A One-Pot, fast, and efficient amidation of carboxylic acids, α-amino acids and sulfonic acids using pph3/n-chlorobenzotriazole system

Article abstract of DOI:10.1080/10426507.2015.1024313

Triphenylphosphine (PPh₃)/N-chlorobenzotriazole (NCBT), and amine (primary and secondary aliphatic amines and also substituted anilines) in CH₂Cl₂ efficiently converted carboxylic acids, α-amino acids, and sulfonic acids to the corresponding amides and sulfonamides at room temperature. Good to excellent yields, inexpensive, and fast reaction conditions are the important features of this procedure.

Full text of DOI:10.1080/10426507.2015.1024313

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Phosphorus, Sulfur, and Silicon and the Related
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A one-pot, fast and efficient amidation of carboxylic
acids, α-amino acids and sulfonic acids using PPh3/ N-
chlorobenzotriazole system
Hamed Rouhi-Saadabada & Batool Akhlaghiniaa
a Department of Chemistry, Faculty of Sciences, Ferdowsi University of Mashhad, Mashhad
9177948974, Iran
Accepted author version posted online: 17 Mar 2015.
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To cite this article: Hamed Rouhi-Saadabad & Batool Akhlaghinia (2015): A one-pot, fast and efficient amidation of carboxylic
acids, α-amino acids and sulfonic acids using PPh3/ N-chlorobenzotriazole system, Phosphorus, Sulfur, and Silicon and the
Related Elements, DOI: 10.1080/10426507.2015.1024313
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A one-pot, fast and efficient amidation
of carboxylic acids, α-amino acids and sulfonic acids
using PPh3 / N-chlorobenzotriazole system
Hamed Rouhi-Saadabad, Batool Akhlaghinia*
Department of Chemistry, Faculty of Sciences,
Ferdowsi University of Mashhad, Mashhad 9177948974, Iran
Running title:
Amidation of carboxylic acids and sulfonic acids
* Corresponding author: Phone: +98-51-3880-5527, Fax: +98-51-3879-5457
E-mail: akhlaghinia@um.ac.ir
Abstract Triphenylphosphine (PPh3) / N-chlorobenzotriazole (NCBT), and amine (primary and
secondary aliphatic amines and also substituted anilines) in CH2Cl2 efficiently converted
carboxylic acids, α-amino acids and sulfonic acids to the corresponding amides and sulfonamides
at room temperature. Good to excellent yields, inexpensive, and fast reaction conditions are the
important features of this procedure.
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Keywords Amidation; Carboxylic acid; Amino acid; Sulfonic acid; Triphenylphosphine; N-
chlorobenzotriazole; One-pot synthesis.
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INTRODUCTION
Among the nitrogen-containing compounds, amides are important due to their vast application in
synthesis and medicinal chemistry.1 This functional group is also found in numerous naturally-
occurring products (e.g., peptides and proteins).2 Sulfonamides, with important functional groups
used in medicinal chemistry, are the first drugs which have been largely used as
chemotherapeutic agents against various diseases.3 They are often found in compounds with
anticancer, anti-hypertensive, anti-inflammatory, anti-allergic, anti-migraine, and antiviral
activities.4 Due to the broad application of amides and sulfonamides, finding new, efficient and
practical methods for their synthesis is desirable.
There are a multitude of well-known methods for efficient amide and sulfonamide bond
formations. Direct condensation of carboxylic and sulfonic acids with amines has been used for
the synthesis of amides and sulfonamides.5 High temperatures requirements and harsh reaction
conditions have limited these methods. The most common method for the preparation of amides
and sulfonamides is the reaction of acyl and sulfonyl halides with ammonia, primary or
secondary amines in the presence of a base.3 Although, this is an efficient method, it needs the
availability of acyl and sulfonyl halides. Acyl and some sulfonyl halides are moisture sensitive,
require care in handling and 6 are difficult to store for long time.
The straightforward method for the synthesis of amides and sulfonamides is the reaction of
activated carboxylic and sulfonic acids with amines.7 In this regard, carboxamides and
sulfonamides were prepared by the reaction of carboxylic and sulfonic acid derivatives with
aromatic and aliphatic amines in the presence of SOCl2,8 POCl3,9 PCl5,10 or SO2Cl2.11 Also,
amidation of carboxylic and sulfonic acids, have been reported by using cyanuric chloride,12
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carbodiimides,13 uronium salts,14 triphosgene,15 PPh3/Cl3CN,16 PPh3/SO2Cl2,17 as acid activators.
