Formamide as an ammonia synthon in amination of acid chlorides

Article abstract of DOI:10.1080/00397910903457373

The use of formamide as a convenient source of ammonia has been explored for the direct transformation of acid chlorides to primary amides. Various aliphatic, alicyclic aromatic, and heterocyclic acid chlorides are converted to the corresponding carboxamides in good yields (75-94%). Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910903457373

This article was downloaded by: [171.67.34.205]
On: 27 March 2013, At: 03:43
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
Formamide as an Ammonia Synthon in
Amination of Acid Chlorides
S. Srinivasan a & P. Manisankar a
a Department of Industrial Chemistry, Alagappa University,
Karaikudi, India
Version of record first published: 05 Nov 2010.
To cite this article: S. Srinivasan & P. Manisankar (2010): Formamide as an Ammonia Synthon
in Amination of Acid Chlorides, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 40:23, 3538-3543
To link to this article: http://dx.doi.org/10.1080/00397910903457373
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, 40: 3538–3543, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903457373
FORMAMIDE AS AN AMMONIA SYNTHON
IN AMINATION OF ACID CHLORIDES
S. Srinivasan and P. Manisankar
Department of Industrial Chemistry, Alagappa University, Karaikudi, India
The use of formamide as a convenient source of ammonia has been explored for the direct
transformation of acid chlorides to primary amides. Various aliphatic, alicyclic aromatic,
and heterocyclic acid chlorides are converted to the corresponding carboxamides in good
yields (75–94%).
Keywords: Acid chlorides; amination; ammonia synthon; formamide; primary amides
The amide bond is an important building unit, whether naturally occur-
ring or synthetically formed.[1] The preparation of primary amides from the corre-
sponding carboxylic acids is a basic and well known transformation in organic
synthesis.[2] In general, the formation of carboxamides from carboxylic acids
requires activation of the carboxylic group. Carboxylic activation can be achieved
by conversion of the carboxyl group to a more reactive functional group such as acyl
halide, mixed anhydride, acyl azide and active ester or by insitu activation by coup-
ling reagents. Variety of mild one-step dehydrocondensation methods have been
developed for synthesizing secondary and tertiary amides from carboxylic acids
and amines.[3–5] In contrast, reports of a similar coupling between carboxylic acid
and ammonia leading to the formation of primary amides are limited. The synthesis
of primary amide is considerably more difficult, this is attributable to both the lower
nucleophilicity of ammonia and difficulties associated with the handling of gaseous
ammonia. Therefore an efficient and convenient method is still being sought.
In traditional thermal methods for direct conversion of carboxylic acids in to
primary amides, a mixture of the acid and ammonia are heated at high tempera-
ture (around 200 ꢀC) for several hours.[6,7] Activated derivatives of carboxylic acids
such as acid chlorides, acid anhydrides or activated esters reportedly undergo
coupling with aqueous ammonia.[8–12] Morera et al.[13] reported hexamethyldisila-
zane (HMDS) as a synthon for ammonia in other reactions.[14] Titanium-nitrogen
complex as a ammonia source[15] and magnesium nitride as a ammonia source[16]
are well documented in literature. McMurray et al.[17] reported a method that
uses a combination of ammonium chloride and expensive coupling agents like
Received August 7, 2009.
Address correspondence to P. Manisankar, Department of Industrial Chemistry, Alagappa
University, Karaikudi, India. E-mail: pms11@rediffmail.com
3538

FORMAMIDE AS AN AMMONIA SYNTHON
3539
DIPEA, HOBt, HBTU, EDCA, DCC, etc. Tsukasa et al.[18] reported direct
method by reaction of acid and ammonia in alcohols using DMT-MM. Similar
reaction was reported in presence of hydrous zirconium (IV) oxide.[19] A drawback
in these reactions is handling of gaseous ammonia. Several general methods for
reduction of aroylazides to amides have also been reported.[20] Nehadi et al.[21]
described the preparation of primary amides from carboxylic acid and urea using
imidazole under microwave irradiation. However; most of these procedures have
lot of usage limitations. Catalytic agents used for amide formation, should be
treated carefully during the reactions because they are harmful to both body
and environment.
