Chemoselective acylation of amines in aqueous media

Article abstract of DOI:10.1002/ejoc.200300620

Amines are efficiently acylated by both cyclic and acyclic anhydrides by dissolving them in an aqueous medium with the help of a surfactant, sodium dodecyl sulfate (SDS). Cyclic and acyclic anhydrides react with equal ease with an amine, and amines with various stereo-electronic factors react at the same rates with an anhydride. Chemoselective acylation of amines in the presence of phenols and thiols and of thiols in the presence of phenols has been achieved. No acidic or basic reagents are used during the reaction. No Chromatographic separation is required for isolation of the acylated products. Reactions in a neutral aqueous medium, easy isolation of products, and innocuous by-products make the present method a green chemical process. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004.

Full text of DOI:10.1002/ejoc.200300620

FULL PAPER
Chemoselective Acylation of Amines in Aqueous Media
Sarala Naik,[a] Gitalee Bhattacharjya,[a] Bandana Talukdar,[a] and Bhisma K. Patel*[a]
Dedicated to Professor Asutosh Nayak[‡]
Keywords: Amines / Amides / Acylation / Aqueous media / Chemoselectivity
Amines are efficiently acylated by both cyclic and acyclic an-
hydrides by dissolving them in an aqueous medium with the
help of a surfactant, sodium dodecyl sulfate (SDS). Cyclic and
acyclic anhydrides react with equal ease with an amine, and
sic reagents are used during the reaction. No chromato-
graphic separation is required for isolation of the acylated
products. Reactions in a neutral aqueous medium, easy isola-
tion of products, and innocuous by-products make the pre-
amines with various stereo-electronic factors react at the sent method a green chemical process.
same rates with an anhydride. Chemoselective acylation of
amines in the presence of phenols and thiols and of thiols in ( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
the presence of phenols has been achieved. No acidic or ba-
Germany, 2004)
Introduction
sphingosines and alkaloids. N-Acyl derivatives are well-
known protecting groups for the amines.[3] Acylation of am-
ines is sometimes carried out using acyl transfer reagents[4]
and at other times with acetic acid,[5] but acylating reagents
such as acyl halides and acid anhydrides are usually em-
ployed in the presence of either acidic[6] or basic catalysts.[7]
These reactions have advantages and drawbacks, extensively
described recently by Katritzky.[8] Most of the acetyl trans-
fer reagents are expensive and are obtained by acetylation
with acetylating agents making them unsuitable for large-
scale reactions. Some of these reagents and catalysts lead to
waste and some reactions involve organic solvents, often
toxic and polluting, both unacceptable in these environmen-
tally conscious days. Thus, desirable features for these reac-
tions would be a neutral medium, innocuous by-products,
mild reaction conditions and greater tolerance towards
other nucleophilic centers. Considering the importance of
acylation and environmental factors, as well as our interest
in green chemical processes,[9] we report here the acylation
of amines in an aqueous medium, which fulfils many of the
above-mentioned requirements.
A crucial factor for green chemical processes in solution
involves the choice of cheap, safe and nontoxic solvents.
Water, being abundant in nature, is the obvious choice.
Water is not just a ‘‘green’’ solvent, but also has special
effects on reactions arising from intra- and inter-molecular
noncovalent interactions leading to novel solvation and as-
sembly processes. Since Breslow’s discovery of a positive ef-
fect on the reaction rates and selectivities of the
DielsϪAlder reaction, which is otherwise known to be in-
sensitive to solvent effects, special attention has been fo-
cused on the origin of the aqueous acceleration.[1] Despite
the solubility problems of organic substrates in water, after
this seminal contribution there has been an upsurge in
interest in using water as the solvent, not only to enhance
the reaction rates but also to perform organic reactions that
would otherwise be impossible. Several books and reviews
have been devoted to such uses.[2] Thus, development of an
efficient and convenient synthetic method in water is an im-
portant subject.
Acylation of amines is a fundamental process in organic
chemistry. Owing to the nucleophilic and basic character of
amines they must be blocked with a protecting group dur-
ing a multi-step synthesis, e.g. in the synthesis of a diverse
array of biological molecules such as amino acids, peptides,
glycopeptides, aminoglycosides, β-lactams, nucleosides,
Results and Discussion
Acetylation of aromatic amines has been carried out in
an aqueous medium using amine, hydrochloric acid, a con-
centrated solution of sodium acetate and acetic anhy-
dride.[10] In addition, there are a few other methods of
aqueous acylation reported in the literature.[11] All the
known aqueous acylation methods use either acids, bases
or combinations of both. One of the reasons for using an
acid in an aqueous medium is to convert the amine into a
[a]
Indian Institute of Technology, Guwahati,
Guwahati 781 039, Assam, India
Fax: (internat.) ϩ 91-3612690762
E-mail: patel@iitg.ernet.in
[‡]
For his encouragement of scientific endeavor.
