Optimized scale up of 3-pyrimidinylpyrazolo[1,5-a]pyridine via Suzuki coupling; A general method of accessing a range of 3-(hetero)arylpyrazolo[1,5-a] pyridines

Article abstract of DOI:10.1016/j.tet.2012.04.094

We have developed an improved synthesis of 3-(hetero)aryl pyrazolo[1,5-a]pyridines (such as 3-(2,5-dichloropyrimidin-4-yl)pyrazolo[1,5-a] pyridine (8)) via an optimized synthesis and Suzuki coupling of 3-pyrazolo[1,5-a]pyridine boronic ester 10. These conditions are applicable to both high throughput chemistry and large scale synthesis of these medicinally important compounds. The scope of this chemistry has been further extended to include the synthesis and coupling of a novel boronic ester, 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-pyrazolo[5,1-b] [1,3]oxazine (43).

Full text of DOI:10.1016/j.tet.2012.04.094

Tetrahedron 68 (2012) 5434e5444
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Optimized scale up of 3-pyrimidinylpyrazolo[1,5-a]pyridine via Suzuki coupling;
a general method of accessing a range of 3-(hetero)arylpyrazolo[1,5-a]pyridines
*
Paul A. Bethel, Andrew D. Campbell, Frederick W. Goldberg, Paul D. Kemmitt , Gillian M. Lamont,
Abid Suleman
AstraZeneca, Oncology iMed, Mereside, Alderley Park, Macclesfield SK10 4TG, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
We have developed an improved synthesis of 3-(hetero)aryl pyrazolo[1,5-a]pyridines (such as 3-(2,5-
dichloropyrimidin-4-yl)pyrazolo[1,5-a]pyridine (8)) via an optimized synthesis and Suzuki coupling of
3-pyrazolo[1,5-a]pyridine boronic ester 10. These conditions are applicable to both high throughput
chemistry and large scale synthesis of these medicinally important compounds. The scope of this
chemistry has been further extended to include the synthesis and coupling of a novel boronic ester, 3-
(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine (43).
Ó 2012 Elsevier Ltd. All rights reserved.
Received 31 January 2012
Received in revised form 23 March 2012
Accepted 24 April 2012
Available online 2 May 2012
Keywords:
3-(Hetero)aryl pyrazolo[1,5-a]pyridines
Boronic esters
Suzuki coupling
High throughput chemistry
1. Introduction
1.1. Synthesis of 3-aryl and heteroaryl-pyrazolo[1,5-a]pyridines
Many compounds containing 3-substituted pyrazolo[1,5-a]pyr-
idines have been found to possess biological activity, with over 400
publications including this bicycle over the last 5 years.1 Certain 3-
substituted pyrazolo[1,5-a]pyridine derivatives have been shown to
be effective adenosine A1 antagonists, e.g., FK-838 (1),2 while
others have been found to be effective as kinase inhibitors (e.g.,
2e4)3e5 (Fig. 1). As part of ongoing discovery chemistry efforts, we
were interested to investigate improvements to the synthetic
methodology towards 3-arylpyrazolo[1,5-a]pyridines.
3-Substituted pyrazolopyridines are typically made via a 1,3-
dipolar cycloaddition between an azomethine imine 5 (formed by
deprotonation of a 1-amino-pyridinium ion 6) with an appropriate
dipolarophile.6 More recently their synthesis by a Michael reaction
between vinylether 7 and 1-amino-pyridinium ion 6, followed by
a cyclizationdoxidative aromatization sequence has been reported,
Scheme 1.7
As part of an ongoing discovery campaign we required multi
gram quantities of 3-(2,5-dichloropyrimidin-4-yl)pyrazolo[1,5-a]
F
O
F
OH
N
O
OMe
N
NH2
H
N
H
N
N
N
N
S
O
N
N
Cl
Cl
N
N
N
NH
4
7
3a
3
5
6
2
N
N
N
N
N
MeO
N
N
N
1
4
3
FK-838, 1
2
O
Fig. 1. Structures of some bioactive compounds containing a pyrazolo[1,5-a]pyridine motif.
pyridine (8) as a key intermediate. We also wanted to be able to
vary the 3-substituent by high throughput chemistry. Initially we
followed the published route to compound 8, which starts with the
* Corresponding author. Tel.: þ44 (0) 1625 516128; e-mail address: paul.kemmitt@
astrazeneca.com (P.D. Kemmitt).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.04.094

P.A. Bethel et al. / Tetrahedron 68 (2012) 5434e5444
1,3 dipolar cycloaddition approach to pyrazolo[1,5-a]pyridines
5435
R
R
spontaneous
oxidation
R
N+
DMF, rt
N
N
N
N
H
NH-
R = CO2Me, Aryl, HeteroAryl
5
Pyrazolo[1,5-a]pyridines from vinyl enol ethers
OnBu
Cl
N+
N
N
N
N
NH2
Cl
I-
(6)
OnBu
, i
Cl
ii
Cl
N
N
Cl
N
N
4-63%
2-50%
Cl
N
Cl
N
Cl
N
Cl
N
7
9
8
Scheme 1. Reported synthesis of pyrazolo[1,5-a]pyridines. Reagents and conditions: (i) 2 mol % Pd(OAc)2, Et3N, PEG-200 or 1,4 dioxane, 80 ꢀC; (ii) DMF, K2CO3, rt, 6 h then 110 ꢀC 2 h
or modified conditions: K2CO3, (0.5 equiv), KOH (1 equiv), rt, 90 min, then 90 ꢀC, 4 h.
Heck reaction of 2,3,5-trichloropyrimidine with n-butyl vinylether
to make the enol ether 7 as the only regioisomer.7 We found that
the yield of this reaction could be improved by switching the sol-
vent from PEG to dioxane, however, the reaction could never be
driven to completion and it occasionally produced an exotherm
(from 70 to 90 ꢀC). Although the reaction to form the pyr-
azolopyridine core using modified conditions (KOH, K2CO3 in
DMSO, Scheme 1) reduced the level of the unoxidized impurity 9,
we still found the reaction capricious and due to its poor solubility
purification of the desired compound 8 was difficult.7 Large scale
synthesis using this chemistry was therefore problematic. In
addition making derivatives would be cumbersome and not ame-
nable to parallel synthesis. Likewise, using dipolar cycloaddition
chemistry would require the synthesis of the acetylene starting
materials.
partner to stable, commercially available or synthesized boronic
acids or esters. This would preclude the pyrimidine example in this
case but also many medicinally relevant alternative heterocycles.
There are only two publications reporting the synthesis of pyr-
azolopyridine boronic ester 10 and it was either isolated in a low
18% yield from a metal halogen exchange3 or taken through crude
after a SuzukieMiyaura coupling with 4.5 mol % Pd(OAc)2, 9 mol %
tricyclohexylphosphine and bis(pinacolato)diboron.13 Searching
our own internal database found several failed attempts to isolate
this boronic ester in acceptable yield and purity.14 Consequently an
improved synthesis of this reagent and optimized cross-coupling
would have significant benefit and allow us to address the scal-
ability concerns and improve the scope of analogue synthesis.
2. Results and discussion
A number of alternative approaches were pursued from decar-
boxylative coupling,8 Negishi Coupling,9 CeH activation,10 and the
Suzuki (or SuzukieMiyaura) reaction, Scheme 2. Due to the avail-
ability of reagents, robustness, and its suitablity to analogue syn-
thesis, the Suzuki reaction is still the single most used reaction in
the pharmaceutical industry for CeC bond formation.11 It surprised
us that despite the prevalence of this ring system this reaction has
rarely been used to make analogues of pyrazolopyridines. Examples
where it has been employed use a pyrazolopyridine halide and an
appropriate boronic ester,12 which thus limits the scope of coupling
Chavant et al.15 have recently described a useful method of
making functionalized aryl boronic esters on moderate scale from
aryl iodides and iPrMgCl.LiCl. This requires the synthesis of 3-
iodopyrazolo[1,5-a]pyridine (11), which was readily made in 75%
yield by treatment of the corresponding carboxylic acid 12 with N-
iodosuccinimide. To our knowledge this is the first direct conver-
sion of a heteroaryl carboxylic acid to its iodide under these con-
ditions and further work is underway to understand the scope of
this methodology.16 However, it was more convenient to prepare 3-
Scheme 2. Alternative strategies to 3-(2,5-dichloropyrimidin-4-yl)pyrazolo[1,5-a]pyridine (8).

5436
P.A. Bethel et al. / Tetrahedron 68 (2012) 5434e5444
O
O
I
B
CO2H
i
iii
N
N
N
N
N
N
12
11
10
ii
N
N
13
Scheme 3. Synthesis of pyrazolo[1,5-a]pyridine-3-boronic ester (10). Reagents and conditions: (i) NIS, NaHCO3, DMF, rt, 75%; (ii) NIS, MeCN, rt, 88%; (iii) iPrMgCl.LiCl, iPrOBPin, 5 ꢀC,
i
THF, 90%, or BuLi, PrOBPin, ꢁ70 ꢀC, THF, 50%.
outsourced to a third party who has made 1 kg of this compound.