During recent years, formamide and N,N0-substituted formamide have been
used in the preparation of amines=amides and N,N0-substitured amines=amides.
Conversion of carboxylic esters to primary amides using formamide in presence of
methanolic sodium methoxide was reported by Jagdmann et al.[22], Schnyder
et al.[23] and Wan et al.[24] reported independently palladium catalyzed amino carbo-
nylation of aryl halides to aryl amides using formamide as an ammonia synthon
using different palladium compounds. N,N0-dimethyl acetamide (DMA),
N,N0-dimethyl formamide (DMF) and N-methyl formamide are well known
reagents for dimethylamination and methylamination of aromatic, heteroaromatic
halides.[25–29] DMF is also known for dimethylamination of acid chlorides to the cor-
responding disubstituted amides.[30,31] There have been no reports, however, of the
direct synthesis of primary amides from carbonyl chlorides by using formamide as
an ammonia synthon. Formamide is known to undergo thermal decomposition just
like DMF.[32] Formamide begins to partially decompose into carbon monoxide and
ammonia at 180 ꢀC. Although formamide has been reported to serve as an ammonia
synthon[23,24] to the best of our knowledge, no example is available in which it has
been exploited for direct amination of acid chlorides. In this communication, we
report amination of acid chlorides 1 to the corresponding primary amides 2 using
formamide as an ammonia source. Since formamide is cheap, easy to handle and
good source of ammonia, it is of special interest to synthesize primary amides using
formamides (Scheme 1).
Benzyl amide was first synthesized to ascertain the reaction conditions.
Benzoylchloride and formamide were put together in a reaction chamber and
initially heated to 60–70 ꢀC. No progress in the reaction at this temperature. So
the temperature increased to 100–120 ꢀC. The heating was continued for 5 to 6 hours
and after ascertaining the absence of acyl chloride in the reaction mixture. The reac-
tion mass quenched in excess water and extracted with dichloromethane. The
organic solvent was washed with saturated NaHCO3 aqueous solution and dried
over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to give
the residue which was purified by column chromatography using silica gel and
Scheme 1. Reaction of acid chlorides with formamide.

3540
S. SRINIVASAN AND P. MANISANKAR
Table 1. Amination of substituted acid chlorides with formamide
Entry
Substituent R1 in 1
Mp in ꢀC (Lit)
Mp in ꢀC (Obs.)
Yield in %
a.
b.
c.
d.
e.
f.
C6H5
2-Cl, 4-FC6H3
2-Cl-C6H4
125–127
192–195
142–144
127–128
191–194
180–181
Not available
182–184
172–176
155–156
184–186
142–148
109–110
164
128–129
195–197
140–144
125–126
190–192
178–182
259–162
180–184
170–172
154–157
180–184
145–149
108–111
161–167
61–62
90
92
93
90
91
89
75
93
92
88
67
92
94
75
88
2-OCH3C6H4
2-Cl, 4-ClC6H3
2-Theinyl
g.
h.
i.
4-Amino imidazole
4-NH2C6H5
4-ClC6H5
j.
Benzyl
k.
l.
4-CF3C6H5
2-NO2, 4-Cl C6H3
2-NH2C6H5
2-CF3C6H5
Pentadecane
m.
n.
o.
Not available
EtOAc=hexane as eluent. High yield of 90% benzyl amide was obtained from this
method. In this reaction, formamide was used as ammonia synthon. No solvent
was used. The temperature was well within the decomposition point. Compared
with the traditional amide synthetic procedure, this method is simple, convenient,
and cost-effective. Harmful catalysts and solvents are not employed here and the
temperature of synthesis is also well within the limit. This approach to synthesize
bezylamide resulted in high yield.
