The Reaction of N -Trimethylsilyl-Substituted Heteroarylamines with Esters and Thioesters: An Efficient Protocol to Access Diheteroarylamides

Article abstract of DOI:10.1055/s-0037-1611435

The S -benzyl thioester and methyl ester derivatives of a representative 4-pyridinone-based carboxylic acid were sufficiently activated to react efficiently in amide coupling reactions with the amide anion generated in situ from the N -trimethylsilyl derivative of different weakly nucleophilic heteroarylamines. In acetonitrile as solvent, the precipitated diheteroarylamide products were isolated in pure form by vacuum filtration. This simple amide bond forming protocol can be readily adapted to the parallel synthesis of compound libraries.

Full text of DOI:10.1055/s-0037-1611435

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2019, 51, A–L
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en
A. Koperniku et al.
Paper
Synthesis
The Reaction of N-Trimethylsilyl-Substituted Heteroarylamines
with Esters and Thioesters: An Efficient Protocol To Access
Diheteroarylamides
Ana Koperniku
Maryam Zamiri
David S. Grierson*
Faculty of Pharmaceutical Sciences, 2405 Westbrook Mall,
The University of British Columbia, Vancouver, V6T 1Z3,
Canada
dgrierso@mail.ubc.ca
Received: 24.09.2018
Cl
Accepted after revision: 07.11.2018
Published online: 18.02.2019
N
DOI: 10.1055/s-0037-1611435; Art ID: ss-2018-m0649-op
C
N
B
Abstract The S-benzyl thioester and methyl ester derivatives of a rep-
resentative 4-pyridinone-based carboxylic acid were sufficiently acti-
vated to react efficiently in amide coupling reactions with the amide
anion generated in situ from the N-trimethylsilyl derivative of different
weakly nucleophilic heteroarylamines. In acetonitrile as solvent, the
precipitated diheteroarylamide products were isolated in pure form by
vacuum filtration. This simple amide bond forming protocol can be
readily adapted to the parallel synthesis of compound libraries.
N
IDC16
S
N
O
S
N
O
O
N
H
N
N
H
Key words amide coupling, diheteroarylamides, N-trimethylsilyl acti-
vation, thioesters, esters, parallel synthesis
N
NO2
NO2
OMe
1
2
For several ongoing compound library based projects in
our laboratory to develop novel antiviral agents that target
host cell factors involved in viral mRNA processing, an effi-
cient amide bond forming protocol is required that can be
adapted to the parallel synthesis of diheteroarylamide
(DHA)-type compounds from diverse sets of heterocyclic
amines. The initial impetus for this need stemmed from a
library screening program that led to the discovery of the
four related anti-HIV agents 1–4 (Figure 1).1 These mole-
cules are structural mimics of the tetracyclic indole anti-
HIV agent IDC16, and like IDC16 they block HIV replication
through perturbation of HIV pre-mRNA alternative splic-
ing.2 However, in contrast to the tetracyclic indole IDC16,
the cytotoxicity3 of the most active compound 1 is very sig-
nificantly reduced, as measured by its selectivity index
(IC50/CC50 >100). This is, in large part, the consequence of
replacing the central B- and C-rings of IDC16 by a simple
amide linker.
S
N
S
N
O
O
O
N
N
H
N
N
H
O
O
NO2
NO2
OMe
OMe
3
4
Figure 1 Amide-based mimics 1–4 of IDC16 displaying anti-HIV activity
of electron-withdrawing atoms/functionality on the aryl
ring, can present a challenge to these existing technologies.5
Indeed, the preparation of compounds 1–4, and the other
diheteroarylamide-type molecules in the library, revealed
that construction of the amide bond using the acid chloride
and different peptide coupling reagents was often compli-
cated by formation of complex polar mixtures. This prob-
lem of reactivity seriously impacted product isolation, as
separation of the amide product from other equally polar
and often poorly soluble byproducts in the reaction mixture
proved difficult using silica gel column chromatography. As
a consequence, isolated product yields rarely exceeded 10%
Although a mainstay synthetic transformation,4 amide
coupling reactions involving weakly nucleophilic heteroar-
omatic amines, or aromatic amines where the amine func-
tion is similarly rendered electron deficient by the presence
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–L

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A. Koperniku et al.
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Synthesis
to 30%. These issues pointed to the need to find a way to: i)
enhance the reactivity of the (hetero)aryl amine compo-
nent used in these transformations, ii) identify an activated
acid component with which it reacts efficiently, and iii)
simplify product isolation.
and O-methyl ester derivatives 12/23 and 16 of 4-pyridi-
none-3-carboxylic acid (initially used to prepare 1) were
employed as the activated acid component. This choice was
motivated by the fact that both starting esters can be pre-
pared in only 2–3 steps from commercial 4-chloronicotinic
acid (8), and by the observation that the scope of applica-
tion of compound 1 and congeners as antiviral agents now
extends beyond use as anti-HIV agents.
Being more stable to hydrolysis, relative to acid fluo-
rides, and more reactive in amide bond forming reactions
than their ester counterparts,8 thioesters were considered
to potentially be ideal substrates for the parallel synthesis
of amides. Initially, thioester 12 was used as the activated
acid component, as the phenyl motif enabled following re-
lease of the liberated benzyl mercaptan (11) on TLC using
UV light. As previously described, the starting N-methyl-4-
pyridinone-3-carboxylic acid (10) was prepared from 4-
chloronicotinic acid (8; 64% yield after two steps).1 Inter-
mediate 10 was converted into thioester 12, a stable crys-
talline solid (mp 163–164 °C), in a ‘one-pot’ process, involv-
ing its reaction with fluoro-N,N,N′,N′-tetramethylformami-
dinium hexafluorophosphate (TFFH)/DIEA,9 followed by
reaction of the in situ generated acid fluoride with thiol 11,
also present in the reaction medium (95% yield; Scheme 1,
b).
One effective solution developed to overcome these ob-
stacles, directed to the synthesis of analogues of the 2-pyr-
idinone compound 4, was to react the acid fluoride 5 with
N-trimethylsilyl (N-TMS) heterocyclic amines 6 in the pres-
ence of catalytic fluoride ion (cf. 5 to 7, Scheme 1, a).6 The
propensity of silicon to react with fluoride ion provides the
driving force for the reaction (Si–F bond strength = 582
kJ/mol), as production of TMSF is accompanied by forma-
tion of a formal amide anion intermediate7 with enhanced
reactivity compared to the parent amine. The other practi-
cal feature of this protocol is the choice of acetonitrile as
the reaction solvent. Under these conditions, the residual
acid fluoride (used in excess) and the TMSF side product re-
main in solution, whereas the polar amide product precipi-
tates from the medium. In this way, the desired dihet-
eroarylamide compound is isolated pure without recourse
to column chromatography or other purification methods.
In the further development of this amide bond forming
protocol, it has been determined that more shelf-stable, S-
and O-alkyl esters also react efficiently with the N-TMS de-
rivatives of otherwise poorly reactive (i.e., weakly nucleop-
hilic) heteroaromatic amines. The observation that simple
O-alkyl esters, which are otherwise used as carboxylic acid
protecting groups in peptide synthesis, participate in this
protocol is of particular note.4a For this study, the S-benzyl
To evaluate the reactivity of thioester 12, it was reacted
with a set of 19 N-silylated amines (TMS-amines 6a–s6,10) of
varying electron density11/nucleophilicity (prepared in neat
TMSCN6,12 and used immediately; see experimental) to give
the diheteroarylamide products 13a–j, 13l–s, and 1 (Table
a)
O
O
TMSHN
Het
TBAF (cat)
N
N
N
F
Het
+
H
MeCN
OMe
OMe
O
O
O
O
5
6
7
b)
O
O
TFFH, DIEA
MeCN, r.t., 16 h
O
O
OH
N
S
TMSHN
SH
N
R
Het
R
R
6a–s
9
R = H
10 R = Me
11 R = H
22 R = CH2OC6H13
12 R = H
23 R = CH2OC6H13
MeI
O
O
TBAF, MeCN
50 °C (r.t. for 6k),
16 h
Het
N
N
H
H2O, reflux
79%
I–
-
13a–j, 13l–s and 1
HN
OMe
O
O
O
R
O
Het
MeI (cat)
OMe
OMe
R'
+
N
N
N
15
16
8 R = Cl, R' = OH
14 R = R' = OMe
MeOH, H+
Scheme 1 Preparation of thioesters 12/23 and ester 16, and their reaction with N-TMS-amines 6a–s to give diheteroarylamides 13 and 1
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–L

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1). In the coupling experiments, TBAF (1 equiv) was added
to the solution of the requisite TMS-amine 6 (1 equiv) and
thioester 12 (2 equiv) in acetonitrile, and the mixture was
stirred at 50 °C under nitrogen overnight. Under these con-
ditions, the added fluoride ion served to generate the amide
anion, and a twofold excess of the thioester was used to
force complete consumption of the amine reactant. The
practical reason for this was that the presence of even trace
amounts of residual amine in the product mix would neces-
sitate an added purification step. Note, also, that for the
oxadiazole-based TMS-amines 6h and 6p (entries 8 and
16), 4 equivalents of thioester were required to observe
conversion into product.
