An efficient and epimerization free synthesis of C-terminal arylamides derived from α-amino acids and peptide acids via T3P activation

Article abstract of DOI:10.1007/s10989-013-9383-7

A high yield and rapid synthesis of enantiomerically pure N ^α -protected amino/peptide acid arylamides using n-propylphosphonic anhydride (T3P) in presence of N-methylmorpholine is described. The generality of the reaction has been studied for various N ^α -protected amino acids with diverse range of aromatic amines and coumarin derivatives.

Full text of DOI:10.1007/s10989-013-9383-7

Int J Pept Res Ther
DOI 10.1007/s10989-013-9383-7
An Efficient and Epimerization Free Synthesis of C-Terminal
Arylamides Derived from a-Amino Acids and Peptide Acids
via T3P Activation
•
Chilakapati Madhu Panguluri NageswaraRao
•
•
N. Narendra Vommina V. Sureshbabu
Accepted: 20 November 2013
Ó Springer Science+Business Media New York 2014
Abstract A high yield and rapid synthesis of enantio-
merically pure Na-protected amino/peptide acid arylamides
using n-propylphosphonic anhydride (T3P) in presence of
N-methylmorpholine is described. The generality of the
reaction has been studied for various Na-protected amino
acids with diverse range of aromatic amines and coumarin
derivatives.
(Kembhavi et al. 1993; Stepanov et al. 1977; Talanian et al.
1997; Ulfohn et al. 1968) but also amino acid derived p-
nitroanilides are often employed as chromogenic substrates
to determine the activity of proteolytic enzymes (Svendsen
et al. 1972).
The reported protocols for the synthesis of Na-protected
amino acid arylamide involve the reaction of Na-protected
amino acid with aryl amine, via coupling reagents such as
N,N00-dicyclohexylcarbodiimide, phosphorous reagents etc.
and mixed anhydride method. (Nedev et al. 1993; Pozdnev
1994; Zimmerman et al. 1976; Fujiwara and Tsuru 1978;
Sharma and Castellino 1990; Okada et al. 1982; Rijkers et al.
1995; Kato et al. 1978; Monatalbetti and Flaque 2005). Due
to weak nucleophilicity of arylamines, highly activated
carboxylic acid is required for complete conversion into
arylamides. Evidently, each of the known methods suffer
from some drawbacks, in-terms of low yield, racemization,
some of the coupling reagents are hazardous, expensive and
consumed in stoichiometric amounts, thus leading to sig-
nificant amount of wastes. Dunetz et al. developed an effi-
cient protocol for amide bond formation using T3P and
pyridine for about 12–24 h (Dunetz et al. 2011). Hu et al.
developed a novel protocol for the preparation of amino/
peptide acid arylamides by the ligation of selenocarboxylate
with an azide (Wu and Hu 2007). However, the bottle neck
in this protocol is the difficulty in preparation of seleno-
carboxylates. Peter et al. synthesized Na-protected amino/
peptide acid arylamides via enzymatic acylation (Nuijens
et al. 2009). The general applicability of this protocol dis-
courages due to longer reaction duration and elevated tem-
perature. Thus, the development of simple, milder and
alternative method for aryl amidation is still of interest.
In recent years, T3P has been found to be efficient cou-
pling reagent for the synthesis of peptides in terms of atom
economy, high yield and lack of epimerization
Keywords Arylamides ꢀ T3P ꢀ 7-Amino-3-methyl
coumarin
Introduction
Carboxamides are the most prevalent organic functional
groups, especially as components of natural products,
pharmaceuticals and backbone of peptides (Pattabiraman
and Bode 2011). Amino acid derived arylamides are a class
of carboxamides, widely used in the synthesis of polymers,
dendrimers, peptidomimetics, inhibitors and as cell signal-
ing molecules (Vemparala et al. 2006; Yin et al. 2006; Vi-
nogradov 2005; Meegalla et al. 2008; Kirkland et al. 2008;
Hang et al. 2006). They are used as substrates in chromo-
genic, fluorogenic and amperogenic enzymatic assays. Not
only C-terminal peptide AMC (7-amino-4-methyl couma-
rin) arylamides have been used in fluorogenic assays to
determine the activity of enzymes in blood coagulation
C. Madhu ꢀ P. NageswaraRao ꢀ N. Narendra ꢀ
V. V. Sureshbabu (&)
#109, Peptide Research Laboratory, Department of Studies in
Chemistry, Bangalore University, Central College Campus, Dr.
B. R. AmbedkarVeedhi, Bangalore 560 001, India
e-mail: sureshabuvommina@rediffmail.com;
hariccb@hotmail.com; hariccb@gmail.com
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Int J Pept Res Ther
(Basavaprabhu et al. 2013). T3P is highly reactive cyclic
phosphonic acid anhydride and also a water scavenger. T3P
offers several advantages over traditional reagents such as
low price, less toxicity, a lower tendency to induce epimer-
ization, excellent purity, broad functional group tolerance
and easy work up procedure leading to high yields. It has
been employed in several other reactions such as conversion
of carboxylic acids to aldehydes, dehydration of amides to
nitriles (Meudt et al. 2005) and formamides to isonitriles
(Meudt et al. 2005). The heterocycles including oxadiazoles
(Augustine et al. 2009), substituted pyrimidines (Crawforth
and Paoletti 2009), indoles (Desroses et al. 2011) and
b–lactams (Crichfield et al. 2000) have also been synthesized
using T3P as a dehydrating agent. Recently we demonstrated
efficient applications of T3P for a range of amino acid,
peptide derivatives i.e. Na-protected amino or peptide acid
derived acid azides (Basavaprabhu et al. 2010), hydroxamic
acids (Vasantha et al. 2010), thio acids (Madhu et al. 2012),
alcohols (Nagendra et al. 2012) and Weinreb amides
(Sharanabai et al. 2013). As part of our continuing endeavor
on the application of T3P, we herein demonstrate an efficient
and high yielding synthesis of Na-protected amino/peptide
acid arylamides with chiral homogenity.