Despite the efficiency of these methods, development a new, simple, fast, efficient, and highly
profitable amidation method under mild reaction conditions is still highly desirable and
demanded.
In the present study, we used PPh3 / NCBT as an efficient mixed reagent system for a one-
pot, fast and efficient preparation of amides, α-amino acid amides and sulfonamides.
RESULTS AND DISCUSSION
Following our interest in the chemistry of PPh3 in functional group transformations,18, 6 we
speculated on the possibility of using PPh3 in conjunction with NCBT, as an N-halo reagent to
activate carboxylic acids, α-amino acids and sulfonic acids for a nucleophilic substitution at the
carbonyl and sulfonyl groups to achieve amide and sulfonamide linkages (Scheme 1).
In order to find out the most effective amidation, reaction of benzoic acid with benzylamine
in the presence of PPh3/NCBT was chosen as a model reaction. The best procedure was adding
benzoic acid (1.0 mmol, 1 equiv.) and benzylamine (2.5 mmol, 2.5 equiv.) to the mixture of
PPh3/NCBT (1.25/1.25) in dry CH2Cl2 at room temperature. Since the intermediates and PPh3 are
reactive species and extremely sensitive to moisture, it is critical to use an anhydrous solvent. To
neutralize the reaction mixture Et3N (1 mmol ) as a base, was then added dropwise into the
suspension. The formation of N-benzylbenzamide was observed after 30 min and in high yield
(monitored by TLC). As shown in Table 1 (entries 2-7), this reaction worked nicely in a number
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of common solvents including CH3CN, THF, CHCl3, 1,4-dioxane, acetone, and hexane. To
prove the reaction was indeed involving PPh3 and NCBT, we carried out several control
experiments (Table 1, entries 8-10). The reaction of benzoic acid with benzylamine only led to
formation of N-benzylbenzamide in trace amounts under solvent free conditions (Table 1, entry
11). Applying the other molar ratios of PPh3/NCBT/benzoicacid/benzylamine led to formation of
N-benzylbenzamide in low yield and in a longer reaction time (Table 1, entries 12-15). Using
1.25/1.25/1/3 molar ratio of PPh3/NCBT/benzoicacid/benzylamine (Table1, entry 16) gave the
same result as entry 1.
To show the efficiency of this mixed reagent in amidation reaction, some of the reported
amidation protocols were summarized in Table 2. As is apparent from Table 2, PPh3/ NCBT
mixed reagent is the most efficient reagent, for conversion of benzoic acid to N-
benzylbenzamide.
After finding the optimal reaction conditions, we studied the methodology with an array of
commercially available aromatic and aliphatic carboxylic acids with benzylamine (Table 3,
entries 1-20). In comparison, aromatic carboxylic acids with electron deficient substituents were
successfully reacted with benzylamine very rapidly than electron-rich aromatic carboxylic acids
(e.g. compare entry 4 and 10). We also determined that the reactions of aliphatic carboxylic acids
with benzylamine proceeded very well to afford the corresponding amides in excellent yields
(Table 3, entries 13-19). Next, other amines were also tried. Similarly, by using primary and
secondary, cyclic and acyclic aliphatic amines, amidation reaction of benzoic acid furnished very
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rapidly as benzylamine (Table 3, entries 22-33). Those amines with lowered nucleophilicity,
such as anilines (as demonstrated in Table 3), appear to require alternative reaction conditions to
undergo efficient reaction with carboxylic acids. We therefore embarked on studies to establish
conditions that would be suitable for efficient amidation of carboxylic acids with lower
nucleophilic amines such as anilines. Extensive studies in our laboratory, employing various
reaction time, solvents and temperatures lead us to perform the amidation reactions in refluxing
CH3CN (Table 3, entries 34-37). Thiophene-3-carboxylic acid was also treated by this mixed
reagent. Nucleophilic thiophene did not interfere with the reaction and the corresponding amide
was obtained with quantitative yield (Table 3, entry 21).
