4-(N,N -dimethylamino)pyridine hydrochloride as a recyclable catalyst for acylation of inert alcohols: Substrate scope and reaction mechanism

Article abstract of DOI:10.1021/ol4030875

4-(N,N-Dimethylamino)pyridine hydrochloride (DMAP·HCl), a DMAP salt with the simplest structure, was used as a recyclable catalyst for the acylation of inert alcohols and phenols under base-free conditions. The reaction mechanism was investigated in detail for the first time; DMAP·HCl and the acylating reagent directly formed N-acyl-4-(N′,N′-dimethylamino) pyridine chloride, which was attacked by the nucleophilic substrate to form a transient intermediate that released the acylation product and regenerated the DMAP·HCl catalyst.

Full text of DOI:10.1021/ol4030875

Letter
pubs.acs.org/OrgLett
4‑(N,N-Dimethylamino)pyridine Hydrochloride as a Recyclable
Catalyst for Acylation of Inert Alcohols: Substrate Scope and
Reaction Mechanism
Zhihui Liu, Qiaoqiao Ma, Yuxiu Liu, and Qingmin Wang*
State Key Laboratory of Elemento-Organic Chemistry, Research Institute of Elemento-Organic Chemistry, Nankai University, Tianjin
300071, China
S
* Supporting Information
ABSTRACT: 4-(N,N-Dimethylamino)pyridine hydrochloride
(DMAP·HCl), a DMAP salt with the simplest structure, was
used as a recyclable catalyst for the acylation of inert alcohols
and phenols under base-free conditions. The reaction
mechanism was investigated in detail for the first time;
DMAP·HCl and the acylating reagent directly formed N-acyl-
4-(N′,N′-dimethylamino)pyridine chloride, which was at-
tacked by the nucleophilic substrate to form a transient
intermediate that released the acylation product and
regenerated the DMAP·HCl catalyst.
a
Table 1. Catalytic Activity of DMAP·HCl
4-(N,N-Dimethylamino)pyridine (DMAP) is an effective
nucleophilic base catalyst. Since its use in acylation reactions
was first reported,1,2 its applications have been extensively
investigated. More active analogues have been developed,3 and
chiral versions have been used as catalysts in asymmetric
synthesis,4 for kinetic resolution of racemic alcohols5 and
amines,6 and for applications in biological7 and supramolecular
chemistry.8
Unfortunately, DMAP and some of its derivatives exhibit
acute dermal toxicity.9 Several strategies have been developed
to circumvent this problem, but all have been accompanied by
activity loss10 or recycling difficulty.11 Connon et al.12 reported
that DMAP supported on magnetic nanoparticles can be reused
up to 32 times without activity loss and can be recovered with
an external magnet. Polymer-supported DMAP derivatives have
also been extensively studied,13 but all these derivatives are
limited by inconvenient handling. Ishihara et al.14 reported a
DMAP-catalyzed acylation under base-free conditions, and
Legros et al.15 reported an acylation employing a fluorous
DMAP salt as a recyclable catalyst that could be recovered by
filtration. Similarly, Lu et al.16 used a saccharin-DMAP salt to
acylate alcohols. Unfortunately, when acylating reagents other
than acid anhydrides are used, salts of DMAP and weak acids
can be destroyed.
b
c
entry
catalyst
none
t (°C) time (h) conv (%)
yield (%)
1
2
3
4
5
6
25
25
25
25
60
110
78
78
18
78
8
<5
−
−
98
98
98
98
5% HCl
<20
5% DMAP
>99
5% DMAP·HCl
5% DMAP·HCl
5% DMAP·HCl
>99
d
>99/<5
>99/<5
d
1
a
The reaction of 2,4,6-trichlorophenol (10.0 mmol) and acetic
anhydride (11.0 mmol) was conducted in 20 mL of toluene.
Conversion was calculated based on recovered substrate. Isolated
b
c
d
yield. Conversion in the absence of DMAP·HCl.
excellent catalytic activity at room temperature, though the
reaction catalyzed by DMAP·HCl required a longer reaction
time (entries 3 and 4); but at elevated temperature (60 or 100
°C), the reaction time was markedly shortened while the
conversion and yield were maintained (entries 5 and 6).