Spectral Data
Fmoc-Ala-Anilide (2a)
White solid, m.p. 193 °C, yield 94 %. 1H NMR (400 MHz,
DMSO-d6): d 1.25 (d, 3H, J = 7.6 Hz), 4.11–4.22 (m, 4H),
6.94 (d, 2H, J = 6.6 Hz), 7.25–7.79 (m, 13H), 9.93 (s, 1H).
13C NMR (75 MHz, DMSO-d6): d 16.7, 46.8, 52.3, 67.4,
121.8, 124.5, 127.4, 128.2, 128.7, 129.5, 139.3, 140.8,
143.5, 156.1, 171.7. HRMS: m/z [M?Na]? calcd for
C24H22N2O3: 409.1528, Found: 409.1523.
Fmoc-Tyr-2-Chloroanilide (2b)
White solid, m.p. 155–156 °C, yield 81 %. 1H NMR
(400 MHz, DMSO-d6) d: 3.10–3.18 (m, 2H, J = 6.6 Hz),
4.45 (t, 1H, J = 5.2 Hz), 4.61 (d, 2H, J = 6.2 Hz),
4.82–4.86 (m, 1H), 5.63 (br, 1H), 6.61 (s, 2H), 6.92 (s, 2H),
7.18–7.54 (m, 12H), 10.15 (s, 1H). 13C NMR (75 MHz,
DMSO-d6) d: 36.8, 48.1, 54.2, 67.6, 115.1, 122.2, 125.4,
126.3, 126.8, 127.5, 128.7, 128.9, 129.5, 130.6, 131.8, 138.5,
141.1, 142.5, 155.1, 156.8, 171.6. HRMS m/z [M?Na]?
calcd for C30H25ClN2O4: 535.1401, Found 535.1404.
Fmoc-Thr-4-Methylanilide (2c)
Materials and Methods
White solid, m.p. 165–166 °C, yield 85 %. 1H NMR
(400 MHz, DMSO-d6) d: 1.37 (d, 3H, J = 6.4 Hz), 2.43 (s,
3H), 3.91–3.97 (m, 1H), 4.35 (t, 1H, J = 4.8 Hz),
4.62–4.70 (m, 3H), 5.86 (br, 1H), 6.91–7.02 (m, 3H),
7.23–7.58 (m, 9H), 9.91 (s, 1H). 13C NMR (75 MHz,
DMSO-d6) d: 14.6, 19.1, 47.3, 58.4, 65.4, 68.3, 120.7,
123.4, 125.9, 126.4, 127.8, 128.2, 128.7, 129.7, 133.4,
137.3, 141.0, 143.3, 156.8, 171.5. HRMS m/z [M?Na]?
calcd for C26H26N2O4: 453.1791, Found 453.1728.
All solvents were freshly distilled before use. Amino
acids were used as received from Sigma-Aldrich com-
1
pany. H NMR and 13C NMR were recorded on a Bruker
AMX 400 MHz and 75 MHz instrument with tetrameth-
ylsilane (TMS) as internal standard. Mass spectra were
recorded on high resolution mass spectra (HRMS) Q–T of
micro mass spectrometer. All the reactions were moni-
tored using TLCs with pre coated silica gel plates pur-
chased from Merck. Column chromatography was
performed with Merck silica gel (100–200 mesh) at nor-
mal atmospheric pressure.
Fmoc-Asp(But)-3-Methylanilide (2d)
White solid, m.p. 131–133 °C, yield 83 %. 1H NMR
(400 MHz, CDCl3) d: 1.41 (s, 9H), 2.38 (s, 3H), 2.87–2.95
(m, 2H), 4.24 (t, 1H, J = 6.8 Hz), 4.45 (d, 2H,
J = 6.8 Hz), 4.65–4.71 (m, 1H), 6.12 (br, 1H), 6.87 (d, 1H,
J = 7.6 Hz), 7.25–7.71 (m, 11H), 8.48 (s, 1H). 13C NMR
(75 MHz, CDCl3) d: 20.9, 27.5, 38.1, 48.8, 52.5, 66.9,
82.6, 116.8, 120.5, 121.1, 125.2, 125.8, 127.5, 128.3,
129.4, 137.8, 139.3, 140.8, 144.5, 156.8, 169.1, 171.8.
HRMS m/z [M?Na]? calcd for C30H32N2O5: 523.2209,
Found 523.2205.
Typical Procedure for the Preparation of N-Protected
Amino/Peptide Acid Arylamides
To a solution of Na-protected amino/peptide acid (1.0 mmol)
in CH3CN, NMM (1.2 mmol) and 50 % T3P in EtOAc
(2.4 mmol) were added at 0 °C and the solution was stirred
for about 10 min then aryl amine (1.0 mmol) was added to
the reaction mixture. The reaction was monitored by TLC.
After completion of the reaction (1–3 h), the solvent was
evaporated and the crude was extracted into EtOAc (20 mL).
The organic layer was washed with 10 % HCl (10 mL 9 2),
5 % Na2CO3 (10 mL 9 2), water, brine and dried over
anhydrous Na2SO4, evaporated the solvent to obtain the aryl
amide in good yields as well as purity (70–94 %).
Fmoc-Phg-3-Methylanilide (2e)
White solid, m.p. 214–217 °C, yield 88 %. 1H NMR
(400 MHz, DMSO-d6) d: 2.31 (s, 3H), 4.22–4.29 (m, 3H),
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Int J Pept Res Ther
Cbz-Ala-4-Methoxyanilide (2j)
5.35 (d, 1H, J = 7.2 Hz), 6.72 (d, 1H, J = 6.6 Hz),
7.15–8.23 (m, 17H), 10.21 (s, 1H). 13C NMR (75 MHz,
DMSO-d6) d: 23.8, 46.1, 67.2, 119.0, 120.7, 125.5, 126.3,
127.7, 128.3, 128.7, 129.2, 129.8, 138.1, 138.7, 156.2,
169.6. HRMS m/z [M ? H]?calcd for C30H26N2O3:
463.2022, Found 463.2025.
