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! Publication: Der Pharma Chemica, 2011, 3, 3, 409-421.
CHAPTER 1
Review on N-acylation Reaction
N-acylation in non-aqueous and aqueous medium i.e. Schotten-Baumann
method of amide synthesis with carboxylic acid and activating reagent such as thionyl
chloride and Phosphine-halogen reagents have been discussed. Limitations,
alternative methods and applications of these reagents are illustrated with some
examples with upto date references.
Publication: Der Pharma Chemica, 2011, 3, 3, 409-421.
CHAPTER 1
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Contents
1. 1 Introduction
1. 2 Intermediate acid halides
1.2.1
Acid chlorides methods of preparation from SOCl2, oxalyl chloride
1.2.2
Acid chloride preparation from phosphine-halogen reagents
1.2.3
Effect of solvents and catalysts in activation reaction
1.2.4
Some reactions of acid chlorides
1.3 N-acylation in non-aqueous medium
1.3.1
General
1.3.2
Effect of substitution and steric effect
1.3.3
Some N-acylation reactions in synthesis
1.4 Aqueous N-acylation –Schotten-Baumann method
1.4.1
General
1.4.2
Schotten-Baumann reaction in amide synthesis
1.5 Other methods of amide synthesis
1.6 Conclusions
1.7 References
Ph. D. Thesis, Mr. Rambhau P. Gore Z. B. Patil College, Deopur, Dhule
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1. 1 Introduction:
In recent years with the introduction of new peptide coupling reagents in
organic synthesis, the methods of amide synthesis have been significantly advanced.
But the two step acylation, activation of carboxylic acid and reaction with amines
have been often used in non-peptide chemistry. Acid chlorides are generally
recognized as key intermediate for acylation, for conversion into many other
functional groups along with amides such as anhydrides, esters and ketones.
The acylation of amines has been known since 1853, when Gerhardt reported
the acylation of anilines. N-acylation is the technique of protecting group in multistep synthetic processes, important synthetic routes for many bioactive compounds
such as Vitamins, agrochemicals, Xanthenes, and in combinatorial peptide synthesis.
Literature survey reveals that various drugs such as Penicillin (antibacterial),
pyrazineamide (anti tubercular) possess their specific activities due to presence of
amide linkage in their structures1.
In a typical N-acylation reaction, the carboxylic acid is first activated by
converting into acid chloride and then reacted with amine (Scheme 1).
O
R
O
activating
R
C
OH
reagent
C
Cl
acylation
R1NH2 /Base
O
R
Base. HCl
C
NHR1
Scheme 1. The two step acylation reaction
Since acid halides are moisture sensitive they are immediately converted to
more stable and inert organic compounds2 , amides and need not necessary to purify,
so when amines are added in situ amides are formed by a ‘one pot’ exothermic
reaction. Although amide synthesis has been continuously studied, convenient
Ph. D. Thesis, Mr. Rambhau P. Gore Z. B. Patil College, Deopur, Dhule
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reaction conditions have not yet been achieved, may be due to molecular diversity and
complexity.
1.2 Intermediate acid halides
Carboxylic acid halides are generally prepared from various starting
compounds by using common and recently introduced reagents such as SOCl23-12,
COCl213,14, (COCl)215, PCl316, PCl517, POCl318, PhCCl3/FeCl3, SOCl2-TPPO19,
Cl3CCOCCl3/ PPh320, Cl3CCN/PPh321-23, PPh3/trichloroisocyanuric acid24, carboxylic
acid esters, Cl3CCONH2/ PPh3, CCl4/PPh3, 1-halo N,N-2-trimethylpropenylamine and
cyanuric chloride (some reagents are illustrated with references in text).
Some of the methods of acid chloride preparations are illustrated (Scheme 2)
with advantages, alternatives and disadvantages.
1.2.1 The methods of preparation from thionyl chloride and Oxalyl
chloride
From thionyl chloride
R
Cl
O
S
C
S
C
O
OH
O
OH
R
Cl
Cl
O
Cl
H
O
SO2
HCl
R
C
Cl
O
O
C
S
R
Cl
O
Cl
From oxalyl chloride
Ph. D. Thesis, Mr. Rambhau P. Gore Z. B. Patil College, Deopur, Dhule
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R
O
O
O
Cl
+
C
C
R
Cl
OH
O
O
Cl
O
O
H Cl
O
HCl + CO
+ CO2 +
R
C
Cl
Scheme 2. Activation of carboxylic acid
Thionyl chloride remains the most popular reagent of preparation of acid
chlorides with advantages while some disadvantages which can be avoided by using
recently developed reagents when required. Thionyl chloride is volatile and excess
can be distilled off at the end, leaving acid chloride. Only gaseous by-products are
given out, no tedious workup is required for purification of acid chlorides. It also
reacts with sterically hindered acids. In variety of conditions SOCl2 works well hence
it has so wide applicability and is non-expensive.