reduce the volume of solvent. Isolation of the amide prod-
uct involved simple vacuum filtration and washing the pre-
cipitated material with cold acetonitrile (note: in certain
cases, acetone and/or Et2O was used; see experimental). In
this way, the TMSF produced, the liberated thiol 11 (and/or
its disulfide), and the residual thioester 12 were completely
removed without need for column chromatography. As de-
1
termined by H NMR spectroscopy (see Supporting Infor-
mation), the diheteroarylamides 13a–j, 13l–s, and 1 were
obtained in >95% purity. For the majority of the amines
studied, the diheteroarylamide products were isolated in
yields ranging from 53–92% (Table 1). In these reactions,
and the reactions with TMS-amines 6a–e, where the isolat-
ed yields were lower (<30%) due to the significant solubility
of the product amides 13a–e in acetonitrile (i.e., less effi-
cient precipitation), no attempt was made to recover addi-
tional product from the mother liquors.
During the course of the reaction, the polar amide prod-
ucts 13 and 1 precipitated progressively from the reaction
medium. To facilitate this process, a stream of nitrogen gas
was passed through the reaction vessel in order to slowly
Table 1 Diheteroarylamide Products 13a–j, 13l–s, and 1 Prepared via Scheme 1, b
Entry
TMS-Aminea
Structure
Electron density
(eV)11
N-Silylation time
Amide product, yield from Amide product, yield
thioesters 12/23b,c
from ester 16d,e
NHTMS
1
6a6
120
30 min
13a 15% (11%)
NA
N
NHTMS
2
6b
119.6
14 h
13b 16% (20%)
NA
N
S
3
4
6c6
6d6
119.5
115
15 min
30 min
13c 14% (25%)
13d 24% (17%)
NA
N
TMSHN
13d 12%
N
O
TMSHN
TMSHN
5
6
6e
114
30 min
30 min
13e 17% (15%)
13f 70% (70%)
NA
N
S
6f6
97.8
13f 75%
TMSHN
TMSHN
N
S
7
6g6
97.8
30 min
13g 68% (68%)
13g 90%
N
Cl
OCH3
8
9
6h
95.7
93.9
30 min
30 min
13h 88% (88%)
13i 92% (96%)
13h 1%
13i 88%
O
N
TMSHN
TMSHN
N
S
6i10
N
N
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Table 1 (continued)
Entry
TMS-Aminea
Structure
Electron density
(eV)11
N-Silylation time
Amide product, yield from Amide product, yield
thioesters 12/23b,c
from ester 16d,e
F
S
N
10
6j
93.7
14 h
13j 68% (68%)
13j 92%
TMSHN
TMSHN
NO2
11
6k6
88.8
30 min
1 33% (25%)
NA
N
S
Cl
Br
S
N
S
N
12
13
6l
81.7
81.5
14 h
14 h
13l 85% (84%)
13l 91%
TMSHN
TMSHN
6m
13m 82% (86%)
13m 78%
Cl
14
15
6n6
6o
77.3
75.9
1 h
13n 66% (65%)
13o 67% (67%)
NA
O
N
S
N
TMSHN
TMSHN
N
OCF3
Cl
14 h
13o 75%
16
6p
75.3
1 h
13p 83% (82%)
NA
O
N
S
N
S
TMSHN
TMSHN
N
CF3
17
18
19
6q
6r
6s
72
14 h
14 h
14 h
13q 69% (63%)
13r 53% (53%)
13s 80% (81%)
13q 56%
NA
SCF3
70.7
26.1
TMSHN
TMSHN
N
S
13s 70%
N
Br
a Reference citations are given for all known compounds.
b Reaction conditions for thioesters 12/23 (2 equiv) (except for entries 8 and 16 (4 equiv) and entry 11 (1 equiv)): MeCN, 50 °C (r.t. only for 1), overnight.
c Isolated yield for the amide product derived from thioester 23 in brackets.
d Reaction conditions for ester 16 (2 equiv): 1 M TBAF in THF (0.25 equiv), MeCN, 50 °C, overnight.
e NA signifies experiment not performed.
Also noteworthy was the unexpectedly low yield for the
formation of the polar amide 1 from the reaction using 1
equivalent of thioester 12 (33%) and the odorless thioester
23 ( 25%) (described further on) with TMS-amine 6k. Inter-
estingly, in the experiment where 2 equivalents of thioester
firmly established. However, the known propensity of the
benzisothiazole system to undergo N–S bond cleavage13
suggested that, under the reaction conditions used, the ini-
tially formed product 1 equilibrated through ring opening
and re-closure to the observed (1:1) mixture of 1 and its
isomer 1′ (Figure 2).
1
23 were employed, the H NMR spectrum (see supporting
Information) revealed the presence of a second ‘isomeric’
compound in equal proportions (two distinct sets of six
peaks for the 4-pyridinone and 5-nitrobenzisothizole
hydrogens). Due to its poorer solubility in DMSO, a small
quantity of the second product precipitated in the NMR
tube and could be isolated pure. The structure of 1′ was not
In light of the ability of thioester 12 to react with the di-
verse set of TMS-substituted heteroaromatic amines in Ta-
ble 1 under mild (sub-reflux) conditions, it was of consider-
able synthetic interest to determine whether esters would
similarly react as efficiently in this amide coupling protocol.
As background, it is well documented that in the absence of
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A. Koperniku et al.
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Synthesis
moderate yield (56%), eight of the amide products were iso-
lated in high to excellent yields (70–92%) by simple vacuum
filtration and washing with cold acetonitrile (>95% product
O2N
O
O
O
NH
1
S
purity by H NMR spectroscopy). On the other hand, the
N
N
N
H
N
N
S
precipitate recovered for the reaction with TMS-amine 6d
corresponded to an 8:2 mixture of amide 13d contaminated
with the starting ester 16 (calculated yield of 13d = 12%),
reflecting the fact that the amide product and the ester
have similar solubility in acetonitrile. Again, as the objec-
tive of this work is to have a simple protocol for parallel
synthesis, no effort was made to isolate further quantities
of 13d by column chromatography of the concentrated
mother liquor.
Interestingly, the yields for the preparation of amide
13h from the thioesters 12/23 (88%) and from ester 16 (1%)
contrasted sharply. In the reaction with ester 16, the major
component in the isolated precipitate was the starting
amine, suggesting that TMS-amine 6h is unstable under the
reaction conditions. One possibility is that there is rapid
loss of the TMS group due to the presence of adventitious
water (hydroxide ions) in the added TBAF solution. In the
reaction with the thioesters, a high yield conversion into
product may be the consequence of using a fourfold excess
of a more reactive activated acid component.
This study established that both esters and thioesters
are valuable starting compounds for the preparation of di-
heteroarylamides through reaction with the in situ generat-
ed anion derived from N-TMS-substituted heterocyclic
amines. However, for the thioester approach to be attractive
as a synthetic procedure, it was necessary to eliminate the
issue of the disagreeable odour associated with the use of
volatile benzyl mercaptan. Numerous reports have shown
this can be achieved by use of a higher molecular weight
‘odourless thiol’. A variety of different odourless thiols have
been described,20 but for our purpose attention was focused
on the benzyl mercaptan derivative 22, bearing a long alkyl
chain alkyl ether component. Thiol 22 was obtained in 29%
overall yield after five steps (Scheme 2), involving reaction
of methyl 4-(bromomethyl)benzoate (17) with sodium hex-
an-1-olate, LAH reduction of the derived ether–ester inter-
mediate 18, conversion of alcohol 19 into the corresponding
benzyl bromide 20 using SOBr2, and, in the fourth step, re-
action of 20 with KSCOMe to give thioacetate 21. Subse-
quent cleavage of the S-acetyl group in 21 was generally
carried out ‘as needed’, as thiol 22 readily dimerizes to its
corresponding disulfide on standing. Under the conditions
used to prepare thioester 12, compound 22 was reacted
with acid 10 to give thioester 23 as an essentially odourless,
off-white solid (mp 68–70 °C) in 50% yield (unoptimized).
