Ferric(III) Chloride Catalyzed Halogenation Reaction of Alcohols and Carboxylic Acids Using α,α-Dichlorodiphenylmethane

Article abstract of DOI:10.1021/acs.orglett.8b00831

A new method for chlorination of alcohols and carboxylic acids, using α,α-dichlorodiphenylmethane as the chlorinating agent and FeCl₃ as the catalyst, was developed. The method enables conversions of various alcohols and carboxylic acids to their corresponding alkyl and acyl chlorides in high yields under mild conditions. Particulary interesting is the observation that the respective alkyl bromides and iodides can be generated from alcohols when either LiBr or LiI are present in the reaction mixtures.

Full text of DOI:10.1021/acs.orglett.8b00831

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Ferric(III) Chloride Catalyzed Halogenation Reaction of Alcohols and
Carboxylic Acids Using α,α-Dichlorodiphenylmethane
Chang-Hee Lee,† Soo-Min Lee, Byul-Hana Min, Dong-Su Kim, and Chul-Ho Jun*
,§
†,§
†
‡
,†
†
Department of Chemistry, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea
‡
New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, Republic of Korea
S Supporting Information
*
ABSTRACT: A new method for chlorination of alcohols and
carboxylic acids, using α,α-dichlorodiphenylmethane as the chlori-
nating agent and FeCl as the catalyst, was developed. The method
3
enables conversions of various alcohols and carboxylic acids to their
corresponding alkyl and acyl chlorides in high yields under mild
conditions. Particulary interesting is the observation that the
respective alkyl bromides and iodides can be generated from alcohols when either LiBr or LiI are present in the reaction mixtures.
alogenation of alcohols and carboxylic acids is an
giving (1-chloroethyl)benzene (4a), were performed at room
H
important and ubiquitous reaction in synthetic organic
temperature using various Lewis acid catalysts and solvents
1
chemistry. Conventional halogenating agents, such as hydrogen
(
Table 1). The results show that the reaction carried out in the
2
3
4
chloride, thionyl chloride/DMF, carbon tetrahalide/PPh3
5
presence of a catalytic amount of ferric chloride (3a, 3 mol %
based on 1a) produces 4a in a 99% yield (entry 1). Other Lewis
(Appel reaction), and phosphorus halides, have been widely
employed for this purpose. However, these methods often
require the use of toxic reagents or harsh conditions. Among
these processes, the Appel reaction is the most utilized method
for halogenation, owing to its simplicity, mild conditions, and
high stereoselectivity. However, this reaction not only forms
triphenylphosphine oxide, a byproduct that is difficult to remove,
Table 1. Chlorination of Alcohol 1a with Chlorinating Agent 2
a
Using Lewis Acids 3 and Various Solvents
but it also uses the toxic halogen source CCl . Therefore,
4
investigations searching for new halogenation agents have been
conducted in order to develop reactions that efficiently produce
alkyl and acyl halides under mild and environmentally friendly
6
conditions.
In 2009, a novel method for chlorination of alcohols using
dearomatization/rearomatization of 3,3-dichloro-1,2-diphenyl-
cyclopropene as the chlorine source was described by Lambert
7
and co-workers. This novel aromatic activation/halogenation
system enables chlorination reactions of alcohols to be
conducted in a highly selective manner with good functional
group tolerance. Based on the Lambert concept, other
halogenating agents, such as 1,1-dichlorocycloheptatriene and
dihaloimidazolidinedione, have been also explored by the
8
Nguyen and Bielawski groups, respectively. However, these
processes add an additional step to the process, which is required
for preparation of the unstable halogenation agents.
In the study described below, we developed the new, stable
9
chlorinating agent, α,α-dichlorodiphenylmethane, which is
a
activated by the Lewis acid FeCl , for transforming alcohols
Unless otherwise noted, reactions were carried out with 1a (0.2
3
mmol), 2 (0.24 mmol), and 3 (0.006 mmol) in 0.1 mL of solvent at
room temperature. Yield of 4a was determined by using GC-MS
analysis with hexadecane as the internal standard.
and carboxylic acids to the corresponding alkyl and acyl
chlorides. Moreover, the addition of lithium bromide or iodide
to the reaction mixture containing an alcohol enables the process
to be utilized to generate respective alkyl bromides or iodides.
