Palladium-Catalyzed C-N Coupling of Pyrazole Amides with Triazolo- And Imidazopyridine Bromides in Ethanol

Article abstract of DOI:10.1021/acs.oprd.0c00437

An efficient palladium-catalyzed coupling between a pyrazole amide and a heteroaryl bromide was developed to enable the streamlined synthesis of a lead candidate for schizophrenia treatment. Process robustness and scalability were achieved using ethanol a

Full text of DOI:10.1021/acs.oprd.0c00437

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Palladium-Catalyzed C−N Coupling of Pyrazole Amides with
Triazolo- and Imidazopyridine Bromides in Ethanol
̈
Fritz Bliss, Serena Fantasia,* Erwann Le Coz, and Kurt Puntener
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ABSTRACT: An efficient palladium-catalyzed coupling between a pyrazole amide and a heteroaryl bromide was developed to
enable the streamlined synthesis of a lead candidate for schizophrenia treatment. Process robustness and scalability were achieved
using ethanol as a solvent. The Xantphos ligand employed in the catalytic system was found to be key to prevent common side
reactions arising from the alcoholic solvent. The scope of the methodology was investigated and is presented.
KEYWORDS: Buchwald−Hartwig coupling, protic solvent, palladium catalysis, dehalogenation, C−O coupling
coupling reactions.6 However, thanks to the development of
INTRODUCTION
■
increasingly efficient catalytic systems, amide couplings have
The pyrazole amide motif is widespread in biologically active
found numerous synthetic applications in the past few years.7
molecules. The number of marketed compounds in the
Notwithstanding this, heteroaromatic substrates containing no
agrochemical and pharmaceutical industries and the number
amide group per se pose a greater challenge because of
of therapeutic clinical candidates containing this moiety
competing coordination to the palladium catalyst, a behavior
undoubtedly point to its extreme relevance.1 As a part of our
that was shown to favor catalyst deactivation.8 In particular,
research program in the field of neuropsychiatric disorders, the
our synthetic strategy envisaged the use of pyrazole amide 8a, a
medicinal chemistry team identified compound 1 (Scheme 1)
substrate that to the best of our knowledge had not been
as a promising lead for the treatment of schizophrenia.2 The
reported as a partner in C−N coupling reactions.9 Notably,
original discovery route involved the classical amide con-
additional complexity stemmed from the presence of a
densation disconnection between heteroaromatic amine 4 and
carboxylic acid 5, to give ethyl ester intermediate 6a, which was
sensitive ester functionality.
converted to the desired amide 1 in two steps (Scheme 1). The
RESULTS AND DISCUSSION
■
synthesis of 4 was accomplished via palladium-catalyzed
Amide 8a was prepared from 5 in excellent yields (92%)
coupling of tert-butyl carbamate with triazolopyridine bromide
23 (to afford intermediate 3) followed by deprotection in an
employing ammonia and 1,1-carbonyldiimidazole in MeTHF
at room temperature. The investigation of the amide coupling
acidic medium. When the suitability of this route for
reaction started with testing of the most promising catalytic
commercial supply was evaluated, several drawbacks were
systems reported in the literature. In particular, we tested the
identified. First of all, the use of a high catalyst loading (4 mol
% palladium) in the amination step was making the palladium
depletion problematic. Also, the need for tert-butyl carbamate
as an ammonia surrogate demanded an additional step in the
activity of the Pd2dba3/Xantphos combination with Cs2CO3 as
the base in dioxane.10a,c Unfortunately, we observed extremely
low conversion. Employing tBuXPhos or Me4tBuXPhos as the
supporting ligand in tert-butyl alcohol also delivered poor
sequence, increasing the overall process budget, waste, and
results.6d On the other hand, the last-generation Buchwald
duration. Finally, intermediate heteroaromatic amine 4
ligand AdBrettPhos in combination with [Pd(allyl)Cl]2
triggered a mutagenic alert in the in silico genotoxic
displayed reasonable conversion but very low selectivity for
assessment4 and was classified as a substance of high hazard,5
the desired product.10b,11 Modification of the base and solvent
meaning that the isolation and handling of the compound
in the published reaction conditions led to the identification of
needed special equipment and personal protection to ensure
tert-butyl alcohol as the optimal solvent for the Pd2dba3/
exposure limits below 1 μg/m3. In this context, we started to
Xantphos combination. With K2CO3 as the base, full
explore alternatives toward a more efficient amine-free route,
conversion and 98% yield were obtained after 3 h at reflux
and we identified the palladium-catalyzed C−N coupling of
aryl bromide 2 and pyrazole amide 8a as the most promising
option (Scheme 1). The synthesis of pyrazole amide 8a from
the corresponding acid 5 in one step was envisaged, resulting
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istry
in an overall synthetic sequence that was one step shorter.
Because of their weak nucleophilicity and their ability to
chelate to transition metal complexes, amides have been
considered challenging substrates in palladium-catalyzed
Received: September 29, 2020
Published: January 15, 2021
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Scheme 1. Synthetic Approaches to 1
a
Table 1. Effect of the Solvent on Scale-Up and on the Impurity Profile
b
c
entry
solvent
tBuOH
Pd2dba3/Xantphos loading (mol %)
0.50/1.00
scale of 2 (g)
conv. (%)
yield (%)
1
2
3
4
5
6
7
8
0.25
2.00
2.00
0.50
2.00
0.50
20.00
20.00
>99
64
>99
98
51
98
92
87
d
e
f
iPrOH/THF (4:1)
EtOH/THF (4:1)
0.50/1.00
0.50/1.00
>99
>99
>99
>99
94 (90)
96 (94)
94 (93)
0.25/0.5
>99
a
b
c
Detailed reaction conditions are given in the Supporting Information. Conversions are based on HPLC area %. HPLC area %. Isolated yields are
d
e
f
given in parentheses. K2CO3 was ground. Main side product: isopropyl ester (5%). Main side product: isopropyl ester (9%).
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Figure 1. Flow diagram of the GMP campaign amidation process.
Figure 2. Scope of the palladium-catalyzed amidation with respect to the amide coupling partner. Detailed reaction conditions are given in the
Experimental Section. Isolated yields are reported. Notes: a74% conversion; the reaction time was not optimized. b0.50 mol % Pd2dba3, 1.00 mol %
c
d
e
f
Xantphos. 95% conversion. 0.30 mol % Pd2dba3, 0.60 mol % Xantphos. 85% conversion. 0.25 mol % Pd2dba3, 0.50 mol % Xantphos.
(Table 1, entry 1). Unfortunately, when we performed the
reaction on an 8 times larger scale, we observed a remarkable
decrease in the reaction rate that caused the conversion to
plummet to 64% after 3 h (entry 2). Examination of the
different reaction parameters pointed to the base particle size
as a possible factor affecting the reaction kinetics in tert-butyl
alcohol. In fact, when the K2CO3 was finely ground, consistent
conversions at different scales were obtained (entry 3). Since
the particle size is often batch- and supplier-dependentand
hence scarcely controllable for the supply chainand grinding
is not feasible for large-scale production, we were forced to find
an alternative solution. An extensive screening of common base
and solvent combinations provided no improvement.11 In
particular, moving away from tert-butyl alcohol completely
suppressed the reactivity, pointing to the key role of a polar
protic solvent.
The use of polar protic solvents in C−N coupling reactions
is limited to tertiary alcohols, while primary and secondary
alcohols have been reported to perform poorly.12 In fact, they
are known to undergo oxidation in the presence of a palladium
catalyst and aryl halides, giving rise to hydrodehalogenation
and homocoupling products.13 On the other hand, isopropanol
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Figure 3. Scope of the palladium-catalyzed amidation with respect to the aryl bromide coupling partner. Detailed reaction conditions are given in
a
the Experimental Section. Isolated yields are reported. Note: 3 mol % Pd2dba3, 6 mol % Xantphos, 66% conversion, HPLC yield (area %).
has been successfully used as a solvent in Suzuki−Miyaura
reactions,14 prompting us to test it in our coupling. As Pd2dba3
and Xantphos are scarcely soluble in alcoholic solvents, we
envisaged premixing them in a minimal volume of THF and
then adding the resulting mixture to the reaction. To our
surprise, full conversion and high selectivity were achieved, and
the results were consistent at different scales. The major side
reaction observed was transesterification to the isopropyl ester
derivative, which was formed in 5−9% yield (Table 1, entries 4
and 5). Consequently, in order to preserve the ethyl ester
functionality, we decided to try ethanol as a solvent. Pleasingly,
the coupling was achieved within 3 h with no major side
product detected on both a 0.5 g scale and a 20 g scale (entries
6 and 7). Additionally, the catalyst loading could be reduced to
0.25 mol % without erosion of conversion and yield (entry 8).
