Preparation of 1,5-Dihydropyrazolo[3′,4′:5,6]pyrano[3,4- b]pyridines via a Microwave-Assisted, Palladium-Catalyzed Regioselective C-H Heteroarylation of Electron-Rich Pyrazoles

Article abstract of DOI:10.1021/acs.joc.9b00144

Here we report the first synthesis of a family of novel heterocyclic compounds based on a 5-dihydropyrazolo[3′,4′:5,6]pyrano[3,4-b]pyridine core. In the course of our drug discovery programs, we had need to access the previously unknown 5-dihydropyrazolo[3′,4′:5,6]pyrano[3,4-b]pyridine core. Initial attempts required long reaction times, which led to degradation and side products. Reaction optimization identified a Pd-catalyzed, microwave-assisted C-H heteroarylation protocol for the rapid, general, and high yielding synthesis of this tricyclic core (as well as related analogs) suitable to drive optimization efforts.

Full text of DOI:10.1021/acs.joc.9b00144

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Note
Preparation of 1,5-dihydropyrazolo[3’,4’:5,6]pyrano[3,4-
b]pyridines via a microwave-assisted, palladium-catalyzed
regioselective C-H heteroarylation of electron-rich pyrazoles
Aaron T Garrison, Elizabeth S. Childress, Dexter C Davis, and Craig W Lindsley
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00144 • Publication Date (Web): 26 Feb 2019
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Preparation of 1,5-dihydropyrazolo[3’,4’:5,6]pyrano[3,4-b]pyridines via a
microwave-assisted, palladium-catalyzed regioselective C-H heteroarylation
of electron-rich pyrazoles.
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Aaron T. Garrison,†‡⊥ Elizabeth S. Childress,†‡⊥ Dexter C. Davis†‡ and Craig W. Lindsley†‡§*
†Vanderbilt Center for Neuroscience Drug Discovery, ‡Department of Pharmacology, §Department of
Chemistry, Vanderbilt University, Nashville, Tennessee 37232, United States
Corresponding Author's E-mail Address ; craig.lindsley@vanderbilt.edu
Table of Contents
R1
Pd2(dba)3 (5 mol%)
SPhos (7.5 mol%)
Bu4NOAc (1.4 equiv.)
N
N
N
N
21 examples
R
X
Br
W, X = CH, N
Y = O, S, NMe
O
O
Y
N
N
W
1,4-dioxane (0.2 M)
wave, 125 oC, 5 min
N
N
28-99%
R2
98%
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Here we report the first synthesis of a family of novel heterocyclic compounds based on a 5-
dihydropyrazolo[3’,4’:5,6]pyrano[3,4-b]pyridine core. In the course of our drug discovery programs, we
had need to access the previously unknown 5-dihydropyrazolo[3’,4’:5,6]pyrano[3,4-b]pyridine core.
Initial attempts required long reaction times, which led to degradation and side products. Reaction
optimization identified a Pd-catalyzed, microwave-assisted C-H heteroarylation protocol for the rapid,
general and high yielding synthesis of this tricyclic core (as well as related analogs) suitable to drive
optimization efforts.
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Heterocyclic compounds are the backbone of drug discovery efforts, and the ability to access
novel heterocyclic scaffolds in a general and rapid manner is essential for the medicinal chemist to drive
structure–activity–relationships (SAR) and address physiochemical and/or disposition liabilities of
common heterocyclic templates.1,2 Moreover, heterocyclic chemical space is limited, and novel
heterocyclic ring systems and/or substitution patterns are favorable to secure intellectual property to
advance therapeutics into the clinic.1-4 Thus, synthetic organic chemistry is a driver of innovation with the
potential to transform drug discovery.3
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R3
N
N
R1
IMHB
planar
R2
S
N
NH2
2
O
cyclize
R1
expand/
add sp3
S
HN R2
N
1
R3
N
N
R2
R1
O
N
3
Figure 1.
Scaffold-hopping and medicinal chemistry design identified the previously unknown 1,5-
dihydropyrazolo[3’,4’:5,6]pyrano[3,4-b]pyridine core (highlighted in red) as a putative scaffold of interest, but no known
synthetic routes for the aza-analog existed.
A case in point centers on our M4 positive allosteric modulator (PAM) program, and a single lead series 1
based on a functionalized 3-amino thieno[2,3-b]pyridine core (Figure 1).5,6 Significant optimization
efforts could not overcome series liabilities that precluded candidate selection.5,6 Therefore, scaffold-
hopping exercises were employed to access new chemical space as well as to eliminate the problematic 3-
amino moiety of 1. Initially, we explored a novel tricyclic scaffold 2, a 1H-pyrazolo[3’,4’:4,5]thieno2,3-
b]pyridine series,7 but the planar, fully conjugated tricyclic system suffered from significant solubility and
disposition issues, despite possessing potent M4 PAM activity. The next design focused on yet another
previously unknown8 tricyclic system based on a 5-dihydropyrazolo[3’,4’:5,6]pyrano[3,4-b]pyridine core,
3. This design added sp3 character and distorted the topography of the system from planarity. The
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challenge now fell to the chemists to develop a general, rapid and high-yielding route to this novel
tricyclic core, while providing opportunities for diverse functionalization.
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While the aza-based system 3 was unknown, the analogous phenyl-based system 5 was a known tricyclic
scaffold (Figure 2) with activity at nicotinic acetylcholine receptors9 and COX-210 but required lengthy
syntheses which proceeded with poor regiochemical control. Although conditions have been reported for
intermolecular C-H arylations, we were drawn to the regioselective, intramolecular palladium-catalyzed
C-H arylation of alkoxy pyrazoles reported by Vernier and Gomez (Figure 2A) as a more attractive
strategy to potentially access 3. Here, from acyclic precursor 4, a one-pot, 18-hour intramolecular
palladium-catalyzed C-H arylation afforded analogs 5 in yields ranging from 14-93%.11-13 The success of
this protocol varied based on the electronic character of the aryl ring and the ligand employed (SPhos or
QPhos). In general, electron deficient systems suffered from lower yields, and in our case, the pyridine
ring was both electron deficient and added the potential complexity of substrates adorned with basic
nitrogens, which were not explored in the Vernier and Gomez report.11
Pd(OAc)2 (5 mol%)
SPhos (7.5 mol%) or
QPhos (7.5 mol%)
A
R2
Br
N
N
R1
X
Bu4NOAc (3.0 equiv.)
1,4-dioxane (0.4 M)
R1
N
N
R2
X
X = O or S
70-85 oC, 18 h
14-93%
4
5
B
Pd(OAc)2 (5 mol%)
SPhos (7.5 mol%)
Br
N
N
O
N
Bu4NOAc (3.0 equiv.)
1,4-dioxane (0.4 M)
N
N
O
N
70-85 o
C
6
7
19%, 15 min
62%, 18 h
Figure 2. A) Previously Reported11 Pd-Catalyzed C-H arylation to access functionalized 1,5-dihydroisochromeno[4,3-
c]pyrazoles 5; B) application of these conditions for a heteroarylation to access 5-dihydropyrazolo[3’,4’:5,6]pyrano[3,4-
b]pyridines 7.
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Preparation of an analogous acyclic precursor 6 (Scheme 1) proved straightforward from commercial 3-
bromo-2-methyl pyridine 8. Benzylic bromination, followed by displacement with 1-methyl-1H-pyrazol-
4-ol provided 6 in good overall yields.14 Other variations on this short two-step synthesis allowed for the
preparation of other functionalized congeners.14
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Scheme 1. Synthesis of Acyclic Precursor 6.a
HO
N
NBS, Bz2O2
CCl4
Br
Br
Br
N
Cs2CO3, THF
O
Br
N
N
Me
N
reflux, 2-4 h
87%
50 °C, 5 h
92%
N
N
8
9
6
Subjecting 6 to the reported reaction conditions (Pd(OAc)2 (5 mol%), SPhos (7.5 mol%), Bu4NOAc (3.0
equiv.), 1,4-dioxane, 85 oC, 18 h)11 did indeed provide, for the first time via a heteroarylation reaction, the
desired 1,5-dihydropyrazolo[3’,4’:5,6]pyrano[3,4-b]pyridine core 7 (Figure 2B). However, like electron
deficient aryl derivatives,11 7 was obtained in low isolated yield (19% after 15 min and 62% after 18 h).14
Clearly, to employ this novel core in a drug discovery campaign, reaction conditions would need to be
optimized in terms of both yield and reaction time. Table 1 summarizes the range of Pd(0) and Pd(II)
catalysts, ligands, bases, and reaction times employed for the optimization of the intramolecular
heteroarylation reaction with 6, and based on previous heterocycle optimization work,15,16 we employed
o
microwave heating throughout. As shown in entry 1, microwave heating for 180 min at 150 C (and
lowering the equivalents of Bu4NOAc from 3.0 to 1.4) dramatically improved the conversion of 6 to 7
(87%) as compared to the original Vernier and Gomez thermal conditions, and with reduced reaction time
(3 versus 18 hours). Across all the entries, 5 mol% Pd2(dba)3 proved to be the optimal Pd catalyst, 7.5
mol% SPhos emerged as the optimal ligand, and 1.4 equivalents of Bu4NOAc was the ideal base. These
o
optimal conditions, coupled with microwave heating at 125 C for 5 min (entry 16) provided 93%
conversion of 6 to 7. Replacement of either the ligand (entries 22 and 23) or the base (entries 18-21)
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under these optimal reaction conditions afforded poor conversion of 6 to 7 (4-33%). With the optimal
conditions in hand, we then explored the generality and scope of the microwave-assisted, Pd(0)-catalyzed
C-H heteroarylation reaction.
