Cyclization of Methyl-Coumalate-Derived Methyl 1-Benzamido-6-oxo-1,6-dihydropyridine-3-carboxylates: Assembly of the [1,2,4]Triazolo[1,5-a]pyridine Ring System

Article abstract of DOI:10.1021/acs.joc.7b00873

An efficient three-step synthesis of a series of fused bicyclic s-[1,2,4]triazolo[1,5-a]pyridines 1 was accomplished utilizing novel intermediates derived from inexpensive, commercially available hydrazides A and methyl coumalate B. A significant feature of this approach was the formation of a dihydrazide intermediate 2, bypassing the need for oxidative N-N bond formation in the 1,2,4-triazole synthesis. Further purification of the dihydrazides 2, beyond simple isolation, proved to be unnecessary owing to the impurity rejection afforded by the crystalline oxadiazolium salts 3. Additionally, the prepared oxadiazolium perchlorate salts showed excellent moisture stability, an unusual feature in compounds of this type.

Full text of DOI:10.1021/acs.joc.7b00873

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Article
Cyclization of Methyl-Coumalate Derived Methyl 1-
benzamido-6-oxo-1,6-dihydropyridine-3-carboxylates:
Assembly of the [1,2,4]Triazolo[1,5-a]pyridine Ring System
Harold Moloney, Nicholas Andrew Magnus, Jonas Y Buser, and Matthew C Embry
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 12 May 2017
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Page 1 of 11
The Journal of Organic Chemistry
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Cyclization of Methyl-Coumalate Derived Methyl 1-benzamido-6-
oxo-1,6-dihydropyridine-3-carboxylates: Assembly of the
[1,2,4]Triazolo[1,5-a]pyridine Ring System
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Harold Moloney*, Nicholas A. Magnus, Jonas Y. Buser, Matthew, C. Embry
Small Molecule Design and Development, Eli Lilly and Company, Indianapolis, Indiana, USA
*Harry.moloney@gmail.com
Supporting Information Placeholder
B
A
2
1
3
ABSTRACT: An efficient three step synthesis of a series of fused bicyclic sꢀ[1,2,4]triazolo[1,5ꢀa]pyridines 1 was accomplished
utilizing novel intermediates derived from inexpensive commercially available hydrazides A and methyl coumalate B. A significant
feature of this approach was the formation of a dihydrazide intermediate 2, bypassing the need for oxidative NꢀN bond formation in
the 1,2,4 triazole synthesis. Further purification of the dihydrazides 2, beyond simple isolation, proved unnecessary due to the imꢀ
purity rejection afforded by the crystalline oxadiazolium salts 3. Additionally, the prepared oxadiazolium perchlorate salts showed
excellent moisture stability, an unusual feature in compounds of this type.xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx.
1.0 INTRODUCTION
utilizing stoichiometric quantities of oxidant. Oxidants such as
lead tetraacetate,20 Cu(OAc)2,21 MnO2 (4eq.),6 NaClO,22 and
PPA23 have all been used to varying degrees of success to
close the triazole ring via NꢀN bond formation. More recent
examples include heterogeneous transition metal catalyzed
cyclization strategies utilizing copper(I)bromide with molecuꢀ
lar oxygen as the oxidant21 and a catalyzed oxidation.24 A variꢀ
ety of hypervalent iodine mediated metal free alternatives have
also been disclosed,25,26 though while being more environmenꢀ
tally friendly than aforementioned metal mediated routes, sufꢀ
fer from the same lack of scope on the pyridine ring.
The sꢀ[1,2,4]triazolo[1,5ꢀa]pyridine system represents a strucꢀ
tural core associated with a diverse range of biologically imꢀ
portant small molecules. Reports in the scientific literature
have made reference to its properties in the inhibition of
JAK1,1 JAK2,2 Pi3K,3–5 as antibacterial and microbial agents6–
9
and its association with antiꢀcancer properties.10 This pharꢀ
macologically active subunit is also frequently mentioned in
patent literature; selected examples mention its properties of
JAK2 inhibition,2 mGlu 2 modulation,11 treatment of cardioꢀ
vascular disorders12 and type 2 diabetes,13,14 in the treatment of
hyperproliferative disorders,15 PDE10 inhibitors16 and for its
herbicidal effects.17 Despite the plethora of therapeutic areas
associated with this heterocyclic system, relatively few distinct
synthetic strategies exist for its construction.18 and references contained
Previously disclosed work from our medicinal chemistry laꢀ
boratories13 has described the synthesis of a series of moleꢀ
cules containing the sꢀ[1,2,4]triazolo[1,5ꢀa]pyridine moiety
under investigation for their GPR40 activation properties. The
sꢀ[1,2,4]triazolo[1,5ꢀ1]pyridine core, 4, of these molecules is
highlighted in Figure 1. A major drawback of the described
route (Scheme 1) was the requirement for a high energy elecꢀ
trophilic aminating agent, Oꢀmesitylsulfonylhydroxylamine
(MSH) to synthesise key intermediate 5. While preparation
and safe use of MSH has been demonstrated,27 the desire reꢀ
mained to move away from this method of synthesis.
therein
The 1,2ꢀ4 triazole moiety does not contain two adjacent
carbon atoms, thus to form a fused ringꢀsystem, one of the
nitrogen ring atoms must also be a component of the second
ring. Bearing this in mind, it is unsurprising that the most freꢀ
quently encountered substrates in its production are the 2ꢀ
amino pyridines. 2ꢀAmino pyridines are industrially important
feedstock chemicals however present sustainability issues due
to their derivation from petroleum sources.19 Use of these
starting materials results in scope limitations due to the reꢀ
quirement for an oxidative NꢀN bond formation, frequently
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Page 2 of 11
A range of iminohydrazides 7 were prepared using the methꢀ
ods described by Pinner32 from the corresponding nitriles via
reaction of the Pinner salt 8 with hydrazine.33 Preparation of
the iminohydrazide pyridine ester proceeded from a Michael
addition via a zwitterionic intermediate C (Scheme 2) which
was stable at 0 °C. Careful control of temperature was imꢀ
portant, rapid decarboxylation of the intermediate adducts C to
D occurred above 5 °C. Treatment of intermediate C with CDI
promotes cyclization to give IHP 6. Unfortunately a range of
efforts to promote a subsequent ring closure of the IHP esters,
6, to 1 were unsuccessful, the ester moiety activating the molꢀ
ecule towards 1,4ꢀaddition. Conversion to the acid derivative 9
facilitated the cyclization to the desired ring system 10 though
isolation issues were associated with this route due to the acid
functionality of 10 and use of acetic acid or trifluoroacetic acid
as solvents. In an effort to promote cyclization to 10, additives
were screened in a sealed reactor system at elevated temperaꢀ
ture. The sealed system permitted heating beyond the solvent
boiling point and ensured containment of ammonia. It was
found that ammonium acetate was an effective additive though
its role in the reaction mechanism was unclear. Understanding
was gained when LCMS analysis of the crude reaction mixꢀ
tures showed the major product of the reaction gave m/z +1
higher than anticipated when the reaction was carried out in
TFA. Further investigation by NMR and high resolution mass
spectrometry indicated that the cyclization reactions were in
fact proceeding via an oxadiazolium cationic intermediate E
(Scheme 3) initially displacing the imidohydrazide nitrogen
instead of displacing the oxygen as desired.
1
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3
4
5
6
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8
9
4
Figure 1. The 1,2,4ꢀtriazole fragment of potential activators of
GPR 40 for treatment of type 2 diabetes.
Scheme 1. Synthesis of 1 from MSH intermediates
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5
1
We envisioned that methyl coumalate B,28 a renewable feedꢀ
stock ultimately derived from glucose29 via malic acid could
be reacted with hydrazides to access the pyridineꢀring via a
pyridine species and facilitate the cyclization to afford the
1,2,4 triazole ring without the requirement for oxidative NꢀN
bond formation. Presently, we disclose two complementary
metal free synthetic routes to 6ꢀmethyl carboxylate substituted
sꢀ[1,2,4]triazolo[1,5ꢀa]pyridine systems previously unknown
in the literature.
2.0 RESULTS AND DISCUSSION
Scheme 3. Proposed Mechanism of 1,2,4-Triazole For-
mation from IHP acids
In the course of synthetic route investigations carried out by
our laboratories, a number of known methods were attempted
to access the desired substituted 1,2,4 triazole core 4. Several
methods involving oxidative NꢀN bond formation performed
poorly or failed completely at the cyclization stage when apꢀ
plied to the substrates required for our work.21,30,31 Bearing this
in mind, it was hoped that methyl coumalate B could be used
as a platform chemical, reducing the overall chemical proꢀ
cessing involved and providing a greener and more sustainable
route to the biologically important pharmacophores discussed
in this work. Scheme 2 details our initial strategy using imꢀ
idohydrazide pyridine (IHP) derivatives 6, planned as potential
intermediates for condensation to the 1,2,4ꢀtriazole system 1.
O
O
NH4OAc
OH
OH
AcOH or TFA
O
N
N
150 - 200 o
C
N
N
HN
NH
Sealed Reactor
R1
R1
O
9
10
O
O
OH
OH
OH
H+
N
N
O
O
N
O
NH
HN
NH
H2N
H2N
NH
R1
R1
R1
9
-NH3
O
Scheme 2. Initial Efforts to s-[1,2,4]Triazolo[1,5-a]pyridine
Ring System
O
O
OH
OH
OH
H2N
H3N
NH3
H+ shift
N
N
N
N
H
O
O
O
TFA
N
N
Ea
R1
R1
R1
8
7
O
O
O
OH
OH
OH
-H+
HN
N
HN
O
N
N
H2N
N
N
O
NH
O
H
H
R1
R1
R1
C
O
OH
-H2O
N
N
HO
R1
10
NH
a1ꢀD and 2ꢀD NMR provided in Supplementary Information
D
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The intermediate E undergoes attack by ammonia, either amꢀ to the hydrazide starting material. Alkyl derivative 2n, reꢀ
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monium acetate derived or from oxygen displaced ammonia.