Because of the low solubility of the product in ethanol, simple
volume concentration followed by filtration allowed the
isolation of the product in 93−96% yield.15 Moreover, thanks
to the combination of low catalyst loading and filtration of the
precipitated product, the procedure delivered the target
compound with only 100−200 ppm residual palladium. This
amount was completely purged in the two downstream steps to
1, where the residual metal content was required to be less
than 10 ppm. Optionally, an additional trituration in hot DMF
could be performed on the crude product 6a, further reducing
the palladium level to 10−50 ppm.
temperature (Ti = 74 °C) in about 1 h, and after 3.5 h in-
process control (IPC) analysis showed >99.9% conversion and
91% selectivity, in line with laboratory experiments. After
cooling to room temperature, an operation that took 2 h, the
reaction mixture was left to stir overnight and then filtered.
The wet cake was rinsed with ethanol, water, and ethanol and
then suspended in DMF. The resulting suspension was stirred
at 100 °C for 1 h and then filtered. The wet cake was rinsed
again with DMF and ethanol, and the crystals were dried at 50
°C under full vacuum for 65 h. The product was obtained in
92% yield with >99.9% purity and contained 52 ppm residual
palladium. Compared with the original discovery chemistry
three-step approach, the direct palladium-catalyzed amidation
displays an increased yield (85% vs 65%), improved atom
economy (83% vs 66%), and higher mass efficiency (80% vs
60%). Overall, the new synthetic route is shorter and more
convergent. Additionally, it avoids compounds 4 and N-
protecting group manipulations and requires 4 times less
palladium catalyst, directly impacting the overall process cost
and purification effort.
Intrigued by the good performance of this ethanol-based
catalytic system, we decided to explore the reaction scope. As a
potential backup program would involve imidazopyridine
derivatives 10 (Figure 2), we included bromide 9 in our
study. Gratifyingly, we found that with amide 8a the coupling
to both bromides 2 and 9 could be achieved with only 0.13
mol % Pd2dba3 and 0.26 mol % Xantphos. However, the
isolated yield of 6a was lower than the one obtained with the
double amount of catalyst (Table 1, entry 8): likely, as the
coupling reaction rate slows down at lower catalyst loading, the
formation of side-products becomes competitive. It is note-
worthy that imidazopyridine 10a underwent hydrolysis of the
ester functionality during the reaction, causing a slight erosion
of the yield.17 Unsubstituted pyrazole amides 8b−d coupled
The new route based on the palladium-catalyzed amide
coupling (Scheme 1) was implemented smoothly in the Good
Manufacturing Practice (GMP) campaign for the clinical phase
IIa supply.16 An overview of the production process is depicted
in Figure 1. The reaction was performed on 16.4 kg of aryl
bromide 2 in a 250 L reactor. The palladium precursor and the
ligand were suspended in THF in a stirrable drum and then
added to the reactor. The mixture reached the target
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c
Table 2. Activities of Various Phosphine Ligands in the Amidation Reaction
a
b
c
1 mol %. [Pd(allyl)Cl]2 (0.75 mol %) instead of Pd2dba3, AdBrettPhos (3 mol %), Cs2CO3 (2 equiv), no THF, 1 h. Data indicated in HPLC
area %; n.o. = not observed.
with triazolopyridine bromide 2 under the same conditions in
moderate to very good isolated yields independent of the
amide position, while higher catalyst amounts were required
for imidazopyridine substrate 9. The introduction of a tertiary
amide group on the pyrazole ring was well-tolerated, affording
products 6e−f and 10e−f in moderate to good isolated yields
employing 0.5 mol % Pd2dba3 and 1 mol % Xantphos (the
catalyst/ligand loading was not further optimized). Other five-
membered heterocycles such as pyrrole, furan, and thiophene
amides posed no issue, and the coupling products 6g−i and
10g−i were isolated in good to very good yields. We observed
as a general trend that imidazopyridine bromides 9 performed
worse than the analogous triazolopyridine bromides 2 in the
coupling reaction, requiring longer reaction times and often
higher catalyst loadings to achieve full conversion. It is worth
mentioning that the reported isolated yields are the results of
nonoptimized processes and would likely improve with the
appropriate process development.
product 12a in 91% yield (Figure 3). Substitution of the
phenyl ring with a morpholine led to partial hydrolysis of the
ethyl ester functionality,18 and product 12b was isolated in
modest yield (66%). An ethyl ester functionality at the 2-
position increased the reaction rate, resulting in full conversion
of bromide 11c within 1 h to afford 12c in 67% isolated yield.
Interestingly the 2,7-dibromo substrate 11d coupled selectively
at the 7-position, allowing isolation of 12d in 62% yield after
only 1 h of reaction time. It is noteworthy that the moderate
isolated yields of products 12c and 12d are likely due to the
nonoptimized workup procedure. Finally, replacing the aryl
substituent with a methyl group dramatically suppressed the
reactivity and selectivity of the catalytic system: only 66% of
11e was converted after 22 h, and product 12e was observed in
a poor 15% HPLC yield. The marked difference in the
reactivity of 11e was quite surprising as the coupling site is
rather far from the 2-position bearing the methyl substituent;
Its electronic and steric properties should be in principle
minimally influenced. This behavior is currently quite difficult
to rationalizepoisoning of the catalyst by a substrate
impurity cannot be excluded. Additionally, whether the
We next explored the effect of substitutions on the
heteroaryl bromide coupling partners, with a particular focus
on the position occupied by the phenyl ring. Addition of a
fluorine at the para position allowed the isolation of coupling
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catalytic system would be effective in the coupling of other,
more general, aryl bromide moieties remains to be explored.
The efficacy of ethanol as the solvent in the cross-coupling
reaction was quite unexpected, and we were intrigued to
benchmark the performance of other phosphines under these
reaction conditions. Hence, we evaluated a selection of ligands
usually employed for Buchwald−Hartwig aminations7 in the
coupling of pyrazole amide 8a with imidazopyridine 9 (Table
2).19
Synthesis of 6a. A 750 mL three-neck flask equipped with
a thermometer, a reflux condenser, and an overhead stirrer was
purged by five vacuum/argon cycles and charged under argon
with ethyl 5-carbamoyl-1-methyl-1H-pyrazole-4-carboxylate
(8a) (15.2 g, 76.3 mmol, 1.06 equiv), 7-bromo-2-phenyl-
[1,2,4]triazolo[1,5-a]pyridine (2) (20 g, 72.2 mmol, 1.00
equiv), K2CO3 (11.6 g, 83.1 mmol, 1.15 equiv), and ethanol
(254 g, 320 mL). The mixture was stirred to obtain a white
suspension, and an additional vacuum/argon purging cycle was
applied. A 50 mL round-bottom flask under argon was charged
with Pd2dba3 (160 mg, 175 μmol, 0.0025 equiv) and THF
(71.0 g, 80.0 mL). The black solution was stirred for 1 min,
and then 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene
(Xantphos) (204 mg, 353 μmol, 0.005 equiv) was added.
The dark-red solution was stirred for 10 min and then
cannulated into the 750 mL flask. The clear brown suspension
was heated at 75 °C for 3 h and 15 min (IPC: >99.9%
conversion). After this time, 118 mL of solvent was distilled,
and the remaining mixture was allowed to cool to room
temperature. The suspension was filtered, and the solid was
washed with ethanol (100 mL), water (160 and 120 mL), and
finally ethanol (60 mL). The solid was dried on a rotary
evaporator (50 °C, 20 mbar) to constant weight to obtain 6a
as an off-white powder (26.2 g, 67.9 mmol, 93.0% yield) with
99.8% purity (HPLC area %) and containing approximately
200 ppm Pd. The crude material was suspended in DMF (262
mL), and the suspension was stirred at 100 °C for 1 h, allowed
to cool to room temperature, and stirred for an additional 1 h.
