Efficient synthesis of primary amides using 2-mercaptopyridone-1-oxide-based uronium salts

Article abstract of DOI:10.1016/S0040-4039(00)01775-5

S-(1-Oxido-2-pyridinyl)-1,1,3,3-tetramethylthiouronium tetrafluoroborate (TOTT) and hexafluorophosphate (HOTT) are cheap and convenient reagents for the rapid and high-yielding preparation of primary amides when reacted with carboxylic acids and ammonium chloride in the presence of diisopropylethylamine. The reaction is chemoselective and undesired ammonolysis of other sensitive functional groups is not observed. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01775-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 9809–9813
Efficient synthesis of primary amides using
2-mercaptopyridone-1-oxide-based uronium salts
Miguel A. Baile´n, Rafael Chinchilla, David J. Dodsworth and Carmen Na´jera*
Departamento de Qu´ımica Orga´nica, Universidad de Alicante, Apartado 99, 03080 Alicante, Spain
Received 10 July 2000; accepted 5 October 2000
Abstract
S-(1-Oxido-2-pyridinyl)-1,1,3,3-tetramethylthiouronium tetrafluoroborate (TOTT) and hexafluorophos-
phate (HOTT) are cheap and convenient reagents for the rapid and high-yielding preparation of primary
amides when reacted with carboxylic acids and ammonium chloride in the presence of diisopropylethy-
lamine. The reaction is chemoselective and undesired ammonolysis of other sensitive functional groups is
not observed. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: aminium salts; primary amides; coupling reagents.
The preparation of primary amides from the corresponding carboxylic acids is a basic and
well-known transformation in organic synthesis.1 Addition of ammonia to carboxylic acid
derivatives such as acyl halides, anhydrides or esters is an easy and effective procedure when
non-sensitive substrates are implied. However, when the starting carboxylic acid presents other
functionalities which could react via addition or substitution reactions with the basic and
nucleophilic ammonia, lower yields and undesirable by-products are obtained. This problem is
especially serious when working in the preparation of amino acid-derived amides due to the
common use of protecting groups, such as the Fmoc, which could be sensitive to these
conditions. Pharmaceutically important peptide amides contain this type of amino acid deriva-
tives, for example thyrotropin-releasing hormone (TRH) analogues such as taltirelin2 and
azetirelin,3 antibiotics such as the amythiamicins4 and berninamycin,5 oxytocin antagonists such
as atosiban,6 gonad-stimulant principles such as ganirelix7 or fungicides such as majusculamide
A.8 For this reason, the development of simple, mild, efficient, cheap and, therefore, easily
scalable methods for achieving this carboxylic acid-to-primary amide transformation is
desirable.
* Corresponding author. Fax: +34 96 5903548; URL: www.ua.es/dept.quimorg; e-mail: cnajera@ua.es
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01775-5

9810
The use of dicyclohexylcarbodiimide (DCC) in presence of 1-hydroxybenzotriazole (HOBt)
for the activation of the carboxylic group and further reaction with ammonia is a known
procedure.9 Moreover, di-tert-butyl pyrocarbonate has also been used for activation and
trapping of ammonia, generated in situ from ammonium hydrogencarbonate and pyridine in
dioxane as solvent.10 Recently, the peptide coupling reagents DCC, EDAC, PyBOP and
HBTU11 have been employed in a similar methodology affording high yields.12 However, the
best results were achieved using expensive HOBt-derived coupling reagents such as PyBOP or
HBTU, the addition of an extra stoichiometric amount of HOBt and 4 equiv. of diisopropy-
lethylamine (DIEA) being even necessary. In this communication we present the use of the
uronium salts S-(1-oxido-2-pyridinyl)-1,1,3,3-tetramethyluronium hexafluorophosphate (1,
HOTT) and tetrafluoroborate (2, TOTT) as cheap and efficient reagents for the selective
preparation of primary amides. HOTT (1) has previously been used for the preparation of
hindered Barton esters, which are precursors of radicals.13 More recently these uronium salts 1
and 2 have been employed for the synthesis of secondary amides and as adequate peptide
coupling reagents, affording final peptides with yields and racemization degrees comparable to
other more expensive and commonly used coupling reagents.14
The uronium reagents 1 (HOTT) and 2 (TOTT) were prepared from N-hydroxy-2-
pyridinethione and 1,1,3,3-tetramethylurea as previously described.5 Reaction of different car-
boxylic acids with HOTT (1) or TOTT (2) in the presence of ammonium chloride and DIEA in
DMF as solvent, afforded pure primary amides (1H NMR, 300 MHz) after extractive work-up
(Scheme 1). Yields were high in almost all cases (Table 1), and quite similar employing 1 or 2,
which would suggest TOTT (2) as the reagent of choice due to its lower cost.5 When
triethylamine was attempted as alternative base, isolated yields were lower (Table 1, entry 10).
The reaction took place with aliphatic and aromatic carboxylic acids, even in hindered cases
(Table 1, entries 1–4). No by-products were observed even if functional groups sensitive to
ammonolysis were present. Thus, no trace of Michael addition product was detected in the
reaction with an a,b-unsaturated acid such as cinnamic acid (Table 1, entry 5), only the pure
amide being isolated. In addition, no competitive addition product was observed when a
carboxylic acid bearing a a,b-unsaturated sulfone moiety was employed (Table 1, entry 6), the
obtained amide being reported as a precursor of the indolizidine skeleton.15 Similarly, no
nucleophilic substitution reaction was observed when the reaction was performed with haloacids
such as o-bromocaproic acid (Table 1, entry 7) or even with the more sensitive a-bromocaproic
acid although in this case the isolated yield was lower (Table 1, entry 8). When the amidation
reaction was carried out with (S)-mandelic acid, the corresponding enantiomerically pure
Scheme 1.