In 1974 Olah and co-workers successfully converted sterically hindered acid
to acid chloride by refluxing25.
A. R. Katritzky and Yuming Zhey in 2003 developed neutral N-acylating
reagent for amides and peptide synthesis, N-acylbenzotriazole, which is also the
reagent of choice when the acid chlorides are unstable or difficult to isolate otherwise
by using SOCl2 , for example in RCOCl where R= 4-diethylaminopyridine, 2-pyridyl,
2-indolyl26,(Scheme 3).
O
O
N
N
N
( Bt )
H
R
SOCl2
DCM / rt.
0. 5 hr
OH
R
Bt
2 hr., stirring
1
THF R NH2
rt.
O
Bt
+
R
C
NHR1 Scheme 3. N-acylbenzotriazole preparation
Ph. D. Thesis, Mr. Rambhau P. Gore Z. B. Patil College, Deopur, Dhule
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In this method, to a solution of N-acylbenzotriazole in THF, amine was added and
reaction mixture was stirred at room temperature.
The method of activation of carboxylic acid using thionyl chloride can be
avoided in event of unwanted reactions. Use of SOCl2 is avoided in acid chloride
preparation of 5-(1-imidazolyl) pentanoic acid, as one would expect it also chlorinate
the imidazole ring under the reaction conditions (Scheme 4).
( COCl )2
N
N
0
N
60 C, 1hr.
. HCl
N
(CH2) 4 COOH
(CH2) 4 COCl
Scheme 4. Use of oxalyl chloride as a alternative
The formation of acid chloride achieved by less aggressive chlorinating agent
oxalyl chloride.But care should be taken of complicated handling and three gaseous
by-products, one more than in reaction of thionyl chloride.
One of the major disadvantage of thionyl chloride is the by-product, HCl
which make the condition acidic which is not tolerated by Boc-protected amines.
Alternatively cyanuric chloride process presents many advantages; the
preparation of acid chloride27 is illustrated (Scheme 5).
Ph. D. Thesis, Mr. Rambhau P. Gore Z. B. Patil College, Deopur, Dhule
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O
R
C
H
R
O
H
O
N
N
C
O
O
O
weak base
O
R
O
Cl
O
3 R
C
N
C
O
Cl
N
N
N
C
R
H
N
R
C
N
O
Cl
O
N
3 HCl
O
O
CH3
H
OH
O
N
3
N
H
R
+
N
N
HO
OH
Scheme 5. Cyanuric chloride in amide synthesis
In presence of weak base particularly N-ethyl morpholine. The procedure is
cost
effective, since only 0.33 equivalent of reagent is needed, which minimizes
reagent utilization and by-products.
Technique of conversion of carboxylic acid to K+ salts is valuable28. Also in
neutral condition acid chlorides can be achieved by Ghosez and co-workers method
that uses 1-halo N, N-trimethylpropenylamine29 and DCM (dichloromethane)
(Scheme 6).
Cl
OH
O
O
Cl
N(CH3) 2
O
DCM /RT
100%
O
Scheme 6. 1-halo N, N-tri methyl propenylamine in activation
Ph. D. Thesis, Mr. Rambhau P. Gore Z. B. Patil College, Deopur, Dhule
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Hildebert B. Maurice et al. in 2009 chlorinated acridonic acids by heating with excess
of thionyl chloride30 (Scheme 7).
Cl
O
SOCl2
800C, 1 hr.
N
H
OH
O
R
N
R
O
Cl
R= H/ Me
Scheme 7. Double chlorination at C-9 and acid
Recently in 2010 David J. Hardee and his group developed a method of
activation of aliphatic carboxylic acids taking 3, 3-dichlorocyclopropenes in presence
of tertiary amine base31, DIPEA (diisopropylethylamine) (Scheme 8).
O
R
1.0 eq. reagent
O
2.2 eq. DIPEA
C
R
OH
C
Cl
DCM, RT
2-10 min.