In initial exploratory studies, chlorination reactions of 1-
phenylethanol (1a) with α,α-dichlorodiphenylmethane (2a),
b
Received: March 14, 2018
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00831
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
acids, including Fe (SO ) (3b, 86%), NiBr (3c, 16%), MnCl
2
common aliphatic alcohol, octanol (4l), forms the desired octyl
chloride (4l) in 86% yield (entry 11). The reaction of aliphatic
alcohols containing carbonyl or olefinic functional group, 1m,n,
was found to produce the respective chlorinated products, 4m
and 4n, in moderate yields (entries 12 and 13). It can be
explained by the functional groups in 1m and 1n slightly
deactivating the activity of the catalyst.
2
4 3
2
(
3d, 31%), BF (OEt) (3e, 23%), and AlCl (3f, 39%) display
3 2 3
reactivities lower than that of 3a (entries 2−6) and in the absence
of Lewis acids, 4a is formed in only 13% yield (entry 7). The
reactivities of other potential chlorinating agents were also
explored (entries 8−10). We observed that chlorination of 1a
using α,α-dichlorophenylmethane (2b) forms 4a in 13% yield
(
entry 8), and that no reaction takes place when α,α,α-
It is also possible to use this halogenation system to carry out
bromination and iodination reactions of alcohols (Table 3). For
trichlorophenylmethane (2c) and 2,2-dichloropropane (2d)
are employed as chlorinating agents (entries 9 and 10). Finally,
among the various solvents tested, CHCl was found to be ideal
for this reaction (entries 1 and 11−13).
Table 3. FeCl -Catalyzed Halogenation of Benzyl Alcohol
Using α,α-Dichlorodiphenylmethane with LiBr and LiI
3
3
The alcohol substrate scope of the chlorination reaction was
investigated using 2a, 3a, and the optimized reaction conditions
described above. Reactions of benzyl alcohols 1b−e, regardless of
whether they contain electron-donating or electron-withdrawing
arene ring substituents, were found to produce the respective
chlorinated products 4b−e in modestly high yields (Table 2,
Table 2. FeCl -Catalyzed Chlorination of Various Alcohols
3
a
Using 2a
a
Unless otherwise noted, reactions were carried out with 1 (0.2
mmol), 2a (0.24 mmol), 3a (0.006 mmol), and 5 (0.8 mmol) in 0.1
b
mL of CHCl at room temperature. Yields of 4 were determined by
3
using GC-MS analysis, and hexadecane was used as the internal
standard.
example, reaction of benzyl alcohol (1b) with 2a and 3a in the
presence of LiBr (5a) produces benzyl bromide (4o) in 98%
yield. In this process, α,α-dibromodiphenylmethane (6a) likely
serves as the actual bromination agent, a proposal that is
supported by the observation that addition of LiBr (5a) to a
CDCl3 solution of 2a generates 6a (see the Supporting
Information (SI)). Furthermore, addition of 1b to a mixture of
6
a in CDCl produces 4o in 98% yield (Scheme 1). When LiI
3
Scheme 1. Mechanistic Investigation of Bromination of
Alcohol Using 2a with LiBr
a
Unless otherwise noted, reactions were carried out with 1 (0.2
(5b) is present in the reaction mixture containing 2a and 3a,
benzyl iodide (4p) is formed in 97% yield (Table 3, entry 2).
Finally, reactions of octanol 1l were also found to produce the
respective halogenated products, 4q,r, in good yields (Table 3,
entries 3 and 4).
mmol), 2a (0.24 mmol), and 3a (0.006 mmol) in 0.1 mL of solvent at
room temperature. Yield of 4 was determined by GC-MS analysis,
and hexadecane was used as an internal standard. The reaction was
carried out for 6 h. 3% of (2-methylallyl)benzene and 3% of (2-
b
c
d
methylprop-1-en-1-yl)benzene were formed.
