A Trimethylsilylamine-Acyl Fluoride Amide Bond Forming Protocol for Weakly Nucleophilic Amines that is Amenable to the Parallel Synthesis of Di(hetero)arylamides

Article abstract of DOI:10.1055/s-0036-1588603

The reaction of a 2-pyridinone-based acid fluoride with the N-TMS derivatives of different weakly nucleophilic heteroaryl/arylamines in acetonitrile containing catalytic fluoride ion provides a clean, efficient and simple means to access a diverse range of polar di(hetero)arylamide structures. This amide bond forming protocol is readily amenable to the parallel synthesis of compound libraries.

Full text of DOI:10.1055/s-0036-1588603

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–H
paper
A
M. Zamiri, D. S. Grierson
Paper
Synthesis
A Trimethylsilylamine-Acyl Fluoride Amide Bond Forming Proto-
col for Weakly Nucleophilic Amines that is Amenable to the Paral-
lel Synthesis of Di(hetero)arylamides
Maryam Zamiri
David S. Grierson*
Faculty of Pharmaceutical Sciences, The University of
British Columbia, 2405 Westbrook Mall, Vancouver,
V6T 1Z3, Canada
dgrierso@mail.ubc.ca
Received: 30.06.2016
Accepted after revision: 31.08.2016
O
Het
Published online: 29.09.2016
DOI: 10.1055/s-0036-1588603; Art ID: ss-2016-n0421-op
OH H2N
Het
parallel
synthesis
Abstract The reaction of a 2-pyridinone-based acid fluoride with the
N–TMS derivatives of different weakly nucleophilic heteroaryl/aryl-
amines in acetonitrile containing catalytic fluoride ion provides a clean,
efficient and simple means to access a diverse range of polar di(hete-
ro)arylamide structures. This amide bond forming protocol is readily
amenable to the parallel synthesis of compound libraries.
O
Het
N
Het
H
diheteroarylamides (DHA's)
Key words amide coupling, di(hetero)arylamide, acid fluoride, het-
eroarylamine, N-TMS activation, parallel synthesis
S
N
O
S
N
O
The screening of compound libraries has repeatedly
demonstrated its effectiveness as a research tool in drug
discovery. In particular, when mechanistic and/or structur-
al details for the therapeutic target are lacking, compound
library screening is one of very few options possible to
identify new and/or groundbreaking avenues for drug de-
velopment. In our laboratory, parallel synthesis is used to
connect and functionalize novel scaffolds into libraries of
bioactive molecules containing different architectures. In
particular, amide bond formation was used to generate
molecules that possess a di(hetero)arylamide (DHA) sub-
structure. The screening of a 256-membered library con-
taining 119 DHA compounds identified four novel and re-
lated molecules 1–4 (Figure 1) that block HIV-1 replication
by a mechanism involving perturbation of the alternative
splicing events leading to production of key HIV regulatory
proteins.1a,b
N
H
N
N
H
N
O
NO2
NO2
OMe
1
2
S
S
N
O
O
N
O
O
N
N
H
N
N
H
O
NO2
NO2
OMe
OMe
3
4
Figure 1 IDC16 (indole compound 16) mimics: di(hetero)arylamide-
type anti-HIV compounds 1–4
the acid chloride method and different peptide coupling re-
agents rarely exceeded 10–30%. In fact, the formation of
complex mixtures of polar compounds was generally ob-
served, complicating workup and isolation/purification of
the desired product. To advance the anti-HIV project, and
other applications for the DHA library, it became important
to develop a new amide synthesis protocol.
For the construction of the amide bond, a wide range of
peptide (amide) bond forming reagents and conditions are
available.2 However, in our library project, where electron-
deficient (weakly nucleophilic) heterocyclic amines were
engaged,3 the yield of the DHA product in reactions using
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

B
M. Zamiri, D. S. Grierson
Paper
Synthesis
In this report, we describe the development of such a
protocol for amide bond construction that is efficient and
amenable to the parallel synthesis of novel di(hetero)aryl-
amides. The procedure is based on the reaction of readily
available N-trimethylsilylamines with acid fluorides in the
presence of catalytic fluoride ion. Formally, the fluoride ion
reacts with the silylated amine to form a ‘hypervalent’ sili-
con species,4 which readily decomposes to produce volatile
TMSF and an amine anion intermediate, which is higher in
energy and more nucleophilic/reactive than the corre-
sponding free amine. Although often stable to water, and
less reactive than acid chlorides toward alcohols, acid fluo-
rides react efficiently with amines to give the expected am-
ide products.5,6 An additional attractive feature of the use of
acid fluorides and silylated amines as the coupling partners
is that these heterocyclic components are nonpolar relative
to their amine/acid precursors and to the amide products
that are generated. Consequently, by choosing a reaction
solvent in which the polar di(hetero)arylamide product se-
lectively precipitates, its isolation is reduced to a simple fil-
tration. For development of the protocol, the acid fluoride
derivative of 2-pyridinone-5-carboxylic acid (6) was used
as the acid component, as beyond the discovery of com-
pound 41 (Figure 1) relatively little development of this
scaffold in amide synthesis has been described.7
peting formation of the symmetrical anhydride 8.9 Com-
pound 7 was isolated pure as a colorless solid (90%) by
washing the crude product mixture with hexane to remove
the tetramethylurea formed, and then taking the solid ma-
terial up in dichloromethane, filtering to remove the excess
CsF, and concentrating to dryness. The structure of 7 was
confirmed by the presence of a peak at 25.43 ppm in the 19
F
NMR spectrum, and by the up-field shift (Δδ 0.14 ppm)
from δ = 8.34 for the peak for H-6 in the 1H NMR spectrum.