R: alkyl
reagent :
Cl
Cl
Scheme 8. 3,3-dichlorocyclopropenes as reagent of activation
Racemization is frequent in the course of coupling reactions at the C-terminal amino
acid residue due to the ionization of the Į-hydrogen atom and formation
of an oxazolone intermediate in peptide synthesis32. This will not be a reagent of
choice in peptide synthesis, where suitable peptide coupling reagent can be selected,
or N-acylbenzotriazole can be applied which is known for avoiding racemisation.
Ph. D. Thesis, Mr. Rambhau P. Gore Z. B. Patil College, Deopur, Dhule.
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1.2.2 The methods of preparation from phosphine-halogen reagents
Phosphine-Halogens reagents are emerging as neutral and mild reagents in
acid chlorides and amide synthesis. Appel’s reaction discovered by Jie Jack Li, in
1971 is a mild and neutral condition reaction among the pioneer works33, (Scheme 9).
O
X
+
X
Ph3P
+ Ph3P
X C X3
Appel's salt
X
X
O
R
CHCX3
O
O
X
H
Ph3P
R
O
O
R
+
X
O
Ph3P
R
PPh3 =O
X
Scheme 9. Appel’s reaction
The reaction is slow and required high temperature. Villeneuve and his group
in 1997 have reported that carboxylic acids can be converted to acid chloride by
Hexachloroacetone-TPP at low temperature34. Similarly Trichloroacetonitrile-TPP
was found on same line.
Recently, Skydow in 2009, introduced a superior reagent, TrichloroacetamideTPP35, (Scheme 10).
O
Cl3CCONH2 (2 eq.)
PPh3 (2 eq.)
OH
DCM, reflux
30 min.
O
Cl
Scheme 10. Trichloroacetamide as activating reagent
Ph. D. Thesis, Mr. Rambhau P. Gore Z. B. Patil College, Deopur, Dhule.
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1.2.3 Effect of solvent and catalyst in activation reaction
In 1959, Bosshard achieved acid chloride of p-nitro benzoic acid, uncreative
as such to thionyl chloride using DMF as a catalyst36, (Scheme 11).
O
O
O
H
N
+
Cl
Cl
Cl
C
Cl
O
Cl
C
+ (CH3)2 N
(CH3)2 N
H
Cl
O
+
H
OH
O
O
O
O
R
C
Cl
unstable adduct
O
R
S
C
.Cl
imminium chloride( I)
+
(CH3)2 N
S
H
+
S O2
O
+
(CH3)2 N
S
R
Cl
+
N
H
+
2HCl
H
. Cl
Scheme 11. DMF as catalyst in activation step
DMF allows milder reaction condition and accelerates the reaction. It effects
conversion in less time. Wilsmayer in 1971 has proposed that, the active reagent is an
imminium chloride (I). He also assumed the possibility of participation of the initially
formed unstable adduct.37
Mastuda in 1985, successfully tuned condition to get acid chloride within 1
min. by combination of solvent and catalyst38, (Scheme 12).
Ph. D. Thesis, Mr. Rambhau P. Gore Z. B. Patil College, Deopur, Dhule.
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O
O
SOCl2
R
Cl
O
SOCl2
Cl
R
Py., 1 hr.
OH
Py., DCM, 6 min.
R
ethylacetate
N
H
O
O
SOCl2
R
O
N
H2
R
within 1min.
Cl
Salt
Scheme 12. Dicyclohexylamine as base in acid chloride preparation
Danuta Bartulewicz et al in 1998, have converted 2,5-pyridine dicarboxylic
acid into corresponding acid chloride using DMF as catalyst39, (Scheme 13).
COCl
COOH
SOCl2, C6H6
DMF
COOH
N
N
COCl
Scheme 13. DMF as catalyst in chlorination
John W. Hull Jr. et al. in 2007 have chlorinated 4-bromo-3-methyl-2thiophenecarboxylic acid by heating in presence of DMF as catalyst3 (Scheme 14).
O
OH
Br
S
O
SOCl2, 1,2-DCE
DMF, 800C
Cl
Br
S
Scheme 14. DMF as catalyst
In place of acid chloride, fluoride is also an alternative and known to be more stable
to hydrolysis than acid chloride but they have been rarely used. This can be prepared
by using cyanuric fluoride or using TFFH2, (Scheme 15).
Ph. D. Thesis, Mr. Rambhau P. Gore Z. B. Patil College, Deopur, Dhule.