Encouraged with the results, we extended this synthetic procedure to several
different acid chlorides with formamide. A solution of variously substituted aryl=
heteroaryl=alicyclic=aliphatic acid chlorides 1a–o in formamide was heated to
100–120 ꢀC After heating the mixture for 5 to 6 hours, the solution was processed
as previously and the desired primary amide 2a–o was obtained with excellent yield
as shown in Table 1.
The structures of primary amides synthesized 2a–o were ascertained by their
1
characteristic FT IR, H NMR and Mass spectroscopic data. In the FT IR spectra
of the amides, characteristic amide peaks were observed for all compounds.
The reaction mechanism giving primary amide may be assumed that forma-
mide decomposes slowly under heating to afford ammonia and carbon monoxide.
So it is possible that the amination could be possible by the reaction of acyl chloride
with the ammonia produced from the decomposition.
In summary, we have described the first application of formamide as a con-
venient source of ammonia to effect the conversion of a range of acid chloride
substrates to primary amides. Noteworthy features of this procedure include the
facile reaction set-up using formamide as bench-stable solution, the ease of reaction
work-up and the excellent yields observed in majority of cases. Above all, it is
new pathway for the synthesis of primary amides without using harmful solvent
or catalysts. It is anticipated that the amides will find further applications within
the field of organic synthesis.

FORMAMIDE AS AN AMMONIA SYNTHON
3541
EXPERIMENTAL
Solvents for chromatography and other reagents were obtained from commer-
cial sources and were used as such without any further purification unless specified.
The melting points are recorded on Buchi-535 apparatus and are uncorrected. The
1H NMR spectra were obtained using a 200 MHz Varian Gemini spectrometer using
tetramethylsilane as internal standard. Infrared spectra were recorded using a
Perkin-Elmer model 1640 instrument (Norwalk, CT, USA). Mass spectra were
recorded on an MS Engine-Hewlett-Packard model 5989 (Santa Clara, CA, USA)
at DIP 20 eV.
Typical Procedure for Amination
All the experiments were carried out in a parallel synthesizer from REDLEYS
Discovery Technologies, UK. A solution of acid chloride 1a (1.0 gm 7.11 mmol) in
formamide (10 ml) was heated to 100–120 ꢀC and maintained at same temperature
for 5 to 6 hours, the reaction mixture was cooled to room temperature. The reaction
mass quenched in excess water and extracted with dichloromethane. The combined
organic solvent was washed with saturated NaHCO3 aqueous solution and dried over
anhydrous Na2SO4. The solvent was evaporated under reduced pressure to give the
residue which was purified by column chromatography using silica gel and EtOAc=
hexane as eluent. An amount of 0.77 g (6.4 mmol, 90%) of 2a was obtained as crystals.
REFERENCES
1. (a) North, M. Amines and amides. Contemp. Org. Synth. 1994, 1(6), 475; (b) Beckwith,
A. L. J. Synthesis of amides. In The Chemistry of Amides: Synthesis of Amides; J. Zabicky
(Ed.); Interscience: New York, 1970; p. 96.
2. (a) March, J. Advanced Organic Chemistry; John Wiley & Sons: New York, 1992; pp. 416–
425; (b) Amide synthesis. In Comprehensive Organic Synthesis; B. M. Trost (Ed.); Pergamon
Press: Oxford, 1991; pp. 381–417.
3. (a) Beckwith, L. J. In The Chemistry of Amides; J. Zabicky (Ed.); Interscience: London,
1970; p. 73; (b) Benz, G. Amide synthesis. In Comprehensive Organic Synthesis; B. M. Trost
(Ed.); Pergamon Press: Oxford, 1991; vol. 6, p. 381; (c) Bailey, P. D.; Collier, I. D.;
Morgan, K. M. In Comprehensive Organic Functional Groups Transformations; A. L. O.