As expected, acid fluoride 7 was much more stable than the
corresponding (and corrosive) acid chloride derivative, and
could be conveniently stored for periods exceeding one
month in an airtight container at 4 °C. In fact, when dis-
solved in dichloromethane and washed with ice water, it
was recovered in greater than 90% yield (purity check by 1H
NMR spectroscopy).
The diversity set of 18 trimethylsilylated het-
eroaryl/arylamines 9a–r (Table 1) used in this study was
prepared by reacting 0.5 mmol of the requisite amine in
neat trimethylsilyl cyanide (TMSCN) (0.5 mL) at 70 °C (30 to
180 min) (Table 1).10 The advancement of each reaction was
1
monitored by H NMR spectroscopy (CDCl3). Interestingly,
the time required to observe complete dissolution of the
amine, that is, an indicator of complete N-silylation, ap-
peared to be a function of both the reactivity of the amine
and its solubility. Indeed, the duration of reaction required
did not follow a clear linear relationship to the electron
density on the exocyclic amine nitrogen (as calculated us-
ing Spartan software11) (see calculated e–-density values in
Table 1). With the exception of TMS-amines 9m and 9p, the
polar amine substrates dissolved in TMSCN as the reaction
progressed. As the only by-product of the reaction was vol-
atile HCN, it and the residual TMSCN were removed under
vacuum.
Carboxylic acid 6 was prepared (Scheme 1) by O4-al-
kylation of 2-pyridinone ester 51,7 with 1-bromo-2-meth-
oxyethane (DMF, Cs2CO3) and subsequent hydrolysis of the
ester group using LiOH in THF–H2O (2:1). Conversion of 6 to
acid fluoride 7 was best achieved through reaction with flu-
oro-N,N,N′,N′-tetramethylformamidinium hexafluorophos-
phate (TFFH)8 and cesium fluoride (CsF) in anhydrous
MeCN at room temperature for 5 hours. The presence of
added fluoride ion was mandatory in order to avoid com-
O
N
OEt
TMSCN
Het
Het
F
O
OH
NH2
+
N
NHTMS
O
5
N
TMS-9a–r
9a–r
N
N
refs. 1a,b
TFFH
O
O
O
O
O
O
Het
TBAF (cat.)
N
N
N
O
OH
N
F
H
CsF, MeCN
OMe
OMe
OMe
O
O
TMSF
(volatile)
6
10a–l, 4, 10n–r
7
OMe
O
O
O
O
N
N
O
O
O
8
OMe
Scheme 1 Preparation of acyl fluoride 7 and its reaction with TMS-9a–r
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

C
M. Zamiri, D. S. Grierson
Paper
Synthesis
Table 1 Synthesis of Di(hetero)arylamides 4 and 10 from TMS-Amines 9a–r
TMS-amine 9a
Electron density
N-Silylation time
7 (91%)c
Amidea,b (yield, %)
TMSHN
TMS-9a
140.1
132.2
10a (78)
10b (7)
N
Cl
TMSHN
N
TMS-9b12
30
30
O
TMSHN
TMSHN
TMS-9c
TMS-9d
120
10c (27)
10d (34)
N
S
119.5
15
N
TMSHN
TMS-9e
115
30
30
10e (53)
10f (55)
10g (89)
O
N
N
S
TMSHN
TMSHN
TMS-9f13a–d
TMS-9g14
112.8
105.9
180
CO2Me
TMSHN
TMSHN
TMSHN
N
N
TMS-9h13a
TMS-9i
100.5
98
90
10h (42)
10i (62)
120
N
S
Cl
TMS-9j
97.8
30
10j (71)
N
TMS-9k
96
180 (96%)c
30
10k (85)
10l (87)
TMSHN
TMSHN
CN
S
N
TMS-9l15
92.9
N
S
N
TMS-9m1b
88.8
30
4 (60)1a,b
TMSHN
NO2
S
TMSHN
TMS-9n
88.7
80.4
30
10n (92)
10o (81)
N
Cl
TMSHN
TMS-9o13a
180
CN
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

D
M. Zamiri, D. S. Grierson
Paper
Synthesis
Table 1 (continued)
TMS-amine 9a
Electron density
77.3
N-Silylation time
60
Amidea,b (yield, %)
TMSHN
O
TMS-9p
10p (63)
N
N
Cl
Cl
N
TMS-9q
TMS-9r
74.7
58.4
30
10q (44)
10r (67)
TMSHN
TMSHN
360 (85%)c
N
CN
a All known compounds are cited by literature references.
b Amide formation: TMS-amine (0.5 mmol) + acid fluoride (0.89 mmol) in MeCN (5 mL), 50 °C, overnight, (isolated yield).
c Percent conversion to TMS-amine.