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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DOI: 10.1002/ejoc.200300620
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Chemoselective Acylation of Amines in Aqueous Media
FULL PAPER
water-soluble ammonium salt and the base is to neutralize such effect was observed by the present method and all the
the acid liberated from the anhydride. The use of mineral substrates react with equal ease. Arylamines gave better
acids or bases makes the above method less attractive. Con- yields than alkylamines. Phenol did not react at all and
sidering the environmental aspects, we looked for a greener thiophenol reacted slowly under identical conditions, giving
alternative, devoid of any acidic or basic reagents. In one of moderate (25%) yields of acetylated product. Thus, by tak-
our ongoing projects we noticed the solubility of several ing advantage of the differential reactivity between nucleo-
aromatic and aliphatic amines in an aqueous medium in the philes, we were able to carry out intermolecular chemoselec-
presence of sodium dodecyl sulfate (SDS). The SDS con- tive acetylation of amines over phenol and thiol (Scheme 1).
centration (2.31 ϫ 10Ϫ4 ) required for the dissolution of Thus, in a competitive acetylation reaction with an equimo-
several aromatic amines is much lower than the critical mi- lar mixture of an amine (7) and a phenol by this procedure,
celle concentration (8.3 ϫ 10Ϫ3 ) of SDS, thus ruling out the amine was acetylated selectively leaving the phenol un-
the possibility of micelle formation for the dissolution of affected. In an analogous reaction between an amine (7)
amines. Initially, we speculated that the dissolution of the and a thiophenol, the thiophenol remained untouched
hydrogen donor amino group might be due to interaction (Scheme 1). However, in a competitive reaction between a
with the hydrogen acceptor sulfonic acid group of SDS. But phenol and a thiophenol, the thiophenol was selectively
when the sodium salt of methane sulfonic acid was used acetylated over phenol (Scheme 1). This observation is in
instead of SDS, the amine did not dissolve at all; hence the
possibility of the above type of interaction is ruled out.
Table 1. Acetylation of amines with acetic anhydride
Other surfactants such as triton-X 100 and hexadodecyl
ammonium bromide and phase transfer reagents such as
tetrabutylammonium bromide can be used instead of SDS,
thereby supporting the presence of hydrophobic-type inter-
actions.
In the earlier methods,[10,11] the protonated ammonium
ion obtained by the dissolution of amines in an acidic me-
dium is nonnucleophilic, requiring a base to regenerate the
nucleophilic amine for acylation. However, when SDS is
used for its dissolution it retains its nucleophilic character.
This was further confirmed by UV spectral analysis. No
change in UV absorption was observed at 226 nm and
276 nm when SDS was added to a dilute solution of 2-
fluoroaniline (10). Thus, when acetic anhydride was added
to an SDS solution of an amine, acetylated products were
obtained in moderate to good yields as shown in Table 1.
It was gratifying to observe that the product also precipi-
tates from the reaction mixture in most of these cases. In-
creasing the ionic strength of the medium by adding sodium
chloride to the reaction medium enhanced the amount of
precipitation. To our utter surprise no base was required
and the pH of the medium recorded at the end of the reac-
tion was ca.7. Several examples illustrating this novel pro-
cedure for acetylation are presented in Table 1. The optim-
ized acetylation reactions were performed by adding acetic
anhydride (7.5 mmol) to the substrate amine (5 mmol) dis-
solved in water (20 mL) with sodium dodecyl sulfate
(20 mg). The method works well for aliphatic amines 1 and
2 when the anhydride was added in portions but gave poor
yields when it was added in one lot. Benzylamine (3) and
furfurylamine (4) gave the corresponding acetamide in good
yields. Chiral amines 5 and 6 can be easily acetylated with
complete retention of optical activity. Primary arylamines
7Ϫ18, with varying steric and electronic factors, were exam-
ined and all gave excellent yields of the corresponding
acetamide. In most of these cases the products precipitated
in less than 5 min. It has been observed that in acetylation
reactions electron-donating groups favor the reaction,
whereas electron-withdrawing groups inhibit the reaction
[a]
Confirmed by comparison with IR, 1H and 13C NMR of the
authentic sample. [b] Isolated yields. [c] The reaction was performed
in 1:1 mixture of acetonitrile water.
starting material. 3 equivalents of Ac2O was used. Rest of the
when performed in organic reaction media. However, no products being 18aa and 18ab (Scheme 2).