α-Amino acid amides are important precursors in the synthesis of pharmaceutical
compounds. Because of their importance, numerous protocols have been developed for their
preparations.51 Consequently, any new methodology that allows for the rapid, cost-effective
synthesis of α-amino acid amides by using readily available reagents would be desirable. To
improve and develop the applicability of the present method, synthesis of α-amino acid amides,
were examined by using PPh3/ NCBT / amines system. At first, N-acetylated α-amino acids were
prepared by the method reported previously,52 to prevent any interference of amino groups.
Acceptable results were obtained, when the above optimized reaction conditions were applied for
the amidation of N-acetylated α-amino acids (Table 4). As shown in Table 4, the mixed reagent
worked nicely in a series of N-acetylated α-amino acids such as glycine, alanine, phenylalanine,
proline and tryptophan. From the screening results, N-acetyl α-amino group did not change the
reactivity of the carboxylic acids toward PPh3/ NCBT / amines system. This fact that,
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nucleophilic indole in tryptophan did not interfere the reaction is also noteworthy (Table 4, entry
5).
As we like to extend the applicability of the present methodology, after establishing the
reaction conditions for the reaction of benzoic acid with benzylamine, in a series of experiments,
we focused our attention on the synthesis of sulfonamides. We continued our study on
sulfonamides by examining the reaction of p-toluenesulfonic acid with benzylamine in the
presence of PPh3/NCBT system and by applying the same reaction conditions used above. As
can be seen from Table 4, dry CH2Cl2 was found to be the most efficient solvent and it was
employed as the preferred solvent for all subsequent sulfonamide preparation reactions (Table 5,
entry 1). CH3CN was acted as the same as CH2Cl2 (Table 5, entry 2). Reasonable yields were
obtained when solvents such as THF, CHCl3, 1,4-dioxane, acetone, and hexane were used (Table
5, entries 3-7). Both PPh3/NCBT system and solvent play essential role in preparation of product
(Table 5, entries 8-11). We also tested the influence of various molar ratios of
PPh3/NCBT/RSO3H/R'R"NH on the model reaction, since it was expected, the reaction rate was
decreased by decreasing the amount of PPh3, NCBT or R'R"NH (Table 5, entries 12-15). In this
context, additional amount of benzylamine was applied and have found to have no influence on
the reaction rate (Table 5, entry 16).
In order to investigate the scope of such amidation reactions in more detail, we tested the
scope of our optimized protocol by applying it to various combinations of sulfonic acids and
amines (Table 6).
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We were pleased to find the new protocol allows extending the method from aliphatic and
aromatic sulfonic acids to the less reactive aromatic sulfonic acids and amines (Table 6).
Aliphatic sulfonic acids reacted smoothly with primary aliphatic amines as well as aromatic
amines (Table 6, entries 1-3). Good yields were obtained in the amidation of aromatic sulfonic
acids with primary, secondary aliphatic amines, too (Table 6, entries 4-10). Treatment of p-
toluenesulfonic
acid
with
p-bromoaniline
afforded
N-(p-bromophenyl)-4-
methylbenzenesulfonamide in high yield (Table 6, entry 11). In the end, in a similar fashion, N-
butyl-4-chlorobenzenesulfonamide was formed in excellent yield from the reaction of p-
chlorobenzenesulfonic acid with n-butyl amine (Table 6, entry 12). We observed that excellent
yields of the sulfonamides could be obtained in most cases without excessive reaction time.
FT-IR spectroscopy of the column chromatography purified products revealed an absorption
band at 3412-3223 or 3295-3220 cm-1 due to NH vibration stretching of carboxamide and
sulfonamide respectively. A strong absorption band at 1661-1607 cm-1 due to carbonyl group
confirmed the formation of carboxamide. N-H bending vibration and C-N stretching vibration
were also appeared as medium bands at 1570-1515 and 1349-1213 cm-1 respectively. Presence of
sulfone group (SO2) was established by appearance of two strong absorption bands at 1346-1340
and 1165-1135 cm-1 (due to asymmetric and symmetric stretching vibration of sulfone) and S-N
vibration stretching was revealed as a medium absorption band at 765-725 cm-1. A broad signal
at 7.1-5.76 and 7.1-4.65 ppm is assigned to NH proton of carboxamide and sulfonamide
13
respectively which are exchangeable with D2O (See Supplemental Materials). In the C NMR
spectra, the quaternary carbon of carboxamides showed an up-field shift as compared to the
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carbonyl carbon of carboxylic acids. All of the products were known compounds and
characterized by the FT-IR spectroscopy, mass spectrometry and comparison of their melting
1
points with known compounds.The structure of selected products was further confirmed by H
NMR and 13C NMR spectroscopy.