As alluded to already, reactions where the acid chloride
derivative of carboxylic acid 6 (and the related compound
containing a 4-OMe substituent1) was coupled to amines 9
using different solvents (DMF, CH2Cl2, THF) and bases (Et3N,
pyridine, K2CO3) at room temperature, or with heating, re-
sulted in incomplete conversion to the desired amide prod-
ucts. Under these conditions, the product mixture con-
tained unreacted amine/acid, as well as copious amounts of
unidentified polar material. This, plus the fact that the
product mixtures were poorly soluble, complicated purifi-
cation and limited applicability to synthesis or parallel syn-
thesis. In contrast, the reaction of the four (nonsilylated)
amines 9c, 9g, 9l, and 9n with excess of acid fluoride 7 in
acetonitrile at 50 °C was remarkably efficient. Under these
conditions the product precipitated from the medium as
the reaction progressed, and was contaminated with much
smaller quantities (up to 15%) of residual amine. Encour-
aged by this result, the reaction of TMS-9n with an excess
(1.8 equiv) of acid fluoride 7 was evaluated. It was observed
that any residual amine that may not have reacted re-
mained in solution, as amide 10n was isolated pure after
filtration and drying in 47% yield. Further, a significant im-
provement in product yield (47% to 92%) was achieved by
addition of a catalytic amount of TBAF (2 mol%) at the out-
set, to initiate reaction of fluoride ion with silicon and for-
mation of the putative amine anion. The protocol that was
subsequently employed for the synthesis of the new DHA
molecules involved adding acid fluoride 7 (0.89 mmol) in
acetonitrile (5 mL) to the requisite TMS-amine TMS-9a–r
(0.5 mmol) (prepared immediately before the reaction).
TBAF was then added, and the resulting mixture was heated
at 50 °C overnight. After cooling, the precipitated material
was collected by suction filtration and dried. As product
purity, and not quantity, was the principle criterion for
these reactions, efforts were generally not made to improve
the amide product yields beyond those indicated in Table 1.
In this context, it was interesting to observe that the yield
for the preparation of amide 10a from the electron-rich
amine TMS-9a was comparable to that for the preparation
of 10r from the electron-deficient amine TMS-9r. In fact,
the initial yield for 10a was 38%, but could be brought up to
78% by washing with a mixture of MeCN/Et2O. This reflect-
ed the fact that amide 10a is more soluble in MeCN than
amide 10r. The relatively lower yields for the isolation of
amides 10b–d also reflects their significant solubility in
MeCN. For our purposes, 1H NMR spectroscopy was used to
determine product purity. In the large majority of cases, no
impurities were detected, and in the few cases where the
presence of the amine component persisted, only trace
amounts were detectable (purity >95%) (see Supporting In-
formation for copies of the 1H NMR spectra for amides 10a–
l, 4, and 10n–r, isolated by filtration).
The results obtained with the test set of 18 different N-
trimethylsilylated heteroaryl/arylamines in acetonitrile
demonstrate the simplicity of the protocol and suggests its
general applicability to a wide range of amines expressing
weak nucleophilic character. Further, as extractive workup
can be avoided and minimum waste is produced. This
‘green’ chemistry method16 can be readily adapted to rapid
parallel synthesis of libraries of di(hetero)arylamide-based
compounds.
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 and 13C NMR
spectra were recorded at 400 and 100 MHz, respectively, on a Bruker
AC 400 Ultrashield 10 spectrometer. Chemical shifts are expressed in
ppm (δ scale). Standard abbreviations are used to report peak multi-
plicities. Coupling constants are reported in hertz (Hz). High-resolu-
tion mass spectra was recorded on a Thermo Scientific Q Exactive
Orbitrap High Resolution Mass Spectrometer. IR spectra (cm–1) were
recorded on a Agilent Technologies (Cary 600 series) FT-IR spectrom-
eter, using a PIKE MIRacle ATR accessory for sampling. Melting points
were obtained using a Mel-Temp II apparatus.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

E
M. Zamiri, D. S. Grierson
Paper
Synthesis
4-(2-Methoxyethoxy)-1-methyl-6-oxo-1,6-dihydropyridine-3-car-
bonyl Fluoride (7)
1H NMR (400 MHz, CDCl3): δ = 7.02 (s, 1 H), 6.40 (s, 1 H), 5.20 (s, 1 H),
0.25 (s, 9 H).
A mixture of 61a,b (1.0 g, 4.40 mmol), TFFH (1.18 g, 4.40 mmol), and
CsF (1.57 g, 10.3 mmol) in MeCN (22 mL) was stirred for 12 h at r.t.
The mixture was then concentrated under reduced pressure and
washed with hexanes to remove the tetramethylurea formed. The
product mixture was then dissolved in CH2Cl2 and filtered to remove
the excess CsF. The filtrate was concentrated and dried under high
vacuum for 2 days to afford 7 as a beige solid (0.91 g, 90%).
Methyl 4-[(Trimethylsilyl)amino]benzoate (TMS-9g)14
Heated for 180 min; yellow oil; 100% conversion.
1H NMR (400 MHz, CDCl3): δ = 7.68 (d, J = 7.8 Hz, 2 H), 6.48 (d, J = 7.9
Hz, 2 H), 3.69 (s, 4 H), 0.14 (s, 9 H).
N-(Trimethylsilyl)pyrazin-2-amine (TMS-9h)13a
IR (ATR): 1814, 1778, 1678, 1617, 1530 cm–1
.
Heated for 90 min; yellow oil; 100% conversion.
1H NMR (400 MHz, CDCl3): δ = 7.83 (t, J = 1.2 Hz, 3 H), 4.23 (s, 1 H),
0.24 (s, 9 H).
1H NMR (400 MHz, CDCl3): δ = 8.20 (s, 1 H), 5.91 (s, 1 H), 4.13 (t, J = 4.3
Hz, 2 H), 3.81 (t, J = 4.3 Hz, 2 H), 3.57 (s, 3 H), 3.46 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 165.6, 163.5, 154.1, 150.8, 148.1, 97.3,
70.1, 69.0, 59.6, 37.8.
19F NMR (400 MHz, CDCl3): δ = 25.43.
6-Chloro-N-(trimethylsilyl)pyridin-3-amine (TMS-9i)
Heated for 120 min; purple solid; 100% conversion.