This is a significant improvement over existing methods (vide su-
pra) and is also better than the reaction of butyllithium with 3-
iodopyrazolo[1,5-a]pyridine (11), which only formed the boronic
ester (10) in 50% yield.19
Table 1
Catalyst screen results
Catalyst system
Product/Internal
Isolated yieldb
standard after 5 ha
Pd(dppf)Cl2
Pd(dtbpf)Cl2
Pd(OAc)2þS-Phos
Pd(OAc)2þDtBPPS
Pd(Amphos)Cl2
0.25
0.30
0.04
0.31
0.51
40%
31%
n.d
n.d
59%
An initial catalyst screen was carried out on the boronic ester
(10) and 2,3,5-trichloropyrimidine with a range of common Suzuki
catalysts, which would be available on scale. The reactions were
carried out with 2M Na2CO3 in DME/water (4:1) and product for-
mation was measured as a ratio of product over an internal stan-
dard (4,40-di-tert-butylbiphenyl) where the higher ratio reflects
higher product yield. The results are outlined in Table 1, Pd(OAc)2
and S-Phos20 gave the lowest conversion while Pd(dppf)Cl2,
Pd(dtbpf)Cl2 and Pd(OAc)2 with 3-(di-tert-butylphosphonium)
propane sulfonate (DtBPPS)21 were all similar. Bis(di-tert-butyl(4-
dimethylaminophenyl)phosphine)dichloropalladium(II) (Pd(Am-
phos)Cl2)22 gave the highest yield. A number of key impurities were
identified from this reaction. They were homocoupled pyrazole
[1,5a]pyridine 14, the product of protodeborylation (13) and
hydrolysed chloropyrimidine 15, Scheme 4. Impurities 13 and 15
were formed quickly during the Suzuki reaction and so a fast
coupling process was needed to avoid these impurities becoming
a
Relative yield measured by the ratio of product/internal standard (4,40-di-tert-
butylbiphenyl).
b
After purification by chromatography, n.d not determined.
iodopyrazolo[1,5-a]pyridine (11) by direct iodination of the parent
pyrazolo[1,5-a]pyridine (13).17 Both of these procedures are an
improvement of the only other published synthesis of this com-
pound.18 With access to the iodide we were now able to investigate
the synthesis of the boronic ester 10. We were pleased to find that
by just using 1 equiv of iPrMgCl.LiCl we obtained 90% isolated yield
of the desired boronic ester, Scheme 3. This has been carried out on
up to 40 g without a significant drop off in yield and has been
N
Cl
O
Cl
N
O
B
i
N
N
N
N
8
10
N
N
OH
Cl
N
N
N
N
N
Cl
N
15
13
14
Scheme 4. Sythesis of 3-(2,5-dichloropyrimidin-4-yl)pyrazolo[1,5-a]pyridine (8). Reagents and conditions: (i) 6 mol % Catalyst and 2M Na2CO3 (2.2eq), 1 equiv boronic ester (10),
1.2 equiv trichloropyrimidine, DME/water (4:1) at 85 ꢀC.

P.A. Bethel et al. / Tetrahedron 68 (2012) 5434e5444
5437
dominant. Varying the solvent (EtOH, tBuOH, DMA/water (4:1),
toluene/water (4:1)) or base (NaHCO3, CsF, DIPEA) failed to offer
any improvement. Reducing the catalyst loading from 6 mol % to
3 mol % led to a reduction in product formation. To confirm these
findings the reactions using Pd(dppf)Cl2, Pd(dtbpf)Cl2 and Pd(Am-
phos)Cl2 were repeated and the isolated yields were 40%, 31% and
59%, respectively.
To replicate the heating profile of a large scale reactor, the re-
action was slowly heated to 85 ꢀC over 1 h and maintained at this
temperature for 5 h. Pleasingly there was no loss of yield, when
compared to the standard heating conditions (85 ꢀC over 15 min).
This has now successfully been scaled up to 25 g in house and has
subsequently been outsourced to a third party. This represents the
most efficient synthesis of 3-pyrimidinylpyrazolo[1,5-a]pyridine
(8) to date, with an added advantage that the product precipitating
from the reaction mixture facilitates purification.
With these conditions in hand we wanted to investigate the scope
of the reaction towards a range of medicinally relevant 3-(hetero)aryl
groups, as shown in Table 2. The design of the scoping set was pri-
marily based on diversity, although we also ensured that we included
the main ring systems reported in 3-(hetero)aryl pyrazolopyridine
patent literature.3e5,7,12,13 Thus we were able to demonstrate that the
coupling worked for phenyl rings with an electronically diverse
range of small substituents and for a series of aromatic heterocycles,
including electron-deficient aromatic heterocycles that have
previously proved difficult to couple. The yields varied from 20 to
71% with the exception of 3-chloropyrazole, which failed and
2-bromoimidazole, which only worked in 6% isolated yield.23
Table 2
Synthesis of 3-(het)aryl pyrazolo[1,5-a]pyridines derivatives by high throughput chemistry
O
O
B
R
+
R-X
N
N
N
N
10
ReX
Product (yield)
ReX
Product (yield)
N
N
N
N
Br
I
O
O
N
N
21 (43%)
16 (24%)
N
N
N
N
S
Br
N
Br
Br
N
S
S
S
22 (42%)
17 (41%)
N
N
N
N
N
Cl
N
N
N
N
N
18 (50%)
23 (32%)
N
N
N
N
I
Br
N
N
F
F
24 (44%)
19 (58%)
(continued on next page)

5438
P.A. Bethel et al. / Tetrahedron 68 (2012) 5434e5444
Table 2 (continued )
ReX
Product (yield)
ReX
Product (yield)
N
N
N
N
Br
S
Br
S
N
N
25 (41%)
20 (50%)
N
N
N
Br
N
N
N
I
N
N
26 (41%)
33 (49%)
N
N
N
N
Br
Br
N
N
34 (44%)
27 (38%)
N
N
OMe
N
OMe
N
I
I
CN
CN
CN
35 (46%)
28 (63%)
N
N
N
N
Br
N
N
Br
N
N
CN
29 (61%)
36 (21%)
N
N
N
N
Br
I
N
N
N
OMe
N
OMe
30 (59%)
37 (33%)

P.A. Bethel et al. / Tetrahedron 68 (2012) 5434e5444
5439
Table 2 (continued )
ReX
Product (yield)
ReX
Product (yield)
N
N
N
Cl
N
N
N
Cl
Cl
N
N
Cl
N
N
9a
N
N
9a
31 (42%)
38 (49%)
N
N
N
N
I
Br
N
N
N
N
F
F
32 (36%)
39 (71%)
N
N
Cl
N
N
N
N
N
Br
Br
N
N
N
N
N
N
42 (0%)
40 (6%)
N
OMe
O
M
e
41 (51%)
After the development of these robust conditions we extended
the scope of this chemistry to the synthesis of a novel boronic ester
43 based on the fused pyrazolo ring system, 6,7-dihydro-5H-pyr-
azolo[5,1-b][1,3]oxazine. The boronic ester 43 was synthesized in
four steps from methyl propiolate. The first step involved the ad-
dition of hydrazine hydrate to methyl propriolate to afford 1H-
pyrazol-3(2H)-one (44) in good yield. Alkylation and cyclization
with 1,3-dibromopropane gave the fused pyrazolo ring system 45,
which was carried through to iodide 46 before purification. Con-
version to boronic ester 43 and subsequent Suzuki coupling with
2,3,5-trichloropyrimidine proceeded successfully, demonstrating
the suitability of more complex boronic esters in this reaction,
Scheme 5. Further work to fully optimize this sequence and expand
the range of products is ongoing.
halogenated (hetero)aromatic rings, including examples with
electron-deficient heterocycles that were difficult to make using
existing methodology. Finally these conditions have been applied
to an efficient synthesis and coupling of a hitherto unreported
boronic ester 43.
4. Experimental
4.1. General methods
All solvents and chemicals used were reagent grade. Pd(OAc)2,
3-(di-tert-butylphosphonium)propane sulfonate (DtBPPS), bis(di-
tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium-
(II) (Pd(Amphos)Cl2) and Pd(dppf)Cl2, were purchased Aldrich.