EXPERIMENTAL
General
The products were purified by column chromatography. The purity of the products was
determined by TLC on silica gel polygram STL G/UV 254 plates (Merck, Germany). Melting
points of the products were determined with an Electrothermal Type 9100 melting point
apparatus (UK). The Fourier transform infrared (FT-IR) spectra were recorded on an Avatar 370
FT-IR Therma Nicolet spectrometer (USA). The nuclear magnetic resonance (NMR) spectra
were provided on Brucker Ultrashield Avance III instruments (Germany) at 400 and 100 MHz
1
13
respectively for H and C NMR spectroscopy, in CDCl3 and DMSO-d6. TMS was used as an
internal standard. Chemical shifts are given in ppm relative to TMS. Coupling constants J are
1
given in Hz. Abbreviations used for H NMR signals are: s = singlet, d= doublet, t = triplet, q =
quartet, m = multiplet. Mass spectra were recorded with a CH7A Varianmat Bremem instrument
(Germany) at 70 eV; in m/z (rel %). Elemental analyses were performed using an Elementar,
Vario EL III and Thermofinnigan Flash EA 1112 Series instrument. Silica gel in the size of 40–
73 µm that used for column chromatography was purchased from Merck, Germany. NCBT was
prepared and purified by the method described in the literature.69 The Supplemental Materials
contains sample 1H and 13C NMR spectra of the products (Figures S 1 – S 18)
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Typical procedure for conversions of carboxylic acids to amides.
N-benzylbenzamide (Table 3, entry 1)
To a cold solution of PPh3 (0.327 g, 1.25 mmol) in CH2Cl2 (3 mL), freshly prepared NCBT
(0.188 g, 1.25 mmol) was added with continuous stirring. Benzoic acid (0.122 g, 1 mmol) was
then added and stirring was continued for 15 min. Benzylamine (0.267 g, 2.5 mmol) was added
and the temperature was raised up to room temperature. The white suspension was neutralized by
triethylamine (0.139 mL). Stirring was continued for 30 min at room temperature. The progress
of the reaction was followed by TLC. Upon completion of the reaction, the concentrated residue
was passed through a short silica-gel column using n-hexane–ethyl acetate (8:1) as eluent. N-
Benzylbenzamide was obtained with 95% (0.201 g) yield after removing the solvent under
reduced pressure.
Typical procedure for conversions of N-acetylated α-amino carboxylic acids to amides. 2-
Acetamido-N-benzyl-3-phenylpropanamide (Table 4, entry 3)
To a cold solution of PPh3 (0.327 g, 1.25 mmol) in CH2Cl2 (3 mL), freshly prepared NCBT
(0.188 g, 1.25 mmol) was added with continuous stirring. 2-Acetamido-3-phenylpropanoic acid
(0.207 g, 1 mmol) was then added and stirring was continued for 15 min. Benzylamine (0.267 g,
2.5 mmol) was added and the temperature was raised up to room temperature. The white
suspension was neutralized by triethylamine (0.139 mL). Stirring was continued for 95 min at
room temperature. The progress of the reaction was followed by TLC. Upon completion of the
reaction, the mixture was filtered and residue was concentrated and passed through a short silica-
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gel column using n-hexane–ethyl acetate (3:1) as eluent. 2-Acetamido-N-benzyl-3-
phenylpropanamide was obtained with 90% (0.266 g) yield after removing the solvent under
reduced pressure.
Typical procedure for conversion of sulfonic acids to sulfonamides.
N-benzyl-4-methylbenzenesulfonamide (Table 6, entry 6)
To a cold solution of PPh3 (0.327 g, 1.25 mmol) in CH2Cl2 (3 mL), freshly prepared NCBT
(0.188 g, 1.25 mmol) was added with continuous stirring. p-Toluenesulfonic acid (0.172 g, 1
mmol) was then added and stirring was continued for 15 min at room temperature. Benzylamine
(0.267 g, 2.5 mmol) was added. The white suspension was neutralized by triethylamine (0.139
mL). Stirring was continued for 80 min at room temperature. The progress of the reaction was
followed by TLC. Upon completion of the reaction, the concentrated residue was passed through
a short silica-gel column using n-hexane–ethyl acetate (3:1) as eluent. N-Benzyl-4-
methylbenzenesulfonamide was obtained with 90% (0.236 g) yield after removing the solvent
under reduced pressure.