The solid was filtered, washed with DMF (16 mL) and ethanol
(2 × 50 mL), and dried in the rotary evaporator (70 °C, 20
mbar) for 1.5 h and then under high vacuum for 24 h. Product
6a was obtained as a white powder (24.4 g, 62.5 mmol, 85%
yield) with >99% HPLC purity and contained approximately
Interestingly we found that the Xantphos open-chain
analogue DPEphos did not form any product despite full
conversion of 9 (Table 2, entry 2). Instead, hydrodebromi-
nated compound 13 was formed in major amounts. The
bidentate ligand BINAP and the ferrocenyl phosphines dppf
and Josiphos led to the same outcome, i.e., heteroaryl bromide
9 was completely consumed, but no coupling was observed
and mostly dehalogenation occurred (entries 3−5). Mono-
phosphine MorDalPhos achieved only 52% conversion with
the formation of a minimal amount of the desired product,
with debromination once again being the main reaction path
(entry 6). The formation of the debrominated product is in
line with the expected behavior of primary and secondary
alcohols in palladium-catalyzed cross-coupling systems, as
detailed in the Introduction. On the other hand, the two
Buchwald phosphines that are reported to be the most efficient
in the amidation of (hetero)aryl bromides6d,10b suppressed the
formation of the debromination side product almost
completely and promoted the coupling with ethanol itself,
giving rise to aryl ether 14 as the main product (entries 7 and
8).20 This is in accordance with the reported ability of bulky
and electron-rich biaryl phosphines to suppress β-hydride
elimination and promote C−O coupling.21
1
13 ppm Pd. H NMR (600 MHz, CDCl3): δ 1.45 (t, J = 7.2
CONCLUSIONS
■
Hz, 3H), 4.38 (s, 3H), 4.45 (q, J = 7.2 Hz, 2H), 7.35 (dd, J =
7.4, 2.2 Hz, 1H), 7.44−7.53 (m, 3H), 8.03 (s, 1H), 8.22−8.31
(m, 2H), 8.39 (d, J = 1.7 Hz, 1H), 8.52 (d, J = 7.4 Hz, 1H),
12.82 (s, 1H). 13C NMR (101 MHz, CDCl3): δ 14.18, 42.25,
62.32, 104.21, 108.33, 112.63, 127.28, 128.15, 128.69, 130.05,
130.85, 136.07, 139.53, 141.57, 152.43, 156.76, 164.90, 166.11.
HRMS: [M + H]+ m/z 391.15309, found by formula [M]
390.14552, theoretical 390.14404.
We have developed an efficient, robust, and scalable catalytic
system for the coupling of five-membered heterocyclic amides
with triazolopyridine and imidazopyridine bromides. The
process, performed on a 16.4 kg scale, relies on the use of
ethanol as a solvent, which to the best of our knowledge is
unprecedented in palladium-catalyzed C−N coupling reac-
tions. It is noteworthy that Xantphos seems to be a ligand with
unique characteristics, as it is able to hinder unwanted side
reactions of primary alcohols such as β-hydride elimination and
C−O bond formation and to selectively promote the amide
coupling at very low catalyst loadings.
Production Run for 6a. A 250 L reactor previously purged
with nitrogen was filled with potassium carbonate (8.68 kg,
62.8 mmol, 1.05 equiv), 8a (12.5 kg, 63.4 mol, 1.06 equiv), and
2 (16.4 kg, 59.8 mol, 1.00 equiv). The reactor was purged with
argon, and ethanol (130 L) was added. A 50 L stirrable drum
was filled with Xantphos (0.35 kg, 0.60 mmol, 0.01 equiv) and
Pd2dba3 (0.28 kg, 0.30 mol, 0.005 equiv). The drum was
purged with nitrogen, and the solid was suspended in THF (20
L). The mixture was stirred for 20 min at room temperature
and then transferred to the 250 L reactor. The drum was rinsed
with THF (20 L). The reaction mixture was heated to 74 °C
(Ti, temperature reached in 1 h) and stirred for 3.5 h. IPC
control showed 0.09% of 2 remaining (specification ≤1%).
The suspension was allowed to cool to room temperature
(reached in 2 h), stirred further for 15 h, and filtered, and the
filter cake was rinsed with ethanol (60 L). The crystals were
dried on the filter and then suspended in water, and the
suspension was stirred for 10 min and filtered. The filter cake
was rinsed with water (30 L) and ethanol (60 L). The wet cake
was suspended in DMF (150 L), and the suspension was
stirred at 100 °C for 1 h. The mixture was allowed to cool to
EXPERIMENTAL SECTION
■
General. Starting materials were purchased from commer-
cial suppliers or synthesized according to published procedures
(see the Supporting Information for details). Solvents, ligands,
palladium precursors, and bases were purchased from
commercial suppliers and used without further purifications.
HPLC chromatograms were recorded on an Agilent 1100 or
Agilent 1290 instrument. High-resolution mass spectrometry
(HRMS) was performed on an Agilent 6520 QTOF LC−MS
instrument. EI spectra were recorded on a SCIEX 4000
QTRAP instrument. NMR spectra were recorded on Bruker
400 MHz and Bruker 600 MHz instruments at ambient
temperature with deuterated solvent and were calibrated with
tetramethylsilane. All of the reactions were performed under
argon with degassed solvents.
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room temperature (reached in 2 h) and then filtered. The wet
cake was washed with DMF (30 L) and ethanol (60 L). The
crystals were dried at 50 °C under full vacuum for 65 h to
obtain 21.3 kg of product 6a in 92% yield with >99.9% purity
and 52 ppm residual palladium.
pyrazole-3-carboxamide (8d) (96.8 mg, 773 μmol, 1.06 equiv),
2 (200 mg, 730 μmol, 1.00 equiv), K2CO3 (116 mg, 839 μmol,
1.15 equiv), and ethanol (8 mL). The mixture was stirred for
12 min at room temperature to obtain a white suspension. A
two-neck round-bottom flask was charged under argon with
Pd2dba3 (839 μg, 0.916 μmol, 0.00126 equiv), Xantphos (1.04
mg, 1.8 μmol, 0.00246 equiv), and THF (2 mL). The resulting
red mixture was stirred for 10 min at room temperature and
then added to the white suspension. The resulting reaction
mixture was stirred for 20 h at 75 °C and then allowed to cool
to room temperature. The solid was filtered and washed with
ethanol (5 mL), water (3 × 6 mL), and finally ethanol (4 mL).
The product was obtained as a white solid (162 mg, 511 μmol,
Synthesis of 6b. A three-neck round-bottom flask
equipped with a thermometer, a reflux condenser, and a
magnetic stirrer was charged under argon with 1-methyl-1H-
pyrazole-5-carboxamide (8b) (290 mg, 2.32 mmol, 1.06
equiv), 2 (600 mg, 2.19 mmol, 1 equiv), K2CO3 (348 mg,
2.52 mmol, 1.15 equiv) and ethanol (20 mL). The mixture was
stirred for 12 min at room temperature to obtain a white
suspension. A two-neck flask was charged under argon with
Pd2dba3 (2.52 mg, 2.75 μmol, 0.00126 equiv), Xantphos (3.12
mg, 5.39 μmol, 0.00246 equiv), and THF (6 mL), and the red
mixture was stirred for 10 min at room temperature. The red
mixture was added to the white suspension, and the mixture
turned yellow-orange. The resulting suspension was stirred for
5 h at 75 °C. HPLC analysis of the reaction mixture showed
74% conversion. The reaction mixture was allowed to cool to
room temperature and then filtered. The solid was washed with
ethanol (5 mL). The filtrate was concentrated to 8 mL and
cooled to 0 °C for 2 h. The resulting suspension was filtered
and washed with water (8 mL) and then dichloromethane (3 ×
6 mL). The product was obtained as a white solid (412 mg,
1
70% yield) in 96% purity (HPLC area %). H NMR (600
MHz, DMSO-d6): δ 4.00 (s, 3H), 6.85 (d, J = 2.3 Hz, 1H),
7.39−7.57 (m, 3H), 7.67 (dd, J = 7.5, 2.3 Hz, 1H), 7.91 (d, J =
2.2 Hz, 1H), 8.13−8.22 (m, 2H), 8.41 (dd, J = 2.1, 0.6 Hz,
1H), 8.89 (dd, J = 7.4, 0.7 Hz, 1H), 10.72 (s, 1H). 13C NMR
(101 MHz, DMSO-d6): δ 39.4, 102.57, 107.62, 109.30, 127.19,
129.21, 129.31, 130.47, 131.24, 133.80, 141.24, 146.15, 152.22,
161.33, 163.85. HRMS: [M + H]+ m/z 319.13185, found by
formula [M] 318.12423, theoretical 318.12291.
