New, efficient, selective, and one-pot method for acylation of amines

Article abstract of DOI:10.1080/00397910801997538

Hydrazine hydrate with acetic and propionic acids was an efficient reagent for acylation of primary and secondary amines at reflux temperatures. The reported one-pot method is high-yielding, simple, mild, and inexpensive. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910801997538

This article was downloaded by: [University of Pennsylvania]
On: 28 February 2013, At: 14:02
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954
Registered office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH,
UK
Synthetic Communications: An
International Journal for Rapid
Communication of Synthetic
Organic Chemistry
Publication details, including instructions for
authors and subscription information:
http://www.tandfonline.com/loi/lsyc20
New, Efficient, Selective, and
One-Pot Method for Acylation
of Amines
Mahantesha Basanagouda a , Manohar V. Kulkarni a
Raj G. Kalkhambkar b & Geeta M. Kulkarni b
,
a Department of Chemistry, Karnatak University,
Dharwad, Karnataka, India
b Department of Chemistry, Karnatak Science
College, Dharwad, Karnataka, India
Version of record first published: 28 Aug 2008.
To cite this article: Mahantesha Basanagouda , Manohar V. Kulkarni , Raj G.
Kalkhambkar & Geeta M. Kulkarni (2008): New, Efficient, Selective, and One-Pot
Method for Acylation of Amines, Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic Chemistry, 38:17, 2929-2940
To link to this article: http://dx.doi.org/10.1080/00397910801997538
PLEASE SCROLL DOWN FOR ARTICLE
Full terms and conditions of use: http://www.tandfonline.com/page/terms-
and-conditions
This article may be used for research, teaching, and private study purposes.
Any substantial or systematic reproduction, redistribution, reselling, loan,

sub-licensing, systematic supply, or distribution in any form to anyone is
expressly forbidden.
The publisher does not give any warranty express or implied or make any
representation that the contents will be complete or accurate or up to
date. The accuracy of any instructions, formulae, and drug doses should be
independently verified with primary sources. The publisher shall not be liable
for any loss, actions, claims, proceedings, demand, or costs or damages
whatsoever or howsoever caused arising directly or indirectly in connection
with or arising out of the use of this material.

Synthetic Communications1, 38: 2929–2940, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910801997538
New, Efficient, Selective, and One-Pot Method for
Acylation of Amines
Mahantesha Basanagouda,1 Manohar V. Kulkarni,1
Raj G. Kalkhambkar,2 and Geeta M. Kulkarni2
1Department of Chemistry, Karnatak University, Dharwad, Karnataka, India
2Department of Chemistry, Karnatak Science College, Dharwad,
Karnataka, India
Abstract: Hydrazine hydrate with acetic and propionic acids was an efficient
reagent for acylation of primary and secondary amines at reflux temperatures.
The reported one-pot method is high-yielding, simple, mild, and inexpensive.
Keywords: Acetic acid, acetylation, amines, hydrazine hydrate, propionic acid,
propionylation
INTRODUCTION
Acylation of amines is an important and routinely utilized method for the
protection of amino group transformation in organic synthesis. Despite a
number of precedents, new efficient methodologies for acylation are still
in demand. A variety of catalysts developed for acylation include Lewis
acids such as metal halides,[1] triflates,[2] perchlorates,[3] and solid-
supported reagents.[4] Recently, other reagents such as I2,[5] La(OiPr)3,[6]
ammonium acetate,[7] vanadyl (V) acetate,[8] ionic liquids,[9] lipase
enzymes,[10] ZrOCl2 ꢀ 8H2O,[11] BiCl3 generated in situ from the procata-
lyst BiOCl and acetyl chloride,[12] silphos [PCl3-n (SiO2)n],[13] La[NO3]3 ꢀ 6
H2O,[14] molecular iodine in isopropenyl acetate [IPA],[15] and BF3 ꢀ Et2O-
NaI-Ac2O,[16] are employed for the acylation. Chemoselective acylation
of amines has been achieved with the help of a surfactant, sodium
dodecylsulphate(SDS).[17]
Received October 21, 2007.
Address correspondence to Manohar V. Kulkarni, Department of Chemistry,
Karnatak University, Dharwad, Karnataka, India 580003. E-mail: profmvk@
rediffmail.com
2929