Characterization data of new compounds
4-Acetamido-N-benzylbenzamide (Table 3, entry 10)
White solid; mp 126-128 °C, yield: 87%; IR (KBr): ῡ = 3395 (NH), 3070, 3039, 2920,
1670(C=O), 1649 (C=O), 1553, 1515, 1489, 753, 699 cm−1; 1H NMR (400 MHz, DMSO-d6): δ =
8.62 (s, 1H, NH), 7.69-7.36 (m, 9H, ArH), 7.28 (s, J= 2 Hz , 1H, NH), 6.32 (s, 1H, NH), 4.43 (d,
J= 4.4 Hz, 2H, CH2), 2.06 (s, 3H, CH3) ppm; 13C NMR (100 MHz; DMSO-d6): δ = 168.3 (C=O),
167.1 (C=O), 134.6, 129.4, 128.9, 128.8, 128.7, 128.5, 127.7, 127.1, 45.7, 24.5 ppm; MS (EI, 70
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eV), C16H16N2O2 (268.31 g.mol-1): m/z (%) = 268 (M+, 10%), 224 (M-CH3CO, 8%), 162 (M-
PhCH2NH, 22%), 106 (PhCH2NH, 75%), 91 (PhCH2, 70%) 77 (Ph, 72%) 43 (CH3CO, 70%);
Elemental anal. (%), Calcd for C16H16N2O2 (268.31): C 71.62, H 6.01, N 10.44; Found: C 72.02,
H 6.23, N 10.67.
N-(3-Ethoxypropyl) benzamide (Table 3, entry 23)
Red wine oil ; yield: 80%; IR (neat): ῡ = 3311 (NH), 3068, 2955, 2925, 2868, 1643 (C=O),
1539, 1113, 747 cm−1; 1H NMR (400 MHz; CDCl3): δ = 7.77-7.75 (m, 2H), 7.46-7.21 (m, 3H),
7.21 (brs, 1H), 3.60-3.41 (m, 6H), 2.11-2.02 (m, 2H), 1.37-1.21 (m, 3H) ppm; 13C NMR (100
MHz; CDCl3): δ = 167.1 (C=O), 134.7, 131.1, 128.4, 126.8, 70.4, 66.5, 39.3, 28.8, 15.3 ppm;
MS (EI, 70 eV), C12H17NO2 (207.27 g.mol-1): m/z (%) = 207 (M+, 15%), 178 (M-Et, 5%), 162
(M-EtO, 20%), 148 (M-EtOCH2, 100%), 106 (PhCO, 75%), 60 (EtOCH2, 25%), 45 (EtO, 72%),
28 (Et, 58%); Elemental anal. (%), Calcd for C12H17NO2 (207.27): C 69.54, H 8.27, N 6.76;
Found: C 69.01, H 7.98, N 6.39.
CONCLUSION
In summary, we presented here a fast, one-pot and novel amide and sulfonamide bond formation
strategy from carboxylic acids, α-amino acids and sulfonic acids using PPh3/ NCBT/amines
system. The reaction has been shown good functional group tolerance and high yielding. We
envisaged that the present protocol would therefore be suitable for less nucleophilic amines such
as anilines. In addition, we have identified suitable reaction conditions that are successful for
amidation of α-amino acids of which are biologically active compounds and possess
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therapeutically useful properties. Compared to other amide and sulfonamide formation methods,
it took place under very mild reaction conditions, and the reaction rate was extremely fast. The
chemistry is easily executed. We hope that this method may be of value to others seeking novel
synthetic fragments with unique properties for medicinal chemistry programs.
ACKNOWLEDGEMENTS
The authors gratefully acknowledge the partial support of this study by Ferdowsi University of
the Mashhad Research Council (Grant no. p/3/19312).