Thioester 23 was subsequently reacted with the 19 TMS-
amines 6, and as anticipated the isolated amide product
yields (Table 1, % yields in brackets) after collecting the pre-
cipitated product by suction filtration were closely similar
to those using thioester 12.
NO2
O
1'
1
Figure 2 Structure of compound 1 and its isomer 1′
metal promoters/catalysts the reaction of esters with
amines, and in particular aromatic and heteroaromatic
amines, is generally inefficient, even at elevated tempera-
tures. However, it has been shown that amide anions, gen-
erated by the reaction of amines with strong bases such as
NaH,14 BuLi,15 and KOt-Bu,16 react with esters to form amide
products. This latter observation, plus the fact that aminos-
ilanes find use as silyl-transfer agents to silylate alcohols,17
suggested that a reaction cycle could be established where
the amide anion generated through reaction of a TMS-
amine with a catalytic quantity of TBAF would react with
esters to produce the desired amide product and alkoxide
ion. Subsequent reaction of the liberated OR– anion with
the TMS-amine would perpetuate the amine ion forming
process through formation of TMSOR. Although the O-ben-
zyl ester equivalent of compound 12 was initially consid-
ered as the candidate for this study, the observation that
methyl ester 16 was soluble in acetonitrile prompted its
use. Compound 16 was prepared in two steps from 4-
chloronicotinic acid (8), involving reaction with methanolic
HCl,18 followed by treatment of the derived 4-methoxypyri-
dine methyl ester intermediate 14 with a substoichiometric
quantity of MeI under microwave heating conditions
(Scheme 1, b). This latter transformation most likely pro-
ceeds by N-methylation of the pyridine nitrogen atom in 14
and iodide ion induced SN2 reaction at the 4-methoxy
methyl group centre in the quaternary salt 15.19 In this step,
the N-alkyl-4-pyridinone system is created and MeI is re-
generated.
To evaluate the influence of varying the amount of TBAF
used in the protocol, methyl ester 16 was initially reacted
with the thiadiazole-based amine 6i. In the presence of 1.1
equivalents of TBAF, the desired amide product 13i was iso-
lated in 78% yield. More exciting, compound 13i was isolat-
ed in 88% yield when only 0.25 equivalents of TBAF was em-
ployed. This latter result demonstrated that methoxide an-
ion contributes to product formation. It further showed
that the efficiency of the reaction is comparable to that ob-
served (92%) for the thioesters 12/23.
Encouraged by this result, methyl ester 16 was reacted
in acetonitrile under the standard conditions (50 °C, over-
night) with 10 other TMS-amines, namely 6d, 6f–h, 6j, 6l,
6m, 6o, 6q, and 6s (Table 1). Precipitate formation was ob-
served in all cases. Although compound 13q was isolated in
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–L

F
A. Koperniku et al.
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Synthesis
reported peak multiplicities, and coupling constants are reported in
hertz (Hz). All low- and high-resolution mass spectra were recorded
on an AB Sciex UHPLC/MS/MS system and a Thermo Scientific Q Ex-
active Orbitrap high-resolution mass spectrometer, respectively. Col-
umn chromatography was carried out using silica gel (SiliCycle, Sil-
iaFlash® F60, 40–63 μm, 230–400 mesh), or on a Biotage Isolera puri-
fication system (PartnerTech ́Åtvidaberg AB) using pre-packed silica
gel columns (Biotage, part no. FSKO-1107-0010, FSKO-1107-0025, or
FSKO-1107-0050). A Biotage Initiator 2.5 apparatus was used for ex-
periments using microwave heating. IR spectra (cm–1) were recorded
on an Agilent Technologies (Cary 600 series) FT-IR spectrometer, us-
ing a PIKE MIRacle ATR accessory for sampling. All melting points
were determined with open capillary tubes on a MEL-TEMP II appara-
tus (USA) and are uncorrected.
O
OC6H13
O
OMe
C6H13O–Na+
40 °C, 4 h
75%
OC6H13
Br
18
17
LAH, THF, r.t., 4 h
77%
SR
R
KSCOMe
64%
N-Trimethylsilylated Amines 6a–s; General Procedure
C6H13O
OC6H13
N-Silylated amines 6a–s were prepared by reaction of the requisite
heteroaromatic amine precursor in neat TMSCN (1 mL of TMSCN per
mmol of the amine) with stirring under N2 at 70 °C. The N-silylation
times for each amine are shown in Table 1. The excess TMSCN was re-
moved under high vacuum and the derived N-silylated amine was
used without purification in the amidation reaction. The % conversion
of each amine into its N-silylated derivative was determined by 1H
NMR spectroscopy (CD3CN; passed through a basic alumina column
K2CO3
MeOH
78%
19 R = OH
20 R = Br
21 R = Ac
22 R = H
SOBr2
Scheme 2 Preparation of the ‘odourless’ benzyl mercaptan 22
In the experiments with thioester 23 as the acid compo-
nent, the final concern addressed was how to best recover
the remaining quantity of the odourless thiol after the cou-
pling reaction. Using UV spectrophotometry (optical densi-
ty measurements) it was determined that, whereas thiol 22
is soluble in hexane, the thioester 23 was soluble at the
same concentration in acetonitrile, approximately 60% solu-
ble in diethyl ether, and insoluble, even at low concentra-
tions, in hexane. Playing on these differences in solubility,
thiol 22 (and/or its disulfide) was isolated by concentrating
the mother liquors from the coupling reactions, then re-
dissolving the residue in a small quantity of acetonitrile and
extracting with heptane. Subsequently, the acetonitrile
phase was concentrated, and the residue was triturated
multiple times with diethyl ether. Concentration of the
ethereal solutions allowed recovery of thioester 23 (30–40%
of expected amount).
1
prior to use). The H NMR data for compounds 6a, 6c, 6d, 6f, 6g, 6k,
6n,6 and 6i10 were identical to the literature data.
N-(Trimethylsilyl)quinolin-6-amine (6b)
Yellow-brown solid; 95% conversion.
1H NMR (CD3CN): δ = 8.53–8.55 (m, 1 H), 7.96–7.98 (dd, 3J = 8.4 Hz,
4J = 1.5 Hz, 1 H), 7.77 (d, 3J = 8.9 Hz, 1 H), 7.25–7.29 (dd, 3J = 8.3 Hz, 4J =
4.1 Hz, 1 H), 7.20–7.23 (dd, 3J = 9 Hz, 4J = 2.7 Hz, 1 H), 6.93 (d, 3J = 2.8
Hz, 1 H), 4.53 (s, 1 H), 0.31 (s, 9 H).
N-(Trimethylsilyl)quinolin-3-amine (6e)
Off-white solid; 100% conversion.
1H NMR (CD3CN): δ = 8.48 (d, 4J = 2.9 Hz, 1 H), 7.83–7.85 (m, 1 H),
7.65–7.68 (m, 1 H), 7.36–7.43 (m, 2 H), 7.26 (d, 4J = 2.8 Hz, 1 H), 4.56
(s, 1 H), 0.32 (s, 9 H).
5-(4-Methoxyphenyl)-N-(trimethylsilyl)-1,3,4-oxadiazol-2-amine
In conclusion, the development of the reaction of N-TMS
derivatives of weakly nucleophilic heterocyclic amines with
thioesters, and in particular O-alkyl esters, offers new op-
tions for the carboxylic acid component in the parallel syn-
thesis of a wide range of diheteroarylamides of potential bi-
ological interest. Further, in light of the efficiency of this
protocol, one can envisage that it may find application in
synthetic strategies where stoichiometric quantities of the
acid and amine components are used (i.e., in scenarios
where product purification is less of an issue).
(6h)
Off-white solid; 90% conversion.
1H NMR (CD3CN): δ = 7.79 (d, 3J = 8.6 Hz, 2 H), 7.02 (d, 3J = 8.6 Hz, 2 H),
5.51 (s, 1 H), 3.84 (s, 3 H), 0.32 (s, 9 H).