The proposed cyclization mechanism in TFA is outlined in
Scheme 3. It is likely that when the reaction is carried out in
acetic acid, the ion pair is insufficient to arrest the oxadiazoliꢀ
um C. Representative examples of prepared imidohydrazide
esters 6 and acids 9 are provided in the experimental section
for information purposes. Taking advantage of this mechanisꢀ
tic insight, the synthetic route was altered (Scheme 4) to proꢀ
ceed directly through the oxadiazolium, shortening the syntheꢀ
sis by 1ꢀ2 steps depending on the aromatic substitution pattern.
quired storage under moisture free conditions, due to the aceꢀ
tate being labile to hydrolysis.
Scheme 5. Dihydrazide Synthesis Substrate Scope
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A series of novel dihydrazides of type 2 (Scheme 5) were
prepared through sequential treatment of a methyl coumalate
THF solution with the corresponding commercially available
hydrazide followed by CDI, in good to excellent yield (40ꢀ
89%). Initial addition to methyl coumalate was complete in
under two hours in all cases. After addition of CDI, cyclization
was complete in 3ꢀ8 h though the reactions were frequently
left overnight. The addition and cyclization reactions were
conducted at 0 ꢀ 5 °C to avoid the decarboxylation encounꢀ
tered previously at the zwitterion stage.
Scheme 4. Revised Synthetic route to the s-
[1,2,4]Triazolo[1,5-a]pyridine Ring Systema
2
Tetrafluoroborate and perchlorate quaternary salts of simple
1,3,4ꢀoxadiazoles were first described by Boyd34 in 1967 and
were noted to be very sensitive to nucleophilic attack, particuꢀ
larly by water. A diazapine synthesis utilizing an oxadiazoliꢀ
um perchlorate intermediate noted the strict requirement for
dry reaction conditions due to their reactivity with even poor
nucleophiles.35
1
3
aReagents and conditions: (i) THF, 0 – 5 °C, 15 – 60 min; (ii)
CDI, 12 h, rt; (iii) 70% HClO4, Ac2O, <35 °C; (iv) NH4OAc,
AcOH, 120 °C, 15ꢀ 90 min.
A selection of novel oxadiazolium perchlorate salts 3 were
prepared through the action of 1.5 ꢀ 5 eq. of aq 70% perchloric
acid on a slurry of the dihydrazides 2 in acetic anhydride
(Scheme 6). The rate of perchloric acid addition was such that
the temperature was not allowed to exceed 35 °C, the slurry
becoming a solution after addition of 1.5 eq. of acid. Salts 3
containing aromatic substituents showed particular stability to
water, in fact the isolation of the 2ꢀ aryl perchlorate salts could
be accomplished through slowly pouring the reaction mixture
into cold water (5 – 10 °C) and subsequent separation of the
perchlorate salts by filtration. Hydrolytic stability was investiꢀ
gated through exposure of 3d to 30 volumes of water at ambiꢀ
ent temperature for 5 days and resulted in no loss of salt poꢀ
tency. Isolated yields of the perchlorate salts were in the range
of 62 ꢀ 87% and were identified by the absence of the NꢀH
signal in their 1H NMR and the presence of their stable cations
observable by mass spectrometry. Analysis of the infrared
spectra showed C=N+ and C=N stretches at 1640 cm−1 and
1610 cm−1 and characteristic perchlorate stretches36 were obꢀ
served at 1090 cm−1. The intact structure of the perchlorate salt
After work up, if desired, dihydrazides 2 could be used crude
in the next synthetic step. Use of 1N HCl in the work up reꢀ
sulted in the removal of the major impurity from the crude
material, residual imidazole. Dihyrazides (2g, 2i - k) precipiꢀ
tated following cyclization with CDI, required no workꢀup,
and lead to increased isolated yields (55 ꢀ 89%). The reaction
also proceeds in EtOAc or CH3CN as reaction solvent and this
leads to more instances of product precipitation, though yields
are lower by 5ꢀ10%.
11
An impurity commonly observed by LCMS were the double
addition products 11, likely derived from an initial 1,2 addiꢀ
tion of A and B. These species were rejected in the workꢀup
and could be kept to a minimum through use of a slight excess
of methyl coumalate, utilized as a dilute solution when added
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was firmly established by Xꢀray crystallographic analysis, the
unit cell being composed of a 1:1 oxadiazolium:perchlorate
salt, no solvent or water detected in the crystal (Scheme 6,
3d).
Page 4 of 11
large quantities of ammonium, swamping the ability of the
sieves to store water.37 Addition of 2 ꢀ 4 eq. of acetic anhyꢀ
dride as a water scavenger achieved a substantial improvement
in product yield (~55% for 1a). Even without the addition of
acetic anhydride, isolated yield of 1g was near quantitative,
highest yields in the series observed when R1 was electron
rich.
1
2
3
4
5
6
Scheme
6.
Perchlorate
Salt
Substrate
Scope
7
8
9
Isolation of the triazole products 1a-l was relatively straightꢀ
forward, the presence of the ester greatly facilitated isolation
and purification relative their acid derivatives 10. Simple coolꢀ
ing of the reaction mixture postꢀreaction to 5 ꢀ 10 °C and addiꢀ
tion of cold water (2 – 5 °C) resulted in precipitation of the
desired products with complete rejection of impurities into the
mother liquor. Triazole 1m was triturated with cold MTBE to
isolate. Alkyl derivatives 1n and 1o were successfully syntheꢀ
sized, however attempts to isolate 1n were hampered by its
general instability. Reactions to produce 1o resulted in poor
yields, significant quantities of dihydrazide 2o present, even
with the addition of acetic anhydride.
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Scheme
7.
Synthetic
Strategy
Towards
s-
[1,2,4]Triazolo[1,5-a]pyridine Ring System
aAfter 36 h, not isolated
Oxadiazolium perchlorates, 3a-j, l appear to be the only exꢀ
amples of compounds of this type with this degree of water
stability under ambient conditions and affording them greater
synthetic utility than literature examples due to their relative
ease of use and stability. When R1 = benzyl or alkyl isolation
was achieved through trituration with cold MTBE, though
hydrolytic instability (2 ꢀ 5°C) was not observed. Difficulties
were encountered in the preparation of a 2ꢀpyridyl derivative
3k, low conversion (~10%) to the oxadiazolium was observed
by LCMS even after long reaction times (36 h). Evidence for
the formation of oꢀtolyl derivative 3h was obtained by LCMS
and HRMS, however all attempts at isolation were unsuccessꢀ
ful. Perchlorate 3n showed substantially less thermal stability
than other analogues in this series, decomposing above 100
°C.
The perchlorate salts, 3, were combined with ammonium aceꢀ
tate in hot acetic acid in a sealed reactor to yield the desired
products in moderate to excellent yields in 15 ꢀ 90 mins
(Scheme 7). Despite the aforementioned hydrolytic stability of
perchlorates, 3, under ambient conditions, cyclization of the
prepared oxadiazolium salts 3 to the bicyclic triazoles 1 was
sensitive to water due to the reaction temperatures involved
(120 °C). The presence of water in the reaction, through assoꢀ
ciation with reagents, moisture in the system, or, from the
resulting cyclization condensation, leads to a competing hyꢀ
drolysis returning oxadiazolium salts, 3, to the dihydrazides 2.
Use of molecular sieves gave minor improvements in yield,
water trapping possibly poor due to the presence of relatively
a Ac2O (3 eq) 130 °C.
3.0 CONCLUSIONS
In summary,
a cost effective synthesis of novel sꢀ
[1,2,4]triazolo[1,5ꢀa]pyridine 1 compounds has been accomꢀ
plished from methyl coumalate and commercially available
hydrazides in three linear steps by a chromatography free proꢀ
cess. Our new synthetic strategy using methyl coumalate as
the primary starting material provides a useful alternative to
literature methods and is particularly effective for the syntheꢀ
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sis of aryl substituted derivatives. The synthesis is metal free, allowed stir until LCMS/TLC analysis indicated the complete
1
2
3
4
5
6
7
8
shows good substrate scope and initial pyridine dihydrazide 2
generation removes the requirement for NꢀN bond formation
in the strategy. Additionally, the oxadiazolium perchlorate
salts generated in the course of the synthesis are unusually
water stable and may be stored for many months without any
sign of degradation.
consumption of the starting material. The reaction slowly beꢀ
came homogenous as the reaction progressed. When reaction
was complete, the solution was acidified to pH 4 with saturatꢀ
ed aqueous citric acid. A white precipitate formed which was
isolated by filtration and washed with water (2 x 5 ml)
Procedure for synthesis of oxadiazolium intermediate E (R =
4-F C6H4)
4.0 EXPERIMENTAL SECTION
General.
9
A solution of 9d (20 mg (0.07 mmol) and ammonium acetate
(27 mg, 0.35 mmol, 5 equiv.) in TFAꢀd1 (0.75 ml) was placed
in a 2 ml Hastelloy port connector reactor and placed inside a
modified GC oven. The reaction was heated at 200 °C for 2
hours, cooled to room temperature and the full contents of the
reactor analysed by NMR spectroscopy.
All reagents were reagent grade, obtained from commercial
suppliers and used without further purification. All solvents
were HPLC grade and used as supplied. Reaction monitoring
was accomplished by TLC or LCMS using an Agilent 6130
Quadropole LCMS fitted with photo diode array detection
and an XBridge C18 2.5 ꢀm, 1.0 x 75mm column at 30 °C.