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Table 1. Optimization of the Heteroarylation Conditionsa
N
Pd catalyst (5 mol%)
Ligand (7.5 mol%)
base (1.4 equiv.)
N
Br
O
O
N
1,4-dioxane (0.2 M)
wave heating
N
N
N
6
7
entry catalyst
Ligand
base
temp time
yield
(oC)
(min (%)b
)
1
Pd(OAc)2
Pd2(dba)3
SPhos
SPhos
SPhos
SPhos
SPhos
SPhos
SPhos
SPhos
SPhos
SPhos
SPhos
SPhos
SPhos
SPhos
SPhos
SPhos
SPhos
SPhos
SPhos
Bu4NOAc
Bu4NOAc
Bu4NOAc
Bu4NOAc
Bu4NOAc
Bu4NOAc
Bu4NOAc
Bu4NOAc
Bu4NOAc
Bu4NOAc
Bu4NOAc
Bu4NOAc
Bu4NOAc
Bu4NOAc
Bu4NOAc
Bu4NOAc
Bu4NOAc
K2CO3
150
150
150
150
150
150
90b
90
180
15
30
15
30
15
15
15
15
15
30
15
15
15
30
5
87
83
87
73
71
96
19
63
21
45
46
22
16
67
80
93c
78
6
2
3
Pd2(dba)3
4
Pd(PPh3)4
5
Pd(PPh3)4
6
Pd(dppf)Cl2
Pd(OAc)2
7
8
Pd2(dba)3
9
Pd(dppf)Cl2
BrettPhosPd G3
BrettPhosPd G3
Pd(OAc)2
90
10
11
12
13
14
15
16
17
18
19
20
21
22
23
150
150
150
100
100
100
125
125
125
125
Pd(dppf)Cl2
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd(dppf)Cl2
Pd2(dba)3
5
5
Pd2(dba)3
DIEPA
5
4
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
SPhos
SPhos
SPhos
XantPhos
(±)-BINAP
KOAc
Cs2CO3
NaOtBu
Bu4NOAc
Bu4NOAc
125
125
125
125
125
5
5
5
5
5
10
12
8
33
10
___________________________________________________________
aPercent conversion determined via LCMS using a calibration curve and
naphthalene as an internal standard (see SI) with 5 mol% catalyst. bReaction
conducted using traditional thermal heating. cAverage of six replicates.
As shown in Scheme 2, the core tricyclic ring system 7 could be obtained in 98% isolated yield, a major
improvement over the reported C-H arylation conditions.11 In addition, substitutions at the benzylic
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position (11a) proceeded in high yield (87%), as did substrates bearing electron-donating groups (11b,
11c and 11d). Substrates with electron-withdrawing groups, such as 11e and 11f, were provided in
moderate yields (50-54%). These optimal conditions also allowed for the preparation of novel tetracyclic
derivatives, such as the 5,9-dihydropyrazolo[3’,4’:5,6]pyrano[4,3-e][1,2,4]triazolo[1,5-a]pyridine 11g
(81%) and the 1,5-dihydropyrazolo[3’,4’:5,6]pyrano[3,4-c]isoquinoline 11h (70%). Finally, a wide
range of substituents were tolerated at the N-1 pyrazole, providing derivatives 11i-j in high isolated yields
(84-91%).14 In line with prior reports of analogous intramolecular C-H heteroarylations, our reaction
conditions afforded desired products with complete regioselectivity (as determined by NOE evaluation of
analog 11c; see Supporting Information).
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Scheme 2. Scope of the Heteroarylation with Pyridines 10.a
R1
Pd2(dba)3 (5 mol%)
SPhos (7.5 mol%)
N
N
Br
Bu4NOAc (1.4 equiv.)
R
R
O
O
N
N
N
1,4-dioxane (0.2 M)
N
N
R1
wave, 125 oC, 5 min
R2
R2
10
11
N
N
N
N
N
N
N
O
O
O
O
N
N
N
N
11b
11c
, 71%
, 99%
7
11a
, 98%
N
, 87%
N
N
N
N
N
N
N
Cl
O
O
O
O
NC
N
N
MeO
N
N
N
N
11g
, 81%
11d
11e
11f
, 50%
, 83%
N
, 54%
N
O
N
N
N
N
O
O
N
N
N
11h
11i
11j
, 87%
, 70%
, 87%
F
N
N
N
N
O
O
N
N
11k
11l
, 84%
, 91%
aStandard Reaction conditions: 10 (1 mmol), Pd2(dba)3 (5 mol%), SPhos (7.5 mol%),
Bu4NOAc (1.4 equiv), 1,4-dioxane (0.2 M), W, 125 oC, 5 min. Isolated yields after
column chromatography.12 See Supporting Information for details regarding
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precursor synthesis.
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6
7
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Encouraged by these results, we wanted to further push the scope of the reaction and assess other pyridine
regiosiomers and alternative heteroatoms, as in 13 (Scheme 3), the acyclic precursors 12 of which were
readily assembled based on the route depicted in Scheme 1.14 Interestingly, the 1,5-
dihydropyrazolo[3’,4’:5,6]pyrano[3,4-c]pyridine congener 12a was readily accessed (64%) under these
conditions, while the 1,5-dihydropyrazolo[3’,4’:5,6]pyrano[4,3-b]pyridine analog 12b was isolated in
only trace amounts. The phenyl analog 12c from the original Vernier and Gomez report could also be
readily obtained under these conditions in an 86% isolated yield, as well as an -methyl derivative 12d
(84%), further highlighting the generality of this microwave-accelerated protocol. Replacement of the
oxygen atom with a sulfur, to provide a 1,5-dihydropyrazolo[3’,4’:5,6]thiopyrano[3,4-b]pyridine system
12e proceeded in moderate yield (39%), but phenyl variant 12f was produced in high yield (90%).
Unlike the ether series, the thioether series suffered a diminution in yield with an -methyl substituent,
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12g.
Finally, employing a tertiary amine linker to arrive at a 4,5-dihydro-1H-pyrazolo[3,4-
f][1,7]naphthyridine core was not successful, as the desired tricyclic ring system oxidized during work-up
to provide the corresponding lactams 12h and 12i in moderate isolated yields. Of note, the 1,4-dihydro-
5H-pyrazolo[3,4-f][1,7]naphthyridin-5-one scaffolds (12h and 12i) represent another novel heterocyclic
ring system never before described in the primary or patent literature.
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Scheme 3. Reaction Scope with Alternate Substrates.a
8
9
N
N
Pd2(dba)3 (5 mol%)
SPhos (7.5 mol%)
Bu4NOAc (1.4 equiv.)