2930
M. Basanagouda et al.
Scheme 1. Acylation of amines.
N-Acetylation is generally brought about by using acetic anhydride
(which is a classified chemical at present), in the presence of bases or
by employing the lachrymatory acetyl chloride. Hence, simple method
for the acetylation of amines without use of these two reagents would
be useful.[18]
However, many of the hitherto known methods suffer from certain
drawbacks. The catalysts are rather expensive and require reagents,
which are not readily available. Thus an efficient and simpler method
is still desirable. To this end, we have developed a convenient and mild
method (Scheme 1) for the N-acylation of anilines and secondary amines
in good yields using hydrazine hydrate, which is a very useful reagent for
the synthesis and transformations of many organic compounds.
RESULTS AND DISCUSSION
As shown in Table 1, a number of substituted anilines and secondary
amines underwent N-acetylation smoothly with hydrazine hydrate and
acetic acid at reflux temperatures in good yields. The course of reaction
was monitored by thin-layer chromatography (TLC). The workup and
isolation of the products was easy. All the acetylated products were
1
characterized by comparison of their TLC, IR, H NMR spectra, and
physical constants with literature reports.[19]
In the case of aromatic amines, the presence of electron-withdrawing
groups such as nitro and chloro reduced the rate of acetylation. In
chloro-substituted anilines, the completion of the reaction required
longer hours (entries 7, 8, 9). In nitro-substituted anilines, for meta-nitro
aniline, it required longer time (entry 5). No acetylated products were
obtained for ortho and para-nitro anilines even on refluxing for 24 h
(entries 4, 6), whereas electron-releasing groups facilitated the reaction.

Acylation of Amines
2931
Table 1. N-Acetylation of amines
Time Yield
(h)
Entry
1
Substrate
Producta
(%)
3
93
2
3
4
3
3
55
66
b
24
—
5
6
7
6
24
8
89
b
—
31
(Continued)

2932
M. Basanagouda et al.
Table 1. Continued
Time Yield
(h)
Entry
8
Substrate
Producta
(%)
4
81
9
5
3
93
93
10
11
12
13
3
91
94
43
3
2.5
14
2.5
54
(Continued)

Acylation of Amines
2933
Table 1. Continued
Time Yield
(h)
Entry
15
Substrate
Producta
(%)
2.5
84
16
17
2.5
2.5
54
95
18
19
20
21
22
3
3
4
4
3
60
77
31
59
71
(Continued)

2934
M. Basanagouda et al.
Table 1. Continued
Time Yield
(h)
Entry
23
Substrate
Producta
(%)
6
83
24
5
86
aAll the products were identified by comparison of their 1H NMR, IR, mp, and
bp with literature reports.[19]
bBased on recovery of the starting material, no acetylation was observed even
after 24 h.
To examine the chemoselectivity of the present method, bifunctional
substrates containing ꢁNH2 and -OH groups were studied (entries 18,
19). Selective acetylation of the ꢁNH2 group in the presence of the
ꢁOH group was observed to give corresponding N-acetylated product,
and no O-acetylated product was found under these conditions. This is
likely due to the greater nucleophilicity of amines than phenols. This is
of significant interest for the preparation for the well-known antipyretic
drug paracetamol (entry 19).
To extend the scope of this method, the propionylation of amines
with propionic acid was carried out under identical conditions. It was
found that a variety of amines could be efficiently propionylated in good
yields as shown in Table 2.
The reactions were also studied in a domestic (Kenstar) microwave
oven. Though the reaction was found to be complete in 5–10 min, it
was accompanied by loss of acetic acid by evaporation. Attempts to opti-
mize the yields by using excess of acids (1:10) and increasing the reaction
times (20–30 min), resulting in a maximum of 60% yields in most of the
cases due to the solubility of the acylated products.
EXPERIMENTAL
Materials
All the anilines, secondary amines, hydrazine hydrate, acetic acid, and
propionic acids were purchased from Sigma-Aldrich Chemicals Pvt. Ltd
(India). All of the solvents used were analytical grade and were purified
according to standard procedures. Thin-layer chromatography was