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Table 1 Conversion of benzoic acid to N-benzylbenzamide with PPh3/NCBT/ benzylamine
system at 0 °C to room temperature, under different reaction conditions
Molar Ratio
PPh3/NCBT/RCO2H/R'R"NH
1.25/1.25/1/2.5
Isolated Yield
Entry
Solvent
Time(min)
(%)
95
1
2
3
4
CH2Cl2
CH3CN
THF
30
30
45
55
1.25/1.25/1/2.5
90
1.25/1.25/1/2.5
80
CHCl3
1.25/1.25/1/2.5
90
1,4-
dioxane
5
1.25/1.25/1/2.5
95
70
6
acetone
n-hexane
CH2Cl2
CH2Cl2
CH2Cl2
none
1.25/1.25/1/2.5
1.25/1.25/1/2.5
0/0/1/2.5
70
95
85
60
0
7
8
120
120
120
120
100
90
9
0/1.25/1/2.5
1.25/0/1/2.5
1.25/1.25/1/2.5
1/1/1/1
0
10
11
12
13
14
15
16
0
10
70
80
80
90
95
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
1/1/1/1.5
1/1/1/2
50
1/1/1/2.5
40
1.25/1.25/1/3
30
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Table 2 Amidation of benzoic acid with benzyl amine by using different reagents
Entr
y
Reaction
condition
Time
(h)
Yield
(%)
Referenc
es
Reagent
O,O′-di(2-pyridyl) thiocarbonate
(DPTC)
1
2
Et2O / r.t.a
2
83
98
19
20
40
min
p-Nitrobenzenesulfonyl chloride
CH3CN/r.t. a
CH2Cl2/ 0 °C - r.t.
3
I2 / trimethoxyphosphine P(OMe)3
3
94
21
a
4
5
PPh3/trichloroacetonitrile (TCA)
Ion supported PPh3/BrCCl3
CH2Cl2/r.t. a
THF / 60 °C
3
6
73
99
22
23
CH2Cl2/ -78 °C -
r.t. a
6
7
8
PPh3/ hexachloroacetone (HCA)
PPh3/azopyridine
1
95
85
95
24
25
CH3CN/reflux
3.5
PPh3/N-chlorobenzotriazole
(NCBT)
CH2Cl2/ 0 °C - r.t.
30
min
-----
a
a r.t.: room temperature
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Table 3 Conversion of carboxylic acids to amides by using PPh3/ NCBT / amines system
Tim
e
Isolated
Yield
(%)
Carboxylic acid
(RCOOH)
Amine
Reference
s
Entry
(R'R"NH)
(min
)
1
2
3
4
5
6
PhCOOH
PhCH2NH2
PhCH2NH2
PhCH2NH2
PhCH2NH2
PhCH2NH2
PhCH2NH2
30
45
50
70
35
25
95
95
92
93
85
90
26
26
27
26
28
26
4-MeC6H4COOH
3,5-Me2C6H3COOH
4-MeOC6H4COOH
2-ClC6H4COOH
4-ClC6H4COOH
7
8
4-BrC6H4COOH
3,4-Cl2C6H3COOH
4-AcOC6H4COOH
4-AcNHC6H4COOH
4-NO2C6H4COOH
PhCH2NH2
PhCH2NH2
PhCH2NH2
PhCH2NH2
PhCH2NH2
25
20
40
40
15
93
90
90
87
95
23
29
30
---
23
9
10
11
12
13
3-NO2C6H4COOH
PhCH2NH2
PhCH2NH2
15
90
90
92
31
26
(E)-PhCH=CHCOOH
22
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14
15
4-ClPhCH=CHCOOH
PhCH2NH2
PhCH2NH2
75
60
80
89
23
32
3-
NO2PhCH=CHCOOH
2,4-
16
PhCH2NH2
60
90
33
Cl2C6H3OCH2COOH
17
18
(Ph)2CHCOOH
PhCH2NH2
PhCH2NH2
85
84
91
34
34
4-MeOPhCH2COOH
120
CH3(CH2)7CH=CH(CH
2)6 CH2COOH
19
PhCH2NH2
90
87
35
20
21
CH3(CH2)3CH2COOH
Thiophene-3-COOH
PhCH2NH2
PhCH2NH2
70
92
94
36
37
100
CH3(CH2)2CH2NH
22
PhCOOH
20
85
38
2
EtO(CH2)2CH2NH
23
24
25
PhCOOH
PhCOOH
PhCOOH
40
30
20
80
80
87
---
39
26
2
Cyclohexyl-NH2
4-
MeOC6H4CH2NH2
2-
26
PhCOOH
20
92
40
MeOC6H4CH2NH2
27
28
29
PhCOOH
PhCOOH
PhCOOH
2-ClC6H4CH2NH2
(Et)2NH
35
40
55
87
92
88
41
42
43
(i-Pr)2NH
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30
31
PhCOOH
PhCOOH
morpholine
piperidine
45
35
90
95
85
80
85
90
92
80
44
45
46
47
48
40
49
50
32
PhCOOH
pyrrolidine
40
33
PhCOOH
furan-2-CH2NH2
4-MeC6H4NH2
PhNH2
35
34a
35a
36a
37a
PhCOOH
100
60
4-NO2C6H4COOH
CH3(CH2)3CH2COOH
4-MeC6H4COOH
4-BrC6H4NH2
4-MeC6H4NH2
110
120
a
The reaction was performed in CH3CN, reflux.