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F
O
O
N
H
N
Pyridine
OH + F
X
H
N
N
DCM, Stir, 3-4 hr., rt.
R
X
F
N
R
F
OH
N
N
PF6
N
F
DIPEA , DCM
rt., 8-15 min.
N
HO
+
N
O
OH
H
N
X
F
R
Scheme 15. Synthesis of acid fluoride
1.2.4 Some reactions of acid chlorides
Acid halides are important intermediate in organic synthesis, highly reactive,
highly sensitive to moisture giving unwanted product or undesirable product leading
to complex workup. So some important reactions of acid halides are discussed in brief
which are supposed to take place under the condition of reaction in presence of
moisture or impurities and some of them are synthetically important.
a) Hydrolysis
b) Esterification
c) SN reaction
d) Ring closure reaction
e) Hydrazide synthesis
f) Synthesis of isothiocynate
g) Unwanted/ side reactions
a) Hydrolysis
Acid halides have pronounced tendency to undergo hydrolysis to hydro halo
acids and corresponding carboxylic acids. The relative ease of hydrolysis of the acid
halides is related to the acid strength of the corresponding acid and with the
solubilities of the acid in medium40, (Scheme 16).
Ph. D. Thesis, Mr. Rambhau P. Gore Z. B. Patil College, Deopur, Dhule.
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O
R
O
OH
H2O
C
R
Cl
C
R
Cl
OH
H2O :
O
+
HCl
R
C
OH
Scheme 16. Hydrolysis of acid chloride
The benzoyl chloride only slowly hydrolyses in aqueous medium while acetyl
chloride vigorously. The hydrolysis of acid halides has been one of the chief
disadvantages of these intermediates and the reaction has no synthetic value as such.
b) Esterification
Primary and secondary alcohols are readily esterified with acid halides in
organic solvents, under Schotten- Baumann reaction conditions. The reaction is
usually quite rapid and proceeds well at rt41. (Scheme 17).
O
O
+
R
R'
OH
Cl
R
HCl
OR'
Scheme 17. Synthesis of ester
Frequently pyridine has been applied as an effective acid acceptor. The reaction is not
reversible as usual esterification of carboxylic acid in presence of acid catalyst.
c) SN reaction
Shahram M-Ataei et al. in 2007, reported Nucleophilic Substitution reaction
of two moles of benzilic acid (alcohol) with terephthaloyl chloride in the presence of
triethylamine hydrochloride42 (Scheme 18).
Ph. D. Thesis, Mr. Rambhau P. Gore Z. B. Patil College, Deopur, Dhule.
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Cl
O
+
O
2 HO
Cl
COOH
1800c 1,2-dichlorobenzene
O
O
O C
C
O
COOH
COOH
Scheme 18. Synthesis of ester
d) Ring closure reaction
Nakajima et al. in 1986 obtained 3-substituted isocoumarins by direct
condensation of acid chloride with homophthalic acid at 2000C43 (Scheme 19).
O
O
O
N
OH
Cl
+
R
O
HO
O
O
R
N
O
O
O
Scheme 19. Synthesis of isocoumarin
Gustavo P. R. et al. in 2009, reported synthesis of 2-substituted benzimidazole
by the condensation of o-phenylenediamine and acyl chlorides in the presence of a
catalytic amount of heteropolyacids44 (Scheme 20).
Ph. D. Thesis, Mr. Rambhau P. Gore Z. B. Patil College, Deopur, Dhule.
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NH2
O
+
NH2
R1
N
HPAs (8mol%)
Cl
R1
AcOH, reflux, 4hr.
N
H
R
R
Scheme 20. Synthesis of heterocyclic molecules
e) Hydrazide synthesis
Acid chlorides are readily converted to important derivatives and intermediate,
hydrazides, (Scheme 21). In such reactions acid chlorides are preferred because
azides undergo rearrangement on heating.
O
O
H2N NH2. H2O
R
HCl
R
Cl
NH NH2
NaN3
O
R
N3
Scheme 21. Hydrazide synthesis
f) Synthesis of isothiocynate
Acid chloride on refluxing with ammonium thiocynate forms thioureides which in
turn can be converted into heterocyclic ring45, (Scheme22).
O
O
NH4SCN
R
Cl
acetone, reflux
R
N
C
S
Scheme 22. Isothiocyanate synthesis
g) Unwanted/ side reactions
Michael Davis et al. in 1977, have reported unexpected side reaction in activation
of carboxylic acid involving methyl group and suggested mechanism, (Scheme 23).