TLC plates were visualized under UV light (254 nm). Flash
chromatography was carried out with silica gel 60 (230−400
ASTM mesh) on a Teledyne Isco CombiFlash Rf+ PurIon
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General Procedure for Products 2a-o
To a suspension of the appropriate hydrazide (16.4 mmol, 1.1
equiv) in THF (20 ml) at 0 °C under a nitrogen atmosphere
was added a solution of methylꢀ6ꢀoxopyranꢀ3ꢀcarboxylate (2.3
g, 15 mmol) in THF (20 ml) dropwise over 10 ꢀ30 mins. The
mixture was stirred until complete consumption of the methylꢀ
coumalate occurredꢀindicated by TLC or LCMS (15ꢀ60 mins).
1,1’ꢀcarbonyldiimidazole (21.3 mmol, 1.3 equiv) was added,
solution proceeding through a number of colour changes to
eventually yield a black solution which was slowly allowed
warm to room temperature overnight. The reaction mixture
was diluted with EtOAc (50 ml), transferred to a separator
funnel and washed with 1N HCl (2x 30 ml), water (40 ml),
brine (40 ml), dried with sodium sulphate and concentrated by
rotary evaporation to yield a brown solid. The products could
be forward processed in their crude form for use in the oxadiaꢀ
zolium synthesis. Isolated yields were determined on analytiꢀ
cally pure samples after, if required, the product was isolated
as a white solid by column chromatography, hexane:ethyl
acetate (40:60) as eluents.
1
with hexane:ethyl acetate as the solvent gradient system. H
and 13C NMR spectra were obtained on a Varian spectrometer
at 400 and 100 MHz respectively. Proton fine splitting reportꢀ
ed as follows: (s = singlet, d = doublet, t = triplet, q = quartet,
m = multiplet, br = broad), dd = doublet of doublets, dt = douꢀ
blet of triplets. Chemical shifts were referenced on residual
1
solvent peaks: CDCl3 (δ = 7.26 ppm for H NMR and 77.00
1
ppm for 13C NMR), DMSO (CD3)2SO (δ = 3.33 ppm for H
NMR and 39.51 ppm for 13C NMR). Structural assignment of
resonances have been performed with the help of 2D NMR
gradients experiments (COSY, multiplicity edited 1H−13C
1
1
HSQC, H−13C HMBC, and H−15N HMBC. Highꢀresolution
mass spectra were measured on Thermo Scientific LTQꢀ
Orbitrap Discovery with electrospray ionization mode (ESI+)
with mass accuracy greater than 2 ppm, applied mass range
from 75 to 1500 Da. IR spectra (4000−400 cm−1 ) were colꢀ
lected performed by ATRꢀFTIR (Attenuated Total Reflecꢀ
tance) on a Nicolet 6700 FTꢀIR with a Smart OMNI sampler
on neat solid samples. DSC was performed on a TA SA+ Disꢀ
covery series instrument running TRIOS Explorer software
(10 °C/min).
General Procedure for Products 3a-o
A suspension of dihydrazide (1a-o) (3 mmol) in acetic anhyꢀ
dride (6 ml) was cooled on an ice bath and purged with nitroꢀ
gen. 70% Perchloric acid solution (9 mmol, 1.5ꢀ5 equiv) was
added dropwise at such a rate that the temperature of the reacꢀ
tion mixture never exceeded 35 °C. Upon acid addition the
contents of the reaction pot slowly went into solution. After
complete acid addition the reaction was removed from the ice
bath and allowed stir for 1ꢀ2 hours until complete consumpꢀ
tion of the starting material was indicated by TLC or LCMS.
The reaction mixture (3a-j,l )was slowly poured into water (20
ml), the resulting crystals filtered and washed with water (2 x
5 ml). Compounds 3m-o were isolated by trituration with
MTBE (10 ml), filtration and washing with cold ether (5ml).
The solids were dried in a vacuum oven at 35 °C and used
without further purification.
General Procedures.
General Procedure for Products 6a,d and k
To a solution of methylꢀ6ꢀoxopyranꢀ3ꢀcarboxylate (6.79 g, 44
mmol) in THF (60 ml) at 0 °C under a nitrogen atmosphere
was added a solution of the appropriate imidohydrazide 7 (44
mmol) in THF (48 ml) via cannula over 5 mins. The mixture
was stirred until complete consumption of the methylꢀ
coumalate occurredꢀindicated by TLC or LCMS (<2h). 1,1’ꢀ
carbonyldiimidazole was added, solution proceeding through a
number of colour changes to eventually yield a black solution
which was slowly allowed warm to room temperature overꢀ
night. The reaction mixture was diluted with EtOAc (50 ml),
transferred to a separator funnel and washed with water (3 x
70 ml), brine (50 ml), dried with sodium sulphate and concenꢀ
trated by rotary evaporation to yield a brown solid which was
used without further purification in the production of 9.
General Procedure for Products 1a-o
A mixture of oxadiazolium perchlorate salt (1 mmol) (3a-o)
and ammonium acetate (3.5 ꢀ 5 equiv) was dissolved in acetic
acid (2.5 ml) in a 20 ml thick walled screwꢀcapped tube,
flushed with nitrogen and heated to 120 °C for 15ꢀ90 min. The
reaction was monitored by LCMS and deemed complete when
the dihydrazide 2 was consumed. The tube was cooled to room
General Procedure for Products 9a,d and k
To a suspension of 6 (3.6 mmol) in methanol (5 mL) was addꢀ
ed 4mL 1N aq NaOH (4 mmol, 1.1 equiv). The mixture was
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temperature and the contents slowly poured into 20 ml of waꢀ
ter (5 – 10 °C). The desired triazole was isolated as a solid by
filtration and the solids washed with water (2 x 10 ml). Where
noted, 2ꢀ4 eq. of acetic anhydride was also added to the reacꢀ
tion in order to suppress hydrolysis of 3 to 2.
NMR (100 MHz, DMSO) δC: 52.5, 56.5, 108.7, 112.8, 119.9,
1
2
3
4
5
6
7
8
120.3, 121.1, 131.5, 133.4, 139.2, 146.7, 158.1, 159.7 164.3,
164.9. m/z 303.1. HRMS (ESI) calcd for C15H15N2O5 [M+H+]
303.0975, found 303.0979.
Methyl
1-(3-methoxybenzamido)-6-oxo-1,6-
dihydropyridine-3-carboxylate (2f) White solid. Yield 2.2 g
(66%). m.p. (DSC) (10 °C/min) onset 186.65 °C, maximum
186.87 °C. IR (ATR) νmax 3234, 1720, 1670, 1661, 1597,
1527, 1490, 1444, 1304, 1293, 1275, 1233, 1120, 1035 cm−1.
1H NMR (400 MHz, DMSO) δH: 3.78 (s, 3H), 3.82, (s, 3H),
6.63, (d, J = 9.2 Hz, 1H), 7.20 (dd, J = 2.4, 5.6 Hz, 1H), 7.49
(m, 3H), 7.89 (dd, J = 2.4, 9.6 Hz, 1H), 8.48 (d, J = 2.4 Hz,
1H), 11.94 (br s, 1H). 13C NMR (100 MHz, DMSO) δC: 52.5,
55.8, 109.1, 113.3, 119.0, 120.2, 120.5, 130.0, 133.0, 139.5,
146.7, 159.7, 159.9, 164.2, 166.2. m/z 303.1. HRMS (ESI)
calcd for C15H15N2O5 [M+H+] 303.0975, found 303.0982.
Methyl
1-benzamido-6-oxo-1,6-dihydropyridine-3-
carboxylate (2a) White solid. Yield: 8.46 g (60%). m.p. (DSC)
(10 °C/min) onset 183.42 °C, maximum 183.86 °C. IR (ATR)
νmax 3259, 1720, 1687, 1668, 1604, 1528, 1492, 1447, 1314,
1293, 1266, 1120, 1108 cm−1.1H NMR (400 MHz, DMSO) δH:
3.79 (s, 3H), 6.63 (d, J = 9.6 Hz, 2H), 7.56 (m, 2H), 7.66, (m,
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1H), 7.93 (m, 3H), 8.48 (d, J = 2.4 Hz, 1H), 11.85 (s, 1H). 13
C
NMR (100 MHz, DMSO) δC: 52.5, 109.1, 120.2, 128.3, 129.1,
131.7, 133.1, 139.5, 146.7, 159.9, 164.3, 166.4. m/z 271.1.
HRMS (ESI) calcd for C14H13N2O4 [M+H+] 273.0870, found
273.0871.
Methyl
1-(4-methoxybenzamido)-6-oxo-1,6-
Methyl 1-(2-fluorobenzamido)-6-oxo-1,6-dihydropyridine-3-
carboxylate (2b) White solid. Yield 1.30 g (68%). m.p. (DSC)
(10 °C/min) onset 129.41 °C, maximum 132.10 °C. IR (ATR)
νmax 3177, 1719, 1660, 1614, 1541, 1447, 1316, 1279, 1260,
dihydropyridine-3-carboxylate (2g) Isolated by filtration, no
workꢀup. White solid. Yield 4.0 g (89%). m.p. (DSC) (10
°C/min) onset 193.02 °C, maximum 193.72 °C. IR (ATR) νmax
3219, 1722, 1679, 1659, 1606, 1535, 1507, 1445, 1312, 1295,
1
1122, cm−1. H NMR (400 MHz, DMSO) δH: 3.79 (s, 3H),
1
1271, 1253, 1196, 1128, 1105, 1025 cm−1. H NMR (400
6.64 (d, J = 10 Hz, 1H), 7.37 (m, 2H), 7.64 (m, 1H), 7.87 (m,
2H), 8.49 (d, J = 2.4 Hz, 1H), 11.71 (brs, 1H). 19F δF: ꢀ112.1.
13C NMR (100 MHz, DMSO) δC: 52.5, 109.1, 116.9 (d, J = 21
Hz), 120.3, 120.9 (d, J = 14 Hz) 125.1, 131.1, 134.5 (d, J = 7.2
Hz), 139.5, 146.5, 159.7, 160.1 (d, J = 252 Hz), 163.7, 164.2.
m/z 291.1. HRMS (ESI) calcd for C14H12N2O4F [M+H+]
291.0776, found 291.0779.