1H NMR (400 MHz, CDCl3): δ = 7.73 (s, 1 H), 6.97 (d, J = 8.7 Hz, 1 H),
6.85 (d, J = 8.7 Hz, 1 H), 3.44 (s, 1 H), 0.20 (s, 9 H).
N-Trimethylsilylated Heteroaryl/arylamines TMS-9a–r; General
Procedure
The starting amines were dried under high vacuum for 12 h. Then, a
solution/mixture of the requisite amine (0.5 mmol) in Me3SiCN (0.5
mL) was heated at 70 °C for the required time (Table 1). Without re-
moving the hot oil bath, the resulting solution was flushed with N2
for 15 min and then concentrated under high vacuum The percent
conversion of each amine to its N-silylated derivative was determined
by 1H NMR analysis in CDCl3 (passed through a basic alumina column
prior to use).
N-(Trimethylsilyl)benzo[d]thiazol-2-amine (TMS-9j)
Heated for 30 min; yellow oil; 100% conversion.
1H NMR (400 MHz, CDCl3): δ = 7.41 (s, 2 H), 7.13 (s, 1 H), 6.93 (s, 1 H),
4.91 (s, 1 H), 0.21 (s, 9 H).
3-[(Trimethylsilyl)amino]benzonitrile (TMS-9k)
Heated for 180 min; yellow oil; 96% conversion.
1H NMR (400 MHz, CDCl3): δ = 7.03 (t, J = 7.8 Hz, 1 H), 6.81 (d, J = 7.5
Hz, 1 H), 6.69 (m, 2 H), 3.51 (s, 1 H), 0.13 (s, 9 H).
N-[(6-Chloropyridin-3-yl)methyl]-1,1,1-trimethylsilanamine
(TMS-9a)
Heated for 7 min; yellow oil; 91% conversion.
1H NMR (400 MHz, CDCl3): δ = 8.22 (s, 1 H), 7.54 (d, J = 8.1 Hz, 1 H),
7.18 (d, J = 8.1 Hz, 1 H), 3.85 (d, J = 8.2 Hz, 2 H), 0.00 (s, 9 H).
N-(Trimethylsilyl)-1,3,4-thiadiazol-2-amine (TMS-9l)15
Heated for 30 min; yellow solid; 100% conversion.
1H NMR (400 MHz, CDCl3): δ = 8.35 (s, 1 H), 6.01 (s, 1 H), 0.32 (s, 9 H).
5-Methyl-N-(trimethylsilyl)isoxazol-3-amine (TMS-9b)12
5-Nitro-N-(trimethylsilyl)benzo[d]isothiazol-3-amine (TMS-9m)1b
Heated for 30 min; yellow solid; 100% conversion.
1H NMR (400 MHz, CDCl3): δ = 5.46 (s, 1 H), 3.75 (s, 1 H), 2.24 (s, 3 H),
0.23 (s, 9 H).
Heated for 30 min; red/orange solid; 100% conversion.
1H NMR (400 MHz, CDCl3): δ = 8.70 (s, 1 H), 7.99 (s, 1 H), 7.40 (s, 1 H),
5.96 (s, 1 H), 0.43 (s, 9 H).
N-(Trimethylsilyl)isoquinolin-4-amine (TMS-9c)
4-Chloro-N-(trimethylsilyl)benzo[d]thiazol-2-amine (TMS-9n)
Heated for 30 min; yellow solid; 100% conversion.
Heated for 30 min; yellow oil; 100% conversion.
1H NMR (400 MHz, CDCl3): δ = 7.37 (d, J = 7.7 Hz, 1 H), 7.23 (d, J =7.8
Hz, 1 H), 6.92 (t, J = 7.7 Hz, 1 H), 5.22 (s, 1 H), 0.30 (s, 9 H).
1H NMR (400 MHz, CDCl3): δ = 8.62 (s, 1 H), 8.03 (s, 1 H), 7.79 (d, J =
7.8 Hz, 1 H), 7.73 (d, J = 8.4 Hz, 1 H), 7.55 (t, J = 7.7 Hz, 1 H), 7.46 (d, J =
7.7 Hz, 1 H), 3.88 (s, 1 H), 0.30 (s, 9 H).
4-[(Trimethylsilyl)amino]benzonitrile (TMS-9o)13a
4-Methyl-N-(trimethylsilyl)thiazol-2-amine (TMS-9d)
Heated for 180 min; yellow oil; 100% conversion.
1H NMR (400 MHz, CDCl3): δ = 7.23 (d, J = 8.0 Hz, 2 H), 6.49 (d, J = 8.0
Hz, 2 H), 3.79 (s, 1 H), 0.14 (s, 9 H).
Heated for 15 min; yellow oil; 100% conversion.
1H NMR (400 MHz, CDCl3): δ = 5.95 (s, 1 H), 4.84 (s, 1 H), 2.14 (s, 3 H),
0.23 (s, 9 H).
5-(2-Chlorophenyl)-N-(trimethylsilyl)-1,3,4-oxadiazol-2-amine
(TMS-9p)
3-Methyl-N-(trimethylsilyl)isoxazol-5-amine (TMS-9e)
Heated for 30 min; orange solid; 100% conversion.
1H NMR (400 MHz, CDCl3): δ = 4.78 (s, 1 H), 4.30 (s, 1 H), 2.08 (s, 3 H),
0.21 (s, 9 H).
Heated for 60 min; white solid; 100% conversion.