6-Fluoro-N-(trimethylsilyl)benzo[d]thiazol-2-amine (6j)
White solid; 95% conversion.
1H NMR (CD3CN): δ = 7.36–7.41 (m, 2 H), 7.00–7.05 (ddd, 3J = 9.4 Hz,
3J = 8.9 Hz, 4J = 2.6 Hz, 1 H), 5.84 (s, 1 H), 0.32 (s, 9 H).
6-Chloro-N-(trimethylsilyl)benzo[d]thiazol-2-amine (6l)
Off-white solid; 100% conversion.
1H NMR (CD3CN): δ = 7.62 (d, 4J = 2.2 Hz, 1 H), 7.36 (d, 3J = 8.5 Hz, 1 H),
7.21–7.24 (dd, 3J = 8.4 Hz, 4J = 2.1 Hz, 1 H), 5.94 (s, 1 H), 0.32 (s, 9 H).
All chemicals were purchased from Sigma Aldrich or Oakwood Chem-
icals and were used without purification, unless otherwise men-
tioned. All solvents were dried and kept under N2. 1H, 13C, and 19F
NMR spectra were recorded at 400, 100, and 376 MHz, respectively,
on a Bruker AC 400 UltraShield 10 spectrometer. Chemical shifts are
expressed in ppm (δ scale), standard abbreviations are used for the
6-Bromo-N-(trimethylsilyl)benzo[d]thiazol-2-amine (6m)
White solid; 95% conversion.
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A. Koperniku et al.
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1H NMR (CD3CN): δ = 7.75 (d, 4J = 2.0 Hz, 1 H), 7.35–7.38 (dd, 3J = 8.3
Hz, 4J = 2.0 Hz, 1 H), 7.30 (d, 3J = 8.5 Hz, 1 H), 5.95 (s, 1 H), 0.32 (s, 9 H).
Diheteroarylamides 13a–j, 13l–s, and 1 from Thioesters 12 and 23;
General Procedure
A solution of thioester 12 or 23 (0.2 mmol, 2 equiv) in MeCN (1–2 mL)
was transferred to a narrow vial (diameter: 1–1.5 cm, height: 8–15
cm) containing the requisite N-silylated amine 6 (1 equiv), and the
mixture was stirred at 50 °C for 10 min under N2 (note: for the prepa-
ration of 13h and 13p, 4 equivalents of thioester 12/23 were used,
and 1 equivalent was employed to prepare amide 1). Then, 1 M TBAF
in THF (1 equiv) was added and heating at r.t. or 50 °C was continued
overnight (16 h) under a slight stream of N2. After heating, the precip-
itated product was collected by suction filtration and washed with
cold MeCN (cold acetone wash for amide product 1). Note: for com-
pound 13d, Et2O was added to the reaction mixture at the end of the
heating period to induce product precipitation, and the product iso-
lated by suction filtration was washed with cold Et2O.
6-(Trifluoromethoxy)-N-(trimethylsilyl)benzo[d]thiazol-2-amine
(6o)
Brown oil; 95% conversion.
1H NMR (CD3CN): δ = 7.59 (d, 4J = 2.2 Hz, 1 H), 7.43 (d, 3J = 8.8 Hz, 1 H),
7.16–7.19 (dd, 3J = 8.6 Hz, 4J = 2.4 Hz, 1 H), 5.97 (s, 1 H), 0.33 (s, 9 H).
5-(4-Chlorophenyl)-N-(trimethylsilyl)-1,3,4-oxadiazol-2-amine
(6p)
Off-white solid; 80% conversion.
1H NMR (CD3CN): δ = 7.83 (d, 3J = 8.5 Hz, 2 H), 7.51 (d, 3J = 8.5 Hz, 2 H),
5.57 (s, 1 H), 0.33 (s, 9 H).
To isolate the thioester 23 used in excess, the filtrates for a series of
reactions of 23 with TMS-amines 6 were concentrated, dissolved in
minimal MeCN, and extracted with heptane to remove the liberated
thiol (isolated after heptane removal as its disulfide); yellowish oil; 1H
NMR (CDCl3): δ = 7.26 (d, 3J = 8.2 Hz, 4 H), 7.18 (d, 3J = 8.2 Hz, 4 H),
4.45 (s, 4 H), 3.57 (s, 4 H), 3.41 (t, 3J = 6.7 Hz, 4 H), 1.53–1.60 (m, 4 H),
1.18–1.35 (m, 12 H), 0.85 (t, 3J = 6.9 Hz, 6 H). The MeCN layer was then
concentrated, and the residue was triturated multiple times with
Et2O. Concentration of the combined ethereal washes allowed recov-
ery of thioester 23 (30–40% of expected amount).
6-(Trifluoromethyl)-N-(trimethylsilyl)benzo[d]thiazol-2-amine
(6q)
Brown oil; 100% conversion.
1H NMR (CD3CN): δ = 7.96 (s, 1 H), 7.50–7.55 (m, 2 H), 6.15 (s, 1 H),
0.34 (s, 9 H).
6-((Trifluoromethyl)thio)-N-(trimethylsilyl)benzo[d]thiazol-2-
amine (6r)
Brown oil; 100% conversion.
1H NMR (CD3CN): δ = 7.96 (d, 4J = 1.8 Hz, 1 H), 7.54–7.56 (dd, 3J = 8.5
Hz, 4J = 1.8 Hz, 1 H), 7.47 (d, 3J = 8.2 Hz, 1 H), 6.13 (s, 1 H), 0.34 (s, 9 H).
Diheteroarylamides 13d, 13f–j, 13l, 13m, 13o, 13q, and 13s from
Methyl Ester 16; General Procedure
A solution of methyl ester 16 (200 mg, 1.2 mmol, 2 equiv) in MeCN (2
mL) was transferred to a narrow vial (diameter: 1–1.5 cm, height: 8–
15 cm) containing the requisite N-silylated amine 6 (0.6 mmol), and
the mixture was stirred for 10 min under N2. Then, 1 M TBAF in THF
(0.15 mmol) was added and the solution was stirred at 50 °C over-
night (16 h). After heating, the precipitated product was collected by
suction filtration and washed with cold MeCN (washed with Et2O for
13d).
5-Bromo-N-(trimethylsilyl)benzo[d]thiazol-2-amine (6s)
White solid; 95% conversion.
1H NMR (CD3CN): δ = 7.58 (d, 4J = 2.0 Hz, 1 H), 7.52 (d, 3J = 8.4 Hz, 1 H),
7.18–7.21 (dd, 3J = 8.3 Hz, 4J = 2.0 Hz, 1 H), 6.03 (s, 1 H), 0.32 (s, 9 H).
S-Benzyl 1-Methyl-4-oxo-1,4-dihydropyridine-3-carbothioate (12)
Benzyl mercaptan (11) (0.46 mL, 3.9 mmol, 1.2 equiv) was added to a
suspension of carboxylic acid 101 (500 mg, 3.26 mmol, 1 equiv), TFFH
(861 mg, 3.26 mmol, 1 equiv), and DIEA (2.8 mL, 16.3 mmol, 5 equiv)
in MeCN (10 mL), and the mixture was stirred under N2 overnight at
r.t. The mixture was subsequently concentrated, and the residue was
taken up in sat. aq NaHCO3 and extracted with DCM. The combined
organic layers were washed with 0.5 N aq HCl, sat. aq NaHCO3, and
brine, then dried over Na2SO4 and concentrated. The solid residue was
washed with Et2O to remove impurities and dried under reduced
pressure. Thioester 12 was obtained as a yellow crystalline solid (845
mg, 95%); mp 163–164 °C.
N-(Isoquinolin-4-yl)-1-methyl-4-oxo-1,4-dihydropyridine-3-car-
boxamide (13a)
From TMS-amine 6a. Compound 13a was isolated as a white solid (for
yields, see Table 1); mp >300 °C.
IR (ATR): 1660, 1774, 3435 cm–1
.
1H NMR (DMSO-d6): δ = 13.69 (s, 1 H), 9.51 (s, 1 H), 9.11 (s, 1 H), 8.75
(s, 1 H), 8.19–8.26 (dd, 3J = 8.2 Hz, 4J = 3.0 Hz, 2 H), 7.95 (s, 2 H), 7.77
(d, 3J = 7.5 Hz, 1 H), 6.65 (d, 3J = 7.0 Hz, 1 H), 3.89 (s, 3 H).