MHz, DMSO) δH: 3.78 (s, 3H), 3.84 (s, 3H), 6.62 (d, J = 9.6
Hz, 1H), 7.09 (d, J = 9.6 Hz, 2H), 7.90 (m, 3H), 7.43 (d, J =
2.4 Hz, 1H), 11.69 (s, 1H). 13C NMR (100 MHz, DMSO) δC:
52.5, 56.0, 109.0, 114.4, 120.2, 123.7, 130.3, 139.4, 146.9,
160.1, 163.1, 164.3, 166.0. m/z 303.1. HRMS (ESI) calcd for
C15H15N2O5 [M+H+] 303.0975, found 303.0982
Methyl 1-(2-methylbenzamido)-6-oxo-1,6-dihydropyridine-
3-carboxylate (2h) White solid. Yield 2.30 g (65%). m.p.
(DSC) (10 °C/min) onset 166.41 °C, maximum 169.01 °C. IR
(ATR) νmax 3209, 1724, 1684, 1663, 1603, 1544, 1513, 1444,
Methyl 1-(3-fluorobenzamido)-6-oxo-1,6-dihydropyridine-3-
carboxylate (2c) White solid Yield 1.27 g (63%). m.p. (DSC)
(10 °C/min) onset 188.85 °C, maximum 190.27 °C. IR (ATR)
νmax 3186, 1723, 1696, 1658, 1608, 1591, 1445, 1311, 1283,
1263, 1208, 1124 cm−1. 1H NMR (400 MHz, DMSO) δH: 3.79
(s, 3H), 6.64 (d, J = 9.6 Hz, 1H), 7.51 (td, J = 6.4 Hz, 2.4 Hz,
1H), 7.62 (q, J = 8 Hz, 1H), 7.73 (d, J = 9.6 Hz, 1H), 7.79 (d, J
= 6.8 Hz, 1H), 7.89, (dd, J = 7.2, 2.4 Hz, 1H), 8.52 (d , J= 2.4
Hz, 1H), 11.98 (br s, 1H). 19F δF: ꢀ112.1; 13C NMR (100 MHz,
DMSO) δC: 52.5, 109.2, 115.1 (d, J = 24 Hz), 120.1 (d, J = 21
Hz), 120.3, 124.5 (d, J= 3 Hz), 131.4 (d, J = 8 Hz), 134.0 (d, J
= 8 Hz, 139.5, 146.6 , 159.8, 162.5 (d, J = 245 Hz), 164.2,
165.2 (d, J= 3 Hz); m/z 291.1; HRMS (ESI) calcd for
C14H12N2O4F [M+H+] 291.0776, found 291.0779
1
1311, 1286, 1259, 1121, 1101 cm−1. H NMR (400 MHz,
DMSO) δH: 2.41 (s, 3H), 3.80 (s, 3H), 6.62 (d, J = 9.6 Hz,
1H), 7.31 (m, 2H), 7.44 (m, 1H), 7.65 (m, 1H), 7.88 (dd, J =
9.2, 2.4 Hz, 1H), 8.52 (d, J= 2.4 Hz, 1H), 11.60 (br s, 1H). 13C
NMR (100 MHz, DMSO) δC: 19.7, 52.5, 109.0, 120.3, 126.0,
128.4, 131.1, 131.2, 133.5, 136.9, 139.5, 146.7, 159.8, 164.3,
168.7; m/z 287.1; HRMS (ESI) calcd for C15H15N2O4 [M+H+]
287.1026, found 287.1032
Methyl 1-(3-methylbenzamido)-6-oxo-1,6-dihydropyridine-
3-carboxylate (2i) White solid. Isolated by filtration, no workꢀ
up. Yield 3.30 g (85%). m.p. (DSC) (10 °C/min) onset 175.59
°C, maximum 177.84 °C. IR (ATR) νmax 3176, 1724, 1702,
1660, 1607, 1533, 1443, 1311, 1268, 1125, 1106, 1069 cm−1.
1H NMR (400 MHz, DMSO) δH: 2.38 (s, 3H), 3.78 (s, 3H),
6.63 (d, J = 9.6 Hz, 1H), 7.45 (m, 2H), 7.75 (m, 2H), 7.88 (dd,
J = 2.4, 9.2 Hz, 1H), 8.46 (d, J = 2.4 Hz, 1H), 11.80 (br s, 1H).
13C NMR (100 MHz, DMSO) δC: 21.3, 52.5, 109.1, 120.2,
125.4, 128.8, 129.0, 131.7, 133.7, 138.5, 139.4, 146.7, 159.92,
164.2, 166.6. m/z 287.1. HRMS (ESI) calcd for C15H15N2O4
[M+H+] 287.1026, found 287.1031.
Methyl 1-(4-fluorobenzamido)-6-oxo-1,6-dihydropyridine-3-
carboxylate (2d) White solid. Yield 0.95 g (66%). m.p. (DSC)
(10 °C/min) onset 260.04 °C, maximum 260.31 °C. IR (ATR)
ν
max 3242, 1718, 1680, 1660, 1603, 1535, 1502, 1446, 1294,
1263, 1223, 1129, 1114 cm−1. H NMR (400 MHz, DMSO)
δH: 3.79 (s, 3H), 6.65 (d, J = 9.6 Hz, 1H), 7.41 (t, J = 8.8 Hz,
2H), 7.90 (dd, J = 2.4, 9.6 Hz, 1H), 8.02 (m, 2H), 8.50 (d, J =
2.4 Hz, 1H). 19F δF: ꢀ106.8. 13C NMR (100 MHz, DMSO) δC:
52.5, 109.1, 116.2 (d, J = 24 Hz), 120.2, 128.3, 131.1, 131.2,
139.5, 146.7, 160.0, 164.2, 165.5; m/z 291.1; HRMS (ESI)
calcd for C14H12N2O4F[M+H+] 291.0776, found 291.0782.
1
Methyl 1-(4-methylbenzamido)-6-oxo-1,6-dihydropyridine-
3-carboxylate (2j) White solid. Isolated by filtration, no workꢀ
up. Yield 5.15 g (87%). m.p. (DSC) (10 °C/min) onset 192.50
°C, maximum 193.74 °C. IR (ATR) νmax 3210, 1701, 1663,
Methyl
1-(2-methoxybenzamido)-6-oxo-1,6-
dihydropyridine-3-carboxylate (2e) White solid. Yield 2.5 g
(75%). m.p. (DSC) (10 °C/min) onset 130.24 °C, maximum
139.42 °C. IR (ATR) νmax 3278, 1710, 1697, 1675, 1602,
1500, 1477, 1452, 1317, 1301, 1275, 1117, 1104, 1015 cm−1.
1H NMR (400 MHz, DMSO) δH: 3.78 (s, 3H), 3.92 (s, 3H) ,
6.61, (d, J = 10 Hz, 1H), 7.08 (m, 1H), 7.30 (m, 1H), 7.59 (m,
1H), 7.87 (m, 2H), 8.35 (d, J = 2.4 Hz, 1H), 11.16 (s, 1H). 13C
1
1610, 1531, 1503, 1445, 1315, 1288, 1270, 1122 cm−1. H
NMR (400 MHz, DMSO) δH: 2.38 (s, 3H), 3.78 (s, 3H), 6.63
(d, J = 9.6 Hz, 1H), 7.35 (d, J = 8 Hz, 2H), 7.85 (m, 3H), 8.45
(d, J = 2 Hz, 1H), 11.77 (br s, 1H). 13C NMR (100 MHz,
DMSO) δC: 21.5, 52.5, 109.1, 120.2, 128.3, 129.6, 139.4,
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The Journal of Organic Chemistry
1
143.3, 146.8, 159.9, 164.25, 166.35. m/z 287.1. HRMS (ESI)
calcd for C15H15N2O4 [M+H+] 287.1026, found 287.1031.
Methyl 6-oxo-1-(picolinamido)-1,6-dihydropyridine-3-
1452, 1437, 1302, 1286, 1209, 1089 cm−1. H NMR (400
MHz, DMSO) δH: 4.01 (s, 3H), 7.81 (m, 2H), 7.93, (m, 1H),
8.28 (d, J = 7.6 Hz, 2H), 8.83 (d, J = 9.2 Hz), 9.12 (d, J = 9.2
Hz, 1H), 10.35 (s, 1H). 13C NMR (100 MHz, DMSO δC: 54.2,
112.0, 120.1, 126.3, 128.9, 130.8, 135.7, 136.3, 144.7, 155.2,
162.4, 166.0. m/z 255.1. HRMS (ESI) calcd for C14H11N2O3
[M+] 255.0764, found 255.0766.
1
2
3
4
5
6
7
8
carboxylate (2k) White solid. Isolated by filtration, no workꢀ
up. Yield 3.4 g (87%). m.p. (DSC) (10 °C/min) onset 222.11
°C, maximum 222.76 °C. IR (ATR) νmax 3301, 1727, 1712,
1682, 1543, 1483, 1443, 1317, 1295, 1281, 1103, 999 cm−1. 1H
NMR (400 MHz, DMSO) δH: 3.78 (s, 3H), 6.61 (d, J = 9.6 Hz,
1H), 7.72 (m, 1H), 7.87 (dd, J = 9.6 Hz, 2.8 Hz, 1H), 8.07 (m,
2H), 8.41 (d, J = 2.4 Hz, 1H), 8.74 (d, J = 4.4 Hz, 1H), 11.95
(br s, 1H). 13C NMR (100 MHz, DMSO) δC: 52.5, 109.0,
120.3, 123.3, 128.2, 138.5, 139.3, 146.7, 148.4, 149.3, 159.6,
163.8, 164.2. m/z 275.1. HRMS (ESI) calcd for C13H12N3O4
[M+H+] 274.0822, found 274.0828
Methyl
2-(2-fluorophenyl)-4λ4-[1,3,4]oxadiazolo[3,2-
a]pyridine-6-carboxylate perchlorate (3b) Offꢀwhite solid.