[d]
Based on the recovery of
[e]
[f]
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S. Naik, G. Bhattacharjya, B. Talukdar, B. K. Patel
FULL PAPER
tained in Ͼ 40% isolated yield, the rest being N-(2-mer-
capto-phenyl)acetamide (18a) and S-[2-(acetylamino)-
phenyl] thioacetic acid ester (18aa), when 2-aminothi-
ophenol (18) was acetylated as shown in Scheme 3. The
formation of 2-methyl-benzothiazole (18ab) further demon-
strates the chemoselective acetylation of amines over thiols.
The proposed mechanism is shown in Scheme 2. It may be
mentioned here that the compound 2-methylbenzothiazole
(18ab) is used in the synthesis of polycarbocyanine and thi-
ocyanine dyes, as well as for (arylfuryl)benzothiazoles. In
most cases, the acetylated product precipitates from the
aqueous reaction medium but in a few cases it was extracted
with ethyl acetate to yield the pure product. However, in
the case of substrates 16 and 18, the products required chro-
matographic separation. It was found that primary amines
underwent smooth acetylation whereas secondary amines
and tertiary amines remained inert under the present exper-
imental conditions.
In order to extend the scope of the method further, the
acylation of amines with propionic anhydride was carried
out under identical conditions to those described for acetic
anhydride. Thus a variety of amines could be efficiently pro-
pionylated in good yields as shown in Table 2. Amine has
been chemoselectively propionylated over phenol and thiol
as demonstrated for p-aminophenol (15) and 2-aminothiol
(18) respectively. No chemoselectivity could be achieved
Scheme 1. Chemoselective acetylation of amines
sharp contrast to selective acetylation of phenol over thio-
phenol in an organic medium.[6g] Thus an exactly opposite
selectivity was observed in an aqueous medium.3
Similar chemoselectivity was observed for intramolecular
reactions. Thus, acetylation of 4-aminophenol (15) and 2-
aminothiophenol (18) produced the corresponding aceta-
mides; the phenolic and thiophenolic moieties remaining
unaffected with one equivalent of the reagent. Selective
acetylation is of significant interest for the preparation of
the antipyretic and analgesic drug paracetamol (15a). Sub-
strate 1,2-phenylenediamine (16) gave exclusively the
monoacetylated product 15a with one equivalent of acetic
anhydride. However, similar chemoselectivity could not be
achieved for substrate 1,4-phenylenediamine (17), which
gave exclusively the diacetylated product even with only one
equivalent of the acetylating agent. An interesting hetero-
cyclic product, 2-methyl-benzothiazole (18ab), was ob-
Table 2. Reaction of amines with propionic anhydride
[a]
Confirmed by comparison with IR, 1H and 13C NMR of the
[b]
[c]
authentic sample.
Isolated yields.
3 equivalent of propionic
anhydride was used. [d] The rest of the products were 18ba and 18bb
(Scheme 2).
Scheme 2. Chemoselective acylation of amines
Scheme 3. Proposed mechanism for the formation of 2-(methyl)benzothiazole (18ab) and 2-(ethyl)benzothiazole (18bb)
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Chemoselective Acylation of Amines in Aqueous Media
FULL PAPER
with the symmetrical diamines o-phenylenediamine (16)
and p-phenylenediamine (17) even with one equivalent of
the anhydride. Substrate 2-aminothiol (18) gave 2-(ethyl)-
benzothiazole (18bb, Scheme 2) as the major product and
N-(2-mercaptophenyl)propionamide (18b) as the minor
product suggesting chemoselective propionylation of
amines over thiols.
Table 3. Reaction of amines with benzoic anhydride
N-Benzoylated products are normally obtained from ben-
zoic acid, benzoyl halides, benzoic anhydride, esters of ben-
zoic acid, and benzoyl transfer reagents under different ex-
perimental conditions.[12] Employing our aqueous method,
various amines could be benzoylated in excellent yields. Al-
though benzoic anhydride can be directly added to an aque-
ous solution of the amine, the reaction times are normally
longer and some benzoic anhydride remained unchanged,
giving lower yields and an impure product. However, better
yields and pure product could be obtained by adding an
acetonitrile (2 mL) solution of benzoic anhydride (5 mmol)
to an aqueous solution of amine (5 mmol) dissolved in
water and SDS. The reaction was usually completed within
5 min. Removal of acetonitrile under reduced pressure led
to precipitation of the benzoylated product along with ben-
zoic acid. The precipitated benzoic acid was converted into
water-soluble sodium benzoate by adding solid sodium hy-
drogen carbonate until effervescence ceases. The benzoyl-
ated product was filtered off to yield the pure compound.