Several chiral secondary alcohols were employed to gain
mechanistic insight into the new halogenation reaction (Scheme
2). As expected, reaction of racemic octan-2-ol (rac-1o),
performed under standard reaction conditions, leads to
formation of a racemic mixture of 2-chlorooctane (rac-4s)
(Scheme 2a). Each enantiomer was identified by using gas
chromatography equipped with a chiral column (see the SI). In
contrast, under the same conditions, (S)-octan-2-ol ((S)-1o) and
(R)-octan-2-ol ((R)-1o) individually react to generate (R)-2-
chlorooctane ((R)-4s) and (S)-2-chloro-octane ((S)-4s) in 99%
ee, respectively, through processes that occur with inversion
stereochemistry at the stereogenic centers (Scheme 2b,c).
However, reaction of (R)-1-phenylethanol ((R)-1p) takes
entries 1−4). However, reaction of phenol (1f) does not take
place under these conditions (entry 5). Heterocyclic alcohols
such as furan-2-ylmethanol (1g) and thiophen-2-ylmethanol
(1h) display reactivities lower than that of benzyl alcohol (1b),
which is likely the result of binding of the Lewis acid FeCl to
3
oxygen or sulfur heteroatoms in these substances (entries 6 and
7
). Moreover, we observed that reactions of aliphatic primary
(1i), secondary (1j), and tertiary (1k) alcohols occur to generate
the corresponding chlorides 4i−k in 92, 78, and 94% respective
yields (entries 8−10). The results suggest that steric hindrance
does not affect this chlorination reaction. The reaction of the
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a
Scheme 2. Mechanistic Investigation of the Chlorination
Reaction
Table 4. Chlorination of Various Carboxylic Acids Using 2a
a
The reactions were carried out with 10 (2 mmol), 2a (2.4 mmol),
b
and 3a (0.06 mmol) in 1.0 mL of CHCl at room temperature. Yield
3
of 11 was determined by GC-MS analysis, and hexadecane was used as
an internal standard.
lower reactivities of these substrates are likely a consequence of
the lower nucleophilicities of carboxylic acid containing electron-
withdrawing substituents that retard their reactions with 2a to
form 12a (Scheme 4).
place to give a racemic mixture of the chlorination product rac-4a
in 99% yield (Scheme 2d).
Scheme 4. Proposed Mechanism of Chlorination of
Carboxylic Acids
These results indicate that chlorination reactions of aliphatic
secondary alcohols take place by an S 2 pathway, whereas an S 1
N
N
pathway is followed in the cases of benzylic alcohols. Thus, it
appears that two closely related mechanisms are responsible for
this chlorination process, both being initiated by nucleophilic
substitution of the alcohol (e.g., (R)-1p) with 2a to generate
intermediate α-chloroether 7a, along with HCl. This step is
followed by reaction of 7a with FeCl to produce the oxonium
3
−
intermediate 8a, along with FeCl . The pathway then diverges
4
depending on the nature of the starting alcohol. Specifically, in
the case of benzylic alcohols, 8a readily loses benzophenone to
form a stable benzylic carbocation 9a that reacts with FeCl4 to
The process can also be utilized for the one-pot synthesis of
amides and esters from carboxylic acids. Specifically, reactions of
carboxylic acids 10 with 2a (1.2 equiv) at room temperature in
CHCl containing FeCl (3a, 5 mol %) followed by addition of
an amine or alcohol in the presence of triethylamine generate the
corresponding amides or esters 13 (Table 5). For example, N-
benzylbenzamide (13a) can be prepared in this manner in 92%
isolated yield starting with benzoic acid (10a), 2a, 3a, and benzyl
amine (entry 1). Reactions of benzoic acid derivatives possessing
electron-donating and electron-withdrawing substituents, such
as methyl (10b), fluoro (10c), trifluoromethyl (10d), and cyano
−
produce the catalyst FeCl and chlorination product 4a as a
3
3
3
