chlorides
Florencio Zaragoza*
Lonza AG, Rottenstrasse 6, CH-3930 Visp, Switzerland
S
* Supporting Information
ABSTRACT: Treatment of aromatic and heteroaromatic methyl
ketones with sulfur monochloride and catalytic amounts of pyridine
in refluxing chlorobenzene leads to the formation of acyl chlorides. Both
electron-rich and electron-poor aryl methyl ketones can be used as
starting materials. The resulting C1-byproduct depends on the precise
reaction conditions chosen.
he direct chlorocarbonylation of arenes or heteroarenes
hypochlorous acid and chlorine during acidification of aqueous
Twith phosgene hardly ever gives high yields of aroyl hypochlorite, which can cause the formation of chlorinated
byproducts,8 and the large number of manipulations, all of
chlorides, giving symmetric ketones instead. Therefore, a
which make this strategy costly and inefficient.
number of alternative reagents have been identified (chloro-
sulfonyl isocyanate,1 other sulfonyl isocyanates,2 other iso-
cyanates,3 carbamyl chlorides,4 carbamates,5 and ureas6) that
enable the conversion of arenes to arenecarboxylic acid amides.
The latter, however, must be hydrolyzed to carboxylic acids to
be converted to acyl chlorides. Only oxalyl chloride enables
direct one-step chlorocarbonylation of arenes,7 but unfortu-
nately, it is rather expensive (Scheme 1).
The use of methyl ketones 2 as intermediates could,
however, become economically attractive if a low-cost, one-
step conversion of methyl ketones to acyl chlorides were to
become available. To my knowledge, no high-yield, one-step
conversion of methyl ketones to acyl chlorides has been
reported to date. Some results in the literature suggested,
however, that such a reaction may be possible. For instance,
treatment of acetophenone or pinacolone with ten equiv of
thionyl chloride in the presence of a catalytic amount of
pyridine, followed by distillation, gave low yields of the
corresponding acyl chlorides (Scheme 2).9,10
Scheme 1. Strategies for the Preparation of Aroyl Chlorides
3 from Arenes 1
Reaction of Aromatic Methyl Ketones with Thionyl
Chloride. The yield of the reaction in Scheme 2 could be
improved by treating methyl ketones 2 with 4−6 equiv of
thionyl chloride first at 60−75 °C for some hours, and then at
140 °C for 15−20 h, while allowing volatiles to evaporate off
(Scheme 3). The only C1-byproduct we were able to detect (by
GC-MS and 13C NMR) was trichloromethanesulfenyl chloride.
Analysis of the reaction mixture by 1H and 13C NMR
suggested that intermediate 4a was not a precursor of benzoyl
chloride but had to be oxidized further to intermediates 6a.
Variable amounts of trichloromethyl ketones were also formed
and were the most unreactive intermediates 6a. These
trichloromethyl ketones, however, were also converted to
aroyl chlorides if enough thionyl chloride had been used and if
the reaction at 140 °C was allowed to proceed for enough time.
Because we were unable to convert isolated, aromatic
trichloromethyl ketones into aroyl chlorides with a variety of
reagents, I assume that this conversion was mediated by some
decomposition product of thionyl chloride.
The protocol with thionyl chloride had several disadvantages.
If less than 4−6 equiv of thionyl chloride was used, the reaction
mixture solidified and only low yields of acyl chlorides resulted.
If solvents were used (e.g., chlorobenzene), the reaction slowed
Another strategy for the conversion of arenes or heteroarenes
1 to aroyl chlorides 3 is Friedel−Crafts acetylation followed by
haloform reaction to obtain the carboxylic acids and, finally,
treatment with thionyl chloride (last equation, Scheme 1).
Disadvantages of this multistep methodology are the high
dilution of the haloform reaction, the formation of
Received: July 23, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.5b01707
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Scheme 2. Reaction of Acetophenone with Thionyl Chloride9,10
When aromatic methyl ketones were treated with S2Cl2
under conditions similar to those used with SOCl2, clean
formation of acyl chlorides was observed (Scheme 4).
Scheme 3. Optimized Reaction Conditions for the
Conversion of Acetophenone to Benzoyl Chloride with
Thionyl Chloride*
Scheme 4. Reaction of 2-Acetylthiophene with Sulfur
Monochloride*
*
1
*
Yield determined by H NMR of crude product mixture with an
1
Yield determined by H NMR of the crude product mixture with an
internal standard.
internal standard.