1H NMR (400 MHz, CDCl3): δ = 7.85 (d, J = 7.3 Hz, 1 H), 7.43 (d, J = 7.5
Hz, 1 H), 7.30 (m, 2 H), 5.45 (s, 1 H), 0.32 (s, 9 H).
N-(Trimethylsilyl)thiazol-2-amine (TMS-9f)13a–d
2-Chloro-N-(trimethylsilyl)pyridin-4-amine (TMS-9q)
Heated for 30 min; orange oil; 100% conversion.
Heated for 30 min; orange oil; 100% conversion.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

F
M. Zamiri, D. S. Grierson
Paper
Synthesis
1H NMR (400 MHz, CDCl3): δ = 7.87 (d, J = 5.7 Hz, 1 H), 6.47 (s, 1 H),
6.38 (d, J = 5.6 Hz, 1 H), 4.09 (s, 1 H), 0.24 (s, 9 H).
HRMS (HESI): m/z [M + H]+ calcd for C19H20N3O4: 354.1448; found:
354.1449.
5-[(Trimethylsilyl)amino]picolinonitrile (TMS-9r)
4-(2-Methoxyethoxy)-1-methyl-N-(4-methylthiazol-2-yl)-6-oxo-
1,6-dihydropyridine-3-carboxamide (10d)
Heated for 6 h; orange solid; 85% conversion.
From TMS-amine 9d. The precipitated product was washed with Et2O
to afford 10d as a yellow solid; yield: 110 mg (34%); mp 189–190 °C.
1H NMR (400 MHz, CDCl3): δ = 8.01 (s, 1 H), 7.37 (d, J = 8.6 Hz, 1 H),
6.88 (d, J = 8.6 Hz, 1 H), 3.99 (s, 1 H), 0.26 (s, 9 H).
IR (ATR): 3308, 1680, 1635, 1530 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 11.07 (s, 1 H), 8.48 (s, 1 H), 6.81 (s,
1 H), 6.00 (s, 1 H), 4.27 (m, 2 H), 3.75 (m, 2 H), 3.47 (s, 3 H), 3.40 (s, 3
H), 2.27 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 163.3, 162.7, 160.3, 156.5, 147.0,
145.8, 108.4, 104.0, 96.4, 69.4, 68.5, 58.5, 36.5, 16.9.
Di(hetero)arylamides 10a–r; General Procedure
Acid fluoride 7 (200 mg, 0.89 mmol) in MeCN (5 mL) was added in
one portion to the silylated amine 9a–r (0.50 mmol) at r.t. This was
quickly followed by addition of 1 M TBAF in THF (10 μL, 0.01 mmol).
The reaction mixture/solution was stirred at 50 °C for 12 h. The pre-
cipitated product was collected with suction filtration and washed
with MeCN or the specified solvent (Table 1).
HRMS (HESI): m/z [M + H]+ calcd for C14H18N3O4S: 324.1013; found:
324.1015.
N-[(6-Chloropyridin-3-yl)methyl]-4-(2-methoxyethoxy)-1-meth-
yl-6-oxo-1,6-dihydropyridine-3-carboxamide (10a)
4-(2-Methoxyethoxy)-1-methyl-N-(3-methylisoxazol-5-yl)-6-oxo-
1,6-dihydropyridine-3-carboxamide (10e)
From TMS-amine 9a. The precipitated product was washed with
MeCN/Et2O (1:1) to afford 10a as a white solid; yield: 274 mg (78%);
mp 187–188 °C.
From TMS-amine 9e. The precipitated product was washed with Et2O
to afford 10e as a white solid; yield: 163 mg (53%); mp 211–213 °C.
IR (ATR): 3306, 1694, 1656, 1610, 1528 cm–1
.
IR (ATR): 3393, 1675, 1632, 1528 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 10.72 (s, 1 H), 8.42 (s, 1 H), 6.24 (s,
1 H), 5.99 (s, 1 H), 4.25 (m, 2 H), 3.74 (m, 2 H), 3.46 (s, 3 H), 3.36 (s, 3
H), 2.21 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 162.7, 160.8, 160.4, 159.1, 145.7,
104.6, 96.4, 89.3, 69.4, 68.3, 58.3, 36.5, 11.4.
1H NMR (400 MHz, DMSO-d6): δ = 8.37 (d, J = 2.4 Hz, 1 H), 8.28 (m, 2
H), 7.78 (dd, J = 2.5, 8.2 Hz, 1 H), 7.50 (d, J = 8.2 Hz, 1 H), 5.92 (s, 1 H),
4.49 (d, J = 5.9 Hz, 2 H), 4.19 (m, 2 H), 3.67 (m, 2 H), 3.42 (s, 3 H), 3.19
(s, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 163.7, 162.7, 162.5, 148.9, 148.8,
144.5, 138.9, 134.5, 124.0, 105.7, 96.3, 69.3, 68.0, 58.1, 36.3.
HRMS (HESI): m/z [M – H]– calcd for C14H16N3O5: 306.1095; found:
306.1102.
HRMS (HESI): m/z [M – H]– calcd for C16H17ClN3O4: 350.0913; found:
350.0916.
4-(2-Methoxyethoxy)-1-methyl-6-oxo-N-(thiazol-2-yl)-1,6-dihy-
dropyridine-3-carboxamide (10f)
4-(2-Methoxyethoxy)-1-methyl-N-(5-methylisoxazol-3-yl)-6-oxo-
1,6-dihydropyridine-3-carboxamide (10b)
From TMS-amine 9f. The precipitated product was washed with Et2O
to afford 10f as a pale yellow solid; yield: 170 mg (55%); mp 185–186
°C.