Pd(dtbpf)Cl2 and S-Phos were purchased from Strem Chemicals,
Inc. Anhydrous solvents tetrahydrofuran (THF), dimethoxyethane
(DME) were purchased from Aldrich and used as such. Iso-
propylmagnesium chloride lithium chloride complex solution
(1.3 M in THF) was purchased from Aldrich and titrated using
3. Conclusion
In summary, we have described an improved synthesis to 3-
pyrazolo[1,5-a]pyridine boronic ester 10, which has allowed us
access to kilo quantities of this important building block. Its sub-
sequent cross-coupling with 2,3,5-trichloropyrimidine has been
optimized, robustly tested, scaled up in our labs and outsourced to
a contract research organization. Ready access to this boronic ester
has allowed us to examine the scope of the coupling with a range of
L-menthol and 1,10-phenanthroline as indicator before use. Flash
column chromatography was carried out using prepacked silica
cartridges (from 4 g up to 330 g) from Crawford and eluted using an
Isco Companion system. Preparative HPLC was carried out on
a Waters XBridge Prep C18 OBD column, 5
m silica, 19 mm diameter,

5440
P.A. Bethel et al. / Tetrahedron 68 (2012) 5434e5444
O
O
O
ii
iii
O
i
N
N
H
N
H
N
44
45
N
Cl
Cl
O
N
O
I
B
O
O
iv
O
v
N
N
N
N
N
N
47
46
43
Scheme 5. . 6,7-Dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-boronic ester synthesis. Reagents and conditions: (i) NH2NH2.H2O, MeOH, 95%; (ii) 1,3-Dibromopropane, K2CO3, DMF,
i
i
130 ꢀC; (iii) NIS, MeCN, 29% over two steps; (iv) PrMgCl.LiCl, PrOBPin, 5 ꢀC, THF, 46%; (v) 2,4,5-trichloropyrimidine, 2 M Na2CO3, 6 mol % Pd(Amphos)Cl2, DME, 85 ꢀC, 50%.
100 mm length (5e95% MeCN/1% NH3 in H2O). Catalytic screening
experiments were assessed using a UPLC Waters Aquity Binary
pump with sample manager, Aquity PDA and SQD Mass spec-
trometer. The solvents used 0.1% ammonium hydroxide (aq) and
0.1% ammonium hydroxide in acetonitrile. At a flow rate of 1 mL/
141.80; m/z (ESþ) 119 (100, MHþ); HRMS (ESI): MHþ, found
119.06036. C7H7N2 requires 119.06037.
4.1.2. 3-Iodopyrazolo[1,5-a]pyridine (11).
min 1 uL of sample is injected onto a 50ꢂ2.1 1.7
m
m Waters BEH
4.1.2.1. From pyrazolo[1,5-a]pyridine-3-carboxylic acid. N-Iodo-
succinimide (1.91 g, 8.51 mmol) was added to a stirred mixture of
pyrazolo[1,5-a]pyridine-3-carboxylic acid (12, 1.15 g, 7.09 mmol)
and NaHCO3 (0.715 g, 8.51 mmol) in DMF (36 mL) and the resulting
mixture was stirred at room temperature for 2 days. The reaction
mixture was diluted with water (50 mL), extracted with EtOAc
(3ꢂ125 mL), the organic extracts were combined, washed with
saturated brine (100 mL), dried (MgSO4), filtered and evaporated to
afford crude product. The crude product was purified by flash
chromatography (0e20% EtOAc/heptane) to give the title compound
(11,1.3 g, 75%) as a brown oil, which solidified on standing.
column. Purity and characterization of compounds were estab-
lished by a combination of liquid chromatographyemass spec-
troscopy (LC-MS), gas chromatographyemass spectroscopy
(GCeMS) and NMR analytical techniques. Purities were all assessed
to be 95% or more. 1H and 13C NMR spectra were recorded on
a Bruker AVANCE 400, DRX 500 or AVANCE 700 spectrometer.
Chemical shifts are reported in parts per million relative to solvent
signal and coupling constant (J) values are reported in Hertz (Hz).
Splitting patterns are indicated as follows: s, singlet; d, doublet; t,
triplet; m, multiplet; br, broad peak. Merck precoated thin layer
chromatography (TLC) plates (silica gel 60 F254, 0.25 mm, art.
5715) were used for TLC analysis.
4.1.2.2. From pyrazolo[1,5-a]pyridine 13. N-Iodosuccinimide
(91 g, 403.18 mmol) was added portionwise over 10 min to a stirred
solution of pyrazolo[1,5-a]pyridine (13, 43.3 g, 366.53 mmol) in
acetonitrile (430 mL) at room temperature. The resulting mixture
was stirred for 1 h, poured into water (2 L), stirred for 1 h and
extracted with MTBE (2ꢂ800 mL). The organic extracts were
combined and washed sequentially with 2 M NaOH (750 mL), 15%
Na2S2O3 (400 mL), and saturated brine (500 mL). The organic layer
was dried (MgSO4), filtered and evaporated to afford crude product,
82.6 g. The crude product was purified by crystallisation from
refluxing heptane (200 mL) to afford the title compound (11, 66.8 g)
as a tan solid. The liquor was concentrated and purified by flash
chromatography (DCM) to give a further 10.6 g of the title com-
pound, (11) in an overall yield of 77.4 g, 87%; dH(400 MHz, CDCl3):
6.80 (1H, td, J 7, 1 Hz ArH-6), 7.17e7.22 (1H, m, ArH-5), 7.48 (1H, d, J
9 Hz, ArH-4), 7.96 (1H, s, ArH-2), 8.46 (1H, d, J 7 Hz, ArH-7);
dC(101 MHz, CDCl3): 47.46, 112.49, 117.92, 124.67, 129.23, 141.02,
146.26; m/z (ESþ) 245 (100, MHþ); HRMS (ESI): MHþ, found
244.95695. C7H6IN2 requires 244.95702.
1
7
N
6
N
2
5
3a
3
4
4.1.1. Pyrazolo[1,5-a]pyridine17 (13). Sulfuric acid (50% v/v in wa-
ter) (200 mL, 410.1 mmol) was added to ethyl pyrazolo[1,5-a]
pyridine-3-carboxylate (78 g, 410.1 mmol) and the reaction was
heated to reflux for 2 h 15 min. The reaction mixture was allowed
to cool to room temperature and NaOH 50% w/w solution
(350 mL) was added dropwise over 60 min while maintaining the
temperature below 35 ꢀC using an ice bath. This was then poured
into water (1 L), further NaOH (50% w/w solution) (w75 mL) was
added until the mixture was basic and the resultant suspension
was stirred until everything dissolved. This was extracted with
MTBE (3ꢂ250 mL), the combined organic extracts were washed
with water (500 mL) and saturated brine (500 mL). The organic
layer was dried (Na2SO4), filtered and concentrated in vacuo to
4.1.3. 3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]
pyridine (10).
4.1.3.1. Usingisopropylmagnesium lithiumchloride. Isopropylmag-
nesium lithium chloride (43.5 mL, 49.99 mmol, 1.15 M solution in
THF) was added dropwise to a stirred solution of 3-iodopyrazolo[1,5-
a]pyridine (11, 12.2 g, 49.99 mmol) and 2-isopropoxy-4,4,5,5-
tetramethyl-1,3,2-dioxaborolane (15.30 mL, 74.99 mmol) in THF
give the title compound (13, 44.6 g, 92%) as
a yellow oil;
dH(400 MHz, CDCl3): 6.51 (1H, d, J 2 Hz, ArH-3), 6.73 (1H, td, J 7,
1 Hz, ArH-6), 7.09 (1H, ddd, J 9, 7, 1 Hz, ArH-5), 7.53 (1H, d, J 9 Hz,
ArH-4), 7.94 (1H, d, J 2 Hz, ArH-2), 8.47 (1H, dd, J 7, 1 Hz, ArH-7);
dC(101 MHz, CDCl3): 96.73, 111.60, 118.16, 123.14, 128.67, 140.16,

P.A. Bethel et al. / Tetrahedron 68 (2012) 5434e5444
5441
(120 mL) at 5 ꢀC (internal temperature kept below 10 ꢀC), over
a period of 10 min, under nitrogen. The resulting solution was stirred
at 5 ꢀC for 2 h and then concentrated under reduced pressure. The
residue was diluted with DCM (50 mL), the suspension was filtered
through a pad of silica, eluting with EtOAc (1000 mL) and evaporated
to afford crude product, which was purified by flash chromatography
(0e20% EtOAc/heptane) to give the title compound (10, 10.96 g, 90%)
as a white solid; dH (400 MHz, CDCl3): 1.36 (12H, s, 2ꢂMe2CO), 6.81
(1H, td, J 7,1 Hz, ArH-6), 7.21 (1H, ddd, J 9, 7,1 Hz, ArH-5), 7.96 (1H, dt,
J 9, 1 Hz, ArH-4), 8.23 (1H, s, ArH-2), 8.51 (1H, dt, J 7, 1 Hz, ArH-7);
dC(101 MHz, CDCl3): 24.94 (4 CH3), 83.12 (2C), 112.47, 120.09, 124.77,
128.82, 145.63, 148.77, CeB not seen; m/z (ESþ) 245 (100, MHþ);
HRMS (ESI): MHþ, found 245.14558. C13H18BN2O2 requires
245.14558.
then allowed to cool to ambient temperature overnight. The pre-
cipitate was collected by filtration, washed with DME (150 mL) and
water (3ꢂ250 mL) and dried under vacuum at 50 ꢀC for 4 h to afford
the title compound (8, 13.64 g) as a pale yellow solid. A precipitate
developed in the aqueous filtrate, which was collected by filtration,
stirred in acetone (250 mL) for w5 min, filtered and dried under
vacuum to afford further title compound (8, 2.01 g) as a cream solid.