Yield 0.95 g (62%). m.p. (DSC) (10 °C/min) 205 °C (decomꢀ
poses). IR (ATR) νmax 3088, 1744, 1641, 1625, 1597, 1484,
1462, 1308, 1290, 1089cm−1. 1H NMR (400 MHz, DMSO) δH:
4.02 (s, 3H), 7.66 (t, J = 8 Hz, 1H), 7.72 (t, J = 10.8 Hz, 1H),
8.00 (q, J = 6 Hz, 1H), 8.30 (t, J = 7.6 Hz, 1H), 8.88 (d, J = 9.2
Hz, 1H), 9.15 (d, J = 9 Hz, 1H). 19F δF: ꢀ106.6. 13C NMR (100
MHz, DMSO δC: 54.2, 108.8 (d, J = 11 Hz), 112.0, 118.4 (d, J
= 20 Hz), 126.4, 126.8 (d, J = 3 Hz), 131.2, 135.8, 138.8 (d, J
= 2 Hz) 145.1, 154.7, 161.0 d, J = 261 Hz), 162.4, 162.8 (d, J=
6 Hz). m/z 273.1. HRMS (ESI) calcd for C14H10N2O3F [M+]
273.0670, found 273.0673.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Methyl
6-oxo-1-(thiophene-2-
carboxamido)-1,
6-
dihydropyridine-3-carboxylate (2l) White solid. Yield 1.69 g
(55%). m.p. (DSC) (10 °C/min) onset 239.60 °C, maximum
239.88 °C. IR (ATR) νmax 3226, 3096, 1715, 1660, 1610,
1536, 1512, 1443, 1419, 1357, 1314, 1272, 1121, 882, 859
cm−1. 1H NMR (400 MHz, DMSO) δH: 3.78 (s, 3H), 6.63 (d, J
= 10 Hz, 1H), 7.26, (t, J = 4 Hz, 1H), 7.89 (m, 1H), 7.95 (m,
2H), 8.46 (d, J = 2Hz, 1H), 11.91 (br s, 1H). 13C NMR (100
MHz, DMSO). δC: 52.5, 109.2, 120.2, 128.8, 131.0, 133.5,
135.9, 139.6, 146.7, 159.9, 161.4, 164.2. m/z 279.0. HRMS
(ESI) calcd for C12H11N2O4S [M+H+] 279.0434, found
274.0439.
Methyl
2-(3-fluorophenyl)-4λ4-[1,3,4]oxadiazolo[3,2-
a]pyridine-6-carboxylate perchlorate (3c) Offꢀwhite solid.
Yield 0.65 g (83%). m.p. (DSC) (10 °C/min) onset 257.26 °C,
maximum 258.12 °C. IR (ATR) νmax 3091, 1733, 1646, 1438,
1288, 1255, 1092cm−1. H NMR (400 MHz, DMSO) δH: 4.01
1
(s, 3H), 7.86 (m, 2H), 8.15 (m, 2H), 8.84 (d, J = 9.2 Hz, 1H),
9.15 (m, 1H), 10.38 (s, 1H). 19F δF: ꢀ109.5. 13C NMR (100
MHz, DMSO) δC: 54.2, 112.1, 115.5 (d, J = 24 Hz), 122.0 (d,
J= 3 Hz), 123.4 (d, J = 26 Hz), 125.4, 126.5, 133.5 (d, J =
8Hz), 135.8, 145.8, 155.1, 162.4, 162.7 (d, J = 248 Hz), 165.0.
m/z 273.1. HRMS (ESI) calcd for C14H10N2O3F [M+]
273.0670, found 273.0675.
Methyl 6-oxo-1-(2-phenylacetamido)-1,6-dihydropyridine-
3-carboxylate (2m) White solid. Yield 6.64 g (69%). m.p.
(DSC) (10 °C/min) onset 107.26 °C, maximum 109.70 °C. IR
(ATR) νmax 3147, 2949, 1720, 1663, 1604, 1540, 1513, 1495,
1
1443, 1309, 1278, 1134, 1112, 1097 cm−1. H NMR (400
MHz, CDCl3) δH: 3.67 (s, 2H), 3.76 (s, 3H), 6.58 (d, J = 10
Hz, 1H), 7.33 (m, 5H), 7.85 (m, 1H), 8.25 (d, J = 2.4 Hz, 1H),
11.59 (s, 1H). 13C NMR (100 MHz, DMSO). δC: 39.3, 52.5,
108.9, 120.2, 127.2, 128.8, 129.7, 135.1, 139.3, 146.3, 159.7,
164.2, 170.5. m/z 287.1. HRMS (ESI) calcd for C15H15N2O4
[M+H+] 287.1026, found 287.1032.
Methyl
2-(4-fluorophenyl)-4λ4-[1,3,4]oxadiazolo[3,2-
a]pyridine-6-carboxylate perchlorate (3d) White solid. Yield
0.56 g (87%). m.p. (DSC) (10 °C/min) onset 250.22 °C, maxꢀ
imum 251.49 °C. IR (ATR) νmax 3100, 1733, 1647, 1615,
1503, 1433, 1301, 1240, 1087cm−1. 1H NMR (400 MHz,
DMSO) δH: 4.01 (s, 3H), 7.67 (t, J = 8.8 Hz, 2H), 8.37 (dd, J =
5.5, 8.4 Hz, 2H), 8.82 (d, J = 9.2 Hz, 1H), 9.12 (m, 1H), 10.35
(s, 1H). 19F δF: ꢀ100.7. 13C NMR (100 MHz, DMSO) δC: 54.2,
112.0, 116.8, 118.4 (d, J = 22 Hz), 119.7, 126.3, 132.1 (d, J =
8 Hz), 135.7, 144.8, 155.1, 162.4, 165.2. m/z 273.1. HRMS
(ESI) calcd for C14H10N2O3F[M+] 273.0670, found 273.0675.
Methyl
1-acetamido-6-oxo-1,6-dihydropyridine-3-
carboxylate (2n) White solid. Yield 6.64 g (69%). m.p. (DSC)
(10 °C/min) 133 °C (decomposes). IR (ATR) νmax 3210, 3031,
1726, 1672, 1612, 1540, 1450, 1375, 1313, 1289, 1261, 1117,
1098 cm−1. 1H NMR (400 MHz, CDCl3) δH: 2.20 (s, 3H), 3.85
(s, 3H), 6.64 (d, J = 9.6 Hz, 1H), 7.95 (dd, J = 2.8, 9.2 Hz),
8.22 (d, J = 2.0 Hz, 1H), 10.12 (s, 1H). 13C NMR (100 MHz,
DMSO). δC: 20.9, 52.3, 110.5, 119.6, 140.0, 144.5, 160.6,
163.9, 170.2. m/z 211.1; HRMS (ESI) calcd for C9H11N2O4
[M+H+] 211.0713, found 211.0718.
Methyl
2-(2-methoxyphenyl)-4λ4-[1,3,4]oxadiazolo[3,2-
a]pyridine-6-carboxylate perchlorate (3e) White solid. Yield
1.01 g (79%). m.p. (DSC) (10 °C/min) onset 238.78 °C, maxꢀ
imum 242.63 °C. IR (ATR) νmax 3078, 1733, 1642, 1608,
1556, 1510, 1495, 1452, 1305, 1287, 1130, 1077, 1053, 1038
Methyl
6-oxo-1-pivalamido-1,6-dihydropyridine-3-
cm−1. H NMR (400 MHz, DMSO) δH: 4.01 (s, 3H), 4.06 (s,
1
carboxylate (2o) White solid. Yield 4.58 g (61%). m.p. (DSC)
(10 °C/min) onset 159.47 °C, maximum 159.60 °C. IR (ATR)
νmax 3270, 1719, 1669, 1536, 1497, 1443, 1309, 1284, 1225,
3H), 7.33, (t, J = 7.6 Hz, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.88 (t,
J = 7.2 Hz, 1H), 8.15 (m, 1H), 8.79 (d, J = 9.2 Hz, 1H), 9.08
(m, 1H), 10.33 (s, 1H). 13C NMR (100 MHz, DMSO) δC:
54.1, 57.1, 108.4, 111.8, 114.1, 122.0, 126.0, 131.6, 135.6,
138.0, 144.2, 154.6, 159.8, 162.5, 164.6. m/z 285.1. HRMS
(ESI) calcd for C15H13N2O4 [M+] 285.0870, found 285.0873
1
1139, 1113, 915 cm−1. H NMR (400 MHz, DMSO) δH: 1.21
(s, 9H), 3.77 (s, 3H), 6.56 (d, J = 9.6 Hz, 1H), 7.83 (m, 1H),
8.21 (d, J = 2 Hz, 1H), 10.90 (br s, 1H). 13C NMR (100 MHz,
DMSO) δC: 27.3, 38.4, 52.5, 108.8, 120.2, 139.3, 146.8, 159.8,
164.3, 177.7. ; m/z 253.1; HRMS (ESI) calcd for C12H17N2O4
[M+H+] 253.1183, found 253.1187.
Methyl 2-phenyl-4λ4-[1,3,4]oxadiazolo[3,2-a]pyridine-6-
carboxylate perchlorate (3a) Offꢀwhite solid. Yield 1.53 g
(68%). m.p. (DSC) (10 °C/min) onset 265.21 °C, maximum
267.87 °C. IR (ATR) νmax 3112, 1729, 1646, 1610, 1567,
Methyl
2-(3-methoxyphenyl)-4λ4-[1,3,4]oxadiazolo[3,2-
a]pyridine-6-carboxylate perchlorate (3f) White solid. Yield
1.01 g (79%). m.p. (DSC) (10 °C/min) onset 211.73 °C, maxꢀ
imum 217.20 °C. IR (ATR) νmax 3103, 1744, 1641, 1617,
1568, 1483, 1461, 1440, 1299, 1289, 1260, 1087, 1027 cm−1.