IR (ATR): 3311, 1678, 1632, 1612, 1530 cm–1
From TMS-amine 9b. The precipitated product was washed with
MeCN to afford 10b as a pale yellow solid; yield: 21 mg (7%); mp 179–
181 °C.
.
1H NMR (400 MHz, DMSO-d6): δ = 11.14 (s, 1 H), 8.50 (s, 1 H), 7.50 (d,
J = 3.5 Hz, 1 H), 7.27 (d, J = 3.5 Hz, 1 H), 6.01 (s, 1 H), 4.28 (m, 2 H),
3.76 (m, 2 H), 3.47 (s, 3 H), 3.38 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 163.3, 162.7, 160.4, 157.3, 145.8,
138.0, 114.2, 104.0, 96.4, 69.4, 68.5, 58.5, 36.5.
IR (ATR): 3337, 1685, 1660, 1612, 1548 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 9.98 (s, 1 H), 8.36 (s, 1 H), 6.71 (s, 1 H),
5.94 (s, 1 H), 4.24 (t, J = 3.8 Hz, 2 H), 3.85 (t, J = 3.7 Hz, 2 H), 3.58 (s, 3
H), 3.54 (s, 3 H), 2.41 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 169.8, 163.9, 163.8, 160.8, 158.2,
145.9, 105.6, 97.3, 97.1, 69.6, 68.7, 59.6, 37.7, 12.8.
HRMS (HESI): m/z [M – H]– calcd for C13H14N3O4S: 308.0711; found:
308.0696.
HRMS (HESI): m/z [M – H]+ calcd for C14H16N3O5: 306.1095; found:
306.1102.
Methyl 4-[4-(2-Methoxyethoxy)-1-methyl-6-oxo-1,6-dihydropyri-
dine-3-carboxamido]benzoate (10g)
N-(Isoquinolin-4-yl)-4-(2-methoxyethoxy)-1-methyl-6-oxo-1,6-
dihydropyridine-3-carboxamide (10c)
From TMS-amine 9g. The precipitated product was washed with
MeCN to afford 10g as a white solid; yield: 321 mg (89%); mp 213–
215 °C.
From TMS-amine 9c. The precipitated product was washed with Et2O
to afford 10c as a white solid; yield: 95 mg (27%); mp 213–214 °C.
IR (ATR): 3286, 1664, 1627, 1543 cm–1
1H NMR (400 MHz, DMSO-d6): δ = 9.88 (s, 1 H), 9.20 (s, 1 H), 8.85 (s, 1
H), 8.48 (s, 1 H), 8.20 (d, J = 8.5 Hz, 1 H), 8.06 (d, J = 8.5 Hz, 1 H), 7.87
(d, J = 15.2 Hz, 1 H), 7.75 (d, J = 15.2 Hz, 1 H), 6.07 (s, 1 H), 4.36 (m, 2
H), 3.80 (m, 2 H), 3.50 (s, 3 H), 3.19 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 163.6, 162.8, 161.8, 149.5, 145.3,
138.4, 130.7, 130.0, 128.4, 128.3, 127.9, 127.7, 121.3, 105.8, 96.5, 69.4,
68.5, 58.2, 36.4.
IR (ATR): 3348, 1688, 1656, 1592, 1527 cm–1
.
.
1H NMR (400 MHz, CDCl3): δ = 9.76 (s, 1 H), 8.41 (s, 1 H), 8.03 (d, J =
8.6 Hz, 2 H), 7.73 (d, J = 8.6 Hz, 2 H), 6.04 (s, 1 H), 4.28 (t, J = 3.9 Hz, 2
H), 3.90 (m, 5 H), 3.61 (s, 3 H), 3.53 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 166.8, 163.9, 163.7, 161.1, 145.7,
142.7, 130.9, 125.6, 119.5, 106.3, 97.3, 69.8, 68.0, 59.1, 52.2, 37.7.
HRMS (HESI): m/z [M – H]– calcd for C18H19N2O6: 359.1249; found:
359.1251.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

G
M. Zamiri, D. S. Grierson
Paper
Synthesis
4-(2-Methoxyethoxy)-1-methyl-6-oxo-N-(pyrazin-2-yl)-1,6-dihy-
HRMS (HESI): m/z [M – H]– calcd for C17H16N3O4: 326.1146; found:
dropyridine-3-carboxamide (10h)
326.1152.
From TMS-amine 9h. The precipitated product was washed with Et2O
to afford 10h as a white solid; yield: 128 mg (42%); mp 191–193 °C.
4-(2-Methoxyethoxy)-1-methyl-6-oxo-N-(1,3,4-thiadiazol-2-yl)-
1,6-dihydropyridine-3-carboxamide (10l)
IR (ATR): 3331, 1693, 1645, 1528 cm–1
.
From TMS-amine 9l. The precipitated product was washed with
MeCN to afford 10l as a white solid; yield: 270 mg (87%); mp 234–236
°C.
1H NMR (400 MHz, DMSO-d6): δ = 10.20 (s, 1 H), 9.44 (d, J = 1.5 Hz, 1
H), 8.53 (s, 1 H), 8.43 (m, 2 H), 6.01 (s, 1 H), 4.29 (m, 2 H), 3.76 (m, 2
H), 3.49 (s, 3 H), 3.36 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 163.3, 162.7, 161.1, 148.3, 146.2,
142.9, 140.2, 136.3, 104.5, 96.4, 69.5, 68.8, 58.4, 36.6.