White solid, m.p. 179–180 °C, yield 82 %. 1H NMR
(400 MHz, DMSO-d6) d: 1.42 (d, 3H, J = 6.8 Hz), 3.78 (s,
3H), 4.71–4.75 (m, 1H), 5.21 (s, 2H), 6.84 (d, 2H,
J = 5.8 Hz), 7.15–7.23 (m, 6H), 7.57 (d, 2H, J = 5.8 Hz),
9.34 (s, 1H). 13C NMR (75 MHz, DMSO-d6) d: 18.5, 48.2,
56.1, 66.3, 114.6. 122.8, 127.5, 127.9, 129.1, 131.7, 140.4,
155.2, 156.5, 171.2. HRMS m/z [M?Na]?, calcd for
C18H20N2O4: 351.1321, Found 351.1327.
Fmoc-Aib-4-Methylanilide (2f)
White solid, m.p. 221–222 °C, yield 65 %. 1H NMR
(400 MHz, DMSO-d6) d: 1.48 (d, 6H, J = 6.4 Hz), 2.41 (s,
3H), 4.37 (t, 1H, J = 5.2 Hz), 4.68 (d, 2H, J = 7.2 Hz), 6.97
(d, 2H, J = 6.8 Hz), 7.13 (br, 1H), 7.28–7.81 (m, 10 H), 9.31
(s, 1H). 13C NMR (75 MHz, DMSO-d6) d: 23.8, 24.9, 46.5,
60.3, 66.9, 121.3, 126.4, 127.8, 128.4, 128.7, 129.5, 134.2,
136.1, 141.1, 143.5, 156.8, 174.2. HRMS m/z [M?Na]?calcd
for C26H26N2O3: 437.4860, Found 437.4852.
Cbz-Phe-3,4-Difluoroanilide (2k)
White solid, m.p. 160–163 °C, yield 71 %. 1H NMR
(400 MHz, DMSO-d6) d: 2.84 (d, 2H, J = 6.8 Hz), 4.32 (t,
1H, J = 5.2 Hz), 5.25 (s, 2H), 6.83 (d, 1H, J = 7.2 Hz),
7.17–7.38 (m, 11H), 7.64–7.72 (m, 2H), 10.21 (br, 1H). 13
C
NMR (75 MHz, DMSO-d6) d: 35.1, 56.7, 67.5, 111.2, 115.8,
117.8, 125.2, 126.1, 126.8, 127.3, 128.8, 129.7, 135.4, 137.8,
141.2, 146.4, 147.3, 156.7, 172.5. HRMS m/z [M?Na]?
calcd for C23H20F2N2O3: 433.1340, Found 433.1325.
Fmoc-Pro-3-Methylanilide (2g)
White solid, m.p. 181 °C, yield 81 %. 1H NMR (400 MHz,
CDCl3) d: 1.82–1.87 (m, 2H), 2.03–2.08 (m, 2H), 3.21 (t,
2H, J = 4.8 Hz), 4.21 (t, 1H, J = 5.4 Hz), 4.43 (t, 1H,
J = 5.0 Hz), 4.69 (d, 2H, J = 7.4 Hz), 6.98 (d, 1H,
J = 7.2 Hz), 7.28–7.53 (m, 11H), 8.97 (s, 1H). 13C NMR
(75 MHz, CDCl3) d: 26.1, 29.3, 47.2, 48.7, 60.5, 67.9,
118.3, 120.1, 120.7, 124.3, 126.1, 127.5, 127.9, 128.5,
131.2, 134.5, 139.7, 140.8, 143.7, 156.5, 171.1. HRMS m/z
[M?Na]? calcd for C26H23ClN2O3: 469.1295, Found
469.1286.
Boc-Ala-3-Chloroanilide (2l)
White solid, m.p. 181–182 °C, yield 81 %. 1H NMR
(400 MHz, DMSO-d6) d: 1.37 (s, 9H), 1.51 (d, 3H, J =),
4.91–4.95 (m, 1H), 5.87 (br, 1H), 6.95 (d, 1H, J =),
7.41–7.63 (m, 3H), 8.95 (s, 1H). 13C NMR (75 MHz,
DMSO-d6) d: 17.4, 27.8, 49.5, 78.1, 119.3, 121.8, 125.1,
130.8, 133.2, 138.1, 156.3, 171.8. HRMS m/z [M?Na]?
calcd for C14H19ClN2O3: 321.7550, Found 321.7549.
Fmoc-Ser-3-Methylanilide (2h)
Cbz-Phe-4-Cyanoanilide (2m)
White solid, m.p. 190–192 °C, yield 88 %. 1H NMR
(400 MHz, DMSO-d6) d: 2.31 (s, 3H), 3.62–3.67 (d, 2H,
J = 6.0 Hz), 4.23–4.32 (m, 4H), 6.79 (d, 1H, J = 6.8 Hz),
7.15–7.91 (m, 11H), 8.17 (s, 1H), 9.92 (s, 1H). 13C NMR
(75 MHz, DMSO-d6) d: 21.5, 46.3, 62.8, 116.3, 120.3,
121.5, 124.8, 125.3, 127.6, 128.2, 129.0, 138.1, 139.5,
141.4, 144.3, 144.7, 156.5, 171.8. HRMS m/z [M?Na]?,
calcd for C25H24N2O4: 439.1634, Found 439.1641.