Acylation of Amines
2935
Table 2. N-Propionylation of amines
Entry Substrate
1
Producta
Time (h) Yield (%)
3
76
b
2
3
24
24
—
b
—
4
6
35
5
6
3
3
94
80
7
3
54
(Continued)

2936
M. Basanagouda et al.
Table 2. Continued
Entry Substrate
8
Producta
Time (h) Yield (%)
3
79
9
3
85
10
11
3
6
46
51
12
5
56
aAll the products were identified by comparison of their 1H NMR, IR, mp, and
bp with literature reports.[19]
bBased on recovery of the starting material, no propionylation was observed
even after 24 h.
carried out on silica-gel plates obtained from Merck (Germany). The
melting points were determined by using a Shital melting-point apparatus
and are uncorrected. IR spectra were recorded on a Nicolet Impact
1
410 FT-IR spectrometer. H NMR spectra were recorded on a Bruker
300-MHz spectrometer using CDCl3 as a solvent and TMS as an internal
standard.
Primary Amines
Acetic acid=propionic acid (4 mL) was added to a mixture of amine
(1 mmol) and hydrazine hydrate (1 mmol), and the reaction mixture
was refluxed for a length of time indicated in Tables 1 and 2. After the

Acylation of Amines
2937
completion of the reaction (monitored by TLC), the reaction mixture was
poured on crushed ice. The obtained product was washed with cold
water, dried, and recrystallized from a suitable solvent.
Secondary Amines
Acetic acid=propionic acid (4 mL) was added to a mixture of amine
(1 mmol) and hydrazine hydrate (1 mmol), and the reaction mixture
was refluxed for a length of time indicated in Tables 1 and 2. After the
completion of the reaction (monitored by TLC), the reaction was neutra-
lized with saturated NaHCO3 solution. The obtained product was
extracted with chloroform (3 ꢂ 15 mL), and combined organic extracts
were washed with cold water and dried over sodium sulphate. After
removal of the solvent under reduced pressure, the product was recrystal-
lized from a suitable solvent.
Data
N-(4-Chloro-phenyl)-acetamide (9); Table 1
IR (KBr). 3303 (-NH), 1669 (C O) cmꢁ1; 1H NMR (300 MHz, CDCl3),
=
2.18 (s, 3H, -COCH3), 7.28 (d, 2H, Ar-H, J ¼ 6.6 Hz), 7.47 (d, 2H, Ar-H,
J ¼ 8.4 Hz), 7.9 (s, 1H, NH).
N-p-Tolyl-acetamide (12); Table 1:
IR (KBr). 3301 (-NH), 1665 (C O) cmꢁ1; 1H NMR (300 MHz, CDCl3),
=
2.18 (s, 3H, -COCH3), 7.12 (d, 2H, Ar-H, J ¼ 7.6 Hz), 7.80 (d, 2H, Ar-H,
J ¼ 7.9 Hz), 8.0 (s, 1H, NH).
N-p-Tolyl-propionamide (6) Table 2:
IR (KBr). 3303 (-NH), 1664 (C O) cmꢁ1; 1H NMR (300 MHz, CDCl3),
=
2.18 (q, 2H, -CH2 of C2H5), 2.31 (s, 3H, p-CH3), 2.38 (t, 3H, CH3of
C2H5), 7.11 (d, 2H, Ar-H, J ¼ 7.8 Hz), 7.40 (d, 2H, Ar-H, J ¼ 8.0 Hz),
8.0 (s, 1H, NH).
CONCLUSION
In conclusion, we have demonstrated a general, very clean method of
N-acylation with good yield and excellent selectivity, in which no side