Katrizky, Meth-Cohn, C. W. Rees (Eds.); Pergamon Press: New York, 1995; vol. 5, p. 257.
4. Maki, T.; Ishihara, K.; Yamamoto, H. 4, 5, 6, 7-Tetrachlorobenzo[d][1,3,2]dioxaborol-
2-ol as an effective catalyst for the amide condensation of sterically demanding carboxylic
acids. Org. Lett. 2006, 8, 1431–1434.
5. Al-Zoubi, R. M.; Marion, O.; Hall, D. G. Direct and waste-free amidations and cyclo-
additions by organocatalytic activation of carboxylic acids at room temperature. Angew.
Chem. Int. 2008, 47, 2876–2879.
6. Coppinger, G. M. Preparation of N,N-dimethylamides. J. Am. Chem. Soc. 1953, 76,
1372–1373.
7. Mitchell, J. A.; Reid, E. E. The preparation of aliphatic amides. J. Am. Chem. Soc. 1931,
53, 1879.
8. Katritzky, R.; He, H.-Y.; Suzuki, K. N-Acylbenzotriazoles: Neutral acylating reagent
for the preparation of primary, secondary and tertiary amides. J. Org. Chem. 2000, 65,
8210–8213.

3542
S. SRINIVASAN AND P. MANISANKAR
9. Chen, S.-T.; Wu, S.-H.; Wang, K.-T. A convenient synthesis of methylamine and
dimethylamino substituted aromatic compounds. Synthesis 1989, 37.
10. Pozdnev, V. F. Activation of carboxylic acids by pyrocarbonates. Application of di-tert-
butylpyrocarbonate as condensing reagent in the synthesis of amides of protected amino
acids and peptides. Tetrahedron Lett. 1995, 36, 7115.
11. Ba¨nteli, R.; Ernst, B. Synthesis of sialyl Lewis mimics: Modification of the 6-position of
galactose. Bioorg. Med. Chem. Lett. 2001, 11, 459.
12. Taylor, J. G.; Li, X.; Oberthur, M.; Zhu, W.; Kahne, D. E. The total synthesis of
¨
moenomycin A. J. Am. Chem. Soc. 2006, 128, 15084–15085.
13. Morera, E.; Qrtar, G. Palladium catalyzed carbonylative route to primary amides.
Tetrahedran Lett. 1998, 39, 2835–2838.
14. (a) Pellegata, R.; Italia, A.; Villa, M.; Palmisano, G.; Lesma, G. A facile preparation
of primary carboxamides. Synthesis 1985, 517–519; (b) Bruning, J. Lithium and potassium
¨
bis(trimethylsilyl) amide: Utilizing non nucleuophilic bases as nitrogen sources.
Tetrahedron Lett. 1997, 38, 3187–3188.
15. Ueda, K.; Sato, Y.; Mori, M. Incorporation of N2 and CO in to organic molecules: Amide
formation by palladium catalyzed carbonization and nitrogenation. J. Am. Chem. Soc.
2000, 122, 10722–10723.
16. Veitch, G. E.; Bridgwood, K. L.; Ley, S. V. Magnesium nitride as a convenient source of
ammonia: Preparations of primary amides. Organic Letters 2008, 10(16), 3623–3625.
17. Wang, W.; McMurray, S. Selective methods for the preparation of primary amides:
Synthesis of Fmoc-L-4 carboxamidophenylalanine and other compounds. Tetrahedron
Lett. 1999, 40, 2501.
18. Mishear, T.; Hioki, K.; Yamada, M.; Sasaki, H.; Morisaki, D.; Kunishima, M. Direct
preparation of primary amides by reaction of carboxylic acids and ammonia in alcohols
using DMT-MM. Chem. Lett. 2008, 37(12), 1190–1191.