1H NMR (400 MHz, DMSO) δH: 3.92 (s, 3H), 4.01, (s, 3H),
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7.50, (dd, J = 8.4 Hz, 2.0 Hz, 1H), 7.70 (t, J = 2.4 Hz, 1H),
162.5, 169.7. m/z 269.1. HRMS (ESI) calcd for C15H13N2O3
[M+] 269.0921, found 269.0924
1
2
3
4
5
6
7
8
7.74 (t, J = 8.0 Hz, 1H), 7.88 (d, J = 8.4 Hz, 1H), 8.80 (d, J =
9.2 Hz, 1H), 9.12 (dd, J = 9.2 Hz, 1.2 Hz, 1H), 10.33 (1H, d, J
= 1.2 Hz). 13C NMR (100 MHz, DMSO) δC: 54.2, 56.3, 109.1,
112.1, 113.1, 121.2, 122.4, 126.3, 132.3, 135.7, 144.8, 155.2,
160.5, 162.4, 165.8. m/z 285.1. HRMS (ESI) calcd for
C15H13N2O4 [M+] 285.0870, found 285.0874
6-(methoxycarbonyl)-2-methyl-[1,3,4]oxadiazolo[3,2-
a]pyridin-4-ium perchlorate (3n) Orange waxy solid. Yield
0.45 g (64%) m.p. (DSC) (10 °C/min) 104 °C (decomposes).
IR (ATR) νmax 3161, 1723, 1647, 1619, 1587, 1439, 1315,
1
1208, 1084 cm−1. H NMR (400 MHz, DMSO) 2.94 (s, 3H),
Methyl
2-(4-methoxyphenyl)-4λ4-[1,3,4]oxadiazolo[3,2-
3.99 (s, 3H), 8.74 (d, J = 9.2 Hz, 1H), 9.06 (d, J = 9.2 Hz, 1H),
10.21 (s, 1H).13C NMR (100 MHz, DMSO) δC: 11.9, 54.1,
111.8, 125.9, 135.5, 144.4, 155.2, 162.5, 168.8. m/z 193.1.
HRMS (ESI) calcd for C9H9N2O3 [M+] 193.0608, found
193.0612
a]pyridine-6-carboxylate perchlorate (3g) White solid. Yield
1.1 g (70%). m.p. (DSC) (10 °C/min) onset 244.17 °C, maxiꢀ
mum 245.03 °C. IR (ATR) νmax 3102, 1738, 1645, 1601, 1505,
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
1322, 1294, 1271, 1093, 1009 cm−1. H NMR (400 MHz,
DMSO) δH: 3.94 (s, 3H), 4.00 (s, 3H), 7.33 (d, J = 9.0 Hz,
2H), 8.23 (d, J = 9.2 Hz, 2H), 8.76 (d, J = 9.2 Hz, 1H), 9.06 (d,
J = 9.2 Hz, 1H), 10.27 (s, 1H). 13C NMR (100 MHz, DMSO)
δC: 54.1, 56.5, 111.8, 116.4, 126.0, 131.2, 135.4, 139.4, 144.1,
155.1, 162.5, 165.5, 165.9. m/z 285.1. HRMS (ESI) calcd for
C15H13N2O4 [M+] 285.0870, found 285.0873
Methyl 2-(m-tolyl)-4λ4-[1,3,4]oxadiazolo[3,2-a]pyridine-6-
carboxylate perchlorate (3i) White solid. Yield 0.83 g (64%).
m.p. (DSC) (10 °C/min) onset 220.15 °C, maximum 221.48
°C. IR (ATR) νmax 3090, 1746, 1645, 1611, 1565, 1611, 1565,
1480, 1431, 1302, 1197, 1088cm−1. 1H NMR (400 MHz,
DMSO) δH: 2.49 (s, 3H), 4.01 (s, 3H), 7.71 (m, 2H), 8.09 (m,
2H), 8.81 (d, J = 9.6 Hz, 1H), 9.11 (dd, J = 1.1, 9.2 Hz, 1H),
10.33 (s, 1H). 13C NMR (100 MHz, DMSO) δC: 21.2, 54.2,
112.0, 120.1, 126.2, 126.2, 128.9, 130.7, 135.7, 137.0, 140.6,
144.6, 155.2, 162.4, 166.0. m/z 269.1. HRMS (ESI) calcd for
C15H13N2O3 [M+] 269.0921, found 269.0924
2-(Tert-butyl)-6-(methoxycarbonyl)-[1,3,4]oxadiazolo[3,2-
a]pyridin-4-ium (3o) White solid. Yield 0.39 g (67%). m.p.
(DSC) (10 °C/min) onset 144.76 °C, maximum 148.46 °C. IR
(ATR) νmax 3083, 2980, 1729, 1647, 1602, 1515, 1458, 1440,
1
1366, 1320, 1310, 1206, 1175, 1123, 1087 cm−1. H NMR
(400 MHz, DMSO) δH: 1.53 (s, 9H), 3.99 (s, 3H), 8.73 (d, J =
9.2 Hz, 1H), 9.06 (d, J = 9.2 Hz, 1H), 10.26 (s, 1H). 13C NMR
(100 MHz, DMSO) δC: 27.4, 33.5, 54.1, 112.1, 125.9, 135.6,
144.4, 155.5, 162.5, 176.1. m/z 235.1. HRMS (ESI) calcd for
C12H15N2O3 [M+] 235.1077, found 235.1080
Methyl
2-phenyl-[1,2,4]triazolo[1,5-a]pyridine-6-
carboxylate (1a) White solid. Yield 0.05 g (28%). With 3 eq.
acetic anhydride, 130 °C, Yield 0.12 g (84%). m.p. (DSC) (10
°C/min) onset 149.27 °C, maximum 150.01 °C. IR (ATR) νmax
2953, 1724, 1638, 1450, 1438, 1319, 1334, 1307, 1297, 1201,
1
1135 cm−1. H NMR (400 MHz, DMSO) δH: 3.90 (s, 3H),
7.54 (m, 3H), 7.92 (d, J = 9.2 Hz, 1H), 8.04 (d, J = 9.2 Hz,
1H), 8.21 (m, 2H), 9.46 (s, 1H). 13C NMR (100 MHz,
DMSO) δC: 53.1, 116.1, 117.9, 127.5, 129.5, 130.1, 130.4,
131.1, 132.5, 152.9, 164.6, 165.3. m/z 254.1. HRMS (ESI)
calcd for C14H12N3O2 [M+H+] 254.0924, found 254.0926
Methyl 2-(p-tolyl)-4λ4-[1,3,4]oxadiazolo[3,2-a]pyridine-6-
carboxylate perchlorate (3j) White solid. Yield 0.80 g (80%).
m.p. (DSC) (10 °C/min) onset 233.77 °C, maximum 235.82
°C. IR (ATR) νmax 3095, 1730, 1644, 1613, 1563, 1505, 1434,
1
1304, 1290, 1188, 1092 cm−1. H NMR (400 MHz, DMSO)
Methyl 2-(2-fluorophenyl)-[1,2,4]triazolo[1,5-a]pyridine-6-
carboxylate (1b) White solid. Yield 0.28 g (53%). m.p. (DSC)
(10 °C/min) onset 157.72 °C, maximum 158.80 °C. IR (ATR)
νmax 2955, 1719, 1639, 1617, 1587, 1512, 1474, 1448, 1439,
δH: 2.49 (s, 3H), 4.01 (s, 3H), 7.61 (d, J = 8 Hz, 2H), 8.09 (d, J
= 8 Hz, 2H), 8.78 (d, J = 9.2 Hz, 1H), 9.09 (dd, J = 8 Hz, 1.2
Hz, 1H), 10.30 (s, 1H). 13C NMR (100 MHz, DMSO) δC: 22.0,
54.2, 111.9, 117.2, 126.1, 128.9, 131.4, 135.6, 144.4, 147.4,
155.1, 162.5, 166.2. m/z 269.1; HRMS (ESI) calcd for
C15H13N2O3 [M+] 269.0921, found 269.0924
1
1321, 1305, 1289, 1197, 1140, 1128 cm−1. H NMR (400
MHz, DMSO) δH: 3.91 (s, 3H), 7.39 (q, J = 6.8 Hz, 2H), 7.59
(m, 1H), 7.64 (d, J = 9.6 Hz, 1H), 8.06 (d, J = 9.2 Hz, 1H),
8.19 (t, J = 7.6 Hz, 1H), 9.51 (br s, 1H). 19F δF: ꢀ111.1. 13C
NMR (100 MHz, DMSO) δC: 53.2, 116.2, 117.3 (d, J = 19
Hz), 118.1, 118.4 (d, J = 9 Hz) 125.3, 130.2, 131.3 (d, J = 3
Hz), 132.5, 133.0 (d, J = 9.5 Hz), 152.2, 160.5 (d, J = 256
Hz), 162.0, 164.6. m/z 272.1. HRMS (ESI) calcd for
C14H11N3O2F[M+H+] 272.0830, found 272.0833
Methyl
2-(thiophen-2-yl)-4λ4-[1,3,4]oxadiazolo[3,2-
a]pyridine-6-carboxylate perchlorate (3l) White solid. Yield
0.53 g (82%). m.p. (DSC) (10 °C/min) onset 200.90 °C, maxꢀ
imum 204.20 °C. IR (ATR) νmax 3093, 1727, 1644, 1608,
1
1580, 1439, 1320, 1300, 1133, 1092, 1078, 1065 cm−1. H
NMR (400 MHz, DMSO) δH: 3.99 (s, 3H), 7.52, (t, J = 8 Hz,
1H), 8.37 (d, J = 3.6 Hz, 1H,), 8.40 (d, J = 4.8 Hz, 1H), 8.78
(d, J = 9.2 Hz, 1H), 9.09 (dd, J = 9.2, 1.2 Hz, 1H), 10.29 (s,
1H). 13C NMR (100 MHz, DMSO) δC: 54.2, 111.8, 120.5,
126.2, 130.8, 135.5, 136.9, 138.8, 144.5, 154.8, 162.2, 162.4.