Overall yield 15.65 g, 59%; dH (400 MHz, DMSO): 7.28 (1H, td, J 7, 1 Hz,
ArH-6), 7.67e7.77 (1H, m, ArH-5), 8.56 (1H, d, J 9 Hz, ArH-4), 8.80 (1H,
s, ArH-2), 8.96 (1H, d, J 7 Hz, ArH-7), 9.08 (1H s, pyrimidine H); dC
(176 MHz, DMSO at 70 ꢀC): 105.78, 115.21, 119.81, 124.33, 128.86,
130.09, 139.76, 143.98, 157.33, 158.13, 159.44; m/z (ESþ) 265 (100,
MHþ); HRMS (ESI): MHþ, found 265.00439. C11H7Cl2N4 requires
265.00423.
4.1.3.2. Using butyllithium. Butyllithium (1.6 M in hexanes)
(1.9 mL, 3.10 mmol) was added dropwise to a stirred solution of 3-
iodopyrazolo[1,5-a]pyridine (11, 504 mg, 2.07 mmol) and 2-
4.2. General procedure for parallel coupling
Reactions were carried out in a Bohdan XT 24 position block
using the appropriate halide indicated.
isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
(1.3
mL,
6.20 mmol) in toluene (3.3 mL) and THF (0.8 mL) at ꢁ70 ꢀC, under
nitrogen. The resulting solution was stirred at ꢁ70 ꢀC for 1 h and
then removed from the cooling bath and allowed to stir at room
temperature for 4 h. The reaction mixture was filtered through
a pad of silica and washed through with EtOAc (250 mL) and
evaporated to afford crude product. The crude product was purified
by flash silica chromatography (0e20% EtOAc/heptane) to afford
the title compound (10, 252 mg, 50%) as a colourless oil, which so-
lidified on standing.
2M Sodium carbonate (0.680 mL, 1.36 mmol) was added to
a stirred mixture of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)
pyrazolo[1,5-a]pyridine (10, 151 mg, 0.62 mmol), the appropriate
halide (0.74 mmol) and bis(di-tert-butyl(4-dimethylaminophenyl)
phosphine)dichloropalladium(II) (Pd(Amphos)Cl2) (26.3 mg,
0.04 mmol) in DME (4 mL) under nitrogen. The resulting mixture
was stirred at 80 ꢀC for 4 h, allowed to cool, diluted with water
(10 mL), extracted with EtOAc (2ꢂ25 mL) and the organic layer was
evaporated to afford crude products. Unless otherwise stated the
crude product was purified by preparative HPLC (Waters XBridge
4.1.3.3. Representative example of a catalytic screening experi-
ment. Reaction 1dPd(dppf)Cl2.
Prep C18 OBD column, 5 m silica, 19 mm diameter, 100 mm length,
5e95% MeCN/1% NH3 in H2O).
Reaction 2dPd(dtbpf)Cl2.
Reaction 3dPd(OAc)2þS-Phos.
4.2.1. 4-(Pyrazolo[1,5-a]pyridin-3-yl)isoxazole (16). Using 4-bromoi-
soxazole; isolated the title compound (16, 28.1 mg, 24%) as
a solid; dH (500 MHz, DMSO): 6.99 (1H, td, J 7, 1 Hz, ArH-6),
7.34e7.39 (1H, m, ArH-5), 8.00 (1H, d, J 9 Hz, ArH-4), 8.40 (1H, s,
ArH-2), 8.74 (1H, d, J 7 Hz, ArH-7), 9.17 (1H, s, isoxazole CHO), 9.45
(1H, s, isoxazole CHN); dC(101 MHz, DMSO): 99.29, 111.86, 112.67,
117.33, 124.62, 129.23, 136.08, 140.31, 148.59, 152.94; m/z (ESþ) 186
(100, MHþ); HRMS (ESI): MHþ, found 186.06610. C10H8N3O re-
quires 186.06619.
Reaction 4dPd(OAc)2þDtBPPS.
Reaction 5dPd(Amphos)Cl2.
3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]
pyridine (10, 70 mg, 0.39 mmol), 4,40-di-tert-butylbiphenyl (20 mg,
0.08 mmol) and the appropriate pre-catalyst (6 mol %) were placed
in a tube in a Bohdan XT 24 position block under an atmosphere of
nitrogen. Degassed DME (5 mL), 2,4,5-trichloropyrimidine
(0.039 mL, 0.34 mmol) then 2M Na2CO3 (0.315 mL, 0.63 mmol)
were then syringed into the tubes and the block was heated to
85 ꢀC. The reactions were sampled after 20 min, 40 min, 90 min and
5 h by UPLC by syringing out 2 drops of the reaction mixture and
diluting with methanol (1 mL).
4.2.2. 3-(Thiophen-2-yl)pyrazolo[1,5-a]pyridine (17). Using 2-bromo-
thiophene; isolated the title compound (17, 52.8 mg, 41%) as a gum; dH
(500 MHz, DMSO): 6.98 (1H, td, J 7,1 Hz, ArH-6), 7.16 (1H, dd, J 5, 4 Hz,
thiophene), 7.34e7.39 (1H, m, ArH-5), 7.40 (1H, dd, J 3, 1 Hz, thio-
phene), 7.49 (1H, dd, J 5,1 Hz, thiophene), 7.94 (1H, dt, J 9,1 Hz, ArH-4),
8.34 (1H, s, ArH-2), 8.74 (1H, dt, J 7, 1 Hz, ArH-7); dC (101 MHz, DMSO):
105.94, 112.70, 117.12, 122.65, 123.26, 125.09, 127.92, 129.34, 134.25,
135.58, 139.90; m/z (ESþ) 201 (100, MHþ); HRMS (ESI): MHþ, found
201.04805. C11H9N2S requires 201.04810.
4.1.4. 3-(2,5-Dichloropyrimidin-4-yl)pyrazolo[1,5-a]pyridine7 (8).
4.1.4.1. Using
cene)-dichloropalladium(II) (104 mg, 0.13 mmol) was added to
degassed solution of 2,4,5-trichloropyrimidine (0.289 mL,
Pd(dppf)Cl2. (1,10-Bis(diphenylphosphino)ferro-
a
2.52 mmol), 2M Na2CO3 (2.3 mL, 4.61 mmol) and 3-(4,4,5,5-
tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine (10,
512 mg, 2.10 mmol) in DME (10 mL) and the resulting mixture was
stirred at 85 ꢀC for 1.5 h. The reaction mixture was allowed to cool,
the precipitate was collected by filtration, washed with water
(30 mL) and dried under vacuum at 50 ꢀC to afford the title com-
pound (8, 224 mg, 40%) as a yellow solid.
4.2.3. 3-(Pyridin-3-yl)pyrazolo[1,5-a]pyridine (18). Using 3-bromo-
pyridine; isolated the title compound (18, 61 mg, 50%) as a solid; dH
(500 MHz, DMSO): 7.05 (1H, td, J 7, 1 Hz, ArH-6), 7.43 (1H, ddd, J 9, 7,
1 Hz, ArH-5), 7.53 (1H, ddd, J 8, 5,1 Hz, pyridine), 8.08 (1H, dt, J 9,1 Hz,
pyridine), 8.15 (1H, ddd, J 8, 2, 2 Hz, ArH-4), 8.51e8.55 (2H, m, ArH-2
and pyridine), 8.83 (1H, dt, J 7, 1, ArH-7), 9.00 (1H, dd, J 2, 1 Hz,
pyridine); dC (101 MHz, DMSO): 108.15, 112.79, 117.16, 123.95, 125.29,
128.79, 129.47, 133.33, 136.34, 140.51, 146.85, 147.18; m/z (ESþ) 196
(100, MHþ); HRMS (ESI): MHþ, found 196.18689. C12H10N3 requires
196.08692.
4.1.4.2. Using Pd(Amphos)Cl2. Bis(di-tert-butyl(4-dimethylami-
nophenyl)phosphine)dichloropalladium(II) (Pd(Amphos)Cl2) (4.24 g,
5.99 mmol) was added to
a degassed mixture of 2,4,5-
trichloropyrimidine (13.72 mL, 119.7 mmol), 3-(4,4,5,5-tetramethyl-
1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine (10, 24.35 g,
0.1 mol) and 2M Na2CO3 (110 mL, 219.46 mmol) in DME (500 mL)
under nitrogen. The resulting mixture was stirred at 85 ꢀC for 3 h and
4.2.4. 3-(4-Fluorophenyl)pyrazolo[1,5-a]pyridine (19). Using 1-fluo-
ro-4-iodobenzene; isolated the title compound (19, 77 mg, 58%) as
an oil; dH (700 MHz, DMSO): 6.97 (1H, t, J 7 Hz, ArH-6), 7.26e7.32

5442
P.A. Bethel et al. / Tetrahedron 68 (2012) 5434e5444
(2H, m, ArHoeF), 7.34 (1H, dd, J 9, 7 Hz, ArH-5), 7.69e7.75 (2H, m,
ArHm-F), 7.94 (1H, d, J 9 Hz, ArH-4), 8.34 (1H, s, ArH-2), 8.73 (1H,
d, J 7 Hz, ArH-7); dC (101 MHz, DMSO): 110.63, 112.46, 115.79 (2C,
d, J 21 Hz), 117.05, 124.74, 128.25 (2C, d, J 8 Hz), 129.18 (d, J 3 Hz),
129.31, 135.98, 140.26, 160.65 (d, J 243 Hz); m/z (ESþ) 213 (100,
MHþ); HRMS (ESI): MHþ, found 213.08212. C13H10FN2 requires
213.08225.