Y
Br
Y
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X
Z
X
Z
N
N
1,4-dioxane (0.2 M)
R
R
wave, 125 oC, 5 min
R = H, Me
12
13
N
O
N
N
N
N
N
N
N
N
O
O
N
O
12c
12d
, 86%
, 84%
12a
12b
, 7%
, 64%
N
N
N
N
N
N
S
S
S
N
b
12e
12f
12g
, 44%
, 39%
, 90%
N
N
N
N
O
N
N
N
O
c
c
12h
12i
, 46%
, 28%
aStandard Reaction conditions: 12 (1 mmol), Pd2(dba)3 (5 mol%), SPhos (7.5 mol%),
Bu4NOAc (1.4 equiv), 1,4-dioxane (0.2 M), W, 125 oC, 5 min. Isolated yields after
column chromatography. bPercent conversion; sample degrades following normal
phase purification. cProduct obtained as a result of oxidation during purification (see SI).12
Finally, evaluation of analogs 3 and 7 as M4 PAMs proved fruitful. Congeners without the ideal
substituents accessed via this methodology afforded only moderately active PAMs (e.g. low micromolar
EC50s), validating the design and scaffold-hopping approach.17
In conclusion, a new microwave-assisted, Pd(0)-catalyzed C-H heteroarylation reaction of electron-
rich pyrazoles has been developed. This new protocol shows complete regioselectivity, broad generality
and requires only five minutes in the microwave. Under this protocol, several previously unknown (in
both the patent and primary literature) heterotricyclic and heterotetracyclic ring systems were produced in
high yield. This report adds new opportunities for medicinal chemists in their drug discovery programs,
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and further highlights the power of synthetic organic chemistry to drive innovation and advance drug
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EXPERIMENTAL SECTION
General methods. All reactions were carried out employing standard chemical techniques under inert
atmosphere. Solvents used for extraction, washing, and chromatography were HPLC grade. All reagents
were purchased from commercial sources and were used without further purification. All microwave
reactions were carried out in sealed tubes in a Biotage Initiator microwave synthesis reactor. Temperature
control was automated via IR sensor and all indicated temperatures correspond to the maximal
temperature reached during each experiment. Analytical HPLC was performed on an Agilent 1200 LCMS
with UV detection at 215 nm along with ELSD detection and electrospray ionization, with all final
compounds showing > 95% purity and a parent mass ion consistent with the desired structure. All NMR
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spectra were recorded on a 400 MHz Brüker AV-400 instrument. H chemical shifts are reported as δ
values in ppm relative to the residual solvent peak (CDCl3 = 7.26). Data are reported as follows: chemical
shift, multiplicity (br. = broad, s = singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublets, m
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= multiplet), coupling constant (Hz), and integration. C chemical shifts are reported as δ values in ppm
relative to the residual solvent peak (CDCl3 = 77.16). High resolution mass spectra were obtained on an
Agilent 6540 UHD Q-TOF with ESI source. Automated flash column chromatography was performed on
an Isolera One by Biotage. Melting points were recorded on an OptiMelt automated melting point system
by Stanford Research Systems.
General procedure for synthesis of acyclic precursors via mesylate intermediates. Triethylamine (1.5
equiv.) was added to a solution of the appropriate pyridylmethanol (1 equiv.) in DCM (0.2 M). The
solution was then cooled to 0 °C and then methanesulfonyl chloride (1.2 equiv.) was added dropwise. The
mixture was allowed to gradually warm to room temperature and was stirred until LCMS indicated full
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conversion to the desired product. The reaction was quenched with saturated NaHCO3 and then washed
three times with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered,
and concentrated via vacuum. The resulting residue was carried forward as is. Cesium carbonate (1.1
equiv.) was added to a solution of the crude pyridylmethyl methanesulfonate (1 equiv.) and substituted
pyrazolol (1.1 equiv.) in THF (0.3 M). The mixture was heated to 50 °C and stirred until LCMS indicated
full conversion to the desired product. The reaction was cooled to room temperature and quenched by
slow addition of water. The aqueous mixture was washed with DCM three times, and the combined
organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated via vacuum. The
resulting residue was purified by flash liquid chromatography on silica gel using 0-60% ethyl acetate in
hexanes to elute the desired product.
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3-Bromo-2-(((1-methyl-1H-pyrazol-4-yl)oxy)methyl)pyridine (6). 212.2 mg (77%) of 6 was obtained
as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 8.56 (dd, J = 4.7, 1.2 Hz, 1H), 7.87 (dd, J = 8.0, 1.3 Hz,
1H), 7.27 (s, 1H), 7.16 – 7.12 (m, 2H), 5.14 (s, 2H), 3.79 (s, 3H); 13C{1H} NMR (100 MHz CDCl3): δ
154.2, 148.1, 145.4, 140.8, 127.6, 124.6, 121.1, 116.6, 74.1, 40.0; LCMS: RT = 0.742 min, m/z = 268.0
[M+H]+; HRMS (ESI) m/z: [M + H]+ calcd for C10H11BrN3O 268.0080, found 268.0080.
3-Bromo-2-(1-((1-methyl-1H-pyrazol-4-yl)oxy)ethyl)pyridine (18). 18.9 mg (91%) of 18 was obtained
as an off-white amorphous solid. 1H NMR (400 MHz, CDCl3): δ 8.58 (dd, J = 4.6, 1.4 Hz, 1H), 7.84 (dd,
J = 8.1, 1.4 Hz, 1H), 7.13 (s, 1H), 7.08 (dd, J = 8.1, 4.6 Hz, 1H), 6.96 (s, 1H), 5.50 (q, J = 6.5 Hz, 1H)
3.72 (s, 3H), 1.63 (d, J = 6.5, 3H); 13C{1H} NMR (100 MHz CDCl3): δ 158.3, 148.7, 144.3, 140.8, 128.1,
124.2, 120.0, 117.2, 78.1, 39.5, 20.20; LCMS: RT = 0.642 min, m/z = 284.2 [M+H]+; HRMS (ESI) m/z:
[M + H]+ calcd for C11H13BrN3O 282.0241, found 282.0239.
3-Bromo-5-methyl-2-(((1-methyl-1H-pyrazol-4-yl)oxy)methyl)pyridine (19). 22.8 mg (57%) of 19
was obtained as an off-white amorphous solid. 1H NMR (400 MHz, CDCl3): δ 8.38 (d, J = 1.0 Hz, 1H),
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7.71 (d, J = 1.0 Hz, 1H), 7.27 (s, 1H), 7.14 (s, 1H), 5.10 (s, 2H) 3.79 (s, 3H), 2.32 (s, 3H); 13C{1H} NMR
(100 MHz CDCl3): δ 151.2, 148.6, 14.4, 141.1, 135.0, 127.6, 120.8, 116.6, 73.9, 39.6, 17.8; LCMS: RT =
0691 min, m/z = 284.2 [M+H]+; HRMS (ESI) m/z: [M + H]+ calcd for C11H13BrN3O 282.0241, found
282.0239.
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3-Bromo-5-chloro-2-(((1-methyl-1H-pyrazol-4-yl)oxy)methyl)pyridine (22). 28.1 mg (95%) of 22 was
obtained as a white amorphous solid. 1H NMR (400 MHz, CDCl3): δ 8.52 (d, J = 2.1 Hz, 1H), 7.91 (d, J
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= 2.1 Hz, 1H), 7.27 (s, 1H), 7.14 (s, 1H), 5.11 (s, 2H) 3.79 (s, 3H); C{1H} NMR (100 MHz CDCl3): δ
152.5, 147.0, 145.2, 140.0, 131.9, 127.5, 120.9, 116.7, 73.5, 39.6; LCMS: RT = 0.750 min, m/z = 304.2
[M+H]+; HRMS (ESI) m/z: [M + H]+ calcd for C10H10BrClN3O 301.9695, found 301.9693.
3-Bromo-2-(((1-cyclopropyl-1H-pyrazol-4-yl)oxy)methyl)pyridine (26). 35.5 mg (74%) of 26 was
obtained as a light yellow oil. 1H NMR (400 MHz, CDCl3): δ 8.56 (dd, J = 4.7, 1.4 Hz, 1H), 7.88 (dd, J =
8.0, 1.4 Hz, 1H), 7.27 (br. s, 1H), 7.23 (br. s, 1H), 7.15 (dd, J = 8.0, 4.7 Hz, 1H), 5.13 (s, 2H) 3.51 – 3.45
(m, 1H), 1.08 – 1.03 (m, 2H), 0.97 – 0.90 (m, 2H); 13C{1H} NMR (100 MHz CDCl3): δ 154.2, 148.1,
144.9, 140.8, 127.8, 124.6, 121.1, 116.2, 74.0, 33.1, 6.4; LCMS: RT = 0.733 min, m/z = 296.1 [M+H]+;
HRMS (ESI) m/z: [M + H]+ calcd for C12H13BrN3O 294.0237, found 294.0241.
3-Bromo-2-(((1-isobutyl-1H-pyrazol-4-yl)oxy)methyl)pyridine (27). 29.7 mg (58%) of 27 was
obtained as a light brown oil. 1H NMR (400 MHz, CDCl3): δ 8.56 (dd, J = 4.7, 1.4 Hz, 1H), 7.88 (dd, J =
8.1, 1.4 Hz, 1H), 7.29 (d, J = 0.4 Hz, 1H), 7.16 – 7.12 (m, 2H), 5.15 (s, 2H) 3.78 (d, J = 7.3 Hz, 2H), 2.19
– 2.04 (m, 1H), 0.86 (d, J = 6.7 Hz, 6H); 13C{1H} NMR (100 MHz CDCl3): δ 154.3, 148.1, 145.0, 140.8,
127.4, 124.6, 121.1, 116.2, 74.1, 60.4, 29.8, 20.0; LCMS: RT = 0.842 min, m/z = 310.2 [M+H]+; HRMS
(ESI) m/z: [M + H]+ calcd for C13H17BrN3O 310.0554, found 310.0552.