Ph. D. Thesis, Mr. Rambhau P. Gore Z. B. Patil College, Deopur, Dhule.
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SOCl
N
N
SOCl2
CH3
Cl
CH3
HCl
O
O
SOCl
SOCl
N
N
SOCl2
CH2
CH2 Cl
O
O
N
CCl3
O
Scheme 23. Chlorination of alkyl group
Boon noted that the heating of 2,4-dimethylthiazole-5-carboxylic acid with thionyl
chloride and subsequent hydrolysis afforded 4-methylthiazole-2,5-dicarboxylic acid46,
(Scheme 24).
HO
O
N
N
SOCl2
OH
reflux
S
OH
O
S
O
Scheme 24. Oxidation of alkyl group
So in those cases where rapid and complete chlorination of methyl group occurs the
present reaction provides a useful route to the corresponding carboxylic acids. They
proposed that the original carboxylic acid function is not involved in the chlorination
reaction. Such type of chlorination is not observed in substrates where methyl group is
not bonded to aromatic moiety as reported in activation of dicarboxylic acid using
thionyl chloride47 (Scheme 25).
Ph. D. Thesis, Mr. Rambhau P. Gore Z. B. Patil College, Deopur, Dhule.
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O
O
HO
O
O
O
N
OH
N
O
rreflux
O
O
O
Cl
SOCl2
O
O
O
N
Cl
N
O
O
Scheme 25. Usual activation
1.3 N-Acylation in non-aqueous medium
1.3.1 General
The treatment of acid halides with NH3 or amines is a very general reaction of
synthesis of amides. The acylation of amines has been known since 1853, when
Gerhardt reported the acylation of anilines48, before that in 1845, Fownes, crystallized
amide from the reaction of oil called furfurole with ammonia. The reaction is highly
exothermic and must be carefully controlled by cooling the reaction mixture or
performing the reaction in very dilute solution.
The typical acylation reaction is carried out by slow drop wise addition of an
amine in suitable dry solvent to solution of acid chloride in situ in presence of nonnucleophilic tertiary organic bases49 like pyridine, DMAP, TEA, 4-picoline, N-methyl
morpholine and sodium 2-ethylhexanoate (Scheme 26).
O
O
activating
R
OH
O
R' NH2
R
Cl
reagent
Base
R'
R
N
intermediate
H
HCl. Base +
Scheme 26. Role of base in N-acylation reaction
Rate determining step in the formation of amide by acylation is usually attack of
nucleophile on the carbonyl group rather than the subsequent reformation of the ʌPh. D. Thesis, Mr. Rambhau P. Gore Z. B. Patil College, Deopur, Dhule.
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bond and displacement of leaving group, therefore, the electron withdrawing X-atom
is able to stabilize the T.S. and tetrahedral intermediate. During acylation the presence
of base is crucial to neutralize the one equivalent of acid formed, otherwise it will
consume the amine and diminish the yield. These organic bases act as catalysts in the
reaction (Scheme 27).
O
O
+
R
Cl
R
N
+.
N Cl
pyridine
R'NH2
H . Cl
N+
O
+
R
NHR'
Scheme 27. Pyridine as catalyst in amide synthesis
Usually hydrochloride acceptor should be a base which is stronger than the
base R1NH2. So the acylation of an equimolar mixture of two amines usually observed
the conversion of weaker amine to amide and hydrochloride of the stronger amine in
number of solvents.
In some cases the selectivity of acylation was also found to depend on steric
effect such as in acylation of mixture of cases like aniline-p-toluidine, aniline-pphenetidine. This can be avoided by use of bases which does not undergo reaction
such as tertiary amines like pyridine, TEA etc.
Similarly Vedejs in 1993 proved that DMAP and TEA combination is superior
in acylation of alcohol with acetic anhydride50. He believed that the reason could be
the TEA which prevents acetic acid from destroying the DMAP catalyst. The same
combination can be applied to acylation of amines.
N-acylation reaction is well studied, using acetyl chloride and acetic
anhydrides reagents, which take place in variety of manners51. Jacobson observed that
the introduction of first aryl group markedly reduces the nucleophilicity of the amine
for the further acylation. So acylation can be tuned to desire aim, to stop at monoacyl
Ph. D. Thesis, Mr. Rambhau P. Gore Z. B. Patil College, Deopur, Dhule.