140.69, 151.28; m/z (ESþ) 202 (100, MHþ); HRMS (ESI): MHþ, found
202.04321. C10H8N3S requires 202.04334.
4.2.11. 3-(Pyrazin-2-yl)pyrazolo[1,5-a]pyridine (26). Using 2-bromo-
pyrazine; isolated the title compound (26, 50.7 mg, 41%) as a solid;
dH (700 MHz, DMSO): 7.09 (1H, td, J 7, 1 Hz, ArH-6), 7.49 (1H, ddd, J 9,
7, 1 Hz, ArH-5), 8.41 (1H, d, J 3 Hz, pyrazineH), 8.50 (1H, d, J 9 Hz, ArH-
4), 8.61e8.66 (1H, m, pyrazineH), 8.83 (1H, d, J 7 Hz, ArH-7), 8.85 (1H,
s, ArH-2), 9.21 (1H, d, J 2 Hz, pyrazineH); dC (101 MHz, DMSO):
108.03, 113.66, 119.17, 126.43, 129.55, 137.84, 140.47, 141.05, 141.58,
143.94, 148.86; m/z (ESþ) 197 (100, MHþ); HRMS (ESI): MHþ, found
197.08203. C11H9N4 requires 197.08217.
4.2.5. 3-m-Tolylpyrazolo[1,5-a]pyridine (20). Using 1-bromo-3-met-
hyl-benzene; isolated the title compound (20, 64.8 mg, 50%) as an
oil; dH (700 MHz, DMSO): 2.39 (3H, s, Me), 6.96 (1H, td, J 7, 1 Hz,
ArH-6), 7.10 (1H, d, J 8 Hz, Ph), 7.31e7.33 (1H, m, ArH-5), 7.35 (1H,
t, J 8 Hz, Ph), 7.48 (1H, d, J 8 Hz, Ph), 7.51 (1H, s, Ph), 7.97 (1H, d, J
9 Hz, ArH-4), 8.34 (1H, s, ArH-2), 8.72 (1H, d, J 7 Hz, ArH-7); dC
(101 MHz, DMSO): 21.09, 111.62, 112.41, 117.35, 123.49, 124.63,
126.63, 126.95, 128.89, 129.32, 132.61, 136.01, 138.13, 140.25; m/z
(ESþ) 209 (100, MHþ); HRMS (ESI): MHþ, found 209.10728.
C14H13N2 requires 209.10732.
4.2.12. 3-(Pyridin-4-yl)pyrazolo[1,5-a]pyridine (27). Using 4-bromo-
pyridine; isolated the title compound (27, 46 mg, 38%) as a solid; dH
(700 MHz, DMSO): 7.03e7.08 (1H, m, ArH-6), 7.46 (1H, dd, J 8, 7 Hz,
ArH-5), 7.74 (2H, dd, J 5, 2 Hz, pyridine), 8.15 (1H, d, J 9 Hz, ArH-4),
8.58 (2H, dd, J5, 2 Hz, pyridine), 8.61 (1H, s, ArH-2), 8.81 (1H, d, J 7 Hz,
ArH-7); dC (101 MHz, DMSO): 108.64, 113.16, 117.44, 120.28 (2C),
126.13,129.78,136.69,140.10,141.23,150.09 (2C); m/z (ESþ) 196 (100,
MHþ); HRMS (ESI): MHþ, found 196.08679. C12H10N3 requires
196.08692.
4.2.6. 3-p-Tolylpyrazolo[1,5-a]pyridine (21). Using 1-iodo-4-methyl-
benzene; isolated the title compound (21, 57.5 mg, 43%) as a solid; dH
(700 MHz, DMSO):2.35 (3H, s, ArMe), 6.94 (1H, td, J 7, 1 Hz, ArH-6),
7.28 (2H, d, J 8 Hz, Ph), 7.31 (1H, dd, J 8, 7 Hz, ArH-5), 7.58 (2H, d, J
8 Hz, Ph), 7.94 (1H, d, J 9 Hz, ArH-4), 8.32 (1H, s, ArH-2), 8.72 (1H, d, J
7 Hz, ArH-7); dC (101 MHz, DMSO): 20.67, 111.59, 112.30, 117.27,
124.44, 126.29 (2C), 129.27, 129.56 (2C), 129.81, 135.07, 135.93,
140.05; m/z (ESþ) 209 (100, MHþ); HRMS (ESI): MHþ, found
209.10722. C14H13N2 requires 209.10732.
4.2.13. 4-(Pyrazolo[1,5-a]pyridin-3-yl)benzonitrile (28). Using 4-iodo-
benzonitrile; the product, which was purified by flash chromatogra-
phy (0e50% EtOAc/heptane) to give the title compound 28, 84.8 mg,
63% as a solid; dH (400 MHz, DMSO): 7.04 (1H, td, J 7,1 Hz, ArH-6), 7.44
(1H, ddd, J 9, 7, 1 Hz, ArH-5), 7.86e7.9 (2H, m, Ph), 7.92e7.96 (2H, m,
Ph), 8.09 (1H, dt, J 9,1 Hz, ArH-4), 8.56 (1H, s, ArH-2), 8.80 (1H, dt, J 7,
1 Hz, ArH-7); dC (101 MHz, DMSO): 107.71, 109.88, 113.13, 117.29,
119.09,126.03,126.47 (2C),129.73,132.86 (2C),136.45,137.73,141.20;
m/z (ESþ) 220 (100, MHþ); HRMS (ESI): MHþ, found 220.08687.
C14H10N3 requires 220.08692.
4.2.7. 4-(Pyrazolo[1,5-a]pyridin-3-yl)thiazole(22). Using 4-bromothi-
azole; isolated the title compound (22, 52.2 mg, 42%) as a solid; dH
(700 MHz, DMSO): 6.98 (1H, td, J 7, 1 Hz, ArH-6), 7.37 (1H, dd, J 9, 7 Hz,
ArH-5), 7.95 (1H, d, J 2 Hz, thiazole CCHS), 8.28 (1H, d, J 9 Hz, ArH-4),
8.52 (1H, s, ArH-2), 8.73 (1H, d, J 7 Hz, ArH-7), 9.24 (1H, d, J 2 Hz,
thiazole NCHS); 13C NMR dC (101 MHz, DMSO): 106.97, 110.78, 112.67,
118.50, 124.74, 129.12, 136.34, 140.42, 148.84, 154.11; m/z (ESþ) 202
(100, MHþ); HRMS (ESI): MHþ, found 202.04323. C10H8N3S requires
202.04334.
4.2.14. 3-(Pyrazolo[1,5-a]pyridin-3-yl)benzonitrile (29). Using 3-bro-
mobenzonitrile; the product, which was purified by flash chroma-
tography (0e50% EtOAc/heptane) to give the title compound (29,
83.2 mg, 61%) as a solid; dH (400 MHz, DMSO): 7.02 (1H, td, J 7, 1 Hz,
ArH-6), 7.40 (1H, ddd, J 9, 7, 1 Hz, ArH-5), 7.62e7.75 (2H, m, Ph),
8.02e8.13 (2H, m, Ph), 8.16 (1H, t, J 2 Hz, Ph), 8.51 (1H, s, ArH-2), 8.77
(1H, d, J 7 Hz, ArH-7); dC (101 MHz, DMSO): 109.53, 112.22, 112.90,
117.24, 118.83, 125.52, 129.25, 129.34, 129.51, 130.16, 130.71, 134.13,
136.26, 140.83; m/z (ESþ) 220 (100, MHþ); HRMS (ESI): MHþ, found
220.08687. C14H10N3 requires 220.08692.
4.2.8. 3-(Pyrimidin-2-yl)pyrazolo[1,5-a]pyridine (23). Using 2-chloro-
pyrimidine; isolated the titlecompound (23, 39.1 mg, 32%)asa solid; dH
(700 MHz, DMSO): 7.10 (1H, td, J 7, 1 Hz, ArH-6), 7.26 (1H, t, J 5 Hz,
pyrimidine, CHCHCH), 7.49e7.55 (1H, m, ArH-5), 8.56 (1H, d, J 9 Hz,
ArH-4), 8.69 (1H, s, ArH-2), 8.82 (2H, d, J 5 Hz, pyrimidine, CHCHCH),
8.83 (1H, d, J 7 Hz, ArH-7); dC (101 MHz, DMSO): 110.72,113.60,117.51,
119.42, 126.66, 129.63, 138.60, 142.85, 157.37 (2C), 161.42; m/z (ESþ)
197 (100, MHþ); HRMS (ESI): MHþ, found 197.08203. C11H9N4 requires
197.08217.