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3-Bromo-2-(((1-(4-fluorophenyl)-1H-pyrazol-4-yl)oxy)methyl)pyridine (28). 24.4 mg (72%) of 28 was
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obtained as a tan amorphous solid. H NMR (400 MHz, CDCl3): δ 8.59 (dd, J = 4.6, 1.4 Hz, 1H), 7.91
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(dd, J = 8.1, 1.4 Hz, 1H), 7.66 (d, J = 0.6 Hz, 1H), 7.60-7.53 (m, 3H), 7.18 (dd, J = 8.0, 4.7 Hz, 1H) 7.14-
7.07 (m, 2H), 5.24 (s, 2H); 13C{1H} NMR (100 MHz CDCl3): δ 160.1 (d, J(C,F) = 244.0 Hz), 154.0,
148.2, 147.0, 140.9, 136.9 (d, J(C,F) = 2.4 Hz), 130.5, 124.8, 121.3, 120.3 (d, J(C,F) = 8.0 Hz), 116.2 (d,
J(C,F) = 22.8 Hz), 112.9, 74.0; LCMS: RT = 0.974 min, m/z = 348.0 [M+H]+; HRMS (ESI) m/z: [M + H]+
calcd for C15H12BrFN3O 348.0147, found 348.0143.
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2-(((1-Benzyl-1H-pyrazol-4-yl)oxy)methyl)-3-bromopyridine (29). 91.5 mg (91%) of 29 was obtained
as a light yellow oil. 1H NMR (400 MHz, CDCl3): δ 8.63 (dd, J = 4.7, 1.4 Hz, 1H), 7.96 (dd, J = 8.0, 1.4
Hz, 1H), 7.44 (s, 1H), 7.43 – 7.34 (m, 3H), 7.28 – 7.20 (m, 4H), 5.27 (s, 2H), 5.22 (s, 2H); 13C{1H} NMR
(100 MHz CDCl3): δ 154.1, 148.0, 145.6, 140.9, 136.6, 128.8, 128.1, 128.0, 127.7, 127.6, 124.6, 121.2,
115.9, 73.9, 56.7; LCMS: RT = 0.826 min, m/z = 346.4 [M+H]+; HRMS (ESI) m/z: [M + H]+ calcd for
C16H15BrN3O 344.0398, found 344.0396.
4-Bromo-3-(((1-methyl-1H-pyrazol-4-yl)oxy)methyl)pyridine (30). 40.9 mg (81%) of 30 was obtained
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as a tan oil. H NMR (400 MHz, CDCl3): δ 8.67 (s, 1H), 8.52 (d, J = 5.0 Hz, 1H), 7.51 (dd, J = 5.0, 0.5
Hz, 1H), 7.25 (d, J = 0.7 Hz, 1H), 7.09 (d, J = 0.7 Hz, 1H), 4.96 (s, 2H), 3.81 (s, 3H); 13C{1H} NMR (100
MHz CDCl3): δ 151.4, 148.5, 145.8, 145.0, 127.2, 122.7, 119.7, 116.2, 71.8, 39.7; LCMS: RT = 0.555
min, m/z = 270.2 [M+H]+; HRMS (ESI) m/z: [M + H]+ calcd for C10H11BrN3O 268.0085, found 268.0082.
3-Bromo-2-(((1-methyl-1H-pyrazol-4-yl)thio)methyl)pyridine (34). 25.4 mg (24%) of 34 was obtained
as a clear oil. 1H NMR (400 MHz, CDCl3): δ 8.42 (dd, J = 4.7, 1.5 Hz, 1H), 7.93 (dd, J = 8.1, 1.5 Hz, 1H),
7.83 (dd, J = 8.1, 1.5 Hz, 1H), 7.31 (s, 1H), 7.24 (s, 1H), 7.05 (dd, J = 8.1, 4.7 Hz, 1H) 4.12 (s, 2H), 3.83
(s, 3H); 13C{1H} NMR (100 MHz CDCl3): δ 156.6, 147.6, 144.2, 140.9, 134.7, 123.4, 121.5, 108.9, 43.2,
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39.2; LCMS: RT = 0.683 min, m/z = 284.0 [M+H]+; HRMS (ESI) m/z: [M + H]+ calcd for C10H11BrN3S
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283.9857, found 283.9856.
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N-((3-Bromopyridin-2-yl)methyl)-N,1-dimethyl-1H-pyrazol-4-amine (37). 20.3 mg (18%) of 37 was
obtained as a tan oil. 1H NMR (400 MHz, CDCl3): δ 8.51 (dd, J = 4.6, 1.4 Hz, 1H), 7.84 (dd, J = 8.0, 1.4
Hz, 1H), 7.18 (s, 1H), 7.08 (dd, J = 8.0, 4.6 Hz, 1H), 6.94 (s, 1H), 4.31 (s, 2H), 3.78 (s, 3H), 2.79 (s, 3H);
13C{1H} NMR (100 MHz CDCl3): δ 156.5, 147.8, 140.8, 138.7, 128.2, 123.7, 121.79, 116.58, 61.27,
41.38, 39.24; LCMS: RT = 0.423 min, m/z = 283.2 [M+H]+; HRMS (ESI) m/z: [M + H]+ calcd for
C11H14BrN4 281.0401, found 281.0393.
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General procedure for synthesis of acyclic precursors via alkyl bromide intermediates. A mixture of
N-bromosuccinimide (1.1 equiv.), the appropriate methylpyridine (1 equiv.), and benzoyl peroxide (0.08
equiv.) in CCl4 (0.1 M) was heated under reflux until LCMS indicated full conversion to the desired
product. The reaction was cooled to room temperature and quenched with water. The aqueous mixture
was washed with DCM three times, and the combined organic layers were washed with brine, dried over
Na2SO4, filtered, and concentrated via vacuum. The resulting residue was carried forward as is. Note:
This procedure afforded crude alkyl bromide intermediates leading to acyclic precursors 21 and 22. To a
mixture of freshly synthesized or commercially available alkyl bromides (1 equiv.) in THF (0.3 M) was
added cesium carbonate (1.1 equiv.) and substituted pyrazolol (1.1 equiv.). The mixture was heated to 50
°C and stirred until LCMS indicated full conversion to the desired product. The reaction was cooled to
room temperature and quenched by slow addition of water. The aqueous mixture was washed with DCM
three times, and the combined organic layers were washed with brine, dried over Na2SO4, filtered, and
concentrated via vacuum. The resulting residue was purified by flash liquid chromatography on silica gel
using 0-60% ethyl acetate in hexanes to elute the desired product.
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3-Bromo-4-methyl-2-(((1-methyl-1H-pyrazol-4-yl)oxy)methyl)pyridine (20). 73.3 mg (65%) of 20
was obtained as a colorless residue. 1H NMR (400 MHz, CDCl3): δ 8.40 (d, J = 4.7 Hz, 1H), 7.28 (s, 1H),
7.16 (s, 1H), 7.13 (d, J = 4.7 Hz, 1H), 5.16 (s, 2H), 3.79 (s, 3H), 2.43 (s, 3H); 13C{1H} NMR (100 MHz
CDCl3): δ 154.3, 148.4, 147.4, 145.5, 127.6, 125.6, 123.8, 116.6, 74.6, 39.6, 23.1; LCMS: RT = 0.608
min, m/z = 284.2 [M+H]+; HRMS (ESI) m/z: [M + H]+ calcd for C11H13BrN3O 282.0241, found 282.0236.
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3-Bromo-6-methoxy-2-(((1-methyl-1H-pyrazol-4-yl)oxy)methyl)pyridine (21). 29.6 mg (56%) of 21
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was obtained as a light brown oil. H NMR (400 MHz, CDCl3): δ 7.68 (d, J = 8.7 Hz, 1H), 7.29 (br. s,
1H), 7.13 (br. s, 1H), 6.60 (d, J = 8.7 Hz, 1H), 5.03 (s, 2H) 3.90 (s, 3H), 3.79 (s, 3H); 13C{1H} NMR (100
MHz CDCl3): δ 162.8, 151.1, 145.6, 142.9, 127.6, 116.5, 112.6, 112.2, 74.0, 53.9, 39.6; LCMS: RT =
0.776 min, m/z = 300.2 [M+H]+; HRMS (ESI) m/z: [M + H]+ calcd for C11H13BrN3O2 298.0191, found
298.0186.