IR (ATR): 3308, 1686, 1636, 1611, 1528 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 11.51 (s, 1 H), 9.20 (s, 1 H), 8.51 (s,
1 H), 6.01 (s, 1 H), 4.28 (m, 2 H), 3.76 (m, 2 H), 3.47 (s, 3 H), 3.39 (s, 3
H).
13C NMR (100 MHz, DMSO-d6): δ = 163.4, 162.7, 160.9, 158.2, 149.2,
HRMS (HESI): m/z [M + Na]+ calcd for C14H16N4O4Na: 327.1064;
found: 327.1062.
146.0, 103.8, 96.4, 69.4, 68.5, 58.5, 36.5.
HRMS (HESI): m/z [M – H]– calcd for C12H13N4O4S: 309.0663; found:
N-(6-Chloropyridin-3-yl)-4-(2-methoxyethoxy)-1-methyl-6-oxo-
1,6-dihydropyridine-3-carboxamide (10i)
309.0647.
From TMS-amine 9i. The precipitated product was washed with
MeCN to afford 10i as a white solid; yield: 209 mg (62%); mp 195–196
°C.
4-(2-Methoxyethoxy)-1-methyl-N-(5-nitrobenzo[d]isothiazol-3-
yl)-6-oxo-1,6-dihydropyridine-3-carboxamide (4)1a,b
IR (ATR): 3329, 1694, 1649, 1596, 1529 cm–1
.
From TMS-amine 9m. The precipitated product was washed with
MeCN and acetone to afford 4 as a yellow solid; yield: 242 mg (60%);
mp 296–298 °C.
1H NMR (400 MHz, DMSO-d6): δ = 9.96 (s, 1 H), 8.63 (d, J = 2.5 Hz, 1
H), 8.41 (s, 1 H), 8.16 (dd, J = 2.8, 8.7 Hz, 1 H), 7.54 (d, J = 8.8 Hz, 1 H),
6.00 (s, 1 H), 4.27 (m, 2 H), 3.79 (m, 2 H), 3.47 (s, 3 H), 3.33 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 163.3, 162.7, 161.4, 145.2, 143.9,
140.8, 134.9, 130.2, 124.3, 105.6, 96.3, 69.4, 67.9, 58.1, 36.5.
IR (ATR): 3297, 1692, 1638, 1610, 1511 cm–1
1H/13C NMR: See references 1a,b.
.
HRMS (HESI): m/z [M – H]– calcd for C17H15N4O6S: 403.0718; found:
HRMS (HESI): m/z [M – H]– calcd for C15H15ClN3O4: 336.0757; found:
403.0695.
336.0765.
N-(4-Chlorobenzo[d]thiazol-2-yl)-4-(2-methoxyethoxy)-1-meth-
N-(Benzo[d]thiazol-2-yl)-4-(2-methoxyethoxy)-1-methyl-6-oxo-
yl-6-oxo-1,6-dihydropyridine-3-carboxamide (10n)
1,6-dihydropyridine-3-carboxamide (10j)
From TMS-amine 9n. The precipitated product was washed with
MeCN to afford 10n as a white solid; yield: 362 mg (92%); mp 266–
267 °C.
From TMS-amine 9j. The precipitated product was washed with
MeCN to afford 10j as a white solid; yield: 255 mg (71%); mp 209–211
°C.
IR (ATR): 3288, 1684, 1638, 1589, 1527 cm–1
.
IR (ATR): 3302, 1684, 1640, 1600, 1530 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 11.61 (s, 1 H), 8.55 (s, 1 H), 7.99
(dd, J = 1.0, 7.9 Hz, 1 H), 7.54 (dd, J = 1.0, 7.8 Hz, 1 H), 7.32 (t, J = 7.9 Hz,
1 H), 6.02 (s, 1 H), 4.29 (m, 2 H), 3.79 (m, 2 H), 3.48 (s, 6 H).
1H NMR (400 MHz, CDCl3): δ = 11.01 (s, 1 H), 8.45 (s, 1 H), 7.81 (dd, J =
7.9, 19.0 Hz, 2 H), 7.44 (t, J = 7.5 Hz, 1 H), 7.30 (t, J = 7.5 Hz, 1 H), 5.99
(s, 1 H), 4.34 (s, 2 H), 3.94 (s, 2 H), 3.64 (s, 3 H), 3.60 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 163.4, 162.7, 161.7, 158.4, 146.2,
145.4, 133.4, 126.3, 124.6, 124.5, 120.9, 103.8, 96.4, 69.5, 68.6, 58.8,
36.5.
13C NMR (100 MHz, CDCl3): δ = 163.7, 161.1, 157.8, 148.4, 146.3,
132.4, 126.3, 124.1, 121.5, 121.1, 104.4, 97.5, 69.8, 68.9, 59.7, 37.8.
HRMS (HESI): m/z [M – H]– calcd for C17H16N3O4S: 358.0867; found:
358.0849.
HRMS (HESI): m/z [M – H]– calcd for C17H15ClN3O4S: 392.0477; found:
392.0461.
N-(3-Cyanophenyl)-4-(2-methoxyethoxy)-1-methyl-6-oxo-1,6-di-
hydropyridine-3-carboxamide (10k)
N-(4-Cyanophenyl)-4-(2-methoxyethoxy)-1-methyl-6-oxo-1,6-di-
hydropyridine-3-carboxamide (10o)
From TMS-amine 9k. The precipitated product was washed with
MeCN and MeOH to afford 10k as a white solid; yield: 278 mg (85%);
mp 236–238 °C.
From TMS-amine 9o. The precipitated product was washed with
MeOH to afford 10o as a white solid; yield: 265 mg (81%); mp 249–
251 °C.