White solid, m.p. 171–172 °C, yield 73 %. 1H NMR
(400 MHz, DMSO-d6) d: 2.53 (d, 2H), 3.15 (t, 1H,
J = 4.4 Hz), 4.93 (s, 2H), 7.12–7.53 (m, 12H), 7.83 (d,
J = 6.6 Hz, 2H), 8.12 (br, 1H), 10.35 (br, 1H). 13C NMR
(75 MHz, DMSO-d6) d: 36.8, 57.1, 65.4, 110.7, 118.6, 120.9,
122.7, 126.5, 126.8, 127.4, 127.9, 128.3, 128.7, 129.1, 130.3,
136.8, 137.5, 139.4, 156.1, 171.0. HRMS m/z [M?Na]?,
calcd for C24H21N3O3: 422.1481, Found 422.1478.
Cbz-Phe-4-Methylanilide (2i)
Boc-Val-3-Bromoanilide (2n)
White solid, m.p. 157–159 °C, yield 83 %. 1H NMR
(400 MHz, DMSO-d6) d: 2.31 (s, 3H), 3.13 (d, 2H,
J = 6.2 Hz), 4.90–4.96 (m, 1H), 5.28 (s, 2H), 7.02 (d, 2H,
J = 6.4 Hz), 7.19–7.41 (m, 10 H), 7.57 (d, 2H,
J = 6.4 Hz), 8.95 (s, 1H). 13C NMR (75 MHz, DMSO-d6)
d: 22.3, 37.1, 53.1, 66.3, 121.8, 126.2, 127.3, 127.8, 128.4,
128.8, 129.5, 129.7, 133.6, 135.1, 139.2, 141.2, 155.8,
172.3. HRMS m/z [M?Na]?, calcd for C24H24N2O3:
411.4487, Found 411.4491.
White solid, m.p. 153–154 °C, yield 90 %. 1H NMR
(400 MHz, DMSO-d6) d: 1.05 (d, 6H, J = 7.2 Hz), 1.43 (s,
9H), 2.69–2.78 (m, 1H), 4.12–4.18 (m, 1H), 7.18–7.41 (m,
4H), 7.92 (br, 1H), 9.82 (s, 1H). 13C NMR (75 MHz,
DMSO-d6) d: 17.3, 26.5, 31.7, 57.8, 79.1, 120.4, 121.5,
123.4, 127.6, 130.1, 139.3, 156.5, 172.1. HRMS m/z
[M?Na]? calcd for C16H23N2O3: 393.0790, Found
393.0788.
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Int J Pept Res Ther
Fmoc-Ala-p-Nitroanilide (2o)
DMSO-d6) d: 17.4, 20.3, 21.9, 41.2, 48.5, 50.3, 51.5, 56.1,
67.6, 115.6, 122.2, 126.0, 127.8, 128.6, 131.5, 140.2, 142.8,
156.5, 156.4, 170.5, 171.8. HRMS m/z [M?Na]? calcd for
C31H35N3O5: 552.2474, Found 552.2478.
White solid, m.p. 184–185 °C, yield 75 %. 1H NMR
(400 MHz, DMSO-d6) d: 1.33 (d, 3H, J = 4.2 Hz), 4.10 (t,
1H, J = 6.0 Hz), 4.35 (d, 2H, J = 6.2 Hz), 4.67–4.71 (m,
1H), 5.18 (br, 1H), 7.21–8.05 (m, 12H), 10.72 (br, 1H). 13
C
Cbz-Phe-Leu-2-Chloroanilide (4d)
NMR (75 MHz, DMSO-d6) d: 16.7, 44.7, 48.4, 67.3, 120.4,
121.5, 125.2, 126.4, 127.3, 127.7, 140.1, 141.5, 143.3,
143.8, 155.7, 170.2. HRMS calcd for C24H21N3O5 m/z
454.1379 [M?Na]?, Found 454.1354.
White solid, m.p. 231–232 °C, yield 88 %. 1H NMR
(400 MHz, DMSO-d6) d: 1.10 (d, 6H, J = 7.2 Hz),
1.81–1.85 (m, 2H), 2.88 (d, 2H, J = 6.6 Hz), 4.37–4.46 (m,
3H), 5.27 (s, 2H), 5.81 (br, 1H), 6.97–7.24 (m, 14H), 7.45 (br,
1H), 9.52 (s, 1H). 13C NMR (75 MHz, DMSO-d6) d: 21.8,
23.4, 35.8, 42.1, 51.4, 53.5, 15.8, 123.7, 125.2, 125.9, 126.4,
127.3, 127.8, 128.0, 128.3, 128.7, 129.3, 131.8, 134.6, 139.1,
141.4, 156.5, 170.8, 171.5. HRMS m/z [M?Na]? calcd for
C29H32ClN3O4: 544.1979, Found 544.1969.
Fmoc-Val-p-Nitroanilide (2p)
White solid, m.p. 198–199 °C, yield 71 %. 1H NMR
(400 MHz, DMSO-d6) d: 0.97 (d, 6H, J = 7.2 Hz),
2.42–2.48 (m, 1H), 4.20–4.27 (m, 2H), 4.54 (d, 2H,
J = 6.8 Hz), 5.31 (br, 1H), 7.28–8.12 (m, 12H), 9.8 (br,
1H). 13C NMR (75 MHz, DMSO-d6) d: 16.8, 30.5, 45.7,
58.5, 67.6, 121.2, 121.6, 125.5, 126.8, 127.4, 127.8, 140.0,
141.5, 143.3, 143.9, 155.0, 171.1. HRMS m/z [M?Na]?
calcd for C26H25N3O5: 482.1692, Found 482.1680.