When compared to the reactions with thionyl chloride, sulfur
monochloride provided higher yields of acyl chlorides,
especially in the case of electron-rich methyl ketones. Under
optimal conditions, the amount of trichloromethyl ketones
remained below 10%. The darkening of the reaction mixture
was less intense than with thionyl chloride, and the scope of
suitable starting materials was broader. Thus, acetophenones
substituted with methoxy, fluorine, trifluoromethyl, nitro, or
phenyl groups, and even 2-acetylfuran, yielded the expected
acyl chlorides under the conditions given in Scheme 4.
Analysis of the volatile components formed during the
reaction of methyl ketones with S2Cl2 revealed that large
amounts of carbon disulfide (CS2) were being formed as C1-
byproduct. Because of the high flammability of CS2, such a
reaction was deemed too dangerous for large scale preparations.
To minimize this problem, a new protocol was developed in
which sulfuryl chloride was added to the reaction mixture after
the initial reaction of the ketone with S2Cl2 in order to
chlorinate any precursor of CS2 or any CS2 to Cl3CSCl, S2Cl2,
or CCl4.13
Reaction of Aromatic Methyl Ketones with Sulfur
Monochloride and Sulfuryl Chloride. Addition of sulfuryl
chloride (or thionyl chloride) to the reaction mixture after the
initial step of the reaction of methyl ketones with S2Cl2 had
occurred provided for a cleaner reaction and enabled the use of
chlorobenzene as solvent (Scheme 5, Table 1). The use of a
solvent was beneficial because the reactions without solvent
(Scheme 4) often became viscous and difficult to stir,
particularly if only three equiv of S2Cl2 had been used.
dramatically, and no complete conversion to the acyl chlorides
could be attained. With electron-rich methyl ketones (e.g., 2-
acetylthiophene), large amounts of dark, insoluble material
were formed, and the yields of the crude electron-rich aroyl
chlorides never exceeded 70%. Moreover, the desired aroyl
chlorides were often contaminated with substantial amounts of
trichloromethyl ketones, and it was unclear which parameters of
the reaction were causing their formation. When the first step
in Scheme 3 was run at lower temperatures with a large excess
of thionyl chloride, the amount of trichloromethyl ketones
decreased. Such a protocol, however, was too expensive because
of the high dilution and large excess of thionyl chloride. For
these reasons, an alternative to the thionyl chloride method was
sought.
Reaction of Aromatic Methyl Ketones with Sulfur
Monochloride. Adiwidjaja et al. had mentioned10 that “yellow,
commercial thionyl chloride” was better suited for reactions
with ketones than freshly distilled thionyl chloride. One of the
known decomposition products of thionyl chloride is sulfur
monochloride11 (S2Cl2, bp 137 °C). It was also known that less
highly oxidized sulfur chlorides (e.g., sulfenyl chlorides, RSCl)
are stronger sulfenylating and weaker chlorinating reagents than
more strongly oxidized sulfur chlorides (e.g., thionyl chloride or
sulfuryl chloride). Because one problem of the thionyl chloride
reaction was the formation of trichloromethyl ketones, it was
decided that the reaction of sulfur monochloride with ketones
should be investigated with the hope that perchlorination of the
ketone would be less extensive with this reagent.12
B
DOI: 10.1021/acs.joc.5b01707
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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.
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DOI: 10.1021/acs.joc.5b01707
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The Journal of Organic Chemistry
Note
Scheme 6. Possible Mechanism of the Formation of Acyl Chlorides 3 from Methyl Ketones 2, Sulfur Monochloride, and Sulfuryl
Chloride
General Procedure for the Synthesis of Acyl Chlorides 3
from Methyl Ketones 2 with Sulfur Monochloride and Sulfuryl
Chloride. To sulfur monochloride (1.6 mL, 20 mmol) at room
temperature was added 1/5th of a solution of methyl ketone 2 (10.0
mmol) and pyridine (0.121 mL, 1.50 mmol) in chlorobenzene (3.5
mL or the minimal amount required to dissolve the ketone upon slight
heating). The mixture was heated for 5−20 min to ∼80 °C until steady
HCl evolution set in. The mixture was then cooled to room
temperature with a water bath, and the remainder of the ketone
solution was added to the stirred reaction mixture at such a rate that
HCl formation did not become too violent (usually 15−30 min). The
mixture was stirred at room temperature for 2−6 h. Sulfuryl chloride
(1.21 mL, 15.0 mmol) was then added dropwise within 20 min (strong
gas evolution, no strong exotherm). The resulting mixture was stirred
at room temperature for 0.5 h and then at slight reflux (oil bath: 137
°C) for 15−20 h.