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Table 1
Preparation of amides employing HOTT (1) and/or TOTT (2)
Entry Acid
Coupling reagent
Amidea
Yieldb (%) Mpc (°C) Lit. mp (°C)
1
2
3
t-BuCO2H
1
2
t-BuCONH2
70
64
154–155
128–129
142–143
154–15717
13018
PhCO2H
1
2
PhCONH2
83
83
1
2
84
85
14218
4
2
77
223
22318
5
6
7
2
2
93
85
146–148
121–123
94–95d
14718
122–12315
105–10619
1
2
93
92
8
9
1
1
55
52–54
57–5820
46e
120–121
123–12418
10
1
2
96
105–107
–
95f,g,h
11
12
13
Fmoc–Leu–OH
1
2
1
2
1
Fmoc–Leu–NH2
99i
99
181–183
184–186
167–169
138–13910
Cbz–Tyr(Bn)–OH
Cbz–Tyr(Bn)–NH2
99j,k
98
–
64
17521
14
2
54
270–271
260–26222
a All compounds gave satisfactory spectroscopic data (1H and 13C NMR, IR and MS).
b Isolated pure compounds (1H NMR, 300 MHz).
c Isolated crude products.
d Mp 105–107°C after recrystallization (hexane/AcOEt).
e [h]D25 +84 (c 1.6, acetone); lit.18 [h]2D0 +73 (c 1.6, acetone).
f 85% yield when triethylamine was used as base.
g [h]2D9 −18.3 (c 1, acetone).
h Anal. calcd for C10H12ClNO2: C, 56.21; H, 5.66; N, 6.56. Found: C, 56.29; H, 5.66; N, 6.68.
i [h]2D5 −13.5 (c 1, EtOH); lit.10 [h]2D0 −17.6 (c 1, EtOH).
j [h]2D8 −7.1 (c 1, acetone).
k Anal. calcd for C24H24N2O4: C, 71.27; H, 5.98; N, 6.93. Found: C, 71.46; H, 5.75; N, 6.97.

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primary amide was isolated (Table 1, entry 9). This direct transformation of a a-hydroxyacid
into a a-hydroxyamide is not very easy, usually requiring harsh conditions, Lewis acid catalysis
or protection/deprotection sequences.16 Protecting groups such as benzyl esters remained intact
as in the case of the reaction of Cbz–Tyr(Bn)–OH (Table 1, entry 12), and the reaction was
quantitative when Cbz- or base-sensitive Fmoc-protected amino acids were used (Table 1, entries
11 and 12). Even a hindered amino acid such as Boc-protected a-aminoisobutyric acid (Aib)
afforded a good yield of the corresponding pure amide (Table 1, entry 13).
In conclusion, the uronium salts HOTT (1) and TOTT (2) are convenient reagents for the
rapid preparation of primary amides under mild and simple reaction conditions. The possibility
of performing the reaction in a selective way, independently of the presence of other sensitive
functionalities, the usual high yields and the low cost of these coupling reagents make them
competitive compared to more expensive HOBt-based reagents. Further studies on other
applications of these peptide coupling reagents are underway.
In a typical procedure, DIEA (340 mL, 2 mmol) and NH4Cl (183 mg, 2 mmol) were added to
a solution of 1 or 2 (1.5 mmol) and of the corresponding acid (1 mmol) in DMF (4 mL) and
the mixture was stirred for 30 min at room temperature. Saturated aqueous NaCl (50 mL) was
added and the mixture was extracted with AcOEt (3×20 mL). The organics were washed with
2N HCl (2×10 mL), water (2×10 mL), saturated NaHCO3 (2×10 mL) and water (4×10 mL),
dried (Na2SO4), filtered and evaporated (15 torr) affording pure amides.
Acknowledgements
We thank the Direccio´n General de Ensen˜anza Superior e Investigacio´n Cient´ıfica (project no.
1FD97-0721) of the Ministerio de Educacio´n y Cultura (MEC) for financial support.
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