Boc-Ala-Ile-4-Methylanlide (4e)
White solid, m.p. 219–222 °C, yield 86 %. 1H NMR
(400 MHz, DMSO-d6) d: 0.90 (t, 3H, J = 5.0 Hz), 1.07 (d,
3H, J = 6.8 Hz), 1.18–1.21 (m, 2H), 1.36 (s, 9H), 1.49 (d,
3H, J = 7.2 Hz), 2.31–2.37 (m, 1H), 2.51 (s, 3H), 4.48 (d,
1H, J = 6.2 Hz), 5.61 (br, 1H), 6.84 (br, 1H), 7.12 (d, 2H,
J = 5.8 Hz), 7.64 (d, 2H, J = 5.6 Hz), 8.67 (s, 1H). 13C
NMR (75 MHz, DMSO-d6) d: 13.1, 15.2, 18.4, 23.5, 24.6,
28.1, 35.4, 49.7, 54.1, 78.5, 120.8, 129.1, 133.5, 135.1,
156.7, 170.1, 172.3. HRMS m/z [M?Na]? calcd for
C29H32ClN3O4: 414.2369, Found 414.2365.
Fmoc-Gly-Phe-3-Methylanilide (4a)
White solid, m.p. 237–238 °C, yield 85 %. 1H NMR
(400 MHz, DMSO-d6) d: 2.35 (s, 3H), 3.12–3.16 (m, 2H,
J = 5.8 Hz), 3.78 (s, 2H), 4.35 (t, 1H, J = 5.4 Hz),
4.42–4.61 (m, 3H), 6.78 (d, 1H, J = 6.8 Hz), 7.21–7.63 (m,
18H), 9.21 (s, 1H). 13C NMR (75 MHz, DMSO-d6) d: 25.8,
33.8, 40.7, 46.9, 52.8, 67.4, 118.4, 121.7, 123.4, 126.2, 126.8,
127.2, 127.8, 128.2, 128.9, 129.4, 137.9, 138.5, 139.8, 140.1,
143.2, 156.7, 169.7, 171.8. HRMS m/z [M?Na]? calcd for
C33H31N3O4: 556.2212, Found 556.2215.
Boc-Gly-Val-4-Pyrrolylanilide (4f)
White solid, m.p. 229 °C, yield 82 %. 1H NMR (400 MHz,
DMSO-d6) d: 1.15 (d, 6H, J = 7.0 Hz), 1.37 (s, 9H),
2.31–2.37 (m, 1H), 3.78 (d, 2H, J = 6.2 Hz), 4.40 (d, 1H,
J = 6.6 Hz), 5.57 (br, 1H), 6.18 (d, 2H, J = 5.8 Hz), 6.80 (d,
Fmoc-Val-Ala-4-Chloroanilide (4b)
White solid, m.p. 239–243 °C, yield 91 %. 1H NMR
(400 MHz, DMSO-d6) d: 1.03 (d, 6H, J = 7.2 Hz), 1.38
(d, 3H, J = 6.8 Hz), 2.51–2.59 (m, 1H), 4.43–4.5 (m, 2H),
4.52 (d, 2H, J = 6.8 Hz), 4.81–4.86 (m, 1H), 6.82 (br, 1H),
7.24–7.91 (m, 13H), 9.51 (s, 1H). 13C NMR (75 MHz,
DMSO-d6) d: 16.7, 18.1, 30.2, 45.8, 49.4, 57.1, 65.2, 123.7,
126.2, 127.4, 128.0, 128.5, 128.9, 129.4, 137.1, 139.2,
143.7, 156.2, 170.3, 172.7. HRMS m/z [M?Na]? calcd for
C29H30ClN3O4: 542.1823, Found 542.1830.
Table 1 Optimization of the reaction conditions for the synthesis of
2a
Entry
Base
Solvent
Yield (%)
Time (h)
1
2
3
4
5
6
7
Pyridine
Pyridine
Pyridine
DIPEA
NMM
EtOAc
THF
65
85
90
78
82
85
95
18
18
15
7
Fmoc-Ala-Leu-4-Methoxyanilidine (4c)
CH3CN
CH3CN
EtOAc
THF
White solid, m.p. 242 °C, yield 93 %. 1H NMR (400 MHz,
DMSO-d6) d: 1.02 (d, 6H, J = 7.0 Hz), 1.35 (d, 3H,
J = 6.4 Hz), 1.81–1.87 (m, 3H), 3.65 (s, 3H), 4.48–4.56 (m,
3H), 4.61 (d, 2H, J = 6.8 Hz), 6.75 (d, 2H, J = 7.0 Hz),
7.28–7.53 (m, 12H), 9.12 (s, 1H). 13C NMR (75 MHz,
3
NMM
2
NMM
CH3CN
1
123

Int J Pept Res Ther
Table 2 List of N-protected amino acid arylamides 2
S.no
Arylamide 2
Yield
(%)
Mp (°C)
S.no
Arylamide 2
Yield
(%)
Mp (°C)
a
94
193
i
83
157–159
b
81
155–156
j
82
179–180
c
85
83
165–166
131–133
k
71
81
160–163
181–182
d
l
e
88
214–217
m
73
171–172
f
65
221–222
n
90
153–154
g
81
181
o
75
184–185
123

Int J Pept Res Ther
Table 2 continued
S.no
Arylamide 2
Yield
(%)
Mp (°C)
S.no
Arylamide 2
Yield
(%)
Mp (°C)
h
88
190–192
p
71
198–199
Fmoc-Leu-7-Amino-3-Methyl Coumarin Amide (5b)
2H, J = 5.8 Hz), 7.25 (d, 2H, J = 6.2 Hz), 7.56 (d, 2H,
J = 6.2 Hz), 7.8 (br, 1H), 9.25 (s, 1H). 13C NMR (75 MHz,
DMSO-d6) d: 17.8, 28.3, 31.1, 45.9, 56.7, 77.3, 109.8, 120.9,
121.5, 124.4, 134.6, 136.1, 156.8, 170.3, 171.5. HRMS m/z
[M?Na]? calcd for C22H30N4O4: 437.2165, Found 437.2151.