S y n t h e s i s o f 6 e .
A s u s p e n s i o n o f t r i s -
(dibenzylideneacetone)dipalladium−chloroform adduct (9.4
mg, 9.1 μmol, 0.005 equiv) and Xantphos (10.8 mg, 18.2
μmol, 0.01 equiv) in THF (2 mL) was added under argon to a
four-neck round-bottom flask containing 4-(dimethylamino-
carbonyl)-1-methyl-1H-pyrazole-5-carboxamide (8e) (376 mg,
1.9 mmol, 1.05 equiv), 2 (500 mg, 1.8 mmol, 1.00 equiv),
potassium carbonate (306 mg, 2.2 mmol, 1.2 equiv), and
EtOH (8 mL). The reaction mixture was heated at 80 °C for 2
h. HPLC analysis of the reaction mixture showed >99%
conversion (97% purity). The yellow suspension was then
cooled to room temperature, and the solvent was evaporated
under reduced pressure. The residue was crystallized from
MeTHF. Product 6e was obtained as a yellow crystalline solid
(382 mg, 0.98 mmol, 54% yield) with >99% purity (HPLC
area %). 1H NMR (400 MHz, CDCl3): δ 3.17 (s, 3H), 3.23 (s,
3H), 4.29 (s, 3H), 7.27−7.29 (m, 1H), 7.44−7.53 (m, 3H),
7.60 (s, 1H), 8.25−8.32 (m, 2H), 8.37 (d, J = 1.6 Hz, 1H),
8.49 (d, J = 7.2 Hz, 1H), 12.40 (s, 1H). 13C NMR (101 MHz,
CDCl3): δ 36.14, 40.29, 40.72, 103.95, 108.45, 115.37, 127.29,
128.09, 128.69, 130.03, 130.90, 135.58, 137.83, 139.66, 152.45,
157.85, 164.85, 166.70. HRMS: [M + H]+ m/z 390.1681,
found by formula [M] 389.1608, theoretical 389.16.
1
1.29 mmol, 59% yield) with >99% purity (HPLC area %). H
NMR (600 MHz, DMSO-d6): δ 4.12 (s, 3H), 7.14 (d, J = 2.1
Hz, 1H), 7.47 (dd, J = 7.5, 2.2 Hz, 1H), 7.50−7.56 (m, 3H),
7.59 (d, J = 2.0 Hz, 1H), 8.12−8.24 (m, 2H), 8.30 (d, J = 2.1
Hz, 1H), 8.80−8.99 (m, 1H), 10.69 (s, 1H). 13C NMR (101
MHz, DMSO-d6): δ 39.66, 102.96, 109.18, 109.25, 127.22,
129.31, 129.45, 130.53, 131.14, 135.20, 137.78, 140.79, 152.13,
159.24, 164.00. HRMS: [M + H]+ m/z 319.13141, found by
formula [M] 318.1239, theoretical 318.12291.
Synthesis of 6c. A three-neck round-bottom flask
equipped with a thermometer, a reflux condenser, and a
magnetic stirrer was charged under argon with 1-methyl-1H-
pyrazole-4-carboxamide (8c) (194 mg, 1.55 mmol, 1.06
equiv), 2 (401 mg, 1.46 mmol, 1.00 equiv), K2CO3 (232
mg, 1.68 mmol, 1.15 equiv), and ethanol (7.2 mL). The
mixture was stirred for 12 min at room temperature to obtain a
white suspension. A two-neck round-bottom flask was charged
under argon with Pd2dba3 (1.68 mg, 1.84 μmol, 0.00126
equiv), Xantphos (2.08 mg, 3.6 μmol, 0.00246 equiv), and
THF (2.4 mL), and the resulting red mixture was stirred for 10
min at room temperature. The red mixture was added to the
white suspension, and the mixture turned yellow. The reaction
mixture was stirred for 7.5 h at 75 °C and then cooled to 4 °C
and kept at this temperature overnight. The solid formed was
filtered and washed with ethanol (5 mL), water (3 × 6 mL),
and finally ethanol (4 mL). The product was obtained as a
white solid (465 mg, 1.24 mmol, 85% yield) in 94% purity
S y n t h e s i s o f 6 f .
A s u s p e n s i o n o f t r i s -
(dibenzylideneacetone)dipalladium−chloroform adduct (9.5
mg, 9.1 μmol, 0.005 equiv) and Xantphos (10.8 mg, 18.2
μmol, 0.01 equiv) in THF (2 mL) was added under argon to a
four-neck round-bottom flask containing 4-(azetidine-1-
carbonyl)-1-methyl-1H-pyrazole-5-carboxamide (8f) (399
mg, 1.9 mmol, 1.05 equiv), 2 (500 mg, 1.8 mmol, 1.00
equiv), potassium carbonate (306 mg, 2.2 mmol), and EtOH
(8 mL). The reaction mixture was heated at 80 °C for 1 h.
HPLC analysis of the reaction mixture showed >99%
conversion (96% purity). The yellow suspension was then
cooled to room temperature, and the solvent was evaporated
under reduced pressure. The residue was crystallized from
MeTHF. Compound 6f was obtained as a yellow crystalline
solid (570 mg, 1.42 mmol, 78% yield) with >99% purity
(HPLC area %). 1H NMR (400 MHz, CDCl3): δ 2.43 (td, J =
7.8, 15.6 Hz, 2H), 4.27 (t, J = 7.9 Hz, 2H), 4.33 (s, 3H), 4.46
(t, J = 7.7 Hz, 2H), 7.27−7.30 (m, 1H), 7.44−7.53 (m, 3H),
1
(HPLC area %). H NMR (600 MHz, DMSO-d6): δ 3.92 (s,
3H), 7.43 (dd, J = 7.4, 2.1 Hz, 1H), 7.46−7.59 (m, 3H), 8.07
(s, 1H), 8.15−8.21 (m, 2H), 8.28−8.34 (m, 1H), 8.41 (s, 1H),
8.87 (d, J = 7.4 Hz, 1H), 9.20−11.53 (m, 1H). 13C NMR (101
MHz, DMSO-d6): δ 39.1, 102.08, 110.02, 119.62, 127.15,
128.92, 129.27, 130.35, 131.39, 133.38, 139.60, 143.54, 152.53,
162.55, 163.63. HRMS: [M + H]+ m/z 319.13162, found by
formula [M] 318.12415, theoretical 318.12291.
Synthesis of 6d. A three-neck round-bottom flask
equipped with a thermometer, a reflux condenser, and a
magnetic stirrer was charged under argon with 1-methyl-1H-
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7.66 (s, 1H), 8.27 (s, 1H), 8.29 (s, 1H), 8.43 (d, J = 1.6 Hz,
1H), 8.49 (d, J = 7.2 Hz, 1H), 13.54 (s, 1H). 13C NMR (101
MHz, CDCl3): δ 16.01, 41.65, 49.36, 53.83, 104.06, 108.63,
113.67, 127.27, 128.00, 128.66, 129.96, 130.97, 135.71, 137.98,
139.91, 152.52, 157.51, 164.76, 165.36. HRMS: [M + H]+ m/z
402.1684, found by formula [M] 401.1611, theoretical 401.16.
Synthesis of 6g. A three-neck round-bottom flask
equipped with a thermometer, a reflux condenser, and a
magnetic stirrer was charged under argon with furan-2-
carboxamide (8g) (103 mg, 928 μmol, 1.06 equiv), 2 (240
mg, 876 μmol, 1.00 equiv), K2CO3 (139 mg, 1.01 mmol, 1.15
equiv), and ethanol (16.7 mL). The mixture was stirred for 12
min at room temperature to obtain a white suspension. A two-
neck round-bottom flask was charged under argon with
Pd2dba3 (2 mg, 2.19 μmol, 0.0025 equiv), Xantphos (2.53
mg, 4.38 μmol, 0.005 equiv), and THF (2.78 mL). The
resulting red mixture was stirred for 10 min at room
temperature and then added to the white suspension. The
mixture was stirred for 3.75 h at 75 °C and then allowed to
cool to 0 °C. The solid was filtered and washed with cold
ethanol (5 mL), water (3 × 6 mL), and finally ethanol (4 mL).