5-Bromo-6-(((1-methyl-1H-pyrazol-4-yl)oxy)methyl)picolinonitrile (23). 19.4 mg (37%) of 23 was
obtained as an off-white solid. 1H NMR (400 MHz, CDCl3): δ 8.05 (d, J = 8.2 Hz, 1H), 7.54 (d, J = 8.2
Hz, 1H), 7.27 (d, J = 0.6 Hz, 1H), 7.17 (d, J = 0.6 Hz, 1H), 5.15 (s, 2H) 3.81 (s, 3H); 13C{1H} NMR (100
MHz CDCl3): δ 156.8, 145.1, 142.0, 132.0, 129.0, 127.6, 125.7, 117.0, 116.5, 73.9, 39.7; LCMS: RT =
0.635 min, m/z = 295.2 [M+H]+; HRMS (ESI) m/z: [M + H]+ calcd for C11H10BrN4O 293.0037, found
293.0038. MP: 105.2 – 108.2 °C.
6-Bromo-5-(((1-methyl-1H-pyrazol-4-yl)oxy)methyl)-[1,2,4]triazolo[1,5-a]pyridine (24). 21.4 mg
(58%) of 24 was obtained as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.37 (s, 1H), 7.67 (s, 2H), 7.33
(d, J = 0.5 Hz, 1H), 7.21 (d, J = 0.5 Hz, 1H), 5.60 (s, 2H), 3.80 (s, 3H); 13C{1H} NMR (100 MHz CDCl3):
δ 154.2, 149.8, 144.8, 135.3, 133.8, 128.0, 117.7, 117.4, 111.6, 68.0, 39.7; LCMS: RT = 0.614 min, m/z =
310.3 [M+H]+; HRMS (ESI) m/z: [M + H]+ calcd for C11H11BrN5O 308.0146, found 308.0144. MP: 157.6
– 159.8 °C.
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4-Bromo-3-(((1-methyl-1H-pyrazol-4-yl)oxy)methyl)isoquinoline (25). 33.4 mg (63%) of 25 was
obtained as a tan oil. 1H NMR (400 MHz, CDCl3): δ 9.12 (s, 1H), 8.24 (dd, J = 8.6, 0.7 Hz, 1H), 7.96 (d,
J = 8.2 Hz, 1H), 7.81 (ddd, J = 8.5, 8.4, 5.7 Hz, 1H), 7.67 (ddd, J = 8.1, 8.0, 6.0 Hz, 1H), 7.32 (d, J = 0.6
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Hz, 1H), 7.18 (d, J = 0.6 Hz, 1H), 5.37 (s, 2H) 3.78 (s, 3H); C{1H} NMR (100 MHz CDCl3): δ 151.4,
147.9, 145.6, 135.5. 132.0, 129.3, 128.5, 127.9, 127.6, 126.4, 120.5, 116.6, 74.7, 39.6; LCMS: RT = 0.776
min, m/z = 320.3 [M+H]+; HRMS (ESI) m/z: [M + H]+ calcd for C14H13BrN3O 318.0241, found 318.0239.
2-Bromo-3-(((1-methyl-1H-pyrazol-4-yl)oxy)methyl)pyridine (31). 22.5 mg (32%) of 31 was obtained
as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 8.32 (dd, J = 4.7, 2.0 Hz, 1H), 7.85 (ddt, J = 7.6, 2.0, 0.9
Hz, 1H), 7.30 (dd, J = 7.6, 4.7 Hz, 1H), 7.27 (d, J = 0.6 Hz, 1H), 7.11 (d, J = 0.6 Hz, 1H), 4.96 (s, 2H),
3.82 (s, 3H); 13C{1H} NMR (100 MHz CDCl3): δ 149.3, 145.1, 141.5, 136.9, 134.0, 127.3, 123.1, 116.2,
71.7, 39.7; LCMS: RT = 0.637 min, m/z = 268.2 [M+H]+; HRMS (ESI) m/z: [M + H]+ calcd for
C10H11BrN3O 268.0080, found 268.0080.
4-((2-Bromobenzyl)oxy)-1-methyl-1H-pyrazole (32). 92.7 mg (87%) of 32 was obtained as a yellow oil.
1H NMR (400 MHz, CDCl3): δ 7.56 (dd, J = 7.9, 1.1 Hz, 1H), 7.52 (m, 1H), 7.33 (ddd, J = 7.6, 7.6, 1.2
Hz, 1H), 7.27 (d, J = 0.7 Hz, 1H), 7.18 (ddd, J = 7.9, 7.9, 1.7 Hz, 1H), 7.08 (d, J = 0.7 Hz, 1H), 4.99 (s,
2H), 3.80 (s, 3H); 13C{1H} NMR (100 MHz CDCl3): δ 145.5, 136.3, 132.7, 129.5, 129.1, 127.6, 127.4,
122.5, 116.2, 73.2, 39.6; LCMS: RT = 0.879 min, m/z = 267.0 [M+H]+; HRMS (ESI) m/z: [M + H]+ calcd
for C11H12BrN2O 267.0128, found 267.0128.
4-(1-(2-Bromophenyl)ethoxy)-1-methyl-1H-pyrazole (33). 92.3 mg (82%) of 33 was obtained as a
yellow oil. 1H NMR (400 MHz, CDCl3): δ 7.43 (dd, J = 8.0, 1.2 Hz, 1H), 7.42 (dd, J = 7.8, 1.7 Hz, 1H),
7.20 (m, 1H), 7.02 (ddd, J = 7.9, 7.9, 1.8 Hz, 1H), 7.01 (d, J = 0.5 Hz, 1H), 6.73 (d, J = 0.5 Hz, 1H), 5.22
(q, J = 6.2 Hz, 1H), 3.61 (s, 3H), 1.47 (d, J = 6.2 Hz, 3H); 13C{1H} NMR (100 MHz CDCl3): δ 144.3,
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283.1 [M+H]+; HRMS (ESI) m/z: [M + H]+ calcd for C12H14BrN2O 281.0283, found 281.0284.
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oil. H NMR (400 MHz, CDCl3): δ 7.52 (dd, J = 7.8, 1.3 Hz, 1H), 7.29 (s, 1H), 7.15 (ddd, J = 7.8, 7.4,
1.3 Hz, 1H), 7.13 (s, 1H), 7.06 (ddd, J = 7.8, 7.4, 1.8 Hz, 1H), 6.99 (dd, J = 7.5, 1.7 Hz, 1H), 3.87 (s,
2H), 3.79 (s, 3H); 13C{1H} NMR (100 MHz CDCl3): δ 144.1, 137.7, 134.7, 133.0, 131.1, 128.7, 127.1,
124.5, 109.2, 42.4, 39.1; LCMS: RT = 1.121 min, m/z = 283.0 [M+H]+; HRMS (ESI) m/z: [M + H]+ calcd
for C11H12BrN2S 282.9900, found 282.9899.
4-((1-(2-Bromophenyl)ethyl)thio)-1-methyl-1H-pyrazole (36). 105.4 mg (93%) of 36 was obtained as a
yellow oil. 1H NMR (400 MHz, CDCl3): δ 7.43 (dd, J = 8.0, 1.2 Hz, 1H), 7.23 (dd, J = 7.9, 2.0 Hz, 1H),
7.21 – 7.16 (m, 2H), 7.07 (s, 1H), (ddd, J = 7.9, 6.9, 2.0 Hz, 1H), 4.44 (q, J = 7.1 Hz, 1H), 3.75 (s, 3H),
1.47 (d, J = 7.1 Hz, 3H); C{1H} NMR (100 MHz CDCl3): δ 144.7, 142.2, 135.1, 132.8, 128.5, 128.2,
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127.5, 124.5, 108.2, 47.0, 39.2, 21.0; LCMS: RT = 1.195 min, m/z = 299.0 [M+H]+; HRMS (ESI) m/z: [M
+ H]+ calcd for C12H14BrN2S 297.0056, found 297.0056.