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Table 4 Conversion of N-acetylated α-amino acids to α-amino acid amides by using
PPh3/NCBT/amines system
Amino acid
(RCOOH)
Amine
Time
(min)
60
Entry
Isolated
Yield (%)
Refrences
*
(R'R"NH)
PhCH2NH2
(AcNH)CH2COOH
95
90
90
96
53
54
53
55
1
2
3
4
(AcNH)(CH3)CHCOOH
PhCH2NH2
PhCH2NH2
PhCH2NH2
70
95
(AcNH)(PhCH2)CHCOOH
120
AcN-pyrolidine-2-COOH
indole-3-
CH2CH(AcNH)COOH
PhCH2NH2
110
95
56
5
* Amino acids were N-acetylated and purified by the method reported in literature. 19
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Table 5 Conversion of p-toluenesulfonic acid to N-benzyl-4methylbenzenesulfonamide with
PPh3/NCBT/benzylamine system at 0 °C to room temperature, under different reaction
conditions
Molar Ratio
PPh3/NCBT/RSO3H/R'R"NH
Time
(min)
Isolated Yield
(%)
Entry
Solvent
1
2
3
4
CH2Cl2
CH3CN
THF
1.25/1.25/1/2.5
1.25/1.25/1/2.5
1.25/1.25/1/2.5
1.25/1.25/1/2.5
80
80
90
95
90
90
90
85
CHCl3
1,4-
dioxane
5
1.25/1.25/1/2.5
95
75
6
7
acetone
n-hexane
CH2Cl2
CH2Cl2
CH2Cl2
none
1.25/1.25/1/2.5
1.25/1.25/1/2.5
0/0/1/2.5
120
100
180
180
180
180
180
150
95
85
70
0
8
9
0/1.25/1/2.5
1.25/0/1/2.5
1.25/1.25/1/2.5
1/1/1/1
0
10
11
12
13
14
15
0
10
40
80
70
80
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
1/1/1/1.5
1/1/1/2
1/1/1/2.5
90
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16
CH2Cl2
1.25/1.25/1/3
80
90
27
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Table 6 Conversion of sulfonic acids to sulfonamides by using PPh3/NCBT/amines system
Sulfonic acid
(RSO3H)
Amine
Time
(min)
Entr
y
IsolatedYiel Refrence
d (%)
s
(R'R"NH)
1
2
MeSO3H
EtSO3H
PhCH2NH2
PhNH2
75
70
85
90
57
58
3
4
MeSO3H
PhSO3H
4-BrC6H4NH2
85
90
90
80
59
60
4-MeOC6H4CH2NH2
5
6
PhSO3H
cyclohexyl-NH2
PhCH2NH2
95
80
80
90
61
62
4-MeC6H4SO3H
7
8
4-MeC6H4SO3H
4-MeC6H4SO3H
(Et)2NH
85
90
92
85
63
64
piperidine
9
4-MeC6H4SO3H
4-MeC6H4SO3H
pyrrolidine
morpholine
90
95
80
80
65
66
10
11
12
4-MeC6H4SO3H
4-ClC6H4SO3H
4-BrC6H4NH2
90
70
92
85
67
68
CH3(CH2)2CH2NH2
28
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Scheme 1
29
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