13C NMR (DMSO-d6): δ = 177.3, 166.1, 148.5, 147.0, 143.8, 134.6,
132.0, 129.8, 129.0, 128.6, 128.1, 120.5, 120.4, 118.2, 44.8.
IR (ATR): 1566, 1650, 3056 cm–1
.
1H NMR (CD3CN): δ = 8.27 (d, 4J = 2.4 Hz, 1 H), 7.46–7.49 (dd, 3J = 7.4
Hz, 4J = 2.2 Hz, 1 H), 7.35–7.37 (m, 2 H), 7.28–7.32 (m, 2 H), 7.21–7.24
(m, 1 H), 6.36 (d, 3J = 7.5 Hz, 1 H), 4.14 (s, 2 H), 3.67 (s, 3 H).
HRMS (HESI): m/z [M + H]+ calcd for C16H13N3O2: 280.1081; found:
280.1079.
13C NMR (CD3CN): δ = 190.0, 176.5, 146.4, 142.5, 140.3, 130.3, 129.8,
1-Methyl-4-oxo-N-(quinolin-6-yl)-1,4-dihydropyridine-3-carbox-
amide (13b)
128.2, 124.2, 123.2, 45.1, 34.1.
HRMS (HESI): m/z [M + Na]+ calcd for C14H13NO2S: 282.0559; found:
282.0561.
From TMS-amine 6b Compound 13b was isolated as a white solid (for
yields, see Table 1); mp 225–226 °C.
IR (ATR): 1635, 1678, 3026, 3416 cm–1
1H NMR (DMSO-d6): δ = 13.19 (s, 1 H), 8.80 (s, 1 H), 8.66 (s, 1 H), 8.42
.
3
3
(s, 1 H), 8.32 (d, J = 7.5 Hz, 1 H), 8.00 (d, J = 8.3 Hz, 1 H), 7.89–7.92
(m, 2 H), 7.49–7.51 (m, 1 H), 6.58 (d, 3J = 6.7 Hz, 1 H), 3.86 (s, 3 H).
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A. Koperniku et al.
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13C NMR (DMSO-d6): δ = 176.5, 162.6, 149.2, 146.1, 144.9, 142.8,
13C NMR (DMSO-d6): δ = 176.5, 162.8, 157.0, 148.7, 147.0, 143.4,
136.5, 135.5, 129.9, 128.5, 123.8, 121.9, 119.9, 117.7, 115.6, 44.0.
131.9, 126.3, 123.7, 121.8, 120.8, 120.2, 115.4, 44.1.
HRMS (HESI): m/z [M + H]+ calcd for C16H13N3O2: 280.1081; found:
HRMS (HESI): m/z [M + Na]+ calcd for C14H11N3O2S: 308.0464; found:
280.1079.
308.0469.
1-Methyl-N-(4-methylthiazol-2-yl)-4-oxo-1,4-dihydropyridine-3-
N-(4-Chlorobenzo[d]thiazol-2-yl)-1-methyl-4-oxo-1,4-dihydropy-
carboxamide (13c)
ridine-3-carboxamide (13g)
From TMS-amine 6c. Compound 13c was isolated as an off-white sol-
From TMS-amine 6g. Compound 13g was isolated as a white solid (for
id (for yields, see Table 1); mp 272–274 °C.
yields, see Table 1); mp >300 °C.
IR (ATR): 1636, 1678, 3010, 3068, 3270, 3439 cm–1
.
IR (ATR): 1637, 1686, 3054 cm–1
.
4
1H NMR (DMSO-d6): δ = 14.04 (s, 1 H), 8.68 (d, 4J = 2.1 Hz, 1 H), 7.90–
7.93 (dd, 3J = 7.4 Hz, 4J = 2.1 Hz, 1 H), 6.81 (s, 1 H), 6.60 (d, 3J = 7.2 Hz,
1 H), 3.85 (s, 3 H), 2.27 (s, 3 H).
13C NMR (DMSO-d6): δ = 176.3, 161.8, 156.3, 147.2, 146.6, 143.2,
120.0, 115.7, 108.5, 44.1, 17.0.
1H NMR (DMSO-d6): δ = 14.57 (s, 1 H), 8.78 (d, J = 2 Hz, 1 H), 7.98–
8.00 (dd, 3J = 8.0 Hz, 4J = 1.0 Hz, 1 H), 7.94–7.97 (dd, 3J = 7.3 Hz, 4J = 2.0
Hz, 1 H), 7.53–7.56 (dd, 3J = 8.0 Hz, 4J = 1.0 Hz, 1 H), 7.32 (t, 3J = 7.8 Hz,
1 H), 6.68 (d, 3J = 7.3 Hz, 1 H), 3.88 (s, 3 H).
13C NMR (DMSO-d6): δ = 176.5, 163.1, 158.0, 147.1, 145.6, 143.5,
133.5, 126.4, 124.6 (2 × C), 121.0, 120.3, 115.2, 44.2.
HRMS (HESI): m/z [M + Na]+ calcd for C14H10ClN3O2S: 342.0075;
HRMS (HESI): m/z [M + Na]+ calcd for C11H11N3O2S: 272.0464; found:
272.0464.
found: 342.0074.
1-Methyl-N-(3-methylisoxazol-5-yl)-4-oxo-1,4-dihydropyridine-
3-carboxamide (13d)
N-(5-(4-Methoxyphenyl)-1,3,4-oxadiazol-2-yl)-1-methyl-4-oxo-
1,4-dihydropyridine-3-carboxamide (13h)
From TMS-amine 6d. Note: in the experiments with thioesters 12/23,
Et2O was added to the reaction mixture to facilitate the precipitation,
and the amide product was washed with Et2O. In both the ester and
thioester experiments, compound 13d was isolated as an off-white
solid (for yields, see Table 1); mp 235–236 °C.
From TMS-amine 6h. Compound 13h was isolated as a white solid
(for yields, see Table 1); mp 276–277 °C.
IR (ATR): 1656, 1704, 2916, 2958, 3066, 3082 cm–1
1H NMR (DMSO-d6): δ = 14.36 (s, 1 H, NH), 8.72 (s, 1 H), 7.97 (d, J =
6.6 Hz, 1 H), 7.90 (d, 3J = 8.2 Hz, 2 H), 7.15 (d, 3J = 8.2 Hz, 2 H), 6.67 (d,
3J = 7.2 Hz, 1 H), 3.88 (s, 3 H), 3.85 (s, 3 H).
13C NMR (DMSO-d6): δ = 176.4, 161.8, 161.1, 160.6, 156.5, 147.0,
143.6, 127.9, 120.0, 115.9, 115.8, 114.9, 55.5, 44.2.
.
3
IR (ATR): 1650, 1693, 3066 cm–1
.
1H NMR (DMSO-d6): δ = 14.04 (s, 1 H), 8.69 (d, 4J = 2.00 Hz, 1 H), 7.92–
7.94 (dd, 3J = 7.2 Hz, 4J = 2.2 Hz, 1 H), 6.62 (d, 3J = 7.2 Hz, 1 H), 6.25 (s,
1 H), 3.86 (s, 3 H), 2.21 (s, 3 H).
13C NMR (DMSO-d6): δ = 176.4, 161.0, 160.6, 160.3, 146.7, 143.4,
120.0, 115.9, 89.3, 44.1, 11.4.
HRMS (HESI): m/z [M + Na]+ calcd for C16H14N4O4: 349.0913; found:
349.0908.
HRMS (HESI): m/z [M + Na]+ calcd for C11H11N3O3: 256.0693; found:
256.0692.
1-Methyl-4-oxo-N-(1,3,4-thiadiazol-2-yl)-1,4-dihydropyridine-3-
carboxamide (13i)
1-Methyl-4-oxo-N-(quinolin-3-yl)-1,4-dihydropyridine-3-carbox-
amide (13e)
From TMS-amine 6i. Compound 13i was isolated as a white solid (for
yields, see Table 1); mp >300 °C.
From TMS-amine 6e. Compound 13e was isolated as a white solid (for
yields, see Table 1); mp 244–245 °C.
IR (ATR): 1637, 1678, 3058, 3079 cm–1
.
1H NMR (DMSO-d6): δ = 14.61 (s, 1 H), 9.21 (s, 1 H), 8.78 (d, 4J = 1.7 Hz,
1 H), 7.95–7.97 (dd, 3J = 7.3 Hz, 4J = 1.6 Hz, 1 H), 6.66 (d, 3J = 7.6 Hz, 1
H), 3.87 (s, 3 H).