The reaction filtrate was reduced to 8 mL and placed in the
refrigerator overnight. The precipitated solid was filtered and
combined with the first precipitate. The product was obtained
as a white solid (211 mg, 692 μmol, 79% yield) with 98%
Synthesis of 6i. A three-neck round-bottom flask equipped
with a thermometer, a reflux condenser, and a magnetic stirrer
was charged under argon with thiophene-2-carboxamide (8i)
(148 mg, 1.16 mmol, 1.06 equiv), 2 (300 mg, 1.09 mmol, 1.00
equiv), K2CO3 (174 mg, 1.26 mmol, 1.15 equiv), and ethanol
(16 mL). The mixture was stirred for 12 min at room
temperature to obtain a white suspension. A two-neck round-
bottom flask was charged under argon with Pd2dba3 (1.68 mg,
1.83 μmol, 0.00167 equiv), Xantphos (2.08 mg, 3.59 μmol,
0.00328 equiv), and THF (4 mL). The resulting red mixture
was stirred for 10 min at room temperature and then added to
the white suspension. The reaction mixture was stirred for 6.5
h at 75 °C and allowed to cool to room temperature, and the
solid was filtered and washed with ethanol (5 mL), water (3 ×
6 mL), and finally ethanol (4 mL). The reaction filtrate was
reduced to 8 mL and placed in the refrigerator for 4 h. The
precipitated solid was filtered, washed with ethanol (3 mL),
water (3 × 4 mL), and ethanol (3 mL), and combined with the
first precipitate. The product was obtained as a white solid
(252 mg, 0.78 mmol, 72% yield) with 98% purity (HPLC area
1
%). H NMR (600 MHz, DMSO-d6): δ 7.29 (dd, J = 4.9, 3.7
Hz, 1H), 7.49 (dd, J = 7.4, 2.3 Hz, 1H), 7.50−7.58 (m, 3H),
7.96 (dd, J = 5.0, 1.1 Hz, 1H), 8.10 (dd, J = 3.8, 1.1 Hz, 1H),
8.15−8.22 (m, 2H), 8.31 (d, J = 2.2 Hz, 1H), 8.88−9.00 (m,
1H), 10.71 (s, 1H). 13C NMR (101 MHz, DMSO-d6): δ
102.71, 109.16, 127.22, 128.74, 129.33, 129.45, 130.53, 130.64,
131.16, 133.53, 139.42, 141.00, 152.19, 161.14, 163.97.
HRMS: [M + H]+ m/z 321.08216, found by formula [M]
320.07462, theoretical 320.07318.
1
purity (HPLC area %). H NMR (600 MHz, DMSO-d6): δ
6.61 (dd, J = 3.3, 1.7 Hz, 1H), 7.13 (br s, 1H), 7.33 (dd, J =
7.3, 2.0 Hz, 1H), 7.44−7.55 (m, 4H), 7.81 (s, 1H), 8.13−8.19
(m, 3H), 8.67 (d, J = 7.4 Hz, 1H). 13C NMR (101 MHz,
DMSO-d6): δ 102.79, 109.21, 112.98, 116.54, 127.21, 129.32,
129.38, 130.52, 131.18, 140.94, 146.92, 147.33, 152.16, 157.26,
163.94. HRMS: [M + H]+ m/z 305.10554, found by formula
[M] 304.09817, theoretical 304.09603.
Synthesis of 10a. A three-neck round-bottom flask
equipped with a thermometer, a reflux condenser, and a
magnetic stirrer was charged under argon with 8a (306 mg,
1.55 mmol, 1.06 equiv), 7-bromo-2-phenylimidazo[1,2-a]-
pyridine (9) (401 mg, 1.47 mmol, 1.00 equiv), K2CO3 (233
mg, 1.69 mmol, 1.15 equiv) and ethanol (7.2 mL). The
mixture was stirred for 12 min at room temperature to obtain a
white suspension. A two-neck round-bottom flask was charged
under argon with Pd2dba3(1.68 mg, 1.84 μmol, 0.00125 equiv),
Xantphos (2.08 mg, 3.6 μmol, 0.00245 equiv) and THF (2.4
mL). The resulting red mixture was stirred for 10 min at room
temperature and then added to the white suspension. The
resulting mixture was stirred for 6 h at 75 °C. The reaction
mixture was then allowed to cool to room temperature, the
solid was filtered and washed with ethanol (5 mL), water (3x 6
mL) and finally with ethanol (4 mL). The product was
obtained as a yellow solid (396 mg, 1.01 mmol, 69% yield)
with 99% purity (HPLC area %). 1H NMR (600 MHz,
DMSO-d6): δ 1.14 (t, J = 7.1 Hz, 3H), 3.96 (s, 3H), 4.19 (q, J
= 7.1 Hz, 2H), 7.10 (dd, J = 7.4, 2.1 Hz, 1H), 7.28−7.34 (m,
1H), 7.41−7.48 (m, 2H), 7.93−7.98 (m, 3H), 8.06−8.10 (m,
1H), 8.35 (s, 1H), 8.51 (dd, J = 7.3, 0.6 Hz, 1H), 11.14 (s,
1H). 13C NMR (101 MHz, DMSO-d6): δ 14.49, 38.7, 60.64,
104.03, 107.55, 109.25, 113.37, 125.97, 127.64, 128.12, 129.15,
134.36, 135.94, 139.69, 140.20, 145.44, 145.49, 158.64, 162.63.
HRMS: [M + H]+ m/z 390.15793, found by formula [M]
389.15041, theoretical 389.14879.
Synthesis of 6h. A three-neck round-bottom flask
equipped with a thermometer, a reflux condenser, and a
magnetic stirrer was charged under argon with 1-methyl-1H-
pyrrole-2-carboxamide (8h) (106 mg, 851 μmol, 1.06 equiv), 2
(220 mg, 803 μmol, 1.00 equiv), K2CO3 (128 mg, 923 μmol,
1.15 equiv), and ethanol (16.7 mL). The mixture was stirred
for 12 min at room temperature to obtain a white suspension.
A two-neck round-bottom flask was charged under argon with
Pd2dba3 (1.84 mg, 2.01 μmol, 0.0025 equiv), Xantphos (2.32
mg, 4.01 μmol, 0.005 equiv), and THF (2.78 mL). The
resulting red mixture was stirred for 10 min at room
temperature and then added to the white suspension. The
reaction mixture was stirred for 3.75 h at 75 °C and then
allowed to cool to room temperature. The solid was filtered
and washed with cold ethanol (3 × 5 mL), and the filtrate was
concentrated. Ethyl acetate (7 mL) was added, and the flask
was placed in the refrigerator overnight. The precipitated solid
was filtered and combined with the first precipitate. The
product was obtained as a white solid (228 mg, 723 μmol, 90%
1
yield) with 98% purity (HPLC area %). H NMR (600 MHz,
DMSO-d6): δ 3.92 (s, 3H), 6.15 (dd, J = 3.9, 2.5 Hz, 1H), 7.09
(t, J = 2.0 Hz, 1H), 7.13 (dd, J = 3.9, 1.7 Hz, 1H), 7.45−7.58
(m, 4H), 8.18 (dd, J = 8.1, 1.5 Hz, 2H), 8.27 (d, J = 1.7 Hz,
1H), 8.86 (d, J = 7.5 Hz, 1H), 10.27 (br s, 1H). 13C NMR
(101 MHz, DMSO-d6): δ 36.94, 101.83, 107.54, 109.41,
115.31, 125.48, 127.18, 129.08, 129.29, 130.25, 130.41, 131.30,
142.21, 152.37, 160.96, 163.75. HRMS: [M − H]− m/z
316.12049, found by formula [M] 317.12766, theoretical
317.12766.
Synthesis of 10b. A three-neck round-bottom flask
equipped with a thermometer, a reflux condenser, and a
magnetic stirrer was charged under argon with 8b (97.1 mg,
776 μmol, 1.06 equiv), 9 (200 mg, 732 μmol, 1.00 equiv),
K2CO3 (116 mg, 842 μmol, 1.15 equiv), and ethanol (18 mL).
The mixture was stirred for 12 min at room temperature to
obtain a white suspension. A two-neck round-bottom flask was
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charged under argon with Pd2dba3(3.35 mg, 3.66 μmol, 0.005
equiv), Xantphos (4.24 mg, 7.32 μmol, 0.01 equiv), and THF
(4.5 mL). The resulting red mixture was stirred for 10 min at
room temperature and then added to the white suspension.