m/z 261.0. HRMS (ESI) calcd for C12H9N2O3S [M+] 261.0328,
found 261.0333
Methyl 2-(3-fluorophenyl)-[1,2,4]triazolo[1,5-a]pyridine-6-
carboxylate (1c) White solid. Yield 0.29 g (55%). m.p. (DSC)
(10 °C/min) onset 150.20 °C, maximum 154.78 °C. IR (ATR)
νmax 2959, 1723, 1638, 1590, 1512, 1434, 1322, 1296, 1217,
1103 cm−1. 1H NMR (400 MHz, DMSO) δH: 3.90 (s, 3H), 7.39
(m, 2H), 7.59 (m, 1H), 7.95 (d, J = 9.4 Hz, 1H), 8.06 (d, J =
9.4 Hz, 1H), 8.19 (t, J = 7.2 Hz, 1H), 9.51 (s, 1H). 19F δF: ꢀ
112.3. 13C NMR (100 MHz, DMSO) δC: 53.2, 113.9 (d, J = 27
Hz), 116.3, 117.9 (d, J = 22 Hz), 118.2, 123.6 (d, J = 3 Hz),
130.3, 131.8 d, J = 9 Hz), 132.5, 132.8, 152.9, 161.6, 164.1,
164.6. m/z 272.1. HRMS (ESI) calcd for C14H11N3O2F[M+H+]
272.0830, found 272.0832
Methyl
2-(4-methylbenzyl)-4λ4-[1,3,4]oxadiazolo[3,2-
a]pyridine-6-carboxylate perchlorate (3m) White solid. Yield
0.35 g (74%). m.p. (DSC) (10 °C/min) onset 178.78 °C, maxꢀ
imum 180.26 °C. IR (ATR) νmax 3083, 2954, 1743, 1636,
1604, 1598, 1495, 1456, 1402, 1324, 1304, 1169, 1084 cm−1.
1H NMR (400 MHz, DMSO) 3.98 (s, 3H), 4.75 (s, 2H), 7.33ꢀ
52 (m, 5H), 8.74 (d, J = 9.2 Hz, 1H), 9.06 (d, J = 9.2 Hz, 1H),
10.25 (s, 1H).13C NMR (100 MHz, DMSO) δC: 31.5, 54.1,
112.0, 125.9, 128.5, 129.4, 130.2, 131.9, 135.7, 144.6, 155.3,
Methyl 2-(4-fluorophenyl)-[1,2,4]triazolo[1,5-a]pyridine-6-
carboxylate (1d) White solid. Yield 0.25 g (43%). m.p. (DSC)
(10 °C/min) onset 152.21 °C, maximum 154.16 °C. IR (ATR)
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13C NMR (100 MHz, DMSO) δC: 21.5, 52.7, 115.4, 117.5,
127.3, 127.4, 129.45, 129.5, 131.6, 140.9, 152.8, 164.5, 166.2.
m/z 268.1.1. HRMS (ESI) calcd for C15H14N3O2 [M+H+]
268.1081, found 268.1085
νmax 2959, 1730, 1641, 1609, 1529, 1457, 1440, 1323, 1300,
1
1261, 1198, 1156, 1139 cm−1. H NMR (400 MHz, DMSO)
1
2
3
4
5
6
7
8
δH: 3.90 (s, 3H), 7.38 (t, J = 8.8 Hz, 2H), 7.91 (d, J = 9.2 Hz,
1H), 8.04 (m, 1H), 8.23 (m, 2H), 9.45 (s, 1H). 19F δF: ꢀ110.1.
13C NMR (100 MHz, DMSO) δC: 53.1, 116.1, 116.5 (d, J = 21
Hz), 118.0, 127.0 (d, J = 3 Hz) 129.8 (d, J = 10 Hz), 130.2,
132.5, 152.9, 164.0 (d, J = 249 Hz), 164.5, 164.6. m/z 272.1.
HRMS (ESI) calcd for C14H11N3O2F [M+H+] 272.0830, found
272.0835
Methyl 2-(thiophen-2-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-
carboxylate (1l) White solid. Yield 0.16 g (30%). m.p. (DSC)
(10 °C/min) onset 174.28 °C, maximum 174.87 °C. IR (ATR)
νmax 3082, 2951, 1710, 1639, 1566, 1509, 1473, 1441, 1393,
1
1356, 1324, 1308, 1291, 1224, 1204, 1140, 1106 cm−1. H
Methyl 2-(2-methoxyphenyl)-[1,2,4]triazolo[1,5-a]pyridine-
6-carboxylate (1e) White solid. Yield 0.46 g (52%). m.p.
(DSC) (10 °C/min) onset 105.35 °C, maximum 106.07 °C. IR
(ATR) νmax 3061, 2956, 1721, 1636, 1608, 1587, 1512, 1477,
NMR (400 MHz, CDCl3) δH: 3.90 (s, 3H), 7.23 (m, 1H), 7.78,
(d, J = 6.7 Hz, 1H), 7.86 (m, 2H), 8.03 (dd, J = 9, 12 Hz, 1H),
9.43 (s, 1H). 13C NMR (100 MHz, DMSO). δC: 53.1, 115.8,
117.9, 128.9, 130.1, 130.4, 132.3, 133.0, 139.6, 152.7, 161.4,
164.6. m/z 260.0.1. HRMS (ESI) calcd for C12H10N3O2S
[M+H+] 260.0488, found 260.0491
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
1445, 1434, 1329, 1300, 1286, 1257, 1247, 1127 cm−1. H
NMR (400 MHz, DMSO) δH: 3.84 (s, 3H), 3.90 (s, 3H), 7.08
(t, J = 7.6 Hz, 1H), 7.20 (d, J = 8.4 Hz, 1H), 7.50 (m, 1H), 7.90
(m, 2H), 8.02 (m, 1H), 9.45 (s, 1H). 13C NMR (100 MHz,
DMSO) δC: 53.1, 56.2, 110.0, 112.8, 115.9, 117.6, 120.8,
129.7, 131.7, 132.1, 132.3, 151.9, 158.1, 164.4, 164.7. m/z
284.1.1. HRMS (ESI) calcd for C15H14N3O3 [M+H+] 284.1030,
found 284.1032
Methyl
2-benzyl-[1,2,4]triazolo[1,5-a]pyridine-6-
carboxylate (1m) White solid. With 3 eq. acetic anhydride,
130 °C. Isolated by trituration with MTBE. Yield 0.14 g
(72%). m.p. (DSC) (10 °C/min) onset 107.54 °C, maximum
108.90 °C. IR (ATR) νmax 3065, 3032, 2956, 1723, 1638,
1518, 1453, 1439, 1337, 1319, 1293, 1205, 1155, 1135, 1020
1
cm−1. H NMR (400 MHz, CDCl3) δH: 3.98 (s, 3H), 4.30 (s,
Methyl 2-(3-methoxyphenyl)-[1,2,4]triazolo[1,5-a]pyridine-
6-carboxylate (1f) White solid. Yield 0.42 g (66%). m.p.
(DSC) (10 °C/min) onset 130.98 °C, maximum 132.13 °C. IR
(ATR) νmax 3079, 2961, 1730, 1640, 1593, 1480, 1433, 1318,
1272, 1239, 1134 cm−1. 1H NMR (400 MHz, DMSO) δH: 3.84
(s, 3H), 3.91 (s, 3H), 7.10 (dd, J = 2.4, 8.4 Hz, 1H), 7.46, (t, J
= 8 Hz, 1H), 7.72 (s, 1H), 7.79 (d, J = 8 Hz, 1H), 7.93 (d, J =
9.6 Hz, 1H), 8.05 (d, J = 9.6 Hz, 1H) 9.49 (s, 1H). 13C NMR
(100 MHz, DMSO) δC: 53.2, 55.7, 112.2, 116.1, 117.1, 118.0,
119.8, 130.2, 130.7, 131.7, 132.5, 152.9, 160.0, 164.6, 165.2.
m/z 284.1.1. HRMS (ESI) calcd for C15H14N3O3 [M+H+]
284.1030, found 284.1032
2H), 7.25 (m, 1H), 7.33 (t, J = 7.6 Hz, 2H), 7.41 (d, J = 7.2 Hz,
2H), 7.71 (d, J = 8.2 Hz, 1H), 8.07 (dd, J = 9.8, 1.2 Hz, 1H),
9.22 (s, 1H).13C NMR (100 MHz, CDCl3) δC: 35.2, 52.8,
115.3, 117.8, 126.9, 128.7, 129.0, 129.8, 131.6, 136.9, 152.1,
164.4, 167.9. m/z 268.1. HRMS (ESI) calcd for C15H14N3O2
[M+H+] 268.1081, found 268.1085
Methyl 2-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-carboxylate
(1n) Not isolated. m/z 192.1
Methyl
2-(tert-butyl)-[1,2,4]triazolo[1,5-a]pyridine-6-
carboxylate (1o) Not isolated. m/z 234.1. HRMS (ESI) calcd
for C12H16N3O2 [M+H+] calcd 234.1237, found 234.1241
Methyl 2-(4-methoxyphenyl)-[1,2,4]triazolo[1,5-a]pyridine-
6-carboxylate (1g) White solid. Yield 0.54 g (94%). m.p.