racemate (Scheme 3a). In the case of secondary aliphatic
Scheme 3. Proposed Mechanism of Chlorination of Alcohols
(
10e), produce the corresponding amides (13b−e) in good to
moderate yields (entries 2−5). Reaction of naphthalenecarbox-
ylic acid and benzyl amine under these conditions occurs to form
N-benzyl-2-naphthamide (13f) in 83% yield (entry 6). Aliphatic
carboxylic acids such as cyclohexanecarboxylic (10g) and
octanoic (10h), 2-methylhexanoic (10i), and 2,2,2-trimethyle-
thanoic acid (10j) also serve as viable substrates for this process
(
entries 7−10). Finally, reactions of benzoic acid (10a) with α,α-
dichlorodiphenylmethane (2a) in the presence of 3a followed by
addition of nucleophiles such as cyclohexylamine and 1-heptanol
lead to formation of the corresponding products, N-cyclo-
hexylbenzamide (13k) and heptyl benzoate (13l) in 86 and 80%
yields, respectively (entries 11 and 12).
−
alcohols, S 2 reaction between 8b and FeCl4 takes place to form
N
the corresponding nonracemic alkyl chloride (S)-4s together
with FeCl and benzophenone (Scheme 3b).
In the next phase of this effort, we extended the scope of the
chlorination process to carboxylic acids (Table 4). We found that
reaction of benzoic acid (10a) with 2a at room temperature in
CHCl containing FeCl (3a) forms benzoyl chloride (11a) in
3
4
-(Hydroxymethyl)benzoic acid (1q) is a potentially interest-
ing substrate for the chlorination reaction because it contains
both a carboxylic acid and benzylic alcohol moiety (eq 1). We
3
3
9
5% yield (entry 1). The benzoic acid derivative 10b possessing a
p-methyl electron-donating group also displays similar reactivity
to form the corresponding acid chloride (entry 2). However, in
the cases of benzoic acids 10c,d, which possess p-electron-
withdrawing substituents (F, CF ), the yields of the respective
3
products 11c,d are lower (78 and 57%) (entries 3 and 4). The
C
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Table 5. FeCl -Catalyzed Halogenation Reactions of
Carboxylic Acids To Produce Amides
ORCID
3
a
Dong-Su Kim: 0000-0003-0388-4633
Chul-Ho Jun: 0000-0002-5578-2228
Author Contributions
§
C.-H.L. and S.-M.L. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by a grant from the National Research
Foundation of Korea (NRF) (Grant 2016-R-1-A2b4009460).
■
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observed that reaction of 1q with 2a in the presence of 3a under
the standard reaction conditions generates the chloromethyl-
10
substituted benzoic acid derivative 4t in 88% isolated yield.
(
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reactive with 2a than is the carbxylic acid group.
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simple, mild, and efficient method for halogenation of alcohols
and carboxylic acid. The process utilizes commercially available
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1
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FeCl as the catalyst. In addition, the conditions used for this
3
(9) α,α-Dichlorodiphenylmethane (2a) is a colorless and odorless oil.
process avoid the use of toxic starting materials and the formation
of stoichiometric amounts of oxidized phosphine and noxious
byproducts.
Because this compound is generally stable but reacts with water to
generate HCl, be sure to handle with care.
(10) The reaction of 1q (2 mmol) with 2a (3 equiv) was carried out in
the presence of 3a (5 mol %) for 3 h to produce 4-(chloromethyl)
benzoyl chloride in 73% GC yield.
ASSOCIATED CONTENT
■
*
S
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b00831.
Compound characterization data, H and 13C NMR
1
spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: junch@yonsei.ac.kr. Fax: +82-2-3147-2644.
D
DOI: 10.1021/acs.orglett.8b00831
Org. Lett. XXXX, XXX, XXX−XXX