CHAPTER 1
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step or to proceed for diacylation, in variety of manners. High conc. and fast addition
of acid halide and less mixing and high temperature combination could give diacyl
derivative in case of acetyl halide and acetic anhydride reagents52. In our attempt to
synthesize diazolylderivative of various substituted anilines treating with azole-1acetylchlorides, yield was found below 12%, the reason may be steric effect of bulkier
azole-1-acetyl chlorides53.
The majority of acylation reactions are conducted in aprotic organic solvents
such as benzene, toluene, diethyl ether, acetone, dioxane, MeCN, DMF, THF, HMPA,
4-picoline, TEA DCM54 DMAC55, pyridine38, acetic acid/MeOH56 and catalysts
utilized are pyridine57, 4-DMAP58, CuO, zinc acetate/ acetic acid59.
The catalytic activity of nucleophiles such as pyridine in acylation reaction has
been known for over a century. In late 1960s the remarkable nucleophilic activity of
4-DMAP first discovered by Litvinenko and Steglich as an acylation catalyst60. In
1993, Vedejs et al. reported novel catalyst, tributylphosphine, in the acylation of
alcohols with carboxylic acid anhydrides and shown that the catalytic activity
increased with phosphorous nucleophilicity50.
1.3.2 Effect of substituents and steric effect
Sudborough in 1901 have shown that a methyl (positive) group or a second
hydrogen residue in the o-position to the amino group favour the formation of
diacetylderivative when refluxed61. L.C. Raiford and co-workers in 1924 observations
supports the study of Sudborough when they studied the acylation of aromatic amines
with acetic anhydrides, found that o-substituent did not retard the reaction, but
frequently accelerate it62.
1.3.3 N-acylation reactions in synthesis
Some N- acylation reactions in synthesis are discussed in following schemesH. R. Snyder and his group in 1954 carried out the acylation of crotonyl chloride in
dry benzene with several hours addition of diethyl amine at 0oC, yielded N, N-diethyl
crotonamide63. Successively as the methodology of the synthesis of amides has been
continuously studied in search of convenient reaction conditions in variety of
substrates, newer challenges and solutions are coming up.
Ph. D. Thesis, Mr. Rambhau P. Gore Z. B. Patil College, Deopur, Dhule.
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P. K. Dubey and co-workers in 2000 reported acylation of 2, 3diaminopyridine by benzoyl chloride in presence of pyridine at rt., obtained
monoacetyl derivative only 64, (Scheme 28).
X
N
NH2
Ph COCl
NH2
Py. /RT
NHCOPh
X
NH2
N
X : H or Br
Scheme 28. Monoacylation substrate selectivity
The unusual resistance of 2-amino group towards acylation can be explained on the
basis of combination of steric and electronic effects. The 2-amino does not acylate
under condition of reaction because of its poor basic nature, further the two aryl
groups in diaroyl derivative cannot be planner with pyridine ring for steric reason.
In 2000 Hongwu Zhao and his group synthesized a macro cycle by acylation
of chiral diamine dihydrobomide intermediate in highly diluted solution when treated
with 2, 6-pyridinedicarbonyl dichloride at rt., using TEA in DCM65, (Scheme 29).
O
O
O
R
NH2
O
H2N
O
O
N
N
Cl
Cl
TEA, DCM/ RT
N
O
O
O
R
NH
HN
R
.2HBr
R= Me
O
N
O
R
O
R=Isopropyl
Scheme 29. Chiral amide synthesis
Similarly S.C.Ligon and his group in 2004 synthesized macromolecule dyads
by acylation in dioxane using TEA at RT66, (Scheme 30).
Ph. D. Thesis, Mr. Rambhau P. Gore Z. B. Patil College, Deopur, Dhule.
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COCl
O
H2N
2
O
NH2
O
+
O
O
OCF=CF2
O
X=1or 2
TEA
dioxane /RT
F2C=FCO
OCF=CF2
O
H
N
O
O
O
O
O
H
N
O
O
X=1or 2
Scheme 30. N-acylation in macro amide synthesis
V. P. Trivedi and his group in 2004 carried out acylation of anthranilic acid with
benzoylchloride in presence of pyridine at 8 0C , which resulted in ring closure within
1hr67, (Scheme 31).
O
COOH
Py.
+ Ph CO Cl
O
0
8 C, 1 hr.,
NH3
Ph N
Scheme 31. Ring closure by N-acylation
Irena Svedaite in 2007 studied acylation of 4-(3, 5-dioxopiperazine-1-yl)-4oxabutanoic acid in chloroform at 0 0C 68(Scheme 32)
O
O
HN
O
O
a
HN
b
N
OH
O
O
O
N
NHR
O
a. SOCl2 , 00C, 1hr. b.RNH2, Pyridine, CHCl3 /00C, 2hr.