The resulting mixture was stirred for 22 h at 75 °C. The
suspension was allowed to cool to room temperature, and the
volume was reduced to 2 mL. Dichloromethane (7 mL) was
added, and the mixture was cooled to 4 °C for 4 h. The solid
was filtered and washed with dichloromethane (4 mL), water
(3 × 4 mL), and finally dichloromethane (4 mL). The product
was obtained as a white solid (138 mg, 432 μmol, 59% yield)
with 99% purity (HPLC area %). 1H NMR (600 MHz,
DMSO-d6): δ 4.12 (s, 3H), 7.10 (d, J = 1.7 Hz, 1H), 7.23 (dd,
J = 7.3, 1.6 Hz, 1H), 7.27−7.35 (m, 1H), 7.44 (t, J = 7.6 Hz,
2H), 7.57 (d, J = 1.7 Hz, 1H), 7.95 (br d, J = 7.5 Hz, 2H), 8.07
(s, 1H), 8.32 (s, 1H), 8.48 (d, J = 7.3 Hz, 1H), 10.44 (s, 1H).
13C NMR (101 MHz, DMSO-d6): δ 39.4, 104.44, 108.33,
108.86, 109.00, 125.95, 127.21, 128.04, 129.13, 134.45, 135.73,
136.58, 137.69, 145.27, 145.67, 159.05. HRMS: [M + H]+ m/z
318.13666, found by formula [M] 317.12907, theoretical
317.12766.
Synthesis of 10c. A three-neck round-bottom flask
equipped with a thermometer, a reflux condenser, and a
magnetic stirrer was charged under argon with 8c (194 mg,
1.55 mmol, 1.06 equiv), 9 (401 mg, 1.47 mmol, 1.00 equiv),
K2CO3 (233 mg, 1.69 mmol, 1.15 equiv), and ethanol (7.2
mL). The mixture was stirred for 12 min at room temperature
to obtain a white suspension. A two-neck round-bottom flask
was charged under argon with Pd2dba3 (4.03 mg, 4.4 μmol,
0.003 equiv), Xantphos (5.09 mg, 8.8 μmol, 0.006 equiv), and
THF (2.4 mL). The resulting red mixture was stirred for 10
min at room temperature and then added to the white
suspension. The resulting mixture was stirred for 16 h at 75 °C.
The suspension was allowed to cool to room temperature, and
the solid was filtered and washed with ethanol (5 mL), water
(3 × 6 mL), and finally ethanol (4 mL). The filtrate and the
ethanol washes were combined, and the solvent was reduced to
8 mL. Water (4 mL) was added, and the precipitate was
filtered and combined with the first crop. The product was
obtained as a white solid (385 mg, 1.22 mmol, 83% yield) with
99% purity (HPLC area %). 1H NMR (600 MHz, DMSO-d6):
δ 3.91 (s, 3H), 7.18 (dd, J = 7.3, 2.1 Hz, 1H), 7.28−7.33 (m,
1H), 7.40−7.46 (m, 2H), 7.94 (dd, J = 8.3, 1.2 Hz, 2H), 8.06
(d, J = 0.6 Hz, 1H), 8.08−8.10 (m, 1H), 8.28 (s, 1H), 8.37 (s,
1H), 8.45 (dd, J = 7.3, 0.7 Hz, 1H), 10.05 (br s, 1H). 13C
NMR (100 MHz, DMSO-d6): δ 39.1, 103.50, 108.13, 108.77,
118.73, 125.91, 127.14, 127.96, 129.11, 133.35, 134.53, 137.09,
139.41, 145.08, 145.88, 161.46. HRMS: [M + H]+ m/z
318.13683, found by formula [M] 317.12932, theoretical
317.12766.
filtered and washed with ethanol (5 mL), water (3 × 6 mL),
and finally ethanol (4 mL). The filtrate and the ethanol washes
were combined, concentrated to 5 mL, and cooled to 4 °C for
4 h. The solid was filtered, and the product was washed with
ethanol (3 mL), water (3 × 4 mL) and finally ethanol (3 mL)
and combined with the first crop. The solid was obtained as a
light-gray solid (148 mg, 468 μmol, 64% yield) with 98%
1
purity (HPLC area %). H NMR (600 MHz, DMSO-d6): δ
3.99 (s, 3H), 6.81 (d, J = 2.3 Hz, 1H), 7.27−7.34 (m, 1H),
7.40 (dd, J = 7.4, 2.1 Hz, 1H), 7.41−7.45 (m, 2H), 7.88 (d, J =
2.2 Hz, 1H), 7.91−7.98 (m, 2H), 8.17 (d, J = 2.0 Hz, 1H),
8.28 (s, 1H), 8.41−8.46 (m, 1H), 10.39 (s, 1H). 13C NMR
(101 MHz, DMSO-d6): δ 39.3, 103.94, 107.36, 108.28, 108.78,
125.91, 127.01, 127.98, 129.11, 133.63, 134.52, 136.66, 145.12,
145.80, 146.45, 160.96. HRMS: [M + H]+ m/z 318.13655,
found by formula [M] 317.129, theoretical 317.12766.
Synthesis of 10e.
A suspension of tris-
(dibenzylideneacetone)dipalladium−chloroform adduct (9.5
mg, 9.2 μmol, 0.005 equiv) and Xantphos (10.8 mg, 18.3
μmol, 0.01 equiv) in THF (2 mL) was added under argon to a
four-neck round-bottom flask containing 8e (377 mg, 1.9
mmol, 1.05 equiv), 9 (500 mg, 1.8 mmol, 1.00 equiv),
potassium carbonate (307 mg, 2.2 mmol, 1.2 equiv), and
EtOH (8 mL). The reaction mixture was heated at 80 °C for 3
h. The yellow suspension was then cooled to room
temperature, and the solvent was evaporated under reduced
pressure. The residue was crystallized from MeTHF. The
product was obtained as a yellow crystalline solid (502 mg,
1
1.26 mmol, 70% yield) with 99% purity (HPLC area %). H
NMR (400 MHz, DMSO-d6): δ 3.03 (br s, 3H), 3.12 (br s,
3H), 4.10 (s, 3H), 6.93 (dd, J = 2.0, 7.4 Hz, 1H), 7.31 (t, J =
7.1 Hz, 1H), 7.44 (t, J = 7.1 Hz, 2H), 7.83 (s, 1H), 7.96 (d, J =
7.6 Hz, 2H), 8.04 (s, 1H), 8.32 (s, 1H), 8.47 (d, J = 7.3 Hz,
1H), 11.86 (br s, 1H). 13C NMR (101 MHz, DMSO-d6): δ
35.90, 39.93, 104.00, 108.19, 109.14, 116.41, 125.96, 127.62,
128.05, 129.14, 134.46, 136.52, 136.97, 138.31, 145.32, 145.74,
158.55, 165.57. HRMS: [M + H]+ m/z 389.1728, found by
formula [M] 388.1654, theoretical 388.1648.
Synthesis of 10f.
A suspension of tris-
(dibenzylideneacetone)dipalladium−chloroform adduct (94.7
mg, 91.5 μmol, 0.005 equiv) and Xantphos (108 mg, 183
μmol, 0.01 equiv) in THF (20 mL) was added under argon to
a four-neck round-bottom flask containing 8f (4.00 g, 19.2
mmol, 1.05 equiv), 9 (5.00 g, 18.3 mmol, 1 equiv), potassium
carbonate (3.10 g, 21.8 mmol, 1.2 equiv), and EtOH (80 mL).
The reaction mixture was heated at 80 °C for 5 h. The yellow
suspension was then cooled to room temperature, and the
solvent was evaporated under reduced pressure. The residue
was crystallized from MeTHF. The product was obtained as a
yellow crystalline solid (4.44 g, 11.1 mmol, 61% yield) with
98% purity (HPLC area %). 1H NMR (400 MHz, DMSO-d6):
δ 2.22−2.34 (m, 2H), 4.11 (br t, J = 7.7 Hz, 2H), 4.16 (s, 3H),
4.45 (br t, J = 7.5 Hz, 2H), 6.94 (dd, J = 1.9, 7.3 Hz, 1H),
7.26−7.38 (m, 1H), 7.44 (t, J = 7.5 Hz, 2H), 7.90−8.00 (m,
3H), 8.11 (s, 1H), 8.33 (s, 1H), 8.50 (d, J = 7.3 Hz, 1H), 12.97
(br s, 1H). 13C NMR (101 MHz, DMSO-d6): δ 15.82, 40.88,
49.39, 53.55, 103.96, 107.82, 109.19, 114.21, 125.97, 127.74,
128.07, 129.14, 134.43, 136.08, 136.45, 138.60, 145.38, 145.68,
157.92, 164.87. HRMS: [M + H]+ m/z 401.1727, found by
formula [M] 400.1654, theoretical 400.1648.
