Convenient one-pot synthesis of N,N′-bis(2-mercaptophenyl)pyridine-2,6-dicarboxamide and N-2-mercaptophenyl-2′-pyridinecarboxamide without protection of the thiol group(s)

Article abstract of DOI:10.1081/SCC-120020209

A rapid and convenient procedure for the synthesis of N,N′-bis(2-mercaptophenyl)pyridine-2,6-dicarboxamide and N-2-mercaptophenyl-2′-pyridinecarboxamide from 2-aminothiophenol and the appropriate acid chloride is reported. The method is compatible only with aromatic acid chlorides containing a heteroatom. Aromatic acid chlorides with no heteroatom yield the corresponding 2-substituted benzothiazoles.

Full text of DOI:10.1081/SCC-120020209

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Convenient One-Pot Synthesis of N,N ′-bis(2-
Mercaptophenyl)pyridine-2,6-dicarboxamide and N-2-
Mercaptophenyl-2′-pyridinecarboxamide Without
Protection of the Thiol Group(s)
Todd C. Harrop a , Karina Rodriguez a & Pradip K. Mascharak a
a Department of Chemistry and Biochemistry, University of California, Santa Cruz, California,
USA
Published online: 17 Aug 2006.
To cite this article: Todd C. Harrop , Karina Rodriguez & Pradip K. Mascharak (2003) Convenient One-Pot Synthesis of N,N ′-
bis(2-Mercaptophenyl)pyridine-2,6-dicarboxamide and N-2-Mercaptophenyl-2′-pyridinecarboxamide Without Protection of the
Thiol Group(s), Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
33:11, 1943-1949, DOI: 10.1081/SCC-120020209
To link to this article: http://dx.doi.org/10.1081/SCC-120020209
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 11, pp. 1943–1949, 2003
Convenient One-Pot Synthesis of N,N 0-bis(2-
Mercaptophenyl)pyridine-2,6-dicarboxamide and
N-2-Mercaptophenyl-20-pyridinecarboxamide
Without Protection of the Thiol Group(s)
*
Todd C. Harrop, Karina Rodriguez, and Pradip K. Mascharak
Department of Chemistry and Biochemistry, University
of California, Santa Cruz, California, USA
ABSTRACT
A rapid and convenient procedure for the synthesis of N,N 0-
bis(2-mercaptophenyl)pyridine-2,6-dicarboxamide and N-2-mercap-
tophenyl-20-pyridinecarboxamide from 2-aminothiophenol and the
appropriate acid chloride is reported. The method is compatible
only with aromatic acid chlorides containing
a heteroatom.
Aromatic acid chlorides with no heteroatom yield the corresponding
2-substituted benzothiazoles.
Key Words: Carboxamido nitrogen; Thiol; Benzothiazole.
*Correspondence: Pradip K. Mascharak, Department of Chemistry and
Biochemistry, University of California, Santa Cruz 95064, California, USA;
Fax: þ1-831-459-2935; E-mail: pradip@chemistry.ucsc.edu.
1943
DOI: 10.1081/SCC-120020209
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

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1944
Harrop, Rodriguez, and Mascharak
Heterocyclic molecules containing both nitrogen and sulfur atoms
are of general interest in synthetic chemistry due to their presence in
pharmacologically active compounds,[1] industrial polymers,[2] and
enzyme active sites.[3] During the past several years, we and others
have directed considerable effort toward the design and synthesis of
N,S-ligands to model the metal-binding domain of the metalloenzyme
nitrile hydratase (NHase).[4] NHase is involved in the assimilation of
organic nitriles by various microorganisms and catalyzes the hydrolysis
of a variety of nitriles into the corresponding amides. The enzyme
contains either a low-spin Fe(III) or Co(III) center at its active site
which is coordinated to two deprotonated carboxamido nitrogens from
the protein backbone and three cysteine sulfur centers. Two of the three
cysteine sulfurs are modified to a sulfenic and a sulfinic acid group. This
unprecedented coordination sphere around the metal center is thought to
play a crucial role in the catalytic activity of the NHases and is of prime
interest in our laboratory.
Syntheses of N,S-ligands required in our modeling work often face
difficulties due to the reactivity of the thiol group. In the conventional
syntheses of amides from carboxylic acids (or derivatives thereof) and
primary or secondary amines, the thiol group must be protected in order
to prevent side reactions that interfere with the formation of the amide
bond. To date, various techniques including the use of benzyl or triphenyl-
methyl (trityl) protecting groups and formation of disulfide have been
employed.[5] Despite their wide use and success, such protection/
deprotection steps do suffer from some drawbacks namely, an increase
in the number of steps needed in the total synthesis, decrease in overall
yield, and the need for using harsh conditions to remove the protecting
groups. In order to generate a faster and milder route to compounds with
carboxamide and thiol groups, we report herein an efficient one-pot
synthesis of such compounds that does not require S-protecting group(s).
As part of our work in the area of modeling NHases, we have
recently reported the synthesis of a N,S-ligand N,N0-bis(2-mercapto-
phenyl)pyridine-2,6-dicarboxamide (PyPSH4, 1).[4a] The reported synth-
esis of this ligand involves the following steps.