19. Takahashi, K.; Shibagaki, M.; Kuno, H.; Kawakami, H. The amidation of carboxylic
acid with amine over hydrous zirconium(IV) oxide. Bull. Chem. Soc. Jpn. 1989, 62,
1333–1334.
20. (a) Ranu, B. C.; Sarkar, A.; Chakraborty, R. Reduction of azides with zinc-borohydride.
J. Org. Chem. 1994, 59, 4114–4116; (b) Baruah, M.; Hussain, A.; Prajapati, D.; Sandhu, J.
S. A new and efficient method for the chemo selective reduction of azidoarenes and aroy-
lazides: Use of zinc–cobalt chloride. Chem. Lett. 1997, 789.
21. Khalafi-Nehadi, A.; Mohatari, B.; Rad, M. N. S. Direct preparation of primary amides
from carboxylic acids and urea using imidazole under microwave irradiation. Tetrahedron
Lett. 2003, 44, 7325–7328.
22. Jagdmann, E. G.; Munson, R. H.; Gero, T. W. A mild efficient procedure for the conver-
sion of carboxylic acid esters to primary amides using formamide=methanolic sodium
methoxide. Synth. Commun. 1990, 20(8), 1203–1208.
23. Schnyder, A.; Beller, M.; Mehltretter, G.; Nsenda, T.; Studer, M.; Indolese, A. F.
Synthesis of primary aromatic amides by aminocarbonylation of aryl halides using
formamide as an ammonia synthon. J. Org. Chem. 2001, 66, 4311–4315.
24. Wan, Y.; Alterman, M.; Larhed, M.; Hallberg, A. Formamide as a combined ammonia
synthon and carbon monoxide source in fast palladium-catalyzed aminocarbonylations
of aryl halides. J. Comb. Chem. 2003, 5(2), 82–84.
25. Zhao, J. K.; Wang, Y. G. A facile and efficient synthesis of N,N-dimethylarylamines
from aryl bromides. Chinese Chem. Lett. 2002, 13(12), 1149–1151.
26. Watanabe, T.; Tanaka, Y.; Sekiya, K.; Akita, Y.; Ohta, A. A convenient synthesis of
methylamino and dimethylamino substituted aromatic compounds. Synthesis 1980, 39–41.
27. Agarwal, A.; Chauhan, P. M. Convenient dimethylamino amination in heterocycles and
aromatics with dimethylformamide. Synth. Commun. 2004, 34(16), 2925–2930.

FORMAMIDE AS AN AMMONIA SYNTHON
3543
28. Cho, Y. H.; Park, J. C. A very convenient dimethylation of activated aromatic halides
using N,N-dimethylformamide and ethanol amides. Tetrahedron Lett. 1997, 38(48),
8331–8334.
29. Yamamoto, H. Anormalous halogen to dimethylamino replacement with N,N-
dimethylformamide catalyzed by ethylenediamine or 2-aminoethanol. Bull. Chem. Soc.
Jpn. 1982, 55, 2685–2686.
30. Coppinger, G. M. Preparations of N,N-dimethylamides. J. Am. Chem. Soc. 1953, 76,
1372–1373.
31. Lee, W. S.; Park, I. H.; Yoona, Y. J. N,N-Dimethylamination of acid chlorides with
DMF. Synth. Commun. 2000, 30(23), 4241–4245.
32. (a) Harada, K. Formation of amino-acids by thermal decomposition of formamide-
oligomerization of hydrogen cyanide. Nature 1967, 214, 479–480; (b) Kakumoto, T.;
Saito, K.; Imamura, A. Thermal decomposition if formamides: Shock tube experiments
and an initio calculations. J. Phys. Chem. 1985, 89, 2286–2291; (c) Parmeter, J. E.;
Weinberg, W. H. The interaction of formamide with hydrogen-presaturated Ru (001):
Conversion of .eta.1 (O)-NH2CHO to .eta.2(C, O)-bonded species. J. Am. Chem. Soc.
1988, 110, 7583–7590.