(DSC) (10 °C/min) onset 185.70 °C, maximum 186.30 °C. IR
(ATR) νmax 2950, 1711, 1637, 1611, 1532, 1460, 1445, 1427,
1320, 1295, 1248, 1200, 1185, 1167, 1027, 837 cm−1. 1H NMR
(400 MHz, DMSO) δH: 3.82 (s, 3H), 3.90 (s, 3H), 7.09 (d, J =
8.8 Hz, 2H), 7.87 (d, J = 9.2 Hz, 1H), 8.02 (d, J = 9.2 Hz, 1H),
8.14 (d, J = 8.8 Hz, 2H), 9.43 (s, 1H). 13C NMR (100 MHz,
DMSO) δC: 53.1, 55.8, 114.9, 115.8, 117.6, 122.8, 129.1,
130.0, 132.3, 152.9, 161.7, 164.7, 165.3. m/z 284.1.1. HRMS
(ESI) calcd for C15H14N3O3 [M+H+] 284.1030, found 284.1032
Methyl
1-benzimidamido-6-oxo-1,6-dihydropyridine-3-
carboxylate 6a Pale yellow solid. Yield 1.21 g (80%). m.p.
(DSC) (10 °C/min) 183 °C (decomposes). IR (ATR) νmax
3425, 3338, 3231, 1720, 1647, 1586, 1550, 1442, 1416, 1272,
1106 cm−1. 1H NMR (400 MHz, DMSO) δH: 3.76 (s, 3H), 6.47
(d, J = 9.2 Hz, 1H), 7.15 (brs, 2H), 7.47 (m, 2H), 7.54 (m,
1H), 7.73 (dd, J = 2.4, 9.2 Hz), 1H), 7.88 (d, J = 9.2 Hz, 1H),
8.10 (d, J = 2.4 Hz, 1H). 13C NMR (100 MHz, DMSO) δC:
52.2, 108.5, 119.9, 127.8, 128.6, 131.4, 133.3, 136.8, 142.6,
158.9, 162.1, 164.8. m/z 272.1. HRMS (ESI) calcd for
C14H14N3O3 [M+H+] 272.1030, found 272.1036
Methyl
2-(m-tolyl)-[1,2,4]triazolo[1,5-a]pyridine-6-
Methyl (Z)-1-((amino(4-fluorophenyl)methylene)amino)-6-
oxo-1,6-dihydropyridine-3-carboxylate 6d Yellow solid. Isoꢀ
lated by filtration. Yield 3.67 g (77%) (DSC) (10 °C/min) onꢀ
set 281.76 °C, maximum 283.15 °C IR (ATR) νmax 3420,
3335, 3225, 1722, 1644, 1606, 1587, 1558, 1535, 1443, 1418,
1308, 1273, 1106 cm−1. 1H NMR (400 MHz, DMSO) δH: 3.75
(s, 3H), 6.47 (d, J = 9.6 Hz, 1H), 7.18 (brs, 2H), 7.31 (t, J =
8.8 Hz, 2H), 7.73 (d, 9.6 Hz, 1H), 7.95 (m, 2H), 8.12 (s, 1H).
19F δF: ꢀ109.8. 13C NMR (100 MHz, DMSO) δC: 53.2, 108.5,
115.20, 119.9, 129.7, 130.3, 136.8, 142.6, 158.9, 161.1,
164.2, 164.8; m/z 290.1; HRMS (ESI) calcd for C14H13N3O3F
[M+H+] 290.0935, found 290.0940.
carboxylate (1i) Offꢀwhite solid. Yield 0.44 g (68%). m.p.
(DSC) (10 °C/min) 142 °C (decomposes). IR (ATR) νmax
3012, 2956, 1721, 1637, 1509, 1439, 1320, 1307, 1296, 1198,
1
1116, 1037 cm−1. H NMR (400 MHz, CDCl3ꢀDMSO) δH:
2.45 (s, 3H), 3.99 (s, 3H), 7.20 (m, 1H), 7.65 (d, J = 6.4 Hz,
1H), 7.98 (m, 3H), 9.19 (s, 1H). 13C NMR (100 MHz, CDCl3)
δC: 21.4, 52.8, 115.5, 117.8, 124.7, 128.1, 128.8, 129.7, 129.8,
131.5, 131.7, 138.6, 152.7, 164.5, 166.0. m/z 268.1.1. HRMS
(ESI) calcd for C15H14N3O2 [M+H+] 268.1081, found 268.1085
Methyl
2-(p-tolyl)-[1,2,4]triazolo[1,5-a]pyridine-6-
carboxylate (1j) White solid. Yield 0.49 g (82%). m.p. (DSC)
(10 °C/min) 91 °C (decomposes). IR (ATR) νmax 3076, 2953,
1721, 1639, 1614, 1459, 1436, 1346, 1323, 1304, 1197, 1186,
1135, 960 cm−1. 1H NMR (400 MHz, CDCl3) δH: 2.42 (s, 3H),
3.98 (s, 3H), 7.30 (d, J = 8.0 Hz, 2H), 7.72 (d, J = 9.2 Hz, 1H),
8.02 (d, J = 9.2 Hz, 1H), 8.16 (d, J = 8.0 Hz, 2H), 9.26 (s, 1H).
Methyl (Z)-1-((amino(pyridin-2-yl)methylene)amino)-6-oxo-
1,6-dihydropyridine-3-carboxylate 6k Yellow solid. Isolated
by filtration, no workꢀup. Yield 12.0 g (90%). m.p. (DSC) (10
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Present Addresses
°C/min) onset 237.30 °C, maximum 238.96 °C. IR (ATR) νmax
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8
3388, 3314, 3260, 1720, 1676, 1643, 1595, 1561, 1443, 1407,
Eli Lilly and Co. Indianapolis, Indiana, USA
1
1313, 1298, 1276, 1262, 1117 cm−1. H NMR (400 MHz,
Author Contributions
DMSO) δH: 3.86 (s, 3H), 6.65 (d, J = 9.6 Hz, 1H), 7.45 (m,
1H), 7.88 (m, 2H), 8.32 (m, 2H), 8.59 (d, J = 3.6 Hz, 1H). 13
C
All authors have given approval to the final version of the manuꢀ
script
NMR (100 MHz, DMSO) δC: 52.1, 109.8, 119.8, 122.1, 126.1,
137.0, 137.5, 146.7,141.9, 148.2, 148.24, 158.0, 159.1, 164.6.
m/z 273.1. HRMS (ESI) calcd for C13H13N4O3 [M+H+]
273.0982, found 273.0988.
ACKNOWLEDGMENT
The authors would like to thank Michael Johnson for
assistance with IR and DSC analysis and Benjamin Disꢀ
eroad for single crystal analysis
(Z)-1-((Amino(phenyl)methylene)amino)-6-oxo-1,6-
dihydropyridine-3-carboxylic acid 9a Pale yellow solid. Yield
0.16 g (50%). m.p. (DSC) (10 °C/min) onset 263.15 °C, maxꢀ
imum 265.27 °C.IR (ATR) νmax 3445, 3311, 3213, 1700,
1634, 1600, 1557, 1535, 1437, 1400, 1242, 1216, 1132 cm−1.
1H NMR (400 MHz, DMSO) δH: 6.45 (d, J = 9.2 Hz, 1H), 7.12
(brs, 2H), 7.46 (m, 2H), 7.53 (m, 1H), 7.72 (dd, J = 2.4, 9.2
Hz), 1H), 7.88 (d, J = 9.2 Hz, 1H), 8.04 (d, J = 2.4 Hz, 1H).
13C NMR (100 MHz, DMSO) δC: 109.5, 119.8, 127.8, 128.6,
131.4, 133.3, 137.2, 142.4, 159.0, 162.0, 165.8. m/z 258.1.
HRMS (ESI) calcd for C13H12N3O3 [M+H+] 258.0873, found
258.0882
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(Z)-1-((amino(4-fluorophenyl)methylene)amino)-6-oxo-1,6-
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filtration. Yield 3.67 g (77%) (DSC) (10 °C/min) onset 281.76
°C, maximum 283.15 °C. IR (ATR) νmax 3431, 3330, 3230,
1699, 1646, 1608, 1562, 1532, 1518, 1449, 1415, 1320, 1272,
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= 8.8 Hz, 2H), 7.73 (d, 9.6 Hz, 1H), 7.94 (m, 2H), 8.04 (s,
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276.0779, found 276.0784.
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dihydropyridine-3-carboxylic acid 9k White solid. Yield 0.90
g (97%). m.p. (DSC) (10 °C/min) onset 300.22 °C, maximum
300.77°C. IR (ATR) νmax 3441, 3224, 1714, 1697.5, 1648,
1623, 1586, 1534, 1440, 1397, 1363, 1282, 1239, 1209, 1132,
1
770, 763 cm−1. H NMR (400 MHz, TFAꢀd1) δH: 7.21 (d, J =
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9.5 Hz, 1H), 8.40 (dd, 1H, J = 8.1, 9.9 Hz), 8.43 (d, J = 9.5 Hz,
1H), 8.68 (d, 1H), 8.76 (d, J = 8.1 Hz, 1H), 8.91 (dd, J = 8.1,
8.1 Hz, 1H), 9.07 (d, J = 9.9 Hz, 1H). 13C NMR (125 MHz,
TFA) δC: 115.1, 119.1, 125.8, 130.1, 141.1, 141.7, 141.8,
143.1, 148.5, 154.51, 161.7, 167.7. m/z 259.1. HRMS (ESI)
calcd for C12H11N4O3 [M+H+] 259.0831, found 259.0833.
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ASSOCIATED CONTENT
Supporting Information
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The Supporting Information is available free of charge on the
ACS Publications website.
Phenylꢀtriazoloꢀpyridine Compounds. Patent WO 2015105786
A1, 2015.
1
1ꢀD and 2ꢀD NMR characterization of E, H NMR, 13C NMR
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R. S.; Smith, A.; Wu, J. K.; Xu, S.; Zhu, B.; Thornberry, N. A.;
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spectra of all other compounds (PDF)
Crystallographic information (cif)
AUTHOR INFORMATION
Corresponding Author
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* Harold Moloney.
Harry.moloney@gmail.com ;Moloney_harry@lilly.com
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