Gum, yield 74 %, 1H NMR (400 MHz, DMSO-d6) d: 1.03 (d,
6H, J = 6.8 Hz), 1.83–1.86 (m, 3H), 1.95 (s, 3H), 4.47–4.52
(m, 4H), 6.43 (br, 1H), 7.25–7.56 (m, 12H), 8.91 (s, 1H). 13
C
NMR (75 MHz, DMSO-d6) d: 18.3, 21.8, 22.3, 41.4, 46.8,
53.1, 66.7, 112.3, 128.3, 128.8, 137.7, 140.3, 141.5, 143.7,
151.3, 156.7, 161.8, 171.4. HRMS m/z [M?Na]? calcd for
C31H30N2O5: 533.2052, Found 533.2058.
Cbz-Phe-Ile-Ala-4-Chloroanilide (4g)
White solid, m.p. 231–233 °C, yield 87 %. 1H NMR
(400 MHz, DMSO-d6) d: 1.05 (t, 3H, J = 7.2 Hz), 1.18 (d,
3H, J = 6.6 Hz), 1.32–1.37 (m, 2H), 1.57 (d, 3H,
J = 6.4 Hz), 2.34–2.39 (m, 1H), 2.91 (d, 2H, J = 6.2 Hz),
3.78 (d, 1H, J = 5.4 Hz), 4.51–4.56 (m, 1H), 4.72–4.78 (m,
1H), 5.27 (s, 2H), 5.80 (br, 1H), 6.64 (br, 1H), 7.17–7.55 (m,
14H), 9.65 (s, 1H). 13C NMR (75 MHz, DMSO-d6) d: 11.4,
15.8, 18.1, 27.2, 37.4, 38.6, 46.7, 53.4, 56.7, 64.6, 122.8,
125.2, 126.8, 127.4, 128.1, 129.4, 129.9, 134.2, 137.9, 140.5,
142.3, 155.4, 167.8, 170.5. HRMS m/z [M?Na]? calcd for
C32H37ClN4O5: 615.235, Found 615.2348.
Fmoc-Val-Leu-7-Amino-3-Methyl Coumarin Amide
(5c)
Gum, yield 69 %, 1H NMR (400 MHz, DMSO-d6) d: 0.93 (d,
6H, J = 7.4 Hz), 1.07 (d, 6H, J = 7.0 Hz), 1.87–1.91 (m,
4H), 1.97(s, 3H),4.41(t, 1H, J = 5.2 Hz), 4.51–4.55(m, 2H),
4.72 (d, 2H, J = 6.4 Hz), 5.23 (br, 1H), 7.25–7.55 (m, 13H),
8.75 (s, 1H). 13C NMR (75 MHz, DMSO-d6) d: 16.8, 17.4,
22.6, 23.9, 32.7, 41.5, 48.1, 52.3, 59.4, 68.2, 112.1, 116.3,
117.9, 123.7, 126.5, 127.2, 128.1, 128.6, 129.7, 137.5, 139.0,
141.5, 142.8, 150.1, 156.3, 162.0, 169.3, 171.5. HRMS m/z
[M?Na]? calcd for C36H39N3O6: 632.2737, Found 632.2731.
Boc-Gly-Ala-Ile-Alilide (4h)
White solid, m.p. 240–241 °C, yield 78 %. 1H NMR
(400 MHz, DMSO-d6) d: 0.84 (t, 3H, J = 5.2 Hz), 1.09 (d,
3H, J = 6.4 Hz), 1.21–1.26 (m, 2H), 1.37 (s, 9H), 1.45 (d, 3H,
J = 6.8 Hz), 2.41–2.47 (m, 1H), 3.57 (s, 2H), 4.35 (d, 1H,
J = 7.2 Hz), 4.82–4.87 (m, 1H), 5.23 (br, 1H), 6.82 (br, 1H),
7.15–7.35 (m, 5H), 10.23 (s, 1H). 13C NMR (75 MHz, DMSO-
d6) d: 12.5, 14.8, 17.4, 25.2, 28.3, 37.8, 43.1, 47.5, 55.9, 79.1,
121.2, 124.5, 129.4, 135.3, 156.7, 169.4, 171.5. HRMS m/z
[M?Na]? calcd for C22H34N4O5: 457.2427, Found 457.2454.
Z-Phe-Gly-7-Amino-3-Methyl Coumarin Amide (5d)
1
Gum, yield 65 %, H NMR (400 MHz, DMSO-d6) d: 1.87
(s, 3H), 3.12 (d, 2H, J = 7.0 Hz), 4.15 (s, 2H), 4.83 (t, 1H,
J = 5.8 Hz), 5.32 (s, 2H), 6.41 (br, 1H), 7.15–7.29 (m,
13H), 7.39 (s, 1H), 7.42 (d, 1H, J = 7.4 Hz), 8.78 (s, 1H).
13C NMR (75 MHz, DMSO-d6) d: 17.8, 38.1, 43.4, 55.6,
67.1, 112.3, 117.6, 118.7, 123.9, 126.3, 126.7, 127.1,
127.5, 128.9, 128.6, 129.1, 137.4, 139.1, 140.2, 141.5,
156.3, 169.4, 172.1. HRMS m/z [M?Na]? calcd for
C29H27N3O6: 536.1798, Found 536.1786.
Z-Ala-7-Amino-3-Methyl Coumarin Amide (5a)
1
Gum, yield 70 %, H NMR (400 MHz, DMSO-d6) d: 1.35
Fmoc-Phe-3-Amino Coumarin Amide (5e)
(d, 3H, J = 6.8 Hz), 1.87 (s, 3H), 4.32 (m, 1H), 5.27 (s,
2H), 6.31 (br, 1H), 7.21–7.35 (m, 9H), 8.82 (s, 1H). 13C
NMR (75 MHz, DMSO-d6) d: 16.8, 17.5, 53.7, 66.1, 112.7,
116.3, 118.5, 124.7, 126.9, 127.5, 127.9, 128.6, 137.3,
139.4, 140.7, 151.4, 156.7, 163.1. HRMS m/z [M?Na]?
calcd for C21H20N2O5: 403.127, Found 403.1265.