Chlorobenzene and sulfur chloride were evaporated (40 mbar, 120
°C), and the residue was diluted with hexane (50 mL). The mixture
was stirred at room temperature, whereupon a clear solution and a
dark, oily precipitate resulted. The solution was decanted off the dark
oil or filtered, the flask was rinsed with hexane (5 mL), and the
combined hexane phases were allowed to crystallize at 5 to −30 °C.
Inverse filtration, washing with cold hexane, and drying under reduced
pressure yielded the acyl chlorides (3). Repeated recrystallization or
distillation was often required to remove residual sulfur, sulfur
chlorides, and Cl3CSCl.
8.40−8.36 (m, 2H), 8.34−8.30 (m, 2H); 13C NMR (CDCl3, 100
MHz) δ 167.0, 151.6, 138.0, 132.2, 124.0.
Naphthalene-2-carbonyl Chloride (3e, CAS Registry 2243-83-6).
Following the general procedure on a 15 mmol scale, using 5 mL of
chlorobenzene yielded, after a single crystallization from hexane (70
mL) at −30 °C, 2.17 g (69% yield) of the product with a purity of
90%; 1H NMR (CDCl3, 400 MHz) δ 8.68 (s, 1H), 8.00 (dd, J = 8 Hz,
1 Hz, 1H), 7.95 (d, J = 8 Hz, 1H), 7.86 (m, 2H), 7.65 (m, 1H), 7.57
(m, 1H); 13C NMR (CDCl3, 100 MHz) δ 168.4, 136.4, 134.8, 132.3,
130.4, 130.0, 129.9, 128.8, 127.9, 127.4, 125.3.
4-Methoxybenzoyl Chloride (3f, CAS Registry 100-07-2). Follow-
ing the general procedure on a 20 mmol scale, using 7 mL of
chlorobenzene yielded, after a single crystallization from hexane (30
mL) at −30 °C, 2.42 g (63% yield) of the product with a purity of
89%; 1H NMR (CDCl3, 400 MHz) δ 8.07 (d, J = 8 Hz, 2H), 6.96 (d,
J = 8 Hz, 2H), 3.90 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 167.1,
165.4, 134.0, 125.5, 114.3, 55.8.
3,4-Dimethoxybenzoyl Chloride (3g, CAS Registry 3535-37-3).
Following the general procedure on a 15 mmol scale, using 5 mL of
chlorobenzene yielded, after a single crystallization from hexane (60
mL) at −30 °C, 1.52 g (47% yield) of the product with a purity of
1
92%; H NMR (CDCl3, 400 MHz) δ 7.83 (dd, J = 8 Hz, 1 Hz, 1H),
7.53 (d, J = 1 Hz, 1H), 6.94 (d, J = 8 Hz, 1H), 3.98 (s, 3H), 3.94 (s,
3H); 13C NMR (CDCl3, 100 MHz) δ 167.2, 155.2, 149.0, 127.2,
125.5, 112.8, 110.4, 56.3, 56.1.
4-Phenylbenzoyl Chloride (3c, CAS Registry 14002-51-8).
Following the general procedure, using 10 mL of chlorobenzene
yielded the product in two crops (1.59 g, purity: 96%, yield: 70%; and
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.5b01707.
1
0.32 g, purity: 92%, yield: 13%; total yield: 83%); H NMR (CDCl3,
400 MHz) δ 8.17 (m, 2H), 7.71 (m, 2H), 7.62 (m, 2H), 7.50−7.40
(m, 3H); 13C NMR (CDCl3, 100 MHz) δ 168.1, 148.1, 139.1, 132.1,
131.9, 129.1, 128.9, 127.5, 127.4.
1
Copies of H and 13C NMR spectra of the isolated acyl
chlorides 3c−3g (PDF)
4-Nitrobenzoyl Chloride (3d, CAS Registry 122-04-3). Following
the general procedure, using 5 mL of chlorobenzene, 1.20 mL (15
mmol) of S2Cl2, and 1.62 mL (2.0 mmol) SO2Cl2 yielded the product
in two crops (882 mg, purity 93%, yield: 44%; and 545 mg, purity:
AUTHOR INFORMATION
Corresponding Author
*E-mail: florencio.zaragoza@lonza.com.
■
1
91%, yield: 27%; total yield: 71%); H NMR (CDCl3, 400 MHz) δ
D
DOI: 10.1021/acs.joc.5b01707
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Notes
The authors declare no competing financial interest.
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DOI: 10.1021/acs.joc.5b01707
J. Org. Chem. XXXX, XXX, XXX−XXX