2938
M. Basanagouda et al.
products have been isolated. In addition, the workup procedure is easy
and chromatographic purification of the acylated product is not required.
Although procedures exist for acylation of amines, the simplicity of
the procedure and the purity of the products obtained make it a better
practical alternative to the existing acylation methods.
ACKNOWLEDGMENTS
The authors thank Karnatak University, Dharwad, and University
Grants Commission, New Delhi, India, for financial support and thank-
ful to the University Sophisticated Instruments Centre, Karnatak Univer-
sity, Dharwad, for providing the spectral data.
REFERENCES
1. (a) Ahmad, S.; Iqbal, J. Cobalt(II) chloride catalysed coupling of thiols and
anhydrides: A new and efficient synthesis of thiol esters. Tetrahedron Lett.
1986, 27, 3791–3794; (b) Chandrashekhar, S.; Ramchander, T.; Takhi, M.
Acylation of alcohols with acetic anhydride catalyzed by TaCl5: Some impli-
cations in kinetic resolution. Tetrahedron Lett. 1998, 39, 3263–3266; (c)
Chakraborti, A. K.; Gulhane, R. Indium(III) chloride as a new, highly
efficient, and versatile catalyst for acylation of phenols, thiols, alcohols,
and amines. Tetrahedron Lett. 2003, 44, 6749–6753; (d) De, S. K. Rutheniu-
m(III) chloride catalyzed acylation of alcohols, phenols, thiols, and amines.
Tetrahedron Lett. 2004, 45, 2919–2922.
2. (a) Kamal, A.; Khan, M. N. A.; Reddy, K. S.; Srikanth, Y. V. V.; Krishnaji,
T. Al(OTf)3 as a highly efficient catalyst for the rapid acetylation of alcohols,
phenols and thiophenols under solvent-free conditions. Tetrahedron Lett.
2007, 48, 3813–3818; (b) Ishihara, K.; Kubota, M.; Kurihara, H.; Yamamoto,
H. Scandium Trifluoromethanesulfonate as an extremely active lewis acid
catalyst in acylation of alcohols with acid anhydrides and mixed anhydrides.
J. Org. Chem. 1996, 61, 4560–4567; (c) Orita, A.; Tanahashi, C.; Kakuda, A.;
Otera, J. Highly powerful and practical acylation of alcohols with acid
anhydride catalyzed by Bi(OTf)3. J. Org. Chem. 2001, 66, 8926–8934; (d)
Dalpozzo, R.; Nino, A. D.; Maiuolo, L.; Procopio, A.; Nardi, M.; Bartoli,
G.; Romeo, R. Highly efficient and versatile acetylation of alcohols catalyzed
by cerium(III) triflate. Tetrahedron Lett. 2003, 44, 5621–5624; (e) Chauhan,
K. K.; Frost, C. G.; Ian, L.; David W. Indium Triflate: An efficient catalyst
for acylation reactions. Synlett. 1999, 1743–1744; (f) Chandra, K. L.; Sarva-
nan, P.; Singh, R. K.; Singh, V. K. Lewis acid catalyzed acylation reactions:
scope and limitations. Tetrahedron 2002, 58, 1369–1374; (g) Procopiou, P. A.;
Baugh S. P. D.; Flack, S. S.; Inglis, G. G. A. An extremely powerful acylation
reaction of alcohols with acid anhydrides catalyzed by Trimethylsilyl tri-
fluoromethanesulfonate. J. Org. Chem. 1998, 63, 2342–2347; (h) Karimi, B.;