Encouraged by these results, we acylated additional
substrates with acetic or benzoic anhydride and DMAP·HCl
(Table 2). Cyclohexanol, 1-phenylethanol, phenol, and 2,4-
dimethylphenol gave high yields of the desired esters at room
temperature (entries 1−8). More inert alcohols and electron-
deficient phenols, such as menthol, 1-cyanocyclohexanol, 1-
Here, we report the use of DMAP·HCl, the simplest salt of
DMAP, as a recyclable catalyst for acylation reactions, and we
describe its unique advantages and catalytic mechanism.
We chose the acylation of 2,4,6-trichlorophenol with acetic
anhydride as a model reaction (Table 1). In the absence of
catalyst, no reaction took place over the course of 78 h (entry
1), and 5% HCl had no obvious catalytic activity (entry 2). In
contrast, both 5% DMAP and 5% DMAP·HCl exhibited
Received: November 9, 2013
Published: December 16, 2013
© 2013 American Chemical Society
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Letter
Table 2. DMAP·HCl-Catalyzed Acylation of Alcohols and
Table 3. DMAP·HCl-Catalyzed Acylation of Alcohols and
a
a
Phenols by Acid Anhydrides under Base-Free Conditions
Phenols by Acyl Chlorides under Base-Free Conditions
a
The reaction of each substrate (10.0 mmol) with the acylating
reagent (11.0 mmol) was conducted in the presence of 5 mol %
DMAP·HCl in 20 mL of toluene at 110 °C. For liquid substrates,
b
reactions were conducted under solvent-free conditions. Isolated
c
yield. Conversion of the corresponding reaction in the absence of
DMAP·HCl.
Table 4. Assessment of DMAP·HCl as a Recyclable Catalyst
a
for Acylation of Various Substrates under Base-Free
The reaction of each alcohol or phenol (10.0 mmol) with acetic
a
Conditions
anhydride or benzoic anhydride (11.0 mmol) was conducted in the
presence of DMAP·HCl (0.5 mmol) in toluene (20 mL); for liquid
b
substrates, no solvent was used. Isolated yield.
ethoxycarbonyl-cyclohexanol, 4-hydroxycoumarin, and o-nitro-
phenol (entries 9−20), as well as 2,4,6-trichlorophenol (Table
1, entry 4), gave high yields of the desired products when the
temperature was raised to 60 °C. Even the most inert alcohols
tested, adamantanol and triethyl citrate (entries 21−24), could
be easily acylated at 110 °C under solvent-free conditions.
When benzoyl or pivaloyl chloride was used as the acylating
reagent, the reaction temperature had to be increased to 110 °C
(Table 3). Because acyl chlorides are highly reactive, we also
performed the corresponding reactions without DMAP·HCl as
control reactions, and we found that the DMAP·HCl-catalyzed
reactions were always faster and higher yielding than the
uncatalyzed reactions. Inert phenols (Table 3, entries 1−6),
tertiary alcohols (entries 9−14), enols (entries 15−18), 2-
hydroxypyridine (entries 19 and 20), a heterocyclic amine
(entry 21), and even an amide (entries 7 and 8) were suitable
substrates, and some of the reactions were complete within a
few minutes.
a
The reaction of each substrate (10.0 mmol) with the acylating
reagent (11.0 mmol) was conducted in toluene (20 mL) with 5 mol %
DMAP·HCl (79.0 mg). For 1-cyanocyclohexanol, no solvent was used.
b
c
Isolated yield. Weight of DMAP·HCl recovered after 8 or 10 cycles.
To further highlight the advantages of the DMAP·HCl-
catalyzed reaction, we evaluated additional acylating reagents, as
well as the recyclability of the catalyst (Table 4). DMAP·HCl
worked well with all the tested substrates and acylating
reagents; the isolated yields of the products exceeded 88%,
and DMAP·HCl was recovered nearly quantitatively from each
run. It is worth mentioning that because HCl is a stronger acid
than carboxylic acid, DMAP·HCl is first formed and separated,
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dx.doi.org/10.1021/ol4030875 | Org. Lett. 2014, 16, 236−239