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N,N 0-bis(2-Mercaptophenyl)pyridine-2,6-dicarboxamide
1945
2-Aminothiophenol is first protected with triphenylmethanol in TFA.
The S-protected 2-aminothiophenol is then mixed with 2,6-pyridinedi-
carbonyl dichloride in CHCl3 and Et3N to yield the S-protected amide
compound. Finally, the S-trityl groups are cleaved in neat TFA with
Et3SiH to yield PyPSH4 (1). Although these reactions are clean and
finally afford 1 in high yield, the use of TFA and the amount of time
needed to acquire reasonable amounts of 1 prompted us to look for an
alternative synthetic route. In the present work, we have synthesized 1
under mild conditions in a one-pot reaction. The reaction involves mixing
2-aminothiophenol and 2,6-pyridinedicarbonyl dichloride in THF at
roomtemperature followed by addition of Et 3N (Sch. 1).
The use of non-protected aminothiols for amide bond formation with
retention of the thiol group is not a new concept. The synthesis of high
molecular weight protein molecules through native chemical ligation
developed by Kent and coworkers utilizes similar chemistry.[6] Here,
two peptide fragments are joined together by reaction of the unprotected
N-terminal cysteine end of one fragment with the thioether end of the
other fragment resulting in a thioether linked intermediate. Rapid
intramolecular rearrangement finally results in the formation of an
amide bond and a cysteine thiol group. We propose a similar mechanism
for the formation of our ligand 1. The initial nucleophilic attack on
the carbonyl carbon by sulfur generates a thioether intermediate with
protonated amine group. Addition of Et3N produces the free amine.
Nucleophilic attack by the amine on the carbonyl carbon (intramolecular
S,N-acyl rearrangement) finally results in formation of 1 with carbox-
amide and thiol groups (Sch. 2). The reaction is notably clean and 1 is the
only product isolated in 91% yield.
To explore the generality of this synthetic method, several other acid
chlorides were used including 2-pyridinecarbonyl chloride, isophthaloyl
dichloride, and benzoyl chloride (Sch. 3). Reaction of 2-aminothiophenol
with 2-pyridinecarbonyl chloride under the conditions described above
afforded the corresponding amide-thiol compound N-2-mercaptophenyl-
20-pyridinecarboxamide (PyPepSH2, 2). Interestingly, the remaining two
acid chlorides produced the 2-arylbenzothiazole species 3 and 4 (Sch. 3).
Scheme 1.

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1946
Harrop, Rodriguez, and Mascharak
Scheme 2.
Scheme 3.

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N,N 0-bis(2-Mercaptophenyl)pyridine-2,6-dicarboxamide
1947
Reaction of acyl chlorides (and other derivatives) with 2-aminothio-
phenol is known to afford substituted 2-arylbenzothiazoles and the
reaction has been used widely to synthesize benzothiazoles with pharma-
cological activities.[7] Our results now show that compounds with carbox-
amide and thiol groups (like 1 and 2) are readily formed when acid
chlorides contain a pyridine ring adjacent to the carbonyl carbon(s).
We propose that the electron donating pyridine ring prevents the forma-
tion of the carbinolamine intermediate normally formed when carbonyl
derivatives react with amines, which then undergoes dehydration to form
the C¼N bond in the thiazole ring. With 2-pyridinecarbonyl chloride and
2,6-pyridinedicarbonyl dichloride, the mechanism is the one noted in
peptide ligation reactions developed by Kent and coworkers and hence
compounds like 1 and 2 are formed instead of benzothiazoles.
In summary, a synthetic procedure has been reported for compounds
with both carboxamide and thiol groups (like 1 and 2). The reaction is
clean, fast, and occurs under mild conditions without the need for any
S-protecting group.
EXPERIMENTAL
All reactions were carried out under an N2 atmosphere. THF was
distilled fromNa in the presence of sodiumbenzophenone ketyl. THF
was degassed by the freeze-thaw technique. 2-pyridinecarbonyl chloride
was synthesized by following a published procedure.[4b] 2-Aminothio-
phenol, 2,6-pyridinedicarbonyl dichloride, isophthaloyl dichloride, and
benzoyl chloride were purchased fromAldrich and used without further
1
purification. Both H and 13C NMR spectra were recorded on a Varian
500 MHz Unity Plus instrument. Infrared spectra were obtained with a
Perkin-Elmer 1600 FTIR spectrophotometer.
General Procedure
To a solution of the aromatic acid chloride (2.6 mmol) in dry/
degassed THF (25 mL) was added dropwise 2-aminothiophenol
(2.6 mmol for mono-acid chlorides, 5.2 mmol for diacid chlorides) at
room temperature. The mixture was allowed to stir at room temperature
for 1 h, after which Et3N (2.6 mmol for mono-acid chlorides, 5.2 mmol
for diacid chlorides) was added. Following stirring for 24 h at room