Sodium benzoate can be quantitatively recovered from the
aqueous filtrate on concentration if required.
[a]
Confirmed by comparison with IR, 1H and 13C NMR of the
[b]
[c]
authentic sample.
used.
Isolated yields.
2 equivalent of Bz2O was
Table 4. Reaction of amines with succinic anhydride
The success of the method has been tested with aliphatic
(1), benzylic (3) and furfurylic (4) amines. Arylamines such
as 7 and 8 gave the corresponding benzamides in quantitat-
ive yields. Excellent intermolecular chemoselective ben-
zoylation of amines over phenols and thiols, and thiols over
phenol, has been demonstrated in Scheme 1, further sup-
porting the preferential S-acylation over O-acylation in an
aqueous medium. Again an intramolecular chemoselective
benzoylation of amine has been shown with p-aminophenol
(15). No chemoselectivity of the symmetrical diamine 1,4-
phenylenediamine (17) was achieved when acetic and propi-
onic anhydrides were used (Table 1). However, excellent
chemoselectivity could be achieved in the benzoylation of
a symmetrical diamine in aqueous medium as shown for
substrate 17. This is probably because the monobenzoylated
[a]
Confirmed by comparison with IR, 1H and 13C NMR of the
[b]
[c]
authentic sample.
anhydride were used. Su ϭ COCH2CH2COOH
Isolated yields.
2.4 equivalents of succinic
product 17c is highly hydrophobic and therefore precipi- reaction took place readily with concurrent precipitation of
tates from the aqueous medium before it can undergo di- the white solid product. This has been tested with a number
benzoylation if one equivalent of benzoic anhydride is used. of aromatic amines and the results are summarized in
However, the dibenzoylated product could be obtained in Table 4. Here again chemoselective succcinylation of amine
quantitative yields with two equivalents of benzoic anhy- has been achieved over phenols as shown for p-amino-
dride.
The (arylcarbamoyl)propenoic acids or maleamic acid
phenol (15).
Amines also react successfully with maleic anhydride giv-
and propanoic acid or succinamic acid have been prepared ing good yields of the desired products under similar con-
by the condensation of amine with maleic anhydride or suc- ditions (Table 5). All the amines tested could be converted
cinic anhydride using a variety of conditions.[6g,13] The no- into the corresponding aryl maleamic acid in good yields.
vel aspect of the present method was further applied to cyc- These reactions were performed analogously to the reaction
lic anhydrides such as succinic anhydride and maleic anhy- using succinic anhydride. It is worth mentioning that male-
dride. In the case of succinic anhydride, the anhydride (1.2 amic and succinamic acids are important classes of com-
equivalents) was added in portions over a period of ten mi- pounds having fungicidal, insecticidal and herbicidal
nutes to an aqueous solution of amine (1 equivalent). The properties.
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S. Naik, G. Bhattacharjya, B. Talukdar, B. K. Patel
FULL PAPER
Table 5. Reaction of amines with maleic anhydride
Conclusion
In conclusion, this method represents a tremendous op-
portunity for the practice of green chemistry. The reactions
are, in general, very clean giving good to moderate yields
with excellent selectivity, and no side products have been
isolated. In addition, chromatographic purification of the
acylated product is not required. The method is environ-
mentally friendly with respect to by-products. Although
procedures exist for acylation of amines, the simplicity and
low cost of our procedure allow it to compete as a better
practical alternative to the existing methods for selective
acylation of primary amines in the presence of phenols and
thiols and particularly of thiols in the presence of phenols.
The reverse order of chemoselectivity, thiol over phenol will
find useful application in the synthesis of complex natural
products where selective protection of thio and amino
groups is required in the presence of thiol.
[a]
Confirmed by comparison with IR, 1H and 13C NMR of the
authentic sample.[b] Isolated yields. Mal ϭ COCHϭCHCOOH
There has been a recent resurgence of interest in N-phe-
nylphthalimide derivatives and their analogues because of
their potential biological activity, such as amino peptidase
inhibition,[14a] anticonvulsant activity,[14b] and promotion
of tumor necrosis factor alpha (TNF alpha) production.[14c]
Substituted N-arylphthalimic acids have been synthesized
by the reaction of phthalic anhydride and arylamines under
different conditions.[15] Again, owing to the insolubility of
phthalic anhydride in water, an acetonitrile (5Ϫ6 mL) solu-
tion of phthalic anhydride (5 mmol) was added to an aque-
ous solution of amine (5 mmol). Arylphthalamic acid pre-
cipitated on evaporation of acetonitrile. The product was
filtered and recrystallized from acetonitrile to yield the crys-
talline compound in excellent yields. The reaction of
phthalic anhydride with various amines is summarized in
Table 6. It may be noted here that cyclic anhydrides react
considerably more slowly than acyclic anhydrides when the
reaction is catalyzed by montmorillonite K-10 in an organic
solvent.[6g] As demonstrated here, both acyclic and cyclic
anhydrides react with different amines with equal ease when
the reaction was performed in an aqueous medium.