IR (ATR): 3364, 2219, 1687, 1645, 1589, 1527 cm-1.
1H NMR (400 MHz, DMSO-d6): δ = 10.06 (s, 1 H), 8.40 (s, 1 H), 7.83 (s,
4 H), 5.99 (s, 1 H), 4.27 (m, 2 H), 3.78 (m, 2 H), 3.47 (s, 3 H), 3.33 (s, 3
H).
IR (ATR): 3356, 2227, 1690, 1649, 1591, 1555 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 9.98 (s, 1 H), 8.40 (s, 1 H), 8.09 (s, 1
H), 7.90 (td, J = 1.9, 7.6 Hz, 1 H), 7.58 (m, 2 H), 5.99 (s, 1 H), 4.27 (m, 2
H), 3.80 (m, 2 H), 3.47 (s, 3 H), 3.35 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 163.3, 162.7, 161.3, 145.2, 139.4,
130.4, 127.2, 124.1, 122.3, 118.6, 111.7, 105.7, 96.3, 69.4, 68.0, 58.0,
36.5.
13C NMR (100 MHz, DMSO-d6): δ = 163.3, 162.7, 161.4, 145.2, 142.8,
133.4, 119.6, 119.0, 105.9, 105.4, 96.3, 69.4, 68.0, 58.1, 36.4.
HRMS (HESI): m/z [M – H]– calcd for C17H16N3O4: 326.1146; found:
326.1153.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

H
M. Zamiri, D. S. Grierson
Paper
Synthesis
N-[5-(2-Chlorophenyl)-1,3,4-oxadiazol-2-yl]-4-(2-methoxy-
ethoxy)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide (10p)
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1588603.
From TMS-amine 9p. The precipitated product was washed with
MeCN to afford 10p as a pale yellow solid; yield: 255 mg (63%); mp
190–192 °C.
S
u
p
p
o
nrtIo
g
f
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S
u
p
p
ortiInfogrmoaitn
IR (ATR): 3289, 1698, 1667, 1594, 1528 cm–1
.
References
1H NMR (400 MHz, DMSO-d6): δ = 11.09 (s, 1 H), 8.41 (s, 1 H), 7.93
(dd, J = 1.7, 7.7 Hz, 1 H), 7.64 (dddd, J = 1.2, 7.8, 15.0, 27 Hz, 3 H), 5.98
(s, 1 H), 4.22 (m, 2 H), 3.71 (m, 2 H), 3.46 (s, 3 H), 3.31 (s, 3 H).
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Chabot, B.; Grierson, D. S. J. Med. Chem. 2016, 59, 1869.
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13C NMR (100 MHz, DMSO-d6): δ = 163.3, 162.7, 160.4, 158.9, 157.6,
145.6, 133.1, 131.6, 131.1, 131.0, 127.9, 122.5, 105.1, 96.3, 69.4, 68.4,
58.3, 36.5.
HRMS (HESI): m/z [M – H]– calcd for C18H16ClN4O5: 403.0815; found:
403.0823.
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N-(2-Chloropyridin-4-yl)-4-(2-methoxyethoxy)-1-methyl-6-oxo-
1,6-dihydropyridine-3-carboxamide (10q)
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From TMS-amine 9q. The precipitated product was washed with
MeCN to afford 10q as a white solid; yield: 148 mg (44%); mp 228–
229 °C.
IR (ATR): 3332, 1700, 1655, 1580, 1509 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 10.16 (s, 1 H), 8.41 (s, 1 H), 8.32 (d,
J = 5.6 Hz, 1 H), 7.75 (d, J = 1.5 Hz, 1 H), 7.58 (dd, J = 1.7, 5.6 Hz, 1 H),
6.00 (s, 1 H), 4.26 (m, 2 H), 3.78 (m, 2 H), 3.47 (s, 3 H), 3.34 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 163.7, 163.1, 162.5, 151.5, 151.0,
148.2, 146.0, 113.5, 113.3, 106.0, 96.7, 69.9, 68.5, 58.5, 37.0.
HRMS (HESI): m/z [M – H]– calcd for C15H15ClN3O4: 336.0757; found:
336.0764.
N-(6-Cyanopyridin-3-yl)-4-(2-methoxyethoxy)-1-methyl-6-oxo-
1,6-dihydropyridine-3-carboxamide (10r)
From TMS-amine 9r. The precipitated product was washed with
MeCN/Et2O (1:1) to afford 10r as a pale yellow solid; yield: 220 mg
(67%); mp 255–256 °C.
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IR (ATR): 3312, 2225, 1684, 1648, 1580, 1540 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 10.22 (s, 1 H), 8.87 (d, J = 2.1 Hz, 1
H), 8.43 (s, 1 H), 8.36 (dd, J = 2.3, 8.6 Hz, 1 H), 8.05 (d, J = 8.7 Hz, 1 H),
6.01 (s, 1 H), 4.27 (m, 2 H), 3.79 (m, 2 H), 3.47 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 163.2, 162.7, 161.9, 145.4, 142.3,
138.5, 129.8, 126.3, 126.2, 117.7, 105.5, 96.3, 69.4, 68.0, 58.0, 36.5.
HRMS (HESI): m/z [M – H]– calcd for C16H15N4O4: 327.1099; found:
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Acknowledgment
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Ryan, J. H.; Holmes, A. B. Chem. Commun. 2008, 2152.
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This work was generously supported by grants from the Canadian In-
stitutes of Health Research (CIHR) (and HOP90183 and HOP120238).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H