13C NMR (DMSO-d6): δ = 176.5, 162.3, 157.7, 149.2, 147.0, 143.4,
120.1, 115.0, 44.1.
IR (ATR): 1633, 1678, 2942, 3369, 3439 cm–1
.
1H NMR (DMSO-d6): δ = 13.27 (s, 1 H), 9.00 (s, 1 H), 8.80 (s, 1 H), 8.67
(s, 1 H), 7.97 (d, 3J = 7.9 Hz, 2 H), 7.91 (d, 3J = 7.3 Hz, 1 H), 7.66 (t, 3J =
7.4 Hz, 1 H), 7.59 (t, 3J = 7.4 Hz, 1 H), 6.59 (d, 3J = 7.3 Hz, 1 H), 3.87 (s, 3
H).
13C NMR (DMSO-d6): δ = 176.4, 163.1, 146.2, 144.9, 144.4, 142.9,
132.4, 128.6, 128.0, 127.8, 127.2, 122.7, 120.0, 117.4, 44.0.
HRMS (HESI): m/z [M + Na]+ calcd for C9H8N4O2S: 259.0260; found:
259.0265.
HRMS (HESI): m/z [M + H]+ calcd for C16H13N3O2: 280.1081; found:
280.1085.
N-(6-Fluorobenzo[d]thiazol-2-yl)-1-methyl-4-oxo-1,4-dihydropy-
ridine-3-carboxamide (13j)
From TMS-amine 6j. Compound 13j was isolated as a white solid (for
yields, see Table 1); mp >300 °C (dec).
N-(Benzo[d]thiazol-2-yl)-1-methyl-4-oxo-1,4-dihydropyridine-3-
carboxamide (13f)
IR (ATR): 1632, 1672, 3061 cm–1
.
From TMS-amine 6f. Compound 13f was isolated as a white solid (for
yields, see Table 1); mp >300 °C.
1H NMR (DMSO-d6): δ = 14.46 (s, 1 H), 8.78 (d, 4J = 2.3 Hz, 1 H), 7.95–
7.97 (dd, 3J = 7.5 Hz, 4J = 2.4 Hz, 1 H), 7.91–7.94 (dd, 3J = 8.8 Hz, 4J = 2.6
IR (ATR): 1634, 1681, 3053 cm–1
.
3
4
Hz, 1 H), 7.77–7.81 (dd, J = 8.9 Hz, J = 4.8 Hz, 1 H), 7.28–7.33 (ddd,
3J = 9.3 Hz, 3J = 8.8 Hz, 4J = 2.6 Hz, 1 H), 6.65 (d, 3J = 7.4 Hz, 1 H), 3.88 (s,
3 H).
1H NMR (DMSO-d6): δ = 14.43 (s, 1 H), 8.77 (s, 1 H), 8.01 (d, 3J = 8.3 Hz,
1 H), 7.95 (d, 3J = 7.3 Hz, 1 H), 7.78 (d, 3J = 8.1 Hz, 1 H), 7.45 (m, 1 H),
7.32 (m, 1 H), 6.65 (d, 3J = 7.3 Hz, 1 H), 3.88 (s, 3 H).
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13C NMR (DMSO-d6): δ = 176.5, 162.9, 158.7 (d, J = 240 Hz), 157.0 (d,
J = 2.9 Hz), 147.0, 145.4, 143.4, 133.1 (d, J = 11.1 Hz), 121.8 (d, J = 9.4
Hz), 120.2, 115.2, 114.4 (d, J = 24.7 Hz), 108.3 (d, J = 26.9 Hz), 44.1.
N-(5-(2-Chlorophenyl)-1,3,4-oxadiazol-2-yl)-1-methyl-4-oxo-1,4-
dihydropyridine-3-carboxamide (13n)
From TMS-amine 6n. Compound 13n was isolated as a white solid
(for yields, see Table 1); mp 220–222 °C.
DEPT-135 NMR (DMSO-d6): δ = 147.0, 143.4, 121.8 (d, J = 9.4 Hz),
120.2, 114.4 (d, J = 24.5 Hz), 108.3 (d, J = 26.9 Hz), 44.1.
HRMS (HESI): m/z [M + Na]+ calcd for C14H10FN3O2S: 326.0370; found:
IR (ATR): 1602, 1645, 3052 cm–1
.
1H NMR (DMSO-d6): δ = 14.55 (s, 1 H), 8.74 (d, J = 2 Hz, 1 H), 7.95–
4
3
3
7.98 (m, 2 H), 7.71 (d, J = 7.9 Hz, 1 H), 7.62–7.66 (td, J = 7.6 Hz, 4J =
1.4 Hz, 1 H), 7.56–7.59 (td, 3J = 7.5 Hz, 4J = 1.2 Hz, 1 H), 6.68 (d, 3J = 7.3
Hz, 1 H), 3.88 (s, 3 H).
326.0372.
1-Methyl-N-(5-nitrobenzo[d]isothiazol-3-yl)-4-oxo-1,4-dihydro-
pyridine-3-carboxamide (1) and 3-(3-Imino-5-nitro-2,3-dihydro-
benzo[d]isothiazol-2-ylcarbonyl)-1-methylpyridin-4(1H)-one (1′)
from TMS-Amine 6k
13C NMR (DMSO-d6): δ = 176.4, 161.0, 158.5, 157.3, 147.1, 143.7,
133.0, 131.6, 131.1 (2 × C), 127.9, 122.6, 120.0, 115.8, 44.2.
HRMS (HESI): m/z [M + Na]+ calcd for C15H11ClN4O3: 353.0412; found:
353.0418.
The precipitated product from the reaction of TMS-amine 6k with
thioester 12/23 (1 equiv) was washed with acetone to afford 1 as a
brownish solid (41 mg, 33/25% in both cases); mp >300 °C. The 1H and
13C NMR spectra for compound 1 were identical to those described in
the literature.1
1-Methyl-4-oxo-N-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)-
1,4-dihydropyridine-3-carboxamide (13o)
From TMS-amine 6o. Compound 13o was isolated as a white solid (for
yields, see Table 1); mp >300 °C (dec).
Using thioester 23 (2 equiv), a 1:1 mixture of 1 and 1′ was obtained as
a brownish solid. The solid material was washed with DMSO-d6 (2 × 1
mL), and from the 1H NMR spectrum of the washing it was estab-
lished that it contained almost exclusively compound 1. The remain-
ing solid material, which solubilized when taken up in further DMSO-
d6 (1 mL), corresponded to pure compound 1′.
IR (ATR): 1637, 1681, 3063 cm–1
.
1H NMR (DMSO-d6): δ = 14.56 (s, 1 H), 8.78 (d, J = 2.0 Hz, 1 H), 8.16
(d, 4J = 2.0 Hz, 1 H), 7.95–7.98 (dd, 3J = 7.2 Hz, 4J = 2.0 Hz, 1 H), 7.86 (d,
3J = 8.6 Hz, 1 H), 7.43–7.46 (dd, 3J = 8.8 Hz, 4J = 2.0 Hz, 1 H), 6.67 (d, 3J =
7.0 Hz, 1 H), 3.88 (s, 3 H).
13C NMR (DMSO-d6): δ = 176.5, 163.0, 158.5, 147.8, 147.1, 144.2
(2 × C), 143.5, 133.1, 124.0, 121.8, 120.2 (q, J = 255.6 Hz), 120.2, 44.1.
4
3
1H NMR (DMSO-d6): δ = 14.26 (s, 1 H), 8.82 (d, J = 9.4 Hz, 1 H), 8.75
(d, 4J = 2.7 Hz, 1 H), 8.72 (d, 4J = 2.3 Hz, 1 H), 8.52–8.55 (dd, 3J = 9.4 Hz,
4J = 2.9 Hz, 1 H), 7.92–7.95 (dd, 3J = 7.4 Hz, 4J = 2.2 Hz, 1 H), 6.63 (d, 3J =
7.2 Hz, 1 H), 3.87 (s, 3 H).
19F NMR (DMSO-d6): δ = –56.98.
HRMS (HESI): m/z [M + H]+ calcd for C15H10F3N3O3S: 370.0465; found:
13C NMR (DMSO-d6): δ = 176.5, 163.8, 147.2, 146.9, 143.4, 129.6,
129.5, 121.1, 120.1, 117.4, 116.4, 102.1, 44.2.