4.2.15. 3-(4-Methoxyphenyl)pyrazolo[1,5-a]pyridine (30). Using 1-
iodo-4-methoxy-benzene; the product, which was purified by
flash chromatography (0e50% EtOAc/heptane) to give the title
compound (30, 86.8 mg, 59%) as a solid; dH (400 MHz, DMSO): 3.81
(3H, s, OMe), 6.92 (1H, td, J 7, 1 Hz, ArH-6), 7.01e7.06 (2H, m, Ph),
7.29 (1H, ddd, J 9, 7,1 Hz, ArH-5), 7.57e7.63 (2H, m, Ph), 7.90 (1H, d, J
9 Hz, ArH-7), 8.27 (1H, s, ArH-2), 8.70 (1H, d, J 7 Hz, ArH-7); dC
(101 MHz, DMSO): 55.13, 111.46, 112.20, 114.52 (2C), 117.19, 124.21,
125.13, 127.66 (2C), 129.19, 135.76, 139.87, 157.72; m/z (ESþ) 225
(100, MHþ); HRMS (ESI): MHþ, found 225.10216. C14H13N3 requires
225.10224.
4.2.9. 3-(Pyridin-3-yl)pyrazolo[1,5-a]pyridine (24). Using 3-bromo-
pyridine; isolated the title compound (24, 56.3 mg, 44%) as
a solid; dH (700 MHz, DMSO): 7.01 (1H, td, J 7, 1 Hz, ArH-6),
7.35e7.42 (1H, m, ArH-5), 7.48 (1H, dd, J 8, 5 Hz, pyridine), 8.03
(1H, d, J 9 Hz, ArH-4), 8.11 (1H, dt, J 8, 2, pyridine), 8.47e8.51 (2H,
m, ArH-2 and pyridine), 8.78 (1H, d, J 7 Hz, ArH-7), 8.95 (1H, d, J
2 Hz, pyridine); dC (101 MHz, DMSO): 108.15, 112.80, 117.17, 123.96,
125.30, 128.79, 129.47, 133.33, 136.34, 140.52, 146.85, 147.18; m/z
(ESþ) 196 (100, MHþ); HRMS (ESI): MHþ, found 196.08681.
C12H10N3 requires 196.08693.
4.2.16. 3-(6-Methylpyridazin-3-yl)pyrazolo[1,5-a]pyridine (31). Using
3-chloro-6-methyl-pyridazine; the product, which was purified by
flash chromatography (0e70% EtOAc/heptane) to give the title
compound (31, 55.2 mg, 42%) as a solid; dH (400 MHz, DMSO): 2.63
(3H, s Me), 7.08 (1H, td, J 7, 1 Hz, ArH-6), 7.50 (1H, ddd, J 9, 7, 1 Hz,
ArH-5), 7.58 (1H, d, J 9 Hz, pyridazine), 8.07 (1H, d, J 9 Hz, pyr-
idazine), 8.55 (1H, dt, J 9, 1 Hz, ArH-4), 8.75 (1H, s, ArH-2),
8.79e8.83 (1H, m, ArH-7); dC (101 MHz, DMSO): 21.50, 108.19,
113.52, 119.66, 123.31, 126.26, 127.22, 129.41, 137.19, 141.33, 153.37,
4.2.10. 5-(Pyrazolo[1,5-a]pyridin-3-yl)thiazole (25). Using 5-bromo-
thiazole; isolated the title compound (25, 52.6 mg, 41%) as a gum; dH
(700 MHz, DMSO): 7.03 (1H, td, J 7,1 Hz, ArH-5), 7.43 (1H, dd, J 9, 7 Hz,
ArH-5), 7.95 (1H, d, J 9 Hz, ArH-4), 8.25 (1H, s, thiazole), 8.42 (1H, s,
ArH-2), 8.78 (1H, d, J 7 Hz, ArH-7), 9.06 (1H, s, thiazole); dC (101 MHz,
DMSO): 102.15, 113.05, 116.95, 125.64, 129.30, 129.48, 136.09, 138.23,

P.A. Bethel et al. / Tetrahedron 68 (2012) 5434e5444
5443
156.43; m/z (ESþ) 211 (100, MHþ); HRMS (ESI): MHþ, found
211.09776. C12H11N4 requires 211.09782.
(38, 70 mg, 49%) as a solid; dH (400 MHz, DMSO): 7.19 (1H, td, J 7,
1 Hz, ArH-6), 7.66 (1H, ddd, J 9, 7, 1 Hz, ArH-5), 7.97 (1H, d, J 5 Hz,
pyrimidine), 8.47e8.52 (1H, m, ArH-4), 8.62 (1H, d, J 5 Hz, pyrim-
idine), 8.90 (1H, dd, J 7, 1 Hz, ArH-7), 8.94 (1H, s, ArH-2); dC
(101 MHz, DMSO): 107.59, 114.59, 114.76, 119.26, 128.32, 130.08,
138.37, 143.35, 159.25, 160.23, 162.39; m/z (ESþ) 231 (100, MHþ);
HRMS (ESI): MHþ, found 231.04327. C11H8ClN4 requires 231.04320.
4.2.17. 3-(1-Methyl-1H-imidazol-5-yl)pyrazolo[1,5-a]pyridine
(32). Using 5-bromo-1-methyl-imidazole; isolated the title com-
pound (32, 43.8 mg, 36%) as a solid; dH (500 MHz, DMSO): 3.67 (3H,
s, NMe), 6.99 (1H, td, J 7, 1 Hz, ArH-6), 7.11 (1H, d, J 1 Hz, imidazole),
7.32 (1H, ddd, J 9, 7, 1 Hz, ArH-5), 7.70 (1H, dt, J 9, 1 Hz, ArH-4), 7.73
(1H, s, imidazole), 8.26 (1H, s, ArH-2), 8.75 (1H, dt, J 7, 1 Hz, ArH-7);
dC (101 MHz, DMSO): 31.88, 100.14, 112.76, 117.10, 123.83, 124.73,
127.09, 129.04, 137.37, 138.78, 140.49; m/z (ESþ) 199 (100, MHþ);
HRMS (ESI): MHþ, found 199.09775. C11H11N4 requires 199.09782.
4.2.24. 3-(3-Fluorophenyl)pyrazolo[1,5-a]pyridine (39). Using 1-
fluoro-3-iodo-benzene; Isolated the title compound (39, 81 mg,
71%) as a yellow oil; dH (400 MHz, DMSO): 6.99 (1H, td, J 7, 1 Hz,
ArH-6), 7.05e7.14 (1H, m, Ph), 7.37 (1H, ddd, J 9, 7, 1 Hz, ArH-5),
7.44e7.59 (3H, m, Ph), 8.03 (1H, dt, J 9, 1 Hz, ArH-4), 8.46 (1H, s,
ArH-2), 8.77 (1H, dt, J 7, 1 Hz, ArH-7); dC (101 MHz, DMSO): 110.34
(d, J 3 Hz), 112.48 (d, J 21 Hz), 112.72, 112.74 (d, J 22 Hz), 117.26,
122.20 (d, J 2 Hz), 125.26, 129.46, 130.90 (d, J 9 Hz), 135.17 (d,
J¼9 Hz), 136.13, 140.71, 162.74 (d, J 243 Hz); m/z (ESþ) 213 (100,
MHþ); HRMS (ESI): MHþ, found 213.08228. C13H10FN2 requires
213.08225.
4.2.18. 3-Phenylpyrazolo[1,5-a]pyridine (33). Using iodobenzene;
isolated the title compound (33, 58.7 mg, 49%) as a gum; dH
(700 MHz, DMSO): 6.97 (1H, td, J 7, 1 Hz, ArH-6), 7.29 (1H, t, J 7 Hz,
Ph), 7.34 (1H, dd, J 9, 7 Hz, ArH-5), 7.47 (2H, t, J 8 Hz, Ph), 7.70 (2H, d,
J 7 Hz, Ph), 7.98 (1H, d, J 9 Hz, ArH-4), 8.37 (1H, s, ArH-2), 8.74 (1H, d,
J 7 Hz, ArH-7); dC (101 MHz, DMSO): 111.57, 112.44, 117.24, 124.71,
125.92, 126.38 (2C), 129.00 (2C), 129.34, 132.74, 136.05, 140.27; m/z
(ESþ) 195 (100, MHþ); HRMS (ESI): MHþ, found 195.09154.
C13H11N2 requires 195.09154.
4.2.25. 3-(1-Methyl-1H-imidazol-2-yl)pyrazolo[1,5-a]pyridine
(40). Using 2-bromo-1-methyl-imidazole; isolated the title com-
pound (40, 6.1 mg, 6%) of a colourless gum; dH (500 MHz, DMSO):
3.83 (3H, s, NMe), 6.98e7.05 (2H, m, ArH-6 and imidazole), 7.20 (1H,
d, J 1 Hz, imidazole), 7.33e7.4 (1H, m, ArH-5), 8.21e8.28 (1H, m,
ArH-4), 8.44 (1H, s, ArH-2), 8.73e8.78 (1H, dd, J 6, 1 Hz, ArH-7); dC
(176 MHz, DMSO): 33.86, 102.25, 113.19, 118.94, 121.68, 124.83,
127.37, 128.76, 137.88, 139.41, 140.73; m/z (ESþ) 199 (100, MHþ);
HRMS (ESI): MHþ, found 199.09792. C11H11N4 requires 199.09782.