N-(2-Bromobenzyl)-N,1-dimethyl-1H-pyrazol-4-amine (38). 108.0 mg (96%) of 38 was obtained as a
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yellow oil. H NMR (400 MHz, CDCl3): δ 7.45 (dd, J = 7.9, 1.1 Hz, 1H), 7.27 (m, 1H), 7.15 (ddd, J =
7.6, 7.6, 1.3 Hz, 1H), 7.02 (d, 0.6 Hz, 1H), 7.01 (ddd, J = 7.8, 7.8. 1.8 Hz, 1H), 6.69 (d, J = 0.6 Hz, 1H),
4.07 (s, 2H), 3.68 (s, 3H), 2.67 (s, 3H). Note: TMS referenced at 0.00 ppm; 13C{1H} NMR (100 MHz
CDCl3): δ 138.5, 137.5, 132.8, 129.6, 128.5, 127.5, 127.4, 123.6, 115.7, 59.9, 40.8, 39.2; LCMS: RT =
1.090 min, m/z = 280.0 [M+H]+; HRMS (ESI) m/z: [M + H]+ calcd for C12H15BrN3 280.0444, found
280.0444.
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General procedure for optimized palladium-catalyzed C-H heteroarylation. To a microwave vial
was added acyclic precursor (1 equiv), tris(dibenzylideneacetone)dipalladium(0) (5 mol%), 2-
dicyclohexylphosphino-2’,6’-dimethoxybiphenyl (7.5 mol%), and tetrabutylammonium acetate (1.4
equiv). The microwave vial was purged with nitrogen for several minutes, then sealed. The reaction was
then heated to 125 °C for 5 minutes (unless otherwise stated) in a microwave reactor. Upon completion of
the reaction by LCMS, the contents were syringe filtered and solvent was removed in vacuo. The crude
solid was then purified via flash column chromatography using 0-20% ethyl acetate in hexanes to elute
desired cyclized products.
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1-Methyl-1,5-dihydropyrazolo[3',4':5,6]pyrano[3,4-b]pyridine (7). 184.4 mg (98%) of 7 was obtained
as a beige solid. 1H NMR (400 MHz, CDCl3): δ 8.40 (dd, J = 5.0, 1.3 Hz, 1H), 7.73 (dd, J = 7.9, 1.5 Hz,
1H), 7.27 (dd, J = 7.9, 5.0 Hz, 1H), 7.18 (s, 1H), 5.22 (s, 2H), 4.09 (s, 3H); 13C{1H} NMR (100 MHz
CDCl3): δ 150.5, 147.3, 142.6, 126.3, 125.0, 124.8, 123.5, 121.3, 72.5, 39.7; LCMS: RT = 0.449 min, m/z
= 188.4 [M+H]+; HRMS (ESI) m/z: [M + H]+ calcd for C10H10N3O 188.0823, found 188.0819. MP: 103.2
– 105.4 °C. Note: Reaction conducted at 1 mmol scale.
1,5-Dimethyl-1,5-dihydropyrazolo[3',4':5,6]pyrano[3,4-b]pyridine (11a). 11.7 mg (87%) of 11a was
obtained as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 8.34 (dd, J = 5.0, 1.5 Hz, 1H), 7.78 (dd, J = 7.9,
1.4 Hz, 1H), 7.29 – 7.25 (m, 1H), 7.19 (s, 1H), 5.37 (q, J = 6.6 Hz, 1H), 4.11 (s, 3H), 1.68 (d, J = 6.7 Hz,
3H); 13C{1H} NMR (100 MHz CDCl3): δ 153.5, 147.0, 141.2, 126.7, 125.5, 124.0, 123.3, 120.4, 78.0,
39.8, 18.8; LCMS: RT = 0.550 min, m/z = 202.4 [M+H]+; HRMS (ESI) m/z: [M + H]+ calcd for
C11H12N3O 202.0980, found 202.0975.
1,8-Dimethyl-1,5-dihydropyrazolo[3',4':5,6]pyrano[3,4-b]pyridine (11b). 11.6 mg (71%) of 11b was
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obtained as a yellow solid. H NMR (400 MHz, CDCl3): δ 8.24 (d, J = 1.0 Hz, 1H), 7.56 (d, J = 1.0 Hz,
1H), 7.19 (s, 1H), 5.22 (s, 2H), 4.10 (s, 3H), 2.40 (s, 3H); 13C{1H} NMR (100 MHz CDCl3): δ 147.5,
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147.2, 142.7, 133.3, 127.2, 125.0, 124.7, 121.0, 72.2, 39.8, 18.7; LCMS: RT = 0.508 min, m/z = 202.4
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[M+H]+; HRMS (ESI) m/z: [M + H]+ calcd for C11H12N3O 202.0975, found 202.0975. MP: 140.0 – 142.8
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1,9-Dimethyl-1,5-dihydropyrazolo[3',4':5,6]pyrano[3,4-b]pyridine (11c). 30.1 mg (99%) of 11c was
obtained as a pale yellow residue. 1H NMR (400 MHz, CDCl3): δ 8.25 (d, J = 5.2 Hz, 1H), 7.31 (s, 1H),
7.08 (d, J = 5.2 Hz, 1H), 5.01 (s, 2H), 3.92 (s, 3H), 2.51 (s, 3H); 13C{1H} NMR (100 MHz CDCl3): δ
153.0, 146.8, 143.4, 139.0, 128.7, 126.4, 126.1, 121.1, 74.0, 41.4, 21.8; LCMS: RT = 0.668 min, m/z =
202.2 [M+H]+; HRMS (ESI) m/z: [M + H]+ calcd for C11H12N3O 202.0975, found 202.0974.
7-Methoxy-1-methyl-1,5-dihydropyrazolo[3',4':5,6]pyrano[3,4-b]pyridine (11d). 17.9 mg (83%) of
11d was obtained as an off-white solid. 1H NMR (400 MHz, CDCl3): δ 7.69 (d, J = 8.6 Hz, 1H), 7.17 (s,
1H), 6.73 (d, J = 8.6 Hz, 1H), 5.13 (s, 2H), 4.07 (s, 3H), 3.93 (s, 3H); 13C{1H} NMR (100 MHz CDCl3): δ
163.2, 148.7, 140.8, 130.0, 125.7, 124.4, 114.4, 110.2, 72.4, 53.9, 39.4; LCMS: RT = 0.705 min, m/z =
218.4 [M+H]+; HRMS (ESI) m/z: [M + H]+ calcd for C11H12N3O2 218.0929, found 218.0928. MP: 110.1 –
113.1 °C.
8-Chloro-1-methyl-1,5-dihydropyrazolo[3',4':5,6]pyrano[3,4-b]pyridine (11e). 11.1mg (54%) of 11e
was obtained as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 8.35 (d, J = 2.2 Hz, 1H), 7.68 (d, J = 2.2
Hz, 1H), 7.20 (s, 1H), 5.19 (s, 2H), 4.09(s, 3H); 13C{1H} NMR (100 MHz CDCl3): δ 148.3, 145.9, 143.1,
131.9, 125.8, 125.1, 123.8, 122.1, 72.1, 39.7; LCMS: RT = 0.675 min, m/z = 222.3 [M+H]+; HRMS (ESI)
m/z: [M + H]+ calcd for C10H9ClN3O 222.0434, found 222.0429. MP: 132.7 – 135.7 °C.
1-Methyl-1,5-dihydropyrazolo[3',4':5,6]pyrano[3,4-b]pyridine-7-carbonitrile (11f). 7.0 mg (50%) of
11f was obtained as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 7.79 (d, J = 8.1 Hz, 1H), 7.68 (d, J =
8.1 Hz, 1H), 7.22 (s, 1H), 5.24 (s, 2H), 4.11(s, 3H); 13C{1H} NMR (100 MHz CDCl3): δ 152.0, 144.3,
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130.5, 128.7, 125.8, 125.3, 124.0, 123.6, 117.2, 72.1, 40.0; LCMS: RT = 0.607 min, m/z = 213.4 [M+H]+;
HRMS (ESI) m/z: [M + H]+ calcd for C11H9N4O 213.0776, found 213.0770. MP: 165.8 – 168.4 °C.
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9-Methyl-5,9-dihydropyrazolo[3',4':5,6]pyrano[4,3-e][1,2,4]triazolo[1,5-a]pyridine (11g). 12.8 mg
(81%) of 11f was obtained as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.41 (s, 1H), 7.86 (d, J = 9.2
Hz, 1H), 7.79 (d, J = 9.2 Hz, 1H), 7.24 (s, 1H), 5.75 (s, 2H), 4.17 (s, 3H); 13C{1H} NMR (100 MHz
CDCl3): δ 154.6, 149.7, 140.6, 129.5, 125.1, 124.1, 122.0, 116.3, 113.5, 65.4, 39.9; LCMS: RT = 0.556
min, m/z = 228.4 [M+H]+; HRMS (ESI) m/z: [M + H]+ calcd for C11H10N5O 228.0885, found 228.0881.
MP: 184.0 – 186.9 °C.