Scheme 32. Derivatization by N-acylation
Ph. D. Thesis, Mr. Rambhau P. Gore Z. B. Patil College, Deopur, Dhule.
CHAPTER 1
P a g e | 22
Jagessar R. C. et al. in 2011, reported N-acylation of cytosine using benzoyl
chloride in presence of TEA69 (Scheme 33).
H
N
O
N
NH
Cl
TEA
+
H
N
O
N
O
NH2
O
Scheme 33. N-acylation by benzoyl chloride
1.4 Aqueous N-acylation Schotten-Baumann method
1.4.1 General
In 1884 C. Schotten reported a method for the synthesis of Nbenzoylpiperidine from piperidine and benzoyl chloride in aqueous medium in
presence of sodium hydroxide. After a couple of year in 1886 E. Baumann showed the
formation of ethyl benzoate from ethanol and benzoyl chloride under the same
reaction conditions.
The method of synthesis of amide from amines and ester from alcohol with
reaction of acid halide or acid anhydride in the presence of aqueous base is known as
Schotten-Baumann method. The reaction has wide applicability in synthesis of simple
amides under aqueous medium70, and can be recognized as green synthesis of amides
utilizing nonhazardous one of the solvent, water of the biphasic system.
The reaction is based on the fact that the reaction of an acid halide with an
amine is much faster than the hydrolysis of the acid halides by aqueous alkali. The
mechanism of the reaction is illustrated (Scheme 34).
The addition of an additional equivalent amount of base to neutralize the acid
formed is required, similar to non-aqueous acylation71.
Ph. D. Thesis, Mr. Rambhau P. Gore Z. B. Patil College, Deopur, Dhule.
CHAPTER 1
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O
O
R
+
X
H2N
H
: NH
R
X
R'
X
R1 + H
H3N
R & R' =1o,2o,3o alkyl or aryl
O
H
R'
+
NH
R
N
+ H
R'
H
R1
NaOH
H2N
R1
H2O
NaX
Scheme 34. Schotten-Baumann N-acylation, Mechanism
In order to conserve amine the reaction is usually run in the presence of hydrogen
chloride acceptor, a suitable base which reacts preferentially with HCl. In usual sense
HCl acceptor should be a base which is stronger than the amine, (Scheme 35).
RCOCl
+
HCl +
R'NH2
B:
RCONHR'
BH +
+
Cl
HCl
Scheme 35. Role of base
The success of process depends on the reactivity of the acyl halide and in
general acyl halides that are less reactive give high yield, more stable under aqueous
condition.
In a typical Schotten-Baumann acylation the amine or its salt is dissolved in a
slight excess of an alkali, sodium hydroxide (8-15%) solution. A small excess of acid
chloride in organic solvent is then added and the mixture is vigorously stirred at rt.
The other solvent used may be DCM, Diethyl ether etc. Alternatively amine
hydrochloride salt in aqueous solution can be treated with acid chloride or acid
anhydride in presence of Na2CO3 which liberates free amine and reacts with activated
derivative of acid and converts the liberated carboxylic acid to sodium-carboxylate in
aqueous medium58.
Alternatively sodium carbonate was added to an aqueous solution of amine
hydrochloride, which liberated free amine and reacted with acetic anhydride and
converted the liberated acetic acid to sodium acetate48, (Scheme 36).
Ph. D. Thesis, Mr. Rambhau P. Gore Z. B. Patil College, Deopur, Dhule.
CHAPTER 1
P a g e | 24
O
NH2. HCl
O
NH2
NaHCO3
O
Stir, 5 min.
H
N
Na+ -O
+
O
O
Scheme 36. N-acylation using amine salt
N-acylation of aromatic amine has been carried out in aqueous medium but
with limited number of substrates. Acid halides and acetic anhydride were some of the
earliest acylating agents used for the synthesis of amides. The practical issue related
to the ease of purification of the amide product. It was found that sodium-2-hexanoate
could be used as a mild base scavenger in the acylation where standard SchottenBaumann method created problem due to water solubility of starting material and
products.
1.4.2 Schotten-Baumann reaction in amide synthesis
S. K. Shrivastava and his group in 1995 reported N-acylation of NH-Het.
System, Imidazole with various substituted 1H-benzotriazole-1-yl- acid chloride in ice
cooled alkaline solutio72, (Scheme 37).