1
Gum, yield 72 %, H NMR (400 MHz, DMSO-d6) d: 2.87
(d, 2H, J = 6.4 Hz), 4.45 (t, 1H, J = 5.6 Hz), 4.62 (d, 2H,
J = 6.8 Hz), 4.81 (t, 1H, J = 5.6 Hz), 6.72 (br, 1H), 7.02
(m, 2H), 7.19–7.78 (m, 16H), 8.91 (s, 1H). 13C NMR
123

Int J Pept Res Ther
(75 MHz, DMSO-d6) d: 38.1, 47.4, 55.7, 67.3, 115.4,
120.8, 122.5, 125.1, 126.2, 126.5, 126.8, 127.7, 128.1,
128.4, 128.8, 19.4, 136.2, 138.8, 140.7, 143.5, 150.7,
156.3, 160.1, 171.2. HRMS m/z [M?Na]? calcd for
C33H26N2O5: 553.1739, Found 553.1812.
128.8, 129.5, 147.2, 148.9, 156.3, 159.1, 171.8. HRMS m/z
[M?Na]? calcd for C21H29N3O3: 394.2107, Found 394.2112.
Fmoc-Ala-Phe-4-Amino-2-Methyl Quinaldine Amide (5h)
1
Gum, yield 71 %, H NMR (400 MHz, DMSO-d6) d: 1.41
Z-Leu-3-Amino Coumarin Amide (5f)
(d, 3H, J = 5.6 Hz), 2.43 (s, 3H), 3.12 (d, 2H,
J = 6.8 Hz), 4.42 (t, 1H, J = 5.2 Hz), 4.61 (d, 2H,
J = 7.2 Hz), 4.81–4.85 (m, 2H), 6.32 (s, 1H), 7.12 (br,
1H), 7.28–7.84 (m, 17H), 8.81 (s, 1H). 13C NMR (75 MHz,
DMSO-d6) d: 17.1, 25.8, 38.1, 47.0, 51.4, 53.7, 66.4, 106.2,
118.7, 120.7, 124.3, 125.8, 126.7, 127.4, 128.0, 128.5,
128.8, 129.3, 129.7, 129.9, 138.3, 141.2, 143.7, 147.0,
148.2, 156.4, 159.7, 169.7, 172.4. HRMS m/z [M?Na]?
calcd for C37H34N4O4: 621.2478, Found 621.2483.
1
Gum, yield 70 %, H NMR (400 MHz, DMSO-d6) d: 1.04
(d, 6H, J = 7.2 Hz), 1.78–1.83 (m, 3H), 4.42 (t, 1H,
J = 4.8 Hz), 5.25 (s, 2H), 6.81 (s, 1H), 7.05 (m, 2H),
7.17–7.23 (m, 8H), 8.74 (s, 1H). 13C NMR (75 MHz,
DMSO-d6) d: 22.0, 22.7, 41.4, 53.2, 65.9, 114.8, 121.4,
122.6, 125.3, 126.7, 127.4, 127.8, 128.5, 129.3, 136.2,
140.8, 150.4, 156.3, 159.7, 171.2. HRMS m/z [M?Na]?
calcd for C23H24N2O5: 431.1583, Found 431.1578.
Boc-Ile-4-Amino-2-Methyl Quinaldine Amide (5g)
Results and Discussion
Gum, yield 67 %, 1H NMR (400 MHz, DMSO-d6) d: 0.95 (t,
3H, J = 6.2 Hz), 1.032 (d, 3H, J = 6.8 Hz), 1.23 (m, 2H),
1.37 (s, 9H), 2.53 (m, 1H), 2.63 (s, 3H), 4.31 (d, 1H,
J = 7.0 Hz), 6.32 (s, 1H), 6.81 (br, 1H), 7.43–7.91 (m, 4H),
8.97 (s, 1H). 13C NMR (75 MHz, DMSO-d6) d: 11.3, 15.1,
23.8, 25.3, 28.4, 37.2, 58.6, 78.8, 105.7, 118.1, 120.3, 124.1,
The literature precedence for the preparation of arylamides
using T3P illustrated only condensation of Z–Phg–OH and Z–
Ala–OH with aniline and pyridine for about 18 h (Dunetz et al.
2011). With our promising results on T3P mediated reactions,
we set forth to synthesize arylamides of N-protected a-amino/
peptide acids in detail. Initially the reaction between
Table 3 List of peptide arylamides 4
S.no
Peptide arylamide 4
Yield (%)
85
S.no
Peptide arylamide 4
Yield (%)
86
a
e
b
c
91
93
f
82
87
g
d
88
h
78
123

Int J Pept Res Ther
R1
2, 3). Whereas the usage of DIPEA with CH3CN reduces
reaction duration to 7 h (Table 1, entry 4). Finally to our delight
NMM was found to be the suitable base which reduces the
reaction duration drastically (Table 1, entries 5–7). Thus a
combination of NMM and CH3CN mediated by T3P provided
satisfactory result in terms of yield and reaction duration
(Table 1, entry 7) for arylamidation. In a typical procedure, T3P
and NMM were added to a solution of Fmoc-Ala-OH 1a in
CH3CN at 0 °C, stirred for 10 min, aniline was added to the
reaction mixture. After complete consumption of starting
materials (1 h), a simple work-up followed by recrystallization
with ether afforded pure product 2a in 95 % yield.
R1
CH3CN, NMM
H
OH
N
T3P
NH2
PgHN
PgHN
R2
O
O
R2
R2 = Me, Cl, Br, OMe, CN
2
1
Scheme 1 Synthesis of Na-protected amino acid arylamides
R1
O
R1
O
CH3CN, TEA
R3
H
H
N
N
T3P
PgHN
OH
PgHN
N
NH2
H
R2
O
R2
O
R3
3
R3 = Me, Cl, Br, OMe
4
Scheme 2 Synthesis of Na-protected peptide arylamides
Employing the optimized reaction conditions, a series of
Na-protected amino acids were reacted with different
substituted aniline derivatives to obtain the corresponding
aryl amides in good to excellent yields (Table 2, Scheme 1).