4.2.19. 3-o-Tolylpyrazolo[1,5-a]pyridine (34). Using 1-bromo-2-
methyl-benzene; isolated the title compound (34, 56.4 mg, 44%) as
a gum; dH (700 MHz, DMSO): 2.29 (3H, s, Me), 6.94 (1H, td, J 7, 1 Hz,
ArH-6), 7.22e7.30 (3H, m, Ph), 7.33e7.38 (2H, m, Ph), 7.51 (1H, d, J
9 Hz, ArH-4), 8.13 (1H, s, ArH-2), 8.73 (1H, d, J 7 Hz ArH-7); dC
(101 MHz, DMSO): 20.26, 110.96, 112.26, 117.03, 124.15, 125.97,
126.91, 129.03, 129.95, 130.53, 131.57, 135.90, 136.92, 141.39; m/z
(ESþ) 209 (100, MHþ); HRMS (ESI): MHþ, found 209.10721.
C14H13N2 requires 209.10732.
4.2.26. 3-(3-Methoxyphenyl)pyrazolo[1,5-a]pyridine (41). Using 1-
bromo-3-methoxy-benzene; Isolated the title compound (41,
72.6 mg, 51%) as a gum; dH (400 MHz, DMSO): 3.84 (3H, s, Me), 6.86
(1H, dd, J 8, 2 Hz, Ph), 6.96 (1H, td, J 7,1 Hz, ArH-6), 7.17e7.23 (1H, m,
Ph), 7.26 (1H, d, J 8 Hz, Ph), 7.29e7.42 (2H, m), 7.97 (1H, d, J 9 Hz),
8.37 (1H, s, ArH-2), 8.73 (1H, d, J 7 Hz, ArH-7); dC (101 MHz, DMSO):
55.07, 111.51, 111.66, 111.84, 112.47, 117.30, 118.74, 124.80, 129.34,
130.05, 134.07, 136.11, 140.44, 159.82; m/z (ESþ) 225 (100, MHþ);
HRMS (ESI): MHþ, found 225.10219. C14H13N2O requires 225.10224.
4.2.20. 3-(2-Methoxyphenyl)pyrazolo[1,5-a]pyridine (35). Using 1-
iodo-2-methoxyebenzene; isolated the title compound (35,
64.5 mg, 46%) as a gum; dH (400 MHz, DMSO): 3.82 (3H, s), 6.92 (1H,
t, J 6 Hz, Ph), 7.05 (1H, td, J 7, 1 Hz, ArH-6), 7.14 (1H, dd, J 8, 1 Hz, Ph),
7.25 (1H, ddd, J 9, 7, 1 Hz, ArH-5), 7.32 (1H, ddd, J 8, 7, 2 Hz, Ph), 7.47
(1H, dd, J 8, 2 Hz, Ph), 7.61e7.68 (1H, m, ArH-4), 8.17 (1H, s, ArH-2),
8.69 (1H, d, J 7 Hz, ArH-7); dC (101 MHz, DMSO): 55.32, 108.13,
111.66, 112.06, 118.12, 120.72, 121.22, 123.77, 127.82, 128.96, 129.60,
136.83, 141.69, 156.04; m/z (ESþ) 225 (100, MHþ); HRMS (ESI):
MHþ, found 225.10217. C14H13N2O requires 225.10224.
4.2.27. 1H-Pyrazol-3(2H)-one (44). Hydrazine hydrate (3.62 mL,
48.53 mmol) was added dropwise to a cooled (ice bath) solution of
methyl propiolate (4.23 mL, 47.58 mmol) in methanol (40 mL). The
reaction was allowed to stir for 30 min at room temperature. Brine
(10 mL) was added and then the methanol was removed under vac-
uum. The remaining aqueous layer was extracted with EtOAc
(4ꢂ75 mL) and the combined organic layers were dried (MgSO4), fil-
tered and concentrated in vacuo to yield the title compound (44, 3.82 g,
95%) as a cream solid; dH (400 MHz, DMSO): 5.44 (1H, d, J 2.27 Hz), 7.35
(1H, d, J 2.23 Hz), 9.50 (1H, br s, NH),11.45 (1H, br s, NH); dC (101 MHz,
DMSO): 89.25, 129.71, 160.73; m/z (ESþ) 85.04 (100, MHþ); HRMS
(ESI): MHþ, found 85.03951. C3H5N2O requires 85.03964.
4.2.21. 3-(1-Methyl-1H-imidazol-4-yl)pyrazolo[1,5-a]pyridine
(36). Using 4-bromo-1-methyl-imidazole; isolated the title com-
pound (36, 26.4 mg, 21%) as a gum; dH (500 MHz, DMSO): 3.76 (3H,
s, NMe), 6.92 (1H, td, J 7, 1 Hz, ArH-6), 7.28 (1H, ddd, J 9, 7, 1 Hz, ArH-
5), 7.53 (1H, d, J 1 Hz, imidazole), 7.70 (1H, s, imidazole), 8.15e8.21
(1H, m, ArH-4), 8.27 (1H, s, ArH-2), 8.68 (1H, d, J 7 Hz, ArH-7); dC
(101 MHz, DMSO): 32.91, 106.93, 111.99, 115.43, 118.59, 123.27,
128.74, 134.32, 135.53, 137.87, 138.68; m/z (ESþ) 199 (100, MHþ);
HRMS (ESI): MHþ, found 199.09782. C11H11N4 requires 199.09775.
4.2.28. 3-Iodo-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine (46). 1H-
Pyrazol-3(2H)-one (44, 5.11 g, 60.78 mmol) and potassium car-
bonate (29.4 g, 212.7 mmol) were heated to 130 ꢀC in DMF
(275 mL). 1,3-Dibromopropane (7.40 mL, 72.93 mmol) was added
and the mixture was heated for 2 h and then concentrated. The
residue was partitioned between DCM (200 mL) and water
(100 mL) and the layers were separated. The aqueous layer was
extracted with DCM (3ꢂ100 mL) and the combined organic extracts
were dried (MgSO4), filtered and concentrated in vacuo to give the
crude 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine (45, 6.0 g) as
a brown oil, which was used without further purification.
4.2.22. 3-(Pyridazin-4-yl)pyrazolo[1,5-a]pyridine (37). Using 4-
bromopyridazine; isolated the title compound (37, 40.5 mg, 33%) as
a solid; dH (500 MHz, DMSO): 7.12 (1H, td, J 7, 1 Hz, ArH-6), 7.53 (1H,
ddd, J 9, 7, 1 Hz, ArH-5), 8.00 (1H, dd, J 6, 3 Hz, pyridazine), 8.26 (1H,
dt, J 9,1 Hz, ArH-4), 8.80 (1H, s, ArH-2), 8.87 (1H, dt, J 7,1 Hz, ArH-7),
9.15 (1H, dd, J 6,1 Hz, pyridazine), 9.69 (1H, dd, J 3,1 Hz, pyridazine);
dC (101 MHz, DMSO): 105.20, 113.71, 117.59, 121.01, 126.94, 130.04,
131.24, 137.27, 141.73, 148.73, 151.26; m/z (ESþ) 197 (100, MHþ);
HRMS (ESI): MHþ, found 197.08206. C11H9N4 requires 197.08217.
4.2.23. 3-(2-Chloropyrimidin-4-yl)pyrazolo[1,5-a]pyridine
N-Iodosuccinimide (3.79 g, 16.84 mmol) was added portionwise
to a solution of crude 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine
(38)9a. Using 2,4-dichloropyrimidine; isolated the title compound

5444
P.A. Bethel et al. / Tetrahedron 68 (2012) 5434e5444
(45, 1.9 g, 15.31 mmol) in acetonitrile (19 mL) at toom temperature
and the reaction was stirred for 30 min. The reaction mixture was
slowly poured into vigorously stirred water. Sodium thiosulphate
solution was added and then the mixture was extracted with EtOAc
(2ꢂ100 mL). The combined organic extracts were washed with
water, dried (MgSO4), filtered and concentrated in vacuo. The crude
product was purified by flash chromatography (0e2% MeOH/DCM)
to give the title compound (46, 1.10 g, 29% for two steps) as a yellow
waxy solid; dH (400 MHz, DMSO): 2.14e2.20 (2H, m), 4.09 (2H, t, J
6 Hz), 4.32e4.35 (2H, m), 7.29 (1H, s); dC (101 MHz, DMSO): 21.50,
36.03, 44.24, 66.38, 141.19, 150.88; m/z (ESþ) 251.03 (100, MHþ);
HRMS (EI): Mþ, found 249.9618. C6H7N2OI requires 249.960.
References and notes
1. Based on a ScifinderÒ search of the pyrazolo[1,5-a]pyridine ring system; per-
fomed in January 2012.
2. (a) Akahane, A.; Katayama, H.; Mitsunaga, T.; Kato, T.; Kinoshita, T.; Kita, Y.;
Kusunoki, T.; Terai, T.; Yoshida, K.; Shiokawa, Y. J. Med. Chem. 1999, 42,
779e783; (b) Kohno, Y.; Nagatomi, I.; Hanaoka, K. W.O. Patent 9325205, 1993;
Chem. Abstr. 1994, 120, 153722.