Synthesis of 10d. A three-neck round-bottom flask
equipped with a thermometer, a reflux condenser, and a
magnetic stirrer was charged under argon with 8d (95 mg, 759
μmol, 1.04 equiv), 9 (200 mg, 732 μmol, 1.00 equiv), K2CO3
(116 mg, 842 μmol, 1.15 equiv), and ethanol (8 mL). The
mixture was stirred for 12 min at room temperature to obtain a
white suspension. A two-neck round-bottom flask was charged
under argon with Pd2dba3 (3.35 mg, 3.66 μmol, 0.005 equiv),
Xantphos (4.24 mg, 7.32 μmol, 0.01 equiv), and THF (2 mL).
The resulting red mixture was stirred for 10 min at room
temperature and then added to the white suspension. The
resulting mixture was stirred for 25 h at 75 °C. The suspension
was allowed to cool to room temperature, and the solid was
Synthesis of 10g. A three-neck round-bottom flask
equipped with a thermometer, a reflux condenser, and a
magnetic stirrer was charged under argon with 8g (103 mg,
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931 μmol, 1.06 equiv), 9 (240 mg, 879 μmol, 1.00 equiv),
K2CO3 (140 mg, 1.01 mmol, 1.15 equiv), and ethanol (16.7
mL). The mixture was stirred for 12 min at room temperature
to obtain a white suspension. A two-neck round-bottom flask
was charged under argon with Pd2dba3 (2.01 mg, 2.2 μmol,
0.0025 equiv), Xantphos (2.54 mg, 4.39 μmol, 0.005 equiv),
and THF (2.78 mL). The resulting red mixture was stirred for
10 min at room temperature and then added to the white
suspension. The resulting mixture was stirred for 22 h at 75 °C.
The suspension was allowed to cool to room temperature, and
the solid was filtered and washed with ethanol (4 mL). The
crude product was purified by flash chromatography (ethyl
acetate/heptane 60:40). The product was obtained as a yellow
solid (234 mg, 774 μmol, 88% yield) with 98% purity (HPLC
area %). 1H NMR (600 MHz, DMSO-d6): δ 6.75 (dd, J = 3.5,
1.8 Hz, 1H), 7.28 (br d, J = 2.1 Hz, 1H), 7.29−7.34 (m, 1H),
7.40 (dd, J = 3.4, 0.7 Hz, 1H), 7.41−7.46 (m, 2H), 7.95 (dd, J
= 8.2, 1.1 Hz, 2H), 7.99 (dd, J = 1.7, 0.8 Hz, 1H), 8.11 (d, J =
1.9 Hz, 1H), 8.30 (s, 1H), 8.46 (d, J = 7.5 Hz, 1H), 10.46 (s,
1H). 13C NMR (101 MHz, DMSO-d6): δ 104.21, 108.15,
108.94, 112.84, 115.89, 125.94, 127.20, 128.03, 129.13, 134.45,
136.30, 145.23, 145.66, 146.57, 147.62, 156.98. HRMS: [M −
H]− m/z 302.09251, found by formula [M] 303.09972,
theoretical 303.10078.
at room temperature and then added to the white suspension.
The resulting mixture was stirred for 6 h at 75 °C. The
suspension was allowed to cool to room temperature and
concentrated to a volume of 2 mL. Dichloromethane (7 mL)
was added, and the mixture was cooled to 4 °C for 4 h. The
suspension was filtered and washed with dichloromethane (4
mL), water (3 × 4 mL), and finally dichloromethane (4 mL).
The product was obtained as a yellow solid (309 mg, 0.97
1
mmol, 88% yield) with 97% purity (HPLC area %). H NMR
(600 MHz, DMSO-d6): δ 7.13−7.22 (m, 2H), 7.26−7.36 (m,
1H), 7.42 (t, J = 7.7 Hz, 2H), 7.80 (d, J = 4.7 Hz, 1H), 7.88−
7.99 (m, 3H), 8.01−8.10 (m, 1H), 8.25 (s, 1H), 8.39 (d, J =
7.4 Hz, 1H), 10.18−10.95 (m, 1H). 13C NMR (101 MHz,
DMSO-d6): δ 104.18, 108.57, 109.61, 125.88, 126.72, 127.85,
128.33, 129.08, 129.35, 131.77, 134.68, 139.37, 142.12, 144.90,
146.29, 161.64. HRMS: [M + H]+ m/z 320.08704, found by
formula [M] 319.07945, theoretical 319.07793.
Synthesis of 12a.
A suspension of tris-
(dibenzylideneacetone)dipalladium−chloroform adduct (7.6
mg, 7.4 μmol, 0.005 equiv) and Xantphos (8.7 mg, 14.8
μmol, 0.01 equiv) in THF (2 mL) was added under argon to a
four-neck round-bottom flask containing 8a (308 mg, 1.6
mmol, 1.05 equiv), 7-bromo-2-(4-fluorophenyl)imidazo[1,2-
a]pyridine (11a) (452 mg, 1.5 mmol, 1.00 equiv), potassium
carbonate (247 mg, 1.8 mmol, 1.2 equiv), and EtOH (8 mL).
The reaction mixture was heated at 80 °C for 3 h. The yellow
suspension was then cooled to room temperature, and the
solvent was evaporated under reduced pressure. The crude
product was washed with an aqueous solution of potassium
carbonate (2 mol/L) and then with water. After drying under
vacuum, the product was obtained as a yellow solid (548 mg,
Synthesis of 10h. A three-neck round-bottom flask
equipped with a thermometer, a reflux condenser, and a
magnetic stirrer was charged under argon with 8h (106 mg,
854 μmol, 1.06 equiv), 9 (220 mg, 805 μmol, 1.00 equiv),
K2CO3 (128 mg, 926 μmol, 1.15 equiv), and ethanol (16.7
mL). The mixture was stirred for 12 min at room temperature
to obtain a white suspension. A two-neck round-bottom flask
was charged under argon with Pd2dba3 (1.84 mg, 2.01 μmol,
0.0025 equiv), Xantphos (2.33 mg, 4.03 μmol, 0.005 equiv),
and THF (2.78 mL). The resulting red mixture was stirred for
10 min at room temperature and then added to the white
suspension. The resulting mixture was stirred for 22 h at 75 °C.
The suspension was allowed to cool to room temperature, and
the solid was filtered and washed with ethanol (3 × 4 mL).
The filtrate was concentrated under reduced pressure to 2 mL,
and ethyl acetate (8 mL) was added. The suspension was
cooled to 4 °C for 2 h, and the solid was filtered and washed
with ethyl acetate (4 mL). The product was obtained as an off-
white solid (173 mg, 547 μmol, 68% yield) with 97% purity
1
1.37 mmol, 91% yield) with 97% purity (HPLC area %). H
NMR (400 MHz, DMSO-d6): δ 1.14 (t, J = 7.1 Hz, 3H), 3.96
(s, 3H), 4.14−4.24 (m, 2H), 7.09 (dd, J = 1.7, 7.4 Hz, 1H),
7.27 (t, J = 9.0 Hz, 2H), 7.93−8.04 (m, 3H), 8.07 (s, 1H), 8.33
(s, 1H), 8.50 (d, J = 7.3 Hz, 1H), 11.15 (br s, 1H). 13C NMR
(101 MHz, DMSO-d6): δ 14.50, 38.72, 60.65, 104.04, 107.75,
109.05, 113.32, 116.03 (JC−F = 21.1 Hz), 127.62, 127.92 (JC−F
= 8.1 Hz), 130.96 (JC−F = 3.0 Hz), 136.31, 139.83, 140.20,
144.53, 145.60, 158.72, 162.26 (JC−F = 243.5 Hz), 162.39.
HRMS: [M + H]+ m/z 408.1466, found by formula [M]
407.1393, theoretical 407.1394.
Synthesis of 12b.