MS (Turbo Spray): m/z = 329.0 [M – H]–.
370.0463.
N-(5-(4-Chlorophenyl)-1,3,4-oxadiazol-2-yl)-1-methyl-4-oxo-1,4-
dihydropyridine-3-carboxamide (13p)
N-(6-Chlorobenzo[d]thiazol-2-yl)-1-methyl-4-oxo-1,4-dihydropy-
ridine-3-carboxamide (13l)
From TMS-amine 6p. Compound 13p was isolated as a white solid (for
From TMS-amine 6l. Compound 13l was isolated as a white solid (for
yields, see Table 1); mp 225–226 °C.
yields, see Table 1); mp >300 °C.
IR (ATR): 1650, 1703, 3061, 3403 cm–1
.
IR (ATR): 1638, 1686, 2917, 3057 cm–1
1H NMR (DMSO-d6): δ = 14.52 (s, 1 H), 8.77 (s, 1 H), 8.16 (s, 1 H), 7.94–
.
1H NMR (DMSO-d6): δ = 14.52 (s, 1 H), 8.72 (s, 1 H), 7.96 (d, 3J = 8.0 Hz,
1 H, and d, 3JA′B′ = 8.3 Hz, 2 H), 7.68 (d, 3JAB = 8.3 Hz, 2 H), 6.68 (d, 3J =
7.5 Hz, 1 H), 3.88 (s, 3 H).
13C NMR (DMSO-d6): δ = 176.4, 161.0, 159.7, 157.1, 147.0, 143.7,
136.3, 129.6, 127.8, 122.4, 120.0, 115.8, 44.2.
3
4
3
7.96 (dd, J = 7.4 Hz, J = 1.9 Hz, 1 H), 7.78 (d, J = 8.5 Hz, 1 H), 7.46–
7.49 (dd, 3J = 8.1 Hz, 4J = 1.6 Hz, 1 H), 6.66 (d, 3J = 7.1 Hz, 1 H), 3.88 (s,
3 H).
13C NMR (DMSO-d6): δ = 176.5, 163.0, 157.8, 147.6, 147.1, 143.5,
133.6, 127.8, 126.7, 122.0, 121.6, 120.2, 115.2, 44.2.
HRMS (HESI): m/z [M + Na]+ calcd for C14H10ClN3O2S: 342.0075;
HRMS (HESI): m/z [M + Na]+ calcd for C15H11ClN4O3: 353.0412; found:
353.0410.
found: 342.0075.
1-Methyl-4-oxo-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)-1,4-
dihydropyridine-3-carboxamide (13q)
N-(6-Bromobenzo[d]thiazol-2-yl)-1-methyl-4-oxo-1,4-dihydropy-
ridine-3-carboxamide (13m)
From TMS-amine 6q. Compound 13q was isolated as a white solid (for
yields, see Table 1); mp >300 °C.
From TMS-amine 6m. Compound 13m was isolated as a white solid
(for yields, see Table 1); mp >300 °C.
IR (ATR): 1638, 1682, 3060 cm–1
.
1H NMR (DMSO-d6): δ = 14.66 (s, 1 H), 8.79 (s, 1 H), 8.53 (s, 1 H), 7.97
(d, 3J = 7.0 Hz, 1 H), 7.90 (d, 3J = 8.7 Hz, 1 H), 7.76 (d, 3J = 7.5 Hz, 1 H),
6.67 (d, 3J = 7.0 Hz, 1 H), 3.89 (s, 3 H).
13C NMR (DMSO-d6): δ = 176.5, 163.2, 160.2, 151.5, 147.1, 143.5,
132.4, 124.5 (q, J = 274.0 Hz), 123.7 (q, J = 31.2 Hz), 123.0 (q, J = 3.7
Hz), 121.1, 120.0 (q, J = 4.3 Hz), 120.0, 115.0, 44.1.
IR (ATR): 1687, 3056, 3084 cm–1
.
1H NMR (DMSO-d6): δ = 14.53 (s, 1 H), 8.77 (s, 1 H), 8.28 (s, 1 H), 7.95
(d, 3J = 7.4 Hz, 1 H), 7.72 (d, 3J = 8.2 Hz, 1 H), 7.59 (d, 3J = 8.2 Hz, 1 H),
6.66 (d, 3J = 6.9 Hz, 1 H), 3.88 (s, 3 H).
13C NMR (DMSO-d6): δ = 176.5, 163.0, 157.8, 147.9, 147.0, 143.5,
134.1, 129.3, 124.4, 122.4, 120.2, 115.7, 115.2, 44.1.
HRMS (HESI): m/z [M + H]+ calcd for C14H10BrN3O2S: 363.9750; found:
363.9749.
19F NMR (DMSO-d6): δ = –59.43.
HRMS (HESI): m/z [M + H]+ calcd for C15H10F3N3O2S: 354.0519; found:
354.0516.
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A. Koperniku et al.
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1-Methyl-4-oxo-N-(6-((trifluoromethyl)thio)benzo[d]thiazol-2-
yl)-1,4-dihydropyridine-3-carboxamide (13r)
1H NMR (CDCl3): δ = 8.01 (d, J = 8.1 Hz, 2 H), 7.40 (d, J = 8.1 Hz, 2 H),
4.55 (s, 2 H), 4.31 (t, J = 6.6 Hz, 2 H), 3.48 (t, J = 6.8 Hz, 2 H), 1.73–
1.79 (m, 2 H), 1.59–1.66 (m, 2 H), 1.30–1.46 (m, 12 H), 0.89 (t, 3J = 7.0
Hz, 6 H).
13C NMR (CDCl3): δ =166.8, 144.2, 129.8, 127.3, 72.5, 71.1, 65.3, 31.9,
31.7, 29.9, 28.9, 26.1, 25.9, 22.8 (2 × C), 14.3, 14.2.
3
3
From TMS-amine 6r. Compound 13r was isolated as a white solid (for
yields, see Table 1); mp >300 °C (dec).
IR (ATR): 1637, 1682, 1758, 3059 cm–1
.
4
1H NMR (DMSO-d6): δ = 14.65 (s, 1 H), 8.78 (d, J = 1.8 Hz, 1 H), 8.50
(d, 4J = 2 Hz, 1 H), 7.96–7.98 (dd, 3J = 7.2 Hz, 4J = 1.9 Hz, 1 H), 7.89 (d,
3J = 8.3 Hz, 1 H), 7.73–7.75 (dd, 3J = 7.8 Hz, 4J = 1.9 Hz, 1 H), 6.67 (d, 3J =
7.6 Hz, 1 H), 3.88 (s, 3 H).
HRMS (HESI): m/z [M + H]+ calcd for C20H32O3: 321.2424; found:
321.2419.
(4-((Hexyloxy)methyl)phenyl)methanol (19)
13C NMR (DMSO-d6): δ = 176.5, 163.1, 159.9, 151.0, 147.1, 143.5,
133.2, 132.8 (q, J = 306.3 Hz), 130.7, 121.7, 120.2, 116.8, 115.1, 44.1.
HRMS (HESI): m/z [M + H]+ calcd for C15H10F3N3O2S2: 386.0239;
A solution of ester 18 (640 mg, 2 mmol, 1 equiv) in THF (5 mL) was
added to a suspension of LAH (305 mg, 8 mmol, 4 equiv) in THF (10
mL), and the mixture was stirred for 4 h at r.t. under N2. The reaction
was stopped by the addition of H2O (0.3 mL), 15% aq NaOH (0.3 mL),
and H2O (0.9 mL), and the solid materials formed were removed by
suction filtration. The filtrate was concentrated to dryness, dissolved
in Et2O, and washed with brine, dried over Na2SO4, and concentrated
under high vacuum to afford alcohol 19 as a colourless liquid (342 mg,
77%).
found: 386.0243.
N-(5-Bromobenzo[d]thiazol-2-yl)-1-methyl-4-oxo-1,4-dihydro-
pyridine-3-carboxamide (13s)
From TMS-amine 6s. Compound 13s was isolated as a white solid (for
yields, see Table 1); mp >300 °C.
IR (ATR): 1644, 1679, 2850, 3047, 3417 cm–1
.
IR (ATR): 2856, 2930, 3343 cm–1
.