3. Katz, J.; Knowles, S. L.; Jewell, J. P.; Sloman, D. L.; Stanton, M. G.; Noucti, N. W.O.
Patent, 2010017046; Chem. Abstr. 2010, 152, 238952.
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Patent 2010016005; Chem. Abstr. 2010, 152, 262750.
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Abstr. 2010, 152, 525869.
6. Hajos, G.; Riedl, Z. In Science of Synthesis; Thieme: 2002; vol. 12; p 658.
7. Ducray, R.; Boutron, P.; Didelot, M.; Germain, H.; Lach, F.; Lamorlette, M.; Le-
ꢀ
griffon, A.; Maudet, M.; Menard, M.; Pasquet, G.; Renaud, F.; Simpson, I.; Young,
4.2.29. 3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-
5H-pyrazolo[5,1-b][1,3]oxazine (43). Isopropylmagnesium lithium
chloride (3.08 mL, 4.00 mmol) was added dropwise to a stirred
solution of 3-iodo-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine (46,
1.0 g, 4.00 mmol) and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-
dioxaborolane (1.2 mL, 6.00 mmol) in THF (10 mL) at 5 ꢀC, over
a period of 10 min, under nitrogen. The resulting solution was
stirred at 5 ꢀC for 2 h and then concentrated in vacuo. The crude
product was purified by flash silica chromatography (0e5% MeOH/
DCM) to afford a pale yellow oil. Crystallisation from heptane
yielded the title compound (43, 0.455 g, 45.5%) as a white solid; dH
(400 MHz, DMSO): 1.22 (12H, s, 2ꢂMe2CO), 2.11e2.18 (2H, m, CH2),
4.05 (2H, t, J 6.2 Hz, CH2), 4.29e4.32 (2H, m, CH2), 7.32 (1H, s, Ar); dC
(101 MHz, DMSO): 21.11, 24.57 (4 CH3), 43.60, 65.64, 82.32 (2C),
143.54, 156.26, CeB not seen; m/z (ESþ) 251.47(100, MHþ); HRMS
(ESI): MHþ, found 251.15598. C12H20BN2O3 requires 251.15615.
G. L. Tetrahedron Lett. 2010, 51, 4755e4758.
8. For a recent example of synthesis of biaryls by decarboxylative coupling see
Mitchell, D.; Coppert, D. M.; Moynihan, H. A.; Lorenz, K. T.; Kissane, M.;
McNamara, O. A.; Maguire, A. R. Org. Process Res. Dev. 2011, 15, 981e985.
9. (a) The Negishi reaction of 3-bromoimidazo[1,2-a]pyridine with tri-
chloropyrimidine has been reported in 32% yield Alam, M.; Beevers, R. E.; Ce-
ska, T.; Davenport, R. J.; Dickson, K. M.; Fortunato, M.; Gowers, L.; Haughan, A.
F.; James, L. A.; Jones, M. W.; Kinsella, N.; Lowe, C.; Meissner, J. W. G.; Nicolas, A.
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L. J. Bioorg. Med. Chem. Lett. 2007, 17, 3463e3467; (b) For metalation of chlor-
opyrimidine derivatives see Mosrin, M.; Knochel, P. Chem.dEur. J. 2009, 15,
1468e1477.
10. The boronic ester of imidazo[1,2-a]pyridine has been described by CeH acti-
vation: Smith, M. R.; Maleczka, R. E.; Kallepalli, V. A.; Onyeozili, E. U.S. Patent
2,008,009,1027, Chem. Abstr. 2008, 148, 449616.
11. Roughley, S. D.; Jordan, A. M. J. Med. Chem. 2011, 54, 3451e3479.
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4.2.30. 3-(2,5-Dichloropyrimidin-4-yl)-6,7-dihydro-5H-pyrazolo
[5,1-b][1,3]oxazine (47). Bis(di-tert-butyl(4-dimethylaminophenyl)
phosphine)dichloropalladium(II) (Pd(Amphos)Cl2) (16.99 mg,
0.02 mmol) was added to
a degassed mixture of 2,4,5-
trichloropyrimidine (0.055 mL, 0.48 mmol), 3-(4,4,5,5-tetra-
methyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-pyrazolo[5,1-b]
[1,3]oxazine (43, 100 mg, 0.40 mmol) and 2 M sodium carbonate
(0.440 mL, 0.88 mmol) in DME (2 mL) under nitrogen. The resulting
mixture was stirred at 85 ꢀC for 2 h and then allowed to cool to
ambient temperature. The reaction mixture was diluted with EtOAc
(50 mL) and washed with water (50 mL), brine (50 mL), dried
(MgSO4), filtered and concentrated in vacuo. The crude product was
purified by flash silica chromatography (0e3% MeOH/DCM) to af-
ford the title compound (47, 54 mg, 50%) as a white solid; dH
13. Bach Tana, J.; Pages Santacana, L. M.; Taltavull Moll, J.; Eastwood, P. R.; Gonzalez
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380329.
14. Although a ScifinderÒ search shows that pyrazolo[1,5-a]pyridine, 3-(4,4,5,5-
tetramethyl-1,3,2-dioxaborolan-2-yl)-CAS Registry Number: 1207557-48-9) is
commercially available from: Anisyn, Inc., Aquila Pharamatech, Essen Scientific
LLC, Gao Chemicals Co., Ltd, J & W PharmLab LLC, Chem-Impex, and J&W
Pharmlab the cost is prohibitively expensive.
(400 MHz, DMSO):
d 2.22e2.29 (2H, m, CH2), 4.17 (2H, t, J 6.2 Hz,
CH2), 4.45e4.49 (2H, m, CH2), 8.11 (1H, s, Ar), 8.72 (1H, s, Ar); dC
(101 MHz, DMSO): 20.66, 44.06, 66.52, 97.85, 124.46, 138.83, 151.52,
157.27, 158.04,159.22; m/z (ESþ) 271 (100, MHþ); HRMS (ESI): MHþ,
found 271.01462. C10H9Cl2N4O requires 271.01479.
15. Demory, E.; Blandin, V.; Einhorn, J.; Chavant, P. Y. Org. Process Res. Dev. 2011, 15,
710e716.
16. The synthesis of 3-bromopyrazolo[1,5-a]pyridine derivatives have reported by
the use of NBS, e.g. Stevens, K. L.; Jung, D. K.; Alberti, M. J.; Badiang, J. G.;
Peckham, G. E.; Veal, J. M.; Cheung, M.; Harris, P. A.; Chamberlain, S. D.; Peel, M.
R. Org. Lett. 2005, 7, 4753e4756 and Ref. 13, but we could find no examples of
the synthesis of the iodo equivalent under these conditions.
€
€
17. Lober, S.; Hubner, H.; Utz, W.; Gmeiner, P. J. Med. Chem. 2001, 44, 2691e2694.
18. Grandberg, I. I.; Nikitina, S. B.; Moskalenko, V. A.; Minkin, V. Chem. Heterocycl.
Compd. 1967, 3, 837e842.
Acknowledgements
19. For a study of the preparation of boronic acids via lithiumehalogen exchange
and in situ quench with triisopropylborate see Li, W.; Nelson, D. P.; Jensen, M.
S.; Hoerrner, R. S.; Cai, D.; Larsen, R. D.; Reider, P. J. J. Org. Chem. 2002, 67,
5394e5397.
20. For a review of SPhos see Martin, R.; Buchwald, S. L. Acc. Chem. Res. 2008, 41,
1461e1473.
21. For an example of 3-(di-tert-butylphosphonium)propane sulfonate (DtBPPS) as
a ligand in Suzuki reactions see Brown, W. S.; Boykin, D. D.; Sonnier, M. Q., Jr.;
Clark, W. D.; Brown, F. V.; Shaughnessy, K. H. Synthesis 2008, 1965e1970.
22. For an example of bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)di-
chloropalladium(II) (Pd(Amphos)Cl2) in Suzuki chemistry see: (a) Guram, A. S.;
King, A. O.; Allen, J. G.; Wang, X.; Schenkel, L. B.; Chan, J.; Bunel, E. E.; Faul, M.
M.; Larsen, R. D.; Martinelli, M. J.; Reider, P. J. Org. Lett. 2006, 8, 1787e1789; (b)
Guram, A. S.; Wang, X.; Bunel, E. E.; Faul, M. M.; Larsen, R. D.; Martinelli., M. M.
J. Organomet. Chem. 2007, 72, 5104e5112.
The authors would like to thank Howard Beeley, Shaun Fillery,
Paul Davey, Julie Demeritt, Peter Barton, Becky Burton, Caroline
McMillan, Nia Lock and Gemma Mayers for their NMR, mass
spectrometry and purification support and Jamie Scott for addi-
tional proof reading.
Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2012.04.094. These data in-
clude MOL files and InChiKeys of the most important compounds
described in this article.
23. All the cross-coupling reactions were carried out thermally using a Bohdan XT
24 position block, microwave heating was not tried.