Additive-free chemoselective acylation of amines and thiols

Article abstract of DOI:10.1007/s00706-006-0564-3

Amines with different stereoelectronic nature were efficiently acylated at room temperature using acetic anhydride in the presence of no solvent or additive. Various thiols also react equally well under the same conditions. Chemoselective protection of amines in the presence of thiols, alcohols, and phenols and of thiols in the presence of alcohols, and phenols were achieved using competitive experiments.

Full text of DOI:10.1007/s00706-006-0564-3

Monatshefte f€ur Chemie 138, 95–99 (2007)
DOI 10.1007/s00706-006-0564-3
Printed in The Netherlands
Short Communication
Additive-Free Chemoselective Acylation
of Amines and Thiols
Mohammad M. Mojtahedi1;ꢀ, M. Saeed Abaee1, Majid M. Heravi2,
and Farahnaz K. Behbahani2
1
Chemistry and Chemical Engineering Research Center of Iran, Tehran, Iran
2
Department of Chemistry, School of Science, Azzahra University, Vanak, Tehran, Iran
Received September 29, 2006; accepted (revised) October 4, 2006
Published online December 8, 2006 # Springer-Verlag 2006
Summary. Amines with different stereoelectronic nature were efficiently acylated at room temperature
using acetic anhydride in the presence of no solvent or additive. Various thiols also react equally well
under the same conditions. Chemoselective protection of amines in the presence of thiols, alcohols, and
phenols and of thiols in the presence of alcohols, and phenols were achieved using competitive
experiments.
Keywords. Solvent-free; Acetylation; Green chemistry; Amines; Thiols.
Introduction
With increasing global environmental concerns, design of green processes with no
use of hazardous and expensive solvents, i.e. ‘‘solvent-free’’ reactions, has gained
special attention by organic chemists [1]. As a result, many reactions are newly
found to proceed cleanly and efficiently in solid state or under solvent-free condi-
tions [2]. Less chemical pollution, lower expenses, and easier procedures to handle
are the main reasons for recent years increasing popularity of solvent-free reactions.
Protection of amine functionalities is a fundamental maneuver in organic chem-
istry. The nucleophilic and basic nature of amines require their protection during
many multi-step syntheses of biological targets [3]. In this context, N-acylation of
amines is a very common synthesis practice and is usually conducted in the pre-
sence of acidic or basic additives using acetic acid [4], acyl transfer reagents [5],
acyl halides [6], or anhydrides of carboxylic acids [7]. However, use of expensive
reagents, harsh conditions requirement, presence of competitive side reactions or
ꢀ
Corresponding author. E-mail: mojtahedi@ccerci.ac.ir

96
M. M. Mojtahedi et al.
production of toxic waste are the drawbacks of many of these procedures [8]. Recent
instances to tackle these limitations involve the use of catalysts under aqueous [9, 10]
or neat [11–13] conditions or application of neutral acylating reagents [8]. In the
framework of our investigations on the protection of various functional moieties
[14], we recently noticed that amines could spontaneously convert to amides when
they are exposed to acetic anhydride alone. Consequently, we were encouraged to
investigate these observations extensively.
Results and Discussion
The isolated yields obtained for room-temperature acylation of selected amines in
the presence of acetic anhydride and no additive are given in Table 1. When a mix-
ture of aniline and acetic anhydride was stirred without solvent or additive, complete
formation of N-phenylacetamide was observed within a few minutes (entry 1). The
1H NMR spectrum showed the presence of N-acylated compound as the sole product
of the reaction. The applicability of this method to other substrates was evaluated
by subjecting electron-withdrawing (entry 2), electron-releasing anilines (entry 3),
and disubstituted amines (entries 4–5) to the same conditions. In all cases, rapid
formation of the respective amides was observed in high yields. Further generality
of this procedure was demonstrated by convenient conversion of ꢀ-naphthylamine
(entry 6), (S)-1-phenylethanamine (entry 7), N-alkylated or N-arylated aniline deri-
vatives (entry 8), and aliphatic amines (entries 9–11) to their respective amides.
In the majority of these reactions, substrates bearing substituents with different
electronic behavior led to spontaneous precipitation of products within few minutes
illustrating the high efficiency of the method. Simple filtration led to separation of
the desired amides as indicated in Table 1. With these in hands, we decided to use
Table 1. Additive-free acetylation of various amines
Entry
Amine
Amide
Yield=% [Ref.]
1
2
C6H5NH2
C6H5NHAc
86 [9]
p-XC6H4NH2
p-XC6H4NHAc
93 (X ¼ Cl) [15]
75 (X ¼ Br) [15]
92 (X ¼ NO2) [9]
90 (X ¼ CO2H) [9]
94 (X ¼ Me) [9]
90 (X ¼ OH) [9]
95 (X ¼ NH2) [9]
80 [16]
3
p-XC6H4NH2
p-XC6H4NHAc
4
5
6
7
8
3,5-Cl2C6H3NH2
2,6-Me2C6H3NH2
2-naphthyl-NH2
(S)-C6H5CH(Me)NH2
C6H5NHR
3,5-Cl2C6H3NHAc
2,6-Me2C6H3NHAc
2-naphthyl-NHAc
(S)-C6H5CH(Me)NHAc
C6H5NRAc
89 [16]
94 [15]
88 [13]
87 (R ¼ Me) [17]
81 (R ¼ Ph) [16]
82 [17]
9
10
11
cyclohexyl-NH2
morpholine
cyclohexyl-NHAc
1-morpholinoethanone
tert-BuNHAc
77 [18]
tert-BuNH2
81 [19]