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1-Methyl-1,5-dihydropyrazolo[3',4':5,6]pyrano[3,4-c]isoquinoline (11h). 17.5 mg (70%) of 11h was
obtained as a tan amorphous solid. 1H NMR (400 MHz, CDCl3): δ 9.09 (s, 1H), 8.08 (d, J = 8.5 Hz, 1H),
8.02 (d, J = 8.0 Hz, 1H), 7.81 – 7.76 (m, 1H), 7.67 – 7.62 (m, 1H), 7.44 (s, 1H), 5.30 (s, 2H), 4.04 (s,
3H); 13C{1H} NMR (100 MHz CDCl3): δ 150.7, 146.3, 143.6, 131.1, 129.5, 129.3, 129.0, 128.7, 127.5,
127.0, 124.4, 116.0, 74.1, 41.3; LCMS: RT = 0.667 min, m/z = 238.4 [M+H]+; HRMS (ESI) m/z: [M + H]+
calcd for C14H12N3O 238.0975, found 238.0975.
1-Cyclopropyl-1,5-dihydropyrazolo[3',4':5,6]pyrano[3,4-b]pyridine (11i). 22.5 mg (87%) of 11i was
obtained as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 8.39 (dd, J = 5.0, 1.5 Hz, 1H), 8.08 (dd, J = 8.0,
1.5 Hz, 1H), 7.30 – 7.25 (m, 1H), 7.15 (s, 1H), 5.22 (s, 2H), 3.66 – 3.60 (m, 1H), 1.31 – 1.26 (m, 2H),
1.19 – 1.35 (m, 2H); 13C{1H} NMR (100 MHz CDCl3): δ 150.2, 147.3, 142.2, 127.2, 125.5, 125.1, 123.4,
121.4, 72.3, 32.7, 8.0; LCMS: RT = 0.571 min, m/z = 214.4 [M+H]+; HRMS (ESI) m/z: [M + H]+ calcd for
C12H12N3O 214.0980, found 214.0975.
1-Isobutyl-1,5-dihydropyrazolo[3',4':5,6]pyrano[3,4-b]pyridine (11j). 19.2 mg (87%) of 11j was
obtained as a light yellow oil. 1H NMR (400 MHz, CDCl3): δ 8.41 (dd, J = 5.1, 1.3 Hz, 1H), 7.71 (dd, J =
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2.15 (m, 1H), 0.96 (d, J = 6.7 Hz, 6H); C{1H} NMR (100 MHz CDCl3): δ 150.0, 147.8, 146.2, 142.9,
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127.0, 125.2, 123.8, 121.9, 71.9, 59.7, 29.8, 20.1; LCMS: RT = 0.725 min, m/z = 230.4 [M+H]+; HRMS
(ESI) m/z: [M + H]+ calcd for C13H16N3O 230.1293, found 230.1289.
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1-(4-Fluorophenyl)-1,5-dihydropyrazolo[3',4':5,6]pyrano[3,4-b]pyridine (11k). 17.0 mg (91%) of 11k
was obtained as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 8.39 (dd, J = 3.9, 2.6 Hz, 1H), 7.53 – 7.49
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(m, 2H), 7.46 (s, 1H), 7.24 – 7.16 (m, 2H), 7.12 (s, 1H), 7.11 (d, J = 1.5 Hz, 1H), 5.34 (s, 2H); C{1H}
NMR (100 MHz CDCl3): δ 162.4 (d, J(C,F) = 247.6 Hz), 149.3, 147.1, 144.3, 136.3 (d, J(C,F) = 3.0 Hz),
128.0, 127.1, 126.5 (d, J(C,F) = 8.6 Hz), 124.1, 123.5, 121.1, 116.7 (d, J(C,F) = 23.0 Hz), 72.3; LCMS:
RT = 0.778 min, m/z = 268.4 [M+H]+; HRMS (ESI) m/z: [M + H]+ calcd for C15H11FN3O 268.0886, found
268.0885. MP: 166.8 – 169.0 °C.
1-Benzyl-1,5-dihydropyrazolo[3',4':5,6]pyrano[3,4-b]pyridine (11l). 19.3 mg (84%) of 11l was
obtained as a tan oil. 1H NMR (400 MHz, CDCl3): δ 8.33 (dd, J = 4.9, 1.0 Hz, 1H), 7.42 (dd, J = 7.9, 1.4
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Hz, 1H), 7.36 – 7.24 (m, 4H), 7.14 – 7.07 (m, 3H), 5.56 (s, 2H), 5.25 (s, 2H); C{1H} NMR (100 MHz
CDCl3): δ 150.4, 147.2, 142.9, 136.5, 129.2, 128.1, 126.8, 126.2, 126.0, 124.7, 123.5, 120.9, 72.4, 55.7;
LCMS: RT = 0.774 min, m/z = 264.4 [M+H]+; HRMS (ESI) m/z: [M + H]+ calcd for C16H14N3O 264.1136,
found 264.1130.
1-Methyl-1,5-dihydropyrazolo[3',4':5,6]pyrano[3,4-c]pyridine (12a). 18.3 mg (64%) of 12a was
obtained as an off-white solid. 1H NMR (400 MHz, CDCl3): δ 8.78 (s, 1H), 8.50 (d, J = 4.9 Hz, 1H), 7.18
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(s, 1H), 7.13 (d, J = 4.9 Hz, 1H), 5.10 (s, 2H), 4.15 (s, 3H); C{1H} NMR (100 MHz CDCl3): δ 149.0,
142.9, 140.5, 137.9, 125.0, 123.8, 121.7, 120.3, 69.9, 40.2; LCMS: RT = 0.206 min, m/z = 188.4 [M+H]+;
HRMS (ESI) m/z: [M + H]+ calcd for C10H10N3O 188.0823, found 188.0821. MP: 109.8 – 112.9 °C.
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1-Methyl-1,5-dihydropyrazolo[3',4':5,6]pyrano[4,3-b]pyridine (12b). Note: Trace amount of 12b (<1
mg, <5% yield). LCMS trace has been included (vide infra).
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1-Methyl-1,5-dihydroisochromeno[4,3-c]pyrazole (12c). 35.2 mg (86%) of 12c was obtained as a
yellow oil. 1H NMR (400 MHz, CDCl3): δ 7.50 (d, J = 7.5 Hz, 1H), 7.37 (ddd, 7.5, 7.5, 1.4 Hz, 1H), (ddd,
J = 7.5, 7.5, 1.2 Hz, 1H), 7.23 – 7.20 (m, 1H), 7.19 (s, 1H), 5.11 (s, 2H), 4.13 (s, 3H); 13C{1H} NMR (100
MHz CDCl3): δ 142.3, 130.1, 128.7, 127.5, 126.7, 125.8, 125.4, 124.7, 119.9, 71.5, 39.8; LCMS: RT =
0.738 min, m/z = 187.2 [M+H]+; HRMS (ESI) m/z: [M + H]+ calcd for C11H11N2O 187.0868, found
187.0866.
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1,5-Dimethyl-1,5-dihydroisochromeno[4,3-c]pyrazole (12d). 92.3 mg (82%) of 12d was obtained as a
yellow oil. 1H NMR (400 MHz, CDCl3): δ 7.51 (d, J = 7.7 Hz, 1H), 7.36 (ddd, J = 7.7, 7.7, 1.3 Hz, 1H),
7.28 (ddd, J = 7.7, 7.7, 1.3 Hz, 1H), 7.21 (d, J = 7.7 Hz, 1H), 7.18 (s, 1H), 5.26 (q, J = 6.7 Hz, 1H), 4.14
(s, 3H), 1.63 (d, J = 6.7 Hz, 3H).; 13C{1H} NMR (100 MHz CDCl3): δ 144.3, 141.9, 132.7, 129.1, 128.1,
127.8, 127.1, 121.9, 116.5, 78.5, 39.4, 22.7; LCMS: RT = 1.114 min, m/z = 283.1 [M+H]+; HRMS (ESI)
m/z: [M + H]+ calcd for C12H13N2O 201.1023, found 201.1022.
1-Methyl-1,5-dihydropyrazolo[3',4':5,6]thiopyrano[3,4-b]pyridine (12e). 39% conversion of 12e was
observed as per LCMS quantification. LCMS: RT = 0.498 min, m/z = 204.4. Note: Although complete
conversion was evident by LCMS, analog decomposes upon concentration in vacuo. LCMS trace
provided (vide infra).