A suspension of tris-
1
(HPLC area %). H NMR (600 MHz, DMSO-d6): δ 3.91 (s,
(dibenzylideneacetone)dipalladium−chloroform adduct (9.1
mg, 8.8 μmol, 0.005 equiv) and Xantphos (10.4 mg, 17.7
μmol, 0.01 equiv) in THF (2 mL) was added under argon to a
four-neck round-bottom flask containing 8a (378 mg, 1.9
mmol, 1.07 equiv), 4-(7-bromo-[1,2,4]triazolo[1,5-a]pyridin-
2-yl)morpholine (11b) (500 mg, 1.8 mmol, 1.00 equiv),
potassium carbonate (296 mg, 2.1 mmol, 1.2 equiv), and
EtOH (8 mL). The reaction mixture was heated at 80 °C for 4
h. The yellow suspension was then cooled to room
temperature, and the solvent was evaporated under reduced
pressure. The residue was suspended in tBuOH and filtered.
The crude product was washed with water and dried under
vacuum. The product was obtained as a light-green solid (467
3H), 6.13 (dd, J = 3.8, 2.6 Hz, 1H), 7.07 (d, J = 11.7 Hz, 2H),
7.24 (dd, J = 7.4, 2.0 Hz, 1H), 7.27−7.35 (m, 1H), 7.43 (t, J =
7.7 Hz, 2H), 7.94 (d, J = 7.2 Hz, 2H), 8.04 (s, 1H), 8.27 (s,
1H), 8.43 (d, J = 7.4 Hz, 1H), 9.98 (s, 1H). 13C NMR (101
MHz, DMSO-d6): δ 36.86, 103.32, 107.42, 108.24, 108.69,
114.77, 125.52, 125.90, 127.00, 127.94, 129.10, 129.89, 134.55,
137.21, 145.03, 145.93, 160.60. HRMS: [M − H]− m/z
315.12404, found by formula [M] 316.13126, theoretical
316.13241.
Synthesis of 10i. A three-neck round-bottom flask
equipped with a thermometer, a reflux condenser, and a
magnetic stirrer was charged under argon with 8i (148 mg,
1.16 mmol, 1.06 equiv), 9 (300 mg, 1.1 mmol, 1.00 equiv),
K2CO3 (175 mg, 1.26 mmol, 1.15 equiv), and ethanol (12
mL). The mixture was stirred for 12 min at room temperature
to obtain a white suspension. A two-neck round-bottom flask
was charged under argon with Pd2dba3 (5.03 mg, 5.49 μmol,
0.005 equiv), Xantphos (6.36 mg, 11 μmol, 0.01 equiv), and
THF (3 mL). The resulting red mixture was stirred for 10 min
1
mg, 63% yield) with 94% purity (HPLC area %). H NMR
(400 MHz, DMSO-d6): δ 1.11 (t, J = 7.1 Hz, 3H), 3.38−3.50
(m, 4H), 3.65−3.76 (m, 4H), 3.93 (s, 3H), 4.12−4.21 (m,
2H), 7.10 (dd, J = 2.3, 7.4 Hz, 1H), 7.86−7.91 (m, 1H), 7.94
(s, 1H), 8.60 (d, J = 7.3 Hz, 1H), 11.26 (br s, 1H). 13C NMR
(101 MHz, DMSO-d6): δ 14.49, 38.59, 46.51, 60.55, 66.19,
100.96, 106.57, 113.18, 128.54, 140.09, 140.35, 141.29, 151.60,
466
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Org. Process Res. Dev. 2021, 25, 457−468

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Article
159.34, 162.34, 167.85. HRMS: [M + H]+ m/z 400.1735,
Authors
Fritz Bliss − Pharmaceutical Division, Synthetic Molecules
Technical Development, F. Hoffmann-La Roche Ltd, 4070
Basel, Switzerland
Erwann Le Coz − Pharmaceutical Division, Synthetic
Molecules Technical Development, F. Hoffmann-La Roche
Ltd, 4070 Basel, Switzerland
found by formula [M] 399.1663, theoretical 399.1655.
Synthesis of 12c.
A suspension of tris-
(dibenzylideneacetone)dipalladium−chloroform adduct (9.6
mg, 9.3 μmol, 0.005 equiv) and Xantphos (10.9 mg, 18.5
μmol, 0.01 equiv) in THF (2 mL) was added under argon to a
four-neck round-bottom flask containing 8f (405 mg, 1.9
mmol, 1.05 equiv), ethyl 7-bromo-[1,2,4]triazolo[1,5-a]-
pyridine-2-carboxylate (11c) (500 mg, 1.9 mmol, 1.00
equiv), potassium carbonate (310 mg, 2.2 mmol, 1.2 equiv),
and EtOH (8 mL). The reaction mixture was heated at 80 °C
for 1 h. The yellow suspension was then cooled to room
temperature, and the solvent was evaporated under reduced
pressure. The residue was crystallized from MeTHF. The
product was obtained as a white solid (496 mg, 1.27 mmol,
Kurt Puntener − Pharmaceutical Division, Synthetic Molecules
̈
Technical Development, F. Hoffmann-La Roche Ltd, 4070
Basel, Switzerland
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.oprd.0c00437
Author Contributions
The manuscript was written through contributions of all
authors. All of the authors approved the final version of the
manuscript.
1
67% yield) with 97% purity (HPLC area %). H NMR (400
MHz, CDCl3): δ 1.49 (t, J = 7.1 Hz, 3H), 2.44 (quin, J = 7.8
Hz, 2H), 4.27 (br t, J = 7.9 Hz, 2H), 4.33 (s, 3H), 4.45−4.60
(m, 4H), 7.36 (dd, J = 7.4, 2.3Hz, 1H), 7.67 (s, 1H), 8.48−
8.59 (m, 2H), 13.72 (s, 1H). 13C NMR (101 MHz, CDCl3): δ
14.33, 16.03, 41.71, 49.41, 53.88, 62.30, 104.92, 110.97,
113.76, 128.50, 135.48, 138.02, 140.82, 152.29, 156.57, 157.65,
160.43, 165.30. HRMS: [M + H]+ m/z 398.1577, found by
formula [M] 397.1504, theoretical 397.1499.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank our Structure Analytics team and Anna-Lena Glass
for their support with compound characterization. The
experimental support of Fabienne Mitterer and Etienne
Trachsel is kindly acknowledged.
Synthesis of 12d.
A suspension of tris-
(dibenzylideneacetone)dipalladium−chloroform adduct (9.3
mg, 9.0 μmol, 0.005 equiv) and Xantphos (10.7 mg, 18.1
μmol. 0.01 equiv) in THF (2 mL) was added under argon to a
four-neck round-bottom flask containing 8f (395 mg, 1.9
mmol, 1.05 equiv), 2,7-dibromo-[1,2,4]triazolo[1,5-a]pyridine
(11d) (500 mg, 1.8 mmol, 1.00 equiv), potassium carbonate
(302 mg, 2.2 mmol, 1.2 equiv), and EtOH (8 mL). The
reaction mixture was heated at 80 °C for 1 h. The yellow
suspension was then cooled to room temperature, and the
solvent was evaporated under reduced pressure. The residue
was suspended in MeTHF and filtered. The crude product was
washed with water and dried under vacuum. The product was
obtained as a white solid (451 mg, 1.12 mmol, 62% yield) with
>99% purity (HPLC area %). 1H NMR (400 MHz, CDCl3): δ
2.39−2.49 (m, 2H), 4.28 (t, J = 7.9 Hz, 2H), 4.33 (s, 3H), 4.48
(t, J = 7.7 Hz, 2H), 7.23−7.31 (m, 1H), 7.67 (s, 1H), 8.35−
8.41 (m, 2H), 13.69 (s, 1H). 13C NMR (101 MHz, CDCl3): δ
16.04, 41.73, 49.43, 53.90, 103.39, 109.09, 113.76, 127.66,
135.49, 138.03, 140.76, 145.26, 152.58, 157.64, 165.30.
HRMS: [M + H]+ m/z 404.0483, found by formula [M]
403.041, theoretical 403.0392.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.oprd.0c00437.
■
sı
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AUTHOR INFORMATION
Corresponding Author
■
Serena Fantasia − Pharmaceutical Division, Synthetic
Molecules Technical Development, F. Hoffmann-La Roche
Ltd, 4070 Basel, Switzerland; orcid.org/0000-0001-
6036-6600; Email: serena_maria.fantasia@roche.com
467
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