Acylation of Amines
2939
Maleki, J. Lithium trifluoromethanesulfonate (LiOTf) as a recyclable catalyst
for highly efficient acetylation of alcohols and diacetylation of aldehydes
under mild and neutral reaction conditions. J. Org. Chem. 2003, 68,
4951–4954.
3. (a) Nakae, Y.; Kusaki, I.; Sato, T. Lithium perchlorate catalyzed acetylation
of alcohols under mild reaction conditions. Synlett. 2001, 1584–1586; (b) Bartoli,
G.; Bosco, M.; Dalpozzo, R.; Marcantoni, E.; Massaccesi, M.; Rinaldi, S.;
Sambri, L. Mg(ClO4)2 as a powerful catalyst for the acylation of alcohols
under solvent-free conditions. Synlett. 2003, 39–42; (c) Chakraborti, A. K.;
Sharma, L.; Gulhane, R.; Shivani. Electrostatic catalysis by ionic aggre-
gates: scope and limitations of Mg(ClO4)2 as acylation catalyst. Tetra-
hedron 2003, 59, 7661–7668; (d) Chakraborti, A. K.; Gulhane, R.;
Shivani. Bismuth oxide perchlorate as a highly efficient catalyst for het-
eroatom acylation under solvent-free conditions. Synlett. 2003, 1805–1808.
4. (a) Chakraborti, A. K.; Gulhane, R. Fluoroboric acid adsorbed on silica gel
as a new and efficient catalyst for acylation of phenols, thiols, alcohols, and
amines. Tetrahedron Lett. 2003, 44, 3521–3525; (b) Chakraborti, A. K.;
Gulhane, R. Perchloric acid adsorbed on silica gel as a new, highly efficient,
and versatile catalyst for acetylation of phenols, thiols, alcohols, and amines.
Chem. Commun. 2003, 1896–1897; (c) Kumar, P.; Pandey, R. K.; Bodas, M.
S.; Dongare, M. K. Yttria-Zirconia based lewis acid: an efficient and chemo-
selective catalyst for acylation reactions. Synlett. 2001, 206–209; (d) Billini,
R.; Bosica,G.; Carloni, S.; Ciaralli, L.; Maggi, R.; Sartori G. Zeolite HSZ-
360 as a new reusable catalyst for the direct acetylation of alcohols and phe-
nols under solventless conditions. Tetrahedron Lett. 1998, 39, 6049–6052; (e)
Li, A. X.; Li, T. S.; Ding, T. H. Montmorillonite K-10 and KSF as remark-
able acetylation catalysts. Chem. Commun. 1997, 1389–1390; (f) Yadav, V.
K.; Babu, K. G.; Mittal, M. KF–Al2O3 is an efficient solid support reagent
for the acetylation of amines, alcohols, and phenols. Impeding effect of sol-
vent on the reaction rate. Tetrahedron 2001, 57, 7047–7051.
5. (a) Borah, R.; Deka N.; Sarma, J. C. J. Iodine as an acetyl transfer catalyst. J.
Chem. Research (S) 1997, 110–111; (b) Kartha, K. P. R.; Field, R. A. Iodine:
A versatile reagent in carbohydrate chemistry IV. Per-O-acetylation, regiose-
lective acylation and acetolysis. Tetrahedron 1997, 53, 11753–11766.
6. Okano, T.; Miyamoto, K.; Kiji, J. Transesterification catalyzed by Lantha-
noid tri-2-propoxides. Chem. Lett. 1995, 24, 246–246.
7. Prasad, H. S.; Srinivasa, G. R.; Gowda, D. C. Convenient, Cost-effective,
and mild method for the N-acetylation of anilines and secondary amines.
Synth. Commun. 2005, 35, 1189–1195.
8. Choudary, B. M.; Kantam, M. L.; Neeraja, V.; Bandyopadhyay, T.; Reddy,
P. N. Vanadyl(IV) acetate, a new reusable catalyst for acetylation of alcohols.
J. Mol. Cat. A 1999, 140, 25–29.
9. Forsyth, S. A.; MacFarlane, D. R.; Thomson, R. J.; Von Itzestein, M. Rapid,
clean, and mild O-acetylation of alcohols and carbohydrates in an ionic
liquid. Chem. Commun. 2002, 714–715.