1-Methyl-1,5-dihydroisothiochromeno[4,3-c]pyrazole (12f). 31.8 mg (90%) of 12f was obtained as a
yellow oil. 1H NMR (400 MHz, CDCl3): δ 7.56 (d, J = 7.5 Hz, 1H), 7.44 (s, 1H), 7.39 (ddd, J = 7.0, 7.0,
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1.9 Hz, 1H), 7.37 – 7.29 (m, 2H), 4.16 (s, 3H), 3.83 (s, 2H); C{1H} NMR (100 MHz CDCl3): δ 138.1,
135.5, 133.2, 128.3, 128.1, 127.9, 126.3, 123.7, 111.8, 39.7, 34.3; LCMS: RT = 0.969 min, m/z = 203.2
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[M+H]+; HRMS (ESI) m/z: [M + H]+ calcd for C11H11N2S 203.0640, found 203.0637. Note: Cyclization
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as a yellow oil. H NMR (400 MHz, CDCl3): δ 7.60 (m, 1H), 7.46 (s, 1H), 7.40 – 7.37 (m, 1H), 7.36 –
7.33 (m, 2H), 4.19 (s, 3H), 4.00 (q, J = 7.0 Hz, 1H), 1.50 (d, J = 7.0 Hz, 3H); C{1H} NMR (100 MHz
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CDCl3): δ 138.4, 137.0, 136.5, 128.6, 127.6, 126.7, 125.1, 124.1, 109.4, 41.5, 39.9, 20.9; LCMS: RT =
1.051 min, m/z = 217.2 [M+H]+; HRMS (ESI) m/z: [M + H]+ calcd for C12H13N2S 217.0794, found
217.0794.
1,4-Dimethyl-1,4-dihydro-5H-pyrazolo[3,4-f][1,7]naphthyridin-5-one (12h). 4.3 mg (28%) of 12h was
obtained as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 9.01 (br. s, 1H), 8.43 (d, J = 7.9 Hz, 1H), 7.72
(dd, J = 7.9, 4.2 Hz, 1H), 7.55 (s, 1H), 4.37 (s, 3H), 3.74 (s, 3H); 13C{1H} NMR (100 MHz CDCl3): δ
159.3, 149.5, 141.4, 129.1, 127.4, 126.4, 123.6, 123.3, 121.7, 40.8, 31.9; LCMS: RT = 0.308 min, m/z =
215.3 [M+H]+; HRMS (ESI) m/z: [M + H]+ calcd for C11H11N4O 215.0932, found 215.0927. MP: 241.0 –
243.6 °C.
1,4-Dimethyl-1,4-dihydro-5H-pyrazolo[4,3-c]isoquinolin-5-one (12i). 20.0 mg (46%) of 12i was
obtained as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.60 (dd, J = 8.1, 1.0 Hz, 1H), 8.00 (d, J = 7.7
Hz, 1H), 7.76 (m, 1H), 7.57 (ddd, J = 8.1, 7.6, 1.1 Hz, 1H), 7.48 (s, 1H), 4.36 (s, 3H), 3.67 (s, 3H). ;
13C{1H} NMR (100 MHz CDCl3): δ 160.7, 132.4, 130.4, 127.3, 127.2, 126.5, 125.4, 123.5, 123.3, 120.5,
40.8, 31.2; LCMS: RT = 0.705 min, m/z = 214.2 [M+H]+; HRMS (ESI) m/z: [M + H]+ calcd for
C12H12N3O 214.0977, found 214.0975. MP: 173.8 – 175.2 °C. Note: Cyclization required 15 minutes at
125 °C.
ASSOCIATED CONTENT
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Supporting Information
1H and 13C NMR spectra for new compounds. The Supporting Information is available free of charge on
the ACS Publications website.
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AUTHOR INFORMATION
Corresponding Author
* E-mail: craig.lindsley@vanderbilt.edu
Author Contributions
⊥ These authors contributed equally to this work. The manuscript was written through contributions of all
authors. All authors have given approval to the final version of the manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
C.W.L. thanks the William K. Warren Family and Foundation for funding the William K. Warren, Jr.
Chair in Medicine and support of our programs.
REFERENCES
1. Taylor, A.P.; Robinson, R.P.; Fobian, Y.M.; Blakemore, D.C.; Jones, L.H.; Fadeyi, O. Modern
advances in heterocyclic chemistry in drug discovery. Org. Biomol. Chem. 2016, 14, 6611-6637.
2. Sun, A.C.; McClain, E.J.; Beatty, J.W.; Stephenson, C.R.J. Visible light-mediated
decarboxylative alkylation of pharmaceutically relevant heterocycles. Org. Lett. 2018, 12, 3487-
3490.
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2
3
4
5
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7
8
3. Blakemore, D.C.; Castro, L.; Churcher, I.; Rees, D.C.; Thomas, A.W.; Wilson, D.M.; Wood, A.
Organic synthesis provides opportunities to transform drug discovery. Nature Chemistry 2018,
10, 383-394.
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
4. Bender, A.M.; Chopko, T.C.; Bridges, T.M.; Lindsley, C.W. Preparation of unsymmetrical
1,2,4,5-tetrazines via a mild Suzuki cross-coupling reaction. Org. Lett. 2017, 19, 5693-5696.
5. Wood, M.R.; Noetzel, M.J.; Melancon, B.J.; Nance, K.D.; Poslunsey, M.S.; Hurtado, M.A.;
Luscombe, V.B.; Weiner, R.L.; Rodriguez, A.L.; Lamsal, A.; Chang, S.; Bubser, M.; Blobaum,
A.L.; Engers, D.W.; Niswender, C.M.; Jones, C.K.; Brandon, N.J.; Wood, M.W.;
Duggan, M.E.; Conn, P.J.; Bridges, T.M.; Lindsley, C.W. Discovery of
VU0467485/AZ13713945: An M PAM Evaluated as a Preclinical Candidate for the Treatment
4
of Schizophrenia. ACS Med. Chem. Lett. 2017, 8, 233-238.
6. Wood, M.R.; Noetzel, M.J.; Poslunsey, M.S.; Melancon, B.J.; Tarr, J.C.; Lamsal, A.; Chang, S.;
Luscombe, V.B.; Weiner, R.L.; Cho, H.P.; Bubser, M.; Jones, C.K.; Niswender, C.M.; Wood,
M.W.; Brandon, N.J.; Engers, D.W.; Duggan, M.E.; Conn, P.J.; Bridges, T.M.;
Lindsley, C.W. Challenges in the development of an M4 PAM in vivo tool compound: The
discovery of VU0467154 and unexpected DMPK profiles of close analogs. Bioorg. Med. Chem.
Lett. 2017, 27, 171-175.
7. Lindsley, C.W.; Conn, P.J.; Wood, M.R.; Salovich, J.M. Substituted
pyrazolo[3',4':4,5]thieno[2,3-c]pyridazin-3-amine analogs as positive allosteric modulators of the
muscarinic acetylcholine receptor M4US 9,056,875, 2015.
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8. Substructure searches of this core in SciFinder, Bielstein and the USPTO databases return no hits
– not the core itself, synthetic protocols or any bioactivity.
7
8
9
9. Herbert, B.; Schumacher, R.; Dai, G.; Xie, W. WO2009055437, 2009.
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
10. Bertenshaw, S.R.; Talley, J.T.; Rogier, D.J.; Graneto, M.J.; Koboldt, C.M.; Zhang, Y.
Conformationally restricted 1,5-diarylpyrazoles are selective COX-2 inhibitors. Bioorg. Med.
Chem. Lett. 1996, 6, 2827–2830.
11. Vernier, W.F.; Gomez, L. Regioselective palladium-catalyzed CH arylation of 4-alkoxy and 4-
thioalkyl pyrazoles. Tetrahedron Lett. 2017, 58, 4587-4590.
12. Beladhria, A.; Beydoun, K.; Ammar, H.B.; Salem, R.B.; Doucet, H. Pd-Catalysed Direct 5-
Arylation of 1-Methylpyrazole with Aryl Bromides. Synthesis. 2011, 16, 2553-2560.
13. Kumpulainen, E.T.T.; Pohjakallio, A. Selective Palladium-Catalyzed Direct C-H Arylation of
Unsubstituted N-Protected Pyrazoles. Adv. Synth. Catal., 2014, 356, 1555-1561.
14. See Supporting Information for full details.
15. Wolkenberg, S.E.; Wisnoski, D.D.; Leister, W.H.; Zhao, Z.; Wang, Y.; Lindsley, C.W. Efficient
synthesis of imidazoles from aldehydes and 1,2-diketones using microwave irradiation. Org.
Lett. 2004, 6, 1453-1456.
16. Shipe, W.D.; Yang, F.; Zhao, Z.; Wolkenberg, S.E.; Nolt, M.B.; Lindsley, C.W. Heterocycles,
2006, 70, 665-679.
17. Manuscript in preparation.
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