Organic Letters
Letter
which is supported by the fact that only signals for DMAP·HCl
Table 5. Reaction of DMAP·HCl with Acetyl Chloride or
Acetic Anhydride
1
were found in the H NMR spectrum of the recycled catalyst.
We demonstrated that DMAP·HCl had excellent catalytic
activity, but the mechanism of its activity was not clear. Various
investigators14−16 have suggested that its activity is due to free
DMAP in the solvent, but we are skeptical of this suggestion
because we observed that the rate of the DMAP-catalyzed
acetylation of cyclohexanol was slowed by the addition of
tetrabutylammonium chloride (the conversion at 1.5 h was 99%
in the absence of the ammonium salt but 53% in its presence
(see Supporting Information)).
acylating
entry
catalyst
DMAP
reagent
t (°C)
result
a
1
AcCl or
Ac2O
rt
IIa formed immediately
a
2
DMAP·HCl
AcCl
Ac2O
AcCl
rt
no reaction happened
even after 7 days
a
3
DMAP·HCl +
10 equiv of HCl
rt
IIa formed within 24 h
b
4
DMAP·HCl
110
IIa formed within 30 min
a
Zipse et al.17 reported a two-step mechanism for DMAP-
catalyzed acetylation (Scheme 1); in step 1, DMAP reacts with
Acylating reagent was added to a CHCl3 solution of DMAP or
DMAP·HCl, and the solution was kept at rt. Acetyl chloride was
added to a toluene solution of DMAP·HCl, and the solution was
refluxed.
b
Scheme 1. Mechanism of DMAP-Catalyzed Acetylation
Proposed by Zipse et al.
free DMAP derived from dissociation of DMAP·HCl. There-
fore, we believe that N-acetylated DMAP chloride (IIa) formed
directly from DMAP·HCl (Scheme 2). The difference in
activity between acetyl chloride and acetic anhydride could be
explained by the fact that Cl− is a weaker conjugate base than
AcO−, which means that it is more difficult for Cl− to capture a
proton from DMAP·HCl to form the transient intermediate
leading to IIa. When we repeated the reaction of acetyl chloride
with DMAP·HCl in refluxing toluene (entry 4), IIa formed
within 30 min. From entries 1 and 4 we also know when acid
chloride is used as an acylating agent under reflux conditions;
both DMAP and DMAP·HCl work through DMAP·HCl, so
they theoretically have the same catalytic activity.
On the basis of these results, we propose the following
mechanism (Scheme 2): first, DMAP·HCl and the acylating
reagent form N-acylated DMAP chloride (II), and second, the
nucleophilic substrate attacks II to form a transient
intermediate that releases the acylation product and regenerates
DMAP·HCl. This mechanism suggests the possibility of using
this reaction as a novel method for kinetic resolution of
alcohols by means of an acylation catalyzed by a salt of DMAP
and a chiral acid. The chiral anion may facilitate stereoselective
dehydrogenation.
In summary, we demonstrated that DMAP·HCl is an
effective, recyclable organocatalyst for acylation under base-
free conditions (liquid substrates could also be acylated under
solvent-free conditions). The catalyst can be reused more than
eight times without loss in activity, and it works with multiple
acylating reagents. Therefore, it might be practical for industrial
applications. We also investigated the catalytic mechanism and
found that N-acyl-4-(N′,N′-dimethylamino)pyridine chloride
formed directly from DMAP·HCl and the acylating reagent,
suggesting that this reaction could be used for kinetic resolution
of alcohols.
acetic anhydride to form N-acetylated DMAP acetate (I), and
in step 2, the alcohol substrate attacks I to form a transient
intermediate that leads to the ester product after proton
transfer and simultaneous release of DMAP and acetic acid.
Step 2 is thought to be the rate-determining step.
However, the slowing of the DMAP-catalyzed acylation when
tetrabutylammonium chloride was added suggests that the rate-
determining step of the DMAP-catalyzed reaction differs from
that of the DMAP·HCl-catalyzed reaction. That is, it is not I
but some other N-acetylated DMAP salt that is attacked by the
1
alcohol substrate. We isolated the intermediate, and H NMR
spectroscopy (see Supporting Information) indicated it to be
N-acetylated DMAP chloride (IIa, Scheme 2). Therefore, we
are sure that the DMAP·HCl-catalyzed acylation proceeds
through the same intermediate (Scheme 2).
Scheme 2. Proposed Mechanism of DMAP·HCl-Catalyzed
Acylation Reaction
To determine whether IIa formed from DMAP·HCl or from
free DMAP, we performed some additional experiments (Table
5). We found that when DMAP and acetyl chloride were mixed
in a CHCl3 solution, IIa formed immediately18 (entry 1),
suggesting that if free DMAP is present in DMAP·HCl
solution, IIa should form after the acylating reagent is added.
However, we found that this was not the case; when acetyl
chloride was mixed with DMAP·HCl at room temperature, no
reaction occurred even after 7 days (entry 2), whereas when
acetic anhydride was used as the acylating reagent at room
temperature, IIa formed within 24 h, even when 10 equiv of
HCl were added in advance (entry 3). These results rule out
the possibility that IIa formed from the acylating reagent and
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures (preparation of DMAP·HCl, general
procedure for DMAP·HCl-catalyzed acylation, and procedure
for catalyst recycling) and compound characterization data are
included in the Supporting Information. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: wang98h@263.net; wangqm@nankai.edu.cn.
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Letter
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Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
We are grateful to the National Key Project for Basic Research
(2010CB126100), the National Natural Science Foundation of
China (21132003, 21121002, 21372131), Tianjin Natural
Science Foundation (11JCZDJC20500), and the Specialized
Research Fund for the Doctoral Program of Higher Education
(20120031110010) for generous financial support for our
research.
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Eur. J. 2010, 16, 1776−1779.
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