N
N
R CH-COCl
N
HN-HET
N
alkaline solution ,
0 0C
N
N
R
CH
C
N-HET
O
Scheme 37. Derivatization of azole, a monoacylation
Luc Neuville’s group in 1997 studied Schotten-Baumann reaction of Nsubstituted aryl piperazines with various acid chlorides at rt. in aq. NaOH-DCM,
biphasic system73, (Scheme 38).
Ph. D. Thesis, Mr. Rambhau P. Gore Z. B. Patil College, Deopur, Dhule.
CHAPTER 1
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O
NH
O2N
N
N
O2N
aq.NaOH-DCM
R
N
RCOCl /RT
R1
R1
Scheme 38. A biphasic synthesis
K. Ramaiah and co-workers in 1999 observed ring opening when
benzimidazole condensed with benzoyl chloride in alkaline solution at rt.74, (Scheme
39).
H
N
N
Ph COCl
H
CO
Na OH/RT
N
Ph
CO
N
H
Ph
H
Scheme 39. Ring opening by acylation
Branko S. J. et al. reported application of Schotten-Baumann reaction in
peptide synthesis with lesser number of steps compared to non-aqueous acylation.
Amino acids were dissolved in equal amount of aqueous sodium hydroxide and the
corresponding acyl chloride was added70b(Scheme 40).
R'
O
R'
NaOH
HOOC
NH2
R'= H, CH3, PhCH2
+
R
Cl
HOOC
O
N
H
R
R= Ph, p-O2NPh
Scheme 40. Peptide synthesis
Mohammad Golam R. et al. have reported N-acyl derivatives of ciprofloxacin
applying standard Schotten-Baumann method75.
Ph. D. Thesis, Mr. Rambhau P. Gore Z. B. Patil College, Deopur, Dhule.
CHAPTER 1
P a g e | 26
O
O
O
O
F
HO
F
HO
5% aq. NaOH
N
N
N
PhCOCl
N
N
NH
Ph
O
Scheme 41. Derivatization in aq. medium
1.5 Other methods of amide synthesis
i) Choudary B. M. et al. in 2001, have reported montmorillonite K10 catalysed
acylation of 10, 20 amines by carboxylic acids76.
AcOH, Cat.
R
NH2
R
NHAc
H2O
+
1160C
Scheme 42. Acylation using cat. montmorillonite K10
ii) Method due to Rogerio da C. Rodrigues et al.77
O
Cl
O
N
Ph 3P
+
Cl
N
O
RCOOH
+
R
N
O
Ph 3P O
Cl
Cl
R1NH2
trichloroisocyanuric acid
O
HX
+
R1
R
N
H
Scheme 43. Trichloroisocyanuric acid mediated acylation
iii) Recently in 2009, Joong-Gon, Khim, used cupric oxide as catalyst and
coupling reagent in N-acylation of aliphatic amines78.
NH2
O
+
Ph
Cl
O
CuO
rt, AcN
Ph
N
H
Ph. D. Thesis, Mr. Rambhau P. Gore Z. B. Patil College, Deopur, Dhule.
CHAPTER 1
P a g e | 27
Scheme 44. Cupric oxide mediated acylation
iv) Acylation using PTC79
Darsi S.S. Praveen kumar et al. have reported acetylation of substituted
anilines with acetyl chloride using PTC like TBAB, TEBAC and DGlucose at rt.
Coupling reagents
i.
CAN: Method due to Reddy Ch. Sanjeeva et al.80
O
ArCHOOH
+
CAN (2mol %)
H2 N
O
Ar
MW. 1-3 min.
NH2
NH2 Scheme 45. CAN mediated synthesis of amides
ii.
DCC, HOBt32, 81 etc.
DCC or HOBt/DCC are used as coupling reagents in peptide synthesis.
1.6 Conclusions:
Methods of amide synthesis in non-peptide compounds are being studied with new
reagents for activation of carboxylic acids and coupling reagents too. Phosphinehalogen reagents, trichloroisocyanuric acids in activation of carboxylic acids,
catalysts in N-acylation like, DMAC, CuO, sodium acetate, PTC are notable. Nacylbenzotriazole, coupling reagent in synthesis of simple amides and
acylation in
aqueous medium in variety of substrates in various conditions are useful to synthesize
simple monosubstituted amides.
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