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1948
Harrop, Rodriguez, and Mascharak
temperature, the reaction mixture was filtered to remove the insoluble
triethylamine hydrochloride salt and the filtrate was evaporated in vacuo.
The isolated oil was dissolved in CHCl3/TFA (25 mL, 24/1) and washed
with 10% aqueous NaHCO3 (25 mL), then saturated aqueous NaCl
(25 mL). The CHCl3 layer was dried (MgSO4), filtered, and the filtrate
was evaporated to dryness. The residual oil (except 1 was a solid) was
triturated with Et2O (2 ꢀ 5 mL) to yield the solid compound.
N,N 0-bis(2-mercaptophenyl)pyridine-2,6-dicarboxamide (1): White
solid (903 mg, 91%), IR (KBr, cmꢁ1): 3300 (N-H), 2525 (S-H), 1684
1
(C¼O). H NMR (500 MHz, CDCl3): ꢀ (ppmfromTMS): 10.49 (s, 2H,
amide NH, D2O exchangeable), 8.53 (d, 2H, ArH), 8.36 (d, 2H, ArH),
8.19 (t, 1H, ArH), 7.56 (d, 2H, ArH), 7.36 (t, 2H, ArH), 7.12 (t, 2H,
ArH), 3.39 (s, 2H, SH, D2O exchangeable). All spectral data were iden-
tical to those reported.[4a]
N-2-Mercaptophenyl-20-pyridinecarboxamide (2): Light yellow solid
(401 mg, 67%), IR (KBr, cmꢁ1): 3285 (N-H), 2511 (S-H), 1688 (C¼O).
1H NMR (500 MHz, CDCl3): ꢀ (ppmfromTMS): 10.80 (s, 1H, amide
NH, D2O exchangeable), 8.68 (d, 1H, ArH), 8.52 (d, 1H, ArH), 8.29 (d,
1H, ArH), 7.91 (t, 1H, ArH), 7.52 (m, 2H, ArH), 7.36 (t, 1H, ArH), 7.06
(t, 1H, ArH), 3.28 (s, 1H, SH, D2O exchangeable). All spectral data were
identical to those reported.[4b]
Meta-bis(2-benzothiazolyl)benzene (3): Off-white solid (681 mg, 76%),
m.p. 170–172ꢂC; H NMR (500 MHz, CDCl3): ꢀ (ppmfromTMS): 8.81
1
(s, 1H, ArH), 8.24 (d, 2H, ArH), 8.14 (d, 2H, ArH), 7.95 (d, 2H, ArH),
7.64 (t, 1H, ArH), 7.54 (t, 2H, ArH), 7.42 (t, 2H, ArH); 13C NMR
(500 MHz, CDCl3): ꢀ (ppmfromTMS): 167.1 (CN), 154.1 (ArC), 135.3
(ArC), 134.6 (ArC), 131.1 (ArC), 129.9 (ArC), 127.6 (ArC), 126.7 (ArC),
125.6 (ArC), 123.5 (ArC), 121.8 (ArC). IR (KBr, cmꢁ1): 1510, 1314, 960,
751, 719. Anal. calcd. for C20H12N2S2 (344.45): C, 69.74; H, 3.51; N, 8.13.
Found: C, 69.23; H, 3.60; N, 8.19.
2-Phenylbenzothiazole (4): White solid, (450 mg, 82%), IR (KBr,
1
cmꢁ1): 1477, 1308, 962, 759, 686. H NMR (500 MHz, CDCl3): ꢀ (ppm
from TMS): 8.10 (m, 3H, ArH), 7.92 (d, 1H, ArH), 7.51 (m, 4H, ArH),
7.40 (t, 1H, ArH). All spectral data were identical to those reported.[8]
ACKNOWLEDGMENTS
Financial support fromNIH (GM 61636) is gratefully acknowl-
edged. K.R. and T.C.H. received support fromthe NIH-IMSD Grant
GM58903.

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N,N 0-bis(2-Mercaptophenyl)pyridine-2,6-dicarboxamide
1949
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Received in the USA September 16, 2002

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