1H NMR (DMSO-d6): δ = 14.55 (s, 1 H), 8.78 (s, 1 H), 7.95–8.0 (m, 3 H),
7.48 (d, 3J = 8.2 Hz, 1 H), 6.66 (d, 3J = 7.2 Hz, 1 H), 3.88 (s, 3 H).
13C NMR (DMSO-d6): δ = 176.5, 163.0, 158.7, 150.3, 147.1, 143.5,
1H NMR (CDCl3): δ = 7.33 (s, 4 H), 4.66 (s, 2 H), 4.49 (s, 2 H), 3.45 (t,
3J = 6.6 Hz, 2 H), 1.94 (s, 1 H), 1.57–1.64 (m, 2 H), 1.26–1.40 (m, 6 H),
0.89 (t, 3J = 7.0 Hz, 3 H).
13C NMR (CDCl3): δ = 140.4, 138.3, 128.0, 127.2, 72.8, 70.7, 65.3, 31.9,
29.9, 26.1, 22.8, 14.3.
131.2, 126.4, 123.7, 123.1, 120.2, 119.0, 115.2, 44.1.
HRMS (HESI): m/z [M + H]+ calcd for C14H10BrN3O2S: 363.9750; found:
HRMS (HESI): m/z [M + Na]+ calcd for C14H22O2: 245.1512; found:
363.9748.
245.1512.
Methyl 1-Methyl-4-oxo-1,4-dihydropyridine-3-carboxylate (16)
MeI (0.2 mL, 3.00 mmol, 0.25 equiv) was added to a solution of meth-
yl ester 14 (2 g, 12 mmol) in MeCN (16 mL), and the mixture was
heated at 120 °C under microwave conditions for 1 h. The solvent was
then removed, and the oily residue was taken up in EtOAc, treated
with charcoal, filtered, and re-concentrated to give 4-pyridinone 16
as a viscous oil that solidified to a near colourless solid on standing (2
g, 95%).
1-(Bromomethyl)-4-((hexyloxy)methyl)benzene (20)
A solution of thionyl bromide (0.77 mL, 9.9 mmol, 1.1 equiv) in DCM
(11 mL) was added to a solution of alcohol 19 (2 g, 9 mmol, 1 equiv) in
DCM (190 mL) under N2 at r.t. The mixture was stirred overnight un-
der N2 at r.t., and then concentrated. The residue was dissolved in
heptane and washed three times with H2O and once with sat. aq
NaHCO3. The heptane layer was dried over Na2SO4 and concentrated
to give 20 as a yellowish liquid which solidified in the fridge (2.7 g,
>98%).
1H NMR (CDCl3): δ = 7.37 (d, 3J = 8.0 Hz, 2 H), 7.31 (d, 3J = 8.0 Hz, 2 H),
4.48 (s, 4 H), 3.47 (t, 3J = 6.5 Hz, 2 H), 1.60–1.63 (m, 2 H), 1.30–1.40
(m, 6 H), 0.89 (t, 3J = 7.1 Hz, 3 H).
IR (ATR): 1645, 1717, 2950, 3013, 3053, 3094 cm–1
.
1H NMR (CDCl3): δ = 8.12 (s, 1 H), 7.21–7.24 (dd, 3J = 7.7 Hz, 4J = 2.5 Hz,
1 H), 6.44 (d, 3J = 7.5 Hz, 1 H), 3.83 (s, 3 H), 3.69 (s, 3 H).
13C NMR (CDCl3): δ = 174.8, 165.3, 146.6, 139.8, 122.7, 118.1, 51.9,
44.9.
13C NMR (CDCl3): δ = 139.4, 137.1, 129.3, 128.1, 72.6, 70.9, 33.6, 31.9,
29.9, 26.1, 22.8, 14.3.
MS (Turbo Spray): m/z = 302.3/304.3 (1:1) [M + NH4]+.
HRMS (HESI): m/z [M + H]+ calcd for C8H9NO3: 168.0655; found:
168.0657.
Hexyl 4-((Hexyloxy)methyl)benzoate (18)
S-(4-((Hexyloxy)methyl)benzyl) Ethanethioate (21)
Sodium (2.5 g, 109 mmol, 10 equiv) was added to anhydrous hexanol
(30 mL), and the mixture was stirred under N2 for 48 h at 90 °C. Meth-
yl 4-(bromomethyl)benzoate (17) (2.5 g, 10.9 mmol, 1 equiv) was
subsequently added, and the resulting mixture was stirred for 4 h at
40 °C. The cooled mixture was then diluted with toluene (30 mL) and
acidified by addition of 6 N aq HCl. The organic and aqueous layers
were separated, and the acidic aqueous layer was extracted with tolu-
ene. The combined organic layers were dried over Na2SO4 and concen-
trated. The residue was flash column chromatographed (silica gel;
heptane/EtOAc, 97:3), affording ester 18 as a yellow-orange liquid
(2.625 g, 75%).
To a solution of bromide 20 (6.2 g, 22 mmol, 1 equiv) in 2-Me-THF (70
mL) was added thioacetic acid (1.70 mL, 24 mmol, 1.1 equiv) and
K2CO3 (3.6 g, 26 mmol, 1.2 equiv). The reaction mixture was stirred
under N2 for up to 6 h at r.t., and then acidified using 6 N aq HCl and
diluted by addition of H2O (40 mL). The organic and aqueous layers
were separated, and the aqueous layer was extracted with 2-Me-THF.
The combined organic layers were washed with H2O, dried over
Na2SO4, and concentrated. The residue was flash column chromato-
graphed (silica gel; heptane/EtOAc, 95:5), affording 21 as a yellow-
brown liquid (3.9 g, 64%).
IR (ATR): 1690, 2928 cm–1
.
IR (ATR): 1718, 2858, 2929 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–L

K
A. Koperniku et al.
Paper
Synthesis
1H NMR (CDCl3): δ = 7.28 (s, 4 H), 4.48 (s, 2 H), 4.13 (s, 2 H), 3.47 (t,
3J = 6.5 Hz, 2 H), 2.36 (s, 3 H), 1.58–1.65 (m, 2 H), 1.28–1.41 (m, 6 H),
0.90 (t, 3J = 7.0 Hz, 3 H).
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1611435.
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13C NMR (CDCl3): δ = 195.3, 138.0, 137.0, 129.0, 128.1, 72.7, 70.8, 33.4,
31.9, 30.5, 29.9, 26.1, 22.8, 14.3.
HRMS (HESI): m/z [M + Na]+ calcd for C16H24O2S: 303.1395; found:
303.1387.
References
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(4-((Hexyloxy)methyl)phenyl)methanethiol (22)
To a solution of thioacetate 21 (280 mg, 1 mmol, 1 equiv) in MeOH (3
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3
3
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261.1281.
S-(4-((Hexyloxy)methyl)benzyl) 1-Methyl-4-oxo-1,4-dihydropyri-
dine-3-carbothioate (23)
Benzyl mercaptan 22 (474 mg, 1.99 mmol, 1.2 equiv) was added to a
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TFFH (438 mg, 1.66 mmol, 1 equiv) in MeCN (5 mL) containing DIEA
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.
1H NMR (CD3CN): δ = 8.22 (d, 4J = 2.4 Hz, 1 H), 7.39–7.42 (dd, 3J = 7.6
Hz, 4J = 2.4 Hz, 1 H), 7.32 (d, 3JA′B′ = 8.1 Hz, 2 H), 7.24 (d, 3J = 8.1 Hz, 2
3
H), 6.37 (d, J = 7.6 Hz, 1 H), 4.42 (s, 2 H), 4.12 (s, 2 H), 3.67 (s, 3 H),
3.42 (t, 3J = 6.6 Hz, 2 H), 1.53–1.57 (m, 2 H), 1.26–1.36 (m, 6 H), 0.88 (t,
3J = 6.8 Hz, 3 H).
13C NMR (CD3CN): δ = 189.9, 176.4, 146.4, 142.5, 139.3, 139.1, 129.0,
124.1, 123.1, 73.3, 71.4, 45.1, 33.8, 32.8, 30.8, 27.0, 23.7, 14.7.
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374.1781.
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Acknowledgment
We gratefully thank the NSERC CREATE Sustainable Synthesis (CSS)
Program for a student scholarship (A.K.). We also thank three foreign
exchange students, Anouk Lecordier, Rodolphe Vatinel, and Christo-
phe Bobin from ENSICAEN, Caen, France for their contribution to the
early phase of this work.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–L

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Synthesis
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–L