Chemoselective Acylation of Amines and Thiols
97
Table 2. Additive-free acetylation of thiols
Entry
RSH
RSAc
Yield=% [19]
1
2
3
C6H5SH
C6H5SAc
90
93
88
p-ClC6H4SH
2-naphthyl-SH
p-ClC6H4SAc
2-naphthyl-SAc
this chemistry for the protection of thiols because of the importance of their mask-
ing in organic chemistry [12, 13, 19] especially in peptide and protein syntheses
[3]. Moreover, bioorganic [20] and electrochemical [21] applications make the pro-
tection of thiols more attractive. Therefore, several thiols were conveniently acy-
lated within few hours under the conditions similar to those employed for amines
(Table 2).
Further studies showed that alcohols and phenols do not react with acetic anhy-
dride under the conditions employed. This behavior and the observation that thiols
are acetylated slower than amines persuaded us to evaluate the feasibility of selec-
tive protection of amines and thiols in the presence of other competing function-
alities. Thus, when a 1:1:1 mixture of aniline, thiophenol, and acetic anhydride was
treated at room temperature, formation of N-phenylacetamide was detected as the
major acylated product (Table 3, entry 1). Similar competition between aniline and
phenol also resulted in nearly exclusive formation of the same product (entry 2).
Interestingly, intramolecular competition between NH2 and OH groups in p-ami-
nophenol resulted in exclusive formation of N-(p-hydroxyphenyl)acetamide, a very
common analgesic drug and industrially important material known as paracetamol
(entry 3) [22].
Next, selective protection of diamines was explored using p- (entry 4) and o-
phenylenediamine (entry 5), and ethylendiamine (entry 6). Use of deficient amounts
of Ac2O resulted in formation of mono protected amines as the major product.
Alternatively, double protected diamines could be obtained in an efficient manner
when an equimolar amount of acetic anhydride was used. Finally, when mixtures
of n-pentanol with aniline (entry 7) or with thiophenol (entry 8) were treated with
an equimolar amount of acetic anhydride, only formation of N-phenylacetamide or
S-phenyl ethanethioate was detected.
Table 3. Competitive acetylation of various functional groups with Ac2O
Entry
Product 1
Product 2
1:2
1
2
3
4
5
6
7
8
C6H5NHAc
C6H5SAc
>95:5
>99:1
99:1
C6H5NHAc
C6H5OAc
p-HOC6H4NHAc
p-H2NC6H4NHAc
o-H2NC6H4NHAc
H2NCH2CH2NHAc
C6H5NHAc
p-H2NC6H4OAc
p-AcHNC6H4NHAc
o-AcHNC6H4NHAc
AcHNCH2CH2NHAc
n-C5H11OAc
>90:10
>90:10
>90:10
>99:1
>99:1
C6H5SAc
n-C5H11OAc

98
M. M. Mojtahedi et al.
In conclusion, we disclose the additive-free conversion of various amines and
thiols to their respective acyl protected products in high yields and short reaction
times. High chemoselectivity and generality of the procedure, lack of formation of
side products, easy work-up, and the environmental safety of the reactions are
among the advantages of the present methodology.
Experimental
General Procedure
An equimolar mixture of acetic anhydride and the amine (thiol) was stirred at room temperature
until TLC showed complete disappearance of the starting amine (thiol). The precipitated product
was filtered off, washed with dilute NaHCO3 solution, and dried. Physical and spectral data of the
products were obtained and compared with those available in the references provided in the
Tables 1 and 2.
Acknowledgements
Partial financial support of this work by the Ministry of Science, Research, and Technology is greatly
appreciated. N. Ghorbani is also acknowledged for conducting some of the experiments.
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