2940
M. Basanagouda et al.
10. Allevi, P.; Ciuffreda, P.; Longo, A.; Anastasia, M. Lipase-catalysed chemo-
selective monoacetylation of hydroxyalkylphenols and chemoselective
removal of a single acetyl group from their diacetates. Tetrahedron: Asym-
metry 1998, 9, 2915–2924.
11. Ghosh, R.; Maiti, S.; Chakraborty, A. Facile catalyzed acylation of alcohols,
phenols, amines and thiols based on ZrOCl2ꢀ8H2O and acetyl chloride in sol-
ution and in solvent-free conditions. Tetrahedron Lett. 2005, 46, 147–151.
12. Ghosh, R.; Maiti, S.; Chakraborty, A. Facile catalyzed acylation of hetero-
atoms using BiCl3 generated in situ from the procatalyst BiOCl and acetyl
chloride. Tetrahedron Lett. 2004, 45, 6775–6778.
13. Iranpoor, N.; Firouzabadi, H.; Jamalian, A. Silphos [PCl3-n(SiO2)n]: a het-
erogeneous phosphine reagent for formylation and acetylation of alcohols
and amines with ethyl formate and acetate. Tetrahedron Lett. 2005, 46,
7963–7966.
14. Reddy, T. S.; Narasimhulu, M.; Suryakiran, N.; Mahesh, K. C.; Ashalatha,
K.; Venkateswarlu, Y. A mild and efficient acetylation of alcohols, phenols
and amines with acetic anhydride using La(NO3)3ꢀ6H2O as a catalyst under
solvent-free conditions. Tetrahedron Lett. 2006, 47, 6825–6829.
15. Ahmed, N.; van Lier, J. E. Molecular iodine in isopropenyl acetate (IPA): a
highly efficient catalyst for the acetylation of alcohols, amines and phenols
under solvent free conditions. Tetrahedron Lett. 2006, 47, 5345–5349.
16. Brar, A.; Vankar, Y. D. A one-pot selective deprotective acetylation of
benzyl ethers and OTBDMS ethers using the BF3ꢀEt2OꢁNaIꢁAc2O reagent
system. Tetrahedron Lett. 2006, 47, 5207–5210.
17. Naik, S.; Bhattacharjya, G.; Talukdar, B.; Patel, B. K. Chemoselective acyla-
tion of amines in aqueous Media. Eur. J. Org. Chem. 2004, 1254–1260.
18. (a) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 3rd
ed.; John Wiley and Sons: New York, 1999; (b) Hanson, J. R. Protective
Groups in Organic Synthesis; Blackwell Science: Malden, MA, 1999; (c)
Hofle, G.; Steglich, W.; Vorbruggen, H. 4-Dialkylaminopyridines as highly
active acylation catalysts. Angew. Chem. Int. Ed. Eng. 1978, 17, 569–583.
19. (a) Furniss, B. S.; Hannaford, A. J.; Smith, P. W. G.; Tatchell, A. R. Vogel’s
Textbook of Practical Organic Chemistry, 5th ed.; Addison Wesley Longman:
Harlow, England (UK), 1997; pp. 1348–1379; (b) Paul, S.; Nanda, P.; Gupta,
R.; Loupy, A. Ac2OꢁPy=basic alumina as a versatile reagent for acetylations
in solvent-free conditions under microwave irradiation. Tetrahedron Lett.
2002, 43, 4261–4265; (c) Shaffer, C. L.; Harriman, S.; Koen, Y. M; Hanzlik,
R. P. Formation of Cyclopropanone during Cytochrome P450-Catalyzed
N-Dealkylation of a Cyclopropylamine. J. Am. Chem. Soc. 2002, 124,
8268–8274; (d) Hwang, Y. C.; Chu, M.; Fowler, F. W. A synthesis of
alpha-substituted amines. J. Org. Chem. 1985, 50, 3885–3890; (e) Hama,
T.; Culkin, D. A.; Hartwig, J. F. Palladium-catalyzed intermolecular
a-arylation of zinc amide enolates under mild conditions. J. Am. Chem.
Soc. 2006, 128, 4976– 4985.