Experimental Section
General Remarks: All the reagents were commercial grade and puri-
fied according to established procedures. Organic extracts were
dried with anhydrous sodium sulfate. Solvents were removed in a
rotary evaporator under reduced pressure. Silica gel (60Ϫ120 mesh
size) was used for column chromatography. Reactions were moni-
tored by TLC on silica-gel 60 F254 (0.25 mm). Elemental analysis
was performed with a PerkinϪElmer 2400 elemental analyzer.
Melting points were recorded with a Büchi B-540 melting point
apparatus. NMR spectra were recorded in CDCl3 or [D6]DMSO
with tetramethylsilane as the internal standard for 1H (200, 300
and 400 MHz) or CDCl3 or [D6]DMSO solvent as the internal
standard for 13C (50, 75 and 100 MHz). For 16a, 18a, 18aa, 18b,
18ba and 18bb the organic solution was concentrated and passed
through silica gel (60Ϫ120 mesh) using EtOAc/hexane to afforded
the analytically pure compound. All the compounds were identified
and confirmed by IR and NMR (1H and 13C) spectroscopy and by
comparison with authentic samples.
General Procedure for Reaction of Amines with Acetic, Propionic,
Succinic and Maleic Anhydride: Sodium dodecyl sulfate (SDS, ca.
20 mg) was added to a stirred heterogeneous suspension of amine
(5 mmol) in water (20 mL) until a homogeneous solution was
formed, (in case of turbidity, the mixture was warmed to obtain a
clear solution). The anhydride (7.5 mmol for acetic and propionic
anhydride and 6 mmol for succinic and maleic anhydride) was ad-
ded to this over a period of 5 min. The acetylated product precipi-
tated within 5Ϫ10 min. The precipitated product was filtered,
washed with water (2 ϫ 1 mL), dried by pressing between folds of
filter paper and finally dried in a vacuum desiccator. In cases where
the product did not precipitate, the reaction mixture was extracted
with ethyl acetate (2 ϫ 25 mL). The combined organic extracts
were dried with anhydrous Na2SO4 and the solvent was removed
in a rotary evaporator under reduced pressure to yield the pure
product which was identified by its NMR and IR spectra and GC
pattern, and by GC co-injection with authentic samples prepared
by known methods.
Table 6. Reaction of amines with phthalic anhydride
General Procedure for Reaction of Amines with Benzoic and Phthalic
Anhydride: Sodium dodecyl sulfate (SDS, ca. 20 mg) was added
to a stirred heterogeneous suspension of amine (5 mmol) in water
[a]
Confirmed by comparison with IR, 1H and 13C NMR of the
[b]
authentic sample. Isolated yields. Pht ϭ COC6H5COOH
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Chemoselective Acylation of Amines in Aqueous Media
FULL PAPER
(20 mL) until a homogeneous solution was formed, (in case of tur-
bidity, the mixture was warmed to obtain a clear solution). Benzoic
or phthalic anhydride (5 mmol) dissolved in acetonitrile (5 mL) was
added to this in one lot. After stirring for 5 min the acetonitrile was
evaporated and the product precipitated from the aqueous layer. To
the aqueous solution containing precipitate, solid sodium hydrogen
carbonate was added pinch-wise until the effervescence ceased and
the pH was near neutral. The remaining precipitated product was
filtered, washed with water (2 ϫ 1 mL), dried by pressing between
folds of filter paper and finally dried in a vacuum desiccator. In
cases where the product did not precipitate, the reaction mixture
was extracted with ethyl acetate (2 ϫ 25 mL). The combined or-
ganic extracts were dried with anhydrous Na2SO4 and the solvent
was removed in a rotary evaporator under reduced pressure to yield
the pure product which were identified by its NMR and IR spectra
and GC pattern, and by GC co-injection with authentic samples
prepared by known methods. Good crystals of the compound can
be obtained either from acetonitrile or from ethyl acetate.
thankful to all three referees for their invaluable comments and
suggestions.
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