Aryl amides were obtained in excellent yields with
aniline derivatives having electron donating groups.
Whereas the electron withdrawing groups on aniline
derivatives usually lowers the nucleophilicity of amine and
Fmoc-Ala-OH 1a and aniline using T3P was performed. The
desired amide 2a was yielded in 65 % after 18 h. In order to
improve the yield and reduce the reaction duration, we further
studied the effect of various bases and solvents on reaction
outcome. Longer duration was observed for the formation of 2a
with THF and CH3CN in presence of pyridine (Table 1, entries
Table 4 List of coumarin arylamides 5
S. no
Arylamide 5
Yield (%)
70
S. no
Arylamide 5
Yield (%)
72
a
e
b
74
f
70
c
69
g
67
d
65
h
71
123

Int J Pept Res Ther
Fig. 1 Chiral HPLC of 2a, 2a* and mixture of 2a and 2a*
thus the corresponding aryl amides were obtained in
moderate yield. In general, the reaction worked well even
with the sterically hindered amino acids such as Fmoc-Pro-
OH, Fmoc-Aib-OH and Fmoc-Val-OH. Additionally, Na-
protected hydroxyl amino acids including Ser, Thr and Tyr
were also converted to respective aryl amides without
protection of the free hydroxy function (2b, 2c , 2h). The
optimized reaction conditions worked well even for the
synthesis of p-nitroanilides but with moderate yields.
The protocol was then extended to synthesize several
peptide aryl amides. In a typical reaction, the dipeptide Z–
Val–Leu–OH 3c was dissolved in CH3CN, NMM and T3P
were added, the mixture was stirred for 10 min at 0 °C and
then p-toluedine was added. The desired peptide aryl amide
4c was obtained in 80 % yield within 1–2 h (Scheme 2,
Table 3).
13.30 min (2a) and 18.30 min (2a*). Further, the inten-
tionally made mixture of 2a and 2a* had two separate
peaks corresponding to the L-and D-isomers (Rt = 13.9 and
18.3 min) (Fig. 1). This clearly confirms that the synthesis
of arylamides through the present protocol is free from
racemization.
Further, peptide arylamides, derived from Fmoc-Phe-
(L)-Ala-OH and Fmoc-Phe-(D)-Ala-OH, were prepared and
subjected to chiral HPLC analysis. The HPLC profiles
reveled single peak at Rt value 9.86 min and 12.06 min.
Further, the intentionally made mixture had two separate
peaks corresponding to the L-and D-isomers (Rt = 10.04
and 12.44 min) (Fig. 2). This confirms that the protocol
employed for synthesis of peptide arylamides is also free
from epimerization.
Similar strategy was employed to ligate fluorogenic
substrates such as coumarin and quinoline derivatives onto
amino acids. Several amine components including
7-amino-3-methyl coumarin (AMC), 3-amino coumarin,
4-amino quinaldine were found to undergo facile amide
bond formation with various Na-protected amino/peptide
acids in presence of T3P. The pure products were isolated
in good yields after column purification (Hexane:EtOAc
80:20, Table 4).
During the course of the study, two enantiomeric Na-
protected arylamides derived from Fmoc-L-Ala-OH 2a and
its epimer Fmoc–D–Ala–OH, 2a* were examined. The
chiral HPLC profiles showed single peaks at Rt value
Conclusion
In conclusion, we have developed a facile and an efficient
method for the conversion of Na-protected amino/peptide
acids into arylamides employing T3P/NMM/CH3CN sys-
tem. Unlike most of the earlier protocols which require
either multiple steps, hazardous coupling reagents etc., the
present approach delivers the product in a most simple and
economic way. A series of carboxylic acids including Na-
Fmoc/Z/Boc amino/peptide acids have been converted into
corresponding arylamides in excellent yields under mild
condition. Further arylamides from chromogenic coumarin,
123

Int J Pept Res Ther
Fig. 2 Chiral HPLC of peptide arylamide
Basavaprabhu Vishwanatha TM, NageswaraRao P, Sureshbabu VV
(2013) Propanephosphonic acid anhydride (T3PÒ)—a benign
reagent for diverse applications inclusive of large-scale synthe-
sis. Synthesis 12:45
Crawforth JM, Paoletti M (2009) A one-pot synthesis of imidazo[1,5-
a]pyridines. Tetrahedron Lett 50:4916
Crichfield KS, Hart JE, Lampert JT, Vaid RK (2000) Propane
phosphonic acid anhydride: a mild reagent for b-lactom synthe-
sis. Synth Commun 30:3737
Desroses M, Wieckowski K, Stevens M, Odell LR (2011) A
microwave-assisted, propylphosphonic anhydride (T3P) medi-
ated one-pot Fischer indole synthesis. Tetrahedron Lett 52:4417
Dunetz JR, Xiang Y, Baldwin A, Ringling J (2011) General and
scalable amide bond formation with epimerization-prone sub-
strates using T3P and pyridine. Org Lett 13:5049
quinalidine and p-nitro anilides were also realized in good
yields.
Acknowledgments We thank Department of Science and Tech-
nology (DST) (Grant No. SR/S1/OC-52/2011) New Delhi, India for
financial assistance. C Madhu thanks to UGC for the award of SRF.
Conflict of interest Chilakapati Madhu, Nageswara Rao Panguluri,
Narendra N and Vommina V Sureshbabu declare that they have no
conflict of interest.
Statement of informed consent Authors declare that there is no
informed consent in the article.
Statement of human and animal rights This article does not
contain any studies with human or animal subjects performed by the
any of the authors.
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